PMID- 25270131 TI - Anatomic comparison of the endonasal and transpetrosal approaches for interpeduncular fossa access. AB - OBJECT: The interpeduncular cistern, including the retrochiasmatic area, is one of the most challenging regions to approach surgically. Various conventional approaches to this region have been described; however, only the endoscopic endonasal approach via the dorsum sellae and the transpetrosal approach provide ideal exposure with a caudal-cranial view. The authors compared these 2 approaches to clarify their limitations and intrinsic advantages for access to the interpeduncular cistern. METHODS: Four fresh cadaver heads were studied. An endoscopic endonasal approach via the dorsum sellae with pituitary transposition was performed to expose the interpeduncular cistern. A transpetrosal approach was performed bilaterally, combining a retrolabyrinthine presigmoid and a subtemporal transtentorium approach. Water balloons were used to simulate space-occupying lesions. "Water balloon tumors" (WBTs), inflated to 2 different volumes (0.5 and 1.0 ml), were placed in the interpeduncular cistern to compare visualization using the 2 approaches. The distances between cranial nerve (CN) III and the posterior communicating artery (PCoA) and between CN III and the edge of the tentorium were measured through a transpetrosal approach to determine the width of surgical corridors using 0- to 6-ml WBTs in the interpeduncular cistern (n = 8). RESULTS: Both approaches provided adequate exposure of the interpeduncular cistern. The endoscopic endonasal approach yielded a good visualization of both CN III and the PCoA when a WBT was in the interpeduncular cistern. Visualization of the contralateral anatomical structures was impaired in the transpetrosal approach. The surgical corridor to the interpeduncular cistern via the transpetrosal approach was narrow when the WBT volume was small, but its width increased as the WBT volume increased. There was a statistically significant increase in the maximum distance between CN III and the PCoA (p = 0.047) and between CN III and the tentorium (p = 0.029) when the WBT volume was 6 ml. CONCLUSIONS: Both approaches are valid surgical options for retrochiasmatic lesions such as craniopharyngiomas. The endoscopic endonasal approach via the dorsum sellae provides a direct and wide exposure of the interpeduncular cistern with negligible neurovascular manipulation. The transpetrosal approach also allows direct access to the interpeduncular cistern without pituitary manipulation; however, the surgical corridor is narrow due to the surrounding neurovascular structures and affords poor contralateral visibility. Conversely, in the presence of large or giant tumors in the interpeduncular cistern, which widen the spaces between neurovascular structures, the transpetrosal approach becomes a superior route, whereas the endoscopic endonasal approach may provide limited freedom of movement in the lateral extension. PMID- 25270132 TI - Endoscopic endonasal surgical management of chondrosarcomas with cerebellopontine angle extension. AB - OBJECT: Skull base chondrosarcomas are slow-growing, locally invasive tumors that arise from the petroclival synchondrosis. These characteristics allow them to erode the clivus and petrous bone and slowly compress the contents of the posterior fossa progressively until the patient becomes symptomatic, typically from cranial neuropathies. Given the site of their genesis, surrounded by the petrous apex and the clival recess, these tumors can project to the middle fossa, cervical area, and posteriorly, toward the cerebellopontine angle (CPA). Expanded endoscopic endonasal approaches are versatile techniques that grant access to the petroclival synchondrosis, the core of these lesions. The ability to access multiple compartments, remove infiltrated bone, and achieve tumor resection without the need for neural retraction makes these techniques particularly appealing in the management of these complex lesions. METHODS: Analysis of the authors' database yielded 19 cases of skull base chondrosarcomas; among these were 5 cases with predominant CPA involvement. The electronic medical records of the 5 patients were retrospectively reviewed for age, sex, presentation, pre- and postoperative imaging, surgical technique, pathology, and follow-up. These cases were used to illustrate the surgical nuances involved in the endonasal resection of CPA chondrosarcomas. RESULTS: The male/female ratio was 1:4, and the patients' mean age was 55.2 +/-11.2 years. All cases involved petrous bone and apex, with variable extensions to the posterior fossa and parapharyngeal space. The main clinical scenario was cranial nerve (CN) palsy, evidenced by diplopia (20%), ptosis (20%), CN VI palsy (20%), dysphagia (40%), impaired phonation (40%), hearing loss (20%), tinnitus (20%), and vertigo/dizziness (40%). Gross-total resection of the CPA component of the tumor was achieved in 4 cases (80%); near total resection of the CPA component was performed in 1 case (20%). Two patients (40%) harbored high-grade chondrosarcomas. No patient experienced worsening neurological symptoms postoperatively. In 2 cases (40%), the symptoms were completely normalized after surgery. CONCLUSIONS: Expanded endoscopic endonasal approaches appear to be safe and effective in the resection of select skull base chondrosarcomas; those with predominant CPA involvement seem particularly amenable to resection through this technique. Further studies with larger cohorts are necessary to test these preliminary impressions and to compare their effectiveness with the results obtained with open approaches. PMID- 25270133 TI - Surgical outcomes after endoscopic management of cholesterol granulomas of the petrous apex: a systematic review. AB - OBJECT: Endoscopic endonasal treatment of petrous apex cholesterol granulomas allows for a natural drainage pathway into the nasopharynx. Because of the limited number of case series in the literature, there is limited evidence of recurrence rates and outcomes following endoscopic endonasal management. The purpose of this study was to determine the surgical outcomes of endoscopic endonasal approaches in the treatment of cholesterol granulomas of the petrous apex. METHODS: A systematic literature review was performed using PubMed for articles published from January 1980 to April 2014 to identify all studies reporting outcomes for endoscopic endonasal surgical management of cholesterol granulomas of the petrous apex. Operative approach, use of a stent, symptom outcome, restenosis, cyst recurrence, reoperation, and complications were extracted from included studies. RESULTS: A total of 53 patient cases were included from 22 relevant studies. The mean age was 41 years, and 26 patients (49%) were female. Stents were used in 45.1% of cases. Symptom resolution or improvement was seen in 98.6% of cases at follow-up (mean follow-up 20 months). Complications were reported in 13.2% of cases, with the most common complication being epistaxis. Restenosis on follow-up office endoscopic examination occurred in 9 of 45 cases (20.0%). Only 4 of these restenosis cases resulted in symptomatic cyst recurrence, resulting in an overall recurrence rate of 7.5%. The mean time from surgery to cyst recurrence was 13.5 months. The rate of symptomatic cyst recurrence was 10.7% in cases without the use of a stent compared with 4.3% in cases with stent placement (p = 0.6). CONCLUSIONS: Based on current literature, endoscopic endonasal approaches result in a high rate of symptom improvement or resolution. Complication rates are lower than prior case series that have utilized open approaches. Asymptomatic restenosis can be managed conservatively, since it is associated with symptomatic cyst recurrence less than half of the time. This study revealed a nonsignificant trend toward a decrease in symptomatic cyst recurrence when a stent was used, but further work is needed to clarify its impact. PMID- 25270134 TI - Evolution from microscopic transoral to endoscopic endonasal odontoidectomy. AB - OBJECT: The goal of this study was to compare the indications, benefits, and complications between the endoscopic endonasal approach (EEA) and the microscopic transoral approach to perform an odontoidectomy. Transoral approaches have been standard for odontoidectomy procedures; however, the potential benefits of the EEA might be demonstrated to be a more innocuous technique. The authors present their experience with 12 consecutive cases that required odontoidectomy and posterior instrumentation. METHODS: Twelve consecutive cases of craniovertebral junction instability with or without basilar invagination were diagnosed at the National Institute of Neurology and Neurosurgery in Mexico City, Mexico, between January 2009 and January 2013. The EEA was used for 5 cases in which the odontoid process was above the nasopalatine line, and was compared with 7 cases in which the odontoid process was beneath the nasopalatine line; these were treated using the transoral microscopic approach (TMA). Odontoidectomy was performed after occipital-cervical or cervical posterior augmentation with lateral mass and translaminar screws. One case was previously fused (Oc-C4 fusion). The senior author performed all surgeries. American Spinal Injury Association scores were documented before surgical treatment and after at least 6 months of follow-up. RESULTS: Neurological improvement after odontoidectomy was similar for both groups. From the transoral group, 2 patients had postoperative dysphonia, 1 patient presented with dysphagia, and 1 patient had intraoperative CSF leakage. The endoscopic procedure required longer surgical time, less time to extubation and oral feeding, a shorter hospital stay, and no complications in this series. CONCLUSIONS: Endoscopic endonasal odontoidectomy is a feasible, safe, and well tolerated procedure. In this small series there was no difference in the outcome between the EEA and the TMA; however, fewer complications were documented with the endonasal technique. PMID- 25270135 TI - Transnasal odontoid resection: is there an anatomic explanation for differing swallowing outcomes? AB - OBJECT: Swallowing dysfunction is common following transoral (TO) odontoidectomy. Preliminary experience with newer endoscopic transnasal (TN) approaches suggests that dysphagia may be reduced with this alternative. However, the reasons for this are unclear. The authors hypothesized that the TN approach results in less disruption of the pharyngeal plexus and anatomical structures associated with swallowing. The authors investigate the histological and gross surgical anatomical relationship between pharyngeal plexus innervation of the upper aerodigestive tract and the surgical approaches used (TN and TO). They also review the TN literature to evaluate swallowing outcomes following this approach. METHODS: Seven cadaveric specimens were used for histological (n = 3) and gross anatomical (n = 4) examination of the pharyngeal plexus with the TO and TN surgical approaches. Particular attention was given to identifying the location of cranial nerves (CNs) IX and X and the sympathetic chain and their contributions to the pharyngeal plexus. S100 staining was performed to assess for the presence of neural tissue in proximity to the midline, and fiber density counts were performed within 1 cm of midline. The relationship between the pharyngeal plexus, clivus, and upper cervical spine (C1-3) was defined. RESULTS: Histological analysis revealed the presence of pharyngeal plexus fibers in the midline and a significant reduction in paramedian fiber density from C-2 to the lower clivus (p < 0.001). None of these paramedian fibers, however, could be visualized with gross inspection or layer-by-layer dissection. Laterally based primary pharyngeal plexus nerves were identified by tracing their origins from CNs IX and X and the sympathetic chain at the skull base and following them to the pharyngeal musculature. In addition, the authors found 15 studies presenting 52 patients undergoing TN odontoidectomy. Of these patients, only 48 had been swallowing preoperatively. When looking only at this population, 83% (40 of 48) were swallowing by Day 3 and 92% (44 of 48) were swallowing by Day 7. CONCLUSIONS: Despite the midline approach, both TO and TN approaches may injure a portion of the pharyngeal plexus. By limiting the TN incision to above the palatal plane, the surgeon avoids the high-density neural plexus found in the oropharyngeal wall and limits injury to oropharyngeal musculature involved in swallowing. This may explain the decreased incidence of postoperative dysphagia seen in TN approaches. However, further clinical investigation is warranted. PMID- 25270136 TI - Surgical management of trigeminal schwannomas: defining the role for endoscopic endonasal approaches. AB - OBJECT: Because multiple anatomical compartments are involved, the surgical management of trigeminal schwannomas requires a spectrum of cranial base approaches. The endoscopic endonasal approach to Meckel's cave provides a minimal access corridor for surgery, but few reports have assessed outcomes of the procedure or provided guidelines for case selection. METHODS: A prospectively acquired database of 680 endoscopic endonasal cases was queried for trigeminal schwannoma cases. Clinical charts, radiographic images, and long-term outcomes were reviewed to determine outcome and success in removing tumor from each compartment traversed by the trigeminal nerve. RESULTS: Four patients had undergone endoscopic resection of trigeminal schwannomas via the transpterygoid approach (mean follow-up 37 months). All patients had disease within Meckel's cave, and 1 patient had extension into the posterior fossa. Gross-total resection was achieved in 3 patients whose tumors were purely extracranial. One patient with combined Meckel's cave and posterior fossa tumor had complete resection of the extracranial disease and 52% resection of the posterior fossa disease. One patient with posterior fossa disease experienced a sixth cranial nerve palsy in addition to a corneal keratopathy from worsened trigeminal neuropathy. There were no CSF leaks. Over the course of the study, 1 patient with subtotal resection required subsequent stereotactic radiosurgery for disease progression within the posterior fossa. CONCLUSIONS: Endoscopic endonasal approaches appear to be well suited for trigeminal schwannomas restricted to Meckel's cave and/or extracranial segments of the nerve. Lateral transcranial skull base approaches should be considered for patients with posterior fossa disease. Further multiinstitutional studies will be necessary for adequate power to help determine relative indications between endoscopic and transcranial skull base approaches. PMID- 25270137 TI - Fully endoscopic microvascular decompression for trigeminal neuralgia: technique review and early outcomes. AB - OBJECT: Fully endoscopicmicrovascular decompression (E-MVD) of the trigeminal nerve was initially described more than 1 decade ago, but has not yet gained wide acceptance. The authors present the experience of their first 47 consecutive E MVDs for trigeminal neuralgia (TN). METHODS: All surgeries were performed by a single surgeon (J.Y.K.L.) at the Pennsylvania Hospital at the University of Pennsylvania. Patients prospectively completed pain scales before and after surgery by using the Brief Pain Inventory-Facial outcomes tool. All patients were called on the telephone, and the same outcome tool was administered without reference to their preoperative pain status. RESULTS: Forty-seven patients (17 men) were identified and enrolled. Forty (85%) had Burchiel Type 1 TN. Vascular compression was observed at surgery in 42 patients (89%). No surgery was aborted or converted to microscope. One patient suffered permanent hearing loss, for a permanent neurological morbidity rate of 2%. Overall improvement in pain outcomes was excellent, with a median maximum pain intensity preoperatively of 10 and postoperatively of 0 (p< 0.0001). The mean interference with global function scores were 6.2 preoperatively and reduced to 1.0 at last follow-up (p < 0.0001). The mean interference with facial function was 7.3 preoperatively and reduced to 1.2 at last follow-up (p < 0.0001). The mean follow-up period after surgery was 15 +/- 8 months. CONCLUSIONS: In experienced hands, E-MVD offers superb visualization and illumination and is both safe and effective, at least in the short term. Further longer-term study is needed to compare E-MVD to traditional microscopic MVD. PMID- 25270138 TI - Endoscopic endonasal optic nerve and orbital apex decompression for nontraumatic optic neuropathy: surgical nuances and review of the literature. AB - OBJECT: While several approaches have been described for optic nerve decompression, the endoscopic endonasal route is gaining favor because it provides excellent exposure of the optic canal and the orbital apex in a minimally invasive manner. Very few studies have detailed the experience with nontraumatic optic nerve decompressions, whereas traumatic cases have been widely documented. Herein, the authors describe their preliminary experience with endoscopic endonasal decompression for nontraumatic optic neuropathies (NONs) to determine the procedure's efficacy and delineate its potential indications and limits. METHODS: The medical reports of patients who had undergone endoscopic endonasal optic nerve and orbital apex decompression for NONs at the Lyon University Neurosurgical Hospital in the period from January 2012 to March 2014 were reviewed. For all cases, clinical and imaging data on the underlying pathology and the patient, including demographics, preoperative and 6-month postoperative ophthalmological assessment results, symptom duration, operative details with video debriefing, as well as the immediate and delayed postoperative course, were collected from the medical records. RESULTS: Eleven patients underwent endoscopic endonasal decompression for NON in the multidisciplinary skull base surgery unit of the Lyon University Neurosurgical Hospital during the 27-month study period. The mean patient age was 53.4 years, and there was a clear female predominance (8 females and 3 males). Among the underlying pathologies were 4 sphenoorbital meningiomas (36%), 3 optic nerve meningiomas (27%), and 1 each of trigeminal neuroma (9%), orbital apex meningioma (9%), ossifying fibroma (9%), and inflammatory pseudotumor of the orbit (9%). Fifty-four percent of the patients had improved visual acuity at the 6-month follow-up. Only 1 patient whose sphenoorbital meningioma had been treated at the optic nerve atrophy stage continued to worsen despite surgical decompression. The 2 patients presenting with preoperative papilledema totally recovered. One case of postoperative epistaxis was successfully treated using balloon inflation, and 1 case of air swelling of the orbit spontaneously resolved. CONCLUSIONS: Endoscopic endonasal optic nerve decompression is a safe, effective, and minimally invasive technique affording the restoration of visual function in patients with nontraumatic compressive processes of the orbital apex and optic nerve. The timing of decompression remains crucial, and patients should undergo such a procedure early in the disease course before optic atrophy. PMID- 25270139 TI - The combined endonasal and transoral approach for the management of skull base and nasopharyngeal pathology: a case series. AB - The posterior skull base and the nasopharynx have historically represented technically difficult regions to approach surgically given their central anatomical locations. Through continued improvements in endoscopic instrumentation and technology, the expanded endonasal approach (EEA) has introduced a new array of surgical options in the management of pathology involving these anatomically complex areas. Similarly, the transoral robotic surgical (TORS) approach was introduced as a minimally invasive surgical option to approach tongue base, nasopharyngeal, parapharyngeal, and laryngeal lesions. Although both the EEA and the TORS approach have been extensively described as viable surgical options in managing nasopharyngeal and centrally located head and neck pathology, both endonasal and transoral techniques have inherent limitations. Given these limitations, several institutions have published feasibility studies with the combined EEA and TORS approaches for a variety of skull base and nasopharyngeal pathologies. In this article, the authors present their clinical experience with the combined endonasal and transoral approach through a case series presentation, and discuss advantages and limitations of this approach for surgical management of the middle and posterior skull base and nasopharynx. In addition, a presentation is included of a unique, simultaneous endonasal and transoral dissection of the nasopharynx through an innovative intraoperative setup. PMID- 25270140 TI - Endoscopic supraorbital eyebrow approach for the surgical treatment of extraaxialand intraaxial tumors. AB - OBJECT: The supraorbital eyebrow approach is a minimally invasive technique that offers wide access to the anterior skull base region and parasellar area through asubfrontal corridor. The use of neuroendoscopy allows one to extend the approach further to the pituitary fossa, the anterior third ventricle, the interpeduncular cistern, the anterior and medial temporal lobe, and the middle fossa. The supraorbital approach involves a limited skin incision, with minimal soft-tissue dissection and a small craniotomy, thus carrying relatively low approach-related morbidity. METHODS: All consecutive patients who underwent the endoscopic supraorbital eyebrow approach were retrospectively analyzed for lesion location, pathology, length of stay, complications, and cosmetic results. RESULTS: During a 56-month period, 97 patients (mean age 58.5 years) underwent an endoscopic eyebrow approach to resect extra- and intraaxial brain lesions. The most common pathologies treated were meningiomas (n = 41); craniopharyngiomas (n = 22); dermoid tumors (n = 7); metastases (n = 4); gliomas (n = 3); and other miscellaneous frontal, parasellar, and midbrain (n = 23) lesions. The median length of postoperative hospital stay was 2.7 days (range 1-8 days). In 82 patients a total removal of the lesion was performed, while in 15 patients a near total or subtotal removal was achieved. There were no postoperative hematomas, cerebrospinal fluid leaks, or severe neurological deficits, with the exception of 2 cases of visual deterioration and 1 case each of meningitis, stroke, and third cranial nerve paresis. Other complications directly related to the approach included 2 cases of skin burn as a direct result of heat transmission from the microscope light, 1 case of right frontal palsy, 2 cases of frontal numbness, and 1 case of bone remodeling 1 year after surgery. CONCLUSIONS: The endoscopic supraorbital eyebrow approach is a safe and effective minimally invasive approach to remove extra- and intraaxial anterior skull base, parasellar, and frontal lesions, promoting a rapid recovery and short hospital stay. The location of the eyebrow incision demands a meticulous cosmetic closure, but, with proper technique, cosmetic results are excellent. PMID- 25270141 TI - Editorial: The endoscopic keyhole supraorbital approach. PMID- 25270142 TI - Letter to the Editor: Kernohan's contributions to neurosurgery. PMID- 25270143 TI - Immediate complications associated with high-flow cerebrospinal fluid egress during endoscopic endonasal skull base surgery. AB - Endoscopic expanded endonasal approaches (EEAs) to the skull base are increasingly being used to address a variety of skull base pathologies. Postoperative CSF leakage from the large skull base defects has been well described as one of the most common complications of EEAs. There are reports of associated formation of delayed subdural hematoma and tension pneumocephalus from approximately 1 week to 3 months postoperatively. However, there have been no reports of immediate complications of high-volume CSF leakage from EEA skull base surgery. The authors describe two cases of EEAs in which complications related to rapid, large-volume CSF egress through the skull base surgical defect were detected in the immediate postoperative period. Preventive measures to reduce the likelihood of these immediate complications are presented. PMID- 25270144 TI - Endoscopic skull base reconstruction: a review and clinical case series of 152 vascularized flaps used for surgical skull base defects in the setting of intraoperative cerebrospinal fluid leak. AB - Endoscopic skull base surgery continues to rapidly evolve, requiring comparable advances in reconstructive techniques. While smaller skull base defects with low intraoperative CSF flow have been successfully managed with a variety of avascular and/or noncellular techniques, larger defects with high CSF flow require more robust repairs often in the form of vascularized flaps, which confer excellent success rates in this setting. Despite these successful outcomes, a paucity of data describing specific patient and operative characteristics and their effects on repair exist. Therefore, a retrospective, consecutive chart review was performed on patients who underwent endoscopic skull base reconstruction with a vascularized flap in the setting of intraoperative CSF leaks. In this series, 151 patients with a mean age of 51 years underwent 152 vascularized flap skull base reconstructions for an array of benign and malignant pathologies. These vascularized flaps included 144 nasoseptal flaps, 6 endoscopic assisted pericranial flaps, 1 facial artery buccinator flap, and 1 inferior turbinate flap that were used throughout all regions of the skull base. Perioperative (< 3 months) and postoperative (> 3 months) flap complications were assessed and revealed 3 perioperative flap defects (2.0%) defined as a visualized defect within the substrate of the flap and a total of 5 perioperative CSF leaks (3.3%). No patient experienced flap death/complete flap loss in the cohort. Assessed postoperative flap complications included 1 case (0.7%) of mucocele formation, 8 cases (5.3%) of prolonged skull base crusting, and 2 cases (1.3%) of donor-site complication, specifically septal perforation secondary to nasoseptal flap harvest. Among the 152 cases identified, 37 patients received radiation therapy while 114 patients did not undergo radiation therapy as part of the treatment profile. No significant association was found between perioperative complication rates and radiation therapy (p = 0.634). However, a significant association was found between postoperative complication rates and radiation therapy, primarily accounted for by an increased risk for prolonged (> 6 months) skull base crusting (p = 0.025). It is clear that larger skull base defects with high intraoperative CSF flow require thoughtful approach and strong consideration for vascularized repair. PMID- 25270145 TI - Editorial: Vascularized flap reconstruction for CSF leaks during endoscopic skull base surgery. PMID- 25270146 TI - Septal transposition: a novel technique for preservation of the nasal septum during endoscopic endonasal resection of olfactory groove meningiomas. AB - Endonasal resection of olfactory groove meningiomas allows for several advantages over transcranial routes, including a direct approach to the bilateral anterior cranial base and dura mater, early tumor devascularization, and avoidance of brain retraction. Although considered minimally invasive, the endoscopic approach to the cribriform plate typically requires resection of the superior nasal septum, resulting in a large superior septal perforation. The septal transposition technique improves preservation of sinonasal anatomy through the elimination of a septal perforation while allowing for wide exposure to the midline anterior cranial base and harvest of a nasal septal flap. Herein, the authors describe a 39-year-old female who presented with a progressively enlarging olfactory groove meningioma. An endoscopic endonasal resection with a septal transposition technique was performed. On follow-up, the nasal cavity had completely normal anatomy with preservation of the turbinates and nasal septum. The authors conclude that septal transposition is a useful technique that allows wide exposure of the anterior cranial base with maximal preservation of normal nasal anatomy and avoidance of a large septal perforation. PMID- 25270147 TI - Introduction: Endoscopic endonasal skull base surgery. PMID- 25270148 TI - The epigonal organ and mature pole of the testis in the recreationally fished blue shark (Prionace glauca): histochemico-functional correlates. AB - The exact role of the immune system in normal spermatogenesis is poorly understood. The attachment, however, of the lymphomyeloid epigonal organ specifically to the testis's mature pole in many shark species is a curious finding. Unlike the histology of the lymphomyeloid tissues of many other elasmobranchs, the epigonal organ leukocytes of wild-caught blue shark (Prionace glauca), besides exhibiting extensive nuclear heterogeneity, contain some of the largest known granules ever seen in vertebrate white blood cells. It was previously shown that the blue shark epigonal organ remains unremarkable and functionally unchanged despite cestode parasites embedded into its surface, suggesting that it might have other functions in addition to microbial defense. We show here that Prionace epigonal leukocytes shed their granule-laden cytoplasm into the cyst resorption zone (RZ) of the testis, i.e. the region separating the spermatogenic tissue from the epigonal organ, as they begin to migrate into the RZ. Using the immunoreactivity of the conserved transcription factor (proliferating cell nuclear antigen) as marker, it is shown that the granule lacking leukocytes exclusively infiltrated spermatozoal cysts leftover after the wave of wide-spread multinuclear cell death in summer-breeding males in a seasonally dependent manner. By contrast, Prionace caught 2 months later showed fully recovered testes containing numerous completely intact spermatozoal cysts. Conversely, degenerating immature spermatids were gradually phagocytized by their accompanying Sertoli cells, and leukocytes did not infiltrate such cysts. The autoimmune response described here resembles in every aspect the testicular autoimmune response induced experimentally in a teleost fish. These observations suggest functional adaptation of shark leukocytes in response to specific changes in the testicular microenvironment. PMID- 25270151 TI - Prior exposure to interpersonal violence and long-term treatment response for boys with a disruptive behavior disorder. AB - Interpersonal violence (IPV) is common in children with a disruptive behavior disorder (DBD) and increases the risk for greater DBD symptom severity, callous unemotional (CU) traits, and neuroendocrine disruption. Thus, IPV may make it difficult to change symptom trajectories for families receiving DBD interventions given these relationships. The current study examined whether IPV prior to receiving treatment for a DBD predicted trajectories of a variety of associated outcomes, specifically DBD symptoms, CU traits, and cortisol concentrations. Boys with a DBD diagnosis (N = 66; age range = 6-11 years; 54.5% of whom experienced IPV prior to treatment) of either oppositional defiant disorder or conduct disorder participated in a randomized clinical trial and were assessed 3 years following treatment. Multilevel modeling demonstrated that prior IPV predicted smaller rates of change in DBD symptoms, CU traits, and cortisol trajectories, indicating less benefit from intervention. The effect size magnitudes of IPV were large for each outcome (d = 0.88-1.07). These results suggest that IPV is a predictor of the long-term treatment response for boys with a DBD. Including trauma-focused components into existing DBD interventions may be worth testing to improve treatment effectiveness for boys with a prior history of IPV. PMID- 25270152 TI - Anti-B cell therapy with rituximab as induction therapy in renal transplantation. AB - Traditionally, antirejection therapy in organ transplantation has mainly been directed at T cells. During recent years, the role of B cells in acute rejection has attracted more attention. In the Radboud University Medical Center (Nijmegen, The Netherlands) we performed a randomized, placebo controlled study to assess the efficacy and safety of rituximab as induction therapy after renal transplantation. In parallel we investigated the effects of rituximab on the numbers and function of B and T cells. An overview of the results, which have largely been published in peer reviewed papers, is presented below. PMID- 25270153 TI - Rare case of severe cholangiopathy following critical illness. AB - Secondary sclerosing cholangitis is a rare condition caused by disorders directly damaging the biliary tree. We present a case of a 34-year-old man with no pre existing hepatobiliary disease who developed significant cholestasis and subsequent cholangitis while in the intensive care unit for multiorgan failure secondary to H1N1 influenza A (swine flu). After discharge from the intensive care unit, jaundice, fevers, abdominal pain, pruritus and ongoing cholestasis persisted, consistent with recurrent cholangitis. Secondary sclerosing cholangitis was confirmed by liver biopsy and endoscopic retrograde cholangiopancreatography. This is a case of the recently described syndrome of secondary sclerosing cholangitis following critical illness, with associated severe hypoxic and ischaemic injury. He subsequently developed recognised complications of sclerosing cholangitis, including fat-soluble vitamin deficiencies, recurrent cholangitis and liver fibrosis. To the best of our knowledge, this is the first reported case of secondary sclerosing cholangitis following critical illness in the UK. PMID- 25270154 TI - A rare native mitral valve endocarditis successfully treated after surgical correction. AB - Mycobacterium abscessus and Kocuria species are rare causes of infections in humans. Endocarditis by these agents has been reported in only 11 cases. M. abscessus is a particularly resistant organism and treatment requires the association of antibiotics for a prolonged period of time. We report a case of native mitral valve bacterial endocarditis due to M. abscessus and Kocuria species in a 48-year-old man with a history of intravenous drug use. The case was complicated by a perforation of the posterior mitral valve leaflet, leading to surgical mitral valve replacement. Cultures from the blood and mitral valve disclosed M. abscessus and Kocuria species. The patient was treated for 6 months with clarithromycin, imipenem and amikacin, with resolution of symptoms. Repeated blood cultures were negative. Acid-fast staining should be done in subacute endocarditis in order to identify rapidly growing mycobacteria. PMID- 25270155 TI - Hepatocellular carcinoma in a patient with chronic lymphocytic leukaemia involving the liver. AB - A relationship between hepatocellular carcinoma and chronic lymphocytic leukaemia has been reported. This is a case of a 75-year-old woman with stable chronic lymphocytic leukaemia, not on treatment with an increased activity of serum alkaline phosphatase and negative liver disease work up. A liver biopsy revealed leukaemic infiltration without evidence of cirrhosis or fatty liver. Four years later, she presented with a rapidly progressive liver mass which was diagnosed as hepatocellular carcinoma histologically. PMID- 25270156 TI - Ocular toxoplasmosis: a very rare presentation in an immunocompetent patient. AB - A 28-year-old man presented with a 2-week history of red eye, photophobia, pain and decreased visual acuity of the right eye. The ophthalmological examination revealed hypertensive non-granulomatous panuveitis, retinal vasculitis with focus of retinochoroiditis with pigmented central area suggestive of ocular toxoplasmosis in the active phase. He started treatment with azithromycin, pyrimethamine, topical steroids and measures for control of intraocular pressure. Serology for Toxoplasma gondii was positive and for HIV, negative. For headache and vomiting, he was hospitalised in order to exclude cerebral toxoplasma. The cerebral CT scan, MRI and lumbar puncture were negative and treatment was changed to pyrimethamine, sulfadiazine and prednisolone. For persistence of vomiting he started clindamycin with clinical and ophthalmological improvement. The patient is currently under prophylaxis with co-trimoxazol for 1 year, and maintains clinical improvement. This case illustrates the rarity of presentation of ocular toxoplasmosis, without cerebral in an immunocompetent patient. PMID- 25270157 TI - Perforated duodenal diverticulae: importance for the surgeon and gastroenterologist. AB - We present the case of a 78-year-old woman who was admitted for an elective left hemicolectomy for diverticular disease. Two days following the elective procedure, bilious fluid was noted in her pelvic drain. The patient returned to theatre, where a perforated duodenal diverticulum was excised and the defect primarily repaired. The patient then developed a low output enterocutaneous fistula which was treated conservatively with nasojejunal feeding and resolved spontaneously. PMID- 25270158 TI - Photodermatosis secondary to hydroxyurea. PMID- 25270159 TI - Gossypiboma: a rare cause of chronic vaginal discharge after laparoscopic hysterectomy. PMID- 25270160 TI - Work-related discrimination and change in self-stigma among people with mental illness during supported employment. AB - OBJECTIVE: The relationship of work-related discrimination to the change in self stigma and stigma stress was assessed among supported employment participants in Switzerland. METHODS: Self-stigma and the cognitive appraisal of mental illness stigma as a stressor were measured at baseline among supported employment participants (N=116). These variables and work-related discrimination in the past year were assessed one year later (N=96). RESULTS: Compared with participants who did not find employment (N=30), those who worked without experiencing discrimination (N=25) had lower levels of self-stigma and stigma stress at one year. Among those who worked and reported work-related discrimination (N=38), these measures did not decrease significantly. CONCLUSIONS: Experiencing discrimination at work may determine whether employment has positive effects in terms of self-stigma and stigma stress among individuals with mental illness. Interventions to reduce discrimination in work settings and to improve coping resources of these individuals could augment the positive effects of supported employment. PMID- 25270161 TI - Is the continued use of UK plasma sourced cryoprecipitate justified? Response to Makris. PMID- 25270162 TI - Gibberellin secreting rhizobacterium, Pseudomonas putida H-2-3 modulates the hormonal and stress physiology of soybean to improve the plant growth under saline and drought conditions. AB - The physiological changes in tolerant soybean plants under salt and drought stress conditions with Pseudomonas putida H-2-3 were investigated. A bacterial isolate H-2-3 was isolated from soil and identified as Pseudomonas putida H-2-3 by 16S rDNA sequences. The treatment of P. putida H-2-3 significantly increased the length, fresh and dry weight of shoot and chlorophyll content in gibberellins (GAs) deficient mutant Waito-c rice seedlings over the control, it might be the presence of GA1, GA4, GA9 and GA20. The soybean plant growth was retarded in salt (120 mM sodium chloride) and drought (15% polyethylene glycol) stress conditions at 10 days treatments, while P. putida H-2-3 effectively enhanced the shoot length and fresh weight of plants suffered at salt and drought stress. The chlorophyll content was lower in abiotic stress conditions and bacterial inoculant P. putida H-2-3 mitigated the stress effects by an evidence of higher quantity of chlorophyll content in plants exposed to salt and drought. The stress hormonal analysis revealed that individual treatment of P. putida H-2-3, salt and drought significantly enhanced the abscisic acid and salicylic acid content than their control. P. putida H-2-3 applied to salt and drought stressed plants showed a lower level of abscisic acid and salicylic acid and a higher level of jasmonic acid content. Under stress condition induced by salt and drought in plants expressed higher level of total polyphenol, superoxide dismutase and radical scavenging activity and no significant changes in flavonoids. The bio-inoculant, P. putida H-2-3 modulated those antioxidants by declining superoxide dismutase, flavonoids and radical scavenging activity. P. putida H-2-3 induced tolerance against abiotic stress was confirmed by a reduction of Na content in abiotic stressed plants. The results suggest that P. putida H-2-3 application reprograms the chlorophyll, stress hormones and antioxidants expression in abiotic stress affected soybean plant and improves their growth under stress environment. PMID- 25270163 TI - The roles of histone acetylation in seed performance and plant development. AB - Histone acetylation regulates gene transcription by chromatin modifications and plays a crucial role in the plant development and response to environment cues. The homeostasis of histone acetylation is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs) in different plant tissues and development stages. The vigorous knowledge of the function and co factors about HATs (e.g. GCN5) and HDACs (e.g. HDA19, HDA6) has been obtained from model plant Arabidopsis. However, understanding individual role of other HATs and HDACs require more work, especially in the major food crops such as rice, maize and wheat. Many co-regulators have been recently identified to function as a component of HAT or HDAC complex in some specific developmental processes. The described findings show a distinctive and interesting epigenetic regulation network composed of HATs, HDACs and co-regulators playing crucial roles in the seed performance, flowering time, plant morphogenesis, plant response to stresses etc. In this review, we summarized the recent progresses and suggested the perspective of histone acetylation research, which might provide us a new window to understand the epigenetic code of plant development and to improve the crop production and quality. PMID- 25270164 TI - Flower color patterning in pansy (Viola * wittrockiana Gams.) is caused by the differential expression of three genes from the anthocyanin pathway in acyanic and cyanic flower areas. AB - The petals of pansy (Viola * wittrockiana Gams.) 'Mengdie' exhibit a cyanic blotched pigmentation pattern. The accumulation of anthocyanins, cyanidin and delphinidin, was detected in the upper epidermal cells of the cyanic blotches. In order to elucidate the mechanism by which cyanic blotches are formed in pansy petal, the expression level of genes involved in anthocyanin synthesis was measured and compared between cyanic blotches and acyanic areas of the flower. The use of primers in conserved regions allowed the successful isolation of six cDNA clones encoding putative anthocyanin enzymes from pansy petals. The clones isolated encoded chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3 hydroxylase (F3H), flavonoid 3'-hydroxylase (F3'H), dihydroflavonol 4-reductase (DFR) and anthocyanidin synthase (ANS). The transcription patterns of seven genes (VwCHS, VwCHI, VwF3H, VwF3'H, VwDFR, VwF3'5'H, and VwANS) in cyanic blotches and acyanic areas of the petals at seven stages of flower development were determined by real-time quantitative PCR. Transcription of VwF3'5'H, VwDFR and VwANS was significantly increased in cyanic blotches at stages III-V of flower development, implicating these genes in the pigmentation of Viola * wittrockiana Gams. petals. PMID- 25270165 TI - Long-term results of up to 12 years of over 700 cases of viscocanalostomy for open-angle glaucoma. AB - PURPOSE: To study the safety and long-term efficacy of classic viscocanalostomy in patients with open-angle glaucoma (OAG) in different populations. METHODS: A total of 726 eyes of 726 patients from Europe or South Africa with primary OAG (POAG) and pseudoexfoliative glaucoma (PXFG) were included in this retrospective multicentre study. Complete (qualified) success was defined as an intraocular pressure (IOP) equal to or lower than 21, 18 and 16 mmHg without (with or without) medications, respectively. A failed procedure was defined if IOP was above 21 mmHg, not controllable by laser goniopuncture or medications. RESULTS: The mean IOP before surgery was 42.6 +/- 14.2 mmHg for all patients, 29.6 +/- 6.6 mmHg for European patients and 48.1 +/- 12.9 mmHg for African patients. The follow-up time was 86.2 +/- 43.1 months. Mean IOP was 15.4 +/- 3.6 mmHg at 5 years, 15.5 +/- 4.4 mmHg at 10 years and 16.8 +/- 4.2 mmHg at 15 years. The qualified success rate for an IOP of 21, 18 or 16 mmHg or less after 5 years was 92% [95% confidence interval (CI) 0.88-0.96], 70% (95% CI 0.63-0.77) and 43% (95% CI 0.36-0.51) in European patients, and 90% (95% CI 0.87-0.93), 77% (95% CI 0.74 0.81) and 67% (95% CI 0.63-0.72) in African patients, respectively. There was no difference between the success rate for POAG and PXFG for an IOP of 21, 18 or 16 mmHg or less at 5 years (p = 0.64, p = 0.20, p = 0.22, respectively). Laser goniopuncture was performed postoperatively on a total of 127 eyes (17.7%), lowering the pressure from 23.1 +/- 1.9 mmHg to 15.0 +/- 2.2 mmHg. There were no significant complications, in particular, no blebitis or endophthalmitis. CONCLUSION: Viscocanalostomy produced a sustained long-term reduction of IOP with a low-risk profile in European and African patients with OAG over 12 years. PMID- 25270166 TI - Sliding humeral osteotomy: medium-term objective outcome measures and reduction of complications with a modified technique. AB - OBJECTIVE: To determine mid-term complication rate associated with a modified sliding humeral osteotomy (SHO) technique and compare clinical outcome with or without focal treatment (FT). ANIMALS: Dogs (n = 46; 60 elbows) with severe or persistent lameness attributable to medial coronoid disease (MCD). METHODS: Signalment, lameness, pain score, and preoperative radiographic findings were recorded. Modified Outerbridge score and fissure/fragmentation were recorded arthroscopically. SHO was performed with technical modifications. Outcome measures included lameness score, elbow pain score, owner function assessment, and force-plate preoperatively, at 6 and 12 weeks, and 6-25 months. RESULTS: SHO was performed on 60 limbs; 22 also had FT of the medial coronoid process. Mean (+/-SD) dog age was 44.17 +/- 33.0 months and weight range was 17.4-49.8 kg. Preoperative duration of lameness was 2.16 +/- 0.69 months. Lameness improved for all limbs by 12 weeks, and resolved in 49 limbs. Significant improvements in postoperative pain scores and most owner function assessments occurred. There was no significant difference with or without FT. There were no major complications and 4.17% minor complications. Force-plate data available for 18 of 46 dogs operated unilaterally preoperatively and at last follow-up showed significant improvement in ground reaction force and reduction of asymmetry index (t-test; P < .05). CONCLUSIONS: SHO with or without focal treatment of the medial aspect of the coronoid process ameliorates lameness and pain associated with MCD at medium term follow-up. Application technique is critical to minimize morbidity. PMID- 25270167 TI - Mechanical properties of carbon nanotube/polymer composites. AB - The remarkable mechanical properties of carbon nanotubes, such as high elastic modulus and tensile strength, make them the most ideal and promising reinforcements in substantially enhancing the mechanical properties of resulting polymer/carbon nanotube composites. It is acknowledged that the mechanical properties of the composites are significantly influenced by interfacial interactions between nanotubes and polymer matrices. The current challenge of the application of nanotubes in the composites is hence to determine the mechanical properties of the interfacial region, which is critical for improving and manufacturing the nanocomposites. In this work, a new method for evaluating the elastic properties of the interfacial region is developed by examining the fracture behavior of carbon nanotube reinforced poly (methyl methacrylate) (PMMA) matrix composites under tension using molecular dynamics simulations. The effects of the aspect ratio of carbon nanotube reinforcements on the elastic properties, i.e. Young's modulus and yield strength, of the interfacial region and the nanotube/polymer composites are investigated. The feasibility of a three-phase micromechanical model in predicting the elastic properties of the nanocomposites is also developed based on the understanding of the interfacial region. PMID- 25270168 TI - The relevance of leukotrienes for bone resorption induced by mechanical loading. AB - 5-Lipoxygenase (5-LO) metabolites are important pro-inflammatory lipid mediators. However, much still remains to be understood about the role of such mediators in bone remodeling. This study aimed to investigate the effect of 5-LO metabolites, LTB4 and CysLTs, in a model of mechanical loading-induced bone remodeling. Strain induced tooth movement and consequently alveolar bone resorption/apposition was achieved by using a coil spring placed on molar and attached to incisors of C57BL6 (wild-type-WT), 5-LO deficient mice (5-LO(-/-)) and mice treated with 5-LO inhibitor (zileuton-ZN) or with antagonist of CysLTs receptor (montelukast-MT). The amount of bone resorption and the number of osteoclasts were determined morphometrically. The expression of inflammatory and bone remodeling markers in periodontium was analyzed by qPCR. Osteoclast differentiation and TNF-alpha production were evaluated in vitro using RAW 264.7 cells treated with LTB4 or LTD4. Bone resorption, TRAP(+) cells and expression of Tnfa, Il10 and Runx2 were significantly diminished in 5-LO(-/-), ZN- and MT-treated mice. The expression of Rank was also reduced in 5-LO(-/-) and MT-treated mice. Accordingly, LTB4 and LTD4 in association with RANKL promoted osteoclast differentiation and increased TNF-alpha release in vitro. These data demonstrate that the absence of 5-LO metabolites, LTB4 and CysLTs reduces osteoclast recruitment and differentiation, consequently diminishing bone resorption induced by mechanical loading. Thus, 5 LO might be a potential target for controlling bone resorption in physiological and pathological conditions. PMID- 25270169 TI - Dedication: in tribute to Noreen M. Clark. PMID- 25270170 TI - A tribute to Noreen M. Clark, 1943-2013. PMID- 25270171 TI - Noreen Clark's enduring legacies to SOPHE. PMID- 25270172 TI - The effect on health and self-confidence of participation in collaborative learning activities. PMID- 25270173 TI - A social cognitive view of self-regulated learning about health. AB - Researchers interested in health-related learning have recently begun to study processes people use to self-regulate their health and their ability to prevent or control chronic disease. This paper represents a social cognitive view of self regulation that involves three classes of influence on self-regulating behavior: personal, behavioral, and environmental. This triadic model assumes that people self-regulate their health through the use of self-care strategies, setting reasonable health goals, and monitoring feedback concerning the effectiveness of strategies in meeting their goals. People's perceptions of self-efficacy are also assumed to play a major role in motivating them to self-regulate their health functioning. According to social cognitive theory, processes entailed in regulating one's health can be taught through social modeling, supports, and feedback; gradually these external supports are withdrawn as one is able to self regulate. This paper will analyze self-regulation processes related to controlling or preventing lung disease, specifically management of asthma and eliminating smoking. The educational implications of the triadic model of self regulation for promoting health and related behavioral functioning will be discussed. PMID- 25270174 TI - Health educators and the future: lead, follow, or get out of the way. AB - In just a few years a new century will dawn. This article posits that with it will come new challenges for health education. Five types of change the field is currently experiencing are discussed. It is suggested that shifts in demographics, conceptions of family, and levels of activism, are demanding new thinking. Approaches based on a new perception of health education are presented. The need for current health educators to shape the direction of change through invigorated leadership is emphasized. PMID- 25270175 TI - A model of self-regulation for control of chronic disease. AB - Chronic disease poses increasing threat to individual and community health. The day-to-day manager of disease is the patient who undertakes actions with the guidance of a clinician. The ability of the patient to control the illness through an effective therapeutic plan is significantly influenced by social and behavioral factors. This article presents a model of patient management of chronic disease that accounts for intrapersonal and external influences on management and emphasizes the central role of self-regulatory processes in disease control. Asthma serves as a case for exploration of the model. Findings from a 5-year study of 637 children with asthma and their care-taking parents supported that the self-regulation elements of the model were reasonably stable over time and baseline values were predictive of important disease management outcomes. PMID- 25270176 TI - Impact of Physician Asthma Care Education on patient outcomes. AB - OBJECTIVE: We evaluated the effectiveness of a continuing medical education program, Physician Asthma Care Education, in improving pediatricians' asthma therapeutic and communication skills and patients' health care utilization for asthma. METHODS: We conducted a randomized trial in 10 regions in the United States. Primary care providers were recruited and randomly assigned by site to receive the program provided by local faculty. The program included 2 interactive seminar sessions (2.5 hours each) that reviewed national asthma guidelines, communication skills, and key educational messages. Format included short lectures, case discussions, and a video modeling communication techniques. We collected information on parent perceptions of physicians' communication, the child's asthma symptoms, and patients' asthma health care utilization. We used multivariate regression models to determine differences between control and intervention groups. RESULTS: A total of 101 primary care providers and a random sample of 870 of their asthma patients participated. After 1 year, we completed follow-up telephone interviews with the parents of 731 of the 870 patients. Compared to control subjects, parents reported that physicians in the intervention group were more likely to inquire about patients' concerns about asthma, encourage patients to be physically active, and set goals for successful treatment. Patients of physicians that attended the program had a greater decrease in days limited by asthma symptoms (8.5 vs 15.6 days), as well as decreased emergency department asthma visits (0.30 vs 0.55 visits per year). CONCLUSIONS: The Physician Asthma Care Education program was used in a range of locations and was effective in improving parent-reported provider communication skills, the number of days affected by asthma symptoms, and asthma health care use. Patients with more frequent asthma symptoms and higher health care utilization at baseline were more likely to benefit from their physician's participation in the program. PMID- 25270177 TI - Heart disease management by women: does intervention format matter? AB - A randomized controlled trial of two formats of a program (Women Take PRIDE) to enhance management of heart disease by patients was conducted. Older women (N = 575) were randomly assigned to a group or self-directed format or to a control group. Data regarding symptoms, functional health status, and weight were collected at baseline and at 4, 12, and 18 months. The formats produced different outcomes. At 18 months, the self-directed format was better than the control in reducing the number (p <= .02), frequency (p <= .03), and bothersomeness (p <= .02) of cardiac symptoms. The self-directed format was also better than the group format in reducing symptom frequency of all types (p <= .04). The group format improved ambulation at 12 months (p <= .04) and weight loss at 18 months (p <= .03), and group participants were more likely to complete the program (p <= .05). The availability of different learning formats could enhance management of cardiovascular disease by patients. PMID- 25270178 TI - Policy and system change and community coalitions: outcomes from allies against asthma. AB - Objectives. We assessed policy and system changes and health outcomes produced by the Allies Against Asthma program, a 5-year collaborative effort by 7 community coalitions to address childhood asthma. We also explored associations between community engagement and outcomes. Methods. We interviewed a sample of 1,477 parents of children with asthma in coalition target areas and comparison areas at baseline and 1 year to assess quality-of-life and symptom changes. An extensive tracking and documentation procedure and a survey of 284 participating individuals and organizations were used to ascertain policy and system changes and community engagement levels. Results. A total of 89 policy and system changes were achieved, ranging from changes in interinstitutional and intrainstitutional practices to statewide legislation. Allies children experienced fewer daytime (P = .008) and nighttime (P = .004) asthma symptoms than comparison children. In addition, Allies parents felt less helpless, frightened, and angry (P = .01) about their child's asthma. Type of community engagement was associated with number of policy and system changes. Conclusions. Community coalitions can successfully achieve asthma policy and system changes and improve health outcomes. Increased core and ongoing community stakeholder participation rather than a higher overall number of participants was associated with more change. PMID- 25270179 TI - Declines with age in childhood asthma symptoms and health care use: an adjustment for evaluations. AB - RATIONALE: Asthma is a variable condition with an apparent tendency for a natural decline in asthma symptoms and health care use occurring as children age. As a result, asthma interventions using a pre-post design may overestimate the intervention effect when no proper control group is available. OBJECTIVES: Investigate patterns of natural decline over time with increasing age in asthma symptoms and health care use of children. Develop a statistical procedure that enables adjustment that accounts for expected declines in these outcomes and is useable when intervention evaluations must rely solely on pre-post data. METHODS: Mixed-effects models with mixture distributions were used to describe the pattern of symptoms and health care use in 3,021 children aged 2 to 15 years in a combined sample from three controlled trials. An adaptive least squares estimation was used to account for overestimation of intervention effects and make adjustments for pre-post only data. Termed "Adjustment for Natural Declines in Asthma Outcomes (ANDAO)," the adjustment method uses bootstrap sampling to create control cohorts comparable to subjects in the intervention study from existing control subjects. ANDAO accounts for expected declines in outcomes and is beneficial when intervention evaluations must rely solely on pre-post data. MEASUREMENTS AND MAIN RESULTS: Children under 10 years of age experienced 18% (95% confidence interval, 15-21%) fewer symptom days and 28% (95% confidence interval, 24-32%) fewer symptom nights with each additional year of age. The decline was less than 10% after age 10 years, depending on baseline asthma severity. Emergency department visits declined regardless of baseline symptom frequency (P = 0.02). The adjustment method corrected estimates to within 2.4% of true effects through simulations using control cohorts. CONCLUSIONS: Because of the declines in symptoms and health care use expected with increasing age of children with asthma, pre-post comparisons will greatly overestimate intervention effects. The ANDAO provides means to adequately estimate treatment effects when a control group design is not possible. PMID- 25270180 TI - Noreen Clark's five lessons on teaching, research, and mentoring. PMID- 25270181 TI - "Lead, follow, or get out of the way": Noreen Clark and commitments to practice. PMID- 25270182 TI - Lessons from a public health leader: Noreen Clark's approaches to public health practice. PMID- 25270183 TI - Noreen M. Clark: reflections on her life and contributions. PMID- 25270185 TI - Population genetic data for 15 autosomal STR markers in Turkish Cypriots from Cyprus. AB - Fifteen autosomal short tandem repeat (STR) markers [D8S1179, D21S11, D7S820, CSF1PO, D3S1358, THO1, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818 and FGA] were analyzed in 501 unrelated, randomly selected Turkish Cypriot individuals from the island of Cyprus. While no locus duplications or null alleles were detected in these samples, eight allelic variants were observed in total, 75% of which were intermediate allelic variants that were absent in the system allelic ladder. Allelic frequencies and statistical parameters of forensic interest were calculated at each locus. For the 15 STR loci tested, combined matching probability (pM) was 2.15717 * 10(-18) and combined power of exclusion (PE) was 0.9999995213. No deviations from the Hardy-Weinberg equilibrium were observed, except for the vWA locus, which became insignificant after the Bonferroni correction for multiple testing. Locus-by-locus comparisons of the Turkish Cypriot allelic frequencies with those published for the neighboring and/or historically related populations with similar loci coverage (Turkish, Greek, Greek Cypriot, Italian and Lebanese) revealed some statistically significant differences at one to five loci. In general, an increase in the number of such significant differences between the Turkish Cypriot data and those for other populations correlated closely with an increase in the geographic distance and/or a decrease in the amount of historical contact. The Turkish Cypriot autosomal STR population study will find immediate use in the Committee on Missing Persons in Cyprus Project on the "Exhumation, Identification and Return of Remains of Missing Persons" and it will also be available for criminal, parentage and other missing person investigations. PMID- 25270186 TI - A parallel-group comparison study of celecoxib with loxoprofen sodium in third mandibular molar extraction patients. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely, but they may damage the upper gastrointestinal mucosa owing to their mechanism of action. Selective cyclooxygenase 2 (COX-2) inhibitors are known to have a reduced risk for such damage. In this comparative study, the efficacy and safety of the selective COX-2 inhibitor celecoxib for pain after third mandibular molar extraction were compared with those of loxoprofen sodium. This was a parallel group comparison study; 107 patients who had undergone third mandibular molar extraction were given celecoxib and 102 were given loxoprofen. The level of pain on a visual analogue scale (VAS) 15 min and 30 min after taking the experimental drug decreased over time, with no significant difference between the two groups. The percentage of patients taking a second dose was 64.5% for celecoxib and 80.4% for loxoprofen. The time to second dose was significantly longer for celecoxib (533.5 min) than for loxoprofen (387.4 min). There was no significant difference in the patients' impression of efficacy between the two groups, with ratings of 'excellent' and 'good' for 77.4% in the loxoprofen group and 74.5% in the celecoxib group. These results demonstrate that celecoxib is of equal clinical value to loxoprofen for acute pain after third mandibular molar extraction. PMID- 25270187 TI - Management-related outcomes and radiographic findings of idiopathic condylar resorption: a systematic review. AB - Idiopathic condylar resorption (ICR) is progressive resorption of the condyle of unknown aetiology. There is no consensus on the approaches for diagnostic imaging and management of this disease. The objective of this systematic review was to examine the best practices for imaging and to appraise the success of surgical and non-surgical therapy of ICR. Eleven search engines were queried via explicit literature searches for studies describing ICR, published until 2012. Two authors independently extracted data using predetermined characteristics. Studies that identified patients as having either ICR or progressive condylar resorption and that described the radiographic findings or treatment options were included. Seventeen studies contributing 178 cases met the eligibility criteria. The major radiographic findings, as assessed mostly by two-dimensional imaging, included decreased ramus height, decreased condylar height, altered volume of the condyle, decreased SNB angle and mandibular plane angle, and a retrognathic profile. Treatments included occlusal splints with orthodontic treatment, condylectomy with costochondral graft, and other surgical approaches. This systematic review was limited by the lack of meta-analysis. Nevertheless, we identified the need for future investigations: characterization of findings on three-dimensional imaging and its contribution to treatment planning, outcomes of non-surgical and pharmacological management of ICR, and randomized trials and comparative studies with longer follow-up periods. PMID- 25270188 TI - Decreased retinal capillary flow is not a mediator of the protective myopia diabetic retinopathy relationship. AB - PURPOSE: The mechanisms supporting the protective relationship between a longer axial length (AL) and a decreased risk of diabetic retinopathy (DR) remain unclear. Previous studies have demonstrated reduced retinal blood flow in axial myopia, and it has been suggested that the compromised retinal capillaries in diabetes are less likely to leak and rupture as a result of this decreased flow. In this study, we therefore investigated if reduced retinal capillary flow (RCF) is a potential mechanism underpinning this protective relationship. METHODS: Retinal capillary flow was assessed using the Heidelberg Retinal Flowmeter in 150 eyes of 85 patients with diabetes aged 18+ years from the Royal Victorian Eye and Ear Hospital and St. Vincent's Hospital (Melbourne), Australia. Axial length was measured using the Intraocular Lens Master. Diabetic retinopathy was graded from two-field retinal photographs into none, mild, moderate, and severe DR using the modified Airlie House classification system. RESULTS: A total of 74 out of 150 eyes (49.3%) had DR. A longer AL was associated with decreased odds of DR presence (per mm increase in AL, odds ratio [OR] 0.61, 95% confidence interval [CI] 0.41-0.91) and DR severity (OR: 0.65; 95% CI: 0.44-0.95). However, no association was found between AL and RCF (per mm increase in AL, regression coefficient [beta] -1.80, 95% CI -13.50 to 9.50) or between RCF and DR (per unit increase in RCF, OR 1.00; 95% CI 0.99-1.00). CONCLUSIONS: Our finding suggests that diminished RCF may not be a major factor underlying the protective association between axial elongation and DR. PMID- 25270189 TI - The acetylcholine signaling network of corneal epithelium and its role in regulation of random and directional migration of corneal epithelial cells. AB - PURPOSE: Because cholinergic drugs are used in ophthalmology and cholinergic stimulation has been shown to facilitate epithelialization of mucocutaneous wounds, we performed a systematic analysis of components of the cholinergic network of human and murine corneal epithelial cells (CECs) and determined the role of autocrine and paracrine acetylcholine (ACh) in regulation of CEC motility. METHODS: We investigated the expression of ACh receptors at the mRNA and protein levels in human immortalized CECs, localization of cholinergic molecules in normal and wounded murine cornea, and the effects of cholinergic drugs on CEC directional and random migration in vitro, intercellular adhesion, and expression of integrin alphaV and E-cadherin. RESULTS: We demonstrated that corneal epithelium expresses the ACh-synthesizing enzyme choline acetyltransferase, the ACh-degrading enzyme acetylcholinesterase, two muscarinic ACh receptors (mAChRs), M3 and M4, and several nicotinic ACh receptors (nAChRs), including both alpha7- and alpha9-made homomeric nAChRs and predominantly the alpha3beta2+/-alpha5 subtype of heteromeric nAChRs. Wounding affected the expression patterns of cholinergic molecules in the murine corneal epithelium. Constant stimulation of CECs through both muscarinic and nicotinic signaling pathways was essential for CEC survival and both directional and random migration in vitro. Both alpha7 and non-alpha7 nAChRs elicited chemotaxis, with the alpha7 signaling exhibiting a stronger chemotactic effect. Cholinergic stimulation of CECs upregulated expression of the integrin and cadherin molecules involved in epithelialization. We found synergy between the proepithelialization signals elicited by different ACh receptors expressed in CECs. CONCLUSIONS: Simultaneous stimulation of mAChRs and nAChRs by ACh may be required to synchronize and balance ionic and metabolic events in a single cell. Localization of these cholinergic enzymes and receptors in murine cornea indicated that the concentration of endogenous ACh and the mode of its signaling differ among corneal epithelial layers. Elucidation of the signaling events elicited upon agonist binding to corneal mAChRs and nAChRs will be crucial for understanding the mechanisms of ACh signaling in CECs, which has salient clinical implications. PMID- 25270190 TI - The phenotypic variability of retinal dystrophies associated with mutations in CRX, with report of a novel macular dystrophy phenotype. AB - PURPOSE: To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the cone-rod homeobox (CRX) gene and to report a novel phenotype. METHODS: Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives. RESULTS: Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod-cone dystrophy (RCD), five had cone-rod dystrophy (CORD), one had cone dystrophy (COD), and six had macular dystrophy with different phenotypes observed within 5 of 11 families. The macular dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients. CONCLUSIONS: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies. PMID- 25270191 TI - Effects of dopaminergic agents on progression of naturally occurring myopia in albino guinea pigs (Cavia porcellus). AB - PURPOSE: Disruption of dopaminergic signaling has been implicated in the abnormalities of ocular development in albinism, and many experiments have shown that retinal dopamine is a major regulator of postnatal eye growth and myopia in animal models. Therefore, in the present study we investigated whether progressive myopia, which can occur in albino guinea pigs without experimental manipulation of visual conditions, is affected by dopaminergic agents. METHODS: Two-week-old albino guinea pigs, selected for being myopic (range refractive error [RE], -2 to -10 diopters [D]), received unilateral peribulbar injections of apomorphine (nonselective dopamine receptor agonist; 0, 7.5, 25, 75, 250, 750, and 2500 ng; n = 112), SKF38393 (D1-like agonist; 0, 10, 100, 1000 ng; n = 63), SCH23390 (D1-like antagonist; 0, 2500 ng; n = 27), quinpirole (D2-like agonist; 0, 10, 100, 1000 ng; n = 58), or sulpiride (D2-like antagonist; 0, 2500 ng; n = 24) once a day for four weeks. One noninjected group (n = 19) served as untreated control. Refractive states and axial dimensions of the eyes were measured without cycloplegia or general anesthetic, using eccentric infrared photoretinoscopy and A-scan ultrasonography, respectively, before treatment, and after 2 and 4 weeks of treatment. The main drug effects were analyzed by paired t-test or 2-way repeated measures ANOVA, as required. RESULTS: The naturally occurring progression of myopic RE was inhibited by apomorphine at relatively high doses (250 and 750 ng), SKF38393 at 100 ng (D1-like agonist), and sulpiride at 2500 ng (D2-like antagonist), but promoted by apomorphine at a lower dose (25 ng), quinpirole at 100 ng (D2-like agonist), and SCH23390 at 2500 ng (D1-like antagonist). All drugs affected primarily vitreous chamber depth, rather than anterior segment dimensions. CONCLUSIONS: Our data suggest that the activation of D1-like receptors inhibits, whereas activation of D2-like receptors promotes, progressive myopia in this animal model. The robust effects of antagonists suggest that ocular dopamine receptors in these albinos may be in a chronic state of partial excitation. The precise location and identity of the receptors responsible for these effects remain to be determined. PMID- 25270192 TI - Myopia control with positively aspherized progressive addition lenses: a 2-year, multicenter, randomized, controlled trial. AB - PURPOSE: To evaluate the effect of newly designed positively aspherized progressive addition lenses (PA-PALs), which reduce both lag of accommodation and hyperopic defocus on the peripheral retina, on the progression of early-onset myopia. METHODS: Positively aspherized-PALs have near addition and high positive distance zone aspherization comparable to the addition power. One hundred ninety seven children were enrolled, 6 to 12 years of age, with spherical equivalent refraction from -1.00 to -4.50 diopters (D). The children were randomized to receive one of three lenses: single vision lenses (SVLs), PA-PALs with +1.0 D addition, or PA-PALs with +1.5 D addition. Follow-up visits occurred every 6 months for 2 years. The primary outcome was myopia progression evaluated by cycloplegic autorefraction. RESULTS: One hundred sixty-nine (86%) children completed the follow-up. Statistical analysis of adjusted progression rates showed a mean (+/-SE) progression of -1.39 +/- 0.09 D in the control group wearing SVLs at the 24-month visit. Statistically significant (P = 0.017) retardation of myopia progression (0.27 +/- 0.11 D during 24-month period or reduction ratio of 20%) by +1.5 D add PA-PALs relative to the SVLs was found, which was within the range of the percentage efficacy of myopia retardation by the conventional PALs in earlier trials over the same follow-up period. Nearly all retardation occurred in the first 12 months with no significant efficacy in the second year. Positively aspherized-PALs with +1.0 D addition showed negligible efficacy. CONCLUSIONS: To the extent that has been tested and that can be tolerated by wearers of spectacle lenses, the high positive aspherization of the distance zone added to PALs does not enhance their therapeutic efficacy in slowing myopia progression. (http://www.anzctr.org.au/ number, ACTRN12608000566336). PMID- 25270193 TI - Neural stem cell-based intraocular administration of ciliary neurotrophic factor attenuates the loss of axotomized ganglion cells in adult mice. AB - PURPOSE: To analyze the neuroprotective effect of intravitreally grafted neural stem (NS) cells genetically modified to secrete ciliary neurotrophic factor (CNTF) on intraorbitally lesioned retinal ganglion cells (RGCs) in adult mice. METHODS: Adherently cultivated NS cells were genetically modified to express a secretable variant of mouse CNTF together with the fluorescent reporter protein Venus. Clonal CNTF-secreting NS cell lines were established using fluorescence activated cell sorting, and intravitreally grafted into adult mice 1 day after an intraorbital crush of the optic nerve. Brn-3a-positive RGCs were counted in flat mounted retinas at different postlesion intervals to evaluate the neuroprotective effect of the CNTF-secreting NS cells on the axotomized RGCs. Anterograde axonal tracing experiments were performed to analyze the regrowth of the injured RGC axons in CNTF-treated retinas. RESULTS: Intravitreally grafted NS cells preferentially differentiated into astrocytes that survived in the host eyes, stably expressed CNTF, and significantly attenuated the loss of the axotomized RGCs over a period of at least 4 months, the latest postlesion time point analyzed. Depending on the postlesion interval analyzed, the number of RGCs in eyes with grafted CNTF-secreting NS cells was 2.8-fold to 6.4-fold higher than in eyes with grafted control NS cells. The CNTF-secreting NS cells additionally induced long-distance regrowth of the lesioned RGC axons. CONCLUSIONS: Genetically modified clonal NS cell lines may serve as a useful tool for preclinical studies aimed at evaluating the therapeutic potential of a sustained cell-based intravitreal administration of neuroprotective factors in mouse models of glaucoma. PMID- 25270194 TI - The association between the foveal avascular zone and retinal thickness. AB - PURPOSE: To investigate the association between the size and shape of the foveal avascular zone and retinal thickness in healthy subjects. METHODS: In vivo imaging of the foveal microvasculature was performed on 32 subjects by using an adaptive optics scanning laser ophthalmoscope (AOSLO). Motion contrast maps of the AOSLO images were used to generate a montage revealing the foveal capillary network. Foveal avascular zone (FAZ) diameters along the horizontal (FAZH) and vertical (FAZV) meridians were measured on the montages. An asymmetry index (AI) of the FAZ was then computed as the ratio of the FAZH to FAZV. Retinal thickness was investigated by using spectral-domain optical coherence tomography (SDOCT). Inner retinal layer (INLFAZ) thickness and outer nuclear layer (ONLFAZ) thickness were measured at the edges of the FAZ on the horizontal and vertical SDOCT scans on the same eye. RESULTS: The foveal capillary network was readily visualized in all subjects. As expected there was individual variation in the size and shape of the FAZ. Along the horizontal and vertical meridians, the mean+/-SD (MUm) of the FAZ diameter was 607+/-217 and 574+/-155, respectively. The INLFAZ thickness was 68+/-9 and 66+/-9, and the ONLFAZ thickness was 103+/-13 and 105+/-11, respectively. The mean+/-SD of the AI was 1.03+/-0.27. The difference between FAZH and FAZV decreases with increasing FAZ area (P=0.004). Mean ONLFAZ was negatively correlated with FAZ effective diameter (P<0.0001). No significant correlation was found between mean INLFAZ and FAZ effective diameter (P=0.16). CONCLUSIONS: Despite large individual variations in size and shape of the FAZ, the INLFAZ has a relatively constant thickness at the margins of the FAZ, suggesting the presence of retinal capillaries is needed to sustain an INLFAZ thickness greater than 60 MUm. A smaller FAZ area is associated with a vertically elongated FAZ. PMID- 25270195 TI - Minimum unit pricing for alcohol. PMID- 25270196 TI - Usefulness of conventional and tissue Doppler echocardiography to predict congestive heart failure in dogs with myxomatous mitral valve disease. AB - BACKGROUND: Systolic and diastolic functions have been evaluated to predict outcome in congestive heart failure (CHF). Recently, tissue Doppler imaging (TDI) has become useful for the estimation of myocardial function in cardiac diseases of humans and animals. OBJECTIVE: This study was designed to assess whether myocardial function as assessed by TDI is associated with the occurrence of CHF in dogs with myxomatous mitral valve disease (MMVD) and whether additional information is gained over conventional Doppler variables. ANIMALS: Forty-one privately owned dogs (15 healthy dogs and 26 dogs with MMVD) were included. Dogs with MMVD were divided into non-CHF (n = 10) and CHF groups (n = 16). METHODS: Conventional echocardiographic examinations were performed. In addition, TDI derived variables, including radial and longitudinal velocities, strain, and strain rate were assessed. RESULTS: Several (12 of 47, 26%) conventional and tissue Doppler echocardiography variables were significant predictors of CHF in a univariate analysis (P < .05). However, TDI-derived E/Em sept was the only load independent significant predictor of CHF (P < .05) after multivariate logistic regression analysis. The E/Em sept cut-off value of >18.7 had a sensitivity of 56% and specificity of 90% in predicting CHF in dogs with MMVD. CONCLUSIONS AND CLINICAL IMPORTANCE: The combination of TDI of the mitral annulus and mitral inflow velocity provided better estimates of diastolic dysfunction in dogs with MMVD and CHF. Additional study is warranted to assess TDI-derived E/Em sept , an index of diastolic function that could contribute to the management of dogs with MMVD and CHF. PMID- 25270197 TI - Repeated treatments of drooling with botulinum toxin B in neurology. AB - OBJECTIVES: To investigate efficacy, saliva flow, and composition in repeated BoNT-B treatments of drooling. MATERIALS AND METHODS: Seventeen neurological patients (median 66 years), referred for treatment of drooling participated in this observational study. Median total doses of 4000 units botulinum toxin type B (BoNT-B, Neurobloc((r))) were injected with at least 3 months intervals into parotid and submandibular glands using ultrasound guidance. Measures of drooling and saliva collection for analysis were obtained before treatment, and 6, 12, and eventually 18 weeks after. RESULTS: Number of treatment series in each patient was 1-7. Compared to baseline, saliva flow rate and drooling were reduced 30-70% 6 weeks after treatment in the first series, while sodium, chloride, and total protein increased 20-80% (t-tests; P < 0.05). After 12 weeks, drooling was still significantly reduced, saliva flow tended to be, and saliva composition was back to baseline. Frequent side effects were viscous saliva and dry mouth. Due to fading effect in eight patients, individual decisions were taken to change from BoNT-B to BoNT-A. Similarly, the outcome was significantly reduced over time in six patients completing five subsequent BoNT-B treatment series (ANOVA; P < 0.05). CONCLUSION: In the first series, BoNT-B treatment resulted in marked reduction of drooling and saliva flow rate with some relapse after 12 weeks. The viscous saliva was ascribed to increased total protein content and compensatory mechanisms related to beta-adrenergic receptor-specific actions. With patients needing long-term treatment, it should be noted that the efficacy of repeated BoNT-B may fade with time. PMID- 25270198 TI - [CD38 protein reduces LPS/D-galactosamine-induced acute damage of liver tissues via down-regulating inflammatory cytokine expressions]. AB - OBJECTIVE: To investigate the role of CD38 in lipopolysaccharide (LPS)/D galactosamine (D-GalN)-induced acute hepatic injury in mice and explore the potential mechanism. METHODS: A mouse model of acute hepatic injury was induced by an intraperitoneal injection (i.p.) of D-GalN and LPS. C57BL/6 wild-type mice (WT) and CD38 gene knockout mice (CD38 KO) were randomly divided into normal control group, early model group (2 hours after i.p. of LPS/D-GalN) and late model group (6 hours after i.p. of LPS/D-GalN), respectively. Two and six hours after administration of D-GalN/LPS, WT mice and CD38 KO mice were sacrificed, and the blood and liver tissue were collected. Serum was used to detect the alanine aminotransferases (ALT) and glutamate oxaloacetate transaminase (AST) levels. The injury of liver was assessed by HE staining. The expressions of IL-1beta, IL-6, TNF-alpha and IFN-gamma were analyzed by real-time quantitative PCR. RESULTS: Compared with the WT mice, CD38 KO mice presented significant increases of serum ALT and AST, mRNA expressions of IL-1beta, IL-6, TNF-alpha and IFN-gamma, as well as hepatocellular necrosis and bleeding in liver tissues after LPS/D-GalN induction. CONCLUSION: CD38 protein effectively reduces the LPS/D-GalN-induced damage of liver tissues via depressing the expressions of inflammatory cytokines and inhibiting the death of liver cells. PMID- 25270199 TI - [Th17/Treg unbalance is involved in the pathogenesis of experimental autoimmune encephalomyelitis]. AB - OBJECTIVE: To investigate the role of Th17/Treg unbalance in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). METHODS: EAE was modeled in mice and the number of regulatory T cells (Tregs) in spleen of EAE mice was detected by flow cytometry. The expressions of Foxp3 and RoR-gammat mRNA in the spleen of EAE mice and IL-17 mRNA in the brain of EAE mice were evaluated by real-time quantitative PCR and the levels of IL-6, TGF-beta and IL-17 in the serum of EAE mice were examined by ELISA. RESULTS: Compared with control group, the number of CD4(+)CD25(+) Foxp3(+) Tregs and the expression of Foxp3 mRNA in the spleen of EAE mice dramatically decreased in the early and peak stage of EAE (P<0.05), but increased in chronic stage of EAE (P<0.05); the RoR-gammat mRNA expression from mouse spleen at the early stage of EAE was significant raised (P<0.05), but was not significantly different at the peak and chronic stage of EAE from that in control group (P>0.05). The levels of IL-6 and TGF-beta in the serum of EAE group dramatically increased compared with control group (P<0.05). With the development of EAE, the level of IL-6 gradually decreased, and there was no statistical difference in the chronic stage of EAE compared with control group (P>0.05). However, the level of TGF-beta was higher than that in control group in the chronic stage of EAE (P<0.05). Compared with those in control group, the concentration of IL-17A and the expression of IL-17 mRNA dramatically increased in different stages of EAE group, especially in peak stage (P<0.05). CONCLUSION: Th17/Treg unbalance may be involved in the pathogenesis of EAE. PMID- 25270200 TI - [Effects of surgical thymectomy on thymic function and peripheral T cell populations in mice]. AB - OBJECTIVE: To investigate the effect of surgical thymectomy on immune function and peripheral blood T lymphocytes of a mouse model. METHODS: Neonatal (aged 72 hours) and infant (aged 1 week) BALB/c mice were randomly divided into two groups with 20 mice in each group, respectively. The mice of surgical group underwent a surgical thymectomy; the sham operation group excluded the thymectomy procedure. Then surgical group and sham operation group were randomly divided into two subgroups with 10 mice in each group, respectively. One subgroup was sacrificed one month after operation; the other was sacrificed two months after operation. To evaluate thymic function and peripheral T cell populations, T cell receptor rearrangement excision circles (TREC) were assessed by real-time quantitative PCR and T lymphocyte and its subset were detected by flow cytometry. RESULTS: The levels of peripheral T cell populations and TREC of the operation group were significantly lower than those of the sham operation group (P<0.01). There were no significant differences in the measurements between neonatal and infant mice or between one month after operation and two months after operation (P>0.05). CONCLUSION: Thymectomy in young mice can make damage on T cell immune system. The damage may continue in a long term and the age of operation maybe don't have an effect on it. PMID- 25270201 TI - [Acteoside enhances expression of neurotrophin-3 in brain tissues of subacute aging mice induced by D-galactose combined with aluminum trichloride]. AB - OBJECTIVE: To study the effect of acteoside on the expression of neurotrophin-3 (NT-3) in brain tissues of subacute aging mice induced by D-galactose (D-Gal) combined with aluminum trichloride (AlCl3). METHODS: Female Kunming mice were randomly divided into vehicle control group, D-Gal combined with AlCl3 group , vitamin E group, piracetam group and acteoside groups [30, 60, 120 mg/(kg.d)]. Mice in D-Gal combined with AlCl3, vitamin E, piracetam and acteoside groups were injected intraperitoneally (i.p.) with D-Gal [60 mg/(kg.d)] and AlCl3 [5 mg/(kg.d)] for 90 days to induce the subacute aging models. The real-time quantitative PCR, Western blotting and immunohistochemistry were respectively used to detect the expression of NT-3 mRNA and protein in cerebral cortex and hippocampus of mouse brain. RESULTS: D-Gal and AlCl3 caused a significant reduction of NT-3 in cerebral cortex and hippocampus. Acteoside, vitamin E and piracetam increased the decreased expression of NT-3 induced by D-Gal and AlCl3, and the difference was statistically significant (P<0.05 or P<0.01). CONCLUSION: Acteoside can up-regulate the expression of brain NT-3 in D-Gal plus AlCl3 treated mice. PMID- 25270202 TI - [Dachengqi decoction reduces the serum levels of mast cell tryptase and inflammatory cytokines in rabbits with post-cardiac arrest syndrome]. AB - OBJECTIVE: To observe the effects of Dachengqi decoction on serum levels of mast cell tryptase, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL 8) in rabbits with post-cardiac arrest syndrome (PCAS). METHODS: Thirty healthy male Japanese rabbits were randomly divided into three groups: sham-operation group, PCAS model group and Dachengqi decoction treatment group. The model of PCAS was established by asphyxia-induced cardiac arrest. Fifteen minutes after return of spontaneous circulation, Dachengqi decoction [15 g/(kg.d), bid] was given by intra-gastric administration in Dachengqi decoction treatment group. The indicators of organ function were evaluated 24, 48 and 72 hours after cardiac arrest. The serum levels of mast cell tryptase, MCP-1 and IL-8 were determined by ELISA. RESULTS: Dachengqi decoction alleviated the dysfunction significantly in heart, brain, liver and kidney. Compared with the sham group, the serum levels of mast cell tryptase, MCP-1 and IL-8 increased significantly in PCAS group (P<0.01). Compared with the PCAS group, the serum levels of mast cell tryptase (at 6 hours), MCP-1 (at 6, 24 and 48 hours) and IL-8 (at 6 and 24 hours) decreased significantly in Dachengqi decoction treatment group (P<0.05 or P<0.01). CONCLUSION: Dachengqi decoction can reduce the serum levels of mast cell tryptase, MCP-1 and IL-8 in rabbits with post-cardiac arrest syndrome. PMID- 25270203 TI - [Regulatory effects of polyporus polysaccharide on the expressions of cytokines released from M1 macrophages]. AB - OBJECTIVE: To investigate the regulatory effects of polyporus polysaccharide (PPS) on mRNA expressions of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), transforming growth factor beta (TGF-beta) and IL-10 in M1 macrophages. METHODS: RAW264.7 macrophages were randomly divided into five groups, negative control, M1 macrophayes, 50 MUg/mL PPS, 100 MUg/mL PPS, and 200 MUg/mL PPS. M1 macrophages was induced by interferon gamma (IFN-gamma). Flow cytometry was subsequently used to examine the expressions of biomakers of M1 macrophages , such as CD16/CD32 and CD86. To observe the effects of PPS on M1 macrophages at graded levels, real-time PCR was performed to evaluate the mRNA expressions of IL-1beta, IL-10, iNOS, TGF-beta and TNF-alpha. RESULTS: The expressions of CD16/CD32 and CD86 in RAW264.7 macrophages significantly increased by IFN-gamma, as compared with the cells without IFN gamma treatment. The mRNA levels of IL-1beta, iNOS, IL-10, TGF-beta and TNF-alpha were raised by 100 MUg/mL PPS at 3, 6, 9, 12 and 24 hours (P<0.01). Moreover, the mRNA expressions of these factors could be elevated by the 6 hour-treatment of PPS at different concentrations (P<0.01). CONCLUSION: M1 macrophages of can be induced from RAW264.7 cells by stimulation of IFN-gamma alone. In addition, PPS can promote the mRNA expressions of IL-1beta, iNOS, IL-10, TGF-beta and TNF-alpha in M1 macrophages. PMID- 25270204 TI - [The cytokine homeostasis was regulated by over-expression of Sirt1 in collagen induced arthritis mice]. AB - OBJECTIVE: To investigate the effects of over-expression of Sirt1 on cytokines in the collagen type 2-induced arthritis (CIA) mice. METHODS: The female DBA/1 mouse CIA model was established by subcutaneous injection of collagen type 2. Recombinant adenovirus carrying Sirt1 gene was infected into CIA mice through tail vein injection. The effects of over-expression of Sirt1 on CIA mice were assessed by measuring arthritis index. The serum levels of cytokines including interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), IL-17, IL 4 and IL-10 in CIA mice were examined by ELISA. The mRNA levels of Sirt1, matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP 1) were detected by real-time quantitative PCR (qRT-PCR). The protein levels of NF-kappaB subunit p65 and acetylated p65 were determined by Western blotting. RESULTS: Compared with control groups, over-expression of Sirt1 significantly ameliorated the symptoms of arthritis in CIA mouse. Furthermore, proinflammatory factors (IL-1beta, TNF-alpha, IL-17) decreased while anti-inflammatory factors (IL-4 and IL-10) increased in CIA mice. The over-expression of Sirt1 significantly down-regulated MMP-13 mRNA level and up-regulated TIMP-1 mRNA level. Additionally, the over-expressed Sirt1 reduced acetylation of p65. CONCLUSION: Over-expression of Sirt1 may regulate the balance of cytokines in CIA mice. PMID- 25270205 TI - [Vascular endothelial growth factor C induces LYVE-1(+) endothelial cells to reconstruct hepatic sinusoid during liver regeneration]. AB - OBJECTIVE: To explore the candidate molecules and mechanism in the reconstruction of hepatic sinusoid after partial liver resection. METHODS: The reconstruction process of hepatic sinusoid after partial liver resection was observed using immunohistochemistry (IHC). The expressions of vascular endothelial growth factor A (VEGF-A), VEGF-C, CD34, and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE 1) were detected. RESULTS: VEGF-C was expressed in the residual liver tissue after partial liver resection. The expression level reached its peak at 12 hours, 2 and 5 days after the operation. The expression of LYVE-1 was similar with VEGF-C, but its peak appeared 1-2 d later than that of VEGF-C. VEGF-A was expressed only in the early and late stages of liver regeneration. CD34 positive cells were gathered around the portal vein and its new branches. CONCLUSION: VEGF C induces CD34 positive cells to express LYVE-1 in the reconstruction of hepatic sinusoid, and the cells eventually differentiate into mature hepatic sinusoid endothelial cells. PMID- 25270206 TI - [Preparation and characterization of mouse monoclonal antibody against outer membrane protein P6 of Haemophilus influenzae]. AB - OBJECTIVE: To prepare and identify monoclonal antibody against Haemophilus influenzae(Hi) outer membrane protein P6. METHODS: Recombinant protein P6 as an immunogen was administered intraperitoneally to BALB/c mice. The splenocytes of the mouse were isolated from spleen and hybridized with Sp2/0 myeloma cells. Indirect ELISA was used for screening hybridoma and the number of chromosomes in hybridoma cells was determined by karyotype analysis. The titers and specificity of monoclonal antibodies in their culture supernatant were detected by indirect ELISA. The immunoglobulin class, subclasses and type of the monoclonal antibody were identified with colloidal gold labeled IsoQuick(TM) strips. RESULTS: Two hybridoma cell lines designated alpha2G3 and gamma2C4 were obtained. Karyotype analysis showed that the chromosome numbers of alpha2G3 and gamma2C4 were 103 and 95, respectively. The highest titers of antibodies in their culture supernatant were 1:256 and 1:512, respectively. Both monoclonal antibodies only reacted with standard or clinical isolated strains of Hi, and they both did not react with other bacteria. A2G3 was IgG2b, and gamma2C4 was IgM, both of which were kappa light chains. They could recognize different antigen epitope of protein P6. CONCLUSION: Two hybridoma cell lines producing the monoclonal antibodies against protein P6 of Hi outer membrane are obtained. PMID- 25270207 TI - [Preparation of a polyclonal antibody of Helicoverpa armigera arginine kinase in mice using DNA immunization with in vivo electroporation]. AB - OBJECTIVE: To prepare a polyclonal antibody against Helicoverpa armigera arginine kinase (HarmAK) in mice by DNA immunization with in vivo electroporation, and verify the specificity of the antibody by Western blotting. METHODS: A recombinant expression plasmid pcDNA3-HarmAK was constructed and sequenced, and then was transferred into Kunming mice five times using electroporation. ELISA and Western blotting were used respectively to determine the titer of HarmAK antibody and detect the specificity of the monoclonal antibody. RESULTS: ELISA showed that the titer of mouse anti-HarmAK serum reached 1:40 000 , and Western blotting demonstrated that this antiserum had a specific binding to both fusion protein His-HarmAK and AK protein of total protein of the Helicoverpa armigera. CONCLUSION: We prepared a polyclonal antibody of HarmAK from the Helicoverpa armigera using DNA immunization with in vivo electroporation and the antibody has a high titer and specificity. PMID- 25270208 TI - [Changes of lymphocyte subsets in peripheral blood of patients with hepatitis C]. AB - OBJECTIVE: To investigate the changes of lymphocyte subsets in the peripheral blood of patients with hepatitis C. METHODS: A total of 219 patients with hepatitis C and 66 healthy individuals served as normal controls were enrolled in the study. The proportions of T-lymphocytes (CD45(+)CD3(+), CD45(+)CD3(+)CD4(+), CD45(+)CD3(+)CD8(+)), B-lymphocytes (CD45(+)CD3(-)CD19(+)), NK-lymphocyte (CD45(+)CD3(-)CD16(+)56(+)) in peripheral blood were detected by flow cytometry. RESULTS: The count of peripheral lymphocyte subsets of patients with hepatitis C decreased from the stage of chronic infection to decompensated cirrhosis. The numbers of CD4(+), CD8(+)and NK lymphocytes of patients with chronic hepatitis C were significantly lower than those in healthy individuals (P<0.05). In the early and decompensated stage of hepatic cirrhosis, the numbers of lymphocyte subsets of patients were significantly lower than those in patients with chronic hepatitis C (P<0.01), and they were significantly lower in decompensated cirrhosis than in early cirrhosis (P<0.01). The proportion of B lymphocyte and CD4/CD8 ratio of patients increased from chronic infection to decompensated cirrhosis. Compared with chronic infection, the proportion of B lymphocyte and CD4/CD8 ratio in early and decompensated cirrhosis increased significantly (P<0.01 or P<0.05), while the proportion of NK lymphocyte was significantly reduced (P<0.01). CONCLUSION: From the stage of chronic infection to decompensated cirrhosis, patients with hepatitis C were found with the decreased numbers of CD4(+)T, CD8(+) T and NK lymphocytes, and the increased proportion of B lymphocyte and CD4/CD8 ratio. PMID- 25270209 TI - [Regulatory effect of ginsenoside Rh2 on HDAC1/2 activity and cyclin in human erythroleukemia K562 cells]. AB - OBJECTIVE: To investigate the effects of the 20(S)-ginsenoside Rh2 [Rh2(S)]on cell proliferation, histone deacetylase 1 (HDAC1) and HDAC2 activity, and expression of cyclin in human erythroleukemia K562 cells. METHODS: The K562 cells were treated with Rh2(S) at various concentrations (10-80 MUmol/L). Cell proliferation activity was detected by CCK-8 assay. Flow cytometry (FCM) was used to detect cell cycle and apoptotic changes. The HDAC activity of cells was measured by chemical colorimetry. The protein expressions of HDAC1, HDAC2, cyclin D1, CDK4, p16INK4A and p21 after 48 hour-treatment of Rh2 (S) (10, 20, 40, 60 MUmol/L) were examined by Western blotting. RESULTS: The proliferation of K562 cells was inhibited by Rh2 (S) (20-80 MUmol/L) in dose-and time-dependent manner. FCM analyses revealed that the number of the K562 cells treated with 60 MUmol/L Rh2(S) was arrested in G0/G1 phase. The apoptosis rates of K562 cells were respectively (8.09+/-0.86)%, (9.44+/-0.53)% and (22.80+/-2.16)% after induced by 20, 40, 60 MUmol/L Rh2(S), which showed statistically significant difference (P<0.05) compared with the control group (2.63+/-0.14)%. HDAC activity of the cells treated with Rh2(S) (40, 60 MUmol/L) was reduced. Western blotting showed that the expressions of HDAC1, HDAC2, cyclin D1 and CDK4 decreased after induced by Rh2(S), and p16INK4A, p21 proteins were enhanced significantly. CONCLUSION: The Rh2(S) can inhibit the proliferation of K562 cells and induce its cycle arrest and apoptosis through inhibiting HDAC1 and HDAC2 activity, down-regulating the expression of cyclin D1 and activating p16INK4A and p21. PMID- 25270210 TI - [Changes and clinical significance of peripheral blood natural killer cells in neonates with bacterial pneumonia]. AB - OBJECTIVE: To detect the percentage of total natural killer (NK) cells and its different populations in the peripheral blood from neonates with bacterial pneumonia and discuss the clinical significance of NK cells in the pathogenesis of bacterial pneumonia. METHODS: Flow cytometry was performed to detect the percentages of NK cells and its subsets in peripheral blood lymphocytes from 38 cases of neonatal bacterial pneumonias and 18 cases of normal neonates. Patients recruited were divided into two groups according to hospitalization days and numbers of peripheral leukocytes: hospitalization days within 10 days (including 10 days) as group A, and more than 10 days as group B; the number of peripheral blood leukocytes <5.0*10(9)/L or >20.0*10(9)/L as severe infection group, and 5.0*10(9)/L< number of peripheral blood leukocytes <20.0*10(9)/L as mild infection group. RESULTS: The percentages of peripheral blood NK cells and CD3( )CD56(neg)CD16(bright) subset in the neonates with bacterial pneumonia were significantly lower than those of the normal newborns (P<0.01), but there were no statistically significant differences in CD3(-)CD56(bright)CD16(neg/dim) and CD3( )CD56(dim)CD16(bright) subsets. The percentage of CD3(-)CD56(neg)CD16(bright) subset in group A was significantly lower than that of the normal newborns (P<0.01), while the percentages of the total NK cells and other subsets had no statistical significance. The neonates with bacterial pneumonia had significantly lower percentages of the total NK cells and CD3(-)CD56(neg)CD16(bright) subset in group B as compared with the normal neonates (P<0.01). And the percentages of the total NK cells and its subsets in group B were also lower than those in group A (P<0.05). The percentages of NK cells and each subset in severe infection group were significantly lower than those in mild infection group (P<0.05). CONCLUSION: To the neonates who suffer from bacterial pneumonia, the more serious and the longer hospital stay, the lower the percentages of NK cells and its subsets are. PMID- 25270211 TI - [Dectection and analysis of miRNA expression in breast cancer-associated fibroblasts]. AB - OBJECTIVE: To investigate the difference of miRNA expression levels of cancer associated fibroblasts (CAFs) and normal fibroblasts (NFs) in human breast cancer microenvironment and its effect on the biological features of CAFs. METHODS: Collagenase-1 was used to digest the cancer and adjacent tissues to isolate CAFs and NFs. The isolated cells were cultured and characterized in purity and biological features. The expression of fibroblast secretory protein (FSP) in CAFs and NFs was detected by immunofluorescence staining and Western blotting. Transwell(TM) assay was adopted to compare the invasion ability of CAFs and NFs. The different expressions of miRNAs in CAFs versus NFs were detected by miRNA microarray and analyzed by Significance Analysis of Microarrays (SAM). The differences in miR-205 and miR-221 expressions were verified by real-time quantitative PCR (qRT-PCR). The common target genes of the miRNAs were predicted using multi-bioinformatics tools. The pathway analysis was conducted through the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7. The secreting products of TGF-beta or IL-6 signaling pathway, matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 were analyzed by ELISA. RESULTS: The primary CAFs and NFs were isolated from breast cancer patients with a purity of over 95%. Compared with NFs, the expression of FSP was obviously elevated in CAFs, and the invasion ability of CAFs was enhanced. The miRNA microarray results showed that there were 10 miRNA genes dysregulated in CAFs, including 3 up regulated (miR-221-5p, miR-31-3p, miR-221-3p) and 7 down-regulated genes (miR 205, miR-200b , miR-200c, miR-141, miR-101, miR-342-3p, let-7g). The common targets genes of the dysregulated miRNAs were mainly focused on HGF, chemokine signaling, insulin signaling, MAPK signaling, tight junction signaling, adherence junction signaling, EGF1 signaling, androgen-receptor signaling, Wnt and IL-7 signaling. In addition, dysregulated miR-200b/c and miR-141 et al. affect TGF beta and IL-6 signaling through inhibiting their target genes in CAFs, thus promoting invasion and migration of CAFs. CONCLUSION: The miRNA expression profile was markedly dysregulated in CAFs. Those dysregulated miRNAs may take part in the transformation from NFs to CAFs, and also have a close relationship with adhesion, migration, proliferation, secretion and cell-cell interaction of CAFs. PMID- 25270212 TI - [miR-143 inhibits proliferation and invasion of hepatocellular carcinoma cells via down-regulation of TLR2 expression]. AB - OBJECTIVE: To detect the expression of microRNA-143 (miR-143) in hepatocellular carcinoma and investigate whether transfection of miR-143 could influence the biological behaviors of hepatocellular carcinoma cells. METHODS: Hepatocellular carcinoma tissues and its corresponding adjacent normal tissues were obtained from patients undergoing radical surgical resection. Real-time quantitative PCR was utilized to detect the relative expression of miR-143 in hepatocellular carcinoma tissues and corresponding adjacent normal tissues. MiR-143 mimics and negative control oligonucleotides were synthesized and transfected into HepG-2 cells in vitro. Proliferation, apoptosis and invasion of the transfected cells were measured by MTT assay, flow cytometry (FCM) combined with annexin V-FITC/PI staining, and Transwell(TM) assay, respectively. The protein levels of Toll-like receptor 2 (TLR2), nuclear factor kappa B (NF-kappaB), matrix metalloproteinase 2 (MMP-2) and MMP-9 were detected by Western blotting. RESULTS: Expression of miR 143 was significantly lower in hepatocellular carcinoma tissues than in paired adjacent normal tissues. The level of miR-143 was significantly up-regulated after transfection of miR-143 mimics. And proliferation and invasion were significantly inhibited, but apoptosis was promoted after transfection. Expressions of TLR2, NF-kappaB, MMP-2 and MMP-9 were reduced by miR-143 mimics' transfection. CONCLUSION: The miR-143 expression was low in hepatic carcinoma and its over-expression could down-regulate the expressions of TLR2, NF-kappaB, MMP-2 and MMP-9. PMID- 25270213 TI - [Aberrant expressions of beta-catenin and ZEB1 in bladder cancer and their significance]. AB - OBJECTIVE: To detect the expressions of beta-catenin and zinc finger E-box binding homeobox 1 (ZEB1) in bladder cancer tissues, and analyze their correlation and significance in bladder cancer occurrence and progression. METHODS: The study collected 79 specimens of bladder cancer. EnVision immunohistochemical staining was used to detect the expressions and distribution of beta-catenin and ZEB1 protein. Their correlation was analyzed and their relationship with clinicopathological characteristics was investigated. RESULTS: There was a significant heterogeneity in the expression of beta-catenin in bladder cancer tissues. It might be distributed in the cell membrane, cytoplasm or nucleus. In low-grade clinical and pathological urothelial carcinoma, beta catenin was mainly expressed in cell membrane and cytoplasm, but in high-grade clinical pathological bladder cancer tissues, it was mostly located in cell cytoplasm and nucleus. ZEB1 in bladder cancer tissues was mainly expressed in cell nucleus, and its expression was elevated with the increased tumor pathological grade and clinical stage. The expressions of the above two proteins were significantly correlated. CONCLUSION: Aberrant expressions of beta-catenin and ZEB1 in bladder cancer tissues are relevant to bladder tumor differentiation and metastasis, and the two expressions are evidently correlated. The two proteins can be simultaneously used as candidate targets for early diagnosis and prognosis prediction. PMID- 25270214 TI - [The effect of Xinfeng capsule treatment on the number of BTLA(+)T cells and oxidative stress of patients with ankylosing spondylitis]. AB - OBJECTIVE: To investigate the changes of B and T lymphocyte attenuator (BTLA), reactive oxygen species (ROS), reactive nitrogen species (RNS), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidative capacity (TAOC) in the patients with ankylosing spondylitis (AS) and the effect of Xinfeng capsule (XFC) on them. METHODS: AS patients (n=140) were randomly divided into two groups, XFC group (3 tablets each time, tid, n=70) and salicylazosulfapyridine (SASP) group (4 pills each time, bid, n=70). Continuous treatment lasts 3 months. The study also enrolled 60 healthy volunteers as a control group. Flow cytometry was used to test BTLA expression. ELISA was performed to detect the oxidative stress indicators (ROS, RNS, MDA, SOD, CAT, TAOC) and cytokines (IL-4, IL-10, IL-1beta, TNF-alpha). Western blotting was adopted to examine the blood sedimentation (ESR). HITACHI 7060 automatic biochemical analyzer was used to determine the level of high sensitive C-reactive protein (Hs-CRP). RESULTS: Clinical efficacy of XFC group was significantly better than that of SASP group (P<0.01). Compared with the healthy control group, AS patients had significantly lower BTLA expression in CD3(+) T cells and CD4(+) T cells from the peripheral blood (P<0.01 or P<0.05), the decreased levels of SOD, CAT and TAOC, and significantly increased ROS, RNS and MDA values (P<0.01 or P<0.05). In addition, the levels of serum IL-1beta, TNF-alpha, ESR and Hs-CRP were significantly higher (P<0.01) and IL-4, IL-10 were significantly lower in AS patients (P<0.01 or P<0.05). Compared with pre-treatment, both XFC and SASP significantly elevated the expressions of BTLA(+)CD3(+) T, BTLA(+)CD4(+) T, BTLA, SOD, TAOC, IL-4, SF-36 (PF, SF, RP, RE, BP, MH, VT, GH) eight dimension scores, and reduced ROS, MDA, TNF-alpha, ESR, Hs-CRP, VAS, BASDAI, BASFI and BAS-G in the peripheral blood (P<0.01 or P<0.05). The differences between XFC group and SASP group were statistically significant (P<0.01 or P<0.05). Pearson correlation analysis showed that BTLA expression level in the peripheral blood was positively correlated with SOD, RP, BP, SF and RE. BTLA(+)CD3(+) T cells and BTLA*CD4(+) T cells were significantly negatively correlated with ROS, MDA, IL-1beta, TNF alpha, ESR, VAS and BASDAI, and they were positively correlated with TAOC, IL-4 and IL-10. BTLA(+)CD3(+) T cells were significantly negatively correlated with RNS, Hs-CRP and BASFI; BTLA(+)CD4(+) T cells were positively correlated with CAT. CONCLUSION: XFC can improve BTLA expression in the peripheral blood of AS patients and regulate negatively the activation and proliferation of T cells. PMID- 25270215 TI - [The establishment of a magnetic nanoparticle-based immunocapturing method for the detection of abrin]. AB - OBJECTIVE: To develop a high sensitive and specific method for the detection of abrin. METHODS: The abrin monoclonal antibody (mAb) 7D1 coated with Fe3O4 magnetic nanoparticles (MNPs) and abrin mAb labeled with horseradish peroxidase (HRP-mAb) were used to establish the immunocapturing method for abrin detection. The results were compared with the traditional double antibody sandwich ELISA. RESULTS: The detecting linear of immunocapture for abrin was 2.5-60 ng/mL, and the linear regression equation was y=0.012x-0.015 with the detection limit of 2.5 ng/mL. Ricin at different concentrations did not interfere the abrin detection results, which demonstrated that the method had a good specificity . This approach showed good reproducibility with relative standard deviation ranging from 5.18%-8.67%. It could be used for analyzing abrin-contaminated specimens such as water, beverage, and milk, etc. The results of comparison with the conventional double antibody sandwich ELISA indicated that the immunocapture have a broader linear scale, higher sensitivity, and a shorter detection time. CONCLUSION: The developed immunocapturing method can be used for detecting traces of abrin. PMID- 25270216 TI - [The modified extracorporeal photochemotherapy promotes apoptosis of spleen lymphocytes]. AB - OBJECTIVE: To explore the efficacy of the modified extracorporeal photochemotherapy (ECP) in improving the apoptotic rate of lymphocytes in vitro. METHODS: The spleens which were obtained from liver transplantation donor under aseptic condition were used as experimental materials. Splenic lymphocytes (SPs) suspensions were prepared by modified and traditional ECP method, respectively. And then the isolated SPs were treated by the irradiation of 8-methoxypsoralen (8 MOP) combined with ultraviolet A (UVA) named PUVA, 8-MOP and UVA, and compared with a blank group meanwhile. The treated SPs were cultured overnight in an incubator at 37 Degrees Celsius, in a humidified atmosphere of 50 mL/L CO2 for 6 8 hours. The morphological changes of cells were observed using an inverted microscope, the apoptotic rates of SPs were detected by flow cytometry, and the difference between groups was analyzed finally. RESULTS: The apoptotic rate at early stage and the total apoptotic rate of SPs prepared by the modified ECP method were respectively (95.33+/-3.03)% and (97.10+/-2.12)% after treated by PUVA, (23.39+/-4.55)% and (36.32+/-6.63)% after treated by 8-MOP, and (66.98+/ 3.60)% and (68.65+/-4.35)% by UVA. Compared with control group (12.82+/-1.86% and 13.4+/-2.65%), there were statistically significant differences (P<0.01). The apoptotic rate at early stage and the total apoptotic rate of SPs prepared by the traditional ECP method were respectively (79.73+/-4.21)% and (82.70+/-4.13)%, (61.42+/-2.28)% and (68.91+/-2.18)%, (19.30+/-1.78)% and (28.06+/-1.88)%, (10.84+/-0.98)% and (12.77+/-1.22)%, and the statistical comparisons between groups also had significant difference (P<0.01). In addition, there was a significant difference in the early and total apoptosis between the modified and traditional ECP (P<0.01), but no obvious variation in the end-stage apoptosis in the two groups (P>0.05). CONCLUSION: The modified ECP method can promote apoptosis of SPs in vitro conveniently, safely and efficiently, especially in the early stage. This can lay a foundation for the further study on dendritic cell immunomodulation induced by ECP method. PMID- 25270218 TI - Supporting rural remote physicians to conduct a study and write a paper: experience of Clinical Research Support Team (CRST)-Jichi. AB - CONTEXT: Jichi Medical University (JMU) is the only medical school in Japan that is devoted solely to producing rural and remote doctors. To support research activities of its graduates, mainly young graduates under obligatory rural service, JMU established a voluntary team, Clinical Research Support Team (CRST) Jichi. ISSUES: CRST-Jichi consists of current and past JMU faculty members; all of them are specialists of certain medical fields and many are also graduates of JMU who have completed rural service. A client who asks the CRST for advice on study design or editing a paper emails the CRST to ask for support in conducting a study. Then, core members of the CRST assign the job to a registered specialist of the corresponding topic, who becomes a 'responsible supporter' and continues to support the client until a paper has been published. During the 3 years from July 2010, 12 English papers have been published in international peer-review journals, two Japanese papers in domestic journals, and 13 studies are in progress. Ninety-one percent of clients were satisfied with the service, and eighty-two percent considered their papers would not have been published if they had not used the service. Sense of commitment, existence of JMU-graduated specialists, and quick response were reported by clients as major strengths of CRST-Jichi. LESSONS LEARNED: The experience of CRST-Jichi can potentially be transferred to not only other Japanese medical schools with rural doctor production programs, which are now rapidly increasing as part of a national policy, but also rural medical education systems in other countries. PMID- 25270217 TI - Comparison of automated and manual purification of total RNA for mRNA-based identification of body fluids. AB - Silica column-based RNA purification procedures have widespread use in mRNA profiling for body fluid identification in forensic samples. Also, automated RNA purification systems employing magnetic bead technology have recently become available. In this preliminary study, to ascertain which RNA purification technology is more suitable for the identification of body fluids by real-time reverse transcription polymerase chain reaction (RT-PCR), comparative analyses of the yield and quality of total RNA were performed between automated purification using an EZ1 Advanced Instrument and manual purification using an RNeasy Mini Kit. The yield and size distribution of total RNA were compared by gene expression analysis of two different sized fragments of the beta-actin gene. In addition, the relative amounts of several target genes were compared between the purification methods, and the integrity of total RNA was determined by chip-based electrophoresis. The results of this study suggest that RNeasy can purify higher quality RNA as compared with automated purification using EZ1. The sensitivity of the RT-PCR analysis, however, was higher in the EZ1-purified samples, likely due to the relative efficiency of EZ1 in extracting short-length RNA from degraded samples. We also show that the quantification of relative levels of body fluid specific genes could be influenced by the purification procedure. Our results indicate that although use of high-quality RNA is generally required for reproducible results in gene expression analysis, the forensic relevance of short RNA fragments in highly degraded samples cannot be ruled out. Furthermore, our results suggest that automated purification procedures as well as silica column based manual purification procedures can be used for mRNA-based body fluid identification in forensic samples. PMID- 25270219 TI - Novel pre-clinical methodologies for pharmacokinetic drug-drug interaction studies: spotlight on "humanized" animal models. AB - Poly-therapy is common due to co-occurrence of several ailments in patients, leading to the elevated possibility of drug-drug interactions (DDI). Pharmacokinetic DDI often accounts for severe adverse drug reactions in patients resulting in withdrawal of drug from the market. Hence, the prediction of DDI is necessary at pre-clinical stage of drug development. Several human tissue and cell line-based in vitro systems are routinely used for screening metabolic and transporter pathways of investigational drugs and for predicting their clinical DDI potentials. However, ample constraints are associated with the in vitro systems and sometimes in vitro-in vivo extrapolation (IVIVE) fail to assess the risk of DDI in clinic. In vitro-in vivo correlation model in animals combined with human in vitro studies may be helpful in better prediction of clinical outcome. Native animal models vary remarkably from humans in drug metabolizing enzymes and transporters, hence, the interpretation of results from animal DDI studies is difficult. With the advent of modern molecular biology and engineering tools, novel pre-clinical animal models, namely, knockout rat/mouse, transgenic rat/mouse with humanized drug metabolizing enzymes and/or transporters and chimeric rat/mouse with humanized liver are developed. These models nearly simulate human-like drug metabolism and help to validate the in vivo relevance of the in vitro human DDI data. This review briefly discusses the application of such novel pre-clinical models for screening various type of DDI along with their advantages and limitations. PMID- 25270220 TI - Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis. AB - Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis. PMID- 25270221 TI - Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. AB - PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. DESIGN: Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005 through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. SETTING: Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. PATIENTS: Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. METHODS: A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. RESULTS: Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every 3 months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI 1 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. CONCLUSIONS: This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock. PMID- 25270223 TI - The Sheffield Alcohol Policy Model - A Mathematical Description. AB - This methodology paper sets out a mathematical description of the Sheffield Alcohol Policy Model version 2.0, a model to evaluate public health strategies for alcohol harm reduction in the UK. Policies that can be appraised include a minimum price per unit of alcohol, restrictions on price discounting, and broader public health measures. The model estimates the impact on consumers, health services, crime, employers, retailers and government tax revenues. The synthesis of public and commercial data sources to inform the model structure is described. A detailed algebraic description of the model is provided. This involves quantifying baseline levels of alcohol purchasing and consumption by age and gender subgroups, estimating the impact of policies on consumption, for example, using evidence on price elasticities of demand for alcohol, quantification of risk functions relating alcohol consumption to harms including 47 health conditions, crimes, absenteeism and unemployment, and finally monetary valuation of the consequences. The results framework, shown for a minimum price per unit of alcohol, has been used to provide policy appraisals for the UK government policy makers. In discussion and online appendix, we explore issues around valuation and scope, limitations of evidence/data, how the framework can be adapted to other countries and decisions, and ongoing plans for further development. (c) 2014 The Authors. Health Economics published by John Wiley & Sons Ltd. PMID- 25270224 TI - Tanshinone IIA inhibits human gastric carcinoma AGS cell growth by decreasing BiP, TCTP, Mcl-1 and Bcl-xL and increasing Bax and CHOP protein expression. AB - Tanshinone IIA (Tan-IIA) is extracted from Danshen (Salviae Miltiorrhizae Radix) and is a natural anti-cancer agent, which possesses antitumor activity in a variety of human cancer cells. Tan-IIA can induce apoptosis and inhibit the proliferation of gastric cancer through different molecular mechanisms. However, the efficacy and molecular mechanism of Tan-IIA in gastric cancer have not been well studied. In the present study, the cytotoxicity of Tan-IIA in human gastric cancer AGS cells by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide assay was examined. The protein expression levels of B-cell lymphoma-extra large (Bcl-xL), Bcl-2-associated X protein (Bax), myeloid cell leukemia 1 protein (Mcl 1), translationally-controlled tumor protein (TCTP), binding immunoglobulin protein (BiP), calnexin, protein kinase-like endoplasmic reticulum kinase, eIF2alpha, activating transcription factor 4 (ATF4), inositol-requiring enzyme 1alpha (IRE1alpha), ATF6, caspase-12, caspase-9, caspase-3, C/EBP-homologous protein (CHOP) and beta-actin in AGS cells were measured by western blot analysis. The results showed that Tan-IIA inhibited AGS cells in a time-and dose dependent manner. AGS cells treated with Tan-IIA upregulated the protein expression of caspase-12, caspase-9, caspase--3, CHOP and Bax, but downregulated the protein expression of BiP, TCTP, Mcl-1 and Bcl-xL. These findings indicated that Tan-IIA inhibits the growth of human gastric cancer AGS cells. One of the molecular mechanisms may be through decreasing the protein expression of BiP to induce the activation of endoplasmic reticulum stress, followed by increasing the protein expression of caspase-12 to upregulate CHOP expression. The other may be through decreasing the protein expression of Mcl-1, Bcl-xL and TCTP, but increasing Bax, caspase-9 and caspase-3 to induce apoptosis. The chemotherapeutic potential of Tan-IIA for human gastric cancer warrants further study in the future. PMID- 25270225 TI - Evaluating multiplexed next-generation sequencing as a method in palynology for mixed pollen samples. AB - The identification of pollen plays an important role in ecology, palaeo climatology, honey quality control and other areas. Currently, expert knowledge and reference collections are essential to identify pollen origin through light microscopy. Pollen identification through molecular sequencing and DNA barcoding has been proposed as an alternative approach, but the assessment of mixed pollen samples originating from multiple plant species is still a tedious and error prone task. Next-generation sequencing has been proposed to avoid this hindrance. In this study we assessed mixed pollen probes through next-generation sequencing of amplicons from the highly variable, species-specific internal transcribed spacer 2 region of nuclear ribosomal DNA. Further, we developed a bioinformatic workflow to analyse these high-throughput data with a newly created reference database. To evaluate the feasibility, we compared results from classical identification based on light microscopy from the same samples with our sequencing results. We assessed in total 16 mixed pollen samples, 14 originated from honeybee colonies and two from solitary bee nests. The sequencing technique resulted in higher taxon richness (deeper assignments and more identified taxa) compared to light microscopy. Abundance estimations from sequencing data were significantly correlated with counted abundances through light microscopy. Simulation analyses of taxon specificity and sensitivity indicate that 96% of taxa present in the database are correctly identifiable at the genus level and 70% at the species level. Next-generation sequencing thus presents a useful and efficient workflow to identify pollen at the genus and species level without requiring specialised palynological expert knowledge. PMID- 25270226 TI - Nutrient intake and nutritional status of newly diagnosed patients with cancer from the East Coast of Peninsular Malaysia. AB - BACKGROUND: Cancer therapy in Malaysia primarily focuses on the clinical management of patients with cancer and malnutrition continues to be one of the major causes of death in these patients. There is a dearth of information on the nutrient intake and status of newly diagnosed patients with cancer prior to the initiation of treatment. The present study aims to assess the nutrient intake and status of newly diagnosed patients with cancer from the East Coast of Peninsular Malaysia. METHODS: A cross-sectional study was conducted using a convenient sample of newly diagnosed adult patients with cancer (n = 70) attending the Oncology clinic, Hospital Universiti Sains Malaysia in the East Coast of Peninsular Malaysia. Information on socio-demographic characteristics, clinical status, anthropometry, dietary intake and biochemical data including blood samples was obtained. RESULTS: The mean (SD) age, triceps skin fold (TSF), mid upper arm circumference (MUAC) and body mass index (BMI) of participants was 21.1(3.9) years, 17.6(7.9) mm, 24.1(5.5) cm, and 21.1(3.9) Kg/m(2), respectively; 39% participants had BMI <18.5 Kg/m(2). One-third of newly diagnosed patients with cancer were undernourished (i.e. women: MUAC <220 mm; men: <230 mm). The proportion (%) of participants with low haemoglobin (<120 g/L) and serum albumin (<38 g/dL) were 62% and 26%, respectively. The older women had significantly lower macro and micro nutrient intakes compared to men in the same age group (P <0.05). CONCLUSIONS: At the time of diagnosis, greater than one-third of patients with cancer from the East Coast of Peninsular Malaysia were underweight and undernourished. The majority of patients with cancer had poor micronutrient intakes; the older women had a poor macro and micronutrient intakes. Before the initiation of rigorous clinical management of patients with cancer, screening for nutritional status, subsequent nutrition counseling, and interventions are essential to improve their nutritional status; consequently, response to cancer therapy, survival and quality of life. PMID- 25270227 TI - Methodological aspects of minimal residual disease assessment by flow cytometry in acute lymphoblastic leukemia: A French multicenter study. AB - Background: Minimal residual disease (MRD) assessment provides a powerful prognostic factor for therapeutic stratification in acute lymphoblastic leukemia (ALL). Multiparameter flow cytometry (MFC) has the potential for a rapid and sensitive identification of high risk patients. Our group has previously published that MRD levels analyzed by clone specific Ig/TcR-QPCR and MFC were concordant at a sensitivity of 10-4 . Here we report the MFC methodological aspects from this multi-center experience. Methods: MRD was assessed by MFC in 1030 follow-up samples from 265 pediatric and adult patients with de novo ALL treated in the FRALLE, EORTC or GRALL clinical trials. MRD assessment as applied by the eight participating MFC laboratories is described in detail regarding cell preparation, leukemia-associated immunophenotype (LAIP) markers and data analysis. Samples were obtained from bone marrow (BM) and peripheral blood (PB). Immunostaining was performed after erythrocyte lysis or Ficoll enrichment. Results: This study confirms the applicability of MFC-based MRD assessment in 97% of patients with ALL at the 10-4 cut-off. MRD values after Ficoll enrichment and erythrocyte lysis were found comparable. Higher MRD values were obtained in BM than in PB, especially for B-lineage ALL. Conclusions: Measurement of MRD by MFC at the 10-4 cut-off is applicable within a few hours for almost all patients and using a comparable analytical strategy allows for multicenter collaborative studies. The method can be introduced in a strategy aimed at defining the risk of failure of patients with childhood or adult ALL. (c) 2014 Clinical Cytometry Society. PMID- 25270228 TI - Risk of subsequent invasive breast cancer after a diagnosis of ductal carcinoma in situ (DCIS). AB - Despite surgical removal of ductal carcinoma in situ (DCIS), recurrences still occur. This retrospective cohort study evaluated the risk of invasive recurrence following surgery and investigated factors which may be predictive of recurrence. We specifically investigated invasive recurrence with respect to mode of detection of DCIS. Patients whose DCIS was detected outside of the NHS Breast Screening Programme have a higher risk of subsequent ipsilateral invasive breast cancer than those whose DCIS is detected through screening. There is no significant difference in risk of subsequent contralateral invasive recurrence according to mode of detection. PMID- 25270229 TI - Risk factors for supplementary posterior instrumentation after anterolateral decompression and instrumentation in thoracolumbar burst fractures. AB - BACKGROUND: In spite of the established benefits of anterolateral decompression and instrumentation (ALDI) for thoracolumbar burst fractures (TLBF), the indications for supplementary posterior instrumentation remain unclear. METHODS: A retrospective review of clinical and radiographic data of a prospective cohort of 73 patients who underwent ALDI for TLBF from T12 to L4. RESULTS: The mean age of the cohort was 42 +/- 15 years, with 49 males and 24 females. Forty-six patients had neurological deficit, and 27 were intact. Owing to symptomatic settling, supplemental posterior instrumentation was performed in 7 out of 73 patients. The age of patients requiring supplemental posterior instrumentation (59 +/- 14 years) exceeded that of patients who did not (41 +/- 16, p=0.004). Otherwise, the patients who required posterior instrumentation were comparable to those treated with ALDI in terms of body mass index (BMI), American Spinal Injury Association (ASIA) scores on admission and follow-up, residual spinal canal, and local kyphosis on admission and follow-up. The posterior ligamentous complex (PLC) integrity was assessed in 38 patients in whom the MRI scans were retrievable, 31 successfully treated with ALDI, and all 7 undergoing supplementary posterior instrumentation. Subgroup analysis demonstrated that there was no difference in the incidence of PLC disruption between the 2 groups (p=0.257). CONCLUSIONS: Secondary supplemental posterior instrumentation was deemed necessary in 10% of cases following ALDI. Age was the only significant risk factor predicating supplemental posterior instrumentation. PMID- 25270231 TI - Physiological analyses of traits associated with tolerance of long-term partial submergence in rice. AB - Floods are major constraints to crop production worldwide. In low-lying, flood prone areas of the tropics, longer-term partial submergence (stagnant flooding [SF]) greatly reduces rice yield. This study assesses shoot growth and several physiological mechanisms associated with SF tolerance in rice. Five rice genotypes with contrasting responses to SF were evaluated in field ponds. Following transplanting, floodwater was gradually increased at a rate of ~2 cm day(-1) to reach a final depth of 50 cm and then maintained until maturity. Although plants were not fully submerged, the yield was reduced by 47 % across genotypes compared with those grown under control conditions (6.1 vs. 3.3 t ha( 1)). This reduction was mainly attributed to the reduction in biomass caused by reduced light interception and leaf growth above the water. Stagnant flooding also reduced panicle number per unit area by 52 % because of reduced tillering. Shoot elongation rate kept pace with rising floodwater and correlated positively with leaf growth and biomass production. Conversely, stem non-structural carbohydrate (NSC) concentration correlated negatively with shoot elongation rate, suggesting that fast-elongating genotypes actively consume NSCs to avoid complete submergence. Moderate shoot elongation rate strongly and positively correlated with grain yield under SF; however, elongation at rates >2.0 cm day( 1) was associated with reduced harvest index due to a smaller panicle size and increased lodging. Tolerant varieties were found to be either inherently tall or elongate moderately with rising floodwater. Our studies suggest that to improve tolerance of SF an appropriate phenotype should combine both of these traits. Fine-tuning for optimum shoot elongation with rising floodwater is, therefore, a priority for future work. PMID- 25270230 TI - Depiction of branch vessels arising from intracranial aneurysm sacs: Time-of flight MR angiography versus CT angiography. AB - BACKGROUND: To evaluate the sensitivity, specificity, and accuracy of time-of flight MR angiography (MRA) compared with CT angiography (CTA) for detection of branch vessels arising from the intracranial aneurysm sac, using a 3-tesla MR scanner and an area detector CT scanner. METHODS: Fifty patients with an intracranial aneurysm (25 patients with a branch vessel arising from the sac and 25 patients without) underwent rotational intraarterial digital subtraction angiography (rotational DSA), MRA, and CTA. The following six image sets were assessed using a 3-point scale for the existence of a branch vessel: (1) volume rendering with MRA (MRA-VR); (2) CTA-VR; (3) source images with MRA; (4) source images with CTA; (5) VR and source images with MRA ('MRA-VR+source images'); and (6) 'CTA-VR+source images'. Each set comprised the data of all 50 patients. Three radiologists then performed consensus review and calculated the sensitivity, specificity, and accuracy for MRA and CTA; rotational DSA was considered as the gold standard. RESULTS: Higher accuracies were obtained in review using VR+source compared with both VR and source alone. In addition, higher accuracies were obtained in review using MRA compared with CTA. The highest accuracy of 0.96 was obtained for 'MRA-VR+source images'; in contrast, accuracy on 'CTA-VR+source images' was 0.86. CONCLUSIONS: The results show that 3-tesla MRA is an ideal non invasive imaging examination for detection of a branch vessel arising from an intracranial aneurysm sac. Higher accuracy, especially sensitivity, with MRA compared with CTA was found in ICA, but accuracy with MRA was same as that with CTA in MCA. PMID- 25270232 TI - Quantitative trait loci mapping for canine hip dysplasia and its related traits in UK Labrador Retrievers. AB - BACKGROUND: Canine hip dysplasia (CHD) is characterised by a malformation of the hip joint, leading to osteoarthritis and lameness. Current breeding schemes against CHD have resulted in measurable but moderate responses. The application of marker-assisted selection, incorporating specific markers associated with the disease, or genomic selection, incorporating genome-wide markers, has the potential to dramatically improve results of breeding schemes. Our aims were to identify regions associated with hip dysplasia or its related traits using genome and chromosome-wide analysis, study the linkage disequilibrium (LD) in these regions and provide plausible gene candidates. This study is focused on the UK Labrador Retriever population, which has a high prevalence of the disease and participates in a recording program led by the British Veterinary Association (BVA) and The Kennel Club (KC). RESULTS: Two genome-wide and several chromosome wide QTLs affecting CHD and its related traits were identified, indicating regions related to hip dysplasia. CONCLUSION: Consistent with previous studies, the genetic architecture of CHD appears to be based on many genes with small or moderate effect, suggesting that genomic selection rather than marker-assisted selection may be an appropriate strategy for reducing this disease. PMID- 25270233 TI - Possible contributions of skin pigmentation and vitamin D in a polyfactorial model of seasonal affective disorder. AB - Seasonal affective disorder (SAD) is a polyfactorial and polygenetic disorder that involves biological and psychological sub-mechanisms that differentially involve depression, seasonality, circadian rhythms, retinal sensitivity, iris pigmentation, sleep factors, and the neurotransmitters involved with these systems. Within the framework of the polyfactorial conceptualization of SAD, we review the possible contributions of vitamin D3 with respect to the aforementioned sub-mechanisms. We hypothesize that rather than functioning primarily as a proximal or direct sub-mechanism in the etiology of SAD, vitamin D likely functions in a more foundational and regulative role in potentiating the sub-mechanisms associated with the depressive and seasonality factors. There are several reasons for this position: 1. vitamin D levels fluctuate in the body seasonally, with a lag, in direct relation to seasonally-available sunlight; 2. lower vitamin D levels have been observed in depressed patients (as well as in patients with other psychiatric disorders) compared to controls; 3. vitamin D levels in the central nervous system affect the production of both serotonin and dopamine; and 4. vitamin D and vitamin D responsive elements are found throughout the midbrain regions and are especially concentrated in the hypothalamus, a region that encompasses the circadian timing systems and much of its neural circuitry. We also consider the variable of skin pigmentation as this may affect levels of vitamin D in the body. We hypothesize that people with darker skin pigmentation may experience greater risks for lower vitamin D levels that, especially following their migration to regions of higher latitude, could contribute to the emergence of SAD and other psychiatric and physical health problems. PMID- 25270234 TI - Guideline adherence for the treatment of advanced schistosomiasis japonica in Hubei, China. AB - This study compared physicians' practices on three treatment procedures and hospitalization days with guideline recommendations to assess guideline adherence in the treatment of advanced schistosomiasis japonica. Descriptive statistics were used to estimate patients' characteristics and rate of guideline adherence. And chi-square tests were used to assess influences of severity of the disease on guideline adherence. The study found no one (0/173) adhered to adequate diagnosis, treatment regimens, and discharge criteria of guidelines completely. And 2.23% of patients in group 1 and 4.23% in group 2 were totally conforming to adequate diagnosis. 91.91% of patients were conforming to adequate treatment regimens among which group 1 and group 2 were 90.32 and 92.25%, respectively. And one (2.23%) patient in group 1 and zero (0%) in group 2 were conforming to discharge criteria of guidelines, and most of the patients left hospital without symptom checks (151/173), liver function and biochemical tests (169/173), and complication checks (91/173). Among 173 inpatients, rate of adequate hospitalization days was 36.42% (63/173). And chi-square test suggested no significant difference (P > 0.05) on guideline adherence in two groups, which implied both of critical and general patients' treatments should be stressed to comply with guidelines. There existed a large gap between guidelines and practices of the treatment of advanced schistosomiasis japonica. PMID- 25270235 TI - Effect of aqueous extract of Azadirachta indica A. Juss (neem) leaf on oocyte maturation, oviposition, reproductive potentials and embryonic development of a freshwater fish ectoparasite Argulus bengalensis Ramakrishna, 1951 (Crustacea: Branchiura). AB - In present study, a microcosm experiment is carried out to investigate the efficacy of 120 and 250-ppm crude aqueous extract of Azadirachta leaf on oocyte maturation, oviposition, embryonic development and hatching of the eggs of a fish ectoparasite Argulus bengalensis. Relative abundance of different maturing oocyte stages in the ovary of the parasite from different age groups was enumerated, and marked variations were obtained. Significant depletion in the abundance of pre vitollogenic, vitellogenic and post-vitellogenic oocytes was recorded, which indicates impairment in maturation. Chromatin condensation of the oocytes of treated parasite indicates apoptosis of oogenic cells. Strong oviposition deterrence was evident by the elevated oviposition deterrence index of 0.18 and 0.52 at respective toxin levels. The treated parasites invested less number of eggs per oviposition, and hatching percentage of the eggs reduced markedly. In vitro treatment of eggs within 70 min of incubation exhibited coagulation of yolk material and subsequent reduction in hatching percentage. However, treatment applied after this critical period, hatching was not significantly altered. In vitro treatment of eggs at 80 min of incubation resulted in normal development. It signifies that azadirachtin affects the early developmental events but not the later. Presumably, azadirachtin either affects early gene expression of the embryo or antagonizes any of the substances of the zygote required for sustaining early developmental process. The result of the present experiment suggests that azadirachtin could be a promising agent to control argulosis through inhibition of the reproductive maturity of the parasite as well as through interference of its embryonic development. PMID- 25270236 TI - 18S rRNA gene sequencing identifies a novel species of Henneguya parasitizing the gills of the channel catfish (Ictaluridae). AB - In the southeastern USA, the channel catfish Ictalurus punctatus is a host to at least eight different species of myxozoan parasites belonging to the genus Henneguya, four of which have been characterized molecularly using sequencing of the small subunit ribosomal RNA (SSU rRNA) gene. However, only two of these have confirmed life cycles that involve the oligochaete Dero digitata as the definitive host. During a health screening of farm-raised channel catfish, several fish presented with deformed primary lamellae. Lamellae harbored large, nodular, white pseudocysts 1.25 mm in diameter, and upon rupturing, these pseudocysts released Henneguya myxospores, with a typical lanceolate-shaped spore body, measuring 17.1 +/- 1.0 MUm (mean +/- SD; range = 15.0-19.3 MUm) in length and 4.8 +/- 0.4 MUm (3.7-5.6 MUm) in width. Pyriform-shaped polar capsules were 5.8 +/- 0.3 MUm in length (5.1-6.4 MUm) and 1.7 +/- 0.1 MUm (1.4-1.9 MUm) in width. The two caudal processes were 40.0 +/- 5.1 MUm in length (29.5-50.0 MUm) with a spore length of 57.2 +/- 4.7 (46.8-66.8 MUm). The contiguous SSU rRNA gene sequence obtained from myxospores of five excised cysts did not match any Henneguya sp. in GenBank. The greatest sequence homology (91% over 1,900 bp) was with Henneguya pellis, associated with blister-like lesions on the skin of blue catfish Ictalurus furcatus. Based on the unique combination of pseudocyst and myxospore morphology, tissue location, host, and SSU rRNA gene sequence data, we report this isolate to be a previously unreported species, Henneguya bulbosus sp. nov. PMID- 25270237 TI - The correlation of Tim-3 and IFN-gamma expressions in mice infected with Toxoplasma gondii during gestation. AB - The immunoinhibitory receptor T cell immunoglobulin domain and mucin domain-1 (Tim-1) and Tim-3 participate in the regulation of Th immune response as well as innate immunity. However, there is no report about the expression of Tim genes in Toxoplasma gondii-infected experimental models during pregnancy. In this study, Kunming outbred pregnant mice were infected with RH strain of T. gondii through vagina at days 10 to 16 of gestation, and the mRNA expressions of Tim-1, Tim-3, interleukin (IL)-4, and interferon (IFN)-gamma in the placentas, uteri, and draining lumber aortic lymph nodes (LALNs) at day 18 of gestation were analyzed using quantitative real-time PCR (qRT-PCR). Compared with uninfected pregnant controls, significantly increased levels of IFN-gamma and Tim-3 were detected in the placentas (P < 0.001), uteri (P = 0.003 and P = 0.017, respectively), and LALNs (P = 0.003 and P = 0.025, respectively) of T. gondii-infected mice; there were positive and significant correlations between Tim-3 and IFN-gamma mRNA expression levels in the placentas (R(2) = 0.6331, P = 0.0011), uteri (R(2) = 0.5658, P = 0.003), and LALNs (R(2) = 0.5583, P = 0.0033) of infected mice. Tim-1 (P = 0.002) and IL-4 (P = 0.003) expressions were significantly increased in the placentas, but Tim-1 were significantly decreased in the uteri (P = 0.013) and LALNs (P < 0.001) of infected pregnant mice in comparison of uninfected pregnant controls. Our data suggested that Tim-3 may play a regulatory role in T. gondii infected pregnant mouse model. PMID- 25270238 TI - 'They think it's all up to the girls': gender, risk and responsibility for contraception. AB - Much research suggests that attitudes towards responsibility for use of contraception amongst young people are strongly gendered. However, decision making, if 'decisions' happen at all, is bound up with notions of hegemonic masculine and feminine roles as well as factors concerning relationship status. Data from two earlier qualitative studies were re-analysed with an emphasis on findings related to gender and responsibility for use of contraception. The first study investigated unintended conceptions amongst 16-20-year-old women. Interviews focused on knowledge and views about contraception, sex education and sexual health services. The second study involved focus groups with two groups of 14-18-year-old men to explore their views on sex education, sexual health and contraception. Almost all the young women said that young men viewed contraception as 'not their job'. In contrast, the young men thought that responsibility should be shared. The key issue, however, related to relationship status, with decision-making being shared in long-term relationships. There are some gender differences in accounting for decisions about use of contraception, however the key issue revolves around relationship status. PMID- 25270240 TI - Motor cortex plasticity in subcortical ischemic vascular dementia: what can TMS say? PMID- 25270241 TI - Optimizing computational feature sets for subthalamic nucleus localization in DBS surgery with feature selection. AB - OBJECTIVE: Microelectrode recording (MER) is used to identify the subthalamic nucleus (STN) during deep brain stimulation (DBS) surgery. Automated STN detection typically involves extracting quantitative features from MERs for classifier training. This study evaluates the ability of feature selection to identify optimal feature combinations for automated STN localization. METHODS: We extracted 13 features from 65 MERs for classifier training. For logistic regression (LR) classification, we compared classifiers identified by feature selection to those containing all possible feature combinations. We used classification error as our metric with hold-one-patient-out cross-validation. We also compared patient-specific vs. independent normalization on classifier performance. RESULTS: Feature selection and patient-specific normalization were superior to non-optimized, patient-independent classifiers. Feature selection, patient-specific normalization, and both produced relative error reductions of 4.95%, 31.36%, and 38.92%, respectively. Three of four feature-selected LR classifiers performed better than 99% of classifiers with all possible feature combinations. Optimal feature combinations were not predictable from individual feature performance. CONCLUSIONS: Feature selection reduces classification error in automated STN localization from MERs. Additional improvement from patient specific normalization suggests these approaches are necessary for clinically reliable automation of MER interpretation. SIGNIFICANCE: These findings represent an incremental advance in automated functional localization of STN from MER in DBS surgery. PMID- 25270239 TI - Dynamics of functional and effective connectivity within human cortical motor control networks. AB - OBJECTIVE: Praxis, the performance of complex motor gestures, is crucial to the development of motor and social/communicative capacities. Praxis relies on a network consisting of inferior parietal and premotor regions, particularly on the left, and is thought to require transformation of spatio-temporal representations (parietal) into movement sequences (premotor). METHOD: We examined praxis network dynamics by measuring EEG effective connectivity while healthy subjects performed a praxis task. RESULTS: Propagation from parietal to frontal regions was not statistically greater on the left than the right. However, propagation from left parietal regions to all other regions was significantly greater during gesture preparation than execution. Moreover, during gesture preparation only, propagation from the left parietal region to bilateral frontal regions was greater than reciprocal propagations to the left parietal region. This directional specificity was not observed for the right parietal region. CONCLUSIONS: These findings represent direct electrophysiological evidence for directionally predominant propagation in left frontal-parietal networks during praxis behavior, which may reflect neural mechanisms by which representations in the human brain select appropriate motor sequences for subsequent execution. SIGNIFICANCE: In addition to bolstering the classic view of praxis network function, these results also demonstrate the relevance of additional information provided by directed connectivity measures. PMID- 25270242 TI - Network hyperexcitability in a patient with partial reading epilepsy: converging evidence from magnetoencephalography, diffusion tractography, and functional magnetic resonance imaging. AB - OBJECTIVE: The pathophysiological mechanisms of partial reading epilepsy are still unclear. We delineated the spatial-temporal characteristics of reading induced epileptic spikes and hemodynamic activation in a patient with partial reading epilepsy. METHODS: Magnetoencephalography (MEG) was recorded during silent letter-by-letter reading, and the source of reading-induced spikes was estimated using equivalent current dipole (ECD) analysis. Diffusion tractography was employed to determine if the white matter pathway connected spike initiation and termination sites. Functional magnetic resonance imaging (fMRI) was employed to determine the spatial pattern of hemodynamic activation elicited by reading. RESULTS: In 91 spike events, ECDs were clustered in the left posterior basal temporal area (pBTA) during Katakana reading. In 8 of these 91 events, when the patient continued to read >30 min, another ECD cluster appeared in the left ventral precentral gyrus/frontal operculum with a time-difference of ~24 ms. Probabilistic diffusion tractography revealed that the long segment of the arcuate fasciculus connected these two regions. fMRI conjunction analysis indicated that both Katakana and Kanji reading activated the left pBTA, but Katakana activated the left lateral frontal areas more extensively than Kanji. CONCLUSIONS: Prolonged reading of Katakana induced hyper-activation of the cortical network involved in normal language function, concurrently serving as the seizure onset and symptomatogenic zones. SIGNIFICANCE: Reflex epilepsy is believed to result from intrinsic hyper-excitability in the cortical regions recruited during behavioral states that trigger seizures. Our case shows that reading epilepsy can arise from a hyperexcitable network of cortical regions. Physiological activation of this network can have cumulative effects, resulting in greater reciprocal network propagation and electroclinical seizures. These effects, in turn, may give insights into the brain networks recruited by reading. PMID- 25270243 TI - Trigemino-cervical-spinal reflexes after traumatic spinal cord injury. AB - OBJECTIVE: After spinal cord injury (SCI) reorganization of spinal cord circuits occur both above and below the spinal lesion. These functional changes can be determined by assessing electrophysiological recording. We aimed at investigating the trigemino-cervical reflex (TCR) and trigemino-spinal reflex (TSR) responses after traumatic SCI. METHODS: TCR and TSR were registered after stimulation of the infraorbital nerve from the sternocleidomastoid, splenius, deltoid, biceps and first dorsal interosseous muscles in 10 healthy subjects and 10 subjects with incomplete cervical SCI. RESULTS: In the control subjects reflex responses were registered from the sternocleidomastoid, and splenium muscles, while no responses were obtained from upper limb muscles. In contrast, smaller but clear short latency EMG potentials were recorded from deltoid and biceps muscles in about half of the SCI patients. Moreover, the amplitudes of the EMG responses in the neck muscles were significantly higher in patients than in control subjects. CONCLUSION: The reflex responses are likely to propagate up the brainstem and down the spinal cord along the reticulospinal tracts and the propriospinal system. Despite the loss of corticospinal axons, synaptic plasticity in pre existing pathways and/or formation of new circuits through sprouting processes above the injury site may contribute to the findings of this preliminary study and may be involved in the functional recovery. SIGNIFICANCE: Trigemino-cervical spinal reflexes can be used to demonstrate and quantify plastic changes at brainstem and cervical level following SCI. PMID- 25270244 TI - A quantum chemical study from a molecular transport perspective: ionization and electron attachment energies for species often used to fabricate single-molecule junctions. AB - The accurate determination of the lowest electron attachment (EA) and ionization (IP) energies for molecules embedded in molecular junctions is important for correctly estimating, for example, the magnitude of the currents (I) or the biases (V) where an I-V curve exhibits significant non-Ohmic behavior. Benchmark calculations for the lowest electron attachment and ionization energies of several typical molecules utilized to fabricate single-molecule junctions characterized by n-type conduction (4,4'-bipyridine, 1,4-dicyanobenzene and 4,4' dicyano-1,1'-biphenyl) and p-type conduction (benzenedithiol, biphenyldithiol, hexanemonothiol and hexanedithiol) based on the EOM-CCSD (equation-of-motion coupled-cluster singles and doubles) state-of-the-art method of quantum chemistry are presented. They indicate significant differences from the results obtained within current approaches to molecular transport. The present study emphasizes that, in addition to a reliable quantum chemical method, basis sets much better than the ubiquitous double-zeta set employed for transport calculations are needed. The latter is a particularly critical issue for correctly determining EAs, which is impossible without including sufficient diffuse basis functions. The spatial distribution of the dominant molecular orbitals (MOs) is another important issue, on which the present study draws attention, because it sensitively affects the MO energy shifts Phi due to image charges formed in electrodes. The present results cannot substantiate the common assumption of a point-like MO midway between electrodes, which substantially affects the actual Phi-values. PMID- 25270245 TI - Low-magnitude high-frequency loading, by whole-body vibration, accelerates early implant osseointegration in ovariectomized rats. AB - Osteoporosis deteriorates jaw bone quality and may compromise early implant osseointegration and early implant loading. The influence of low-magnitude, high frequency (LMHF) vibration on peri-implant bone healing and implant integration in osteoporotic bones remains poorly understood. LMHF loading via whole-body vibration (WBV) for 8 weeks has previously been demonstrated to significantly enhance bone-to-implant contact, peri-implant bone fraction and implant mechanical properties in osteoporotic rats. In the present study, LMHF loading by WBV was performed in osteoporotic rats, with a loading duration of 4 weeks during the early stages of bone healing. The results indicated that 4-week LMHF loading by WBV partly reversed the negative effects of osteoporosis and accelerated early peri-implant osseointegration in ovariectomized rats. PMID- 25270246 TI - Mechanism and biological significance of the overexpression of IFITM3 in gastric cancer. AB - Interferon-induced transmembrane protein 3 (IFITM3) has been recently identified as a potential molecular marker. IFITM3 has been reported to be upregulated in various human diseases, including colon and breast cancer, astrocytoma, as well as ulcerative colitis. However, the clinical significance and underlying mechanisms of IFITM3 dysregulated expression in gastric cancer (GC) remain to be determined. The present study aimed to evaluate the expression of IFITM3 in human gastric tumor cells and specimens and investigate the effects of IFITM3 knockdown in the regulation of GC growth and its potential mechanism. IFITM3 expression was significantly overexpressed in the GC cell lines and GC tissues compared with corresponding normal controls by RT-qPCR, western blot analysis and immunohistochemistry, and this overexpression was correlated with tumor differentiation, lymph node and distant metastasis, and advanced tumor node metastasis stages. Furthermore, knockdown of IFITM3 expression suppressed tumor cell migration, invasion and proliferation significantly in vitro, arrested tumor cells at the G0/G1 phase and reduced the cell numbers in the S phase of the cell cycle. We preliminarily confirmed that IFITM3 can be mediated by the activities of Wnt/beta-catenin signaling. Further investigation revealed that silencing of IFITM3 effectively reversed the epithelial-to-mesenchymal transition (EMT) phenotype and reduced the activities of MMP-2 and MMP-9 expression. Taken together, these data suggested that IFITM3 is a potential therapeutic target for GC. PMID- 25270247 TI - Prenatal drinking-water exposure to tetrachloroethylene and ischemic placental disease: a retrospective cohort study. AB - BACKGROUND: Prenatal drinking water exposure to tetrachloroethylene (PCE) has been previously related to intrauterine growth restriction and stillbirth. Pathophysiologic and epidemiologic evidence linking these outcomes to certain other pregnancy complications, including placental abruption, preeclampsia, and small-for-gestational-age (SGA) (i.e., ischemic placental diseases), suggests that PCE exposure may also be associated with these events. We examined whether prenatal exposure to PCE-contaminated drinking water was associated with overall or individual ischemic placental diseases. METHODS: Using a retrospective cohort design, we compared 1,091 PCE-exposed and 1,019 unexposed pregnancies from 1,766 Cape Cod, Massachusetts women. Exposure between 1969 and 1990 was estimated using water distribution system modeling software. Data on birth weight and gestational age were obtained from birth certificates; mothers self-reported pregnancy complications. RESULTS: Of 2,110 eligible pregnancies, 9% (N = 196) were complicated by >=1 ischemic placental disease. PCE exposure was not associated with overall ischemic placental disease (for PCE >= sample median vs. no exposure, risk ratio (RR): 0.90; 95% confidence interval (CI): 0.65, 1.24), preeclampsia (RR: 0.36; 95% CI: 0.12-1.07), or SGA (RR: 0.98; 95% CI: 0.66-1.45). However, pregnancies with PCE exposure >= the sample median had 2.38-times the risk of stillbirth >=27 weeks gestation (95% CI: 1.01, 5.59), and 1.35-times of the risk of placental abruption (95% CI: 0.68, 2.67) relative to unexposed pregnancies. CONCLUSIONS: Prenatal PCE exposure was not associated with overall ischemic placental disease, but may increase risk of stillbirth. PMID- 25270248 TI - Can conservation contracts co-exist with change? Payment for ecosystem services in the context of adaptive decision-making and sustainability. AB - This paper considers the ability of payment for ecosystem services (PES) programs to operate in the context of dynamic and complex social-ecological systems. Drawing on the experiences of two different PES programs in Latin America, we examine how PES institutions fit with the tenets of adaptive decision-making for sustainable resource management. We identify how the program goals and the connection to the market influence the incentive structure, information gathering, learning and feedback processes, and the structure of decision-making rights, specifically the ability to make and modify resource-use rules. Although limited in their generalizability, findings from the two case studies suggest a tension between the contractual model of PES and adaptive decision-making in natural resource systems. PES programs are not inherently decentralized, flexible management tools, as PES contracts tend to restrict decision-making rights and offer minimal flexibility mechanisms to change resource-use practices over the duration of the contract period. Furthermore, PES design and flexibility is heavily dependent on the goals and mission of the buyer and the respective market. If PES is to facilitate sustainable resource management, greater attention is needed to assess how the institutional design of the PES contracts influence the motivation and capacity of participants and program officers alike to adaptively manage the respective resource systems. PMID- 25270249 TI - The early life origin theory in the development of cardiovascular disease and type 2 diabetes. AB - Life expectancy has been examined from a variety of perspectives in recent history. Epidemiology is one perspective which examines causes of morbidity and mortality at the population level. Over the past few 100 years there have been dramatic shifts in the major causes of death and expected life length. This change has suffered from inconsistency across time and space with vast inequalities observed between population groups. In current focus is the challenge of rising non-communicable diseases (NCD), such as cardiovascular disease and type 2 diabetes mellitus. In the search to discover methods to combat the rising incidence of these diseases, a number of new theories on the development of morbidity have arisen. A pertinent example is the hypothesis published by David Barker in 1995 which postulates the prenatal and early developmental origin of adult onset disease, and highlights the importance of the maternal environment. This theory has been subject to criticism however it has gradually gained acceptance. In addition, the relatively new field of epigenetics is contributing evidence in support of the theory. This review aims to explore the implication and limitations of the developmental origin hypothesis, via an historical perspective, in order to enhance understanding of the increasing incidence of NCDs, and facilitate an improvement in planning public health policy. PMID- 25270250 TI - Development and imprinted gene expression in uniparental preimplantation mouse embryos in vitro. AB - Increasing numbers of reports show that imprinted genes play a crucial role in fetal development, and uniparental embryos, which possess two paternally or two maternally derived pronuclei, are excellent tools for investigating the biological significance of imprinted genes. In the present study, to examine the in vitro developmental ability and expression pattern of eight imprinted genes in uniparental embryos, we produced androgenones, gynogenones, and parthenogenones using enucleation. Our data confirmed the previously observed restriction in haploid androgenetic development potential and first indicated that diploid androgenetic embryos were arrested in the 3/4-cell stage. Some imprinted genes were expressed in androgenetic, gynogenetic, and parthenogenetic blastocysts, suggesting that they were unable to maintain their imprinted expression status in uniparental embryos and that both paternal and maternal alleles are required for the specific expression of some imprinted genes. PMID- 25270252 TI - Neurovascular involvement in central odontogenic fibroma: a potential source of confusion with invasive carcinoma. PMID- 25270251 TI - Association of variants on ADIPOQ and AdipoR1 and the prognosis of gastric cancer patients after gastrectomy treatment. AB - Adiponectin is a protein hormone secreted exclusively by adipocytes and it is responsible for insulin sensitization in the human body. Deregulation of adiponectin and its downstream signaling pathway genes have been found to be involved in the gastric cancer carcinogenesis; however, whether the variants on adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) affect the prognosis of gastric cancer patients are still unknown. Here we have recruited 455 gastric cancer patients, who have received the gastrectomy treatment to evaluate the prognostic effects of variants on ADIPOQ (rs266729 and rs822395) and AdipoR1 (rs12733285 and rs1342387) for the gastric cancer patients. No significant association between the four variants and the overall survival of the gastric cancer patients was found. However, for those patients without a previous history of alcohol drinking, the rs266729 GG/CG genotype carriers showed a significantly decreased gastric cancer mortality compared to homogeneity CC patients (HR 0.74, 95 % CI 0.56-0.97; p = 0.032) after adjustment for variants age, sex, smoking status, tumor stage, tumor location and post-surgery chemotherapy. No significant association between the variant rs266729 genotypes and overall survival for the gastric cancer patients with an alcohol drinking habit. These data suggested that the variant rs266729 was an independent prognostic factor for the never drinking gastric cancer patients who received surgical treatment. PMID- 25270254 TI - Prefrontal hemodynamic responses and the degree of flow experience among occupational therapy students during their performance of a cognitive task. AB - PURPOSE: Although flow experience is positively associated with motivation to learn, the biological basis of flow experience is poorly understood. Accumulation of evidence on the underlying brain mechanisms related to flow is necessary for a deeper understanding of the motivation to learn. The purpose of this study is to investigate the relationship between flow experience and brain function using near-infrared spectroscopy (NIRS) during the performance of a cognitive task. METHODS: Sixty right-handed occupational therapy (OT) students participated in this study. These students performed a verbal fluency test (VFT) while 2-channel NIRS was used to assess changes in oxygenated hemoglobin concentration (oxygenated hemoglobin [oxy-Hb]) in the prefrontal cortex. Soon after that, the OT students answered the flow questionnaire (FQ) to assess the degree of flow experience during the VFT. RESULTS: Average oxy-Hb in the prefrontal cortex had a significant negative correlation with the satisfaction scores on the FQ. CONCLUSION: Satisfaction during the flow experience correlated with prefrontal hemodynamic suppression. This finding may assist in understanding motivation to learn and related flow experience. PMID- 25270255 TI - Learning how to improve healthcare delivery: the Swedish Quality Registers. PMID- 25270256 TI - Focus issue: TGF-beta and the mesenchymal transition in physiology and disease. AB - The ability of cells to alter their phenotypic and morphological characteristics, known as cellular plasticity, is critical in normal embryonic development and adult tissue repair and contributes to the progression of diseases like organ fibrosis and cancer. Signaling mediated by the transforming growth factor-beta (TGF-beta) superfamily of extracellular protein ligands is one pathway that is integral to these processes. Content published in Science Signaling highlights the roles and complexities of TGF-beta signaling in physiology and disease. PMID- 25270257 TI - TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. AB - The process of epithelial-to-mesenchymal transition (EMT) is an essential type of cellular plasticity associated with a change from epithelial cells that function as a barrier consisting of a sheet of tightly connected cells to cells with properties of mesenchyme that are not attached to their neighbors and are highly motile. This phenotypic change occurs during development and also contributes to pathological processes, such as cancer progression. The molecular mechanisms controlling the switch between the fully epithelial and fully mesenchymal phenotypes and cells that have characteristics of both (partial EMT) are controversial, and multiple theoretical models have been proposed. To test these theoretical models, we systematically measured the changes in the abundance of proteins, mRNAs, and microRNAs (miRNAs) that represent the core regulators of EMT induced by transforming growth factor-beta1 (TGF-beta1) in the human breast epithelial cell line MCF10A at the population and single-cell levels. We provide experimental confirmation for a model of cascading switches in phenotypes associated with TGF-beta1-induced EMT of MCF10A cells that involves two double negative feedback loops: one between the transcription factor SNAIL1 and the miR 34 family and another between the transcription factor ZEB1 and the miR-200 family. Furthermore, our data showed that whereas the transition from epithelial to partial EMT was reversible for MCF10A cells, the transition from partial EMT to mesenchymal was mostly irreversible at high concentrations of TGF-beta1. PMID- 25270258 TI - Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-beta-catenin mediated intestinal tumor growth and regeneration. AB - Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-beta-catenin pathway in the intestinal epithelium. Because Wnt-beta catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-beta-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer. PMID- 25270260 TI - Emerging from the shade of p53 mutants: N-terminally truncated variants of the p53 family in EMT signaling and cancer progression. AB - The prevailing view has been that N-terminally truncated p53 family isoforms (DeltaNp53, DeltaNp63, and DNp73) predominantly counteract cell cycle arrest and apoptosis. Recent progress in the field extend these well-known functions and place these isoforms in the center of a comprehensive regulatory network controlling major epithelial-to-mesenchymal transition (EMT)-relevant signaling pathways [such as transforming growth factor-beta (TGF-beta), wingless-int (WNT), insulin-like growth factor (IGF), and signal transducer and activator of transcription (STAT)], microRNAs, and EMT-associated transcription factors that promote invasion, loss of tumor cell polarity, and metastatic behavior in conjunction with a chemoresistant phenotype. These observations add new weight to the concept that currently underappreciated truncated forms of this tumor suppressor family play an equally important role in promoting cancer aggressiveness as do mutant p53 proteins, and illustrate how the consequences of DeltaN/DN expression depend on cellular contexts. The tumor microenvironment contributes to the emergence of these variants, thereby linking inflammation to the activation of the mesenchymal program. In addition, molecular connections between DeltaN/DN forms and self-renewal have arisen, suggesting their potential function in the generation of cancer stem cells (CSCs) from bulk tumor cells. These intriguing insights provoke a new understanding of the acquisition of aggressive traits by carcinoma cells in the absence of p53 mutations, and may help direct the development of new therapies for a broad range of cancers. PMID- 25270259 TI - Association of the EF-hand and PH domains of the guanine nucleotide exchange factor SLAT with IP3 receptor 1 promotes Ca2+ signaling in T cells. AB - The guanine nucleotide exchange factor SLAT (SWAP-70-like adaptor of T cells) regulates T cell activation and differentiation by enabling Ca(2+) release from intracellular stores in response to stimulation of the T cell receptor (TCR). We found a TCR-induced association between SLAT and inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1). The N-terminal region of SLAT, which contains two EF-hand motifs that we determined bound Ca(2+), and the SLAT pleckstrin homology (PH) domain independently bound to IP3R1 by associating with a conserved motif within the IP3R1 ligand-binding domain. Disruption of the SLAT-IP3R1 interaction with cell-permeable, IP3R1-based fusion peptides inhibited TCR-stimulated Ca(2+) signaling, activation of the transcription factor NFAT (nuclear factor of activated T cells), and production of cytokines, suggesting that this interaction is required for optimal T cell activation. The finding that SLAT is an IP3R1 interacting protein required for T cell activation suggests that this interaction could be a potential target for a selective immunosuppressive drug. PMID- 25270262 TI - Abstracts 2014. PMID- 25270261 TI - Dynamic modelling of hepatitis C virus transmission among people who inject drugs: a methodological review. AB - Equipment sharing among people who inject drugs (PWID) is a key risk factor in infection by hepatitis C virus (HCV). Both the effectiveness and cost effectiveness of interventions aimed at reducing HCV transmission in this population (such as opioid substitution therapy, needle exchange programmes or improved treatment) are difficult to evaluate using field surveys. Ethical issues and complicated access to the PWID population make it difficult to gather epidemiological data. In this context, mathematical modelling of HCV transmission is a useful alternative for comparing the cost and effectiveness of various interventions. Several models have been developed in the past few years. They are often based on strong hypotheses concerning the population structure. This review presents compartmental and individual-based models to underline their strengths and limits in the context of HCV infection among PWID. The final section discusses the main results of the papers. PMID- 25270263 TI - Interleukin-31 is associated with uremic pruritus in patients receiving hemodialysis. AB - BACKGROUND: Interleukin (IL)-31 induces severe pruritus and dermatitis in transgenic mice, and is associated with many itching skin diseases. OBJECTIVE: We sought to investigate the association of serum IL-31 levels with uremic pruritus in patients undergoing hemodialysis. METHODS: Patients receiving maintenance hemodialysis in a referral medical center were recruited. Serum IL-31 levels were determined by the enzyme-linked immunosorbent assay methodology. The various characteristics of pruritus were assessed using an interview questionnaire. RESULTS: Among the 178 study participants, 34.8% had uremic pruritus. The patients with pruritus had higher serum IL-31 levels than those without pruritus symptoms (median 8.68 [first quartile 0.43, third quartile 35.04] vs 4.91 [0, 15.78], P = .04). A multivariate linear regression analysis showed that higher serum levels of IL-31, high-sensitivity C-reactive protein, and alanine transaminase, and a lower dialysis dose assessed by Kt/V, were independent predictors for higher pruritus intensity. The generalized additive model also showed a positive exposure-response relationship between serum levels of IL-31 and visual analog scale scores of pruritus intensity. LIMITATIONS: The cause effect relationship between IL-31 and uremic pruritus could not be assessed by the cross-sectional study design. CONCLUSION: IL-31 may play an important role in the pathophysiology of uremic pruritus. PMID- 25270264 TI - Patient-specific ultrasound liver phantom: materials and fabrication method. AB - PURPOSE: An anatomically realistic ultrasound liver phantom with tissue-specific distinct signal properties is needed for training of novices in diagnostic and interventional procedures. The main objective of this work was development and testing of a new durable liver ultrasound training phantom for use with a hybrid simulator. METHODS: A liver ultrasound phantom was fabricated in four main phases: materials selection, segmentation of CT images and realization of 3D models, vessel and lesion realization, and final assembly with silicone casting. Silicone was used as basic material due to its durability and stability over time. Several additives were analyzed and mixed with the polymer to reproduce the echogenicity of three simulated soft tissue types: parenchyma, lesions, and veins. RESULTS: Cysts and vessel trees appear anechoic in the B mode ultrasound images when realized with pure silicone. The liver parenchyma, hypoechoic, and hyperechoic lesions were realized with different concentrations of graphite and Vaseline oil to increase their relative echogenicity. These materials were successful for creation of an ultrasound liver phantom containing simulated blood vessels and lesions. CONCLUSION: The phantom reproduces the human liver morphology and provides vessels and lesions ultrasound images with recognizable differences in echogenicity. The speed of sound in the simulated materials is inaccurate, but the problem can be overcome via software adjustment in a hybrid simulator. PMID- 25270265 TI - Deciphering clonality in aneuploid breast tumors using SNP array and sequencing data. AB - Intra-tumor heterogeneity concerns the existence of genetically different subclones within the same tumor. Single sample quantification of heterogeneity relies on precise determination of chromosomal copy numbers throughout the genome, and an assessment of whether identified mutation variant allele fractions match clonal or subclonal copy numbers. We discuss these issues using data from SNP arrays, whole exome sequencing and pathologist purity estimates on several breast cancers characterized by ERBB2 amplification. We show that chromosomal copy numbers can only be estimated from SNP array signals or sequencing depths for subclonal tumor samples with simple subclonal architectures under certain assumptions. PMID- 25270267 TI - Separation of a heavy metal from water through a membrane containing boron nitride nanotubes: molecular dynamics simulations. AB - Molecular dynamics simulations were performed to investigate the separation of zinc ions as a heavy metal from water using boron nitride nanotubes. The studied systems included boron nitride (BN) nanotubes embedded in a silicon-nitride membrane immersed in an aqueous solution of ZnCl2. An external electric field was applied to the system along the axis of the BN nanotubes. The results show that the (7,7) and (8,8) BN nanotubes were exclusively selective of ions. The (7,7) BN nanotube selectively conducted Zn(2+) ions, while the (8,8) BN nanotube selectively conducted Cl(-) ions. The results were confirmed using additional simulated parameters. The results indicate that the passage of ions through nanotubes is related to the diameter of the BN nanotubes. PMID- 25270266 TI - Predictors for early introduction of solid food among Danish mothers and infants: an observational study. AB - BACKGROUND: Early introduction of complementary feeding may interfere with breastfeeding and the infant's self-controlled appetite resulting in increased growth. The aim of the present study was to investigate predictors for early introduction of solid food. METHODS: In an observational study Danish mothers filled in a self-administered questionnaire approximately six months after birth. The questionnaire included questions about factors related to the infant, the mother, attachment and feeding known to influence time for introduction of solid food. The study population consisted of 4503 infants. Data were analysed using ordered logistic regression models. Outcome variable was time for introduction to solid food. RESULTS: Almost all of the included infants 4386 (97%) initiated breastfeeding. At weeks 16, 17-25, 25+, 330 infants (7%); 2923 (65%); and 1250 (28%), respectively had been introduced to solid food. Full breastfeeding at five weeks was the most influential predictor for later introduction of solid food (OR = 2.52 CI: 1.93-3.28). Among infant factors male gender, increased gestational age at birth, and higher birth weight were found to be statistically significant predictors. Among maternal factors, lower maternal age, higher BMI, and being primipara were significant predictors, and among attachment factors mother's reported perception of the infant as being temperamental, and not recognising early infant cues of hunger were significant predictors for earlier introduction of solid food. Supplementary analyses of interactions between the predictors showed that the association of maternal perceived infant temperament on early introduction was restricted to primiparae, that the mother's pre-pregnancy BMI had no impact if the infant was fully breastfed at week five, and that birth weight was only associated if the mother had reported early uncertainty in recognising infant's cues of hunger. CONCLUSIONS: Breastfeeding was the single most powerful indicator for preventing early introduction to solid food. Modifiable predictors pointed to the importance of supporting breastfeeding and educating primipara and mothers with low birth weight infants to be able to read and respond to their infants' cues to prevent early introduction to solid food. PMID- 25270268 TI - Symmetry-Breaking Charge Transfer of Visible Light Absorbing Systems: Zinc Dipyrrins. AB - Zinc dipyrrin complexes with two identical dipyrrin ligands absorb strongly at 450-550 nm and exhibit high fluorescence quantum yields in nonpolar solvents (e.g., 0.16-0.66 in cyclohexane) and weak to nonexistent emission in polar solvents (i.e., <10-3, in acetonitrile). The low quantum efficiencies in polar solvents are attributed to the formation of a nonemissive symmetry-breaking charge transfer (SBCT) state, which is not formed in nonpolar solvents. Analysis using ultrafast spectroscopy shows that in polar solvents the singlet excited state relaxes to the SBCT state in 1.0-5.5 ps and then decays via recombination to the triplet or ground states in 0.9-3.3 ns. In the weakly polar solvent toluene, the equilibrium between a localized excited state and the charge transfer state is established in 11-22 ps. PMID- 25270269 TI - Gastric neuropeptide W is regulated by meal-related nutrients. AB - Neuropeptide W (NPW) is secreted from gastrin (G) cells in the stomach in response to food intake. The mechanisms underlying food intake-induced regulation of gastric NPW is largely unknown. We hypothesized that specific macronutrients were responsible for food-induced NPW secretion. We evaluated the acute effects of fat, carbohydrate and protein on plasma NPW concentrations in humans and mice. The effect of different nutrients on expression of NPW in the antral stomach was also determined in mice. Primary cell cultures of mouse gastric antral mucosal cells were used to investigate the signaling pathway of NPW expression. Plasma NPW concentrations did not change after nutrient ingestion in either humans or mice. NPW mRNA expression and the number of NPW positive cells in the mouse antrum were increased in mice gavage fed with protein or glucose, but not lipid. In primary antral mucosal cell culture, NPW mRNA expression was stimulated by l phenylalanine, but not glucose. Calcium-sensing receptor (CaSR) positive cells were largely co-localized with NPW in mouse gastric antral mucosal cells, and NPW mRNA expression was inhibited by a selective antagonist of CaSR NPS2143. However, the l-phenylalanine-induced increase in NPW expression was not affected by NPS2143. In conclusion, these studies indicated an inconsistency between plasma and gastric NPW expression in response to nutrient ingestion, suggesting food induced gastric NPW expression may play a more important role locally. Moreover, glucose and especially protein are potent regulators of gastric NPW, via distinct mechanisms. PMID- 25270270 TI - Peer review for biomedical publications: we can improve the system. AB - The lack of formal training programs for peer reviewers places the scientific quality of biomedical publications at risk, as the introduction of 'hidden' bias may not be easily recognized by the reader. The exponential increase in the number of manuscripts submitted for publication worldwide, estimated in the millions annually, overburdens the capability of available qualified referees. Indeed, the workload imposed on individual reviewers appears to be reaching a 'breaking point' that may no longer be sustainable. Some journals have made efforts to improve peer review via structured guidelines, courses for referees, and employing biostatisticians to ensure appropriate study design and analyses. Further strategies designed to incentivize and reward peer review work include journals providing continuing medical education (CME) credits to individual referees by defined criteria for timely and high-quality evaluations. Alternative options to supplement the current peer review process consist of 'post publication peer review,' 'decoupled peer review,' 'collaborative peer review,' and 'portable peer review'. This article outlines the shortcomings and flaws in the current peer review system and discusses new innovative options on the horizon. PMID- 25270271 TI - Classics in chemical neuroscience: levodopa. AB - Levodopa was the first and most successful breakthrough in the treatment of Parkinson's disease (PD). It is estimated that PD affects approximately 1 million people in the United States alone. Although PD was discovered in 1817, prior to levodopa's discovery there was not an effective treatment for managing its symptoms. In 1961, Hornykiewicz pioneered the use of levodopa to enhance dopamine levels in the striatum, significantly improving symptoms in many patients. With the addition of carbidopa in 1974, the frequency of gastrointestinal adverse drug reactions (ADRs) was significantly reduced, leading to the modern treatment of PD. Although levodopa treatment is more than 50 years old, it remains the "gold standard" for PD treatment. This Review describes in detail the synthesis, metabolism, pharmacology, ADRs, and importance of levodopa therapy to neuroscience in the past and present. PMID- 25270272 TI - Significance of AKT in gastric cancer (Review). AB - AKT is a serine/threonine kinase activated downstream of integrin, which is a receptor for various pro-proliferation and bioactive substances as well as the extracellular matrix receptor. The activation of AKT often contributes to tumorigenesis and plays a role in regulating cell motility, which is critical for local invasion and metastasis. In recent years, it has also drawn attention as a target of new molecular-targeted agents. When analyzing the role of AKT in cancer cells, it is important to consider the microenvironment and variations of cancers. In this review, a basic overview of the role of AKT in normal and malignant tissues is provided, along with an in-depth discussion of its role in gastric cancer and its potential as a target for therapy. PMID- 25270273 TI - Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. AB - OBJECTIVE: AR-13324 is a small-molecule inhibitor of Rho kinase and a norepinephrine transporter. The objective of this 28-day study was to evaluate the ocular hypotensive efficacy and safety of AR-13324 ophthalmic solution compared with a positive control, latanoprost ophthalmic solution, in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Double masked, randomized study in 22 private practice ophthalmology clinics. PARTICIPANTS: Participants were required to be adults with a diagnosis of OAG or OHT with unmedicated intraocular pressure (IOP) in the range of 22 to 36 mmHg. METHODS: Patients were randomized to receive AR-13324 ophthalmic solution 0.01%, daily (pm), AR-13324 ophthalmic solution 0.02% daily (pm), or latanoprost 0.005% daily (pm) for 28 days. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean diurnal IOP across subjects within the treatment group at day 28. RESULTS: Randomized and treated were 224 patients, 213 (95.1%) of whom completed the study. On day 28, mean diurnal IOP was 20.1, 20.0, and 18.7 mmHg in the AR 13324 0.01%, 0.02%, and latanoprost groups, respectively, representing a decrease from unmedicated baseline of 5.5, 5.7, and 6.8 mmHg (P<0.001). The 5.7-mmHg reduction in IOP by AR-13324 0.02% did not meet the criterion for noninferiority to latanoprost. The most frequently reported adverse event was conjunctival/ocular hyperemia, with a combined incidence of 52%, 57%, and 16%, respectively. On day 28 at 08:00 hours, the incidence of mild to moderate hyperemia by biomicroscopy was 18%, 24%, and 11%, respectively. CONCLUSIONS: AR 13324 0.02% was less effective than latanoprost by approximately 1 mmHg in patients with unmedicated IOPs of 22 to 35 mmHg. The major safety finding was ocular hyperemia, which was more common for both concentrations of AR-13324 than for latanoprost. PMID- 25270274 TI - Long-term physical activity and risk of age-related cataract: a population-based prospective study of male and female cohorts. AB - OBJECTIVE: To examine the association of total and specific types of physical activity, including walking or bicycling, exercising, work or occupational activity, home or housework, and leisure time inactivity with the risk of age related cataract in women and men. DESIGN: Population-based prospective cohort study. PARTICIPANTS: A total of 52 660 participants (23 853 women and 28 807 men) 45 to 83 years of age from the Swedish Mammography Cohort and the Cohort of Swedish Men. METHODS: Physical activity was assessed using a self-administered questionnaire at baseline. Cataract diagnosis and extraction were identified through linkage to registers. MAIN OUTCOME MEASURES: Incident age-related cataract diagnosis and cataract extraction. RESULTS: During a mean 12.1 years of follow-up (between January 1, 1998, and December 31, 2011; 634 631 person-years), 11 580 incident age-related cataract cases were identified. After adjusting for potential confounders, the highest quartile of total physical activity was statistically significantly associated with 13% decreased risk of cataract compared with the lowest (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.82-0.92). Walking or bicycling (>60 minutes/day vs. hardly ever; HR, 0.88; 95% CI, 0.82-0.95) and work or occupational activity (heavy manual labor vs. mostly sitting; HR, 0.84; 95% CI, 0.78-0.91) also were associated with decreased risk of cataract. Exercise training and home or housework were not associated with cataract risk. Leisure time inactivity was associated with increased risk of cataract (>6 vs. <1 hours/day; HR, 1.27; 95% CI, 1.07-1.50). The HR for high long term total physical activity compared with low levels both at 30 years of age and at baseline was 0.76 (95% CI, 0.69-0.85). CONCLUSIONS: Our findings indicate that high total physical activity, especially in the long term, and such specific types of physical activity as walking or bicycling and work or occupational activity, may be associated with decreased risk of age-related cataract. Conversely, high inactivity levels may be associated with increased risk of cataract. PMID- 25270276 TI - Transfusion threshold of 7 g per deciliter--the new normal. PMID- 25270277 TI - Erectile function recovery in patients after non-nerve sparing radical prostatectomy. AB - Few studies have looked at erectile function recovery (EFR) rates in men undergoing non-nerve sparing resection during radical prostatectomy (RP). Existing studies show great variation in EFR rates owing to multiple factors that minimize their utility in counselling RP patients. We investigated the EFR rate and its predictors in unilateral cavernous nerve resection and bilateral cavernous nerve resection patients 24 months after RP. We conducted a population based, prospective cohort study of 966 patients who underwent RP at a tertiary cancer centre from 2008 to 2012. Cavernous nerve condition was evaluated on a 4 point nerve sparing score and assigned to one of three groups: bilateral sparing, unilateral resection (UNR) and bilateral nerve resection (BNR). EF was assessed pre-RP and 24-30 months post-op using a validated 5-point patient-reported scale (1 = fully rigid; 5 = no tumescence). EFR was defined as a post-op EF grade of 1 2. Statistical analysis included descriptive statistics, anova, chi-square, Fisher's exact test and logistic regression. Mean baseline EF was 1.84 +/- 1.3 and 2.74 +/- 1.5 for UNR and BNR patients respectively. Thirty-three percent of UNR patients and 13% of BNR patients exhibited EFR. Age, baseline EF were predictors of EFR. Multivariable analysis showed baseline EF was a significant predictor of EFR at 24 months for UNR. For BNR patients, pre-RP EF was the only factor predictive of EFR. Patients undergoing nerve resection still have a significant chance of achieving true EFR, with UNR surgery patients showing more potential for improvement than patients undergoing BNR surgery. Age and baseline EFR characterize recovery prospects in these two groups. Physicians should thus measure and account for baseline EF in addition to age and the degree of nerve resection when advising patients about expectations for successful EF following RP. PMID- 25270275 TI - Lower versus higher hemoglobin threshold for transfusion in septic shock. AB - BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. METHODS: In this multicenter, parallel group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. RESULTS: We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower threshold group, as compared with 223 of 496 (45.0%) assigned to the higher threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.). PMID- 25270278 TI - Wine consumption throughout life is inversely associated with type 2 diabetes risk, but only in overweight individuals: results from a large female French cohort study. AB - Alcohol has previously been shown to have a U-shaped association with type 2 diabetes (T2D) risk, but less is known regarding the specific association with wine. To evaluate for the first time the associations between T2D risk and both baseline wine consumption and trajectories of wine consumption frequency throughout life, estimated using an innovative group-based trajectory modeling strategy. A total of 66,485 women from the French prospective E3N-EPIC cohort were followed between 1993 and 2007; 1,372 incident cases of T2D were diagnosed during the follow-up. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (95 % CI) for T2D risk. The average consumption of wine, among alcohol consumers, was 0.81 drinks/day (1 drink = 150 mL). Associations between wine and T2D were restricted to overweight women (P interaction = 0.0084). Among them, wine consumption was inversely associated with T2D risk (P trend = 0.0022). A lower risk was observed for overweight women having two or more drinks/day [HR 0.59 (0.43-0.82)] when compared with non-alcohol consumers. Women who started to drink wine early in life (around age 10-15 years) were at a significantly lower risk than lifetime abstainers. In our study, wine drinking was inversely associated with T2D risk but only in overweight women. Our results also suggest a potential beneficial, cumulative effect of moderate wine consumption throughout life for overweight women, who would already be at higher risk of T2D. We encourage other cohort studies with information on wine consumption to investigate these associations. PMID- 25270279 TI - Technical decision making with higher order structure data: impact of a formulation change on the higher order structure and stability of a mAb. AB - Changes in formulation may be required during the development of protein therapeutics. Some of the changes may alter the protein higher order structure (HOS). In this note, we show how the change from a trehalose-based formulation to an arginine-based formulation concomitantly impacted the tertiary structure and the thermal stability of a mAb (mAb1). The secondary structure was not disrupted by the formulation change. The destabilization of the tertiary structure did not affect the long-term stability or the bioactivity of mAb1. This indicates that loss of conformational stability was likely compensated by improvements in the colloidal stability of mAb1 in the arginine-based formulation. The formulation induced changes in HOS were reversible as proven by measurements after dilution in a common buffer (phosphate-buffered saline). For aggregation driven by assembly of aggregates (colloidally limited), small changes in conformational structure and stability as measured by HOS methods may not necessarily be predictive of long-term stability. PMID- 25270280 TI - Audiological results after total ossicular reconstruction for stapes fixation. AB - The objective was to assess audiological results after total ossicular reconstruction for stapes fixation. The study is a retrospective evaluation conducted in a tertiary referral centre. The patients were 16 adults with conductive or mixed hearing loss and stapes fixation due to tympanosclerosis or otosclerosis. A total or partial stapedectomy with perichondrium interposition on the oval window and ossicular reconstruction with titanium total prosthesis were done. To assess pre- and post-operative (1 and 4 years) air and bone-conduction thresholds (frequencies 0.5, 1, 2, 3 kHz), pure-tone average air and bone conduction, and air-bone gaps were measured and the number of decibels of closure of the air-bone gap at 1 year and at 4 years were compared. One year after surgery, air conduction thresholds and pure-tone average air conduction were improved for all frequencies, and there were no significant differences in bone conduction thresholds or in pure-tone average bone conduction. There were no differences in air and bone conduction thresholds, pure-tone average air or bone conduction between 1 and 4 years. The air-bone gap was significantly reduced 1 year after surgery and remained so at 4 years. (Preoperative air-bone gap, 34.04 dB; at 1 year, 16.40 dB; at 4 years, 17.3 dB. Decibels of closure of the air-bone gap at 1 year, 17.64 dB; at 4 years, 16.74 dB.) No differences were found between otosclerosis subjects and all other cases combined. Total ossicular reconstruction in stapes fixation due to tympanosclerosis or otosclerosis produces satisfactory short- and long-term auditory results. PMID- 25270281 TI - Cultural translation and Tunisian validation of the Drug Attitude Inventory (DAI 30) in outpatients with schizophrenia. AB - BACKGROUND: Non-adherence to treatment in patients with schizophrenia is associated with increased hospitalization, higher health care costs, and poorer long-term outcomes in terms of relapse rates. It is established that a negative drug attitude was a risk factor for non-adherence in long-term schizophrenia. The scale "Drug Attitude Inventory" is one of the scales designed to assess this concept. It has been translated and validated in different languages. However, its psychometric properties have not yet been studied in our sociocultural context. OBJECTIVES: The aims of this study were to translate into Tunisian Arabic dialect the scale "Drug Attitude Inventory" with 30 dichotomous items (DAI 30) and validate it in Tunisian sociocultural context in patients with schizophrenia. MATERIALS AND METHODS: This study was performed in 234 outpatients with schizophrenia, recruited through a random drawing. These patients are in remission and meet remission criteria proposed by "The Remission in schizophrenia Working Group". We recruited 30 patients for pretest and 204 patients for linguistic validation. Forward and backward translation of the DAI-30 was performed according to the protocol of the "MAPI Research Institute". This final version was submitted to 24 experts and followed by a pretest. Construct validity has been established by performing a principal component analysis factor on a sample of 204 patients. Internal consistency was assessed by Cronbach alpha coefficient and inter-rater reliability was assessed by the use of Intra-Class Correlation coefficient (ICC). For the test-retest reliability evaluation, the "r" Pearson's coefficient was used between the DAI scores obtained in the initial evaluation and those obtained at 15 days. RESULTS: Regarding construct validity, factor analysis revealed seven factors that were responsible for 59.9% of the variance. The study of internal consistency between the 30 items was rated good (alpha=0.88). The test-retest reliability was satisfactory (r=0.99, p<10(-3)), as well as inter-rater reliability (ICC=0.99). CONCLUSION: In the Tunisian cultural context, the DAI-30 presented seven factors with good consistency and an inter rater reliability. PMID- 25270282 TI - Overexpression of miR-223 correlates with tumor metastasis and poor prognosis in patients with colorectal cancer. AB - The purpose of the study was to investigate microRNA-223 (miR-223) expression in colorectal cancer (CRC) and its relationship with tumorigenesis and disease prognosis. Quantitative real-time PCR was used to measure levels of miR-223 in tumor samples and adjacent non-cancerous tissues from 62 patients undergoing radical resection for the treatment of CRC. The associations between miR-223 expression and patient age, sex, as well as clinicopathologic parameters, such as tumor size, differentiation, location, invasion depth, metastasis, tumor-node metastasis (TNM) stage, and overall patient survival, were analyzed by Mann Whitney U and Kruskal-Wallis tests. Kaplan-Meier method and Cox proportional hazards regression analyses were performed to estimate the prognostic factors for patient survival prediction. The expression of miR-223 was significantly upregulated in CRC tissues compared with adjacent non-cancerous tissues (P < 0.05). This overexpression was associated with TNM stage and lymph node and distant metastases, (P < 0.05). Moreover, Kaplan-Meier analysis demonstrated that patients with high miR-223 expression had a poorer overall survival (OS) than those with low miR-223 expression (P = 0.002). Univariate analysis revealed a statistically significant correlation between OS and miR-223 level, histology grade, metastasis and TNM stage (P < 0.001). Furthermore, miR-223 levels and histology grade were independently associated with OS (HR 0.204, 95 % CI 0.101 0.415, P < 0.05 and HR 2.252, 95 % CI 1.429-3.546, P < 0.05, respectively). The overexpression of miR-223 may play an important role in the progression of CRC and can be used as an independent factor to determine CRC prognosis. PMID- 25270283 TI - p53 is an independent prognostic factor in operable esophageal squamous cell carcinoma: a large-scale study with a long follow-up. AB - The p53 protein is involved in many biological functions in cancer, such as cell cycle arrest, DNA repair, apoptosis, senescence, DNA metabolism, angiogenesis, and cellular differentiation. However, the association between p53 expression and clinicopathological findings or prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. We designed a large-scale study of 830 operable ESCC patients with a long follow-up to investigate the relationship between p53 expression and the clinicopathological characteristics and prognosis of patients. Immunohistochemistry was used to detect p53 protein expression. When the patients were divided into two groups, a positive expression group and a negative expression group, p53-positive expression positively correlated with a poorer differentiation level (P = 0.044). The overexpression of p53 was associated with a more advanced clinical stage (P = 0.015). A total of 775 patients were available for survival analysis. The median OS of 160 patients who had p53 positive expression and 486 patients who had p53-negative expression were 58.8 and 46.3 months, respectively (P = 0.021); the median PFS of the two groups were 39.6 and 27.5 months, respectively (P = 0.015). Lymph node metastasis, gender, differentiation, depth of invasion, and p53 protein expression were proven to have an influence on both OS and PFS in a univariate analysis. In the multivariate analysis, p53-positive expression maintained its independent prognostic impact on OS (P = 0.048) and PFS (P = 0.039), as did lymph node metastasis, differentiation, and depth of invasion. We identified that p53 protein-positive expression can serve as an independent, unfavorable prognosis biomarker in ESCC. PMID- 25270284 TI - Aberrant miR-215 expression is associated with clinical outcome in breast cancer patients. AB - Dysregulation of microRNA plays critical roles in various malignancies. However, whether the aberrant expression of miR-215 in breast cancer is associated with malignancy, metastasis, or prognosis remains unknown. In this study, we demonstrated that the relative level of miR-215 expression was lower in cancer tissues compared with adjacent non-malignant tissues (p < 0.001). Low-miR-215 expression was observed to be closely correlated with higher tumor grade (p = 0.008), human epidermal growth factor receptor 2 (HER2) positivity (p = 0.006), HER2 positive breast cancer subtype (p = 0.016), and lymph node metastasis (p = 0.039). Moreover, patients with low-miR-215 expression showed shorter 5-year disease-specific survival (DSS) than the high-miR-215 expression group (p = 0.007). Multivariate analysis results revealed that miR-215 downexpression was an unfavorable prognostic factor for DSS in addition to tumor size, ER, and lymph node metastasis. Our results support the potential of miR-215 as a prognostic predictor for breast cancer with its high expression in cancer tissues and its relationship with other clinicopathologic factors and survival. PMID- 25270285 TI - A genetic variant (rs17251221) in the calcium-sensing receptor relates to hepatocellular carcinoma susceptibility and clinical outcome treated by transcatheter hepatic arterial chemoembolization (TACE) therapy. AB - Experimental and epidemiologic studies indicated that calcium-sensing receptor (CaSR) polymorphisms were associated with cancer risk, yet no data are available for candidate gene and hepatocellular carcinoma (HCC) risk. To address this, we evaluated whether CaSR rs17251221 polymorphism is associated with HCC susceptibility, clinicopathological parameters, and prognosis in HCC patients treated by TACE. A TaqMan assay was used to genotype rs17251221 SNP in this case (n = 843)-control (n = 783) study. A significant increased risk of HCC was observed in patients carrying rs17251221 GG (adjusted OR 1.355, 95 % CI 1.024 1.793, P = 0.033), AG/GG genotype (adjusted OR 1.254, 95 % CI 1.007-1.561, P = 0.043), and G allele (adjusted OR 1.163, 95 % CI 1.013-1.335, P = 0.032). Furthermore, a significant association was found between Child-Pugh class, serum BCLC stage, and AFP level and rs17251221 genotypes. More importantly, individuals carrying rs17251221 AG, GG genotype showed significantly longer MST than AA genotype and significant hazard ration (AG: adjusted HR 0.484, 95 % CI 0.406 0.577, P < 0.001; GG: adjusted HR 0.633, 95 % CI 0.575-0.697, P < 0.001, respectively). Meanwhile, we found a favorable HR for AG/GG genotype carriers (adjusted HR 0.645, 95 % CI 0.542-0.768, P < 0.001). These results indicated that CaSR rs17251221 polymorphism is associated with susceptibility to HCC, and rs17251221 G allele genotype showed significant independent better prognosis of HCC patients treated with TACE. PMID- 25270286 TI - Coloured filters may reduce symptoms of dyslexia in those with visual stress. PMID- 25270287 TI - School day and weekend patterns of physical activity in urban 11-year-olds: a cross-cultural comparison. AB - OBJECTIVES: This multi-center study was conducted to objectively evaluate energy expenditure and physical activity (PA) patterns on school days and weekends in urban 11-year-olds. METHODS: The sample consisted of 241 children from three cities: Zagreb, Ljubljana (both in Central Europe) and Ann Arbor (United States). Energy expenditure and PA were assessed during two school days and two weekend days using a multiple-sensor body monitor. RESULTS: Differences between the cities were observed for all PA variables. The highest level of moderate to vigorous PA (MVPA) was noted in Ljubljana boys [284 (98) min/day] and the lowest in Zagreb girls [179 (95) min/day]. In Zagreb and Ljubljana, boys were more physically active than girls, while in Ann Arbor the opposite was observed. In contrast, no gender difference in sedentary behavior was observed in any of the cities. A decline in PA from school days to weekends was noted in all city groups in both genders. However, the magnitude of the reduction in daily energy expenditure differed between the cities, with the largest differences being observed in Ljubljana and the smallest in Ann Arbor. In all three city groups, the great majority of boys and girls achieved current recommendations of 60 min of MVPA either during school days or weekends. CONCLUSIONS: Weekends seem to be an appropriate target when promoting PA in 11-year-olds in all the cities included in the study. Increasing vigorous activity on weekends seems to be of particular importance in Zagreb and Ljubljana. PMID- 25270290 TI - Individually assessed boldness predicts Perca fluviatilis behaviour in shoals, but is not associated with the capture order or angling method. AB - Selectivity of recreational angling on fish behaviour was studied by examining whether capture order or lure type (natural v. artificial bait) in ice-fishing could explain behavioural variation among perch Perca fluviatilis individuals. It was also tested if individually assessed personality predicts fish behaviour in groups, in the presence of natural predators. Perca fluviatilis showed individually repeatable behaviour both in individual and in group tests. Capture order, capture method, condition factor or past growth rate did not explain variation in individual behaviour. Individually determined boldness as well as fish size, however, were positively associated with first entrance to the predator zone (i.e. initial risk taking) in group behaviour tests. Individually determined boldness also explained long-term activity and total time spent in the vicinity of predators in the group. These findings suggest that individual and laboratory-based boldness tests predict boldness of P. fluviatilis in also ecologically relevant conditions, i.e. in shoals and in the presence of natural predators. The present results, however, also indicate that the above-mentioned two angling methods may not be selective for certain behavioural types in comparison to each other. PMID- 25270291 TI - Inflammatory markers, oxidative stress, and antioxidant capacity in healthy allo HSCT donors during hematopoietic stem cell mobilization. AB - The aim of this study is to investigate the impact of mobilization with granulocyte colony stimulating factor (G-CSF) and apheresis procedure on inflammatory and oxidative stress markers, and antioxidant capacity in healthy allo-HSCT donors. The study was conducted in the Stem Cell Transplantation Unit of Gazi University Hospital between October 2010 and March 2011, and 25 consecutive allo-HSCT donors were included. The alteration in the serum levels of iron, iron binding capacity, albumin, ferritin, IL-6, hs-CRP, TAC, MDA, and AOPP were determined at five different time points. (1) Prior to the first dose of G CSF (T0), (2) preapheresis (on the fourth day of G-CSF before the apeheresis procedure) (T1), (3) immediately postapheresis (T2), (4) 24 h postapheresis (T3), and (5) a week after apheresis (T4). Serum ferritin levels increased steadily after administration of G-CSF and remained high up toT4. Both serum IL-6 and hs CRP levels began to increase in the T1 sampling and reached to a maximum level at T3 and decreased even below the basal levels at T4. Serum AOPP levels decreased at preapheresis and postapheresis time points, while they increased at T3 and T4 samples. Serum MDA levels decreased at T1, T2, T3, and T4 samples. Serum TAC increased significantly and steadily at all time points post G-CSF. In conclusion; mobilization with G-CSF and apheresis caused a transient inflammatory reaction and a protein limited oxidative stress in healthy allo-HCT donors. PMID- 25270292 TI - Bioinspired engineering of thermal materials. AB - In the development of next-generation materials with enhanced thermal properties, biological systems in nature provide many examples that have exceptional structural designs and unparalleled performance in their thermal or nonthermal functions. Bioinspired engineering thus offers great promise in the synthesis and fabrication of thermal materials that are difficult to engineer through conventional approaches. In this review, recent progress in the emerging area of bioinspired advanced materials for thermal science and technology is summarized. State-of-the-art developments of bioinspired thermal-management materials, including materials for efficient thermal insulation and heat transfer, and bioinspired materials for thermal/infrared detection, are highlighted. The dynamic balance of bioinspiration and practical engineering, the correlation of inspiration approaches with the targeted applications, and the coexistence of molecule-based inspiration and structure-based inspiration are discussed in the overview of the development. The long-term outlook and short-term focus of this critical area of advanced materials engineering are also presented. PMID- 25270294 TI - Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis. AB - Changes in ion channel expression are implicated in the etiology of epilepsy. However, the molecular leading to long-term aberrant expression of ion channels are not well understood. The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons. mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology. In contrast, we found that mTOR activity and the microRNA miR-129-5p reduce the expression of the voltage-gated potassium channel Kv1.1 in an animal model of temporal lobe epilepsy (TLE). When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low. However, as behavioral seizure activity rises, mTOR activity increases and Kv1.1 protein levels drop. In CA1 pyramidal neurons, the reduction in Kv1.1 lowers the threshold for action potential firing. Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated. Overtime, seizure activity increases and Kv1.1 protein decreases in all animals, even those treated with rapamycin. Notably, the concentration of miR-129-5p, the negative regulator of Kv1.1 mRNA translation, increases by 21days post-status epilepticus (SE), sustaining Kv1.1 mRNA translational repression. Our results suggest that following kainic-acid induced status epilepticus there are two phases of Kv1.1 repression: (1) an initial mTOR-dependent repression of Kv1.1 that is followed by (2) a miR-129-5p persistent reduction of Kv1.1. PMID- 25270295 TI - Diet, age, and prior injury status differentially alter behavioral outcomes following concussion in rats. AB - Mild traumatic brain injury (mTBI) or concussion affects a large portion of the population and although many of these individuals recover completely, a small subset of people experience lingering symptomology and poor outcomes. Little is known about the factors that affect individual susceptibility or resilience to poor outcomes after mTBI and there are currently no biomarkers to delineate mTBI diagnosis or prognosis. Based upon the growing literature associated with caloric intake and altered neurological aging and the ambiguous link between repetitive mTBI and progressive neurodegeneration, the current study was designed to examine the effect of a high fat diet (HFD), developmental age, and repetitive mTBI on behavioral outcomes following a mTBI. In addition, telomere length was examined before and after experimental mTBI. Sprague Dawley rats were maintained on a HFD or standard rat chow throughout life (including the prenatal period) and then experienced an mTBI/concussion at P30, P30 and P60, or only at P60. Behavioral outcomes were examined using a test battery that was administered between P61-P80 and included; beam-walking, open field, elevated plus maze, novel context mismatch, Morris water task, and forced swim task. Animals with a P30 mTBI often demonstrated lingering symptomology that was still present during testing at P80. Injuries at P30 and P60 rarely produced cumulative effects, and in some tests (i.e., beam walking), the first injury may have protected the brain from the second injury. Exposure to the high fat diet exacerbated many of the behavioral deficits associated with concussion. Finally, telomere length was shortened following mTBI and was influenced by the animal's dietary intake. Diet, age at the time of injury, and the number of prior concussion incidents differentially contribute to behavioral deficits and may help explain individual variations in susceptibility and resilience to poor outcomes following an mTBI. PMID- 25270296 TI - Factors associated with suicide in the month following contact with different types of health services in Quebec. AB - OBJECTIVE: The aim of the study was to identify factors associated with suicide death occurring in the month following an outpatient visit, emergency room contact, or hospitalization. METHODS: The results of this study are based on data for 8,851 individuals ages 11 years and older who died between January 1, 2000, and December 15, 2007, and whose death was confirmed as suicide by the coroner's office in Quebec, Canada. Health service use in the year prior to death was assessed by review of data from the province's public health insurance agency. Multivariate logistic regression models were used to assess the association of clinical and sociodemographic factors and the occurrence of suicide death in the month following versus more than one month after the last use of health services. RESULTS: A total of 81.6% of suicide decedents had consulted on an outpatient basis, 48.7% had visited an emergency department, and 28.5% were hospitalized in the year prior to death. Among individuals who had been discharged from an emergency department or a hospital closest to their death, 29.5% and 75.3%, respectively, died in the month following discharge. The most consistent modifiable factor associated with death in the month following last contact was number of outpatient consultations following discharge. CONCLUSIONS: Ensuring follow-up care after an emergency department visit or hospitalization may be associated with a longer period between discharge and suicide, allowing for more time to intervene and, possibly, prevent suicide. PMID- 25270293 TI - Side effects of cytokines approved for therapy. AB - Cytokines, currently known to be more than 130 in number, are small MW (<30 kDa) key signaling proteins that modulate cellular activities in immunity, infection, inflammation and malignancy. Key to understanding their function is recognition of their pleiotropism and often overlapping and functional redundancies. Classified here into 9 main families, most of the 20 approved cytokine preparations (18 different cytokines; 3 pegylated), all in recombinant human (rh) form, are grouped in the hematopoietic growth factor, interferon, platelet derived growth factor (PDGF) and transforming growth factor beta (TGFbeta) families. In the hematopoietin family, approved cytokines are aldesleukin (rhIL 2), oprelvekin (rhIL-11), filgrastim and tbo-filgrastim (rhG-CSF), sargramostim (rhGM-CSF), metreleptin (rh-leptin) and the rh-erythropoietins, epoetin and darbepoietin alfa. Anakinra, a recombinant receptor antagonist for IL-1, is in the IL-1 family; recombinant interferons alfa-1, alfa-2, beta-1 and gamma-1 make up the interferon family; palifermin (rhKGF) and becaplermin (rhPDGF) are in the PDGF family; and rhBMP-2 and rhBMP-7 represent the TGFbeta family. The main physicochemical features, FDA-approved indications, modes of action and side effects of these approved cytokines are presented. Underlying each adverse events profile is their pleiotropism, potency and capacity to release other cytokines producing cytokine 'cocktails'. Side effects, some serious, occur despite cytokines being endogenous proteins, and this therefore demands caution in attempts to introduce individual members into the clinic. This caution is reflected in the relatively small number of cytokines currently approved by regulatory agencies and by the fact that 14 of the FDA-approved preparations carry warnings, with 10 being black box warnings. PMID- 25270297 TI - Risk of venous thromboembolism in people with epilepsy. AB - OBJECTIVE: Risk of venous thromboembolism (VTE) among people with epilepsy (PWEs) has not been previously reported. Standard VTE prevention methods may increase the risk of complications in this population. This statewide study assessed the risk of VTE in PWEs. METHODS: Main risk categories were grouped into definite epilepsy (DE), probable epilepsy (PE), and migraine, a comparable neurologic condition. All inpatient, emergency department, and hospital-based outpatient encounters in South Carolina from January 1, 2000 through December 31, 2011, were evaluated for the primary outcome variable of VTE, defined as having a diagnosis of VTE at or after the diagnosis of epilepsy or migraine. Coagulopathies and common comorbidities of epilepsy were enumerated. Differences in VTE proportions were assessed using 95% confidence intervals (CIs). Association of VTE with epilepsy and migraine was evaluated with Cox proportional hazard modeling. RESULTS: A total of 138,497 people with migraine (PWMs) and 67,900 PWEs (32,186 DE, 35,714 PE) were included. VTE occurred in 2.7% of PWEs (4.2% among DE), and 0.6% of PWMs. The hazard ratio for VTE in DE compared with PWMs was 3.08 (95% CI 2.76-3.42), adjusted for all covariables. Higher numbers of comorbidities were strongly associated with VTE. PWE had higher numbers of comorbidities (52% with 2+ comorbidities versus 23% of PWM), but the impact of comorbidities on VTE risk was larger in PWM. SIGNIFICANCE: Higher VTE risk in PWE than PWM suggests risk factors associated with epilepsy, independent of chronic neurologic illness. VTE occurrence in PWE is comparable to published rates among people with cancer. PMID- 25270298 TI - Atypical birefringence pattern and the diagnostic ability of scanning laser polarimetry with enhanced corneal compensation in glaucoma. AB - PURPOSE: To evaluate the effect of typical scan score (TSS), when within the acceptable limits, on the diagnostic performance of retinal nerve fibre layer (RNFL) parameters with the enhanced corneal compensation (ECC) protocol of scanning laser polarimetry (SLP) in glaucoma. METHODS: In a cross-sectional study, 203 eyes of 160 glaucoma patients and 140 eyes of 104 control subjects underwent RNFL imaging with the ECC protocol of SLP. TSS was used to quantify atypical birefringence pattern (ABP) images. Influence of TSS on the diagnostic ability of SLP parameters was evaluated by receiver operating characteristic (ROC) regression models after adjusting for the effect of disease severity [based on mean deviation (MD)] on standard automated perimetry). RESULTS: Diagnostic abilities of all RNFL parameters of SLP increased when the TSS values were higher. This effect was statistically significant for TSNIT (coefficient: 0.08, p<0.001) and inferior average parameters (coefficient: 0.06, p=0.002) but not for nerve fibre indicator (NFI, coefficient: 0.03, p=0.21). In early glaucoma (MD of 5 dB), predicted area under ROC curve (AUC) for TSNIT average parameter improved from 0.642 at a TSS of 90 to 0.845 at a TSS of 100. In advanced glaucoma (MD of 15 dB), AUC for TSNIT average improved from 0.832 at a TSS of 90 to 0.947 at 100. CONCLUSION: Diagnostic performances of TSNIT and inferior average RNFL parameters with ECC protocol of SLP were significantly influenced by TSS even when the TSS values were within the acceptable limits. Diagnostic ability of NFI was unaffected by TSS values. PMID- 25270299 TI - Comparison of Laparoscopic and Open Cystopexy in a Cadaveric Canine Model. AB - OBJECTIVE: To describe a technique for laparoscopic cystopexy using knotless barbed suture and to compare this technique with traditional cystopexy using standard suture in a cadaveric canine model. STUDY DESIGN: Cadaveric study. ANIMALS: Male canine cadavers (n = 12). METHODS: Cadavers were randomly assigned to 2 groups: laparoscopic (n = 6) and open (n = 6) cystopexy. Laparoscopic cystopexy was performed intracorporeally using barbed, glycomer 631 suture. Open cystopexy was performed using standard glycomer 631 suture. Pre- and postoperative positive contrast cystography was performed in all dogs. Cystopexy procedure time, length and adherence, as well as number of bladder mucosal suture penetrations were compared between groups. RESULTS: Mean +/- SD cystopexy procedure time was 14.0 +/- 3.0 minutes and 5.2 +/- 0.5 minutes for the laparoscopic and open groups, respectively (P = .0007). Laparoscopic and open cystopexy lengths were 2.5 +/- 0.4 and 2.4 +/- 0.5 cm, respectively (P = .43). Partial suture pullout occurred in 1 dog in the laparoscopic group but subjective cystopexy adherence was adequate in all dogs. Bladder mucosal suture penetration occurred in 3 dogs in both groups (P = .86). Two of 6 cadavers with luminal suture penetration had minor contrast leakage on postoperative contrast cystography. Pre- and postoperative contrast cystography revealed appropriate bladder position in all cadavers. CONCLUSION: Laparoscopic cystopexy using knotless suture was comparable to an open cystopexy but was associated with a slightly longer procedure time and should be suitable for laparoscopic cystopexy in vivo. PMID- 25270300 TI - Improved assemblies using a source-agnostic pipeline for MetaGenomic Assembly by Merging (MeGAMerge) of contigs. AB - Assembly of metagenomic samples is a very complex process, with algorithms designed to address sequencing platform-specific issues, (read length, data volume, and/or community complexity), while also faced with genomes that differ greatly in nucleotide compositional biases and in abundance. To address these issues, we have developed a post-assembly process: MetaGenomic Assembly by Merging (MeGAMerge). We compare this process to the performance of several assemblers, using both real, and in-silico generated samples of different community composition and complexity. MeGAMerge consistently outperforms individual assembly methods, producing larger contigs with an increased number of predicted genes, without replication of data. MeGAMerge contigs are supported by read mapping and contig alignment data, when using synthetically-derived and real metagenomic data, as well as by gene prediction analyses and similarity searches. MeGAMerge is a flexible method that generates improved metagenome assemblies, with the ability to accommodate upcoming sequencing platforms, as well as present and future assembly algorithms. PMID- 25270301 TI - Author's reply: To PMID 25012060. PMID- 25270303 TI - Public-private partnerships in the response to HIV: experience from the resource industry in Papua New Guinea. AB - CONTEXT: Although Papua New Guinea (PNG) has made some progress in social development over the past 30 years, the country's Human Development Index has slowed in recent years, placing it below the regional average. In 2012, the estimated HIV prevalence for adults aged 15-49 years was 0.5% and an estimated 25,000 people were living with HIV. Although reduced from previous estimates, the country's HIV prevalence remains the highest in the South Pacific region. While the faith-based and non-governmental sectors have engaged in HIV interventions since the epidemic began, until recently the corporate sector has remained on the margins of the national response. In 2008, the country's largest oil and gas producer began partnering with national and provincial health authorities, development partners and global financing institutions to contribute to the national HIV strategy and implementation plan. This article provides an overview of public-private partnerships (PPPs) and their application to public health program management, and then describes the PPP that was developed in PNG. ISSUES: Innovative national and local PPPs have become a core component of healthcare strategy in many countries. PPPs have many forms and their use in low- and middle income countries has progressively demonstrated increased service outputs and health outcomes beyond what the public sector alone could achieve. A PPP in PNG has resulted in an oil and gas producer engaging in the response to HIV, including managing the country's US$46 million HIV grant from the Global Fund to Fight AIDS, Tuberculosis and Malaria. LESSONS LEARNED: Given the increasing expectations of the international community in relation to corporate responsibility and sustainability, the role of the corporate sector in countries like PNG is critical. Combining philanthropic investment with business strategy, expertise and organisational resource can contribute to enhancing health system structures and capacity. PMID- 25270302 TI - Quantitative contrast-enhanced ultrasonographic assessment of naturally occurring pancreatitis in dogs. AB - BACKGROUND: Quantitative contrast-enhanced ultrasonography (CEUS) can detect pancreatic perfusion changes in experimentally induced canine pancreatitis. However, its usefulness in detecting perfusion changes in naturally occurring pancreatitis is unclear. HYPOTHESIS/OBJECTIVES: To determine the feasibility of using CEUS to detect pancreatic and duodenal perfusion changes in naturally occurring canine pancreatitis. ANIMALS: Twenty-three client-owned dogs with pancreatitis, 12 healthy control dogs. METHODS: Dogs diagnosed with pancreatitis were prospectively included. CEUS of the pancreas and duodenum were performed. Time-intensity curves were created from regions of interest in the pancreas and duodenum. Five perfusion parameters were obtained for statistical analyses: time to initial up-slope, peak time (Tp), time to wash-out (TTW), peak intensity (PI), and area under the curve (AUC). RESULTS: For the pancreas, Tp of the pancreatitis group was prolonged when compared to controls (62 +/- 11 seconds versus 39 +/- 13 seconds; P < .001). TTW also was prolonged but not significantly (268 +/- 69 seconds versus 228 +/- 47 seconds; P = .47). PI and AUC were increased when compared to controls (95 +/- 15 versus 78 +/- 13 MPV; P = .009 and 14,900 +/- 3,400 versus 11,000 +/- 2,800 MPV*s; P = .013, respectively). For the duodenum, PI and AUC were significantly increased in the pancreatitis group when compared to controls. CONCLUSIONS AND CLINICAL IMPORTANCE: Contrast-enhanced ultrasonography can detect pancreatic perfusion changes in naturally occurring canine pancreatitis characterized by delayed peak with prolonged hyperechoic enhancement of the pancreas on CEUS. Additionally, duodenal perfusion changes secondary to pancreatitis were observed. PMID- 25270304 TI - [Ecchymosis during montelukast therapy: about one case]. AB - A young girl aged 13-years-old treated with montelukast, fluticasone/salmeterol, desloratadine, fluticasone furoate and salbutamol has presented numerous spontaneous bruises after that treatment with montelukast was substituted by the generic form. Stopping montelukast allow a significant improvement in bruises. PMID- 25270306 TI - Long-term community reintegration: concepts, outcomes and dilemmas in the case of a military service member with a spinal cord injury. AB - PURPOSE: Despite growing knowledge about medical and functional recovery in clinical settings, the long-term issue of community reintegration with a spinal cord injury (SCI) in the military context remains virtually unexamined. Thus, the U.S. Department of Defense created the SCI Qualitative Research Program to advance knowledge about service members' reintegration into civilian life. The purpose of this paper is to better characterize the long-term outcomes related to the community participation experienced and desired vis-a-vis a case study of a military veteran who suffered a service-related traumatic SCI. METHODS: An in depth anthropological interview was used with Jake, a 28-year old marine with a service-related C5/C6 SCI. Data were analyzed using content analysis. FINDINGS: Three significant themes were identified: opportunities for better engaging socially meaningful others may not be adequately included in so-called "client centered" interventions; how management of the social self in inter-personal interactions and public spaces is critical to gaining broader societal acceptance; and how meaningful age normative relationships and activities are essential to establish lasting inclusive social connections. CONCLUSIONS: Jake's case challenges existing models of rehabilitation predominantly focused on physical capacity building. Study findings point to the need for rehabilitation to invest more resources in efforts to address the existential and social elements of long-term social reintegration. Implications for Rehabilitation Both the veteran with SCI and their meaningful support network face challenges socially reintegrating after injury and rehabilitation. Empowering clients to envision future possibilities in terms of family, intimate relationships, and meaningful work are important to successful long-term social reintegration. Addressing the existential desires and social capacities of the individual may be as important as addressing physical functioning skills after SCI. PMID- 25270305 TI - The same self-peptide selects conventional and regulatory CD4+ T cells with identical antigen receptors. AB - The role of the T-cell receptor (TCR) in commitment of thymocytes to regulatory CD4(+)Foxp3(+) and conventional CD4(+)Foxp3(-) T-cell lineages remains controversial. According to the prevailing view, commitment to the former lineage, in contrast to the latter, requires that high affinity TCRs bind rare class II MHC/peptide complexes presented in 'thymic niches', which could explain differences between their TCR repertoires. Here we challenge this view and show that the binding of identical TCRs to the same ubiquitously expressed MHC/peptide complex often directs thymocytes to both CD4(+) lineages, indicating that the TCR affinity does not play the instructive role, and that restricted presentation of peptides in 'thymic niches' is not necessary for selection of CD4(+)Foxp3(+) T cells. However, depending on whether immature thymocytes bound the ligand predominantly with low or high affinity, the repertoires of regulatory and conventional CD4(+) T cells were correspondingly similar or mostly different, suggesting that negative rather than positive selection sets them apart. PMID- 25270307 TI - The effect of dual-task functional exercises on postural balance in adolescents with intellectual disability - a preliminary report. AB - PURPOSE: The study aimed to assess the effectiveness of an original intervention programme of unstable surface dual-task functional exercises on postural stability in adolescents with intellectual disability (ID). METHODS: A total of 34 adolescents with ID, aged 14-16 years, were engaged in our study. A 17-person experimental group (E) took part in a 12-week intervention programme which consisted of unstable surface functional exercises, designed after activities of daily living (ADLs). Another group of 17 youngsters constituted a control group (C). Within a span of 12 weeks, the postural stability assessment was conducted twice in both groups, employing a stabilometric platform ALFA AC International East. RESULTS: After taking part in the intervention programme, the experimental group (E) improved all their scores (p < 0.05). The path length of the COG and the time in which the dynamic test was performed were shorter in the experimental group (E), while the control group (C) scored worse in comparison with their initial results. CONCLUSIONS: A distinctly positive effect of unstable-surface dual-task functional exercises on postural stability in individuals with ID was also revealed in our tests. Implications for Rehabilitation Rehabilitation of intellectually disabled persons should be carried out individually and contain ADL-based exercises. The use of unstable surfaces, making the above training more difficult, naturally stimulates the trainee to focus more closely on the task being performed. Implementation of dual-task exercises, consisting in compiling functional tasks with balance training, in the intervention programme for adolescents with ID is likely to improve efficiency of their everyday living and the quality of their lives. PMID- 25270308 TI - D4 Receptor Activation Differentially Modulates Hippocampal Basal and Apical Dendritic Synapses in Freely Moving Mice. AB - Activation of D4 receptors (D4Rs) has been shown to improve cognitive performance, potentially affecting synaptic strength. We investigated the D4R agonist PD 168077 (PD) in hippocampal CA1 of freely moving mice. We electrically stimulated in stratum oriens (OR) or radiatum (RAD) and evoked local field potentials (LFPs). Intraperitoneally injected PD dose-dependently and reversibly attenuated LFPs for longer time in basal (OR) than apical (RAD) dendrites. High frequency stimulation induced LTP that was stronger and more stable in OR than RAD. LTP lasted at least 4 h during which the paired-pulse ratio remained reduced. A PD concentration not affecting synaptic transmission was sufficient to reduce LTP in OR but not in RAD. A PD concentration reducing synaptic transmission reduced the early phase LTP in OR additionally and the late phase LTP in RAD exclusively. Furthermore, cell type-specific expression of mCherry in DATCre mice generated fluorescence in dorsal CA1 that was highest in lacunosum moleculare and similar in OR/RAD, indicating that midbrain dopaminergic fibers distribute evenly in OR/RAD. Together, the D4R-mediated modulation of hippocampal synaptic transmission and plasticity is stronger in OR than RAD. This could affect information processing in CA1 neurons, since signals arriving via basal and apical afferents are distinct. PMID- 25270310 TI - Is the private sector a good thing for the NHS? PMID- 25270309 TI - The DCDC2 intron 2 deletion impairs illusory motion perception unveiling the selective role of magnocellular-dorsal stream in reading (dis)ability. AB - Developmental dyslexia (DD) is a heritable neurodevelopmental reading disorder that could arise from auditory, visual, and cross-modal integration deficits. A deletion in intron 2 of the DCDC2 gene (hereafter DCDC2d) increases the risk for DD and related phenotypes. In this study, first we report that illusory visual motion perception-specifically processed by the magnocellular-dorsal (M-D) stream is impaired in children with DD compared with age-matched and reading-level controls. Second, we test for the specificity of the DCDC2d effects on the M-D stream. Children with DD and DCDC2d need significantly more contrast to process illusory motion relative to their counterpart without DCDC2d and to age-matched and reading-level controls. Irrespective of the genetic variant, children with DD perform normally in the parvocellular-ventral task. Finally, we find that DCDC2d is associated with the illusory motion perception also in adult normal readers, showing that the M-D deficit is a potential neurobiological risk factor of DD rather than a simple effect of reading disorder. Our findings demonstrate, for the first time, that a specific neurocognitive dysfunction tapping the M-D stream is linked with a well-defined genetic susceptibility. PMID- 25270312 TI - Xuebijing attenuates hypotension through the upregulation of angiotensin II type 1 receptor-associated protein 1 in rats suffering from heat stroke. AB - In our previous study, we demonstrated that Xuebijing (XBJ), a traditional Chinese medicine, attenuates hypotension in rats suffering from heatstroke (HS). However, the underlying mechanisms have not yet been fully elucidated. Thus, the current study was carried out to investigate the mechanisms underlying the effects of XBJ on hypotension n rats suffering from HS. For this purpose, 72 anesthetized rats were randomized into 3 groups and intravenously injected twice daily for 3 days with XBJ (4 ml/kg body weight, XBJ group) or phosphate-buffered saline (PBS) (HS and sham-operated groups). Models of HS were established in the HS and XBJ groups by placing the rats in a simulated climate chamber with a temperature of 40C and a humidity of 60%. Rectal temperature, arterial pressure and heart rate were monitored and recorded. Angiotensin II (Ang II) levels were increased during HS (shown by ELISA), and XBJ had no apparent effect on Ang II levels. The levels of Ang II type 1 (AT1) receptor surface expression and AT1 receptor-associated protein 1 (Arap1) were decreased during HS; however, these effects were attenuated by pre-treatment with XBJ (shown by RT-qPCR and western blot analysis). For in vitro experiments, rat macrophages pre-treated with XBJ were stimulated with lipopolysaccharide (LPS). Pre-treatment with XBJ induced a marked inhibitory effect on the release of pro-inflammatory cytokines in the LPS stimulated macrophages. Furthermore, XBJ inhibited the activation of nuclear factor kappaB (NF-kappaB) induced by LPS in the macrophages. Taken together, our data demonstrate that XBJ promotes Arap1 expression by inhibiting the activation of the NF-kappaB signaling pathway and the release of pro-inflammatory cytokines, which may be the molecular mechanisms through which XBJ alleviates blood pressure reduction in rats suffering from HS. PMID- 25270314 TI - The role of mindfulness. PMID- 25270313 TI - Intraoperative molecular sentinel node analysis: the way of the future or great technology with limited indication? PMID- 25270315 TI - Mindfulness for surgeons. PMID- 25270316 TI - Shoelace technique plus vacuum-assisted closure in leg fasciotomy. PMID- 25270317 TI - Response to Re: Augmenting pancreatic anastomosis during whipple operation with fibrin glue: a beneficial technical modification? PMID- 25270318 TI - Re: Internal herniation of the caecum through the foramen of Winslow. PMID- 25270319 TI - Response to Re: Accuracy of visual prediction of pathology of colorectal polyps: how accurate are we? PMID- 25270320 TI - Pneumothorax complicating total extraperitoneal repair of inguinal hernia under combined spinal epidural anaesthesia. PMID- 25270321 TI - The future of surgical outpatients. PMID- 25270322 TI - Re: Barriers for students pursuing a surgical career and where the Surgical Interest Association can intervene. PMID- 25270323 TI - Rib plating of acute and sub-acute non-union rib fractures in an adult with cystic fibrosis: a case report. AB - BACKGROUND: Rib fractures associated with osteoporosis have been reported to occur ten times more frequently in adults with cystic fibrosis. Fractures cause chest pain, and interfere with cough and sputum clearance leading to worsened lung function and acute exacerbations which are the two main contributors to early mortality in cystic fibrosis. Usual treatment involves analgesics and time for healing; however considerable pain and disability result due to constant re injury from chronic repetitive cough. Recently, surgical plating of rib fractures has become commonplace in treating acute, traumatic chest injuries. We describe here successful surgical plating in a White cystic fibrosis patient with multiple, non-traumatic rib fractures. CASE PRESENTATION: A-37-year old White male with cystic fibrosis was readmitted to Intermountain Medical Center for a pulmonary exacerbation. He had developed localized rib pain while coughing 2 months earlier, with worsening just prior to hospital admission in conjunction with a "pop" in the same location while bending over. A chest computerized tomography scan at admission demonstrated an acute 5th rib fracture and chronic non-united 6th and 7th right rib fractures. An epidural catheter was placed both for analgesia and to make secretion clearance possible in preparation for the surgery performed 2 days later. Under general anesthesia, he had open reduction and internal fixation of the right 5th, 6th and 7th rib fractures with a Synthes Matrix rib set. After several days of increased oxygen requirements, fever, fluid retention, and borderline vital signs, he stabilized. Numerical pain rating scores from his ribs were lower post-operatively and he was able to tolerate chest physical therapy and vigorous coughing. CONCLUSIONS: In our case report, rib plating with bone grafting improved rib pain and allowed healing of the fractures and recovery, although the immediate post-op period required close attention and care. We believe repair may be of benefit in selected cystic fibrosis patients, such as our patient who had suffered multiple rib fractures that were healing poorly. PMID- 25270326 TI - Low back pain and postural control, effects of task difficulty on centre of pressure and spinal kinematics. AB - Association of low back pain and standing postural control (PC) deficits are reported inconsistently. Demands on PC adaptation strategies are increased by restraining the input of visual or somatosensory senses. The objectives of the current study are, to investigate whether PC adaptations of the spine, hip and the centre of pressure (COP) differ between patients reporting non-specific low back pain (NSLBP) and asymptomatic controls. The PC adaption strategies of the thoracic and lumbar spine, the hip and the COP were measured in fifty-seven NSLBP patients and 22 asymptomatic controls. We tested three "feet together" conditions with increasing demands on PC strategies, using inertial measurement units (IMUs) on the spine and a Wii balance board for centre of pressure (COP) parameters. The differences between NSLBP patients and controls were most apparent when the participants were blindfolded, but remaining on a firm surface. While NSLBP patients had larger thoracic and lumbar spine mean absolute deviations of position (MADpos) in the frontal plane, the same parameters decreased in control subjects (relative change (RC): 0.23, 95% confidence interval: 0.03 to 0.45 and 0.03 to 0.48). The Mean absolute deviation of velocity (MADvel) of the thoracic spine in the frontal plane showed a similar and significant effect (RC: 0.12 95% CI: 0.01 to 0.25). Gender, age and pain during the measurements affected some parameters significantly. PC adaptions differ between NSLBP patients and asymptomatic controls. The differences are most apparent for the thoracic and lumbar parameters of MADpos, in the frontal plane and while the visual condition was removed. PMID- 25270324 TI - Early pregnancy sex steroids and maternal risk of epithelial ovarian cancer. AB - Well-established associations between reproductive characteristics and epithelial ovarian cancer (EOC) support an involvement of sex steroid hormones in the etiology of EOC. Limited previous studies have evaluated circulating androgens and the risk of EOC, and estrogens and progesterone have been investigated in only one of the previous studies. Furthermore, there is little data on potential heterogeneity in the association between circulating hormones and EOC by histological subgroup. Therefore, we conducted a nested case-control study within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort to investigate the associations between circulating pre-diagnostic sex steroid concentrations and the histological subtypes of EOC. We identified 1052 EOC cases among cohort members diagnosed after recruitment (1975-2008) and before March 2011. Up to three controls were individually matched to each case (n=2694). Testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), progesterone, estradiol (E2), and sex hormone-binding globulin levels were measured in serum samples collected during the last pregnancy before EOC diagnosis. We used conditional logistic regression to estimate odds ratios (ORs) and 95% CIs. Associations between hormones and EOC differed with respect to tumor histology and invasiveness. Sex steroid concentrations were not associated with invasive serous tumors; however, doubling of testosterone and 17-OHP concentration was associated with approximately 40% increased risk of borderline serous tumors. A doubling of androgen concentrations was associated with a 50% increased risk of mucinous tumors. The risk of endometrioid tumors increased with higher E2 concentrations (OR: 1.89 (1.20-2.98)). This large prospective study in pregnant women supports a role of sex steroid hormones in the etiology of EOC arising in the ovaries. PMID- 25270327 TI - Gait attentional load at different walking speeds. AB - Gait is an attention-demanding task even in healthy young adults. However, scant evidence exists about the attentional load required at various walking speeds. The aim of this study was to investigate motor-cognitive interference while walking at spontaneous, slow and very slow speed on a treadmill while carrying out a backward counting task, in a group (n = 22) of healthy young participants. Cognitive performance was also assessed while sitting. Higher DT cost on the cognitive task was found at spontaneous and very slow walking speed, while at slow walking speed the cognitive task was prioritized with higher DT cost on the motor task. The attentional allocation during DT depends on walking speed with gait prioritization at spontaneous and very slow speed that likely represent more challenging motor conditions. PMID- 25270328 TI - Genetic barrier for attachment inhibitor BMS-626529 resistance in HIV-1 B and non B subtypes. AB - OBJECTIVES: The genetic barrier (defined as the number of genetic transitions/transversions needed to produce a resistance mutation) can differ between HIV-1 subtypes. The genetic barrier for the new attachment inhibitor BMS 626529 was evaluated in five HIV-1 subtypes. METHODS: Nine substitutions associated with BMS-626529 resistance at seven amino acid positions (116, 204, 375, 426, 434, 475 and 506) were analysed in 300 nucleotide sequences of the env gene encoding the gp120 protein from antiretroviral-naive patients (60 for each subtype and recombinant: B, C, D, CRF01_AE and CRF02_AG). RESULTS: Differently from the B subtype, some resistance mutations were found as natural polymorphisms in the C and D subtypes and the CRF02_AG and CRF01_AE recombinants for four positions of the env gene encoding the gp120 protein (375, 426, 434 and 475). The majority (five out of seven) of amino acid positions studied (116, 426, 434, 475 and 506) were relatively conserved (>63%) between the five HIV-1 subtypes, leading to a similar genetic barrier to mutations associated with resistance to BMS-626529. However, at positions 116 and 506 a minority of C and CRF02_AG subtypes had codons leading to a higher genetic barrier. Different predominant codons were observed at two out of seven positions (204 and 375) between the subtypes, with no effect on the calculated genetic barrier. However, for position 375, a minority of CRF02_AG sequences showed a lower genetic barrier to S375M/T resistance mutations. CONCLUSIONS: In non-B HIV-1 subtypes, four out of seven studied positions presented mutations implicated in BMS-626529 resistance. Despite great variability of the HIV-1 envelope, there was no major impact of polymorphisms on the genetic barrier to acquisition of BMS-626529 resistance. PMID- 25270329 TI - Alpha amylase assisted synthesis of TiO2 nanoparticles: structural characterization and application as antibacterial agents. AB - The enzyme alpha amylase was used as the sole reducing and capping agent for the synthesis of TiO2 nanoparticles. The biosynthesized nanoparticles were characterized by X-ray diffraction (XRD) and transmission electron microscopic (TEM) methods. The XRD data confirms the monophasic crystalline nature of the nanoparticles formed. TEM data shows that the morphology of nanoparticles depends upon the enzyme concentration used at the time of synthesis. The presence of alpha amylase on TiO2 nanoparticles was confirmed by FTIR. The nanoparticles were investigated for their antibacterial effect on Staphylococcus aureus and Escherichia coli. The minimum inhibitory concentration value of the TiO2 nanoparticles was found to be 62.50 MUg/ml for both the bacterial strains. The inhibition was further confirmed using disc diffusion assay. It is evident from the zone of inhibition that TiO2 nanoparticles possess potent bactericidal activity. Further, growth curve study shows effect of inhibitory concentration of TiO2 nanoparticles against S. aureus and E. coli. Confocal microscopy and TEM investigation confirm that nanoparticles were disrupting the bacterial cell wall. PMID- 25270330 TI - Mapping iron in human heart tissue with synchrotron x-ray fluorescence microscopy and cardiovascular magnetic resonance. AB - BACKGROUND: MRI assessment of cardiac iron is particularly important for assessing transfusion-dependent anaemia patients. However, comparing the iron distribution from histology or bulk samples to MRI is not ideal. Non-destructive, high-resolution imaging of post-mortem samples offers the ability to examine iron distributions across large samples at resolutions closer to those used in MRI. The aim of this ex vivo case study was to compare synchrotron X-ray fluorescence microscopy (XFM) elemental iron maps with magnetic resonance transverse relaxation rate maps of cardiac tissue samples from an iron-loaded patient. METHODS: Two 5 mm thick slices of formalin fixed cardiac tissue from a Diamond Blackfan anaemia patient were imaged in a 1.5 T MR scanner. R2 and R2* transverse relaxation rate maps were generated for both slices using RF pulse recalled spin echo and gradient echo acquisition sequences. The tissue samples were then imaged at the Australian Synchrotron on the X-ray Fluorescence Microscopy beamline using a focussed incident X-ray beam of 18.74 keV and the Maia 384 detector. The event data were analyzed to produce elemental iron maps (uncalibrated) at 25 to 60 microns image resolution. RESULTS: The R2 and R2* maps and profiles for both samples showed very similar macro-scale spatial patterns compared to the XFM iron distribution. Iron appeared to preferentially load into the lateral epicardium wall and there was a strong gradient of decreasing iron, R2 and R2* from the epicardium to the endocardium in the lateral wall of the left ventricle and to a lesser extent in the septum. On co-registered images XFM iron was more strongly correlated to R2* (r = 0.86) than R2 (r = 0.79). There was a strong linear relationship between R2* and R2 (r = 0.87). CONCLUSIONS: The close qualitative and quantitative agreement between the synchrotron XFM iron maps and MR relaxometry maps indicates that iron is a significant determinant of R2 and R2* in these ex vivo samples. The R2 and R2* maps of human heart tissue give information on the spatial distribution of tissue iron deposits. PMID- 25270331 TI - Population history and genomic signatures for high-altitude adaptation in Tibetan pigs. AB - BACKGROUND: The Tibetan pig is one of domestic animals indigenous to the Qinghai Tibet Plateau. Several geographically isolated pig populations are distributed throughout the Plateau. It remained an open question if these populations have experienced different demographic histories and have evolved independent adaptive loci for the harsh environment of the Plateau. To address these questions, we herein investigated ~ 40,000 genetic variants across the pig genome in a broad panel of 678 individuals from 5 Tibetan geographic populations and 34 lowland breeds. RESULTS: Using a series of population genetic analyses, we show that Tibetan pig populations have marked genetic differentiations. Tibetan pigs appear to be 3 independent populations corresponding to the Tibetan, Gansu and Sichuan & Yunnan locations. Each population is more genetically similar to its geographic neighbors than to any of the other Tibetan populations. By applying a locus specific branch length test, we identified both population-specific and -shared candidate genes under selection in Tibetan pigs. These genes, such as PLA2G12A, RGCC, C9ORF3, GRIN2B, GRID1 and EPAS1, are involved in high-altitude physiology including angiogenesis, pulmonary hypertension, oxygen intake, defense response and erythropoiesis. A majority of these genes have not been implicated in previous studies of highlanders and high-altitude animals. CONCLUSION: Tibetan pig populations have experienced substantial genetic differentiation. Historically, Tibetan pigs likely had admixture with neighboring lowland breeds. During the long history of colonization in the Plateau, Tibetan pigs have developed a complex biological adaptation mechanism that could be different from that of Tibetans and other animals. Different Tibetan pig populations appear to have both distinct and convergent adaptive loci for the harsh environment of the Plateau. PMID- 25270333 TI - Being perceived as 'a real woman' or following one's own convictions: a qualitative study to understand individual, family, and community influences on the place of childbirth in Busia, Kenya. AB - Despite potentially playing a key role in improving maternal and child health, including the prevention of mother-to-child transmission (PMTCT) of HIV, health facility delivery rates remain low in Kenya. Understanding how place of childbirth is determined is therefore important when developing interventions to improve safe motherhood and childbirth outcomes. As part of a qualitative study, we conducted 25 in-depth interviews with mothers (13) and healthcare staff (12) and held 10 focus group discussions with traditional birth attendants (6) and female relatives (4) in Busia, rural Kenya. Our findings show that mothers prefer facility delivery; however, the choice is not theirs alone but involves both their family and the community. Furthermore, facility delivery poses a risk of being viewed as disloyal to tradition and not 'a real woman', which causes a strained relationship between healthcare staff, family and the community. Our interpretation of the findings is that mothers feel trapped between loyalty to sociocultural norms and awareness of the benefits of facility delivery. Also, we believe healthcare staff's disinclination to recognise certain traditional birth attendant services as a potential asset poses a barrier to increased facility deliveries. Interventions to link traditional birth attendants with formal healthcare combined with sociocultural sensitivity training for healthcare staff may increase facility delivery and PMTCT. PMID- 25270332 TI - Diminazene aceturate liposomes: morphometric and biochemical liver, kidney, and spleen of rats infected with Trypanosoma evansi. AB - The aim of this study was to evaluate the effect of treatment with liposomal (L DMZ) and conventional (C-DMZ) diminazene aceturate formulations on hepatic and renal functions of rats, experimentally infected with Trypanosoma evansi. For this purpose, 72 Wistar rats (Rattus norvegicus) were divided into six groups (A, B, C, D, E, and F). Each group was subdivided into two other subgroups in order to assess the biochemical and histological results on days 7 and 40 post treatment (PT). Treatments were carried out based on two different therapeutic protocols: L-DMZ and C-DMZ at 3.5mg/kg(-1), single dose (groups C and D), and five successive doses within intervals of 24h (groups E and F). Groups A and B corresponded to uninfected and infected (without treatment) animals, respectively. Sample collections were held on days 7 and 40 PT for the assessment of hepatic [alkaline phosphatase (AP), alanine transferase (ALT), albumin, gamma glutamil transferase (GGT) and renal functions (creatinine and urea). Additionally, the histology of fragments of liver, kidney, and spleen was performed. Animals in group B showed a significant increase in AP, GGT, ALT, and urea when compared with group A. On day 7 post-inoculation (PI), the biochemical analysis showed a reduction (P<0.05) of AP and GGT, while the levels of urea were increased in groups C, D, E, F. On day 40 PT, ALT was increased in these same groups when compared with group A. In histopathology, changes in liver samples were observed on day 7 PT in groups D and F, especially regarding the area and density of the hepatocytes. Renal analysis exhibited changes in glomerular space, glomerular, and corpuscular areas in group E. Therefore, these results allowed us to conclude that the treatment with L-DMZ and C-DMZ led to variable biochemical changes, which defined the functions of the liver and kidneys of treated animals, since the main histopathology alterations were observed in animals treated with liposomes, at their higher dosages. Thus, treatments with L-DMZ and C-DMZ in five consecutive doses were effective although being followed by liver toxicity. PMID- 25270334 TI - Must every child with long QT syndrome take a beta blocker? AB - Long QT syndrome is the most commonly recognised cause of sudden cardiac death in children. With a prevalence of 1 in 2000, family screening is identifying large numbers of hitherto asymptomatic gene carriers in the community, about a third of whom have a normal QT interval. The mainstay of treatment is long term uninterrupted beta blocker therapy, a treatment with many potential side effects. This article reviews the evidence and suggests a cohort who may, after assessment in a specialised cardiac-genetic clinic, be spared this treatment because of very low baseline risk. These are asymptomatic boys and prepubertal girls with a heart rate corrected QT interval persistently less than 470 ms who do not indulge in high risk activities (especially swimming) and do not have a missense mutation in the c-loop region of the KCNQ1 (long QT 1) gene. PMID- 25270336 TI - Learning rate and temperament in a high predation risk environment. AB - Living in challenging environments can influence the behavior of animals in a number of ways. For instance, populations of prey fish that experience frequent, nonlethal interactions with predators have a high proportion of individuals that express greater reaction to risk and increased activity and exploration collectively known as temperament traits. Temperament traits are often correlated, such that individuals that are risk-prone also tend to be active and explore more. Spatial learning, which requires the integration of many sensory cues, has also been shown to vary in fish exposed to different levels of predation threat. Fish from areas of low predation risk learn to solve spatial tasks faster than fish from high predation areas. However, it is not yet known whether simpler forms of learning, such as learning associations between two events, are similarly influenced. Simple forms of associative learning are likely to be affected by temperament because a willingness to approach and explore novel situations could provide animals with a learning advantage. However, it is possible that routine-forming and inflexible traits associated with risk-prone and increased exploratory behavior may act in the opposite way and make risk prone individuals poorer at learning associations. To investigate this, we measured temperament in Panamanian bishop fish (Brachyrhaphis episcopi) sampled from a site known to contain many predators. The B. episcopi were then tested with an associative learning task. Within this population, fish that explored more were faster at learning a cue that predicted access to food, indicating a link between temperament and basic learning abilities. PMID- 25270335 TI - The dilemma of foraging herbivores: dealing with food and fear. AB - For foraging herbivores, both food quality and predation risk vary across the landscape. Animals should avoid low-quality food patches in favour of high quality ones, and seek safe patches while avoiding risky ones. Herbivores often face the foraging dilemma, however, of choosing between high-quality food in risky places or low-quality food in safe places. Here, we explore how and why the interaction between food quality and predation risk affects foraging decisions of mammalian herbivores, focusing on browsers confronting plant toxins in a landscape of fear. We draw together themes of plant-herbivore and predator-prey interactions, and the roles of animal ecophysiology, behaviour and personality. The response of herbivores to the dual costs of food and fear depends on the interplay of physiology and behaviour. We discuss detoxification physiology in dealing with plant toxins, and stress physiology associated with perceived predation risk. We argue that behaviour is the interface enabling herbivores to stay or quit food patches in response to their physiological tolerance to these risks. We hypothesise that generalist and specialist herbivores perceive the relative costs of plant defence and predation risk differently and intra specifically, individuals with different personalities and physiologies should do so too, creating individualised landscapes of food and fear. We explore the ecological significance and emergent impacts of these individual-based foraging outcomes on populations and communities, and offer predictions that can be clearly tested. In doing so, we provide an integrated platform advancing herbivore foraging theory with food quality and predation risk at its core. PMID- 25270337 TI - [Andersen-Tawil syndrome: a review of its clinical and genetic diagnosis with emphasis on cardiac manifestations]. AB - The Andersen-Tawil syndrome is a cardiac ion channel disease that is inherited in an autosomal dominant way and is classified as type 7 of the congenital long QT syndromes. Affected gene is KCNJ2, which forms the inward rectifier potassium channel designated Kir2.1. This protein is involved in stabilizing the resting membrane potential and controls the duration of the action potential in skeletal muscle and heart. It also participates in the terminal repolarization phase of the action potential in ventricular myocytes and is a major component responsible for the correction in the potassium current during phase 3 of the action potential repolarization. Kir 2.1 channel has a predominant role in skeletal muscle, heart and brain. Alterations in this channel produce flaccid paralysis, arrhythmias, impaired skeletal development primarily in extremities and facial area. In this review we address the disease from the point of view of clinical and molecular diagnosis with emphasis on cardiac manifestations. PMID- 25270338 TI - Pressure stabilizer for reproducible picoinjection in droplet microfluidic systems. AB - Picoinjection is a promising technique to add reagents into pre-formed emulsion droplets on chip however, it is sensitive to pressure fluctuation, making stable operation of the picoinjector challenging. We present a chip architecture using a simple pressure stabilizer for consistent and highly reproducible picoinjection in multi-step biochemical assays with droplets. Incorporation of the stabilizer immediately upstream of a picoinjector or a combination of injectors greatly reduces pressure fluctuations enabling reproducible and effective picoinjection in systems where the pressure varies actively during operation. We demonstrate the effectiveness of the pressure stabilizer for an integrated platform for on demand encapsulation of bacterial cells followed by picoinjection of reagents for lysing the encapsulated cells. The pressure stabilizer was also used for picoinjection of multiple displacement amplification (MDA) reagents to achieve genomic DNA amplification of lysed bacterial cells. PMID- 25270339 TI - Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: a TMA-based immunohistochemical study on 2,197 breast cancer patients. AB - Activated leukocyte cell adhesion molecule (ALCAM) is a membranous cell adhesion protein that is often expressed in breast cancer. Data on the prognostic impact of ALCAM expression is highly controversial in this cancer. To evaluate the clinical impact of ALCAM expression in a sufficiently large patient cohort, we utilized a tissue microarray (TMA) containing more than 2,100 primary breast cancers with clinical follow-up data by immunohistochemistry. TMA spots containing normal breast epithelium showed moderate to strong membranous ALCAM staining. ALCAM staining was strong in 66.2%, moderate in 10.9%, weak in 11.1% and absent in 11.8% of 1,778 (80.9%) interpretable breast cancer tissue spots. Decreased ALCAM expression was significantly associated with advanced tumor size (p=0.0017), unfavorable tumor grade (p<0.0001), negative ER and PR status (p<0.0001 each) as well as high Ki67 labeling index (p<0.0001). Cancers with ACLAM expression loss had a significantly poorer overall (p<0.0001) and disease specific survival (p=0.0088). This association also held true in the subset of nodal positive cancers (p<0.0001). In conclusion, these data demonstrate that ALCAM is generally expressed in normal and cancerous breast epithelium and that a marked reduction of ALCAM expression characterizes a subset of breast cancer patients with adverse tumor characteristics and unfavorable clinical outcome. PMID- 25270341 TI - Inhibition of the p38 MAPK pathway sensitizes human gastric cells to doxorubicin treatment in vitro and in vivo. AB - Gastric cancer is the second most common cause of cancer-related deaths worldwide. Doxorubicin-based chemotherapeutic regimes have been the mainstay of systemic treatment for disseminated gastric cancer for numerous years. However, the efficacy of doxorubicin is severely limited due to chemoresistance. Chemoresistance is a tightly regulated process, under the control of numerous signal transduction pathways. Amongst these, the mitogen-activated protein kinase (MAPK) pathway has received much attention. This study assessed whether the p38 MAPK pathway is involved in doxorubicin resistance in gastric cancer cells. Doxorubicin alone or combined with the p38 MAPK pathway inhibitor SB203580 was used to treat gastric cancer cells (SGC7901 and BGC823 lines). The effect of doxorubicin on the growth and apoptosis of gastric cancer cells in the presence or absence of SB203580 was investigated by western blot analysis, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst staining, Annexin V-FITC/propidium iodide staining followed by flow cytometry analysis, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Next, the effects of doxorubicin and SB203580, on the sensitivity of BGC-823 cells were assessed in a tumor xenograft model. The results showed that the p38 MAPK inhibitor significantly increases gastric cancer cell sensitivity to doxorubicin. Doxorubicin in combination with SB203580 significantly reduced cell viability (P<0.01) and increased cell death (P<0.01), which may be associated with the inactivation of the p38 MAPK signaling pathway, followed by the induced expression of the pro-apoptotic protein Bax and a concomitant decrease in Bcl-2 expression. These findings suggest that p38 MAPK is involved in gastric cancer cell survival, and that the inhibition of p38 MAPK signaling can reduce the tolerance of gastric cancer cells to doxorubicin treatment. PMID- 25270342 TI - Geographically weighted regression of land cover determinants of Plasmodium falciparum transmission in the Ashanti Region of Ghana. AB - BACKGROUND: Malaria is a mosquito-borne parasitic disease that causes severe mortality and morbidity, particularly in Sub-Saharan Africa. As the vectors predominantly bite between dusk and dawn, risk of infection is determined by the abundance of P. falciparum infected mosquitoes in the surroundings of the households. Remote sensing is commonly employed to detect associations between land use/land cover (LULC) and mosquito-borne diseases. Due to challenges in LULC identification and the fact that LULC merely functions as a proxy for mosquito abundance, assuming spatially homogenous relationships may lead to overgeneralized conclusions. METHODS: Data on incidence of P. falciparum parasitaemia were recorded by active and passive follow-up over two years. Nine LULC types were identified through remote sensing and ground-truthing. Spatial associations of LULC and P. falciparum parasitaemia rate were described in a semi parametric geographically weighted Poisson regression model. RESULTS: Complete data were available for 878 individuals, with an annual P. falciparum rate of 3.2 infections per person-year at risk. The influences of built-up areas (median incidence rate ratio (IRR): 0.94, IQR: 0.46), forest (median IRR: 0.9, IQR: 0.51), swampy areas (median IRR: 1.15, IQR: 0.88), as well as banana (median IRR: 1.02, IQR: 0.25), cacao (median IRR: 1.33, IQR: 0.97) and orange plantations (median IRR: 1.11, IQR: 0.68) on P. falciparum rate show strong spatial variations within the study area. Incorporating spatial variability of LULC variables increased model performance compared to the spatially homogenous model. CONCLUSIONS: The observed spatial variability of LULC influence in parasitaemia would have been masked by traditional Poisson regression analysis assuming a spatially constant influence of all variables. We conclude that the spatially varying effects of LULC on P. falciparum parasitaemia may in fact be associated with co-factors not captured by remote sensing, and suggest that future studies assess small-scale spatial variation of vegetation to circumvent generalised assumptions on ecological associations that may in fact be artificial. PMID- 25270343 TI - Reappraisal of evidence of microscopic portal vein involvement by hepatocellular carcinoma cells with stratification of tumor size. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death internationally, it is necessary to reappraise evidences of HCC cells involving the portal vein, especially considering tumor size. MATERIALS AND METHODS: Histopathological evidence and dynamic evidences of radiology and cytology from publication were collected and analyzed. RESULTS: Frequencies of microscopic portal vein involvement (MPVI) and microscopic intrahepatic metastasis (MIM) in resected specimens with single nodule HCC were lower than that of multi nodule HCC, although not significantly. Early HCC (<=1.5 cm) was with extremely low to 0 frequencies of MPVI and MIM. HCC >5 cm showed a tendency of flowing HCC cells into portal vein, which was coincident with significantly high frequency (64.1 %) of MPVI for HCC >5 cm. There were no significant difference of frequencies of MPVI and MIM between groups of tumor <=2, <=3, and <=5 cm. CONCLUSIONS: Single nodule HCC >5 cm needs anatomic resection and the root of portal vein should be firstly ligated because of tendency of flowing HCC cells into portal vein. For single nodule HCC <=2 cm, there was a risk of about 16.2 % of MPVI, and a risk of about 16.2-26.4 % of MPVI for those single nodule HCC <=5 cm, however, there was a risk of extremely low to 0 of MPVI for early HCC (<=1.5 cm). Surgeons have to balance liver reserve and risk of MPVI for HCC <=5 cm before deciding anatomic or nonanatomic resection. PMID- 25270344 TI - Resection margin clearance in pancreatic cancer after implementation of the Leeds Pathology Protocol (LEEPP): clinically relevant or just academic? AB - BACKGROUND AND OBJECTIVES: The aim of this study was to assess the overall survival (OS) after R0/R1 resections in patients with pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head after implementation of a standardized histopathologic protocol (Leeds Pathology Protocol, LEEPP). METHODS: One hundred and twenty-five patients underwent surgical resection because of PDAC of the pancreatic head. Patients were histopathologically examined according to a standardized protocol. Their oncologic outcome and clinicopathologic data were compared with those of a patient group before implementation of the LEEPP (n = 116). RESULTS: The R1 rate increased significantly from 13 to 52 %. There was no significant difference in OS between R0 and R1 resections. The median OS in patients with a tumor clearance of less than 2 mm from the resection margin was 15.1 months (12.1-18.1 months) versus 22.2 months (7.8-36.7 months) (P = 0.046). Multivariate analysis revealed a margin clearance or 2 mm and more as an independent prognosticator for OS. CONCLUSIONS: With applying the LEEPP, there was still no significant correlation between the R-status and OS in patients with PDAC. However, since a margin clearance of 2 mm or more is a predictive factor for OS, the R1 definition might have to be adapted in PDAC. PMID- 25270345 TI - Clinicopathologic analysis of gastrointestinal stromal tumors in duodenum and small intestine. AB - BACKGROUND: The prognosis about duodenal GISTs is debatable. The purpose of this study is to compare the characteristics and the prognostic factors in patients with gastrointestinal stromal tumor (GIST) located in the duodenum with those located in the small intestine. METHODS: One hundred-one patients with GIST located in the duodenum (n = 40), or small intestine (n = 61) underwent resection between 1996 and 2010. We analyzed clinicopathologic features, surgical outcomes, and prognostic factors. RESULTS: Five-year survival rate in patients with GIST located in the duodenum and small intestine were 66.6 and 80.8%, respectively (p = 0.018). After survival analysis, high mitotic count and tumor rupture were identified as independent adverse prognostic factors. Advanced T stage and absence of adjuvant imatinib treatment were adverse prognostic factors with marginal statistical significance. The rate of progressive disease was significantly higher in patients with duodenal GISTs (36.8%) than in those with small intestinal GIST (29.6%) (p = 0.024). CONCLUSIONS: The clinicopathologic findings of duodenal GIST differ from those of small intestinal GIST. Patients with duodenal GIST have a worse prognosis than those with small intestinal GIST. Aggressive treatment including surgical resection should be considered for duodenal GIST, even if the risk is relatively low. PMID- 25270346 TI - Does prior percutaneous endoscopic gastrostomy alter post-operative outcome after esophagectomy. AB - BACKGROUND: With the introduction of neoadjuvant chemoradiotherapy in patients with esophageal carcinoma, nutritional access has become essential to counter deleterious effects of dysphagia. Current NCCN guidelines do not recommend PEG prior to esophagectomy in these patients, but there is little evidence for this recommendation. The objective of this study was to compare outcomes in patients who underwent esophagectomy with or without prior PEG placement. METHODS: We retrospectively reviewed 96 patients who underwent esophagectomy between 2005 and 2012 for esophageal carcinoma. Patients were divided into two groups; Group I (PEG +ve) and Group II (PEG -ve). Patient characteristics, operative variables, and post-operative complications were compared. chi (2) and Fisher's test were used for categorical, while t test was used for interval variables. RESULTS: Median age was 51(18-70) years. Lower thoracic tumors were more common in Group I (69 vs. 63 %) (P = 0.04) and more patients underwent minimally invasive surgery in this group (50 vs. 2.6 %) (P < 0.0001). Mean blood loss (326 vs. 465 ml) (P = 0.02) and ICU stay (1.6 vs. 4.3 days) (P = 0.01) were significantly lower in Group I. There was no 30-day mortality in Group I versus 10.5 % in Group II (P = 0.01). No significant difference in anastomotic leak and stricture rate was observed. Gastric conduit was used in all patients for reconstruction. One patient had malignancy in PEG site biopsy. CONCLUSION: Percutaneous endoscopic gastrostomy before esophagectomy is safe and does not adversely impact post operative outcomes. PMID- 25270347 TI - The role of preoperative biliary drainage in severely jaundiced patients. PMID- 25270348 TI - Costs and cost-effectiveness of pediatric inguinal hernia repair in Uganda. AB - BACKGROUND: Surgically treatable diseases contribute approximately 11% of disability-adjusted life years (DALYs) worldwide yet they remain a neglected public health priority in low- and middle-income countries (LMICs). Pediatric inguinal hernia is the most common congenital abnormality in newborns and a major cause of morbidity and mortality yet elective repair remains largely unavailable in LMICs. This study is aimed to determine the costs and cost-effectiveness of pediatric inguinal hernia repair (PIHR) in a low-resource setting. METHODS: Medical costs of consecutive elective PIHRs were recorded prospectively at two centers in Uganda. Decision modeling was used to compare two different treatment scenarios (adoption of PIHR and non-adoption) from a provider perspective. A Markov model was constructed to estimate health outcomes under each scenario. The robustness of the cost-effectiveness results in the base case analysis was tested in one-way and probabilistic sensitivity analysis. The primary outcome of interest was cost per DALY averted by the intervention. RESULTS: Sixty-nine PIHRs were performed in 65 children (mean age 3.6 years). Mean cost per procedure was $86.68 US (95% CI 83.1-90.2 USD) and averted an average of 5.7 DALYs each. Incremental cost-effectiveness ratio was $12.41 per DALY averted. The probability of cost-effectiveness was 95% at a cost-effectiveness threshold of $35 per averted DALY. Results were robust to sensitivity analysis under all considered scenarios. CONCLUSION: Elective PIHR is highly cost-effective for the treatment and prevention of complications of hernia disease even in low-resource settings. PIHR should be prioritized in LMICs alongside other cost-effective interventions. PMID- 25270349 TI - Choroid plexus tumor epidemiology and outcomes: implications for surgical and radiotherapeutic management. AB - Choroid plexus tumors (CPTs) are rare neoplasms of the central nervous system whose optimal management is not well defined. The Surveillance Epidemiology and End Results (SEER) Database from 1978 to 2009 was queried to define population based outcomes for all patients with CPTs. Patient demographic data, histological classification (choroid plexus papilloma [CPP], atypical CPP [aCPP], and choroid plexus carcinoma [CPC]), extent of surgery, and use of radiation therapy (RT) as part of an initial course of therapy were analyzed for impact on overall survival (OS) and cause-specific survival (CSS). Chemotherapy data were not available within the SEER database. A total of 349 patients with CPTs were identified (120 CPCs, 26 aCPPs, and 203 CPPs). Patients with CPC presented at a younger age (median 3, mean 14.8 years) relative to CPP (median 25, mean 28.4 years; p < 0.0001). Histology was a significant predictor of OS, with 5-year OS rates of 90, 77, and 58 % for CPP, aCPP, and CPC, respectively. Older age and male sex were prognostic for worse OS and CSS for CPP. Only extent of surgery had a significant impact on survival for CPC. The use of adjuvant RT in patients with CPC undergoing surgery was not associated with a significantly improved OS (p = 0.17). For patients undergoing GTR without RT as part of an initial course of therapy, estimated 5- and 10-year OS were 70 % (+/-7 %) and 67 % (+/-8 %), respectively. Prospective data are required to define the optimal combination of surgery with adjuvant therapies, including chemotherapy. PMID- 25270350 TI - Split of Descemet's membrane and pre-Descemet's layer in fungal keratitis: new definition of corneal anatomy incorporating new knowledge of fungal infection. PMID- 25270352 TI - The benefits of compression methods in acoustic coherence tomography. AB - Pulse compression methods improve the quality of ultrasonic medical images. In comparison with standard broadband pulse techniques, these methods enhance the contrast-to-noise ratio (CNR) and increase the probing depth without any perceptible loss of spatial resolution. The Golay compression technique is analyzed here in the context of ultrasonic computed tomography, first on a one dimensional target and second on a very low-contrast phantom probed using a half ring array tomograph. The imaging performances were assessed based on the image CNR. The improvement obtained (up to 40%) depends, however, on the number of coherently associated diffraction projections. Beyond a certain number, few advantages were observed. Advances in ultrasound computed tomography suggest that pulse compression methods should provide a useful means of optimizing the trade off between the image quality and the probing sampling density. PMID- 25270353 TI - Aspergillus fumigatus proteases, Asp f 5 and Asp f 13, are essential for airway inflammation and remodelling in a murine inhalation model. AB - BACKGROUND: In susceptible individuals, exposure to Aspergillus fumigatus can lead to the development of atopic lung diseases such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). Protease allergens including Asp f 5 and Asp f 13 from Aspergillus fumigatus are thought to be important for initiation and progression of allergic asthma. OBJECTIVE: To assess the importance of secreted protease allergens Asp f 5 (matrix metalloprotease) and Asp f 13 (serine protease) in Aspergillus fumigatus-induced inflammation, airway hyperactivity, atopy and airway wall remodelling in a murine model following chronic exposure to secreted allergens. METHODS: BALB/c mice were repeatedly intranasally dosed over the course of 5 weeks with culture filtrate from wild-type (WT), Asp f 5 null (?5) or Asp f 13 null (?13) strains of Aspergillus fumigatus. Airway hyper-reactivity was measured by non-invasive whole body plethysmography, Th2 response and airway inflammation by ELISA and cell counts, whilst airway remodelling was assessed by histological analysis. RESULTS: Parent WT and ?5 culture filtrates showed high protease activity, whilst protease activity in ?13 culture filtrate was low. Chronic intranasal exposure to the three different filtrates led to comparable airway hyper-reactivity and Th2 response. However, protease allergen deleted strains, in particular ?13 culture filtrate, induced significantly less airway inflammation and remodelling compared to WT culture filtrate. CONCLUSION: Aspergillus fumigatus-secreted allergen proteases, Asp f 5 and Asp f 13, are important for recruitment of inflammatory cells and remodelling of the airways in this murine model. However, deletion of a single allergen protease fails to alleviate airway hyper-reactivity and allergic immune response. Targeting protease activity of Aspergillus fumigatus in conditions such as SAFS or ABPA may have beneficial effects in preventing key aspects of airway pathology. PMID- 25270354 TI - Preclinical evaluation of recombinant T cell receptor ligand RTL1000 as a therapeutic agent in ischemic stroke. AB - Recombinant T cell Receptor Ligand 1000 (RTL1000), a partial human major histocompatibility complex (MHC) molecule coupled to a human myelin peptide, reduces infarct size after experimental stroke in HLA-DRB1*1502 transgenic (DR2 Tg) mice. In this study, we characterized the therapeutic time window of opportunity for RTL1000; we explored the efficacy of a single dose of RTL1000 administration and determined if RTL1000 affords long-term neurobehavioral functional improvement after ischemic stroke. Male DR2-Tg mice underwent 60 min of intraluminal reversible middle cerebral artery occlusion (MCAO). RTL1000 or vehicle was injected 4, 6, or 8 h after MCAO, followed by three daily injections. In the single-dose study, one-time injection of RTL1000 was applied 4 h after MCAO. Cortical, striatal, and hemispheric infarct sizes were measured 24 or 96 h after stroke. Behavioral testing, including neuroscore evaluation, open field, paw preference, and novel object recognition, was performed up to 28 days after stroke. Our data showed that RTL1000 significantly reduced the infarct size 96 h after MCAO when the first injection was given at 4 and 6 h, but not 8 h, after the onset of stroke. A single dose of 400 or 100 MUg RTL1000 also significantly reduced the infarct size 24 h after MCAO. Behavioral testing showed that RTL1000 treatment used 4 h after MCAO improved long-term cognitive outcome 28 days after stroke. Taken together, RTL1000 protects against acute injury if applied within a 6-h time window and improves long-term functional recovery after experimental stroke in DR2-Tg mice. PMID- 25270355 TI - Diagnostic utility of musculoskeletal ultrasound in patients with suspected arthritis--a probabilistic approach. AB - INTRODUCTION: This study aimed to assess the utility of musculoskeletal ultrasound (MSUS) in patients with joint symptoms using a probabilistic approach. METHODS: One hundred and three patients without prior rheumatologic diagnosis and referred to our clinic for evaluation of inflammatory arthritis were included. Patients were assessed clinically including joint examination, laboratory testing including acute-phase reactants, rheumatoid factor (RF) and anti citrulinated protein antibody (ACPA), and radiographs of hands and feet if clinically indicated. A diagnostic assessment was then performed by the responsible rheumatologist where the probability of a) any inflammatory arthritis and b) rheumatoid arthritis was given on a 5-point scale ranging from 0 to 20% up to 80 to 100% probability. Subsequently, an ultrasound examination of the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP) joints 2 to 5 in both hands, metatarsophalangeal (MTP) joints 2 to 5 in both feet and any symptomatic joints was performed and the results presented to the same rheumatologist. The latter then assessed the diagnostic probabilities again, using the same scale. RESULTS: The rheumatologists' certainty for presence/absence of inflammatory arthritis and rheumatoid arthritis was increased significantly following ultrasound performance. The proportion of patient for whom diagnostic certainty for inflammatory arthritis was maximal was 33.0% before and 71.8% after musculoskeletal ultrasound (P <0.001). With regard to a diagnosis of RA, the proportions were 31.1% pre-test and 61.2% post-test (P <0.001). MSUS findings agreed with the final diagnosis in 95% of patients. CONCLUSION: Musculoskeletal ultrasound, when added to routine rheumatologic investigation, greatly increases the diagnostic certainty in patients referred for the evaluation of inflammatory arthritis. The changes from pre-test to post-test probability quantify the diagnostic utility of musculoskeletal ultrasound in probabilistic terms. PMID- 25270356 TI - Parenting stress: a cross-sectional analysis of associations with childhood obesity, physical activity, and TV viewing. AB - BACKGROUND: Parents influence their children's obesity risk through feeding behaviours and modeling of weight-related behaviours. Little is known about how the general home environment, including parental stress, may influence children's weight. The objective of this study was to explore the association between parenting stress and child body mass index (BMI) as well as obesity risk factors, physical activity and television (TV) viewing. METHODS: We used cross-sectional data from 110 parent-child dyads participating in a community-based parenting intervention. Child heights and weights were measured by trained research assistants. Parents (93% mothers) reported level of parenting stress via the Parenting Stress Index- Short Form (PSI-3-SF) as well as children's activity behaviours and TV viewing. This was an ethnically diverse (55% Hispanic/Latino, 22% Black), low-income (64% earning < $45,000/year) sample. RESULTS: Level of parenting stress was not associated with children's risk of being overweight/obese. Children with highly stressed parents were less likely to meet physical activity guidelines on weekdays than children with normally stressed parents (OR = 0.33, 95% CI, 0.12-0.95). Parents experiencing high stress were less likely to set limits on the amount of TV their children watched (OR = 0.32, 95% CI, 0.11, 0.93). CONCLUSION: Results suggest stress specific to parenting may not be associated with increased obesity risk among children. However, future interventions may need to address stress as a possible underlying factor associated with unhealthful behaviours among preschoolers. PMID- 25270357 TI - Predictive factors and outcomes of cochlear implantation in patients with connexin 26 mutation: a comparative study. AB - PURPOSE: To compare hearing outcomes in patients with connexin 26 (Cx 26) mutations undergoing cochlear implantation to age matched controls and to examine whether age at implantation, gender and type of mutation were correlated with hearing outcome. MATERIALS AND METHODS: Retrospective chart review of 21 patients with Cx 26 mutations that underwent cochlear implantation compared to 18 age matched controls. Patients' characteristics, type of mutation and pre- and postoperative short and long-term hearing thresholds, word and sentence scores were analyzed. RESULTS: There was no statistically significant difference between the Cx 26 and control group in the mean short term and mean long term post operative pure tone averages (PTA), speech reception thresholds (SRT), word and sentence scores. Gender, age at implantation and type of connexin 26 mutation did not predict hearing outcomes. CONCLUSIONS: In patients with connexin 26 mutation, cochlear implantation provides an effective mean of auditory habilitation. Mutational status, age and gender do not seem to predict hearing outcomes. PMID- 25270359 TI - Halogen bonds in organic synthesis and organocatalysis. AB - In contrast to hydrogen bonding, halogen bonding has so far found very little use in organic synthesis and organocatalysis. Although there are multiple reports on the use of elemental iodine in a wide range of organic reactions, the understanding of the actual mode of activation in these cases is very rudimentary. Recently, first proof-of-principle reactions have been established towards the use of carbon-based halogen-bond donors as activators or organocatalysts. These halogen-based Lewis acids offer more structural variety and potential than elemental iodine itself, and the mode of activation is better understood. Yet, the reported cases still only cover simple benchmark reactions, and there is a clear need for further and more complex applications. PMID- 25270360 TI - Anthelmintic resistance in sheep gastrointestinal nematodes in Slovakia detected by in-vitro methods. AB - BACKGROUND: The intensive use of anthelmintics for the control of helminthic infections has resulted in the development of anthelmintic resistance, which has become a major practical problem in many countries. A variety of tests are available to monitor anthelmintic resistance but most of them are expensive, laborious and time consuming and therefore unpractical for large field surveys. The main aim of this survey was thus to detect the occurrence of benzimidazole (BZ) and macrocyclic lactone resistance on sheep farms in Slovakia by using novel and modified in vitro methods that are inexpensive, easy to use and quick and therefore practical for large surveys. RESULTS: BZ-resistant gastrointestinal nematodes were found on all 27 farms. Two farms (7.4%) had high levels of resistance (>40% of hatching), and 22 farms had low levels (<20% of hatching) of resistant nematodes. IVM-resistant populations were found on 14 of 49 sheep farms. The prevalence of BZ and IVM resistance has slightly increased on Slovak sheep farms during the last two decades. CONCLUSIONS: Both the BZ and IVM surveys indicated that resistance against anthelmintics was present on Slovak sheep farms. Resistance against the BZ class of anthelmintics had been stable for two decades, but a slight increase on IVM resistance was confirmed. Farmers must thus observe the preventive measures to avoid a faster onset of IVM resistance, otherwise the presence of resistant parasites and ineffective treatment may harm the economy of their farms. PMID- 25270362 TI - Evolutionary game theory: cells as players. AB - In two papers we review game theory applications in biology below the level of cognitive living beings. It can be seen that evolution and natural selection replace the rationality of the actors appropriately. Even in these micro worlds, competing situations and cooperative relationships can be found and modeled by evolutionary game theory. Also those units of the lowest levels of life show different strategies for different environmental situations or different partners. We give a wide overview of evolutionary game theory applications to microscopic units. In this first review situations on the cellular level are tackled. In particular metabolic problems are discussed, such as ATP-producing pathways, secretion of public goods and cross-feeding. Further topics are cyclic competition among more than two partners, intra- and inter-cellular signalling, the struggle between pathogens and the immune system, and the interactions of cancer cells. Moreover, we introduce the theoretical basics to encourage scientists to investigate problems in cell biology and molecular biology by evolutionary game theory. PMID- 25270361 TI - A phase I dose-escalation study to a predefined dose of a transforming growth factor-beta1 monoclonal antibody (TbetaM1) in patients with metastatic cancer. AB - Transforming growth factor beta (TGF-beta) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-beta ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TbetaM1 is a humanized mAb optimized for neutralizing activity against TGF-beta1. The objective of this clinical trial was to assess the safety and tolerability of TbetaM1 in patients with metastatic cancer. In this phase I, uncontrolled, non randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of <= 2 on the ECOG scale were administered TbetaM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TbetaM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TbetaM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-beta1 expression signature in patients' whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study. PMID- 25270363 TI - ALDH1 is a prognostic factor for patients treated with neoadjuvant chemoradiotherapy and radical resection for stage III rectal cancer. AB - BACKGROUND AND OBJECTIVES: The factors relating to changes within a tumor after preoperative chemoradiotherapy associated with rectal cancer prognosis remain to be determined. The aim of this study was to investigate the expression of CD133 and ALDH1 and to analyze the predictive and prognostic roles in patients with rectal cancer after chemoradiotherapy. METHODS: We analyzed the expression levels of ALDH1 and CD133 in patients with middle and lower rectal cancers who underwent preoperative chemoradiotherapy between March 2005 and December 2011. RESULTS: The expression of CD133 was not associated with survival. The 5-year overall survival rates were lower in patients with high ALDH1 expression compared to low ALDH1 expression in stage III rectal cancer (61.0% vs. 89.7%, P=0.031). Cox multivariate analysis demonstrated that high ALDH1 expression (HR, 5.425; 95% CI, 1.116-26.373; P=0.036), cT (HR, 12.861; 95% CI, 2.188-75.591; P=0.005), and pN2 (HR, 28.481; 95% CI, 4.757-170.518; P<0.001) were independently associated with overall survival in 51 patients with stage III rectal cancer. CONCLUSIONS: Expression of ALDH1 indicates a more aggressive feature of stage III rectal cancer and can stratify stage III rectal cancer into different survival groups. PMID- 25270364 TI - Navigational memory functional magnetic resonance imaging: a test for concussion in children. AB - Concussions are high incidence injuries with potentially devastating consequences. Youths are at risk because of a higher threat of repeated injury, and cumulative effects of concussions exist, making accurate diagnosis and follow up essential. This study examines a navigational memory functional magnetic resonance imaging (fMRI) task to determine whether activation differences exist between children with concussion and uninjured controls. Fifty adolescents were recruited-35 controls and 15 with concussion. All subjects underwent structural and fMRI testing using our navigational memory task, and a battery of neuropsychological testing. The activation patterns of the 15 subjects with concussion were compared with those of 15 age and sex-matched controls. Subtraction and regression analyses were performed using the matched controls along with scatter-plots using means and 95% quantiles of the 35 controls. While no differences were seen with neuropsychological testing or task performance, subjects with concussion had significantly diminished activation in the retrosplenial, thalamic, and parahippocampal areas bilaterally, along with the right dorsolateral prefrontal cortex and left precuneus. Interestingly, they had increased activation in the left hippocampus and right middle temporal gyrus. Regression analysis demonstrated negative correlations between activation and post-concussive symptoms in the left premotor cortex, superior and inferior parietal lobules, and parahippocampal gyrus. Subjects with concussion show both diminished and increased activation in specific cerebral regions, differentiating them from controls. This is one of the first studies to look at such a task using fMRI and its applicability in testing for concussion in children. These findings support navigational memory fMRI as a potential objective test for concussions. PMID- 25270365 TI - Distribution of selected carcinogenic hydrocarbon and heavy metals in an oil polluted agriculture zone. AB - Owing to the importance of clean and fertile agricultural soil for the continued existence of man, this study investigated the concentrations of total petroleum hydrocarbons (TPHs), polycyclic aromatic hydrocarbons (PAHs) and some heavy metals in soils and selected commonly consumed vegetables and tubers from oil polluted active agricultural farmland in Gokana of Ogoniland, Rivers State, Nigeria. Samples from Umuchichi, Osisioma Local Government Area in Abia State, Nigeria, a non-oil-polluted area constituted the control. In test and control, up to 3,830 +/- 19.6 mgkg(-1) dw and 6,950 +/- 68.3 mgkg(-1) dw (exceeding DPR set limits) and 11.3 +/- 0.04 mgkg(-1) dw and 186 +/- 0.02 mgkg(-1) dw for TPH and PAHs, respectively, were recorded in test soil and plant samples, respectively. Among the metals studied (Pb, Cd, Cr, Mn, Fe and Zn), Pb and Cr uptake exceeded WHO set limits for crops in test samples. Combined sources of pollution were evident from our studies. Bitterleaf and Waterleaf could be tried as bioindicators owing to expressed contaminants uptake pattern. PMID- 25270366 TI - Epididymal contraction and sperm parameters are affected by clonidine. AB - The use of clonidine, a selective agonist of alpha2-adrenoceptors, is related to the fertility impairment. Thus, it has been described that changes in the epididymal function are related to the loss of fertility. Therefore, this study was sought to further evaluate the effects of clonidine in the rat distal cauda epididymis contractions and its consequence in the sperm parameters. The in vitro effects of clonidine in the isolated distal cauda epididymis were evaluated by pharmacological experiments. The consecutive contractile responses for clonidine in distal cauda epididymis showed desensitization. The noradrenaline-induced contractions were desensitized after in vitro clonidine pre-treatment (10(-5) M for 10 min). Clonidine was unable to alter the noradrenaline contractions if the in vitro pre-treatment was made in the presence of idazoxan (alpha2-adrenoceptor antagonist), whereas prazosin (alpha1-adrenoceptor antagonist) was ineffective. Moreover, the in vitro clonidine pre-treatment increased frequency and amplitude of spontaneous contraction of distal cauda epididymis. In addition, to induce in vivo desensitization of alpha2-adrenoceptors, male Wistar rats were treated with crescent doses of clonidine and distal cauda of epididymis contraction and sperm parameters were analyzed. The in vivo treatment with clonidine diminished the potency of the contractions induced by adrenergic agonists and augmented the frequency and amplitude of spontaneous contraction of distal cauda epididymis. This treatment also altered the sperm transit time in epididymis, epididymal sperm reserves, sperm lipid peroxidation, and antioxidant enzymes activity. The results suggest that clonidine was able to affect the sperm quantity and quality by decreasing the transit time related to the increase in the frequency and amplitude of spontaneous contractions in epididymis, although the contractions induced by adrenergic agonists were desensitized. PMID- 25270367 TI - Authors' reply to Evans and Allen. PMID- 25270368 TI - Performance of three-dimensional power Doppler angiography as third-step assessment in differential diagnosis of adnexal masses. AB - OBJECTIVE: To evaluate the contribution of three-dimensional (3D) power Doppler angiography (3D-PDA) to the differential diagnosis of adnexal masses. METHODS: This was a prospective study in women diagnosed with a persistent adnexal mass and subsequently scheduled for surgery in a tertiary university hospital. All women were evaluated by transvaginal/transrectal ultrasound according to a predetermined three-step protocol, with transabdominal ultrasound being performed in some cases. First, morphological evaluation of the mass was performed using gray-scale 'pattern recognition' (first step). Lesions diagnosed as having a benign pattern were considered as being at low risk of malignancy whereas tumors with solid components, ascites and/or signs of carcinomatosis were considered as being at high risk of malignancy. In both cases no further test was performed and a decision regarding clinical management, either for follow-up or surgery, was taken. Tumors with solid components but without signs of ascites or carcinomatosis were considered as being at intermediate risk of malignancy. These lesions were assessed by two-dimensional (2D) PDA to evaluate tumor vascularity (color score) (second step). Solid tumors with a color score of 1 or 2 were considered as benign and no further test was performed, while tumors with a color score of 2, 3 or 4 within solid components or a color score of 3 or 4 in the case of a solid tumor were considered as malignant. The latter group underwent 3D-PDA assessment (third step). Vascularization index (VI) was calculated in a 1-mL sphere of the most vascularized area of the tumor. When a VI >= 24.015% was found, the tumor was considered as malignant. All masses were removed surgically and definitive histological diagnosis was used as the gold standard. Sensitivity and specificity for each strategy were calculated and compared. In the case of bilateral tumors, only the more suspicious one was used for analysis. RESULTS: A total of 367 adnexal masses diagnosed in 367 women (mean age, 46.5 (range, 18-80) years) were evaluated during the study period. Of these, 86 masses were malignant and 281 were benign. The sensitivity and specificity for each assessment strategy were as follows: one-step, 97.7% and 78.6%; two-step, 94.2% and 97.9% (P < 0.001 for specificity when compared with that of one-step); three-step, 90.7% and 98.9% (not statistically significant when compared with that of two-step). CONCLUSIONS: The addition of 2D-PDA in the differential diagnosis of an adnexal mass significantly increases specificity while sensitivity remains high; however performing subsequent 3D-PDA does not provide additional information or further improve diagnostic performance subsequent to 2D-PDA. PMID- 25270369 TI - Mild Lafora disease: clinical, neurophysiologic, and genetic findings. AB - We report clinical, neurophysiologic, and genetic features of an Italian series of patients with Lafora disease (LD) to identify distinguishing features of those with a slowly progressive course. Twenty-three patients with LD (17 female; 6 male) were recruited. Mean age (+/- SD) at the disease onset was 14.5 +/- 3.9 years and mean follow-up duration was 13.2 +/- 8.0 years. NHLRC1 mutations were detected in 18 patients; EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as "mild" and were compared with the remaining LD patients with a typical course. Six of 23 patients were mild and presented significantly delay in the age at onset, lower neurologic disability score at 4 years after the onset, less severe seizure phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to patients with typical LD. However, in both mild and typical LD patients, EEG showed disorganization of background activity and frequent epileptiform abnormalities. Mild LD patients had NHLRC1 mutations and five of six carried homozygous or compound heterozygous D146N mutation. This mutation was found in none of the patients with typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD should be taken into account in clinical practice for appropriate management and counseling. PMID- 25270370 TI - Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration. AB - Rhodopsin is a G protein-coupled receptor essential for vision and rod photoreceptor viability. Disease-associated rhodopsin mutations, such as P23H rhodopsin, cause rhodopsin protein misfolding and trigger endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR). The pathophysiologic effects of ER stress and UPR activation on photoreceptors are unclear. Here, by examining P23H rhodopsin knock-in mice, we found that the UPR inositol-requiring enzyme 1 (IRE1) signaling pathway is strongly activated in misfolded rhodopsin expressing photoreceptors. IRE1 significantly upregulated ER-associated protein degradation (ERAD), triggering pronounced P23H rhodopsin degradation. Rhodopsin protein loss occurred as soon as photoreceptors developed, preceding photoreceptor cell death. By contrast, IRE1 activation did not affect JNK signaling or rhodopsin mRNA levels. Interestingly, pro-apoptotic signaling from the PERK UPR pathway was also not induced. Our findings reveal that an early and significant pathophysiologic effect of ER stress in photoreceptors is the highly efficient elimination of misfolded rhodopsin protein. We propose that early disruption of rhodopsin protein homeostasis in photoreceptors could contribute to retinal degeneration. PMID- 25270371 TI - Degradation of betaII-Spectrin Protein by Calpain-2 and Caspase-3 Under Neurotoxic and Traumatic Brain Injury Conditions. AB - A major consequence of traumatic brain injury (TBI) is the rapid proteolytic degradation of structural cytoskeletal proteins. This process is largely reflected by the interruption of axonal transport as a result of extensive axonal injury leading to neuronal cell injury. Previous work from our group has described the extensive degradation of the axonally enriched cytoskeletal alphaII spectrin protein which results in molecular signature breakdown products (BDPs) indicative of injury mechanisms and to specific protease activation both in vitro and in vivo. In the current study, we investigated the integrity of betaII spectrin protein and its proteolytic profile both in primary rat cerebrocortical cell culture under apoptotic, necrotic, and excitotoxic challenge and extended to in vivo rat model of experimental TBI (controlled cortical impact model). Interestingly, our results revealed that the intact 260-kDa betaII-spectrin is degraded into major fragments (betaII-spectrin breakdown products (betasBDPs)) of 110, 108, 85, and 80 kDa in rat brain (hippocampus and cortex) 48 h post-injury. These betasBDP profiles were further characterized and compared to an in vitro betaII-spectrin fragmentation pattern of naive rat cortex lysate digested by calpain-2 and caspase-3. Results revealed that betaII-spectrin was degraded into major fragments of 110/85 kDa by calpain-2 activation and 108/80 kDa by caspase-3 activation. These data strongly support the hypothesis that in vivo activation of multiple protease system induces structural protein proteolysis involving betaII spectrin proteolysis via a specific calpain and/or caspase-mediated pathway resulting in a signature, protease-specific betasBDPs that are dependent upon the type of neural injury mechanism. This work extends on previous published work that discusses the interplay spectrin family (alphaII-spectrin and betaII spectrin) and their susceptibility to protease proteolysis and their implication to neuronal cell death mechanisms. PMID- 25270372 TI - Spatial distribution of malignant tissue in gliomas: correlations of 11C-L methionine positron emission tomography and perfusion- and diffusion-weighted magnetic resonance imaging. AB - BACKGROUND: The prognosis of glioma patients is contingent on precise target selection for stereotactic biopsies and the extent of tumor resection. (11)C-L methionine (MET) positron emission tomography (PET) demonstrates tumor heterogeneity and invasion with high diagnostic accuracy. PURPOSE: To compare the spatial tumor distribution delineated by MET PET with that by perfusion- and diffusion-weighted magnetic resonance imaging (MRI), in order to understand the diagnostic value of these MRI methods, when PET is not available. MATERIAL AND METHODS: Presurgical MET PET and MRI, including perfusion- and diffusion-weighted MRI, were acquired in 13 patients (7 high-grade gliomas, 6 low-grade gliomas). A quantitative volume of interest analysis was performed to compare the modalities objectively, supplemented by a qualitative evaluation that assessed the clinical applicability. RESULTS: The inaccuracy of conventional MRI was confirmed (area under the curve for predicting voxels with high MET uptake = 0.657), whereas cerebral blood volume (CBV) maps calculated from perfusion data improved accuracy (area under the curve = 0.760). We considered CBV maps diagnostically comparable to MET PET in 5/7 cases of high-grade gliomas, but insufficient in all cases of low-grade gliomas when evaluated subjectively. Cerebral blood flow and apparent diffusion coefficient maps did not contribute to further accuracy. CONCLUSION: Adding perfusion-weighted MRI to the presurgical protocol can increase the diagnostic accuracy of conventional MRI and is a simple and well-established method compared to MET PET. However, the definition of low-grade gliomas with subtle or no alterations on cerebral blood volume maps remains a diagnostic challenge for stand-alone MRI. PMID- 25270373 TI - High resolution in vivo 31P-MRS of the liver: potential advantages in the assessment of non-alcoholic fatty liver disease. AB - BACKGROUND: Biopsy remains the current gold-standard for assessing non-alcoholic fatty liver disease (NAFLD). To develop a non-invasive means of assessing the disease, 31P magnetic resonance spectroscopy (31P-MRS) has been explored, but the severe spectral overlaps and low signal-to-noise-ratio in 31P-MRS spectra at clinical field strength are clearly limiting factors. PURPOSE: To investigate potential advantages of high resolution in vivo 31P-MRS in assessing NAFLD. MATERIAL AND METHODS: The study was conducted at 9.4T in control and carbon tetrachloride (CCl4)-treated rats. Rats were divided according to histopathologic findings into a control group (n = 15), a non-alcoholic steatohepatitis group (n = 17), and a cirrhosis group (n = 12). Data were presented with different reference peaks that are commonly used for peak normalization such as total phosphorous signal, phosphomonoester + phosphodiester (PME + PDE), and nucleotide triphosphate (NTP). Then, multivariate analyses were performed. RESULTS: In all spectra PME and PDE were well resolved into phosphoethanolamine (PE) and phosphocholine (PC), and into glycerophosphorylethanolamine (GPE) and glycerophosphorylcholine (GPC), respectively. Those MRS measures quantifiable only in highly resolved spectra had higher correlations with histology than those conventional MRS measures such as PME, PDE, and NTP. The optimized partial least squares discriminant analysis (PLS-DA) model correctly classified 79% (22/28) of the rats in the training set and correctly predicted 69% (11/16) of the rats in the test set. CONCLUSION: PE, PC, GPE, GPC, and nicotinamide adenine dinucleotide phosphate (NADP) that can be separately quantifiable in highly resolved spectra may further improve the potential efficacy of 31P-MRS in the diagnosis of NAFLD. PMID- 25270374 TI - Locally advanced rectal cancer: post-chemoradiotherapy ADC histogram analysis for predicting a complete response. AB - BACKGROUND: The value of diffusion-weighted imaging (DWI) for reliable differentiation between pathologic complete response (pCR) and residual tumor is still unclear. Recently, a few studies reported that histogram analysis can be helpful to monitor the therapeutic response in various cancer research. PURPOSE: To investigate whether post-chemoradiotherapy (CRT) apparent diffusion coefficient (ADC) histogram analysis can be helpful to predict a pCR in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: Fifty patients who underwent preoperative CRT followed by surgery were enrolled in this retrospective study, non-pCR (n = 41) and pCR (n = 9), respectively. ADC histogram analysis encompassing the whole tumor was performed on two post-CRT ADC600 and ADC1000 (b factors 0, 600 vs. 0, 1000 s/mm(2)) maps. Mean, minimum, maximum, SD, mode, 10th, 25th, 50th, 75th, 90th percentile ADCs, skewness, and kurtosis were derived. Diagnostic performance for predicting pCR was evaluated and compared. RESULTS: On both maps, 10th and 25th ADCs showed better diagnostic performance than that using mean ADC. Tenth percentile ADCs revealed the best diagnostic performance on both ADC600 (AZ 0.841, sensitivity 100%, specificity 70.7%) and ADC1000 (AZ 0.821, sensitivity 77.8%, specificity 87.8%) maps. In comparison between 10th percentile and mean ADC, the specificity was significantly improved on both ADC600 (70.7% vs. 53.7%; P = 0.031) and ADC1000 (87.8% vs. 73.2%; P = 0.039) maps. CONCLUSION: Post-CRT ADC histogram analysis is helpful for predicting pCR in LARC, especially, in improving the specificity, compared with mean ADC. PMID- 25270375 TI - Effect of diabetes mellitus on Corvis ST measurement process. AB - PURPOSE: Diabetes mellitus (DM) affects corneal biomechanical parameters. We compared analyses using ORA (Ocular response analyser) and Corvis ST to determine the influence of disease duration, hyperglycaemia and haemoglobin A1c (HbA1c) levels on these parameters. METHODS: This observational, cross-sectional, observer-masked study assessed one eye of 94 consecutive DM patients and 41 healthy subjects. Two DM groups were analysed: the uncontrolled DM group (n = 54) (HbA1c >= 7%) and the controlled DM group (n = 40) (HbA1c < 7%). Central corneal thickness (CCT) was measured by ultrasonic pachymetry and intraocular pressure (IOP) by Goldmann applanation tonometry. ORA and Corvis ST analyses were performed to evaluate the changes. RESULTS: Most of the Corvis ST parameters [Deformation amplitude (DA), A1 and A2 times, A1 velocity] in the uncontrolled DM group eyes were found to be significantly different to controls and controlled DM group eyes (p = 0.005, p = 0.001, p < 0.0001, p = 0.002, respectively). DA on the Corvis ST was correlated with blood glucose concentration (p = 0.004) and HbA1c percentage (p = 0.002). ORA corneal hysteresis was significantly lower in diabetic patients with elevated HbA1c than in control subjects (p = 0.001) and was affected by disease duration (p = 0.037), whereas the corneal resistance factor remained unaltered. CONCLUSIONS: A poor glucose control in DM affects corneal biomechanics measured by ORA and Corvis ST, which may cause high IOP measurements independent of CCT. The measurement of the corneal biomechanics should be taken into consideration in the clinical practice. PMID- 25270376 TI - Revisiting the NMR solution structure of the Cel48S type-I dockerin module from Clostridium thermocellum reveals a cohesin-primed conformation. AB - Dockerin modules of the cellulosomal enzyme subunits play an important role in the assembly of the cellulosome by binding tenaciously to cohesin modules of the scaffoldin subunit. A previously reported NMR-derived solution structure of the type-I dockerin module from Cel48S of Clostridium thermocellum, which utilized two-dimensional homonuclear (1)H-(1)H NOESY and three-dimensional (15)N-edited NOESY distance restraints, displayed substantial conformational differences from subsequent structures of dockerin modules in complex with their cognate cohesin modules, raising the question whether the source of the observed differences resulted from cohesin-induced structural rearrangements. Here, we determined the solution structure of the Cel48S type-I dockerin based on (15)N- and (13)C-edited NOESY-derived distance restraints. The structure adopted a fold similar to X-ray crystal structures of dockerin modules in complex with their cohesin partners. A unique cis-peptide bond between Leu-65 and Pro-66 in the Cel48S type-I dockerin module was also identified in the present structure. Our structural analysis of the Cel48S type-I dockerin module indicates that it does not undergo appreciable cohesin-induced structural alterations but rather assumes an inherent calcium dependent cohesin-primed conformation. PMID- 25270377 TI - Dabigatran etexilate: a review of its use in the treatment of acute venous thromboembolism and prevention of venous thromboembolism recurrence. AB - Dabigatran etexilate (Pradaxa((r)), Prazaxa((r))) has recently been approved for the treatment of acute venous thromboembolism (VTE) and prevention of VTE recurrence. Dabigatran etexilate is an oral prodrug of dabigatran, a selective, reversible, competitive, direct thrombin inhibitor. Dabigatran etexilate has a wide therapeutic range that allows for fixed-dose administration without the need for routine monitoring, a requirement of standard vitamin K antagonist (VKA) therapy. In randomized phase III trials in patients with acute VTE (RE-COVER and RE-COVER II), long-term treatment with oral dabigatran etexilate 150 mg twice daily for 6 months after initial parenteral anticoagulation was noninferior to dose-adjusted warfarin with regard to the incidence of recurrent symptomatic VTE or related death. In randomized trials of patients with previously treated VTE, extended dabigatran etexilate treatment was noninferior to warfarin (RE-MEDY) and significantly more effective than placebo (RE-SONATE) with regard to the incidence of recurrent VTE or related death. Dabigatran etexilate was generally well tolerated, with a similar incidence of major bleeding to that with warfarin in individual studies (although pooled data showed a significantly lower incidence in patients with acute VTE), and significantly lower incidences of the combined endpoint of major or clinically relevant nonmajor bleeding and of any bleeding than with warfarin. However, in the RE-SONATE trial, dabigatran etexilate was associated with a higher risk of bleeding than placebo. In conclusion, dabigatran etexilate is a valuable treatment option for acute VTE and prevention of VTE recurrence, providing an effective and convenient alternative to standard VKA therapy with the potential for a lower overall rate of bleeding. PMID- 25270378 TI - A determinant of odorant specificity is located at the extracellular loop 2 transmembrane domain 4 interface of an Anopheles gambiae odorant receptor subunit. AB - To explore the structural basis for odorant specificity in odorant receptors of the human malaria vector mosquito, Anopheles gambiae, odorant-binding subunits (Agam?Ors) expressed in Xenopus oocytes in combination with Agam?Orco (coreceptor subunit) were assayed by 2-electrode voltage clamp against 25 structurally related odorants. Agam?Or13 and Agam?Or15 display 82% amino acid identity and had similar, but somewhat distinct odorant response profiles. The ratio of acetophenone to 4-methylphenol responses was used in a mutation-based analysis of Agam?Or15, interchanging 37 disparate residues between Agam?Or15 and Agam?Or13. Eleven mutations caused significant changes in odorant responsiveness. Mutation of alanine 195 resulted in the largest shift in response ratio from Agam?Or15 toward Agam?Or13. Concentration-response analysis for a series of mutations of residue 195 revealed a large effect on acetophenone sensitivity, with EC50 values varying by >1800-fold and correlating with residue side chain length. Similar results were obtained for propiophenone and benzaldehyde. But, for other odorants, such as 4-methylphenol, 4-methylbenzaldehyde, and 4 methylpropiophenone, the effect of mutation was much smaller (EC50 values varied by <=16-fold). These results show that alanine 195, putatively located at the second extracellular loop/fourth transmembrane domain interface, plays a critical role in determining the odorant response specificity of Agam?Or15. PMID- 25270380 TI - Exploiting space-group symmetry in fragment-based molecular crystal calculations. AB - Recent developments in fragment-based methods make it increasingly feasible to use high-level ab initio electronic structure techniques to molecular crystals. Such studies remain computationally demanding, however. Here, we describe a straightforward algorithm for exploiting space-group symmetry in fragment-based methods which often provides computational speed-ups of several fold or more. This algorithm does not require a priori specification of the space group or symmetry operators. Rather, the symmetrically equivalent fragments are identified automatically by aligning the individual fragments along their principle axes of inertia and testing for equivalence with other fragments. The symmetry operators relating equivalent fragments can then be worked out easily. Implementation of this algorithm for computing energies, nuclear gradients with respect to both atomic coordinates and lattice parameters, and the nuclear hessian is described. PMID- 25270382 TI - Evidence on safety of implanted devices is often not publicly available, study finds. PMID- 25270381 TI - Tobacco use and mental illness: a wake-up call for psychiatrists. AB - Tobacco use results in numerous consequences for individuals with mental illnesses and other substance use disorders, yet it is not adequately addressed by behavioral health professionals, including psychiatrists. This column describes current inaction among behavioral health professionals and some possible reasons for it and recommends next steps. Psychiatrists should provide treatment for all patients with a co-occurring tobacco use disorder and provide leadership to change policies and practices in treatment centers. Psychiatrists can be vital leaders of the effort to reduce the toll of tobacco use among people with mental illnesses, addictions, or both. A national movement for addressing tobacco use in the behavioral health field can be galvanized if more psychiatrists participate. PMID- 25270379 TI - Leukocytes as carriers for targeted cancer drug delivery. AB - INTRODUCTION: Metastasis contributes to over 90% of cancer-related deaths. Numerous nanoparticle platforms have been developed to target and treat cancer, yet efficient delivery of these systems to the appropriate site remains challenging. Leukocytes, which share similarities to tumor cells in terms of their transport and migration through the body, are well suited to serve as carriers of drug delivery systems to target cancer sites. AREAS COVERED: This review focuses on the use and functionalization of leukocytes for therapeutic targeting of metastatic cancer. Tumor cell and leukocyte extravasation, margination in the bloodstream, and migration into soft tissue are discussed, along with the potential to exploit these functional similarities to effectively deliver drugs. Current nanoparticle-based drug formulations for the treatment of cancer are reviewed, along with methods to functionalize delivery vehicles to leukocytes, either on the surface and/or within the cell. Recent progress in this area, both in vitro and in vivo, is also discussed, with a particular emphasis on targeting cancer cells in the bloodstream as a means to interrupt the metastatic process. EXPERT OPINION: Leukocytes interact with cancer cells both in the bloodstream and at the site of solid tumors. These interactions can be utilized to effectively deliver drugs to targeted areas, which can reduce both the amount of drug required and various nonspecific cytotoxic effects within the body. If drug delivery vehicle functionalization does not interfere with leukocyte function, this approach may be utilized to neutralize tumor cells in the bloodstream to prevent the formation of new metastases, and also to deliver drugs to metastatic sites within tissues. PMID- 25270383 TI - Effects of intratesticular and incisional local anesthetic administration for castration of alpacas anesthetized with intramuscular ketamine-xylazine butorphanol. AB - OBJECTIVE: To determine the effects of intratesticular and incisional injection of local anesthetics on response to castration, surgical ease, and recovery in alpacas. STUDY DESIGN: Prospective, blinded, randomized, and clinical trial. ANIMALS: Intact male alpacas (n = 38). METHODS: Alpacas were anesthetized with intramuscular butorphanol, ketamine, and xylazine (BKX). Once recumbent, alpacas were instrumented with electrocardiogram, pulse oximeter, oscillometric blood pressure, and capnography. Heart rate (HR), respiratory rate (RR), and blood pressure (BP) were recorded every minute. Treatment drug (lidocaine, bupivacaine, or saline) was infiltrated along the incision and into both testicles followed by a prescrotal closed castration. Timing of major events, presence of movement during the procedure, need for additional anesthesia, and ease of surgery were recorded. Alpacas were administered postoperative oral meloxicam and assessment was made 24 hours after recovery. RESULTS: Median RR and mean BP (MBP) were lower in the lidocaine compared with the saline treated group. Median RR, HR, and MBP were significantly lower in the bupivacaine group compared with the saline group. Fewer alpacas displayed physical response to surgical stimulus with bupivacaine. No significant differences were found between groups for timing of events, need for additional anesthesia, ease of surgery, or postoperative assessment. CONCLUSION: Intratesticular local anesthetic blunts autonomic response and facilitates castration in alpacas anesthetized with BKX with minimal negative effects. Bupivacaine may have some benefit for local anesthesia during castration compared with lidocaine. PMID- 25270384 TI - Endoscopic management of esophageal discontinuity. AB - BACKGROUND: The management of esophageal discontinuity remains challenging and often involves complex reconstructive surgeries. METHODS AND RESULTS: We describe a unique and successful treatment of esophageal discontinuity using a modification of the natural orifice translumenal surgery (NOTES) approach in a patient presenting with long-standing esophageal discontinuity resulting from an iatrogenic esophageal injury. CONCLUSION: This case provided an opportunity to affirm the efficacy of endoscopy for treating esophageal discontinuities to minimize the degree of morbidity and mortality normally associated with the surgical treatment of this type of injury. Our case reveals a novel and possibly more direct means of evaluating and treating esophageal injuries in which the degree of discontinuity and/or stenosis initially remains unknown. PMID- 25270385 TI - Seroepidemiological study of Q fever in small ruminants from Southeast Iran. AB - The aim of the present study was to determine the prevalence of Coxiella burnetii antibodies in small ruminants in Southeast Iran. A total of 368 small ruminant blood samples (241 caprine blood samples and 127 ovine blood samples) were collected from January to May of 2011 in Southeast Iran. A commercial ELISA test kit was employed to identify specific antibodies against C. burnetii in the sheep and goats. Seropositivity in the examined counties ranged from 17.1% to 39.2%. Of the animals tested, 97 animals (26.4%), including 43 sheep (33.9%) and 54 goats (22.4%), had antibodies to C. burnetii. The results of the current study reveal the high prevalence of antibody positivity in small ruminants in Southeast Iran. Thus, sheep and goats are important reservoirs in this area. Additionally, we performed a logistic regression to the identify risk factors for positivity and concluded that age was an important risk factor (P<0.001). PMID- 25270386 TI - Heterophile antibody positive, acute cytomegaloviral infection in an immunocompetent pre-teen: an atypical presentation of an atypical infection. AB - Mononucleosis and mononucleosis-like illnesses comprise a significant proportion of pediatric and adolescent infectious illnesses. By far, the most common cause of these illnesses is Epstein-Barr virus, which causes mononucleosis, and a distant second is cytomegalovirus, which is the most common cause of mononucleosis-like illnesses. This case provides an interesting juxtaposition of laboratory findings of an adolescent who was heterophile antibody positive but acute Epstein-Barr virus antigen-antibody negative. A subsequent immunologic assay resulted in a final diagnosis of an acute cytomegaloviral infection. This is, to our knowledge, the first such report in the literature. PMID- 25270387 TI - The impact of the International Nosocomial Infection Control Consortium (INICC) multicenter, multidimensional hand hygiene approach in two cities of India. AB - The fundamental tool for preventing and controlling healthcare-acquired infections is hand hygiene (HH). Nonetheless, adherence to HH guidelines is often low. Our goal was to assess the effect of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Hand Hygiene Approach (IMHHA) in three intensive care units of three INICC member hospitals in two cities of India and to analyze the predictors of compliance with HH. From August 2004 to July 2011, we carried out an observational, prospective, interventional study to evaluate the implementation of the IMHHA, which included the following elements: (1) administrative support, (2) supplies availability, (3) education and training, (4) reminders in the workplace, (5) process surveillance and (6) performance feedback. The practices of health care workers were monitored during randomly selected 30-min periods. We observed 3612 opportunities for HH. Overall adherence to HH increased from 36.9% to 82% (95% CI 79.3-84.5; P=0.0001). Multivariate analysis indicated that certain variables were significantly associated with poor HH adherence: nurses vs. physicians (70.5% vs. 74%; 95% CI 0.62-0.96; P=0.018), ancillary staff vs. physicians (43.6% vs. 74.0%; 95% CI 0.48 0.72; P<0.001), ancillary staff vs. nurses (43.6% vs. 70.5%; 95% CI 0.51-0.75; P<0.001) and private vs. academic hospitals (74.2% vs. 66.3%; 95% CI 0.83-0.97; P<0.001). It is worth noticing that in India, the HH compliance of physicians is higher than in nurses. Adherence to HH was significantly increased by implementing the IMHHA. Programs targeted at improving HH are warranted to identify predictors of poor compliance. PMID- 25270388 TI - Immunomagnetic separation combined with RT-qPCR for determining the efficacy of disinfectants against human noroviruses. AB - Little is known about the effectiveness of disinfectants against human noroviruses (NoV) partially because human NoV cannot be routinely cultured in laboratory. The objective of this study was to develop a NoV monoclonal antibody conjugated immunomagnetic separation (IMS) procedure combined with real-time reverse transcription polymerase chain reaction (RT-qPCR) assays to study the in vitro efficacy of disinfectants against human NoV. Monoclonal antibodies against Norwalk virus (NV, GI.1) and NoV GII.4 were produced using unique NoV capsid proteins, and the antibodies were conjugated to magnetic Dynalbeads. The immunomagnetic beads were used to simultaneously capture intact NoV in samples and effectively remove PCR inhibitors. We examined the efficacy of ethanol, sodium hypochlorite, nine commercially available disinfectants, and one prototype disinfectant using the IMS/RT-qPCR. The sensitivity of this procedure was approximately 100 virus particles for both the NV and GII.4 viruses. The average log reductions in in vitro activities varied between disinfectants. The prototype disinfectant produced an average 3.19-log reduction in NV and a 1.38-log reduction in GII.4. The prototype disinfectant is promising of inactivating NoV. This method can be used to evaluate in vitro activity of disinfectants against human NoV. The IMS/RT-qPCR method is promising as an effective method to remove PCR inhibitors in disinfectants and enable the evaluation of the efficacy of disinfectants. PMID- 25270389 TI - Roles of FGF-2 and TGF-beta/FGF-2 on differentiation of human mesenchymal stem cells towards nucleus pulposus-like phenotype. AB - Human mesenchymal stem cells (MSCs) are reported to have the capability of differentiating towards nucleus pulposus (NP)-like phenotype under specific culture conditions. So far, the effects of fibroblast growth factor (FGF)-2 and the cocktail effects of transforming growth factor (TGF)-beta and FGF-2 on MSCs remain unclear. Therefore, we designed this study to clarify these effects. MSCs were cultured in conditioned medium containing FGF-2 or TGF-beta/FGF-2, and compared with basal or TGF-beta medium. The groups with FGF-2 showed the increase of cell proliferation. Functional gene markers and novel NP markers decreased in FGF-2 group, together with functional protein expression. Pho-ERK1/2 and pho Smad3 differed significantly in the two conditioned groups. All these results suggest FGF-2 promotes MSCs' proliferation, synergistically with TGF-beta. However, FGF-2 plays a negative role in cartilage homeostasis. We also demonstrate that FGF-2 has no positive effect in differentiating MSCs into NP like cells, but hinders the acceleration effect of TGF-beta. PMID- 25270390 TI - Pneumocandin biosynthesis: involvement of a trans-selective proline hydroxylase. AB - Echinocandins are cyclic nonribosomal hexapeptides based mostly on nonproteinogenic amino acids and displaying strong antifungal activity. Despite previous studies on their biosynthesis by fungi, the origin of three amino acids, trans-4- and trans-3-hydroxyproline, as well as trans-3-hydroxy-4-methylproline, is still unknown. Here we describe the identification, overexpression, and characterization of GloF, the first eukaryotic alpha-ketoglutarate/Fe(II) dependent proline hydroxylase from the pneumocandin biosynthesis cluster of the fungus Glarea lozoyensis ATCC 74030. In in vitro transformations with L-proline, GloF generates trans-4- and trans-3-hydroxyproline simultaneously in a ratio of 8:1; the latter reaction was previously unknown for proline hydroxylase catalysis. trans-4-Methyl-L-proline is converted into the corresponding trans-3 hydroxyproline. All three hydroxyprolines required for the biosynthesis of the echinocandins pneumocandins A0 and B0 in G. lozoyensis are thus provided by GloF. Sequence analyses revealed that GloF is not related to bacterial proline hydroxylases, and none of the putative proteins with high sequence similarity in the databases has been characterized so far. PMID- 25270391 TI - Graphene based flexible electrochromic devices. AB - Graphene emerges as a viable material for optoelectronics because of its broad optical response and gate-tunable properties. For practical applications, however, single layer graphene has performance limits due to its small optical absorption defined by fundamental constants. Here, we demonstrated a new class of flexible electrochromic devices using multilayer graphene (MLG) which simultaneously offers all key requirements for practical applications; high contrast optical modulation over a broad spectrum, good electrical conductivity and mechanical flexibility. Our method relies on electro-modulation of interband transition of MLG via intercalation of ions into the graphene layers. The electrical and optical characterizations reveal the key features of the intercalation process which yields broadband optical modulation up to 55 per cent in the visible and near-infrared. We illustrate the promises of the method by fabricating reflective/transmissive electrochromic devices and multi-pixel display devices. Simplicity of the device architecture and its compatibility with the roll-to-roll fabrication processes, would find wide range of applications including smart windows and display devices. We anticipate that this work provides a significant step in realization of graphene based optoelectronics. PMID- 25270392 TI - The CoRe Outcomes in WomeN's Health (CROWN) Initiative: journal editors invite researchers to develop core outcomes in women's health. PMID- 25270393 TI - Revisiting telegony: offspring inherit an acquired characteristic of their mother's previous mate. AB - Newly discovered non-genetic mechanisms break the link between genes and inheritance, thereby also raising the possibility that previous mating partners could influence traits in offspring sired by subsequent males that mate with the same female ('telegony'). In the fly Telostylinus angusticollis, males transmit their environmentally acquired condition via paternal effects on offspring body size. We manipulated male condition, and mated females to two males in high or low condition in a fully crossed design. Although the second male sired a large majority of offspring, offspring body size was influenced by the condition of the first male. This effect was not observed when females were exposed to the first male without mating, implicating semen-mediated effects rather than female differential allocation based on pre-mating assessment of male quality. Our results reveal a novel type of transgenerational effect with potential implications for the evolution of reproductive strategies. PMID- 25270394 TI - Anisotropic failure of Fourier theory in time-domain thermoreflectance experiments. AB - The applicability of Fourier's law to heat transfer problems relies on the assumption that heat carriers have mean free paths smaller than important length scales of the temperature profile. This assumption is not generally valid in nanoscale thermal transport problems where spacing between boundaries is small (<1 MUm), and temperature gradients vary rapidly in space. Here we study the limits to Fourier theory for analysing three-dimensional heat transfer problems in systems with an interface. We characterize the relationship between the failure of Fourier theory, phonon mean free paths, important length scales of the temperature profile and interfacial-phonon scattering by time-domain thermoreflectance experiments on Si, Si0.99Ge0.01, boron-doped Si and MgO crystals. The failure of Fourier theory causes anisotropic thermal transport. In situations where Fourier theory fails, a simple radiative boundary condition on the heat diffusion equation cannot adequately describe interfacial thermal transport. PMID- 25270395 TI - Astragalus polysaccharides exert protective effects in newborn rats with bronchopulmonary dysplasia by upregulating the expression of EGFL7 in lung tissue. AB - The aim of this study was to explore the effects of Astragalus polysaccharides (APS) on the mRNA expression of epidermal growth factor-like domain 7 (EGFL7) in lung tissue in newborn rats with bronchopulmonary dysplasia (BPD). For this purpose, a total of 96 newborn SD rats were randomly divided into 4 groups (n=24): the control group, air room plus APS group, BPD group and the APS group (20 mg/kg/day). Lung tissues were obtained on days 4, 10 and 14 after birth. Morphological changes were observed and the protein and mRNA expression levels of EGFL7, Bax and Bcl-2 were determined. The rats in the BPD group (BPD induced by hyperoxia) presented with an arrest in alveolar and vascular development and low mRNA and protein expression levels of of EGFL7, Bcl-2 and high levels of Bax compared with the rats in the control group. However, lung damage in the APS intervention group was attenuated compared with the BPD group. The protein and mRNA expression levels of EGFL7 and Bcl-2 were also increased and the level of Bax was decreased in the APS intervention group (P<0.01) compared with the BPD model group after birth on days 4, 10 and 14. Our data demonstrate that APS reduce airway remodeling and alveolar damage by upregulating the expression of EGFL7 and exert protective effects against BPD in neonatal rats. Thus, APS may have potential for use as a therapeutic strategy for BPD. PMID- 25270396 TI - Increased serum fibroblast growth factor-23 and decreased bone turnover in patients with systemic lupus erythematosus under treatment with cyclosporine and steroid but not steroid only. AB - SUMMARY: In patients with systemic lupus erythematosus (SLE), low bone mineral density (BMD) is associated with increased age, prolonged disease, low body mass index (BMI), and overlap with rheumatoid arthritis (RA). Elevated fibroblast growth factor (FGF)-23 in cyclosporine A (CsA) users with SLE are associated with decreased active vitamin D and osteocalcin. INTRODUCTION: The objective of this study was to investigate the steroid and CsA effect on bone metabolism and serum FGF-23 in SLE patients. METHODS: Seventy-two SLE patients and 10 age- and sex matched healthy individuals underwent blood tests for bone metabolic biomarkers and FGF-23, and lumbar spine dual-energy X-ray absorptiometry for BMD. RESULTS: Comparisons between patients and controls were made in premenopausal women/men younger than 50 years and postmenopausal women/men older than 50 years separately. SLE patients had more frequent low Z-score (<=-2.0, 8.5 vs. 0%), osteopenia (-2.5 80%). A mixture of green and red teas had a synergism in CUPRAC and TPC, whereas a mixture of yellow and red teas had a positive effect on CUPRAC and DPPH. An optimization was performed to maximize the antioxidant activity and flavan-3-ol content and to render a tea with mild bitterness, and results showed that a mixture of 14.81% green, 56.86% yellow, and 28.33% red teas would be the most suitable combination of factors. PMID- 25270399 TI - Unexpected interference in cell surface staining by monoclonal antibodies to unrelated antigens. AB - Background: The possible occurrence of an erroneous immunophenotyping due to interference between monoclonal antibodies (MoAbs) is often overlooked when the epitopes are assumed to be not close to each other. This is particularly important when exploring immune cell populations whose identification is still investigational. The commonly held view is that myeloid derived suppressor cells (MDSC) can be identified as either HLA-DRneg/dim cells or interleukin-4 receptor alpha (CD124)+ cells among peripheral blood monocytes. We made the serendipitous observation that the fluorescence signal provided by the PE-CD124 MoAb was attenuated when the PE-CF594-HLA-DR MoAb was added to the staining tube. Methods: Peripheral blood mononuclear cells (PBMC) from healthy donors were stained with the PE-CD124 MoAb and, as control, PE -CD40, -CD4 and -CD14, and either the PE CF594-HLA-DR MoAb or its unlabeled form. B cells, which also express CD124, were analyzed for comparison. Results: The PE-CF594-HLA-DR MoAb but not its unlabeled form reduced PE-CD124 MoAb staining on monocytes and B cells. No other monocyte and B cell surface marker staining was affected by the PE-CF594-HLA-DR MoAb. The PE-CF594-HLA-DR MoAb interfered with the PE-CD124 MoAb likely because of steric hindrance by bulky fluorochromes, although a quenching due to fluorescence resonance energy transfer might also cooperate to the PE-CD124 MoAb staining attenuation. Conclusions: Present observations highlight the importance of interference between MoAbs as a source of error when analyzing multicolor flow cytometry data. (c) 2014 Clinical Cytometry Society. PMID- 25270397 TI - Telmisartan treatment of refractory proteinuria in a dog. PMID- 25270400 TI - Grammar tests increase the ability to lateralize language function in the Wada test. AB - INTRODUCTION: Grammar is a core component of the language system, yet it is rarely assessed during the Wada (intracarotid amobarbital) test. It is hypothesized that adding grammar tests to the recovery phase of the Wada test will increase our ability to lateralize language function. METHOD: Sixteen individuals (nine females, fifteen right-handed, mean age 38.4 years, SD=10.7) with medically refractory temporal lobe epilepsy participated in the study. On EEG ten patients had seizures originating in the left hemisphere (LH), five in the right hemisphere (RH), and one was insufficiently lateralized. We included only patients who were LH-dominant on the standard test in the encoding phase of the Wada test. In the recovery phase of Wada testing the participants underwent evaluation with a standard language and a new test of grammar, the CYCLE-N. Ten patients underwent bilateral injections, six unilateral (one RH, five LH). RESULTS: As expected, injection in the LH decreased language performance to a greater extent than injection to the RH on both tests. However, the CYCLE-N produced more profound language deficits in the injected LH compared to the RH (p=0.01), whereas the standard tests did not cause such pronounced differences (p=0.2). CONCLUSION: The results suggest that the standard tests did not significantly differentiate the effects of the injections and the CYCLE-N, for the most part, did. Our results are of particular relevance to patients who are too obtunded to speak in the encoding phase. In sum, the CYCLE-N may be helpful in assessing hemispheric dominance for language. PMID- 25270401 TI - An interictal EEG spectral metric for temporal lobe epilepsy lateralization. AB - OBJECTIVE: Visually-obvious abnormalities in the resting baseline EEG--slowing, spiking and high-frequency oscillations (HFOs)--are cardinal, though incompletely understood, features of the seizure onset zone in focal epilepsy. We hypothesized that evidence of cortical network dysfunction in temporal lobe epilepsy (TLE) would persist in the absence of visually-classifiable abnormalities in the baseline EEG recorded within the conventional passband, and that metrics of such dysfunction could serve as a lateralizing diagnostic in TLE. METHODS: Epochs of resting EEG without significant abnormalities in light sleep over several days were compared between a group of 10 patients with proven TLE and 10 subjects without epilepsy. A novel laterality metric computed from the line length of normalized power spectra from the temporal channels was compared between the two groups. RESULTS: Significant group differences in spectral line length laterality metric were found between the TLE and control group. At the individual level, seven of 10 TLE patients had highly significant laterality metrics, all concordant with the known laterality of their disease. SIGNIFICANCE: Detailed spectral analysis offers novel insight into TLE network behavior, independent of the orthodox abnormalities of EEG slowing, spikes or HFOs. The results may be deployed in a practical diagnostic manner, offer insight into the EEG manifestations of disordered cellular network architecture in TLE, and maybe understood through simple analogy with the theory of linear time-invariant physical systems. PMID- 25270402 TI - Pax8 modulates the expression of Wnt4 that is necessary for the maintenance of the epithelial phenotype of thyroid cells. AB - BACKGROUND: The transcription factor Pax8 is expressed during thyroid development and is involved in the morphogenesis of the thyroid gland and maintenance of the differentiated phenotype. In particular, Pax8 has been shown to regulate genes that are considered markers of thyroid differentiation. Recently, the analysis of the gene expression profile of FRTL-5 differentiated thyroid cells after the silencing of Pax8 identified Wnt4 as a novel target. Like the other members of the Wnt family, Wnt4 has been implicated in several developmental processes including regulation of cell fate and patterning during embryogenesis. To date, the only evidence on Wnt4 in thyroid concerns its down-regulation necessary for the progression of thyroid epithelial tumors. RESULTS: Here we demonstrate that Pax8 is involved in the transcriptional modulation of Wnt4 gene expression directly binding to its 5'-flanking region, and that Wnt4 expression in FRTL-5 cells is TSH-dependent. Interestingly, we also show that in thyroid cells a reduced expression of Wnt4 correlates with the alteration of the epithelial phenotype and that the overexpression of Wnt4 in thyroid cancer cells is able to inhibit cellular migration. CONCLUSIONS: We have identified and characterized a functional Pax8 binding site in the 5'-flanking region of the Wnt4 gene and we show that Pax8 modulates the expression of Wnt4 in thyroid cells. Taken together, our results suggest that in thyroid cells Wnt4 expression correlates with the integrity of the epithelial phenotype and is reduced when this integrity is perturbed. In the end, we would like to suggest that the overexpression of Wnt4 in thyroid cancer cells is able to revert the mesenchymal phenotype. PMID- 25270403 TI - Discovery of 4-aminoquinazoline--urea derivatives as Aurora kinase inhibitors with antiproliferative activity. AB - Two series of 20 novel 4-aminoquinazoline-urea derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activity against six human cancer cell lines (K562, U937, A549, NCI-H661, HT29 and LoVo) using the MTT-based assay. Most compounds showed significant antiproliferative activities against four solid tumor cell lines, but no or poor activities against two leukemia cell lines. Furthermore, the target compounds were screened for Aurora A/B kinases inhibitory activity. Among them, 7c, 7d, 8c, and 8d are more potent against Aurora A kinase than ZM447439. Docking study of compounds 7d and ZM447439 revealed that they bound strongly to the ATP binding sites of Aurora A and B. Thus, they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting Aurora kinases. PMID- 25270404 TI - Direct evidence for the function of crustacean insulin-like androgenic gland factor (IAG): total chemical synthesis of IAG. AB - Insulin-like androgenic gland factor (IAG) is presumed to be a sex differentiation factor so-called androgenic gland hormone (AGH) in decapod crustacean, although the function of IAG peptide has not yet been reported. In this study, we synthesized IAG from the prawn, Marsupenaeus japonicus, and its function was assessed by an in vitro bioassay. As a result, IAG with the insulin type disulfide bond arrangement showed biological activity, whereas its disulfide isomer did not. These results strongly suggest that the native IAG peptide has an insulin-type disulfide, and it is the decapod AGH. PMID- 25270405 TI - A simple method for decomposition of peracetic acid in a microalgal cultivation system. AB - A cost-efficient process devoid of several washing steps was developed, which is related to direct cultivation following the decomposition of the sterilizer. Peracetic acid (PAA) is known to be an efficient antimicrobial agent due to its high oxidizing potential. Sterilization by 2 mM PAA demands at least 1 h incubation time for an effective disinfection. Direct degradation of PAA was demonstrated by utilizing components in conventional algal medium. Consequently, ferric ion and pH buffer (HEPES) showed a synergetic effect for the decomposition of PAA within 6 h. On the contrary, NaNO3, one of the main components in algal media, inhibits the decomposition of PAA. The improved growth of Chlorella vulgaris and Synechocystis PCC6803 was observed in the prepared BG11 by decomposition of PAA. This process involving sterilization and decomposition of PAA should help cost-efficient management of photobioreactors in a large scale for the production of value-added products and biofuels from microalgal biomass. PMID- 25270406 TI - Cultivation of Chlorella protothecoides in anaerobically treated brewery wastewater for cost-effective biodiesel production. AB - The use of wastewater has been investigated to overcome the economic challenge involved with a production of microalgae-based biodiesel. In this study, to achieve economical biodiesel production along with effective wastewater treatment at the same time, anaerobically treated brewery wastewater (ABWW) was utilized as a low-cost nutrient source, in the cultivation of Chlorella protothecoides. About 96 and 90 % of total nitrogen and phosphorus in ABWW were removed, respectively, while C. protothecoides was accumulating 1.88 g L(-1) of biomass. The C. protothecoides grown in ABWW showed increases in cell size and cell aggregation, resulting in a near 80 % enhanced harvesting efficiency within 20 min, as compared with only 4 % in BG-11. In addition, the total fatty acid content of the C. protothecoides grown in ABWW increased by 1.84-fold (35.94 +/- 1.54 % of its dry cell weight), relative to that of BG-11. PMID- 25270407 TI - Mining rich health data from Canadian physician claims: features and face validity. AB - BACKGROUND: Physician claims data are one of the largest sources of coded health information unique to Canada. There is skepticism from data users about the quality of this data. This study investigated features of diagnostic codes used in the Alberta physician claims database. METHODS: Alberta physician claims from January 1 to March 31, 2011 are analyzed. Claims contain coded diagnoses using the International Classification of Diseases, 9th revision (ICD-9), procedures, physician specialty and service-fee type. Descriptive statistics examined the diversity and frequency of unique ICD-9 diagnostic codes used and the level of code extension (e.g. 3- or 4-digit coding). RESULTS: A total of 7,441,005 claims by 6,601 physicians were analyzed. The average number of claims per physician was 1,079, with ranges between 1,330 for family medicine, 690 for internal medicine, 722 for surgery, 516 for pediatrics and 409 for neurology. Family physicians used an average of 121 diagnostic codes, internal medicine physicians 32, surgery 36, pediatrics 46 and neurology 27. Overall, 43.5% of claims had a more detailed diagnosis (ICD code with >3 digits). Physicians on a fee-for-service plan submitted 1,184 claims and used 88 unique diagnosis codes on average compared to 438 claims and 44 unique diagnosis codes from physicians on an alternative payment plan (APP). CONCLUSIONS: Face validity of diagnosis coded in physician claims is substantially high and the features of diagnosis codes seem to reasonably reflect the clinical specialty. Physicians submit a diverse array of ICD 9 diagnostic codes and nearly half of the ICD-9 diagnostic codes examined were more detailed than required (i.e. ICD code with >3 digits). Finally, guidelines and policies should be explored to assess the submission of shadow billings for physicians on APPs. PMID- 25270408 TI - A moral tragedy: patricide and step-patricide. PMID- 25270409 TI - A systematic review of intermittent pneumatic compression for critical limb ischaemia. AB - Intermittent pneumatic compression (IPC) is designed to aid wound healing and limb salvage for patients with critical limb ischaemia who are not candidates for revascularisation. We conducted a systematic review of the literature to identify and critically appraise the evidence supporting its use in this population. A search was conducted in Embase, MEDLINE and clinical trial registries up to the end of March 2013. No date or language restrictions were applied. Quality assessment was performed by two people independently. Quality was assessed using the Cochrane risk of bias tool and the NICE case-series assessment tool. Two controlled before-and-after (CBA) studies and six case series were identified. One retrospective CBA study involving compression of the calf reported improved limb salvage and wound healing (OR 7.00, 95% CI 1.82 to 26.89, p<0.01). One prospective CBA study involving sequential compression of the foot and calf reported statistically significant improvements in claudication distances and SF 36 quality of life scores. No difference in all-cause mortality was found. Complications included pain associated with compression, as well as skin abrasion and contact rash as a result of the cuff rubbing against the skin. All studies had a high risk of bias. In conclusion, the limited available results suggest that IPC may be associated with improved limb salvage, wound healing and pain management. However, in the absence of additional well-designed analytical studies examining the effect of IPC in critical limb ischaemia, this treatment remains unproven. PMID- 25270410 TI - 'If you have children, you have responsibilities': motherhood, sex work and HIV in southern Tanzania. AB - Many female sex workers begin sex work as mothers, or because they are mothers, and others seek childbearing. Motherhood may influence women's livelihoods as sex workers and their subsequent HIV risks. We used qualitative research methods (30 in-depth interviews and three focus group discussions) and employed Connell's theory of Gender and Power to explore the intersections between motherhood, sex work, and HIV-related risk. Participants were adult women who self-reported exchanging sex for money within the past month and worked in entertainment venues in southern Tanzania. Participants had two children on average, and two-thirds had children at home. Women situated their socially stigmatised work within their respectable identities as mothers caring for their children. Being mothers affected sex workers' negotiating power in complex manners, which led to both reported increases in HIV-related risk behaviours (accepting more clients, accepting more money for no condom, anal sex), and decreases in risk behaviours (using condoms, demanding condom use, testing for HIV). Sex workers/mothers were aware of risks at work, but with children to support, their choices were constrained. Future policies and programming should consider sex workers' financial and practical needs as mothers, including those related to their children such as school fees and childcare. PMID- 25270420 TI - Global increase of p16INK4a in APC-deficient mouse liver drives clonal growth of p16INK4a-negative tumors. AB - Reduction of beta-catenin (CTNNB1) destroying complex components, for example, adenomatous polyposis coli (APC), induces beta-catenin signaling and subsequently triggers activation of genes involved in proliferation and tumorigenesis. Though diminished expression of APC has organ-specific and threshold-dependent influence on the development of liver tumors in mice, the molecular basis is poorly understood. Therefore, a detailed investigation was conducted to determine the underlying mechanism in the development of liver tumors under reduced APC levels. Mouse liver at different developmental stages was analyzed in terms of beta catenin target genes including Cyp2e1, Glul, and Ihh using real-time RT-PCR, reporter gene assays, and immunohistologic methods with consideration of liver zonation. Data from human livers with mutations in APC derived from patients with familial adenomatous polyposis (FAP) were also included. Hepatocyte senescence was investigated by determining p16(INK4a) expression level, presence of senescence-associated beta-galactosidase activity, and assessing ploidy. A beta catenin activation of hepatocytes does not always result in beta-catenin positive but unexpectedly also in mixed and beta-catenin-negative tumors. In summary, a senescence-inducing program was found in hepatocytes with increased beta-catenin levels and a positive selection of hepatocytes lacking p16(INK4a), by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc(580S) mice). The lack of p16(INK4a) was also detected in liver tumors of mice with triggers other than APC reduction. IMPLICATIONS: Epigenetic silencing of p16(Ink4a) in selected liver cells bypassing senescence is a general principle for development of liver tumors with beta-catenin involvement in mice independent of the initial stimulus. PMID- 25270421 TI - Cryptosporidium spp. and Giardia duodenalis as pathogenic contaminants of water in Galicia, Spain: the need for safe drinking water. AB - The objectives of this cross-sectional study were to detect the presence of Cryptosporidium spp. and Giardia duodenalis in drinking water treatments plants (DWTPs) in Galicia (NW Spain) and to identify which species and genotype of these pathogenic protozoans are present in the water. Samples of untreated water (surface or ground water sources) and of treated drinking water (in total, 254 samples) were collected from 127 DWTPs and analysed by an immunofluorescence antibody test (IFAT) and by PCR. Considering the untreated water samples, Cryptosporidium spp. were detected in 69 samples (54.3%) by IFAT, and DNA of this parasite was detected in 57 samples (44.8%) by PCR, whereas G. duodenalis was detected in 76 samples (59.8%) by IFAT and in 56 samples (44.0%) by PCR. Considering the treated drinking water samples, Cryptosporidium spp. was detected in 52 samples (40.9%) by IFAT, and the parasite DNA was detected in 51 samples (40.1%) by PCR, whereas G. duodenalis was detected in 58 samples (45.6%) by IFAT and in 43 samples (33.8%) by PCR. The percentage viability of the (oo)cysts ranged between 90.0% and 95.0% in all samples analysed. Cryptosporidium andersoni, C. hominis, C. parvum and assemblages A-I, A-II, E of G. duodenalis were identified. The results indicate that Cryptosporidium spp. and G. duodenalis are widespread in the environment and that DWTPs are largely ineffective in reducing/inactivating these pathogens in drinking water destined for human and animal consumption in Galicia. In conclusion, the findings suggest the need for better monitoring of water quality and identification of sources of contamination. PMID- 25270422 TI - EU Tobacco Products Directive trumps debate on regulation of electronic cigarettes. PMID- 25270423 TI - NHS will pay for boy's proton beam therapy in Prague. PMID- 25270424 TI - Shu-Yu capsule, a Traditional Chinese Medicine formulation, attenuates premenstrual syndrome depression induced by chronic stress constraint. AB - The present study aimed to investigate the therapeutic effect of the Shu-Yu capsule (SYC), a Traditional Chinese Medicine formulation, on premenstrual syndrome (PMS) depression and the ratio of glutamate (Glu) to gamma-aminobutyric acid (GABA) in a rat model of PMS depression. Rats were randomly divided into a control group, model group, fluoxetine group, SYC group and saikosaponins (SS) group. The therapeutic effect of SYC was evaluated using a sucrose preference test (SPT), open field test (OFT) and body mass following four days of treatment. Hippocampal extracellular fluid was collected by microdialysis and the levels of Glu and GABA in the microdialysate were measured by high performance liquid chromatography. The results revealed that, compared with the control group, the sucrose preference coefficient (SC%), total score of OFT and body mass of the model group were significantly lower (P<0.01, P<0.05 and P<0.01, respectively). However, the sucrose preference coefficient, total score of OFT and body mass of the SYC group were all significantly increased compared with the model group (P<0.05). Furthermore, SYC inhibited the decrease of the Glu/GABA ratio in the hippocampus of rats with PMS depression. It was concluded that SYC effectively improved the symptoms of PMS depression, possibly by inhibiting the dysregulation of the Glu/GABA balance in the central nervous system. PMID- 25270425 TI - Can we predict allergen-induced asthma in patients with allergic rhinitis? AB - BACKGROUND: A high percentage of patients with allergic rhinitis (AR) exhibit signs of bronchial hyperreactivity (BHR), and approximately 30% may develop asthma later in life. OBJECTIVE: The aim of this study was to identify predictors for allergen-induced asthma in patients with AR. METHODS: Hundred patients with AR selected by public posting and 20 healthy controls were enrolled. Twenty-three patients with concomitant physician-diagnosed asthma and four with a negative allergy test were excluded from further analysis. The remaining 73 subjects with AR underwent bronchial allergen provocation (BAP), which is considered the gold standard for the diagnosis of clinically relevant allergen-specific asthma. The following parameters were measured to explore predictors for an early and late asthmatic response (EAR and LAR): standardised questionnaire, skin prick test (SPT), total IgE, specific IgE to grass pollen, FEV1, PD20FEV1 methacholine, exhaled nitric oxide (eNO) and eosinophils. RESULTS: Early asthmatic reaction was equally distributed between patients with and without signs of possible asthma by questionnaire (56.8% vs. 48.3%). The following cut-off values showed the best combination of sensitivity and specificity for an EAR: specific IgE grass pollen 18.5 kU/L (AUC 0.83), SPT 8.5 mm (AUC 0.76), total IgE 95.5 kU/L (AUC 0.73), FEV1 102.4% (AUC 0.69), PD20FEV1 methacholine 1.67 mg (AUC 0.74), eNO 18.05 ppB (AUC 0.64) and eosinophils 115/mm(3) (AUC 0.58). CONCLUSIONS AND CLINICAL RELEVANCE: There is a considerable discordance between reported asthma signs and diagnosed disease by BAP. Simple measurement of allergen-specific IgE for grass pollen was the best predictor of allergen-induced asthma in patients with AR. PMID- 25270426 TI - Cost-utility of cognitive behavioral therapy versus U.S. Food and Drug Administration recommended drugs and usual care in the treatment of patients with fibromyalgia: an economic evaluation alongside a 6-month randomized controlled trial. AB - INTRODUCTION: Cognitive behavioral therapy (CBT) and U.S. Food and Drug Administration (FDA)-recommended pharmacologic treatments (RPTs; pregabalin, duloxetine, and milnacipran) are effective treatment options for fibromyalgia (FM) syndrome and are currently recommended by clinical guidelines. We compared the cost-utility from the healthcare and societal perspectives of CBT versus RPT (combination of pregabalin + duloxetine) and usual care (TAU) groups in the treatment of FM. METHODS: The economic evaluation was conducted alongside a 6 month, multicenter, randomized, blinded, parallel group, controlled trial. In total, 168 FM patients from 41 general practices in Zaragoza (Spain) were randomized to CBT (n = 57), RPT (n = 56), or TAU (n = 55). The main outcome measures were Quality-Adjusted Life Years (QALYs, assessed by using the EuroQoL 5D questionnaire) and improvements in health-related quality of life (HRQoL, assessed by using EuroQoL-5D visual analogue scale, EQ-VAS). The costs of healthcare use were estimated from patient self-reports (Client Service Receipt Inventory). Cost-utility was assessed by using the net-benefit approach and cost effectiveness acceptability curves (CEACs). RESULTS: On average, the total costs per patient in the CBT group (1,847 ?) were significantly lower than those in patients receiving RPT (3,664 ?) or TAU (3,124 ?). Patients receiving CBT reported a higher quality of life (QALYs and EQ-VAS scores); the differences between groups were significant only for EQ-VAS. From a complete case-analysis approach (base case), the point estimates of the cost-effectiveness ratios resulted in dominance for the CBT group in all of the comparisons performed, by using both QALYs and EQ-VAS as outcomes. These findings were confirmed by bootstrap analyses, net-benefit curves, and CEACs. Two additional sensitivity analyses (intention-to-treat analysis and per-protocol analysis) indicated that the results were robust. The comparison of RPT with TAU yielded no clear preference for either treatment when using QALYs, although RPT was determined to be more cost-effective than TAU when evaluating EQ-VAS. CONCLUSIONS: Because of lower costs, CBT is the most cost-effective treatment for adult FM patients. Implementation in routine medical care would require policymakers to develop more widespread public access to trained and experienced therapists in group-based forms of CBT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10804772. Registered 29 September 2008. PMID- 25270427 TI - Cypermethrin alters the status of oxidative stress in the peripheral blood: relevance to Parkinsonism. AB - Parkinson's disease (PD) is a motor scarcity disorder characterized by the striatal dopamine deficiency owing to the selective degeneration of the nigrostriatal dopaminergic neurons. While oxidative stress is implicated in PD, prolonged exposure to moderate dose of cypermethrin induces Parkinsonism. The study aimed to investigate the status of oxidative stress indicators and antioxidant defence system of the polymorphonuclear leukocytes (PMNs), platelets and plasma to delineate the effect of Parkinsonian dose of cypermethrin in the peripheral blood of rats and its subsequent relevance to Parkinsonism. Nitrite content, lipid peroxidation (LPO) and activity of superoxide dismutase (SOD), catalase, glutathione reductase (GR) and glutathione-S-transferase (GST) were measured in the PMNs, platelets and plasma of control and cypermethrin-treated rats in the presence or absence of a microglial activation inhibitor, minocycline or a dopamine precursor containing the peripheral 3,4-dihydroxyphenylalanine decarboxylase inhibitor, named syndopa, employing the standard procedures. The striatal dopamine was measured to assess the degree of neurodegeneration/neuroprotection. Cypermethrin increased nitrite and LPO in the plasma, platelets and PMNs while it reduced the striatal dopamine content. Catalase and GST activity were increased in the PMNs and platelets; however, it was reduced in the plasma. Conversely, SOD and GR activities were reduced in the PMNs and platelets but increased in the plasma. Minocycline or syndopa reduced the cypermethrin-mediated changes towards normalcy. The results demonstrate that cypermethrin alters the status of oxidative stress indicators and impairs antioxidant defence system of the peripheral blood, which could be effectively salvaged by minocycline or syndopa. The results could be of value for predicting the nigrostriatal toxicity relevant to Parkinsonism. PMID- 25270428 TI - Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model. AB - Ischemia-reperfusion (IR) has been reported to be associated with augmented reactive oxygen radicals and cytokines. Currently, we aimed to examine the influence of fluoxetine, which is already used as a preoperative anxiolytic, in the context of IR induced by occlusion of infrarenal abdominal aorta (60 min of ischemia) and its effects on renal oxidative status, inflammation, renal function, and cellular integrity in reperfusion (120 min post-ischemia). Male rats were randomly assigned as control, IR, and pretreated groups. The pretreated group animals received fluoxetine (20 mg/kg, i.p.) once daily for 3 days. Renal tissue oxidative stress, myeloperoxidase activity, proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), histology, and function were assessed. As an anti-inflammatory cytokine, interleukin-10 was also assessed. IR led to a significant increase in lipid hydroperoxide, malondialdehyde, and pro-oxidant antioxidant balance and decrease in superoxide dismutase activity and ferric reducing/antioxidant power level (p < 0.05), but fluoxetine was able to restore these parameters. High concentrations of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and myeloperoxidase activity caused by IR were significantly decreased in kidney tissue with fluoxetine. In addition, interleukin-10 levels were high in fluoxetine pretreated group. IR resulted in disrupted cellular integrity, infiltration of tissue with leukocytes, and decreased serum creatinine-urea levels (p < 0.05). Fluoxetine significantly restored impaired redox balance and inflammation parameters of rats subjected to IR to baseline values. This beneficial effect of fluoxetine on redox balance might be addressed to an improvement in renal function. PMID- 25270429 TI - Chronic phencyclidine induces inflammatory responses and activates GSK3beta in mice. AB - Use of phencyclidine (PCP) in rodents can mimic some aspects of schizophrenia. However, the underlying mechanism is still unclear. Growing evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. In this study, we focused on inflammatory responses as target of PCP for inducing schizophrenia-like symptoms. 3-month-old C57BL/6J mice received daily injections of PCP (20 mg/kg, i.p.) or saline for one week. PCP-injected mice produced schizophrenia-like behaviours including impaired spatial short-term memory assessed by the Y-maze task and sensorimotor gating deficits in a prepulse inhibition task. Simultaneously, chronic PCP administration induced astrocyte and microglial activation in both the cortex and hippocampus. Additionally, the proinflammatory cytokine interleukin-1beta was significantly up-regulated in PCP administrated mice. Furthermore, PCP treatment decreased ratio of the phospho Ser9 epitope of glycogen synthase kinase-3beta (GSK3beta) over total GSK3beta, which is indicative of increased GSK3beta activity. These data demonstrate that chronic PCP in mouse produces inflammatory responses and GSK3beta activation. PMID- 25270430 TI - SREBF1 gene variations modulate insulin sensitivity in response to a fish oil supplementation. AB - BACKGROUND: An important inter-individual variability in the response of insulin sensitivity following a fish oil supplementation has been observed. The objective was to examine the associations between single nucleotide polymorphisms (SNPs) within sterol regulatory element binding transcription factor 1 (SREBF1) gene and the response of insulin sensitivity to a fish oil supplementation. METHODS: Participants (n = 210) were recruited in the greater Quebec City area and followed a 6-week fish oil supplementation protocol (5 g/day: 1.9-2.2 g EPA; 1.1 g DHA). Insulin sensitivity was assessed by the quantitative insulin sensitivity check index (QUICKI). Three tag SNPs (tSNPs) within SREBF1 gene were genotyped according to TAQMAN methodology. RESULTS: Three tSNPs (rs12953299, rs4925118 and rs4925115) covered 100% of the known genetic variability within SREBF1 gene. None of the three tSNPs was associated with either baseline fasting insulin concentrations (rs12953299, rs4925118 and rs4925115) (p = 0.29, p = 0.20 and p = 0.70, respectively) or QUICKI (p = 0.20, p = 0.18 and p = 0.76, respectively). The three tSNPs (rs12953299, rs4925118 and rs4925115) were associated with differences in the response of plasma insulin levels (p = 0.01, p = 0.005 and p = 0.004, respectively) and rs12953299 as well as rs4925115 were associated with the insulin sensitivity response (p = 0.009 and p = 0.01, respectively) to the fish oil supplementation, independently of the effects of age, sex and BMI. CONCLUSIONS: The genetic variability within SREBF1 gene has an impact on the insulin sensitivity in response to a fish oil supplementation. TRIAL REGISTRATION: clinicaltrials.gov: NCT01343342. PMID- 25270432 TI - Effects of social activation and physical mobilization on sleep in nursing home residents. AB - Age-related changes in sleep physiology, frequent occurrence of health impairments, and a sedentary lifestyle make nursing home residents particularly vulnerable to sleep disturbances. Despite the high prevalence of sleep disturbances in nursing homes, there is a lack of research concerning the use of non-pharmacological approaches for improving residents' sleep. This study aimed to promote residents' sleep by improving their social activation and physical mobilization. An experimental group of residents attending an activation program four times a week during an eight-week study course was compared to a non-treated control group in a cluster-randomized intervention trial among 85 residents of 20 nursing homes. Sleep was assessed by the Insomnia Severity Index (ISI), nurses' ratings of residents' sleep disturbances and actigraphy-based sleep parameters. Although no changes in actigraphy-based sleep parameters were observed, the subjective sleep quality ratings of the intervention participants significantly improved compared to the control group members (p = 0.004). This study suggests that physical mobilization and social activation may improve residents' subjective sleep quality. Further efforts to improve residents' sleep by increasing their physical and social activity should consider existing obstacles to encourage participation and adherence to the program. PMID- 25270433 TI - Talk is not enough--now it is time for action. PMID- 25270431 TI - Targeting DNA vaccines to myeloid cells using a small peptide. AB - Targeting DNA vaccines to dendritic cells (DCs) greatly enhances immunity. Although several approaches have been used to target protein Ags to DCs, currently there is no method that targets DNA vaccines directly to DCs. Here, we show that a small peptide derived from the rabies virus glycoprotein fused to protamine residues (RVG-P) can target DNA to myeloid cells, including DCs, which results in enhanced humoral and T-cell responses. DCs targeted with a DNA vaccine encoding the immunodominant vaccinia B8R gene via RVG-P were able to restimulate vaccinia-specific memory T cells in vitro. Importantly, a single i.v. injection of B8R gene bound to RVG-P was able to prime a vaccinia-specific T-cell response that was able to rapidly clear a subsequent vaccinia challenge in mice. Moreover, delivery of DNA in DCs was enough to induce DC maturation and efficient Ag presentation without the need for adjuvants. Finally, immunization of mice with a DNA-vaccine encoding West Nile virus (WNV) prM and E proteins via RVG-P elicited high titers of WNV-neutralizing Abs that protected mice from lethal WNV challenge. Thus, RVG-P provides a reagent to target DNA vaccines to myeloid cells and elicit robust T-cell and humoral immune responses. PMID- 25270434 TI - Trust earns highest CQC rating for leadership and exemplary care. PMID- 25270435 TI - NMC set to vote on fee increase, despite L55m projected savings. PMID- 25270436 TI - Miliband makes nurses key to his election strategy. PMID- 25270437 TI - Government will spend L5 million to lure ex-registrants back to practice. PMID- 25270439 TI - Three unions prepare to strike in anger over pay later this month. PMID- 25270440 TI - Super slimmer runs for charity. PMID- 25270442 TI - Nurses trial 'huddle' technique that aims to improve communication. PMID- 25270444 TI - Handheld devices are saving hundreds of lives, study claims. PMID- 25270445 TI - 'How to complain' campaign launched. PMID- 25270447 TI - NICE urges employers to make roles compatible with wellbeing. PMID- 25270449 TI - Longer shifts are a threat to patient safety, Europe-wide survey shows. PMID- 25270450 TI - Malawi clinicians praise VSO work. PMID- 25270451 TI - Debate on English devolution could have repercussions on health policy. PMID- 25270457 TI - Varicose veins. PMID- 25270458 TI - Deadly situation. AB - Most healthcare workers in developing countries have a basic level of training and little access to up-to-date knowledge and skills. Tens of thousands of deaths a year could be prevented if nurses had the expertise they need. Healthcare Information For All is working to share know-how. PMID- 25270459 TI - Ethnicity no barrier to career heights. AB - The newly appointed regional director for the RCN in the North West region of England, Estephanie Dunn, will provide support to nursing directors in trusts on special measures. She hopes employers will support BME nurses with leadership potential to 'navigate the system'. PMID- 25270460 TI - Eating for health. AB - People of black African and African Caribbean heritage are at increased risk of type 2 diabetes. There is great potential for nurses to help people in these communities to prevent and manage the condition. In particular, people can be encouraged to make traditional diets healthier. PMID- 25270475 TI - Embracing spirituality through the practice of meditation. PMID- 25270476 TI - Empowerment is not an issue for patients who are satisfied. PMID- 25270477 TI - How does evidence-based care fit in with empowerment and choice? PMID- 25270480 TI - 'Pre-diabetes' is a misleading label covering up disagreement. PMID- 25270481 TI - Fragile economies in West Africa are being devastated by Ebola. PMID- 25270482 TI - Type 2 diabetes: a case study. AB - Increased prevalence of diabetes in the community has been accompanied by an increase in diabetes in hospitalised patients. About a quarter of these patients experience a hypoglycaemic episode during their admission, which is associated with increased risk of mortality and length of stay. This article examines the aetiology, pathophysiology, diagnosis and treatment of type 2 diabetes using a case study approach. The psychosocial implications for the patient are also discussed. The case study is based on a patient with diabetes who was admitted to hospital following a hypoglycaemic episode and cared for during a practice placement. The importance of early diagnosis of diabetes and the adverse effects of delayed diagnosis are discussed. PMID- 25270483 TI - Enabling ICU patients to die at home. AB - There is often an overlap between intensive care medicine and palliative medicine. When all curative treatment options have been explored, keeping the patient comfortable and free from pain is the main concern for healthcare practitioners. Patient autonomy in end of life decisions has not been encouraged in the intensive care unit (ICU), until now, because of its specialised and technical nature. Staff at the Royal Bolton Hospital have broken down the barriers to enabling ICU patients to die in their own homes, and have developed a system of collaborative working that can help to fulfil a patient's final wish to go home. This article describes how ICU staff developed a process that enabled two ventilated patients to be transferred home for end of life care. PMID- 25270484 TI - Preparing a successful, role-specific curriculum vitae. AB - An internet search reveals just how many articles there are on preparing a curriculum vitae (CV). The preparation of a CV should not be regarded as a 'one off' event, to be updated periodically. A successful CV requires thoughtful preparation to ensure it is directed towards a specific post and should consider two important perspectives. First, an understanding of what is required of the practitioner in the nursing post (demand), and second, what the nurse can offer in terms of his or her skills, experience, qualities and qualifications (supply). The demands of the post will also include meeting professional standards, such as those that have emerged following consideration of the Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry (Francis 2013). This article explores how to prepare a successful CV for a specific role, using a demand and supply perspective--where a nurse seeks to match the specific requirements of the post by summarising what he or she has to offer. PMID- 25270485 TI - Nursing research. PMID- 25270486 TI - A strategic approach. PMID- 25270488 TI - Clinical nurse specialist--'Patients value our judgement'. PMID- 25270489 TI - Offering continuity and advice. PMID- 25270490 TI - Student life--'I know this is my life now'. PMID- 25270491 TI - How I stopped fearing technology-based interventions. PMID- 25270493 TI - Hall v. Florida: defining intellectual disability in the shadow of the death penalty. AB - When the U.S. Supreme Court held that persons with mental retardation (now called intellectual disability) could not be sentenced to death, it left the question of how to define the condition to the states. That issue was raised in Hall v. Florida, which challenged one state's "bright-line rule" barring consideration of defendants with IQs over 70. In an endorsement of the professional consensus, the justices ruled that a more flexible approach that takes into account both intellectual and adaptive functioning is required. The Court's posture may bode well for its acceptance of mental health expertise in future cases. PMID- 25270494 TI - Treatment participation and medication adherence: effects on criminal justice costs of persons with mental illness. AB - Little empirical research has directly examined the extent to which early and consistent participation in outpatient services and adherence to prescribed psychotropic medications after a psychiatric hospitalization can help people with serious mental illnesses avoid arrest and incarceration and what impact this might have on state and local costs. The authors examined effects of medication adherence in the first 90 days after a psychiatric hospitalization among 1,367 adults with schizophrenia or bipolar disorder served by the public behavioral health systems of Miami-Dade County and Pinellas County in Florida. Better adherence was associated with lower subsequent criminal justice costs and greater use of treatment services. A modest investment in promoting treatment participation and medication adherence may reduce criminal justice involvement and costs for persons with serious mental illness. PMID- 25270495 TI - How I learned to live with schizophrenia. PMID- 25270496 TI - Stigma and public support for parity and government spending on mental health: a 2013 national opinion survey. AB - OBJECTIVE: The study examined attitudes among Americans about policies to require insurance parity for mental health and substance abuse benefits and to increase government spending on mental health treatment. METHODS: A Web-based public opinion survey was conducted with a national sample (N=1,517). Analyses examined how sociodemographic characteristics, political affiliation, personal experience with mental illness, and attitudes toward persons with mental illness were associated with policy support. RESULTS: Sixty-nine percent supported insurance parity, and 59% supported increasing government spending. Democrats were more supportive than Republicans or Independents. Personal experience was associated with higher support for both policies, and stigmatizing attitudes were associated with less support. CONCLUSIONS: Most Americans favored policies to expand insurance and funding, but stigma was associated with lower support for both policies. This finding highlights the importance of developing robust antistigma efforts, particularly in an era when mental illness is increasingly linked to dangerousness in news media portrayals. PMID- 25270497 TI - Stigma, discrimination, treatment effectiveness, and policy: public views about drug addiction and mental illness. AB - OBJECTIVE: Public attitudes about drug addiction and mental illness were compared. METHODS: A Web-based national survey (N=709) was conducted to compare attitudes about stigma, discrimination, treatment effectiveness, and policy support in regard to drug addiction and mental illness. RESULTS: Respondents held significantly more negative views toward persons with drug addiction. More respondents were unwilling to have a person with drug addiction marry into their family or work closely with them. Respondents were more willing to accept discriminatory practices against persons with drug addiction, more skeptical about the effectiveness of treatments, and more likely to oppose policies aimed at helping them. CONCLUSIONS: Drug addiction is often treated as a subcategory of mental illness, and insurance plans group them together under the rubric of "behavioral health." Given starkly different public views about drug addiction and mental illness, advocates may need to adopt differing approaches to reducing stigma and advancing public policy. PMID- 25270498 TI - Antidepressant prescribing in elderly populations. PMID- 25270499 TI - Antidepressant prescribing in elderly populations: in reply. PMID- 25270500 TI - Assessing online dietary information for people with schizophrenia. PMID- 25270501 TI - Do organizations forming ACOs have mental health providers? PMID- 25270504 TI - Basal metabolic rate and maternal energetic investment durations in mammals. AB - BACKGROUND: The Metabolic Theory of Ecology (MTE) predicts that gestation duration, lactation duration, and their sum, total development time, are constrained by mass-specific basal metabolic rate such that they should scale with body mass with an exponent of 0.25. However, tests of the MTE's predictions have yielded mixed results. In an effort to resolve this uncertainty, we used phylogenetically-controlled regression to investigate the allometries of gestation duration, lactation duration, and total development time in four well studied mammalian orders, Artiodactyla, Carnivora, Primates, and Rodentia. RESULTS: The results we obtained are not consistent with the predictions of the MTE. Gestation duration scaling exponents are below 0.25 in all four orders. The scaling exponent for lactation duration is below 0.25 in Carnivora and Rodentia, indistinguishable from 0.25 in Artiodactyls, and steeper than 0.25 in Primates. Total development time scales with body mass as predicted by the MTE in Primates, but not in artiodactyls, carnivores, and rodents. In the latter three orders, the exponent is 0.15. CONCLUSIONS: Together, these results indicate that the influence of basal metabolic rate on mammalian maternal investment durations must be more complicated than the MTE envisages, and that other factors must play an important role. Future research needs to allow for the possibility that different factors drive gestation duration and lactation duration, and that the drivers of the two durations may differ among orders. PMID- 25270505 TI - Intimacy and Sexuality in Institutionalized Dementia Care: Clinical-Ethical Considerations. AB - Intimacy and sexuality expressed by nursing home residents with dementia remains an ethically sensitive issue for care facilities, nursing staff and family members. Dealing with residents' sexual longings and behaviour is extremely difficult, putting a burden on the caregivers as well as on the residents themselves and their relatives. The parties in question often do not know how to react when residents express themselves sexually. The overall aim of this article is to provide a number of clinical-ethical considerations addressing the following question: 'How can expressions of intimacy and sexuality by residents with dementia be dealt with in an ethically responsible way?' The considerations formulated are based on two cornerstones: (1) the current literature on older peoples' experiences regarding intimacy and sexuality after the onset of dementia, and (2) an anthropological-ethical framework addressing four fundamental pillars of human existence namely the decentred self, human embodiment, being-in-the-world and being-with-others. The resulting considerations are oriented toward the individual sphere, the partnership sphere, and the institutional sphere. The continuous interaction between these spheres leads to orientations that both empower the residents in question and respect the complex network of relationships that surrounds them. PMID- 25270506 TI - Accuracy of ultrasonography performed by examiners with varied training and experience in predicting specific pathology of adnexal masses. AB - OBJECTIVES: To assess the diagnostic performance of subjective assessment by Level II ultrasound examiners in predicting the specific histology of adnexal masses. METHODS: The women included in this prospective multicenter cross sectional study were older than 16 years of age and had at least one adnexal mass. They underwent transvaginal sonography (TVS) performed by Level II examiners, all of whom were familiar with the International Ovarian Tumor Analysis (IOTA) group definitions of ultrasound features of ovarian masses. The final outcome was histology. Specific diagnoses were categorized into 16 groups. Agreement between subjective assessment and final histology was measured using unweighted kappa coefficients. Sensitivities and specificities were obtained for subjective assessment. RESULTS: Of the 1279 women who underwent TVS, 313 were included in the final analysis. Overall agreement (16 * 16 table) between subjective assessment and histology was moderate, with a Cohen's kappa coefficient of 0.59 (95% CI, 0.53-0.65). The specificity of subjective assessment ranged between 91% and 100% for all histological subgroups. Highest sensitivities were achieved in the diagnosis of simple cysts (100% (95% CI, 61-100%)), hydrosalpinges (100% (95% CI, 34-100%)), mature teratomas (88% (95% CI, 74-96%)), endometriomas (75% (95% CI, 61-85%)), ovarian fibromas (88% (95% CI, 47-100%)), tubo-ovarian abscesses (88% (95% CI, 47-100%)) and serous cystadenocarcinomas (82% (95% CI, 66-93%)). Serous cystadenomas were misdiagnosed most commonly (40.5%). The sensitivity of subjective assessment in diagnosing adnexal torsion was 54% (95% CI, 25-81%); the 17 confirmed and/or suspected cases of adnexal torsion were not included in the 313 cases examined and analyzed for diagnostic performance. CONCLUSION: Overall, subjective assessment by Level II examiners was good for the detection of simple cysts, endometriomas, mature teratomas, hydrosalpinges, fibroma, tubo-ovarian abscess and serous cystadenocarcinomas. PMID- 25270507 TI - Nrf2 induces fibroblast growth factor 21 in diabetic mice. AB - Transcription factor Nrf2 (nuclear factor E2-related factor 2) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein Keap1 (Kelch-like ECH associated protein 1). Nrf2 also plays a pivotal role in metabolic homeostasis, such as lipid metabolism and energy expenditure as well as redox homeostasis. FGF21 (fibroblast growth factor 21) is known as a key mediator of glucose and lipid metabolism. Here, we found that Nrf2 is involved in FGF21 regulation in diabetic model mice. Nrf2 induction by genetic knockdown of Keap1 increased plasma FGF21 level and hepatic Fgf21 expression in diabetic db/db mice and high calorie-diet-induced obesity model mice. Administration of CDDO-Im (oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleane-1, 9(11)-dien-28-oyl] imidazole), a potent Nrf2 inducer, up-regulated plasma FGF21 level and hepatic Fgf21 expression in db/db mice, whereas CDDO-Im did not induce FGF21 in db/db mice with Nrf2 knockout background. Furthermore, in Keap1-knockdown db/db mice, Nrf2 enhanced expression of glucose- and lipid-metabolism-related genes in adipose tissues, which improved plasma lipid profiles. These results show that Nrf2 positively regulates FGF21 expression in diabetic mice. We propose that FGF21 is a potential efficacy biomarker that mediates metabolic regulation by the Keap1-Nrf2 system. PMID- 25270508 TI - Additional B-cell deficiency does not affect growth and angiogenesis of ectopic human endometrium in T-cell-deficient endometriosis mouse models during long-term culture. AB - Heterologous endometriosis mouse models characterized by transplantation of human endometrial tissue into immunodeficient mice are widely used to develop novel treatment strategies for this gynecological disease. The majority of these experiments have been performed for up to one month in athymic T-cell-deficient nude mice, which, however, still exhibit intact B-lymphocytes possibly affecting growth and persistence of the xenografts. We describe here the heterologous mouse models used so far and comparatively analyze the characteristics of human endometrial tissue after subcutaneous and intraperitoneal transplantation in nude and in Rag-1-deficient mice exhibiting T- and B-cell deficiency. Moreover, we extended the time of culturing to three months in both mouse strains. Size, histomorphology, and vascularization of xenografts of intraperitoneal and subcutaneous localization did not differ significantly nor did those of the two immunodeficient mouse strains for up to three months of culturing. Whereas the rate of lesions was similar at both localizations in nude mice, in Rag-1 knockout mice significantly more intraperitoneal than subcutaneous lesions could be recovered. Interestingly, in both mouse strains a considerable number of xenografts completely invaded the peritoneal lining after intraperitoneal transplantation and could only be recovered histomorphologically. This has to be taken into account in studies depending on the quantitative analysis of ectopic peritoneal lesions. In conclusion, T-cell deficiency seems to be sufficient for the long-term culture of human endometrial tissue in subcutaneous and intraperitoneal localizations. Additional B-cell deficiency does not provide advantages with regard to the maintenance, morphology, and blood vessel supply of the ectopic endometrial lesions. PMID- 25270509 TI - Preference pulses induced by reinforcement. AB - Eight rats responded on concurrent Variable-Ratio 20 Extinction schedules for food reinforcement. The assignment of variable-ratio reinforcement to a left or right lever varied randomly following each reinforcer, and was cued by illumination of a stimulus light above that lever. Postreinforcement preference levels decreased substantially and reliably over time when the lever that just delivered reinforcement was now in extinction; however, if that lever was once again associated with variable ratio, this decrease in same-lever preference tended to be small, and for some subjects, not in evidence. The changes in preference level to the extinction lever were well described by a modified version of Killeen, Hanson, and Osborne's (1978) induction model. Consistent with this model's attribution of preference change to induction, we attribute preference change in this report to a brief period of reinforcer-induced arousal that energizes responding to the lever that delivered the last reinforcer. After a few seconds, this induced responding diminishes, and the operant responding that remains comes under the control of the stimulus light cuing the lever providing variable-ratio reinforcement. PMID- 25270510 TI - Clot-targeted micellar formulation improves anticoagulation efficacy of bivalirudin. AB - Application of anticoagulants remains the primary strategy for prevention and treatment of thrombosis. However, high rate of bleeding complications limits their use. The peptide anticoagulant bivalirudin has been reported to exhibit a lower rate of bleeding complications than heparin, and it also has the advantage of not causing thrombocytopenia, which is a problem with heparin. Nonetheless, hemorrhage is the most common complication of bivalirudin therapy, and there is no effective antidote. Here we use a thrombus-binding peptide, CR(NMe)EKA, to accomplish selective delivery of the bivalirudin-carrying micellar nanocarrier to sites of thrombosis. Bivalirudin and CR(NMe)EKA, each with a PEG-lipid tail, spontaneously assembled into 30 nm micelles, which almost completely retained the anticoagulant activity of bivalirudin. The micellar formulations exhibited high stability both in vitro and in vivo. In a thromboplastin-induced mouse thrombosis model, the targeted micelles accumulated in lung thrombi 10-fold more than nontargeted micelles. Moreover, the micellar formulation significantly prolonged the half-life and thereby increased the bioavailability of bivalirudin. The micellar bivalirudin had significantly higher anticoagulant activity than free bivalirudin in both the lung thrombosis model and a ferric chloride-induced carotid artery thrombosis model. The specific targeting of thrombi demonstrated here makes it possible to increase the efficacy of bivalirudin as an anticoagulant. Alternatively, the dose could be reduced without loss of efficacy to lower the systemic exposure and improve safety. PMID- 25270511 TI - A peptide probe for the detection of neurokinin-1 receptor by disaggregation enhanced fluorescence and magnetic resonance signals. AB - We report a novel peptide probe for the detection of neurokinin-1 receptor using disaggregation-caused signal enhancement. The probe was obtained via the aggregation of a modified substance P in a terpyridine-Fe (II) complex with Gd (III)-DOTA into well-defined nanostructures, which effectively weaken ligand fluorescence and slow the exchange rate of inner-sphere water molecules. This probe disaggregates upon binding to the neurokinin-1 receptor and activates the contrast agents to generate a fluorescent signal that positively enhances magnetic resonance imaging contrast and allows for the detection of overexpressed receptors on tumor cells and the identification of lung cancer using serum samples. PMID- 25270512 TI - Effect of nitric oxide pathway regulation on water/sodium balance and renal function in a rodent model of acute liver and renal failure. AB - BACKGROUND: The pathomechanism of acute hepatorenal syndrome (HRS), a particular form of acute renal failure that occurs in the course of acute liver injury, is still poorly understood. The aim of our study was to estimate the influence of the activation and inhibition of the nitric oxide pathway on the water/sodium balance and development of acute renal failure in the course of HRS. MATERIAL AND METHODS: We used male Sprague-Dawley rats in the acute galactosamine (Ga1N) model of HRS. The nitric oxide synthase (NOS) inhibitors L-NAME and L-arginine were administered intraperitoneally before and after liver damage. RESULTS: HRS developed in all tested groups. L-NAME increased osmotic clearance and urine volume more effectively before liver injury. Furthermore, administration of L NAME increased creatinine clearance both before and after Ga1N injection. A double dose of L-NAME did not yield further improvement before Ga1N injection, but improved creatinine clearance after Ga1N intoxication. Injection of L arginine increased sodium excretion and urine volume, but only after liver injury. Moreover, L-arginine injected after Ga1N caused significant improvement of the creatinine clearance in a dose-dependent manner. CONCLUSIONS: Our study shows that inhibition of the nitric oxide pathway improves parameters of water and sodium balance and prevents development of acute renal failure in the course of acute liver injury and liver failure. Activation of the nitric oxide system also has a favorable influence on water/sodium balance and renal failure, but only after liver injury. PMID- 25270513 TI - Topical rapamycin systematically suppresses the early stages of pulsed dye laser induced angiogenesis pathways. AB - BACKGROUND: Administration of topical rapamycin (RPM) suppresses the regeneration and revascularization of photocoagulated blood vessels induced by pulsed dye laser (PDL). OBJECTIVE: To systematically elucidate the molecular pathophysiology of the inhibition of PDL-induced angiogenesis by topical RPM in a rodent model. METHODS: The mRNA expression profiles of 86 angiogenic genes and phosphorylation levels of ribosomal protein S6 kinase (P70S6K) in rodent skin were examined with or without topical RPM administration post-PDL exposure. RESULTS: The PDL-induced systematic increases in transcriptional levels of angiogenic genes showed a peak expression at days 3-7 post-PDL in rodent skin. Topical application of 1% RPM significantly and systematically suppressed the PDL-induced increase in mRNA levels of the examined angiogenic genes during the first five days post-PDL. The phosphorylation levels of P70S6K increased after PDL exposure but those increases were suppressed by the topical RPM. After topical application, RPM penetrated to an approximate depth of 768.4 MUm into rodent skin. CONCLUSION: Topical application of 1% RPM can significantly and systematically suppress the PDL induced early stage of angiogenesis via inhibition of the AKT/mTOR/P70S6K pathway in a rodent model. PMID- 25270514 TI - Emotion processing deficits in alexithymia and response to a depth of processing intervention. AB - Findings on alexithymic emotion difficulties have been inconsistent. We examined potential differences between alexithymic and control participants in general arousal, reactivity, facial and subjective expression, emotion labeling, and covariation between emotion response systems. A depth of processing intervention was introduced. Fifty-four participants (27 alexithymic), selected using the Toronto Alexithymia Scale-20, completed an imagery experiment (imagining joy, fear and neutral scripts), under instructions for shallow or deep emotion processing. Heart rate, skin conductance, facial electromyography and startle reflex were recorded along with subjective ratings. Results indicated hypo reactivity to emotion among high alexithymic individuals, smaller and slower startle responses, and low covariation between physiology and self-report. No deficits in facial expression, labeling and emotion ratings were identified. Deep processing was associated with increased physiological reactivity and lower perceived dominance and arousal in high alexithymia. Findings suggest a tendency for avoidance of intense, unpleasant emotions and less defensive action preparation in alexithymia. PMID- 25270515 TI - Diabetic retinopathy and its risk factors in a society with a type 2 diabetes epidemic: a Saudi National Diabetes Registry-based study. AB - PURPOSE: To assess diabetic retinopathy prevalence and its risk factors in a society with type 2 diabetes epidemic using the Saudi National Diabetes Registry (SNDR). METHOD: This is a cross-sectional study using patient's clinical data found in SNDR data base. A cohort of 50,464 Saudi patients with type 2 diabetes aged >=25 years were selected to assess for the prevalence and risk factors for diabetic retinopathy. RESULTS: The overall prevalence of diabetic retinopathy is 19.7%, where 9.1% have non-proliferative diabetic retinopathy (NPDR), 10.6% have proliferative diabetic retinopathy (PDR) and 5.7% have macular oedema (ME). Duration of diabetes and age are the most significant risk factors for diabetic retinopathy with odds ratio (OR) and 95% confidence interval (95% CI) 8.88 (8.30 9.50) and 5.76 (5.10-6.55), respectively. Nephropathy, neuropathy, insulin use, poor glycemic control, hypertension and male gender significantly increased the risk for diabetic retinopathy. Smoking, hyperlipidemia and obesity significantly reduced the risk for diabetic retinopathy among type 2 Saudi diabetic cohort. CONCLUSION: vThe low prevalence of diabetic retinopathy in our registry may be a result of the shortage or absence of well-structured screening programmes. Therefore, many patients with NPDR might have been missed. A prevention programme is needed to reduce the effect of diabetic retinopathy risk factors in this society. PMID- 25270516 TI - Association of physical activity and polymorphisms in FGFR2 and DNA methylation related genes with breast cancer risk. AB - PURPOSE: Physical activity, a protective factor for breast cancer, increases the level of DNA methylation. Fibroblast growth factor receptor 2 (FGFR2), a confirmed breast cancer susceptibility gene, is predisposed to be methylated. Therefore, DNA methylation related genes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and DNA methyltransferase (DNMT), together with physical activity and FGFR2, may interact with each other to effect breast cancer risk. METHODS: A total of 839 incident breast cancer cases and 863 age-matched controls from Guangzhou, China were included in this study. We used questionnaires to assess physical activity in metabolic equivalent (MET) h/week/year and a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform to ascertain genotypes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models. RESULTS: Exercise activity and FGFR2 rs2981582 were confirmed to be associated with breast cancer risk, and were found to significantly interact (P for multiplicative and additive interactions = 0.045 and 0.021, respectively). Women who had CT/TT genotypes of FGFR2 rs2981582 and experienced exercise activity <3 MET-h/week/year had significantly increased risk (OR = 3.15, 95% CI = 2.28-4.35) compared to women with CC genotype and >= 3 MET-h/week/year. There was also a significant interaction between FGFR2 rs2981582 and MTHFR rs1801133 on breast cancer risk (P for multiplicative and additive interactions = 0.039 and 0.023, respectively). CONCLUSION: We found both a gene-environment (FGFR2 exercise activity) and a gene-gene (FGFR2-MTHFR) interaction on breast cancer risk. Our results suggest that environmental factors, such as physical activity, may be able to counteract genetic susceptibility to breast cancer. PMID- 25270517 TI - Relationship between sniff nasal inspiratory pressure and BODE index in patients with COPD. AB - PURPOSE: The aims of this study were to investigate the relationship between sniff nasal inspiratory pressure (SNIP) and severity of chronic obstructive pulmonary disease (COPD) as defined by the BODE index, and to investigate the capacity of different SNIP cutoffs to predict a BODE index score >=5 (i.e., worse disease severity). METHODS: Thirty-eight subjects with COPD (21 men, 66 +/- 8 years, forced expiratory volume in the first second (FEV(1)) 42 +/- 16 % predicted) underwent assessments of SNIP, airflow limitation, body mass index (BMI), dyspnea (Medical Research Council scale), and exercise capacity (6-min walking test, 6MWT). The BODE index was calculated, and patients were separated into two groups according to the BODE quartiles (1 and 2, or 3 and 4). RESULTS: Patients from quartiles 3 and 4 presented lower values of SNIP than patients from quartiles 1 and 2 (73 +/- 18 vs 56 +/- 21 cmH(2)O, respectively; p = 0.01). There was significant and inverse correlation between SNIP and the BODE index (r = 0.62; p<0.001). A logistic regression model revealed that a SNIP value below 63 cmH(2)O presented higher sensitivity and specificity (70 and 67 %, respectively) for predicting a BODE score equivalent to quartiles 3 or 4. CONCLUSION: SNIP is moderately and significantly related to COPD severity as assessed by the BODE index. Moreover, the cutoff point of 63 cmH2O showed the best combination of sensitivity and specificity for predicting worse scores in the BODE index. PMID- 25270518 TI - Two sides of a coin: the dual roles of chitinase 3-like 1 in idiopathic pulmonary fibrosis. PMID- 25270519 TI - HPV-DNA sperm infection and infertility: from a systematic literature review to a possible clinical management proposal. AB - The objectives of this study were to investigate the implications of human papillomavirus (HPV) sperm infection on male fertility, impairment of sperm parameters, and possible alteration of sperm nuclear status and to identify a possible effective management of infertile men with HPV sperm infection. We employed a systematic review and clinical management proposal at the Centers for Reproductive and Health care for treating infertile male patients with HPV infection. Literature search was carried out in electronic databases in the last two decades. We focused our attention on: (i) HPV sperm prevalence (ii) HPV related alteration of sperm parameters; (iii) molecular mechanisms of HPV semen infection and infertility. The main outcome measures were HPV prevalence in infertile male patients and semen parameters. The prevalence of HPV sperm infection ranges between 2 and 31% in men from general population and between 10 and 35.7% in men affected by unexplained infertility. The presence of HPV in semen is associated with an impairment of sperm motility and the presence of anti sperm antibodies. The molecular mechanisms underlying impairment of sperm motility apparatus need further evaluations. A greater attention should be applied to assess HPV sperm infection, particularly in men undergoing assisted reproduction techniques cycle for male infertility or sperm banking. It would be useful to perform HPV test and fluorescent in situ hybridization analysis for HPV in semen from these patients both at first admission, to define the possible presence and localization of semen infection, and after 6 months, to assess the possible virus clearance retrieval on normal sperm parameters. PMID- 25270520 TI - MicroRNA-200 family members and ZEB2 are associated with brain metastasis in gastric adenocarcinoma. AB - Although the incidence of brain metastasis in gastric cancer is relatively low, its prevalence may increase with improved therapy and longer survival tumors. The molecular mechanisms underlying brain metastases are not well understood. To gain insight into the mechanism of brain metastasis, we studied differences in microRNA (miRNA) expression levels in 8 cases of matched primary gastric adenocarcinoma and brain metastatic adenocarcinoma using the Illumina microRNA microarray chip. We identified 6 upregulated and 2 downregulated miRNAs in all 8 cases simultaneously. Interestingly, 2 out of 8 miRNAs (hsa-miR-141-3p and hsa miR-200b-3p) belonged to the miR-200 family. Online microRNA database searching revealed that ZEB2 is the top-ranked target gene for hsa-miR141-3p and hsa-miR 200b-3p, prompting us to focus ZEB2 expression in brain metastatic adenocarcinoma. We confirmed that ZEB2 expression was markedly downregulated in some brain metastatic samples. In addition, decreased ZEB2 expression was noted by western blot analysis of 2 metastatic gastric adenocarcinoma cell types that were derived by in vivo selection following intracardiac injection of gastric cancer cell lines. In conclusion, we demonstrate that expression of miRNA-200 family members and ZEB2 are associated with brain metastases of gastric adenocarcinoma, not only in matched patient samples, but also in metastatic cell lines that were derived by in vivo selection. PMID- 25270521 TI - Safety of antiandrogen therapy for treating prostate cancer. AB - INTRODUCTION: Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509). AREAS COVERED: This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone naive or in castration-resistant patients. EXPERT OPINION: Non-steroidal antiandrogens are widely used in the management of hormone-sensitive disease in combination with luteinizing hormone-releasing hormone agonists or in patients failing front-line treatment with androgen-deprivative maneuvers. In selected patients, non-steroidal antiandrogen monotherapy appears to yield comparable results as castration. Novel non-steroidal antiandrogens have been investigated with promising results in castration-resistant prostate cancer. Beyond the safety profile specific to any individual compound, increased testosterone and 17beta estradiol levels are commonly observed during antiandrogen monotherapy, leading to gynecomastia and breast pain. The safety profile of old and novel antiandrogens should be taken into account by clinicians in decision making and in selecting the most suitable patients. Beyond patient selection, full clinical evaluation of patient co-morbidities that might affect the drug tolerability and clinical monitoring are anyway required. PMID- 25270522 TI - The year for our new endeavor: 2015. PMID- 25270523 TI - Presence of anaplastic lymphoma kinase translocation in sarcomatoid carcinoma of head and neck and treatment effect of crizotinib: A case series. AB - BACKGROUND: Sarcomatoid carcinoma of the upper aerodigestive tract, a variant of squamous cell carcinoma, is a rare biphasic tumor consisting of epithelial and mesenchymal components. METHODS AND RESULTS: We report a case of 34-year-old woman with a relapsed refractory sarcomatoid carcinoma in the maxillary sinus. Because anaplastic lymphoma kinase (ALK) translocation is common in sarcoma, ALK fluorescence in situ hybridization (FISH) was performed and the result was positive. After crizotinib was administered, clinical improvement and stable disease lasted for 4 months. To identify the incidence of ALK rearrangement in this disease entity, ALK FISH was performed on tumor samples of 10 patients. Among them, 2 patients were positive. CONCLUSION: To the best of our knowledge, this is the first case report demonstrating the clinical benefit of crizotinib in sarcomatoid carcinoma of the head and neck with ALK translocation. Our results suggest that the ALK FISH test may be suitable and encouraged for patients with sarcomatoid carcinoma of the head and neck. PMID- 25270524 TI - Thoracic renal artery: a rare variant. A case study and literature review. AB - BACKGROUND: Variations in the course of paired renal arteries are common and are known causes of iatrogenic injury. However, a thoracic origin of the renal artery is rare and poses a greater risk for iatrogenic injury especially during thoracic endovascular or surgical interventions. PURPOSE: To describe a renal artery variant, its clinical implications in the context of procedural interventions, and to provide a literature review on renal artery variations. METHODS: An abdominal CT scan with IV contrast was obtained using a GE 64-slice helical CT scanner with subsequent sagittal, coronal, and 3-D reformations. A literature review was performed using Index Medicus. RESULTS: Right renal artery variant arising from the thoracic aorta at the lower aspect of the T10 vertebral body, coursing posteroinferiorly through the right diaphragmatic crux before reaching the right kidney hilum. CONCLUSION: A thoracic origin of the renal artery is an uncommon but important risk factor for vascular injury during endovascular and surgical interventions especially in the thorax. 3-D CT or CT angiography prior to an indicated procedure may prove useful for pre-interventional planning. PMID- 25270525 TI - Saturable absorption of intense hard X-rays in iron. AB - In 1913, Maurice de Broglie discovered the presence of X-ray absorption bands of silver and bromine in photographic emulsion. Over the following century, X-ray absorption spectroscopy was established as a standard basis for element analysis, and further applied to advanced investigation of the structures and electronic states of complex materials. Here we show the first observation of an X-ray induced change of absorption spectra of the iron K-edge for 7.1-keV ultra brilliant X-ray free-electron laser pulses with an extreme intensity of 10(20) W cm(-2). The highly excited state yields a shift of the absorption edge and an increase of transparency by a factor of 10 with an improvement of the phase front of the transmitted X-rays. This finding, the saturable absorption of hard X-rays, opens a promising path for future innovations of X-ray science by enabling novel attosecond active optics, such as lasing and dynamical spatiotemporal control of X-rays. PMID- 25270526 TI - Exploration of interactions between membrane proteins embedded in supported lipid bilayers and their antibodies by reflectometric interference spectroscopy-based sensing. AB - A microfluidic reflectometric interference spectroscopy (RIfS)-based sensor was fabricated to investigate the activity of multidrug resistance-associated protein 1 (MRP1), applied as a model membrane protein. Vesicles containing MRP1 were immobilized simply by injecting a vesicle solution (50 MUg mL(-1)) onto a zirconium oxide (ZrO2) chip under constant flow conditions. Monitoring the shift of the minimum reflectance wavelength (Deltalambda) of the RIfS demonstrated that the vesicles were adsorbed onto the ZrO2 chip in a Langmuir-like fashion and suggested that the lipid bilayer structure was preserved on the ZrO2 chip. The theoretical maximum physical thickness of the layer was 4.97 nm, which was close to the values previously reported for supported lipid bilayers (4.2 to 5.2 nm). When a model protein, the anti-MRP1 antibody (1-50 MUg mL(-1)), was injected onto the MRP1-immobilizing ZrO2 chip a concentration-dependent increase in Deltalambda was observed. In contrast, a ZrO2 chip on which the supported lipid bilayers did not contain MRP1 exhibited no response. Moreover, an anti-human IgG antibody generated no change in Deltalambda, confirming that anti-MRP1 antibodies were selectively bound to the MRP1 immobilized on the chip. These results show that the RIfS sensor can follow specific binding events of biologically active membrane proteins and represents a simple, label-free system capable of facilitating biomedical investigations. PMID- 25270527 TI - Down-regulation of connexin43 and connexin32 in keratocystic odontogenic tumours: potential association with clinical features. AB - AIMS: The objective of this study was to explore the potential involvement of connexin43 (Cx43) and connexin32 (Cx32), two vital members of the connexin families, in the pathogenesis of keratocystic odontogenic tumours (KCOT). METHODS AND RESULTS: The expression levels of Cx43 and Cx32 in human KCOT and normal oral mucosa (OM) tissues were measured using immunohistochemistry and real-time quantitative polymerase chain reaction (qPCR). The relationship between Cx43 and Cx32 expression and markers of proliferation [proliferating cell nuclear antigen (PCNA), cyclin D1], anti-apoptosis [B cell lymphoma 2 (Bcl-2)] and autophagy [light chain 3 (LC3), Sequestosome 1 p62 (p62)] was then investigated in the KCOT samples. The results showed that Cx43 and Cx32 expression was down-regulated significantly in KCOT samples relative to OM samples. Meanwhile, the expression levels of Cx43 and Cx32 were correlated negatively with the expression levels of PCNA, cyclin D1, Bcl-2, LC3 and p62, as confirmed further by double-labelling immunofluorescence analyses. CONCLUSIONS: This study reveals for the first time that Cx43 and Cx32 are down-regulated in KCOT and suggests an association with growth regulation, anti-apoptosis and autophagy in KCOT. PMID- 25270528 TI - Comparison of body temperature readings between an implantable microchip and a cloacal probe in lorikeets (Trichoglossus haematodus sp.). AB - Body temperature readings can be a useful diagnostic tool for identifying the presence of subclinical disease. Traditionally, rectal or cloacal thermometry has been used to obtain body temperatures. The use of implantable microchips to obtain these temperatures has been studied in a variety of animals, but not yet in avian species. Initially, timepoint one (T1), nine lorikeets were anesthetized via facemask induction with 5% isoflurane and maintained at 2-3% for microchip placement and body temperature data collection. Body temperature was measured at 0 and 2 min post-anesthetic induction both cloacally, using a Cardell veterinary monitor and also via implantable microchip, utilizing a universal scanner. On two more occasions, timepoints two and three (T2, T3), the same nine lorikeets were manually restrained to obtain body temperature readings both cloacally and via microchip, again at minutes 0 and 2. There was no statistical difference between body temperatures, for both methods, at T1. Microchip temperatures were statistically different than cloacal temperatures at T2 and T3. Body temperatures at T1, were statistically different from those obtained at T2 and T3 for both methods. Additional studies are warranted to verify the accuracy of microchip core body temperature readings in avian species. PMID- 25270529 TI - Polymorphisms of heat shock protein 90 (Hsp90) in the sea cucumber Apostichopus japonicus and their association with heat-resistance. AB - Heat shock protein 90 (Hsp90) functions as a molecular chaperone and plays an important role in the resistance of organisms to stress, particularly heat stress. In our study, 12 exons and 11 introns of hsp90 were identified in the sea cucumber Apostichopus japonicus. Twenty-two single nucleotide polymorphisms (SNPs), including three non-synonymous mutations, were detected in the exons. Susceptible and resistant individuals were distinguished using a high-temperature (32 degrees C) challenge experiment. Three blocks with high linkage disequilibrium were detected among these SNPs. Five of the twenty-two SNPs were shown to be significantly associated with susceptibility/resistance to high temperature by correlation analysis (chi-square test, P < 0.05). To confirm the importance of these five SNPs, a heat-resistance strain (HRS) was selected through three generations. Using the common population as the control group, it was shown that the distributions of genotypes and alleles of SNP e10-1 and e11-6 were significantly different between the two groups (P < 0.05). SNP e10-1 was trimorphic, with three alleles (A, C and T) and five genotypes (AA, CC, AT, CT and AC). The allele frequency of SNP e2-3 was also significantly associated with this trait (P < 0.05). This is the first demonstration of SNPs related to heat resistance in A. japonicus and supports the use of SNP markers in the selective breeding of sea cucumbers. PMID- 25270530 TI - The response of porcine monocyte derived macrophages and dendritic cells to Salmonella Typhimurium and lipopolysaccharide. AB - BACKGROUND: Following infection and initial multiplication in the gut lumen, Salmonella Typhimurium crosses the intestinal epithelial barrier and comes into contact with cells of the host immune system. Mononuclear phagocytes which comprise macrophages and dendritic cells (DC) are of key importance for the outcome of Salmonella infection. Although macrophages and DC may differentiate from a common precursor, their capacities to process and present antigen differ significantly. In this study, we therefore compared the response of porcine macrophages and DC differentiated from peripheral blood monocytes to S. Typhimurium and one of the most potent bacterial pathogen associated molecular patterns, bacterial lipopolysaccharide. To avoid any bias, the expression was determined by protein LC-MS/MS and verified at the level of transcription by quantitative RT-PCR. RESULTS: Within 4 days of culture, peripheral blood monocytes differentiated into two populations with distinct morphology and expression of MHC II. Mass spectrometry identified 446 proteins in macrophages and 672 in DC. Out of these, 433 proteins were inducible in macrophages either after infection with S. Typhimurium or LPS exposure and 144 proteins were inducible in DC. The expression of the 46 most inducible proteins was verified at the level of transcription and the differential expression was confirmed in 22 of them. Out of these, 16 genes were induced in both cell types, 3 genes (VCAM1, HMOX1 and Serglycin) were significantly induced in macrophages only and OLDLR1 and CDC42 were induced exclusively in DC. Thirteen out of 22 up-regulated genes contained the NF-kappaB binding site in their promoters and could be considered as either part of the NF-kappaB feedback loop (IkappaBalpha and ISG15) or as NF kappaB targets (IL1beta, IL1alpha, AMCF2, IL8, SOD2, CD14, CD48, OPN, OLDLR1, HMOX1 and VCAM1). CONCLUSIONS: The difference in the response of monocyte derived macrophages and DC was quantitative rather than qualitative. Despite the similarity of the responses, compared to DC, the macrophages responded in a more pro-inflammatory fashion. PMID- 25270531 TI - Violence against primary school children with disabilities in Uganda: a cross sectional study. AB - BACKGROUND: 150 million children live with disabilities globally, and a recent systematic review found 3 to 4 times the levels of violence versus non-disabled children in high income countries. However, almost nothing is known about violence against disabled children in lower income countries. We aim to explore the prevalence, patterns and risk factors for physical, sexual and emotional violence among disabled children attending primary school in Luwero District, Uganda. METHODS: We performed a secondary analysis of data from the baseline survey of the Good Schools Study. 3706 children and young adolescents aged 11-14 were randomly sampled from 42 primary schools. Descriptive statistics were computed and logistic regression models fitted. RESULTS: 8.8% of boys and 7.6% of girls reported a disability. Levels of violence against both disabled and non disabled children were extremely high. Disabled girls report slightly more physical (99.1% vs 94.6%, p = 0.010) and considerably more sexual violence (23.6% vs 12.3%, p = 0.002) than non-disabled girls; for disabled and non-disabled boys, levels are not statistically different. The school environment is one of the main venues at which violence is occurring, but patterns differ by sex. Risk factors for violence are similar between disabled and non-disabled students. CONCLUSIONS: In Uganda, disabled girls are at particular risk of violence, notably sexual violence. Schools may be a promising venue for intervention delivery. Further research on the epidemiology and prevention of violence against disabled and non disabled children in low income countries is urgently needed. PMID- 25270532 TI - The effect of bilateral superior laryngeal nerve lesion on swallowing: a novel method to quantitate aspirated volume and pharyngeal threshold in videofluoroscopy. AB - The purpose was to determine the effect of bilateral superior laryngeal nerve (SLN) lesion on swallowing threshold volume and the occurrence of aspiration, using a novel measurement technique for videofluoroscopic swallowing studies (VFSS) in infant pigs. We used a novel radiographic phantom to assess volume of the milk containing barium from fluoroscopy. The custom made phantom was firstly calibrated by comparing image intensity of the phantom with known cylinder depths. Secondly, known volume pouches of milk in a pig cadaver were compared to volumes calculated with the phantom. Using these standards, we calculated the volume of milk in the valleculae, esophagus and larynx, for 205 feeding sequences from four infant pigs feeding before and after had bilateral SLN lesions. Swallow safety was assessed using the tested and validated IMPAS (Dysphagia 28(2):178 187, 2013). The log-linear correlation between image intensity values from the phantom filled with barium milk and the known phantom cylinder depths was strong (R (2) > 0.95), as was the calculated volumes of the barium milk pouches. The threshold volume of bolus in the valleculae during feeding was significantly larger after bilateral SLN lesion than in control swallows (p < 0.001). The IMPAS score increased in the lesioned swallows relative to the controls, indicating substantially impaired swallowing (p < 0.001). Bilateral SLN lesion dramatically increased the aspiration incidence and the threshold volume of bolus in valleculae. The use of this phantom permits quantification of the aspirated volume of fluid, allowing for more accurate 3D volume estimation from 2D X-ray in VFSS. PMID- 25270533 TI - Herpes Simplex Virus Clearance during Purification of a Recombinant Adeno associated Virus Serotype 1 Vector. AB - Gene delivery vectors based on adeno-associated virus (AAV) have potential utility in the treatment of many genetic disorders. Current AAV vector manufacturing methods employ helper viruses to deliver functions needed to produce replication-defective recombinant AAV (rAAV) vectors, and clearance of infectious helper virus from the drug substance is essential for ensuring the safety of rAAV-based therapies. We have developed a manufacturing method for the production of rAAV vectors using a recombinant herpes simplex virus type 1 (rHSV) complementation system in suspension baby hamster kidney (sBHK) cells. The manufacturing process includes three primary unit operations, detergent lysis of the cell harvest and two downstream column chromatography steps, which achieve viral clearance. These unit operations inactivate and remove HSV, including replication-competent HSV present at low levels in rHSV helper stocks. Here we report results quantifying the reduction in HSV achieved during rAAV vector purification. Clearance of HSV was at least 6.84 log10 with 1% Triton X-100, 4.34 log10 with CIM Q column chromatography and 2.86 log10 with AVB affinity chromatography. Combined, these three orthogonal methods achieved clearance of at least 14.04 log10 of HSV. The total input quantity of rHSV in a 100 L production batch is approximately 1.2 * 1012 plaque-forming units (pfu) and after purification the concentration of residual rHSV in the resulting drug substance of approximately 450 mL would be less than 2.43* 10-5 pfu/mL. A rAAV vector produced using this method was used in a clinical trial in which subjects receive up to 100 IM injections of 1.35 mL each, which would contain a maximum of 2.28* 10 3 pfu of HSV. These results support the safety of rAAV vectors produced using our rHSV complementation method. PMID- 25270535 TI - Quality and safety during the off hours in medicine units: a mixed methods study of front-line provider perspectives. AB - BACKGROUND: Hospital off-hours care is associated with poor outcomes. Mutual conceptualization among provider groups may facilitate improvement efforts. Provider-perceived threats to quality are unreported. OBJECTIVES: The objectives of this study were to identify perceived off-hours quality and safety issues, assess the most significant, and evaluate differences between nurses, and attending and housestaff physicians, and providers with day and night experience. DESIGN: Prospective, sequential, exploratory mixed-methods study. MEASURES: Open ended descriptions of adverse events/near misses occurring overnight (n = 190) were analyzed using thematic analysis. From these results, a survey was developed to assess perceptions of quality/frequency of each issue (7-point scale, 7 = the highest rating) and highest-quality overnight period (7-10 pm, 10 pm-1 am, 1-4 am, 4-7 am). RESULTS: Primary issues related to mismanagement, delivery processes, and communication/coordination. Of 214 surveys, 160 responses (75%) were received. Least-optimal issues related to "communication" (2.93) and "timeliness/safety" (3.89) of emergency department transfers; most-optimal issues related to timely lab reporting (4.70). On the 7-point scale, comparisons among nurses, and attending and housestaff physicians revealed differences in quality of "communication between physicians" (4.29 vs 6.00 vs 5.14) and "communication between consultants-primary providers" (3.46 vs 5.75 vs 4.35, P < 0.001). Comparisons between day-night providers revealed lower ratings from day providers in 12/24 items (P < 0.05), including "communication during emergency department transfers" (4.81 vs 3.86). All groups ranked 4 to 7am lowest in quality. CONCLUSIONS: Nurses, and attending and housestaff physicians lack a shared mental model of off-hours care. Several issues, including emergency department transfers and timeliness of consults, were identified by all providers as problematic, meriting further investigation and intervention. PMID- 25270534 TI - Multiple hypersensitivities including recurrent airway obstruction, insect bite hypersensitivity, and urticaria in 2 warmblood horse populations. AB - BACKGROUND: Multiple hypersensitivities (MHS) have been described in humans, cats, and dogs, but not horses. HYPOTHESES: Horses suffering from recurrent airway obstruction (RAO), insect bite hypersensitivity (IBH), or urticaria (URT) will have an increased risk of also being affected by another one of these hypersensitivities. This predisposition for MHS also will be associated with decreased shedding of strongylid eggs in feces and with a single nucleotide polymorphism (SNP BIEC2-224511), previously shown to be associated with RAO. ANIMALS: The first population (P1) included 119 randomly sampled horses representative of the Swiss sporthorse population; the replication population (P2) included 210 RAO-affected Warmblood horses and 264 RAO-unaffected controls. All horses were Warmbloods, 14 years or older. METHODS: Associations between disease phenotypes (RAO, IBH, URT, MHS) fecal egg counts, the SNP BIEC2-224511 as well as management and environmental factors were investigated. RESULTS: In P1, RAO-affected horses had a 13.1 times higher odds ratio (OR) of also suffering from IBH (P = .004). In P2, the respective OR was 7.4 (P = .002) and IBH-affected horses also showed a 7.1 times increased OR of concomitantly suffering from URT (P < .001). IBH, URT, and MHS phenotypes were significantly associated with the absence of nematode eggs in the feces. CONCLUSIONS AND CLINICAL IMPORTANCE: This is the first report of MHS in horses. Specifically, an increased risk for IBH should be expected in RAO-affected horses. PMID- 25270536 TI - Ecological genomics meets community-level modelling of biodiversity: mapping the genomic landscape of current and future environmental adaptation. AB - Local adaptation is a central feature of most species occupying spatially heterogeneous environments, and may factor critically in responses to environmental change. However, most efforts to model the response of species to climate change ignore intraspecific variation due to local adaptation. Here, we present a new perspective on spatial modelling of organism-environment relationships that combines genomic data and community-level modelling to develop scenarios regarding the geographic distribution of genomic variation in response to environmental change. Rather than modelling species within communities, we use these techniques to model large numbers of loci across genomes. Using balsam poplar (Populus balsamifera) as a case study, we demonstrate how our framework can accommodate nonlinear responses of loci to environmental gradients. We identify a threshold response to temperature in the circadian clock gene GIGANTEA 5 (GI5), suggesting that this gene has experienced strong local adaptation to temperature. We also demonstrate how these methods can map ecological adaptation from genomic data, including the identification of predicted differences in the genetic composition of populations under current and future climates. Community level modelling of genomic variation represents an important advance in landscape genomics and spatial modelling of biodiversity that moves beyond species-level assessments of climate change vulnerability. PMID- 25270537 TI - Comment on "current understanding of ZIP and ZnT zinc transporters in human health and diseases". PMID- 25270538 TI - Effects of icariin on the regulation of the OPG-RANKL-RANK system are mediated through the MAPK pathways in IL-1beta-stimulated human SW1353 chondrosarcoma cells. AB - Arthrodial cartilage degradation and subchondral bone remodeling comprise the most predominant pathological changes in osteoarthritis (OA). Moreover, accumulating evidence indicates that the abnormal expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL) and receptor activator of nuclear factor kappa-B (RANK) plays a vital role in the collapse of cartilage and subchondral bone. In the present study, the effects of icariin on the expression levels of these 3 factors in interleukin (IL)-1beta-stimulated SW1353 chondrosarcoma cells were investigated. The SW1353 chondrosarcoma cells were cultured in the presence or absence of icariin and mitogen-activated protein kinase signaling pathway inhibitors, and were then stimulated with IL-1beta. Cell viability was assessed by MTT assay. The mRNA and protein expression of OPG, RANKL and RANK was analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and ELISA, respectively. In addition, the levels of phosphorylated p38 (p-p38) and phosphorylated extracellular signal-regulated kinase (p-ERK)1/2 were detected by western blot analysis. The results from western blot analysis revealed that treatment with icariin decreased the levels of p-p38 and increased the levels of p-ERK1/2 in the IL-1beta-stimulated SW1353 cells. In addition, treatment with icariin decreased the levels of RANK and RANKL. Furthermore, the suppressive effects of icariin on OPG and OPG/RANKL were greater than those exhibited by the p38 signaling pathway inhibitor (SB203580). The findings of the the present study suggest that icariin has therapeutic potential for use in the treatment of OA. PMID- 25270540 TI - Determination of the influence of substrate concentration on enzyme selectivity using whey protein Isolate and Bacillus licheniformis protease. AB - Increasing substrate concentration during enzymatic protein hydrolysis results in a decrease in hydrolysis rate. To test if changes in the mechanism of hydrolysis also occur, the enzyme selectivity was determined. The selectivity is defined quantitatively as the relative rate of hydrolysis of each cleavage site in the protein. It was determined from the identification and quantification of the peptides present in the hydrolysates. Solutions of 0.1-10% (w/v) whey protein isolate (WPI) were hydrolyzed by Bacillus licheniformis protease at constant enzyme-to-substrate ratio. The cleavage sites were divided into five groups, from very high (>10%) to very low selectivity (<0.1%). The selectivity toward cleavage sites after Glu 62 and 134 was 2 times higher at 10% (w/v) WPI than at the lower protein concentrations. This finding shows that both the rate of hydrolysis and the enzyme selectivity were influenced by the substrate concentration. PMID- 25270541 TI - Non-medical use of prescription stimulants for academic purposes among college students: a test of social learning theory. AB - OBJECTIVE: The current research examines whether measures associated with Akers' social learning theory are related to non-medical use of prescription stimulants for academic reasons among college students. METHODS: We examine data from a sample of 549 undergraduate students at one public university in the Southeastern United States. We estimate several logistic regression models to test our hypotheses. RESULTS: The findings indicated that roughly 17% of students reported non-medical use of prescription stimulants for academic reasons during the past year. In separate models, all four of the social learning measures were significantly correlated to non-medical use. In the complete model, the risk of non-medical prescription stimulant use for academic reasons was increased for respondents who reported more of their friends used and also for respondents who believed that prescription stimulants were an effective study aid. CONCLUSIONS: The current research fills an important gap in the literature regarding theoretical explanations for non-medical prescription stimulant use. Given the high prevalence of non-medical prescription stimulant use and the known risks associated with non-medical use this research can help inform intervention strategies for college populations. PMID- 25270542 TI - Early occlusion control of the intrapericardial inferior vena cava under femoral femoral extracorporeal circulation using a technique to prevent pulmonary embolism during nephrectomy for renal cell carcinoma with tumor thrombus: two case reports. AB - BACKGROUND: Renal cell carcinoma with tumor thrombus extension into the inferior vena cava occurs in approximately 5% of cases. Despite such situations, an aggressive surgical approach is recommended. However, intraoperative prevention of pulmonary embolism by a fragmended tumor thrombus is necessary. To prevent pulmonary embolism, placement of a temporary suprarenal filter has been attempted, however, the precise placement of a temporary filter between the level of the hepatic vein and right atrium is not always easy because of its migration, tilting, and strut fracture. Here we report a method for early occlusion control of the intrapericardial inferior vena cava to prevent pulmonary embolism during nephrectomy in level II or III renal cell carcinoma tumor thrombus. CASE PRESENTATION: Our first case was a 37-year-old Japanese man with left renal cell carcinoma extending into the inferior vena cava below the main hepatic vein (level II) and our second was a 75-year-old Japanese man with right renal cell carcinoma extending into the retrohepatic inferior vena cava at the main hepatic vein (level III). En block resection of the kidney and the tumor thrombus was performed with the aid of partial extracorporeal circulation; the postoperative course of both patients was uneventful. CONCLUSION: Control of intrapericardial inferior vena cava is a feasible method to prevent pulmonary embolism. PMID- 25270543 TI - A plastic surgery resident's view of aesthetic training and the future. PMID- 25270544 TI - An alternative outpatient care model: postoperative guest suite-based care. AB - BACKGROUND: Patients recovering from outpatient surgery are responsible for managing their pain, managing ambulation, and even implementing thromboembolism prophylaxis after discharge. Because of the importance of postoperative care to prevent complications, a model of care that helps a patient transition to independent self-care could provide optimal results. OBJECTIVES: The authors investigated the safety and morbidity rate for patients who underwent body contouring procedures and overnight care at an attached, nurse-staffed guest suite facility. METHODS: A retrospective review was conducted of 246 patients who underwent major body contouring and who stayed at least 1 night in the guest suite facility. Major complications included a return to the operating room within 48 hours, major wound infection, and unplanned hospitalization within 48 hours. Minor complications included any postsurgical effect necessitating unplanned physician intervention within the first 30 days. Univariate analyses correlating patient characteristics and complication rates were conducted, as well as comparison of complication rates among same procedures reported in the literature. RESULTS: The complication rate (major and minor complications) was 25.20%. Surgical site infection occurred in 8.13% of patients. The most common wound complication was erythema around the incision site (12.20%). Death, deep vein thrombosis, or pulmonary embolism did not occur. Comparison with relevant results reported in the literature indicated a significant reduction in the occurrence of postoperative venous thromboembolism. CONCLUSIONS: Patient education after surgery is essential to healing and adequate care. The guest suite model provides improved care and education for the patient and family postsurgery by addressing some of the known risk factors of plastic surgery. LEVEL OF EVIDENCE: 4. PMID- 25270545 TI - Evidence-based evaluation technique to assess augmentation mammaplasty results: a simple method to objectively analyze mammary symmetry and position. AB - BACKGROUND: Despite the great variety of mammaplasty techniques, outcome assessment remains a challenging issue. OBJECTIVES: The authors devised an objective method to evaluate mammary symmetry based on statistical analysis of objective manual breast measurements and validated the method by applying it to results of a randomized controlled trial on the correction of breast asymmetry. METHODS: Sixty consecutive patients with hypoplastic breasts and small-volume asymmetry were enrolled in the study and randomly assigned to 1 of 2 groups. One group received a fixed-volume implant in 1 breast and an adjustable-volume implant in the other. The other group received 2 fixed-volume implants of different sizes. The differences in specific breast and chest measurements, obtained before surgery and during follow-up, were analyzed statistically with the Wilcoxon signed rank test. RESULTS: Correction of the asymmetry resulted in the reduction of the differences between left and right values for each specific breast measurement. Placement of an adjustable implant on 1 side yielded better symmetry than placement of 2 fixed-volume prostheses of different sizes. Patient and physician satisfaction was high for both groups. CONCLUSIONS: This objective analysis of clinical parameters enables comparing results for different patients in large clinical trials and for the same patient at different follow-up periods. LEVEL OF EVIDENCE: 3. PMID- 25270546 TI - Changes in gene expression and methylation in the blood of patients with first episode psychosis. AB - Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n=51) and healthy controls (n=51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was observed in FEP patients relative to controls. Also, when we compare the FEP patients after risperidone treatment with controls, this difference remains significant, and no significant differences were observed in GCH1 mRNA levels when comparing patients before and after risperidone treatment. Additionally, although the differences were non-significant after Bonferroni correction, the expression of GCH1 seemed to be correlated with PANSS scores, and the GCH1 promoter region was more methylated in FEP than in controls, thus corroborating the results obtained at the mRNA level. Few studies have been conducted on GCH1, and future studies are needed to clarify its potential role in the progression of schizophrenia. PMID- 25270548 TI - A pilot study of the effect of Kinesiology tape on knee proprioception after physical activity in healthy women. AB - OBJECTIVES: Kinesiology tape has gained significant popularity in recent years and is widely used as an adjunct for treatment and prevention of musculoskeletal injuries. However, evidence regarding its influence on knee proprioception is scarce. The purpose of this study was to evaluate the effect of Kinesiology tape on knee proprioception after physical activity in healthy women. It was hypothesized that Kinesiology tape enhances knee proprioception. DESIGN: Longitudinal analysis, pretest-posttest design. METHODS: Twelve young women with healthy knees were tested for knee proprioception without the use of Kinesiology tape and wearing Kinesiology tape at the knee. The joint position sense was measured at the start and after a 30-min uphill walking protocol on a treadmill. Outcome was the knee angle deviation. RESULTS: No significant difference of proprioceptive performance between the application with Kinesiology tape and without Kinesiology tape was found after uphill walking (p > 0.05). However, when the participants' results for knee angle deviation were graded into good (< 6.1 degrees ) and poor ( > 6.1 degrees ), Kinesiology tape significantly enhanced those with poor proprioceptive ability after uphill walking, compared to the untaped knee (p = 0.002). CONCLUSIONS: This study has shown that the application of Kinesiology tape did not improve knee proprioception in a group of healthy young women. However, it also has demonstrated that Kinesiology tape provided significant proprioceptive enhancement at the knee joint after uphill walking in healthy women with poor proprioceptive ability. This may support its use in sports medicine for preventing knee injuries. PMID- 25270547 TI - The somatic common deletion in mitochondrial DNA is decreased in schizophrenia. AB - Large deletions in mitochondrial DNA (mtDNA) can occur during or result from oxidative stress leading to a vicious cycle that increases reactive oxygen species (ROS) damage and decreases mitochondrial function, thereby causing further oxidative stress. The objective of this study was to determine if disease specific brain differences of the somatic mtDNA common deletion (4977 bp) could be observed in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) compared to a control group. The accumulation of the mtDNA common deletion was measured using a quantitative assay across 10 brain regions (anterior cingulate cortex, amygdala, caudate nucleus, dorsolateral prefrontal cortex, hippocampus, nucleus accumbens, orbitofrontal cortex, putamen, substantia nigra, and thalamus). The correlation with age of the mtDNA deletion was highly significant across brain regions as previously shown. A significant decrease in the global accumulation of common deletion in subjects with SZ compared to MDD, BD, and controls was observed after correcting for age, pH, PMI, and gender. The decreases in SZ were largest in dopaminergic regions. One potential side effect of antipsychotic drugs on mitochondria is the impairment of mitochondria function, which might explain these findings. The decreased global brain mtDNA common deletion levels suggests that mitochondrial function is impaired and might be part of an overall mitochondria dysfunction signature in subjects with schizophrenia. PMID- 25270549 TI - Configuring the users of new HIV-prevention technologies: the case of HIV pre exposure prophylaxis. AB - HIV pre-exposure prophylaxis (PrEP) is a prevention technology that involves prescribing antiretroviral drugs to HIV-negative people to protect them from infection. This paper considers how the development of the technology has necessitated the parallel configuration of its users, and how this process has affected the perception and uptake of the technology. In designing a technology, potential users are typically defined, enabled and constrained, partly to create a target population (or market) for the technology, but also to reassure people that it can be used safely and effectively. This process may or may not be helpful for the uptake and use of the technology. Published research on PrEP indicates that while the technology was under trial, the primary focus was on the 'at-risk' subject in need of PrEP, with little or no consideration of the other qualities necessary for successful use. Post-trial accounts of PrEP have begun to outline desirable qualities of successful PrEP use, such as caution, compliance and being organised. It appears that the PrEP user was only partially configured during the technology's development, and the initial focus on risk has done little to counter fears of the technology, which may partially account for its slow uptake. PMID- 25270550 TI - Covered versus uncovered self-expandable metallic stents for palliation of malignant gastric outlet obstruction: a systematic review and meta-analysis. AB - BACKGROUND: Self-expandable metallic stents (SEMSs) are widely used for palliation of malignant gastric outlet obstruction (GOO). There are two types of SEMS, covered and uncovered, each with its own advantages and disadvantages. We aimed to compare the efficacy and safety between uncovered and covered SEMSs in the palliation of malignant gastric outlet obstruction. METHODS: Databases including PubMed, EMBASE, the Cochrane Library, the Science Citation Index and momentous meeting abstracts were searched and evaluated by two reviewers independently. RESULTS: Nine trials involving 849 patients were analyzed. Meta analysis showed there was no significant difference in technical success rate (RR 1.0, 95% CI [0.98, 1.01]), clinical success rate (RR 1.04, 95% CI [0.98, 1.11]), post-stenting dysphagia score (WMD -0.01, 95% CI [-0.52, 0.50]), stent patency (WMD -0.31, 95% CI [-1.73, 1.11]), overall complications (RR 1.07, 95% CI [0.87, 1.32]) and reintervention rate (RR 1.30, 95% CI [0.92, 1.83]) between covered and uncovered SEMSs group. However, covered SEMSs were associated with higher migration rate (RR 3.48, 95% CI [2.16, 5.62], P < 0.00001) and lower obstruction rate (RR 0.42, 95% CI [0.24, 0.73], P = 0.002). CONCLUSIONS: In the palliative treatment of malignant gastric outlet obstruction, both covered and uncovered SEMSs are safely and effective. Covered stents can reduce the risk of restenosis, whereas uncovered stents are effective in decreasing stent migration. PMID- 25270551 TI - How rhinovirus infections cause exacerbations of asthma. AB - Rhinovirus (RV) infections are closely linked to exacerbations of asthma, and yet most RV infections of patients with asthma cause only upper respiratory symptoms. These findings suggest that RV and other viral infections contribute to the causation of acute exacerbations of asthma, but that additional cofactors are generally required. In fact, factors related to the host, virus, and environment have been identified that affect the severity of RV infections, and propensity to develop lower respiratory tract symptoms. This review will discuss these factors and how their effects may act alone or in combination to increase the probability of RV-induced exacerbations of asthma. PMID- 25270552 TI - Silencing of the glypican-3 gene affects the biological behavior of human hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in the world. The gene glypican-3 (GPC3) is reported to be a potential therapeutic target for HCC. In this study, we use RNA interference with lentiviral vectors to explore the effect of GPC3 silencing on the biological behavior of HCC cells and the potential role of the GPC3 protein in the activation of epithelial mesenchymal transition (EMT), which relates to HCC cell invasion and migration. Our data suggest that GPC3 silencing leads to a decrease in HCC cell proliferation and to an increase in apoptosis. We demonstrated that GPC3 silencing regulates cell invasion and migration, most probably through the activation of the EMT cellular program. In conclusion, GPC3 is associated with the HCC cell biological behavior, while the relationship between GPC3 and EMT in tumorigenesis of HCC deserves future investigation. PMID- 25270553 TI - Dynamic contrast-enhanced magnetic resonance imaging of metacarpophalangeal joints reflects histological signs of synovitis in rheumatoid arthritis. AB - INTRODUCTION: Synovial inflammation and joint destruction in rheumatoid arthritis (RA) may progress despite clinical remission. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly used to detect synovial inflammation in RA. Although small joints such as metacarpophalangeal (MCP) joints are mainly affected by RA, MRI findings have never been directly compared to histological synovitis in MCP synovial tissue. The objective of the current study was therefore to analyse if DCE-MRI relates to histological signs of synovitis small RA joints. METHODS: In 9 RA patients, DCE-MRI (3 Tesla, dynamic 2D T1 weighted turbo-flash sequence) of the hand was performed prior to arthroscopically-guided synovial biopsies from the second MCP of the imaged hand. Maximum enhancement (ME), rate of early enhancement, and maximum rate of enhancement were assessed in the MCP. Synovial biopsies were stained for determination of sublining CD68 and the Synovitis Score. Correlations between MRI and histological data were calculated according to Spearman. RESULTS: ME of the MCP significantly correlated to sublining CD68 staining (r = 0.750, P = 0.02), the Synovitis Score (r = 0.743, P = 0.02), and the subscores for lining layer hypertrophy (r = 0.789, P = 0.01) and cellular density (r = 0.842; P = 0.004). CONCLUSIONS: Perfusion imaging of synovial tissue in RA finger joints employing DCE-MRI reflects histological synovial inflammation. According to our study, ME is the most closely associated parameter amongst the measures considered. PMID- 25270554 TI - Predictors of cancer fear: the association between mass media and fear of cancer among cancer diagnosed and nondiagnosed individuals. AB - Few studies have explored the impact of mass media on fear of cancer levels. This study investigates whether television and Internet use are associated with fear of cancer, and whether this association is different for cancer diagnosed and nondiagnosed individuals. A quantitative, standardized survey was used and administered to 2008 respondents in Flanders (Belgium), of which 621 individuals were diagnosed with cancer. For statistical analyses, hierarchical regression analyses, independent samples T-tests and post hoc mediation analyses were conducted. The results indicated that cancer diagnosed individuals differed from nondiagnosed individuals in terms of perceived cancer susceptibility, perceived cancer severity, fear of cancer, and media use. Furthermore, television exposure was directly and positively related to fear of cancer, whereas Internet use was not. The relationship between television and Internet use and fear of cancer was not different for cancer diagnosed and nondiagnosed individuals. Additional post hoc mediation analyses, however, seemed to suggest that watching more television and surfing more on the Internet could both lead to having a more negative perceived health and this was in turn associated with higher fear of cancer. To help reduce the burden of fear of cancer, cancer educators and individuals working with cancer patients need to be aware of the possible negative effects media use might have on health perception and on the levels of fear of cancer. PMID- 25270555 TI - Evaluation of the Impact of Different Types of Health Education on the Adoption and Preservation of Prohealth Attitudes in Preventing Cancer in Juveniles Younger than 18 Years. AB - Reduction in the incidence of cancer can be achieved through appropriate health behaviors. We hypothesized that education would improve knowledge of cancer prevention, and this, in turn, will affect and individual's readiness to modify lifestyle. The aim of this study was to assess the impact of cancer prevention education on adopting and preserving prohealth attitudes among high school students in Poland. Research participants were 307 high school students varying by gender, place of residence, parents' education, and type of school education. Participants were divided into five groups, of which four were educated using different methods according to classification methods based on the concept of multilateral learning. The fifth (control) group was not educated. The effects of education were assessed 1 month and 1 year after education. General knowledge about cancer and healthy lifestyle level before education was low. After education, both increased compared with the control group. There was a clear relationship between level of knowledge and readiness to adopt and healthy attitudes and behavior. The most effective method of education was a discussion and a lecture by means of teaching complex. Education significantly improved generally low knowledge about cancer and healthy lifestyle in high school students. This indicates the urgent need to implement such educational programs. PMID- 25270556 TI - Medical Advocacy and Supportive Environments for African-Americans Following Abnormal Mammograms. AB - African-American women experience disproportionately adverse outcomes relative to non-Latina White women after an abnormal mammogram result. Research has suggested medical advocacy and staff support may improve outcomes among this population. The purpose of the study was to understand reasons African-American women believe medical advocacy to be important and examine if and how staff can encourage and be supportive of medical advocacy. A convenience-based sample of 30-74-year-old women who self-identified as African-American/Black/of African descent and who had received an abnormal mammogram result was recruited from community-based organizations, mobile mammography services, and the local department of health. This qualitative study included semi-structured interviews. Patients perceived medical advocacy to be particularly important for African-Americans, given mistrust and discrimination present in medical settings and their own familiarity with their bodies and symptoms. Respondents emphasized that staff can encourage medical advocacy through offering information in general in a clear, informative, and empathic style. Cultural competency interventions that train staff how to foster medical advocacy may be a strategy to improve racial disparities following an abnormal mammogram. PMID- 25270557 TI - Objective of study of associations between active commuting, body fat, and body mass index seems not to have been directly addressed. PMID- 25270558 TI - The time course of the aversive conflict signal. AB - The idea that conflicts are aversive signals recently has gained strong support by both physiological as well as psychological evidence. However, the time course of the aversive signal has not been subject to direct investigation. In the present study, participants had to judge the valence of neutral German words after being primed with conflict or non-conflict Stroop stimuli in three experiments with varying SOA (200 ms, 400 ms, 800 ms) and varying prime presentation time. Conflict priming effects (i.e., increased frequencies of negative judgments after conflict as compared to non-conflict primes) were found for SOAs of 200 ms and 400 ms, but absent (or even reversed) with a SOA of 800 ms. These results imply that the aversiveness of conflicts is evaluated automatically with short SOAs, but is actively counteracted with prolonged prime presentation. PMID- 25270559 TI - The influence of acute intense exercise on exogenous spatial attention depends on physical fitness level. AB - We investigated the effect of a previous bout of intense exercise on exogenous spatial attention. In Experiment 1, a group of participants performed an exogenous spatial task at rest (without prior effort), immediately after intense exercise, and after recovering from an intense exercise. The analyses revealed that the typical "facilitation effect" (i.e., faster reaction times on cued than on uncued trials) immediately after exercise was positively correlated with participants' fitness level. In Experiment 2, a high-fit and a low-fit group performed the same task at rest (without prior effort) and immediately after an intense exercise. Results revealed that, after the bout of exercise, only low-fit participants showed reduced attentional effects compared to the rest condition. We argue that the normal functioning of exogenous attention was influenced by intense effort, affecting low-fit participants to a larger extent than to high fit participants. As a consequence, target processing was prioritized over irrelevant stimuli. PMID- 25270560 TI - Distraction by deviance: comparing the effects of auditory and visual deviant stimuli on auditory and visual target processing. AB - We report the results of oddball experiments in which an irrelevant stimulus (standard, deviant) was presented before a target stimulus and the modality of these stimuli was manipulated orthogonally (visual/auditory). Experiment 1 showed that auditory deviants yielded distraction irrespective of the target's modality while visual deviants did not impact on performance. When participants were forced to attend the distractors in order to detect a rare target ("target distractor"), auditory deviants yielded distraction irrespective of the target's modality and visual deviants yielded a small distraction effect when targets were auditory (Experiments 2 & 3). Visual deviants only produced distraction for visual targets when deviant stimuli were not visually distinct from the other distractors (Experiment 4). Our results indicate that while auditory deviants yield distraction irrespective of the targets' modality, visual deviants only do so when attended and under selective conditions, at least when irrelevant and target stimuli are temporally and perceptually decoupled. PMID- 25270561 TI - Orthographic and morphemic effects in the written syllable counting task. AB - According to a recent hypothesis, the organization of letters into groups of successive consonants and vowels (i.e., CV pattern) constrains the orthographic structure of words. Here, we examined to what extent the morphological structure of words modifies the influence of the CV pattern in a syllable counting task. Participants were presented with written words matched for the number of syllables and comprising either one vowel cluster less than the number of syllables (hiatus words, e.g., creation) or the same number of vowel clusters (control words, e.g., crepiter). Participants were slower and less accurate for hiatus than control stimuli, be it words (Experiments 1, 3) or pseudowords (Experiment 2). More importantly, this hiatus effect was present even when the stimuli had a morphemic boundary falling within the hiatus (e.g., re-agir). The results suggest that the CV pattern of items more strongly influences performance in the syllable counting task than the morphological structure. PMID- 25270562 TI - Is elapsing time really recoded into spatial linear representation in working memory? AB - A growing body of evidence suggested that elapsing time is tightly associated with space in a specific way (e.g., Spatial Temporal Association of Response Codes or STARC effect). However, existing findings cannot justify a hypothesis that elapsing time is recoded directly into a spatial linear representation in working memory. The present study addresses this fundamental question by using three modified STARC-related working memory paradigms. In different experiments, participants were asked to give order judgment, order-irrelevant STM recognition judgment, or motor-related free-choice judgment, immediately after successive presentation of a set of disparate stimuli. Results show that responses to early stimuli were faster or more often with the left key and responses to late stimuli were faster or more often with the right key. These findings clearly support the hypothesis that elapsing time is directly and automatically recoded into a spatial linear representation in working memory. PMID- 25270563 TI - Doctors are urged to be alert to signs of child sexual exploitation. PMID- 25270564 TI - Comment on "Sweat but no gain": inhibiting proliferation of multidrug resistant cancer cells with "ersatzdroges". PMID- 25270565 TI - Factors Related to Self-Reported Attention Deficit Among Incoming University Students. AB - OBJECTIVE: This study was designed to explore physical, social/behavioral, and mental health factors among incoming university students with elevated self reported ADHD symptoms. METHOD: A total of 5,240 incoming university students were recruited. The test battery included the ADHD Self-Report Scale, the Measurement of Support Functions, the Chinese Internet Addiction Scale-Revision, Quality of Life assessment, the Brief Symptoms Rating Scale, and the 10-item Social Desirability Scale. RESULTS: ADHD symptoms were elevated in 8.6% of the sample. Only individuals with a lower social desirability score, however, were recruited for further analysis. Significant influential factors for higher self reported levels for ADHD symptoms included greater suicidal ideation and emotional disturbance, as well as a higher Internet addiction tendency, lower levels of social support, and a greater amount of exercise. CONCLUSION: Given the elevated prevalence of self-reported ADHD symptoms among this sample of university students, screening for these kinds of problems to detect early challenges before students fail in college as well as identify youth with undiagnosed ADHD should be considered. PMID- 25270566 TI - Examination of the Effects of Intelligence on the Test of Variables of Attention for Elementary Students. AB - OBJECTIVE: To examine the performance differences on the Test of Variables of Attention (TOVA) among different IQ level groups. METHOD: The present study examined the results of the TOVA with 138 elementary students aged 6 to 10 years who were assigned to one of four different groups based on their scores from the Wechsler Nonverbal Scale of Ability (WNV; low average: IQ < 90, average: IQ between 90 and 109, high average: IQ between 110 and 119, superior: IQ between 120 and 129, and very superior: IQ > 129). The latter two groups were combined. RESULTS: On all TOVA measures (response time, response time variability, errors of omission and commission, and ADHD scores), intellectual functioning significantly influenced performance. CONCLUSION: The results of the present study indicate that performance on the TOVA was affected by intellectual functioning. PMID- 25270567 TI - Nonradiographic axial spondyloarthritis background and confounding factors of this new terminology: an appraisal. AB - The advent of biologic therapy in the treatment of rheumatic diseases has intensified the need to further define and characterize spondyloarthritis (SpA). There has been a long debate over nomenclature of the SpA subtypes. There are those who are considered "lumpers," favoring the notion that different entities of the SpA groups are manifestations of the same disease, and "splitters," those who believe the different SpA groups represent separate diseases with shared clinical features. The influential work by Moll et al. has led to separation of entities and recognition of etiological processes of SpA subtypes. Among these subtypes has emerged nonradiographic axial spondyloarthritis (nr-axSpA), which is believed to be either an early form of ankylosing spondylitis (AS) or perhaps a different disease entity altogether. Recently attention has shifted to the characterization of early SpA, with special emphasis on nonradiographic axial SpA. The Assessment of Spondyloarthritis International Society (ASAS) has developed new criteria for the classification of this disease entity. Along with the advent of these criteria have come several unanswered questions. Although data suggests that nr-axSpA will evolve into AS over time, the natural evolution of disease is still undetermined since a proportion of cases do not progress. A number of questions also remain regarding features of patients with AS compared to those with nonradiographic disease. This appraisal highlights the differences in disease characteristics between men and women in regards to measures of disease activity, inflammatory markers, and radiologic findings. Recent studies also suggest fibromyalgia as a potential confounding factor in assessing disease activity and establishing a diagnosis of axSpA in the female population. Nonradiographic axial SpA is a relevant disease subgroup of axial SpA, and several questions have been left unanswered with more research needed regarding diagnosis (particularly in women), treatment, and long-term disease course. PMID- 25270570 TI - The glucose-lowering potential of exenatide delivered orally via goblet cell targeting nanoparticles. AB - PURPOSE: Exenatide, a potent insulinotropic agent, can be used for the treatment of non-insulin-dependent diabetes mellitus. However, the need for frequent injections seriously limits its therapeutic utility. The aim of present report was to develop an orally available exenatide formulation using goblet cell targeting nanoparticles (NPs). METHOD: The exenatide-loaded nanoparticles were prepared with modified chitosan which was conjugated with a goblet cell-target peptide, CSKSSDYQC (CSK) peptide. RESULTS: The CSK-chitosan nanoparticles shown reduced chitosan toxicity and enhanced the permeation of drugs across the Caco 2/HT-29 co-cultured cell monolayer, which simulated the intestinal epithelium. Following the oral administration of near-infrared fluorescent probe Cy-7-loaded NPs to mice, the distribution of the drugs was investigated with a near-infrared in vivo image system (FX Pro, Bruker, USA). The results showed that Cy-7 fluorescence disseminated from the oesophagus, then to stomach and small intestine and then was absorbed into hepatic, finally into the bladder; over time, Cy-7 was metabolized and excreted. The bioavailability of the modified nanoparticles was found to be 1.7-fold higher compared with the unmodified ones, and the hypoglycemic effect was also better. CONCLUSION: CSK peptide-modified chitosan nanoparticles could be a potential therapeutics for Type II diabetes patients. PMID- 25270571 TI - Effect of ultra-high pressure homogenization on the interaction between bovine casein micelles and ritonavir. AB - PURPOSE: The aim of this work was to develop a milk-based powder formulation appropriate for pediatric delivery of ritonavir (RIT). METHODS: Ultra-high pressure homogenization (UHPH) at 0.1, 300 and 500 MPa was used to process a dispersion of pasteurized skim milk (SM) and ritonavir. Loading efficiency was determined by RP-HPLC-UV; characterization of RIT:SM systems was carried out by apparent average hydrodynamic diameter and rheological measurements as well as different analytical techniques including Trp fluorescence, UV spectroscopy, DSC, FTIR and SEM; and delivery capacity of casein micelles was determined by in vitro experiments promoting ritonavir release. RESULTS: Ritonavir interacted efficiently with milk proteins, especially, casein micelles, regardless of the processing pressure; however, results suggest that, at 0.1 MPa, ritonavir interacts with caseins at the micellar surface, whilst, at 300 and 500 MPa, ritonavir is integrated to the protein matrix during UHPH treatment. Likewise, in vitro experiments showed that ritonavir release from micellar casein systems is pH dependent; with a high retention of ritonavir during simulated gastric digestion and a rapid delivery under conditions simulating the small intestine environment. CONCLUSIONS: Skim milk powder, especially, casein micelles are potentially suitable and efficient carrier systems to develop novel milk-based and low-ethanol powder formulations of ritonavir appropriate for pediatric applications. PMID- 25270572 TI - Molecular indicators of surface and bulk instability of hot melt extruded amorphous solid dispersions. AB - PURPOSE: To identify molecular indicators of bulk and surface instabilities of amorphous dispersions prepared by hot melt extrusion. METHODS: Four model drugs with different physicochemical properties were formulated with EUDRAGIT((r)) E PO using hot melt extrusion. Samples were aged under a range of conditions for up to 6 months and characterized using SEM, ATR-FTIR, PXRD and MTDSC. The effects of a range of thermodynamic, kinetic and molecular parameters, including glass transition temperature, molecular mobility, the crystallization tendency of the amorphous drug and drug-polymer miscibility, on the bulk and surface stabilities of the solid dispersions were evaluated. RESULTS: For all drug-containing systems, a higher degree of instability was observed at the surface of the material in comparison to the bulk. Stressed humidity showed a more profound effect on the dispersions in comparison to stress temperature, reducing both their surface and bulk stabilities. For supersaturated systems the order of the bulk and surface instabilities of the samples was found following the same order of the molecular mobilities of the amorphous model drugs. This was attributed to the presence of phase separation of amorphous drug-rich domains in the supersaturated extrudates. CONCLUSIONS: The stability of the amorphous drug-rich domains appears to be governed by the physical stabilities of the amorphous drugs. The more commonly used indicators such as Tg, fragility of the amorphous drug and the theoretically predicted drug-polymer solubility showed less influence on the bulk and surface stabilities of the extrudates in comparison to the molecular mobility of the amorphous drug. PMID- 25270573 TI - The effect of actuator nozzle designs on the electrostatic charge generated in pressurised metered dose inhaler aerosols. AB - PURPOSE: To investigate the influence of different actuator nozzle designs on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs). METHODS: Four actuator nozzle designs (flat, curved flat, cone and curved cone) were manufactured using insulating thermoplastics (PET and PTFE) and conducting metal (aluminium) materials. Aerosol electrostatic profiles of solution pMDI formulations containing propellant HFA 134a with different ethanol concentration and/or model drug beclomethasone dipropionate (BDP) were studied using a modified electrical low-pressure impactor (ELPI) for all actuator designs and materials. The mass of the deposited drug was analysed using high performance liquid chromatography (HPLC). RESULTS: Both curved nozzle designs for insulating PET and PTFE actuators significantly influenced aerosol electrostatics and aerosol performance compared with conducting aluminium actuator, where reversed charge polarity and higher throat deposition were observed with pMDI formulation containing BDP. Results are likely due to the changes in plume geometry caused by the curved edge nozzle designs and the bipolar charging nature of insulating materials. CONCLUSIONS: This study demonstrated that actuator nozzle designs could significantly influence the electrostatic charges profiles and aerosol drug deposition pattern of pMDI aerosols, especially when using insulating thermoplastic materials where bipolar charging is more dominant. PMID- 25270574 TI - A stochastic optimization model for shift scheduling in emergency departments. AB - Excessive waiting time in Emergency Departments (ED) can be both a cause of frustration and more importantly, a health concern for patients. Waiting time arises when the demand for work goes beyond the facility's service capacity. ED service capacity mainly depends on human resources and on beds available for patients. In this paper, we focus on human resources organization in an ED and seek to best balance between service quality and working conditions. More specifically, we address the personnel scheduling problem in order to optimize the shift distribution among employees and minimize the total expected patients' waiting time. The problem is also characterized by a multi-stage re-entrant service process. With an appropriate approximation of patients' waiting times, we first propose a stochastic mixed-integer programming model that is solved by a sample average approximation (SAA) approach. The resulting personnel schedules are then evaluated using a discrete-event simulation model. Numerical experiments are then performed with data from a French hospital to compare different personnel scheduling strategies. PMID- 25270575 TI - Chloroplast phylogenomic analysis resolves deep-level relationships within the green algal class Trebouxiophyceae. AB - BACKGROUND: The green algae represent one of the most successful groups of photosynthetic eukaryotes, but compared to their land plant relatives, surprisingly little is known about their evolutionary history. This is in great part due to the difficulty of recognizing species diversity behind morphologically similar organisms. The Trebouxiophyceae is a species-rich class of the Chlorophyta that includes symbionts (e.g. lichenized algae) as well as free-living green algae. Members of this group display remarkable ecological variation, occurring in aquatic, terrestrial and aeroterrestrial environments. Because a reliable backbone phylogeny is essential to understand the evolutionary history of the Trebouxiophyceae, we sought to identify the relationships among the major trebouxiophycean lineages that have been previously recognized in nuclear-encoded 18S rRNA phylogenies. To this end, we used a chloroplast phylogenomic approach. RESULTS: We determined the sequences of 29 chlorophyte chloroplast genomes and assembled amino acid and nucleotide data sets derived from 79 chloroplast genes of 61 chlorophytes, including 35 trebouxiophyceans. The amino acid- and nucleotide-based phylogenies inferred using maximum likelihood and Bayesian methods and various models of sequence evolution revealed essentially the same relationships for the trebouxiophyceans. Two major groups were identified: a strongly supported clade of 29 taxa (core trebouxiophyceans) that is sister to the Chlorophyceae + Ulvophyceae and a clade comprising the Chlorellales and Pedinophyceae that represents a basal divergence relative to the former group. The core trebouxiophyceans form a grade of strongly supported clades that include a novel lineage represented by the desert crust alga Pleurastrosarcina brevispinosa. The assemblage composed of the Oocystis and Geminella clades is the deepest divergence of the core trebouxiophyceans. Like most of the chlorellaleans, early-diverging core trebouxiophyceans are predominantly planktonic species, whereas core trebouxiophyceans occupying more derived lineages are mostly terrestrial or aeroterrestrial algae. CONCLUSIONS: Our phylogenomic study provides a solid foundation for addressing fundamental questions related to the biology and ecology of the Trebouxiophyceae. The inferred trees reveal that this class is not monophyletic; they offer new insights not only into the internal structure of the class but also into the lifestyle of its founding members and subsequent adaptations to changing environments. PMID- 25270576 TI - Uptake of non-invasive prenatal testing by Japanese women. PMID- 25270577 TI - Health-related quality of life in patients with cutaneous rosacea: a systematic review. AB - Health-related quality of life (HRQoL) of rosacea patients is a relevant outcome measure in research and clinical practice. A review of the literature was systematically carried out regarding levels of HRQoL of patients with rosacea, including associations between HRQoL scores, demographic and clinical characteristics. Searches were performed in Cochrane, PubMed, EMBASE, PsycINFO, CINAHL and LILACS. HRQoL studies in patients with cutaneous rosacea, using validated HRQoL instruments, published between 1991 and 2014, were included. Data extraction was performed independently by 2 authors. Study design, demographics, clinical characteristics and HRQoL scores were summarized per HRQoL questionnaire. Associations between HRQoL, demographic and clinical characteristics were explored. Out of 984 references, 12 studies were included. Three HRQoL instruments were used: Short Form-36 (SF-36), Dermatology Life Questionnaire Index (DLQI) and Rosacea Quality of Life Index (RosaQoL). Because of the heterogeneity of the included studies, data synthesis was hardly feasible. All studies reported a negative impact on HRQoL, which appeared to be associated with disease severity and age. Results regarding the association with sex and subtype were mixed. With regard to the clinical relevance of HRQoL scores of rosacea patients, it seems that rosacea has a small to moderate effect on HRQoL. PMID- 25270578 TI - In silico screening for inhibitors of p-glycoprotein that target the nucleotide binding domains. AB - Multidrug resistances and the failure of chemotherapies are often caused by the expression or overexpression of ATP-binding cassette transporter proteins such as the multidrug resistance protein, P-glycoprotein (P-gp). P-gp is expressed in the plasma membrane of many cell types and protects cells from accumulation of toxins. P-gp uses ATP hydrolysis to catalyze the transport of a broad range of mostly hydrophobic compounds across the plasma membrane and out of the cell. During cancer chemotherapy, the administration of therapeutics often selects for cells which overexpress P-gp, thereby creating populations of cancer cells resistant to a variety of chemically unrelated chemotherapeutics. The present study describes extremely high-throughput, massively parallel in silico ligand docking studies aimed at identifying reversible inhibitors of ATP hydrolysis that target the nucleotide-binding domains of P-gp. We used a structural model of human P-gp that we obtained from molecular dynamics experiments as the protein target for ligand docking. We employed a novel approach of subtractive docking experiments that identified ligands that bound predominantly to the nucleotide binding domains but not the drug-binding domains of P-gp. Four compounds were found that inhibit ATP hydrolysis by P-gp. Using electron spin resonance spectroscopy, we showed that at least three of these compounds affected nucleotide binding to the transporter. These studies represent a successful proof of principle demonstrating the potential of targeted approaches for identifying specific inhibitors of P-gp. PMID- 25270579 TI - Greater number of group identifications is associated with healthier behaviour: Evidence from a Scottish community sample. AB - OBJECTIVES: This paper investigates the interplay between group identification (i.e., the extent to which one has a sense of belonging to a social group, coupled with a sense of commonality with in-group members) and four types of health behaviour, namely physical exercise, smoking, drinking, and diet. Specifically, we propose a positive relationship between one's number of group identifications and healthy behaviour. DESIGN: This study is based on the Scottish portion of the data obtained for Wave 1 of the two-wave cross-national Health in Groups project. Totally 1,824 patients from five Scottish general practitioner (GP) surgeries completed the Wave 1 questionnaire in their homes. METHODS: Participants completed measures of group identification, group contact, health behaviours, and demographic variables. RESULTS: Results demonstrate that the greater the number of social groups with which one identifies, the healthier one's behaviour on any of the four health dimensions considered. CONCLUSIONS: We believe our results are due to the fact that group identification will generally (1) enhance one's sense of meaning in life, thereby leading one to take more care of oneself, (2) increase one's sense of responsibility towards other in-group members, thereby enhancing one's motivation to be healthy in order to fulfil those responsibilities, and (3) increase compliance with healthy group behavioural norms. Taken together, these processes amply overcompensate for the fact that some groups with which people may identify can actually prescribe unhealthy behaviours. PMID- 25270580 TI - Innovative native MS methodologies for antibody drug conjugate characterization: High resolution native MS and IM-MS for average DAR and DAR distribution assessment. AB - Antibody drug conjugates (ADCs) are macromolecules composed of cytotoxic drugs covalently attached via a conditionally stable linker to monoclonal antibodies (mAbs). ADCs are among the most promising next generation of empowered mAbs foreseen to treat cancers. Compared to naked mAbs, ADCs have an increased level of complexity as the heterogeneity of conjugation cumulates with the inherent microvariability of the biomolecule. An increasing need underlying ADC's development and optimization is to improve its analytical and bioanalytical characterization by assessing three main ADC quality attributes: drug distribution, amount of naked antibody, and average drug to antibody ratio (DAR). Here, the analytical potential of native mass spectrometry (MS) and native ion mobility MS (IM-MS) is compared to hydrophobic interaction chromatography (HIC), the reference method for quality control of interchain cysteinyl-linked ADCs. Brentuximab vedotin, first in class and gold standard, was chosen for a proof of principle. High resolution native MS provided accurate mass measurement (<30 ppm) of intact ADCs together with average DAR and drug distribution, confirming the unique ability of native MS for simultaneous detection of mixtures of covalent and noncovalent products. Native IM-MS was next used for the first time to characterize an ADC. IM-MS evidenced ADC multiple drug loading, collisional cross sections measurement of each payload species attesting slight conformational changes. A semiquantitative interpretation of IM-MS data was developed to directly extrapolate average DAR and DAR distribution. Additionally, HIC fractions were collected and analyzed by native MS and IM-MS, assessing the interpretation of each HIC peak. Altogether, our results illustrate how native MS and IM-MS can rapidly assess ADC structural heterogeneity and how easily these methods can be implemented into MS workflows for in-depth ADC analytical characterization. PMID- 25270581 TI - Quantifying nicotine's value-enhancement effect using a behavioral economic approach. AB - Nicotine increases the value of some reinforcing stimuli, and this effect may contribute to nicotine's widespread abuse. We aimed to quantify this effect using a behavioral economic analysis. Six Long- Evans rats were exposed to a modified observing response procedure. In this procedure, presses to one lever resulted either in food according to a variable-interval 15 s schedule or extinction; presses to a second, observing lever illuminated stimuli correlated with the schedule in effect on the food/extinction lever (i.e., conditioned reinforcers). The FR requirement on the observing lever increased across sessions. The number of presentations of the conditioned reinforcers was plotted as a function of FR value to generate a demand curve. Nicotine was then administered at a dose of 0.3 mg/kg. All demand curves were fitted to the exponential demand equation and a parameter reflecting reinforcer value was evaluated. Nicotine increased the value of the conditioned reinforcers as measured by this equation; nicotine also increased responding on the food/extinction lever. This analysis demonstrates that nicotine increases the value of conditioned reinforcers under certain conditions. The current procedure allows for a novel method of analyzing demand for conditioned reinforcers. PMID- 25270582 TI - Positive feedback of NR2B-containing NMDA receptor activity is the initial step toward visual imprinting: a model for juvenile learning. AB - Imprinting in chicks is a good model for elucidating the processes underlying neural plasticity changes during juvenile learning. We recently reported that neural activation of a telencephalic region, the core region of the hyperpallium densocellulare (HDCo), was critical for success of visual imprinting, and that N Methyl-D-aspartic (NMDA) receptors containing the NR2B subunit (NR2B/NR1) in this region were essential for imprinting. Using electrophysiological and multiple site optical imaging techniques with acute brain slices, we found that long-term potentiation (LTP) and enhancement of NR2B/NR1 currents in HDCo neurons were induced in imprinted chicks. Enhancement of NR2B/NR1 currents as well as an increase in surface NR2B expression occurred even following a brief training that was too weak to induce LTP or imprinting behavior. This means that NR2B/NR1 activation is the initial step of learning, well before the activation of alpha amino-3-hydroxy-5-methylisoxazole-4-propionate receptors which induces LTP. We also showed that knockdown of NR2B/NR1 inhibited imprinting, and inversely, increasing the surface NR2B expression by treatment with a casein kinase 2 inhibitor successfully reduced training time required for imprinting. These results suggest that imprinting stimuli activate post-synaptic NR2B/NR1 in HDCo cells, increase NR2B/NR1 signaling through up-regulation of its expression, and induce LTP and memory acquisition. The study investigated the neural mechanism underlying juvenile learning. In the initial stage of chick imprinting, NMDA receptors containing the NMDA receptor subunit 2B (NR2B) are activated, surface expression of NR2B/NR1 (NMDA receptor subunit 1) is up-regulated, and consequently long-term potentiation is induced in the telencephalic neurons. We suggest that the positive feedback in the NR2B/NR1 activation is a unique process of juvenile learning, exhibiting rapid memory acquisition. PMID- 25270583 TI - The subtelomeric region is important for chromosome recognition and pairing during meiosis. AB - The process of meiosis results in the formation of haploid daughter cells, each of which inherit a half of the diploid parental cells' genetic material. The ordered association of homologues (identical chromosomes) is a critical prerequisite for a successful outcome of meiosis. Homologue recognition and pairing are initiated at the chromosome ends, which comprise the telomere dominated by generic repetitive sequences, and the adjacent subtelomeric region, which harbours chromosome-specific sequences. In many organisms telomeres are responsible for bringing the ends of the chromosomes close together during early meiosis, but little is known regarding the role of the subtelomeric region sequence during meiosis. Here, the observation of homologue pairing between a pair of Hordeum chilense chromosomes lacking the subtelomeric region on one chromosome arm indicates that the subtelomeric region is important for the process of homologous chromosome recognition and pairing. PMID- 25270584 TI - Efficacy and safety of bone marrow cell transplantation for chronic ischemic heart disease: a meta-analysis. AB - BACKGROUND: Although bone marrow-derived cells (BMCs) have shown great therapeutic potential in patients with chronic ischemic heart disease (CIHD), the exact efficacy and safety of BMCs therapy is still not completely defined. MATERIAL/METHODS: We searched PubMed, OVID, EMBASE, the Cochrane Library, and ClinicalTrials.gov and finally identified 20 qualified trials in this meta analysis. Assessment of efficacy was based on left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end diastolic volume (LVEDV) improvement, by weighted mean difference (WMD) with 95% confidence intervals (CIs). RESULTS of all-cause death, ventricular arrhythmia, recurrent myocardial infarction, and cerebrovascular accident were pooled to assess safety. Subgroup analysis was performed by stratifying RCTs into 2 subgroups of those with revascularization and without revascularization. RESULTS: BMC transplantation significantly improved LVEF in patients with revascularization (3.35%, 95% CI 0.72% to 5.97%, p=0.01; I2=85%) and without revascularization (3.05%, 95% CI 0.65% to 5.45%, p=0.01; I2=86%). In patients without revascularization, BMC transplantation was associated with significantly decreased LVESV (-11.75 ml, 95% CI -17.81 ml to -5.69 ml, p=0.0001; I2=81%), and LVEDV (-7.80 ml, 95% CI -15.31 ml to -0.29 ml, p=0.04; I2=39%). Subgroup analysis showed that the route of transplantation, baseline LVEF, and type of cells delivered could influence the efficacy of BMC transplantation. CONCLUSIONS: Autologous transplantation of BMCs was safe and effective for patients who were candidates for revascularization with CABG/PCI and those who were not. However, large clinical trials and long-term follow-up are required to confirm these benefits. PMID- 25270586 TI - Suicidal ideation in patients with chronic pain: The risk-benefit of pharmacotherapy. PMID- 25270587 TI - Retinal hemodynamic oxygen reactivity assessed by perfusion velocity, blood oximetry and vessel diameter measurements. AB - PURPOSE: To test the oxygen reactivity of a fundus photographic method of measuring macular perfusion velocity and to integrate macular perfusion velocities with measurements of retinal vessel diameters and blood oxygen saturation. METHODS: Sixteen eyes in 16 healthy volunteers were studied at two examination sessions using motion-contrast velocimetry and retinal oximetry with vessel diameter corrections. To test oxygen reactivity, participants were examined during normoxia, after 15 min of hyperoxia and finally after 45 min of normoxia. Repeatability was assessed by intraclass correlation coefficients (ICC) and limits of agreement. RESULTS: Fifteen minutes of hyperoxia was accompanied by mean reductions in arterial and venous perfusion velocities of 14% and 16%, respectively (p = 0.0080; p = 0.0019), constriction of major arteries and veins by 5.5% and 8.2%, respectively (p < 0.0001), increased retinal arterial oxygen saturation from 95.1 +/- 5.0% to 96.6 +/- 6.4% (p = 0.038) and increased retinal venous oxygen saturation from 62.9 +/- 6.7% to 70.3 +/- 7.8% (p = 0.0010). Parameters returned to baseline levels after subsequent normoxia. Saturation and vessel diameter ICCs were 0.88-0.98 (range). For perfusion velocities, short-term ICCs were 0.79-0.82 and long-term ICCs were 0.06-0.11. Intersession increases in blood glucose were associated with reductions in perfusion velocities (arterial p = 0.0067; venous p = 0.018). CONCLUSION: Oxygen reactivity testing supported that motion-contrast velocimetry is a valid method for assessing macular perfusion. Results were consistent with previous observations of hyperoxic blood flow reduction using blue field entoptic and laser Doppler velocimetry. Retinal perfusion seemed to be regulated around individual set points according to blood glucose levels. Multimodal measurements may provide comprehensive information about retinal metabolism. PMID- 25270585 TI - Transcutaneous electrical nerve stimulation for the control of pain during rehabilitation after total knee arthroplasty: A randomized, blinded, placebo controlled trial. AB - This study evaluated the efficacy of transcutaneous electrical nerve stimulation (TENS) in reducing pain and hyperalgesia and increasing function after total knee arthroplasty (TKA). We hypothesized that participants using TENS during rehabilitation exercises would report significantly lower pain during range-of motion (ROM) activity and fast walking but not at rest, would have less hyperalgesia, and would have better function than participants receiving placebo TENS or standard care. We also hypothesized that change in ROM pain would differ based on psychological characteristics (trait anxiety, pain catastrophizing, and depression) and treatment group. This prospective, randomized study used intent to-treat analyses in 317 participants after primary, unilateral TKA. Assessors, blinded to treatment allocation, measured pain, function (ROM and gait speed), and hyperalgesia (quantitative sensory tests) postoperatively and 6 weeks after surgery. Analgesic intake, anxiety, depression, and pain catastrophizing were also assessed. TENS participants used it 1 to 2 times per day at 42 mA (on average) and had less pain postoperatively during active knee extension (P=.019) and fast walking (P=.006) than standard care participants. TENS and placebo-TENS were not significantly different. TENS participants who scored low on anxiety and pain catastrophizing had a greater reduction in ROM pain at 6 weeks than those who scored high on these factors (P=.002 and P=.03). Both TENS and placebo-TENS participants had less postoperative mechanical hyperalgesia (P=.03-.01) than standard care participants. Supplementing pharmacologic analgesia with TENS during rehabilitation exercises reduces movement pain postoperatively, but a placebo influence exists and the effect is gone by 6 weeks. Patients with low anxiety and pain catastrophizing may benefit most from TENS. PMID- 25270588 TI - Sex prediction from the femur and hip bone using a sample of CT images from a Spanish population. AB - Sex estimation and the analysis of sexual dimorphism is an essential part of forensic and archaeological studies of skeletons. However, osteologists often have to rely on single measurements, such as femoral head diameters, to estimate sex, especially when skeletons are incomplete. We have obtained a sex-prediction model based on CT images by applying the logistic regression technique to the measurements obtained for the proximal femoral epiphyses and coxal. Nine variables for 114 Spaniards (58 females and 56 males) of known age and sex from a region close to Madrid have been studied. The prediction equation obtained using these nine variables correctly classifies 99.1 % of these individuals. Reducing the equation to the three most explanatory variables (VDH, HDH and MIB) resulted in the correct classification of 98.3 %. These findings suggest that this procedure is highly effective for sex prediction. However, a lack of expertise may produce biases in the measurements obtained from CT images. Moreover, these equations are only most effective for the population for which they were calculated as human growth and body size are sensitive to nutritional variations, environmental stress and the so-called secular trend. PMID- 25270589 TI - Mandibular ramus length as an indicator of chronological age and sex. AB - Age and sex estimation is crucial in forensic investigations, whether in legal situations that involve living people or to identify mortal remains. The aim of this study was to establish reference values in a Brazilian population to estimate age and sex by measuring the length of the mandibular ramus on lateral cephalometric radiographs, and to determine the probability that an individual being is 18 years or older, based on the results that were obtained. Two hundred and eighteen scanned lateral cephalograms of individuals between 6 and 20 years of age (101 males and 117 females) were measured with reference to mandibular ramus length (the distance between Condylion superior (Cs) and Gonion (Go)) using ImageJ 1.41 software (NIH, Bethesda, MA, USA). The results showed that sexual dimorphism was not observed until 16 years and, based on the ramus length measurements in this sample, it is possible to predict sex with an accuracy of only 54 %. There was a positive correlation between age and ramus length (r = 0.90; p < 0.001). From the linear regression analysis, one formula was derived; therefore, it was possible to calculate the individual's age, given his or her ramus length. The results showed that if an individual's ramus length is 7.0 cm or more, then there is an 81.25 % chance that the individual is 18 years old or older. In conclusion, the mandibular ramus length was not effective in discriminating sex. Mandibular length is strongly related to chronological age and can be used to predict whether an individual is 18 years or older with high degree of expected accuracy. PMID- 25270592 TI - Modification of D-A-pi-A configuration toward a high-performance triphenylamine based sensitizer for dye-sensitized solar cells: a theoretical investigation. AB - In an attempt to shed light on how the addition of a benzothiadiazole (BTD) moiety influences the properties of dyes, a series of newly designed triphenylamine-based sensitizers incorporating a BTD unit as an additional electron-withdrawing group in a specific donor-acceptor-pi-acceptor architecture has been investigated. We found that different positions of the BTD unit provided significantly different responses for light absorption. Among these, it was established that the further the BTD unit is away from the donor part, the broader the absorption spectra, which is an observation that can be applied to improve light-harvesting ability. However, when the BTD unit is connected to the anchoring group a faster, unfavorable charge recombination takes place; therefore, a thiophene unit was inserted between these two acceptors, providing redshifted absorption spectra as well as blocking unfavorable charge recombination. The results of our calculations provide valuable information and illustrate the potential benefits of using computation-aided sensitizer design prior to further experimental synthesis. PMID- 25270590 TI - Association of serum inorganic phosphate with sex steroid hormones and vitamin D in a nationally representative sample of men. AB - Defects in bone regulatory pathways have been linked to chronic diseases including cardiovascular disease and cancer. In men, a link between bone metabolism and gonadal hormones has been suggested. However, to date, there is lack of evidence on the association between serum inorganic phosphate (Pi) and sex steroid hormones. The objective of this study was to investigate the association between Pi, sex steroid hormones and a known Pi metabolic regulator, vitamin D, in men in the National Health and Nutrition Examination Survey III (NHANES III). From NHANES III, we selected 1412 men aged 20+ who participated in the morning session of Phase I (1988-1991) with serum measurements of Pi, sex hormones, and vitamin D. Multivariable linear regression was used to calculate crude and geometric mean Pi by total and estimated free testosterone and estradiol, sex hormone-binding globulin, androstanediol glucuronide (AAG), and vitamin D. Similar analyses were performed while stratifying by race/ethnicity and vitamin D levels. We found a lack of statistically significant difference in geometric means of Pi across quintiles of concentrations of sex hormones, indicating a tight regulation of Pi. However, Pi levels were inversely associated with calculated free testosterone in non-Hispanic black men, with geometric mean levels of Pi of 1.16 and 1.02 ng/mL for those in the lowest and highest quintiles of free testosterone, respectively (p-trend < 0.05). A similar but weaker pattern was seen between total testosterone and Pi. An inverse association was also seen between AAG and Pi in men with vitamin D concentration below the median (<24.2 ng/mL). No associations were observed among men with vitamin D levels at or above the median. Our findings suggest a weak link among sex hormones, vitamin D, and Pi in men. The observed effects of race/ethnicity and vitamin D indicate a complex association involving various regulators of Pi homeostasis. PMID- 25270593 TI - Are incretin mimetics and enhancers linked to pancreatitis and malignant transformations in pancreas? AB - INTRODUCTION: Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are new options in the treatment of type 2 diabetes mellitus. However, due to accumulating reports on the occurrence of acute pancreatitis (AP), a suspicion of an association between incretin-based therapies and pancreatic disease has arisen. AREAS COVERED: A review of the literature on the safety of incretin-based therapies in regard to AP and pancreatic cancer was undertaken with discussion of potential mechanisms as well as limitations. EXPERT OPINION: Until now, several preclinical and clinical studies have been published; however, they present conflicting results. Common risk factors, low incidence rates, long latency periods (in regard to pancreatic malignancy), lack of availability of human pancreatic tissues during lifetime among others hamper the confirmation or exclusion of a causal association. The results of the ongoing large randomized controlled trials will add further data. In line with current recommendations by European Medicines Agency and FDA, incretin-based therapies should be discontinued in patients with suspicion of AP, and incretin mimetics should not be administered to patients with a history of AP. However, based on current knowledge, there is no sound reason for depriving type 2 diabetic patients in general of a beneficial and effective therapy. However, this conclusion cannot be final and should be subject to constant reevaluation and, if necessary, change. PMID- 25270594 TI - Single-stage cholecystectomy at the time of pancreatic necrosectomy is safe and prevents future biliary complications: a 20-year single institutional experience with 217 consecutive patients. AB - INTRODUCTION: Current guidelines recommend cholecystectomy (CCY) during the index admission for mild to moderate biliary pancreatitis as delayed CCY is associated with a substantial risk of recurrent biliary events. Delayed CCY is recommended in severe pancreatitis. The optimal timing of CCY in necrotizing pancreatitis, however, has not been well studied. We sought to determine the safety of single stage CCY performed at the time of necrosectomy and its effectiveness in preventing subsequent biliary complications. METHODS: We retrospectively queried our institutional database of patients who underwent pancreatic necrosectomy for necrotizing pancreatitis from 1992 to 2012. RESULTS: We identified 217 consecutive patients who underwent pancreatic necrosectomy during the study period. The most common etiologies of pancreatitis were biliary (41 %) and alcoholic (24%), with a median computed tomography (CT) severity index score of 6 +/- 1.6 and a 63.6% incidence of infected necrosis. Ninety-eight patients had undergone CCY prior to necrosectomy. Seventy patients (59% of those with gallbladders in situ) underwent CCY at the time of pancreatic necrosectomy. CCY was not performed in the remaining 49 due to a clear non-biliary etiology (35%), technical difficulty (29%), intraoperative hemodynamic instability (18%), or surgeon preference (18%). Postoperative morbidity and mortality was no different between the CCY and no CCY groups, with no bile duct injury or bile leaks in patients undergoing CCY at the time of necrosectomy. Of the patients undergoing CCY, 43% of patients without cholelithiasis or biliary sludge on preoperative imaging had gallstones or sludge identified pathologically after single-stage CCY. Of those who did not receive a single-stage CCY, biliary complications developed in 17 (35%) of patients (21% cholecystitis, 14% recurrent gallstone pancreatitis) at a median time to incidence of 10 months. Seventeen (35%) patients eventually received a postnecrosectomy cholecystectomy, of which 75% required an open procedure. CONCLUSION: Single-stage CCY at the time of pancreatic necrosectomy is safe in selected patients and should be performed if technically feasible to prevent future biliary complications and reduce the need for a subsequent separate, often open, CCY. PMID- 25270595 TI - Epidermal growth factor receptor inhibition by anti-CD147 therapy in cutaneous squamous cell carcinoma. AB - BACKGROUND: Advanced cutaneous squamous cell carcinoma (SCC) is an uncommon and aggressive malignancy. As a result, there is limited understanding of its biology and pathogenesis. CD147 and epidermal growth factor receptor (EGFR) have been identified as oncologically important targets, but their relationship remains undefined in cutaneous SCC. METHODS: Multiple cutaneous SCC cell lines (Colo-16, SRB-1, and SRB-12), were treated in vitro with a range of chimeric anti-CD147 monoclonal antibody (mAb) (0, 50, 100, and 200 ug/mL) or transfected with a small interfering RNA against CD147 (SiCD147). Cell proliferation, migration (scratch wound healing assay), and protein expression was then assessed. In vivo, Colo-16 flank xenografts were treated anti-CD147 mAb (150 ug i.p. triweekly). RESULTS: After treatment with anti-CD147 (200 ug/mL), there was a significant decrease in proliferation for all cell lines relative to controls (p < .005). In addition, treatment with anti-CD147 (200 ug/mL) resulted in decreased cell migration for all cell lines, with an average of 43% reduction in closure compared to controls (p < .001). Colo-16 SiCD147 expression demonstrated similar reduction in proliferation and wound closure. Anti-CD147 antibody therapy and siRNA mediated reduction in CD147 expression were both found to decrease protein expression of EGFR, which correlated with a reduction in downstream total and phosphorylated protein kinase B (pAKT). Tumor growth in vivo was reduced for both the anti-CD147 treatment group and the SiCD147 group relative to controls. CONCLUSION: Inhibition and downregulation of CD147 in cutaneous SCC resulted in suppression of the malignant phenotype in vitro and in vivo, which may be mediated in part by an alteration in EGFR expression. As a result, CD147 may serve as a potential therapeutic target for advanced cutaneous SCC. PMID- 25270596 TI - Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options. AB - Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by clonal expansion of a hematopoietic progenitor, erythrocytosis, often leukocytosis and/or thrombocytosis, and nearly always an activating mutation in Janus kinase 2 (JAK2). The PV symptom burden can be considerable, in part driven by small or large vessel thrombotic tendency, splenomegaly, fatigue, pruritus, and a chronic risk of disease transformation to myelofibrosis or acute myeloid leukemia. In addition, patients with PV have an increased risk of mortality compared with the general population that often results from cardiovascular complications or disease transformation. Further, healthcare utilization and costs are higher in patients with PV than noncancer controls. First-line therapy options for high-risk patients may effectively manage PV in some instances; however, some patients do not receive adequate benefit from current treatment options and experience a more severe disease burden as a result. This may be especially true for those patients who are resistant to or intolerant of hydroxyurea or interferon-based therapies. New treatments currently being investigated in phase 3 clinical trials may alleviate disease burden in this patient population. PMID- 25270597 TI - Should off-label drugs be included as comparators in pharmacoeconomic studies? PMID- 25270599 TI - Label-free technology for the amplified detection of microRNA based on the allosteric hairpin DNA switch and hybridization chain reaction. AB - By using the allosteric hairpin DNA switch, a novel assay for the detection of microRNA (miRNA) let-7a via a hybridization chain reaction (HCR) was introduced. Briefly, the hairpin DNA switch probe is a single-stranded DNA consisting of a streptavidin (SA) aptamer sequence, a target binding sequence and a certain sequence that acts as a trigger of the HCR. In the presence of target let-7a, the hairpin DNA switch would open and expose the stem region sequences, where a part of this sequence acts as initiator sequence strands for the HCR and triggers a cascade of hybridization events that yields nicked double helices analogous to alternating copolymers, another part is the SA aptamer sequence which activates its binding affinity to SA on SA-coated magnetic particles. The hybridization event could be sensitively detected via an instantaneous derivatization reaction between a special chemiluminescence (CL) reagent, 3,4,5-trimethoxylphenylglyoxal (TMPG) and the guanine nucleotides within the target, the hairpin DNA switch probe, and HCR helices to form an unstable CL intermediate for the generation of light. Our results show that the coupling of the hairpin DNA switch probe and the HCR for the amplified detection of let-7a achieves a better performance (e.g. wide linear response range: 0.1-1000 fmol, low detection limit: 0.1 fmol, and high specificity). Furthermore, this approach could be easily applied to the detection of let-7a in human lung cells, and extended to detect other types of miRNA and proteins such as PDGF based on aptamers. We believe such advancements will represent a significant step towards improved diagnostics and more personalized medical treatment. PMID- 25270598 TI - Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension. AB - Primary cilia are microtubule-based sensory organelles that organize numerous key signals during developments and tissue homeostasis. Ciliary microtubule doublet, named axoneme, is grown directly from the distal end of mother centrioles through a multistep process upon cell cycle exit; however, the instructive signals that initiate these events are poorly understood. Here we show that ubiquitin proteasome machinery removes trichoplein, a negative regulator of ciliogenesis, from mother centrioles and thereby causes Aurora-A inactivation, leading to ciliogenesis. Ciliogenesis is blocked if centriolar trichoplein is stabilized by treatment with proteasome inhibitors or by expression of non-ubiquitylatable trichoplein mutant (K50/57R). Started from two-stepped global E3 screening, we have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis. PMID- 25270600 TI - Y-box binding protein 1 is correlated with lymph node metastasis in intestinal type gastric cancer. AB - AIMS: Y-box binding protein-1 (YB-1) is known to modulate gene transcription and protein translation, as well as cellular response to drug treatment. The aim of this study is to correlate YB-1 protein expression levels with clinicopathological parameters in intestinal-type gastric cancer tissue samples (as categorized by the Lauren classification) and substantiate the findings with in vitro experimentation. METHODS AND RESULTS: Paraffin-embedded samples from 167 patients with intestinal-type gastric cancer were used for the construction of tissue microarrays (TMAs). TMA slides were immunostained and YB-1 immunoreactivity score was based on the weighted average intensity score. Univariate analysis revealed that YB-1 immunohistochemical expression was correlated significantly with lymph node status (P = 0.054, borderline significance) and perforation (P = 0.043). YB-1 expression was also found to be an independent predictor of lymph node spread by multivariate analysis. Furthermore, siRNA-mediated YB-1 gene knockdown in MKN7 gastric cancer cells (which is known to originate from an intestinal-type gastric cancer tissue) inhibited cell migration (P = 0.0002) and invasion in vitro (P = 0.0129) significantly. CONCLUSION: YB-1 expression is associated with lymph node spread in intestinal-type gastric cancer and is a potential prognostic biomarker in this subtype of gastric cancer. PMID- 25270601 TI - Inhibition of insect glutathione S-transferase (GST) by conifer extracts. AB - Insecticide synergists biochemically inhibit insect metabolic enzyme activity and are used both to increase the effectiveness of insecticides and as a diagnostic tool for resistance mechanisms. Considerable attention has been focused on identifying new synergists from phytochemicals with recognized biological activities, specifically enzyme inhibition. Jack pine (Pinus banksiana Lamb.), black spruce (Picea mariana (Mill.) BSP.), balsam fir (Abies balsamea (L.) Mill.), and tamarack larch (Larix laricina (Du Roi) Koch) have been used by native Canadians as traditional medicine, specifically for the anti-inflammatory and antioxidant properties based on enzyme inhibitory activity. To identify the potential allelochemicals with synergistic activity, ethanol crude extracts and methanol/water fractions were separated by Sephadex LH-20 chromatographic column and tested for in vitro glutathione S-transferase (GST) inhibition activity using insecticide-resistant Colorado potato beetle, Leptinotarsa decemlineata (Say) midgut and fat-body homogenate. The fractions showing similar activity were combined and analyzed by ultra pressure liquid chromatography-mass spectrometry. A lignan, (+)-lariciresinol 9'-p-coumarate, was identified from P. mariana cone extracts, and L. laricina and A. balsamea bark extracts. A flavonoid, taxifolin, was identified from P. mariana and P. banksiana cone extracts and L. laricina bark extracts. Both compounds inhibit GST activity with taxifolin showing greater activity compared to (+)-lariciresinol 9'-p-coumarate and the standard GST inhibitor, diethyl maleate. The results suggested that these compounds can be considered as potential new insecticide synergists. PMID- 25270602 TI - Integrated RF/shim coil array for parallel reception and localized B0 shimming in the human brain. AB - The purpose of this work was to develop a novel integrated radiofrequency and shim (RF/shim) coil array that can perform parallel reception and localized B0 shimming in the human brain with the same coils, thereby maximizing both the signal-to-noise ratio and shimming efficiency. A 32-channel receive-only head coil array was modified to enable both RF currents (for signal reception) and direct currents (for B0 shimming) to flow in individual coil elements. Its in vivo performance was assessed in the frontal brain region, which is affected by large susceptibility-induced B0 inhomogeneities. The coil modifications did not reduce their quality factor or signal-to-noise ratio. Axial B0 maps and echo planar images acquired in vivo with direct currents optimized to shim specific slices showed substantially reduced B0 inhomogeneities and image distortions in the frontal brain region. The B0 root-mean-square error in the anterior half of the brain was reduced by 60.3% as compared to that obtained with second-order spherical harmonic shimming. These results demonstrate that the integrated RF/shim coil array can perform parallel reception and localized B0 shimming in the human brain and provide a much more effective shimming than conventional spherical harmonic shimming alone, without taking up additional space in the magnet bore and without compromising the signal-to-noise ratio or shimming performance. PMID- 25270603 TI - Inhibitory motor control based on complex stopping goals relies on the same brain network as simple stopping. AB - Much research has modeled action-stopping using the stop-signal task (SST), in which an impending response has to be stopped when an explicit stop-signal occurs. A limitation of the SST is that real-world action-stopping rarely involves explicit stop-signals. Instead, the stopping-system engages when environmental features match more complex stopping goals. For example, when stepping into the street, one monitors path, velocity, size, and types of objects and only stops if there is a vehicle approaching. Here, we developed a task in which participants compared the visual features of a multidimensional go-stimulus to a complex stopping-template, and stopped their go-response if all features matched the template. We used independent component analysis of EEG data to show that the same motor inhibition brain network that explains action-stopping in the SST also implements motor inhibition in the complex-stopping task. Furthermore, we found that partial feature overlap between go-stimulus and stopping-template led to motor slowing, which also corresponded with greater stopping-network activity. This shows that the same brain system for action-stopping to explicit stop-signals is recruited to slow or stop behavior when stimuli match a complex stopping goal. The results imply a generalizability of the brain's network for simple action-stopping to more ecologically valid scenarios. PMID- 25270604 TI - Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal. AB - BACKGROUND: Excessive levels of methylglyoxal (MG) encountered in diabetes foster enhanced leukocyte-endothelial cell interactions, mechanisms of which are incompletely understood. MG genomically upregulates endothelial serum- and glucocorticoid-inducible kinase 1 (SGK1) which orchestrates leukocyte recruitment by regulating the activation and expression of transcription factors and adhesion molecules. SGK1 regulates a myriad of ion channels and carriers including the Na+/H+ exchanger NHE1. Here, we explored the effect of MG on SGK1-dependent NHE1 activation and the putative role of NHE1 activation in MG-induced leukocyte recruitment and microvascular hyperpermeability. METHODS: Using RT-PCR and immunoblotting, we analyzed NHE1 mRNA and protein levels in murine microvascular SVEC4-10EE2 endothelial cells (EE2 ECs). NHE1 phosphorylation was detected using a specific antibody against the 14-3-3 binding motif at phospho-Ser703. SGK in EE2 ECs was silenced using targeted siRNA. ROS production was determined using DCF-dependent fluorescence. Leukocyte recruitment and microvascular permeability in murine cremasteric microvasculature were measured using intravital microscopy. The expression of endothelial adhesion molecules was determined by immunoblotting and confocal imaging analysis. RESULTS: MG treatment significantly upregulated NHE1 mRNA and dose-dependently increased total- and phospho-NHE1. Treatment with SGK1 inhibitor GSK650394, antioxidant Tempol and silencing SGK all blunted MG triggered phospho-NHE1 upregulation in EE2 ECs. NHE1 inhibitor cariporide attenuated MG-triggered ROS production, leukocyte adhesion and emigration and microvascular hyperpermeability, without affecting leukocyte rolling. Cariporide treatment did not alter MG-triggered upregulation of P- and E-selectins, but reduced endothelial ICAM-1 expression. CONCLUSION: MG elicits SGK1-dependent activation of endothelial Na+/H+ exchanger NHE1 which participates in MG-induced ROS production, upregulation of endothelial ICAM-1, leukocyte recruitment and microvascular hyperpermeability. Pharmacological inhibition of NHE1 attenuates the proinflammatory effects of excessive MG and may, thus, be beneficial in diabetes-associated inflammation. PMID- 25270605 TI - Differential patterns of recurrence and specific survival between luminal A and luminal B breast cancer according to recent changes in the 2013 St Gallen immunohistochemical classification. AB - INTRODUCTION: In 2011, the St Gallen panel introduced several changes in breast cancer classification, thereby creating the luminal B Her2- subtype. In 2013, the panel also included Ki67 overexpression and PR <20 % as risk factors, while excluding GH3 in the absence of increased Ki67. We compared the classification of 2011 modified with the new 2013 St Gallen classification. PATIENTS AND METHOD: Consecutive breast cancer patients referred to the Breast Unit of the University Hospital Mutua Terrassa and Hospital of Terrassa for surgical treatment of either primary or recurrent tumors were prospectively included between 1997 and 2014. Eventually, 1,874 cases were included for the four-subtype analysis. The median follow-up was of 66 months. RESULTS: Using the 2013 St Gallen classification no significant differences were found in specific mortality rates between luminal A and B subtypes. There were significant differences at 5, 10, and, 15 years if we excluded luminal A GH3 patients in the absence of increased Ki67 (p = 0.004, 0.005, and 0.007). Luminal A sub-type patients showed significantly less distant metastases than the rest, including luminal B Her2- patients (p < 0.001). Also, luminal B patients showed significantly less distant metastases than pure Her2 (0.05) and triple negative (TN) (p < 0.001). There were no differences between pure Her2 and TN patients (0.055), neither among the different luminal B sub types. CONCLUSION: GH3, PR, and Ki67 may all be discriminatory factors for metastasis and specific mortality. Therefore, we suggest including GH3 in the luminal B subtype in the absence of Ki67. PMID- 25270606 TI - A study comparing two consecutive historical periods in breast cancer with a focus on surgical treatment, loco-regional recurrence, distant metastases and mortality. AB - BACKGROUND AND AIM: Recent introduction of breast units, mass-screening programmes (SP) and sentinel node biopsy (SNB) has impacted on the clinical care of breast cancer patients (BC), resulting in a significant increase of breast conserving surgery with the goal of achieving completely free margins and good cosmetic outcome, along with significantly less axillary morbidity. In order to ascertain the combined impact of SP and SNB on BC patients, we have reviewed the primary therapeutic approach of patients diagnosed with invasive breast carcinoma in our centre, both before and after implementation of the two new procedures. METHODS: 1,942 patients operated for BC between 1997 and 2013 in two clinical centres. Two historical periods were considered: before and after the advent of the Breast Unit in our institutions and the concurrent implementation of SP and SNB (September 2002). RESULTS: Rates of breast-conserving surgery and re operations improved in the second period. Intraoperative margin re-excision increased in the second period. Breast-conserving surgery decreased in parallel to stage: from 79 % for stage I to 31 % for stage III. The Cox analysis, including stage as adjusted for all significant variables, showed statistically significant differences in favour of the initial stages but only for specific mortality, not overall mortality. CONCLUSIONS: Combined implementation of breast units, SP, and SNB have resulted in a significant improvement of BC treatment leading to increased rates of breast-conserving surgery and decreased disease recurrence and mortality. PMID- 25270607 TI - Employment and work safety among 12 to 14 year olds: listening to parents. AB - BACKGROUND: Survey research indicates that a surprising number of 12 to 14 year olds in North America engage in some form of paid work, and work-related injuries for this age group are reported at rates similar to older teens. Parents exhibit significant involvement in many aspects of their teens' work and may influence perceptions of work safety, yet few studies have explored this phenomenon from a qualitative perspective with parents of working 12 to 14 year olds. METHODS: This paper focuses on parental perceptions and understandings of work safety based on focus groups conducted with urban Canadian parents of young teens who work for pay. Parents discussed the types of job held by their 12 to 14 year olds, the perceived costs and benefits to working at this age, and their understanding of risk and supervision on the job. A grounded theory approach was used to thematically analyze the focus group transcripts. RESULTS: Parents in this study held favourable attitudes towards their 12 to 14 year olds' working. Parents linked pro-social moral values and skills such as responsibility, work ethic, time management, and financial literacy with their young teen's employment experience. Risks and drawbacks were generally downplayed or discounted. Perceptions of workplace safety were mitigated by themes of trust, familiarity, sense of being in control and having discretion over their 12 to 14 year olds' work situation. Further, parental supervision and monitoring fell along a continuum, from full parental responsibility for monitoring to complete trust and delegation of supervision to the workplace. CONCLUSIONS: The findings suggest that positive parental attitudes towards working overshadow occupational health and safety concerns. Parents may discount potential hazards based on the presence of certain mitigating factors. PMID- 25270608 TI - Phyllodes tumours of the breast: radiological presentation, management and follow up. AB - OBJECTIVE: Phyllodes tumours (PTs) are rare neoplasms accounting for <1% of breast lesions. With increased breast awareness and screening programmes, smaller PTs are being detected. The purpose of this study was to determine the clinical, radiological and pathological presentation of PTs and to evaluate the role of imaging follow-up, for which there are no specific guidelines. METHODS: A retrospective study of all patients diagnosed with PT in a symptomatic unit between January 2006 and March 2013 was carried out. Patients were identified using breast care and electronic patient record databases. RESULTS: 53 patients with 54 lesions were diagnosed as having a PT. The median age was 27.5, 35.0 and 38.5 years for benign, borderline and malignant PT, respectively. Borderline and malignant PTs were larger than benign PTs, with mean sizes of 33 and 42 mm compared with 29 mm. 38% of PTs were labelled by the reporting radiologist as fibroadenomas, including two borderline PTs and one malignant PT. In 24% of cases, the radiologist raised the possibility of PT in the report. 17 patients (40%) developed a new fibroepithelial breast lesion during follow-up of which 4 were recurrent PTs. CONCLUSION: Despite adequate surgical management, the development of further fibroepithelial lesions in the ipsilateral breast is common. 3-year clinical surveillance, with the addition of 6-monthly ultrasound is advised for females with initial borderline or malignant PT histology. ADVANCES IN KNOWLEDGE: We propose a follow-up protocol with ultrasound based on the grade of the PT diagnosed for 3 years to detect recurrence. PMID- 25270609 TI - Single port/incision laparoscopic surgery compared with standard three-port laparoscopic surgery for appendicectomy: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to compare the effectiveness of single port/incision laparoscopic surgery (SPILS) with standard three-port laparoscopic surgery for appendicectomy in adults. Feasibility data was collected to evaluate generalizability to other single-port techniques such as cholecystectomy. METHODS: This was a single-center, randomized controlled trial. Participants were randomized to receive either SPILS or standard three-port laparoscopic appendicectomy. The primary patient-reported outcomes were body image and cosmesis at 6 weeks. The primary clinical outcome was pain at 1-7 days. Secondary outcomes included duration of operation, conversion rates, complication rates, use of analgesia, hospital re-admission rates, re-operation rates, and time to return to normal activities. RESULTS: Seventy-nine patients were randomized. Sixty-seven completed the day 1-7 diary and 53 completed the 6-week follow-up. SPILS patients answered significantly more favorably to the items in the body image scale [mean (SD) 5.6 (1.0) vs. 7.0 (3.3); -1.4 (95 % CI -2.8 to 1.5; p = 0.03)] and the cosmetic scale [18.9 (4.1) vs. 15.3 (5.8); 3.6 (95 % CI 0.7-6.5; p = 0.016)] compared with patients in the Standard group. The duration of operation was shorter for SPILS, and patients required less morphine in recovery; however, there were no statistically significant differences in other outcomes. CONCLUSIONS: Patient-reported body image and cosmesis outcomes were better, and surgical outcomes were similar following SPILS. However, the SPILS procedure is more technically demanding and may not be achievable or necessary in routine clinical care. Further assessment of the findings is needed through larger multicenter studies. PMID- 25270610 TI - Hysterectomy via transvaginal natural orifice transluminal endoscopic surgery for nonprolapsed uteri. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery has shown its prospection as a minimally invasive endoscopic surgery. This study aimed to examine the safety and feasibility of transvaginal natural orifice transluminal endoscopic hysterectomy (tVNOTEH) for nonprolapsed uteri in the management of benign gynecological diseases. METHODS: Records were reviewed for the 147 consecutive tVNOTEH procedures between April 2011 and October 2013. Age, body mass index, number of vaginal delivery, and specimen weight were used to select comparable patient who had undergone laparoscopically assisted vaginal hysterectomy (LAVH). RESULTS: A total of 512 patients were recruited in this study (147 tVNOTEHs and 365 LAVHs, respectively). These patients were stratified into six subgroups according to the uterine weight and type of hysterectomy. There was no incidence of switching to abdominal laparatomy. Length of operation, estimated blood loss (EBL), requirement of blood transfusion, and length of postoperative stay were significantly greater in the LAVH group than in the tVNOTEH group but total hospital charges were higher in the tVNOTEH group (p < 0.001). There was no difference in overall incidence of operative complications between the two groups but more complications in LAVH for uterine weight more than 500 g (4.3 vs. 0 %, p < 0.001); this likely reflects higher hospital charges in this subgroup. Significant linear correlations of uterine weight with operating time and EBL existed in both groups. CONCLUSION: tVNOTEH can be safely performed for large and nonprolapsed uterus. Besides, as uterine weight increased, the operative efficiency of tVNOTEH increases compared with LAVH. PMID- 25270611 TI - Endoscopic endonasal transsphenoidal surgery of 1,166 pituitary adenomas. AB - AIM: To report the results of a series of patients undergoing pure endoscopic endonasal pituitary surgery and to evaluate the efficacy and safety of this procedure. MATERIALS AND METHODS: The data of 1,166 patients that underwent endoscopic endonasal transsphenoidal adenoma removal between December 2006 and June 2013 were retrospectively reviewed. Pre- and postoperative hormonal status (3 months after surgery) were analyzed and compared with the clinical parameters originally presented by the patients. The incidences of tumor removal, hormonal control, and tumor removal complications were retrospectively analyzed. RESULT: Out of 577 nonfunctioning adenomas, 180 were growth hormone (GH) secreting, 308 prolactin (PRL) secreting, 26 mixed GH/PRL adenomas, 68 adrenocorticotropin secreting, and 7 thyroid-stimulating hormone-secreting adenomas. The gross total removal of pituitary adenomas was achieved in 98 % of microadenomas, 92 % of macroadenomas, and 76 % of giant adenomas. Hormonal control was achieved in 47 (69 %) cases of ACTH adenomas, 119 (66 %) GH adenomas, 262 (85 %) PRL adenomas, and 6 (86 %) TSH adenomas. Postoperative complications were observed in 168 (14.4 %) patients. The most frequent complications were diabetes insipidus (7 %), epistaxis (1.7 %), hyposmia (1.5 %), anterior lobe insufficiency (1.3 %) ,and CSF leaks (0.6 %). CONCLUSION: The pure endoscopic approach is a safe, efficacious, and minimally invasive technique for the removal of pituitary adenomas. A higher gross total resection rate is vital for non-functional and functional adenomas. For patients with functional adenomas, while hormonal remission is unlikely to be achieved by surgery, the use of adjuvant therapy is advocated to obtain long-term hormonal control. PMID- 25270612 TI - A new intracorporeal Billroth II stapled anastomosis technique in totally laparoscopic distal gastrectomy. AB - BACKGROUND: We introduced a new, safe and simple intracorporeal Billroth II (B II) gastrojejunostomy technique using laparoscopic linear staplers with totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. We further compared the short-term operative outcomes between intracorporeal B-II gastrojejunostomy with TLDG and extracorporeal B-II gastrojejunostomy with laparoscopy-assisted distal gastrectomy (LADG). METHODS: From January 01, 2012 to January 31, 2013, a total of 36 patients with gastric cancer underwent TLDG and LADG. Overall, 11 patients underwent intracorporeal B-II gastrojejunostomy with TLDG, and 25 patients underwent a mini-laparotomy incision for extracorporeal B-II anastomosis with LADG. Perioperative parameters, including patient and tumor characteristics, short-term postoperative outcomes, and anastomosis-related complications, were analyzed to compare the two operations. RESULTS: The time to first flatus, the time on a liquid diet, and the mean postoperative length of hospital stay were significantly different between the groups (P < 0.05). In the TLDG group, the postoperative time to first flatus and the mean postoperative length of hospital stay were significantly shorter than in the LADG group (2.6 +/- 0.20 vs. 3.8 +/- 0.1 days; 10 +/- 1.84 vs. 12.7 +/- 3.35 days). However, the operation-related costs were significantly greater for totally laparoscopic distal gastrectomy (P < 0.001). The mean number of staples used in TLDG was six compared with four in LADG. CONCLUSION: Our new intracorporeal B-II anastomosis method using laparoscopic linear staplers with TLDG was safe, feasible, and minimally invasive compared with extracorporeal B-II gastrojejunostomy with LADG. At the same time, one of its characteristics of our technique is to avoid stricturing of the efferent loop or afferent loop of the jejunum when the entry hole is closed with a stapler. PMID- 25270613 TI - Stability of person ability measures in people with acquired brain injury in the use of everyday technology: the test-retest reliability of the Management of Everyday Technology Assessment (META). AB - AIM: To evaluate the test-retest reliability of the Management of Everyday Technology Assessment (META) in a sample of people with acquired brain injury (ABI). METHOD: The META was administered twice within a two-week period to 25 people with ABI. A Rasch measurement model was used to convert the META ordinal raw scores into equal-interval linear measures of each participant's ability to manage everyday technology (ET). Test-retest reliability of the stability of the person ability measures in the META was examined by a standardized difference Z test and an intra-class correlations analysis (ICC 1). RESULTS: The results showed that the paired person ability measures generated from the META were stable over the test-retest period for 22 of the 25 subjects. The ICC 1 correlation was 0.63, which indicates good overall reliability. CONCLUSION: The META demonstrated acceptable test-retest reliability in a sample of people with ABI. The results illustrate the importance of using sufficiently challenging ETs (relative to a person's abilities) to generate stable META measurements over time. Implications for Rehabilitation The findings add evidence regarding the test-retest reliability of the person ability measures generated from the observation assessment META in a sample of people with ABI. The META might support professionals in the evaluation of interventions that are designed to improve clients' performance of activities including the ability to manage ET. PMID- 25270614 TI - Living with an electric wheelchair--the user perspective. AB - PURPOSE: To explore the experiences of using an electric wheelchair in daily living. METHODS: Fifteen participants, eight women and seven men, living in different parts of a Nordic country were interviewed. The interviews were conducted in the home or at the workplace. Open-ended questions were used. The data were collected and analyzed according to the grounded theory. RESULTS: Analysis resulted in one core category: "Integrating the electric wheelchair - a manifold process", describing a process commencing from initial resistance against use of an electric wheelchair, to acceptance with various extent of integration. Six categories emerged that represent this core process: incorporating the electric wheelchair into the self-identity process, calculating functional consequences, encountering the reactions of others, facing duality in movability, using proactive strategies, and being at the mercy of the system. Findings indicate that the integration process is complex and manifold. Practical, personal, and social dimensions were intertwined and significantly involved. CONCLUSIONS: Integrating an electric wheelchair is a process closely connected to symbolic value, usability, community mobility and identity. These aspects should be considered in the production, prescription, and adaptation processes. Implications for Rehabilitation Integrating an electric wheelchair is a process closely connected to symbolic value, usability, community mobility, and identity. These aspects should be considered in the wheelchair production, prescription, and adaptation processes. PMID- 25270615 TI - Training to use a commercial brain-computer interface as access technology: a case study. AB - PURPOSE: This case study describes how an individual with spastic quadriplegic cerebral palsy was trained over a period of four weeks to use a commercial electroencephalography (EEG)-based brain-computer interface (BCI). METHOD: The participant spent three sessions exploring the system, and seven sessions playing a game focused on EEG feedback training of left and right arm motor imagery and a customised, training game paradigm was employed. RESULTS: The participant showed improvement in the production of two distinct EEG patterns. The participant's performance was influenced by motivation, fatigue and concentration. Six weeks post-training the participant could still control the BCI and used this to type a sentence using an augmentative and alternative communication application on a wirelessly linked device. CONCLUSIONS: The results from this case study highlight the importance of creating a dynamic, relevant and engaging training environment for BCIs. Implications for Rehabilitation Customising a training paradigm to suit the users' interests can influence adherence to assistive technology training. Mood, fatigue, physical illness and motivation influence the usability of a brain computer interface. Commercial brain-computer interfaces, which require little set up time, may be used as access technology for individuals with severe disabilities. PMID- 25270616 TI - Engineering of fluorescent emission of silk fibroin composite materials by material assembly. AB - This novel materials assembly technology endows the designated materials with additional/enhanced performance by fixing "functional components" into the materials. Such functional components are molecularly recognized and accommodated by the designated materials. In this regard, two-photon fluorescence (TPF) organic molecules and CdTe quantum dots (QDs) are adopted as functional components to functionalize silk fibers and films. TPF organic molecules, such as, 2,7-bis[2-(4-nitrophenyl) ethenyl]-9,9-dibutylfluorene (NM), exhibit TPF emission quenching because of the molecular stacking that leads to aggregation in the solid form. The specific recognition between -NO2 in the annealed fluorescent molecules and the -NH groups in the silk fibroin molecules decouples the aggregated molecules. This gives rise to a significant increase in the TPF quantum yields of the silk fibers. Similarly, as another type of functional components, CdTe quantum dots (QDs) with different sizes were also adopted in the silk functionalization method. Compared to QDs in solution the fluorescence properties of functionalized silk materials display a long stability at room temperature. As the functional materials are well dispersed at high quantum yields in the biocompatible silk a TPF microscope can be used to pursue 3D high resolution imaging in real time of the TPF-silk scaffold. PMID- 25270617 TI - A pulse-dose topical 1% 5-fluorouracil treatment regimen in a young dog with corneal squamous cell carcinoma. AB - PURPOSE: To describe the use of a pulse-dose topical 5-fluorouracil (5-FU) treatment regimen in a Pug dog with corneal squamous cell carcinoma (SCC). METHODS: A 1-year-old, spayed female Pug was evaluated for a corneal perforation of the right eye, which was surgically stabilized with a conjunctival pedicle graft. At the time of medial canthoplasty 7 weeks later, two areas of gray-white discoloration had developed medial and lateral to the graft. Biopsy samples were obtained via superficial keratectomy while under general anesthesia. RESULTS: Definitive diagnosis of corneal SCC was made through histopathological examination of the surgical biopsies. Thoracic radiography and submandibular lymph node cytology revealed no evidence of metastatic neoplasia. Following healing of the corneal biopsy sites, topical 1% 5-FU ointment was applied four times daily for four consecutive days once a month, for six treatment cycles. Twenty-three months after diagnosis, the patient remains visual and comfortable with no evidence of SCC recurrence. Long-term therapy with once daily topical 1% cyclosporine solution was used to manage corneal pigmentation bilaterally. CONCLUSIONS: The pulse-therapy 1% 5-FU protocol was a successful, convenient, and cost-effective adjunctive treatment with few adverse effects. PMID- 25270618 TI - Kidney diseases in Roma and non-Roma children from eastern Slovakia: are Roma children more at risk? AB - OBJECTIVES: To compare the occurence of primary renal diseases (PRD) in Roma and non-Roma children. METHODS: Data on all outpatients (n = 921) from a tertiary pediatric nephrology centre (<19 years) in eastern Slovakia were collected. We assessed early signs and symptoms and PRD for Roma and non-Roma children. RESULTS: The proportion of Roma among patients was relatively small regarding early signs like proteinuria but large regarding PRD with gross clinically apparent symptoms (e.g. Alport syndrome, p < 0.01 and systemic lupus erythematosus, p < 0.05). CONCLUSIONS: The overall proportion of Roma children in outpatients with kidney problems is smaller than the estimated proportion of Roma in all children in Slovakia, in particular for early signs, but not for major renal diseases. PMID- 25270619 TI - Mutant hypoxia-inducible factor 1alpha modified bone marrow mesenchymal stem cells ameliorate cerebral ischemia. AB - Hypoxia-inducible factor 1alpha (HIF1alpha) plays stimulatory roles in revascularization in the ischemic area of cerebral ischemia. However, the hydroxylation of proline at 564 and asparagine at 803 in the HIF1alpha coding sequence facilitated the degradation of HIF1alpha and inhibited the transcription activity of the HIF1alpha promoter under normoxic conditions and confined the pro angiogenic efficacy of HIF1alpha. In the present study, the HIF1alpha mutant containing P564A and N803A was constructed by site-directed mutagenesis. Rat bone marrow mesenchymal stem cells (BMSCs) were infected with adenoviral particles containing HIF1alpha mutant at multiplicity of infection of 150. The HIF1alpha mRNA and protein levels under hypoxia and normoxic conditions were compared using reverse transcription-polymerase chain reaction and western blot analysis. To explore the therapeutic effect of mutant HIF1alpha on the cerebral ischemia, BMSCs overexpressing mutant HIF1alpha were transplanted in the rat middle cerebral artery occlusion model (MCAO). The motor function and cerebral infarct size were evaluated using modified neurological severity score and triphenyltetrazolium chloride (TTC) staining within four weeks after MCAO. Vascular endothelial growth factor (VEGF) protein expression was detected by western blot analysis. Microvessel density and angiogenesis were detected by immunohistochemistry to evaluate the recovery of the brain ischemia. The HIF1alpha mutant containing P564A and N803A could be expressed under normoxic conditions. Transplantation of BMSCs stably expressing mutant HIF1alpha significantly improved motor function, reduced cerebral infarction and increased VEGF protein expression revascularization at days 7, 14 and 28 (p<0.05). Therefore, the HIF1alpha mutant containing P564A and N803A may be a potential target for the treatment of the cerebral ischemia. PMID- 25270620 TI - A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens. AB - Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic. PMID- 25270621 TI - Ninety-day oral toxicity studies on two genetically modified maize MON810 varieties in Wistar Han RCC rats (EU 7th Framework Programme project GRACE). AB - The GMO Risk Assessment and Communication of Evidence (GRACE; www.grace-fp7.eu ) project is funded by the European Commission within the 7th Framework Programme. A key objective of GRACE is to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of two 90-day feeding trials with two different GM maize MON810 varieties, their near isogenic non-GM varieties and four additional conventional maize varieties are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 408. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after subchronic exposure, independently of the two different genetic backgrounds of the event. PMID- 25270622 TI - Di-(2-ethylhexyl) phthalate accelerates atherosclerosis in apolipoprotein E deficient mice. AB - Di-(2-ethylhexyl) phthalate (DEHP) is associated with atherosclerosis-related cardiovascular disease complications, but we lack direct evidence of its unfavorable effect on atherogenesis. In this study, we aimed to clarify in vivo and in vitro the contribution of DEHP to the development of atherosclerosis and its underlying mechanisms. Apolipoprotein E-deficient (apoE(-/-)) mice chronically treated with DEHP for 4 weeks showed exacerbated hyperlipidemia, systemic inflammation, and atherosclerosis. In addition, DEHP promoted low density lipoprotein (LDL) oxidation, which led to inflammation in endothelial cells as evidenced by increased protein expression of pro-inflammatory mediators. Furthermore, chronic DEHP treatment increased hepatic cholesterol accumulation by downregulating the protein expression of key regulators in cholesterol clearance including LDL receptor, cholesterol 7alpha-hydrolase, ATP-binding cassette transporter G5 and G8, and liver X receptor alpha. Moreover, the adiposity and inflammation of white adipose tissues were promoted in DEHP-treated apoE(-/-) mice. In conclusion, DEHP may disturb cholesterol homeostasis and deregulate the inflammatory response, thus leading to accelerated atherosclerosis. PMID- 25270623 TI - Human metabolism and renal excretion of selenium compounds after oral ingestion of sodium selenate dependent on trimethylselenium ion (TMSe) status. AB - An in vivo metabolism study in humans was carried out to investigate the toxicokinetics and metabolism of sodium selenate differentiating by the trimethylselenium (TMSe) status. Therefore, the changes in blood plasma concentration and the urinary excretion within 24 h of seven healthy subjects after oral administration of a dietary supplement containing sodium selenate (50 MUg selenium) were analyzed. Three subjects belong to the subgroup of TMSe eliminators, and four subjects were related to the non-TMSe eliminators subgroup. The concentrations of total selenium in blood plasma and urine samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS). Additionally, speciation analysis of urine samples was performed using ICP-MS coupled to a liquid chromatography system. Plasma selenium concentration changed from 82.5 +/- 12.5 MUg Se/L before to 85.1 +/- 12.0 MUg Se/L 2-3 h after supplementation. Considering the individual 24-hour background amounts of renal excreted selenium, the ingestion caused an additional excretion of 15.4 +/- 3.3 MUg Se/24 h (?31.1 +/- 7.6 % of the administered dose) with a maximum elimination already 2 h after exposure. The differentiated analysis revealed that in all subjects, the main elimination product (30.1 +/- 6.9 % of the administered dose) was unmetabolized selenate. TMSe was only detected in the urine of the TMSe eliminators. This subgroup excreted in comparison with the non-TMSe eliminators a significantly lower amount of selenate. Only one subject metabolized selenate to a larger portion to methyl-2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside (SeSug1) and methyl-2-amino-2-deoxy-1-seleno-beta-D-galactopyranoside (SeSug3). All other subjects showed only a minor metabolism of selenate to selenium containing carbohydrates. By individuals, which do not excrete TMSe in urine basically, selenate is metabolized only marginally and is excreted rapidly via urine generally. In contrast, a considerable portion of this inorganic selenium compound is metabolized by individuals, which eliminate TMSe basically. An elevated metabolism may also be provided by individuals, which eliminate high levels of selenium-containing carbohydrates basically. The difference in metabolism may imply a different disposition for pharmacological or toxic effects by exposure to inorganic selenium compounds. PMID- 25270624 TI - Uncommon external abdominal oblique muscle strain in a professional soccer player: a case report. AB - BACKGROUND: This is the first report of external abdominal oblique muscle injury occurring in a professional soccer player. CASE PRESENTATION: A 28-year-old Caucasian professional soccer player presented after experiencing a popping sensation associated with strong parietal pain localized between the left 11th and 12th ribs. Ultrasound examination revealed a collection of fluid under the 11th rib, suggesting injury of the left external oblique muscle. Platelet-rich plasma treatment was administered and the soccer player returned to competition on the 21st day after treatment. CONCLUSION: This rare injury results from a sudden intrinsic eccentric contraction of the internal oblique muscle while in a stretched position. Ultrasound can help to confirm the diagnosis and to monitor clinical follow-up. Platelet-rich plasma treatment could aid recovery in high level athletes. PMID- 25270625 TI - Hemorrhagic stroke and cerebral paragonimiasis. AB - BACKGROUND AND PURPOSE: We retrospectively analyzed the clinical and imaging characteristics, diagnosis, and treatment outcomes of 10 patients with hemorrhagic cerebral paragonimiasis (CP), and we evaluated the influence of Paragonimus infection on cerebrovascular damage. METHODS: Ten patients (7 male and 3 female; median age 15.7 years, range 4-46 years) with hemorrhagic CP were diagnosed between April 2009 and January 2013. All patients underwent the head computed tomography scans and 9 patients underwent MRI examinations. Four patients underwent computed tomographic angiography, magnetic resonance angiography, and digital subtraction angiography. Liquid-based cytological examination of cerebrospinal fluid was performed in 7 patients. Follow-up examinations were performed for 9 cases for a period of 12 to 62 months. RESULTS: Hemorrhagic CP accounted for 37% of CP cases (10/27). No patients were initially diagnosed with CP. The major symptoms of hemorrhagic CP included acute headache, vomiting, hemiparalysis, epilepsy, blurred vision, sensory impairment, and tinnitus. Four cases were surgically treated. Most symptoms markedly improved, but fine motor dysfunction and mental dysfunction remained in 3 surgical patients. CONCLUSIONS: Hemorrhagic stroke typically occurred during the acute stage and in the early stages of further Paragonimus migration. Delay of treatment increased the risk of initial and recurrent stroke. PMID- 25270626 TI - Response to letter regarding article, "fibrinolysis for intraventricular hemorrhage: an updated meta-analysis and systematic review of the literature". PMID- 25270627 TI - Letter by Gaberel et al regarding article, "fibrinolysis for intraventricular hemorrhage: an updated meta-analysis and systematic review of the literature". PMID- 25270628 TI - Ethnic disparities in ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage incidence in the Netherlands. AB - BACKGROUND AND PURPOSE: Data on the incidence of stroke subtypes among ethnic minority groups are limited. We assessed ethnic differences in the incidence of stroke subtypes in the Netherlands. METHODS: A Dutch nationwide register-based cohort study (n=7 423 174) was conducted between 1998 and 2010. We studied the following stroke subtypes: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Cox proportional hazard models were used to estimate incidence differences between first-generation ethnic minorities and the Dutch majority population (ethnic Dutch). RESULTS: Compared with ethnic Dutch, Surinamese men and women had higher incidence rates of all stroke subtypes combined (adjusted hazard ratios, 1.43; 95% confidence interval, 1.35-1.50 and 1.34; 1.28-1.41), ischemic stroke (1.68; 1.57-1.81 and 1.57; 1.46-1.68), intracerebral hemorrhage (2.08; 1.82-2.39 and 1.74; 1.50-2.00), and subarachnoid hemorrhage (1.25; 0.92-1.69 and 1.26; 1.04-1.54). By contrast, Moroccan men and women had lower incidence rates of all stroke subtypes combined (0.42; 0.36-0.48 and 0.37; 0.30-0.46), ischemic stroke (0.35; 0.27-0.45 and 0.34; 0.24-0.49), intracerebral hemorrhage (0.61; 0.41-0.92 and 0.32; 0.16-0.72), and subarachnoid hemorrhage (0.42; 0.20-0.88 and 0.34; 0.17-0.68) compared with ethnic Dutch counterparts. The results varied by stroke subtype and sex for the other minority groups. For example, Turkish women had a reduced incidence of subarachnoid hemorrhage, whereas Turkish men had an increased incidence of ischemic stroke and intracerebral hemorrhage compared with ethnic Dutch. CONCLUSIONS: Our findings suggest that Surinamese have an increased risk, whereas Moroccans have a reduced risk for all the various stroke subtypes. Among other ethnic minorities, the risk seems to depend on the stroke subtype and sex. These findings underscore the need to identify the root causes of these ethnic differences to assist primary and secondary prevention efforts. PMID- 25270629 TI - Phase II trial of the Sigma-1 receptor agonist cutamesine (SA4503) for recovery enhancement after acute ischemic stroke. AB - BACKGROUND AND PURPOSE: The sigma-1 receptor (Sig-1R) agonist cutamesine (SA4503) enhanced functional recovery after experimental stroke with a treatment initiation window of 48 hours and chronic treatment for 28 days. We conducted a phase 2 clinical trial exploring the safety, tolerability, dose range, and functional effects of cutamesine in patients with ischemic stroke. METHODS: Subjects were randomized between 48 and 72 hours after stroke to receive cutamesine 1 mg/d, 3 mg/d, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (day 28), and at end of follow-up (day 56). RESULTS: In 60 patients, treatment with both cutamesine dosages was safe and well tolerated without significant differences in numbers of treatment emergent or serious adverse events. No significant effect was observed on the primary efficacy measure (change in National Institutes of Health Stroke Scale from baseline to day 56) or modified Rankin Scale and Barthel Index scores. Post hoc analysis of moderately and severely affected patients (baseline National Institutes of Health Stroke Scale, >=7 and >=10) showed greater National Institutes of Health Stroke Scale improvements in the 3 mg/d cutamesine group when compared with placebo (P=0.034 and P=0.038, respectively). A trend toward a higher proportion being able to complete a 10m timed walk was observed for cutamesine-treated subjects. CONCLUSIONS: Cutamesine was safe and well tolerated at both dosage levels. Although no significant effects on functional end points were seen in the population as a whole, greater improvement in National Institutes of Health Stroke Scale scores among patients with greater pretreatment deficits seen in post hoc analysis warrants further investigation. Additional studies should focus on the patient population with moderate-to-severe stroke. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov/show/NCT00639249. Unique identifier: NCT00639249. The EudraCT number is 2007-004840-60 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004840-60/GB). PMID- 25270630 TI - Comparison between a standardized questionnaire and expert clinicians for capacity assessment in stroke clinical trials. PMID- 25270631 TI - [Influence of birth weight on lipid profile in later life]. PMID- 25270632 TI - PA-824 is as effective as isoniazid against latent tuberculosis infection in C3HeB/FeJ mice. AB - The bicyclic nitroimidazole-like molecule PA-824 has activity both against replicating and hypoxic non-replicating Mycobacterium tuberculosis, raising the possibility that it may have a role in the treatment of latent tuberculosis infection (LTBI). This study aimed to examine the bactericidal and sterilising activities of PA-824 against LTBI in C3HeB/FeJ mice, which develop hypoxic, necrotic granulomas histologically resembling their human counterparts. Female 5 6-week-old C3HeB/FeJ mice were immunised via the aerosol route with a recombinant BCG strain overexpressing the 30-kDa major secretory protein (rBCG30) and were aerosol-infected 6 weeks later with virulent M. tuberculosis H37Rv. Six weeks after M. tuberculosis infection, separate groups of mice were left untreated (negative controls) or were treated with either rifampicin, isoniazid (INH) or PA 824. Culture-positive relapse was assessed in subgroups of mice after 2 months and 4 months of treatment. Human-equivalent doses of PA-824 given five times weekly showed similar bactericidal activity as INH at Months 1, 2 and 4 of treatment, and 15/15 mice treated with either PA-824 or INH showed lung-culture relapse 3 months after completion of treatment. To the best of our knowledge, this is the first report examining the sterilising activity of PA-824 in an animal model of LTBI. This model may be useful for screening the efficacy of novel drugs against LTBI, particularly those with specific activity against bacilli residing within necrotic lung granulomas. PMID- 25270633 TI - Mycobacterial interspersed repetitive unit typing and mutational profile for multidrug-resistant and extensively drug-resistant tuberculosis surveillance in Portugal: a 3-year period overview. AB - Multidrug tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR TB) cases constitute a serious health problem in Portugal, of which the majority of isolates belong to the Lisboa family and the Q1 cluster, highly related to the Lisboa family. Here we sought to investigate the molecular basis of resistant TB as well as to determine the prevalence of specific drug resistance mutations and their association with MDR-TB and/or XDR-TB. In total, 74 Mycobacterium tuberculosis clinical isolates collected in Lisbon Health Region were genotyped by 24-loci mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR), and the mutational profile associated with first- and second line drug resistance was studied. Seven new mutations were found, whilst the remaining 28 mutations had been previously associated with drug resistance. None of the mutations was specifically associated with MDR-TB. The mutational patterns observed among isolates belonging to Lisboa3 and Q1 clusters were also observed in isolates with unique MIRU-VNTR patterns but closely related to these strains. Such data suggest that the genotyping technique employed discriminates isolates with the same mutational profile. To establish the most adequate genotyping technique, the discriminatory power of three different MIRU-VNTR sets was analysed. The 15-loci MIRU-VNTR set showed adequate discriminatory power, comparable with the 24-loci set, allowing clustering of 60% and 86% of the MDR-TB and XDR-TB isolates, respectively, the majority of which belonged to the Lisboa3 and Q1 clusters. From an epidemiological standpoint, this study suggests combined mutational and genotyping analysis as a valuable tool for drug resistance surveillance. PMID- 25270634 TI - Growing dissecting aneurysm of basilar trunk treated with stent-assisted coiling. AB - Growing basilar dissecting aneurysm is a scarce but increasingly recognized entity, accounting for a significant risk of death and disability. Controversy exists regarding the optimal management. A 61-year-old man presented with dysarthria and left hemiparesis attributable to a basilar trunk dissecting aneurysm. Antiplatelet therapy was instituted, and the patient's clinical condition markedly improved. However, he developed severe headache, dysarthria, and left hemiparesis 35 days later. Angiography revealed significant enlargement of the aneurysm, and stent-assisted coiling was then uneventfully performed. The patient remained clinically stable with only mild left-sided hemiparesis at the 2 year clinical follow-up. PMID- 25270635 TI - Synchronous thymoma and lung adenocarcinoma treated with a single mini-invasive approach. AB - A 75 year-old man with a lesion in the middle lobe of the lung was discovered to also have, during the follow-up period, a mass in the mediastinum, diagnosed as a multi-thymic cyst. Both pathologies were successfully treated with a single surgical approach by video-assisted thoracoscopy. We performed a middle VATS lobectomy with complete lymphadenectomy followed by radical thymectomy without additional incision. The postoperative course was uneventful. PMID- 25270636 TI - Comparison of a radiofrequency powered flexible needle with a classic rigid Brockenbrough needle for transseptal punctures in terms of safety and efficacy. AB - INTRODUCTION: This study aimed to evaluate the safety and efficacy of utilising an innovative radiofrequency (RF) powered flexible needle to achieve transseptal puncture (TSP). METHODS AND RESULTS: A RF powered flexible needle (Toronto catheter, Baylis Medical Company Inc.) associated with a stiffer dilator (Torflex Superstrong, Baylis Medical Company Inc.) was used in 125 consecutive patients referred for left sided ablations (mean age=55.6, male=86.5%) and compared with a standard transseptal set (BRK needle, SL0 sheath and dilator, St Jude Medical, Inc.) used in the previous 100 patients (mean age=56, male 82%). TSP was achieved in 95/100 patients in the Brockenbrough group and in all 125 patients in the Toronto group (p=0.01) despite an equivalent proportion of difficult situations (8 and 9% respectively) and patients with a prior TSP (17% vs 24%). 7/100 needle related events (failure, aborted attempt or pericardial effusion) occurred in the Brockenbrough group and none in the Toronto group (p=0.01). The Toronto needle crossed the septum at the first attempt in 123/125 (98.4%) patients and the Brockenbrough needle in 84/95 (88%) patients (p<0.001). CONCLUSION: Our data suggest that the Toronto RF powered flexible needle is safer and more efficient than a standard Brockenbrough needle and can be used not only in difficult situations but routinely to achieve TSP. PMID- 25270637 TI - Cross-sex hormone use, functional health and mental well-being among transgender men (Toms) and Transgender Women (Kathoeys) in Thailand. AB - There exists limited understanding of cross-sex hormone use and mental well-being among transgender women and, particularly, among transgender men. Moreover, most studies of transgender people have taken place in the Global North and often in the context of HIV. This exploratory study compared 60 transgender men (toms) with 60 transgender women (kathoeys) regarding their use of cross-sex hormones, mental well-being and acceptance by their family. Participants also completed a dispositional optimism scale (the Life Orientation Test Revised), the Social Functioning Questionnaire and the Short Form Health Survey 36 assessing their profile of functional health and mental well-being. Cross-sex hormones were used by 35% of toms and 73% of kathoeys and were largely unsupervised by health related personnel. There were no differences in functional health and mental well being among toms and kathoeys. However, toms currently using cross-sex hormones scored on average poorer on bodily pain and mental health, compared to non-users. Furthermore, compared to non-users, cross-sex hormone users were about eight times and five times more likely to be associated with poor parental acceptance among toms and kathoeys, respectively. This study was the first to compare cross sex hormone use, functional health and mental well-being among transgender women and transgender men in Southeast Asia. PMID- 25270638 TI - Consensus Genotyper for Exome Sequencing (CGES): improving the quality of exome variant genotypes. AB - MOTIVATION: The development of cost-effective next-generation sequencing methods has spurred the development of high-throughput bioinformatics tools for detection of sequence variation. With many disparate variant-calling algorithms available, investigators must ask, 'Which method is best for my data?' Machine learning research has shown that so-called ensemble methods that combine the output of multiple models can dramatically improve classifier performance. Here we describe a novel variant-calling approach based on an ensemble of variant-calling algorithms, which we term the Consensus Genotyper for Exome Sequencing (CGES). CGES uses a two-stage voting scheme among four algorithm implementations. While our ensemble method can accept variants generated by any variant-calling algorithm, we used GATK2.8, SAMtools, FreeBayes and Atlas-SNP2 in building CGES because of their performance, widespread adoption and diverse but complementary algorithms. RESULTS: We apply CGES to 132 samples sequenced at the Hudson Alpha Institute for Biotechnology (HAIB, Huntsville, AL) using the Nimblegen Exome Capture and Illumina sequencing technology. Our sample set consisted of 40 complete trios, two families of four, one parent-child duo and two unrelated individuals. CGES yielded the fewest total variant calls (N(CGES) = 139 degrees 897), the highest Ts/Tv ratio (3.02), the lowest Mendelian error rate across all genotypes (0.028%), the highest rediscovery rate from the Exome Variant Server (EVS; 89.3%) and 1000 Genomes (1KG; 84.1%) and the highest positive predictive value (PPV; 96.1%) for a random sample of previously validated de novo variants. We describe these and other quality control (QC) metrics from consensus data and explain how the CGES pipeline can be used to generate call sets of varying quality stringency, including consensus calls present across all four algorithms, calls that are consistent across any three out of four algorithms, calls that are consistent across any two out of four algorithms or a more liberal set of all calls made by any algorithm. AVAILABILITY AND IMPLEMENTATION: To enable accessible, efficient and reproducible analysis, we implement CGES both as a stand-alone command line tool available for download in GitHub and as a set of Galaxy tools and workflows configured to execute on parallel computers. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25270639 TI - BioVLAB-MMIA-NGS: microRNA-mRNA integrated analysis using high-throughput sequencing data. AB - MOTIVATION: It is now well established that microRNAs (miRNAs) play a critical role in regulating gene expression in a sequence-specific manner, and genome-wide efforts are underway to predict known and novel miRNA targets. However, the integrated miRNA-mRNA analysis remains a major computational challenge, requiring powerful informatics systems and bioinformatics expertise. RESULTS: The objective of this study was to modify our widely recognized Web server for the integrated mRNA-miRNA analysis (MMIA) and its subsequent deployment on the Amazon cloud (BioVLAB-MMIA) to be compatible with high-throughput platforms, including next generation sequencing (NGS) data (e.g. RNA-seq). We developed a new version called the BioVLAB-MMIA-NGS, deployed on both Amazon cloud and on a high performance publicly available server called MAHA. By using NGS data and integrating various bioinformatics tools and databases, BioVLAB-MMIA-NGS offers several advantages. First, sequencing data is more accurate than array-based methods for determining miRNA expression levels. Second, potential novel miRNAs can be detected by using various computational methods for characterizing miRNAs. Third, because miRNA-mediated gene regulation is due to hybridization of an miRNA to its target mRNA, sequencing data can be used to identify many-to-many relationship between miRNAs and target genes with high accuracy. AVAILABILITY AND IMPLEMENTATION: http://epigenomics.snu.ac.kr/biovlab_mmia_ngs/. PMID- 25270640 TI - The Chinese Verbal Learning Test specifically assesses hippocampal state. AB - BACKGROUND: Recently, the Chinese Verbal Learning Test (ChVLT) was developed to assess episodic memory in Chinese speakers. The goal of this analysis was to determine whether memory consolidation as measured by the ChVLT was specifically associated with hippocampal volume in patients with cognitive impairment. METHODS: We administered the ChVLT to 22 Chinese-speaking patients with mild cognitive impairment and 9 patients with dementia and obtained hippocampal and cortical volumes from T1-weighted magnetic resonance imaging. RESULTS: Linear regression revealed that hippocampal volume explained 9.9% of the variance in delayed memory (P = .018) after controlling for the effects of age, education, immediate recall after the last learning trial, overall level of cognitive impairment, and volumes of other cortical regions. CONCLUSION: These results indicate that the ChVLT is specifically correlated with hippocampal volume, supporting its utility for detecting hippocampal disease and monitoring hippocampal state over time. PMID- 25270641 TI - Retinal changes in visceral leishmaniasis by retinal photography. AB - BACKGROUND: In visceral leishmaniasis (VL), retinal changes have previously been noted but not described in detail and their clinical and pathological significance are unknown. A prospective observational study was undertaken in Mymensingh, Bangladesh aiming to describe in detail visible changes in the retina in unselected patients with VL. METHODS: Patients underwent assessment of visual function, indirect and direct ophthalmoscopy and portable retinal photography. The photographs were assessed by masked observers including assessment for vessel tortuosity using a semi-automated system. RESULTS: 30 patients with VL were enrolled, of whom 6 (20%) had abnormalities. These included 5 with focal retinal whitening, 2 with cotton wool spots, 2 with haemorrhages, as well as increased vessel tortuosity. Visual function was preserved. CONCLUSIONS: These changes suggest a previously unrecognized retinal vasculopathy. An inflammatory aetiology is plausible such as a subclinical retinal vasculitis, possibly with altered local microvascular autoregulation, and warrants further investigation. PMID- 25270642 TI - Characterization of sphere-forming cells with stem-like properties from the gastric cancer cell lines MKN45 and SGC7901. AB - Traditionally, it was presumed that gastric cancer was derived from tumor cells with stem-like properties. In the present study, stem-like cells from the gastric cancer cell lines MKN45 and SGC7901 were enriched by growing them as spheres in a defined serum-free medium. Following enrichment for stem-like cells, cluster of differentiation (CD)24 and CD44 were applied as candidate stem cell markers to examine the expression profile. It was revealed that the sphere-derived cells contained a higher proportion of cells expressing the stem cell surface markers CD24 and CD44 when compared with the parental cells. It was also identified that the expression of cytokeratin 18 in sphere-derived cells was decreased and the expression of vimentin and aldehyde dehydrogenase 1 (ALDH1) was increased compared with the parental cells. This finding supports the existence of a population of tumor sphere-forming cells with stem cell properties in the MKN45 and SGC7901 cell lines. Furthermore, the stem cell population was enriched in cells expressing CD24, CD44, vimentin and ALDH1 cell surface markers. These results support the existence of gastric cancer stem cells and provide an alternative approach to the diagnosis and treatment of gastric cancer. PMID- 25270643 TI - Obituary: Axel Rethwilm (1959-2014). PMID- 25270644 TI - Exposure to 'farming' and objective markers of atopy: a systematic review and meta-analysis. AB - There is growing interest in the 'farm effect' on the spectrum of allergy. Evidence concerning the farm effect on asthma, eczema, and allergic rhinitis has been systematically synthesized, but without a specific focus on objective markers of sensitization. This focus is important, as farm exposures may be related to allergy but not to non-allergic phenotypes of disease. We aimed to systematically review and meta-analyse literature that has investigated associations between farm exposure at any age and objective measures of atopy, that is serum IgE or skin prick tests results. Using predefined inclusion and exclusion criteria, we identified 29 articles for review. IgE levels were measured in either childhood or adulthood by eighteen studies, while skin prick testing was performed in sixteen studies. Newcastle-Ottawa Scale quality assessments indicated that the majority of these studies demonstrated a representative sample of selected participants. Due to significant heterogeneity in study measures and methodology between studies, only few were meta-analysed. This meta-analysis showed a significant protective effect of farm exposure before 1 year of life on allergic sensitization (OR = 0.60 [0.52-0.70]). Farm exposure during childhood was also associated with a reduced risk of sensitization to cat or timothy (OR = 0.60 [0.51-0.70]; OR=0.46 [0.41-0.51]). Studies investigating the effect of farm exposure in adult life could not be meta-analysed, and their results were inconsistent. Insufficient studies investigated food sensitization as an outcome to allow synthesis. The majority of studies included in this review investigated childhood farm exposure, finding evidence to support a protective childhood 'farm effect' against subsequent atopy. There is inconsistent evidence on the association between farm exposure in adulthood and allergic sensitization. Further studies are needed to tease out the exact exposures and timing associated with farming environments that protect against allergic disease. PMID- 25270645 TI - Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons. AB - BACKGROUND: Recent studies suggest that influenza vaccination in the previous season may influence the effectiveness of current-season vaccination, but this has not been assessed in a single population over multiple years. METHODS: Patients presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2012-2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged >=9 years using logistic regression models with an interaction term for vaccination history. RESULTS: There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A(H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protection against H3N2 (adjusted VE range, 31%-36%) and B (52%-66%). In the analysis using 5 years of historical vaccination data, current season VE against H3N2 was significantly higher among vaccinated individuals with no prior vaccination history (65%; 95% confidence interval [CI], 36%-80%) compared with vaccinated individuals with a frequent vaccination history (24%; 95% CI, 3%-41%; P = .01). VE against B was 75% (95% CI, 50%-87%) and 48% (95% CI, 29%-62%), respectively (P = .05). Similar findings were observed when analysis was restricted to adults 18-49 years. CONCLUSIONS: Current- and previous-season vaccination generated similar levels of protection, and vaccine-induced protection was greatest for individuals not vaccinated during the prior 5 years. Additional studies are needed to understand the long-term effects of annual vaccination. PMID- 25270646 TI - Contact investigation of melioidosis cases reveals regional endemicity in Puerto Rico. AB - BACKGROUND: Melioidosis results from infection with Burkholderia pseudomallei and is associated with case-fatality rates up to 40%. Early diagnosis and treatment with appropriate antimicrobials can improve survival rates. Fatal and nonfatal melioidosis cases were identified in Puerto Rico in 2010 and 2012, respectively, which prompted contact investigations to identify risk factors for infection and evaluate endemicity. METHODS: Questionnaires were administered and serum specimens were collected from coworkers, neighborhood contacts within 250 m of both patients' residences, and injection drug user (IDU) contacts of the 2012 patient. Serum specimens were tested for evidence of prior exposure to B. pseudomallei by indirect hemagglutination assay. Neighborhood seropositivity results guided soil sampling to isolate B. pseudomallei. RESULTS: Serum specimens were collected from contacts of the 2010 (n = 51) and 2012 (n = 60) patients, respectively. No coworkers had detectable anti-B. pseudomallei antibody, whereas seropositive results among neighborhood contacts was 5% (n = 2) for the 2010 patient and 23% (n = 12) for the 2012 patient, as well as 2 of 3 IDU contacts for the 2012 case. Factors significantly associated with seropositivity were having skin wounds, sores, or ulcers (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.2-17.8) and IDU (OR, 18.0; 95% CI, 1.6-194.0). Burkholderia pseudomallei was isolated from soil collected in the neighborhood of the 2012 patient. CONCLUSIONS: Taken together, isolation of B. pseudomallei from a soil sample and high seropositivity among patient contacts suggest at least regional endemicity of melioidosis in Puerto Rico. Increased awareness of melioidosis is needed to enable early case identification and early initiation of appropriate antimicrobial therapy. PMID- 25270647 TI - Editorial commentary: Contact tracing in children exposed to an index case of tuberculosis: the need, the challenge, and the impact. PMID- 25270648 TI - Editorial commentary: melioidosis in Puerto Rico: the iceberg slowly emerges. PMID- 25270649 TI - A prospective evaluation of the symptom-based screening approach to the management of children who are contacts of tuberculosis cases. AB - BACKGROUND: Child tuberculosis contact screening and management can enhance case finding and prevent tuberculosis disease. It is universally recommended but rarely implemented in tuberculosis-endemic settings. The World Health Organization (WHO)-recommended symptom-based screening approach could improve implementation but has not been prospectively evaluated. METHODS: We conducted a cohort study of children who were close contacts of pulmonary tuberculosis patients in Indonesia from August 2010 to December 2012. We performed clinical assessment, tuberculin skin test, and chest radiography in all eligible children irrespective of symptoms at baseline. Mycobacterial culture and Xpert MTB/RIF assay were performed on sputum from children with persistent symptoms of suspected tuberculosis. Children were managed according to WHO guidelines and were prospectively followed for 12 months. RESULTS: A total of 269 child contacts of 140 index cases were evaluated. At baseline, 21 (8%) children had tuberculosis diagnosed clinically; an additional 102 (38%) had evidence of infection without disease. Of children with any tuberculosis-related symptoms at baseline, 21% had tuberculosis diagnosed compared with none of the asymptomatic children (P < .001). After 12 months of follow-up, none of the 99 eligible young child contacts (<5 years) who received isoniazid preventive therapy (IPT) had developed disease compared with 4 of 149 (2.6%) asymptomatic older children who did not receive IPT. CONCLUSIONS: Symptom-based screening is an effective and simple approach to child tuberculosis contact management that can be implemented at the primary healthcare level. PMID- 25270650 TI - Authors' reply to McGregor and Foley. PMID- 25270651 TI - Teaching veterinary anesthesia and surgery: the impact of instructor availability on anesthesia, operative, and recovery times in dogs undergoing ovariohysterectomy or castration. AB - Veterinary students learning to perform elective ovariohysterectomy (OVH) and castration procedures have traditionally been taught by a few instructors supervising many student groups simultaneously. This study, using a historical control group, explored the impacts of having a dedicated instructor with each student group for anesthetic induction and an entire surgical procedure. Our hypothesis was that preparation, surgical, and anesthesia times would be shorter and, consequently, post-operative recovery times would be shorter with a dedicated instructor compared to traditional methods. Anesthesia records of dogs undergoing elective surgery by third-year veterinary students were reviewed over 3 consecutive years. Traditional instruction was used in year 1 (Y1), and a dedicated instructor per student group was used in year 2 (Y2) and year 3 (Y3). Anesthesia time, surgical time, recovery time, and pre- and post-operative rectal temperature were analyzed, and a stepwise regression model was developed for factors influencing recovery time. Of 206 records reviewed (Y1, 33; Y2, 98; Y3, 75), there were 101 OVH procedures and 105 castration procedures. Preparation, surgery, and anesthesia times were longer in animals undergoing surgery in Y1, when the traditional instruction method was used. Recovery time was not influenced by instructor assignment. Using dedicated instructors to teach OVH and castration to third-year veterinary students decreased overall anesthesia time by 36 to 49 minutes for OVH and 29 to 32 minutes for castration. A teaching model of dedicated instructors requires excellent coordination between surgeons and anesthesiologists to ensure that a similar number of animals can undergo procedures in the time allotted for teaching. PMID- 25270652 TI - Making clinical case-based learning in veterinary medicine visible: analysis of collaborative concept-mapping processes and reflections. AB - The value of collaborative concept mapping in assisting students to develop an understanding of complex concepts across a broad range of basic and applied science subjects is well documented. Less is known about students' learning processes that occur during the construction of a concept map, especially in the context of clinical cases in veterinary medicine. This study investigated the unfolding collaborative learning processes that took place in real-time concept mapping of a clinical case by veterinary medical students and explored students' and their teacher's reflections on the value of this activity. This study had two parts. The first part investigated the cognitive and metacognitive learning processes of two groups of students who displayed divergent learning outcomes in a concept mapping task. Meaningful group differences were found in their level of learning engagement in terms of the extent to which they spent time understanding and co-constructing knowledge along with completing the task at hand. The second part explored students' and their teacher's views on the value of concept mapping as a learning and teaching tool. The students' and their teacher's perceptions revealed congruent and contrasting notions about the usefulness of concept mapping. The relevance of concept mapping to clinical case-based learning in veterinary medicine is discussed, along with directions for future research. PMID- 25270653 TI - Microscope use in clinical veterinary practice and potential implications for veterinary school curricula. AB - Microscopy (skill of using a microscope) and the concepts of cytology (study of cells) and histology (study of tissues) are most often taught in professional veterinary medicine programs through the traditional method of glass slides and light microscopes. Several limiting factors in veterinary training programs are encouraging educators to explore innovative options for teaching microscopy skills and the concepts of cytology and histology. An anonymous online survey was administered through the Colorado Veterinary Medical Association to Colorado veterinarians working in private practice. It was designed to assess their current usage of microscopes for cytological and histological evaluation of specimens and their perceptions of microscope use in their veterinary education. The first part of the survey was answered by 183 veterinarians, with 104 indicating they had an onsite diagnostic lab. Analysis pertaining to the use of the microscope in practice and in veterinary programs was conducted on this subset. Most respondents felt the amount of time spent in the curriculum using a microscope was just right for basic microscope use and using the microscope for viewing and learning about normal and abnormal histological sections and clinical cytology. Participants felt more emphasis could be placed on clinical and diagnostic cytology. Study results suggest that practicing veterinarians frequently use microscopes for a wide variety of cytological diagnostics. However, only two respondents indicated they prepared samples for histological evaluation. Veterinary schools should consider these results against the backdrop of pressure to implement innovative teaching techniques to meet the changing needs of the profession. PMID- 25270654 TI - Inactivition of CDKL3 mildly inhibits proliferation of cells at VZ/SVZ in brain. AB - CDKL3 has an important role in regulating cell growth and/or differentiation, and its inactivation is recently reported to be related to non-syndromic mild mental retardation (MR). MR is a common neurological disorder, predominantly characterized by impaired cognitive function. Though genetic factors play a very important role in the pathogenesis of MR, to date, only few genes linked to MR have been characterized and understood very well. Here, we investigated the role of the CDKL3 in the proliferation of cells surrounding the brain ventricle, and the results showed down-regulating CDKL3 by the method of RNAi in the cells surrounding the brain ventricle of the mouse embryo at E15 may inhibit their proliferation. As our previous study had shown that Cdkl3 mRNA expression is developmentally regulated in the central nervous system, peaking during late embryonic and early postnatal stages which are the key stages of neurite formation and maturation, furtherly, the present findings indicated that CDKL3 may be involved in proliferation of cells surrounding the brain ventricle where neuronal progenitor cells are enriched during the late embryo stage, supporting the notion that CDKL3 inactivation contributes to non-syndromic mild MR. PMID- 25270655 TI - Listeria brain abscesses during administration of mycophenolate mofetil for systemic lupus erythematosus: a case report. PMID- 25270656 TI - Association of HTR2A T102C and A-1438G polymorphisms with susceptibility to major depressive disorder: a meta-analysis. AB - Serotonin 2A receptor (HTR2A) gene was implicated to be associated with major depressive disorder (MDD) susceptibility due to its role of key neurotransmitter in many physiologic processes. A great number of related studies reported in different populations have emerged. The results of these studies, however, have been inconsistent and thereby definite conclusions are difficult to establish. With the cumulative data in recent years, it was necessary to carry out a comprehensive analysis of previous findings. Electronic databases were systematically searched for studies published before May 2013. Pooled odds ratios (OR) and 95 % confidence interval (CI) were estimated under three different genetic models. Subgroup and sensitivity analyses were also performed. A total of 21 studies, 3,299 patients and 4,092 controls, met the selection criteria. 15 studies included HTR2A T102C polymorphism (with a total of 2,409 patients and 3,130 controls), and 9 studies included HTR2A A-1438G polymorphism (with a total of 1,510 patients and 2,281 controls). Our results showed that no significant association of MDD susceptibility with T102C polymorphism was found in allelic analysis and genotypic analysis (For T vs. C: OR = 1.06, 95 % CI = 0.95-1.18, P = 0.307; For TT + TC vs. CC: OR = 1.07, 95 % CI = 0.90-1.28, P = 0.451; For TT vs. TC + CC: OR = 1.08, 95 % CI = 0.95-1.22, P = 0.235). With respect to A-1438G polymorphism, however, carriers with A allele tend to suffer from MDD (AA + AG vs. GG: OR = 1.20, 95 % CI = 1.02-1.43, P = 0.030). When stratified by race for T102C polymorphism and A-1438G polymorphism of the HTR2A, we found no significant association. In conclusions, our study suggests that the A allele of A-1438G polymorphism might play a role in susceptibility to MDD. On the contrary, T102C polymorphism does not seem to be capable of modifying MDD risk. PMID- 25270657 TI - Cervical epidural abscess of odontogenic origin. PMID- 25270658 TI - Erythropoietin reduces acute lung injury and multiple organ failure/dysfunction associated to a scald-burn inflammatory injury in the rat. AB - Erythropoietin (EPO) is an endogenous regulator of erythropoiesis and is given exogenously as a replacement therapy for selected red blood cell disorders. In the past years, EPO has been emerging as a multifunctional, cytoprotective cytokine with anti-apoptotic, anti-inflammatory, and immunomodulatory properties. We aimed to evaluate the cytoprotective effect of rhEPO (recombinant human EPO) treatment on a rat model of multiorgan dysfunction induced by thermal injury. rhEPO was administered at 1000 U/kg (i.v.) 5 min prior to induction of injury and significantly reduced multiorgan dysfunction markers (liver, kidney, lung, serum cytokine levels). In the lung, rhEPO reduced: histological signs of tissue injury, inflammatory/injury markers on the bronchoalveolar fluid, neutrophil chemotaxis/infiltration, GSK-3beta activation, and apoptosis. Our study showed that erythropoietin has the potential to exhibit pleiotropic cytoprotective effects and that it might be an interesting pharmacological strategy in the modulation of acute lung injury, such as the one associated to severe burn. PMID- 25270659 TI - The US Network of Pediatric Multiple Sclerosis Centers: Development, Progress, and Next Steps. AB - Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network. PMID- 25270661 TI - Mechanistic studies on the indole prenyltransferases. AB - Covering: up to 2014. Prenylated indole alkaloids comprise a large and structurally diverse family of natural products that often display potent biological activities. In recent years a large family of prenyltransferases that install prenyl groups onto the indole core have been discovered. While the vast majority of these enzymes are evolutionarily related and share a common protein fold, they are remarkably versatile in their ability to catalyze reverse and normal prenylations at all positions on the indole ring. This highlight article will focus on recent studies of the mechanisms utilized by indole prenyltransferases. While all of the prenylation reactions may follow a direct electrophilic aromatic substitution mechanism, studies of structure and reactivity suggest that in some cases prenylation may first occur at the nucleophilic C-3 position, and subsequent rearrangements then generate the final product. PMID- 25270660 TI - Occurrence of genetic modifications in core, 5'UTR and NS5b of HCV associated with viral response to treatment. AB - BACKGROUND: It is becoming progressively more understandable that genetic variability of viruses is a major challenge in translating the laboratory findings to clinic. Genetic variability is the underlying cause of variant viral proteins which are not targetable by host immunological machinery. METHODS: 500 patients were enrolled in study and amongst them, 451 patients were followed and categorized into two groups on the basis of their treatment response. Group 1 consisting of the 376 patients exhibited SVR while group 2 comprised 75 patients who were non-responders on the basis of viral load as evidenced by Real-Time PCR. Comparative sequence analysis was done between 75 non-responders and 75 responders (randomly picked from 376) by targeting three genomic regions, 5'UTR, core and NS5B and amplified products were directly sequenced and obtained sequences were cleaned, aligned and submitted to GenBank. Maximum Parsimony (MP) method was used for phylogenetic analysis and dendrograms were dragged using MEGA 5. Heterogeneity at nucleotide and amino acid level was determined using software BioEdit and DNAman while phosphorylation and N-linked glycosylation sites were determined using NetPhos 2.0 and SignalP-NN. RESULTS: Genotype 3 was prevalent in group 1 whereas non-responders indicated rare genotypes of Pakistan i.e. 4 and 5, genotype 6q and 6v were reported first time from Pakistan in this study. At nucleotide and amino acid level, the genetic distance and mutation, number of predicted N-phosphorylation and N-glycosylation sites was higher in group 2 as compared to group 1. Difference in percentage composition of individual amino acids was noted to be different between the two groups. CONCLUSIONS: It can be concluded that heterogeneity both at nucleotide and amino acid level contributed in developing drug resistant phenotype. Moreover, occurrence of rare genotypes might hurdle the way to positive response of conventional treatment. Furthermore, prediction of phosphorylation and glycosylation sites could help in targeting the proper sites for drug designing. PMID- 25270663 TI - Hybridizing ultraviolet photodissociation with electron transfer dissociation for intact protein characterization. AB - We report a hybrid fragmentation method involving electron transfer dissociation (ETD) combined with ultraviolet photodissociation (UVPD) at 193 nm for analysis of intact proteins in an Orbitrap mass spectrometer. Integrating the two fragmentation methods resulted in an increase in the number of identified c- and z-type ions observed when compared to UVPD or ETD alone, as well as generating a more balanced distribution of a/x, b/y, and c/z ion types. Additionally, the method was shown to decrease spectral congestion via fragmentation of multiple (charge-reduced) precursors. This hybrid activation method was facilitated by performing both ETD and UVPD within the higher energy collisional dissociation (HCD) cell of the Orbitrap mass spectrometer, which afforded an increase in the total number of fragment ions in comparison to the analogous MS(3) format in which ETD and UVPD were undertaken in separate segments of the mass spectrometer. The feasibility of the hybrid method for characterization of proteins on a liquid chromatography timescale characterization was demonstrated for intact ribosomal proteins. PMID- 25270662 TI - Role of Porphyromonas gingivalis gingipains in multi-species biofilm formation. AB - BACKGROUND: Periodontal diseases are polymicrobial diseases that cause the inflammatory destruction of the tooth-supporting (periodontal) tissues. Their initiation is attributed to the formation of subgingival biofilms that stimulate a cascade of chronic inflammatory reactions by the affected tissue. The Gram negative anaerobes Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola are commonly found as part of the microbiota of subgingival biofilms, and they are associated with the occurrence and severity of the disease. P. gingivalis expresses several virulence factors that may support its survival, regulate its communication with other species in the biofilm, or modulate the inflammatory response of the colonized host tissue. The most prominent of these virulence factors are the gingipains, which are a set of cysteine proteinases (either Arg-specific or Lys-specific). The role of gingipains in the biofilm forming capacity of P. gingivalis is barely investigated. Hence, this in vitro study employed a biofilm model consisting of 10 "subgingival" bacterial species, incorporating either a wild-type P. gingivalis strain or its derivative Lys gingipain and Arg-gingipan isogenic mutants, in order to evaluate quantitative and qualitative changes in biofilm composition. RESULTS: Following 64 h of biofilm growth, the levels of all 10 species were quantified by fluorescence in situ hybridization or immunofluorescence. The wild-type and the two gingipain deficient P. gingivalis strains exhibited similar growth in their corresponding biofilms. Among the remaining nine species, only the numbers of T. forsythia were significantly reduced, and only when the Lys-gingipain mutant was present in the biofilm. When evaluating the structure of the biofilm by confocal laser scanning microscopy, the most prominent observation was a shift in the spatial arrangement of T. denticola, in the presence of P. gingivalis Arg-gingipain mutant. CONCLUSIONS: The gingipains of P. gingivalis may qualitatively and quantitatively affect composition of polymicrobial biofilms. The present experimental model reveals interdependency between the gingipains of P. gingivalis and T. forsythia or T. denticola. PMID- 25270664 TI - Job satisfaction of Malaysian registered nurses: a qualitative study. AB - BACKGROUND: Job satisfaction is an important factor in health care settings. Strong empirical evidence supports a causal relationship between job satisfaction, patient safety and quality of care. However, there have not been any studies exploring the job satisfaction of Malaysian nurses. AIM: The main purpose of this qualitative descriptive study was to explore the factors related to feelings of job satisfaction as well as job dissatisfaction experienced by registered nurses in Malaysia. METHOD: A convenient sample of 46 Malaysian nurses recruited from a large hospital (number of beds = 895) participated in the study. A total of seven focus group discussions were conducted with nurses from surgical, medical and critical care wards. A semi-structured interview guide was used to facilitate the interviews, which were audio-recorded, transcribed verbatim and checked. The transcripts were used as data and were analysed using a thematic approach. FINDING: The study identified three main themes that influenced job satisfaction: (1) nurses' personal values and beliefs; (2) work environment factors and (3) motivation factors. Concerning the nurses' personal values and beliefs, the ability to help people made the nurses felt honoured and happy, which indirectly contributed to job satisfaction. For work environment factors, team cohesion, benefit and reward, working conditions play an important role in the nurses' job satisfaction. Motivation factors, namely, professional development and clinical autonomy contributed to job satisfaction. CONCLUSION: It is important for nurse leaders to provide more rewards, comfortable work environments and to understand issues that affect nurses' job satisfaction. RELEVANCE TO CLINICAL PRACTICE: Our findings highlight the importance of factors that can improve nurses' job satisfaction. The study provides basic information for hospital administrators in planning effective and efficient policies to improve nursing job satisfaction in order to increase the quality of patient care and decrease nursing turnover. PMID- 25270665 TI - High-affinity glutamate transporters in chronic pain: an emerging therapeutic target. AB - Neurons responsible for sensing noxious stimuli and conducting pain signals from periphery to the spinal cord are predominantly glutamatergic. Members of the SLC1A family of high-affinity glutamate transporters (GluTs) are differentially expressed in sensory neurons and surrounding glial cells. These plasma membrane proteins along with glutamate/cystine exchanger, light chain of cystine/glutamate exchanger, are responsible for fine tuning of extracellular glutamate concentrations and, thus, for modulation of excitatory signalling in the spinal cord. Emerging data point at key roles of GluTs in molecular mechanisms of chronic pain and analgesia, incl. development of opioid tolerance. Pharmacological inhibition or antisense down-regulation of spinal GluTs can induce/aggravate pain behaviours, whereas increasing of expression of GluTs by viral gene transfer or positive pharmacological modulators can mitigate chronic pain. Furthermore, some drugs, originally introduced for targeting different pathological conditions, but in parallel exhibiting analgesic properties (e.g. anti-convulsants valproate and riluzole, beta-lactam- and tetracycline antibiotics, tricyclic anti-depressants), can enhance glutamate transport in the spinal cord. Thus, molecular modulation of GluTs may turn into prospective therapeutic approach for the management of chronic pain. However, precise pharmacological targeting of this transport system requires in-depth elucidation of molecular factors and signalling pathways underlying expression and activity of individual GluT subtypes, including their splice variants. Neurons conducting pain signals from periphery to the spinal cord are predominantly glutamatergic. High-affinity glutamate transporters (GluTs) regulate extracellular glutamate concentrations and, thus, modulate excitatory signalling in pain circuits. The present review critically analyses accumulated data on the roles of GluTs in molecular mechanisms of chronic pain, as well as perspectives for targeting this transport system in pain therapies. PMID- 25270666 TI - Body attention, ignorance and awareness scale: assessing relevant concepts for physical and psychological functioning in psoriasis. AB - A certain level of attention to bodily signals may be adaptive in the management of chronic skin conditions, as a lack of attention may lead to inadequate self care behaviour and, consequently, may affect functioning and treatment outcomes. The purpose of this study was to develop a body awareness questionnaire and to investigate its psychometric properties and physical and psychological correlates in a cross-sectional study in patients with psoriasis (n = 475). The 16-item Body Attention, Ignorance and Awareness Scale demonstrated a 3-factor structure that could be interpreted as body ignorance, body attention, and body awareness (Cronbach's alpha of 0.73, 0.74, and 0.68, respectively). Higher body ignorance was significantly related to more physical symptoms and worse psychological functioning. Body attention and body awareness showed small significant correlations with coping and personality. Given the negative influence of impaired psychological functioning on treatment outcomes, it may be clinically important to screen for theses constructs of body awareness in chronic skin conditions. PMID- 25270667 TI - Cognitive complaints of adults with attention deficit hyperactivity disorder. AB - Executive dysfunction of adults with ADHD is often associated with poor self awareness of problems, such as in emotional competence, emotional recognition, and driving competence. However, with regard to cognitive functioning, little is known about how adults with ADHD evaluate their own cognitive performance. A total of 77 adults with ADHD and 116 healthy adults were assessed with self report scales measuring several aspects of cognition. Significance and effect sizes as well as the proportion of patients perceiving impairments were calculated. Further analysis was carried out on the frequency of patients perceiving various types of impairments. Adults with ADHD perceived themselves to have significant and severe dysfunction in all areas of cognition assessed as a group. Furthermore, the majority of patients reported multiple impairments in attention, memory and executive functioning. The present study demonstrated that adults with ADHD are aware of problems in cognitive functioning as shown by considerable perceived neuropsychological impairment in the majority of patients. Patients with ADHD tended to report cognitive impairments in multiple domains rather than impairments in specific functions. PMID- 25270668 TI - RNA sequencing of microglia and monocyte-derived macrophages from mice with experimental autoimmune encephalomyelitis illustrates a changing phenotype with disease course. AB - The role of microglia and monocyte-derived macrophages in experimental autoimmune encephalomyelitis pathogenesis has been controversial. To gain insight into their respective roles, we developed a method for differentiating between microglia and monocyte-derived macrophages in the CNS by flow cytometry utilizing anti-CD44 antibodies. We used this system to monitor changes in cell number, activation status, and gene expression by RNA sequencing over the course of disease. This in vivo characterization and RNA-Seq dataset improves our understanding of macrophage biology in the brain under inflammatory conditions and may lead to strategies to identify therapies for neuroinflammatory diseases. PMID- 25270669 TI - Vanillin - Bioconversion and Bioengineering of the most popular plant flavour and its de novo biosynthesis in the vanilla orchid. AB - During recent years, biotechnology derived production of flavours and fragrances have expanded rapidly. The world's most popular flavour vanillin is no exception. This review outlines the current state of biotechnology-based vanillin synthesis with the use of ferulic acid, eugenol and glucose as substrates and bacteria, fungi and yeasts as microbial production hosts. The elucidated de novo biosynthetic pathway of vanillin in the vanilla orchid and the possible applied uses of this new knowledge in the biotechnology derived and pod-based vanillin industries are also highlighted. PMID- 25270670 TI - Volume of intracranial structures on three-dimensional ultrasound in fetuses with congenital heart disease. AB - OBJECTIVE: To investigate the volume of intracranial structures in fetuses with congenital heart disease (CHD). METHODS: Total intracranial volume, frontal lobes volume, thalamus volume and cerebellar volume were prospectively evaluated and compared in 73 fetuses with CHD and 168 normal fetuses using three-dimensional ultrasound combined with post-processing software at 20 + 0 to 36 + 6 weeks of gestation. Multiple regression analyses were performed to identify risk factors for reduced volume of intracranial structures. RESULTS: From the 28th week of gestation onwards, total brain volumes and those of specific structures became progressively smaller in fetuses with CHD relative to those in controls (P < 0.05). The decrease was largest in frontal lobes volume, followed by total intracranial volume and cerebellar volume, and the smallest decrease was in thalamus volume (P < 0.05). Multivariable analysis showed that the diagnostic category (P < 0.001) was independently associated with smaller brain volumes in fetuses with CHD. The largest differences from controls occurred in hypoplastic left heart syndrome (HLHS), followed by aortic hypoplasia, transposition of the great arteries (TGA) and tetralogy of Fallot (TOF). CONCLUSIONS: The volume of intracranial structures is smaller in fetuses with CHD, particularly in those with HLHS, aortic hypoplasia or TGA. This study highlights the need for routine brain screening and early intervention to improve neurodevelopmental outcomes in fetuses with CHD. PMID- 25270671 TI - Determining the size of retinal features in prematurely born children by fundus photography. AB - PURPOSE: The purpose was to study the effect of prematurity on the macula-disc centre distance and whether it could be used as a reference tool for determining the size of retinal features in prematurely born children by fundus photography. METHODS: The macula-disc centre distance of the left eye was measured in pixels from digital fundus photographs taken from 27 prematurely born children aged 10 11 years with Topcon fundus camera. A conversion factor for Topcon fundus camera (194.98 pixel/mm for a 50 degrees lens) was used to convert the results in pixels into metric units. RESULTS: The macula-disc centre distance was 4.74 mm, SD 0.29. No correlation between ametropia and the macula-disc centre distance was found (r = -0.07, p > 0.05). One child (subject 20) had high myopia and retinopathy of prematurity (ROP), and the macula-disc centre distance was longer than average (6.35 mm). DISCUSSION: The macula-disc centre distance in prematurely born children at the age of 10-11 years provides an easy-to-use reference tool for evaluating the size of retinal features on fundus photographs. However, if complications of ROP, for example temporal macular dragging or high ametropia, are present, the macula-disc centre distance is potentially altered and a personal macula-disc centre distance should be determined and used as a refined reference tool. PMID- 25270672 TI - A new erythrocyte-based biochemical approach to predict the antiproliferative effects of heterocyclic scaffolds: The case of indolone. AB - BACKGROUND: The indole core is a key structural feature of many natural products and biomolecules with broad spectrum chemotherapeutic properties. Some of us have recently synthesized a library of biologically promising indolone-based compounds. The present study focuses on the effects of one of them, namely DPIT, on human erythrocytes. METHODS: We have examined the influence of DPIT on band 3 protein, intracellular ATP concentration and transport, caspase 3 activation, metabolic adaptation and membrane stability. RESULTS: Our study elucidates that DPIT, intercalated into the phospholipid bilayer, decreases the anion transport, the intracellular ATP concentration and the cytosolic pH, inducing a direct activation of caspase 3. CONCLUSIONS: Starting from the metabolic similarity between erythrocytes and cancer cells, we investigate how the metabolic derangements and membrane alterations induced by selected heterocycles could be related to the antiproliferative effects. GENERAL SIGNIFICANCE: Our work aims to propose a new model of study to predict the antiproliferative effects of heterocyclic scaffolds, pointing out that only one of the listed conditions would be unfavorable to the life cycle of neoplastic cells. PMID- 25270673 TI - Stretchable and high-performance supercapacitors with crumpled graphene papers. AB - Fabrication of unconventional energy storage devices with high stretchability and performance is challenging, but critical to practical operations of fully power independent stretchable electronics. While supercapacitors represent a promising candidate for unconventional energy-storage devices, existing stretchable supercapacitors are limited by their low stretchability, complicated fabrication process, and high cost. Here, we report a simple and low-cost method to fabricate extremely stretchable and high-performance electrodes for supercapacitors based on new crumpled-graphene papers. Electrolyte-mediated-graphene paper bonded on a compliant substrate can be crumpled into self-organized patterns by harnessing mechanical instabilities in the graphene paper. As the substrate is stretched, the crumpled patterns unfold, maintaining high reliability of the graphene paper under multiple cycles of large deformation. Supercapacitor electrodes based on the crumpled graphene papers exhibit a unique combination of high stretchability (e.g., linear strain ~300%, areal strain ~800%), high electrochemical performance (e.g., specific capacitance ~196 F g(-1)), and high reliability (e.g., over 1000 stretch/relax cycles). An all-solid-state supercapacitor capable of large deformation is further fabricated to demonstrate practical applications of the crumpled-graphene-paper electrodes. Our method and design open a wide range of opportunities for manufacturing future energy-storage devices with desired deformability together with high performance. PMID- 25270674 TI - Toward improving selectivity in affinity chromatography with PEGylated affinity ligands: the performance of PEGylated protein A. AB - Chemical modification of macromolecular affinity chromatography ligands with polyethylene glycol chains or "PEGylation" can potentially improve selectivity by sterically suppressing non-specific binding interactions without sacrificing binding capacity. For a commercial protein A affinity media and with yeast extract (YE) and fetal bovine serum (FBS) serving as mock contaminants, we found that the ligand accounted for more than 90% of the media-associated non-specific binding, demonstrating an opportunity for improvement. The IgG static binding affinity of protein A mono-PEGylated with 5.0 and 20.7 kDa poly(ethylene glycol) chains was found to be preserved using a biomolecular interaction screening platform. Similar in situ PEGylations of the commercial protein A media were conducted and the modified media was functionally characterized with IgG solutions spiked with YE and FBS. Ligand PEGylation reduced the mass of media associated contaminants by a factor of two to three or more. Curiously, we also found an increase of up to 15% in the average recovery of IgG on elution after PEGylation. Combined, these effects produced an order of magnitude increase in the IgG selectivity on average when spiked with YE and a two- to three-fold increase when spiked with FBS relative to the commercial media. Dynamic binding capacity and mass-transfer resistance measurements revealed a reduction in dynamic capacity attributed to a decrease in IgG effective pore diffusivity and possibly slower IgG association kinetics for the PEGylated protein A ligands. Ligand PEGylation is a viable approach to improving selectivity in affinity chromatography with macromolecular ligands. PMID- 25270675 TI - Roles of F-box proteins in human digestive system tumors (Review). AB - F-box proteins (FBPs), the substrate-recognition subunit of E3 ubiquitin (Ub) ligase, are the important components of Ub proteasome system (UPS). FBPs are involved in multiple cellular processes through ubiquitylation and subsequent degradation of their target proteins. Many studies have described the roles of FBPs in human cancers. Digestive system tumors account for a large proportion of all the tumors, and their mortality is very high. This review summarizes for the first time the roles of FBPs in digestive system tumorige-nesis and tumor progression, aiming at finding new routes for the rational design of targeted anticancer therapies in digestive system tumors. PMID- 25270676 TI - Benign intranodal thyroid tissue mimicking nodal metastasis in a patient with papillary thyroid carcinoma: A case report. AB - BACKGROUND: A case of benign intranodal thyroid tissue mimicking nodal metastasis on ultrasound and CT in a patient with papillary thyroid carcinoma has not been reported. METHODS: The clinical, imaging, and histopathological findings of the patient are presented. A 52-year-old woman who underwent ultrasound-guided fine needle aspiration for 2 small, suspicious thyroid nodules in both lobes at a local clinic was referred to our hospital for surgical treatment. Ultrasound guided fine-needle aspiration for a suspicious lymph node in the left upper neck was performed. According to the imaging and cytology results, total thyroidectomy and nodal dissection for both central and left lateral nodes were performed. RESULTS: In the histopathology, the lymph node was confirmed as a benign lymph node with intranodal thyroid tissue. CONCLUSION: This case illustrates that benign intranodal thyroid tissue may mimic nodal metastasis on ultrasound or CT in a patient with papillary thyroid carcinoma. PMID- 25270677 TI - Hepatoprotective effect of Taraxacum officinale leaf extract on sodium dichromate induced liver injury in rats. AB - Taraxacum officinale (L.) Weber, commonly known as Dandelion, has been widely used as a folkloric medicine for the treatment of liver and kidney disorders and some women diseases such as breast and uterus cancers. The main objective of the present study was to assess the efficiency of T. officinale leaf extract (TOE) in treating sodium dichromate hazards; it is a major environmental pollutant known for its wide toxic manifestations witch induced liver injury. TOE at a dose of 500 mg/kg b.w was orally administered once per day for 30 days consecutively, followed by 10 mg/kg b.w sodium dichromate was injected (intraperitoneal) for 10 days. Our results using Wistar rats showed that sodium dichromate significantly increased serum biochemical parameters. In the liver, it was found to induce an oxidative stress, evidenced from increase in lipid peroxidation and changes in antioxidative activities. In addition, histopathological observation revealed that sodium dichromate causes acute liver damage, necrosis of hepatocytes, as well as DNA fragmentation. Interestingly, animals that were pretreated with TOE, prior to sodium dichromate administration, showed a significant hepatoprotection, revealed by a significant reduction of sodium dichromate-induced oxidative damage for all tested markers. These finding powerfully supports that TOE was effective in the protection against sodium dichromate-induced hepatotoxicity and genotoxicity and, therefore, suggest a potential therapeutic use of this plant as an alternative medicine for patients with acute liver diseases. PMID- 25270678 TI - X-linked agammaglobulinemia with hearing impairment, dystonia-parkinsonism, and progressive neurodegeneration. PMID- 25270679 TI - A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. AB - Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0-10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increase with time (up to 9 months); at least half of all patients reported a 30 % improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality 0-10 NRS scores, neuropathic pain scale scores, subject global impression of change and EQ-5D questionnaire scores. THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use. In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia. PMID- 25270680 TI - Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study. AB - We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386% in the placebo group vs increases of 0.129% (p = 0.0027) and 0.096% (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392% with placebo vs increases of 0.190% (p = 0.0006) and 0.115% (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment. PMID- 25270681 TI - Real life cost and quality of life associated with continuous intraduodenal levodopa infusion compared with oral treatment in Parkinson patients. AB - Advanced-stage Parkinson's disease (PD) strongly affects quality of life (QoL). Continuous intraduodenal administration of levodopa (IDL) is efficacious, but entails high costs. This study aims to estimate these costs in routine care. 10 patients with advanced-PD who switched from oral medication to IDL were assessed at baseline, and subsequently at 3, 6, 9 and 12 months follow-up. We used the Unified PD Rating Scale (UPDRS) for function and 15D for Quality of Life (QoL). Costs were assessed using quarterly structured patient questionnaires and hospital registries. Costs per quality adjusted life year (QALY) were estimated for conventional treatment prior to switch and for 1-year treatment with IDL. Probabilistic sensitivity analysis was based on bootstrapping. IDL significantly improved functional scores and was safe to use. One-year conventional oral treatment entailed 0.63 QALY while IDL entailed 0.68 (p > 0.05). The estimated total 1-year treatment cost was NOK419,160 on conventional treatment and NOK890,920 on IDL, representing a cost of NOK9.2 million (?1.18 mill) per additional QALY. The incremental cost per unit UPDRS improvement was NOK25,000 (?3,250). Medication was the dominant cost during IDL (45% of total costs), it represented only 6.4% of the total for conventional treatment. IDL improves function but is not cost effective using recommended thresholds for cost/QALY in Norway. PMID- 25270683 TI - Attachment of Escherichia coli to Listeria monocytogenes for pediocin-mediated killing. AB - Listeria phage endolysin cell wall-binding domain (CBD) from the Listeria phage A500 was fused with flagellar subunit FliC in Escherichia coli, aiming at binding of E. coli cells to Listeria cells, followed by enhanced killing of Listeria by pediocin production. FliC::CBD chimeric flagella were expressed and detected by Western blot. However, only few chimeric flagella could be isolated from the recombinant cells compared with sufficient amount of wild-type flagella obtained from the host cells. Interestingly, wild-type flagella extract showed capacity of binding Listeria cells. Pediocin-secreting E. coli cells with Listeria-binding flagella killed approximately 40 % of the Listeria cells, whereas cell-free spent growth medium with the same pediocin concentration only inhibited Listeria growth. These results suggested that binding the Listeria to bacteriocin secreting cells improves killing. PMID- 25270682 TI - In vitro screening of selected probiotic properties of Lactobacillus strains isolated from traditional fermented cabbage and cucumber. AB - Most important during probiotic selection are gastric acid and bile tolerance, the adhesion to the luminal epithelium to colonize the lower gastrointestinal tract of a human and safety for human consumption. The aim of this study was to evaluate the selected probiotic in vitro properties of Lactobacillus spp. Strains isolated from traditional fermented food. A total 38 strains were isolated from the pickled samples and 14 were identified as Lactobacillus spp. The survival of almost all strains after incubation at pH 2.5 did not change markedly, and remained at above 90 % (10(9) CFU/mL). The strains also exhibited a high survival rate at pH 3.5 (>90 %), whereas pH 1.5 all were died. Just four strains could survive 90 min. at pH 1.5 (<39 %). The incubation with 0.2 % bile salt solution resulted in a survival rates of 81-94 % after 24 h, whereas after incubation in 2 and 4 % bile salt solution it was 59-94 %. All tested strains showed very good and good resistance to 0.4 % phenol addition, however only Lb. johnsonii K4 was able to multiply. The hydrophobic nature of the cell surface of the tested strains was moderated recording hydrophobicity of Lb. johnsonii K4 and Lb. rhamnosus K3 above 60 %. Safety evaluation excluded four of tested strains as candidate probiotics, according to antibiotic resistance patterns and certain metabolic activities. On the basis on the results 10 of the selected Lactobacillus strains are safe and can survive under gastrointestinal conditions, which requires them to future in vitro and in vivo probiotic studies. PMID- 25270684 TI - Development of parthenote following in vivo transfer of embryos in Capra hircus. AB - The aim of this study is to generate parthenogenetic embryos from chemically activated in vitro matured caprine oocytes and to study the in vivo developmental potency of such embryos. The parthenogenetic embryos (2-8 and 16 cells to morula stage) were surgically transferred in 26 recipients. Pregnancy in recipients following embryo transfer was monitored by ultrasonography. The recipient aborted a foetus on day 34 post transfer. Sexing of parthenogenetic foetus showed a single band of amelogenin gene indicating female cell DNA. Microsatellite analysis revealed that the recipient has not contributed genetically to the parthenogenetic foetus confirming the identity of aborted foetus of parthenogenetic origin. The authors believe that this is the first authentic report on in vivo development of parthenogenetic foetus in Capra hircus. PMID- 25270685 TI - Cell differentiation mediated by co-culture of human umbilical cord blood stem cells with murine hepatic cells. AB - In the present study, purified human cord blood stem cells were co-cultivated with murine hepatic alpha mouse liver 12 (AML12) cells to compare the effect on endodermal stem cell differentiation by either direct cell-cell interaction or by soluble factors in conditioned hepatic cell medium. With that approach, we want to mimic in vitro the situation of preclinical transplantation experiments using human cells in mice. Cord blood stem cells, cultivated with hepatic conditioned medium, showed a low endodermal differentiation but an increased connexin 32 (Cx32) and Cx43, and cytokeratin 8 (CK8) and CK19 expression was monitored by reverse transcription polymerase chain reaction (RT-PCR). Microarray profiling indicated that in cultivated cord blood cells, 604 genes were upregulated 2-fold, with the highest expression for epithelial CK19 and epithelial cadherin (E cadherin). On ultrastructural level, there were no major changes in the cellular morphology, except a higher presence of phago(ly)some-like structures observed. Direct co-culture of AML12 cells with cord blood cells led to less incisive differentiation with increased sex-determining region Y-box 17 (SOX17), Cx32 and Cx43, as well as epithelial CK8 and CK19 expressions. On ultrastructural level, tight cell contacts along the plasma membranes were revealed. FACS analysis in co cultivated cells quantified dye exchange on low level, as also proved by time relapse video-imaging of labelled cells. Modulators of gap junction formation influenced dye transfer between the co-cultured cells, whereby retinoic acid increased and 3-heptanol reduced the dye transfer. The study indicated that the cell-co-cultured model of human umbilical cord blood cells and murine AML12 cells may be a suitable approach to study some aspects of endodermal/hepatic cell differentiation induction. PMID- 25270687 TI - Effects of pharmaceutical PEGylation on drug metabolism and its clinical concerns. AB - INTRODUCTION: PEGylation refers to covalent conjugation of one or more polyethylene glycol chains to a drug molecule. It also refers to formulation of a drug into PEGylated drug-delivery vehicles in pharmacy. It is well-known that PEGylation can greatly influence the pharmacokinetics and pharmacodynamics of drugs. AREAS COVERED: This article describes the importance of PEGylation in drug development and research. The impact of PEGylation on drug metabolism and the clinical safety of PEGylated drugs (or formulations) are also discussed. Information and data from the literature were collected, analyzed and summarized. EXPERT OPINION: PEGylation is an effective approach to potentiate drugs with undesirable properties. Currently, PEGylation has penetrated into every field of pharmaceutical practice, involving biomacromolecules, small drugs and drug delivery systems. Efficacy enhancement is attained through modification of the pharmacokinetics and toxicity profiles of parent drugs. As a result of PEGylation, the drugs tend to display enhanced solubility, prolonged circulatory time and reduced immunogenicity/antigenicity. The bottleneck of PEGylation is how to break through the limitation of chemical conjugation and to properly preserve the pharmacological activity of the drug. PEGylated formulation is an area deserving more attention in terms of systemic delivery of insoluble small drugs. PMID- 25270686 TI - New Developments for Case Conceptualization in Emotion-Focused Therapy. AB - Emotion-focused therapy (EFT) has increasingly made use of case conceptualization. The current paper presents a development in the case conceptualization approach of EFT. It takes inspiration from recent research on emotion transformation in EFT. The case conceptualization presented here can guide the therapist in listening to the client's narrative and in observing the client's emotional presentation in sessions. Through observing regularities, the therapist can tentatively determine core emotion schemes' organizations, triggers that bring about the emotional pain, the client's self-treatment that contributes to the pain, the fear of emotional pain that drives avoidance and emotional interruption strategies. The framework recognizes global distress, into which the client falls, as a result of his or her inability to process the underlying pain, the underlying core pain and the unmet needs embedded in it. This conceptual framework then informs therapists as to which self-organizations (compassion and protective anger based) have to be facilitated to respond to the pain and unmet needs, so that they might transform it. The conceptual framework can guide the therapist's thinking/perceptions and actions in the session. KEY PRACTITIONER MESSAGE: Therapists can better facilitate emotional transformation when they understand the dynamics involved in the client's distress. Emotion transformation is facilitated by first helping the client to access the core underlying painful feelings and unmet needs embedded in them and then by helping the client to generate adaptive emotional responses to those unmet needs. PMID- 25270688 TI - Spray-coated all-solid-state potentiometric sensors. AB - A novel fully spray coating-based method of the preparation of all-solid-state ion-selective electrodes of simplified construction is proposed. This method is an alternative for screen-printed electrodes used sometimes in potentiometric applications. The benefits of the herein-proposed approach include fully automatic sensor preparation and minimized use of chemicals allowing for the production of low-cost sensors that can be applied as disposables. A layer of spray-coated carbon nanotubes on an inert support was used both as an electrical lead and as a transducer, to simplify sensor layout and to avoid the possible problems of changing in-time composition of this layer, as previously observed in the case of screen-printed supporting electrodes in potentiometric applications. The ion-selective poly(vinyl chloride)-based membrane and the insulator layer were also spray-coated. The obtained sensors, as the model system potassium selective sensors were prepared and characterized with analytical parameters well comparable with that of conventional, all-solid-state, ion-selective electrodes. In addition, the applicability of the herein-proposed approach to prepare other ion-selective electrodes was tested on examples of H(+) and Cl(-) sensors. PMID- 25270689 TI - Helping callers to the National Suicide Prevention Lifeline who are at imminent risk of suicide: the importance of active engagement, active rescue, and collaboration between crisis and emergency services. AB - In 2012, the SAMHSA-funded National Suicide Prevention Lifeline (Lifeline) completed implementation of the first national Policy for Helping Callers at Imminent Risk of Suicide across its network of crisis centers. The policy sought to: (1) provide a clear definition of imminent risk; (2) reflect the state of evidence, field experience, and promising practices related to reducing imminent risk through hotline interventions; and (3) provide a uniform policy and approach that could be applied across crisis center settings. The resulting policy established three essential principles: active engagement, active rescue, and collaboration between crisis and emergency services. A sample of the research and rationale that underpinned the development of this policy is provided here. In addition, policy implementation, challenges and successes, and implications for interventions to help Lifeline callers at imminent risk of suicide are detailed. PMID- 25270691 TI - Femoral and tibial blood supply: A trigger for non-union? PMID- 25270690 TI - Functional-mixed effects models for candidate genetic mapping in imaging genetic studies. AB - The aim of this paper is to develop a functional-mixed effects modeling (FMEM) framework for the joint analysis of high-dimensional imaging data in a large number of locations (called voxels) of a three-dimensional volume with a set of genetic markers and clinical covariates. Our FMEM is extremely useful for efficiently carrying out the candidate gene approaches in imaging genetic studies. FMEM consists of two novel components including a mixed effects model for modeling nonlinear genetic effects on imaging phenotypes by introducing the genetic random effects at each voxel and a jumping surface model for modeling the variance components of the genetic random effects and fixed effects as piecewise smooth functions of the voxels. Moreover, FMEM naturally accommodates the correlation structure of the genetic markers at each voxel, while the jumping surface model explicitly incorporates the intrinsically spatial smoothness of the imaging data. We propose a novel two-stage adaptive smoothing procedure to spatially estimate the piecewise smooth functions, particularly the irregular functional genetic variance components, while preserving their edges among different piecewise-smooth regions. We develop weighted likelihood ratio tests and derive their exact approximations to test the effect of the genetic markers across voxels. Simulation studies show that FMEM significantly outperforms voxel wise approaches in terms of higher sensitivity and specificity to identify regions of interest for carrying out candidate genetic mapping in imaging genetic studies. Finally, FMEM is used to identify brain regions affected by three candidate genes including CR1, CD2AP, and PICALM, thereby hoping to shed light on the pathological interactions between these candidate genes and brain structure and function. PMID- 25270692 TI - Factors associated with outcome of spinopelvic dissociation treated with lumbopelvic fixation. AB - Spinopelvic dissociation is a rare high-energy injury, which is frequently associated with lumbosacral plexus and cauda equina deficits. During an 18-year period, 36 consecutive patients with a H-type sacral fracture and spinopelvic dissociation were treated using lumbopelvic fixation with a minimum follow-up of 18 months. We evaluated factors prognostic of outcome after standardised surgical fixation and neural decompression. Neurological recovery was assessed by Gibbons' criteria. Pelvis Outcome Scale (POS clinical score) was used to evaluate the clinical outcome. Despite excellent or good radiological results in the vertical components of the sacral fractures having been achieved in all patients, 15 patients (42%) had a poor clinical outcome. The degree of initial translational displacement in the transverse sacral fracture was significantly associated with neurological recovery (as defined by a change in Gibbons score) (p = 0.038) and final POS clinical score (p < 0.001). Both neurological recovery and clinical outcome were worse in patients with completely displaced fractures than in patients with a partially displaced sacral fracture. The degree of residual translational displacement and kyphosis in the transverse sacral fracture were also associated with clinical outcome (POS clinical score) (p = 0.011 and p = 0,018, respectively). However, Roy-Camille classification (type 2 vs. type 3), age, gender, ISS, timing of surgery, and sacral laminectomy did not have a statistically significant association with the outcome. Based on the results, Roy Camille sacral fracture classification (type 2 vs. type 3) was not prognostic of neurological impairment. Thus further categorisation of the transverse sacral fractures as partially displaced or completely displaced could be used to predict the rate of neurological recovery following lumbopelvic fixation. Accurate reduction of all sacral fracture components seems to be associated with better clinical outcome. PMID- 25270693 TI - Do trauma systems work? A comparison of major trauma outcomes between Aberdeen Royal Infirmary and Massachusetts General Hospital. AB - Trauma is an important matter of public health and a major cause of mortality. Since the late 1980s trauma care provision in the United Kingdom is lacking when compared to the USA. This has been attributed to a lack of organisation of trauma care leading to the formation of trauma networks and Major Trauma Centres in England and Wales. The need for similar centres in Scotland is argued currently. We assessed the activity of two quite different trauma systems by obtaining access to comparative data from two hospitals, one in the USA and the other in Scotland. Aggregate data on 5604 patients at Aberdeen Royal Infirmary (ARI) from 1993 to 2002 was obtained from the Scottish Trauma Audit Group. A comparable data set of 16,178 patients from Massachusetts General Hospital (MGH). Direct comparison of patient demographics; injury type, mechanism and Injury Severity Score (ISS); mode of arrival; length of stay and mortality were made. Statistical analysis was carried out using Chi-squared and Cochran-Mantel-Haenszel. There were significant differences in the data sets. There was a higher proportion of penetrating injuries at MGH, (8.6% vs 2.6%) and more severely injured patients at MGH, patients with an ISS>16 accounted for nearly 22.1% of MGH patients compared to 14.0% at ARI. ISS 8-15 made up 54.6% of ARI trauma with 29.6% at MGH. Falls accounted for 50.1% at ARI and 37.9% at MGH. Despite the higher proportion of severe injuries at MGH and crude mortality rates showing no difference (4.9% ARI vs 5.2% MGH), pooled odds ratio of mortality was 1.4 (95% confidence interval 1.2 1.6) showing worse mortality outcomes at ARI compared to MGH. In conclusion, there were some differences in case mix between both data sets making direct comparison of the outcomes difficult, but the effect of consolidating major trauma on the proportion and number of severely injured patients treated in the American Level 1 centre was clear with a significant improvement in mortality in all injury severity groups. PMID- 25270694 TI - The restructuring of dental practice: dentists as employees or owners. PMID- 25270695 TI - Implants study. PMID- 25270696 TI - Implants study II. PMID- 25270697 TI - Implants study III. PMID- 25270698 TI - Implants study IV. PMID- 25270699 TI - Authors' response. PMID- 25270700 TI - At-home oral care for adults with developmental disabilities: a survey of caregivers. AB - BACKGROUND: Little is known about effective at-home oral care methods for people with developmental disabilities (DDs) who are unable to perform personal preventive practices themselves and rely on caregivers for assistance. METHODS: A convenience sample of 808 caregivers (84.5 percent paid, 15.5 percent family members) who accompanied adults with DDs (20 years or older) to appointments at a specialized statewide dental care system completed computer-assisted personal interview surveys. The authors used these data to investigate caregivers' at-home oral care experiences and to explore differences between caregivers who were paid and those who were family members. RESULTS: Caregivers reported that a high proportion (85 percent) of dentate adults with DDs received assistance with tooth cleaning. They also reported a high prevalence of dental problems, and low adherence to brushing (79 percent) and flossing (22 percent) recommendations. More caregivers reported that they felt confident assisting with brushing than with flossing (85 percent versus 54 percent). Family members and paid caregivers differed with respect to confidence and training. CONCLUSIONS: At-home oral care, particularly flossing, presents substantial challenges for adults with DDs. Solutions must be tailored to address the different experiences and distinct needs of the family members and paid caregivers who assist these adults. PRACTICAL IMPLICATIONS: Caregivers play an important role in providing at-home oral care, and they must be included in efforts to improve oral health outcomes for people with DDs. PMID- 25270701 TI - Implications of medical screenings of patients arriving for dental treatment: the results of a comprehensive laboratory screening. AB - BACKGROUND: The authors conducted medical laboratory screenings in a dental setting to determine the relationships between the laboratory test results and self-reported medical health findings. METHODS: The authors collected serum, urine and medical histories from 171 patients (116 [68 percent] women; mean age, 43.4 years) who arrived for dental treatment as a component of a clinical trial and performed complete blood cell counts, standard blood chemistry panels and urinalysis on the samples. RESULTS: The authors found 414 abnormal laboratory test results (an average of 2.42 per patient). Eighty-three percent of participants had one or more abnormal test results, 83 percent had abnormal test results and did not indicate a relevant disease in their medical history, and 18 percent had laboratory test results outside the 99 percent reference range (that is, > three standard deviations from the mean). Abnormal test results were significantly associated with sex, age, race and medical history (P< .05). Abnormal test results associated with kidney disease were related to patients with cardiovascular disease and diabetes, as well as those who tended to be on average older than 50 years. CONCLUSIONS: The high frequency of significant abnormal laboratory test results detected in this study suggests that many patients may be unaware of their medical statuses. PRACTICAL IMPLICATIONS: Abnormal laboratory test results are detected frequently in the serum and urine of patients arriving for dental treatment, which could indicate undiagnosed disease and less than optimal medical management. PMID- 25270702 TI - A clinical evaluation of a giomer restorative system containing surface prereacted glass ionomer filler: results from a 13-year recall examination. AB - BACKGROUND: The authors' objective was to evaluate the long-term performance of a resin-based composite restorative material (Beautifil, Shofu, Kyoto, Japan) in combination with a self-etching primer (FL-Bond, Shofu) for posterior restorations. METHODS: Two clinicians placed 61 restorations, 26 Class I and 35 Class II, in 31 patients. They placed restorations while using rubber dam isolation. Two other clinicians examined the restorations according to the modified U.S. Public Health Service (USPHS) criteria, observing color match, marginal adaptation, anatomy, surface roughness, marginal staining, interfacial staining, proximal and occlusal contacts, secondary caries, postoperative sensitivity and luster. Clinicians examined restorations at baseline as well as at one-, two-, four-, eight- and 13-year recall visits. RESULTS: All restorations were examined at one year, 58 (95 percent) at two years, 39 (64 percent) at four years and 41 (67 percent) at eight years; at the 13-year recall examination, 41 (67 percent) either were examined or had a known outcome. Of the 41 restorations seen at the 13-year examination, 25 restorations (14 Class I and 11 Class II) were intact and acceptable, two had secondary caries and 14 either were not present or had failed (two were missing, 10 had received crowns and two had been replaced). No changes were observed in the modified USPHS criteria for 12 of the 25 restorations that were intact (48 percent). Areas of change observed in 13 of the 25 intact restorations included color match (12 percent), marginal adaptation at the occlusal (20 percent) and proximal surfaces (4 percent), marginal staining on occlusal (24 percent) and proximal surfaces (8 percent), and interfacial staining on occlusal (4 percent) and proximal surfaces (12 percent). CONCLUSION: The study results showed that most of the restorations observed at the 13-year recall examination maintained acceptable clinical qualities. PRACTICAL IMPLICATIONS: Beautifil restorative material demonstrated long-term successful results for restoration of posterior teeth. PMID- 25270704 TI - Metastatic melanoma misdiagnosed as a temporomandibular disorder: a case report and review of the literature. AB - BACKGROUND: Malignancies in the head and neck region are difficult to diagnose because of their deep location and presence of symptoms mimicking those of temporomandibular disorders or other orofacial pain disorders. CASE DESCRIPTION: A 75-year-old woman reported experiencing right-sided jaw pain, temporal discomfort and paresthesia. She had undergone conservative therapy for temporomandibular joint disorder, which was unsuccessful. A magnetic resonance image of the midface revealed a mass on the base of the tongue along with possible metastatic lesions to the brain. Further investigation of the lesions revealed them to be metastatic melanoma. PRACTICAL IMPLICATIONS: Patients with atypical symptoms of facial pain, including neurological signs, should undergo further investigation with advanced imaging to determine the source of the symptoms, which could include neoplasms. PMID- 25270703 TI - Use of restorative procedures by allied dental health professionals in Minnesota. AB - BACKGROUND: In 2003, the Minnesota legislature revised the Dental Practice Act to include restorative procedures in the scope of practice for registered dental assistants (RDAs) and registered dental hygienists (RDHs). The authors examined these practitioners' characteristics and made comparisons on the basis of their use of restorative function (RF) training and their practices' locations. They also examined practice type, models of implementation and perceived outcomes. METHODS: The authors mailed a survey to all RF-certified RDAs and RDHs in Minnesota (N = 387). They used descriptive statistics to summarize the data and t tests and Fisher exact tests (P <.0001) to make comparisons between groups. RESULTS: The authors received 243 surveys (63 percent). Less than one-half (38 percent) of the RF-certified practitioners performed RFs. Of these, 29 percent were RDHs and 71 percent were RDAs. These practitioners performed RFs most often by working with a dentist or when time allowed. They perceived increased access to dental care and an increase in the number of patients treated to be outcomes of performing RFs. CONCLUSIONS: The results of this survey indicated use of restorative procedures varied greatly by practitioner type. The perceptions of those who performed RFs indicated they had a positive effect on dental practice. PRACTICAL IMPLICATIONS: The addition of RF-certified personnel to the dental team has the potential to increase the number of patients seen in practice and the job satisfaction of team members. PMID- 25270705 TI - Repair of peri-implant bone loss after occlusal adjustment: a case report. AB - BACKGROUND: Peri-implantitis generally is attributed to a bacterial challenge, with occlusion being a modifying factor. The author presents a case of peri implant marginal bone loss that was treated successfully with only occlusal adjustment. CASE DESCRIPTION: A 63-year-old female patient with a history of bruxism reported for a yearly periodontal examination 38 months after restoration of an implant in the tooth no. 30 position. A radiograph indicated that this implant had significant peri-implant bone loss. The evaluation showed very heavy occlusion on the implant restoration, and the author performed an occlusal adjustment. A radiograph obtained five months later showed significant repair of the lost alveolar bone. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Patients with dental implants require periodic examination and maintenance therapy to prevent peri-implantitis. The examination should include a periodontal, prosthetic, radiographic and occlusal evaluation. PMID- 25270706 TI - Hepatocellular carcinoma metastasis to the condyle: a case report and review of the literature. AB - BACKGROUND: Metastatic tumor invasion of the condyle from the liver is rare. It is important for dental practitioners to differentiate tumor involvement from musculoskeletal disorders such as temporomandibular disorders. CASE DESCRIPTION: The authors present a case report of a patient with temporomandibular joint pain and dysfunction consistent with musculoskeletal disorders. Because of the patient's medical history, comprehensive examination results and findings of imaging studies performed, the dental practitioners referred him to other health care providers for further and more in-depth investigation. This resulted in the establishment of an accurate diagnosis, with treatment directed at the primary source. PRACTICAL IMPLICATIONS: A thorough medical history, comprehensive clinical examination and adjunctive testing, when necessary, are paramount in establishing a definitive diagnosis for patients with orofacial pain, thereby enabling the delivery of appropriate treatment. PMID- 25270707 TI - Patients who received preoperative antibiotics showed fewer early implant failures. PMID- 25270708 TI - When to add staff members. PMID- 25270709 TI - Exploring everyday ethics. PMID- 25270710 TI - Tomotherapy concomitant with cetuximab, followed by cetuximab as single-agent therapy for unresectable squamous cell carcinoma of the skin: a case report. AB - BACKGROUND: Cutaneous squamous cell carcinoma (SCC) is the second most frequency of all skin tumors. Incidence of SCC has risen significantly due to an increased sun exposure and the number of immunodeficient patients. Cutaneous SCC is characterized by high Epidermal growth factor receptor (EGFR) expression with low frequency of RAS mutations. Generally, locoregional surgery is curative and systemic therapy is not indicated. We evaluated the activity and toxicity profile of tomotherapy concomitant with Cetuximab, followed by Cetuximab as single agent therapy in a patient affected by unresectable, locally advanced cutaneous SCC. CASE PRESENTATION: At our institution, on March 2012 we treated a 45 years-old patient affected by locally advanced, unresectable G1 SCC of the lumbar region. At our first observation, the patient was asthenic, with severe pain and functional limitations. There was also a superinfection due to Pseudomonas Aeruginosa resistant to antibiotics, and a G3 anemia secondary to the bleeding lesion. ECOG Performance Status was 2. Tomotherapy has been performed concomitant with the Cetuximab (400 mg/m2, followed by weekly doses of 250 mg/m2) at the total dose of 60 Gy (2 Gy/fx), followed by Cetuximab monotherapy.The lesion reduced progressively until disappear even after the suspension of the treatment and the patient achieved complete response. Toxicity resulted in G1 cutaneous rash and G2 toxicity to the nails, appeared after 5 months of treatment, typical toxicity profile of the anti-EGFR therapies. After one month of therapy the Pseudomonas Aeruginosa superinfection totally disappeared. Quality of life resulted significantly improved with reduction until discontinuation of the anti pain drugs, and progressive increase of the hemoglobin levels. At follow up of 15 months there was no evidence of active disease and the ECOG Performance Status was 0 (zero). CONCLUSION: The treatment was effective and feasible. Considering these excellent results, further studies about concomitant tomotherapy with Cetuximab for advanced/inoperable SCC of the skin are needed. PMID- 25270711 TI - Association between survival and maximum standardized uptake value of liver metastases detected by 18-fluoro-2-deoxy-D-glucose positron emission tomography computed tomography in patients with adenocarcinoma of unknown primary origin. AB - OBJECTIVE: The objective of this retrospective study is to investigate the association between survival and maximum standardized uptake values (SUVmax) of liver metastases detected by pre-treatment positron emission tomography-computed tomography (PET-CT) in patients with adenocarcinoma of unknown primary origin (ACUP). METHODS: A total of 58 patients with ACUP and liver metastases confirmed histopathologically by liver biopsy and pre-treatment PET-CT were included in this study. SUVmax values of the liver lesions were measured and their association with survival was investigated. RESULTS: The median age was 62 years; 63.8 % of the patients were males and 36.2 % were females. The median overall survival was calculated as 10.7 months (OS). The median SUVmax of the liver metastases was 8.6. Accordingly, two groups were established: one with values <8.6 and the other with ones >=8.6. No differences were detected between the two groups with respect to general characteristics. Median OS was 13.2 months in the group with SUVmax <8.6 compared to 7.4 months in the group with SUVmax >=8.6. This difference was statistically significant (p = 0.033). SUVmax (HR 1.104, 95 % CI 1.013-1.204, p = 0.025), age (HR 1.033, 95 % CI 1.002-1.064, p = 0.034), presence of chemotherapy (HR 2.296, 95 % CI 1.136-4.641, p = 0.021) and LDH level (HR 1.002, 95 % CI 1.001-1.003, p = 0.007) were identified as independent prognostic factors affecting survival in the multivariable analysis. This is the first report evaluating the impact of SUVmax for liver metastases on ACUP patient survival. CONCLUSION: The SUVmax of liver metastases evaluated by PET-CT is a prognostic factor influencing survival of patients with ACUP. PMID- 25270712 TI - Regional glucose metabolic reduction in dementia with Lewy bodies is independent of amyloid deposition. AB - PURPOSE: There is evidence that some cases of patients with dementia with Lewy bodies (DLB) can demonstrate Alzheimer disease (AD) like reduced glucose metabolism without amyloid deposition. The aim of this study was to clarify whether regional hypometabolism is related to amyloid deposits in the DLB brain and measure the degree of regional hypometabolism. METHODS: Ten consecutive subjects with DLB and 10 AD patients who underwent both Pittsburgh compound B (PiB)-PET and (18)F-fluoro-2-deoxyglucose (FDG)-PET were included in this study. Regional standardized uptake value ratio (SUVR)s normalised to cerebellar cortices were calculated in the FDG- and PiB-PET images. RESULTS: All AD patients and five DLB patients showed amyloid deposits (PiB positive). In the DLB group the parietotemporal and occipital metabolism were significantly lower than those in the AD group but there was no difference between the posterior cingulate hypometabolism between DLB and AD groups. There were no differences in regional glucose metabolism between PiB positive and negative DLB patients. CONCLUSIONS: In the DLB brain, it is suggested that decreased regional glucose metabolism is unrelated to amyloid deposits, although the hypometabolic area overlaps with the AD hypometabolic area and the degree of parietotemporal and occipital hypometabolism in DLB brain is much larger than that in AD brain. PMID- 25270713 TI - Feasibility of automated pancreas segmentation based on dynamic MRI. AB - OBJECTIVE: MRI-guided radiotherapy is particularly attractive for abdominal targets with low CT contrast. To fully utilize this modality for pancreas tracking, automated segmentation tools are needed. A hybrid gradient, region growth and shape constraint (hGReS) method to segment two-dimensional (2D) upper abdominal dynamic MRI (dMRI) is developed for this purpose. METHODS: 2D coronal dynamic MR images of two healthy volunteers were acquired with a frame rate of 5 frames per second. The regions of interest (ROIs) included the liver, pancreas and stomach. The first frame was used as the source where the centres of the ROIs were manually annotated. These centre locations were propagated to the next dMRI frame. Four-neighborhood region transfer growth was performed from these initial seeds before refinement using shape constraints. RESULTS from hGReS and two other automated segmentation methods using integrated edge detection and region growth (IER) and level set, respectively, were compared with manual contours using Dice's index (DI). RESULTS: For the first patient, the hGReS resulted in the organ segmentation accuracy as a measure by the DI (0.77) for the pancreas, superior to the level set method (0.72) and IER (0.71). The hGReS was shown to be reproducible on the second subject, achieving a DI of 0.82, 0.92 and 0.93 for the pancreas, stomach and liver, respectively. Motion trajectories derived from the hGReS were highly correlated to respiratory motion. CONCLUSION: We have shown the feasibility of automated segmentation of the pancreas anatomy on dMRI. ADVANCES IN KNOWLEDGE: Using the hybrid method improves segmentation robustness of low contrast images. PMID- 25270714 TI - What is old is now new: insights into cardiorenal physiology. PMID- 25270715 TI - Cell factories for insulin production. AB - The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Manufacturing of therapeutic recombinant proteins require an appropriate host organism with efficient machinery for posttranslational modifications and protein refolding. Recombinant human insulin has been produced predominantly using E. coli and Saccharomyces cerevisiae for therapeutic use in human. We would focus in this review, on various approaches that can be exploited to increase the production of a biologically active insulin and its analogues in E. coli and yeast. Transgenic plants are also very attractive expression system, which can be exploited to produce insulin in large quantities for therapeutic use in human. Plant-based expression system hold tremendous potential for high capacity production of insulin in very cost-effective manner. Very high level of expression of biologically active proinsulin in seeds or leaves with long-term stability, offers a low-cost technology for both injectable as well as oral delivery of proinsulin. PMID- 25270716 TI - WNT signaling in bone development and homeostasis. AB - The balance between bone formation and bone resorption controls postnatal bone homeostasis. Research over the last decade has provided a vast amount of evidence that WNT signaling plays a pivotal role in regulating this balance. Therefore, understanding how the WNT signaling pathway regulates skeletal development and homeostasis is of great value for human skeletal health and disease. PMID- 25270718 TI - [Concept for a department of intensive care]. AB - BACKGROUND: Demographic change and increasing complexity are among the reasons for high-tech critical care playing a major and increasing role in today's hospitals. At the same time, intensive care is one of the most cost-intensive departments in the hospital. PREREQUISITES: To guarantee high-quality care, close cooperation of specialised intensive care staff with specialists of all other medical areas is essential. A network of the intensive care units within the hospital may lead to synergistic effects concerning quality of care, simultaneously optimizing the use of human and technical resources. GOAL: Notwithstanding any organisational concepts, development and maintenance of the highest possible quality of care should be of overriding importance. PMID- 25270717 TI - Copy-number variation associated with congenital anomalies of the kidney and urinary tract. AB - BACKGROUND: The most common cause of end-stage renal disease in children can be attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Despite this high incidence of disease, the genetic mutations responsible for the majority of CAKUT cases remain unknown. METHODS: To identify novel genomic regions associated with CAKUT, we screened 178 children presenting with the entire spectrum of structural anomalies associated with CAKUT for submicroscopic chromosomal imbalances (deletions or duplications) using single-nucleotide polymorphism (SNP) microarrays. RESULTS: Copy-number variation (CNV) was detected in 10.1 % (18/178) of the patients; in 6.2 % of the total cohort, novel duplications or deletions of unknown significance were identified, and the remaining 3.9 % harboured CNV of known pathogenicity. CNVs were inherited in 90 % (9/10) of the families tested. In this cohort, patients diagnosed with multicystic dysplastic kidney (30 %) and posterior urethral valves (24 %) had a higher incidence of CNV. CONCLUSIONS: The genes contained in the altered genomic regions represent novel candidates for CAKUT. This study has demonstrated that a significant proportion of patients with CAKUT harbour submicroscopic chromosomal imbalances, warranting screening in clinics for CNV. PMID- 25270719 TI - [Myocardial ischemia caused by overuse of headache medications]. AB - Myocardial infarction as the most severe clinical manifestation of coronary atherosclerosis is the major cause of death in western countries. Although rupture of an atherosclerotic plaque is generally causal for this event, in recent years differential diagnoses have been discussed to further optimize diagnosis and treatment of myocardial ischemia. The "universal definition of myocardial infarction" defines five subtypes of myocardial infarction: in particular, type 2 myocardial infarction includes other diseases related to myocardial ischemia such as hyper- or hypotension, coronary artery spasms, arrhythmia, etc. Some medications for the acute therapy of migraine like triptans can lead to myocardial infarction. PMID- 25270720 TI - Atractylenolide I inhibits lipopolysaccharide-induced inflammatory responses via mitogen-activated protein kinase pathways in RAW264.7 cells. AB - Atractylenolide I (ATL-I) is a bioactive component of Rhizoma Atractylodis macrocephalae. Although increasing evidence shows that ATL-I has an anti inflammatory effect, the anti-inflammatory molecular mechanism of ATL-I is still unknown. In this study, we investigated the effect of ATL-I on cell viability by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and the level of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) by enzyme-linked immunosorbent assay (ELISA) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further, we examined the effect of ATL-I on the activation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38) by Western blot. We also investigated the effect of ATL-I on the expression of myeloid differentiation protein-2 (MD-2), CD14, complement receptor 3 (CR3), scavenger receptor class A (SR-A), toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). We found that ATL-I showed no inhibitory effect on cell viability at concentrations ranging from 1 uM to 100 uM and markedly reduced the release of IL-6 and TNF-alpha at a concentrate-dependent manner. In addition, ATL-I suppressed the activity of nuclear NF-kappaB and the phosphorylation of ERK1/2 and p38 in LPS-treated RAW264.7 cells. Further analysis showed that ATL-I inhibited the expression of MD-2, CD14, SR-A, TLR4 and MyD88, but the expression of CR3 was unaffected. These data suggest that ATL-I shows an anti-inflammatory effect by inhibiting TNF-alpha and IL-6 production. The anti inflammatory effects of ATL-I may be associated with the inhibition of the NF kappaB, ERK1/2 and p38 signaling pathways. PMID- 25270721 TI - Anti-inflammatory effects of galangin on lipopolysaccharide-activated macrophages via ERK and NF-kappaB pathway regulation. AB - Inflammation is the major symptom of the innate immune response to microbial infection. Macrophages, immune response-related cells, play a role in the inflammatory response. Galangin is a member of the flavonols and is found in Alpinia officinarum, galangal root and propolis. Previous studies have demonstrated that galangin has antioxidant, anticancer, and antineoplastic activities. However, the anti-inflammatory effects of galangin are still unknown. In this study, we investigated the anti-inflammatory effects of galangin on RAW 264.7 murine macrophages. Galagin was not cytotoxic to RAW 264.7 cells, and nitric oxide (NO) production induced by lipopolysaccharide (LPS)-stimulated macrophages was significantly decreased by the addition of 50 MUM galangin. Moreover, galangin treatment reduced mRNA levels of cytokines, including IL-1beta and IL-6, and proinflammatory genes, such as iNOS in LPS-activated macrophages in a dose-dependent manner. Galangin treatment also decreased the protein expression levels of iNOS in activated macrophages. Galangin was found to elicit anti inflammatory effects by inhibiting ERK and NF-kappaB-p65 phosphorylation. In addition, galangin-inhibited IL-1beta production in LPS-activated macrophages. These results suggest that galangin elicits anti-inflammatory effects on LPS activated macrophages via the inhibition of ERK, NF-kappaB-p65 and proinflammatory gene expression. PMID- 25270722 TI - Race/ethnic disparities in the utilization of treatment for drug dependent inmates in U.S. state correctional facilities. AB - BACKGROUND: Research has documented racial and ethnic disparities in utilization, access, continuity, and quality of care for psychiatric disorders including treatment for substance use disorders among those with similar need in the general community. Currently, the extent of racial and ethnic disparities in treatment within U.S. correctional facilities is unknown. METHODS: This study examines race/ethnic disparities in treatment for drug dependent inmates using the 2004 Survey of Inmates in State Correctional Facilities. Fixed effects logistic regression is used to analyze treatment outcomes for 5180 inmates housed within 286 prisons. The analysis accounts for differences in background characteristics (i.e., age, gender, marital status, foreign born status, veteran status), socioeconomic characteristics (i.e., education, employment prior to incarceration), mental health (i.e., diagnosis with a serious mental illness), and incarceration experiences (i.e., current conviction, previous incarceration episodes, time served, additional sentencing requirements, external social support, disciplinary violations). RESULTS: The findings identify a remarkable unmet need among drug dependent inmates in that less than one-half of drug dependent inmates had received any type of treatment in prison at the time of the interview with the most common treatment type being self-help groups. Compared to whites, drug dependent Latino inmates have significantly lower odds of utilizing treatment, yet there are no significant black--white disparities found. CONCLUSION: The current study suggests that treatment for drug dependent inmates needs to be expanded to include clinically or medically based treatment since the failure to address addictions in the criminal legal system has been identified as the single most significant reason for rearrest and recidivism once released. PMID- 25270723 TI - miR-494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTEN. AB - Accumulating evidence has shown that micro-RNAs (miRNAs) are involved in multiple processes in cancer development and progression. Upregulation of miRNA-494 (miR 494) has been identified as an oncogenic miRNA and is associated with poor prognosis in several types of human cancer. However, the specific function of miR 494 in colorectal cancer remains unclear. In this study we found that the expression of miR-494 in colorectal cancer tissues and cell lines was much higher than in normal control tissues and cells, respectively. In addition, upregulation of miR-494 more frequently occurred in tissue specimens with adverse clinical stage and the presence of distant metastasis. Moreover, multivariate survival analyses demonstrated that overexpression of miR-494 is an independent prognostic factor for both progression-free and overall survival. In addition miR-494 promoted invasion and migration in colorectal cancer cells, and miR-494 directly inhibited the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression by targeting its 3'-untranslated region (3'-UTR). Moreover, PTEN is down regulated and inversely correlated with miR-494 expression in tissues. Thus, for the first time, we provided convincing evidence that upregulation of miR-494 was associated with tumor aggressiveness and tumor metastasis and promoted cell migration and invasion by targeting PTEN gene in colorectal cancer, and miR-494 is an independent prognostic marker for colorectal cancer patients. PMID- 25270724 TI - Culicoides (Avaritia) gornostaevae Mirzaeva, 1984 (Diptera: Ceratopogonidae)--a possible vector species of the Obsoletus group new to the European fauna. AB - BACKGROUND: Culicoides gornostaevae Mirzaeva, 1984, known previously only from Siberia, is a boreal species included into the Obsoletus group of Culicoides sg. Avaritia. Members of the subgenus can act as vectors of various diseases. In Europe they are involved in the transmission of the Schmallenberg virus and bluetongue virus. FINDINGS: Culicoides gornostaevae Mirzaeva, 1984 is reported for the first time in Europe with new country records from Norway, Poland and Sweden. CONCLUSIONS: Culicoides gornostaevae Mirzaeva, 1984 has not been previously mentioned from Europe, even though there has been an extensive monitoring of Culicoides species during the last decades. Most probably this species has been notoriously overlooked in the materials, because of the problems with identification of the females of the subgenus Avaritia. Similar to other species of the Obsoletus group, C. gornostaevae should be regarded as a possible vector for Schmallenberg and bluetongue virus. PMID- 25270725 TI - Using mobile phones in healthcare management for the elderly. AB - The increasing average life expectancy is simultaneously increasing the incidence of chronic diseases and the number of healthy elderly people, consequently leading to an increased demand for healthcare management methods that do not involve hospital visits. The development of health management services involving mobile phones will change the focus of medical services from hospital visits and treatments to managing the health decisions made by individuals in their daily lives. However, the elderly may experience specific difficulties in adapting to constantly evolving services. This study reviews various health-related devices such as mobile phones that are available for providing healthcare to the elderly, and the different ways of using them. As the use of mobile phone increases, it is expected that elderly mobile phone users will also be able to regularly check their health status at any time and place. The issues of an ageing population pertain to the entire society rather than only to the elderly, which make mobile phone-based medical informatics as a health management service a worthy goal. PMID- 25270727 TI - The price of pulchritude, the cost of concupiscence: how to have sex in late modernity. AB - Research and scholarship on sexuality has grown exponentially over the last 60 years; but what is this 'sexuality' that so fascinates us. During those 60 years, three academic traditions or paradigms have emerged and evolved to provide that main ways we understand sexuality. These are: (1) sexology; (2) sex research; and (3) critical sexuality studies. These paradigms do not always agree; at times, they are incommensurable in the picture of sexuality they paint. However, they each affect how sexuality is researched and written about, and how it is understood in the popular imagination. After discussing these paradigms, attention is focused on the contemporary challenges facing the third paradigm: critical sexuality studies. The contribution of sexology and sex research to these challenges is noted. Three key issues are discussed: the body; how we commonly understand sexuality; and the commodification of sexuality in late modernity. PMID- 25270726 TI - Role of ionotropic glutamate receptors in delay and probability discounting in the rat. AB - RATIONALE: Discounting of delayed and probabilistic reinforcement is linked to increased drug use and pathological gambling. Understanding the neurobiology of discounting is important for designing treatments for these disorders. Glutamate is considered to be involved in addiction-like behaviors; however, the role of ionotropic glutamate receptors (iGluRs) in discounting remains unclear. OBJECTIVES: The current study examined the effects of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor blockade on performance in delay and probability discounting tasks. METHODS: Following training in either delay or probability discounting, rats (n = 12, each task) received pretreatments of the NMDA receptor antagonists MK-801 (0, 0.01, 0.03, 0.1, or 0.3 mg/kg, s.c.) or ketamine (0, 1.0, 5.0, or 10.0 mg/kg, i.p.), as well as the AMPA receptor antagonist CNQX (0, 1.0, 3.0, or 5.6 mg/kg, i.p.). Hyperbolic discounting functions were used to estimate sensitivity to delayed/probabilistic reinforcement and sensitivity to reinforcer amount. RESULTS: An intermediate dose of MK-801 (0.03 mg/kg) decreased sensitivity to both delayed and probabilistic reinforcement. In contrast, ketamine did not affect the rate of discounting in either task but decreased sensitivity to reinforcer amount. CNQX did not alter sensitivity to reinforcer amount or delayed/probabilistic reinforcement. CONCLUSIONS: These results show that blockade of NMDA receptors, but not AMPA receptors, decreases sensitivity to delayed/probabilistic reinforcement (MK-801) and sensitivity to reinforcer amount (ketamine). The differential effects of MK-801 and ketamine demonstrate that sensitivities to delayed/probabilistic reinforcement and reinforcer amount are pharmacologically dissociable. PMID- 25270728 TI - Impact of isoniazid resistance on virulence of global and south Indian clinical isolates of Mycobacterium tuberculosis. AB - Isoniazid (INH) is the only anti-tuberculous drug for which a relationship has been noticed between acquisition of resistance and lack of virulence. Mutation in katG gene is the chief cause for INH resistance in Mycobacterium tuberculosis (MTB). Classical studies have demonstrated that INH-resistant (INH(r)) mutants with a defective katG gene were catalase deficient and markedly attenuated in guinea pigs. Also, earlier studies on south Indian INH(r) isolates were shown to have lower virulence and higher susceptibility to H2O2. However, later studies including that of our's suggest that INH resistance is not always accompanied by compromised virulence and/or survival. Therefore, this review focuses on the influence of INH resistance on virulence of MTB from global and south Indian isolates. PMID- 25270729 TI - Novel nelfinavir mesylate loaded d-alpha-tocopheryl polyethylene glycol 1000 succinate micelles for enhanced pediatric anti HIV therapy: In vitro characterization and in vivo evaluation. AB - Worldwide more than 35 million people are living with Human Immunodeficiency Virus (HIV) where 3.3 million are children. This translates in approximately 700 new daily infections in children only in 2012. Prolonged High Activity Antiretroviral Therapy (HAART) regimes could present low-patient compliance, especially in children, affecting therapeutic success. Nelfinavir mesylate (NFV) is a non-peptidic HIV-1 protease inhibitor (IP) which was the first IP recommended for pediatric use (>2 years-old). It exhibits pH-dependant aqueous solubility which results highly restricted at physiological pH values. The former represents a main clinical limitation due to the reduction on drug absorption along the small intestine after an oral administration, leading to unpredictable drug bioavailability. Moreover a liquid formulation of NFV is not available worldwide, preventing appropriate dose adjustment and more convenient administration. In this framework, the present investigation reports the development of a NFV highly concentrated aqueous formulation for a more appropriate management of pediatric anti-HIV therapy. The aim was to encapsulate NFV within D-alpha-tocopheryl polyethylene glycol 1000 succinate micelles to improve its aqueous solubility and its oral pharmacokinetic parameters. Results show that NFV aqueous solubility was increased up to 80.3 mg/mL. NFV-loaded micelles exhibited a hydrodynamic diameter of 5.6 nm and a spherical morphology as determined by dynamic light scattering and transmission electronic microscopy, respectively. In vitro NFV release profile demonstrated a cumulative drug release of 56% at 6 h. Finally, in vivo data showed a significant (p<0.01) increase of Area-Under-the-Curve between 0 and 24 h for NFV encapsulated in micelles in comparison with a NFV suspension prepared with glycerin 20% v/v and carboxymethylcellulose sodium 0.5% w/v, representing an increment on drug oral relative bioavailability of 1.71-fold. Thereby, this formulation represents an innovative nanotechnological platform to improve pediatric HIV pharmacotherapy. PMID- 25270730 TI - Effect of peptide content on the regulation of transgene expression by protein kinase Calpha-responsive linear polyethylenimine-peptide conjugates. AB - We examined a series of linear polyethylenimine (LPEI)-based nanocarriers that activate transgene expression in response to cancer-specific protein kinase Calpha (PKCalpha). Eight types of LPEI-peptide conjugate differing in peptide content and number were synthesized using click chemistry. The conjugates could form polyplexes with pDNA through electrostatic interaction, but the degree of pDNA condensation, sizes, and surface charges of the resulting polyplexes depended on the pendant-peptide content and number. None of the polyplexes showed significant cytotoxicity toward human hepatoma cells (HepG2). Furthermore, pendant peptide content and number markedly affected transgene activation in response to PKCalpha. To achieve an all-or-none response to PKCalpha, we determined the optimum peptide content and number in LPEI-peptide conjugates as ~6 mol% and ~40 peptides/conjugate. PMID- 25270731 TI - Modulation of hepatitis B surface antigen secretion by annexin II expressed in hepatitis B virus-producing hepatoma cells. AB - The role of annexin II in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) remains to be elucidated. Intracellular hepatitis B surface antigen (HBsAg)-retention contributes to the induction of hepatocarcinogenesis. The present study aimed to investigate the regulation of HBsAg secretion by annexin II expressed in HBV-producing hepatoma cells. The expression of annexin II was analyzed using western blot analysis in SMMC-7721, HepG2, HepG2.2.15, 293T and Chinese hamster ovary (CHO) cells. CHO cells transfected with an annexin II plasmid were used as a positive control. The localization of annexin II and HBsAg was observed in the HepG2 and HepG2.2.15 cells using indirect immunofluorescence. HepG2.2.15 cells were transfected with a human immunodeficiency virus-type 1 viral infectivity factor-hemagglutinin (Vif-HA) plasmid or a control vector and, 24 h post-transfection, MG132 was added to the Vif-complemented HepG2.2.15 cells. Western blot analysis was performed to detect the expression of annexin II and Vif-HA. HepG2 cells were cotransfected with HBV and annexin II expression vectors. Western blot analysis was performed to examine the expression of annexin II and an Abbott chemiluminescence immunoassay was used to assess the levels of HBsAg. The expression of annexin II was lower in the HepG2.2.15 cells compared with the SMMC-7721 and HepG2 cells and the fluorescence signal of annexin II in the HepG2 cells was brighter than in the HepG2.2.15 cells. Annexin II colocalized with HBsAg in the cytosol of the HepG2.2.15 cells. MG132 was not able to increase the stability of annexin II expression in HepG2.2.15 cells. Annexin II reduced the secretion of HBsAg when compared with the control-transfected HepG2 cells. In conclusion, HBV downregulated the expression of annexin II and annexin II decreased the secretion of HBsAg in HBV-producing hepatoma cells in favor of intracellular HBsAg storage. PMID- 25270732 TI - High colonization rates of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in Swiss travellers to South Asia- a prospective observational multicentre cohort study looking at epidemiology, microbiology and risk factors. AB - BACKGROUND: International travel contributes to the worldwide spread of multidrug resistant Gram-negative bacteria. Rates of travel-related faecal colonization with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae vary for different destinations. Especially travellers returning from the Indian subcontinent show high colonization rates. So far, nothing is known about region specific risk factors for becoming colonized. METHODS: An observational prospective multicentre cohort study investigated travellers to South Asia. Before and after travelling, rectal swabs were screened for third-generation cephalosporin- and carbapenem-resistant Enterobacteriaceae. Participants completed questionnaires to identify risk factors for becoming colonized. Covariates were assessed univariately, followed by a multivariate regression. RESULTS: Hundred and seventy persons were enrolled, the largest data set on travellers to the Indian subcontinent so far. The acquired colonization rate with ESBL-producing Escherichia coli overall was 69.4% (95% CI 62.1-75.9%), being highest in travellers returning from India (86.8%; 95% CI 78.5-95.0%) and lowest in travellers returning from Sri Lanka (34.7%; 95% CI 22.9-48.7%). Associated risk factors were travel destination, length of stay, visiting friends and relatives, and eating ice cream and pastry. CONCLUSIONS: High colonization rates with ESBL-producing Enterobacteriaceae were found in travellers returning from South Asia. Though risk factors were identified, a more common source, i.e. environmental, appears to better explain the high colonization rates. PMID- 25270734 TI - The Museum as a platform for tobacco promotion in China. AB - The China Tobacco Museum in Shanghai is the largest in China, consisting of seven pavilions of tobacco-related exhibits. A focus group and previous survey data revealed that the museum conveys messages that make tobacco use appealing. Of the pavilions, three were found to contain blatant misinformation about tobacco and tobacco consumption. We argue that the China Tobacco Museum is a platform for tobacco promotion, a form of tobacco advertising, promotion and sponsorship, and thus contravenes the FCTC. PMID- 25270733 TI - ABC goal achievement predicts microvascular but not macrovascular complications over 6-years in adults with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes Study. AB - HYPOTHESIS: Vascular complications of type 1 diabetes are thought to cluster. We examined the prevalence and incidence of vascular complications and American Diabetes Association's ABC goal achievements in a prospective cohort of adults with type 1 diabetes. We hypothesized that ABC achievement at baseline would predict both micro- and macrovascular complications over 6-years. METHODS: Participants (N=652) were 19-56 year old at baseline and re-examined 6-years later. Microvascular complications included diabetic nephropathy (DN), defined as incident albuminuria (AER>=20 MUg/min) or rapid GFR decline (>3.3%/year) by CKD EPI cystatin C and proliferative diabetic retinopathy (PDR), defined as laser eye therapy. Macrovascular complications were defined as coronary artery calcium progression (CACp), measured by electron-beam computed-tomography. ABC goals were defined as HbA1c<7.0%, BP<130/80 mmHg and LDL-C<100mg/dL. RESULTS: ABC control was suboptimal with only 6% meeting all goals. Meeting no ABC goals at baseline compared to meeting all goals was associated with increased odds of developing microvascular complications (OR: 8.5, 2.3-31.5, p=0.001), but did not reach significance for CACp (OR: 1.7, 0.8-3.9, p=0.19). CONCLUSION: ABC achievement at baseline strongly predicted microvascular but not macrovascular complications over 6-years in adults with type 1 diabetes, suggesting a need for novel therapeutic targets to complement conventional risk factors in treating macrovascular complications. PMID- 25270735 TI - Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model. AB - Previous studies in the field of cancer research have suggested a possible role for statins in the reduction of risk in certain malignancies. The purpose of these studies was to examine the chemopreventive effects of pravastatin alone and in combination with pineal hormone melatonin in the N-methyl-N-nitrosourea induced mammary carcinogenesis model. Pravastatin was given orally (1 00 mg/kg) and melatonin was added to the water (20 MUg/ml). Chemoprevention began seven days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, angiogenesis and proliferation) and side effects after long-term treatment in animals were assessed. Pravastatin alone suppressed tumour frequency by 20.5% and average tumour volume by 15% compared with controls. Combined administration of the drugs decreased tumour frequency by 69% and lengthened tumour latency by nine days compared with control animals. The ration between high and low grade carcinomas was apparently reduced in both treated groups. The analysis of carcinoma cells showed significant expression increase in caspase-3 and caspase-7 after pravastatin treatment; however, combined treatment even more pronounced increase in the expression of both caspases. Regarding VEGFR-2 expression, a small effect in carcinomas of both treated groups was found. In plasma metabolism evaluation, pravastatin alone significantly decreased levels of glucose and triacylglycerols. Our results suggest a mild anti-neoplastic effect of pravastatin in this rat mammary gland carcinoma model. Statins co-administered with other suitable drug (e.g. melatonin) should be further evaluated for tumour-preventive properties. PMID- 25270737 TI - An Education- and Telephone-Based Intervention to Improve Follow-up to Vision Care in Patients With Diabetes: A Prospective, Single-Blinded, Randomized Trial. AB - The aim was to evaluate the effectiveness of a multipronged intervention on diabetic dilated fundus examination (DFE) adherence. In a prospective trial, 521 patients with diabetes who were due for follow-up DFEs were randomized to usual care or the intervention group. Usual care received a form letter reminder to schedule and an automated reminder phone call prior to their appointment. Intervention participants received an educational brochure about diabetic eye disease and a personalized letter reminder to schedule. A research assistant called intervention participants to help schedule the appointment, and they received a reminder letter and an automated phone call prior to the scheduled visit. Patients in the intervention group were significantly more likely to schedule (63% vs 40%; P < .0001) and complete their appointment (48% vs 30%; P < .0001) compared with usual care. A multipronged intervention, including an educational mailing and telephone assistance with scheduling an appointment, significantly improved diabetic DFE adherence. PMID- 25270736 TI - Testing for risk and protective trends in genetic analyses of HIV acquisition. AB - Host genetics studies of HIV-1 acquisition are critically important for the identification of new targets for drug and vaccine development. Analyses of such studies typically focus on pairwise comparisons of three different groups: HIV-1 positive individuals, HIV-1 high-risk seronegative individuals, and population controls. Because there is a clear expectation of how gene frequencies of risk or protective alleles would be ordered in the three groups, we are able to construct a statistical framework that offers a consistent increase in power over a wide range of the magnitude of risk/protective effects. In this paper, we develop tests that constrain the alternative hypothesis to appropriately reflect risk or protective trends jointly across the three groups and show that they lead to a substantial increase in power over the naive pairwise approach. We develop both likelihood-ratio and score statistics that test for genetic effects across the three groups while constraining the alternative hypothesis to reflect biologically motivated trends of risk or protection. The asymptotic distribution of both statistics (likelihood ratio and score) is derived. We investigate the performance of our approach via extensive simulation studies using a biologically motivated model of HIV-1 acquisition, and find that our proposed approach leads to an increase in power of roughly 10-28%. We illustrate our approach with an analysis of the effect of the CCR5Delta32 mutation on HIV acquisition. PMID- 25270738 TI - Downregulation of Runx3 is closely related to the decreased Th1-associated factors in patients with gastric carcinoma. AB - Runt-related transcription factor 3 (Runx3) is a tumor-suppressor gene and plays an important role in immune regulation, whose reduced expression may play an important role in the development and progression of gastric carcinoma. The aim of this study was to investigate the role of Runx3 on the levels of transcription factors in patients with gastric carcinoma and analyze the relationship between the expression of Runx3 and Th1-type cytokines in peripheral blood mononuclear cells (PBMCs). Our results showed that the expression levels of Runx3, T-bet, and IFN-gamma in patients with gastric carcinoma were obviously lower than those in control groups, and there was a positive correlation between the expression of Runx3 and T-bet or IFN-gamma in patients (p < 0.01). In order to further confirm this result, the Runx3 gene was constructed into pIRES2-eGFP and the recombined plasmid was transfected into SGC-7901 cells with liposome in vitro, the results obtained from the reverse transcription PCR indicated that the mRNA of Runx3, T bet, or IFN-gamma was significantly upregulated individually in Runx3 gene transfected SGC-7901 cells. It suggested that the Runx3 and Th1-associated factors including T-bet and IFN-gamma synchronization declines in gastric carcinoma may contribute to the development of cancer. PMID- 25270739 TI - Increased PTOV1 expression is related to poor prognosis in epithelial ovarian cancer. AB - Altered expression of prostate tumor overexpressed-1 (PTOV1) is observed in various types of human cancers. However, the role of PTOV1 in epithelial ovarian cancer (EOC) remains unclear. PTOV1 messenger (m)RNA expression in EOC patients was evaluated by quantitative real-time PCR (qRT-PCR). PTOV1 protein expression was also analyzed in archived paraffin-embedded EOC tissues using immunohistochemistry (IHC), and its association with overall survival of patients was analyzed by statistical analysis. Results from qRT-PCR analysis show that the expression level of PTOV1 mRNA was significantly higher in tumor tissues of EOC, compared to that in adjacent noncancerous tissues (P < 0.001). IHC staining showed that high expression of PTOV1 was detected in 57.2 % (87/152) of EOC cases. High expression of PTOV1 was significantly associated with pathological grade (P = 0.029) and clinical stage (P = 0.001). Moreover, the results of Kaplan Meier analysis indicated that a high expression level of PTOV1 resulted in a significantly poor prognosis of EOC patients. Multivariate analysis showed that high expression of PTOV1 was an independent prognostic factor for overall survival (P < 0.001). In conclusion, PTOV1 protein abnormal expression might contribute to the malignant progression of EOC. High expression of PTOV1 predicts poor prognosis in patients with EOC. PMID- 25270740 TI - Comparative proteomic analysis of fibrosarcoma and skin fibroblast cell lines. AB - Comparative proteomic analysis of normal and cancer cell lines provides for a better understanding of the molecular mechanism of cancer development and is essential for developing more effective strategies for new biomarker or drug target discovery. The purpose of this study is to compare protein expression levels between fibrosarcoma and fibroblast cell lines. In our study, two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) techniques were carried out to compare the protein profile between fibrosarcoma and fibroblast cell lines. We prepared cell lysate samples to analyze intracellular proteins and secretome samples to analyze extracellular proteins in both cell lines. Our results revealed 13 upregulated proteins and 1 downregulated protein of which all of them identified in fibrosarcoma cell line after the comparison with fibroblast cell line cell lysates. When comparing secretome profiles of both cell lines, we found and identified 13 proteins only expressed in fibrosarcoma cell line. These identified proteins have common functions such as cell proliferation, cell differentiation, invasion, metastasis, and apoptosis in cancer. The data obtained from this study indicates that these proteins have importance on understanding the molecular mechanism of fibrosarcoma. These proteins may serve as candidate biomarkers and drug targets for future clinical studies. PMID- 25270741 TI - Two-dimensional global longitudinal strain rate is a preload independent index of systemic right ventricular contractility in hypoplastic left heart syndrome patients after Fontan operation. AB - BACKGROUND: Assessment of systemic right ventricular (RV) function in patients with hypoplastic left heart syndrome is important during long-term follow-up after Fontan repair. Traditional echocardiographic parameters to evaluate systolic ventricular function are affected by loading conditions. The only generally accepted load-independent parameter of systolic function, end systolic elastance (Ees), requires invasive catheterization. Therefore, we sought to determine if parameters obtained by 2-dimensional speckle tracking (2DST) were affected by acute changes in preload and correlated with catheterization-derived indices of RV contractility in hypoplastic left heart syndrome patients after Fontan palliation. METHODS AND RESULTS: Fifty-two patients with hypoplastic left heart syndrome (median age, 6.6; range 2.9-22.2 years) were prospectively enrolled to have echocardiography and conductance catheter studies performed simultaneously. We compared traditional echo, 2-dimensional speckle tracking and catheterization-derived parameters during different states of preload at baseline and during dobutamine infusion. Global longitudinal strain (S) showed a tendency to decrease with preload reduction, whereas global longitudinal strain rate (SR) did not change (S: -17.7 +/- 3.4% versus -16.9 +/- 3.8%, P=0.08; SR: -1.30 +/- 0.29 versus -1.34 +/- 0.34 s(-1), P=0.3). S did not change with dobutamine infusion (-17.7 +/- 3.4% versus -18.4 +/- 3.9%, P=0.24), whereas SR increased significantly (-1.30 +/- 0.29 versus -2.26 +/- 0.49 s(-1), P<0.001). RV Ees correlated with SR (rs= -0.47, P<0.001), but not with S (rs=0.07, P=0.5) or other echocardiographic parameters. CONCLUSIONS: In contrast to S, SR was not affected by preload and correlated with Ees of the systemic RV. SR may be a useful noninvasive surrogate of RV contractility and suitable for follow-up of patients with hypoplastic left heart syndrome after Fontan palliation. PMID- 25270742 TI - Diversity of avipoxviruses in captive-bred Houbara bustard. AB - Implementation of conservation breeding programs is a key step to ensuring the sustainability of many endangered species. Infectious diseases can be serious threats for the success of such initiatives especially since knowledge on pathogens affecting those species is usually scarce. Houbara bustard species (Chlamydotis undulata and Chlamydotis macqueenii), whose populations have declined over the last decades, have been captive-bred for conservation purposes for more than 15 years. Avipoxviruses are of the highest concern for these species in captivity. Pox lesions were collected from breeding projects in North Africa, the Middle East and Central Asia for 6 years in order to study the diversity of avipoxviruses responsible for clinical infections in Houbara bustard. Molecular and phylogenetic analyses of 113 and 75 DNA sequences for P4b and fpv140 loci respectively, revealed an unexpected wide diversity of viruses affecting Houbara bustard even at a project scale: 17 genotypes equally distributed between fowlpox virus-like and canarypox virus-like have been identified in the present study. This suggests multiple and repeated introductions of virus and questions host specificity and control strategy of avipoxviruses. We also show that the observed high virus burden and co-evolution of diverse avipoxvirus strains at endemic levels may be responsible for the emergence of novel recombinant strains. PMID- 25270743 TI - Potential benefits of minimum unit pricing for alcohol versus a ban on below cost selling in England 2014: modelling study. AB - OBJECTIVE: To evaluate the potential impact of two alcohol control policies under consideration in England: banning below cost selling of alcohol and minimum unit pricing. DESIGN: Modelling study using the Sheffield Alcohol Policy Model version 2.5. SETTING: England 2014-15. POPULATION: Adults and young people aged 16 or more, including subgroups of moderate, hazardous, and harmful drinkers. INTERVENTIONS: Policy to ban below cost selling, which means that the selling price to consumers could not be lower than tax payable on the product, compared with policies of minimum unit pricing at L0.40 (?0.57; $0.75), 45 p, and 50 p per unit (7.9 g/10 mL) of pure alcohol. MAIN OUTCOME MEASURES: Changes in mean consumption in terms of units of alcohol, drinkers' expenditure, and reductions in deaths, illnesses, admissions to hospital, and quality adjusted life years. RESULTS: The proportion of the market affected is a key driver of impact, with just 0.7% of all units estimated to be sold below the duty plus value added tax threshold implied by a ban on below cost selling, compared with 23.2% of units for a 45 p minimum unit price. Below cost selling is estimated to reduce harmful drinkers' mean annual consumption by just 0.08%, around 3 units per year, compared with 3.7% or 137 units per year for a 45 p minimum unit price (an approximately 45 times greater effect). The ban on below cost selling has a small effect on population health-saving an estimated 14 deaths and 500 admissions to hospital per annum. In contrast, a 45 p minimum unit price is estimated to save 624 deaths and 23,700 hospital admissions. Most of the harm reductions (for example, 89% of estimated deaths saved per annum) are estimated to occur in the 5.3% of people who are harmful drinkers. CONCLUSIONS: The ban on below cost selling, implemented in the England in May 2014, is estimated to have small effects on consumption and health harm. The previously announced policy of a minimum unit price, if set at expected levels between 40 p and 50 p per unit, is estimated to have an approximately 40-50 times greater effect. PMID- 25270744 TI - [Asperger syndrome - of the difficulties with diagnosis and treatment]. PMID- 25270745 TI - [Renal denervation - a novel therapeutic option for resistant hypertension?]. PMID- 25270747 TI - [Urinary incontinence - what can be done by the family doctor and when is the urologist needed?]. AB - About 15% of the women and 10% of the men past the age of 65 years suffer from urinary incontinence. In most cases, accurate history taking can help differentiate between urge incontinence, stress incontinence and overflow incontinence, and is essential in choosing the appropriate treatment. Initial diagnostic testing can be conducted by the general practitioner, especially tests to exclude urinary tract infections or to rule out an overactive bladder. Patient education on changes to fluid intake and voiding habits as well as advice on suitable incontinence products are important first steps in the management of urinary continence. Also, drug treatment can be initiated in general practice. Patients with refractory urinary incontinence, particularly those who did not respond to anticholinergic medication, should be referred to a urologist for further evaluation since there may be an underlying tumour or other disorder of the bladder that is causing the incontinence. PMID- 25270748 TI - [Asperger syndrome - a fashionable diagnosis?]. AB - The Asperger Syndrome is - in contrast to early childhood autism - a disorder at the lighter end of the autism spectrum. Although first described in 1943, it was included in the ICD-10 not before 1992. The knowledge about this lighter autistic disorder spread only slowly. The increasing prevalence rates can be explained by the increased knowledge about this disorder and the growing clinical experience. In contrast to the public that gives repeated medial attention to it, and to would-be affected who seem to see an attractive excuse for social problems in an Asperger diagnosis, many psychiatrists appear cautious to state a diagnosis with which they are not familiar and which is discredited as a fashionable diagnosis. PMID- 25270749 TI - [On the impact of sample size calculation and power in clinical research]. AB - The aim of a clinical trial is to judge the efficacy of a new therapy or drug. In the planning phase of the study, the calculation of the necessary sample size is crucial in order to obtain a meaningful result. The study design, the expected treatment effect in outcome and its variability, power and level of significance are factors which determine the sample size. It is often difficult to fix these parameters prior to the start of the study, but related papers from the literature can be helpful sources for the unknown quantities. For scientific as well as ethical reasons it is necessary to calculate the sample size in advance in order to be able to answer the study question. PMID- 25270750 TI - [Phosphate disorders: hyperphosphatemia or pseudohyperphosphatemia?]. AB - We report the case of a 79 year old woman presenting with progressive confusion and drowsiness. Renal insufficiency with hyperkalemia as well as hypercalcemia and severe hyperphosphatemia were diagnosed. Renal insufficiency improved with treatment. However, hyperphosphatemia persisted without apparent explanation. We discuss possible causes of hyper- and pseudohyperphosphatemia. Specifically, phosphate analysis may be disturbed by the paraproteins in patients with multiple myeloma, resulting in pseudohyperphosphatemia. We review the standard laboratory phosphate measurement and the mechanisms of interference with paraproteins. PMID- 25270752 TI - [CPAP (continuous positive pressure ventilation) reduces blood pressure in comparison with nocturnal oxygen therapy]. PMID- 25270753 TI - [Tomosynthesis combined with mammography detects more breast cancers than mammography alone]. PMID- 25270757 TI - Decellularized periodontal ligament cell sheets with recellularization potential. AB - The periodontal ligament is the key tissue facilitating periodontal regeneration. This study aimed to fabricate decellularized human periodontal ligament cell sheets for subsequent periodontal tissue engineering applications. The decellularization protocol involved the transfer of intact human periodontal ligament cell sheets onto melt electrospun polycaprolactone membranes and subsequent bi-directional perfusion with NH4OH/Triton X-100 and DNase solutions. The protocol was shown to remove 92% of DNA content. The structural integrity of the decellularized cell sheets was confirmed by a collagen quantification assay, immunostaining of human collagen type I and fibronectin, and scanning electron microscopy. ELISA was used to demonstrate the presence of residual basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) in the decellularized cell sheet constructs. The decellularized cell sheets were shown to have the ability to support recellularization by allogenic human periodontal ligament cells. This study describes the fabrication of decellularized periodontal ligament cell sheets that retain an intact extracellular matrix and resident growth factors and can support repopulation by allogenic cells. The decellularized hPDL cell sheet concept has the potential to be utilized in future "off-the-shelf" periodontal tissue engineering strategies. PMID- 25270758 TI - Mental health service user experience of positive psychotherapy. AB - OBJECTIVE: Service user satisfaction with therapy is a key part of the therapeutic process. The aim of this study was to investigate service user experiences of an 11-week group positive psychology intervention for psychosis (WELLFOCUS PPT) in the context of a randomized controlled trial (ISRCTN04199273). METHOD: Participants were 37 individuals (51% male; mean age 45.6 years) receiving the intervention as part of the trial. Semistructured interviews and focus groups were conducted to investigate participants' views of WELLFOCUS PPT. Transcripts were analyzed both deductively and inductively to identify common themes. RESULTS: Feedback about the group experience was positive throughout. Components found helpful included learning to savor experiences, identifying and developing strengths, forgiveness, gratitude, and therapist self-disclosure. CONCLUSION: Findings emphasize the importance of considering service users' perceptions of therapy and can be used to guide clinicians in deciding whether to include one or more of the components of WELLFOCUS PPT in therapy. PMID- 25270760 TI - Structures, chemotaxonomic significance, cytotoxic and Na(+),K(+)-ATPase inhibitory activities of new cardenolides from Asclepias curassavica. AB - Five new cardenolide lactates (1-5) and one new dioxane double linked cardenolide glycoside (17) along with 15 known compounds (6-16 and 18-21) were isolated from the ornamental milkweed Asclepias curassavica. Their structures were elucidated by extensive spectroscopic methods (IR, UV, MS, 1D- and 2D-NMR). The molecular structures and absolute configurations of 1-3 and 17 were further confirmed by single-crystal X-ray diffraction analysis. Simultaneous isolation of dioxane double linked cardenolide glycosides (17-21) and cardenolide lactates (1-5) provided unique chemotaxonomic markers for this genus. Compounds 1-21 were evaluated for the inhibitory activities against DU145 prostate cancer cells. The dioxane double linked cardenolide glycosides showed the most potent cytotoxic effect followed by normal cardenolides and cardenolide lactates, while the C21 steroids were non-cytotoxic. Enzymatic assay established a correlation between the cytotoxic effects in DU145 cancer cells and the Ki for the inhibition of Na(+),K(+)-ATPase. Molecular docking analysis revealed relatively strong H-bond interactions between the bottom of the binding cavity and compounds 18 or 20, and explained why the dioxane double linked cardenolide glycosides possessed higher inhibitory potency on Na(+),K(+)-ATPase than the cardenolide lactate. PMID- 25270761 TI - Prof. Fred Volkmar and Ben Popple: Yale Seminar on Autism: Autism and Dentistry : Yale Child Study Center, 2014, Itunes U. PMID- 25270759 TI - Phosphite-induced changes of the transcriptome and secretome in Solanum tuberosum leading to resistance against Phytophthora infestans. AB - BACKGROUND: Potato late blight caused by the oomycete pathogen Phytophthora infestans can lead to immense yield loss. We investigated the transcriptome of Solanum tubersoum (cv. Desiree) and characterized the secretome by quantitative proteomics after foliar application of the protective agent phosphite. We also studied the distribution of phosphite in planta after application and tested transgenic potato lines with impaired in salicylic and jasmonic acid signaling. RESULTS: Phosphite had a rapid and transient effect on the transcriptome, with a clear response 3 h after treatment. Strikingly this effect lasted less than 24 h, whereas protection was observed throughout all time points tested. In contrast, 67 secretome proteins predominantly associated with cell-wall processes and defense changed in abundance at 48 h after treatment. Transcripts associated with defense, wounding, and oxidative stress constituted the core of the phosphite response. We also observed changes in primary metabolism and cell wall-related processes. These changes were shown not to be due to phosphate depletion or acidification caused by phosphite treatment. Of the phosphite-regulated transcripts 40% also changed with beta-aminobutyric acid (BABA) as an elicitor, while the defence gene PR1 was only up-regulated by BABA. Although phosphite was shown to be distributed in planta to parts not directly exposed to phosphite, no protection in leaves without direct foliar application was observed. Furthermore, the analysis of transgenic potato lines indicated that the phosphite-mediated resistance was independent of the plant hormones salicylic and jasmonic acid. CONCLUSIONS: Our study suggests that a rapid phosphite-triggered response is important to confer long-lasting resistance against P. infestans and gives molecular understanding of its successful field applications. PMID- 25270763 TI - Developing a critical care bowel management assessment tool to manage faecal incontinence. AB - BACKGROUND: Critical care patients with faecal incontinence are at high risk of developing moisture lesions, pressure ulcers and secondary infection. AIMS: The aims of this quality improvement programme were to identify the level of harm caused by faecal incontinence in critical care, and to review current critical care nursing practice on the use of bowel management systems, with the intent to implement changes to prevent delayed insertion. THE IMPROVEMENT PROGRAMME: A four step approach was used to guide the improvement programme. A total of seven case studies across three critical care units were reviewed and information was collected on stool type and frequency, duration of diarrhoea and skin integrity prior to bowel management system insertion. DISCUSSION: Critical care nurses may not always use a consistent approach to the assessment of patients at risk of moisture or pressure damage due to faecal incontinence. Lack of knowledge about the maintenance of bowel management systems was viewed as a likely reason for the inconsistent approach. A Critical Care Bowel Management Assessment Tool was created, to contribute towards a more standardised approach to bowel assessment and management. CONCLUSIONS: Inadequate assessment and management of faecal incontinence may have implications for critically ill patients. Further evaluation is required in order to demonstrate over time whether the changes made, as a result of this quality improvement programme, have led to sustainable improvement. PMID- 25270762 TI - HTLV-1 proviral integration sites differ between asymptomatic carriers and patients with HAM/TSP. AB - BACKGROUND: HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients. Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and HAM/TSP patients, and between individuals with strong or weak HBZ presentation. METHODS: We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA class I alleles predicted to bind HBZ peptides were classified 'strong' HBZ binders; the remainder were classified 'weak binders'. RESULTS: The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak HBZ binders. CONCLUSION: Clonal abundance is correlated with integration in a transcriptionally active genomic region, and these regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who can present HBZ peptides or those who remain asymptomatic. PMID- 25270764 TI - Ceftriaxone modulates uptake activity of glial glutamate transporter-1 against global brain ischemia in rats. AB - Ceftriaxone(Cef) selectively increases the expression of glial glutamate transporter-1 (GLT-1), which was thought to be neuroprotective in some circumstances. However, the effect of Cef on glutamate uptake of GLT-1 was mostly assayed using in vitro studies such as primary neuron/astrocyte cultures or brain slices. In addition, the effect of Cef on neurons in different ischemic models was still discrepant. Therefore, this study was undertaken to observe the effect of Cef on neurons in global brain ischemia in rats, and especially to provide direct evidence of the up-regulation of GLT-1 uptake for glutamate contributing to the neuronal protection of Cef against brain ischemia. Neuropathological evaluation indicated that administration of Cef, especially pre-treatment protocols, significantly prevented delayed neuronal death in hippocampal CA1 subregion normally induced by global brain ischemia. Simultaneously, pre administration of Cef significantly up-regulated the expression of GLT-1. Particularly, GLT-1 uptake assay with (3) H-glutamate in living cells from adult rats showed that up-regulation in glutamate uptake accompanied up-regulated GLT-1 expression. Inhibition of GLT-1 by antisense oligodeoxynucleotides or dihydrokainate significantly inhibited the Cef-induced up-regulation in GLT-1 uptake and the neuroprotective effect against global ischemia. Thus, we may conclude that Cef protects neurons against global brain ischemia via up regulation of the expression and glutamate uptake of GLT-1. Glutamate uptake by glial glutamate transporter-1 (GLT-1) is the principal way to regulate extracellular glutamate homeostasis in central nervous system. Over-accumulation of glutamate results in excitotoxicity and injures neurons after cerebral ischemia. Ceftriaxone up-regulates GLT-1 expression and uptake of glutamate, diminishes the excitotoxicity of glutamate and then protects neurons against global brain ischemia. PMID- 25270765 TI - Atopic diathesis in hypohidrotic/anhidrotic ectodermal dysplasia. AB - Recently, patients with hypohidrotic/anhidrotic ectodermal dysplasia (H/AED) have been reported to have a higher prevalence of symptoms suggestive of atopic disorders than the general population. To better understand atopic diathesis in H/AED, 6 cases of clinically or genetically diagnosed H/AED were examined. The following criteria were evaluated with patient consent: sweating, blood test results, histopathology and filaggrin staining. Five of 6 H/AED cases displayed atopic dermatitis-like manifestations, and 3 of these 5 cases experienced periorbital lesions. H/AED patients tended to present with atopic dermatitis-like eruptions with characteristics potentially indicative of periorbital lesions. Atopic diathesis in H/AED appeared not to be associated with filaggrin. We could speculate that hypohidrosis or anhidrosis itself might impair skin barrier function and contribute to atopic diathesis. PMID- 25270766 TI - Comment on: 'effect of otitis media with effusion and its clinical intervention on the development of mastoid in children'. PMID- 25270767 TI - Targeting autophagy in neurodegenerative diseases. AB - The most prevalent neurodegenerative disorders involve protein misfolding and the aggregation of specific proteins. Autophagy is becoming an attractive target to treat neurodegenerative disorders through the selective degradation of abnormally folded proteins by the lysosomal pathway. However, accumulating evidence indicates that autophagy impairment at different regulatory steps may contribute to the neurodegenerative process. Thus, a complex scenario is emerging where autophagy may play a dual role in neurodegenerative diseases by causing the downstream effect of promoting the degradation of misfolded proteins and an upstream effect where its deregulation perturbs global proteostasis, contributing to disease progression. Challenges in the future development of therapeutic strategies to target the autophagy pathway are discussed. PMID- 25270768 TI - Oxytocin and analgesia: future trends. PMID- 25270769 TI - How can we measure bladder volumes in women with advanced pelvic organ prolapse? AB - OBJECTIVES: To compare bladder volumes determined by three different formulae using measurements obtained from two-dimensional translabial ultrasound (2D-US), with true bladder volumes, in women with advanced pelvic organ prolapse (POP). METHODS: This was a prospective observational multicenter study of consecutive women on the waiting list for prolapse surgery in 24 gynecology departments. All women had a symptomatic genital prolapse Stage 2 or higher according to the Pelvic Organ Prolapse Quantification System (POP-Q). Bladder volumes were calculated before and after spontaneous voiding by 2D-US, and true bladder volumes were determined by micturition and catheterization. Volumes determined by US were calculated using three formulae (Haylen, Dietz and Dicuio). Correlation was calculated between the volume determined by US measurement before micturition and the true volume, and also between the volume determined by US measurements after micturition and the true volume. Correlations (Spearman's rho) and concordance (intraclass correlation coefficient (ICC)) were estimated for each of the three formulae considered. RESULTS: One-hundred and eighty-six women with POP were included in the study. A total of 349 bladder volumes (186 before micturition and 163 after micturition) were obtained. Good correlation (rho, 0.818-0.849) and concordance (ICC, 0.827-0.898) were found between total measured volume (volume of spontaneous bladder voiding + volume obtained from catheterization) and the volume determined by US using the three different formulae, as well as between the post-void residual volume measured by catheterization and the post-void volume calculated by US using the three formulae (rho, 0.739-0.777; ICC, 0.840-0.877). CONCLUSIONS: Bladder volumes in women with advanced POP can be measured easily by 2D-US. Volumes determined using the three different formulae show good correlations and concordance with true bladder volume. PMID- 25270770 TI - Decision making in prenatal screening: money matters. AB - The aim of this study is to determine the influence of withdrawal of reimbursement on the uptake of the first-trimester combined test. Until January 2007 the combined test was offered to all pregnant women in a designated geographical area as a pilot study before the introduction of the national screening program in the Netherlands, to test the logistic procedures. In January 2007 the insurance companies suddenly stopped paying for the combined test with respect to women aged <=35 years by decision of the government. In 2006 the combined test was performed in 4616 women compared with 3459 who had the combined test in 2007, a reduction of 25% (95% CI 23.8-26.3%, p < 0.001). A decline was observed in the uptake of the combined test in women aged <=35 years (p < 0.001) as opposed to an increase in uptake in women aged >=36 years (p < 0.001). The financial impact on the uptake of the first-trimester combined test should not be underestimated. PMID- 25270771 TI - Clinical verification of the formula of Bennett et al. (1994) of determining the size of retinal features by fundus photography. AB - PURPOSE: To clinically verify the formula of Bennett et al. (Graefes Arch Clin Exp 1994; 232: 361) of determining the size of retinal features and to study the previously unknown conversion factor of Topcon fundus camera. METHODS: Fundus photographs were taken from 17 healthy volunteers with Topcon and telecentric Zeiss fundus cameras. The macula-disc centre distance was measured from Zeiss fundus photographs in metric units using the formula of Bennett et al. (Graefes Arch Clin Exp 1994; 232: 361). The conversion factor of Topcon fundus camera and the macula-disc centre distance in degrees were calculated. The latter was further used to calculate the theoretical location of the blind spot. The results of 12 participants were compared to the location of their physiological blind spot determined with visual field examination by octopus custom-made blind spot visual field program. RESULTS: The theoretical location of the blind spot correlated well with the corresponding location of the physiological blind spot in the visual field. The magnification of Topcon fundus camera was close to a constant, and thus, the previously unknown conversion factor could be determined. CONCLUSIONS: The location of the physiological blind spot in the visual field can be derived from fundus photographs using the formula of Bennett et al. (Graefes Arch Clin Exp 1994; 232: 361), proving it to give a close approximation of the size of retinal features. Furthermore, the conversion factor of Topcon fundus camera was close to a constant, and thus, it can be considered to function close to telecentric design. PMID- 25270772 TI - Nrf2, the master redox switch: the Achilles' heel of ovarian cancer? AB - Ovarian cancer is the most lethal gynecological tumor type in the world due to late stage detection, and resistance to chemotherapy. Therefore, alternative additional therapies are required. The etiology of ovarian cancer remains largely unknown, but risk factors point toward an important role for oxidative stress. Both healthy and tumor cells can cope with oxidative stress by activating the transcription factor Nrf2 (also known as Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most ovarian cancers, aberrant activation of Nrf2 is observed, which is often associated with a copy number loss within the Nrf2-inhibitory complex KEAP1-CUL3-RBX1. A key role for Nrf2 in ovarian carcinogenesis has been validated by siRNA studies. However, to exploit the Nrf2 pathway for therapeutic interventions, potential side-effects should be minimized. In this review, we explore ovarian cancer specific factors with links to aberrant activity of Nrf2, to be exploited in future combination strategies, synergistic with direct Nrf2 inhibitory drugs. Particularly, we propose to stratify patients based on common ovarian cancer mutations (KRAS, BRAF, ERBB2, BRCA1 and its link with estradiol, TP53) for future NRF2 targeting strategies. PMID- 25270773 TI - Elementary depinning processes of magnetic domain walls under fields and currents. AB - The probability laws associated to domain wall depinning under fields and currents have been studied in NiFe and FePt nanowires. Three basic domain wall depinning processes, associated to different potential landscapes, are found to appear identically in those systems with very different anisotropies. We show that these processes constitute the building blocks of any complex depinning mechanism. A Markovian analysis is proposed, that provides a unified picture of the depinning mechanism and an insight into the pinning potential landscape. PMID- 25270775 TI - Comparison of the effects of active, passive and mixed warm ups on swimming performance. AB - AIM: The aim of this paper was to compare the effects of an active (AWU), passive (PWU) and mixed warm up (MWU) on swimming performance. METHODS: Eight male competitive swimmers completed each type of WU and, following a 20-minute rest, performed a maximum 100m test on their specialised stroke. The order of WUs was randomized and there was a 7-day period between subsequent testing sessions. The time taken to complete the 100m trial was the performance measure. The rating of perceived exertion (RPE) was measured immediately post WU, while heart rate (HR) was measured pre and post WU and pre and post the maximum swim. During the 20 minute rest, the swimmers' psychological state was assessed with the CSAI-2 questionnaire. RESULTS: Post WU HR and RPE had the lowest values following the AWU and the highest values following the PWU (P<0.01). No other significant differences were found in any variables. Pre performance HR increased significantly relative to pre WU HR for all conditions (P<=0.01). Swimmers had relatively low levels of anxiety and modest to high levels of self confidence for all conditions. CONCLUSIONS: No WU appeared to be superior to the others with respect to swimming performance. The MWU produced nearly identical values to the AWU for most variables, and was therefore found to be an appropriate alternative WU type that swimmers may use before competition. The PWU also seemed to be appropriate, but the somewhat worse performance and lower cognitive anxiety and self confidence scores recorded, albeit non-significant, suggested that more swimmers and distances are tested before any firm conclusions regarding its effectiveness can be drawn. PMID- 25270774 TI - OBLA is a better predictor of performance than Dmax in long and middle-distance well-trained runners. AB - AIM: The main purpose of this study was to investigate if the lactate threshold estimated by the maximal deviation method (LTDmax) and the onset of blood lactate accumulation speed (LTOBLA) are good correlates of middle- and long-distance running performance in well-trained endurance runners. METHODS: Eleven long- and eleven middle-distance runners participated in this study. All participants completed a maximal incremental running test on a treadmill to determine maximal physiological variables and velocities corresponding to LTDmax and LTOBLA (4 mmol.L-1 of lactate concentration). The relationships between LTDmax, LTOBLA and the best 10-km (S10km) and 3-km (S3km) race pace were analyzed in the long- and middle distance runners, respectively. RESULTS: The velocities for LTDmax and LTOBLA were 17.0+/-0.7 km.h-1 and 17.5+/-1.3 km.h-1 for the long-distance runners and 16.9+/-1.1 km.h-1 and 17.4+/-1.3 km.h-1 for the middle-distance runners. A positive linear relationship was found between LTDmax and S10km (r=0.873, P<0.001), as well as between LTOBLA and S10km (r=0.919, P<0.001) in the long distance runners. Similarly, LTDmax and LTOBLA were significantly correlated with S3km in the middle-distance runners (r=0.825, P<0.01 and r=0.849, P<0.001, respectively). CONCLUSION: These results indicate that both LTOBLA and LTDmax are highly associated to running performance according to S10km and S3km in well trained long- and middle-distance runners. Thus, we conclude that competitive middle- and long-distance athletes may find these measures useful to monitor running performance within 3 weeks of laboratory testing. PMID- 25270776 TI - Simulated moderate hypoxia reduces intermittent sprint performance in games players. AB - BACKGROUND: Exercise at altitude places additional physiological stress on the individual in comparison with sea-level performance. This study examines the effect of a moderate hypoxic environment (FiO2=~17%) on intermittent sprint exercise performance. METHODS: Nine male games players completed two consecutive sets of a 40 minute cycling intermittent sprint protocol (CISP*2) in a hypoxic (HYP; FiO2=~17%) and normoxic (NORM; FiO2=~21%) environment. During each sprint peak power output (PPO; the highest power during each 5 s sprint), mean power output (MPO; the average power during the 3 s sprint) were measured and total work done (WD; force applied from the highest 3 s period of power output) was calculated. Physiological responses were recorded throughout the testing procedure. RESULTS: Reductions were found in PPO (944+/-155 vs. 983+/-167 W), MPO (900+/-176 vs. 853+/-177 W) and WD (102+/-20 vs. 108+/-20 kJ) during the CISP*2 (P<0.05) at HYP compared to NORM. Reductions in PPO, MPO and WD were also found between the 1st half and 2nd half CISP (P<0.05) and there was a greater decline from the 1st half CISP to the 2nd half CISP in PPO, MPO and WD at HYP. Heart rate was higher and peripheral arterial oxygen saturation lower during HYP compared to NORM (P<0.05). CONCLUSION: Moderate hypoxia significantly reduced PPO (~4%), MPO (~5%) and WD (~5%) compared to normoxia. The results suggest athletes will be at a disadvantage when performing intermittent sprinting at moderate altitude. PMID- 25270777 TI - Muscle activity of the erector spinae during Pilates isometric exercises on and off Swiss Ball. AB - BACKGROUND: The purpose of this study was to investigate the muscle activity of the Erector spinae (ES) during Pilates isometric exercises on and off Swiss ball. METHODS: Fifteen women (22.9+/-2.1years, 171.7+/-4.7 cm, 65.7+/-5.3 kg and 11.2+/ 3.2% of body fat) with previous Pilates experience (1+/-0.9 years) participated as subjects in this study. In the first test session, the anthropometric data and maximal voluntary contraction (MVC) was measured. In the second test session, three isometric exercises were conducted on and off the Swiss ball: back extension (BE), back extension with elbows flexed (BTF) and back extension with elbows extended (BTE). During all exercises, average integrated electromyography (IEMG) from ES muscle was collected and analyzed. A one-way ANOVA with repeated measures followed by Bonferroni post hoc was adopted to compare the muscle activity (P<0.05). RESULTS: ES activity was higher for BT, BTF and BTE on stable surface than on Swiss ball, respectively. Significant differences were observed for the ES activity during BTE exercise when compared to BTF and BT on and off Swiss ball, respectively. CONCLUSION: The Swiss ball may not provide a potential effect on ES activity during Pilates isometric exercises with similar posture when compared to stable surfaces. Therefore, the combination of BT, BTF and BTE exercises may be an interesting alternative to provide progressive increases in the ES activity. PMID- 25270778 TI - Influence of a sport-specific training background on vertical jumping and throwing performance in young female basketball and volleyball players. AB - AIM: The purpose of this study was to evaluate the influence of 3 years of sport specific training background (SSTB) on vertical jumping and throwing performance in young female basketball and volleyball players. METHODS: Thirty-one healthy adolescent girls, of which 11 age-matched control subjects [C], 10 basketballers (BP) and 10 volleyballers (VP) participated to the study. The throwing performance was assessed by seated backward overhead ball throw (SBOMBT) and seated chest pass throw (SCPT) using a 3-kg rubber medicine ball. Instead, the vertical jumping performance was evaluated by squat jump (SJ) and countermovement jump with (CMJ-AS) and without arm swing (CMJ) using Optojump system (Microgate srl, Italy). RESULTS: During SJ and CMJ with and without arm swing VP group showed a higher vertical jump performance than BP and C ones. In particular we showed that VP exhibited a higher flight time and jump height than C (P<0.05) in SJ, CMJ and CMJ-AS tests. Players showed higher performances than C in SCPT and SBOMBT. However, we found only a significant difference (P<0.05) in the comparison between BP and C during SCPT. Moreover, we found significant correlations between SBOBMT performances and CMJ-AS jump heights in C (r= 0.60; p= 0.02) and VP (r= 0.81; p<0.01) groups compared to BP one (r= -0.47; p= 0.08). CONCLUSION: These data suggest that 3 years of SSTB might be able to promote significant neuromuscular adaptations in volleyball and basketball athletes' maximal power compared to age-matched control subjects. PMID- 25270779 TI - Do physical fitness measures influence internal training load responses in high level futsal players? AB - BACKGROUND: The aim of the present study was to verify whether aerobic fitness and ability to perform repeated high-intensity efforts influence the internal training load (ITL), which consists of the actual stress imposed in the athletes' organisms, in professional futsal players. METHODS: Twelve high-level futsal players (age: 26.3+/-4.9 years, body mass: 73.5+/-7.5 kg) participated in the study. The investigated athletes took part in a 5-week pre-season period. The ITL was quantified by means of the session-Rating of Perceived Exertion method. The athletes performed the Yo-yo Intermittent Recovery Test level 2 (YYIR2) in order to assess the ability to perform repeated high-intensity actions, and the multistage shuttle-run test (MSRT) in order to evaluate aerobic fitness, before (T0) and after (T1) the pre-season period. Maximal oxygen uptake (VO2max.), oxygen uptake at Respiratory compensation point (VO2-RCP) and maximal aerobic speed (MAS) obtained in MSRT were retained for analyses. RESULTS: The results from Pearson's correlation test showed significant and a very large correlation between ITL and YYIR2 performance (r=-0.75). Moreover, a significant and large correlation between ITL and VO2max. (r=-0.62), ITL and MAS (r=-0.67), and ITL and VO2-RCP (r=-0.58) were also observed. CONCLUSION: It can be concluded that aerobic fitness and ability to perform repeated high-intensity actions may influence ITL responses in professional futsal players. PMID- 25270780 TI - The acute effects of stretching on presynaptic inhibition and peak power. AB - AIM: Stretching before and after physical activity is a controversial aspect of exercise preparation and recovery. Minimal research has been conducted regarding the neuromuscular effects of stretching including changes in the H-reflex, motor neuron excitability and presynaptic inhibition of muscle. The aim of this study was to examine the effects of static and dynamic stretching on the neuromuscular aspects and power output of the M. Soleus. METHODS: Twenty-one healthy college students (13 F, 8 M; 19.81+/-0.75 y; 171+/-8.40 cm; 70.71+/-11.32 kg) participated. On separate days, participants completed either static and dynamic stretching protocols. A double electrical stimulus, assessed via electromyography, was used to elicit the H-reflex and M-wave before and after each stretching protocol. Participants performed pre- and post-stretching countermovement jumps to produce power measurements. RESULTS: After a single bout of dynamic stretching, presynaptic inhibition significantly decreased (P<0.001), whereas the static stretching produced no change (P=0.296). There was a slightly significant increase in power post-static stretching (369.03+/-808.3 W, P=0.049). CONCLUSION: While dynamic stretching is beneficial in decreasing presynaptic inhibition, it did not lead to the hypothesized increase in power output. This study is the first to compare neurological mechanisms and power output, giving a comprehensive view of how stretching affects muscle. PMID- 25270781 TI - Playing level and playing position differences of anthropometric and physical fitness characteristics in elite junior handball players. AB - AIM: The purpose of the study was to identify the playing level (Under 16: U16, Under 18: U18 and Under 20: U20) and the playing position (Goalkeepers, Backs, Wings, Pivots, Centers) differences of elite junior handball players expressed in the anthropometric and physical fitness characteristics. METHODS: The anthropometric characteristics of body height, arm span, hand length, hand width, body mass, adipose tissue percentage, somatotype components and the physical fitness characteristics of ball throwing velocity, sprinting time, standing long jump, aerobic capacity, lower back and hamstring flexibility were measured in a total of sixty (60) handball players all members of the Greek Junior National Teams. RESULTS: There were significant (P<=0.05) differences among playing levels regarding hand length, hand width, ball velocity (U18>U16), body mass, ball velocity and standing long jump (U20>U16). Significant differences among playing positions (P<=0.05) were found for body height (Backs>Wings and Centres, Pivots>Wings), arm span (Goalkeepers and Backs>Wings), body mass (Pivots>Wings and Centres) and 5 m sprint time (Pivots>Centres). CONCLUSION: The anthropometric differences among playing positions may indicate the advantageous characteristics that the respective position demands, whereas the absence of playing position differences in physical fitness characteristics may indicate training specificity issues that must be addressed cautiously. The anthropometric and physical fitness differences between playing levels may be attributed to developmental maturation and the progressive increase of training intensity. PMID- 25270782 TI - Effect of a sports drink based on highly-branched cyclic dextrin on cytokine responses to exhaustive endurance exercise. AB - BACKGROUND: Aim of the present study was to compare the effects of highly branched cyclic dextrin (HBCD) drink with a glucose-based control drink on immunoendocrine responses to endurance exercise. METHODS: Using a randomized, double-blind placebo-controlled cross-over design, seven male triathletes participated in two duathlon races separated by one month, consisting of 5 km of running, 40 km of cycling and 5 km of running. In the first race, four athletes consumed the HBCD-based drink and three athletes consumed the glucose-based drink. In the second race, three athletes consumed the HBCD-based drink and four athletes consumed the glucose-based drink. We collected blood and urine samples before and after the races to analyze leukocyte count and concentrations of hormones and cytokines. RESULTS: Lymphocyte and neutrophil counts increased significantly after exercise in both trials (P<0.05), but were not significantly different between the trials. Plasma noradrenalin concentration increased significantly (P<0.05) during exercise in the glucose trial, but not in the HBCD trial. Plasma concentrations of interleukin (IL)-8 and IL-10 increased significantly during exercise in both trials (P<0.05) but were not significantly different between the trials. Post-race urinary IL-8, IL-10 and IL-12p40 concentrations were significantly lower in the HBCD trial compared with the glucose trial (P<0.05), although the plasma concentrations of these cytokines were not significantly different between both trials. CONCLUSION: These results suggest that the HBCD-based drink may attenuate the stress hormone response, and reduce the urinary cytokine levels following exhaustive exercise. PMID- 25270783 TI - Cross-cultural adaptation and reliability of the Italian version of the Foot Function Index (FFI-I) for patients with plantar fasciitis. AB - AIM: The aim of this paper was to translate and cross-culturally adapt the FFI to the Italian language, and to assess the reliability of the Italian version of the FFI (FFI-I) for plantar fasciitis. METHODS: Fifty symptomatic patients affected by plantar fasciitis completed the FFI-I scale twice, at interval of one week. The translation of the FFI was performed according to international standards for translation of questionnaires. Test-retest reliability was evaluated using intraclass correlation coefficient (ICC). Internal consistency was measured by Cronbach alpha coefficient. Ceiling and floor effects were assessed. RESULTS: The process resulted in an intelligible version of the questionnaire. The reliability of the FFI-I was adequate, with an ICC ranging from 0.86 to 0.98 for test-retest reliability. The FFI-I showed an excellent internal consistency, ranging from 0.93 to 0.99 for all subscales. Three items involving disability and four items involving activities restrictions had highest proportion of floor score. CONCLUSION: The FFI-I is a reliable and valid instrument to assess clinical severity in patients with plantar fasciitis and it is suitable for daily practice. We suggest evaluating the total FFI-I score along with the distinct scores of the three subscales of the FFI-I in order to interpret more correctly minor changes in patient status during repetitive outcome assessments. PMID- 25270784 TI - Muscle damage and adaptation after the second bout of eccentric exercise of the knee extensors. AB - This study examined the muscles ability to adapt to eccentric exercise by the changes in serum myoglobin (Mb), creatine kinase (CK) activity and muscle soreness. The study involved 54 healthy young men from the 23+/- 2yr age group. These were distributed as subjects for three types of experiments with 18 men in each. Subjects performed 300 maximal eccentric exercises. In experiment I, after performing the first bout of exercise, they were split into three subgroups to perform the second bout after a period of 4, 6, and 8 weeks (WK), respectively. In experiment II, performed the second exercise after a period of 2, 3, and 5 wk, respectively. In experiment III, they performed four exercise bouts spaced 1 wk apart. in experiment II a significant (P<0.05) decrease in muscle soreness, serum Mb and CK was found on exercise bout 2. In experiment III, serum CK, Mb and muscle soreness responses were highest following bout 1. It was concluded that performance of a single exercise bout had a prophylactic effect on muscle soreness and serum protein responses that lasts approximately 2 wk, with the greatest adaptation occurring after one bout. PMID- 25270785 TI - Effect of eccentric contractions of elbow flexor on bone formation and resorption markers. AB - AIM: This study aimed to investigate the effects of eccentric contractions (ECs) of the biceps brachii muscle on bone metabolism markers. METHODS: Eight untrained subjects (20.0+/-0.5 years) performed 5 sets of 6 maximal ECs of the elbow flexors with a 2-min rest interval between each set. Blood samples were collected at 6 time points: before (Pre) ECs, immediately after (Post) ECs, and two hours (2 hours), 1 (day 1), 3 (days 3), and 5 days (days 5) after ECs. We measured the levels of the bone formation marker osteocalcin (OC) and the resorption marker tartrate-resistant acid phosphatase 5b (TRACP-5b). In addition, we measured the isometric tetanic torque and the levels of myoglobin (Mb), creatine kinase (CK), blood lactate, and insulin-like growth factor-1 (IGF-1). RESULTS: The results showed 1) CK and Mb levels increased significantly by days 3 and 5 (P<0.05); 2) OC levels significantly decreased in Post and 2 hours (P<0.01) and TRACP-5b levels significantly increased in Post (P<0.01); 3) OC positively correlated with the total work output in Post, 2 hours, and days 5 (Post: r=0.79, P<0.05; 2 hours: r=0.82, P<0.01; days 5: r=0.79, P<0.05); and 4) TRACP-5b levels positively correlated with IGF-1 levels (r=0.69, P<0.01). CONCLUSION: We conclude that a single bout of ECs of the biceps has a negative effect on bone metabolism in the acute phase. PMID- 25270786 TI - Modifications of biochemical parameters related to protein metabolism and renal function in male soccer players after a match. AB - AIM: The impact of a soccer match on parameters related to protein catabolism and renal function was evaluated in male players. METHODS: Blood was collected before and immediately after a 90 minutes soccer match from 19 athletes of two first division teams in Brazil. Red blood cells (RBC), hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC), ammonia, uric acid, urea and creatinine were analyzed. The modification of plasma volume was calculated, and biochemical values were corrected for this change. Urea/creatinine ratio and equations to estimate the glomerular filtration rate (eGFR) were used to assess kidney function. RESULTS: Plasma volume decreased from pre- to post-match. Post match values higher than the pre-match ones were observed for RBC, Hb and Ht, as a consequence of plasma volume decrease. An increase in ammonia and creatinine concentrations post-match in comparison with pre-match values was registered, without changes in uric acid and urea levels. A reduction in urea/creatinine ratio and in eGFR was observed post-match, suggesting a decrease of renal function. CONCLUSION: A soccer match induced alterations in parameters linked to renal function and protein metabolism in male athletes. Particular attention should be paid in the monitoring of the ammonia concentration as an indicator of metabolic activity and energy requirement during prolonged exercise. PMID- 25270787 TI - Effects of vitamin C and exercise on lipid profile, platelet and erythrocyte indices in young soccer players. AB - AIM: Exercise may increase production of reactive oxygen species (ROS) enhancing oxidative stress. Antioxidants can efficiently scavenge ROS before they initiate oxidative damage of biomolecules such as enzymes, nucleic acids, lipids and lipoproteins in the body. Vitamin C, an important antioxidant, may affect oxidative stress in living organism. Therefore, this study was carried out to investigate the effects of exercise and vitamin C on thiobarbituric acid-reactive substance (TBARS), lipid profile, erythrocyte and platelet indices in young soccer players. METHODS: This investigation was carried out on twenty two male volunteer players in three groups. The first group was examined as a control. The second group was only exposed to exercise. The third group was exposed to exercise plus vitamin C (500 mg/day) administered per oral. The players were 23.50+/-0.59 year-old, 67.66+/-1.52 kg body weight and 1.74+/-0.03 m height. Blood samples were collected in vacutainer tubes for analysis of biochemical and hematological parameters. RESULTS: While the levels of high density lipoprotein cholesterol (HDL-C) were significantly increased (P<0.05) with only exercise, the cholesterol and low density lipoprotein-cholesterol (LDL-C) were decreased (P<0.05 to P<0.01) with exercise and exercise plus vitamin C treatment. While TBARS levels were increased (P<0.05) with exercise training, it was decreased (P<0.05) with exercise plus vitamin C treatment. The platelet counts (PLT), mean platelet volume (MPV), plateletcrit (PCT) and red blood cell distribution width (RDW) were significantly decreased (P<0.05) with exercise plus vitamin C. There were significantly correlations (P<0.05 to P<0.01) between lipid values and erythrocyte and platelet indices. CONCLUSION: In light of these results, exercise may play a role in decreasing of LDL-C and in increasing of HDL-C. In addition, exercise plus vitamin C may diminish TBARS-levels and may affect the values of PLT, MPV, PCT and RDW in young soccer players. PMID- 25270788 TI - Physical activity during pregnancy and offspring characteristics at 8-10 years. AB - AIM: We evaluated relationships between mothers' physical activity (PA) during pregnancy and child blood pressure, aerobic fitness, and birth weight. METHODS: Anthropometrics, systolic (SBP) and diastolic (DBP) blood pressures, and aerobic fitness were measured on 20 mother/child pairs, 8-10 years postpartum. Pregnancy PA (kJ/kg.wk) was calculated from historical recall. Women were classified as meeting, or not meeting ACOG PA recommendations. RESULTS: Twelve women met ACOG recommendations, and their children had significantly lower birth weights (3.51+/ 0.45 kg) than the more sedentary women (4.05+/-0.67 kg). Third trimester maternal PA was inversely related to child SBP (rs=-0.46, P=0.04) but not aerobic fitness. Birth weight was inversely related to SBP (rs=-0.75, P=0.03) if mothers did not meet PA recommendations. CONCLUSION: Results from our preliminary study suggest that maternal PA is associated with an alteration in the relationship between birth weight and SBP. PMID- 25270789 TI - Cardiac biomarkers response to high-intensity interval exercise in collegiate basketball players. PMID- 25270790 TI - Bacterial community structure of a lab-scale anammox membrane bioreactor. AB - Autotrophic nitrogen removal technologies have proliferated through the last decade. Among these, a promising one is the membrane bioreactor (MBR) Anammox, which can achieve very high solids retention time and therefore sets a proper environment for the cultivation of anammox bacteria. In this sense, the MBR Anammox is an efficient technology for the treatment of effluents with low organic carbon and high ammonium concentrations once it has been treated under partial nitrification systems. A lab-scale MBR Anammox bioreactor has been built at the Technological University of Delft, The Netherlands and has been proven for efficient nitrogen removal and efficient cultivation of anammox bacteria. In this study, next-generation sequencing techniques have been used for the investigation of the bacterial communities of this MBR Anammox for the first time ever. A strong domination of Candidatus Brocadia bacterium and also the presence of a myriad of other microorganisms that have adapted to this environment were detected, suggesting that the MBR Anammox bioreactor might have a more complex microbial ecosystem that it has been thought. Among these, nitrate-reducing heterotrophs and primary producers, among others, were identified. Definition of the ecological roles of the OTUs identified through metagenomic analysis was discussed. PMID- 25270791 TI - Inonotus obliquus-derived polysaccharide inhibits the migration and invasion of human non-small cell lung carcinoma cells via suppression of MMP-2 and MMP-9. AB - Polysaccharides isolated from the fruiting body of Inonotus obliquus (PFIO) are known to possess various pharmacological properties including antitumor activity. However, the anti-metastatic effect and its underlying mechanistic signaling pathway involved these polysaccharides in human non-small cell lung carcinoma remain unknown. The present study therefore aimed to determine the anti metastatic potential and signaling pathways of PFIO in the highly metastatic A549 cells. We found that PFIO suppressed the migration and invasive ability of A549 cells while decreasing the expression levels and activity of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, PFIO decreased the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) as well as the expression level of COX-2, and inhibited the nuclear translocation of nuclear factor kappaB (NF-kappaB) in A549 cells. These results suggested that PFIO could suppress the invasion and migration of human lung carcinoma by reducing the expression levels and activity of MMP-2 and MMP-9 via suppression of MAPKs, PI3K/AKT, and NF-kappaB signaling pathways. PMID- 25270792 TI - Vascularized composite autograft for adult laryngotracheal stenosis and reconstruction. AB - BACKGROUND: Adult laryngotracheal reconstruction for airway stenosis and after oncologic ablation can be extremely challenging. METHODS: Patients with the above conditions not amenable to or refractory to conventional treatments were offered specialized reconstruction by wrapping a contoured costal cartilage graft with a vascularized microvascular carrier. All constructs were lined with buccal mucosa grafts. Decannulation rates, quality of life questionnaires, and pulmonary function tests were performed and analyzed. RESULTS: Eleven patients underwent this procedure, 6 for stenosis and 5 for laryngotracheal oncologic defects. Ten patients were successfully decannulated after the procedure (91%). Median time to decannulation was 4 months. At mean follow-up of 76 months, all evaluated patients had a serviceable voice, tolerated a normal diet, and had minimal subjective shortness of breath. CONCLUSION: Vascularized composite autograft can be successfully used to treat severe subglottic stenosis or reconstruct large laryngotracheal defects not amenable to or refractory to conventional treatments. PMID- 25270793 TI - Aquaporin-9 is expressed in rat Sertoli cells and interacts with the cystic fibrosis transmembrane conductance regulator. AB - Men with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are usually subfertile/infertile. Besides playing a role in Cl( )/HCO3(-) transport, it has been proposed that CFTR interacts with water membrane transport systems, particularly aquaporins, to control seminiferous tubular secretion, which is regulated by the somatic Sertoli cells (SCs). As aquaporin-9 (AQP9) is highly expressed throughout the male reproductive tract, we hypothesized that it is also present in rat SCs and that it physically interacts with CFTR. To test this hypothesis, primary cultures of rat SCs were established, and expression of CFTR and AQP9 was assessed by RT-polymerase chain reactions (mRNA) and Western blot analysis (protein). A coimmunoprecipitation assay was used to evaluate the physical interaction between CFTR and AQP9. Our results show that CFTR and AQP9 are expressed in rat SCs. We were also able to detect a molecular interaction between CFTR and AQP9 in rat SCs. This is the first report describing the presence of AQP9, and its interaction with CFTR, in rat SCs. Moreover, our results provide evidence that CFTR is involved in water homeostasis of the seminiferous tubular secretion. These mechanisms may open new insights on therapeutic targets to counteract subfertility/infertility in men with cystic fibrosis and mutations in the CFTR gene. PMID- 25270794 TI - Effectiveness of B vitamin supplementation following bariatric surgery: rapid increases of serum vitamin B12. AB - BACKGROUND: Few prospective studies have compared changes of nutrient intake while assessing effectiveness of thiamin, vitamin B12, and folate supplementation to prevent B vitamin deficiencies immediately following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Therefore, we determined the response to 3 months supplementation on maintaining blood B vitamin concentrations. METHODS: Women undergoing RYGB (n = 11) and SG (n = 11) consumed bariatric vitamin supplements (12 mg thiamin, 350 MUg vitamin B12, 800 MUg folic acid) daily for 3 months. Height, weight, body mass index, and blood vitamin concentrations were measured preoperatively and at 3 months. Wilcoxon signed-rank analyses compared body weight parameters, laboratory indices, and nutrient intake at baseline and 3 months. RESULTS: Supplementation for 3 months maintained blood thiamin, increased serum folate from 13.1 +/- 5.4 to 16.3 +/- 6.0 nmol/L (P = 0.049), and increased serum vitamin B12 concentrations from 498 +/- 150 to 736 +/- 340 pg/mL (P = 0.005). Dietary intake of thiamin and folate decreased in the combined surgical groups, while dietary intake of B12 was maintained. Bariatric B vitamin supplements provided multiple intakes of the Recommended Dietary Allowances (1090% thiamin, 14,583% vitamin B12, 200% folate). CONCLUSIONS: Although energy intake decreased 64%, B vitamin supplementation for 3 months resulted in a 48% increase of serum vitamin B12, a modest increase of serum folate, and no reduction of blood thiamin concentrations. Long-term effects of the rapid rise of serum B12 levels attributed to the high content of supplements warrant further investigation. PMID- 25270795 TI - [Detritic synovitis and rare skeletal diseases]. AB - Detritic synovitis represents a common finding in routine orthopedic pathology. Microscopically, the synovium displays cartilaginous and bony fragments in the synoviocyte layer or within the subsynovial soft tissues associated with resorptive changes. In the vast majority of cases, detritic synovitis is associated with conditions leading to the destruction of articular cartilage and subchondral bone, such as severe osteoarthritis, collapsed avascular necrosis, diabetes mellitus, Charcot arthropathy or non-union fractures. The objective of this article is to review the literature regarding the microscopic findings in ochronosis, rapidly destructive hip disease and apatite crystal depositions that can enable a confident diagnosis or a limited differential diagnosis of detritic synovitis. PMID- 25270796 TI - Clinical Endocrinology in the near future: a post-modern challenge. PMID- 25270797 TI - Give patients and relatives hope. AB - Holistic care can be difficult to achieve in emergency care settings and one aspect of such care that is often neglected involves meeting patients' spiritual needs. PMID- 25270798 TI - Hip database shows drop in number of deaths after fracture. AB - THE NUMBER of people with hip fracture who died within 30 days of being admitted to hospital fell by 300 between 2011/12 and 2012/13, according to a new report. PMID- 25270800 TI - Schools to store spare asthma inhalers for children who need them. AB - YOUNG PEOPLE at risk of asthma attacks will have access to emergency inhalers at school for the first time this month. PMID- 25270802 TI - NHS England issues alert and resource packs for managing sepsis. AB - THE GOVERNMENT has been criticised by MPs for its lack of urgency in preventing deaths from sepsis. An estimated 37,000 patients in England die of the condition every year because of failings such as delayed examination and inadequate record taking. PMID- 25270801 TI - Monitor to investigate trust for making patients wait too long. AB - HEALTH REGULATOR Monitor has launched an investigation into Yorkshire Teaching Hospital NHS Foundation Trust after finding that some patients had been waiting too long to be assessed for emergency care. The regulator believes that repeated failures to ensure patients were seen soon enough may indicate wider problems at the trust, which has failed to meet the quarterly national emergency department waiting time target five times in nearly two years. PMID- 25270804 TI - Call for extra funding to employ more alcohol health workers. AB - LIAISON NURSES need more financial support to tackle unhealthy drinking, according to researchers at Leeds Metropolitan University and the University of York. PMID- 25270803 TI - 'Exit block' affects half a million a year. AB - OVERCROWDING IN emergency departments (EDs) must be addressed urgently to ensure patients waiting to be admitted to wards are not put at risk, the College of Emergency Medicine (CEM) has warned. PMID- 25270805 TI - Urgent care staff to share patient data with police. AB - EMERGENCY DEPARTMENTS (EDs) in England will be expected to share with the police non-confidential information about attendances that involve violent crime, under a standard coming into force next year. PMID- 25270806 TI - 'Breakthrough' in reforms but little change to services. AB - EMERGENCY DEPARTMENTS (EDs) are being warned to brace themselves for a difficult winter. PMID- 25270807 TI - Clinical Evidence Made Easy Harris Michael , Taylor Gordon and Jackson Daniel Clinical Evidence Made Easy 224pp L18.50 Scion 9781907904202 1907904204 [Formula: see text]. AB - ALTHOUGH THE stated purpose of this book is to explain evidence-based practice to all healthcare professionals, it appears to be intended for medical staff only. PMID- 25270809 TI - Board's eye view - Just the job. AB - EMPLOYMENT OPPORTUNITIES for emergency nurse practitioners (ENPs) have never been better. Over the past few years, they have been sought and recruited by acute NHS trusts for emergency departments, community trusts managing minor injury and urgent care services, and ambulance trusts. PMID- 25270810 TI - Training in dementia care. AB - THE RISING number of people with dementia is making more and more demands on the country's healthcare budget, with the cost of caring for this patient group to the NHS in England, Wales and Northern Ireland being about L23 billion a year ( Alzheimer's Society 2012 ). PMID- 25270812 TI - Diary. AB - Our roundup of what's on. PMID- 25270811 TI - Janet Youd - The bigger picture. AB - One day recently, let's call it wobbly Wednesday, I was reminded of why emergency nurses must nurture their mental wellbeing. PMID- 25270813 TI - Noticeboard. AB - Courses, events, grants, and awards to progress your career. PMID- 25270815 TI - Traumatic brain injury. AB - THIS META-ANALYSIS compares randomised controlled trials of two approaches to the management of raised intracranial pressure (ICP) in traumatic brain injury: the use of mannitol versus that of hypertonic sodium. PMID- 25270814 TI - Thunderstorm asthma. AB - AN ASSOCIATION between asthma and thunderstorms based on retrospective data has been noted in several papers. This study, however, draws on almost-real-time, anonymised attendance data from 35 emergency departments (EDs) in the UK, and lightning-strike plots from the Met Office. PMID- 25270816 TI - Bedside monitoring. AB - SEMI-AUTOMATIC BEDSIDE monitors are increasingly being used in acute and critical care areas to record patients' vital signs and alert clinical staff to potentially life-threatening situations. PMID- 25270817 TI - Making better decisions during triage. AB - Interactions between nurses and patients during triage are crucial if the urgency of patient need is to be assessed accurately. This article reports on the results of a study of emergency nurses' perspectives and experience of triage in the United States. Findings indicate that triage encounters are multifaceted and that emergency nurses require experience as well as knowledge to make good decisions. Two themes emerged from the study's findings: the need for nurses to connect with patients and the ability of nurses to 'read between the lines'. Nurses who connect with patients can take more detailed histories, while those who can read between the lines can identify the salient points and subtle signs from patients. Nurses with these skills can make better triage decisions. PMID- 25270818 TI - Managing acute shoulder injuries in the emergency department. AB - Patients with shoulder injuries commonly present to emergency departments (EDs) and minor injury units and it is vital that they receive the same high standard of care regardless of where they receive it or who delivers it. The author, therefore, developed an algorithm to help standardise diagnosis and management of shoulder injuries. This article describes acute shoulder injuries often seen in EDs and advanced health assessments of these injuries, including specific tests, and uses a case study to illustrate how the algorithm helped diagnose and manage care of a patient with a dislocated shoulder. PMID- 25270819 TI - Identifying foot fractures and dislocations. AB - As the roles of emergency nurse practitioners expand, more patients with minor injuries are being managed independently by nursing staff. Injuries to the foot and ankle are common among such patients, and X-rays are frequently performed to aid their diagnoses. Some of these fractures and dislocations are subtle and difficult to identify, so practitioners must adopt a structured approach to reading X-rays. This article describes some of these injuries and offers advice, including X-ray illustrations, on how to identify them. PMID- 25270820 TI - Should emergency nurses attempt to meet patients' spiritual needs? AB - Research suggests there is a positive correlation between addressing some patients' spiritual needs and the outcomes of their care. This article describes a case study in which a patient with mental health problems who frequently re attended an emergency department (ED) sought spiritual support from a hospital chaplain. The patient was referred to a charitable organisation that offers spiritual care and her re-attendance at the ED has become less frequent. PMID- 25270821 TI - Risk-taking in disorders of natural and drug rewards: neural correlates and effects of probability, valence, and magnitude. AB - Pathological behaviors toward drugs and food rewards have underlying commonalities. Risk-taking has a fourfold pattern varying as a function of probability and valence leading to the nonlinearity of probability weighting with overweighting of small probabilities and underweighting of large probabilities. Here we assess these influences on risk-taking in patients with pathological behaviors toward drug and food rewards and examine structural neural correlates of nonlinearity of probability weighting in healthy volunteers. In the anticipation of rewards, subjects with binge eating disorder show greater risk taking, similar to substance-use disorders. Methamphetamine-dependent subjects had greater nonlinearity of probability weighting along with impaired subjective discrimination of probability and reward magnitude. Ex-smokers also had lower risk-taking to rewards compared with non-smokers. In the anticipation of losses, obesity without binge eating had a similar pattern to other substance-use disorders. Obese subjects with binge eating also have impaired discrimination of subjective value similar to that of the methamphetamine-dependent subjects. Nonlinearity of probability weighting was associated with lower gray matter volume in dorsolateral and ventromedial prefrontal cortex and orbitofrontal cortex in healthy volunteers. Our findings support a distinct subtype of binge eating disorder in obesity with similarities in risk-taking in the reward domain to substance use disorders. The results dovetail with the current approach of defining mechanistically based dimensional approaches rather than categorical approaches to psychiatric disorders. The relationship to risk probability and valence may underlie the propensity toward pathological behaviors toward different types of rewards. PMID- 25270822 TI - Congenital heart disease in pregnancy in a low-income country. AB - OBJECTIVE: To assess maternal and perinatal outcomes among pregnant women with congenital heart disease (CHD) in a low-resource country. METHODS: A prospective, observational study was conducted at a teaching hospital in Kolkata, India, between January 1, 2008, and December 31, 2010. All pregnant women with CHD were followed up from first prenatal visit to discharge. Both maternal and perinatal outcomes were analyzed. RESULTS: Of 174 pregnant women with heart disease, 27 (16%) had CHD. Mean age was 23.5+/-3.6 years. Four (15%) patients were diagnosed with CHD during the index pregnancy. Nine (33%) women had undergone surgical correction before conception. Cesarean delivery was performed in 12 (44%) women. Fifteen (56%) neonates weighed less than 2500 g, and 4 (15%) were born preterm. Mean birth weight was slightly higher in women with corrected heart lesions than in those with uncorrected ones (2593+/-480 g vs 2294+/-620 g; P=0.22). Three (11%) neonates died, but no stillbirths occurred. One (4%) woman died after delivery owing to atonic postpartum hemorrhage. CONCLUSION: Delayed diagnosis, lack of treatment, and unplanned pregnancy are major challenges for women with CHD, which need to be addressed to improve maternal and neonatal outcomes in low resource countries. PMID- 25270823 TI - A hospital-centered approach to improve emergency obstetric care in South Sudan. AB - OBJECTIVE: To assess provision of emergency obstetric care (EmOC) in Greater Yirol, South Sudan, after implementation of a hospital-centered intervention with an ambulance referral system. METHODS: In a descriptive study, data were prospectively recorded for all women referred to Yirol County Hospital for delivery in 2012. An ambulance referral system had been implemented in October 2011. Access to the hospital and ambulance use were free of charge. RESULTS: The number of deliveries at Yirol County Hospital increased in 2012 to 1089, corresponding to 13.3% of the 8213 deliveries expected to have occurred in the catchment area. Cesareans were performed for 53 (4.9%) deliveries, corresponding to 0.6% of the expected number of deliveries in the catchment area. Among 950 women who delivered a newborn weighing at least 2500 g at the hospital, 6 (0.6%) intrapartum or very early neonatal deaths occurred. Of 1232 women expected to have major obstetric complications in 2012 in the catchment area, 472 (38.3%) received EmOC at the hospital. Of 115 expected absolute obstetric indications, 114 (99.1%) were treated in the hospital. CONCLUSION: A hospital-centered approach with an ambulance referral system effectively improves the availability of EmOC in underprivileged remote settings. PMID- 25270824 TI - Incidence and risk factors for early neonatal mortality in newborns with severe perinatal morbidity in Uganda. AB - OBJECTIVE: To determine the incidence and risk factors for early neonatal death among newborns with severe perinatal morbidity. METHODS: A prospective cohort study was performed of 341 newborns with severe perinatal morbidity admitted to the neonatal intensive care unit of Mulago Hospital, Uganda. All newborns were followed up for 7 days or until time of death. Information surrounding the mother's obstetric history and pregnancy, the birth, and the neonatal history was collected using an interviewer-administered questionnaire and by review of relevant records. Multivariate logistic regression analysis was performed to assess factors independently associated with early neonatal death. RESULTS: A total of 37 (10.9%) neonates died within 7 days, giving an incidence of early neonatal death of 109 deaths per 1000 live births (3 per 100 person-days). In multivariate analysis, respiratory distress (adjusted risk ratio [aRR] 31.29; 95% CI, 4.17-234.20; P=0.001) and inadequate fetal heart monitoring during labor (aRR 6.0; 95% CI 1.40-25.67; P=0.016) were significantly associated with an increased risk of early neonatal death. CONCLUSION: Approximately one in 10 neonates with severe perinatal morbidity died within 7 days of birth. Respiratory distress and poor monitoring of labor were risk factors for early neonatal death. PMID- 25270825 TI - Pregnancy complications after liver transplantation. AB - OBJECTIVE: To review complications in pregnancy after liver transplantation and assess the time interval since transplantation on fetal development and preterm birth rate. METHOD: A retrospective review of 53 pregnancies after liver transplantation among 45 women who delivered at the Medical University of Warsaw between 2001 and 2013. RESULTS: Mean duration of pregnancy was 37+/-2.3 weeks. Main complications were liver dysfunction, small-for-gestational-age, and preterm delivery. Mean time from transplant to pregnancy was 54+/-36 months for women who delivered before 34 weeks (n=9), 42+/-43 months for delivery at 34-36 weeks (n=10), and 57+/-36 months for delivery after 37 weeks. Mean neonatal weight was 2838+/-626 g (<34 weeks, 1897+/-382 g; 34-36, 2324+/-330 g; >37, 3125+/-474 g). Fourteen (26%) neonates had low birth weight (<2500 g) and 30 (56%) weighed <3000 g. Pregnancy proceeded without complication in 13 (29%), with a mean time from transplantation to conception of 52 months. CONCLUSION: Although physiological gestation and delivery at term are possible for women after liver transplantation, pregnancy is considered high risk. Counselling before pregnancy is required and patients must be managed by an obstetrician and a hepatologist. PMID- 25270826 TI - Individual and household predictors of adolescents' adherence to a web-based intervention. AB - BACKGROUND: Adherence to e-health obesity interventions is a significant challenge. PURPOSE: We examined the individual and household predictors of adolescents' adherence to a Web-based lifestyle intervention. METHODS: One hundred sixty overweight/obese adolescents and one of their parents enrolled in the 8-month e-health intervention. Structural equation modeling was used to examine individual factors from the theory of planned behavior and self determination theory and household factors (food/soda availability, parenting, environment) that predict adolescents' adherence to components of the intervention. RESULTS: We explained 10.8 to 36.9% of the total variance in adherence to components of the intervention. Intrinsic motivation and parenting practices and styles directly predicted adherence. Relatedness and autonomy support indirectly predicted adherence via intrinsic motivation. Finally, household income modulated these effects. CONCLUSION: Taking a self-regulatory perspective (i.e., accounting for intrinsic motivation) contributes to our understanding of intervention adherence, but the household environment may play a greater role in facilitating adolescent behavior change. PMID- 25270827 TI - Advancing research on engagement in Internet interventions: a comment on Owen et al. PMID- 25270828 TI - Forgoing dental care for economic reasons in Switzerland: a six-year cross sectional population-based study. AB - BACKGROUND: While oral health is part of general health and well-being, oral health disparities nevertheless persist. Potential mechanisms include socioeconomic factors that may influence access to dental care in the absence of universal dental care insurance coverage. We investigated the evolution, prevalence and determinants (including socioeconomic) of forgoing of dental care for economic reasons in a Swiss region, over the course of six years. METHODS: Repeated population-based surveys (2007-2012) of a representative sample of the adult population of the Canton of Geneva, Switzerland. Forgone dental care, socioeconomic and insurance status, marital status, and presence of dependent children were assessed using standardized methods. RESULTS: A total of 4313 subjects were included, 10.6% (457/4313) of whom reported having forgone dental care for economic reasons in the previous 12 months. The crude percentage varied from 2.4% in the wealthiest group (monthly income >= 13,000 CHF, 1 CHF ~ 1$) to 23.5% among participants with the lowest income (<3,000 CHF). Since 2007/8, forgoing dental care remained stable overall, but in subjects with a monthly income of <3,000 CHF, the adjusted percentage increased from 16.3% in 2007/8 to 20.6% in 2012 (P trend = 0.002). Forgoing dental care for economic reasons was independently associated with lower income, younger age, female gender, current smoking, having dependent children, divorced status and not living with a partner, not having a supplementary health insurance, and receipt of a health insurance premium cost-subsidy. CONCLUSIONS: In a Swiss region without universal dental care insurance coverage, prevalence of forgoing dental care for economic reasons was high and highly dependent on income. Efforts should be made to prevent high-risk populations from forgoing dental care. PMID- 25270830 TI - The growth of Scenedesmus sp. attachment on different materials surface. AB - BACKGROUND: Microalgae has been concerned as a potential source of biodiesel in the recent years. However, it is costly to harvest microalgae as it is commonly cultured in water and the cells are too small to harvest. In order to reduce the cost of cultivation and harvesting, it is important to improve the biomass productivity of microalgae. Here, we utilized the attachment method to culture microalgae to cut off the cost of culture and harvest. RESULTS: In this paper, various supporting surface with different hydrophility including polyvinylidene fluoride (PVDF), polyacrylonitrile (PAN), polysulfone (PS), which are not easy to be degraded in the culture medium, were used for microalgae culture by the attachment method. The results showed that PVDF supporting cloth was suitable for the algae growth, and its average biomass productivity was to 4.0 g/m2/day. Furthermore, a series of PVDF concentrations were tested, and cloth treated with 3% or 5% PVDF solution was better for the algae culture. In addition, Polyvinylpyrrolidone (PVP) with different molecular weight was added to the PVDF solution as porogens to produce rough surface. And the addition of PVP resulted in better growth with 6.0 g/m2/day of average biomass productivity. CONCLUSION: This attachment method makes the harvest of microalgae easy and energy-saving, because the microalgae grow on the supporting material and is easy to be scraped. The results indicate that the PVDF-treated cloth is a potential alternative for the microalgae attachment culture. PMID- 25270829 TI - Connexin 43 channels are essential for normal bone structure and osteocyte viability. AB - Connexin (Cx) 43 serves important roles in bone function and development. Targeted deletion of Cx43 in osteoblasts or osteocytes leads to increased osteocyte apoptosis, osteoclast recruitment, and reduced biomechanical properties. Cx43 forms both gap junction channels and hemichannels, which mediate the communication between adjacent cells or between cell and extracellular environments, respectively. Two transgenic mouse models driven by a DMP1 promoter with the overexpression of dominant negative Cx43 mutants were generated to dissect the functional contribution of Cx43 gap junction channels and hemichannels in osteocytes. The R76W mutant blocks the gap junction channel, but not the hemichannel function, and the Delta130-136 mutant inhibits activity of both types of channels. Delta130-136 mice showed a significant increase in bone mineral density compared to wild-type (WT) and R76W mice. Micro-computed tomography (uCT) analyses revealed a significant increase in total tissue and bone area in midshaft cortical bone of Delta130-136 mice. The bone marrow cavity was expanded, whereas the cortical thickness was increased and associated with increased bone formation along the periosteal area. However, there is no significant alteration in the structure of trabecular bone. Histologic sections of the midshaft showed increased apoptotic osteocytes in Delta130-136, but not in WT and R76W, mice which correlated with altered biomechanical and estimated bone material properties. Osteoclasts were increased along the endocortical surface in both transgenic mice with a greater effect in Delta130-136 mice that likely contributed to the increased marrow cavity. Interestingly, the overall expression of serum bone formation and resorption markers were higher in R76W mice. These findings suggest that osteocytic Cx43 channels play distinctive roles in the bone; hemichannels play a dominant role in regulating osteocyte survival, endocortical bone resorption, and periosteal apposition, and gap junction communication is involved in the process of bone remodeling. PMID- 25270831 TI - Antibacterial activity of Pinus elliottii against anaerobic bacteria present in primary endodontic infections. AB - Endodontic infections have a polymicrobial nature, but anaerobic bacteria prevail among the infectious microbes. Considering that it is easy to eliminate planktonic bacteria, biofilm-forming bacteria still challenge clinicians during the fight against endodontic diseases. The chemical constituents of the oleoresin of Pinus elliottii, a plant belonging to the family Pinaceae, stand out in the search for biologically active compounds based on natural products with potential application in the treatment of endodontic infections. Indeed, plant oleoresins are an abundant natural source of diterpenes that display significant and well defined biological activities as well as potential antimicrobial action. In this context, this study aimed to (1) evaluate the in vitro antibacterial activity of the oleoresin, fractions, and subfractions of P. elliottii as well as the action of dehydroabietic acid against 11 anaerobic bacteria that cause endodontic infection in both their planktonic and biofilm forms and (2) assess the in vitro antibiofilm activity of dehydroabietic acid against the same group of bacteria. The broth microdilution technique helped to determine the minimum inhibitory concentration (MIC) of the oleoresin and fractions. This same technique aided determination of the MIC values of nine subfractions of Fraction 1, the most active fraction. The MIC, minimum bactericidal concentration, and antibiofilm activity of dehydroabietic acid against the tested anaerobic bacteria were also examined. The oleoresin and fractions, especially fraction PE1, afforded promising MIC values, which ranged from 0.4 to 50 MUg/mL. Concerning the nine evaluated subfractions, PE1.3 and PE1.4 furnished the most noteworthy MIC values, between 6.2 and 100 MUg/mL. Dehydroabietic acid displayed antibacterial activity, with MIC values lying from 6.2 to 50 MUg/mL, as well as bactericidal effect for all the investigated bacteria, except for Prevotella nigrescens. Assessment of the antibiofilm activity revealed significant results--MICB50 lay between 7.8 and 62.5 MUg/mL, and dehydroabietic acid prevented all the evaluated bacteria from forming a biofilm. Hence, the chemical constituents of P. elliottii are promising biomolecules to develop novel therapeutic strategies to fight against endodontic infections. PMID- 25270832 TI - Probiotic characteristics of Lactobacillus fermentum strains isolated from tulum cheese. AB - The aim of this study was to characterize the probiotic characteristics of Lactobacillus fermentum strains isolated from Tulum cheese. Seven L. fermentum strains were selected among the isolated and identified lactobacillus strains due to their abundance. When the gastric condition was considered, L. fermentum LP3 and LP4 were able to tolerate pH 2.5 and 1% bile salt. All L. fermentum strains had similar enzymatic activity and antibiotic resistance pattern but the highest antagonistic effect was detected within LP3, LP4 and LP6. Cholesterol assimilation amount of L. fermentum strains ranged between 12.1 and 45.3% in MRS and 20.7-71.1% in MRS with bile. The highest cholesterol assimilation in MRS and MRS with bile was occurred by LP3 and LP4, respectively. L. fermentum LP2 adhered to caco-2 cells more than Lactobacillus rhamnosus LGG where LP3, LP4 and LP5 adhered at similar level. In conclusion, L. fermentum LP3 and LP4 fulfilled sufficient criteria to be probiotics for use as a starter culture in the production of tulum cheese or other dairy products. Also this study indicated that some food-associated Lactobacillus strains non-predominant for gut biota have significant probiotic potential. PMID- 25270833 TI - Dynamic MR urography in children with uropathic disease with a combined 2D and 3D acquisition protocol--comparison with MAG3 scintigraphy. AB - OBJECTIVE: The aim of this study was to evaluate combined two-dimensional (2D) and three-dimensional (3D) dynamic MR urography with respiratory compensation in children with anomalies of the genitourinary tract, allowing for computation of split renal function and assessment of urinary tract obstruction. METHODS: Dynamic MR urography was performed in 53 children (3 months-16 years of age) with anomalies of the urinary tract. A protocol for dynamic MR urography and nephrography was implemented at 1.5 T using a navigator-triggered 2D TurboFLASH sequence. Split renal function and contrast-medium excretion were assessed after the bolus injection of 0.05 mmol kg(-1) body weight of gadolinium dimeglumine. In the excretory phase, a 3D gradient-echo data set with high spatial resolution was acquired. In all patients, mercaptoacetyltriglycine (MAG3) scintigraphy was obtained as a reference standard. RESULTS: In all children, dynamic MR nephrography and urography could be performed with excellent compensation of breathing artefacts providing region of interest analysis in nearly identical kidney positions. The assessment of contrast-medium excretion into the ureter allowed for discrimination of functional from non-functional stenosis. Split renal function assessed by MRI showed an excellent agreement with the MAG3 reference standard with a correlation coefficient r = 0.95. Additionally recorded 3D data sets offered good depiction of anatomical anomalies in all patients. CONCLUSION: The proposed protocol provides a robust technique for assessment of ureteral obstruction and split renal function with compensation of breathing artefacts, short post-processing time and excellent 3D spatial resolution. ADVANCES IN KNOWLEDGE: The combined protocol of 2D and 3D MR urography is an efficient technique for assessment of renal morphology and function. PMID- 25270834 TI - [Invasive orbital aspergillosis: Rare but important differential diagnosis in the case of immunosuppression]. AB - Invasive aspergillosis originating from the paranasal sinuses is a rare disease that is associated with high mortality rates. We report on a 77-year-old patient with myelodysplastic syndrome and progressive left-sided proptosis persisting for 5 days. Antibiotic therapy and endonasal orbital decompression yielded insufficient improvement. Only upon application of complementary antifungal therapy was remission observed. Rapid diagnosis and treatment are essential in order to prevent life-threatening complications. PMID- 25270835 TI - [Detection of hearing loss in dementia patients : pilot study and literature survey]. AB - There is a higher incidence of dementia among people with hearing loss, although the complex interrelation is not yet understood. The potential influence of hearing rehabilitation is also unclear. A previously published retrospective study on this topic throws doubt on the ability of dementia patients to accomplish audiometric tests. Therefore, we conducted a pilot study to analyse the feasibility of applying conventional speech and pure tone audiometry in patients with dementia. In contrast to previously published data, we were able to achieve reproducible results in almost all patients. The difficulty associated with audiometric testing in dementia patients does thus not seem to lie in the application of pure tone and speech audiometry. On the basis of evidence indicating the importance of central hearing loss in the elderly, these tests alone do not appear sufficient. It is of greater interest to ascertain whether central hearing loss is relevant in patients suffering from dementia and whether corresponding audiometric tests are feasible. PMID- 25270836 TI - [Advances in the surgical treatment of tumors of the pituitary region : rhino neurosurgical transnasal endoscopic surgery]. AB - Conventional microscopic surgery of pituitary adenomas offers excellent results with regard to local tumour control and endocrine function. Overall patient morbidity and mortality is low. However, recent studies demonstrate further improvements in tumour resection control and more favourable endocrine/ophthalmologic results when endoscopic techniques are applied, as well as an overall reduction in peri-interventional morbidity. Additionally, use of endoscopic techniques in rhino-neurosurgical cooperation achieved better specifically rhinologic results and improved subjective comfort for patients. The cooperative rhino-neurosurgical approach not only allows for optimal treatment of the primary pituitary pathology, but also treatment of additional nasal and paranasal pathologies, such as a deviated septum or disturbed drainage of the paranasal sinus. PMID- 25270837 TI - [Complex fracture of the larynx caused by a horse kick]. AB - Every blunt laryngeal trauma requires examination by an ENT physician and may necessitate observation for a number of hours. The literature shows a heterogeneous picture regarding airway management (tracheotomy vs. intubation). Extremely violence forces such as horse kicks require a tracheotomy, as demonstrated by case studies. In such cases, a high level of responsibility lies with the emergency physician providing the initial treatment. We present the case of a 37-year-old horse trainer, who suffered a horse kick to the larynx with a complex laryngeal fracture. Intubation of the patient by the emergency physician would most probably have led to incorrect placement of the tube or complete displacement of larynx and trachea. In addition to securing a vital airway by tracheotomy, a timely reconstruction of the airways, where necessary by employing the temporary insertion of a tracheal stent, is the treatment of choice. The latter therapy should be applied within the first 6 hours following the accident. PMID- 25270838 TI - [Chronic complex tinnitus: does day care unit-based short-term psychotherapy help?]. AB - BACKGROUND: Results of empirical research on the effectiveness of psychotherapeutic treatment of chronic complex tinnitus are still unclear and require further studies for clarification. OBJECTIVE: The objective of this study is to investigate the effectiveness of multimodal treatment of patients with chronic complex tinnitus in a day care unit setting. PATIENTS AND METHODS: In this prospective study, the effectiveness of an intense 5-day multimodal treatment delivered to 93 patients was assessed using a pre-post design. Tinnitus specific effects were captured by the Mini-TQ-12 measurement instrument and psychiatric comorbidity assessed using the Brief Symptom Inventory (BSI). In statistical analyses, t-tests, chi(2) tests and Wilcoxon signed ranks tests were performed to determine statistical significance; effect sizes (ES) were calculated according to Cohen's d. RESULTS: The pre-post difference in Mini-TQ-12 was highly significant in t-test (p < 0.001); the ES was small (ES = 0.45). In BSI, the pre-post difference in the Global Severity Index (GSI) as a global measure was also highly significant in t-test (p < 0.001); ES was small (ES = 0.40). Nonparametric tests (Wilcoxon test) confirmed these results. CONCLUSION: This study demonstrates the statistically significant effectiveness of a multimodal therapeutic approach. Moreover, the results indicate that patients could benefit from more intensive therapeutic interventions. PMID- 25270839 TI - [Olfactory disorders and their therapy]. AB - Among the main causes of olfactory disorders are chronic rhinosinusitis, head trauma, acute infections of the upper respiratory tract and neurodegenerative diseases. Olfactory disorders can impose major restrictions on our lives. Although there are numerous approaches for the therapy of olfactory disorders, double-blind comparison studies are needed to distinguish between the effects of these therapies and spontaneous remission of olfactory disorders. The most significant aspects of treatments seem to be anti-inflammatory measures and the regenerative capabilities of the olfactory neuroepithelium. PMID- 25270840 TI - Allergy-related diseases and recurrent abdominal pain during childhood - a birth cohort study. AB - BACKGROUND: Allergy and immune dysregulation may have a role in the pathophysiology of recurrent abdominal pain of functional origin, but previous studies of allergy-related diseases and abdominal pain have contradictory results. AIM: To examine the association between allergy-related diseases or sensitisation during childhood and abdominal pain at age 12 years. METHODS: In this birth cohort study of 4089 children, parents answered questionnaires regarding asthma, allergic rhinitis, eczema and food hypersensitivity ('allergy related diseases') at ages 0,1,2,4,8 and 12 years. Blood for analyses of allergen specific IgE was sampled at 4 and 8 years. At 12 years, the children answered questions regarding abdominal pain. Children with coeliac disease or inflammatory bowel disease were excluded. Associations were examined using multivariable logistic regression. RESULTS: Among 2610 children with complete follow-up, 9% (n = 237) reported abdominal pain at 12 years. All allergy-related diseases were associated with concurrent abdominal pain at 12 years and the risk increased with increasing number of allergy-related diseases (P for trend <0.001). Asthma at 1 and 2 years and food hypersensitivity at 8 years were significantly associated with abdominal pain at 12 years. There was an increased risk of abdominal pain at 12 years in children sensitised to food allergens at 4 or 8 years, but in stratified analyses, this was confined to children whose parents had not reported food hypersensitivity at time of sensitisation. CONCLUSION: Allergy-related diseases as well as sensitisation to food allergens were associated with an elevated risk of abdominal pain, and the risk increased with the number of allergy-related diseases. PMID- 25270841 TI - Editorial: "Biotech Methods" and the Biotechnology Journal mobile app. PMID- 25270846 TI - A kinetic study of ferrocenium cation decomposition utilizing an integrated electrochemical methodology composed of cyclic voltammetry and amperometry. AB - A novel, easy, quick, and inexpensive integrated electrochemical methodology composed of cyclic voltammetry and amperometry has been developed for the determination of the kinetic stability of higher oxidation states for inorganic complexes. In this study, ferrocene and its derivatives have been used as model systems and the corresponding ferrocenium cations were generated in situ during the electrochemical experiments to determine their kinetic stabilities. The study found that the ferrocenium cations decompose following the first-order kinetics at 27 +/- 3 degrees C in the presence of ambient oxygen and water. The half lives of the ferrocenium, carboxylate ferrocenium, and decamethyl ferrocenium cations were found to be 1.27 * 10(3), 1.52 * 10(3), and ?11.0 * 10(3) s, respectively, in acetonitrile solvent having a 0.5 M tetrabutylammonium hexafluorophosphate electrolyte. These results are in agreement with the previous reports, i.e. the ferrocenium cation is unstable whereas the decamethyl ferrocenium cation has superior stability. The new methodology has been established by performing various experiments using different concentrations of ferrocene, variable scan rates in cyclic voltammetry, different time periods for amperometry, and in situ spectroelectrochemical experiments. PMID- 25270847 TI - Burden of skeletal-related events in prostate cancer: unmet need in pain improvement. AB - PURPOSE: Up to 75% of patients with prostate cancer experience metastatic bone disease, which leads to an increased risk for skeletal-related events (SREs) including pathological bone fracture, spinal cord compression, and hypercalcemia of malignancy. Our objective was to systematically review the literature on the impact of SREs on quality of life (QOL), morbidity, and survival with a primary focus on the impact of SREs on pain in prostate cancer patients. METHODS: We searched PubMed, limiting to peer-reviewed English-language human studies published in 2000-2010. The search was based on the US Food and Drug Administration and European Medicines Agency definition of an SRE, which includes pathologic fracture, spinal cord compression (SCC), hypercalcemia of malignancy, and radiotherapy or surgery to bone resulting from severe bone pain. RESULTS: A total of 209 articles were screened, of which 173 were excluded, and 36 were included in this review. Patients with SREs had more pain and worse survival compared with no SREs. Pathologic bone fractures worsened QOL and were associated with shorter survival. Radiation therapy of SCC alleviated pain and improved morbidity. SCC was associated with decreases in patient survival. Radiation therapy and surgery to bone improved pain. CONCLUSIONS: Specific SREs are associated with worse outcomes, including increased pain, poorer QOL, morbidity, and survival. Treatment of SREs is associated with improved pain, although there remains a need for more effective treatment of SREs in prostate cancer patients. PMID- 25270848 TI - C-reactive protein and the MASCC risk index identify high-risk patients with febrile neutropenia and hematologic neoplasms. AB - OBJECTIVE: The objective of this study is to assess the prognostic usefulness of the Multinational Association of Supportive Care in Cancer (MASCC) risk score in association with the value of C-reactive protein (CRP) to identify high-risk patients with febrile neutropenia and hematologic neoplasms. METHODS: A retrospective cohort study in which the MASCC score and the CRP values were used to assess the mortality risk at 30 days among patients with febrile neutropenia and hematologic malignancies was performed. RESULTS: Two hundred thiry-seven patients with febrile neutropenia were analyzed; the mortality rate within 30 days was 9 %. High-risk patients according to the MASCC score were significantly more likely to experience adverse outcomes, such as being transferred to the intensive care unit (RR 3.55; CI 95 % 2.73-6.62, p < 0.001) and death (RR 2.21; CI 95 % 1.74-2.79, p < 0.001). Multivariate analysis showed a strong association between the high-risk group identified by the MASCC score (HR 3.0; CI 95 % 1.12 13.54, p = 0.032) and the mean levels of CRP (HR 17; CI 95 % 2.21-136.48, p = 0.007) and survival. The survival rate within 30 days was 100 % for the patients with a low-risk MASCC score and a mean CRP less than 15 mg/dL. This rate was only 64 % for high-risk patients with a mean CRP greater than 15 mg/dL. CONCLUSION: The MASCC risk score combined with the mean CRP value successfully identifies patients with febrile neutropenia and hematological malignancies and a high risk of death. PMID- 25270850 TI - Disseminated tuberculosis: A neglected entity in immunocompromised hemodialysis patients. AB - End-stage renal disease is considered a factor predisposing to increased risk of tuberculosis with frequent extrapulmonary localization. Although extrapulmonary tuberculosis has been observed for decades, disseminated tuberculosis, a major cause of morbidity and mortality in immunocompromised hosts, remains rather neglected. We report an unusual case of an immunocompromised patient with a late diagnosis and delayed treatment of genitourinary tuberculosis that subsequently led to the diagnosis of vertebral and miliary tuberculosis (disseminating tuberculosis). Therefore, increased awareness is warranted from physicians dealing with hemodialysis patients in order to avoid delays in diagnosis and treatment initiation. PMID- 25270849 TI - Dietary habits changes and quality of life in patients undergoing chemotherapy for epithelial ovarian cancer. AB - PURPOSE: The aim of this study was to evaluate dietary habit changes in patients undergoing chemotherapy for epithelial ovarian cancer. METHODS: Sixty one patients undergoing chemotherapy for epithelial ovarian cancer were enrolled to the study and 44 completed. The dietary intake was evaluated by 7-day food records, and the changes in dietary intake and food-preparing methods were estimated based on a 101-item semiquantitative food frequency questionnaire. Nutritional status was checked with the use of body weight and height, waist and hip circumferences, skinfolds and subjective global assessment tool. Quality of life was measured with the use of EORTC QLQ-C30 and EORTC QLQ-OV28. RESULTS: Despite high average body mass index (BMI) (26.7-28.0 kg/m(2)), malnutrition risk was observed in 43.7 and 10.7 % of patients receiving first-line and subsequent line chemotherapy, respectively (p < 0.001). Dietary intake and quality of life did not differ between the studied groups. A lot of dietary habits changes were observed. Women undergoing subsequent-line chemotherapy consumed more frequently rye bread, pasta, buttermilk, vegetable, fruit, oils, nuts, and juices. Women undergoing first-line chemotherapy consumed more milk, cottage cheese, cream, eggs, fish and seafood, meat offal, salty snacks, and jam. Additionally, women undergoing subsequent-line chemotherapy more often applied cooking in water (p < 0.0001) and baking (p < 0.05). CONCLUSIONS: Women undergoing chemotherapy for ovarian cancer change their dietary habits in a pro healthy direction, and these changes are more expressed in patients undergoing subsequent-line chemotherapy. PMID- 25270851 TI - Protective effects of deep sea water against doxorubicin-induced cardiotoxicity in H9c2 cardiac muscle cells. AB - Doxorubicin (DOX) is one of the most effective chemotherapeutic agents in the treatment of a variety of tumors. However, its clinical use has been compromised by the risk of cardiotoxicity. Thus, many efforts have been focused on exploring new strategies to prevent or reverse DOX-induced cardiotoxicity. Recently, deep sea water (DSW) has drawn much scientific interest for therapeutic intervention due to its enrichment in nutrients and minerals. In this study, we investigated whether DSW has protective effects against DOX-induced cardiotoxicity. Pre treatment with DSW significantly increased the viability of DOX-treated rat H9c2 cardiac muscle cells. This protective effect of DSW appears to be mediated through the inhibition of DNA damage rather than suppression of reactive oxygen species (ROS) production in DOX-treated H9c2 cardiac muscle cells. The inhibitory effect of DSW on DOX-induced DNA damage subsequently attenuated apoptotic signaling such as activation of cysteine-aspartic acid protease-3 (caspase-3) and fragmentation of poly(ADP-ribose) polymerase (PARP), whereas the expression of anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) was increased. Moreover, DSW treatment rescued the activation of protein kinase B (Akt) to protect cells from DOX-triggered apoptosis. Taken together, our data showed that DSW has protective effects against DOX-induced cardiotoxicity, suggesting that DSW has some promise as a novel protective supplement for promoting the successful use of DOX in clinical regimen. PMID- 25270852 TI - Risk of bias in industry-funded oseltamivir trials: comparison of core reports versus full clinical study reports. AB - BACKGROUND: The Cochrane risk of bias tool is a prominent instrument used to evaluate potential biases in clinical trials. In three updates of our Cochrane review on neuraminidase inhibitors, we assessed risk of bias on the same trials using different levels of detail: the trials in journal publications, in core reports, and in full clinical study reports. Here we analyse whether progressively greater amounts of information and detail in full clinical study reports (including trial protocols, statistical analysis plans, certificates of analyses, individual participant data listings and randomisation lists) affected our risk of bias assessments. METHODS AND FINDINGS: We used the Cochrane risk of bias tool to assess and compare risk of bias in 14 oseltamivir trials (reported in 10 clinical study reports) obtained from the European Medicines Agency (EMA) and the manufacturer, Roche. With more detailed information, reported in clinical study reports, no previous assessment of 'high' risk of bias was reclassified as 'low' or 'unclear' in the main analysis, and over half (55%, 34/62) of the previous assessments of 'low' risk of bias were reclassified as 'high'. Most assessments of 'unclear' risk of bias (67%, or 28/42) were reclassified as 'high' risk of bias when our judgements were based on full clinical study reports. The limits of our study were our relative inexperience in dealing with large information sets, sometimes subjective bias judgements and focus on industry trials. Comparison with journal publications was not possible because of the low number of trials published. CONCLUSIONS: We found that as information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications. PMID- 25270853 TI - Change in prevalence of chronic kidney disease in England over time: comparison of nationally representative cross-sectional surveys from 2003 to 2010. AB - OBJECTIVES: To determine whether the prevalence of chronic kidney disease (CKD) in England has changed over time. DESIGN: Cross-sectional analysis of nationally representative Health Survey for England (HSE) random samples. SETTING: England 2003 and 2009/2010. SURVEY PARTICIPANTS: 13,896 adults aged 16+ participating in HSE, adjusted for sampling and non-response, 2009/2010 surveys combined. MAIN OUTCOME MEASURE: Change in prevalence of estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 (as proxy for stage 3-5 CKD), from 2003 to 2009/2010 based on a single serum creatinine measure using an isotope dilution mass spectrometry traceable enzymatic assay in a single laboratory; eGFR derived using Modified Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) eGFR formulae. ANALYSIS: Multivariate logistic regression modelling to adjust time changes for sociodemographic and clinical factors (body mass index, hypertension, diabetes, lipids). A correction factor was applied to the 2003 HSE serum creatinine to account for a storage effect. RESULTS: National prevalence of low eGFR (<60) decreased within each age and gender group for both formulae except in men aged 65-74. Prevalence of obesity and diabetes increased in this period, while there was a decrease in hypertension. Adjustment for demographic and clinical factors led to a significant decrease in CKD between the surveyed periods. The fully adjusted OR for eGFR<60 mL/min/1.73 m2 was 0.75 (0.61 to 0.92) comparing 2009/2010 with 2003 using the MDRD equation, and was similar using the CKDEPI equation 0.73 (0.57 to 0.93). CONCLUSIONS: The prevalence of a low eGFR indicative of CKD in England appeared to decrease over this 7-year period, despite the rising prevalence of obesity and diabetes, two key causes of CKD. Hypertension prevalence declined and blood pressure control improved but this did not appear to explain the fall. Periodic assessment of eGFR and albuminuria in future HSEs is needed to evaluate trends in CKD. PMID- 25270854 TI - Does a 'direct' transfer protocol reduce time to coronary angiography for patients with non-ST-elevation acute coronary syndromes? A prospective observational study. AB - OBJECTIVE: National guidelines recommend 'early' coronary angiography within 96 h of presentation for patients with non-ST elevation acute coronary syndromes (NSTE ACS). Most patients with NSTE-ACS present to their district general hospital (DGH), and await transfer to the regional cardiac centre for angiography. This care model has inherent time delays, and delivery of timely angiography is problematic. The objective of this study was to assess a novel clinical care pathway for the management of NSTE-ACS, known locally as the Heart Attack Centre Extension or HAC-X, designed to rapidly identify patients with NSTE-ACS while in DGH emergency departments (ED) and facilitate transfer to the regional interventional centre for 'early' coronary angiography. METHODS: This was an observational study of 702 patients divided into two groups; 391 patients treated before the instigation of the HAC-X pathway (Pre-HAC-X), and 311 patients treated via the novel pathway (Post-HAC-X). Our primary study end point was time from ED admission to coronary angiography. We also assessed the length of hospital stay. RESULTS: Median time from ED admission to coronary angiography was 7.2 (IQR 5.1 10.2) days pre-HAC-X compared to 1.0 (IQR 0.7-2.0) day post-HAC-X (p<0.001). Median length of hospital stay was 3.0 (IQR 2.0-6.0) days post-HAC-X v 9.0 (IQR 6.0-14.0) days pre-HAC-X (p<0.0005). This equates to a reduction of six hospital bed days per NSTE-ACS admission. CONCLUSIONS: The introduction of this novel care pathway was associated with significant reductions in time to angiography and in total hospital bed occupancy for patients with NSTE-ACS. PMID- 25270855 TI - Prescriber preference for a particular tumour necrosis factor antagonist drug and treatment discontinuation: population-based cohort. AB - OBJECTIVE: To assess the effect of physician preference for a particular tumour necrosis factor alpha (TNF) antagonist on the risk of treatment discontinuation in rheumatoid arthritis. DESIGN: Population-based cohort study. SETTING: British Columbia administrative health data (inpatients, outpatients and pharmacy). PARTICIPANTS: 2742 British Columbia residents who initiated a first course of a TNF antagonist between 2001 and December 2008, had been diagnosed with rheumatoid arthritis, and were treated by 1 of 58 medium-volume to high-volume prescribers. INDEPENDENT VARIABLE: A level of physician preference for the drug (higher or lower) was assigned based on preceding prescribing records of the care-providing physician. Higher preference was defined as at least 60% of TNF antagonist courses initiated in the preceding year. Sensitivity analysis was conducted with different thresholds for higher preference. MAIN OUTCOME MEASURE: Drug discontinuation was defined as a drug-free interval of 180 days or switching to another TNF antagonist, anakinra, rituximab or abatacept. The risk of discontinuation was compared between different levels of physician preference using survival analysis. RESULTS: Higher preference for the prescribed TNF antagonist was associated with improved persistence with the drug (4.28 years (95% CI 3.70 to 4.90) vs 3.27 (2.84 to 3.84), with log rank test p value of 0.017). The adjusted HR for discontinuation was significantly lower in courses of drugs with higher preference (0.85 (0.76 to 0.96)). The results were robust in a sensitivity analysis. CONCLUSIONS: Higher physician preference was associated with decreased risk of discontinuing TNF antagonists in patients with rheumatoid arthritis. This finding suggests that physicians who strongly prefer a specific treatment help their patients to stay on treatment for a longer duration. Similar research on other treatments is warranted. PMID- 25270856 TI - Enlarged pulmonary artery is predicted by vascular injury biomarkers and is associated with WTC-Lung Injury in exposed fire fighters: a case-control study. AB - OBJECTIVES: We hypothesise that there is an association between an elevated pulmonary artery/aorta (PA/A) and World Trade Center-Lung Injury (WTC-LI). We assessed if serum vascular disease biomarkers were predictive of an elevated PA/A. DESIGN: Retrospective case-cohort analysis of thoracic CT scans of WTC exposed firefighters who were symptomatic between 9/12/2001 and 3/10/2008. Quantification of vascular-associated biomarkers from serum collected within 200 days of exposure. SETTING: Urban tertiary care centre and occupational healthcare centre. PARTICIPANTS: Male never-smoking firefighters with accurate pre-9/11 forced expiratory volume in 1 s (FEV1)>=75%, serum sampled <=200 days of exposure was the baseline cohort (n=801). A subcohort (n=97) with available CT scans and serum biomarkers was identified. WTC-LI was defined as FEV1<=77% at the subspecialty pulmonary evaluation (n=34) and compared with controls (n=63) to determine the associated PA/A ratio. The subcohort was restratified based on PA/A>=0.92 (n=38) and PA/A<0.92(n=59) to determine serum vascular biomarkers that were predictive of this vasculopathy. OUTCOME MEASURES: The primary outcome of this study was to identify a PA/A ratio in a cohort of individuals exposed to WTC dust that was associated with WTC-LI. The secondary outcome was to identify serum biomarkers predictive of the PA/A ratio using logistic regression. RESULTS: PA/A>=0.92 was associated with WTC-LI, OR of 4.02 (95% CI 1.21 to 13.41; p=0.023) when adjusted for exposure, body mass index and age at CT. Elevated macrophage derived chemokine and soluble endothelial selectin were predictive of PA/A>=0.92, (OR, 95% CI 2.08, 1.05 to 4.11, p=0.036; 1.33, 1.06 to 1.68, p=0.016, respectively), while the increased total plasminogen activator inhibitor 1 was predictive of not having PA/A>=0.92 (OR 0.88, 0.79 to 0.98; p=0.024). CONCLUSIONS: Elevated PA/A was associated with WTC-LI. Development of an elevated PA/A was predicted by biomarkers of vascular disease found in serum drawn within 6 months of WTC exposure. Increased PA/A is a potentially useful non-invasive biomarker of WTC-LI and warrants further study. PMID- 25270857 TI - Short-term use of remifentanil during endotracheal extubation for prophylactic analgesia in neurosurgical patients after craniotomy (SURE after Craniotomy Study): a study protocol and statistical analysis plan for a randomised controlled trial. AB - INTRODUCTION: Acute pain is common during the endotracheal extubation period, and is related to complications and adverse outcomes. Patients with delayed extubation after craniotomy are vulnerable to pain and complications of extubation. However, pain control during extubation is still inadequate. Remifentanil, a new opioid with rapid onset and short duration of action, provides adequate analgesia during procedures with minimal effect of respiratory depression. METHODS AND ANALYSIS: The study is a prospective, randomised, double blinded, controlled parallel-group design. Patients with delayed extubation after intracranial surgery are screened daily. Adult patients ready for extubation are enrolled and assigned randomly to one of the two treatment study groups, labelled as the 'Remi group' or 'Saline group'. Patients in the Remi group receive an intravenous bolus dose of remifentanil 0.5 MUg/kg over 60 s followed by a continuous infusion 0.05 MUg/kg/min for 20 min. Patients in the Saline group receive an intravenous infusion of 0.9% sodium chloride at a volume and rate equal to that of remifentanil. Pain intensity is measured by the visual analogue scale (VAS) pain score. Adverse events during drug infusion are documented and reported. Patients will be followed up until hospital discharge, death or 60 days after the trial intervention on a first come, first served basis. Details of the incidence of reintubation and reoperation within 72 h after extubation, length of stay in the intensive care unit and hospital and mortality are collected. The primary end point is the incidence of severe pain (defined as a VAS pain score more than 5 cm) during the periextubation period (defined as the period of time from immediately before extubation to 20 min after extubation). ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board (IRB) of the Beijing Tiantan Hospital, Capital Medical University. The study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials (NCT): ChiCTR-PRC-13003879. PMID- 25270858 TI - Beyond the 'dyad': a qualitative re-evaluation of the changing clinical consultation. AB - OBJECTIVE: To identify characteristics of consultations that do not conform to the traditionally understood communication 'dyad', in order to highlight implications for medical education and develop a reflective 'toolkit' for use by medical practitioners and educators in the analysis of consultations. DESIGN: A series of interdisciplinary research workshops spanning 12 months explored the social impact of globalisation and computerisation on the clinical consultation, focusing specifically on contemporary challenges to the clinician-patient dyad. Researchers presented detailed case studies of consultations, taken from their recent research projects. Drawing on concepts from applied sociolinguistics, further analysis of selected case studies prompted the identification of key emergent themes. SETTING: University departments in the UK and Switzerland. PARTICIPANTS: Six researchers with backgrounds in medicine, applied linguistics, sociolinguistics and medical education. One workshop was also attended by PhD students conducting research on healthcare interactions. RESULTS: The contemporary consultation is characterised by a multiplicity of voices. Incorporation of additional voices in the consultation creates new forms of order (and disorder) in the interaction. The roles 'clinician' and 'patient' are blurred as they become increasingly distributed between different participants. These new consultation arrangements make new demands on clinicians, which lie beyond the scope of most educational programmes for clinical communication. CONCLUSIONS: The consultation is changing. Traditional consultation models that assume a 'dyadic' consultation do not adequately incorporate the realities of many contemporary consultations. A paradox emerges between the need to manage consultations in a 'super-diverse' multilingual society, while also attending to increasing requirements for standardised protocol-driven approaches to care prompted by computer use. The tension between standardisation and flexibility requires addressing in educational contexts. Drawing on concepts from applied sociolinguistics and the findings of these research observations, the authors offer a reflective 'toolkit' of questions to ask of the consultation in the context of enquiry-based learning. PMID- 25270859 TI - The role and significance of nurses in managing transitions to palliative care: a qualitative study. AB - OBJECTIVES: Nurses are generally present, and often influential, in supporting patient and family acceptance of medical futility and in assisting doctors in negotiating referral to palliative care. Yet the specificities of the nursing role and how nurses may contribute to timely and effective referrals is not well understood. This study aimed to systematically explore hospital-based nurses' accounts of the transition to palliative care, and the potential role of nurses in facilitating more effective palliative care transitions. DESIGN: Qualitative study using semistructured interviews. SETTING: Two health services with public as well as private clinical environments in a major metropolitan area of Australia. PARTICIPANTS: Hospital-based nurses (n=20) who regularly work with patients at the point of referral and in managing transitions to palliative care. RESULTS: Four significant themes emerged from thematic analysis. These include: (1) professional dynamics and the roles played by nurses in initiating the transition to palliative care; (2) the value of nurses' informal interactions in timely and effective transitions; (3) the emerging challenge of managing task oriented nursing versus intense emotional nursing work at the point of medical futility and (4) the emotional burden experienced by nurses within this clinical context. Nurses self-reported occupying critical albeit complex roles in the management of medical futility and the transition to palliative care. They reported experiencing significant emotional burden in balancing interpersonal and interprofessional relationships during this time. CONCLUSIONS: The results suggest that nurses may be utilised in a more formalised and systematic fashion in the context of managing medical futility and the need to topicalise the transition, with the focus shifted away from medical referrals towards more team based and patient-centred timely transitions. Further research focused on the experiences of doctors, allied health professionals, patients and families is required to provide a broader interdisciplinary understanding of futility and contributions to the negotiation of palliative care. PMID- 25270860 TI - Changes in left ventricular relaxation after azelnidipine treatment in hypertensive patients with diabetes: subanalysis of a prospective single-arm multicentre study. AB - OBJECTIVES: We previously demonstrated that a calcium channel blocker, azelnidipine, improves left ventricular relaxation in patients with hypertension and diastolic dysfunction in a multicentre, Clinical impact of Azelnidipine on Left VentricuLar diastolic function and OutComes in patients with hypertension (CALVLOC) trial. The objectives of the present subanalysis were to investigate the differences in diastolic function in hypertensive patients with and without diabetes, and the efficacy of azelnidipine on diastolic function among them. DESIGN: Subanalysis of a prospective single-arm multicentre study. PARTICIPANTS: 228 hypertensive patients with normal ejection fraction and impaired left ventricular relaxation (septal e' velocity<8 cm/s on echocardiography) enrolled for CALVLOC trial. They were divided into two groups based on presence or absence of diabetes. INTERVENTIONS: Administration of 16 mg of azelnidipine for 8 months (range 6-10 months). MAIN OUTCOME MEASURES: Septal e' velocity before and at the end of the study. RESULTS: Whereas patients with diabetes (n=53, 23.2%) had lower systolic blood pressure (BP) than patients without diabetes (155+/-17 vs 161+/-16 mm Hg, p=0.03), they had lower e' velocity (5.7+/-1.5 vs 6.1+/-1.4 cm/s, p=0.04) at baseline. Azelnidipine decreased BP and heart rate, and increased e' velocity similarly in patients with diabetes (5.7+/-1.5 to 6.3+/-1.5 cm/s, p=0.0003) and without diabetes (6.1+/-1.4 to 6.9+/-1.4 cm/s, p<0.0001). Increase in e' velocity was not influenced by presence of diabetes, and patients with diabetes still had lower e' velocity after treatment (p=0.006). There was a significant correlation between increase in e' velocity and decrease in systolic BP (R=0.25, p=0.0001), which was not influenced by diabetes. CONCLUSIONS: Comorbid diabetes could impair left ventricular relaxation independently in patients with hypertension, which might not be improved solely by BP lowering. PMID- 25270862 TI - Lateral skull base approaches in the management of benign parapharyngeal space tumors. AB - OBJECTIVE: To evaluate the role of lateral skull base approaches in the management of benign parapharyngeal space tumors and to propose an algorithm for their surgical approach. METHODS: Retrospective study of patients with benign parapharyngeal space tumors. The clinical features, radiology and preoperative management of skull base neurovasculature, the surgical approaches and overall results were recorded. RESULTS: 46 patients presented with 48 tumors. 12 were prestyloid and 36 poststyloid. 19 (39.6%) tumors were paragangliomas, 15 (31.25%) were schwannomas and 11 (23%) were pleomorphic adenomas. Preoperative embolization was performed in 19, stenting of the internal carotid artery in 4 and permanent balloon occlusion in 2 patients. 19 tumors were approached by the transcervical, 13 by transcervical-transparotid, 5 by transcervical-transmastoid, 6, 1 and 2 tumors by the infratemporal fossa approach types A, B and D, respectively. Total radical tumor removal was achieved in 46 (96%) of the cases. CONCLUSION: Lateral skull base approaches have an advantage over other approaches in the management of benign tumors of the parapharyngeal space due to the fact that they provide excellent exposure with less morbidity. The use of microscope combined with bipolar cautery reduces morbidity. Stenting of internal carotid artery gives a chance for complete tumor removal with arterial preservation. PMID- 25270861 TI - Study protocol for a double blind, randomised, placebo-controlled trial of continuous subpectoral local anaesthetic infusion for pain and shoulder function following mastectomy: SUB-pectoral Local anaesthetic Infusion following MastEctomy (SUBLIME) study. AB - INTRODUCTION: Over 16 000 mastectomies are performed in England and Wales annually. Acute postoperative pain and nausea are common. The most frequently occurring long-term complications are chronic pain (up to 50%) and reduced shoulder function (reported at 35%). Regional techniques that improve acute postoperative pain relief may reduce the incidence of these complications. This study assesses the effectiveness of a 24-hour continuous local anaesthetic in the subpectoral plane in improving postoperative pain and quality of life in patients undergoing mastectomy. METHODS AND ANALYSIS: This is a randomised, double blind, placebo-controlled, two-centre, parallel group trial in women undergoing mastectomy with or without axillary involvement. One hundred and sixty participants will be randomised in a 1:1 ratio to receive either 0.25% levobupivacaine or 0.9% saline by subpectoral infusion postoperatively for 24 h. All participants will be provided with an intravenous morphine patient-controlled analgesia (PCA) system. Participants will be followed-up for 24 h in hospital and at approximately 14 days and 6 months postoperatively. Joint primary outcome measures are total morphine consumption and total pain score (captured via patient-recorded visual analogue scale (VAS) 4 hourly) during the first 24 h postoperatively. Primary statistical analysis of total pain is based on the area under the curve of pain versus time graph. Secondary outcomes include PCA attempts in first 24 h; VAS pain scores and shoulder function by goniometry at 24 h, 14 days (approximately) and 6 months; Verbal Rating Scale pain scores in first 24 h; Brief Pain Inventory and Oxford Shoulder Score at 6 months; duration of hospital stay; incidence of postoperative nausea and vomiting; cost effectiveness. ETHICS AND DISSEMINATION: The study is approved by the South West England Research Ethics Committee (12/SW/0149). RESULTS: will be published in a peer-reviewed journal and presented at local, national and international scientific meetings. TRIAL REGISTRATION: ISRCTN46621916. EudraCT 2011-005775-16. PMID- 25270863 TI - Differential expression of periostin in the nasal polyp may represent distinct histological features of chronic rhinosinusitis. AB - OBJECTIVE: Chronic rhinosinusitis (CRS) is thought to be a multifactorial disease, and it is classified into a number of subtypes according to clinicohistological features. Periostin, a 90-kDa secreted protein, was reported to exist in nasal polyps (NPs) associated with CRS. We compared the expression of periostin with the degree of eosinophilic infiltration as well as tissue remodeling. MATERIALS AND METHODS: Tissue samples were collected from 28 patients of CRS with NPs, and clinicohistological features were evaluated. The pattern of periostin expression was assessed immunohistochemically. RESULT: Two patterns of periostin expression was observed in nasal polyps: "diffuse type", in which periostin was expressed throughout the lamina propria starting just below the basement membrane, and "superficial type", in which the protein was detected only in the subepithelial layers between the basement membrane and the nasal gland. The average infiltrated eosinophil count in the diffuse type was significantly higher than that in the superficial type (diffuse type 360.5+/-393.0 vs. superficial type 8.46+/-13.81, p=0.001). Tissue remodeling was observed in 17 (85.0%) of the 20 diffuse-type nasal polyps, but only in one (12.5%) of the eight superficial-type nasal polyps (p<0.001). CONCLUSION: At least two distinct patterns of periostin expression were observed in the nasal polyps associated with CRS in accordance with the heterogeneous mechanisms underlying the pathogenesis of CRS with NPs. PMID- 25270864 TI - Trends in single-cell analysis by use of ICP-MS. AB - The analysis of single cells is a growing research field in many disciplines such as toxicology, medical diagnosis, drug and cancer research or metallomics, and different methods based on microscopic, mass spectrometric, and spectroscopic techniques are under investigation. This review focuses on the most recent trends in which inductively coupled plasma mass spectrometry (ICP-MS) and ICP optical emission spectrometry (ICP-OES) are applied for single-cell analysis using metal atoms being intrinsically present in cells, taken up by cells (e.g., nanoparticles), or which are artificially bound to a cell. For the latter, especially element tagged antibodies are of high interest and are discussed in the review. The application of different sample introduction systems for liquid analysis (pneumatic nebulization, droplet generation) and elemental imaging by laser ablation ICP-MS (LA-ICP-MS) of single cells are highlighted. Because of the high complexity of biological systems and for a better understanding of processes and dynamics of biologically or medically relevant cells, the authors discuss the idea of "multimodal spectroscopies." PMID- 25270865 TI - A micropixelated ion-imaging detector for mass resolution enhancement of a QMS instrument. AB - An in-vacuum position-sensitive micropixelated detector (Timepix) is used to investigate the time-dependent spatial distribution of different charge state (and hence different mass-to-charge (m/z)) ions exiting an electrospray ionization (ESI)-based quadrupole mass spectrometer (QMS) instrument. Ion images obtained from the Timepix detector provide a detailed insight into the positions of stable and unstable ions of the mass peak as they exit the QMS. With the help of image processing algorithms and by selecting areas on the ion images where more stable ions impact the detector, an improvement in mass resolution by a factor of 5 was obtained for certain operating conditions. Moreover, our experimental approach of mass resolution enhancement was confirmed by in-house developed novel QMS instrument simulation software. Utilizing the imaging-based mass resolution enhancement approach, the software predicts instrument mass resolution of ~1,0000 for a single-filter QMS instrument with a 210-mm long mass filter and a low operating frequency (880 kHz) of the radio frequency (RF) voltage. PMID- 25270866 TI - Mass spectrometric analysis of pharmaceutical adulterants in products labeled as botanical dietary supplements or herbal remedies: a review. AB - The increased availability and use of botanical dietary supplements and herbal remedies among consumers has been accompanied by an increased frequency of adulteration of these products with synthetic pharmaceuticals. Unscrupulous producers may add drugs and analogues of various classes, such as phosphodiesterase type 5 (PDE-5) inhibitors, weight loss, hypoglycemic, antihypertensive and anti-inflammatory agents, or anabolic steroids, to develop or intensify biological effects of dietary supplements or herbal remedies. The presence of such adulterated products in the marketplace is a worldwide problem and their consumption poses health risks to consumers. Analytical methods that allow rapid and reliable testing of dietary supplements for the presence of synthetic drugs are needed to address such fraudulent practices. Mass spectrometry (MS) and hyphenated techniques such as liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) have become primary tools in this endeavor. The present review critically assesses the role and summarizes the applications of MS in the analysis of pharmaceutical adulterants in botanical dietary supplements and herbal remedies. The uses of MS techniques in detection, confirmation, and quantification of known pharmaceutical adulterants as well as in screening for and structure elucidation of unexpected adulterants and novel designer drugs are discussed. PMID- 25270867 TI - Computer-aided method for identification of major flavone/flavonol glycosides by high-performance liquid chromatography-diode array detection-tandem mass spectrometry (HPLC-DAD-MS/MS). AB - A new computational tool is proposed here for tentatively identifying major (UV quantifiable) flavone/flavonol glycoside peaks of high performance liquid chromatogram (HPLC)-diode array detection (DAD)-tandem mass spectrometry (MS/MS) profiles based on a MATLAB-based script implementing an in-house algorithm. The HPLC-DAD-MS/MS profiles of red onion, Chinese lettuce, carrot leaf, and celery seed extracts were analyzed by the proposed computer-aided screening method for identifying possible flavone/flavonol glycoside peaks from the HPLC-UV and MS total ion current (TIC) chromatograms. The number of identified flavone/flavonol glycoside peaks of the HPLC-UV chromatograms is four, four, six, and nine for red onion, Chinese lettuce, carrot leaf, and celery seed, respectively. These results have been validated by human(s) experts. For the batch processing of nine HPLC DAD-MS/MS profiles of celery seed extract, the entire script execution time was within 15 s while manual calculation of only one HPLC-DAD-MS/MS profile by a flavonoid expert could take hours. Therefore, this MATLAB-based screening method is able to facilitate the HPLC-DAD-MS/MS analysis of flavone/flavonol glycosides in plants to a large extent. PMID- 25270868 TI - Treatment of nanofiltration concentrates of mature landfill leachate by a coupled process of coagulation and internal micro-electrolysis adding hydrogen peroxide. AB - In this study, a coupled process of coagulation and aerated internal micro electrolysis (IME) with the in situ addition of hydrogen peroxide (H2O2) was investigated for the treatment of nanofiltration (NF) concentrate from mature landfill leachate. The acceptable operating conditions were determined as follows: initial pH 4, polymeric aluminium chloride dosage of 525 mg-Al2O3/L in the coagulation process, H2O2 dosage of 0.75 mM and an hydraulic retention time of 2 h in an aerated IME reactor. As a result, the removal efficiencies for chemical oxygen demand (COD), total organic carbon, UV254 and colour were 79.2%, 79.6%, 81.8% and 90.8%, respectively. In addition, the ratio of biochemical oxygen demand (BOD5)/COD in the final effluent increased from 0.03 to 0.31, and that of E2/E4 from 12.4 to 38.5, respectively. The results indicate that the combined process is an effective and economical way to remove organic matters and to improve the biodegradability of the NF concentrate. Coagulation process reduces the adverse impact of high-molecular-weight organic matters such as humic acids, on the aerated IME process. A proper addition of H2O2 in the aerated IME can promote the corrosion of solid iron (Fe2+/Fe3+) and cause a likely domino effect in the enhancement of removal efficiencies. PMID- 25270869 TI - Infrequent enuresis, the uninvestigated majority comparisons between children with enuresis of varying severity. AB - OBJECTIVE: The main objective was to compare children with frequent enuresis (FE) and children with infrequent enuresis (IE) using anamnestic data and variables related to bladder and kidney function. A secondary aim was to look at the group of children who wet their beds every single night, a phenomenon we chose to call constant enuresis (CE). SUBJECTS AND METHODS: The parents recorded the number of wet and dry nights for a period of 14 days, and measured the voided volumes as well as nocturnal urine production for 48 h. History data relevant to bladder and bowel function was also recorded. RESULTS: The children could be grouped as follows: IE, n = 14; FE, n = 18; and CE, n = 22. The children with IE were slightly older than the other groups, IE mean 7.57; FE mean 6.22; CE, mean 6.56 (p = 0.004). When comparing the groups in terms of the measured parameters, only one significant difference was found: the FE group had larger average daytime voided volumes, but only when the first morning void was included. The only significantly differing anamnestic variable was previous daytime incontinence, which was more common among the children in the IE group. CONCLUSIONS: When comparing children with varying enuresis severity, no major differences regarding bladder function and urine production were found. Furthermore, children with infrequent enuresis tend to be slightly older when they seek medical help. PMID- 25270870 TI - Experimental studies of remarkable monoamine releases and neural resistance to the transient ischemia and reperfusion. AB - INTRODUCTION: The literature described that neural damage caused by ischemia definitely occurs in brain areas. However, few studies have shown real-time changes of extracellular monoamine levels at the time of transient ischemia. METHODS: We examined changes in the responses of dopamine (DA) and serotonin (5 HT) release in the nucleus accumbens (ACC) of rats treated with four-vessel occlusion (4VO) in experiment 1. In the second experiment, we investigated the selective neural vulnerabilities among the ACC, lateral hypothalamus (LH), and frontal cortex (FC) of rats treated with 4VO and four days of reperfusion. RESULTS: The extracellular levels of DA and 5-HT were remarkably increased 200- and 20-fold upon the 10-min clipping of both common carotid arteries in transient cerebral ischemia, respectively. Each increased monoamine release returned to the baseline levels immediately. The release of DA in the ACC and FC was significantly decreased in the rats treated with the coagulation of bilateral vertebral arteries (2VO), compared with that of sham-operated rats. K(+)-induced DA release in the ACC and FC of 4VO-treated rats was increased without alteration of DA content. DISCUSSION: Surviving dopaminergic neurons in the ACC and FC showed neural hyperfunction associated with the monoamine release, serotonergic neurons in particular these areas exhibiting functional resistance to the transient ischemic change. CONCLUSION: It is suggested that the remarkable extracellular release of DA and 5-HT was not the cause of the ischemic delayed neural degeneration in each brain area, and that the functions of neurotransmitter release involved remarkable resistance to the transient ischemia. PMID- 25270871 TI - Effects of gastrokine-2 expression on gastric cancer cell apoptosis by activation of extrinsic apoptotic pathways. AB - Gastrokine-2 is a putative gastric cancer-specific tumor suppressor gene, the loss of which is known to be involved in the development and progression of gastric cancer, and restoration of gastrokine-2 expression inhibits growth of gastric cancer cells in vitro. However, the underlying mechanism of these effects requires elucidation. In the present study, expression patterns of gastrokine-2 protein were examined in gastric cancer tissues and cell lines. Expression of gastrokine-2 was restored in gastric cancer cells in order to assess its effect on cell viability, apoptosis and gene expression. A total of 76 gastric cancer tissues with corresponding normal mucosae samples, and two gastric cancer cell lines (SGC-7901 and AGS) were subjected to western blot analysis of gastrokine-2 expression. SGC-7901 cells were transiently transfected with gastrokine-2 cDNA and then treated with anti-CD95 and/or anti-Fas antibodies prior to analysis of cell viability, apoptosis and gene expression levels. Expression of gastrokine-2 protein was reduced or absent in gastric cancer tissues and gastric cancer cell lines. Following restoration of gastrokine-2 expression, the protein expression level of Fas was significantly increased, but no marked change was observed in the levels of bcl-2 and Bax proteins. Expression of gastrokine-2 protein reduced gastric cancer cell viability and induced apoptosis. Activity of caspase-3 and caspase-8 was increased, but caspase-9 activity remained unchanged in the SGC 7901 cells. Reduction or knockout of gastrokine-2 protein expression may contribute to gastric cancer development or progression, as the current study demonstrated that restoration of gastrokine-2 expression induces apoptosis of gastric cancer cells through the extrinsic apoptosis pathway. PMID- 25270872 TI - A rare association between Fabry's disease and granulomatosis with polyangiitis: a potential pathogenic link. AB - BACKGROUND: Fabry's disease is a rare X-linked, hereditary lysosomal storage disease caused by a deficiency of the enzyme alpha-galactosidase A. Granulomatosis with polyangiitis is characterized by the involvement of the respiratory tract and kidneys. Here, we report the first case of the coexistence of these diseases. CASE PRESENTATION: We describe a 29-year-old man suffering from fever with maxillary sinusitis, multiple lung nodules, and proteinuria. He was diagnosed with Fabry's disease accompanying granulomatosis with polyangiitis on the basis of the low activity of peripheral leukocyte alpha-galactosidase A and pathological findings in the lung and kidney. Glucocorticoid and cyclophosphamide were administered, followed by enzyme replacement therapy. Progression to end-stage renal disease has not been observed for 6 years until the time of drafting this manuscript. CONCLUSION: Because both Fabry's disease and granulomatosis with polyangiitis or crescentic glomerulonephritis are rare diseases, their concurrence in this and related cases suggests there may be a pathogenic link between these two conditions. Fabry's disease may be underdiagnosed, particularly in cases of granulomatosis with polyangiitis or crescentic glomerulonephritis. PMID- 25270875 TI - Structure of the complete bacterial SRP Alu domain. AB - The Alu domain of the signal recognition particle (SRP) arrests protein biosynthesis by competition with elongation factor binding on the ribosome. The mammalian Alu domain is a protein-RNA complex, while prokaryotic Alu domains are protein-free with significant extensions of the RNA. Here we report the crystal structure of the complete Alu domain of Bacillus subtilis SRP RNA at 2.5 A resolution. The bacterial Alu RNA reveals a compact fold, which is stabilized by prokaryote-specific extensions and interactions. In this 'closed' conformation, the 5' and 3' regions are clamped together by the additional helix 1, the connecting 3-way junction and a novel minor groove interaction, which we term the 'minor-saddle motif' (MSM). The 5' region includes an extended loop-loop pseudoknot made of five consecutive Watson-Crick base pairs. Homology modeling with the human Alu domain in context of the ribosome shows that an additional lobe in the pseudoknot approaches the large subunit, while the absence of protein results in the detachment from the small subunit. Our findings provide the structural basis for purely RNA-driven elongation arrest in prokaryotes, and give insights into the structural adaption of SRP RNA during evolution. PMID- 25270874 TI - What do mouse models of muscular dystrophy tell us about the DAPC and its components? AB - There are over 30 mouse models with mutations or inactivations in the dystrophin associated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated. PMID- 25270877 TI - CODEX: a next-generation sequencing experiment database for the haematopoietic and embryonic stem cell communities. AB - CODEX (http://codex.stemcells.cam.ac.uk/) is a user-friendly database for the direct access and interrogation of publicly available next-generation sequencing (NGS) data, specifically aimed at experimental biologists. In an era of multi centre genomic dataset generation, CODEX provides a single database where these samples are collected, uniformly processed and vetted. The main drive of CODEX is to provide the wider scientific community with instant access to high-quality NGS data, which, irrespective of the publishing laboratory, is directly comparable. CODEX allows users to immediately visualize or download processed datasets, or compare user-generated data against the database's cumulative knowledge-base. CODEX contains four types of NGS experiments: transcription factor chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-Seq), histone modification ChIP-Seq, DNase-Seq and RNA-Seq. These are largely encompassed within two specialized repositories, HAEMCODE and ESCODE, which are focused on haematopoiesis and embryonic stem cell samples, respectively. To date, CODEX contains over 1000 samples, including 221 unique TFs and 93 unique cell types. CODEX therefore provides one of the most complete resources of publicly available NGS data for the direct interrogation of transcriptional programmes that regulate cellular identity and fate in the context of mammalian development, homeostasis and disease. PMID- 25270876 TI - Paramecium tetraurelia chromatin assembly factor-1-like protein PtCAF-1 is involved in RNA-mediated control of DNA elimination. AB - Genome-wide DNA remodelling in the ciliate Paramecium is ensured by RNA-mediated trans-nuclear crosstalk between the germline and the somatic genomes during sexual development. The rearrangements include elimination of transposable elements, minisatellites and tens of thousands non-coding elements called internally eliminated sequences (IESs). The trans-nuclear genome comparison process employs a distinct class of germline small RNAs (scnRNAs) that are compared against the parental somatic genome to select the germline-specific subset of scnRNAs that subsequently target DNA elimination in the progeny genome. Only a handful of proteins involved in this process have been identified so far and the mechanism of DNA targeting is unknown. Here we describe chromatin assembly factor-1-like protein (PtCAF-1), which we show is required for the survival of sexual progeny and localizes first in the parental and later in the newly developing macronucleus. Gene silencing shows that PtCAF-1 is required for the elimination of transposable elements and a subset of IESs. PTCAF-1 depletion also impairs the selection of germline-specific scnRNAs during development. We identify specific histone modifications appearing during Paramecium development which are strongly reduced in PTCAF-1 depleted cells. Our results demonstrate the importance of PtCAF-1 for the epigenetic trans-nuclear cross-talk mechanism. PMID- 25270878 TI - CancerPPD: a database of anticancer peptides and proteins. AB - CancerPPD (http://crdd.osdd.net/raghava/cancerppd/) is a repository of experimentally verified anticancer peptides (ACPs) and anticancer proteins. Data were manually collected from published research articles, patents and from other databases. The current release of CancerPPD consists of 3491 ACP and 121 anticancer protein entries. Each entry provides comprehensive information related to a peptide like its source of origin, nature of the peptide, anticancer activity, N- and C-terminal modifications, conformation, etc. Additionally, CancerPPD provides the information of around 249 types of cancer cell lines and 16 different assays used for testing the ACPs. In addition to natural peptides, CancerPPD contains peptides having non-natural, chemically modified residues and D-amino acids. Besides this primary information, CancerPPD stores predicted tertiary structures as well as peptide sequences in SMILES format. Tertiary structures of peptides were predicted using the state-of-art method, PEPstr and secondary structural states were assigned using DSSP. In order to assist users, a number of web-based tools have been integrated, these include keyword search, data browsing, sequence and structural similarity search. We believe that CancerPPD will be very useful in designing peptide-based anticancer therapeutics. PMID- 25270879 TI - Weak base pairing in both seed and 3' regions reduces RNAi off-targets and enhances si/shRNA designs. AB - The use of RNA interference is becoming routine in scientific discovery and treatment of human disease. However, its applications are hampered by unwanted effects, particularly off-targeting through miRNA-like pathways. Recent studies suggest that the efficacy of such off-targeting might be dependent on binding stability. Here, by testing shRNAs and siRNAs of various GC content in different guide strand segments with reporter assays, we establish that weak base pairing in both seed and 3' regions is required to achieve minimal off-targeting while maintaining the intended on-target activity. The reduced off-targeting was confirmed by RNA-Seq analyses from mouse liver RNAs expressing various anti-HCV shRNAs. Finally, our protocol was validated on a large scale by analyzing results of a genome-wide shRNA screen. Compared with previously established work, the new algorithm was more effective in reducing off-targeting without jeopardizing on target potency. These studies provide new rules that should significantly improve on siRNA/shRNA design. PMID- 25270880 TI - Quantifying the physical and socio-economic burden of filarial lymphoedema in Chikwawa District, Malawi. AB - BACKGROUND: Lymphatic filariasis (LF) is a disfiguring parasitic disease and one of the leading causes of disability in the world. This study aimed to assess the severity of lymphoedema, the physical restrictions and socio-economic impact on affected individuals living in an endemic community in Malawi. METHODS: In a single health centre catchment area, a follow-up survey was conducted to assess 69 lymphoedema cases, and the impact of their condition in eight different areas of their lives. Differences were examined by sex, age and severity of disease. The overall level of disability was quantified and the impact of acute dermatolymphangioadenitis (ADLA) attacks was examined. RESULTS: Lymphoedema cases were most affected by pain/discomfort and anxiety/depression, which also had an economic impact. Male and older (>60 years) individuals reported more problems. Higher disability levels based on a quantified score were significantly associated with decreased walking distance and working hours. ADLA significantly increased pain/discomfort and reduced cognition, and also affected the individuals' self-care, social participation and ability to work. CONCLUSIONS: Filarial lymphoedema causes significant hardship, particularly in relation to ADLAs, and the scale of the problem needs to be better defined with new specific tools so that the best support and care can be provided to those in greatest need. PMID- 25270881 TI - Hydration energies of protonated and sodiated thiouracils. AB - Hydration reactions of protonated and sodiated thiouracils (2-thiouracil, 6 methyl-2-thiouracil, and 4-thiouracil) generated by electrospray ionization have been studied in a gas phase at 10 mbar using a pulsed ion-beam high-pressure mass spectrometer. The thermochemical data, DeltaH(o)n, DeltaS(o)n, and DeltaG(o)n, for the hydrated systems were obtained by equilibrium measurements. The water binding energies of protonated thiouracils, [2SU]H(+) and [6Me2SU]H(+), were found to be of the order of 51 kJ/mol for the first, and 46 kJ/mol for the second water molecule. For [4SU]H(+), these values are 3-4 kJ/mol lower. For sodiated complexes, these energies are similar for all studied systems, and varied between 62 and 68 kJ/mol for the first and between 48 and 51 kJ/mol for the second water molecule. The structural aspects of the precursors for hydrated complexes are discussed in conjunction with available literature data. PMID- 25270882 TI - Country progress towards the Millennium Development Goals: adjusting for socioeconomic factors reveals greater progress and new challenges. AB - BACKGROUND: The health Millennium Development Goals (4, 5, 6) impose the same ambitious 2015 targets on every country. Few low-income countries are on track to reach them. Some authors have proposed country-specific targets as a more informative method by which countries can measure their progress against their potential. METHODS: This paper demonstrates a supplementary approach to assess individual country progress that complements the global goals by adjusting for socioeconomic resources and prior time trends. A minimum performance target adjusts for time and national GDP. Fast-track targets, based on best-performing countries' progress within regional and income groups, adjust for health and non health sector factors known to affect maternal and child health. RESULTS: Measuring by the minimum performance target, 74% and 59% of low- and middle income countries are on track for reducing child mortality and maternal mortality, respectively, compared with 69% and 22% using global MDGs. Only 20% and 7% of low- and middle-income countries are on track for the child and maternal mortality fast-track targets. CONCLUSIONS: Supplementary targets in maternal and child health, adjusted for each country's resources and policy performance can help countries know if they are truly underperforming relative to their potential. Adjusted targets can also flag countries that have surpassed their potential, and open opportunities for learning from success. FUNDING: Partnership for Maternal, Newborn & Child Health and the Alliance for Health Policy and Systems Research, as part of the Success Factors Study on reducing maternal and child mortality. PMID- 25270883 TI - Collateral Vessel Formation Causes Clinical Recovery From Limb Ischemia in a Mouse Model. AB - Experimental models of recovery from limb ischemia are required for evaluating novel means of treating ischemia. We describe a mouse model to assess gait after inducing limb ischemia. Gait analysis was performed using a Plexiglass tube, the floor of which contained load cells. Gait was measured in 20 mice; 10 underwent ligation of the right hind limb artery and the other 10 underwent a sham operation. The gait of the animals was measured at 1, 2, and 4 weeks following the procedure. In sham-operated animals, the gait showed no measurable change. In the ligated animals, the ratio of the right fore-to-hind limb changed from 1.07 at baseline to 1.4 at day 0 (P = .001), 1.16 (P = .012 compared with control), and 1.04 (P = .37 compared with control) at weeks 2 and 4, respectively. Gait returned to normal within 4 weeks of induction of ischemia. This model may be helpful in testing potential novel therapies. PMID- 25270884 TI - Citation analysis in health care sciences. Innovative investigation or seductive pseudo-science? AB - BACKGROUND: Citations of scientific papers in health care have become a subject of interest, as in any scientific sector. However, such a metric, while useful in a simple way, can become subject to too much credibility, and therefore to advanced analyses which are not soundly grounded even if methodologically valid. OBJECTIVES: The objective was to contextualise citation indices in health care science, juxtaposed with a parallel analytic paper. METHODS: The literature was reviewed and set against the objectives of metrics of literature and of researchers. RESULTS: The strengths and weaknesses of citation indices in the health sector were identified, with practical examples of perverse effects, and compared with the core objectives of health care development. CONCLUSIONS: Citation indices in health care science have a value, but this is limited to giving a broad overview. Other measures of effectiveness, including impact on education, on health care development, and on stimulation of applied developments, are needed rather than spuriously scientific advanced analyses of citation counts. PMID- 25270885 TI - Solution structure of a C-terminal fragment (175-257) of CV_0373 protein from Chromobacterium violaceum adopts a winged helix-turn-helix (wHTH) fold. PMID- 25270887 TI - The effect of self efficacy and meaning in life on posttraumatic stress disorder and depression severity among veterans. AB - OBJECTIVE: The current study examined the relationships among combat exposure, presence of and search for meaning in life, general and social self-efficacy, and both posttraumatic stress disorder (PTSD) and depression symptom severity for a Veteran sample (N = 93). METHOD: Participants completed an online survey comprising the Combat Exposure Scale, Meaning in Life Questionnaire, Self Efficacy Scale, Depression subscale of the Depression, Anxiety, Stress Scales-21, and PTSD Checklist-Specific Stressor version. The majority of participants were male and Caucasian. Participants served in various service eras RESULTS: To determine factors that predicted PTSD and depression severity, separate hierarchical linear regressions were performed. In the final PTSD model, rank, combat exposure, and general self-efficacy were significant predictors, with officer rank, lower combat exposure, and higher general self-efficacy associated with lower PTSD severity. The interaction between combat exposure and general self-efficacy was also significant, with self-efficacy moderating the relationship between combat exposure and PTSD severity. For depression, rank, presence of meaning in life, and general self-efficacy were significant predictors in the model, with officer rank, higher presence of meaning in life, and general self-efficacy associated with lower depression severity. CONCLUSION: A focus on strengthening self-efficacy may assist with lower levels of PTSD and depression symptomatology after combat trauma. PMID- 25270886 TI - Prevention of generalized anxiety disorder using a web intervention, iChill: randomized controlled trial. AB - BACKGROUND: Generalized Anxiety Disorder (GAD) is a high prevalence, chronic disorder. Web-based interventions are acceptable, engaging, and can be delivered at scale. Few randomized controlled trials evaluate the effectiveness of prevention programs for anxiety, or the factors that improve effectiveness and engagement. OBJECTIVE: The intent of the study was to evaluate the effectiveness of a Web-based program in preventing GAD symptoms in young adults, and to determine the role of telephone and email reminders. METHODS: A 5-arm randomized controlled trial with 558 Internet users in the community, recruited via the Australian Electoral Roll, was conducted with 6- and 12-month follow-up. Five interventions were offered over a 10-week period. Group 1 (Active website) received a combined intervention of psycho-education, Internet-delivered Cognitive Behavioral Therapy (ICBT) for anxiety, physical activity promotion, and relaxation. Group 2 (Active website with telephone) received the identical Web program plus weekly telephone reminder calls. Group 3 (Active website with email) received the identical Web program plus weekly email reminders. Group 4 (Control) received a placebo website. Group 5 (Control with telephone) received the placebo website plus telephone calls. Main outcome measures were severity of anxiety symptoms as measured by the GAD 7-item scale (GAD-7) (at post-test, 6, and 12 months). Secondary measures were GAD caseness, measured by the Mini International Neuropsychiatric Interview (MINI) at 6 months, Centre for Epidemiologic Studies Depression scale (CES-D), Anxiety Sensitivity Index (ASI), Penn State Worry Questionnaire (PSWQ), and Days out of Role. RESULTS: GAD-7 symptoms reduced over post-test, 6-month, and 12-month follow-up. There were no significant differences between Group 4 (Control) and Groups 1 (Active website), 2 (Active website with telephone), 3 (Active website with email), or 5 (Control with telephone) at any follow-up. A total of 16 cases of GAD were identified at 6 months, comprising 6.7% (11/165) from the Active groups (1, 2, 3) and 4.5% (5/110) from the Control groups (4, 5), a difference that was not significant. CES-D, ASI, and PSWQ scores were significantly lower for the active website with email reminders at post test, relative to the control website condition. CONCLUSIONS: Indicated prevention of GAD was not effective in reducing anxiety levels, measured by GAD 7. There were significant secondary effects for anxiety sensitivity, worry, and depression. Challenges for indicated prevention trials are discussed. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 76298775; http://www.controlled-trials.com/ISRCTN76298775 (Archived by WebCite at http://www.webcitation.org/6S9aB5MAq). PMID- 25270888 TI - Photoactive chitosan: a step toward a green strategy for pollutant degradation. AB - This article is a highlight of the paper by Ferrari et al. in this issue of Photochemistry and Photobiology. It describes the innovative use of rose bengal conjugated chitosan as a reusable green catalyst that photo-degrades phenolic compounds in aqueous media, and thereby has decontamination potential of polluted waters. Whether a next-generation photoactive polymer that produces singlet oxygen is a solution to pollutant degradation can be argued. It is as yet unclear what polymeric sensitizer would be practical on a large scale. Nonetheless pursuing this goal is worthwhile. PMID- 25270889 TI - Treatment of potato tubers with the synthetic cytokinin 1-(alpha-ethylbenzyl)-3 nitroguanidine results in rapid termination of endodormancy and induction of transcripts associated with cell proliferation and growth. AB - Perennial plants undergo repression of meristematic activity in a process called dormancy. Dormancy is a complex metabolic process with implications for plant breeding and crop yield. Endodormancy, a specific subclass of dormancy, is characteristic of internal physiological mechanisms resulting in growth suppression. In this study, we examine transcriptional changes associated with the natural cessation of endodormancy in potato tuber meristems and in endodormant tubers treated with the cytokinin analog 1-(alpha-ethylbenzyl)-3 niroguanidine (NG), which terminates dormancy. RNA-sequencing was used to examine transcriptome changes between endodormant and non-dormant meristems from four different harvest years. A total of 35,091 transcripts were detected with 2132 differentially expressed between endodormant and non-dormant tuber meristems. Endodormant potato tubers were treated with the synthetic cytokinin NG and transcriptome changes analyzed using RNA-seq after 1, 4, and 7 days following NG exposure. A comparison of natural cessation of dormancy and NG-treated tubers demonstrated that by 4 days after NG exposure, potato meristems exhibited transcriptional profiles similar to the non-dormant state with elevated expression of multiple histones, a variety of cyclins, and other genes associated with proliferation and cellular replication. Three homologues encoding for CYCD3 exhibited elevated expression in both non-dormant and NG-treated potato tissues. These results suggest that NG terminates dormancy and induces expression cell cycle-associated transcripts within 4 days of treatment. PMID- 25270891 TI - Oligosaccharides composition in eight food legumes species as detected by high resolution mass spectrometry. AB - BACKGROUND: As probiotics, soy oligosaccharides have become popular as healthy foods to reduce disease risk. However, comprehensive information about oligosaccharides in different food legumes is limited. RESULTS: In this study, eight oligosaccharides were well detected and quantified in different varieties of eight legume species using high-resolution mass spectrometry. It was determined that species could be distinguished by total content of oligosaccharides and their distribution modes. Among the studied species, Vigna unguiculata is a better resource of non-digestible oligosaccharides, while Vicia faba and black soybean (Glycine max) are at a disadvantage. Normally, stachyose predominates in non-digestible oligosaccharides, except in mung bean and broad bean, where verbascose predominates. For mung bean and green soybean, the seed coat should be taken into account for oligosaccharide consumption. The developed high-resolution mass spectrometry method greatly simplified the sample preparation process and permitted the identification of oligosaccharides without reference compounds. CONCLUSION: This work involved extensive sample collecting and provided useful information for consumers. The developed method may be useful for rapid quantification of oligosaccharides in related foods. PMID- 25270890 TI - Differential expression of peroxidase and ABC transporter as the key regulatory components for degradation of azo dyes by Penicillium oxalicum SAR-3. AB - Fungal species are potential dye decomposers since these secrete spectra of extracellular enzymes involved in catabolism. However, cellular mechanisms underlying azo dye catalysis and detoxification are incompletely understood and obscure. A potential strain designated as Penicillium oxalicum SAR-3 demonstrated broad-spectrum catabolic ability of different azo dyes. A forward suppression subtractive hybridization (SSH) cDNA library of P. oxalicum SAR-3 constructed in presence and absence of azo dye Acid Red 183 resulted in identification of 183 unique expressed sequence tags (ESTs) which were functionally classified into 12 functional categories. A number of novel genes that affect specifically organic azo dye degradation were discovered. Although the ABC transporters and peroxidases emerged as prominent hot spot for azo dye detoxification, we also identified a number of proteins that are more proximally related to stress responsive gene expression. Majority of the ESTs (29.5%) were grouped as hypothetical/unknown indicating the presence of putatively novel genes. Analysis of few ESTs through quantitative real-time reverse transcription polymerase chain reaction revealed their possible role in AR183 degradation. The ESTs identified in the SSH library provide a novel insight on the transcripts that are expressed in P. oxalicum strain SAR-3 in response to AR183. PMID- 25270892 TI - Sleep in the intensive care unit - nurses' documentation and patients' perspectives. AB - BACKGROUND: Inability to sleep is one of the most distressing factors for patients in the intensive care unit (ICU). Sleep is perceived as light and awakenings are numerous. Nurses' documentations of sleep are narrow, mainly concentrating on the quantity and general quality. Nurses should diversely evaluate, document and promote sleep to provide patient centered care. AIM: To investigate the content of nurses' documentation about the sleep of ICU patients, patients' own perceptions of sleep, and the correspondence of the two. DESIGN AND METHODS: Nurses' documentations (n = 90) were analysed retrospectively with quantitative content analysis. A cross-sectional survey of patients' (n = 114) perspectives was collected with the five-item Richards-Campbell Sleep Questionnaire (RCSQ), on a visual analogue scale from 0 (the poorest quality sleep) to 100 (optimum sleep). The data was analysed statistically. Correspondence was tested with cross-tabulation. RESULTS: Nurses documented sleep quantity for 71% and quality for 27% of patients, along with the needs assessment, used interventions and their effect on sleep. Patients' perspectives varied widely. Sleep depth was rated the lowest and falling asleep highest of the RCSQ sleep domains. Age of the patients correlated positively with general quality of sleep, sleep depth and falling asleep. Nurses' documentations and patients' perceptions correlated in over half of the cases. CONCLUSIONS: Nurses' documentation of ICU patients' sleep is not systematic or comprehensive and corresponds only partially with patients' own perception. The sleep of non intubated patients is light and awakenings are frequent. Documentation of ICU patients' sleep should include the whole nursing process, i.e. needs assessment, interventions used, and evaluation of sleep and the effects of the interventions, along with patients' own perspective to promote patient-centered care. RELEVANCE TO CLINICAL PRACTICE: Evaluation and documentation of patients' sleep must include patients' own perception to be comprehensive. Nurses' documentation should include all elements of nursing process. PMID- 25270893 TI - Decrease in chymase activity is associated with increase in IL-6 expression in mast cells in atopic dermatitis. AB - Mast cell chymase and interleukin (IL)-6 can be involved in atopic dermatitis and chymase can degrade IL-6. Our aim was therefore to study the expression of mast cell chymase and IL-6 in atopic skin using enzyme- and immunohistochemistry and to analyse their interaction in vitro. Chymase activity was significantly reduced in mast cells in skin lesions whereas the percentage of IL-6(+) mast cells was increased. Low recombinant human (rh)-chymase concentration (10-100 ng/ml) stimulated and higher concentration (1,000 ng/ml) inhibited the proliferation of T cells and peripheral blood mononuclear cells. Rh-IL-6 inhibited T-cell proliferation, and even inhibited the proliferation induced by rh-chymase. Pretreatment of rh-IL-6 with a high rh-chymase concentration prevented the IL-6 induced inhibition in T-cell proliferation. The results suggest that reduction in chymase activity can give rise to increased cellular effects of mast cell IL-6 and that chymase and IL-6 can modify each other's effects. PMID- 25270894 TI - Augmented screws in angular stable plating of the proximal humerus: what to do when revision is needed? AB - BACKGROUND: Bone cement augmentation of modified cannulated locking screws shows biomechanically and clinically good results for osteoporotic fracture management. Nevertheless, complications need to be considered. Therefore implant removal should be tested for feasibility. METHODS: Implant removal was simulated in 7 pairs of osteoporotic cadaveric humeri: During screw removal from an angular stable proximal humerus plate, we measured the maximum torque of 14 augmented screws and the corresponding 14 non-augmented screws on the contralateral humeri. After screw removal, specimens were cut along the screw axes to macroscopically investigate the impact of screw removal on the surrounding bone. In addition, we established a technique for cement removal in cases in which the screw head is obstructed with cement and therefore disables the insertion of the screwdriver. FINDINGS: The screw extraction torque measurements showed no significant differences between the two groups regarding one screw (screw 4 augmented: 1.52Nm, SD 0.25Nm vs. screw 4 non-augmented: 1.80Nm, SD 0.40Nm; P=0.20), whereas torque values for the second screw in the augmented group were lower than in the control group (screw 5 augmented: 0.72Nm, 0.31Nm vs. screw 5 non-augmented: 1.42Nm, 0.52Nm; P=0.009). Macroscopy of the bone showed no damage to the trabeculae within the humeral head due to the removal. INTERPRETATION: The removal of cannulated, polymethylmethacrylate-augmented, 2.8mm titanium screws from an angular stable plate was uncomplicated, without the need for special instruments or increased torque for screw removal. No additional damage was visible at the bone-cement interface. PMID- 25270895 TI - The methodical work approach and the reduction in the use of seclusion: how did it work? AB - The prevention of seclusion and other coercive measures has become a priority for mental health facilities, and numerous comprehensive programs to reduce the use of these containment procedures, have been developed. It is, however, poorly understood which interventions or elements of programs are effective and by which mechanisms or processes change is mediated. The present study explores the effects of an intervention by which a reduction in the use of seclusion was achieved. The intervention concerned a transformation of the treatment process, based on the principles of the methodical work approach, at a ward for the intensive treatment of patients with psychosis and substance use disorders. Changes in the working practice and team process were analyzed on the basis of case examples and team evaluation. The methodical work approach appears to have provided a guidance for the multidisciplinary team, the patient and the family to work together in a systematic and goal-directed way with cyclic evaluation and readjustment of the treatment and nurse care plan. Also implicit, positive changes were found in the team process: increased interdisciplinary collaboration, team cohesion, and professionalization. It is argued that the implicit or non-specific effects of an intervention to prevent seclusion may constitute a major contribution to the results and therefore merit further research. PMID- 25270896 TI - Factors predicting risk for PTSD among highly exposed civilians: two longitudinal studies. AB - The impact of exposure to constant, prolonged, life threatening, war-related stress is understudied. Previous studies did not examine stressors with an objective history of exposure to a traumatic event such as armed conflict. A set of predictors were assessed in two longitudinal studies. The studies included a civilian population (Study 1, N = 194; Study 2, N = 26) that was exposed to war related stress. Both groups had a documented objective history of the stressor. A set of logistic regression models in Study 1 and an hierarchical multiple regression in Study 2 were conducted in order to assess the relationship between various predictors from the aforementioned domains and PTSD symptoms. In Study 1, having an elevated risk for clinical level of ASD led to a higher probability of elevated risk for clinical level of PTSD (odds ratio = 7.772, 95% CI 1.225 49.300; p < .01). Similar results were found in Study 2, where ASD symptoms were the best predictor of PTSD symptoms (standardized beta = .644; t = 3.183; p < .01). Whereas ASD was a moderate predictor of PTSD in studies which focused mainly on the impact of a single traumatic event, ASD was a major and potent predictor of PTSD in the current studies which focused on prolonged traumatic exposure to war-related stress. PMID- 25270897 TI - Enantioseparation and thermodynamic study of naphthalene derivatives, new melatoninergic agonists, on coated amylose [tris(S)-1-phenylethylcarbamate] stationary phase. Transposition to preparative scale. AB - This work reports a high-performance liquid chromatography normal-phase methodology to elucidate enantiomers of naphthalene derivatives, evaluated as melatoninergic agonists. For this purpose four different polysaccharide based chiral stationary phases were evaluated, namely Chiralcel OD-H (cellulose tris 3,5-dimethylphenylcarbamate), Chiralcel OJ (cellulose tris-methylbenzoate), Chiralpak AD (amylose tris-3,5-dimethylphenylcarbamate) and Chiralpak AS (amylose tris-(S)-1-phenylethylcarbamate) with different alcoholic modifiers on different amounts in n-heptane. A temperature study was carried out, between 20 and 40 degrees C and the apparent thermodynamic parameters were calculated thanks to the Van't Hoff linearization. For all compounds (except 3), DeltaDeltaH degrees and DeltaDeltaS degrees exhibited positive values ranging from 791.2 to 9999.3 J/mol and from 3.9 to 37.8 J/K/mol respectively, indicating entropically driven separations. Optimized conditions led to goof resolution of 2.37 for compound 1 on Chiralpak AS, with heptane-2-propanol 90:10 (v/v), at a temperature of 30 degrees C. Then they were transposed to the preparative scale for compound 1, generating 22 mg of each enantiomer with an 80% yield. The limits of detection and of quantification were determined to allow the calculation of the enantiomeric excess. They were found with very low values, equal to 0.32 and 1.05 u m and 0.33 and 1.11 u m, respectively, for peaks 1 and 2 of compound 1. PMID- 25270898 TI - A minimal model of protein-protein binding affinities. AB - A minimal model of protein-protein binding affinity that takes into account only two structural features of the complex, the size of its interface, and the amplitude of the conformation change between the free and bound subunits, is tested on the 144 complexes of a structure-affinity benchmark. It yields Kd values that are within two orders of magnitude of the experiment for 67% of the complexes, within three orders for 88%, and fails on 12%, which display either large conformation changes, or a very high or a low affinity. The minimal model lacks the specificity and accuracy needed to make useful affinity predictions, but it should help in assessing the added value of parameters used by more elaborate models, and set a baseline for evaluating their performances. PMID- 25270899 TI - Effect of omission of population-based eye screening at age 6-9 months in the Netherlands. AB - PURPOSE: To investigate omission of population-based eye screening at age 6-9 months in the Netherlands. METHODS: Prospective population-based consecutive birth cohort study was used. In two consecutive birth cohorts, children were eye screened at 1-2 and 3-4 months, but at general-health screening at 6-9 months, the second cohort was not eye screened, unless anything conspicuous was noted or in case of positive family history. Data were collected from screening records and anonymous questionnaires. Semi-structured daylong observations were made of physicians examining children aged 0-4 years, including children from the cohorts, by two orthoptic students. RESULTS: 58 of 6059 children (0.96%), in the screened, and 48 of 5482 children (0.88%) in the unscreened group were referred to orthoptist or ophthalmologist, mostly for observed strabismus. Amblyopia, all combined with strabismus, was diagnosed in ten screened (0.17%) versus six unscreened children (0.11%). Most physicians found preverbal examinations and decisions to refer difficult. The observations by orthoptic students revealed that cover test, pupillary reflexes, pursuit movements and eye motility were frequently performed inadequately, contrary to the Hirschberg test, at this age. CONCLUSION: The screened and unscreened group differed little regarding the number of children referred and found to have amblyopia. Referral was mostly based on observed strabismus. PMID- 25270900 TI - Targeted temperature management at 33 degrees C versus 36 degrees C and impact on systemic vascular resistance and myocardial function after out-of-hospital cardiac arrest: a sub-study of the Target Temperature Management Trial. AB - BACKGROUND: Cardiovascular dysfunction is common after out-of-hospital cardiac arrest as part of the postcardiac arrest syndrome, and hypothermia may pose additional impact on hemodynamics. The aim was to investigate systemic vascular resistance index (SVRI), cardiac index, and myocardial performance at a targeted temperature management of 33 degrees C (TTM33) versus 36 degrees C (TTM36). METHODS AND RESULTS: Single-center substudy of 171 patients included in the Target Temperature Management Trial (TTM Trial) randomly assigned to TTM33 or TTM36 for 24 hours after out-of-hospital cardiac arrest. Mean arterial pressure >=65 mm Hg and central venous pressure of 10 to 15 mm Hg were hemodynamic treatment goals. Hemodynamic evaluation was performed by serial right heart catheterization and transthoracic echocardiography. Primary end point was SVRI after 24 hours of cooling and secondary end points included mean SVRI, cardiac index, systolic function, and lactate levels. The TTM33 group had a significant increase in SVRI compared with TTM36 (2595; 95% confidence interval, 2422-2767) versus 1960 (95% confidence interval, 1787-2134) dynes m(2)/s per cm(5); P<0.0001, respectively) after 24 hours of cooling with an overall difference of 556 dynes m(2)/s per cm(5) (P(group) <0.0001). TTM33 was associated with decreased cardiac index (-0.4 L/min per m(2); P(group) <0.0001), decreased heart rate (P(group)=0.01), and stroke volume index (P(group)=0.004) compared with TTM36. Left ventricular ejection fraction (P=0.39) and peak systolic myocardial velocity (P=0.62) did not differ between TTM groups. Lactate levels were significantly higher in the TTM33 group (P=0.0008). CONCLUSIONS: Targeted temperature management at 33 degrees C with target mean arterial pressure >=65 mm Hg is associated with increased SVRI and lower cardiac index because of lower heart rate with unaffected left ventricular systolic function compared with 36 degrees C. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01020916. PMID- 25270901 TI - Impact of aortic annulus size on valve hemodynamics and clinical outcomes after transcatheter and surgical aortic valve replacement: insights from the PARTNER Trial. AB - BACKGROUND: The objective was to evaluate the effects of aortic annulus size on valve hemodynamics and clinical outcomes in those patients included in the Placement of Aortic Transcatheter Valves (PARTNER) randomized controlled trial cohort A and the nonrandomized continued access cohort. METHODS AND RESULTS: Patients included the randomized controlled trial (n=574) and nonrandomized continued access (n=1358) cohorts were divided in tertiles according to aortic annulus diameter (small aortic annulus tertile, medium aortic annulus tertile, and large aortic annulus tertile [LAA], respectively) as measured by transthoracic echocardiography. Severe prosthesis-patient mismatch was defined as an effective aortic orifice area of <0.65 cm(2)/m(2). In the randomized controlled trial cohort, patients in the small aortic annulus tertile who underwent transcatheter aortic valve replacement had a lower incidence of severe prosthesis-patient mismatch (19.7% versus 37.5%; P=0.03) and only a trend toward a higher incidence of moderate-to-severe paravalvular leaks compared with surgical aortic valve replacement (5.7% versus 0%; P=0.06). In the LAA tertile, there were no differences in the rate of prosthesis-patient mismatch between groups, and a significant increase in moderate-to-severe paravalvular leaks was associated with transcatheter aortic valve replacement (9% versus 0%; P=0.01). There were no differences in mortality between transcatheter aortic valve replacement and surgical aortic valve replacement. In the nonrandomized continued access cohort, there were no differences in prosthesis-patient mismatch between the small aortic annulus and LAA tertiles, but a higher rate of moderate-to severe paravalvular leaks was observed in the LAA tertile (5.9% versus 11.5%; P=0.009). Patients in the LAA tertile had a higher mortality rate at 1-year follow-up (P=0.02), and differences persisted in multivariable analysis (P=0.048 for LAA versus medium aortic annulus tertile, P=0.035 for LAA versus small aortic annulus tertile). CONCLUSIONS: Aortic annulus size had a major impact on valve hemodynamics and clinical outcomes after transcatheter aortic valve replacement and surgical aortic valve replacement. This study highlights the importance of considering aortic annulus size in the evaluation of high-risk patients who are candidates for aortic valve replacement. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894. PMID- 25270902 TI - GSI Mann-Kendall Toolkit for quantitative analysis of plume concentration trends. PMID- 25270903 TI - A new cellular model of pathological TDP-43: The neurotoxicity of stably expressed CTF25 of TDP-43 depends on the proteasome. AB - The C-terminal fragments-25(CTF25) of TDP-43 is a fragment of TAR DNA-binding protein 43kDa (TDP-43), which is involved in RNA metabolism, neurite outgrowth, and neuronal development and stress granules. Not until recently did evidence suggest that CTF25 might play an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. However, mechanical details on CTF25 causing motor neuron degeneration still remain unknown. To study the toxicity of CTF25 of TDP-43, we established a cellular model stably expressing CTF25 of TDP-43. Herein, we found that stably expressed CTF25 could induce significant oxidative stress and was mainly degraded by the proteasome pathway in cells. Furthermore, the neurotoxicity of CTF25 of TDP-43 was dependent on proteasome activity. In addition, electron microscopy showed mitochondrial swelling and cristae dilation in cells expressing CTF25 and that CTF25 aggregates were characterized by filamentous bundles and electron dense granular material. In conclusion, the new cellular model mimics classical toxic TDP-43 cellular model and interestingly the toxicity of CTF25 is dependent on the proteasome. PMID- 25270904 TI - A novel rat model of Alzheimer's disease based on lentiviral-mediated expression of mutant APP. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by progressive and irreversible cognitive and memory impairment. The discovery of familial forms of AD (fAD) in association with specific gene mutations facilitated the generation of numerous rodent models. These models in turn proved valuable for the study of molecular mechanisms underlying AD pathogenesis, and facilitated translational research and preclinical drug development. This study aimed to introduce a new rat model of AD simulating some aspects of the sporadic cases of disease. METHODS: Lentiviruses (LV) encoding human amyloid protein precursor (APP) bearing the fAD-linked Swedish and Indiana mutations (APPSw/Ind) were injected bilaterally in the hippocampus of adult rats. Passive avoidance and spatial memory performance were assessed 30 and 45 days post-injection, respectively. APP overexpression, intracellular accumulation of beta-amyloid (Abeta) peptide, and astrogliosis were also evaluated using immunohistochemical procedures. RESULTS: Passive avoidance memory deficit was followed by impairments in spatial memory retrieval in LV (APPSw/Ind)-injected rats, compared to control animals. In addition, LV expression of APPSw/Ind was associated with intraneuronal accumulation of Abeta, and reactive astrocytosis, two major AD hallmarks. CONCLUSION: Results from this work suggest that LV-mediated delivery of APPSw/Ind in adult rats represents a cost and time-effective animal model for the study of mechanisms underlying APP-linked fAD pathogenesis. The relevance of this animal model to the study of sporadic AD is discussed. PMID- 25270905 TI - Distinct temperature sensitivity of soil carbon decomposition in forest organic layer and mineral soil. AB - The roles of substrate availability and quality in determining temperature sensitivity (Q10) of soil carbon (C) decomposition are still unclear, which limits our ability to predict how soil C storage and cycling would respond to climate change. Here we determined Q10 in surface organic layer and subsurface mineral soil along an elevation gradient in a temperate forest ecosystem. Q10 was calculated by comparing the times required to respire a given amount of soil C at 15 and 25 degrees C in a 350-day incubation. Results indicated that Q10 of the organic layer was 0.22-0.71 (absolute difference) higher than Q10 of the mineral soil. Q10 in both the organic layer (2.5-3.4) and the mineral soil (2.1-2.8) increased with decreasing substrate quality during the incubation. This enhancement of Q10 over incubation time in both layers suggested that Q10 of more labile C was lower than that of more recalcitrant C, consistent with the Arrhenius kinetics. No clear trend of Q10 was found along the elevation gradient. Because the soil organic C pool of the organic layer in temperate forests is large, its higher temperature sensitivity highlights its importance in C cycling under global warming. PMID- 25270906 TI - Violently reactive women and their relationship with an abusive mother. AB - This article sheds light on the abuse of mothers toward their daughters and its potential influence on the violent behavior of the latter as adults. It contributes to the scarce knowledge on the effects of abuse of each parent on their children by gender. The article is part of a larger study describing the experience of 30 women in Israel who were abusive or violent toward their male partners. It presents the stories of 14 women from the sample who, when sharing their memories of childhood and family-of-origin, spoke of an abusive relationship with their mothers. The various types of these relationships are presented along a continuum based on the severity of violence and emotional detachment of the mothers toward the interviewees, ranging from physical and emotional distancing, through chronic expressions of bitterness and criticism, and ending with severe physical violence. The findings are analyzed through the prism of social construction, relating to the interviewees' use of the psychodynamic discourse when accounting for their past and present abusive relationships. Some limitations and clinical implementations of the study, and needs for further research, are addressed. PMID- 25270907 TI - Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations. AB - MYC translocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of ~6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of 2 types; those rearranged with the T-cell receptor loci and those with other partners. MYC translocations were significantly associated with the TAL/LMO subtype of T-ALL (P = .018) and trisomies 6 (P < .001) and 7 (P < .001). Within the TAL/LMO subtype, gene expression profiling identified 148 differentially expressed genes between patients with and without MYC translocations; specifically, 77 were upregulated and 71 downregulated in those with MYC translocations. The poor prognostic marker, CD44, was among the upregulated genes. MYC translocations occurred as secondary abnormalities, present in subclones in one-half of the cases. Longitudinal studies indicated an association with induction failure and relapse. PMID- 25270910 TI - Accelerated hyperfractionated radiotherapy for small cell carcinoma of the nasopharynx. AB - BACKGROUND: The purpose of this study was to report the treatment outcome of a patient with nasopharyngeal small cell carcinoma. METHODS: The patient received concurrent chemoradiotherapy (CRT). Chemotherapy consisted of 4 cycles of cisplatin and etoposide. Accelerated hyperfractionated radiotherapy (RT) was performed with a dose of 45 Gy in 30 fractions over 3 weeks for the nasopharynx and upper neck region, whereas conventional fractionated RT was performed with a dose of 50 Gy in 25 fractions over 5 weeks for the lower neck region. RESULTS: Complete response was achieved 1 month after the completion of CRT. Prophylactic cranial irradiation was not performed. Isolated brain metastasis was diagnosed 18 months after the completion of CRT. Finally, the patient died because of the brain and cord metastases 32 months after the completion of CRT. CONCLUSION: The administration of prophylactic cranial irradiation may be considered for nasopharyngeal small cell carcinoma. PMID- 25270909 TI - TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19 deficient hematopoietic progenitors. AB - Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25% of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well understood. We found that RPS19 deficiency in hematopoietic progenitor cells leads to decreased GATA1 expression in the erythroid progenitor population and p53-dependent upregulation of tumor necrosis factor-alpha (TNF-alpha) in nonerythroid cells. The decrease in GATA1 expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-alpha or p53. The anemia phenotype in rps19 deficient zebrafish was reversed by treatment with the TNF-alpha inhibitor etanercept. Our data reveal that RPS19 deficiency leads to inflammation, p53 dependent increase in TNF-alpha, activation of p38 MAPK, and decreased GATA1 expression, suggesting a novel mechanism for the erythroid defects observed in DBA. PMID- 25270908 TI - Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. AB - The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio >= 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242. PMID- 25270911 TI - Unfolding properties of recombinant human serum albumin products are due to bioprocessing steps. AB - We have used differential scanning calorimetry (DSC) to determine the unfolding properties of commercial products of human serum albumin (HSA) prepared from pooled human blood, transgenic yeast, and transgenic rice. The initial melting temperatures (Tm1 ) for the unfolding transitions of the HSA products varied from 62 degrees C to 75 degrees C. We characterized the samples for purity, fatty acid content, and molecular weight. The effects of adding fatty acids, heat pasteurization, and a low pH defatting technique on the transition temperatures were measured. Defatted HSA has a structure with the lowest stability (Tm of ~62 degrees C). When fatty acids are bound to HSA, the structure is stabilized (Tm of ~64-72 degrees C), and prolonged heating (pasteurization at 60 degrees C) results in a heat-stabilized structural form containing fatty acids (Tm of ~75-80 degrees C). This process was shown to be reversible by a low pH defatting step. This study shows that the fatty acid composition and bioprocessing history of the HSA commercial products results in the large differences in the thermal stability. PMID- 25270912 TI - Experimental fitness landscapes to understand the molecular evolution of RNA based life. AB - In evolutionary biology, the relationship between genotype and Darwinian fitness is known as a fitness landscape. These landscapes underlie natural selection, so understanding them would greatly improve quantitative prediction of evolutionary outcomes, guiding the development of synthetic living systems. However, the structure of fitness landscapes is essentially unknown. Our ability to experimentally probe these landscapes is physically limited by the number of different sequences that can be identified. This number has increased dramatically in the last several years, leading to qualitatively new investigations. Several approaches to illuminate fitness landscapes are possible, ranging from tight focus on a single peak to random speckling or even comprehensive coverage of an entire landscape. We discuss recent experimental studies of fitness landscapes, with a special focus on functional RNA, an important system for both synthetic cells and the origin of life. PMID- 25270913 TI - Methylation-associated inactivation of LATS1 and its effect on demethylation or overexpression on YAP and cell biological function in human renal cell carcinoma. AB - Large tumor suppressor 1 (LATS1) gene is one of the key factors in Hippo signaling pathway. Inactivation of LATS1 by promoter methylation was found in colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), astrocytoma, breast cancer and it was proved to be a tumor suppressor. However, its role is unclear in renal cell carcinoma (RCC). In this study, the expression of LATS1 was determined by reverse transcription polymerase chain reaction (RT PCR) and immunohistochemistry in 30 pairs of RCC tissues and matched normal kidney tissues and RCC cells. We found that the expression of LATS1 was markedly reduced in RCC tissues and cells, in the RCC tissue in 46.7% (14/30), while in the normal kidney tissues in 76.7% (23/30), and was associated with pathological grade and clinical stage of RCC. We detected methylation status of LATS1 by bisulfite sequence-PCR (BSP) in renal cancer cell line 786-O which lowers expression of LATS1, and we found it hypermethy-lated (in 97.5%). In addition, pharmacological demethylation using 5-Aza-2'-deoxycytidine (5-Aza) restored the expression of LATS1 mRNA and protein in 786-O cells, both LATS1 demethylation and overexpression of LATS1 downregulated the expression of Yes-associated protein (YAP), inhibited cell proliferation, induced cell apoptosis and cell cycle G1 arrest in 786-O cells. Thus, this report for the first time demonstrates the inactivation of LATS1 by promoter methy-lation and it is a tumor suppressor in kidney cancer. LATS1 may serve as a biomarker for possible early diagnosis and as a potential therapeutic target for human RCC. PMID- 25270914 TI - Bicarbonate transport in health and disease. AB - Bicarbonate (HCO3(-)) has a central place in human physiology as the waste product of mitochondrial energy production and for its role in pH buffering throughout the body. Because bicarbonate is impermeable to membranes, bicarbonate transport proteins are necessary to enable control of bicarbonate levels across membranes. In humans, 14 bicarbonate transport proteins, members of the SLC4 and SLC26 families, function by differing transport mechanisms. In addition, some anion channels and ZIP metal transporters contribute to bicarbonate movement across membranes. Defective bicarbonate transport leads to diseases, including systemic acidosis, brain dysfunction, kidney stones, and hypertension. Altered expression levels of bicarbonate transporters in patients with breast, colon, and lung cancer suggest an important role of these transporters in cancer. PMID- 25270915 TI - Further international adaptation and validation of the Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire. AB - The Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire was developed directly from rheumatoid arthritis (RA) patients in the United Kingdom and the Netherlands to measure quality of life (QoL). Since then, it has become widely used in clinical studies and trials and has been adapted for use in 24 languages. The objective was to develop and validate 11 additional language versions of the RAQoL in US English, Mexican Spanish, Argentinean Spanish, Belgian French, Belgian Flemish, French, Romanian, Czech, Slovakian, Polish and Russian. The language adaptation and validation required three stages: translation, cognitive debriefing interviews and validation survey. The translation process involved a dual-panel methodology (bilingual panel followed by a lay panel). The validation survey tested the psychometric properties of the new scales and included either the Nottingham Health Profile (NHP) or the Health Assessment Questionnaire (HAQ) as comparators. Internal consistency of the new language versions ranged from 0.90 to 0.97 and test-retest reliability from 0.85 to 0.99. RAQoL scores correlated as expected with the HAQ. Correlations with NHP sections were as expected: highest with energy level, pain and physical mobility and lowest with emotional reactions, sleep disturbance, and social isolation. The adaptations exhibited construct validity in their ability to distinguish subgroups of RA patients varying by perceived disease severity and general health. The new language versions of the RAQoL meet the high psychometric standards of the original UK English version. The new adaptations represent valid and reliable tools for measuring QoL in international clinical trials involving RA patients. PMID- 25270916 TI - Validity of juvenile idiopathic arthritis diagnoses using administrative health data. AB - Administrative health databases are valuable sources of data for conducting research including disease surveillance, outcomes research, and processes of health care at the population level. There has been limited use of administrative data to conduct studies of pediatric rheumatic conditions and no studies validating case definitions in Canada. We report a validation study of incident cases of juvenile idiopathic arthritis in the Canadian province of Nova Scotia. Cases identified through administrative data algorithms were compared to diagnoses in a clinical database. The sensitivity of algorithms that included pediatric rheumatology specialist claims was 81-86%. However, 35-48% of cases that were identified could not be verified in the clinical database depending on the algorithm used. Our case definitions would likely lead to overestimates of disease burden. Our findings may be related to issues pertaining to the non-fee for-service remuneration model in Nova Scotia, in particular, systematic issues related to the process of submitting claims. PMID- 25270917 TI - Association of characteristics of delivery and medical conditions during the first month of life with developmental defects of enamel. AB - BACKGROUND: Developmental defects of enamel (DDE) may be influenced by health problems and illness in children. The aim of the study was to identify the main characteristics of birth (delivery) and adverse medical conditions during the first month of life that may be related to DDE in permanent teeth. METHODS: 1000 schoolchildren between the ages of 9 and 11 years were selected for this cross sectional study by multistage randomization from four educational zones in Shiraz in 2013. Intraoral examination was used to diagnose DDE according to World Health Organization screening guidelines and the Modified DDE Index. The data on seven birth factors as well as health and nutritional conditions during the first month of life were collected by a questionnaire completed by the parents, and were analyzed with the chi-squared test, Spearman's correlation and binary logistic regression. RESULTS: 469 (48.2%) out of 974 schoolchildren had at least one permanent tooth with DDE. The defects were significantly related with Apgar score at birth <7 (p = 0.003) and illness during the first month (p = 0.035). The frequency of DDE was significantly lower in the third child in families compared to the first and second child (p = 0.005). However, DDE showed no significant relationship with gestational age, delivery type, birth weight, gender or type of feeding during early infancy. CONCLUSIONS: Three associated factors were identified (birth Apgar score, illness during the first month of life, birth order) for DDE in permanent teeth. No specific illness was found to be significantly associated with DDE. PMID- 25270918 TI - Proxy assessment of personal dignity: we need to be aware of the limitations. PMID- 25270920 TI - Global metabolic profiling using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - Currently, liquid chromatography-mass spectrometry (LC-MS) is one of the most important analytical technologies for detecting hundreds of metabolites in the field of metabolomics. A recent advance in LC that has impacted metabolomics is the development of UPLC (ultra-performance liquid chromatography). In this chapter, we describe the analytical methodologies for the global metabolic profiling of serum, urine, and tissue samples using UPLC-Q-TOF (quadrupole-time of-flight)-MS. Aqueous metabolites are extracted after adding methanol/acetonitrile/acetone and then analyzed by UPLC-MS under positive and/or negative ionization mode. With the aid of multivariate statistical analysis, separation between various groups can be observed in the score plots, and biomarkers are screened in the loading/weight/VIP (variable importance in the projection) scatterplots. Furthermore, putative markers can be identified through comparison with the authentic standards based on tandem mass spectrometry (MS/MS) fragmentation pattern and LC retention. We expect that our protocol, with modifications if necessary, can be useful in many metabolomics studies and a wide range of research areas related to small molecules and LC-MS. PMID- 25270919 TI - Overview of mass spectrometry-based metabolomics: opportunities and challenges. AB - The field of metabolomics has witnessed an exponential growth in the last decade driven by important applications spanning a wide range of areas in the basic and life sciences and beyond. Mass spectrometry in combination with chromatography and nuclear magnetic resonance are the two major analytical avenues for the analysis of metabolic species in complex biological mixtures. Owing to its inherent significantly higher sensitivity and fast data acquisition, MS plays an increasingly dominant role in the metabolomics field. Propelled by the need to develop simple methods to diagnose and manage the numerous and widespread human diseases, mass spectrometry has witnessed tremendous growth with advances in instrumentation, experimental methods, software, and databases. In response, the metabolomics field has moved far beyond qualitative methods and simple pattern recognition approaches to a range of global and targeted quantitative approaches that are now routinely used and provide reliable data, which instill greater confidence in the derived inferences. Powerful isotope labeling and tracing methods have become very popular. The newly emerging ambient ionization techniques such as desorption ionization and rapid evaporative ionization have allowed direct MS analysis in real time, as well as new MS imaging approaches. While the MS-based metabolomics has provided insights into metabolic pathways and fluxes, and metabolite biomarkers associated with numerous diseases, the increasing realization of the extremely high complexity of biological mixtures underscores numerous challenges including unknown metabolite identification, biomarker validation, and interlaboratory reproducibility that need to be dealt with for realization of the full potential of MS-based metabolomics. This chapter provides a glimpse at the current status of the mass spectrometry-based metabolomics field highlighting the opportunities and challenges. PMID- 25270921 TI - LC-MS profiling to link metabolic and phenotypic diversity in plant mapping populations. AB - Numerous studies have revealed the extent of genetic, phenotypic, and metabolic variation between different plant cultivars/varieties. We present a specialized protocol for large-scale targeted and untargeted metabolite profiling for samples from large plant mapping populations using both reversed-phase and aqueous normal phase LC-MS. This methodology provides a fast and combined targeted/nontargeted workflow as a powerful tool to discriminate related plant phenotypes and describes methods to combine mass features and agronomic traits to link phenotypic to metabolic traits independent of putative metabolite identities. This easily reproducible analytical strategy, in combination with a sophisticated data processing and analysis workflow, can be applicable to a wide range of plant mapping populations. PMID- 25270923 TI - Sample preparation methods for LC-MS-based global aqueous metabolite profiling. AB - Metabolite extraction is a key step in metabolomic analyses, particularly for untargeted studies. The extraction determines the types of metabolites that will be detected and the analytical platform to be used. In this chapter we describe two protocols aimed at detecting polar metabolites from biological samples; the first is aimed at detecting reduced species by LC/MS, and the second satisfies the requirements for both NMR and LC/MS analysis simultaneously. PMID- 25270924 TI - Methods of discovery-based and targeted metabolite analysis by comprehensive two dimensional gas chromatography with time-of-flight mass spectrometry detection. AB - The investigation of naturally volatile and derivatized metabolites in biological tissues by comprehensive two-dimensional gas chromatography coupled with time-of flight mass spectrometry (GC * GC-TOFMS) can provide highly complex and information-rich data for comprehensive metabolomics analysis. The addition of the second separation dimension with GC * GC provides additional chemical selectivity, and the fast scanning time of TOFMS offers benefits in chemical selectivity and overall peak capacity compared to traditional one-dimensional (1D) GC. Furthermore, methods of derivatization to facilitate volatility and thermal stability, the most prominent being the silylation of organic compounds, have extended the use of GC as an important metabolomics tool. The highly information-rich data from GC * GC-TOFMS benefits from sophisticated comprehensive targeted and nontargeted algorithmic software methods. Herein, we detail a robust derivatization and instrumental method for metabolomics analysis and provide a brief overview of possible methods for data analysis. PMID- 25270922 TI - Mitochondrial metabolomics using high-resolution Fourier-transform mass spectrometry. AB - High-resolution Fourier-transform mass spectrometry (FTMS) provides important advantages in studies of metabolism because more than half of common intermediary metabolites can be measured in 10 min with minimal pre-detector separation and without ion dissociation. This capability allows unprecedented opportunity to study complex metabolic systems, such as mitochondria. Analysis of mouse liver mitochondria using FTMS with liquid chromatography shows that sex and genotypic differences in mitochondrial metabolism can be readily distinguished. Additionally, differences in mitochondrial function are readily measured, and many of the mitochondria-related metabolites are also measurable in plasma. Thus, application of high-resolution mass spectrometry provides an approach for integrated studies of complex metabolic processes of mitochondrial function and dysfunction in disease. PMID- 25270925 TI - Analysis of mouse liver metabolites by GC * GC-TOF MS. AB - Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC * GC-TOF MS) is a powerful analytical platform for analysis of metabolites in mouse liver. Metabolites are extracted using a solvent mixture of methanol/water (4:1, v/v). The metabolite extracts are analyzed on GC * GC-TOF MS after derivatization. The experimental data are further processed for metabolite identification and quantification. A three-tier method is used for high-accuracy metabolite identification, while metabolite quantification is performed to recognize metabolites with significant abundance differences between sample groups. PMID- 25270926 TI - Metabolite fingerprinting by capillary electrophoresis-mass spectrometry. AB - Changes in metabolite concentrations in response to specific diseases, treatments, diets, or other factors can be used to understand the complex mechanisms that control and regulate the human body and potentially detect the onset of disease prior to the observation of symptoms in a patient. Different analytical and chemometric platforms are necessary to detect as many metabolites as possible in different biological fluids. Capillary electrophoresis (CE) coupled to mass spectrometry (MS) is a particularly attractive, although still not common, approach for metabolomics for the detection of mainly polar and ionic metabolites. Among its main features, CE provides the capability to separate complex mixtures with high resolution and minimum sample treatment. However, the routine, automated use of CE-MS is not without challenges. In this chapter we describe a well-tested method for fingerprinting serum and urine using CE-TOF-MS. We describe below a sensitive and quite robust method for metabolomics with CE-MS including sample treatment, separation conditions, instrumental setup, and identification of 76 metabolites in the profile. Useful advice for daily practice is also included for every step of the procedure. PMID- 25270927 TI - Quantitative metabolomic profiling using dansylation isotope labeling and liquid chromatography mass spectrometry. AB - Differential chemical isotopic labeling (CIL) LC-MS has been used for quantifying a targeted metabolite in biological samples with high precision and accuracy. Herein we describe a high-performance CIL LC-MS method for generating quantitative and comprehensive profiles of the metabolome for metabolomics applications. After mixing two comparative samples separately labeled by light or heavy isotopic tags through chemical reactions, the peak intensity ratio of the labeled analyte pair can provide relative or absolute quantitative information on the metabolites. We describe the use of (12)C2- and (13)C2-dansyl chloride (DnsCl) as the isotope reagents to profile the metabolites containing amine and phenolic hydroxyl functional groups by LC-MS. This method can be used to compare the relative concentration changes of hundreds or thousands of amine- and phenol containing metabolites among many comparative samples and generate absolute concentration information on metabolites for which the standards are available. Combined with statistical analysis and metabolite identification tools, this method can be used to identify key metabolites involved in differentiating comparative samples such as disease cases vs. healthy controls. PMID- 25270928 TI - Quantitative analysis of amino and organic acids by methyl chloroformate derivatization and GC-MS/MS analysis. AB - Alkyl chloroformates are known for their ability to produce mixed anhydrides, and they have found use as versatile derivatization reagents for gas chromatographic (GC) separation of amino- and organic acids. Triple-quadrupole mass spectrometers are excellent detectors for high sensitive and selective analysis. Here, we describe a methyl chloroformate (MCF) GC-MS/MS method for the quantitative analysis of metabolites containing amino- and/or carboxylic groups. The method covers over 60 metabolites with quantitation limits down to the low picomole range injected on column, and any metabolite with amino- and/or carboxylic acid functional groups that yield a stable and volatile MCF derivative can be included in the method. Absolute quantitation can be achieved by including a stable isotope-coded derivatization agent (d3-MCF) and deuterated alcohol solvent (e.g., d4-methanol). As the carboxylic and amino groups are differently labeled, the former from the solvent methanol while the latter from MCF, this approach can also be used to identify a number of amino and carboxylic groups in unknown analytes in an extract. PMID- 25270930 TI - Multiplexed, quantitative, and targeted metabolite profiling by LC-MS/MRM. AB - Targeted metabolomics, which focuses on a subset of known metabolites representative of biologically relevant metabolic pathways, is a valuable tool to discover biomarkers and link disease phenotypes to underlying mechanisms or therapeutic modes of action. A key advantage of targeted metabolomics, compared to discovery metabolomics, is its immediate readiness for extracting biological information derived from known metabolites and quantitative measurements. However, simultaneously analyzing hundreds of endogenous metabolites presents a challenge due to their diverse chemical structures and properties. Here we report a method which combines different chromatographic separation conditions, optimal ionization polarities, and the most sensitive triple-quadrupole MS-based data acquisition mode, multiple reaction monitoring (MRM), to quantitatively profile 205 endogenous metabolites in 10 min. PMID- 25270929 TI - Stable isotope-labeled tracers for metabolic pathway elucidation by GC-MS and FT MS. AB - Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), over the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly widespread metabolic diseases such as cancer, diabetes, and obesity. Emerging NMR and MS atom-tracking technologies and informatics are poised to revolutionize metabolomics-based research because they deliver the high information throughput (HIT) that is needed for deciphering systems biochemistry. In particular, stable isotope-resolved metabolomics (SIRM) enables unambiguous tracking of individual atoms through compartmentalized metabolic networks in a wide range of experimental systems, including human subjects. MS offers a wide range of instrumental capabilities involving different levels of initial capital outlay and operating costs, ranging from gas-chromatography (GC) MS that is affordable by many individual laboratories to the HIT-supporting Fourier-transform (FT) class of MS that rivals NMR in cost and infrastructure support. This chapter focuses on sample preparation, instrument, and data processing procedures for these two extremes of MS instrumentation used in SIRM. PMID- 25270931 TI - Multidimensional mass spectrometry-based shotgun lipidomics. AB - Multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) has become a foundational analytical technology platform among current lipidomics practices due to its high efficiency, sensitivity, and reproducibility, as well as its broad coverage. This platform has been broadly used to determine the altered content and/or composition of lipid classes, subclasses, and individual molecular species induced by diseases, genetic manipulations, drug treatments, and aging, among others. Herein, we briefly discuss the principles underlying this technology and present a protocol for routine analysis of many of the lipid classes and subclasses covered by MDMS-SL directly from lipid extracts of biological samples. In particular, lipid sample preparation from a variety of biological materials, which is one of the key components of MDMS-SL, is described in detail. The protocol for mass spectrometric analysis can readily be expanded for analysis of other lipid classes not mentioned as long as appropriate sample preparation is conducted, and should aid researchers in the field to better understand and manage the technology for analysis of cellular lipidomes. PMID- 25270932 TI - Comprehensive quantitative determination of PUFA-related bioactive lipids for functional lipidomics using high-resolution mass spectrometry. AB - A wide range of biologically active lipids such as eicosanoids, docosanoids, and other lipid mediators are known for their physiological and pathophysiological effects in almost every organ system. It is essential that the full spectrum of these compounds is comprehensively captured, to fully characterize their biological activity. The analytical determination of these lipid mediators is challenging, however, mainly because of their biological diversity and their physicochemical similarity. LC-MS/MS, in particular in combination with high resolution instruments, is currently the most powerful tool for analysis of lipid mediators. This chapter describes a comprehensive analytical protocol that allows for simultaneous profiling of over 100 polyunsaturated fatty acid (PUFA)-derived metabolites using a single analytical method from a wide range of biological matrices. PMID- 25270933 TI - Ultra-performance liquid chromatography-mass spectrometry targeted profiling of bile acids: application to serum, liver tissue, and cultured cells of different species. AB - Currently, there is increasing interest in developing accurate methods for the quantitative analysis of bile acids (BAs) in biological samples. We have developed a sensitive, fast, and reproducible UPLC-MRM-MS method for BA profiling in serum, liver tissue, or cultured cells of different species (human, rat, and mouse). This method, validated according to FDA guidelines, allows the quantification of 12 non-conjugated, 8 glycine-conjugated, and 11 taurine conjugated BAs, using 5 additional deuterated BAs as internal standards in a single analytical run. The main features of this analytical approach are its high sensitivity, low sample requirements, versatility, and comprehensive capacity to profile a considerable number of BAs in samples of different species, which make it a valuable tool with potential applications in many research areas focusing on BAs, particularly in toxicological studies. PMID- 25270934 TI - Analysis of volatile organic compounds in exhaled breath by gas chromatography mass spectrometry combined with chemometric analysis. AB - Analysis of exhaled breath samples reveals the presence of many volatile organic compounds (VOCs). The VOC composition of the breath, the so-called breath profile, contains a variety of information including the health status and condition of the organism that produced the sample. Therefore, breath profiling can be used in diagnosing and monitoring disease and other characteristics of the organism, such as phenotype, diet, and exercise. Among various techniques available for breath analysis, GC-MS provides the most extensive information with regard to the qualitative and quantitative presence of VOCs in breath. PMID- 25270935 TI - Headspace SPME-GC-MS metabolomics analysis of urinary volatile organic compounds (VOCs). AB - In this chapter, we describe the procedure for metabolic profiling of hundreds of urinary volatile organic compounds (VOCs) using headspace solid-phase microextraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS). SPME is a solvent-free technology that is reproducible, fast, cost effective, and versatile in extracting small molecular weight organic compounds (metabolites) from biofluids using a fiber that is coated with an extracting phase. After extraction, the SPME fiber can be directly injected to the GC-MS, where the extracted metabolites will desorb thermally from the fiber, elute along a GC column, and finally enter into the MS for detection. The analysis of urine samples is presented using this approach. PMID- 25270936 TI - Metabolite profiling by direct analysis in real-time mass spectrometry. AB - Untargeted metabolite profiling is a discovery tool for the identification of metabolites associated with the responses of perturbations to biological systems, such as a disease. Direct analysis in real-time mass spectrometry (DART MS) promises to be a powerful analytical technique for high-throughput metabolome analysis of human blood sera. Here, we describe the steps involved in untargeted blood sera metabolic profiling experiments using DART MS with two different sample introduction methods: probe-mode and transmission-mode geometries. Information regarding the optimization of different DART parameters that directly affect metabolite desorption and ionization, which thus influence sensitivity, is included. PMID- 25270937 TI - Analysis of dried blood spots using DESI mass spectrometry. AB - Dried blood spot (DBS) analysis using mass spectrometry is an invaluable technique for examining blood markers of inborn metabolic diseases in clinical laboratories. Implementation of DBS sampling and analysis in pharmaceutical development have more recently gained traction due to the advantages of convenience in sample procurement and logistics, as well as the innate advantages associated with the collection of lower blood volumes. While there are several realized advantages of DBS, the bioanalytical laboratory is disadvantaged and burdened with additional preparative steps prior to analysis. Therefore, improvements in the laboratory workflow for DBS analysis are necessary. Here, we describe direct blood spot analysis using desorption electrospray ionization (DESI) mass spectrometry for quantitative determination of drugs in whole blood. PMID- 25270938 TI - DESI-MS imaging of lipids and metabolites from biological samples. AB - Desorption electrospray ionization mass spectrometry (DESI-MS) is a powerful technique used to image the distribution of hundreds of small molecules directly from biological samples, without the need of extensive sample preparation. Operated at ambient temperature and in the open-air environment, DESI-MS employs a fine spray of charged droplets to rapidly extract molecules from the sample surface into the solvent droplets and to transfer the analytes to the mass spectrometer. When operated in the imaging mode, a two-dimensional map of the compounds within the sample surface is obtained with a typical spatial resolution of hundreds of micrometers or less. Here, we describe the imaging of complex lipids from a mouse brain tissue section using a histologically compatible solvent system. The imaging experiment described is performed in the negative ion mode using an Orbitrap mass spectrometer for mass analysis. Following DESI-MS imaging, the same tissue section is subjected to histochemistry allowing molecular information to be correlated to histological information. PMID- 25270939 TI - Metabolic imaging using nanostructure-initiator mass spectrometry (NIMS). AB - Nanostructure-initiator mass spectrometry (NIMS) imaging using soft laser desorption/ionization has proven to be a powerful tool in localizing the spatial distribution of intact biomolecules. NIMS specifically has been demonstrated to have high sensitivity and low background, particularly in the low mass range <1,000 Da, making this technique well suited for metabolic imaging studies. Here, we describe NIMS imaging for direct analysis of metabolite composition across a sectioned biospecimen. PMID- 25270940 TI - Statistical analysis and modeling of mass spectrometry-based metabolomics data. AB - Multivariate statistical techniques are used extensively in metabolomics studies, ranging from biomarker selection to model building and validation. Two model independent variable selection techniques, principal component analysis and two sample t-tests are discussed in this chapter, as well as classification and regression models and model related variable selection techniques, including partial least squares, logistic regression, support vector machine, and random forest. Model evaluation and validation methods, such as leave-one-out cross validation, Monte Carlo cross-validation, and receiver operating characteristic analysis, are introduced with an emphasis to avoid over-fitting the data. The advantages and the limitations of the statistical techniques are also discussed in this chapter. PMID- 25270941 TI - Good long-term outcome of the untreated contralateral hip in unilateral slipped capital femoral epiphysis : Forty hips with a mean follow-up of 41 years. AB - PURPOSE: There is no consensus regarding prophylactic fixation of the contralateral hip in slipped capital femoral epiphysis (SCFE). In order to further study this question, we evaluated the long-term natural history of untreated contralateral hips. METHODS: Forty patients treated for unilateral SCFE without evidence of subsequent contralateral slip during adolescence were reviewed with a mean follow-up of 36 years (range 21-50 years). The deformity after SCFE may demonstrate radiographic signs of cam-type femoroacetabular impingement. We, therefore, measured alpha-angles in the contralateral hips on anteroposterior (AP) and frog-leg lateral radiographs. The angles were compared with those of a control group of adults without SCFE. Five years after the radiographic examination, with a mean follow-up of 41 years, all patients were evaluated by telephone interview. As range of motion and deformity could not be examined, a modified Harris hip score (HHS) (maximum score of 91 points) was used. A modified HHS <76 points and/or radiographic osteoarthritis (OA) was classified as a poor long-term outcome. RESULTS: The mean value of the AP alpha angle was significantly higher in the contralateral hips in SCFE patients than in the control group (55 degrees vs. 46 degrees ), while the mean value of the lateral alpha-angle was not. Abnormally high values for one or both alpha-angles were found in 16 contralateral hips (40 %), of which five patients had abnormal values for both alpha-angles and were considered to have had an asymptomatic contralateral slip. Five patients (13 %) had a poor outcome in the contralateral hip, of which three patients (8 %) had OA. There was a significant association between hips with both alpha-angles that were abnormal and poor outcome. CONCLUSIONS: Since the natural history showed good long-term radiographic and clinical outcome in 35 of 40 patients and only three had OA, we conclude that routine prophylactic fixation of the contralateral hip is not indicated. PMID- 25270942 TI - The medial approach open reduction for developmental dysplasia of the hip: do the long-term outcomes validate this approach? A systematic review of the literature. AB - INTRODUCTION: Developmental dysplasia of the hip (DDH) is one of the most commonly diagnosed and treated paediatric orthopaedic conditions. OBJECTIVE: To systematically identify, appraise and synthesise the best evidence for the long term outcomes of the medial approach open reduction (MAOR) for DDH. METHODS: MEDLINE, EMBASE and the Cochrane databases were searched up to July 2013. All study designs that reported on the long-term outcomes of the MAOR as the primary treatment modality for DDH were included. The risk of bias in each study was evaluated using the Cochrane risk of bias assessment tool with some modification to accommodate different study designs. RESULTS: From the 162 citations screened, five retrospective observational studies that fulfilled the eligibility criteria were included. The mean age at surgery varied from 10 to 17 months with an average follow-up period of 16-25 years. Acetabular development, as defined by the Severin Classification, was reported as satisfactory (Severin I/II) in between 38 and 79 % of study cohorts. However these good and excellent outcomes were less promising when patients who had additional operations were considered as unsatisfactory results. Avascular necrosis, as predominantly defined by the Kalamchi criteria, varied from 5 to 43 %. Negative prognostic factors implicated were mean age at surgery >17 months, the absence of the ossific nucleus and eccentric posturing of the femoral head postoperatively. The rate of secondary operations reported varied from 11 to 50 %. There were no reported total hip replacements. CONCLUSION: There is a paucity of robust evidence pertaining to the long-term outcomes of the MAOR for developmental dysplasia of the hip. The trends from observational studies suggest that the long-term outcomes are not as positive as short- to intermediate-term studies suggest. Further prospective, controlled and rigorously designed studies are required to validate this approach. PMID- 25270943 TI - Oxygen uptake kinetics in trained adolescent females. AB - Little evidence exists with regard to the effect that exercise training has upon oxygen uptake kinetics in adolescent females. PURPOSE: The aim of the study was to compare [Formula: see text] and muscle deoxygenation kinetics in a group of trained (Tr) and untrained (Utr) female adolescents. METHOD: Twelve trained (6.4 +/- 0.9 years training, 10.3 +/- 1.4 months per year training, 5.2 +/- 2.0 h per week) adolescent female soccer players (age 14.6 +/- 0.7 years) were compared to a group (n = 8) of recreationally active adolescent girls (age 15.1 +/- 0.6 years) of similar maturity status. Subjects underwent two, 6-min exercise transitions at a workload equivalent to 80 % of lactate threshold from a 3-min baseline of 10 W. All subjects had a passive rest period of 1 h between each square-wave transition. Breath-by-breath oxygen uptake and muscle deoxygenation were measured throughout and were modelled via a mono-exponential decay with a delay relative to the start of exercise. RESULT: Peak [Formula: see text] was significantly (p < 0.05) greater in the Tr compared to the Utr (Tr: 43.2 +/- 3.2 mL kg(-1 )min(-1) vs. Utr: 34.6 +/- 4.0 mL kg(-1 )min(-1)). The [Formula: see text] time constant was significantly (p < 0.05) faster in the Tr compared to the Utr (Tr: 26.3 +/- 6.9 s vs. Utr: 35.1 +/- 11.5 s). There was no inter-group difference in the time constant for muscle deoxygenation kinetics (Tr: 8.5 +/- 3.0 s vs. Utr: 12.4 +/- 8.3 s); a large effect size, however, was demonstrated ( 0.804). CONCLUSION: Exercise training and/or genetic self-selection results in faster kinetics in trained adolescent females. The faster [Formula: see text] kinetics seen in the trained group may result from enhanced muscle oxygen utilisation. PMID- 25270944 TI - Antimicrobial innovation: combining commitment, creativity and coherence. AB - Enhanced antibiotic innovation depends on many things--defining and validating new and better targets, resourcing and facilitating high-quality preclinical and clinical research, streamlining regulation and solving market problems so as to provide incentives to the private sector. Further detail is provided in our recent report (see further information). Acting on these critical steps in concert to provide long-term solutions requires that urgent attention be paid to tackling policy disconnects. Sustaining the political commitment depends on raising the visibility of the problems and their solutions worldwide. The academies of science in the EU recognize their continuing responsibility to help do this. PMID- 25270945 TI - Momentum builds around new antibiotic business models. PMID- 25270946 TI - False dawn for cystic fibrosis disease modifiers? PMID- 25270950 TI - Trial watch: Next-generation antimalarial from phenotypic screen shows clinical promise. PMID- 25270951 TI - Story Landis. PMID- 25270952 TI - The cystic fibrosis drug market. PMID- 25270953 TI - Cancer: Lipid kinase PIP5K1alpha as a new target in prostate cancer. PMID- 25270954 TI - Neuromuscular disorders: Beefing up the right splice variant to treat spinal muscular atrophy. PMID- 25270955 TI - Anticancer therapy: Bacterial treatment for cancer. PMID- 25270956 TI - Alleviating mucositis: are we on track for a novel therapeutic? AB - Oral and gastrointestinal mucositis has emerged as an important toxicity of cancer therapy. In addition to supportive care measures, agents for the prevention or treatment of mucositis in specific patient populations are described in the evidence-based clinical practice guidelines published by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. However, there still remains an unmet clinical need for preventive and therapeutic agents in several patient populations. The successful development of such agents will rely on our improved understanding of the pathogenic mechanisms underlying mucositis. Studies are also underway on novel delivery mechanisms and risk prediction models that can facilitate the selective use of interventions for mucositis in a targeted and cost-effective manner. A large number of agents are at various stages in the clinical development pipeline. Enhanced management of this dose-limiting toxicity will allow the delivery of optimal cancer therapy and improve patient prognosis. PMID- 25270957 TI - CD34+ cell dose in allogeneic transplantation: weight considerations. PMID- 25270959 TI - Diaphyseal osteotomy after post-traumatic malalignment. AB - Tibia and femur shaft fractures can sometimes lead to post-traumatic deformities. Correction by means of circular external frames is a valuable option. The aim of this article is to give an overview of the problem and to focus on some important technical issues of the preoperative planning, the surgical procedures, and the postsurgical management of circular external fixators. PMID- 25270960 TI - Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. AB - BACKGROUND: In the past decade, a number of population-based studies have examined the prevalence of coeliac disease in individuals with type 1 diabetes but prevalences have differed considerably. AIM: To examine the prevalence of coeliac disease in individuals with type 1 diabetes. METHODS: A systematic review of English-language articles published in PubMed Medline between 2000 and May 2014. Search terms included 'celiac disease' or 'coeliac disease' and 'diabetes mellitus'. Studies were selected with at least 100 individuals with type 1 diabetes being screened for coeliac disease where the coeliac diagnosis was later confirmed through small intestinal biopsy. Data synthesis used random-effects inverse variance-weighted models, and metaregression was used to examine heterogeneity in subgroups. RESULTS: A pooled analysis, based on 26,605 patients with type 1 diabetes, found a prevalence of biopsy-confirmed coeliac disease of 6.0% (95% CI = 5.0-6.9%). Heterogeneity was large (I(2) = 93.2%). The prevalence was lower in adults with type 1 diabetes (2.7%), and in mixed populations with both children and adults with type 1 diabetes (4.7%) than in children (6.2%) with type 1 diabetes (P < 0.001). Additional subgroup analyses could not explain the large variation in coeliac disease prevalence between studies. CONCLUSION: More than one in twenty patients with type 1 diabetes have biopsy-verified coeliac disease. This prevalence is high enough to motivate screening for coeliac disease among patients with type 1 diabetes. PMID- 25270958 TI - TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521). AB - Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFalpha in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly * 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS. PMID- 25270961 TI - AOPPs (advanced oxidation protein products) promote apoptosis in trophoblastic cells through interference with NADPH oxidase signaling: implications for preeclampsia. AB - PURPOSE: To investigate the role of placental advanced oxidation protein products (AOPPs) in the pathogenesis of preeclampsia (PE). METHODS: Expression of AOPPs in human placental tissues collected from women with or without PE was examined by immunohistochemistry. The effect of AOPPs on in vitro trophoblast cell function was also examined. Specifically, we exposed trophoblastic cells to AOPPs and measured the production of human chorionic gonadotropin (hCG) as well as their invasion capacity using an in vitro Transwell invasion assay. We also investigated the effect of AOPPs on trophoblastic apoptosis and whether this effect could be mediated through interference in NADPH oxidase signaling. RESULTS: AOPPs were expressed in placental tissues, and were significantly increased in placentas from women with PE versus normotensive controls. AOPPs also affected trophoblast cell function in vitro by significantly reducing beta HCG production and inhibiting trophoblas cell invasive capacity. Exposure to AOPPs significantly increased apoptosis in trophoblastic cells, which was mediated through the NADPH oxidase pathway. CONCLUSIONS: AOPPs expression is increased in PE placentas and exposure to AOPPs adversely affects trophoblast cell function, which may contribute to the shallow trophoblast invasion that characterizes this disorder. Additional studies are needed to investigate further to determine whether AOPPs can be used as a biomarker for PE. PMID- 25270962 TI - Maternal anemia during pregnancy and subsequent risk for cardiovascular disease. AB - OBJECTIVE: To investigate the association between anemia during pregnancy and subsequent future maternal cardiovascular morbidity and mortality. METHODS: A retrospective cohort study was conducted, comparing women with and without anemia during pregnancy. Deliveries occurred during 1988-1998 and had followed for more than a decade. Incidence of long-term cardiovascular morbidity was compared between the two groups. RESULTS: During the study period, 47 657 deliveries met the inclusion criteria; of these 12 362 (25.9%) occurred in women with anemia at least once during their pregnancies. Anemia of pregnancy was noted as a risk factor for long-term complex cardiovascular events (OR = 1.6, 95% CI 1-2.8, p = 0.04). Using a Cox multivariable regression model, controlling for ethnicity and maternal age, anemia was found to be an independent risk factor for long-term maternal cardiovascular hospitalization (OR for total hospitalizations = 1.2, 95% CI 1.1-1.4, p < 0.001). CONCLUSIONS: Anemia of pregnancy is an independent risk factor for long-term cardiovascular morbidity in a follow-up period of more than a decade. PMID- 25270964 TI - Epigenetic silencing of miRNA-9 is correlated with promoter-proximal CpG island hypermethylation in gastric cancer in vitro and in vivo. AB - Silencing of protein-coding tumor suppressor genes (TSGs) by CpG island hypermethylation is a common occurrence in gastric cancer (GC). Here, we examine if tumor suppressor microRNAs (miRNAs) are silenced in a similar manner. Real time quantitative PCR (RTQ-PCR) was employed to investigate the expression level of four candidate miRNAs in GC tissues (n=30) and cell lines. Basing on RTQ-PCR results and bioinformatics approach, miR-9 was chosen for further study on epigenetic regulation. Bisulfite genomic sequencing PCR (BSP) was performed to assess the methylation status of miR-9 in GC tissues. In both GC cell lines and animal models, demethylation was performed either by treatment with 5-aza-2' deoxycytidine (5-AZA-CdR) or by siRNA targeting DNMT1. We also analyzed the relationship between miRNAs and several clinicopathological features. Candidate miRNAs (miR-9, miR-433, miR-19b, and miR-370) were found strongly downregulated in GC tissues and cell lines. Their expression was increased following 5-AZA-CdR treatment. CpG island methylation of miR-9 was significantly higher in GC tissues compared to normal controls. After two demethylation treatments, miR-9 methylation degree was significantly decreased and miR-9 expression was ob viously restored in GC cells and animal models. Deregulation of miR-9 was positively correlated with tumor lesion size. Three other miRNAs, miR-19b, miR 433, and miR-370 were assomicronciated with lymph node metastasis, decreased curvature, and poorly differentiated carcinoma. miR-19b and miR-433 were positively correlated with male gender. Of four candidate miRNAs downregulated in GC, miR-9 is epigenetically regulated by DNA methylation both in vitro and in vivo. PMID- 25270967 TI - Celiac disease autoimmunity and hip fracture risk: findings from a prospective cohort study. AB - The impact of celiac disease autoimmunity on bone health is unclear. We investigated the associations of seropositivity for tissue transglutaminase antibodies (tTGA) and endomysial antibodies (EMA) with incident hip fractures using data from a prospective cohort study, Mini-Finland Health Survey. Baseline serum samples, taken in 1978-80, were tested for tTGA and EMA. Incident hip fractures up to the year 2011 were ascertained from a national hospitalization register. Associations between seropositivity and hip fractures were modeled using Cox proportional hazards regression adjusted for age, sex, body mass index, vitamin D, gamma-glutamyl transferase, smoking, and self-rated health. Our analyses were based on 6919 men and women who had no record of celiac disease or hip fracture before the study baseline. A total of 382 individuals had a hip fracture during a median follow-up of 30 years. Compared with the tTGA-negative individuals (n = 6350), tTGA-positive participants (n = 569; with hip fracture, n = 51) had a higher risk of hip fractures (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.17, 2.14). The findings were similar for another tTGA test (n 200; with hip fracture, n = 26; HR = 2.23, 95% CI 1.49, 3.34). We found no evidence for an association between EMA positivity and hip fracture risk (HR = 0.92, 95% CI 0.34, 2.47; n = 74; with hip fracture, n = 4). In our prospective population-based study of Finnish adults, seropositivity for tTGA was associated with an increased hip fracture risk. PMID- 25270966 TI - Prospective evaluation of endoscopic criteria characteristic of sessile serrated adenomas/polyps. AB - BACKGROUND: Differentiating sessile serrated adenoma/polyp (SSA/P) from hyperplastic polyp (HP) is clinically important in determining the necessity of endoscopic resection or recommending appropriate surveillance. There are few reports of characterization of SSA/P using narrowband imaging and chromoendoscopy with and without magnification. We aimed to establish imaging criteria to aid real-time diagnosis of SSA/P. METHODS: Patients with pale sessile or flat lesions of 6 mm or greater were prospectively enrolled in this multicenter trial. Nine endoscopic criteria, determined in real time, were investigated for possible association with SSA/P. Endoscopic mucosal resection was performed; specimens were retrieved and analyzed by histopathological examination. RESULTS: In 63 patients, 89 lesions were detected, including 41 HP, 38 SSA/P, five mixed polyps, and five other lesions. Right-side colon location, lesion size of 10 mm or greater, excessive mucus, the presence of a varicose microvascular vessel (VMV) noted with high-magnification narrowband imaging, and type III(H) pit pattern were each commonly associated with SSA/P compared with HP. Multivariate analysis substantiated three independent endoscopic criteria for SSA/P: the presence of VMV (p = 0.001), lesion size of 10 mm or greater (p = 0.0017), and right-side location (p = 0.0041), with odds ratios of 8.2, 7.2, and 6.1, respectively. The presence of VMV had a significantly higher specificity (87.8%) than the other two independent endoscopic criteria (p = 0.0007 and p = 0.0008, respectively), but a lower sensitivity (57.9%), whereas a combination of the three criteria (two or more positive) increased the sensitivity significantly (89.5% and p = 0.0033) and had a higher degree of accuracy (82.3%). CONCLUSIONS: Three endoscopic criteria individually and in combination were effective in predicting a diagnosis of SSA/P without the need for chromoendoscopy. PMID- 25270965 TI - MICA SNPs and the NKG2D system in virus-induced HCC. AB - Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer related death globally. Above well-known risk factors for HCC development ranging from various toxins to diseases such as diabetes mellitus, chronic infection with hepatitis B virus and hepatitis C virus (HCV) poses the most serious threat, constituting the cause in more than 80 % of cases. In addition to the viral genes intensively investigated, the pathophysiological importance of host genetic factors has also been greatly and increasingly appreciated. Genome-wide association studies (GWAS) comprehensively search the host genome at the single nucleotide level, and have successfully identified the genomic region associated with a whole variety of diseases. With respect to HCC, there have been reports from several groups on single nucleotide polymorphisms (SNPs) associated with hepatocarcinogenesis, among which was our GWAS discovering MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for HCV-induced HCC. MICA is a natural killer (NK) group 2D (NKG2D) ligand, whose interaction with NKG2D triggers NK cell-mediated cytotoxicity toward the target cells, and is a key molecule in tumor immune surveillance as its expression is induced on stressed cells such as transformed tumor cells for the detection by NK cells. In this review, the latest understanding of the MICA-NKG2D system in viral HCC, particularly focused on its antitumor properties and the involvement of MICA SNPs, is summarized, followed by a discussion of targets for state-of-the-art cancer immunotherapy with personalized medicine in view. PMID- 25270968 TI - [Objective diagnostic methods in pediatric audiology]. AB - Objective methods based on the measurement of otoacoustic emissions (OAE) and auditory evoked potentials (AEP) are indispensable in pediatric audiology especially for the early detection and therapy of congenital hearing impairment. The correct and efficient use requires knowledge and skills which are beyond the basic equipment of many users and require continuous updating. In the present review many aspects relevant for the safe handling of the methods and interpretation of the results are addressed. The presentation does not focus on the methods themselves but on the core problem of the practical daily routine, namely the qualitative and quantitative description of hearing loss in terms of its extent, the frequency range affected and the identity with respect to the type and site of the lesion. The certainty of the diagnosis can be optimized by observing few and simple rules. Central importance is attached to the thorough discussion of the interrelated parameters residual noise, signal-to-noise ratio and reproducibility in order to promote their correct use. Further subjects of this article are the recognition of pitfalls, the description of new developments, such as chirp and auditory steady-state responses (ASSR) and finally the consideration of the extraordinarily important aspect of maturation. PMID- 25270969 TI - [High-resolution distortion-product otoacoustic emissions: method and clinical applications]. AB - Unlike pure tone thresholds that assess both peripheral and central sound processing, distortion-product otoacoustic emissions (DPOAEs) selectively mirror the functioning of the cochlear amplifier. High resolution DPOAEs are missing in the toolbox of routine audiometry due to the fact that high resolution DPOAE measurements are more time-consuming when compared to normal clinical DP grams with rough frequency resolution. Measurements of high resolution DPOAEs allow an early assessment of beginning sensory cell damage due to sound overexposure or administration of ototoxic drugs. When using a rough grid, sensory cell damage would be overlooked as in the early state damage only appears at some distinct cochlear sites. A review is given on the method and application of high resolution DPOAEs. PMID- 25270970 TI - [Intraoperative audiological-technical diagnostics during cochlear implant surgery]. AB - During cochlear implant (CI) surgery, audiological-technical diagnostics is required which includes the proof of the implant function as well as the verification of its physiological coupling to the auditory nerve in order to undertake required interventions before the end of the surgery in case of need. The technical function check implies the coupling check, the implant integrity check, as well as impedance and field telemetry, and allows for assessment of implant electronics and electrode function. The audiological diagnostics used for verification of the physiological implant function incorporate visual registration of the electrically evoked stapedius reflexes and measurement of electrically evoked compound action potentials of the cochlear nerve, including their stimulation thresholds. PMID- 25270971 TI - [Tracheotomy or planned prolonged intubation after surgery for patients with OSAS]. AB - BACKGROUND: Patients suffering from obstructive sleep apnea syndrome (OSAS) and obesity have an elevated risk of postoperative complications independent of each other. Within the framework of expert opinions for courts the question arose whether postoperative prolonged intubation or tracheotomy are standard routine approaches which are to be carried out in the normal course of operations on patients with OSAS. MATERIAL AND METHODS: A search of the literature was performed using PubMed, Web of Science, Scopus, EMBASE, the Cochrane database of systematic reviews and the Cochrane central register of controlled trials. Furthermore, 78 German otorhinolaryngology (ENT) departments participated in a nationwide survey. RESULTS: The results of the survey showed that after normal complication-free surgery planned postoperative prolonged intubation is not performed in the majority of ENT departments and no department performs a tracheotomy. In contrast, the standard approach for patients with OSAS and obesity who undergo two-level surgery is intubation and subsequent monitoring without ventilation for the first postoperative day. In the literature no evidence of a scientific basis for carrying out prolonged intubation or a tracheotomy could be found. CONCLUSION: Neither tracheotomy nor prolonged intubation are standard procedures for OSAS patients with obesity after complication-free surgery. PMID- 25270972 TI - Intention to change nutrition-related behaviors in adult participants of a Supplemental Nutrition Assistance Program-Education. AB - OBJECTIVE: To determine whether participation in selected Supplemental Nutrition Assistance Program-Education (SNAP-Ed) lessons had an impact on the intent to improve nutrition-related behaviors of participants. METHODS: A quantitative study using a retrospective post-then-pre design to measure SNAP-Ed outcomes of 203 adult participants after selected nutrition lessons in 14 counties across the state of Utah. After the intervention participants completed a retrospective post then-pre survey evaluating intent to improve nutrition behaviors related to the SNAP-Ed lessons. Wilcoxon signed rank test with Bonferroni correction and paired t test were used. RESULTS: Participants reported sometimes engaging in nutrition related behaviors before attending SNAP-Ed lessons and intent to usually engage in these behaviors after attending SNAP-Ed lessons. CONCLUSION AND IMPLICATIONS: This study demonstrated that participation in selected SNAP-Ed lessons was positively related to the intent of participants to improve nutrition-related behaviors. PMID- 25270973 TI - Outcome analysis of hemoglobin A1c, weight, and blood pressure in a VA diabetes education program. AB - OBJECTIVE: To determine the effect of a specific diabetes education class (Basics) on hemoglobin A1c values, weight, and systolic blood pressure. DESIGN: In this retrospective study, the researchers compared 2 groups of male veterans with a recent diagnosis of type 2 diabetes. One group received diabetes group education (n = 175) over a 4-month period, and the other received standard diabetes management follow-up (n = 184). SETTING: Outpatient clinic setting in the Midwest. INTERVENTIONS: Basics class compared with standard level of care. MAIN OUTCOME MEASURES: Pre- and post-laboratory values for hemoglobin A1c, weight, and systolic blood pressure. ANALYSIS: Multivariate analysis of covariance and follow-up univariate statistics for significant differences. RESULTS: Findings revealed significant differences in hemoglobin A1c (P < .001) and weight (P < .001) in the treatment group compared with the control group. No significant difference was found in systolic blood pressure readings between the 2 groups. There was a significant difference in weight change between groups, with the treatment group demonstrating greater weight loss. CONCLUSIONS AND IMPLICATION: There was an association between participation in the Basics diabetes education curriculum and reduction of hemoglobin A1c values. Some participants also had added benefit of significant weight loss. PMID- 25270974 TI - Study on lead-induced activation of rat renal interstitial fibroblasts and the related mechanisms. AB - CONTEXT: Lead is a common industrial toxicant and has been proved to be associated with the kidney damage. OBJECTIVE: To investigate the effect and mechanism of lead on expression of rat renal interstitial fibroblast activation related protein. MATERIALS AND METHODS: The expression of activation related protein mRNA was measured by real-time PCR in the NRK/49F treated by lead acetate with different concentrations (0, 0.5, 1 and 2 umol/L). The effects of lead acetate on the level of fibronectin (FN) and signal transduction factors (Smads protein) expression were observed by Western blot. RESULTS: The mRNA expression of activation-related protein increased significantly after the cells were stimulated by lead acetate for 24 h. The lead acetate-treated group could upregulate the p-Smad2, p-Smad3 and FN protein expression compared with the control group. The level of Smad2/3 protein expression did not change in all groups, the expression of SnoN decreased significantly compared with the control group. DISCUSSION AND CONCLUSION: Lead acetate could increase the mRNA expression of activation-related factors. It could promote inflammatory reaction induced by TGF-beta via Smad signaling pathway. Lead acetate has the effect on inducing the renal fibrosis. PMID- 25270975 TI - Reported ingested dose of paracetamol as a predictor of risk following paracetamol overdose. AB - PURPOSE: To evaluate reported ingested dose of paracetamol as a risk assessment tool in acute paracetamol overdose. METHODS: Data was retrospectively obtained from a clinical toxicology database linked to one Australian and two United Kingdom hospitals. Plasma paracetamol concentrations (PPCs) of adult patients presenting with acute single ingestion, non-staggered paracetamol deliberate self poisoning between 2006 and 2012 were recorded and plotted on a treatment nomogram to determine accuracy of reported dose ingested as an indicator for antidotal treatment. PPC plotted on a treatment nomogram with a line intersecting a 4-h concentration of 100 mg/L [667 MUmol/L] was considered an indication for antidotal treatment in the UK; the corresponding Australasian population utilised a line intersecting 150 mg/L [1000 MUmol/L]. RESULTS: Of 1246 patients, 65.7 % were female and 88 % were from the UK. Fifty-two percent of patients reporting ingestion of >=8 g paracetamol had a PPC above the 100 mg/L treatment line; PPV 52 % [95 % confidence interval (CI) 49 %, 55 %], sensitivity 81 % [95 %CI 78 %, 85 %]. Forty-four of patients reporting percent ingestion of >=10 g had a PPC above the 150 mg/L treatment line; PPV 44 % [95 % CI 41 %, 49 %], sensitivity 85 % [95 % CI 78 %, 89 %], 72 % of patients reporting ingestion of >=16 g had a PPC above the 100 mg/L treatment line; PPV 72 % [95% CI 67 %, 77 %], sensitivity 50 % [95 % CI 45 %, 54 %]. Overall, there was moderate correlation (R = 0.58) between reported paracetamol dose ingested and extrapolated 4-h PPC. CONCLUSIONS: There is a positive correlation between reported ingested dose of paracetamol and subsequent chance of a PPC being above a defined treatment line; however, ingested dose of paracetamol alone is a poor risk assessment tool in accurately determining need for treatment with an antidote. PMID- 25270977 TI - The limits of global health diplomacy: Taiwan's observer status at the world health assembly. AB - In 2009, health authorities from Taiwan (under the name "Chinese Taipei")a formally attended the 62nd World Health Assembly (WHA) of the World Health Organization as observers, marking the country's participation for the first time since 1972. The long process of negotiating this breakthrough has been cited as an example of successful global health diplomacy. This paper analyses this negotiation process, drawing on government documents, formal representations from both sides of the Taiwan Strait, and key informant interviews. The actors and their motivations, along with the forums, practices and outcomes of the negotiation process, are detailed. While it is argued that non-traditional diplomatic action was important in establishing the case for Taiwan's inclusion at the WHA, traditional concerns regarding Taiwanese sovereignty and diplomatic representation ultimately played a decisive role. The persistent influence of these traditional diplomatic questions illustrates the limits of global health diplomacy. PMID- 25270976 TI - Detection of renal allograft rejection using blood oxygen level-dependent and diffusion weighted magnetic resonance imaging: a retrospective study. AB - BACKGROUND: Acute rejection (AR) and acute tubular necrosis (ATN) are main causes of early renal allograft dysfunction. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) and Diffusion weighted (DW) MRI can provide valuable information about changes of oxygen bioavailability and water diffusion by measuring R2* or apparent diffusion coefficient (ADC) respectively. We aimed to determine the value of BOLD MRI and DW MRI in detecting causes for early allograft dysfunction in renal allograft recipients. METHODS: Fifty patients received renal allografts from deceased donors were analyzed, including 35 patients with normal renal function (control group), 10 AR patients and 5 ATN patients. Cortical R2* (CR2*) and medullary R2* (MR2*) were measured by BOLD MRI. Ten diffusion gradient b values (0, 5, 10, 20, 50, 100, 200, 400, 800, 1200s/mm2) were used in DW MRI. ADC values were measured in renal cortex (CADC) and medulla (MADC). CADCl and MADCl were measured under low b values (b <= 200 s/mm2), while CADCh and MADCh were measured under high b values (b > 200 s/mm2). RESULTS: MR2* was significantly lower in AR group (18.2 +/- 1.5/s) than control group (23.8 +/- 5.0/s, p = 0.001) and ATN group (25.8 +/- 5.0/s, p = 0.004). There was a tendency of lower levels on CADCl, MADCl, CADCh or MADCh in AR group than in control group. There were no differences on ADC values between AR group and ATN group. CONCLUSIONS: BOLD MRI was a valuable method in detection of renal allografts with acute rejection. PMID- 25270978 TI - Dosimetric challenges of small animal irradiation with a commercial X-ray unit. AB - INTRODUCTION: A commercial X-ray unit was recently installed at the Medical University Vienna for partial and whole body irradiation of small experimental animals. For 200 kV X-rays the dose deviations with respect to the reference dose measured in the geometrical center of the potential available field size was investigated for various experimental setup plates used for mouse irradiations. Furthermore, the HVL was measured in mm Al and mm Cu at 200 kV for two types of filtration. MATERIAL AND METHODS: Three different setup constructions for small animal irradiation were dosimetrically characterized, covering field sizes from 9*20 mm2 to 210*200 mm2. Different types of detectors were investigated. Additionally LiF:MG,Ti TLD chips were used for mouse in-vivo dosimetry. RESULTS: The use of an additional 0.5 mm Cu filter reduced the deviation of the dose between each irradiation position on the setup plates. Multiple animals were irradiated at the same time using an individual setup plate for each experimental purpose. The dose deviations of each irradiation position to the center was measured to be +/-4% or better. The depth dose curve measured in a solid water phantom was more pronounced for smaller field sizes. The comparison between estimated dose and measured dose in a PMMA phantom regarding the dose decline yielded in a difference of 3.9% at 20 mm depth. In-vivo measurements in a mouse snouts irradiation model confirmed the reference dosimetry, accomplished in PMMA phantoms, in terms of administered dose and deviation within different points of measurement. DISCUSSION AND CONCLUSION: The outlined experiments dealt with a wide variety of dosimetric challenges during the installation of a new X-ray unit in the laboratory. The depth dose profiles measured for different field sizes were in good agreement with literature data. Different field sizes and spatial arrangement of the animals (depending on each purpose) provide additional challenges for the dosimetric measurements. Thorough dosimetric commissioning has to be performed before a new experimental setup is approved for biological experiments. PMID- 25270979 TI - Scan time reduction in 23Na-Magnetic Resonance Imaging using the chemical shift imaging sequence: Evaluation of an iterative reconstruction method. AB - AIM: To evaluate potential scan time reduction in (23)Na-Magnetic Resonance Imaging with the chemical shift imaging sequence (CSI) using undersampled data of high-quality datasets, reconstructed with an iterative constrained reconstruction, compared to reduced resolution or reduced signal-to-noise ratio. MATERIALS AND METHODS: CSI (23)Na-images were retrospectively undersampled and reconstructed with a constrained reconstruction scheme. The results were compared to conventional methods of scan time reduction. The constrained reconstruction scheme used a phase constraint and a finite object support, which was extracted from a spatially registered (1)H-image acquired with a double-tuned coil. The methods were evaluated using numerical simulations, phantom images and in-vivo images of a healthy volunteer and a patient who suffered from cerebral ischemic stroke. RESULTS: The constrained reconstruction scheme showed improved image quality compared to a decreased number of averages, images with decreased resolution or circular undersampling with weighted averaging for any undersampling factor. Brain images of a stroke patient, which were reconstructed from three-fold undersampled k-space data, resulted in only minor differences from the original image (normalized root means square error < 12%) and an almost identical delineation of the stroke region (mismatch < 6%). CONCLUSION: The acquisition of undersampled (23)Na-CSI images enables up to three-fold scan time reduction with improved image quality compared to conventional methods of scan time saving. PMID- 25270980 TI - Design, performance characteristics and application examples of a new 4D motion platform. AB - In this publication, a three-dimensionally movable motion phantom is described and its performance characteristics are evaluated. The intended primary fields of application for the phantom are the quality assurance (QA) of respiratory motion management devices in radiation therapy (RT) like gating or tumour tracking systems, training for clinical use of these techniques, and related 4DRT research. Considering especially the QA aspect, the phantom was designed as a motion platform that can be equipped with an appropriate add-on like standard QA phantoms for dosimetric measurements. The platform is driven by three computer controlled independent linear motors (motion range: 40 * 50 * 50 mm in anterior posterior/superior-inferior/lateral direction; max. velocity: 3.9 m/s; max. acceleration: 10 m/s(2)), which allow the simulation of normal breathing patterns as well as arbitrary trajectories and anomalous events like coughing or baseline drift. For normal breathing patterns (here: sinusoidal curves with an amplitude of 20mm and a period of 3 s/6 s), the accuracy of the simulated motion paths was measured to be within 0,521 mm even for the ArcCHECK (weight: 20 kg) as a platform load - values that we consider to be sufficient for the intended fields of application. The respective use of the motion phantom is illustrated. PMID- 25270981 TI - Prognosis and demographic characteristics of SSPE patients in Istanbul, Turkey. AB - AIM: SSPE is a rare progressive, invariably fatal long-term complication of measles infection. In this study, we assessed the demographic and prognostic characteristics of 64 consecutive SSPE patients diagnosed at a tertiary center. METHODS: The study had a retrospective design; data were obtained from patient records. RESULTS: The study includes 64 patients diagnosed with SSPE. There was history of consanguineous marriage in 27 (42.2%) patients. The average patient lifespan was 3.8years (45days-12years). The average patient age at diagnosis was 12.3 (range, 5-17)years. A statistically significant correlation was found between the age at diagnosis and lifespan (p=0.002). A statistically significant correlation was found between the incubation period and patient lifespan (p<0.001). No significant correlation was found between duration in the intensive care unit and lifespan (p=0.122). Routine physical therapy had no significant impact on the average lifespan (p=0.619). No significant difference was found between the vaccination dose and lifespan (p=0.651). CONCLUSIONS: High frequency of parental consanguinity in SSPE patients need to be evaluated as there might a genetic influence. Physical therapy and supportive treatments seems to have no affect on lifespan in SSPE patients. The age at diagnosis and incubation period might have an affect on prognosis and lifespan. PMID- 25270982 TI - [Documents and transfusion acts: heterogeneous practices]. AB - Blood transfusion is currently a delegated medical act in patient care services. Blood transfusion safety depends on the strict respect of processes from the prescription of blood products and required patient immuno-hematology exams to the administration of blood products and follow-up of the patient. We conducted a survey among haemovigilance correspondents to establish the documents needed to practice blood transfusion. Blood products delivery depends on the hospitals local organizations and blood products traceability relies on hospitals levels of computerization. We notice heterogeneous practices. Consequently, an updating of the December 15th 2003 circular relative to the transfusion act seems necessary and could thus lead to blood transfusions homogenous practices. PMID- 25270983 TI - Anti-fibrotic effects of Acremoniumterricola milleretal mycelium on immunological hepatic fibrosis in rats. AB - Acremoniumterricola milleretal mycelium (AMM) exerts numerous protective effects on organs, and has been used in Chinese herb prescriptions to treat refractory diseases. The aim of this study was to investigate the effects of AMM on immunological hepatic fibrosis induced by porcine serum (PS) in rats. Male Sprague Dawley rats were administered 0.5 ml sterile PS by intraperitoneal injections twice a week for 18 weeks. AMM (175, 350 or 700 mg/kg) and colchicine (0.1 mg/kg) were administered intragastrically each day until the rats were sacrificed. PS administration resulted in marked hepatic fibrosis, as assessed by increased oxidative stress and hepatic collagen content, as well as alpha-smooth muscle actin (alpha-SMA) expression. AMM significantly reduced liver damage and fibrosis. In addition, AMM decreased the elevation in hydroxyproline, hyaluronic acid, laminin and procollagen type III; increased the activity of superoxide dismutase and glutathione peroxidase; decreased alpha-SMA expression; and eliminated hepatic collagen deposits. Furthermore, AMM inhibited Smad2/3 phosphorylation and Smad7 expression. These results indicate that AMM is able to reduce oxidative stress, inhibit collagen synthesis and block the transforming growth factor-beta/Smad signaling pathway in a dose-dependent manner. PMID- 25270984 TI - Investigating category- and shape-selective neural processing in ventral and dorsal visual stream under interocular suppression. AB - Recent behavioral and neuroimaging studies using continuous flash suppression (CFS) have suggested that action-related processing in the dorsal visual stream might be independent of perceptual awareness, in line with the "vision-for perception" versus "vision-for-action" distinction of the influential dual-stream theory. It remains controversial if evidence suggesting exclusive dorsal stream processing of tool stimuli under CFS can be explained by their elongated shape alone or by action-relevant category representations in dorsal visual cortex. To approach this question, we investigated category- and shape-selective functional magnetic resonance imaging-blood-oxygen level-dependent responses in both visual streams using images of faces and tools. Multivariate pattern analysis showed enhanced decoding of elongated relative to non-elongated tools, both in the ventral and dorsal visual stream. The second aim of our study was to investigate whether the depth of interocular suppression might differentially affect processing in dorsal and ventral areas. However, parametric modulation of suppression depth by varying the CFS mask contrast did not yield any evidence for differential modulation of category-selective activity. Together, our data provide evidence for shape-selective processing under CFS in both dorsal and ventral stream areas and, therefore, do not support the notion that dorsal "vision-for-action" processing is exclusively preserved under interocular suppression. PMID- 25270985 TI - The cell wall-targeted purple acid phosphatase AtPAP25 is critical for acclimation of Arabidopsis thaliana to nutritional phosphorus deprivation. AB - Plant purple acid phosphatases (PAPs) belong to a relatively large gene family whose individual functions are poorly understood. Three PAP isozymes that are up regulated in the cell walls of phosphate (Pi)-starved (-Pi) Arabidopsis thaliana suspension cells were purified and identified by MS as AtPAP12 (At2g27190), AtPAP25 (At4g36350) and AtPAP26 (At5g34850). AtPAP12 and AtPAP26 were previously isolated from the culture medium of -Pi cell cultures, and shown to be secreted by roots of Arabidopsis seedlings to facilitate Pi scavenging from soil-localized organophosphates. AtPAP25 exists as a 55 kDa monomer containing complex NX(S/T) glycosylation motifs at Asn172, Asn367 and Asn424. Transcript profiling and immunoblotting with anti-AtPAP25 immune serum indicated that AtPAP25 is exclusively synthesized under -Pi conditions. Coupled with potent mixed-type inhibition of AtPAP25 by Pi (I50 = 50 MUm), this indicates a tight feedback control by Pi that prevents AtPAP25 from being synthesized or functioning as a phosphatase except when Pi levels are quite low. Promoter-GUS reporter assays revealed AtPAP25 expression in shoot vascular tissue of -Pi plants. Development of an atpap25 T-DNA insertion mutant was arrested during cultivation on soil lacking soluble Pi, but rescued upon Pi fertilization or complementation with AtPAP25. Transcript profiling by quantitative RT-PCR indicated that Pi starvation signaling was attenuated in the atpap25 mutant. AtPAP25 exhibited near-optimal phosphatase activity with several phosphoproteins and phosphoamino acids as substrates. We hypothesize that AtPAP25 plays a key signaling role during Pi deprivation by functioning as a phosphoprotein phosphatase rather than as a non specific scavenger of Pi from extracellular P-monoesters. PMID- 25270986 TI - Extrinsic tau-coupling and the regulation of interceptive reaching under varying task constraints. AB - We investigated a general theory accounting for the guidance of ongoing movements in an interceptive reaching task. The aim was to assess the premise of tau coupling that the coupling constant k, the ratio of taus (taus) of motion gaps between hand and object, reflects the kinematics of the on-going movement. The spatial and temporal constraints of the interceptive action were manipulated in three task conditions. While the time dependent counterpart of k, K(t) exhibited task effects, k itself could not distinguish between task manipulations. K(t) showed large variability during the initial acceleration phase, small variability during the rest of the movement, and task dependent changes during the final deceleration phase of interception. The findings highlight the importance of clarifying what constitutes as t-coupling. PMID- 25270987 TI - Hypoxic guard systems do not prevent rapid hypoxic inspired mixture formation. AB - Because a case report and theoretical mass balances suggested that hypoxic guard systems may not prevent the formation of hypoxic inspired mixtures (FIO2 <= 21 %) over the clinically used fresh gas flow (FGF) range, we measured FIO2 over a wide range of hypoxic guard limits for O2/N2O and O2/air mixtures. After IRB approval, 16 ASA I-II patients received sevoflurane in either O2/N2O (n = 8) or O2/air (n = 8) using a Zeus((r)) anesthesia machine in the conventional mode. After using an 8 L/min FGF with FDO2 = 25% for 10 min, the following hypoxic guard limits were tested for 4 min each, expressed as [total FGF in L/min; FDO2 in %]: [0.3;85], [0.4;65], [0.5;50], [0.7;36], [0.85;30], [1.0;25], [1.25;25], [1.5;25], [2;25], [3;25], [5;25], and [8;25]. In between these [FGF;FDO2] combinations, 8 L/min FGF with 25% O2 was used for 4 min to return to the same baseline FIO2 (25%) before the start of the next combination. This sequence was studied once in each patient receiving O2/air (n = 8), but twice in each patient who received O2/N2O (n = 8) to examine the effect of decreasing N2O uptake over time, resulting in three groups: early O2/N2O, late O2/N2O, and O2/air group. The [FGF;FDO2]-FIO2 relationship was examined. The overall [FGF;FDO2]-FIO2 relationship in the three groups was similar. In all 1, 1.25, and 1.5 L/min FGF groups, FIO2 decreased below 21% in all but one patient; this occurred within 1 min in at least one patient. In the 0.7 L/min O2/air group and the 3 L/min late O2/N2O and O2/air groups, FIO2 decreased below 21% in one patient. Current hypoxic guard systems do not reliably prevent a hypoxic FIO2 with O2/N2O and O2/air mixtures, particularly between 0.7 and 3 L/min. PMID- 25270988 TI - Psychiatrists with substance use disorders: positive treatment outcomes from physician health programs. AB - OBJECTIVE: The objective of this study was to compare outcomes of psychiatrists and nonpsychiatrist physicians enrolled in state physician health programs for substance use disorders. METHODS: The study used the data set from a five-year, longitudinal cohort study of 904 physicians, including 55 psychiatrists, with diagnoses of substance abuse or dependence consecutively admitted to one of 16 state physician health programs between 1995 and 2001. RESULTS: There was a higher proportion of women among psychiatrists than among other physicians, but there were no other significant differences between the cohorts. Five-year outcomes were similar between psychiatrists and the other physicians, with at least 75% of psychiatrists continuing their medical practice after five years of monitoring and treatment. CONCLUSIONS: Psychiatrists were not overrepresented compared with other physician groups and had similar clinical outcomes at the five-year follow-up. Physician health programs appeared to be effective treatment programs for psychiatrists with substance use disorders. PMID- 25270990 TI - The first step in modern lesion-deficit analysis. PMID- 25270991 TI - Preparing facilitators from community-based organizations for evidence-based intervention training in Second Life. AB - BACKGROUND: A major barrier to the use and scale-up of evidence-based interventions are challenges related to training and capacity building. A cost effective and highly interactive multi-user virtual environment, Second Life (SL) is a promising alternative for comprehensive face-to-face facilitator training. OBJECTIVE: The purpose of this study was to examine the feasibility of using SL to train facilitators from community-based organizations to use !Cuidate! (Take Care of Yourself), one of the few evidence-based interventions developed and tested with Latino youth to reduce sexual risk behaviors. METHODS: We recruited 35 participants from community-based organizations throughout the United States to participate in the SL !Cuidate! Training of Facilitators. Preparation to use SL consisted of four phases: (1) recruitment and computer capacity screening, (2) enrollment, (3) orientation to the SL program, and (4) technical support throughout the synchronous training sessions. Technical difficulties, the associated cause, and the mitigation strategy implemented were recorded during each session. Participants completed evaluations including perceptions of self efficacy and confidence to complete the necessary skills to participate in SL training. RESULTS: Overall, participants reported high levels of self-efficacy for all skills necessary to participate in SL training. Based on an 11-point scale (0-10), self-efficacy to download and access the software was rated the highest: mean 8.29 (SD 2.19). Interacting with items in SL had the lowest mean score: mean 7.49 (SD 2.89). The majority of technical difficulties experienced by participants were related to inadequate Internet connections or computer malfunctions. CONCLUSIONS: Our findings support the feasibility of using SL for the !Cuidate! Training of Facilitators. The process used in this study to prepare participants to use SL can be used as a basis for other evidence-based intervention training in SL. This study is an important contribution to developing cost-effective and accessible training options for evidence-based interventions. PMID- 25270992 TI - Beta-cryptoxanthin as a source of vitamin A. AB - Beta-cryptoxanthin is a common carotenoid that is found in fruit, and in human blood and tissues. Foods that are rich in beta-cryptoxanthin include tangerines, persimmons and oranges. Beta-cryptoxanthin has several functions that are important for human health, including roles in antioxidant defense and cell-to cell communication. Most importantly, beta-cryptoxanthin is a precursor of vitamin A, which is an essential nutrient needed for eyesight, growth, development and immune response. We evaluate the evidence for beta-cryptoxanthin as a vitamin A-forming carotenoid in this paper. Observational, in vitro, animal model and human studies suggest that beta-cryptoxanthin has greater bioavailability from its common food sources than do alpha- and beta-carotene from theirs. Although beta-cryptoxanthin appears to be a poorer substrate for beta-carotene 15,15' oxygenase than is beta-carotene, animal model and human studies suggest that the comparatively high bioavailability of beta-cryptoxanthin from foods makes beta-cryptoxanthin-rich foods equivalent to beta-carotene-rich foods as sources of vitamin A. These results mean that beta-cryptoxanthin-rich foods are probably better sources of vitamin A, and more important for human health in general, than previously assumed. PMID- 25270989 TI - Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. AB - Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer's disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer's disease. PMID- 25270993 TI - A proteomic analysis of rice seed germination as affected by high temperature and ABA treatment. AB - Seed germination is a critical phase in the plant life cycle, but the specific events associated with seed germination are still not fully understood. In this study, we used two-dimensional gel electrophoresis followed by mass spectrometry to investigate the changes in the proteome during imbibition of Oryza sativa seeds at optimal temperature with or without abscisic acid (ABA) and high temperature (germination thermoinhibition) to further identify and quantify key proteins required for seed germination. A total of 121 protein spots showed a significant change in abundance (1.5-fold increase/decrease) during germination under all conditions. Among these proteins, we found seven proteins specifically associated with seed germination including glycosyl hydrolases family 38 protein, granule-bound starch synthase 1, Os03g0842900 (putative steroleosin-B), N carbamoylputrescine amidase, spermidine synthase 1, tubulin alpha-1 chain and glutelin type-A; and a total of 20 imbibition response proteins involved in energy metabolism, cell growth, cell defense and storage proteins. High temperature inhibited seed germination by decreasing the abundance of proteins involved in methionine metabolism, amino acid biosynthesis, energy metabolism, reserve degradation, protein folding and stress responses. ABA treatment inhibited germination and decreased the abundance of proteins associated with methionine metabolism, energy production and cell division. Our results show that changes in many biological processes including energy metabolism, protein synthesis and cell defense and rescue occurred as a result of all treatments, while enzymes involved in methionine metabolism and weakening of cell wall specifically accumulated when the seeds germinated at the optimal temperature. PMID- 25270994 TI - The desire of parents to be involved and present. AB - BACKGROUND: Intensive care of children means not only caring for a child; it means care for the whole family. AIM: The aim of the study was to describe parents' experiences of having a critically ill child in an intensive care unit (ICU). PARTICIPANTS: A purposive sample of seven parents who had their child treated in an ICU during 2012 in Sweden. DESIGN: The design uses an inductive, qualitative approach with data collected by means of qualitative interviews. METHODS: The interviews were transcribed verbatim and subjected to qualitative content analysis. RESULTS: The analysis resulted in one theme: the desire of parents to be involved and present, with four categories such as wanting to understand and know what is happening, feeling frustration about their child's care and treatment, a health care environment that arouses emotions, and needs for support and processing. CONCLUSION: It is of great importance to parents to be informed continuously about their child's condition and the care and treatment that are planned. This may increase parents' sense of ownership, control and security. RELEVANCE TO CLINICAL PRACTICE: Providing answers to those questions that can be answered and being available to parents when they have questions about their critically ill child, the meaning of it all, and what the future will hold are suggested in clinical practice. PMID- 25270995 TI - Serum infliximab concentrations in psoriatic patients treated with infliximab: a systematic review. AB - The efficacy of infliximab is influenced by individual variability in its pharmacokinetics and pharmacodynamics. Serum infliximab concentrations could therefore be related to the efficacy and tolerance of infliximab, and assist adjustment of treatment. The aim of this systematic review was to assess the value of measuring serum infliximab concentrations in psoriatic patients. A bibliographic search was performed on MEDLINE, CENTRAL, EMBASE, LILACS for original studies on serum infliximab concentrations in psoriatic patients treated with infliximab. Ten articles were included, representing evaluation of serum infliximab concentrations in 733 patients. Predictive value of higher serum infliximab concentrations on long-term response maintenance was suggested in 3 studies. There was no information regarding the value of such measurements for adjustment of infliximab dosage. Trough serum infliximab concentrations that are at least detectable (>0.1 mg/L) at steady state (week 22) seem to be associated with maintaining a clinical response in the long term. PMID- 25270996 TI - Approach to design space from retrospective quality data. AB - CONTEXT: Nowadays, the entire manufacturing process is based on the current GMPs, which emphasize the reproducibility of the process, and companies have a lot of recorded data about their processes. OBJECTIVE: The establishment of the design space (DS) from retrospective data for a wet compression process. MATERIALS AND METHODS: A design of experiments (DoE) with historical data from 4 years of industrial production has been carried out using the experimental factors as the results of the previous risk analysis and eight key parameters (quality specifications) that encompassed process and quality control data. RESULTS: Software Statgraphics 5.0 was applied, and data were processed to obtain eight DS as well as their safe and working ranges. DISCUSSION AND CONCLUSION: Experience shows that it is possible to determine DS retrospectively, being the greatest difficulty in handling and processing of high amounts of data; however, the practicality of this study is very interesting as it let have the DS with minimal investment in experiments since actual production batch data are processed statistically. PMID- 25270997 TI - A prospective study of excessive postural heart rate change on head-up tilt. AB - PURPOSE: Healthy subjects with asymptomatic postural tachycardia (>=30 bpm) at baseline were evaluated over a 1-year period to determine whether they developed orthostatic symptoms. METHODS: Subjects were evaluated at baseline and at 1 year using the autonomic reflex screen and autonomic symptom profile (ASP). RESULTS: Heart rate increment on HUT did not differ at baseline (40.6 +/- 7.5 bpm) or at 1 year (37.1 +/- 11.1 bpm; n = 26; p > 0.05). Orthostatic symptoms measured by the ASP did not reveal significant orthostatic dysfunction throughout follow-up (baseline, 7.88 +/- 7.61; 1 year, 9.04 +/- 6.64; n = 26; p > 0.05). The ten autonomic domains of the ASP did not reveal a change in autonomic symptoms from baseline (13.56 +/- 13.66) to 1-year follow-up (15.12 +/- 11.62; n = 26; p > 0.05). Cardiovagal function was unchanged between baseline and follow-up for both heart rate variability to deep breathing (baseline, 23.9 +/- 11.6 bpm; 1 year, 23.0 +/- 9.3 bpm; n = 26; p > 0.05) and Valsalva ratio (baseline, 2.16 +/- 0.39; 1 year, 2.15 +/- 0.33; n = 26; p > 0.05). CONCLUSIONS: These findings further argue that heart rate criteria (>=30 bpm) for Postural Tachycardia Syndrome (POTS) are not appropriate in younger individuals and higher postural heart rates do not predispose individuals to the development of POTS. PMID- 25270998 TI - Body dissatisfaction and dietary restraint influence binge eating behavior. AB - As binge eating is a common behavior throughout the general population, we hypothesized that body dissatisfaction would produce binge eating via its prediction of dieting. Six hundred eight individuals were nonrandomly recruited from the community. The mean age and body mass index of participants were 34.76 years (SD, 14.41) and 27.82 kg/m(2) (SD, 9.54), respectively. Participants were asked to complete several self-report questionnaires, which included measures of dieting status, binge eating behavior, body dissatisfaction, overvaluation of weight and shape, and self-esteem. The results showed that dieting was a common behavior; 38.1% of participants reported dieting during the past year. Binge eating during the previous 6 months was reported by 9.9% of the sample and was associated with a higher body mass index as well as more frequent dieting. A model including dieting status, overvaluation of weight and shape, shape satisfaction, and self-esteem showed the best fit for the prediction of binge eating behavior. Moreover, those who dieted and overvalued their weight and shape were 2.01 and 2.31 times more likely, respectively, to binge eat. Structural equation modeling revealed that body dissatisfaction caused dietary restraint, thus triggering binge eating. Both dieting and overvaluation of weight and shape are important risk factors for the development of binge eating disorders. Dieting and binge eating are common behaviors that represent a risk for the development of both excess weight and eating disorders. The structural model proposed in this study could be beneficial in understanding this causal relationship. PMID- 25270999 TI - Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion. AB - Cachexia is a frequent complication in patients with respiratory failure, such as lung fibrosis, and it is a determining factor for functional capacity, health status, and mortality. Reductions in body weight and skeletal muscle mass are key features of cachexia that are resistant to current therapies. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment for patients with gastrointestinal symptoms and known to stimulate ghrelin secretion. By using bleomycin (BLM)-induced lung fibrosis mice in this study, we tested our hypothesis that RKT administration could ameliorate pulmonary cachexia. After BLM administration, mice were provided with either RKT or distilled water on a daily basis. Compared with the BLM-injected mice, the RKT-treated mice had smaller reductions of food intake and body weight. Skeletal muscle weights were retained in the RKT-treated mice, in conjunction with reduced expressions of MuRF-1 and atrogin-1 in the lysates of skeletal muscle found in lung fibrosis. Rikkunshito administration restored the plasma concentrations of ghrelin in BLM-injected mice. The anticachectic efficacies of RKT administration in BLM-injected mice were canceled by the concurrent treatment of a ghrelin receptor antagonist. Rikkunshito administration did not decrease the degree of loss of body weight or food intake reduction in either ghrelin-deficient mice or growth hormone secretagogue receptor-deficient mice. Our results indicate that RKT administration exerts protective effects on pulmonary cachexia by ameliorating skeletal muscle wasting and food intake reduction as mediated by the ghrelin system and, thus, highlight RKT as a potential therapeutic agent for the management of lung fibrosis. PMID- 25271000 TI - Differing coagulation profiles of patients with monoclonal gammopathy of undetermined significance and multiple myeloma. AB - The link between myeloma and thrombosis is well established. Monoclonal gammopathy of undetermined significance (MGUS) has also been associated with an increased risk of thrombosis. It was recently demonstrated that patients with myeloma display changes in thromboelastometry that may indicate a prothrombotic state. There is little data with regard to changes in thromboelastography in patients with myeloma or MGUS. The aim of this study was to investigate the differing coagulation profiles of patients of patients with myeloma and MGUS by means of conventional coagulation tests and thromboelastography. Blood was taken by direct venepuncture from patients with myeloma, MGUS and normal controls. Routine coagulation tests were performed in an accredited hospital laboratory. Thromboelastography (TEG((r))) was performed as per the manufacturer's protocol. Eight patients were recruited in each group. Patients with myeloma had a significantly lower mean haemoglobin level than patients with MGUS or normal controls (p < 0.001). Patients with myeloma had a significantly more prolonged mean prothrombin time than normal controls (p = 0.018) but not patients with MGUS. Patients with myeloma had significantly higher median D-dimer levels than normal controls (p = 0.025), as did patients with MGUS (p = 0.017). Patients with myeloma had a significantly higher mean factor VIII level than normal controls (p = 0.009) and there was a non-significant trend towards patients with MGUS having higher factor VIII levels than normal controls (p = 0.059). There was no significant difference in thromboelastographic parameters between the three groups. Patients with MGUS appear to have a distinct coagulation profile which is intermediate between patients with myeloma and normal controls. PMID- 25271001 TI - Regulatory MiR-148a-ACVR1/BMP circuit defines a cancer stem cell-like aggressive subtype of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cancer in Asia. HCC has heterogeneous etiologic and molecular profiles and a varied response to therapeutics. The high recurrence rate and curtailed survival in this cancer are attributed to its resistance to therapy. The ultimate goal is to develop a more effective personalized therapeutic strategy for HCC, but the first step is to develop a system for classifying the disease on the basis of molecular biomarkers. To that end, we performed mRNA and microRNA (miRNA) expression profiling in 100 HCC tissues. Clustering analysis of informative genes identified two robust subtypes, which were validated by an independent dataset. The subtype characterized by a cancer stem cell-like signature was clinically aggressive and associated with poor survival. Integrated analysis of miRNA and mRNA expression in this subtype showed that miR-148a was expressed at a significantly lower level in these tumors than in the other subtype. MiR-148a has been shown to directly suppress the expression of activin A receptor type 1 (ACVR1), a key receptor in the signaling pathway of the bone morphogenetic proteins (BMPs), which regulate many stem cell markers as well as the clinically important cytokine interleukin-8 (IL-8). Increased expression of ACVR1 and its downstream genes EPCAM, CD24, CD90, and IL-8 was associated with shorter survival in a larger cohort of 227 HCC cases. Introduction of miR-148a resulted in suppressed tumor phenotypes both in vitro and in vivo. CONCLUSION: We identified a clinically aggressive stem cell-like subtype of HCC that is characterized by an miR-148a-ACVR1-BMP-Wnt circuit. We propose that miR-148a may serve as a prognostic biomarker and therapeutic target for this subtype of HCC. PMID- 25271002 TI - Nucleic acid induced unfolding of recombinant prion protein globular fragment is pH dependent. AB - Nucleic acid can catalyze the conversion of alpha-helical cellular prion protein to beta-sheet rich Proteinase K resistant prion protein oligomers and amyloid polymers in vitro and in solution. Because unfolding of a protein molecule from its ordered alpha-helical structure is considered to be a necessary step for the structural conversion to its beta-sheet rich isoform, we have studied the unfolding of the alpha-helical globular 121-231 fragment of mouse recombinant prion protein in the presence of different nucleic acids at neutral and acid pH. Nucleic acids, either single or double stranded, do not have any significant effect on the secondary structure of the protein fragment at neutral pH; however the protein secondary structure is modified by the nucleic acids at pH 5. Nucleic acids do not show any significant effect on the temperature induced unfolding of the globular prion protein domain at neutral pH which, however, undergoes a gross conformational change at pH 5 as evidenced from the lowering of the midpoint of thermal denaturation temperatures, Tm, of the protein. The extent of Tm decrease shows a dependence on the nature of nucleic acid. The interaction of nucleic acid with the nonpolar groups exposed from the protein interior at pH 5 probably contributes substantially to the unfolding process of the protein. PMID- 25271003 TI - Effect of chromogranin A-derived vasostatin-1 on laser-induced choroidal neovascularization in the mouse. AB - PURPOSE: To verify the effect of vasostatin-1 (VS-1), an anti-angiogenic fragment of chromogranin A, in the prevention of choroidal neovascularization (CNV) in an established mouse model of laser-induced ocular neovascularization. METHODS: Bruch's membrane, the innermost layer of the choroid, was broken by laser photocoagulation in C57/Bl6 mice, to induce CNV. Mice were then treated daily for 14 days by intraperitoneal injection of VS-1 or vehicle (6 mice/group). CNV and vascular leakage were measured at three time-points (day 0, 7 and 14) in vivo by spectral domain optical coherence tomography (OCT) and fluorescein angiography (FA). Ex vivo analysis of CNV was also performed at day 14 by confocal microscopy analysis of dextran-perfused choroidal flat-mounts. RESULTS: In vivo analyses showed that VS-1 significantly reduced CNV at day 14 (p = 0.03) and vascular leakage at day 7 (p = 0.01) and 14 (p = 0.04). Ex vivo confocal microscopy analysis of CNV performed on dextran-perfused choroidal flat-mounts at day 14 confirmed the protective activity of VS-1 (p = 0.01). A significant correlation between the results of in vivo and ex vivo analyses of CNV was also observed (p = 0.001, R(2) = 0.81). CONCLUSION: The results indicate that VS-1 can prevent CNV and vascular leakage in a mouse model of ocular neovascularization, suggesting that this polypeptide might have therapeutic activity in human ocular diseases that are complicated by neovascularization or excessive vascular permeability. PMID- 25271004 TI - Discussion of papers: determination of hydraulic conductivity from grain-size distribution for different depositional environments. PMID- 25271005 TI - Assessment of toxic potential of mycotoxin contaminated bread during in vitro human digestion on human B lymphoid cell line. AB - Ingestion of food is considered a major route of exposure to many contaminants including mycotoxins. The amount of mycotoxin resisting to the digestion process and potentially absorbable by the systemic circulation is only a smaller part of that ingested. In vitro digestion models turn useful for evaluating mycotoxins bioaccessibility during the intestinal transit and can be intended as a valuable tool for the assessment of mycotoxin bioavailability in food. In this paper we describe a study aimed at investigating toxicity of in vitro gastro-duodenal digests of mycotoxin contaminated bread collected along the digestion time course. Toxicity tests were carried out on a sensitive RPMI lymphoid B cell line chosen as the most suitable lineage to assess toxicity retained by gastro duodenal digests. In parallel, a chemical quantification of T-2 and HT-2 toxins contaminating the bread digests was accomplished during the gastric and duodenal transit. The digestive fluids undergoing chemical and toxicological analysis were collected at the beginning and end of gastric phase, and after completion of the duodenal phase. Results proved that a correlation between HT-2 content and toxicity did exist although a more persistent toxic activity was displayed in the later stage of the duodenal phase. This persistent toxicity might be explained by the co-occurrence of unknown HT-2-related conjugates or metabolites formed during digestion. PMID- 25271007 TI - Confirmatory Factor Analysis of the Patient Version of the Working Alliance Inventory--Short Form Revised. AB - The working alliance concerns the quality of collaboration between patient and therapist in psychotherapy. One of the most widely used scales for measuring the working alliance is the Working Alliance Inventory (WAI). For the patient-rated version, the short form developed by Hatcher and Gillaspy (WAI-SR) has shown the best psychometric properties. In two confirmatory factor analyses of the WAI-SR, approximate fit indices were within commonly accepted norms, but the likelihood ratio chi-square test showed significant ill-fit. The present study used Bayesian structural equations modeling with zero mean and small variance priors to test the factor structure of the WAI-SR in three different samples (one American and two Swedish; N = 235, 634, and 234). Results indicated that maximum likelihood confirmatory factor analysis showed poor model fit because of the assumption of exactly zero residual correlations. When residual correlations were estimated using small variance priors, model fit was excellent. A two-factor model had the best psychometric properties. Strong measurement invariance was shown between the two Swedish samples and weak factorial invariance between the Swedish and American samples. The most important limitation concerns the limited knowledge on when the assumption of residual correlations being small enough to be considered trivial is violated. PMID- 25271008 TI - Wechsler Adult Intelligence Scale-IV Dyads for Estimating Global Intelligence. AB - All possible two-subtest combinations of the core Wechsler Adult Intelligence Scale-IV (WAIS-IV) subtests were evaluated as possible viable short forms for estimating full-scale IQ (FSIQ). Validity of the dyads was evaluated relative to FSIQ in a large clinical sample (N = 482) referred for neuropsychological assessment. Sample validity measures included correlations, mean discrepancies, and levels of agreement between dyad estimates and FSIQ scores. In addition, reliability and validity coefficients were derived from WAIS-IV standardization data. The Coding + Information dyad had the strongest combination of reliability and validity data. However, several other dyads yielded comparable psychometric performance, albeit with some variability in their particular strengths. We also observed heterogeneity between validity coefficients from the clinical and standardization-based estimates for several dyads. Thus, readers are encouraged to also consider the individual psychometric attributes, their clinical or research goals, and client or sample characteristics when selecting among the dyadic short forms. PMID- 25271006 TI - Disease burden and risk profile in referred patients with moderate chronic kidney disease: composition of the German Chronic Kidney Disease (GCKD) cohort. AB - BACKGROUND: A main challenge for targeting chronic kidney disease (CKD) is the heterogeneity of its causes, co-morbidities and outcomes. Patients under nephrological care represent an important reference population, but knowledge about their characteristics is limited. METHODS: We enrolled 5217 carefully phenotyped patients with moderate CKD [estimated glomerular filtration rate (eGFR) 30-60 mL/min per 1.73 m(2) or overt proteinuria at higher eGFR] under routine care of nephrologists into the German Chronic Kidney Disease (GCKD) study, thereby establishing the currently worldwide largest CKD cohort. RESULTS: The cohort has 60% men, a mean age (+/-SD) of 60 +/- 12 years, a mean eGFR of 47 +/- 17 mL/min per 1.73 m(2) and a median (IQR) urinary albumin/creatinine ratio of 51 (9-392) mg/g. Assessment of causes of CKD revealed a high degree of uncertainty, with the leading cause unknown in 20% and frequent suspicion of multifactorial pathogenesis. Thirty-five per cent of patients had diabetes, but only 15% were considered to have diabetic nephropathy. Cardiovascular disease prevalence was high (32%, excluding hypertension); prevalent risk factors included smoking (59% current or former smokers) and obesity (43% with BMI >30). Despite widespread use of anti-hypertensive medication, only 52% of the cohort had an office blood pressure <140/90 mmHg. Family histories for cardiovascular events (39%) and renal disease (28%) suggest familial aggregation. CONCLUSIONS: Patients with moderate CKD under specialist care have a high disease burden. Improved diagnostic accuracy, rigorous management of risk factors and unravelling of the genetic predisposition may represent strategies for improving prognosis. PMID- 25271009 TI - Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in patients with type 2 diabetes. AB - BACKGROUND/OBJECTIVE: Artificial sweeteners were thought to be metabolically inactive, but after demonstrating that the gustatory mechanism was also localized in the small intestine, suspicions about the metabolic effects of artificial sweeteners have emerged. The objective of this study was to determine the effect of artificial sweeteners (aspartame and sucralose) on blood glucose, insulin, c peptide and glucagon-like peptide-1 (GLP-1) levels. SUBJECTS/METHODS: Eight newly diagnosed drug-naive type 2 diabetic patients (mean age 51.5+/-9.2 years; F/M: 4/4) and eight healthy subjects (mean age 45.0+/-4.1 years; F/M: 4/4) underwent 75 g oral glucose tolerance test (OGTT). During OGTT, glucose, insulin, c-peptide and GLP-1 were measured at 15- min intervals for 120 min. The OGTTs were performed at three settings on different days, where subjects were given 72 mg of aspartame and 24 mg of sucralose in 200 ml of water or 200 ml of water alone 15 min before OGTT in a single-blinded randomized order. RESULTS: In healthy subjects, the total area under the curve (AUC) of glucose was statistically significantly lower in the sucralose setting than in the water setting (P=0.002). There was no difference between the aspartame setting and the water setting (P=0.53). Total AUC of insulin and c-peptide was similar in aspartame, sucralose and water settings. Total AUC of GLP-1 was significantly higher in the sucralose setting than in the water setting (P=0.04). Total AUC values of glucose, insulin, c-peptide and GLP-1 were not statistically different in three settings in type 2 diabetic patients. CONCLUSIONS: Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in newly diagnosed type 2 diabetic patients. PMID- 25271010 TI - Clinical workout for the early detection of cognitive decline and dementia. AB - Aging is the major risk factor for the development of human neurodegenerative maladies such as Alzheimer's, Huntington's and Parkinson's diseases (PDs) and prion disorders, all of which stem from toxic protein aggregation. All of these diseases are correlated with cognitive decline. Cognitive Decline is a dynamic state from normal cognition of aging to dementia. According to the original criteria for Alzheimer's Disease (AD) (1984), a clinical diagnosis was possible only when someone was already demented. The prevalence rates of Cognitive Decline (mild cognitive impairment plus dementia) are very high now and will be higher in future because of the increasing survival time of people. Many neurological and psychiatric diseases are correlated with cognitive decline. Diagnosis of cognitive decline is mostly clinical (clinical criteria), but there are multiple biomarkers that could help us mostly in research programs such as short or long, paper and pencil or computerized neuropsychological batteries for cognition, activities of daily living and behavior, electroencephalograph, event-related potentials, and imaging-structural magnetic resonance imaging (MRI) and functional (fMRI, Pittsburgh bound positron emission tomography, FDG-PET, single photon emission computerized tomography and imaging of tau pathology) cerebrospinal fluid proteins (Abeta, tau and phospho-tau in AD and alpha synuclein (alphaSyn) for PD). Blood biomarkers need more studies to confirm their usefulness. Genetic markers are also studied but until now are not used in clinical praxis. Finally, in everyday clinical praxis and in research workout for early detection of cognitive decline, the combination of biomarkers is useful. PMID- 25271011 TI - The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND/OBJECTIVES: Although single, high doses of vitamin D effectively maintain vitamin D sufficiency in several populations, no studies have evaluated healthy adults over winter, during which vitamin D status declines. This study investigated whether high-dose vitamin D3 given once to healthy adults before winter will (1) prevent the wintertime decline in vitamin D status, (2) promote vitamin D sufficiency 1 year following the dose and (3) prevent the rise of parathyroid hormone (PTH) concentrations. SUBJECTS/METHODS: In this double-blind, placebo-controlled trial, we assessed plasma 25(OH)D and PTH concentrations at baseline, 5, 90 and 365 days after drug administration in 28 healthy adults. In all, >80% of subjects returned at each time point. RESULTS: At baseline, the young, healthy participants had a mean plasma 25(OH)D concentration of 17.5+/-6.1 ng/ml. Only two subjects exhibited plasma 25(OH)D concentrations >30 ng/ml. At 5 days, subjects randomized to vitamin D3 had a higher mean plasma 25(OH)D concentration compared with the placebo group (39.1 vs 19.1 ng/ml, P<0.001). Plasma 25(OH)D concentrations returned to baseline at 90 and 365 days in the vitamin D3 group and remained unchanged in the placebo group. PTH and calcium concentrations were unrelated to changes in 25(OH)D levels and similar between groups over time. CONCLUSIONS: A dose of 250,000 IU of vitamin D3 given once in November resulted in a robust increase in plasma 25(OH)D after 5 days, but it was unable to sustain this increase after 90 days. A larger or more frequent dosing regimen may be needed for long-term vitamin D sufficiency. PMID- 25271013 TI - A comparison of gluten levels in labeled gluten-free and certified gluten-free foods sold in the United States. PMID- 25271012 TI - Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review. AB - OBJECTIVE: Bioelectrical impedance analysis (BIA) is a commonly used method for the evaluation of body composition. However, BIA estimations are subject to uncertainties.The aim of this systematic review was to explore the variability of empirical prediction equations used in BIA estimations and to evaluate the validity of BIA estimations in adult surgical and oncological patients. SUBJECTS: Studies developing new empirical prediction equations and studies evaluating the validity of BIA estimations compared with a reference method were included. Only studies using BIA devices measuring the entire body were included. Studies that included patients with altered body composition or a disturbed fluid balance and studies written in languages other than English were excluded.To illustrate variability between equations, fixed normal reference values of resistance values were entered into the existing empirical prediction equations of the included studies and the results were plotted in figures. The validity was expressed by the difference in means between BIA estimates and the reference method, and relative difference in %. RESULTS: Substantial variability between equations for groups (including men and women) was found for total body water (TBW) and fat free mass (FFM). The gender-specific existing general equations assume less variability for TBW and FFM. BIA mainly underestimated TBW (range relative difference -18.8% to +7.2%) and FFM (range relative differences -15.2% to +3.8%). Estimates of the fat mass (FM) demonstrated large variability (range relative difference -15.7 to +43.1%). CONCLUSIONS: Application of equations validated in healthy subjects to predict body composition performs less well in oncologic and surgical patients. We suggest that BIA estimations, irrespective of the device, can only be useful when performed longitudinally and under the same standard conditions. PMID- 25271014 TI - Body mass index in dementia. AB - This review comprehensively examines the current knowledge on the relationship between body mass index (BMI) and dementia. The association between BMI and cognition is complex: in younger adults, higher BMIs are associated with impaired cognition. Overweight and obesity in middle age are linked to increased future dementia risk in old age. However, when examined in old age, higher BMIs are associated with better cognition and decreased mortality. Little is known about the optimal BMI for well-being and survival in populations already suffering from dementia. Lifetime trends in weight, rather than single measures, might predict prognosis better and help untangle these apparent contradictions. Thus, the need arises to properly monitor BMI trends in affected dementia patients. Registries can include BMI, improving the management of dementia patients throughout the whole course of the disease. The role of central obesity and systemic inflammation on brain pathology and cognitive decline are discussed in this review. Understanding the life-course changes in BMI and their influence on dementia risk, cognitive prognosis and mortality after diagnosis may provide new insights into the underlying pathophysiology of dementia and shape possible intervention and treatment strategies. PMID- 25271015 TI - Acute effects of plant stanol esters on postprandial metabolism and its relation with changes in serum lipids after chronic intake. AB - BACKGROUND/OBJECTIVES: Plant stanol esters lower serum low-density lipoprotein (LDL)-cholesterol (LDL-C), but responses between individuals vary widely. As the ability of subjects to respond to acute dietary challenges may reflect the flexibility to adapt to changes on the longer term, we related subjects' acute postprandial metabolic changes to changes in serum lipoproteins after chronic intake of plant stanol esters. SUBJECTS/METHODS: In a double-blind crossover design, 20 healthy subjects received in random order a high-fat shake enriched with or without plant stanol esters (4 g). Blood samples were taken during 4 h to examine lipid, glucose and lipoprotein profiles. Two subjects dropped out. For the 3 weeks after this postprandial test, the subjects who received the shake with plant stanol esters continued the consumption of plant stanol-enriched (3g/day) margarine and subjects receiving the control shake in the postprandial test consumed for the next 3 weeks a control margarine. After the washout period, subjects received the other shake and margarines. RESULTS: The margarine enriched with plant stanol esters lowered concentrations of total cholesterol by 7.3% (P<0.01), LDL-C by 9.5% (P<0.01) and apoB100 by 8.6% (P<0.01). Furthermore, particle concentrations of total very low-density lipoprotein (VLDL), small VLDL and large LDL were reduced by 26.6% (P=0.02), 27.6% (P=0.02) and 12.3% (P=0.04), respectively. Plant stanol esters did not affect parameters related to lipid and glucose metabolism during the postprandial phase. However, the incremental area under the curve (iAUC) of the postprandial glucose concentration after consuming the control shake correlated positively with changes in fasting concentrations of total cholesterol, LDL-C, apoB100, total VLDL, small VLDL and intermediate density lipoprotein after 3 weeks. CONCLUSIONS: A single dose of plant stanol esters does not change postprandial lipid and lipoprotein profiles. However, postprandial glucose responses may predict the effects of chronic plant stanol ester consumption. PMID- 25271017 TI - Encoding through the host-guest structure: construction of multiplexed fluorescent beads. AB - A new encoding strategy based on the host-guest structure was developed, where encoding is achieved by combinational use of a set of guest particles with different fluorescence intensity levels at various ratios. This system was proven to be well-defined and highly controllable. PMID- 25271018 TI - Is parathyroidectomy always good for the heart? PMID- 25271016 TI - Alpha-linolenic acid (ALA) is inversely related to development of adiposity in school-age children. AB - BACKGROUND/OBJECTIVES: Studies in adults indicate that dietary polyunsaturated fatty acid (PUFA) composition may play a role in development of adiposity. Because adipocyte quantity is established between late childhood and early adolescence, understanding the impact of PUFAs on weight gain during the school age years is crucial to developing effective interventions. SUBJECTS/METHODS: We quantified N-3 and N-6 PUFAs in serum samples of 668 Colombian schoolchildren aged 5-12 years at the time of recruitment into a cohort study, using gas-liquid chromatography. Serum concentrations of N-3 (alpha-linolenic acid (ALA), eicosapentaenoic acid, docosahexaenoic acid) and N-6 PUFAs (linoleic acid, gamma linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid) were determined as percentage total fatty acids. Children's anthropometry was measured annually for a median of 30 months. We used mixed-effects models with restricted cubic splines to construct population body mass index-for-age z-score (BAZ) growth curves for age- and sex-specific quartiles of each PUFA. RESULTS: N-3 ALA was inversely related to BAZ gain after adjustment for sex, baseline age and weight status, as well as household socioeconomic level. Estimated BAZ change between 6 and 14 years among children in the highest quartile of ALA compared with those in the lowest quartile was 0.45 (95% confidence interval: 0.07, 0.83) lower (P trend=0.006). CONCLUSIONS: N-3 ALA may be protective against weight gain in school-age children. Whether improvement in PUFA status reduces adiposity in pediatric populations deserves evaluation in randomized trials. PMID- 25271019 TI - Hypoxia influences protein transport and epigenetic repression of CHO cell cultures in shake flasks. AB - Shake flasks and bench-top bioreactors are widely used for cell culture process development, however, culture performances significantly differ between them. In order to apply the results received from small-scale cultures to production scale, it is important to understand the mechanisms underlying the differences between various culture systems. This study analyzes the expression patterns of Chinese hamster ovary (CHO) cells producing IgG-fusion protein B0 cultured in shake flasks and 5-L bench-top bioreactors by CHO-specific DNA microarrays. The data show that hypoxia was present in shake flask cultures but not in controlled, bench-top bioreactors. Hypoxic conditions appeared to be associated with epigenetic repression resulting in decreased cell culture performance and protein productivity, which is also present during large-scale bioreactor operations due to oxygen gradients. High protein productivity was associated with increased cellular machinery for protein transport and secretion in conjunction with decreased epigenetic repression in bench-top bioreactor cultivation. Metal ions could improve cell growth and protein production under hypoxia and this condition could be mimicked in small-scale bioreactors to facilitate cell culture process scale-up. PMID- 25271020 TI - Soluble production and function of vascular endothelial growth factor/basic fibroblast growth factor complex peptide. AB - Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are important proangiogenic factors in tumor procession. The autocrine and paracrine bFGF and the VEGF in tumor tissue can promote tumor angiogenesis, tumor growth, and metastasis. A VEGF/bFGF Complex Peptide (VBP3) was designed on the basis of epitope peptides from both VEGF and bFGF to elicit in vivo production of anti-bFGF and anti-VEGF antibodies. In this study, we reported on the production of recombinant VBP3 using high cell density fermentation. Fed-batch fermentation for recombinant VBP3 production was conducted, and the production procedure was optimized in a 10-L fermentor. The fraction of soluble VBP3 protein obtained reached 78% of total recombinant protein output under fed-batch fermentation. Purified recombinant VBP3 could inhibit tumor cell proliferation in vitro and stimulate C57BL/6 mice to produce high titer anti-VEGF and anti-bFGF antibodies in vivo. A melanoma-grafted mouse model and an immunohistochemistry assay showed that tumor growth and tumor angiogenesis were significantly inhibited in VBP3 vaccinated mice. These results demonstrated that soluble recombinant VBP3 could be produced by large-scale fermentation, and the product, with good immunogenicity, elicited production of high-titer anti-bFGF and anti-VEGF antibodies, which could be used as a therapeutic tumor vaccine to inhibit tumor angiogenesis and tumor growth. PMID- 25271021 TI - Human T cells use CD1 and MR1 to recognize lipids and small molecules. AB - For decades immunologists thought that T cells solely recognize peptides bound to Major Histocompatibility Complex (MHC) proteins. Therefore, nearly all medical technology that seeks to measure and manipulate human T cells during immunization, infection, allergy and autoimmune diseases relies on peptide antigens. Newer insights into alphabeta and gammadelta T cell activation by CD1 or MR1 proteins greatly expand the biochemical range of T cell antigens to include lipids and non-peptidic small molecules. Moving beyond in vitro studies, the recent development of human CD1a, CD1b, CD1c and MR1 tetramers allows direct and specific enumeration of lipid-reactive and small molecule-reactive T cells, providing a new approach to study of T cell-mediated diseases. PMID- 25271022 TI - Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer. AB - The use of interleukin-2 (IL-2) for the stimulation of an effector immune response against metastatic cancer dates back to the early 1980s. Administration of unmodified IL-2, either alone or together with antigen-specific approaches, has resulted in remarkably long-term survival of some patients suffering from metastatic melanoma. However, such treatment is usually hampered by the appearance of toxic adverse effects, which has motivated the engineering of modified IL-2 formulations showing reduced toxicity while being more potent at stimulating anti-tumor effector immune cells. In this review we summarize and discuss the features and biological relevance of several enhanced IL-2 formulations, compare these to IL-15-based therapeutics, and try to foreshadow their potential in immunological research and immunotherapy. PMID- 25271023 TI - Expression and clinical significance of CXCR5/CXCL13 in human non-small cell lung carcinoma. AB - CXCR5 and/or CXCL13 expression is elevated in certain carcinomas and lymphomas. To determine if these factors are involved in progression of non-small cell lung cancer (LuCa), we evaluated their expression in patients with various forms of this disease. Lung biopsies from patients with non-neoplastic cells (n=8), squamous cell carcinoma (SCC; n=24), or adenocarcinoma (AC; n=54) were stained for CXCR5. Histopathological analysis of these samples showed significantly higher expression of CXCR5 (p<0.001) in carcinomas (i.e., SCCs and ACs) relative to non-neoplastic lung tissue. Nuclear and membrane CXCR5 intensities were highest in ACs, with median values of 185 and 130, respectively, followed by SCCs with median values of 170 and 110, respectively. The lowest nuclear and membrane expressions of CXCR5 were found in non-neoplastic tissues, having median values of 142 and 90, respectively. Sera from SCC patients (n=17), AC patients (n=14), and healthy controls (n=9) were tested for the presence of CXCL13. Serum CXCL13 levels in LuCa patients were higher than in healthy controls. CXCR5 expression in cell lines of human non-small cell lung carcinoma (NCI-H1915) and small cell lung carcinoma (SW-1271) were evaluated by flow cytometry. CXCR5 expression was higher in NCI-H1915 cells relative to SW-1271 cells. The functional significance of CXCR5 expression was tested in a migration assay. In response to CXCL13, more NCI H1915 cells migrated than SW-1271 cells. These findings suggest that the CXCR5 CXCL13 axis influences LuCa progression. After validation in larger patient groups, CXCR5 and CXCL13 may prove useful as biomarkers for LuCa. Correspondingly, blockade of this axis could serve as an effective therapy for LuCa. PMID- 25271024 TI - A novel system of galangin-potassium permanganate-polyphosphoric acid for the determination of tryptophan and its chemiluminescence mechanism. AB - A novel galangin-potassium permanganate (KMnO4)-polyphosphoric acid (PPA) system was found to have an outstanding response to tryptophan (Trp). Trp determination using this KMnO4 -PPA system was enhanced significantly in the presence of galangin. A highly sensitive flow-injection chemiluminescence (CL) method to determine Trp was developed based on the CL reaction of galangin-KMnO4 -Trp in PPA media. The presence of galangin, a member of the flavonol class of flavonoid complexes, greatly increased the luminous intensity of Trp in KMnO4 -PPA systems. Under optimized conditions, Trp was determined in the 0.05-10 ug/mL range, with a detection limit (3sigma) of 5.0 * 10(-3) ug/mL. The relative standard deviation (RSD) was 1.0% for 11 replicate determinations of 1.0 ug/mL Trp. Two synthetic samples were determined selectively with recoveries of 98.4-100.1% in the presence of other amino acids. The possible mechanism is summarized as follows: excited states of Mn(II)(*) and Mn(III(*) types are the main means of generating chemical luminescent species, and Trp concentration and luminescence intensity have a linear relationship, which enables quantitative analysis. PMID- 25271025 TI - Integrating HIV testing into cervical cancer screening in Tanzania: an analysis of routine service delivery statistics. AB - BACKGROUND: While the lifetime risk of developing cervical cancer (CaCx) and acquiring HIV is high for women in Tanzania, most women have not tested for HIV in the past year and most have never been screened for CaCx. Good management of both diseases, which have a synergistic relationship, requires integrated screening, prevention, and treatment services. The aim of this analysis is to assess the acceptability, feasibility and effectiveness of integrating HIV testing into CaCx prevention services in Tanzania, so as to inform scale-up strategies. METHODS: We analysed 2010-2013 service delivery data from 21 government health facilities in four regions of the country, to examine integration of HIV testing within newly introduced CaCx screening and treatment services, located in the reproductive and child health (RCH) section of the facility. Analysis included the proportion of clients offered and accepting the HIV test, reasons why testing was not offered or was declined, and HIV status of CaCx screening clients. RESULTS: A total of 24,966 women were screened for CaCx; of these, approximately one-quarter (26%) were referred in from HIV care and treatment clinics. Among the women of unknown HIV status (n = 18,539), 60% were offered an HIV test. The proportion of women offered an HIV test varied over time, but showed a trend of decline as the program expanded. Unavailability of HIV test kits at the facility was the most common reason for a CaCx screening client not to be offered an HIV test (71% of 6,321 cases). Almost all women offered (94%) accepted testing, and 5% of those tested (582 women) learned for the first time that they were HIV-positive. CONCLUSION: Integrating HIV testing into CaCx screening services was highly acceptable to clients and was an effective means of reaching HIV-positive women who did not know their status; effectiveness was limited, however, by shortages of HIV test kits at facilities. Integration of HIV testing into CaCx screening services should be prioritized in HIV-endemic settings, but more work is needed to eliminate logistical barriers. The coverage of CaCx screening among HIV care and treatment-enrolled women in Tanzania may be low and should be examined. PMID- 25271026 TI - Optimization of a preparative multimodal ion exchange step for purification of a potential malaria vaccine. AB - In 2000 the implementation of quality by design (QbD) was introduced by the Food and Drug Administration (FDA) and described in the ICH Q8, Q9 and Q10 guidelines. Since that time, systematic optimization strategies for purification of biopharmaceuticals have gained a more important role in industrial process development. In this investigation, the optimization strategy was carried out by adopting design of experiments (DoE) in small scale experiments. A combination method comprising a desalting and a multimodal ion exchange step was used for the experimental runs via the chromatographic system AKTATM avant. The multimodal resin CaptoTM adhere was investigated as an alternative to conventional ion exchange and hydrophobic interaction resins for the intermediate purification of the potential malaria vaccine D1M1. The ligands, used in multimodal chromatography, interact with the target molecule in different ways. The multimodal functionality includes the binding of proteins in spite of the ionic strength of the loading material. The target protein binds at specific salt conditions and can be eluted by a step gradient decreasing the pH value and reducing the ionic strength. It is possible to achieve a maximized purity and recovery of the product because degradation products and other contaminants do not bind at specific salt concentrations at which the product still binds to the ligands. PMID- 25271027 TI - [Considering body ethics in the healthcare profession]. AB - This article uses the theory of body phenomenology and Watson's caring theory to develop and apply body ethics to the clinical healthcare profession. This attempt is meant to facilitate deep, humanistic experiences for healthcare personnel. The analysis of body phenomenology reveals that the soul is banished from her familiar and comfortable "at-home" status when illness and pain invade the body. In such situations, the body becomes an external object that is self-alienated. This experience induces experiences such as solitude and violence. However, it also holds the potential to expose the original morality of the body. Additionally, this article discusses popular tools used in clinical ethics such as principalism and virtual-based ethics, which are based on moral reasoning and moral feeling. In contrast to these, body ethics seek a more profound and humble level of sensibility that is able to implant authenticity into the ethics. Finally, we offer some suggestions related to Watson's caring theory. PMID- 25271028 TI - [A reconsideration of nursing ethics from the perspective of techne]. AB - Our current age of technology sets high expectations for clarity and exactness in all professions, including nursing. This article introduces nursing ethics as a nebulous form of art (techne) and then considers the new aspects that may be developed from nursing ethics. We first introduce the Aristotelian concept of techne and then explain how techne addresses experiential knowledge without claims to exactness. A discussion then follows about the relationship of techne to rigorous and serious philosophy. While techne is not an exact science, this concept addresses the difference between the exactness claimed by ancient Greek physical science (phusis) and wisdom and the exactness claimed by Westerners today due to the changes in modern Western attitudes toward beings. In discussing nursing ethics as techne, this article shows that the discussions of ethics within the medical and nursing professions nowadays are still influenced by age of-technology claims to exactness. Finally, we propose the following: 1) nursing ethics should develop standards for ethics of care (or care ethics) wherein action is more important than theoretical argument and 2) some ideas and methods of rhetoric and narration should be integrated into the process of communication between nurses and patients. PMID- 25271029 TI - [Exactly what is ethical nursing care? the perspective of the clinical humanities]. AB - As Taiwan enters the post-modern era of professional medical care, a host of issues relating to nursing care are becoming increasingly pressing. On the one hand, the wide range of ailments of body and mind requiring treatment is placing a major financial burden on the national health care system. On the other hand, few hospitals are able to provide "comprehensive care of body and mind." In addition to primary prevention, the most effective way to reduce the overall cost of medical care is to effectively bring volunteer caregivers (those who have an "ethical connection" with the patient, i.e., family, friends, neighbors, volunteers, etc.) into all levels of the caregiving process. Moreover, as medical ethics becomes increasingly focused on the well-being of the patient, more attention is being given to the healing relationship itself. Due to its ability to swiftly relieve a wide variety of ailments, the Western medical model has become widely accepted in Asia. Yet, a patient may feel a greater sense of healing when treatment is based on the principles of ethical caregiving. For example, in the way it quickly relieves the prevailing symptoms, psychiatric medication is like a freeway. By contrast, volunteer caregiving is more like a local road, which may be slower, but eventually takes one all the way home. Thus, making nursing care more person-centered and indigenized gives the patient a sense of not only being cured, but also being "cared for." However, for a long time the theory and practice of nursing education in Taiwan has been based on the Western model of nursing. In this model nursing is treated as a branch of the biological sciences, an overall approach quite different from the traditional view of caregiving in Asian societies. Nonetheless, recent research and clinical practice indicates that an indigenized form of nursing care may be a more suitable approach to comprehensive care, and that such an approach has much potential for widespread application in Taiwan and other Chinese societies. PMID- 25271030 TI - [The medical autonomy of elderly in Taiwan]. AB - The elderly population is increasing rapidly in Taiwan. With the average life expectancy on the rise, the elderly have become major consumers of healthcare products and services. Factors that influence respect for autonomy, a core value of medical ethics, may be related to family, society, and the medical culture. Especially in patients who are already elderly, aging causes declines in physical, mental and societal capacities. Practicing a respect for patient autonomy is particularly challenging for healthcare professionals in Taiwan due the unique culture background of elderly Taiwanese patients. This article reviews and integrates the literature related to the issue of patient autonomy and elaborates on medical decision-making among elderly patients in Taiwan in the contexts of: the disadvantages faced by the elderly, the background of Chinese culture, and the current medical decision-making environment. A few suggestions are proposed to help preserve the medical-decision-making autonomy of elderly patients in Taiwan. PMID- 25271031 TI - [The practical wisdom gained in the provision of end-of-life care]. AB - BACKGROUND: The suffering experienced by nurses while providing end-of-life care to patients influences the lived experience of these nurses. The perspectives of "for the other" and "practical wisdom" may be used to elicit the experience of nurses in caring for dying patients and to help illustrate the ethical contents and meanings of end-of-life care. PURPOSE: This study describes the experiences of nurses who have provided end-of life care in hospital settings. METHODS: In depth interviews were used to explore the respective experiences of 7 nurses. Data were analyzed using interpretative phenomenological analysis (IPA). RESULTS: The findings show that practicing and engaging in end-of-life care provide nurses the opportunity to acquire practical care wisdom in three categories, including (1) the emotional difficulties of patient care; (2) the limitations of the self; and (3) learning to adjust to the needs and pace of the patient. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: End-of-life care is an opportunity for both dying patients and nurses to transform and grow spiritually. Dealing with the emotional difficulties of end-of-life care, recognizing their self-limitations in care, and adjusting their care provision to meet the needs and pace of their patients help increase the awareness of nurses to the ethical responsibility they have toward patients. These findings give nurses new perspectives on caring for others. PMID- 25271032 TI - [HIV/AIDS: an exploration of the knowledge, attitude, infection risk perceptions, and willingness to care of nurses]. AB - BACKGROUND: The number of people infected with HIV/AIDS continues to increase across the world. The awareness of HIV/AIDS and attitudes toward this disease among nurses and their willingness to care for those infected directly impacts upon the quality of HIV/AIDS-patient care. PURPOSE: This study explores the knowledge, attitudes, infection-risk perceptions, and willingness to care for HIV/AIDS patients among nurses and the correlations among these variables. METHODS: This study used a descriptive, correlational design. Scales on HIV/AIDS related knowledge, attitudes, perceived risk of infection, and willingness to care were used to collect data from 219 nurses who attended the course series on HIV/AIDS held by the Nurses AIDS Prevention Foundation in 2010. RESULTS: The mean score for HIV/AIDS knowledge was 79.6%, with knowledge related to disease transmission pathways earning the highest score and knowledge related to HIV/AIDS protective measures earning the lowest. Participating nurses with higher knowledge scores held a more positive attitude toward HIV/AIDS (p < .001), a lower perceived risk of HIV/AIDS infection (p < .001), and a higher willingness to care for HIV/AIDS-positive patients (p = .001). In addition, those participants who had received in-service HIV/AIDS education training earned higher willingness-to-care scores (p = .046). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results of the present study underscore the importance of HIV/AIDS education and may be referenced by health authorities and hospitals for promoting HIV/AIDS education. Further, the results suggest that nurses with a greater knowledge of HIV/AIDS protection and of prophylaxis after occupational exposure are more willing to care for HIV/AIDS patients. PMID- 25271033 TI - [A pilot study of the professional autonomy, job satisfaction, and related factors of nurses at a regional hospital]. AB - BACKGROUND: Professional autonomy often causes confusion in nursing staffs that limit their ability to perform to the best of their professional capabilities. Moreover, heavy and busy workloads reduce the energy available for work resulting in lower working efficiency and lower job satisfaction. PURPOSE: This study explores the status and factors related to professional autonomy and job satisfaction in nurses. METHODS: A cross-sectional design was used to target the nurses employed at a regional hospital in southern Taiwan. Data on locus of control, professional autonomy, and job satisfaction were collected for analysis. RESULTS: Data were collected from 207 nurses, with 196 valid responses (response rate: 94.69%). One hundred and forty-six subjects (74.5%) were found to have an internal locus of control personality type. Scores for both professional autonomy and job satisfaction were above the "moderate" level (averages: 3.37 and 3.32, respectively, on a maximum scale of 5). Social demographic differences contributed to the variance in professional autonomy and job satisfaction among participants. Professional autonomy was found to be positively associated with job satisfaction. CONCLUSIONS: The findings of this study indicate that nurses with an internal locus of control personality exhibit higher professional autonomy and job satisfaction and that higher professional autonomy is associated with higher job satisfaction. PMID- 25271034 TI - [Effects of head posture on oxygenation saturation, comfort, and dyspnea in patients with liver cirrhosis-related ascites]. AB - BACKGROUND: Chronic liver disease and cirrhosis are collectively ranked as the ninth most prevalent cause of death in Taiwan. Ascites is the most common comorbidity associated with liver cirrhosis. Different body postures affect pulmonary ventilation and arterial oxygen partial pressure. Thus, ensuring proper body posture in patients is an important clinical nursing intervention that significantly affects the recovery of patients. PURPOSE: This study investigates the effects of head posture on oxygenation saturation, comfort, and dyspnea in patients with liver cirrhosis-related ascites. METHODS: A quasi-experimental study design was used. A total of 252 participants were recruited from a medical centre hospital in Taiwan. Participants were allocated randomly into three groups of bed-elevation angles: 15 degrees, 30 degrees, and 45 degrees. The physiological indices were measured at 5, 10, 15, 20, 25, and 30 minutes in order to investigate the change in oxygenation saturations that were attributable to the different angles. Data were analyzed using descriptive statistics. The generalized estimating equation (GEE) was used for statistical analysis, with the level of significance set at: alpha = .05. RESULTS: After controlling for confounding variables, the results showed that patients in the three groups earned similar scores for the degree of difficulty in the oxygen values. The supine group earned significantly different scores than the other two groups in terms of blood oxygen values related to time to change the angle of the three groups at five minutes after adjusting the angle (p < .01). This study found no differences among the three groups in terms of comfort. In terms of breathing, this study found a significant difference between 45-degree and 15-degree supine dyspnea (p < .05). Therefore, patients with ascites at 15 degrees supine and with better access to better oxygen saturation had superior results to their peers at 30 degrees and 45 degrees supine. Furthermore, this group was less likely to perceive breathing difficulties. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results of this study may guide health education and care for nurses in order to improve the quality of care for patients with chronic liver disease / cirrhosis with concomitant ascites. PMID- 25271035 TI - [Effects of tai chi in postmenopausal women with osteoporosis: a systematic review]. AB - BACKGROUND: Tai chi has been increasingly applied in osteoporosis patients. However, systematic reviews of the efficacy of this practice have been few and of limited scope. PURPOSE: This study reviews previous experimental research work using tai chi as an intervention in postmenopausal women with osteoporosis and to appraise the reported research designs used, tai chi methods used, and outcomes. METHODS: A systematic review method was used to search 14 databases for articles published between January 1980 and July 2013. Searched keywords included: "tai chi," "osteoporosis," and "postmenopausal women". The 2,458 articles initially identified were reduced to 4 valid articles based on considerations of criteria and repeatability. The 4 valid articles used either a randomized clinical trial (RCT) or a controlled clinical trial (CCT). They were further analyzed and synthesized in terms of common variables such as balance, muscle strength, and quality of life. RESULTS: RESULT: Three of the 4 studies identified significant pretest / posttest differences in physiological aspects of quality of life in participants but did not obtain consistent results in terms of the psychological aspects. While reports identified a significant and positive tai chi effect on balance, they all used different measurements to do so. Only one of the four studies identified significant improvement in muscle strength. Therefore, this review could not identify clear support for the effectiveness of tai chi on balance or muscle strength. CONCLUSIONS: This review did not definitively support the positive effects of tai chi on balance, muscle strength, and quality of life in postmenopausal women with osteoporosis. The designs used in the tai chi interventions may be referenced for future studies. We suggest that future studies use data triangulation rather than a single-item tool to validate the research in order to cross-verify the same information. This may strengthen the research and increase the credibility and the validity of related findings. PMID- 25271036 TI - [The long road home: a discussion of the autonomy of schizophrenia patients after their discharge from the hospital]. AB - Every adult has the right to self-determination and to have his or her autonomy respected. While schizophrenia patients have the right to be discharged from the hospital, their needs subject their caregivers to high care loadings. This situation presents a dilemma for the medical team. The authors justify the patient's autonomy to request and to be granted a discharge. Then, present the decision-making process related to discharge for the reference of medical teams. Capacity is necessary to autonomy. There is currently no standard for assessing the capacity of patients that clearly defines their competence. A sliding scale approach to decision making distinguishes between decisions involving significant potential risk and, therefore, involving higher level of capacity requirements and decisions on minimal potential risk. In order to protect the interests of patients, the sliding scale approach takes into account different decisions. Cases in which schizophrenia patients choose to self-discharge involve a high level of risk. Poor preparations for follow-up care lead to poor-quality patient care and may cause harm to the patients. In a share decision model, the medical team plays the role of negotiator between the patient and the family and respects the autonomy of the patient while supporting the family through the hospital discharge process. Medical team must have a discharge planning for the patient and family, follow-up care system, and support network. During hospitalization, the discharge plan aims to facilitate the life adaptation and disease recovery for patients with the goal of restoring their normal home life. PMID- 25271037 TI - [Improving care for transitional-stage clients in the emergency department: a family-centered approach]. AB - The focus of emergency departments on resolving immediate threats to patient survival and wellbeing distinguishes their services from those provided by all other hospital departments. The high-pressure environment in the emergency department is a source of significant stress for patients and their families, with some experiencing serious physical and mental impacts that result in high tension, acute stress, anxiety, and other mental and physical reactions. The concepts of family-centered care and transition theory have been shown to help promote a sense of wellbeing and adjustment to unfamiliar experiences. Therefore, these concepts may be applied to help facilitate the successful transition of patients and their families to the emergency department and thus help maintain normal family functions during the transition from the emergency department to other departments. PMID- 25271038 TI - [Nursing experience with a schizophrenic breast cancer patient after mastectomy]. AB - This case study used cognitive therapy to improve the life quality of a 46-year old woman with chronic schizophrenia who had undergone a mastectomy for breast cancer. This case had suffered from schizophrenia for over 24 years and was hospitalized in the chronic ward of our hospital. Breast cancer was revealed during an annual comprehensive physical checkup. In May 2012, this case received a right mastectomy at a local hospital. After the surgery, she was readmitted to the psychiatric acute ward for further care from May 30th to August 28th, 2012. A holistic nursing assessment was conducted that addressed five major aspects. The major nursing problems found during hospitalization were: acute pain, body image disturbance, and low self-esteem. A decline in pain score from 10 to 4 was achieved by developing rapport with the patient, empathizing with her distress, and providing active care to the wound. Her body image changed because of loosing her breast. Her acceptance of the loss improved through helping her to explore her feelings of change. To improve her self-esteem, we offered cognitive therapy to change her negative thinking process. She became more sanguine and cheerful. Moreover, her dependence in terms of activities of daily living decreased. This individualized intervention contributed to the recovery of a post-mastectomy, schizophrenic patient from low self-esteem. PMID- 25271039 TI - [Applying a creative art activity in care: report on an experience with a newly admitted resident]. AB - Doing creative art has been shown to increase activity, reduce anxiety, promote confidence and self-esteem, increase sense of achievement, and facilitate participation in life activities in the elderly. This article describes a nursing experience that used creative art activities to help an elderly resident adjust to the environment and living conditions at a long-term care facility. During the care period from October 20th to December 16th, 2012, we evaluated the health problems of the resident, which included anxiety, loneliness, and low self esteem. The creative art activity was a 30-minute intervention held 1~2 times per week for a total of 13 sessions. This article reports on the positive effects of this intervention on reducing the resident's negative emotions such as anxiety and loneliness and, in the long run, promoting self-esteem and sense of achievement. PMID- 25271040 TI - Functional polymorphisms of caveolin-1 variants as potential biomarkers of esophageal squamous cell carcinoma. AB - OBJECTIVE: To investigate the association of caveolin-1 (CAV1) genetic variants (C239A (rs1997623), G14713A (rs3807987), G21985A (rs12672038), T29107A (rs7804372)) with esophageal squamous cell carcinoma (ESCC) susceptibility. METHODS: A total of 427 patients with ESCC and 427 healthy controls were genotyped using the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: There were significant differences between patients and controls in distributions of their genotypes and allelic frequencies in G14713A and T29107A polymorphisms. Furthermore, haplotype analysis revealed that haplotypes CAAT and CAGT were associated with high risk for ESCC, while haplotype CGGA was protective against ESCC. Stratified analysis showed the associations between the SNPs (G14713A and T29107A) and ESCC risk were noteworthy among female patients and patients who never smoke or drank alcohol. CONCLUSIONS: Genetic polymorphisms of CAV1 G14713A and T29107A might affect an individual's susceptibility in developing ESCC, making them efficient potential genetic biomarkers for early detection of ESCC. PMID- 25271041 TI - Mortality prediction by acute kidney injury biomarkers in comparison with serum creatinine. AB - OBJECTIVES: To investigate the performance of acute kidney injury (AKI) biomarkers for mortality prediction. MATERIALS AND METHODS: Cutoff values of urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-beta-d glucosaminidase (NAG) for AKI diagnosis in ICU were determined in the derivation cohort. The performance of these AKI biomarkers for mortality prediction was evaluated in the validation cohort with stratification of serum-creatinine based AKI diagnosis. RESULTS: Mortality in the AKI patients diagnosed by serum creatinine was increased remarkably when urinary L-FABP and NAG were positive. CONCLUSIONS: These AKI biomarkers can specifically detect high-risk patients among creatinine-base diagnosed AKI. PMID- 25271042 TI - Effects of MDM2 promoter polymorphisms on the development of cervical neoplasia in a Southeastern Brazilian population. AB - We investigated the importance of two adjacent functional polymorphisms in the Murine Double Minute 2 (MDM2) gene, SNP285 G > C and SNP309 T > G, for the development of cervical lesions in a Southeastern Brazilian population (293 cases and 184 controls). MDM2 genotyping was performed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) and/or DNA sequencing. MDM2 SNP309 has potential as a biomarker of cervical neoplasia in non-smokers, patients with family history of cancer, or those who had late sexual debut (>16 years). Besides, this polymorphism may help identify women at risk of developing severe cervical lesion at a young age (<30 years). PMID- 25271044 TI - Green silver nanoparticles of Phyllanthus amarus: as an antibacterial agent against multi drug resistant clinical isolates of Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa infection is a leading cause of morbidity and mortality in burn and immune-compromised patients. In recent studies, researchers have drawn their attention towards ecofriendly synthesis of nanoparticles and their activity against multidrug resistant microbes. In this study, silver nanoparticles were synthesized from aqueous extract of Phyllanthus amarus. The synthesized nanoparticles were explored as a potent source of nanomedicine against MDR burn isolates of P. aeruginosa. RESULTS: Silver nanoparticles were successfully synthesized using P. amarus extract and the nature of synthesized nanoparticles was analyzed by UV-Vis spectroscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, dynamic light scattering, zeta potential, X- ray diffraction and fourier transform infra-red spectroscopy. The average size of synthesized nanoparticles was 15.7, 24 +/- 8 and 29.78 nm by XRD, TEM and DLS respectively. The antibacterial activity of AgNPs was investigated against fifteen MDR strains of P. aeruginosa tested at different concentration. The zone of inhibition was measured in the range of 10 +/- 0.53 to 21 +/- 0.11mm with silver nanoparticles concentration of 12.5 to 100 MUg/ml. The zone of inhibition increased with increase in the concentration of silver nanoparticles. The MIC values of synthesized silver nanoparticles were found in the range of 6.25 to12.5 MUg/ml. The MIC values are comparable to the standard antibiotics. CONCLUSION: The present study suggests that silver nanoparticles from P. amarus extract exhibited excellent antibacterial potential against multidrug resistant strains of P. aeruginosa from burn patients and gives insight of their potential applicability as an alternative antibacterial in the health care system to reduce the burden of multidrug resistance. PMID- 25271045 TI - In Planta Microsphere-Based Lateral Flow Leaf Biosensor in Maize. AB - Low-cost and quick detection of biotic stresses is critically important for protection of staple food crops such as maize in smallholder farms in developing countries, where access to improved seed varieties, fertilizers, and pesticides is limited due to financial and geographical reasons. Here, we report a new lateral flow detection technology directly integrated in a maize leaf, in which microspheres conjugated with analyte-specific capture antibodies are non invasively injected. The antibody-conjugated microspheres capture and detect an analyte in a concentration-specific manner. In this study, we optimized microsphere size for effective infiltration and immobilization in the leaf, and further demonstrated detection of a fluorescent mock biomarker, fluorescein, in a live maize plant. This in planta lateral flow biosensor is the first of its kind and is expected to provide a low-cost and user-friendly detection method for biotic stresses in the field. PMID- 25271043 TI - Evidence for a causal link between adaptor protein PDZK1 downregulation and Na+/H+ exchanger NHE3 dysfunction in human and murine colitis. AB - A dysfunction of the Na(+)/H(+) exchanger isoform 3 (NHE3) significantly contributes to the reduced salt absorptive capacity of the inflamed intestine. We previously reported a strong decrease in the NHERF family member PDZK1 (NHERF3), which binds to NHE3 and regulates its function in a mouse model of colitis. The present study investigates whether a causal relationship exists between the decreased PDZK1 expression and the NHE3 dysfunction in human and murine intestinal inflammation. Biopsies from the colon of patients with ulcerative colitis, murine inflamed ileal and colonic mucosa, NHE3-transfected Caco-2BBe colonic cells with short hairpin RNA (shRNA) knockdown of PDZK1, and Pdzk1-gene deleted mice were studied. PDZK1 mRNA and protein expression was strongly decreased in inflamed human and murine intestinal tissue as compared to inactive disease or control tissue, whereas that of NHE3 or NHERF1 was not. Inflamed human and murine intestinal tissues displayed correct brush border localization of NHE3 but reduced acid-activated NHE3 transport activity. A similar NHE3 transport defect was observed when PDZK1 protein content was decreased by shRNA knockdown in Caco-2BBe cells or when enterocyte PDZK1 protein content was decreased to similar levels as found in inflamed mucosa by heterozygote breeding of Pdzk1-gene deleted and WT mice. We conclude that a decrease in PDZK1 expression, whether induced by inflammation, shRNA-mediated knockdown, or heterozygous breeding, is associated with a decreased NHE3 transport rate in human and murine enterocytes. We therefore hypothesize that inflammation-induced loss of PDZK1 expression may contribute to the NHE3 dysfunction observed in the inflamed intestine. PMID- 25271046 TI - Automated acid and base number determination of mineral-based lubricants by fourier transform infrared spectroscopy: commercial laboratory evaluation. AB - The Fluid Life Corporation assessed and implemented Fourier transform infrared spectroscopy (FTIR)-based methods using American Society for Testing and Materials (ASTM)-like stoichiometric reactions for determination of acid and base number for in-service mineral-based oils. The basic protocols, quality control procedures, calibration, validation, and performance of these new quantitative methods are assessed. ASTM correspondence is attained using a mixed-mode calibration, using primary reference standards to anchor the calibration, supplemented by representative sample lubricants analyzed by ASTM procedures. A partial least squares calibration is devised by combining primary acid/base reference standards and representative samples, focusing on the main spectral stoichiometric response with chemometrics assisting in accounting for matrix variability. FTIR(AN/BN) methodology is precise, accurate, and free of most interference that affects ASTM D664 and D4739 results. Extensive side-by-side operational runs produced normally distributed differences with mean differences close to zero and standard deviations of 0.18 and 0.26 mg KOH/g, respectively. Statistically, the FTIR methods are a direct match to the ASTM methods, with superior performance in terms of analytical throughput, preparation time, and solvent use. FTIR(AN/BN) analysis is a viable, significant advance for in-service lubricant analysis, providing an economic means of trending samples instead of tedious and expensive conventional ASTM(AN/BN) procedures. PMID- 25271047 TI - Inappropriate prescribing in a large community-dwelling older population: a focus on prevalence and how it relates to patient and physician characteristics. AB - WHAT IS KNOWN AND OBJECTIVE: The prescription of potentially inappropriate medications (PIMs) for older adults is a well-known population health concern. Updated country-specific estimates of inappropriate prescribing in older adults using germane explicit criteria are needed to facilitate physician-tailored quality improvement strategies. Therefore, we sought to determine the prevalence of PIMs for older adults in Emilia-Romagna, Italy, using the updated Maio criteria. We also evaluated patient and general practitioner (GP) characteristics related to inappropriate prescribing. METHODS: Older adults (>= 65) in 2012 were evaluated in a one-year retrospective study using administrative health care data. The 2011 Maio criteria includes 25 medications reimbursed by the Italian National Formulary, in the following categories in terms of severity: 16 medications that 'should always be avoided,' 3 that are 'rarely appropriate,' and 6 that have 'some indications although they are often misused.' To evaluate the extent of associations between patient and GP related characteristics, we used generalized estimating equations with an exchangeable covariance design to fit robust logistic regression models. RESULTS AND DISCUSSION: A total of 865,354 older adults were in the cohort and 28% had at least one PIM. Of the entire cohort, 8%, 10%, and 14% of individuals were prescribed at least one medication that 'should always be avoided,' is 'rarely appropriate,' and has 'some indications but are often misused,' respectively. Older patients (>= 75) and females were more likely to be exposed to PIMs. 2,923 GPs were identified in the region, each having prescribed at least one PIM, of which older GPs (>= 56), male GPs, and solo practice GPs were more likely to prescribe PIMs to their older patients. WHAT IS NEW AND CONCLUSION: The high prevalence of PIM exposure among older adults is a substantial issue in the region. Knowing how patient and GP characteristics relate to PIMs exposure may improve the design and targeting of initiatives for improving prescribing safety in this population. PMID- 25271048 TI - Higher integrity health care: evidence-based shared decision making. PMID- 25271049 TI - beta-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial. AB - BACKGROUND: The long-term efficacy of beta-blockers in patients with and without myocardial infarction (MI) is controversial. METHODS AND RESULTS: This is post hoc analysis from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial of 4772 patients with prior MI, 7804 patients with known atherothrombosis, and 2101 patients with risk factors alone but without heart failure. Primary outcome was a composite of nonfatal MI, stroke, or cardiovascular mortality. The cohorts were divided into 2 groups based on baseline beta-blocker use. In the propensity score-matched prior MI cohort, after 28 months of follow-up, beta-blocker use was associated with a 31% lower risk of the primary outcome (70 [7.1%] versus 100 [10.2%]; hazards ratio, 0.69; 95% confidence interval, 0.50-0.94; P=0.021), driven by a lower risk of recurrent MI (33 [3.4%] versus 48 [4.9%]; hazards ratio, 0.62; 95% confidence interval, 0.39-1.00; P=0.049) with no difference in mortality (52 [5.3%] versus 66 [6.7%]; P=0.20). In the known atherothrombotic disease and the risk factors alone cohorts, beta-blocker use was not associated with lower ischemic outcomes, whereas a trend toward a higher risk of stroke (3.5% versus 1.5%; hazards ratio, 2.13; 95% confidence interval, 0.92-4.92; P=0.079) was observed in the risk factors alone cohort. This higher stroke risk was significant in the regression model adjusted to the propensity score (hazards ratio, 2.69; 95% confidence interval, 1.33-5.44; P=0.006) and in the multivariable models. CONCLUSIONS: beta blocker use in patients with prior MI but no heart failure was associated with a lower composite cardiovascular outcome driven by lower risk of recurrent MI with no difference in mortality. However, beta-blocker use was not associated with lower cardiovascular events in those without MI, with a suggestion of inferior outcome with regard to stroke risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817. PMID- 25271050 TI - Randomized trial of a virtual cardiac rehabilitation program delivered at a distance via the Internet. PMID- 25271051 TI - Risk of a biased assessment of the evidence when limiting literature searches to the English language: macrolides in asthma as an illustrative example. PMID- 25271052 TI - A case of classic neuromyelitis optica (Devic's syndrome) triggered by pegylated interferon alpha. AB - BACKGROUND: Despite recent development of direct acting antivirals for treatment of hepatitis C, the current standard of care may still include pegylated interferon, which is associated with frequent and, at times, serious adverse events. CASE PRESENTATION: Here we report for the first time on a severe case of classic neuromyelitis optica (i.e., optic-spinal form) in a 32 year-old Egyptian man with chronic hepatitis C treated with pegylated-interferon alpha2a for 4 months. CONCLUSIONS: Treating physicians must be alerted on rare but important unexpected complications of interferon, in order to consider carefully its use especially when they deal with patients not in dire need of urgent treatment. PMID- 25271053 TI - Skin cancer preventative behaviors in state park workers: a pilot study. AB - OBJECTIVES: Considering the potential for occupational sun exposure among state park workers, the purpose of this pilot study was to identify skin cancer knowledge, health beliefs, self-efficacy, and sun protection behaviors (SPBs) among state park employees. METHODS: The current study used a cross-sectional survey research design with state park workers in a Southern state. Of the 94 possible employees who could have participated in the study, 87 completed the survey. RESULTS: Assessment of the participants' skin cancer knowledge demonstrated an average correct response rate of 68.8 %. While the vast majority (87.4 %) believed that skin cancer is a serious disease, a minority (42.5 %) believed they would develop skin cancer sometime during their lifetime, and even fewer (35.6 %) believed their risk was higher than average. Collectively, workers reported low levels of SPBs. The most commonly reported barriers to sun protection were "inconvenient," "too hot to wear," and "forget to protect." Half of the participants (50.6 %) were highly confident in their ability to wear long pants while in the sun. About the same proportion of participants was highly confident they could wear a wide-brimmed hat (21.8 %) and sunscreen (20.7 %). CONCLUSIONS: Based on available evidence, a need exists to develop individual and worksite programs and interventions to increase skin cancer prevention behaviors among this occupational group. This data could serve as a baseline to monitor and evaluate the efficacy of these interventions. PMID- 25271054 TI - In-depth quantitative proteomic analysis of de novo protein synthesis induced by brain-derived neurotrophic factor. AB - Measuring the synthesis of new proteins in the context of a much greater number of pre-existing proteins can be difficult. To overcome this obstacle, bioorthogonal noncanonical amino acid tagging (BONCAT) can be combined with stable isotope labeling by amino acid in cell culture (SILAC) for comparative proteomic analysis of de novo protein synthesis (BONLAC). In the present study, we show that alkyne resin-based isolation of l-azidohomoalanine (AHA)-labeled proteins using azide/alkyne cycloaddition minimizes contamination from pre existing proteins. Using this approach, we isolated and identified 7414 BONCAT labeled proteins. The nascent proteome isolated by BONCAT was very similar to the steady-state proteome, although transcription factors were highly enriched by BONCAT. About 30% of the methionine residues were replaced by AHA in our BONCAT samples, which allowed for identification of methionine-containing peptides. There was no bias against low-methionine proteins by BONCAT at the proteome level. When we applied the BONLAC approach to screen for brain-derived neurotrophic factor (BDNF)-induced protein synthesis, 53 proteins were found to be significantly changed 2 h after BDNF stimulation. Our study demonstrated that the newly synthesized proteome, even after a short period of stimulation, can be efficiently isolated by BONCAT and analyzed to a depth that is similar to that of the steady-state proteome. PMID- 25271055 TI - HDAC5 controls MEF2C-driven sclerostin expression in osteocytes. AB - Osteocytes secrete paracrine factors that regulate the balance between bone formation and destruction. Among these molecules, sclerostin (encoded by the gene SOST) inhibits osteoblastic bone formation and is an osteoporosis drug target. The molecular mechanisms underlying SOST expression remain largely unexplored. Here, we report that histone deacetylase 5 (HDAC5) negatively regulates sclerostin levels in osteocytes in vitro and in vivo. HDAC5 shRNA increases, whereas HDAC5 overexpression decreases SOST expression in the novel murine Ocy454 osteocytic cell line. HDAC5 knockout mice show increased levels of SOST mRNA, more sclerostin-positive osteocytes, decreased Wnt activity, low trabecular bone density, and reduced bone formation by osteoblasts. In osteocytes, HDAC5 binds and inhibits the function of MEF2C, a crucial transcription factor for SOST expression. Using chromatin immunoprecipitation, we have mapped endogenous MEF2C binding in the SOST gene to a distal intergenic enhancer 45 kB downstream from the transcription start site. HDAC5 deficiency increases SOST enhancer MEF2C chromatin association and H3K27 acetylation and decreases recruitment of corepressors NCoR and HDAC3. HDAC5 associates with and regulates the transcriptional activity of this enhancer, suggesting direct regulation of SOST gene expression by HDAC5 in osteocytes. Finally, increased sclerostin production achieved by HDAC5 shRNA is abrogated by simultaneous knockdown of MEF2C, indicating that MEF2C is a major target of HDAC5 in osteocytes. PMID- 25271056 TI - Receptor heterodimerization as a novel mechanism for the regulation of Wnt/beta catenin signaling. AB - The Wnt pathway plays important roles in multiple physiological and pathophysiological processes. Here, we report a novel mechanism that regulates the Wnt pathway through heterodimerization of the Wnt co-receptor low-density lipoprotein-receptor-related protein 6 (LRP6) and very low-density lipoprotein receptor (VLDLR); the latter belongs to the same protein family as LRP6 and was originally known as a receptor for lipoproteins. Knockdown of Vldlr expression elevated LRP6 protein levels and activated Wnt/beta-catenin signaling, whereas overexpression of Vldlr suppressed Wnt signaling. Moreover, we demonstrate that the VLDLR ectodomain is essential and sufficient for inhibition of Wnt signaling. The VLDLR ectodomain accelerated internalization and degradation of LRP6 through heterodimerization with the LRP6 extracellular domain. Monoclonal antibodies specific for the VLDLR ectodomain blocked VLDLR-LRP6 heterodimerization, resulting in enhanced Wnt/beta-catenin signaling in vitro and in vivo. Taken together, these findings suggest that heterodimerization of receptors in the membrane accelerates the turnover of LRP6, and represent a new mechanism for the regulation of Wnt/beta-catenin signaling. PMID- 25271057 TI - The ubiquitin-like modifier FAT10 decorates autophagy-targeted Salmonella and contributes to Salmonella resistance in mice. AB - Bacterial invasion of eukaryotic cells is counteracted by cell-autonomous innate immune mechanisms including xenophagy. The decoration of cytosolic bacteria by ubiquitylation and binding of galectin-8 leads to recruitment of autophagy adaptors like p62 (also known as SQSTM1), NDP52 (also known as CALCOCO2) and optineurin, which initiate the destruction of bacteria by xenophagy. Here, we show that the functionally barely characterized IFNgamma- and TNFalpha-inducible ubiquitin-like modifier FAT10 (also known as ubiquitin D, UBD), which binds to the autophagy adaptor p62, but has not been shown to associate with pathogens before, is recruited to cytosolic Salmonella Typhimurium in human cells. FAT10 decorated S. Typhimurium were simultaneously decorated with ubiquitin, p62, NDP52 and the autophagy marker LC3B (MAP1LC3B). FAT10 colocalized with p62-positive microdomains on S. Typhimurium, whereas colocalization with NDP52 was only partial. A kinetic analysis revealed an early, but only transient, decoration of bacteria by FAT10, which resembled that of p62. Although bacterial replication was not detectably altered in FAT10-depleted or overexpressing cells in vitro, survival experiments revealed that NRAMP1-transgenic mice that were FAT10 deficient had a higher susceptibility to orally inoculated S. Typhimurium bacteria than NRAMP1-transgenic mice that were wild-type for FAT10. Taken together, our data suggest a role for FAT10 in the intracellular defense against bacteria. PMID- 25271058 TI - MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria. AB - Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here, we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive production of mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylation-resistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6-knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria. PMID- 25271059 TI - Galactosyltransferase 4 is a major control point for glycan branching in N-linked glycosylation. AB - Protein N-glycosylation is a common post-translational modification that produces a complex array of branched glycan structures. The levels of branching, or antennarity, give rise to differential biological activities for single glycoproteins. However, the precise mechanism controlling the glycan branching and glycosylation network is unknown. Here, we constructed quantitative mathematical models of N-linked glycosylation that predicted new control points for glycan branching. Galactosyltransferase, which acts on N-acetylglucosamine residues, was unexpectedly found to control metabolic flux through the glycosylation pathway and the level of final antennarity of nascent protein produced in the Golgi network. To further investigate the biological consequences of glycan branching in nascent proteins, we glycoengineered a series of mammalian cells overexpressing human chorionic gonadotropin (hCG). We identified a mechanism in which galactosyltransferase 4 isoform regulated N-glycan branching on the nascent protein, subsequently controlling biological activity in an in vivo model of hCG activity. We found that galactosyltransferase 4 is a major control point for glycan branching decisions taken in the Golgi of the cell, which might ultimately control the biological activity of nascent glycoprotein. PMID- 25271060 TI - P2Y6 receptor inhibition perturbs CCL2-evoked signalling in human monocytic and peripheral blood mononuclear cells. AB - The chemokine CCL2 serves to target circulating monocytes and other leukocytes to tissue during innate immune responses, and modulates the progression of chronic inflammatory disease through activation of the receptor CCR2. Here, we show that co-activation of the P2Y6 purinergic receptor (encoded by P2RY6) occurs when THP 1 cells and human peripheral blood mononuclear cells sense CCL2 through CCR2. Furthermore, P2Y6 receptor activation accounts for ~80% of the intracellular Ca2+ signal evoked by CCL2. Scavenging extracellular nucleotides with apyrase caused a fourfold reduction in THP-1 sensitivity to CCL2, whereas inhibition of CD39-like ectonucleotidases potentiated CCL2-evoked Ca2+ responses. Pharmacological inhibition of P2Y6 impaired CCL2-evoked Ca2+ signalling and chemotaxis in peripheral blood mononuclear cells and THP-1 cells. Furthermore, stable P2Y6 receptor knockdown (of twofold) in THP-1 cells impaired CCL2-evoked Ca2+ signalling, chemotaxis and adhesion to TNFalpha-treated HUVECs. We demonstrate that THP-1 cells rapidly secrete ATP during signalling downstream of the CCL2 CCR2 axis and suggest this might act as a mechanism for P2Y6 receptor co activation following CCL2 activation of the CCR2 receptor. The discovery that P2Y6 receptor mediates leukocyte responsiveness to CCL2 represents a new mechanism by which to modulate CCL2 signals. PMID- 25271061 TI - Postnatal growth outcomes and influence of maternal gestational weight gain: a prospective cohort study in rural Vietnam. AB - BACKGROUND: Suboptimal weight gain during pregnancy may result in adverse outcomes for both the mother and child, including increased risk of pre-eclampsia and gestational diabetes, delivery of low birth weight and small-for-gestational age (SGA) infants, and preterm delivery. The objectives of this study were to identify maternal predictors of rate of weight gain in pregnancy, and to evaluate the association of gestational weight gain with infant postnatal growth outcomes. METHODS: We conducted a prospective cohort study of infants born to women who had previously participated in a double-blind cluster randomized controlled trial of antenatal micronutrient supplementation, in Ha Nam province, Vietnam. Pregnant women (n = 1258) were seen at enrolment and 32 weeks gestation, and infants (n = 965) were followed until 6 months of age. Primary outcome was infant anthropometric indicators at 6 months of age (weight for age, length for age, weight for height z scores), and infant weight gain velocity during the first 6 months of life. RESULTS: Low body mass index (<18.5 kg/m2) was present in 26% of women, and rate of gestational weight gain was 0.4 kg per week [SD 0.12]. Rate of weight gain during pregnancy was significantly associated with infant weight-for age (MD 1.13, 95% CI 0.58 to 1.68), length-for-age (MD 1.11, 95% CI 0.66 to 1.55), weight-for-length z scores (MD 0.63, 95% CI 0.07 to 1.19), and infant weight gain velocity during the first 6 months of life (MD 93.6 g per month, 95% CI 8.2 to 179.0). CONCLUSIONS: Rate of gestational weight gain is predictive of postnatal growth at six months of age in this setting. Public health programs should be targeted towards improving body mass index and weight gain in pregnant women in rural Vietnam. PMID- 25271062 TI - Metabolomics and the great obstetrical syndromes--GDM, PET, and IUGR. AB - Gestational diabetes mellitus, intrauterine growth restriction, and preeclamptic toxemia are common pregnancy complications that can have detrimental effects on morbidity and mortality of the mother and fetus as well as long-term health outcomes. Although they are distinct conditions, they may occur together and are often considered together as they share a common etiology of inadequate placental perfusion. The discovery and study of preventative treatments is hampered by a lack of effective screening tools to accurately identify women at the highest risk of disease. Metabolomics, an omic science, is the global quantitative assessment of endogenous metabolites within a biological system. It has proven to be a rapid approach in the identification of biomarkers predictive of the outcome of a pathological condition and the individual's response to a pharmacological treatment. We review the current and potential applications of metabolomics in maternal-fetal medicine, focusing on its use as a biomarker for great obstetrical syndromes diagnosis. PMID- 25271063 TI - Breast-feeding after transplantation. AB - Transplantation affords recipients the potential for a full life and, for some, parenthood. Female transplant recipients must continue to take immunosuppression during pregnancy and breast-feeding. This article reviews case and series reports regarding breast-feeding in those taking transplant medications. Avoidance of breast-feeding has been the customary advice because of the potential adverse effects of immunosuppressive exposure on the infant. Subsequent studies have demonstrated that not all medication exposure translates to risk for the infant, that the exposure in utero is greater than via breast milk and that no lingering effects due to breast-feeding have been found to date in infants who were breast fed while their mothers were taking prednisone, azathioprine, cyclosporine, and/or tacrolimus. Thus, except for those medications where clinical information is inadequate (mycophenolic acid products, sirolimus, everolimus, and belatacept), the recommendation for transplant recipients regarding breast feeding has evolved into one that is cautiously optimistic. PMID- 25271064 TI - Recanalization of acute basilar artery occlusion improves outcomes: a meta analysis. AB - OBJECTIVE: Acute basilar artery occlusion (BAO) is a catastrophe with high mortality and disability. Randomized controlled trial (RCT) data supporting/refuting reperfusion treatment are sparse in acute BAO. The study objective was to pool risk estimates for death or dependency (DoD), mortality, and intracerebral hemorrhage (ICH) from published studies on BAO. METHODS: Medline, Embase, The Cochrane Library, and clinicaltrials.gov were searched through August 2013 for studies of reperfusion therapies in acute BAO. Two independent authors selected studies and abstracted the data. Pooled risk ratios (RR) and mean weighted probabilities (MWP) were calculated using random effects model. RESULTS: 45 studies (n=2056) met the inclusion criteria. Recanalization was associated with a lower risk of DoD (RR 0.67; number needed to treat (NNT) 3) and mortality (RR 0.49; NNT 2.5). ICH rate (MWP) with acute therapies was 13%. With recanalization, RR for DoD in those treated <=12 h was 0.63, and for those treated >12 h, it was 0.67. With recanalization, RR for DoD in the intravenous thrombolysis (IVT) subgroup was 0.68; in the intra-arterial/endovascular therapy (IA/EVT) subgroup, DoD RR was 0.67. Recanalization resulted in mortality RR of 0.46 in those treated <=12 h; for >12 h group, RR was 0.50. Recanalization resulted in mortality RR of 0.53 in the IVT subgroup, and RR of 0.48 in the IA/EVT subgroup. ICH rate for <=12 h was 10%; ICH rate for >12 h was 14%. With IVT, the ICH rate was 9%, and with IA/EVT the ICH rate was 14%. CONCLUSIONS: Recanalization of acute BAO leads to reduction in mortality by two-fold and reduction in the risk of DoD by 1.5-fold. This study underscores the equipoise in acute BAO for comparing systemic and endovascular therapies, and testing different time windows through RCTs. PMID- 25271066 TI - The use of a biostatic fascia lata thigh allograft as a scaffold for autologous human culture of fibroblasts--An in vitro study. AB - The method for covering gingival recession defects and augmenting keratinized gingiva involves the use of autogenuous connective tissue grafts obtained from palatal mucosa in combination with various techniques of flap repositioning or tunnel techniques. In the case of multiple gingival recession defects the amount of connective tissue available for grafting is insufficient. Therefore, the use of substitutes is necessary. The most widely used material in recent years has been the acellular dermal matrix allograft. The disadvantage of its application lies in the absence of cells and blood vessels, which increases incorporation time. Primary cultured human autologic fibroblasts are commonly used to optimize the healing process. The aim of this study was to examine the in vitro biocompatibility of human fascia lata allograft as a new scaffold for primary cultured human autologic fibroblasts. For that, a fibroblast culture obtained from a fragment of gingival tissue taken from the hard palate mucosa of a subject was used. After 14 days the colony cells were inoculated on a fragment of human fascia lata allograft. After a further 7 days of incubation the material was frozen, cut and prepared for histochemical examination. After two weeks of incubation, and 7 days after inoculation on a fragment of fascia lata allograft numerous accumulations of the cultured fibroblast were found that had a typical structure and produced collagen fibres. A human fascia lata allograft can be used as a scaffold for primary cultured human autologic fibroblasts. Further studies should confirm the clinical efficacy of this solution. PMID- 25271067 TI - Impact of radiation history, gender and age on bone quality in sites for orthodontic skeletal anchorage device placement. AB - AIMS: Stability of orthodontic miniscrew implants is prerequisite to their success and durability in orthodontic treatment. As investigations revealed a positive correlation of miniscrew stability to periimplant bone quality, it has been the aim of this study to analyze the bone structure of resection preparations of human mandibles histologically by investigating the samples according to age, gender and exposure to radiotherapy. METHODS: Inflammation- and tumor-free alveolar bone sections from human mandibles (n = 31) with previously diagnosed carcinoma, chronic osteomyelitis or cysts were analyzed histomorphologically and histomorphometrically as to the dimension of trabeculae in cancellous areas. Group A investigated the impact of a history of radiation therapy, group B of gender and group C contrasted biopsies from individuals aging under 60 or over 60 years. Statistics were performed using the Kruskal-Wallis test. RESULTS: Radiation, gender and age did not significantly influence bone density. The mean bone density averaged 40.7 +/- 15.0% of spongiosa for the total collective with a median age of 58.4 years +/- 14.7 years. CONCLUSIONS: Our findings provide new information on bone quality, thus contributing to a more precise evaluation of the parameters affecting and those not affecting miniscrew implant stability. On the basis of these results, the formulation of clinical guidelines for risk assessment of therapeutic approaches in patients prior to insertion of orthodontic skeletal anchorage devices seems to be conceivable. PMID- 25271068 TI - The effects of dynamic hyperinflation on CT emphysema measurements in patients with COPD. AB - OBJECTIVES: Dynamic hyperinflation (DH) significantly affects dyspnea and intolerance to exercise in patients with chronic obstructive pulmonary disease (COPD). Quantitative computed tomography (QCT) of the chest is the modality of choice for quantification of the extent of anatomical lung damage in patients with COPD. The purpose of this article is to assess the effects of DH on QCT measurements. METHODS: The study sample comprised patients with Global initiative for Chronic Obstructive Lung Disease (GOLD) stages III and IV COPD referred for chest CT. We examined differences in total lung volume (TLV), emphysema volume (EV), and emphysema index (EI) determined by QCT before and after DH induction by metronome-paced tachypnea (MPT). Initial (resting) and post-MPT CT examinations were performed with the same parameters. RESULTS: Images from 66 CT scans (33 patients) were evaluated. EV and EI, but not TLV, increased significantly (p<0.0001) after DH induction. CONCLUSION: QCT showed significant increases in EV and EI after MPT-induced DH in patients with GOLD stages III and IV COPD. For longitudinal assessment of patients with COPD using QCT, we recommend the application of a pre-examination rest period, as DH could mimic disease progression. QCT studies of the effects of DH-preventive therapy before exercise could expand our knowledge of effective measures to delay DH-related progression of COPD. PMID- 25271069 TI - A multi-component treatment to reduce packing in children with feeding and autism spectrum disorders. AB - Despite the high prevalence and potential negative consequences of feeding disorders in children with autism spectrum disorder (ASD), there are surprisingly few studies that examine the efficacy of treatment exclusively with these children. Children with feeding disorders also frequently exhibit packing (holding or pocketing food without swallowing). Investigators have evaluated procedures in the general pediatric population to treat packing, and some have shown that procedures need to be combined to form an effective treatment. Although investigators have evaluated the efficacy of re-distribution, swallow facilitation, and a chaser, these procedures have not been evaluated specifically with children with ASD. Prior to the current investigation, we successfully used nonremoval procedures to increase acceptance of pureed foods and liquids and decrease the inappropriate mealtime behavior of two children diagnosed with ASD and feeding problems; however, in each case, packing emerged during initial treatment. We then used different combinations of re-distribution, swallow facilitation, and chaser treatments to decrease packing for both children. PMID- 25271070 TI - Effects of antecedent exercise on academic engagement and stereotypy during instruction. AB - Antecedent physical exercise has emerged as a potentially promising treatment for reducing challenging behavior and increasing academic behavior in individuals with autism spectrum disorder (ASD). The purpose of this study was to evaluate the effects of physical exercise conducted prior to instructional sessions (antecedent physical exercise) on academic engagement and stereotypy during instructional sessions for two children diagnosed with ASD. Functional analysis results suggested stereotypy was maintained by automatic reinforcement for both participants. A multielement design was employed to evaluate academic engagement and stereotypy during instructional sessions following randomly sequenced conditions involving either (a) no antecedent exercise, (b) brief durations of antecedent exercise, or (c) antecedent exercise that continued until the participant engaged in a systematically determined behavioral indicator of satiation. Both participants demonstrated higher levels of academic engagement and reduced levels of stereotypy during the instructional sessions which followed antecedent physical exercise that continued until behavioral indicators of satiation occurred. This study replicates previous research suggesting that individuals with ASD may benefit from physical exercise prior to academic instruction and further suggests that the duration of antecedent exercise may be optimally individualized based on behavioral indicators of satiation. PMID- 25271071 TI - Expert's comment concerning Grand Rounds case entitled "progressive kyphotic deformity in comminuted burst fractures treated non-operatively: the Achilles tendon of the Thoracolumbar Injury Classification and Severity Score (TLICS)" (T.A. Mattei, J. Hanovnikian, D. Dinh). PMID- 25271072 TI - Diffuse idiopathic skeletal hyperostosis (DISH) is a risk factor for further surgery in short-segment lumbar interbody fusion. AB - PURPOSE: To elucidate the effect of diffuse idiopathic skeletal hyperostosis (DISH) on the clinical results of short-segment lumbar interbody fusion (LIF) for the treatment of degenerative lumbar spinal diseases. METHODS: The 208 patients who underwent one- or two-level LIF were selected as the subjects of this study. Patients with prior lumbar fusion surgery or follow-up <1 year were excluded. Outcome measures were surgery-free survival or the need for further surgery for pseudoarthrosis and/or adjacent segment disease (ASD). The Cox proportional hazards model was used to identify possible risk factors (DISH, age, sex, number of levels fused, level of the lowest instrumented vertebra, and laminectomy adjacent to the index fused levels) for further surgery. RESULTS: Among the 208 patients (39 with DISH), 21 patients required further surgery during follow-up. Cox analysis showed that DISH (hazard ratio = 5.46) and two-level fusion (hazard ratio = 2.83) were significant independent predictors of further surgery. Age, sex, level of the lowest instrumented vertebra, and laminectomy adjacent to the index fused levels were not significant predictors. CONCLUSIONS: DISH after short segment LIF surgery is a significant risk factor for further surgery because of pseudoarthrosis or ASD. PMID- 25271073 TI - Parcellation of the human orbitofrontal cortex based on gray matter volume covariance. AB - The human orbitofrontal cortex (OFC) is an enigmatic brain region that cannot be parcellated reliably using diffusional and functional magnetic resonance imaging (fMRI) because there is signal dropout that results from an inherent defect in imaging techniques. We hypothesise that the OFC can be reliably parcellated into subregions based on gray matter volume (GMV) covariance patterns that are derived from artefact-free structural images. A total of 321 healthy young subjects were examined by high-resolution structural MRI. The OFC was parcellated into subregions-based GMV covariance patterns; and then sex and laterality differences in GMV covariance pattern of each OFC subregion were compared. The human OFC was parcellated into the anterior (OFCa), medial (OFCm), posterior (OFCp), intermediate (OFCi), and lateral (OFCl) subregions. This parcellation scheme was validated by the same analyses of the left OFC and the bilateral OFCs in male and female subjects. Both visual observation and quantitative comparisons indicated a unique GMV covariance pattern for each OFC subregion. These OFC subregions mainly covaried with the prefrontal and temporal cortices, cingulate cortex and amygdala. In addition, GMV correlations of most OFC subregions were similar across sex and laterality except for significant laterality difference in the OFCl. The right OFCl had stronger GMV correlation with the right inferior frontal cortex. Using high-resolution structural images, we established a reliable parcellation scheme for the human OFC, which may provide an in vivo guide for subregion-level studies of this region and improve our understanding of the human OFC at subregional levels. PMID- 25271074 TI - "Determination of hydraulic conductivity from grain-size distribution for different depositional environments,": authors' reply. PMID- 25271075 TI - [Comparison of set-up control for head and neck patients between radiation oncologist and therapists with the aim of partial delegation]. AB - PURPOSE: The aim of this prospective study was to evaluate daily set-up by a radiation oncologist and by radiation therapists using on-board imaging of patients with head and neck cancer in order to calculate margin to PTV (planning target volume) and intent partial delegation of positioning images control. PATIENTS AND METHODS: The files of 11 patients with head and neck cancer treated on a SynergyTM (ElektaTM) accelerator with on-board imaging system were evaluated. Daily kV-kV images were double-blind reviewed by radiation therapists (7 participants) and by one radiation oncologist. The radiation oncologist's measures were used for margin calculation from CTV to PTV. The difference of measures and the concordance of decisions between radiation therapists and the radiation oncologist were calculated. RESULTS: The 325 measures made by the radiation oncologist resulted in a margin of 5mm to be applied to the CTV in each direction. Nine hundred seventy-seven measures were made by the radiation oncologist and radiation therapists with a difference of 3mm or less in 98.46%. The concordance of decision for a 4mm difference or less to the isocenter was 96.7%. CONCLUSION: This study confirms the 5mm PTV margin mostly used in ORL. The small gap between the radiation oncologist's and therapists' measures allows a partial delegation of positioning images control. PMID- 25271076 TI - Drug-inducible synergistic gene silencing with multiple small hairpin RNA molecules for gene function study in animal model. AB - Gene targeting is a critical tool for construction of disease models. However, the application of traditional homologous recombination-mediated gene knockout technology is limited by the absence of rapid frequency-guaranteed targeting methods. Although conventional small hairpin RNA (shRNA)-mediated gene silencing offers an alternative for gene targeting, its application is frequently compromised by lower expression efficiency via RNA interference compared to gene knockout. Here we provide an efficient gene targeting strategy involving drug inducible synergistic silencing with multiple shRNA molecules. On induction, the levels of the target proteins decreased to undetectable levels in all the tested stable transgenic mammalian cell lines, including HEK293 and embryonic stem cell derived progenies carrying shRNA silencing cassettes. In a transgenic mouse model carrying a silencing cassette targeting the rhodopsin gene, short-time inducer treatment was sufficient to ablate the rhodopsin protein in the retina, resulting in similar retinal phenotypic changes as those observed in rhodopsin mutant mice. Therefore, on a broad basis, this inducible shRNA gene targeting strategy offers a true gene knockout alternative comparable to conventional RNA interference approaches. PMID- 25271077 TI - A mesoporous silicon/poly-(DL-lactic-co-glycolic) acid microsphere for long time anti-tuberculosis drug delivery. AB - In this study, drug delivery systems for controlling release of hydrophobic anti tuberculosis (TB) drug-rifampicin (RIF) or hydrophilic anti-TB drug-isoniazid (INH) from mesoporous silica (MS) were fabricated. The drug was first filled into the mesopores of MS particles, and then the drug-laden MS constructs were incorporated into the bulk of poly-(DL-lactic-co-glycolic) acid (PLGA) microspheres. In comparison with mono-component construct (drug-laden MS and drug laden PLGA), this multi-component system significantly improved the release time of RIF and INH. For drug-laden MS, about 100% INH was released after 15 h, and about 70% RIF was released after 50 h. For drug-laden PLGA, about 100% INH and RIF were released after 30 and 40 days, respectively. After 60 days, the total RIF and INH release from MS/PLGA had only reached around only 48% and 57%, respectively. This MS/PLGA system could significantly prolong RIF or INH release compared to MS and PLGA. CCK-8 assay demonstrated that this MS/PLGA system had no cytotoxicity. And there has not been study of documenting the controlled release of anti-TB drugs such as RIF or INH from MS/PLGA. Considering the long time release of RIF and INH from MS/PLGA, a new door to bone TB would be opened. PMID- 25271078 TI - Linking 3D and 2D binding kinetics of membrane proteins by multiscale simulations. AB - Membrane proteins are among the most functionally important proteins in cells. Unlike soluble proteins, they only possess two translational degrees of freedom on cell surfaces, and experience significant constraints on their rotations. As a result, it is currently challenging to characterize the in situ binding of membrane proteins. Using the membrane receptors CD2 and CD58 as a testing system, we developed a multiscale simulation framework to study the differences of protein binding kinetics between 3D and 2D environments. The association and dissociation processes were implemented by a coarse-grained Monte-Carlo algorithm, while the dynamic properties of proteins diffusing on lipid bilayer were captured from all-atom molecular dynamic simulations. Our simulations show that molecular diffusion, linker flexibility and membrane fluctuations are important factors in adjusting binding kinetics. Moreover, by calibrating simulation parameters to the measurements of 3D binding, we derived the 2D binding constant which is quantitatively consistent with the experimental data, indicating that the method is able to capture the difference between 3D and 2D binding environments. Finally, we found that the 2D dissociation between CD2 and CD58 is about 100-fold slower than the 3D dissociation. In summary, our simulation framework offered a generic approach to study binding mechanisms of membrane proteins. PMID- 25271081 TI - Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. AB - PURPOSE: We developed a novel systemic immune-inflammation index (SII) based on lymphocyte, neutrophil, and platelet counts and explored its prognostic value in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: The SII was developed based on a retrospective study of 133 patients with HCC undergoing resection between 2005 and 2006, and validated in a prospective study of 123 patients enrolled from 2010 to 2011. The circulating tumor cell (CTC) level in the validation cohort was measured using the CellSearch system. Prediction accuracy was evaluated with area under the receiver operating characteristic curve (AUC). RESULTS: An optimal cutoff point for the SII of 330 * 10(9) stratified the patients with HCC into high (>=330) and low SII (<330) groups in the training cohort. Univariate and multivariate analyses revealed the SII was an independent predictor for overall survival and relapse-free survival, and prognostic for patients with negative alpha-fetoprotein and Barcelona Clinic Liver Cancer stage 0+A. The AUCs of the SII for survival and recurrence were higher than other conventional clinical indices. An SII >= 330 was significantly associated with vascular invasion, large tumors, and early recurrence. CTC levels were significantly higher in the SII >= 330 group (1.71 +/- 0.34 vs. 4.37 +/- 1.04, P = 0.029). In patients with detectable CTCs, those with SII >= 330 had higher recurrence rates and shorter survival time than patients with SII < 330. CONCLUSION: The SII was a powerful prognostic indicator of poor outcome in patients with HCC and is a promising tool for HCC treatment strategy decisions. The dismal outcome in patients with high SII scores might be related to higher CTC levels. PMID- 25271082 TI - Performance feedback, paraeducators, and literacy instruction for students with significant disabilities. AB - Literacy skills are fundamental for all learners. For students with significant disabilities, strong literacy skills provide a gateway to generative communication, genuine friendships, improved access to academic opportunities, access to information technology, and future employment opportunities. Unfortunately, many educators lack the knowledge to design or implement appropriate evidence-based literacy instruction for students with significant disabilities. Furthermore, students with significant disabilities often receive the majority of their instruction from paraeducators. This single-subject design study examined the effects of performance feedback on the delivery skills of paraeducators during systematic and explicit literacy instruction for students with significant disabilities. The specific skills targeted for feedback were planned opportunities for student responses and correct academic responses. Findings suggested that delivery of feedback on performance resulted in increased pacing, accuracy in student responses, and subsequent attainment of literacy skills for students with significant disabilities. Implications for the use of performance feedback as an evaluation and training tool for increasing effective instructional practices are provided. PMID- 25271083 TI - A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure. AB - Myosin light-chain kinase (MYLK) is a gene known to be significantly associated with severe asthma in African Americans. Here we further examine the molecular function of a single-nucleotide polymorphism (SNP), located in the non-muscle myosin light-chain kinase isoform (nmMLCK), in asthma susceptibility and pathobiology. We identified nmMLCK variant (reference SNP: rs9840993, NM_053025: 721C>T, c.439C>T) with a distinct mRNA secondary structure from the other variants. The nmMLCK variant (721C) secondary structure exhibits increased stability with an elongated half-life in the human endothelial cell, and greater efficiency in protein translation initiation owing to an increased accessibility to translation start site. Finally, nmMLCK expression of 721C- and 721T containing MYLK transgenes were compared in nmMLCK(-/-) mice and confirmed deleterious effects of nmMLCK expression on asthmatic indices and implicated the augmented influence of MYLK 721C>T (c.439C>T) SNP on asthma severity. The confirmation of the novel mechanism of the regulation of asthmatic inflammation by a MYLK advances knowledge of the genetic basis for asthma disparities, and further suggests the potential of nmMLCK as a therapeutic target. Our study suggests that in addition to altering protein structure and function, non synonymous SNPs may also lead to phenotypic disparity by altering protein expression. PMID- 25271084 TI - MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes. AB - Individuals with autism spectrum disorders (ASD) who have an identifiable single gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders. PMID- 25271086 TI - Homogeneous case subgroups increase power in genetic association studies. AB - Genome-wide association studies of clinically defined cases against controls have transformed our understanding of the genetic causes of many diseases. However, there are limitations to the simple clinical definitions used in these studies, and GWAS analyses are beginning to explore more refined phenotypes in subgroups of the existing data sets. These analyses are often performed ad hoc without considering the power requirements to justify such analyses. Here we derive expressions for the relative power of such subgroup analyses and determine the genotypic relative risks (GRRs) required to achieve equivalent power to a full analysis for relevant scenarios. We show that only modest increases in GRRs may be required to offset the reduction in power from analysing fewer cases, implying that analyses of more genetically homogenous case subgroups may have the potential to identify further associations. We find that, for lower genotypic relative risks in the full sample, subgroup analyses of more homogeneous cases have relatively more power than for higher index genotypic relative risks and that this effect is stronger for rare as opposed to common variants. As GWA studies are likely to have now identified the majority of SNPs with stronger effects, these results strongly advocate a renewed effort to identify phenotypically homogeneous disease groups, in which power to detect genetic variants with small effects will be greater. These results suggest that analysis of case subsets could be a powerful strategy to uncover some of the hidden heritability for common complex disorders, particularly in identifying rarer variants of modest effect. PMID- 25271085 TI - Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants. AB - Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up. PMID- 25271087 TI - Five children with deletions of 1p34.3 encompassing AGO1 and AGO3. AB - Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this. PMID- 25271089 TI - Conducting real-time multiplayer experiments on the web. AB - Group behavior experiments require potentially large numbers of participants to interact in real time with perfect information about one another. In this paper, we address the methodological challenge of developing and conducting such experiments on the web, thereby broadening access to online labor markets as well as allowing for participation through mobile devices. In particular, we combine a set of recent web development technologies, including Node.js with the Socket.io module, HTML5 canvas, and jQuery, to provide a secure platform for pedagogical demonstrations and scalable, unsupervised experiment administration. Template code is provided for an example real-time behavioral game theory experiment which automatically pairs participants into dyads and places them into a virtual world. In total, this treatment is intended to allow those with a background in non-web based programming to modify the template, which handles the technical server client networking details, for their own experiments. PMID- 25271088 TI - Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene. AB - We performed gene-environment interaction genome-wide association analysis (G * E GWAS) to identify SNPs whose effects on metabolic traits are modified by chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis (MESA). In Whites, the G * E GWAS for hip circumference identified five SNPs within the Early B-cell Factor 1 (EBF1) gene, all of which were in strong linkage disequilibrium. The gene-by-stress interaction (SNP * STRESS) term P-values were genome-wide significant (Ps = 7.14E-09 to 2.33E-08, uncorrected; Ps = 1.99E-07 to 5.18E-07, corrected for genomic control). The SNP-only (without interaction) model P-values (Ps = 0.011-0.022) were not significant at the conventional genome wide significance level. Further analysis of related phenotypes identified gene by-stress interaction effects for waist circumference, body mass index (BMI), fasting glucose, type II diabetes status, and common carotid intimal-medial thickness (CCIMT), supporting a proposed model of gene-by-stress interaction that connects cardiovascular disease (CVD) risk factor endophenotypes such as central obesity and increased blood glucose or diabetes to CVD itself. Structural equation path analysis suggested that the path from chronic psychosocial stress to CCIMT via hip circumference and fasting glucose was larger (estimate = 0.26, P = 0.033, 95% CI = 0.02-0.49) in the EBF1 rs4704963 CT/CC genotypes group than the same path in the TT group (estimate = 0.004, P = 0.34, 95% CI = -0.004-0.012). We replicated the association of the EBF1 SNPs and hip circumference in the Framingham Offspring Cohort (gene-by-stress term P-values = 0.007-0.012) as well as identified similar path relationships. This observed and replicated interaction between psychosocial stress and variation in the EBF1 gene may provide a biological hypothesis for the complex relationship between psychosocial stress, central obesity, diabetes, and cardiovascular disease. PMID- 25271090 TI - A power fallacy. AB - The power fallacy refers to the misconception that what holds on average -across an ensemble of hypothetical experiments- also holds for each case individually. According to the fallacy, high-power experiments always yield more informative data than do low-power experiments. Here we expose the fallacy with concrete examples, demonstrating that a particular outcome from a high-power experiment can be completely uninformative, whereas a particular outcome from a low-power experiment can be highly informative. Although power is useful in planning an experiment, it is less useful-and sometimes even misleading-for making inferences from observed data. To make inferences from data, we recommend the use of likelihood ratios or Bayes factors, which are the extension of likelihood ratios beyond point hypotheses. These methods of inference do not average over hypothetical replications of an experiment, but instead condition on the data that have actually been observed. In this way, likelihood ratios and Bayes factors rationally quantify the evidence that a particular data set provides for or against the null or any other hypothesis. PMID- 25271091 TI - Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. AB - Recently, the beneficial effects of increased physical activity (PA) on nonalcoholic fatty liver disease (NAFLD) in obese subjects were reported. However, the optimal strength and volume of PA in lifestyle modification to improve NAFLD pathophysiology and be recommended as an appropriate management of this condition are unclear. The primary goal of this retrospective study was to estimate the beneficial effects of a varying volume of moderate to vigorous intensity PA (MVPA) on the improvement of NAFLD. A total of 169 obese, middle aged men were enrolled in a 12-week weight reduction program through lifestyle modification consisting of dietary restrictions plus aerobic exercise. Among these obese subjects, 40 performed MVPA for <150 min.wk(-1) , 42 performed MVPA for 150-250 min.wk(-1) , and 87 performed MVPA for >250 min.wk(-1) . The subjects in the MVPA >=250 min.wk(-1) group, in comparison with those in the MVPA <250 min.wk(-1) group, showed significantly attenuated levels of hepatic steatosis ( 31.8% versus -23.2%). This attenuation was likely independent of the detectable weight reduction. MVPA for >=250 min.wk(-1) in comparison with that for <150 min.wk(-1) led to a significant decrease in the abdominal visceral adipose tissue severity (-40.6% versus -12.9%), levels of ferritin (-13.6% versus +1.5%), and lipid peroxidation (-15.1% versus -2.8%), and a significant increase in the adiponectin levels (+17.1% versus +5.6%). In association with these changes, the gene expression levels of sterol regulatory element-binding protein-1c and carnitine palmitoyltransferase-1 in peripheral blood mononuclear cells also significantly decreased and increased, respectively. CONCLUSION: MVPA for >=250 min.wk(-1) as part of lifestyle management improves NAFLD pathophysiology in obese men. The benefits seem to be acquired through reducing inflammation and oxidative stress levels and altering fatty acid metabolism. PMID- 25271092 TI - Tumor-to-bone distance of invasive subungual melanoma: an analysis of 30 cases. AB - Subungual melanoma (SUM) is rare and represents approximately 2-3% and 20% of all cutaneous melanomas in Caucasians and Asians, respectively. Amputation has usually been performed for invasive SUM; however, not all invasive SUMs invade or attach to the distal phalanx. To investigate the possibility of non-amputative surgery for patients with invasive SUM, the distances between the deepest base of the melanoma cells and the bony surface in the surgical specimens of invasive SUM were measured. Thirty surgical specimens of invasive SUM were retrospectively reviewed. The contents of the specimens were as follows: 14 first toes, 10 thumbs, three second fingers, two third fingers, and one fifth finger. Four specimens showed bone invasion, and the tumor was attached to the bone in four specimens. The tumor-to-bone distance exceeded 0.9 mm in all the specimens with thicknesses <4 mm. In the non-ulcerated SUMs (nine specimens), only one SUM specimen showed bone attachment. There was a higher likelihood of bone attachment or invasion when tumor thickness (TT) exceeded 4 mm (Pearson chi-square test, P = 0.009; Fisher exact test, P = 0.004; student t test, 0.033). Univariate and multivariate analysis also revealed that thick TT had a statistically significant affect (odds ratio 1.807 and 1.865, 95% CI 1.11-3.01 and 1.11-3.13, P = 0.023 and 0.018). Non-amputative surgery may be possible for SUM tumors that are of intermediate-thickness. However, there has been little evidence demonstrating survival with non-amputative surgery for invasive SUM. A large, randomized, prospective clinical study is required to address this issue. PMID- 25271093 TI - Expression studies of a novel splice site mutation in the LIPH gene identified in a Japanese patient with autosomal recessive woolly hair. AB - Autosomal recessive woolly hair (ARWH) is characterized by short and tightly curled scalp hair without any obvious complications. The disease is known to be caused by either lipase H (LIPH) or LPAR6 genes. Proteins encoded by these two genes are closely related to each other in a lipid-signaling pathway that is believed to play crucial roles in hair follicle development and hair growth. In the Japanese population, most affected individuals with ARWH have been shown to carry two prevalent founder mutations in the LIPH gene, c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn), while other LIPH mutations have been occasionally identified. In this study, we analyzed a Japanese patient with ARWH, and identified compound heterozygous mutations in the LIPH gene, c.736T>A (p.Cys246Ser) and c.982+5G>T. The latter one was a novel splice site mutation in intron 7. Expression studies using blood-derived RNA from the patient detected the LIPH transcript from the c.736T>A mutant allele, but not from the c.982+5G>T mutant allele. Furthermore, in vitro transcription assay in cultured cells showed that the mutation c.982+5G>T caused an aberrant splicing event, leading to a frame-shift and a premature termination codon (p.Met328Serfs*41). To the best of our knowledge, this is the second splice site mutation in the LIPH gene, and our findings further expand the spectrum of the LIPH mutations underlying ARWH. PMID- 25271094 TI - Fatal case of clinically amyopathic dermatomyositis: cotton-wool spots as a sign of an aggressive subtype of dermatomyositis. PMID- 25271095 TI - CD109 expression is increased in cutaneous squamous cell carcinoma. PMID- 25271096 TI - Effect of web-based messages on girls' knowledge and risk perceptions related to cigarette smoke and breast cancer: 6-month follow-up of a randomized controlled trial. AB - BACKGROUND: Evidence indicating an association between cigarette smoke exposure and an increase in breast cancer risk highlights the need for health messages that aim to prevent smoking initiation and reduce secondhand smoke (SHS) exposure among adolescent girls. OBJECTIVE: This study aimed to evaluate the efficacy of targeted gender-sensitive, breast cancer-specific, Web-based messages about the increased risk of breast cancer associated with cigarette smoke exposure. Outcomes assessed 6 months postmessage delivery included nonsmoking adolescent girls' knowledge of the link between cigarette smoke exposure and breast cancer, perceptions of breast cancer risk associated with cigarette smoke, smoking behavior and intentions, and stage of change related to avoidance of secondhand smoke. METHODS: A prospective randomized controlled trial was used to compare standard (control) messages with targeted gender- and Aboriginal status sensitive, breast cancer-specific (intervention) messages. Messages were delivered online to 618 nonsmoking girls, aged 13 to 15 years, clustered in 74 Canadian secondary schools. RESULTS: Compared with the control group, girls in the intervention group were significantly more likely to report that breast cancer is an illness caused by cigarette smoke (adjusted relative risk [ARR] 1.33, 95% CI 1.05-1.68) and to agree that exposure to SHS increases their risk of breast cancer (ARR 1.10, 95% CI 1.02-1.20). No significant effects were observed for a change in smoking status, intention to try smoking, or stage of change related to avoidance of SHS. CONCLUSIONS: Compared with standard messages, targeted gender-sensitive, breast cancer-specific messages had a stronger influence on girls' knowledge and perceived risk of cigarette smoke exposure as a risk factor for breast cancer. Brief information-based interventions delivered over the Internet have the potential to provide effective health promotion that could be broadly disseminated and lead to long-term effects on girls' knowledge and risk perceptions about cigarette exposure and breast cancer. PMID- 25271097 TI - Electrotherapy modalities for adhesive capsulitis (frozen shoulder). AB - BACKGROUND: Adhesive capsulitis (also termed frozen shoulder) is a common condition characterised by spontaneous onset of pain, progressive restriction of movement of the shoulder and disability that restricts activities of daily living, work and leisure. Electrotherapy modalities, which aim to reduce pain and improve function via an increase in energy (electrical, sound, light, thermal) into the body, are often delivered as components of a physical therapy intervention. This review is one in a series of reviews which form an update of the Cochrane review 'Physiotherapy interventions for shoulder pain'. OBJECTIVES: To synthesise the available evidence regarding the benefits and harms of electrotherapy modalities, delivered alone or in combination with other interventions, for the treatment of adhesive capsulitis. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, CINAHL Plus and the ClinicalTrials.gov and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) clinical trials registries up to May 2014, unrestricted by language, and reviewed the reference lists of review articles and retrieved trials to identify any other potentially relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials using a quasi-randomised method of allocation that included adults with adhesive capsulitis and compared any electrotherapy modality to placebo, no treatment, a different electrotherapy modality, or any other intervention. The two main questions of the review focused on whether electrotherapy modalities are effective compared to placebo or no treatment, or if they are an effective adjunct to manual therapy or exercise (or both). The main outcomes of interest were participant-reported pain relief of 30% or greater, overall pain, function, global assessment of treatment success, active shoulder abduction, quality of life, and the number of participants experiencing any adverse event. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, performed a risk of bias assessment, and assessed the quality of the body of evidence for the main outcomes using the GRADE approach. MAIN RESULTS: Nineteen trials (1249 participants) were included in the review. Four trials reported using an adequate method of allocation concealment and six trials blinded participants and personnel. Only two electrotherapy modalities (low-level laser therapy (LLLT) and pulsed electromagnetic field therapy (PEMF)) have been compared to placebo. No trial has compared an electrotherapy modality plus manual therapy and exercise to manual therapy and exercise alone. The two main questions of the review were investigated in nine trials.Low quality evidence from one trial (40 participants) indicated that LLLT for six days may result in improvement at six days. Eighty per cent (16/20) of participants reported treatment success with LLLT compared with 10% (2/20) of participants receiving placebo (risk ratio (RR) 8.00, 95% confidence interval (CI) 2.11 to 30.34; absolute risk difference 70%, 95% CI 48% to 92%). No participants in either group reported adverse events.We were uncertain whether PEMF for two weeks improved pain or function more than placebo at two weeks because of the very low quality evidence from one trial (32 participants). Seventy-five per cent (15/20) of participants reported pain relief of 30% or more with PEMF compared with 0% (0/12) of participants receiving placebo (RR 19.19, 95% CI 1.25 to 294.21; absolute risk difference 75%, 95% CI 53% to 97%). Fifty-five per cent (11/20) of participants reported total recovery of joint function with PEMF compared with 0% (0/12) of participants receiving placebo (RR 14.24, 95% CI 0.91 to 221.75; absolute risk difference 55%, 95% CI 31 to 79).Moderate quality evidence from one trial (63 participants) indicated that LLLT plus exercise for eight weeks probably results in greater improvement when measured at the fourth week of treatment, but a similar number of adverse events, compared with placebo plus exercise. The mean pain score at four weeks was 51 points with placebo plus exercise, while with LLLT plus exercise the mean pain score was 32 points on a 100 point scale (mean difference (MD) 19 points, 95% CI 15 to 23; absolute risk difference 19%, 95% CI 15% to 23%). The mean function impairment score was 48 points with placebo plus exercise, while with LLLT plus exercise the mean function impairment score was 36 points on a 100 point scale (MD 12 points, 95% CI 6 to 18; absolute risk difference 12%, 95% CI 6 to 18). Mean active abduction was 70 degrees with placebo plus exercise, while with LLLT plus exercise mean active abduction was 79 degrees (MD 9 degrees, 95% CI 2 to 16; absolute risk difference 5%, 95% CI 1% to 9%). No participants in either group reported adverse events. LLLT's benefits on function were maintained at four months.Based on very low quality evidence from six trials, we were uncertain whether therapeutic ultrasound, PEMF, continuous short wave diathermy, Iodex phonophoresis, a combination of Iodex iontophoresis with continuous short wave diathermy, or a combination of therapeutic ultrasound with transcutaneous electrical nerve stimulation (TENS) were effective adjuncts to exercise. Based on low or very low quality evidence from 12 trials, we were uncertain whether a diverse range of electrotherapy modalities (delivered alone or in combination with manual therapy, exercise, or other active interventions) were more or less effective than other active interventions (for example glucocorticoid injection). AUTHORS' CONCLUSIONS: Based upon low quality evidence from one trial, LLLT for six days may be more effective than placebo in terms of global treatment success at six days. Based upon moderate quality evidence from one trial, LLLT plus exercise for eight weeks may be more effective than exercise alone in terms of pain up to four weeks, and function up to four months. It is unclear whether PEMF is more or less effective than placebo, or whether other electrotherapy modalities are an effective adjunct to exercise. Further high quality randomised controlled trials are needed to establish the benefits and harms of physical therapy interventions (that comprise electrotherapy modalities, manual therapy and exercise, and are reflective of clinical practice) compared to interventions with evidence of benefit (for example glucocorticoid injection or arthrographic joint distension). PMID- 25271098 TI - Bias due to selective inclusion and reporting of outcomes and analyses in systematic reviews of randomised trials of healthcare interventions. AB - BACKGROUND: Systematic reviews may be compromised by selective inclusion and reporting of outcomes and analyses. Selective inclusion occurs when there are multiple effect estimates in a trial report that could be included in a particular meta-analysis (e.g. from multiple measurement scales and time points) and the choice of effect estimate to include in the meta-analysis is based on the results (e.g. statistical significance, magnitude or direction of effect). Selective reporting occurs when the reporting of a subset of outcomes and analyses in the systematic review is based on the results (e.g. a protocol defined outcome is omitted from the published systematic review). OBJECTIVES: To summarise the characteristics and synthesise the results of empirical studies that have investigated the prevalence of selective inclusion or reporting in systematic reviews of randomised controlled trials (RCTs), investigated the factors (e.g. statistical significance or direction of effect) associated with the prevalence and quantified the bias. SEARCH METHODS: We searched the Cochrane Methodology Register (to July 2012), Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO and ISI Web of Science (each up to May 2013), and the US Agency for Healthcare Research and Quality (AHRQ) Effective Healthcare Program's Scientific Resource Center (SRC) Methods Library (to June 2013). We also searched the abstract books of the 2011 and 2012 Cochrane Colloquia and the article alerts for methodological work in research synthesis published from 2009 to 2011 and compiled in Research Synthesis Methods. SELECTION CRITERIA: We included both published and unpublished empirical studies that investigated the prevalence and factors associated with selective inclusion or reporting, or both, in systematic reviews of RCTs of healthcare interventions. We included empirical studies assessing any type of selective inclusion or reporting, such as investigations of how frequently RCT outcome data is selectively included in systematic reviews based on the results, outcomes and analyses are discrepant between protocol and published review or non significant outcomes are partially reported in the full text or summary within systematic reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently selected empirical studies for inclusion, extracted the data and performed a risk of bias assessment. A third review author resolved any disagreements about inclusion or exclusion of empirical studies, data extraction and risk of bias. We contacted authors of included studies for additional unpublished data. Primary outcomes included overall prevalence of selective inclusion or reporting, association between selective inclusion or reporting and the statistical significance of the effect estimate, and association between selective inclusion or reporting and the direction of the effect estimate. We combined prevalence estimates and risk ratios (RRs) using a random-effects meta analysis model. MAIN RESULTS: Seven studies met the inclusion criteria. No studies had investigated selective inclusion of results in systematic reviews, or discrepancies in outcomes and analyses between systematic review registry entries and published systematic reviews. Based on a meta-analysis of four studies (including 485 Cochrane Reviews), 38% (95% confidence interval (CI) 23% to 54%) of systematic reviews added, omitted, upgraded or downgraded at least one outcome between the protocol and published systematic review. The association between statistical significance and discrepant outcome reporting between protocol and published systematic review was uncertain. The meta-analytic estimate suggested an increased risk of adding or upgrading (i.e. changing a secondary outcome to primary) when the outcome was statistically significant, although the 95% CI included no association and a decreased risk as plausible estimates (RR 1.43, 95% CI 0.71 to 2.85; two studies, n = 552 meta-analyses). Also, the meta-analytic estimate suggested an increased risk of downgrading (i.e. changing a primary outcome to secondary) when the outcome was statistically significant, although the 95% CI included no association and a decreased risk as plausible estimates (RR 1.26, 95% CI 0.60 to 2.62; two studies, n = 484 meta-analyses). None of the included studies had investigated whether the association between statistical significance and adding, upgrading or downgrading of outcomes was modified by the type of comparison, direction of effect or type of outcome; or whether there is an association between direction of the effect estimate and discrepant outcome reporting.Several secondary outcomes were reported in the included studies. Two studies found that reasons for discrepant outcome reporting were infrequently reported in published systematic reviews (6% in one study and 22% in the other). One study (including 62 Cochrane Reviews) found that 32% (95% CI 21% to 45%) of systematic reviews did not report all primary outcomes in the abstract. Another study (including 64 Cochrane and 118 non-Cochrane reviews) found that statistically significant primary outcomes were more likely to be completely reported in the systematic review abstract than non-significant primary outcomes (RR 2.66, 95% CI 1.81 to 3.90). None of the studies included systematic reviews published after 2009 when reporting standards for systematic reviews (Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement, and Methodological Expectations of Cochrane Intervention Reviews (MECIR)) were disseminated, so the results might not be generalisable to more recent systematic reviews. AUTHORS' CONCLUSIONS: Discrepant outcome reporting between the protocol and published systematic review is fairly common, although the association between statistical significance and discrepant outcome reporting is uncertain. Complete reporting of outcomes in systematic review abstracts is associated with statistical significance of the results for those outcomes. Systematic review outcomes and analysis plans should be specified prior to seeing the results of included studies to minimise post-hoc decisions that may be based on the observed results. Modifications that occur once the review has commenced, along with their justification, should be clearly reported. Effect estimates and CIs should be reported for all systematic review outcomes regardless of the results. The lack of research on selective inclusion of results in systematic reviews needs to be addressed and studies that avoid the methodological weaknesses of existing research are also needed. PMID- 25271099 TI - Metamorphopsia and interocular suppression in monocular and binocular maculopathy. PMID- 25271100 TI - Protein post-translational modification in host defense: the antimicrobial mechanism of action of human eosinophil cationic protein native forms. AB - Knowledge on the contribution of protein glycosylation in host defense antimicrobial peptides is still scarce. We have studied here how the post translational modification pattern modulates the antimicrobial activity of one of the best characterized leukocyte granule proteins. The human eosinophil cationic protein (ECP), an eosinophil specific granule protein secreted during inflammation and infection, can target a wide variety of pathogens. Previous work in human eosinophil extracts identified several ECP native forms and glycosylation heterogeneity was found to contribute to the protein biological properties. In this study we analyze for the first time the antimicrobial activity of the distinct native proteins purified from healthy donor blood. Low and heavy molecular weight forms were tested on Escherichia coli cell cultures and compared with the recombinant non-glycosylated protein. Further analysis on model membranes provided an insight towards an understanding of the protein behavior at the cytoplasmic membrane level. The results highlight the significant reduction in protein toxicity and bacteria agglutination activity for heavy glycosylated fractions. Notwithstanding, the lower glycosylated fraction mostly retains the lipopolysaccharide binding affinity together with the cytoplasmic membrane depolarization and membrane leakage activities. From structural analysis we propose that heavy glycosylation interferes with the protein self-aggregation, hindering the cell agglutination and membrane disruption processes. The results suggest the contribution of post-translational modifications to the antimicrobial role of ECP in host defense. PMID- 25271101 TI - How to achieve adherence to a ventilation algorithm for critically ill children? AB - AIMS AND OBJECTIVES: To evaluate to what extent physicians on a paediatric intensive care unit (PICU) adhered to a newly implemented ventilation algorithm. BACKGROUND: PICUs worldwide use different ventilators with a wide variety of ventilation modes. We developed an algorithm, as part of a larger protocol, for choice of ventilation mode at time of admission. DESIGN: This study was performed in a level III PICU of a university children's hospital and had an uncontrolled, pre-post test design with a period before implementation (T0) and two periods after implementation (T1 and T2). METHODS: An invasive ventilation algorithm targeted at two patient groups was implemented in October 2008. The algorithm distinguished between lung disease, in which pressure control was considered as the preferred mode, and no lung disease, in which pressure-regulated volume control was preferred. Nurses and physicians were instructed in the use of the algorithm before implementation. RESULTS: During three test periods, a total of 507 children with a median age of 5 months [interquartile range (IQR) 0-50] on conventional invasive mechanical ventilation were included. In patients with lung disease, pre-implementation adherence rate was 79% (67/85). At T1 it was 71% (51/72); at T2 84% (46/55). The slight improvement from T1 to T2 was statistically not significant (p = 0.092). In patients with no lung disease, the adherence rate rose statistically significantly from 66% at T0 (62/93) to 78% (79/101) at T1, and 84% at T2 (85/101) (p = 0.015). CONCLUSION: Implementation of a new ventilation algorithm increased physicians' adherence to this ventilation algorithm and the effect was sustained over time. This was achieved by education, reminders and organizational changes such as admission of postcardiac surgery patients with protocolized nursing care including preset ventilator settings. RELEVANCE TO CLINICAL PRACTICE: Interdisciplinary collaboration, effective communication, leadership support and organizational aspects may be effective strategies to improve adherence to protocols. PMID- 25271102 TI - Long-term follow-up of women with breast cancer: rationale for policy change. AB - BACKGROUND: The number of breast cancer survivors in our ageing population continues to rise. Policy makers internationally are seeking to identify alternatives to follow-up care in an acute setting. AIMS: The National Cancer Control Programme set out to develop a new policy for long-term follow-up of breast cancer survivors in Ireland. METHODS: Policy development was informed by analysis of current attendances at breast surgical clinics for routine follow-up, extraction of the necessary components of follow-up from international guidelines and focus group research with Irish patients. RESULTS: Intensive follow-up investigations, other than mammography, do not confer additional survival benefit or improved quality of life. Provision of routine follow-up care of breast cancer survivors by GPs has been shown to be equivalent to follow-up by specialist clinics, in terms of clinical outcomes, patient quality of life and patient satisfaction. In Ireland, routine follow-up accounted for 15.4% (95% CI: 13.8 17.0%) of clinic appointments. A third were at least 5 years post-operative. Women highlighted issues such as attachment to specialist services, importance of communication and need for clarity as to where responsibility of care lies. Reassurance, confidence in the primary care practitioner, and coordination of multiple appointments were also identified as important issues. CONCLUSION: A significant proportion of breast cancer survivors attending hospital surgical clinics for long-term follow-up could be safely discharged at 5 years, with the hospital maintaining responsibility for annual mammography. Successful implementation will depend on informed patients, clinicians' acceptance and communication between primary and secondary care. PMID- 25271103 TI - In vitro metabolic conversion of the organic breakdown products of glucosinolate to goitrogenic thiocyanate anion. AB - BACKGROUND: Glucosinolates are abundant in Brassicaceae vegetables, and they are degraded into various organic breakdown products (BPs) (R-CN, -NCS and -SCN) by myrosinase when plant tissues are damaged. This study was designed to investigate whether these BPs could be broken further into goitrogenic thiocyanate anions (SCN(-) ) metabolically and/or spontaneously. Ten glucosinolates were chosen for this study based on the various structures of their side chains. SCN(-) and cyanide anions (CN(-) ) liberated from the BPs of these glucosinolates were quantified after incubation with human liver S9 and rhodanese. RESULTS: Upon treatment with metabolic enzymes, CN(-) was produced from all organic thiocyanates, aliphatic and benzyl nitriles, then a substantial amount of produced CN(-) was further metabolized to SCN(-) by rhodanese. All organic thiocyanates and allyl isothiocyanate were metabolized to produce SCN(-), without involving CN(-) production. Spontaneous degradation to SCN(-) in an aqueous environment was observed only in 4-(methylthio)butyl thiocyanate, though the enzymatic reaction rate exceeded the spontaneous one. Among these BPs, the major source of SCN(-) was organic thiocyanates. CONCLUSION: The results show that some organic nitriles, organic thiocyanates and allyl isothiocyanate may be regarded as potential sources of SCN(-) through metabolism when people ingest glucosinolate-containing vegetables. PMID- 25271104 TI - Induction of Pi form of glutathione S-transferase by carnosic acid is mediated through PI3K/Akt/NF-kappaB pathway and protects against neurotoxicity. AB - Carnosic acid (CA), a diterpene found in the rosemary (Rosmarinus officinalis), has been reported to have a neuroprotective effect. Glutathione S-transferase (GST) P (GSTP) is a phase II detoxifying enzyme that provides a neuroprotective effect. The aim of this study was to explore whether the neuroprotective effect of CA is via an upregulation of GSTP expression and the possible signaling pathways involved. SH-SY5Y cells were pretreated with 1 MUM CA followed by treatment with 100 MUM 6-hydroxydopamine (6-OHDA). Both immunoblotting and enzyme activity results show that CA also induced protein expression and enzyme activity of GSTP. Moreover, CA significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt, the nuclear translocation of p65, but not mitogen-activated protein kinases (p < 0.05). Pretreatment with LY294002 (a PI3K/Akt inhibitor) suppressed the CA-induced phosphorylation of IkappaB kinase (IKK) and IkappaBalpha, p65 nuclear translocation, and nuclear factor-kappa B (NF kappaB)-DNA binding activity as well as GSTP protein expression. Furthermore, CA attenuated 6-OHDA-induced caspase 3 activation, and cell death was reversed by GSTP siRNA or LY294002 treatment. Additionally, male Wistar rats with lesions induced by 6-OHDA treatment in the right striatum responded to treatment with CA, which significantly reversed the reduction in GSTP protein expression that resulted from lesioning. We suggest that CA prevents 6-OHDA-induced apoptosis through an increase in GSTP expression via activation of the PI3K/Akt/NF-kappaB pathway. Therefore, CA may be a promising candidate for use in the prevention of Parkinson's disease. PMID- 25271105 TI - Description of a modular mentorship programme for holmium laser enucleation of the prostate. AB - INTRODUCTION: Since its introduction around 15 years ago, many urologists have been interested in learning the technique of holmium laser enucleation of the prostate (HoLEP), but have not known how to achieve this efficiently and safely. MATERIALS AND METHODS: In the UK, a Holmium User Group (HUG) was established in 2006. The main purpose was to provide structured HoLEP training. RESULTS AND CONCLUSION: Since 2010, the first modular HoLEP training programme has been provided by HUG. This paper describes the HUG HoLEP training programme in detail including the incorporation of recently available HoLEP simulators. PMID- 25271106 TI - Utility of urodynamics in the management of asymptomatic tethered cord in children. AB - BACKGROUND: We have noted a recent increase in neurosurgical requests at our institution for urodynamics (UDS) prior to release of asymptomatic tethered cord. Our aim was to determine how preoperative UDS results are used in the clinical management of asymptomatic tethered cord. METHODS: A retrospective review was performed of 120 patients diagnosed with primary tethered cord from 2007 to 2010. Inclusion criteria included MRI diagnosis of tethered cord and UDS performed by three pediatric urologists. Excluded were any neurologic or urologic dysfunction or associated syndromes, as well as other significant comorbidities. RESULTS: Thirty-eight patients (female 26; male 12), mean age of 3 years (0.2-16.3) were diagnosed with an asymptomatic tethered cord. The majority of the patients had normal preoperative renal ultrasounds. Thirty-one (82 %) of the children had normal baseline UDS, yet twenty-one (68 %) of these patients still underwent neurosurgical intervention. Of the 27 patients untethered, 15 patients (55 %) had follow-up UDS performed. Three patients had improved UDS parameters and one had worsening UDS parameters, including high PVR and DSD. Of the seven patients with abnormal baseline UDS, all had normal renal ultrasound findings and had no other significant differences in presentation from the patients with normal UDS. CONCLUSION: In children with asymptomatic tethered cord, abnormal preoperative UDS may prompt intervention, while normal UDS do not appear to prevent intervention. There is no significant correlation between abnormal preoperative UDS and abnormal preoperative imaging. Further study is needed to evaluate the utility of this procedure in the preoperative setting in this asymptomatic patient population. PMID- 25271107 TI - Calcium binding to Procambarus clarkii sarcoplasmic calcium binding protein splice variants. AB - Sarcoplasmic calcium binding protein (SCP) is a high-affinity calcium buffering protein expressed in muscle of crayfish and other invertebrates. In previous work, we identified three splice variants of Procambarus clarkii SCP (pcSCP1a, pcSCP1b, and pcSCP1c) that differ in a 37 amino acid region that lies mainly between the 2nd and 3ed EF-hand calcium binding domain. To evaluate the function of the proteins encoded by the pcSCP1 transcripts, we produced recombinant pcSCP1 and used tryptophan fluorescence to characterize calcium binding. Tryptophan fluorescence of pcSCP1a decreased in response to increased calcium, while tryptophan fluorescence of the pcSCP1b and pcSCP1c variants increased. We estimated calcium binding constants and Hill coefficients with two different equations: the standard Hill equation and a modified Hill equation that accounts for contributions from two different tryptophans. The approaches gave similar results. Steady-state calcium binding constants (Kd) ranged from 2.7+/-0.7*10( 8)M to 5.6+/-0.1*10(-7)M, consistent with previous work. Variants displayed significantly different apparent calcium affinities, which were decreased in the presence of magnesium. Calcium Kd was lowest for pcSCP1a and highest for pcSCP1c. Site-directed mutagenesis of pcSCP1c residues to the amino acids of pcSCP1b decreased the calcium Kd, identifying residues outside the EF-hand domains that contribute to calcium binding in crayfish SCP. PMID- 25271109 TI - Benign chondroid syringoma (mixed tumor of skin) on the flank with satellites: case report and literature review. AB - BACKGROUND: Mixed tumor of skin (chondroid syringoma) is a rare skin tumor. METHODS: We report on the rare occasion of an atypical mixed tumor of skin (chondroid syringoma) in a 71-year old Caucasian male patient. RESULTS: The tumor presented as a firm subcutaneous nodule on his flank. Histopathologic investigations revealed a focally increased proliferative activity and satellites in the adipose tissue. This is in accordance with the diagnosis of an atypical chondroid syringoma. The differential diagnosis to malignant chondroid syringoma is discussed. The tumor was removed by delayed Mohs surgery. CONCLUSIONS: Atypical chondroid syringoma is a very rare subtype of mixed tumor of skin. It is an important differential diagnosis to malignant chondroid syringoma of skin. PMID- 25271108 TI - Interplay of drug metabolizing enzymes with cellular transporters. AB - Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug-drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes. PMID- 25271110 TI - Blockade of co-stimulation in chronic inflammatory diseases. AB - Costimulatory molecules are key elements in T cell activation. Therapeutic inhibition of costimulatory pathways have been recognized as valid therapeutic strategies in the treatment of various inflammatory diseases. This article will describe their mechanisms of action and will summarize the results from clinical trials in the field of rheumatologic diseases. PMID- 25271111 TI - Do primary health care nurses address cardiovascular risk in diabetes patients? AB - AIMS: To identify factors associated with assessment and nursing management of blood pressure, smoking and other major cardiovascular risk factors by primary health care nurses in Auckland, New Zealand. METHODS: Primary health care nurses (n = 287) were randomly sampled from the total (n=1091) identified throughout the Auckland region and completed a self-administered questionnaire (n = 284) and telephone interview. Nurses provided details for 86% (n =265) of all diabetes patients they consulted on a randomly selected day. RESULTS: The response rate for nurses was 86%. Of the patients sampled, 183 (69%) patients had their blood pressure measured, particularly if consulted by specialist (83%) and practice (77%) nurses compared with district (23%, p = 0.0003). After controlling for demographic variables, multivariate analyses showed patients consulted by nurses who had identified stroke as a major diabetes-related complication were more likely to have their blood pressure measured, and those consulted by district nurses less likely. Sixteen percent of patients were current smokers. Patients consulted by district nurses were more likely to smoke while, those >66 years less likely. Of those who wished to stop, only 50% were offered nicotine replacement therapy. Patients were significantly more likely to be advised on diet and physical activity if they had their blood pressure measured (p < 0.0001). CONCLUSIONS: Measurement of blood pressure and advice on diet or physical activity were not related to patient's cardiovascular risk profile and management of smoking cessation was far from ideal. Education of the community based nursing workforce is essential to ensure cardiovascular risk management becomes integrated into diabetes management. PMID- 25271112 TI - Follow-up of postpartum women with gestational diabetes mellitus (GDM). AB - AIM: The incidence of type 2 diabetes in postpartum women with gestational diabetes mellitus (GDM) is high, and blood glucose screening for postpartum women is recommended. Follow-up procedures for women with GDM in the postnatal period need to be improved. We investigated the incidence of GDM and the follow-up of women with GDM in Tianjin, China. METHODS: Postpartum women who delivered at Tianjin Obstetrics and Gynecology Hospital from January 1st, 2008 to December 31st, 2010 were interviewed by telephone about their blood glucose screening. Thirty obstetricians were interviewed to evaluate awareness about the importance of follow-up. RESULTS: The incidence rate of GDM increased from 6.9% in 2008, to 8.8% in 2009, and 9.9% in 2010. A total of 2152 women were interviewed, including 282 women (13.1%) screened for blood glucose. The top three reasons for failed blood glucose screening included: not being informed by their physicians, believing that GDM would disappear after delivery, and being occupied with the baby. Methods for GDM screening included testing of random blood glucose levels, fasting blood glucose levels, oral glucose tolerance, and glycosylated hemoglobin. Of the 30 obstetricians interviewed, 25 were aware of the need for blood glucose screening for women with GDM after delivery, but only 15 of them had informed their patients. CONCLUSION: In China, most women with GDM are not screened for type 2 diabetes after delivery. Standard clinical procedures that will enable and encourage all women to return for glucose screening following GDM are needed. PMID- 25271113 TI - Response of incretins (GIP and GLP-1) to an oral glucose load in female and male subjects with normal glucose tolerance. AB - The aim of this study was to analyze the blood glucose profile and the response of incretins in healthy young subjects by the 75 g oral glucose tolerance test (OGTT). We first reported that plasma glucose and GIP levels were higher in males during the early phase of the OGTT. PMID- 25271114 TI - Prediabetes is not independently associated with microalbuminuria in Korean general population: the Korea National Health and Nutrition Examination Survey 2011-2012 (KNHANES V-2,3). AB - We investigated the association between microalbuminuria and prediabetes in Korean population using data from the KNHANES 2011-2012. Prevalence of microalbuminuria was significantly increased in prediabetes group. However, the odds ratio became insignificant after adjustment for blood pressure, and the prevalence of microalbuminuria was not increased in prediabetic subjects without hypertension. PMID- 25271115 TI - Performance of glycated haemoglobin (HbA1c) as a screening test for diabetes and impaired glucose tolerance (IGT) in a high risk population--the Brazilian Xavante Indians. AB - AIMS: To examine the properties of HbA1c to detect diabetes and IGT in adult Brazilian Xavante Indians, a high risk population for diabetes. METHODS: The survey was carried out between October 2010 and January 2012 and based on a 75 g oral glucose tolerance test (OGTT). Basal and 2h capillary glycaemia were measured by HemoCue Glucose 201+; HbA1c using an automated high-performance liquid chromatography analyzer (Tosoh G7). RESULTS: 630 individuals aged >= 20 years were examined and 80 had a previous diagnosis of diabetes. Sensitivity, specificity and accuracy for HbA1c >= 6.5% (>= 48 mmol/mol) were 71.3%, 90.5% and 87.2%. The areas under the ROC curve (AUC) was 0.88 (95%CI: 0.83-0.93). To identify IGT, HbA1c values between 5.7% and 6.4% (39-47 mmol/mol) presented sensitivity, specificity and accuracy of 87.2%, 24.7% and 51.4%, with an AUC of 0.62 (95%CI: 0.57-0.67). CONCLUSIONS: The ADA/WHO proposed cut-off of 6.5% (48 mmol/mol) for HbA1c was adequate to detect diabetes among the Xavante. However, the performance of the ADA proposed cut-off points for pre-diabetes, when used to detect IGT was inadequate and should not be recommended. PMID- 25271116 TI - Randomization to a low-carbohydrate diet advice improves health related quality of life compared with a low-fat diet at similar weight-loss in Type 2 diabetes mellitus. AB - AIMS: To compare the effects on health-related quality of life (HRQoL) of a 2 year intervention with a low-fat diet (LFD) or a low-carbohydrate diet (LCD) based on four group-meetings to achieve compliance. To describe different aspects of taking part in the intervention following the LFD or LCD. METHODS: Prospective, randomized trial of 61 adults with Type 2 diabetes mellitus. The SF 36 questionnaire was used at baseline, 6, 12 and 24 months. Patients on LFD aimed for 55-60 energy percent (E%) and those on LCD for 20 E% from carbohydrates. The patients were interviewed about their experiences of the intervention. RESULTS: Mean body-mass-index was 32.7 +/- 5.4 kg/m(2) at baseline. Weight-loss did not differ between groups and was maximal at 6 months, LFD: -3.99 +/- 4.1 kg, LCD: 4.31 +/- 3.6 kg (p<0.001 within groups). There was an increase in the physical component score of SF-36 from 44.1 (10.0) to 46.7 (10.5) at 12 months in the LCD group (p < 0.009) while no change occurred in the LFD group (p < 0.03 between groups). At 12 months the physical function, bodily pain and general health scores improved within the LCD group (p values 0.042-0.009) while there was no change within the LFD group. CONCLUSIONS: Weight-changes did not differ between the diet groups while improvements in HRQoL only occurred after one year during treatment with LCD. No changes of HRQoL occurred in the LFD group in spite of a similar reduction in body weight. PMID- 25271117 TI - An exploratory trial of basal and prandial insulin initiation and titration for type 2 diabetes in primary care with adjunct retrospective continuous glucose monitoring: INITIATION study. AB - AIMS: To evaluate basal and prandial insulin initiation and titration in people with type 2 diabetes mellitus (T2DM) in primary care and to explore the feasibility of retrospective-continuous glucose monitoring (r-CGM) in guiding insulin dosing. The new model of care features General Practitioners (GPs) and Practice Nurses (PNs) working in an expanded role, with Credentialed Diabetes Educator - Registered Nurse (CDE-RN) support. METHODS: Insulin-naive T2DM patients (HbA1c >7.5% [>58 mmol/mol] despite maximal oral therapy) from 22 general practices in Victoria, Australia commenced insulin glargine, with glulisine added as required. Each was randomised to receive r-CGM or self monitoring of blood glucose (SMBG). Glycaemic control (HbA1c) was benchmarked against specialist ambulatory patients referred for insulin initiation. RESULTS: Ninety-two patients mean age (range) 59 (28-77) years; 40% female; mean (SD) diabetes duration 10.5 (6.1) years participated. HbA1c decreased from (median (IQR)) 9.9 (8.8, 11.2)%; 85 (73, 99) mmol/mol to 7.3 (6.9, 7.8)%; 56 (52, 62) mmol/mol at 24 weeks (p < 0.0001). Comparing r-CGM (n = 46) with SMBG (n = 42), there were no differences in major hypoglycaemia (p=0.17) or DeltaHbA1c (p = 0.31). More r-CGM than SMBG participants commenced glulisine (26/48 vs. 7/44; p < 0.001). Results were comparable to 82 benchmark patients, with similar low rates of major hypoglycaemia (2/89 vs. 0/82; p = 0.17) and less loss to follow up in the INITIATION group (3/92 vs. 14/82; p = 0.002). CONCLUSIONS: Insulin initiation and titration for T2DM patients in primary care was safe and improved HbA1c with low rates of major hypoglycaemia. CDE-RNs were effective in a new consultant role. r-CGM use in primary care was feasible and enhanced post-prandial hyperglycaemia recognition. Trial registration ACTRN12610000797077. PMID- 25271118 TI - Symptoms of attention-deficit hyperactivity disorder, nonsyndromic orofacial cleft children, and dopamine polymorphisms: a pilot study. AB - PURPOSE: Attention-deficit hyperactivity disorder (ADHD) is a common childhood neurobehavioral disorder characterized by inattention, poor impulse control, and motor restlessness. Risk factors include familial stressors, anxiety disorders, learning disabilities, abnormal brain development, heritability, and dopamine polymorphisms. Children with an orofacial clefting (OFC) history are at increased risk of familial stressors, anxiety disorders, learning disabilities, and abnormal brain development. Given this overlap, we present a conceptual model proposing that children with OFC may be more likely to exhibit ADHD symptoms than children without and explore this relationship using pilot data. DESIGN: This cross-sectional pilot study included 29 children with OFC or a first-degree relative with OFC recruited through a cleft research registry. METHODS: The Disruptive Behavior Disorder Scale was used to collect data on children's ADHD symptoms. Saliva or whole blood samples were collected from children and parents for DNA analyses. ADHD-associated dopamine polymorphisms within the DRD4, DRD2, and DAT1 genes were genotyped. We tested for associations between presence of OFC and dopamine polymorphisms. Mixed-effects models tested whether children with OFC and dopamine polymorphisms had more ADHD symptoms. RESULTS: The DRD4 4-repeat allele was associated with increased inattentive ADHD symptoms (p = .03). Having the DRD2 Taq1A1 allele and OFC predicted fewer (p = .02) inattentive ADHD symptoms. Children with OFC were significantly less likely to have the DAT1 10 repeat allele (p = .04). CONCLUSIONS: Results indicate that further investigation among a larger sample of children with OFC is warranted, particularly for relationships with inattentive ADHD. PMID- 25271120 TI - Games of life and death: antibiotic resistance and production through the lens of evolutionary game theory. AB - In this review, we demonstrate how game theory can be a useful first step in modeling and understanding interactions among bacteria that produce and resist antibiotics. We introduce the basic features of evolutionary game theory and explore model microbial systems that correspond to some classical games. Each game discussed defines a different category of social interaction with different resulting population dynamics (exclusion, coexistence, bistability, cycling). We then explore how the framework can be extended to incorporate some of the complexity of natural microbial communities. Overall, the game theoretical perspective helps to guide our expectations about the evolution of some forms of antibiotic resistance and production because it makes clear the precise nature of social interaction in this context. PMID- 25271119 TI - Collective antibiotic resistance: mechanisms and implications. AB - In collective resistance, microbial communities are able to survive antibiotic exposures that would be lethal to individual cells. In this review, we explore recent advances in understanding collective resistance in bacteria. The population dynamics of 'cheating' in a system with cooperative antibiotic inactivation have been described, providing insight into the demographic factors that determine resistance allele frequency in bacteria. Extensive work has elucidated mechanisms underlying collective resistance in biofilms and addressed questions about the role of cooperation in these structures. Additionally, recent investigations of 'bet-hedging' strategies in bacteria have explored the contributions of stochasticity and regulation to bacterial phenotypic heterogeneity and examined the effects of these strategies on community survival. PMID- 25271121 TI - Functional adaptation underpinned the evolutionary assembly of the earliest vertebrate skeleton. AB - Conodonts are the first vertebrates to bear a mineralized skeleton, restricted to an array of tooth-like feeding elements. The functional implications for the development of tooth-like elements differentiated into two tissues is tested using 2D finite element modeling, mapping the patterns of stress and strain that elements with differing material properties exhibited during function. Addition of a stiff crown does not change the patterns of stress, rather it reduces the deformation of the element under the same force regime, and distributes stress more evenly across the element. The euconodont crown, like vertebrate dental enamel, serves to stiffen the element and protect the underlying dentine. Stiffness of the crown may be a contributing factor to the subsequent diversity of euconodont form, and logically function, by allowing a greater range of feeding strategies to be employed. The euconodont crown also serves as an analogue to enamel and enameloid, demonstrating that enamel-like tissues have evolved multiple times in independent vertebrate lineages, likely as a response to similar selective pressures. Conodonts can, therefore, serve as an independent test on hypotheses of the effect of ecology on the development of the vertebrate skeleton. PMID- 25271122 TI - Transfer and control of molecular chirality in the 1 : 2 host-guest supramolecular complex consisting of Mg(II)bisporphyrin and chiral diols: the effect of H-bonding on the rationalization of chirality. AB - A clear rationalization of the origin of chirality transfer from an optically active diol guest to an achiral Mg(ii)bisporphyrin host in a series of 1 : 2 host guest supramolecular complexes has been reported here that has so far remained the most outstanding issue for the chirogenic process. PMID- 25271123 TI - LC-MS-based urinary metabolite signatures in idiopathic Parkinson's disease. AB - Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). These body fluids include urine; however, the relationship between, specifically, urinary metabolic phenotypes and PD is not fully understood. In this study, urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using high-performance liquid chromatography coupled to high-resolution mass spectrometry. Our study revealed significant correlation between clinical phenotype and urinary metabolite profile. Metabolic profiles of idiopathic PD patients differed significantly and consistently from normal controls, with related metabolic pathway variations observed in steroidogenesis, fatty acid beta oxidation, histidine metabolism, phenylalanine metabolism, tryptophan metabolism, nucleotide metabolism, and tyrosine metabolism. In the fruit fly Drosophila melanogaster, the alteration of the kynurenine pathway in tryptophan metabolism corresponded with pathogenic changes in the alpha-synuclein overexpressed Drosophila model of PD. The results suggest that LC-MS-based urinary metabolomic profiling can reveal the metabolite signatures and related variations in metabolic pathways that characterize PD. Consistent PD-related changes across species may provide the basis for understanding metabolic regulation of PD at the molecular level. PMID- 25271124 TI - Relative quantification of multi-components in Panax notoginseng (Sanqi) by high performance liquid chromatography with mass spectrometry using mobile phase compensation. AB - Relative quantification of multi-components in complex mixture is significantly affected by the ionization variance caused by mobile phase composition in high performance liquid chromatography with electrospray ionization mass spectrometry (HPLC-ESI-MS) analyses. The normalization methods for eliminating the variance are still less investigated. Herein, the mobile-phase compensation (MPC) method was applied to overcome the above problem. The developed method was firstly used for convenient evaluation of the coeluent interference and subsequently applied for relative quantification of the identified multi-components in Panax notoginseng (Sanqi) samples. The good linearity, precision and low limit of quantification of targeted analytes confirmed that the MPC-HPLC-ESI-MS method in gradient elution could achieve the isocratic test results compared with classical HPLC-ESI-MS. The established method was used for relative quantification of the minor Sanqi saponins by their detected peak areas divided by that of ginsenoside Rd. The results demonstrated the potential of the newly developed method for obtaining the normalized data shared in different laboratories. PMID- 25271125 TI - Retirement, age, gender and mental health: findings from the 45 and Up Study. AB - OBJECTIVES: To examine the relationships of retirement and reasons for retirement with psychological distress in men and women at the age of 45-79 years. METHOD: Data from 202,584 Australians participating in the large-scale 45 and Up Study was used. Psychological distress was measured by the Kessler psychological distress scale. Associations between different work status and reasons for retirement with psychological distress were assessed for men and women at different ages using logistic regression. RESULTS: Being fully retired or unemployed was associated with the high levels of psychological distress compared to being in paid work for men and women aged 45-64 (p < 0.0001), and for men aged 65-74 years (p <= 0.0014). At the age of 75-79 years, there was no difference in psychological distress between different work statuses. Among retirees, retirement due to ill health, being made redundant or caring duty was associated with the high level of psychological distress. CONCLUSION: The association between work and mental health underscores the importance of policies and strategies to encourage and enable people to continue in the workforce after age 55, particularly for men. Important reasons for retirement with worse mental health outcomes include redundancy, ill health and needing to care for family or a friend. These circumstances will affect whether a person can continue working and their risk of poor mental health, and both considerations should be addressed in developing approaches for maintaining older workers or assisting them with their retirement transition. PMID- 25271126 TI - A prawn core histone 4: derivation of N- and C-terminal peptides and their antimicrobial properties, molecular characterization and mRNA transcription. AB - This study investigates the complete molecular characterization including bioinformatics characterization, gene expression, synthesis of N and C terminal peptides and their antimicrobial activity of the core histone 4 (H4) from freshwater giant prawn Macrobrachium rosenbergii (Mr). A cDNA encoding MrH4 was identified from the constructed cDNA library of M. rosenbergii during screening and the sequence was obtained using internal sequencing primers. The MrH4 coding region possesses a polypeptide of 103 amino acids with a calculated molecular weight of 11kDa and an isoelectric point of 11.5. The bioinformatics analysis showed that the MrH4 polypeptide contains a H4 signature at (15)GAKRH(19). Multiple sequence alignment of MrH4 showed that the N-terminal (21-42) and C terminal (87-101) antimicrobial peptide regions and the pentapeptide or H4 signature (15-19) are highly conserved including in humans. The phylogenetic tree formed two separate clades of vertebrate and invertebrate H4, wherein MrH4 was located within the arthropod monophyletic clade of invertebrate H4 groups. Three dimensional model of MrH4 was established using I-TASSER program and the model was validated using Ramachandran plot analysis. Schiffer-Edmundson helical wheel modeling was used to predict the helix propensity of N (21-42) and C (87-101) terminal derived Mr peptides. The highest gene expression was observed in gills and is induced by viral [white spot syndrome baculovirus (WSBV) and M. rosenbergii nodovirus (MrNV)] and bacterial (Aeromonas hydrophila and Vibrio harveyi) infections. The N and C terminal peptides were synthesized and their antimicrobial and hemolytic properties were examined. Both peptides showed activity against the tested Gram negative and Gram positive bacteria; however, the highest activity was noticed against Gram negative bacteria. Among the two peptides used in this study, C-terminal peptide yielded better results than the N terminal peptide. Therefore, C terminal peptide can be recommended for the development of an antimicrobial agent. PMID- 25271127 TI - Diagnosis of Takotsubo syndrome via the electrocardiogram. PMID- 25271128 TI - Role of PRC2-associated factors in stem cells and disease. AB - The Polycomb group (PcG) of proteins form chromatin-binding complexes with histone-modifying activity. The two main PcG repressive complexes studied (PRC1 and PRC2) are generally associated with chromatin in its repressed state. PRC2 is responsible for methylation of histone H3 at lysine 27 (H3K27me3), an epigenetic mark that is linked with numerous biological processes, including development, adult homeostasis and cancer. The core canonical complex PRC2, which contains the EZH1/2, SUZ12 and EED proteins, may be extended and functionally manipulated through interactions with several other proteins. In this review, we focus on these PRC2-associated proteins. As PRC2 functions are diverse, the variability conferred by these sub-stoichiometrically associated members may help to understand specific changes in PRC2 activity, chromatin recruitment and distribution required for gene repression. PMID- 25271131 TI - Human papillomavirus infection and pathogenesis in urothelial cells: a mini review. AB - Several recent studies described that high-risk human papillomavirus (HPV) infection could have a potential role in the development of malignancies other than cervical cancer, such as laryngeal carcinoma, penile carcinoma, and anal carcinoma. However, the etiological role of HPV infection in the pathogenesis of urinary tract has not been clarified. Many epidemiological studies demonstrated that HPV infections frequently occur in the external genitalia through sexual contact; however, it was reported that HPV infection could also occur in the urinary tract, including the urethra and urinary bladder. Some morphological changes of cells associated with HPV infection and mild atypical cells, suspected to be intraneoplasia, were seen in HPV-positive samples obtained from the urinary tract. Some clinical studies and meta-analysis have indicated that HPV infection is likely to have a certain etiological correlation with the development of bladder carcinoma, although its prevalence may vary according to HPV type, study population, region, histological type, detection methods, and other variables. According to the results of previous studies, the prevalence of HPV greatly widely varies in cases of bladder carcinoma. Further research by case-control or large-scales studies is thus required to reach a more definite conclusion. PMID- 25271132 TI - Spatial and temporal functional connectivity changes between resting and attentive states. AB - Remote brain regions show correlated spontaneous activity at rest within well described intrinsic connectivity networks (ICNs). Meta-analytic coactivation studies have uncovered networks similar to resting ICNs, suggesting that in task states connectivity modulations may occur principally within ICNs. However, it has also been suggested that specific "hub" regions dynamically link networks under different task conditions. Here, we used functional magnetic resonance imaging at rest and a continuous visual attention task in 16 participants to investigate whether a shift from rest to attention was reflected by within network connectivity modulation, or changes in network topography. Our analyses revealed evidence for both modulation of connectivity within the default-mode (DMN) and dorsal attention networks (DAN) between conditions, and identified a set of regions including the temporoparietal junction (TPJ) and posterior middle frontal gyrus (MFG) that switched between the DMN and DAN depending on the task. We further investigated the temporal nonstationarity of flexible (TPJ and MFG) regions during both attention and rest. This showed that moment-to-moment differences in connectivity at rest mirrored the variation in connectivity between tasks. Task-dependent changes in functional connectivity of flexible regions may, therefore, be understood as shifts in the proportion of time specific connections are engaged, rather than a switch between networks per se. This ability of specific regions to dynamically link ICNs under different task conditions may play an important role in behavioral flexibility. PMID- 25271133 TI - Protective effects of nutritional supplementation with arginine and glutamine on the penis of rats submitted to pelvic radiation. AB - Radiotherapy is widely used to treat pelvic malignancies, but normal tissues near the target tumour are often affected. Our aims were thus to determine whether the structural organization of the rat penis is altered by radiation, and whether supplementation with L-arginine (ARG) or L-glutamine (GLN) would have protective effects against these alterations. Groups of rats were treated with: no intervention (CONTR); pelvic radiation, followed by sacrifice 7 (RAD7) or 15 (RAD15) days later; and pelvic radiation, daily supplementation with ARG or GLN, followed by sacrifice 7 (RAD7+ARG, RAD7+GLN) or 15 (RAD15+ARG, RAD15+GLN) days after radiation. Structural components in the corpus cavernosum (CC), tunica albuginea of the corpus spongiosum (TACS) and urethral epithelium (UE) were analysed using stereological and immunohistochemical methods. The results showed that in the CC, connective tissue was increased by 18% in RAD15 (p < 0.04), but this change was partially prevented in RAD15+GLN (p < 0.05) and RAD15+ARG (p < 0.04). The fibrous matrix of the CC trabeculae stained evenly for collagen type I. In RAD15, the intensity of the labelling was increased, whereas in RAD15+GLN and RAD15+ARG the staining was similar to that of CONTR. No staining changes were seen in the groups that were sacrificed 7 days after radiation. Cavernosal elastic fibre content in RAD15 was increased by 61% (p < 0.004), and this was prevented in RAD15+ARG (p < 0.004) but not in RAD15+GLN. In TACS, the amino acids protected (p < 0.02) against the radiation-induced 92% increase in elastic fibre content, but only in RAD15. Cell density in the UE, as well as UE thickness, were reduced by 30% in RAD15 (p < 0.004), and there were protective effects of both amino acids. In conclusion, radiation-induced alterations in penile structures tend to be more pronounced 15 days after radiation session. Both ARG and GLN have protective effects against these changes, with the former being slightly more effective. PMID- 25271134 TI - Correlates of poor perinatal outcomes in non-hospital births in the context of weak health system: the Nigerian experience. AB - BACKGROUND: Nigeria's high perinatal mortality rate (PNMR) could be most effectively reduced by targeting factors that are associated with increased newborn deaths. Low access to skilled birth attendants (SBAs) and weak health system are recognized factors associated with high PNMR but other socio demographic and reproductive factors could have significant influences as well. Identification of the major factors associated with high PNMR would be required in designing interventions to improve perinatal outcomes. METHODS: For this cross sectional study, data from the Nigeria Demographic and Health Survey 2008 were used to estimate the PNMR of non-hospital births in identified socio-demographic and reproductive situations that are known to influence PNMR. The estimated PNMR were compared using logistic regression analysis. RESULTS: The PNMR was 36 per 1000 live births. North central region had the lowest PNMR while the south east region had the highest rate (odds ratio 1.59; 95% CI: 1.03, 2.45). Other correlates of high PNMR were belonging to the poorest wealth quintile (odds ratio 1.87; 95% CI: 1.30, 2.70), maternal age group 15-19 years (odds ratio 1.59; 95% CI: 1.05, 2.22), multiple birth (odds ratio 3.12; 95% CI: 2.11, 4.59), history of previous perinatal death (odds ratio 3.31; 95% CI: 2.73, 4.02), birth interval shorter than 18 months (odds ratio 1.65; 95% CI: 1.26, 2.17) and having a small birth size (odds ratio 2.56; 95% CI 1.79, 3.69). Birth attendant, place of birth, parity, maternal education and rural/urban residence had no association with PNMR. CONCLUSIONS: Reproductive factors that require midwifery skills were found to contribute most to PNMR. We recommend general strengthening of the health system, recruitment of SBAs and retraining of available birth attendants with emphasis on identification and referral of complicated cases. Family planning should be a core MCH activity to address the issues of teenage pregnancy and short pregnancy intervals. PMID- 25271135 TI - Prediction of early response to uterine artery embolization in fibroids: value of MR signal intensity ratio. AB - OBJECTIVE: To quantitatively assess magnetic resonance (MR) imaging findings that help predict early post-therapeutic response in fibroids following uterine artery embolization (UAE). METHODS: Fifteen patients with a total of 52 fibroids underwent UAE. The signal intensity ratio (SIR) on T1-, T2-, diffusion weighted and gadolinium-enhanced images was calculated by dividing the mean signal intensity of fibroids by that of the abdominal rectus muscle. Fibroids were divided into the two groups: affected (post-UAE volume reduction rate>median of all fibroids) and unaffected (=12 and >=6 months of continuous eligibility preinitiation (baseline) and postinitiation (study period), respectively. Patients were stratified by preinitiation T assay. Maintenance dose attainment month was determined using unadjusted generalized estimating equations regression to compare dose relative to RSD month by month. Outcomes included maintenance dose attainment month, time to stopping of index TTA refills or a claim for nonindex testosterone replacement therapy (TRT), and proportion of patients with study period T assay or diagnosis of hypogonadism (HG) or another low testosterone condition, and were compared using chi-square and Wilcoxon rank sum tests for categorical and continuous variables, respectively. Maintenance dose was attained in Month 4 postinitiation, at 115.2% of RSD. Approximately 46% of patients had a preinitiation T assay; these men were more likely to receive a diagnosis of HG or another low testosterone condition, to have a follow-up T assay, to continue treatment by filling a nonindex TRT, and less likely to stop refilling treatment with their index TTA. Differences in care following TTA initiation suggest that preinitiation T assays (i.e., guideline-based care) may be helpful in ensuring treatment benefits. PMID- 25271143 TI - Intervention to improve intensive care nurses' knowledge of sedation assessment and management. AB - BACKGROUND: Sedation management is an integral component of critical care practice. It requires the greatest attention of critical care practitioners because it carries significant risks to patients. Therefore, it is imperative that nurses are aware of potential adverse consequences of sedation therapy and current sedation practice recommendations. AIMS AND OBJECTIVES: To evaluate the impact of an educational intervention on nurses' knowledge of sedation assessment and management. DESIGNS AND METHODS: A quasi-experimental design with a pre- and post-test method was used. The educational intervention included theoretical sessions on assessing and managing sedation and hands-on sedation assessment practice using the Richmond Agitation Sedation Scale. Its effect was measured using self-administered questionnaire, completed at the baseline level and 3 months following the intervention. RESULTS: Participants were 68 registered nurses from an intensive care unit of a teaching hospital in Malaysia. Significant increases in overall mean knowledge scores were observed from pre- to post-intervention phases (mean of 79.00 versus 102.00, p < 0.001). Nurses with fewer than 5 years of work experience, less than 26 years old, and with a only basic nursing education had significantly greater level of knowledge improvement at the post-intervention phase compared to other colleagues, with mean differences of 24.64 (p = 0.001), 23.81 (p = 0.027) and 27.25 (p = 0.0001), respectively. A repeated-measures analysis of variance revealed a statistically significant effect of educational intervention on knowledge score after controlling for age, years of work and level of nursing education (p = 0.0001, etap (2) = 0.431). CONCLUSION: An educational intervention consisting of theoretical sessions and hands-on sedation assessment practice was found effective in improving nurses' knowledge and understanding of sedation management. RELEVANCE TO CLINICAL PRACTICE: This study highlighted the importance of continuing education to increase nurses' understanding of intensive care practices, which is vital for improving the quality of patient care. PMID- 25271144 TI - Liver cancer biopsy--back to the future?! PMID- 25271145 TI - Prevalence of refractive error, presbyopia and spectacle coverage in Kahama District, Tanzania: a rapid assessment of refractive error. AB - BACKGROUND: In Tanzania, the prevalence of refractive error and presbyopia have not been comprehensively assessed, limiting appropriate planning and implementation of delivery of vision care. This study sought to determine the prevalence of refractive error and presbyopia, spectacle coverage and the barriers to uptake of refractive services in people aged 15 years and older in the Kahama district of Tanzania. METHODS: A cross-sectional community-based survey was conducted using 54 randomly selected clusters. Respondents 15 years and older were interviewed and underwent standardised clinical eye examinations. Uncorrected refractive error (URE) was defined as presenting vision worse than 6/12 that could be corrected to better than 6/12 using a pinhole. Spectacle coverage was defined as the proportion of need that was met (those that improved from unaided vision with their own spectacle correction). RESULTS: A total of 3,230 subjects (99.75 per cent of 3,240 eligible) participated in the study with 57.2 per cent males and the median age of participants was 35 years (inter quartile range, 24 to 49). The prevalence of visual impairment was 10.4 per cent (95% CI 9.4 to 11.4) and was lower in those who had completed their primary school education (odds ratio (OR) 0.54, 95% CI: 0.40 to 0.72) and highest in subjects 40 years and older (OR 3.17, 95% CI: 2.14 to 4.70) and farmers (OR 8.57 95% CI: 2.27 to 32.43). Refractive error prevalence was 7.5 per cent (95% CI: 6.65 to 8.54) and this was highest in participants over 40 years (OR 1.60, 95% CI: 1.14 to 2.25) and in students (OR 3.64, 95% CI: 1.35 to 9.86). Prevalence of presbyopia was 46.5 per cent (773/1,663, 95% CI: 44.34 to 48.75). Spectacle coverage for refractive error and presbyopia was 1.69% (95% CI: 0 to 3.29) and 0.42% (95% CI: 0 to 1.26), respectively. CONCLUSION: Uncorrected refractive error is a public health challenge in the Kahama district and sustainable service delivery and health promotion efforts are needed. PMID- 25271146 TI - Novel role of cystic fibrosis transmembrane conductance regulator in maintaining adult mouse olfactory neuronal homeostasis. AB - The olfactory epithelium (OE) of mice deficient in cystic fibrosis transmembrane conductance regulator (CFTR) exhibits ion transport deficiencies reported in human CF airways, as well as progressive neuronal loss, suggesting defects in olfactory neuron homeostasis. Microvillar cells, a specialized OE cell-subtype, have been implicated in maintaining tissue homeostasis. These cells are endowed with a PLCbeta2/IP3 R3/TRPC6 signal transduction pathway modulating release of neuropeptide Y (NPY), which stimulates OE stem cell activity. It is unknown, however, whether microvillar cells also mediate the deficits observed in CFTR null mice. Here we show that Cftr mRNA in mouse OE is exclusively localized in microvillar cells and CFTR immunofluorescence is coassociated with the scaffolding protein NHERF-1 and PLCbeta2 in microvilli. In CFTR-null mice, PLCbeta2 was undetectable, NHERF-1 mislocalized, and IP3 R3 more intensely stained, along with increased levels of NPY, suggesting profound alteration of the PLCbeta2/IP3 R3 signaling pathway. In addition, basal olfactory neuron homeostasis was altered, shown by increased progenitor cell proliferation, differentiation, and apoptosis and by reduced regenerative capacity following methimazole-induced neurodegeneration. The importance of CFTR in microvillar cells was further underscored by decreased thickness of the OE mucus layer and increased numbers of immune cells within this tissue in CFTR-KO mice. Finally, we observed enhanced immune responses to an acute viral-like infection, as well as hyper-responsiveness to chemical and physical stimuli applied intranasally. Taken together, these data strengthen the notion that microvillar cells in the OE play a key role in maintaining tissue homeostasis and identify several mechanisms underlying this regulation through the multiple functions of CFTR. PMID- 25271147 TI - Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus. AB - Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK-801. Further work revealed that the NR2A-type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A-preferring antagonist (NVP-A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B-preferring antagonist (Ro25) was without effect. Post C significantly up regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca(2+) influx and activation/phosphorylation of CamKIIalpha at Thr(286), effects that were NR2A mediated as they were blocked by NVP-A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB-dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP-A. Taken as a whole, the current study provides evidence that NR2A-activation and downstream prosurvival signaling is a critical mediator of Post C-induced neuroprotection and cognitive enhancement following GCI. PMID- 25271149 TI - Risk factors associated with adverse events of acupuncture: a prospective study. AB - OBJECTIVE: Mild adverse events (AEs) are common with acupuncture, but the risk factors remain unclear. A prospective study using a standardised AE assessment and acupuncture protocol was undertaken to address the question. METHODS: A 20 item AE report form investigated local and systemic AEs in 150 adults with insomnia randomised to receive traditional, minimal and non-invasive sham acupuncture. Sociodemographic, clinical and psychological variables at baseline and past history and perceived credibility of acupuncture were assessed. RESULTS: The incidence of any AEs per patient was 42.4% with traditional acupuncture, 40.7% with minimal acupuncture and 16.7% with non-invasive sham acupuncture. Traditional and minimal acupuncture were associated with a greater number of local AEs, while the presence of a chronic medical condition was predictive of fewer local and systemic AEs. Greater severity of insomnia, anxiety, depression, somatic symptoms and pain catastrophising thoughts were associated with lower risk, but most of the significant correlations disappeared after logistic regression. Divorce and widowhood were the only significant sociodemographic variables, while previous acupuncture treatment and perceived credibility of acupuncture were found to be unrelated. The risk of any AEs was higher in participants receiving traditional acupuncture (OR 4.26) and minimal acupuncture (OR 4.27) and in those without medical comorbidity (OR 3.39). CONCLUSIONS: The prevalence of AEs was higher than usual, probably due to the low threshold in our definition of AEs and the systematic collection from the patients' perspective. Baseline variables were largely unable to predict AEs associated with acupuncture. Further studies should explore the roles of practitioners, patients' anxiety during treatment and patient-practitioner interactions. TRIAL REGISTRATION NUMBER: NCT01707706. PMID- 25271148 TI - Placenta growth factor induces invasion and activates p70 during rapamycin treatment in trophoblast cells. AB - PROBLEM: Aberrant trophoblast invasion has been associated with human intrauterine growth restriction (IUGR) and preeclampsia (PE). Our objective was to determine placenta growth factor (PlGF)-mediated regulation of cell invasion in trophoblast cells with reduced mammalian target of Rapamycin (mTOR) signaling. METHOD OF STUDY: First trimester SW 71 trophoblast cells were subjected to invasion assays with the following conditions: 10% FBS, 10% FBS with Rapamycin, and 10% FBS with Rapamycin and PlGF. mTOR siRNA was also done in these cells. Western blots were performed on cell lysates with antibodies against phospho- and total mTOR, 70-kDa ribosomal protein kinase I (p70), 4EBP1, extracellular regulated kinase (ERK), and phosphatidylinositol-3 kinase (AKT). RESULTS: Compared to controls, trophoblast cells showed: (i) a 33% decrease in invasion following Rapamycin treatment, (ii) protection from decreased invasion following Rapamycin and PlGF treatment, (iii) a 31% decrease in mTOR phosphorylation with Rapamycin, (iv) increased phosphorylation of p70 (43%) with Rapamycin and PlGF, and (v) a 76% decrease in invasion following mTOR depletion. CONCLUSION: We conclude that first trimester trophoblast invasion is functionally decreased when phosphorylation of mTOR is prevented and this decrease is recovered with the addition of PlGF. Mechanistically, this recovery involves the phosphorylation of p70 independent of mTOR. PMID- 25271150 TI - Influence of pig rennet on fatty acid composition, volatile molecule profile, texture and sensory properties of Pecorino di Farindola cheese. AB - BACKGROUND: Pig rennet is traditionally used in Pecorino di Farindola cheese. In this study, different Pecorino cheeses obtained using calf, kid and pig rennets were compared in terms of fatty acids, volatile molecule profile, texture and sensory properties during ripening. RESULTS: The rennet type influenced the fatty acid composition of cheeses, though palmitic, myristic and oleic acids were always predominant. The analysis of volatiles by SPME-GC/MS showed that Pecorino from calf rennet, at the end of ripening, was the least 'evolved' in terms of volatile profile. SPME-GC/MS analysis revealed that cheeses from calf rennet showed the slowest accumulation of free fatty acids over ripening time. Volatile data permitted the differentiation of cheese samples ripened from 30 to 180 days according to the rennet used. Texture analysis differentiated cheeses made with pig and calf rennet from those made with kid rennet, which were less hard and more elastic than the former. Also sensory analysis differentiated cheese samples on the basis of rennet type, and cheeses made with pig rennet showed the lowest elasticity, bitter taste and fruity and hay flavour intensities. CONCLUSION: Pig rennet is fundamental to determine the quality parameters of Pecorino di Farindola cheese and could be used to impart peculiar quality features to ewe's milk cheeses. PMID- 25271151 TI - Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. AB - Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tumoral resistance to immune rejection. In humans, constitutive expression of IDO1 has been observed in several tumor types. However, a comprehensive analysis of its expression in normal and tumor tissues is still required to anticipate the risks and potential benefits of IDO1 inhibitors. Using a newly validated monoclonal antibody to human IDO1, we performed an extensive immunohistochemical analysis of IDO1 expression in normal and tumor tissues. In normal tissues, IDO1 was expressed by endothelial cells in the placenta and lung and by epithelial cells in the female genital tract. In lymphoid tissues, IDO1 was expressed in mature dendritic cells with a phenotype (CD83(+), DC-LAMP(+), langerin(-), CD123( ), CD163(-)) distinct from plasmacytoid dendritic cells. Importantly, IDO1 expressing dendritic cells were not enriched in tumor-draining lymph nodes, in contrast with previously reported findings. IDO1-expressing cells were observed in a large fraction (505/866, 58%) of human tumors. They comprised tumor cells, endothelial cells, and stromal cells in proportions that varied depending on the tumor type. Tumors showing the highest proportions of IDO1-immunolabeled samples were carcinomas of the endometrium and cervix, followed by kidney, lung, and colon. This hierarchy of IDO1 expression was confirmed by gene expression data mined from The Cancer Genome Atlas database. Expression of IDO1 may be used to select tumors likely to benefit from targeted therapy with IDO1 inhibitors. PMID- 25271152 TI - Class IIa histone deacetylases are conserved regulators of circadian function. AB - Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID- 25271153 TI - Forkhead transcription factor FOXO3a levels are increased in Huntington disease because of overactivated positive autofeedback loop. AB - Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by an increased number of CAG repeats in the HTT gene coding for huntingtin. Decreased neurotrophic support and increased mitochondrial and excitotoxic stress have been reported in HD striatal and cortical neurons. The members of the class O forkhead (FOXO) transcription factor family, including FOXO3a, act as sensor proteins that are activated upon decreased survival signals and/or increased cellular stress. Using immunocytochemical screening in mouse striatal Hdh(7/7) (wild type), Hdh(7/109) (heterozygous for HD mutation), and Hdh(109/109) (homozygous for HD mutation) cells, we identified FOXO3a as a differentially regulated transcription factor in HD. We report increased nuclear FOXO3a levels in mutant Hdh cells. Additionally, we show that treatment with mitochondrial toxin 3-nitropropionic acid results in enhanced nuclear localization of FOXO3a in wild type Hdh(7/7) cells and in rat primary cortical neurons. Furthermore, mRNA levels of Foxo3a are increased in mutant Hdh cells compared with wild type cells and in 3-nitropropionic acid-treated primary neurons compared with untreated neurons. A similar increase was observed in the cortex of R6/2 mice and HD patient post-mortem caudate tissue compared with controls. Using chromatin immunoprecipitation and reporter assays, we demonstrate that FOXO3a regulates its own transcription by binding to the conserved response element in Foxo3a promoter. Altogether, the findings of this study suggest that FOXO3a levels are increased in HD cells as a result of overactive positive feedback loop. PMID- 25271154 TI - Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet beta cell. AB - Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in beta cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of beta cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca(2+), which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1(+/-) mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca(2+) regulation in Pdx-1-deficient states. PMID- 25271156 TI - Identification of serine 348 on the apelin receptor as a novel regulatory phosphorylation site in apelin-13-induced G protein-independent biased signaling. AB - Phosphorylation plays vital roles in the regulation of G protein-coupled receptor (GPCR) functions. The apelin and apelin receptor (APJ) system is involved in the regulation of cardiovascular function and central control of body homeostasis. Here, using tandem mass spectrometry, we first identified phosphorylated serine residues in the C terminus of APJ. To determine the role of phosphorylation sites in APJ-mediated G protein-dependent and -independent signaling and function, we induced a mutation in the C-terminal serine residues and examined their effects on the interaction between APJ with G protein or GRK/beta-arrestin and their downstream signaling. Mutation of serine 348 led to an elimination of both GRK and beta-arrestin recruitment to APJ induced by apelin-13. Moreover, APJ internalization and G protein-independent ERK signaling were also abolished by point mutation at serine 348. In contrast, this mutant at serine residues had no demonstrable impact on apelin-13-induced G protein activation and its intracellular signaling. These findings suggest that mutation of serine 348 resulted in inactive GRK/beta-arrestin. However, there was no change in the active G protein thus, APJ conformation was biased. These results provide important information on the molecular interplay and impact of the APJ function, which may be extrapolated to design novel drugs for cardiac hypertrophy based on this biased signal pathway. PMID- 25271155 TI - The mammalian circadian clock protein period counteracts cryptochrome in phosphorylation dynamics of circadian locomotor output cycles kaput (CLOCK). AB - The circadian transcription factor CLOCK exhibits a circadian oscillation in its phosphorylation levels. Although it remains unclear whether this phosphorylation contributes to circadian rhythm generation, it has been suggested to be involved in transcriptional activity, intracellular localization, and degradative turnover of CLOCK. Here, we obtained direct evidence that CLOCK phosphorylation may be essential for autonomous circadian oscillation in clock gene expression. Importantly, we found that the circadian transcriptional repressors Cryptochrome (CRY) and Period (PER) showed an opposite effect on CLOCK phosphorylation; CRY impaired BMAL1-dependent CLOCK phosphorylation, whereas PER protected the phosphorylation against CRY. Interestingly, unlike PER1 and PER2, PER3 did not exert a protective action, which correlates with the phenotypic differences among mice lacking the Per genes. Further studies on the regulatory mechanism of CLOCK phosphorylation would thus lead to elucidation of the mechanism of CRY-mediated transcriptional repression and an understanding of the true role of PER in the negative feedback system. PMID- 25271157 TI - Identification of palmitoyltransferase and thioesterase enzymes that control the subcellular localization of axon survival factor nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). AB - The NAD-synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is a critical survival factor for axons and its constant supply from neuronal cell bodies into axons is required for axon survival in primary culture neurites and axon extension in vivo. Recently, we showed that palmitoylation is necessary to target NMNAT2 to post-Golgi vesicles, thereby influencing its protein turnover and axon protective capacity. Here we find that NMNAT2 is a substrate for cytosolic thioesterases APT1 and APT2 and that palmitoylation/depalmitoylation dynamics are on a time scale similar to its short half-life. Interestingly, however, depalmitoylation does not release NMNAT2 from membranes. The mechanism of palmitoylation-independent membrane attachment appears to be mediated by the same minimal domain required for palmitoylation itself. Furthermore, we identify several zDHHC palmitoyltransferases that influence NMNAT2 palmitoylation and subcellular localization, among which a role for zDHHC17 (HIP14) in neuronal NMNAT2 palmitoylation is best supported by our data. These findings shed light on the enzymatic regulation of NMNAT2 palmitoylation and highlight individual thioesterases and palmitoyltransferases as potential targets to modulate NMNAT2-dependent axon survival. PMID- 25271158 TI - Glucocorticoid-induced S-adenosylmethionine enhances the interferon signaling pathway by restoring STAT1 protein methylation in hepatitis B virus-infected cells. AB - Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon alpha (IFN-alpha). An alternative approach to increase the response rate of IFN-alpha might be to immunologically stimulate the host with glucocorticoids (GCs) before treatment with IFN-alpha, but the underlying mechanism remains unclear. We hypothesized that the GCs enhance IFN signaling by inducing S-adenosylmethionine (AdoMet) when hepatitis B virus (HBV) replication was effectively suppressed by IFN-alpha. Here, we investigated the effect of GCs and IFN-alpha on AdoMet production and methionine adenosyltransferase 1A (MAT1A) expression in vitro. Furthermore, we determined whether post-transcriptional regulation is involved in HBV-repressed MAT1A expression and AdoMet production induced by dexamethasone (Dex). We found that AdoMet homeostasis was disrupted by Dex and that Dex directly regulated MAT1A expression by enhancing the binding of the glucocorticoid receptor (GR) to the glucocorticoid-response element (GRE) of the MAT1A promoter. HBV reduced AdoMet production by increasing methylation at GRE sites within the MAT1A promoter. The X protein of hepatitis B virus led to hypermethylation in the MAT1A promoter by recruiting DNA methyltransferase 1, and it inhibited GR binding to the GRE in the MAT1A promoter. Dex could increase an antiviral effect by inducing AdoMet production via a positive feedback loop when HBV is effectively suppressed by IFN-alpha, and the mechanism that involves Dex induced AdoMet could increase STAT1 methylation rather than STAT1 phosphorylation. These findings provide a possible mechanism by which GC-induced AdoMet enhances the antiviral activity of IFN-alpha by restoring STAT1 methylation in HBV-infected cells. PMID- 25271159 TI - Loss of vacuolar H+-ATPase activity in organelles signals ubiquitination and endocytosis of the yeast plasma membrane proton pump Pma1p. AB - Yeast mutants lacking the intracellular V-ATPase proton pump (vma mutants) have reduced levels of the Pma1p proton pump at the plasma membrane and increased levels in organelles including the vacuolar lumen. We examined the mechanism and physiological consequences of Pma1p mislocalization. Pma1p is ubiquitinated in vma mutants, and ubiquitination depends on the ubiquitin ligase Rsp5p and the arrestin-related adaptor protein Rim8p. vma mutant strains containing rsp5 or rim8 mutations maintain Pma1p at the plasma membrane, suggesting that ubiquitination is required for Pma1p internalization. Acute inhibition of V ATPase activity with concanamycin A triggers Pma1p ubiquitination and internalization. In an endocytosis-deficient mutant (end4Delta) Pma1p is ubiquitinated but retained at the plasma membrane during concanamycin A treatment. Consistent with specificity in signaling loss of V-ATPase activity to Pma1p, another plasma membrane transporter, Mup1p, is not internalized in a vma mutant, and loss of the Mup1p adaptor Art1p does not prevent Pma1p internalization in a vma mutant. Very poor growth of vma2 rsp5-1 and vma2 rim8Delta double mutants suggests that Pma1p internalization benefits the vma mutants. We hypothesize that loss of V-ATPase-mediated organelle acidification signals ubiquitination, internalization, and degradation of a portion of Pma1p as a means of balancing overall pH homeostasis. PMID- 25271160 TI - Mutational analysis of cysteine residues of the insect odorant co-receptor (Orco) from Drosophila melanogaster reveals differential effects on agonist- and odorant tuning receptor-dependent activation. AB - Insect odorant receptors are heteromeric odorant-gated cation channels comprising a conventional odorant-sensitive tuning receptor (ORx) and a highly conserved co receptor known as Orco. Orco is found only in insects, and very little is known about its structure and the mechanism leading to channel activation. In the absence of an ORx, Orco forms homomeric channels that can be activated by a synthetic agonist, VUAA1. Drosophila melanogaster Orco (DmelOrco) contains eight cysteine amino acid residues, six of which are highly conserved. In this study, we replaced individual cysteine residues with serine or alanine and expressed Orco mutants in Flp-In 293 T-Rex cells. Changes in intracellular Ca(2+) levels were used to determine responses to VUAA1. Replacement of two cysteines (Cys-429 and Cys-449) in a predicted intracellular loop (ICL3), individually or together, gave variants that all showed similar increases in the rate of response and sensitivity to VUAA1 compared with wild-type DmelOrco. Kinetic modeling indicated that the response of the Orco mutants to VUAA1 was faster than wild-type Orco. The enhanced sensitivity and faster response of the Cys mutants was confirmed by whole-cell voltage clamp electrophysiology. In contrast to the results from direct agonist activation of Orco, the two cysteine replacement mutants when co expressed with a tuning receptor (DmelOR22a) showed an ~10-fold decrease in potency for activation by 2-methyl hexanoate. Our work has shown that intracellular loop 3 is important for Orco channel activation. Importantly, this study also suggests differences in the structural requirements for the activation of homomeric and heteromeric Orco channel complexes. PMID- 25271161 TI - Molecular basis determining inhibition/activation of nociceptive receptor TRPA1 protein: a single amino acid dictates species-specific actions of the most potent mammalian TRPA1 antagonist. AB - The transient receptor potential ankyrin 1 (TRPA1) is a Ca(2+)-permeable, nonselective cation channel mainly expressed in a subset of nociceptive neurons. TRPA1 functions as a cellular sensor detecting mechanical, chemical, and thermal stimuli. Because TRPA1 is considered to be a key player in nociception and inflammatory pain, TRPA1 antagonists have been developed as analgesic agents. Recently, by utilizing species differences, we identified the molecular basis of the antagonistic action of A967079, one of the most potent mammalian TRPA1 antagonists. Here, we show a unique effect of A967079 on TRPA1 from diverse vertebrate species, i.e. it acts as an agonist but not as an antagonist for chicken and frog TRPA1s. By characterizing chimeric channels of human and chicken TRPA1s, as well as point mutants, we found that a single specific amino acid residue located within the putative fifth transmembrane domain was involved in not only the stimulatory but also the inhibitory actions of A967079. AP18, structurally related to A967079, exerted similar pharmacological properties to A967079. Our findings and previous reports on species differences in the sensitivity to TRPA1 antagonists supply useful information in the search for novel analgesic medicines targeting TRPA1. PMID- 25271162 TI - Kinetics of cellobiohydrolase (Cel7A) variants with lowered substrate affinity. AB - Cellobiohydrolases are exo-active glycosyl hydrolases that processively convert cellulose to soluble sugars, typically cellobiose. They effectively break down crystalline cellulose and make up a major component in industrial enzyme mixtures used for deconstruction of lignocellulosic biomass. Identification of the rate limiting step for cellobiohydrolases remains controversial, and recent reports have alternately suggested either association (on-rate) or dissociation (off rate) as the overall bottleneck. Obviously, this uncertainty hampers both fundamental mechanistic understanding and rational design of enzymes with improved industrial applicability. To elucidate the role of on- and off-rates, respectively, on the overall kinetics, we have expressed a variant in which a tryptophan residue (Trp-38) in the middle of the active tunnel has been replaced with an alanine. This mutation weakens complex formation, and the population of substrate-bound W38A was only about half of the wild type. Nevertheless, the maximal, steady-state rate was twice as high for the variant enzyme. It is argued that these opposite effects on binding and activity can be reconciled if the rate limiting step is after the catalysis (i.e. in the dissociation process). PMID- 25271163 TI - Chemical structure and morphology of dorsal root ganglion neurons from naive and inflamed mice. AB - Fourier transform infrared spectromicroscopy provides label-free imaging to detect the spatial distribution of the characteristic functional groups in proteins, lipids, phosphates, and carbohydrates simultaneously in individual DRG neurons. We have identified ring-shaped distributions of lipid and/or carbohydrate enrichment in subpopulations of neurons which has never before been reported. These distributions are ring-shaped within the cytoplasm and are likely representative of the endoplasmic reticulum. The prevalence of chemical ring subtypes differs between large- and small-diameter neurons. Peripheral inflammation increased the relative lipid content specifically in small-diameter neurons, many of which are nociceptive. Because many small-diameter neurons express an ion channel involved in inflammatory pain, transient receptor potential ankyrin 1 (TRPA1), we asked whether this increase in lipid content occurs in TRPA1-deficient (knock-out) neurons. No statistically significant change in lipid content occurred in TRPA1-deficient neurons, indicating that the inflammation-mediated increase in lipid content is largely dependent on TRPA1. Because TRPA1 is known to mediate mechanical and cold sensitization that accompanies peripheral inflammation, our findings may have important implications for a potential role of lipids in inflammatory pain. PMID- 25271164 TI - Synthesis and assembly of a novel glycan layer in Myxococcus xanthus spores. AB - Myxococcus xanthus is a Gram-negative deltaproteobacterium that has evolved the ability to differentiate into metabolically quiescent spores that are resistant to heat and desiccation. An essential feature of the differentiation processes is the assembly of a rigid, cell wall-like spore coat on the surface of the outer membrane. In this study, we characterize the spore coat composition and describe the machinery necessary for secretion of spore coat material and its subsequent assembly into a stress-bearing matrix. Chemical analyses of isolated spore coat material indicate that the spore coat consists primarily of short 1-4- and 1-3 linked GalNAc polymers that lack significant glycosidic branching and may be connected by glycine peptides. We show that 1-4-linked glucose (Glc) is likely a minor component of the spore coat with the majority of the Glc arising from contamination with extracellular polysaccharides, O-antigen, or storage compounds. Neither of these structures is required for the formation of resistant spores. Our analyses indicate the GalNAc/Glc polymer and glycine are exported by the ExoA-I system, a Wzy-like polysaccharide synthesis and export machinery. Arrangement of the capsular-like polysaccharides into a rigid spore coat requires the NfsA-H proteins, members of which reside in either the cytoplasmic membrane (NfsD, -E, and -G) or outer membrane (NfsA, -B, and -C). The Nfs proteins function together to modulate the chain length of the surface polysaccharides, which is apparently necessary for their assembly into a stress-bearing matrix. PMID- 25271165 TI - G Protein signaling modulator-3 inhibits the inflammasome activity of NLRP3. AB - Inflammasomes are multi-protein complexes that regulate maturation of the interleukin 1beta-related cytokines IL-1beta and IL-18 through activation of the cysteine proteinase caspase-1. NOD-like receptor family, pyrin domain containing 3 (NLRP3) protein is a key component of inflammasomes that assemble in response to a wide variety of endogenous and pathogen-derived danger signals. Activation of the NLRP3-inflammasome and subsequent secretion of IL-1beta is highly regulated by at least three processes: transcriptional activation of both NLRP3 and pro-IL-1beta genes, non-transcriptional priming of NLRP3, and final activation of NLRP3. NLRP3 is predominantly expressed in cells of the hematopoietic lineage. Using a yeast two-hybrid screen, we identified the hematopoietic-restricted protein, G protein signaling modulator-3 (GPSM3), as a NLRP3-interacting protein and a negative regulator of IL-1beta production triggered by NLRP3-dependent inflammasome activators. In monocytes, GPSM3 associates with the C-terminal leucine-rich repeat domain of NLRP3. Bone marrow derived macrophages lacking GPSM3 expression exhibit an increase in NLRP3 dependent IL-1beta, but not TNF-alpha, secretion. Furthermore, GPSM3-null mice have enhanced serum and peritoneal IL-1beta production following Alum-induced peritonitis. Our findings suggest that GPSM3 acts as a direct negative regulator of NLRP3 function. PMID- 25271166 TI - SLO3 K+ channels control calcium entry through CATSPER channels in sperm. AB - Here we show how a sperm-specific potassium channel (SLO3) controls Ca(2+) entry into sperm through a sperm-specific Ca(2+) channel, CATSPER, in a totally unanticipated manner. The genetic deletion of either of those channels confers male infertility in mice. During sperm capacitation SLO3 hyperpolarizes the sperm, whereas CATSPER allows Ca(2+) entry. These two channels may be functionally connected, but it had not been demonstrated that SLO3-dependent hyperpolarization is required for Ca(2+) entry through CATSPER channels, nor has a functional mechanism linking the two channels been shown. In this study we show that Ca(2+) entry through CATSPER channels is deficient in Slo3 mutant sperm lacking hyperpolarization; we also present evidence supporting the hypothesis that SLO3 channels activate CATSPER channels indirectly by promoting a rise in intracellular pH through a voltage-dependent mechanism. This mechanism may work through a Na(+)/H(+) exchanger (sNHE) and/or a bicarbonate transporter, which utilizes the inward driving force of the Na(+) gradient, rendering it intrinsically voltage-dependent. In addition, the sperm-specific Na(+)/H(+) exchanger (sNHE) possess a putative voltage sensor that might be activated by membrane hyperpolarization, thus increasing the voltage sensitivity of internal alkalization. PMID- 25271167 TI - A group 6 late embryogenesis abundant protein from common bean is a disordered protein with extended helical structure and oligomer-forming properties. AB - Late embryogenesis-abundant proteins accumulate to high levels in dry seeds. Some of them also accumulate in response to water deficit in vegetative tissues, which leads to a remarkable association between their presence and low water availability conditions. A major sub-group of these proteins, also known as typical LEA proteins, shows high hydrophilicity and a high percentage of glycine and other small amino acid residues, distinctive physicochemical properties that predict a high content of structural disorder. Although all typical LEA proteins share these characteristics, seven groups can be distinguished by sequence similarity, indicating structural and functional diversity among them. Some of these groups have been extensively studied; however, others require a more detailed analysis to advance in their functional understanding. In this work, we report the structural characterization of a group 6 LEA protein from a common bean (Phaseolus vulgaris L.) (PvLEA6) by circular dichroism and nuclear magnetic resonance showing that it is a disordered protein in aqueous solution. Using the same techniques, we show that despite its unstructured nature, the addition of trifluoroethanol exhibited an intrinsic potential in this protein to gain helicity. This property was also promoted by high osmotic potentials or molecular crowding. Furthermore, we demonstrate that PvLEA6 protein is able to form soluble homo-oligomeric complexes that also show high levels of structural disorder. The association between PvLEA6 monomers to form dimers was shown to occur in plant cells by bimolecular fluorescence complementation, pointing to the in vivo functional relevance of this association. PMID- 25271168 TI - Global ablation of the mouse Rab11a gene impairs early embryogenesis and matrix metalloproteinase secretion. AB - Rab11a has been conceived as a prominent regulatory component of the recycling endosome, which acts as a nexus in the endo- and exocytotic networks. The precise in vivo role of Rab11a in mouse embryonic development is unknown. We globally ablated Rab11a and examined the phenotypic and molecular outcomes in Rab11a(null) blastocysts and mouse embryonic fibroblasts. Using multiple trafficking assays and complementation analyses, we determined, among multiple important membrane associated and soluble cargos, the critical contribution of Rab11a vesicular traffic to the secretion of multiple soluble MMPs. Rab11a(null) embryos were able to properly form normal blastocysts but died at peri-implantation stages. Our data suggest that Rab11a critically controls mouse blastocyst development and soluble matrix metalloproteinase secretion. PMID- 25271170 TI - Association of the CYP2B6 gene with anti-tuberculosis drug-induced hepatotoxicity in a Brazilian Amazon population. AB - OBJECTIVES: The treatment of tuberculosis (TB) remains a challenge owing to the high incidence of drug-induced hepatotoxicity. The aim of this study was to examine the effect of two gene polymorphisms, one in the CYP2B6 (rs3745274) gene and one in the CYP3A5 (rs776746) gene, on the development of hepatotoxicity in patients treated with anti-TB drugs in a Brazilian Amazon population. METHODS: TB patients who were treated with anti-TB drugs were examined for hepatotoxicity, an adverse effect that is characterized by liver damage. The genotype frequencies of the CYP2B6 and CYP3A5 genes examined in this study were assessed using RT-PCR. RESULTS: Thirty-one of the 220 subjects (14.1%) included in this study developed drug-induced hepatotoxicity. The result was significant when the TT homozygous mutant of the CYP2B6 gene was analyzed with additional key variables (p=0.046; odds ratio (OR) 0.063, 95% confidence interval (CI) 0.004-0.955), which may explain the hepatotoxicity results in this study. Using a univariate statistical model to associate the CYP3A5 gene A6986G polymorphism with the examined drugs, the results did not differ between samples from individuals with and without hepatotoxicity (p=0.176; OR 0.562, 95% CI 0.255-1.238). CONCLUSIONS: The G516T polymorphism in the CYP2B6 gene is a key predictor of the therapeutic response to treatment in TB patients. PMID- 25271169 TI - Glutamine stimulates biosynthesis and secretion of insulin-like growth factor 2 (IGF2), an autocrine regulator of beta cell mass and function. AB - IGF2 is an autocrine ligand for the beta cell IGF1R receptor and GLP-1 increases the activity of this autocrine loop by enhancing IGF1R expression, a mechanism that mediates the trophic effects of GLP-1 on beta cell mass and function. Here, we investigated the regulation of IGF2 biosynthesis and secretion. We showed that glutamine rapidly and strongly induced IGF2 mRNA translation using reporter constructs transduced in MIN6 cells and primary islet cells. This was followed by rapid secretion of IGF2 via the regulated pathway, as revealed by the presence of mature IGF2 in insulin granule fractions and by inhibition of secretion by nimodipine and diazoxide. When maximally stimulated by glutamine, the amount of secreted IGF2 rapidly exceeded its initial intracellular pool and tolbutamide, and high K(+) increased IGF2 secretion only marginally. This indicates that the intracellular pool of IGF2 is small and that sustained secretion requires de novo synthesis. The stimulatory effect of glutamine necessitates its metabolism but not mTOR activation. Finally, exposure of insulinomas or beta cells to glutamine induced Akt phosphorylation, an effect that was dependent on IGF2 secretion, and reduced cytokine-induced apoptosis. Thus, glutamine controls the activity of the beta cell IGF2/IGF1R autocrine loop by increasing the biosynthesis and secretion of IGF2. This autocrine loop can thus integrate changes in feeding and metabolic state to adapt beta cell mass and function. PMID- 25271171 TI - Is it worth reorganising cancer services on the basis of multidisciplinary teams (MDTs)? A systematic review of the objectives and organisation of MDTs and their impact on patient outcomes. AB - Multidisciplinary teams (MDTs) are considered the gold standard of cancer care in many healthcare systems, but a clear definition of their format, scope of practice and operational criteria is still lacking. The aims of this review were to assess the impact of MDTs on patient outcomes in cancer care and identify their objectives, organisation and ability to engage patients in their care. We conducted a systematic review of the literature in the Medline database. Fifty one peer-reviewed papers were selected from November 2005 to June 2012. MDTs resulted in better clinical and process outcomes for cancer patients, with evidence of improved survival among colorectal, head and neck, breast, oesophageal and lung cancer patients in the study period. Also, it was observed that MDTs have been associated with changes in clinical diagnostic and treatment decision-making with respect to urological, pancreatic, gastro-oesophageal, breast, melanoma, bladder, colorectal, prostate, head and neck and gynaecological cancer. Evidence is consistent in showing positive consequences for patients' management in multiple dimensions, which should encourage the development of structured multidisciplinary care, minimum standards and exchange of best practices. PMID- 25271172 TI - Pharmacokinetics of metronidazole in foals: influence of age within the neonatal period. AB - Neonatal foals have unique pharmacokinetics, which may lead to accumulation of certain drugs when adult horse dosage regimens are used. Given its lipophilic nature and requirement for hepatic metabolism, metronidazole may be one of these drugs. The purpose of this study was to determine the pharmacokinetic profiles of metronidazole in twelve healthy foals at 1-2.5 days of age when administered as a single intravenous (IV) and intragastric (IG) dose of 15 mg/kg. Foals in the intravenous group were studied a second time at 10-12 days of age to evaluate the influence of age on pharmacokinetics within the neonatal period. Blood samples were collected at serial time points after metronidazole administration. Metronidazole concentration in plasma was measured using LC-MS. Pharmacokinetic parameters were determined using noncompartmental analysis and compared between age groups. At 1-2.5 days of age, the mean peak plasma concentration after IV infusion was 18.79 +/- 1.46 MUg/mL, elimination half-life was 11.8 +/- 1.77 h, clearance was 0.84 +/- 0.13 mL/min/kg and the volume of distribution (steady state) was 0.87 +/- 0.07 L/kg. At 10-12 days of age, the mean peak plasma concentration after IV infusion was 18.17 +/- 1.42 MUg/mL, elimination half-life was 9.07 +/- 2.84 h, clearance was 1.14 +/- 0.21 mL/min/kg and the volume of distribution (steady-state) was 0.88 +/- 0.06 L/kg. Oral approximated bioavailability was 100%. Cmax and Tmax after oral dosing were 14.85 +/- 0.54 MUg/mL and 1.75 (1-4) h, respectively. The elimination half-life was longer and clearance was reduced in neonatal foals at 1-2.5 days as compared to 10-12 days of age (P = 0.006, P = 0.001, respectively). This study warrants consideration for altered dosing recommendations in foals, especially a longer interval (12 h). PMID- 25271174 TI - Novel compounds targeting bacterial DNA topoisomerase/DNA gyrase. AB - Among the targets for the development of new antibacterial agents, bacterial topoisomerases remain a vibrant area of discovery. A structurally diverse set of inhibitors that bind to the adenosine 5'-triphosphate (ATP) site of type II topoisomerases have been disclosed recently. Seven compounds with this mechanism are highlighted, focusing on antibacterial potency and spectrum, as well as examples of in vivo efficacy against pathogens including Staphylococcus aureus and Mycobacterium tuberculosis. Five compounds from two structural classes are exemplified that are inhibitors that bind to the catalytic site of DNA gyrase and topoisomerase IV. The pharmacokinetic and pharmacodynamic properties of these molecules, derived from in vivo efficacy against Gram-positive and Gram-negative pathogens, define the potential for these agents with broad-spectrum and targeted spectrum clinical utilities. PMID- 25271173 TI - Providing Care for Patients with Chronic Migraine: Diagnosis, Treatment, and Management. AB - Chronic migraine, a subtype of migraine defined as >= 15 headache days per month for >= 3 months, in which >= 8 days per month meet criteria for migraine with or without aura or respond to migraine-specific treatment, is a disabling, underdiagnosed, and undertreated disorder associated with significant disability, poor health-related quality of life, and high economic burden. The keys to caring for chronic migraine patients include: (1) making a proper diagnosis; (2) identifying and eliminating exacerbating factors; (3) assessing for medication overuse (patients with chronic headache often overuse acute medications); and (4) continued management. Communication between patient and physician about treatment goals is important. The patient management guidelines presented in this article should help physicians improve treatment success and proactively address common comorbidities among their patients with chronic migraine. PMID- 25271175 TI - Nano-labelled cells-a functional tool in biomedical applications. AB - Nanotechnology offers an unprecedented number of opportunities for biomedical research, utilizing the unusual functionalities of nanosized materials. Here we describe the recent advances in fabrication and utilization of nanoparticle labelled cells. We present a brief overview of the most promising techniques, namely layer-by-layer polyelectrolyte assembly on cells and intracellular and extracellular labelling with magnetic nanoparticles. Several important practical application of nanofucntionalized cells, including tissue engineering and tumour therapy, are reviewed. PMID- 25271176 TI - Measuring anxiety in late life: a psychometric examination of the geriatric anxiety inventory and geriatric anxiety scale. AB - We examined the psychometric properties, internal scale reliability and validity, of two geriatric anxiety measures: the Geriatric Anxiety Inventory (GAI) and Geriatric Anxiety Scale (GAS). We also determined the extent to which memory ability influenced the psychometric properties of these measures. Older adult participants (N=110; M age=75 years) completed self-report, clinician-rated and diagnostic psychiatric measures and a neuropsychiatric battery. GAI and GAS scores had good internal consistency, adequate reliability, and strong convergent validity. GAI scores had better discriminant validity than GAS scores relative to a health rating. Both measures had strong associations with depression scores. Psychometric properties were decreased in participants with average delayed memory recall compared with those with superior recall. Both measures had good psychometric support, particularly in those with strong memory abilities. Psychometric performance characteristics indicate that the GAI and GAS may be good alternatives to anxiety measures not designed specifically for older adults. PMID- 25271177 TI - The effectiveness of a student volunteer program for research in a pediatric Emergency Department. AB - BACKGROUND: Emergency Department (ED) student-based research assistant programs have been shown to be effective in enrolling patients when the students receive university course credit or pay. However, the impact on research outcomes when university students act as volunteers in this role is relatively unknown. OBJECTIVES: The main objective of this study was to determine how often potentially eligible children were accurately identified by volunteer research assistants for enrollment into prospective research in the ED. We also examined the frequency of successful enrollments and the accuracy of data capture. METHODS: This was a prospective cross-sectional study of university student volunteer research assistant performance in a tertiary care pediatric ED between March 2011 and July 2013. The participant's primary role was to screen and facilitate enrollment of ED patients into clinical research. For each volunteer, we recorded demographics, number of screenings, enrollments, and data capture accuracy. RESULTS: Over five 6-month sessions, 151 student volunteers participated. Of these, 77.3% were female, 58.8% were undergraduate students, and 61.1% were interested in medical school. Student volunteers accurately screened 11,362/13,067 (87.0%) children, and they accurately identified 4407/4984 (88.4%) potentially eligible children for study enrollment. Of the 3805 eligible for enrollment exclusively by the students, 3228 (84.8%) families/children consented and completed all study procedures. Furthermore, students correctly entered 11,660/12,567 (92.8%) data points. CONCLUSIONS: Utilizing university student volunteers to facilitate research enrollment in the ED is effective and allows for the capture of a high percentage of potentially eligible patients into prospective clinical research studies. PMID- 25271179 TI - A comparison of three self-report pain scales in adults with acute pain. AB - BACKGROUND: Several pain rating methods are used to quantify pain. Although these instruments have been extensively studied, their inter-agreement, especially in emergency department (ED) settings, has yet to be determined. OBJECTIVE: This study was designed to assess the agreement between Visual Analog Scale (VAS), Color Analog Scale (CAS), and verbally administered Numeric Rating Scale (NRS) in the emergency setting. METHODS: A sample of 150 adult patients presenting with acute pain to two EDs was recruited. Patients' pain severity at presentation, 30 and 60 min later was assessed using the three pain scales. The agreement between pain scales was assessed using Bland-Altman method and Spearman correlation. We described a composite measure to serve as the gold standard and to be compared with each score. Factor analysis was also performed to assess the underlying construct. RESULTS: Spearman correlation coefficients between NRS and CAS, NRS and VAS, and CAS and VAS were 0.95, 0.94, and 0.94, respectively (p < 0.001). On a scale of 0 to 10, the 95% limits of agreement between the paired NRS and VAS, VAS and CAS, and CAS and NRS as measured by Bland-Altman method ranged from -2.0 to 2.6, from -2.7 to 2.0, and from -2.1 to 2.0, respectively. The Kaiser-Meyer Oklin measure of sampling adequacy was 0.785 and Bartlett's test for sphericity was significant (p < 0.001). CONCLUSIONS: The three pain scales were strongly correlated at all time periods. The findings suggest that NRS, CAS, and VAS can be interchangeably applied for acute pain measurement in adult patients. PMID- 25271178 TI - Assessment of emergency airway management techniques in Korea using an online registration system: a multicenter study. AB - BACKGROUND: The investigators developed a Web-based online registration system to identify the current status of trauma airway management. OBJECTIVES: The purpose of the study was to identify first-pass success (FPS) rate of the intubation methods and devices that are currently used, as well as the factors that affect FPS in trauma patients. METHODS: This study was designed as a prospective, observational multi-center study. We obtained clinical data of intubated trauma patients in 13 academic emergency departments in Korea. After performing an intubation, each patient's data were entered into a Web-based registry. Logistic regression analyses were conducted to identify the factors that affect FPS. RESULTS: The FPS rate was 80.6% in all trauma patients. The curved-blade laryngoscope was the most commonly used instrument, and was applied to 1395 patients (76.2%) during first attempt. Video laryngoscopy was applied to 341 patients (18.6%). In the multivariate logistic regression analysis, factors that affected FPS in difficult airway trauma patients were emergency physicians, senior physicians, and video laryngoscopy (odds ratio 2.42, 95% confidence interval 1.04-5.65; 1.80, 1.16-2.79; and 2.16, 1.39-3.33, respectively). CONCLUSIONS: Emergency physicians in Korea are prepared for trauma patient airway management. The backup by experienced senior physicians, and preparation and training for video laryngoscope could assist FPS for trauma patients. PMID- 25271181 TI - Response to "regarding the benefits and harms of blood transfusion in septic patients". PMID- 25271180 TI - Reducing anxiety in the pediatric emergency department: a comparative trial. AB - BACKGROUND: Anxiety among patients in a pediatric emergency department (PED) can be significant, but often goes unaddressed. OBJECTIVE: Our aim was to determine whether exposure to Child Life (CL) or hospital clowning (HC) can reduce anxiety in children presenting to a PED. METHODS: Patients were randomized to CL, HC, or control and assessed upon entry to examination room (T1), before physician arrival (T2), and during physician examination (T3), using the modified Yale Preoperative Anxiety Scale (m-YPAS). CL and HC interventions occurred for 5 to 10 min before physician entry. Effects were analyzed using mixed analysis of variance. RESULTS: m-YPAS scores ranged from 23 to 59, with a higher score indicating increased anxiety. Mixed analysis of variance on the study sample (n = 113) showed a significant interaction between groups (CL, HC, control) and time (p = 0.02). Additional analyses indicated effect of group only at T2 (CL: mean = 23.8; 95% confidence interval [CI] 23.2-24.5; HC: mean 25.2; 95% CI 24.2-26.2; control: mean = 26.1; 95% CI 24.2-27.9; p = .02). Subanalysis of patients with T1 m-YPAS score >= 28 (n = 56) showed a significant interaction between group and time (p = 0.01). Additional analysis showed effect of group only at T2 (CL: mean 24.4; 95% CI 23.3-25.6; HC: mean 27.0; 95% CI 25.2-28.7; control: mean 29.2; 95% CI 25.6-32.7; p = 0.003). CONCLUSIONS: CL services can reduce state anxiety for patients presenting to a PED with heightened anxiety at baseline. This reduction occurred immediately after CL intervention, but was not observed in patients exposed to HC or during physician examination. PMID- 25271182 TI - Utility of diagnosis of tuberculosis in an overcrowded emergency department. PMID- 25271183 TI - Lipid emulsion use precluding renal replacement therapy. AB - BACKGROUND: Intralipid emulsion (ILE) is a nutritional fatty acid supplementation that is emerging as a potential therapy for local anesthetic systemic toxicity and is also being considered as a therapy for other lipophilic medication intoxications. Isolated reports of pulmonary edema or severe lipemia exist as a complication of therapy. CASE REPORT: A 26-year-old hypertensive, male, kidney transplant recipient presented to an outside emergency department (ED) after an intentional overdose of his medications (ie, amlodipine, metoprolol, lisinopril). At presentation, he had hypotension and bradycardia that was unresponsive to treatment with intravenous saline, calcium, glucagon, and vasopressors. After failure of conventional therapy, an initial bolus of ILE (20%) was given with some improvement in his heart rate, and the dose was repeated. A continuous intravenous infusion of ILE therapy was started. The patient deteriorated, with development of both acute respiratory and renal failure. Continuous venovenous hemofiltration (CVVHF) was attempted to remove volume and correct metabolic abnormalities. Lipemic blood was immediately observed in the CVVHF filter. After 15 min, the transmembrane pressures of the filter began to rise in the absence of observed clotting of the blood and the filter then became completely obstructed. An attempt was made to remove the lipid by plasmapheresis to restart CVVHF, but the patient continued to deteriorate despite maximal vasopressor support. The patient's family decided to withdraw care and the patient expired. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians treat patients with toxic ingestions on a regular basis. Being aware of possible complications of experimental antidote therapy, like ILE, can improve the treatment approach and outcomes for these patients. PMID- 25271184 TI - The professional benefits for volunteer research assistants in a pediatric emergency department. AB - BACKGROUND: Emergency departments (EDs) have utilized university student volunteers to facilitate enrollment of patients into prospective studies; however, the impact of this experience on participant careers is relatively unknown. OBJECTIVES: We determined the proportion of successful postgraduate school/research job applications supported by our program reference letter. We also examined participant satisfaction. METHODS: This was a prospective cohort study of volunteer research assistants in a tertiary care pediatric ED from September 2011 to July 2013. Students volunteered one 5-h shift per week for at least 6 months. They completed three surveys: 1) Entrance - demographics and goals for entering the ED research assistant program; 2) Exit - program satisfaction, reasons for leaving the program, and future career goals; 3) Follow up - survey and e-mails were sent to record positions secured since leaving the program. RESULTS: There were a total of 920 applicants over the study period, and 127 volunteers were selected to participate in the program. Response rates for entrance, exit, and follow-up surveys were 100%, 84.9%, and 96.2%, respectively. Of the participants who left and responded, 89/101 (88.9%) obtained school/research positions supported by our program reference letter. Further, 72.6% ranked their satisfaction with the program at least a 7 on a 10-point categorical scale, and 82.9% reported that they "agreed/strongly agreed" that the program helped with their career goals. CONCLUSIONS: A volunteer student program is in high demand for university students interested in health sciences/research and potentially has a beneficial career impact for its participants. PMID- 25271185 TI - Comparison of the effects of ketamine and morphine on performance of representative military tasks. AB - BACKGROUND: When providing care under combat or hostile conditions, it may be necessary for a casualty to remain engaged in military tasks after being wounded. Prehospital care under other remote, austere conditions may be similar, whereby an individual may be forced to continue purposeful actions despite traumatic injury. Given the adverse side-effect profile of intramuscular (i.m.) morphine, alternative analgesics and routes of administration are of interest. Ketamine may be of value in this capacity. OBJECTIVES: To delineate performance decrements in basic soldier tasks comparing the effects of the standard battlefield analgesic (10 mg i.m. morphine) with 25 mg i.m. ketamine. METHODS: Representative military skills and risk propensity were tested in 48 healthy volunteers without pain stimuli in a double-blind, placebo-controlled, crossover design. RESULTS: Overall, participants reported more symptoms associated with ketamine vs. morphine and placebo, chiefly dizziness, poor concentration, and feelings of happiness. Performance decrements on ketamine, when present, manifested as slower performance times rather than procedural errors. CONCLUSIONS: Participants were more symptomatic with ketamine, yet the soldier skills were largely resistant to performance decrements, suggesting that a trained task skill (autonomous phase) remains somewhat resilient to the drugged state at this dosage. The performance decrements with ketamine may represent the subjects' adoption of a cautious posture, as suggested by risk propensity testing whereby the subject is aware of impairment, trading speed for preservation of task accuracy. These results will help to inform the casualty care community regarding appropriate use of ketamine as an alternative or opioid-sparing battlefield analgesic. PMID- 25271187 TI - The association between serum selenium and gestational diabetes mellitus: a systematic review and meta-analysis. AB - BACKGROUND: Results of the studies about association between serum selenium concentration and gestational hyperglycemia are inconsistent. Some studies have demonstrated that women with gestational diabetes mellitus (GDM) have lower Se concentrations while contrary results are reported in other studies. AIM: The aim of this study is to compare the serum Se concentration in women with GDM and normoglycemic pregnant women via a systematic review and meta-analysis. METHODS: A computerized literature search on four databases (PubMed, Cochrane register of control trials, Scopus and Google scholar) was performed from inception through August 2013. Necessary data were extracted and random effects model was used to conduct the meta-analysis. RESULTS: Six observational studies (containing 147 women with GDM and 360 normoglycemic pregnant women) were found, which had compared serum Se concentration in women suffering from GDM with normal pregnant ones. Our meta-analysis revealed that serum Se concentration was lower in women with GDM compared to normoglycemic pregnant women (Hedges=-1.34; 95% CI: -2.33 to -0.36; P<0.01). Stratified meta-analysis demonstrated that concentration of Se in the sera of women with GDM was lower than normal pregnant women both in second and third trimesters, but the result was not significant in second trimester (second trimester: Hedges=-0.68; 95% CI: -1.60-0.25; P=0.15, third trimester: Hedges=-2.81; 95% CI: -5.21 to -0.42; P<0.05). It was also demonstrated that serum Se status was lower in pregnant women with impaired glucose tolerance (IGT) compared to normoglycemic pregnant women (Hedges=-0.85; 95% CI: -1.18 to -0.52). CONCLUSION: The available evidences suggest that serum Se concentration is significantly lower in pregnant women with gestational hyperglycemia compared to normal pregnant women. PMID- 25271186 TI - Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation. AB - BACKGROUND: Bariatric surgery is widely performed to improve obesity-related disorders, but can lead to nutrient deficiencies. In this study we examined serum trace element concentrations before and after bariatric surgery. METHODS: We obtained serum trace element concentrations by inductively coupled plasma-mass spectrometry (ICP-MS) method in 437 patients (82% women, median preoperative body mass index 46.7 kg/m(2) [interquartile range 42-51]) undergoing either gastric banding (22.7%), sleeve gastrectomy (20.1%), or gastric bypass (57.3%) procedures. Trace element data were available for patients preoperatively (n = 44); and 3 (n = 208), 6 (n = 174), 12 (n = 122), 18 (n = 39), 24 (n = 44) and 36 months (n = 14) post-operatively. All patients were recommended to take a multivitamin-mineral supplement after surgery. RESULTS: Copper deficiency was found in 2% of patients before surgery; and after surgery deficiency rates ranged from 0 to 5% with no significant change in median concentrations during follow-up (p = 0.68). Selenium deficiency was reported in 2% of patients before surgery; and after surgery deficiency rates ranged from 11 to 15% with a near-significant change in median concentrations (p = 0.056). Zinc deficiency was reported in 7% before surgery; and after surgery deficiency rates ranged from 7 to 15% with no significant change in median concentrations (p = 0.39). CONCLUSIONS: In bariatric surgery patients recommended to take multivitamin-mineral supplements, serum copper, zinc and selenium concentrations were mostly stable during the first years after bariatric surgery. There was a possible tendency for selenium concentrations to decline during the early postoperative period. PMID- 25271188 TI - Determination of behaviorally effective tobacco constituent doses in rats. AB - INTRODUCTION: While nicotine has been established as the primary addictive drug that promotes tobacco use, recent peer-reviewed studies suggest that tobacco smoke contains additional chemical constituents that may have addictive potential. Additional research is necessary to determine the addictive potential of these tobacco constituents individually and in combination with tobacco smoke condensate; however, the behaviorally effective constituent doses necessary to conduct such studies are unclear. The primary objective of this study was to conduct behavioral studies in adult rats to determine the relevant behaviorally effective doses of the tobacco constituents, cotinine, myosmine, and anatabine to be used in future studies assessing the addictive potential of these compounds. METHODS: Separate groups of adult male Sprague Dawley rats were treated with vehicle, nicotine, or various doses of cotinine, mysomine, or anatabine. Effects on locomotor activity were measured in 10-min bins for 60min. RESULTS: Nicotine (0.8mg/kg) produced a biphasic effect on locomotor activity, with hypoactivity during the first 10min and hyperactivity at 40-50min. In contrast, cotinine (0.1mg/kg) and myosmine (10-50mg/kg) decreased activity without a later increase. Anatabine significantly increased locomotor activity at 1mg/kg, but decreased it at 10mg/kg. Prominent effects on overt behavior were observed at anatabine doses of 10mg/kg and above. CONCLUSION: Nicotine, cotinine, myosmine, and anatabine produced distinct time- and dose-dependent patterns of effects on locomotor activity. Results from the study will aid in the selection of relevant doses for future studies assessing the addictive potential of these non-nicotine tobacco constituents. PMID- 25271189 TI - A multi-disciplinary model of risk factors for fatal outcome in posterior reversible encephalopathy syndrome. AB - PURPOSE: To evaluate the relative impact of clinical data, imaging findings, and CSF laboratory values on clinical outcome in patients with posterior reversible encephalopathy syndrome (PRES). METHODS: 47 patients with PRES who underwent a lumbar puncture were retrospectively evaluated. Fatal outcome was defined as death directly ascribed to PRES toxicity. Univariate and multivariate analyses were used to evaluate the association between fatal outcome and clinical factors (demographics, PRES etiology), imaging findings (signal abnormality severity, atypical distribution, restricted diffusion, hemorrhage, enhancement, angiographic abnormalities), and lumbar puncture results (appearance, cell count, glucose, protein, culture results). RESULTS: Nine patients (19.1%) had a fatal outcome. Odds of a fatal outcome increased nearly 5-fold with hemorrhage on imaging (Adjusted Odds Ratio (AOR) 4.8, 95% CI 3.8-6.0, p=0.03) and nearly doubled with low CSF glucose (AOR 1.9, 95% CI 1.5-2.5, p=0.02). Hypertensive encephalopathy as an etiology was associated with a fatal outcome (AOR 1.6, 95% CI 1.3-2.9, p=0.02), while toxemia of pregnancy was protective, with a 75% decreased risk (AOR 0.25, 95% CI 0.15-0.43, p=0.02). CONCLUSION: Clinical, imaging, and CSF laboratory findings all influence outcome in PRES, with a low CSF glucose, hypertensive encephalopathy, and imaging findings of hemorrhage associated with increased risk of fatal outcome. PMID- 25271190 TI - Evaluation of the humoral response against mycobacterial peptides, homologous to MOG35-55, in multiple sclerosis patients. AB - Bacillus Calmette-Guerin (BCG) and Mycobacterium avium subspecies paratuberculosis (MAP) have been associated with multiple sclerosis (MS). Clinical data indicates that BCG vaccination exerts anti-inflammatory effects in MS; conversely, MAP is thought to be one of the possible infectious factors responsible of MS through a molecular mimicry mechanism. A peptide-based indirect ELISA was used to detect antibodies against the encephalitogenic myelin oligodendrocyte glycoprotein (MOG)35-55 epitope, and two mycobacterial peptides sharing sequence homology with the latter: MAP_2619c352-361/BCG_1224355-364 and BCG_3329c64-74. Among 40 MS patients and 39 healthy volunteers included in the study, only MOG35-55 was capable of inducing a significantly higher humoral response in MS subjects compared to controls. Indeed, 11 out of 40 MS subjects (27.5%) and only 2 out of 39 controls (5%) were antibody-positive for MOG35-55 (p=0.01, AUC=0.65). These findings strengthen the importance of MOG35-55 in MS pathogenesis. The MAP and BCG MOG-homologues epitopes investigated were not recognized in MS patients. Overall, the results allow us concluding that sharing homology of linear epitopes is necessary but not sufficient to induce antibody mediated cross-reactivity. PMID- 25271191 TI - Image-based vs. mesh-based statistical appearance models of the human femur: implications for finite element simulations. AB - Statistical appearance models have recently been introduced in bone mechanics to investigate bone geometry and mechanical properties in population studies. The establishment of accurate anatomical correspondences is a critical aspect for the construction of reliable models. Depending on the representation of a bone as an image or a mesh, correspondences are detected using image registration or mesh morphing. The objective of this study was to compare image-based and mesh-based statistical appearance models of the femur for finite element (FE) simulations. To this aim, (i) we compared correspondence detection methods on bone surface and in bone volume; (ii) we created an image-based and a mesh-based statistical appearance models from 130 images, which we validated using compactness, representation and generalization, and we analyzed the FE results on 50 recreated bones vs. original bones; (iii) we created 1000 new instances, and we compared the quality of the FE meshes. Results showed that the image-based approach was more accurate in volume correspondence detection and quality of FE meshes, whereas the mesh-based approach was more accurate for surface correspondence detection and model compactness. Based on our results, we recommend the use of image-based statistical appearance models for FE simulations of the femur. PMID- 25271192 TI - Assessing the bilateral geometrical differences of the tibia--are they the same? AB - Contralateral bones are often used in many medical applications but it is assumed that their bilateral differences are insignificant. Previous studies used a limited number of distance measurements in quantifying the corresponding differences; therefore, little is known about their bilateral 3D surface asymmetries. The aim of the study is to develop a comprehensive method to quantify geometrical asymmetries between the left and right tibia in order to provide first results on whether the contralateral tibia can be used as an equivalent reference. In this study, 3D bone models were reconstructed from CT scans of seven tibiae pairs, and 34 variables consisting of 2D and 3D measurements were measured from various anatomical regions. All 2D measurements, and lateral plateau and distal subchondral bone surface measurements showed insignificant differences (p>0.05), but the rest of the surfaces showed significant differences (p<0.05). Our results suggest that the contralateral tibia can be used as a reference especially in surgical applications such as articular reconstructions since the bilateral differences in the subchondral bone surfaces were less than 0.3mm. The method can also be potentially transferable to other relevant studies that require the accurate quantification of bone bilateral asymmetries. PMID- 25271193 TI - Diabetes mellitus as a risk factor for functional and cognitive decline in very old people: the Octabaix study. AB - OBJECTIVES: To examine the incidence of functional or cognitive impairment and its associated factors in a sample of individuals aged 85 years or older with and without diabetes mellitus, who were free of significant impairment at baseline. DESIGN: Longitudinal study. SETTING: Community-based survey study of 7 primary health care centers. PARTICIPANTS: A total of 167 individuals born in 1924 who completed 2 years of follow-up. MEASUREMENTS: Sociodemographic variables, the Barthel Index (BI), the Spanish version of Mini-Mental State Examination (MEC), the Mini Nutritional Assessment (MNA), the Charlson Comorbidity Index, and a list of chronic drug prescriptions. A comparative analysis was performed between diabetic and nondiabetic patients regarding the rate of functional and cognitive impairment. In addition, in older people with diabetes experiencing incident disability, an analysis of the potential factors involved was carried out. RESULTS: The prevalence of diabetes (DM) at baseline in this population was 25.1%. After 2 years of follow-up, 66.8% of patients with DM had developed a new impairment measured as 38.1% for the defined target of loss of BI of 10 or more and 33.3% for the cognitive target (MEC scores lower than 24 or loss >4 points in MEC). In a multivariate analysis, diabetic patients had an increased risk of any new disability (OR 2.05, 95% CI 1.01-4.36; P = .04). Logistic regression showed an association between any new disability and baseline scores of MNA (OR 1.35, 95% CI 1.01-1.82; P = .04) and MEC (OR 1.38, 95% CI 1.02-1.85; P = .003). CONCLUSION: This study has identified that in the oldest old, community-dwelling individuals without evidence of severe functional impairment at baseline, diabetes increases the risk of incident disability in only 2 years. PMID- 25271194 TI - Mobility of Vulnerable Elders study: effect of the sit-to-stand activity on mobility, function, and quality of life. AB - OBJECTIVES: The aim of this study is to assess the effect of the sit-to-stand activity on the mobility, function, and health-related quality of life of nursing home residents with dementia. DESIGN: A longitudinal quasi-experimental intervention study with intervention and control groups. SETTING: The study was conducted in 7 nursing homes (4 intervention; 3 control) in Edmonton, Canada. PARTICIPANTS: Eligible residents had a diagnosis of dementia and were able to transfer independently, or with the assistance of 1 person. INTERVENTION: Health care aides prompted residents to repeat the sit-to-stand activity daily during care routines on day and evening shifts. MEASUREMENTS: Mobility was measured using the 30-second sit-to-stand test and the time to complete one sit-to-stand. Function (Functional Independence Measure), health status (Health Utilities Index Mark 2 & 3) and disease-specific quality of life (Quality of Life-Alzheimer's Disease instrument) were also measured. Outcome measures were collected at baseline, and at 3 and 6 months. The covariates cognition, depression, and medical instability were derived from the Resident Assessment Instrument Minimum Data Set (Version 2.0), and the facility context covariate was measured using the Alberta Context Tool. RESULTS: A total of 111 residents completed the 6-month trial (56 intervention; 55 control). Residents in the intervention facilities maintained mobility, as measured by the time to complete one sit-to-stand (P = .01), and experienced a slower functional decline, as measured by the Functional Independence Measure (P = .01), from baseline to 6 months compared with residents in the control facilities, after adjusting for age, sex, cognition, depression, medical instability, and context. CONCLUSIONS: Maintaining the ability to transfer using the sit-to-stand activity is a promising means of optimizing the mobility and function for residents with dementia in nursing homes. PMID- 25271195 TI - Individual peak gamma frequency predicts switch rate in perceptual rivalry. AB - Perceptual rivalry-the experience of alternation between two mutually exclusive interpretations of an ambiguous image-provides powerful opportunities to study conscious awareness. It is known that individual subjects experience perceptual alternations for various types of bistable stimuli at distinct rates, and this a stable, heritable trait. Also stable and heritable is the peak frequency of induced gamma-band (30-100 Hz) oscillation of a population-level response in occipital cortex to simple visual patterns, which has been established as a neural correlate of conscious processing. Interestingly, models for rivalry alternation rate and for the frequency of population-level oscillation have both cited inhibitory connections in cortex as crucial determinants of individual differences, and yet the relationship between these two variables has not yet been investigated. Here, we used magnetoencephalography to compare differences in alternation rate for binocular and monocular types of perceptual rivalry to differences in evoked and induced gamma-band frequency of neuromagnetic brain responses to simple nonrivalrous grating stimuli. For both types of bistable images, alternation rate was inversely correlated with the peak frequency of late evoked gamma activity in primary visual cortex (200-400 ms latency). Our results advance models of inhibition that account for subtle variation in normal visual cortex, and shed light on how small differences in anatomy and physiology relate to individual cognition and performance. PMID- 25271196 TI - Functional performance and plasma cytokine levels in elderly women with and without low back pain. AB - BACKGROUND AND OBJECTIVES: Low back pain (LBP) is a complaint of great importance among the elderly due to its significant impact on function. LBP could contribute to changes in the regulatory process of inflammatory mediators observed in elders. The aim of this study was to compare plasma levels of interleukin(IL)-6, soluble tumor necrosis factor receptor 1(sTNF-R1), and functionality among 3 groups of elderly women: GI, with LBP; GII, without LBP but reports of other pain; and GIII, without any reported pain. MATERIAL AND METHOD: This was an observational study of a subsample of the international Back Complaints in the Elders cohort study. IL-6 and sTNF-R1 were measured using the enzyme-linked immunosorbent assay. Functionality was assessed using the Timed Up and Go, gait speed and Roland Morris Disability Questionnaire; and pain, using the numerical pain scale. RESULTS: Two hundred and thirteen women aged 71.35 +/- 4.76 years were included. GI presented the highest sTNF-R1 levels (p=0.016), worst TUG performance (p< 0.001) and slowest gait speed (p< 0.01) compared to GII and GIII, which were similar (p > 0.05). No difference was found between the IL-6 plasma levels in any of the groups. CONCLUSION: Elderly women with LBP had the highest sTNF-R1 plasma levels and the worst functional performance compared to elderly women with reports of other pain (not LBP) or no pain. PMID- 25271197 TI - Women's experiences of low back pain during pregnancy. AB - OBJECTIVES: This study investigated the self-reported prevalence and impact of low back pain (LBP) during pregnancy in primiparous and multiparous women, and their treatment-seeking rationales and experiences, including their use of physiotherapy. METHODS: A sample of 105 post-partum women was recruited. All participants answered a questionnaire; women who experienced LBP during pregnancy (n=71) continue in the study and later they were also interviewed. Content analysis, descriptive and inferential statistics were used to analyse the data. RESULTS: Reports of LBP were common (n=71; 67.6%) and slightly more frequent in primiparous (n=40; 56.3%) than multiparous (n=31; 43.7%) women. Multiparous women with LBP were significantly older (p< 0.001) and reported more sleep disturbances (p=0.026) than primiparous women with LBP. LBP prevented women performing their daily activities (n=41; 57.7%) and worsened with the advance of pregnancy (n=55; 77.5%), yet 93.0% (n=66) of these women received no treatment. CONCLUSION: LBP is a prevalent and important clinical condition affecting the daily life of many pregnant women. Nevertheless, few women seek any treatment and physiotherapy is rarely considered. Given the significant impact on quality of life, health professionals need to be proactive in asking women about LBP. PMID- 25271198 TI - The effects of an exercise with a stick on the lumbar spine and hip movement patterns during forward bending in patients with lumbar flexion syndrome. AB - BACKGROUND AND OBJECTIVE: Forward bending is frequently performed in daily activities. However, excessive lumbar flexion during forward bending has been reported as a risk factor for low back pain. Therefore, we examined the effects of an exercise strategy using a stick on the angular displacement and movement onset of lumbar and hip flexion during forward-bending exercises in patients with lumbar flexion syndrome. METHODS: Eighteen volunteers with lumbar flexion syndrome were recruited in this study. Subjects performed forward-bending exercises with and without a straight stick in standing. The angular displacement and movement onset of lumbar and hip flexion during forward-bending exercises were measured by using a three dimensional motion analysis system. The significances of differences between the two conditions (with stick vs. without stick) was assessed using a one-way repeated analysis of variance. RESULTS: When using a stick during a forward-bending exercise, the peak angular displacement of lumbar flexion decreased significantly, and those of right and left-hip flexion increased significantly compared with those without a stick. The movement onset of lumbar flexion occurred significantly later, and the onset of right-hip flexion occurred significantly earlier with than without a stick. CONCLUSIONS: Based on these findings, a stick exercise was an effective method to prevent excessive lumbar flexion and more helpful in developing hip flexion during a forward-bending exercise. These findings will be useful for clinicians to teach self-exercise during forward bending in patients with lumbar flexion syndrome. PMID- 25271199 TI - Low back pain among Italian rowers: A cross-sectional survey. AB - BACKGROUND: Low Back Pain is commonly reported to be a very frequent disorder in rowing, but it is still unclear if its prevalence is higher than in other sports or even in a non-athletes group. OBJECTIVES: To determine prevalence of low back pain (LBP) with and without irradiated pain and possibly related risk factors in a group of elite Italian rowers. METHODS: The study was conducted during the 2010 Italian Indoor Rowing Championship held in Bari from 30th to 31st January. All the 415 rowers who qualified for the national championship were asked to complete a three-page questionnaire on LBP, assisted by a physiotherapist. RESULTS: One hundred and thirty-three athletes (32%) completed the assessment. LBP was very common, with a lifetime and 1 year prevalence of 64.7% and 40.6% respectively. During the last episode, the LBP intensity, measured by a numeric rating scale (NRS), presented a median value of 6/10, and 40% of rowers reported some limitation in daily living activities (ADL). Odds ratio (OR) to suffer from LBP was 2.62 in males compared to females; athletes who row both in sculling and sweep or only sweep showed an OR of 4.43 and 3.32 respectively. CONCLUSIONS: The prevalence of low back pain among rowers seems to be comparable to the one of the general population, even if the recovery appears to be faster. The risk of developing LBP is associated with the rowing typology and the gender, but a prospective study with an adequate sample size is necessary to clearly identify risk factors for LBP in rowers and to implement effective prevention strategies. PMID- 25271200 TI - Relationship between cross sectional area of Longus Colli muscle and pain laterality in patients with cervicogenic headache. AB - BACKGROUND AND OBJECTIVES: Cervicogenic headache (CGH) originated from impaired cervical musculoskeletal structures. Dysfunction of deep neck flexor muscles has been reported in CGH subjects. The purpose of this study was to assess relationship between the size of these muscles and headache laterality in CGH subjects. MATERIAL AND METHOD: A cross sectional single blind study designed to investigate 37 CGH subjects compared with 37 healthy controls. Longus colli (LC) muscle Cross Sectional Area (CSA) in both sides was measured in supine position utilizing diagnostic ultrasonography. RESULTS: The mean CSA of LC muscle in healthy subjects was 0.74 +/- 0.06 cm2 and in patients suffering from CGH was 0.74 +/- 0.06 cm2 in left and 0.75 +/- 0.06 cm<2 in right side. No significant difference was found between subjects suffering from CGH compared with healthy controls. Also no difference was found between muscle size of affected and non affected side in unilateral CGH subjects. CONCLUSIONS: Results indicated that there was no relationship between size of LC muscle and pain laterality in patients with CGH. PMID- 25271201 TI - Disc extrusions and bulges in nonspecific low back pain and sciatica: Exploratory randomised controlled trial comparing yoga therapy and normal medical treatment. AB - BACKGROUND: Previous trials of yoga therapy for nonspecific low back pain (nsLBP) (without sciatica) showed beneficial effects. OBJECTIVE: To test effects of yoga therapy on pain and disability associated with lumbar disc extrusions and bulges. METHODS: Parallel-group, randomised, controlled trial. Sixty-one adults from rural population, aged 20-45, with nsLBP or sciatica, and disc extrusions or bulges. Randomised to yoga (n=30) and control (n=31). Yoga: 3-month yoga course of group classes and home practice, designed to ensure safety for disc extrusions. CONTROL: normal medical care. OUTCOME MEASURES (3-4 months) Primary: Roland Morris Disability Questionnaire (RMDQ); worst pain in past two weeks. Secondary: Aberdeen Low Back Pain Scale; straight leg raise test; structural changes. RESULTS: Disc projections per case ranged from one bulge or one extrusion to three bulges plus two extrusions. Sixty-two percent had sciatica. Intention-to-treat analysis of the RMDQ data, adjusted for age, sex and baseline RMDQ scores, gave a Yoga Group score 3.29 points lower than Control Group (0.98, 5.61; p=0.006) at 3 months. No other significant differences in the endpoints occurred. No adverse effects of yoga were reported. CONCLUSIONS: Yoga therapy can be safe and beneficial for patients with nsLBP or sciatica, accompanied by disc extrusions and bulges. PMID- 25271202 TI - Development and validation of the Dutch version of the London Handicap Scale. AB - BACKGROUND: The London Handicap Scale (LHS) was found to be a valid and reliable scale for measuring participation restrictions in adults. OBJECTIVE: This paper describes the development and assesses the construct-related validity of a Dutch version of the London Handicap Scale (DLHS). METHODS: The DLHS was tested in 798 adults (mean age: 50.7 years, SD=14.5, range 16 to 85) and validated with the 'Impact on Participation and Autonomy' (IPA) questionnaire, the Dutch version of the EQ-5D and questions concerning comorbidity and use of medical devices. The study population consisted of patients with rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), epilepsy, laryngectomy and multiple sclerosis. RESULTS: Feasibility was satisfactory. Large correlations (rho > 0.6) for the DLHS sum score were found with the IPA subscales 'autonomy outdoors', 'perceiving problems', 'family role', autonomy indoors', 'work and education' and with the EQ-5D. The DLHS sum score differs significantly between subgroups based on the number of chronic diseases, number of medical devices and self-reported burden of disease or handicap (p< 0.001). CONCLUSIONS: Based on this evaluation the questionnaire seems feasible and valid for assessing differences in level of participation between subgroups of chronically ill or disabled persons in the Netherlands. PMID- 25271203 TI - Methods for the assessment of neuromotor capacity in non-specific low back pain: Validity and applicability in everyday clinical practice. AB - BACKGROUND: Physiotherapists and clinicians require methods that can be used in everyday practice for measuring proprioception of the trunk in individuals with non-specific low back pain (NSLBP). OBJECTIVE: Our objective was to conduct a systematic literature review of methods used for assessment of proprioception of the trunk in individuals with non-specific low back pain. METHOD: Data were obtained from MEDLINE, CINAHL, Embase, PEDro and CENTRAL databases from their inception to December 2011. Reference lists of the selected reviews were hand searched for other potentially relevant studies. Randomized and nonrandomized controlled studies proprioception of the trunk in individuals with low back pain were selected. Thirty-six studies satisfied the selection criteria and were included in this review. RESULTS: Two reviewers independently selected the studies, conducted the quality assessment, and extracted data from each study. The Strobe scale was used to evaluate the scientific rigor of each selected study. CONCLUSIONS: This systematic review covered all the relevant literature, but none of the included studies offered a valid, reliable and feasible method to assess neuromotor capacity in everyday physiotherapy clinical practice. PMID- 25271204 TI - Value of F-wave inversion in diagnosis of carpal tunnel syndrome and it's relation with anthropometric measurements. AB - BACKGROUND: The clinical importance of F-wave inversion in the diagnosis of Carpal Tunnel Syndrome (CTS) is not yet well known. OBJECTIVE: This study aims to investigate the value of F-wave inversion in diagnosing CTS, and to evaluate the relationship of F-wave inversion with age, gender, diabetes mellitus, body mass index (BMI), wrist or waist circumferences. METHODS: Patients (n=744) who were considered to have CTS with clinical findings were included in the study. In order to confirm the diagnosis of CTS, standard electrophysiological parameters were studied with electroneuromyography. In addition, median nerve F-wave measurements were done and we determined if F-wave inversion was present or not. Sensitivity and specificity of F-wave inversion were investigated for its value in showing CTS diagnosed by electrophysiological examination. RESULTS: CTS diagnosis was confirmed by routine electrophysiological parameters in 307 (41.3%) patients. The number of the patients with the presence of F-wave inversion was 243 (32.7%). Sensitivity of F-wave inversion was found as 56% and specificity as 83.8%. BMI and wrist circumference values were significantly higher in patients with F-wave inversion present than those with F-wave inversion absent (p=0.0033, p=0.025 respectively). CONCLUSIONS: F-wave inversion can be considered as a valuable electrophysiological measurement for screening of CTS. PMID- 25271205 TI - Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta analytic study. AB - A meta-analysis was performed to systematically analyse the results of gonadotropin and GnRH therapy in inducing spermatogenesis in subjects with hypogonadotropic hypogonadism (HHG) and azoospermia. An extensive Medline and Embase search was performed including the following words: 'gonadotropins' or 'GnRH', 'infertility', 'hypogonadotropic', 'hypogonadism' and limited to studies in male humans. Overall, 44 and 16 studies were retrieved for gonadotropin and GnRH therapy, respectively. Of those, 43 and 16 considered the appearance of at least one spermatozoa in semen, whereas 26 and 10 considered sperm concentration upon gonadotropin and GnRH, respectively. The combination of the study results showed an overall success rate of 75% (69-81) and 75% (60-85) in achieving spermatogenesis, with a mean sperm concentration obtained of 5.92 (4.72-7.13) and 4.27 (1.80-6.74) million/mL for gonadotropin and GnRH therapy, respectively. The results upon gonadotropin were significantly worse in studies involving only subjects with a pre-pubertal onset HHG, as compared with studies involving a mixed population of pre- and post-pubertal onset [68% (58-77) vs. 84% (76-89), p = 0.011 and 3.37 (2.25-4.49) vs. 12.94 (8.00-17.88) million/mL, p < 0.0001; for dichotomous and continuous data, respectively]. A similar effect was observed also upon GnRH. No difference in terms of successful achievement of spermatogenesis and sperm concentration was found for different FSH preparations. Previous use of testosterone replacement therapy (TRT) did not affect the results obtained with gonadotropins. Finally, a higher success rate was found for subjects with lower levels of gonadotropins at the baseline and for those using both human chorionic gonadotropin and FSH. Gonadotropin therapy, even with urinary derivatives, is a suitable option in inducing/restoring fertility in azoospermic HHG subjects. Gonadotropins appear to be more efficacious in subjects with a pure secondary nature (low gonadotropins) and a post-pubertal onset of the disorder, whereas previous TRT does not affect outcome. PMID- 25271206 TI - Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. AB - OBJECTIVE: To investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension. RESEARCH DESIGN AND METHODS: Patients (N = 825) with type 2 diabetes and hypertension (mean seated systolic blood pressure [SBP] 130-159 mmHg and diastolic blood pressure [DBP] 80-99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks. RESULTS: At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring [ABPM]) was -3.44 mmHg (95% CI -4.78, -2.09) with 10 mg empagliflozin and -4.16 mmHg (-5.50, -2.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was -1.36 mmHg (95% CI -2.15, -0.56) with 10 mg empagliflozin and -1.72 mmHg (95% CI -2.51, -0.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was -0.62% (95% CI -0.72, -0.52) (-6.8 mmol/mol [95% CI -7.9, -5.7]) with 10 mg empagliflozin and -0.65% (95% CI -0.75, 0.55) (-7.1 mmol/mol [95% CI -8.2, -6.0]) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion. CONCLUSIONS: Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension. PMID- 25271207 TI - Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. AB - OBJECTIVE: Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODS: A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTS: Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24 h daily average blood glucose; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo. CONCLUSIONS: This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes. PMID- 25271208 TI - How do people with diabetes describe their experiences in primary care? Evidence from 85,760 patients with self-reported diabetes from the English General Practice Patient Survey. AB - OBJECTIVE: Developing primary care is an important current health policy goal in the U.S. and England. Information on patients' experience can help to improve the care of people with diabetes. We describe the experiences of people with diabetes in primary care and examine how these experiences vary with increasing comorbidity. RESEARCH DESIGN AND METHODS: Using data from 906,578 responders to the 2012 General Practice Patient Survey (England), including 85,760 with self reported diabetes, we used logistic regressions controlling for age, sex, ethnicity, and socioeconomic status to analyze patient experience using seven items covering three domains of primary care: access, continuity, and communication. RESULTS: People with diabetes were significantly more likely to report better experience on six out of seven primary care items than people without diabetes after adjusting for age, sex, ethnicity, and socioeconomic status (adjusted differences 0.88-3.20%; odds ratios [ORs] 1.07-1.18; P < 0.001). Those with diabetes and additional comorbid long-term conditions were more likely to report worse experiences, particularly for access to primary care appointments (patients with diabetes alone compared with patients without diabetes: OR 1.22 [95% CI 1.17-1.28] and patients with diabetes plus three or more conditions compared with patients without diabetes: OR 0.87 [95% CI 0.83-0.91]). CONCLUSIONS: People with diabetes in England report primary care experiences that are at least as good as those without diabetes for most domains of care. However, improvements in primary care are needed for diabetes patients with comorbid long term conditions, including better access to appointments and improved communication. PMID- 25271209 TI - Effect of low perceived social support on health outcomes in young patients with acute myocardial infarction: results from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study. AB - BACKGROUND: Social support is an important predictor of health outcomes after acute myocardial infarction (AMI), but social support varies by sex and age. Differences in social support could account for sex differences in outcomes of young patients with AMI. METHODS AND RESULTS: Data from the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study, an observational study of AMI patients aged <=55 years in the United States and Spain, were used for this study. Patients were categorized as having low versus moderate/high perceived social support using the ENRICHD Social Support Inventory. Outcomes included health status (Short Form-12 physical and mental component scores), depressive symptoms (Patient Health Questionnaire), and angina related quality of life (Seattle Angina Questionnaire) evaluated at baseline and 12 months. Among 3432 patients, 21.2% were classified as having low social support. Men and women had comparable levels of social support at baseline. On average, patients with low social support reported lower functional status and quality of life and more depressive symptoms at baseline and 12 months post-AMI. After multivariable adjustment, including baseline health status, low social support was associated with lower mental functioning, lower quality of life, and more depressive symptoms at 12 months (all P<0.001). The relationship between low social support and worse physical functioning was nonsignificant after adjustment (P=0.6). No interactions were observed between social support, sex, or country. CONCLUSION: Lower social support is associated with worse health status and more depressive symptoms 12 months after AMI in both young men and women. Sex did not modify the effect of social support. PMID- 25271210 TI - Identification of genes whose expression is altered by obesity throughout the arterial tree. AB - We used next-generation RNA sequencing (RNA-Seq) technology on the whole transcriptome to identify genes whose expression is consistently affected by obesity across multiple arteries. Specifically, we examined transcriptional profiles of the iliac artery as well as the feed artery, first, second, and third branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles from obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats. Within the gastrocnemius and soleus muscles, the number of genes differentially expressed with obesity tended to increase with increasing branch order arteriole number (i.e., decreasing size of the artery). This trend was opposite in the diaphragm. We found a total of 15 genes that were consistently upregulated with obesity (MIS18A, CTRB1, FAM151B, FOLR2, PXMP4, OAS1B, SREBF2, KLRA17, SLC25A44, SNX10, SLFN3, MEF2BNB, IRF7, RAD23A, LGALS3BP) and five genes that were consistently downregulated with obesity (C2, GOLGA7, RIN3, PCP4, CYP2E1). A small fraction (~9%) of the genes affected by obesity was modulated across all arteries examined. In conclusion, the present study identifies a select number of genes (i.e., 20 genes) whose expression is consistently altered throughout the arterial network in response to obesity and provides further insight into the heterogeneous vascular effects of obesity. Although there is no known direct function of the majority of 20 genes related to vascular health, the obesity-associated upregulation of SREBF2, LGALS3BP, IRF7, and FOLR2 across all arteries is suggestive of an unfavorable vascular phenotypic alteration with obesity. These data may serve as an important resource for identifying novel therapeutic targets against obesity-related vascular complications. PMID- 25271211 TI - Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review. AB - The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition. PMID- 25271212 TI - Fibroblast growth factor receptor 2 overexpression is predictive of poor prognosis in rectal cancer patients receiving neoadjuvant chemoradiotherapy. AB - AIMS: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is an increasingly used therapeutic strategy for advanced rectal cancer, but risk stratification and final outcomes remain suboptimal. Recently, the oncogenic role of the fibroblast growth factor/fibroblast growth factor receptor (FGFR) signalling pathway has been recognised; however, its clinical significance in rectal cancer has not been elucidated. In this study, we identify and validate targetable drivers associated with the FGFR signalling pathway in rectal cancer patients treated with CCRT. METHODS: Using a published transcriptome of rectal cancers, we found FGFR2 gene significantly predicted response to CCRT. The expression levels of FGFR2, using immunohistochemistry assays, were further evaluated in 172 rectal cancer specimens that had not received any treatment. Expression levels of FGFR2 were statistically correlated with major clinicopathological features and clinical survival in this valid cohort. RESULTS: High expression of FGFR2 was significantly related to advanced pretreatment tumour (p=0.022) and nodal status (p=0.026), post-treatment tumour (p<0.001) and nodal status (p=0.004), and inferior tumour regression grade (p<0.001). In survival analyses, high expression of FGFR2 was significantly associated with shorter local recurrence-free survival (p=0.0001), metastasis-free survival (MeFS; p=0.0003) and disease-specific survival (DSS; p<0.0001). Notably, high expression of FGFR2 was independently predictive of worse outcomes for MeFS (p=0.002, HR=5.387) and DSS (p=0.004, HR=4.997). CONCLUSIONS: High expression of FGFR2 is correlated with advanced tumour stage, poor therapeutic response and worse survival in rectal cancer patients receiving neoadjuvant CCRT. These findings indicate that FGFR2 is a prognostic factor for treating rectal cancer. PMID- 25271213 TI - Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes. AB - AIMS: The causes of intellectual disability, which affects 1%-3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases. METHODS: Whole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes. RESULTS: We present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose. CONCLUSIONS: The accessibility to next-generation sequencing allows clinicians to save much time and cost in identifying the aetiology of rare diseases. The presented cases are excellent examples that demonstrate the efficacy of next generation sequencing in rare disease diagnosis. PMID- 25271214 TI - Treating drug dependence with the aid of ibogaine: a retrospective study. AB - Ibogaine is an alkaloid purported to be an effective drug dependence treatment. However, its efficacy has been hard to evaluate, partly because it is illegal in some countries. In such places, treatments are conducted in underground settings where fatalities have occurred. In Brazil ibogaine is unregulated and a combined approach of psychotherapy and ibogaine is being practiced to treat addiction. To evaluate the safety and efficacy of ibogaine, we conducted a retrospective analysis of data from 75 previous alcohol, cannabis, cocaine and crack users (72% poly-drug users). We observed no serious adverse reactions or fatalities, and found 61% of participants abstinent. Participants treated with ibogaine only once reported abstinence for a median of 5.5 months and those treated multiple times for a median of 8.4 months. This increase was statistically significant (p < 0.001), and both single or multiple treatments led to longer abstinence periods than before the first ibogaine session (p < 0.001). These results suggest that the use of ibogaine supervised by a physician and accompanied by psychotherapy can facilitate prolonged periods of abstinence, without the occurrence of fatalities or complications. These results suggest that ibogaine can be a safe and effective treatment for dependence on stimulant and other non-opiate drugs. PMID- 25271216 TI - Acute phase plasma proteins are altered by electroconvulsive stimulation. AB - Electroconvulsive therapy (ECT) is an effective antidepressant treatment, but its molecular mechanisms of action remain to be fully elucidated. To better understand the effects of ECT, we conducted a proteomic study to characterize global changes in plasma protein abundance induced by electroconvulsive stimulation (ECS) in the animal model equivalent of ECT. Male Sprague-Dawley rats were administered a single or repeat (10 sessions) course of ECS, and compared with sham-ECS administered animals. Quantitative differential protein expression analysis was performed, using 2-dimensional difference in gel electrophoresis (2D DiGE), on immunodepleted plasma. Proteins were selected for identification by liquid chromatography tandem mass spectrometry (LC-MS/MS): 150 protein spots were significantly altered following a single ECS and 178, following repeated ECS. In total, 18 proteins were identified by LC-MS/MS. Many of these were acute-phase response proteins, previously reported to be increased in depressed patients. Changes in the abundance of two proteins of interest were confirmed by other measures. Repeat ECS was found to significantly reduce plasma levels of haptoglobin and apolipoprotein A-IV, although these changes were no longer evident 4 weeks after the repeated ECS. Our results implicate the immune system induced acute phase protein response in ECS action while identifying potential plasma biomarkers for ECS. PMID- 25271215 TI - The effects of acute nicotine on contextual safety discrimination. AB - Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the 'dangerous context', whereas CXB was designated as the 'safe context'. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients. PMID- 25271217 TI - Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes. AB - Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic beta-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of beta-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic beta-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis. PMID- 25271218 TI - Developing personalised integrated psychotherapy for patients with personality disorders. PMID- 25271219 TI - Hypertonic saline for acute viral bronchiolitis: take the evidence with a grain of salt. PMID- 25271221 TI - The COPD Assessment Test: what have we learned over its first 5 years? PMID- 25271220 TI - Club cells, CC10 and self-control at the epithelial surface. PMID- 25271222 TI - Obstructive sleep apnoea and hypertension: the ESADA study. PMID- 25271223 TI - Connective tissue disease-associated pulmonary arterial hypertension: "Beijing style". PMID- 25271224 TI - Is inflammation a potential therapeutic target in chronic thromboembolic pulmonary hypertension? PMID- 25271225 TI - Protein quality control in lung disease: it's all about cloud networking. PMID- 25271226 TI - Lung cancer in never-smokers: radon exposure and environmental tobacco smoke. PMID- 25271227 TI - The expert patient: towards a novel definition. PMID- 25271229 TI - Using cerebrospinal fluid for the diagnosis of tuberculous meningitis with GeneXpert. PMID- 25271230 TI - Using cerebrospinal fluid for the diagnosis of tuberculous meningitis with GeneXpert. PMID- 25271231 TI - Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. PMID- 25271232 TI - Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. PMID- 25271233 TI - Manuscript cited in "Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement". PMID- 25271234 TI - Manuscript cited in "Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement". PMID- 25271237 TI - Vaginitis emphysematosa: a rare entity scarcely known to gynecologists. PMID- 25271238 TI - Risk factors for frequent falls in people with Parkinson's disease. AB - Fall frequency varies among individuals with Parkinson's disease (PD). We aimed to determine whether risk factors that distinguish PD fallers from non-fallers are influenced by frequent falls. 205 people with PD participated in a 6-month prospective study. Factors in previously published fall risk models were analyzed for their associations with fall rates and frequent fallers. Fall history, freezing and impaired reactive balance were associated with fall rates and the proportion of frequent fallers (p < 0.05). These models were highly accurate in discriminating frequent fallers (area under curve 0.84-0.87). Interventions to manage freezing and reduce balance impairment may reduce fall frequency. PMID- 25271239 TI - A survey of Parkinson's disease patients: most bothersome symptoms and coping preferences. AB - BACKGROUND: Treatment for Parkinson's disease (PD) is symptomatic. Health professionals must therefore understand which of the many motor and non-motor problems that patients experience are the most troublesome, and what types of assistance patients believe would best help them cope with these problems. OBJECTIVE: To identify and understand potential issues of importance to patients with Parkinson's Disease. METHODS: We conducted surveys with 75 patients with PD in a Movement Disorders Program. We asked about: the two most bothersome PD related problems, methods for coping with these problems, what motor and non motor PD-related problems patients needed the most help with, and what a comprehensive assistance program for PD patients and caregivers should include. We used qualitative data analysis techniques to summarize responses. RESULTS: The most bothersome problems cited were: tremors, lack of mobility, pain, imbalance, lack of energy/fatigue, having to give up previously enjoyed activities, dysarthria, and anxiety or depression. Frequently cited ways to cope with different types of problems included medications, physical activity, instrumental or practical support, and emotional support. When asked specifically about which non-motor problems elicited the most need for help, respondents most commonly mentioned depression and anxiety, "nothing," or cognitive problems. Participants suggested that a comprehensive assistance program for people with PD and their caregivers should include education, physical activity, and emotional support. CONCLUSIONS: RESULTS from this survey highlight the diversity of patient experiences with PD, and the importance of strategies for coping with both motor and non-motor symptoms associated with Parkinson's Disease (in addition to medications). PMID- 25271240 TI - Resolving distinct genetic regulators of tomato leaf shape within a heteroblastic and ontogenetic context. AB - Leaf shape is mutable, changing in ways modulated by both development and environment within genotypes. A complete model of leaf phenotype would incorporate the changes in leaf shape during juvenile-to-adult phase transitions and the ontogeny of each leaf. Here, we provide a morphometric description of >33,000 leaflets from a set of tomato (Solanum spp) introgression lines grown under controlled environment conditions. We first compare the shape of these leaves, arising during vegetative development, with >11,000 previously published leaflets from a field setting and >11,000 leaflets from wild tomato relatives. We then quantify the changes in shape, across ontogeny, for successive leaves in the heteroblastic series. Using principal component analysis, we then separate genetic effects modulating (1) the overall shape of all leaves versus (2) the shape of specific leaves in the series, finding the former more heritable than the latter and comparing quantitative trait loci regulating each. Our results demonstrate that phenotype is highly contextual and that unbiased assessments of phenotype, for quantitative genetic or other purposes, would ideally sample the many developmental and environmental factors that modulate it. PMID- 25271241 TI - How vacuolar sorting receptor proteins interact with their cargo proteins: crystal structures of apo and cargo-bound forms of the protease-associated domain from an Arabidopsis vacuolar sorting receptor. AB - In plant cells, soluble proteins are directed to vacuoles because they contain vacuolar sorting determinants (VSDs) that are recognized by vacuolar sorting receptors (VSR). To understand how a VSR recognizes its cargo, we present the crystal structures of the protease-associated domain of VSR isoform 1 from Arabidopsis thaliana (VSR1PA) alone and complexed with a cognate peptide containing the barley (Hordeum vulgare) aleurain VSD sequence of 1ADSNPIRPVT10. The crystal structures show that VSR1PA binds the sequence, Ala-Asp-Ser, preceding the NPIR motif. A conserved cargo binding loop, with a consensus sequence of 95RGxCxF100, forms a cradle that accommodates the cargo-peptide. In particular, Arg-95 forms a hydrogen bond to the Ser-3 position of the VSD, and the essential role of Arg-95 and Ser-3 in receptor-cargo interaction was supported by a mutagenesis study. Cargo binding induces conformational changes that are propagated from the cargo binding loop to the C terminus via conserved residues in switch I-IV regions. The resulting 180 degrees swivel motion of the C-terminal tail is stabilized by a hydrogen bond between Glu-24 and His-181. A mutagenesis study showed that these two residues are essential for cargo interaction and trafficking. Based on our structural and functional studies, we present a model of how VSRs recognize their cargos. PMID- 25271243 TI - Free and total cortisol levels are useful prognostic markers in critically ill patients: a prospective observational study. AB - OBJECTIVE: The role of cortisol in the prediction of mortality risk in critical illness is controversial in the literature. The aim of this study was to evaluate the prognostic value of cortisol concentrations in a mixed population of critically ill patients in medical emergencies. DESIGN: In this prospective, observational study, measurement of total (TC) and free cortisol (FC) levels was made in the serum samples of 69 critically ill patients (39 males and 30 females, median age of 74 years) at admission (0 h) and 6, 24, 48, and 96 h after admission. METHODS: Cortisol levels were determined using HPLC coupled high resolution ESI-TOF mass spectrometry. The severity of disease was calculated by prognostic scores. Statistical analyses were performed using the SPSS 22.0 software. RESULTS: The range of TC varied between 49.9 and 8797.8 nmol/l, FC between 0.4 and 759.9 nmol/l. The levels of FC at 0, 6, 24, and 48 h and TC at 0, 6 h were significantly elevated in non-survivors and correlated with the predicted mortality. The prognostic value of these cortisol levels was comparable with the routinely used mortality scores. In predictive models, FC at 6, 24, and 48 h proved to be an independent determinant of mortality. CONCLUSIONS: The predictive values of FC in the first 2 days after admission and TC within 6 h are comparable with the complex, routinely used mortality scores in evaluating the prognosis of critically ill patients. The cortisol response probably reflects the severity of disease. PMID- 25271242 TI - Spatio-temporal dynamics of fructan metabolism in developing barley grains. AB - Barley (Hordeum vulgare) grain development follows a series of defined morphological and physiological stages and depends on the supply of assimilates (mainly sucrose) from the mother plant. Here, spatio-temporal patterns of sugar distributions were investigated by mass spectrometric imaging, targeted metabolite analyses, and transcript profiling of microdissected grain tissues. Distinct spatio-temporal sugar balances were observed, which may relate to differentiation and grain filling processes. Notably, various types of oligofructans showed specific distribution patterns. Levan- and graminan-type oligofructans were synthesized in the cellularized endosperm prior to the commencement of starch biosynthesis, while during the storage phase, inulin-type oligofructans accumulated to a high concentration in and around the nascent endosperm cavity. In the shrunken endosperm mutant seg8, with a decreased sucrose flux toward the endosperm, fructan accumulation was impaired. The tight partitioning of oligofructan biosynthesis hints at distinct functions of the various fructan types in the young endosperm prior to starch accumulation and in the endosperm transfer cells that accomplish the assimilate supply toward the endosperm at the storage phase. PMID- 25271244 TI - Preventive effects of zingerone on altered lipid peroxides and nonenzymatic antioxidants in the circulation of isoproterenol-induced myocardial infarcted rats. AB - The present study was designed to evaluate the preventive effects of zingerone on circulatory lipid peroxides and nonenzymatic antioxidants in isoproterenol induced myocardial infarcted rats. Rats were pretreated with zingerone (6 mg/kg body weight) daily for a period of 14 days and were then induced myocardial infarction with isoproterenol (100 mg/kg body weight) on 15th and 16th day. Increased intensities of serum lactate dehydrogenase isoenzymes 1 and 2 bands enhanced plasma lipid peroxidation products and lowered nonenzymatic antioxidant system were noted in isoproterenol-induced rats. Pretreatment with zingerone daily for 14 days revealed significant preventive effects on the electrophoretic and biochemical parameters evaluated in isoproterenol-induced rats. Furthermore, the in vitro study confirmed the potent antioxidant activity of zingerone. The results of our study showed that zingerone protected the rat's heart against isoproterenol-induced myocardial infarction by its antioxidant effect. PMID- 25271245 TI - Clinic offering affordable radiation therapy to increase access to care for patients enrolled in hospice. AB - PURPOSE: A majority of patients enrolled in hospice have advanced cancer. Most of them are burdened by symptoms related to uncontrolled tumor growth. Although palliative radiation therapy (RT) is highly effective, only 1% of hospice patients are ever referred. Commonly cited concerns include high treatment cost, burden of travel for multiple visits, and a perceived reluctance of radiation oncologists to deliver single-fraction RT. METHODS: A clinic offering affordable RT to patients in hospice was developed to simplify the intake, reduce cost, and minimize travel to a single visit. The goal was to evaluate, simulate and plan treatment, and treat patients with a single fraction of palliative RT within a 4 hour period. RESULTS: The initial 18-month experience is reported in this Health Information Portability and Accountability Act-compliant report that was approved by the Virginia Commonwealth University Institutional Review Board. Eight referrals were received from local hospice agencies that had not referred any patients in previous years. A telephone screening process avoided unnecessary travel for two patients who were not candidates for RT. Two additional patients who were evaluated with a same-day computed tomography simulation were not good candidates for RT. Ultimately, four patients were successfully treated with single-fraction palliative RT of 8 Gy. None had to disenroll from hospice. CONCLUSION: This novel program increased access to palliative RT for patients in hospice who would otherwise not have been referred. The main challenge identified was a need for ongoing educational activities at hospice agencies where staff turnover may be high and understanding about palliative RT can be limited. PMID- 25271246 TI - Are Patients With Thoracic Malignancies at Risk for Uncontrolled Symptoms? AB - PURPOSE: Patients with cancer often develop symptoms and contact their oncologists and care teams after normal clinic operating hours. Better understanding of these after-hours telephone calls can inform efforts to improve cancer care and to reduce health care spending. We sought to evaluate after-hours calls at Stanford Cancer Institute (SCI) Thoracic Oncology Clinic. METHODS: We retrospectively analyzed content of telephone call notes made to SCI during weekends and from 5 pm to 8 am on weekdays. Chief complaint, caller and patient demographics, patient diagnosis, advice given, and disposition were analyzed. chi(2) tests were used to analyze differences in proportions. RESULTS: There were a total of 263 after-hours telephone calls during the 6 months of the study. After exclusions, there were 241 telephone calls for analysis. The majority of calls occurred between 5 pm to 11 pm (n = 175 [73%]; P < .001), followed by daytime calls on weekends (n = 157 [65%]; P < .001). Common symptoms were cough (28%) and dyspnea (27%). Of the calls, 62% (150 patients) resulted in emergency department (ED) referral, and 77% of patients (115 of 150) evaluated in the ED were admitted to the hospital. CONCLUSION: Most after-hours telephone calls from patients with lung cancer are related to symptoms. Many patients were referred to the ED and subsequently required hospitalization. Analysis of call content and prior events leading to after-hours calls may predict hospital admissions in this group of patients and can inform development of proactive interventions to improve quality of care and patient-centered outcomes. PMID- 25271247 TI - Associations of chronic individual-level and neighbourhood-level stressors with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Several individual-level stressors have been linked to incident coronary heart disease (CHD), but less attention has focused on the influence of neighbourhood-level sources of stress. In this study we examined prospective associations of individual-level and neighbourhood-level stressors with incident CHD. METHODS: Multi-Ethnic Study of Atherosclerosis participants aged 45-84 years at baseline (2000-2002) with complete data were included in the analyses (n=6678 for individual-level and n=6105 for neighbourhood-level stressors). CHD was defined as non-fatal myocardial infarction, resuscitated cardiac arrest or CHD death. Median follow-up was 10.2 years. Multivariable Cox proportional hazards models were fitted to estimate associations of individual-level and neighbourhood level stressors (categorised into approximate tertiles) with incident CHD. RESULTS: Higher reported individual-level stressors were associated with higher incident CHD. Participants in the high individual-level stressor category had 65% higher risk of incident CHD (95% CI 1.23 to 2.22) than those in the low category after adjusting for sociodemographics (P for trend=0.002). This association weakened but remained significant with further adjustment for behavioural and biological risk factors. There was a non-linear relationship between neighbourhood-level stressors and incident CHD (P for quadratic term=0.01). Participants in the medium category had 49% higher CHD risk (95% CI 1.06 to 2.10) compared with those in the low category; those in the high category had only 27% higher CHD risk (95% CI 0.83 to 1.95). These associations persisted with adjustment for risk factors and individual-level stressors. CONCLUSIONS: Individual-level and neighbourhood-level stressors were independently associated with incident CHD, though the nature of the relationships differed. PMID- 25271249 TI - Adult asthma increases dementia risk: a nationwide cohort study. AB - BACKGROUND: Studies on the association between adult asthma and dementia are few. We investigated the risk of dementia in patients diagnosed with adult asthma compared with that of people without asthma who were age and sex matched to the study patients. METHODS: We used data from the National Health Insurance Research Database. A total of 12 771 patients with newly diagnosed asthma between 2001 and 2003 were evaluated and 51 084 people without asthma were used as the comparison cohort. Cox proportional hazard regression analysis was used to measure the HR of dementia for the asthmatic cohort, compared with that of the non-asthmatic cohort. RESULTS: The HR of dementia was 1.27 (95% confidence interval (CI) 1.15 to 1.41) for the asthmatic cohort, compared with the non-asthmatic cohort after adjusting for age, sex, comorbidities, annual outpatient department visits and medicine used. The HR of dementia development increased substantially as frequency of asthma exacerbation and hospitalisation increased. CONCLUSIONS: This nationwide cohort study suggests that the risk of dementia development is significantly increased in patients with asthma compared with that of the general population. In addition, dementia risk increases substantially with asthma exacerbation and hospitalisation frequency increases. PMID- 25271248 TI - Hormesis and public health: can glutathione depletion and mitochondrial dysfunction due to very low-dose chronic exposure to persistent organic pollutants be mitigated? AB - BACKGROUND: Exposure to persistent organic pollutants (POPs) is linked to many chronic diseases, including diabetes and cardiovascular diseases. Among several possible mechanisms are gradual glutathione depletion and mitochondrial dysfunction after chronic exposure to very low doses of POP mixtures. However, it is biologically noteworthy that glutathione status and mitochondrial function is subject to hormesis, defined broadly as mild stress-induced stimulation of cellular protective mechanisms, including increased synthesis of glutathione and promotion of mitochondrial biogenesis. Although high levels of reactive oxygen/nitrogen species (ROS) can cause cellular damage, certain levels of ROS function as signalling molecules to induce hormetic effects. Thus, similar to many other stressors generating ROS, glutathione status and mitochondrial function can be improved at higher POP doses. However, higher POP levels are dangerous despite their hormetic effects due to other adverse phenomena. Also, the persistent nature of POPs can make hormetic effects less effective in humans as hormesis may be the most active with transient stressors. Hormesis-inducing stressors should be placed into three categories for public health purposes: (1) disadvantageous: chemicals like POPs and radiation, that could harm humans by endocrine disruption, action of chemical mixtures and susceptible populations; (2) neutral: cold, heat, and gravity; and (3) advantageous: moderate exercise, phytochemical intake, and calorie restriction. Noting that regulation of POPs, while critical, has provided insufficient protection because POPs persist in human bodies and the food chain, advantageous stressors should be used by the public to mitigate glutathione depletion and mitochondrial dysfunction due to POPs. PMID- 25271250 TI - Long-term effects of adrenalectomy or spironolactone on blood pressure control and regression of left ventricle hypertrophy in patients with primary aldosteronism. AB - INTRODUCTION: Primary aldosteronism (PA) represents the most common cause of secondary hypertension. Beyond increased blood pressure, additional harmful effects of aldosterone excess including inappropriate left ventricle (LV) hypertrophy were found. We evaluated the effect of adrenalectomy and spironolactone on blood pressure and myocardial remodelling in a long-term follow up study. METHODS: Thirty-one patients with PA were recruited. Fifteen patients with confirmed aldosterone-producing adenoma underwent adrenalectomy; in the remaining 16 patients, treatment with spironolactone was initiated. Laboratory data, 24-hour ambulatory blood pressure monitoring (ABPM) and echocardiography parameters were evaluated at baseline and at a median follow-up of 64 months. RESULTS: Both approaches reduced blood pressure (p = 0.001 vs. baseline). In both groups we observed a decrease in end-diastolic (p = 0.04, p = 0.01) and end systolic LV cavity diameters (p = 0.03, p = 0.01). Interventricular septum and posterior wall thickness reduction was significant only after adrenalectomy (p = 0.01, p = 0.03) as was reduction of LV mass index (p = 0.004). A trend to lower LV mass on spironolactone was caused predominantly by diminution of the LV cavity, which was reflected in increased relative wall thickness (p = 0.05). CONCLUSIONS: Although both surgical and conservative treatment can induce a long term decrease of blood pressure, adrenalectomy seems to be more effective in reduction of LV mass, as it reverses both wall thickening and enlargement of the LV cavity. PMID- 25271251 TI - Area epidemiological research on hypertension risk factors of Keriyans in the Taklimakan Desert. AB - INTRODUCTION: The Keriyans live in the hot, arid areas of Taklimakan Desert and maintain a primitive way of life. They have a low incidence of hypertension. However, little is known about the adaptive compensation in the organism. In the present study, we explored the the traditional risk factors of hypertension in the Keriyans. MATERIALS AND METHODS: We performed an epidemiological survey of Keriyans in a randomly selected natural population including 508 individuals aged 16 years or more, using the WHO MONICA scheme and 151 randomly selected age/gender-matched controls, Uighurs, from the nearest villagers to the Keriyans. RESULTS: The incidence of hypertension in the Keriyans was significantly lower than that in the controls(p<0.001). Multivariate logistic regression analysis indicated that age, hyperglycemia and salt consumption as well as sodium intake in diet were associated with traditional hypertension risk factors. Correlation between water quality and hypertension showed that calcium was positively associated with the detection rate of hypertension. CONCLUSIONS: Age, hyperglycemia and salt consumption as well as sodium intake in diet were correlated with hypertension risk factors, which leads to the speculation that the water of the desert draught area which is characterized by low calcium and high magnesium levels might account for the low incidence of hypertension in Keriyans. PMID- 25271252 TI - Effects of a restricted fetal growth environment on human kidney morphology, cell apoptosis and gene expression. AB - OBJECTIVE: Kidney development is key to the onset of hypertension and cardiovascular diseases in adults, and in the fetal stage will be impaired by a lack of nutrients in utero in animal models. However, few human studies have been performed. METHODS: Kidney samples from fetuses in a fetal growth restriction (FGR) environment were collected and the morphological characteristics were observed. Potentially molecular mechanisms were explored by analyzing apoptosis and kidney-development related gene expression. RESULTS: The results indicated that no malformations were observed in the kidney samples of the FGR group, but the mean kidney weight and volume were significantly decreased. Moreover, the ratio of apoptotic cells and Bax-positive cells was increased and the ratio of Bcl-2-positive cells was decreased in the FGR group, indicating potential apoptosis induction under an in utero FGR environment. Finally, aberrant expression of renin and angiotensinogen indicated potential kidney functional abnormalities in the FGR group. CONCLUSIONS: Our study suggested increased apoptosis and decreased renin and angiotensinogen expression during human kidney development in an FGR environment. The current results will be helpful to further explore the molecular mechanism of FGR and facilitate future studies of hypertension and cardiovascular diseases and the establishment of preventive methods. PMID- 25271253 TI - The effect of renin-angiotensin system inhibitors on intact parathyroid hormone levels in peritoneal dialysis patients. AB - HYPOTHESIS/INTRODUCTION: The objective of this article is to investigate the effect of renin-angiotensin system inhibitors (RASIs) on intact parathyroid hormone (iPTH) levels in continuous ambulatory peritoneal dialysis (CAPD) patients. MATERIALS AND METHODS: All patients were divided into RASI-treated and non-treated groups. The relationships between the iPTH levels in CAPD patients and the clinical parameters and medication use were analyzed via linear regression. RESULTS: A total of 149 CAPD patients were included in this study. The average iPTH level of the entire group was 189.4 pg/ml (range, 102.8-373.4 pg/ml). There were 79 (53.0%) and 70 (47.0%) cases in the RASI-treated and non treated groups, respectively, with average iPTH levels of 139.0 pg/ml (range, 91.6-258.4 pg/ml) and 253.0 pg/ml (range, 134.3-467.2 pg/ml), respectively; this difference was statistically significant (p = 0.001). Multilinear regression analysis showed that age, dialysis vintage, serum phosphatemia, ALP, Hb and RASI use were independent factors that were associated with iPTH level. CONCLUSION: RASI use may be associated with a lower iPTH level in CAPD patients, although the underlying mechanism requires further study. PMID- 25271254 TI - The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density. AB - Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels. PMID- 25271255 TI - Crystal structure of a c-di-AMP riboswitch reveals an internally pseudo-dimeric RNA. AB - Cyclic diadenosine monophosphate (c-di-AMP) is a second messenger that is essential for growth and homeostasis in bacteria. A recently discovered c-di-AMP responsive riboswitch controls the expression of genes in a variety of bacteria, including important pathogens. To elucidate the molecular basis for specific binding of c-di-AMP by a gene-regulatory mRNA domain, we have determined the co crystal structure of this riboswitch. Unexpectedly, the structure reveals an internally pseudo-symmetric RNA in which two similar three-helix-junction elements associate head-to-tail, creating a trough that cradles two c-di-AMP molecules making quasi-equivalent contacts with the riboswitch. The riboswitch selectively binds c-di-AMP and discriminates exquisitely against other cyclic dinucleotides, such as c-di-GMP and cyclic-AMP-GMP, via interactions with both the backbone and bases of its cognate second messenger. Small-angle X-ray scattering experiments indicate that global folding of the riboswitch is induced by the two bound cyclic dinucleotides, which bridge the two symmetric three-helix domains. This structural reorganization likely couples c-di-AMP binding to gene expression. PMID- 25271257 TI - Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration. AB - Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6 disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5 a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5 a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease. PMID- 25271256 TI - Tolerance and cross-tolerance to head twitch behavior elicited by phenethylamine- and tryptamine-derived hallucinogens in mice. AB - The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a potential therapeutic target to a host of neuropsychiatric conditions, but agonist actions at this site are linked to abuse-related hallucinogenic effects that may limit therapeutic efficacy of chronic drug administration. Tolerance to some effects of hallucinogens has been observed in humans and laboratory animals, but the understanding of tolerance and cross-tolerance between distinct structural classes of hallucinogens is limited. Here, we used the drug-elicited head twitch response (HTR) in mice to assess the development of tolerance and cross-tolerance with two phenethylamine-derived [DOI (2,5-dimethoxy-4-iodoamphetamine) and 2C-T-7 (2,5-dimethoxy-4-propylthiophenethylamine)] and two tryptamine-derived [DPT (N,N dipropyltryptamine) and DIPT (N,N-diisopropyltryptamine)] drugs with agonist affinity for 5-HT2A receptors. Tolerance developed to HTR elicited by daily DOI or 2C-T-7, but not to HTR elicited by DPT or DIPT. DOI-elicited tolerance was not surmountable with dose, and a similar insurmountable cross-tolerance was evident when DOI-tolerant mice were tested with various doses of 2C-T-7 or DPT. These studies suggest that the use of phenethylamine-derived hallucinogens as therapeutic agents may be limited not only by their abuse potential, but also by the rapid development of tolerance that would likely be maintained even if a patient were switched to a different 5-HT2A agonist medication from a distinct structural class. However, these experiments also imply that tryptamine-derived hallucinogens might have a reduced potential for tolerance development, compared with phenethylamine-derived 5-HT2A agonists, and might therefore be more suitable for chronic administration in a therapeutic context. PMID- 25271258 TI - Pharmacology of a novel central nervous system-penetrant P2X7 antagonist JNJ 42253432. AB - In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1beta. In this study, we characterized JNJ-42253432 [2-methyl-N ([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5 carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pKi 9.1 +/- 0.07) and human (pKi 7.9 +/- 0.08) P2X7 channel. The compound blocked the ATP-induced current and Bz-ATP [2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate tri(triethylammonium)]-induced release of IL-1beta in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1beta induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the alpha-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel. PMID- 25271259 TI - Interplay between insects and plants: dynamic and complex interactions that have coevolved over millions of years but act in milliseconds. AB - In an environment with changing availability and quality of host plants, phytophagous insects are under selection pressure to find quality hosts. They need to maximize their fitness by locating suitable plants and avoiding unsuitable ones. Thus, they have evolved a finely tuned sensory system, for detection of host cues, and a nervous system, capable of integrating inputs from sensory neurons with a high level of spatio-temporal resolution. Insect responses to cues are not fixed but depend on the context in which they are perceived, the physiological state of the insect, and prior learning experiences. However, there are examples of insects making 'mistakes' and being attracted to poor quality hosts. While insects have evolved ways of finding hosts, plants have been under selection pressure to do precisely the opposite and evade detection or defend themselves when attacked. Once on the plant, insect-associated molecules may trigger or suppress defence depending on whether the plant or the insect is ahead in evolutionary terms. Plant volatile emission is influenced by defence responses induced by insect feeding or oviposition which can attract natural enemies but repel herbivores. Conversely, plant reproductive fitness is increased by attraction of pollinators. Interactions can be altered by other organisms associated with the plant such as other insects, plant pathogens, or mycorrhizal fungi. Plant phenotype is plastic and can be changed by epigenetic factors in adaptation to periods of biotic stress. Space and time play crucial roles in influencing the outcome of interactions between insects and plants. PMID- 25271260 TI - Fertility of CMS wheat is restored by two Rf loci located on a recombined acrocentric chromosome. AB - Cytoplasmic male sterility (CMS) results from incompatibility between nuclear and cytoplasmic genomes, and is characterized by the inability to produce viable pollen. The restoration of male fertility generally involves the introgression of nuclear genes, termed restorers of fertility (Rf). CMS has been widely used for hybrid seed production in many crops but not in wheat, partly owing to the complex genetics of fertility restoration. In this study, an acrocentric chromosome that restores pollen fertility of CMS wheat in Hordeum chilense cytoplasm (msH1 system) is studied. The results show that this chromosome, of H. chilense origin and named H(ch)ac, originated from a complex reorganization of the short arm of chromosomes 1H(ch) (1H(ch)S) and 6H(ch) (6H(ch)S). Diversity arrays technology (DArT) markers and cytological analysis indicate that H(ch)ac is a kind of 'zebra-like' chromosome composed of chromosome 1H(ch)S and alternate fragments of interstitial and distal regions of chromosome 6H(ch)S. PCR-based markers together with FISH, GISH, and meiotic pairing analysis support this result. A restorer of fertility gene, named Rf6H(ch)S, has been identified on the short arm of chromosome 6H(ch)S. Moreover, restoration by the addition of chromosome 1H(ch)S has been observed at a very low frequency and under certain environmental conditions. Therefore, the results indicate the presence of two Rf genes on the acrocentric chromosome: Rf6H(ch)S and Rf1H(ch)S, the restoration potential of Rf6H(ch)S being greater. The stable and high restoration of pollen fertility in the msH1 system is therefore the result of the interaction between these two restorer genes. PMID- 25271261 TI - The trehalose pathway in maize: conservation and gene regulation in response to the diurnal cycle and extended darkness. AB - Energy resources in plants are managed in continuously changing environments, such as changes occurring during the day/night cycle. Shading is an environmental disruption that decreases photosynthesis, compromises energy status, and impacts on crop productivity. The trehalose pathway plays a central but not well-defined role in maintaining energy balance. Here, we characterized the maize trehalose pathway genes and deciphered the impacts of the diurnal cycle and disruption of the day/night cycle on trehalose pathway gene expression and sugar metabolism. The maize genome encodes 14 trehalose-6-phosphate synthase (TPS) genes, 11 trehalose-6-phosphate phosphatase (TPP) genes, and one trehalase gene. Transcript abundance of most of these genes was impacted by the day/night cycle and extended dark stress, as were sucrose, hexose sugars, starch, and trehalose-6-phosphate (T6P) levels. After extended darkness, T6P levels inversely followed class II TPS and sucrose non-fermenting-related protein kinase 1 (SnRK1) target gene expression. Most significantly, T6P no longer tracked sucrose levels after extended darkness. These results showed: (i) conservation of the trehalose pathway in maize; (ii) that sucrose, hexose, starch, T6P, and TPS/TPP transcripts respond to the diurnal cycle; and(iii) that extended darkness disrupts the correlation between T6P and sucrose/hexose pools and affects SnRK1 target gene expression. A model for the role of the trehalose pathway in sensing of sucrose and energy status in maize seedlings is proposed. PMID- 25271262 TI - Accumulation of 5-hydroxynorvaline in maize (Zea mays) leaves is induced by insect feeding and abiotic stress. AB - Plants produce a wide variety of defensive metabolites to protect themselves against herbivores and pathogens. Non-protein amino acids, which are present in many plant species, can have a defensive function through their mis-incorporation during protein synthesis and/or inhibition of biosynthetic pathways in primary metabolism. 5-Hydroxynorvaline was identified in a targeted search for previously unknown non-protein amino acids in the leaves of maize (Zea mays) inbred line B73. Accumulation of this compound increases during herbivory by aphids (Rhopalosiphum maidis, corn leaf aphid) and caterpillars (Spodoptera exigua, beet armyworm), as well as in response to treatment with the plant signalling molecules methyl jasmonate, salicylic acid and abscisic acid. In contrast, ethylene signalling reduced 5-hydroxynorvaline abundance. Drought stress induced 5-hydroxynorvaline accumulation to a higher level than insect feeding or treatment with defence signalling molecules. In field-grown plants, the 5 hydroxynorvaline concentration was highest in above-ground vegetative tissue, but it was also detectable in roots and dry seeds. When 5-hydroxynorvaline was added to aphid artificial diet at concentrations similar to those found in maize leaves and stems, R. maidis reproduction was reduced, indicating that this maize metabolite may have a defensive function. Among 27 tested maize inbred lines there was a greater than 10-fold range in the accumulation of foliar 5 hydroxynorvaline. Genetic mapping populations derived from a subset of these inbred lines were used to map quantitative trait loci for 5-hydroxynorvaline accumulation to maize chromosomes 5 and 7. PMID- 25271264 TI - Editorial. PMID- 25271263 TI - Evaluation of endogenous control gene(s) for gene expression studies in human blood exposed to 60Co gamma-rays ex vivo. AB - In gene expression studies, it is critical to normalize data using a stably expressed endogenous control gene in order to obtain accurate and reliable results. However, we currently do not have a universally applied endogenous control gene for normalization of data for gene expression studies, particularly those involving (60)Co gamma-ray-exposed human blood samples. In this study, a comparative assessment of the gene expression of six widely used housekeeping endogenous control genes, namely 18S, ACTB, B2M, GAPDH, MT-ATP6 and CDKN1A, was undertaken for a range of (60)Co gamma-ray doses (0.5, 1.0, 2.0 and 4.0 Gy) at 8.4 Gy min(-1) at 0 and 24 h post-irradiation time intervals. Using the NormFinder algorithm, real-time PCR data obtained from six individuals (three males and three females) were analyzed with respect to the threshold cycle (Ct) value and abundance, DeltaCt pair-wise comparison, intra- and inter-group variability assessments, etc. GAPDH, either alone or in combination with 18S, was found to be the most suitable endogenous control gene and should be used in gene expression studies, especially those involving qPCR of gamma-ray-exposed human blood samples. PMID- 25271265 TI - Systemic therapy and attachment narratives: Attachment Narrative Therapy. AB - This article outlines an integration of attachment theory with narrative theory and systemic theory and practice: Attachment Narrative Therapy (ANT). This integration offers a more powerful explanatory formulation of the development and maintenance of human distress in relationships, families and communities, and gives direction to psychotherapeutic intervention. PMID- 25271266 TI - Capturing Arabidopsis root architecture dynamics with ROOT-FIT reveals diversity in responses to salinity. AB - The plant root is the first organ to encounter salinity stress, but the effect of salinity on root system architecture (RSA) remains elusive. Both the reduction in main root (MR) elongation and the redistribution of the root mass between MRs and lateral roots (LRs) are likely to play crucial roles in water extraction efficiency and ion exclusion. To establish which RSA parameters are responsive to salt stress, we performed a detailed time course experiment in which Arabidopsis (Arabidopsis thaliana) seedlings were grown on agar plates under different salt stress conditions. We captured RSA dynamics with quadratic growth functions (root fit) and summarized the salt-induced differences in RSA dynamics in three growth parameters: MR elongation, average LR elongation, and increase in number of LRs. In the ecotype Columbia-0 accession of Arabidopsis, salt stress affected MR elongation more severely than LR elongation and an increase in LRs, leading to a significantly altered RSA. By quantifying RSA dynamics of 31 different Arabidopsis accessions in control and mild salt stress conditions, different strategies for regulation of MR and LR meristems and root branching were revealed. Different RSA strategies partially correlated with natural variation in abscisic acid sensitivity and different Na(+)/K(+) ratios in shoots of seedlings grown under mild salt stress. Applying root-fit to describe the dynamics of RSA allowed us to uncover the natural diversity in root morphology and cluster it into four response types that otherwise would have been overlooked. PMID- 25271267 TI - Malaria and HIV infection in Mozambican pregnant women are associated with reduced transfer of antimalarial antibodies to their newborns. AB - BACKGROUND: Malaria and human immunodeficiency virus (HIV) infection during pregnancy affect the transplacental transfer of antibodies against several pathogens from mother to fetus, although the effect of malaria and HIV infection on the transfer of antimalarial antibodies remains unclear. METHODS: Levels of total immunoglobulin G (IgG), immunoglobulin M (IgM), and IgG subtypes against the following Plasmodium falciparum antigens were measured in 187 pairs of mother cord plasma specimens from Mozambique: 19-kDa fragment of merozoite surface protein 1 (MSP119), erythrocyte binding antigen 175 (EBA175), apical membrane antigen 1 (AMA1), and parasite lysate. Placental antibody transfer was defined as the cord-to-mother ratio (CMR) of antibody levels. RESULTS: Maternal malaria was associated with reduced CMR of EBA175 IgG (P = .014) and IgG1 (P = .029), AMA1 IgG (P = .002), lysate IgG1 (P = .001), and MSP1 IgG3 (P = .01). Maternal HIV was associated with reduced CMR of MSP1 IgG1 (P = .022) and IgG3 (P = .023), lysate IgG1 (P = .027) and IgG3 (P = .025), AMA1 IgG1 (P = .001), and EBA175 IgG3 (P = .001). Decreased CMR was not associated with increased adverse pregnancy outcomes or augmented risk of malaria in the infant during the first year of life. CONCLUSIONS: Placental transfer of antimalarial antibodies is reduced in pregnant women with malaria and HIV infection. However, this decrease does not contribute to an increased risk of malaria-associated morbidity during infancy. PMID- 25271268 TI - Prediction of patient survival by change in daily opioid dosage in advanced cancer patients: a prospective hospital-based epidemiologic study. AB - OBJECTIVE: Pain control helps improve quality of life for advanced cancer patients, yet it is unknown whether opioid use increases risk of death. Analyzing the association between time-varying pain medication and the risk of death presents a challenge. This prospective observational study examined the predictability of the patients' survival by variations of daily opioid dosage during the last few days of life. METHODS: Of the 231 cancer patients admitted to a hospice ward between July 2007 and June 2008 was conducted using Cox's model and adjusting for the effects of demography, clinical symptoms/signs, intravenous fluid supplements, antibiotics use and laboratory tests. RESULTS: We found a 3 day negative slope in daily oral morphine equivalent 1 day before each death event to be an independently significant predictor of short time to death (hazard ratio = 1.55; 95% confidence interval: 1.06-2.27). The other significant predictors including faster heart-rate (hazard ratio = 1.01, 95% confidence interval: 1.00-1.02), comorbidity with diabetes (hazard ratio = 1.57, 95% confidence interval: 1.00-2.47), Eastern Cooperative Oncology Group with performance status of 3 or 4 (hazard ratio = 1.78, 95% confidence interval: 1.23 2.58), jaundice (hazard ratio = 2.01, 95% confidence interval: 1.29-3.15), hypercalcemia (hazard ratio = 2.05, 95% confidence interval: 1.40-3.00) and higher serum creatinine level (hazard ratio = 1.36, 95% confidence interval: 1.18 1.57), but use first generation of cephalosporin was a negative predictor of short time to death (hazard ratio = 0.44, 95% confidence interval: 0.28-0.68). CONCLUSION: A reduction of daily oral morphine equivalent over three consecutive days suggests worsening physical condition significantly and independently predicting imminent death ~1 day later. PMID- 25271269 TI - Possible role of template-based lymphadenectomy in reducing the risk of regional node recurrence after nephroureterectomy in patients with renal pelvic cancer. AB - OBJECTIVE: It remains unclear whether lymphadenectomy alters regional node recurrence after nephroureterectomy in patients with urothelial carcinoma of the renal pelvis. The predictive factors for regional node recurrence are still unclear. In this study, we retrospectively examined how the extent of lymphadenectomy influences regional node recurrence in patients with urothelial carcinoma of the renal pelvis. METHODS: From January 1988 through July 2013, we performed nephroureterectomy in 180 patients with non-metastatic (cN0M0) urothelial carcinoma of the renal pelvis at two Japanese institutes. Regional nodes were determined according to our previous mapping study: complete lymphadenectomy designates that all regional sites were dissected; incomplete lymphadenectomy that all sites were not dissected. A third group included those without lymphadenectomy. RESULTS: The 5-year cancer-specific and recurrence-free survival was significantly higher in the complete lymphadenectomy group than in the incomplete lymphadenectomy or without lymphadenectomy groups (P = 0.03). The incidence of regional node recurrence was significantly lower in the complete lymphadenectomy group at 2.9% (2/67) than in the incomplete lymphadenectomy at 18.1% (4/22) or without lymphadenectomy at 10.9% (10/91) groups (P = 0.03). In patients with incomplete lymphadenectomy, 75% of regional node recurrence occurred outside of the dissected sites. Complete lymphadenectomy is shown to be a likely predictive factor of reduced risk of recurrence at the regional nodes by multivariate analysis, after adjusting for patient age, pathological T stage, and pathological nodal metastases. CONCLUSIONS: This study shows that template-based lymphadenectomy reduced the risk of regional node recurrence in patients with urothelial carcinoma of the renal pelvis and appears to result in improved survival. PMID- 25271270 TI - From the NHS reforms to the neurological examination: further evaluation required. PMID- 25271271 TI - Science for sale: the rise of predatory journals. PMID- 25271272 TI - 'If we want things to stay as they are, things will have to change'*. PMID- 25271273 TI - The NHS reforms in England: four challenges to evaluating success and failure. PMID- 25271274 TI - Successfully widening access to medicine. Part 2: Curriculum design and student progression. PMID- 25271275 TI - UK doctors and equal opportunities in the NHS: national questionnaire surveys of views on gender, ethnicity and disability. AB - OBJECTIVES: To seek doctors' views about the NHS as an employer, our surveys about doctors' career intentions and progression, undertaken between 1999 and 2013, also asked whether the NHS was, in their view, a good 'equal opportunities' employer for women doctors, doctors from ethnic minority groups and doctors with disabilities. DESIGN AND SETTING: Surveys undertaken in the UK by mail and Internet. PARTICIPANTS: UK medical graduates in selected graduation years between 1993 and 2012. MAIN OUTCOME MEASURES: Respondents were asked to rate their level of agreement with three statements starting 'The NHS is a good equal opportunities employer for...' and ending 'women doctors', 'doctors from ethnic minorities' and 'doctors with disabilities'. RESULTS: Of first-year doctors surveyed in 2013, 3.6% (78/2158) disagreed that the NHS is a good equal opportunities employer for women doctors (1.7% of the men and 4.7% of the women); 2.2% (44/1968) disagreed for doctors from ethnic minorities (0.9% of white doctors and 5.8% of non-white doctors) and 12.6% (175/1387) disagreed for doctors with disabilities. Favourable perceptions of the NHS in these respects improved substantially between 1999 and 2013; among first-year doctors of 2000-2003, combined, the corresponding percentages of disagreement were 23.5% for women doctors, 23.1% for doctors from ethnic minorities and 50.6% for doctors with disabilities. CONCLUSIONS: Positive views about the NHS as an equal opportunities employer have increased in recent years, but the remaining gap in perception of this between women and men, and between ethnic minority and white doctors, is a concern. PMID- 25271276 TI - The Medical Research Council and treatments for tuberculosis before streptomycin. PMID- 25271277 TI - Use and abuse of physical signs in neurology. PMID- 25271281 TI - Nurses' autonomy in end-of-life situations in intensive care units. AB - BACKGROUND: The intensive care unit environment focuses on interventions and support therapies that prolong life. The exercise by nurses of their autonomy impacts on perception of the role they assume in the multidisciplinary team and on their function in the intensive care unit context. There is much international research relating to nurses' involvement in end-of-life situations; however, there is a paucity of research in this area in Brazil. In the Brazilian medical scenario, life support limitation generated a certain reluctance of a legal nature, which has now become unjustifiable with the publication of a resolution by the Federal Medical Council. In Brazil, the lack of medical commitments to end of-life care is evident. OBJECTIVE: To understand the process by which nurses exercise autonomy in making end-of-life decisions in intensive care units. RESEARCH DESIGN: Symbolic Interactionism and Corbin and Strauss theory methodology were used for this study. PARTICIPANTS AND RESEARCH CONTEXT: Data were collected through single audio-recorded qualitative interviews with 14 critical care nurses. The comparative analysis of the data has permitted the understanding of the meaning of nurse's experience in exercising autonomy relating to end-of-life decision-making. ETHICAL CONSIDERATIONS: Institutional ethics approval was obtained for data collection. Participants gave informed consent. All data were anonymized. FINDINGS: The results revealed that nurses experience the need to exercise autonomy in intensive care units on a daily basis. Their experience expressed by the process of increase opportunities to exercise autonomy is conditioned by the pressure of the intensive care unit environment, in which nurses can grow, feel empowered, and exercise their autonomy or else can continuously depend on the decisions made by other professionals. CONCLUSION: Nurses exercise their autonomy through care. They work to create new spaces at the same time that they acquire new knowledge and make decisions. Because of the complexity of the end-of-life situation, nurses must adopt a proactive attitude that inserts them into the decision-making process. PMID- 25271282 TI - A comprehensive functional map of the hepatitis C virus genome provides a resource for probing viral proteins. AB - Pairing high-throughput sequencing technologies with high-throughput mutagenesis enables genome-wide investigations of pathogenic organisms. Knowledge of the specific functions of protein domains encoded by the genome of the hepatitis C virus (HCV), a major human pathogen that contributes to liver disease worldwide, remains limited to insight from small-scale studies. To enhance the capabilities of HCV researchers, we have obtained a high-resolution functional map of the entire viral genome by combining transposon-based insertional mutagenesis with next-generation sequencing. We generated a library of 8,398 mutagenized HCV clones, each containing one 15-nucleotide sequence inserted at a unique genomic position. We passaged this library in hepatic cells, recovered virus pools, and simultaneously assayed the abundance of mutant viruses in each pool by next generation sequencing. To illustrate the validity of the functional profile, we compared the genetic footprints of viral proteins with previously solved protein structures. Moreover, we show the utility of these genetic footprints in the identification of candidate regions for epitope tag insertion. In a second application, we screened the genetic footprints for phenotypes that reflected defects in later steps of the viral life cycle. We confirmed that viruses with insertions in a region of the nonstructural protein NS4B had a defect in infectivity while maintaining genome replication. Overall, our genome-wide HCV mutant library and the genetic footprints obtained by high-resolution profiling represent valuable new resources for the research community that can direct the attention of investigators toward unidentified roles of individual protein domains. IMPORTANCE: Our insertional mutagenesis library provides a resource that illustrates the effects of relatively small insertions on local protein structure and HCV viability. We have also generated complementary resources, including a website (http://hangfei.bol.ucla.edu) and a panel of epitope-tagged mutant viruses that should enhance the research capabilities of investigators studying HCV. Researchers can now detect epitope-tagged viral proteins by established antibodies, which will allow biochemical studies of HCV proteins for which antibodies are not readily available. Furthermore, researchers can now quickly look up genotype-phenotype relationships and base further mechanistic studies on the residue-by-residue information from the functional profile. More broadly, this approach offers a general strategy for the systematic functional characterization of viruses on the genome scale. PMID- 25271283 TI - Clostridium ramosum promotes high-fat diet-induced obesity in gnotobiotic mouse models. AB - The intestines of obese humans and mice are enriched with Erysipelotrichi, a class within the Firmicutes. Clostridium ramosum, a member of the Erysipelotrichi, is associated with symptoms of the metabolic syndrome in humans. To clarify the possible obesogenic potential of this bacterial species and to unravel the underlying mechanism, we investigated the role of C. ramosum in obesity development in gnotobiotic mice. Mice were associated with a simplified human intestinal (SIHUMI) microbiota of eight bacterial species, including C. ramosum, with the SIHUMI microbiota except C. ramosum (SIHUMIw/oCra), or with C. ramosum only (Cra) and fed a high-fat diet (HFD) or a low-fat diet (LFD). Parameters related to the development of obesity and metabolic diseases were compared. After 4 weeks of HFD feeding, the mouse groups did not differ in energy intake, diet digestibility, gut permeability, and parameters of low-grade inflammation. However, SIHUMI and Cra mice fed the HFD gained significantly more body weight and body fat and displayed higher food efficiency than SIHUMIw/oCra mice fed the HFD. Gene expression of glucose transporter 2 (Glut2) in jejunal mucosa and of fatty acid translocase (CD36) in ileal mucosa was significantly increased in the obese SIHUMI and Cra mice compared with the less obese SIHUMIw/oCra mice. The data demonstrate that the presence of C. ramosum in SIHUMI and Cra mice enhanced diet-induced obesity. Upregulation of small intestinal glucose and fat transporters in these animals may contribute to their increased body fat deposition. IMPORTANCE: Obesity is a growing health problem worldwide. Changes in the proportions of Bacteroidetes and Firmicutes, the two dominant phyla in the human and the murine intestinal tract, link the intestinal microbiota to obesity. Erysipelotrichi, a class within the Firmicutes, increase in response to high-fat feeding in mice. Clostridium ramosum, a member of the Erysipelotrichi, has been linked to symptoms of the metabolic syndrome. We hypothesized that C. ramosum promotes obesity development and related pathologies. Our experiments in gnotobiotic mice show that C. ramosum promoted diet-induced obesity, probably by enhancing nutrient absorption. Identification of obesogenic bacteria and understanding their mode of action enable the development of novel strategies for the treatment of this epidemic disease. Pharmaceuticals that target obesogenic bacteria or their metabolism could help to prevent and treat obesity and related disorders in the future. PMID- 25271284 TI - Intestinal dysbiosis associated with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease in humans and is characterized by the presence of hyperactive immune cells and aberrant antibody responses to nuclear and cytoplasmic antigens, including characteristic anti-double-stranded DNA antibodies. We performed a cross-sectional study in order to determine if an SLE-associated gut dysbiosis exists in patients without active disease. A group of 20 SLE patients in remission, for which there was strict inclusion and exclusion criteria, was recruited, and we used an optimized Ion Torrent 16S rRNA gene-based analysis protocol to decipher the fecal microbial profiles of these patients and compare them with those of 20 age- and sex-matched healthy control subjects. We found diversity to be comparable based on Shannon's index. However, we saw a significantly lower Firmicutes/Bacteroidetes ratio in SLE individuals (median ratio, 1.97) than in healthy subjects (median ratio, 4.86; P < 0.002). A lower Firmicutes/Bacteroidetes ratio in SLE individuals was corroborated by quantitative PCR analysis. Notably, a decrease of some Firmicutes families was also detected. This dysbiosis is reflected, based on in silico functional inference, in an overrepresentation of oxidative phosphorylation and glycan utilization pathways in SLE patient microbiota. IMPORTANCE: Growing evidence suggests that the gut microbiota might impact symptoms and progression of some autoimmune diseases. However, how and why this microbial community influences SLE remains to be elucidated. This is the first report describing an SLE-associated intestinal dysbiosis, and it contributes to the understanding of the interplay between the intestinal microbiota and the host in autoimmune disorders. PMID- 25271285 TI - LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in Gram-negative pathogens. AB - The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor. IMPORTANCE: New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic. PMID- 25271286 TI - Metagenome-wide association of microbial determinants of host phenotype in Drosophila melanogaster. AB - Animal-associated bacteria (microbiota) affect host behaviors and physiological traits. To identify bacterial genetic determinants of microbiota-responsive host traits, we employed a metagenome-wide association (MGWA) approach in two steps. First, we measured two microbiota-responsive host traits, development time and triglyceride (TAG) content, in Drosophila melanogaster flies monoassociated with each of 41 bacterial strains. The effects of monoassociation on host traits were not confined to particular taxonomic groups. Second, we clustered protein-coding sequences of the bacteria by sequence similarity de novo and statistically associated the magnitude of the host trait with the bacterial gene contents. The animals had been monoassociated with genome-sequenced bacteria, so the metagenome content was unambiguous. This analysis showed significant effects of pyrroloquinoline quinone biosynthesis genes on development time, confirming the results of a published transposon mutagenesis screen, thereby validating the MGWA; it also identified multiple genes predicted to affect host TAG content, including extracellular glucose oxidation pathway components. To test the validity of the statistical associations, we expressed candidate genes in a strain that lacks them. Monoassociation with bacteria that ectopically expressed a predicted oxidoreductase or gluconate dehydrogenase conferred reduced Drosophila TAG contents relative to the TAG contents in empty vector controls. Consistent with the prediction that glucose oxidation pathway gene expression increased bacterial glucose utilization, the glucose content of the host diet was reduced when flies were exposed to these strains. Our findings indicate that microbiota affect host nutritional status through modulation of nutrient acquisition. Together, these findings demonstrate the utility of MGWA for identifying bacterial determinants of host traits and provide mechanistic insight into how gut microbiota modulate the nutritional status of a model host. IMPORTANCE: To understand how certain gut bacteria promote the health of their animal hosts, we need to identify the bacterial genes that drive these beneficial relationships. This task is challenging because the bacterial communities can vary widely among different host individuals. To overcome this difficulty, we quantified how well each of 41 bacterial species protected Drosophila fruit flies from high fat content. The genomes of the chosen bacterial strains were previously sequenced, so we could statistically associate specific bacterial genes with bacterially mediated reduction in host fat content. Bacterial genes that promote glucose utilization were strongly represented in the association, and introducing these genes into the gut bacteria was sufficient to lower the animal's fat content. Our method is applicable to the study of many other host microbe interactions as a way to uncover microbial genes important for host health. PMID- 25271287 TI - Differential genome evolution between companion symbionts in an insect-bacterial symbiosis. AB - Obligate symbioses with bacteria allow insects to feed on otherwise unsuitable diets. Some symbionts have extremely reduced genomes and have lost many genes considered to be essential in other bacteria. To understand how symbiont genome degeneration proceeds, we compared the genomes of symbionts in two leafhopper species, Homalodisca vitripennis (glassy-winged sharpshooter [GWSS]) and Graphocephala atropunctata (blue-green sharpshooter [BGSS]) (Hemiptera: Cicadellidae). Each host species is associated with the anciently acquired "Candidatus Sulcia muelleri" (Bacteroidetes) and the more recently acquired "Candidatus Baumannia cicadellinicola" (Gammaproteobacteria). BGSS "Ca. Baumannia" retains 89 genes that are absent from GWSS "Ca. Baumannia"; these underlie central cellular functions, including cell envelope biogenesis, cellular replication, and stress response. In contrast, "Ca. Sulcia" strains differ by only a few genes. Although GWSS "Ca. Baumannia" cells are spherical or pleomorphic (a convergent trait of obligate symbionts), electron microscopy reveals that BGSS "Ca. Baumannia" maintains a rod shape, possibly due to its retention of genes involved in cell envelope biogenesis and integrity. Phylogenomic results suggest that "Ca. Baumannia" is derived from the clade consisting of Sodalis and relatives, a group that has evolved symbiotic associations with numerous insect hosts. Finally, the rates of synonymous and nonsynonymous substitutions are higher in "Ca. Baumannia" than in "Ca. Sulcia," which may be due to a lower mutation rate in the latter. Taken together, our results suggest that the two "Ca. Baumannia" genomes represent different stages of genome reduction in which many essential functions are being lost and likely compensated by hosts. "Ca. Sulcia" exhibits much greater genome stability and slower sequence evolution, although the mechanisms underlying these differences are poorly understood. IMPORTANCE: In obligate animal-bacterial symbioses, bacteria experience extreme patterns of genome evolution, including massive gene loss and rapid evolution. However, little is known about this process, particularly in systems with complementary bacterial partners. To understand whether genome evolution impacts symbiont types equally and whether lineages follow the same evolutionary path, we sequenced the genomes of two coresident symbiotic bacteria from a plant sap-feeding insect and compared them to the symbionts from a related host species. We found that the older symbiont has a highly reduced genome with low rates of mutation and gene loss. In contrast, the younger symbiont has a larger genome that exhibits higher mutation rates and varies dramatically in the retention of genes related to cell wall biogenesis, cellular replication, and stress response. We conclude that while symbiotic bacteria evolve toward tiny genomes, this process is shaped by different selection intensities that may reflect the different ages and metabolic roles of symbiont types. PMID- 25271288 TI - Genomic evidence for a globally distributed, bimodal population in the ovine footrot pathogen Dichelobacter nodosus. AB - Footrot is a contagious, debilitating disease of sheep, causing major economic losses in most sheep-producing countries. The causative agent is the Gram negative anaerobe Dichelobacter nodosus. Depending on the virulence of the infective bacterial strain, clinical signs vary from a mild interdigital dermatitis (benign footrot) to severe underrunning of the horn of the hoof (virulent footrot). The aim of this study was to investigate the genetic relationship between D. nodosus strains of different phenotypic virulences and between isolates from different geographic regions. Genome sequencing was performed on 103 D. nodosus isolates from eight different countries. Comparison of these genome sequences revealed that they were highly conserved, with >95% sequence identity. However, single nucleotide polymorphism analysis of the 31,627 nucleotides that were found to differ in one or more of the 103 sequenced isolates divided them into two distinct clades. Remarkably, this division correlated with known virulent and benign phenotypes, as well as with the single amino acid difference between the AprV2 and AprB2 proteases, which are produced by virulent and benign strains, respectively. This division was irrespective of the geographic origin of the isolates. However, within one of these clades, isolates from different geographic regions generally belonged to separate clusters. In summary, we have shown that D. nodosus has a bimodal population structure that is globally conserved and provide evidence that virulent and benign isolates represent two distinct forms of D. nodosus strains. These data have the potential to improve the diagnosis and targeted control of this economically significant disease. IMPORTANCE: The Gram-negative anaerobic bacterium Dichelobacter nodosus is the causative agent of ovine footrot, a disease of major importance to the worldwide sheep industry. The known D. nodosus virulence factors are its type IV fimbriae and extracellular serine proteases. D. nodosus strains are designated virulent or benign based on the type of disease caused under optimal climatic conditions. These isolates have similar fimbriae but distinct extracellular proteases. To determine the relationship between virulent and benign isolates and the relationship of isolates from different geographical regions, a genomic study that involved the sequencing and subsequent analysis of 103 D. nodosus isolates was undertaken. The results showed that D. nodosus isolates are highly conserved at the genomic level but that they can be divided into two distinct clades that correlate with their disease phenotypes and with a single amino acid substitution in one of the extracellular proteases. PMID- 25271289 TI - Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2 deoxystreptamines as next-generation aminoglycoside antibiotics. AB - The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4' alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides-irreversible hearing loss. Compounds were evaluated for target activity in in vitro ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and in vivo ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity. IMPORTANCE: The ever widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms. PMID- 25271290 TI - Clinical characteristics and outcomes of prosthetic joint infection caused by small colony variant staphylococci. AB - Small colony variants (SCVs) are naturally occurring subpopulations of bacteria. The clinical characteristics and treatment outcomes of patients with prosthetic joint infection (PJI) caused by staphylococcal SCVs are unknown. This study was a retrospective series of 113 patients with staphylococcal PJI, with prospective testing of archived sonicate fluid samples. SCVs were defined using two investigator review. Treatment failure was defined as (i) subsequent revision surgery for any reason, (ii) PJI after the index surgery, (iii) prosthesis nonreimplantation due to ongoing infection, or (iv) amputation of the affected limb. There were 38 subjects (34%) with SCVs and 75 (66%) with only normal phenotype (NP) bacteria. Subjects with SCVs were more likely to have been on chronic antimicrobials prior to surgery (P = 0.048), have had prior surgery for PJI (P = 0.03), have had a longer duration of symptoms (P = 0.0003), and have had a longer time since joint implantation (P = 0.007), compared to those with only NP bacteria. Over a median follow-up of 30.6 months, 9 subjects (24%) with SCVs and 23 (32%) with only NP bacteria experienced treatment failure (P = 0.51). Subjects infected with Staphylococcus aureus were more likely to fail than were those infected with Staphylococcus epidermidis (hazard ratio [HR], 4.03; 95% confidence interval [CI], 1.80 to 9.04). While frequently identified in subjects with PJI and associated with several potential predisposing factors, SCVs were not associated with excess treatment failure compared to NP infections in this study, where they were primarily managed with two-stage arthroplasty exchange. IMPORTANCE: Bacteria with the small colony variant (SCV) phenotype are described in small case series as causing persistent or relapsing infection, but there are insufficient data to suggest that they should be managed differently than infection with normal-phenotype bacteria. In an effort to investigate the clinical importance of this phenotype, we determined whether SCVs were present in biofilms dislodged from the surfaces of arthroplasties of patients with staphylococcal prosthetic joint infection and assessed the clinical outcomes associated with detection of SCVs. We found that prosthetic joint infection caused by SCV staphylococci was associated with a longer duration of symptoms and more prior treatment for infection but not with an increased rate of treatment failure, compared to infection caused by normal-phenotype staphylococci. PMID- 25271292 TI - Editorial: Gigantism: a new way to prolong neutrophil life. PMID- 25271293 TI - Editorial: Does immune dysfunction persist into adulthood after adolescent use of marijuana? PMID- 25271291 TI - Mycobacterial membrane vesicles administered systemically in mice induce a protective immune response to surface compartments of Mycobacterium tuberculosis. AB - Pathogenic and nonpathogenic species of bacteria and fungi release membrane vesicles (MV), containing proteins, polysaccharides, and lipids, into the extracellular milieu. Previously, we demonstrated that several mycobacterial species, including bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis, release MV containing lipids and proteins that subvert host immune response in a Toll-like receptor 2 (TLR2)-dependent manner (R. Prados-Rosales et al., J. Clin. Invest. 121:1471-1483, 2011, doi:10.1172/JCI44261). In this work, we analyzed the vaccine potential of MV in a mouse model and compared the effects of immunization with MV to those of standard BCG vaccination. Immunization with MV from BCG or M. tuberculosis elicited a mixed humoral and cellular response directed to both membrane and cell wall components, such as lipoproteins. However, only vaccination with M. tuberculosis MV was able to protect as well as live BCG immunization. M. tuberculosis MV boosted BCG vaccine efficacy. In summary, MV are highly immunogenic without adjuvants and elicit immune responses comparable to those achieved with BCG in protection against M. tuberculosis. IMPORTANCE: This work offers a new vaccine approach against tuberculosis using mycobacterial MV. Mycobacterium MV are a naturally released product combining immunogenic antigens in the context of a lipid structure. The fact that MV do not need adjuvants and elicit protection comparable to that elicited by the BCG vaccine encourages vaccine approaches that combine protein antigens and lipids. Consequently, mycobacterium MV establish a new type of vaccine formulation. PMID- 25271297 TI - Lipid phosphate phosphatases: more than one way to put the brakes on LPA signaling? PMID- 25271296 TI - A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice. AB - Intracellular lipids and their synthesis contribute to the mechanisms and complications of obesity-associated diseases. We describe an NMR approach that provides an abbreviated lipidomic analysis with concurrent lipid biosynthetic fluxes. Following deuterated water administration, positional isotopomer analysis by deuterium NMR of specific lipid species was used to examine flux through de novo lipogenesis (DNL), FA elongation, desaturation, and TG-glycerol synthesis. The NMR method obviated certain assumptions regarding sites of enrichment and exchangeable hydrogens required by mass isotope methods. The approach was responsive to genetic and pharmacological gain or loss of function of DNL, elongation, desaturation, and glyceride synthesis. BDF1 mice consuming a high-fat diet (HFD) or matched low-fat diet for 35 weeks were examined across feeding periods to determine how flux through these pathways contributes to diet induced fatty liver and obesity. HFD mice had increased rates of FA elongation and glyceride synthesis. However DNL was markedly suppressed despite insulin resistance and obesity. We conclude that most hepatic TGs in the liver of HFD mice were formed from the reesterification of existing or ingested lipids, not DNL. PMID- 25271298 TI - Matrix metalloproteinase-1-mediated mesenchymal stem cell tumor tropism is dependent on crosstalk with stromal derived growth factor 1/C-X-C chemokine receptor 4 axis. AB - Human bone marrow-derived mesenchymal stem cells (MSCs) have the unique ability to home toward injuries or tumor sites. We have previously shown that the tumor tropic property is dependent on the intrinsic expression and activity of the matrix remodeling gene, matrix metalloproteinase 1 (MMP-1). Herein, crosstalk between MMP-1/protease activated receptor 1 (PAR-1) and the G-protein coupled receptor stromal-derived growth factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR 4) in facilitating cell migration was investigated. Gain-of-function and RNA interference (RNAi) technology were used to evaluate the interplay between the key players. The downstream effect on the tumor-tropic migration of MSCs was investigated using modified Boyden chamber assay. Neutralizing PAR-1 activation using monoclonal antibody and targeted knockdown of MMP-1 using RNAi resulted in decreased expression of SDF-1, which was not observed in control-RNAi-transfected cells. Overexpression of CXCR-4 failed to promote MSC migration; the percentage of migrated cells toward tumor cell conditioned medium was similar to the vector transduced and the CXCR-4-transduced MSCs. Furthermore, inhibition of SDF-1/CXCR 4 signaling using AMD3100 reduced MSC migration through the deregulation of MMP-1 promoter activities, protein expression, and metalloproteinase activity. Collectively, our results showed that MMP-1-mediated MSC tumor tropism is dependent on crosstalk with the SDF-1/CXCR-4 axis. PMID- 25271300 TI - Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication. AB - Ovarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell-cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication. PMID- 25271302 TI - A flexible bayesian model for testing for transmission ratio distortion. AB - Current statistical approaches to investigate the nature and magnitude of transmission ratio distortion (TRD) are scarce and restricted to the most common experimental designs such as F2 populations and backcrosses. In this article, we describe a new Bayesian approach to check TRD within a given biallelic genetic marker in a diploid species, providing a highly flexible framework that can accommodate any kind of population structure. This model relies on the genotype of each offspring and thus integrates all available information from either the parents' genotypes or population-specific allele frequencies and yields TRD estimates that can be corroborated by the calculation of a Bayes factor (BF). This approach has been evaluated on simulated data sets with appealing statistical performance. As a proof of concept, we have also tested TRD in a porcine population with five half-sib families and 352 offspring. All boars and piglets were genotyped with the Porcine SNP60 BeadChip, whereas genotypes from the sows were not available. The SNP-by-SNP screening of the pig genome revealed 84 SNPs with decisive evidences of TRD (BF > 100) after accounting for multiple testing. Many of these regions contained genes related to biological processes (e.g., nucleosome assembly and co-organization, DNA conformation and packaging, and DNA complex assembly) that are critically associated with embryonic viability. The implementation of this method, which overcomes many of the limitations of previous approaches, should contribute to fostering research on TRD in both model and nonmodel organisms. PMID- 25271301 TI - Integrated omic analysis of oropharyngeal carcinomas reveals human papillomavirus (HPV)-dependent regulation of the activator protein 1 (AP-1) pathway. AB - HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcomes relative to HPV-negative patients, but the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n = 27) and HPV-negative (n = 26) formalin-fixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis, and immune response. The differential abundances of cortactin and methylthioadenosine phosphorylase were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p = 0.023 and p = 0.009, respectively). An additional 1,124 proteins were independently corroborated through comparison to a published proteomic dataset of OPC. Furthermore, utilizing the Cancer Genome Atlas, we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundances to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs. These proteins might contribute to reduced survival in these patients via their established role in radiation resistance. Through interrogation of Cancer Genome Atlas data, we demonstrated that activation of the beta1 integrin/FAK/cortactin/JNK1 signaling axis and associated differential regulation of activator protein 1 transcription factor target genes are plausible consequences of elevated cortactin protein levels. PMID- 25271303 TI - Mapping eQTL networks with mixed graphical Markov models. AB - Expression quantitative trait loci (eQTL) mapping constitutes a challenging problem due to, among other reasons, the high-dimensional multivariate nature of gene-expression traits. Next to the expression heterogeneity produced by confounding factors and other sources of unwanted variation, indirect effects spread throughout genes as a result of genetic, molecular, and environmental perturbations. From a multivariate perspective one would like to adjust for the effect of all of these factors to end up with a network of direct associations connecting the path from genotype to phenotype. In this article we approach this challenge with mixed graphical Markov models, higher-order conditional independences, and q-order correlation graphs. These models show that additive genetic effects propagate through the network as function of gene-gene correlations. Our estimation of the eQTL network underlying a well-studied yeast data set leads to a sparse structure with more direct genetic and regulatory associations that enable a straightforward comparison of the genetic control of gene expression across chromosomes. Interestingly, it also reveals that eQTLs explain most of the expression variability of network hub genes. PMID- 25271304 TI - A mouse geneticist's practical guide to CRISPR applications. AB - CRISPR/Cas9 system of RNA-guided genome editing is revolutionizing genetics research in a wide spectrum of organisms. Even for the laboratory mouse, a model that has thrived under the benefits of embryonic stem (ES) cell knockout capabilities for nearly three decades, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 technology enables one to manipulate the genome with unprecedented simplicity and speed. It allows generation of null, conditional, precisely mutated, reporter, or tagged alleles in mice. Moreover, it holds promise for other applications beyond genome editing. The crux of this system is the efficient and targeted introduction of DNA breaks that are repaired by any of several pathways in a predictable but not entirely controllable manner. Thus, further optimizations and improvements are being developed. Here, we summarize current applications and provide a practical guide to use the CRISPR/Cas9 system for mouse mutagenesis, based on published reports and our own experiences. We discuss critical points and suggest technical improvements to increase efficiency of RNA-guided genome editing in mouse embryos and address practical problems such as mosaicism in founders, which complicates genotyping and phenotyping. We describe a next-generation sequencing strategy for simultaneous characterization of on- and off-target editing in mice derived from multiple CRISPR experiments. Additionally, we report evidence that elevated frequency of precise, homology-directed editing can be achieved by transient inhibition of the Ligase IV-dependent nonhomologous end-joining pathway in one celled mouse embryos. PMID- 25271305 TI - Linkage disequilibrium with linkage analysis of multiline crosses reveals different multiallelic QTL for hybrid performance in the flint and dent heterotic groups of maize. AB - Multiparental designs combined with dense genotyping of parents have been proposed as a way to increase the diversity and resolution of quantitative trait loci (QTL) mapping studies, using methods combining linkage disequilibrium information with linkage analysis (LDLA). Two new nested association mapping designs adapted to European conditions were derived from the complementary dent and flint heterotic groups of maize (Zea mays L.). Ten biparental dent families (N = 841) and 11 biparental flint families (N = 811) were genotyped with 56,110 single nucleotide polymorphism markers and evaluated as test crosses with the central line of the reciprocal design for biomass yield, plant height, and precocity. Alleles at candidate QTL were defined as (i) parental alleles, (ii) haplotypic identity by descent, and (iii) single-marker groupings. Between five and 16 QTL were detected depending on the model, trait, and genetic group considered. In the flint design, a major QTL (R(2) = 27%) with pleiotropic effects was detected on chromosome 10, whereas other QTL displayed milder effects (R(2) < 10%). On average, the LDLA models detected more QTL but generally explained lower percentages of variance, consistent with the fact that most QTL display complex allelic series. Only 15% of the QTL were common to the two designs. A joint analysis of the two designs detected between 15 and 21 QTL for the five traits. Of these, between 27 for silking date and 41% for tasseling date were significant in both groups. Favorable allelic effects detected in both groups open perspectives for improving biomass production. PMID- 25271308 TI - How Dementia Affects Personal Dignity: A Qualitative Study on the Perspective of Individuals With Mild to Moderate Dementia. AB - OBJECTIVE: This article examines how dementia affects personal dignity in individuals with mild to moderate dementia from their perspective. METHOD: In this qualitative cross-sectional study, in-depth interviews were carried out with 14 individuals, aged 50-94, with mild to moderate dementia who lived at home. Verbatim transcripts were analyzed making use of the principles of thematic analysis. RESULTS: Although mild to moderate dementia resulted in a diminished sense of personal dignity, in general participants still felt reasonably dignified. The decline in personal dignity was generally caused by cognitive impairments resulting in diminished autonomy and changes to the individual's former identity. However, the intensity with which the decline in personal dignity was experienced depended to a large degree on the social context of the individual, with a marked difference between the private sphere of the home and the external, social environment. The study gives recommendations how others can help to sustain personal dignity in people with mild to moderate dementia. CONCLUSION: Given the considerable impact the social environment has on the personal dignity of people with mild to moderate dementia, it is important in caregiving not to confine attention to health-related or even any individual aspects alone, but also to take interpersonal aspects into consideration. PMID- 25271307 TI - Voluntary Aerobic Exercise Reverses Frailty in Old Mice. AB - Frailty is a major cause of disability and loss of independence in the elderly. Using clinically relevant criteria from our previously established mouse frailty index, we investigated the effects of aerobic exercise on frailty in male C57BL/6 mice. In order to measure the effect of treatment on the individual animals, we constructed a composite score, the Frailty Intervention Assessment Value. We hypothesized voluntary aerobic exercise would improve individual criteria and reverse or prevent frailty in the old mice. Five adult and 11 old mice (6 and 28+ months, respectively) were housed individually in cages with running wheels for 4 weeks. Controls (adult, n = 5 and old, n = 17) were housed without wheels. Inverted cling grip and rotarod tests were performed pre- and postintervention. Hind limb muscles were used for biochemical analysis and contractility experiments. We conclude that the exercise stimulus reversed frailty and was sufficient to maintain or improve functional performance in old mice, as well as to produce measurable morphological changes. In addition, the Frailty Intervention Assessment Value proved to be a valuable tool with increased power to detect treatment effects and to examine the intervention efficacy at the level of the individual mouse. PMID- 25271306 TI - H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells. AB - In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors. PMID- 25271310 TI - Should clinical hematologists put their microscopes on eBay? PMID- 25271309 TI - Combining Formal and Informal Caregiving Roles: The Psychosocial Implications of Double- and Triple-Duty Care. AB - OBJECTIVES: Women who combine formal and informal caregiving roles represent a unique, understudied population. In the literature, healthcare employees who simultaneously provide unpaid elder care at home have been referred to as double duty caregivers. The present study broadens this perspective by examining the psychosocial implications of double-duty child care (child care only), double duty elder care (elder care only), and triple-duty care (both child care and elder care or "sandwiched" care). METHOD: Drawing from the Work, Family, and Health Study, we focus on a large sample of women working in nursing homes in the United States (n = 1,399). We use multiple regression analysis and analysis of covariance tests to examine a range of psychosocial implications associated with double- and triple-duty care. RESULTS: Compared with nonfamily caregivers, double duty child caregivers indicated greater family-to-work conflict and poorer partner relationship quality. Double-duty elder caregivers reported more family to-work conflict, perceived stress, and psychological distress, whereas triple duty caregivers indicated poorer psychosocial functioning overall. DISCUSSION: Relative to their counterparts without family caregiving roles, women with combined caregiving roles reported poorer psychosocial well-being. Additional research on women with combined caregiving roles, especially triple-duty caregivers, should be a priority amidst an aging population, older workforce, and growing number of working caregivers. PMID- 25271311 TI - Disease severity in chronic graft-versus-host disease: doctors' gut feeling versus biostatistics? PMID- 25271312 TI - Stem cell transplants for myelodysplastic syndromes: refining the outcome predictions. PMID- 25271313 TI - Three major uncertainties in the antibody therapy of cancer. AB - Antibodies against surface molecules of human tumors are now frequently administered in combination with strong chemotherapy, increasing therapeutic efficacy but making the task of elucidating immunological events more difficult. Experiments on genetically manipulated mice indicate that antibody efficacy is greatest when IgG antibody coating tumor cells is engaged by the Fcgamma receptors of effector cells, chiefly the monocyte/macrophage lineage. Evidence suggests lesser roles for NK cells, neutrophils, receptor-mediated cytotoxicity and complement-mediated cytotoxicity. The classical mode of killing employed by macrophages is phagocytosis, but much has to be learned about optimally activating macrophages for this task, and about any other modes of cytotoxicity used. There is renewed interest in antigenic modulation, which implies removal of therapeutic antibody linked with antigen from target-cell surfaces. It is now apparent that this removal of immune complexes can be achieved either by internalization by the target cell, or by transfer of the complexes to another cell by trogocytosis. In trials, anti-idiotype antibodies surprisingly proved therapeutically more effective than anti-CD20, despite anti-idiotype being more effectively removed from target-cell surfaces by antigenic modulation. This anomalous result might reflect the fact that persistence of anti-CD20 immune complexes in large amounts induces serious effector modulation, which paralyzes macrophage attacks on antibody-coated cells. The case for effector modulation is argued by analogy with the therapeutic suppression of autoimmune inflammation by effector modulation, achieved by infusion either of normal IgG in large amounts, or of anti-red cell IgG in relatively small amounts. PMID- 25271314 TI - Treatment of autoimmune hemolytic anemias. AB - Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life threatening anemia. The treatment of AIHA is still not evidence-based. The first line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment. PMID- 25271316 TI - A straightforward guide to the sarcomeric basis of cardiomyopathies. AB - The sarcomere is the principal contractile unit of striated muscle. Mutations in genes encoding sarcomeric proteins are responsible for a range of diseases including hypertrophic, dilated and restrictive cardiomyopathies and ventricular non-compaction. The downstream molecular pathways leading to these heterogeneous phenotypes include changes in acto-myosin cross-bridge kinetics, altered mechanosensation, disturbed calcium sensitivity, de-regulated signalling pathways, inefficient energetics, myocardial ischaemia and fibrosis. The elucidation of the genetic causes of cardiomyopathy has helped in understanding the structure and function of the sarcomere and a more detailed knowledge of the sarcomere and its associated proteins has suggested additional gene candidates. The new hope is that these advances will stimulate the discovery of disease modifying drugs. PMID- 25271315 TI - Risk of esophageal cancer following radiotherapy for Hodgkin lymphoma. PMID- 25271318 TI - Rice SPX1 and SPX2 inhibit phosphate starvation responses through interacting with PHR2 in a phosphate-dependent manner. AB - In plants, sensing the levels of external and internal nutrients is essential for reprogramming the transcriptome and adapting to the fluctuating environment. Phosphate (Pi) is a key plant nutrient, and a large proportion of Pi starvation responsive genes are under the control of Phosphate Starvation Response Regulator 1 (PHR1) in Arabidopsis (AtPHR1) and its homologs, such as Oryza sativa (Os)PHR2 in rice. AtPHR1 and OsPHR2 expression is not very responsive to Pi starvation, raising the question as to how plants sense changes in cellular Pi levels to activate the central regulator. SPX [named after SYG1 (suppressor of yeast gpa1), Pho81 (CDK inhibitor in yeast PHO pathway), and XPR1 (xenotropic and polytropic retrovirus receptor)] proteins that harbor only the SPX domain are reported to be involved in the negative regulation of Pi starvation responses. Here, we show that the nuclear localized SPX proteins SPX1 and SPX2 are Pi-dependent inhibitors of the activity of OsPHR2 in rice. Indeed, SPX1 and SPX2 proteins interact with PHR2 through their SPX domain, inhibiting its binding to P1BS (the PHR1-binding sequence: GNATATNC). In vivo data, as well as results from in vitro experiments using purified SPX1, SPX2, and OsPHR2 proteins, showed that SPX1 and SPX2 inhibition of OsPHR2 activity is Pi-dependent. These data provide evidence to support the involvement of SPX1 and SPX2 in the Pi-sensing mechanism in plants. PMID- 25271319 TI - Solid-to-fluid-like DNA transition in viruses facilitates infection. AB - Releasing the packaged viral DNA into the host cell is an essential process to initiate viral infection. In many double-stranded DNA bacterial viruses and herpesviruses, the tightly packaged genome is hexagonally ordered and stressed in the protein shell, called the capsid. DNA condensed in this state inside viral capsids has been shown to be trapped in a glassy state, with restricted molecular motion in vitro. This limited intracapsid DNA mobility is caused by the sliding friction between closely packaged DNA strands, as a result of the repulsive interactions between the negative charges on the DNA helices. It had been unclear how this rigid crystalline structure of the viral genome rapidly ejects from the capsid, reaching rates of 60,000 bp/s. Through a combination of single-molecule and bulk techniques, we determined how the structure and energy of the encapsidated DNA in phage lambda regulates the mobility required for its ejection. Our data show that packaged lambda-DNA undergoes a solid-to-fluid-like disordering transition as a function of temperature, resulting locally in less densely packed DNA, reducing DNA-DNA repulsions. This process leads to a significant increase in genome mobility or fluidity, which facilitates genome release at temperatures close to that of viral infection (37 degrees C), suggesting a remarkable physical adaptation of bacterial viruses to the environment of Escherichia coli cells in a human host. PMID- 25271320 TI - Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues. AB - Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF based antiangiogenic drugs. PMID- 25271321 TI - Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. AB - Memory CD8(+) T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8(+) T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen experienced CD8(+) T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen reexposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells while promoting short-lived effector cell differentiation. Transcriptome analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation, and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated glycolytic and oxidative metabolism in response to IL-15 stimulation. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8(+) T-cell development and function. PMID- 25271322 TI - Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin. AB - Natural products continue to provide vital treatment options for cancer. Although their translation into chemotherapeutics is complex, collaborative programs continue to deliver productive pipelines for cancer chemotherapy. A new natural product, seriniquinone, isolated from a marine bacterium of the genus Serinicoccus, demonstrated potent activity over a select set of tumor cell lines with particular selectivity toward melanoma cell lines. Upon entering the cell, its journey began by localization into the endoplasmic reticulum. Within 3 h, cells treated with seriniquinone underwent cell death marked by activation of autophagocytosis and gradually terminated through a caspase-9 apoptotic pathway. Using an immunoaffinity approach followed by multipoint validation, we identified the target of seriniquinone as the small protein, dermcidin. Combined, these findings revealed a small molecule motif in parallel with its therapeutic target, whose potential in cancer therapy may be significant. This discovery defines a new pharmacophore that displayed selective activity toward a distinct set of cell lines, predominantly melanoma, within the NCI 60 panel. This selectivity, along with the ease in medicinal chemical modification, provides a key opportunity to design and evaluate new treatments for those cancers that rely on dermcidin activity. Further, the use of dermcidin as a patient preselection biomarker may accelerate the development of more effective personalized treatments. PMID- 25271323 TI - Human DNA tumor viruses generate alternative reading frame proteins through repeat sequence recoding. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are human DNA tumor viruses that express nuclear antigens [latency-associated nuclear antigen 1 (LANA1) and Epstein-Barr nuclear antigen 1 (EBNA1)] necessary to maintain and replicate the viral genome. We report here that both LANA1 and EBNA1 undergo highly efficient +1/-2 programmed ribosomal frameshifting to generate previously undescribed alternative reading frame (ARF) proteins in their repeat regions. EBNA1(ARF) encodes a KSHV LANA-like glutamine- and glutamic acid-rich protein, whereas KSHV LANA1(ARF) encodes a serine/arginine-like protein. Repeat sequence recoding has not been described previously for human DNA viruses. Programmed frameshifting (recoding) to generate multiple proteins from one RNA sequence can increase the coding capacity of a virus, without incurring a selective penalty against increased capsid size. The presence of similar repeat sequences in cellular genes, such as huntingtin, suggests that a comparison of repeat recoding in virus and human systems may provide functional and mechanistic insights for both systems. PMID- 25271324 TI - Species formation by host shifting in avian malaria parasites. AB - The malaria parasites (Apicomplexa: Haemosporida) of birds are believed to have diversified across the avian host phylogeny well after the origin of most major host lineages. Although many symbionts with direct transmission codiversify with their hosts, mechanisms of species formation in vector-borne parasites, including the role of host shifting, are poorly understood. Here, we examine the hosts of sister lineages in a phylogeny of 181 putative species of malaria parasites of New World terrestrial birds to determine the role of shifts between host taxa in the formation of new parasite species. We find that host shifting, often across host genera and families, is the rule. Sympatric speciation by host shifting would require local reproductive isolation as a prerequisite to divergent selection, but this mechanism is not supported by the generalized host-biting behavior of most vectors of avian malaria parasites. Instead, the geographic distribution of individual parasite lineages in diverse hosts suggests that species formation is predominantly allopatric and involves host expansion followed by local host-pathogen coevolution and secondary sympatry, resulting in local shifting of parasite lineages across hosts. PMID- 25271327 TI - Woody Hastings: 65 years of fun. PMID- 25271326 TI - SPX1 is a phosphate-dependent inhibitor of Phosphate Starvation Response 1 in Arabidopsis. AB - To cope with growth in low-phosphate (Pi) soils, plants have evolved adaptive responses that involve both developmental and metabolic changes. Phosphate Starvation Response 1 (PHR1) and related transcription factors play a central role in the control of Pi starvation responses (PSRs). How Pi levels control PHR1 activity, and thus PSRs, remains to be elucidated. Here, we identify a direct Pi dependent inhibitor of PHR1 in Arabidopsis, SPX1, a nuclear protein that shares the SPX domain with yeast Pi sensors and with several Pi starvation signaling proteins from plants. Double mutation of SPX1 and of a related gene, SPX2, resulted in molecular and physiological changes indicative of increased PHR1 activity in plants grown in Pi-sufficient conditions or after Pi refeeding of Pi starved plants but had only a limited effect on PHR1 activity in Pi-starved plants. These data indicate that SPX1 and SPX2 have a cellular Pi-dependent inhibitory effect on PHR1. Coimmunoprecipitation assays showed that the SPX1/PHR1 interaction in planta is highly Pi-dependent. DNA-binding and pull-down assays with bacterially expressed, affinity-purified tagged SPX1 and DeltaPHR1 proteins showed that SPX1 is a competitive inhibitor of PHR1 binding to its recognition sequence, and that its efficiency is highly dependent on the presence of Pi or phosphite, a nonmetabolizable Pi analog that can repress PSRs. The relative strength of the SPX1/PHR1 interaction is thus directly influenced by Pi, providing a link between Pi perception and signaling. PMID- 25271329 TI - Key characteristics of successful quality improvement curricula in physician education: a realist review. AB - PURPOSE: Quality improvement (QI) is a common competency that must be taught in all physician training programmes, yet, there is no clear best approach to teach this content in clinical settings. We conducted a realist systematic review of the existing literature in QI curricula within the clinical setting, highlighting examples of trainees learning QI by doing QI. METHOD: Candidate theories describing successful QI curricula were articulated a priori. We searched MEDLINE (1 January 2000 to 12 March 2013), the Cochrane Library (2013) and Web of Science (15 March 2013) and reviewed references of prior systematic reviews. Inclusion criteria included study design, setting, population, interventions, clinical and educational outcomes. The data abstraction tool included categories for setting, population, intervention, outcomes and qualitative comments. Themes were iteratively developed and synthesised using realist review methodology. A methodological quality tool assessed the biases, confounders, secular trends, reporting and study quality. RESULTS: Among 39 studies, most were before-after design with resident physicians as the primary population. Twenty-one described clinical interventions and 18 described educational interventions with a mean intervention length of 6.58 (SD=9.16) months. Twenty-eight reported successful clinical improvements; no studies reported clinical outcomes that worsened. Characteristics of successful clinical QI curricula include attention to the interface of educational and clinical systems, careful choice of QI work for the trainees and appropriately trained local faculty. CONCLUSIONS: This realist review identified success characteristics to guide training programmes, medical schools, faculty, trainees, accrediting organisations and funders to further develop educational and improvement resources in QI educational programmes. PMID- 25271330 TI - Trans-Atlantic debate: Whether venous perforator surgery reduces recurrences. PMID- 25271328 TI - MAGI-2 scaffold protein is critical for kidney barrier function. AB - MAGUK Inverted 2 (MAGI-2) is a PTEN-interacting scaffold protein implicated in cancer on the basis of rare, recurrent genomic translocations and deletions in various tumors. In the renal glomerulus, MAGI-2 is exclusively expressed in podocytes, specialized cells forming part of the glomerular filter, where it interacts with the slit diaphragm protein nephrin. To further explore MAGI-2 function, we generated Magi-2-KO mice through homologous recombination by targeting an exon common to all three alternative splice variants. Magi-2 null mice presented with progressive proteinuria as early as 2 wk postnatally, which coincided with loss of nephrin expression in the glomeruli. Magi-2-null kidneys revealed diffuse podocyte foot process effacement and focal podocyte hypertrophy by 3 wk of age, as well as progressive podocyte loss. By 5.5 wk, coinciding with a near-complete loss of podocytes, Magi-2-null mice developed diffuse glomerular extracapillary epithelial cell proliferations, and died of renal failure by 3 mo of age. As confirmed by immunohistochemical analysis, the proliferative cell populations in glomerular lesions were exclusively composed of activated parietal epithelial cells (PECs). Our results reveal that MAGI-2 is required for the integrity of the kidney filter and podocyte survival. Moreover, we demonstrate that PECs can be activated to form glomerular lesions resembling a noninflammatory glomerulopathy with extensive extracapillary proliferation, sometimes resembling crescents, following rapid and severe podocyte loss. PMID- 25271331 TI - The good, the bad (and the ugly): The role of curiosity in subjective well-being and risky behaviors among adolescents. AB - Previous studies have shown that enhanced trait curiosity has positive influence on well-being. It remains an open question, however, whether curiosity has any detrimental effects on behavioral outcomes in adolescence. The main aim of this research was to investigate the role of trait curiosity in the prediction of risky behavior engagement and subjective well-being (SWB) among adolescents. A total of 371 Serbian adolescents (mean age 15.5, SD = 0.57) participated in the 5 month follow up study. The results showed that the embracing component of curiosity (but not stretching) predicted risky behavior engagement, while the stretching component of curiosity (but not embracing) predicted positive affect. In addition, neither embracing nor stretching was a significant predictor of negative affect and life satisfaction. The results of this study call into question the conceptualization of curiosity as a completely positive emotional motivational system, and suggest that curiosity can contribute to negative outcomes in adolescence. PMID- 25271332 TI - The prospective relationship between role stressors and new cases of self reported workplace bullying. AB - In line with the "Work environment hypothesis," role stressors have been proposed as important antecedents of bullying in the workplace. Only a few longitudinal studies on the relationship between role stressors and bullying exist, however, and earlier studies have largely been cross-sectional. The aim of the present prospective study was to determine whether role stressors at baseline predict new cases of workplace bullying at follow-up. A total of 2,835 Norwegian employees participated at both baseline and follow-up, with an interval of two years between the measurements. The study supports the hypotheses that role ambiguity and role conflict, independently, contribute to subsequent new reports of workplace bullying. However, there was a weak reverse effect: reporting being bullied at work at baseline predicted reporting increased levels of role ambiguity and role conflict at follow-up. Even though the results may indicate a circular relationship between the variables at hand, the weak reverse relationship seems to have little practical impact compared to the stronger relationship from role stressors to bullying. Hence, the results mainly support the hypotheses stating that role ambiguity and role conflict, independently, predict subsequent exposure to workplace bullying. PMID- 25271333 TI - Novel thermo-responsive fucose binding ligands for glycoprotein purification by affinity precipitation. AB - Novel thermo-responsive affinity sugar binders were developed by fusing a bacterial fucose lectin with a thermo-responsive polypeptide. These designer affinity ligand fusions were produced using an Escherichia coli system capable of extracellular secretion of recombinant proteins and were isolated with a high recovery yield (95%) directly from growth medium by Inverse Temperature Cycling (ITC). With horse radish peroxidase (HRP) as a model protein, we demonstrate here that the designer thermo-responsive ligands are capable of interacting with glycans on a glycoprotein, a property that was used to develop a novel affinity precipitation method for glycoprotein purification. The method, requiring only simple process steps, affords full recovery of a target glycoprotein, and is effective at a target glycoprotein concentration as low as 1.4 pM in the presence of large amounts of contaminants. By developing other sugar binders in the similar fashion, the method should be highly useful for glycoprotein purification and detection. PMID- 25271334 TI - Journal roundup. PMID- 25271335 TI - Viral infection: Seeding the HIV-1 reservoir. PMID- 25271336 TI - Proceedings of the 37th Annual Meeting of the Japanese Society for Biomedical Mass Spectrometry, October 25-26th, 2012, Nagoya, Japan. PMID- 25271337 TI - Festschrift in honor of Ranzo Dionigi. PMID- 25271338 TI - Proceedings of the International Meeting on Antimicrobial Peptides 2012 (IMAP 2012), Aug 30-31, 2012, Leipzig, Germany. PMID- 25271339 TI - Proceedings of the 50th North American Chemical Residue Workshop (NACRW),July 21 24, 2013, FL. PMID- 25271340 TI - Resident rounds part III: plasma cell leukemia with initial cutaneous presentation. PMID- 25271341 TI - [Intravitreal surgical drug administration - the die is cast]. PMID- 25271342 TI - [Ophthalmologist liable for gross treatment errors in laser coagulation]. PMID- 25271343 TI - [Warning: what employers and employee should pay attention to]. PMID- 25271344 TI - Writing the macrocycle manual: new computational and biochemical tools and informatic rules should spur research on a relatively underexplored class of molecules. PMID- 25271345 TI - Glutamate receptors: mechanistic twists and turns. PMID- 25271347 TI - [Certain regular features of "fountaining" blood stain formation depending on the height, angle of incidence, and properties of the barrier material]. AB - The objective of the present study was to elucidate the mechanisms of formation and morphological features of blood stains during arterial hemorrhage. "Fountaining" blood stains were simulated with the use of the specially designed device with an output pressure of 116.5 mm Hg. Blood droplets were allowed to fall down at different angles onto the surfaces differing in the stain-receptive properties. A total of 2200 blood stains were simulated and analysed. The data obtained indicate that traces of blood may be significantly different depending on the character of the blood-receptive surface, the height of fall and the angle of incidence of blood droplets. The results of the study can be used to improve the quality of forensic medical expertise of material evidence and reconstruct the circumstances of an event or offence. PMID- 25271346 TI - Endosomal generation of cAMP in GPCR signaling. AB - It has been widely assumed that the production of the ubiquitous second messenger cyclic AMP, which is mediated by cell surface G protein-coupled receptors (GPCRs), and its termination take place exclusively at the plasma membrane. Recent studies reveal that diverse GPCRs do not always follow this conventional paradigm. In the new model, GPCRs mediate G-protein signaling not only from the plasma membrane but also from endosomal membranes. This model proposes that following ligand binding and activation, cell surface GPCRs internalize and redistribute into early endosomes, where trimeric G protein signaling can be maintained for an extended period of time. This Perspective discusses the molecular and cellular mechanistic subtleties as well as the physiological consequences of this unexpected process, which is considerably changing how we think about GPCR signaling and regulation and how we study drugs that target this receptor family. PMID- 25271348 TI - [Specific regular features of trace formation depending on the properties of the trace-receptive surface and the height of blood droplet fall]. AB - The objective of the present work was to study the morphological characteristics of blood stains resulting from the static fall of blood droplets onto a sloping stain-receptive surface depending on its properties and the height of fall. The blood droplets were allowed to fall down from a specially designed device onto the sloping surfaces at an angle of 45 degrees from the height varying from 5 to 200 cm. The receptive surfaces had different absorbing capacity (non-absorbing, moderately absorbing, and well-absorbing surfaces). The analysis of the blood stains thus obtained showed that they differed in the size, shape, and morphological features depending on the height of fall of the droplets, the absorbing properties of the trace-receptive surfaces, and the angle of incidence of blood droplets. The results of the study can be used to improve the quality of forensic medical expertise of the surfaces soiled with blood stains. PMID- 25271349 TI - [Caregivers of victims of stroke: screening for depression]. PMID- 25271350 TI - [Hepatitis C: a study predicts a costly future if nothing is done now]. PMID- 25271351 TI - Technology system commissioning. A comprehensive approach to activating high level communications. PMID- 25271352 TI - Mitochondrial haplotype-based identification of ethanol-preserved root-knot nematodes from Africa. AB - The asexual root-knot nematodes (RKNs) (Meloidogyne spp.) exemplified by Meloidogyne incognita are widespread and damaging pests in tropical and subtropical regions worldwide. Comparison of amplification products of two adjacent polymorphic regions of the mitochondrial genome using DNA extracts of characterized RKN strains, including 15 different species, indicate that several species are derived from the same or closely related female lineages. Nevertheless, M. javanica, M. enterolobii, M. incognita, and other key species could each be assigned unique mitochondrial haplotypes based on polymerase chain reaction fragment size and restriction cleavage patterns. M. arenaria isolates did not group as a single haplotype, consistent with other reports of diversity within this species. To test the utility of this assay, we characterized ethanol preserved samples from 103 single-species isolates from four countries in sub Saharan Africa (Benin, Nigeria, Kenya, and Tanzania). Mitochondrial haplotypes corresponding to M. javanica and M. incognita were the most prevalent. Samples from western Africa included several instances of M. enterolobii but this species was not detected in samples from East Africa. This protocol provides progress toward a standardized strategy for identification of RKN species from small, preserved samples and a rational starting point for classifying species present in regions where previous knowledge has been limited. PMID- 25271353 TI - Mechanisms of Resistance to an Azole Fungicide in the Grapevine Powdery Mildew Fungus, Erysiphe necator. AB - We studied the mechanisms of azole resistance in Erysiphe necator by quantifying the sensitivity to myclobutanil (EC50) in 65 isolates from the eastern United States and 12 from Chile. From each isolate, we sequenced the gene for sterol 14alpha-demethylase (CYP51), and measured the expression of CYP51 and homologs of four putative efflux transporter genes, which we identified in the E. necator transcriptome. Sequence variation in CYP51 was relatively low, with sequences of 40 U.S. isolates identical to the reference sequence. Nine U.S. isolates and five from Chile carried a previously identified A to T nucleotide substitution in position 495 (A495T), which results in an amino acid substitution in codon 136 (Y136F) and correlates with high levels of azole resistance. We also found a nucleotide substitution in position 1119 (A1119C) in 15 U.S. isolates, whose mean EC50 value was equivalent to that for the Y136F isolates. Isolates carrying mutation A1119C had significantly greater CYP51 expression, even though A1119C does not affect the CYP51 amino acid sequence. Regression analysis showed no significant effects of the expression of efflux transporter genes on EC50. Both the Y136F mutation in CYP51 and increased CYP51 expression appear responsible for azole resistance in eastern U.S. populations of E. necator. PMID- 25271354 TI - Aortic remodelling following the treatment and regression of hypertensive left ventricular hypertrophy: a cardiovascular magnetic resonance study. AB - BACKGROUND: Increased arterial stiffness independently predicts adverse prognosis. While different antihypertensive strategies produce different magnitudes of left ventricular hypertrophy (LVH) regression, there are no comparative data on how these strategies affect arterial stiffness. The aim was to determine the longitudinal change in aortic stiffness following the treatment of essential hypertension with two mechanistically different antihypertensive treatment strategies. METHODS AND RESULTS: Forty-two patients with essential hypertension and CMR confirmed with LVH were randomly assigned to antihypertensive regimes for 6 months. Treatment strategies were designed either to inhibit the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) (valsartan and moxonidine, group VM) or to have neutral effect on these systems (bendroflumethiazide and amlodipine, group BA). Both treatment groups underwent identical baseline and a 6-month follow-up CMR and were compared with a healthy age-matched control group. Baseline aortic distensibility (AD) was lower in both hypertensive groups compared with controls (2.8 * 10(-3 )mmHg(-1) in group VM (p = 0.001) and 3.3 * 10(-3 )mmHg(-1) group BA (p = 0.039) compared with 4.5 * 10(-3 )mmHg(-1) in the control group). AD increased after antihypertensive therapy (VM: 2.8 * 10(-3 )mmHg(-1)-4.2 * 10(-3 )mmHg(-1) (p = 0.001); BA 3.3 * 10(-3 )mmHg(-1)-4.6 * 10(-3 )mmHg(-1) (p < 0.01)). In both treatment groups AD returned to a level comparable with the normal control group (p = 0.81) after 6 months. CONCLUSIONS: In patients with essential hypertension and LVH, AD was lower than in matched normal controls. Despite the opposing pharmacological mechanisms utilised across the treatment groups, the improvement in AD was similar, suggesting that blood pressure reduction per se may be more important than RAAS and SNS inhibition for the improvement of aortic remodelling. PMID- 25271356 TI - Ingestible gastrointestinal sampling devices: state-of-the-art and future directions. AB - Despite the significant contribution of gastrointestinal diseases to the global disease burden and the increasing recognition of the role played by the intestinal microbiota in human health and disease states, conventional methods of exploring and collecting samples from the gastrointestinal tract remain invasive, resource intensive, and often unable to capture all the information contained in these heterogeneous samples. A new class of gastrointestinal sampling capsules is emerging in the literature, which contains the components required for an autonomous intra-luminal device and preserves the spatial and temporal information of the gastrointestinal samples. In this paper, we identify the primary design requirements for gastrointestinal sampling capsules, and we review the state-of-the-art for different components and functionalities. We also suggest two design concepts, and we highlight future directions for this class of biomedical devices. PMID- 25271357 TI - GERD and obesity: is the autonomic nervous system the missing link? AB - Gastroesophageal reflux disease (GERD) is a common chronic condition that not only impairs the quality of life of those who are affected by it but also poses a significant economic burden. It encompasses a wide spectrum of symptoms as a result of gastric content moving into the esophagus. The most common cause of GERD, other than a hiatus hernia, is considered to be transient lower esophageal sphincter relaxation. The lower esophageal sphincter (LES) normally has a higher resting tone than the stomach, thus preventing the reflux of gastric contents into the esophagus. The greater prevalence of GERD and GERD symptoms in obese individuals has generated significant interest in understanding the association between these 2 conditions and the underlying physiological mechanisms. The potential relationship between GERD and obesity and the exact mechanism by which obesity may cause reflux, however, remains uncertain. It has been proposed that patients with GERD have altered autonomic nervous function and, more specifically, have reduced parasympathetic activity. Obese individuals also have shown diminished parasympathetic activity, which may be reversed after weight reduction through exercise, diet control, and bariatric surgery. Given that contraction and relaxation of the LES are vagally mediated, the question that arises is whether the autonomic nervous system is, in fact, the missing link between obesity and GERD. In this article we examine the current evidence and hypothesize that the potential imbalance in sympathovagal stimulation to the LES is a key contributing factor to the increased prevalence of GERD symptoms in obese individuals. PMID- 25271355 TI - The metabolic basis of pollen thermo-tolerance: perspectives for breeding. AB - Crop production is highly sensitive to elevated temperatures. A rise of a few degrees above the optimum growing temperature can lead to a dramatic yield loss. A predicted increase of 1-3 degrees in the twenty first century urges breeders to develop thermo-tolerant crops which are tolerant to high temperatures. Breeding for thermo-tolerance is a challenge due to the low heritability of this trait. A better understanding of heat stress tolerance and the development of reliable methods to phenotype thermo-tolerance are key factors for a successful breeding approach. Plant reproduction is the most temperature-sensitive process in the plant life cycle. More precisely, pollen quality is strongly affected by heat stress conditions. High temperature leads to a decrease of pollen viability which is directly correlated with a loss of fruit production. The reduction in pollen viability is associated with changes in the level and composition of several (groups of) metabolites, which play an important role in pollen development, for example by contributing to pollen nutrition or by providing protection to environmental stresses. This review aims to underline the importance of maintaining metabolite homeostasis during pollen development, in order to produce mature and fertile pollen under high temperature. The review will give an overview of the current state of the art on the role of various pollen metabolites in pollen homeostasis and thermo-tolerance. Their possible use as metabolic markers to assist breeding programs for plant thermo-tolerance will be discussed. PMID- 25271358 TI - Modeling the weaning of intensive care unit patients from mechanical ventilation: a review. AB - In the intensive care unit, mechanical ventilation is a life-saving procedure, and as many as 90% of patients require the intervention. For a mechanically ventilated patient, the principal goal of a health care team is to free the patient from mechanical ventilation through weaning as soon as possible. Weaning, however, still is mostly a manual process. To achieve quick and efficient weaning, the process is needs to be automated. The first step toward automating the weaning process is building a precise model of it. The path to achieving this precision in weaning modeling, if at all possible, is laden with challenges such as the use of imprecise terms, lack of evidence, complexities in data representation as well as process specification, and uncertainty in data values as well as their implication in process evaluation. This eventually leads to a lack of universally accepted and followed standards and guidelines. Despite the magnitude of these challenges, various weaning automations have been attempted through mathematical modeling or knowledge-based modeling. Some of these have been available as commercial mechanical ventilator modes since the 1990s. Even though much potential has been demonstrated through clinical trials, their infrequent usage indicates a lack of consensus concerning their applicability. PMID- 25271359 TI - Classification of fractional order biomarkers for anomalous diffusion using q space entropy. AB - In this study, we applied continuous random walk theory (CTRW) to develop a new model that characterizes anomalous diffusion in magnetic resonance imaging experiments. Furthermore, we applied a classification scheme based on information theoretic a techniques to characterize the degree of heterogeneity and complexity in biological tissues. From a CTRW approach, the Fourier transform of the generalized solution to the diffusion equation comes in the form of the Mittag Leffler function. In this solution form, the relative stochastic uncertainty in the diffusion process can be computed with spectral entropy. We interrogated both white and gray matter regions of a fixed rat brain with diffusion - weighted magnetic resonance imaging experiments up to 26,000 s/mm2 by independently weighting q and Delta. to investigate the effects on the diffusion phenomena. Our model fractional order parameters, alpha and beta, and entropy measure, H(q, Delta), differentiated between tissue types and extracted differing information within a region of interest based on the type of diffusion experiment performed. By combining fractional order modeling and information theory, new and powerful biomarkers are available to characterize tissue microstructure and provide contextual information about the anatomical complexity. PMID- 25271360 TI - Approaches for modeling magnetic nanoparticle dynamics. AB - Magnetic nanoparticles are useful biological probes as well as therapeutic agents. Several approaches have been used to model nanoparticle magnetization dynamics for both Brownian as well as Neel rotation. Magnetizations are often of interest and can be compared with experimental results. Here we summarize these approaches, including the Stoner-Wohlfarth approach and stochastic approaches including thermal fluctuations. Non-equilibrium-related temperature effects can be described by a distribution function approach (Fokker-Planck equation) or a stochastic differential equation (Langevin equation). Approximate models in several regimes can be derived from these general approaches to simplify implementation. PMID- 25271361 TI - O'nyong-nyong virus infection imported to Europe from Kenya by a traveler. PMID- 25271362 TI - The SARS-coronavirus membrane protein induces apoptosis via interfering with PDK1 PKB/Akt signalling. AB - A number of viral gene products are capable of inducing apoptosis by interfering with various cellular signalling cascades. We previously reported the pro apoptotic property of the SARS-CoV (severe acute respiratory syndrome coronavirus) M (membrane)-protein and a down-regulation of the phosphorylation level of the cell-survival protein PKB (protein kinase B)/Akt in cells expressing M-protein. We also showed that overexpression of PDK1 (3-phosphoinositide dependent protein kinase 1), the immediate upstream kinase of PKB/Akt, suppressed M-induced apoptosis. This illustrates that M-protein perturbs the PDK1 and PKB/Akt cell survival signalling pathway. In the present study, we demonstrated that the C-terminus of M-protein interacts with the PH (pleckstrin homology) domain of PDK1. This interaction disrupted the association between PDK1 and PKB/Akt, and led to down-regulation of PKB/Akt activity. This subsequently reduced the level of the phosphorylated forkhead transcription factor FKHRL1 and ASK (apoptosis signal-regulating kinase), and led to the activation of caspases 8 and 9. Altogether, our data demonstrate that the SARS-CoV M-protein induces apoptosis through disrupting the interaction of PDK1 with PKB/Akt, and this causes the activation of apoptosis. Our work highlights that the SARS-CoV M protein is highly pro-apoptotic and is capable of simultaneously inducing apoptosis via initiating caspases 8 and 9. Preventing the interaction between M protein and PDK1 is a plausible therapeutic approach to target the pro-apoptotic property of SARS-CoV. PMID- 25271363 TI - Treatment of giardiasis after nonresponse to nitroimidazole. AB - During January 2008-October 2013, a total of 12 cases of giardiasis at the Chaim Sheba and Shaare Zedek Medical Centers, Israel, did not respond to nitroimidazole; 83.3% were associated with travel and 33% with immunoglobulin deficiency. Among 110 published cases, the most effective treatment was quinacrine (efficacy 90%-100%), but its availability is limited. PMID- 25271364 TI - Formation of three new bonds and two stereocenters in acyclic systems by zinc mediated enantioselective alkynylation of acylsilanes, Brook rearrangement, and ene-allene carbocyclization reactions. AB - Diastereoisomerically pure (dr > 99:1) and enantiomerically enriched (er up to 98:2) substituted propargyl diols possessing a tertiary hydroxyl group were synthesized in a single-pot operation from simple acylsilanes through a combined catalytic enantioselective alkynylation of acylsilanes, followed by an allenyl-Zn Brook rearrangement and Zn-ene-allene (or Zn-yne-allene) cyclization reaction. Two remarkable features of these reactions are the near complete transfer of chirality in the allenyl-Zn-Brook rearrangement and the highly organized six membered transition state of the Zn-ene-allene carbocyclization found by DFT calculations. In this process, three new bonds and two new stereogenic centers are created in a single-pot operation in excellent diastereo- and enantiomeric ratios. DFT calculations show that the allenyl-Zn-Brook rearrangement occurs in preference to the classic [1,2]-Zn-Brook rearrangement owing to its significantly lower activation barrier. PMID- 25271365 TI - Who are the New South Wales Aboriginal drug and alcohol workforce? A first description. AB - INTRODUCTION AND AIMS: Historically, Aboriginal alcohol and other drug (AOD) workers had little formal training, but this situation has changed rapidly in recent years. To understand how to better support and develop the workforce, we present the most detailed profile yet published of Aboriginal AOD workers in Australia. DESIGN AND METHODS: Workers were identified through the Aboriginal Drug and Alcohol Network, New South Wales. Participants completed a modified version of the Work Practice Questionnaire by pen-and-paper or interview in 2009. RESULTS: Fifty-one workers were identified, representing 85% of the known New South Wales workforce at the time. Two in three (62.7%) were male, and over half (56.9%) were aged 30-49. More workers were employed in non-government than government (60.8% vs. 39.2%) workplaces. Workers were employed under more than four different awards and with approximately eight position titles, spanning prevention and early intervention, clinical care and workforce development. Nearly all (n = 49/51, 96.1%) felt they had the necessary experience to respond to AOD issues. However, over half (n = 27/51, 52.9%) felt too much was expected of them. Just under a third (n = 15/51, 29.4%) reported no formal supervision, with fewer non-government workers compared with government receiving supervision (P = 0.02). Over half (n = 27/40, 67.5%%) earned AUD <= $50,000 annually, with government (vs. non-government) employment and female gender predicting a salary of >$50,000. DISCUSSION AND CONCLUSIONS: To improve worker retention and encourage professional skills development, discrepancies in salary and award conditions need addressing. Clarifying position descriptions and improving access to formal supervision are important to maximise workforce potential and reduce stress. PMID- 25271366 TI - The oral iron chelator deferasirox inhibits NF-kappaB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia. AB - The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-kappaB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-kappaB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies. PMID- 25271367 TI - Synthesis of phosphaguanidines by hydrophosphination of carbodiimides with phosphine boranes. AB - The direct addition of anionic secondary phosphine boranes to carbodiimides yields both chiral and achiral phosphaguanidine boranes under ambient temperature conditions. An analogous preparation of menthol-derived phosphinite boranes is also described. These products can be deborinated to give the corresponding phosphines, and subsequently oxidized to give phosphine oxides. The robustness of this method was further demonstrated in the synthesis of structurally novel cyclic phosphaguanidines. PMID- 25271368 TI - Temperature modulation of thermal tolerance of a CAM-tank bromeliad and the relationship with acid accumulation in different leaf regions. AB - Physiological changes that increase plant performance during exposure to high temperatures may play an inverse role during exposure to low temperatures. The objective of this study was to test variations in photosystem II response to heat and cold stress in the leaves of a bromeliad with crassulacean acid metabolism submitted to high or low temperatures. Leaves were maintained under constant temperatures of 10 and 35 degrees C and used to examine possible relationships among physiological responses to high and low temperatures and organic acid accumulation. We also tested if distinct parts of bromeliad leaves show differences in photosynthetic thermotolerance. The samples from leaves maintained at 35 degrees C showed greater heat tolerance values, while those from leaves maintained at 10 degrees C showed lower cold tolerance values. Our results identified a strong negative relationship between the organic acid accumulation and thermal tolerance of bromeliad leaves that largely explained the differences in thermal tolerance among groups. One of these differences occurred among regions of a single leaf, with the base showing critical heat values of up to 8 degrees C higher than the top region, suggesting a possible partitioning of leaf response among its regions. Differences in thermal tolerance were also observed between sampling times, with higher values observed in the morning. PMID- 25271369 TI - Changing the hemoglobin A1c goals for children with type 1 diabetes. PMID- 25271370 TI - Dengue expansion in Africa-not recognized or not happening? AB - An expert conference on Dengue in Africa was held in Accra, Ghana, in February 2013 to consider key questions regarding the possible expansion of dengue in Africa. Four key action points were highlighted to advance our understanding of the epidemiology of dengue in Africa. First, dengue diagnostic tools must be made more widely available in the healthcare setting in Africa. Second, representative data need to be collected across Africa to uncover the true burden of dengue. Third, established networks should collaborate to produce these types of data. Fourth, policy needs to be informed so the necessary steps can be taken to provide dengue vector control and health services. PMID- 25271372 TI - Identification of human TERT elements necessary for telomerase recruitment to telomeres. AB - Human chromosomes terminate in telomeres, repetitive DNA sequences bound by the shelterin complex. Shelterin protects chromosome ends, prevents recognition by the DNA damage machinery, and recruits telomerase. A patch of amino acids, termed the TEL-patch, on the OB-fold domain of the shelterin component TPP1 is essential to recruit telomerase to telomeres. In contrast, the site on telomerase that interacts with the TPP1 OB-fold is not well defined. In this study, we identify separation-of-function mutations in the TEN-domain of human telomerase reverse transcriptase (hTERT) that disrupt the interaction of telomerase with TPP1 in vivo and in vitro but have very little effect on the catalytic activity of telomerase. Suppression of a TEN-domain mutation with a compensatory charge-swap mutation in the TEL-patch indicates that their association is direct. Our findings define the interaction interface required for telomerase recruitment to telomeres, an important step towards developing modulators of this interaction as therapeutics for human disease. PMID- 25271373 TI - Allosteric signalling in the outer membrane translocation domain of PapC usher. AB - PapC ushers are outer-membrane proteins enabling assembly and secretion of P pili in uropathogenic E. coli. Their translocation domain is a large beta-barrel occluded by a plug domain, which is displaced to allow the translocation of pilus subunits across the membrane. Previous studies suggested that this gating mechanism is controlled by a beta-hairpin and an alpha-helix. To investigate the role of these elements in allosteric signal communication, we developed a method combining evolutionary and molecular dynamics studies of the native translocation domain and mutants lacking the beta-hairpin and/or the alpha-helix. Analysis of a hybrid residue interaction network suggests distinct regions (residue 'communities') within the translocation domain (especially around beta12-beta14) linking these elements, thereby modulating PapC gating. Antibiotic sensitivity and electrophysiology experiments on a set of alanine-substitution mutants confirmed functional roles for four of these communities. This study illuminates the gating mechanism of PapC ushers and its importance in maintaining outer membrane permeability. PMID- 25271374 TI - Kinetic competition during the transcription cycle results in stochastic RNA processing. AB - Synthesis of mRNA in eukaryotes involves the coordinated action of many enzymatic processes, including initiation, elongation, splicing, and cleavage. Kinetic competition between these processes has been proposed to determine RNA fate, yet such coupling has never been observed in vivo on single transcripts. In this study, we use dual-color single-molecule RNA imaging in living human cells to construct a complete kinetic profile of transcription and splicing of the beta globin gene. We find that kinetic competition results in multiple competing pathways for pre-mRNA splicing. Splicing of the terminal intron occurs stochastically both before and after transcript release, indicating there is not a strict quality control checkpoint. The majority of pre-mRNAs are spliced after release, while diffusing away from the site of transcription. A single missense point mutation (S34F) in the essential splicing factor U2AF1 which occurs in human cancers perturbs this kinetic balance and defers splicing to occur entirely post-release. PMID- 25271375 TI - Reconstitution of self-organizing protein gradients as spatial cues in cell-free systems. AB - Intracellular protein gradients are significant determinants of spatial organization. However, little is known about how protein patterns are established, and how their positional information directs downstream processes. We have accomplished the reconstitution of a protein concentration gradient that directs the assembly of the cell division machinery in E.coli from the bottom-up. Reconstituting self-organized oscillations of MinCDE proteins in membrane-clad soft-polymer compartments, we demonstrate that distinct time-averaged protein concentration gradients are established. Our minimal system allows to study complex organizational principles, such as spatial control of division site placement by intracellular protein gradients, under simplified conditions. In particular, we demonstrate that FtsZ, which marks the cell division site in many bacteria, can be targeted to the middle of a cell-like compartment. Moreover, we show that compartment geometry plays a major role in Min gradient establishment, and provide evidence for a geometry-mediated mechanism to partition Min proteins during bacterial development. PMID- 25271377 TI - Tri- and tetra-dentate imine vanadyl complexes: synthesis, structure and ethylene polymerization/ring opening polymerization capability. AB - Reaction of the ligand 2,4-tert-butyl-6-[(2-methylquinolin-8 ylimino)methyl]phenol (L(1)H) with [VOCl3] in the presence of triethylamine afforded the complex [VOCl2L(1)] (1), whereas use of [VO(OnPr)3] led to the isolation of [VO2L(1)] (2) or [VO2L(1)].2/3MeCN (2.2/3MeCN). Reaction of 2-((2 (1H-benzo[d]imidazol-2-yl)quinolin-8-ylimino)methyl)-4,6-R(1),R(2)-phenols (R(1) = R(2) = (t)Bu; L(2)H), (R(1) = R(2) = Me; L(3)H) or (R(1) = Me, R(2) = Ad; L(4)H) with [VO(OnPr)3] afforded complexes of the type [L(2-4)VO] (where L(2) = 3, L(3) = 4, L(4) = 5). The molecular structures of 1 to 3 are reported; the metal centre adopts a distorted octahedral, trigonal bipyramidal or square-based pyramidal geometry respectively. In Schlenk line tests, all complexes have been screened as pre-catalysts for the polymerization of ethylene using diethylaluminium chloride (DEAC) as co-catalyst in the presence of ethyltrichloroacetate (ETA), and for the ring opening polymerization (ROP) of epsilon-caprolactone in the presence of benzyl alcohol. All pre-catalyst/DEAC/ETA systems are highly active ethylene polymerization catalysts affording linear polyethylene with activities in the range 3000-10,700 g (mol h bar)(-1); the use of methylaluminoxane (MAO) or modified MAO as co-catalyst led to poor or no activity. In a parallel pressure reactor, 3-5 have been screened as pre-catalysts for ethylene polymerization in the presence of either DEAC or DMAC (dimethylaluminium chloride) and ETA at various temperatures and for the co polymerization of ethylene with propylene. The use of DMAC proved more promising with 3 achieving an activity of 63,000 g (mol h bar)(-1) at 50 degrees C and affording UHMWPE (M(w) ~ 2,000,000). In the case of the co-polymerization, the incorporation of propylene was 6.9-8.8 mol%, with 3 exhibiting the highest incorporation when using either DEAC or DMAC. In the case of the ring opening polymerization (ROP) of epsilon-caprolactone, systems employing complexes 1-5 were virtually inactive at temperatures <110 degrees C; on increasing the CL : V ratio at 110 degrees C, conversions of the order of 80% were achievable. PMID- 25271378 TI - Cost-effectiveness of insulin degludec compared with insulin glargine in a basal bolus regimen in patients with type 1 diabetes mellitus in the UK. AB - OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of insulin degludec (IDeg) vs insulin glargine (IGlar) as part of a basal-bolus treatment regimen in adults with T1DM, using a short-term economic model. METHODS: Data from two phase III clinical studies were used to populate a simple and transparent short-term model. The costs and effects of treatment with IDeg vs IGlar were calculated over a 12-month period. The analysis was conducted from the perspective of the UK National Health Service. Sensitivity analyses were conducted to assess the degree of uncertainty surrounding the results. The main outcome measure, the incremental cost-effectiveness ratio (ICER), was the cost per quality-adjusted life-year (QALY). RESULTS: IDeg is a cost-effective treatment option vs IGlar in patients with T1DM on a basal-bolus regimen. The base case ICER was estimated at L16,895/QALY, which is below commonly accepted thresholds for cost-effectiveness in the UK. Sensitivity analyses demonstrated that the ICER was stable to variations in the majority of input parameters. The parameters that exerted the most influence on the ICER were hypoglycemia event rates, daily insulin dose, and disutility associated with non-severe nocturnal hypoglycemic events. However, even under extreme assumptions in the majority of analyses the ICERs remained below the commonly accepted threshold of L20,000 L30,000 per QALY gained. CONCLUSIONS: This short-term modeling approach accommodates the treat-to-target trial design required by regulatory bodies, and focuses on the impact of important aspects of insulin therapy such as hypoglycemia and dosing. For patients with T1DM who are treated with a basal bolus insulin regimen, IDeg is a cost-effective treatment option compared with IGlar. IDeg may be particularly cost-effective for sub-groups of patients, such as those suffering from recurrent nocturnal hypoglycemia and those with impaired awareness of hypoglycemia. PMID- 25271379 TI - Characteristics of hip fracture patients with and without muscle atrophy/weakness: predictors of negative economic outcomes. AB - OBJECTIVE: Hip fractures have negative humanistic and economic consequences. Predictors and sub-groups of negative post-fracture outcomes (high costs and extensive healthcare utilization) were identified in patients with and without muscle atrophy/weakness (MAW). METHODS: Truven Health MarketScan data identified patients >=50 years old with inpatient hospitalizations for hip fracture. Patients had >=12 months of continuous healthcare insurance prior to and following index hospitalization and no hip fracture diagnoses between 7 days and 1 year prior to admission. Predictors and sub-groups of negative outcomes were identified via multiple logistic regression analyses and classification and regression tree (CART) analyses, respectively. RESULTS: Post-fracture 1-year all cause healthcare costs (USD$31,430) were higher than costs for the prior year ($18,091; p < 0.0001). Patients with MAW had greater post-fracture healthcare utilization and costs than those without MAW (p < 0.05). Greater post-fracture costs were associated with a higher number of prior hospitalizations and emergency room visits, length of index hospitalization, Charlson Comorbidity Index (CCI), and discharge status; diagnosis of rheumatoid arthritis, osteoarthritis, or osteoporosis; and prior use of antidepressants, anticonvulsants, muscle relaxants, benzodiazepines, opioids, and oral corticosteroids (all p < 0.009). High-cost patient sub-groups included those with MAW and high CCI scores. CONCLUSIONS: Negative post-fracture outcomes were associated with MAW vs no MAW, prior hospitalizations, comorbidities, and medications. PMID- 25271376 TI - Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. AB - Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication. PMID- 25271381 TI - Enantioselective synthesis of (-)-dihydrocodeine and formal synthesis of (-) thebaine, (-)-codeine, and (-)-morphine from a deprotonated alpha-aminonitrile. AB - The alpha-benzylation of a deprotonated bicyclic alpha-aminonitrile, followed by Noyori's asymmetric transfer hydrogenation combined with the Grewe cyclization onto a symmetrical A-ring precursor, are the key steps of a short and high yielding enantioselective synthesis of the morphinan (-)-dihydrocodeine. This compound can be converted to (-)-thebaine in high yield by known transformations, while (-)-codeine and (-)-morphine are available from an advanced intermediate. PMID- 25271380 TI - Impaired heart rate regulation and depression of cardiac chronotropic and dromotropic function in polymicrobial sepsis. AB - The scope of cardiac pathophysiology in sepsis has not been fully defined. Accordingly, we evaluated the effects of sepsis on heart rate (HR), HR variability, and conduction parameters in a murine model of sepsis. Electrocardiograms were recorded noninvasively from conscious mice before and after cecal ligation and puncture (CLP) or sham surgery. Responses of isolated atria to tyramine and isoproterenol were quantified to assess the functional state of sympathetic nerves and postjunctional sensitivity to adrenergic stimulation. Cecal ligation and puncture mice had lower HR compared with sham at 16 to 18 h postsurgery (sham, 741 +/- 7 beats/min; CLP, 557 +/- 31 beats/min; n = 6/group; P < 0.001), and there was significant prolongation of the PR, QRS, and QTc intervals. Slowing of HR and conduction developed within 4 to 6 h after CLP and were preceded by a decrease in HR variability. Treatment of CLP mice with isoproterenol (5 mg/kg, intraperitoneally) at 25 h after surgery failed to increase HR or decrease conduction intervals. The lack of in vivo response to isoproterenol cannot be attributed to hypothermia because robust chronotropic and inotropic responses to isoproterenol were evoked from isolated atria at 25 degrees C and 30 degrees C. These findings demonstrate that impaired regulation of HR (i.e., reduced HR variability) develops before the onset of overt cardiac rate and conduction changes in septic mice. Subsequent time-dependent decreases in HR and cardiac conduction can be attributed to hypothermia and would contribute to decreased cardiac output and organ perfusion. Because isolated atria from septic mice showed normal responsiveness to adrenergic stimulation, we conclude that impaired effectiveness of isoproterenol in vivo can be attributed to reversible effects of systemic factors on adrenergic receptors and/or postreceptor signaling. PMID- 25271382 TI - Noradrenaline transmission reducing drugs may protect against a broad range of diseases. AB - 1 A growing body of evidence suggests that the signalling molecule, noradrenaline (NA), plays a pathophysiological role in a broad range of psychiatric, neurological and peripheral disorders. Both preclinical and clinical data suggest that elevated NA signalling may be involved in the aetiology of major diseases such as depression, Alzheimer's disease and diabetes mellitus. 2 The molecular pathways by which NA may cause the manifestation of disease remain poorly understood, although they may include G protein-coupled receptor modulation of the Ras/MAP kinase, Stat3 and PI3K pathways, among others. In both individual animals and humans, NA tone may be elevated largely due to genetics, but also because of the exposure to marked psychological stress or trauma, or other environmental factors. 3 As NA is involved in the 'fight or flight' response by the sympathetic nervous system, this transmitter may be elevated in a large number of organisms due to evolutionary selection of enhancing responses to immediate environmental dangers. Likewise, acetylcholine signalling by the parasympathetic ('rest and digest') nervous system may be relatively diminished. This putative autonomic imbalance may result in diminished engagement in homeostatic processes, resulting in the emergence and progression of a number of diseases throughout the body. 4 In this scenario, a large number of individuals may benefit from chronic use of pharmacological agents - such as clonidine, guanfacine, propranolol or prazosin - that diminish NA signalling throughout the body. If so, NA transmission lowering drugs may protect against a wide range of diseases. PMID- 25271383 TI - A complex transition: lessons learned as three young adults with complex care needs transition from an inpatient paediatric hospital to adult community residences. AB - BACKGROUND: Whether young adults with complex care needs live at home with their family, in institutional or group home settings finding appropriate care as they transition from paediatric to adult systems can be difficult. Our objective was to understand the experiences, barriers and enablers entailed in transitioning three young adults with complex care needs from an institutional paediatric hospital setting to an adult community residence. METHOD: A descriptive design involving in-depth, semi-structured, qualitative interviews and a review of 14 h of meeting minutes. Interviews were conducted over the phone, in participants' homes, and at a paediatric rehabilitation hospital. Twenty-three participants, including 10 clinicians, 11 community partners, two young adults (21-23 years old) with complex care needs from [metropolitan area] Ontario, Canada. RESULTS: Our findings indicate that clinicians, community partners and young adults with complex care needs encountered several enablers and barriers influencing their transition from a paediatric hospital to adult supportive housing. Enablers included structural factors (leadership, advocacy, timing/funding), availability of care (inter-agency partnerships), organization of care (model of care, inter professional teamwork, extension of roles), and relational factors (communication, development of trust and rapport, family involvement). Barriers included structural factors (timing, funding), availability of care (appropriateness of housing), organization of care (changes in model of care, teamwork, role clarity), relational factors (communication, trust/rapport, family involvement) and personal factors (transition readiness). CONCLUSIONS: There are several challenges to overcome in preparing long-term hospitalized young adults with complex care needs to transition to adult supportive housing; however, these challenges may be overcome with targeted supports in several key areas. PMID- 25271384 TI - Release of nitrous acid and nitrogen dioxide from nitrate photolysis in acidic aqueous solutions. AB - Nitrate (NO3(-)) is an abundant component of aerosols, boundary layer surface films, and surface water. Photolysis of NO3(-) leads to NO2 and HONO, both of which play important roles in tropospheric ozone and OH production. Field and laboratory studies suggest that NO3- photochemistry is a more important source of HONO than once thought, although a mechanistic understanding of the variables controlling this process is lacking. We present results of cavity-enhanced absorption spectroscopy measurements of NO2 and HONO emitted during photodegradation of aqueous NO3(-) under acidic conditions. Nitrous acid is formed in higher quantities at pH 2-4 than expected based on consideration of primary photochemical channels alone. Both experimental and modeled results indicate that the additional HONO is not due to enhanced NO3(-) absorption cross sections or effective quantum yields, but rather to secondary reactions of NO2 in solution. We find that NO2 is more efficiently hydrolyzed in solution when it is generated in situ during NO3(-) photolysis than for the heterogeneous system where mass transfer of gaseous NO2 into bulk solution is prohibitively slow. The presence of nonchromophoric OH scavengers that are naturally present in the environment increases HONO production 4-fold, and therefore play an important role in enhancing daytime HONO formation from NO3(-) photochemistry. PMID- 25271385 TI - Local public health department adoption and use of electronic health records. AB - CONTEXT: Electronic health records (EHRs) may help local health departments (LHDs) to improve services and thereby promote and protect population health. Yet, little is known about nationwide trends and correlates of EHR use by LHDs. OBJECTIVE: We examine relative contributions of LHD finances, leadership, and governance to EHR adoption and use from 2010 to 2013. The impact of LHD service provision and meaningful use factors on EHR use is explored in depth. DESIGN: Combining data from the National Association of County & City Health Officials Profile survey and the Area Health Resource File, logistic regression models were used to examine EHR use in 2013. Multinomial logistic models examined EHR adoption, use, or discontinuation from 2010 to 2013. PARTICIPANTS: EHR usage data were available for 514 and 488 LHDs in 2010 and 2013, respectively. A total of 117 LHDs had data for both 2010 and 2013. MAIN OUTCOME MEASURES: Outcomes included dichotomized measures of LHD self-reported use of EHRs in 2010 and 2013. For LHDs with 2 years of data, a 4-category variable measuring self-reported EHR use, nonuse, adoption, or discontinuation was analyzed. RESULTS: Overall LHD EHR use did not increase significantly between 2010 (19.3%) and 2013 (22.0%). While 15% of LHDs reported adopting EHRs from 2010 to 2013, another 8.5% reported discontinuing use of EHRs during this time. Likelihood of EHR use was strongly associated with LHD clinical service characteristics, per capita expenditures, and state governance structure. CONCLUSIONS: EHRs do not appear to be rapidly diffusing across LHDs, and retention of current systems may be a concern. Given trends away from clinical service provision and other pressing demands for LHD resources, the benefits of EHR adoption are unclear. PMID- 25271386 TI - Association of Employee Attributes and Exceptional Performance Rating at a National Center of the US Centers for Disease Control and Prevention, 2011. AB - CONTEXT: Employee performance evaluation motivates and rewards exceptional individual performance that advances the achievement of organizational goals. The Centers for Disease Control and Prevention (CDC) and its operating units evaluate employee performance annually and reward exceptional performance with a cash award or quality step increase in pay. A summary performance rating (SPR) of "exceptional" indicated personal achievements in 2011 that were beyond expectations described in the employee's performance plan. OBJECTIVE: To determine whether personal attributes and job setting of civil service employees were associated with an exceptional SPR in National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP) in 2011. DESIGN: Data from the CDC 2011 performance management database collected in 2012 were analyzed in 2013 to identify SPR, personal attributes, and job settings of full-time civil service employees. Multivariate logistic regression controlled for confounding and stratified analysis detected effect modifiers of the association between receiving an exceptional SPR in 2011 and gender, race/ethnicity, education, job location, job series, grade level, years in grade, years of federal service, supervisory role, and NCHHSTP division. RESULTS: Among the 1037 employees, exceptional SPR was independently associated with: female gender (adjusted odds ratio: 1.7 [1.3, 2.3]), advanced degrees (doctorate: 1.7 [1.1, 2.5] master's: [1.1, 2.0]), headquarters location (2.8 [1.9, 4.1]), higher pay grade (3.3 [2.4, 4.5]) and years in grade (0-1 years: 1.7 [1.3, 2.4]; 2-4 years: 1.5 [1.1, 2.0]), division level (Division A: 5.0 [2.5, 9.9]; Division B: 5.5 [3.5, 8.8]), and supervisory status (at a lower-pay grade) (odds ratio: 3.7 [1.1, 11.3]). CONCLUSIONS: Exceptional SPR is independently associated with personal employee attributes and job settings that are not modifiable by interventions designed to improve employee performance based on accomplishments. PMID- 25271387 TI - Stimulant use and progression to AIDS or mortality after the initiation of highly active antiretroviral therapy. AB - BACKGROUND: HIV-positive persons who use stimulants (eg, methamphetamine) experience profound health disparities, but it remains unclear whether these persist after highly active antiretroviral therapy (HAART) initiation. Conducted within the Multicenter AIDS Cohort Study, this investigation examined whether stimulant use is associated with progression to AIDS or all-cause mortality after the initiation of HAART. METHODS: Using marginal structural modeling, the cumulative proportion of visits where any stimulant use was reported (ie, 0%, 1% 49%, 50%-99%, and 100%) was examined as a time-varying predictor of (1) all-cause mortality and (2) AIDS or all-cause mortality. RESULTS: Among the 1313 men who have sex with men (MSM) who initiated HAART, findings showed no significant association of any level of stimulant use with all-cause mortality. A competing risk analysis indicated that no level of stimulant use was associated with increased AIDS-related or non-AIDS mortality separately. Among the 648 participants without AIDS at HAART initiation, a secondary analysis indicated that stimulant use at 50% or more of study visits was associated with a 1.5-fold increase in the odds of progression to AIDS or all-cause mortality (adjusted odds ratio = 1.54; 95% confidence interval: 1.02 to 2.33; P < 0.05). CONCLUSIONS: HIV positive stimulant-using MSM receiving HAART seem to face no greater overall risks for all-cause, AIDS-related, or non-AIDS mortality compared with nonusers. However, men without AIDS at HAART initiation who more frequently reported stimulant use demonstrated modestly increased odds of progression to AIDS or all cause mortality. Comprehensive approaches are needed to optimize the effectiveness of HAART with stimulant-using MSM. PMID- 25271388 TI - The route of early nutrition in critical illness. PMID- 25271390 TI - Pharmacokinetics of intravenous, plain oral and enteric-coated oral omeprazole in the horse. AB - The objectives were to document the pharmacokinetics of intravenous, enteric coated oral and plain oral omeprazole in fasted horses and to investigate the impact of feeding on the bioavailability of an enteric-coated omeprazole. Twelve horses received four treatments: intravenous omeprazole (0.5 mg/kg) in the fasted state (IV-Fasted), enteric-coated omeprazole (4 mg/kg) orally in the fasted state (ECO-Fasted), enteric-coated omeprazole (4 mg/kg) orally in the fed state (ECO Fed) and plain omeprazole (4 mg/kg) orally in the fasted state (PL-Fasted). Plasma omeprazole concentrations were determined by UHPLC-MS. Bioavailability was higher (P = 0.038) in the ECO-Fasted group (21.5 [9.0-27.7]%) than the PL-Fasted group (10.1 [7.7-13.3]%). Similarly, AUC0-infinity was higher in the ECO-Fasted group than the PL-Fasted group (P = 0.027). No significant differences were present between the ECO-Fasted and ECO-Fed groups with regards to bioavailability, Cmax , Tmax or AUC0-infinity . When the half-life data from the oral formulations was pooled, it was longer than that observed in the IV-Fasted group (100 [73-118] min) and 35 [34-39] min, respectively; P < 0.0001). Bioavailability of enteric-coated omeprazole was higher than previously reported and feeding had minimal impact. Bioavailability of plain omeprazole was approximately half that of enteric-coated omeprazole. The longer half-life observed following oral administration was consistent with the flip-flop effect and has not previously been described for omeprazole in the horse. PMID- 25271391 TI - Molecular anisotropy analysis of single-ion magnets using an effective electrostatic model. AB - Simple electrostatic models have been shown to successfully rationalize the magnetic properties of mononuclear single molecule magnets based on f-elements and even to predict the direction of the magnetic anisotropy axis in these nanomagnets. In this Article, we go a step forward by showing that these models, conveniently modified to account for the covalency effects, are able to predict not only the easy axis direction but also the three components of the magnetic anisotropy. Thus, by using a lone pair effective charge (LPEC) model we can fully reproduce the angular dependence of the magnetic susceptibility in single crystals of pentamethylcyclopentadienyl-Er-cyclooctatetraene single-ion magnet. Furthermore, the parametrization of the ligands obtained in this study has been extrapolated to successfully reproduce spectroscopic data of a set of mononuclear lanthanoid complexes based on the same kind of ligands, thus emphasizing the predictive character of this model. PMID- 25271392 TI - H-Bonded adducts of [2,4,6-{(C10H21O)3C6H2NH}3C3N3] with [LnM{PPh2(C6H4CO2H)}] displaying columnar mesophases at room temperature. AB - Displacement of a labile ligand from appropriate precursor complexes by 2- or 4 PPh2C6H4COOH yields neutral gold(I) and gold(III) [AuXn(PPh2C6H4COOH)] (n = 1, X = Cl; n = 3, X = C6F5), cationic gold(I) [Au(PPh2C6H4COOH)2](CF3SO3), and neutral chromium(0) [Cr(CO)5(PPh2C6H4COOH)] metallo-organic acids. [AuCl(4 PPh2C6H4COOH)], [Au(C6F5)3(4-PPh2C6H4COOH)], and [Cr(CO)5(2-PPh2C6H4COOH)] have dimeric structures with typical carboxylic H-bond bridges, whereas [Au(C6F5)3(2 PPh2C6H4COOH)] gives a monomeric species with the carboxylic acid H bonded to cocrystallized solvent molecules. All gold-containing acids are emissive at 77 K in the range 404-520 nm and some of them also at 298 K with emission maxima from 441 to 485 nm. Reaction of these acid metal complexes with the triazine mesogen 2,4,6-{(C10H21O)3C6H2NH}3C3N3 affords some new hydrogen-bonded gold(I) and chromium(0) supramolecular adducts, but the related gold(III) complexes do not form adducts. The 4-diphenylphosphinobenzoic adducts display a columnar hexagonal mesophase (Colhex) at room temperature, with a random one-dimensional stacking of the pseudo-discoid triazine-metallo-organic adducts into columns, where the metallo-phosphinoacid fragments act as the fourth branch of the trifold triazine core. The 2-diphenylphosphinobenzoic mixtures do not display mesophases, as they appear in the X-ray studies as mixtures of the triazine and the metallo phosphinoacid complex. The aggregates are luminescent at 77 K, with emission maxima in the range 419-455 nm. PMID- 25271393 TI - Wasting Our Time? Allocated Versus Accumulated Physical Activity in Afterschool Programs. AB - BACKGROUND: Afterschool programs (ASPs) can provide opportunities for children to accumulate moderate-to-vigorous physical activity (MVPA). The optimal amount of time ASPs should allocate for physical activity (PA) on a daily basis to ensure children achieve policy-stated PA recommendations remains unknown. METHODS: Children (n = 1248, 5 to 12 years) attending 20 ASPs wore accelerometers up to 4 nonconsecutive week days for the duration of the ASPs during spring 2013 (February-April). Daily schedules were obtained from each ASP. RESULTS: Across 20 ASPs, 3 programs allocated <= 30min, 5 approximately 45 min, 4 60 min, 4 75 min, and 4 >= 105 min for PA opportunities daily (min.d-1). Children accumulated the highest levels of MVPA in ASPs that allocated >= 60 min.d-1 for PA opportunities (24.8-25.1 min.d-1 for boys and 17.1-19.4 min.d-1 for girls) versus ASPs allocating <= 45 min.d-1 for PA opportunities (19.7 min.d-1 and 15.6 min.d-1 for boys and girls, respectively). There were no differences in the amount of MVPA accumulated by children among ASPs that allocated 60 min.d-1 (24.8 min.d-1 for boys and 17.1 min.d-1 for girls), 75 min.d-1 (25.1 min.d-1 for boys and 19.4 min.d-1 for girls) or >= 105 min.d-1 (23.8 min.d-1 for boys and 17.8 min.d-1 for girls). Across ASPs, 26% of children (31% for boys and 14% for girls) met the recommended 30 minutes of MVPA. CONCLUSIONS: Allocating more than 1 hour of PA opportunities is not associated with an increase in MVPA during ASPs. Allocating 60 min.d-1, in conjunction with enhancing PA opportunities, can potentially serve to maximize children's accumulation of MVPA during ASPs. PMID- 25271394 TI - MOFs synthesized by the ionothermal method addressing the leaching problem of IL polymer composite membranes. AB - The liquid nature of ionic liquids (ILs) limits their use in potential electrolytes due to the problem of leakage. Herein, we design a new strategy to immobilize an ionic liquid by incorporating it within ZIF-8 (ZIF = zeolitic imidazolate framework) by the ionothermal method. PMID- 25271389 TI - Trial of the route of early nutritional support in critically ill adults. AB - BACKGROUND: Uncertainty exists about the most effective route for delivery of early nutritional support in critically ill adults. We hypothesized that delivery through the parenteral route is superior to that through the enteral route. METHODS: We conducted a pragmatic, randomized trial involving adults with an unplanned admission to one of 33 English intensive care units. We randomly assigned patients who could be fed through either the parenteral or the enteral route to a delivery route, with nutritional support initiated within 36 hours after admission and continued for up to 5 days. The primary outcome was all-cause mortality at 30 days. RESULTS: We enrolled 2400 patients; 2388 (99.5%) were included in the analysis (1191 in the parenteral group and 1197 in the enteral group). By 30 days, 393 of 1188 patients (33.1%) in the parenteral group and 409 of 1195 patients (34.2%) in the enteral group had died (relative risk in parenteral group, 0.97; 95% confidence interval, 0.86 to 1.08; P=0.57). There were significant reductions in the parenteral group, as compared with the enteral group, in rates of hypoglycemia (44 patients [3.7%] vs. 74 patients [6.2%]; P=0.006) and vomiting (100 patients [8.4%] vs. 194 patients [16.2%]; P<0.001). There were no significant differences between the parenteral group and the enteral group in the mean number of treated infectious complications (0.22 vs. 0.21; P=0.72), 90-day mortality (442 of 1184 patients [37.3%] vs. 464 of 1188 patients [39.1%], P=0.40), in rates of 14 other secondary outcomes, or in rates of adverse events. Caloric intake was similar in the two groups, with the target intake not achieved in most patients. CONCLUSIONS: We found no significant difference in 30-day mortality associated with the route of delivery of early nutritional support in critically ill adults. (Funded by the United Kingdom National Institute for Health Research; CALORIES Current Controlled Trials number, ISRCTN17386141.). PMID- 25271395 TI - Changing trends in phthalate exposures: Zota and Woodruff respond. PMID- 25271397 TI - Facile fabrication of porous CL-20 for low sensitivity high explosives. AB - A facile solvent/non-solvent co-crystallization technology is applied to fabricate porous CL-20, which exhibits interesting morphologies and low sensitivity with beta-cyclodextrin as a crystal modifier. PMID- 25271396 TI - Randomised controlled trial of expressive writing and quality of life in men and women treated for colon or rectal cancer. AB - OBJECTIVE: This randomised trial tested (i) whether a home-based expressive writing (EW) intervention improves quality of life in patients with colorectal cancer (CRC) and (ii) whether the intervention is more beneficial for men or for people who feel constrained in disclosing cancer-related concerns and feelings. DESIGN: Patients treated for CRC were randomised to an EW (n = 101) or control writing (CW; n = 92) group. Assessments were completed at 1 month pre- and post intervention. Sex and perceived social constraints on disclosure were evaluated as moderators. MAIN OUTCOME MEASURES: Primary outcomes were depressive symptoms, sleep problems and quality of life indicators. RESULTS: Eighty-one per cent of participants completed all writing assignments. Consistent with hypotheses, relative to the CW group, participants in the EW group expressed more negative emotion in writing and rated their writings as more meaningful, personal and emotionally revealing. There were no significant main effects of EW or moderating effects of sex or social constraints on outcomes. CONCLUSIONS: Although EW is feasible to use with persons who have CRC, it was not effective as a stand-alone psychotherapeutic intervention. Neither was it more effective for men nor for people who felt they could not freely disclose cancer-related concerns and feelings. PMID- 25271399 TI - A Comparison of HIV Knowledge, Attitudes, and Sources of STI Information Between Female and Male College Students in Taiwan. AB - Taiwan withdrew from the United Nations in 1971, which led to missed opportunities for participating in global HIV/AIDS programs and made Taiwan more vulnerable to HIV. Employing a questionnaire of 996 college students in Taiwan, the authors assessed and compared female and male HIV/AIDS-related knowledge, attitudes, and sources of HIV/sexually transmitted infections (STI) information. Students reported moderate knowledge and attitudes. Females had more positive attitudes toward people with HIV/AIDS than males. Most participants reported learning about HIV and STIs from traditional media, school teachers, and the Internet. We suggest evidence-based educational interventions for students should include targeted electronic and cultural awareness strategies. PMID- 25271400 TI - Cystadenofibromas: Can transvaginal ultrasound appearance reduce some surgical interventions? AB - PURPOSE: Cystadenofibromas are benign ovarian neoplasms. Their most typical features on sonography (US) are unilocular cysts with small, shadowing hyperechoic, solid papillae without internal vascularity. In the past, they were virtually always surgically removed to exclude malignancy. This study was undertaken to review the sonographic appearances of benign cystadenomas. METHODS: We retrospectively reviewed the transvaginal US studies of 32 cases of pathologically proven ovarian cystadenofibromas. RESULTS: Twenty-two of the tumors presented as unilocular cystic structures with one or more solid, hyperechoic, shadowing, mural nodules with no discernible blood flow projecting from the inner cyst wall. Ten lesions were multiloculated with multiple small solid areas, with scant or no blood vessels. CONCLUSIONS: Cystadenofibromas do not always have a classic appearance on transvaginal US and color Doppler imaging. In our series, however, the majority (69%) presented as unilocular cysts with one or more small solid, avascular projections from the inner cyst wall. These features had 100% reliability for a diagnosis of benign cystadenofibroma in this small series. Further study is necessary to confirm the reliability of this finding for benign cystadenofibroma, thus possibly avoiding or minimizing any surgical exploration. PMID- 25271401 TI - Neutron diffraction reveals hydrogen bonds critical for cGMP-selective activation: insights for cGMP-dependent protein kinase agonist design. AB - High selectivity of cyclic-nucleotide binding (CNB) domains for cAMP and cGMP are required for segregating signaling pathways; however, the mechanism of selectivity remains unclear. To investigate the mechanism of high selectivity in cGMP-dependent protein kinase (PKG), we determined a room-temperature joint X ray/neutron (XN) structure of PKG Ibeta CNB-B, a domain 200-fold selective for cGMP over cAMP, bound to cGMP (2.2 A), and a low-temperature X-ray structure of CNB-B with cAMP (1.3 A). The XN structure directly describes the hydrogen bonding interactions that modulate high selectivity for cGMP, while the structure with cAMP reveals that all these contacts are disrupted, explaining its low affinity for cAMP. PMID- 25271402 TI - Pumping of water by rotating chiral carbon nanotube. AB - Water transportation inside carbon nanotubes is of great importance for designing novel nanodevices. In this article, by using molecular dynamics simulations, we systematically investigate the pumping of water by rotating carbon nanotube (CNT). It is found that the chirality and rotation of the CNT are two preconditions for stable water flux inside it. Besides, we find that the water flux shows an approximately logarithmic dependence on the angular velocity of the rotation, a linear dependence on the radius of the CNT, and interestingly, independence of its length within a certain range of CNT size and angular velocity. Further, we also use a dragging theory which successfully describes the water flux behaviors inside the CNT and can fit well with the results obtained from simulations. The present study provides insight into the designing of nanodevices based on the CNT for real applications. PMID- 25271404 TI - Beyond spatial relationships: residential greenness and birth outcomes. PMID- 25271403 TI - The complete structure of the large subunit of the mammalian mitochondrial ribosome. AB - Mitochondrial ribosomes (mitoribosomes) are extensively modified ribosomes of bacterial descent specialized for the synthesis and insertion of membrane proteins that are critical for energy conversion and ATP production inside mitochondria. Mammalian mitoribosomes, which comprise 39S and 28S subunits, have diverged markedly from the bacterial ribosomes from which they are derived, rendering them unique compared to bacterial, eukaryotic cytosolic and fungal mitochondrial ribosomes. We have previously determined at 4.9 A resolution the architecture of the porcine (Sus scrofa) 39S subunit, which is highly homologous to the human mitoribosomal large subunit. Here we present the complete atomic structure of the porcine 39S large mitoribosomal subunit determined in the context of a stalled translating mitoribosome at 3.4 A resolution by cryo electron microscopy and chemical crosslinking/mass spectrometry. The structure reveals the locations and the detailed folds of 50 mitoribosomal proteins, shows the highly conserved mitoribosomal peptidyl transferase active site in complex with its substrate transfer RNAs, and defines the path of the nascent chain in mammalian mitoribosomes along their idiosyncratic exit tunnel. Furthermore, we present evidence that a mitochondrial tRNA has become an integral component of the central protuberance of the 39S subunit where it architecturally substitutes for the absence of the 5S ribosomal RNA, a ubiquitous component of all cytoplasmic ribosomes. PMID- 25271405 TI - Long-term outcomes of bariatric surgery: a National Institutes of Health symposium. AB - IMPORTANCE: The clinical evidence base demonstrating bariatric surgery's health benefits is much larger than it was when the National Institutes of Health last held a consensus panel in 1991. Still, it remains unclear whether ongoing studies will address critical questions about long-term complication rates and the sustainability of weight loss and comorbidity control. OBJECTIVE: To summarize findings from a multidisciplinary workshop convened in May 2013 by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. The workshop aimed to summarize the current state of knowledge of bariatric surgery, review research findings on the long-term outcomes of bariatric surgery, and establish priorities for future research directions. EVIDENCE REVIEW: The evidence presented at the workshop was selected by the planning committee for both its quality and duration of follow-up. The data review emphasized randomized clinical trials and large observational studies with long-term follow-up, with or without a control group. FINDINGS: Several small randomized clinical trials showed greater weight loss and type 2 diabetes mellitus remission compared with nonsurgical treatments within the first 2 years of follow-up after bariatric surgery. Large, long-term observational studies have shown durable (>5 years) weight loss, diabetes, and lipid improvements with bariatric surgery. Still unclear are predictors of outcomes, long-term complications, long-term survival, microvascular and macrovascular events, mental health outcomes, and costs. The studies needed to address these knowledge gaps would be expensive and logistically difficult to perform. CONCLUSIONS AND RELEVANCE: High-quality evidence shows that bariatric surgical procedures result in greater weight loss than nonsurgical treatments and are more effective at inducing initial type 2 diabetes mellitus remission in obese patients. More information is needed about the long-term durability of comorbidity control and complications after bariatric procedures and this evidence will most likely come from carefully designed observational studies. PMID- 25271406 TI - Clinical isolates of Shiga toxin 1a-producing Shigella flexneri with an epidemiological link to recent travel to Hispaniola. AB - Shiga toxins (Stx) are cytotoxins involved in severe human intestinal disease. These toxins are commonly found in Shigella dysenteriae serotype 1 and Shiga toxin-producing Escherichia coli; however, the toxin genes have been found in other Shigella species. We identified 26 Shigella flexneri serotype 2 strains isolated by public health laboratories in the United States during 2001-2013, which encode the Shiga toxin 1a gene (stx1a). These strains produced and released Stx1a as measured by cytotoxicity and neutralization assays using anti-Stx/Stx1a antiserum. The release of Stx1a into culture supernatants increased ~100-fold after treatment with mitomycin C, suggesting that stx1a is carried by a bacteriophage. Infectious phage were found in culture supernatants and increased ~1,000-fold with mitomycin C. Whole-genome sequencing of several isolates and PCR analyses of all strains confirmed that stx1a was carried by a lambdoid bacteriophage. Furthermore, all patients who reported foreign travel had recently been to Hispaniola, suggesting that emergence of these novel strains is associated with that region. PMID- 25271409 TI - Capsule endoscopy for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis. AB - BACKGROUND: Current guidelines recommend performance of oesophago-gastro duodenoscopy at the time of diagnosis of hepatic cirrhosis to screen for oesophageal varices. These guidelines require people to undergo an unpleasant invasive procedure repeatedly with its attendant risks, despite the fact that half of the people do not have identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Video capsule endoscopy is a non-invasive test proposed as an alternative method for the diagnosis of oesophageal varices. OBJECTIVES: To determine the diagnostic accuracy of capsule endoscopy for the diagnosis of oesophageal varices in children or adults with chronic liver disease or portal vein thrombosis, irrespective of the aetiology. To investigate the accuracy of capsule endoscopy as triage or replacement of oesophago-gastro duodenoscopy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register (October 2013), MEDLINE (Ovid SP) (1950 to October 2013), EMBASE (Ovid SP) (1980 to October 2013), ACP Journal Club (Ovid SP) (1991 to October 2013), Database of Abstracts of Reviews of Effects (DARE) (Ovid SP) (third quarter), Health Technology Assessment (HTA) (Ovid SP) (third quarter), NHS Economic Evaluation Database (NHSEED) (Ovid SP) (third quarter), and Science Citation Index Expanded (SCI-EXPANDED) (ISI Web of Knowledge) (1955 to October 2013). We applied no language or document type restrictions. SELECTION CRITERIA: Studies that evaluated the diagnostic accuracy of capsule endoscopy for the diagnosis of oesophageal varices using oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age, with chronic liver disease or portal vein thrombosis. DATA COLLECTION AND ANALYSIS: We followed the available guidelines provided in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews. We calculated the pooled estimates of sensitivity and specificity using the bivariate model due to the absence of a negative correlation in the receiver operating characteristic (ROC) space and of a threshold effect. MAIN RESULTS: The search identified 16 eligible studies, in which only adults with cirrhosis were included. In one study, people with portal thrombosis were also included. We classified most of the studies at high risk of bias for the 'Participants selection' and the 'Flow and timing' domains. One study assessed the accuracy of capsule endoscopy for the diagnosis of large (high risk) oesophageal varices. In the remaining15 studies that assessed the accuracy of capsule endoscopy for the diagnosis of oesophageal varices of any size in people with cirrhosis, 936 participants were included; the pooled estimate of sensitivity was 84.8% (95% confidence interval (CI) 77.3% to 90.2%) and of specificity 84.3% (95% CI 73.1% to 91.4%). Eight of these studies included people with suspected varices or people with already diagnosed or even treated varices, or both, introducing a selection bias. Seven studies including only people with suspected but unknown varices were at low risk of bias; the pooled estimate of sensitivity was 79.7% (95% CI 73.1% to 85.0%) and of specificity 86.1% (95% CI 64.5% to 95.5%). Six studies assessed the diagnostic accuracy of capsule endoscopy for the diagnosis of large oesophageal varices, associated with a higher risk of bleeding; the pooled sensitivity was 73.7% (95% CI 52.4% to 87.7%) and of specificity 90.5% (95% CI 84.1% to 94.4%). Two studies also evaluated the presence of red marks, which are another marker of high risk of bleeding; the estimates of sensitivity and specificity varied widely. Two studies obtained similar results with the use of a modified device as index test (string capsule). Due to the absence of data, we could not perform all planned subgroup analyses. Interobserver agreement in the interpretation of capsule endoscopy results and any adverse event attributable to capsule endoscopy were poorly assessed and reported. Only four studies evaluated the interobserver agreement in the interpretation of capsule endoscopy results: the concordance was moderate. The participants' preferences for capsule endoscopy or oesophago-gastro-duodenoscopy were reported differently but seemed in favour of capsule endoscopy in nine of 10 studies. In 10 studies, participants reported some minor discomfort on swallowing the capsule. Only one study identified other significant adverse events, including impaction of the capsule due to previously unidentified oesophageal strictures in two participants. No adverse events were reported as a consequence of the reference standard. AUTHORS' CONCLUSIONS: We cannot support the use of capsule endoscopy as a triage test in adults with cirrhosis, administered before oesophago-gastro-duodenoscopy, despite the low incidence of adverse events and participant reports of being better tolerated. Thus, we cannot conclude that oesophago-gastro-duodenoscopy can be replaced by capsule endoscopy for the detection of oesophageal varices in adults with cirrhosis. We found no data assessing capsule endoscopy in children and in people with portal thrombosis. PMID- 25271410 TI - Cousins, siblings, or copies: the genomics of recurrent Staphylococcus aureus infections in chronic rhinosinusitis. AB - BACKGROUND: Staphylococcus aureus infection is known to play a role in recalcitrant chronic rhinosinusitis (CRS). However, it is unknown if recurrent S. aureus infections are caused by the same strain or are due to independent acquisitions of different strains. METHODS: Samples were collected from patients with CRS from July 2011 to August 2012. S. aureus was isolated from mucosal swabs and tissue specimens from patients who underwent surgery during the study period, or from swabs of areas of purulence taken in the postoperative period under endoscopic guidance. Pulsed-field gel electrophoresis was used to characterize S. aureus isolates. RESULTS: Thirty-four patients were included in the study; 79% showed persistence of the same S. aureus strain in their paranasal sinuses (p = 0.001; H1 ? 50%). Furthermore, a significantly high frequency of patients with known biofilm status were positive for S. aureus biofilm (p = 0.002; H1 ? 50%). When patients were stratified according to disease evolution postsurgery, certain strains appeared to be more commonly associated with symptom persistence. CONCLUSION: The same S. aureus strain appears to persist in the paranasal sinuses of CRS patients despite multiple courses of culture-directed antibiotics. This suggests that conventional antimicrobial therapies in patients with CRS may not eliminate the organism. This may be partly explained by the formation of biofilms in the paranasal sinus region. PMID- 25271411 TI - 'We Just Call Them People': Positive Regard as a Dimension of Culture in Group Homes for People with Severe Intellectual Disability. AB - BACKGROUND: A dimension of the culture in group homes is staff regard for residents. In underperforming group homes, staff regard residents as being not 'like us' (Bigby, Knox, Beadle-Brown, Clement & Mansell, 2012). We hypothesized the opposite pole of this dimension, in higher performing group homes, would be that staff regard residents positively. METHOD: Three in-depth qualitative case studies were conducted in higher performing group homes using participant observation, interviews and document review. RESULTS: Consistent pattern of staff practices and talk, as well as artefacts, demonstrated staff had a positive regard for residents, who were seen as being 'like us'. Explicit and continuing attention was given to sustaining positive regard for residents in everyday staff practices and to turning abstract values into concrete realities. CONCLUSIONS: This positive cultural norm was established, operationalized and embedded through structures, such as a formal policy about language, and processes such as peer monitoring and practice leadership. PMID- 25271412 TI - Mesenteric panniculitis: prevalence, clinicoradiological presentation and 5-year follow-up. AB - OBJECTIVE: To determine prevalence, clinicoradiological characteristics and outcome of patients with mesenteric panniculitis (MP) in a large hospital-based population. METHODS: Consecutive abdominal CT examinations of 3820 patients were evaluated for MP. Clinical characteristics, therapy and outcome of patients with MP were evaluated during a 5-year follow-up period. A matched pair analysis was performed to further investigate the relation between MP and malignancy. RESULTS: 94 (2.5%) patients with MP were identified (mean age, 66.6 +/- 11.2 years, 70.2% male). MP coexisted with malignancy (especially prostatic carcinoma) in 48.9% of patients, and this was slightly but significantly higher than in age- and sex matched control patients (n = 188, 46.3%). In 48 patients, MP was presumed to be idiopathic. The most frequent presenting symptom was pain (54.3%). Laboratory findings revealed increased acute-phase reactants in half of the patients with MP. CT findings included increased density of mesenterial fat (mean, -56.8 +/- 10.8 HU), fat ring sign, tumoural pseudocapsule and small soft-tissue nodules. Patients with MP (14.6%) developed significantly more malignancies during a 5 year follow-up than did the control group (6.9%). One patient was treated with prednisone without satisfactory response. CONCLUSION: The prevalence of MP in this study was 2.5%. In most patients, radiologic features included increased mesenteric fat density, fat ring sign and small soft-tissue nodules. MP was associated with a significant higher prevalence of coexisting malignancies and a higher prevalence of future cancer development. ADVANCES IN KNOWLEDGE: A more accurate prevalence of MP on CT is demonstrated. An underlying malignancy may play a role. PMID- 25271415 TI - Rational use of antibiotics in the ICU: balancing stewardship and clinical outcomes. PMID- 25271416 TI - Selection pressure in alternative reading frames. AB - Overlapping genes are two protein-coding sequences sharing a significant part of the same DNA locus in different reading frames. Although in recent times an increasing number of examples have been found in bacteria the underlying mechanisms of their evolution are unknown. In this work we explore how selective pressure in a protein-coding sequence influences its overlapping genes in alternative reading frames. We model evolution using a time-continuous Markov process and derive the corresponding model for the remaining frames to quantify selection pressure and genetic noise. Our findings lead to the presumption that, once information is embedded in the reverse reading frame -2 (relative to the mother gene in +1) purifying selection in the protein-coding reading frame automatically protects the sequences in both frames. We also found that this coincides with the fact that the genetic noise measured using the conditional entropy is minimal in frame -2 under selection in the coding frame. PMID- 25271417 TI - Prediction of cardiovascular risk using Framingham, ASSIGN and QRISK2: how well do they predict individual rather than population risk? AB - BACKGROUND: The objective of this study was to evaluate the performance of risk scores (Framingham, Assign and QRISK2) in predicting high cardiovascular disease (CVD) risk in individuals rather than populations. METHODS AND FINDINGS: This study included 1.8 million persons without CVD and prior statin prescribing using the Clinical Practice Research Datalink. This contains electronic medical records of the general population registered with a UK general practice. Individual CVD risks were estimated using competing risk regression models. Individual differences in the 10-year CVD risks as predicted by risk scores and competing risk models were estimated; the population was divided into 20 subgroups based on predicted risk. CVD outcomes occurred in 69,870 persons. In the subgroup with lowest risks, risk predictions by QRISK2 were similar to individual risks predicted using our competing risk model (99.9% of people had differences of less than 2%); in the subgroup with highest risks, risk predictions varied greatly (only 13.3% of people had differences of less than 2%). Larger deviations between QRISK2 and our individual predicted risks occurred with calendar year, different ethnicities, diabetes mellitus and number of records for medical events in the electronic health records in the year before the index date. A QRISK2 estimate of low 10-year CVD risk (<15%) was confirmed by Framingham, ASSIGN and our individual predicted risks in 89.8% while an estimate of high 10-year CVD risk (>= 20%) was confirmed in only 48.6% of people. The majority of cases occurred in people who had predicted 10-year CVD risk of less than 20%. CONCLUSIONS: Application of existing CVD risk scores may result in considerable misclassification of high risk status. Current practice to use a constant threshold level for intervention for all patients, together with the use of different scoring methods, may inadvertently create an arbitrary classification of high CVD risk. PMID- 25271418 TI - Dance communication affects consistency, but not breadth, of resource use in pollen-foraging honey bees. AB - In groups of cooperatively foraging individuals, communication may improve the group's performance by directing foraging effort to where it is most useful. Honey bees (Apis mellifera) use a specialized dance to communicate the location of floral resources. Because honey bees dance longer for more rewarding resources, communication may shift the colony's foraging effort towards higher quality resources, and thus narrow the spectrum of resource types used. To test the hypothesis that dance communication changes how much honey bee colonies specialize on particular resources, we manipulated their ability to communicate location, and assessed the relative abundance of different pollen taxa they collected. This was repeated across five natural habitats that differed in floral species richness and spatial distribution. Contrary to expectation, impairing communication did not change the number or diversity of pollen (resource) types used by individual colonies per day. However, colonies with intact dance communication were more consistent in their resource use, while those with impaired communication were more likely to collect rare, novel pollen types. This suggests that communication plays an important role in shaping how much colonies invest in exploring new resources versus exploiting known ones. Furthermore, colonies that did more exploration also tended to collect less pollen overall, but only in environments with greater floral abundance per patch. In such environments, the ability to effectively exploit highly rewarding resources may be especially important-and dance communication may help colonies do just that. This could help explain how communication benefits honey bee colonies, and also why it does so only under certain environmental conditions. PMID- 25271419 TI - Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability. AB - We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET) radiation such as X-rays or high-charge and high-energy (HZE) particle high-LET radiation such as (56)Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS) levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization. PMID- 25271420 TI - Resveratrol modulates cytokine-induced Jak/STAT activation more efficiently than 5-aminosalicylic acid: an in vitro approach. AB - BACKGROUND: Many advances have been recently made focused on the valuable help of dietary polyphenols in chronic inflammatory diseases. On the other hand, current treatment options for intestinal bowel disease patients are unsatisfying and, for this reason, it is estimated that many patients use dietary supplements to achieve extra benefits. AIM: The aim of this work was to analyze under a mechanistic perspective the anti-inflammatory potential of resveratrol, a natural polyphenolic compound, and to compare it with a pharmaceutical agent, 5 aminosalicylic acid, using the intestinal HT-29 cell line, as a cellular model. METHODOLOGY AND PRINCIPAL FINDINGS: In the present study, HT-29 colon epithelial cells were pre-treated with 25 uM resveratrol and/or 500 uM 5-aminosalicylic acid and then exposed to a combination of cytokines (IL-1alpha, TNF-alpha, IFN-gamma) for a certain period of time. Our data showed that resveratrol, used in a concentration 20 times lower than 5-aminosalicylic acid, was able to significantly reduce NO and PGE2 production, iNOS and COX-2 expression and reactive oxidant species formation induced by the cytokine challenge. However, as already verified with 5-aminosalicylic acid, in spite of not exhibiting any effect on IkB-alpha degradation, resveratrol down-regulated JAK-STAT pathway, decreasing the levels of activated STAT1 in the nucleus. Additionally, resveratrol decreased the cytokine-stimulated activation of SAPK/JNK pathway but did not counteract the cytokine-triggered negative feedback mechanism of STAT1, through p38 MAPK. CONCLUSION/SIGNIFICANCE: Taken together, our results show that resveratrol may be considered a future nutraceutical approach, promoting remission periods, limiting the inflammatory process and preventing colorectal cancer, which is common in these patients. PMID- 25271421 TI - Meloxicam blocks neuroinflammation, but not depressive-like behaviors, in HIV-1 transgenic female rats. AB - Adolescents living with human immunodeficiency virus (HIV) comprise approximately 12% of the HIV-positive population worldwide. HIV-positive adolescents experience a higher rate of clinical depression, a greater risk of sexual and drug abuse behaviors, and a decreased adherence to highly active antiretroviral therapies (HAART). Using adolescent HIV-1 transgenic rats (HIV-1 tg) that display related immune response alterations and pathologies, this study tested the hypothesis that developmental expression of HIV-1-related proteins induces a depressive-like phenotype that parallels a decrease in hippocampal cell proliferation and an increase in pro-inflammatory cytokine expression in the hippocampus. Consistent with this hypothesis, adolescent HIV-1 tg rats demonstrated a depressive-like behavioral phenotype, had decreased levels of cell proliferation, and exhibited elevated expression of monocyte chemotactic protein-1 (Mcp-1) in the hippocampus relative to controls. Subsequently, we tested the ability of meloxicam, a selective COX-2 inhibitor, to attenuate behavioral deficits via inflammatory mechanisms. Daily meloxicam treatments did not alter the behavioral profile despite effectively reducing hippocampal inflammatory gene expression. Together, these data support a biological basis for the co-morbid manifestation of depression in HIV-positive patients as early as in adolescence and suggest that modifications in behavior manifest independent of inflammatory activity in the hippocampus. PMID- 25271422 TI - BMP-2 promotes oral squamous carcinoma cell invasion by inducing CCL5 release. AB - Bone morphogenetic protein-2 (BMP-2)-containing bone grafts are useful regenerative materials for oral and maxillofacial surgery; however, several in vitro and in vivo studies previously reported cancer progression-related adverse effects caused by BMP-2. In this study, by quantifying the rhBMP-2 content released from bone grafts, the rhBMP-2 concentration that did not show cytotoxicity in each cell line was determined and applied to the in vitro monoculture or coculture model in the invasion assay. Our results showed that 1 ng/ml rhBMP-2, while not affecting cancer cell viability, significantly increased the invasion ability of the cancer cells cocultured with fibroblasts. Cocultured medium with rhBMP-2 also contained increased levels of matrix metalloproteinases. rhBMP-2-treated cocultured fibroblasts did not show a prominent difference in mRNA expression profile. Some cytokines, however, were detected in the conditioned medium by a human cytokine antibody array. Among them, the cancer invasion-related factor CCL5 was quantified by ELISA. Interestingly, CCL5 neutralizing antibodies significantly reduced the invasion of oral cancer cells. In conclusion, our results suggest that 1 ng/ml rhBMP-2 may induce invasion of oral squamous cell carcinoma (OSCC) cells by CCL5 release in coculture models. Therefore, we propose that a careful clinical examination before the use of rhBMP 2-containing biomaterials is indispensable for using rhBMP-2 treatment to prevent cancer progression. PMID- 25271423 TI - Weak population structure in European roe deer (Capreolus capreolus) and evidence of introgressive hybridization with Siberian roe deer (C. pygargus) in northeastern Poland. AB - We investigated contemporary and historical influences on the pattern of genetic diversity of European roe deer (Capreolus capreolus). The study was conducted in northeastern Poland, a zone where vast areas of primeval forests are conserved and where the European roe deer was never driven to extinction. A total of 319 unique samples collected in three sampling areas were genotyped at 16 microsatellites and one fragment (610 bp) of mitochondrial DNA (mtDNA) control region. Genetic diversity was high, and a low degree of genetic differentiation among sampling areas was observed with both microsatellites and mtDNA. No evidence of genetic differentiation between roe deer inhabiting open fields and forested areas was found, indicating that the ability of the species to exploit these contrasting environments might be the result of its phenotypic plasticity. Half of the studied individuals carried an mtDNA haplotype that did not belong to C. capreolus, but to a related species that does not occur naturally in the area, the Siberian roe deer (C. pygargus). No differentiation between individuals with Siberian and European mtDNA haplotypes was detected at microsatellite loci. Introgression of mtDNA of Siberian roe deer into the genome of European roe deer has recently been detected in eastern Europe. Such introgression might be caused by human-mediated translocations of Siberian roe deer within the range of European roe deer or by natural hybridization between these species in the past. PMID- 25271424 TI - Pinocembrin protects the brain against ischemia-reperfusion injury and reverses the autophagy dysfunction in the penumbra area. AB - The aim of this study was to investigate the effects of pinocembrin on brain ischemia/reperfusion (I/R) injury and the potential involvement of autophagy activity changes in the penumbra area in the mechanisms of pinocembrin activity. Focal cerebral I/R model was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 24 h reperfusion. Pinocembrin was administered intravenously at different doses (1, 3, and 10 mg/kg, respectively) at the onset of reperfusion. Neurological function, brain infarction and brain swelling ratio were evaluated. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and immunohistochemical analysis (Caspase-3) were used to evaluate apoptosis in the penumbra cortex. Two key proteins of autophagy, LC3B and Beclin1, were detected by western blot. The results showed that pinocembrin treatment could significantly reduce neurological deficit scores, infarct volume, cerebral edema and improve pathological lesion in the I/R rats. Pinocembrin treatment could also reduce the number of TUNEL-positive and Caspase-3-positive neurons, and upregulate the expression of LC3B and Beclin1 in penumbra area. These results suggested that pinocembrin could protect the brain against I/R injury, and the possible mechanisms might be attributed to inhibition of apoptosis and reversed autophagy activity in penumbra area. PMID- 25271425 TI - Arbutus unedo L.: chemical and biological properties. AB - Arbutus unedo L. (strawberry tree) has a circum-Mediterranean distribution, being found in western, central and southern Europe, north-eastern Africa (excluding Egypt and Libya) and the Canary Islands and western Asia. Fruits of the strawberry tree are generally used for preparing alcoholic drinks (wines, liqueurs and brandies), jams, jellies and marmalades, and less frequently eaten as fresh fruit, despite their pleasing appearance. An overview of the chemical composition of different parts of the plant, strawberry tree honey and strawberry tree brandy will be presented. The biological properties of the different parts of A. unedo and strawberry tree honey will be also overviewed. PMID- 25271426 TI - A starting point for fluorescence-based single-molecule measurements in biomolecular research. AB - Single-molecule fluorescence techniques are ideally suited to provide information about the structure-function-dynamics relationship of a biomolecule as static and dynamic heterogeneity can be easily detected. However, what type of single molecule fluorescence technique is suited for which kind of biological question and what are the obstacles on the way to a successful single-molecule microscopy experiment? In this review, we provide practical insights into fluorescence-based single-molecule experiments aiming for scientists who wish to take their experiments to the single-molecule level. We especially focus on fluorescence resonance energy transfer (FRET) experiments as these are a widely employed tool for the investigation of biomolecular mechanisms. We will guide the reader through the most critical steps that determine the success and quality of diffusion-based confocal and immobilization-based total internal reflection fluorescence microscopy. We discuss the specific chemical and photophysical requirements that make fluorescent dyes suitable for single-molecule fluorescence experiments. Most importantly, we review recently emerged photoprotection systems as well as passivation and immobilization strategies that enable the observation of fluorescently labeled molecules under biocompatible conditions. Moreover, we discuss how the optical single-molecule toolkit has been extended in recent years to capture the physiological complexity of a cell making it even more relevant for biological research. PMID- 25271427 TI - New derivatives of 3,4-dihydroisoquinoline-3-carboxylic acid with free-radical scavenging, D-amino acid oxidase, acetylcholinesterase and butyrylcholinesterase inhibitory activity. AB - A series of 3,4-dihydroisoquinoline-3-carboxylic acid derivatives were synthesised and tested for their free-radical scavenging activity using 2,2 diphenyl-1-picrylhydrazyl radical (DPPH.), 2,2'-azino-bis(3-ethylbenzothiazoline 6-sulfonic acid) radical (ABTS.+), superoxide anion radical (O2.-) and nitric oxide radical (.NO) assays. We also studied d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Almost each of newly synthesised compounds exhibited radical scavenging capabilities. Moreover, several compounds showed moderate inhibitory activities against DAAO, AChE and BuChE. Compounds with significant free-radical scavenging activity may be potential candidates for therapeutics used in oxidative-stress related diseases. PMID- 25271428 TI - Photochemical aryl radical cyclizations to give (E)-3-ylideneoxindoles. AB - (E)-3-Ylideneoxindoles are prepared in methanol in reasonable to good yields, as adducts of photochemical 5-exo-trig of aryl radicals, in contrast to previously reported analogous radical cyclizations initiated by tris(trimethylsilyl)silane and azo-initiators that gave reduced oxindole adducts. PMID- 25271429 TI - Acoustic divergence with gene flow in a lekking hummingbird with complex songs. AB - Hummingbirds have developed a remarkable diversity of learned vocalizations, from single-note songs to phonologically and syntactically complex songs. In this study we evaluated if geographic song variation of wedge-tailed sabrewings (Campylopterus curvipennis) is correlated with genetic divergence, and examined processes that explain best the origin of intraspecific song variation. We contrasted estimates of genetic differentiation, genetic structure, and gene flow across leks from microsatellite loci of wedge-tailed sabrewings with measures for acoustic signals involved in mating derived from recordings of males singing at leks throughout eastern Mexico. We found a strong acoustic structure across leks and geography, where lek members had an exclusive assemblage of syllable types, differed in spectral and temporal measurements of song, and song sharing decreased with geographic distance. However, neutral genetic and song divergence were not correlated, and measures of genetic differentiation and migration estimates indicated gene flow across leks. The persistence of acoustic structuring in wedge-tailed sabrewings may thus best be explained by stochastic processes across leks, in which intraspecific vocal variation is maintained in the absence of genetic differentiation by postdispersal learning and social conditions, and by geographical isolation due to the accumulation of small differences, producing most dramatic changes between populations further apart. PMID- 25271431 TI - Liposome-based approaches for delivery of mainstream chemotherapeutics: preparation methods, liposome designs, therapeutic efficacy. AB - We review liposome-based delivery approaches that aim to address toxicities and to improve the therapeutic efficacy of mainstream chemotherapeutics, namely, doxorubicin, paclitaxel, and cisplatin. A brief review of the biomolecular mechanism(s) of action of these agents is followed by a description of characteristic examples of therapeutic approaches and of liposome membrane designs. Short reports on clinical studies are also included when applicable. The technical issues of different loading/encapsulation methods of these agents into liposomes are also discussed in terms of the physicochemical properties of both the agents themselves and of the lipid-based self-assemblies. PMID- 25271432 TI - Nanoparticle drug formulations for cancer diagnosis and treatment. AB - Over the past ten years, more than a billion dollars in U.S. government funding has been awarded to the development of nanomaterials for clinical diagnosis and therapy. In this article we will focus on one subset of nanotechnology: nanoparticle formulations of drugs intended to diagnose or treat cancer. Several nanoparticle drug preparations are now in widespread clinical use, and dozens are in the pipeline. In some cases the nanoparticles are simply passive drug carriers or contrast agents; in others, the nanoparticles have active therapeutic properties. Cancer, particularly solid tumors, is one of nanotechnology's key targets. The specific challenges involved in cancer treatment are those addressed by multifunctional materials, in particular, inaccessibility, widespread metastasis, low oxygen concentrations, and resistance to drugs and radiation. Nonetheless, major barriers still remain to effective nanoparticle design and approval. PMID- 25271433 TI - Progress in lipid-based nanoparticles for cancer therapy. AB - Most conventional cancer therapeutics gain limited access to many types of tumors while having considerable adverse effects, resulting in low therapeutic efficacy and high toxicity. Therefore, research has now focused on the development of novel drug delivery systems (DDS) with the goal of maintaining high therapeutic drug levels at malignant cells and as low as possible drug levels in other cells. The introduction of nanotechnology has addressed some of these problems and opened up new avenues for improved cancer therapy. The design of nanoparticles for DDS takes into consideration issues such as targeting, controlled drug release and enhanced penetration via biological barriers. In this review we describe the design principles of targeted DDS for cancer therapy and the types of nanoparticles that are under development. Emphasis is put on lipid-based nanoparticles, particularly bolaamphiphilic vesicles that have tremendous potential in delivering therapeutic and diagnostic agents to specific cells following systemic administration. PMID- 25271434 TI - Fibrillous carbon nanotube: an unexpected journey. AB - The emergence of nanomedicine, a discipline at the nexus of materials engineering, chemistry, biology, and pharmacology, has generated much excitement in the field of translational medical research and provided some unexpected results. Nanomedicine seeks to introduce nanoscale technology to the practice of medicine via the design and development of nanomaterials possessing therapeutic or diagnostic functions. However, as expected, any modification of the base nanomaterial platform to decorate it with solublizing, targeting, therapeutic, or diagnostic modalities yields a material with a very different pharmacological profile than the original platform. Clearly, the goal of nanotechnology is to put into practice a novel synthetic substance in which the function of the complex is greater than the sum of its components. These new compositions must be thoroughly evaluated in vivo. Therefore, reliance on pharmacokinetic predictions based solely on the baseline profile of the original platform can confuse the field and delay progress. Carbon nanotube pharmacokinetic profiles provide an interesting example of this situation. Covalently functionalized nanotubes exhibit fibrillar pharmacology while those nanotubes that are not covalently functionalized transiently behave as fibers and then tend toward an overall colloidal profile in vivo. PMID- 25271430 TI - Dawn of advanced molecular medicine: nanotechnological advancements in cancer imaging and therapy. AB - Nanotechnology plays an increasingly important role not only in our everyday life (with all its benefits and dangers) but also in medicine. Nanoparticles are to date the most intriguing option to deliver high concentrations of agents specifically and directly to cancer cells; therefore, a wide variety of these nanomaterials has been developed and explored. These span the range from simple nanoagents to sophisticated smart devices for drug delivery or imaging. Nanomaterials usually provide a large surface area, allowing for decoration with a large amount of moieties on the surface for either additional functionalities or targeting. Besides using particles solely for imaging purposes, they can also carry as a payload a therapeutic agent. If both are combined within the same particle, a theranostic agent is created. The sophistication of highly developed nanotechnology targeting approaches provides a promising means for many clinical implementations and can provide improved applications for otherwise suboptimal formulations. In this review we will explore nanotechnology both for imaging and therapy to provide a general overview of the field and its impact on cancer imaging and therapy. PMID- 25271435 TI - Exploiting the tumor phenotype using biodegradable submicron carriers of chemotherapeutic drugs. AB - Tumor tissues possess characteristics that distinguish them from healthy tissues and make them attractive targets for submicron carriers of chemotherapeutic drugs (CTX). CTX are generally administered systemically in free form to cancer patients resulting in unwanted cytotoxic effects and placing limitations on the deliverable CTX dose. In an effort to raise the therapeutic index of CTX there are now liposome-based CTX formulations in clinical use that are more tumor specific than the free form of CTX. However, progression to liposome-based chemotherapy in the clinic has been slow and there have been no approved formulations introduced in the last decade. Alternative carrier systems such as those made from the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA) have been investigated in preclinical settings with promising outcomes. Here we review the principle behind biodegradable submicron carriers as CTX delivery vehicles for solid tumors with a specific focUS on liposomes and PLGA-based carriers, highlighting the strengths and weaknesses of each system. PMID- 25271437 TI - Multiple complexes of nitrogen assimilatory enzymes in spinach chloroplasts: possible mechanisms for the regulation of enzyme function. AB - Assimilation of nitrogen is an essential biological process for plant growth and productivity. Here we show that three chloroplast enzymes involved in nitrogen assimilation, glutamate synthase (GOGAT), nitrite reductase (NiR) and glutamine synthetase (GS), separately assemble into distinct protein complexes in spinach chloroplasts, as analyzed by western blots under blue native electrophoresis (BN PAGE). GOGAT and NiR were present not only as monomers, but also as novel complexes with a discrete size (730 kDa) and multiple sizes (>120 kDa), respectively, in the stromal fraction of chloroplasts. These complexes showed the same mobility as each monomer on two-dimensional (2D) SDS-PAGE after BN-PAGE. The 730 kDa complex containing GOGAT dissociated into monomers, and multiple complexes of NiR reversibly converted into monomers, in response to the changes in the pH of the stromal solvent. On the other hand, the bands detected by anti GS antibody were present not only in stroma as a conventional decameric holoenzyme complex of 420 kDa, but also in thylakoids as a novel complex of 560 kDa. The polypeptide in the 560 kDa complex showed slower mobility than that of the 420 kDa complex on the 2D SDS-PAGE, implying the assembly of distinct GS isoforms or a post-translational modification of the same GS protein. The function of these multiple complexes was evaluated by in-gel GS activity under native conditions and by the binding ability of NiR and GOGAT with their physiological electron donor, ferredoxin. The results indicate that these multiplicities in size and localization of the three nitrogen assimilatory enzymes may be involved in the physiological regulation of their enzyme function, in a similar way as recently described cases of carbon assimilatory enzymes. PMID- 25271438 TI - New starch phenotypes produced by TILLING in barley. AB - Barley grain starch is formed by amylose and amylopectin in a 1:3 ratio, and is packed into granules of different dimensions. The distribution of granule dimension is bimodal, with a majority of small spherical B-granules and a smaller amount of large discoidal A-granules containing the majority of the starch. Starch granules are semi-crystalline structures with characteristic X-ray diffraction patterns. Distinct features of starch granules are controlled by different enzymes and are relevant for nutritional value or industrial applications. Here, the Targeting-Induced Local Lesions IN Genomes (TILLING) approach was applied on the barley TILLMore TILLING population to identify 29 new alleles in five genes related to starch metabolism known to be expressed in the endosperm during grain filling: BMY1 (Beta-amylase 1), GBSSI (Granule Bound Starch Synthase I), LDA1 (Limit Dextrinase 1), SSI (Starch Synthase I), SSIIa (Starch Synthase IIa). Reserve starch of nine M3 mutant lines carrying missense or nonsense mutations was analysed for granule size, crystallinity and amylose/amylopectin content. Seven mutant lines presented starches with different features in respect to the wild-type: (i) a mutant line with a missense mutation in GBSSI showed a 4-fold reduced amylose/amylopectin ratio; (ii) a missense mutations in SSI resulted in 2-fold increase in A:B granule ratio; (iii) a nonsense mutation in SSIIa was associated with shrunken seeds with a 2-fold increased amylose/amylopectin ratio and different type of crystal packing in the granule; (iv) the remaining four missense mutations suggested a role of LDA1 in granule initiation, and of SSIIa in determining the size of A-granules. We demonstrate the feasibility of the TILLING approach to identify new alleles in genes related to starch metabolism in barley. Based on their novel physicochemical properties, some of the identified new mutations may have nutritional and/or industrial applications. PMID- 25271436 TI - Development of nanoscale approaches for ovarian cancer therapeutics and diagnostics. AB - Ovarian cancer is the deadliest of all gynecological cancers and the fifth leading cause of death due to cancer in women. This is largely due to late-stage diagnosis, poor prognosis related to advanced-stage disease, and the high recurrence rate associated with development of chemoresistance. Survival statistics have not improved significantly over the last three decades, highlighting the fact that improved therapeutic strategies and early detection require substantial improvements. Here, we review and highlight nanotechnology based approaches that seek to address this need. The success of Doxil, a PEGylated liposomal nanoencapsulation of doxorubicin, which was approved by the FDA for use on recurrent ovarian cancer, has paved the way for the current wave of nanoparticle formulations in drug discovery and clinical trials. We discuss and summarize new nanoformulations that are currently moving into clinical trials and highlight novel nanotherapeutic strategies that have shown promising results in preclinical in vivo studies. Further, the potential for nanomaterials in diagnostic imaging techniques and the ability to leverage nanotechnology for early detection of ovarian cancer are also discussed. PMID- 25271440 TI - The neural basis of mark making: a functional MRI study of drawing. AB - Compared to most other forms of visually-guided motor activity, drawing is unique in that it "leaves a trail behind" in the form of the emanating image. We took advantage of an MRI-compatible drawing tablet in order to examine both the motor production and perceptual emanation of images. Subjects participated in a series of mark making tasks in which they were cued to draw geometric patterns on the tablet's surface. The critical comparison was between when visual feedback was displayed (image generation) versus when it was not (no image generation). This contrast revealed an occipito-parietal stream involved in motion-based perception of the emerging image, including areas V5/MT+, LO, V3A, and the posterior part of the intraparietal sulcus. Interestingly, when subjects passively viewed animations of visual patterns emerging on the projected surface, all of the sensorimotor network involved in drawing was strongly activated, with the exception of the primary motor cortex. These results argue that the origin of the human capacity to draw and write involves not only motor skills for tool use but also motor-sensory links between drawing movements and the visual images that emanate from them in real time. PMID- 25271441 TI - Rickettsia felis and changing paradigms about pathogenic rickettsiae. PMID- 25271439 TI - Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice. AB - BACKGROUND: Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice. METHODS AND FINDINGS: Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma. CONCLUSION: This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction. PMID- 25271442 TI - Defining and developing expertise in tracheal intubation using a GlideScope((r)) for anaesthetists with expertise in Macintosh direct laryngoscopy: an in-vivo longitudinal study. AB - Although videolaryngoscopy can provide excellent views of the laryngeal structures as both the primary method of tracheal intubation and as a rescue technique for difficult direct laryngoscopy, the existing literature is inadequate to define expertise or even competence. We observed the performance of nine trainees during 890 intubations, with an additional 72 intubations performed by expert anaesthetists used as a control group. Univariate and multivariate mixed-effects logistic regression models were applied to detect potential predictors of successful intubation and define the number of intubations necessary for a trainee to achieve expertise (> 90% probability of optimal performance). Optimal performance was predicted by single laryngoscope insertion (p < 0.001) and a Cormack and Lehane grade-1 view (p < 0.001), and not by normal lifting force applied to the device (p = 0.15), with expertise reached after 76 attempts. These results indicate that expertise in videolaryngoscopy requires prolonged training and practice. PMID- 25271443 TI - The SWI/SNF subunit/tumor suppressor BAF47/INI1 is essential in cell cycle arrest upon skeletal muscle terminal differentiation. AB - Myogenic terminal differentiation is a well-orchestrated process starting with permanent cell cycle exit followed by muscle-specific genetic program activation. Individual SWI/SNF components have been involved in muscle differentiation. Here, we show that the master myogenic differentiation factor MyoD interacts with more than one SWI/SNF subunit, including the catalytic subunit BRG1, BAF53a and the tumor suppressor BAF47/INI1. Downregulation of each of these SWI/SNF subunits inhibits skeletal muscle terminal differentiation but, interestingly, at different differentiation steps and extents. BAF53a downregulation inhibits myotube formation but not the expression of early muscle-specific genes. BRG1 or BAF47 downregulation disrupt both proliferation and differentiation genetic programs expression. Interestingly, BRG1 and BAF47 are part of the SWI/SNF remodeling complex as well as the N-CoR-1 repressor complex in proliferating myoblasts. However, our data show that, upon myogenic differentiation, BAF47 shifts in favor of N-CoR-1 complex. Finally, BRG1 and BAF47 are well-known tumor suppressors but, strikingly, only BAF47 seems essential in the myoblasts irreversible cell cycle exit. Together, our data unravel differential roles for SWI/SNF subunits in muscle differentiation, with BAF47 playing a dual role both in the permanent cell cycle exit and in the regulation of muscle-specific genes. PMID- 25271444 TI - Human infection with highly pathogenic A(H7N7) avian influenza virus, Italy, 2013. AB - During an influenza A(H7N7) virus outbreak among poultry in Italy during August September 2013, infection with a highly pathogenic A(H7N7) avian influenza virus was diagnosed for 3 poultry workers with conjunctivitis. Genetic analyses revealed that the viruses from the humans were closely related to those from chickens on affected farms. PMID- 25271445 TI - Ketamine safety and tolerability in clinical trials for treatment-resistant depression. AB - OBJECTIVE: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD. METHOD: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation. RESULTS: The overall antidepressant response rate, defined as a >= 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information. CONCLUSIONS: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430. PMID- 25271447 TI - Comparative morphology of the species of Libyostrongylus and Codiostomum, parasites from ostriches, Struthio camelus, with a identification key to the species. AB - One of the most common problems in breeding of ostriches in captivity is the control of parasitic diseases. This work presents keys for the identification of adult nematodes and infective larvae by morphologic and morphometric characteristics. These keys will allow the scientific community to identify the species that infect the ostriches either based on the characteristics of the posterior end of the infective larvae found through a simple fecal exam or by observing the morphology and morphometry of adult worms recovered during necropsies. These keys will facilitate ecological and systematic studies, as well as increase the understanding of the epidemiology of these parasitosis in ostriches. PMID- 25271448 TI - Genetic diversity of Ehrlichia canis strains from naturally infected dogs in Rio de Janeiro, Brazil. AB - The aim of this study was to characterize Ehrlichia canis strains from naturally infected dogs in Rio de Janeiro, Brazil. In addition, all the clinical and hematological findings observed in these dogs were reported. PCR targeting the 16S rRNA gene was used for diagnostic purposes, and the TRP19 and TRP36 genes were sequenced to evaluate the genetic diversity. Fifteen samples were positive for E. canis. The polymerase chain reaction for the TRP19 gene resulted in 11 amplicons (11/15), which were cloned into the pGEM-T easy vector for sequencing. The complete sequence of TRP19 gene was compared to those in the GenBank, revealing high identicalness. Phylogenetic analysis on the TRP36 gene sequences demonstrated two distinct strains from two dogs, named 56C and 70C. The 56C strain was grouped with the strain Cuiaba 16, which is a hybrid strain formed by Brazilian and US genogroups; and the 70C strain was grouped with other strains of the US genogroup, thus suggesting that there are at least two genogroups of E. canis in Rio de Janeiro (US and Brazilian). Those animals, in which the 70C and 56C strains were isolated, showed distinct clinical and hematological manifestations of the disease. The appearance of different genotypes may express new phenotypes, thus resulting in different forms of presentation of the disease and making its diagnosis more complex. PMID- 25271446 TI - Biomaterial-based delivery for skeletal muscle repair. AB - Skeletal muscle possesses a remarkable capacity for regeneration in response to minor damage, but severe injury resulting in a volumetric muscle loss can lead to extensive and irreversible fibrosis, scarring, and loss of muscle function. In early clinical trials, the intramuscular injection of cultured myoblasts was proven to be a safe but ineffective cell therapy, likely due to rapid death, poor migration, and immune rejection of the injected cells. In recent years, appropriate therapeutic cell types and culturing techniques have improved progenitor cell engraftment upon transplantation. Importantly, the identification of several key biophysical and biochemical cues that synergistically regulate satellite cell fate has paved the way for the development of cell-instructive biomaterials that serve as delivery vehicles for cells to promote in vivo regeneration. Material carriers designed to spatially and temporally mimic the satellite cell niche may be of particular importance for the complete regeneration of severely damaged skeletal muscle. PMID- 25271449 TI - Metabolic alterations in broiler chickens experimentally infected with sporulated oocysts of Eimeria maxima. AB - Metabolic and morphometric alterations of the duodenal villi caused by parasitism of chickens by Eimeria maxima were evaluated, using 100 male Cobb birds, randomly distributed into two groups (control and infected). The infected group was inoculated with 0.5 ml of a solution containing 5 * 103 sporulated oocysts of Eimeria maxima. Ten birds per sample were sacrificed on the 6th, 11th, 22nd and 41st days post-infection (dpi). In order to evaluate the alterations, samples of duodenum, jejunum and ileum fragments were collected after necropsy for histological analysis. Villus biometry was determined by means of a slide graduated in microns that was attached to a binocular microscope. To evaluate the biochemical data, 5 ml of blood were sampled from the birds before sacrifice. The statistical analyses were performed using the GraphPad 5 statistical software for Windows. Tukey's multiple comparison test (p <0.05) was performed for the different dpi's and the unpaired t test for the difference between the groups. Infection by E. maxima causes both qualitative and quantitative alterations to the structure of the intestinal villi, thereby interfering with the absorption of nutrients such as calcium, phosphorus, magnesium, protein and lipids, with consequent reductions in the birds' weights. PMID- 25271450 TI - Trichobius longipes (Diptera, Streblidae) as a parasite of Phyllostomus hastatus (Chiroptera, Phyllostomidae). AB - Among the factors that influence the diversity of ectoparasites on bat hosts are the kind of roost and the host's social behavior. Other factors such as sex, reproductive condition and host size may influence the distribution and abundance of ectoparasites. The aim of the present study was to analyze the variation in Streblidae ectoparasites on the bat Phyllostomus hastatus, according to sex and roost type. We caught bats in four houses on Marambaia Island, municipality of Mangaratiba, and in one house at the Federal Rural University of Rio de Janeiro, municipality of Seropedica. We caught 65 females and 50 males of P. hastatus and 664 streblids of four species: Aspidoptera phyllostomatis, Strebla consocia, Trichobius "dugesii" complex and Trichobius longipes. The species T. longipes accounted for more than 99% of all the ectoparasites caught. Female bats were more parasitized than males, in terms of both prevalence and average intensity. The total number of parasites did not vary between resident and non-resident bats. The relationship between the number of individuals of T. longipes and sex and roost type was significant for resident bats. The total number of parasites on males did not differ between bachelor roosts and mixed-sex roosts. The differences found between roosts reflected the differences between the sexes. PMID- 25271451 TI - Ecology of Lutzomyia longipalpis and Lutzomyia migonei in an endemic area for visceral leishmaniasis. AB - The main vector for visceral leishmaniasis (VL) in Brazil is Lutzomyia longipalpis. However, the absence of L. longipalpis in a region of autochthonous VL demonstrates the participation of other species in the transmission of the parasite. Studies conducted in La Banda, Argentina, and Sao Vicente Ferrer, Pernambuco State, Brazil, have correlated the absence of L. longipalpis and the presence of L. migonei with autochthonous cases of VL. In Sao Vicente Ferrer, Pernambuco, there was evidence for the natural infection of L. migonei with Leishmania infantum chagasi. Thus, the objective of this work was to assess the ecology of the sand flies L. longipalpis and L. migonei in Fortaleza, an endemic area for VL. Insect capture was conducted at 22 sampling points distributed across four regions of Fortaleza. In total, 32,403 sand flies were captured; of these, 18,166 (56%) were identified as L. longipalpis and 14,237 (44%) as L. migonei. There were significant density differences found between the vectors at each sampling site (indoors and outdoors) (p <0.0001). These findings confirm that L. migonei and L. longipalpis are distributed throughout Fortaleza, where they have adapted to an indoor environment, and suggest that L. migonei may share the role as a vector with L. longipalpis in the transmission of VL in Fortaleza. PMID- 25271452 TI - Bovine babesiosis and anaplasmosis complex: diagnosis and evaluation of the risk factors from Bahia, Brazil. AB - Direct diagnoses were made by using - blood smears and nested PCR (nPCR) tests on 309 blood samples from crossbred dairy cattle in the municipality of Ibicarai, Bahia. From diagnostic blood smear slides, the observed parasitic frequencies were 31.1% for Anaplasma marginale and 20.4% for Babesia sp. From nPCR diagnoses, they were 63% for A. marginale, 34% for Babesia bigemina and 20.4% for Babesia bovis. There were significant differences (P <0.01) between the two diagnostic methods (nPCR and blood smear slides). The compliance obtained from the kappa test was 0.41 and 0.48 for A. marginale and Babesia sp., respectively. The tick samples from the six farms analyzed using nPCR were only positive for A. marginale. Evaluation of the risk factors relating to the presence of ticks and the age of the animals showed that there was a significant association (P <0.01) with the frequency of animals infected with both pathogens. Therefore, under the conditions studied, nPCR proved to be a good tool for diagnosing the agents of the bovine babesiosis and anaplasmosis complex because of its sensitivity and specificity in comparison with blood smears. The municipality of Ibicarai is an area with endemic prevalence of bovine babesiosis and anaplasmosis confirmed by nPCR and A. marginale is the main agent of the disease. PMID- 25271453 TI - Rhipicephalus (Boophilus) microplus in the western-central region of Rio Grande do Sul, Brazil: multiresistant tick. AB - The aim of the present study was to assess the acaricide resistance of tick populations in the western-central region of Rio Grande do Sul (Brazil), which has not previously been reported. Fifty-four cattle farms were visited and specimens of Rhipicephalus (Boophilus) microplus were collected and subjected to the adult immersion test, using nine commercial acaricides in the amidine, pyrethroid and organophosphate groups. Climatic data, including monthly precipitation, were recorded. The results from the present study demonstrated that seven of the acaricides analyzed presented mean efficacy values of less than 95%, with large differences among the products tested. Nine of them exhibited satisfactory and unsatisfactory acaricide results on at least one farm. In conclusion, the farms located in the western-central region of Rio Grande do Sul, Brazil, exhibited populations of R. (Boophilus) microplus with variable degrees of susceptibility to different acaricides, thus suggesting that resistance to the active compounds exists. It is suggested that treatment protocols should be implemented at the beginning of winter and summer, using the acaricides that showed efficacy in the adult immersion test. PMID- 25271454 TI - First study on parasites of Hemibrycon surinamensis (Characidae), a host from the eastern Amazon region. AB - This study was the first investigation of communities and infracommunities of parasites of Hemibrycon surinamensis. All the fish collected in a tributary of the Amazon river were parasitized by one or more parasite species. The Brillouin diversity index (HB) was 0.46 +/- 0.28 and the mean species richness was 3.5 +/- 1.2 parasites per host. A total of 14,734 parasites were collected, including Ichthyophthirius multifiliis and Piscinoodinium pillulare (Protozoa); Jainus hexops and Tereancistrum sp. (Monogenoidea); Ergasilus turucuyus and Argulus sp. (Crustacea); metacercariae of Derogenidae gen. sp.; metacercariae and adults of Genarchella genarchella (Digenea); and Cucullanus larvae and Contracaecum larvae (Nematoda). The dominant parasite was I. multifiliis, followed by P. pillulare. The parasites showed aggregated dispersion, except for E. turucuyus, which had random dispersion. The condition factor (Kn) indicated that the parasitism levels had not affected host body condition. The high levels of infection observed were due to host behavior, and this was discussed. This was the first report of I. multifiliis, P. pillulare, Argulus sp., E. turucuyus, G. genarchella, J. hexops and Tereancistrum sp. in H. surinamensis, and it expanded the occurrence of E. turucuyus and G. genarchella to the eastern Amazon region. PMID- 25271455 TI - Gastrointestinal nematode infections in sheep raised in Botucatu, state of Sao Paulo, Brazil. AB - Gastrointestinal nematode infections were evaluated in sheep raised in Botucatu, state of Sao Paulo, Brazil between April 2008 and March 2011. Every month, two tracer lambs grazing with a flock of sheep were exposed to natural infection with gastrointestinal nematodes for 28 consecutive days. At the end of this period, the lambs were sacrificed for worm counts. Haemonchus contortus presented 100% of prevalence. The seasons exerted no significant influence on the mean intensity of H. contortus, which ranged from 315 worms in November 2010 to 2,5205 worms in January 2011. The prevalence of Trichostrongylus colubriformis was also 100%, with the lowest mean intensity (15 worms) recorded in February 2011 and the highest (9,760 worms) in October 2009. In the case of T. colubriformis, a significant correlation coefficient was found between worm counts vs. rainfall (r = -0.32; P <0.05). Three other nematodes species were found in tracer lambs, albeit in small numbers. Their prevalence and mean intensity (in parenthesis) were as follows: Oesophagostomum columbianum 28% (25.2), Cooperia curticei 7% (4.5) and Trichuris spp. 2% (1). In conclusion, the environmental conditions of the area proved to be highly favorable for the year-round transmission of H. contortus and T. colubriformis. PMID- 25271456 TI - Sicarius uncinipenis and Deletrocephalus cesarpintoi in captive greater rheas of Minas Gerais State, Brazil. AB - The present study details the pathological and parasitological findings of parasitic ventriculitis and nematode infections in the large intestines of two female Rhea americana americana birds. The birds were housed in captivity, and both exhibited poor body condition and lethargy. The rheas were sent to the Veterinary Hospital of the Veterinary School, Universidade Federal de Minas Gerais (UFMG) and, despite medical care, the clinical condition of the birds did not improve. The birds died two days after admission, and were submitted to necropsy. Gross, histopathology and parasitological analysis resulted in the identification of Sicarius uncinipenis, which is associated with parasitic ventriculitis, while Deletrocephalus cesarpintoi was identified in the large intestine of both rheas. The apparent clinical indications, including loss of appetite and death, combined with the discovery of numerous parasites and other pathology changes, supported the conclusion that the death of the birds was caused by the parasitic infection. Further investigations of these infections in free-living and captive rheas are required, such that accurate data on the incidence and pathogenicity of these parasites can be obtained. PMID- 25271457 TI - Seroprevalence and risk factors for Neospora caninum in goats in Santa Catarina state, Brazil. AB - Neosporosis is an infectious disease caused by the parasite Neospora caninum. Knowledge regarding neosporosis in goats is still quite limited, especially in the state of Santa Catarina (SC), southern Brazil. Therefore, this study aimed to assess the seroprevalence and risk factors for N. caninum in goats in the western and mountain regions of SC. Blood samples were collected from 654 goats in 57 municipalities. The indirect immunofluorescence test was used for antibody detection against N. caninum. Thirty samples (4.58%) were seropositive, with titers ranging from 1:50 to 1:6400. An epidemiological survey was also conducted in order to identify risk factors for neosporosis in goats. It was found that reproductive problems on the farms, as well as the diet and direct contact with dogs were casual risks for neosporosis. These results indicate that N. caninum infects goats in these regions, which may lead to reproductive problems. PMID- 25271458 TI - Parasite community of Cichla kelberi (Perciformes, Cichlidae) in the Tres Marias Reservoir, Minas Gerais, Brazil. AB - A total of 112 specimens of yellow peacock bass, Cichla kelberi, were collected in the Tres Marias Reservoir, upper Sao Francisco River, State of Minas Gerais, between 2004 and 2005. Twelve species of parasites were collected: two species of ectoparasites (the monogenetic Gussevia sp. and the copepod Ergasilus sp.); and ten species of endoparasites, including four species of adult endoparasites: the cestodes Proteocephalus macrophallus and P. microscopicus, and the nematodes: Capillostrongyloides sentinosa and Rhabdochona acuminata, and six species of larval endoparasites: the metacercariae of Austrodiplostomum compactum and the nematodes: Hysterothylacium sp., Contracaecum sp. Type 1, Procamallanus (Spirocamallanus) inopinatus, Spiroxys sp., and Goezia sp.. A significant positive correlation in the abundance of the two adult endoparasites species, P. macrophallus and P. microscopicus, may indicate that such associated species had the same ecological requirements. The positive correlations between the prevalence of the larval endoparasites, Hysterothylacium sp. and A. compactum, may indicate that there was opportunism for the two generalists species. Ergasilus sp., C. sentinosa, R. acuminata and Hysterothylacium sp. were recorded for the first time in C. kelberi, and this increased their list of known hosts. In addition, both proteocephalid species and C. sentinosa can extend their known biogeographical distribution to the Tres Marias Reservoir. PMID- 25271459 TI - Helminth fauna parasitizing Pimelodus pohli (Actinopterygii: Pimelodidae) from the upper Sao Francisco River, Brazil. AB - The parasite fauna of catfish, Pimelodus pohli, from the Sao Francisco River Basin is presented. A total of 45 catfish from the upper Sao Francisco River (45 degrees 15'44"W 18 degrees 13'25"S), were examined from July 2009 to September 2011. Forty-three catfish (95.5%) were infected by at least one parasite species, with 885 parasite specimens being found, distributed across 17 species: Monogenea (Demidospermus uncusvalidus, Pavanelliella pavanellii, and Scleroductus sp.); Eucestoda (plerocercoids of Proteocephalidea); Digenea (metacercariae of Austrodiplostomum compactum, adults of Auriculostoma platense and Kalipharynx sp., and juvenile of Prosthenhystera obesa); Nematoda (larvae of Contracaecum sp., Hysterothylacium sp., Procamallanus pimelodus, Procamallanus sp., and unidentified of Cucullanidae, and adults of Cucullanus caballeroi, Philometra sp., and Procamallanus freitasi); and Acanthocephala (adults of Neoechinorhynchus pimelodi). Procamallanus freitasi and Scleroductus sp. were the taxa with the highest prevalence. Demidospermus uncusvalidus, P. freitasi, and Scleroductus sp. were the dominant species. The host's sex did not influence parasitic indexes; however, the total length of the catfish did appear to have some influence. The parasites, with except for P. obesa, were registered for the first time in P. pohli, as well as the occurrence of Kalipharynx sp. and C. caballeroi among pimelodid hosts from Sao Francisco River and South America. PMID- 25271460 TI - Molecular characterization of Eurytrema coelomaticum in cattle from Parana, Brazil. AB - This study investigated the occurrence of Eurytrema spp. in cattle by analysis of the partial 18S rRNA gene sequence. Trematodes from 44 bovine pancreas were collected and classified based on typical morphological features. PCR assay and sequence analyses of amplified products confirmed that the trematodes classified as Eurytrema coelomaticum were phylogenetically distinct from those identified as E. pancreaticum. The results of this study represent the first molecular characterization of E. coelomaticum within the Americas, and provide an efficient method to differentiate digenean trematodes of domestic animals. PMID- 25271461 TI - Amblyomma auricularium (Acari: Ixodidae): underwater survival of the non parasitic phase of feeding females. AB - To determine the effects of immersion in water on the biological parameters of engorged females of the tick species Amblyomma auricularium, 60 females were distributed in six groups, each comprising 10 individuals. The control group - G1 (not immersed) was fixed dorsally in a Petri dish and incubated at 27 +/- 1 degrees C and 80% RH. The other groups were subjected to immersion periods of 24, 48, 72 and 96 hours, and the sixth group to continuous immersion. After the immersion period, the females were placed in Petri dishes to begin laying. Eggs were collected every 72 hours and kept in biological chambers. All the groups showed significant differences (p <0.05) during the pre-oviposition period. The laying period and the average weight of overall posture did not change. The egg incubation period also did not differ significantly, but the hatching rate in the group immersed for 96h showed a significant difference. Thus, immersion for up to 96 hours does not impair the survival of A. auricularium females, although it may delay egg laying and reduce the number of offspring. PMID- 25271462 TI - First record of intestinal parasites in a wild population of jaguar in the Brazilian Atlantic Forest. AB - Small and isolated wildlife populations may be more susceptible to disease, which makes illness an important issue to investigate regarding the conservation of large carnivores. Here, we present the results of the first investigation of intestinal parasites in one of the last remaining populations of jaguars in the Brazilian Atlantic Forest. We studied parasites from fecal samples using three different techniques for parasitological examination: floatation in saturated sodium chloride solution, sedimentation and formalin-ether centrifugation. Intestinal parasites were detected in 70% of the analyzed samples, and seven taxa (mean = 3.7 taxa/sample) were identified. All the groups of parasites that were identified have been recorded in previous jaguar studies. However, the records of Class Trematoda and nematodes Trichuridae are the first evidence of these groups of worms in free-ranging jaguars in Brazil. Although our results do not provide conclusive evidence on the health of this jaguar population, given its very small size (approximately 20 animals) we stress the need to properly understand the dynamics of disease in this wild population and to evaluate the risk of contracting new diseases from domestic species inhabiting the neighboring areas. These represent imperative actions for the successful conservation of this threatened population of jaguar. PMID- 25271463 TI - Redescription and taxonomical considerations about Aonchotheca (Aonchotheca) pulchra n. comb. (Enoplida: Trichuridae), a nematode of Nyctinomops spp. AB - Pterothominx pulchra (Freitas, 1934) are little known gastric nematodes of Nyctinomops laticaudatus (Chiroptera: Molossidae). Information about the occurrence and host range of these parasites in Neotropical region is still scanty, and the only two morphological descriptions available in the literature are divergent about the presence or absence of a spiny spicular sheath in males, which may lead to incorrect taxonomical positioning, since this feature represents the main difference between the genera Pterothominx and Aonchotheca. Based on the absence of this morphological feature in specimens of this nematode obtained from N. laticaudatus and Nyctinomops macrotis bats captured in two municipalities in the state of Sao Paulo, Brazil, the present study reclassifies the aforementioned species in the genus Aonchotheca and allocates it to the subgenus Aonchotheca. Additional morphometric data and new host and locality records are also provided. PMID- 25271464 TI - Determination of IgG avidity in BALB/c mice experimentally infected with Toxocara canis. AB - Toxocariasis is a zoonotic disease in that IgM titers can remain high for long periods making difficult to determine the stage of the disease. The aim of this study is to investigate the applicability of indirect ELISA, associated with urea, to discriminate between the acute and chronic toxocariasis. IgG avidity was evaluated in 25 BALB/c mice experimentally infected with 1000 Toxocara canis eggs. Blood samples were collected, and sera treated with 6 M urea and assayed by ELISA every two weeks. The percent IgG avidity was determined using the mean absorbance of sera treated with urea, divided by the mean absorbance of untreated sera. In the first 15 days post-inoculation, was observed a low percentage, between 7.25 and 27.5%, IgG avidity, characteristic of an acute infection. After 60 days of infection, all the mice showed between 31.4 and 58% IgG avidity, indicating a chronic infection. PMID- 25271465 TI - Study on coinfecting vector-borne pathogens in dogs and ticks in Rio Grande do Norte, Brazil. AB - Since dogs presenting several vector borne diseases can show none or nonspecific clinical signs depending on the phase of infection, the assessment of the particular agents involved is mandatory. The present study aimed to investigate the presence of Babesia spp., Ehrlichia spp., Anaplasma spp., Hepatozoon spp. and Leishmania spp. in blood samples and ticks, collected from two dogs from Rio Grande do Norte showing suggestive tick-borne disease by using molecular techniques. DNA of E. canis, H. canis and L. infantum were detected in blood samples and R. sanguineus ticks collected from dogs. Among all samples analyzed, two showed the presence of multiple infections with E. canis, H. canis and L. infantum chagasi. Here we highlighted the need for molecular differential diagnosis in dogs showing nonspecific clinical signs. PMID- 25271466 TI - Autochthonous infection of buffaloes and cattle by Fasciola hepatica in Minas Gerais, Brazil. AB - Fasciola hepatica is a digenetic trematode that parasitizes the bile ducts of different species of vertebrate hosts. In Brazil, this parasitosis is expanding and occurrences have been reported in the southern, southeastern, central-western and northeastern regions. This study aimed to report the first case of naturally infection of buffaloes by this parasite in the state of Minas Gerais. A total of 250 stool samples, 176 from cattle and 74 from buffaloes, from the districts of Sao Jose da Lapa and Pedro Leopoldo, were examined. Also, 402 snails of the genus Lymnaea were collected on the same farms and the viability of the eggs from naturally infected buffaloes and cattle and the susceptibility of the snails to infection were tested. A total of 54 animals were found to be positive, 33 cattle (18.75%) and 21 buffaloes (28.37%), and two molluscs showed immature forms of F. hepatica. In experimental infection of specimens of Lymnaea, cercariae were obtained through spontaneous elimination from the 57th day post-infection onwards. The importance of this first case report can be emphasized because it confirms that this parasite is being dispersed in municipalities in this state that had previously been considered to be unaffected. PMID- 25271467 TI - Frequency of Toxoplasma gondii antibodies in bovines in the state of Pernambuco, Brazil. AB - Toxoplasmosis is a parasitic disease caused by Toxoplasma gondii that affects homeothermic animals, including humans. Felines are considered the definitive host of this parasite, while other animals act as intermediate hosts. The purpose of this study was to assess the frequency of anti-T. gondii IgG antibodies in bovines in the state of Pernambuco, Brazil. Serum samples (n = 427) from animals in 13 municipalities of the coastal forest/plantation region of the state were analyzed using the immunofluorescent antibody test (IFAT). The overall results revealed a prevalence rate of 16.63% (27/427). High percentages of positivity were found among animals aged 25 to 36 months (28.57%; 30/42) and in males (22.22%; 2/9). The present findings suggest that bovine toxoplasmosis is endemic in the area under study. PMID- 25271468 TI - Challenges in researching migration status, health and health service use: an intersectional analysis of a South London community. AB - OBJECTIVES: This study aimed to investigate the associations between migration status and health-related outcomes and to examine whether and how the effect of migration status changes when it is disaggregated by length of residence, first language, reason for migration and combined with ethnicity. DESIGN: A total of 1698 adults were interviewed from 1076 randomly selected households in two South London boroughs. We described the socio-demographic and socio-economic differences between migrants and non-migrants and compared the prevalence of health-related outcomes by migration status, length of residence, first language, reason for migration and migration status within ethnic groups. Unadjusted models and models adjusted for socio-demographic and socio-economic indicators are presented. RESULTS: Migrants were disadvantaged in terms of socio-economic status but few differences were found between migrant and non-migrants regarding health or health service use indicators; migration status was associated with decreased hazardous alcohol use, functional limitations due to poor mental health and not being registered with a general practitioner. Important differences emerged when migration status was disaggregated by length of residence in the UK, first language, reason for migration and intersected with ethnicity. The association between migration status and functional limitations due to poor mental health was only seen in White migrants, migrants whose first language was not English and migrants who had moved to the UK for work or a better life or for asylum or political reasons. There was no association between migration status and self rated health overall, but Black African migrants had decreased odds for reporting poor health compared to their non-migrant counterparts [odds ratio = 0.15 (0.05 0.48), p < 0.01]. CONCLUSIONS: Disaggregating migration status by length of residence, first language and reason for migration as well as intersecting it with ethnicity leads to better understanding of the effect migration status has on health and health service use. PMID- 25271469 TI - Hand-arm bimanual intensive therapy including lower extremities (HABIT-ILE) for children with cerebral palsy. AB - Hand-arm bimanual intensive therapy and constrained-induced movement therapy have shown evidence of effectiveness in improvement of upper extremity use in children with unilateral spastic cerebral palsy (CP). The effectiveness of interventions that are based on intensive practice of activities that combine UE and LE functions has not been reported. We propose that bimanual UE activities that simultaneously require trunk and LE postural adaptations uniquely address motor control limitations of children with unilateral spastic CP. The aim of this perspective is to present such an approach Hand Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE). HABIT-ILE is unique in selection of tasks and activities that require simultaneous control and coordination of UE and LE movements. It is a motor-learning-based approach using problem solving and highly structured practice. During the intervention, activities and tasks are progressively graded toward more complex bimanual coordination for the UE and increasing demands of the LE. HABIT-ILE is provided in small groups for 90 hr using a camp model. Future research (randomized controlled trial) is needed to determine the effectiveness of HABIT-ILE. PMID- 25271470 TI - Antibiotic resistance--problems, progress, and prospects. PMID- 25271472 TI - Protecting our children from climate change. PMID- 25271471 TI - Consumption of dried apple peel powder increases joint function and range of motion. AB - The goal for this study was to evaluate the effects of consumption of dried apple peel powder (DAPP) on joint function and range of motion (ROM). Additional in vitro and clinical testing was performed to suggest specific mechanisms of action. An open-label clinical pilot study involved 12 healthy people with moderate loss of joint ROM and associated chronic pain. The subjects consumed 4.25 g DAPP daily for 12 weeks, with evaluations at baseline, 2, 4, 8, and 12 weeks. ROM was evaluated at each visit using dual digital inclinometry. Pain scores were collected using Visual Analogue Scales. Blood draws enabled testing of serum antioxidant protective capacity using the cellular antioxidant protection (CAP-e) bioassay. Additional in vitro testing involved testing of cyclooxygenase-2 (COX-2) and lipoxygenase inhibition, cellular antioxidant protection by the CAP-e bioassay, and formation of reactive oxygen species (ROS) by polymorphonuclear (PMN) cells by flow cytometry. Twelve weeks of consumption of DAPP was associated with improved ROM. DAPP provided antioxidants that were available to enter into and protect cells from oxidative damage in vitro, and consumption of DAPP for 12 weeks was associated with a statistically significant improvement in serum antioxidant protective status. DAPP inhibited both COX-2 and lipoxygenase enzymes, and pretreatment of inflammatory PMN cells with DAPP before inflammatory stimulus resulted in reduced ROS formation. This suggests multifaceted anti-inflammatory properties of DAPP. Consumption of DAPP was associated with improved joint function and improved serum antioxidant protection status. The observed pain reduction may be associated with the improved antioxidant status and linked to the apple polyphenols' anti-inflammatory effects. PMID- 25271473 TI - QSAR analyses of DDT analogues and their in silico validation using molecular docking study against voltage-gated sodium channel of Anopheles funestus. AB - DDT has enjoyed the reputation of a successful pesticide in disease control programme and agricultural practices along with the serious opposition and ban later on due to its biomagnification and toxic action against non-target organisms. The present work was carried out to develop QSAR models for analysing DDT analogues for their pesticidal activity and in silico validation of these models. A 2D-QSAR model was generated using stepwise with multiple regression, and the model with a value of r(2) = 0.7324; q(2) = 0.6215; pred r(2) = 0.7038, containing five descriptors, was selected for further study. The 3D QSAR with CoMFA analysis showed that steric contribution of 21% and electrostatic contribution of about 79% were required for larvicidal activity of DDT analogues. A set of 3430 molecules was generated using the basic DDT skeleton as template, and these were evaluated for their mosquito larvicidal activity using the generated QSAR models and DDT as standard. Eleven molecules were selected for in silico validation of these models. For this, a docking study of the selected molecules against the homology-modelled voltage-gated sodium channel of Anopheles funestus was conducted. The study showed that the activities of these analogues as predicted by 2D-QSAR, 3D-QSAR with CoMFA and dock score were observed to be well correlated. PMID- 25271474 TI - Detection of airborne carbon nanotubes based on the reactivity of the embedded catalyst. AB - A previously described method for detecting catalyst particles in workplace air((1,2)) was applied to airborne carbon nanotubes (CNT). It infers the CNT concentration indirectly from the catalytic activity of metallic nanoparticles embedded as part of the CNT production process. Essentially, one samples airborne CNT onto a filter enclosed in a tiny chemical reactor and then initiates a gas phase catalytic reaction on the sample. The change in concentration of one of the reactants is then determined by an IR sensor as measure of activity. The method requires a one-point calibration with a CNT sample of known mass. The suitability of the method was tested with nickel containing (25 or 38% by weight), well characterized multi-walled CNT aerosols generated freshly in the lab for each experiment. Two chemical reactions were investigated, of which the oxidation of CO to CO2 at 470 degrees C was found to be more effective, because nearly 100% of the nickel was exposed at that temperature by burning off the carbon, giving a linear relationship between CO conversion and nickel mass. Based on the investigated aerosols, a lower detection limit of 1 MUg of sampled nickel was estimated. This translates into sampling times ranging from minutes to about one working day, depending on airborne CNT concentration and catalyst content, as well as sampling flow rate. The time for the subsequent chemical analysis is on the order of minutes, regardless of the time required to accumulate the sample and can be done on site. PMID- 25271475 TI - Evaluation of the Physical Activity and Public Health Course for Researchers. AB - BACKGROUND: From 1995-2013, an 8-day Physical Activity and Public Health Course for Researchers has been offered yearly in the United States. METHODS: In 2013, an evaluation quantified time that fellows spent in different course offerings, surveyed fellows on course impact, documented grant funding, and identified fellow participation on leading physical activity-related journals. RESULTS: The number of fellows that attended the course ranged from 20 per year to 35 per year. Fellows who participated in the web survey (n = 322) agreed that the course: met their expectations (99%), had a positive impact on the physical activity research or practice work they did (98%), and helped increase their professional networking in the field (93%). Following the course, 73% of fellows had further contact with course faculty and 71% had further contact with other fellows. From the National Institutes of Health, 117 grants were awarded to 82 fellows (21% of eligible fellows). Out of 14 journals reviewed, 11 had at least 1 fellow on their staff as editor, associate editor, or editorial board member. CONCLUSION: The Physical Activity and Public Health Course for Researchers helps address a training need by providing instruction and building capacity in the US and abroad for conducting research on physical activity and public health. PMID- 25271476 TI - Zeroing in on a risk factor? PBDE exposure and acute lymphoblastic leukemia. PMID- 25271477 TI - Haemophilus ducreyi associated with skin ulcers among children, Solomon Islands. AB - During a survey of yaws prevalence in the Solomon Islands, we collected samples from skin ulcers of 41 children. Using PCR, we identified Haemophilus ducreyi infection in 13 (32%) children. PCR-positive and PCR-negative ulcers were phenotypically indistinguishable. Emergence of H. ducreyi as a cause of nongenital ulcers may affect the World Health Organization's yaws eradication program. PMID- 25271478 TI - Tri- and tetra-nuclear polypyridyl ruthenium(II) complexes as antimicrobial agents. AB - A series of inert tri- and tetra-nuclear polypyridylruthenium(II) complexes that are linked by the bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane ligand ("bb(n)" for n = 10, 12 and 16) have been synthesised and their potential as antimicrobial agents examined. Due to the modular nature of the synthesis of the oligonuclear complexes, it was possible to make both linear and non-linear tetranuclear ruthenium species. The minimum inhibitory concentrations (MIC) of the ruthenium(II) complexes were determined against four strains of bacteria--Gram positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). In order to gain an understanding of the relative antimicrobial activities, the cellular uptake and water-octanol partition coefficients (log P) were determined for a selection of the ruthenium complexes. Although the trinuclear complexes were the most lipophilic based upon log P values and showed the greatest cellular uptake, the linear tetranuclear complexes were generally more active, with MIC values <1 MUM against the Gram positive bacteria. Similarly, although the non-linear tetranuclear complexes were slightly more lipophilic and were taken up to a greater extent by the bacteria, they were consistently less active than their linear counterparts. Of particular note, the cellular accumulation of the oligonuclear ruthenium complexes was greater in the Gram negative strains compared to that in the Gram positive S. aureus and MRSA. The results demonstrate that the lower antimicrobial activity of polypyridylruthenium(II) complexes towards Gram negative bacteria, particularly P. aeruginosa, is not strongly correlated to the cellular accumulation but rather to a lower intrinsic ability to kill the Gram negative cells. PMID- 25271479 TI - TRPC1, CaN and NFATC3 signaling pathway in the pathogenesis and progression of left ventricular hypertrophy in spontaneously hypertensive rats. AB - Spontaneously hypertensive rats (SHR) was used to study left ventricular hypertrophy (LVH) and its dynamic change after the interventions with Telmisartan and Amlodipine. The results showed that the expression of TRPC1, CaN and NFATC3 increased gradually with the pathogenesis and progression of LVH. Telmisartan reduced blood pressure and LVH, and down-regulated the expression of TRPC1, CaN and NFATC3 in left ventricle of SHR. Amlodipine reduced the blood pressure in SHR but had no impact on the hypertrophy and expression of above factors. Our data suggest that the pathogenesis and progression of LVH in SHR are related to upregulation of TRPC1, CaN and NFATC3 signaling pathway. PMID- 25271481 TI - Podosome rosettes precede vascular sprouts in tumour angiogenesis. AB - Expansion of a vascular network requires breaking through the basement membrane, a highly crosslinked barrier that tightly adheres to mature vessels. Angiogenic endothelial cells are now shown to form podosome rosettes that are able to focally degrade the extracellular matrix, prior to vascular sprouting in tumour angiogenesis. PMID- 25271483 TI - Origin of discrete current fluctuations in a single molecule junction. AB - A series of fresh molecular junctions at a single molecule level were created and the current fluctuations were studied as electrons passed through them. Our results indicate that telegraph-like current fluctuations at room temperature neither originate from electron trapping/detrapping processes nor from molecule re-conformation. Our results will be helpful in better understanding the mechanism of current fluctuations. PMID- 25271484 TI - Catalytic asymmetric Diels-Alder reactions involving aryl vinyl ketones. AB - A catalytic asymmetric Diels-Alder reaction of an aryl vinyl ketone with 1,3 dienylcarbamate has been developed. Cyclohexenes bearing vicinal amino and aroyl groups in a cis-configuration were prepared in excellent ee (>99%) and endo (single diastereomer) selectivity. The absolute configuration of one DA product was unambiguously confirmed using XRD analysis. The transition state structure was proposed on the basis of DFT calculations. PMID- 25271480 TI - Single-cell technologies sharpen up mammalian stem cell research. AB - Analysis of the mechanisms underlying cell fates requires the molecular quantification of cellular features. Classical techniques use population average readouts at single time points. However, these approaches mask cellular heterogeneity and dynamics and are limited for studying rare and heterogeneous cell populations like stem cells. Techniques for single-cell analyses, ideally allowing non-invasive quantification of molecular dynamics and cellular behaviour over time, are required for studying stem cells. Here, we review the development and application of these techniques to stem cell research. PMID- 25271485 TI - Remarkable changes in the photoluminescent properties of Y2Ce2O7:Eu(3+) red phosphors through modification of the cerium oxidation states and oxygen vacancy ordering. AB - A new series of red phosphors based on Eu(3+)-doped yttrium cerate [Y1.9Ce2O7:0.1Eu(3+), Y2Ce1.9O7:0.1Eu(3+) and Y2Ce2-xO7:xEu(3+) (x = 0.05, 0.10, 0.15, 0.20, 0.25 and 0.50)] was prepared via a conventional solid-state method. The influence of the substitution of Eu(3+) at the aliovalent site on the photoluminescent properties was determined by powder X-ray diffraction, FT Raman spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, scanning electron microscopy with energy-dispersive spectroscopy, UV-visible absorption spectroscopy, photoluminescence spectroscopy and lifetime measurements. The substitution of Eu(3+) at the Ce(4+) site induces a structural transition from a defect fluorite to a C-type structure, which increases the oxygen vacancy ordering and the distortion of the Eu(3+) environment, and decreases the formation of Ce(3+) states. In contrast, phosphors with isovalent substitution at the Y(3+) site exhibit the biphasic nature of defect fluorite and a C-type structure, thereby increasing the number of Ce(3+) oxidation states. These modifications resulted in remarkable changes in the photoluminescent properties of Y2Ce1.9O7:0.1Eu(3+) red phosphors, with emission intensities 3.8 times greater than those of the Ce0.9O2:0.1Eu(3+) and Y1.9Ce2O7:0.1Eu(3+). The photoluminescent properties of Y2Ce2-xO7:xEu(3+) were studied at different Eu(3+) concentrations under excitation with blue light. These phosphors emit intense red light due to the (5)D0-(7)F2 transition under excitation at 466 nm and no concentration quenching is observed with up to 50 mol% Eu(3+). They show increased lifetimes in the range 0.62-0.72 ms at Eu(3+) concentrations. The cation ordering linked to the oxygen vacancy ordering led to the uniform distribution of Eu(3+) ions in the lattice, thus allowing higher doping concentrations without quenching and consequently increasing the lifetime of the (5)D0 states. Our results demonstrate that significant improvements in the photoluminescence properties can be achieved by the structural alteration of a fluorite CeO2 to a C-type lattice. PMID- 25271486 TI - Guest editorial: the impact of hearing loss on listening effort and fatigue. PMID- 25271487 TI - Hemorrhagic panniculitis caused by delayed microemboli from intravascular device. AB - IMPORTANCE: The breakdown of previously inserted intravascular devices can lead to microemboli that can clinically mimic the symptoms of common disorders, such as senile purpura, and have subtle histologic findings. However, device failure can occur gradually and start months after placement. If not identified early, microemboli to noncutaneous sites can cause significant morbidity and mortality. OBSERVATIONS: A woman in her 70s presented 6 months after a complex aortic aneurysm repair with several large ecchymoses radiating from firm subcutaneous nodules on the buttocks, arms, and thighs. Skin biopsy specimens revealed extensive hemorrhage and a panniculitis with sparse, subtle, intra-arteriole, gray amorphous deposits that, on analysis by scanning electron microscopy with energy-dispersive radiography analysis and infrared spectrometry, were most consistent with a hydrophilic polymer. This type of hydrophilic polymer coats catheters and stents such as those used in aortic aneurysm repair. CONCLUSIONS AND RELEVANCE: This is an unusual case of microemboli from the polymer coating intra-arterial stents starting months after placement and causing a panniculitis. Prior observations show that polymers coating intravascular devices have the potential to break down gradually and long after the device's placement, but clinical consideration for delayed microembolization is underrecognized until catastrophic impairment or death. PMID- 25271488 TI - Feasibility and patient-reported outcomes after outpatient single-level instrumented posterior lumbar interbody fusion in a surgery center: preliminary results in 16 patients. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To report surgical and patient reported outcomes after outpatient lumbar fusions in an ambulatory setting. SUMMARY OF BACKGROUND DATA: There is growing interest in the potential benefits of outpatient spine surgery such as reduced costs, consistent operative team, and decreased postoperative complications during in-hospital recovery. However, there are limited studies on outcomes after outpatient lumbar fusions, to guide patient selection, treatment techniques and postoperative expectations. METHODS: Medical records of 16 consecutive patients, who underwent outpatient direct open, single level, posterior lumbar interbody fusions, were examined by a single surgeon. Outcome measures included visual analogue scale (VAS) scores for lower back and Oswestry Disability Indices (ODIs). Mean body mass indices (BMIs), estimated blood loss, surgical times and complications, and fusion rates were evaluated. RESULTS: Males represented 56% of patients. Mean age was 42.81 +/- 3.05 years (mean +/- standard error) and mean body mass index was 28.95 +/- 1.04. History of smoking and narcotics use were statistically noncontributory. Mean final follow up was 15 (range, 5.52-34.2 mo) months. Mean postoperative scores were determined by the final follow-up VAS and ODI. L5-S1 was the most common level of the 16 levels operated on (69%). Preoperative and postoperative VAS and ODI scores for lower back were obtained for 15 patients (93.75%). Mean lower back VAS score of 8.4 +/- 0.37 preoperatively reduced to 4.96 +/- 0.73 postoperatively, (P = 0.001). Mean ODI improved from 52.71 +/- 0.04 preoperatively, to 37.43 +/- 0.06 postoperatively, (P = 0.04). One patient experienced postoperative worsened back pain with clinical and radiological signs of possible aseptic discitis. Estimated blood loss was 161 +/- 32 mL and average operating time was 124.85 +/- 7.10 minutes. The overall fusion rate was 87.5%. CONCLUSION: Direct open posterior lumbar interbody fusions were done safely with statistically significant reduction in average pain and ODI scores. Surgical times were approximately 2 hours with minimal blood loss, allowing patients to be comfortably discharged the same day without a drain. PMID- 25271490 TI - Re: Poetscher AW, Gentil AF, Lenza M, et al. Radiofrequency denervation for facet joint low back pain: a systematic review. Spine (Phila Pa 1976) 2014;39:E842-9. PMID- 25271491 TI - In response. PMID- 25271493 TI - Changes in health utility, disability, and health-related quality of life in patients after spinal fusion: a 2-year follow-up study. AB - STUDY DESIGN: Prospective longitudinal database study. OBJECTIVE: To evaluate changes in health utility, disability, and health-related quality of life (HRQOL) in patients undergoing spinal fusion. SUMMARY OF BACKGROUND DATA: Recently, measuring disability, HRQOL, and health utility has become important when defining the value of surgical interventions. METHODS: Data of spinal fusion patients from a prospective longitudinal database were analyzed. Health utility was captured by SF-6D (six dimensional health state classification from the 36 dimensional Short Form Health Survey) score, disability by Oswestry Disability Index, and HRQOL by the 36-Item Short Form Health Survey. The changes in these scores were compared between the groups during the 2-year follow-up. RESULTS: Altogether 242 patients were stratified into 5 groups according to the surgical indication: degenerative spondylolisthesis (n = 140), isthmic spondylolisthesis (n = 39), spinal stenosis (n = 23), disc pathology (n = 15), and postoperative conditions (n = 25). The mean age varied from 48 years in isthmic spondylolisthesis group to 66 years in the groups with degenerative spondylolisthesis or spinal stenosis. Preoperatively, the surgical indication subgroups differed significantly from each other according to utility, disability, and the physical component summary score of the HRQOL. Isthmic spondylolisthesis group had the best and the group of postoperative conditions the worst preoperative values. Nevertheless, the SF-6D, the Oswestry Disability Index, and the physical component summary in all diagnostic groups had improved significantly already by 3 months of follow-up, and the improvement remained stable until 2 years of follow-up. Interestingly, the biggest improvement in Oswestry Disability Index (-27), physical component summary (13) and SF-6D (0.19) was found in a group with disc pathology. The mental component summary score values were similar preoperatively (P = 85), and the improvement in the mental component summary was significant in the groups with degenerative olisthesis, spinal stenosis, and postoperative conditions. CONCLUSION: The 5 surgical indication groups showed significantly different scores preoperatively in health utility, disability, and the physical aspect of HRQOL. At 2 years, however, all groups benefitted from the fusion surgery significantly. LEVEL OF EVIDENCE: 3. PMID- 25271494 TI - The effects of a semiconstrained integrated artificial disc on zygapophyseal joint pressure and displacement. AB - STUDY DESIGN: Measurement of zygapophyseal joint pressure and displacement was performed after placement of a semiconstrained integrated artificial disc (SIAD) in a cadaver model. OBJECTIVE: To understand the likelihood of accelerated zygapophyseal joints degeneration as a result of the implant. SUMMARY OF BACKGROUND DATA: A SIAD has been developed to treat lumbar spondylosis secondary to segmental disc degeneration and spinal stenosis. The SIAD replaces the stenotic segment's disc. Previous studies have demonstrated that nonconstrained artificial disc (NAD) replacements fail to achieve their optimal long-term outcomes likely because of significantly increased zygapophyseal joint pressure and displacement at the implanted level. Moreover, clinical studies have reported an increased incidence of zygapophyseal joint degeneration after lumbar disc replacement. METHODS: Eight cadaver lumbar specimens (L2-L5) were loaded in flexion, neutral, extension, left bend, and right rotation. Zygapophyseal joint pressure and displacement were measured during each of the 5 positions at each of the 3 levels with the ratio of deformation calculated under the different loads. An artificial disc was placed at the L3-L4 level, and the measurements were repeated. RESULTS: After L3-L4 segment implantation, the pressure in the zygapophyseal joint at operative segment was not significantly changed by SIAD and NAD implantation in axial compression and flexion, compared with physiological disc. Notable differences in zygapophyseal joint pressure between the SIAD and NAD were identified at the operative level in extension, left bend, and right rotation. The adjacent-level effect of NAD was significantly greater than that of SIAD. The ratio of deformation difference between the 2 discs was increased by load experienced in extension, flexion, left bend, and right rotation. CONCLUSION: The SIAD provided a superior biomechanical milieu for zygapophyseal joints at the implanted and adjacent levels compared with NAD, which may avoid the acceleration of postoperative zygapophyseal joint degeneration. LEVEL OF EVIDENCE: 1. PMID- 25271495 TI - Odontoid fracture biomechanics. AB - STUDY DESIGN: In vitro biomechanical study. OBJECTIVES: To investigate mechanisms of odontoid fracture. SUMMARY OF BACKGROUND DATA: Odontoid fractures in younger adults occur most often due to high-energy trauma including motor vehicle crashes and in older adults due to fall from standing height. METHODS: Horizontally aligned head impacts into a padded barrier were simulated using a human upper cervical spine specimen (occiput through C3) mounted to a surrogate torso mass on a sled and carrying a surrogate head. We divided 13 specimens into 3 groups on the basis of head impact location: upper forehead in the midline, upper lateral side of the forehead, and upper lateral side of the head. Post-impact fluoroscopy and anatomical dissection documented the injuries. Time-history biomechanical responses were determined. RESULTS: Four of the 5 specimens subjected to impact to the upper forehead in the midline sustained type II or high type III odontoid fractures due to abrupt deceleration of the head and continued forward torso momentum. Average peak force reached 1787.1 N at the neck at 50.3 milliseconds. Subsequently, the motion peaks occurred for the head relative to C3 reaching 15.2 degrees for extension, 2.1 cm for upward translation, and 5.3 cm for horizontal compression, between 62 and 68 milliseconds. CONCLUSION: We identified impact to the upper forehead in the midline as a mechanism that produced odontoid fracture and associated atlas and ligamentous injuries similar to those observed in real life trauma. We were not able to create odontoid fractures during impacts to the upper lateral side of the forehead or upper lateral side of the head. Dynamic odontoid fracture was caused by rapid deceleration of the head, which transferred load inferiorly combined with continued torso momentum, which caused spinal compression and anterior shear force and forward displacement of the axis relative to the atlas. PMID- 25271496 TI - Cross-cultural translation, adaptation, and psychometric testing of the Roland Morris disability questionnaire into modern standard Arabic. AB - STUDY DESIGN: Cross-cultural translation, adaptation, and psychometric testing. OBJECTIVE: To cross-culturally translate and adapt the Roland-Morris Disability Questionnaire (RMDQ) into Modern Standard Arabic and examine its validity with Arabic-speaking patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: The English RMDQ is valid, reliable, and commonly used to assess LBP disability in clinical practice and research. There is no valid and reliable version of the RMDQ in Modern Standard Arabic. METHODS: The RMDQ was forward translated and back translated. An expert committee of musculoskeletal physiotherapists reviewed the translation. Eight patients with LBP evaluated item-by-item comprehensibility. Ten patients piloted the RMDQ for overall comprehensibility and acceptability. Seventeen bilingual patients tested the agreement of the Arabic and English RMDQs. Two-hundred one patients completed the RMDQ and the visual analogue scale. Sixty-four patients were followed-up for test-retest reliability. RESULTS: Translation of most items was uncontroversial. The expert committee found the Arabic RMDQ clinically and culturally appropriate. They reviewed item 11, addressing bending and kneeling, because this has a clinical significance and cultural/religious implication regarding prayer positions. All patients reported that it was easy to understand and complete. The Arabic RMDQ had high overall agreement with the English RMDQ for the global score (intraclass correlation coefficient [ICC] = 0.925; 0.811-0.972). Kappa statistics showed good item-by item agreement (none <=0.30). Mean (SD) RMDQ and visual analog scale scores of 201 patients were 10.53 (4.80) and 5.11 (2.28), respectively. The RMDQ had a low correlation against pain intensity (r = 0.259; P < 0.01). A Cronbach alpha of 0.729 showed high internal consistency. Test-retest reliability of the Arabic RMDQ was good (ICC = 0.900; 95% confidence interval, 0.753-0.951). Kappa statistics were high for 18 items and fair for 6. CONCLUSION: The Arabic version of the RMDQ has good comprehensibility and acceptability, high internal consistency and reliability, low correlation against pain intensity, and good agreement with the English RMDQ. We recommend its use with Arabic-speaking patients with LBP. LEVEL OF EVIDENCE: 3. PMID- 25271498 TI - Risk Factors for Postoperative Infections After Single-Level Lumbar Fusion Surgery. AB - STUDY DESIGN: Retrospective multivariate analysis of a prospectively collected, multicenter database. OBJECTIVE: To identify patient characteristics and perioperative risk factors associated with postoperative infectious complications after single-level lumbar fusion (SLLF) surgery. SUMMARY OF BACKGROUND DATA: Postoperative infection is a known complication after lumbar fusion. Risk factors for infectious complications after lumbar fusion have not been investigated using select set of SLLF procedures. METHODS: Patients who underwent SLLF between 2006 and 2011 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Multivariate logistic regression analyses were performed to identify pre- and intraoperative risk factors associated with postoperative infection. RESULTS: A total of 3353 patients were analyzed in this study. Overall, 173 (5.2%) patients experienced a postoperative infection, including 86 (2.6%) surgical site infections (SSIs) and 111 (3.3%) non-SSI infectious complications (pneumonia, urinary tract infection, sepsis/septic shock). Twenty-four (0.7%) patients experienced both SSI and non-SSI infectious complications. Postoperative SSI were associated with obesity (odds ratio [OR], 1.628; 95% confidence interval [CI], 1.042-2.544), American Society of Anesthesiologists class more than 2 (OR, 2.078; 95% CI, 1.309-3.299), and operative time more than 6 hours (OR, 2.573; 95% CI, 1.310-5.056). Risk factors for non-SSI infectious complications included age (60-69 yr; OR, 3.279; 95% CI, 1.541-6.980; and >=70 yr; OR, 3.348; 95% CI, 1.519-7.378), female sex (OR, 1.791; 95% CI, 1.183-2.711), creatinine more than 1.5 mg/dL (OR, 2.400; 95% CI, 1.138 5.062), American Society of Anesthesiologists class more than 2 (OR, 1.835; 95% CI, 1.177-2.860), and operative time more than 6 hours (OR, 3.563; 95% CI, 2.082 6.097). CONCLUSION: Across a wide study population, we identified that obesity, advanced American Society of Anesthesiologists classification, and longer operative time were predictive of postoperative SSI. We also demonstrated that increased age, female sex, serum creatinine more than 1.5 mg/dL, and prolonged operative duration are associated with non-SSI infectious complications after SLLF. Continued efforts to elucidate and optimize perioperative risk factors are warranted to improve outcomes in patients requiring spinal fusion. LEVEL OF EVIDENCE: 3. PMID- 25271497 TI - Results of selective thoracic versus nonselective fusion in Lenke type 3 curves. AB - STUDY DESIGN: A retrospective analysis of a prospectively collected multicenter database. OBJECTIVE: To identify the radiographical and clinical outcomes in Lenke 3 curves fused selectively (S) versus nonselectively (NS). SUMMARY OF BACKGROUND DATA: Surgical treatment options for Lenke 3 curves include fusion of both curves (NS) or selective thoracic curve fusion (S). Selective fusion of the thoracic curve spares lumbar motion segments; however, it may result in marked residual deformity. METHODS: A prospectively collected multicenter database was retrospectively reviewed for adolescent idiopathic scoliosis Lenke 3 curves treated with posterior spinal fusion with a minimum of 2 years of follow-up. Patients were divided into 2 groups: NS (nonselective fusion) and S (selective thoracic fusion). Radiographical and clinical data were compared between the groups using the unpaired Student t test and analysis of variance. RESULTS: A total of 74 patients met our inclusion criteria, with 49 (66.2%) in the NS group and 25 (33.8%) in the S group. Overall, both groups were similar preoperatively except for lumbar Cobb (NS = 56.3 degrees , S = 47.2 degrees , P < 0.001), lumbar lordosis (NS = 56.9 degrees , S = 67.2 degrees , P = 0.001), lumbar rotational prominence (NS = 11.2 degrees , S = 8.2 degrees , P < 0.05), and lumbar apical translation (NS = 3.2 cm, S = 1.9 cm, P < 0.05). Postoperatively, NS fusion demonstrated significantly less coronal imbalance of 2 cm or less (NS = 10.2%, S = 56.0%, P < 0.001), better lumbar curve correction (NS = 68.2%, S = 51.9%, P < 0.001), better lumbar apical translation correction (NS = 1.2 cm, S = 2.1 cm, P < 0.01), and better percent correction of the lumbar prominence (NS = 66.5%, S = 40.4%, P < 0.05). Scoliosis Research Society Questionnaire 22 scores at 2 years were similar between the groups. CONCLUSION: Despite preoperatively smaller lumbar curves with less apical translation and lumbar prominence, most patients with selective fusions were out of balance postoperatively and had inferior radiographical outcomes as compared with their nonselective comparison cohort with similar patient-reported outcomes. Long-term follow-up is required to determine whether the trade-off of sparing motion segments at the expense of somewhat lessened radiographical outcomes is worthwhile. PMID- 25271499 TI - The effect of work-focused rehabilitation among patients with neck and back pain: a randomized controlled trial. AB - STUDY DESIGN: Multicenter randomized trial with patients listed as sick for 1 to 12 months due to neck or back pain and referred to secondary care. OBJECTIVE: To compare the return-to-work (RTW) rate among patients offered work-focused rehabilitation or multidisciplinary rehabilitation. SUMMARY OF BACKGROUND DATA: A growing number of studies have focused on the RTW processes associated with patients with back pain. Many studies have combined a workplace focus with multidisciplinary treatments; however, this focus has not been evaluated in Norway among patients with neck and back pain thus far. METHODS: A total of 405 patients who were referred to the spine clinics at 2 university hospitals in Norway were randomly assigned into work-focused and control intervention groups. The existing treatments at each hospital were used as the control interventions, which entailed either a comprehensive multidisciplinary intervention or a brief multidisciplinary intervention. The RTW rates and proportions were compared at 12 months. RESULTS: During the first 12 months after inclusion, 142 (70%) participants in the work-focused rehabilitation group and 152 (75%) participants in the control group returned to work. The median time to RTW was 161 days in the work-focused group and 158 days in the control group. A comparison of the work focused and control interventions revealed a relative RTW probability (hazard ratio) of 0.94 (95% confidence interval = 0.75-1.17) after adjusting for age, sex, and education. CONCLUSION: The results suggest that a focus on the workplace in specialist care does not substantially alter the RTW rate compared with standard multidisciplinary treatments. PMID- 25271500 TI - Axial gout is frequently associated with the presence of current tophi, although not with spinal symptoms. AB - STUDY DESIGN: Prospective cross-sectional study. OBJECTIVE: To analyze the association of tomographically identified axial gouty lesions with clinical and laboratory characteristics. SUMMARY OF BACKGROUND DATA: Axial gout might be more common than previously thought. The true relationship of these lesions to symptoms or other gout-associated features is poorly understood. METHODS: Forty two patients with gout underwent thoracic and lumbar spine computed tomographic (CT) scans. CT scans were read by an experienced radiologist blinded to the features of the patients. Axial gout was defined as the presence of bony erosions, facet joints, or disc calcification and tophi in the axial skeleton. Epidemiological and clinical data were collected from medical records. At study entry, patients were evaluated for axial symptoms (back pain or neurological complaints) and subcutaneous tophi. The Fisher exact test and the Student t test were performed for statistical analyses of data. RESULTS: Twelve (29%) of the 42 patients had CT evidence of axial gout. Axial tophi were identified in 5 patients (12%), interapophyseal joints erosions or calcifications in 7 patients (17%), and discal abnormalities in 9 patients (21%). Lumbar spine involvement was a universal finding. Five patients (42%) had thoracic spine involvement and 2 patients (18%) had sacroiliac lesions. No association was found between symptoms and axial gout (P = 0.62). Duration of gout, mechanism of disease (overproduction vs. underexcretion), and metabolic comorbidities were not related to axial involvement. A higher prevalence of axial gout was found between patients with current peripheral tophi (67% vs. 30%; P = 0.03); however, no association was found in patients with a past history of tophi (P = 0.72). CONCLUSION: Our study demonstrated a high prevalence of axial gout not associated with spine symptoms. This finding introduces a differential diagnosis in axial lesions in patients with gout. In addition, the unique association with a current but not previous history of peripheral tophi suggests that gout treatment might be effective in preventing or solving gout axial lesions. LEVEL OF EVIDENCE: 3. PMID- 25271501 TI - Competing effects of pain and fear of pain on postural control in low back pain? AB - STUDY DESIGN: A cross-sectional, observational study. OBJECTIVE: To determine whether pain and fear of pain have competing effects on postural sway in patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: Competing effects of pain and pain-related fear on postural control can be proposed as the likely explanation for inconsistent results regarding postural sway in the LBP literature. We hypothesized that although pain might increase postural sway, fear of pain might reduce sway through an increased cognitive effort or increased cocontraction to restrict body movement. The cognitive strategy would be less effective under dual-task conditions and the cocontraction strategy was expected to be less effective when standing on a narrow base of support surface. METHODS: Postural sway was measured in combined conditions of base of support (full and narrow) and cognitive loading (single and dual tasks) in 3 experimental groups with current LBP, recent LBP, and no LBP. Sway amplitude, path length, mean power frequency, and sample entropy were extracted from center-of-pressure data. RESULTS: The current-LBP group and recent-LBP group reported significantly different levels of pain, but similar levels of pain catastrophizing and kinesiophobia. The current-LBP group tended to display larger sway amplitudes in the anteroposterior direction compared with the other 2 groups. Mean power frequency values in mediolateral direction were lower in patients with the current LBP compared with recent LBP. Smaller sample entropy was found in the current-LBP group than the other groups in most experimental conditions, particularly when standing on a narrow base of support. CONCLUSION: Alterations of postural sway are mostly mediated by pain but not pain-related fear. LBP tends to increase sway amplitude, which seems to be counteracted by increased effort invested in postural control leading to decreased frequency and increased regularity of sway particularly under increased task demands. LEVEL OF EVIDENCE: Cross-sectional study. PMID- 25271502 TI - Re: Yu CC, Bajwa NS, Toy JO, et al. Pedicle morphometry of upper thoracic vertebrae: an anatomic study of 503 cadaveric specimens. Spine (Phila Pa 1976) 2014;39:E1201-9. PMID- 25271503 TI - Increased flow signal in compressed segments of the spinal cord in patients with cervical spondylotic myelopathy. AB - STUDY DESIGN: Prospective controlled trial. OBJECTIVE: To describe a newly found increased flow signal in phase-contrast magnetic resonance imaging observed in compressed segments of the spinal cord in patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Derangement of cerebrospinal fluid movement in the spine is a well-known cause of syringomyelia. However, its possible role in CSM has not been studied well, despite the fact that similar derangement takes place in CSM. METHODS: In a consecutive series of 57 patients with CSM, cardiac-gated phase-contrast magnetic resonance imaging was analyzed. The amplitude of the flow signal obtained in the compressed segment of the spinal cord was compared with that obtained in the lesion-free C2 segment. It was also compared with controls obtained from 10 healthy volunteers. We also studied whether the amplitude was correlated with the severity of cervical canal stenosis, neurological symptoms, indication of surgery, and the presence of intramedullary high-intensity signal on T2-weighted images. In 33 patients who underwent decompression surgical procedures, we compared the amplitude of the flow signal between the preoperative and the postoperative study. RESULTS: Increased flow signal on phase-contrast study was seen in compressed segments of the spinal cord in 36 (63%) patients. The mean amplitude of the signal in the compressed segment was 0.64 +/- 0.06 cm/s, whereas that in the C2 segment was 0.27 +/- 0.01 and that in the controls was 0.28 +/- 0.01. The flow signal linearly increased as the severity of canal stenosis increased. It significantly correlated with the symptom of upper-extremity dysesthesia, and the indication of surgery in these patients. The mean amplitude of the signal tended to be higher in those with intramedullary high-intensity signal than in those without. After decompression surgery, the increased flow signal was markedly diminished, and returned to a level comparable with the controls. CONCLUSION: Phase-contrast imaging demonstrated increased flow signal in compressed segments of the spinal cord in a majority of patients with CSM. This suggests a possible role played by derangement of cerebrospinal fluid movement in CSM. It also suggests potential usefulness of phase-contrast study in the management of patients with CSM. LEVEL OF EVIDENCE: 2. PMID- 25271504 TI - Does extracorporeal shock wave introduce alteration of microenvironment in cell therapy for chronic spinal cord injury? AB - STUDY DESIGN: Animal experimental study. OBJECTIVE: To present experimental evidence for cell therapy for spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: In chronic SCI, the efficacy of cell engraftment has been known to be low due to its distinct pathology. Alteration of microenvironment was tried using extracorporeal shock waves (ESW) for chronic SCI, and the efficacy of cell therapy was investigated. METHODS: A chronic contusive SCI model was made in 36 Sprague-Dawley rats. The rats were allocated into (1) control group (SCI only), (2) ESW control group (SCI + ESW), (3) IV group (SCI + intravenous transplantation of mesenchymal stem cells; MSCs), and (4) ESW + IV group (SCI + MSCs IV transplantation after ESW). ESW were applied at the energy determined by our preliminary trials. Engraftment of the cells and expressions of growth factors (brain-derived neurotrophic factor, neuronal growth factor) and cytokines (SDF-1, CXCR4, VEGF) at the epicenter were assessed. The Basso, Beattie, and Bresnahan locomotor scale was used for the clinical assessment. RESULTS: The mean numbers of engrafted cells were higher in the ESW+ IV than that in the IV with a statistical significance. The expression of SDF-1 was higher in the ESW groups than that in the control or IV group. CXCR4 was highly expressed in the transplanted groups. The expressions of growth factors in the treated group were higher in the treated group than those in the control group. However, various statistical significances were noted. The improvement of locomotor was higher in the transplanted groups than that in the control and ESW only group. CONCLUSION: At a given energy level, ESW presented more engraftment of the transplanted MSCs without any clinical deterioration in a chronic SCI. Based on this promising result and possible explanations, ESW may cause an alteration of the microenvironment for the cell therapy in chronic SCI. LEVEL OF EVIDENCE: N/A. PMID- 25271505 TI - Acute spinal subdural hematoma after vigorous back massage: a case report and review of literature. AB - STUDY DESIGN: A case report and review of literature. OBJECTIVE: We report on a patient with traumatic spinal subdural hematoma after vigorous back massage while on vacation. SUMMARY OF BACKGROUND DATA: Traumatic spinal subdural hematoma is extremely rare, and to our knowledge, this is the first case reported after violent back massage. We emphasize a high index of suspicion for early recognition and treatment for a good neurological recovery. METHODS: A 41-year old male was brought to our hospital with severe back pain, motor and sensory impairments of the bilateral lower extremities, and urinary dysfunction after vigorous back massage. Magnetic resonance images revealed an acute spinal subdural hematoma in the thoracolumbar region. After careful monitoring of his neurological status, the patient was successfully managed with conservative treatment. RESULTS: After 2 weeks of hospitalization, complete motor power recovery was achieved with only minor sensory deficit. At a follow-up of more than 12 months, the patient has no residual neurological deficits. CONCLUSION: Spinal subdural hematoma secondary to physical trauma is quite rare. This case brings new information that traumatic spinal subdural hematoma can be caused by violent massage. LEVEL OF EVIDENCE: N/A. PMID- 25271506 TI - Malaligned dynamic anterior cervical plate: a biomechanical analysis of effectiveness. AB - STUDY DESIGN: Biomechanical evaluation. OBJECTIVE: To evaluate the kinematic and load-sharing differences of dynamic anterior cervical plates when placed in-line at 0 degrees and off-axis at 20 degrees . SUMMARY OF BACKGROUND DATA: The use of dynamic anterior cervical plating systems has recently gained popularity due to the theoretical benefit of improved load sharing with graft subsidence. Occasionally, due to anatomical restraints, the anterior cervical plate may be placed off-axis in the coronal plane. This may potentially decrease the dynamization capability of the plate, leading to less load sharing and potentially decreased fusion rates. The purpose of this study was to comprehensively evaluate the kinematic and load-sharing differences of a dynamic plate placed in-line versus off-axis in the coronal plane. METHODS: Thirteen fresh-frozen human cadaveric cervical spines (C2-T1) were used. Nondestructive range-of-motion testing was performed with a pneumatically controlled spine simulator in flexion/extension, lateral bending, and axial rotation using the OptoTrak motion measurement system. A C5 corpectomy was performed, and a custom interbody spacer with an integrated load cell collected load-sharing data under axial compression at varying loads. A dynamic anterior cervical plate was placed in-line at 0 degrees and then off-axis at 20 degrees . Testing conditions ensued using a full-length spacer, followed by simulated subsidence by removing 10% of the height of the original spacer. RESULTS: There were no kinematic differences noted in the in-line model versus the off-axis model. After simulated subsidence, the small decreases in stiffness and increases in motion were similar whether the plate was placed in-line or off-axis in all 3 planes of motion. There were also no significant differences in the load-sharing characteristics of the in-line plate versus the off-axis plate in either the full-length model or the subsided interbody model. CONCLUSION: This study suggests that off-axis dynamic plate positioning does not significantly impact construct kinematics or graft load sharing. As such, we do not recommend removal or repositioning of an off-axis placed dynamic plate because the kinematic and load-sharing biomechanical properties are similar. LEVEL OF EVIDENCE: N/A. PMID- 25271507 TI - C1 lateral mass screw placement in occipitalization with atlantoaxial dislocation and basilar invagination: a report of 146 cases. AB - STUDY DESIGN: Retrospective study of 146 patients with the diagnosis of occipitalization, atlantoaxial dislocation (AAD) and basilar invagination, using a novel surgical treatment strategy. OBJECTIVE: To introduce a novel fixation and reduction technique. SUMMARY OF BACKGROUND DATA: Atlas occipitalization associated with basilar invagination often result in fixed AAD that need reduction and occipitocervical fixation. The widely used occipitocervical fixation with suboccipital screws has several limitations such as the poor screw purchase in maldevelopment of the occipital bone, limited area available for implants in previous suboccipital craniectomy. The placement of occipitalized C1 lateral mass screw is an alternative option. METHODS: From June 2007 to June 2013, 146 patients of occipitalized atlas with fixed AAD and basilar invagination, underwent fixation and reduction via C1 lateral mass and C2 pars/pedicle screw. RESULTS: A total of 143 patients achieved the follow-up in the range from 6 months to 4 years (average, 30 mo). Neurological improvement was seen in all the 143 patients, with the averaged Japanese Orthopedic Association scores increasing from 11.6 to 15.5. Radiographical evaluation showed that solid bony fusion was achieved in all patients, and complete reduction was attained in 95 patients, and partial reduction (>60%) in 40 patients, and no effective reduction in 8 patients who had additional transoral decompression. Magnetic resonance imaging demonstrated that the ventral cervicomedullary compression was relieved in all patients. CONCLUSION: Although technically demanding, the C1 lateral mass placement in occipitalization is very useful in the rescue situation where more conventional stabilization alternatives are not technically possible, or as routine occipitocervical stabilization. It provides firm stabilization offering an optimum situation for bony fusion, and meanwhile the effective reduction of fixed AAD and basilar invagination. An extremely high fusion rate can be expected with minimal complications and minimal postoperative immobilization with this technique. PMID- 25271508 TI - T1 pelvic angle: a new predictor for postoperative sagittal balance and clinical outcomes in adult scoliosis. AB - STUDY DESIGN: A retrospective radiographical study. OBJECTIVE: To compare the prediction abilities of T1 pelvic angle (TPA) and other parameters for postoperative sagittal balance, and investigate the relationships between these parameters and health-related quality of life. SUMMARY OF BACKGROUND DATA: Using sagittal vertical axis (SVA) to assess sagittal alignment fails to take account of the pelvic compensation. A new parameter, TPA, has been recommended to represent the global sagittal balance of adult scoliosis. METHODS: A retrospective review was performed on patients with adult scoliosis undergoing correction surgery from May 2009 to March 2013. The Spearman rho was used to determine the correlations between the radiographical parameters (preoperative, postoperative, and changes) and the overall Oswestry Disability Index (ODI), visual analogue scale (VAS), and Scoliosis Research Society-22 (SRS-22) questionnaire scores. RESULTS: Significant correlations were found between the changes of TPA and the changes of lumbar lordosis, pelvic tilt, sacral slope, pelvic incidence, SVA, spinosacral angle, ODI, VAS, SRS-22, and pedicle subtraction osteotomy (PSO) degrees (P < 0.05). The changes of SVA were significantly related to the changes of lumbar lordosis, TPA, C7-sacrofemoral distance, ODI, VAS, SRS-22 (P < 0.05) but not PSO degrees (P > 0.05). Significant correlations were found between the changes of spinosacral angle and the changes of thoracolumbar kyphosis, TPA, ODI, VAS, SRS-22, and PSO degrees (P < 0.05). The changes of C7 plumb line to sacrofemoral distance ratio were significantly related to the changes of SVA (P < 0.05), but not the changes of ODI, VAS, SRS 22, or PSO degrees (P > 0.05). CONCLUSION: TPA could better reflect the postoperative changes of sagittal alignment and health-related quality of life for patients with adult scoliosis. Moreover, the changes of TPA are strongly correlated to the osteotomy degrees for PSO and, TPA could be used as a reference parameter in surgical planning. LEVEL OF EVIDENCE: 4. PMID- 25271509 TI - The effect of chronic low back pain on trunk accuracy in a multidirectional isometric tracking task. AB - STUDY DESIGN: A cross-sectional study to quantify trunk motor control during multidirectional isometric tracking tasks. OBJECTIVE: To investigate the effect of chronic low back pain (LBP) on trunk neuromuscular performance while participants performed isometric exertions of trunk muscles to track targets in different angles with various magnitudes. SUMMARY OF BACKGROUND DATA: Tracking tasks especially in multidirectional activities are among the common research methods to quantify human motor control in different conditions. However, little information is available on trunk motor control during these tasks. There is no study investigating trunk accuracy during multidirectional isometric tracking tasks in patients with LBP. MATERIALS AND METHODS: Twelve patients with chronic LBP and 16 asymptomatic participants performed isometric target tracking tasks in 12 different directions with varying magnitude, from 0% to 80% of individual maximum voluntary exertion, in upright standing posture. The tracking system included a moving target object that moved on a straight line in a predefined angle with the rate of 6% maximum voluntary exertion/s. Trunk accuracy was quantified by computing constant error and variable error during each trial. A mixed model repeated measure analysis of variance was conducted to assess statistical analysis. RESULTS: Patients with chronic LBP track the target object with higher error compared with healthy controls across almost all of the target angles (P < 0.01). Trunk accuracy decreased significantly in higher level of exertions (P < 0.01). CONCLUSION: The results provided additional evidence of a change in trunk control strategies in patients with chronic LBP. Decreased accuracy of trunk during isometric tracking tasks especially in higher levels of asymmetric exertions may explain higher risk of low back injuries in these activities. LEVEL OF EVIDENCE: 4. PMID- 25271510 TI - Anterior surgical management of single-level cervical disc disease: a cost effectiveness analysis. AB - STUDY DESIGN: Cost-effectiveness analysis with decision analysis and meta analysis. OBJECTIVE: To determine the relative cost-effectiveness of anterior cervical discectomy with fusion (with autograft, allograft, or spacers), anterior cervical discectomy without fusion (ACD), and cervical disc replacement (CDR) for the treatment of 1-level cervical disc disease. SUMMARY OF BACKGROUND DATA: There is debate as to the optimal anterior surgical strategy to treat single-level cervical disc disease. Surgical strategies include 3 techniques of anterior cervical discectomy with fusion (autograft, allograft, or spacer-assisted fusion), ACD, and CDR. Several controlled trials have compared these treatments but have yielded mixed results. Decision analysis provides a structure for making a quantitative comparison of the costs and outcomes of each treatment. METHODS: A literature search was performed and yielded 156 case series that fulfilled our search criteria describing nearly 17,000 cases. Data were abstracted from these publications and pooled meta-analytically to estimate the incidence of various outcomes, including index-level and adjacent-level reoperation. A decision analytic model calculated the expected costs in US dollars and outcomes in quality-adjusted life years for a typical adult patient with 1-level cervical radiculopathy subjected to each of the 5 approaches. RESULTS: At 5 years postoperatively, patients who had undergone ACD alone had significantly (P < 0.001) more quality-adjusted life years (4.885 +/- 0.041) than those receiving other treatments. Patients with ACD also exhibited highly significant (P < 0.001) differences in costs, incurring the lowest societal costs ($16,558 +/- $539). Follow-up data were inadequate for comparison beyond 5 years. CONCLUSION: The results of our decision analytic model indicate advantages for ACD, both in effectiveness and costs, over other strategies. Thus, ACD is a cost-effective alternative to anterior cervical discectomy with fusion and CDR in patients with single-level cervical disc disease. Definitive conclusions about degenerative changes after ACD and adjacent-level disease after CDR await longer follow-up. LEVEL OF EVIDENCE: 4. PMID- 25271511 TI - Novel 2 radiographical measurements for atlantoaxial instability in children with Down syndrome. AB - STUDY DESIGN: A retrospective case-control study. OBJECTIVE: To assess the usefulness and reproducibility of 2 novel safe and simple radiographical measurements for atlantoaxial instability in children with Down syndrome. SUMMARY OF BACKGROUND DATA: In pediatric atlantoaxial instability, early diagnosis is important for improved outcomes because of poor postoperative recovery in progressed neurological symptoms. Conventional dynamic radiography of the cervical spine is associated with a potential risk of worsening neurological symptoms. METHODS: We retrospectively reviewed the medical records of 50 patients (24 boys and 26 girls) with atlantoaxial instability associated with Down syndrome. Of the 50 children, 11 had undergone and 4 had been scheduled for surgery (surgical group). In this investigation, in addition to the atlas-dens interval (ADI) and space available for spinal cord (SAC), we measured C1 inclination angle and C1/4 SAC ratio on lateral radiographs of the cervical spine in the neutral position. To assess the diagnostic abilities of these indices to determine indication for surgery, receiver operating characteristic analysis of each index was performed, and their diagnostic abilities were compared using the area under the receiver operating characteristic curve. Moreover, we assessed reproducibility of our 2 proposed indices. RESULTS: The discriminatory abilities of C1/4 SAC ratio (area under the receiver operating characteristic curve, 1.00) and C1 inclination angle (0.91) were comparable with those of ADI (0.98) and SAC (0.95). For the interobserver and intraobserver reliability of the novel indices, the correlation coefficients were in the range from 0.88 to 0.99. Correlation was observed between the ADI and C1/4 SAC ratio (r = 0.507, P < 0.01) and between the ADI and C1 inclination angle (r = 0.407, P < 0.01). CONCLUSION: The diagnostic abilities of the 2 novel radiographical measurements were comparable with those of ADI and SAC. Moreover, these novel measurements can be obtained safely on lateral radiographs of the cervical spine in the neutral position. LEVEL OF EVIDENCE: 4. PMID- 25271512 TI - The revision rate and occurrence of adjacent segment disease after anterior cervical discectomy and fusion: a study of 672 consecutive patients. AB - STUDY DESIGN: LEVEL III: retrospective cohort study. OBJECTIVE: The aim of this study was to determine the rate of revision surgery and the occurrence of adjacent segment disease of patients undergoing ACDF for cervical radiculopathy and myelopathy using more modern-day instrumentation techniques. SUMMARY OF BACKGROUND DATA: Anterior cervical discectomy and fusion (ACDF) has long been the preferred treatment for cervical radiculopathy and myelopathy. METHODS: All patients undergoing ACDF between January of 2000 and December of 2010 were included. Age, sex, height, weight, body mass index, symptoms at presentation, number of levels fused, graft type, and smoking status were recorded. Outcomes included revision rate, reason for revision surgery, time to revision surgery, presence and grade of adjacent segment disease, distance from the instrumentation to the cranial and caudal endplate (plate-to-disc distance), and reporting of symptoms of adjacent segment disease at the final follow-up. RESULTS: A total of 672 patients were included in this study. The average duration of follow-up was 31 months. One hundred one (15%) patients underwent revision surgery. The reason for revision surgery was adjacent segment disease in 47 (47.5%), pseudarthrosis in 45 (45.5%) and a new problem at a nonadjacent level in 7 (7.1%) of those patients. The need for revision surgery was not affected by patient age, sex, body mass index, smoking status, symptoms at presentation, number of levels fused, plate-to-disc distance or graft type. CONCLUSION: The revision rate after ACDF is 15%. Most revisions were done for either adjacent segment disease or pseudarthrosis. No specific risk factors for revision surgery were identified in this study. LEVEL OF EVIDENCE: 3. PMID- 25271513 TI - Successful percutaneous retrieval of a large pulmonary cement embolus caused by cement leakage during percutaneous vertebroplasty: case report and literature review. AB - STUDY DESIGN: A case report and literature review. OBJECTIVE: To present a case of dynamic detection of a large pulmonary cement embolus as it formed and migrated during percutaneous vertebroplasty, which was successfully managed by percutaneous endovascular retrieval. SUMMARY OF BACKGROUND DATA: Pulmonary embolism resulting from cement leakage after percutaneous vertebroplasty to treat osteoporotic vertebral compression fracture has been described rarely; however, the frequency of this complication may increase secondary to the expanding use of percutaneous vertebral augmentation techniques. METHODS: The formation of a large embolus of acrylic cement and its migration into the pulmonary artery was observed in real time in a 55-year-old female with osteoporotic vertebral compression fracture of L4 during percutaneous vertebroplasty. RESULTS: Pulmonary arteriography confirmed the presence of the cement embolism in the right pulmonary artery during the operation. Percutaneous endovascular retrieval of the cement fragments was performed successfully via an interventional catheter procedure and subsequent incision of the femoral vein. The patient made an uneventful recovery. CONCLUSION: As illustrated by our case, large cement emboli may be primarily associated with technical aspects of the surgery. When considering the appropriate treatment strategy, percutaneous endovascular retrieval may be considered first. However, risks and benefits should be carefully evaluated on a case-by-case basis. LEVEL OF EVIDENCE: N/A. PMID- 25271514 TI - Does preoperative T1 slope affect radiological and functional outcomes after cervical laminoplasty? AB - STUDY DESIGN: Retrospective comparative study. OBJECTIVE: To analyze changes in the clinical and radiological factors related to cervical sagittal balance, relative to preoperative T1 slope, in patients with cervical myelopathy after laminoplasty (LP). SUMMARY OF BACKGROUND DATA: T1 slope is an important factor that should be considered before LP. However, until now, there have been no studies on how preoperative T1 slope affects the sagittal balance of cervical spine and various functional outcomes after LP. METHODS: Seventy-six patients with cervical myelopathy (M:F ratio = 50:26; mean age = 64.7 +/- 9.1 yr) underwent a cervical LP and were followed for more than 2 years. Radiological measurements were performed to analyze the following parameters: (1) C2-C7 sagittal vertical axis; (2) T1 slope; (3) C2-C7 lordosis; and (4) thoracic kyphosis. The visual analogue scale, Japanese Orthopedic Association, neck disability index, and 36-Item Short-Form Health Survey were also investigated. Patients were divided into 2 groups according to preoperative T1 slope, with the cutoff value being the median preoperative T1 slope. Changes in clinical and radiological parameters were compared between the preoperative evaluation and final visit. RESULTS: Overall, C2-C7 sagittal vertical axis increased from 21.2 to 24.5 mm (P = 0.004) and C2-C7 lordosis decreased from 13.9 degrees to 10.3 degrees (P = 0.007) postoperatively. The T1 slope did not show any postoperative differences. Preoperative C2-C7 lordosis was larger in the high-T1 group (19.1 degrees ) than in the low-T1 group (9.0 degrees ). However, postoperative changes in C2-C7 sagittal vertical axis and C2-C7 lordosis did not show any between-group differences. Clinical outcomes (except neck pain) demonstrated overall improvement in both groups. Comparing changes in both groups showed no differences in neck pain, arm pain, neck disability index, or 36-Item Short-Form Health Survey physical component score between groups. CONCLUSION: Cervical sagittal balance is compromised after cervical LP. However, the degree of aggravation does not correlate with the preoperative T1 slope. Most clinical parameters demonstrate overall improvement regardless of preoperative T1 slope. LEVEL OF EVIDENCE: 3. PMID- 25271515 TI - Number of recent inpatient admissions as a risk factor for increased complications, length of stay, and cost in patients undergoing posterior lumbar fusion. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To identify risk factors for increased complication rate, hospital charges, and length of stay in patients undergoing posterior lumbar fusion. SUMMARY OF BACKGROUND DATA: A better understanding of risk factors for perioperative complications in patients undergoing posterior lumbar fusion can aid with patient selection and postoperative monitoring. Previous studies have assessed the impact of factors such as body mass index, age, and American Society of Anesthesiologists physical status classification on complication rate. METHODS: Data were acquired from the institution's quality improvement data set. Preoperative demographic factors included sex, age, number of inpatient admissions in the prior year, body mass index, Charlson comorbidity score, American Society of Anesthesiologists physical status classification, number of levels fused, operative duration, and medications on admission. Complications recorded included pneumonia, myocardial infarction, venous thromboembolic event, hardware failure, readmission, or unplanned return to the operating room. Multivariate regression was used to identify predictors of increased complication rate, hospital charges, and length of stay. RESULTS: A total of 462 patients were included. A history of more than 1 admission in the prior year was the only variable significantly associated with increased complication rate (odds ratio 10.56, P < 0.0001). History of more than 1 admission in the prior year (+1.92 d, P < 0.0001), operative duration more than 5 hours (+0.81 d, P = 0.008), and American Society of Anesthesiologists physical status classification 3 or greater (+0.75 d, P = 0.01) were associated with increased length of stay, whereas history of more than 1 admission in the prior year (+$27,798, P < 0.0001), fusion of 4 or more levels (+$38,043, P < 0.0001), and operative duration more than 5 hours (+$40,298, P < 0.0001) were associated with increased total charges. CONCLUSION: The number of inpatient admissions in the prior year was found to be a more powerful predictor of perioperative risk after lumbar fusion than metrics evaluated in prior studies, such as age, body mass index, and comorbidities. LEVEL OF EVIDENCE: 3. PMID- 25271516 TI - Proximal junctional kyphosis and failure after spinal deformity surgery: a systematic review of the literature as a background to classification development. AB - STUDY DESIGN: Systematic review of literature. OBJECTIVE: To perform a comprehensive English language systematic literature review of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF), concentrating on incidence, risk factors, health related quality of life impact, prevention strategy, and classification systems. SUMMARY OF BACKGROUND DATA: PJK and PJF are well described clinical pathologies and are a frequent cause of revision surgery. The development of a PJK classification that correlates with clinical outcomes and guides treatment decisions and possible prevention strategies would be of significant benefit to patients and surgeons. METHODS: The phrases "proximal junctional," "proximal junctional kyphosis," and "proximal junctional failure" were used as search terms in PubMed for all years up to 2014 to identify all articles that included at least one of these terms. RESULTS: Fifty-three articles were identified overall. Eighteen articles assessed for risk factors. Eight studies specifically reviewed prevention strategies. There were no randomized prospective studies. There were 3 published studies that have attempted to classify PJK. The reported incidence of PJK ranged widely, from 5% to 46% in patients undergoing spinal instrumentation and fusion for adult spinal deformity. It is reported that 66% of PJK occurs within 3 months and 80% within 18 months after surgery. The reported revision rates due to PJK range from 13% to 55%. Modifiable and nonmodifiable risk factors for PJK have been characterized. CONCLUSION: PJK and PJF affect many patients after long segment instrumentation after the correction of adult spinal deformity. The epidemiology and risk factors for the disease are well defined. A PJK and PJF scoring system may help describe the severity of disease and guide the need for revision surgery. The development and prospective validation of a PJK classification system is important considering the prevalence of the problem and its clinical and economic impact. LEVEL OF EVIDENCE: N/A. PMID- 25271517 TI - Intraoperative neurological deterioration secondary to spinal kyphotic change after cervicothoracic junction laminectomy. AB - STUDY DESIGN: Case report. OBJECTIVE: We report a case in which intraoperative spinal kyphosis after laminectomy led to neurological deterioration during intramedullary spinal cord tumor surgery at the cervicothoracic junction (CTJ). SUMMARY OF BACKGROUND DATA: CTJ is a transitional zone between the cervical and thoracic spine; this region can be easily affected by mechanical stress. Although postoperative spinal instability or kyphosis after laminectomy at CTJ has been reported, no reports of intraoperative neurological deterioration after laminectomy exist. METHODS: The patient was a 40-year-old female with an intramedullary spinal cord tumor at T2-T4, which was suspected to be an ependymoma. She had no neurological deficit before the surgery. Although tumor removal surgery using a posterior approach was planned, the waves observed on intraoperative neurophysiological monitoring in the bilateral lower extremity disappeared soon after laminectomy. RESULTS: The waveform reappeared when we manually corrected the kyphosis at CTJ by pushing the spine. However, when we stopped the manual correction, the waveform disappeared again. The cause of neurological deterioration was strongly suspected to be a spinal kyphosis secondary to laminectomy. We removed the tumor after posterior instrumentation, and her neurological status was restored in 3 months postoperatively. CONCLUSION: A minimal change in spinal alignment secondary to laminectomy could be a cause of intraoperative neurological deterioration during surgery at CTJ. Spinal fixation using spinal instrumentation should be performed before laminectomy, particularly in patients with preoperative neurological damage or severe spinal cord compression at CTJ. LEVEL OF EVIDENCE: 4. PMID- 25271518 TI - The effect of deviated center of rotation on flexion-extension range of motion after single-level cervical arthroplasty: an in vivo study. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To report the clinical outcomes and sagittal kinematics after cervical total disc replacement (TDR). To evaluate the in vivo effect of deviated center of rotation (COR) on flexion-extension range of motion (ROM) at the instrumented level. SUMMARY OF BACKGROUND DATA: A few studies showed that the location of COR after cervical TDR deviated from its preoperative location or inherent location in healthy subjects. However, little is known about the effect of deviated COR on ROM at the instrumented level. METHODS: A total of 24 patients who underwent C5-C6 single-level TDR with Prestige LP (Medtronic Sofamor Danek) were retrospectively included. Japanese Orthopedic Association score and visual analogue scale were used to assess the clinical outcomes. ROM and COR were measured for radiographical analysis. Patients were categorized into 2 groups according to the change of ROM for further evaluation. Group 1, characterized by decreased postoperative ROM, consisted of 16 patients; group 2, characterized by increased postoperative ROM, consisted of 8 patients. RESULTS: Ten males and 14 females comprised the study cohort. The mean age was 45.05 years, and the mean follow-up time was 15.5 months. The Japanese Orthopedic Association score increased significantly and the neck and arm visual analogue scale decreased significantly after cervical TDR. On average, ROM was preserved after cervical TDR. The postoperative COR had a significant cranial shift from its preoperative location. The COR shift in anterior-posterior direction was larger in group 2 than that in group 1. No difference was observed in the COR shift in cranial-caudal direction between the 2 groups. CONCLUSION: Single-level cervical TDR with Prestige LP obtained satisfactory clinical outcomes and partially restored the natural cervical kinematics. At instrumented level, the deviated COR had a negative correlation with the flexion-extension ROM. PMID- 25271524 TI - The ventral route to intracranial aneurysm: from the origin towards modern transsphenoidal surgery. An historical review and current perspective. AB - OBJECTIVE: A review of the main studies that have explored the use of the ventral pathway for treatment of intracranial aneurysms,including the recent reported extended transsphenoidal approaches. METHODS: A comprehensive literature review was performed using the PubMed database. We recovered 48 cases of cerebral aneurysms, approached via the transcervical-transclival, transoral-transclival, transfacial-transclival ventral pathways and the extended transsphenoidal route. The overall rates of complications and surgical success were evaluated and compared for both traditional ventral and transsphenoidal approaches. RESULTS: For traditional routes, the overall complications and surgical success rates were 74% (26/35) and 87% (13115), respectively.For extended transsphenoidal approaches were 44% (4/9) and 78% (7 /9), respectively. CONCLUSION: Our paper is a reconnaissance of what has been done via "the anterior route" and a notification of the existence of this "surgical window': Present and future of cerebral aneurysm treatment is represented by the endovascular technique. A few selected cases in specialized centers, where transsphenoidal approaches with the aid of the endoscope are routinely performed,may be treated with such techniques alone or in combination with other different procedures. Further studies in large numbers of patients will be required to validate the full benefit of this approach. PMID- 25271519 TI - Increased risk of complications after anterior cervical discectomy and fusion in the elderly: an analysis of 6253 patients in the American College of Surgeons National Surgical Quality Improvement Program database. AB - STUDY DESIGN: Retrospective cohort analysis of anterior cervical discectomy and fusion (ACDF) surgical procedures using a prospectively collected database. OBJECTIVE: To characterize the 30-day postoperative outcomes in elderly patients undergoing ACDF after adjustment for comorbidities using a multi-institutional database. SUMMARY OF BACKGROUND DATA: Prior studies on the effect of age after ACDF have mostly focused on in-hospital complications, have come from single institutions, or have included ACDF in pooled analyses and have not distinctly analyzed the specific complications associated with age after ACDF. METHODS: Patients undergoing ACDF were selected in the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2012. Patients were stratified into 4 age-groups: 18 to 39 years, 40 to 64 years, 65 to 74 years, and 75 years or more (based on standard deviation cohorts). Patients in the different age categories were compared using the chi statistic, the Fisher exact test, and analysis of variance. Multivariate linear/logistic regression models were used to adjust for preoperative comorbidities. Significance was defined as P < 0.05. RESULTS: Data were available for 6253 patients who underwent ACDF. On multivariate logistic regression, both groups of elderly patients (65-74 and >=75 yr) were more likely to have blood transfusions, reoperations, urinary complications, extended length of stays, and 1 or more complication, overall. Only patients 65 to 74 years were more likely to have a pulmonary embolism/deep vein thrombosis, whereas only patients aged 75 years or older were more likely to experience respiratory complications, central nervous system complications, or death. There were no differences in complication rates between the 18- to 39-year age-group and 40- to 64-year age-group. The 18- to 39-year age-group and 75-year age-group had shorter operating room times. CONCLUSION: Older age is an independent risk factor for greater morbidity and longer hospitalizations after ACDF, even after adjustment for comorbidities when compared with younger patients. Surgeons should be aware of the increased risk of multiple complications for patients of advanced age in their surgical decision making. LEVEL OF EVIDENCE: 3. PMID- 25271525 TI - The association of frontal recess anatomy and mucosal disease on the presence of chronic frontal sinusitis: a computed tomographic analysis. AB - OBJECTIVES: The frontal sinus has the most complex and variable drainage routes of all paranasal sinus regions. The goal of this study was to identify these anatomical factors and inflammation areas relating to chronic frontal sinusitis by comparing radiological presentations in patients with and without frontal sinusitis. METHODS: All adult patients with chronic rhinosinusitis who had received computed tomography (CT) scans of the nasal cavities and paranasal sinuses between October 2010 and September 2011. Logistic regression analysis was used to compare the distribution of various frontal recess cells and surrounding inflammatory conditions in patients with and without frontal sinusitis. RESULTS: Analysis of 240 sides of CT scans was performed with 66 sides excluded. The opacification of the frontal recess and sinus lateralis demonstrated a strong association with an increased presence of frontal sinusitis by multiple logistic regression models. CONCLUSION: Opacification of the frontal recess and sinus lateralis was found to be associated with a significantly increased risk of frontal sinusitis and developing severe blockage of drainage pathways. It provides evidence that mucosal inflammation disease in these two areas is a very important factor leading to chronic frontal sinusitis. PMID- 25271526 TI - Rhinosinusitis in secondary school children-part 1: pilot study of the MSNOT-20 Young Person Questionnaire (MSYPQ). AB - BACKGROUND: The SNOT-20 questionnaire, a valid disease related quality of life instrument for rhinosinusitis, was modified for use in secondary school children and became the Modified Sino Nasal Outcome Test -20 Young Person Questionnaire, MSYPQ. METHODODOLOGY: MSYPQ was evaluated in a pilot study of disease (rhinosinusitis) and non-disease according to criteria in the European Position Paper on Rhinosinusitis and Nasal polyposis (EPOS). RESULTS: Those children who were suffering from rhinosinusitis according to the EPOS criteria showed significantly high scores on MSYPQ, whereas those who did not have rhinosinusitis had very low to zero scores on the MSYPQ. CONCLUSION: This pilot study confirmed that the MSYPQ recognises rhinosinusitis symptoms in the 11-16 year age group with its effect on quality of life and is a suitable instrument to investigate the prevalence and impact of this problem in young people. PMID- 25271527 TI - Rhinosinusitis in secondary school children-part 2: main project analysis of MSNOT-20 Young Persons Questionnaire (MSYPQ). AB - BACKGROUND: There is little data on rhinosinusitis in adolescent schoolchildren. We have employed a validated, disease specific quality of life questionnaire to determine the extent of this problem and its effects on their lives. METHODOLOGY: The MSYPQ, a disease specific quality of life questionnaire, previously evaluated in a pilot study of adolescent sino-nasal disease, was used in secondary school children in East London to identify the prevalence of rhinosinusitis plus its effects on quality of life. One group of the secondary school children completed ARIA based questions for comparison with MSYPQ rhinitis sub-scores. RESULTS: 71% scored an abnormal value on the MSYPQ for at least one symptom, 32% of those assessed suffered from symptoms compatible with rhinitis, similar to the prevalence of 30% previously found in adults. Unlike adults cough was one of the most significant symptoms. Over 21% of secondary school students had their quality of life affected and 11% took time off school due to their symptoms. The ARIA assessment group showed that symptoms were intermittent in 44% and confirmed significant impairment of sleep and daily activities. CONCLUSION: The MSYPQ demonstrates a high prevalence and impact on quality of life of rhinitis and rhinosinusitis symptoms in the 11-16 age group, with levels comparable to the results from an adult population. The MSYPQ rhinitis sub group of questions was concordant with ARIA based questions. PMID- 25271528 TI - Nasal septal body and inferior turbinate sizes differ in subjects grouped by sex and age. AB - OBJECTIVES: To compare the size of the nasal septal body (SB) and inferior turbinate (IT) of subjects grouped by sex and age. METHOD: We measured SB and IT areas (in cm2) bilaterally in computed tomography (CT) sections of 150 para nasal sinuses from 72 males and 78 females. RESULTS: The right and left SB areas were smaller in females than in males. In the s25-year-old group, the right IT (RIT) was significantly smaller in females than in males. In the 26-35 and 46-45 age groups, the right SB (RSB) was significantly smaller in females than in males. CONCLUSION: The nasal SB may play a role in nasal physiology similar to a turbinate and help support optimal airflow. The vascular and glandular structures of the SB should be investigated in detail, and minimal invasive procedures should be performed in nasal surgery to avoid damaging essential structures. PMID- 25271529 TI - Extraocular muscle injury during endoscopic sinus surgery: a series of 10 cases at a single center. AB - BACKGROUND: Extraocular muscle (EOM) injury is a rare but serious complication of endoscopic sinus surgery (ESS). The aim of this study is to describe the clinical characteristics and course of EOM injury occurring during ESS. DESIGN: Retrospective case series. METHODS: Medical records and CT images of patients who suffered from EOM injury after ESS between 2006 and 2012 were retrospectively reviewed. Patient demographics, endoscopic anatomy, type of surgery (primary or revision), predisposing risk factors, site and extent of injury on CT imaging, and associated complications were evaluated. In addition, data regarding ophthalmologic management and clinical outcomes were collected. RESULTS: Ten patients with EOM injuries after ESS were included in this study. One patient was undergoing revision ESS. All patients sustained medial rectus muscle injury and one patient suffered concurrent ipsilateral inferior rectus muscle injury. A microdebrider was used in nine cases. Right-sided injury (90% of patients) was more prevalent than left-sided injury, and 70% of injured medial rectus muscles were completely transected. After subsequent strabismus surgery, 8/9 patients regained binocular single vision in primary gaze despite residual diplopia in some gaze positions. CONCLUSION: Although proper ophthalmologic surgery after EOM injury may improve deviation in the primary gaze position, none of the patients regained normal EOM movement. Therefore, prevention of this complication through adequate surgical technique and precautions is important. PMID- 25271530 TI - Tumour necrosis factor inhibitor-associated sinusitis. AB - AIM: To describe the features of chronic sinusitis associated with the use of tumour necrosis factor (TNF) inhibitors. METHODOLOGY: A retrospective review of the medical records between 2003 and 2011 revealed that five patients had developed chronic sinusitis after the start of TNF inhibitor administration and required rhinological evaluation and treatment. RESULTS: The incidence of refractory sinusitis associated with TNF inhibitors was approximately 2%. Of the five patients identified, four patients were medicated with etanercept and one with infliximab. The maxillary sinus was most commonly involved and cultures of the sinus discharge revealed Pseudomonas aeruginosa in three cases. Two patients showed improvement of sinusitis with antibiotic medication, despite the continuous use of TNF inhibitor, while in two other patients, sinusitis was resistant to antibiotic medication. Another patient who had developed recurrence of sinusitis after complete remission of previous chronic sinusitis by endoscopic sinus surgery showed remission only after cessation of TNF inhibitor. CONCLUSION: Chronic sinusitis associated with TNF inhibitors is considered to be a new disease entity, and it will become more common due to the increasing use of TNF inhibitors. PMID- 25271531 TI - Japanese traditional medicine, Senn-kinn-naidaku-sann up-regulates Toll-like receptor 4 and reduces murine allergic rhinitis. AB - OBJECTIVE: To determine the mechanisms by which a traditional herbal medicine, Senkinnaidakusan (SKNS), controls Th2 responses, we examined the production of IL 12 by murine macrophages treated with SKNS. RESULTS: Treatment with SKNS significantly increased TLR4 mRNA in macrophages. Furthermore, pre-treatment with SKNS enhanced the production of IL-12 by macrophages stimulated with LPS. When SKNS was orally administered to C3H/HeN mice at the induction phase after OVA sensitization, the serum levels of OVA-specific immunoglobulin (Ig)E and IgG1 decreased, Interleukin (IL)-4 production by spleen T cells in response to OVA was significantly suppressed, while interferon (IFN)-gamma production was increased. After nasal challenge of OVA, eosinophilic infiltration in the nasal mucosa and the number of sneezes were significantly inhibited in SKNS-treated mice compared with control mice. Besides, expression of IL-5 in the nasal mucosa was also inhibited. Using another strain of mice, C3H/HeJ (TLR4 negative), there was no difference in OVA-specific Igs or splenic cytokine production between the SKNS treatment and non-treatment groups. The eosinophilic infiltration in the nasal mucosa, the number of sneezes and IL-5 expression in the nasal mucosa were also not effected even after SKNS treatment. CONCLUSION: These results suggest that oral administration of SKNS inhibits Th2 responses by enhancement of IL-12 release from macrophages via up-regulation of TLR4 expression. PMID- 25271532 TI - Mono-allergic and poly-allergic rhinitis patients have comparable numbers of mucosal Foxp3+CD4+ T lymphocytes. AB - BACKGROUND: We previously found that allergic rhinitis patients with an isolated pollen sensitization responded more strongly to a nasal provocation with grass pollen (GP) than patients who had an additional house dust mite (HDM) sensitization. To elucidate this phenomenon, we investigated the dynamics of Foxp3+CD4+ T lymphocytes in allergic rhinitis patients with distinct allergen sensitizations. METHODS: Three groups of allergic rhinitis patients with skin prick test confirmed allergic sensitizations were investigated and compared to 14 healthy controls: 14 subjects with an isolated grass pollen sensitization (Mono GP); 9 subjects with isolated housedust mite sensitization (Mono-HDM); 29 subjects with grass pollen and house dust mite sensitization (poly-sensitized). Subjects in the Mono-GP group were challenged with grass pollen extract, subjects in the Mono-HDM group were challenged with house dust mite extract, subjects in the poly-sensitized group and the healthy controls were randomly challenged with either grass pollen or house dust mite. Nasal biopsies were taken before and after nasal provocation. We compared the distribution of FoxP3+CD4+ cells in nasal biopsies before and after nasal provocation using immunohistochemistry. RESULTS: There was no difference in the number of FoxP3+CD4+ cells between healthy and the three allergic groups at baseline.Nasal provocation did result in an increase in eosinophils in the three allergic groups, but did not result in a change in the number of FoxP3+CD4+ cells in any of the groups or induced differences between any of the groups. CONCLUSION: Clinical differences in the response between mono-GP and multiple-sensitized allergic individuals are not related to differences in the number of regulatory T cells in the nasal mucosa. PMID- 25271533 TI - Frontal sinus mucocoeles: new algorithm for surgical management. AB - BACKGROUND: Frontal sinus mucocoeles require a structured approach to their surgical management. We share our experience of a novel method of positional classification for frontal mucocoele and corresponding surgical algorithm. METHODS: A retrospective case-note review examined all frontal sinus surgery for mucocoele, spanning three years (2008-2010). Patients had pre-operative nasendoscopy, multi-planar CT and MRI when indicated. Several important variables (position, drainage dimensions, fronto-ethmoidal cells and degree of neo osteogenesis) were noted. A systematic algorithm was used for surgical drainage based on these characteristics. The three year outcomes using this approach are presented. RESULTS: Thirty-six patients were identified with a total of 43 frontal mucocoeles. Using our classification, 30 mucocoeles were medial; seven were intermediate; six were lateral. Thirty-four patients underwent a primary endoscopic procedure; six required a combined primary osteoplastic-flap (OPF) and endoscopic approach. Six patients required revision surgery for polypoidal change or neo-ostium stenosis. All patients were eventually rendered asymptomatic. CONCLUSION: Implementation of our positional classification and surgical algorithm was successful with a revision rate of 19%. Presence of frontal sinus wall dehiscence and extra-sinus mucocoele extension are invalid indicators for external approach. We feel our classification and treatment algorithm, with its associated indicators for surgical escalation (i.e. limited dimensions of frontal ostium, presence of Type III / IV front-ethmoidal cells etc), are applicable for future management of frontal mucocoeles. PMID- 25271534 TI - A novel technique for mitomycin-c application in frontal sinus surgery. AB - OBJECTIVE: Local application of mitomycin-c (MMC) seems to be effective in reducing adhesions and stenosis after FESS. However this is not clearly seen in frontal sinusotomy. This study assesses the effectiveness of local MMC in the frontal ostium using a foamy material (otowick) and compared with cottonoids. METHODS: Forty-seven patients with chronic rhinosinusitis without polyps enrolled in this study. Two subgroups were studied: one with MMC application in one nostril using cottonoids and a second with MMC injected in an otowick. In all patients MMC was applied twice, intraoperatively and 4 weeks later. In both groups normal saline was applied to the other nostril on the same material with the MMC side. Six months postoperatively all patients were assessed endoscopically by a clinician blinded to the MMC side. RESULTS: Overall, MMC application was more effective than normal saline in both groups. Otowick use presented favorable initial results especially in primary cases regarding ostium patency, and need for revision surgery. The use of MMC cottonoids did not show any benefit in primary cases. CONCLUSION: The described technique seems to be effective in maintaining frontal ostium patency as it provides a more precise and deeper drug delivery to this area. PMID- 25271535 TI - The effect of two sphenoidotomy approaches on the sense of smell: trans-ethmoidal versus trans-sphenoethmoidal. AB - BACKGROUND: There are generally two methods to access the sphenoid sinus: either through the natural ostium {trans-sphenoethmoidalor via sphenoethmoidal recess), or by creating a second opening through the posterior ethmoids (trans ethmoidal).This study psychophysically and subjectively evaluates the effect of the trans-sphenoethmoidal technique to the trans-ethmoidal technique for sphenoid sinusotomy on olfactory function. METHODS: Prospective cohort analysis of 48 patients with comparable sinus disease underwent primary sphenoidotomy via transsphenoethmoidal(n = 24) versus trans-ethmiodal (n = 24) technique between September 2011 and February 2012. The patients had their olfaction measured psychophysically with "Sniffin' Sticks" and subjectively with a visual analogue scale (VAS) pre-operatively and at 5 weeks post-operatively. RESULTS: Psychophysical scores from the Sniffin' sticks provide a Threshold, Discrimination and Identification (TDI) score out of 48.The TDI change (post operative TDI score minus pre-operative score) as well as VAS change (post operative VAS minus pre-operativeVAS) were analyzed using t-test analysis, which showed no significant difference between the two measurements. CONCLUSION: If the trans-sphenoethmoidal technique is done meticulously, patients have the same olfactory relief, psychophysically and subjectively, as those undergoing the trans-ethmoidal technique. PMID- 25271536 TI - Patient-centered medical home implementation and primary care provider turnover. AB - BACKGROUND: The Veterans Health Administration (VHA) began implementing a patient centered medical home (PCMH) model of care delivery in April 2010 through its Patient Aligned Care Team (PACT) initiative. PACT represents a substantial system reengineering of VHA primary care and its potential effect on primary care provider (PCP) turnover is an important but unexplored relationship. This study examined the association between a system-wide PCMH implementation and PCP turnover. METHODS: This was a retrospective, longitudinal study of VHA-employed PCPs spanning 29 calendar quarters before PACT and eight quarters of PACT implementation. PCP employment periods were identified from administrative data and turnover was defined by an indicator on the last quarter of each uncensored period. An interrupted time series model was used to estimate the association between PACT and turnover, adjusting for secular trend and seasonality, provider and job characteristics, and local unemployment. We calculated average marginal effects (AME), which reflected the change in turnover probability associated with PACT implementation. RESULTS: The quarterly rate of PCP turnover was 3.06% before PACT and 3.38% after initiation of PACT. In adjusted analysis, PACT was associated with a modest increase in turnover (AME=4.0 additional PCPs per 1000 PCPs per quarter, P=0.004). Models with interaction terms suggested that the PACT related change in turnover was increasing in provider age and experience. CONCLUSIONS: PACT was associated with a modest increase in PCP turnover, concentrated among older and more experienced providers, during initial implementation. Our findings suggest that policymakers should evaluate potential workforce effects when implementing PCMH. PMID- 25271537 TI - A phase 1 dose-escalation study of XmAb(r) 2513 in patients with relapsed or refractory Hodgkin lymphoma. PMID- 25271538 TI - Masticatory Muscles Dysfunction after CT-guided Percutaneous Trigeminal Radiofrequency Thermocoagulation for Trigeminal Neuralgia: A Detailed Analysis. AB - OBJECTIVE: The aim of this study was to investigate the severity and the natural course of masticatory muscles weakness that developed after CT-guided percutaneous trigeminal radiofrequency thermocoagulation (PT-RFT) for the treatment of idiopathic trigeminal neuralgia (ITN). METHODS: Twenty-seven patients with ITN were treated by CT-guided percutaneous trigeminal radiofrequency thermocoagulation. Each patients' occlusal function and surface electromyographic (sEMG) activity of the ipsilateral anterior temporalis (TA) and masseter muscles (MM) at mandibular postural position (MPP), and during a fast maximum voluntary clenching (MVC) from MPP to intercuspal position (ICP), were simultaneously recorded by the T-Scan III system and Bio-pak sEMG III system before (baseline), 3 days, 3 months, and 12 months after procedure. The incidence, degree, and prognosis of masticatory muscles dysfunction related to trigeminal nerve motor-branch injury were analyzed. RESULTS: Three days and 3 months after procedure, both the occlusal symmetry and the sEMG activity of ipsilateral TA and MM became significantly decreased compared to the baseline (P < 0.05). However, they demonstrated a gradual improvement toward preoperative values in follow-up, returning to complete in 23 patients at 12 months after procedure. None reported permanent masticatory paralysis. Pain relief was most significant on the third day after procedure. At the final clinical visit, a pain free status was observed in 25 patients (92.6%). Meanwhile, the intensity of facial dysesthesia was mildest, whereas there were statistic differences compared with baseline. CONCLUSION: CT-guided PT-RFT for ITN remains an effective and safe surgical procedure, but there is a high rate of temporary masticatory dysfunction during a short time after procedure, appearing to be reversible in a period of 12 months. PMID- 25271539 TI - Vertically scanned laser sheet microscopy. AB - Laser sheet microscopy is a widely used imaging technique for imaging the three dimensional distribution of a fluorescence signal in fixed tissue or small organisms. In laser sheet microscopy, the stripe artifacts caused by high absorption or high scattering structures are very common, greatly affecting image quality. To solve this problem, we report here a two-step procedure which consists of continuously acquiring laser sheet images while vertically displacing the sample, and then using the variational stationary noise remover (VSNR) method to further reduce the remaining stripes. Images from a cleared murine colon acquired with a vertical scan are compared with common stitching procedures demonstrating that vertically scanned light sheet microscopy greatly improves the performance of current light sheet microscopy approaches without the need for complex changes to the imaging setup and allows imaging of elongated samples, extending the field of view in the vertical direction. PMID- 25271540 TI - Real-time brightfield, darkfield, and phase contrast imaging in a light-emitting diode array microscope. AB - We demonstrate a single-camera imaging system that can simultaneously acquire brightfield, darkfield, and phase contrast images in real time. Our method uses computational illumination via a programmable light-emitting diode (LED) array at the source plane, providing flexible patterning of illumination angles. Brightfield, darkfield, and differential phase contrast images are obtained by changing the LED patterns, without any moving parts. Previous work with LED array illumination was only valid for static samples because the hardware speed was not fast enough to meet real-time acquisition and processing requirements. Here, we time multiplex patterns for each of the three contrast modes in order to image dynamic biological processes in all three contrast modes simultaneously. We demonstrate multicontrast operation at the maximum frame rate of our camera (50 Hz with 2160 * 2560 pixels). PMID- 25271541 TI - Laser line scanning for fluorescence reflectance imaging: a phantom study and in vivo validation of the enhancement of contrast and resolution. AB - Intraoperative fluorescence imaging in reflectance geometry is an attractive imaging modality to noninvasively monitor fluorescence-targeted tumors. In some situations, this kind of imaging suffers from poor resolution due to the diffusive nature of photons in tissue. The objective of the proposed technique is to tackle this limitation. It relies on the scanning of the medium with a laser line illumination and the acquisition of images at each position of excitation. The detection scheme proposed takes advantage of the stack of images acquired to enhance the resolution and the contrast of the final image. The experimental protocol is described to fully understand why we overpass the classical limits and validate the scheme on tissue-like phantoms and in vivo with a preliminary testing. The results are compared with those obtained with a classical wide-field illumination. PMID- 25271542 TI - Selective perfluoro- and polyfluoroarylation of Meldrum's acid. AB - This work describes the facile and mono-selective per- and polyfluoroarylation of Meldrum's acid to generate a versatile synthon for highly fluorinated alpha phenyl acetic acid derivatives, which provide straightforward access to fluorinated building blocks. The reaction takes place quickly, and most products were isolated without the need for chromatography. Importantly, this method provides an alternative strategy to access alpha-arylated Meldrum's acids, which avoids the need for aryl-Pb(IV) salts or diaryliodonium salts. Furthermore, we demonstrate the synthetic versatility and utility of the Meldrum's acid products by subjecting our products to several derivatizations of the Meldrum's acid products as well as photocatalytic hydrodefluorination. PMID- 25271543 TI - Skin mast cells develop non-synchronized changes in typical lineage characteristics upon culture. AB - Despite their hematopoietic origin, mast cells (MCs) develop exclusively in tissues, hampering their ample use in research. To circumvent this problem, tissue-derived MCs are typically first expanded in culture, but the changes MCs may undergo in the novel micromilieu are poorly defined. Here, we monitor skin MCs from a number of donors over time, revealing profound yet non-synchronized modulations in culture. While tryptase and chymase, the most specific markers, strongly decline, FcepsilonRI surface expression, and FcepsilonRI-mediated histamine release steeply increase (from ~15.5% to ~60%), replicated by similar increments in TNF-alpha secretion. Interestingly, the modulations are independent of cell cycle progression, as they are comparable in the growth and postgrowth phase, implying they primarily result from microenvironmental conditioning. The data highlight a high degree of MC versatility, but also advise that results based on cultured MCs should be viewed with some caution, as they may not accurately reflect their counterparts in situ. PMID- 25271546 TI - Assessment of atrial electromechanical delay and P-wave dispersion in patients with psoriasis. AB - BACKGROUND: In this study, we sought to evaluate atrial electromechanical properties and conduction homogeneity by tissue Doppler imaging and electrocardiography in patients with psoriasis. METHODS: Thirty-four patients with psoriasis and 30 age- and gender-matched healthy controls were included in the study. Atrial electromechanical coupling intervals were assessed by means of tissue Doppler echocardiography and P-wave dispersion (Pd) was calculated from electrocardiogram. RESULTS: A total of 64 subjects (33 male) with a mean age of 36.8 +/- 11.9 years were included in the study. Basal characteristics were similar between 2 groups. Intra-atrial (15 +/- 7 ms vs. 12 +/- 5 ms, P = 0.009) and inter-atrial (28 +/- 7 ms vs. 23 +/- 7 ms, P = 0.002) electromechanical delays were significantly higher in patients with psoriasis compared with control groups. P-maximum (112 +/- 16 ms vs. 103 +/- 8 ms, P = 0.006) and Pd (35 +/- 9 ms vs. 20 +/- 6 ms, P < 0.001) were also prolonged in patients with psoriasis. CONCLUSION: This study demonstrated that atrial electromechanical coupling intervals and P-wave dispersion were prolonged in patients with psoriasis, which may cause an increased risk of atrial fibrillation in this patient group. PMID- 25271544 TI - Effects of decontamination of the oropharynx and intestinal tract on antibiotic resistance in ICUs: a randomized clinical trial. AB - IMPORTANCE: Selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) are prophylactic antibiotic regimens used in intensive care units (ICUs) and associated with improved patient outcome. Controversy exists regarding the relative effects of both measures on patient outcome and antibiotic resistance. OBJECTIVE: To compare the effects of SDD and SOD, applied as unit-wide interventions, on antibiotic resistance and patient outcome. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, cluster randomized crossover trial comparing 12 months of SOD with 12 months of SDD in 16 Dutch ICUs between August 1, 2009, and February 1, 2013. Patients with an expected length of ICU stay longer than 48 hours were eligible to receive the regimens, and 5881 and 6116 patients were included in the clinical outcome analysis for SOD and SDD, respectively. INTERVENTIONS: Intensive care units were randomized to administer either SDD or SOD. MAIN OUTCOMES AND MEASURES: Unit-wide prevalence of antibiotic resistant gram-negative bacteria. Secondary outcomes were day-28 mortality, ICU acquired bacteremia, and length of ICU stay. RESULTS: In point-prevalence surveys, prevalences of antibiotic-resistant gram-negative bacteria in perianal swabs were significantly lower during SDD compared with SOD; for aminoglycoside resistance, average prevalence was 5.6% (95% CI, 4.6%-6.7%) during SDD and 11.8% (95% CI, 10.3%-13.2%) during SOD (P < .001). During both interventions the prevalence of rectal carriage of aminoglycoside-resistant gram-negative bacteria increased 7% per month (95% CI, 1%-13%) during SDD (P = .02) and 4% per month (95% CI, 0%-8%) during SOD (P = .046; P = .40 for difference). Day 28-mortality was 25.4% and 24.1% during SOD and SDD, respectively (adjusted odds ratio, 0.96 [95% CI, 0.88-1.06]; P = .42), and there were no statistically significant differences in other outcome parameters or between surgical and nonsurgical patients. Intensive care unit-acquired bacteremia occurred in 5.9% and 4.6% of the patients during SOD and SDD, respectively (odds ratio, 0.77 [95% CI, 0.65 0.91]; P = .002; number needed to treat, 77). CONCLUSIONS AND RELEVANCE: Unit wide application of SDD and SOD was associated with low levels of antibiotic resistance and no differences in day-28 mortality. Compared with SOD, SDD was associated with lower rectal carriage of antibiotic-resistant gram-negative bacteria and ICU-acquired bacteremia but a more pronounced gradual increase in aminoglycoside-resistant gram-negative bacteria. TRIAL REGISTRATION: trialregister.nlIdentifier: NTR1780. PMID- 25271547 TI - Reference values of the mitral annular peak systolic velocity (Sm) in 690 healthy pediatric patients, calculation of Z-score values, and comparison to the mitral annular Plane systolic excursion (MAPSE). AB - BACKGROUND: The mitral annular peak systolic velocity (Sm) is an echocardiographic measurement using tissue Doppler imaging to assess longitudinal left ventricular (LV) systolic function in children and adults. We determined growth-related changes in Sm to establish reference values for the entire pediatric age group. METHODS AND RESULTS: A prospective study was conducted in a group of 690 healthy pediatric patients (age: 1 day-18 years). We determined the effects of age, sex, and body surface area (BSA) on the Sm values. Regression analysis was used to estimate Sm from age, BSA, and sex. In addition, a correlation of normal Sm with normal age-matched values of the M-mode parameter mitral annular plane systolic excursion (MAPSE) was measured. The Sm ranged from a mean of 5.8 cm/sec (Z-score +/-2: 3.6-8.0 cm/sec) in the newborn to 11.8 cm/sec (Z-score +/-2: 8.5-15.1 cm/sec) in the 18-year-old adolescent. The Sm values showed a positive correlation with age and BSA with a nonlinear course. There was no significant difference in Sm values between females and males. A significant correlation was found between Sm and MAPSE values. CONCLUSION: Z-scores of Sm values were calculated and percentile charts were established to serve as reference data in patients with congenital heart diseases. PMID- 25271548 TI - Incremental value of three-dimensional transesophageal echocardiography over the two-dimensional technique in percutaneous closure of aortic paraprosthetic regurgitation. AB - We describe 2 patients with significant aortic paraprosthetic regurgitation who underwent percutaneous closure where live/real time three-dimensional transesophageal echocardiography provided incremental value over two-dimensional transesophageal echocardiography. PMID- 25271549 TI - Neutrophil-to-lymphocyte ratio may predict subclinical atherosclerosis in patients with psoriasis. PMID- 25271550 TI - Reply: To PMID 24447343. PMID- 25271553 TI - Discrimination and classification of liver cancer cells and proliferation states by Raman spectroscopic imaging. AB - Discrimination of nodular lesions in cirrhotic liver is a challenge in the histopathologic diagnostics. For this reason, there is an urgent need for new detection methods to improve the accuracy of the diagnosis of liver cancer. Raman imaging allows to determine the spatial distribution of a variety of molecules in cells or tissue label-free and to correlate this molecular information with the morphological structures at the same sample location. This study reports investigations of two liver cancer cell lines, - HepG2 and SK-Hep1, - as well as HepG2 cells in different cellular growth phases using Raman micro-spectroscopic imaging. Spectral data of all cells were recorded as a color-coded image and subsequentially analyzed by hierarchical cluster and principal component analysis. A support vector machine-based classification algorithm reliably predicts previously unknown cancer cells and cell cycle phases. By including selectively the Raman spectra of the cytoplasmic lipids in the classifier, the accuracy has been improved. The main spectral differences that were found in the comparative analysis can be attributed to a higher expression of unsaturated fatty acids in the hepatocellular carcinoma cells and during the proliferation phase. This corresponds to the already examined de novo lipogenesis in cells of liver cancer. PMID- 25271554 TI - Controlling regiochemistry in the gold-catalyzed synthesis of unsaturated spiroketals. AB - A novel gold-catalyzed synthesis of unsaturated spiroketals that addresses regioselectivity issues commonly reported in metal-catalyzed spiroketalization of alkynes is reported. The reaction sequence is regulated by an acetonide protecting group which undergoes extrusion of acetone to deliver the desired spiroketals in good yields and diastereoselectivities. The reaction, which is carried out under very mild conditions employing AuCl as the catalyst, should be widely applicable in the synthesis of a broad range of spiroketals. PMID- 25271555 TI - Detection of Ichthyophonus by chromogenic in situ hybridization. PMID- 25271557 TI - Current nanotechnological strategies for treating glaucoma. AB - Glaucoma is a common cause of blindness worldwide, and the development of treatments is difficult for pharmaceutical scientists because successful delivery of drugs to the anterior and posterior segments of eye is challenging due to anatomical and physiological constraints. Conventional treatments use various dosage forms (solutions, suspensions, and ointments) that are hindered by poor intraocular penetration and/or rapid ocular elimination. Therefore, effective, safe, and comfortable methods of drug delivery are needed. One approach to improving ocular therapy is the use of nanotechnology for drug delivery. Recent drug delivery approaches using gels, liposomes, niosomes, ocular inserts, contact lenses, microparticles, nanoparticles, nanosuspensions, and other materials have produced exciting new therapies for ocular diseases, especially glaucoma. In this review, we discuss the importance of nanotechnology in novel drug delivery systems and the future possibilities for an effective treatment of glaucoma. PMID- 25271558 TI - Phospholipids: a novel adjuvant in herbal drug delivery systems. AB - Phytoconstituents have been used extensively in modern science because of their various pharmacological actions with few side effects. Regardless of their excellent therapeutic activity, several phytoconstituents have shown poor bioavailability in vivo. Phytoconstituents possess properties such as poor lipid solubility, large molecular size, and degradation in the gut due to the acidic environment. Gastric enzymes always limit their use. Phospholipids seem to be a major carrier for plant active molecules, which not only interact with the plant constituents on a molecular level but also protect the active components of the plant from degradation and increase the bioavailability of the active components by imparting lipid solubility to them. Complexation techniques enable researchers to convert the phytophospholipids into various dosage forms, including tablets and capsules. In the cosmetic industry, however, these complexes have acquired wider applicability in the form of gels and emulsions. Complexation of phospholipids with active components of plants improves their bioavailability and is being extensively studied by researchers, and further research in this regard is expected in the future. This review highlights the unique property of phospholipids in drug delivery, their health benefits, and their use in the herbal medicine systems to improve the bioavailability of active herbal components. PMID- 25271556 TI - Novel 19F activatable probe for the detection of matrix metalloprotease-2 activity by MRI/MRS. AB - Matrix metalloproteases (MMPs) have been found to be highly expressed in a variety of malignant tumor tissues. Noninvasive visualization of MMP activity may play an important role in the diagnosis of MMP associated diseases. Here we report the design and synthesis of a set of fluorine-19 dendron-based magnetic resonance imaging (MRI) probes for real-time imaging of MMP-2 activity. The probes have the following features: (a) symmetrical fluorine atoms; (b) the number of fluorine atoms can be increased through facile chemical modification; (c) readily accessible peptide sequence as the MMP-2 substrate; (d) activatable (19)F signal (off/on mode) via paramagnetic metal ion incorporation. Following optimization for water solubility, one of the probes was selected to evaluate MMP 2 activity by (19)F magnetic resonance spectroscopy (MRS). Our results showed that the fluorine signal increased by 8.5-fold in the presence of MMP-2. The specific cleavage site was verified by mass spectrometry. The selected probe was further applied to detect secreted MMP-2 activity of living SCC7 squamous cell carcinoma cells. The fluorine signal was increased by 4.8-fold by MRS analysis after 24 h incubation with SCC7 cells. This type of fluorine probe can be applied to evaluate other enzyme activities by simply tuning the substrate structures. This symmetrical fluorine dendron-based probe design extends the scope of the existing (19)F MRI agents and provides a simple but robust method for real-time (19)F MRI application. PMID- 25271559 TI - Lipid materials for topical and transdermal delivery of nanoemulsions. AB - Over the past two decades, nanoemulsions have gained significant scientific attention because of their unique features such as high solubilization capacity, spontaneous formation, enhanced thermodynamic stability, ability to load both hydrophilic and hydrophobic drug molecules, enhanced stability of the encapsulated therapeutic molecule, and high diffusion/absorption rates. Further, they have applications in dermal and epidermal targeting for various skin disorders. The materials used in nanoemulsion formulations can greatly influence the in vitro and in vivo performance of the therapeutic moiety. This review describes various lipid materials used in the preparation of nanoemulsions for topical and transdermal drug delivery. The lipids are classified as vegetable oils, fatty acids, fatty alcohols, medium chain glycerides, and fatty acid esters. PMID- 25271560 TI - Glutathione adduct of methylmercury activates the Keap1-Nrf2 pathway in SH-SY5Y cells. AB - Methylmercury (MeHg) reacts readily with GSH, leading to the formation of a MeHg SG adduct that is excreted into extracellular space through multidrug-resistance associated protein (MRP), which is regulated by the transcription factor Nrf2. We previously reported that MeHg covalently modifies Keap1 and activates Nrf2 in human neuroblastoma SH-SY5Y cells. In the study presented here, we examined whether the MeHg-SG adduct could also modulate the Keap1-Nrf2 pathway because the formation of the Hg-S bond is believed to be reversible in the presence of a nucleophile. SH-SY5Y cells exposed to the synthetic ethyl monoester of the MeHg SG adduct (which is hydrolyzed by cellular esterase(s) to give the MeHg-SG adduct) exhibited a concentration-dependent cellular toxicity that was enhanced by pretreatment with a specific MRP inhibitor. As expected, the MeHg-SG adduct was able to modify cellular proteins in the SH-SY5Y cells and purified Keap1. We also found that this prodrug, as well as MeHg, causes the cellular Keap1 in the cells to be modified, resulting in Nrf2 activation and, thereby, the upregulation of the downstream genes. These results suggest that the MeHg-SG adduct is not electrophilic but that it modifies protein thiols (including Keap1) through S transmercuration and that rapid Nrf2-dependent excretion of the MeHg-SG adduct is essential in decreasing the cytotoxicity of MeHg. PMID- 25271562 TI - Variant parameter values-as defined by the Chicago Criteria-produced by ManoScan and a new system with Unisensor catheter. AB - BACKGROUND: Recently reported normal values for esophageal motility obtained by high-resolution manometry (HRM) using a system with a Unisensor catheter were significantly different from those obtained by the ManoScan((r)) , which could result in a wrong diagnosis. To clarify whether these differences were due to system or subject differences, we compared the manometric parameter values between ManoScan and a new system with a Unisensor catheter (Starlet) in the same subjects. METHODS: A total of 103 volunteers without any symptoms related to esophageal motility disorders were recruited. Esophageal HRM was performed using both the ManoScan and the Starlet in all subjects. Data from the ManoScan were analyzed using ManoView, and data from the Starlet were analyzed by a program with e-sleeve function. Integrated relaxation pressure, distal contractile integral, contractile front velocity (CFV), intrabolus pressure, and distal latency were calculated by both analyzing programs, and the values of these parameters were compared between the two systems by a signed rank test. KEY RESULTS: Data from a total of 97 participants were analyzed. The values of all parameters, except CFV, measured by the Starlet were significantly higher than those obtained by the ManoScan (p < 0.01). CONCLUSIONS & INFERENCES: Both systems can measure esophageal motility appropriately; nevertheless, we confirmed that the two systems showed different values of the parameters defined by the Chicago criteria. These differences should be recognized to evaluate esophageal motility precisely. PMID- 25271563 TI - Reporting the characteristics of the policy context for population-level alcohol interventions: a proposed 'Transparent Reporting of Alcohol Intervention ContExts' (TRAICE) checklist. AB - ISSUES: Effectiveness of alcohol policy interventions varies across times and places. The circumstances under which effective polices can be successfully transferred between contexts are typically unexplored with little attention given to developing reporting requirements that would facilitate systematic investigation. APPROACH: Using purposive sampling and expert elicitation methods, we identified context-related factors impacting on the effectiveness of population-level alcohol policies. We then drew on previous characterisations of alcohol policy contexts and methodological-reporting checklists to design a new checklist for reporting contextual information in evaluation studies. KEY FINDINGS: Six context factor domains were identified: (i) baseline alcohol consumption, norms and harm rates; (ii) baseline affordability and availability; (iii) social, microeconomic and demographic contexts; (iv) macroeconomic context; (v) market context; and (vi) wider policy, political and media context. The checklist specifies information, typically available in national or international reports, to be reported in each domain. IMPLICATIONS: The checklist can facilitate evidence synthesis by providing: (i) a mechanism for systematic and more consistent reporting of contextual data for meta-regression and realist evaluations; (ii) information for policy-makers on differences between their context and contexts of evaluations; and (iii) an evidence base for adjusting prospective policy simulation models to account for policy context. CONCLUSIONS: Our proposed checklist provides a tool for gaining better understanding of the influence of policy context on intervention effectiveness. Further work is required to rationalise and aggregate checklists across interventions types to make such checklists practical for use by journals and to improve reporting of important qualitative contextual data. PMID- 25271564 TI - Urban area extent extraction in spaceborne HR and VHR data using multi-resolution features. AB - Detection of urban area extents by means of remotely sensed data is a difficult task, especially because of the multiple, diverse definitions of what an "urban area" is. The models of urban areas listed in technical literature are based on the combination of spectral information with spatial patterns, possibly at different spatial resolutions. Starting from the same data set, "urban area" extraction may thus lead to multiple outputs. If this is done in a well structured framework, however, this may be considered as an advantage rather than an issue. This paper proposes a novel framework for urban area extent extraction from multispectral Earth Observation (EO) data. The key is to compute and combine spectral and multi-scale spatial features. By selecting the most adequate features, and combining them with proper logical rules, the approach allows matching multiple urban area models. Experimental results for different locations in Brazil and Kenya using High-Resolution (HR) data prove the usefulness and flexibility of the framework. PMID- 25271565 TI - Energy efficient cooperation in underlay RFID cognitive networks for a water smart home. AB - Shrinking water resources all over the world and increasing costs of water consumption have prompted water users and distribution companies to come up with water conserving strategies. We have proposed an energy-efficient smart water monitoring application in [1], using low power RFIDs. In the home environment, there exist many primary interferences within a room, such as cell-phones, Bluetooth devices, TV signals, cordless phones and WiFi devices. In order to reduce the interference from our proposed RFID network for these primary devices, we have proposed a cooperating underlay RFID cognitive network for our smart application on water. These underlay RFIDs should strictly adhere to the interference thresholds to work in parallel with the primary wireless devices [2]. This work is an extension of our previous ventures proposed in [2,3], and we enhanced the previous efforts by introducing a new system model and RFIDs. Our proposed scheme is mutually energy efficient and maximizes the signal-to-noise ratio (SNR) for the RFID link, while keeping the interference levels for the primary network below a certain threshold. A closed form expression for the probability density function (pdf) of the SNR at the destination reader/writer and outage probability are derived. Analytical results are verified through simulations. It is also shown that in comparison to non-cognitive selective cooperation, this scheme performs better in the low SNR region for cognitive networks. Moreover, the hidden Markov model's (HMM) multi-level variant hierarchical hidden Markov model (HHMM) approach is used for pattern recognition and event detection for the data received for this system [4]. Using this model, a feedback and decision algorithm is also developed. This approach has been applied to simulated water pressure data from RFID motes, which were embedded in metallic water pipes. PMID- 25271566 TI - Electron transfer dissociation mass spectrometry of peptides containing free cysteine using group XII metals as a charge carrier. AB - Electron transfer dissociation (ETD) has been used for peptide sequencing. Since ETD preferentially produces the c'/z(*) fragment pair, peptide sequencing is generally performed by interpretation of mass differences between series of consecutive c' and z(*) ions. However, the presence of free cysteine residues in a precursor promotes peptide bond cleavage, hindering interpretation of the ETD spectrum. In the present study, the divalent group XII metals, such as Zn(2+), Cd(2+) and Hg(2+), were used as charge carriers to produce metal-peptide complexes. The thiol group is deprotonated by complexation with the group XII metal. The formation of b and y' ions was successfully suppressed by using the zinc-peptide complex as a precursor, indicating Zn(2+)-aided ETD to be a useful method for sequencing of cysteine-containing peptides. By contrast, ETD of Cd(2+) and Hg(2+)-peptide complexes mainly led to SH2 loss and radical cation formation, respectively. These processes were mediated by recombination energy between the metal cation and an electron. The presence of monovalent cadmium and neutral mercury in ETD products was confirmed by MS(3) analysis with collision induced dissociation. PMID- 25271567 TI - Photoinduced electron transfer in rhenium(I)-oligotriarylamine molecules. AB - Two molecular triads with an oligotriarylamine multielectron donor were synthesized and investigated with a view to obtaining charge-separated states in which the oligotriarylamine is oxidized 2-fold. Such photoinduced accumulation of multiple redox equivalents is of interest for artificial photosynthesis. The first triad was comprised of the oligotriarylamine and two rhenium(I) tricarbonyl diimine photosensitizers each of which can potentially accept one electron. In the second triad the oligotriarylamine was connected to anthraquinone, in principle an acceptor of two electrons, via a rhenium(I) tricarbonyl diimine unit. With nanosecond transient absorption spectroscopy (using an ordinary pump probe technique) no evidence for the generation of 2-fold oxidized oligotriarylamine or 2-fold reduced anthraquinone was found. The key factors limiting the photochemistry of the new triads to simple charge separation of one electron and one hole are discussed, and the insights gained from this study are useful for further research in the area of charge accumulation in purely molecular (nanoparticle-free) systems. An important problem of the rhenium-based systems considered here is the short wavelength required for photoexcitation. In the second triad, photogenerated anthraquinone monoanion is protonated by organic acids, and the resulting semiquinone species leads to an increase in lifetime of the charge-separated state by about an order of magnitude. This shows that the proton-coupled electron transfer chemistry of quinones could be beneficial for photoinduced charge accumulation. PMID- 25271568 TI - Quantum dynamics of the abstraction reaction of H with cyclopropane. AB - The dynamics of the abstraction reaction of H atoms with the cyclopropane molecule is studied using quantum mechanical scattering theory. The quantum scattering calculations are performed in hyperspherical coordinates with a two dimensional (2D) potential energy surface. The ab initio energy calculations are carried out with CCSD(T)-F12a/cc-pVTZ-F12 level of theory with the geometry and frequency calculations at the MP2/cc-pVTZ level. The contribution to the potential energy surface from the spectator modes is included as the projected zero-point energy correction to the ab initio energy. The 2D surface is fitted with a 29-parameter double Morse potential. An R-matrix propagation scheme is carried out to solve the close-coupled equations. The adiabatic energy barrier and reaction enthalpy are compared with high level computational calculations as well as experimental data. The calculated reaction rate constants shows very good agreement when compared with the experimental data, especially at lower temperature highlighting the importance of quantum tunnelling. The reaction probabilities are also presented and discussed. The special features of performing quantum dynamics calculation on the chemical reaction of a cyclic molecule are discussed. PMID- 25271569 TI - Prevalence of Arcobacter species among humans, Belgium, 2008-2013. AB - We examined fecal samples from 6,774 patients with enteritis in Belgium, 2008 2013. Members of the genus Arcobacter were the fourth most common pathogen group isolated, and the isolation rate was higher than previously reported. Culturing Arcobacter in a microbiology laboratory is feasible and should thus be tested for in cases of diarrheal disease. PMID- 25271570 TI - DNA-binding studies of a tetraalkyl-substituted porphyrin and the mutually adaptive distortion principle. AB - This investigation explores DNA-binding interactions of various forms of an alkyl substituted cationic porphyrin, H2TC3 (5,10,15,20-tetra[3-(3'-methylimidazolium 1'-yl)]porphyrin). The motivating idea is that incorporating alkyl rather than aryl substituents in the meso positions will enhance the prospects for intercalative as well as external binding to DNA hosts. The ligands may also be applicable for photodynamic and/or anticancer therapy. Methods employed include absorbance, circular dichroism, and emission spectroscopies, as well as viscometry and X-ray crystallography. By comparison with the classical H2T4 system, H2TC3 exhibits a higher molar extinction coefficient but is more prone to self-association. Findings of note include that the copper(II)-containing form Cu(TC3) is adept at internalizing into single-stranded as well as B-form DNA, regardless of the base composition. Surprisingly, however, external binding of H2TC3 occurs within domains that are rich in adenine-thymine base pairs. The difference in the deformability of H2TC3 versus Cu(TC3) probably accounts for the reactivity difference. Finally, Zn(TC3) binds externally, as the metal center remains five-coordinate. PMID- 25271571 TI - Nursing education: quality, innovation and accountability. PMID- 25271572 TI - [Teaching and learning in the clinical field: perspective of teachers, nurses and nursing students]. AB - This is a qualitative research, which used the social phenomenology of Alfred Schutz approach. Its purpose was meeting and discussing the expectations of teachers, nurses and students about teaching in the clinical field. Nine teachers, eleven nurses and eleven students of the Nursing Graduation grade from a public university of Sao Paulo were included in this study. Data were collected in 2012. As the results showed, there are expectations about the link between theory and practice that clinical teaching can offer and also the desire that such instruction enable the learners to develop a pro-active and participatory attitude. The reciprocity of perspectives was evident and should be considered when academic projects focused on nursing education are developed. PMID- 25271573 TI - [Analysis of teaching of the discipline Nursing in Surgical Center in schools of Sao Paulo]. AB - The study aimed to characterize the teaching of Nursing in Surgical Center in relation to work load, content and specific curriculum component; and to identify the perspectives and experiences of teachers in teaching this content. This is a descriptive study of quantitative and qualitative approach, that used a semi structured instrument for data collection, with questions related to teaching discipline, sent by email to the coordinators of the courses of Bachelor of Nursing from 219 schools in the state of Sao Paulo, registered in the website of the Brazilian Ministry of Education. Of the 52 respondents, 90.4% were from private schools, mostly located in the interior of the state (71.1%). From the total of courses, 53.8% ministered the content surgical center within another discipline. The median of content hours was of 64h (40-300h). The respondents commented on the extensive content for a small work load, both practical and theoretical, and its importance for the formation of the generalist nurse. PMID- 25271574 TI - [Inter-organizational relationship in the integration teaching-nursing service at the primary health care]. AB - This study aimed to characterize the stages of the inter-organizational relationships between educational and caring aspects of Nursing, operating in the context of primary health care in a municipality of Santa Catarina, Brazil. The qualitative approach of the case study was used by deliberately selecting the cooperation between two organizations. Eight teaching nurses and eight assistant nurses were interviewed. The data were submitted to content analysis, and the results demonstrated a number of elements in the phases of interaction (negotiation, commitment and execution of activities), as well as the variability of their content over time. It was concluded that the interaction, at an operational level, is characterized by dynamics that happen during relationship cycles, usually spanning through the school-semester, producing new negotiations and commitments for the following semester. PMID- 25271575 TI - [Educational game of medication administration: a validation study]. AB - This is a methodological research, which aimed to determine the validity of an educational technology (ET) in the form of educational game of medicine administration, according to the judges and audience, using the theoretical stage of Pasquali model. Data were collected between September 2011 and May 2012 in two stages: 1) application and validation of TE by forty students of the 4th period of Nursing, at the Fluminense Federal University (target audience); 2) observation and validation of TE by 8 teachers (judges). The questionnaires were organized in Likert scale, with items distributed in blocks and analyzed quantitatively. The game was validated, since it has over 80% approval by the two groups, and may therefore be used as a TE in the discipline of Fundamentals of Nursing. The results were positive, demonstrating that students and teachers are more interested in content taught when most dynamic technologies are used in the classroom. PMID- 25271576 TI - [Project HOPE contribution to the setting up of the professional identity of the first nurses from Alagoas, 1973-1977]. AB - Social-historical study conducted to examine the contribution of the American Nurses of Project HOPE to the configuration of the professional identity of the first trained nurses in Alagoas, in the period of 1973-1977. The theoretical framework was the "Civilizing Process" of Norbert Elias. Primary sources were official documents and personal files of 13 respondents by oral history; the secondary sources were authors of the History of Brazil/Alagoas. Data analysis showed that the configuration of the professional identity of the first trained nurses in Alagoas was a civilizing process, with all the nuances that make up the power relations. There was a significant contribution of American Nursing. However the movement of resistance to this domination was very strong, resulting in a Course that could take advantage of technological advancement and prestige brought by the United States, to build a unique Nursing from the social fabric embroidery at this meeting with so many different cultures. PMID- 25271577 TI - [Change in glomerular filtration rate in hypertensive patients in Vitoria-ES]. AB - As monitoring of renal function, it is used the estimation of glomerular filtration rate (GFR). This study aimed to estimate the GFR by means of the Cockcroft-Gault equation in hypertensive patients in the Municipality of Vitoria ES. It is a transversal study of secondary data with 754 hypertensive patients attended in health facilities in 2009. For statistical analysis, there has been used the chi-square test. The female sex, overweight and uncontrolled blood pressure predominated. The average age was 58.18 years (+/- 13.52) and the serum creatinine (SCr) 0.81 mg / dl (+/- 0.28). The prevalence of reduced GFR was 19% when from 30 to 59 ml/min and 1.6% when from 29 to 15 ml/min. The prevalence of reduced GFR was 15 times higher in the elderly, 4.93 times higher in those with elevated SCr, 2.19 times in low-weight hypertensives and 1.6 times more prevalent in men. The study showed the importance of monitoring renal function with a view to early intervention and postponement of kidney function loss in hypertensive patients. PMID- 25271578 TI - [Adherence of hypertensive patients to drug treatment]. AB - This is a descriptive, cross-sectional study, conducted in a center of Hypertension and Metabolism, which aimed to identify adherence to drug therapy in hypertensive patients, and to identify the factors, directly related to the patient, associated with this adherence. The sample consisted of 77 patients and the instrument used to verify patient compliance was the Measure of Adherence to Treatment and a semi-structured questionnaire consisting of factors for non adherence to drug treatment. The results showed adherence of 87% of hypertensive patients. Factors directly related to the patient, which were associated with the adherence, were: the place of origin; patients' self-assessment of blood pressure levels; willingness to abandon treatment and patient acceptance of the disease. PMID- 25271579 TI - [Adherence and difficulties related to drug treatment in patients with depression]. AB - This research verified adherence and knowledge of people with depression regarding prescribed pharmacotherapy, satisfaction with the health team and difficulties related to drug treatment. This is descriptive and cross-sectional study, with quail-quantitative approach. The study included 27 people assisted in an outpatient clinic in the interior of the state of Sao Paulo - Brazil. Data were collected through semi-structured interviews and review of medical records and analyzed using descriptive statistics and content analysis. It was found that 29.6% of patients were no adherent to medication and 51.9% were unaware of the dose of prescribed drugs. Impact of drug therapy in depressive symptoms on self care, dissatisfaction with effects of psychoactive drugs, lack of support, use of multiple medications and lack of knowledge about the disorder and treatment were reported as difficulties in following drug therapy. This study shows critical factors to the promotion of patient safety in following drug therapy. PMID- 25271580 TI - [Administration of medication to use when needed and the care of psychiatric nursing]. AB - This qualitative study aimed to analyze the clinical criteria used for the administration of prescribed medications for use when needed (SOS); and discuss the implication of the findings in this research to clinical psychiatric nursing. The records of female patients admitted to a psychiatric institution in the city of Rio de Janeiro, in the time frame from May to June 2009, were analyzed. In the 38 patient records, 16 prescriptions for medications SOS were found. The mean age of patients was around 45-55 years with a clinical diagnosis of Bipolar Mood Disorder. The medication category most prescribed as SOS was of benzodiazepines, followed by antipsychotics. It was noticed a tendency to not valuing the administration of medication in SOS notes. The study points out the importance to establish clinical criteria to indicate the need, or not, to administer prescribed SOS medications. PMID- 25271581 TI - [Systematized care in cardiac preoperative: theory of human caring in the perspective of nurses and users]. AB - This is a case study research that aimed to know, with the adoption of the Theory of Human Caring, the meanings of therapeutic interpersonal relationship between nurse and user on the preoperative nursing visit after the experience of the surgical process. The convenience sample was composed of three nurses and three users of an institution that has updated records to perform highly complex cardiovascular surgery, comprising nine combinations of therapeutic interactions. It was used instruments, structured according to the theory of Jean Watson and North American Nursing Diagnosis Association, Nursing Intervention Classification and Nursing Outcomes Classification taxonomies. The legal and ethical aspects of research involving human subjects were assured. The results revealed three clusters to grasp the significance of preoperative visits by users and five clusters to capture the perception of nurses when they experience this clinical experience. PMID- 25271582 TI - [Protocol for embracement and attention to users that underwent upper gastrointestinal endoscopy and persons accompanying them]. AB - This is a quantitative and qualitative research aimed at building a Welcome Protocol for users and their companions referred to the Endoscopic Centre at the University Hospital Dr. Polydoro Ernani Sao Thiago, at the Federal University of Santa Catarina (UFSC), and submitted to Upper Digestive Endoscopy. The research was elaborated in two stages. The first stage was the building of a collective protocol with a group of nurses; the second stage was the sending of this material, organized as a protocol, for validation by the three experts. The study's supporting theoretical background was the National Humanization Policy and the Basic Human Needs theory. The protocol built aims at detailing the procedures conducted in the pre, trans and post-endoscopy exam stages, permitting the organization of the service and the instrumentalization of the professional team and, thus, ensuring a safer welcome and service to the user and his/her companion. PMID- 25271583 TI - [Validation of an instrument for assessing the ability of blood pressure measurement]. AB - This study aimed to validate an instrument for evaluation the ability of nursing students to measure the blood pressure. It is a methodological study, developed with 27 nurses, teachers of semiology and/or semiotic disciplines, with at least 1 year of experience in disciplines, which acted as judges of the study. It was accomplished in two steps: first, a review of the literature to build the checklist instrument and subsequent submission for content validation by applying the Kappa, accepting the value > 0.61 (good level); and second, it was accomplished a Content Validity Index (CVI) > 0.75. Based on the literature review, 28 items were included in the checklist, with all of them showing Kappa index and CVI accepted for content validity, and nine of those items needed changes. The instrument can be considered valid in its content, with all its items being considered appropriate separately, as well as globally. PMID- 25271584 TI - [International Nursing Minimum Data Set: a comparative study with tools of a pediatric clinic]. AB - Descriptive and comparative study, developed from two historical used to implement the Systematization of Nursing Care in a Pediatric clinic of a teaching hospital. It aimed to compare the International Nursing Minimum Data Set (i-NMDS) with the data contained in nursing clinical assessment tools that are used in the application of the Nursing Process in the area of Children and Teenagers Health in a Pediatric Clinic. From the sixteen items evaluated that belong to the proposal of the i-NMDS, the nursing clinical assessment tool for hospitalized teenagers included 12 (75%), while the instrument for children from 0 to 5 years old presented 7 (43.75%). It was concluded that the nursing clinical assessment tools analyzed did not include the i-NMDS data in its entirety. It is suggested that there should be an improvement on the development of the nursing clinical assessment tools, using standardized nursing language for planning assistance, documenting activities, identify and measure the results of practice. PMID- 25271585 TI - [Preterm infants: breastfeeding and weight gain]. AB - The objective was to identify factors associated with the practice of breastfeeding (BF), weight gain and nutritional status of preterm infants during the first six months of life and verify the relationship between these variables and maternal and neonatal characteristics. Analytical studies, cohort, performed with 42 preterm infants born between May and October 2008. The prevalence of BF was 40.5% at six months and mean weight gain ranged between 18 and 40 g/day. The practice of BF was associated with lower weight and lower gestational age at birth. Weight gain was positively correlated with gestational age and birth weight, maternal age and the practice of breastfeeding at 15 days after discharge. Being premature has not stopped the practice of BF; however, weight gain was higher among those born with better growth and maturation in utero. PMID- 25271586 TI - [Old age for adolescents: a social representations approach]. AB - Qualitative research, based on the Theory of Social Representations, which aimed to apprehend the social representations of teenagers in a public school and a private on ageing, and to compare them between these two groups. Participants were 60 adolescents, 30 from the private school and 30 from the public school, who responded to semi-structured interviews in the period May-June 2012. The collected data were subjected to content analysis techniques, from which emerged three categories, namely: representations of ageing, the treatment of the elderly, and the recognition of oneself as a subject in the aging process. The adolescents' social representations have showed negative and positive aspects in relation to old age, marked by the influence of socio-cultural aspects. PMID- 25271587 TI - [Institutionalized elderly: chronological organization of daily routines and sleep quality]. AB - This is a descriptive cross-sectional study, which aimed to identify the perception of nursing home elderly residents related to the chronological organization of their daily routines and to their sleep quality. The study was conducted with 37 elderly (14 women and 23 men, mean age of 75 years) who lived in a long term care facility located in the municipality of Campinas-SP, Brazil. The results showed that 81% of the elderlies had complaints compatible with poor sleep, but 70% of them reported that they had good sleep quality when directly questioned about it. All elderlies adequately realized the chronological organization of their routines, but this perception did not appear to contribute to the good sleep quality, as most of them had complaints compatible with poor sleep. It becomes evident that nurses should perform detailed assessment of sleep quality in order to minimize or prevent these problems and their possible consequences. PMID- 25271588 TI - [Walking performance of elderly practitioners of psychomotricity]. AB - Quasi-experimental study conducted with fifteen elderlies, developed at the Physiotherapy Clinical School, Federal University of Paraiba, in 2011. The study aimed to evaluate the performance of gait in elderly practitioners of psychomotor activities. It was conducted a structured interview focusing on social, clinical and functional data, in order to be able to correlate various information which supported the aim of the study. The average cognitive performance was 19.4 at the first assessment and 23.2 in the second. The average performance of activities related to the gait was 11.6 at the first assessment, and 15.5 in the second, after the practice of psychomotor activities. It was found a significant improvement in the performance of activities related to the gait, with irregularities persisting in height and continuity of the step, as well as in the midline deviation. PMID- 25271589 TI - [Fatigue in the elderly undergoing chemotherapy]. AB - This is a cross-sectional survey conducted from August to December 2010, which aimed to identify the presence and severity of fatigue in 140 elderly (mean age 69.8 years, 52.1% female) diagnosed with cancer undergoing chemotherapy in an outpatient unit. It was used a questionnaire for sociodemographic and clinical data and Piper Fatigue Scale-revised. The presence of fatigue was identified in 60 elderly (42.9%) and the attributed cause was cancer (64.1%), chemotherapy (32.8%) and treatment (3.1%). As relief factors, the elderly respondents reported "sleeping", "pray" and "dying", while 45% of them said "there was nothing to do" because fatigue could not be relieved. We hope that this study will alert the nurses to the relevance of fatigue and encourage them to identify and carry out nursing interventions aimed at proper management of this symptom in elderly cancer patient. PMID- 25271590 TI - [Use of musical experiences as therapy for symptoms of nausea and vomiting in chemotherapy]. AB - The study aimed to evaluate the therapeutic effects of musical experiments in nausea and vomiting associated with antineoplastic chemotherapy, and to identify changes in vital parameters of the patients who participated in the experience. This is a descriptive, transversal study, level II, which used a quantitative approach, conducted with thirteen patients from an outpatient chemotherapy unit, of a private hospital in Sao Paulo City. Two instruments were used, one of them proposed by MASCC (Multinational Association on Supportive Care in Cancer). The participants were predominantly females, aged 40 to 60 years, married and with breast cancer. Heart rate has decreased in 77% of the sample, and the reduction of nausea occurred in 100% of patients after the first musical experience, and in 85% after the second one. Patients reported disbelief in music in relieving nausea and vomiting before the sessions, and relief of nausea after them. It was concluded that there was a statistically significant reduction of the symptoms nausea and vomiting after the musical experiences. PMID- 25271591 TI - [Incorporation of controlling dengue by community health agent]. AB - The purpose of this study was to identify self-perceived differences in the work processes of community health agents (CHA) in two counties of Mato Grosso do Sul, regarding dengue control and Family Health Strategy (FHS) activities. Structured interviews were applied to 57 CHA. The subjects had similar sociodemographic characteristics. Agents in Rio Verde de Mato Grosso county, who performed only FHS tasks, failed to complete essential data of the Form A. In Sao Gabriel do Oeste county, CHA currently perform tasks pertaining to dengue fever control, previously conducted by Endemic Disease Control Agents (now abolished), while in Rio Verde de Mato Grosso county, dengue control remained assigned to the latter group. In Sao Gabriel do Oeste county, CHA did not view the double workload of two programs as affecting their professional productivity. The pooling of tasks from the two programs proved to be feasible, with no detrimental effects on performance. PMID- 25271592 TI - [Not Available]. PMID- 25271593 TI - Polyhalogenated carbazoles in sediments of Lake Michigan: a new discovery. AB - Previously unknown halogenated compounds were detected during the analysis of halogenated flame retardants in two sediment cores collected from Lake Michigan. Gas chromatography coupled with high- or low-resolution mass spectrometry (MS) was used to determine the chemical structures for a total of 15 novel polyhalogenated carbazoles (PHCs) with the general molecular formula C12H9-x-y zNClxBryIz. On the basis of the mass spectra generated by electron impact (EI) and electron capture negative ionization (ECNI) MS, eight PHCs were tentatively identified as polybrominated carbazoles, while the others were mixed halogenated carbazoles containing, in addition to bromine, either chlorine or iodine or both. Patterns of halogen substitution of PHCs included Br2 to Br5, ClBr2, ClBr3, ClBr4, ClBr3I, Br4I, and Br3I2. 3,6-Dibromocarbazole and 1,3,6,8 tetrabromocarbazole were also found among the PHCs. Profiles of the concentration versus depth of sediment at the two sites showed various patterns among polybrominated carbazoles. The abundance of mixed halogenated carbazoles peaked at depths of 12-16 cm, remained at relatively constant levels in deeper sediment, but declined markedly in more recently deposited sediments. This is the first study discovering the seven mixed halogenated carbazoles in the environment. Detailed methods for their detection and identification are provided. PMID- 25271594 TI - Pulmonary disease caused by Mycobacterium marseillense, Italy. PMID- 25271596 TI - The indirect costs of psoriatic arthritis: systematic review and meta-analysis. AB - The aim of this systematic review is to collect all current data on the indirect costs (IC) related to psoriatic arthritis (PsA). The search was conducted using MEDLINE (via PubMed), Embase and Centre for Reviews and Dissemination databases. We considered original studies, systematic reviews, economic evaluations, conference abstracts and posters. All collected data were recalculated to average annual cost per patient, expressed using the consumer price index for 2013 and converted to US dollars using purchasing power parity. Eight of the identified publications presented IC of PsA. Average annual IC per patient calculated using the friction cost approach range from US$1693.83 to $12,318.45, while using the human capital approach they range from US$1750.68 to $50,270.52. Result of the meta-analysis was a basis for calculating cost of work disability equaled US$10,754.04 per patient per year in 2013 prices. This systematic review revealed a great economic burden of the disease to the society. A small number of studies on IC in PsA justify further investigations. PMID- 25271597 TI - Quantifying and communicating peri-operative risk. PMID- 25271595 TI - Effects of L-carnitine, erythritol and betaine on pro-inflammatory markers in primary human corneal epithelial cells exposed to hyperosmotic stress. AB - PURPOSE: To explore the effects of osmoprotectants on pro-inflammatory mediator production in primary human corneal epithelial cells (HCECs) exposed to hyperosmotic stress. METHODS: HCECs cultured in iso-osmolar medium (312 mOsM) were switched to hyperosmotic media with or without prior incubation with 2-20 mM of l-carnitine, erythritol or betaine for different time periods. The mRNA expression and protein production of pro-inflammatory markers in HCECs were evaluated by RT-qPCR and ELISA. RESULTS: Hyperosmolar media significantly stimulated the mRNA and protein expression of pro-inflammatory cytokines, TNF alpha, IL-1beta and IL-6, and chemokines, IL-8, CCL2 and CCL20 in HCECs in an osmolarity dependent manner. The stimulated expression of these pro-inflammatory mediators was significantly but differentially suppressed by l-carnitine, erythritol or betaine. l-Carnitine displayed the greatest inhibitory effects and down-regulated 54-77% of the stimulated mRNA levels of TNF-alpha (down from 12.3 5.7 fold), IL-1beta (2.2-0.9 fold), IL-6 (7.3-2.9 fold), IL-8 (4.6-2.0 fold), CCL2 (15.3-3.5 fold) and CCL20 (4.1-1.5 fold) in HCECs exposed to 450 mOsM. The stimulated protein production of TNF-alpha, IL-1beta, IL-6 and IL-8 was also significantly suppressed by l-carnitine, erythritol and betaine. l-carnitine suppressed 49-79% of the stimulated protein levels of TNF-alpha (down from 81.3 to 17.4 pg/ml), IL-1beta (56.9-29.2 pg/ml), IL-6 (12.8-4.6 ng/ml) and IL-8 (21.2 10.9 ng/ml) by HCECs exposed to 450 mOsM. Interestingly, hyperosmolarity stimulated increase in mRNA and protein levels of TNF-alpha, IL-1beta and IL-6 were significantly suppressed by a transient receptor potential vanilloid channel type 1 (TRPV1) activation inhibitor capsazepine. CONCLUSIONS: l-carnitine, erythritol and betaine function as osmoprotectants to suppress inflammatory responses via TRPV1 pathway in HCECs exposed to hyperosmotic stress. Osmoprotectants may have efficacy in reducing innate inflammation in dry eye disease. PMID- 25271598 TI - Potential mental health needs of US adult residents under different provisions of the Affordable Care Act. AB - OBJECTIVE: This study examined different groups of the US population who may be affected by the expansion of Medicaid and creation of health insurance exchanges under the Affordable Care Act (ACA). METHOD: Data were based on structured interviews with a nationally representative sample of 34,587 adults from the 2004 2005 Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Psychiatric diagnoses were assessed with the Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV. RESULTS: Of the total sample, 6.4% were currently on Medicaid; 3.9% were uninsured and likely eligible for the Medicaid expansion (LEME); 8.6% were uninsured and not LEME but likely to participate in the health insurance exchanges; 4.6% were insured and LEME; and 76.6% were insured and not LEME. Among those uninsured, those LEME had a significantly higher prevalence of mood and anxiety disorders than those not LEME (odds ratios = 1.26-1.41). Among those insured, those LEME had a higher prevalence of mood, anxiety, substance use, and personality disorders than those not LEME (odds ratios = 1.78-2.41). Although there were few clinical differences between those currently on Medicaid and those LEME, those currently on Medicaid were more likely to use all types of services for mood, anxiety, and substance use disorders. CONCLUSIONS: The ACA may directly affect the 12.5% of the US adult population who are uninsured by requiring them to obtain insurance coverage. Given the high prevalence for various psychiatric disorders among those uninsured, state plans to expand Medicaid and create health insurance exchanges have potential to offer coverage to many adults with mental health needs, and states should carefully plan for comprehensive services. PMID- 25271599 TI - Time after time--health policy implications of a three-generation case study. PMID- 25271600 TI - Rethinking the social history. PMID- 25271601 TI - Swimming against the current--what might work to reduce low-value care? PMID- 25271602 TI - Introduction of gluten, HLA status, and the risk of celiac disease in children. AB - BACKGROUND: The relationship between the risk of celiac disease and both the age at which gluten is introduced to a child's diet and a child's early dietary pattern is unclear. METHODS: We randomly assigned 832 newborns who had a first degree relative with celiac disease to the introduction of dietary gluten at 6 months (group A) or 12 months (group B). The HLA genotype was determined at 15 months of age, and serologic screening for celiac disease was evaluated at 15, 24, and 36 months and at 5, 8, and 10 years. Patients with positive serologic findings underwent intestinal biopsies. The primary outcome was the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age. RESULTS: Of the 707 participants who remained in the trial at 36 months, 553 had a standard-risk or high-risk HLA genotype and completed the study. At 2 years of age, significantly higher proportions of children in group A than in group B had celiac disease autoimmunity (16% vs. 7%, P=0.002) and overt celiac disease (12% vs. 5%, P=0.01). At 5 years of age, the between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P=0.59) or overt disease (16% and 16%, P=0.78 by the log-rank test). At 10 years, the risk of celiac disease autoimmunity was far higher among children with high-risk HLA than among those with standard-risk HLA (38% vs. 19%, P=0.001), as was the risk of overt celiac disease (26% vs. 16%, P=0.05). Other variables, including breast-feeding, were not associated with the development of celiac disease. CONCLUSIONS: Neither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease. (Funded by the Fondazione Celiachia of the Italian Society for Celiac Disease; CELIPREV ClinicalTrials.gov number, NCT00639444.). PMID- 25271603 TI - Randomized feeding intervention in infants at high risk for celiac disease. AB - BACKGROUND: A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled dietary intervention study involving 944 children who were positive for HLA-DQ2 or HLA DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age. RESULTS: Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention. CONCLUSIONS: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.). PMID- 25271604 TI - Provision of no-cost, long-acting contraception and teenage pregnancy. AB - BACKGROUND: The rate of teenage pregnancy in the United States is higher than in other developed nations. Teenage births result in substantial costs, including public assistance, health care costs, and income losses due to lower educational attainment and reduced earning potential. METHODS: The Contraceptive CHOICE Project was a large prospective cohort study designed to promote the use of long acting, reversible contraceptive (LARC) methods to reduce unintended pregnancy in the St. Louis region. Participants were educated about reversible contraception, with an emphasis on the benefits of LARC methods, were provided with their choice of reversible contraception at no cost, and were followed for 2 to 3 years. We analyzed pregnancy, birth, and induced-abortion rates among teenage girls and women 15 to 19 years of age in this cohort and compared them with those observed nationally among U.S. teens in the same age group. RESULTS: Of the 1404 teenage girls and women enrolled in CHOICE, 72% chose an intrauterine device or implant (LARC methods); the remaining 28% chose another method. During the 2008-2013 period, the mean annual rates of pregnancy, birth, and abortion among CHOICE participants were 34.0, 19.4, and 9.7 per 1000 teens, respectively. In comparison, rates of pregnancy, birth, and abortion among sexually experienced U.S. teens in 2008 were 158.5, 94.0, and 41.5 per 1000, respectively. CONCLUSIONS: Teenage girls and women who were provided contraception at no cost and educated about reversible contraception and the benefits of LARC methods had rates of pregnancy, birth, and abortion that were much lower than the national rates for sexually experienced teens. (Funded by the Susan Thompson Buffett Foundation and others.). PMID- 25271605 TI - Microcytic anemia. PMID- 25271606 TI - Images in clinical medicine. Chronic obstructive pyelonephritis. PMID- 25271607 TI - Clinical problem-solving. Against the grain. PMID- 25271608 TI - The missing environmental factor in celiac disease. PMID- 25271609 TI - Targeting the inflammatory response in tuberculosis. PMID- 25271610 TI - Exemestane with ovarian suppression in premenopausal breast cancer. PMID- 25271611 TI - Exemestane with ovarian suppression in premenopausal breast cancer. PMID- 25271612 TI - Exemestane with ovarian suppression in premenopausal breast cancer. PMID- 25271613 TI - Exemestane with ovarian suppression in premenopausal breast cancer. PMID- 25271614 TI - Evidence for camel-to-human transmission of MERS coronavirus. PMID- 25271615 TI - Evidence for camel-to-human transmission of MERS coronavirus. PMID- 25271616 TI - Case 18-2014: A man with a rash, myalgia, and weakness. PMID- 25271617 TI - Case 18-2014: A man with a rash, myalgia, and weakness. PMID- 25271618 TI - Anticoagulation for central venous catheters in patients with cancer. PMID- 25271620 TI - Images in clinical medicine. Evolving infarction in the anterior circulation. PMID- 25271622 TI - Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials. PMID- 25271621 TI - Cholestenoic acids regulate motor neuron survival via liver X receptors. AB - Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3beta,7alpha-dihydroxycholest-5-en-26-oic acid (3beta,7alpha-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3beta-hydroxy-7-oxocholest-5-en-26-oic acid (3betaH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3beta,7alpha-diHCA and 3betaH,7O-CA, 3beta hydroxycholest-5-en-26-oic acid (3beta-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3beta-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3beta,7alpha diHCA. Moreover, 3beta,7alpha-diHCA prevented the loss of motor neurons induced by 3beta-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death. PMID- 25271623 TI - VEGF-C and aortic cardiomyocytes guide coronary artery stem development. AB - Coronary arteries (CAs) stem from the aorta at 2 highly stereotyped locations, deviations from which can cause myocardial ischemia and death. CA stems form during embryogenesis when peritruncal blood vessels encircle the cardiac outflow tract and invade the aorta, but the underlying patterning mechanisms are poorly understood. Here, using murine models, we demonstrated that VEGF-C-deficient hearts have severely hypoplastic peritruncal vessels, resulting in delayed and abnormally positioned CA stems. We observed that VEGF-C is widely expressed in the outflow tract, while cardiomyocytes develop specifically within the aorta at stem sites where they surround maturing CAs in both mouse and human hearts. Mice heterozygous for islet 1 (Isl1) exhibited decreased aortic cardiomyocytes and abnormally low CA stems. In hearts with outflow tract rotation defects, misplaced stems were associated with shifted aortic cardiomyocytes, and myocardium induced ectopic connections with the pulmonary artery in culture. These data support a model in which CA stem development first requires VEGF-C to stimulate vessel growth around the outflow tract. Then, aortic cardiomyocytes facilitate interactions between peritruncal vessels and the aorta. Derangement of either step can lead to mispatterned CA stems. Studying this niche for cardiomyocyte development, and its relationship with CAs, has the potential to identify methods for stimulating vascular regrowth as a treatment for cardiovascular disease. PMID- 25271624 TI - Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection. AB - Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS (31P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with 1H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity. PMID- 25271625 TI - Neuropilin-1 mediates myeloid cell chemoattraction and influences retinal neuroimmune crosstalk. AB - Immunological activity in the CNS is largely dependent on an innate immune response and is heightened in diseases, such as diabetic retinopathy, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. The molecular dynamics governing immune cell recruitment to sites of injury and disease in the CNS during sterile inflammation remain poorly defined. Here, we identified a subset of mononuclear phagocytes (MPs) that responds to local chemotactic cues that are conserved among central neurons, vessels, and immune cells. Patients suffering from late-stage proliferative diabetic retinopathy (PDR) had elevated vitreous semaphorin 3A (SEMA3A). Using a murine model, we found that SEMA3A acts as a potent attractant for neuropilin-1-positive (NRP-1-positive) MPs. These proangiogenic MPs were selectively recruited to sites of pathological neovascularization in response to locally produced SEMA3A as well as VEGF. NRP-1 positive MPs were essential for disease progression, as NRP-1-deficient MPs failed to enter the retina in a murine model of oxygen-induced retinopathy (OIR), a proxy for PDR. OIR mice with NRP-1-deficient MPs exhibited decreased vascular degeneration and diminished pathological preretinal neovascularization. Intravitreal administration of a NRP-1-derived trap effectively mimicked the therapeutic benefits observed in mice lacking NRP-1-expressing MPs. Our findings indicate that NRP-1 is an obligate receptor for MP chemotaxis, bridging neural ischemia to an innate immune response in neovascular retinal disease. PMID- 25271626 TI - Prostanoid induces premetastatic niche in regional lymph nodes. AB - The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2-derived prostaglandin E2 (PGE2) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell-derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE2 receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. Compared with WT CD11c+ DCs, injection of EP3-deficient CD11c+ DCs dramatically reduced accumulation of SDF-1+CD11c+ DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, which may influence the fate of metastasized tumor cells, was also COX-2/EP3-dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1 and suggest that inhibition of this signaling axis may be an effective strategy to suppress premetastatic niche formation and LNM. PMID- 25271627 TI - HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial. AB - BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5 seronegative subjects were randomized to receive 2 * NYVAC-B followed by 1 * 1010 PFU rAd5 (NYVAC/Ad5hi); 1 * 108 PFU rAd5 followed by 2 * NYVAC-B (Ad5lo/NYVAC); 1 * 109 PFU rAd5 followed by 2 * NYVAC-B (Ad5med/NYVAC); 1 * 1010 PFU rAd5 followed by 2 * NYVAC-B (Ad5hi/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-gamma and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4+ T cell response rates ranged from 42.9% to 93.3%. NYVAC/Ad5hi response rates (P <= 0.01) and magnitudes (P <= 0.03) were significantly lower than those of other groups. CD8+ T cell response rates ranged from 65.5% to 85.7%. NYVAC/Ad5hi magnitudes were significantly lower than those of other groups (P <= 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5hi and 21.4%, 84.6%, and 100% for Ad5lo/NYVAC, Ad5med/NYVAC, and Ad5hi/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5med/NYVAC and Ad5hi/NYVAC than for NYVAC/Ad5hi. CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies. TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883. FUNDING. NIAID, NIH UM1AI068618, AI068635, AI068614, and AI069443. PMID- 25271628 TI - TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen. AB - The transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) controls differentiation of long-lived plasma cells, and almost 10% of individuals with common variable immunodeficiency (CVID) express either the C104R or A181E variants of TACI. These variants impair TACI function, and TACI deficient mice exhibit a CVID-like disease. However, 1%-2% of normal individuals harbor the C140R or A181E TACI variants and have no outward signs of CVID, and it is not clear why TACI deficiency in this group does not cause disease. Here, we determined that TACI-deficient mice have low baseline levels of Ig in the blood but retain the ability to mutate Ig-associated genes that encode antigen-specific antibodies. The antigen-specific antibodies in TACI-deficient mice were produced in bursts and had higher avidity than those of WT animals. Moreover, mice lacking TACI were able to clear Citrobacter rodentium, a model pathogen for severe human enteritis, more rapidly than did WT mice. These findings suggest that the high prevalence of TACI deficiency in humans might reflect enhanced host defense against enteritis, which is more severe in those with acquired or inherited immunodeficiencies. PMID- 25271629 TI - IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction. AB - The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1-/- mice had higher airway responsiveness. Tracheal rings from Iqgap1-/- mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1-/ mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1-/- trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma. PMID- 25271630 TI - The actin-sequestering protein thymosin beta-4 is a novel target of hypoxia inducible nitric oxide and HIF-1alpha regulation. AB - The actin-sequestering protein thymosin beta-4 (Tbeta4) is involved in various cellular and physiological processes such as proliferation, motility, growth and metastasis. Nitric oxide (NO) promotes tumor invasiveness and metastasis by activating various enzymes. Herein, we investigated whether hypoxia-inducible NO regulates Tbeta4 expression and cancer cell migration using HeLa cervical cancer cells. NO production and Tbeta4 expression were increased in a hypoxic condition. The treatment with N-(beta-D-Glucopyranosyl)-N2-acetyl-S-nitroso-D, L penicillaminamide (SNAP-1), to generate NO, enhanced the transcription of Tbeta4 and cancer cell migration. SNAP-1-induced cell migration was decreased by the inhibition of Tbeta4 with small interference (si) RNA. In a hypoxic condition, treatment with N(G)-monomethyl-L-arginine (L-NMMA), nitric oxide synthase (NOS) inhibitor, reduced Tbeta4 transcriptional activity, and hypoxia-inducible factor (HIF)-1alpha. Hypoxia-induced cancer cell migration was also decreased by L-NMMA treatment. In a normoxic condition, Tbeta4 transcriptional activity was decreased in the cells incubated in the presence of L-NMMA after co-transfection with Tbeta4 promoter and GST-conjugated HIF-1alpha. Collectively, these results suggest that NO could regulate the expression of Tbeta4 by direct or indirect effect of HIF-1alpha on Tbeta4 promoter. PMID- 25271631 TI - BosR functions as a repressor of the ospAB operon in Borrelia burgdorferi. AB - The Lyme disease spirochete, Borrelia burgdorferi, must abundantly produce outer surface lipoprotein A (OspA) in the tick vector but downregulate OspA in mammals in order to evade the immune system and maintain its natural enzootic cycle. Here, we show that BosR binds two regulatory elements of the ospAB operon and that increasing BosR expression leads to downregulation of OspA. Both regulatory sequences, cisI and cisII, showed strong BosR-binding and cisII bound much tighter than cisI. A promoterless bosR gene fused with an inducible promoter was introduced into an rpoS mutant and a wild-type strain to assess RpoS-independent and -dependent downregulation of OspA by BosR. With the induction of BosR expression, OspA expression was reduced more significantly in the RpoS-deficient than wild-type background, but not completely repressed. In the presence of constitutive expression of OspC, DbpA and DbpB, increasing BosR production resulted in complete repression of OspA in the RpoS mutant. Taken together, the study clearly demonstrated BosR serves as a repressor that binds both regulatory elements of the ospAB operon and shuts off expression. PMID- 25271632 TI - Peroxidase-like catalytic activity of Ag3PO4 nanocrystals prepared by a colloidal route. AB - Nearly monodispersed Ag3PO4 nanocrystals with size of 10 nm were prepared through a colloidal chemical route. It was proven that the synthesized Ag3PO4 nanoparticles have intrinsic peroxidase-like catalytic activity. They can quickly catalyze oxidation of the peroxidase substrate 3, 3, 5, 5-tetramethylbenzidine (TMB) in the presence of H2O2, producing a blue color. The catalysis reaction follows Michaelis-Menten kinetics. The calculated kinetic parameters indicate a high catalytic activity and the strong affinity of Ag3PO4 nanocrystals to the substrate (TMB). These results suggest the potential applications of Ag3PO4 nanocrystals in fields such as biotechnology, environmental chemistry, and medicine. PMID- 25271633 TI - Olfactory dysfunction predicts 5-year mortality in older adults. AB - Prediction of mortality has focused on disease and frailty, although antecedent biomarkers may herald broad physiological decline. Olfaction, an ancestral chemical system, is a strong candidate biomarker because it is linked to diverse physiological processes. We sought to determine if olfactory dysfunction is a harbinger of 5-year mortality in the National Social Life, Health and Aging Project [NSHAP], a nationally representative sample of older U.S. adults. 3,005 community-dwelling adults aged 57-85 were studied in 2005-6 (Wave 1) and their mortality determined in 2010-11 (Wave 2). Olfactory dysfunction, determined objectively at Wave 1, was used to estimate the odds of 5-year, all cause mortality via logistic regression, controlling for demographics and health factors. Mortality for anosmic older adults was four times that of normosmic individuals while hyposmic individuals had intermediate mortality (p<0.001), a "dose-dependent" effect present across the age range. In a comprehensive model that included potential confounding factors, anosmic older adults had over three times the odds of death compared to normosmic individuals (OR, 3.37 [95%CI 2.04, 5.57]), higher than and independent of known leading causes of death, and did not result from the following mechanisms: nutrition, cognitive function, mental health, smoking and alcohol abuse or frailty. Olfactory function is thus one of the strongest predictors of 5-year mortality and may serve as a bellwether for slowed cellular regeneration or as a marker of cumulative toxic environmental exposures. This finding provides clues for pinpointing an underlying mechanism related to a fundamental component of the aging process. PMID- 25271634 TI - Prevention of immune nephritis by the small molecular weight immunomodulator iguratimod in MRL/lpr mice. AB - OBJECTIVE: This study was performed to investigate the therapeutic effects of iguratimod in a lupus mouse model. METHODS: Female MRL/lpr mice were treated with iguratimod, vehicle solution or cyclophosphamide. Proteinuria was monitored and kidney injury was blindly scored by a renal pathologist. Serum anti-double stranded DNA antibodies were monitored by radioimmunoassay. Kidney IgG and CD20 were stained by immunohistochemistry. Splenic lymphocyte phenotypes were analyzed by flow cytometry. BAFF, IL-17A, IL-6, and IL-21 levels in serum and splenic lymphocytes were detected by ELISA or quantitative PCR. RESULTS: Compared with the vehicle-treated controls, MRL/lpr mice treated with iguratimod showed less protenuria, less acute pathological lesions and no chronic changes in the kidneys. There were significant differences in glomerular injury and vasculitis scores, as well as in the semi-quantitative analysis of immune complex deposition between the two groups. Disease activity markers in sera (anti-dsDNA antibodies and immunoglobulin levels) were reduced and hypocomplementemia was attenuated. Lymphocyte expression of BAFF, IL-6, IL-17A and IL-21 was decreased. The abnormal splenic B220+ T cell and plasma cell populations in MRL/lpr mice were reduced by iguratimod treatment, with recovery of the total B cell population and inhibition of B cell infiltration of the kidney tissue. The dosage of iguratimod used in this study showed no significant cytotoxic effects in vivo and no overt side effects were observed. CONCLUSION: Iguratimod ameliorates immune nephritis in MRL/lpr mice via a non-antiproliferative mechanism. Our data suggest a potential therapeutic role of iguratimod in lupus. PMID- 25271636 TI - Feeling what an insect feels. AB - We describe a manually operated, bilateral mechanical scaling instrument that simultaneously magnifies microscopic forces and reduces displacements with quasi perfect transparency. In contrast with existing micro-teleoperation designs, the system is unconditionally stable for any scaling gains and interaction curves. In the present realization, the work done by the hand is more than a million times that done by a microscopic probe so that one can feel complete interaction cycles with water and compare them to what is felt when an insect leg interacts with a wet surface. PMID- 25271635 TI - Immune suppressive effect of cinnamaldehyde due to inhibition of proliferation and induction of apoptosis in immune cells: implications in cancer. AB - BACKGROUND: Besides its anti-inflammatory effects, cinnamaldehyde has been reported to have anti-carcinogenic activity. Here, we investigated its impact on immune cells. METHODS: Activation of nuclear factor-kappaB by cinnamaldehyde (0 10 ug/ml) alone or in combination with lipopolysaccharide was assessed in THP1XBlue human monocytic cell line and in human peripheral blood mononuclear cells (PBMCs). Proliferation and secretion of cytokines (IL10 and TNFalpha) was determined in primary immune cells and the human cell lines (THP1, Jurkat E6-1 and Raji cell lines) stimulated with cinnamaldehyde alone or in conjunction with lipopolysaccharide. Nitric oxide was determined in mouse RAW264.7 cells. Moreover, different treated PBMCs were stained for CD3, CD20 and AnnexinV. RESULTS: Low concentrations (up to 1 ug/ml) of cinnamaldehyde resulted in a slight increase in nuclar factor-kB activation, whereas higher concentrations led to a dose-dependent decrease of nuclear factor-kB activation (up to 50%) in lipopolysachharide-stimulated THP1 cells and PBMCs. Accordingly, nitric oxide, interleukin 10 secretion as well as cell proliferation were reduced in lipopolysachharide-stimulated RAW264.7 cells, PBMCs and THP1, Raji and Jurkat-E6 immune cells in the presence of cinnamaldehyde in a concentration-dependent manner. Flow cytometric analysis of PBMCs revealed that CD3+ were more affected than CD20+ cells to apopotosis by cinnamaldehyde. CONCLUSION: We attribute the anti-inflammatory properties of cinnamaldehyde to its ability to block nuclear factor-kappaB activation in immune cells. Treatment with cinnamaldehyde led to inhibition of cell viability, proliferation and induced apoptosis in a dose dependent manner in primary and immortalized immune cells. Therefore, despite its described anti-carcinogenic property, treatment with cinnamaldehyde in cancer patients might be contraindicated due to its ability to inhibit immune cell activation. PMID- 25271637 TI - AltitudeOmics: rapid hemoglobin mass alterations with early acclimatization to and de-acclimatization from 5260 m in healthy humans. AB - It is classically thought that increases in hemoglobin mass (Hbmass) take several weeks to develop upon ascent to high altitude and are lost gradually following descent. However, the early time course of these erythropoietic adaptations has not been thoroughly investigated and data are lacking at elevations greater than 5000 m, where the hypoxic stimulus is dramatically increased. As part of the AltitudeOmics project, we examined Hbmass in healthy men and women at sea level (SL) and 5260 m following 1, 7, and 16 days of high altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260 m following descent to 1525 m for either 7 or 21 days. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7 +/- 5.8% (mean +/- SD; n = 20; p<0.01) at ALT7 and 7.6 +/- 6.6% (n = 21; p<0.001) at ALT16. Following descent to 1525 m, Hbmass was reduced compared to ALT16 (-6.0 +/- 3.7%; n = 20; p = 0.001) and not different compared to SL, with no difference in the loss in Hbmass between groups that descended for 7 (-6.3 +/- 3.0%; n = 13) versus 21 days (-5.7 +/- 5.0; n = 7). The loss in Hbmass following 7 days at 1525 m was correlated with an increase in serum ferritin (r = -0.64; n = 13; p<0.05), suggesting increased red blood cell destruction. Our novel findings demonstrate that Hbmass increases within 7 days of ascent to 5260 m but that the altitude-induced Hbmass adaptation is lost within 7 days of descent to 1525 m. The rapid time course of these adaptations contrasts with the classical dogma, suggesting the need to further examine mechanisms responsible for Hbmass adaptations in response to severe hypoxia. PMID- 25271638 TI - Effects of predictability of load magnitude on the response of the Flexor Digitorum Superficialis to a sudden fingers extension. AB - Muscle reflexes, evoked by opposing a sudden joint displacement, may be modulated by several factors associated with the features of the mechanical perturbation. We investigated the variations of muscle reflex response in relation to the predictability of load magnitude during a reactive grasping task. Subjects were instructed to flex the fingers 2-5 very quickly after a stretching was exerted by a handle pulled by loads of 750 or 1250 g. Two blocks of trials, one for each load (predictable condition), and one block of trials with a randomized distribution of the loads (unpredictable condition) were performed. Kinematic data were collected by an electrogoniometer attached to the middle phalanx of the digit III while the electromyography of the Flexor Digitorum Superficialis muscle was recorded by surface electrodes. For each trial we measured the kinematics of the finger angular rotation, the latency of muscle response and the level of muscle activation recorded below 50 ms (short-latency reflex), between 50 and 100 ms (long-latency reflex) and between 100 and 140 ms (initial portion of voluntary response) from the movement onset. We found that the latency of the muscle response lengthened from predictable (35.5 +/- 1.3 ms for 750 g and 35.5 +/- 2.5 ms for 1250 g) to unpredictable condition (43.6 +/- 1.3 ms for 750 g and 40.9 +/- 2.1 ms for 1250 g) and the level of muscle activation increased with load magnitude. The parallel increasing of muscle activation and load magnitude occurred within the window of the long-latency reflex during the predictable condition, and later, at the earliest portion of the voluntary response, in the unpredictable condition. Therefore, these results indicate that when the amount of an upcoming perturbation is known in advance, the muscle response improves, shortening the latency and modulating the muscle activity in relation to the mechanical demand. PMID- 25271639 TI - A comparative assessment of hand preference in captive red howler monkeys, Alouatta seniculus and yellow-breasted capuchin monkeys, Sapajus xanthosternos. AB - There are two major theories that attempt to explain hand preference in non-human primates-the 'task complexity' theory and the 'postural origins' theory. In the present study, we proposed a third hypothesis to explain the evolutionary origin of hand preference in non-human primates, stating that it could have evolved owing to structural and functional adaptations to feeding, which we refer to as the 'niche structure' hypothesis. We attempted to explore this hypothesis by comparing hand preference across species that differ in the feeding ecology and niche structure: red howler monkeys, Alouatta seniculus and yellow-breasted capuchin monkeys, Sapajus xanthosternos. The red howler monkeys used the mouth to obtain food more frequently than the yellow-breasted capuchin monkeys. The red howler monkeys almost never reached for food presented on the opposite side of a wire mesh or inside a portable container, whereas the yellow-breasted capuchin monkeys reached for food presented in all four spatial arrangements (scattered, on the opposite side of a wire mesh, inside a suspended container, and inside a portable container). In contrast to the red howler monkeys that almost never acquired bipedal and clinging posture, the yellow-breasted capuchin monkeys acquired all five body postures (sitting, bipedal, tripedal, clinging, and hanging). Although there was no difference between the proportion of the red howler monkeys and the yellow-breasted capuchin monkeys that preferentially used one hand, the yellow-breasted capuchin monkeys exhibited an overall weaker hand preference than the red howler monkeys. Differences in hand preference diminished with the increasing complexity of the reaching-for-food tasks, i.e., the relatively more complex tasks were perceived as equally complex by both the red howler monkeys and the yellow-breasted capuchin monkeys. These findings suggest that species-specific differences in feeding ecology and niche structure can influence the perception of the complexity of the task and, consequently, hand preference. PMID- 25271640 TI - Experimental Infection of voles with Francisella tularensis indicates their amplification role in tularemia outbreaks. AB - Tularemia outbreaks in humans have been linked to fluctuations in rodent population density, but the mode of bacterial maintenance in nature is unclear. Here we report on an experiment to investigate the pathogenesis of Francisella tularensis infection in wild rodents, and thereby assess their potential to spread the bacterium. We infected 20 field voles (Microtus agrestis) and 12 bank voles (Myodes glareolus) with a strain of F. tularensis ssp. holarctica isolated from a human patient. Upon euthanasia or death, voles were necropsied and specimens collected for histological assessment and identification of bacteria by immunohistology and PCR. Bacterial excretion and a rapid lethal clinical course with pathological changes consistent with bacteremia and tissue necrosis were observed in infected animals. The results support a role for voles as an amplification host of F. tularensis, as excreta and, in particular, carcasses with high bacterial burden could serve as a source for environmental contamination. PMID- 25271641 TI - Stability, bifurcation and chaos analysis of vector-borne disease model with application to Rift Valley fever. AB - This paper investigates a RVF epidemic model by qualitative analysis and numerical simulations. Qualitative analysis have been used to explore the stability dynamics of the equilibrium points while visualization techniques such as bifurcation diagrams, Poincare maps, maxima return maps and largest Lyapunov exponents are numerically computed to confirm further complexity of these dynamics induced by the seasonal forcing on the mosquitoes oviposition rates. The obtained results show that ordinary differential equation models with external forcing can have rich dynamic behaviour, ranging from bifurcation to strange attractors which may explain the observed fluctuations found in RVF empiric outbreak data, as well as the non deterministic nature of RVF inter-epidemic activities. Furthermore, the coexistence of the endemic equilibrium is subjected to existence of certain number of infected Aedes mosquitoes, suggesting that Aedes have potential to initiate RVF epidemics through transovarial transmission and to sustain low levels of the disease during post epidemic periods. Therefore we argue that locations that may serve as RVF virus reservoirs should be eliminated or kept under control to prevent multi-periodic outbreaks and consequent chains of infections. The epidemiological significance of this study is: (1) low levels of birth rate (in both Aedes and Culex) can trigger unpredictable outbreaks; (2) Aedes mosquitoes are more likely capable of inducing unpredictable behaviour compared to the Culex; (3) higher oviposition rates on mosquitoes do not in general imply manifestation of irregular behaviour on the dynamics of the disease. Finally, our model with external seasonal forcing on vector oviposition rates is able to mimic the linear increase in livestock seroprevalence during inter-epidemic period showing a constant exposure and presence of active transmission foci. This suggests that RVF outbreaks partly build upon RVF inter-epidemic activities. Therefore, active RVF surveillance in livestock is recommended. PMID- 25271642 TI - Air sac nematode Monopetalonema alcedinis in a Belted Kingfisher (Megaceryle alcyon) in Maryland, USA. AB - Sporadic and geographically widespread reports of parasites affecting the Belted Kingfisher (Megaceryle alcyon) have been published but few have described details of the pathology. A female, adult kingfisher was found dead in a heavily wooded area of a zoo in Maryland, USA. At necropsy, numerous sexually dimorphic, 4.4 40.5-cm adult Monopetalonema alcedinis nematodes were found tightly wound within the coelomic cavity between organs and completely filling the caudal thoracic and abdominal air sacs. Abundant, 30-60-um diameter, larvated, thick-walled ova were found in the bronchi and parabronchi, within the mesentery, and in the serosa of multiple coelomic organs. Monopetalonema alcedinis is a characteristic member of the superfamily Diplotriaenoidea, a group of nematodes occurring in birds and reptiles. Infective larvae within an invertebrate intermediate host are ingested and penetrate the intestine, traveling to the lungs and then into the air sacs, where the adult females release eggs. The ova are coughed up by the avian host and passed in feces. Specimens of M. alcedinis have been found in the Belted Kingfisher, although typically intensity of infection is low and infections remain asymptomatic. In contrast, we report the second documented case of high numbers of M. alcedinis resulting in pathologic changes in which parasitism contributed to host mortality. PMID- 25271644 TI - Preparation, characterization and application of magnetic Fe3O4-CS for the adsorption of orange I from aqueous solutions. AB - Fe3O4 (Fe3O4-CS) coated with magnetic chitosan was prepared as an adsorbent for the removal of Orange I from aqueous solutions and characterized by FTIR, XRD, SEM, TEM and TGA measurements. The effects of pH, initial concentration and contact time on the adsorption of Orange I from aqueous solutions were investigated. The decoloration rate was higher than 94% in the initial concentration range of 50-150 mg L(-1) at pH 2.0. The maximum adsorption amount was 183.2 mg g-1 and was obtained at an initial concentration of 400 mg L(-1) at pH 2.0. The adsorption equilibrium was reached in 30 minutes, demonstrating that the obtained adsorbent has the potential for practical application. The equilibrium adsorption isotherm was analyzed by the Freundlich and Langmuir models, and the adsorption kinetics were analyzed by the pseudo-first-order and pseudo-second-order kinetic models. The higher linear correlation coefficients showed that the Langmuir model (R(2) = 0.9995) and pseudo-second-order model (R(2) = 0.9561) offered the better fits. PMID- 25271646 TI - Pregnancy termination in Matlab, Bangladesh: maternal mortality risks associated with menstrual regulation and abortion. AB - CONTEXT: In Bangladesh, both menstrual regulation (MR), which is thought to be a relatively safe method, and abortion, which in this setting is often performed using unsafe methods, are used to terminate pregnancies (known or suspected). However, little is known about changes over time in the use of these methods or their relative mortality risks. METHODS: Data from the Demographic Surveillance System in Matlab, Bangladesh, on 110,152 pregnancy outcomes between 1989 and 2008 were used to assess changes in mortality risks associated with MR (and a small number of dilation and curettage procedures), abortion and live birth. Tabulation and logistic regression analyses were used to compare outcomes in two areas of Matlab--the comparison area, which receives standard government health and family planning services, and the Maternal and Child Health-Family Planning (MCH-FP) area, which receives enhanced health and family planning services. RESULTS: In Matlab as a whole, the proportion of pregnancies ending in MR increased from 1.9% in 1989-1999 to 4.2% in 2000-2008, while the proportion ending in abortion decreased from 1.6% to 1.1%. The odds of mortality from MR were 4.1 times those from live birth in 1989-1999, but were no longer elevated in 2000-2008. The odds of mortality from abortion were 12.0 and 4.9 times those of live birth in 1989 1999 and 2000-2008, respectively. Reduction in mortality risk was greater in the MCH-FP area than the comparison area (90% vs. 75%). CONCLUSION: MR is no longer associated with higher mortality risk than live birth in Bangladesh, but abortion is. PMID- 25271645 TI - Interaction between Nbp35 and Cfd1 proteins of cytosolic Fe-S cluster assembly reveals a stable complex formation in Entamoeba histolytica. AB - Iron-Sulfur (Fe-S) proteins are involved in many biological functions such as electron transport, photosynthesis, regulation of gene expression and enzymatic activities. Biosynthesis and transfer of Fe-S clusters depend on Fe-S clusters assembly processes such as ISC, SUF, NIF, and CIA systems. Unlike other eukaryotes which possess ISC and CIA systems, amitochondriate Entamoeba histolytica has retained NIF & CIA systems for Fe-S cluster assembly in the cytosol. In the present study, we have elucidated interaction between two proteins of E. histolytica CIA system, Cytosolic Fe-S cluster deficient 1 (Cfd1) protein and Nucleotide binding protein 35 (Nbp35). In-silico analysis showed that structural regions ranging from amino acid residues (P33-K35, G131-V135 and I147 E151) of Nbp35 and (G5-V6, M34-D39 and G46-A52) of Cfd1 are involved in the formation of protein-protein complex. Furthermore, Molecular dynamic (MD) simulations study suggested that hydrophobic forces surpass over hydrophilic forces between Nbp35 and Cfd1 and Van-der-Waal interaction plays crucial role in the formation of stable complex. Both proteins were separately cloned, expressed as recombinant fusion proteins in E. coli and purified to homogeneity by affinity column chromatography. Physical interaction between Nbp35 and Cfd1 proteins was confirmed in vitro by co-purification of recombinant Nbp35 with thrombin digested Cfd1 and in vivo by pull down assay and immunoprecipitation. The insilico, in vitro as well as in vivo results prove a stable interaction between these two proteins, supporting the possibility of its involvement in Fe-S cluster transfer to target apo-proteins through CIA machinery in E. histolytica. Our study indicates that initial synthesis of a Fe-S precursor in mitochondria is not necessary for the formation of Cfd1-Nbp35 complex. Thus, Cfd1 and Nbp35 with the help of cytosolic NifS and NifU proteins can participate in the maturation of non mitosomal Fe-S proteins without any apparent assistance of mitosomes. PMID- 25271647 TI - Pregnancy termination in Matlab, Bangladesh: trends and correlates of use of safer and less-safe methods. AB - CONTEXT: Menstrual regulation (MR), a relatively safe form of pregnancy termination, is legal in Bangladesh during the early stages of pregnancy. However, little is known about the factors associated with whether women who terminate pregnancies choose this method or a less-safe one. METHODS: Data from the Matlab Demographic Surveillance System on 122,691 pregnancies-5,221 (4.3%) of which were terminated-were used to examine trends between 1989 and 2008 in termination and in use of safer methods (MR or dilation and curettage) and less safe (all other) methods of pregnancy termination. Logistic and multinomial logistic regressions were used to assess factors associated with whether women terminate pregnancies and whether they use safer methods. RESULTS: Sixty-seven percent of pregnancy terminations were by safer methods and 33% by less-safe means. The proportion of pregnancies that were terminated increased between 1989 and 2008; this increase was entirely due to increased use of safer methods. Women younger than 18 and those 25 or older were more likely than women aged 20-24 to terminate their pregnancies (odds ratios ranged from 1.5 among women aged 16-17 or 25-29 to 26.1 among those aged 45 or older). Among women who terminated their pregnancies, those aged 25-44 were more likely than those aged 20-24 to use a safer method. Compared with women who had no formal education, those with some education were more likely to terminate their pregnancies and to do so using safer methods. CONCLUSION: A growing proportion of pregnancies in Matlab are terminated, and these terminations are increasingly done using safer methods. PMID- 25271648 TI - Repeat use of emergency contraceptive pills in urban Kenya and Nigeria. AB - CONTEXT: Little is known about the frequency and patterns of use of emergency contraceptive pills among women in urban Kenya and Nigeria. METHODS: To recruit women who had used emergency contraceptive pills, individuals aged 18-49 were intercepted and interviewed at shopping venues in Nairobi, Kenya, and Lagos, Nigeria, in 2011. Information was collected on 539 Nairobi and 483 Lagos respondents' demographic and behavioral characteristics, attitudes toward the method, and frequency of use. Multinomial logistic regression analyses were used to identify associations between these characteristics and frequency of pill use. RESULTS: Eighteen percent of the women interviewed in Nairobi and 17% in Lagos had ever used emergency contraceptive pills. On average, these respondents had used the pills less than once per month, but greater use and acceptance were seen in Lagos. In multivariate analysis, women who had sex at least once in a typical week were generally more likely than others to have used the pills 2-5 times in the last six months, rather than once or never, or to have used them six or more times. Furthermore, Lagos respondents who said their main contraceptive method was the condom, the pill or injectable, or a natural method were generally less likely than those who did not report these methods to have used the emergency pills multiple times in the last six months. CONCLUSIONS: Repeated use of emergency contraceptive pills was not common in this sample. PMID- 25271649 TI - Fertility decisions and contraceptive use at different stages of relationships: windows of risk among men and women in accra. AB - CONTEXT: Despite declining fertility in Ghana, modern contraceptive use-even in urban areas-is low for reasons that remain unclear. Few studies have explored what drives fertility decisions and contraceptive use among contemporary urban residents within a relationship context. METHODS: In-depth contraceptive life history interviews were conducted among a purposive sample of 80 sexually active women and men living in Accra. RESULTS: Contraception is viewed favorably, although the timing and choice of method strongly depends on the type and stage of relationship. At sexual debut and at first sex with a new partner, sex is usually unprotected. Many women show agency in subsequently negotiating condom use; men also show motivation to practice contraception. As relationships stabilize, couples abandon condoms and adopt traditional methods, out of fear that modern methods could affect fertility. After a first birth, couples prefer modern contraceptives to space children, but side effects often lead women to switch methods or discontinue use; women in supportive relationships are more likely than those in unsupportive relationships to continue use of modern contraceptives despite side effects. After reproductive goals have been realized, couples revert to using traditional methods to avoid further exposure to "chemicals." CONCLUSIONS: Contraceptive programs may be more successful if they target messages according to stage of relationship, involve men and work with people's desires to use traditional methods at certain times to ensure that they can do so safely. PMID- 25271650 TI - Contraceptive method skew and shifts in method mix in low- and middle-income countries. AB - CONTEXT: Method mix-the percentage distribution of contraceptive users in a given country, by method-is one measure that reflects the availability of a range of contraceptive methods. A skewed method mix-one in which 50% or more of contraceptive users rely on a single method-could be cause for concern as a sign of insufficiency of alternative methods or provider bias. Shifts in method mix are important to individual countries, donors and scholars studying contraceptive dynamics. METHODS: To determine current patterns and recent changes in method mix, we examined 109 low- and middle-income countries. A variety of statistical methods were used to test four factors as correlates of skewed method mix: geographic region, family planning program effort index, modern contraceptive prevalence rate and human development index. An assessment of changes in reliance on female and male sterilization, the IUD, the implant and the injectable was conducted for countries with available data. RESULTS: Of the 109 countries included in this analysis, 30% had a skewed method mix-a modest decrease from 35% in a 2006 analysis. Only geographic region showed any correlation with method skew, but it was only marginally significant. The proportion of users relying on female sterilization, male sterilization or the IUD decreased in far more countries than it increased; the pattern was reversed for the injectable. CONCLUSION: Method mix skew is not a definitive indicator of lack of contraceptive choice or provider bias; it may instead reflect cultural preferences. In countries with a skewed method mix, investigation is warranted to identify the cause. PMID- 25271651 TI - Self-perception and insight. PMID- 25271652 TI - The road from Bethlehem to Bedlam to compassion. PMID- 25271653 TI - When a physician is afflicted with addiction. PMID- 25271654 TI - Drug overdose, addiction and binge drinking: medical problems with public health consequences. PMID- 25271656 TI - Long-term opioid therapy for chronic pain and the risk of opioid addiction. PMID- 25271655 TI - Medications for addiction treatment: an opportunity for prescribing clinicians to facilitate remission from alcohol and opioid use disorders. AB - Substance use disorders are a leading cause of morbidity and mortality in the United States. Medications for the treatment of substance use disorders are effective yet underutilized. This article reviews recent literature examining medications used for the treatment of alcohol and opioid use disorders. The neurobehavioral rationale for medication treatment and the most common ways medications work in the treatment of substance use disorders are discussed. Finally, the medications and the evidence behind their effectiveness are briefly reviewed. Physicians and other prescribing clinicians should take an active role in facilitating remission and recovery from substance use disorders by prescribing these effective medications with brief medical management counseling. PMID- 25271657 TI - Responding to opioid overdose in Rhode Island: where the medical community has gone and where we need to go. AB - The number of opioid overdose events in Rhode Island has increased dramatically/catastrophically in the last decade; Rhode Island now has one of the highest per capita overdose death rates in the country. Healthcare professionals have an important role to play in the reduction of unintentional opioid overdose events. This article explores the medical community's response to the local opioid overdose epidemic and proposes strategies to create a more collaborative and comprehensive response. We emphasize the need for improvements in preventing, identifying and treating opioid addiction, providing overdose education and ensuring access to the rescue medicine naloxone. PMID- 25271658 TI - The Rhode Island community responds to opioid overdose deaths. AB - The challenge of addressing the epidemic of opioid overdose in Rhode Island, and nationwide, is only possible through collaborative efforts among a wide breadth of stakeholders. This article describes the range of efforts by numerous partners that have come together to facilitate community, and treatment-related approaches to address opioid-involved overdose and substance use disorder. Strategies to address this crisis have largely focused on increasing access both to the opioid overdose antidote naloxone and to high quality and timely treatment and recovery services. [Full text available at http://rimed.org/rimedicaljournal-2014-10.asp, free with no login]. PMID- 25271659 TI - Emergency department naloxone distribution: a Rhode Island department of health, recovery community, and emergency department partnership to reduce opioid overdose deaths. AB - In response to increasing rates of opioid overdose deaths in Rhode Island (RI), the RI Department of Health, RI emergency physicians, and Anchor Community Recovery Center designed an emergency department (ED) naloxone distribution and peer-recovery coach program for people at risk of opioid overdose. ED patients at risk for overdose are offered a take home naloxone kit, patient education video, and, when available, an Anchor peer recovery coach to provide recovery support and referral to treatment. In August 2014, the program launched at Kent, Miriam, and Rhode Island Hospital Emergency Departments. PMID- 25271660 TI - Response of colleges to risky drinking college students. AB - Heavy drinking and related consequences continue to affect college campuses due to fatalities, assaults, serious injuries, and arrests that occur among students. Several approaches aimed at reducing the harm incurred by students and the college communities as a result of heavy drinking are being used with varying success. A review of interventions including educational, individual, and environmental approaches are described, as well as new, promising, strategies. Despite some success, elevated and risky drinking patterns continue. As such, concerns over implementation of evidence-based treatments and areas in need of further study are discussed. [Full text available at http://rimed.org/rimedicaljournal-2014-10.asp, free with no login]. PMID- 25271661 TI - Prospective analysis of a novel orthopedic residency advocacy education program. AB - INTRODUCTION: Future physician leaders must be able to critically assess health care policy and patient advocacy issues. Currently, no nationally accepted, standardized curriculum to provide advocacy education during orthopedic residency training exists. We therefore developed an "Advocacy" curriculum for our orthopedic residents designed to direct particular attention to patient advocacy, specialty advocacy, and healthcare policy. METHODS: Residents were given pre- and post-curriculum questionnaires to gauge their perception of the importance, strengths, and weaknesses of this curriculum. A paired t-test was used to compare pre- and post-curriculum responses. RESULTS: Twenty-one of 24 orthopedic residents completed the pre-curriculum and post-curriculum questionnaire regarding the importance of advocacy education (87.5% response rate). Overall, 85.7% (18/21) of responders ranked the curriculum on orthopedic advocacy as good or excellent. Prior to the advocacy curriculum, 33.3% (7/21) of residents felt that learning about orthopedic advocacy was important to their education, while following the curriculum 100% (21/21) felt so (p<0.05). The percentage of residents who considered health policy to be important increased from 71.4% (15/21) to 95.2% (20/21) following the curriculum(p<0.05). Following the advocacy curriculum, 90.5% (19/21) of responders would be interested in getting involved in orthopedic advocacy. DISCUSSION: This curriculum significantly increased residents' belief in the importance of advocacy issues. Following the curriculum, 100% of responding residents considered orthopedic advocacy education as important. An advocacy curriculum may serve as an integral preparatory educational core component to residency training. PMID- 25271662 TI - Primary spine care services: responding to runaway costs and disappointing outcomes in spine care. AB - Efforts are underway to reform our health care system to improve efficiency, outcomes, patient satisfaction and costs. In no field is this more critical than that of spine- related disorders, where escalating costs combined with decreasing clinical benefits for patients has reached a breaking point. Traditionally, practitioners have grouped together based on their specialty (orthopedics, otolaryn- gology, etc.). There has been a recent movement to restructure health care delivery into a patient-centered model that teams professionals based on their ability to serve specific patient needs. This article introduces a new service line - primary spine care services - led by a new type of professional - the primary spine practitioner (PSP). This new practitioner type requires a refined and focused skill set and ideally functions within an integrated spine care pathway. The challenges and opportunities presented by primary spine care services are discussed. This service line has already been implemented in a variety of settings. PMID- 25271663 TI - An evaluation of career paths among 30 years of general internal medicine/primary care internal medicine residency graduates. AB - BACKGROUND: Interest in primary care careers has been dwindling among medical trainees over the past decade, with poor quality of life among the perceived disadvantages. We sought to evaluate factors influencing career satisfaction among graduates of Brown's General Internal Medicine (GIM)/Primary Care residency program and assess its contribution to the primary care work force. METHODS: Using an anonymous online survey, we queried GIM alumni from 1981-2012 to obtain information about demographics, job characteristics and career satisfaction measures. RESULTS: Fifty-nine percent of Brown's GIM/Primary Care residency graduates practice primary care, a rate higher than most primary care track programs. Seventy-six percent of respondents were "satisfied" or "very satisfied" with their current jobs. Career satisfaction correlated with self-rating of physical and emotional health and did not correlate with age, gender, income, debt burden, or practice setting. CONCLUSION: Among the diverse factors associated with attaining career satisfaction, attention to personal health plays a central role. PMID- 25271664 TI - Patients with PD describe hallucinations in new video with Dr. Friedman. PMID- 25271665 TI - HIT implementation by Rhode Island physicians, advanced practice registered nurses and physician assistants, 2014. PMID- 25271666 TI - Influenza vaccination coverage among healthcare workers during the 2013-14 influenza season in Rhode Island. PMID- 25271667 TI - Professional responsibilities for treatment of patients with Ebola: can a healthcare provider refuse to treat a patient with ebola? PMID- 25271668 TI - 'Dr. Tim' Flanigan lending a hand and hope in Liberia. PMID- 25271669 TI - RIMS and insurer coverys announce new partnership. PMID- 25271670 TI - Adipose-derived stem cells attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling in monocrotaline-induced pulmonary hypertensive rats. AB - We investigated the effect of adipose-derived stem cells (ADSCs) transplantation effects on structural remodeling and pulmonary artery pressure in monocrotaline (MCT)-induced pulmonary hypertensive rats. In the first experiment, 32 male Sprague-Dawley (SD) rats were randomly divided into four groups (n = 8/group): 3 ADSCs treated groups and normal control (Ctrl). ADSCs were administered through the left jugular vein at 10(5), 10(6) and 10(7) cells, respectively, and a cell density of 10(6)cells/ml was shown to be optimal. The GFP-tagged ADSCs were identified in the lungs and differentiated into endothelial-like cells. In the second experiment, 96 male SD rats were randomly divided into three groups (n = 32/group): Ctrl, MCT-induced pulmonary arterial hypertension (PAH), and PAH treated with ADSCs (ADSCs). Two weeks post-MCT administration, the ADSCs group received 1 * 10(6) ADSCs via the external jugular vein. Compared to PAH rats, mean pulmonary arterial pressure was decreased in rats at 1, 2, and 3 weeks after ADSCs-treatment (18.63 +/- 2.15 mmHg versus 24.53 +/- 2.90 mmHg; 23.07 +/- 2.84 mmHg versus 33.18 +/- 2.30 mmHg; 22.98 +/- 2.34 mmHg versus 36.38 +/- 3.28 mmHg, p < 0.05). Meanwhile, the right heart hypertrophy index (36.2 1 +/- 4.27% versus 41.01 +/- 1.29%; 39.47 +/- 4.02% versus 48.75 +/- 2 .13%; 41.02 +/- 0.9% versus 50.52 +/- 1.49%, p < 0.05, respectively), ratio of wall/lumen thickness, as well as the wall/lumen area were significantly reduced in PAH rats at these time points following ADSCs-treatment, as compared with untreated PAH rats. In summary, ADSCs may colonize the pulmonary arteries, attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling. PMID- 25271671 TI - Seizures associated with hypoglycaemia and subsequent epilepsy. PMID- 25271673 TI - Step-Count Guidelines for Children and Adolescents: A Systematic Review. AB - BACKGROUND: The aim of this systematic review was to identify the most optimal step-count cutoff for children and adolescents (5-19 years old) among guidelines currently available in the literature. METHODS: The databases searched were PubMed, SportDiscus, Science Direct, Web of Science and LILACS. Studies were categorized into Health Cohort studies or Physical Activity (PA) Cohort studies according to the reference standard used. The quality of the studies was assessed using the QUADAS-2 instrument. RESULTS: Six Health and 3 PA Cohort studies were included in the final pool of papers after Full Text reading. With the exception of a single study, studies demonstrated a high risk of methodological bias in at least 1 of the QUADAS-2 domains. Guidelines ranged from 10,000 to 16,000 steps/day for the Health studies (5-16 years old), and from 9,000 to 14,000 steps/day for PA studies (6-19 years old). Due to the high risk of methodological bias, none of the Health Cohort guidelines were endorsed. The PA Cohort study with the lowest risk of methodological bias suggested 12,000 steps/day for children and adolescents irrespective of gender. CONCLUSION: PA Cohort studies demonstrated lower risk of methodological bias than Health Cohort studies. The optimal youth step-count guideline of 12,000 steps/day was endorsed. PMID- 25271674 TI - Iron(III) chloride and diorganyl diselenides-mediated 6-endo-dig cyclization of arylpropiolates and arylpropiolamides leading to 3-organoselenyl-2H-coumarins and 3-organoselenyl-quinolinones. AB - Combination of iron(III) chloride and diorganyl diselenides was used for cyclization of arylpropiolates and arylpropiolamides in formation of 3 organoselenyl-2H-coumarins and 3-organoselenyl-quinolinones, respectively. Systematic study to determine the ideal conditions revealed that the two substrates reacted in the same way using identical reaction conditions. The versatility of this method has been demonstrated by extension of the best reaction conditions to substrate having a variety of substituents. Analyses of the optimization reaction also showed that diorganyl diselenides have a dual role by acting as cycling agent and base to restore the aromatic system. Mechanistic investigation studies and analyses of the products obtained have revealed that the cyclization reactions follow an initial 6-endo-dig process to give the six membered heterocycles without involving an intramolecular ipso-cyclization route. PMID- 25271672 TI - Amyloids, melanins and oxidative stress in melanomagenesis. AB - Melanoma has traditionally been viewed as an ultraviolet (UV) radiation-induced malignancy. While UV is a common inducing factor, other endogenous stresses such as metal ion accumulation or the melanin pigment itself may provide alternative pathways to melanoma progression. Eumelanosomes within melanoma often exhibit disrupted membranes and fragmented pigment which may be due to alterations in their amyloid-based striated matrix. The melanosomal amyloid can itself be toxic, especially in combination with reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by endogenous NADPH oxidase (NOX) and nitric oxide synthase (NOS) enzymes, a toxic mix that may initiate melanomagenesis. Further understanding of the loss of the melanosomal organization, the behaviour of the exposed melanin and the induction of ROS/RNS in melanomas may provide critical insights into this deadly disease. PMID- 25271675 TI - Sleep-wake transition in narcolepsy and healthy controls using a support vector machine. AB - Narcolepsy is characterized by abnormal sleep-wake regulation, causing sleep episodes during the day and nocturnal sleep disruptions. The transitions between sleep and wakefulness can be identified by manual scorings of a polysomnographic recording. The aim of this study was to develop an automatic classifier capable of separating sleep epochs from epochs of wakefulness by using EEG measurements from one channel. Features from frequency bands alpha (0-4 Hz), beta (4-8 Hz), delta (8-12 Hz), theta (12-16 Hz), 16 to 24 Hz, 24 to 32 Hz, 32 to 40 Hz, and 40 to 48 Hz were extracted from data by use of a wavelet packet transformation and were given as input to a support vector machine classifier. The classification algorithm was assessed by hold-out validation and 10-fold cross-validation. The data used to validate the classifier were derived from polysomnographic recordings of 47 narcoleptic patients (33 with cataplexy and 14 without cataplexy) and 15 healthy controls. Compared with manual scorings, an accuracy of 90% was achieved in the hold-out validation, and the area under the receiver operating characteristic curve was 95%. Sensitivity and specificity were 90% and 88%, respectively. The 10-fold cross-validation procedure yielded an accuracy of 88%, an area under the receiver operating characteristic curve of 92%, a sensitivity of 87%, and a specificity of 87%. Narcolepsy with cataplexy patients experienced significantly more sleep-wake transitions during night than did narcolepsy without cataplexy patients (P = 0.0199) and healthy subjects (P = 0.0265). In addition, the sleep-wake transitions were elevated in hypocretin deficient patients. It is concluded that the classifier shows high validity for identifying the sleep-wake transition. Narcolepsy with cataplexy patients have more sleep-wake transitions during night, suggesting instability in the sleep wake regulatory system. PMID- 25271676 TI - Topographical distribution of fast and slow sleep spindles in medicated depressive patients. AB - PURPOSE: To compare the properties of sleep spindles between healthy subjects and medicated patients with major depressive episode, including frequency range, spectra power, and spatial distribution of spindle power. METHODS: Continuous 16 channel EEG was used to record nocturnal sleep in healthy control subjects and medicated depressive patients. Recordings were analyzed for changes in EEG power spectra and power topography. Additionally, we graphically demonstrated the pattern of spatial distribution of each type of sleep spindle, divided into fast (12.5-14 Hz) and slow spindles (11-12.5 Hz). RESULTS: Sleep EEG records of depressive subjects exhibited a significantly higher amplitude of slow spindles in the prefrontal region, compared with the healthy controls (P < 0.01). Fast spindles were dominant in the centroparietal region in both depressive patients and the control group. Enhanced slow spindles in the prefrontal region were observed in the medicated depressive patients and not in the healthy controls. The frequency of fast spindles in depressive patients was globally higher than that in healthy participants. CONCLUSIONS: The alteration in sleep spindles seen in medicated depressive subjects may reflect a pharmacological modulation of synaptic function involving the thalamic-reticular and thalamocortical mechanisms. PMID- 25271677 TI - Early automatic detection of Parkinson's disease based on sleep recordings. AB - SUMMARY: Idiopathic rapid-eye-movement (REM) sleep behavior disorder (iRBD) is most likely the earliest sign of Parkinson's Disease (PD) and is characterized by REM sleep without atonia (RSWA) and consequently increased muscle activity. However, some muscle twitching in normal subjects occurs during REM sleep. PURPOSE: There are no generally accepted methods for evaluation of this activity and a normal range has not been established. Consequently, there is a need for objective criteria. METHOD: In this study we propose a full-automatic method for detection of RSWA. REM sleep identification was based on the electroencephalography and electrooculography channels, while the abnormal high muscle activity was detected from the electromyography channels, in this case the submentalis combined with left and right anterior tibialis. RSWA was identified by considering it an outlier problem, in which the number of outliers during REM sleep was used as a quantitative measure of muscle activity. RESULTS: The proposed method was able to automatically separate all iRBD test subjects from healthy elderly controls and subjects with periodic limb movement disorder. CONCLUSION: The proposed work is considered a potential automatic method for early detection of PD. PMID- 25271678 TI - An audit of continuous EEG monitoring in the neurological-neurosurgical intensive care unit. AB - PURPOSE: The use of long-term continuous EEG (cEEG) monitoring in neurological neurosurgical intensive care units (NSICU) has witnessed an exponential increase. We decided to do an audit of the long-term cEEG monitoring in our NSICU over the past 7 years (2005-2011). The study was performed to determine technical and staffing consideration for the future. METHODS: An audit of all long-term cEEG monitoring studies in our NSICU from 2005 through 2011. RESULTS: We found a dramatic increase in the use of the cEEG monitoring in our NSICU over the 7-year period. CONCLUSIONS: The use of long-term cEEG monitoring in the NSICU is expected to further increase in the coming years. Stricter clinical criteria for undertaking cEEG recordings are likely to increase the role and usefulness of this procedure. PMID- 25271679 TI - SIRPIDs: prevalence and outcome in critically ill patients. AB - PURPOSE: To determine the prevalence, associated factors, and outcomes of critically ill patients with stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) on long-term video-EEG (VEEG). METHODS: After IRB approval, we retrospectively reviewed patient characteristics and VEEG findings of all consecutive critical care unit patients who underwent VEEG monitoring between January 2012 and September 2012. RESULTS: The prevalence of SIRPIDs was 12.1% (4 of 33 patients; exact 95% confidence interval, 3.4%-28.2%). Factors associated with SIRPIDs versus non-SIRPIDs patients included a higher prevalence of subclinical status epilepticus (100% vs. 17.2%, P = 0.003), longer total VEEG recording time (286 vs. 56.9 hours, P = 0.0004), and acute traumatic brain injury (75.0% vs. 17.2%, P = 0.036). Sex, age, a history of epilepsy, nonstatus epileptic seizures, other EEG periodic patterns, and background rhythm reactivity on VEEG did not correlate with the presence of SIRPIDs. The presence or absence of SIRPIDs had no bearing on outcome; however, the population studied was very small. CONCLUSIONS: This small series suggests that the presence of subclinical status epilepticus and traumatic brain injury correlated with the presence of SIRPIDs signifying that SIRPIDs may be due to a more focal etiology and may represent a more ictal pattern than previously thought. Longer recording times in those patient populations may yield more cases of SIRPIDs in which to base further studies. PMID- 25271680 TI - Subcortical vascular cognitive impairment, no dementia: EEG global power independently predicts vascular impairment and brain symmetry index reflects severity of cognitive decline. AB - BACKGROUND AND PURPOSE: Vascular cognitive impairment, no dementia (vCIND) is a prevalent and potentially preventable disorder. Clinical presentation of the small-vessel subcortical subtype may be insidious, and differential difficulties can arise with mild cognitive impairment. We investigated EEG parameters in subcortical vCIND in comparison with amnestic multidomain mild cognitive impairment to determine the additional diagnostic value of quantitative EEG in this setting. METHODS: Fifty-seven community-residing patients with an uneventful central neurologic history and first presentation of cognitive decline without dementia were included. Neuropsychological test results were correlated with EEG parameters. Predictive values for vCIND and amnestic multidomain mild cognitive impairment were calculated using receiver operating characteristic curves and logistic regression modeling. RESULTS: Vascular cognitive impairment, no dementia and amnestic multidomain mild cognitive impairment differed with regard to the EEG (delta + theta)/(alpha + beta) ratio (DTABR) and pairwise derived brain symmetry index. We found statistically significant correlations between pairwise derived brain symmetry index and immediate verbal memory, immediate global memory, verbal recognition, working memory, and mean memory score in vCIND. Verbal fluency (odds ratio: 1.54, 95% confidence interval: 1.04-2.28, P = 0.033) and (delta + theta)/(alpha + beta) ratio (odds ratio: 2.28, 95% confidence interval: 1.06-4.94, P = 0.036) emerged as independent diagnostic predictors for vCIND with an overall correct classification rate of 95.0%. CONCLUSION: Our data indicate that EEG is of additional value in the differential diagnosis and follow up of patients presenting with cognitive decline. These findings may have an impact on memory care. PMID- 25271681 TI - A method for the inclusion of sphenoidal electrodes in realistic EEG source imaging. AB - SUMMARY: Although EEG source imaging (ESI) has become more popular over the last few years, sphenoidal electrodes (SPE) have never been incorporated in ESI using realistic head models. This is in part because of the true locations of these electrodes are not exactly known. In this study, we demonstrate the feasibility of determining the true locations of SPE and incorporating this information into realistic ESI. The impact of including these electrodes in ESI in mesial temporal lobe epilepsy is also discussed. Seventeen patients were retrospectively selected for this study. To determine the positions of SPE in each case, two orthogonal x rays (sagittal and coronal) of the SPE needle stilette were taken in the presence of previously digitized scalp electrodes. An in-house computer program was then used to find the locations of the tip of the needle stilette relative to the surface electrodes. These locations were then incorporated in a realistic head model based on the finite element method. EEG source imaging was then performed using averaged spikes for included patients suspected of having mesial temporal lobe epilepsy. Including SPE significantly shifted the ESI result even in the presence of subtemporal electrodes, resulting in an inferior and mesial displacement. PMID- 25271682 TI - Significance of quantitative sensory testing in the diagnosis of diabetic peripheral neuropathy. AB - PURPOSE: To investigate the significance of quantitative sensory testing in the diagnosis of early diabetic peripheral neuropathy. METHODS: One hundred ninety six patients with diabetes with neurological deficits were determined by nerve conduction studies and quantitative sensory testing. Seventy-seven age-matched healthy controls were determined by quantitative sensory testing. Results were analyzed statistically. RESULTS: Cold thresholds of shorter-term patients (course of disease <= 5 years) were lower than controls. Warm thresholds of longer-term patients (course of disease >5 years) were higher than with shorter-term patients. Warm thresholds of patients with normal nerve conduction studies were higher than controls (P < 0.05). The frequency of abnormality of quantitative sensory testing of longer-term patients was higher than with shorter duration patients. The frequency of abnormality was 36.7% and 72.3%, respectively, in the dorsum (P < 0.05). CONCLUSIONS: Quantitative sensory testing is sensitive for the diagnosis of diabetic peripheral neuropathy, especially for warm thresholds in the dorsum of the foot. Quantitative sensory testing is necessary to assist nerve conduction studies in the diagnosis of early diabetic peripheral neuropathy. PMID- 25271683 TI - Duration of the distal compound muscle action potential for diagnosis of chronic inflammatory demyelinating polyneuropathy: effects of low-cut filters. AB - PURPOSE: In current electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy, the cutoff values of distal compound muscle action potential (DCMAP) duration are defined using electromyogram low-cut filter setting of 20 Hz. We aimed to assess effects of low-cut filter on DCMAP duration (10 vs. 20 Hz). METHODS: We prospectively measured DCMAP duration in 130 normal controls and 42 patients, fulfilling diagnostic criteria for typical chronic inflammatory demyelinating polyneuropathy by European Federation of Neurological Societies/Peripheral Nerve Society. RESULTS: Distal compound muscle action potential duration was significantly shortened with 20-Hz than 10-Hz filtering. When the cutoff values were defined as the upper limit of normal (ULN, mean + 2.5SD), the sensitivity/specificity was 67%/95% in 10-Hz recordings, and 69%/95% in 20-Hz recordings. This diagnostic accuracy was similar to that defined by receiver operating characteristic analyses. CONCLUSIONS: Distal compound muscle action potential duration significantly affected by the low-cut electromyogram filter setting, but with at least 10 and 20 Hz, the diagnostic accuracy is similar. PMID- 25271684 TI - Ulnar nerve compression at the wrist: diagnostic role of palmar stimulation. AB - OBJECTIVE: Electrophysiological diagnosis of ulnar nerve entrapment at the wrist is sometimes difficult. The aim was to evaluate the diagnostic role of ulnar nerve stimulation above and below the Guyon channel in ulnar nerve entrapment at the wrist. METHODS: Supramaximal ulnar nerve stimulation at the wrist and palm, in addition to the standard nerve conduction studies, in 10 patients with ulnar nerve entrapment at the wrist and 40 controls. RESULTS: Motor latencies to the first dorsal interosseous muscle with wrist stimulation were prolonged unilaterally in six and bilaterally in four patients. Palmar stimulation showed partial conduction blocks on the more symptomatic side in all. In two bilateral cases, there were 28.8% and 44.3% amplitude loss on the less symptomatic side. Motor responses elicited with palm stimulation were also found to have prolonged latencies and decreased amplitudes. CONCLUSIONS: Stimulation of the deep branch of the ulnar nerve can expand the information about ulnar nerve entrapment at the wrist by providing evidence about its nature, prognosis, precise localization, and distal extent. PMID- 25271685 TI - Single-fiber electromyography of facial and limb muscles in diabetic patients with or without neuropathy. AB - PURPOSE: In diabetic patients, single-fiber electromyography (SFEMG) is often abnormal in the limb muscles and is considered unreliable in diagnosis of synaptic disorders. We aimed to compare SFEMG abnormalities of frontalis muscle (FM) and extensor digitorum communis muscle in diabetic patients with neuropathy and without neuropathy. METHODS: Stimulation SFEMG of FM and extensor digitorum communis muscle was performed in matched groups of 30 diabetic patients with neuropathy and 20 diabetic patients without neuropathy. RESULTS: Single-fiber electromyography in the FM was abnormal in four diabetic patients with neuropathy and in one diabetic patient without neuropathy. Changes were rather mild. Extensor digitorum communis abnormalities were significantly more frequent-in 20 diabetic patients with neuropathy and in 7 diabetic patients without neuropathy (P < 0.001). We never observed a patient with abnormal FM but normal extensor digitorum communis muscle. CONCLUSIONS: In diabetes, FM exhibits rare and quite mild SFEMG changes. This muscle may be suitable for SFEMG in diabetic patients with clinical suspicion for synaptic disorder. PMID- 25271686 TI - Occipital lobe lesions result in a displacement of magnetoencephalography visual evoked field dipoles. AB - PURPOSE: The pattern-reversal visual evoked potential measured electrically from scalp electrodes is known to be decreased, or absent, in patients with occipital lobe lesions. We questioned whether the measurement and source analysis of the neuromagnetic visual evoked field (VEF) might offer additional information regarding visual cortex relative to the occipital lesion. METHODS: We retrospectively examined 12 children (6-18 years) with occipital lesions on MRI, who underwent magnetoencephalography and ophthalmology as part of their presurgical assessment. Binocular half-field pattern-reversal VEFs were obtained in a 151-channel whole-head magnetoencephalography. Data were averaged and dipole source analyses were performed for each half-field stimulation. RESULTS: A significant lateral shift (P < 0.02) in the dipole location was observed in the lesional hemisphere compared with those in the nonlesional hemisphere, regardless of the lesion location. No differences were observed in latency, strength (moment), and residual errors of VEF dipoles between the lesional and nonlesional hemispheres. CONCLUSIONS: Magnetoencephalography demonstrated the mass effect on the dipole location of VEF in children with occipital lesions. Magnetoencephalography may be useful as a screening test of visual function in young patients. We discuss potential explanations for this lateral shift and emphasize the utility of adding the magnetoencephalography pattern-reversal visual evoked field protocol to the neurologic work-up. PMID- 25271687 TI - Age-related visual signal changes induced by hypoxemic hypoxia: a study on aircraft pilots of different ages. AB - PURPOSE: Exposure to high altitude leads to a series of alterations of higher nervous functions because of hypobaric hypoxia. Sensory systems, mainly the visual one, seem to be particularly involved. This study aimed to assess the effects of hypoxemic hypoxia on the transmission of the visual stimulus simulating a condition of breathing at an altitude of 18,000 feet (5,486 m) through the administration of an air mixture with 10% O2. METHODS: The subjects involved in the study were 98 pilots of military aircraft (male, acclimated, healthy, 20/20 Uncorrected Visual Acuity (UCVA)/Best Corrected Visual Acuity (BCVA), and aged between 26 and 49 years) divided into 2 groups according to age (A: 26-36 years; B: 37-49 years). The visual evoked potentials were initially recorded at sea level (760 mm Hg) and subsequently at a simulated altitude of 18,000 feet (5,486 m) through the administration of an air mixture with 10% O2 that induced a blood saturation of 80% O2 after 15 minutes. The analysis was carried out using two different kinds of stimulus (15' and 60' of arc). The latency and the amplitude of N-75 (N1) and P-100 (P1) waves have been evaluated. Results obtained from visual evoked potentials were analyzed with Student t-test. RESULTS: In the first group (pilots aged 26-36 years), an increase in both latency and amplitude of P-100 wave was observed and in the second group (pilots aged 37-49 years), an increase was found in latency and a significant reduction in amplitude. CONCLUSIONS: The study suggests the existence of a mechanism or a particular anatomic and physiologic condition (probably the neurovascular coupling) that connects the local neuronal activity and the resulting changes in cerebral perfusion. This complex series of events binds together different structures and cell types, and it seems that younger people have a better resistance against the hypoxic insult to the central nervous system because of more efficient compensatory mechanisms. PMID- 25271688 TI - A setup for administering TMS to medial and lateral cortical areas during whole brain FMRI recording. AB - SUMMARY: Stimulating brain areas with transcranial magnetic stimulation (TMS) while concurrently and noninvasively recording brain activity changes through functional MRI enables a new range of investigations about causal interregional interactions in the human brain. However, standard head-coil arrangements for current methods for concurrent TMS-functional MRI somewhat restrict the cortical brain regions that can be targeted with TMS because space in typical MR head coils is limited. Another limitation for concurrent TMS-functional MRI approaches concerns the estimation of the precise stimulation site, which can limit the interpretation of the activity changes induced by TMS and increase the variability of the stimulation effects. Here, we present a novel approach using flexible MR receiver coils, allowing for stimulation of a large part of the cortex including more lateral areas. Furthermore, we present a fast and economical method to determine the precise location of the stimulation coil during scanning. This point-based registration method can accurately compute, during scanning, where TMS pulses are delivered. We validated this approach by stimulating medial (M1) and more lateral (dorsal part of the supramarginal gyrus) brain areas concurrently with functional MRI. Activation close to but not directly at the stimulated location and in distal areas connected to the targeted site was observed. This study provides a proof of concept that TMS of medial and lateral brain areas is feasible without significantly compromising brain coverage and that one can precisely determine the exact coil location inside the bore to verify targeting of brain areas. PMID- 25271689 TI - Passive event-related potentials to a single tone in treatment-resistant depression, generalized anxiety disorder, and borderline personality disorder patients. AB - PURPOSE: Treatment-resistant depression is comorbid with personality or anxiety disorder; how passive attention functions in these disorders remains unknown. A single tone-elicited event-related potential P3 component (passive P3) might help to characterize the passive attention in these disorders. METHODS: The passive P3 test was applied to 32 patients with treatment-resistant depression, 35 with generalized anxiety disorder, and 21 with borderline personality disorder, as well as to 31 healthy volunteers. The Zung Self-rating Depression and Anxiety Scales were used to measure the respective depression and anxiety levels in these participants. RESULTS: All patients scored significantly higher on depression and anxiety than the healthy participants did. P3 amplitude was significantly reduced in groups with treatment-resistant depression and generalized anxiety disorder but not in the group with borderline personality disorder or healthy controls. Anxiety level was negatively correlated with P3 amplitude in healthy controls rather than in other groups. CONCLUSIONS: This study did not discriminate treatment-resistant depression and generalized anxiety disorder regarding the passive P3 but suggested that there was a generalized impairment of passive attention in these disorders. PMID- 25271690 TI - P300 component of event-related potentials in persons with asperger disorder. AB - In the present study, we investigated auditory event-related potentials in adults with Asperger disorder and normal controls using an auditory oddball task and a novelty oddball task. Task performance and the latencies of P300 evoked by both target and novel stimuli in the two tasks did not differ between the two groups. Analysis of variance revealed that there was a significant interaction effect between group and electrode site on the mean amplitude of the P300 evoked by novel stimuli, which indicated that there was an altered distribution of the P300 in persons with Asperger disorder. In contrast, there was no significant interaction effect on the mean P300 amplitude elicited by target stimuli. Considering that P300 comprises two main subcomponents, frontal-central-dominant P3a and parietal-dominant P3b, our results suggested that persons with Asperger disorder have enhanced amplitude of P3a, which indicated activated prefrontal function in this task. PMID- 25271691 TI - Appropriate time to establish baseline responses for brain stem auditory evoked potentials during microvascular decompression for hemifacial spasm. AB - PURPOSE: To evaluate the appropriate time to establish baseline responses for brain stem auditory evoked potentials (BAEPs) during microvascular decompression for hemifacial spasm and its implications on the alarm criteria and outcomes. METHODS: Overall, 61 patients who had intraoperative monitoring with BAEP during microvascular decompression were retrospectively identified. The latencies and amplitudes of wave V before skin incision and at dura opening (before major manipulation) were compared with the latency and amplitude of wave V at change start (first alarm reported to the surgeon). Also, the results with respect to postoperative outcomes were evaluated. RESULTS: More alarms would have been communicated to the surgeon when baseline values were set at the beginning of the procedure, when compared with baseline values reset at dura opening (before major manipulation). CONCLUSIONS: Significant variations in BAEP latency exist before any major manipulations during microvascular decompression. Despite a false negative case, baselines can be set before any major manipulations (e.g., just before dura opening), with an understanding of the etiology of changes to BAEPs during microvascular decompression. SIGNIFICANCE: This is the first study to establish that during intraoperative BAEP monitoring, baselines that are reset before any significant manipulations are performed, rather than at the beginning of the procedure, have a higher level of sensitivity with regards to hearing outcomes. PMID- 25271692 TI - Reducing the cost of continuous EEG monitoring. PMID- 25271693 TI - Response to: reducing the cost of continuous EEG monitoring. PMID- 25271694 TI - Respiratory artifact on EEG independent of the respirator. AB - Recognizing EEG artifacts is important to correctly interpret and avoid unnecessary intervention. EEG artifacts from mechanical ventilation have been described as periodic, frontally maximal high amplitude waveforms, occurring at the same rate as the ventillator. Here, we describe a non-periodic respiratory artifact that was independent of the ventilator rate. The concomitant use of audio was helpful in identifying this artifact. PMID- 25271695 TI - Design and synthesis of epicocconone analogues with improved fluorescence properties. AB - Epicocconone is a natural latent fluorophore that is widely used in biotechnology because of its large Stokes shift and lack of fluorescence in its unconjugated state. However, the low photostability and quantum yields of epicocconone have limited its wider use, and in the absence of a total synthesis, this limitation has been a long-standing problem. Here we report a general strategy for the synthesis of epicocconone analogues that relies on a 2-iodoxybenzoic acid mediated dearomatization and on the replacement of the triene tail of the natural product by an aromatic ring. This design element is general and the synthesis is straightforward, providing ready access to libraries of polyfunctional fluorophores with long Stokes shifts based on the epicocconone core. Our structural modifications resulted in analogues with increased photostability and quantum yields compared with the natural product. Staining proteomic gels with these new analogues showed significant lowering of the detection limit and a 30% increase in the number of low-abundance proteins detected. These epiccoconone analogues will substantially improve the discovery rate of biomarker needles in the proteomic haystack. PMID- 25271696 TI - Real-time imaging and elemental mapping of AgAu nanoparticle transformations. AB - We report the controlled alloying, oxidation, and subsequent reduction of individual AgAu nanoparticles in the scanning transmission electron microscope (STEM). Through sequential application of electron beam induced oxidation and in situ heating and quenching, we demonstrate the transformation of Ag-Au core-shell nanoparticles into: AgAu alloyed, Au-Ag core-shell, hollow Au-Ag2O core-shell, and Au-Ag2O yolk-shell nanoparticles. We are able to directly image these morphological transformations in real-time at atomic resolution and perform energy dispersive X-ray (EDX) spectrum imaging to map changing elemental distributions with sub-nanometre resolution. By combining aberration corrected STEM imaging and high efficiency EDX spectroscopy we are able to quantify not only the growth and coalescence of Kirkendall voids during oxidation but also the compositional changes occurring during this reaction. This is the first time that it has been possible to track the changing distribution of elements in an individual nanoparticle undergoing oxidation driven shell growth and hollowing. PMID- 25271699 TI - White Crucifixion and Listening to the Cockerel: Marc Chagall. PMID- 25271700 TI - Ramelteon and the prevention of delirium. PMID- 25271701 TI - Family-based replication study of schizophrenia genes. PMID- 25271702 TI - Water-exchange rates of lanthanide ions in an ionic liquid. AB - The first ligand-exchange rate measurements of lanthanide ions in an ionic liquid are reported here. The trend of water-exchange rates in the ionic liquid is the opposite of the trend in water. PMID- 25271703 TI - What are preferred water-aromatic interactions in proteins and crystal structures of small molecules? AB - The distribution of water molecules around aromatic rings in the protein structures and crystal structures of small molecules shows quite a small number of the strongest OH-pi interactions, a larger number of parallel interactions, and the largest number of the weakest CH-O interactions. PMID- 25271704 TI - Studying orthogonal self-assembled systems: microstructure of gelled bicontinuous microemulsions. AB - An orthogonal self-assembled system consists of different structures which coexist independently. Furthermore, the characteristic properties of the respective "base systems", i.e. of the systems which contain only one of the structures, are retained in the orthogonal self-assembled system. We have identified gelled bicontinuous microemulsions as orthogonal self-assembled systems and reported in a preceding paper (Soft Matter, 2013, 9, 3661) that their phase behaviour and rheological properties are in perfect agreement with those of the two base systems, namely a non-gelled bicontinuous microemulsion and a binary gel. In the paper at hand we present the results of structural investigations. With FT-PGSE (1)H-NMR measurements we verified the bicontinuity of our gelled model system H2O-n-decane/12-hydroxyoctadecanoic acid (12-HOA)-tetraethylene glycol monodecyl ether (C10E4) at appropriate temperatures. Apart from that, we proved the coexistence of the bicontinuous microemulsion domains with the gelator network in a small angle neutron scattering (SANS) study. A qualitative comparison between the SANS data of the gelled bicontinuous microemulsion and those of its base systems reveals that the characteristic scattering features of both base systems are present. Moreover, we were able to quantitatively describe and interpret the SANS data, yielding at the same time the structural parameters of the bicontinuous microemulsion and the gelator network. PMID- 25271705 TI - History of anaesthesia: the conception and birth of the European Academy of Anaesthesiology. PMID- 25271706 TI - IgE-specific immunoadsorption for treatment of recalcitrant atopic dermatitis. PMID- 25271707 TI - Numerical analysis for elucidation of nonlinear frictional characteristics of a deformed erythrocyte moving on a plate in medium subject to inclined centrifugal force. AB - Complex interactions between blood cells, plasma proteins, and glycocalyx in the endothelial surface layer are crucial in microcirculation. To obtain measurement data of such interactions, we have previously performed experiments using an inclined centrifuge microscope, which revealed that the nonlinear velocity friction characteristics of erythrocytes moving on an endothelia-cultured glass plate in medium under inclined centrifugal force are much larger than those on plain or material-coated glass plates. The purpose of this study was to elucidate the nonlinear frictional characteristics of an erythrocyte on plain or material coated glass plates as the basis to clarify the interaction between the erythrocyte and the endothelial cells. We propose a model in which steady motion of the cell is realized as an equilibrium state of the force and moment due to inclined centrifugal force and hydrodynamic flow force acting on the cell. Other electrochemical effects on the surfaces of the erythrocyte and the plate are ignored for the sake of simplicity. Numerical analysis was performed for a three dimensional flow of a mixture of plasma and saline around a rigid erythrocyte model of an undeformed biconcave shape and a deformed shape with a concave top surface and a flat bottom surface. A variety of conditions for the concentration of plasma in a medium, the velocity of the cell, and the minimum gap width and the angle of attack of the cell from the plate, were examined to obtain the equilibrium states. A simple flat plate model based on the lubrication theory was also examined to elucidate the physical meaning of the model. The equilibrium angle of attack was obtained only for the deformed cell model and was represented as a power function of the minimum gap width. A simple flat plate model qualitatively explains the power function relation of the frictional characteristics, but it cannot explain the equilibrium relation, confirming the computational result that the deformation of the cell is necessary for the equilibrium. The frictional characteristics obtained from the present computation qualitatively agree with those of former experiments, showing the validity of the proposed model. PMID- 25271708 TI - The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. AB - A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2 p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation. SP-141 has strong in vitro and in vivo antibreast cancer activity, with no apparent host toxicity. While further investigation is needed, our data indicate that SP-141 is a novel targeted therapeutic agent that may especially benefit patients with advanced disease. PMID- 25271709 TI - Redox cycling without reference electrodes. AB - The reference electrode is a key component in electrochemical measurements, yet it remains a challenge to implement a reliable reference electrode in miniaturized electrochemical sensors. Here we explore experimentally and theoretically an alternative approach based on redox cycling which eliminates the reference electrode altogether. We show that shifts in the solution potential caused by the lack of reference can be understood quantitatively, and determine the requirements for accurate measurements in miniaturized systems in the absence of a reference electrode. PMID- 25271710 TI - The Navigation Guide: systematic review for the environmental health sciences. PMID- 25271711 TI - Monophasic ligand-free alloy nanoparticle synthesis determinants during pulsed laser ablation of bulk alloy and consolidated microparticles in water. AB - Chemical syntheses of homogenous solid solution alloy nanoparticles of noble metals require high temperature above 100 degrees C. Beside this, aqueous co reduction methods lead to phase separation. In contrast, pulsed laser ablation in liquid (PLAL) allows synthesis of alloy nanoparticles with totally homogeneous ultrastructure in aqueous media at room temperature without reducing agents or organic ligands. However, to date, the dominant alloy formation process during PLAL is not fully understood. Based on the model of Ag-Au alloy, we elucidate that the underlying mechanism is not affected by post-irradiation or interactions with colloidal particles in solution but is caused directly by ablation. In this context we analyzed nanoparticles generated from alloy targets with 9 different compositions as well as pure Ag and Au references using UV-Vis spectroscopy, TEM and TEM-EDX line scans. The obtained results highlight that the total composition but not the microstructure of the applied target is the dominant parameter ruling elemental composition in the resulting solid solution alloy nanoparticles. Based on these findings, the application of pressed targets of metal powder mixtures in a continuous laser process with residence time <60 s allows economical fabrication of alloy nanoparticles ideally suited for applications in catalysis or biomedicine. PMID- 25271712 TI - Overview of peptide and protein analysis by mass spectrometry. AB - Mass spectrometry is an indispensable tool for peptide and protein analysis owing to its speed, sensitivity, and versatility. It can be used to determine amino acid sequences of peptides, and to characterize a wide variety of post translational modifications such as phosphorylation and glycosylation. Mass spectrometry can also be used to determine absolute and relative protein quantities, and can identify and quantify thousands of proteins from complex samples, which makes it an extremely powerful tool for systems biology studies. The main goals of this unit are to familiarize peptide and protein chemists and biologists with the types of mass spectrometers that are appropriate for the majority of their analytical needs, to describe the kinds of experiments that can be performed with these instruments on a routine basis, and to discuss the kinds of information that these experiments provide. PMID- 25271713 TI - Production of Disulfide-Bonded Proteins in Escherichia coli. AB - Production of recombinant proteins at high yields in Escherichia coli requires extensive optimization of expression conditions. Production is further complicated for proteins that require specific post-translational modifications for their eventual folding. One common and particularly important post translational modification is oxidation of the correct pair of cysteines to form a disulfide bond. This unit describes methods to produce disulfide-bonded proteins in E. coli in either the naturally oxidizing periplasm or the cytoplasm of appropriately engineered cells. The focus is on variables key to improving the oxidative folding of disulfide-bonded proteins, with the aim of helping the researcher optimize expression conditions for a protein of interest. PMID- 25271715 TI - Protein synthesis using a reconstituted cell-free system. AB - Most cell-free protein-synthesis systems are based on cell extracts, which often contain undesirable activities. Reconstituted systems, by contrast, are composed of a defined number of purified and recombinant components with minimal nuclease and protease activities. This unit describes the use of a particular commercial reconstituted system, PURExpress. This system allows in vitro synthesis of proteins from mRNA and circular and linear DNA templates, as well as co translational labeling of proteins. Unique to this system, all recombinant protein components of the system are His-tagged, allowing purification of the synthesized untagged protein by removing the rest of the system's components. Newly synthesized proteins can often be visible on an SDS-PAGE gel and directly assayed for their functions without labeling and purification. Certain components of the system, such as ribosomes or release factors, can be omitted for specific applications. Such "delta" versions of the system are well suited for studies of bacterial translation, assays of ribosome function, incorporation of unnatural amino acids, and ribosome display of protein libraries. PMID- 25271714 TI - Overview of cell-free protein synthesis: historic landmarks, commercial systems, and expanding applications. AB - During the early days of molecular biology, cell-free protein synthesis played an essential role in deciphering the genetic code and contributed to our understanding of translation of protein from messenger RNA. Owing to several decades of major and incremental improvements, modern cell-free systems have achieved higher protein synthesis yields at lower production costs. Commercial cell-free systems are now available from a variety of material sources, ranging from "traditional" E. coli, rabbit reticulocyte lysate, and wheat germ extracts, to recent insect and human cell extracts, to defined systems reconstituted from purified recombinant components. Although each cell-free system has certain advantages and disadvantages, the diversity of the cell-free systems allows in vitro synthesis of a wide range of proteins for a variety of downstream applications. In the post-genomic era, cell-free protein synthesis has rapidly become the preferred approach for high-throughput functional and structural studies of proteins and a versatile tool for in vitro protein evolution and synthetic biology. This unit provides a brief history of cell-free protein synthesis and describes key advances in modern cell-free systems, practical differences between widely used commercial cell-free systems, and applications of this important technology. PMID- 25271717 TI - Next-Gen Sequencing-Based Mapping and Identification of Ethyl Methanesulfonate Induced Mutations in Arabidopsis thaliana. AB - Forward genetic analysis using ethyl methanesulfonate (EMS) mutagenesis has proven to be a powerful tool in biological research, but identification and cloning of causal mutations by conventional genetic mapping approaches is a painstaking process. Recent advances in next-gen sequencing have greatly invigorated the process of identifying EMS-induced mutations corresponding to a specific phenotype in model genetic hosts, including the plant Arabidopsis thaliana and the nematode Caenorhabditis elegans. Next-gen sequencing of bulked F2 mutant recombinants produces a wealth of high-resolution genetic data, provides enhanced delimitation of the genomic location of mutations, and greatly reduces hands-on time while maintaining high accuracy and reproducibility. In this unit, a detailed procedure to simultaneously map and identify EMS mutations in Arabidopsis is described. PMID- 25271716 TI - Genome-Wide Analysis of Nucleosome Positions, Occupancy, and Accessibility in Yeast: Nucleosome Mapping, High-Resolution Histone ChIP, and NCAM. AB - Because histones bind DNA very tightly, the location on DNA and the level of occupancy of a given DNA sequence by nucleosomes can profoundly affect accessibility of non-histone proteins to chromatin, affecting virtually all DNA dependent processes, such as transcription, DNA repair, DNA replication and recombination. Therefore, it is often necessary to determine positions and occupancy of nucleosomes to understand how DNA-dependent processes are regulated. Recent technological advances made such analyses feasible on a genome-wide scale at high resolution. In addition, we have recently developed a method to measure nuclease accessibility of nucleosomes on a global scale. This unit describes methods to map nucleosome positions, to determine nucleosome density, and to determine nuclease accessibility of nucleosomes using deep sequencing. PMID- 25271720 TI - Happy birthday JCI. AB - On the occasion of the ninetieth anniversary of the JCI, I am again humbled by the remarkable insight and passion of our pioneering founders when they created the Journal of Clinical Investigation in 1924. PMID- 25271721 TI - Twenty-six compelling conversations. PMID- 25271722 TI - A tribute to Arnold S. Relman (1923-2014). PMID- 25271723 TI - Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. AB - The past decade has been one of rapid innovation in genome-editing technology. The opportunity now exists for investigators to manipulate virtually any gene in a diverse range of cell types and organisms with targeted nucleases designed with sequence-specific DNA-binding domains. The rapid development of the field has allowed for highly efficient, precise, and now cost-effective means by which to generate human and animal models of disease using these technologies. This review will outline the recent development of genome-editing technology, culminating with the use of CRISPR-Cas9 to generate novel mammalian models of disease. While the road to using this same technology for treatment of human disease is long, the pace of innovation over the past five years and early successes in model systems build anticipation for this prospect. PMID- 25271724 TI - The microbiome revolution. AB - The collection of bacteria, viruses, and fungi that live in and on the human body, collectively known as the microbiome, has recently emerged as an important factor in human physiology and disease. The gut in particular is a biological niche that is home to a diverse array of microbes that influence nearly all aspects of human biology through their interactions with their host; new technologies are beginning to reveal important aspects of host-microbe interactions. Articles in this Review series address how perturbations of the microbiota, such as through antibiotic use, influence its overall structure and function; how our microbiome influences the impact of infectious agents, such as C. difficile; how our microbiome mediates metabolism of xenobiotics; how the microbiota contribute to immunity as well as to metabolic and inflammatory diseases; and the role of commensal microbes in oncogenesis. PMID- 25271725 TI - The contributory role of gut microbiota in cardiovascular disease. AB - Our group recently discovered that certain dietary nutrients possessing a trimethylamine (TMA) moiety, namely choline/phosphatidylcholine and L-carnitine, participate in the development of atherosclerotic heart disease. A meta organismal pathway was elucidated involving gut microbiota-dependent formation of TMA and host hepatic flavin monooxygenase 3-dependent (FMO3-dependent) formation of TMA-N-oxide (TMAO), a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks. Collectively, these studies reveal that nutrient precursors, gut microbiota, and host participants along the meta-organismal pathway elucidated may serve as new targets for the prevention and treatment of CVD. PMID- 25271727 TI - TDM Journal Club: Safety and Immunogenicity of Tetanus Diphtheria and Acellular Pertussis Immunization During Pregnancy. PMID- 25271726 TI - Antibiotics and the gut microbiota. AB - Antibiotics have been a cornerstone of innovation in the fields of public health, agriculture, and medicine. However, recent studies have shed new light on the collateral damage they impart on the indigenous host-associated communities. These drugs have been found to alter the taxonomic, genomic, and functional capacity of the human gut microbiota, with effects that are rapid and sometimes persistent. Broad-spectrum antibiotics reduce bacterial diversity while expanding and collapsing membership of specific indigenous taxa. Furthermore, antibiotic treatment selects for resistant bacteria, increases opportunities for horizontal gene transfer, and enables intrusion of pathogenic organisms through depletion of occupied natural niches, with profound implications for the emergence of resistance. Because these pervasive alterations can be viewed as an uncoupling of mutualistic host-microbe relationships, it is valuable to reconsider antimicrobial therapies in the context of an ecological framework. Understanding the biology of competitive exclusion, interspecies protection, and gene flow of adaptive functions in the gut environment may inform the design of new strategies that treat infections while preserving the ecology of our beneficial constituents. PMID- 25271728 TI - Which Genetic Determinants Should be Considered for Tacrolimus Dose Optimization in Kidney Transplantation? A Combined Analysis of Genes Affecting the CYP3A Locus. AB - BACKGROUND: Tacrolimus is established as immunosuppressant after kidney transplantation. Polymorphism of the cytochrome P450 3A5 (CYP3A5) gene contributes significantly to tacrolimus dose requirements. Recently, CYP3A4*22 was reported to additionally affect tacrolimus pharmacokinetics (PK). In addition, there are further polymorphic genes, possibly influencing CYP3A activity [pregnane x receptor NR1I2, P450 oxidoreductase (POR), and peroxisome proliferator-activator receptor alpha (PPARA)]. We aimed to investigate combined effects of these gene variants on tacrolimus maintenance dose and PK in patients with stable kidney transplantation of 2 study centers. METHODS: A total of 223 white patients (German cohort, 136; Danish cohort, 87) was included and genotyped for CYP3A5 (rs776746), CYP3A4 (rs35599367), NR1I2 (rs2276707), POR (rs1057868), and PPARA (rs4253728). Dosage and trough concentration/dose ratios were considered separately. A subset was investigated for comprehensive PK parameters. RESULTS: Tacrolimus dose, trough concentration, and trough concentration/dose ratio did not differ between the German and Danish cohort. CYP3A5*3 and CYP3A4*22 contributed to dose requirements only in the German and in the total cohort. Homozygous carriers of both variants required 4.8 +/- 3.1 mg, whereas carriers of the wild types required 165% higher mean tacrolimus doses (12.5 +/- 7.7 mg, P = 1.4 * 10). The PK investigation revealed only nonsignificant impact of CYP3A4 genotypes on AUC12h in CYP3A5 nonexpressers (P = 0.079, power = 57%). For the entire sample, the final multiple linear regression model for trough concentration/dose ratio included CYP3A5, CYP3A4, and age. It explained 18.3% of the interindividual variability of tacrolimus trough concentration/dose ratios (P = 8.8 * 10). CONCLUSIONS: Therapeutic drug monitoring remains essential in clinical care of patients with kidney transplantation. Genotyping of CYP3A5 and CYP3A4, however, could facilitate rapid dose finding to adapt the appropriate immunosuppressant dose, whereas other genetic factors had only little or no effect. PMID- 25271729 TI - Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study. AB - BACKGROUND: Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided individualized dosing to reduce the interpatient variability in pazopanib exposure. METHODS: Thirteen patients were treated with pazopanib for 3 consecutive periods of 2 weeks. During the first period, all patients received 800 mg of pazopanib once daily to reach steady-state exposure. During the second period, the patients either received a PK-guided individualized pazopanib dose or the registered fixed 800-mg dose. During the third period, these 2 dosing regimens were switched. RESULTS: The interpatient variability in pazopanib AUC0-24h during fixed dosing (27.3 coefficient of variation) was not significantly different when compared with the variability in AUC0-24h during PK-guided dosing (24.8 coefficient of variation). The percentage of patients within the target window during PK-guided dosing (53.9%) was not significantly different from the percentage during fixed dosing (46.2%). Both Ctrough and C24 were significantly (P < 0.001) correlated to pazopanib AUC0-24h (R = 0.596 and R = 0.940, respectively). Pazopanib AUC0-24h decreased 17% over time. CONCLUSIONS: PK-guided dosing did not reduce the interpatient variability in pazopanib exposure. In this study, the intrapatient variability in pazopanib exposure was relatively large compared with interpatient variability. This makes it challenging to achieve a target exposure within a predefined window. The causes of intrapatient variability must first be better understood and controlled, before PK-guided dosing can reduce the interpatient variability. PMID- 25271730 TI - Biogeography of human infectious diseases: a global historical analysis. AB - OBJECTIVES: Human pathogen richness and prevalence vary widely across the globe, yet we know little about whether global patterns found in other taxa also predict diversity in this important group of organisms. This study (a) assesses the relative importance of temperature, precipitation, habitat diversity, and population density on the global distributions of human pathogens and (b) evaluates the species-area predictions of island biogeography for human pathogen distributions on oceanic islands. METHODS: Historical data were used in order to minimize the influence of differential access to modern health care on pathogen prevalence. The database includes coded data (pathogen, environmental and cultural) for a worldwide sample of 186 non-industrial cultures, including 37 on islands. Prevalence levels for 10 pathogens were combined into a pathogen prevalence index, and OLS regression was used to model the environmental determinants of the prevalence index and number of pathogens. RESULTS: Pathogens (number and prevalence index) showed the expected latitudinal gradient, but predictors varied by latitude. Pathogens increased with temperature in high latitude zones, while mean annual precipitation was a more important predictor in low-latitude zones. Other environmental factors associated with more pathogens included seasonal dry extremes, frost-free climates, and human population density outside the tropics. Islands showed the expected species-area relationship for all but the smallest islands, and the relationship was not mediated by habitat diversity. Although geographic distributions of free-living and parasitic taxa typically have different determinants, these data show that variables that influence the distribution of free-living organisms also shape the global distribution of human pathogens. Understanding the cause of these distributions is potentially important, since geographical variation in human pathogens has an important influence on global disparities in human welfare. PMID- 25271731 TI - OTC supplements: healthy or not? PMID- 25271732 TI - Best practices for engaging patients with dementia. PMID- 25271734 TI - Assessment of risk factors for delayed colonic post-polypectomy hemorrhage: a study of 15553 polypectomies from 2005 to 2013. AB - BACKGROUND AND AIM: Delayed colonic postpolypectomy bleeding is the commonest serious complication after polypectomy. This study aimed to utilize massive sampling data of polypectomy to analyze risk factors for delayed postpolypectomy bleeding. PATIENTS AND METHODS: The endoscopic data of 5600 patients with 15553 polyps removed (2005 to 2013) were analyzed retrospectively through univariate analysis and multiple logistic regression analysis to evaluate the risk factors for delayed bleeding. RESULTS: Delayed postpolypectomy bleeding occurred in 99 polyps (0.6%). The rates of bleeding for different polypectomy methods including hot biopsy forcep, biopsy forcep, Argon Plasma Coagulation (APC), Endoscopy piecemeal mucosal resection (EPMR), Endoscopic Mucosal Resection (EMR), and snare polypectomy were 0.1%, 0.0%, 0.0%, 6.9%, 0.9% and 1.0%, respectively. The risk factors for delayed bleeding were the size of polyps over 10 mm (odds ratio [OR] = 4.6, 95% CI, 2.9-7.2), pathology of colonic polyps (inflammatory/hyperplastic, OR = 1; adenomatous, OR = 1.4, 95% CI, 0.7-2.6; serrated, OR = 1.5, 95% CI, 0.2 11.9; juvenile, OR = 4.3, 95% CI, 1.8-11.0; Peutz-Jegher, OR = 3.3, 95% CI, 1.0 10.7), and immediate postpolypectomy bleeding (OR = 2.9, 95% CI, 1.4-5.9). In addition, although polypectomy method was not a risk factor, compared with hot biopsy forcep, snare polypectomy, EMR, and EPMR had increased risks of delayed bleeding, with ORs of 3.2 (0.4-23.3), 2.8 (0.4-21.7) and 5.1 (0.5-47.7), respectively. CONCLUSION: Polyp size over 10 mm, pathology of colonic polyps (especially juvenile, Peutz-Jegher), and immediate postpolypectomy bleeding were significant risk factors for delayed postpolypectomy bleeding. PMID- 25271735 TI - Pre- and postovulatory aging of murine oocytes affect the transcript level and poly(A) tail length of maternal effect genes. AB - Maternal effect genes code for oocyte proteins that are important for early embryogenesis. Transcription in oocytes does not take place from the onset of meiotic progression until zygotic genome activation. During this period, protein levels are regulated posttranscriptionally, for example by poly(A) tail length. Posttranscriptional regulation may be impaired in preovulatory and postovulatory aged oocytes, caused by delayed ovulation or delayed fertilization, respectively, and may lead to developmental defects. We investigated transcript levels and poly(A) tail length of ten maternal effect genes in in vivo- and in vitro- (follicle culture) grown oocytes after pre- and postovulatory aging. Quantitative RT-PCR was performed using random hexamer-primed cDNA to determine total transcript levels and oligo(dT)16-primed cDNA to analyze poly(A) tail length. Transcript levels of in vivo preovulatory-aged oocytes remained stable except for decreases in Brg1 and Tet3. Most genes investigated showed a tendency towards increased poly(A) content. Polyadenylation of in vitro preovulatory-aged oocytes was also increased, along with transcript level declines of Trim28, Nlrp2, Nlrp14 and Zar1. In contrast to preovulatory aging, postovulatory aging of in vivo- and in vitro-grown oocytes led to a shortening of poly(A) tails. Postovulatory aging of in vivo-grown oocytes resulted in deadenylation of Nlrp5 after 12 h, and deadenylation of 4 further genes (Tet3, Trim28, Dnmt1, Oct4) after 24 h. Similarly, transcripts of in vitro-grown oocytes were deadenylated after 12 h of postovulatory aging (Tet3, Trim28, Zfp57, Dnmt1, Nlrp5, Zar1). This impact of aging on poly(A) tail length may affect the timed translation of maternal effect gene transcripts and thereby contribute to developmental defects. PMID- 25271737 TI - Human granulocytic anaplasmosis, South Korea, 2013. AB - We report a patient with human granulocytic anaplasmosis in South Korea. The patient had fever and thrombocytopenia. Human granulocytic anaplasmosis was confirmed by seroconversion, PCR, and sequence analysis for Anaplasma phagocytophilum. Morulae were observed in the cultured HL-60 cells inoculated with blood from the patient. PMID- 25271738 TI - Invasion of melanoma to angiolipoma in a male Siamese fighting fish, Betta splendens, Regan. PMID- 25271736 TI - Androgen suppresses the proliferation of androgen receptor-positive castration resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2. AB - The majority of prostate cancer (PCa) patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC). We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR) and induced G1 cell cycle arrest in androgen-independent LNCaP 104 R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1); and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1) and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2. PMID- 25271739 TI - Socioeconomic disparity in breast cancer detection in Hong Kong--a high income city: retrospective epidemiological study using the Breast Cancer Registry. AB - BACKGROUND: It is not known whether socioeconomic disparities affect the detection of breast cancer in Asian countries where the incidence of breast cancer is a rising trend. In this study, we explore the socioeconomic profiles of women and the stage of the disease at the time of diagnosis in breast cancer patients aged 40 or over in Hong Kong. METHOD: During the period 2008 to 2011, 5393 breast cancer patients registered with the Hong Kong Breast Cancer Registry. Participants and their clinicians were asked to complete standardised questionnaires including patient socio-demographics, health history and risk factors, the course of the disease, post-treatment physical discomfort and psychosocial impact, follow-up recurrence and survival status. RESULTS: Monthly household incomes, educational levels and the practice of regular screening are independently associated with the stage of the disease at diagnosis. Higher socioeconomic status and a higher educational level were associated with an earlier stage of the disease at the time of diagnosis. Yearly clinical examinations, ultrasound and mammographic screening every 2 to 3 years were significantly associated with the earlier detection of breast cancer. CONCLUSION: There were socioeconomic disparities among Hong Kong women who were found to have breast cancer. Population-based screening policies, including raising awareness among women at risk, should be implemented. PMID- 25271740 TI - Defining the roles of IL-33, thymic stromal lymphopoietin, and IL-25 in human asthma. PMID- 25271741 TI - Bridging genetics, epidemiology, and respiratory medicine. PMID- 25271742 TI - HIV-related chronic obstructive pulmonary disease. Are lung CD4 T cells bothered? PMID- 25271743 TI - Former preterm infants, caffeine was good for you, but now beware of snoring! PMID- 25271744 TI - Update in pulmonary vascular diseases 2013. PMID- 25271745 TI - An official American Thoracic Society/American Association of Critical-Care Nurses/American College of Chest Physicians/Society of Critical Care Medicine policy statement: the Choosing Wisely(r) Top 5 list in Critical Care Medicine. AB - RATIONALE: The high costs of health care in the United States and other developed nations are attributable, in part, to overuse of tests, treatments, and procedures that provide little to no benefit for patients. To improve the quality of care while also combating this problem of cost, the American Board of Internal Medicine Foundation developed the Choosing Wisely Campaign, tasking professional societies to develop lists of the top five medical services that patients and physicians should question. OBJECTIVES: To present the Critical Care Societies Collaborative's Top 5 list in Critical Care Medicine and describe its development. METHODS: Each professional society in the Collaborative nominated members to the Choosing Wisely task force, which established explicit criteria for evaluating candidate items, generated lists of items, performed literature reviews on each, and sought external input from content experts. Task force members narrowed the list to the Top 5 items using a standardized scoring system based on each item's likely overall impact and merits on the five explicit criteria. MEASUREMENTS AND MAIN RESULTS: From an initial list of 58 unique recommendations, the task force proposed a Top 5 list that was ultimately endorsed by each Society within the Collaborative. The five recommendations are: (1) do not order diagnostic tests at regular intervals (such as every day), but rather in response to specific clinical questions; (2) do not transfuse red blood cells in hemodynamically stable, nonbleeding ICU patients with an Hb concentration greater than 7 g/dl; (3) do not use parenteral nutrition in adequately nourished critically ill patients within the first 7 days of an ICU stay; (4) do not deeply sedate mechanically ventilated patients without a specific indication and without daily attempts to lighten sedation; and (5) do not continue life support for patients at high risk for death or severely impaired functional recovery without offering patients and their families the alternative of care focused entirely on comfort. CONCLUSIONS: These five recommendations provide a starting point for clinicians and patients to make decisions leading to higher-quality, lower-cost care. Future work is needed to promote adherence to these recommendations and to develop additional ways for intensive care clinicians to take leadership in reining in health-care costs. PMID- 25271746 TI - Protocol-based treatment of septic shock, fibrinolysis for submassive pulmonary embolism, and use of corticosteroids in acute exacerbations of chronic obstructive pulmonary disease requiring mechanical ventilation. PMID- 25271747 TI - Disseminated tuberculosis with splenic tuberculosis abscess rupture. A rare presentation. PMID- 25271749 TI - Inoculation of QuantiFERON-TB tubes with skin microbiota causes false-positive results. PMID- 25271748 TI - The allocation of intensivists' rounding time under conditions of intensive care unit capacity strain. PMID- 25271750 TI - Phrenic nerve stimulation increases human diaphragm fiber force after cardiothoracic surgery. PMID- 25271751 TI - Primary and secondary prevention of chronic obstructive pulmonary disease: where to next? PMID- 25271752 TI - Reply: primary and secondary prevention of chronic obstructive pulmonary disease: where to next? PMID- 25271753 TI - Two faces of vitamin e in the lung. PMID- 25271754 TI - Reply: Understanding the roles of the vitamin E isoforms alpha- and gamma tocopherol in allergic airway disease. PMID- 25271756 TI - Malignant uveitis masquerade syndrome. PMID- 25271757 TI - Pulmonary artery aneurysms. PMID- 25271758 TI - The prognostic value of HPV status and p16 expression in patients with carcinoma of the anal canal. AB - BACKGROUND: In anal cancer studies, the detection frequency of high-risk HPV (human papillomavirus) is variable, depending on the method used. There are limited data reporting results of different HPV detection techniques in the same clinical series, and very few correlating results with clinical outcome. OBJECTIVES: To evaluate tumor expression of p16/HPV16 using three different methods, and to determine their association with clinical outcome in patients with anal canal squamous cell carcinomas (SCC). DESIGN: This retrospective study included patients with anal canal SCC treated with definitive radiotherapy or chemoradiotherapy at a single institution between 1992 and 2005. Formalin-fixed paraffin-embedded tumor samples from 53 of the 89 (60%) patient pre-treatment biopsies were adequate for tissue microarray construction. HPV status was determined using: p16 expression by conventional immunohistochemistry (IHC) and quantitative IHC (AQUA), HPV genotype analysis by chromogenic in situ hybridization (CISH) and HPV linear array sub-typing. Expression status was correlated with clinical outcome. RESULTS: 80% (28/35) of patient tumors had high p16 expression using conventional IHC. HPV16 CISH was positive in 81% (34/42) of tumors, and 78% (28/36) of tumors were HPV subtype 16. HPV16 CISH correlated with p16 evaluated by conventional IHC (correlation coefficient 0.46; p = 0.01) and by p16 AQUA score (correlation coefficient 0.49; p = 0.001). A subset of cases (15%) had very high p16 quantitative IHC scores (>244) and were associated with a higher incidence of local or distant recurrence (p = 0.04). CONCLUSIONS: The vast majority (80%) of anal canal SCC in our series were positive for HPV16/p16, regardless of the testing method used. The exploratory analysis of automated quantitative IHC scoring was the only technique to define a subset of patients with a worse prognosis by p16 expression status on univariate analysis. Further exploration of the molecular mechanisms of treatment resistance in association with very high p16 expression is warranted. PMID- 25271759 TI - New insights into muscle function during pivot feeding in seahorses. AB - Seahorses, pipefish and their syngnathiform relatives are considered unique amongst fishes in using elastic recoil of post-cranial tendons to pivot the head extremely quickly towards small crustacean prey. It is known that pipefish activate the epaxial muscles for a considerable time before striking, at which rotations of the head and the hyoid are temporarily prevented to allow energy storage in the epaxial tendons. Here, we studied the motor control of this system in seahorses using electromyographic recordings of the epaxial muscles and the sternohyoideus-hypaxial muscles with simultaneous high-speed video recordings of prey capture. In addition we present the results from a stimulation experiment including the muscle hypothesised to be responsible for the locking and triggering of pivot feeding in seahorses (m. adductor arcus palatini). Our data confirmed that the epaxial pre-activation pattern observed previously for pipefish also occurs in seahorses. Similar to the epaxials, the sternohyoideus hypaxial muscle complex shows prolonged anticipatory activity. Although a considerable variation in displacements of the mouth via head rotation could be observed, it could not be demonstrated that seahorses have control over strike distance. In addition, we could not identify the source of the kinematic variability in the activation patterns of the associated muscles. Finally, the stimulation experiment supported the previously hypothesized role of the m. adductor arcus palatini as the trigger in this elastic recoil system. Our results show that pre-stressing of both the head elevators and the hyoid retractors is taking place. As pre-activation of the main muscles involved in pivot feeding has now been demonstrated for both seahorses and pipefish, this is probably a generalized trait of Syngnathidae. PMID- 25271761 TI - In situ CO2 efflux from leaf litter layer showed large temporal variation induced by rapid wetting and drying cycle. AB - We performed continuous and manual in situ measurements of CO2 efflux from the leaf litter layer (R(LL)) and water content of the leaf litter layer (LWC) in conjunction with measurements of soil respiration (RS) and soil water content (SWC) in a temperate forest; our objectives were to evaluate the response of R(LL) to rainfall events and to assess temporal variation in its contribution to R(S). We measured R(LL) in a treatment area from which all potential sources of CO2 except for the leaf litter layer were removed. Capacitance sensors were used to measure LWC. R(LL) increased immediately after wetting of the leaf litter layer; peak R(LL) values were observed during or one day after rainfall events and were up to 8.6-fold larger than R(LL) prior to rainfall. R(LL) declined to pre-wetting levels within 2-4 day after rainfall events and corresponded to decreasing LWC, indicating that annual R(LL) is strongly influenced by precipitation. Temporal variation in the observed contribution of R(LL) to RS varied from nearly zero to 51%. Continuous in situ measurements of LWC and CO2 efflux from leaf litter only, combined with measurements of RS, can provide robust data to clarify the response of R(LL) to rainfall events and its contribution to total R(S). PMID- 25271760 TI - Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity. AB - Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of alpha-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure-activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with Ki values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R(2) of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood-brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26-1.8 MUM) against glioma cells with the IDH1 R132H mutation. PMID- 25271762 TI - Predicting the effects of nanoscale cerium additives in diesel fuel on regional scale air quality. AB - Diesel vehicles are a major source of air pollutant emissions. Fuel additives containing nanoparticulate cerium (nCe) are currently being used in some diesel vehicles to improve fuel efficiency. These fuel additives also reduce fine particulate matter (PM2.5) emissions and alter the emissions of carbon monoxide (CO), nitrogen oxides (NOx), and hydrocarbon (HC) species, including several hazardous air pollutants (HAPs). To predict their net effect on regional air quality, we review the emissions literature and develop a multipollutant inventory for a hypothetical scenario in which nCe additives are used in all on road and nonroad diesel vehicles. We apply the Community Multiscale Air Quality (CMAQ) model to a domain covering the eastern U.S. for a summer and a winter period. Model calculations suggest modest decreases of average PM2.5 concentrations and relatively larger decreases in particulate elemental carbon. The nCe additives also have an effect on 8 h maximum ozone in summer. Variable effects on HAPs are predicted. The total U.S. emissions of fine-particulate cerium are estimated to increase 25-fold and result in elevated levels of airborne cerium (up to 22 ng/m3), which might adversely impact human health and the environment. PMID- 25271763 TI - Dynamics and thermodynamics of crystalline polymorphs. 3. gamma-Glycine, analysis of variable-temperature atomic displacement parameters, and comparison of polymorph stabilities. AB - In a series of systematic studies, we have investigated the molecular motion in crystals of the glycine polymorphs and determined their thermodynamic functions from an analysis of multitemperature atomic displacement parameters (ADPs) combined with ONIOM calculation on 15-molecule clusters. The studies are aimed at providing insight into the factors governing the relative stabilities of the alpha-, beta-, and gamma-polymorphs. This Article, the last in the series, focuses on the most stable polymorph, gamma-glycine. Multitemperature diffraction data of the gamma-glycine polymorph have been collected to 0.5 A resolution between 10 and 300 K at two synchrotron beamlines, KEK Photon Factory and ID11 of the ESRF. The ADPs of gamma-glycine from these sources differ significantly, as previously observed also for the other two polymorphs. A simple model of rigid body motion explains the ADPs from KEK and their temperature dependence. It provides lattice vibration frequencies that are in line with those from Raman spectroscopy. Together with the internal vibration frequencies from an ONIOM calculation, the thermodynamic functions are estimated using the Einstein, Debye, and Nernst-Lindemann models of heat capacity. The relative stabilities of the three polymorphs of glycine are discussed on the basis of the contributions to their free energies as obtained in this work and from various experimental and theoretical studies. The comparison shows that the free-energy differences are determined primarily by differences in lattice and zero-point vibrational energies. PMID- 25271764 TI - Citrulline reduces glyceroneogenesis and induces fatty acid release in visceral adipose tissue from overweight rats. AB - SCOPE: High-fat diet (HFD) increases visceral adipose tissue (AT). Our aim was to evaluate whether citrulline (CIT) affected nonesterified fatty acid (NEFA) metabolism in AT from HFD-fed rats. METHODS AND RESULTS: Rats were fed for 8 weeks with either a control diet (CD) or HFD. Retroperitoneal AT explants were exposed to 2.5 mmol/L CIT for 24 h. We analyzed lipolysis, beta-oxidation, glyceroneogenesis, and the expression of the key associated enzymes. CIT doubled NEFA release selectively in HFD AT. Phosphorylation of hormone-sensitive lipase was upregulated 50 and 100% by CIT in CD and HFD AT, respectively. Under CIT, beta-oxidation increased similarly whatever the diet, whereas glyceroneogenesis, which permits NEFA re-esterification, was downregulated 50 and 80% in CD and HFD AT, respectively. In the latter, the important decrease in re-esterification probably explains the rise of NEFA release. A pretreatment with the nitric oxide synthase inhibitor N omega-nitro-l-arginine methyl ester abolished CIT effects. CONCLUSION: These results demonstrate direct lipolytic and antiglyceroneogenic effects of CIT on CD and HFD AT. The selective CIT-mediated NEFA release from HFD AT was probably the consequence of the drastic decrease in glyceroneogenesis and nitric oxide was a mediator of CIT effects. These results provide evidence for a direct action of CIT on AT to reduce overweight. PMID- 25271766 TI - Is complete umbilical cord scanning possible at the second-trimester ultrasound scan? AB - PURPOSE: To evaluate the feasibility of umbilical cord scanning during the second trimester sonographic examination, we looked at the method of scanning, the findings, and the time spent. METHODS: Five hundred forty-nine singleton pregnancies were evaluated at 18-23 weeks' menstrual age with two-dimensional sonography (US). Color Doppler US was used when needed. The umbilical cord was traced from the fetal insertion site to the placental insertion site. Fetal and placental sites of insertion; number of vessels; presence of knots, cysts, tumors, nuchal cords, or placental anomalies; time spent for scanning; and the use of color Doppler US were noted. RESULTS: The mean maternal age was 33.1 +/- 4.1 years, and the mean menstrual age of the fetuses during scanning was 20.4 +/- 2.4 weeks. The mean time spent for umbilical cord scanning was 41.5 +/- 46.7 seconds. In one case (0.2%), the umbilical cord could not be scanned completely. Color Doppler US was needed in 125 (22.8%) of the scans. Scan results were positive in 153 (27.9%) cases. We observed six cases (1.1%) of a single umbilical artery, two (0.4%) umbilical cord knots, one (0.2%) umbilical cord hernia, and 104 (18.9%) nuchal cords. We also documented 27 (5.0%) marginal insertions, four placenta previa totalis (0.7%), four placenta previa marginalis (0.7%), and eight velamentous insertions (1.5%). CONCLUSIONS: Umbilical cord US scanning is feasible during the second trimester of pregnancy, and complete scanning can be performed in the majority of the cases. Color Doppler analysis may aid scanning when needed. (c) 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:249-253, 2015. PMID- 25271765 TI - Engineering an enhanced, thermostable, monomeric bacterial luciferase gene as a reporter in plant protoplasts. AB - The application of the luxCDABE operon of the bioluminescent bacterium Photorhabdus luminescens as a reporter has been published for bacteria, yeast and mammalian cells. We report here the optimization of fused luxAB (the bacterial luciferase heterodimeric enzyme) expression, quantum yield and its application as a reporter gene in plant protoplasts. The fused luxAB gene was mutated by error prone PCR or chemical mutagenesis and screened for enhanced luciferase activity utilizing decanal as substrate. Positive luxAB mutants with superior quantum yield were subsequently shuffled by DNase I digestion and PCR assembly for generation of recombinants with additional increases in luciferase activity in bacteria. The coding sequence of the best recombinant, called eluxAB, was then optimized further to conform to Arabidopsis (Arabidopsis thaliana) codon usage. A plant expression vector of the final, optimized eluxAB gene (opt-eluxAB) was constructed and transformed into protoplasts of Arabidopsis and maize (Zea mays). Luciferase activity was dramatically increased for opt-eluxAB compared to the original luxAB in Arabidopsis and maize cells. The opt-eluxAB driven by two copies of the 35S promoter expresses significantly higher than that driven by a single copy. These results indicate that the eluxAB gene can be used as a reporter in plant protoplasts. To our knowledge, this is the first report to engineer the bacterium Photorhabdus luminescens luciferase luxAB as a reporter by directed evolution which paved the way for further improving the luxAB reporter in the future. PMID- 25271767 TI - Abnormal accumulation of intestinal fluid following ingestion of an unabsorbable carbohydrate in patients with irritable bowel syndrome: an MRI study. AB - BACKGROUND: Postprandial discomfort following intake of poorly absorbable, but fermentable carbohydrates is a common complaint in patients with irritable bowel syndrome (IBS). We used lactulose as a model substance for this group of symptom triggering carbohydrates, aiming to visualize the intestinal response in IBS patients compared to healthy controls. METHODS: Patients with IBS according to Rome III criteria (n = 52) and healthy controls (n = 16) underwent a lactulose challenge test. By using magnetic resonance imaging, we measured small bowel water content (SBWC), and distension (diameter) of the distal ileum and the colon, both in fasting state and 1 h after ingestion of 10 g lactulose. We recorded symptoms after lactulose ingestion. KEY RESULTS: Lactulose provoked significantly more symptoms in IBS patients than in healthy controls (p < 0.0001). SBWC increased more in the patient group compared to the control group (p = 0.0005). The postprandial diameter of the terminal ileum was larger in patients with IBS and the postprandial diameter of the ascending colon was smaller in patients with diarrhea-predominant phenotype (IBS-D). Symptoms were not correlated with change in SBWC (r = 0.05; p = 0.11), nor to the diameters of the terminal ileum or the colon. CONCLUSIONS & INFERENCES: Compared to healthy controls, IBS patients developed more symptoms and had an abnormal accumulation of fluid in the small bowel in response to ingestion of the unabsorbable carbohydrate lactulose. This may be due to impaired motor activity of the small intestine or impaired function of the ileocecal segment. PMID- 25271768 TI - Who pays for health care in China? The case of Heilongjiang province. AB - BACKGROUND: Health spending by the Chinese government has declined and traditional social health insurance collapsed after economic reforms in the early 1980s; accordingly, the low-income population is exposed to potentially significant healthcare costs. Financing an equitable healthcare system represents a major policy objective in China's current healthcare reform efforts. The current research presents an examination of the distribution of healthcare financing in a north-eastern Chinese province to compare equity status between urban and rural areas at two different times. METHODS: To analyze the progressivity of healthcare financing in terms of ability-to-pay, the Kakwani index was used to assess four healthcare financing channels: general taxes, social and commercial health insurance, and out-of-pocket payments. Two rounds of surveys were conducted in 2003 (11,572 individuals in 3841 households) and 2008 (15,817 individuals in 5530 households). Household socioeconomic status, healthcare payment, and utilization information were recorded using household interviews. RESULTS: China's healthcare financing equity is unsound. Kakwani indices for general taxation were -0.0212 (urban) and -0.0297 (rural) in 2002, and -0.0097 (urban) and -0.0112 (rural) in 2007. Social health insurance coverage has expanded, however different financing distributions were found with respect to urban (0.0969 in 2002 vs. 0.0984 in 2007) and rural (0.0283 in 2002 vs. 0.3119 in 2007) areas. While progressivity of out-of-pocket payments decreased in both areas, the equity of financing was found to have improved among poorer respondents. CONCLUSIONS: Overall, China's healthcare financing distribution is unequal. Given the inequity of general taxes, decreasing the proportion of indirect taxes would considerably improve healthcare financing equity. Financial contribution mechanisms to social health insurance are equally significant to coverage extension. The use of flat rate contributions for healthcare funding places a disproportionate pressure upon the poor. Out-of-pocket payments have become equitable, but progressivity has decreased. PMID- 25271769 TI - Usutu virus in bats, Germany, 2013. PMID- 25271770 TI - Response to comment on "Determining the ecological impacts of organic contaminants in biosolids using a high-throughput colorimetric denitrification assay: a case study with antimicrobial agents". PMID- 25271771 TI - Rickettsia parkeri and Rickettsia montanensis, Kentucky and Tennessee, USA. AB - We found that 14.3% (15/105) of Amblyomma maculatum and 3.3% (10/299) of Dermacentor variabilis ticks collected at 3 high-use military training sites in west-central Kentucky and northern Tennessee, USA, were infected with Rickettsia parkeri and Rickettsia montanensis, respectively. These findings warrant regional increased public health awareness for rickettsial pathogens and disease. PMID- 25271772 TI - A survey of canine heartworm awareness in Grenada, West Indies. AB - Heartworm is a common parasite of dogs in Grenada, West Indies, due to the tropical climate and large number of mosquitoes. Because Grenada is a developing country and a small island, resources and education on heartworm are limited. In an effort to raise awareness of canine heartworm and the preventive measures available, observations and surveys were performed to determine the following: (a) heartworm knowledge among Grenadian dog caregivers seeking veterinary care at the Grenada Society for the Prevention of Cruelty to Animals (GSPCA), (b) dissemination of heartworm information by GSPCA staff to Grenadian dog caregivers, and (c) reasons Grenadians are not administering heartworm prevention to their dogs. Results indicated a marked deficiency in both heartworm knowledge among Grenadian dog caregivers and heartworm knowledge acquisition and dissemination. Lack of knowledge was also cited as a major reason Grenadian dog caregivers were not using heartworm prevention. These results are currently being utilized to modify heartworm education practices at the GSPCA by incorporating Grenada-specific educational tools, with the ultimate goal of reducing illness and death by canine heartworm. PMID- 25271773 TI - Drug delivery to the nail: therapeutic options and challenges for onychomycosis. AB - Onychomycosis is one of the most common nail disorders. It affects 10-30% of the world population and is caused by dermatophytes, non-dermatophytes, molds, and yeasts. Present treatment methods of onychomycosis include oral therapy, topical therapy, and a combination of both; they have mild-to-moderate efficacy, with a relapse and reinfection rate of 20-25%. For oral therapy, newer antifungal compounds (azole class and allylamine class) are being investigated to increase efficacy and minimize side effects. Oral therapy with antifungal agents have severe side effects, with lesser bioavailability and longer duration of treatment. By contrast, topical therapy of onychomycosis is associated with greater patient compliance and fewer systemic side effects and drug interactions. Current topical treatment options of onychomycosis are nail lacquers, ointments, lotions, solutions, and gels, but these formulations have been unsuccessful due to poor penetration and distribution of drugs at the infected site. Therefore, novel therapeutic options are constantly being researched to improve the efficacy of onychomycosis treatment by enhancing the permeation of the drug across the nail to reach the infected site. Various physical and chemical enhancement methods have been studied to increase the permeation of drugs across the nail plate to the nail bed. Device-based therapeutic options have also been investigated to increase the antifungal drug concentration and its effects in the onychomycotic nail. Randomized clinical trials of these novel therapies have demonstrated better efficacy. The present review discusses the anatomy of the human nail, onychomycosis and its types, onycholysis, and conventional and novel therapies. We also review patents granted as well as design challenges facing optimal drug formulation for onychomycosis treatment. PMID- 25271774 TI - Advanced aerosol delivery devices for potential cure of acute and chronic diseases. AB - In recent years, the inhalation route has gained importance for the treatment of both pulmonary and extrapulmonary diseases. Delivery of drugs or bioactive molecules through this route has great potential for achieving maximum therapeutic effect, and many effective inhalation devices have been developed. A wide range of aerosol delivery devices are available in the marketplace for the treatment and management of pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD); many others are currently under development. Various advancements and innovations have improved the performance and efficiency of existing aerosol delivery devices. In this article, we review these inhalation devices (i.e., nebulizers, metered-dose inhalers, and dry powder inhalers) and the recent advances in inhalation technology that have significantly impacted the treatment and potential cure of many acute as well as chronic diseases. PMID- 25271775 TI - Gastroretentive drug delivery systems for therapeutic management of peptic ulcer. AB - A peptic ulcer, stomach ulcer, or gastric ulcer, also known as peptic ulcer disease (PUD), is a very common chronic disorder of the stomach which is mainly caused by damage or impairment of the stomach lining. Various factors such as pepsin, gastric acid, H. pylori, NSAIDs, prostaglandins, mucus, bicarbonate, and blood flow to mucosa play an important role in causing peptic ulcers. In this review article, our main focus is on some important gastroretentive drug delivery systems (GRDDS) (floating, bioadhesive, high density, swellable, raft forming, superporous hydrogel, and magnetic systems) which will be helpful in gastroretention of different dosage forms for treatment of peptic ulcer. GRDDS provides a mean for controlled release of compounds that are absorbed by active transport in the upper intestine. It also enables controlled delivery for paracellularly absorbed drugs without a decrease in bioavailability. The above approaches are specific for targeting and leading to a marked improvement in the quality of life for a large number of patients. In the future, it is expected that they will become of growing significance, finally leading to improved efficiencies of various types of pharmacotherapies. PMID- 25271776 TI - Association Between SNPs (rs1533428, rs12994401, rs10202118) on chromosome 2p16.3 and primary open angle glaucoma. AB - AIMS: A meta-analysis was conducted to evaluate the association of rs1533428, rs12994401, rs10202118 polymorphism on chromosome 2p16.3 with POAG susceptibility. METHODS: Systematic searches were performed on the electronic databases, the Cochrane Central Register of Controlled Trials, PubMed, ISI Web of Knowledge (Version 4.5), Chinese national knowledge infrastructure (CNKI), and Wanfang (Chinese) before March 2014. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of associations. Heterogeneity and Sensitivity analysis was also performed. RESULTS: Seven published articles with 25 datasets were included in the meta-analysis. The overall results showed no evidence for significant association of rs1533428, rs12994401, rs10202118 polymorphism with POAG risk in allelic model (rs1533428: OR = 1.23 [1.01, 1.49], p = 0.03; rs12994401: OR = 1.32 [0.96, 1.81], p = 0.08; rs10202118: OR = 0.95 [0.76, 1.20], p = 0.68), and similar results were obtained in the dominant, additive and the recessive models and subgroup analysis based on the ethnicity. CONCLUSIONS: Our study indicated that rs1533428, rs12994401, rs10202118 polymorphism on chromosome 2p16.3 might not be a risk factor for POAG. Further studies with well-designed among different ethnicity populations are required. PMID- 25271778 TI - Predictability in cellular automata. AB - Modelled as finite homogeneous Markov chains, probabilistic cellular automata with local transition probabilities in (0, 1) always posses a stationary distribution. This result alone is not very helpful when it comes to predicting the final configuration; one needs also a formula connecting the probabilities in the stationary distribution to some intrinsic feature of the lattice configuration. Previous results on the asynchronous cellular automata have showed that such feature really exists. It is the number of zero-one borders within the automaton's binary configuration. An exponential formula in the number of zero one borders has been proved for the 1-D, 2-D and 3-D asynchronous automata with neighborhood three, five and seven, respectively. We perform computer experiments on a synchronous cellular automaton to check whether the empirical distribution obeys also that theoretical formula. The numerical results indicate a perfect fit for neighbourhood three and five, which opens the way for a rigorous proof of the formula in this new, synchronous case. PMID- 25271777 TI - Association between polymorphisms of the IKZF3 gene and systemic lupus erythematosus in a Chinese Han population. AB - OBJECTIVE: It has been reported that IKAROS family of zinc finger 3 (IKZF3) deficient mice spontaneously develop human systemic lupus erythematosus (SLE) like phenotypes and produce anti-dsDNA Ab leading to immune complex-mediated glomerulonephritis. Polymorphism of the IKZF3 gene corresponds with the susceptibility to several immune-related diseases. Our intention was to establish an association between polymorphisms in the IKZF3 gene and SLE in the Chinese Han population. METHODS: The study involved obtaining blood samples for DNA extraction and genotyping the 4 selected single-nucleotide polymorphisms (SNPs) in IKZF3, including rs12150079, rs9909593, rs907091, and rs2872507, by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP). A group of 366 SLE patients were compared to 455 healthy controls. RESULTS: A significant decrease in frequencies of the rs907091 CC genotype and C allele appeared in the SLE patients unlike that observed in the controls (p = 0.001 and 0.015, respectively). The frequencies of the rs12150079 genotype and allele were different between the SLE patients and the control individuals, although the significance was only marginal (p = 0.046 and 0.049, respectively). In addition, a significantly low frequency of the GGCG haplotype was observed in the SLE patients, suggesting that it may provide protection against SLE (p = 0.011). CONCLUSION: To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IKZF3 and SLE in the Chinese Han population. A strong association between rs907091 in the IKZF3 gene and SLE was identified. PMID- 25271779 TI - Group treatment for trichotillomania: cognitive-behavioral therapy versus supportive therapy. AB - OBJECTIVE: Trichotillomania is a psychiatric condition characterized by the chronic pulling and plucking of one's own hair. Cognitive-behavioral therapy shows promise as a treatment for trichotillomania and might be preferable to pharmacotherapy. However, there have been no randomized, controlled studies of the efficacy of group cognitive-behavioral therapy. METHOD: We evaluated 44 subjects, recruited from April 2009 to May 2010, all of whom met DSM-IV criteria for a diagnosis of trichotillomania. Subjects were randomized to receive 22 sessions of either group cognitive-behavioral therapy or group supportive therapy (control). Treatment evaluation was non-blind and used self-report scales. The primary outcome measure was the improvement of hair-plucking behavior as assessed by the Massachusetts General Hospital Hairpulling Scale. Secondary measures included scores on the Beck Depression Inventory, the Beck Anxiety Inventory, and the Social Adjustment Scale-Self-Report. RESULTS: Both groups showed significant posttreatment improvement in the scores from the Massachusetts General Hospital Hairpulling Scale (F = 23.762, P < .001) and the Beck Depression Inventory (F = 6.579, P = .003). The decrease in hair-plucking behavior over time was significantly greater in the study group than in the control group (F = 3.545, P < .038). There were no significant differences between the pretreatment and posttreatment time points or between the groups in the scores from the Beck Anxiety Inventory and the Social Adjustment Scale-Self-Report. CONCLUSIONS: We conclude that group cognitive-behavioral therapy is a valid treatment for trichotillomania. This treatment model should be further revised and expanded to address comorbidities such as anxiety and social maladjustment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01968343. PMID- 25271781 TI - Fluctuation scaling, Taylor's law, and crime. AB - Fluctuation scaling relationships have been observed in a wide range of processes ranging from internet router traffic to measles cases. Taylor's law is one such scaling relationship and has been widely applied in ecology to understand communities including trees, birds, human populations, and insects. We show that monthly crime reports in the UK show complex fluctuation scaling which can be approximated by Taylor's law relationships corresponding to local policing neighborhoods and larger regional and countrywide scales. Regression models applied to local scale data from Derbyshire and Nottinghamshire found that different categories of crime exhibited different scaling exponents with no significant difference between the two regions. On this scale, violence reports were close to a Poisson distribution (alpha = 1.057 +/- 0.026) while burglary exhibited a greater exponent (alpha = 1.292 +/- 0.029) indicative of temporal clustering. These two regions exhibited significantly different pre-exponential factors for the categories of anti-social behavior and burglary indicating that local variations in crime reports can be assessed using fluctuation scaling methods. At regional and countrywide scales, all categories exhibited scaling behavior indicative of temporal clustering evidenced by Taylor's law exponents from 1.43 +/- 0.12 (Drugs) to 2.094 +/- 0081 (Other Crimes). Investigating crime behavior via fluctuation scaling gives insight beyond that of raw numbers and is unique in reporting on all processes contributing to the observed variance and is either robust to or exhibits signs of many types of data manipulation. PMID- 25271782 TI - The similarity law for the Joule-Thomson inversion line. AB - We show that the expression for the Joule-Thomson inversion temperature following from the van der Waals equation and recorded in a form reduced to the Boyle values has a universal character and can be applied to many real substances and model systems. PMID- 25271780 TI - pH-triggered echogenicity and contents release from liposomes. AB - Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%). PMID- 25271783 TI - Spontaneous redox synthesis and characterization of the tetrathiafulvalene vanadium-substituted polyoxometalate charge-transfer material TTF4[SVW11O40]: comparison with the Mo analogue. AB - Both conventional solution-phase and direct solid-solid redox reactions between tetrathiafulvalene (TTF) and the vanadium-substituted polyoxometalate (n Bu4N)3[SV(V)W11O40] give rise to microcrystalline or powdered semiconducting charge transfer solid material. A single-crystal X-ray structure derived from growing crystals from a MeCN-CH2Cl2 solution-phase redox reaction gives a stoichiometry of TTF4[SVW11O40].2H2O.2CH2Cl2 and reveals that there are two crystallographically different TTF cation moieties based on (TTF2)(2+) dimers. While the color and morphology of the microcrystalline or powdered TTF4[SVW11O40] differ from the single crystals prepared for structural analysis, all materials are spectroscopically (infrared (IR), Raman with respect to the TTF bands, and electron paramagnetic resonance (EPR)) indistinguishable. Raman spectra suggest that the charge transfer is unevenly distributed across the (TTF2)(2+) dimers, which is postulated to give rise to enhanced mixed-valence features. Structural, spectral, and other properties, such as conductivity, are compared with results available on the recently published molybdenum TTF4[SVMo11O40].2H2O.2CH2Cl2 analogue, where the charge distribution is uniform on all TTF cations. In both examples, the position of the V atom is located over several sites. Elemental analysis and voltammetric data also are consistent with the formulations deduced from structural and spectroscopic studies. The conductivity at room temperature is in the semiconducting range, but significantly greater than that for the Mo analogue. EPR spectra at temperatures down to the liquid helium regime confirm the presence of paramagnetic V(IV) and paramagnetic oxidized TTF. The newly isolated TTF-SV(IV)W11O40 material also has magnetic functionality derived from the cationic and anionic components. PMID- 25271784 TI - Nitrogen limitation promotes accumulation and suppresses release of cylindrospermopsins in cells of Aphanizomenon sp. AB - As the biosynthesis of cylindrospermopsin (CYN) is assumed to depend on nitrogen availability, this study investigated the impact of nitrogen availability on intra- and extracellular CYN and deoxy-CYN (D-CYN) contents in three Aphanizomenon strains from temperate waters. Nitrogen deficient (-N) cultures showed a prolonged growth phase and intracellular toxin accumulation by a factor of 2-6. In contrast, cultures with additional nitrate supply (+N) did not accumulate CYN within the cells. Instead, the maximum conceivable CYN release estimated for dead cells (identified by SYTOX Green staining) was much lower than the concentrations of dissolved CYN actually observed, suggesting these cultures actively release CYN from intact cells. Furthermore, we found remarkably altered proportions of CYN to D-CYN: as batch cultures grew, the proportion of D-CYN increased by up to 40% in +N medium, whereas D-CYN remained constant or decreased slightly in -N medium. Since +N cultures showed similar toxin patterns as -P cultures with increased extracellular CYNs and higher proportion of D-CYN we conclude that nitrogen limitation may affect the way the cells economize resources, especially the yield from phosphorus pools, and that this has an impact on CYN production and release. For water management, these result imply that nutrient availability not only determines the abundance of potentially CYN producing cyanobacteria, but also the amount of extracellular CYNs (challenging drinking-water treatment) as well as the ratio of D-CYN to CYN (affecting toxicity). PMID- 25271785 TI - Toxins vapC and pasB from prokaryotic TA modules remain active in mammalian cancer cells. AB - Among the great number of addictive modules which have been discovered, only a few have been characterized. However, research concerning the adoption of toxins from these systems shows their great potential as a tool for molecular biology and medicine. In our study, we tested two different toxins derived from class II addictive modules, pasAB from plasmid pTF-FC2 (Thiobacillus ferrooxidans) and vapBC 2829Rv (Mycobacterium tuberculosis), in terms of their usefulness as growth inhibitors of human cancer cell lines, namely KYSE 30, MCF-7 and HCT 116. Transfection of the pasB and vapC genes into the cells was conducted with the use of two different expression systems. Cellular effects, such as apoptosis, necrosis and changes in the cell cycle, were tested by applying flow cytometry with immunofluorescence staining. Our findings demonstrated that toxins VapC and PasB demonstrate proapoptotic activity in the human cancer cells, regardless of the expression system used. As for the toxin PasB, observed changes were more subtle than for the VapC. The level of expression for both the genes was monitored by QPCR and did not reveal statistically significant differences within the same cell line. PMID- 25271786 TI - Causes of hospital admission of AIDS patients in southern Brazil, 2007 to 2012. AB - INTRODUCTION: The acquired immunodeficiency syndrome (AIDS) epidemic is a worldwide phenomenon that has been modified with the implementation of effective antiretroviral therapy. The objective of this study was to determine the leading causes of hospitalization among human immunodeficiency virus (HIV)-positive individuals. METHODS: A cross-sectional study with patients admitted to a general hospital in southern Brazil, between January 2007 and May 2012. RESULTS: Medical records of 550 hospital admissions (230 patients) were reviewed, with an average of 2.4 hospitalizations per patient. Infectious diseases were the most prevalent causes of hospitalization. Overall, 44.8% patients died and their deaths were associated with longer hospital stays. CONCLUSIONS: Opportunistic infections remained the leading causes of hospitalization. PMID- 25271787 TI - The exotic palm Roystonea oleracea (Jacq.) O.F. Cook as a rural biotype for Rhodnius neglectus Lent, 1954, in Cacu, State of Goias. AB - INTRODUCTION: Rhodnius neglectus is a triatomine that colonizes different palm species. In this study, we aimed to describe the presence of this triatomine bug in the royal palms (Roystonea oleracea) in a rural region of the State of Goias. METHODS: Palm infestation was investigated by dissecting the palms or by using live-bait traps. RESULTS: Two palm trees were infested by R. neglectus negative for Trypanosoma cruzi, the etiological agent for Chagas disease. In the study area, R. neglectus is frequently found in households. CONCLUSIONS: The adaptation of this species to palm trees introduced in Brazil for landscaping purposes poses another challenge for controlling the vectors of Chagas disease. PMID- 25271788 TI - High similarity of Trypanosoma cruzi kDNA genetic profiles detected by LSSP-PCR within family groups in an endemic area of Chagas disease in Brazil. AB - INTRODUCTION: Determining the genetic similarities among Trypanosoma cruzi populations isolated from different hosts and vectors is very important to clarify the epidemiology of Chagas disease. METHODS: An epidemiological study was conducted in a Brazilian endemic area for Chagas disease, including 76 chronic chagasic individuals (96.1% with an indeterminate form; 46.1% with positive hemoculture). RESULTS: T. cruzi I (TcI) was isolated from one child and TcII was found in the remaining (97.1%) subjects. Low-stringency single-specific-primer polymerase chain reaction (LSSP-PCR) showed high heterogeneity among TcII populations (46% of shared bands); however, high similarities (80-100%) among pairs of mothers/children, siblings, or cousins were detected. CONCLUSIONS: LSSP PCR showed potential for identifying similar parasite populations among individuals with close kinship in epidemiological studies of Chagas disease. PMID- 25271789 TI - In memoriam, Dr. E. Chester Ridgway, 1942-2014. PMID- 25271790 TI - Editorial: advances in neuroscience: the BRAIN initiative and implications for neuroendocrinology. PMID- 25271791 TI - Socioeconomic differences in alcohol-related risk-taking behaviours. AB - INTRODUCTION AND AIMS: There is substantial research showing that low socioeconomic position is a predictor of negative outcomes from alcohol consumption, while alcohol consumption itself does not exhibit a strong social gradient. This study aims to examine socioeconomic differences in self-reported alcohol-related risk-taking behaviour to explore whether differences in risk taking while drinking may explain some of the socioeconomic disparities in alcohol-related harm. DESIGN AND METHODS: Cross-sectional data from current drinkers (n = 21 452) in the 2010 wave of the Australian National Drug Strategy Household Survey were used. Ten items on risk-taking behaviour while drinking were combined into two risk scores, and zero-inflated Poisson regression was used to assess the relationship between socioeconomic position and risk-taking while controlling for age, sex and alcohol consumption. RESULTS: Socioeconomically advantaged respondents reported substantially higher rates of alcohol-related hazardous behaviour than socioeconomically disadvantaged respondents. Controlling for age, sex, volume of drinking and frequency of heavy drinking, respondents living in the most advantaged quintile of neighbourhoods reported significantly higher rates of hazardous behaviour than those in the least advantaged quintile. A similar pattern was evident for household income. DISCUSSION AND CONCLUSIONS: Socioeconomically advantaged Australians engage in alcohol-related risky behaviour at higher rates than more disadvantaged Australians even with alcohol consumption controlled. The significant socioeconomic disparities in negative consequences linked to alcohol consumption cannot in this instance be explained via differences in behaviour while drinking. Other factors not directly related to alcohol consumption may be responsible for health inequalities in outcomes with significant alcohol involvement. PMID- 25271792 TI - Hypothermia in the setting of experimental acute myocardial infarction: a comprehensive review. AB - A door-to-balloon time of less than 90 minutes is the gold standard for reperfusion therapy to treat acute myocardial infarction (MI). Because 30-day mortality remains ~ 10%, new methods must be cultivated to limit myocardial injury. Therapeutic hypothermia has long been experimentally used to attenuate myocardial necrosis during MI with promising results, but the treatment has yet to gain popularity among most clinicians. Hypothermia, in the basic science setting, has been achieved using many techniques. In our review, we examine past and current methods of inducing hypothermia, benefits and setbacks of such methods, current and future clinical trials, and potential mechanisms. PMID- 25271793 TI - The effect of a solid surface on the segregation and melting of salt hydrates. AB - Considering the importance of salt and water on earth, the crystallization of salt hydrates next to solid surfaces has important implications in physical and biological sciences. Heterogeneous nucleation is driven by surface interactions, but our understanding of hydrate formation near surfaces is limited. Here, we have studied the hydrate formation of three commonly prevalent salts, MgCl2, CaCl2, and NaCl, next to a sapphire substrate using surface sensitive infrared visible sum frequency generation (SFG) spectroscopy. SFG spectroscopy can detect the crystallization and melting of salt hydrates at the interface by observing the changes in the intensity and the location of the cocrystallized water hydroxyl peaks (3200-3600 cm(-1)). The results indicate that the surface crystal structures of these three hydrates are similar to those in the bulk. For the NaCl solution, the brine solution is segregated next to the sapphire substrate after the formation of the ice phase. In contrast, the MgCl2 and CaCl2 surface hydrate crystals are interdispersed with nanometer-size ice crystals. The nanosize ice crystals melt at much lower temperatures than bulk ice crystals. For NaCl and MgCl2 solution, the NaCl hydrates prefer to crystallize next to the sapphire substrate instead of the ice crystals and MgCl2 hydrates. PMID- 25271794 TI - The effect of grain boundaries on the mechanical properties and failure behavior of hexagonal boron nitride sheets. AB - In this work, the effect of grain boundaries (GBs) on the mechanical properties and failure behavior of two-dimensional hexagonal boron nitride (h-BN) sheets are systematically and comprehensively investigated using density functional theory. Results show that the formation of homoelemental bonds on GBs is an important factor, which could affect the atomic structures and stability of the h-BN sheet. The relationship between the formation energy and the misorientation angles is downward opening parabolic. The intrinsic strength shows an obvious decreasing trend with increasing inflection angles, while it shows a periodic dependence on the increase in misorientation angles. Thus, the mechanical properties of h-BN are significantly influenced by GBs. The h-BN sheets with different types of GBs show varied failure behavior, which are caused by the distinct stress distribution on GBs. The information obtained in this study would be useful for the understanding of GBs on the h-BN surface. PMID- 25271795 TI - Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) in adults and profile of skin barrier proteins and inflammatory cytokines. OBJECTIVE: Evaluation of the expression of skin barrier proteins such as filaggrin, claudins 1 and 4 and of circulating inflammatory cytokines (Th1/Th2/Th17) in adults with AD. METHODS: Thirty-three adult patients with AD diagnosed according to the Hanifin & Rajkacriteria, and 25 healthy controls were enrolled in the study. AD severity was measured by Eczema Area and Severity Index (EASI). Laboratory assays included immunohistochemistry analysis of skin barrier proteins, such as filaggrin, claudins 1 and 4 and interleukin-17 (IL-17) from skin samples and determination of circulating cytokine levels (IL-2, 4, 5, 6, 10, 17A, TNF and IFN-gamma) by flow cytometry (Cytometric Bead Array). RESULTS: We observed a reduced expression of filaggrin and claudin 1 in lesional skin of AD patients, when compared to controls. There was an inverse correlation of filaggrin expression and disease severity. In addition, IL-17 expression was enhanced in AD patients. Similarly, higher levels of inflammatory cytokines (IL-2, 5, 6, 10, 17A and IFN-gamma) were found in AD patients. CONCLUSION: Our data reinforce the role of an altered skin barrier in the pathogenesis of AD. Our results show not only reduced expression of filaggrin and claudin 1 in lesional atopic skin but also inverse correlation of filaggrin expression and disease severity. Moreover, elevation of in situ IL-17 and of circulating interleukin levels in AD emphasize the systemic, inflammatory profile of this defective skin barrier dermatosis. PMID- 25271796 TI - Comparative study of Poincare plot analysis using short electroencephalogram signals during anaesthesia with spectral edge frequency 95 and bispectral index. AB - The return or Poincare plot is a non-linear analytical approach in a two dimensional plane, where a timed signal is plotted against itself after a time delay. Its scatter pattern reflects the randomness and variability in the signals. Quantification of a Poincare plot of the electroencephalogram has potential to determine anaesthesia depth. We quantified the degree of dispersion (i.e. standard deviation, SD) along the diagonal line of the electroencephalogram Poincare plot (named as SD1/SD2), and compared SD1/SD2 values with spectral edge frequency 95 (SEF95) and bispectral index values. The regression analysis showed a tight linear regression equation with a coefficient of determination (R(2) ) value of 0.904 (p < 0.0001) between the Poincare index (SD1/SD2) and SEF95, and a moderate linear regression equation between SD1/SD2 and bispectral index (R(2) = 0.346, p < 0.0001). Quantification of the Poincare plot tightly correlates with SEF95, reflecting anaesthesia-dependent changes in electroencephalogram oscillation. PMID- 25271797 TI - Dual regulating effects of gastrodin on extracellular dopamine concentration in rats models of Tourette's syndrome. AB - PURPOSE: Evaluate the dual regulating effects of gastrodin on striatal extracellular dopamine (DA) concentration in Tourette's syndrome (TS) rat models, and explore the underlying pharmacological mechanisms. MATERIALS AND METHODS: Seventy Wistar rats were randomly divided into control group and TS model group. The former was intraperitoneally injected with saline (0.9%), while in the later, the rats were injected with Apomorphine (Apo) and 3,3'-iminodipropionitrile (IDPN) respectively to manipulate two kinds of TS rat models. Both Apo and IDPN induced rats were further assigned to three conditions, and the related rats were treated respectively by oral gavage with saline, gastrodin and Haloperidol (Hal). Data of stereotypy of the rats were collected. After 8 weeks, the extracellular content of DA and HVA in striatum were examined by intracerebral microdialysis and follow-up high-performance liquid chromatography (HPLC), and the expression of dopamine transporter (DAT) was probed by Western blot. RESULTS: Gastrodin improved the stereotyped behaviors in TS rats. Furthermore, it down-regulated the elevated striatal extracellular DA concentration in Apo-induced rats and up regulated the decreased DA content in the rats exposed to IDPN. Meanwhile, a dramatic down-regulation was detected in DAT protein expression in Apo + GAS group, while an opposite profile was showed in the IDPN + GAS group. CONCLUSIONS: The dual regulating effects of gastrodin on extracellular DA level have been established, and the related mechanisms would be the dual regulating effects of gastrodin on the expression of DAT, a glycoprotein in the regulation of the extracellular DA concentration. PMID- 25271798 TI - Experience with fingolimod in clinical practice. AB - AIM: To report experience with fingolimod in clinical practice. DESIGN/METHODS: Patients in an academic medical center who were prescribed fingolimod from October 2010 to August 2011 were identified through the electronic medical record and followed for 12 months after fingolimod initiation. Adverse effects (AEs), clinical measures, MRI data, and quality of life measures were assessed. RESULTS: Three hundred seventeen patients started fingolimod. Eleven patients were treatment naive (3.5%) and 76 (24.0%) had remote disease modifying therapy (DMT) use prior to fingolimod. One hundred fifty-one (47.6%) switched because of patient preference and 79 (24.9%) switched because of breakthrough disease. About 11.6% transitioned from natalizumab. Follow-up data were available for 306 patients (96.5%) with mean follow-up time 332 days. Fingolimod was discontinued in 76 of 306 patients (24.8%) at mean 248 days after fingolimod start. Discontinuation most often was due to AEs (n = 40) or breakthrough disease (n = 22). Among patients who started fingolimod with available 12 month follow-up data, 267 (87.3%) remained relapse free and 256 (83.7%) had no relapses or gadolinium enhancement. Time to first relapse occurred at mean 282 days after fingolimod initiation. Quality of life measures remained stable at follow-up. CONCLUSIONS: Fingolimod was discontinued at a higher rate in clinical practice than in clinical trials. Discontinuation was primarily due to AEs or breakthrough disease. Disease activity was adequately controlled in most patients who started fingolimod. This clinical practice cohort is consistent with efficacy data from phase 3 trials and describes the most common tolerability issues in clinical practice. PMID- 25271799 TI - Co-treatment effect of pulsed electromagnetic field (PEMF) with human dental pulp stromal cells and FK506 on the regeneration of crush injured rat sciatic nerve. AB - PURPOSE: The purpose of this study was to determine whether crush injured rat sciatic nerve could be benefit from pulsed electromagnetic field (PEMF) combined with human dental pulp stromal cells (hDPSCs), with FK506 (Tacrolimus) for immune suppression and neuropromotion. MATERIALS AND METHODS: Male Sprague-Dawley rats (200-250 g, 6 week old) were distributed into 6 groups (n = 18 each): control, PEMF, FK506, PEMF + hDPSCs, PEMF + FK506, and PEMF + hDPSCs + FK506 groups. hDPSCs (cell = 1 * 106/10 MUl/rat) were injected at the crush site immediate after injury. FK506 was administered 3 weeks in FK506 group (0.5 mg/kg/d) while pre-op 1 d and post-op 7 d in PEMF + FK506 and PEMF + hDPSCs + FK506 group; cell tracking was done with PKH26-labeled hDPSCs (cell = 1 * 106/10 MUl/rat). The rats were follow-up for 3 weeks. RESULTS: PEMF + FK506 and PEMF + hDPSCs + FK506 group showed a sharp increase in sciatic function index (SFI), axon counts, densities, and labeled neurons in dorsal root ganglia (DRG) than control at 3 weeks. Other three treatment groups also showed higher axon counts, densities, and labeled neurons than control. Higher axon counts and densities were found in PEMF + FK506 and PEMF + hDPSCs + FK506 groups comparing with PEMF group. Brain-derived neurotrophic factor (BDNF) mRNA expression pattern in nerve segment and DRG was almost same. Higher expression level in all the treatment groups was discovered in the follow-up period, but there was no significant difference. CONCLUSIONS: All treatment groups can improve regeneration of neurons following crushed injury, PEMF + FK506 and PEMF + hDPSCs + FK506 groups showed higher regeneration ability than other three groups. FK506 plays an important role during hDPSCs transplantation. PMID- 25271800 TI - The dilemma of treatments for epileptic patients with depression. AB - Depression is a state of low mood and aversion to activity. It may occur due to existence of other mental or physical diseases or from the medications for those illnesses. It is one of the leading sources of disability. Among these physical diseases, epilepsy is widely recognized as one of the main causes of depression. Patients with epilepsy are at high risk of developing depressive symptoms, and the suicide rates in patients with epilepsy have been reported to be much higher than in the general population. However, due to fears of lowering seizure threshold and adverse drug interactions between antidepressants and antiepileptic drugs, physician are reluctant to place patients with epilepsy on antidepressant medication. As a result, the question has been raised that what the best managements should be used to treat epileptic patients with depression. In this review, the currently used medications for antidepressants and antiepileptic drugs were summarized by their working targets in order to establish appropriate pharmacological management of depression and epilepsy. Despite the complex relationship between epilepsy and depression, coadministration of antidepressants and AEDs can still be done safely and effectively under the conditions of good clinical management. The ideal antidepressants for people with epilepsy should be efficacious but with few adverse effects, which will not antagonize GABAergic mechanisms or interfere with plasma anticonvulsant concentrations. PMID- 25271801 TI - The Nitric oxide/CGMP/KATP pathway mediates systemic and central antinociception induced by resistance exercise in rats. AB - Resistance exercise (RE) is characterized to increase strength, tone, mass, and/or muscular endurance and also for produces many beneficial effects, such as blood pressure and osteoporosis reduction, diabetes mellitus control, and analgesia. However, few studies have investigated endogenous mechanisms involved in the RE-induced analgesia. Thus, the aim of this study was evaluate the role of the NO/CGMP/KATP pathway in the antinociception induced by RE. Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by mechanical nociceptive test (paw-withdrawal). To investigate the involvement of the NO/CGMP/KATP pathway the following nitric oxide synthase (NOS) non-specific and specific inhibitors were used: N-nitro-l-arginine (NOArg), Aminoguanidine, N5-(1-Iminoethyl)-l-ornithine dihydrocloride (l-NIO), Nomega Propyl-l-arginine (l-NPA); guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolo[4,3 a]quinoxalin-1-one (ODQ); and KATP channel blocker, Glybenclamide; all administered subcutaneously, intrathecally and intracerebroventricularly. Plasma and cerebrospinal fluid (CSF) nitrite levels were determined by spectrophotometry. The RE protocol produced antinociception, which was significantly reversed by NOS specific and unspecific inhibitors, guanylyl cyclase inhibitor (ODQ) and KATP channel blocker (Glybenclamide). RE was also responsible for increasing nitrite levels in both plasma and CSF. These finding suggest that the NO/CGMP/KATP pathway participates in antinociception induced by RE. PMID- 25271802 TI - Palmar cutaneous nerve conduction in patients with carpal tunnel syndrome. AB - OBJECTIVE: This study aimed to assess palmar cutaneous branch of the median nerve (PCBm) conduction in patients with clinically diagnosed carpal tunnel syndrome (CTS), to compare PCBm conduction with that of the median and ulnar nerves, and to determine the PCBm conduction abnormality rate in patients with CTS. MATERIALS AND METHODS: The study included 99 hands of 60 patients with clinical CTS and 38 hands of 38 healthy controls. Sensory nerve conduction study (NCS) was performed on the median nerve, ulnar nerve, and PCBm, and onset latency, conduction velocity and amplitude were recorded. Additionally, differences in latency and velocity between the median nerve and PCBm, and the difference in latency between the median and ulnar nerves were calculated. RESULTS: In all, 56% of the patients with CTS had abnormal PCBm conduction. Additionally, in 7 of 8 hands with abnormal sensation--both in the thenar eminence and abnormal sensory distribution along the main branch--NCS of the PCBm was also abnormal. CONCLUSIONS: The PCBm is not ideal as a comparator nerve for the neurophysiological diagnosis of CTS. The frequency of PCBm abnormality in CTS patients may be related to the concomitant damage in both of these nerves. Additionally, the present findings may help explain, at least in part, why patients with CTS often exhibit sensory involvement beyond the classical median nerve sensory borders. PMID- 25271803 TI - The Hand: Shall We Ever Understand How it Works? AB - The target article presents a review of the neural control of the human hand. The review emphasizes the physical approach to motor control. It focuses on such concepts as equilibrium-point control, control with referent body configurations, uncontrolled manifold hypothesis, principle of abundance, hierarchical control, multidigit synergies, and anticipatory synergy adjustments. Changes in aspects of the hand neural control with age and neurological disorder are discussed. The target article is followed by six commentaries written by Alexander Aruin, Kelly Cole, Monica Perez, Robert Sainburg, Marco Sanello, and Wei Zhang. PMID- 25271805 TI - Capillary tube wetting induced by particles: towards armoured bubbles tailoring. AB - In this paper, we report on the strongly modified dynamics of a liquid finger pushed inside a capillary tube, when partially wettable particles are lying on the walls. Particles promote the appearance of new regimes and enable the tailored synthesis of bubbles encapsulated in a monolayer of particles (so-called "armoured bubbles"). This remarkable behavior arises due to the collection of particles at the air-liquid interface, which modify the global energy balance and stabilize the interface. Armoured-bubbles are of primary interest in industrial processes since they display increased stability, interfacial rigidity and can even sustain non-spherical shapes. This work opens perspective for a low cost bubbles-on-demand technology enabling the synthesis of armoured bubbles with specific sizes, shapes and composition. PMID- 25271804 TI - [Can the antibiotic prescription practice in a hospital be influenced by in-house guidelines? An interventional study at the University Hospital Halle (Saale), Germany]. AB - BACKGROUND: In-house guidelines are an essential tool of antibiotic stewardship (ABS) programs to guide antimicrobial therapy. We studied the effect of in-house guidelines adapted to the local pathogen and resistance epidemiology on prescribing behavior. METHODS: At the University Hospital Halle (Saale) guidelines for the antimicrobial therapy and essential microbiological diagnostics were introduced. Main objectives were reducing the use of third generation cephalosporines and fluoroquinolones, decreasing selection pressure for enterococci and multidrug-resistant Gram-negative bacteria, minimizing Clostridium difficile infections (CDI), and improving microbiological diagnostics to enhance de-escalation strategies. 12 months thereafter a comparison of antibiotic consumption, pathogen and resistance statistics and use of blood cultures was performed. RESULTS: There was a decrease of third-generation cephalosporines (-18.6%) and fluoroquinolones (-9.8%), while consumption of broad and intermediate-spectrum penicillins (+23.8% and +37%) as well as carbapenems (+11.9%) increased. The total volume of prescribed anti-infectives remained unchanged. The number of enterococcal isolates (-18.3%) and CDI (-26.3%) decreased considerably. Gram-negatives, particulary ESBL-producing Enterobacteriaceae, were detected more frequently due to an expanded screening program. The rate of blood cultures/1000 patient-days was unaffected. CONCLUSION: In-house guidelines for the empiric antiinfective therapy appear to be suitable to influence the prescribing behavior and the selection pressure on individual pathogen groups. The total volume of antibiotic prescriptions was not affected in this study. PMID- 25271806 TI - Mechanism of DNA trapping in nanoporous structures during asymmetric pulsed-field electrophoresis. AB - We investigate the trapping mechanism of individual DNA molecules in ordered nanoporous structures generated by crystalline particle arrays. Two requisites for trapping are revealed by the dynamics of single trapped DNA, fully-stretched U/J shapes and hernia formation. The experimental results show there is a stronger possibility for hernias to lead the reorientation upon switching directions of the voltage at high field strengths, where trapping occurs. Fully stretched DNA has longer unhooking times than expected by a classic rope-on pulley model. We propose a dielectrophoretic (DEP) force reduces the mobility of segments at the apex of the U or J, where field gradients are highest, based on simulations and observations of the trapping force dependence on field strength. A modified model for unhooking time is obtained after the DEP force is introduced. The new model explains the unhooking time data by predicting an infinite trapping time when the ratio of arm length differences (of the U or J) to molecule length Deltax/L < beta, where beta is a DEP parameter that is found to strongly increase with electric field. The DNA polarizability calculated with the DEP model and experimental value of beta is of the same magnitude of reported value. The results indicate the tension at the apex of U/J shape DNA is the primary reason for DNA trapping during pulsed field separation, instead of hernias. PMID- 25271807 TI - Gross motor function measure (GMFM-66) trajectories in children recovering after severe acquired brain injury. PMID- 25271808 TI - Optimal allocation of resources in female sex worker targeted HIV prevention interventions: model insights from Avahan in South India. AB - BACKGROUND: The Avahan programme has provided HIV prevention activities, including condom promotion, to female sex workers (FSWs) in southern India since 2004. Evidence suggests Avahan averted 202,000 HIV infections over 4 years. For replicating this intervention elsewhere, it is essential to understand how the intervention's impact could have been optimised for different budget levels. METHODS: Behavioural data were used to determine how condom use varied for FSWs with different levels of intervention intensity. Cost data from 64 Avahan districts quantified how district-level costs related to intervention scale and intensity. A deterministic model for HIV transmission amongst FSWs and clients projected the impact and cost of intervention strategies for different scale and intensity, and identified the optimal strategies that maximise impact for different budget levels. RESULTS: As budget levels increase, the optimal intervention strategy is to first increase intervention intensity which achieves little impact, then scale-up coverage to high levels for large increases in impact, and lastly increase intensity further for small additional gains. The cost-effectiveness of these optimal strategies generally improves with increasing resources, while straying from these strategies can triple costs for the same impact. Projections suggest Avahan was close to being optimal, and moderate budget reductions (>= 20%) would have reduced impact considerably (>40%). DISCUSSION: Our analysis suggests that tailoring the design of HIV prevention programmes for FSWs can improve impact, and that a certain level of resources are required to achieve demonstrable impact. These insights are critical for optimising the use of limited resources for preventing HIV. PMID- 25271810 TI - HIF-2alpha regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox cis regulatory element. AB - Low O2 tension is beneficial for human embryonic stem cell (hESC) maintenance but the mechanism of regulation is unknown. HIF-2alpha was found to bind directly to predicted hypoxic response elements (HREs) in the proximal promoter of OCT4, NANOG and SOX2 only in hESCs cultured under hypoxia (5% O2). This binding induced an array of histone modifications associated with gene transcription while a heterochromatic state existed at atmospheric O2. Interestingly, an enhanced euchromatic state was found when hESCs were exposed to hypoxia followed by 72 hours reoxygenation. This was sustained by HIF-2alpha which enhanced stemness by binding to an oct-sox cis-regulatory element in the NANOG promoter. Thus, these data have uncovered a novel role of HIF-2alpha as a direct regulator of key transcription factors controlling self-renewal in hESCs but also in the induction of epigenetic modifications ensuring a euchromatic conformation which enhances the regenerative potential of these cells. PMID- 25271811 TI - Efficacy and safety of fixed-dose losartan/hydrochlorothiazide/amlodipine combination versus losartan/hydrochlorothiazide combination in Japanese patients with essential hypertension. AB - Japanese patients with uncontrolled essential hypertension received single-blind losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/H12.5) for 8 weeks. Patients whose blood pressure (BP) remained uncontrolled were randomized double-blind to fixed-dose losartan 50 mg/hydrochlorothiazide 12.5 mg/amlodipine 5 mg (L50/H12.5/A5) or L50/H12.5 for 8 weeks followed by open-label L50/H12.5/A5 for 44 weeks. Adverse events were assessed. After 8 weeks, diastolic and systolic BP were reduced significantly more with L50/H12.5/A5 versus L50/H12.5 (both p < 0.001). Mean changes in diastolic and systolic BP were sustained for 44 weeks. L50/H12.5/A5 was well-tolerated and improved BP significantly versus L50/H12.5 in Japanese patients with uncontrolled essential hypertension. PMID- 25271812 TI - Fuel mediated solution combustion synthesis of ZnO supported gold clusters and nanoparticles and their catalytic activity and in vitro cytotoxicity. AB - Nanocomposites of gold nanoparticles and semiconductor ZnO with wurtzite structure, made by solution combustion synthesis (SCS), as a function of the Zn/fuel ratio with polyethylene glycol (PEG) as fuel exhibit the presence of both nanoparticles and clusters. Atomic gold clusters present on the surface of ZnO nanorods which can be identified by XPS and SEM are easily monitored and characterized by positive ion MALDI experiments as mostly odd numbered clusters, Au3 to Au11 in decreasing amounts. Low concentrations of the fuel produce AuClO and nanoparticles (NPs), with no clusters. Au-ZnO nanocomposites at all [Au] exhibit single blue shifted plasmon absorption and corresponding photoluminescence (PL). Increasing particle size prefers surface plasmon resonance (SPR) scattering of metal that could lead to PL enhancement; however, available ZnO surface in the Au-ZnO composite becomes more important than the particle size of the composite with higher [Au]. The catalytic activity of these Au-ZnO nanocomposites tested on 4-nitrophenol clearly revealed the presence of an intermediate with both NPs and clusters playing different roles. An in vitro study of cytotoxicity on MCF-7 cell lines revealed that these gold nanostructures have turned out to be powerful nanoagents for destruction of cancer cells even with small amounts of gold particles/clusters. The nanorods of ZnO, known to be nontoxic to normal cells, play a lesser role in the anticancer activity of these Au-ZnO nanocomposites. PMID- 25271813 TI - Annular plaques with raised erythematous-violaceous borders on the face and torso. PMID- 25271814 TI - Effect of atomoxetine on hyperactivity in an animal model of attention deficit/hyperactivity disorder (ADHD). AB - BACKGROUND: Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention deficit/hyperactivity disorder (ADHD). PURPOSE: To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus. METHODS: Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined. RESULTS: The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner. CONCLUSION: Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway. PMID- 25271815 TI - Inaccuracy of perceived competence ratings is associated with problem behaviors in 5-year-old children. AB - The authors examined problem behaviors in preschool children as a function of perceived competence. Prior research has demonstrated a link between inaccuracy of self-perceptions and teacher-reported externalizing behaviors in preschool aged boys. This study extended past research by adding data collected from observed behaviors in a laboratory setting, as well as parent reports of internalizing and externalizing behaviors. Five-year-old children completed the Pictorial Scale of Perceived Competence and Social Acceptance for Young Children (PSPCSA) in the lab, participated in a 10-min puzzle interaction task with their cotwin and mother, and completed a short task assessing cognitive abilities. Children were grouped into 3 self-esteem categories (unrealistically low, realistic, and unrealistically high) based on comparisons of self-reported (PSPCSA) versus actual competencies for maternal acceptance, peer acceptance, and cognitive competence. Results showed that children who overreported their maternal acceptance and peer acceptance had significantly more parent-reported externalizing problems as well as internalizing problems. There were no significant differences in accuracy for cognitive competence. The findings from this study underscore the negative impact of unrealistically high self-appraisal on problem behaviors in young children. PMID- 25271816 TI - Emotion perception accuracy and bias in face-to-face versus cyberbullying. AB - The authors investigated the association of traditional and cyber forms of bullying and victimization with emotion perception accuracy and emotion perception bias. Four basic emotions were considered (i.e., happiness, sadness, anger, and fear); 526 middle school students (280 females; M age = 12.58 years, SD = 1.16 years) were recruited, and emotionality was controlled. Results indicated no significant findings for girls. Boys with higher levels of traditional bullying did not show any deficit in perception accuracy of emotions, but they were prone to identify happiness and fear in faces when a different emotion was expressed; in addition, male cyberbullying was related to greater accuracy in recognizing fear. In terms of the victims, cyber victims had a global problem in recognizing emotions and a specific problem in processing anger and fear. It was concluded that emotion perception accuracy and bias were associated with bullying and victimization for boys not only in traditional settings but also in the electronic ones. Implications of these findings for possible intervention are discussed. PMID- 25271817 TI - Intentional teaching facilitates young children's comprehension and use of a symbolic object. AB - Children are exposed to symbolic objects that they have to learn to use very early in life. The authors' aim was to examine whether it is possible to intentionally teach young children the symbolic function of an object. They employed a search task in which children had to use a map to find a toy. Experiment 1 revealed that with no instruction 3-year-, 10-month-old children were quite successful; 3-year-, 6-month-olds showed a divided performance; and 3 year-, 0-month-olds failed. With this baseline, Experiment 2 compared the performance of 3-year-, 0-month-olds in three different conditions: no instruction, complete instruction (before the task begins), and teaching (complete instruction plus corrective feedback); only children in the teaching condition succeeded. However, children 6 months younger, 2-year-, 6-month-olds, failed despite teaching that was provided (Study 3). This research shows that at some points in development instruction is not enough; intentional teaching in communicative contexts is the mechanism that boosts symbolic understanding in early childhood. PMID- 25271818 TI - Children's ability to recognize emotions from partial and complete facial expressions. AB - The authors investigated children's ability to recognize emotions from the information available in the lower, middle, or upper face. School-age children were shown partial or complete facial expressions and asked to say whether they corresponded to a given emotion (anger, fear, surprise, or disgust). The results indicate that 5-year-olds were able to recognize fear, anger, and surprise from partial facial expressions. Fear was better recognized from the information located in the upper face than those located in the lower face. A similar pattern of results was found for anger, but only in girls. Recognition improved between 5 and 10 years old for surprise and anger, but not for fear and disgust. PMID- 25271819 TI - Does the thought count? Gratitude understanding in elementary school students. AB - Gratitude, although studied throughout history by scholars from diverse backgrounds, has been largely understudied in psychology until recently. The psychological literature on gratitude is expanding, but it is still particularly limited with children. The authors compared younger (first- and second-grade students; n = 30) and older (fourth- and fifth-grade students; n = 27) children on gratitude-related ratings surrounding gift giving vignettes that included either a desirable (e.g., a birthday cupcake) or an undesirable (e.g., a melted ice cream cone) gift. Empathy was also measured. Hierarchical regressions revealed different patterns of predictors for desirable and undesirable gifts. For desirable gifts, liking significantly predicted gratitude and liking predicted effort. For undesirable gifts, older children and those who perceived the target as liking the gift more predicted higher gratitude ratings. Finally, higher gratitude rating predicted both higher ratings of giver effort (i.e., intention or how hard did the giver try to give a nice gift) and liking of the undesirable gifts. More research on children's understanding of gratitude is needed but these results suggest that school-aged children take into account givers' intentions and thoughts behind gift giving in determining feelings of gratitude. Limitations and directions for future research are also discussed. PMID- 25271821 TI - A short designed semi-aromatic organic nanotube--synthesis, chiroptical characterization, and host properties. AB - The first generation of an organic nanotube based on the enantiomerically pure bicyclo[3.3.1]nonane framework is presented. The helical tube synthesised is the longest to date having its aromatic systems oriented parallel to the axis of propagation (length ~26 A and inner diameter ~11 A according to molecular dynamics simulations in chloroform). The synthesis of the tube, a heptamer, is based on a series of Friedlander condensations and the use of pyrido[3,2 d]pyrimidine units as masked 2-amino aldehydes, as a general means to propagate organic tubular structures and the introduction of a methoxy group for modification toward solubility and functionalization are described. The electronic CD spectra of the tube and molecular intermediates are correlated with theoretical spectra calculated with time-dependent density functional theory to characterize the chirality of the tube. Both experimental (NMR-titrations) and theoretical (molecular dynamics simulations) techniques are used to investigate the use of the tube as a receptor for the acetylcholine and guanidinium cations, respectively. PMID- 25271823 TI - More than you think I am. PMID- 25271822 TI - Increased release of dopamine in the striata of young adults with hearing impairment and its relevance for the social defeat hypothesis of schizophrenia. AB - IMPORTANCE: An increased risk for psychosis is observed in people with hearing impairment. According to the social defeat hypothesis, the long-term experience of exclusion leads to enhanced baseline activity and/or sensitization of the dopamine system and puts the individual at increased risk for psychosis. OBJECTIVE: To investigate whether young adults with severe hearing impairment (SHI) experience more feelings of social defeat, show greater dopamine release in response to dexamphetamine, and report a stronger subjective reaction to this substance than normal-hearing young adults and to examine whether dopamine release is associated with both self-reported social exclusion and dexamphetamine induced psychotic experiences. DESIGN, SETTING, AND PARTICIPANTS: A sample of 19 participants with SHI and 19 smoking-, age-, and sex-matched healthy controls underwent single-photon emission computed tomography with iodine 123-labeled iodobenzamide as a radiotracer before and after an amphetamine challenge at an academic hospital. EXPOSURES: Dexamphetamine sulfate (0.3 mg/kg) administered intravenously. MAIN OUTCOMES AND MEASURES: Baseline D2/3 receptor binding and endogenous dopamine release. RESULTS: The participants with SHI reported experiencing more feelings of social defeat (U=109, z=-2.09, P=.04) and loneliness (U=87.5, z=-2.72, P=<.001) than did healthy controls, but they did not differ from healthy controls with regard to baseline psychotic symptoms (U=156.5, z=-0.70, P=.48). There were no significant group differences in baseline D2/3 receptor binding. However, repeated-measures multivariate analysis of covariance with age (in months) and tobacco smoking (in pack-years) as covariates showed that there was a greater amphetamine-induced striatal dopamine release among the participants with SHI than among the healthy controls (F1,34=4.55, P=.04). After amphetamine administration, the participants with SHI reported more changes in affect than the healthy controls, but not a greater increase in psychotic symptoms. Likewise, reports of social exclusion and an increase in psychotic symptoms were not associated with dopamine release. CONCLUSIONS AND RELEVANCE: Our study presents preliminary evidence of dopamine sensitization in a socially excluded group of people with hearing impairment. If replicated by future studies in other excluded groups, this finding may have major implications for our understanding of the underlying mechanism and for prevention of psychotic disorders. PMID- 25271824 TI - The dilemma of liver transplant allocation for alcoholic patients. AB - Liver transplantation for alcoholic liver disease (ALD) has been, and continues to be, a subject of great controversy. Although ALD is one of the most common causes of cirrhosis of the liver and one of the most prominent indications for orthotopic liver transplantation, arguments arise regarding liver transplantation as a suitable treatment for this disease. In many documented studies, the rate of alcoholic recidivism and rates of noncompliance with antirejection regimens have been examined. Many of these studies demonstrate that the rate of recidivism is high and medication compliance is low. Now is a time in which medicine is experiencing an increased need for organ allografts with a profound shortage of suitable matches for patients in need. Therefore, transplanting viable and vital liver allografts into patients with ALD, considering high rates of alcoholic recidivism and noncompliance, is more ethically controversial than ever. It is the responsibility of the medical personnel-including nurses-who sit on ethical advisory boards to distribute an exceptional gift of liver transplants. Also, it is the duty of nurses who are involved with the care of transplant recipients to help the patients assume full respect and treat their liver well. This article discusses the ethical implications and ethical obligations of medical staff when continuing to consider ALD appropriate grounds for liver transplantation. PMID- 25271825 TI - Asian flushing: genetic and sociocultural factors of alcoholism among East asians. AB - Alcohol use can lead to a cascade of problems such as increased chances of risky behavior and negative health consequences, including alcoholic liver disease and upper gastric and liver cancer. Ethanol is metabolized mainly by 2 major enzymes: alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Genetic variations of genes encoding the 2 enzymes are very common among East Asians but relatively rare for most other populations. Facial flushing and other physical discomforts after alcohol drinking triggered by accumulation of acetaldehyde through defective genes for ADH and ALDH have been reported. Approximately 40% of East Asians (Chinese, Japanese, and Korean) show facial flushing after drinking alcohol, known as "Asian flush," which is characterized by adverse reactions on alcohol drinking in individuals possessing the fasting metabolizing alleles for ADH, ADH1B*2, and ADH1C*1, and the null allele for ALDH and ALDH2*2. Alcoholism is determined not only by the genetic deficiency but also by behaviors that involve complex interactions between genetic and sociocultural factors. The purpose of this article was to provide nurses with the most current information about genetic and sociocultural influences on alcoholism and alcohol-related health problems specifically for East Asians and implications of this knowledge to nursing practice. The physiological phenomenon of genes and genetics in relation to alcohol metabolism in this special population is emphasized. PMID- 25271827 TI - Impact of the early initiation of feedings on hospital length of stay in children post-PEG tube placement. AB - Delays in feeding patients post-percutaneous endoscopic gastrostomy (PEG) tube placement may result in unnecessary prolongation of hospital stay, deprivation of nutrition, and increased healthcare costs. Common practice has been to wait overnight before initiating feedings post-PEG tube placement. Our facility changed existing policy and began feeding children 6 hours post-PEG. The objectives of this article are to (a) describe the effect of early feeding (6 hours postprocedure) on length of hospital stay, and (b) add to the existing data on safety of early feeding post-PEG tube placement in children. A retrospective chart review of 70 patients admitted for PEG tube placement was performed. Patients admitted pre- and postpolicy change were compared for length of hospitalization, time NPO (nothing by mouth), pain scores, pain medication use, and adverse events (Group A: before policy change; Group B: after policy change). No adverse events were identified in either group. Both median time to feeding initiation and hospital length of stay were shorter in Group B. There was no significant difference in reported pain scores or the number of pain medication doses between the two groups. Early initiation of feedings post-PEG led to a shortened length of hospital stay with no increase in adverse events or reported pain. PMID- 25271826 TI - The effects of a designer music intervention on patients' anxiety, pain, and experience of colonoscopy: a short report on a pilot study. AB - There is a controversy on whether listening to music before or during colonoscopy reduces anxiety and pain and improves satisfaction and compliance with the procedure. This study aimed to establish whether specifically designed music significantly affects anxiety, pain, and experience associated with colonoscopy. In this semirandomized controlled study, 34 patients undergoing a colonoscopy were provided with either muted headphones (n = 17) or headphones playing the investigator-selected music (n = 17) for 10 minutes before and during colonoscopy. Anxiety, pain, sedation dose, and overall experience were measured using quantitative measures and scales. Participants' state anxiety decreased over time (P < .001). However, music did not significantly reduce anxiety (P = .441), pain scores (P = .313), or midazolam (P = .327) or fentanyl doses (P = .295). Despite these findings, 100% of the music group indicated that they would want music if they were to repeat the procedure, as compared with only 50% of those in the nonmusic group wanting to wear muted headphones. Although no significant effects of music on pain, anxiety, and sedation were found, a clear preference for music was expressed, therefore warranting further research on this subject. PMID- 25271828 TI - Increased incidence of bowel and psychological symptoms in Chinese female D-IBS patients with premenstrual syndrome. AB - The purpose of this study was to investigate levels of stress, gynecological events, bowel, and psychological symptoms in Chinese women of reproductive age who experienced both diarrhea-predominant irritable bowel syndrome (D-IBS) and premenstrual syndrome. A cross-sectional study used the self-reported questionnaire based on previous studies done abroad with the Rome III criteria and Symptom Checklist-90 Scale. The research was performed on 233 reproductive age women in China. A descriptive, comparative approach was used to (a) describe general characteristics and the history of disease both of the overlapping group and the D-IBS group, (b) compare stress and gynecological experience of the 2 groups, (c) compare the characteristics of defecation and bowel habits by group, and (d) compare psychological symptoms between groups. Percentage distribution and chi-square tests were used to analyze data. The results revealed that compared to simple D-IBS patients, the patients in the overlapping syndromes group had increased stress and gynecological events and more severe bowel and psychological symptoms. Overlapping syndromes were associated with repeated episodes of longer duration and delayed recovery. Future studies with expanded sample size and blood collection may verify and explain the results of this study. PMID- 25271829 TI - Dopamine antagonists for nausea and vomiting: special considerations. AB - The dopamine antagonists, particularly droperidol, are effective at treating N&V. Because dopamine plays many roles in the body, especially in the brain, a degree of alteration in mental status should be expected, especially with higher doses. Other less frequent side effects include QT prolongation. When given for non- chemotherapy-induced N&V treatment QT prolongation is rare. Higher doses warrant clinical awareness and ability to identify and treat prolonged QT and its sequelae. Invited authors for a following column will discuss QT prolongation and implications. PMID- 25271830 TI - The noncancer effects of smoking on the gastrointestinal tract. PMID- 25271831 TI - Dynamic MRI of an orbital varix. PMID- 25271832 TI - Identification and characterization of a late gene encoded by grouper iridovirus 2L (GIV-2L). AB - Grouper iridovirus (GIV) belongs to the Ranavirus genus and is one of the most important viral pathogens in grouper, particularly at the fry and fingerling stages. In this study, we identified and characterized the GIV-2L gene, which encodes a protein of unknown function. GIV-2L is 1242 bp in length, with a predicted protein mass of 46.2 kDa. It displayed significant identity only with members of the Ranavirus and Iridovirus genera. We produced mouse monoclonal antibodies against the GIV-2L protein by immunizing mice with GIV-2L-His-tag recombinant protein. By inhibiting de novo protein and DNA synthesis in GIV infected cells, we showed that GIV-2L was a late gene during the viral replication. Finally, immunofluorescence microscopy revealed that GIV-2L protein accumulated in both the nucleus and cytoplasm of infected cells. These results offer important insights into the pathogenesis of GIV. PMID- 25271833 TI - Gefitinib plus interleukin-2 in advanced non-small cell lung cancer patients previously treated with chemotherapy. AB - The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3-4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2-3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2-3.8) and 4.1 (CI 95% = 2.6-5.7) months; a median overall survival of 20.1 (CI 95% = 5.1-35.1) and 6.9 (CI 95% = 4.9-8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16-0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18-0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib. PMID- 25271834 TI - Chloroquine is a zinc ionophore. AB - Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concentration dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compound, indicating the specificity of the zinc uptake. Furthermore, addition of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examination of intracellular zinc distribution demonstrated that free zinc ions are more concentrated in the lysosomes after addition of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity. PMID- 25271835 TI - A novel potentiometric biosensor for determination of L-lysine in commercial pharmaceutical L-lysine tablet and capsule. AB - The construction of an L-lysine biosensor on ammonium-selective poly(vinylchloride) (PVC) membrane electrode is described in this study. The construction procedure occurs in two stages: (I) the preparation of ammonium selective poly(vinylchloride) (PVC) membrane electrode and (II) the chemical immobilization of lysine oxidase on this ammonium-selective electrode by using glutaraldehyde. The ammonium ions produced after enzymatic reaction were determined potentiometrically. The sensitivity of the lysine biosensor against ammonium ions and lysine were studied. The response time, linear working range, reproducibility and life time of the biosensor were also determined. The interfering effect of other amino acids on the biosensor performance was also studied and potentiometric selectivity coefficients were calculated. Although the biosensor responded mainly against tyrosine, a lot of amino acids and ascorbic acid that can be present in some real samples did not show any important interference. Additionally, lysine assay in commercial pharmaceutical lysine tablets and capsules was also successfully carried out. The results were in good agreement with previously reported values. PMID- 25271837 TI - Analysis of genetic linkage data for Mendelian traits. AB - This unit describes linkage analysis, an invaluable tool in mapping human disease genes. Linkage analysis is one of several methods used to map genes. Specifically, in linkage analysis, cosegregation of two or more genes (traits) is examined in a family unit to determine if they segregate independently of each other according to Mendel's laws or if they do not segregate independently because of their close physical proximity. The procedures outlined in this unit are not always straightforward, and a number of caveats are presented in the commentary regarding possible complications and confounding factors that may arise. Specific examples are given, but it is not possible to cover all possible scenarios or variables. The intention is to enable the reader to master basic principles used in the linkage approach, and thus be in a position to undertake, with proper consultation, a linkage-analysis study. This unit deals specifically with lod score analysis in Mendelian disorders. PMID- 25271836 TI - Genital human papillomavirus infection among women in Bangladesh: findings from a population-based survey. AB - BACKGROUND: There has been no population-based study on human papillomavirus (HPV) prevalence or its genotypes in Bangladesh; a country eligible for GAVI funding for HPV vaccine. METHODS: We used baseline survey data of a prospective cohort study that was conducted in one urban and one rural area of Bangladesh. A total of 997 urban and 905 rural married women, aged 13 to 64 years, were enrolled in the baseline during July-December, 2011. Information was collected on socio-demographic characteristics and potential risk factors for HPV infection followed by gynecological examination and collection of endocervical samples using the cervical cytobrush (Digene cervical sampler). HPV DNA testing was done by Polymerase Chain Reaction (PCR) using a consensus primer set. RESULTS: Prevalence of any HPV infection was 7.7% with no significant difference between urban and rural women. Most common high-risk genotypes were HPV16, HPV66, HPV18, HPV45, HPV31 and HPV53. Urban women working as housemaids or garment workers were at higher risk of any HPV infection (OR = 2.15, 95% CI: 1.13-4.11) compared to housewives. Rural women whose husband lived overseas were almost two times more likely to have any HPV infection (OR = 1.93; 95% CI 1.05-3.55) compared to women whose husbands lived with them. CONCLUSION: The prevalence of HPV infection among Bangladeshi women is similar to other regions of Asia. However, type-specific patterns are different. The study findings will inform the formulation of HPV vaccination policies in Bangladesh, monitoring the impact of vaccination programmes, and the identification of target populations for screening. PMID- 25271838 TI - RNA-seq Data: Challenges in and Recommendations for Experimental Design and Analysis. AB - RNA-seq is widely used to determine differential expression of genes or transcripts as well as identify novel transcripts, identify allele-specific expression, and precisely measure translation of transcripts. Thoughtful experimental design and choice of analysis tools are critical to ensure high quality data and interpretable results. Important considerations for experimental design include number of replicates, whether to collect paired-end or single-end reads, sequence length, and sequencing depth. Common analysis steps in all RNA seq experiments include quality control, read alignment, assigning reads to genes or transcripts, and estimating gene or transcript abundance. Our aims are two fold: to make recommendations for common components of experimental design and assess tool capabilities for each of these steps. We also test tools designed to detect differential expression, since this is the most widespread application of RNA-seq. We hope that these analyses will help guide those who are new to RNA-seq and will generate discussion about remaining needs for tool improvement and development. PMID- 25271840 TI - Diagnosing Lysosomal Storage Disorders: The GM2 Gangliosidoses. AB - The GM2 gangliosidoses are a group of autosomal recessive lysosomal storage disorders caused by defective beta-hexosaminidase. There are three clinical conditions in this group: Tay-Sachs disease (TSD), Sandhoff disease (SD), and hexosaminidase activator deficiency. The three conditions are clinically indistinguishable. TSD and SD have been identified with infantile, juvenile, and adult onset forms. The activator deficiency is only known to present with infantile onset. Diagnosis of TSD and SD is based on decreased hexosaminidase activity and a change in the percentage of activity between isoforms. There are no biochemical tests currently available for activator deficiency. This unit provides a detailed procedure for identifying TSD and SD in affected individuals and carriers from leukocyte samples, the most robust sample type available. PMID- 25271839 TI - Mouse Genome Editing Using the CRISPR/Cas System. AB - The availability of techniques to create desired genetic mutations has enabled the laboratory mouse as an extensively used model organism in biomedical research including human genetics. A new addition to this existing technical repertoire is the CRISPR/Cas system. Specifically, this system allows editing of the mouse genome much more quickly than the previously used techniques, and, more importantly, multiple mutations can be created in a single experiment. Here we provide protocols for preparation of CRISPR/Cas reagents and microinjection into one-cell mouse embryos to create knockout or knock-in mouse models. PMID- 25271841 TI - Molecular diagnosis of Duchenne muscular dystrophy. AB - Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular disorder caused by mutations in the dystrophin gene (DMD; locus Xp21.2). The mutation spectrum of DMD is unique in that 65% of causative mutations are intragenic deletions, with intragenic duplications and point mutations (along with other sequence variants) accounting for 6% to 10% and 30% to 35%, respectively. The strategy for molecular diagnostic testing for DMD involves initial screening for deletions/duplications using microarray-based comparative genomic hybridization (array-CGH) followed by full-sequence analysis of DMD for sequence variants. Recently, next-generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants (small insertions, deletions, and indels). This unit initially discusses the strategic algorithm for establishing a molecular diagnosis of DMD and later provides detailed protocols of current molecular diagnostic methods for DMD, including array-CGH, PCR-based Sanger sequencing, and NGS-based sequencing assay. PMID- 25271842 TI - Knemidocoptic mange in wild golden eagles, California, USA. AB - During 2012-2013 in California, USA, 3 wild golden eagles were found with severe skin disease; 2 died. The cause was a rare mite, most closely related to Knemidocoptes derooi mites. Cautionary monitoring of eagle populations, habitats, and diseases is warranted. PMID- 25271843 TI - Optimization of a free water elimination two-compartment model for diffusion tensor imaging. AB - Diffusion tensor imaging is used to measure the diffusion of water in tissue. The diffusion properties carry information about the relative organization and structure of the underlying tissue. In the case of a single voxel containing both tissue and a fast diffusing component such as free water, a single diffusion tensor is no longer appropriate. A two-tensor free water elimination model has previously been proposed to correct for the case of volume mixing. Here, this model was implemented in a straightforward but novel manner without the use of spatial constraints. The optimal acquisition parameters were investigated through Monte Carlo simulations and human brain imaging studies. At a signal-to-noise ratio of 40 with 64 diffusion-weighted encoding images, the most accurate estimates of fast diffusion signal were obtained with two diffusion-weighted shells (b-value in s/mm(2)*number of directions) of 500*32 and 1500*32. The potential bias in fractional anisotropy induced by this two-compartment model was more than an order of magnitude less than the error of using the single diffusion tensor model in the presence of partial volume effects with free water. This strategy may be useful for characterizing the diffusion of tissues adjacent to cerebral spinal fluid (CSF), tissues affected by edema, and removing artifacts from blurring and ghosting of the CSF signal. PMID- 25271847 TI - Microwave-assisted liquid-liquid microextraction based on solidification of ionic liquid for the determination of sulfonamides in environmental water samples. AB - An easy, quick, and green method, microwave-assisted liquid-liquid microextraction based on solidification of ionic liquid, was first developed and applied to the extraction of sulfonamides in environmental water samples. 1-Ethy 3-methylimidazolium hexafluorophosphate, which is a solid-state ionic liquid at room temperature, was used as extraction solvent in the present method. After microwave irradiation for 90 s, the solid-state ionic liquid was melted into liquid phase and used to finish the extraction of the analytes. The ionic liquid and sample matrix can be separated by freezing and centrifuging. Several experimental parameters, including amount of extraction solvent, microwave power and irradiation time, pH of sample solution, and ionic strength, were investigated and optimized. Under the optimum experimental conditions, good linearity was observed in the range of 2.00-400.00 MUg/L with the correlation coefficients ranging from 0.9995 to 0.9999. The limits of detection for sulfathiazole, sulfachlorpyridazine, sulfamethoxazole, and sulfaphenazole were 0.39, 0.33, 0.62, and 0.85 MUg/L, respectively. When the present method was applied to the analysis of environmental water samples, the recoveries of the analytes ranged from 75.09 to 115.78% and relative standard deviations were lower than 11.89%. PMID- 25271848 TI - Insights into the electronic structure of disulfur tetrafluoride isomers from generalized valence bond theory. AB - Sulfur and fluorine can participate in a variety of bonding motifs, lending significant diversity to their chemistry. Prior work has identified three distinct minima for disulfur tetrafluoride (S2F4) compounds: two FSSF3 isomers and one SSF4 species. We used a combination of sophisticated explicitly correlated coupled cluster calculations and generalized valence bond (GVB) theory to characterize the electronic structure of these species as well as additional stationary points on the potential energy surface with F2SSF2 connectivity. On the singlet surface, the two stationary points considered in this work with an F2SSF2 structure are first- or second-order saddle points and not minima. However, on the triplet surface, we discovered a novel C2 symmetric F2SSF2 minimum that was anticipated from the structure of an excited state ((3)B1) of SF2. Analysis using the GVB wave function in conjunction with the recoupled pair bonding model developed by our group provides a straightforward explanation of the bonding in all of the S2F4 structures considered here. In addition, the model predicted the existence of the F2SSF2((3)B) minimum. PMID- 25271846 TI - Selective vulnerability related to aging in large-scale resting brain networks. AB - Normal aging is associated with cognitive decline. Evidence indicates that large scale brain networks are affected by aging; however, it has not been established whether aging has equivalent effects on specific large-scale networks. In the present study, 40 healthy subjects including 22 older (aged 60-80 years) and 18 younger (aged 22-33 years) adults underwent resting-state functional MRI scanning. Four canonical resting-state networks, including the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN) and salience network, were extracted, and the functional connectivities in these canonical networks were compared between the younger and older groups. We found distinct, disruptive alterations present in the large-scale aging-related resting brain networks: the ECN was affected the most, followed by the DAN. However, the DMN and salience networks showed limited functional connectivity disruption. The visual network served as a control and was similarly preserved in both groups. Our findings suggest that the aged brain is characterized by selective vulnerability in large-scale brain networks. These results could help improve our understanding of the mechanism of degeneration in the aging brain. Additional work is warranted to determine whether selective alterations in the intrinsic networks are related to impairments in behavioral performance. PMID- 25271849 TI - Characterization of polar organosulfates in secondary organic aerosol from the green leaf volatile 3-Z-hexenal. AB - Evidence is provided that the green leaf volatile 3-Z-hexenal serves as a precursor for biogenic secondary organic aerosol through the formation of polar organosulfates (OSs) with molecular weight (MW) 226. The MW 226 C6-OSs were chemically elucidated, along with structurally similar MW 212 C5-OSs, whose biogenic precursor is likely related to 3-Z-hexenal but still remains unknown. The MW 226 and 212 OSs have a substantial abundance in ambient fine aerosol from K-puszta, Hungary, which is comparable to that of the isoprene-related MW 216 OSs, known to be formed through sulfation of C5-epoxydiols, second-generation gas phase photooxidation products of isoprene. Using detailed interpretation of negative-ion electrospray ionization mass spectral data, the MW 226 compounds are assigned to isomeric sulfate esters of 3,4-dihydroxyhex-5-enoic acid with the sulfate group located at the C-3 or C-4 position. Two MW 212 compounds present in ambient fine aerosol are attributed to isomeric sulfate esters of 2,3 dihydroxypent-4-enoic acid, of which two are sulfated at C-3 and one is sulfated at C-2. The formation of the MW 226 OSs is tentatively explained through photooxidation of 3-Z-hexenal in the gas phase, resulting in an alkoxy radical, followed by a rearrangement and subsequent sulfation of the epoxy group in the particle phase. PMID- 25271850 TI - Distributed patterns of event-related potentials predict subsequent ratings of abstract stimulus attributes. AB - Exposure to pleasant and rewarding visual stimuli can bias people's choices towards either immediate or delayed gratification. We hypothesised that this phenomenon might be based on carry-over effects from a fast, unconscious assessment of the abstract 'time reference' of a stimuli, i.e. how the stimulus relates to one's personal understanding and connotation of time. Here we investigated whether participants' post-experiment ratings of task-irrelevant, positive background visual stimuli for the dimensions 'arousal' (used as a control condition) and 'time reference' were related to differences in single channel event-related potentials (ERPs) and whether they could be predicted from spatio-temporal patterns of ERPs. Participants performed a demanding foreground choice-reaction task while on each trial one task-irrelevant image (depicting objects, people and scenes) was presented in the background. Conventional ERP analyses as well as multivariate support vector regression (SVR) analyses were conducted to predict participants' subsequent ratings. We found that only SVR allowed both 'arousal' and 'time reference' ratings to be predicted during the first 200 ms post-stimulus. This demonstrates an early, automatic semantic stimulus analysis, which might be related to the high relevance of 'time reference' to everyday decision-making and preference formation. PMID- 25271852 TI - Chikungunya virus imported into French Polynesia, 2014. PMID- 25271851 TI - Adult limbal neurosphere cells: a potential autologous cell resource for retinal cell generation. AB - The Corneal limbus is a readily accessible region at the front of the eye, separating the cornea and sclera. Neural colonies (neurospheres) can be generated from adult corneal limbus in vitro. We have previously shown that these neurospheres originate from neural crest stem/progenitor cells and that they can differentiate into functional neurons in vitro. The aim of this study was to investigate whether mouse and human limbal neurosphere cells (LNS) could differentiate towards a retinal lineage both in vivo and in vitro following exposure to a developing retinal microenvironment. In this article we show that LNS can be generated from adult mice and aged humans (up to 97 years) using a serum free culture assay. Following culture with developing mouse retinal cells, we detected retinal progenitor cell markers, mature retinal/neuronal markers and sensory cilia in the majority of mouse LNS experiments. After transplantation into the sub-retinal space of neonatal mice, mouse LNS cells expressed photoreceptor specific markers, but no incorporation into host retinal tissue was seen. Human LNS cells also expressed retinal progenitor markers at the transcription level but mature retinal markers were not observed in vitro or in vivo. This data highlights that mouse corneal limbal stromal progenitor cells can transdifferentiate towards a retinal lineage. Complete differentiation is likely to require more comprehensive regulation; however, the accessibility and plasticity of LNS makes them an attractive cell resource for future study and ultimately therapeutic application. PMID- 25271855 TI - Neuropathy after sodium tetradecyl sulfate sclerotherapy of venous malformations in children. AB - PURPOSE: To estimate the risk of nerve injuries and assess outcomes after sodium tetradecyl sulfate (STS) sclerotherapy of venous malformations (VMs) in children. MATERIALS AND METHODS: Sclerotherapy is the treatment of choice for most VMs, but all sclerotherapy agents are associated with the risk of complications. Neuropathy is considered a rare but potentially serious complication of venous sclerotherapy. The institutional review board waived ethical approval for this retrospective review, in which 647 sclerotherapy procedures were performed in 204 patients (104 female and 100 male patients; mean age, 9 years 6 months [range, 6 months to 17 years 11 months]) as treatment for symptomatic VMs. Technical and clinical success of the treatment was evaluated. Complications were reviewed with a particular focus on nerve injury. Informed consent, specifying the risk of neuropathy, as well as pain, swelling, infection, risks of anesthesia, skin injury, nonresolution or worsening of symptoms, and possible need for further or multiple procedures, was obtained for all patients. Standard sclerotherapy techniques were used. Technical details of all procedures were recorded prospectively. Follow-up included immediate postprocedural assessment and outpatient clinic review. All nerve injuries were recorded. Patients were monitored and treated according to clinical need. Confidence intervals were calculated by using the Wilson method, without correction for continuity. RESULTS: Treatment was technically successful in 197 of 204 patients (96.6%), and clinical success was achieved in 174 of 204 (85.3%). Thirty-seven of the 647 procedures (5.7%) resulted in a complication, including 11 cases of excessive swelling, nine cases of skin injury, two patients with infection, and two with pain. Motor and/or sensory nerve injuries occurred after seven procedures (1.1%). Five of the seven children had undergone at least one previous sclerotherapy procedure. Neuropathy resolved spontaneously in four patients and partially recovered in three, of whom two underwent surgery. Surgery included debridement of necrotic tissue, carpal tunnel decompression, and external neurolysis. CONCLUSION: Nerve injury is an unusual but not rare complication of STS sclerotherapy. A degree of recovery, which may be complete, can be expected in most patients. PMID- 25271853 TI - IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases. AB - The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1beta. Treatment of PBMCs with IL-6 induced production of TNF alpha, CXCL8, and CCL2, but not IL-1beta. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1beta and CXCL8, but not TNF-alpha production compared with TLR ligands alone. This enhanced production of IL-1beta and CXCL8 paralleled increased p65 NF-kappaB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1beta, TNF alpha and CXCL8 with reduced p65 NF-kappaB activation. IL-6/IL-1beta co stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1beta production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-kappaB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands. PMID- 25271856 TI - Robot-assisted radical prostatectomy: Multiparametric MR imaging-directed intraoperative frozen-section analysis to reduce the rate of positive surgical margins. AB - PURPOSE: To investigate whether use of multiparametric magnetic resonance (MR) imaging-directed intraoperative frozen-section (IFS) analysis during nerve sparing robot-assisted radical prostatectomy reduces the rate of positive surgical margins. MATERIALS AND METHODS: This retrospective analysis of prospectively acquired data was approved by an institutional ethics committee, and the requirement for informed consent was waived. Data were reviewed for 134 patients who underwent preoperative multiparametric MR imaging (T2 weighted, diffusion weighted, and dynamic contrast-material enhanced) and nerve-sparing robot-assisted radical prostatectomy, during which IFS analysis was used, and secondary resections were performed when IFS results were positive for cancer. Control patients (n = 134) matched for age, prostate-specific antigen level, and stage were selected from a pool of 322 patients who underwent nerve-sparing robot assisted radical prostatectomy without multiparametric MR imaging and IFS analysis. Rates of positive surgical margins were compared by means of the McNemar test, and a multivariate conditional logistic regression model was used to estimate the odds ratio of positive surgical margins for patients who underwent MR imaging and IFS analysis compared with control subjects. RESULTS: Eighteen patients who underwent MR imaging and IFS analysis underwent secondary resections, and 13 of these patients were found to have negative surgical margins at final pathologic examination. Positive surgical margins were found less frequently in the patients who underwent MR imaging and IFS analysis than in control patients (7.5% vs 18.7%, P = .01). When the differences in risk factors are taken into account, patients who underwent MR imaging and IFS had one-seventh the risk of having positive surgical margins relative to control patients (adjusted odds ratio: 0.15; 95% confidence interval: 0.04, 0.61). CONCLUSION: The significantly lower rate of positive surgical margins compared with that in control patients provides preliminary evidence of the positive clinical effect of multiparametric MR imaging-directed IFS analysis for patients who undergo prostatectomy. PMID- 25271857 TI - Assessment of BI-RADS category 4 lesions detected with screening mammography and screening US: utility of MR imaging. AB - PURPOSE: To investigate the utility of magnetic resonance (MR) imaging according to different types of Breast Imaging Reporting and Data System (BI-RADS) category 4 findings from screening mammography and/or screening ultrasonography (US). MATERIALS AND METHODS: This institutional review board-approved prospective study included 340 patients in whom 353 lesions were detected at screening mammography or US and were rated BI-RADS category 4 after appropriate conventional work-up. Written informed consent was obtained from all patients. Women underwent standard dynamic contrast material-enhanced MR imaging for further assessment. Women with negative or benign MR findings who did not proceed to biopsy underwent intensified follow-up for at least 18 months. Pure clustered microcalcifications were followed up for at least 24 months. RESULTS: Of the 353 study findings, 66 (18.7%) were finally shown to be true-positive (23 cases of ductal carcinoma in situ [DCIS], 43 invasive cancers) and 287 (81.3%) were false-positive. Assessment of MR imaging findings led to a correct diagnosis of no breast cancer in 264 of the 287 false-positive findings (92%) and helped confirm the presence of breast cancer in 63 of 66 malignancies. The false-negative rate for pure clustered microcalcifications was 12% (three of 25 cases) because of three nonenhancing low grade DCIS cases; in turn, MR imaging depicted additional invasive cancers in three women with false-positive findings from mammography and US. For mammographic findings other than pure clustered microcalcifications, MR imaging increased the positive predictive value (PPV) from 17.5% (21 of 120 cases; 95% confidence interval [CI]: 10.7%, 24.3%) to 78% (21 of 27 cases; 95% CI: 62.1%, 93.5%), with a false-negative rate of 0%. For all US findings, MR imaging increased the PPV from 12.9% (20 of 155 cases; 95% CI: 7.6%, 18.2%) to 69% (20 of 29 cases; 95% CI: 52.2%, 85.8%), again with a false-negative rate of 0%. MR imaging resulted in false-positive findings that led to MR imaging-guided biopsy in five of the 340 patients (1.5%). CONCLUSION: MR imaging is useful for the noninvasive work-up of lesions classified as BI-RADS category 4 at mammography or US and can help avoid 92% of unnecessary biopsies. The false-negative rate was 0% for all US findings and for all mammographic findings except pure clustered microcalcifications. Additional invasive cancers were identified in three women with false-positive findings from mammography and US. PMID- 25271858 TI - Treatment options beyond IFNalpha and NUCs for chronic HBV infection: expectations for tomorrow. AB - Chronic hepatitis B virus (HBV) infection may progress to cirrhosis, hepatocellular carcinoma (HCC) and end-stage liver failure with time. Interruption of this process can only be achieved through effective antiviral treatment. This approach has so far involved the use of immunomodulators such as pegylated interferon alpha (Peg-IFNalpha) for a finite period of up to a year and nucleos-(t)ide analogues (NUCs) for treatment over much longer periods of time. The latter act by suppressing HBV replication at the level of DNA synthesis by inhibiting the viral reverse transcriptase/DNA polymerase and causing premature termination of DNA synthesis. The ideal treatment end point is loss of HBsAg in both HBeAg+ve and HBeAg-ve patients following monotherapy. This, however, is only achievable in a minority of patients. Secondary outcomes are durable HBeAg loss and seroconversion to anti-HBe, which occur in about 18-30% of HBeAg+ve patients depending on the antiviral used, and sustained suppression of HBV-DNA accompanied by biochemical normalization and histological improvement in non-HBeAg+ve seroconverting and HBeAg-ve patients. There is therefore a need for additional direct-acting antivirals (DAAs) targeting different stages of the life cycle of the virus, as well as immunotherapeutic approaches. Such developments may pave the way for their use either alone or more likely in combination in the fight against chronic HBV infection. Such drugs or approaches, which are currently undergoing preclinical or clinical testing, are the subject of this review. PMID- 25271859 TI - Hepato- and nephroprotective activities of a Nigerian local king tuber oyster mushroom, Pleurotus tuberregium (higher Basidiomycetes), in chemically induced organ toxicities in rats. AB - Chronic kidney disease, end-stage renal failure, and liver diseases are increasing worldwide and constitute a huge burden on health care costs, with attendant high morbidity and debility. Despite advances in modern medicine, there are still no licensed drugs that satisfactorily restore lost kidney or hepatic functions. In this study the chemoprotective effects of the hot aqueous extract of a local edible oyster mushroom, Pleurotus tuberregium (APTR), was evaluated in experimental liver and kidney toxicities. The effect of APTR on carbon tetrachloride (CCl4)- and paracetamol (PCM)-induced hepatotoxicity in rats was investigated by determining serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Short-term oral treatment with APTR (100 and 250 mg/kg) significantly reduced (P < 0.05) the increased concentrations of AST, ALT, and ALP induced in both PCM and CCl4 models of liver toxicity. APTR (100 and 250 mg/kg) decreased the mean serum AST concentrations by as much as 73.00% and 99.37%, respectively, in PCM-treated rats. Nephroprotection was assessed by determining the serum concentrations of creatinine and urea, as well as antioxidant enzymes, in kidney tissue homogenates after a repeated high dose of gentamicin. APTR (100 and 250 mg/kg) produced a significant decrease (P < 0.05) in the escalated serum concentrations of creatinine and urea by as much as 48.36% and 41.53%, respectively, compared to control. Similarly, levels of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in kidney tissue were increased in a dose related manner in groups that received oral APTR supplementation. The results of this study suggest that the consumption of our local edible mushroom, P. tuberregium, could, in addition to its high nutritive value, protect the liver and kidneys from oxidative damage caused by drugs and toxicants such as CCl4 and high doses of gentamicin and PCM. PMID- 25271860 TI - Anti-inflammatory activity of mycelial extracts from medicinal mushrooms. AB - Medicinal mushrooms have been essential components of traditional Chinese herbal medicines for thousands of years, and they protect against diverse health-related conditions. The components responsible for their anti-inflammatory activity have yet to be fully studied. This study investigates the anti-inflammatory activity of n-hexane, chloroform, ethyl acetate, and methanol extracts of mycelia in submerged culture from 5 commercially available medicinal mushrooms, namely Cephalosporium sinensis, Cordyceps mortierella, Hericium erinaceus, Ganoderma lucidum, and Armillaria mellea. MTT colorimetric assay was applied to measure the cytotoxic effects of different extracts. Their anti-inflammatory activities were evaluated via inhibition against production of lipopolysaccharide (LPS)-induced nitric oxide (NO) in murine macrophage-like cell line RAW264.7 cells. Of the 20 extracts, n-hexane, chloroform, ethyl acetate, and methanol extracts from C. sinensis, C. mortierella, and G. lucidum; chloroform extracts from H. erinaceus and A. mellea; and ethyl acetate extracts from A. mellea at nontoxic concentrations (<300 MUg/mL) dose-dependently inhibited LPS-induced NO production. Among them, the chloroform extract from G. lucidum was the most effective inhibitor, with the lowest half maximal inhibitory concentration (64.09 +/- 6.29 MUg/mL) of the LPS-induced NO production. These results indicate that extracts from medicinal mushrooms exhibited anti-inflammatory activity that might be attributable to the inhibition of NO generation and can therefore be considered a useful therapeutic and preventive approach to various inflammation related diseases. PMID- 25271861 TI - Anticancer and antimicrobial activities and chemical composition of the birch mazegill mushroom Lenzites betulina (higher Basidiomycetes). AB - The anticancer properties, antibiotic activity, and chemical composition of Lenzites betulina ethanol extract (EE) were evaluated. Eight compounds including 5 sterols were isolated from L. betulina, and 7 compounds were isolated from L. betulina for the first time. The EE displayed strong anticancer activity against tumor cell line MDA-MB-231, with a half maximal inhibitory concentration of 51.46 MUg/mL, and there was 83.15% inhibition at a concentration of 200 MUg/mL (MTT assay). The antimicrobial activity of the EE was evaluated against 6 microorganisms-Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Fusarium graminearum, Gibberella zeae, and Cercosporella albo-maculans-and the EE showed moderate antibiotic activity. These results suggest that L. betulina could be a good anticancer and antibiotic agent. PMID- 25271862 TI - Antihypoxic activities of the golden Chanterelle Mushroom, Cantharellus cibarius (higher Basidiomycetes). AB - Cantharellus cibarius is an edible mushroom with worldwide distribution. Because of its good radical scavenging and strong iron-chelating activity, this mushroom was nominated for assay of antihypoxic activity. Protective effects of Chanterelle extract against hypoxia-induced lethality in mice were evaluated by 3 experimental models of hypoxia: asphyctic, hemic, and circulatory. Antihypoxic activity was especially pronounced in the hemic model. The effect was dose dependent. C. cibarius extract (600 mg kg-1) kept the mice alive for 10.07 +/- 1.18 min. It significantly (P < 0.0001) and dose dependently prolonged survival time compared to control group (7.00 +/- 0.63 min). Extract at 300 mg kg-1 prolonged survival time to 9.94 +/- 0.87 min, which was statistically significant (P < 0.0001) compared to control group. In circulatory model, C. cibarius extract (600 mg kg-1) was effective. It prolonged latency for death significantly with regard to the control group (15.18 +/- 4.21 vs. 9.84 +/- 0.75 min; P < 0.001). At 300 mg kg-1, the extract also prolonged survival time (13.57 +/- 0.87 min), and this effect was also statistically significant compared to the control group (P < 0.01). Extract showed no activity in the asphyctic model. Mice in the control group died of hypoxia in 28.20 +/- 3.27 min. Extract (600 mg kg-1) prolonged latency for death, but this activity was not statistically significant (P < 0.05). Phenytoin prolonged latency for death to 55.00 +/- 6.05 min (P < 0.0001). PMID- 25271863 TI - Wound healing activity of an aqueous extract of the Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes). AB - The Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes) is popular because of its health-promoting properties. The effects of G. lucidum extract on cancer, hypertension, hypercholesterolemia, and hepatitis have been reported by many researchers. This investigation was undertaken to evaluate the healing efficacy of an aqueous lyophilized extract of G. lucidum from the Indian Himalayan region on dermal excision wound in experimental rats. The extract used in the study was found to be rich in total polyphenol and flavonoid contents. The healing efficacy was comparatively assessed with a reference povidone-iodine ointment. The G. lucidum extract showed significant enhanced healing activity, evidenced by an increase in wound contraction, collagen accumulation (hydroxyproline), hexosamine, and total protein contents. Histopathological findings further supported the biochemical indices. The results suggest that aqueous lyophilized extract of G. lucidum possesses significant wound-healing activity. PMID- 25271865 TI - Mycelial growth rate and macro- and micromorphological characteristics of medicinal species of genus Ganoderma (higher Basidiomycetes) from Iran. AB - Mycelial growth rate is a distinguishing quality that demonstrates continuous variation in different isolates collected from various hosts and locations. The objectives of this research were (1) to reinvestigate the previous identification of Iranian species, and (2) to recognize the best native isolate(s) for cultivation of different Ganoderma species. Of 78 samples collected from different hosts and sites, only 43 mycelia could be purified and examined for further study. Growth rate (GR; Deltad/Deltat) and growth coefficient (GC; dgh/t) were analyzed by growing isolate culture on 2% malt-extract agar medium (pH 5.5) incubated at 25 degrees C. Macro- and micromorphological studies on mycelia and fruiting bodies such as basidiospore and cutis microcharacters as well as fruiting body quality were used for precise identification. Results revealed that samples belonged to 4 species: G. lucidum, G. applanatum, G. resinaceum, and G. australe. Among all samples, the isolate morphologically identified as G. applanatum showed the best GR (12 mm/day) and good GC (128 mm/day), followed by the 2 other isolates identified as G. resinaceum (GRs and GCs of 11 and 55 mm/day and 10.9 and 43.6 mm/day, respectively). PMID- 25271864 TI - Characterization of interspecific hybrid dikaryons of the oyster mushrooms, Pleurotus florida PAU-5 and P. sajor-caju PAU-3 (higher Basidiomycetes) from India. AB - Five Pleurotus hybrid dikaryons, developed through cross-breeding of P. florida PAU-5 (PF-5) and P. sajor-caju PAU-3 (PSC-3) were characterized with respect to textural properties, color, and enzymatic and genetic variability. Texture profile revealed significant differences in springiness, resilience, cohesiveness, and chewiness between all hybrids compared to the parents. Among the hybrid cultures, maximum whiteness was reported in hybrid 37, whereas hybrid 8 had minimum whiteness. Three hybrids (16, 37, 42) showed an increased linear growth rate in relation to PF-5, whereas no hybrid showed a higher growth rate than PSC-3. Maximum endoglucanase and xylanase activity was observed in hybrid 46, whereas minimum activity occurred in hybrid 42. Laccase and protease activity was higher in hybrid 37 and 46, respectively. Four hybrids (16, 37, 42, 46) showed increased peroxidase activity in relation to PF-5, whereas hybrid 46 showed activity higher than the parent PSC-3. Comparison of isozyme patterns confirmed the hybrid nature of hybrid 16. The large variation in the intensity of bands could be a result of recombination. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of extracellular enzymes revealed 60.3- and 43-KDa bands in all the hybrids. An additional 25-KDa band was reported in hybrids 37, 42, and 46 and the parent PF-5, indicating their close relatedness. Parental strains showed higher divergence in small-subunit ribosomal DNA region compared with the internal transcribed spacer region, indicating their significance in varietal discrimination. Hybrid 46 had a small-subunit ribosomal DNA region more similar to that of PSC-3 compared with PF-5, whereas the internal transcribed spacer region of hybrids 42 and 46 revealed close resemblance to that of PF-5 and PSC-3, respectively. PMID- 25271866 TI - Cloning and characterization of laccase DNA from the Royal Sun medicinal mushroom, Agaricus brasiliensis (higher Basidiomycetes). AB - Laccase isozymes have been identified in several fungi. We report the cloning of 4 laccase genes from the medicinal mushroom Agaricus brasiliensis. The lac1 gene contained a 1560-base pair (bp) open reading frame (ORF) encoding 520 amino acids that was interrupted with 14 introns in genomic DNA. The deduced amino acid sequence indicated a multicopper oxidase signature 1 and 2 multicopper oxidase signature 2. The lac2 gene contained a 1566-bp ORF encoding 522 amino acids that was interrupted with 13 introns in genomic DNA. A number of different nucleotides were observed in whole regions containing the substitution of amino acid residues (lac2a and lac2b). The partial DNA fragments of lac3 and lac4 genes were subcloned using the semi-random two-step polymerase chain reaction method. The lac3 and lac4 genes contained coding sequences with a 1575-bp ORF encoding 525 amino acids and a 1584-bp ORF encoding 528 amino acids, respectively. However, the whole complementary DNA fragment of both laccases could not be amplified with polymerase chain reaction against the complementary DNA library; therefore, introns were deduced based on the GT-AG rule and multiple alignment of laccases from other fungi, which showed high identity. All laccases from A. brasiliensis conserved the fungal laccase signature sequence and suggest 2 subfamilies according to the location of introns and phylogenetic analysis. The genes lac2 and lac4 had a high degree of identity, and the lac2a gene was located upstream of the lac4 gene. PMID- 25271867 TI - Screening of biological, morphological, and molecular characteristics of single spore isolate collections of the straw mushroom, Volvariella volvacea (higher Basidiomycetes) from India. AB - Of the 2 parent strains and 6 single-spore isolates (SSIs) used in this study, the SSIs BBSR-007 and BBSR-002 of the culinary-medicinal straw mushroom Volvariella volvacea exhibited superior growth characteristics on different growth media. These also took less time until first harvest (days after spawning), gave higher numbers of fruiting bodies per unit weight of substrate, and provided a higher mushroom yield on composted substrate. The fruiting body weight of isolate BBSR-007 was significantly higher compared to BBSR-002. On pasteurized paddy straw, the SSI BBSR-007 had a higher mushroom yield than BBSR 002. The contents of dry matter, protein, and other elements (sodium, potassium, and calcium) were on par in both the parent strains and different SSIs, except SSI OE-55-08, which had highest dry matter, protein content, and potassium/-to odium ratio. In amplified ribosomal DNA restriction analysis, the SSIs did not show any distinctness, whereas in amplified fragment length polymorphism, the SSI OE-55-08 of parent strain OE-55 formed a separate clade; of 4 SSIs of strain OE 274, the SSI BBSR-003 formed a separate clade than other SSIs. The genetically distinct SSI OE-55-08 produced the highest numbers of fruit bodies per unit weight of substrate and exhibited the highest amounts of dry matter and protein in its fruit bodies. Another slightly distinct SSI, BBSR-003, formed white aerial mycelia on growth substrate, and its fruit bodies exhibited the highest levels of sodium and calcium. PMID- 25271868 TI - Identification of new provisional simian adenovirus species from captive monkeys, China. PMID- 25271869 TI - Decreased dickkopf-1 levels in chronic lymphocytic leukemia and increased osteopontin levels in non-Hodgkin's lymphoma at initial diagnosis: Could they be playing roles in pathogenesis? AB - Aims We determined plasma levels of dickkopf-1 (DKK-1) and osteopontin (OPN) which have roles in the Wnt pathway in chronic lymphocytic leukemia (CLL) and non Hodgkin lymphoma (NHL) patients and in healthy controls. We also tested whether DKK-1 and OPN levels could be of clinical or prognostic significance in CLL and NHL. Methods We included 36 CLL, 24 NHL patients, and 21 healthy controls. Patients' clinical and demographic features, treatment modalities, and response to treatment were recorded. DKK-1 and OPN levels in plasma obtained at initial diagnosis were determined with enzyme-linked immunosorbent assay. Results CLL patients had significantly lower DKK-1 levels than NHL and control groups (P levels, respectively, 0.048 and 0.017). OPN level was significantly higher in NHL group than in CLL and control groups (P values, 0.017 and <0.001). CLL patients with early and late Rai stages of disease had similar DKK-1 and OPN levels. After a median follow-up of 48 months, 13 CLL patients died. Univariate analysis showed that advanced Rai stages and older age were significantly poor prognostic factors. DKK-1 level in CLL patients who have died was significantly lower than those who were alive (P = 0.035). NHL patients with extranodal involvement had significantly higher OPN levels than those with no involvement (P = 0.04). Conclusions Our results demonstrated that the Wnt pathway inhibitor DKK-1 was decreased in CLL. OPN was increased in NHL and associated with extranodal involvement. In order to reveal the pathogenic and clinical roles of DKK-1 and OPN in CLL and NHL, larger studies need to be conducted. PMID- 25271870 TI - Effect of Optical Defocus on the Kinetic Perimetry in Young Myopic Participants. AB - PURPOSE: The prospective study evaluated the effects of optical defocus on kinetic sensitivity using automated kinetic perimetry. MATERIALS AND METHODS: The 17 eyes of 17 healthy young participants were evaluated. All of the participants had myopia (>= -5.00 D) and mild to no astigmatism (<1.00 D). Automated kinetic perimetry was performed using the Octopus 900 perimeter with Goldmann stimuli III4e, I4e, I3e, I2e, and I1e, with stimuli presented at 14 predetermined meridians, and a velocity of 3 degrees /s. Optical defocus was induced with soft contact lenses, and varied in 1 D increments between 0 and +7 D. Kinetic sensitivity at each defocus was evaluated and compared to sensitivity with no defocus. RESULTS: Although kinetic sensitivity with the III4e and I4e stimuli decreased slightly at the inferior nasal, total kinetic sensitivity measured with the III4e and I4e stimuli was unaffected by optical defocus. Conversely, kinetic sensitivity measured with the I3e, I2e, and I1e stimuli decreased at defocus greater than +6 D (p < 0.05), + 3 D (p < 0.01), and at a defocus greater than +1 D (p < 0.01), respectively. CONCLUSIONS: Kinetic sensitivity was unaffected by defocus when measured with III4e and I4e stimuli. However, measurements with I3e, I2e, and I1e stimuli were affected, in particular measurements with I2e and I1e stimuli. Therefore, we conclude that optimal refractive correction with a contact lens or a spectacle lens is required in order to obtain accurate kinetic perimetry results, particularly for lower intensity stimuli. PMID- 25271872 TI - Comment on "Determining the ecological impacts of organic contaminants in biosolids using a high-throughput colorimetric denitrification assay: a case study with antimicrobial agents". PMID- 25271871 TI - A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. AB - OBJECTIVE: Transcranial magnetic stimulation (TMS) is an effective and safe acute treatment for patients not benefiting from antidepressant pharmacotherapy. Few studies have examined its longer term durability. This study assessed the long term effectiveness of TMS in naturalistic clinical practice settings following acute treatment. METHOD: Adult patients with a primary diagnosis of unipolar, nonpsychotic major depressive disorder (DSM-IV clinical criteria), who did not benefit from antidepressant medication, received TMS treatment in 42 clinical practices. Two hundred fifty-seven patients completed a course of acute TMS treatment and consented to follow-up over 52 weeks. Assessments were obtained at 3, 6, 9, and 12 months. The study was conducted between March 2010 and August 2012. RESULTS: Compared with pre-TMS baseline, there was a statistically significant reduction in mean total scores on the Clinical Global Impressions Severity of Illness scale (primary outcome), 9-Item Patient Health Questionnaire, and Inventory of Depressive Symptoms-Self Report (IDS-SR) at the end of acute treatment (all P < .0001), which was sustained throughout follow-up (all P < .0001). The proportion of patients who achieved remission at the conclusion of acute treatment remained similar at conclusion of the long-term follow-up. Among 120 patients who met IDS-SR response or remission criteria at the end of acute treatment, 75 (62.5%) continued to meet response criteria throughout long-term follow-up. After the first month, when the majority of acute TMS tapering was completed, 93 patients (36.2%) received reintroduction of TMS. In this group, the mean (SD) number of TMS treatment days was 16.2 (21.1). CONCLUSIONS: TMS demonstrates a statistically and clinically meaningful durability of acute benefit over 12 months of follow-up. This was observed under a pragmatic regimen of continuation antidepressant medication and access to TMS retreatment for symptom recurrence. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01114477. PMID- 25271873 TI - Theoretical modeling of spin crossover in metal-organic frameworks: [Fe(pz)2Pt(CN)4] as a case study. AB - Metal-organic frameworks (MOFs) with spin-crossover behavior are promising materials for applications in memory storage and sensing devices. A key parameter that characterizes these materials is the transition temperature T1/2, defined as the temperature with equal populations of low-spin and high-spin species. In this study, we describe the development, implementation, and application of a novel hybrid Monte Carlo/molecular dynamics method that builds upon the Ligand Field Molecular Mechanics approach and enables the modeling of spin-crossover properties in bulk materials. The new methodology is applied to the study of a spin-crossover MOF with molecular formula [Fe(pz)2Pt(CN)4] (pz = pyrazine). The total magnetic moment of the material is determined as a function of the temperature from direct calculations of the relative equilibrium populations of both low-spin and high-spin states of each Fe(II) center of the framework. The T1/2 value, calculated from the temperature dependence of the magnetization curve, is in good agreement with the available experimental data. A comparison between the spin-crossover behavior of the isolated secondary building block of the framework and the bulk material is presented, which reveals the origin of the different spin-crossover properties of the isolated molecular system and corresponding MOF structure. PMID- 25271874 TI - Mini-review: the morphology, mineralogy and microbiology of accumulated iron corrosion products. AB - Despite obvious differences in morphology, substratum chemistry and the electrolyte in which they form, accumulations of iron corrosion products have the following characteristics in common: stratification of iron oxides/hydroxides with a preponderance of alpha-FeOOH (goethite) and accumulation of metals. Bacteria, particularly iron-oxidizing and sulfate-reducing bacteria have been identified in some accumulations. Both biotic and abiotic mechanisms have been used to rationalize observations for particular sets of environmental data. This review is the first to compare observations and interpretations. PMID- 25271876 TI - Cold weather is a predisposing factor for testicular torsion in a tropical country. A retrospective study. AB - CONTEXT AND OBJECTIVE: Testicular torsion is a medical and urological emergency because it can lead to loss of the organ. The theory of seasonal testicular torsion occurrence is based on studies from institutions located in cold and temperate regions. The objective here was to determine whether cold weather is associated with higher incidence of testicular torsion in a tropical country, such as Brazil. DESIGN AND SETTING: Retrospective study, conducted in a tertiary and teaching hospital. METHODS: Patients with acute testicular torsion confirmed by surgery between April 2006 and March 2011 were studied. Information on weather conditions at the time of symptom onset was collected. RESULTS: A total of 64 testicular torsion cases were identified. The months with the highest incidences of testicular torsion were June (16%), July (19%) and August (11%), which had the lowest mean temperatures, of 17.6 degrees C, 16.4 degrees C and 18.2 degrees C, respectively. Eleven percent of cases occurred during spring (October to December), 16% occurred in summer (January to March), 34% occurred in fall (April to June) and 39% occurred in winter (July to September). There was a significant association between the incidence of testicular torsion and the season (fall and winter), P < 0.001. CONCLUSIONS: Testicular torsion follows a seasonal association even in a tropical country, and is more frequent in the colder months of the year, namely fall and winter, when almost three-quarters of the cases occurred. These observations add further evidence that cold weather has an etiologic role in testicular torsion occurrence. PMID- 25271875 TI - A call to action to enhance filovirus disease outbreak preparedness and response. AB - The frequency and magnitude of recognized and declared filovirus-disease outbreaks have increased in recent years, while pathogenic filoviruses are potentially ubiquitous throughout sub-Saharan Africa. Meanwhile, the efficiency and effectiveness of filovirus-disease outbreak preparedness and response efforts are currently limited by inherent challenges and persistent shortcomings. This paper delineates some of these challenges and shortcomings and provides a proposal for enhancing future filovirus-disease outbreak preparedness and response. The proposal serves as a call for prompt action by the organizations that comprise filovirus-disease outbreak response teams, namely, Ministries of Health of outbreak-prone countries, the World Health Organization, Medecins Sans Frontieres, the Centers for Disease Control and Prevention-Atlanta, and others. PMID- 25271877 TI - Angiosarcoma in previously irradiated breast in patient with Li-Fraumeni syndrome. A case report. AB - CONTEXT: Li-Fraumeni syndrome is a rare disease with an autosomal dominant inheritance pattern and high penetrance that defines a 50% chance of developing cancer before the age of 30 years, including cases of breast sarcoma. Patients with this syndrome who require radiotherapy have an increased risk of developing secondary malignancies including angiosarcomas. CASE REPORT: This was a case report on a female patient with Li-Fraumeni syndrome. In October 2005, she was diagnosed with invasive ductal carcinoma of the right breast and underwent sectorectomy. She then received chemotherapy and adjuvant radiotherapy. Trastuzumab and tamoxifen were also part of the treatment. She recently sought care at our hospital, complaining of hyperemia and nodulation in the right breast, and underwent surgical resection that revealed epithelioid angiosarcoma. CONCLUSIONS: When genetic predisposition due to Li-Fraumeni syndrome is documented, the therapy should be adapted so as to minimize the risk. Thus, conservative surgical treatments should be avoided and mastectomy without radiation should be prioritized. In cases in which use of radiotherapy is justified, patients should be followed up intensively. PMID- 25271878 TI - Perceptions about penis size among supposedly healthy 40 to 60-year-old Brazilian men: a cross-sectional pilot study. AB - CONTEXT AND OBJECTIVE: Many men seek medical treatments complaining that their penises are too small (short) when in fact they are not (they are not cases of micropenis). The objective of the present study was to evaluate men's satisfaction with their own bodies and sex life and the prevalence of erectile dysfunction, among men who were not seeking medical or psychological advice. DESIGN AND SETTING: Cross-sectional study in a private, philanthropic hospital in Sao Paulo, Brazil. METHODS: In this study, 300 male blood donors aged between 40 and 60 years old answered a questionnaire, in privacy, about their sex life and their satisfaction with their own bodies. They were also screened for erectile dysfunction by means of the International Index of Erectile Function questionnaire. RESULTS: Seven men (2.3%) reported that they were dissatisfied with their penis size (they thought that it was small), and among these, one was found to have mild erectile dysfunction. However, none of them had sought medical attention. Among these seven, only two had normal body mass index; the other five were overweight (three) or obese (two). CONCLUSION: The prevalence of dissatisfaction with penis size was low. Among the seven dissatisfied men, only one had erectile dysfunction, of mild type, and all of them felt potent. PMID- 25271879 TI - Central diabetes insipidus: alert for dehydration in very low birth weight infants during the neonatal period. A case report. AB - CONTEXT: Central diabetes insipidus (CDI) is a rare cause of hypernatremia during the neonatal period. The diagnosis is particularly difficult in very low birth weight (VLBW) newborns. CASE REPORT: We report on a preterm newborn who presented CDI soon after birth. On the third day of life, signs of dehydration were present despite normal fluid supply. The diuresis rate was 4.4 ml/kg/h. Although the fluid supply was then increased, the dehydration continued, with hypernatremia, normal glycemia, diuresis of 7.4 ml/kg/h and urine density of 1005 mOsmol/l. Thus, a diagnostic hypothesis of diabetes insipidus was raised. A test with a nasal vasopressin analogue (dDAVP) was performed and CDI was confirmed. Reduction of the fluid supply became possible through appropriate treatment. CONCLUSION: The diagnosis of CDI is rarely made during the neonatal period, especially in VLBW newborns, because of the difficulty in detecting elevated diuresis. Persistent hypernatremia, usually accompanied by hyperthermia despite abundant fluid supply, weight loss and low urine osmolality are important signs of alert. PMID- 25271880 TI - Deficits in working memory, reading comprehension and arithmetic skills in children with mouth breathing syndrome: analytical cross-sectional study. AB - CONTEXT AND OBJECTIVE: Mouth breathing syndrome is very common among school-age children, and it is possibly related to learning difficulties and low academic achievement. In this study, we investigated working memory, reading comprehension and arithmetic skills in children with nasal and mouth breathing. DESIGN AND SETTING: Analytical cross-sectional study with control group conducted in a public university hospital. METHODS: 42 children (mean age = 8.7 years) who had been identified as mouth breathers were compared with a control group (mean age = 8.4 years) matched for age and schooling. All the participants underwent a clinical interview, tone audiometry, otorhinolaryngological evaluation and cognitive assessment of phonological working memory (numbers and pseudowords), reading comprehension and arithmetic skills. RESULTS: Children with mouth breathing had poorer performance than controls, regarding reading comprehension (P = 0.006), arithmetic (P = 0.025) and working memory for pseudowords (P = 0.002), but not for numbers (P = 0.76). CONCLUSION: Children with mouth breathing have low academic achievement and poorer phonological working memory than controls. Teachers and healthcare professionals should be aware of the association of mouth breathing with children's physical and cognitive health. PMID- 25271882 TI - Resurgence of cutaneous leishmaniasis in Israel, 2001-2012. AB - Cutaneous leishmaniasis has long been endemic in Israel. After a 15-year period of moderate illness rates, reported incidence increased from 0.4 cases per 100,000 population in 2001 to 4.4 cases per 100,000 population in 2012, and the disease emerged in areas where its presence had previously been minimal. We analyzed all cases reported to the national surveillance system and found that outbreak patterns revealed an expansion of Leishmania major infections over large areas in the southern part of the country and the occurrence of spatially focused L. tropica outbreaks in the northern part of the country. Outbreaks often followed new construction in populated areas. Further study of factors affecting the transmission of cutaneous leishmaniasis is needed in Israel, as well as the development of effective methods to control the disease, an increase in awareness among health care professionals, and intensive public education regarding control measures in areas of known leishmaniasis foci. PMID- 25271883 TI - The Transcription Factor Con7-1 Is a Master Regulator of Morphogenesis and Virulence in Fusarium oxysporum. AB - Previous studies have demonstrated the essential role of morphogenetic regulation in Fusarium oxysporum pathogenesis, including processes such as cell-wall biogenesis, cell division, and differentiation of infection-like structures. We identified three F. oxysporum genes encoding predicted transcription factors showing significant identities to Magnaporthe oryzae Con7p, Con7-1, plus two identical copies of Con7-2. Targeted deletion of con7-1 produced nonpathogenic mutants with altered morphogenesis, including defects in cell wall structure, polar growth, hyphal branching, and conidiation. By contrast, simultaneous inactivation of both con7-2 copies caused no detectable defects in the resulting mutants. Comparative microarray-based gene expression analysis indicated that Con7-1 modulates the expression of a large number of genes involved in different biological functions, including host-pathogen interactions, morphogenesis and development, signal perception and transduction, transcriptional regulation, and primary and secondary metabolism. Taken together, our results point to Con7-1 as general regulator of morphogenesis and virulence in F. oxysporum. PMID- 25271884 TI - Enhanced electrical conductivity in a substitutionally doped spiro bis(phenalenyl)boron radical molecular solid. AB - We report the crystallization of a subsitutionally doped organic conductor based on a host lattice composed of spiro-bis(phenalenyl)boron radicals. Co crystallization of solutions of spiro-bis(9-oxidophenalenone)boron radical [PLY(O,O)]2B mixed with selected amounts of spiro-bis(9 oxidophenalenone)beryllium [PLY(O,O)]2Be leads to the formation of a series of solid-state solutions of composition [PLY(O,O)]2B(1-x)Be(x). The dopant molecules [PLY(O,O)]2Be serve to introduce holes into the lattice of spins provided by the [PLY(O,O)]2B radicals and lead to a systematic increase in the conductivity while decreasing the activation energy of the conduction process and leaving the solid state structure relatively unperturbed. While the energies of the hole sites are expected to be high, the results are consistent with the interpretation of the electronic structure of [PLY(O,O)]2B in terms of the resonating valence bond model. PMID- 25271881 TI - Role of LARP6 and nonmuscle myosin in partitioning of collagen mRNAs to the ER membrane. AB - Type I collagen is extracellular matrix protein composed of two alpha1(I) and one alpha2(I) polypeptides that fold into triple helix. Collagen polypeptides are translated in coordination to synchronize the rate of triple helix folding to the rate of posttranslational modifications of individual polypeptides. This is especially important in conditions of high collagen production, like fibrosis. It has been assumed that collagen mRNAs are targeted to the membrane of the endoplasmic reticulum (ER) after translation of the signal peptide and by signal peptide recognition particle (SRP). Here we show that collagen mRNAs associate with the ER membrane even when translation is inhibited. Knock down of LARP6, an RNA binding protein which binds 5' stem-loop of collagen mRNAs, releases a small amount of collagen mRNAs from the membrane. Depolimerization of nonmuscle myosin filaments has a similar, but stronger effect. In the absence of LARP6 or nonmuscle myosin filaments collagen polypeptides become hypermodified, are poorly secreted and accumulate in the cytosol. This indicates lack of coordination of their synthesis and retro-translocation due to hypermodifications and misfolding. Depolimerization of nonmuscle myosin does not alter the secretory pathway through ER and Golgi, suggesting that the role of nonmuscle myosin is primarily to partition collagen mRNAs to the ER membrane. We postulate that collagen mRNAs directly partition to the ER membrane prior to synthesis of the signal peptide and that LARP6 and nonmuscle myosin filaments mediate this process. This allows coordinated initiation of translation on the membrane bound collagen alpha1(I) and alpha2(I) mRNAs, a necessary step for proper synthesis of type I collagen. PMID- 25271885 TI - A second-order high-resolution finite difference scheme for a size-structured model for the spread of Mycobacterium marinum. AB - We present a second-order high-resolution finite difference scheme to approximate the solution of a mathematical model of the transmission dynamics of Mycobacterium marinum (Mm) in an aquatic environment. This work extends the numerical theory and continues the preliminary studies on the model first developed in Ackleh et al. [Structured models for the spread of Mycobacterium marinum: foundations for a numerical approximation scheme, Math. Biosci. Eng. 11 (2014), pp. 679-721]. Numerical simulations demonstrating the accuracy of the method are presented, and we compare this scheme to the first-order scheme developed in Ackleh et al. [Structured models for the spread of Mycobacterium marinum: foundations for a numerical approximation scheme, Math. Biosci. Eng. 11 (2014), pp. 679-721] to show that the first-order method requires significantly more computational time to provide solutions with a similar accuracy. We also demonstrated that the model can be a tool to understand surprising or nonintuitive phenomena regarding competitive advantage in the context of biologically realistic growth, birth and death rates. PMID- 25271888 TI - Low ambient temperature elevates plasma triiodothyronine concentrations while reducing digesta mean retention time and methane yield in sheep. AB - Ruminant methane yield (MY) is positively correlated with mean retention time (MRT) of digesta. The hormone triiodothyronine (T3 ), which is negatively correlated with ambient temperature, is known to influence MRT. It was hypothesised that exposing sheep to low ambient temperatures would increase plasma T3 concentration and decrease MRT of digesta within the rumen of sheep, resulting in a reduction of MY. To test this hypothesis, six Merino sheep were exposed to two different ambient temperatures (cold treatment, 9 +/- 1 degrees C; warm control 26 +/- 1 degrees C). The effects on MY, digesta MRT, plasma T3 concentration, CO2 production, DM intake, DM digestibility, change in body weight (BW), rumen volatile fatty acid (VFA) concentrations, estimated microbial protein output, protozoa abundance, wool growth, water intake, urine output and rectal temperature were studied. Cold treatment resulted in a reduction in MY (p < 0.01); digesta MRT in rumen (p < 0.01), hindgut (p = 0.01) and total digestive tract (p < 0.01); protozoa abundance (p < 0.05); and water intake (p < 0.001). Exposure to cold temperature increased plasma T3 concentration (p < 0.05), CO2 production (p = 0.01), total VFA concentrations (p = 0.03) and estimated microbial output from the rumen (p = 0.03). The rate of wool growth increased (p < 0.01) due to cold treatment, but DM intake, DM digestibility and BW change were not affected. The results suggest that exposure of sheep to cold ambient temperatures reduces digesta retention time in the gastrointestinal tract, leading to a reduction in enteric methane yield. Further research is warranted to determine whether T3 could be used as an indirect selection tool for genetic selection of low enteric methane-producing ruminants. PMID- 25271886 TI - Hypogammaglobulinemia in BLT humanized mice--an animal model of primary antibody deficiency. AB - Primary antibody deficiencies present clinically as reduced or absent plasma antibodies without another identified disorder that could explain the low immunoglobulin levels. Bone marrow-liver-thymus (BLT) humanized mice also exhibit primary antibody deficiency or hypogammaglobulinemia. Comprehensive characterization of B cell development and differentiation in BLT mice revealed other key parallels with primary immunodeficiency patients. We found that B cell ontogeny was normal in the bone marrow of BLT mice but observed an absence of switched memory B cells in the periphery. PC-KLH immunizations led to the presence of switched memory B cells in immunized BLT mice although plasma cells producing PC- or KLH- specific IgG were not detected in tissues. Overall, we have identified the following parallels between the humoral immune systems of primary antibody deficiency patients and those in BLT mice that make this in vivo model a robust and translational experimental platform for gaining a greater understanding of this heterogeneous array of humoral immunodeficiency disorders in humans: (i) hypogammaglobulinemia; (ii) normal B cell ontogeny in bone marrow; and (iii) poor antigen-specific IgG response to immunization. Furthermore, the development of strategies to overcome these humoral immune aberrations in BLT mice may in turn provide insights into the pathogenesis of some primary antibody deficiency patients which could lead to novel clinical interventions for improved humoral immune function. PMID- 25271889 TI - Group-living herbivores weigh up food availability and dominance status when making patch-joining decisions. AB - Two key factors that influence the foraging behaviour of group-living herbivores are food availability and individual dominance status. Yet, how the combination of these factors influences the patch-joining decisions of individuals foraging within groups has scarcely been explored. To address this, we focused on the patch-joining decisions of group-living domestic goats (Capra hircus). When individuals were tested against the top four ranked goats of the herd, we found that at patches with low food availability they avoided these dominant patch holders and only joined subordinates (i.e. costs outweighed benefits). However, as the amount of food increased, the avoidance of the top ranked individuals declined. Specifically, goats shifted and joined the patch of an individual one dominance rank higher than the previous dominant patch holder when the initial quantity of food in the new patch was twice that of the lower ranking individual's patch (i.e. benefits outweighed costs). In contrast, when individuals chose between patches held by dominant goats, other than the top four ranked goats, and subordinate individuals, we found that they equally joined the dominant and subordinate patch-holders. This joining was irrespective of the dominance gap, absolute rank of the dominant patch-holder, sex or food availability (i.e. benefits outweighed costs). Ultimately, our results highlight that herbivores weigh up the costs and benefits of both food availability and patch-holder dominance status when making patch-joining decisions. Furthermore, as the initial quantity of food increases, food availability becomes more important than dominance with regard to influencing patch-joining decisions. PMID- 25271887 TI - Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes. AB - The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of -15.8 (SD 77.3) m at 12 months, of -58.9 (SD 125.7) m at 24 months and -104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available. PMID- 25271890 TI - Thermodynamic study of benzene and hydrogen coadsorption on Pd(111). AB - Periodic density functional theory (DFT) has been used to study the coadsorption of hydrogen and benzene on Pd(111). The most stable coverages are predicted by constructing the thermodynamic phase diagram as a function of gas-phase temperature and pressure. The common approximation that neglects vibrational contributions to the surface Gibbs free energy, using the PW91 functional, is compared to the one that includes vibrational contributions. Higher coverages are predicted to be thermodynamically the most stable including vibrational frequencies, mainly due to the different entropy contributions. The first approach is also compared to the one using a (optPBE-vdW) vdW-DF functional without vibrational contributions, which predicts higher benzene coverages for benzene adsorption, and lower hydrogen coverages for hydrogen adsorption and coadsorption with a fixed benzene coverage. Inclusion of vibrational contributions using the vdW-DF method has not been implemented due to computational constraints. However, an estimate of the expected result is proposed by adding PW91 vibrational contributions to the optPBE-vdW electronic energies, and under typical hydrogenation conditions high coverages of about thetaH = 0.89 are expected. Inclusion of vibrational contributions to the surface Gibbs free energy and a proper description of van der Waals interaction are recommended to predict the thermodynamically most stable surface coverage. PMID- 25271891 TI - The relationship between age and minimum alveolar concentration of sevoflurane for maintaining bispectral index below 50 in children. AB - We evaluated the minimum alveolar concentration of sevoflurane required to maintain the bispectral index below 50 in children. We studied 55 children, divided into 1-year-old, 2- to 4-year-old and 5- to 9-year-old groups and used Dixon's up-and-down method and probit analysis. In the 1-year-old group, the bispectral index values remained above 50, with the end-tidal sevoflurane concentration reaching 4.0% or higher. The minimum alveolar concentration of sevoflurane for maintaining the bispectral index below 50 was significantly higher in the 2- to 4-year-old group (2.33%, 95% CI 2.25-2.57) than in the 5- to 9-year-old group (2.10%, 95% CI 1.94-2.25; p = 0.005). We conclude that assessing the depth of anaesthesia using bispectral index is unreliable in children aged < 2 years anaesthetised with sevoflurane. PMID- 25271892 TI - The relationship between internal medicine residency graduate performance on the ABIM certifying examination, yearly in-service training examinations, and the USMLE Step 1 examination. AB - PURPOSE: To explore the relationship between United States Medical Licensing Examination (USMLE) Step 1 scores, yearly in-service training exam (ITE) scores, and passing the American Board of Internal Medicine certifying examination (ABIM CE). METHOD: The authors conducted a retrospective database review of internal medicine residents from the Medical College of Wisconsin from 2004 through 2012. Residents' USMLE Step 1, ITE, and ABIM-CE scores were extracted. Pearson rho, chi square, and logistic regression were used to determine whether relationships existed between the scores and if Step 1 and ITE scores correlate with passing the ABIM-CE. RESULTS: There were 241 residents, who participated in 728 annual ITEs. There were Step 1 scores for 195 (81%) residents and ABIM-CE scores for 183 (76%). Step 1 and ABIM-CE scores had a modest correlation (rho: 0.59), as did ITE and ABIM-CE scores (rho: 0.48-0.67). Failing Step 1 or being in the bottom ITE quartile during any year of testing markedly increased likelihood of failing the boards (Step 1: relative risk [RR]: 2.4; 95% CI: 1.0-5.9; first-year residents' RR: 1.3; 95% CI: 1.0-1.6; second-year residents' RR: 1.3; 95% CI: 1.1-1.5; third year residents' RR: 1.3; 95% CI: 1.1-1.5). CONCLUSIONS: USMLE Step 1 and ITE scores have a modest correlation with board scores. Failing Step 1 or scoring in the bottom quartile of the ITE increased the risk of failing the boards. What effective intervention, if any, program directors may use with at-risk residents is a question deserving further research. PMID- 25271893 TI - Failure to cope: the hidden curriculum of emergency department wait times and the implications for clinical training. AB - PURPOSE: The study explored optimal intraprofessional collaboration between physicians in the emergency department (ED) and those from general internal medicine (GIM). Prior to the study, a policy was initiated that mandated reductions in ED wait times. The researchers examined the impact of these changes on clinical practice and trainee education. METHOD: In 2010-2011, an ethnographic study was undertaken to observe consults between GIM and ED at an urban teaching hospital in Ontario, Canada. Additional ad hoc interviews were conducted with residents, nurses, and faculty from both departments as well as formal one-on-one interviews with 12 physicians. Data were coded and analyzed using concepts of institutional ethnography. RESULTS: Participants perceived that efficiency was more important than education and was in fact the new definition of "good" patient care. The informal label "failure to cope" to describe high-needs patients suggested that in many instances, patients were experienced as a barrier to optimal efficiency. This resulted in tension during consults as well as reduced opportunities for education. CONCLUSIONS: The authors suggest that the emphasis on wait times resulted in more importance being placed on "getting the patient out" of the ED than on providing safe, compassionate, person-centered medical care. Resource constraints were hidden within a discourse that shifted the problem of overcrowding in the ED to patients with complex chronic conditions. The term "failure to cope" became activated when overworked physicians tried to avoid assuming care for high-needs patients, masking institutionally produced stress and possibly altering the way patients are perceived. PMID- 25271894 TI - Practicing what we teach: in order to teach patient-centered care, we need to deliver it. AB - In this issue of Academic Medicine, Webster and colleagues explore the impact of a government-imposed mandate in Ontario, Canada, to limit the length of time patients can stay in the emergency department. The rule is aimed at emergency department crowding, which has been shown to result in poorer-quality care, longer hospital stays, and higher mortality. Webster and colleagues found that learners were concerned about the effect of a time target on both their education and on patient-centered care, and sensed a "hidden curriculum" refocusing teaching on "efficiency rather than safe, compassionate care."The introduction of time targets in emergency departments may seem like a threat to both the education of learners and the quality of patient care. However, one aspect of quality is patient-centered care, which requires sensitivity to patients' need for information, physical comfort, and reassurance. In this Commentary, the author describes the patient experience in the typical teaching hospital emergency department, arguing that for too long, teaching institutions have given only lip service to patient-centered care in favor of traditional teaching models. It is time to rebalance the scales so that the patient's experience is a central feature of the curriculum, and putting a time limit on how long patients stay in the emergency department may be one way to do it. PMID- 25271895 TI - Alcohol consumption and visual impairment in a rural Northern Chinese population. AB - PURPOSE: To investigate alcohol drinking status and the association between drinking patterns and visual impairment in an adult population in northern China. METHODS: Cluster sampling was used to select samples. The protocol consisted of an interview, pilot study, visual acuity (VA) testing and a clinical examination. Visual impairment was defined as presenting VA worse than 20/60 in any eye. Drinking patterns included drinking quantity (standard drinks per week) and frequency (drinking days in the past week). RESULTS: Information on alcohol consumption was obtained from 8445 subjects, 963 (11.4%) of whom reported consuming alcohol. In multivariate analysis, alcohol consumption was significantly associated with older age (p < 0.001), male sex (p < 0.001), and higher education level (p < 0.01). Heavy intake (>14 drinks/week) was associated with higher odds of visual impairment. However, moderate intake (>1-14 drinks/week) was significantly associated with lower odds (adjusted odds ratio, OR, 0.7, 95% confidence interval, CI, 0.5-1.0) of visual impairment (p = 0.03). Higher drinking frequency was significantly associated with higher odds of visual impairment. Multivariate analysis showed that older age, male sex, and higher education level were associated with visual impairment among current drinkers. Age- and sex-adjusted ORs for the association of cataract and alcohol intake showed that higher alcohol consumption was not significantly associated with an increased prevalence of cataract (OR 1.2, 95% CI 0.4-3.6), whereas light and moderate alcohol consumption appeared to reduce incidence of cataract. CONCLUSION: Drinking patterns were associated with visual impairment. Heavy intake had negative effects on distance vision; meanwhile, moderate intake had a positive effect on distance vision. PMID- 25271896 TI - Bolometer detection of magnetic resonances in nanoscaled objects. AB - We report on a nanoscaled thermocouple (ThC) as a temperature sensor of a highly sensitive bolometer for probing the dissipative damping of spin dynamics in nanosized Permalloy (Py) stripes. The Au-Pd ThC based device is fabricated by standard electron beam lithography on a 200 nm silicon nitride membrane to minimize heat dissipation through the substrate. We show that this thermal sensor allows not only measurements of the temperature change on the order of a few mK due to the uniform resonant microwave (MW) absorption by the Py stripe but also detection of standing spin waves of different mode numbers. Using a 3D finite element method, we estimate the absorbed MW power by the stripe in resonance and prove the necessity of using substrates with an extremely low heat dissipation like a silicon nitride membrane for successful thermal detection. The voltage responsivity and the noise equivalent power for the ThC-based bolometer are equal to 15 V W(-1) and 3 nW Hz(-1/2), respectively. The ThC device offers a magnetic resonance response of 1 nV/(MU(B) W) corresponding to a sensitivity of 10(9) spins and a temperature resolution of 300 MUK under vacuum conditions. PMID- 25271897 TI - Design of FeBi nanoparticles for imaging applications. AB - A variety of imaging technologies are now routinely used in the medical field, their use being continuously enlarged through the development of contrast agents. Recently nanoparticles (NPs) proved efficient to improve imaging in vivo by increasing contrast and targeting capabilities. The current trend is now focused on the development of dual contrast agents combining two or more functionalities on the same NP. Motivated by this new challenge we developed FeBi NPs as new nanomaterials with potential application as a contrast agent for MRI and CT imaging. In addition to the well-known use of iron in the development MRI contrast agents, we chose Bi as a CT imaging agent rather than the more documented gold, because it possesses a larger X-ray attenuation coefficient and is much less expensive. Two sets of NPs, with sizes around 150 nm and 14 nm, were synthesized using organometallic approaches. In both cases, the NPs are spherical, and contain distinct domains of Fe and Bi, with the surface being enriched with Fe, and a hydrophobic coating. This coating differs from one sample to the other: the surfaces of the 150 nm large NPs are coated by amine ligands, while those of the 14 nm large NPs are coated by a mixture of an amine and its hydrochloride salt. Exchange of the surface ligands to afford water soluble NPs has been attempted. We show that only the larger NPs could be functionalized with water soluble ligands, which is in agreement with the lability of their initial surface coating. Colloidal aqueous solutions of FeBi NPs with glycoPEG ligands have been obtained. PMID- 25271898 TI - Chemiluminescence detection with water-soluble iridium(III) complexes containing a sulfonate-functionalised ancillary ligand. AB - The chemiluminescence from four cyclometalated iridium(III) complexes containing an ancillary bathophenanthroline-disulfonate ligand exhibited a wide range of emission colours (green to red), and in some cases intensities that are far greater than the commonly employed benchmark reagent, [Ru(bpy)3](2+). A similar complex incorporating a sulfonated triazolylpyridine-based ligand enabled the emission to be shifted into the blue region of the spectrum, but the responses with this complex were relatively poor. DFT calculations of electronic structure and emission spectra support the experimental findings. PMID- 25271899 TI - Novel susceptibility loci were found in Chinese genetic generalized epileptic patients by genome-wide association study. PMID- 25271900 TI - Staining and magnifying the mucosa: are biopsies no longer required? PMID- 25271901 TI - Endoscopic submucosal dissection - just add water(jet)? PMID- 25271902 TI - Clip or loop? Which modality can we call "A stitch in time saves nine"? PMID- 25271903 TI - Reply to Thoufeeq. PMID- 25271906 TI - Correlation between the surface electronic structure and CO-oxidation activity of Pt alloys. AB - The surface electronic structure and CO-oxidation activity of Pt and Pt alloys, Pt3T (T = Ti, Hf, Ta, Pt), were investigated. At temperatures below 538 K, the CO oxidation activities of Pt and Pt3T increased in the order Pt < Pt3Ti < Pt3hHf < Pt3Ta. The center-of-gravity of the Pt d-band (the d-band center) of Pt and Pt3T was theoretically calculated to follow the trend Pt3Ti < Pt3Ta < Pt3Hf < Pt. The CO-oxidation activity showed a volcano-type dependence on the d-band center, where Pt3Ta exhibited a maximum in activity. Theoretical calculations demonstrated that the adsorption energy of CO on the catalyst surface monotonically decreases with the lowering of the d-band center because of diminished hybridization of the surface d-band and the lowest-unoccupied molecular orbital (LUMO) of CO. The observed volcano-type correlation between the d-band center and the CO oxidation activity is rationalized in terms of the CO adsorption energy, which counterbalances the surface coverage by CO and the rate of CO oxidation. PMID- 25271907 TI - Growth and condition of juvenile coho salmon Oncorhynchus kisutch relate positively to species richness of trophically transmitted parasites. AB - The aims of this study were first, to test the hypothesis that metrics of fish growth and condition relate positively to parasite species richness (S(R)) in a salmonid host; second, to identify whether S(R) differs as a function of host origin; third, to identify whether acquisition of parasites through marine v. freshwater trophic interactions was related to growth and condition of juvenile salmonids. To evaluate these questions, species diversity of trophically transmitted parasites in juvenile coho salmon Oncorhynchus kisutch collected off the coast of the Oregon and Washington states, U.S.A. in June 2002 and 2004 were analysed. Fish infected with three or more parasite species scored highest in metrics of growth and condition. Fish originating from the Columbia River basin had lower S(R) than those from the Oregon coast, Washington coast and Puget Sound, WA. Parasites obtained through freshwater or marine trophic interactions were equally important in the relationship between S(R) and ocean growth and condition of juvenile O. kisutch salmon. PMID- 25271908 TI - Activation of upregulated angiotensin II type 2 receptors decreases carotid pulse pressure in rats with suprarenal abdominal aortic coarctation. AB - Our aim was to determine whether angiotensin type 2 receptors (AT2R) are involved in the depression of carotid pulse pressure (PP) in rats with suprarenal aortic coarctation (SrC). We tested the effects of losartan, PD123319, and CGP42112 on PP in SrC and Sham-operated anesthetized rats. PP increased in SrC rats. Neither losartan nor PD123319 affected PP in SrC and Sham-operated rats. CGP42112 reduced PP, in SrC rats, combined with losartan. Moreover, PD123319 blocked this effect. AT2R protein increased in the thoracic aortas of SrC rats. Thus, upregulated AT2R stimulation by CGP42112 mediates depression of PP in rats under pressure overloading. PMID- 25271909 TI - A new method using xenogeneicacellular dermal matrix in the reconstruction of lacrimal drainage. AB - AIMS: To prospectively evaluate the reliability and efficacy of a new treatment for the reconstruction of the lacrimal duct using a new histo-engineered material, xenogeneic (bovine) acellular dermal matrix. METHOD: Five patients (five eyes) with partial or total absence of the lacrimal duct were included in the study. Four patients (four eyes) suffered from traumatic injuries to the lacrimal duct and one patient (one eye) had congenital absence of the lacrimal drainage system. A pedal graft of conjunctiva was taken from the fornix area and rolled into a tube structure after being attached to the acellular dermal matrix. RESULTS: The average duration of follow-up for the patients was 7.2 months (ranging from 6 to 12 months). After surgery, the new duct in the nasal cavity could be observed above the middle turbinate by nasal endoscopy. Patency was confirmed by pressing in the area of the lacrimal sac and visualising air bubbles in the nasal cavity. Additionally, the meatus above the middle turbinate of the nasal cavity was stained and visualised after patients underwent Jones dye test 1 (JDT1). Five tear ducts proved to be effective through irrigation testing and epiphora symptoms were alleviated in all cases. CONCLUSIONS: The newly reconstructed lacrimal duct, formed by the shift of autogenous conjunctival petal and the attachment of acellular dermal matrix, was successful in all five cases and suggests a new solution for the complex lacrimal duct lesion and congenital anomalies of the lacrimal duct. PMID- 25271910 TI - Validity and reliability of head posture measurement using Microsoft Kinect. AB - AIMS: To investigate the validity and reliability of Microsoft Kinect-based head tracker (KHT) for measuring head posture. METHODS: Considering the cervical range of motion (CROM) as a reference, one-dimensional and three-dimensional (1D and 3D) head postures of 12 normal subjects (28-58 years of age; 6 women and 6 men) were obtained using the KHT. The KHT was validated by Pearson's correlation coefficient and intraclass correlation (ICC) coefficient. Test-retest reliability of the KHT was determined by its 95% limit of agreement (LoA) with the Bland Altman plot. Face recognition success rate was evaluated for each head posture. RESULTS: Measurements of 1D and 3D head posture performed using the KHT were very close to those of the CROM with correlation coefficients of 0.99 and 0.97 (p<0.05), respectively, as well as with an ICC of >0.99 and 0.98, respectively. The reliability tests of the KHT in terms of 1D and 3D head postures had 95% LoA angles of approximately +/-2.5 degrees and +/-6.5 degrees , respectively. CONCLUSIONS: The KHT showed good agreement with the CROM and relatively favourable test-retest reliability. Considering its high performance, convenience and low cost, KHT could be clinically used as a head posture-measuring system. PMID- 25271911 TI - Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age related macular degeneration: a trade-off analysis. AB - TOPIC: To quantify the gain in visual acuity and serious side effects of ranibizumab, bevacizumab and aflibercept in age-related macular degeneration (AMD). CLINICAL RELEVANCE: There is an ongoing debate about the optimal treatment of AMD with these three antivascular endothelial growth factor (anti-VEGF) treatments. METHODS: Network meta-analyses. (Pre)Medline, EMBASE, SCOPUS, Cochrane Library (until April 2013), Science Citation Index and reference lists were searched for placebo-controlled randomised trials or head-to-head comparisons. Outcomes were 1-year follow-up data of visual acuity (letters gained) and serious (vascular death, any death, stroke, myocardial infarction, transient ischaemic attack) and thrombotic events. Two investigators independently assessed eligibility and quality of included studies and extracted data. RESULTS: 11 trials (enrolling 8341 patients) assessing five active treatments were included. Compared with placebo, all anti-VEGF treatments had a significantly higher percentage of letters gained: ranibizumab 0.3 mg 2.39% (95% CI 1.59 to 3.19; p<0.001), ranibizumab 0.5 mg 3.56% (95% CI 2.58 to 4.13; p<0.001), bevacizumab 1.25 mg 2.14% (95% CI 0.47 to 3.82; p=0.012), aflibercept 0.5 mg 2.91% (95% CI 0.99 to 4.82; p=0.003) and aflibercept 2 mg 3.44% (95% CI 1.73 to 5.14; p<0.001). Compared with placebo, serious side effects were higher in all other treatments: ranibizumab 0.3 mg 4.41% (95% CI 3.42 to 5.40; p<0.001), ranibizumab 0.5 mg 5.33% (95% CI 4.37 to 6.30; p<0.001), bevacizumab 1.25 mg 5.58% (95% CI 3.567 to 7.60; p<0.001), aflibercept 0.5 mg 5.65% (95% CI (3.28 to 8.02; p<0.001) and aflibercept 2 mg 5.29% (95% CI 3.18 to 7.39; p<0.001). Compared with placebo, systemic thrombotic events also occurred more often in all other treatments. CONCLUSIONS: The study revealed only a modest superiority of aflibercept 2 mg and ranibizumab 0.5 mg over other formulations and dosages. PMID- 25271912 TI - A striking, localized eruption. PMID- 25271913 TI - High natriuretic peptide levels and low DBP: companion markers of cardiovascular risk? PMID- 25271914 TI - Should we still consider blood pressure measurements in the clinic? PMID- 25271915 TI - Combination effect of hypertension and diabetes mellitus on urinary protein excretion. PMID- 25271916 TI - Combination effect of hypertension and diabetes mellitus on urinary protein excretion. PMID- 25271917 TI - Effects of continuous positive airway pressure on blood pressure in hypertensive patients with obstructive sleep apnoea. PMID- 25271918 TI - Effects of continuous positive airway pressure on blood pressure in hypertensive patients with obstructive sleep apnoea. PMID- 25271919 TI - Aldosterone-induced oxidative stress: a potential mechanism of aldosterone autonomy in primary aldosteronism. PMID- 25271920 TI - Aldosterone-induced oxidative stress: a potential mechanism of aldosterone autonomy in primary aldosteronism. PMID- 25271921 TI - Antibody responses to influenza a virus infection. PMID- 25271923 TI - Effects of winter cover crops straws incorporation on CH4 and N2O emission from double-cropping paddy fields in southern China. AB - Residue management in cropping systems is believed to improve soil quality. However, the effects of residue management on methane (CH4) and nitrous oxide (N2O) emissions from paddy field in Southern China have not been well researched. The emissions of CH4 and N2O were investigated in double cropping rice (Oryza sativa L.) systems with straw returning of different winter cover crops by using the static chamber-gas chromatography technique. A randomized block experiment with three replications was established in 2004 in Hunan Province, China, including rice-rice-ryegrass (Lolium multiflorum L.) (Ry-R-R), rice-rice-Chinese milk vetch (Astragalus sinicus L.) (Mv-R-R) and rice-rice with winter fallow (Fa R-R). The results showed that straw returning of winter crops significantly increased the CH4 emission during both rice growing seasons when compared with Fa R-R. Ry-R-R plots had the largest CH4 emissions during the early rice growing season with 14.235 and 15.906 g m(-2) in 2012 and 2013, respectively, when Ry-R-R plots had the largest CH4 emission during the later rice growing season with 35.673 and 38.606 g m(-2) in 2012 and 2013, respectively. The Ry-R-R and Mv-R-R also had larger N2O emissions than Fa-R-R in both rice seasons. When compared to Fa-R-R, total N2O emissions in the early rice growing season were increased by 0.05 g m(-2) in Ry-R-R and 0.063 g m(-2) in Mv-R-R in 2012, and by 0.058 g m(-2) in Ry-R-R and 0.068 g m(-2) in Mv-R-R in 2013, respectively. Similar result were obtained in the late rice growing season, and the total N2O emissions were increased by 0.104 g m(-2) in Ry-R-R and 0.073 g m(-2) in Mv-R-R in 2012, and by 0.108 g m(-2) in Ry-R-R and 0.076 g m(-2) in Mv-R-R in 2013, respectively. The global warming potentials (GWPs) from paddy fields were ranked as Ry-R-R>Mv-R R>Fa-R-R. As a result, straw returning of winter cover crops has significant effects on increase of CH4 and N2O emission from paddy field in double cropping rice system. PMID- 25271924 TI - Fully porous GaN p-n junction diodes fabricated by chemical vapor deposition. AB - Porous GaN based LEDs produced by corrosion etching techniques demonstrated enhanced light extraction efficiency in the past. However, these fabrication techniques require further postgrown processing steps, which increases the price of the final system. Also, the penetration depth of these etching techniques is limited, and affects not only the semiconductor but also the other elements constituting the LED when applied to the final device. In this paper, we present the fabrication of fully porous GaN p-n junctions directly during growth, using a sequential chemical vapor deposition (CVD) process to produce the different layers that form the p-n junction. We characterized their diode behavior from room temperature to 673 K and demonstrated their ability as current rectifiers, thus proving the potential of these fully porous p-n junctions for diode and LEDs applications. The electrical and luminescence characterization confirm that high electronic quality porous structures can be obtained by this method, and we believe this investigation can be extended to other III-N materials for the development of white light LEDs, or to reduce reflection losses and narrowing the output light cone for improved LED external quantum efficiencies. PMID- 25271926 TI - Quantification of RF-exposure of the fetus using anatomical CAD-models in three different gestational stages. AB - This study analyzes the exposure of pregnant women and their fetuses in three different gestational stages to electromagnetic radiation in the radio frequency range in the near- and the far-field using numerical modeling. For far-field exposure, the power density at which the basic restriction for the whole body SAR is reached is calculated for both the mother and the fetus at whole body resonance and at frequencies between 450 MHz and 2,450 MHz. The near-field exposure is assessed at 450 MHz, 900 MHz, and 2,450 MHz using half wavelength dipoles as generic sources located at different locations around the abdomen of the mother. For the investigated cases, the exposure of the mother is always below or on the order of magnitude of the basic restriction for exposure at the reference level. When applying the reference levels for the general public, the fetus is sufficiently shielded by the mother. However, the basic restrictions for general public exposure can be exceeded in the fetus when the mother is exposed at reference levels for occupational conditions. For plane wave exposure at occupational levels, the whole body SAR in the fetus can exceed the basic restrictions for the general population by at least 1.8 dB, and in the near-field of professional devices, the 10 g SAR can be non-compliant with the product standard for the general public by > 3.5 dB. PMID- 25271925 TI - QTL analysis and candidate gene mapping for the polyphenol content in cider apple. AB - Polyphenols have favorable antioxidant potential on human health suggesting that their high content is responsible for the beneficial effects of apple consumption. They control the quality of ciders as they predominantly account for astringency, bitterness, color and aroma. In this study, we identified QTLs controlling phenolic compound concentrations and the average polymerization degree of flavanols in a cider apple progeny. Thirty-two compounds belonging to five groups of phenolic compounds were identified and quantified by reversed phase liquid chromatography on both fruit extract and juice, over three years. The average polymerization degree of flavanols was estimated in fruit by phloroglucinolysis coupled to HPLC. Parental maps were built using SSR and SNP markers and used for the QTL analysis. Sixty-nine and 72 QTLs were detected on 14 and 11 linkage groups of the female and male maps, respectively. A majority of the QTLs identified in this study are specific to this population, while others are consistent with previous studies. This study presents for the first time in apple, QTLs for the mean polymerization degree of procyanidins, for which the mechanisms involved remains unknown to this day. Identification of candidate genes underlying major QTLs was then performed in silico and permitted the identification of 18 enzymes of the polyphenol pathway and six transcription factors involved in the apple anthocyanin regulation. New markers were designed from sequences of the most interesting candidate genes in order to confirm their co-localization with underlying QTLs by genetic mapping. Finally, the potential use of these QTLs in breeding programs is discussed. PMID- 25271927 TI - Screening of alpha- and beta-emitting radionuclides using liquid scintillation counting and monitoring procedures in radiation emergencies. AB - Urine gross alpha and beta activity analysis was conducted, and an internal contamination screening method was adopted to monitor visitors to Japan after the Fukushima accident. In particular, spot urine samples were used to evaluate internal contamination for 16 mo, and a total of 90 people participated in gross alpha and beta emitter screening. An ultra-low-background liquid scintillation counter was used for measurement, and optimal pulse shape analysis values were determined by measuring alpha- and beta-emitting certified reference materials. Moreover, linearity and reproducibility were assessed to validate the adopted methods, and international intercomparison was conducted using synthetic urine samples by measuring alpha- and beta-emitting radionuclides in multi-contaminated samples. Here, the measurement results of visitors to Japan are discussed, and a screening procedure is established for gross alpha and beta activity analysis during radiation emergencies. PMID- 25271928 TI - Scientific foundation of regulating ionizing radiation: application of metrics for evaluation of regulatory science information. AB - This paper starts by describing the historical evolution of assessment of biologic effects of ionizing radiation leading to the linear non-threshold (LNT) system currently used to regulate exposure to ionizing radiation. The paper describes briefly the concept of Best Available Science (BAS) and Metrics for Evaluation of Scientific Claims (MESC) derived for BAS. It identifies three phases of regulatory science consisting of the initial phase, when the regulators had to develop regulations without having the needed scientific information; the exploratory phase, when relevant tools were developed; and the standard operating phase, when the tools were applied to regulations. Subsequently, an attempt is made to apply the BAS/MESC system to various stages of LNT. This paper then compares the exposure limits imposed by regulatory agencies and also compares them with naturally occurring radiation at several cities. Controversies about LNT are addressed, including judgments of the U.S. National Academies and their French counterpart. The paper concludes that, based on the BAS/MESC system, there is no disagreement between the two academies on the scientific foundation of LNT; instead, the disagreement is based on their judgment or speculation. PMID- 25271929 TI - Calculating an unknown source activity using modeled and experimental results. AB - A method is presented that provides a way to calculate the unknown activity of a source by using experimental exposure rate measurements from an ion chamber and exposure rates calculated using the MCNP radiation transport code. The method consists of fitting experimental data to MCNP results with both data sets in the form of (Equation is included in full-text article.)where r is the distance from the source at which the measurement was taken, X is the exposure rate, and An is an assumed nominal activity of the source. The fit is done by calculating a correction factor for the nominal activity that shifts the experimental data to match the MCNP results. The actual activity of the source in question is found by multiplying the assumed nominal activity by the activity correction factor. The method was used to calculate the activities of the three Cs sources used in the Ohio Emergency Management Agency's instrument calibration range. It was found that the activities were less than the decay-corrected nominal activities by factors ranging from 3% to 10%. PMID- 25271930 TI - Worker protection implications of the solubility and human metabolism of modern uranium mill products in the U.S. AB - This paper presents an analysis of the implications of some recent studies performed to characterize uranium products from modern uranium recovery facilities important for worker protection. Assumptions about the solubility (related to the molecular species being produced) of these materials in humans are critical to properly assess radiation dose from intakes, understand chemotoxic implications, and establish protective exposure standards (airborne concentrations, limits on intake, etc.). Recent studies, as well as information in the historical professional literature, were reviewed that address the issue of solubility and related characteristics. These data are important for the design of programs for assessment of both chemical and radiological aspects of worker exposure to the products of modern uranium recovery plants (conventional uranium mills and in situ recovery plants; i.e., ISRs). The data suggest strongly that the oxide form produced by these facilities (and therefore, product solubility) is related to precipitation chemistry and thermal exposure (dryer temperature). Given the peroxide precipitation and low temperature drying methods being used at many modern uranium recovery facilities in the U.S. today, very soluble products are being produced. The dosimetric impacts of these products to the pulmonary system (except perhaps in case of an extreme acute insult) would be small, and any residual pulmonary retention beyond a month or two would most likely be too small to measure by traditional urinalysis sampling or the current state-of-the-art of natural uranium in vivo lung counting techniques. Uranium recovery plants should revisit the adequacy of current bioassay programs in the context of their process and product specifics. Workers potentially exposed to these very soluble yellowcake concentrates should have urine specimens submitted for uranium analysis on an approximately weekly basis, including analysis for the biomarkers associated with potential renal injury [e.g., glucose, lactate dehydrogenase (LDH) and protein albumen]. Additionally, implications for compliance with current U.S. Nuclear Regulatory Commission (NRC) regulations (e.g., 10 CFR20) are discussed. NRC, the applicable Agreement State agencies, and licensees need to recognize the importance of the uranium chemotoxicity versus dose relationship in the interest of worker protection. PMID- 25271931 TI - Measurement of radiation exposure in relatives of thyroid cancer patients treated with (131)I. AB - This work evaluates the radiological risk that patients treated with I for differentiated thyroid cancer could present to relatives and occupationally exposed workers. Recently, the International Atomic Energy Agency issued document K9010241, which recommends that patient discharge from the hospital must be based on the particular status of each patient. This work measures effective dose received by caregivers of patients treated with I at the Instituto Nacional de Cancerologia, Mexico City. Thermoluminescent dosimeters were carried during a 15 d period by 40 family caregivers after patient release from hospital. Relatives were classified into two groups, ambulatory and hospitalized, according to the release mode of the patient, and three categories according to the individual patient home and transport facilities. Categories A, B, and C were defined going from most to least adequate concerning public exposure risk. Measurements were performed for 20 family caregivers in each group. The effective dose received by all caregivers participating in this study was found to be less than 5 mSv, the recommended limit per event for caregivers suggested by ICRP 103. In addition, 70 and 90% of ambulatory and hospitalized groups, respectively, received doses lower than 1 mSv. Caregivers belonging to category C, with home situations that are not appropriate for immediate release, received the highest average doses; i.e., 2.2 +/- 1.3 and 3.1 +/- 1.0 mSv for hospitalized and ambulatory patients, respectively. Results of this work have shown that the proper implementation of radiation protection instructions for relatives and patients can reduce significantly the risk that differentiated thyroid cancer patients treated with I can represent for surrounding individuals. The results also stress the relevance of the patient's particular lifestyle and transport conditions as the prevailing factors related to the dose received by the caregiver. Therefore, the patient's status should be the criterion used to decide his/her release modality. This work provides support to recommend the implementation of the "patient specific release criteria" in accordance with ICRP 94, IAEA Safety Report No. 63, and IAE document K9010241 A for patients treated with radiopharmaceuticals. PMID- 25271933 TI - GEANT4 calibration of gamma spectrometry efficiency for measurements of airborne radioactivity on filter paper. AB - A simple method of efficiency calibration for gamma spectrometry was performed. This method, which focused on measuring airborne radioactivity collected on filter paper, was based on Monte Carlo simulations using the toolkit GEANT4. Experimentally, the efficiency values of an HPGe detector were calculated for a multi-gamma disk source. These efficiency values were compared to their counterparts produced by a computer code that simulated experimental conditions. Such comparison revealed biases of 24, 10, 1, 3, 7, and 3% for the radionuclides (photon energies in keV) of Ce (166), Sn (392), Cs (662), Co (1,173), Co (1,333), and Y (1,836), respectively. The output of the simulation code was in acceptable agreement with the experimental findings, thus validating the proposed method. PMID- 25271932 TI - Further evaluations of the toxicity of irradiated advanced heavy water reactor fuels. AB - The neutron economy and online refueling capability of heavy water moderated reactors enable them to use many different fuel types, such as low enriched uranium, plutonium mixed with uranium, or plutonium and/or U mixed with thorium, in addition to their traditional natural uranium fuel. However, the toxicity and radiological protection methods for fuels other than natural uranium are not well established. A previous paper by the current authors compared the composition and toxicity of irradiated natural uranium to that of three potential advanced heavy water fuels not containing plutonium, and this work uses the same method to compare irradiated natural uranium to three other fuels that do contain plutonium in their initial composition. All three of the new fuels are assumed to incorporate plutonium isotopes characteristic of those that would be recovered from light water reactor fuel via reprocessing. The first fuel investigated is a homogeneous thorium-plutonium fuel designed for a once-through fuel cycle without reprocessing. The second fuel is a heterogeneous thorium-plutonium-U bundle, with graded enrichments of U in different parts of a single fuel assembly. This fuel is assumed to be part of a recycling scenario in which U from previously irradiated fuel is recovered. The third fuel is one in which plutonium and Am are mixed with natural uranium. Each of these fuels, because of the presence of plutonium in the initial composition, is determined to be considerably more radiotoxic than is standard natural uranium. Canadian nuclear safety regulations require that techniques be available for the measurement of 1 mSv of committed effective dose after exposure to irradiated fuel. For natural uranium fuel, the isotope Pu is a significant contributor to the committed effective dose after exposure, and thermal ionization mass spectrometry is sensitive enough that the amount of Pu excreted in urine is sufficient to estimate internal doses, from all isotopes, as low as 1 mSv. In addition, if this method is extended so that Pu is also measured, then the combined amount of Pu and Pu is sufficiently high in the thorium-plutonium fuel that a committed effective dose of 1 mSv would be measurable. However, the fraction of Pu and Pu in the other two fuels is sufficiently low that a 1 mSv dose would remain below the detection limit using this technique. Thus new methods, such as fecal measurements of Pu (or other alpha emitters), will be required to measure exposure to these new fuels. PMID- 25271934 TI - Potential hazard due to induced radioactivity secondary to radiotherapy: the report of task group 136 of the American Association of Physicists in Medicine. AB - External-beam radiation therapy mostly uses high-energy photons (x-rays) produced by medical accelerators, but many facilities now use proton beams, and a few use fast-neutron beams. High-energy photons offer several advantages over lower energy photons in terms of better dose distributions for deep-seated tumors, lower skin dose, less sensitivity to tissue heterogeneities, etc. However, for beams operating at or above 10 MV, some of the materials in the accelerator room and the radiotherapy patient become radioactive due primarily to photonuclear reactions and neutron capture, exposing therapy staff and patients to unwanted radiation dose. Some recent advances in radiotherapy technology require treatments using a higher number of monitor units and monitor-unit rates for the same delivered dose, and compared to the conventional treatment techniques and fractionation schemes, the activation dose to personnel can be substantially higher. Radiotherapy treatments with proton and neutron beams all result in activated materials in the treatment room. In this report, the authors review critically the published literature on radiation exposures from induced radioactivity in radiotherapy. They conclude that the additional exposure to the patient due to induced radioactivity is negligible compared to the overall radiation exposure as a part of the treatment. The additional exposure to the staff due to induced activity from photon beams is small at an estimated level of about 1 to 2 mSv y. This is well below the allowed occupational exposure limits. Therefore, the potential hazard to staff from induced radioactivity in the use of high-energy x-rays is considered to be low, and no specific actions are considered necessary or mandatory. However, in the spirit of the "As Low as Reasonably Achievable (ALARA)" program, some reasonable steps are recommended that can be taken to reduce this small exposure to an even lower level. The dose reduction strategies suggested should be followed only if these actions are considered reasonable and practical in the individual clinics. Therapists working with proton beam and neutron beam units handle treatment devices that do become radioactive, and they should wear extremity monitors and make handling apertures and boluses their last task upon entering the room following treatment. Personnel doses from neutron-beam units can approach regulatory limits depending on the number of patients and beams, and strategies to reduce doses should be followed. PMID- 25271939 TI - Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition. AB - Body weight/body surface area-based and/or tiered fixed dosing strategies are widely utilized for monoclonal antibodies with linear clearance to scale adult clinical doses to children. However, there is limited knowledge on whether or not body weight-based dosing strategies also yield comparable dose-concentration response relationships in adults and children for monoclonal antibodies that exhibit target-mediated drug disposition. Our findings indicate that it is important to interpret pharmacokinetics information in a pharmacokinetics/pharmacodynamics context as similar systemic drug exposure in adults and children may not be reflective of the corresponding target occupancy. They further indicate that BW-based dosing is superior to fixed dosing for the same target concentration, whereas the opposite holds true for the same target amount in adults and children. Michaelis-Menten approximations yielded similar profiles compared to the full target-mediated drug disposition model for all simulation scenarios and may be used to guide the selection of appropriate dosing regimens in children. PMID- 25271938 TI - Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. AB - IMPORTANCE: Prior studies have demonstrated reduced dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. However, it remains unclear how generalizable this finding is in schizophrenia and if it is seen in bipolar disorder, a historically distinct psychiatric condition. OBJECTIVE: To assess whether spine loss is present in the DLPFC of individuals with schizophrenia and individuals with bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS: This study used postmortem human brain tissue from individuals with schizophrenia (n=14), individuals with bipolar disorder (n=9), and unaffected control participants (n=19). Tissue samples containing the DLPFC (Brodmann area 46) were Golgi-stained, and basilar dendrites of pyramidal cells in the deep half of layer III were reconstructed. MAIN OUTCOMES AND MEASURES: The number of spines per dendrite, spine density, and dendrite length were compared across groups. We also assessed for the potential effects of clinical and demographic variables on dendritic parameters. RESULTS: The mean (SD) spine density was significantly reduced (ie, by 10.5%) in individuals with bipolar disorder (0.28 [0.04] spines/MUm) compared with control participants (0.31 [0.05] spines/MUm) (P=.02). In individuals with schizophrenia, the mean (SD) spine density was also reduced (by 6.5%; 0.29 [0.03] spines/MUm) but just missed significance when compared with control participants (P=.06). There was a significant reduction in the mean (SD) number of spines per dendrite in both individuals with schizophrenia (72.8 [24.9] spines per dendrite) and individuals with bipolar disorder (68.9 [12.9] spines per dendrite) compared with controls (92.8 [31.1] spines per dendrite) (individuals with schizophrenia vs controls: 21.6% reduction [P=.003]; individuals with bipolar disorder vs controls: 25.8% reduction [P=.005]). In addition, both individuals with schizophrenia and individuals with bipolar disorder had a reduced mean (SD) dendrite length (246.5 [67.4] and 245.6 [29.8] MUm, respectively) compared with controls (301.8 [75.1] MUm) (individuals with schizophrenia vs controls: 18.3% reduction [P=.005]; individuals with bipolar disorder vs controls: 18.6% reduction [P=.005]). CONCLUSIONS AND RELEVANCE: Dendritic spine loss in the DLPFC was seen in both individuals with schizophrenia and individuals with bipolar disorder, suggesting that the 2 disorders may share some common pathophysiological features. PMID- 25271940 TI - Realization of the meminductor. AB - The meminductor was proposed to be a fundamental circuit memdevice parallel with the memristor, linking magnetic flux and current. However, a clear material model or experimental realization of a meminductor has been challenging. Here we demonstrate pinched hysteretic magnetic flux-current signals at room temperature based on the spin Hall magnetoresistance effect in several-nanometer-thick thin films, exhibiting the nonvolatile memorizing property and magnetic energy storage ability of the meminductor. Similar to the parameters of the capacitor, resistor, and inductor, meminductance, LM, is introduced to characterize the capability of the prepared meminductor. Our findings present an indispensable element of memdevices and open an avenue for nanoscale meminductor design and manufacture, which might contribute to low-power electronic circuits, information storage, and artificial intelligence. PMID- 25271942 TI - Changes in hospital case management through the years. AB - "Going Forward: What Is Case Management?," a recent HeartBeat of Case Management column in this journal, set off a wave of positive comments to the author. Hospital case management has been at the forefront of many of the changes in the past several decades. Even today, these changes should be reevaluated to enhance what is best for the patient, the business of health care, quality, and evidence based care. PMID- 25271941 TI - Fecal bacterial community changes associated with isoflavone metabolites in postmenopausal women after soy bar consumption. AB - Soy isoflavones and their metabolism by intestinal microbiota have gained attention because of potential health benefits, such as the alleviation of estrogen/hormone-related conditions in postmenopausal women, associated with some of these compounds. However, overall changes in gut bacterial community structure and composition in response to addition of soy isoflavones to diets and their association with excreted isoflavone metabolites in postmenopausal women has not been studied. The aim of this study was to determine fecal bacterial community changes in 17 postmenopausal women after a week of diet supplementation with soy bars containing isoflavones, and to determine correlations between microbial community changes and excreted isoflavone metabolites. Using DGGE profiles of PCR amplified 16S rRNA genes (V3 region) to compare microbial communities in fecal samples collected one week before and one week during soy supplementation revealed significant differences (ANOSIM p<0.03) before and after soy supplementation in all subjects. However, between subjects comparisons showed high inter-individual variation that resulted in clustering of profiles by subjects. Urinary excretion of isoflavone (daidzein) metabolites indicated four subjects were equol producers and all subjects produced O-desmethylangolensin (ODMA). Comparison of relative proportions of 16S rRNA genes from 454 pyrosequencing of the last fecal samples of each treatment session revealed significant increases in average proportions of Bifidobacterium after soy consumption, and Bifidobacterium and Eubacterium were significantly greater in equol vs non-S-(-)equol producers. This is the first in vivo study using pyrosequencing to characterize significant differences in fecal community structure and composition in postmenopausal women after a week of soy diet supplementation, and relate these changes to differences in soy isoflavones and isoflavone metabolites. TRIAL REGISTRATION: Clinicaltrials.gov NCT00244907. PMID- 25271943 TI - Reduce readmissions with service-based care management. AB - PURPOSE OF STUDY: In response to the U.S. Affordable Care Act, the Centers for Medicare & Medicaid Services proposed a change in reimbursement penalties for hospitals beginning October 1, 2012. Reducing the occurrence of unplanned readmissions has become a more urgently focused topic. As part of the health care system, care management aligns with physicians to significantly improve service, financial, and clinical care outcomes. To address the changing health care climate in 2008, care management services were restructured at an academic university medical center located in 1 of the 3 largest counties in California. Changing from a unit-based to a service-based care management model partnered care managers and social workers with physician services. We sought to assess the effect of this change on surrogates for patient experience and clinical quality of care. PRIMARY PRACTICE SETTING: Tertiary academic medical center in southern California. METHODOLOGY AND SAMPLE: Retrospective data were collected from 2 databases for all hospital patient care services from November 2008 to January 2010 to determine whether clinical quality of care and experiential service improvements were realized. Primary outcomes included all-cause and related readmission rates. Secondary outcomes were Hospital Consumer Assessment of Healthcare Providers and Systems (H-CAHPS) scores. An interrupted time series analysis compared data from the single institution for the diffusion and postintervention periods. RESULTS: Comparing data from the diffusion and postintervention periods, the rate of disease-related readmissions decreased significantly (mean 5.43-4.58, p < .05), and all-cause readmissions also decreased, although the difference failed to achieve statistical significance (11.42-10.49, p = .056). H-CAHPS scores with the patient response of "recommend this hospital" was unchanged over the 2 time points (mean 78.9%-77.8%, p = .26731). Data also showed stable care management staffing rates whereas average daily census (ADC) increased over time (ADC 274-297). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: With health reform driving value-driven care transformation, partnering care managers and social workers with physician services has the potential to impact the patient's experience as well as financial and clinical care outcomes. Care managers serve a significant role in improving the clinical quality of care by reinforcing a consistent and clear message by the health care team to the patient during the entire hospitalization, not just at the time of discharge. At one institution, partnering physicians with care managers through the acute care continuum (service-based care management) appeared to reduce readmissions without compromising patient satisfaction. Both readmission reduction and effective patient satisfaction scores impact the Centers for Medicare & Medicaid Services value-based purchasing reimbursement calculations. PMID- 25271944 TI - Reduce readmissions with service-based care management. PMID- 25271945 TI - Evidence-based nurse case management practice in community health. AB - PURPOSE OF STUDY: The purpose of this study was to investigate and compare the type of nurse case managers' (NCMs') practice on patients' quality outcomes in community settings. PRIMARY PRACTICE SETTING(S): Nurse case management (CM) practice with NCMs in community-based settings. METHODOLOGY AND SAMPLE: The design of this study was an exploratory, descriptive secondary analysis of 4 types of service by 11 NCMs, delivered to selected Medicare beneficiaries in community settings. Descriptive statistics and ANOVA tests were calculated. RESULTS: The majority of CM services were delivered in home care services in the community. Most of the 4 types of services-home, telephone, clinic, and mixed care-positively changed patients' quality measure outcomes-self-care activities of daily life, quality of life, and well-being. However, there were no modes that were statistically significant in patients' quality measure outcomes at the p < .05 level in the 2-year time frame. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: It is imperative to know the most effective and efficient types of CM services in community health for evidence-based NCMs practice. The results contribute to understanding how community health nurses may choose to select home care interventions for effectiveness. Thus, NCMs' practice needs to be capitalized on by practicing health administrators for health care management services within the current dynamic health policy environment. PMID- 25271947 TI - A heart failure initiative to reduce the length of stay and readmission rates. AB - PURPOSE/OBJECTIVES: The purpose of this pilot was to improve multidisciplinary coordination of care and patient education and foster self-management behaviors. The primary and secondary outcomes achieved from this pilot were to decrease the 30-day readmission rate and heart failure length of stay. PRIMARY PRACTICE SITE: The primary practice site was an inpatient medical-surgical nursing unit. FINDING AND CONCLUSIONS: The length of stay decreased from 6.05% to 4.42% for heart failure diagnostic-related group 291 as a result of utilizing the model. The length of stay decreased from 3.9% to 3.09%, which was also less than the national rate of 3.8036% for diagnostic-related group 292. In addition, the readmission rate decreased from 23.1% prior to January 2013 to 12.9%. Implementation of standards of care coordination can decrease length of stay, readmission rate, and improve self-management. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Implementation of evidence-based heart failure guidelines, improved interdisciplinary coordination of care, patient education, self-management skills, and transitional care at the time of discharge improved overall heart failure outcome measures. Utilizing the longitudinal model of care to transition patients to home aided in evaluating social support, resource allocation and utilization, access to care postdischarge, and interdisciplinary coordination of care. The collaboration between disciplines improved continuity of care, patient compliance to their discharge regimen, and adequate discharge follow-up. PMID- 25271948 TI - Lessons in how not to deliver patient-centered care. PMID- 25271949 TI - Vaccinations: eliminating preventable illness. PMID- 25271950 TI - Under the "umbrella" of case management: pharmacists add to professional diversity of the practice. PMID- 25271951 TI - Ethical Dilemmas in Managed Care: One Case Manager's Reflections. PMID- 25271952 TI - Construction of Aeromonas salmonicida subsp. achromogenes AsaP1-toxoid strains and study of their ability to induce immunity in Arctic char, Salvelinus alpinus L. AB - The metalloendopeptidase AsaP1 is one of the major extracellular virulence factors of A. salmonicida subsp. achromogenes, expressed as a 37-kDa pre-pro peptide and processed to a 19-kDa active peptide. The aim of this study was to construct mutant strains secreting an AsaP1-toxoid instead of AsaP1-wt, to study virulence of these strains and to test the potency of the AsaP1-toxoid bacterin and the recombinant AsaP1-toxoids to induce protective immunity in Arctic char. Two A. salmonicida mutants were constructed that secrete either AsaP1E294A or AsaP1Y309F . The secreted AsaP1Y309F -toxoid had weak caseinolytic activity and was processed to the 19-kDa peptide, whereas the AsaP1E294A -toxoid was found as a 37-kDa pre-pro-peptide suggesting that AsaP1 is auto-catalytically processed. The LD50 of the AsaP1Y309F -toxoid mutant in Arctic char was significantly higher than that of the corresponding wt strain, and LD50 of the AsaP1E294A -toxoid mutant was comparable with that of an AsaP1-deficient strain. Bacterin based on AsaP1Y309F -toxoid mutant provided significant protection, comparable with that induced by a commercial polyvalent furunculosis vaccine. Detoxification of AsaP1 is very hard, expensive and time consuming. Therefore, an AsaP1-toxoid-secreting mutant is more suitable than the respective wt strain for production of fish bacterins aimed to protect against atypical furunculosis. PMID- 25271953 TI - High-Performance Integrated Virtual Environment (HIVE) Tools and Applications for Big Data Analysis. AB - The High-performance Integrated Virtual Environment (HIVE) is a high-throughput cloud-based infrastructure developed for the storage and analysis of genomic and associated biological data. HIVE consists of a web-accessible interface for authorized users to deposit, retrieve, share, annotate, compute and visualize Next-generation Sequencing (NGS) data in a scalable and highly efficient fashion. The platform contains a distributed storage library and a distributed computational powerhouse linked seamlessly. Resources available through the interface include algorithms, tools and applications developed exclusively for the HIVE platform, as well as commonly used external tools adapted to operate within the parallel architecture of the system. HIVE is composed of a flexible infrastructure, which allows for simple implementation of new algorithms and tools. Currently, available HIVE tools include sequence alignment and nucleotide variation profiling tools, metagenomic analyzers, phylogenetic tree-building tools using NGS data, clone discovery algorithms, and recombination analysis algorithms. In addition to tools, HIVE also provides knowledgebases that can be used in conjunction with the tools for NGS sequence and metadata analysis. PMID- 25271954 TI - Evaluation of dental age and associated developmental anomalies in subjects with impacted mandibular canines. AB - OBJECTIVES: To assess the null hypothesis that there is no difference in the rate of dental development and the occurrence of selected developmental anomalies related to shape, number, structure, and position of teeth between subjects with impacted mandibular canines and those with normally erupted canines. MATERIALS AND METHODS: Pretreatment records of 42 subjects diagnosed with mandibular canines impaction (impaction group: IG) were compared with those of 84 subjects serving as a control reference sample (control group: CG). Independent t-tests were used to compare mean dental ages between the groups. Intergroup differences in distribution of subjects based on the rate of dental development and occurrence of selected dental anomalies were assessed using chi(2) tests. Odds of late, normal, and early developers and various categories of developmental anomalies between the IG and the CG were evaluated in terms of odds ratios. RESULTS: Mean dental age for the IG was lower than that for the CG in general. Specifically, this was true for girls (P < .05). Differences in the distribution of the subjects based on the rate of dental development and occurrence of positional anomalies also reached statistical significance (P < .05). The IG showed a higher frequency of late developers and positional anomalies compared with controls (odds ratios 3.00 and 2.82, respectively; P < .05). CONCLUSIONS: The null hypothesis was rejected. We identified close association of female subjects in the IG with retarded dental development compared with the female orthodontic patients. Increased frequency of positional developmental anomalies was also remarkable in the IG. PMID- 25271955 TI - Evaluation of long-term soft tissue changes after bimaxillary orthognathic surgery in Class III patients. AB - OBJECTIVE: To assess soft tissues in the short and long term after bimaxillary surgery in Class III patients by comparing the hard tissue changes and results between time periods. MATERIALS AND METHODS: Twenty-six Class III adult patients treated with bimaxillary surgery were included in the study. Cephalometric records were taken before surgery (T1) and 5 months (T2), 1.4 years (T3), 3 years (T4), and 5 years (T5) after surgery. RESULTS: There was no significant relapse in skeletal parameters. Overjet was significantly reduced between T4-T3 time intervals (P < .01). There were significant increases in Sn-HR, ULA-HR, LLA-HR, B B(?) (P < .01), and B(?)-HR (P < .05) between T4-T3 time intervals. There was no significant change in the soft tissue parameters between T5-T4 time intervals. CONCLUSION: Soft tissue vertical relapse occurs in skeletally stabile Class III bimaxillary surgery patients in the first 3 years after surgery. PMID- 25271957 TI - Universality of the network-dynamics of the cell nucleus at high frequencies. AB - The interior of the cell nucleus is comparable to a solid network bathed in an interstitial fluid. From the extrapolation of low frequency data, it is expected that such network should dictate the response of the nucleus to mechanical stress at high frequencies, described by unique elastic moduli. However, none of the existing techniques that can probe the mechanical properties of cells can exceed the kHz range, and the mechanics of the nuclear network remain poorly understood. We use laser-generated acoustic waves to probe remotely the stiffness and viscosity of nuclei in single cells in the previously unexplored GHz range with a ~100 nm axial resolution. The probing of cells at contrasted differentiation stages, ranging from stem cells to mature cells originating from different tissues, demonstrates that the mechanical properties of the nuclear network are common across various cell types. This points to an asymptotically increasing influence of a solid meshwork of connected chromatin fibers. PMID- 25271956 TI - Differential susceptibility of human peripheral blood T cells to suppression by environmental levels of sodium arsenite and monomethylarsonous acid. AB - Human exposure to arsenic in drinking water is known to contribute to many different health outcomes such as cancer, diabetes, and cardiopulmonary disease. Several epidemiological studies suggest that T cell function is also altered by drinking water arsenic exposure. However, it is unclear how individual responses differ to various levels of exposure to arsenic. Our laboratory has recently identified differential responses of human peripheral blood mononuclear cell (HPMBC) T cells as measured by polyclonal T cell activation by mitogens during sodium arsenite exposure. T cells from certain healthy individuals exposed to various concentrations (1-100 nM) of arsenite in vitro showed a dose-dependent suppression at these extremely low concentrations (~ 0.1-10 ppb) of arsenite, whereas other individuals were not suppressed at low concentrations. In a series of more than 30 normal donors, two individuals were found to be sensitive to low concentration (10 nM equivalent ~ 1 ppb drinking water exposure) to sodium arsenite-induced inhibition of T cell proliferation produced by phytohemagglutinin (PHA) and anti-CD3/anti-CD28. In an arsenite-susceptible individual, arsenite suppressed the activation of Th1 (Tbet) cells, and decreased the percentage of cells in the double positive Th17 (RORgammat) and Treg (FoxP3) population. While the majority of normal blood donors tested were not susceptible to inhibition of proliferation at the 1-100 nM concentrations of As(+3), it was found that all donors were sensitive to suppression by 100 nM monomethylarsonous acid (MMA+3), a key metabolite of arsenite. Thus, our studies demonstrate for the first time that low ppb-equivalent concentrations of As(+3) are immunosuppressive to HPBMC T cells in some individuals, but that most donor HPBMC are sensitive to suppression by MMA(+3) at environmentally relevant exposure levels. PMID- 25271958 TI - Novel influenza A(H7N2) virus in chickens, Jilin province, China, 2014. AB - In February 2014, while investigating the source of a human infection with influenza A(H7N9) virus in northern China, we isolated subtypes H7N2 and H9N2 viruses from chickens on the patient's farm. Sequence analysis revealed that the H7N2 virus is a novel reassortant of H7N9 and H9N2 viruses. Continued surveillance is needed. PMID- 25271960 TI - FRET Imaging by Laser Scanning Cytometry on Large Populations of Adherent Cells. AB - The application of FRET (fluorescence resonance energy transfer) sensors for monitoring protein-protein interactions under vital conditions is attracting increasing attention in molecular and cell biology. Laser-scanning cytometry (LSC), a slide-based sister procedure to flow cytometry, provides an opportunity to analyze large populations of adherent cells or 2-D solid tissues in their undisturbed physiological settings. Here we provide an LSC-based three-laser protocol for high-throughput ratiometric FRET measurements utilizing cyan and yellow fluorescent proteins as a FRET pair. Membrane labeling with Cy5 dye is used for cell identification and contouring. Pixel-by-pixel and single-cell FRET efficiencies are calculated to estimate the extent of the molecular interactions and their distribution in the cell populations examined. We also present a non high-throughput donor photobleaching FRET application, for obtaining the required instrument parameters for ratiometric FRET. In the biological model presented, HeLa cells are transfected with the ECFP- or EYFP-tagged Fos and Jun nuclear proteins, which heterodimerize to form active AP1 transcription factor. PMID- 25271959 TI - Correlative fluorescence and electron microscopy. AB - Correlative fluorescence and electron microscopy (CFEM) is a multimodal technique that combines dynamic and localization information from fluorescence methods with ultrastructural data from electron microscopy, to give new information about how cellular components change relative to the spatiotemporal dynamics within their environment. In this review, we will discuss some of the basic techniques and tools of the trade for utilizing this attractive research method, which is becoming a very powerful tool for biology labs. The information obtained from correlative methods has proven to be invaluable in creating consensus between the two types of microscopy, extending the capability of each, and cutting the time and expense associated with using each method separately for comparative analysis. The realization of the advantages of these methods in cell biology has led to rapid improvement in the protocols and has ushered in a new generation of instruments to reach the next level of correlation--integration. PMID- 25271961 TI - High-resolution cytometry for high-content cell cycle analysis. AB - One of the major limitations of flow cytometry (FCM) is the absence of an intracellular view. Automated microscopy and image analysis, together with technological developments, led to new approaches in cytometry that bypass the above limitation, introducing high resolution, high content, and large statistical sampling. However, few attempts have been made, until now, to translate the wide repertoire of FCM assays into high-content image screening. This unit describes the implementation of an acquisition and analysis protocol for evaluation of the cell cycle by automated microscopy. The approach grants the possibility to perform simultaneous analysis of a high number of different parameters. A large part of this unit is devoted to the description of hardware features that can optimize the recorded information together with the acquisition and analysis procedures employed to produce good-quality data. PMID- 25271962 TI - Confocal microscopy for high-resolution and high-content analysis of the cell cycle. AB - Optical fluorescence microscopy offers a wide range of technological solutions to address many questions in biomedical research. Spatial resolution has been greatly improved by the use of confocal microscopes, providing a 3-D analysis of the intracellular space. Automation has contributed to make confocal analysis available for high-content image cytometry studies. However, the storage, browsing, and analysis of the amount of data generated can challenge the feasibility of such studies. Presented in this chapter is a multistep acquisition and analysis protocol that can bypass such difficulties by an analysis-driven data collection. Cell-cycle analysis of low-resolution data can be employed to select cell populations of interest that can then be imaged at extremely high resolution and subjected to high-content analysis. PMID- 25271964 TI - Decalcifying efficacy of different irrigating solutions: effect of cetrimide addition. AB - The objective of the present study was to evaluate and compare the influence of cetrimide on decalcifying capability of different irrigating solutions. Fifteen maxillary central incisor teeth has been collected. The canals were prepared in order to obtain four samples from each root. The specimens were randomly divided into 6 experimental groups (n=10) according to tested irrigating agents. Irrigating agents consisted in different composition of EDTA and citric acid solutions, addicted or not with cetrimide. Each specimen was submitted to three successive 5-min immersions in each solution. After exposures, the concentration of Ca2+ extracted was measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES). Data were analysed by means of Kruskal Wallis and Mann Whitney tests. Significance was predetermined at p < 0.05. For all irrigants, the amounts of Ca2+ extracted from root canal dentin samples at 10 minutes were not significantly different from values reported after 15 minutes respectively. Therefore, for all irrigants tested, 10 minutes of application are sufficient to obtain maximum Ca2+ release. Moreover citric acid based agents observed a higher release of Ca2+. The addition of cetrimide did not affect the decalcifying capability of the EDTA and citric acid solutions. PMID- 25271963 TI - Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. AB - Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile. PMID- 25271965 TI - Clinical assessment of oral mucositis and candidiasis compare to chemotherapic nadir in transplanted patients. AB - Oral mucositis is a chief complication in patients undergoing hematopoietic stem cell transplantation (HSCT). It is considered a toxic inflammatory reaction that interferes with the patient's recuperation and quality of life. Oral candidiasis is a common fungal infection observed in dental practice, particularly in immunocompromised patients. The aim of this study was to evaluate the presence of oral mucositis and oral candidiasis in patients who underwent HSCT and their correlation with the chemotherapeutic nadir (lowest possible outcome). We evaluated patients with different diagnoses who underwent HSCT at the Hospital Erasto Gaertner. No chemotherapeutic nadir curves could be associated with mucositis, and patients had different presentations of mucositis. No patient developed oral candidiasis during hospitalization. Together with cell counts, we collected demographic data including age, oral hygiene, habits harmful to health, and the use of oral prostheses. It was observed that patients who smoked cigarettes before hospitalization showed less mucositis, resulting in no feeding problems or other comorbid conditions due to the effect of mucositis. However, the nadir of the chemotherapy curve, in isolation, is not a predictive tool for the appearance (or no appearance) of oral mucositis. PMID- 25271966 TI - Effect of needle insertion depth and apical diameter on irrigant extrusion in simulated immature permanent teeth. AB - The aim of this study was to compare the amount of irrigant extrusion in simulated immature permanent teeth when the apical diameter and needle insertion depth were varied. Thirty single-rooted maxillary incisors with straight root canals were selected. The root length was standardized to a length of 9 mm. The teeth were divided into two experimental groups according to the degree of apical enlargement (n = 15). The apices were enlarged to a diameter of 1.10 mm or 1.70 mm by using a #3 or #6 peeso reamer, respectively, to simulate immature teeth. The irrigation solution was applied 2 or 4 mm short of the working length (WL) in each experimental group. The glass vial model was used for the collection of extruded irrigant beyond the root apex. A two-way repeated measures analysis of variance test showed that there was no significant difference between different needle insertion depths (2 and 4 mm short of the WL) in the group with an apical diameter of 1.70 mm (p > 0.05). In the group with an apical diameter of 1.10 mm, a 32% increase in irrigant extrusion was observed when the needle was positioned at 2 mm (p < 0.05). Regarding the effect of apical diameter, the group with a diameter of 1.70 mm showed more apical extrusion of the irrigant (34% increase for the needle positioned at 2 mm and 68% increase for the needle positioned at 4 mm). It was observed that the needle insertion depth and apical diameter have a significant effect on irrigant extrusion in immature permanent teeth. PMID- 25271968 TI - Simultaneous extraction and determination of various pesticides in environmental waters. AB - A simple and rapid method was developed for the simultaneous analysis of nine different pesticides in water samples by gas chromatography with mass spectrometry. A number of parameters that may affect the recovery of pesticides, such as the type of solid-phase extraction cartridge, eluting solvent in single or combination and their volumes, and water pH value were investigated. It showed that three solid-phase extraction cartridges (Strata-X, Oasis HLB, and ENVI-18) produced the greatest recovery while ethyl acetate/dichloromethane/acetone (45:10:45, 12 mL) followed by dichloromethane (6 mL) was efficient in eluting target pesticides from solid-phase extraction cartridges. Different water pH values (4-9) did not show a significant effect on the pesticides recovery. The optimized method was verified by performing spiking experiments with a series of concentrations (0.002-10 MUg/L) in waters, with good linearity, recovery, and reproducibility for most compounds. The limit of detection and limit of quantification of this optimized method were 0.01-2.01 and 0.02-6.71 ng/L, respectively, much lower than the European Union environmental quality standard for the pesticides (0.1 MUg/L) in waters. The proposed method was further validated by participation in an interlaboratory trial. It was then subsequently applied to river waters from north-east Scotland, UK, for the determination of the target pesticides. PMID- 25271967 TI - Effects of deletion of mutant huntingtin in steroidogenic factor 1 neurons on the psychiatric and metabolic phenotype in the BACHD mouse model of Huntington disease. AB - Psychiatric and metabolic features appear several years before motor disturbances in the neurodegenerative Huntington's disease (HD), caused by an expanded CAG repeat in the huntingtin (HTT) gene. Although the mechanisms leading to these aspects are unknown, dysfunction in the hypothalamus, a brain region controlling emotion and metabolism, has been suggested. A direct link between the expression of the disease causing protein, huntingtin (HTT), in the hypothalamus and the development of metabolic and psychiatric-like features have been shown in the BACHD mouse model of HD. However, precisely which circuitry in the hypothalamus is critical for these features is not known. We hypothesized that expression of mutant HTT in the ventromedial hypothalamus, an area involved in the regulation of metabolism and emotion would be important for the development of these non motor aspects. Therefore, we inactivated mutant HTT in a specific neuronal population of the ventromedial hypothalamus expressing the transcription factor steroidogenic factor 1 (SF1) in the BACHD mouse using cross-breeding based on a Cre-loxP system. Effects on anxiety-like behavior were assessed using the elevated plus maze and novelty-induced suppressed feeding test. Depressive-like behavior was assessed using the Porsolt forced swim test. Effects on the metabolic phenotype were analyzed using measurements of body weight and body fat, as well as serum insulin and leptin levels. Interestingly, the inactivation of mutant HTT in SF1-expressing neurons exerted a partial positive effect on the depressive-like behavior in female BACHD mice at 4 months of age. In this cohort of mice, no anxiety-like behavior was detected. The deletion of mutant HTT in SF1 neurons did not have any effect on the development of metabolic features in BACHD mice. Taken together, our results indicate that mutant HTT regulates metabolic networks by affecting hypothalamic circuitries that do not involve the SF1 neurons of the ventromedial hypothalamus. PMID- 25271969 TI - Theoretical kinetics studies on the reaction of CF3CF?CF2 with hydroxyl radical. AB - The potential energy surface for the reaction of hexafluoropropene with hydroxyl radical is explored by using BB1K density functional method. Single-point energy calculations are performed at CBS-Q level of theory. Semiclassical transition state theory and a modified strong collision/RRKM model are employed to calculate the thermal rate coefficients for the formation of major products as a function of temperature and pressure. It is revealed from the computed rate constants that the major product channels at low temperatures and high pressures are the formation of the primary adducts formed through OH addition to the double bond of CF3?CFCF2. At high temperatures and low pressures, however, many products arising from unimolecular decomposition of the chemically activated intermediates become important. P9A (CF3CFCOF + HF) and P7B (CF3COCF2 + HF) are dominant products at elevated temperatures. Semiclassical transition state theory is used to compute the overall high-pressure rate constants over the temperature range of 200-1500 K. The computed rate constants are in accordance with the available experimental data. PMID- 25271972 TI - Conventional Chiralpak ID vs. capillary Chiralpak ID-3 amylose tris-(3 chlorophenylcarbamate)-based chiral stationary phase columns for the enantioselective HPLC separation of pharmaceutical racemates. AB - A comparative enantioselective analysis using immobilized amylose tris-(3 chlorophenylcarbamate) as chiral stationary phase in conventional high performance liquid chromatography (HPLC) with Chiralpak ID (4.6 mm ID * 250 mm, 5 um silica gel) and micro-HPLC with Chiralpak ID-3 (0.30 mm ID * 150 mm, 3 um silica gel) was conducted. Pharmaceutical racemates of 12 pharmacological classes, namely, alpha- and beta-blockers, anti-inflammatory drugs, antifungal drugs, dopamine antagonists, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, diuretics, antihistaminics, anticancer drugs, and antiarrhythmic drugs were screened under normal phase conditions. The effect of an organic modifier on the analyte retentions and enantiomer recognition was investigated. Baseline separation was achieved for 1-acenaphthenol, carprofen, celiprolol, cizolirtine carbinol, miconazole, tebuconazole, 4-hydroxy-3 methoxymandelic acid, 1-indanol, 1-(2-chlorophenyl)ethanol, 1-phenyl-2-propanol, flavanone, 6-hydroxyflavanone, 4-bromogluthethimide, and pentobarbital on the 4.6 mm ID packed with a 5 um silica column using conventional HPLC. Nonetheless, baseline separation was achieved for aminoglutethimide, naftopidil, and thalidomide on the 0.3 mm ID packed with a 3 um silica capillary column. PMID- 25271973 TI - Proposing application of results in sport and exercise research reports. AB - The application of sport and exercise research findings to practice requires careful interpretation and integration of evidence. This paper reviews principles of evidence-based practice and the application of research in sports and exercise, in order to provide recommendations on developing appropriate application sections in research reports for sport and exercise journals. The strength of recommendations for application fall into one of four levels, with potential applications qualified as strong, limited, preliminary, or hypothesized. Specific limitations that should be discussed in framing recommendations for practice are also noted for each of these levels that should be useful for authors, and for practitioners and clinicians in interpreting these recommendations. PMID- 25271970 TI - Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure. AB - The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I(KCa) blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I(KCa) blockade in all of the groups studied. I(KCa) blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I(KCa) blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I(KCa) blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I(KCa) in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles. PMID- 25271971 TI - Trenbolone acetate metabolite transport in rangelands and irrigated pasture: observations and conceptual approaches for agro-ecosystems. AB - To assess the relative ecological risks of trenbolone acetate (TBA) use in agro ecosystems, we evaluated the spatiotemporal dynamics of TBA metabolite transport during irrigation and rainfall events. Within a pasture, TBA-implanted heifers (40 mg TBA, 8 mg estradiol) were briefly penned (24 h) at high stocking densities (500 animal units (AU)/ha), prior to irrigation. Irrigation runoff concentrations of 17alpha-trenbolone (17alpha-TBOH) 0.3 m downslope were 11 ng/L in the wetting front, but quickly decreased to ~0.5 ng/L, suggesting mass transfer limitations to transport. At 3 and 30 m downslope, efficient attenuation of 17alpha-TBOH concentrations is best explained by infiltration and surface partitioning. At plot scales, transport through vegetated filter strips resulted in <0.5-7 ng/L 17alpha-TBOH concentrations in rainfall-induced runoff with partial subsequent attenuation. Thus, even under intense grazing scenarios, TBA-metabolite transport potential is expected to be low in rangelands, with ecological risks primarily arising from uncontrolled animal access to receiving waters. However, 17alpha TBOH concentrations in initial runoff were predicted to exceed threshold levels (i.e., no observed adverse effect levels [NOAELs]) for manure concentrations exceeding 2.0 ng/g-dw, which occurs throughout most of the implant life. For comparison, estrone and 17beta-estradiol were modeled and are likely capable of exceeding NOAELs by a factor of ~2-5 in irrigation runoff, suggesting that both endogenous and exogenous steroids contribute to endocrine disruption potential in agro-ecosystems. PMID- 25271974 TI - Probable importation of dengue virus type 4 to Angola from Brazil. PMID- 25271976 TI - Three-toed sloth as putative reservoir of Coxiella burnetii, Cayenne, French Guiana. PMID- 25271975 TI - Institutional (mis)trust in colorectal cancer screening: a qualitative study with Greek, Iranian, Anglo-Australian and Indigenous groups. AB - INTRODUCTION: Colorectal cancer (CRC) has the second highest cancer mortality rate in Australia. The Australian National Bowel Cancer Screening Program (NBCSP) aims to increase early detection of CRC by offering free Faecal Occult Blood Testing (FOBT), although uptake is low for culturally and linguistically diverse (CALD) groups. AIM OF PAPER: To present data on trust and mistrust in the NBCSP by population groups with low uptake and thus to highlight areas in need of policy change. METHODS: A qualitative study was undertaken in South Australia, involving interviews with 94 people from four CALD groups: Greek, Iranian, Anglo Australian, and Indigenous peoples. RESULTS: Our study highlights the complexities of institutional trust, which involves considerations of trust at interpersonal, local and national levels. In addition, trust and mistrust was found in more abstract systems such as the medical knowledge of doctors to diagnose or treat cancer or the scientific procedures in laboratories to test the FOBTs. The object of institutional (mis)trust differed between cultural groups - Anglo-Australian and Iranian groups indicated a high level of trust in the government, whereas Indigenous participants were much less trusting. CONCLUSION: The level and nature of trust in the screening process varied between the CALD groups. Addressing program misconceptions, clarifying the FOBT capabilities and involving medical services in collecting and transporting the samples may increase trust in the NBCSP. However, broader and more enduring mistrust in services and institutions may need to be dealt with in order to increase trust and participation. PMID- 25271977 TI - Development of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (Higher Basidiomycetes) polysaccharides injection formulation. AB - Biochemical and pharmacological research has demonstrated that Lingzhi or Reishi medicinal mushroom Ganoderma lucidum polysaccharides (GLPS) have significant anticancer, antitumor, and antioxidant activities. To investigate the effect of injecting GLPS into hosts for clinical studies, aqueous polysaccharide extracts from G. lucidum fruit bodies were purified by deproteinization using the Sevage method, anion-exchange chromatography elution (cellulose DEAE-52 chromatography), dialysis, ethanol precipitation, and active carbon and millipore membrane filtration techniques. The purified GLPS were used for injection in mice. Polysaccharide indexes, protein, tannin, heavy metal, arsenic salt, oxalate, potassium ion, resin, pH, ignition residue measurements, evaluation criterion for allergic reactions, and total solids content of the GLPS injection were all performed using the reference methods in the Chinese Pharmacopoeia. Our results showed that polysaccharide was the key component of injection mixtures. The ignition residue and total solids content in the injection mixture were 1.4% and 2.4%, respectively. The other indices were all within the expected safety ranges. Furthermore, studies from mice functional assays showed that the injection mixture improved the antifatigue capacity of mice without any effect on weight loss/gain. In addition, the injection mixture was safe, which was confirmed by allergy testing in guinea pigs. The development of a GLPS injection offers a novel approach for future medicinal mushroom utilization and holds great commercial promise. PMID- 25271978 TI - Biological characteristics of teleomorph and optimized in vitro fruiting conditions of the Hoelen medicinal mushroom, Wolfiporia extensa (Higher Basidiomycetes). AB - Wolfiporia extensa is a basidiomycetous brown rot fungus and is of well-known medicinal import in China, Japan, and other Asiatic countries. Fruiting body induction is of major relevance for basic biological research and for their use in industrial applications. Based on the evaluation of the effects of temperature, time in the dark before induction and culture, and wounding treatment on fruiting, this report describes the most efficient protocol for inducing fruiting of W. extensa growing on agar plates. Furthermore, several biological characteristics of teleomorph, such as the locations of hymenium, the configuration of basidiospores and primary mycelia, and events involved in basidiosporogenesis in W. extensa, were analyzed for the first time using fluorescence microscopy. The results showed that the hymenium born on both sides of the wall of the honeycomb-like structure on the surface of fruiting bodies and the hymenophoral trama situated in the middle. Each basidia has 4 binuclear basidiospores, and the primary mycelia are multinucleate without clamp connections. These results broaden our knowledge about this brown rot fungus and promote further studies of the sexual reproduction, fruiting body development, and advancement of breeding program, new topics related to the contents of pharmacologically active substances in W. extensa fruiting bodies. PMID- 25271979 TI - Effects of medium components and culture conditions on mycelial biomass and the production of bioactive ingredients in submerged culture of Xylaria nigripes (Ascomycetes), a Chinese medicinal fungus. AB - The optimal culture conditions were investigated to maximize the production of mycelial biomass and bioactive ingredients in submerged cultivation of Xylaria nigripes, a Chinese medicinal fungus. The one-factor-at-a-time method was used to explore the effects of medium components, including carbon, nitrogen, mineral sources, and initial pH of the medium and environmental factors, such as culture temperature and rotation speed, on mycelial growth and production of bioactive ingredients. The results indicated that the optimal culture temperature and rotation speed were 25 degrees C and 100 rpm in a medium with 20 g fructose, 6 g yeast extract, and 2 g magnesiun sulfate heptahydrate as carbon, nitrogen, and mineral sources, respectively, in 1 L distilled water with an initial medium pH of 5.5. With optimal medium components and conditions of cultivation, the maximal production of mycelial biomass was 6.64 +/- 0.88 g/L, with maximal production of bioactive ingredients such as extracellular polysaccharides (2.36 +/- 0.18 mg/mL), intracellular polysaccharides (2.38 +/- 0.07 mg/g), adenosine (43.27 +/- 2.37 mg/g), total polyphenols (36.57 +/- 1.36 mg/g), and triterpenoids (31.29 +/- 1.17 mg/g) in a shake flask culture. These results suggest that different bioactive ingredients including intracellular polysaccharides, adenosine, total polyphenols and triterpenoids in mycelia and extracellular polysaccharides in broth can be obtained from one simple medium for submerged cultivation of X. nigripes. PMID- 25271980 TI - Cloning of mating-type gene MAT1-1 from the caterpillar medicinal mushroom, Cordyceps militaris (Ascomycetes) using TAIL-PCR technology. AB - Cordyceps militaris and Ophiocordyceps sinensis (syn. Cordyceps sinensis), 2 well known traditional Chinese medicines, contain the same bioactive components and share a similar developmental process. In this study, one C. militaris strain preserved in our laboratory was proven to be a MAT1 mating-type strain using a polymerase chain reaction-based mating-type assay. A 5000-bp nucleotide sequence of the mating-type MAT1-1 from C. militaris was amplified by thermal asymmetric interlaced polymerase chain reaction, but genes within the mating-type MAT1-2 remain undetectable. Sequence analysis shows that the mating-type gene MAT1-1 idiomorph contains 2 genes, MAT1-1-1 and MAT1-1-2. The MAT1-1-1 gene consists of 1480-bp nucleotides that encode 456 amino acids and contain the conserved a-box domain interrupted by 2 introns; the MAT1-1-2 gene consists of 1066 nucleotides that encode 377 amino acids interrupted by one intron. The intervening distance between MAT1-1-1 and MAT1-1-2 is 778 bp. The C. militaris MAT1-1 idiomorph organization is the same as that of Cordyceps takaomontana. The MAT1-1 mating type idiomorph of both Cordyceps species lacks the MAT1-1-3 gene, which is typically present in Pyrenomycetes. These studies provide some insights for further study of the morphological development of C. militaris and will eventually benefit the domestication of O. sinensis. PMID- 25271981 TI - Purification, characterization, and antioxidant activities of selenium-containing proteins and polysaccharides in royal sun mushroom, Agaricus brasiliensis (Higher Basidiomycetes). AB - The Agaricus brasiliensis proves to be the main source of many minerals, especially selenium (Se). In this study, Se-containing polysaccharides and proteins were isolated, purified, and characterized. The 1,1-diphenyl-2 picrylhydrazyl (DPPH) and hydroxyl radical scavenging activity of Se-containing proteins and polysaccharides were also studied. Selenium in A. brasiliensis is present mostly in organic forms, accounting for 81.57% of the total Se. The organic forms of selenium mainly present in Se proteins account for 73.53%, while 12.23% is in Se polysaccharides. Two Se-containing proteins (AB-SePA-22) and (AB SePG-22) with Se contents of 4.935 ug/g and 6.083 ug/g were obtained. AB-SePA-22 appeared as four bands with molecular masses of 16.7, 21.7, 26.3, and 33.6 kDa, respectively. The Se content of the three Se-containing polysaccharides, namely AB-SeP-1, AB-SeP-2, and AB-SeP-3, were 1.911, 0.613, and 0.671 ug/g, respectively. AB-SeP-1 (3.1*103 Da) was composed of glucose and galactose in a 7.494:1 molar ratio, whereas AB-SeP-2 (2.1*104 Da and 3.5*104 Da) and AB-SeP-3 (1.1*105 Da) were composed of glucose, galactose, and mannose with molar ratios of 27.01:1.55:1 and 9.805:1:1.22, respectively. Moreover, crude Se polysaccharide and total soluble Se protein had good antioxidant activities on scavenging DPPH and hydroxyl radical, and further research is needed. PMID- 25271982 TI - HS/GC-MS analyzed chemical composition of the aroma of fruiting bodies of two species of genus Lentinus (Higher Basidiomycetes). AB - The chemical composition of the aroma of fresh fruiting bodies of the cultivated mushroom Lentinus boryanus is described here and compared with medicinal shiitake mushroom L. edodes. Volatile compounds were analyzed through headspace sampling coupled with gas chromatography-mass spectrometry. The mushrooms under study were grown on different substrates based on barley straw, sugarcane bagasse, oak wood sawdust, and beech leaf litter. It was determined that L. boryanus as well as L. edodes contain an abundant amount of a volatile compound identified as 3-octanone with a sweet fruity aroma. On the other hand, only L. boryanus produced 3-octanol a characteristic aroma of cod liver oil. In total, 10 aromatic compounds were identified, some of which were obtained exclusively in one species or substrate. PMID- 25271983 TI - A comparative study of the antimicrobial, antioxidant, and cytotoxic activities of methanol extracts from fruit bodies and fermented mycelia of caterpillar medicinal mushroom Cordyceps militaris (Ascomycetes). AB - Cordyceps militaris is one of the most popular mushrooms and nutraceuticals in Eastern Asia. This study assayed and compared the antimicrobial, antioxidant, and cytotoxic properties of the methanol extracts from fruiting bodies and fermented mycelia of C. militaris, as well as the contents of total phenol, flavonoids, and cordycepin. The results showed that the extracts from fruiting bodies possessed broad antimicrobial activities against all microorganisms tested (both bacteria and fungi), whereas that from the fermented mycelia showed selective activity. The antioxidant potential of two extracts is significant in the four tested systems in vitro, including total antioxidant capacity, scavenging abilities on 1,1-diphenyl-2-picrylhydrazyl (DPPH.) radicals, reducing power, and chelating ability on ferrous ions. The fruiting bodies had stronger DPPH. radical scavenging activity, whereas the fermented mycelia had stronger total antioxidant capacity, chelating ability, and reducing power, which suggested that they had their own role and worked in different ways. Both extracts present strong activities against tumor cell line A549. The results obtained indicated that extracts from C. militaris might be valuable antimicrobial, antioxidant, and cytotoxic natural sources and seemed to be applicable in health and medicine as well as in the food industry. PMID- 25271984 TI - Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: a preliminary clinical trial. AB - This preliminary randomized study investigated the efficacy of medicinal mushrooms, Trametes versicolor (TV), Ganoderma lucidum (GL), and Laetiporus sulphureus (LS), on the clearance of oral human papillomavirus (HPV, serotypes 16 and 18). Among 472 patients who underwent oral swabs for gingivitis, 61 patients were positive for HPV16 or HPV18. Twenty patients were included in group 1 (LS) and 41 patients were included in group 2 (TV+GL) for 2 months. Polymerase chain reaction (PCR) for HPV was performed at inclusion and after 2 months. In group 1, the clearance was equal to 5% after 2 months of treatment. In group 2, the clearance was equal to 88% (P<0.001). The detection of HPV16 or HPV18 could become relevant in routine since positivity is frequent and because a harmless and costless treatment may exist. The use of TV+GL for the clearance of oral HPV deserves further investigation. PMID- 25271985 TI - Modulatory effect of crude aqueous extract of Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Higher Basidiomycetes), on hematological and antioxidant indices in Plasmodium berghei-infected mice. AB - Hematological and antioxidant effects of the aqueous extract of fruiting bodies of Ganoderma lucidum were evaluated in Plasmodium berghei-infected mice. Extract was administered at doses of 100, 250, and 500 mg/kg body weight by an intragastric tube once daily for 14 d starting from the fourth day after parasite inoculation. At the end of treatment period, mice in each group were sacrificed and blood was collected for hematological and biochemical analyses. A significant (P<0.05) decrease was observed in serum malondialdehyde content with a corresponding significant (P<0.05) increase in superoxide dismutase, glutathione peroxidase, glutathione S-transferase, and glucose 6-phosphate dehydrogenase activities in the extract-treated groups compared to the infected but untreated group. The results obtained suggest that crude aqueous extract of G. lucidum fruiting bodies possesses potent antioxidant activity that protects hemoglobin against Plasmodium-induced oxidative damage. These findings seem to justify the use of the plant in traditional African and Chinese medicine as an anti inflammatory and antimicrobial agent. PMID- 25271987 TI - Do dielectric nanostructures turn metallic in high-electric dc fields? AB - Three-dimensional dielectric nanostructures have been analyzed using field ion microscopy (FIM) to study the electric dc field penetration inside these structures. The field is proved to be screened within a few nanometers as theoretically calculated taking into account the high-field impact ionization process. Moreover, the strong dc field of the order of 0.1 V/A at the surface inside a dielectric nanostructure modifies its band structure leading to a strong band gap shrinkage and thus to a strong metal-like optical absorption near the surface. This metal-like behavior was theoretically predicted using first principle calculations and experimentally proved using laser-assisted atom probe tomography (APT). This work opens up interesting perspectives for the study of the performance of all field-effect nanodevices, such as nanotransistor or super capacitor, and for the understanding of the physical mechanisms of field evaporation of dielectric nanotips in APT. PMID- 25271986 TI - Gemcitabine induces poly (ADP-ribose) polymerase-1 (PARP-1) degradation through autophagy in pancreatic cancer. AB - Poly (ADP-ribose) polymerase-1 (PARP-1) and autophagy play increasingly important roles in DNA damage repair and cell death. Gemcitabine (GEM) remains the first line chemotherapeutic drug for pancreatic cancer (PC). However, little is known about the relationship between PARP-1 expression and autophagy in response to GEM. Here we demonstrate that GEM induces DNA-damage response and degradation of mono-ADP ribosylated PARP-1 through the autophagy pathway in PC cells, which is rescued by inhibiting autophagy. Hypoxia and serum starvation inhibit autophagic activity due to abrogated GEM-induced mono-ADP-ribosylated PARP-1 degradation. Activation of extracellular regulated protein kinases (ERK) induced by serum starvation shows differences in intracellular localization as well as modulation of autophagy and PARP-1 degradation in GEM-sensitive KLM1 and -resistant KLM1-R cells. Our study has revealed a novel role of autophagy in PARP-1 degradation in response to GEM, and the different impacts of MEK/ERK signaling pathway on autophagy between GEM-sensitive and -resistant PC cells. PMID- 25271988 TI - Glutamatergic dysregulation in pediatric psychiatric disorders: a systematic review of the magnetic resonance spectroscopy literature. AB - OBJECTIVE: As the major excitatory neurotransmitter in the brain, glutamate plays a critical role in normal brain function; thus, its dysregulation could lead to psychopathology in youth. A growing body of literature has investigated the role of glutamate in the pathophysiology of childhood psychiatric disorders through magnetic resonance spectroscopy (MRS). The aim of this study was to review the existing literature to gauge the specificity of such findings. DATA SOURCES: PubMed was searched for all scientific, peer-reviewed articles published in English that included MRS measurements of glutamatergic metabolites in pediatric psychiatric populations through August 14, 2013. STUDY SELECTION: 50 articles were included in this review. These studies included measurements of glutamate or related metabolites with MRS in children with psychiatric disorders. DATA EXTRACTION: All relevant data (eg, population; number, sex, and age of subjects; method of comparison; treatment history; MRS Tesla; brain regions of interest; glutamatergic findings; other findings; and comorbidities) were extracted from the included articles. The direction and significance of glutamate dysregulation and brain region(s) examined were used to compare the studies. RESULTS: Most consistently, increases in glutamatergic metabolites were found in the anterior cingulate cortex (ACC) and other regions in youth with attention deficit/hyperactivity disorder (ADHD). Limited data suggested increases in glutamatergic metabolites in youth with autism spectrum disorders, emotional dysregulation, and high risk for schizophrenia and decreases in youth with major depression, bipolar disorder, and obsessive-compulsive disorder. There was limited but consistent evidence for normalization of glutamatergic levels with treatment, particularly in bipolar disorder and ADHD. CONCLUSIONS: A relatively small number of studies have examined the role of glutamatergic dysregulation in pediatric psychiatric disorders. Some consistencies can be found, but interpretation of the data is limited by differences in methodology, including age of subjects, severity of current symptoms, treatment, and scanning parameters. PMID- 25271990 TI - A new natural nucleotide and other antibacterial metabolites from an endophytic Nocardia sp. AB - Nine compounds were isolated from Nocardia sp. YIM 64630, and their structures were elucidated as 5'-O-acetyl-2'-deoxyuridine (1), 22E,24R-5alpha,6alpha epoxyergosta-8(14),22-diene-3beta,7alpha-diol (2), 22E,24R-5alpha,6alpha epoxyergosta-8,22-diene-3beta,7alpha-diol (3), 22E,24R-ergosta-7,22-diene 3beta,5alpha,6beta-triol (4), 5alpha,8alpha-epidioxyergosta-6,22-dien-3beta-ol (5), 4',5,6-trihydroxy-7-methoxyisoflavone (6), 2,4,4'-trihydroxy-deoxybenzoin (7), methyl [4-hydroxyphenyl]acetate (8) and daidzein by extensive spectroscopic analyses. Compound 1 was isolated from natural resources for the first time. The antimicrobial and antioxidant activities of compounds 1-8 were investigated. PMID- 25271989 TI - Interruption of Wnt signaling in Muller cells ameliorates ischemia-induced retinal neovascularization. AB - Retinal Muller cells are major producers of inflammatory and angiogenic cytokines which contribute to diabetic retinopathy (DR). Over-activation of the Wnt/beta catenin pathway has been shown to play an important pathogenic role in DR. However, the roles of Muller cell-derived Wnt/beta-catenin signaling in retinal neovascularization (NV) and DR remain undefined. In the present study, mice with conditional beta-catenin knockout (KO) in Muller cells were generated and subjected to oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetes. Wnt signaling was evaluated by measuring levels of beta-catenin and expression of its target genes using immunoblotting. Retinal vascular permeability was measured using Evans blue as a tracer. Retinal NV was visualized by angiography and quantified by counting pre-retinal nuclei. Retinal pericyte loss was evaluated using retinal trypsin digestion. Electroretinography was performed to examine visual function. No abnormalities were detected in the beta catenin KO mice under normal conditions. In OIR, retinal levels of beta-catenin and VEGF were significantly lower in the beta-catenin KO mice than in littermate controls. The KO mice also had decreased retinal NV and vascular leakage in the OIR model. In the STZ-induced diabetic model, disruption of beta-catenin in Muller cells attenuated over-expression of inflammatory cytokines and ameliorated pericyte dropout in the retina. These findings suggest that Wnt signaling activation in Muller cells contributes to retinal NV, vascular leakage and inflammation and represents a potential therapeutic target for DR. PMID- 25271991 TI - Comparison of Intraocular Pressure Measurements between Icare Pro Rebound Tonometer and Tono-Pen XL Tonometer in Supine and Lateral Decubitus Body Positions. AB - PURPOSE: To compare intraocular pressure (IOP) measurements obtained using the Icare Pro rebound tonometer and Tono-Pen XL tonometer in supine and lateral decubitus body positions. METHODS: One-hundred eyes of 50 subjects (normal volunteers or glaucoma suspects) were enrolled in this prospective observational study. IOP was measured in both eyes using the Icare Pro and Tono-Pen XL in the sitting position and the recumbent positions including supine, right lateral decubitus and left lateral decubitus. IOP was measured five minutes after assuming each of the recumbent postures in a randomized sequence. The eye on the lower side in the lateral decubitus position was termed as the dependent eye. Agreement of IOP readings between the Icare Pro and Tono-Pen was assessed in all recumbent positions. Differences of IOP readings (DeltaIOP) between the two tonometers and their correlations with ocular parameters were also assessed in all positions. RESULTS: The IOP readings obtained using Icare Pro and Tono-Pen showed good correlations in supine and lateral decubitus positions (all r > 0.7, p < 0.005), although Icare Pro readings were higher than Tono-Pen readings (all p < 0.001) in all positions. The DeltaIOP showed a weakly positive correlation with central corneal thickness in both eyes, whereas such a positive correlation was found only in the dependent eye in the lateral decubitus positions (r = 0.307 0.531, all p < 0.005). Both the spherical equivalents and axial lengths were not correlated with DeltaIOP in all positions. CONCLUSION: IOP readings obtained with Tono-Pen and Icare Pro tonometers showed good agreement in supine as well as in lateral decubitus positions, although Icare readings were higher than Tono-Pen readings in all positions. Such differences in IOP readings between the different tonometers need to be considered when measuring IOPs in various body positions. PMID- 25271992 TI - Blood typing profile of a school-aged population of a North Togo township. AB - The aim of this study was the determination of hemoglobin (Hb) variants and ABO blood groups in a school population aged 6 to 9 years in the township of Agbande Yaka in North Togo. A cross-sectional study was carried out on 570 children of four primary schools at Agbande-Yaka, between March and July 2010. Hemoglobin characterization was done by alkaline buffer electrophoresis and the blood types ABO-Rhesus (Rh) D by immuno-hematological methods. A Hb variant was detected in 37.0% of the schoolchildren. Among them, the AS trait accounted for 11.9% and the AC trait for 20.2%. Homozygous Hb S (HBB: c.20A>T) was not found but Hb C (HBB: c.19G>A) appeared at a frequency of 3.3%, while compound heterozygotes carrying Hb SC were seen at a frequency of 1.6%. The O, B and A blood groups accounted for 49.0, 26.8 and 21.9%, respectively. The Hb anomalies reached a high prevalence in this school population. These results are remarkable by the absence of homozygous Hb S individuals compared to homozygous Hb C individuals, which were as numerous as expected. The frequencies of the ABO blood groups are similar to what has been found in other West African populations. PMID- 25271993 TI - Priapism, an emerging complication in beta-thalassemia intermedia patients. AB - The increase in survival rate of beta-thalassemia (beta-thal) patients allowed for the appearance and manifestation of several complications in almost every organ system. Priapism in beta-thal patients is rarely reported in the literature. We herein report and investigate the occurrence of two cases of priapism in two young patients with beta-thal intermedia (beta-TI). The potential mechanisms are due to either a cellular mechanism involving a thrombus obstructing the efferent venules of the corpora cavernosa leading to priapism, or a recently elucidated functional mechanism that causes alteration of nitric oxide (NO) response of the penis, ultimately causing priapism. This should incite clinicians for a close follow-up and monitoring of high risk patients who are susceptible to developing priapism. PMID- 25271994 TI - Two new gamma chain variants: Hb F-Augusta GA [(G)gamma59(E3)Lys -> Arg; HBG2: c.179A > G] and Hb F-Port Royal-II [(A)gamma125(H3)Glu -> Ala; HBG1: c.377A > C]. AB - The total number of hemoglobin (Hb) variants so far reported to the HbVar database is 1598 (April 9 2014) and 130 of them are fetal Hb variants. Fetal Hb are categorized as two different subunits, (G)gamma- and (A)gamma-globin chains, and gamma chain variants can be observed in both subunits. There are 72 (G)gamma- and 58 (A)gamma-globin chain variants. Most of them are clinically silent and detected during newborn screening programs in the USA and outside the USA. In this report, we discuss the molecular characteristics and diagnostic difficulties of two new gamma-globin chain variants found in an African American baby with no clinical symptoms. One is a new (G)gamma-globin chain variant, Hb F-Augusta GA [(G)gamma59(E3)Lys -> Arg; HBG2: c.179A > G] and the other one is Hb F-Port Royal II [(A)gamma125(H3)Glu -> Ala; HBG1: c.377A > C]. PMID- 25271996 TI - Dual application of (aqua)(chlorido)(porphyrinato)chromium(III) as hypersensitive amine-triggered ON switch and for dioxygen activation. AB - Although synthesis and substitution reactions of chlorido chromium(III) porphyrins Cr(III)(TPP)(Cl)(L) (H2TPP = 5,10,15,20-tetraphenyl porphyrin, L = pyridine, H2O, ROH, etc.), have been well-established in coordination chemistry for decades, an unexpected dichotomous reactivity of Cr(III)(TPP)(Cl)(H2O) (1) toward amines is disclosed here. This reactivity leads to the application of 1 as highly sensitive substoichiometric and irreversible ON switch for amine detection by an autocatalytic pathway. The concomitant activation of O2 by the 1/amine system is furthermore exploited in an electrochemically driven epoxidation of norbonene using O2 as initial oxidant. PMID- 25271995 TI - Cloning and characterization of tesk1, a novel spermatogenesis-related gene, in the tongue sole (Cynoglossus semilaevis). AB - Testis-specific protein kinase 1 (Tesk1) is a serine/threonine kinase with unique structural features. In the present study, we cloned and characterized the tesk1 gene of tongue sole, Cynoglossus semilaevis. The full-length tesk1 cDNA consists of 1,672 nucleotides, encoding a 331 amino acid polypeptide with a characteristic structure composed of an N-terminal kinase domain and a C-terminal proline-rich domain. The tesk1 genomic sequence contains eight exons and seven introns. Real time quantitative PCR revealed that tesk1 mRNA is expressed predominantly in the testis, though the level of expression varied throughout development. We used in situ hybridization to show that tesk1 mRNA is expressed in the spermatids of males and pseudo-males, but not in triploid males. Our results suggest that tongue sole Tesk1 may play a role in spermatogenesis. PMID- 25271998 TI - Willingness to pay... What??? PMID- 25271997 TI - Non-traumatic myositis ossificans in the lumbar spine. AB - BACKGROUND: Myositis ossificans is a non-neoplastic benign reactive bone and cartilage matrix-producing pseudotumor that develops in skeletal muscles adjacent to the joint. The clinical and pathologic appearance of myositis ossificans varies depending on the time elapsed after heterotopic bone formation. Although its etiology is unclear, it usually occurs at the site of the injured muscle, most commonly in large muscles of the extremities, especially the quadriceps and brachialis. It rarely occurs in the paravertebral muscle of the lumbar spine. CASE REPORT: We present the rare case of a 31-year-old Turkish man with calcifying myositis ossificans not associated with trauma, referred to our hospital with severe low back pain with restriction of low back motions. Radiological investigation suggested a sclerotic osteoblastic on the left facet joint of L4-5. To confirm the diagnosis, the patient was managed surgically by total excision of the mass, which resulted in a good functional recovery. At his 12-month follow-up examination, he was neurologically intact and no recurrence was seen. CONCLUSIONS: Cases like this should be investigated well, so careful correlation of the clinical and radiologic findings with taking a biopsy is necessary to confirm diagnosis. PMID- 25271999 TI - Effects of underwater birth on the newborn. PMID- 25272000 TI - Physical training for asthma. AB - BACKGROUND: People with asthma may show less tolerance to exercise due to worsening asthma symptoms during exercise or other reasons such as deconditioning as a consequence of inactivity. Some may restrict activities as per medical advice or family influence and this might result in reduced physical fitness. Physical training programs aim to improve physical fitness, neuromuscular coordination and self confidence. Subjectively, many people with asthma report that they are symptomatically better when fit, but results from trials have varied and have been difficult to compare because of different designs and training protocols. Also, as exercise can induce asthma, the safety of exercise programmes needs to be considered. OBJECTIVE: To gain a better understanding of the effect of physical training on the respiratory and general health of people with asthma, from randomised trials. METHODS: SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials up to January 2013. SELECTION CRITERIA: We included randomised trials of people over eight years of age with asthma who were randomised to undertake physical training or not. Physical training had to be undertaken for at least 20 minutes, two times a week, over a minimum period of four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility for inclusion and undertook risk of bias assessment for the included studies. MAIN RESULTS: Twenty-one studies (772 participants) were included in this review with two additional 2012 studies identified as 'awaiting classification'. Physical training was well tolerated with no adverse effects reported. None of the studies mentioned worsening of asthma symptoms following physical training. Physical training showed marked improvement in cardiopulmonary fitness as measured by a statistically and clinically significant increase in maximum oxygen uptake (mean difference (MD) 4.92 mL/kg/min; 95% confidence interval (CI) 3.98 to 5.87; P < 0.00001; 8 studies on 267 participants); however, no statistically significant effects were observed for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), minute ventilation at maximal exercise (VEmax) or peak expiratory flow rate (PEFR). Meta-analysis of four studies detected a statistically significant increase in maximum heart rate, and following a sensitivity analysis and removal of two studies significance was maintained (MD 3.67 bpm; 95% CI 0.90 to 3.44; P = 0.01). Although there were insufficient data to pool results due to diverse reporting tools, there was some evidence to suggest that physical training may have positive effects on health-related quality of life, with four of five studies producing a statistically and clinically significant benefit. AUTHORS' CONCLUSIONS: This review demonstrated that physical training showed significant improvement in maximum oxygen uptake, though no effects were observed in other measures of pulmonary function. Physical training was well tolerated among people with asthma in the included studies and, as such, people with stable asthma should be encouraged to participate in regular exercise training, without fear of symptom exacerbation. More research is needed to understand the mechanisms by which physical activity impacts asthma management. PMID- 25272001 TI - Exercise programs for people with dementia. AB - BACKGROUND: This is an update of our previous 2008 review. Several recent trials and systematic reviews of the impact of exercise on people with dementia are reporting promising findings. OBJECTIVE: Primary: Do exercise programs for older people with dementia improve cognition, activities of daily living (ADLs), challenging behaviour, depression, and mortality in older people with dementia? Secondary: Do exercise programs for older people with dementia have an indirect impact on family caregivers' burden, quality of life, and mortality? Do exercise programs for older people with dementia reduce the use of healthcare services (e.g. visits to the emergency department) by participants and their family caregivers? METHODS: SEARCH METHODS: We identified trials for inclusion in the review by searching ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, on 4 September 2011, and again on 13 August 2012. The search terms used were: 'physical activity' OR exercise OR cycling OR swim* OR gym* OR walk* OR danc* OR yoga OR 'tai chi'. SELECTION CRITERIA: In this review, we included randomized controlled trials in which older people, diagnosed with dementia, were allocated either to exercise programs or to control groups (usual care or social contact/activities) with the aim of improving cognition, ADLs, behaviour, depression, and mortality. Secondary outcomes related to the family caregiver(s) and included caregiver burden, quality of life, mortality, and use of healthcare services. DATA COLLECTION AND ANALYSIS: Independently, at least two authors assessed the retrieved articles for inclusion, assessed methodological quality, and extracted data. Data were analysed for summary effects using RevMan 5.1 software. We calculated mean differences or standardized mean difference (SMD) for continuous data, and synthesized data for each outcome using a fixed-effect model, unless there was substantial heterogeneity between studies, when we used a random-effects model. We planned to explore heterogeneity in relation to severity and type of dementia, and type, frequency, and duration of exercise program. We also evaluated adverse events. MAIN RESULTS: Sixteen trials with 937 participants met the inclusion criteria. However, the required data from three trials and some of the data from a fourth trial were not published and not made available. The included trials were highly heterogeneous in terms of subtype and severity of participants' dementia, and type, duration and frequency of exercise. Only two trials included participants living at home. Our meta-analysis suggested that exercise programs might have a significant impact on improving cognitive functioning (eight trials, 329 participants; SMD 0.55, 95% confidence interval (CI) 0.02 to 1.09). However, there was substantial heterogeneity between trials (I 2 value 80%), most of which we were unable to explain. We repeated the analysis omitting one trial, an outlier, that included only participants with moderate or severe dementia. This reduced the heterogeneity somewhat (I2 value 68%), and produced a result that was no longer significant (seven trials, 308 participants; SMD 0.31, 95% CI -0.11 to 0.74). We found a significant effect of exercise programs on the ability of people with dementia to perform ADLs (six studies, 289 participants; SMD 0.68, 95% CI 0.08 to 1.27). However, again we observed considerable unexplained statistical heterogeneity (I2 value 77%) in this meta-analysis. This means that there is a need for caution in interpreting these findings. In further analyses, we found that the burden experienced by informal caregivers providing care in the home may be reduced when they supervise the participation of the family member with dementia in an exercise program (one study, 40 participants; MD -15.30, 95% CI -24.73 to -5.87), but we found no significant effect of exercise on challenging behaviours (one study, 110 participants; MD -0.60, 95% CI -4.22 to 3.02), or depression (six studies, 341 participants; MD -0.14, 95% CI -0.36 to 0.07). We could not examine the remaining outcomes, quality of life, mortality, and healthcare costs, as either the appropriate data were not reported, or we did not retrieve trials that examined these outcomes. AUTHORS' CONCLUSIONS: There is promising evidence that exercise programs can have a significant impact in improving ability to perform ADLs and possibly in improving cognition in people with dementia, although some caution is advised in interpreting these findings. The programs revealed no significant effect on challenging behaviours or depression. There was little or no evidence regarding the remaining outcomes of interest. PMID- 25272002 TI - A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity. AB - Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred. PMID- 25272003 TI - Population distribution of the sagittal abdominal diameter (SAD) from a representative sample of US adults: comparison of SAD, waist circumference and body mass index for identifying dysglycemia. AB - BACKGROUND: The sagittal abdominal diameter (SAD) measured in supine position is an alternative adiposity indicator that estimates the quantity of dysfunctional adipose tissue in the visceral depot. However, supine SAD's distribution and its association with health risk at the population level are unknown. Here we describe standardized measurements of SAD, provide the first, national estimates of the SAD distribution among US adults, and test associations of SAD and other adiposity indicators with prevalent dysglycemia. METHODS AND FINDINGS: In the 2011-2012 National Health and Nutrition Examination Survey, supine SAD was measured ("abdominal height") between arms of a sliding-beam caliper at the level of the iliac crests. From 4817 non-pregnant adults (age >= 20; response rate 88%) we used sample weights to estimate SAD's population distribution by sex and age groups. SAD's population mean was 22.5 cm [95% confidence interval 22.2-22.8]; median was 21.9 cm [21.6-22.4]. The mean and median values of SAD were greater for men than women. For the subpopulation without diagnosed diabetes, we compared the abilities of SAD, waist circumference (WC), and body mass index (BMI, kg/m(2)) to identify prevalent dysglycemia (HbA1c >= 5.7%). For age-adjusted, logistic-regression models in which sex-specific quartiles of SAD were considered simultaneously with quartiles of either WC or BMI, only SAD quartiles 3 (p<0.05 vs quartile 1) and 4 (p<0.001 vs quartile 1) remained associated with increased dysglycemia. Based on continuous adiposity indicators, analyses of the area under the receiver operating characteristic curve (AUC) indicated that the dysglycemia model fit for SAD (age-adjusted) was 0.734 for men (greater than the AUC for WC, p<0.001) and 0.764 for women (greater than the AUC for WC or BMI, p<0.001). CONCLUSIONS: Measured inexpensively by bedside caliper, SAD was associated with dysglycemia independently of WC or BMI. Standardized SAD measurements may enhance assessment of dysfunctional adiposity. PMID- 25272004 TI - Community structure of skipper butterflies (Lepidoptera, Hesperiidae) along elevational gradients in Brazilian Atlantic forest reflects vegetation type rather than altitude. AB - Species turnover across elevational gradients has matured into an important paradigm of community ecology. Here, we tested whether ecological and phylogenetic structure of skipper butterfly assemblages is more strongly structured according to altitude or vegetation type along three elevation gradients of moderate extent in Serra do Mar, Southern Brazil. Skippers were surveyed along three different mountain transects, and data on altitude and vegetation type of every collection site were recorded. NMDS ordination plots were used to assess community turnover and the influence of phylogenetic distance between species on apparent community patterns. Ordinations based on ecological similarity (Bray-Curtis index) were compared to those based on phylogenetic distance measures (MPD and MNTD) derived from a supertree. In the absence of a well-resolved phylogeny, various branch length transformation methods were applied together with four different null models, aiming to assess if results were confounded by low-resolution trees. Species composition as well as phylogenetic community structure of skipper butterflies were more prominently related to vegetation type instead of altitude per se. Phylogenetic distances reflected spatial community patterns less clearly than species composition, but revealed a more distinct fauna of monocot feeders associated with grassland habitats, implying that historical factors have played a fundamental role in shaping species composition across elevation gradients. Phylogenetic structure of community turned out to be a relevant additional tool which was even superior to identify faunal contrasts between forest and grassland habitats related to deep evolutionary splits. Since endemic skippers tend to occur in grassland habitats in the Serra do Mar, inclusion of phylogenetic diversity may also be important for conservation decisions. PMID- 25272006 TI - Ten-year experience of remote medical education in Asia. AB - BACKGROUND: Moving images are often essential in medical education, to learn new procedures and advanced skills, but, in the past, high-quality movie transmission was technically much more challenging than transmitting still pictures because of technological limitations and cost. MATERIALS AND METHODS: We established a new system, taking advantage of two advanced technologies, the digital video transport system (DVTS) and the research and education network (REN), which enabled satisfactory telemedicine on a routine basis. RESULTS: Between 2003 and 2013, we organized 360 programs connecting 221 hospitals or facilities in 34 countries in Asia and beyond. The two main areas were endoscopy and surgery, with 113 (31%) and 106 (29%) events, respectively. Teleconferences made up 76% of the total events, with the remaining 24% being live demonstrations. Multiple connections were more popular (63%) than one-to-one connections (37%). With continuous technological development, new high-definition H.323 and Vidyo((r)) (Hackensack, NJ) systems were used in 47% and 39% of events in 2011 and 2012, respectively. The evaluation by questionnaires was favorable on image and sound quality as well as programs. CONCLUSIONS: Remote medical education with moving images was well accepted in Asia with changing needs and developing technologies. PMID- 25272005 TI - Identification of host-immune response protein candidates in the sera of human oral squamous cell carcinoma patients. AB - One of the most common cancers worldwide is oral squamous cell carcinoma (OSCC), which is associated with a significant death rate and has been linked to several risk factors. Notably, failure to detect these neoplasms at an early stage represents a fundamental barrier to improving the survival and quality of life of OSCC patients. In the present study, serum samples from OSCC patients (n = 25) and healthy controls (n = 25) were subjected to two-dimensional gel electrophoresis (2-DE) and silver staining in order to identify biomarkers that might allow early diagnosis. In this regard, 2-DE spots corresponding to various up- and down-regulated proteins were sequenced via high-resolution MALDI-TOF mass spectrometry and analyzed using the MASCOT database. We identified the following differentially expressed host-specific proteins within sera from OSCC patients: leucine-rich alpha2-glycoprotein (LRG), alpha-1-B-glycoprotein (ABG), clusterin (CLU), PRO2044, haptoglobin (HAP), complement C3c (C3), proapolipoprotein A1 (proapo-A1), and retinol-binding protein 4 precursor (RBP4). Moreover, five non host factors were detected, including bacterial antigens from Acinetobacter lwoffii, Burkholderia multivorans, Myxococcus xanthus, Laribacter hongkongensis, and Streptococcus salivarius. Subsequently, we analyzed the immunogenicity of these proteins using pooled sera from OSCC patients. In this regard, five of these candidate biomarkers were found to be immunoreactive: CLU, HAP, C3, proapo A1 and RBP4. Taken together, our immunoproteomics approach has identified various serum biomarkers that could facilitate the development of early diagnostic tools for OSCC. PMID- 25272009 TI - Great spotted cuckoo fledglings often receive feedings from other magpie adults than their foster parents: which magpies accept to feed foreign cuckoo fledglings? AB - Natural selection penalizes individuals that provide costly parental care to non relatives. However, feedings to brood-parasitic fledglings by individuals other than their foster parents, although anecdotic, have been commonly observed, also in the great spotted cuckoo (Clamator glandarius)--magpie (Pica pica) system, but this behaviour has never been studied in depth. In a first experiment, we here show that great spotted cuckoo fledglings that were translocated to a distant territory managed to survive. This implies that obtaining food from foreign magpies is a frequent and efficient strategy used by great spotted cuckoo fledglings. A second experiment, in which we presented a stuffed-cuckoo fledgling in magpie territories, showed that adult magpies caring for magpie fledglings responded aggressively in most of the trials and never tried to feed the stuffed cuckoo, whereas magpies that were caring for cuckoo fledglings reacted rarely with aggressive behavior and were sometimes disposed to feed the stuffed cuckoo. In a third experiment we observed feedings to post-fledgling cuckoos by marked adult magpies belonging to four different possibilities with respect to breeding status (i.e. composition of the brood: only cuckoos, only magpies, mixed, or failed breeding attempt). All non-parental feeding events to cuckoos were provided by magpies that were caring only for cuckoo fledglings. These results strongly support the conclusion that cuckoo fledglings that abandon their foster parents get fed by other adult magpies that are currently caring for other cuckoo fledglings. These findings are crucial to understand the co-evolutionary arms race between brood parasites and their hosts because they show that the presence of the host's own nestlings for comparison is likely a key clue to favour the evolution of fledgling discrimination and provide new insights on several relevant points such as learning mechanisms and multiparasitism. PMID- 25272008 TI - Drinking patterns and alcohol use disorders in Sao Paulo, Brazil: the role of neighborhood social deprivation and socioeconomic status. AB - BACKGROUND: Research conducted in high-income countries has investigated influences of socioeconomic inequalities on drinking outcomes such as alcohol use disorders (AUD), however, associations between area-level neighborhood social deprivation (NSD) and individual socioeconomic status with these outcomes have not been explored in Brazil. Thus, we investigated the role of these factors on drink-related outcomes in a Brazilian population, attending to male-female variations. METHODS: A multi-stage area probability sample of adult household residents in the Sao Paulo Metropolitan Area was assessed using the WHO Composite International Diagnostic Interview (WMH-CIDI) (n = 5,037). Estimation focused on prevalence and correlates of past-year alcohol disturbances [heavy drinking of lower frequency (HDLF), heavy drinking of higher frequency (HDHF), abuse, dependence, and DMS-5 AUD] among regular users (RU); odds ratio (OR) were obtained. RESULTS: Higher NSD, measured as an area-level variable with individual level variables held constant, showed an excess odds for most alcohol disturbances analyzed. Prevalence estimates for HDLF and HDHF among RU were 9% and 20%, respectively, with excess odds in higher NSD areas; schooling (inverse association) and low income were associated with male HDLF. The only individual level association with female HDLF involved employment status. Prevalence estimates for abuse, dependence, and DSM-5 AUD among RU were 8%, 4%, and 8%, respectively, with excess odds of: dependence in higher NSD areas for males; abuse and AUD for females. Among RU, AUD was associated with unemployment, and low education with dependence and AUD. CONCLUSIONS: Regular alcohol users with alcohol-related disturbances are more likely to be found where area-level neighborhood characteristics reflect social disadvantage. Although we cannot draw inferences about causal influence, the associations are strong enough to warrant future longitudinal alcohol studies to explore causal mechanisms related to the heterogeneous patterns of association and male-female variations observed herein. Hopefully, these findings may help guide future directions for public health. PMID- 25272010 TI - Upregulated UHRF1 promotes bladder cancer cell invasion by epigenetic silencing of KiSS1. AB - Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), as an epigenetic regulator, plays important roles in the tumorigenesis and cancer progression. KiSS1 functions as a metastasis suppressor in various cancers, and epigenetic silencing of KiSS1 increases the metastatic potential of cancer cells. We therefore investigated whether UHRF1 promotes bladder cancer cell invasion by inhibiting KiSS1. The expression levels of UHRF1 and KiSS1 were examined by quantitative real-time PCR assay in vitro and in vivo. The role of UHRF1 in regulating bladder cancer metastasis was evaluated in bladder cancer cell. We found that UHRF1 levels are upregulated in most clinical specimens of bladder cancer when compared with paired normal tissues, and UHRF1 expression levels are significantly increased in primary tumors that subsequently metastasized compared with non-metastatic tumors. Forced expression of UHRF1 promotes bladder cancer cell invasion, whereas UHRF1 knockdown decreases cell invasion. Overexpression of UHRF1 increases the methylation of CpG nucleotides and reduces the expression of KiSS1. UHRF1 and KiSS1 expression level is negatively correlated in vivo and in vitro. Knockdown of KiSS1 promotes bladder cancer cell invasion. Importantly, forced expression of KiSS1 partly abrogates UHRF1-induced cell invasion. These data demonstrated that upregulated UHRF1 increases bladder cancer cell invasion by epigenetic silencing of KiSS1. PMID- 25272011 TI - Effects of electron charge density and particle size of alkali metal titanate nanotube-supported Pt photocatalysts on production of H2 from neat alcohol. AB - Pt nanoparticles (PtNPs) in the range of 1.0-3.0 nm were deposited on alkali titanate nanotubes (MTNTs = M2-xHxTi3O7, M = Li(+), Na(+), K(+) and Cs(+)) by wet impregnation. While most of the physical properties of Pt/MTNTs remained almost constant, the oxidation state and size of PtNPs varied systematically with the size of the cations of MTNTs. XPS indicated that the binding energy of Pt in Pt/MTNTs was reduced to a lower value than that of Pt(0), yielding a Pt(delta-) oxidation state. Diffuse-reflectance infrared Fourier transform spectroscopy coupling with CO adsorption studies confirmed the formation of the Pt(delta-) state in Pt/MTNTs. Thus, electrons were transferred from MTNTs to PtNPs establishing an electric double layer at the interface between PtNP and MTNT supports, and the degree of electron transfer increased with the size of the cations in MTNTs. HRTEM revealed that the mean sizes of PtNPs followed the order, Pt/LiTNTs < Pt/NaTNTs < Pt/KTNTs < Pt/CsTNTs. TPR showed that the reducibility of PtOx/MTNTs determined the order of PtNPs size. In the photocatalytic production of H2 (2H(+) + 2e(-)-> H2), since H2 is produced at the interfacial Pt sites, the electron charge density and the particle size of PtNPs are the two competing factors in producing H2. Photoluminescence studies revealed that the initial increase in electron density on PtNPs reduced the recombination of h(+)-e(-) pairs and increased H2 yields, but a further increase in charge density enhanced the recombination of h(+)-e(-) pairs and lowered the H2 yield. PtNPs in Pt/KTNTs had a moderate charge density and a moderate particle size, and so, produced a maximum amount of H2 among Pt/MTNTs. PMID- 25272012 TI - Structural insights into RNA polymerase recognition and essential function of Myxococcus xanthus CdnL. AB - CdnL and CarD are two functionally distinct members of the CarD_CdnL_TRCF family of bacterial RNA polymerase (RNAP)-interacting proteins, which co-exist in Myxococcus xanthus. While CarD, found exclusively in myxobacteria, has been implicated in the activity of various extracytoplasmic function (ECF) sigma factors, the function and mode of action of the essential CdnL, whose homologs are widespread among bacteria, remain to be elucidated in M. xanthus. Here, we report the NMR solution structure of CdnL and present a structure-based mutational analysis of its function. An N-terminal five-stranded beta-sheet Tudor like module in the two-domain CdnL mediates binding to RNAP-beta, and mutations that disrupt this interaction impair cell growth. The compact CdnL C-terminal domain consists of five alpha-helices folded as in some tetratricopeptide repeat like protein-protein interaction domains, and contains a patch of solvent-exposed nonpolar and basic residues, among which a set of basic residues is shown to be crucial for CdnL function. We show that CdnL, but not its loss-of-function mutants, stabilizes formation of transcriptionally competent, open complexes by the primary sigmaA-RNAP holoenzyme at an rRNA promoter in vitro. Consistent with this, CdnL is present at rRNA promoters in vivo. Implication of CdnL in RNAP sigmaA activity and of CarD in ECF-sigma function in M. xanthus exemplifies how two related members within a widespread bacterial protein family have evolved to enable distinct sigma-dependent promoter activity. PMID- 25272014 TI - A breakthrough in schizophrenia genetics. PMID- 25272013 TI - Hemizygous Le-Cre transgenic mice have severe eye abnormalities on some genetic backgrounds in the absence of LoxP sites. AB - Eye phenotypes were investigated in Le-Cre(Tg/-); Pax6(fl/+) mice, which were expected to show tissue-specific reduction of Pax6 in surface ectoderm derivatives. To provide a better comparison with our previous studies of Pax6(+/ ) eye phenotypes, hemizygous Le-Cre(Tg/-) and heterozygous Pax6(fl/+)mice were crossed onto the CBA/Ca genetic background. After the Le-Cre transgene had been backcrossed to CBA/Ca for seven generations, significant eye abnormalities occurred in some hemizygous Le-Cre(Tg/-); Pax6(+/+) controls (without a floxed Pax6(fl) allele) as well as experimental Le-Cre(Tg/-); Pax6(fl/+) mice. However, no abnormalities were seen in Le-Cre(-/-); Pax6(fl/+) or Le-Cre(-/-); Pax6(+/+) controls (without the Le-Cre transgene). The severity and frequency of the eye abnormalities in Le-Cre(Tg/-); Pax6(+/+) control mice diminished after backcrossing Le-Cre(Tg/-) mice to the original FVB/N strain for two generations, showing that the effect was reversible. This genetic background effect suggests that the eye abnormalities are a consequence of an interaction between the Le-Cre transgene and alleles of unknown modifier genes present in certain genetic backgrounds. The abnormalities were also ameliorated by introducing additional Pax6 gene copies on a CBA/Ca background, suggesting involvement of Pax6 depletion in Le-Cre(Tg/-); Pax6(+/+) mice rather than direct action of Cre recombinase on cryptic pseudo-loxP sites. One possibility is that expression of Cre recombinase from the Pax6-Le regulatory sequences in the Le-Cre transgene depletes cofactors required for endogenous Pax6 gene expression. Our observation that eye abnormalities can occur in hemizygous Le-Cre(Tg/-); Pax6(+/+) mice, in the absence of a floxed allele, demonstrates the importance of including all the relevant genetic controls in Cre-loxP experiments. PMID- 25272015 TI - A new role for carbonic anhydrase 2 in the response of fish to copper and osmotic stress: implications for multi-stressor studies. AB - The majority of ecotoxicological studies are performed under stable and optimal conditions, whereas in reality the complexity of the natural environment faces organisms with multiple stressors of different type and origin, which can activate pathways of response often difficult to interpret. In particular, aquatic organisms living in estuarine zones already impacted by metal contamination can be exposed to more severe salinity variations under a forecasted scenario of global change. In this context, the present study aimed to investigate the effect of copper exposure on the response of fish to osmotic stress by mimicking in laboratory conditions the salinity changes occurring in natural estuaries. We hypothesized that copper-exposed individuals are more sensitive to osmotic stresses, as copper affects their osmoregulatory system by acting on a number of osmotic effector proteins, among which the isoform two of the enzyme carbonic anhydrase (CA2) was identified as a novel factor linking the physiological responses to both copper and osmotic stress. To test this hypothesis, two in vivo studies were performed using the euryhaline fish sheepshead minnow (Cyprinodon variegatus) as test species and applying different rates of salinity transition as a controlled way of dosing osmotic stress. Measured endpoints included plasma ions concentrations and gene expression of CA2 and the alpha1a-subunit of the enzyme Na+/K+ ATPase. Results showed that plasma ions concentrations changed after the salinity transition, but notably the magnitude of change was greater in the copper-exposed groups, suggesting a sensitizing effect of copper on the responses to osmotic stress. Gene expression results demonstrated that CA2 is affected by copper at the transcriptional level and that this enzyme might play a role in the observed combined effects of copper and osmotic stress on ion homeostasis. PMID- 25272016 TI - Physiological performance of quails that underwent dietary and pharmacological manipulation of cholesterol. AB - The present work evaluated whether dietary and pharmacological interference on cholesterol synthesis were capable of inducing alterations in blood and yolk cholesterol levels and the secretion of corticosterone metabolites. Forty-five 40 day-old quails were divided into three experimental groups: vegetal fat diet, 2% beef fat (tallow) diet and vegetal fat diet with simvastatin administration (3.13 mg/kg/day). During all experiments, the animal weights and food consumption were recorded and blood and faecal samples (days 0, 15, 30, 45 and 60), as well as eggs (days 30, 45 and 60), were collected. Analysis of serum and yolk cholesterol was performed and faecal corticosterone levels were measured. No differences were observed on blood cholesterol or faecal corticosterone between all treatments, despite a tendency of increased cholesterol in the group with the animal fat diet. However, quails submitted to an animal fat diet displayed an increase in yolk cholesterol at day 30 of the treatment and the egg yolks of quails treated with simvastatin exhibited a decrease in cholesterol content by the end of the treatment at 60 days. These results improved the knowledge regarding the physiology of quails and offered support to other studies concerning the consequences of the pharmacological treatment and the dietary manipulation of cholesterol levels. PMID- 25272017 TI - UTF1, a putative marker for spermatogonial stem cells in stallions. AB - Spermatogonial stem cells (SSCs) continuously undergo self-renewal and differentiation to sustain spermatogenesis throughout adulthood in males. In stallions, SSCs may be used for the production of progeny from geldings after cryopreservation and therapy for infertile and subfertile stallions. Undifferentiated cell transcription factor 1 (UTF1) is a putative marker for undifferentiated spermatogonia in humans and rats. The main purposes of this study are to determine the following: 1) changes in the expression pattern of UTF1 at various reproductive stages of stallions, 2) subpopulations of spermatogonia that express UTF1. Testicular samples were collected and categorized based on the age of the horses as follows: pre-pubertal (<1 yr), pubertal (1-1.5 yr), post-pubertal (2-3 yr), and adult (4-8 yr). Western blot analysis was utilized to determine the cross-activity of the UTF1 antibody to horse testes tissues. Immunohistochemistry was conducted to investigate the UTF1 expression pattern in germ cells at different reproductive stages. Whole mount staining was applied to determine the subpopulation of UTF1-positive spermatogonia. Immunohistological analysis showed that most germ cells in the pre pubertal and pubertal stages were immunolabeled with UTF1, whereas only a few germ cells in the basal compartment of the seminiferous tubule cross-sections of post-pubertal and adult tissues were UTF1-positive. No staining was observed in the Sertoli or Leydig cells at any reproductive stages. Whole mount staining showed that A(s), A(pr), and chains of 4, 8, 16 A(al) spermatogonia were immunolabeled with UTF1 in the post-pubertal stallion tubule. Isolated single germ cells were also immunolabeled with UTF1. In conclusion, UTF1 is expressed in undifferentiated spermatogonia, and its antibody can be used as a putative marker for SSCs in stallions. PMID- 25272018 TI - Houttuynia cordata alleviates high-fat diet-induced non-alcoholic fatty liver in experimental rats. AB - CONTEXT: Houttuynia cordata Thunb. (Saururaceae) is used traditionally in Asian countries to treat various disease symptoms. OBJECTIVE: To study the effect of H. cordata ethyl acetate (HC-EA) extract on high-fat diet (HFD)-induced hepatic steatosis. MATERIALS AND METHODS: HFD fed rats were orally dosed with HC-EA (100, 200, or 300 mg/kg) once daily for 8 weeks and the lipid profiles and protein expressions in hepatocytes were evaluated. RESULTS: HFD rats showed an increase (p < 0.05) in the plasma lipid levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), free fatty acids (FFAs), and reduced the high-density lipoprotein (HDL) levels. Treatment with HC-EA extract (300 mg/kg) restored the changes in plasma lipid levels of TC, TG, LDL, FFA, and HDL in HFD fed rats by 34.8, 31.1, 51.4, 32.4, and 56.3%, respectively, compared with control rats (p < 0.01). HC-EA treatment also decreased the hepatic lipid accumulation (p < 0.001 at 300 mg/kg) and improved hepatic histological lesions. HC-EA extract enhanced AMPK phosphorylation and its primary downstream targeting enzyme, acetyl-CoA carboxylase (ACC), up-regulated the gene expression of carnitine palmitoyl transferase-1 (CPT-1), and down-regulated sterol regulatory element binding protein 1, fatty acid synthase, and glutamate pyruvate transaminase protein levels in the livers of HFD-fed rats. Further, the increased expression of hepatic cytochrome P450 (CYP) composition such as CYP2E1 and CYP4A was also suppressed. DISCUSSION AND CONCLUSION: Data suggest that HC-EA extract might act by regulating the AMPK-dependent pathway and related mediators and might be used in treating obesity-related liver diseases. PMID- 25272019 TI - Using models of social transmission to examine the spread of longline depredation behavior among sperm whales in the Gulf of Alaska. AB - Fishing, farming and ranching provide opportunities for predators to prey on resources concentrated by humans, a behavior termed depredation. In the Gulf of Alaska, observations of sperm whales depredating on fish caught on demersal longline gear dates back to the 1970s, with reported incidents increasing in the mid-1990s. Sperm whale depredation provides an opportunity to study the spread of a novel foraging behavior within a population. Data were collected during National Marine Fisheries Service longline surveys using demersal longline gear in waters off Alaska from 1998 to 2010. We evaluated whether observations of depredation fit predictions of social transmission by fitting the temporal and spatial spread of new observations of depredation to the Wave of Advance model. We found a significant, positive relationship between time and the distance of new observations from the diffusion center (r(2) = 0.55, p-value = 0.003). The data provide circumstantial evidence for social transmission of depredation. We discuss how changes in human activities in the region (fishing methods and regulations) have created a situation in which there is spatial-temporal overlap with foraging sperm whales, likely influencing when and how the behavior spread among the population. PMID- 25272021 TI - DNA-hosted Hoechst dyes: application for label-free fluorescent monitoring of endonuclease activity and inhibition. AB - A simple and facile approach was developed for monitoring EcoRI endonuclease activity and inhibition, in which a hairpin-like DNA containing restriction cutting site for EcoRI endonuclease acts as the sensing element and Hoechst dyes as the signal indicator in a label-free format. PMID- 25272020 TI - Adenosine deaminase acting on RNA-1 (ADAR1) inhibits HIV-1 replication in human alveolar macrophages. AB - While exploring the effects of aerosol IFN-gamma treatment in HIV-1/tuberculosis co-infected patients, we observed A to G mutations in HIV-1 envelope sequences derived from bronchoalveolar lavage (BAL) of aerosol IFN-gamma-treated patients and induction of adenosine deaminase acting on RNA 1 (ADAR1) in the BAL cells. IFN-gamma induced ADAR1 expression in monocyte-derived macrophages (MDM) but not T cells. ADAR1 siRNA knockdown induced HIV-1 expression in BAL cells of four HIV 1 infected patients on antiretroviral therapy. Similar results were obtained in MDM that were HIV-1 infected in vitro. Over-expression of ADAR1 in transformed macrophages inhibited HIV-1 viral replication but not viral transcription measured by nuclear run-on, suggesting that ADAR1 acts post-transcriptionally. The A to G hyper-mutation pattern observed in ADAR1 over-expressing cells in vitro was similar to that found in the lungs of HIV-1 infected patients treated with aerosol IFN-gamma suggesting the model accurately represented alveolar macrophages. Together, these results indicate that ADAR1 restricts HIV-1 replication post-transcriptionally in macrophages harboring HIV-1 provirus. ADAR1 may therefore contribute to viral latency in macrophages. PMID- 25272022 TI - Degeneration and regeneration of GABAergic interneurons in the dentate gyrus of adult mice in experimental models of epilepsy. AB - AIMS: Mounting evidence showed that GABAergic interneurons play an important role in the generation of seizures by regulating excitatory/inhibitory balance in the hippocampus; however, there is a continuous debate regarding the alteration in the number of hippocampal GABAergic interneurons during epileptogenesis. Here, we investigated the degeneration and regeneration of GABAergic interneurons in the dentate gyrus during epileptogenesis using glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mice. METHODS AND RESULTS: Pentylenetetrazol (PTZ)-induced chronic kindling model and lithium-pilocarpine induced status epilepticus (SE) model were used in this study. We found a progressive loss of GABAergic interneurons in the dentate gyrus during post-SE epileptogenesis rather than PTZ kindling. Both types of epileptogenic insults significantly promoted the proliferation of neural progenitor cells in the dentate gyrus; however, compared to 80% neuronal differentiation ratio in the control group, there was a remarkable decrease in PTZ kindling and pilocarpine models, that is 58% and 29%, respectively. Double/triple immunofluorescence labeling revealed no newborn neurons colabeled with GFP in both intact and epileptic dentate gyrus. In addition, valproate (a first-line antiepileptic drug) treatment prevented the loss of GABAergic interneurons but still failed to induce the regeneration of GAD67-positive interneurons in the dentate gyrus during post SE epileptogenesis. CONCLUSIONS: These results indicate that degeneration of GABAergic interneurons may depend on the type of epileptogenic insult and that no newborn GABAergic interneurons occur in the adult dentate gyrus during epileptogenesis. PMID- 25272025 TI - Probing the kinetic energy-release dynamics of H-atom products from the gas-phase reaction of O(3P) with vinyl radical C2H3. AB - The gas-phase radical-radical reaction dynamics of ground-state atomic oxygen O((3)P) with vinyl radicals C2H3 has been studied by combining the results of vacuum-ultraviolet laser-induced fluorescence spectroscopy in a crossed beam configuration with ab initio calculations. The two radical reactants O((3)P) and C2H3 were produced by photolysis of NO2 and supersonic flash pyrolysis of C2H3I, respectively. Doppler profile analysis of the kinetic energy release of the nascent H-atom products from the title reaction O((3)P) + C2H3-> H((2)S) + CH2CO (ketene) revealed that the average translational energy of the products and the average fraction of the total available energy were 7.03 +/- 0.30 kcal mol(-1) and 7.2%. The empirical data combined with CBS-QB3 level ab initio theory and statistical calculations demonstrated that the title oxygen-hydrogen exchange reaction is a major reaction channel, through an addition-elimination mechanism involving the formation of a short-lived, dynamical complex on the doublet potential energy surface. On the basis of systematic comparison with several exchange reactions of hydrocarbon radicals, the observed kinetic energy release can be explained in terms of the weak impulse at the moment of decomposition in the loose transition state with a product-like geometry and a small reverse barrier along the exit channel. PMID- 25272026 TI - ORS interview with Will Pate. PMID- 25272023 TI - Effects of mefloquine use on Plasmodium vivax multidrug resistance. AB - Numerous studies have indicated a strong association between amplification of the multidrug resistance-1 gene and in vivo and in vitro mefloquine resistance of Plasmodium falciparum. Although falciparum infection usually is not treated with mefloquine, incorrect diagnosis, high frequency of undetected mixed infections, or relapses of P. vivax infection triggered by P. falciparum infections expose non-P. falciparum parasites to mefloquine. To assess the consequences of such unintentional treatments on P. vivax, we studied variations in number of Pvmdr-1 (PlasmoDB accession no. PVX_080100, NCBI reference sequence NC_009915.1) copies worldwide in 607 samples collected in areas with different histories of mefloquine use from residents and from travelers returning to France. Number of Pvmdr-1 copies correlated with drug use history. Treatment against P. falciparum exerts substantial collateral pressure against sympatric P. vivax, jeopardizing future use of mefloquine against P. vivax. A drug policy is needed that takes into consideration all co-endemic species of malaria parasites. PMID- 25272027 TI - 90Sr content in 90Y-labeled SIR-spheres and Zevalin. AB - Three different 90Y internally administered radionuclide therapies are currently used in both standard-of-care and clinical trial procedures atMD Anderson Cancer Center. TheraSphere and SIR-Spheres therapies utilize 90Y-labeled microspheres, while Zevalin is an 90Y-labeled radioimmunotherapeutic agent. Several publications have indicated radionuclidic impurities resulting from 90Y production methods. The 90Y in SIR-Spheres and Zevalin are produced from a 90Sr/90Y generator, which leaves measurable quantities of 90Sr in the final product. TheraSphere 90Y is produced in a nuclear reactor which results in a large number of impurities, most notably 88Y and 91Y. Product information sheets reference these impurities with specific limits given. These limits represent a tiny fraction of the total product activity, and in the case of TheraSphere and SIR-Spheres gamma-emitting impurities, this has been verified in the literature. An analysis of 90Sr impurities in SIR-Spheres and Zevalin is presented in this paper. Impurity quantities were found to be within the vendors' documented limits. PMID- 25272028 TI - Managing uncertainty in complex interventional fluoroscopic procedures. AB - There was a concern for potential patient skin burns indicated by air kerma as recorded by fluoroscopy equipment during two interventional fluoroscopic procedures. Two sentinel events as defined by The Joint Commission were indicated. Dose reconstruction based on measurements of machine output showed the air kerma readings were high by approximately a factor of four and no patient injury or sentinel event occurred. The radiation safety program in effect at the time of the incidents allowed discovery of equipment problems before a serious patient injury occurred, but additional controls have been implemented as a result, including quality control checks performed by cardiology, additional training, a database for tracking equipment maintenance, and mandatory entry of patient dose into electronic health records with follow-up orders automatically generated by the electronic health records. Most unexpected injuries are a result of multiple failures, but there are also multiple opportunities to prevent the injury. This paper provides a comprehensive look at patient safety concerns during two interventional cardiology fluoroscopic procedures and offers ways to further reduce risks to patients. It focuses on lessons learned and a systems based approach to improving and promoting radiation safety during complex interventional fluoroscopic procedures. PMID- 25272029 TI - Portal monitor characterization for internally and externally deposited radionuclides. AB - In this evaluation, both the internal and external radionuclide detection efficiencies for a portal monitor were evaluated as a function of photon energy using an anthropomorphic phantom. Pass-through and static measurements were completed using 241Am, 57Co, 133Ba, 137Cs, 60Co, 109Cd, and 54Mn in various locations both external and internal to the phantom. Other parameters, such as single detector uniformity, total detector uniformity, background linearity, and activity linearity have been analyzed. It was found that the minimum detectable activity for internally deposited 137Cs in the abdomen was approximately ten times higher for pass-through versus static measurements. Additionally, it was found that the minimum detectable activity for 137Cs in the abdominal region for both internal and external pass-through scenarios are nearly equivalent. In general, if the expected radionuclide source term is primarily non-transuranic, the pass-through mode offers sufficient sensitivity to identify potential overexposures while providing much greater personnel throughput. However, minimum detectable committed effective doses for transuranics such as 241Am, show potential for personnel over exposure if the radionuclide mixture contains a significant fraction of transuranics. It is therefore recommended that nuclear facilities evaluate their radionuclide source term in order to bound potential personnel doses. PMID- 25272030 TI - Optimization of radiation doses received by personnel in PET uptake rooms. AB - Reduction of dose to exposed personnel during positron emission tomography (PET) installation usually relies on physical shielding. While the major contribution of shielding is unquestioned, it is usually the only method applied. Other methods of reduction, such as working procedure optimization, the position of the furniture, and rooms are usually disregarded in these installations. This paper presents a design and work optimization procedure used in a particular institution. The influence on the dose received by personnel due to the positioning of injection chairs, injection room configuration, and working procedures is studied. Using this optimization strategy, it is possible to reduce the technician dose due to patients by a factor of 0.59. Injection room design is much more important for optimizing the received dose than is work-flow management. The influence of the order of patient entrance on received dose was the aspect that produced the smallest variation in received doses. It is recommended that the optimization be carried out for the installation proposed in the design phase, when no additional cost is required, because the position of the doors of the injection rooms depends on the where the injection chairs are situated. PMID- 25272031 TI - Investigation of qualitative and quantitative factors related to radiological exposure to nursing staff during computed tomography examinations. AB - Radiologists or nurses intermittently stay in computed tomography rooms during computed tomography examinations; these actions are defined as "entrance actions." The qualitative and quantitative factors related to radiological exposure to computed tomography nursing staff were investigated to identify the protective measures against entrance actions. A questionnaire survey was used to investigate the frequency, motives, and causalities of entrance actions. Individual and area monitoring were simultaneously performed. The mean frequency of entrance actions was 1.2 times mo(-1). The primary motive for entrance actions was to dispel anxieties regarding collateral accidents during computed tomography. The nursing staff particularly engaged in close supervision to help the patients cope with contrast media extravasation. The average personal dose equivalent [Hp(10)] to the nurses was 0.21 mSv mo(-1). The ambient dose equivalent [H*(10)] rate was 1.4-3.7 mSv min(-1) at a distance of 1 m from CT gantry centre. Avoidance of entrance actions and collateral accidents would decrease the occupational exposures to nurses. PMID- 25272032 TI - Jaw function in Smilodon fatalis: a reevaluation of the canine shear-bite and a proposal for a new forelimb-powered Class 1 Lever Model. AB - The jaw function of Smilodon fatalis has long been a source of debate. Although modern-day lions subdue large prey through the use of a suffocating throat bite, the dramatically elongated maxillary canines of S. fatalis suggest an alternative bite mechanism. The current literature favors a "canine shear-bite," in which the depression of the cranium by the ventral neck flexors assists the mandibular adductors in closing the jaws. Although the model makes intuitive sense and appears to be supported by scientific data, the mechanical feasibility of "neck powered" biting has not been experimentally demonstrated. In the present study, the computer-assisted manipulation of digitized images of a high-quality replica of an S. fatalis neck and skull shows that a rotation of the cranium by the ventral neck flexors will not result in jaw closure. Instead, the cranium and mandible rotate ventrally together (at the atlantooccipital joint), and the jaws remain in an open configuration. The only manner by which rotation of the cranium can simultaneously result in jaw closure is by an anterior rotation at the temporomandibular joint. Based on this finding, the author proposes a new Class 1 lever mechanism for S. fatalis jaw function. In this model, the mandible is immobilized against the neck of the prey and a dorsally directed force from the extension of the forelimbs rotates the cranium anteriorly at the temporomandibular joint. The maxillary canines pierce the prey's neck and assist in clamping the ventral neck structures. The model is based on a maximum gape angle of approximately 90 degrees and incorporates a secondary virtual point of rotation located slightly anteroventral to the temporomandibular joint. The Class 1 Lever Model is mechanically feasible, consistent with current data on S. fatalis anatomy and ecology, and may provide a basis for similar studies on other fossil taxa. PMID- 25272033 TI - Spontaneous brain activity in type 2 diabetics revealed by amplitude of low frequency fluctuations and its association with diabetic vascular disease: a resting-state FMRI study. AB - PURPOSE: To investigate correlations between altered spontaneous brain activity, diabetic vascular disease, and cognitive function for patients with type 2 diabetes mellitus (T2DM) using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Rs-fMRI was performed for T2DM patients (n = 26) and age-, gender-, and education-matched non-diabetic control subjects (n = 26). Amplitude of low frequency fluctuations (ALFF) were computed from fMRI signals to measure spontaneous neuronal activity. Differences in the ALFF patterns between patients and controls, as well as their correlations with clinical variables, were evaluated. RESULTS: Compared with healthy controls, T2DM patients exhibited significantly decreased ALFF values mainly in the frontal and parietal lobes, the bilateral thalumi, the posterior lobe of the cerebellum, and increased ALFF values mainly in the visual cortices. Furthermore, lower ALFF values in the left subcallosal gyrus correlated with lower ankle-brachial index values (r = 0.481, p = 0.020), while lower ALFF values in the bilateral medial prefrontal gyri correlated with higher urinary albumin-creatinine ratio (r = -0.418, p = 0.047). In addition, most of the regions with increased ALFF values in the visual cortices were found to negatively correlate with MoCA scores. CONCLUSIONS: These results confirm that ALFF are altered in many brain regions in T2DM patients, and this is associated with the presence of diabetic vascular disease and poor cognitive performance. These findings may provide additional insight into the neurophysiological mechanisms that mediate T2DM-related cognitive dysfunction, and may also serve as a reference for future research. PMID- 25272034 TI - The effect of pylorus removal on delayed gastric emptying after pancreaticoduodenectomy: a meta-analysis of 2,599 patients. AB - BACKGROUND: Delayed gastric emptying is a serious complication of pancreaticoduodenectomy. The effect of pylorus removal on delayed gastric emptying has not been well evaluated. STUDY DESIGN: We searched five databases (PubMed, EMBASE and the Cochrane Central Register of Controlled Trials, Scopus and Web of Science) up to July 2014. The meta-regression analysis was performed to evaluate any factors accountable for the heterogeneity. Publication bias was assessed by Egger's test, and corrected by Duval's trim and fill method. Subgroup analyses were conducted for different surgical techniques of pyloric removal. Other intraoperative and postoperative parameters were compared between two groups. RESULTS: We included 27 studies involving 2,599 patients, with a moderate high heterogeneity for primary outcome (I(2) = 63%). Meta-regression analysis showed that four variables primarily contributed to the heterogeneity, namely nasogastric tube intubation time, solid food start time, preoperative diabetes percentage and the number of patients in pylorus-preserving group. After excluding four studies, the remaining twenty-three studies showed reduced heterogeneity (I(2) = 51%). Then we used Duval's trim and fill method to correct publication bias. The corrected MH odds ratio was 0.78 (95% CI: 0.52-1.17). A subgroup analysis showed that pylorus removal tends to reduce delayed gastric emptying incidence for subtotal stomach-preserving pancreaticoduodenectomy or pylorus-resecting pancreaticoduodenectomy, compared with pylorus-preserving group. However, standard Whipple procedure failed to show any significant reduction of DGE compared with pylorus-removal group. No significant differences were observed in terms of length of hospital stay, infection and pancreatic fistula; however, pylorus removal resulted in longer operation time, more blood loss and higher mortality. CONCLUSION: The pylorus removal does not significantly reduce the overall incidence of delayed gastric emptying. Subtotal stomach preserving pancreaticoduodenectomy or pylorus-resecting pancreaticoduodenectomy tends to reduce delayed gastric emptying incidence, but needs further validation. PMID- 25272035 TI - Bacteria-based analysis of HIV-1 Vpu channel activity. AB - HIV-1 Vpu is a small, single-span membrane protein with two attributed functions that increase the virus' pathogenicity: degradation of CD4 and inactivation of BST-2. Vpu has also been shown to possess ion channel activity, yet no correlation has been found between this attribute and Vpu's role in viral release. In order to gain further insight into the channel activity of Vpu we devised two bacteria-based assays that can examine this function in detail. In the first assay Vpu was over-expressed, such that it was deleterious to bacterial growth due to membrane permeabilization. In the second and more sensitive assay, the channel was expressed at low levels in K(+) transport deficient bacteria. Consequently, Vpu expression enabled the bacteria to grow at otherwise non permissive low K(+) concentrations. Hence, Vpu had the opposite impact on bacterial growth in the two assays: detrimental in the former and beneficial in the latter. Furthermore, we show that channel blockers also behave reciprocally in the two assays, promoting growth in the first assay and hindering it in the second assay. Taken together, we investigated Vpu's channel activity in a rapid and quantitative approach that is amenable to high-throughput screening, in search of novel blockers. PMID- 25272036 TI - Eosinophils and megakaryocytes support the early growth of murine MOPC315 myeloma cells in their bone marrow niches. AB - Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315.BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315.BM cell growth in vitro, IL 5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient DeltadblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma. PMID- 25272037 TI - Strepsiptera, phylogenomics and the long branch attraction problem. AB - Insect phylogeny has recently been the focus of renewed interest as advances in sequencing techniques make it possible to rapidly generate large amounts of genomic or transcriptomic data for a species of interest. However, large numbers of markers are not sufficient to guarantee accurate phylogenetic reconstruction, and the choice of the model of sequence evolution as well as adequate taxonomic sampling are as important for phylogenomic studies as they are for single-gene phylogenies. Recently, the sequence of the genome of a strepsipteran has been published and used to place Strepsiptera as sister group to Coleoptera. However, this conclusion relied on a data set that did not include representatives of Neuropterida or of coleopteran lineages formerly proposed to be related to Strepsiptera. Furthermore, it did not use models that are robust against the long branch attraction artifact. Here we have sequenced the transcriptomes of seven key species to complete a data set comprising 36 species to study the higher level phylogeny of insects, with a particular focus on Neuropteroidea (Coleoptera, Strepsiptera, Neuropterida), especially on coleopteran taxa considered as potential close relatives of Strepsiptera. Using models robust against the long branch attraction artifact we find a highly resolved phylogeny that confirms the position of Strepsiptera as a sister group to Coleoptera, rather than as an internal clade of Coleoptera, and sheds new light onto the phylogeny of Neuropteroidea. PMID- 25272038 TI - Disc1 variation leads to specific alterations in adult neurogenesis. AB - Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain. PMID- 25272039 TI - Usability testing and piloting of the Mums Step It Up program--a team-based social networking physical activity intervention for women with young children. AB - BACKGROUND: Women's physical activity levels decline during their transition to parenthood. Facebook is widely used by Australian mothers and provides the opportunity to target social networks in order to maintain and increase physical activity. METHOD: This mixed method study aimed to pilot and assess the usability of the Mums Step It Up Facebook app, a new team-based physical activity intervention for mothers with young children. A purposive sample of five "Captain" women with young children, were recruited through personal contacts. These women used the app to recruit 3-7 Facebook friends (with children under 5) to join their respective teams (total n = 25). The app encourages women to take 10,000 steps a day measured by a pedometer. Women used the app for 28 days to log steps, interact with team mates and monitor progress. Physical activity was assessed at two time points (baseline and final week) using the Active Australia Survey. Usability testing with the five "Captain" women took place over two one hour face-to-face sessions. A questionnaire seeking feedback on the app was completed at time point two. RESULTS: Participants' total physical activity increased by an average of 177 minutes per week (p = 0.01). The complexity of the team forming process and issues using the Facebook environment, where a variety of devices and software platforms are used, was highlighted. DISCUSSION: A team based Facebook app shows considerable promise for the recruitment and retention of participants to a social network-based physical activity intervention. A randomised controlled trial to further evaluate the effectiveness of the intervention is warranted. PMID- 25272041 TI - SERS-fluorescence monitored drug release of a redox-responsive nanocarrier based on graphene oxide in tumor cells. AB - A redox-responsive drug carrier based on nanoscale graphene oxide (NGO) loaded with Ag nanoparticles, whose intracellular release behavior can be investigated by SERS-fluorescence combined spectroscopy, is presented. In this demonstrated drug carrier, to make the carrier integrated with the redox responsive property, we utilized disulfide linkages to load drug molecules to the surfaces of NGO directly, which can be cleaved by glutathione (GSH). Covalent drug loading and GSH-responsive release strategy can reduce the influence of the surface diffusion barriers introduced by multifunctionalization. Interestingly, the intracellular real-time drug release dynamics can be monitored by the combined SERS fluorescence signals of the drugs, while the distribution of the drug carrier can simultaneously be tracked by the intrinsic SERS signals of NGO in the whole process. Our results show that upon the internalization of doxorubicin (DOX) loaded nanocarriers into living cells, DOX was efficiently released under a GSH regulated reducing environment. Because tumor cells generally exhibit a higher concentration of GSH than normal ones, this drug carrier should have potential in the field of tumor therapy. PMID- 25272040 TI - XB130 deficiency affects tracheal epithelial differentiation during airway repair. AB - The repair and regeneration of airway epithelium is important for maintaining homeostasis of the respiratory system. XB130 is an adaptor protein involved in the regulation of cell proliferation, survival and migration. In the human trachea, XB130 is expressed on the apical site of ciliated epithelial cells. We hypothesize that XB130 may play a role in epithelial repair and regeneration after injury. Xb130 knockout (KO) mice were generated, and a mouse isogenic tracheal transplantation model was used. Adult Xb130 KO mice did not show any significant anatomical and physiological phenotypes in comparison with their wild type (WT) littermates. The tracheal epithelium in Xb130 KO mice, however, was significantly thicker than that in WT mice. Severe ischemic epithelial injury was observed immediately after the tracheal transplantation, which was followed by epithelial cell flattening, proliferation and differentiation. No significant differences were observed in terms of initial airway injury and apoptosis. However, at Day 10 after transplantation, the epithelial layer was significantly thicker in Xb130 KO mice, and associated with greater proliferative (Ki67+) and basal (CK5+) cells, as well as thickening of the connective tissue and fibroblast layer between the epithelium and tracheal cartilages. These results suggest that XB130 is involved in the regulation of airway epithelial differentiation, especially during airway repair after injury. PMID- 25272042 TI - Apelin and APLN single nucleotide polymorphisms and combined hypertension and central retinal artery stenosis in a Chinese population. AB - Apelin activity plays a role in regulating blood pressure. This study explored the relationship between single nucleotide polymorphisms (SNPs) in the Apelin gene (APLN) with hypertension and hypertension with central retinal artery equivalent (CRAE) stenosis in a coastal Chinese population. All subjects answered an epidemiological survey for demographic and disease characteristics. Apelin levels were determined and three APLN SNPs, rs56204867, rs3115757, and rs3761581, were evaluated. CRAE was measured using fundus photography. Apelin levels were significantly lower in subjects with hypertension and hypertension with CRAE stenosis (0.23 +/- 0.10 ng/ml and 0.21 +/- 0.08 ng/ml, respectively) compared with control subjects (0.25 +/- 0.11 ng/ml; p < 0.001). Linear regression analysis showed hypertension and hypertension with CRAE stenosis was associated with age, being male, systolic blood pressure, abnormal blood lipids, and Apelin levels. Genetic analysis indicated that in both males and females SNP rs3761581 was associated with hypertension and that more males carrying rs56204867 and rs3761581 T-A haplotype had hypertension (61.88%) and hypertension with CRAE stenosis (56.82%) than control males (39.33%). In this Chinese population, Apelin and APLN SNP rs3761581 was associated with combined hypertension with CRAE, indicating that the expression of APLN gene products may be involved in vascular injury. PMID- 25272043 TI - The polyphenols (-)-epigallocatechin-3-gallate and luteolin synergistically inhibit TGF-beta-induced myofibroblast phenotypes through RhoA and ERK inhibition. AB - The presence of reactive stroma, predominantly composed of myofibroblasts, is directly associated with and drives prostate cancer progression. We have previously shown that (-)-Epigallocatechin-3-gallate (EGCG), in the form of Polyphenon E, significantly decreases serum levels of HGF and VEGF in prostate cancer patients. Given that HGF and VEGF are secreted from surrounding tumor myofibroblasts, these observations suggested that EGCG may inhibit prostate cancer-associated myofibroblast differentiation. Herein, we demonstrate that micromolar combinations of EGCG and a second polyphenol, luteolin, synergistically inhibit TGF-beta-induced myofibroblast phenotypes in prostate fibroblast cell lines, as observed primarily by potentiation of fibronectin expression. Functionally, EGCG and luteolin inhibited TGF-beta-induced extracellular matrix contraction, an enhancer of tumor cell invasion. EGCG and luteolin inhibited downstream TGF-beta-induced signaling, including activation of ERK and AKT, respectively, but mechanistically, only ERK appeared to be necessary for TGF-beta-induced fibronectin expression. Furthermore, neither EGCG nor luteolin affected Smad signaling or nuclear translocation. Rho signaling was found to be necessary for TGF-beta-induced fibronectin expression and EGCG and luteolin each reduced RhoA activation. Finally, EGCG and luteolin were shown to reverse TGF-beta-induced fibronectin expression, implicating that these natural compounds may be useful not only in preventing but also in treating already activated myofibroblasts and the diseases they cause, including cancer. The ability of EGCG and luteolin to synergistically target myofibroblasts suggests that combined clinical use of these compounds could prevent or reverse cancer progression through targeting the tumor microenvironment, in addition to the tumor itself. PMID- 25272044 TI - Insights into deep-sea sediment fungal communities from the East Indian Ocean using targeted environmental sequencing combined with traditional cultivation. AB - The fungal diversity in deep-sea environments has recently gained an increasing amount attention. Our knowledge and understanding of the true fungal diversity and the role it plays in deep-sea environments, however, is still limited. We investigated the fungal community structure in five sediments from a depth of ~ 4000 m in the East India Ocean using a combination of targeted environmental sequencing and traditional cultivation. This approach resulted in the recovery of a total of 45 fungal operational taxonomic units (OTUs) and 20 culturable fungal phylotypes. This finding indicates that there is a great amount of fungal diversity in the deep-sea sediments collected in the East Indian Ocean. Three fungal OTUs and one culturable phylotype demonstrated high divergence (89%-97%) from the existing sequences in the GenBank. Moreover, 44.4% fungal OTUs and 30% culturable fungal phylotypes are new reports for deep-sea sediments. These results suggest that the deep-sea sediments from the East India Ocean can serve as habitats for new fungal communities compared with other deep-sea environments. In addition, different fungal community could be detected when using targeted environmental sequencing compared with traditional cultivation in this study, which suggests that a combination of targeted environmental sequencing or traditional cultivation alone. This study is the first to report new insights into the fungal communities in deep-sea sediments environmental sequencing and traditional cultivation will generate a more diverse fungal community in deep-sea environments than using either from the East Indian Ocean, which increases our knowledge and understanding of the fungal diversity in deep-sea environments. PMID- 25272045 TI - MiR-410 is overexpressed in liver and colorectal tumors and enhances tumor cell growth by silencing FHL1 via a direct/indirect mechanism. AB - FHL1 is an important tumor-suppressor that is downregulated in multiple tumors by unknown mechanisms. We demonstrated that miR-410 specifically targets the 3'UTR of FHL1. Furthermore, using DNA bisulfite modification and sequencing experiments, we demonstrated that the FHL1 promoter is hypermethylated in cancer cells. FHL1 methylation is increased upon miR-410 expression, suggesting that the regulation of FHL1 by miR-410 occurs by a dual mechanism. Using chromatin immunoprecipitation assays, we observed that miR-410 overexpression results in the increased binding of DNMT3A at the FHL1 promoter, which could explain how miR 410 regulates FHL1 methylation. Importantly, in vitro and in vivo results suggest that miR-410 may have oncogenic properties. Furthermore, both miR-410 and DNMT3A are upregulated in clinical human liver and colorectal tumors cancers. Our results suggest that miR-410 may function as an oncomiR and are consistent with its key function in regulating FHL1 in certain digestive system cancers. PMID- 25272048 TI - Perceptual changes of interaction between hand and object in an experimental phantom hand. AB - The authors examined whether the wrist and elbow were perceived as flexed when a stick was fixed to the hand while the joints were extended during anesthesia. Ten healthy participants lay on their back on a bed with their eyes closed, and a stick was fixed to their right hand. Surprisingly, while the perceived position of the wrist and elbow moved toward flexion from 10 to 40 min after the ischemic block, the stick fixed to the hand was also perceived as having moved toward flexion from 10 to 20 min after the block. Such coupling the change in the perceived stick position with the change in body image suggests a new type of hand-object illusion. PMID- 25272047 TI - In vivo imaging reveals a pioneer wave of monocyte recruitment into mouse skin wounds. AB - The cells of the mononuclear phagocyte system are essential for the correct healing of adult skin wounds, but their specific functions remain ill-defined. The absence of granulation tissue immediately after skin injury makes it challenging to study the role of mononuclear phagocytes at the initiation of this inflammatory stage. To study their recruitment and migratory behavior within the wound bed, we developed a new model for real-time in vivo imaging of the wound, using transgenic mice that express green and cyan fluorescent proteins and specifically target monocytes. Within hours after the scalp injury, monocytes invaded the wound bed. The complete abrogation of this infiltration in monocyte deficient CCR2(-/-) mice argues for the involvement of classical monocytes in this process. Monocyte infiltration unexpectedly occurred as early as neutrophil recruitment did and resulted from active release from the bloodstream toward the matrix through microhemorrhages rather than transendothelial migration. Monocytes randomly scouted around the wound bed, progressively slowed down, and stopped. Our approach identified and characterized a rapid and earlier than expected wave of monocyte infiltration and provides a novel framework for investigating the role of these cells during early stages of wound healing. PMID- 25272046 TI - Long-term aerobic exercise protects against cisplatin-induced nephrotoxicity by modulating the expression of IL-6 and HO-1. AB - Nephrotoxicity is substantial side effect for 30% of patients undergoing cancer therapy with cisplatin and may force them to change or even abandon the treatment. Studies regarding aerobic exercise have shown its efficacy for the treatment of many types of diseases and its capacity to reduce tumors. However, little is known about the impact of physical exercise on cisplatin-induced acute kidney injury (AKI). In the present study, our aim was to investigate the role of physical exercise in AKI induced by cisplatin. We submitted C57Bl6 male mice to seven weeks of chronic exercise on a training treadmill and treated them with single i.p. injection of cisplatin (20 mg/kg) in the last week. Exercise efficacy was confirmed by an increased capillary-to-fiber ratio in the gastrocnemius muscle of exercised groups (EX and CIS-EX). The group submitted to exercise before cisplatin administration (CIS-EX) exhibited less weight loss and decreased serum urea levels compared to the cisplatin group (CIS). Exercise also showed a protective role against cisplatin-induced cell death in the kidney. The CIS-EX group showed a lower inflammatory response, with less TNF and IL-10 expression in the kidney and serum. In the same group, we observed an increase of IL-6 and HO-1 expression in the kidney. Taken together, our results indicate that chronic aerobic exercise is able to attenuate AKI by inducing IL-6 and HO-1 production, which results in lower inflammatory and apoptotic profiles in the kidney. PMID- 25272049 TI - alpha-Lipoic acid protects kidney from oxidative stress and mitochondrial dysfunction associated to inflammatory conditions. AB - An adequate redox status is important for maintaining mitochondrial function in inflammatory conditions. The aim of this work was to evaluate the effects of alpha-lipoic acid (LA) in kidney oxidative metabolism and mitochondrial function in lipopolysaccharide (LPS) treated rats. Sprague-Dawley rats (female, 45 +/- 5 days old) were treated with LPS (10 mg kg(-1)) and/or LA (100 mg kg(-1)). It was observed in LPS-treated animals that the LA prevented the increase in 1.2 fold of NO production, decreased (30-40%) mitochondrial complex I-III and IV activities, and decreased (26%) membrane potential and cardiolipin oxidation (76%). No differences were observed in mitochondrial O2 consumption, mitochondrial complex II-III activity, and ATP production when LPS group was compared to LA + LPS group. Based on the improvement of mitochondrial function, the decreased production of mitochondrial NO and restoration of cardiolipin levels, this work provides a new evidence that alpha-lipoic acid protects kidney from oxidative stress and mitochondrial dysfunction. PMID- 25272050 TI - A single dose of EGLN1 siRNA yields increased erythropoiesis in nonhuman primates. AB - Decreased production of erythropoietin (EPO) causes anemia in patients with chronic kidney disease, and recombinant human EPO is used to treat renal failure associated anemia. The liver, the main EPO-producing organ in utero, maintains the capacity to produce EPO in the adult but in insufficient quantities to restore hemoglobin levels to normal in patients with impaired renal function. Inhibition of prolyl-4-hydroxylase domain (PHD) proteins is known to cause an increase in EPO production through its effects on hypoxia inducible factor. Here, we utilized small interfering RNA (siRNA) targeting EGLN1, the gene encoding the PHD2 protein, to investigate the phenotypic consequences in nonhuman primates. A single, well-tolerated intravenous dose of an optimized EGLN1 siRNA encapsulated in a lipid nanoparticle formulation caused robust mRNA silencing in the liver, leading to increases in serum EPO and hemoglobin. The siRNA-induced erythropoiesis was dose-dependent and was sustained for at least 2 months. These data point to the potential for an RNA interference-based, liver-targeted therapeutic approach for the treatment of anemia. PMID- 25272051 TI - Nanoparticles for fingermark detection: an insight into the reaction mechanism. AB - This publication presents one of the first uses of silicon oxide nanoparticles to detect fingermarks. The study is not confined to showing successful detection of fingermarks, but is focused on understanding the mechanisms involved in the fingermark detection process. To gain such an understanding, various chemical groups are grafted onto the nanoparticle surface, and parameters such as the pH of the solutions or zeta potential are varied to study their influence on the detection. An electrostatic interaction has been the generally accepted hypothesis of interaction between nanoparticles and fingermarks, but the results of this research challenge that hypothesis, showing that the interaction is chemically driven. Carboxyl groups grafted onto the nanoparticle surfaces react with amine groups of the fingermark secretion. This formation of amide linkage between carboxyl and amine groups has further been favoured by catalyzing the reaction with a compound of diimide type. The research strategy adopted here ought to be applicable to all detection techniques using nanoparticles. For most of them the nature of the interaction remains poorly understood. PMID- 25272052 TI - Astrocytes mediate HIV-1 Tat-induced neuronal damage via ligand-gated ion channel P2X7R. AB - During human immunodeficiency virus (HIV)-1 infection, perturbations in neuron glia interactions may culminate in neuronal damage. Recently, purinergic receptors have been implicated in the promotion of virus-induced neurotoxicity and supporting the viral life cycle at multiple stages. The astrocytes robustly express purinergic receptors. We therefore sought to examine if P2X7R, a P2X receptor subtype, can mediate HIV-1 Tat-induced neuronal apoptosis. Tat augmented the expression of P2X7R in astrocytes. Our data reveal the involvement of P2X7R in Tat-mediated release of monocyte chemoattractant protein (MCP-1) /chemokine (C C motif) ligand 2 (CCL2) from the astrocytes. P2X7R antagonists, such as the oxidized ATP, A438079, brilliant blue G, and broad spectrum P2 receptor antagonist suramin, attenuated Tat-induced CCL2 release in a calcium- and extracellular signal-regulated kinase (ERK)1/2-dependent manner. Calcium chelators, (1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid) acetoxymethyl ester and EGTA, and ERK1/2 inhibitor U0126 abolished chemokine (C-C motif) ligand 2 release from astrocytes. Furthermore, in human neuronal cultures, we demonstrated P2X7R involvement in Tat-mediated neuronal death. Importantly, in the TUNEL assay, the application of P2X7R-specific antagonists or the knockdown of P2X7R in human astrocytes reduced HIV-Tat-induced neuronal death significantly, underlining the critical role of P2X7R in Tat-mediated neurotoxicity. Our study provides novel insights into astrocyte-mediated neuropathogenesis in HIV-1 infection and a novel target for therapeutic management of neuroAIDS. We investigated the role of P2X7R in Tat-mediated neuroinflammation and neuronal damage. We proposed the following cascade for Tat mediated CCL2 release from astrocytes: Tat mediates increase in P2X7R expression, which on activation evokes increase in intracellular calcium, which further leads to phosphorylation of ERK1/2 followed by the release of CCL2 from astrocytes. Tat also leads to direct and indirect (mediated via astrocytes) neuronal death that can be abrogated by inhibiting P2X7R. We believe that these finding should provide new insights into the role of astrocytes in HIV-1 Tat-mediated neurotoxicity. PMID- 25272053 TI - Trophodynamic behavior of hydrophobic organic contaminants in the aquatic food web of a tidal river. AB - The bioaccumulation and biomagnification of sediment-bound hydrophobic organic contaminants (HOCs) are of major concern for environmental and human health. In dynamic estuaries, HOCs can be taken up from sediments, porewater, or the overlying water column concentrations directly or via the diet. The transfer of HOCs including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) to resident/migratory biota was investigated in 11 finfish species and blue crabs (Callinectes sapidus) in the Passaic River estuary. Concurrently, passive samplers were deployed to assess porewater and overlying water column concentrations. Biota were assigned to three trophic levels based on their tissue 15N isotope values and published life history strategies. There were no significant differences in trophic magnification factors (TMFs) calculated based on life-history scenarios, implying that the migratory species, mostly juveniles, had equilibrated with in situ sources of pollutants at the time they were sampled. Bioaccumulation factors and TMFs were >1 for most PCBs and tetra- and penta-CDD/DFs, indicating that they underwent biomagnification in the food web. All PAHs, PCB 11, and other lower chlorinated PCBs and PCDD/Fs did not magnify. Results from the analysis of HOC profiles implied that biota accumulated HOCs from sediments, porewater, and diet but not from overlying water. PMID- 25272054 TI - The role of emotion regulation on social participation following stroke. AB - Following stroke, individuals often experience reduced social participation, regardless of physical limitations. Impairments may also occur in a range of cognitive and emotional functions. Successful emotion regulation, which has been identified as important in psychological adaptation to chronic illness, is associated with better perceived psychological well-being and social functioning. However, there is little evidence about the effect of stroke on emotion regulation difficulties, and associated impact on important outcomes in recovery from stroke. OBJECTIVES: The objectives were (1) to determine whether people who have had a stroke reported greater difficulties in emotion regulation than controls and (2) to establish whether emotion regulation difficulties relate to social participation. METHODS: 75 stroke and 40 healthy participants completed measures of emotion regulation (DERS), social participation (Modified Functional Limitation Profile [mFLP], WHOQoL-Bref) and activity limitations (mFLP). Stroke participants were seen at the acute stage (63 days post-stroke) for Study 1 and 18 months post-stroke for Study 2. RESULTS: In Study 1, acute-stage stroke patients had significant impairments on impulse control, awareness of emotions, and strategies for emotion regulation. There was also evidence that emotion regulation difficulties (impulse control, awareness and clarity about emotions) were associated with social participation in the stroke sample, even after controlling for potential confounders. In Study 2, there was evidence that, in the chronic-stage post-stroke, difficulties with strategy and acceptance of emotions were associated with social participation restrictions. Whilst emotion regulation as a whole in the acute phase predicted social participation in the chronic phase of stroke, no one domain of emotion regulation was a significant predictor of social participation >1 year later. DISCUSSION: These results indicate that multiple aspects of emotion regulation are impaired following stroke, with implications for social participation and recovery. PRACTITIONER POINTS: This research highlights the following important clinical implications: Following a stroke, emotion regulation can be immediately and persistently affected, with post-stroke individuals experiencing greater difficulties with their emotion regulation than control participants. Emotion regulation can significantly predict important stroke outcomes including social participation and quality of life, over and above physical limitations and other post-stroke confounders. This study highlights the potential for developing a behaviour change intervention to address emotion regulation difficulties and thus ensuring individuals maximize their potential rehabilitation outcome. Cautions of the study for consideration: Emotion regulation was a self-report measure, and proxy measures would have been desirable. We are unable to establish if the post-stroke individuals differed from the controls on their emotion regulation prior to stroke. PMID- 25272055 TI - Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2. AB - A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5) isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations. PMID- 25272058 TI - Naringenin, a citrus flavonoid, ameliorates arsenic-induced toxicity in Swiss albino mice. AB - In the present study, we evaluated the ameliorative potential of a citrus flavonoid, naringenin (NRG), against experimentally induced arsenic toxicity in Swiss albino mice. NRG (5 and 10 mg kg-l) was administered orally to mice 30 minutes before oral administration of arsenic trioxide (3 mg kg-l) for 14 consecutive days. On day 15, the following parameters were evaluated: body weight; organ weight; hematological profile; serum biochemical profile; hepatic and renal tissue antioxidative parameters including lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase levels; and DNA fragmentation. Co-treatment with NRG markedly and significantly normalized body weights, organ weights, hematological profiles, and serum biochemical profiles and significantly modulated all of the hepatic and renal tissue biochemical parameters and DNA fragmentation in arsenic-intoxicated mice. The present findings indicate that naringenin remarkably ameliorated the effects of arsenic induced toxicity in albino mice due to its strong antioxidant property. PMID- 25272059 TI - Curative effect of Amorphophallus campanulatus (Roxb.) Blume. tuber on N nitrosodiethylamine- induced hepatocellular carcinoma in rats. AB - In this study, we investigated the curative effect of Amorphophallus campanulatus tuber methanolic extract (ACME) on N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma (HCC) in experimental rats. All of the rats except those in the normal control group received 0.02% NDEA orally (2 mL, 5 days/week) for the first 20 weeks of the experiment. In different treatment groups, after 20 weeks of NDEA challenge, rats were supplemented with ACME (125 and 250 mg/kg body weight, orally) for the following 28 days. In addition, a standard drug control group was supplemented with silymarin (100 mg/kg bw, orally), a known tumorsuppressive agent against HCC. Administration of ACME significantly inhibited the NDEA-induced increase of hepatic nodule incidence, nodule multiplicity, and serum biochemical indices, and improved the hepatocellular architecture in a dose-dependent manner. The biochemical analysis of hepatic tissues further demonstrated that ACME counteracts NDEA-induced oxidative stress through the restoration of antioxidant enzymes. NDEAadministered rats also showed amplified expression of proliferating cell nuclear antigen in the liver, and decreased expression of this proliferative marker was clearly observed upon the supplementation of ACME. Notably, 250 mg/kg bw ACME supplementation showed better results than the other treatment regimens; this result might be associated with the enhancement of antioxidant activity and inhibition of hepatic cell proliferation. PMID- 25272057 TI - A review of molecular events of cadmium-induced carcinogenesis. AB - Cadmium (Cd) is a toxic, heavy industrial metal that poses serious environmental health hazards to both humans and wildlife. Recently, Cd and Cd-containing compounds have been classified as known human carcinogens, and epidemiological data show causal associations with prostate, breast, and lung cancer. The molecular mechanisms involved in Cd-induced carcinogenesis are poorly understood and are only now beginning to be elucidated. The effects of chronic exposure to Cd have recently attracted great interest due to the development of malignancies in Cd-induced tumorigenesis in animals models. Briefly, various in vitro studies demonstrate that Cd can act as a mitogen, can stimulate cell proliferation and inhibit apoptosis and DNA repair, and can induce carcinogenesis in several mammalian tissues and organs. Thus, the various mechanisms involved in chronic Cd exposure and malignant transformations warrant further investigation. In this review, we focus on recent evidence of various leading general and tissue specific molecular mechanisms that follow chronic exposure to Cd in prostate-, breast-, and lung-transformed malignancies. In addition, in this review, we consider less defined mechanisms such as epigenetic modification and autophagy, which are thought to play a role in the development of Cd-induced malignant transformation. PMID- 25272060 TI - Luteolin induces cell cycle arrest and apoptosis through extrinsic and intrinsic signaling pathways in MCF-7 breast cancer cells. AB - Luteolin is a common flavonoid that exists in medicinal herbs, fruits, and vegetables. Luteolin has biochemical functions including anti-allergy, anti inflammation, and anti-cancer functions. However, its efficacy and precise mode of action against breast cancer are still under study. To elucidate whether luteolin exhibits an anticancer effect in breast cancer, MCF-7 breast cancer cells were incubated with luteolin, and apoptosis was assessed by observing nuclear morphological changes and by performing cell viability assay, cell cycle analysis, annexin V-FITC/PI double staining, western blotting, RT-PCR, and mitochondrial membrane potential measurements. Luteolin inhibited growth through perturbation of cell cycle progression at the sub-G1 and G1 phases in MCF-7 cells. Furthermore, luteolin enhanced the expression of death receptors, such as DR5, and activated caspase cascades. It enhanced the activities of caspase-8/-9/ 3 in a dose-dependent manner, followed by inactivation of PARP. Activation of caspase-8 and caspase-9 induced caspase-3 activity, respectively, in apoptosis of extrinsic and intrinsic pathways. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and increased Bax expression by inhibiting expression of Bcl-2. Taken together, these results suggest that luteolin provokes cell cycle arrest and induces apoptosis by activating the extrinsic and intrinsic pathways. PMID- 25272061 TI - Silence of PTEN in colorectal cancer cells via siRNA inhibits cell growth. AB - Colorectal cancer is one of the most commonly diagnosed cancers and is a leading cause of cancerrelated death worldwide. In this study, we aimed to examine the expression of PTEN in human colorectal cancer cell lines HCT-8 and to further investigate the functions of PTEN in colorectal cancer cells. Therefore, we established stably transfected HCT-8 cell lines expressing siRNA targeting the PTEN gene. Cell proliferation and cell migration of the siPTEN cells were characterized by the CCK-8 assay and the Transwell assay, respectively. Our results show that constitutive knockdown of the PTEN gene in siPTEN cells significantly promoted cell proliferation and migration. These results suggest that PTEN may play important roles in colorectal cancer cell proliferation and migration. PMID- 25272062 TI - In utero exposure and breast cancer development: an epigenetic perspective. AB - The ubiquitous and detrimental disease of breast cancer requires continual research into new and alternative forms of treatment and prevention. The emerging field of epigenetics is beginning to unfold an array of contemporary approaches to reduce the risk and improve the clinical approach to breast cancer. The information contained in this non-systematic review highlights and expands on the estrogen-based model of breast cancer epigenetics to provide an overview of epigenetic alterations induced by nutrition and environmental exposure. The majority of evidence suggests that various sources of excess estrogen correlate to future breast cancer development. In addition, maternal macro- and micronutrient balance appear to play a role in genomic regulation, and preliminary data suggest that specific superfoods, such as blueberries, have a protective epigenetic effect. Identifying the influence of environmental toxicants, hormonal exposure, maternal nutrition, and maternal disease on fetal epigenetics may have potential for development of new therapeutic approaches for the prevention of breast cancer. PMID- 25272063 TI - Curcumin augments the efficacy of antitumor drugs used in leukemia by modulation of heat shock proteins via HDAC6. AB - Heat shock proteins (HSPs) and histone deacetylase 6 (HDAC6) are induced under oxidative stress, which promotes oncogenesis. HSPs are regulated by heat shock factor1 (HSF1). HDAC6, a class IIb deacetylase, plays an essential role in tumorigenesis and cell stress response. HSPs, HSF1 and HDAC6 are up-regulated in cancer. In the present study, we explored the effect of curcumin, a phytochemical, on HSPs (27, 70, 90), HSF1 and HDAC6 in two different leukemia cell lines (K-562 and HL-60). The association between HDAC6, HSPs, and intrinsic oxidative stress was also investigated. Overexpression of HSPs (27, 70, 90), HSF1, and HDAC6 in leukemia cells were down-regulated by curcumin, and the effects on HSPs 27and 70 were less than that on HSP 90. This resulted in cell cycle arrest at the G2/M stage, leading to apoptosis. Different cell cycle regulatory proteins (p53, p21, cyclin B1, CDK1, Cdc25C) and some apoptosis related proteins (Bcl-2, Bax, Bid, Bad, Apaf1, AIF and Cyt c) were altered by curcumin. Increased ROS levels in leukemia cells were quenched by curcumin. A probable association between high ROS level and the overexpression of the tumor markers was established in this study. Thus, curcumin enhanced the efficacy of anti-tumor drugs imatinib-mesylate and cytarabine through the inhibition of the tumor markers. PMID- 25272064 TI - Mechanism of cytotoxicity by Psoralea corylifolia extract in human breast carcinoma cells. AB - Psoralea corylifolia has been widely used in herbal medicine, and a few studies show its anticancer activity. However, the detailed mechanism of the anticancer activity of P. corylifolia seed extract (PC extract) was not studied. This study evaluates the anticancer activity and underlying mechanism of PC extract in a human breast cancer cell line (MCF7). PC extract caused a concentration-dependent decrease in the proliferation of MCF7 cells and an increase in apoptotic death as measured by annexin-V-FITC and TUNEL assays. Increased cleavage of poly(ADP ribose) polymerase in cells treated with PC extract further confirmed the apoptotic mode of cell death. There was a decrease (~2-fold) of mitochondrial membrane potential in cells treated with PC extract. In cells treated with PC extract, an increase in intracellular reactive oxygen species (ROS) and a decrease in mitochondrial ROS was observed. A significant decrease in ATP (~1.8 fold) was observed in extract-treated cells. Moreover, MCF7 cells treated with extract showed cleavage of caspase-9 and caspase-7, upregulation of Bax, release of cytochrome-c, and loss of mitochondrial integrity. Taken together, these results suggest the involvement of the mitochondrial pathway in PC extract induced apoptosis in MCF7 cells. PMID- 25272065 TI - Measuring and Improving First Case On-Time Starts and Analysis of Factors Predicting Delay in Neurosurgical Operating Rooms. AB - BACKGROUND: We undertook an operating room (OR) process improvement project to increase first case on-time starts (FCOTS) in the neurosurgical ORs at a tertiary care academic medical center. We engaged the neurosurgical perioperative team which included neurosurgeons, neuroanesthesiologists, and nurses in a shared goal of improving FCOTS. METHODS: Our project involved hiring a new service manager and a focused shared effort on improving FCOTS. After project completion, we conducted a retrospective analysis of FCOTS in 6 neurosurgical ORs. If patients were not in the OR within 5 minutes of scheduled start time, it was considered a late start. Factors predicting delayed start were also identified. During the same period, first cases performed outside the neurosurgical ORs served as a control group. RESULTS: A total of 2328 elective neurosurgical cases were evaluated. The baseline FCOTS from November 2009 to March 2010 was 33%. The first performance shift occurred during March 2010 to January 2011 when FCOTS increased to 44%. In the second performance shift between January 2011 and November 2011 during the implementation phase of this quality improvement project, FCOTS rose to 68% and has continued to increase. Multivariate logistic regression analysis identified the following as significant predictors of delayed start: female sex (odds ratio [OR]=0.771; 95% confidence interval [CI], 0.599-0.943), certified registered nurse anesthetists on the case (OR=0.750; 95% CI, 0.576-0.924), cases done on Friday (OR=0.551; 95% CI, 0.312-0.791), and American Society of Anesthesiologists status IV (OR=0.530; 95% CI, 0.157-0.903). CONCLUSION: The quality improvement project, which was implemented in 2 phases, successfully increased the FCOTS rate in our neurosurgical ORs from 33% to 68%. PMID- 25272067 TI - Natural control of bacteria affecting meat quality by a neem (Azadirachta indica A. Juss) cake extract. AB - The antibacterial activity of an ethylacetate neem cake extract (NCE) against bacteria that affect meat quality, namely Campylobacter jejuni, Carnobacterium spp., Lactobacillus curvatus, Lactobacillus sakei and Leuconostoc sp., is reported. The antibacterial activity was detected using standardised disc diffusion and macrodilution methods. The bacterial growth inhibition zone ranged from 11.33 +/- 0.58 to 22.67 +/- 0.58 mm (100 MUL NCE). There is significant difference between the growth inhibition zone of NCE and the control (ciprofloxacin 100 MUg). The percent of bacterial growth reduction range was 79.75 +/- 1.53 to 90.73 +/- 1.53 (100 MUg NCE) as compared with control (without NCE). NCE in different amounts counteracted the growth of all tested bacteria. PMID- 25272068 TI - Reference intervals for total bilirubin, ALT, AST and creatinine in healthy Chinese elderly. AB - BACKGROUND: The aim of this study was to establish the reference intervals (RIs) of total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate transaminase (AST), and creatinine (CREA) for apparently healthy elderly (Han ethnicity) in Shuyang, China. MATERIAL AND METHODS: A total of 54 912 blood specimens from elderly residents age 65-104 years were collected by standard procedures in Shuyang county of Jiangsu province. TBIL, ALT, AST, and CREA for each participant were determined by automatic biochemical analyzer. Distribution and differences of TBIL, ALT, AST, and CREA were analyzed and compared between the elderly of the same age of different sexes and different ages of the same sex. RIs of TBIL, ALT, AST, and CREA were compared with the current RIs. The RIs and 95% confidence intervals were calculated using nonparametric method (2.5th-97.5th percentiles) according to the guideline of the Clinical and Laboratory Standards Institute. RESULTS: RIs established for the healthy elderly include: TBIL 7.8~30.6 umol/L for males and 7.3~26.1 umol/L for females; ALT 8.7~47.3 U/L for males and 8.4~45.2 U/L for females; AST 15.7~46.9 U/L for males and 15.1~46.2 U/L for females; and CREA 45.1~100.9 umol/L for males and 38.7~85.0 umol/L for females. Reference intervals of TBIL, ALT, AST, and CREA for male elderly were higher than those of females, and values of CREA increased with increasing age. CONCLUSIONS: We have established a panel of locally relevant RIs. It is necessary to establish scientific and reasonable RIs of TBIL, ALT, AST, and CREA for the healthy elderly in our region, which will provide a reference for clinicians and inspection officers. PMID- 25272069 TI - Pediatric procedural sedation with propofol using a higher initial bolus dose. AB - OBJECTIVES: We sought to describe the doses of propofol used for sedation in our pediatric emergency department, along with the range of procedures performed under propofol sedation. We also planned to describe clinically important physiologic changes seen and physician satisfaction with propofol at the doses observed. METHODS: This was a prospective observational case series. Physicians completed a data collection form after the propofol sedation. The physicians were asked to report physiologic changes that occurred during sedation and rate their satisfaction with propofol as a sedation agent on a 100-mm visual analog scale. RESULTS: Eight hundred eighty-six sedation events were reported. The median initial dose of propofol given was 2.0 mg/kg and the median total dose was 3.6 mg/kg. Propofol was used for a wide range of procedures. The most common physiologic change was desaturation/hypoxia (desaturation to <90% in 7.2%). No deaths, unplanned intubations, or surgical airway placements were reported. Treating physicians reported a median satisfaction score of 97 mm. CONCLUSIONS: A 2-mg/kg initial bolus dose of propofol for pediatric sedation was well tolerated and useful for a wide range of procedures. Physicians should expect to find a high level of satisfaction with this dose. PMID- 25272070 TI - Efficacy of vibration on venipuncture pain scores in a pediatric emergency department. AB - OBJECTIVE: Venipuncture is a frequent source of painful procedures for infants. It has been well documented that infants react to pain with a combination of physiologic and behavioral responses. Infants are unable to describe pain and at particularly high risk for inadequate pain management. The Vibration Anesthesia Device is a specifically designed device for management of pain from minor procedures. It has been shown to reduce venipuncture pain in older children but has not been studied in infants. The mechanism of its effects has been described by a gate control theory, which states that vibration stimulates the dorsal horn neurons where the pain signal is being modulated. The objective of this study was to investigate the efficacy of this device on pain during and after venipuncture procedures in infants. METHODS: Study participants were 60 healthy infants undergoing venipuncture procedure for routine laboratory tests. Infants were divided into 2 groups as follows: group 1 (n = 30) was placed vibration anesthesia device 5 to 10 cm proximally through the site of venipuncture, and group 2 (n = 30) underwent venipuncture only. A single observer rated pain responses using the Face, Legs, Activity, Cry, and Consolability scale before, during, and after the procedure. The chi distribution and Student t test were used for statistical analysis. RESULTS: Groups did not differ by sex. Mean age of group 2 is less than group 1 and is statistically significant (P = 0.026). There were no differences between pain scores of groups assessed by Face, Legs, Activity, Cry, and Consolability scale before, during, and after venipuncture procedure (P = 0.359, P = 0.907, and P = 0.400 respectively). CONCLUSIONS: We assessed the efficacy of a vibration anesthesia device, and our results suggested that this device did not reduce pain scores in infants during and after venipuncture procedure. PMID- 25272071 TI - Changes in practice patterns with the opening of a dedicated pediatric emergency department. AB - OBJECTIVES: Dedicated pediatric emergency departments (ED) staffed by pediatric emergency medicine physicians are becoming more common. We compared processes of care and outcomes before and after opening a dedicated pediatric ED. METHODS: A before and after trial design was used to estimate whether there were any changes in ordering of laboratory tests, radiographic imaging, admission rates, ED length of stay (LOS), rates of left without being seen (LWBS) and patient satisfaction scores after opening a dedicated pediatric ED staffed by pediatric emergency medicine physicians. RESULTS: There were 34,961 pediatric patients; 16,311 (47%) presented before and 18,650 (53%) after opening the pediatric ED. Overall radiologic imaging decreased (42.5% vs. 39.3%; difference, 3.2%; 95% confidence interval [95% CI], 2.1%-4.2%) as did computed tomography (8.9% vs. 7.6%; difference, 1.2%; 95% CI, 0.7%-1.8%) but not magnetic resonance imaging. Laboratory testing decreased from 33.1% to 30.1% (difference, 3%; 95% CI, 2.1% 4.0%) of patients. Mean [SD] ED LOS (3.1 [2.5] vs. 2.8 [2.2] hours; difference, 0.36; 95% CI, 0.31-0.41) as well as the rate of LWBS (1.0% vs. 0.6%; difference, 0.4%; 95% CI, 0.2%-0.5%) also decreased. Admission rates (9.4% vs. 9.4%) and unscheduled return visits within 72 hours (3.2% vs. 3.5%) were unchanged. Mean (SD) monthly satisfaction scores increased from 81.3 (2.2) to 86.3 (2.2) (difference, 5; 95% CI, 3%-7%). CONCLUSIONS: Opening of a pediatric ED with pediatric emergency physicians was associated with decreases in ED LOS, rates of LWBS, general radiographic, and computed tomography imaging as well as laboratory testing, and increases in patient satisfaction scores. The clinical significance of these changes is unclear. PMID- 25272072 TI - Infant head injury in falls and nonaccidental trauma: does injury pattern correlate with mechanism? AB - OBJECTIVES: Nonaccidental trauma (NAT) is most common and most lethal in infants. Falls are the most frequently given explanation for NAT, and head injuries can result from both mechanisms. We hypothesized that infant head injuries from NAT have a distinct injury profile compared to falls. METHODS: The trauma registry and patient records were reviewed from 2004 to 2008. Infants with at least 1 head computed tomography were included. RESULTS: Ninety-nine infants were identified. Falls (67 patients) and NAT (21 patients) were the most common mechanism of injury. Falls had lower injury severity scores, 5 versus 17 compared to NAT (P < 0.001). Nonaccidental trauma patients had injuries to face, chest, abdomen, or extremities much more frequently, 62% versus 3% in falls (P < 0.001). Isolated intracranial hemorrhage was higher in NAT (60% vs. 23%, P = 0.002), whereas isolated skull fracture was higher in falls (42% vs. 5%, P = 0.005). Outcomes for NAT showed longer intensive care unit stays (4 days vs. 1 day; P < 0.001), longer hospital stays (7 days vs. 1 day; P < 0.001), and more intracranial operations (9 vs. 1; P < 0.001). CONCLUSIONS: We recommend that all children younger than 1 year, with an isolated intracranial hemorrhage, have a full NAT work-up. Injury severity score greater than 20, Glasgow Coma Scale less than 13, and extracranial injuries should also increase suspicion of NAT. PMID- 25272073 TI - Frequent pediatric emergency department use in infancy and early childhood. AB - OBJECTIVE: To define the threshold and population factors associated with pediatric emergency department (PED) use above the norm during the first 36 months of life. METHODS: We conducted a cross-sectional study of children born between 2003 and 2006, treated in a single PED within the first 36 months of life. Exclusion criteria included out-of-county residence or history of abuse or neglect. The primary outcome, frequent PED use, was defined by the 90th percentile for PED visits per patient. Multivariate analysis was used to identify factors associated with frequent PED use. RESULTS: A total of 41,912 visits occurred for 16,664 patients during the study. Pediatric ED use skewed heavily toward less than 2 visits per patient (median, 2; range, 1-39; interquartile range, 2). The threshold for frequent PED use was 5 or more visits per patient and occurred for 14% (95% confidence interval [95% CI], 13%-15%) of patients. Most visits were coded with low acuity International Classifications of Diseases, 9th Revision, Clinical Modification codes. The following factors were strongly associated with frequent PED use: lack of primary care physician (odds ratio [OR], 6.03; 95% CI, 5.39%-6.80%; P < 0.0001), non private insurance (OR, 3.64; 95% CI, 2.99%-4.46%; P<0.0001), and history of inpatient admission (OR, 3.09; 95% CI, 1.66%-2.24%; P < 0.0001). Leaving without being seen, black race, Hispanic ethnicity, and residence in a poverty-associated zip code were also significantly associated, but less strongly predictive of, frequent PED use. CONCLUSIONS: The threshold for frequent PED use was more than 5 visits per patient within the first 36 months of life. Further study is needed to better define this population and develop targeted interventions to ensure care provision occurs in the ideal setting. PMID- 25272074 TI - Clinical signs and symptoms associated with intussusception in young children undergoing ultrasound in the emergency room. AB - OBJECTIVE: The purpose of this study was to evaluate all patients suspected of having intussusception and identify which signs and symptoms were associated with the disease. METHODS: We performed a retrospective review of 553 charts from 2006 to 2010 of patients' age 2 months to 5 years who had an abdominal ultrasound obtained to evaluate for intussusception. Charts were reviewed for signs and symptoms previously shown to be associated with intussusception. RESULTS: There were 452 patients (mean age, 21.5 months, 43% female) evaluated and 101 (22.3%) were found to have intussusception. Of the 18 signs and symptoms, crying (adjusted odds ratio [OR], 3.3; 95% confidence interval [95% CI], 1.3-8.1), abdominal mass (adjusted OR, 15.7; 95% CI, 4.4-55.3), pallor (adjusted OR, 6.5; 95% CI, 1.8-23.5), and vomiting (adjusted OR, 3.1; 95% CI, 1.4-6.5) were associated with disease confirmation in logistic regression analysis. The presence of all 4 clinical signs/symptoms together resulted in a 95% probability of intussusception. Intussusception was unlikely if all 4 clinical indicators were absent (probability = 1.6%). CONCLUSIONS: The presence of crying, abdominal mass, pallor, and vomiting were clinical indicators of intussusception. Individually, none of these variables were helpful in confirming the diagnosis but in the presence of all 4, there is a 95% probability of having the disease. The absence of all 4 of these made the likelihood of having the disease very low. PMID- 25272075 TI - Pediatric emergencies admitted in the resuscitation room of a Swiss university hospital. AB - OBJECTIVES: Pediatric resuscitation is an intense, stressful, and challenging process. The aim of this study was to review the life-threatening pediatric (LTP) emergencies admitted in a Swiss university hospital with regards to patients' demographics, reason for admission, diagnosis, treatment, significant events, critical incidents, and outcomes. METHODS: A retrospective observational cohort study of prospectively collected data was conducted, including all LTP emergencies admitted over a period of 2 years in the resuscitation room (RR). Variables, including indication for transfer, mode of prehospital transportation, diagnosis, and time spent in RR, were recorded. RESULTS: Of the 60,939 pediatric emergencies treated in our university hospital over 2 years, a total of 277 LTP emergencies (0.46%) were admitted in the RR. They included 160 boys and 117 girls, aged 6 days to 15.95 years (mean, 6.69 years; median, 5.06). A medical problem was identified in 55.9% (n = 155) of the children. Of the 122 children treated for a surgical problem, 35 (28.3%) went directly from the RR to the operating room. Hemodynamic instability was noted in 19.5% of all LTP emergencies, of which 1.1% benefited from O negative transfusion. Admission to the intensive care unit was necessary for 61.6% of the children transferred from another hospital. The average time spent in the RR was 46 minutes. The overall mortality rate was 7.2%. CONCLUSIONS: The LTP emergencies accounted for a small proportion of all pediatric emergencies. They were more medical than surgical cases and resuscitation measures because of hemodynamic instability were the most frequent treatment. PMID- 25272076 TI - Prevalence of serious bacterial infections in return visits to the emergency department among infants aged 90 days or younger. AB - OBJECTIVE: The main objective of this study was to describe the epidemiology of return visits (RVs) in well-appearing infants to an urban emergency department (ED) who were evaluated for serious bacterial infection (SBI) at their index ED visit. METHODS: We conducted a retrospective chart review on infants aged 90 days and younger who were evaluated for SBI at their initial ED visit from 2003 through 2009. A parent database of all febrile infants evaluated for SBI was queried to identify patients who had an RV within 7 days of the index visit. We collected demographic variables including age, sex, and past medical history as well as laboratory test results including white blood cell count, blood, urine, and cerebrospinal fluid cultures and viral studies. RESULTS: Of eligible febrile infants, 10.8% (350/3220) had an RV to the ED within 7 days. The prevalence of SBI in the RV cohort was 6.0% (21/350), which included 1.7% (6/350) bacteremia, 3.7% (13/350) urinary tract infection, and 0.6% (2/350) combined urinary tract infection and bacteremia. The blood culture contamination rate was 88%. CONCLUSIONS: Infants aged 90 days or younger who are evaluated for SBI have high RV rates. A substantial number of RVs are due to contaminated blood cultures. Future studies should be conducted to identify predictors for false-positive blood cultures. PMID- 25272066 TI - Aneurysmal Subarachnoid Hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (SAH) is a worldwide health burden with high fatality and permanent disability rates. The overall prognosis depends on the volume of the initial bleed, rebleeding, and degree of delayed cerebral ischemia (DCI). Cardiac manifestations and neurogenic pulmonary edema indicate the severity of SAH. The International Subarachnoid Aneurysm Trial (ISAT) reported a favorable neurological outcome with the endovascular coiling procedure compared with surgical clipping at the end of 1 year. The ISAT trial recruits were primarily neurologically good grade patients with smaller anterior circulation aneurysms, and therefore the results cannot be reliably extrapolated to larger aneurysms, posterior circulation aneurysms, patients presenting with complex aneurysm morphology, and poor neurological grades. The role of hypothermia is not proven to be neuroprotective according to a large randomized controlled trial, Intraoperative Hypothermia for Aneurysms Surgery Trial (IHAST II), which recruited patients with good neurological grades. Patients in this trial were subjected to slow cooling and inadequate cooling time and were rewarmed rapidly. This methodology would have reduced the beneficial effects of hypothermia. Adenosine is found to be beneficial for transient induced hypotension in 2 retrospective analyses, without increasing the risk for cardiac and neurological morbidity. The neurological benefit of pharmacological neuroprotection and neuromonitoring is not proven in patients undergoing clipping of aneurysms. DCI is an important cause of morbidity and mortality following SAH, and the pathophysiology is likely multifactorial and not yet understood. At present, oral nimodipine has an established role in the management of DCI, along with maintenance of euvolemia and induced hypertension. Following SAH, hypernatremia, although less common than hyponatremia, is a predictor of poor neurological outcome. PMID- 25272077 TI - Imaging of pediatric head injury in the emergency department. AB - OBJECTIVES: Computed tomography (CT) is the standard for immediate imaging of head-injured children, but it uses radiation that predisposes to malignancy. The study goals were to describe imaging practices in this population and to identify barriers to rapid magnetic resonance imaging (MRI) use. METHODS: A cross sectional survey of physicians who care for pediatric patients in emergency departments was conducted. Survey questions included hospital characteristics, access to imaging technology, use of imaging studies, and use of radiation reduction practices. RESULTS: A total of 459 eligible respondents completed the questionnaire, which represented a response rate of 24.1%. Almost all the respondents (97.7%) reported that radiation concerns influence clinical management of children and adolescents with head trauma. Head CT use was more frequently reported than MRI (55.3% vs 1.5% reported use in more than 10% of patients, respectively). Frequent CT use was associated with practice in community hospitals (P = 0.005), whereas pediatric residency training and pediatric volumes greater than 30,000 visits per year were associated with less frequent use (P = 0.015 and P = 0.028, respectively). In 94.5% of the respondents, reported CT was always available compared with 24.3% reporting MRI as always available (P < 0.001). Reported obstacles to MRI as a screening tool for head-injured children included limited scanner availability (93.5%), patient intolerance of MRI (87.2%), and longer acquisition times (83.3%). CONCLUSIONS: Concerns about radiation exposure motivate change of practice in the management of head-injured children and adolescents. Head CT use is greater at hospitals with lower pediatric volumes, community hospitals, and by providers without pediatric residency training. Obstacles to increased use of MRI or head-injured children include availability, patient intolerance, and long scan acquisition times. PMID- 25272078 TI - Changes in access to health services of the immigrant and native-born population in Spain in the context of economic crisis. AB - AIM: To analyze changes in access to health care and its determinants in the immigrant and native-born populations in Spain, before and during the economic crisis. METHODS: Comparative analysis of two iterations of the Spanish National Health Survey (2006 and 2012). Outcome variables were: unmet need and use of different healthcare levels; explanatory variables: need, predisposing and enabling factors. Multivariate models were performed (1) to compare outcome variables in each group between years, (2) to compare outcome variables between both groups within each year, and (3) to determine the factors associated with health service use for each group and year. RESULTS: unmet healthcare needs decreased in 2012 compared to 2006; the use of health services remained constant, with some changes worth highlighting, such as the decline in general practitioner visits among autochthons and a narrowed gap in specialist visits between the two populations. The factors associated with health service use in 2006 remained constant in 2012. CONCLUSION: Access to healthcare did not worsen, possibly due to the fact that, until 2012, the national health system may have cushioned the deterioration of social determinants as a consequence of the financial crisis. Further studies are necessary to evaluate the effects of health policy responses to the crisis after 2012. PMID- 25272079 TI - Bacterial meningitis: a density-equalizing mapping analysis of the global research architecture. AB - Bacterial meningitis is caused by a variety of pathogens and displays an important public health threat all over the world. Despite the necessity to develop customized public health-related research projects, a thorough study of global meningitis research is not present, so far. Therefore, the aim of this study was a combined density-equalizing and scientometric study. To evaluate the scientific efforts of bibliometric methods, density-equalizing algorithms and large-scale data analysis of the Web of Science were applied in the period between 1900 and 2007. From this, 7998 publications on bacterial meningitis have been found. With a number of 2698, most publications have been written by U.S. authors, followed by the UK (912), Germany (749) and France (620). This dominance can also be shown in the international cooperation. The specific citation analyses reveal that the nation with the highest average citation rate (citations per publications) was Norway (26.36), followed by Finland (24.16) and the U.S. (24.06). This study illustrates the architecture of global research on bacterial meningitis and points to the need for customized research programs with a focus on local public health issues in countries with a low development index, but high incidences, to target this global public health problem. PMID- 25272080 TI - MRSA: a density-equalizing mapping analysis of the global research architecture. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has evolved as an alarming public health thread due to its global spread as hospital and community pathogen. Despite this role, a scientometric analysis has not been performed yet. Therefore, the NewQIS platform was used to conduct a combined density-equalizing mapping and scientometric study. As database, the Web of Science was used, and all entries between 1961 and 2007 were analyzed. In total, 7671 entries were identified. Density equalizing mapping demonstrated a distortion of the world map for the benefit of the USA as leading country with a total output of 2374 publications, followed by the UK (1030) and Japan (862). Citation rate analysis revealed Portugal as leading country with a rate of 35.47 citations per article, followed by New Zealand and Denmark. Country cooperation network analyses showed 743 collaborations with US-UK being most frequent. Network citation analyses indicated the publications that arose from the cooperation of USA and France as well as USA and Japan as the most cited (75.36 and 74.55 citations per collaboration article, respectively). The present study provides the first combined density-equalizing mapping and scientometric analysis of MRSA research. It illustrates the global MRSA research architecture. It can be assumed that this highly relevant topic for public health will achieve even greater dimensions in the future. PMID- 25272081 TI - Immunogenicity and safety of a two-dose live attenuated varicella vaccine given to adults following autologous hematopoietic stem cell transplantation. AB - BACKGROUND: Immunogenicity and safety of varicella vaccine (Varilrix(TM) [Oka RIT]; GlaxoSmithKline Vaccines) in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT) were assessed (September 2003 to September 2007; NCT00792623). METHODS: Two Oka-RIT doses were given at 4.5 and 6.5 months post transplantation. Humoral immune responses were assessed using an immunofluorescence assay (anti-varicella zoster virus [VZV] antibody; cutoff 1:4) after each vaccine dose. Solicited local (8 day) and general (43 day), unsolicited (until day 43) adverse events (AEs) after each vaccine dose and serious adverse events (SAEs) (until 17.5 months post dose 2) were recorded. RESULTS: Of 45 patients, 19 were included in the according to protocol cohort for immunogenicity; 15 patients had pre- and post-vaccination serum samples positive for anti-VZV antibodies. Vaccine responses (anti-VZV antibody titer >=1:4 in seronegative patients, and >=4-fold increase in anti-VZV antibody titer in seropositive patients) were elicited by only 2 patients 2 months post dose 1, and by a single patient 1.5 months post dose 2. Although no major safety signals were detected, any and Grade 3 solicited AEs that were causally related to vaccination were reported by 44.8% and 10.3% patients, respectively. During the 43-day follow up period, 3 patients developed varicella-like rash (1 vaccine-type VZV). Beyond 43 days, herpes zoster was reported in 2 patients and wild-type varicella infection in 2 patients (1 was breakthrough infection). Four non-fatal SAEs were reported by patients and considered causally unrelated to vaccination. CONCLUSION: Oka-RIT was poorly immunogenic but safe when given to adults up to 6 months post autologous HSCT, and alternative strategies are required to prevent VZV-associated complications in these populations. PMID- 25272082 TI - [Meningioma of the lacrimal fossa]. PMID- 25272083 TI - [One-year results of small incision lenticule extraction (SMILE) in myopia]. AB - BACKGROUND: This clinical trial is focused on the 12-month results of a new method for refractive correction in myopia, called "small incision lenticule extraction" (SMILE). PATIENTS AND METHODS: In a prospective study 91 eyes were treated with the new refractive procedure and the results were published after 6 months. A lenticule of intrastromal corneal tissue is cut utilising the Carl Zeiss Meditec AG (Jena, Germany) VisuMax femtosecond laser system. Thereafter, this lenticule is manually removed without lifting a flap. 55 eyes of 33 patients volunteered for a 12-month follow-up. UCVA and BSCVA after 12 months, objective and manifest refraction as well as slit-lamp examination and late side effects were documented. RESULTS: 55 eyes of 33 patients were re-examined in this study 12 months after surgery. The spherical equivalent before surgery was - 4.66 (+/- 1.75) D; after 12 months - 0.11 (+/- 0.42) D was manifest. No significant change was observed compared to the 6-month control. Starting with UCVA of 0.1 (+/- 0.06) before surgery. UCVA was 1.02 (+/- 0.3) after 12 months. One eye lost more than two lines. All other patients did not have any late side effects. CONCLUSION: The one-year results of this new procedure are encouraging. Especially stability of the correction of myopia and myopic astigmatism with the SMILE procedure is very good. PMID- 25272084 TI - [Diverse effectiveness of the trabectome for different types of glaucoma]. AB - PURPOSE: Ab interno trabeculotomy using the trabectome device is a intraocular pressure (IOP) decreasing operation by ablation of the trabecular meshwork and the inner wall of Schlemm's channel. This prospective study analyses the effectiveness of the trabectome operation in 122 patients. PATIENTS AND METHODS: The operation was conducted when topical medication was maxed out with the intraocular pressure (IOP) remaining above the desired target range. In addition to the evaluation of the whole study group further analysis concerned the effectiveness of the trabectome in different subclassifications of glaucoma. In some cases the procedure was combined with cataract surgery and subsequently the results were compared to the plain trabectome OP. The results were split into two groups: "complete success" (without postoperative medication) and "qualified success" (with medication). The evaluation was processed for the IOP levels <= 21 mmHg, <= 18 mmHg, <= 15 mmHg und <= 12 mmHg. Follow-up dates were 6 and 12 months after surgery. RESULTS: Baseline IOP was 20.15 +/- 7.1 mmHg. After 6 months the average IOP of all patients was 16.53 +/- 5.89 mmHg, after 12 months the IOP amounted to 15.6 +/- 4.45 mmHg. At both follow-ups approximately 90 % of the "complete success" group exhibited an IOP <= 18 mmHg. Also at both follow-ups 75 % of the "qualified success" group achieved a range <= 18 mmHg - whereas 50 % gained an IOP <= 15 mmHg. In secondary glaucoma an IOP decrease of 36 % was achieved. In open-angle glaucomas and those with dysgenetic altered angles the operation evoked a pressure loss of ca. 20 %. The trabectome-only group as well as the group of combined surgery exhibited a significant lowering of IOP. This was accomplished by a significant reduction of eye drops. After surgery nearly half of all patients required none or 1 eye drop at most. CONCLUSION: The trabectome offers a safe and significant lowering of IOP for around 36 % and seems to be very effective in secondary glaucomas. In dysgenetic alterations and open-angle glaucoma a moderate lowering of IOP (ca. 20 %) may be expected. The amount of eye drops can be reduced for about 42 %. After surgery every second patient requires at most 1 eye drop. The technique can be combined with cataract surgery and permits a penetrating operation at a later date. PMID- 25272085 TI - [Complications after corneal cross-linking]. AB - PURPOSE: The introduction of corneal cross-linking was associated with great expectations from patients as well as ophthalmologists. Previous results indicate that corneal cross-linking can slow down, stabilise or even reverse the progression of corneal ectasia in patients with keratoconus as well as in patients with ectasia after excimer laser ablations. We now describe our own experience with different protocols for corneal cross-linking and put these into perspective with the existing literature. METHODS: We undertook a retrospective analysis of all of our corneal cross-linking treatments from January 2007 to July 2014 using different protocols. In addition, we provide an overview of the literature regarding complications of corneal cross-linking. RESULTS: In our patient cohort we observed sterile infiltrates, transient cloudy opacifications, diffuse lamellar keratitis and a mycotic infection leading to corneal scarring. Moreover, even after transepithelial corneal cross-linking with different protocols, we have observed pain perception and epithelial disruption. At present there are few reports about infections or endothelial damage in the literature, however, induction of neoplasia is described. The incidence of complications appears to be low. CONCLUSION: Corneal cross-linking appears to have a high success rate and a low complication rate. Endothelial damage seems to be a far smaller problem than initially suspected. However, prospective studies with long term follow-up are still lacking and it remains to be seen whether more cases of neoplasia following cross-linking will be reported. In our literature research we found no reports on re-treatments. Similarly, we found no study other than some case reports on keratoplasty after cross-linking. In view of rapidly changing treatment protocols further trials are warranted to monitor the benefits and complications of these modifications. PMID- 25272086 TI - [Minimally invasive glaucoma surgery using the trabectome]. AB - The main barrier reducing outflow of aqueous humor in open angle glaucomas is the juxtacanalicular trabecular meshwork. The trabectome removes this pathophysiologically altered tissue by electroablation, thus allowing for the collector channels draining Schlemm's canal to directly communicate with the anterior chamber. In studies published so far, about 30% decrease of intraocular pressure and a simultaneous 42% reduction of pressure-lowering eyedrops could be achieved in primary and secondary open angle glaucomas. A clear cornea tunnel is used to advance the trabectome to the trabecular meshwork, leaving the conjunctiva unaffected. Hence minimally invasive chamber angle surgery using this device is in particular suitable for patients with an altered ocular surface. Lowering of intraocular pressure and reduction of needed topical medication seems to be distinct in pseudoexfoliative glaucoma. Surgery with the trabectome and phacoemulsification can easily be combined in one procedure. Using a minimally invasive approach, the complication profile of the trabectome is rather advantageous, not exceeding the general risks of globe-opening surgery. Ab interno trabeculotomy is a safe and effective method for treatment of patients with primary or secondary open angle glaucomas and moderate target pressures. PMID- 25272087 TI - Quasiperiodic energy dependence of exciton relaxation kinetics in the sexithiophene crystal. AB - Femtosecond kinetics of fluorescence rise in the sexithiophene crystal is studied on a microscopic model of intraband relaxation, where exciton energy is assumed to be dissipated by phonon-accompanied scattering, with the rates calculated earlier. The temporal evolution of the exciton population is described by a set of kinetic equations, solved numerically to yield the population buildup at the band bottom. Not only the time scale but also the shape of the rise curves is found to be unusually sensitive to excitation energy, exhibiting unique quasiperiodic dependence thereon, which is rationalized in terms of the underlying model. Further simulations demonstrate that the main conclusions are robust with respect to experimental factors such as finite temperature and inherent spectral broadening of the exciting pulse, while the calculated fluorescence rise times are found to be in excellent agreement with experimental data available to date. As the rise profiles are composed of a number of exponential contributions, which varies with excitation energy, the common practice of characterizing the population buildup in the emitting state by a single value of relaxation time turns out to be an oversimplification. New experiments giving further insight into the kinetics and mechanism of intraband exciton relaxation are suggested. PMID- 25272088 TI - Identification of a new disease cluster of pemphigus vulgaris with autoimmune thyroid disease, rheumatoid arthritis and type I diabetes. AB - BACKGROUND: Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering skin disease. It is known that individuals with autoimmune diseases such as PV, as well as their family members, are at increased risk of developing other autoimmune diseases. However, it is unknown whether there are specific autoimmune diseases that cluster with PV. OBJECTIVES: To investigate the frequency of coexisting autoimmune diseases in patients with PV and their relatives, to determine the prevalence of specific autoimmune diseases in patients with PV vs. the general population and to identify statistically significant clinical clusters linking PV with other autoimmune disorders. METHODS: We performed a cross-sectional study and meta-analysis of patient data from our own patient database (n = 230), an anonymous online survey conducted by our laboratory (n = 171) and the International Pemphigus & Pemphigoid Foundation registry (n = 393). RESULTS: We found that the prevalences of autoimmune thyroid disease (AITD), rheumatoid arthritis and type 1 diabetes were significantly increased in patients with PV compared with the general population. These diseases were also among the most frequent in family members of patients with PV, in addition to systemic lupus erythematosus (SLE). Descriptive cluster analysis using basic principle components methods revealed that PV forms a distinct cluster with AITD, rheumatoid arthritis and type 1 diabetes, and another cluster with SLE, AITD and rheumatoid arthritis. CONCLUSIONS: PV belongs to an established autoimmune disease cluster that includes AITD, rheumatoid arthritis and type 1 diabetes. Our data suggest the possibility of common genetic elements across clinically distinct diseases that might underlie autoimmune susceptibility. PMID- 25272089 TI - Monoammonium glycyrrhizate suppresses tumor necrosis factor-alpha induced chemokine production in HMEC-1 cells, possibly by blocking the translocation of nuclear factor-kappaB into the nucleus. AB - Monoammonim glycyrrhizate (MAG) derived from licorice has been shown to have anti inflammatory properties. Chemokines are vital inflammatory mediators that are involved with endothelial damage from leukocyte infiltrates in various inflammatory skin diseases. In this study, we investigated the anti-inflammatory effects and mechanisms of MAG on tumor necrosis factor-alpha (TNF-alpha) induced chemokine production in a human dermal microvascular endothelial cell line (HMEC 1). HMEC-1 cells were treated with TNF-alpha, with or without MAG. The results showed that MAG suppressed TNF-alpha-induced chemokine (including CXCL8, CX3CL1, and CXCL16) mRNA expression in HMEC-1 cells, in a dose-dependent manner, and reduced the secretion of these chemokines in culture supernatant. Moreover, endothelial activation in the presence of MAG blocked the chemotactic activities of TNF-alpha-stimulated HMEC-1 cell supernatant on the migration of primary neutrophils and primary monocytes. In addition, Western blot and immunofluorescence data revealed that MAG inhibited nuclear translocation of nuclear factor-kappaB p65 (NF-kappaB p65). It is the first report to demonstrate that MAG suppresses TNF-alpha-induced chemokine production in HMEC-1 cells, and that the mechanism may be inhibiting the translocation of NF-kappaB p65 into the nucleus to prevent the starting of inflammatory signaling pathway. Our results revealed that MAG is a potential anti-inflammatory agent capable of improving inflammatory skin diseases. PMID- 25272090 TI - Age- and gender-related changes in glucose homeostasis in glucocorticoid-treated rats. AB - The disruption to glucose homeostasis upon glucocorticoid (GC) treatment in adult male rats has not been fully characterized in older rats or in females. Thus, we evaluated the age- and gender-related changes in glucose homeostasis in GC treated rats. We injected male and female rats at 3 months and 12 months of age with either dexamethasone (1.0 mg/kg body mass, intraperitoneally) or saline, daily for 5 days. All of the GC-treated rats had decreased body mass and food intake, and adrenal hypotrophy. Increased glycemia was observed in all of the GC treated groups and only the 3-month-old female rats were not glucose intolerant. Dexamethasone treatment resulted in hyperinsulinemia and hypertriacylglyceridemia in all of the GC-treated rats. The glucose-stimulated insulin secretion (GSIS) was higher in all of the dexamethasone-treated animals, but it was less pronounced in the older animals. The beta-cell mass was increased in the younger male rats treated with dexamethasone. We conclude that dexamethasone treatment induces glucose intolerance in both the 3- and 12-month-old male rats as well as hyperinsulinemia and augmented GSIS. Three-month-old female rats are protected from glucose intolerance caused by GC, whereas 12-month-old female rats developed the same complications that were present in 3- and 12-month-old male rats. PMID- 25272091 TI - Suberoylanilide hydroxamic acid suppresses inflammation-induced neovascularization. AB - Histone deacetylases (HDACs) regulate gene transcription by modifying the acetylation of histone and nonhistone proteins. Deregulated expression of HDACs has been implicated in tumorigenesis and angiogenesis. In this study, we examined the effect of suberoylanilide hydroxamic acid (SAHA), a potent inhibitor of HDACs, on inflammatory corneal angiogenesis. In a mouse model of alkali-induced corneal neovascularization (CNV), topical application of SAHA to the injured corneas attenuated CNV. In addition, in vivo treatment with SAHA downregulated the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor beta 1 (TGFbeta1), and epidermal growth factor (EGF), but upregulated the expression of the anti-angiogenic factors thrombospondin (TSP)-1, TSP-2, and ADAMTS-1 in the injured corneas. Furthermore, SAHA inhibited the expression of pro-angiogenic factors, migration, proliferation, and tube formation by human microvascular endothelial cells (HEMC-1) in vitro. These data indicate that SAHA has therapeutic potential for CNV. PMID- 25272092 TI - Smoothelin-B is not a target of matrix metalloproteinase (MMP)-2 in the vasculature of endotoxemic rats. AB - Smoothelin-B (SMTL-B) and calponin-1 are important regulators of vascular contraction. SMTL-B contains a calponin-homology domain and is structurally similar to cardiac troponin T. As calponin-1 and troponin T are proteolyzed by intracellular matrix metalloproteinase (MMP)-2 in oxidative stress injury, we hypothesized that SMTL-B is also cleaved by MMP-2 and contributes to lipopolysaccharide (LPS)-induced vascular hypocontractility. Rats received ONO 4817 (an MMP inhibitor) or its vehicle, 2 h prior to being administered lipopolysaccharide (LPS). LPS-induced aorta hypocontractility to potassium chloride or phenylephrine, and reduction of calponin-1 levels, were abolished by ONO-4817 at 6 but not 3 h after LPS. However, the level of SMTL-B was unaltered in LPS aortas and further unaffected by ONO-4817. Despite the importance of SMTL B in vascular tone, it is not a target of MMP-2 in LPS-induced hypocontractility. PMID- 25272093 TI - Azimuthal polarization filtering for accurate, precise, and robust single molecule localization microscopy. AB - Many single nanoemitters such as fluorescent molecules produce dipole radiation that leads to systematic position errors in both particle tracking and super resolution microscopy. Via vectorial diffraction equations and simulations, we show that imaging only azimuthally polarized light in the microscope naturally avoids emission from the z-component of the transition dipole moment, resulting in negligible localization errors for all emitter orientations and degrees of objective lens misfocus. Furthermore, localization accuracy is maintained even in the presence of aberrations resulting from imaging in mismatched media. PMID- 25272094 TI - Examining the Time to Improvement of Sleep Interference With Pregabalin in Patients With Painful Diabetic Peripheral Neuropathy and Postherpetic Neuralgia. AB - Pregabalin has been shown to be a safe, effective treatment for neuropathic pain associated with painful diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN), with average time to reduction in pain of 2 days. Pain-related sleep interference is commonly reported in both painful DPN and PHN. These post hoc analyses examined the time to improvement in sleep with pregabalin in patients with painful DPN or PHN, measured by reduction in daily sleep interference (DSI) scores on an 11-point numeric rating scale. A total of 4527 patients from 16 placebo-controlled trials of pregabalin for treatment of painful DPN or PHN were included in the analysis. In these trials, there were a total of 16 pregabalin treatment arms for painful DPN (75-600 mg/d), 10 for PHN (150-600 mg/d), and 3 for painful DPN/PHN (150-600 mg/d). Time to improvement in DSI scores was calculated for all treatment arms that demonstrated statistically significant reductions in DSI scores during the first 14 days of treatment compared with placebo (23 of 29; 79.3%) and was defined as the first day DSI scores for that day and the following day were significantly lower than placebo (P < 0.001). Mean (SD) time to improvement in DSI scores was 1.6 (1.3) days. Sustained improvement (>=1-point improvement in mean DSI score) was seen significantly earlier for pregabalin DSI responders than patients receiving placebo. These findings demonstrate that statistically significant and sustained improvement in sleep occurs rapidly (within 1 day for some patients) in response to treatment with pregabalin. PMID- 25272102 TI - An epizootic of chilodonelliasis in farmed barramundi Lates calcarifer (Bloch), a case report. PMID- 25272105 TI - [Environmental justice: integrating science and social movements]. PMID- 25272104 TI - Marburgvirus resurgence in Kitaka Mine bat population after extermination attempts, Uganda. PMID- 25272106 TI - [(Un)sustainable development of the sugarcane agribusiness]. AB - In the past few years the sugarcane agribusiness has been experiencing considerable expansion, being presented as a symbol of progress and the most developed industry in the country. In this article, we investigate the myths surrounding this sector of the Brazilian economy, revealing the environmental injustices and suffering experienced by northeastern workers who relocate every year to work in the sugarcane regions. We conducted a methodological study of the specialized literature on the sugarcane agribusiness and its interface with the migration of northeastern workers and the labor conditions and relations to which these individuals are subjected. We also use data from our own research developed in the micro regions of Pajeu in the State of Pernambuco and Princesa Isabel in the State of Paraiba. The data reveal the human and environmental unsustainability of the sugarcane agribusiness, demystifying the sweetness of sugarcane and purity of ethanol produced in Brazil, since this production is strongly influenced by perverse conditions, the social consequences of which have been the destruction of the environment and the flora and fauna, the exploitation of labor and workers in this process marked by illness and, in many cases, death. PMID- 25272107 TI - [Adhering to or resisting tobacco cultivation? Stories of rural workers from a producing region in southern Brazil]. AB - This study sought to understand the standpoints of farming families who have resisted or abandoned tobacco cultivation and also the perceptions of State representatives, civil society organizations and the tobacco industry regarding the implementation and the continuity of this cultivation in a producing region in southern Brazil. In this ethnographic study, 27 semi-structured interviews were conducted with farming families and key informants. Besides that, participant observation was conducted. For those who abandoned tobacco cultivation, the main reason mentioned was indebtedness, and for those who have never planted, the main reasons alleged were fear of indebtedness, a limited workforce or religious issues. State representatives and civil society organizations highlighted illusory financial returns as the main reason for tobacco cultivation. Tobacco industry representatives insisted on the difficulty of commercializing the production and the low price of foodstuffs as a stimulus to adhere to the integrated system. It is therefore concluded that the formation of associations and the development of crop rotation plans are important strategies to be adopted to facilitate the change of cultivation in order to promote better working and living conditions for the rural population. PMID- 25272108 TI - [Health and environment in the rubber-tree plantations in the Bolivian Acre (1870 1903): the role of exogenous factors and processes]. AB - A peculiar situation marks the conditions of human and environmental health in the first major cycle of rubber production in the Acre region of the Western Amazon, whereby the bulk of the boom (1870-1903) occurred in the territory that at that time still belonged to Bolivia. Based on this historical background, this work seeks to describe and comprehend how these factors and processes, which are exogenous to these two fields of analysis mediated the risks that originated in the environment, gave rise to sickness and death in the population of the "Brazilian" rubber-tree plantations established in Bolivian territory. In this manner, the inter-relations between health and environment linked to historically specific configurations of the physical-natural, socioeconomic, political, and cultural conditions, are examined. The work shows that these extrinsic factors and processes to the productive activities exerted an influence not only on its organizational but also functional aspects, while also resulting in the unhealthy conditions observed in the productive regions. It further highlights the fact that the extant infrastructure of the time was sufficient for extractive production and reproduction. PMID- 25272109 TI - [Deterritorialization of artisanal fisheries in Sepetiba Bay (State of Rio de Janeiro, Brazil): an overview of occupational health and environmental issues]. AB - This paper outlines the consequences of deterritorialization of artisan fishing folk in Sepetiba Bay in the State of Rio de Janeiro on the occupational and health status of this population living in the area. By means of the concept of social determinants in health, it compares the new patterns of growth in the region with the living and occupational health conditions of these workers. This relationship was explained after conducting semi-structured interviews and focus groups. The results point to a strong relationship between the port undertakings and the installations of the nuclear program of the Brazilian Navy with subsistence and extractive fishing, contributing to an increase in the time spent at sea and the inherent occupational risks involved in subsistence fishing. This is in addition to the economic and environmental impacts on the productivity and quality of fishing production, which are a direct consequence of the dredging works and the new navigation and anchoring norms established and imposed by the state. PMID- 25272110 TI - [Towards a dialogue of knowledge between subsistence fishermen, shellfish gatherers and environmental labor law]. AB - The dialogue of knowledge between subsistence fishermen and shellfish gatherers on the right to a healthy working environment is established as a new process for claims for an improvement in working conditions by populations affected by environmental problems, and especially in Todos os Santos Bay (BTS). The communities surrounding the BTS have complained to the State Public Prosecutor about the harmful effects to health and the environment caused by the Aratu Industrial Complex and the Port of Aratu. Researchers in the fields of, chemistry, toxicology, oceanography, biology and medicine from the Federal University of Bahia (UFBA) have demonstrated the effects of contamination on the BTS in sundry scientific publications. The scope of this article is to reflect on the contribution of that dialogue on environmental labor law (DAT) in Brazil. The methodology of this study involved semi-structured interviews, participant observation and document analysis. The conclusion reached is that environmental labor law in Brazil must include the dialogue of knowledge to ensure access to a healthy working environment for subsistence fishermen and shellfish gatherers. PMID- 25272111 TI - [The implications of economic development on work, the environment and health in port communities in the State of Ceara, Brazil]. AB - This paper discusses aspects of economic development and the implications on work, the environment and health in the surrounding communities of the Industrial and Harbor Complex in Pecem in the State of Ceara. Qualitative research was adopted as the methodological strategy, by conducting participatory research with document analysis and a focus group. The reports of the subjects involved in the fieldwork were analyzed as being representative of their perceptions regarding the changes occurring in the territory and the impacts on health. Results observed in the use and appropriation of land by entrepreneurs are based on a belief in progress and development, contradicting the way of living, producing and interacting with nature submitted by the community that seeks to resist this intervention supported by social movements. These changes are out of step with the development of other public policies to mitigate the impacts with regard to environmental protection of the territory and the promotion of the health of this population. PMID- 25272112 TI - [Between everyday practices and interventions: narrative fragments on environmental degradation and health in Aracaju, Brazil]. AB - The scope of this paper is to describe the relationship between health production, urban growth and environmental degradation in the community of the "Urban Expansion Zone" of Aracaju in the State of Sergipe. It also touches on the impacts on the health of the population due to tourism and real estate speculation associated with the absence of basic services. Based on the assumption that illnesses caused by such changes only appear on the public health care system as a worsening of symptoms, neglecting the complex health-environment relationship, this paper highlights the possibility of pondering the bases upon which urban growth occurs in the light of imminent environmental degradation. The activities of health community agents were monitored duly connecting them to regional growth and environmental degradation. This was done from March 2010 and June 2011 adopting the ethnographic perspective as the method of choice. Other ways of inclusion in the community were mapped: contact with older residents, religious leaderships and the members of the traditional professions, etc. The results show the changes that have been occurring in the region, especially with respect to the extinction of traditional practices, increase in violence, unemployment, loss of community ties and illness. PMID- 25272113 TI - ["'Vazanteiros' in motion": the process of "environmentalization" of their territorial fights in the context of ecological modernization policies]. AB - This text presents the process of environmentalization of the social campaigns of Pau Preto, Pau de Legua and Quilombo da Lapinha in the north of the State of Minas Gerais that culminated in their being re-named as "'Vazanteiros' in Motion." The analysis of the territorial environmental conflict examines it from the perspective of Political Ecology and Critical Sociology. Documents from public environmental and judicial institutions were analyzed as well as meeting and research reports referring to the process of social mobilization and political formation of the "Vazanteiros in Motion." Ethnographic fieldwork was conducted from 2006 to 2012 and the different actors involved in the conflict were interviewed. The "extended-case method" or "situational analyses" were also used in order to demonstrate the ethnographic social events from a procedural and historical perspective. The results revealed the contradictions in sustainable development ideology, which made it possible to consolidate the agribusiness in that region through the creation of parks for irrigated fruit production projects as an environmental compensation strategy and the emergence of an important social movement of territorial claims in the environmental field. PMID- 25272114 TI - [Socio-ecological super-determination of health in rural areas in Humaita, State of Amazonas, Brazil]. AB - The scope of this article is to apply a trans-disciplinary socio-ecological approach to discuss the super-determination of health in rural areas of the southern Amazon region from a case study developed in Humaita in the State of Amazonas in Brazil. Field data were collected using ethnographic techniques applied during three expeditions in Humaita's rural area between 2012 and 2014. Based on the 'socio-ecological metabolism' analytical category, a descriptive and theoretical analysis of four crucial components in the process of super determination of local health are presented: (1) the composition of the local rural population; (2) fixed and changing territorial aspects; (3) construction of socio-ecological identities; (4) ethnic conflict between Indians and non-Indians. The conclusion reached is that the incorporation of a socio-ecological approach in territorial-based health research provides input for analyses of the local health situation through the systematization of information related to the process of super-determination of health. It also helps in the construction of trans-disciplinarity, which is a necessary epistemological condition for addressing the complex reality at the interfaces of social production, the environment and health. PMID- 25272115 TI - [Health, globalization and interculturalism: an anthropological approach to the situation of indigenous peoples in South America]. AB - This article reflects upon the impact of globalization and interculturalism on the living conditions of indigenous peoples in South America. Through two examples - Bolivia and Argentina - it is seen how health interculturalism has transformed into a discourse and a practice that both global organizations and most Latin American countries have used to assimilate and attract indigenous communities. Traditional medicine is respected and valued without proposing changes to improve the living conditions of these population groups. This is especially true in those areas where land is being expropriated or contaminated with the extraction of gas, oil, minerals and the construction of dams, along with indiscriminate deforestation of the rainforest. Health/illness cannot be separated from the territorial conditions of these peoples since environmental health is critical for their survival. PMID- 25272116 TI - [Collective health, territorial and environmental conflicts: bases for a critical socio-environmental approach]. AB - The phenomenon of globalization and the increase in neo-extractivism in the global periphery intensify the search for new territories and natural resources for the economy, resulting in significant impacts on ecosystems and on the lives of vulnerable populations. It is considered that the environmental crisis imposes new challenges and requires an updating of the theoretical and methodological foundations of collective health and the social determinants of health. The scope of this paper is to present theoretical contributions to the construction of a critical socio-environmental approach from a review of the literature structured around previous work on the mapping of environmental conflicts, and conducting empirical studies in conflicting areas. The contributions of sociology, political ecology, postcolonial studies and geography is summarized for the discussion of the socio-environmental determinants of health, as well as experiences that integrate emancipatory knowledge, political subjects, resistances and alternatives for society. PMID- 25272117 TI - [Challenges for the construction of 'Health and Environment "in view of its Thematic Group in the Brazilian Association of Collective Health]. AB - 'Health and Environment' is the nucleus of knowledge and practices surrounding the relations between society and nature, mediated by the mode of production and human labor, which help to understand the determination of the health-disease process of different social classes and groups. This paper discusses the challenges to build this field from the perspective of its Thematic Group of the Association of Collective Health. The three core themes of the 2nd Brazilian Symposium on Environmental Health are taken as the theoretical framework for analysis. A timeline of the group's trajectory, in its historical context, helps to identify the contemporary challenges. Among the main challenges identified, the challenge of building an interdisciplinary, intersectoral and participatory scientific practice, which could build knowledge and dialogue with social movements, is highlighted. PMID- 25272118 TI - [The applicability of the ecology of knowledge in health and environment and its permeability in the scientific literature]. AB - A new epistemology makes it imperative for different knowledge to be incorporated in order to understand and interact with the complex problems that affect humanity, especially those associated with health and the environment. The study aims to explore the applicability of the ecology of knowledge in the midst of traditional scientific literature, focusing on participatory approaches to questions of health and the environment. The methodology involved a bibliographic review of an international scientific database, with the inclusion of 170 papers that were classified by their participatory approaches as: timely; multi-tool; and ongoing/cyclic. Although timely and multi-tool approaches may be effective in terms of aggregating popular knowledge, which is systematically marginalized by traditional science, it is in the ongoing/cyclic approaches that a higher level of potential dialogue is achieved, since it is possible to identify aspects inherent to more symmetric participation processes, with the prospect of empowerment of the social actors and legitimate incorporation of subjectivity and diversity. This corresponds to the premise that promoting global cognitive justice is indispensable for achieving global social justice. PMID- 25272119 TI - [Epistemological/methodological contributions to the fortification of an emancipatory con(science)]. AB - This article conducts a critical and reflective analysis into the paths of elaboration, sistematization and communication of the results of research in conjunction with colleges, social movements and individuals in the territory under scrutiny. For this, the article embraces as the core analytical theme the process of shared production of knowledge, both in the epistemological methodological field and with respect to its social destination. The case study was adopted as the methodology, preceded by the use of focused groups and in depth interviews as technique. To analyze the qualitative material discourse analysis was adopted in line with the assumptions of in-depth hermeneutics. The results are presented in two stages: Firstly, the new possibilities for a paradigmatic reorientation are discussed from the permanent and procedural interlocution with the empirical field and it's different contexts and authors. Secondly, it analyzes in the praxiological dimension, the distinct ways of appropriation of knowledge produced in dialogue with the social movements and the individuals in the territory under scrutiny. It concludes by highlighting alternative and innovative paths to an edifying academic practice. which stresses solidarity and is sensitive to the vulnerable population and its requests. PMID- 25272120 TI - [Health, environment and territory: a necessary discussion in health training]. AB - Environmental degradation has been affecting ecosystems and causing the imbalance of various life forms that comprise natural diversity, and consequently produce risks and hazards to public health. Therefore, an attempt was made to examine interdisciplinary health and environmental health in public undergraduate institutions of higher education involving the application of the concept of territory. It adopted qualitative research with a descriptive and exploratory approach to undergraduate courses in health of the seventeen undergraduate programs in health in the four state universities of the State of Bahia. It was detected that despite curriculum changes in undergraduate courses in health over the past few years, the model of professional training has focused on technical and non-preventive practices, which highlights a gap in the relationship between health/environment and the protection of life. This causes the undergraduate courses in health to minimize the association between diseases, health and environmental issues, taking into account that such issues should be addressed as a cross-sectional theme in undergraduate health, emphasizing the need for more discussion and better incorporation of environmental issues in the healthcare field. PMID- 25272121 TI - [Congenital defects in the cities with high use of pesticides in the state of Mato Grosso, Brazil]. AB - Mato Grosso is the largest agricultural producer and the largest national consumer of pesticides in Brazil. Maternal exposure to pesticides in the periconceptional period has been associated with increased risk of congenital malformations. This article aims to analyze the association between the use of pesticides and congenital malformations in cities with highest exposure to pesticides in Mato Grosso. It was a case-control study conducted with 219 live births with congenital malformations and 862 live births. The average use of pesticides was estimated in the prior and subsequent trimester to the date of fertilization and throughout the periconceptional period per city, month and year of use. Subsequently, these measures were quartilized and transformed into indicator-type (dummy) variables, attributing an exposure level for each interquartile interval. Bivariate and multivariate logistic regression analysis was conducted. Significant associations were observed (p < 0.05) in the third (OR = 1.66, 95% CI 0.98 to 2.79) and fourth quartile (OR = 1.88, 95% CI 1.09 to 3.24) of the post-fertilization period and the fourth quartile (OR = 2.04, 95% CI 1.17 to 3.56) throughout the periconceptional period. Maternal exposure to pesticides was associated with higher incidence of congenital malformations. PMID- 25272122 TI - [Spatial analysis of integrated determinant indicators of mortality from acute diarrhea in children under 1 year of age in geographical regions]. AB - The scope of this study is to perform spatial analysis of integrated environmental and health indicators related to the factors affecting mortality due to diarrhea in children under 1 year of age in Brazilian regions in 2010. Seven environmental indicators, compiled from the IBGE System for Automatic Recovery of the Population Census 2010 database, were formulated. The data with respect to deaths due to diarrhea in children under 1 year of age and live births were obtained from the databases of the Mortality Information Systems and the Live Births Information System of the IT Department of the Unified Health System. The microregions located in the North and Northeast regions revealed 5 and 4 times the rate of mortality in 2009, respectively, due to diarrhea in children under 1 year of age than the Southern Region. Children under 1 year of age living in the microregions located in the North and Northeast are more exposed to risk of death from diarrhea, since the worst figures for the environmental indicators related to poverty and sanitation are concentrated in these locations. In this sense, social, economic, environmental, cultural and health public policies should be based on the principle of equity to address the different local needs of each region. PMID- 25272123 TI - [Costs of air pollution in Brazilian metropolitan regions]. AB - This study evaluated the economic impact of health events associated with air pollution in Brazilian metropolitan regions. From the estimated mortality attributable to concentrations of particulate matter (PM) in 29 metropolitan areas, with a total of 20,050 deaths, the costs associated with mortality were calculated by means of the use of DALY (Disability Adjusted Life Years) methodology. The cost of premature deaths in Brazil resulted in $ 1.7 billion annually. Translating losses in public health to economic values served to compare this data with the expense budget of the Ministry of Health and highlight priorities in decision-making of public policies that minimize the magnitude of these impacts. PMID- 25272124 TI - [The climate change policy of the city of Sao Paulo, Brazil: reflexivity and permeability of the health sector]. AB - Sao Paulo is today an unsustainable city in which social and environmental vulnerabilities are obliged to tackle the uncertainties of climate change. To face up to this situation, in 2009 the city unveiled its Climate Change Policy. The scope of this paper is to analyze how the health sector is preparing to contribute to the implementation of this policy by 2012. Content analysis was the method adopted by examining official documents and conducting semi-structured interviews. In a context of social transformation affected by environmental degradation and socio-environmental consequences there is a need for the cessation of inertia and a demand for new knowledge systems. The outcomes of the study showed a positive intersectorial dialectic relationship, since the research hypothesis was that the health sector would be called upon to back actions on air quality monitoring. Its verification showed a broad scope introducing health promotion and preventive actions as the determinant focus, especially influencing other public policies. Thus, the process under scrutiny acquired reflexivity when evolving with interactive measures breaking with the traditional sectorial and reductionist policy model. It shows an intersectorial perspective based on the importance of issues related to local public health. PMID- 25272125 TI - [Construction and validation of a socio-environmental vulnerability index for monitoring and management of natural disasters in the state of Rio de Janeiro, Brazil]. AB - Floods account for approximately 40% of natural disasters that occur around the world and they are therefore considered a major public health problem. While floods constitute a global problem, data from the International Strategy for Disaster Reduction showed that almost all of the deaths or individuals affected are concentrated in developing countries. It is assumed that, although they have natural causes, the consequences of floods also involve social issues. To try to predict such vulnerability in the occurrence of natural disasters, a social and environmental index that shows the degree of vulnerability of a location was developed in this paper. This index was developed using multivariate analysis involving factor analysis and demographic, social and environmental variables. The index was applied in the municipalities of the state of Rio de Janeiro and compared with the official figures of the Civil Defense Unit. The results found suggest that the proposed index meets the expectation of predicting the vulnerability of the local population. PMID- 25272126 TI - [Surveillance of drinking-water quality: assessing the degree of implementation of actions]. AB - This study aims to evaluate the Drinking-Water Quality Surveillance Programme (DWQS) implemented in Colombia. The study was conducted using methodology for assessing the implementation, integrating a normative assessment and evaluation research. For this assessment, Delphi methodology was developed that allowed the definition of an evaluation matrix, composed of 14 attributes and 62 criteria, as well as the building of a score system and parameters that permitted the evaluation of each of the defined criteria. Data collection involved conducting semi-structured interviews with institutional actors from 39 territorial units. The system evaluation showed that the DWQS in Colombia is partially implemented, with different stages of implementation in territorial units. The system showed a strengthening in actions related to data production on the aspect for improving water quality and DWQS actions from the standpoint of health promotion. However, some conceptual limitations were identified in terms of legislation thereby affecting the fulfilment of the universality of DWQS actions. PMID- 25272127 TI - [The sorting of recyclable waste and the variables inherent to the process: a case study in a cooperative]. AB - Informal labor with recyclable materials is marked by social exclusion and discrimination, besides this activity being conducted in unsanitary conditions. The literature suggests that the problems associated with the sorting of recyclable waste are associated with lack of structure, contact with the "garbage", lack of government support, lack of training, lack of safety equipment, among others. The scope of this paper is to describe the process of sorting recyclable waste in a cooperative in Franca in the state of Sao Paulo. The specific objective was to identify the variables inherent to the process and investigate how workers adjust their work schedules to deal with these variables. The research method used is the case study with an operationalized ergonomic approach at some stages of the ergonomic analysis of work. Exploratory visits, indirect observations and semi-structured interviews were conducted. The results showed that the variables inherent to the process require that workers perform timely management sessions, which can be either collective or individual, though this invariably results in overload in the workplace, either by speeding up the work output or by demanding the increased concentration of those involved. PMID- 25272128 TI - [Rural work and health risks: a review into de "safe use" of pesticides in Brazil]. AB - The paradigm of the "safe use" of pesticides is based on measures to control risks in the handling of these products. However, studies carried out in various regions of Brazil reveal a situation of widespread exposure and health damages among rural workers, revealing the ineffectiveness of this paradigm. This work presents a critical review of the "safe use" approach for pesticides in scientific papers published in Brazil in the past 15 years. Results indicate that these studies do not address, simultaneously, all the work activities that involve exposure and risk of intoxication (acquisition, transportation, storage, preparation and application, final disposal of empty containers and sanitization of contaminated clothes/ PPEs), nor do they comprehensively address the "safe use" measures recommended in safety manuals, which are mandatory for each activity. A total of 25 studies were selected and analyzed, revealing a high number of results and analyses regarding activities of preparation and application and final disposal of empty containers. The range of the approaches was seen to be timely in the six work activities. For future studies, a broader approach of the "safe use" of pesticides is recommended, seeking to reveal the complete infeasibility of this safety paradigm. PMID- 25272129 TI - [Decision modeling for economic evaluation of health technologies]. AB - Most economic evaluations that participate in decision-making processes for incorporation and financing of technologies of health systems use decision models to assess the costs and benefits of the compared strategies. Despite the large number of economic evaluations conducted in Brazil, there is a pressing need to conduct an in-depth methodological study of the types of decision models and their applicability in our setting. The objective of this literature review is to contribute to the knowledge and use of decision models in the national context of economic evaluations of health technologies. This article presents general definitions about models and concerns with their use; it describes the main models: decision trees, Markov chains, micro-simulation, simulation of discrete and dynamic events; it discusses the elements involved in the choice of model; and exemplifies the models addressed in national economic evaluation studies of diagnostic and therapeutic preventive technologies and health programs. PMID- 25272130 TI - [Excluded mountain populations, unsustainable cities: the enigma of public participation]. AB - By highlighting the extreme event of 11-12 January 2011 in the mountain cities of the state of Rio de Janeiro, Brazil, an attempt is made to exemplify the triad paradigmatically: contemporary problems / government inability to adapt / low public participation, and highlight the issue with some reflections on the gap between discourse on social participation and its inexistence. The goal is to elicit reflection that generates a polemic regarding the technical nature of the scientific reports produced and thus be able to integrate the overriding question into the set of reflections: How can one plan more resilient locations that are simultaneously socially equitable, have economic vitality, are environmentally compatible and less vulnerable to disasters? The reflections are the result of the analysis of technical and scientific documents. PMID- 25272131 TI - [External evaluation of hospital organizations in Brazil: could things be done differently?]. AB - This paper addresses different aspects related to the use of external evaluation models of health services in Brazil, especially hospital accreditation. It is based upon the author's experience in implementing quality evaluation models in hospitals, as well as on her master and PhD works. The author presents a few aspects concerning the impact of the use of these models in hospitals and the specificities of their application. The results are listed: management enhancement, standardization of processes, personnel training, teamwork, patient focused care, motivation, external recognition, culture change. The author points out the sundry aspects concerning the way such models are used in Brazilian hospitals. PMID- 25272132 TI - [Maternity during adolescence: negative emotional indicators and associated factors in 14 to 16-year-old mothers from Porto Alegre in the State of Rio Grande do Sul, Brazil]. AB - The prevalence of negative emotional indicators and associated factors in 430 adolescent mothers between 14 to 16 years of age in Porto Alegre in the State of Rio Grande do Sul was detected. Socio-demographic variables, social and family relationships, reproductive aspects, abuse and violence were studied. The prevalence rate (PR) was obtained by Poisson regression using hierarchical analyses. The prevalence of intense psychological distress was 32.6%, and it was associated with low social class, grade repetition, bad relationship with the mother, lack of acceptance of the pregnancy by the father, and lack of family support during pregnancy. The prevalence of negative self-esteem was 15.4%, and it was associated with the bad relationship with the mother and not having a person to confide in. Little or no expectation for the future was found in 7.5% of the adolescents and was associated with grade repetition, nurturing by the biological mother, early sexual initiation, and the occurrence of physical abuse. The high prevalence of psychological distress found in the adolescent mothers of this study deserves special attention from the public policies in health in order to include qualified professionals to manage the emotional aspects of early motherhood. PMID- 25272133 TI - [The use of dental services among preschool children: a population-based study]. AB - The prevalence and factors associated with the use of dental services in a representative, probabilistic, complex sample with two-stage clusters of preschoolers aged 18 to 36 months was estimated. Structured questionnaires were answered by parents/guardians and the preschoolers were assessed by trained and qualified dental surgeons. In the analysis the corrections for the design effect were considered and the magnitudes of the associations based on logistic regression (OR/IC 95%) were estimated. 809 preschool children were evaluated, 15.5% of which had used dental services. Being older (3.27/1.71-6.24), having higher per capita income (2.65/1.50-4.65), having their own house (1.83/104 3.23), having access to preventive oral health information (5.44/3.00-9.86), flossing (2.75/1.50-5.02) established higher odds of the use of these service. Not having the experience of caries (0.22/0.13- 0.38) and not having basic lesions in soft tissues (0.10/0.01-0.77) reduced these odds. The prevalence of the use of dental services was low, indicating the need for greater provision of such services and the broadening of preventive actions and health promotion and the greater the odds of use among those with better socio-economic conditions suggests inequality. PMID- 25272134 TI - [Reliability of the diagnoses of hospital admissions for external causes financed by the Brazilian Unified Health System-SUS in two cities in the State of Parana, Brazil]. AB - The scope of this article is to analyze the reliability of the diagnoses of hospital admissions for external causes financed by the Brazilian Unified Health System (SUS). The diagnoses for hospital admissions from the Hospital Information System (SIH-SUS) data were compared with those from the research panel created from information culled from authorizations for hospital admission (AIH) complemented with information from other sources. The reliability was analyzed in groups using crude agreement and Kappa statistics. The crude agreement was 41.1% in Londrina and 15.8% in Maringa and the highest reliability was found for groupings for self-inflicted lesions and traffic accidents in Londrina (Kappa 0.57 and 0.56) while in Maringa reliability was acceptable for self-inflicted lesions (Kappa 0.28). The low agreement with differentiated standards according to groupings of causes and according to the municipalities highlight the fact that efforts must be made to improve the quality and use of the SIH-SUS in order to understand and intervene in accidents and violence in Brazil. PMID- 25272135 TI - [Factors associated with the report and adolescent abuse in primary healthcare]. AB - This study aimed to analyze factors associated with the reporting of child and adolescent abuse in primary healthcare. It is a cross-sectional study conducted with 381 professionals (physicians, nurses and dental surgeons) from three healthcare regions of the state of Ceara, Brazil. It used a self-administered questionnaire asking for socio-demographic data, vocational education and training, instrumentation and knowledge on the issue, identification and reporting of abuse cases. Bivariate and multivariate analyses using logistic regression were performed. There was a frequency of 17% of abuse reporting by basic healthcare professionals. The multivariate analysis showed that participating in the training on the issue (OR = 2.18; CI95% = 1.05-4.53), being familiar with the reporting form (OR = 3.03; CI95% = 1.47-6.24) and knowing how to refer the case properly (OR = 2.55; CI95% = 1.01-6.43) increased the chance of professionals reporting child and adolescent abuse. The variables identified in the final model showed a direct association between the act of reporting and matters related to knowledge and training on the issue. Investments in the training of healthcare professionals are required in order to favor the qualification of the practice for this public health problem. PMID- 25272138 TI - Chikungunya: emerging threat to the United States. PMID- 25272139 TI - Borrelia garinii and Rickettsia monacensis in Ixodes ricinus ticks, Algeria. PMID- 25272140 TI - Anion-induced supramolecular isomerism in two Preyssler P5W30 polyoxometalate based hybrid materials. AB - Two extended Preyssler P5W30 polyoxometalate-based inorganic-organic hybrid materials exhibiting anion-induced supramolecular isomerism were reported. Because of the cis-trans isomerism in the octahedral CoN2O4 coordination geometry, the Preyssler P5W30 polyoxometalates are extended by double O-Co-O bridges in 1alpha and a single O-Co-O bridge in 1beta to form the isomeric 2D 4 connected 4(4)-sql and 3D 8-connected bcu networks, respectively. Both compounds show electrocatalytic abilities on the reduction of H2O2. PMID- 25272141 TI - The telehealth satisfaction scale: reliability, validity, and satisfaction with telehealth in a rural memory clinic population. AB - INTRODUCTION: Patient satisfaction is a key aspect of quality of care and can inform continuous quality improvement. Of the few studies that have reported on patient satisfaction with telehealth in programs aimed at individuals with memory problems, none has reported on the psychometric properties of the user satisfaction scales used. MATERIALS AND METHODS: We evaluated the construct validity and internal consistency reliability of the Telehealth Satisfaction Scale (TeSS), a 10-item scale adapted for use in a rural and remote memory clinic (RRMC). The RRMC is a one-stop interprofessional clinic for rural and remote seniors with suspected dementia, located in a tertiary-care hospital. Telehealth videoconferencing is used for preclinic assessment and for follow-up. Patients and caregivers completed the TeSS after each telehealth appointment. With data from 223 patients, exploratory factor analysis was conducted using the principal components analysis extraction method. RESULTS: The eigenvalue for the first factor (5.2) was greater than 1 and much larger than the second eigenvalue (0.92), supporting a one-factor solution that was confirmed by the scree plot. The total variance explained by factor 1 was 52.1%. Factor loadings (range, 0.54 0.84) were above recommended cutoffs. The TeSS items demonstrated high internal consistency reliability (Cronbach's alpha=0.90). Satisfaction scores on the TeSS items ranged from 3.43 to 3.72 on a 4-point Likert scale, indicating high satisfaction with telehealth. CONCLUSIONS: The study findings demonstrate high user satisfaction with telehealth in a rural memory clinic and the sound psychometric properties of the TeSS in this population. PMID- 25272142 TI - Abundance and size of Gulf shrimp in Louisiana's coastal estuaries following the Deepwater Horizon oil spill. AB - The Deepwater Horizon oil spill impacted Louisiana's coastal estuaries physically, chemically, and biologically. To better understand the ecological consequences of this oil spill on Louisiana estuaries, we compared the abundance and size of two Gulf shrimp species (Farfantepeneus aztecus and Litopeneus setiferus) in heavily affected and relatively unaffected estuaries, before and after the oil spill. Two datasets were used to conduct this study: data on shrimp abundance and size before the spill were available from Louisiana Department of Wildlife and Fisheries (LDWF). Data on shrimp abundance and size from after the spill were independently collected by the authors and by LDWF. Using a Before After-Control-Impact with Paired sampling (BACIP) design with monthly samples of two selected basins, we found brown shrimp to become more abundant and the mean size of white shrimp to become smaller. Using a BACIP with data on successive shrimp year-classes of multiple basins, we found both species to become more abundant in basins that were affected by the spill, while mean shrimp size either not change after the spill, or increased in both affected and unaffected basins. We conclude that following the oil spill abundances of both species increased within affected estuaries, whereas mean size may have been unaffected. We propose two factors that may have caused these results: 1) exposure to polycyclic aromatic hydrocarbons (PAHs) may have reduced the growth rate of shrimp, resulting in a delayed movement of shrimp to offshore habitats, and an increase of within-estuary shrimp abundance, and 2) fishing closures established immediately after the spill, may have resulted in decreased fishing effort and an increase in shrimp abundance. This study accentuates the complexities in determining ecological effects of oil spills, and the need of studies on the organismal level to reveal cause-and-effect relationships of such events. PMID- 25272144 TI - An updated National Institutes of Health consensus panel on bariatric surgery. PMID- 25272143 TI - Persistence and change in community composition of reef corals through present, past, and future climates. AB - The reduction in coral cover on many contemporary tropical reefs suggests a different set of coral community assemblages will dominate future reefs. To evaluate the capacity of reef corals to persist over various time scales, we examined coral community dynamics in contemporary, fossil, and simulated future coral reef ecosystems. Based on studies between 1987 and 2012 at two locations in the Caribbean, and between 1981 and 2013 at five locations in the Indo-Pacific, we show that many coral genera declined in abundance, some showed no change in abundance, and a few coral genera increased in abundance. Whether the abundance of a genus declined, increased, or was conserved, was independent of coral family. An analysis of fossil-reef communities in the Caribbean revealed changes in numerical dominance and relative abundances of coral genera, and demonstrated that neither dominance nor taxon was associated with persistence. As coral family was a poor predictor of performance on contemporary reefs, a trait-based, dynamic, multi-patch model was developed to explore the phenotypic basis of ecological performance in a warmer future. Sensitivity analyses revealed that upon exposure to thermal stress, thermal tolerance, growth rate, and longevity were the most important predictors of coral persistence. Together, our results underscore the high variation in the rates and direction of change in coral abundances on contemporary and fossil reefs. Given this variation, it remains possible that coral reefs will be populated by a subset of the present coral fauna in a future that is warmer than the recent past. PMID- 25272146 TI - A turn-on fluorogenic Zn(II) chemoprobe based on a terpyridine derivative with aggregation-induced emission (AIE) effects through nanofiber aggregation into spherical aggregates. AB - The self-assembly of a terpyridine-based ligand in a DMSO/water solvent mixture (1 : 99 v/v) with a high content of water formed a nanofibrillar structure and showed a non-emissive process. On the other hand, the self-assembly of the terpyridine-based ligand exhibited strong emission in the presence of Zn(2+) due to the formation of coordination bonds between the terpyridine moieties and the Zn(2+) by the aggregation-induced emission effect. The morphology of this aggregate represented a spherical structure. PMID- 25272145 TI - Human babesiosis, Maine, USA, 1995-2011. AB - We observed an increase in the ratio of pathogenic Babesia microti to B. odocoilei in adult Ixodes scapularis ticks in Maine. Risk for babesiosis was associated with adult tick abundance, Borrelia burgdorferi infection prevalence, and Lyme disease incidence. Our findings may help track risk and increase the focus on blood supply screening. PMID- 25272147 TI - Effects of surface-active organic matter on carbon dioxide nucleation in atmospheric wet aerosols: a molecular dynamics study. AB - Organic matter (OM) uptake in cloud droplets produces water-soluble secondary organic aerosols (SOA) via aqueous chemistry. These play a significant role in aerosol properties. We report the effects of OM uptake in wet aerosols, in terms of the dissolved-to-gas carbon dioxide nucleation using molecular dynamics (MD) simulations. Carbon dioxide has been implicated in the natural rainwater as well as seawater acidity. Variability of the cloud and raindrop pH is assumed in space and time, as regional emissions, local human activities and geophysical characteristics differ. Rain scavenging of inorganic SOx, NOx and NH3 plays a major role in rain acidity in terms of acid-base activity, however carbon dioxide solubility also remains a key parameter. Based on the MD simulations we propose that the presence of surface-active OM promotes the dissolved-to-gas carbon dioxide nucleation in wet aerosols, even at low temperatures, strongly decreasing carbon dioxide solubility. A discussion is made on the role of OM in controlling the pH of a cloud or raindrop, as a consequence, without involving OM ionization equilibrium. The results are compared with experimental and computational studies in the literature. PMID- 25272148 TI - Challenges and opportunities in using wastewater analysis to measure drug use in a small prison facility. AB - INTRODUCTION AND AIMS: Wastewater analysis (WWA) is intended to be a direct and objective method of measuring substance use in large urban populations. It has also been used to measure prison substance use in two previous studies. The application of WWA in this context has raised questions as to how best it might be used to measure illicit drug use in prisons, and whether it can also be used to measure prescription misuse. We applied WWA to a small regional prison to measure the use of 12 licit and illicit substances. We attempted to measure the non-medical use of methadone and buprenorphine and to compare our findings with the results of the prison's mandatory drug testing (MDT). DESIGN AND METHODS: Representative daily composite samples were collected for two periods of 12 consecutive days in May to July 2013 and analysed for 18 drug metabolites. Prescription data and MDT results were obtained from the prison and compared with the substance use estimates calculated from WWA data. RESULTS: Daily use of methamphetamine, methadone, buprenorphine and codeine was detected, while sporadic detection of ketamine and methylone was also observed. Overall buprenorphine misuse appeared to be greater than methadone misuse. DISCUSSION AND CONCLUSIONS: Compared with MDT, WWA provides a more comprehensive picture of prison substance use. WWA also has the potential to measure the misuse of medically prescribed substances. However, a great deal of care must be exercised in quantifying the usage of any substance in small populations, such as in prisons. PMID- 25272149 TI - A double-blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression. AB - OBJECTIVE: To compare 2 omega-3 (n-3) preparations enriched with eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) as monotherapy for major depressive disorder (MDD) in a 2-site, placebo-controlled, randomized, double-blind clinical trial. METHOD: 196 adults (53% female; mean [SD] age = 44.7 [13.4] years) with DSM-IV MDD and a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score >= 15 were randomized equally from May 18, 2006, to June 30, 2011, to 8 weeks of double-blind treatment with oral EPA-enriched n-3 1000 mg/d, DHA enriched n-3 1,000 mg/d, or placebo. RESULTS: 154 subjects completed the study. Modified intent-to-treat (mITT) analysis (n = 177 subjects with >= 1 postbaseline visit; 59.3% female, mean [SD] age 45.8 [12.5] years) employed mixed-model repeated measures (MMRM). All 3 groups demonstrated statistically significant improvement in the HDRS-17 (primary outcome measure), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR-16), and Clinical Global Improvement-Severity Scale (CGI-S) (P < .05), but neither n-3 preparation separated from placebo (P > .05). Response and remission rates were in the range of 40%-50% and 30%, respectively, for all treatments, with no significant differences between groups. One subject receiving EPA-enriched n-3 discontinued due to worsening depression, and 1 subject receiving placebo discontinued due to an unspecified "negative reaction" to pills. CONCLUSIONS: Neither EPA-enriched nor DHA-enriched n-3 was superior to placebo for the treatment of MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00517036. PMID- 25272150 TI - The clinical characteristics and pathological patterns of postinfectious glomerulonephritis in HIV-infected patients. AB - BACKGROUND: Postinfectious glomerulonephritis (PIGN), a form of immune complex GN, is not well-defined in HIV-infected patients. This study characterizes PIGN in this patients' population and determine the impact of histopathological patterns on renal outcome and mortality. METHODS: HIV-infected patients with PIGN from September 1998 to July 2013 were identified. Archived slides were reviewed by a blinded renal pathologist, classified into acute, persistent and healed PIGN. Groups were compared using Wilcoxon rank-sum and Fisher's exact test. Survival analyses were performed to determine association of histopathological pattern with renal outcome and mortality. RESULTS: Seventy-two HIV-infected predominantly African American males were identified with PIGN. Median (interquartile range) age and creatinine at the time of renal biopsy was 48 years (41, 53) and 2.5 mg/dl (1.5, 4.9) respectively. Only 2 (3%) had acute PIGN, 42 (58%) had persistent PIGN and 28 (39%) had healed PIGN. Three patients (4%) had IgA-dominant PIGN. Only 46% of the patients had confirmed positive cultures with Staphylococcus the most common infectious agent. During a median follow up of 17 months, the pathological pattern had no impact on renal outcome (P = 0.95). Overall mortality was high occurring in 14 patients (19%); patients with healed PIGN had significantly increased mortality (P = 0.05). CONCLUSION: In HIV infected patients, Staphylococcus is the most common cause of PIGN. Renal outcome was not influenced by the histopathological pattern but those with healed PIGN had greater mortality which was potentially due to a confounder not accounted for in the study. PMID- 25272151 TI - Silver-zeolite combined to polyphenol-rich extracts of Ascophyllum nodosum: potential active role in prevention of periodontal diseases. AB - The purpose of this study was to evaluate various biological effects of silver zeolite and a polyphenol-rich extract of A. nodosum (ASCOP) to prevent and/or treat biofilm-related oral diseases. Porphyromonas gingivalis and Streptococcus gordonii contribute to the biofilm formation associated with chronic periodontitis. In this study, we evaluated in vitro antibacterial and anti biofilm effects of silver-zeolite (Ag-zeolite) combined to ASCOP on P. gingivalis and S. gordonii growth and biofilm formation capacity. We also studied the anti inflammatory and antioxidant capacities of ASCOP in cell culture models. While Ag zeolite combined with ASCOP was ineffective against the growth of S. gordonii, it showed a strong bactericidal effect on P. gingivalis growth. Ag-zeolite combined with ASCOP was able to completely inhibit S. gordonii monospecies biofilm formation as well as to reduce the formation of a bi-species S. gordonii/P. gingivalis biofilm. ASCOP alone was ineffective towards the growth and/or biofilm formation of S. gordonii and P. gingivalis while it significantly reduced the secretion of inflammatory cytokines (TNFalpha and IL-6) by LPS-stimulated human like-macrophages. It also exhibited antioxidant properties and decreased LPS induced lipid peroxidation in gingival epithelial cells. These findings support promising use of these products in future preventive or therapeutic strategies against periodontal diseases. PMID- 25272152 TI - Mechanism of the exchange reaction in HRAS from multiscale modeling. AB - HRAS regulates cell growth promoting signaling processes by cycling between active (GTP-bound) and inactive (GDP-bound) states. Understanding the transition mechanism is central for the design of small molecules to inhibit the formation of RAS-driven tumors. Using a multiscale approach involving coarse-grained (CG) simulations, all-atom classical molecular dynamics (CMD; total of 3.02 us), and steered molecular dynamics (SMD) in combination with Principal Component Analysis (PCA), we identified the structural features that determine the nucleotide (GDP) exchange reaction. We show that weakening the coupling between the SwitchI (residues 25-40) and SwitchII (residues 59-75) accelerates the opening of SwitchI; however, an open conformation of SwitchI is unstable in the absence of guanine nucleotide exchange factors (GEFs) and rises up towards the bound nucleotide to close the nucleotide pocket. Both I21 and Y32, play a crucial role in SwitchI transition. We show that an open SwitchI conformation is not necessary for GDP destabilization but is required for GDP/Mg escape from the HRAS. Further, we present the first simulation study showing displacement of GDP/Mg away from the nucleotide pocket. Both SwitchI and SwitchII, delays the escape of displaced GDP/Mg in the absence of GEF. Based on these results, a model for the mechanism of GEF in accelerating the exchange process is hypothesized. PMID- 25272153 TI - Myocardial creatine levels do not influence response to acute oxidative stress in isolated perfused heart. AB - BACKGROUND: Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury. OBJECTIVES: To determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS) exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare worse. METHODS AND RESULTS: CrT-OE mice were pre-selected for creatine levels 20 100% above wild-type using in vivo (1)H-MRS. Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min equilibration, hearts were perfused with either H2O2 0.5 uM (30 min), or the anti neoplastic drug doxorubicin 15 uM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCdelta expression were quantified in perfused hearts as markers of oxidative damage and apoptotic signalling. Wild type hearts responded to ROS challenge with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wild-type controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to protect hearts from doxorubicin-induced dysfunction. CONCLUSIONS: Intracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart, arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity. PMID- 25272155 TI - Influence of productivity and processing method on physicochemical characteristics of white button mushrooms in Brazil. AB - BACKGROUND: The white button mushroom is the edible fungus most commonly cultivated and commercialized in Brazil and worldwide. This work assesses the productivity of the different strains ABI 07/06 and ABI 06/05 of Agaricus bisporus grown under the conditions normally employed by growers in the southeast of Brazil, and the influence of four different chemical conservation methods on the physicochemical characteristics and storage properties of the fruit bodies. RESULTS: The productivities of strains ABI 07/06 and ABI 06/05 of white button mushrooms were found to be comparable. The colorimetric characteristics and chemical compositions (fat, fiber and protein contents) of the mushroom strains were similar, and these parameters were not influenced significantly by the conservation processes. Texture was negatively affected by all processing methods employed. CONCLUSION: It was concluded that chemical methods of processing mushrooms were not fully effective and novel alternative technologies should be considered by mushroom processors in Brazil. Some methods of mushroom storage using chemicals such as sodium metabisulfite are harmful to the human organism, so processing using autoclaving may be the best form of conservation of canned mushrooms. PMID- 25272154 TI - A model for visual memory encoding. AB - Memory encoding engages multiple concurrent and sequential processes. While the individual processes involved in successful encoding have been examined in many studies, a sequence of events and the importance of modules associated with memory encoding has not been established. For this reason, we sought to perform a comprehensive examination of the network for memory encoding using data driven methods and to determine the directionality of the information flow in order to build a viable model of visual memory encoding. Forty healthy controls ages 19-59 performed a visual scene encoding task. FMRI data were preprocessed using SPM8 and then processed using independent component analysis (ICA) with the reliability of the identified components confirmed using ICASSO as implemented in GIFT. The directionality of the information flow was examined using Granger causality analyses (GCA). All participants performed the fMRI task well above the chance level (>90% correct on both active and control conditions) and the post fMRI testing recall revealed correct memory encoding at 86.33 +/- 5.83%. ICA identified involvement of components of five different networks in the process of memory encoding, and the GCA allowed for the directionality of the information flow to be assessed, from visual cortex via ventral stream to the attention network and then to the default mode network (DMN). Two additional networks involved in this process were the cerebellar and the auditory-insular network. This study provides evidence that successful visual memory encoding is dependent on multiple modules that are part of other networks that are only indirectly related to the main process. This model may help to identify the node(s) of the network that are affected by a specific disease processes and explain the presence of memory encoding difficulties in patients in whom focal or global network dysfunction exists. PMID- 25272157 TI - Molecular characterization of three PRORP proteins in the moss Physcomitrella patens: nuclear PRORP protein is not essential for moss viability. AB - RNase P is a ubiquitous endonuclease that removes the 5' leader sequence from pre tRNAs in all organisms. In Arabidopsis thaliana, RNA-free proteinaceous RNase Ps (PRORPs) seem to be enzyme(s) for pre-tRNA 5'-end processing in organelles and the nucleus and are thought to have replaced the ribonucleoprotein RNase P variant. However, the evolution and function of plant PRORPs are not fully understood. Here, we identified and characterized three PRORP-like proteins, PpPPR_63, 67, and 104, in the basal land plant, the moss Physcomitrella patens. PpPPR_63 localizes to the nucleus, while PpPPR_67 and PpPPR_104 are found in both the mitochondria and chloroplasts. The three proteins displayed pre-tRNA 5'-end processing activity in vitro. Mutants with knockout (KO) of the PpPPR_63 gene displayed growth retardation of protonemal colonies, indicating that, unlike Arabidopsis nuclear RPORPs, the moss nuclear PpPPR_63 is not essential for viability. In the KO mutant, nuclear-encoded tRNAAsp (GUC) levels were slightly decreased, whereas most nuclear-encoded tRNA levels were not altered. This indicated that most of the cytosolic mature tRNAs were produced normally without proteinaceous RNase P-like PpPPR_63. Single PpPPR_67 or 104 gene KO mutants displayed different phenotypes of protonemal growth and chloroplast tRNA(Arg) (ACG) accumulation. However, the levels of all other tRNAs were not altered in the KO mutants. In addition, in vitro RNase P assays showed that PpPPR_67 and PpPPR_104 efficiently cleaved chloroplast pre-tRNA(Arg) (CCG) and pre-tRNA(Arg) (UCU) but they cleaved pre-tRNA(Arg) (ACG) with different efficiency. This suggests that the two proteins have overlapping function but their substrate specificity is not identical. PMID- 25272156 TI - Population structure and comparative genome hybridization of European flor yeast reveal a unique group of Saccharomyces cerevisiae strains with few gene duplications in their genome. AB - Wine biological aging is a wine making process used to produce specific beverages in several countries in Europe, including Spain, Italy, France, and Hungary. This process involves the formation of a velum at the surface of the wine. Here, we present the first large scale comparison of all European flor strains involved in this process. We inferred the population structure of these European flor strains from their microsatellite genotype diversity and analyzed their ploidy. We show that almost all of these flor strains belong to the same cluster and are diploid, except for a few Spanish strains. Comparison of the array hybridization profile of six flor strains originating from these four countries, with that of three wine strains did not reveal any large segmental amplification. Nonetheless, some genes, including YKL221W/MCH2 and YKL222C, were amplified in the genome of four out of six flor strains. Finally, we correlated ICR1 ncRNA and FLO11 polymorphisms with flor yeast population structure, and associate the presence of wild type ICR1 and a long Flo11p with thin velum formation in a cluster of Jura strains. These results provide new insight into the diversity of flor yeast and show that combinations of different adaptive changes can lead to an increase of hydrophobicity and affect velum formation. PMID- 25272158 TI - Excimer formation in cofacial and slip-stacked perylene-3,4:9,10 bis(dicarboximide) dimers on a redox-inactive triptycene scaffold. AB - Excitation energy transfer in perylene-3,4:9,10-bis(dicarboximide) (PDI) aggregates is of interest for light-harvesting applications of this strongly absorbing and pi-pi stacking chromophore. Here we report the synthesis and characterization of two PDI dimers in which the chromophores are covalently linked by a redox-inactive triptycene bridge in orientations that are cofacial (1) and slip-stacked along their N-N axes (2). Femtosecond transient absorption experiments on 1 and 2 reveal rapid exciton delocalization resulting excimer formation. Cofacial pi-pi stacked dimer 1 forms a low-energy excimer state absorption (lambdamax = 1666 nm) in tau = ~2 ps after photoexcitation. Inserting a phenyl spacer on the bridge to generate a slip-stacked PDI-PDI geometry in 2 results in a less stable excimer state (lambdamax = 1430 nm), which forms in tau = ~12 ps due to decreased electronic coupling. The near-infrared (NIR) excimer absorption of cofacial dimer 1 is ~120 meV lower in energy than that of slip stacked dimer 2, further highlighting electronic differences between these states. PMID- 25272159 TI - Hypothalamic expression and moonlight-independent changes of Cry3 and Per4 implicate their roles in lunar clock oscillators of the lunar-responsive Goldlined spinefoot. AB - Lunar cycle-associated physiology has been found in a wide variety of organisms. Studies suggest the presence of a circalunar clock in some animals, but the location of the lunar clock is unclear. We previously found lunar-associated expression of transcripts for Cryptochrome3 gene (SgCry3) in the brain of a lunar phase-responsive fish, the Goldlined spinefoot (Siganus guttatus). Then we proposed a photoperiodic model for the lunar phase response, in which SgCry3 might function as a phase-specific light response gene and/or an oscillatory factor in unidentified circalunar clock. In this study, we have developed an anti SgCRY3 antibody to identify SgCRY3-immunoreactive cells in the brain. We found immunoreactions in the subependymal cells located in the mediobasal region of the diencephalon, a crucial site for photoperiodic seasonal responses in birds. For further assessment of the lunar-responding mechanism and the circalunar clock, we investigated mRNA levels of Cry3 as well as those of the other clock(-related) genes, Period (Per2 and Per4), in S. guttatus reared under nocturnal moonlight interruption or natural conditions. Not only SgCry3 but SgPer4 mRNA levels showed lunar phase-dependent variations in the diencephalon without depending on light condition during the night. These results suggest that the expressions of SgCry3 and SgPer4 are not directly regulated by moonlight stimulation but endogenously mediated in the brain, and implicate that circadian clock(-related) genes may be involved in the circalunar clock locating within the mediobasal region of the diencephalon. PMID- 25272160 TI - Relationship between watershed infarcts and recent intra plaque haemorrhage in carotid atherosclerotic plaque. AB - OBJECTIVE: Watershed infarcts (WSI) are thought to result from hemodynamic mechanism, but studies have suggested that microemboli from unstable carotid plaques may distribute preferentially in watershed areas, i.e., between two cerebral arterial territories. Intraplaque haemorrhage (IPH) is an emerging marker of plaque instability and microembolic activity. We assessed the association between WSI and IPH in patients with recently symptomatic moderate carotid stenosis. METHODS AND RESULTS: We selected 65 patients with symptomatic moderate (median NASCET degree of stenosis = 31%) carotid stenosis and brain infarct on Diffusion-Weighted Imaging (DWI) on Magnetic Resonance Imaging (MRI) from a multicentre prospective study. Fourteen (22%) had WSI (cortical, n = 8; internal, n = 4; cortical and internal, n = 2). Patients with WSI were more likely to have IPH than those without WSI although the difference was not significant (50% vs. 31%, OR = 2.19; 95% CI, 0.66-7.29; P = 0.20). After adjustment for degree of stenosis, age and gender, the results remained unchanged. CONCLUSION: About one in fifth of brain infarcts occurring in patients with moderate carotid stenosis were distributed in watershed areas. Albeit not significant, an association between IPH--more generally plaque component--and WSI, still remains possible. PMID- 25272161 TI - Abstract knowledge in the broken-string problem: evidence from nonhuman primates and pre-schoolers. AB - There is still large controversy about whether abstract knowledge of physical problems is uniquely human. We presented 9 capuchin monkeys, 6 bonobos, 6 chimpanzees and 48 children with two versions of a broken-string problem. In the standard condition, participants had to choose between an intact and a broken string as means to a reward. In the critical condition, the functional parts of the strings were covered up and replaced by perceptually similar, but non functional cues. Apes, monkeys and young children performed significantly better in the standard condition in which the cues played a functional role, indicating knowledge of the functional properties involved. Moreover, a control experiment with chimpanzees and young children ruled out that this difference in performance could be accounted for by differences of perceptual feedback in the two conditions. We suggest that, similar to humans, nonhuman primates partly rely on abstract concepts in physical problem-solving. PMID- 25272162 TI - Ratiometric electrochemical sensor for selective monitoring of cadmium ions using biomolecular recognition. AB - A selective, accurate, and sensitive method for monitoring of cadmium ions (Cd(2+)) based on a ratiometric electrochemical sensor was developed, by simultaneously modifying with protoporphyrin IX and 6-(ferroceney) hexanethiol (FcHT) on Au particle-deposited glassy carbon electrode. On the basis of high affinity of biomolecular recognition between protoporphyrin IX and Cd(2+), the functionalized electrode showed high selectivity toward Cd(2+) over other metal ions such as Cu(2+), Fe(3+), Ca(2+), and so on. Electroactive FcHT played the role as the inner reference element to provide a built-in correction, thus improving the accuracy for determination of Cd(2+) in the complicated environments. The sensitivity of the electrochemical sensor for Cd(2+) was enhanced by ~3-fold through the signal amplification of electrodeposited gold nanoparticles. Accordingly, the present ratiometric method demonstrated high sensitivity, broad linear range from 100 nM to 10 MUM, and low detection limit down to 10 nM (2.2 ppb), lower than EPA and WHO guidelines. Finally, the ratiometric electrochemical sensor was successfully applied in the determination of Cd(2+) in water samples, and the obtained results agreed well with those obtained by the conventional ICP-MS method. PMID- 25272165 TI - Updating the journal's submission categories and format. PMID- 25272163 TI - Coenzyme Q10 protects human endothelial cells from beta-amyloid uptake and oxidative stress-induced injury. AB - Neuropathological symptoms of Alzheimer's disease appear in advances stages, once neuronal damage arises. Nevertheless, recent studies demonstrate that in early asymptomatic stages, beta-amyloid peptide damages the cerebral microvasculature through mechanisms that involve an increase in reactive oxygen species and calcium, which induces necrosis and apoptosis of endothelial cells, leading to cerebrovascular dysfunction. The goal of our work is to study the potential preventive effect of the lipophilic antioxidant coenzyme Q (CoQ) against beta amyloid-induced damage on human endothelial cells. We analyzed the protective effect of CoQ against Abeta-induced injury in human umbilical vein endothelial cells (HUVECs) using fluorescence and confocal microscopy, biochemical techniques and RMN-based metabolomics. Our results show that CoQ pretreatment of HUVECs delayed Abeta incorporation into the plasma membrane and mitochondria. Moreover, CoQ reduced the influx of extracellular Ca(2+), and Ca(2+) release from mitochondria due to opening the mitochondrial transition pore after beta-amyloid administration, in addition to decreasing O2(.-) and H2O2 levels. Pretreatment with CoQ also prevented beta-amyloid-induced HUVECs necrosis and apoptosis, restored their ability to proliferate, migrate and form tube-like structures in vitro, which is mirrored by a restoration of the cell metabolic profile to control levels. CoQ protected endothelial cells from Abeta-induced injury at physiological concentrations in human plasma after oral CoQ supplementation and thus could be a promising molecule to protect endothelial cells against amyloid angiopathy. PMID- 25272164 TI - Nectar yeasts in the tall Larkspur Delphinium barbeyi (Ranunculaceae) and effects on components of pollinator foraging behavior. AB - Microorganisms frequently colonize the nectar of angiosperm species. Though capable of altering a suite of traits important for pollinator attraction, few studies exist that test the degree to which they mediate pollinator foraging behavior. The objective of our study was to fill this gap by assessing the abundance and diversity of yeasts associated with the perennial larkspur Delphinium barbeyi (Ranunculaceae) and testing whether their presence affected components of pollinator foraging behavior. Yeasts frequently colonized D. barbeyi nectar, populating 54-77% of flowers examined depending on site. Though common, the yeast community was species-poor, represented by a single species, Metschnikowia reukaufii. Female-phase flowers of D. barbeyi were more likely to have higher densities of yeasts in comparison to male-phase flowers. Pollinators were likely vectors of yeasts, as virgin (unvisited) flowers rarely contained yeasts compared to flowers open to pollinator visitation, which were frequently colonized. Finally, pollinators responded positively to the presence of yeasts. Bombus foragers both visited and probed more flowers inoculated with yeasts in comparison to uninoculated controls. Taken together, our results suggest that variation in the occurrence and density of nectar-inhabiting yeasts have the potential to alter components of pollinator foraging behavior linked to pollen transfer and plant fitness. PMID- 25272167 TI - [Not Available]. PMID- 25272168 TI - [Not Available]. PMID- 25272169 TI - [Not Available]. PMID- 25272170 TI - [Not Available]. PMID- 25272171 TI - [Not Available]. PMID- 25272172 TI - [Not Available]. PMID- 25272173 TI - [Not Available]. PMID- 25272174 TI - [Not Available]. PMID- 25272175 TI - [Evaluation of home collection performed by a human milk bank in a university hospital in Brazil]. AB - OBJECTIVE: Evaluation of procedures during household milking and transport of human milk associated with their quality control. MATERIALS AND METHODS: 48 donors registered in the Human Milk Bank of the Clinics Hospital of the Federal University at Uberlandia. Observations were made during home visits. A checklist was elaborated according to the technical standards for human milk banks, been associated with physical-chemical, and microbiological controls. The chi-square test, logistic regression and Spearman test (p< 0.05) were used for data analysis. RESULTS: The results suggest that most donors assimilated the guidelines of the milk bank staff and procedures were satisfactorily performed. CONCLUSION: It could be demonstrated that milking and home collection are safe and effective ways for obtaining donated human milk. PMID- 25272176 TI - Socioeconomic status and misperception of body mass index among Mexican adults. AB - OBJECTIVE: To estimate the association between perceived body mass index (BMI) and socioeconomic variables in adults in Mexico. MATERIALS AND METHODS: We studied 32052 adults from the Mexican National Health and Nutrition Survey of 2006. We estimated BMI misperception by comparing the respondent's weight perception (as categories of BMI) with the corresponding category according to measured weight and height. Misperception was defined as respondent's perception of a BMI category different from their actual category. Socioeconomic status was assessed using household assets. Logistic and multinomial regression models by gender and BMI category were estimated. RESULTS: Adult women and men highly underestimate their BMI category. We found that the probability of a correct classification was lower than the probability of getting a correct result by chance alone. Better educated and more affluent individuals are more likely to have a correct perception of their weight status, particularly among overweight adults. CONCLUSIONS: Given that a correct perception of weight has been associated with an increased search of weight control and that our results show that the studied population underestimated their BMI, interventions providing definitions and consequences of overweight and obesity and encouraging the population to monitor their weight could be beneficial. PMID- 25272177 TI - [Evaluation of the impact of a control program against taeniasis-cysticercosis (Taenia solium)]. AB - OBJETIVE: The impact of a control program is evaluated to eventually eradicate taeniasis-cysticercosis (Taenia solium) based on education and vaccination of pigs. MATERIALS AND METHODS: The prevalence of porcine cysticercosis was estimated using tongue inspection, ultrasound and determination of antibodies, before and three years after the application in three regions of the state of Guerrero. RESULTS: A significant reduction in the prevalence of porcine cysticercosis of 7 to 0.5% and 3.6 to 0.3% estimated by tongue examination or ultrasound respectively (p<0.01) and a no significant decrease in seroprevalence from 17.7 to 13.3% were observed. CONCLUSIONS: The reduction of the prevalence of taeniasis-cysticercosis establishes the program's effectiveness in preventing infection. The sustained presence of antibodies, compatible with contact of Taenia solium or other related helminths, underlines the importance of maintaining interventions to achieve eradication. PMID- 25272178 TI - [Prevalence of Streptococcus pneumoniae serotype 19A before and after the introduction of the heptavalent conjugate vaccine in Mexico]. AB - OBJECTIVE: To determine the prevalence of S. pneumoniae serotype 19A (Spn19A), before and after the introduction of heptavalent pneumococcal conjugate vaccine (PCV7) in Mexico. MATERIALS AND METHODS: Descriptive study carried out in Mexico with surveillance information of pneumococcal disease, generated from the Sireva network. We performed lineal regression analysis with the proportion of Spn19A by year in two study periods. Data were analyzed using SPSS v.18 software. RESULTS: A total of 1825 S. pneumoniae strains causing infection in pediatric population were recovered in the period 2000-2012, 225/12.3% were Spn19A, and of these, 75/6.3% were isolated in 2000-2008 and 150/23.6% in 2009-2012. There was an increase in antimicrobial resistance post-vaccination for all drugs except vancomycin. CONCLUSION: It was observed that the frequency of this serotype and antimicrobial resistance increased after the introduction of PCV7. PMID- 25272179 TI - [Economic benefits of using a dose dispensing system at hospital units of the Mexican Institute of Social Security]. AB - OBJECTIVE: To estimate the potential economic benefits at The Mexican Institute of Social Security (IMSS per its abbreviation in spanish) according to the drug expenditure of using drug dispensing system, based on literature information. MATERIALS AND METHODS: A systematic review was performed to identify savings from drugs and reduction of medication errors. The total and mean health expenditure by level of medical attention was calculated using the dispensed collective prescriptions at IMSS during 2009. Three savings scenarios were applied. RESULTS: The total drug savings were in a range of 870.49 Mexican million pesos to 4050.05 Mexican million pesos. Reductions of medication errors can contribute with additional savings up to 3455.56 Mexican million pesos. CONCLUSION: The drug dispensing system unit generates savings opportunities at the second and third level of attention. The maximum economic benefit was observed in the last level. PMID- 25272180 TI - [Validation of a cutoff point for the short version of the Depression Scale of the Center for Epidemiologic Studies in older Mexican adults]. AB - OBJECTIVE: To identify a valid cutoff point associated with Center for Epidemiologic Studies, Depression Scale (CES-D) of seven items, which allows the classification of older adults according to presence/absence of clinically significant depressive symptoms. MATERIALS AND METHODS: Screening study with 229 older adults residing in two states of Mexico (Morelos and Tlaxcala), which were part of the sample from the National Survey of Health and Nutrition, 2012. We estimated the sensitivity and specificity associated with the selected cutoff points using the diagnostic criteria of ICD-10 (International Classification of Diseases, 10th revision) and DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition). RESULTS: The cutoff point estimated was CES-D=5. According to the ICD-10 sensitivity and specificity were 83.3 and 90.2%, and ROC was 87%. Using DSM-IV, the values were 85, 83.2, and 84%, respectively. CONCLUSIONS: The short version of the CES-D can be used as a screening test to identify probable cases of older adults with clinically significant depressive symptoms. PMID- 25272181 TI - [Mexican adolescentes' goals as determinants in the prevention of early pregnancies]. AB - OBJECTIVE: This study aims to explore adolescents' intentions related to the early formation of a family. MATERIALS AND METHODS: We administered a survey to students in eight schools in Morelos and Mexico City, in 2010. We analyzed intentions of marrying or having a child and fitted an exploratory path model to assess predictors of the intentions of having a child before the age of 20 (n=2974). RESULTS: Around 77% of adolescents expect to have their first child at 20 years or later; 21% show ambivalence or incongruence regarding this, whereas 2% expect to have a child before the age of 20. Parents' expectations for their child's education influence the importance that adolescents give to education. The latter promotes the idea of postponing childbearing until 20 years or later (beta=0.13). CONCLUSIONS: In order to prevent early pregnancies, interventions and programs should encourage the construction of personal and professional goals. PMID- 25272182 TI - [Microbial risk assessment of Vibrio spp. in seafood products in Mexico]. AB - Food-borne diseases are among the major public health problems that currently exist. Microbiological risk assessment is a process used to evaluate the hidden hazards in food, the likelihood of exposure to these hazards and their impact on public health. Risk assessment is performed in four steps: hazard identification, hazard characterization, assessment of exposure and risk characterization. According to the process/response microbial risk assessment is classified in two categories, qualitative and quantitative. The aim of this review is to underline the importance of implementing assessments in seafood that is usually consumed raw, strengthening access to good quality and safe food for the consumer's benefit and to stress the necessity of microbiological risks assessments in Mexico. PMID- 25272184 TI - Dry mouth as a novel indicator of hoarseness caused by inhalation therapy. AB - OBJECTIVE: To investigate the influence of dry mouth on the incidence and severity of inhalation therapy-induced hoarseness. METHODS: The volume of saliva secreted without stimulation was measured in patients with asthma or chronic obstructive pulmonary disease (COPD) who also answered a questionnaire on subjective ratings for hoarseness. The relationship between salivary secretion and hoarseness was analyzed by the Pearson correlation and multiple linear regression. The prediction accuracy of salivary secretion for the grade of hoarseness was evaluated using a receiver-operating characteristic (ROC) analysis. RESULTS: A total of 232 patients participated in this study. The subjective rating score of hoarseness was negatively correlated with the volume of saliva secreted (r = -0.273, p < 0.001). A stepwise multiple linear regression analysis revealed that salivary secretion (p < 0.001) and the dose of fluticasone administered (p < 0.05) were significant variables for predicting hoarseness. The ROC analysis for predicting severe hoarseness by salivary secretion showed significant prediction accuracy (AUC = 0.690, 95% CI: 0.614-0.766, p < 0.001) and was higher in patients administered fluticasone (AUC = 0.732, 95% CI: 0.644 0.821, p < 0.001). CONCLUSIONS: Hyposalivation is a significant prediction factor of hoarseness induced by inhaled corticosteroids (ICS). The prediction accuracy was higher in patients administered fluticasone than in those administered another inhalation drug. Although the pharmaceutical efficacy of fluticasone is high, patients with hyposalivation should be prescribed other inhalation drugs. PMID- 25272185 TI - A perspective on point-of-care tests to detect eosinophilic bronchitis. AB - Approximately 50% of asthma exacerbations and a third of COPD exacerbations are associated with an eosinophilic bronchitis. Quantitative cell counts reliably identify the number of eosinophils in sputum and treatment strategies that are guided by sputum eosinophil counts lead to significantly better outcomes than strategies guided by conventional assessments of symptoms and airflow. However, cell counts are not widely available and the results are not available in real time. Similarly, more sophisticated detection methods using immunoassays or genetic analysis via polymerase chain reaction are too costly and thus not amenable to rapid point-of-care diagnosis. Blood eosinophil counts and fraction of exhaled nitric oxide correlate poorly with airway eosinophilia, particularly in patients with severe airway diseases who are on corticosteroid therapy. Point of care assessments of eosinophil-specific activity may be provided by breathomics that employ metabolomics profiling of volatile compounds in breath. However, it is too early to decide if this would provide quantitative data to monitor therapy and disease activities longitudinally. Herein we provide a perspective on the potential for developing simple point-of-care tests with special emphasis on the potential for a bio-active paper diagnostic test to quantitatively assay the amount of eosinophil peroxidase in sputum samples by employing different types of detection systems. PMID- 25272186 TI - Th2 cytokine-primed airway smooth muscle cells induce mast cell chemotaxis via secretion of ATP. AB - OBJECTIVE: Mast cell infiltration into airway smooth muscle (ASM) bundle is an important feature of asthma. Extracellular adenosine triphosphate (eATP) contributes to the initiation of airway inflammation. eATP induces mast cells migration by acting through purinergic receptors. CD39 is an ectonucleotidase that degrades ATP to ADP and AMP. Whether eATP participates in the migration of mast cell towards ASM cells is still unknown. METHODS: Airway smooth muscle cells (ASMCs) were isolated from C57/BL6J mice sensitized and challenged with OVA. ASMCs were in vitro cultured and stimulated with IL-4 + IL-13 in the presence or absence of exogenous CD39 or CD39 inhibitor ARL67156. ATP level in the supernatants was measured with ATP content determination kit. CXCL10 concentration in the ASMCs supernatants was measured by ELISA, the mRNA expression of CXCL10 in ASMCs was determined with real-time PCR. Human mast cell line HMC-1 was cultured in Iscove's-Modified Dubecco's Medium. The expression of CXCR3 in HMC-1 cells was determined with flow cytometry and real-time PCR, respectively. HMC-1 migration rates were determined with transwell system. RESULTS: In the supernatants of Th2 cytokine-stimulated ASMCs, ATP level was higher than that without stimulation. CD39 decreased, whereas ARL67156 increased ATP level in the supernatants. Both ATP and the supernatants of Th2 cytokine stimulated ASMCs induced migration of HMC-1 cells. The surface and mRNA expression of CXCR3 in HMC-1 cells, and the mRNA expression and secretion of CXCL10 in ASMCs were increased after stimulation with ATP or Th2 cytokines. All these effects were partially inhibited by CD39. CONCLUSION: Our data suggested ASMCs in the asthma microenvironment promoted the migration of mast cells via secretion of ATP and the expression of CXCL10/CXCR3 axis. CD39 could reverse this effect and may be a new target for the treatment of asthma. PMID- 25272187 TI - Designed phosphoprotein recognition in Escherichia coli. AB - Protein phosphorylation is a central biological mechanism for cellular adaptation to environmental changes. Dysregulation of phosphorylation signaling is implicated in a wide variety of diseases. Thus, the ability to detect and quantify protein phosphorylation is highly desirable for both diagnostic and research applications. Here we present a general strategy for detecting phosphopeptide-protein interactions in Escherichia coli. We first redesign a model tetratricopeptide repeat (TPR) protein to recognize phosphoserine in a sequence-specific fashion and characterize the interaction with its target phosphopeptide in vitro. We then combine in vivo site-specific incorporation of phosphoserine with split mCherry assembly to observe the designed phosphopeptide protein interaction specificity in E. coli. This in vivo strategy for detecting and characterizing phosphopeptide-protein interactions has numerous potential applications for the study of natural interactions and the design of novel ones. PMID- 25272188 TI - IL-17RA in intestinal inflammation: structure, signaling, function, and clinical application. AB - : Interleukin-17 receptor A (IL-17RA) is responsible for both IL-17A and IL-25 (IL-17E) signaling pathways. Current evidences suggest distinct but interactive responses between IL-17A and IL-25 signaling, both of which are critical for intestinal immune homeostasis. IL-17RA is assumed to regulate this counterbalance and therefore becomes a crucial molecule in mucosal immunology. In this review, we will describe the structure of IL-17RA, compare IL-17A and IL-25 signaling pathways, and emphasize on the function of IL-17RA in intestinal inflammation and discuss current evidences of accomplished and ongoing clinical trials with monoclonal antibodies targeting Th17 pathway, especially IL-17RA. PMID- 25272190 TI - Comparative study of the effectiveness and safety of porcine and bovine atelocollagen in Asian nasolabial fold correction. AB - Bovine-derived collagen has been used for soft-tissue augmentation since 1977. However, there are issues regarding the possibility of bovine spongiform encephalopathy (BSE). Researchers discovered that the histologic structure of porcine-derived collagen is similar to that of human dermal collagen and that it is free from the risk of BSE. This study was conducted to establish the effectiveness and safety of porcine-derived collagen compared to bovine-derived collagen. The 73 patients included in this study were healthy volunteers who responded to an advertisement approved by the Institutional Review Board (IRB). They had visited the authors' hospital complaining of wrinkles on their nasolabial fold. Either porcine (TheraFill(r)) or bovine atelocollagen was randomly injected into each side of their nasolabial folds, and the five-grade Wrinkle Severity Rating Scale (WSRS) was used to evaluate the wrinkles before and after the injection. The average age of the 73 study patients was 46.18 years. The WSRS scores of the porcine and bovine atelocollagen-injected patients were 2.90 +/- 0.71 and 2.85 +/- 0.72 at the baseline and 2.15 +/- 0.70 and 2.21 +/- 0.67 after 6 months. There were no statistically significant differences between the two groups. Adverse effects of the porcine atelocollagen injection were seen in 12 patients, with the most common symptom being redness. This study showed that porcine atelocollagen can be used easily and without the need for the skin testing which is necessary before bovine atelocollagen injection. The efficacy of porcine atelocollagen is also similar to that of bovine atelocollagen. PMID- 25272191 TI - Prophylactic venous cannulation of the pedicled TRAM flap in breast reconstruction. AB - Since its inception nearly 30 years ago, the pedicled TRAM flap has remained a reliable technique of breast reconstruction. However, venous congestion of the flap in the early postoperative period is well recognised and may lead to partial or total flap loss. This study describes a simple technique routinely employed by the senior author over 15 years involving intraoperative cannulation of the deep inferior epigastric vein and externalisation into an ileostomy bag, in order to facilitate drainage and reduce the likelihood of venous congestion. In addition to its role in breast reconstruction, this technique may be a useful adjunct to any form of free or pedicled tissue transfer. PMID- 25272189 TI - Person-to-person household and nosocomial transmission of andes hantavirus, Southern Chile, 2011. AB - Andes hantavirus (ANDV) causes hantavirus cardiopulmonary syndrome in Chile and is the only hantavirus for which person-to-person transmission has been proven. We describe an outbreak of 5 human cases of ANDV infection in which symptoms developed in 2 household contacts and 2 health care workers after exposure to the index case-patient. Results of an epidemiologic investigation and sequence analysis of the virus isolates support person-to-person transmission of ANDV for the 4 secondary case-patients, including nosocomial transmission for the 2 health care workers. Health care personnel who have direct contact with ANDV case patients or their body fluids should take precautions to prevent transmission of the virus. In addition, because the incubation period of ANDV after environmental exposure is longer than that for person-to-person exposure, all persons exposed to a confirmed ANDV case-patient or with possible environmental exposure to the virus should be monitored for 42 days for clinical symptoms. PMID- 25272192 TI - Late volar plate repair for chronic, post-traumatic hyperextension deformity of the proximal interphalangeal joint of the little finger. AB - A chronic traumatic hyperextension of the proximal interphalangeal (PIP) joint can result from traumatic volar plate (VP) disruption. For the treatment of this disorder, reconstruction procedures have been traditionally recommended, because the condition of the VP was not considered susceptible to repair due to retraction or attenuation. The purpose of this paper is to present the operative technique and report the clinical results of late VP repair. Late VP repair was performed for chronic, post-traumatic hyperextension deformity of the PIP joint of the little finger resulting from VP disruption in seven consecutive patients. The range of motion and the lateral stability of the PIP joint were evaluated. The radiographic images were also used to evaluate the alignment and degenerative changes of the PIP joint. Clinical results were classified according to Catalano's criteria. Intraoperative findings showed that the VP could be mobilised and repaired in all cases. The hyperextension was well corrected, and none showed recurrence of the initial deformity. Average flexion of the PIP joint was 92 degrees (range = 75-98 degrees ), and flexion contracture was 9 degrees (range = 0-20 degrees ). On clinical evaluation, there were two excellent, three good, and two fair results. The postoperative radiographs revealed no degenerative change in the PIP joint in six patients. Late VP repair is a successful and reliable alternative and more physiologic than other reconstruction methods. One should first consider late VP repair, despite a long interval between injury and repair. PMID- 25272193 TI - Genome-wide association study of grain polyphenol concentrations in global sorghum [Sorghum bicolor (L.) Moench] germplasm. AB - Identifying natural variation of health-promoting compounds in staple crops and characterizing its genetic basis can help improve human nutrition through crop biofortification. Some varieties of sorghum, a staple cereal crop grown worldwide, have high concentrations of proanthocyanidins and 3 deoxyanthocyanidins, polyphenols with antioxidant and anti-inflammatory properties. We quantified total phenols, proanthocyanidins, and 3 deoxyanthocyanidins in a global sorghum diversity panel (n = 381) using near infrared spectroscopy (NIRS), and characterized the patterns of variation with respect to geographic origin and botanical race. A genome-wide association study (GWAS) with 404,628 SNP markers identified novel quantitative trait loci for sorghum polyphenols, some of which colocalized with homologues of flavonoid pathway genes from other plants, including an orthologue of maize (Zea mays) Pr1 and a homologue of Arabidopsis (Arabidopsis thaliana) TT16. This survey of grain polyphenol variation in sorghum germplasm and catalog of flavonoid pathway loci may be useful to guide future enhancement of cereal polyphenols. PMID- 25272194 TI - Differential effects of angiotensin II receptor blocker and losartan/hydrochlorothiazide combination on central blood pressure and augmentation index. AB - Central systolic blood pressure (CSBP) may be a better predictor of cardiovascular risk than clinic brachial (B)SBP. The effects of dose increment from medium dose of angiotensin II receptor blockers (ARBs) to the maximum dose of ARBs (maximum) and changing from medium dose of ARBs to losartan 50 mg/hydrochlorothiazide 12.5 mg combination (combination) were compared in hypertensive patients in whom monotherapy with a medium ARB dose did not achieve goal home SBP (135 mmHg). Four weeks after treatment with a medium ARB dose monotherapy, those whose home SBP level was above 135 mmHg were randomized to receive the maximum ARB dose (n = 101) or the combination (n = 99) once daily for 8 weeks. Both regimens significantly decreased BSBP and CSBP, while a decrease in BSBP and CSBP was greater with combination. The maximum significantly decreased augmentation index (AIx), while the combination did not. The rate of a decrease in reflection to decrease in CSBP was greater in the maximum than in the combination. In the elderly subgroup, the combination more effectively lowered BSBP than the maximum, and only the combination decreased CSBP. However, in the young subgroup, the maximum decreased AIx more than combination, while both regimens lowered CSBP and BSBP to a similar extent. It is explained in part that the maximum may affect pulse wave reflection more predominantly than the combination, especially in young subjects. A weak effect on pulse wave reflection and, thus, on CSBP, of the combination may be overcome by the potent antihypertensive effect of this regimen. PMID- 25272196 TI - Delusion proneness and 'jumping to conclusions': relative and absolute effects. AB - BACKGROUND: That delusional and delusion-prone individuals 'jump to conclusions' is one of the most robust and important findings in the literature on delusions. However, although the notion of 'jumping to conclusions' (JTC) implies gathering insufficient evidence and reaching premature decisions, previous studies have not investigated whether the evidence gathering of delusion-prone individuals is, in fact, suboptimal. The standard JTC effect is a relative effect but using relative comparisons to substantiate absolute claims is problematic. In this study we investigated whether delusion-prone participants jump to conclusions in both a relative and an absolute sense. METHOD: Healthy participants (n = 112) completed an incentivized probabilistic reasoning task in which correct decisions were rewarded and additional information could be requested for a small price. This combination of rewards and costs generated optimal decision points. Participants also completed measures of delusion proneness, intelligence and risk aversion. RESULTS: Replicating the standard relative finding, we found that delusion proneness significantly predicted task decisions, such that the more delusion prone the participants were, the earlier they decided. This finding was robust when accounting for the effects of risk aversion and intelligence. Importantly, high-delusion-prone participants also decided in advance of an objective rational optimum, gathering fewer data than would have maximized their expected payoff. Surprisingly, we found that even low-delusion-prone participants jumped to conclusions in this absolute sense. CONCLUSIONS: Our findings support and clarify the claim that delusion formation is associated with a tendency to 'jump to conclusions'. In short, most people jump to conclusions, but more delusion-prone individuals 'jump further'. PMID- 25272195 TI - Application of an acoustofluidic perfusion bioreactor for cartilage tissue engineering. AB - Cartilage grafts generated using conventional static tissue engineering strategies are characterised by low cell viability, suboptimal hyaline cartilage formation and, critically, inferior mechanical competency, which limit their application for resurfacing articular cartilage defects. To address the limitations of conventional static cartilage bioengineering strategies and generate robust, scaffold-free neocartilage grafts of human articular chondrocytes, the present study utilised custom-built microfluidic perfusion bioreactors with integrated ultrasound standing wave traps. The system employed sweeping acoustic drive frequencies over the range of 890 to 910 kHz and continuous perfusion of the chondrogenic culture medium at a low-shear flow rate to promote the generation of three-dimensional agglomerates of human articular chondrocytes, and enhance cartilage formation by cells of the agglomerates via improved mechanical stimulation and mass transfer rates. Histological examination and assessment of micromechanical properties using indentation-type atomic force microscopy confirmed that the neocartilage grafts were analogous to native hyaline cartilage. Furthermore, in the ex vivo organ culture partial thickness cartilage defect model, implantation of the neocartilage grafts into defects for 16 weeks resulted in the formation of hyaline cartilage-like repair tissue that adhered to the host cartilage and contributed to significant improvements to the tissue architecture within the defects, compared to the empty defects. The study has demonstrated the first successful application of the acoustofluidic perfusion bioreactors to bioengineer scaffold-free neocartilage grafts of human articular chondrocytes that have the potential for subsequent use in second generation autologous chondrocyte implantation procedures for the repair of partial thickness cartilage defects. PMID- 25272197 TI - Patterns and trends in brominated flame retardants in bald eagle nestlings from the upper midwestern United States. AB - We report on patterns and trends in polybrominated diphenyl ethers (PBDEs) in the plasma of 284 bald eagle nestlings sampled between 1995 and 2011 at six study areas in the upper Midwestern United States. Geometric mean concentrations of total PBDEs (Sigma of nine congeners) ranged from 1.78 ng/mL in the upper St. Croix River watershed to 12.0 ng/mL on the Mississippi River. Lake Superior nestlings fell between these two extremes. Between 2006 and 2011, trends differed among study areas with three declining, two remaining stable, and one increasing. Variation in SigmaPBDE trends among study areas was linked to trends in individual congeners. The lower brominated PBDEs (BDE-47, -99, and -100) declined 4-10% while the higher brominated congeners (BDE-153 and -154) increased by about 7.0% annually from 2006 to 2011. This increase was the greatest in nestlings from the St. Croix River and below its confluence with the Mississippi River. Region wide, our data suggest SigmaPBDEs increased in bald eagle nestlings from 1995 through the mid-2000s and then declined by 5.5% annually from 2006 to 2011. These regional trends are consistent with the removal of penta- and octa-PBDEs from the global market. PMID- 25272198 TI - Chitosan nanoparticles for siRNA delivery: optimization of processing/formulation parameters. AB - Chitosan nanoparticles were prepared using ultrasonication methodology at specific amplitudes and times of sonication. Subsequently, small interfering RNA (siRNA) was added to the solution at predetermined values of nitrogen to phosphorous ratio (N/P), and stirring time. Employing response surfaces generated from a statistical model, the effect of sonication time and amplitude, stirring time, and N/P ratio was studied on the particle size, polydispersity, and loading efficiency of prepared siRNA/chitosan nanoparticles. It was found that to obtain the smallest size, amplitude and time of sonication as well as stirring time should be kept at ~45%, 165 seconds, and 50 minutes, respectively. Minimum polydispersity values were also obtained at similar values of sonication time/amplitude and stirring time in addition to N/P values of ~28. Also, the maximum proportion of siRNA loading was observed at approximate values of 300 seconds, 80% and 280 for sonication time, amplitude, and N/P ratio, respectively. The optimum conditions (i.e., to prepare a sample with minimum values of particle size and polydispersity index and maximum values of loading efficiency) were determined as 60.6, 30.0 (seconds), 28.0, and 12.5 (minutes) for amplitude, time of sonication, N/P, and stirring time, respectively. In this scrutiny, the predicted values of optimum formulation were 456 nm size, 89.6% loading efficiency, and 0.4 polydispersity index. PMID- 25272199 TI - Dimension effect on the performance of carbon nanotube nanobolometers. AB - Carbon nanotube (CNT) film nanobolometers take advantages of high infrared absorption of CNTs, proving a promising alternative for low-cost, uncooled infrared detection. The performance of the CNT nanobolometers is determined by the optoelectronic process on CNTs at a microscopic scale, which links intimately to the diameter of the CNT-a critical parameter that intrinsically affects the band gap and hence infrared absorption, as well as extrinsically affects the surface oxygen adsorption effect and thermal-link of the CNT detector element to the environment. Both the intrinsic and extrinsic factors play important roles in the photoresponse, noise spectrum and the figure-of-merit detectivity D* of the CNT nanobolometers and their interplay determines the device's ultimate performance. In this work, we present a systematic study of the effect of CNT diameter in the range of 1-50 nm on the physical properties relevant to CNT nanobolometers. The optimal CNT diameter was found to be in the range of 2-12 nm with the D* up to 3.3 * 10(7) cm(Hz)(1/2) W(-1), which represents an order of magnitude improvement over the best D* reported previously on CNT film nanobolometers. PMID- 25272202 TI - Retrograde intramedullary fixation of long bone fractures through ipsilateral traumatic amputation sites. AB - The technique of retrograde intramedullary fixation of fractures through open traumatic amputations has not been previously described. We performed a retrospective case series at a tertiary-care military hospital setting. Ten patients met inclusion criteria. All were male, and all were injured through improvised explosive device. Outcome measures included the incidence of fracture nonunion, osteomyelitis or acute infection, heterotopic ossification (HO), as well as successful prosthesis fitting and ambulation. Average time to fixation after injury and amputation closure was 11.7 and 12.2 days, respectively. Follow up averaged 20.2 months. The radiographic union rate was 100%, and time to osseous union averaged 7.5 months. One patient had an amputation site infection requiring revision, but none of the nails was removed for infectious reasons. HO occurred in 7 patients, and 2 patients required revision for symptomatic HO. All patients were successfully fitted with prostheses and able to ambulate. To our knowledge, this is the only series in the literature to specifically describe retrograde intramedullary fixation of long bone fractures through the zone of traumatic amputation sites. The infectious risk is relatively low, whereas the union rate (100%) and successful prosthesis fitting are high. For patients with similar injuries, retrograde intramedullary fixation through the zone of amputation is a viable treatment option. PMID- 25272201 TI - Childhood socioeconomic disadvantage and prediabetes and diabetes in later life: a study of biopsychosocial pathways. AB - OBJECTIVE: We examined the relationship between childhood socioeconomic status (SES) and glucoregulation in later life and used a life-course framework to examine critical periods and underlying pathways. METHODS: Data came from the Midlife in the US (MIDUS) national study (n = 895). Childhood SES indicators retrospectively reported at MIDUS I were used to create a childhood SES disadvantage index. Adult SES disadvantage and potential pathways were measured at MIDUS I and included waist circumference, depressive symptoms, and physical activity. Glucose and hemoglobin A1c, measured approximately 9 to 10 years later at MIDUS II, were used to create the ordinal outcome measure (no diabetes/prediabetes/diabetes). RESULTS: Childhood SES disadvantage predicted increased odds of prediabetes and diabetes net of age, sex, race, and smoking (odds ratio = 1.11, 95% confidence interval = 1.01-1.22). Childhood SES disadvantage predicted adult SES disadvantage (beta = .26, p = .001) and the three key mediators: waist circumference (beta = 0.10, p = .002), physical activity (beta = -0.11, p = .001), and depressive symptoms (beta = 0.07, p = .072). When childhood and adult SES disadvantage were in the same model, only adult SES predicted glucoregulation (odds ratio = 1.07, 95% confidence interval = 1.01-1.13). The SES disadvantage measures were no longer significantly associated with glucoregulation after including waist circumference, physical activity, and depressive symptoms, all of which were significant predictors of glucoregulation. CONCLUSIONS: The consequences of childhood SES disadvantage are complex and include both critical period and pathway effects. The lack of a direct effect of childhood SES on glucoregulation does not negate the importance of early environment but suggests that early-life socioeconomic factors propel unequal life-course trajectories that ultimately influence health. PMID- 25272203 TI - A Lower Extremity Musculoskeletal and Vascular Trauma Protocol in a Children's Hospital May Improve Treatment Response Times and Appropriate Microvascular Coverage. AB - OBJECTIVES: Pediatric lower extremity (LE) vascular injuries present many issues: microvascular surgeons are usually unavailable to stand-alone pediatric institutions, and the rate of morbidity including limb loss can be high if revascularization is delayed beyond the critical period of 8 hours. We assessed if time to revascularization was impacted by institution of a lower extremity vascular trauma protocol (LEVP). DESIGN: Level II retrospective prognostic. SETTING: Level I pediatric trauma center. PATIENTS/PARTICIPANTS: Pediatric patients presenting with ischemic lower extremities requiring urgent management (2000-2013). INTERVENTION: LEVP-a team of specialized microvascular surgeons, who have developed and manage a call schedule for our pediatric trauma center to offer care 24 h-1.d-1, 7 d-1.wk-1, and 365 d-1.y-1 to our children's hospital. MAIN OUTCOME MEASUREMENTS: Treatment team expertise, time to revascularization, and use of time-delaying preoperative radiographic vascular studies performed before and after initiation of LEVP. RESULTS: We identified 22 patients with ischemic LEs (16 patients treated before/6 patients treated after LEVP initiation). Mean time from admission to definitive vascular care was 6.4 hours preprotocol (20% > 8 hours)/4.6 hours postprotocol (0% > 8 hours). Before protocol initiation, 38% of LE vascular injuries were treated by LE microvascular repair-capable surgeons, and 37.5% had a preoperative radiographic vascular study compared with 100% and 0%, respectively, postprotocol initiation. Before protocol initiation, 37.5% had a preoperative radiographic vascular study compared with 0% after protocol initiation. CONCLUSIONS: Since LEVP initiation, we have required no preoperative radiographic vascular studies, there has not been a revascularization delay of >8 hours, and with appropriate staff surgeon coverage, the flow of care has improved with the new ability to address and care for these challenging injuries. To potentially improve the timeliness of vascular care and better match the skills of the practitioner to the injury, pediatric centers should consider implementation of an LEVP within their institutions. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25272204 TI - Differences in cold hardiness, carbohydrates, dehydrins and related gene expressions under an experimental deacclimation and reacclimation in Prunus persica. AB - To boost our understanding of a recent outbreak of freezing injury, we sought to confirm distinctive features between the shoot tissues of the peach (Prunus persica) cultivars Daewol and Kiraranokiwami by mimicking unseasonable changes of temperatures that occur in the early spring through repeated deacclimation and reacclimation treatments. Patterns of cold hardiness declined dramatically during the deacclimation and rose during the reacclimation in both cultivars. Our results indicated that 'Daewol' possessed higher capacity in response to repeated deacclimation and reacclimation treatments than 'Kiraranokiwami'. 'Daewol' showed more sensitive changes in the carbohydrates in response to warm and low temperatures compared with 'Kiraranokiwami'. 'Daewol' indicated almost similar repeated down- and up-patterns in soluble sugar content in response to repeated deacclimation and reacclimation, whereas it indicated repeated up- and down patterns in starch content. However, 'Kiraranokiwami' showed a progressive increase in the soluble sugar content and a progressive decrease in starch content. Notably, patterns of accumulation of a 60-kDa dehydrin protein encoded by the PpDhn1 gene were confirmed through western blotting and paralleled fluctuations of cold hardiness in both cultivars. Expression of this dehydrin was weak in both cultivars during deacclimation but its band intensity increased during reacclimation. Changes in related genes (beta-amylase, PpDhn1, PpDhn2 and PpDhn3) were positively correlated with changes in cold hardiness throughout the experiment. Our results indicate that recent repeated warm periods may cause premature deacclimation in the early spring, and that more cold-tolerant cultivar may be more resilient to freezing injury caused by unstable temperature conditions. PMID- 25272205 TI - Systematic reviews: perhaps "the answer to policy makers' prayers"? PMID- 25272207 TI - Antibiotic-loaded bone cement and periprosthetic joint infection. AB - Antibiotic-loaded bone cement (ALBC) is commonly used for antibiotic delivery during total joint arthroplasty (TJA) for prevention or treatment of periprosthetic joint infection (PJI). ALBC is commonly used in two-stage exchange arthroplasty with static and dynamic spacers, beads, rods, and other custom spacers. The use of commercially available or hand-made ALBC for primary and revision TJA to prevent infection has also been studied. Commonly used antibiotics include gentamicin, tobramycin, and vancomycin powder, and these antibiotics can be used alone or in combination, depending on the organism present. ALBC can be prepared by hand mixing to increase porosity and improve antibiotic elution or by vacuum-mixing to improve tensile fatigue strength. Vacuum-mixed cement is predominantly used in primary TJA, whereas hand-mixed cement is often used in two-stage exchange arthroplasty for shaping spacers and beads. Inadequate strength of ALBC spacers can result in mechanical failure, including fracture or dislocation of spacers. Additionally, studies have demonstrated that the use of antibiotics in cement, especially aminoglycosides like gentamicin and tobramycin that can elute into the bloodstream, may result in acute renal failure. Using antibiotics in ALBC can also theoretically increase antibiotic resistance and the likelihood of obtaining a negative culture if subsequent aspirations are performed. Overall, ALBC is an effective medical implant tool that can be used for treating and preventing PJI. PMID- 25272206 TI - CB2-selective cannabinoid receptor ligands: synthesis, pharmacological evaluation, and molecular modeling investigation of 1,8-Naphthyridin-2(1H)-one-3 carboxamides. AB - We have recently identified 1,8-naphthyridin-2(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high selectivity and affinity in the nanomolar range for the CB2 receptor. Furthermore, we found that their functional activity is controlled by the presence of the substituents at position C-6 of the naphthyridine scaffold. In fact, the introduction of substituents in this position determined a functionality switch from agonist to antagonists/inverse agonists. Finally, docking studies showed that the difference between the pharmacology of these ligands may be in the ability/inability to block the Toggle Switch W6.48(258) (chi1 g+ -> trans) transition. PMID- 25272208 TI - Optimization of spinal implant screw for lower vertebra through finite element studies. AB - The increasing older population is suffering from an increase in age-related spinal degeneration that causes tremendous pain. Spine injury is mostly indicated at the lumbar spine (L3-L5) and corresponding intervertebral disks. Finite element analysis (FEA) is now one of the most efficient and accepted tools used to simulate these pathological conditions in computer-assisted design (CAD) models. In this study, L3-L5 spines were modeled, and FEA was performed to formulate optimal remedial measures. Three different loads (420, 490.5, and 588.6 N) based on three body weights (70, 90, and 120 kg) were applied at the top surface of the L3 vertebra, while the lower surface of the L5 vertebra remained fixed. Models of implants using stainless steel and titanium alloy (Ti6Al4V) pedicle screws and rods with three different diameters (4, 5, and 6 mm) were inserted into the spine models. The relative strengths of bone (very weak, weak, standard, strong, and very strong) were considered to determine the patient specific effect. A total of 90 models were simulated, and von Mises stress and strain, shear stress, and strain intensity contour at the bone-implant interface were analyzed. Results of these analyses indicate that the 6-mm pedicle screw diameter is optimal for most cases. Experimental and clinical validation are needed to confirm these theoretical results. PMID- 25272209 TI - Comparison of the effects of different implant apical designs on the magnitude and distribution of stress and strain in bone: a finite element analysis study. AB - OBJECTIVES: The aim of this study was to investigate the effects of implant design on the apex area and on stress and stress patterns within surrounding bone. METHODS: Three commercially available implants with the same diameter (3.5 mm), same length (10-11 mm), and same complement abutment were selected for modeling as follows: (1) flat apical design with light tapering degree, (2) dome shaped apical design with light tapering, and (3) flat apical design with intense tapering in one-third of the apical area. According to human conebeam computed tomography (CBCT), the bone was modeled using a cortical thickness of 2 mm and cancellous bone. Forces of 100 N and 300 N in the vertical and 15 degrees angle directions were applied to the entire abutment surface, and the equivalent stress and strain were calculated using finite element analysis (FEA) methods. RESULTS: In all models, stress was concentrated on the cortical bone around the implant neck; in non-axial loads, stress was concentrated on the buccal side. The maximum strain recorded was a microstrain of 7200 MUm MUm-1 around the apex of sample C, which also showed the highest level of stress detected in cancellous bone (4.4 MPa). We observed the pathologic overload in the apical area of sample B (with a dome-shaped apex); however, the strain value was less than that of sample C. CONCLUSION: FEA revealed that great sudden changes in diameter along the fixture increases stress and strain in peri-implant bone. Therefore, uniform tapering should be considered as a standard feature for most clinical situations, and a flat apical design, which creates a better stress and strain distribution in surrounding bone than dome-shaped bone, should also be used. PMID- 25272210 TI - Hemiepiphysiodeses for guided growth in children. AB - Lower-extremity angular deformities are among the most common non-traumatic conditions in children being referred to pediatric orthopedists. Understanding of this abnormality and knowledge of current treatment is essential for pediatricians and primary caregivers. A development in the surgical management of these problems has improved the quality of care of affected children and adolescents. Traditionally, angular deformities are treated by means of osteotomy. In patients who are skeletally immature, this major intervention can be avoided by influencing or guiding the growth of the affected physis using hemiepiphysiodesis techniques. Recently, alternative surgical techniques and implants have been described for improved control of the guided growth. PMID- 25272211 TI - Role of bacterial biofilms in patients after reconstructive and aesthetic breast implant surgery. AB - INTRODUCTION: Capsular contracture is a feared complication following both reconstructive and aesthetic breast surgery. The etiology is uncertain, but bacterial biofilms have been suggested as trigger for chronic peri-implant inflammation, eventually leading to capsular contracture. METHODS: Data were extracted from patient records included in a prospective cohort between 2008 and 2010. We compared patients who underwent submuscular breast reconstruction using expander implants and those needing implant removal for capsular contracture after aesthetic submuscular breast augmentation. RESULTS: Of 36 included breast implants from 27 patients, 18 implants were inserted for reconstructive reasons and 18 for aesthetic reasons. The median indwelling time was 3 years for aesthetic implants and 3 months for reconstructive expanders. Overall, sonication cultures were positive in 13 implants (36%). In aesthetic implants, sonication cultures were positive in 28% and sonication cultures were positive in expander implants in 44%. Propionibacterium acnes and coagulasenegative staphylococci were predominant. CONCLUSION: Sonication cultures were positive in approximately 33% of removed breast implants and were comparable for reconstructive expander and aesthetic implants. These findings support the hypothesis that bacterial biofilms play a role in the pathogenesis of capsular contracture, especially after expander reconstruction, as these implants are at the highest risk of contamination during repeated implant-filling procedures. PMID- 25272212 TI - Wear of acrylic cement (methylene-polymethacrylate) can manifest as extraosseous cement granuloma or false aneurysm of the popliteal artery after total knee arthroplasty. AB - Wear particles of acrylic cement, similar to other biomaterials, can cause periprosthetic osteolysis and formation of extraosseous cement granuloma (ECG). Expansive granuloma can manifest as a tumorous mass adjacent to the knee prosthesis, or it even can damage the popliteal artery and lead to false aneurysm formation. Suspicion of these two conditions requires a complex diagnostic approach and eventually revision of the endoprosthesis itself or reparation of the popliteal artery. Despite the beneficial fixative properties of acrylic cement (methylene-polymethacrylate), which are important for implantation of joint prostheses, the acrylic cement can also cause severe complications related to the wear process. PMID- 25272213 TI - Severe metallosis following polyethylene dislocation in a mobile-bearing medial unicompartmental knee replacement. AB - Metallosis is a rare cause of failure after unicompartmental knee replacement (UKR) and has only previously been reported when there has been abnormal metal-on metal contact. We present a case report of a 67-year-old woman who was admitted to our department with a 5-month history of a painful right knee. There was no history of trauma and her past medical history was unremarkable. She had undergone a primary mobile bearing medial UKR of her right knee 5 years ago. During the preceding 5 months, the patient complained that the knee was becoming unstable, was painful, and was making frequent clicking noises associated with metallic friction. Plain radiographs of the right knee showed dislocation of the polyethylene bearing and the patient was taken to the operating room for revision of the implant. Intraoperatively, severe evidence of metallosis was found in the periprosthetic soft tissues. The tibial component was found to be loose and the polyethylene bearing was dislocated posteriorly. The implants were revised. Postoperative recovery was uneventful. Microscopic examination revealed findings consistent with metallosis. At the latest follow-up, the patient had a good clinical and radiological outcome. In conclusion, such a complication of UKR requires early diagnosis and treatment as it can result in implant loosening and metallosis. PMID- 25272214 TI - Hydrogel encapsulation to improve cell viability during syringe needle flow. AB - This work examines pluronic F-127 poloxamer for cell protection during injection through a syringe needle. Direct cell injection is a minimally invasive method for cell transplantation; however, it often results in poor cell viability. We proposed that encapsulating cells in this hydrogel would protect cells from detrimental mechanical forces during injection and increase cell viability. The hydrogel was tested at multiple weights and carbon nanobrush concentrations to determine how gel weight affects cell viability as well as to allow the gels to remain as electrically conductive scaffolds. This work assessed the ability of the hydrogel to prevent cell membrane bursting. We used D1 multipotent mouse bone marrow stromal precursor cells for this study. We found that the pressure drop increases with increasing weight of the gels. However, cell viability also increases as the weight of the gels increases. These results support the proposition that hydrogels can be used to protect cells during syringe needle injection. Since these hydrogels undergo a reverse phase transition, the gels can be used to transplant cells into the body in solution form through injection. The gels will then harden in situ to allow for cell proliferation and tissue regeneration at the desired site. PMID- 25272215 TI - Hardware complications related to the surgical fixation of slipped capital femoral epiphyses. AB - Slipped upper femoral epiphysis is a disabling condition with an annual incidence of 2-13 per 100,000. In situ surgical fixation is the preferred initial treatment for both stable and unstable slipped capital femoral epiphysis (SCFE) cases. The main aim is to avoid further slippage and complications such as osteonecrosis and chondrolysis. The choice of medical implants in managing this condition has changed along the years from large nail-like devices to cannulated screws. The biomechanical properties of different fixation techniques have been studied. All implants have been associated with complications that can occur intraoperatively as well as in the early and late postoperative periods. This report examines a number of different implants used and identifies complications and ways on how to avoid such complications. It also looks at the complications directly related to medical implants in the management of SCFE. We looked at published literature in peer-reviewed journals describing the use of the different medical implants and the documented complications. We also examined literature that suggests ways on how to avoid and manage these complications. A review of the current literature is presented in this text. PMID- 25272216 TI - Cost effectiveness of a novel 10 kHz high-frequency spinal cord stimulation system in patients with failed back surgery syndrome (FBSS). AB - OBJECTIVES: Spinal cord stimulation (SCS) is an effective method of relieving chronic intractable pain, and one of its key indications is failed back surgery syndrome (FBSS). The objective of the current study was to evaluate the cost effectiveness of 10 kHz high-frequency SCS (HF10 SCS) compared to conventional medical management (CMM), reoperation, and traditional nonrechargeable (TNR-SCS) and rechargeable SCS (TR-SCS). METHODS: A health economic model of SCS in the United Kingdom was reproduced in the perspective of the health care system to simulate costs and quality adjusted life years (QALYs) over 15 years. In the model, both a decision tree and the Markov model were used to describe the health outcomes of the evaluated therapies. RESULTS: HF10 SCS therapy showed a favorable incremental cost-effectiveness ratio (ICER) of L3,153 per QALY gained as compared to CMM and established dominance (less costly, more QALYs) compared to TNR-SCS (L8,802 per QALY vs. CMM) and TR-SCS (L5,101 per QALY vs. CMM). CONCLUSION: This first analysis of the cost effectiveness of HF10 SCS suggests that it is more cost effective and provides a greater number of QALYs than both TNR-SCS and TR SCS. PMID- 25272217 TI - Catastrophic stem taper wear in ceramic on polyethylene bearing couple: a case report. AB - A severe abrasion occurred at the stem taper 13 years after total hip arthroplasty. The bearing couple was 28 mm ceramic on polyethylene. The ceramic head had almost no damage, whereas the stem taper had severe damage. An ectopic bone probably contributed to the abrasion. The ectopic bone had grown to restrict the normal motion in the bearing couple and all stress and torque seemed to concentrate in the junction until the junction obtained mobility instead of the original bearing couple. PMID- 25272218 TI - Musculoskeletal health disparities: health literacy, cultural competency, informed consent, and shared decision making. AB - The factors that contribute to musculoskeletal healthcare disparities may influence the results of studies regarding the long-term outcome of orthopaedic implants. Patient decisions regarding their healthcare and their subsequent outcomes are influenced by health literacy. Providing patients with the information that they need to consent to treatment must be provided in a culturally competent manner. The influence of the physician or healthcare provider on the treatment choice varies depending on the type of decision-making process: patient-based, physician-based, or shared decision making. Respecting the patient's autonomy while acknowledging the knowledge and experience of the physician, we advocate for shared decision making. This may require modification of existing regulations regarding informed consent. Furthermore, federal and state directives have been put into place to address healthcare disparities, especially with respect to culturally competent care and access to proper healthcare. PMID- 25272219 TI - A qualitative study of factors underlying decision making for joint replacement among African Americans and Latinos with osteoarthritis. AB - To support patients in making decisions that align with their unique cultural beliefs, an understanding of factors underlying patient preferences is needed. We sought to identify psychosocial factors that influenced decision making among African-American and Hispanic patients referred for knee or hip arthroplasty. Thirty-six participants deciding on surgery were interviewed. Responses were audio-taped, transcribed, and read. Codes were assigned to the raw data and then clustered into categories that were analyzed to yield overarching themes. This process was repeated independently by two corroborators. Six categories described the mental calculations made in patients' decision-making processes: 1) self assessment of fit for surgery based on age and comorbidity, 2) research and development of mental report cards of their surgeons, 3) reliving of social network experiences, 4) reliance on faith and spirituality for guidance, 5) acknowledgment of fear and anxiety, and 6) setting expectations for recovery. This study advanced the understanding of how decisions about joint replacement are constructed and identified cultural levers that can be targeted for intervention. Developing culturally tailored health information that addresses some of our findings and disseminating messages through social networks may reduce the underutilization of joint replacement among racial and ethnic minority populations. PMID- 25272220 TI - Total hip arthroplasty: differences in outcome measures between men and women. AB - INTRODUCTION: Patient-related factors impact the long-term survival of hip arthroplasty. This study evaluated whether there were differences in outcome measures between men and women undergoing total hip arthroplasty. METHODS: A retrospective study of prospectively collected data on 75 primary total hip arthroplasties in 72 patients was conducted. Medical history, physical examination, Harris Hip scores, and Quality of Life forms (SF-36) were obtained for each patient preoperatively and postoperatively. Preoperative radiographs were assessed using the Kellgren and Lawrence scoring system. Only patients with a minimum follow-up of 2 years were included. RESULTS: Preoperatively, women and men had comparable Kellgren and Lawrence scores and Harris Hip scores. Of the 8 subscores for the SF-36, only the Physical Functioning subscore was significantly different preoperatively. Similar results were noted postoperatively; again, only the Physical Functioning subscores were significantly different between men and women. CONCLUSIONS: Physician assessments were not significantly different preoperatively and postoperatively for men or women. The results for the SF-36 were similar except for a significant difference in the Physical Functioning subscore preoperatively and postoperatively. According to the Medical Outcomes Trust, the SF-36 Physical Functioning score has been shown to be the best all around measure of physical health. PMID- 25272221 TI - Management strategies for total hip arthroplasty in sickle cell patients. AB - Sickle cell anemia is an inherited hemoglobinopathy in which there is a structural change to the erythrocyte from round to crescent shaped or sickled. These abnormally shaped cells can block small vessels resulting in compromise of vascular supply, pain, and end-organ damage. These patients are particularly susceptible to hip osteonecrosis, which in late stages may require a total hip arthroplasty. Historically, total hip arthroplasty had inferior outcomes in this patient population due to poorer clinical outcomes and higher perioperative complications. During recent decades, however, there have been some improvements in the medical management of these patients, which has potentially improved the clinical outcomes of this procedure. In this article, we review all reported management strategies for the perioperative care of sickle cell anemia patients undergoing total hip arthroplasty. PMID- 25272222 TI - Prevalence of post-traumatic osteoarthritis in morbidly obese patients after acetabular fracture fixation. AB - BACKGROUND: Morbid obesity and osteoarthritis are conditions that place a significant burden on the US healthcare system. Acetabular fracture is a known cause of post-traumatic osteoarthritis (PTOA) and morbid obesity contributes to the development of osteoarthritis. This study aimed to determine the prevalence of PTOA in morbidly obese patients who underwent acetabular fracture fixation. METHODS: A retrospective review of morbidly obese patients who underwent acetabular fracture repair was performed. Patient information included demographics, body mass index, patient age, and length of hospital stay. The prevalence of PTOA was determined by radiographic review with a minimum follow-up of 4 years. RESULTS: There were 299 acetabular fracture fixations performed from 2007 to 2012 at our institution and 39 of these were in morbidly obese patients. One patient was excluded due to preoperative osteoarthritis of the hip. Of the 38 patients, 26 (68%) went on to develop PTOA after acetabular fracture fixation. This is significantly higher than previously reported rates of PTOA after acetabular fracture fixation. There was a higher rate of PTOA in morbidly obese males compared with females (P=0.008). CONCLUSION: Morbid obesity appears to pose a significantly increased risk for the development of PTOA after fixation of acetabular fractures. PMID- 25272223 TI - Musculoskeletal healthcare disparities: influence of patient sex, race, and ethnicity on utilization of total joint arthroplasty. AB - Total joint arthroplasty is an effective treatment of musculoskeletal diseases including osteoarthritis, rheumatoid arthritis, trauma, and other diseases of the major joints. Based on data obtained from the National Inpatient Survey from 2000 through 2010, substantial differences in the rates of utilization of total hip, knee, and shoulder arthroplasty were detected with respect to race, ethnicity, and gender/sex. The results of this study support the likelihood that it is the interaction between multiple factors (patient, physician, and system/institutional) that contributes to musculoskeletal health disparities. Our study shows that disparities in the utilization of total joint arthroplasty that were evident in 2000 continue to exist. Additional studies evaluating innovative approaches to reducing musculoskeletal disparities relating to total joint arthroplasty are needed. PMID- 25272225 TI - De novo assembly and characterization of pericarp transcriptome and identification of candidate genes mediating fruit cracking in Litchi chinensis Sonn. AB - Fruit cracking has long been a topic of great concern for growers and researchers of litchi (Litchi chinensis Sonn.). To understand the molecular mechanisms underlying fruit cracking, high-throughput RNA sequencing (RNA-Seq) was first used for de novo assembly and characterization of the transcriptome of cracking pericarp of litchi. Comparative transcriptomic analyses were performed on non cracking and cracking fruits. A total of approximately 26 million and 29 million high quality reads were obtained from the two groups of samples, and were assembled into 46,641 unigenes with an average length of 993 bp. These unigenes can be useful resources for future molecular studies of the pericarp in litchi. Furthermore, four genes (LcAQP, 1; LcPIP, 1; LcNIP, 1; LcSIP, 1) involved in water transport, five genes (LcKS, 2; LcGA2ox, 2; LcGID1, 1) involved in GA metabolism, 21 genes (LcCYP707A, 2; LcGT, 9; Lcbeta-Glu, 6; LcPP2C, 2; LcABI1, 1; LcABI5, 1) involved in ABA metabolism, 13 genes (LcTPC, 1; Ca2+/H+ exchanger, 3; Ca2+-ATPase, 4; LcCDPK, 2; LcCBL, 3) involved in Ca transport and 24 genes (LcPG, 5; LcEG, 1; LcPE, 3; LcEXP, 5; Lcbeta-Gal, 9; LcXET, 1) involved in cell wall metabolism were identified as genes that are differentially expressed in cracked fruits compared to non-cracked fruits. Our results open new doors to further understand the molecular mechanisms behind fruit cracking in litchi and other fruits, especially Sapindaceae plants. PMID- 25272224 TI - Circulating RNA molecules as biomarkers in liver disease. AB - Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell free circulating RNA molecules have been recently acknowledged as an important source of potential medical biomarkers. However, many aspects related to the biology of these molecules remain to be elucidated. In this review, we summarize current concepts related to the origin, transportation and possible functions of cell-free RNA. We outline current development of extracellular RNA-based biomarkers in the main forms of non-inherited liver disease: chronic viral hepatitis, hepatocellular carcinoma, non-alcoholic fatty liver, hepato-toxicity, and liver transplantation. Despite recent technological advances, the lack of standardization in the assessment of these markers makes their adoption into clinical practice difficult. We thus finally review the main factors influencing quantification of circulating RNA. These factors should be considered in the reporting and interpretation of current findings, as well as in the proper planning of future studies, to improve reliability and reproducibility of results. PMID- 25272226 TI - EGF potentiation of VEGF production is cell density dependent in H292 EGFR wild type NSCLC cell line. AB - Non-small cell lung cancer (NSCLC) affects millions of patients each year worldwide. Existing therapies include epidermal growth factor receptor (EGFR) inhibition using small molecules or antibodies with good efficacy. Unfortunately, intrinsic and acquired resistance to EGFR therapy remains a persistent complication for disease treatment. A greater understanding of the role of EGFR in NSCLC etiology is crucial to improving patient outcomes. In this study, the role of EGFR in tumor angiogenesis was examined in H292 NSCLC cells under the pretense that confluent cells would exhibit a more angiogenic and growth-centered phenotype. Indeed, confluent H292 cells potentiated endothelial cell angiogenesis in co-culture models in an EGFR-dependent manner. While confluent H292 cells did not exhibit any change in EGFR protein expression, EGFR localization to the extracellular membrane was increased. EGFR membrane localization coincided with a comparable potentiation of maximal EGFR phosphorylation and was followed by a 3 fold increase in vascular endothelial growth factor A (VEGF-A) production as compared to subconfluent cells. EGFR-mediated VEGF-A production was determined to be dependent on signal transducer and activator of transcription 3 (STAT3) activation and not phosphoinositide 3-kinase (PI3K) signaling. These results identify unique cell density dependent phenotypes within a monoclonal NSCLC cell line and provide a potential mechanism of resistance to anti-EGFR therapy in metastatic NSCLC. PMID- 25272228 TI - TCDD induces the hypoxia-inducible factor (HIF)-1alpha regulatory pathway in human trophoblastic JAR cells. AB - The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1alpha) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD induced HIF-1alpha stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1alpha stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor gamma (PPARgamma), PPARgamma coactivator-1alpha, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1alpha pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development. PMID- 25272229 TI - Recombinant expression of a novel fungal immunomodulatory protein with human tumor cell antiproliferative activity from Nectria haematococca. AB - To our best knowledge, all of the fungal immunomodulatory proteins (FIPs) have been successfully extracted and identified in Basidomycetes, with only the exception of FIP from ascomycete Nectria haematococca (FIP-nha) discovered through homology alignment most recently. In this work, a gene encoding FIP-nha was synthesized and recombinantly expressed in an Escherichia coli expression system. SDS-PAGE and MALDI-MS analyses of recombinant FIP-nha (rFIP-nha) indicated that the gene was successfully expressed. The yield of the bioactive FIP-nha protein was 42.7 mg/L. In vitro assays of biological activity indicated that the rFIP-nha caused hemagglutination of human and rabbit red blood cells, significantly stimulated mouse spleen lymphocyte proliferation, and enhanced expression of interleukin-2 (IL-2) released from mouse splenocytes, revealing a strong antitumor effect against HL60, HepG2 and MGC823. Through this work, we constructed a rapid and efficient method of FIP production, and suggested that FIP-nha is a valuable candidate for use in future medical care and pharmaceutical products. PMID- 25272227 TI - Local melatoninergic system as the protector of skin integrity. AB - The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a "guardian" of the genome and cellular integrity with clinical applications in UVR induced pathology that includes carcinogenesis and skin aging. PMID- 25272230 TI - Influence of unmodified and beta-glycerophosphate cross-linked chitosan on anti Candida activity of clotrimazole in semi-solid delivery systems. AB - The combination of an antifungal agent and drug carrier with adjunctive antimicrobial properties represents novel strategy of complex therapy in pharmaceutical technology. The goal of this study was to investigate the unmodified and ion cross-linked chitosan's influence on anti-Candida activity of clotrimazole used as a model drug in hydrogels. It was particularly crucial to explore whether the chitosans' structure modification by beta-glycerophosphate altered its antifungal properties. Antifungal studies (performed by plate diffusion method according to CLSI reference protocol) revealed that hydrogels obtained with chitosan/beta-glycerophosphate displayed lower anti-Candida effect, probably as a result of weakened polycationic properties of chitosan in the presence of ion cross-linker. Designed chitosan hydrogels with clotrimazole were found to be more efficient against tested Candida strains and showed more favorable drug release profile compared to commercially available product. These observations indicate that novel chitosan formulations may be considered as promising semi-solid delivery system of clotrimazole. PMID- 25272231 TI - The beneficial effects of combined grape pomace and omija fruit extracts on hyperglycemia, adiposity and hepatic steatosis in db/db mice: a comparison with major index compounds. AB - This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic beta cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice. PMID- 25272233 TI - Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody-associated small vessel vasculitis. AB - Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies. PMID- 25272232 TI - Results from the Atherosclerosis Risk in Communities study suggest that low serum magnesium is associated with incident kidney disease. AB - Low serum magnesium has been associated with kidney function decline in persons with diabetes as well as cardiovascular disease in the general population. As the association of serum magnesium with incident kidney disease in the general population is unknown, we assessed this in 13,226 participants (aged 45-65) in the Atherosclerosis Risk in Communities study with baseline estimated glomerular filtration rate of at least 60 ml/min per 1.73 m(2) in years 1987-89 and followed through 2010. The risks for incident chronic kidney disease (CKD) and end-stage renal disease (ESRD) associated with baseline total serum magnesium levels were evaluated using Cox regression. There were 1965 CKD and 208 ESRD events during a median follow-up of 21 years. In adjusted analysis, low serum magnesium levels (0.7 mmol/l or less) had significant associations with incident CKD and ESRD compared with the highest quartile with adjusted hazard ratio of 1.58 (95% CI: 1.35-1.87) for CKD and 2.39 (95% CI: 1.61-3.56) for ESRD. These associations remained significant after excluding users of diuretics and across subgroups stratified by hypertension, diabetes, and self-reported race. Thus, in a large sample of middle-aged adults, low total serum magnesium was independently associated with incident CKD and ESRD. Further studies are needed to determine whether modification of serum magnesium levels might alter subsequent incident kidney disease rates. PMID- 25272234 TI - Elevation of circulating TNF receptors 1 and 2 increases the risk of end-stage renal disease in American Indians with type 2 diabetes. AB - In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2 (TNFR2) predict end-stage renal disease (ESRD). Here we examined this relationship in a longitudinal cohort study of American Indians with type 2 diabetes with measured glomerular filtration rate (mGFR, iothalamate) and urinary albumin-to-creatinine ratio (ACR). ESRD was defined as dialysis, kidney transplant, or death attributed to diabetic kidney disease. Age-gender-adjusted incidence rates and incidence rate ratios of ESRD were computed by Mantel Haenszel stratification. The hazard ratio of ESRD was assessed per interquartile range increase in the distribution of each TNFR after adjusting for baseline age, gender, mean blood pressure, HbA1c, ACR, and mGFR. Among the 193 participants, 62 developed ESRD and 25 died without ESRD during a median follow-up of 9.5 years. The age-gender-adjusted incidence rate ratio of ESRD was higher among participants in the highest versus lowest quartile for TNFR1 (6.6, 95% confidence interval (CI) 3.3-13.3) or TNFR2 (8.8, 95% CI 4.3-18.0). In the fully adjusted model, the risk of ESRD per interquartile range increase was 1.6 times (95% CI 1.1-2.2) as high for TNFR1 and 1.7 times (95% CI 1.2-2.3) as high for TNFR2. Thus, elevated serum concentrations of TNFR1 or TNFR2 are associated with increased risk of ESRD in American Indians with type 2 diabetes after accounting for traditional risk factors including ACR and mGFR. PMID- 25272235 TI - Effects of intraperitoneal thymoquinone on chronic neuropathic pain in rats. AB - In this study, we evaluated the protective effects of thymoquinone, the major constituent of Nigella sativa seeds on the neuropathic pain of rats with chronic constrictive injury of the sciatic nerve. Rats received repeated administration of thymoquinone (1.25, 2.5, and 5 mg/kg, i. p.) once a day for 14 days, beginning immediately after the nerve injury. Mechanical allodynia, cold allodynia, and thermal hyperalgesia were assessed with the von Frey filament, acetone drop, or radiant heat stimulus, respectively. Recent evidence points towards a role of oxidative stress, spinal glia activation, and cell death in the pathogenesis of neuropathic pain. Ionized calcium-binding adapter molecule 1 (a marker of microglia), glial fibrillary acidic protein (a marker of astroglia), Bcl2 associated X protein (a proapoptotic protein), and B-cell lymphoma protein 2 (an antiapoptotic protein) were measured using Western blot on days 3, 7, and 14 post chronic constrictive injury. The changes in the protein levels of malondialdehyde and glutathione, biomarkers of oxidative stress, were assessed by spectrophotometric assay on day 14 post chronic constrictive injury. Repeated treatment with thymoquinone (2.5 and 5 mg/kg) significantly alleviated behavioral signs of neuropathic pain. In the lumbar spinal cord of neuropathic rats, ionized calcium-binding adapter molecule 1 and Bcl2-associated X protein increased on day 3 post chronic constrictive injury, whereas B-cell lymphoma protein 2 did not significantly change. After repeated thymoquinone administration, the elevated Bcl2-associated X protein and ionized calcium-binding adapter molecule reduced on day 3, while the level of B-cell lymphoma protein 2 was even stimulated. Ionized calcium-binding adapter molecule and Bcl2-associated X protein/B-cell lymphoma protein 2 ratio declined by days 7 and 14; consequently, there were no significant differences among groups. No or little change was observed in the glial fibrillary acidic protein content during the study. Chronic constrictive injury produced a significant increase in the levels of malondialdehyde and decrease in the contents of glutathione on day 14. Thymoquinone treatment (2.5 and 5 mg/kg) restored the levels of malondialdehyde. High dose of thymoquinone (5 mg/kg) also reversed the decreased glutathione in the injured animals. Our results indicate that, microglia, apoptotic factors, and oxidative stress rather than astroglia contribute to the pathogenesis of chronic constrictive injury, and thymoquinone plays an anti-nociceptive role possibly by antioxidant effects and inhibition of microglia activity. PMID- 25272236 TI - Ionomers of intrinsic microporosity: in silico development of ionic functionalized gas-separation membranes. AB - This work presents the predictive molecular simulations of a functionalized polymer of intrinsic microporosity (PIM) with an ionic backbone (carboxylate) and extra-framework counterions (Na(+)) for CO2 gas storage and separation applications. The CO2-philic carboxylate-functionalized polymers are predicted to contain similar degrees of free volume to PIM-1, with Brunauer-Emmett-Teller (BET) surface areas from 510 to 890 m(2)/g, depending on concentration of ionic groups from 100% to 17%. As a result of ionic groups enhancing the CO2 enthalpy of adsorption (to 42-50 kJ/mol), the uptake of the proposed polymers at 293 K exceeded 1.7 mmol/g at 10 kPa and 3.3 mmol/g at 100 kPa for the polymers containing 100% and 50% ionic functional groups, respectively. In addition, CO2/CH4 and CO2/N2 mixed-gas separation performance was evaluated under several industrially relevant conditions, where the IonomIMs are shown to increase both the working capacity and selection performance in certain pressure swing applications (e.g., natural gas separations). These simulations reveal that intrinsically microporous ionomers show great potential as the future of energy efficient gas-separation polymeric materials. PMID- 25272237 TI - Associations between children's video game playing and psychosocial health: information from both parent and child reports. AB - Video games are a highly heterogeneous form of entertainment. As recent reviews highlight, this heterogeneity makes likely that video games have both positive and negative consequences for child development. This study investigated the associations between gaming frequency and psychosocial health among children younger than 12 years of age, an understudied cohort in this field. Both parents and children reported children's gaming frequency, with parents also reporting on children's psychosocial health. Given that children may be too young to report the time they spend playing video games accurately, children's reports were scaffolded by a developmentally appropriate measure. We further investigated the potential bias of having parents report both their children's gaming frequency and their children's psychosocial health (i.e., a single source bias). Parental reports of children's gaming frequency were higher than their children's reports. However, a direct test of the potential single source bias rendered null results. Notably, however, while parental reports showed negative associations between gaming and psychosocial health, children's reports showed no associations. Specifically, based on parent reports, children's gaming was associated with more conduct and peer problems, and less prosocial behavior. As children's reports produced no associations between gaming and psychosocial health, parental reports in this study may belie an erroneous set of conclusions. We therefore caution against relying on just one reporter when assessing children's gaming frequency. PMID- 25272238 TI - Ethical media competence as a protective factor against cyberbullying and cybervictimization among german school students. AB - The use of digital information and communication technologies is an integral part of adolescents' everyday life. Besides various opportunities for information, entertainment, and communication, media use is associated with risks such as cyberbullying. Cyberbullying refers to aggressive behavior in the context of computer-mediated communication, characterized by repetition, an intention to harm, and power imbalance. Previous studies have shown that increased media use is a major risk factor for cyberbullying and cybervictimization. Given that restricting media use is not a practical way to reduce the negative effects inherent in media use, the present study examines the relevance of ethical media competence. We expected ethical media competence to buffer the effect of increased media use on cyberbullying and cybervictimization. A survey was conducted with 934 students (53% female) aged 10-17 years (M=13.26, SD=1.63). As expected, hierarchical regression analyses showed a positive main effect of media use, a negative main effect of ethical media competence, and a negative interaction effect of media use and media competence on cyberbullying and cybervictimization. Simple slope analyses revealed that at high levels of ethical media competence, media use has almost no effect on cybervictimization and a significant negative effect on cyberbullying. Consequently, promoting ethical media competence constitutes a potential measure to prevent the risks of increased media use for cyberbullying and cybervictimization. PMID- 25272242 TI - Donor-transmitted malaria after heart transplant managed successfully with artesunate. AB - Donor-transmitted malaria is a rare complication in solid organ transplantation, which causes high mortality. Data concerning the use of artesunate in solid organ transplant recipients are lacking. We report a heart transplant patient who developed donor-derived severe Plasmodium falciparum malaria, successfully treated with artesunate. Transmission of malaria to 2 of the other transplant recipients from the same donor was also documented. PMID- 25272241 TI - Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia. AB - Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2.62 (larger unit) and 2.02 (smaller unit) x 10(7) /kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80-96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51 76) and 36% (95%CI: 24-49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26-52), and the 3-year relapse incidence was 11% (95%CI: 4-21). With a median 37-month (range 23-71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37-63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed. PMID- 25272243 TI - Sum frequency generation vibrational spectroscopy of 1,3-butadiene hydrogenation on 4 nm Pt@SiO2, Pd@SiO2, and Rh@SiO2 core-shell catalysts. AB - 1,3-Butadiene (1,3-BD) hydrogenation was performed on 4 nm Pt, Pd, and Rh nanoparticles (NPs) encapsulated in SiO2 shells at 20, 60, and 100 degrees C. The core-shells were grown around polyvinylpyrrolidone (PVP) coated NPs (Stober encapsulation) prepared by colloidal synthesis. Sum frequency generation (SFG) vibrational spectroscopy was performed to correlate surface intermediates observed in situ with reaction selectivity. It is shown that calcination is effective in removing PVP, and the SFG signal can be generated from the metal surface. Using SFG, it is possible to compare the surface vibrational spectrum of Pt@SiO2 (1,3-BD is hydrogenated through multiple paths and produces butane, 1 butene, and cis/trans-2-butene) to Pd@SiO2 (1,3-BD favors one path and produces 1 butene and cis/trans-2-butene). In contrast to Pt@SiO2 and Pd@SiO2, SFG and kinetic experiments of Rh@SiO2 show a permanent accumulation of organic material. PMID- 25272244 TI - Printable nanostructured silicon solar cells for high-performance, large-area flexible photovoltaics. AB - Nanostructured forms of crystalline silicon represent an attractive materials building block for photovoltaics due to their potential benefits to significantly reduce the consumption of active materials, relax the requirement of materials purity for high performance, and hence achieve greatly improved levelized cost of energy. Despite successful demonstrations for their concepts over the past decade, however, the practical application of nanostructured silicon solar cells for large-scale implementation has been hampered by many existing challenges associated with the consumption of the entire wafer or expensive source materials, difficulties to precisely control materials properties and doping characteristics, or restrictions on substrate materials and scalability. Here we present a highly integrable materials platform of nanostructured silicon solar cells that can overcome these limitations. Ultrathin silicon solar microcells integrated with engineered photonic nanostructures are fabricated directly from wafer-based source materials in configurations that can lower the materials cost and can be compatible with deterministic assembly procedures to allow programmable, large-scale distribution, unlimited choices of module substrates, as well as lightweight, mechanically compliant constructions. Systematic studies on optical and electrical properties, photovoltaic performance in experiments, as well as numerical modeling elucidate important design rules for nanoscale photon management with ultrathin, nanostructured silicon solar cells and their interconnected, mechanically flexible modules, where we demonstrate 12.4% solar to-electric energy conversion efficiency for printed ultrathin (~ 8 MUm) nanostructured silicon solar cells when configured with near-optimal designs of rear-surface nanoposts, antireflection coating, and back-surface reflector. PMID- 25272246 TI - Accuracy of malignant hyperthermia diagnoses in hospital discharge records. AB - BACKGROUND: In 1997, the International Classification of Diseases (ICD), 9th Revision Clinical Modification (ICD-9) coding system introduced the code for malignant hyperthermia (MH) (995.86). The aim of this study was to estimate the accuracy of coding for MH in hospital discharge records. METHODS: An expert panel of anesthesiologists reviewed medical records for patients with a discharge diagnosis of MH based on ICD-9 or ICD-10 codes from January 1, 2006 to December 31, 2008 at six tertiary care medical centers in North America. All cases were categorized as possible, probable, or fulminant MH, history of MH (family or personal) or other. RESULTS: A total of 47 medical records with MH diagnoses were reviewed; 68.1% had a documented surgical procedure and general anesthesia, and 23.4% (95% CI, 12.3-38.0%) had a possible, probable, or fulminant MH event. Dantrolene was given in 81% of the MH events. All patients judged to have an incident MH event survived to discharge. Family and personal history of MH accounted for 46.8% of cases. High fever without evidence of MH during admission accounted for 23.4%, and the reason for MH coding was unclear in 6.4% of cases. CONCLUSIONS: Approximately one quarter of ICD-9 or ICD-10 coded MH diagnoses in hospital discharge records refer to incident MH episodes and an additional 47% to MH susceptibility (including personal history or family history). Information such as surgical procedure, anesthesia billing data, and dantrolene administration may aid in identifying incident MH cases among those with an ICD-9 or ICD-10 coded MH diagnosis in their hospital discharge records. PMID- 25272247 TI - Detection of measles virus genotype B3, India. PMID- 25272245 TI - Importance of Toll-like receptor 2 in mitochondrial dysfunction during polymicrobial sepsis. AB - BACKGROUND: Toll-like receptor 2 (TLR2) contributes to sepsis pathogenesis such as deleterious systemic inflammation, cardiac dysfunction, and high mortality in animal studies. Mitochondrial dysfunction is a key molecular event that is associated with organ injury in sepsis. The role of TLR2 in sepsis-induced mitochondrial dysfunction remains unclear. METHODS: Intracellular hydrogen peroxide (H2O2), mitochondrial superoxide (O2), mitochondrial membrane potential (DeltaPsim), and intracellular adenosine triphosphate (ATP) were measured in peritoneal leukocytes. A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). Wild-type and TLR2-deficient (TLR2) mice were subjected to sham or CLP. Mitochondrial functions including reactive oxygen species (ROS), DeltaPsim, intracellular ATP, and complex III activity were measured. RESULTS: TLR2/1 activation by Pam3Cys enhanced intracellular H2O2 and mitochondrial O2 production in leukocytes, but had no effect on mitochondrial DeltaPsim and ATP production. The effect was specific for TLR2/1 as TLR3 or TLR9 ligands did not induce ROS production. Polymicrobial sepsis induced mitochondrial dysfunction in leukocytes, as demonstrated by increased H2O2 and mitochondrial O2 production (CLP vs. sham; H2O2: 3,173+/-498, n=5 vs. 557+/-38, n=4; O2-: 707+/ 66, n=35 vs. 485+/-35, n=17, mean fluorescence intensity, mean+/-SEM), attenuated complex III activity (13+/-2, n=16 vs. 30+/-3, n=7, millioptical densities/min), loss of mitochondrial DeltaPsim, and depletion of intracellular ATP (33+/-6, n=11 vs. 296+/-29, n=4, nmol/mg protein). In comparison, there was significant improvement in mitochondrial function in septic TLR2-/- mice as evidenced by attenuated mitochondrial ROS production, better-maintained mitochondrial DeltaPsim, and higher cellular ATP production. CONCLUSIONS: TLR2 signaling plays a critical role in mediating mitochondrial dysfunction in peritoneal leukocytes during polymicrobial sepsis. PMID- 25272248 TI - From amino acids to nature-inspired molecular scaffolds: incorporation of medium sized bridged heterocycles into a peptide backbone. AB - Novel molecular scaffolds comprising two to four bridged and fused heterocycles were synthesized from amino acids using seven-membered endocyclic N-acyliminium ions as key intermediates in acid-mediated tandem reactions with internal nucleophiles. This complexity-generating synthesis proceeds with high efficiency and with full stereocontrol of the newly generated stereogenic center. These results have extended the scope of medium-sized cyclic iminium ion chemistry, making it applicable as a regio- and stereoselective synthetic strategy for the generation of complex polycyclic structures. Furthermore, its compatibility with the traditional Merrifield synthesis of peptides on solid supports allowed the incorporation of the previously unexplored conformationally restricted cyclic systems into peptides without a need to independently synthesize the scaffold. PMID- 25272249 TI - Microencapsulation of a putative probiotic Enterobacter species, C6-6, to protect rainbow trout, Oncorhynchus mykiss (Walbaum), against bacterial coldwater disease. AB - Flavobacterium psychrophilum is the causative agent of bacterial coldwater disease (BCWD), which has a major impact on salmonid aquaculture globally. An Enterobacter species, C6-6, isolated from the gut of rainbow trout, Oncorhynchus mykiss (Walbaum), has been identified as a potential probiotic species providing protection against BCWD. This study examined the effects of alginate microencapsulation on the protective efficacy of C6-6 against BCWD in vivo when administered to rainbow trout fry orally or by intraperitoneal (IP) injection. Viable C6-6 bacteria were microencapsulated successfully, and this process (microencapsulation) did not significantly deteriorate its protective properties as compared to the administration of non-microencapsulated C6-6 bacteria. Both oral and IP delivery of C6-6 achieved significantly better protection than control treatments that did not contain C6-6 bacteria. The highest relative percent survival (RPS) resulted from IP delivery (71.4%) and was significantly greater than the highest oral RPS (38.6%). Successful intestinal colonization was not critical to protective effects of C6-6. The study showed that C6-6 administration, with or without encapsulation, was a viable choice for protecting fry from BCWD especially when administered intraperitoneally. PMID- 25272250 TI - Remote-sensing applications for environmental health research. PMID- 25272251 TI - Two human cases of Rickettsia felis infection, Thailand. PMID- 25272252 TI - Long-term risks and benefits of bariatric surgery: a research challenge. PMID- 25272253 TI - Prevalence of fatigue reported by physiotherapists operating diathermy equipment for microwave. AB - OBJECTIVE: To Analyze the association between prevalence of fatigue referred by physical therapists and their occupational exposure to radiation emitted by therapeutic microwave diathermy equipment. METHODS: A Cross-sectional study conducted in 193 physical therapists from four cities of the west of Parana State, Brazil. A specified structured web questionnaire was applied for collecting data about microwave diathermy exposition and potential confounders, plus the Multidimensional Assessment of Fatigue (MAF). Statistical analysis included logistic regression and Student's t-test. RESULTS: The prevalence of fatigue in the category exposed to microwave diathermy was higher (15.0%) than in non-exposed (2.9%). On multivariate logistic regression, a significant independent association between exposure to microwave diathermy and prevalence of fatigue was observed (odds ratio 4.93; 95% confidence interval 1.04 - 23.25; p = 0.04). The Student's t-test showed significant difference between the number of hours exposed to diathermy microwave, being 3,839.1 within physical therapists who referred fatigue and 497.6 within others (p = 0.004). CONCLUSION: The results demonstrate a significant and independent association between occupational exposure of physical therapists to radiation of microwave diathermy and prevalence of fatigue. Therefore, occupational safety guidelines aimed at these professionals as a prevention of possible adverse effects, as well as the replication of this study are suggested. PMID- 25272254 TI - Epidemiological, serological and molecular aspects of hepatitis B and C in children and teenagers of municipal daycare facilities schools and schools in the city of Santos. AB - OBJECTIVE: To estimate the prevalence of the serological markers anti-HBc, HBsAg and anti-HBs of hepatitis B and anti-HCV of hepatitis C among children and teenagers enrolled at daycare facilities, kindergartens and municipal elementary education network in the city of Santos, Sao Paulo, Brazil. METHODS: A cross sectional study was carried out from June 28 to December 14, 2007, in which 4,680 finger-prick blood samples were collected from children and teenagers. A survey questionnaire was applied to their family members. The sample was dimensioned using the software Epi Info version 6 with expected frequency of 1%, acceptable error of 0.5% and confidence interval of 95%. The serological tests were performed using the ELISA technique. The molecular analysis was performed using the technique of polymerase chain reaction in House. RESULTS: Age of the studied population ranged from 7 months to 18 years and 1 month. The general prevalence of anti-HBc reagent was 0.1%, HBsAg was 0.02% and anti-HCV was 0.02%. CONCLUSIONS: In children, the general prevalence of serological markers for hepatitis B and C in the city of Santos was low when compared with literature data. PMID- 25272255 TI - Why do tuberculosis patients look for urgency and emergency unities for diagnosis: a study on social representation. AB - OBJECTIVE: To understand the social representations of patients and professionals working in the field of tuberculosis, on the reasons for seeking diagnosis and treatment in the emergency room and not in the primary health care units called Unidades Basicas de Saude (UBS) or in the health program Programa de Saude da Familia near their residence. METHODS: The survey was conducted in the health services in the municipalities of Sao Paulo and Guarulhos, Brazil, in hospitals and UBS. We interviewed 20 patients and 20 employees of these units, using the Collective Subject Discourse methodology to analyze their statements. The question presented to the users was: "Why did you seek the urgent emergency hospital and not the UBS to see if you had tuberculosis?" For professionals it was asked: "Why do you think the patient seeks diagnosis in the hospital and not in the UBS?" RESULTS: As a result, two categories were found: (A) the cultural patterns; and (B) faults of the basic network. CONCLUSION: Analysis of the two explanatory dimensions show that the actions triggered by the health services should take into account the cultural patterns present in the social imaginary of the population; the health staff should receive training on specific knowledge of tuberculosis; there is a necessity of hiring human resources for the UBS and more inputs for programming. PMID- 25272256 TI - Spatial dependence of malaria epidemics in municipalities of the Amazonian Ecosystem. AB - INTRODUCTION: In 2010, there were 305 (37.8%) municipalities with malaria epidemics in the Brazilian Amazon. The epidemics spread can be explained by the spatial distribution pattern. OBJECTIVE: To analyze the spatial dependence, autocorrelation, of the malaria epidemics in the municipalities of this region. METHODS: An automated algorithm was used for the detection of epidemic municipalities in 2003, 2007 and 2010. Spatial dependence was analyzed by applying the global and local Moran index on the epidemic months proportion variable. The epidemic municipalities clusters were identified using the TerraView software. RESULTS: The global Moran index values were 0.4 in 2003; 0.6 in 2007; and 0.5 in 2010 (p = 0.01), confirming the spatial dependence among the epidemic municipalities. Box Map and Moran Map identified inter-municipal, interstate and borders clusters with spatial autocorrelation (p < 0.05). There were 10 epidemic municipalities clusters in 2003; 9 in 2007 and 8 in 2010. DISCUSSION: The epidemic municipalities clusters may be linked to the health facilities difficulties on acting together. The structural limitations of the health services can be overcome by territorial integration to support planning and control activities, strengthening the interventions. CONCLUSION: The routine analysis of the epidemic municipalities clusters with spatial and temporal persistence may provide a new indicator of planning and integrated control prioritization, contributing to malaria epidemics reducing in inter-municipal, interstate and borders areas. PMID- 25272257 TI - Inequities in intraurban areas in the distribution of risk factors for non communicable diseases, Belo Horizonte, 2010. AB - OBJECTIVE: In order to identify intraurban differentials, the prevalence of major protection and risk factors for non communicable chronic diseases were analyzed in nine health districts of Belo Horizonte, Minas Gerais, Brazil. METHODS: Analysis of data from a telephone survey conducted with 2,000 adults in Belo Horizonte, in 2010, using the average linkage method for cluster analysis among the health districts, using sociodemographic variables (education, race and marital status). The study compared the prevalence of risk factors for non communicable diseases among the health districts. RESULTS: Four clusters were identified. The best socio-demographic indicators were found in cluster 4 (South Central health district), which also showed a higher prevalence of protective factors such as higher consumption of fruits and vegetables, higher frequency of physical activity practice in the free time, use of ultraviolet protection, higher proportion of ex-smokers, and lower prevalence of whole milk and high-fat meat consumption. As a risk factor, cluster 4 showed a higher proportion of alcohol abuse. Cluster 1, with the worst socio-demographic indicators, concentrated more risk factors such as consumption of whole milk, low regular consumption of fruit and vegetables, and lower practice of physical activity in the free time. The most frequent protective indicators in cluster 1 were the regular consumption of beans, having breakfast at home, and lower alcohol abuse. CONCLUSION: Intra-urban differences were found in the distribution of risk and protection factors or non transmissible diseases, these differences can support planning aimed at actions for greater equity in health. PMID- 25272258 TI - Female homicide in Rio Grande do Sul, Brazil. AB - This study aimed to assess the female homicide rate due to aggression in Rio Grande do Sul, Brazil, using this as a "proxy" of femicide. This was an ecological study which correlated the female homicide rate due to aggression in Rio Grande do Sul, according to the 35 microregions defined by the Brazilian Institute of Geography and Statistics (IBGE), with socioeconomic and demographic variables access and health indicators. Pearson's correlation test was performed with the selected variables. After this, multiple linear regressions were performed with variables with p < 0.20. The standardized average of female homicide rate due to aggression in the period from 2003 to 2007 was 3.1 obits per 100 thousand. After multiple regression analysis, the final model included male mortality due to aggression (p = 0.016), the percentage of hospital admissions for alcohol (p = 0.005) and the proportion of ill-defined deaths (p = 0.015). The model have an explanatory power of 39% (adjusted r2 = 0.391). The results are consistent with other studies and indicate a strong relationship between structural violence in society and violence against women, in addition to a higher incidence of female deaths in places with high alcohol hospitalization. PMID- 25272259 TI - Intermunicipal inequities in access and use of secondary health services in the metropolitan area of Curitiba. AB - The aim of this study was to identify and analyze inequities in the access to specialized services in the municipalities of the metropolitan area of Curitiba, Parana, Brazil. This is an ecological study. In its preparatory stage, this study focused on the socioeconomic, epidemiologic, healthcare network and sectoral financing network profiles of the 26 municipalities comprising this area. Factor analysis was employed to obtain the six principal components, and a synthetic index was calculated from them, allowing municipalities to be ranked according to living conditions and health situation. Primary data was collected from 24 municipalities, regarding their capacity, directed and repressed demand of specialized healthcare services. The context analysis revealed accentuated intermunicipal inequities. The synthetic index allowed municipalities to be classified in four relatively homogeneous groups regarding living and health conditions. Municipalities located in Vale do Ribeira obtained the worse outcomes for the Living Conditions and Health Situation Synthetic Index, as well as the higher repressed demand for specialized healthcare services. The geographical distance from the capital showed to contribute to worse living and health conditions and greater difficulties in access to healthcare services. PMID- 25272260 TI - Mahalanobis' distance and propensity score to construct a controlled matched group in a Brazilian study of health promotion and social determinants. AB - In observational epidemiology it is usual to select a control group to study the effects of certain exposures on human health. Intervention studies are well known among epidemiologists but it is not very frequent in other areas of research. In this paper we propose the same idea of intervention studies and the use of three methods for a health promotion research control group selection: Propensity score, Mahalanobis' distance and Mahalanobis within Propensity Calipers. In the original project, "Health and Local Development: a progress review towards the millennium goals with relation to health in the Brazilian cities which develop social agendas", cities with social agendas from Brazil were matched separately by state. In the state of Parana there are 397 cities. Of these, 34 presented social agendas implemented and active since, at least, 2004. Five variables measured in 2000 were considered for the matching: population size, human development index of income, human development index of education, percentage of literacy and vaccine coverage. As a result, among these three methods, the Mahalanobis by itself was considered the less efficient. In conclusion, the propensity, which is a very simple linear score, presented very good matched sample. However, the Mahalanobis within Calipers was the method that provided the best result. PMID- 25272261 TI - Survival rates of patients with cancer of the lip, mouth and pharynx: a cohort study of 10 years. AB - INTRODUCTION: Cancer of the lip, mouth and pharynx is a serious health problem. High incidence rates are found worldwide. In Brazil, the Southern and Southeastern regions have the highest incidences in the country. OBJECTIVE: To describe 5 and 10-year survival rates in patients with cancer of the lip, mouth and pharynx at a referral center in Florianopolis, Santa Catarina, Brazil. METHODS: Retrospective cohort study using data from patients diagnosed between January 1st and December 31st, 2001, with follow-up until December 31st, 2011. Descriptive analysis was performed and survival was estimated by Kaplan-Meier method. Cox semi-parametric model was used to estimate death risk. RESULTS: Survival rates at 5 and 10 years were 33.3 and 26.9%, respectively. Advanced clinical stage in the diagnosis increased death risk by 2.88 and 2.51, respectively. Sex, ethnicity, level of education, previous diagnosis and treatment, as well as age, did not show significant association. CONCLUSION: Survival rate at 5 years was 33.3% and, at 10 years, was 26.9%. Advanced stage was an independent risk factor for death due to cancer of the lip, mouth and pharynx in both periods analyzed. PMID- 25272262 TI - Factors associated to medical consultations by elderly adults in southern Brazil: a population based study. AB - OBJECTIVE: To analyze the prevalence of medical consultations in the last three months among elderly adults and associated factors. METHODS: A cross-sectional, population-based study was carried out with 1,705 elderly adults (60+ years of age) in the urban region of Florianopolis, Santa Catarina, Brazil, in 2009 and 2010. The sampling selection was performed in two stages. The sample was complex, with census tracts as primary and households as secondary sampling units. For association analysis, Poisson regression was performed using predisposing factors, enabling factors and need as independent variables, according to Andersen's theoretical model. RESULTS: The response rate was 89.2%. The prevalence of medical appointments by elderly adults was 70.4% (95%CI 67.5 - 73.4). Factors associated with higher prevalence of medical consultations in the crude analysis were female gender, accumulation of chronic diseases, negative self-perception of health, and report of chronic pain. The multivariate analysis showed that having at least one chronic disease and negative self-perception of health was positively associated with the outcome. CONCLUSION: Only variables from the need dimension were associated with medical consultations, indicating an equal use of this service. PMID- 25272263 TI - Falls among the elderly: risk factors in a population-based study. AB - PURPOSE: The aim of the present study was to identify factors associated with the occurrence of falls among elderly adults in a population-based study (ISACamp 2008). METHODS: A population-based cross-sectional study was carried out with two stage cluster sampling. The sample was composed of 1,520 elderly adults living in the urban area of the city of Campinas, Sao Paulo, Brazil. The occurrence of falls was analyzed based on reports of the main accident occurred in the previous 12 months. Data on socioeconomic/demographic factors and adverse health conditions were tested for possible associations with the outcome. Prevalence ratios (PR) were estimated and adjusted for gender and age using the Poisson multiple regression analysis. RESULTS: Falls were more frequent, after adjustment for gender and age, among female elderly participants (PR = 2.39; 95% confidence interval (95% CI) 1.47 - 3.87), elderly adults (80 years old and older) (PR = 2.50; 95% CI 1.61 - 3.88), widowed (PR = 1.74; 95% CI 1.04 - 2.89) and among elderly adults who had rheumatism/arthritis/arthrosis (PR = 1.58; 95% CI 1.00 - 2.48), osteoporosis (PR = 1.71; 95% CI 1.18 - 2.49), asthma/bronchitis/emphysema (PR = 1,73; 95% CI 1.09 - 2.74), headache (PR = 1.59; 95% CI 1.07 - 2.38), mental common disorder (PR = 1.72; 95% CI 1.12 - 2.64), dizziness (PR = 2.82; 95% CI 1.98 - 4.02), insomnia (PR = 1.75; 95% CI 1.16 - 2.65), use of multiple medications (five or more) (PR = 2.50; 95% CI 1.12 - 5.56) and use of cane/walker (PR = 2.16; 95% CI 1.19 - 3,93). CONCLUSION: The present study shows segments of the elderly population who are more prone to falls through the identification of factors associated with this outcome. The findings can contribute to the planning of public health policies and programs addressed to the prevention of falls. PMID- 25272264 TI - Expenditures on the treatment of osteoporosis in the elderly in Brazil (2008 - 2010): analysis of associated factors. AB - OBJECTIVE: To analyze the expenditure of the Ministry of Health with osteoporosis treatment in the Brazilian Public Health System (SUS) in 2008-2010 triennium and estimate the influence of demographic, regional and disease related variables on average expenditure per procedures performed. METHODS: A cross-sectional, descriptive and analytical study based on secondary data from DATASUS related to procedures for the elderly with a diagnosis of osteoporosis and related fractures. For the statistical analysis and multivariate model, Stata 11.0 was used. RESULTS: According to the findings, 3,252,756 procedures related to the osteoporosis treatment among the elderly were carried out in Brazil during the 2008 - 2010 period, totalizing R$ 288,986,335.15. The age group that most had procedures was 60 - 69 years (46.3%); the population of 80 years or older showed the highest spending per procedure, around R$ 106 million in three years. The women were majority in terms of quantity (95.6%) and expense (76%) of procedures. The average cost per procedure showed a large gap between men and women, nearly 7 times (R$ 480.14 versus R$ 70.85, respectively). The ambulatory care procedures predominated in quantity (96.4%) and the hospital procedures predominated in resources (70.4%). It was found that there is no single standard for groups of procedures when these are analyzed separately. CONCLUSION: A disaggregated analysis of expenditure by procedures groups extracted from the SUS Management System of the Table of Procedures, Medicines, Orthotics, Prosthetics and Special Materials allowed a detailed overview of federal spending on the osteoporosis treatment in the elderly from Brazil. PMID- 25272265 TI - Validation and calibration of self-reported weight and height from individuals in the city of Sao Paulo. AB - OBJECTIVE: To evaluate the validity of self-reported weight and height measurements among residents of Sao Paulo, as well as the accuracy of these measurements for determining nutritional status, and to present calibration coefficients. METHODS: A cross-sectional, population-based study was performed with a sample of 299 adolescents, adults and elderly of both genders, in Sao Paulo in 2008. Bland-Altman difference plot and intraclass correlation were used to determine agreement between measured and self-reported parameters. Sensitivity and specificity were assessed for overweight, and calibration coefficients were estimated for correction of weight, height and body mass index data. RESULTS: The intraclass correlation was high between self-reported and measured parameters for weight (r > 0,94) and body mass index (BMI) (r > 0,85). The agreement between measured and self-reported weight, height and BMI was good. Sensibility was > 91% and specificity was > 83%. CONCLUSION: Self-reported weight measurements can substitute measured parameters in this population, in both genders and in the age groups studied. Self-reported height measurements should be used with caution. Calibration coefficients can be used to adjust self-reported measurements. PMID- 25272266 TI - Agreement and association between different indicators of body image and body mass index in adolescents. AB - The aim of the study was to examine the correlation among different indicators of body image; between each one of these and nutritional status; and the association of these indicators with the Body Mass Index (BMI) of adolescents. A random sample of 152 students from public and private schools in the city of Rio de Janeiro, Brazil, was studied. On four occasions, two silhouette scales and two questions regarding the opinion of the student about his/her body and weight were applied and weight and height were measured. The BMI was examined both as a continuous and as a categorical variable. The agreement between the variables was analyzed using the quadratic weighted Kappa statistics. The association between body image variables and BMI was examined by the comparison among median, mean, standard deviation and 95% confidence interval of BMI for each category of the body image variables. In general, the correlation among the body image variables ranged from reasonable to good; between these and the variable nutritional status, correlation ranged from regular to reasonable. Best results were observed among boys and students from private schools. All body image variables showed good discriminatory power for BMI, when it was analyzed as a continuous variable, even when controlling for potential confounders. The question about body seems to be better than that about weight to compose the questionnaire of a surveillance system for risk and protective factors for adolescent health. PMID- 25272267 TI - The performance of various anthropometric assessment methods for predicting low birth weight in adolescent pregnant women. AB - OBJECTIVE: To evaluate the performance of various anthropometric evaluation methods for adolescent pregnant women in the prediction of birth weight. METHODS: It is a cross-sectional study including 826 adolescent pregnant women. In the pre pregnancy body mass index (BMI) classification, the recommendations of the World Health Organization were compared with that of the Brazilian Ministry of Health and the Institute of Medicine (IOM) of 1992 and 2006. The gestational weight gain adequacy was evaluated according to the classification of IOM of 1992, of 2006 and of the Brazilian Ministry of Health. The newborns were classified as low birth weight (LBW) or macrosomic. Multinomial logistic regression was used for statistical analysis and sensibility, specificity, accuracy, positive and negative predictive values were calculated. RESULTS: The evaluation, according to the Brazilian Ministry of Health, showed the best prediction for LBW among pregnant women with low weight gain (specificity = 69.5%). The evaluation according to the IOM of 1992 showed the best prediction for macrosomia among pregnant women with high weight gain (specificity = 50.0%). The adequacy of weight gain according to the IOM of 1992 classification showed the best prediction for LBW (OR = 3.84; 95%CI 2.19 - 6.74), followed by the method of the Brazilian Ministry of Health (OR = 2.88, 95%CI 1.73 - 4.79), among pregnant women with low weight gain. CONCLUSION: It is recommended the adoption of the Brazilian Ministry of Health proposal, associated with BMI cut-offs specific for adolescents as an anthropometric assessment method for adolescent pregnant women. PMID- 25272268 TI - Satisfaction with physical and social surroundings and the habit of smoking cigarettes in the metropolitan area of Belo Horizonte, Brazil. AB - The objective of this study was to examine the association between individual satisfaction with social and physical surroundings and the habit of smoking cigarettes. Data from the Health Survey of Adults from the metropolitan area of Belo Horizonte, Minas Gerais, Brazil, were used. Based on a probability sample, participants (n = 12,299) were selected among residents aged 20 years old or more. The response variable was the smoking habit and the explanatory variable of interest was the neighborhood perception. Potential confounding variables included demographic characteristics, health behaviors and other indicators of socioeconomic position. The prevalence of current smokers, former smokers and never smokers were 20.8, 14.1 and 65.1%, respectively; 74.4 and 25.5% of the participants were categorized as being more satisfied and less satisfied with the neighborhood, respectively. Compared to those who never smoked, former smokers (adjusted odds ratio = 1.40, 95% confidence interval 1.20 - 1.62) and current smokers (adjusted odds ratio = 1.17, 95% confidence interval 1.03 - 1.34) were less satisfied with the neighborhood compared to those who never smoked. The results of this study indicate there is an independent association between the smoking habit and a less satisfying neighborhood perception in the metropolitan region of Belo Horizonte, which does not depend on individual characteristics, traditionally reported as being associated with smoking. PMID- 25272269 TI - Oral health status of the ethnic group Xukuru from Ororuba: multilevel analysis. AB - OBJECTIVE: To analyse the oral health status of the indigenous people Xukuru from Ororuba aged 10 to 14 years old, in Pernambuco, Brazil. METHOD: A cross-sectional population-based study developed within the limits of the Indigenous Land Xukuru, from January to March 2010. Oral examinations were performed on a sample of 233 indigenous people. The software SPSS 13.0(r) was used for descriptive analysis. Later, in order to measure the effect of factors associated with the absence of caries, Poisson log-linear multilevel models were tested with the statistical software MLwiN 2.02(r). RESULTS: Oral examinations identified a DMFT Index average of 2.38 (+/- 2.62). Among all individuals examined, 26.61% were caries free. Multiple regression analysis revealed a negative association between the absence of caries and the variables: higher average of people per household in the villages, higher number of residents per household, older age, male sex, not knowing how to read and write, and very dissatisfied/dissatisfied with teeth/mouth. The variables higher income per capita, not sleeping due to dental problems, had never been to the dentist, no occurrence of toothache, and no need for dental treatment were positively associated with the absence of caries. CONCLUSION: The absence of caries is associated with contextual and individual factors of the indigenous people Xukuru from Ororuba, aged 10 to 14 years old. PMID- 25272270 TI - [Carlos Barbosa cohort]. PMID- 25272272 TI - Design and synthesis of a new layered thermoelectric material LaPbBiS3O. AB - A new quinary oxysulfide LaPbBiS3O was designed and successfully synthesized via a solid-state reaction in a sealed evacuated quartz tube. This material, composed of stacked NaCl-like [M4S6] (where M = Pb, Bi) layers and fluorite-type [La2O2] layers, crystallizes in the tetragonal space group P4/nmm with a = 4.0982(1) A, c = 19.7754(6) A, and Z = 2. Electrical resistivity and Hall effect measurements demonstrate that it is a narrow gap semiconductor with an activation energy of ~17 meV. The thermopower and the figure of merit at room temperature were measured to be -52 MUV/K and 0.23, respectively, which makes LaPbBiS3O and its derivatives be promising for thermoelectric applications. PMID- 25272271 TI - Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models. AB - Intra-lesional chemotherapy for treatment of cutaneous malignancies has been used for many decades, allowing higher local drug concentrations and less toxicity than systemic agents. Here we describe a novel diterpene ester, EBC-46, and provide preclinical data supporting its use as an intra-lesional treatment. A single injection of EBC-46 caused rapid inflammation and influx of blood, followed by eschar formation and rapid tumor ablation in a range of syngeneic and xenograft models. EBC-46 induced oxidative burst from purified human polymorphonuclear cells, which was prevented by the Protein Kinase C inhibitor bisindolylmaleimide-1. EBC-46 activated a more specific subset of PKC isoforms (PKC-betaI, -betaII, -alpha and -gamma) compared to the structurally related phorbol 12-myristate 13-acetate (PMA). Although EBC-46 showed threefold less potency for inhibiting cell growth than PMA in vitro, it was more effective for cure of tumors in vivo. No viable tumor cells were evident four hours after injection by ex vivo culture. Pharmacokinetic profiles from treated mice indicated that EBC-46 was retained preferentially within the tumor, and resulted in significantly greater local responses (erythema, oedema) following intra lesional injection compared with injection into normal skin. The efficacy of EBC 46 was reduced by co-injection with bisindolylmaleimide-1. Loss of vascular integrity following treatment was demonstrated by an increased permeability of endothelial cell monolayers in vitro and by CD31 immunostaining of treated tumors in vivo. Our results demonstrate that a single intra-lesional injection of EBC-46 causes PKC-dependent hemorrhagic necrosis, rapid tumor cell death and ultimate cure of solid tumors in pre-clinical models of cancer. PMID- 25272273 TI - Evidence of recombinant strains of porcine epidemic diarrhea virus, United States, 2013. AB - To investigate the evolutionary process by which porcine epidemic diarrhea virus (PEDV) in the United States hypothetically descended from strains in China, we analyzed PEDV-positive samples collected in China during January 2012-July 2013. Recombination in 2 strain sublineages was likely associated with identification of PEDV in the United States in 2013. PMID- 25272274 TI - Acute fibular sesamoid fracture: one part of the spectrum of sesamoid pathologies. AB - A 35-year-old male athlete presented with acute pain plantar to the hallux metatarsophalangeal joint following jumping to catch a basketball. PMID- 25272275 TI - Percutaneous femoral derotational osteotomy for excessive femoral torsion. PMID- 25272276 TI - Beware of ultra-low-velocity knee dislocation. PMID- 25272278 TI - The phosphatase mechanism of bifunctional kinase/phosphatase AceK. AB - We have revealed that bifunctional AceK kinase/phosphatase utilizes a stepwise addition-elimination mechanism in its dephosphorylation reaction. This work explains how AceK enables opposite kinase and phosphatase activities with Asp477 and a single Mg(2+) ion. PMID- 25272279 TI - The association between hospital care intensity and surgical outcomes in medicare patients. AB - IMPORTANCE: Hospitals' care intensity varies widely across the United States. Payers and policy makers have become focused on promoting quality, low-cost, efficient health care. OBJECTIVE: To evaluate whether increased hospital care intensity (HCI) is associated with improved outcomes following major surgery. DESIGN, SETTING, AND PARTICIPANTS: Using national Medicare data in this retrospective cohort study, we identified 706,520 patients at 2544 hospitals who underwent 1 of 7 major cardiovascular, orthopedic, or general surgical operations. EXPOSURE: The HCI Index, which is validated and publicly available through the Dartmouth Atlas of Healthcare. MAIN OUTCOMES AND MEASURES: Risk- and reliability-adjusted mortality, major complication, and failure-to-rescue rates. RESULTS: Hospital care intensity varied 10-fold. High-HCI hospitals had greater rates of major complications when compared with low-HCI centers (risk ratio, 1.04; 95% CI, 1.03-1.05). There was a decrease in failure to rescue at high compared with low-HCI hospitals (risk ratio, 0.95; 95% CI, 0.94-0.97). Using multilevel-models, HCI reduced the variation in failure-to-rescue rates between hospitals by 2.7% after accounting for patient comorbidities and hospital resources. Patients treated at high-HCI hospitals had longer hospitalizations, more inpatient deaths, and lower hospice use during the last 2 years of life. CONCLUSIONS AND RELEVANCE: Failure-to-rescue rates were lower at high-care intensity hospitals. Conversely, care intensity explains a very small proportion of variation in failure-to-rescue rates across hospitals. PMID- 25272280 TI - A hematite photoanode with gradient structure shows an unprecedentedly low onset potential for photoelectrochemical water oxidation. AB - Ultra-high onset potential hinders the application of hematite for photoelectrochemical (PEC) water splitting. Herein, a hematite photoanode with an unprecedentedly low onset potential of 0.50 V vs. the reversible hydrogen electrode for PEC water oxidation is reported. The drastically reduced onset potential is mainly ascribed to the passivation of the hematite surface states and the gradient structure made by H2-O2 flame at high temperature. PMID- 25272277 TI - A Ras-like domain in the light intermediate chain bridges the dynein motor to a cargo-binding region. AB - Cytoplasmic dynein, a microtubule-based motor protein, transports many intracellular cargos by means of its light intermediate chain (LIC). In this study, we have determined the crystal structure of the conserved LIC domain, which binds the motor heavy chain, from a thermophilic fungus. We show that the LIC has a Ras-like fold with insertions that distinguish it from Ras and other previously described G proteins. Despite having a G protein fold, the fungal LIC has lost its ability to bind nucleotide, while the human LIC1 binds GDP preferentially over GTP. We show that the LIC G domain binds the dynein heavy chain using a conserved patch of aromatic residues, whereas the less conserved C terminal domain binds several Rab effectors involved in membrane transport. These studies provide the first structural information and insight into the evolutionary origin of the LIC as well as revealing how this critical subunit connects the dynein motor to cargo. PMID- 25272281 TI - Working together: Expanding the availability of naloxone for peer administration to prevent opioid overdose deaths in the Australian Capital Territory and beyond. AB - ISSUE: Since the mid-1990s, there have been calls to make naloxone, a prescription-only medicine in many countries, available to heroin and other opioid users and their peers and family members to prevent overdose deaths. CONTEXT: In Australia there were calls for a trial of peer naloxone in 2000, yet at the end of that year, heroin availability and harm rapidly declined, and a trial did not proceed. In other countries, a number of peer naloxone programs have been successfully implemented. Although a controlled trial had not been conducted, evidence of program implementation demonstrated that trained injecting drug-using peers and others could successfully administer naloxone to reverse heroin overdose, with few, if any, adverse effects. APPROACH: In 2009 Australian drug researchers advocated the broader availability of naloxone for peer administration in cases of opioid overdose. Industrious local advocacy and program development work by a number of stakeholders, notably by the Canberra Alliance for Harm Minimisation and Advocacy, a drug user organisation, contributed to the rollout of Australia's first prescription naloxone program in the Australian Capital Territory (ACT). Over the subsequent 18 months, prescription naloxone programs were commenced in four other Australian states. IMPLICATIONS: The development of Australia's first take-home naloxone program in the ACT has been an 'ice-breaker' for development of other Australian programs. Issues to be addressed to facilitate future scale-up of naloxone programs concern scheduling and cost, legal protections for lay administration, prescribing as a barrier to scale-up; intranasal administration, administration by service providers and collaboration between stakeholders. PMID- 25272282 TI - Optimizing the design and synthesis of supported silver nanoparticles for low cost water disinfection. AB - Silver nanoparticles (AgNPs) were successfully synthesized and impregnated on silica using chemical reduction methods. XPS and Ag K-edge XANES analysis revealed that the impregnation of AgNPs onto silica using a chitosan + sodium borohydride (NaBH4) method results in higher silver loading and Ag(0)/Ag(I) ratio compared to that obtained using NH3 + NaBH4/glucose methods. The effects of the dosage of chitosan on silver loading, Ag(I) release, and bactericidal activities of AgNP-impregnated silica were investigated, with results showing that, at high dosages of chitosan, Ag(I) released from AgNP-impregnated silica plays an important role in disinfection, while AgNP-mediated bactericidal action dominates at low dosages of chitosan. To further decrease the manufacturing cost, partially oxidized "black rice husk ash" containing substantial residual carbon was applied as AgNP support and found to lead to a greater degree of silver impregnation and to exhibit a longer disinfection lifetime than that of lower carbon content silica supports. On the basis of these findings, it is clear that considerable scope exists for careful optimization in the design and production of AgNP-based bactericidal materials for water treatment purposes. PMID- 25272283 TI - What are we putting in our ears? A consumer product analysis of aural foreign bodies. AB - OBJECTIVES/HYPOTHESIS: Rapid identification of foreign bodies may be crucial in deciding the appropriate course of action; and knowledge of consumer products that most commonly become aural foreign bodies (AFB) may potentially guide patient education strategies. Our objectives were to estimate the nationwide incidence of emergency department (ED) visits for consumer products presenting as AFBs and describe products encountered, demographic trends, general outcomes, and other reported aspects of injury. METHODS: The authors searched the National Electronic Injury Surveillance System for AFB ED visits from 2008 to 2012. Consumer product, patient demographics, and outcomes were analyzed. RESULTS: There were 9,472 case entries amounting to an estimated 280,939 ED visits for AFBs. Of these, 49.3% of patients were male and 50.7% were female, with 98.2% of all patients being treated/examined and then released. Jewelry was the most common foreign body (39.4%), followed by cotton swabs/first aid equipment, paper products, pens/pencils, and desk supplies. Children between 2 and 8 years of age were most commonly affected, with jewelry as the most common item. Cotton swabs/first aid equipment predominated among adults. CONCLUSIONS: Aural foreign bodies considerably affect health care expenditures; over 250,000 ED visits over a 5-year span were noted. Age- and gender-specific patterns reported in this analysis can serve as a valuable adjunct for history taking and clinical examination. Jewelry products predominated among children, while cotton swab/first aid products, hearing aids, and other ear-specific accessories significantly affected adults. Although children were most commonly affected, these findings highlight the need for sustained education and prevention strategies among all age groups. PMID- 25272284 TI - The neurosurgical telecounseling network in the Veneto Region: 4 years of experience of HEALTH OPTIMUM. AB - BACKGROUND: Neurosurgery is a highly specialized service that, because of high costs, is often centralized. Since 2005, a neurosurgical telecounseling service was defined and then deployed in the Veneto Region. It was aimed at creating the same range of services for head trauma by using standardized protocols at regional levels and at rationalizing the use of human and technological resources by providing a network of services that manages patients at the local level. The main objective of the study was to evaluate the use of this service. MATERIALS AND METHODS: Interoperability and flexibility were granted by creating a technological framework based on international standards. Physicians of local hospitals electronically transmit patients' clinical data and images to neurosurgeons located at a central hospital. These physicians respond to the requesting physicians by providing all the necessary recommendations. RESULTS: The outcomes were collected over a period of 41 months. The service is now available in 34 hospitals. Every year 3,181 telecounselings are conducted for patients with an average age of 65.5 years (55% male, 45% female) whose health status is mainly not serious. Within 30 min from the request of telecounseling, 49% of responses are sent. In 84% of cases the patient was not moved. The overall appreciation of clinicians is positive (4.3/5). Intervention time was reduced, and resources were optimized. CONCLUSIONS: The service brought remarkable benefits at the organizational level. The reorganization of the processes and patient management leads to rationalization of both human and technological resources. PMID- 25272286 TI - Inter-annual variation in characteristics of endozoochory by wild Japanese macaques. AB - Endozoochory is important to the dynamics and regeneration of forest ecosystems. Despite the universality of inter-annual variation in fruit production, few studies have addressed the sign (seed predation versus seed dispersal) and strength (frequency and quantity) of fruit-frugivore interaction and the effectiveness of endozoochory in response to the long-term temporal context. In this study I evaluated the characteristics of endozoochorous dispersal by wild Japanese macaques Macaca fuscata inhabiting deciduous forest in northern Japan for five different years. I collected 378 fecal samples from the macaques in fall (September to November) and quantified the proportion of feces containing seeds, number of seeds per fecal sample, ratio of intact seeds, and seed diversity. The proportion of feces containing seeds of any species (five-year mean: 85.9%, range: 78-97%) did not show significant inter-annual variation, while species level proportions did. The intact ratio of seeds (mean: 83%, range: 61-98%) varied significantly both between years and between months, and this varied among dominant plant species. The number of seeds per fecal sample (mean: 78, range: 32 102) varied monthly but did not between years, and the seed diversity (mean: 0.66, range: 0.57-0.81) did not show significant inter-annual variation, both of which were attributed to longer duration of macaques' gastro-intestinal passage time of seeds exceed their feeding bouts. This study demonstrated that frequency and success of seed dispersal over seed predation of macaque endozoochory showed inter-annual variation, indicating low specificity across the seed-macaque network. The temporal variability in the quality of seed dispersal may provide evidence of high resilience in response to fluctuating environmental conditions in the temperate forests. PMID- 25272287 TI - UHV-FTIRS studies on molecular competitive adsorption: 12CO, 13CO and CO2 on reduced TiO2(110) surfaces. AB - Competitive adsorption of prototype molecules such as (12)CO, (13)CO and CO2 at the two typical fivefold coordinated Ti5c(4+) cation sites of reduced rutile TiO2(110) surfaces was studied in a newly designed UHV-FTIR system. The measured binding energies of (12)CO, (13)CO or CO2 adsorbed at two kinds of Ti5c(4+) sites are different. The molecular occupying probability at these sites depends on the binding energy of the adsorbed molecules; while, the molecular exchanging probability at these sites depends on their binding energy difference due to the presence of competitive adsorption. A simple thermodynamic equilibrium model was proposed to qualitatively interpret the adsorption and competitive adsorption mechanisms. These results will contribute to the elucidation of the (photo)catalytic process on TiO2(110) surfaces. PMID- 25272285 TI - MSC therapy attenuates obliterative bronchiolitis after murine bone marrow transplant. AB - RATIONALE: Obliterative bronchiolitis (OB) is a significant cause of morbidity and mortality after lung transplant and hematopoietic cell transplant. Mesenchymal stromal cells (MSCs) have been shown to possess immunomodulatory properties in chronic inflammatory disease. OBJECTIVE: Administration of MSCs was evaluated for the ability to ameliorate OB in mice using our established allogeneic bone marrow transplant (BMT) model. METHODS: Mice were lethally conditioned and received allogeneic bone marrow without (BM) or with spleen cells (BMS), as a source of OB-causing T-cells. Cell therapy was started at 2 weeks post-transplant, or delayed to 4 weeks when mice developed airway injury, defined as increased airway resistance measured by pulmonary function test (PFT). BM derived MSC or control cells [mouse pulmonary vein endothelial cells (PVECs) or lung fibroblasts (LFs)] were administered. Route of administration [intratracheally (IT) and IV] and frequency (every 1, 2 or 3 weeks) were compared. Mice were evaluated at 3 months post-BMT. MEASUREMENTS AND MAIN RESULTS: No ectopic tissue formation was identified in any mice. When compared to BMS mice receiving control cells or no cells, those receiving MSCs showed improved resistance, compliance and inspiratory capacity. Interim PFT analysis showed no difference in route of administration. Improvements in PFTs were found regardless of dose frequency; but once per week worked best even when administration began late. Mice given MSC also had decreased peribronchiolar inflammation, lower levels of hydroxyproline (collagen) and higher frequencies of macrophages staining for the alternatively activated macrophage (AAM) marker CD206. CONCLUSIONS: These results warrant study of MSCs as a potential management option for OB in lung transplant and BMT recipients. PMID- 25272288 TI - The diurnal logic of the expression of the chloroplast genome in Chlamydomonas reinhardtii. AB - Chloroplasts are derived from cyanobacteria and have retained a bacterial-type genome and gene expression machinery. The chloroplast genome encodes many of the core components of the photosynthetic apparatus in the thylakoid membranes. To avoid photooxidative damage and production of harmful reactive oxygen species (ROS) by incompletely assembled thylakoid protein complexes, chloroplast gene expression must be tightly regulated and co-ordinated with gene expression in the nucleus. Little is known about the control of chloroplast gene expression at the genome-wide level in response to internal rhythms and external cues. To obtain a comprehensive picture of organelle transcript levels in the unicellular model alga Chlamydomonas reinhardtii in diurnal conditions, a qRT-PCR platform was developed and used to quantify 68 chloroplast, 21 mitochondrial as well as 71 nuclear transcripts in cells grown in highly controlled 12 h light/12 h dark cycles. Interestingly, in anticipation of dusk, chloroplast transcripts from genes involved in transcription reached peak levels first, followed by transcripts from genes involved in translation, and finally photosynthesis gene transcripts. This pattern matches perfectly the theoretical demands of a cell "waking up" from the night. A similar trend was observed in the nuclear transcripts. These results suggest a striking internal logic in the expression of the chloroplast genome and a previously unappreciated complexity in the regulation of chloroplast genes. PMID- 25272290 TI - Statement on surgical pre-residency preparatory courses. PMID- 25272289 TI - Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. AB - CONTEXT: Clomiphene citrate (CC) is the first line drug for ovulation induction but because of its peripheral antiestrogenic effect, letrozole was introduced as the 2nd line drug. It lacks the peripheral antiestrogenic effect and is associated with similar or even higher pregnancy rates. Since letrozole is a drug for breast cancer, its use for the purpose of ovulation induction became controversial in the light of studies indicating an increased incidence of congenital malformations. AIMS: To evaluate and compare the incidence of congenital malformations among offsprings of infertile couples who conceived naturally or with clomiphene citrate or letrozole treatment. SETTINGS AND DESIGN: A retrospective cohort study done at a tertiary infertility centre. METHODS AND MATERIAL: A total of 623 children born to infertile women who conceived naturally or following clomiphene citrate or letrozole treatment were included in this study. Subjects were sorted out from medical files of both mother and newborn and follow up study was done based on the information provided by parents through telephonic conversations. Babies with suspected anomaly were called and examined by specialists for the presence of major and minor congenital malformations. Other outcomes like multiple pregnancy rate and birth weight were also studied. RESULTS: Overall, congenital malformations, chromosomal abnormalities were found in 5 out of 171 (2.9%) babies in natural conception group and 5 out of 201 babies in the letrozole group (2.5%) and in 10 of 251 babies in the CC group (3.9%). CONCLUSIONS: There was no significant difference in the overall rate of congenital malformations among children born to mothers who conceived naturally or after letrozole or CC treatment. KEY MESSAGES: Congenital malformations have been found to be comparable following natural conception, letrozole and clomiphene citrate. Thus, the undue fear against letrozole may be uncalled for. PMID- 25272291 TI - A philosophy for CNS radiotracer design. AB - Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test-retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood-brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible. PMID- 25272293 TI - The immunohistochemistry signature of mismatch repair (MMR) proteins in a multiethnic Asian cohort with endometrial carcinoma. AB - Endometrial cancer is the most common gynecologic cancer in developed countries and is rising in incidence globally. Although the 5-year survival rates are >80%, factors beyond conventional pathologic features that predict clinical outcomes are still being elucidated. The aims of this study were to define the prevalence and associations of deficient mismatch repair (dMMR) protein expression (MLH1, MSH2, MSH6, PMS2) by immunohistochemistry in a multiethnic Southeast Asian cohort with endometrioid endometrial cancer. A total of 77 patients with adequate formalin-fixed paraffin-embedded specimens were identified. The sections were stained in 2 centers for 4 MMR proteins and examined by 2 independent specialist histopathologists. The mean age for the cohort was 58.6 yr, with 19.4% (15/77) of patients' cancers showing loss of 2 MMR proteins. All 13 cancers with absent MLH1 showed PMS2 loss (13/15), whereas absent MSH2 correlated with MHS6 loss (2/15). There were no significant differences for dMMR cases in age, body mass index, histopathologic characteristics, and clinical outcomes. In dMMR cases, an overrepresentation of patients of Indian ethnic origin was observed compared with Chinese and Malays. These findings suggest that dMMR protein expression in a Southeast Asian endometrial cancer cohort does not correlate with disease outcomes. PMID- 25272292 TI - Histologic effects of medroxyprogesterone acetate on endometrioid endometrial adenocarcinoma: a Gynecologic Oncology Group study. AB - Progestins have been used in the treatment of recurrent endometrial adenocarcinoma for almost 50 yr. Some endometrial carcinomas respond to hormonal therapy, but the mechanism of action remains incompletely known. We wished to determine the efficacy of progestins to induce a histologic response in endometrioid carcinomas and explore its effects on histologic and immunohistochemical measures of growth and cell death. The Gynecologic Oncology Group initiated a study of 75 women with endometrioid endometrial adenocarcinoma, 59 of whom received the progestin, medroxyprogesterone acetate for 21 to 24 d immediately before hysterectomy and had available slides. Initial biopsies and hysterectomies were hematoxylin and eosin-stained and immunostained for estrogen receptor (ER) and progesterone receptor (PR), progesterone receptor-beta (PRB), Bcl-2, Ki-67, and cleaved caspase-3 (Casp3). A histologic response was defined subjectively, following which specific histologic measurements and semiquantitative scores of immunohistologic variables of initial biopsies were compared with posttreatment slides. Only 1 complete histologic response was seen, but 37 tumors (63%) had a partial histologic response. Specific histologic changes included the following: a decrease in the nuclear grade, the number of mitotic figures, nucleoli, and mean gland cellularity, and acquisition of more abundant eosinophilic cytoplasm, squamous metaplasia, and secretion. The tumors that displayed a subjectively defined histologic response following treatment differed initially from those that did not only with respect to initial nuclear grade and the mitotic index. Statistically significant differences in the specific histologic features in carcinomas of responders versus nonresponders following treatment were found only with respect to acquisition of pale eosinophilic cytoplasm and luminal secretion. More than 90% of tumors were initially ER positive and 76% were PR positive. The initial presence of ER or PR was not related to subjective histologic response. PR and PRB were significantly downregulated following progestin therapy, as were Ki-67 and Bcl-2. However, ER and Casp3 did not change significantly. Tumors that displayed a histologic response had significantly lower pretreatment levels of Ki-67. Mean Ki-67 and Bcl 2 decreases following medroxyprogesterone acetate were greater in histologic responders than nonresponders, but not decreases in ER, PR, PRB, and Casp3. The histologic response in the tumors and their stroma differed quantitatively and qualitatively from that of the adjacent benign endometrium, where decidual change accompanied luminal secretion and secretory exhaustion of glands. Three weeks of medroxyprogesterone acetate therapy induces partial histologic responses in most endometrioid adenocarcinomas. Previously suggested features of histologic response do not capture the entire spectrum of changes seen. Downregulation of ER, PR, PRB, Ki-67, and Bcl-2 occurs without a significant change in Casp3. These alterations suggest that progestins act by differentiation of neoplastic cells with diminished proliferation rather than tumor cell death. As stromal decidualization was confined to areas surrounding benign glands, a paracrine effect may be involved in complete response to progestins. PMID- 25272294 TI - Current morphologic criteria perform poorly in identifying hereditary leiomyomatosis and renal cell carcinoma syndrome-associated uterine leiomyomas. AB - The contemporary oncologic pathology report conveys diagnostic, prognostic, predictive, and hereditary predisposition information. Each component may be premised on a morphologic feature or a biomarker. Clinical validity and reproducibility are paramount as is standardization of reporting and clinical response to ensure individualization of patient care. Regarding hereditary predisposition, morphology-based genetic referral systems in some instances have eclipsed genealogy-based systems, for example, cell type in ovarian cancer and BRCA screening. In other instances such as Lynch syndrome, morphology-based schemas supplement clinical schemas and there is an emerging standard of care for reflex biomarker testing. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome predisposes patients to uterine and cutaneous leiomyomas (LMs) and renal cell carcinomas (RCCs). Several authors have emphasized the role pathologists may play in identifying this syndrome by recognizing the morphologic characteristics of syndromic uterine LMs and RCCs. Recently immunohistochemical overexpression of S-(2-succinyl) cysteine (2SC) has been demonstrated as a robust biomarker of mutation status in tumors from HLRCC patients. In this blinded control-cohort study we demonstrate that the proposed morphologic criteria used to identify uterine LMs in HLRCC syndrome are largely irreproducible among pathologists and lack sufficient robustness to serve as a trigger to triage cases for 2SC immunohistochemistry or patients for further family/personal history inquiry. Although refinement of morphologic criteria can be considered, in view of the availability of a clinically robust biomarker, consideration should be given to reflex testing of uterine LMs with an appropriate age cut off or in the setting of a suspicious family history. PMID- 25272295 TI - Uterine fibroids: do we deal with more than one disease? AB - Uterine fibroids rank among the most frequent symptomatic human tumors at all. Recent data suggest that mutations of the mediator subcomplex 12 gene (MED12) and rearrangements of the gene-encoding high-mobility group protein AT-hook 2 (HMGA2) characterize major genetic subtypes of these tumors, which, for example, differ by their average size. Herein, we have investigated a total of 289 fibroids from 120 patients. Of these fibroids, 256 were fully genetically analyzed. Of the latter group, 20 (7.8%) fibroids had a chromosomal rearrangement of 12q14-15 reflecting a rearranged allele of HMGA2 and 179 (69.9%) fibroids had a mutation of MED12. The remaining tumors had either another genetic abnormality or no detectable abnormality at all. We were able to demonstrate that tumors of both groups also display striking differences of their frequency in individual patients. Whereas 70.0% (14/20) HMGA2-mutated fibroids made their appearance as solitary nodules, 85.5% (153/179) MED12-mutated fibroids occurred as multiple nodules as a rule of independent clonal origin, as reflected by different MED12 mutations. These findings are likely to point to a different pathogenesis of both types of fibroids. In the predominant of these groups so far, an unknown "mutator" may cause independent mutations of MED12, resulting in an independent clonal outgrowth of nodules. Furthermore, the low but existing risk of MED12 mutated fibroids to undergo malignant transformation after a leiomyoma-STUMP (smooth muscle tumors of uncertain malignant potential)-leiomyosarcoma sequence excludes the latter mutation as a suitable stand-alone marker for benign growth. PMID- 25272296 TI - Mullerian adenosarcoma of the uterus with low-grade sarcomatous overgrowth characterized by prominent hydropic change resulting in mimicry of a smooth muscle tumor. AB - A 28-y-old woman was found to have a large subserosal uterine mass that was excised and interpreted as a "clear cell leiomyoma." Five years later, the tumor recurred as serosal-based ileal and uterine masses; they were treated by partial ileal resection and hysterectomy. All 3 masses were predominantly characterized by conspicuous edema separating bland cells growing in cords and clusters, with scant to moderately conspicuous clear cytoplasm. The edema was indistinguishable from the hydropic change commonly seen in benign smooth muscle tumors and the cords similar to those often present in them. However, the mass from the hysterectomy specimen had a small, grossly recognizable cystic region, which on microscopic examination was a typical low-grade mullerian adenosarcoma. The stroma of the latter ranged from cellular endometrial-type to edematous and hypocellular similar to that dominating the other specimens. The cellular and edematous regions focally had cords and tubules of sex cord-like type confirmed by inhibin and calretinin positivity. Smooth muscle differentiation was also seen as a "starburst" pattern. This case of adenosarcoma is unusual due to its (1) serosal location, (2) overgrowth of stroma, which differed from typical adenosarcoma with sarcomatous overgrowth by its low-grade nature, (3) hydropic change associated with cords and nests of cells with clear cytoplasm, which prompted the initial specimen to be considered an epithelioid leiomyoma, and (4) prominent smooth muscle metaplasia mostly with a "starburst" morphology. All these features have only rarely been documented in prior mullerian adenosarcomas. PMID- 25272297 TI - Characterization of the immune cell repertoire in the normal fallopian tube. AB - Recent studies implicating the fallopian tube as the site of putative precursors of ovarian serous carcinoma, and the hypothesis that injury, inflammation, and repair of the ovarian surface epithelium at the time of ovulation, may be contributing factors to ovarian carcinogenesis, prompted us to undertake a comprehensive analysis of the immune cells in the normal fallopian tube. Accordingly, the aim of this study was to provide a baseline for future studies exploring the relationship of inflammation with the early events of ovarian carcinogenesis by characterizing the immune cell repertoire in 13 normal human fallopian tubes, combining digital microscopy of immunostained slides and flow cytometry of fresh single-cell suspensions, with a panel of markers that identify the most important adaptive and innate immune cells. We found that CD45(+) leukocytes are regularly observed in the fallopian tube and are mainly composed of CD163(+) macrophages, CD11c dendritic cells, and CD8(+) T cells. In addition, there are minor populations of CD56(+) NK cells, CD4(+) T cells, CD20(+) B cells, TCRgammadelta(+) T cells, and, among dendritic cells, CD207(Langerin)(+) Langerhans cells. The cellular mapping that we performed indicates that the local immune system in the human fallopian tube is composed of a mixture of innate and adaptive immune cells, many of which are recognized as playing a role in cancer immune surveillance. This local immune system could provide a first line of defense against early precancerous lesions and could potentially be exploited for immune-based therapies. PMID- 25272298 TI - Monoclonal origin of peritoneal implants and lymph node deposits in serous borderline ovarian tumors (s-BOT) with high intratumoral homogeneity. AB - Molecular studies have shown that the most prevalent mutations in serous ovarian borderline tumors (s-BOT) are BRAF and/or KRAS alterations. About one third of s BOT represent peritoneal implants and/or lymph node involvement. These extraovarian deposits may be monoclonal or polyclonal in origin. To test both the hypotheses, mutational analyses using pyrosequencing for BRAF codon 600 and KRAS codon 12/13 and 61 of microdissected tissue was performed in 15 s-BOT and their invasive and noninvasive peritoneal implants. Two to 6 implants from different peritoneal sites were examined in 13 cases. Lymph node deposits were available for the analysis in 3 cases. Six s-BOT showed mutation in exon 2 codon 12 of the KRAS proto-oncogen. Five additional cases showed BRAF p.V600E mutation representing an overall mutation rate of 73.3%. Multiple (2-6) peritoneal implants were analyzed after microdissection in 13 of 15 cases. All showed identical mutational results when compared with the ovarian site of the disease. All lymph node deposits, including those with multiple deposits in different nodes, showed identical results, suggesting high intratumoral mutational homogeneity. The evidence presented in this study and the majority of data reported in the literature support the hypothesis that s-BOT with their peritoneal implants and lymph node deposits show identical mutational status of BRAF and KRAS suggesting a monoclonal rather than a polyclonal disease regarding these both tested genetic loci. In addition, a high intratumoral genetic homogeneity can be suggested. In conclusion, the results of the present study support the monoclonal origin of s-BOT and their peritoneal implants and lymph node deposits. PMID- 25272299 TI - The N-methyl-D-aspartate receptor, a precursor to N-methyl-D-aspartate receptor encephalitis, is found in the squamous tissue of ovarian teratomas. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common antibody-mediated limbic encephalitis and is associated with underlying ovarian teratoma. Previous studies suggest that expression of NMDAR on teratoma neural tissue initiates an autoimmune response to NMDAR in the brain. As some teratomas of patients with anti-NMDAR encephalitis lack neuronal tissue, we questioned if there could be an alternate mechanism of the disease. We performed immunohistochemical analyses for NMDAR and correlated its expression with histology on 10 control teratomas and 5 teratomas associated with anti-NMDAR encephalitis. Both control and case teratomas expressed NMDAR-bearing neural tissue. All 15 teratomas contained large amounts of NMDAR bearing squamous epithelium; in 2 cases this was the only tissue expressing NMDAR. NMDAR-bearing neural tissue is not the sole source of encephalitis in all patients. Furthermore, we speculate that NMDAR expression by squamous epithelium may contribute to the disease development in some patients. PMID- 25272300 TI - Disseminated struma ovarii containing focal anaplastic carcinoma in peritoneal implants: a case report. AB - Malignant changes in struma ovarii have been defined using histopathologic criteria for carcinomas of the cervical thyroid gland. We report a case of struma ovarii with extensive extraovarian spread containing a small focus of anaplastic carcinoma (AC) in peritoneal implants. AC arising in benign-looking struma ovarii with peritoneal implants has not been reported. Multiple pelvic masses were identified on abdominopelvic computed tomography in a 38-yr-old woman. An exploratory laparotomy revealed multiple, variable-sized masses on the omentum, and colonic and uterine serosa. A microscopic but grossly unidentifiable lesion in the right ovary had a histologic appearance that mimicked hyperplastic follicular epithelium of nodular thyroid goiter. Multiple peritoneal implants showed histology similar to the ovarian lesions except a focal area of AC in the omental mass. Anaplastic cells demonstrated characteristic immunoreactivity for p53, cyclin D1, and a high Ki-67 index of about 30%, with loss of expression of thyroid transcription factor-1 and thyroglobulin, whereas the remaining goitrous background showed opposite expression patterns in all aspects. Furthermore, the areas of AC showed p53 mutation by molecular analysis. The AC harboring p53 mutation within extraovarian spread suggests that disseminated struma ovarii mimicking nodular goiter has potential for histologic progression through similar pathogenetic mechanism with cervical thyroid carcinoma despite the innocuous appearance. PMID- 25272301 TI - Differential patterns of PAX8, p16, and ER immunostains in mesonephric lesions and adenocarcinomas of the cervix. AB - Mesonephric remnants, usually located deep in the lateral cervical wall, may become hyperplastic resulting in a florid proliferation. These can be misinterpreted as malignant and confused with endocervical adenocarcinomas. Recent data have shown that PAX2 is diffusely expressed in mesonephric remnants and hyperplasias. PAX8 is a related transcription protein that is expressed in tissues of mullerian and wolffian origin. In this study, we have investigated the utility of an immunohistochemical panel comprising of PAX8, estrogen receptor (ER), and p16 in the differential diagnosis between mesonephric proliferations and cervical adenocarcinomas. A database search was conducted for cases of mesonephric remnants/hyperplasia/carcinoma of cervix and invasive cervical adenocarcinomas. Immunohistochemical stains for PAX8, ER, and p16 were performed using the avidin-biotin peroxidase technique on the most representative tissue. The search yielded 28 cases of mesonephric proliferations of cervix (15 mesonephric remnants, 12 mesonephric hyperplasias, and 1 mesonephric adenocarcinoma) and 16 cases of cervical adenocarcinomas (15 usual type and 1 adenoma malignum). Immunohistochemically, all the mesonephric proliferations, regardless of being benign or malignant, displayed a consistent staining pattern diffusely and strongly positive for PAX8, negative for ER, and patchy cytoplasmic staining for p16. The usual type cervical adenocarcinomas exhibited a variable staining pattern with PAX8 and ER but all were strongly and diffusely positive for p16. The case of adenoma malignum was PAX8 positive, ER negative, and showed weak and patchy staining with p16. Our study suggests that a panel of immunohistochemical stains composed of PAX8, p16, and ER is useful in the distinction between mesonephric proliferations and cervical adenocarcinomas. PMID- 25272302 TI - Endocervicosis involving axillary lymph nodes: first case report. AB - The occurence of Mullerian epithelial inclusions, especially endosalpingiosis, in pelvic and other subdiaphragmatic lymph nodes is well known. In contrast, Mullerian inclusions involving lymph nodes above the diaphragm is uncommon, although occasional cases of endosalpingiosis have been reported. We report a case of benign Mullerian inclusions of mucinous endocervical type (endocervicosis) coexistent with metastatic breast-infiltrating ductal carcinoma in 2 axillary lymph nodes. The inclusions exhibited diffuse positive staining with CK7, PAX8, CA125, and estrogen receptor and were WT1 negative. To our knowledge, this is the first report of endocervicosis involving supradiaphragmatic lymph nodes. Close morphologic examination and immunohistochemistry assists in distinguishing Mullerian inclusions from metastatic adenocarcinoma. PMID- 25272303 TI - Mesonephric carcinosarcoma involving uterine cervix and vagina: report of 2 cases with immunohistochemical positivity For PAX2, PAX8, and GATA-3. AB - Mesonephric carcinomas are rare tumors predominantly arising in the uterine cervix from mesonephric remnants. Although the tumor has classic morphologic features, some cases can mimic Mullerian adenocarcinoma and be misdiagnosed, especially those with significant ductal pattern. Moreover, there is an overlap in immunohistochemical results with endometrial and endocervical carcinomas. In this study, we report 2 cases of mesonephric carcinosarcoma, originally diagnosed as Mullerian carcinomas, 1 presenting in the vagina; review immunohistochemical results including positivity for GATA-3, not previously reported and comment on the proposed panel of PAX8, p16, and estrogen receptors as discriminators of Mullerian adenocarcinoma (endocervical or endometrial) versus mesonephric carcinoma. PMID- 25272305 TI - Enantioselective synthesis of 3-substituted 1,2-oxazinanes via organocatalytic intramolecular aza-Michael addition. AB - A highly enantioselective intramolecular 6-exo-trig aza-Michael addition was developed to afford chiral 3-substituted 1,2-oxazinanes in high yields (up to 99% yield) and good enantioselectivities (up to 98/2 er). These reactions were enabled by a quinine-derived primary-tertiary diamine as a catalyst and pentafluoropropionic acid (PFP) as a co-catalyst. PMID- 25272304 TI - Targeted laser ablation of the zebrafish larval heart induces models of heart block, valvular regurgitation, and outflow tract obstruction. AB - Mammalian models of cardiac disease have provided unique and important insights into human disease but have become increasingly challenging to produce. The zebrafish could provide inexpensive high-throughput models of cardiac injury and repair. We used a highly targeted laser, synchronized to fire at specific phases of the cardiac cycle, to induce regional injury to the ventricle, atrioventricular (AV) cushion, and bulbus arteriosus (BA). We assessed the impact of laser injury on hearts of zebrafish early larvae at 72 h postfertilization, to different regions, recording the effects on ejection fraction (EF), heart rate (HR), and blood flow at 2 and 24 h postinjury (hpi). Laser injury to the apex, midzone, and outflow regions of the ventricle resulted in reductions of the ventricle EF at 2 hpi with full recovery of function by 24 hpi. Laser injury to the ventricle, close to the AV cushion, was more likely to cause bradycardia and atrial-ventricular dysfunction, suggestive of an electrical conduction block. At 2 hpi, direct injury to the AV cushion resulted in marked regurgitation of blood from the ventricle to the atrium. Laser injury to the BA caused temporary outflow tract obstruction with cessation of ventricle contraction and circulation. Despite such damage, 80% of embryos showed complete recovery of the HR and function within 24 h of laser injury. Precision laser injury to key structures in the zebrafish developing heart provides a range of potentially useful models of hemodynamic overload, injury, and repair. PMID- 25272306 TI - Ghrelin receptor (GHS-R1a) and its constitutive activity in somatotroph adenomas: a new co-targeting therapy using GHS-R1a inverse agonists and somatostatin analogs. AB - CONTEXT: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. OBJECTIVE: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target. DESIGN: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. RESULTS: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. CONCLUSIONS: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist. PMID- 25272307 TI - Hashimoto's thyroiditis, risk of coronary heart disease, and L-thyroxine treatment: a nationwide cohort study. AB - OBJECTIVE: Our objective was to investigate the risk of coronary heart disease (CHD) in patients with Hashimoto's thyroiditis (HT). METHODS: The Taiwan National Health Insurance Research Database was used to conduct a retrospective cohort analysis. The cohort study consisted of 1165 newly diagnosed HT patients and 4660 matched controls (non-HT patients) from 2000 to 2010. The median follow-up time was 5.46 years. The risk of developing CHD for HT patients was measured using the Cox proportional hazards model. RESULTS: The risk of developing CHD in HT patients was increased compared with the non-HT controls, with an adjusted hazard ratio (HR) of 1.44 (95% confidence interval [CI] = 1.05-1.99). The risk was significant in women but not in men, and restricted to subjects younger than 49 years. HT remained an independent risk factor after adjusting for comorbidities; however, combining with hypertension or hyperlipidemia further increased the risk of CHD (adjusted HR = 2.06, 95% CI = 1.46-2.92; and adjusted HR = 1.83, 95% CI = 1.31-2.55, respectively). Furthermore, HT without T4 treatment and HT with treatment for less than 1 year were associated with higher risk of CHD (adjusted HR = 1.55, 95% CI = 0.98-2.46; and adjusted HR = 2.42, 95% CI = 1.43-3.97, respectively). The risk of CHD decreased after treatment with T4 for more than 1 year and did not differ from the non-HT cohort (adjusted HR = 0.84, 95% CI = 0.0.47-1.52). CONCLUSION: Patients with HT, are at higher risk of developing CHD compared with the general population. Treatment with T4 reduces the risk of CHD. PMID- 25272308 TI - Lyme disease, Virginia, USA, 2000-2011. AB - Lyme disease, caused by the bacterium Borrelia burgdorferi and transmitted in the eastern United States by the black-legged tick (Ixodes scapularis), is increasing in incidence and expanding geographically. Recent environmental modeling based on extensive field collections of host-seeking I. scapularis ticks predicted a coastal distribution of ticks in mid-Atlantic states and an elevational limit of 510 m. However, human Lyme disease cases are increasing most dramatically at higher elevations in Virginia, a state where Lyme disease is rapidly emerging. Our goal was to explore the apparent incongruity, during 2000-2011, between human Lyme disease data and predicted and observed I. scapularis distribution. We found significantly higher densities of infected ticks at our highest elevation site than at lower elevation sites. We also found that I. scapularis ticks in Virginia are more closely related to northern than to southern tick populations. Clinicians and epidemiologists should be vigilant in light of the changing spatial distributions of risk. PMID- 25272309 TI - Stem cells show promising results for lymphoedema treatment--a literature review. AB - Lymphoedema is a debilitating condition, manifesting in excess lymphatic fluid and swelling of subcutaneous tissues. Lymphoedema is as of yet still an incurable condition and current treatment modalities are not satisfactory. The capacity of mesenchymal stem cells to promote angiogenesis, secrete growth factors, regulate the inflammatory process, and differentiate into multiple cell types make them a potential ideal therapy for lymphoedema. Adipose tissue is the richest and most accessible source of mesenchymal stem cells and they can be harvested, isolated, and used for therapy in a single stage procedure as an autologous treatment. The aim of this paper was to review all studies using mesenchymal stem cells for lymphoedema treatment with a special focus on the potential use of adipose derived stem cells. A systematic search was performed and five preclinical and two clinical studies were found. Different stem cell sources and lymphoedema models were used in the described studies. Most studies showed a decrease in lymphoedema and an increased lymphangiogenesis when treated with stem cells and this treatment modality has so far shown great potential. The present studies are, however, subject to bias and more preclinical studies and large-scale high quality clinical trials are needed to show if this emerging therapy can satisfy expectations. PMID- 25272310 TI - Concentric double cables fixation as an alternative suspension method for the endoscopic forehead lift. AB - Fixation of the elevated eyebrow is an important final step in endoscopic forehead lifting. One of the most common methods of fixation includes temporal fasciae sutures for the tail of the eyebrow, and mini-screws for the body of the eyebrow. The concentric cables fixation is an alternative method for elevation of both the tail and the body of the eyebrow. This technique is compared to temporal fasciae suture and mini-screws fixation. Thirty-one patients were included in this study. They were divided into two groups; group I included patients who underwent fixation using fascia sutures and mini-screws, while group II patients underwent concentric cables suspension. Traditional screw and suture technique elevated the eyebrow tail by 7.2, 6.7, 6.3, and 6.0 mm, while the concentric cables resulted in 7.6, 6.8, 6.5, and 6.3 mm elevation at 1, 3, 6, and 12 months postoperatively, respectively. The mean values of brow body elevation were 6.8, 6.4, 6.2, and 5.9 mm for group I, while the mean values of group II were 6, 5.4, 4.8, and 4.7 mm. The concentric cables technique showed a fewer complications rate compared to traditional fixation. The concentric cables fixation offers an alternative inexpensive method to suspend the tail, and to a lesser extent the body, of both eyebrows simultaneously with long-term stability. A fewer complications rate was documented compared to traditional temporal fasciae sutures and mini-screws fixation. PMID- 25272311 TI - Influence of oxygen on wound healing dynamics in healing-impaired diabetic mice. AB - A previous experiment using an in vivo mouse model has proved that hypoxia increased angiogenesis during wound healing. It was hypothesised that one of the mechanisms for wound healing impairment in diabetes includes insufficient angiogenic ability in response to hypoxia. The current study aims to investigate the influence of hypoxia on wound healing in diabetic mice. Oxygen-impermeable (hypoxic group) and -permeable membranes (normoxic group) were used to control topical oxygen tension. Membranes were applied to symmetrical excisional wounds on diabetic mice. Wound area, granulated tissue thickness, and vascular density were analyzed. As results, a decrease in wound size on day 7 was observed in the normoxic group (20.7 +/- 3.64%) compared with the hypoxic group (34.1 +/- 4.98%). The normoxic group also showed significantly thicker granulated tissue than the hypoxic group (225.7 +/- 54.7 vs 128.7 +/- 42.4 um). There was no significant difference in mean vascular density between normoxic and hypoxic groups (0.046 +/ 0.022 vs 0.038 +/- 0.017 mm(2)/mm(2), p = 0.80). Contrary to healthy mice, diabetic mice have shown no enhancement of angiogenesis in hypoxic condition. The findings illustrate that neovascularisation in response to hypoxia is diminished in diabetic wounds. PMID- 25272312 TI - Effect of fungal and plant metabolites on broomrapes (Orobanche and Phelipanche spp.) seed germination and radicle growth. AB - Orobanche and Phelipanche species (the broomrapes) are root parasitic plants, some of which cause heavy yield losses on important crops. The development of herbicides based on natural metabolites from microbial and plant origin, targeting early stages on parasitic plant development, might contribute to the reduction of broomrape seed bank in agricultural soils. Therefore, the effect of metabolites belonging to different classes of natural compounds on broomrape seed germination and radicle development was assayed in vitro. Among the metabolites tested, epi-sphaeropsidone, cyclopaldic acid, and those belonging to the sesquiterpene class induced broomrape germination in a species-specific manner. epi-Epoformin, sphaeropsidin A, and cytochalasans inhibited germination of GR24 treated broomrape seeds. The growth of broomrape radicle was strongly inhibited by sphaeropsidin A and compounds belonging to cyclohexene epoxide and cytochalasan classes. Broomrape radicles treated with epi-sphaeropsidone developed a layer of papillae while radicles treated with cytochalasans or with sphaeropsidin A turned necrotic. These findings allow new lead natural herbicides for the management of parasitic weeds to be identified. PMID- 25272313 TI - Polymer- and silica-supported iron BPMEN-inspired catalysts for C-H bond functionalization reactions. AB - Direct catalytic C-H bond functionalization is a key challenge in synthetic chemistry, with many popular C-H activation methodologies involving precious metal catalysts. In recent years, iron catalysts have emerged as a possible alternative to the more common precious-metal catalysts, owing to its high abundance, low cost, and low toxicity. However, iron catalysts are plagued by two key factors: the ligand cost and the low turnover numbers (TONs) typically achieved. In this work, two approaches are presented to functionalize the popular N(1),N(2)-dimethyl-N(1),N(2)-bis(pyridin-2-ylmethyl)ethane-1,2-diamine (BPMEN) ligand, so that it can be supported on porous silica or polymer resin supports. Four new catalysts are prepared and evaluated in an array of catalytic C-H functionalization reactions by using cyclohexane, cyclohexene, cyclooctane, adamantane, benzyl alcohol, and cumene with aqueous hydrogen peroxide. Catalyst recovery and recycling is demonstrated by using supported catalysts, which allows for a modest increase in the TON achieved with these catalysts. PMID- 25272315 TI - Modulation of Zn/Cd P(1B2)-ATPase activities in Arabidopsis impacts differently on Zn and Cd contents in shoots and seeds. AB - Zn is an essential microelement for all living cells and Zn deficiency is widespread in world's population. At the same time, high Zn concentration and low Cd concentration are toxic to the environment. Both Zn and Cd are transported in planta via Zn/Cd HMA transporters. Engineering of HMAs expression in plants may provide a way for Zn biofortification of food as well as phytoremediation of polluted soils. In the present study we have assessed the impact of Zn/Cd HMAs invalidation/overexpression in Arabidopsis thaliana on Zn and Cd translocation from the roots to the shoots and in Zn grain filling. Overexpression of AtHMA4 had a large impact on Zn and Cd translocation and resulted in a 3-fold higher potential of Cd and Zn extraction from an industrial soil highly contaminated by Zn, Pb and Cd. Despite AtHMA4 overexpressing lines presenting a higher Zn concentration in the shoot, the Zn content in the seeds was found to be lower than in wild type plants. Our results indicate that AtHMA4 overexpression is an efficient tool to increase the root to shoot translocation of Zn and Cd in plants. Concerning biofortification of seeds, this study underlines the need for specific promoters to drive an expression pattern of the transporters in favour of Zn grain filling. PMID- 25272317 TI - Luminescent dinuclear Cu(I) complexes containing rigid tetraphosphine ligands. AB - The synthesis and the photophysics of three dinuclear copper(I) complexes containing bis(bidentate)phosphine ligands are described. The steric constraint imposed by tetrakis(di(2-methoxyphenyl)phosphanyl)cyclobutane) (o-MeO-dppcb) in combination with 2,9-dimethyl-1,10-phenanthroline in one of the complexes leads to interesting photophysical properties. The compound shows an intense emission at room temperature in deoxygenated acetonitrile solution (Phi = 49%) and a long excited-state lifetime (13.8 MUs). Interestingly, at low temperature, 77 K, the emission maximum shifts to lower energy, and the excited-state lifetime increases. This observation leads to the conclusion that a mixing between the excited triplet and singlet states is possible and that the degree of mixing and population of state strongly depends on temperature, as the energy difference is quite small. The electroluminescent properties of this compound were therefore tested in light-emitting electrochemical cells (LEECs), proving that the bright emission can also be obtained by electrically driven population of the singlet state. PMID- 25272318 TI - A randomized controlled trial of panretinal photocoagulation with and without intravitreal ranibizumab in treatment-naive eyes with non-high-risk proliferative diabetic retinopathy. AB - PURPOSE: To compare the efficacy of panretinal photocoagulation (PRP) and intravitreal ranibizumab injection with PRP alone in patients with treatment naive bilateral non-high-risk proliferative diabetic retinopathy. METHODS: Sixty eyes of 30 patients were randomized either to the study group (SG) receiving PRP plus 2 ranibizumab injections or to the control group (CG) receiving PRP alone. Mean change in best-corrected visual acuity and in optical coherence tomography were compared at baseline and 1, 3, and 6 months. RESULTS: Best-corrected visual acuity was significantly better at 6 months in the SG; however, there was decrease in best-corrected visual acuity in the CG. Central macula thickness decreased significantly at 6 months in SG when compared with baseline (-47.6 MUm, P < 0.001) and did not reveal significant difference in the CG. In eyes with diabetic macular edema, best-corrected visual acuity increased by 3.6 letters (P = 0.06) in the SG and decreased by 4.4 letters in the CG (P = 0.003). Central macula thickness decreased by 69.3 MUm (P = 0.001) in the SG and decreased by 45.5 MUm (P = 0.11) in the CG. CONCLUSION: Intravitreal ranibizumab in combination with PRP can be an effective treatment in eyes with non-high-risk proliferative diabetic retinopathy and diabetic macular edema. PMID- 25272319 TI - Association between prevalence of hypertension and components of metabolic syndrome: the data from Kailuan community. AB - This study aimed to investigate the potential association between prevalence of hypertension and components of metabolic syndrome (MetS) in general population of North China. A cross-section survey was conducted from September to December 2013 in Kailuan community of a Northern China city, Tangshan. Anthropometric measurements, blood tests and questionnaire surveys were administered to a total of 4675 subjects enrolled in this study. In this study, hypertension was defined as blood pressure>140/90 mmHg or medication for previously diagnosed hypertension. The definition of MetS adapted the IDF/AHA/NHLBI criteria. The prevalence of hypertension among population with or without individual or clustered components of MetS was compared and the respective contribution of every component of MetS to prevalence of hypertension was analyzed using multivariate logistic analysis. The overall prevalence of hypertension was 31.6% in enrolled subjects. People with components of MetS such as central obesity, elevated TG, high blood pressure, and abnormal glucose metabolism had a higher prevalence of hypertension compared with those without. The prevalence of hypertension in people with 0, 1, 2, 3, 4, and 5 components of MetS was 18.4%, 27.8%, 32.6%, 35.6%, 43.9%, and 54.7% (p < 0.05), respectively. After adjusting for age, gender, BMI, smoking and alcohol drinking, the prevalence of hypertension was significantly correlated with the following component of MetS including central obesity (OR 1.23 (1.04-1.46), p < 0.05), elevated TG (OR 1.21 (1.03-1.43), p < 0.05), high blood pressure (OR 3.34 (2.86-3.90), p < 0.05), and abnormal glucose metabolism (OR 1.23 (1.04-1.45), p < 0.05). Components of MetS could significantly contribute to the development of hypertension. Overall lifestyle improvement and control of metabolic associated risk factors should be the cornerstone of hypertension control in China. PMID- 25272320 TI - Follow-up after pH-metry and pH impedance in pediatric gastroesophageal reflux disease. AB - OBJECTIVES: It is unclear how diagnostic tests for gastroesophageal reflux disease (GERD) in children relate to the course of symptoms during follow-up. METHODS: During 1 year, all children (ages 0-18 years), who underwent pH-metry and/or pH multichannel intraluminal impedance (MII), were included after written informed consent was obtained. pH-metry and pH-MII test characteristics, such as reflux index (RI, % time that esophageal pH < 4), were obtained from the measurements. A questionnaire containing subcategories (medical history, gastrointestinal [GI] symptoms, extraesophageal symptoms, symptom burden, and therapeutic agents) was used; subjects were asked to fill the questionnaire at the time of inclusion and 3, 6, and 12 months afterward. RESULTS: A total of 162 infants and 42 children were included. pH-MII was performed in 15.4% and 57.4% of infants and children, respectively. All of the other subjects underwent pH-metry. Median RI was 2.0% (interquartile range 3.4) in infants and 1.7% (interquartile range 2.3) in children. RI was considered positive in 6.8% and 12.8% of infants and children, respectively. In infants, RI at baseline was significantly associated with symptom burden at baseline and at 3 and 12 months of follow-up. RI at baseline and reported GI symptoms at 3 months were also significantly associated. In infants and children using medication, symptom burden was significantly higher compared with those not using medication. This difference was found at baseline, after 3 and 12 months. CONCLUSIONS: In infants, an initial high RI is associated with persistence of GI symptoms at 3 months and a higher burden of symptoms during the course of 1 year. In children there were no such findings. PMID- 25272323 TI - Pediatric urology patients with megaureter may have a risk of contracting Crohn disease. AB - Crohn disease (CD) may develop at any age, but is most typically diagnosed in late adolescence and early adulthood. To the best of our knowledge, there are no reports showing that congenital urological abnormalities may be associated to CD. We describe 5 pediatric patients who had ureteral/urethral abnormalities in their infancy and developed CD during subsequent years. The occurrence of CD in these patients constitutes a novel potential association. PMID- 25272321 TI - Eating behaviors and quality of life in preadolescents at risk for obesity with and without abdominal pain. AB - OBJECTIVES: We evaluated eating behaviors and quality of life (QOL) in preadolescent children at risk for obesity, with and without abdominal pain (AP). METHODS: Participants were parent-child dyads enrolled in a randomized, controlled obesity prevention trial. The children were between 5 and 10 years of age and at risk for obesity (70th-95th percentile of body mass index, n = 420). Parents completed measures of their child's eating behaviors, QOL, AP, and bowel function and their own depression status, concern about child weight, and feeding practices. Children's height and weight were also measured. RESULTS: Children with frequent AP (>=2/month, n = 103) were compared with children reporting infrequent AP (<2/month, n = 312). Age and body mass index did not differ between groups, but AP was more prevalent in girls. Child emotional overeating and parental depression scores were higher in the frequent AP group (P < 0.01), and child QOL was lower (P < 0.01). In multivariable analysis, female gender (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.20-3.97), emotional overeating (OR 2.28, 95% CI 1.37-3.81), and parental depression (OR 1.23, 95% CI 1.12-1.35) were associated with more frequent AP. Secondary analyses were completed for children who met Rome III criteria for irritable bowel syndrome. CONCLUSIONS: Clinicians working with children with AP at risk for obesity should consider assessing for and, when appropriate, addressing parent and child factors that could exacerbate AP. PMID- 25272324 TI - Intestinal failure-associated liver disease: a position paper of the ESPGHAN Working Group of Intestinal Failure and Intestinal Transplantation. AB - Intestinal failure-associated liver disease is the most prevalent complication affecting children with intestinal failure receiving long-term parenteral nutrition. This paper reviews the definition, diagnostic criteria, pathogenesis, and risk factors. The authors discuss the role of enteral nutrition, parenteral nutrition, and its components, especially lipid emulsions. The authors also discuss the surgical treatment, including intestinal transplantation, its indications, technique, and results, and emphasise the importance of specialised intestinal failure centres. PMID- 25272325 TI - A novel method for determination of the (15) N isotopic composition of Rubisco in wheat plants exposed to elevated atmospheric carbon dioxide. AB - Although ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is mostly known as a key enzyme involved in CO2 assimilation during the Calvin cycle, comparatively little is known about its role as a pool of nitrogen storage in leaves. For this purpose, we developed a protocol to purify Rubisco that enables later analysis of its (15) N isotope composition (delta(15) N) at the natural abundance and (15) N-labeled plants. In order to test the utility of this protocol, durum wheat (Triticum durum var. Sula) exposed to an elevated CO2 concentration (700 vs 400 umol mol(-1) ) was labeled with K(15) NO3 (enriched at 2 atom %) during the ear development period. The developed protocol proves to be selective, simple, cost effective and reproducible. The study reveals that (15) N labeling was different in total organic matter, total soluble protein and the Rubisco fraction. The obtained data suggest that photosynthetic acclimation in wheat is caused by Rubisco depletion. This depletion may be linked to preferential nitrogen remobilization from Rubisco toward grain filling. PMID- 25272316 TI - Goal-directed resuscitation for patients with early septic shock. AB - BACKGROUND: Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain. METHODS: In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization. RESULTS: Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (+/-SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964+/-1415 ml vs. 1713+/ 1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay. CONCLUSIONS: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.). PMID- 25272326 TI - The Oxeatamides: nitrogenous spongian diterpenes from the New Zealand marine sponge Darwinella oxeata. AB - As part of our ongoing search for novel and bioactive compounds from New Zealand marine organisms, we investigated the extracts of the sponge Darwinella oxeata. NMR-guided fractionation led to the isolation of nine new nitrogenous spongian diterpenes, oxeatamide A (1), iso-oxeatamide A (2), oxeatamides B-G (3-8), and oxeatamide A 23-methyl ester (9), as well as two known compounds, membranolides C and D (10, 11). PMID- 25272327 TI - Changing trends in phthalate exposures. PMID- 25272329 TI - Methylthio-aspochalasins from a marine-derived fungus Aspergillus sp. AB - Two novel aspochalasins, 20-beta-methylthio-aspochalsin Q (named as aspochalasin V), (1) and aspochalasin W (2), were isolated from culture broth of Aspergillus sp., which was found in the gut of a marine isopod Ligia oceanica. The structures were determined on the basis of NMR and mass spectral data analysis. This is the first report about methylthio-substituted aspochalasin derivatives. Cytotoxicity against the prostate cancer PC3 cell line and HCT116 cell line was assayed using the MTT method. Apochalasin V showed moderate activity at IC50 values of 30.4 and 39.2 MUM, respectively. PMID- 25272330 TI - Antibiotics prior to amniotomy for reducing infectious morbidity in mother and infant. AB - BACKGROUND: Amniotomy (the deliberate rupture of membranes) was described almost two centuries ago and since then has been used both for induction and augmentation of labour - which are common obstetric practices. Trends have shown a rise in the induction rates over the last decade and data suggest that the rate of labour inductions is increasing faster than the rate of pregnancy complications. Recent years have seen the emergence of a variety of other methods of induction of labour but amniotomy combined with oxytocin infusion remains the most commonly used method of augmentation of labour. The newer agents for induction are expensive and in resource-poor settings amniotomy is still the chosen method for both induction and augmentation.As with any invasive procedure amniotomy can lead to infection, ascending from the vagina into the uterine cavity and can contribute significantly to both maternal and neonatal infectious morbidity. OBJECTIVES: The objective of this review was to evaluate the prophylactic use of antibiotics versus placebo or no treatment prior to amniotomy on maternal and neonatal infectious morbidity and mortality. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2014), the International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov (12 September 2014). SELECTION CRITERIA: Randomised controlled trials or cluster-randomised trials comparing antibiotics prior to amniotomy versus placebo (or no treatment) were eligible for inclusion in this review but none were identified. Quasi-randomised trials or cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed one trial report for inclusion. In future updates of this review, two review authors will independently assess risk of bias and carry out data extraction. Data will be checked for accuracy. MAIN RESULTS: We identified one trial report but this was excluded. No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: High-quality trials are needed to justify or refute the routine use of antibiotics at amniotomy for prevention of infection in the mother and infant.Future studies should be conducted, especially in resource constrained settings where amniotomy is still used as a means of induction of labour, in order to evaluate the routine use of antibiotics at amniotomy in these settings. Future research in this area should include important maternal and infant outcomes listed in this review and also consider cost effectiveness and side effects of antibiotic use, including the emergence of antibiotic-resistant strains. PMID- 25272328 TI - Microbial communities and bioactive compounds in marine sponges of the family irciniidae-a review. AB - Marine sponges harbour complex microbial communities of ecological and biotechnological importance. Here, we propose the application of the widespread sponge family Irciniidae as an appropriate model in microbiology and biochemistry research. Half a gram of one Irciniidae specimen hosts hundreds of bacterial species-the vast majority of which are difficult to cultivate-and dozens of fungal and archaeal species. The structure of these symbiont assemblages is shaped by the sponge host and is highly stable over space and time. Two types of quorum-sensing molecules have been detected in these animals, hinting at microbe microbe and host-microbe signalling being important processes governing the dynamics of the Irciniidae holobiont. Irciniids are vulnerable to disease outbreaks, and concerns have emerged about their conservation in a changing climate. They are nevertheless amenable to mariculture and laboratory maintenance, being attractive targets for metabolite harvesting and experimental biology endeavours. Several bioactive terpenoids and polyketides have been retrieved from Irciniidae sponges, but the actual producer (host or symbiont) of these compounds has rarely been clarified. To tackle this, and further pertinent questions concerning the functioning, resilience and physiology of these organisms, truly multi-layered approaches integrating cutting-edge microbiology, biochemistry, genetics and zoology research are needed. PMID- 25272331 TI - Mothers' and health care providers' perspectives of the barriers and facilitators to attendance at Canadian neonatal follow-up programs. AB - BACKGROUND: Despite the benefits of Neonatal Follow-Up (NFU) programs for infants at risk for developmental problems subsequent to preterm birth, non-attendance continues to be a problem within Canada and beyond. This study investigated the barriers and facilitators to attendance at Canadian NFU programs from mothers' and health care providers' (HCP) perspectives. METHODS: In this multi-site qualitative descriptive study, we conducted semi-structured individual interviews with 12 mothers, six from each of two NFU programs; and focus groups with 20 HCPs from nine NFU programs. Interviews were audio-recorded and transcribed and then subjected to thematic analysis. RESULTS: The predominant barriers represented a complex interplay of cumulative factors: mothers' isolation and feeling overwhelmed, with limited support, experiencing difficulty attending because of limited resources, who viewed NFU as not needed until problems arose for their child. Other barriers included vulnerability and fear of bad news. Mothers reported the need to protect their vulnerable child from risks, whereas HCPs reported creating vulnerability by monitoring the child's development over time. HCPs perceived fear of bad news as a barrier, whereas mothers viewed that impending bad news increased their need to attend to address the issue. The predominant facilitators were support, family centred-care and mothers with adequate resources. CONCLUSIONS: Attendance is most problematic for mothers with limited support, capacity and resources. First and foremost, targeted approaches to NFU service provision are needed to address the cumulative barriers and improve experiences for mothers who find it difficult to attend NFU. A continuous relationship with a single point of contact is needed and merits further investigation - a provider who works across the traditional silos of neonatal intensive care, NFU and community services, minimizes duplication and navigates transitions. PMID- 25272332 TI - Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes. AB - The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0.018), poor performance status (i.e., ECOG of 2-4) (P < 0.001) and lower levels of haemoglobin (Hb) (P = 0.026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29.2 [standard deviation (SD), 18.3] and 69.0 (SD, 18.8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue. PMID- 25272334 TI - Continuous and scalable production of well-controlled noble-metal nanocrystals in milliliter-sized droplet reactors. AB - Noble-metal nanocrystals are essential to applications in a variety of areas, including catalysis, electronics, and photonics. Despite the large number of reports, there still exists a gap between academic studies and industrial applications due to the lack of ability to produce the nanocrystals in large quantities while still maintaining the good uniformity and precise controls. Because the nucleation and growth of colloidal nanocrystals are highly sensitive to experimental conditions, it is impractical to scale up their production by simply increasing the reaction volume. Here we report a new and practical approach based on milliliter-sized droplet reactors to the scalable production of nanocrystals. The droplets of 0.25 mL in volume were produced as a continuous flow in a fluidic device assembled from commercially available components. As a proof of concept, we have synthesized Pd, Au, and Pd-M (M = Au, Pt, and Ag) nanocrystals with controlled sizes, shapes, compositions, and structures on a scale of 1-10 g per hour (e.g., 3.6 g per hour for Pd cubes of 10 nm in edge length). PMID- 25272333 TI - Pericarp anatomy and hormone profiles of cypselas in dormant and non-dormant inbred sunflower lines. AB - The pericarp anatomy and the effects of storage after harvest, storage temperature and early cypsela imbibition on phytohormone profiles were studied in inbred sunflower lines B123 and B91. On day 0, germination of B123 cypselas was near 0%, indicating dormancy, whereas that of B91 cypselas was near 100%, indicating non-dormancy. The germination of B123 and B91 on day 33 at room temperature (25 degrees C) storage was similar. Cell wall thickness and sclerification of the pericarp were higher in B123 than B91, suggesting that structural characteristics may contribute to physical dormancy in B123. Jasmonates (JAs), salicylic acid (SA) and abscisic acid (ABA) were measured in dry and imbibed pericarps. SA content of dry pericarp was higher on day 33 than day 0. SA content during imbibition on day 33 was similar for room and low (-20 degrees C) storage temperatures. ABA content after 12 h imbibition was similar on days 0 and 33 at low temperature, but it increased on day 33 at room temperature for B123. 12-Oxo-phytodienoic acid (OPDA) was maximal on day 0 for B123, but peaked at day 33 at low temperature for B91. JA was higher on days 0 and 33 at room temperature as compared with low temperature. Our findings indicate that pericarp hormone profiles are affected in the two lines with different dormancy degree depending on storage conditions and imbibition processes. PMID- 25272335 TI - Zinc-mediated one-pot tandem reaction of nitriles with propargyl bromides: an access to 3-alkynylpyridines. AB - A one-pot procedure for the synthesis of 3-alkynylpyridines via a zinc-mediated tandem reaction of nitriles with propargyl bromides under extremely mild reaction conditions has been developed. This reaction exhibits high efficiency, broad substrate scope, and good functional group tolerance. In addition, the 3 alkynylpyridines obtained herein were found to be versatile and convenient intermediates for the preparation of fused-heterocyclic compounds with potential biological and material interests. PMID- 25272336 TI - Investigating the underlying mechanisms of temperature-related skin diseases in Atlantic salmon, Salmo salar L., as measured by quantitative histology, skin transcriptomics and composition. AB - Skin integrity is recognized as of vital consideration for both animal welfare and final product quality of farmed fish. This study examines the effects of three different rearing temperatures (4, 10 and 16 degrees C) on the skin of healthy Atlantic salmon post-smolts. Changes in skin condition were assessed by the means of skin composition analyses, quantitative histology assessments and transcriptome analysis. Level of protein, vitamin C and vitamin E was significantly higher at 16 degrees C compared with 4 degrees C. Quantitative histology measurements showed that the epidermal thickness decreased from low to high temperature, whereas the epidermal area comprising mucous cells increased. The difference was only significant between 4 and 16 degrees C. Both high and low temperature exhibited significant changes in the skin transcriptome. A number of immune-related transcripts responded at both temperatures. Contrary to well described immunosuppressive effects of low water temperature on systemic immunity, a subtle increase in skin-mediated immunity was observed, suggesting a pre-activation of the mucosal system at 4 degrees C. Upregulation of a number of heat-shock proteins correlating with a decrease in epidermal thickness suggested a stress response in the skin at high temperature. The results demonstrate distinctive temperature-related effects on the skin of Atlantic salmon. PMID- 25272337 TI - Risk perception: it's personal. PMID- 25272338 TI - Antidepressants in bipolar I disorder: never as monotherapy. PMID- 25272339 TI - Raising the bar in the empirical investigation of psychotherapy. PMID- 25272340 TI - Improving remission and preventing relapse in youths with major depression. PMID- 25272341 TI - Starting from something: augmenting exposure therapy and methods of inquiry. PMID- 25272342 TI - What the BRAIN Initiative means for psychiatry. PMID- 25272343 TI - Out of sight, out of mind: mental illness behind bars. PMID- 25272345 TI - Depression: a case study from Cambodia. PMID- 25272344 TI - Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects. AB - Glucocorticoids are the most commonly prescribed anti inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as ways to prevent and treat these disturbances. An illustrative case vignette is presented describing a patient's experience of cycles of manic-like behavior and depression while on high-dosage prednisone, with long-term cognitive disorganization, vulnerability to stress, and personality changes. Severe neuropsychiatric consequences (including suicide, suicide attempt, psychosis, mania, depression, panic disorder, and delirium, confusion, or disorientation) have been reported to occur in 15.7 per 100 person-years at risk for all glucocorticoid courses, and 22.2 per 100 person-years at risk for first courses. The majority of patients experience less severe but distressing and possibly persistent changes in mood, cognition, memory, or behavior during glucocorticoid treatment or withdrawal. Although prediction of such effects is difficult, risks vary with age, gender, dosage, prior psychiatric history, and several biological markers. Key mechanisms thought to underlie these risk factors are briefly described. Recommendations are given for identifying individual risk factors and for monitoring and managing adverse neuropsychiatric effects of glucocorticoids. PMID- 25272346 TI - Wassily Kandinsky, 1866-1944. PMID- 25272347 TI - Early evidence of the Affordable Care Act's impact on the medically indigent population consuming emergency mental health care in Los Angeles County. PMID- 25272349 TI - Response to Pearlman and Najjar. PMID- 25272356 TI - APA Council Reports. PMID- 25272348 TI - Neuroinflammation versus decreased Zif268 mRNA expression as causal mediators of decreased GAD67 mRNA expression within dorsolateral prefrontal cortex in schizophrenia. PMID- 25272358 TI - Noninvasive prenatal testing of aneuploidies: where are we now? PMID- 25272359 TI - [Rupture and dehiscence of uterine scar: cases study at a low-risk maternity in the Brazilian Southeast]. AB - PURPOSE: To evaluate the cases of uterine rupture and dehiscence of the uterine scar at a low-risk maternity and to point out possibilities for an improved approach to these complications. METHODS: A descriptive study was conducted at a 30-bed low-risk maternity hospital that provides care to users of the public health system. The investigation was carried out by searching for cases in the delivery room registry book and later reading the medical records in order to obtain the data. The information was inserted on a form previously elaborated for this study. Cases of uterine rupture and dehiscence of the uterine scar diagnosed from 1998 to 2012 were included, with the determination of incidence, aspects related to risk factors and diagnosis, association with the use of misoprostol and oxytocin, and the outcomes observed. RESULTS: A total of 39,206 deliveries were performed in this maternity during the study period, with 12 cases of uterine rupture and 16 cases of dehiscence of uterine scar being observed. The most relevant results were a high perinatal mortality associated with uterine rupture and the unsuccessful diagnosis of this complications. It was not possible to demonstrate an association with the use of misoprostol or oxytocin. CONCLUSION: The adverse outcomes of uterine rupture could be minimized if efforts were directed at improving the diagnostic performance of the assisting teams. PMID- 25272360 TI - Internal quality control indicators of cervical cytopathology exams performed in laboratories monitored by the External Quality Control Laboratory. AB - PURPOSE: To evaluate the impact of continued education provided by an external quality control laboratory on the indicators of internal quality control of cytopathology exams. METHODS: The internal quality assurance indicators for cytopathology exams from 12 laboratories monitored by the External Quality Control Laboratory were evaluated. Overall, 185,194 exams were included, 98,133 of which referred to the period preceding implementation of a continued education program, while 87,061 referred to the period following this intervention. Data were obtained from the Cervical Cancer Database of the Brazilian National Health Service. RESULTS: Following implementation of the continued education program, the positivity index (PI) remained within recommended limits in four laboratories. In another four laboratories, the PI progressed from below the limits to within the recommended standards. In one laboratory, the PI remained low, in two laboratories, it remained very low, and in one, it increased from very low to low. The percentage of exams compatible with a high-grade squamous intraepithelial lesion (HSIL) remained within the recommended limits in five laboratories, while in three laboratories it progressed from below the recommended levels to >0.4% of the total number of satisfactory exams, and in four laboratories it remained below the standard limit. Both the percentage of atypical squamous cells of undetermined significance (ASC-US) in relation to abnormal exams, and the ratio between ASC-US and intraepithelial lesions remained within recommended levels in all the laboratories investigated. CONCLUSION: An improvement was found in the indicators represented by the positivity index and the percentage of exams compatible with a high-grade squamous intraepithelial lesion, showing that the role played by the external quality control laboratory in providing continued education contributed towards improving laboratory staff skills in detecting cervical cancer precursor lesions. PMID- 25272361 TI - [Effect of a short-term functional training program on body composition in postmenopausal women]. AB - PURPOSE: To evaluate the effect of 8 weeks of functional training on body composition in postmenopausal women. METHODS: The study was conducted on 38 postmenopausal women, divided into two groups: Training Group (TG) and Control Group (CG). TG women (n = 21) performed a program of physical exercise for a period of 8 weeks, 3 times a week on nonconsecutive days, with 90 minutes per session. For the same period, CG women (n = 17) did not perform any systematic physical activity. All participants were assessed at baseline and after 8 weeks. The evaluations were performed by the same trained raters. Analysis of body composition was performed using dual-energy X-ray absorptiometry (DEXA), which allows estimation of body composition in the whole body and by segment. TG participants performed a functional exercise program 3 days a week (non consecutive), with 11 stations consisting of exercises developed in circuit format sessions. The objectives of the exercises were the development of strength, agility, coordination and proprioception, followed by aerobic exercise (walking). After normality of the data was determined by the Shapiro-Wilk test (p < 0.05), we applied the Student t-test for independent samples to check for possible differences in anthropometric variables and body composition between groups at both times of intervention (pre and post-test). All analyses were performed using the SPSS software v. 17.0 (SPSS Inc., Chicago, IL, USA) with the level of significance set at 5%. RESULTS: At baseline, no significant difference was observed between groups regarding anthropometric body variables or age composition, indicating homogeneity of the groups. After 8 weeks of training, significant differences were observed between TG and CG regarding fat - CG = 0.2 +/- 0.7 and TG = -0.4 +/- 0.5, total body fat (kg) - CG = 0.2 +/- 1.3 and TG = 0.7 +/- 0.8, and total weight - CG = 0.4 +/- 1.4 and TG = -0.6 +/- 1.1. Percent body fat was reduced in terms of absolute values, although without significance: CG = 0.1 +/- 1.5 and TG = -0.8 +/- 1.5. CONCLUSION: Functional training in circuit format can be used as a strategy to alter body composition in postmenopausal women, particularly in terms of reduction of adipose tissue. This is a model that promotes high adhesion on the part of the participants, suggesting that it is an attractive proposal for the investigated age group. PMID- 25272362 TI - [Acanthosis nigricans: metabolic interrelations inherent to the polycystic ovary syndrome]. AB - PURPOSE: To establish the prevalence of acanthosis nigricans (AN) within the context of polycystic ovary syndrome (PCOS) and its associations with obesity, insulin resistance, insulinemia, and metabolic syndrome (MS). METHODS: A cross sectional prospective study was conducted on 100 patients with PCOS diagnosed according to the Rotterdam Consensus (2003). The skin test included, in addition to the detection of the presence of AN, the presence of hirsutism (score >= 8) and acne. In addition to clinical and biochemical data, we investigated cardiovascular risk factors present in MS such as abdominal circumference, obesity, hypertension and HDL and triglyceride levels. Insulin resistance was determined by the HOMA-IR test. RESULTS: The prevalence of AN (53%) was significantly correlated with hirsutism (p = 0.02), body mass index (p < 0.01), basal insulinemia (p < 0.01), (HOMA-IR) (p < 0.01), and MS (p < 0.01). The prevalence of MS reached 36% and was significantly associated only with AN (p < 0.01). Although diabetes mellitus was absent, there was a significant association of altered HOMA-IR (p < 0.01) with MS (p < 5%) and AN (p < 0.01). CONCLUSION: AN is part of the severe phenotypic profile of PCOS as an additional predictable sign of the risks of cardiovascular disease. PMID- 25272363 TI - [Genotype distribution of human papillomavirus in women from the state of Bahia, Brazil]. AB - PURPOSE: The aim of this study was to evaluate the human papillomavirus genotypes and the frequency of multiple human papillomavirus infections, as well as to assess the association between human papillomavirus genotype, cyto histopathological abnormalities and age range. METHODS: A retrospective cross sectional study was carried out between June 2010 and October 2013 in Salvador, Bahia, Brazil. We analyzed 351 results of positive human papillomavirus genotyping performed using the PapilloCheck(r) test, designed to detect 24 human papillomavirus types. The cyto-histopathological abnormalities were classified as negative (negative cytology and histopathology), low-grade lesions (cytologic low grade squamous intraepithelial lesion diagnosis or histopathologic cervical intraepithelial neoplasia 1 or vaginal intraepithelial neoplasia 1 diagnosis) and high-grade lesions (cytologic high-grade squamous intraepithelial lesion diagnosis or histopathologic cervical intraepithelial neoplasia 2+ or vaginal intraepithelial neoplasia 2+ diagnosis). RESULTS: The most frequently detected high risk human papillomavirus genotype was HPBV 16, with 18.5%, 95% confidence interval (95%CI) 14.6-23.0, followed by HPV 56 (14%; 95%CI 10.5-18.0) and HPV 39 (13.4%; 95%CI 9.5-16.8). HPV 18 (5.4%; 95%CI 3.3-8.3) was among the least frequent types. Among the low risk types, HPV 42 (15.7%; 95%CI 12.0-20.0), HPV 6 (11.4%; 95%CI 8.3-15.2) and HPV 44/55 (11.1%; 95%CI 8.0-14.9) were the most frequent, while HPV 11 (2.8%; 95%CI 1.4-5.2) was the least common. The proportion of HPV 16-positive women increased with severity of cyto-histopathological abnormalities: 13.8% (12/87) in low-grade lesion and 42.4% (14/33) in high-grade lesion. There was association between low- or high-grade cyto-histopathological lesion and the high risk genotypes, HPV16, HPV 52, HPV 73 and HPV 82, and the low risk type, HPV 43. Women under 30 years showed a significantly higher frequency of HPV 16 (22.2 versus 12.9%, p =0.01), HPV 42 (19.7 versus 10.9%, p=0.01) and HPV 45 (6.6 versus 1.4%, p=0.01), and multiple human papillomavirus infections (58.1 versus 47.4%, p=0.04). CONCLUSIONS: We observed variability of human papillomavirus genotype distribution in women from the state of Bahia. HPV 16 was the most frequently detected high risk human papillomavirus, as also reported for other geographic areas of Brazil and for the world in general. HPV 56 and HPV 39 were the second and the third most common genotypes, whereas HPV 18 was among the least frequent types. HPV 42, 6 and 44/55 were the most frequently detected low risk human papillomavirus, and HPV 11 was the least common. PMID- 25272364 TI - Interactions of octahedral ruthenium(II) polypyridyl complexes with the RNA triplex poly(U)*poly(A)*poly(U) effect on the third-strand stabilization. AB - Stable triplexes play key roles in many biological processes. Due to the Hoogsteen base pairing, triplexes are, however, thermodynamically less stable than the corresponding duplexes. The poor stabilization of these structures limits their practical applications under physiological conditions. To understand the factors effect on the stabilization of RNA triplexes by octahedral ruthenium(II) complexes, the interactions of [RuL2(uip)](2+) {where L = 2,2' bipyridine (bpy) or 1,10-phenanthroline phen, uip = 2-(5-uracil)-1H-imidazo[4,5 f][1,10]phenanthroline} with the RNA triplex poly(U)*poly(A)*poly(U) are examined by spectrophotometry, spectrofluorometry, circular dichroism, and viscosimetry in this work. The main results obtained here suggest that the third-strand stabilization depends on the hydrophobicity effects of ancillary ligands bpy and phen. PMID- 25272365 TI - Autochthonous melioidosis in humans, Madagascar, 2012 and 2013. AB - Melioidosis is an often fatal infectious disease affecting humans and animals in the tropics. Only sporadic cases have been reported from Africa and the Indian Ocean region. We describe 2 confirmed autochthonous cases of human melioidosis in Madagascar, both from novel genotypes of Burkholderia pseudomallei. PMID- 25272366 TI - Establishment of an immortalized laryngeal posterior commissure cell line as a tool for reflux research. AB - OBJECTIVES/HYPOTHESIS: Laryngopharyngeal reflux (LPR) has been implicated as a promoter of laryngeal cancer. Within the larynx, the posterior commissure (PC) is the region that usually comes into direct contact with refluxed materials. Specific laryngeal cell lines useful for in vitro studies are not widely available, and noncancer-derived PC laryngeal cell line has not yet been described. STUDY DESIGN: Experimental study. METHODS: Specimens of squamous epithelium from the PC of the larynx were collected from patients without a history or evidence of laryngeal inflammatory or neoplastic diseases. Harvested tissue was cultured and then immortalized by transduction with human papillomavirus E6/E7-encoding lentivirus. PC primary and transformed cells were characterized by light microscopy and immunohistochemistry. RESULTS: Primary cultures established from PC contained < 5% fibroblasts and displayed normal epithelial cell morphology and cytokeratin expression. These cells survived nine passages in culture. Following lentiviral-mediated immortalization, cells retained normal squamous epithelial morphology and survived > 20 passages in culture. Methods were optimized for culture of PC laryngeal epithelial cells, resulting in 90% success rate of culture. CONCLUSION: A novel immortalized PC laryngeal epithelial cell line has been established. This cell line provides a unique tool for investigating the mechanism of LPR in the development and progression of laryngeal cancer. LEVEL OF EVIDENCE: N/A. PMID- 25272368 TI - Micellization behavior of Aerosol OT in alcohol/water systems. AB - This paper examines the effects of solvent composition on the micellization behavior of the surfactant Aerosol OT (AOT). The critical micelle concentrations of AOT in the pure solvents methanol, ethanol, propanol, and isopropanol were measured using conductiometric techniques. These solvents were then mixed with water to create solvent spectra from pure alcohol to pure water in 12 increments. Critical micelle concentrations were measured at each solvent composition. Dynamic light scattering was used to verify the presence or absence of micelles in the solvent mixtures. It was found that inverse micelles exist over a range of solvent compositions where epsiloneff < 48 with CMCs increasing with increasing solvent polarity. Micellization was found not to occur when 48 < epsiloneff < 80. Regular micelles formed in pure water, with the measured CMC agreeing with the literature value of 2.25 mM. PMID- 25272367 TI - Modified bleomycin disaccharides exhibiting improved tumor cell targeting. AB - The bleomycins (BLMs) are a family of antitumor antibiotics used clinically for anticancer chemotherapy. Their antitumor selectivity derives at least in part from their ability to target tumor cells, a property that resides in the carbohydrate moiety of the antitumor agent. In earlier studies, we have demonstrated that the tumor cell selectivity resides in the mannose carbamoyl moiety of the BLM saccharide and that both the BLM disaccharide and monosaccharide containing the carbamoyl moiety were capable of the delivery/uptake of a conjugated cyanine dye into cultured cancer cell lines. Presently, the nature of the participation of the carbamoyl moiety has been explored further to provide compounds of utility for defining the nature of the mechanism of tumor cell recognition and uptake by BLM saccharides and in the hope that more efficient compounds could be identified. A library of seven disaccharide-Cy5** dye conjugates was prepared that are structural analogues of the BLM disaccharide. These differed from the natural BLM disaccharide in the position, orientation, and substitution of the carbamoyl group. Studies of these compounds in four matched sets of tumor and normal cell lines revealed a few that were both tumor cell selective and internalized 2-4-fold more efficiently than the natural BLM disaccharide. PMID- 25272369 TI - Pesticides and autism spectrum disorders: new findings from the CHARGE study. PMID- 25272370 TI - Population pharmacokinetic modeling and simulation of amprenavir following fosamprenavir/ritonavir administration for dose optimization in HIV infected pediatric patients. AB - Fosamprenavir (FPV) is the phosphate ester prodrug of the HIV-1 protease inhibitor amprenavir (APV). A pediatric population pharmacokinetic model for APV was developed and simulation was used to identify dosing regimens for pediatric patients receiving FPV in combination with ritonavir (RTV) which resulted in concentrations similar to those in adults receiving FPV/RTV 700/100 mg BID. Pharmacokinetic data was obtained from HIV infected subjects aged 2 months to 18 years receiving either FPV or FPV/RTV. A two-compartment model with first order absorption and elimination was an appropriate structural model. Significant covariates in the model included RTV coadministration on clearance, fed status on bioavailability for the oral suspension, body weight on clearance and volume terms, black race on clearance, and age on clearance. The following FPV/RTV twice daily dosing regimens in pediatric patients delivered plasma APV exposure similar to adults: 45/7 mg/kg in patients weighing <11 kg, 30/3 mg/kg in patients weighing 11 to <15 kg, 23/3 mg/kg in patients weighing 15 to <20 kg, and 18/3 mg/kg in patients weighting >=20 kg. Additionally children weighing >=39 kg can receive the adult regimen. PMID- 25272372 TI - Editorial. PMID- 25272371 TI - Mussel-inspired hydrophobic coatings for water-repellent textiles and oil removal. AB - A series of catechol derivatives with a different number of linear alkyl chain substituents, and different length, have been shown to polymerize in the presence of aqueous ammonia and air, yielding hydrophobic coatings that present the ability to provide robust and efficient water repellency on weaved textiles, including hydrophilic cotton. The polymerization strategy presented exemplifies an alternative route to established melanin- and polydopamine-like functional coatings, affording designs in which all catechol (adhesive) moieties support specific functional side chains for maximization of the desired (hydrophobic) functionality. The coatings obtained proved effective in the transformation of polyester and cotton weaves, as well as filter paper, into reusable water repellent, oil-absorbent materials capable of retaining roughly double their weight in model compounds (n-tetradecane and olive oil), as well as of separating water/oil mixtures by simple filtration. PMID- 25272374 TI - Statin side effects: how common are they? You are unlikely to experience side effects from these drugs. If you do, there are ways to reverse them. PMID- 25272373 TI - Hollow microgel based ultrathin thermoresponsive membranes for separation, synthesis, and catalytic applications. AB - Thermoresponsive core-shell microgels with degradable core are synthesized via surfactant based free radical polymerization using N,N'-(1,2-dihydroxy ethylene)bis(acrylamide) (DHEA) as a cross-linker for core preparation. The 1,2 glycol bond present in DHEA is susceptible to NaIO4 solution, and thus, the structure can be cleaved off resulting in hollow microgel. Ultrathin membranes are prepared by suction filtration of a dilute suspension of core-shell microgels over a sacrificial layer of Cd(OH)2 nanostrand coated on track etched membrane. After removal of the degraded cores from microgels, the membranes are cross linked with glutaraldehyde and the nanostrands are removed by passing a 10 mM HCl solution. The prepared membranes are thoroughly characterized using scanning electron microscopy (SEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and dynamic contact angle for morphology, thermoresponsive, and hydrophilic properties, respectively. The prepared membranes showed thermoresponsive permeation behavior and remarkable separation performance for low molecular weight dyes and lysozyme protein. These membranes are also used to synthesize gold nanoparticles and immobilize lactate dehydrogenase enzyme for catalytic and biocatalytic application. The results for water permeation, solute rejection, and ability to immobilize gold nanoparticles and enzymes showed its wide range of applicability. Furthermore, the synthesis of hollow microgel is simple and environmentally friendly, and the membrane preparation is easy, scalable, and other microgel systems can also be used. These responsive membranes constitute a significant contribution to advanced separation technology. PMID- 25272375 TI - On call. I've noticed that my ejaculations are weaker and lower-volume than in my youth. Is that normal? Could something be wrong with my prostate gland? PMID- 25272377 TI - Influenza alert: when you need an antiviral boost. If you are at risk of severe flu complications, start on antiviral medications as soon as you feel sick. PMID- 25272378 TI - Choose a hearing aid that works for you. Look for one that offers ample volume and the ability to turn it up and down as needed. PMID- 25272379 TI - Late deposits in the "brain bank" may still help delay mental decline. PMID- 25272380 TI - New generation of blood-thinning drugs found safe for older adults. PMID- 25272381 TI - Older treatment may be best overall for treating new Parkinson's. PMID- 25272382 TI - Tea: a cup of good health? Tea drinking isn't harmful and fits well with a healthy lifestyle. PMID- 25272383 TI - UW creates tampon-like HIV prevention option. PMID- 25272384 TI - Behavior. Certain youth demographics fall short on HIV prevention efforts. PMID- 25272385 TI - Outcomes of surgical site infections in orthopedic trauma surgeries in developing countries: Need for baseline data and identification of risk factors. PMID- 25272386 TI - Breast cancer in the Geriatric population. PMID- 25272387 TI - Combating the spread of HIV among Indian migrants. PMID- 25272389 TI - Treatment. Allowing ART initiation in the home increases participation. PMID- 25272388 TI - Diabetic peripheral neuropathy in India: underestimated and overlooked? PMID- 25272390 TI - Adult circumcision does not lead to risky behaviors. PMID- 25272391 TI - Toll like receptors and acute retinal necrosis syndrome- evaluating the association. PMID- 25272392 TI - Urge primary care physicians to test. PMID- 25272394 TI - Military. Air Force reservist not entitled to active duty reinstatement. PMID- 25272393 TI - ABCB1 variant provides important leads for pharmacogenetics of epilepsy. PMID- 25272395 TI - Prison adequately complied with HIV-positive inmate's diet. PMID- 25272397 TI - International. Court holds that man likely contracted HIV after bombing. PMID- 25272396 TI - Monitoring to prevent brachial plexus injury. PMID- 25272398 TI - SSI. Court holds that ALJ's decision was supported by evidence. PMID- 25272399 TI - Authors' reply. PMID- 25272400 TI - Robert E. Reisman, MD: 1932 - 2012. PMID- 25272401 TI - Edmund Yendt, MD: 1925-2013. PMID- 25272402 TI - Notice to readers: final 2013 reports of nationally notifiable infectious diseases. PMID- 25272403 TI - School nurses--new roles for better outcomes. PMID- 25272404 TI - Celebrating and sustaining the NASN Endowment Fund. PMID- 25272405 TI - NASN's first evidence-based clinical guidelines: asthma. AB - Evidence-based clinical guidelines assist health care providers to ensure best practices. The National Association of School Nurses (NASN) has developed the organization's first evidence-based clinical guidelines to assist school nurses to practice at their highest level and in response to a direct request by members. This guideline focuses on asthma; more guidelines will follow. This article provides an overview identifying why clinical guidelines are important, how the guidelines were developed, and guidance to school nurses on how to interpret and use the guidelines. PMID- 25272406 TI - Increasing immunization rates through the immunization neighborhood recognizing school-located immunization programs. AB - Vaccines are considered one of the top 10 public health achievements in the United States; however, coverage rates for many of the recommended child and adolescent vaccines fall short of Healthy People 2020 goals. The vaccine delivery infrastructure in our country might be the most important limiting factor in achieving the vaccine uptake targets. Renewing the focus on schools for both vaccine delivery and vaccine promotion has the potential to augment other emerging alternate vaccination sites within the immunization neighborhood. School nurses are leading the way, and three national award winners are recognized for their immunization programming efforts. All school nurses can be immunization champions, advocating for the role of schools as key sites to promote the importance of vaccines in protecting the health and ensuring academic success of the students they serve. PMID- 25272407 TI - Nutrition issues for youth with diabetes. AB - For both type 1 and type 2 diabetes, eating healthy is key to blood glucose management. To that end, the school nurse must have a basic understanding of nutrition recommendations for children with diabetes. This article describes basic nutrition guidelines as well as action steps for school nurses to assist children in following their meal plan at school and to support children when diabetes-related emergencies arise. PMID- 25272408 TI - Managing concussion in the school setting. AB - Concussion is a significant injury that can occur in physical education, during recreational activities, and during sports. School nurses should be included as an integral member of the concussion management team and assist with education, evaluation, and management of a concussed student. Recent and updated sport related concussion management recommendations from the National Athletic Trainers' Association Research and Education Foundation as published in the March 2014 Journal of Athletic Training are reviewed to provide an understanding of best practices for concussion management in the school setting. PMID- 25272409 TI - National standardized data set for school health-services: step up and be counted! AB - The National Association of School Nurses and National Association of State School Nurse Consultants Joint Work Group agreed on identified common data points and an initial process for nationwide data collection by school nurses. The emerging process was presented at both the 2014 National Association of School Nurses and the National Association of State School Nurse Consultants annual meetings in San Antonio. The time is now to begin the process for ALL school nurses to collect data to begin building a national school nursing data set. This article is the second of a series and outlines the how, why, and when for collecting identified data indicators. It provides the talking points and collection tool necessary to Step Up and Be Counted! PMID- 25272410 TI - Increasing prevalence of autism: implications for school nursing. PMID- 25272411 TI - The student health collaboration: an innovative approach to enhancing communication and improving student health. AB - Students, families, school staff and school nurses all benefit from successful community partnerships. School nurses requested improved communication with local clinicians and access to the health information of their students. School nurses were not routinely recognized as part of the care team and therefore were not able to access protected health information found in the medical record, which would improve health outcomes for their students. With a goal of improving student health outcomes, a local pediatric health care delivery system partnered with school nurses to share student health information. School nurses were included as part of the health care team, with access to electronic health records. This is an innovative coordinated care team approach with parents, nurses, and community clinicians able to communicate, plan, intervene, and evaluate student health. PMID- 25272412 TI - Unlicensed administration of medication. the California Supreme Court decision. AB - This article summarizes the California Supreme Court's decision in American Nurses Association v. Torlakson concerning the administration of prescription medications, such as insulin injections for students with diabetes, by school personnel who are not licensed nurses. More specifically, the coverage includes (a) an overview of the legal history of this California case; (b) an analysis of the specific contours of the court's ruling along with their applications and effects in California; and (c) a discussion of the more general legal implications for school nurses and school districts in other states. PMID- 25272413 TI - The expanding role of school nurses: an ozone awareness flag program. AB - Children with asthma are at risk of experiencing the effects of ozone on the respiratory system at a lower concentration than normal or with a greater morbidity. The North Texas Asthma Consortium partnered with the U.S. Environmental Protection Agency, the Department of Health and Human Services, and the Asthma Coalition of Texas to implement an ozone awareness program in schools in North Texas. The goal of the ozone awareness program was to introduce and support a process for schools to raise ozone awareness in the school and community. Schools participating in the program fly a green, yellow, orange, or redflag each day alerting students, school staff parents, and community members about the ozone. Activities for an active indoor curriculum on high ozone days, education about asthma and the effect of ozone, tools for implementing the program, and flags were provided. The program has been presented to almost 250 schools with 85 schools participating. PMID- 25272414 TI - Does school scoliosis screening make the grade? AB - School nurses have provided routine health screenings of school-age children for decades. During the 1970s, recommendations for school scoliosis screening, which were based upon poor access to health care, led state boards of education to mandate that school nurses screen for scoliosis. The history of mandated scoliosis screening in U.S. schools is reviewed, and current school nurse practices for scoliosis screening are presented. Elevated referral rates for repeat scoliosis examination following school scoliosis screenings have led to questions of efficacy. Further controversy exists regarding school nurses screening for scoliosis due to a lack of evidence indicating a decreased need for scoliosis surgery. This article contains evidence-based recommendations for discontinuing school scoliosis screening to help school nurses refocus their efforts on complex health needs and preventive health issues more likely to impact the majority of their students. PMID- 25272415 TI - School-sponsored before, after, and extended school year programs--the role of the school nurse: position statement. AB - It is the position of the National Association of School Nurses (NASN) that the registered professional school nurse (hereinafter referred to as school nurse) has the educational and clinical background to coordinate the necessary school health services to provide students with the same health, nutrition, and safety needs while attending school-sponsored before, after, and extended school year programs as the students receive during the traditional school day/year. In 2010, the White House Task Force on Obesity called for an increase in access to safe supervised physical activities beyond the school day (White House Task Force on Childhood Obesity Report to the President, 2010), and as these programs have expanded, the necessity for providing quality, effective health care services during these hours has developed. As the expert in school health services delivery models of health care, the school nurse is an essential facilitator for student access to these programs. The school nurse plays a vital role in preparing the school-sponsored before and after school and extended school year program personnel with the necessary resources to respond to a health emergency. PMID- 25272416 TI - Reimbursement for school nursing health care services: position statement. AB - Children come to school with a variety of health conditions, varying from moderate health issues to multiple, severe chronic health illnesses that have a profound and direct impact on their ability to learn. The registered professional school nurse (hereinafter referred to as school nurse) provides medically necessary services in the school setting to improve health outcomes and promote academic achievement. The nursing services provided are reimbursable services in other health care settings, such as hospitals, clinics, and home care settings. The National Association of School Nurses (NASN) believes that school nursing services that are reimbursable nursing services in other health care systems should also be reimbursable services in the school setting, while maintaining the same high quality care delivery standards. Traditionally, local and state tax revenues targeted to fund education programs have paid for school nursing health services. School nurses are in a strategic position to advocate for improving clinical processes to better fit with community health care providers and to align reimbursements with proposed changes. Restructuring reimbursement programs will enable health care funding streams to assist in paying for school nursing services delivered to students in the school setting. Developing new innovative health financing opportunities will help to increase access, improve quality, and reduce costs. The goal is to promote a comprehensive and cost-effective health care delivery model that integrates schools, families, providers, and communities. PMID- 25272417 TI - Looking forward. A dedication to Ernest Amory Codman, MD. PMID- 25272418 TI - A new era begins for ACS online properties. PMID- 25272419 TI - The SAGES FUSE program: bridging a patient safety gap. PMID- 25272420 TI - The benefits of PQRS participation and what the college is doing on your behalf. PMID- 25272421 TI - Surgeons as state advocates. PMID- 25272422 TI - Founding surgeon reflects on 25 years of UNICAR, the Guatemalan Heart Institute. PMID- 25272423 TI - Surgical training abroad: it's not about the cases. PMID- 25272424 TI - Statement on bicycle safety and the promotion of bicycle helmet use. PMID- 25272425 TI - Statement on intimate partner violence. PMID- 25272426 TI - Statement on older adult falls and falls prevention. PMID- 25272427 TI - Physician Payments Sunshine Act data scheduled for release. PMID- 25272428 TI - Frequently asked questions about coding for breast surgery. PMID- 25272429 TI - Treating metastatic prostate cancer now and in the future. PMID- 25272430 TI - "Everything old is new again". PMID- 25272431 TI - NTDB data points: Don't chance it: use your seatbelt. PMID- 25272432 TI - Matrix conferences needed. PMID- 25272433 TI - Google Glass implications. PMID- 25272434 TI - Sunshine Act. PMID- 25272435 TI - Disciplinary actions. PMID- 25272436 TI - Fellows honored for volunteerism. PMID- 25272437 TI - Headstone honoring Ernest A. Codman, MD, FACS, placed at Mount Auburn Cemetery. PMID- 25272438 TI - Surgeons influence AMA policy. PMID- 25272439 TI - Report of the 2014 ACS Traveling Fellow to Japan. PMID- 25272440 TI - [Sequential effect in attractiveness judgement of multiple faces]. AB - A large number of studies have demonstrated the sequential effect, in which the response in the current trial is assimilated towards that of the immediately preceding trial in a decision making task. However, most previous studies have only examined the effect in situations where the response was given after each stimulus presentation. In this study, we examined whether the sequential effect existed when observers responded after the presentation of two stimuli. After two pictures of male faces were presented successively, participants rated the attractiveness of each face on a 9-point scale. The results showed that the second response was assimilated towards the first (Experiment 1), but the first response contrasted with (shifted away from) the second (Experiment 2). These findings suggest that preceding and succeeding contexts may differentially modulate our decision making. PMID- 25272441 TI - [Effects of exposure frequency and background information on preferences for photographs of cars in different locations]. AB - This study examined the influence of familiarity and novelty on the mere exposure effect while manipulating the presentation of background information. We selected presentation stimuli that integrated cars and backgrounds based on the results of pilot studies. During the exposure phase, we displayed the stimuli successively for 3 seconds, manipulating the background information (same or different backgrounds with each presentation) and exposure frequency (3, 6, and 9 times). In the judgment phase, 18 participants judged the cars in terms of preference, familiarity, and novelty on a 7-point scale. As the number of stimulus presentations increased, the preference for the cars increased during the different background condition and decreased during the same background condition. This increased preference may be due to the increase in familiarity caused by the higher exposure frequency and novelty resulting from the background changes per exposure session. The rise in preference judgments was not seen when cars and backgrounds were presented independently. Therefore, the addition of novel features to each exposure session facilitated the mere exposure effect. PMID- 25272442 TI - [Twelve-month-old infants show social preferences for native-dialect speakers]. AB - Recent research demonstrates that social preferences for native language speakers emerge early in development, indicating that infants prefer speakers from their own society. Dialect may also be a reliable cue to group membership because it provides information about an individual's social and ethnic identity. We investigated whether infants showed social preferences toward native-dialect speakers over those with unfamiliar dialects. Infants at 9 and 12 months of age were shown videos in which two adults (a native-dialect speaker and an unfamiliar dialect speaker) each spoke to and then offered an identical toy to the participating infants. Next, two real versions of the toys were presented to the infants in person. The 12-month-old infants preferentially reached for the toy offered by the native-dialect speaker. The 9-month-old infants also showed a preference for native-dialect speakers but this finding was not statistically significant. Our results suggest that dialects may be a reliable cue to group membership, and that infants' orientation toward members of their native community may guide their social and cultural learning. PMID- 25272443 TI - [Importance of stressful events moderates dispositional optimism, pessimism and coping strategies]. AB - Prior research has reported that dispositional optimists tend to take approach type coping strategies in response to health threats, and as a result, experience positive health benefits. This study investigated whether dispositional optimism or pessimism interacted with the importance that a participant assigned to stressful events to predict their coping behavior. College students (N = 178) participated in the study. The results indicated that the importance participants assigned to stressful events moderated the relationship between dispositional optimism and positive interpretations, as well as the relationship between dispositional pessimism and positive interpretations, abandonment, and avoiding of responsibility. It was concluded that optimistic individuals used positive interpretations for highly important events but not for less- important events. Moreover, less pessimistic individuals also used positive interpretations for highly significant events, and did not use abandonment or avoidance of responsibility; there was no such relationship with less- important events. These findings suggest that individuals high in optimism and low in pessimism are flexible, which plays a valuable role in their self-regulatory behavior. PMID- 25272444 TI - [Effects of explanation expectancy on text comprehension: an experiment and a meta-analysis]. AB - Prior studies have investigated whether the expectation that one will explain learned materials after learning (explanation expectancy) promotes text comprehension. Such researches, however, have had inconsistent results. In Study 1, we examined whether an elaborative explanation orientation, which refers to the belief that it is important to elaborate and organize a passage when explaining, moderated the effect of explanation expectancy. The results showed neither a moderation effect nor an effect of explanation expectancy. This suggests that the effect size of explanation expectancy was not large, so that a single experimental research with limited sample size could not reliably find a positive effect. In Study 2, a meta-analysis was conducted to infer more accurately the influence of explanation expectancy on text comprehension. Based on a sample of 7 reports (n = 289), the results showed that the effect size g for explanation expectancy was 0.51 (95% CI = (0.10, 0.91)). This finding demonstrates that the inconsistent results of previous research could be caused by small sample sizes, and explanation expectancy improves text comprehension. PMID- 25272445 TI - [Role of connectedness in early object-based attentional selection]. AB - It has been suggested that uniform connectedness is the most fundamental factor in forming units of attentional selection, while there are evidences that attention can select a perceptual group that consists of separate elements with similar features. The present study examined the effects of connectedness and a boundary-feature similarity on early spatial-selection processes using a sustained-focal-attention paradigm of event-related potentials (ERPs). Bilateral stimuli were manipulated to have an orthogonal combination of connectedness (C-, C+) and a similarity in boundary feature (S-, S+). ERPs were recorded from 15 participants who were instructed to pay attention to the left or the right visual field and to respond to a target shape that appeared infrequently in the attended field. The ERP attention effect in the N1 latency range (125-185 ms) was decreased for stimuli with connectedness and/or boundary-feature similarity, and the effects of the two grouping factors were independent of each other. The present result suggests that multiple grouping factors, including connectedness, operate in parallel in early processes of object-based attention-spreading. PMID- 25272446 TI - [Development of a short-form self-report measure to assess relaxation effects]. AB - The present study aimed to develop a short-form self-report measure to assess relaxation effects (S-MARE). Participants (N = 190) responded to a questionnaire comprised of 45 items assessing relaxation and non-relaxation based on the Relaxation Inventory (Crist et al., 1989). Exploratory factor analysis identified three factors: physiological tension, psychological relaxation, and anxiety. Each factor was related to 5 items and each had an acceptable Cronbach's coefficient (alpha = .93, .94, and .85). S-MARE scores pre- and post- relaxation instruction were significantly correlated with the Emotional Relaxation Scale (Tokuda, 2011) (r = .446) and with State Anxiety (r = -.531) (N = 172). There was a significant correlation between the amplitude of the high frequency component of heart rate variability during relaxation instruction and physiological tension scores on the S-MARE (r = .456-.474, N = 24). These results confirmed the reliability and validity of the S-MARE in terms of physiological correlation with cardiac parasympathetic tone, suggesting that the S-MARE is a valid measure of relaxation effects. PMID- 25272447 TI - [An attempt to construct a Japanese version of the Implicit Positive and Negative Affect Test (IPANAT)]. AB - The Implicit Positive and Negative Affect Test (IPANAT) is an instrument for the indirect assessment of positive and negative affect. A Japanese version of the IPANAT was developed and its reliability and validity were examined. In Study 1, factor analysis identified two independent factors that could be interpreted as implicit positive and negative affect, which corresponded to the original version. The Japanese IPANAT also had sufficient internal consistency and acceptable test-retest reliability. In Study 2, we demonstrated that the Japanese IPANAT was associated with explicit state affect (e.g., PANAS), extraversion, and neuroticism, which indicated its adequate construct validity. In Study 3, we examined the extent to which the Japanese IPANAT was sensitive to changes in affect by assessing a set of IPANAT items after the presentation of positive, negative, or neutral photographs. The results indicated that the Japanese IPANAT was sufficiently sensitive to changes in affect resulting from affective stimuli. Taken together, these studies suggest that the Japanese version of the IPANAT is a useful instrument for the indirect assessment of positive and negative affect. PMID- 25272448 TI - [Psychometric properties of the Japanese version of the Autism Spectrum Screening Questionnaire (ASSQ): development of a short form]. AB - We examined the psychometric properties of the Japanese version of the Autism Spectrum Screening Questionnaire (ASSQ) and developed a short-form. This study included 157 children with autism spectrum disorders (ASD, ages 7-18, 128 boys) and 4,101 healthy controls (ages 7-15, 3,344 boys) from a general population with a controlled male-female ratio. Four factors (Unusual Interests, Sociality, Peer Relations, and Repetitive Behaviors) were extracted by exploratory factor analysis of control group data. Confirmatory factor analysis revealed that the 4 factor model fit well with data for another sample of the control and ASD groups. Logistic analysis showed that the former 3 factors could significantly predict ASD diagnosis. Thus, a short form of the ASSQ was developed, consisting of 11 items for these 3 factors. This short form showed sufficient internal consistency and high discrimination power for ASD diagnosis that was comparable to that of the 22-item version. Receiver operating characteristic analysis indicated an optimal cut-off of 7 for the 22-item version (sensitivity .949, specificity .801) and 5 for the short-form (sensitivity .936, specificity .818). PMID- 25272449 TI - [The effect of hikikomori on quality of life]. AB - The purpose of the present study was to examine the effect of hikikomori, a Japanese term denoting "prolonged social withdrawal", on quality of life (QOL). Individuals with hikikomori at present (n = 26) and in the past (n = 31), as well as mildly depressed individuals without hikikomori (n = 114) and highly depressed individuals without hikikomori (n = 27) were requested to complete the WHO Quality of Life 26 (QOL26). The results of MANOVA indicated that the present hikikomori group's scores on the social relationships domains of the QOL26 were significantly lower than the scores of the highly depressed group. The results of this study suggest that it might be important to intervene to improve QOL in individuals with hikikomori. PMID- 25272450 TI - [The role of calpains in the regulation of synaptic function]. AB - Calpains are calcium-activated neutral cysteine proteases, involved in the regulation of a number of physiological functions. Substrates of calpains include receptors, kinases, phosphatases, cytoskeleton and synaptosomal proteins. Some of them undergo complete degradation, though most of the substrates are subjected to limited proteolysis, which results in proteins having new properties. In the following review, we discuss involvement of calpains in the regulation of synapse structure and function. Namely, calpains participate in the regulation of synthesis, release and reuptake of neurotransmitters, modulation of receptors, stabilization or destabilization of the neuronal cytoskeleton. However, uncontrolled hyperactivation of calpains leads to dysregulation of these processes causing neuronal death. PMID- 25272451 TI - [The ability of hamadryas baboons' adolescents to decide the modified Piaget's A not-B error test]. AB - We investigated the ability to the inhibition of a forced instrumental food procuring reflex in hamadryas baboons (Papio hamadryas). The subjects of the study were immature animals of the two age groups: the eighteen-month-old group (six males and five females) and three-year-old group (seven males and seven females). To determine the capability we used the modified Piaget's A-not-B error test. Four monkeys correctly decided the test only. The inhibition of the forced conditioned reflex occurred in females only and in the equal degree in each age group. The findings also show the big variation in an activity among the individuals of the different sex and age during the decision of the task. Regarding animals have shown the ability to inhibit consolidation of the conditioned reflex, we tend to treat it as a manifestation of conscious choice, but more research is needed. PMID- 25272452 TI - [Influence of environmental enrichment on parameters of behavior in open field test in the rats born from females with chronic alcoholization]. AB - The aim of this work was studying of morphology of a brain and the analysis of behavior at posterity of females of rats with a chronic alcoholic intoxication. As object of research were taken 60-day animals received from mothers with chronic alcoholic injury of hepatobiliary systems. During certain time (1.5 months) the part of animals grew in standard conditions, and another--in the "enriched" environment. The behavior analysis was spent in the open field test. Also was carried out research of a thickness of a cortex and a molecular layer of a forebrain. Work included three series of experiments. It is established, that the posterity of mothers with chronic injury of the hepatobiliary systems is characterized by the lowered motorial and research activity, increased by emotional reactivity that is accompanied by changes of structure of a cortex. The long finding of "alcoholic" animals in the "enriched" environment within 1.5 months promoted increasing of motorial and research activity, emotional reactance, change of structure of a cortex. PMID- 25272453 TI - [Differences of activations in visual and associative zones during figurative and verbal activity]. AB - The study considers correlates of figurative and verbal tasks performance during attention paid to visual stimuli. There are 34 subjects (20 female, mean age 21, 2.5 [SD]) took parts in the study. During subjects performance of the task, there was carried out EEG registration from 19 sites according to 10-20%. Performance of the figurative creative task in comparison with control non-creative task of the same modality was accompanied by activation of occipital and parietal zones of the cerebral cortex (decrease of EEG spectral power in alpha 1 (7.5-9.5 Hz) and alpha2 (10-12.5 Hz) frequency bands was observed) whereas performance of a verbal creative task in the similar test-control comparison was accompanied by decrease of activation in occipital zones (revealed through increase of EEG spectral in alphal and alpha2 frequency bands). As visual stimuli were shown during the whole time of the creative and control tasks fulfilment was made an assumption observed distinction can be connected with redistribution of attention focus at various types of creative activity (figurative or verbal). PMID- 25272454 TI - [The special role of inducible NO-synthase in the mechanism of rat coronary vessels tone regulation during immobilization stress, combined with diabetes mellitus]. AB - Persistent hyperglycemia after intraperitoneal injection of streptozocin (50 mg/kg) to the rats prevents decrease of coronary vessels myogenic tone and myocardial contractility during subsequent 6-hr immobilization stress. The intensity of these abnormalities in all experimental groups is significantly reduced with the supplement of the perfusate with inducible NO-synthase (iNOS) selective blocker S-methylisothiourea. Similar rise of the NO2-/NO3- concentration in the rats' blood after "stress", "diabetes mellitus" and "diabetes mellitus + stress" combines with an increase of iNOS transcripts in the myocardium to 6, 5.8 and 51 times compared with control. These data testify to a substantial modification of the cells from coronary vessels in the presence of marked and persistent hyperglycemia. Inducible NO-synthase uncoupling caused by excessive formation of the reactive oxygen and nitrogen species in the myocardium may be one of number mechanisms responsible for such phenotypic vascular alteration in the "stress + diabetes mellitus" group. PMID- 25272455 TI - [Influence exogenous nicotinamide adenine dinucleotide (NAD+) on contractile and bioelectric activity of the rat heart]. AB - This study is aimed to the investigation of the nicotinamide adenine dinucleotide (NAD+) effects and mechanisms of action in a heart. NAD+ (mcM) induces multiphase alternation of contractile activity of isolated rat heart: short positive inotropic action is followed by a negative inotropic phase. NAD+ (1-100 mcM) induces decreasing of action potential duration (APD) in rat atrial myocardium (from 45 +/- 0.82 ms in control experiments to 39 +/- 1.05 (n = 8) and 32 +/- 2 (n = 8) during application of 10 and 100 mcM of NAD+, respectively). Significant APD increase (from 45 +/- 0.82 ms to 74 +/- 1.89 (n = 8) ms) was observed during washing out of NAD+ (100 mcM). ATP or adenosine was unable to increase APD both during application or washing out. NAD+ induced APD decrease was not suppressed by P1-antagonist theophylline. P1-purinoreceptor and metabolite independent direct action of NAD+ in rat heart is suggested. Activation of P2X or P2Y receptors, cyclic ADP-ribose accumulation in cardiomyocytes is proposed as a main mechanism of NAD(+)-induced effects in the heart. PMID- 25272456 TI - [The influence of melatonin on the content of lipid peroxidation metabolites and antioxidant enzyme activity in the liver of rats after immobilization]. AB - The modeling of acute immobilization stress caused the increase of the content of lipid peroxidation metabolites and the decrease of the activity of superoxiddismutase and catalase in liver tissue within 4 days after stress. Melatonin in dose 0.2 mg/kg had a weak antioxidant effect and increased superoxiddismutase activity. The injection of melatonin in dose 1.0 mg/kg caused the significant decrease of lipoperoxidation metabolites content in liver tissue 39 hours after stress. On fourth and seventh days of the experiment there were no differences in malonic dyaldehyde content between these animals and naive ones. The concentration of acylhydroperoxides was significantly less than in control and naive groups at these days. The activity of superoxiddismutase and catalase was significantly more than in control rats at the fourth day after stress. PMID- 25272457 TI - [Testicular testosterone production in male mice of inbred strains PT and CBA/Lac after a long-term period of stable social hierarchy]. AB - Social dominance can alter testicular testosterone production, although there is pronounced variability in the relationship between social status and pattern of the testosterone response. The study designed to investigate how a long-term period of stable social hierarchy effects on testicular testosterone production in male mice of inbred strains PT and CBA/Lac. Paired males of different genotypes were housed together for 32 days beginning 38 day of age. Dyadic interactions of males generated dominance-subordination relationships during the first day after a social group has been produced and the social rank of each opponent was assessed by asymmetry in agonistic behaviour. Serum level of testosterone and its testicular content were evaluated in male mice of both inbred strains at 70 day of age after pair housing. Control animals were age- and genotype-matched single males that were housed in conventional cages. After a long-term period of pair housing, the serum testosterone level and its testicular content in males of both PT and CBA/Lac strains were not significantly different from the control. There were no significant differences in androgenic parameters between social ranks in male mice of both strains. The results indicate that in laboratory mice the pattern of testicular testosterone response to social hierarchy determined by a social situation, for example, a stability of social interactions, when the importance of aggressive competition for rank is minimal. PMID- 25272458 TI - [The time course of experimentally altered thyroid status manifestations in female C3H-A mice]. AB - The female C3H-A mice with agouty fur color were used to model hyper- and hypothyroidism in the long lasting experiment. The study was carried out for 44 weeks. Hyperthyroidism was induced by the administration of the L-thyroxine injections on alternate days during the whole period of the investigation. Hypothyroidism was achieved by adding propylthiouracil to the drinking water. The change of thyroid state was characterized by biphasic change in body weight. At the beginning of the experiment the hypothyroid animals were retarding by their weight. Otherwise the hyperthyroid animals were advancing by their weight. But since the 18th-21st week the initial trends changed, i. e. the hypothyroid mice body weight started ahead the hyperthyroid one. In the open field test both hypo- and hyperthyroid animals demonstrated the higher level of the investigating activity in comparison with the euthyroid mice. In the hyperthyroid mice the frequency of side-activity acts (grooming) increased significantly. Thus, the hyperthyroid animals appeared to be more anxious. To the 18th week of the experiment the animals of study groups started to demonstrate the apparent visual difference in their fur color. The hyperthyroid mice fur color became darker than one of the hypothyroid and the euthyroid mice. It is worthy of note that the hyperthyroid mice fur color was getting lighter than one of the euthyroid animals. The results are discussed in the context of hypothalamic-pituitary thyroid axis functioning. The possible mechanisms of hormonal regulation of the fur color in mice are considered to include the hypothalamic-pituitary-thyroid axis hormones activities. PMID- 25272459 TI - [Electrophysiological mechanisms of spinal systems plasticity in people with dysfunctions of the locomotor system]. AB - The reflex motor responses of some bilateral muscles of hip, shin and foot were evoked by percutaneous surface electrical spinal cord stimulation at the lumbosacral levels (T11-L3) in the patients with marked lumbosacral radiculopathy caused by spinal osteochondrosis and in neurologically healthy physically inactive individuals, as well as in healthy qualified athletes and athletes with knee joint injuries. There was used the technique of registration of posterior root-muscle reflexes. In the subjects with neurologic pathology and in the group of athletes with knee joint injuries the data demonstrated similar signs of plasticity of spinal neural circuits, innervating the muscles of the low extremities. PMID- 25272460 TI - Ultrastructural study of protective envelopes in Dioecocestus asper (Cestoda: Dioecocestidae) megalocercus. AB - The megalocercus of Dioecocestus asper (Mehlis 1831) from the haemocoele of dragonfly larvae possesses two envelopes: outer (exocyst) and inner (endocyst) ones. The exocyst contains the large endocyst and larval strobila with scolex attached to the latter. Outer and inner surfaces of these envelopes are organized as the tegument and have some structural differences. The exocyst is covered with slender microvilli. Its outer tegument contains numerous mitochondria; the inner one is filled with lipid droplets released into the exocyst's cavity. The well developed protonephridial (excretory) system consisting of flame cells, collecting ducts and canals is the unique feature of the exocyst, noted for the first time. Thick (more, then 50 microm) distal cytoplasm of the outer tegument of the endocyst is the place of accumulation of uniform globules looking like a hyaloid layer. This outer layer together with underlying fibrous layer (up to 20 microm), apparently, protect the scolex and larval strobila during the transfer through feather clump in the stomach of grebes, definitive hosts of D. asper. Muscle cells of both envelopes retain their synthetic activity even in the fully developed metacestode. Probably, they are the main structural element, which produces fibers of the extracellular matrix and maintains the integrity of protective envelopes of the megalocercus. PMID- 25272461 TI - [Fleas of small mammals from the northeastern Russian Far East]. AB - Results of the study of fleas (Siphonaptera) collected from small mammals (insectivores and rodents) in the Russian Far East (Magadan Province, and Khabarovsk and Kamchatka Territories) are represented. Fourteen flea species were revealed in 17 species of small mammals. PMID- 25272462 TI - Co-adaptation mechanisms in plant-nematode systems. AB - The review is aimed to analyze the biochemical and immune-breaking adaptive mechanisms established in evolution of plant parasitic nematodes. Plant parasitic nematodes are obligate, biotrophic pathogens of numerous plant species. These organisms cause dramatic changes in the morphology and physiology of their hosts. The group of sedentary nematodes which are among the most damaging plant parasitic nematodes cause the formation of special organs called nematode feeding sites in the root tissue called syncytium (cyst nematodes, CN; Heterodera and Globodera spp.) or giant cells (root-knot nematodes, RKN; Meloidogyne spp.). The most pronounced morphological adaptations of nematodes for plant parasitism include a hollow, protrusible stylet (feeding spear) connected to three esophageal gland cells that express products secreted into plant tissues through the stylet. Several gene products secreted by the nematode during parasitism have been identified. The current battery of candidate parasitism proteins secreted by nematodes to modify plant tissues for parasitism includes cell-wall-modifying enzymes, multiple regulators of host cell cycle and metabolism, proteins that can localize near the plant cell nucleus, potential suppressors of host defense, and mimics of plant molecules. Plants are usually able to recognize and react to parasites by activating various defense responses. When the response of the plant is too weak or too late, a successful infection (compatible interaction) will result. A rapid and strong defense response (e. g. due to the presence of a resistance gene) will result in the resistant (incompatible) reaction. Defense responses include the production of toxic oxygen radicals and systemic signaling compounds as well as the activation of defense genes that lead to the production of structural barriers or other toxins. PMID- 25272463 TI - [Genetic diversity of the tick-borne encephalitis virus in Ixodes persulcatus ticks in northeastern European Russia]. AB - The genetic diversity of the tick-borne encephalitis virus (TBEV) in the PCR positive Taiga ticks collected in the Republic of Komi in 2010 was evaluated. The analyses of nucleotide sequences of the 5'-NCR fragments of viral genome from ticks had shown that 13 isolates of TBEV from 16 sequencing variants were represented by the highly pathogenic Far Eastern genotype of the TBEV and only 3 isolates were identified as the Siberian genotype of TBEV. The nucleotide sequences of 5'-NCR of viral genome strongly varied variable in individual ticks. Variability for the A1 element has been observed in all the tested samples, and for elements C1, B2, CS B--in more than 50%. A2 element and ATG codon of the 5' NCR remained completely conservative. Computer simulation of conformations of the 5'-NCR of TBEV genome demonstrated the possibility of significant changes of the spatial structure of the 5'-NCR of viral genome in individual taiga ticks. The obtained data confirm the hypothesis that the variability in the 5'-NCR of TBEV genome can be crucial for efficient replication of TBEV in different hosts. PMID- 25272464 TI - [Contribution to the black fly fauna of the subfamily Prosimuliinae (Diptera: Simuliidae) of the Sakha Republik (Yakutia)]. AB - Examination of river basins of Yakutia and the study of the previously collected material resulted in revealing of 34 species of the subfamily Prosimuliinae belonging to 8 genera (Gymnopais, Prosimulium, Helodon, Stegopterna, Greniera, Cnephia, Metacnephia, and Sulcicnephia). The fauna of Yakutia was supplemented with two black fly species Cnephia angarensis Rubzov, 1956 and Gymnopais frontatus Yankovsky, 1982. The distribution of the species Prosimulium tridentatum, Helodon alpestris, H. irkutensis, H. rubicundus, Stegopterna asema, and Cnephia lyra) was clarified. The combined table of species distribution with GPS coordinates of collecting sites has been composed. PMID- 25272465 TI - [The data on helminth infestation of the Siberian tree frog (Rana amurensis Boulenger, 1886) in the western boundary of the range]. AB - Helminth species composition and infection rates of the Siberian tree frog Rana amurensis in Western Siberia were studied. Four species of helminthes--nematodes Rhabdias bufonis, Oswaldocruzia filiformis, Cosmocerca ornata and the trematode Haplometra cylindracea were found. Prevalence of helminths in the Siberian tree frog is 100%, and mean abundance is 27.5 +/- 4.8. Helminth species richness in the Siberian tree frog in the western periphery of their distribution area is lower than in the center of the range, in Yakutia and Transbaikalia, and is approximately equal to that in the northeastern boundary of the range, in Magadan Province. R. bufonis, a highly pathogenic nematode species, dominates in prevalence and abundance in the Siberian tree frog in Western Siberia as well as in other parts of the geographical range of this species. PMID- 25272466 TI - Ethics, dentistry and business. PMID- 25272467 TI - Mouth, Head and Neck Cancer Awareness Campaign in Ireland. PMID- 25272468 TI - Swapping scrums for scrubs. PMID- 25272469 TI - Ethics and dentistry. PMID- 25272470 TI - Reading a panoramic radiograph. PMID- 25272471 TI - Management of primary molar infraocclusion in general practice. AB - Statement of the problem: Infraoccluded primary molars can be managed in general dental practice but clinicians need to understand when intervention is necessary. PURPOSE OF THE STUDY: To review the current literature on infraocclusion in primary molars, and to demonstrate diagnosis and management strategies for general dental practitioners. METHODS AND MATERIALS: Current literature was sourced via PubMed search using multiple key words. Relevant articles are summarised within the article. Different management strategies will be illustrated using a section of cases of differing severities and age at diagnosis. All interventions, including conservative management, restorative, and surgical management will be reviewed. The importance of early diagnosis, continued monitoring, and interdisciplinary team work will be emphasised. RESULTS: Infraocclusion of primary molars is a common clinical finding, which can be diagnosed both clinically and radiographically. The severity of infraocclusion is classified according to the relationship of the occlusal surface of the tooth relative to adjacent teeth. The age of the child at diagnosis and rate of infraocclusion play a pivotal role in case management. The majority of primary molar teeth exfoliate naturally when the permanent successor is present, however active intervention may be required in some cases. Possible management techniques include extraction, restoration, and luxation of these teeth. CONCLUSIONS: All children in the mixed and primary dentition should be assessed for infraocclusion of primary molars, particularly mandibular molars. Accurate dental records are essential to assess the severity and monitor the rate of progression of infraocclusion so that the condition can be appropriately managed. PMID- 25272472 TI - Handling a complaint after patient has moved. PMID- 25272473 TI - English as a barrier. PMID- 25272474 TI - 2013 Hannah lecture. Disasters, nursing, and community responses: a historical perspective. PMID- 25272475 TI - 2013 Eleanor Krohn Herrmann lecture. The most admired woman in the world: forgetting and remembering in the history of nursing. PMID- 25272476 TI - Ellen N. La Motte: the making of a nurse, writer, and activist. AB - This article examines the early career of Ellen N. La Motte (1873-1961) to trace how her training at the Johns Hopkins Training School for Nurses and years spent as a tuberculosis nurse in Baltimore shaped her perception of tuberculosis prevention and women's suffrage. Although studies of tuberculosis have frequently alluded to her work, no sustained biocritical discussion of her development as a nurse and scholar exists. Between 1902, when she graduated from nursing school, and 1914, the start of the Great War, La Motte published a textbook and dozens of articles in journals devoted to nursing and social reform and delivered many speeches at local, regional, and national meetings. In addition, as her reputation as an expert in the field of tuberculosis nursing grew, her advocacy for the vote for women increased, and she used her writing and speaking skills on behalf of the suffrage cause. This article assesses how the skills La Motte acquired during these years helped mold her into a successful and respected nurse, writer, and activist. PMID- 25272477 TI - Negotiating relationships of power in a maternal and child health centre: the experience of WHO nurse Margaret Campbell Jackson in Iran, 1954-1956. AB - From November 1954 to November 1956, Canadian nurse Margaret Campbell Jackson was employed by the World Health Organization (WHO) and was stationed in Tehran, Iran, where she participated in the establishment of a Maternal and Child Health (MCH) Centre. The objective of the project, known as Iran 10, was twofold: to set up a health service for mothers and children and to initiate a field training program for Iranian physicians, nurses, and other health care providers. Drawing on 180 letters Jackson wrote to her family in Canada from Iran, this article analyzes the MCH Centre as a contact zone and considers the relationships Jackson developed with staff affiliated with the project. The Centre became a space of cross-cultural encounters, where locally and foreign-trained Iranian staff and expatriates mingled and shared working relationships. I argue that authority was negotiated and contested through interactions and associations that were often unequal and framed by notions of progress, modernization, race, and health. Personality also played an important role. PMID- 25272478 TI - Signe Skott Cooper, RN, MEd, FAAN: January 29, 1921-July 16, 2013. PMID- 25272479 TI - [Clinical implication of urinary protein markers in diabetic nephropathy and interventional effects of Chinese herbal medicine]. AB - In clinic, some urinary protein makers can dynamically and noninvasively reflect the degree of renal tubular injury in patients with diabetic nephropathy (DN). These urinary biomarkers of tubular damage are broadly divided into two categories. One is newfound, including kidney injury molecule-1 (Kim-1), neutrophil getatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP) and cystatin C (CysC); the other one is classical, including beta2 microglobulin (beta2-MG), retinal binding protein (RBP) and N-acetyl-beta-D glucosaminidase (NAG). It is reported that, the increases in urinary protein markers are not only closely related to the damage of tubular epithelial cells in DN patients, but also can be ameliorated by the treatment with Chinese herbal compound preparations or Chinese herbal medicine. Recently, although urinary proteomics are used in the protein separation and identification, the traditional associated detection of urinary protein markers is more practical in clinic. At present, it is possible that the associated detection of urinary biomarkers of glomerular and tubular damages may be a feasible measure to reveal the clinical significance of urinary protein markers in DN patients and the interventional effects of Chinese herbal medicine. PMID- 25272480 TI - [Application of chemometrics in composition-activity relationship research of traditional Chinese medicine]. AB - Chemometrics is a new branch of chemistry which is widely applied to various fields of analytical chemistry. Chemometrics can use theories and methods of mathematics, statistics, computer science and other related disciplines to optimize the chemical measurement process and maximize access to acquire chemical information and other information on material systems by analyzing chemical measurement data. In recent years, traditional Chinese medicine has attracted widespread attention. In the research of traditional Chinese medicine, it has been a key problem that how to interpret the relationship between various chemical components and its efficacy, which seriously restricts the modernization of Chinese medicine. As chemometrics brings the multivariate analysis methods into the chemical research, it has been applied as an effective research tool in the composition-activity relationship research of Chinese medicine. This article reviews the applications of chemometrics methods in the composition-activity relationship research in recent years. The applications of multivariate statistical analysis methods (such as regression analysis, correlation analysis, principal component analysis, etc. ) and artificial neural network (such as back propagation artificial neural network, radical basis function neural network, support vector machine, etc. ) are summarized, including the brief fundamental principles, the research contents and the advantages and disadvantages. Finally, the existing main problems and prospects of its future researches are proposed. PMID- 25272481 TI - [Advance in studies on neuroprotective mechanism of Uncariae Ramulus Cum Uncis]. AB - The Uncariae Ramulus Cum Uncis is a commonly used traditional Chinese medicine. In recent years, many studies have revealed its prominent neuroprotection function. The active ingredients in Uncariae Ramulus Cum Uncis could protect the nervous system in a multi-path and multi-target manner. Uncariae Ramulus Cum Uncis shows the neuroprotective effect by resisting oxidation, scavenging free radicals, modulating neurotransmitters and their related receptors, regulating the inflammatory factors and their related pathways, attenuating neuron apoptosis, reducing intracellular Ca2+ overloads and mitigating neurodegeneration. In this paper, the authors summarized the advance in studies on neuroprotective mechanisms of Uncariae Ramulus Cum Uncis. PMID- 25272482 TI - [Investigation and analysis of heavy metal pollution related to soil-Panax notoginseng system]. AB - OBJECTIVE: In this study, five heavy metals contamination of soil and different parts of Panax notoginseng in the plantation area was investigated. Analysis of heavy metals correlation between the planting soil and P. notoginseng; and the absorption and accumulation characteristics and translocation of soil heavy metals by P. notoginseng plants was revealed. METHOD: Through field investigation and laboratory analytical methods, analysis of China's 30 different soil P. notoginseng origin and content of heavy metals in five different parts of the P. notoginseng plant content of heavy metals. RESULT: The results revealed that the soil heavy metals should not be neglected in the plantation area Referring to the national soil quality standards (GB15608-1995), the excessive degree of soil heavy metals pollution showed Hg > As > Cd > Cr in the plantation area, and Pb content of soil was in the scope of the standard. Refer to 'Green Industry Standards for Import and Export of Medical Plants and Preparations', the excessive degree of heavy metals content of P. notoginseng plants showed As > Pb > Cr > Cd, and Hg content of plants was in the scope of the standard. Concentrations of five heavy metals of underground parts of P. notoginseng plants are higher than aboveground, and heavy metals elements are more concentrated in the root, followed by the rhizome of P. notoginseng plants. Heavy metal accumulation characteristics of the different parts of the P. notoginseng of the overall performance is the root > the rhizome > the root tuber > leaves > stems. From the point of view BCF value analysis of various parts of the P. notoginseng plants to absorb heavy metals in soil, BCF values of all samples were less than 1, description P. notoginseng not belong Hyperaccumulator. From the view of transportation and related analysis of the soil-P. notoginseng systems, the rhizome of P. notoginseng and the content of As and Cr in soil was significantly correlated, the root of P. notoginseng and the content of Cd in soil was significantly correlated, and no significant correlation between the other indicators. Through the analysis of transportation transfer coefficient showed: Pb, As and Cr are not easy to transport aboveground part from the underground, but Cd and Hg are relatively easy to transport stems from rhizome, the migration of five heavy metals in the aerial part is relatively strong, and heavy metal of stems is easily transported to the leaves. CONCLUSION: P. notoginseng does not belong to the enrichment of heavy metals in crops, especially for Hg in soil with strong patience. In survey area, the content of heavy metals of P. notoginseng's planting soil is relatively high, and the heavy metals As, Pb, Cr, Cd of P. notoginseng also exist heavy metals exceeded problems. Due to the presence of heavy metals in crops internal absorption and translocation of special laws, accumulation of heavy metals varied significantly in different parts of P. notoginseng. The overall, the performance for the heavy metal content of the underground parts is more than aboveground, it explain heavy metals of P. notoginseng plants is still the main source of the soiL Therefore, the key to control of planting area soil environmental quality and reduce exogenous harmful substances secondary pollution of soil in the cultivation process are to study and solve the heavy metals pollution problem of P. notoginseng. PMID- 25272483 TI - [Effects of Ca2+ on photosynthetic parameters of Pinellia ternata and accumulations of active components in heat stress]. AB - OBJECTIVE: To study the effect of exogenous Ca2+ on photosynthetic parameters of Pinellia ternate and accumulations of active components under high temperature stress. METHOD: The pigment contents of P. ternata leaves, photosynthesis parameters and chlorophyll fluorescence parameters of P. ternata leaves, the contents of guanosine, adenosine and polysaccharide in P. ternata tubers were measured based on different concentrations of exogenous Ca2+ in heat stress when the plant height of P. ternata was around 10 cm. RESULT: The contents of total chlorophyll and ratio of chlorophyll a/b were relatively higher by spaying Ca2+. Compared with the control, spaying 6 mmol x L(-1) Ca2+ significantly enhanced the net photosynthetic rate (Pn), transpiration (Tr) and stomatal limitation (L8), but reduced intercellular CO2 concentration (C) in P. ternata leaves. With the increase of Ca2+ concentration, maximal PS II efficiency (Fv/Fm), actual photosynthetic efficiency (Yield) and photochemical quenching coefficient (qP) initially increased and then decreased, however, minimal fluorescence (Fo) and non-photochemical quenching coefficient (NPQ) went down first and then went up. The contents of guanosine and polysaccharide and dry weight of P. ternata tubers showed a tendency of increase after decrease, and the content of adenosine increased with the increase of Ca2+ concentration. The content of guanosine and polysaccharide in P. ternata tubers and its dry weight reached maximum when spaying 6 mmol x L(-1) Ca2+. CONCLUSION: With the treatment of calcium ion, the inhibition of photosynthesis and the damage of PS II system were relieved in heat stress, which increased the production of P. ternata tubers. PMID- 25272484 TI - [In situ investigation to three dimensional structures of Chinese medicines seeds]. AB - This paper is aimed to microscopic identification of traditional Chinese medicines (TCMs) using an in situ imaging method. In this study, two kinds of Zingiberaceae seeds, Amomi Rotundus Fructus and Alpiniae Katsumadai Semen, were investigated by synchrotron radiation in-line X-ray phase-contrast computed tomography (IXPCT) imaging method. The results showed that the microstructures of these Zingiberaceae seeds could be clearly obtained from the virtual slices information in different observing angles. It proves that IXPCT is an effective imaging method, which can provide the imaging information for the microscopic identification of the intact TCMs in situ and non-destructively. PMID- 25272485 TI - [Fermentation of Bacillus subtilis ge25 strain and preliminary study on its antagonistic substances]. AB - Panax ginseng is one of the most important traditional Chinese herbal medicine, soil borne diseases influenced the yield and quality severely. In our previous work, endophytic Bacillus subtilis ge25 strain was isolated from ginseng root, and which showed significant antagonistic activity against several most destructive ginseng phytopathogens. In the present work, crude protein and lipopeptid extracts were prepared from LB and Landy supernate by salting out, acid precipitation methods respectively. The antagonistic activity of crude extracts and stability to temperature and protease digestion were examined by ginseng phytopathogen Alternaria panax. Results showed that, the antagonistic activity of crude protein extracts from LB culture was complete and partially lost when treated by high temperature and proteinase K. However, crude lipopeptid from Landy culture showed significant stabile antagonistic activity to them. Acid hydrolyzation and TLC-bioautography analysis showed, that the crude lipopeptide contained at least one cyclic lipopeptide. In consideration of the stability and perfect antagonistic activity of ge25, further researches will promote the biocontrol of ginseng diseases in the field. PMID- 25272486 TI - [Anatomical characteristics of laminae and petioles of 11 species of Salvia and their taxonomic significance]. AB - Anatomical features of the lamina and petiole of 11 species of Salvia had been compared. The microstructures of 11 species of Salvia were observed by paraffin method, and indexes such as the epidermis, xylems and phloems were measured. The data set was analyzed by principal components analysis method and cluster analysis method. The results indicated that the laminae of 11 species of Salvia were bifacial leaf, and the surface of laminae and petioles were covered with villous. The upper epidermis and lower epidermis of the laminae of 11 species of Salvia were constituted by a dense cuticular layer without stratum corneum. Differences existed in the structure of cross sectio mn of laminae and petioles of 11 species of Salvia. Among them, upper epidermal thickness of nine different micromorphological characters could serve as one of the criteria to identify species of taxonomic Salvia. The identification of genetic relationship of these characters in Salvia were discussed in the paper to provide an evidence of anatomy in Salvia. PMID- 25272487 TI - [Optimum harvest study of Gentiana crassicaulis in Ludian]. AB - The paper is aimed to study the difference in yield and quality at different harvest time and determine the optimum harvest of planting Gentiana in Ludian traditional harvest period. The authors analyzed the variation in fresh weight, dry weight, dry discount rate, length, diameter, volume and the content of gentiopicroside, loganin acid, alcohol-soluble extract and total ash and made a comprehensive appraisal of yield, appearance quality and intrinsic quality by gray relational distance ideal Comprehensive Evaluation method. The results showed that there is a big difference in yield and quality both 2-year-old and 3 year-old Gentiana harvested in traditional harvest period and the comprehensive evaluation more better when harvested more later. It can be seen, Gentiana harvested the later had a better yield and quality in Ludian traditional harvest period. The harvest of Gentiana can be appropriate delayed depending on the particular circumstances of production. PMID- 25272488 TI - [Optimization of synthetic pathway and fermentation process of yeast cell factories for production of oleanoic acid]. AB - OBJECTIVE: To optimize the synthetic pathway and fermentation process of yeast cell factories for production of oleanoic acid. METHOD: Using the DNA assembler method, one copy of Glycyrrhiza glabra beta-amyrin synthase (GgbAS), Medicago truncatula oleanolic acid synthase (MtOAS) and Arabidopsis thaliana cytochrome P450 reductase 1 (AtCPR1) genes were introduced into Saccharomyces cerevisiae strain BY-OA, resulting in strain BY-20A. YPD medium with different glucose concentration were then used to cultivate strain BY-2OA. RESULT: Increasing gene copies of GgbAS, MtOAS and AtCPR1 resulted in increased beta-amyrin and oleanolic acid production. The strain BY-2OA produced 136.5 mg x L(-1) beta-amyrin and 92.5 mg x L(-1) oleanolic acid, which were 54% and 30% higher than the parent strain BY-OA. Finally, the titer of oleanolic acid increased to 165.7 mg x L(-1) when cultivated in YPD medium with 40 mg x L(-1) glucose. CONCLUSION: Production of oleanoic acid increased significantly in the yeast strain BY-2OA, which can provide the basis for creating an alternative way for production of oleanoic acid in place of extraction from plant sources. PMID- 25272489 TI - [Study on release kinetics for gel of Aconitum brachypodum based on nonlinear mixed effect model]. AB - OBJECTIVE: To establish the analytical method for the release kinetic (RK) of Aconitum Brachypodum gel based on the nonlinear mixed effect model (NLMEM), in order to rationally evaluate the drug release process and explain the release mechanism. METHOD: The zero-order kinetic model containing for non-corroded drug system with the random effect was taken as the base model. The fixed effect and random effect factors impacting the drug release were analyzed by PROC NLMIXED of SAS to establish the final typical model. Subsequently, 10 training subsets were randomly extracted from the primary data to respectively their RK models, calculate the corresponding predicted root-mean-square error and average relative error, and evaluate the model stability and prediction accuracy. RESULT: The burst effect F0 had a very significant effect on the RK model. Among the component factors, carbopol 940 showed an obvious effect on the inherence release speed constant k0 and the concentration gradient change constant a, with different variations on the basis of dosage range. The random effect factors of k0 and a had a significant impact. The final RK model was proved to be stable, effective and reliable in the cross validation. CONCLUSION: The drug release kinetic analysis method could be used to rationally evaluate the drug release process and explain the release mechanisms. PMID- 25272490 TI - [Analysis of variation of coumarin and volatile compounds in Angelica Dahuricae radix in different drying methods and conditions]. AB - To explore the effect of different processing methods and conditions of coumarin and volatile compounds in Angelica Dahuricae Radix and their change regularity, in order to optimize and establish appropriate drying methods and conditions. After being cleaned, fresh Angelica Dahuricae Radix herbs were baked, sun-dried, shade-dried, sun-dried after sulfur-fumigation, dried by quick-lime embedding, freeze-dried, microwave-dried. Finally, 24 groups of samples were obtained after being mashed and passing through the 60-mesh screen. The HPLC-PDA method was adopted to simultaneously determine the content of coumarin compounds. The GC-MS method was used to determine the content of volatile compounds. The principal component analysis (PCA) was made on the standardized analysis results for the 24 groups of samples processed with different drying methods. According to the PCA results, the comprehensive scores of coumarin and volatile compounds in Angelica Dahuricae Radix herbs processed with different methods in the order from high to low were that unpeeled and dried by quicklime embedding > unpeeled and dried with hot-air at 100 degrees C > unpeeled and dried with hot-air at 40 degrees C > peeled and infrared-dried > peeled and dried with hot-air at 60 degrees C > peeled and dried with hot-air at 40 degrees C > peeled and sun-dried > peeled and dried with hot-air at 60 degrees C > peeled and dried with hot-air at 100 degrees C > peeled and microwave-dried > peeled and dried with hot-air at 80 degrees C > unpeeled and sun-dried > unpeeled and dried with sulfur-fumigation > peeled and dried with sulfur-fumigation > unpeeled and dried with hot-air at 120 degrees C > unpeeled and freeze-dried > unpeeled and infrared-dried > peeled and dried with hot-air at 120 degrees C > peeled and freeze-dried > peeled and dried by quicklime embedding > unpeeled and dried with hot-air at 80 degrees C > peeled and shade-dried > unpeeled and shade-dried > unpeeled and microwave-dried. According to the findings, different drying processing methods have certain impacts on the content coumarin and volatile compounds in Angelica Dahuricae Radix herbs. The traditional method of drying by quicklime embedding is recommended as the optimum origin processing method of Angelica Dahuricae Radix, which is followed by the method for being peeled and dried with hot-air at 100 degrees C. PMID- 25272491 TI - [Dynamic predictive modeling of extraction process for red ginseng using near infrared spectroscopy]. AB - It is the objective of this study to develop dynamic predictive model for the extraction process of red Ginseng using NIR spectroscopy. NIR spectroscopy was collected online and PLSR models were developed for total quantity of ginsenosides. The performance of NIR prediction model achieved R, RMSEC, RMSEP of 0.996 09, 0.018 9, 0.016 8, respectively. A first order dynamic mass transfer model was combined with NIR prediction of the quality indicator to predict the trajectory of the extraction process based upon the initial 3 or 4 data points. The results showed good agreement with actual measurements indicating reasonable accuracy of the predictive model. It could potentially be used for advanced predictive control of the extraction process. PMID- 25272492 TI - [Influence of different processing methods on Lonicerae Japonicae Flos from Donghai cultivation base in Jiangsu province]. AB - To study the impact of five different origin processing methods, namely natural drying, drying in baking shop, drying by microwave heating, drying in drum and drying with sulphur fumigation, on the quality of Lonicerae Japonicae Flos from Donghai cultivation base in Jiangsu Province, with the contents of chlorogenic acid and galuteolin and the similarity in HPLC fingerprints as the evaluation indicators. The results showed that different origin processing methods had significant impact on the content of chlorogenic acid and the similarity in HPLC fingerprints, but with no significant difference on the content of galuteolin. By means of drying by microwave heating and drying in drum, the samples showed higher contents of chlorogenic acid, respectively 3.67% and 3.39%. The similarities of HPLC fingerprints were 0.815 and 0.793, respectively. By means of the drying in baking shop and the drying with sulphur fumigation, the contents of chlorogenic acid in the samples were 2. 87% and 2. 53% , respectively. The similarities of HPLC fingerprints were 0.964 and 0.765, respectively. The lowest content of chlorogenic acid in naturally dried samples was 1.92%. The similarity of HPLC fingerprints was 0.940. According to the findings as well as the internal control standards for Lonicerae Japonicae Flos herbs of Jiangsu Kanion Pharmaceutical Co. , Ltd. , the optimum processing method for Lonicerae Japonicae Flos from Donghai cultivation base was the drying in baking shop. This study provided a theoretical basis for determining the processing method for Lonicerae Japonicae Flos from Donghai cultivation base of Jiangsu Province. PMID- 25272493 TI - [A new neolignan from fruit of Solanum torvum]. AB - One new neolignan identified as 2, 3-( trans) -dihydro-2-(4-hydroxy-3 methoxyphenyl) -3-[(beta-D-glucopyranosyloxy) methyl]-7-methoxybenzofuran-5 propenoic acid (1) and five known steroidal glycosides namely torvoside A(2), torvoside C(3), torvoside H(4), solanolactoside A (5), (25S)-6alpha-hydroxy 5alpha-spirostan-3-one-6-0-[alpha-L-rhamnopyranosyl-(1-->3-beta3)-beta-D-D quinovopyr-anoside] (6) were isolated from the fruits of Solanum torvum. Their structures were elucidated on the basis of 1D, 2D NMR and MS spectroscopic analysis. PMID- 25272494 TI - A new flavonone from seeds of Alpinia katsumadai and its neuroprotective effect on PC12 cells. AB - A new flavonone, named as (2R, 3S)-pinobanksin-3-cinnamate(1), together with six known compounds, pinocem-brin (2), pinobanksin (3), 3-O-acetylpinobanksin (4), galangin (5), kumatakenin(6), and 3-methylkaempferol (7), were isolated from a 95% ethanol extract of seeds of Alpinia katsumadai through a combination of various chromatographic techniques, including silica gel and Sephadex LH-20. The structure of compound 1 was elucidated by spectroscopic data analysis. Compound 1 exhibits a potent neuroprotective effect against the corticosterone-damaged PC12 cells, which may be underlying the effect by scavenging intracellular ROS. PMID- 25272495 TI - [Synthesis and protective effect of ligustrazine intermediates against CoCl2 induced neurotoxicity in differentiated PC12 cell]. AB - Ligustrazine, one of the major effective components of the Chinese traditional medicinal herb Ligusticum Chuanxiong Hort, has been reported plenty of biological activities, such as protect cardiovascular and cerebrovascular, neuroprotection and anti-tumor, et al. Because of its remarkable effects, studies on structural modification of ligustrazine have attracted much attention. Ligustrazine synthetic derivatives reported in recent decades are mainly derived from four primary intermediates (TMP-COOH, TMP-OH, TMP-NH2, HO-TMP-OH). To explore the neuroprotection activitiy of ligustrazine intermediates, six ligustrazine intermediates (2, 5, 8, 11, 12, 13) were synthesized and their protective effects against CoCl2-induced neurotoxicity in differentiated PC12 cells were studied. The target compounds were prepared via different chemical methods, including oxidation, substitution, esterification and amidation without changing the structure nucleus of ligustrazine. Compared with TMP (EC50 = 56.03 micromol x L( 1)), four compounds (2, 5, 12 and 13) exhibited higher activity (EC50 < 50 micromol x L(-1)) respectively, of which, compound 2 displayed the highest protective effect against the damaged PC12 cells (EC50 = 32.86 micromol x L(-1)), but target compounds 8 and 11 appeared lower activity (EC50 > 70 micromol x L( 1)). By structure-activity relationships analysis, the introduction of carboxyl, amino to the side chain of ligustrazine and appropriately increase the proportion of ligustrazine may contribute to enhance its neuroprotective activity, which provides a reference for the design, synthesis and activity screening of relevant series of ligustrazine derivatives in the future. PMID- 25272496 TI - [Lignans isolated from stems of Sambucus williamsii and their proliferation effects on UMR106 cells]. AB - The present study aims to investigate the lignan constituents from Sambucus williamsii and their proliferation effects on osteoblast-like UMR106 cells. Seven compounds were isolated and purified by macroporous resin D101, silica gel, Sephadex LH-20, Toyopearl HW-40, ODS column chromatographies and Preparative HPLC(C-18). Their structures were elucidated by spectroscopic methods as threo guaiacylglycerol-beta-0-4'-conifery ether (1), lirioresinol A (2), 1 hydroxypinoresinol (3), 5-methoxybalanophonin (4), balanophonin (5), 5-methoxy trans-dihydrodehydrodiconiferyl alcohol (6), and p-hydroxybenzaldehyde (7). Compounds 3-7 were obtained from this genus for the first time. The proliferation effects of all isolated compounds on osteoblast-like UMR106 cells were determined. Compounds 1-7 (1 x 10(-12)-1 x 10(-7) mol x L(-1)) increased UMR106 cell proliferation to some extent. PMID- 25272497 TI - [Chemical constituents from roots of Illicium majus]. AB - Ten compounds, including seven sesquiterpenes, two phenols and one phenylpropanoid, were isolated from the roots of Illicium majus by means of silica gel, ODS, Sephadex LH-20, and preparative HPLC. On analysis of MS and NMR spectroscopic data , their structures were established as cycloparviflorolide (1), cycloparvifloralone (2), tashironin (3), tashironin A (4), anislactone A(5), anislactone B (6), pseudomajucin (7), syringaldehyde (8), methyl-4-hydroxy-3, 5 dimethoxybenzoate (9), and (E)-3-methoxy-4,5-methylenedioxycinnamic alchol (10), respectively. Compounds 1-4 and 8-10 were first isolated from this plant. In the in vitro assays, at a concentration of 1.0 x 10(-5) mol x L(-1), compounds 5 and 6 were active against LPS induced NO production in microglia with a inhibition rate of 75.31% and 53.7%, respectively. PMID- 25272498 TI - [Simultaneous determination of seven constituents in Euodiae Fructus and two related species by HPLC]. AB - This study is to develop a HPLC method for quality evaluation of Euodiae Fructus and related species by simultaneous determination limonin, indole alkaloids (14 fomyldihydroxyrutaecarpine, evodiamine, rutaecarpine), and quinolone alkaloids [1 methyl-2-undecyl-4 (1H)-quinolone, evocarpine, dihydroevocarpine] in the fruits of five Evodia species. Samples were analyzed on a YMC C18 column (4.6 mm x 250 mm, 5 microm) eluted with mobile phases of acetonitrile (A), tetrahydrofuran (B), and a buffer solution of 5 mmol x L(-1) ammonium acetate (pH 3.8) (C) in a linear gradient mode. The column temperature was 30 degrees C and the flow rate was 1.0 mL x min(-1). The PDA detector wavelengths were set at 220 and 250 nm. The seven compounds were well separated and showed good linearity (r = 0.999 9) within the concentration ranges tested. The mean recoveries were between 96.7%-102.4% (RSD 1.4%-3.1%). Through the validation, the method was proved to be accurate and repeatable. All the seven constituents were detected in the fruits of five species, but the contents of them varied widely in different samples. The total contents of seven constituents in 16 batches of Euodiae Fructus were 9.46-69.9 mg x g(-1), and the mean content was 28.2 mg x g(-1). The total content of seven constituents in E. compacta and E. fargesii was 25.8, 7.69 mg x g(-1), respectively. PMID- 25272499 TI - [UPLC fingerprint spectra for discrimination of Aucklandiae radix and Vladimiriae radix]. AB - It's difficult to identify Aucklandiae Radix and Vladimiriae Radix because of their similar composition. In this paper, UPLC method was used to establish their UPLC fingerprint to identify them with the mobile of acetonitrile -0. 05% phosphoric acid water solution by gradient elution at the detection wavelength of 238 nm. Clustering analysis and principal components analysis showed that Vladimiriae Radix was significantly different from Aucklandiae Radix. Eight common peaks and twelve common peaks were defined respectively in Aucklandiae Radix and Vladimiriae Radix herbs by fingerprint analysis. Six of them were identified as syringoside, chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B, costunolide and dehydrocostuslactone by comparing with standard references. There are four peaks in all of Vladimiriae Radix samples and in none of Aucklandiae Radix samples. So UPLC fingerprint can be used to identify these two herbs. PMID- 25272500 TI - [Icariin promote maturation of osteoblasts in vitro by an estrogen-independent mechanism]. AB - OBJECTIVE: To investigate the estrogenic activity of icariin and genistein with estrogen-dependent human breast cancer (MCF-7) cells. METHOD: MCF-7 cells were incubated with media containing 5% charcoal dextran-treated FBS in phenol red free media for 48 h. CCK-8 kit was used to study the impact of defferent concentration of icariin and genistein on MCF-7 proliferation in vitro. Optimal concentration icariin and genistein were added into medium and total RNA was isolated after 12, 24, 36, 48 h. The gene expression of ERalpha, ERbeta, PS2, and PR were investigated by Real-time RT-PCR Total protein was also isolated and secretion of ERalpha, ERbeta, PS2, and PR were examined by Western blot. RESULT: 10 micromol x L(-1) icariin and genistein could promote the proliferation of MCF 7 evidently. However, the ability of genistein to promote the proliferation was better than icariin. With the concentration of 10 micromol x L(-1), genistein group had a stronger expression of ERa, PS2 and PR mRNA levels than icariin while ERbetaexpression had no significant difference in two group. The same effects were detected by western blotting. CONCLUSION: Both genistein and icariin have a strong estrogen-like effect, but the estrogenic activity of genistein is stronger than icariin. It showed that the activity of icariin is stron-ger than genistein to promote ROB maturation. So it must be that icariin promotes the maturation of osteoblasts in vitro by a estogen-independent mechanism. PMID- 25272501 TI - [Protective effect and action mechanism of petroleum ether extracts from Saussurea involucrate on brain tissues of hypoxia rats]. AB - OBJECTIVE: To investigate the protective effect and action mechanism of petroleum ether extracts from Saussurea involucrate on brain tissues of hypoxia rats under constant pressure and closed conditions. METHOD: The PESI dosage-dependent experiment for hypoxia rats was conducted under constant pressure and closed conditions by intraperitoneally injecting 125, 250, 500 mg x kg(-1) to finalize that the optimum dosage is the high dose of PESI. Afterwards, 90 Wistar rats were randomly divided into the hypoxic model group, the acetazolamide 250 mg x kg(-1) group and the PESI high dose group. Each group was further divided into three subgroups according to different hypoxia times, with 10 rats in each subgroup. Under the same hypoxia and administration conditions, the rats were sacrificed after 0, 3, 6 h respectively. Their brain samples were collected for common pathological observation and immunohistochemical staining of HIF-1alpha. Real time RT-PCR was used to detect HIF-1alpha, EPO, HO-1 and Caspase-3 gene expressions. And the Western blot assay was adopted to detect HIF-1alpha protein expression. RESULT: The brain tissues of the hypoxia model group were severely damaged with the increase in the hypoxia time. The acetazolamide group and the PESI high does group were damaged in a much lower degree. According to the gene expression and the Western blot assay, high dose of PESI could inhibit HIF-1alpha expression. According to the pure gene expression test, high dose of PESI could increase EPO and HO-1 mRNA expressions, but inhibit Caspase-3 mRNA expression. CONCLUSION: PESI's protective mechanism for brain tissues of hypoxia rats under constant pressure and closed conditions may be related to its effects in inhibiting HIF-1alpha expression, increasing EPO expression and resisting cell apoptosis. PMID- 25272502 TI - [Study on anti-oxidative effect of extracts from Cichorium endivia on HepG2 cells and its mechanism]. AB - OBJECTIVE: To investigate the protective effect of extracts from Cichorium endivia (CEE) in H2O2-induced HepG2 cell oxidative stress injury, and explore the antioxidant mechanism of CEE in HepG2 cells. METHOD: The viability of H2O2 induced HepG2 cells and the intracellular ROS level were measured by MTT assay and DCFH-DA fluorescence staining assay. The antioxidant-response element (ARE) Luciferase activity was tested in HepG2 cells stably transected by ARE reporter gene. The fluorescence quantitative RT-PCR was adopted to determine the mRNA expressions of genes containing ARE sequence in HepG2 cells. RESULT: The cell viability reduced, while the ROS level increased after HepG2 cells were treated by H2O2. Different concentrations of CEE could be added to significantly improve the above results. After HepG2 cells transected by ARE reporter gene were treated with different concentrations of CEE, the intracellular ARE activity could increase in a concentration-dependent manner. In addition, the mRNA expressions of regulatory genesGCLC, GCLM and HMOX-1 containing ARE sequence in HepG2 cells were up-regulated in a concentration-dependent manner by CEE. CONCLUSION: CEE inhibited the H2O2-injured HepG2 cells by reducing the ROS level. CEE's antioxidant mechanism for HepG2 cells may be closely related to the antioxidant defense system associated with its effect of activating Nrf2-ARE pathway in HepG2 cells. PMID- 25272503 TI - [Effects and mechanisms of punicosides on acute alcoholic liver damage in mice]. AB - OBJECTIVE: To evaluate the protective effects of punicosides on alcohol induced acute liver injury in mice and its possible mechanisms as well. METHOD: The 60 mice were randomly divided into normal control, model group, three dose groups of punicosides with low, medium and high, then there is silibinin group. Three dose groups of punicosides and silibinin were given in advance by gavage for 4 weeks, then the mouse model of alcoholic acute liver injury was established. The serum levels of ALT, AST and TG were determined, and the mice were killed to calculate somatic index of liver, thymus as well as spleen. MDA, SOD, GSH-Px and GSH-ST were detected in the liver homogenate. Histopathological changes of the liver were observed by HE staining. The expression of MCP-1 and NF-kappaB in the liver tissues were detected by immunohistochemistry. RESULT: Mid and high dose of punicosides reduced the liver index in mice significantly, improved liver steatosis, decreased the level of ALT, AST and TG in serum and the content of MDA in liver homogenate, furthermore the two dose groups increased the activity of SOD, GSH-Px and GSH-ST, inhibited the expression of MCP-1 and NF-kappaB in liver tissue. CONCLUSION: Punicosides can protect the acute liver damage induced by alcohol. PMID- 25272504 TI - [Effect of Gansui Banxia Tang plus-minus Gansui and Gancao anti-drug combination that preferred dose close to clinical application on diuretic effect in malignant ascites rats]. AB - OBJECTIVE: To observe the effect of Gansui Banxia Tang plus-minus Gansui and Gancao anti-drug combination on hepatic and renal functions in malignant ascites rats to explore whether the efficacy or toxicity associated with the anti-drug combination. METHOD: The male wistar rats were randomly divided into a blank group, model group, furosemide group, Gansui Banxia Tang group, Gansui Banxia Tang removed Zhigancao group, Gansui Banxia Tang removed Cugansui group, Gansui Banxia Tang removed Zhigancao and Cugansui group. In addition to normal feeding, every morning except for the blank group and model group, the rest of the group was given drugs, the control group and the model group was given distilled water, the volume is 10 mL x kg(-1). Administered five days, all rats were fasted but except water for 24 hours to collect urine. Administered nine days all rats were fasted but except water for 12 hours, we need to weigh weight of rats. When we remove the ascites, we also need to weigh weight of rats. We use the weight before removing ascites minus weight after removing ascites to indirectly measure the amount of ascites. When we remove the ascites, we need to abdominal aortic blood, centrifuge testing renin, angiotensin II, aldosterone, antidiuretic hormone and other indicators. RESULT: The effect of Gansui Banixa Tang on increasing the net weight, lowering abdominal circumference and body weight ratio, lowering renin, angiotensin, aldosterone, antidiuretic hormone is better than the other treatment group. CONCLUSION: In diuresis party, the group of Gansui Banxia Tang is better than the group of Gansui Banxia Tang remove Zhigancao or Cugansui or Zhigancao and Cugansui, renin-angiotensin-aldosterone system may play a diuretic effect of its one way. PMID- 25272505 TI - [Comparative study of Coptidis Rhizoma and Aconiti Kusnezoffii Radix on cell differentiation in lewis lung cancer]. AB - Coptidis Rhizoma and Aconiti Kusnezoffii Radix represent hot Chinese medicine and cold Chinese medicine respectively. The purpose of this study is to observe the differentiation effect of Coptidis Rhizoma and Aconiti Kusnezoffii Radix on lewis lung cancer and compare effect of hot Chinese medicine and cold Chinese medicine on tumor progression. In this study, the rat serum containing Coptidis Rhizoma or Aconiti Kusnezoffii Radix was prepared to treat lewis lung cancer cells in vitro, and effects of the serum containing Coptidis Rhizoma or Aconiti Kusnezoffii Radix on cell differentiation, proliferation, adhesion, succinic dehydrogenase (SDH) activity and gap-junction intercellular communication (GJIC) were investigated. In vivo, the subcutaneous implant model and pulmonary metastasis model of lewis lung cancer were established. Tumor bearing mice were taken water decoction of coptis chinensis or aconite by intragastric administration bid for four weeks, and the influences of coptis chinensis and aconite on tumor progression were evaluated by body temperature, blood oxygen saturation, red cell ATPase, blood rheology, intratumor hypoxia, capillary permeability and GJIC. The results showed that the serum containing aconite could induce cell differentiation, inhibit cell proliferation and migration, promote SDH activity and GJIC in lewis lung cancer cells. The serum containing Coptidis Rhizoma increased cell adhesion and decreased SDH activity and GJIC without cell differentiation although it also suppressed cell proliferation. Aconiti Kusnezoffii Radix water decoction could keep body temperature, blood oxygen saturation, red cell ATPase and blood rheology, and improve intratumor hypoxia, capillary permeability and GJIC in tumor bearing mice, which led to slower tumor growth and less metastasis. Coptidis Rhizoma water decoction decreased body temperature, blood oxygen saturation, red cell ATPase, blood rheology and GJIC, and promoted intratumor hypoxia and capillary permeability, which resulted to more tumor metastasis although it also prevented tumor growth. These results suggested that the hot Chinese medicine could induce tumor cell differentiation and prevent tumor poison invagination, which is better for tumor treatment than cold Chinese medicine. PMID- 25272506 TI - [Proteomics research of bufalin-induced apoptosis in osteosarcoma cell lines]. AB - OBJECTIVE: To study the apoptosis inducing effects of bufalin on various human osteosarcoma cells and the concerning molecular mechanisms. METHOD: MTT assay was used to detect the growth inhibition rates of osteosarcoma cells U-20S, U 20S/MTX300, SaOS-2, IOR/OS9 treated with bufalin in different concentrations and times. The apoptosis of cells was observed flow cytometry 48 h following bufalin treatment. The proteomic techniques were used to separate and compare the treated and control groups 48 h after bufalin-incubation. Then, the proteomic results were validated by western blot. RESULT: Bufalin inhibited the growth of human osteosarcoma cells U20S, U20S/MTX300 (methotrexate resistant cells), SAOS2, IOR/OS9 in a dose- and time-dependent manner. The 72 h IC50 were (37.43 +/- 4.1), (32.24 +/- 5.3) nmol x L(-1) in U20S,U20S/MTX300 cells,respectivly. Flow cytometry showed that the apoptosis cells were increased following bufalin treatment. The protein expression profile showed 24 differentiated expression proteins. Among these proteins, the level of an anti-apoptotic protein, heat shock protein 27 (Hsp27) decreased significantly and the result was then validated by western blot. Ectopic expression of Hsp27 could reduce the bufalin induced apoptosis remarkably in U20S and U20S/MTX300 cells. CONCLUSION: Bufalin could inhibit the cell growth and induce apoptosis on human osteosarcoma cells. The effect of bufalin may be related to the joint intervention with multiple protein targets. Among them, downregulation of Hsp27 plays a critical role in the bufalin-induced apoptosis in human osteosarcoma cells. PMID- 25272507 TI - [Anti-depressant effect and mechanism of supercritical CO2 extract from Compound Chaigui Fang]. AB - The tail suspension test (TST), forced swimming test (FST) and chronic unpredictable mild stress (CUMS) model were used to evaluate the anti-depressant effect of supercritical CO2 extract from Compound Chaigui Fang (FFCGF). A nuclear magnetic resonance (NMR)-based metabonomics combined with multivariate statistical analysis was performed to explore the mechanism of FFCGF. Rats were conducted by CUMS procedure for 28 days and drugs were administrated at the same time. The body weight, sucrose preference, crossings and rearings in open-field tests were evaluated and the urine was collected simultaneously. The metabonomic profiles of rats' urine were analyzed by NMR and potential biomarkers were searched by multivariate statistical analysis. The results showed that administration of FFCGF significantly decreasing the immobility time in FST and TST and improving rats' body weight, sucrose preference, crossings and rearings in CUMS, which were indication that the anti-depressant effect of FFCGF was abvious. Significant differences in the metabolic profile of the CUMS treated group and the control group were observed, which were consistent with the results of behavioral tests. Decreased levels of acetic acid, succinic acid, 2-oxidation glutaric acid and citric acid and increased glycine and pyruvic acid in urine were significantly affected by the CUMS procedure and the 6 biomarkers were reversed evidently after administration of FFCGF. These changes were suggestion that the anti-depressant mechanism of FFCGF was associated with energy metabolism, lipid metabolism and amino acid metabolism. PMID- 25272508 TI - [Study on pharmacokinetics-pharmacodynamics correlation of Danshensu in rats with focal cerebral ischemia]. AB - To study the pharmacokinetic process of Danshensu in cerebal ischemia injury model rats and the correlation with its anti-cerebral ischemia effect. In this study, the middle cerebral artery occlusion (MCAO) model was established, in which all of the rats were intravenously injected of Danshensu at a single dose of 40 mg x kg(-1). The HPLC-DAD method was applied to determine the plasma concentration of Danshensu at different time points and draw the drug-time curve. Meanwhile, the superoxide dismutase (SOD) and the lactate dehydrogenase (LDH) activity were determined to draw the time-effect curve. The DAS 3.2. 6 software was used to process the data, analyze their correlation, compare the pharmacokinetic difference between model and normal rats after the administration of the same doses of Danshensu and the changes in pharmacodynamic indicators of model rats after the administration, and evaluate the effect of Danshensu in treating the cerebral ischemia disease. According to the results, the pharmacokinetic processes of Danshensu in the cerebral ischemia-reperfusion and normal rats were consistent to the two-compartment model. The main pharmacokinetic parameters were: t1/2alpha were (0.267 +/- 0.026), (0.148 +/- 0.020) h;t1/2beta were (1.226 +/- 0.032), (1.182 +/- 0.082) h; AUC0-infinity were (42.168 +/- 4.007), (26.881 +/- 1.625) mg x L(-1) x h. After the cerebral ischemia-reperfusion, the activity of SOD decreased and the activity of LDH increased. Danshensu could inhibit the decrease in the SOD activity and the increase in the LDH activity within a certain period of time. This indicated that Danshensu could stay longer in cerebral ischemia-reperfusion rats than in normal rats and eliminated more slowly, which reflected the rationality of Danshensu in the clinical treatment of cerebral ischemia diseases. Danshensu's effect against the cerebral ischemic injury may be related with its level in vivo. Its plasma concentration is positively related to the SOD activity and negatively related to the LDH activity. PMID- 25272509 TI - [Effect of adjuvant therapy with Dingguier umbilical paste on intestinal flora of diarrhea infants and its action characteristics]. AB - The applicator therapy is a unique method to treat infant diarrhea in traditional Chinese medicines and widely applied in clinical practice. Currently, many researchers have proved the rationality of the therapy based on the traditional Chinese medicine mechanism and on the data from clinical practice, but its action mechanism is uncertain at present. In this study, with the assistance of pediatric practitioners, the automated ribosomal intergenic-spacer analysis (ARISA) was adopted to study the effect of the adjuvant therapy with Dingguier umbilical paste on intestinal flora of diarrhea infants, in which Dingguier umbilical paste served as the adjuvant therapy in oral traditional Chinese medicines and fecal samples of infants with different diarrhea symptoms were collected and used as the study materials. The results showed that the adjuvant therapy had a significant effect on the shift of intestinal flora, which was associated with the decrease in the similarity difference to the normal control group and the increase in the number of operational taxonomic units (OTUs) shared with the normal control group. Additionally, adjuvant therapy with Dingguier umbilical paste also showed long action duration and increased OTUs number. These results indicated that Dingguier umbilical paste has the effect in restoring the micro-ecosystem of unbalanced intestinal bacteria. Intestinal flora may be one of major targets for the applicator therapy for the infant diarrhea, but not for the single oral traditional Chinese medicine for infant diarrhea. PMID- 25272510 TI - [Study on medication regularity of grand master of traditional Chinese medicine YAN Zheng-hua's Ostreae Concha-containing prescriptions based on data mining]. AB - In this study, prescriptions were collected to establish a database based on the traditional Chinese medicine inheritance support system (TCMISS). Such data mining methods as software's statistical statement module, data analysis module and apriori algorithm were used to analyze the frequency of single drug, the frequency of drug combination, the association rules and the core drug combinations of ostreae concha-containing prescriptions. The results showed that Ostreae Concha-containing prescriptions were frequently used to treat insomnia, vertigo, stomach-ache and other syndromes. The frequently used drugs included Ossis Mastodi Fossilia, Parched Ziziphi Spinosae Semen, Polygoni Multiflori Caulis, Salviae Miltiorrhizae Radix and Paeoniae Rubra Radix. The frequently used drug combinations included "Ostreae Concha and Ossis Mastodi Fossilia", "Ostreae Concha and Parched Ziziphi Spinosae Semen", and "Ostreae Concha and Polygoni Multiflori Caulis". The drug association rules with the confidence coefficient of more than 0. 95 included "Ossis Mastodi Fossilia-->Ostreae Concha", "Cocos Poria Ossis Mastodi Fossilia-Ostreae Concha", "Ossis Mastodi Fossilia-Parched Ziziphi Spinosae Semen-->Ostreae Concha", and "Salviae Miltiorrhizae Radix-Ossis Mastodi Fossilia--Ostreae Concha". PMID- 25272511 TI - [Three new records of medical plant in Hubei, China]. AB - In order to have a better understanding of the species diversity of medical plants in Enshi, Hubei of China, extensive field investigations and specimen collections were conducted in Enshi and adjacent regions. Based on field observations of plants in their living habitats and comparative morphological studies on specimens in herbarium of Hubei minzu University and other available herbaria as well, three new records of medical plants in Hubei, Scutellaria yunnanensis, Alangium faberi var. heterophyllum, and Drymaria diandra, were reported in this paper. PMID- 25272512 TI - [Analysis of photosynthetic characteristics and its influencing factors of medicinal plant Mirabilis himalaica]. AB - To study photosynthetic characteristics and its influencing factors in leaves of medicinal plant Mirabilis himalaica, and provide an evidence for guiding artificial planting and improving the quantity. The light-response and diurnal photosynthesis course of leaves at the booting stages of 1-3 year old M. himalaica were measured with LI-6400 system. The Results showed that the light response curves were fitted well by non rectangle hyperbola equation (R2 > or = 0.98). The values of the maximum photosynthetic rate (Pmax) and light use efficiency of three-year old M. himalaica leaves were higher than those of 1-2 year old individuals. The diurnal variation of net photosynthetic rate (Pn) and stomatal conductance (Gs) of 2-3 year old M. himalaica were typical double-peak curves determinately regulated by stomatal conductance. However, transpiration rate (Tr) of 1-3 year old plants leaves were single-peak curve, which was self protection of harm reduction caused by the higher temperature at noontime. Correlation analysis showed that the changes between photosynthetic active radiation (PFD), air temperature (T ) and Pn, were significant positive related. Therefore, M. himalaica is a typical sun plant, which should be planted under the sufficient sunshine field and prolong the growing ages suitably in order to improve the yield. PMID- 25272513 TI - [Determination of polysaccharides content of Gentiana farreri from different producing areas based on anthrone-sulfuric acid method]. AB - Study a method for the detemination of the content of polysaccharides in Gentiana farreri, and analysis of the content of polysaccharides from different producing areas. The results showed that using the anthrone-sulfuric acid method, simple operation, accurate result. Sample was measured at 620 nm absorbance after anthrone-sulfuric acid color, at this wavelength, solution absorption and glucose showed a good linear relationship; The linearity was in the range of 0.01-0.07 g x L(-1) (r = 0.996 7). The recovery rate was 99.41%, with RSD of 2.0%. Considering the experimental conditions, to determine the solid-liquid ratio 1:60, extracting time 50 min, concentration of ethanol 80%. The mass fraction of polysaccharides was the highest to reached 0.743% in G. farreri from Gansu Xiahe. This experiment has laid a good foundation for further study on G. farreri. PMID- 25272514 TI - [Study of changes in Chinese herbal medicine distribution channel]. AB - Distribution channel of Chinese herbal medicines has been changing. From Han to Ming Dynasty, Chinese herbal medicine were mainly trafficked to urban by dealers or farmers; From the Ming Dynasty to the foundation of new China, distribution channels are primarily intermediated with township "bazaar" and national distribution center with fixed place and regularly trading hours. In the planned economy period, the state-owned herbal medicine company was the sole medium with monopoly nature. From the mid1980s to the end of last century, planned economy and market economy have been co-existing. Stepping into 21st century, producing area highlighted in the distribution channels. Presence or absence and rise or fall of different types of distribution market went throughout the changing process of distribution channels, which became an important clue. Changes were motivated by economical consideration of channel subject, which originated from commodity characteristic and social environment changes. PMID- 25272515 TI - [New exploration on effect of characteristics of traditional Chinese medicine components structure on multi-ingredient/component pharmacokinetics]. AB - The study on the pharmacokinetics of traditional Chinese medicines (TCMs) is a linking science during the modernization of TCMs, and plays an important role in the studies on the complex material base of TCMs, the in vivo process of ingredient/ component and the pharmacokinetics-pharmacodynamics correlation. However, because of the multi-ingredient/component system of TCMs, how to scientifically reveal the pharmacokinetics that is consistent with TCMs' characteristics has long been a hotspot and difficulty for the exploration. The optimal composition structure of the material basis of TCMs shows the best efficacy, while the difference between the multi-ingredient/component composition structures in the efficacy is closely related to their absorption, transport, metabolism and excretion in vivo. In this article, the authors systematically review the study methods for pharmacokinetics of TCMs and their compounds, and explore the pharmacokinetics of TCMs based on the "component structure theory". As a result, the method for integrating TCM component structure and the TCM pharmacokinetics was proposed to be adopted to intensively study the effect of the component structure on the in vivo TCM multi-ingredient/component pharmacokinetic characteristics, in order to promote the TCM modernization and innovation in China. PMID- 25272516 TI - [Study thought of pharmaceutical preparations quality standards by dynamic quality control technology]. AB - Pharmaceutical preparations, particularly as a "secret recipe" of traditional Chinese medicine in medical institutions, are the product of China's medical and health industry, and they are also an important means of competing of different medical institutions. Although pharmaceutical preparations have advantages and characteristics than institutes for drug and pharmaceutical companies, the quality standards of pharmaceutical preparations in medical institutions has not reached the desired level over the years. As we all know, the quality of pharmaceutical preparations is important to ensure the efficacy, especially under the environment of people pay more sttention on drug safety and effectiveness and contry increase emphasis on the stste of pharmaceutical preparations. In view of this, we will improve the grade, stability, and clinical efficacy of pharmaceutical preparations by the advanced equipment, testing instruments and the process dynamic quality control technology. Finally, we hope we can provide new ideas for the quality control of pharmaceutical preparations. PMID- 25272517 TI - [The characteristic of oral status and dental treatment of leprosy sequelae patients]. AB - The leprosy sequelae especially the handicap of eyes and hands makes difficult to maintain the oral health status. So, leprosy sequelae patients are controlling themselves by creative and original methods. However even such efforts have hardly reached the level to stop of caries and periodontal disease. More support is required in order for them to maintain the oral health status. Therefore, in National Sanatorium Nagashima Aiseien, we started the periodic preventive system containing oral check-up, mouth cleaning, and early detection early treatment 15 years before. It is the report about this activity. First, the leprosy sequelae handicap which makes oral control difficult is described. Secondly, our periodic preventive system in National Sanatorium Nagashima Aiseien is explained. In order to evaluate this activity, the number of patients and the contents of dental treatment were compared. Furthermore, the number of remaining teeth was compared with the adult Japanese. Our periodic preventive system was received and they have many remaining teeth now. It is sure that this activity for 15 years was successful. PMID- 25272518 TI - 50 years on: the United States-Japan Cooperative Medical Science Program 1965 2015 (Part 1). PMID- 25272519 TI - [Is the fight against dengue complicated with the emergence of a new viral serotype?]. AB - Dengue is a viral acute febrile illness, currently considered one of the most important arbovirosis worldwide in terms of morbidity, mortality and economic impact. Various theories have been proposed to explain the pathogenesis of severe forms of dengue, involving among other factors, features related to the virus, such as the presence of more virulent strains and/or strains with increased replicative capacity. A crucial point at this time is the discovery of a new viral type, dengue 5, from nonhuman primates in Malaysia-Borneo, which could result in greater difficulties for control and vaccine production (currently in efficacy tests). Once the circulation of this viral type has been demonstrated in the human population, the high risk of infection will have extreme or controversial public health implications. Therefore, a worldwide program to combat dengue should include an urgent need to implement continuous vector elimination, community education and prevention and control of the disease. Only then, we will be aiming to reduce the morbidity and transmission risk of dengue, while new technological and effective alternatives come about. PMID- 25272521 TI - [Psychological resistance to use insulin in type 2 diabetes mellitus patients from Venezuela]. AB - The psychological resistance to use insulin (PIR) is a condition where the patient with type 2 diabetes mellitus (T2DM) refuses to use insulin. Our objective was to determine the frequency of PIR in a Venezuelan population and their beliefs regarding insulin and current medication. In several states of Venezuela, from January to March 2013, 254 patients with T2DM, over 18 years old and naive to insulin treatment were interviewed. We applied an interview to evaluate the disposition of the patients to use insulin if their doctor prescribes it and to determine their beliefs about insulin and their current medication. The patients were categorized in: not willing (PIR group), ambivalent and willing to use insulin. The beliefs about insulin and their current medication were grouped into positive or negative. The mean age was 56.2 years, with 7.1 years of duration of the T2DM; 58.6% were females. One third (32.7%) had PIR, 20.9% were ambivalent and 46.4% were willing to use insulin. PIR patients showed lower frequency of positive beliefs and more frequency of negative beliefs to insulin and to their current treatment (p < 0.0001). Negative beliefs to insulin increased 14 times the risk of PIR, and people without university studies had a four times increase in the risk of PIR compared to the willing group. In conclusion, a high frequency of PIR in patients with T2DM (32.7%) was found in Venezuela; they showed low frequency of positive beliefs and high frequency of negative beliefs about insulin use. It is necessary to improve T2DM patient education on this issue. PMID- 25272520 TI - [Mutations in the GATA4 gen in patients with non-syndromic congenital heart disease]. AB - Congenital heart diseases are defined as any heart or large vessel structural abnormality resulting from abnormal embryonic development, usually described between the 3rd and 10th week of gestation. They comprise the second cause of death in children under a year of age in Colombia, with a prevalence of 7.5-9.5 per 1,000 births, including live and still births. We analyzed 33 heart tissue samples collected at the Clinica Shaio (Bogota, Colombia). Blood and tissue samples were collected from patients with non-syndromic congenital heart disease. Tissue was isolated near the defect. Electropherograms obtained from samples were analyzed using bioinformatic tools: ChromasPro and ClustalW. The whole gen covering its six exons was analyzed in forward and reverse orientation. We identified 17 mutations, including five non-synonymous sequence changes, one synonymous variant and one variation in the 5' UTR, three intronic changes and seven deletions. We found no evidence of gene GATA4 somatic sequence variants in any of the samples analyzed. PMID- 25272522 TI - [Trypanosoma cruzi infection decreases malignant melanoma development and increases survival in C57BL/6 mice]. AB - Some infectious pathogens have the capacity to affect cancer progression. In the present paper we studied the effect of infection or immunization with Trypanosoma cruzi (Tc) against malignant melanoma development. We worked on 258 C57BL/6 male mice divided in five melanoma groups: control melanoma, melanoma Tc acutely infected, melanoma Tc chronically infected, melanoma Tc immunized and infected melanoma; and three control groups: healthy, Tc acutely infected and Tc chronically infected. 100.000 B16-BL6 melanoma cells were inoculated in the thigh of melanoma groups; 3 or 20 trypomastigotes/g were inoculated intraperitoneally in chronic or acute Tc groups, before the melanoma injection, respectively; melanoma Tc immunized were subcutaneously inoculated with 30.000 formaldehide fixed epimastigotes diluted in complete Freund's adjuvant and the infected melanoma group was inoculated with melanoma cells obtained from melanoma Tc acutely infected mice. We evaluated survival, parasitemia, tumor volume and tumor histopathology. Results showed that in mice infected with Tc, the tumor development and survival were significantly lower as compared with control melanoma and melanoma Tc immunized. Histopathologically, the tumor displayed necrosis areas with melanin deposits, cytopathic degeneration and amastigotes in parasitophorous vacuoles. In conclusion, Tc inhibits the development of malignant melanoma, increasing C57BL/6 survival, a phenomena that could be related to the parasite tumoral invasive capacity, its ability to produce melanoma cell lysis and to induce a robust immune response. PMID- 25272523 TI - [P16(INK4alpha)/Ki-67 immunocytochemical dual staining for detection of cervical lesions associated to papillomavirus infection]. AB - We aimed to explore the expression pattern of p16(INK4alpha)/Ki-67 immunocytochemical dual-staining and to establish the potential clinical utility for early detection of cervical lesions. Liquid-based cytologies of cervical specimens of cervical cancer screening were processed for p16(INK4alpha)/Ki-67 immunocytochemical dual-staining using the CINtec Plus Kit. HPV testing was performed with the INNO-LiPA HPV genotyping Extra Reverse Hybridization Line Probe Assay kit. One hundred and fifteen cervical cytologies were analyzed with the following results: 11(9.6%) were negative for intraepithelial lesions or malignancy (NILM); 32 (27.8%) presented atypical squamous cells of undetermined significance (ASC-US); 62 (53.9%) exhibited low grade squamous intraepithelial lesions (LSIL) and 10 (8.7%) showed high grade squamous intraepithelial lesions (HSIL). No cases of cervical cancer were detected. The overall prevalence of DNA HPV detection was 81.7% (94/115). The following specific HPV genotypes were identified in 42 (45.0%) cases: HPV16 (26.2%), HPV51 (21.4%), HPV52 (14.3%) and HPV66 (7.1%). Viral sequences of an unknown single HPV were detected in 23.8% of the cases. A total of 42/115 (36.5%) were p16(IVK4alpha)/Ki-67 dual-staining positive, being more frequent in HSIL (70.0%), decreasing in LSIL (44.0%), detected in a minority of ASC-US (25.0%) and negative in NILM cases (p < 0.001). 40/115 cases (34.8%) were positive for both oncogenic HPV and p16(INK4alpha)/Ki 67 dual-staining, including 6/32 (18.8%) ASC-US, 26/62 (42.0%) LSIL and 8/10 (80.0%) HSIL, which represent a strong association between positivity for HPV, p16(INK4alpha)/Ki-67 staining and severe cytological abnormalities (p < 0.001). This methodology could be used to detect unnoticed cervical lesions. PMID- 25272524 TI - [Relationship between serum levels of C-reactive protein and alpha1-antitrypsin and insulin resistance in obese women]. AB - Adipose tissue produces cytokines involved in insulin resistance (IR) such as IL 6, IL-8, TNF-alpha and proinflammatory molecules such as C reactive protein (CRP). alpha1-antitrypsin is an inflammation-sensitive plasma protein. The objective of this study is to determine the correlation between serum CRP high sensitivity (CRPhs) and alpha1-antitrypsin levels with IR indices in obese Venezuelan women. The study population consisted of 15 normal weight women (BMI 21.8 +/- 1.9 kg/m2) and 15 obese women (BMI 35.3 +/- 5.3 kg/m2). Obese and lean women underwent a 2 h-75 g oral glucose tolerance test and the following indices were calculated: homeostatic model assessment of insulin resistance (HOMA-IR), homeostatic model assessment of beta cell function (HOMA-beta), Matsuda Index and Insulinogenic Index. The relationship between serum CRPhs and alpha1-antitrypsin levels and these indices were determined. Obese women had higher CRPhs levels (p = 0.001) compared with normal weight women. In obese women, serum CRPhs levels were positively correlated with HOMA-IR (r = 0.73, p = 0.0021), HOMA-beta (r = 0.53, p = 0.031) and negatively correlated with the Matsuda Index (r = -0.60, p = 0.017). No correlation between serum levels of alpha1-antitrypsin and IR indices in the obese group and the lean group was observed. There was a relation between serum CRPhs levels and insulin resistance, suggesting a role of subclinical inflammation in IR. PMID- 25272525 TI - [Smith-Lemli-Opitz syndrome and hypothyroidism: the first Venezuelan case]. AB - The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder due to an abnormal cholesterol synthesis. It was first described by Smith, Lemli and Opitz in 1964. Many cases of SLOS have been described since then, leading to the recognition as a relatively common malformation syndrome. Affected individuals have dysmorphism, microcephaly, multiple congenital malformations, mental retardation, aggressiveness and hyperactivity. The severity of physical defects correlates with the severity of the cholesterol deficiency, which is caused by an abnormally low activity of 7-dehydrocholesterol reductase, the enzyme responsible for conversion of 7-dehydrocholesterol to cholesterol. The occurrence of hypothyroidism in association with SLOS is very unusual. We describe the first Venezuelan case in which both anomalies are associated. PMID- 25272526 TI - [Macrophage migration inhibitory factor and its relationship with obesity and diabetes]. AB - Several studies have found that obesity and increased adiposity mainly in the abdominal region, are associated with low-grade inflammation, insulin resistance (IR), impaired glucose homeostasis and comorbidities such as type 2 diabetes mellitus (T2D) and cardiovascular disease. The macrophage migration inhibitory factor (MIF), is a proinflammatory cytokine involved in autoimmune and inflammatory diseases. However, currently it is suggested that MIF is involved in the inflammatory process associated with obesity and the metabolic control of the complications associated with obesity. Different studies show consistently, increased serum levels of MIF in subjects with obesity, type 2 diabetes and diabetics with microvascular complications (nephropathy, retinopathy and diabetic foot syndrome). The relationship of the MIF to the regulation of glucose metabolism and apoptosis of pancreatic beta cells, and the association of some functional polymorphisms in the promoter of the MIF gene with obesity and diabetes. This review summarizes, the knowledge based on clinical and epidemiological studies on the role of MIF in obesity and type 2 diabetes. PMID- 25272527 TI - [Relevance of hyperglycemia on the course and outcome of aneurysmal subarachnoid hemorrhage: evidence and mechanisms]. AB - Aneurysmal subarachnoid hemorrhage (aSAH) may have a fatal outcome after a few weeks from ictus, due to its complications, like cerebral vasospasm and edema along with hyperglycemia. Hyperglycemia may be involved in the development of brain vasospasm and edema. It is possible that hyperglycemia plays a central role in the outcome of aSAH. Several mechanisms may explain this relationship; they include ion balance, excitatory amino acid release, stimulation of vasoconstrictor molecules and reduced synthesis of vasorelaxants. However, some studies do not support this hypothesis regarding the role of hyperglycemia in aSAH. Taken together, the evidence suggests that the control of glucose levels may influence the aSAH outcome depending on the complications that may develop. PMID- 25272528 TI - [Increasing difficulties for the scientific publication in Venezuela]. PMID- 25272529 TI - Umbilical cord blood transplantation: an insight. PMID- 25272530 TI - What do trainers think about trainer training courses? AB - OBJECTIVE: To evaluate the effectiveness of the training-of-trainer courses given to medical school faculty members, and to ensure the standardisation of training.. METHODS: The study comprised faculty members attending seven training of-trainer courses held at the Ataturk University, Turkey, from November 2010 to May 2011. Tests were administered to the participants evaluating their level of knowledge on course content before and after the five-day course, which covered topics including concepts of teaching/learning, curriculum development, assessment and evaluation, training methods, and training skills. Oral and written feedbacks were obtained from all participants on the last day of each course. Volunteers from among the participants evaluated the impact of training through a questionnaire after at least two months. SPSS 20 was used for statistical analysis. RESULTS: A total of 136 faculty members participated in the 7 training-of-trainer courses. The mean scores for the pretest and post-test were 6.6 +/- 2.2 vs. 13.9 +/- 3.7, (p < 0.001). Questions with highest percentage of correct answers in the pre-test were those about learning style 78 (70.9%) and the one about presentation skills (66.4%). CONCLUSION: A structured training-of trainer course is effective in increasing faculty members' level of knowledge about training. Such programmes are necessary for faculty members who work in the academic field without receiving formal training in teaching as it is the case with medical education in several countries. PMID- 25272531 TI - Dyslipidaemia among renal transplant recipients: cyclosporine versus tacrolimus. AB - OBJECTIVES: To compare new onset dyslipidaemia in live-related renal transplant recipients taking cyclosporine versus tacrolimus after 3 months of therapy. METHODS: The randomised controlled trial was conducted at the Sindh Institute of Urology and Transplantation (SIUT) Karachi, from September 2010 to April 2011, and included 182 End Stage Renal Disease patients on maintenance haemodialysis with pre-transplant normal lipid profile. The patients, who had live-related renal transplant, were randomly allocated to two equal groups using lottery. Group A received cyclosporine (3 mg/kg) and group B was treated with tacrolimus (0.1 mg/kg). All patients had pre-transplant fasting lipid profile checked when they were on maintenance haemodialysis and 3 months after renal transplantation. Serum fasting lipid profile was collected by taking 5 ml blood by venipuncture after an overnight fast of 9-12 hours. SPSS 10 was used for statistical analyses. RESULTS: Of the 182 patients, 144 (79.1%) were males and 38 (20.9%) were females. The overall mean age was 30.18 +/- 9.57 years, and the mean weight was 54.41 +/- 11.144 kg. Significant difference was not observed between the two groups regarding age and weight of the patients. Dyslipidaemia was found in 115(63.2%) subjects; 61(67%) in group A and 54 (59.3%) in group B. There was no statistical difference (p=0.28) when comparison was done after 3 months of therapy. CONCLUSIONS: The occurrence of new onset hyperlipidaemia is similar in renal transplant recipients receiving either cyclosporine or tacrolimus in first 3 months post-transplant, but there is room for more research in this field as dyslipidaemia following successful renal transplantation is a frequent and persistent complication. PMID- 25272532 TI - Effective education to decrease elective caesarean section. AB - OBJECTIVE: To examine the effect of education on deciding about natural delivery in women opting for elective caesarean section. METHODS: The quasi-experimental study was carried out between January and March 2012 and comprised a sample of 200 women in their third trimester of pregnancy attending women's clinics of Imam Ali Hospital, Zahedan, Iran, with the intention of having elective caesarean section. The subjects were voluntarily classified into three groups: one group received an educational package; the other had educational package along with group discussion, and the last one without any intervention was considered the control group. Post-test was conducted a month after intervention. Data were analysed using Kruskal Wallis, and logistic regression tests. RESULTS: Group A represented the controls and had 100 (50%) women; Group B with the educational package had 40 (20%), while there were 60 (30%) women in Group C who had exposure to the educational package as well as group discussion.There were significant changes in behaviour in Group B and C (p < 0.01) but no change among the controls in Group A. In Group C, 25 (42%) women decided to go for natural delivery, while 1 (2.5%) woman had a change of opinion in Group B. Four (4%) women in the control Group A had ultimately natural delivery, but they were all emergency cases. CONCLUSION: The two educational methods increased model construct scores, including awareness, attitude, perceived behaviour control, subjective norms and behavioural intention. Nevertheless, educational package in conjunction with group discussion was more effective in influencing the choice towards natural delivery. PMID- 25272533 TI - Investigation of the preparedness level of the hospitals against disasters in Bandar Abbas, Iran, in 2012. AB - OBJECTIVE: To determine the preparedness level of hospitals against natural disasters in Bandar Abbas, Iran. METHODS: The cross-sectional, descriptive study was conducted in all the 9 hospitals in Bandar Abbas, Iran, during 2012. The required data was collected using a standard checklist comprising 220 items in 10 areas. It was completed for each hospital using observations and interviews. SPSS 16.0 was used to analyse the data. RESULTS: The overall level of preparedness against disasters in Bandar Abbas hospitals was 38.6%. They were at a poor level in the areas of reception (31.4%), evacuation (28.1%), traffic (33.3%), security (34.6%), communication (30.6%), human resources (38.6%), and commanding and management (20.1%). Areas of emergency services (55.1%), training (53.5%), and logistics (53.5%) were moderate, while none of the areas could score enough to be in the good or very good category. CONCLUSION: Preparedness was poor and hospital administrators should establish necessary technical and communication infrastructures through sufficient budgets to improve weak areas. PMID- 25272534 TI - Diltiazem vs. glyceryl tri-nitrate for symptomatic relief in anal fissure: a randomised clnical study. AB - OBJECTIVE: To further resolve the clinical equipoise on the choice of chemical sphincterotomy agent for early symptomatic relief of anal fissure by comparing the effectiveness of 2% Diltiazem gel with 0.2% Glyceryl TriNitrate. METHODS: The randomized clinical trial was conducted at Aga Khan University Hospital, Karachi, from February 1, to July 30, 2008, and comprised 60 adult patients with anal fissure who were equally randomised to either Diltiazem or Glyceryl TriNitrate after taking informed consent. The creams were applied locally; the former twice daily, and the latter three times a day for a period of two weeks. The rest of the treatment was standard. Patients were followed up in clinic by the principal investigator at two weeks for primary outcome i.e. self-reported symptomatic relief on Visual Analogue Scale, and secondary outcomes i.e. side effects and the overall cost of treatment. RESULTS: Of the total, 31 (52%) patients were males and the overall mean age was 37 +/- 11 years. Patients, who used Diltiazem reported more symptomatic relief than Glyceryl TriNitrate (p < 0.01). Side effects were found more in Glyceryl TriNitrate than Diltiazem (p < 0.01), and most common side effect in the former group was headache in 12 (40%) patients. Cost of the treatment was not significantly different between both treatment arms (p < 0.28). CONCLUSION: Chemical sphincterotomy with topical 2% Diltiazem gel is an effective first-line treatment for early symptomatic relief of anal fissures, owing to negligible side effects. PMID- 25272535 TI - Prevalence and risk factors of tinea capitis and tinea pedis in school children in Turkey. AB - OBJECTIVE: To evaluate the prevalence and risk factors of tinea capitis and tinea pedis in school children in Turkey. METHODS: The study included 8122 students from 24 schools in the rural and urban areas around Kayseri,Turkey. We asked every student for their personal identification and also for their sanitation in order to get an idea about dermatophytosis. Samples taken from suspicious lesions were collected and inoculated onto Sabouraud dextrose agar slants. For identification of grown fungi, macroscopic appearance of colonies, microscopic examination and biochemical tests were used. RESULTS: There were 41 (0.5%) suspicious lesions in feet and 31 (0.3%) in scalp and 22 (0.2%) students were diagnosed as tinea pedis and 9 (0.1%) as tinea capitis by fungal culture. The predominant etiologic agents in feet were Trichophyton rubrum 8 (36%), Trichophyton mentagrophytes 1 (4%), Rhodotorula 8 (36%), Trichosporon 2 (9%), Candida glabrata 2 (9%), Candida albicans 1 (4%), while Trichophyton verrucosum 8 (88%) and Trichophyton mentagrophytes 1 (12%) were identified in scalp samples. School settlement was found as risk factors on the frequency of tinea pedis and capitis. Age and gender were also found as risk factors on the frequency of tinea pedis. CONCLUSION: The results of this study demonstrate a low prevalence of tinea capitis and tinea pedis in school children of central Anatolia of Turkey. School settlement is a very important factor affecting the prevalence of tinea capitis and pedis in school children in central Anatolia of Turkey. PMID- 25272536 TI - Frequency of class B carbapenemases (MbetaL) in enterobacteriacae. AB - OBJECTIVE: To determine the frequency of Metallo- -lactamase producing Enteriobacteriaceae species. METHOD: The descriptive cross-sectional study was carried out from January to December 2011 in the Department of Microbiology, Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre, Karachi. A total of 500 specimens were initially collected. The culture positive samples were analysed for further identification, and antimicrobial sensitivity was done according to Clinical and Laboratory Standards Institute guidelines 2009. The Carbapenemases Producing Enterobacteriaceae strains were screened by the Modified Hodge Test, and Metallo-beta-Lactamase production was confirmed by the EDTA combined disc test. RESULT: From amongst 402 organisms detected, 200 (49.75%) were Enterobacteriaceae, while Escherichia coli was the leading pathogen (65%). Only 6% were identified as Carbapenemases Producing Enterobacteriaceae and 9 (75%) of them were Metallo-beta-Lactamase producing strains, while 3 (25%) contained other enzymes. CONCLUSION: Metallo-beta-Lactamase producing Enterobacteriaceae species are causing problems in tertiary care hospitals. PMID- 25272537 TI - Trend over time; a structural review of articles published in Journal of Pakistan Medical Association from 1953-2009. AB - OBJECTIVE: To review the articles published in the Journal of Pakistan Medical Association from 1953 to 2009 and to assess the components of each article by a pretested proforma containing a checklist of items based on modified 'Strengthening the Reporting of Observational Studies in Epidemiology' statement. METHODS: The retrospective study was conducted at the office of the Journal of Pakistan Medical Association, Karachi, from February to November 2010. A checklist of items in the modified 'Strengthening the Reporting of Observational Studies in Epidemiology' statement was made after discussion among the authors of the study to finally include a revised checklist of 45 items instead of the checklist of 22 items of the statement. A total sample size of 370 was calculated. Simple randomisation was done for selection of articles from each year. For each article, major and minor items were documented. Data was fed into SPSS version 15. RESULTS: The scientific quality of reporting of most of the components of Introduction, Results and Discussion sections have improved progressively with time (p < 0.001) whereas most components of Methodology have remained consistent. CONCLUSION: A change in trend over time was observed over the study period in major and minor items of the articles in the Journal, showing improved reporting of various sub-components of articles.The modified 'Strengthening the Reporting of Observational Studies in Epidemiology' statement provides a checklist that may be used to improve the quality of articles. PMID- 25272538 TI - Risk factors for carbapenem resistant bacteraemia and mortality due to gram negative bacteraemia in a developing country. AB - OBJECTIVE: To identify the risk factors for carbapenem resistant bacteraemia and mortality due to gram negative bacteraemia in a developing country. METHODS: A prospective cohort study was conducted at the Sindh Institute of Urology and Transplantation (SIUT) from June to October 2012. Hospitalized patients > 15 years of age with gram negative bacteraemia were included and followed for a period of 2 weeks for in hospital mortality. Data was collected and analyzed for 243 subjects. Multivariate analysis was used to determine the risk factors for carbapenem resistant bacteraemia and mortality due to gram negative bacteraemia. Crude and adjusted odds ratio and 95% CI are reported. RESULTS: A total of 729 out of 1535 (47.5%) cultures were positive for gram negative isolates. Out of 243 subjects, 117 (48%) had an MDR isolate. Having an MDR isolate on culture (AOR, 2.33; 95% CI, 1.35-4.0), having multiple positive cultures (AOR, 1.8; 95% CI, 0.94-3.4) and stay in ICU > 48 hours (AOR, 2.0; 95% CI, 1.12-3.78) were identified as significant risk factors for mortality due to gram negative organisms. Risk factors for carbapenem resistant bacteraemia were age > 50 years (AOR, 1.83; 95% CI, 1.0-3.5), septic shock on presentation (AOR 2.53; 95% CI, 1.03-6.2), ICU stay of > 72 hours (AOR 2.40; 95% CI, 1.14-5.0) and receiving immunosuppressant medications (AOR 2.23; 95% CI, 0.74-6.7). CONCLUSION: There is a high burden of MDR and carbapenem resistant gram negative bacteraemia, with a high mortality rate. PMID- 25272539 TI - The relationship of psychological empowerment and readiness for organizational changes in health workers, Lorestan, Iran. AB - OBJECTIVE: To determine the relationship between psychological empowerment and readiness for organisational change among primary healthcare workers in Iran. METHODS: This descriptive-analytical cross-sectional study comprised 64 primary health workers in Noorabad, western Iran, and was conducted in 2012. A multi stage cluster sampling was used for the study. Information was collected using two validated questionnaires related to psychological empowerment and readiness for organisational changes. Data was analysed using SPSS 16. RESULTS: Overall, 33 (51%) health workers were men and 31 (49%) were women.The attitude towards organisational change had significant relationships with impact, education level and job experience, and the behaviour towards organisational change had a significant relationship with competence (p<0.05). CONCLUSION: Psychological empowerment could raise the readiness for organisational changes. Health centre managers should pay more attention to their primary healthcare workers and their empowerment. PMID- 25272540 TI - Prediction of successful trial of labour in patients with a previous caesarean section. AB - OBJECTIVE: To determine the prediction rate of success in trial of labour after one previous caesarean section. METHODS: The cross-sectional study was conducted at the Department of Obstetrics and Gynaecology, Cantonment General Hospital, Rawalpindi, from January 1, 2012 to January 31, 2013, and comprised women with one previous Caesarean section and with single alive foetus at 37-41 weeks of gestation. Women with more than one Caesarean section, unknown site of uterine scar, bony pelvic deformity, placenta previa, intra-uterine growth restriction, deep transverse arrest in previous labour and non-reassuring foetal status at the time of admission were excluded. Intrapartum risk assessment included Bishop score at admission, rate of cervical dilatation and scar tenderness. SPSS 21 was used for statistical analysis. RESULTS: Out of a total of 95 women, the trial was successful in 68 (71.6%). Estimated foetal weight and number of prior vaginal deliveries had a high predictive value for successful trial of labour after Caesarean section. Estimated foetal weight had an odds ratio of 0.46 (p < 0.001), while number of prior vaginal deliveries had an odds ratio of 0.85 with (p = 0.010). Other factors found to be predictive of successful trial included Bishop score at the time of admission (p < 0.037) and rate of cervical dilatation in the first stage of labour (p < 0.021). CONCLUSION: History of prior vaginal deliveries, higher Bishop score at the time of admission, rapid rate of cervical dilatation and lower estimated foetal weight were predictive of a successful trial of labour after Caesarean section. PMID- 25272541 TI - Follow-up of P dispersion after transcatheter closure of an atrial septal defect in children. AB - OBJECTIVES: To determine in paediatric patients with atrial septal defects whether differences in P wave dispersion occurred with transcatheter closures using the Amplatzer septal occluder. METHOD: A total of 31 children who had undergone transcatheter closures were evaluated. P maximum, P minimum, and P dispersion were measured with 12-lead surface electrocardiography, before the procedure and one week, one month, three months, six months and one year following the procedure. SPSS 10 was used for statistical analysis. RESULTS: There were 23 (74.2%) females and 8 (25.8%) males with an overall mean age of 7.5 +/- 4.1 years and mean weight of 26.2 +/- 16.9 kg. The P maximum and P minimum measurements differed between patients during the follow-up period. Both measurements decreased with time. However, P dispersion was not significantly different throughout the follow-up period (before the procedure P maximum 95.4 +/ 15.6 ms, P minimum 64.5 +/- 15.4 ms, and P dispersion 30.8 +/- 11.4 ms; one year later, P maximum 76.1 +/- 14.6 ms, P minimum 47.1 +/- 12.1 ms, and P dispersion 29.1 +/- 9.1 ms). CONCLUSION: Over time, there are no P dispersion differences in transcatheter closures using the Amplatzer septal occluder. PMID- 25272542 TI - Vancouver winters: environmental influences on inpatient adult orthopaedic trauma demographics. AB - OBJECTIVE: To compare the pattern of adult inpatient orthopaedic injuries admitted at three Vancouver hospitals following one of the worst winter snowstorms in the region with the preceding control winter period. METHODS: The surveillance study was conducted at the University of British Columbia, Vancouver, Canada, 2007 to 2010. Inpatient adult admissions for orthopaedic injuries at three hospitals were recorded, including age, gender, anatomic location of injury, type of fracture (open or closed), fixation method (internal versus external fixation), and length of acute care hospital stay. Comparisons between admissions during this weather pattern and admission during a previous winter with minimal snow were made. SPSS 19 was used for statistical analysis. RESULTS: Of the 511 patients admitted under Orthopaedic trauma service during the significant winter snowstorms of December 2008-January 2009, 100 (19.6%) (Cl: 16.2%-23.2%) were due to ice and snow, whereas in the preceding mild winter only 18 of 415 (4.3%) (CI: 2.5%-6.8%) cases were related to snow (p < 0.05). Ankle and wrist fractures were the most frequent injuries during the index snow storm period (p < 0.05). At all the three institutions, 97 (96.5%) fractures were closed during the snowstorm as opposed to 17 (95%) during the control winter period. Internal fixation in 06 (89%) fractures as opposed to external fixation in 12 (11%) patients was the predominant mode of fixation across the board during both time periods. CONCLUSION: The study demonstrated a significantly higher inpatient orthopaedic trauma volume during the snowstorm. More rigorous prospective studies need to be designed to gain further insight to solving these problems from a public health perspective. PMID- 25272543 TI - Dengue fever in patients admitted in tertiary care hospitals in Pakistan. AB - OBJECTIVES: To assess the gaps in the diagnosis and management of dengue fever cases. METHODS: The retrospective descriptive analytical study was done with a case record analysis of patients with dengue fever admitted from January to December 2010 at five tertiary care hospitals in different Pakistani cities. Using a questionnaire, information was gathered on demography, haematological profile, management, use of blood and platelet transfusions and the outcome. For comparison, data of serologically-confirmed dengue patients from a private laboratory in Islamabad was collected to see the age, gender and month-wise distribution of cases tested over the same period. SPSS 16 was used for statistical analysis. RESULTS: Out of the 841 confirmed dengue cases, 514 (79%) were males and 139 (21%) females. The overall mean age was 31.3 +/- 14.0 years. Dengue fever was seen in 653 (78%) and dengue haemorrhagic fever (DHF) in 188 (22%) patients. Most cases were between 20 and 49 years of age. A gradual increase in dengue fever and dengue haemorrhagic fever was seen from August, with a peak in October/November. Tourniquet test was done only in 20 (2.3%) cases, out of which 11 (55%) were positive and 9 (45%) were negative. Serial haematocrit was not done in any case. Total deaths were 5 (0.6%). CONCLUSIONS: Most cases were seen in October/November with the majority being in the 20-39 age group. Tourniquet test and serial haematocrit were infrequently used. No standard national guidelines were employed. PMID- 25272544 TI - Epidemiological analysis of poisoning cases in Van, Turkey. AB - OBJECTIVE: To investigate the etiological and demographical characteristics of acute adult poisoning cases in eastern Turkey. METHODS: The retrospective study was conducted at the Emergency Department of Yuzuncu Yil University, School of Medicine, and comprised data related to the period between 2007 and 2009. The data obtained included age, gender, referrals, manner of poisoning, manner of application, the department which followed up on the patients, duration of hospital stay. All data was noted on proforma. SPSS 15 was used for statistical analysis. RESULTS: Of the total cases visiting the Emergency Department, 1207 (1.1%) related to poisoning. Of them, 880 (72.9%) had attempted suicide; 858 (71.1%) were female; 349 (29%) were male. The average age of the females was 25.4 +/- 8.5 years, and that of the males 28.3 +/- 14.3 years. Single-medicine was noted in poisoning 544 (45.1%) patients. Other poisoning types were multidrugs 373 (30.9%); rat poisoning, insecticide and pesticides, 145 (12%); corrosives 38 (3.1%); and weed, mushroomang; food 47 (3.8%). Oral poisoning was noted in 1141 (94.5%) cases. A total of 1019 (84.4%) patients received treatment and were followed up in the Emergency Department. Six (0.6%) patients died. CONCLUSION: There is a need to generate more awareness about the hazards of domestic cleaning products and to keep it away at some distinct place to minimised chances of confusion. PMID- 25272545 TI - Impact of the Follicular Lymphoma International Prognostic Index risk categorization on survival of patients with follicular lymphoma in Pakistani population: a single centre experience. AB - OBJECTIVE: To determine the impact of Follicular Lymphoma International Prognostic Index risk categorisation on the survival of patients with follicular lymphoma treated in one centre. METHOD: The retrospective study comprised follicular lymphoma patients treated from 1997 to 2010 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore. Their baseline prognostic index score, stage, bone marrow involvement and high-grade transformation were recorded. Risk categorisation was done according to the index score. SPSS 19 was used for statistical analysis. RESULTS: Median age of the 70 patients studied was 54 years (range: 23-98). There were 42 (60%) males. Overall, 58 (83%) patients presented with stage III/IV disease. Bone marrow was involved in 42 (60%) cases. High-grade transformation was reported in 12 (17.1%). According to risk categorisation, 21 (30%) were low risk, 21 (30%) intermediate and 28 (40%) were in high-risk category. Patients were treated with standard chemotherapy. Median follow-up was 3 years (range: 1-9). Median overall survival was 4.1 years (95% Cl: 4.7-6.4).The Kaplan Meier estimated overall survival at 5 years was 26 (43%). Five-year overall survival in the low, intermediate and high risk groups was 14 (66%), 10 (47%) and 7 (25%), respectively (p < 0.02). CONCLUSION: The Follicular Lymphoma International Prognostic Index showed significant prognostic value with high scores having poor overall survival compared to patients with low and intermediate scores. PMID- 25272546 TI - Motivating employees through incentives: productive or a counterproductive strategy. AB - The disparity between human resource in health and provision of health services is a growing concern worldwide. Many developing countries are facing this crisis and therefore human resource in health is considered a high priority on their agenda.This imbalance between supplies of human resource is exacerbated by migration of health workers in many countries. Understanding the motivational factor is an important aspect to retain the migrating health workforce. This paper analyses the role of financial and non financial incentives in motivating the health work force. A review of available literature was conducted to understand the role of motivational factor in retaining health workforce. A review of current literature found that an incentive plays a key role in motivating a health worker. Financial incentives are useful in improving the compliance to standard policies and procedures. Comprehensive integrated incentive system approach should be established to develop a sustainable health workforce with required skill. Likewise monetary incentives should be linked to adherence to provincial and national guidelines and procedures. Sustainability could be ensured by commitment of government, political will and involvement of key stakeholders and decision makers. PMID- 25272547 TI - Honey in the treatment of Fournier's gangrene as an adjuvant: a cross sectional study. AB - Fournier's gangrene is a progressive polymicrobial necrotising infection. The purpose of this study was to assess the outcome of Fournier's gangrene infection in patients who received topical honey with their therapeutic regimens. The cross sectional study included 17 patients with Fournier's gangrene. Under spinal anaesthesia, the necrotic areas were debrided. In the first week, every day, the wounds were cleansed with Betadine, normal saline, and 2% oxygenated water, then 30-50cc of honey was used after the wounds were dried. The wounds were then dressed. This method of dressing was taught to the patients' attendants. The granulation tissues, generally bright pink, were observed on the 10th day. Four (23.5%) patients underwent colostomy and 1 (5.9%) died. All the patients were discharged two weeks after the initial debridement. Compared with other studies, honey reduced the healing and hospitalisation time as well as additional costs. PMID- 25272548 TI - Level of awareness regarding diabetes and its management in diabetic population of Pakistan, and highlighting the role of consultant pharmacist. PMID- 25272549 TI - Risks of drowning and safety concerns at the beaches of Karachi--perspective from lifeguards. AB - Going to beaches is a popular pastime for many people in Karachi. Lifeguards have been deployed on many beaches for the safety and protection of beachgoers. This cross-sectional survey was conducted to study the opinions and experiences of lifeguards posted at eight beaches of Karachi. Ignorance among beachgoers about how dangerous it could be at seaside, was reported by 19 (61.3%) out of 31 lifeguards interviewed. Lifeguards had to put up with verbal and physical abuse while discharging their duties, with verbal abuse being the universal experience. Improved record keeping of drowning and near-drowning data would help make better evidence-informed beach-safety decisions in Karachi for reducing the morbidity and mortality burden owing to drowning. PMID- 25272550 TI - An alternative treatment model: the combination therapy of narrow band ultraviolet B phototherapy and tacrolimus ointment 0.1% in biphasic amyloidosis. AB - Primary localized cutaneous amyloidosis (PLCA) is caused by the extracellular deposition of amyloid material in the skin without other cutaneous or systemic organ involvement. PCLA is classified into lichen, macular,and nodular amyloidosis. Macular amyloidosis and lichen amyloidosis are named as biphasic amyloidosis when they are concurrently seen in a patient. The treatment of this disease is insufficient,even if there are several alternatives for treatment. Here we present a case of biphasic amyloidosis that responded well to topical tacrolimus ointment 0.1% plus narrow band ultraviolet B (NBUVB) treatment treatment to be able to generate a new treatment alternative model. With this case presentation, by reviewing of the treatment modalities of this rarely observed case, will contribute to the solution of the disease. PMID- 25272551 TI - Condensing osteitis of the clavicle in a man: any relationship with tooth decay? AB - Condensing osteitis of the clavicle is a rarely seen pathology since its first description in 1974. Although mechanical stress is claimed for aetiology, but remains a dilemma for physicians. The intermittent or steady pain is variable in intensity and generally localised at the medial end of the involved clavicle, supraclavicular fossa, ipsilateral anterior thorax and shoulder. In this report, we present a 28-year-old man with the regression of the condensing osteitis of the clavicle after the extraction of a decayed tooth. PMID- 25272552 TI - Chronic non puerperal uterine inversion secondary to sub-mucosal fibroid. AB - Inversion of uterus is a rare clinical condition, if not associated with puerperium or third stage of labour. Non-puerperal uterine inversion usually results secondary to tumour implanted at fundus of the uterus. An unusual case of non-puerperal uterine inversion caused by a large submucosal fundal fibroid is reported where a 39-year-old woman presented with heavy bleeding per vaginum and profuse vaginal discharge. Uterine inversion was corrected abdominally by Haultain's procedure after vaginal myomectomy followed by abdominal hysterectomy. Both the ovaries were conserved. PMID- 25272553 TI - Conversion of cardiac bypass into an extracorporeal membrane oxygenation circuit: a case from Pakistan. AB - A 35 days old neonate with d-loop transposition of great arteries, underwent an arterial switch operation following which he developed hypotension attributed to left ventricular failure. During cardiopulmonary resuscitation decision was made to place him on cardiac bypass again. Due to limited resources and unavailability of a specialized extracorporeal membrane oxygenator machine, the CPB was modified and converted an ECMO. The neonate was successfully decannulated after 72 hours and discharged home after 3 weeks of the operation without any sequel. ECMO is a viable option in developing countries and may help in improving the outcome especially in neonatal congenital heart disease. PMID- 25272554 TI - Glutaric aciduria type 1--importance of early diagnosis and treatment. AB - Glutaric aciduria type 1 is a rare inherited organic academia. Untreated patients characteristically develop dystonia secondary to striatal injury during early childhood, which results in high morbidity and mortality. In patients diagnosed during neonatal period, striatal injury can be prevented by metabolic treatment including low lysine diet, carnitine supplementation and aggressive emergency treatment during acute episode of inter current illnesses. However, after the onset of neurological damage initiation of treatment is generally not effective. Therefore; glutaric aciduria type 1 is included in newborn screening panel for inherited metabolic diseases in many countries. We describe two children in a family with glutaric aciduria type 1 and their different long term outcomes. The first child was diagnosed late leading to severe neurological damage. The second child was diagnosed in the neonatal period as a result of selective high-risk screening and was treated appropriately giving a normal growth. PMID- 25272555 TI - t(1:14) and trisomy 4 in a patient with concomitant leukaemias. AB - Cytogenetic abnormalities have long been recognized as the genetic basis of the occurrence of various malignancies. Specific cytogenetic abnormalities have shown to occur recurrently in particular subtypes of leukaemias and lymphomas. t(1;14) is an infrequently occurring recurrent chromosomal translocation that has been described in literature to be associated with haematological malignancies. Trisomy 4 is another rare genetic abnormality which has been reported in association with both acute myeloid and lymphoid leukaemias. The concomitant occurrence of a myeloid malignancy in association with a lymphoproliferative disorder is a distinctly unusual phenomenon. We report the case of a young patient with concomitant T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia with a novel cytogenetic abnormality i.e. t(1;14) with trisomy 4. We believe this is the first reported case where a patient with two concomitant haematological malignancies, harboured this karyotype. PMID- 25272556 TI - The Budd Chiari syndrome: a 22 year male treated successfully with mesocaval shunt. AB - Budd Chiari syndrome (BCS) is a heterogeneous group of disorders characterized by hepatic venous outflow obstruction at any level from the small hepatic veins to the atrio cava junction. BCS could have serious consequences if not treated promptly. Comprehensive angiographic studies, computerised tomography, liver ultrasonography, histology and pathologic analyses are essential for establishing the disease severity, stratifying risk factors, choosing the appropriate therapy and objectively assessing the response. The main objective of therapy is to alleviate portal and IVC hypertension. Here we present a report of a young man with BCS who underwent mesocaval shunt. The eight months follow up showed that patient was free of symptoms and duplex scans confirmed the patency of the shunt. PMID- 25272557 TI - Pharmacotherapy for pre diabetes: moving ahead. PMID- 25272558 TI - Should I prevent my patient from developing depression after stroke? What is the best available option? PMID- 25272559 TI - Shisha..... modern society killer. PMID- 25272560 TI - Myelodysplastic syndrome and aortic valve replacement: additions. PMID- 25272561 TI - Using skeletonised grafts for coronary artery bypass grafting. AB - Coronary artery bypass graft surgery relieves angina symptoms and reduces mortality among ischaemic heart disease patients. It remains the gold standard for the treatment of multi-vessel and left main coronary artery disease. It is a well-known fact that internal mammary artery conduits have excellent and long lasting patency when used for coronary artery bypass grafting. Its supremacy is largely because it prevents atherosclerosis. The old-style internal mammary artery bypass grafting, classically known as pedicle grafting, includes a circular rim of tissue around the graft. Bilateral pedicled internal mammary arteries, especially among diabetic patients, have been reported to cause complications in the sternum like sternal osteomyelitis. In many studies it has been reported that dissection of pedicled internal mammary artery can lead to sternal devascularisation which can lead to higher incidence of infections. Considering the higher incidence of deep sternal infections in patients with double pedicled arterial grafts, dissection of internal mammary artery in skeletonised manner was proposed. In this review, we outline the advantages of skeletonised grafting with respect to incidence of sternal infection, patency rates, blood flow, post-coronary artery bypass graft pain and the length of the graft. PMID- 25272562 TI - Psychiatric comorbidity in children with high-functioning pervasive developmental disorder. AB - BACKGROUND: In previous studies for children with pervasive developmental disorder (PDD), the prevalence for psychiatric comorbidities has varied because of their methodological differences. In this research, our PDD subjects were strictly limited by age and IQ scores, and we utilized a semi-structured interview to diagnose their coexisting disorders. The purpose of this study is to identify reliable prevalence and types of psychiatric comorbidities in children with high-functioning PDD (HFPDD). METHODS: The subjects were 49 children aged 6 15 years with HFPDD. In order to diagnose the comorbidities among them, we used the Japanese version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version. RESULTS: Forty-eight cases (98%) met the criteria for at least one comorbidity. The median number of the present comorbidities per child was 2, and the mode was 2. Depression (37%), attention deficit hyperactivity disorder (49%), and oppositional defiant disorder (45%) were frequently observed. CONCLUSIONS: Our finding indicates the high prevalence of comorbidities and the variety of the comorbid disorders in children with HFPDD. It is important to be aware of those comorbid disorders to provide the children with effective treatments. PMID- 25272563 TI - Use of tricyclic antidepressants as analgesic adjuvants results in nonhazardous prolongation of the QTc interval. AB - BACKGROUND: Tricyclic antidepressants (TCAs) are known to prolong QTc interval. However, little is known about the QTc lengthening effect of TCAs at analgesic dosages and the predictive factors for abnormal QTc prolongation. METHODS: We conducted a single-center, retrospective observational study, and evaluated 87 patients (65 amitriptyline, 22 nortriptyline) who underwent 12-lead electrocardiogram (ECG) examinations both before and after receiving TCAs for herpes zoster pain or postherpetic neuralgia from May 2007 to January 2012. Data on QTc interval, age, gender, the type and daily dosage of TCAs, the medication period until the second ECG examination, and ECG findings were obtained from electronic medical charts. RESULTS: The median daily dosages were 25 mg/day for amitriptyline and 10 mg/day for nortriptyline. The median medication period for all participants was 62 days. TCAs significantly prolonged the QTc interval (before, 413.2 +/-17.0 ms; after, 419.9 +/- 18.9 ms, p < 0.01). Three patients showed marked QTc prolongation, but it did not exceed 500 ms, or deltaQTc of 60 ms, and none had an episode of fatal arrhythmia. Univariate logistic regression analysis revealed left ventricular hypertrophy (LVH) to be the sole risk factor for abnormal QTc prolongation. The adjusted odds ratio was 4.09 (95% CI, 1.01 16.55, p < 0.05) by multivariate logistic regression analysis. CONCLUSIONS: TCAs as analgesic adjuvant significantly prolonged the QTc interval, but within an acceptable range. LVH was a significant predictor of abnormal QTc prolongation. PMID- 25272564 TI - Efficacy of single-incision laparoscopic appendectomy in adults and adolescents using an endolinear stapler. AB - BACKGROUND: Some investigators recently introduced transumbilical single incisional laparoscopic appendectomy (SILA), however, those SILA require expensive surgical instruments, or difficult technique. We uniquely propose performing SILA using with endolinear stapler, and compare the clinical results of the present SILA with those of conventional laparoscopic appendectomy. MATERIALS AND METHODS: In brief, the skin of the umbilical hollow is cut, the anterior layer of the rectus sheath and subcutaneous fat is exfoliated widely, and the linea alba is opened. Two low-profile 5-mm-diameter trocars are stabbed through the right rectus sheath, and a 12-mm-diameter trocar is inserted from the opened linea alba. Using a 5-mm laparoscope, and endolinear stapler, the appendix is dissected. Some clinical and operative data of 16 cases treated the present SILA are compared with those of 35 cases treated conventional laparoscopic appendectomy. RESULTS: We performed the present SILA for 16 patients consisted of young women mostly, compared with cases treated conventional laparoscopic appendectomy (mean, 26-year-old vs 51-year-old, p < 0.0001). The results of the SILA we have proposed in adults and adolescents are good in terms of operation time (mean, 64 minutes vs 89.3 minutes, p = 0.049), duration of hospitalization (mean, 4.2 days vs 8.1 days, p = 0.0038), and low frequency of intra- and postoperative complications (one patient of postoperative umbilical granuloma). CONCLUSIONS: We assume that convenience of surgical procedure of the present SILA would affect the shortness of operation time, and that minimal invasive surgical stress of the present SILA would reduce perioperative stress of appendicitis, and ameliorate adolescents with appendicitis earlier. We believe that the SILA we have proposed offers advantages in diversion of conventional surgical instruments, similarity to conventional manipulation of laparoscopic forceps, usage of an endoscopic stapler able to cut cecum in cases of advanced appendicitis extending to the cecum, and obviation of extra-abdominal appendectomy demanding excessive traction of the appendix. PMID- 25272565 TI - Role of levothyroxine supplementation in extremely low birth weight infants who have transient hypothyroidism without thyroid-stimulating hormone elevation. AB - BACKGROUND: Preterm infants show transient hypothyroxinemia without thyroid stimulating hormone (TSH) elevation. In addition, the degree of neurodevelopmental delay in preterm infants become severe according to the decreasing gestational age (GA). Because of the crucial role of thyroid hormones in brain development, hypothyroxinemia has the potential to cause developmental delay; however, the effectiveness of thyroxine (T4) supplementation on developmental outcomes remains controversial. To resolve these issues, we evaluated the clinical course of transient hypothyroxinemia and the effects of levothyroxine (LT4) supplementation in extremely low birth weight (ELBW) infants. METHODS: Serum levels of free T4 (FT4) and TSH were examined in 36 ELBW infants from 7 days after birth. LT4 (5-10 microg/kg/day) was orally administered to 18 of 36 infants with a low serum FT4 level (< 0.4 ng/dL) or normal serum FT4 levels and a clinical manifestation of hypothyroidism, whereas remaining 18 patients without a low serum FT4 level or clinical hypothyroidism were not given LT4 supplementation as control subjects. Infants were followed-up at a corrected age of 12 months, and clinical outcome was compared between infants that received LT4 and those that did not. RESULTS: ELBW infants showed low serum FT4 levels without TSH elevation. During hospitalization and at follow-up, LT4-administered infants with low serum FT4 levels showed a shorter GA compared with the control group. There were no other statistically significant differences in clinical outcomes at 12 months of corrected age between LT4-administered and control groups. CONCLUSIONS: Our results show that shorter GA is associated with lower serum FT4 levels. Shorter GA is known to cause developmental delay, however, LT4 supplementation prevents the developmental delay of ELBW infants with transient hypothyroxinemia. PMID- 25272566 TI - Cholangiocarcinoma in a middle-aged patient working at a printing plant. AB - A 39-year-old male with elevated serum transferases consulted our hospital in September 2010. Since 1999, he had worked at a printing company using organic solvents. Cholangiography revealed stenosis of the left hepatic duct with peripheral dilation, stricture of the right hepatic duct, and irregularity of the extrahepatic bile duct. As a preoperative diagnosis of sclerosing cholangitis and cholangiocarcinoma was made, extended left hepatectomy with resection of the extrahepatic bile duct and anastomosis of the anterior and posterior branches of the bile duct and the jejunum (Roux-en Y reconstruction) were performed. A histological examination showed papillary carcinoma of the medial hepatic bile duct with intraductal growth, and biliary intraepithelial neoplasia-2/3 lesions from the medial hepatic bile duct to the right hepatic and the common bile ducts. Chronic cholangitis was shown around the tumors. Postoperatively, the patient was treated with adjuvant chemo-radiation, and he is doing well 30 months after the operation, without recurrence. Unknown causes, including exposure to organic solvents, might have induced chronic bile duct injury and contributed to the development of cholangiocarcinoma. PMID- 25272567 TI - Diffusion-weighted magnetic resonance imaging findings in a patient with struma ovarii. AB - In this report, the magnetic resonance imaging (MRI) appearance of struma ovarii (SO) in a patient who underwent diffusion-weighted imaging (DWI) of the pelvis and subsequent histological analysis is described. The solid portion of SO showed a high apparent diffusion coefficient (ADC) value, indicating unrestricted diffusion, and each loculus of SO showed different ADC values due to the different viscosity of the cyst contents in each loculus. These unique and characteristic DWI findings may serve as a helpful sign in making the correct diagnosis of SO when DWI findings are interpreted in conjunction with conventional MRI findings. PMID- 25272568 TI - [The quiet woman, or the story of the doll Alma--meetings of painters]. PMID- 25272569 TI - [The return of clinical ethics]. PMID- 25272570 TI - [Reorganisation: a dialogue with posterity--permanent exhibitions of the Museum of Fine Arts]. PMID- 25272571 TI - [Current bioethical issues in Germany]. PMID- 25272572 TI - Flavonoids--food sources and health benefits. AB - Flavonoids are a group of bioactive compounds that are extensively found in foodstuffs of plant origin. Their regular consumption is associated with reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD) and neurodegenerative disorders. Flavonoids are classified into subgroups based on their chemical structure: flavanones, flavones, flavonols, flavan-3-ols, anthocyanins and isoflavones. Their actions at the molecular level include antioxidant effects, as well the ability to modulate several key enzymatic pathways. The growing body of scientific evidence indicates that flavonoids play a beneficial role in disease prevention, however further clinical and epidemiological trials are greatly needed. Among dietary sources of flavonoids there are fruits, vegetables, nuts, seeds and spices. Consumption of these substances with diet appears to be safe. It seems that a diet rich in flavonoids is beneficial and its promotion is thus justifiable. PMID- 25272573 TI - Diacetyl exposure as a pneumotoxic factor: a review. AB - Diacetyl (2,3-butanedione) is a natural ingredient in foodstuffs which is not generally regarded health risk to consumers. Nevertheless, when manufactured for use as a synthetic flavouring/additive in processed foods (e.g. microwave popcorn), it poses a human health threat at the workplace. Its pneumotoxic action consists of inflammation, obstruction and restriction in the distal respiratory tract. One of the factors causing bronchiolitis obliterans is also recognised to be diacetyl. The scientific literature mostly describes human exposure to diacetyl in factory settings where functional disorders and structural changes of the respiratory system have been recorded, particularly bronchiolitis obliterans. Moreover, differential diagnosis shows pathological changes in the distal respiratory tract and in the pneumotoxic actions of diacetyl. PMID- 25272574 TI - Development and validation of a method for determination of selected polybrominated diphenyl ether congeners in household dust. AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs) belong to group of so-called persistent organic pollutants (POPs). These compounds occur in nearly all elements of the environment, including household dust which constitutes one of a major route for human exposure. Their main adverse effects on human health are associated mainly with endocrine disruption--they interfere with thyroid function exhibit anti-androgenic action. OBJECTIVES: To develop and validate analytical method for determination of BDE-47, BDE-99, BDE-153, and BDE-209 congeners in household dust. MATERIAL AND METHODS: Household dust was sampled in residences from Warsaw and the surrounding areas. An automated Soxhlet extraction of samples was then performed and PBDE congeners were subsequently measured in cleaned-up extracts by GC-microECD. The identity of quantified compounds was confirmed by GC/MS. RESULTS: Household dust samples were fortified at levels of 2.88, and 28.8 ng g(-1) for BDE-47, BDE-999, and BDE-153, and for BDE-209 at levels of 101.2, and 540 ng g(-1). Recoveries ranged between 72 - 106%. The relative standard deviations (RSD) were less than 16% for all PBDE congeners analysed. The relative error determined on the basis of multiple analyses of certified reference material ranged from 1.07 - 20.41%. The method's relative expanded uncertainty varied between 16 - 21%. CONCLUSION: The presented method was successfully validated and can be used to measure concentrations of BDE-47, BDE-99, BDE-153 and BDE-209 congeners in household dust. PMID- 25272575 TI - Variations of niacin content in saltwater fish and their relation with dietary RDA in Polish subjects grouped by age. AB - INTRODUCTION: A rich and natural source of readily assimilated dietary protein together with invaluable vitamins and minerals are fish, particularly the saltwater species. The quality of any given foodstuff is determined by its nutritional value, which in turn depends on the food type and methods used for manufacture, processing and storage. Many fish products contain fewer water soluble vitamins than the source foodstuff as a result of using various technologies during food processing, such as smoking or deep freezing, where vitamins are often either degraded or leached out. In the case of niacin it is relatively easy to make good such losses by eating niacin-rich foods or by taking dietary supplements e.g. the essential amino acid L-tryptophan. OBJECTIVES: To determine niacin content in sea fish that are commonly available on the Polish market and to assess whether this dietary source is sufficient to satisfy the RDA requirements for various age groups of selected subjects living in Poland. MATERIAL AND METHODS: Niacin levels were measured firstly in 10 saltwater fish species together with butterfish and Norwegian salmon that formed a separate group. Altogether, 15 types of fish products were analysed in all. They consisted of smoked fish: whitefish, butterfish, sprat, trout, herring (kippers) and mackerel, and frozen fish: butterfish, Norwegian salmon, sole, grenadier and panga. Each product was measured as ten replicates, thus in total 150 analyses were performed. A microbiologically-based method was used for the niacin determination, with enzyme hydrolysis by 40 mg papain and diastase on a 2 g sample (according to the AOAC procedure) to release the free form from the bioavailable form that is bound to NAD and NADP. RESULTS: The most plentiful sources of niacin were found in smoked fish with the highest amounts in butterfish, after warm temperature smoking, and in mackerel; respectively 9.03 and 8.90 mg/100 g. Such 100 g portions of smoked fish are a good dietary source of niacin, in that for men and women above 19 years of age, they constitute respectively 22% - 56% and 25% - 64% of the RDA (Recommended Daily Allowance). The highest levels of niacin in frozen fish were found in butterfish and Norwegian salmon; respectively 8.05 and 5.75 mg/100 g which in turn represent respectively 10% - 50% and 11% - 56% of the RDA in men and women aged above 19 years. CONCLUSIONS: Niacin concentrations varied according to fish species. The richest dietary sources were smoked fish consisting of butterfish, after warm temperature smoking, and mackerel. In frozen fish, butterfish and Norwegian salmon had the highest niacin amounts. A 100 g serving of such sea fish can, to quite a large extent, satisfy the adult RDA. PMID- 25272576 TI - Evaluating adult dietary intakes of nitrate and nitrite in Polish households during 2006-2012. AB - INTRODUCTION: Nitrates and nitrites commonly occur throughout nature as well as in foodstuffs. Their excess consumption can however pose health risks, for example, arising from methaemoglobinaemia or from the formation of N nitrosamines. OBJECTIVES: To determine whether the levels of domestic nitrate and nitrite consumption are safe in Polish households during 2006-2012. MATERIAL AND METHODS: Appropriate consumption data was obtained from the Central Statistical Office in Poland (GUS), whilst nitrate and nitrite intakes were estimated from nationally available data on foodstuff content taken from the literature. RESULTS: Mean nitrate and nitrite intakes were respectively 147 mg NaNO3 and 3.26 mg NaNO2/per person/day, corresponding to 41% and 45% of the ADI (acceptable daily intake). Statistically significant differences in intakes were observed between types of households, with the highest seen in those of retired subjects; however the ADIs were not exceeded. CONCLUSIONS: Domestic intakes of nitrates and nitrites were found to be at safe levels; nevertheless control over their intake should be maintained because of potentially adverse health threats. PMID- 25272577 TI - School pupils and university students surveyed for drinking beverages containing caffeine. AB - BACKGROUND: Caffeine is a commonly found ingredient in many beverages. Its main dietary source is coffee, cola drinks and in recent years, energy drinks. OBJECTIVES: To compare the consumption of drinks containing caffeine (coffee, colas and energy drinks) and the reasons and circumstances under which they were drunk by middle school (junior high school) pupils and university students. MATERIAL AND METHODS: Surveyed subjects were 90 middle school pupils from Warsaw and Kutno together with 100 students attending the Warsaw University of Life Sciences (SGGW). A questionnaire, designed by the authors, was used to determine the amounts, frequency and the reasons or circumstances in which coffee, colas and energy drinks were consumed. Statistics used, consisted of the Mann-Whitney U and Chi-square (chi2) tests, with significance taken as alpha < or = 0.05. RESULTS: Cola drinks were found to be the most popularly consumed beverages containing caffeine; 97% pupils and 93% students. Coffee was however drunk twice less by pupils compared to students, whilst similar amounts of energy drinks were consumed by both groups; respectively 48% and 53%. Gender differences were observed for the energy drinks with young men drinking the most. Coffee and energy drink consumption also rose with age by respectively 39% and 57%. The mean caffeine intake in pupils and students were respectively estimated to be 141 and 163 mg/day(d). The reasons why these beverages were drunk varied, from drinking coffee to keeping awake and drinking cola because of its good taste. Pupils also drank energy drinks due to its taste but students because of improved mental performance and in staying awake. CONCLUSIONS: Drinking caffeine containing drinks by adolescents can be very variable and comes from many different sources. Thus, its intakes may be very high and so require monitoring, particularly for the youngest. Further observational studies are needed to assess the consumption of energy drinks in relation to physical activity. PMID- 25272578 TI - The use of vitamin supplements among adults in Warsaw: is there any nutritional benefit? AB - BACKGROUND: The use of dietary supplements is widespread and can contribute substantially to total nutrient intake. However, it also generates some potential risks in the case of unreasonable and excessive use of such products. OBJECTIVE: To estimate the prevalence of supplementation and the vitamin supplement contribution to total intake among Warsaw population aged 20-74 years. MATERIAL AND METHODS: Nutrient intake and supplement use were studied in a representative sample of Warsaw population in years 2011/12 (486 men and 421 women) and in 2001 (658 and 671 respectively). The vitamin levels were analyzed in reference to the Recommended Dietary Allowance (RDA) and the tolerable upper intake level (UL). RESULTS: In the years 2011/12 the use of dietary supplements (vitamins and minerals) was reported by 31% men and 40% women. Vitamin intake from food showed the deficiency of vitamins D, B1 and folates and adequate intake of vitamins A, C, E, B2, B6, B12. Supplementing with vitamins D and B1 as well as folic acid contributed to better RDA fulfillment. Supplementing with vitamins A, C, E, B2, B6 and B12 was not justified because these vitamins were taken in sufficient amounts with food. In 1.3%-14.9% supplement users, the total intake of vitamins A, C, E and B6 exceeded the UL. The prevalence of supplementation of vitamins A, C and E did not change between 2001 and 201 1/12, but the total intake of vitamin A in both sexes and vitamins C, E in women was significantly higher in 2001. CONCLUSIONS: The use of dietary supplements in Warsaw population was widespread and in case of some vitamins- unreasonable. PMID- 25272579 TI - Energy and nutritional value of the meals in kindergartens in Nis (Serbia). AB - BACKGROUND: It is well known that high-energy diet, rich in fat and carbohydrates, increases the risk of obesity. Preschool age is an important period to acquire the eating habits continued later in adulthood. Therefore, evaluation of child nutrition in kindergartens is especially important in the prevention of future obesity. OBJECTIVES: To determine the energy value and energy density of meals consumed by children in kindergartens in Nis (Serbia), including the different types of food, in respect to a probable risk of obesity. MATERIAL AND METHODS: The study had been conducted in the years 1998-2012. Three hundred samples of the meals were gathered and analysed, and the amount of selected food groups used to prepare the meals in kindergartens was calculated (weight, protein, fat and carbohydrate content) in the accredited laboratory of the Public Health Institute in Nis according to the ISO 17025 recommendation. RESULTS: The mean energy value of meals was 978.9 kcal (range: 810 - 1144 kcal). The energy density was low (mean: 1.02 kcal/g, range: 0.92 - 1.42 kcal/g) and decreased over the years, what would imply a reduction in the risk of obesity. The intake of same high-energy food products, such as fats and oils as well as sweets (13.9% and 7.3%, respectively) was higher compared to low-energy foods (fruits - 5.2% and vegetables - 10.8%). CONCLUSIONS: The results of our study indicate that children in kindergarten in Nis, in general, were properly nourished in total energy content. The energy value and energy density of the meals consumed did not pose a risk of developing obesity. However, the distribution of food groups differentiated by the energy density level was unfavourable; the deficit of low-energy foods was observed. Planning the child nutrition in kindergartens, with laboratory control of meals, may be an effective strategy in adequate energy intake and prevention of obesity. Providing the higher amount of low-energy foods (fruits and vegetables) in meals in kindergartens is recommended. PMID- 25272580 TI - Comparing diabetic with non-diabetic overweight subjects through assessing dietary intakes and key parameters of blood biochemistry and haematology. AB - INTRODUCTION: An important way of preventing type 2 diabetes is by adopting a proper diet by which means appropriate control over blood glycaemia and lipids can be achieved. OBJECTIVES: To assess selected biochemical and haematological markers in overweight subjects or those suffering from type 2 diabetes in relation to their estimated dietary intake. MATERIAL AND METHODS: The study was conducted in 2012 on n = 86 overweight or obese subjects living in Warsaw or its environs, of whom n = 43 had type 2 diabetes. Dietary intakes were compared between non-diabetics (control group) and diabetics (test group) by 3 day records, whilst the relevant blood biochemistry and haematology results were obtained from medical records; with patient consent. RESULTS: Diabetic subjects had significantly higher serum glucose and CRP levels than controls, respectively; 190 vs 98 mg/ dl and 1.4 vs 1.1 mg/dl. Lipid profiles were however more significantly abnormal in controls, compared to diabetics with respectively; total cholesterol 220 vs 194 mg/dl, LDL-cholesterol 131 vs 107 mg/dl and triglycerides 206 vs 157 mg/dl. There were no significant differences in HDL cholesterol; respectively 55 vs 51 mg/dl. In the diabetics, calorific intakes from carbohydrates, especially sugars, were significantly lower than controls i.e. 9% vs 13%. The proportional share of calories derived from dietary fats did not differ between groups, nevertheless a positive correlation was observed between dietary fat content with blood cholesterol concentrations in diabetics. CONCLUSIONS: Disorders of carbohydrate metabolism were confirmed in both overweight and diabetic (type 2) subjects. In addition, both groups demonstrated untoward lipid profiles that correlated with their improper nutrition. PMID- 25272581 TI - Nutritional values of diets consumed by women suffering unipolar depression. AB - BACKGROUND: Previous studies have shown that patients suffering from depression are more likely to adversely change their eating habits (eg. through increases in appetite, comfort eating and compulsive eating), which may result in an abnormal nutritional status. OBJECTIVES: To evaluate selected dietary habits, such as the number and type of meals consumed during a normal day and comparing dietary calorific values and nutritional content between women suffering unipolar depression to those without this condition. MATERIAL AND METHODS: Subjects were a group of 110 women aged 18-65 years consisting of a test group of 55 women undergoing treatment for unipolar depression at the Department of Psychiatry, Medical University of Bialystok and a control group of 55 women, without depression, attending an Obesity and Diet Related Treatment Centre. A study questionnaire was used to determine their eating habits along with other relevant data. The 24-hour diet recall method was used to obtain quantitative data collected on 3 weekdays and 1 weekend day; results being averaged. The calorific values and nutrient content of selected components, according to mealtimes, were evaluated using the Diet 5.0 computer programme. RESULTS: Those patients with depression showed that the 3 meals/day model dominated whilst the 4 meals/day model was predominant in the control group. The most frequently missed meals for both groups were afternoon tea and the mid-morning meal. Abnormalities in the calorific intake and nutritional contents from various meals were observed in women suffering depression. CONCLUSIONS: It seems appropriate to recommend that those women especially suffering from depression should consult with dieticians about their changing dietary habits, particularly for achieving the proper calorific and nutritional values/ balance from their meals. PMID- 25272582 TI - Awareness of factors affecting osteoporosis obtained from a survey on retired Polish subjects. AB - BACKGROUND: Osteoporosis is a growing problem facing modern society and currently poses one of the most serious health challenges. It is a progressive skeletal disease characterised by low bone mineral density whose development depends on multiple factors. These principally include increasing age, nutrition, physical activity, endocrine changes, lifestyles, general health condition and taken drugs. OBJECTIVES: To assess how much subjects (aged > 50 years) are aware of the dangers in contracting osteoporosis along with the effects that lifestyle and dairy product consumption can have on this condition developing. MATERIAL AND METHODS: A questionnaire, designed in-house, was used to survey a group of 150 randomly selected individuals aged above 50 years. This was performed in June 2012. Questions were on socio-demographics, milk and dairy product consumption, physical activity as well as assessing knowledge about osteoporosis that included issues such as its incidence, prevention and morbidity. RESULTS: Osteoporosis was established in 60.7% subjects of whom 69.2% were women. Only 9.3% never consumed any dairy products. Physical activity of some kind was undertaken by 77.3% subjects. Within the last year, 38.0% reported having fractures of whom 46.0% had osteoporosis and 25% were healthy. Respondents were aware that consuming dairy products is beneficial to bone health and this awareness was higher among those with osteoporosis. Physical activity was also recognised to be important in preventing this condition. CONCLUSIONS: Subjects suffering from osteoporosis had twice as many more fractures than healthy subjects. PMID- 25272583 TI - Responsiveness to the hospital patient needs in Poland. AB - BACKGROUND: The health system responsiveness, defined as non-medical aspect of treatment relating to the protection of the patients' legitimate rights, is the intrinsic goal of the WHO strategy for 21st century. OBJECTIVE: To describe the patients' opinions on treatment they received in hospital, namely: admission to hospital, the role of patient in hospital treatment, course of treatment, medical workforce attitude, hospital environment, contact with family and friends, and the efficacy of hospital treatment in respect to responsiveness to patient's needs and expectations (dignity, autonomy, confidentiality, communication, prompt attention, social support, basic amenities and choice of provider). MATERIAL AND METHODS: The data were collected in 2012 from 998 former patients of the randomly selected 73 hospital in Poland. RESULTS: Dignity: Over 80% of patients experienced kindness, empathy, care and gentleness, and over 90% of them had the sense of security in hospital, met with friendliness during the admission to hospital and never encountered inappropriate comments from medical staff. Autonomy: About 80% of patients accepted the active role of patients in hospital, they perceived they had influence on procedures related to hospitalization and course of treatment, and they felt medical staff responded to their requests and concerns. Over 90% of them had opportunity to communicate their concerns to medical staff and to discuss the course of treatment. On the other hand, the explanation of the reason for the refusal to meet their requests was given to only 23% of the patients interested. Confidentiality: 70-80% of patients declared the respect for privacy and confidentiality during collecting the health information and during medical examinations, and were not examined in presence of other people. Nevertheless, only 23% of patients examined so were asked of their consent. Communication: About 90% of patients declared they trusted their physician, received from him explanation regarding the course of treatment and information about further treatment after discharge from hospital, but physicians devoted the time and attention to only 70% of them. Prompt attention: Over 90% of patients perceived simplicity of the formalities of admission to hospital, and short waiting for treatment and additional tests in hospital (but only 50% received explanation of reason if they waited long). Nevertheless, 10% of them % of them perceived they waited for admission to hospital too long, and over 20% for admission to a ward as long. Social support: The unlimited direct and phone contact with family and friends was declared by 96% of patients. Basic amenities: The high percentage of patients assessed positively the marking in hospital (97%) and cleanliness of linen (89%), followed by the general indoor appearance room in which patient stayed, lack of noise (70-80%), hospital meals, furniture (60-70%), availability of personal hygienic articles (50-60%), cleanliness of hospital room, toilet, showers and bathtubs, and availability of soap (40-50%). Choice of provider: Only 41% of patients declared that they had influence on choice of the hospital. CONCLUSION: Responsiveness of Polish hospital patient needs is similar to that of the OECD countries of the lowest health system responsiveness. Compared to the Central European countries, the responsiveness in Polish hospitals is lower than that of Czech Republic and only slightly higher of those of Slovenia, Slovakia and Hungary. PMID- 25272584 TI - [Complete genomic analysis of a novel infectious bronchitis virus isolate]. AB - The genome of CK/CH/SD09/005, an isolate of infectious bronchitis virus (IBV), was characterized to enable the further understanding of the epidemiology and evolution of IBV in China. Twenty-five pairs of primers were designed to amplify the full-length genome of CK/CH/SD09/005. The nucleotide sequence of CK/CH/SD09/005 was compared with reference IBV strains retrieved from GenBank. The phylogenic relationship between CK/CH/SD09/005 and the reference strains was analyzed based on S1 gene sequences. The complete genome of CK/CH/SD09/005 consisted of 27691 nucleotides (nt), excluding the 5' cap and 3' poly A tail. The whole-genome of CK/CH/SD09/005 shared 97 - 99% nucleotide sequence homology with the GX-NN09032 strain, which was the only complete genome that was closely related to CK/CH/SD09/005. When compared with all reference strains except GX NN09032, CK/CH/SD09/005 showed the highest similarity to ck/CH/LDL/091022 and SDIB821/2012 (QX-like) in the replicase gene (Gene 1) and 3'UTR, with a sequence identity rate of 97% and 98%, respectively. However, CK/CH/SD09/005 exhibited lower levels of similarity with ck/CH/LDL/091022 and SDIB821/2012 in S-3a-3b-3c/ E-M-5a-5b-N with a sequence identity of 72% - 90%. CK/CH/SD09/005 showed the highest level of nucleotide identity with Korean strain 1011, and Chinese strains CK/CH/LXJ/02I, DK/CH/HN/ZZ2004 and YX10, in ORF 3c/E (97%), 5a (96%), 5b (99%) and N (96%), respectively. ORFs 3a, 3b and M of CK/CH/SD09/005 exhibited no more than 90% homology with the reference strains, excluding GX-NN09032. The phylogenic analysis based on the S1 gene revealed that CK/CH/SD09/005 and 39 published strains were classified into seven clades (genotypes). CK/CH/SD09/005 was distributed in clade IV with several isolates collected between 2007 and 2012. CK/CH/SD09/005 showed 66% - 69% and 72% - 81% nucleotide identities with the IBV strains of other six clades in the S1 and S2 subunits, respectively. More over, multiple substitutions were found throughout the entire S gene of CK/CH/SD09/005, while insertions and deletions were located within the S1 gene. These results indicated that CK/CH/SD09/005 is a novel variant that may be derived from the QX-like strains that are prevalent in China. Multiple genetic mechanisms, including recombinations, mutations, insertions and deletions, are likely to have contributed to the emergence of this IBV strain. PMID- 25272585 TI - [Identification of prototype foamy virus Bel1 nuclear localization signal and its corresponding importins]. AB - Bel1, a transactivator of prototype foamy virus (PFV), plays pivotal roles in the replication of PFV. Previous studies have shown that Bel1 bears a nuclear localization signal (NLS), but its amino acid sequence remains unclear and the corresponding importins have not been identified. In this report, we inserted various fragments of Bel1 into an EGFP-GST fusion protein and investigated their subcellular localization by fluorescence microscopy. We found that the 215PRQKRPR221 fragment could direct nuclear localization, which accords with the consensus sequence K(K/R)X(K/R) of monopartite NLS. Point mutation experiments revealed that K218, R219, and R221 are essential for the nuclear localization of Bel1. The results of the GST-pulldown showed that the Bel1 fragment with residues 215-223, which bears the NLS, interacts with KPNA1, KPNA6, and KPNA7. This result suggests that KPNA1, KPNA6, and KPNA7 maybe involved in Bel1 nuclear translocation. PMID- 25272586 TI - [Dynamic distribution of the avian infectious bronchitis virus isolate strain Jin 13 in SPF chickens]. AB - This study aimed to understand the dynamic distribution of infectious bronchitis virus (IBV) Jin-13 strain in SPF chickens. Ninety-day-old SPF chickens were inoculated with Jin-13, a virulent strain, and dissected at day 1, 4, 7, 10, 14, 21, 28 or 35 post-inoculation (dpi). Samples of heart, liver, spleen, lung, trachea, kidney and duodenum were collected and the N gene was detected by Sybr Green I real-time quantitative RT-PCR assays. The established method had a good linear correlation from 7.77 x 10(8) to 10(0) copies/microL. SPF chickens developed typical clinical signs of IBV at the 4th dpi, and the IBV viral concentration of tissues and organs gradually increased with a peak of up to 7.13 x 10(4) copies/microL. The viral concentration of most organs decreased by the 10th dpi, but those of the kidney, trachea and lung remained positive for IBV at 28 dpi and the heart was still positive for IBV at > 35 dpi. The results of this study, showed that the Jin-13 strain can cause prolonged virus excertion in chickens with severe renal damage. PMID- 25272588 TI - [Detection of an NA gene molecular marker in H7N9 subtype avian influenza viruses by pyrosequencing]. AB - This study aimed to establish a method for the detection and identification of H7N9 avian influenza viruses based on the NA gene by pyrosequencing. According to the published NA gene sequences of the avian influenza A (H7N9) virus, a 15-nt deletion was found in the NA gene of H7N9 avian influenza viruses. The 15-nt deletion of the NA gene was targeted as the molecular marker for the rapid detection and identification of H7N9 avian influenza viruses by pyrosequencing. Three H7N9 avian influenza virus isolates underwent pyrosequencing using the same assay, and were proven to have the same 15-nt deletion. Pyrosequencing technology based on the NA gene molecular marker can be used to identify H7N9 avian influenza viruses. PMID- 25272587 TI - [Isolation, identification and genetic analysis of a murine norovirus strain]. AB - Murine norovirus (MNV) was first discovered in mice in 2003. MNV is a member of the genus Norovirus in the family Caliciviridae. It is one of the most important and prevalent pathogens of laboratory mice, and almost all mouse strains are susceptible to MNV infection. In this study, a MNV strain was isolated from the cecal contents of infected mice and identified by the cytopathic effect (CPE) assay, virus plaque assay, 50% tissue culture infectious dose (TCID50) assay, electron microscopy, indirect immunofluorescence assay (IFA) and nucleotide sequencing. On infection, the RAW264.7 cell line showed obvious cytopathic effects within 24 to 48 hours post-inoculation, as infected cells became rounded, bright and shrunken, with ultimate disintegration of the cell sheet. After the isolation of the MNV virus, the virus was plaque-purified in RAW264.7 cells. The TCID50 of the virus was 10(5.25/0.1 mL. Electron microscopic observations of the purified virus showed the presence of spherical and non-enveloped viral particles that were 30 to 35 nm in diameter. According to the identification results, the isolate was named as MNV Guangzhou/K162/09/CHN. Thereafter, five overlapping gene fragments that covered the entire open reading frame (ORF) were amplified by RT PCR, and the 3'-untranslated region (UTR) and 5'-UTR were amplified using the 3' rapid amplification of cDNA ends (RACE) and the 5'-RACE method, respectively. Each of the gene fragments were cloned and sequenced, and whole genome sequences of the strain were obtained by assembling the cDNA fragment sequences. The results showed that the length of the complete genome was 7 380 nucleotides (GenBank accession number: HQ317203). The comparison of nucleotide and deduced amino acid sequences of the isolate was performed against other MNV strains in the GenBank database. A phylogenetic tree based on VP1 nucleotide sequences was constructed using MEGA5.0 software. The homology of nucleotides between the MNV Guangzhou/K162/09/CHN strain and other MNV isolates ranged from 87.4% to 89.7%. Phylogenetic analysis showed that there was a close genetic relationship between the Guangzhou/K162/09/CHN strain and MNV strains isolated from Japan (S7-P2 and S7-PP3 isolates), Korea (K4 isolate), and Germany (Berlin/04/06/DE and Berlin/05/06/DE isolates). This is the first report of the isolation and identification of MNV in China, and the first report of the genetic analysis of its complete genome. PMID- 25272589 TI - [Isolation, identification and full-length genome sequence analysis of encephalomyocarditis virus from local aardvarks]. AB - Encephalomyocarditis virus (EMCV) is a natural epidemic zoonotic pathogen. However, no reports have been published regarding the isolation, identification and full-length genome of EMCV from a local aardvark population. In present study, an EMCV isolate HNXX13 was isolated from aardvarks named Huainan-pig in Henan Province. The systematic identification, full-length genome sequencing and molecular characteristic analysis of the isolate HNXX13 were conducted. The result showed that the isolate was spherical with a diameter of 24-30 nm, neither heat- nor acid-resistant, sensitive to trypsin, insensitive to chloroform, not protected by bivalent cationic, and the specific fluorescence was observed in the cytoplasm of BHK-21 cells infected with the isolate by using indirect fluorescence assay. The full-length genome of EMCV HNXX13 generated a 7 725bp sequence (GenBank: F771002), with 81.0%-99.9% nucleotide identity to reference strains from different animals, and 99.5% with a Chinese reference strain isolated earlier from a commercial pig herd. The phylogenetic tree based on the full-length genome and ORF sequences identified that all EMCV strains were divided into three groups G1, G2 and G3, and strain HNXX13 belonging to the G1 group with other Chinese reference strains. The result also identified that this EMCV infection could cause severe clinical signs in a local aardvark population, and enriches the molecular epidemiological data of EMCV in China. Regional differences exist in EMCV genome and transmission is limited within a certain area. However, the cross-infection and transmission of EMCV between aardvark and mice appears most likely. Mutations have occurred in some amino acids of EMCV strain HNXX13 during the transmission in local aardvark herd and these mutations might make the virus easier to infect the aardvark. PMID- 25272590 TI - [Establishment of a method to detect duck hepatitis B virus covalently closed circular DNA based on rolling circle amplification]. AB - Rolling circle amplification (RCA) is a newly developed experimental technique that can specific ally amplify circular DNA. Since 2008, RCA has been extensively used in hepatitis B virus (HBV) research, such as the amplification of the full length sequence of the HBV genome, and the analysis of the drug-resistant mutations of HBV covalently closed circular DNA (cccDNA), amongst others. To create an easy assay for the analysis of duck hepatitis B virus (DHBV) cccDNA, this study established an RCA-based method. DHBV cccDNA was amplified from the DHBV DNA samples of duck liver with four pairs of sulfur-modified primers, which were designed according to the highly conserved sequence of DHBV using sera DHBV DNA as the negative control. DHBV cccDNA was detected in the obtained RCA products by the sequencing of RCA amplicons that were amplified with primer pairs on both sides of the gap of DH BV relaxed circular DNA, rather than by digesting RCA products with a restriction enzyme. The liver and sera DHBV DNA samples of 39 ducks infected with DHBV were examined with the RCA-based DHBV cccDNA detection method, and the results showed that while DHBV cccDNA was detected from all 39 liver DHBV DNA samples, no DHBV cccDNA was found in any of the sera DHBV DNA samples. These results suggest that the method established in the study is highly specific and sensitive for the detection of DHBV cccDNA. The establishment of this RCA-based DHBV method for cccDNA detection lays the groundwork for using a DHBV model to study the role of cccDNA in the pathogenesis of hepatitis B and to evaluate the effect of anti-virus therapies. PMID- 25272591 TI - [Study on serological cross-reactivity of six pathogenic phleboviruses]. AB - This article aimed to study the antigenicity of nucleocapsid proteins (NPs) in six pathogenic phleboviruses and to provide theoretical evidence for the development of serological diagnostic reagents. NPs of six pathogenic phleboviruses were expressed and purified using a prokaryotic expression system and rabbits were immunized with individual recombinant NPs. Cross-reactions among NPs and rabbit sera were determined by both indirect ELISA and Western blotting analyses, and the sera titer was determined by indirect ELISA. Furthermore, sera from SFTS patients were also detected by each recombinant NP as a coating antigen using indirect ELISA. The cross-reactions and the sera titer were subsequently determined. Both the concentration and purity of recombinant NPs of six pathogenic phleboviruses met the standards for immunization and detection. The results of indirect ELISA and Western blotting showed that each anti-phlebovirus NP rabbit immune serum had potential serological cross-reactivity with the other five virus NP antigens. Furthermore, the sera from SFTS patients also had cross reactivity with the other five NP antigens to a certain extent. Our preliminary study evaluated the antigenicity and immune reactivity of six pathogenic phleboviruses NPs and laid the foundation for the development of diagnostic reagents. PMID- 25272592 TI - [Detection of respiratory viruses in influenza-like illness in Shijiazhuang, China in 2011]. AB - This study aimed to investigate viral infections and the prevalence of influenza like illness (ILI) in Shijiazhuang, China, in 2011 and to provide a scientific basis for the diagnosis and control of respiratory tract infections. Throat swab specimens were collected from 483 cases of ILI who were outpatients in the influenza surveillance sentinel hospitals in Shijiazhuang between January and December 2011. All specimens were examined by multiplex RT-PCR for the following 15 respiratory tract viruses: adenovirus (ADV), human rhinovirus (HRV), human parainfluenza virus (PIV types 1-4), influenza virus A (FluA), influenza virus B (FluB), human enterovirus (HEV), respiratory syncytial virus (RSV-A and -B), human metapneumovirus (HMPV), human coronavirus (HCoV-229E/NL63 and -OC43/HKU1), and human bocavirus (HBoV). Among the 483 cases of ILI, 214 (44.31%) were positive for viruses, including ADV (8.7%), HEV (8.7%), RSV-A (8.07%), HRV (7.45%), FluA (5.38%), HCoV-OC43/ HKU1 (2.9%), PIV-3 (2.9%), HMPV (1.86%), PIV-1 (1.24%), HCoV-229E/NL63 (1.04%), PIV-2 (1.04%), HBoV (0.83%), and FluB (0.41%). Twenty-six (5.38%) of all cases were co-infected with two or more viruses, most commonly HEV/HRV with other viruses. Cases of viral infection were detected throughout the year, with peaks in January and February. ADV and HRV were detected throughout almost the whole year without obvious seasonality. HEV was detected between April and November, with a peak of prevalence in summer and autumn. FluA and FluB reached epidemic levels mainly in winter and spring. All cases of RSV were identified to be subtype A. PIV infection was mainly caused by PIV-3. The positive rate of HCoV-OC43/HKU1 infection was significantly higher than that of HCoV-229E/NL63. The leading five viruses that resulted in ILI Shijiazhuang in 2011 were HEV, ADV, RSV-A, HRV, and FluA, and these viruses have different epidemiological features. PMID- 25272593 TI - [Drug susceptibility of wild-type and mutant H7N9 neuraminidase to zanamivir and oseltamivir]. AB - This study aimed to investigate the drug susceptibility of wild-type and mutant avian influenza A (H7N9) virus neuraminidase (NA) to oseltamivir and zanamivir. Codon optimized DNA of H7N9 (A/ Hangzhou/1/2013) NA was synthesized and constructed into the pcDNA3.1/His vector (NA(H7N9-WT)). Mutant NA(H7N9-H274Y) and NA(H7N9-R292K) plasmids were constructed by directed mutagenesis PCR using NA(H7N9-WT) plasmid as the template followed by sequencing. NA plasmids were transfected into 293T cells and cell lysates containing NAs were collected 48 h post-transfection. Wild-type and mutant NAs were analyzed by Western blotting and their activities were tested by the 4-MUNANA-based assay. All three NAs were expressed and enzymatic activities were confirmed. The effects of oseltamivir and zanamivir on all three NAs were then tested. It showed that the half maximal inhibitory concentrations (IC50s) of oseltamivir carboxylate on NA(H7N9-WT), NA(H7N9-H274Y) and NA(H7N9-R292K) were 1.6 nM, 15.1 nM, and > 1 000 nM with fold changes of 9 and > 625, respectively. The IC50 values of zanamivir on NA(H7N9 WT), NA(H7N9-H274Y), and NA(H7N9-R292K) were 1.1 nM, 1.4 nM, and 38.0 nM with fold changes of 1.3 and 34, respectively. These results indicated that oseltamivir and zanamivir could significantly inhibit NA(H7N9-WT). NA(H7N9-R292K) showed high-level resistance to both drugs (34-fold and 625-fold) and NA(H7N9 H274Y) was sensitive to both (1.3-fold and 9-fold). These results indicated that both oseltamivir and zanamivir could be used for patients infected with the H7N9 virus. However, when patients carried the H7N9 virus with a NA R292K mutation, other medications would be preferred over oseltamivir or zanamivir. PMID- 25272594 TI - [Etiological study of human bocavirus 1-4 in children with acute diarrhea in Lanzhou, China]. AB - This study aimed to study the epidemiological and clinical characteristics of human bocavirus 1-4 (HBoV1-4) in children with acute diarrhea in Lanzhou and to investigate the association between HBoV and acute gastroenteritis. A total of 331 stool samples were collected from children aged under 5 years with acute diarrhea at the Department of Pediatrics, the First Hospital, Lanzhou University, between July 2012 and June 2013. Nested PCR was used to screen for HBoV and a general PCR was employed to screen other common diarrhea viruses. We found human bocavirus 1, 2, 3 and 4 in 26, 15, 7 and 1 cases, respectively. There was no specific seasonal distribution of HBoV, with infections occurring throughout the year. HBoV was mostly found in children aged between 7 and 12 months, with a mean age of 11.04 months (+/- 6.92 months), and 93.88% of affected children were aged under 2 years. Overall, 71.3% of mixed infections were mixed and the majority of other infections were caused by rotavirus. There was no statistical difference in the incidence of fever and vomiting associated with HBoV infection. A rare virus strain, HBoV4 (LZFB086), was identified, which showed highest levels of nucleotide sequence identity (99.0%) with a single Thai HBoV strain (JQ267789). No case of HBoV2B was found. In conclusion, HBoV1 was a major etiological pathogen of HBoV in pediatric cases in Lanzhou. HBoV4 was detected in feces for the first time in China. The rate of mixed infections was high and rotavirus was dominant. The data presented suggests that HBoV is not a major causative agent of gastroenteritis. PMID- 25272595 TI - [Analysis of epidemiological and clinical features of adenovirus infection in 80 children with acute respiratory tract infection]. AB - By analyzing the epidemiological and clinical features of adenovirus in children with acute respiratory tract infection (ARTI), we provide a theoretical basis for early clinical diagnosis and treatment. Nasopharyngeal secretions were collected from 3480 children with ARTI, who were hospitalized at the No. 2 Hospital of Changzhou from January 2011 to December 2012. Adenovirus were detected using direct immunofluorescence assays. A total of 80 samples were positive for adenovirus (2.30%). The rate of adenovirus infection during 2011 was significantly higher than that in 2012, and the infection rate was higher in summer and autumn than in winter and spring. The infection rate was 1.14% among children aged < 1-year-old and the rates were higher among children in other age ranges. Adenovirus was found to be an important ARTI pathogen in children in Changzhou, mainly affecting children older than 1 year. ADV infections have various clinical presentations, but affected children tend to be severely ill with poor outcomes. PMID- 25272596 TI - [Analysis of genetic characteristics of ECHO6 virus isolated from an epidemic outbreak of encephalitis in Longyan, China]. AB - This study aimed to analyze the etiology of the encephalitis outbreak in Longyan, Fujian Province, China in 2010, in order to provide valuable information for this prevention and control of this disease. Pathogens were confirmed from cerebrospinal fluid samples with fluorescent RT-PCR, virus isolation (RD cells), and neutralization tests. Then, the VP1 fragments or whole genome nucleotide sequences were determined for four virus strains using PCR. Homology was assessed using the MegAlign software, and a phylogenetic evolutionary tree was drawn using Mega 4.0 software. The results confirmed that the etiology of the outbreak was the ECHO6 intestinal virus, and the nucleotide sequence of the VP1 segment indicated that the C2 subtype was responsible. The genome sequence consisted of 7407 nucleotides, and resembled the genome of other ECHO and CoxB viruses with homology levels of 78.5%-87.3%. The encephalitis outbreak in Longyan in 2010 was caused by the ECHO6 C2 subtype intestinal virus, and its complete genome sequence length is similar to the standard strain (U16283) with a sequence homology of 80.4%. PMID- 25272597 TI - [Evolutionary relationships of G3 GARV isolated from pigs and humans in Lulong County, Hebei Province, China]. AB - This study aimed to amplify major genome segments (VP7, VP4, VP6, VP2 and NSP2-5) of porcine G3 group A rotavirus (GARV) LLZ212 isolated in our laboratory, determine their genotypes, and explore the evolutionary relationships between G3 GARV strains isolated from humans and pigs in Lulong County, Hebei Province, China. Major genome segments of seven GARV strains were amplified by reverse transcription-polymerase chain reaction (RT-PCR) and the segments were sequenced. The genome segments of seven GARV strains were determined by the online RotaC genotyping tool (RotaC v2.0). The reference sequences of each GARV genome segment were downloaded from GenBank. Homology and phylogenetic evolutionary analyses were conducted using the MEGA 5.0 and DNAStar software packages. LLZ212 isolated from pigs in Lulong had the following genotype: G3-P[8]-I5-C1-N1-T1-E1-H1. All human GARV strains had the following genotype: G3-P[8]-I1-C1-N1-T1-E1-H1. The VP7, VP4, NSP4 and NSP5 genes of the LLZ212 strain had the highest nucleotide identities with the human GARV E885, CMH014/07, Wa and RMC321 strains, respectively, and these clustered together in a sublineage. The VP6, NSP4 and NSP5 genes of the LLZ212 strain shared the highest nucleotide identities with the porcine GARV PRG921 strain, while VP2 associated most closely with porcine GARV OSU strain, and these also clustered in a sublineage. A rare porcine G3-P[8]-I5 C1-N1-T1-E1-H1 GARV strain was identified, which may represent a reassortment between porcine and human viruses. In conclusion, the VP7, VP4, NSP4 and NSP5 genes of LLZ212 share high levels of sequence identity with human GARV, while VP2, VP6, NSP2 and NSP3 cluster with porcine GARV. PMID- 25272599 TI - [Construction and immunological responses of recombinant adenovirus containing Epstein-Barr nuclear antigen 1 in mice]. AB - This study aimed to construct recombinant adenovirus expressing Epstein-Barr nuclear antigen 1 (EBNA1) against nasopharyngeal carcinoma (NPC). The C-terminal region fragment of the ebna1 gene of Epstein-Barr virus was amplified from the standard strain B95-8 by polymerase chain reaction (PCR). The gene fragment was inserted into the pDC316 shuttle plasmid using the EcoRI and BgIII restriction enzyme sites. The pDC316-ebna1 shuttle plasmid and pBHG helper plasmid were cotransfected into HEK293 cells after sequencing. The soluble protein was extracted from HEK293 cells, which caused apparent cytopathic effects. The transcription and expression of the ebna1 gene were confirmed using flow cytometry and Western blotting. rAd-ebna1 titers were measured by the TCID50. rAd ebna1 was injected into BALB/c mice at a dose of 2 x 10(8) VP per mouse, EBNA1 epitope-specific responses were measured at 1st, 2nd, 4th and 8th weeks post immunization. The target fragment of ebna1 (939 bp) was obtained by PCR, and was in consensus with the sequence from the standard strain B95-8. Cytopathic effects were observed after the pDC316-ebna1 shuttle plasmid and pBHG helper plasmid were cotransfected into HEK293 cells. rAd-ebna1 was successfully recombined in HEK293 cells. EBNA1 protein was detected in HEK293 cells, rAd-ebna1 titers reached 10(8) TCID50/mL. Specific responses to CD4+ epitopes of EBNA1 were detected in the immunized mice. In conclusion, rAd-ebna1 was successfully constructed and induced specific responses to CD4+ epitopes of EBNA1 in immunized mice. PMID- 25272598 TI - [Effects of cell-mediated immunity induced by intramuscular chitosan-pJME/ GM-CSF nano-DNA vaccine in BAlb/c mice]. AB - This study aimed to investigate the immune adjuvant effect and mechanism induced by chitosan nanoparticles carrying pJME/GM-CSF. In this study, plasmid DNA (pJME/GM-CSF) was encapsulated in chitosan to prepare chitosan-pJME/GM-CSF nanoparticles using a complex coacervation process. Immunohistochemistry was used to detect the type of infiltrating cells at the site of intramuscular injection. The phenotype and functional changes of splenic DCs were measured by flow cytometry after different immunogens were injected intramuscularly. The killing activity of CTLs was assessed using the lactate dehydrogenase (LDH) release assay. The preparation of chitosan-pJME/GM-CSF nanoparticles matched the expected theoretical results. Our results also found that, after pJME/GM-CSF injection, the incoming cells were a mixture of macrophages, neutrophils, and immature DCs. Meanwhile, pJME/GM-CSF increased the expression of MHC class II molecules on splenic DCs, and enhanced their Ag capture and presentation functions. Cell mediated immunity was induced by the vaccine. Furthermore, chitosan-pJME/GM-CSF nanoparticles outperformed the administration of standard pJME/GM-CSF in terms of DC recruitment, antigen processing and presentation, and vaccine enhancement. These findings reveal that chitosan could be used as delivery vector for DNA vaccine intramuscular immunizations, and enhance pJME/GM-CSF-induced cellular immune responses. PMID- 25272600 TI - [Identification of nuclear localization signals of pseudorabies virus gene UL49]. AB - Tegument protein VP22 is encoded by Pseudorabies Virus (PRV) UL49. To identify the nuclear localization signals of UL49, it is necessary to determine the transport mechanism and biological functions of the VP22 protein. In this study, we identified two nuclear localization signals from UL49, NLS1 (5RKTRVA ADETASGARRR21) and NLS2 (241PGRKGKV247). The functional nuclear localization signal (NLS) of UL49 was identified by constructing truncated or site-specific UL49 mutants. The deletion of both NLS1 and NLS2 abrogated UL49 nuclear accumulation, whereas the deletion of NLS1 or NLS2 did not. Therefore, both NLS1 and NLS2 are critical for the nuclear localization of UL49. And our resuts showed that NLS2 is more important in this regard. PMID- 25272601 TI - [Investigation of etiology of massive infection with porcine pseudorabies virus in Henan and neighboring Provinces]. AB - In early 2011, the serious outbreak of porcine pseudorabies virus (PRV) infection suddenly recurred in Henan and neighboring Provinces. To investigate the etiology of massive infection with PRV, 16 800 serum samples, 905 porcine epidemic diarrhea virus (PEDV) back-feeding tissues, and 56 PR gene deleted live vaccines were colleted from January 2011 to May 2013 to detect PRV field infection using a PRV gE antibody test kit. The gE and TK genes of 11 new epidemic PRV strains were sequenced by PCR, and their molecular characteristics were analyzed. Moreover, virus titer determination, protective test against PRV, and vaccine potency testing were performed. The results showed that the detection rate of PRV field infection-positive pig farms was 68.06%, and the overall positive rate of PRV field infection in serum was 38.47%; the positive rates in breeding sows, breeding boars, reserve pigs, and commercial pigs were 40.12%, 30.88%, 54.67%, and 26.52%, respectively. The new epidemic strains were in the same evolutionary branch and belonged to the virulent strain group. Compared with the classical PRV strain, the virulence of new epidemic strains changed a little. The length of gE gene was 1 787 bp, and the length of TK gene was 963 bp. The nucleotide homologies of gE and TK genes to Chinese reference strains were 98.2%-99.8% and 98.90%-99.6%, respectively, and the amino acid homologies were 97.1%-99.8% and 97.5%-99.4%, respectively. Commercial vaccine had a 100% protective effect against the new epidemic strains. The positive rate of PRV field infection was 0% in vaccine and 40.44% in back-feeding tissues. The results confirmed that PRV field infection rates were rising sharply among pigs in Henan and neighboring Provinces after 2011. The main virulence genes of new epidemic PRV strains did not change significantly over the years. PR gene deleted live vaccines had no PRV field infection and could completely resist the attack of new strains. The virus carriage of breeding boars and reserve pigs and the serious PRV field infection in PEDV back-feeding tissues were the main causative factors for massive infection with PRV and epidemic outbreak in Henan and neighboring Provinces from 2011 to 2013. PMID- 25272602 TI - [Eenie, Meenie, Miney, Moe, who is responsible for the antibody-dependent enhancement of Aleutian mink disease parvovirus infection?]. AB - Aleutian mink disease parvovirus (AMDV) causes a persistent infection associated with immune complex disease, hypergammaglobulinemia, and high levels of antiviral antibodies. Despite the presence of an antibody, the virus is not cleared in vivo. Pre-existing antibodies may enhance viral infections, by Fc-receptor mediated antibody-dependent enhancement (ADE), but the mechanism that underlies ADE has not been fully defined. Three models have been proposed, including: (1) interactions between antibody and FcR, complement C3 fragment and CR, or between C1q and C1qR, which promotes viral attachment to cells; (2) suppression of IFN gamma-mediated host-cell antiviral gene expression by the upregulation of negative regulators of pathogen pattern recognition; and (3) the promotion of early IL-10 secretion. In addition, the role of cytokine IL-6 in ADE mediated disease development is discussed, to facilitate a better understanding of the pathogenesis of AMDV infection, as well as give insights into rational vaccine design approaches. PMID- 25272603 TI - [Recent progress in interferon induced protein GBP1 research]. AB - Guanylate-binding protein 1 (GBP1) is an interferon induced protein, that belongs to the guany late-binding protein family. GBP1 is widely involved in anti infection immune responses, anti-tumor activity and various biological reactions. Recent studies have proved that IFN-alpha, IFN-beta, IFN-gamma, IL1alpha, IL1beta, TNF-alpha and LPS can induce GBP1 expression; hence, the diverse biological functions of GBP1 have been gradually deduced and exploited. Many studies have been performed over recent years to understand the exact mechanisms that underlie the anti-infection and anti-tumor properties of GBP1. This review describes the molecular structure, biological activity, anti-infective properties and other functions of GBP1, in order to provide insights into the divergent roles of GBP1 in the regulation of various biological processes. PMID- 25272604 TI - [Structure and function of 3'- untranslated region in picornavirus]. AB - Both sides of the picornavirus genome have 5'-untranslated region (5'UTR) and 3'- untranslated region (3'UTR). This study demontrated that both the 5'-and 3'-UTR can form complex structures, such as stem-loop, clover and pseudoknot structure, These structures play an important role in the regulaton of the replication and translation of the viruses. This article reviewed the progress of research on the structure and function of picornavirus' 3'-UTR over recent years. PMID- 25272605 TI - [Advance in loop-mediated isothermal amplification technique and its applications in point-of-care testing platforms]. AB - Loop-mediated isothermal amplification (LAMP) is a novel in vitro nucleic acid amplification method conducted under isothermal conditions with the advantages of high specificity, sensitivity, rapidity and easy detection. Since it was established in 2000, it has been widely applied in various fields of analytical science including the diagnosis of a variety of pathogens, identification of embryo sex, detection of genetically modified organisms and cancer gene identification. Additionally, significant progress has been made in the optimization of the LAMP method, such as accelerated reactions, simplified sample processing, the realization of multiplex amplification, and the enhanced specificity of reaction and detection methods. LAMP technology also shows much potential to be adopted as part of point-of-care testing platforms by the micromation, automation and integration with other technologies such as Lab-on-a Chip and digital nucleic acid amplification. This review summarizes the latest advances in the LAMP technique and its applications in developing point-of-care testing platforms. PMID- 25272606 TI - [The entry of Epstein-Barr virus into B lymphocytes and epithelial cells during infection]. AB - Epstein-Barr virus (EBV) is a human herpesvirus associated with important human diseases, including infectious mononucleosis syndrome, malignant lymphoma, and nasopharyngeal carcinoma. The mechanism of EBV entry into host cells remains a subject of intensive research. After decades of study, researchers have identified several key proteins and different patterns of EBV intrusion into host cells. The viral surface glycoproteins, gp350/220, gp42, gB, gH, and gL, are involved in interactions with the CR2 receptor on the surface of B lymphocytes during viral entry. However, the majority of epithelial cells lack CR2 receptor expression, which makes viral invasion much more complex than in B lymphocytes. Three different models have been proposed to explain how EBV enters epithelial cells: (1) "transfer of infection", mediated by B lymphocytes or Langerhans cells; (2) EBV utilizes its own proteins during the process of fusion with the cell membrane; and (3) progeny virions arising from EBV-infected epithelial cells cross lateral membranes into adjacent epithelial cells. This review will discuss the relevant mechanism of viral entry into B lymphocytes and epithelial cells during EBV infection. PMID- 25272607 TI - [Research advances in molecular epidemiology and vaccines of Coxsackievirus A16]. AB - Epidemics of hand, foot and mouth disease (HFMD) have mainly been caused by Coxsackievirus A16 (CVA16) and Enterovirus A 71 (EV-A71), which circulated alternatively or together in the affected area. CVA16 has caused numerous outbreaks and epidemics in multiple countries and geographical regions, and has become an important public health problem. Based on an analysis of the complete VP1 coding region, all CVA16 strains can be divided into genotypes A, B1, and B2. Furthermore, genotype B1 can be divided into subgenotypes B1a, B1b, and B1c. After 2000, no reports of genotype B2 virus strains have been reported. All of the CVA16 strains reported in mainland China have belonged to subgenotypes B1a and B1b. Most CVA16-associated infections cause only mild symptoms; however, some CVA16 infections can lead to severe complications and even death. Vaccination is considered to be the most effective method to control the transmission and infection rate of this virus. A number of research groups are studying various vaccine types, including inactivated vaccines, genetic engineering vaccines, and DNA vaccines, amongst others. In this review, an overview is provided of the research advances in molecular epidemiology and vaccines of CVA16. PMID- 25272608 TI - Neoliberal pharmaceutical science and the Chicago School of Economics. AB - In recent years, science studies scholars have critically examined several methods used by the pharmaceutical industry to exert control over knowledge about drugs. Complementary literatures on 'medical neoliberalism' and 'neoliberal science' draw attention to the economic ideas justifying such methods of organizing knowledge, and in so doing suggest that neoliberal thinkers may play an important role in developing them. As yet, the nature of this role remains unexplored. Relying on heretofore-unexamined archival evidence, this article establishes a direct link between the Chicago School of Economics and the mobilization of the pharmaceutical industry in the 1970s. It argues that economists affiliated with the Chicago School of Economics sought to influence pharmaceutical policy and science and constructed institutions to do so. These institutions--most notably the Center for the Study of Drug Development--remain highly influential. This article contributes to a historical understanding of how neoliberal ideas came to assume prominence in pharmaceutical policy, the management of science, and scientific practice. PMID- 25272609 TI - The shipwreck of the singular. AB - In 1962, Louis Lasagna was one of the central figures in the creation of our current drug regulation systems. His influence on the practice of modern medicine, through a series of unanticipated consequences of these systems, has been profound. In the 1960s, he was one of the most progressive thinkers in medicine. By the 1980s, he had apparently become one of the most reactionary. This article attempts to delineate the dilemmas he believed he was dealing with, dilemmas that stemmed from a system he had helped create, that produced this apparent change in orientation. The problems with which he grappled are ones that remain unresolved and indeed, have become more acute. The example of how he attempted to remedy what had gone wrong may provide pointers as to how to solve or how not to solve current difficulties. PMID- 25272610 TI - 'Power to the people': a reply to Healy, Mangin and Applbaum. AB - In challenging one portion of the history presented in my article, Healy et al. argue that Louis Lasagna was a 'classical liberal' who sought only to increase the scientific stature of the physician--patient encounter. They advance this interpretation to encourage science and technology studies scholars to heed Lasagna's ideas about how to organize the medical marketplace. I argue that Healy et al. mischaracterize Lasagna's ideas. I conclude with an example of these ideas being put into practice, Lasagna's efforts on behalf of Wyeth in the approval and marketing of Redux and Fen-Phen. PMID- 25272611 TI - Physician-industry collaboration: conflicts of interest and the imputation of motive. AB - Policies about physicians' involvement with pharmaceutical companies spawn contradictory ideas. One set of policies aims to stimulate collaboration between private companies and publicly employed researchers to spur innovation and economic growth, another addresses what is seen as the problem of physicians' conflicts of interest stemming from industry collaboration. This article explores how these contradictory policies interact with everyday practice in clinical hypertension research in Denmark. I argue that 'corporate' and 'academic' research is entangled as physicians participate in industry trials to pursue their own research. Building on document analysis, observations of contract research, and interviews with clinician researchers and industry executives, I show how the establishment of industry 'ties' can serve as a way for physicians to navigate the constraints of research infrastructures and live up to intergenerational norms that knit the medical collective together. I discuss how this entanglement shapes medical research in ways that may run counter to the aims of medical innovation policies and that conflicts of interest policies do little to address. I conclude that appreciation of the ways in which economic and moral valuations come together is necessary to understand the conditions for medical research in an intertwined public-private research environment. PMID- 25272612 TI - Multivariate statistics and the enactment of metabolic complexity. AB - This ethnographic study, based on fieldwork at the Computational and Systems Medicine laboratory at Imperial College London, shows how researchers in the field of metabolomics--the post-genomic study of the molecules and processes that make up metabolism--enact and coproduce complex views of biology with multivariate statistics. From this data-driven science, metabolism emerges as a multiple, informational and statistical object, which is both produced by and also necessitates particular forms of data production and analysis. Multivariate statistics emerge as 'natural' and 'correct' ways of engaging with a metabolism that is made up of many variables. In this sense, multivariate statistics allow researchers to engage with and conceptualize metabolism, and also disease and processes of life, as complex entities. Consequently, this article builds on studies of scientific practice and visualization to examine data as material objects rather than black-boxed representations. Data practices are not merely the technological components of experimentation, but are simultaneously technologies and methods and are intertwined with ways of seeing and enacting the biological world. Ultimately, this article questions the increasing invocation and role of complexity within biology, suggesting that discourses of complexity are often imbued with reductionist and determinist ways of thinking about biology, as scientists engage with complexity in calculated and controlled, but also limited, ways. PMID- 25272614 TI - Epidemiology and 'developing countries': writing pesticides, poverty and political engagement in Latin America. AB - The growth of the field of global health has prompted renewed interest in discursive aspects of North-South biomedical encounters, but analysis of the role of disciplinary identities and writing conventions remains scarce. In this article, I examine ways of framing pesticide problems in 88 peer-reviewed epidemiology papers produced by Northerners and their collaborators studying pesticide-related health impacts in Latin America. I identify prominent geographic frames in which truncated and selective histories of Latin America are used to justify research projects in specific research sites, which nevertheless function rhetorically as generic 'developing country' settings. These frames legitimize health sector interventions as solutions to pesticide-related health problems, largely avoiding more politically charged possibilities. In contrast, some epidemiologists appear to be actively pushing the bounds of epidemiology's traditional journal article genre by engaging with considerations of political power, especially that of the international pesticide industry. I therefore employ a finer-grained analysis to a subsample of 20 papers to explore how the writing conventions of epidemiology interact with portrayals of poverty and pesticides in Latin America. Through analysis of a minor scientific controversy, authorial presence in epidemiology articles, and variance of framing strategies across genres, I show how the tension between 'objectivity' and 'advocacy' observed in Northern epidemiology and public health is expressed in North-South interaction. I end by discussing implications for postcolonial and socially engaged approaches to science and technology studies, as well as their relevance to the actual practice of global health research. In particular, the complicated interaction of the conflicted traditions of Northern epidemiology with Latin American settings on paper hints at a far more complex interaction in the form of public health programming involving researchers and research participants who differ by nationality, ethnicity, gender, profession, and class. PMID- 25272613 TI - Homogeneity and heterogeneity as situational properties: producing--and moving beyond?--race in post-genomic science. AB - In this article, we explore current thinking and practices around the logics of difference in gene-environment interaction research in the post-genomic era. We find that scientists conducting gene-environment interaction research continue to invoke well-worn notions of racial difference and diversity, but use them strategically to try to examine other kinds of etiologically significant differences among populations. Scientists do this by seeing populations not as inherently homogeneous or heterogeneous, but rather by actively working to produce homogeneity along some dimensions and heterogeneity along others in their study populations. Thus we argue that homogeneity and heterogeneity are situational properties--properties that scientists seek to achieve in their study populations, the available data, and other aspects of the research situation they are confronting, and then leverage to advance post-genomic science. Pointing to the situatedness of homogeneity and heterogeneity in gene-environment interaction research underscores the work that these properties do and the contingencies that shape decisions about research procedures. Through a focus on the situational production of homogeneity and heterogeneity more broadly, we find that gene environment interaction research attempts to shift the logic of difference from solely racial terms as explanatory ends unto themselves, to racial and other dimensions of difference that may be important clues to the causes of complex diseases. PMID- 25272615 TI - A taxonomy of motives to cite. AB - In this study, we explicate citing behavior in the writing of scientific papers by presenting a taxonomy of motives to cite. The suggested taxonomy consists of four main categories, which are purely descriptive: Argumentation, Social Alignment, Mercantile Alignment, and Data. These categories are divided into a suggested set of subcategories. We argue that the complexities of citing practice show how little can be assumed about actual citing behavior when studying a finished paper. The discussion supports the claim that it might be misleading to treat all citations as equal in quantitative citation analysis. PMID- 25272616 TI - Academic urban legends. AB - Many of the messages presented in respectable scientific publications are, in fact, based on various forms of rumors. Some of these rumors appear so frequently, and in such complex, colorful, and entertaining ways that we can think of them as academic urban legends. The explanation for this phenomenon is usually that authors have lazily, sloppily, or fraudulently employed sources, and peer reviewers and editors have not discovered these weaknesses in the manuscripts during evaluation. To illustrate this phenomenon, I draw upon a remarkable case in which a decimal point error appears to have misled millions into believing that spinach is a good nutritional source of iron. Through this example, I demonstrate how an academic urban legend can be conceived and born, and can continue to grow and reproduce within academia and beyond. PMID- 25272617 TI - Top Chief Executives. The here and now. PMID- 25272618 TI - Leading the way. Our Foundation trust's got talent. PMID- 25272619 TI - Let's unlock our people's potential. PMID- 25272620 TI - Avert disaster using the NHS's core principles. PMID- 25272621 TI - Great leaders naturally have the right qualities. PMID- 25272622 TI - Millenials are the NHS's future leaders. PMID- 25272623 TI - Primary care. It takes more than a magic wand to redesign care. PMID- 25272625 TI - Leadership. Nurture the network to overcome work barriers. PMID- 25272624 TI - Training and development. The 18 week waiting game. PMID- 25272626 TI - UnitedHealthcare cuts providers from Medicare Advantage plans. PMID- 25272627 TI - Can the doctor-patient relationship survive? PMID- 25272628 TI - Do high deductibles mean high risk for physicians? PMID- 25272629 TI - How to keep toxic employees from harming your practice. PMID- 25272630 TI - Physicians face new rules for durable medical equipment orders. PMID- 25272631 TI - EHRs: the need for speed. PMID- 25272632 TI - Managing risk: how to prevent patient injury and avoid lawsuits. PMID- 25272633 TI - Theft in a medical practice: why it happens and how to stop it. PMID- 25272634 TI - Fix the primary-care shortage without more physicians. PMID- 25272635 TI - [Chapter 1. A contemporary history of the Japanese pharmaceutical industry (1980 2010). A contemporary history of the Japanese Pharmaceutical Industry (1980-2010) Task Force]. AB - This publication, commemorating the sixty years since the founding of Japan Society for the History of Pharmacy (JSHP), provides an overview of the Japanese pharmaceutical industry over a thirty-year span from 1980 to 2010. In the first section, entitled Medical Evolution: The Growth Period for Pharmaceutical Products, and the second section, "Patient-Based Medicine: The Period of Information Prioritization, the following themes are examined. Changes in Drug Pricing Policies, Promotion of Bungyo (separation of prescription from dispensing), Measures to Improve the Safety of Pharmaceutical Products; Appropriate Use of Pharmaceutical Products, Drug Discovery: Changes in Pharmaceutical Product Development and Actual Conditions in the Domestic Launch of New Medicines; Marketing (Medical Representative) Reforms, Pharmaceutical Industry Mergers and Acquisitions, Internationalization of the Pharmaceutical Industry. The following papers are provided as further references to support the conclusions made in the sections above. Changes in Japanese Drug Discovery Technologies and Drug Development. Japan's Pharmaceutical Market and Shifts in Manufacturing and Sales. Changes in Clinical Trials in Japan and Appropriate Use of Pharmaceuticals. Internationalization of the Japanese Pharmaceutical Industry. PMID- 25272636 TI - [Chapter 2. Transitions in drug-discovery technology and drug-development in Japan (1980-2010)]. AB - In 1970s, the material patent system was introduced in Japan. Since then, many Japanese pharmaceutical companies have endeavored to create original in-house products. From 1980s, many of the innovative products were small molecular drugs and were developed using powerful medicinal-chemical technologies. Among them were antibiotics and effective remedies for the digestive organs and circulatory organs. During this period, Japanese companies were able to launch some blockbuster drugs. At the same time, the pharmaceutical market, which had grown rapidly for two decades, was beginning to level off. From the late 1990s, drug development was slowing down due to the lack of expertise in biotechnology such as genetic engineering. In response to the circumstances, the research and development on biotechnology-based drugs such as antibody drugs have become more dynamic and popular at companies than small molecule drugs. In this paper, the writers reviewed in detail the transitions in drug discovery and development between 1980 and 2010. PMID- 25272637 TI - [Chapter 3. Transitions in clinical trials and appropriate use of drugs in Japan (1980-2010)]. AB - This paper reviews the status of clinical trials and appropriate use of drugs from historical perspectives in the last 30 years in Japan. Industry-sponsored clinical trials in Japan began being regulated under the revised Pharmaceutical Affairs Law in 1980. Japanese modifications were made to the ICH-GCP, which reached step 4 in May 1996, and a notification called the "New GCP" was issued in March 1997. This was fully implemented as of April 1998. The number of clinical trials, however, dropped sharply after 1998. Patients worldwide who have no drugs for their diseases are waiting for new medicines. Clinical trials must be held as part of a scientific and valid process. Physicians have a duty to use new medicines considering a balance of effectiveness and safety. In Japan, several "yakugai" cases were observed in the past. They were not only caused by the toxicological effects of drugs but were also due to social factors in drug use. Responding to these scandals, new regulations were developed and contributed to the appropriate use of drugs in Japan. PMID- 25272638 TI - [Chapter 4. Transitions in pharmaceutical market, production and sales in Japan (1980-2010)]. AB - In this paper, the writers reviewed in detail the pharmaceutical market and the shifts in manufacturing and sales including the trade balance in Japan over a thirty-year period from 1980 to 2010. From the 1980s to the 1990s, many innovative pharmaceutical products were developed and launched in the Japanese market. During the same period, some Japanese companies managed to develop their first internationally marketable drugs, which were antibiotics and effective remedies for the digestive and circulatory organs. During this period, Japanese pharmaceutical companies were also able to launch some of blockbuster drugs. For two decades, the pharmaceutical market grew rapidly. For this reason, it can be called "The Growth Period for Pharmaceutical Products" in Japan. After that period, drug development and sales slowed down due to a lack of expertise in genetic engineering and biotechnologies. This situation caused a large deficit in the trade balance for Japanese pharmaceutical products. However, with regard to the trade balance (including technical royalties) for pharmaceutical product technologies, Japan remains in the black even today. PMID- 25272639 TI - [Chapter 5. The internationalization of the Japanese pharmaceutical industry (1980-2010)]. AB - The Japanese pharmaceutical industry experienced a period of rapid and economic growth following the introduction of the national healthcare system in 1961. Triggered by a major revision in Japanese legislation from process to substance patents, leading Japanese pharmaceutical companies began to invest in research and development (R&D). By the mid-1980s, some had managed to develop their first internationally marketable drugs, many of which were antibiotics. The emergence of novel drugs gave companies the impetus to engage in progressively more appreciable investments in Asia, Europe and the United States. In the 1980s, internationalization was mainly inwardly focused so as to limit firms' exposure to risk. However, as profits increased in the 1990s from the sale of new drugs, Japanese pharmaceutical companies were able to engage in even more sizeable, outwardly focused investments. By 2010, Japan's leading pharmaceutical enterprises had succeeded in putting place three types of global operations: manufacturing, marketing and R&D. PMID- 25272640 TI - Modern industrial and pharmacological applications of indigo dye and its derivatives--a review. AB - Plant sources, chemical properties, bioactivities, as well as the synthesis of indigo dye and its derivatives, are reviewed in this paper. These compounds were chosen because of their significant benefits and scope of application as both coloring agents in the textile industry and as pharmacologically active natural products. Their use in traditional chinese medicine (TCM) has directed the attention of European researchers and medical doctors alike. The preparation of indigoferous plants--Indigo naturalis is currently about to be introduced into the European Pharmacopoeia. PMID- 25272641 TI - Application of CPC and related methods for the isolation of natural substances--a review. AB - A review of research on the isolation of various alkaloids from plant material by centrifugal partition chromatography (CPC) and related preparative techniques was made, in order to provide various conditions for separation of these important plant derived secondary metabolites. First of all, the construction of the CPC apparatus was presented as well as the principle of isolation of natural products with its help, and then the influence of operating apparatus parameters on the separation efficiency. Finally, a review of the alkaloids separation conditions was made, specifying used parameters and best solvent system. PMID- 25272642 TI - G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. AB - The aim of this review is to present the research results and draw new conclusions about the impact of alterations in the signal transmission through the G protein-coupled receptors (GPCRs) on the formation of diseases and drug therapy. GPCR family is the largest and the most diverse group of membrane receptors. They transmit signals into the cell by interaction with different ligands, which include, inter alia, hormones, neurotransmitters, and photons. GPCRs are responsible for the proper conduction of many physiological processes such as vision, intercellular communication, the neuronal transmission, hormonal signaling and are involved in many pathological processes. They are also point on the binding pathway of multiple drugs. They are targets of nearly one third of the drugs at the current pharmaceutical market. The genes encoding GPCRs represent about 4% of the human genome. Mutations that occur in them are associated with a broad spectrum of diseases of diverse etiology. As a mutations result, there is a change in receptor activity (GPCR become inactive, overactive, or constitutively active), in the process of ligand binding and signal transduction. Changes in the GPCRs functioning can cause diseases such as retinitis pigmentosa (rhodopsin mutations), nephrogenic diabetes insipidus (vasopressin receptor mutations), obesity (melanocortin receptor mutations). Many mutational changes in genes encoding GPCR can change drug therapy of already existed diseases: heart failure (adrenergic receptors), asthma (cysteinyl leukotriene receptors). Studies concerning the structure and function of genetically modified GPCRs allow to get know a variety of mechanisms of its action, which in turn can contribute to broaden the knowledge on the etiology and pharmacotherapy of many currently incurable diseases. PMID- 25272643 TI - Preparation and radiochemical control of 99mTc labeled blood pool agent for in vivo labelling of the red blood cells. AB - Our aim was to prepare cheap blood pool imaging kits by simplified method to overcome the burden on purchase department of MINAR, Nishtar Hospital, Multan, Pakistan. Secondarily, prompt supply of kits should save the time of patient during transportation. A total of 24 subjects selected for this study were equally divided into two groups. Mixture of stannous chloride and sodium pyrophosphate solution at pH 7 was injected to these subjects. Various concentrations (ranging from 200 to 800 microg) of stannous chloride dihydrate were injected to group one, followed by intravenous administration of technetium 99m (99mTc) pertechnetate at 30 min interval in 12 subjects. Labeling percentage of each sample was calculated afterwards followed by imaging under gamma camera. Each parameter was tested on three different patients and average of these three was calculated. In second set of experiments done on group two the same procedure was repeated in another 12 subjects, while keeping the concentration of Sn PYP constant at 400 microg. In this case, 99mTc was administered at different time intervals in different subjects ranging from 15 to 120 min (15, 30, 60 and 120 min) followed by calculation of labeling percentage and imaging under gamma camera. In group one, average percentage values of binding of red blood cells with 99mTc were 23.24, 84.88, 83.78 and 60.33% for concentrations of 200, 400, 600 and 800 microg, respectively. In group two, average percentage binging values of 22.26, 84.36. 55.54 and 28.67% were calculated at time intervals of 15, 30, 60 and 120 min, respectively. It is concluded from the results that the best blood pool imaging under gamma camera was observed for the concentration of 400 microg and the time interval of 30 min. The maximum percentage binding of red blood cells with 99mTc was calculated at concentration of 400 microg after 30 min interval that also correlated with imaging results. PMID- 25272644 TI - Stability-indicating HPLC method for the determination of cefquinome sulfate. AB - A novel and sensitive stability-indicating RP-HPLC method for the quantitative determination of cefquinome sulfate has been developed. Chromatographic separation and quantitative determination were performed using a high-performance liquid chromatograph with UV detection. As the stationary phase a LiChroCART RP 18 column (5 microm particle size, 125 mm x 4 mm, Merck, Darmstadt, Germany) was used. The mobile phase consisted of 10 volumes of acetonitrile and 90 volumes of an 0.02 M phosphate buffer (pH = 7.0). The flow rate of the mobile phase was 1.0 mL/min. The eluents were monitored by a UV-VIS detector at 268 nm. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. Significant degradation was found under basic, oxidizing stress and UV light. The developed method was validated with respect to linearity, accuracy, precision and robustness. PMID- 25272645 TI - Development and validation of stability-indicating HPLC method for simultaneous determination of meropenem and potassium clavulanate. AB - A stability-indicating LC assay method was developed and validated for a simultaneous determination of meropenem and potassium clavulanate in the presence of degradation products formed during acid-base hydrolysis, oxidation and thermolysis. The isocratic RP-HPLC method was developed with a LiChrospher RP-18 (250 mm x 4.6 mm, 5 microm) column and gradient elution of 12 mmol/L ammonium acetate and acetonitrile. The flow rate of the mobile phase was 1.0 mL/min, the detection wavelength 220 nm and the temperature 303 K. The method was validated with regard to linearity, accuracy, precision, selectivity and robustness, and was applied successfully for the determination of meropenem and potassium clavulanate separately as well as jointly in pharmaceutical formulations. PMID- 25272646 TI - Stability of new anticonvulsant derivatives of picolinic, nicotinic, cyclocarboxylic acids in body fluids and tissues. AB - The stability of new compounds with established anticonvulsant activity: picolinic acid 4-pyridyl-methylamide (Pic-4-PMA), cyclopentanecarboxylic acid benzylamide (Cpc-BZA), cycloheptanecarboxylic acid benzylamide (Chc-BZA), picolinic acid 2-fluoro-3-trifluoromethylbenzylamide (Pic-2F-3TFM-BZA), 2 chloronicotinic acid benzylamide (2-Cl-Na-BZA), 6-chloronicotinic acid benzylamide (6-Cl-Na-BZA) and 6-trifluoromethylnicotinic acid benzylamide (6-TFM Na-BZA) in homogenates of body organs and in body fluids was determined after incubation. It was found that three compounds were stable against enzymes present in body fluids and organs and two were found to decompose in liver and kidney homogenates and two decomposed only in liver homogenate. PMID- 25272647 TI - Analysis of compounds with phytoestrogenic activity in dietary supplements with use of HPTLC-densitometry method. AB - Soy (Glycine max L., Fabaceae) and soy products are becoming more popular because of their low toxicity and therapeutic effects. Soy possesses antioxidant, anti inflammatory and anti-allergic properties, however, the most important is its estrogenic activity associated with occurrence of phytoestrogens. Isoflavones with phytoestrogenic effects were determined in four commercially available soya formulations. Analyses were performed with the use of high performance thin-layer chromatography (HPTLC) combined with densitometry. The compounds were extracted, hydrolyzed in order to obtain aglycone forms and separated on HPTLC silica gel 60 F254 plates with the use of mobile phase consisting of chloroform--ethyl acetate- formic acid 4:6:0.1 (v/v/v). After drying, the spots on the plates were determined in absorbance/reflectance mode at a wavelength of 260 nm using a computer-controlled densitometer Desaga CD 60. PMID- 25272648 TI - Antioxidant and anxiolytic activities of Crataegus nigra Wald. et Kit. berries. AB - Hawthorn has been present for a long time in traditional medicine as antihypertensive, hypolipidemic, anti-inflammatory, gastroprotective, antimicrobial agent. Hawthorn can be used for the cure of stress, nervousness but there is no published paper about actions of Crataegus nigra Wald. et Kit. fruits. The present study was carried out to test free-radical-scavenging and anxiolytic activity of C. nigra fruits. DPPH (alpha,alpha-diphenyl-beta picrylhydrazyl) assay was used to measure antioxidant activity. BHT, BHA, PG, quercetin and rutin were used as standards. The total amount of phenolic compounds, procyanidins, and flavonoids in the extracts, was determined spectrophotometrically. Results were expressed as equivalents of gallic acid, cyanidin chloride and quercetin equivalents, respectively. LC-MS/MS was used for identification and quantification of phenolic composition. The anxiety effect, expressed as the difference in time spent in the open and closed arms, was measured and compared between groups. Phenolic compound content of Crataegus nigra fruits was 72.7 mg/g. Yield of total flavonoid aglycones was 0.115 mg/g. Procyanidins were 5.6 mg/g. DPPH radical-scavenging capacity of the extracts showed linear concentration dependency, IC50 value were 27.33 microg/mL. Anxiolytic effect was observed. Species Crataegus nigra fruits hydroalcoholic extract showed antioxidant and anxiolytic activity. PMID- 25272649 TI - In vitro evaluation of transdermal patches of flurbiprofen with ethyl cellulose. AB - This study was aimed to determine effects of penetration enhancers and plasticizers on drug release from rationally designed formulations of flurbiprofen based transdermal drug delivery system. Matrix type transdermal patches were formulated with ethyl cellulose (EC) as a polymer by using plate casting method. The plasticizers such as propylene glycol (PG) and dibutyl phthalate (DBP), and enhancers such as Span 20, Tween 20, sodium lauryl sulfate (SLS), isopropyl myristate (IPM) and ethanol (EtOH) were formulated in different concentrations in the patches. Such different combinations of polymer with various enhancers and plasticizers in patches were evaluated for their effect on the physicochemical properties and drug release behavior of flurbiprofen. The drug release study was carried out by the paddle-over-disk method and permeation of drug was performed by Franz diffusion cell using rabbit skin. Patches having ethanol with ethyl cellulose showed more uniformity in the physical properties while the smoothness and clarity of patches containing sodium lauryl sulfate were not satisfactory. The drug release from patches followed Higuchi and Korsmeyer Pappas model while maximum drug release was obtained by isopropyl myristate (903 microg). It was concluded that the patches having ethyl cellulose with isopropyl myristate and propylene glycol are more useful for transdermal patches of flurbiprofen. PMID- 25272650 TI - Permeation study through bacterial cellulose membrane. AB - Abstract: The objective of this study was to fabricate topical formulations of diclofenac diethylamine (DD) using isopropyl myristate (IPM) and isopropyl palmitate (IPP) as permeation enhancers. Franz cell and bacterial cellulose were used as analytical instrument and diffusion membrane, respectively. Permeation enhancers exhibited significant effect on the permeation characteristics of DD. It was concluded from the results that improved permeation of DD was observed when IPP was used as enhancer. PMID- 25272651 TI - Identification of phases of various oil, surfactant/ co-surfactants and water system by ternary phase diagram. AB - The objective of this study was to select appropriate surfactants or blends of surfactants and oil to study the ternary phase diagram behavior and identify various phases obtained from the oil and surfactant/surfactant mixture combinations of different HLB. The phases include conventional emulsion, gel/viscous and transparent/translucent microemulsion. Pseudoternary phase diagrams of water, oil and S/Smix of various HLB values range of 9.65-15 were constructed by using water titration method at room temperature. Visual analysis, conductivity and dye dilution test (methylene blue) were performed after each addition and mixing of water, to identify phases as microemulsion, o/w or w/o emulsion (turbid/milky) and transparent gel/turbid viscous. High gel or viscous area was obtained with Tween 80 and surfactant mixture of Tween 80 and Span 80 with all oils. The results indicated that non-ionic surfactants and PG of different HLB values exhibited different pseudoternary phase diagram characteristics but no microemulsions originated from mineral and olive oils. The w/o emulsion occupied a large area in the ternary phase triangle when HLB value of the surfactant/Smix decreased. The o/w emulsion area was large with increasing HLB value of surfactant/Smix. PMID- 25272652 TI - Optimization and evaluation of clarithromycin floating tablets using experimental mixture design. AB - The purpose of the study was to prepare and evaluate clarithromycin (CLA) floating tablets using experimental mixture design for treatment of Helicobacter pylori provided by prolonged gastric residence time and controlled plasma level. Ten different formulations were generated based on different molecular weight of hypromellose (HPMC K100, K4M, K15M) by using simplex lattice design (a sub-class of mixture design) with Minitab 16 software. Sodium bicarbonate and anhydrous citric acid were used as gas generating agents. Tablets were prepared by wet granulation technique. All of the process variables were fixed. Results of cumulative drug release at 8th h (CDR 8th) were statistically analyzed to get optimized formulation (OF). Optimized formulation, which gave floating lag time lower than 15 s and total floating time more than 10 h, was analyzed and compared with target for CDR 8th (80%). A good agreement was shown between predicted and actual values of CDR 8th with a variation lower than 1%. The activity of clarithromycin contained optimizedformula against H. pylori were quantified using well diffusion agar assay. Diameters of inhibition zones vs. log10 clarithromycin concentrations were plotted in order to obtain a standard curve and clarithromycin activity. PMID- 25272653 TI - Effects of antidepressants and soybean association in depressive menopausal women. AB - Depression in menopausal women has been widely described for many years ago and is related to hormonal decrease, mainly estrogens. The use of soy has been proposed as a possible coadjutant alternative to treat menopausal depressive disorder. In the present pilot clinical trial the effect of soybean, antidepressants and the association of soybean with antidepressants was studied in 40 depressive menopausal women for three months. Patients were divided in four groups of 10 women: fluoxetine (10 mg), soybean (100 mg), sertraline (50 mg), and sertraline (50 mg) plus soybean (100 mg). The Hamilton and Zung Depression Scales were used to measure the treatment effects. Values at the beginning and at the end of the study were compared. In all cases a significant difference was observed when the treated groups were compared vs. their untreated situation in both scales (p < 0.001). When a comparison between pre- minus post-treatment Zung scale scores was done, the effect induced by the association of sertraline and soybean was significantly higher than the other groups (p < 0.05). These effects were also seen using the Hamilton scale scores, showing significant differences between the association vs. soybean (p < 0.05) and setraline (p < 0.05) groups, but not vs. fluoxetine group. We conclude that soybean has an antidepressant effect per se, and the association of soybean and antidepressants increases their effects. PMID- 25272654 TI - Consumption of osteoanabolic drugs and strontium ranelate in the treatment of osteoporosis in the Czech Republic in 2005-2011. AB - Anti-osteoporosis drugs with osteoanabolic (teriparatide, intact parathormone) and dual (strontium ranelate) mechanism of action are currently available for the treatment of postmenopausal, glucocorticoid induced or male osteoporosis in the Czech Republic (CZ). These expensive drugs are subjects of special prescribing limitations (2nd line treatments). The objective was to analyze trends in consumption of osteoanabolic and dual drugs in the treatment of osteoporosis since their introduction onto the market in CZ (2005-2011). The prescription based database of the General Health insurance Company of the Czech Republic that covers approximately 60% of the Czech population was used as the data source. An insured person with a recorded prescription for teriparatide (TRPD), intact parathormone (iPTH) or strontium ranelate (SR) in the period of interest was defined as a patient; 271 (224), 77 (75) and 5930 (5545) patients (women) treated with TRPD, iPTH and SR in 2011, respectively, were identified. The median age of patients on TRPD and SR ranged from 71 to 74 years in 2006-2011. The number of patients treated with TRPD between 2009 and 2011 has been stable, while in iPTH the number increased 2.8 times in the same time period. The number of patients treated with SR has been steadily rising since its introduction in 2005. SR was prescribed most often by physicians specialized in internal medicine (42%) and rheumatology (25%). Male patients accounted for 6% of the SR consumers in 2011. The consumption of dual and osteoanabolic drugs has been rapidly increasing. Consumption rates in men (both absolute and relative) have been increasing but still remain relatively low. PMID- 25272656 TI - Docking of thiopurine derivatives to human serum albumin and binding site analysis with Molegro Virtual Docker. PMID- 25272655 TI - A questionnaire based survey study for the evaluation of knowledge of Pakistani University teachers regarding their awareness about ibuprofen as an over the counter analgesic. AB - In recent time, due to convenient availability of number of over the counter (OTC) drugs, patients are able to treat minor ailments by themselves. The self medicated regimen has lead to certain health problems in all age groups irrespective of their professions. People are usually unaware about the safe use of NSAIDs (non-steroidal anti-inflammatory drugs) and currently there is no study carried out in COMSATS Institute of Information Technology (CIIT), Abbottabad, regarding the choice of faculty members for NSAIDs to relieve pain and their knowledge about its safety and use. A questionnaire based survey was carried out to collectdata about the choice of CIIT faculty for a specific NSAID and their cognition related to ibuprofen. Two hundred fifty faculty members (comprising of 53 pharmacy faculty members and 197 faculty members who belonged to other departments) of which 87 were females, took part in this study. Average age of participants was 34.86 +/- 9.02 years. Ibuprofen was the drug of choice NSAID among the participants. Four percent participants experienced pain almost every day. Analgesia was the well known indication for ibuprofen (31%) by both the groups and in general more educated and younger participants showed better apprehension related to indications. Sixty one percent participants comprising of non-pharmacy faculty were unaware of any undesirable effects and 79% (comprising of 72% pharmacists and 5% non-pharmacists) were affirmative that ibuprofen had no adverse effects. Fifteen percent participants of department other than pharmacy were not aware of any interactions of ibuprofen. 34% of participants (comprising of 32% non-pharmacists and 2% pharmacists) entrusted their physician for an analgesic. Regardless that many participants suffered from pain almost every day and their drug of choice would be ibuprofen, they had inadequate information related to the safety and use of ibuprofen. PMID- 25272657 TI - [PKV (private health insurance) - good protection for all life circumstances]. PMID- 25272658 TI - [Feasibility and limits of clinical neurophysiology with regard to the objective evaluation of neurological consequences following accidents]. AB - It is not unusual for a neurological expert to have problems defining the precise anatomical location and the required objective proof of damage, especially if the medical history and the neurological report released by the clinic prove inadequate in terms of providing a reliable assessment. This may well result from somatoform disorders, dissociation, aggravation and simulation, as well as dissimulation and complex organic diagnostic findings. A range of standardised neurophysiologic procedures is available for the objective measuring of motor, vegetative and sensory systems; a brief summary of the most frequent occurrences is given here, along with their significance for appraising damage resulting from an accident. Target groups primarily include surgeons, orthopaedists, lawyers and insurance specialists. Structural improvements and measures to integrate immigrant doctors is essential. PMID- 25272659 TI - [The transient ischemic attack (TIA)--a valid instrument for intern process analyses in neurological departments]. AB - BACKGROUND: The aim of this study was to develop a valid tool for internal process analysis of stroke management in order to identify possible improvements. METHOD: 939 stroke patients were classified into DRG diagnoses. Specific parameters known to influence the length of stay were analysed. Subgroup analyses were carried out in patients with TIA regarding a) differences between the neurological sections/ wards, and b) length of stay in correlation with resident level of training and the physician staffing in the particular department/ ward over the year. RESULTS: A difference in the length of stay of 1-2 days was revealed between the neurological departments/wards. Transfer to rehabilitation centres increased the length of stay by 5 days. Length of stay correlated with the training level of residents and staffing in the department/ward. Capacity overload due to reduced staffing or high fluctuation of staff increased the length of stay significantly. CONCLUSION: TIA patients were shown to be a homogeneous subtype of stroke patients, who can be used as a valid tool to analyse internal processes. This analysis revealed that length of stay depends on resident level of training and workload. PMID- 25272660 TI - [Impact of potentially inappropriate drug usage on health insurance business results]. AB - In Germany a list was drawn up that included 83 potentially inappropriate drugs. The PRISCUS list published in 2010 was intended to highlight certain problems in the pharmakotherapy of elderly patients and serve as a support for improved medicine safety. Almost a third of the insurance portfolio of the HALLESCHE Krankenversicherung aged over 75 years takes drugs that are on the PRISCUS list. Benzodiazepine and Z-drugs are taken most frequently. The costs per insurant with potentially inappropriate medication are on average higher than for policyholders who do not take drugs on the PRISCUS list. The costs per insurant are rising, with an increase in the number of PRISCUS agents being taken as well. However, there is still no scientific proof that potentially inappropriate drugs lead to adverse drug events. PMID- 25272661 TI - [The picture of malingered symptom presentation in public opinion]. AB - The views held by health experts on certain topics may differ drastically from what appears to be obvious from observations in daily living or public opinion. This is true for a number of myths which continue to haunt the literature with respect to feigned health problems. Such myths tend to ignore or to distort the results of modern research. We performed two pilot studies: first a content analysis of 67 German- and English-language articles from newspapers, magazines or internet journals, and second, a survey on the experience of, and beliefs related to, exaggeration and symptom invention in health care and forensic assessment. A non-representative sample of 15 adults from the general population was interviewed. Most of them reported their own experiences or incidents in their social networks involving feigned health problems. Base rate estimates of malingering in five prototypical contexts ranged between 46 and 67 percent of cases. While the participants showed a preference for an adaptational explanatory model of malingering (selected for about 53% of cases of malingering), journalistic sources often employed pejorative language and combat rhetoric, aiming to arouse indignation or outrage in the readership. The majority of articles were classified to adhere to a criminological explanatory model. While the pilot character of the studies limits their generalisability, the results may be suited to question the validity of some long-held expert beliefs. PMID- 25272662 TI - [Miracle mineral supplement - a new universal specific formula]. PMID- 25272663 TI - [Is acupuncture medically necessary in irritable bowel syndrome?]. PMID- 25272664 TI - [Obligation in health insurance - law for practitioners]. PMID- 25272665 TI - [Functional disorders - problems in expert assessment]. PMID- 25272666 TI - [Letter to M. A. Scherer: ruptures of extensor tendons as a complication of internal plate fixation of distal radius fractures]. PMID- 25272667 TI - [Answer]. PMID- 25272668 TI - [Is it necessary to call into question the benefits of glycemic control in type-2 diabetes?]. PMID- 25272669 TI - [Treatment of dyslipidemia in 2014: European versus American guidelines]. AB - The recent American guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults have confused the debate in comparison with the European guidelines. These US guidelines prefer the notion of intensity of reduction of blood cholesterol based on the level of cardiovascular risk rather than a LDL cholesterol level target recommended by the European guidelines. Moreover, only the use of statins is recommended without any consideration for alternative pharmacological approaches in special situations. Even if we can find some similarities between these two guidelines, it is of interest to compare them carefully in order to justify the reasons why preference should be given to European guidelines. PMID- 25272670 TI - [The role of mesenchymal stromal cells in solid organ transplantation]. AB - Solid organ transplantation (SOT) currently represents the best therapeutic option in end-stage diseases caused by the irrevocable functional loss of an organ. Still, SOT is associated with immunological and non-immunological injuries, whose severity impacts on early functional recovery and long-term survival of the transplant. Current research focuses on the identification of innovative approaches to 1) attenuate ischemia/reperfusion-induced damage, 2) accelerate processes of tissue repair, and 3) induce in fine graft tolerance. Encouraging observations from both preclinical studies and clinical trials suggest that the administration of mesenchymal stromal cells at the time of SOT might be beneficial, as a result of theirs immunomodulatory, anti-inflammatory and regenerative properties. PMID- 25272671 TI - [Bronchial thermoplasty: a real advancement in the treatment of asthma]. AB - New treatments are needed to improve the care of severe asthmatic patients. Bronchial thermoplasty aims to lessen the airway smooth muscles via the heating of bronchial walls by radiofrequency. The preliminary studies showed a good tolerance and some good efficacy. Randomized controlled trials have been undertaken on moderate to severe asthmatic patients, demonstrating an improvement in quality of life, rate of severe exacerbations and unscheduled medical visits. The main side-effects consist of asthma exacerbations, atelectasis and infections. Bronchial thermoplasty is an innovative treatment with good efficacy and acceptable tolerance for moderate to severe asthmatic patients. More studies are needed to better understand its mechanism of action and more clearly delineate the precise indications of this innovative technique. PMID- 25272672 TI - [Potential of a GLP-1 receptor agonist combined with basal insulin in the treatment of type 2 diabetes]. AB - The complex pathophysiology of type 2 diabetes and its natural evolution, characterized by a progressive loss of glucose control due to the exhaustion of insulin secretion, lead to consider new complementary therapeutic options. Even at the insulin-requiring stage, the addition of a glucagon-like peptide-1 (GLP-1) receptor agonist is beneficial. Besides their incretinomimetic activity (which may decrease with the loss of beta-cell mass/function), GLP-1 receptor agonists reduce glucagon secretion, slow down gastric emptying and diminish appetite through a central effect. These combined effects permit to improve glucose control, while reducing daily insulin doses, together with less weight gain (or even weight loss) and generally less hypoglycaemia. Fixed insulin glargine lixisenatide and insulin degludec-liraglutide are currently in development. PMID- 25272673 TI - [Hormonal deficiencies in the elderly: is there a role for replacement therapy?]. AB - Biological aging is characterized by a progressive loss of the secretion of various hormones, a phenomenon that leads some physicians to propose an anti aging hormonal therapy. It is mandatory to differentiate: 1) the physiological functional loss, which is a natural phenomenon without clear deleterious consequences on health and should not be compensated by the administration of hormones only to restore plasma levels similar to those measured in young people and 2) a pathological defect that deserves a replacement therapy to correct the endocrine deficiency and improve the health status of older individuals. This article considers the deficiencies in insulin, thyroid hormones, growth hormone, dehydroepiandrosterone (DHEA) and testosterone. For each hormone, a benefit/risk ratio of a so-called replacement therapy will be analyzed. PMID- 25272674 TI - [The role of new oral anticoagulants]. AB - New oral anticoagulants (NOACs) are going to deeply modify the treatment of non valvular atrial fibrillation and thromboembolic disease. They are non-inferior to warfarin and trials show a similar bleeding rate (even lower for some NOACs). Nevertheless one must be cautious when dealing with patients at risk (elderly patients, frail ones, renal or liver impairment...) and practicians must be well aware of doses and contraindications. NOACs' long- term tolerance is not yet well known. In cancer, their benefit-risk ratio compared to low molecular weight heparin remains to be determined. PMID- 25272675 TI - [Exit - individual and collective values]. PMID- 25272676 TI - [Potential vaccine candidates against Ebola and the first vaccine against chikungunya virus infection]. PMID- 25272677 TI - [The electronic cigarette becomes a more political practice by the day]. PMID- 25272678 TI - [Vacations, absence and muscle strength]. PMID- 25272679 TI - [Summer 2014. Miscellaneous items in connection with alcohol]. PMID- 25272680 TI - [The world (almost) lost to the public purse]. PMID- 25272681 TI - [Risk stratification in cardiovascular surgery]. PMID- 25272682 TI - [Prolonged epidural analgesia and ozonated autohemotherapy in complex surgical treatment at patients with thromboangiitis obliterans and critical limb ischemia]. PMID- 25272683 TI - [Surgical treatment of gastro-esophageal reflux disease]. PMID- 25272684 TI - [Intraperitoneal arrosive bleeding after pancreas surgery]. PMID- 25272685 TI - [Laboratory sepsis diagnostic in multidisciplinary hospital]. PMID- 25272686 TI - [Aspects of surgical treatment of gastroesophageal reflux relapse in children and teens]. PMID- 25272687 TI - [Spontaneous rupture of the esophagus]. PMID- 25272688 TI - [D.A.Arapov - surgeon, teacher, public figure (125th Anniversary)]. PMID- 25272689 TI - Authors' reply. PMID- 25272690 TI - Zen-good medicine. PMID- 25272691 TI - Unity and professionalism wins respect and reverence. PMID- 25272692 TI - Politics as usual? PMID- 25272693 TI - A healthily functioning democracy: small incremental changes. PMID- 25272695 TI - TMA public health champion: Dr. David Reagan. PMID- 25272694 TI - A collaborative team effort in diabetes prevention. PMID- 25272696 TI - As a Tennessee delegate, in the AMA House of Delegates. PMID- 25272697 TI - Effective strategic alliances & partnerships: closing the gaps in medicine. PMID- 25272698 TI - A tale of lost innocents. PMID- 25272699 TI - Education and the professional medical biller. PMID- 25272700 TI - Five years ... five reasons. PMID- 25272701 TI - [Statistically significant reproducible differences of pericranial muscles EMG in beta and gamma frequency ranges when different emotional and cognitive states are compared]. AB - Results of comparison of power of EMG of six pericranial muscles in electroencephalographic frequency ranges beta1, beta2 and gamma are presented corresponding to performances of the tasks bound to inductions of affective experiences-external by means of presentation of images and internal by means of autobiographical memoirs revived. The tasks were focused on an induction of affective experiences with different emotional valencies--positive, negative and neutral. The EMG was derived, registered and processed by means of a computer electroencephalography techniques. Self-ratings of signs and intensities of tested emotions were recorded as well. The study involved two groups of healthy subjects--students-actors (N = 39), and students of other majors (N = 32). Statistically reliable, reproducible and diverse differences of averaged EMG power of the pericranial muscles took place as in comparisons of psychophysiological conditions with different valencies of emotions, as well in comparisons of conditions without expressed emotional differences, but differing in the direction of attention. Therefore it is obviously necessary for an assessment of a degree of muscular contamination in records of high-frequency scalp EEG to supplement psychophysiological EEG methods with EMG registration and statistical analysis and to do such registration for several facial muscles. PMID- 25272702 TI - [Investigation of muscle tone in patients with Parkinson's disease in unloading conditions]. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder, ones of the main symptoms of which are hypertonicity and emergent difficulties during performance of stepping movements due to increased muscle stiffness. Biomechanical (stiffness) and electrophysiological (shorting reaction) characteristics of hip and shank muscles were examined in 25 patients with mild and moderate stages of PD (1 to 3 of Hoehn & Yahr Rating Scale, 61 +/- 9 years) and 22 age-matched healthy controls in unloading leg conditions during passive flexion/extension of hip, knee and ankle joints, as well as the changes of tonic state under levodopa influence. The data obtained were compared with similar findings of healthy subjects. Essentially greater stiffness in all leg muscle groups (with the exception of foot extensors) were observed in patients as compared with healthy. During passive movements the shorting reactions (SR) in hip and shank muscles were often observed, in healthy subjects the SR were observed more rarely. In patients with PD the values of SR in extensors of hip and shank, as well as in flexor and extensor muscles of foot were essentially greater then in healthy. The medicine essentially reduced the stiffness of hip flexors and flexors and foot extensors. The SR were persisted but the frequency of its appearance was decreased in half of investigated muscles, and significant decreasing of SR amount was observed in extensors of foot. The medicine did not exert influence upon SR in proximal muscles. Thus, increasing muscle stiffness in patients with PD is manifested in uncorrected reactions on external disturbances and reflected in increasing of reflectory reaction of muscles. PMID- 25272703 TI - [Relationship between inertial features of the upper extremity and simple reaction time in boys and girls aged 17-18]. AB - The latent period of visual sensor-motor reaction depends, in part, on the sensory and integrative processes in the brain, but is also influenced by the rate of the muscle contraction. There is no clear evidence in the literature whether the rotational inertia of segments of limbs has any direct effect on the reaction time. The aim of our study was to identify this relationship. The study involved 566 right handed students aged 16-17 of both genders beginning their post puberty period. Reaction time was measured during experimental adduction of the forearm and hand, using a special rotating handle and lever connected to a computer that recorded the reaction time (+/- 1 ms). Calculations of the rotational inertia were carried out using regression models by Zatsiorsky and other authors. Each gender group was divided into three subgroups: with high, medium and low values of rotational inertia. It was found that individuals with high values of rotational inertia of forearm and wrist demonstrated significantly longer reaction times. This pattern was apparent in both gender groups. Although males illustrated greater values of rotational inertia than females they demonstrated relatively shorter reaction times. This contradiction can be explained by greater muscle power of young men. We recommend taking into account the amount of rotational inertia of the responsive segment in all kinds of research which require measurement of reaction time. PMID- 25272704 TI - [EEG alpha indices in dependence on the menstrual cycle phase and salivary progesterone]. AB - The effects of the neurohumoral status on the EEG alpha - activity indices were studied in a within-subject design with 78 women aged 18-27 years during 1-2 menstrual cycle. Psychometric and EEG indices of alpha waves basal body temperature, saliva progesterone and cortisol level were monitored every 2-3 days. Menstrual and follicular recording sessions occurred before the ovulatory temperature rise, luteal recording session--after increasing progesterone level more than 20% respect to previous day and premenstrual sessions after decreasing progesterone level more that 20% respect to previous day. The design consisted of rest and task periods EEG, EMG and ECG recordings. Half the subjects began during their menstrual phase and half began during their luteal phase. All 5 phases were compared for differences between psychometric features EEG alpha activity, EMG and ECG baseline resting levels, as well as for reactivity to cognitive task. The results showed menstrual phase differences in all psychometric and alpha EEG indices. The cognitive fluency, alpha peak frequency, alpha band width, power in alpha-2 frequency range are maximal at luteal, alpha visual activation and reactivity to cognitive task performance--at follicular phase. The hypothesis that the EEG alpha activity depends on the hormonal status supported by the positive association salivary progesterone level with the alpha peak frequency, power in the alpha-2 band and negative--with the power of the alpha-1 band. According these results, we conclude that psycho-physiological recording sessions with women might be provided with a glance to phase of menstrual cycle. PMID- 25272705 TI - [The influence of dehydroepiandrosterone (DHEA) on the behavior in old non-human primates]. AB - At present time there is a lack of satisfactory understanding of how DHEA affects cognition and nervous system function. Aim of the present study to evaluate effects of long-term DH EA administration of physiological doses on the Higher Brain Activity (HBA) in rhesus macaques (RM) at the limits of their biological age. The study included 9 male RM aged 24-30 years. Five of them were given im injections of DHEA (1 mg/kg each two days for 3 months). 4 control monkeys were administered the vehicle alone. Cortisol, testosterone, and free thyroxin were measured by chemiluminescent immunoassay. HBA was studied by classical motor-food conditioning (to estimate long-term memory) and by determining delayed response time (a measure of short-term memory). RM had to respond to a positive signal (1000 Hz) and no bar-pressing was required in response to a negative signal (400 Hz). MR were free to move in the cage during the experiment. Their behavior was tested before, within 1, 2, 3 months of DHEA administration and 3 months after its termination. The HBA increased of all 5 RM within 1, 2, and 3 month after the beginning of DHEA administration. Both long- and short-term memory stably improved while response time decreased from 5 to 1-1.5 s. The behavior of RM changed radically from passive one to enhanced motor activity and food motivation. These effects of DHEA persisted as long as 3 months after DHEA treatment. During DHEA treatment the steady tendency to rising in a blood concentrations of a free thyroxine, testosterone and DHEA was observed. DHEA administration caused a rise in testosterone, free thyroxin levels and DHEAS levels. In three months after DHEA treatment the hairs lost in the old monkeys was restored and this effect remained within one years of observation. Conclusion. Administration of physiological doses of DHEA to old RM induced a stable increase of Higher Brain Activity with harmonization of excitation and inhibition processes; radically enhanced motor and food activity; completely restored body hairiness which already remained within one year. PMID- 25272706 TI - [Neurophysiological correlates of pyramidal insufficiency of ischemic and traumatic genesis in conditions of distraction osteosynthesis application]. AB - Analyzed main trends in variations of quantitative electroneuromyographic characteristics at patients with stroke and severe craniocerebral trauma consequences in the treatment process using transosseous distraction osteosynthesis. Studied specific features of central nervous system reaction on present surgical treatment at patients depending on age, etiology and severity of initial brain structures damage. Formulated notions about staging and mechanisms of reactive change in the brain-cortex under the influence of rehabilitation by transosseous distraction osteosynthesis at patients of noted nosological groups. PMID- 25272707 TI - [Functional state feature of erythrocytes in healthy term newborn infants]. AB - Hematological parameters and functional status of erythrocytes were studied by the osmotic and ammonium loads in healthy newborns and in adults. Mean erythrocyte volume of newborns more than in adults. Significant difference index of osmotic fragility of neonates were observed in the transition from swelling to hemolysis. Kinetic of erythrocyte's hemolysis in the ammonium load was studied by low-angle light scattering (LaSca-analyzer). The percentage of erythrocyte hemolysis is lower and the velocity of hemolysis is 2.5 times slower in newborns than in adults. PMID- 25272708 TI - [The mechanism of change in speed of agglutination of human erythrocytes under the influence of adrenaline]. AB - In the study of red blood cells of 80 men found that adrenaline (10(-10) - 10(-6) g/mL) and phenylephrine (10-(10) - 10(-6) g/mL) dose-dependently increase the speed of agglutination of red blood cells, according to the decrease in agglutination of the start time and ginipral (10(-10) - 10(-7) g/mL), on the contrary, decreases it. The effect of adrenaline and phenylephrine is blocked by nicergoline (10(-6) g/mL), increased obzidan (10(-6) g/mL) and does not change under the action ofyohimbine (10(-6) g/mL) and atenolol (10(-6) g/mL). These data indicate that the speed of agglutination increases with activation alpha1 adrenergic receptor (AR) and decreases in the activation of beta2-AR, while the activation of alpha2- and beta1-AR does not affect it. Trifluoperazine (10(-6) g/mL) as the calmodulin antagonist, barium chloride (10(-6) g/mL) as a blocked of Ca(2+)-dependent K(+)-channels and indomethacine (10(-6) g/mL) as an inhibitor of cyclooxygenase and phospholipase A2 inhibit the ability of adrenaline to increases the speed of agglutination of red blood cells. This suggests that the effect of adrenaline caused an increase in erythrocyte entry of Ca2+, activation of calmodulin, cyclooxygenase, phospholipase A2 and the release of K+ from red blood cell through the Ca(2+)-dependent K+ channels, which is regarded as a manifestation of eryptosis. Indirectly, this means that more efficient activation of alpha1-AR and beta2-AR, respectively, increases or, conversely, decreases the rate of eryptosis. PMID- 25272709 TI - [Interpopulation differeces biochemical adaptation at population of Gorny Altai]. AB - The factual nutrition of aborigines Russian, altay and kazah nationalities of Gorny Altai were studied. As a result, interpopulating differences of population's nutrition witch quantitative consumption macronutrients have been influence and dependence on the nationality has been determined. Biochemical parameters of blood with quantitative composition of ration's macronutrients are correlated. PMID- 25272710 TI - [Adaptation-compensatory response in adolescents, indigenous people North of Irkutsk region]. AB - A study of pro- and antioxidant status in healthy boys and girls adolescents' representatives Tofalars and Evenks compared to Caucasians newcomers. Revealed activation of the adaptive-compensatory processes in the body young men and women, indigenous peoples of the North as compared to Caucasians alien population, which was reflected statistically significant increase in non enzymatic components of antioxidant defense system. PMID- 25272711 TI - [The impact of increased physical exertion on adrenal cortex state and puberty of the boys]. AB - The research of the adrenal cortex (AC) functional state of 11-15-year-old boys sportsmen, conducted on the basis of free and bound cortisol (Cf, C) daily excretion indicators, as well as their comparative characteristics with the test class boys revealed that the increased physical activities in the form of regular sport trainings have the overwhelming impact on the age dynamic of AC and puberty of the young sportsmen. It is shown that the Cfexcretion of the 12-14-year-old sportsmen is characterized by the consistently high indices, and by age of 15 it is observed a significant decrease in the setting of high C values. In contrast to the boys that do not go in for sports and cortisol in urine of which is significantly lower (p < 0.05), but for the age of 13 to 15 it is noted its progressive increase (p < 0.05). A relative slowing ofthe boys-sportsmen puberty process (secondary sexual characters development) is revealed, AC glucocorticoid function pubertal transformation of these boys are completed earlier and in a greater degree reflect its adaptive behavior, that provides raise of child's body resistance to increased physical exertion's influence. PMID- 25272712 TI - [Respiratory system response to cooling in subjects with single nucleotide polymorphism rs11562975 in gene of thermosensitive TRPM8 ion channel]. AB - On the basis of genomic studies in subjects belonged to Russian ethnic group it was identified individuals with heterozygous genotype, containing the C-allele in single nucleotide polymorphism rs11562975, located in 6 exon of the gene encoding the temperature-sensitive ion channel TRPM8. Subjects with heterozygous genotype GC were characterized by not only increased sensation to cold but also hypometabolic response to local skin cooling and non-temperature activation of TRPM8 ion channel by menthol--decrease in total metabolism, pulmonary ventilation and coefficient of oxygen extraction. The subjects with homozygous genotype GG had a lower cold sensation and adequate response to local skin cooling in respect to thermoregulation--decrease in respiratory heat loss and increase in the lipid metabolism. PMID- 25272713 TI - [Forced expiratory tracheal noise time in young men under health and bronchial obstruction conditions]. AB - The group of 270 young men (16-25 years) is tested which includs healthy nonsmokers, healthy smokers, bronchial asthma patients with spirometry confirmed obstruction and without it. Forced expiratory tracheal time is registered in the frequency band of 200-2000 Hz. Spirometry indexes and anthropometric parameters are measured. It is shown that forced expiratory time and its ratios to body height, mass and chest circumference reflect airway resistance and these indexes are perspective to reveal bronchial obstruction. PMID- 25272714 TI - [Heart rate variability in young hockey players at rest and during active orthostatic test]. AB - Heart rate variability of twenty seven young athlete (ice hockey) was investigated. Special autonomic mechanism that function both at a supine position and during orthostatic test were found, which probably reflect the adaptation of the cardiovascular system to the sport. PMID- 25272715 TI - [Analysis of the medicinal leech effects on the state of arterial functions of aged probationers, using hardwarily software system "Angioscan-01"]. AB - The state of elderly patients arterial wall after the putting of one medicinal leech was estimated by use hardwarily software system "Angioscan-01". There was compared the effect of one medicinal leech on indicators of vasomotor function of endothelium of small resistance arteries and of middle arteries of muscular type. Stickiness index and augmentation index were determined in order to evaluate the medicinal leech effect on the rigidity state of arterial wall. It is shown that the putting of one leech stimulates the improving of endothelium vasomotor function and of normalization arterial wall stickiness. It is supposed the participation in this process the secretion of the medicinal leech salivary cells, which, as has been shown recently, is able to activate e-NOS and n-NOS in human endothelium culture (HUVEC) and increase NO level. Elevation of share stress during occlusion test is also stimulated NO production in vascular endothelium. PMID- 25272716 TI - [Hardware and software for EMG recording and analysis of respiratory muscles of human]. AB - This paper presents a new hardware and software system that allows to not only record the EMG of different groups of the respiratory muscles, but also hold its amplitude-frequency analysis, which allows to determine the change in the contribution to the work of breathing of a respiratory muscles and detect early signs of fatigue of the respiratory muscles. Presented complex can be used for functional diagnostics of breath in patients and healthy people and sportsmen. PMID- 25272717 TI - [Cortisol as a marker of stress]. AB - The role of cortisol (Crt), dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA S) in stress responses were shown. The fluctuations in concentration of Crt, DHEA and DHEA-S depending on age, sex and time of the day in norm and under acute and chronic stress were quoted. The main techniques of assessment of serum, urine and saliva Crt concentrations were discussed. A special attention had been paid to the use of Crt concentration in anthropological and psychological research. Bibliography comprises 181 works. PMID- 25272718 TI - [Specific features of interpretation of myocardial perfusion single-photon emission computed tomography with computed tomographic absorption correction]. AB - OBJECTIVE: To study the capabilities of a hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) system during myocardial perfusion imaging study, to evaluate the impact of absorption correction (AC), and to reveal factors influencing the contribution of AC to the diagnostic result of the study. MATERIAL AND METHODS: The study included 167 patients who underwent myocardial perfusion SPECT with and without CT AC. Differences between AC and non AC studies were visually analyzed; the results of the analysis were used to form groups of visual differences. The supposed factors influencing the contribution of AC were studied, by assigning visual differences to a particular group. RESULTS: The possible variants of the impact of AC were described in the baseline scintigrams. AC made a significant contribution in 68% of cases. With AC, the perfusion defects visible during non-AC study recovered in 80% of these cases. The factors predicting substantial differences between the AC and non-AC studies included weight, end diastolic volume, male sex, patients with small focal perfusion defects and transient ischemia, and inadequate injected activity. Factors, such as body mass index, large perfusion defects, CT subsystem and orbit settings, and time from the injection of a radiotracer to the initiation of a study, had no substantial impact on the contribution of AC. During AC studies, SRS and transient ischemic dilatation were significantly higher than during non AC studies, requiring a shift of standard criteria. There were some methodical features of interpretation of myocardial perfusion SPECT using CT correction. CONCLUSION: Myocardial SPECT with AC enhances the diagnostic value of the technique, simplifies the interpretation of myocardial perfusion SPECT, and reduces the number of false-positive and questionable results. PMID- 25272719 TI - [Cerebral artery fenestrations: incidence, association with cerebral arterial aneurysms and other vascular diseases according to the data of multislice spiral computed tomography angiography]. AB - OBJECTIVE: To determine the incidence of fenestrations from multislice spiral computed tomography angiography (CTA) series and to establish the possible association of fenestrations with aneurysms and other vascular diseases of the brain. MATERIAL AND METHODS: Four hundred and eighty-six persons who had undergone brachiocephalic artery (BA) CTA for different clinical indications were selected for retrospective analysis. Postprocessor data processing was made to detect extra- and intracranial artery fenestrations. Saccular and fusiform cerebral aneurysms, arteriovenous malformations (AVMs), and venous angiomas were detected in addition to fenestrations. When aneurysms were concurrent with fenestrations, their locations were compared. RESULTS: Among the 486 patients, fenestrations were revealed in 50 (10.3%) cases, of which there were 46 (9.5%) intracranial artery fenestrations and 4 (0.8%) vertebral artery (VA) ones in the extracranial segments. Aneurysms of different locations were found in 163 (33.5%) patients. Venous angiomas of different locations were seen in 9 (1.9%) persons; AVMs were observed in 21 (4.3%) patients. Fifty-four multiple fenestrations were identified. The bulk of fenestrations were located in the area of the anterior communicating artery (ACA) in 28 (51.9%) patients. Aneurysms were found in 11 (22%) patients with fenestrations. Aneurysms were detected in 152 (34.9%) of 436 patients without fenestrations. The incidence of aneurysms was not statistically different in patients with and without fenestrations (p > 0.05); moreover, aneurysms were somewhat more common in patients without fenestrated vessels. Aneurysm located in the area of fenestration was in only one (9.1%) patient. In other cases aneurysms were located in the vessels having no fenestrations. Aneurysms were relatively frequently encountered in 5 (45.5%) patients with BA fenestration. There was no statistical difference in the incidence of AVMs in the fenestration and non-fenestration groups. Venous angiomas significantly more frequently occurred in patients with fenestrations (p < 0.05). CONCLUSION: CTA findings showed fenestrations 10.3% of patients. Fenestrations were located most frequently in the area of ACA and less frequently in the area of BA and middle cerebral artery. Those of other locations, concomitant and extracranial ones, were very rare. According to our data, there was no direct relationship of fenestrations to arterial aneurysms and AMVs. When fenestrations were in the area of BA, the incidence of aneurysms increased up to 45.5%. Venous angiomas occurred more commonly in patients with fenestrations. PMID- 25272720 TI - [Single-photon emission computed tomography in combination with X-ray computed tomography in the study of lacrimal passages. First results]. AB - OBJECTIVE: To explore the capabilities of single-photon emission computed tomography (SPECT) in combination with x-ray computed tomography (SPECT/CT) in the study of the anatomy and drainage function of lacrimal passages. MATERIAL AND METHODS: Twelve scans were carried out in 6 healthy volunteers and in patients with different lacrimal drainage disorders (dacryostenoses, varying obstructive lacrimal passage, dacryocystitis and post-dacryocystorhinostomy). Sodium pertechnetate (99mTc) solution and a radiocontrast agent were instilled into the conjunctival sac during the study. RESULTS: SPECT is an objective procedure to study lacrimal drainage function. It cannot provide data on the anatomic structure of lacrimal passages and determine the location of their stenosis or obstruction. SPECT/CT makes it possible to simultaneously obtain information on the anatomic structure of lacrimal passages, to visualize the sites of their pathological changes, and to evaluate the drainage function of lacrimal passages. PMID- 25272721 TI - [Mini-invasive interventions under magnetic resonance guidance in the clarifying diagnosis of small pelvic tumors]. AB - OBJECTIVE: To perfect and estimate the possibilities of using a mini-invasive diagnostic procedure under magnetic resonance (MR) guidance in the complex anatomic situations in cases of pathological small pelvic changes of unknown origin. MATERIAL AND METHODS: Ten small pelvic interventions were made under MR guidance. The indications for bone biopsy under MR guidance were poor visualization of bone changes or their absence during radiography, including computed tomography. Small pelvic organ and soft tissue biopsies were carried out in the situations of complex location of pathological changes adjacent to critical organs, large vascular and neural structures. All interventions were done using a high-field MR scanner. Freehand biopsy was performed in a stepwise fashion under axial and sagittal T2-weighted image control. RESULTS: Informative histological material was obtained in 100% of cases. No complications were observed. CONCLUSIONS: It became possible to verify the diagnosis based on morphological findings and to timely determine management tactics only by target biopsy under MR guidance in these 10 patients with small pelvic changes of unknown origin. PMID- 25272722 TI - [Capabilities of diffusion-weighted magnetic resonance imaging to evaluate the efficiency of treatment for prostate cancer]. AB - OBJECTIVE: To study the diagnostic capabilities of diffusion-weighted magnetic resonance imaging (MRI) to evaluate the efficiency of treatment, the presence of progressive or recurrent prostate cancer (PC). MATERIAL AND METHODS: The results of small pelvic MRI in 44 patients who had medical (26 (59.1%) patients) or surgical (18 (40.9%) patients) treatment for PC were analyzed. Examinations were performed on a 1.5-Tesla superconducting MRI scanner with a multichannel phased array surface coil. Diffusion-weighted imaging (DWI) at b values of 1000 s/mm(-2) was used in addition to the standard MRI protocol in all the cases. The measurable diffusion coefficient (MDC) was calculated when estimating DWI. RESULTS: Analysis of the results of DWI MRI has indicated that the criteria for the positive impact of medical treatment are a progressive decrease in the prostate volume, a reduction in a MRI signal of a tumor on isotropic DWI, and an increase in MDC. Progressive PC is suggested by a local increase in the MRI signal of a tumor on isotropic DWI and a low MDC. The study has establishes that after radical prostate vesiculectomy, the pattern of tissue masses at the site of cystourethral anastomosis should be assessed not earlier than 6 months postsurgery. CONCLUSION: The performed studies have shown that DWI MRI is an objective technique to assess medical and surgical treatment for PC. PMID- 25272723 TI - [Difficulties in the radiodiagnosis of lung injuries in phthisiatric practice]. AB - The paper describes clinical cases of concomitant lung and intrathoracic lymph node involvements as evidenced by conventional radiography and computed tomography (CT). It shows difficulties in the differential diagnosis of different nosological entities in pulmonary tuberculosis. The x-ray semiotics of concomitant lung injuries is also depicted. PMID- 25272724 TI - [Transradial approach during percutaneous coronary interventions. Part 2. Practical guidelines and the authors' data]. AB - The paper describes the technical features of a transradial approach; indications and patient selection for this arterial approach; and stepwise patient preparation. It depicts the anatomic variants of the origin of the radial artery, which affect the success of this approach. The suitable instruments for this approach are described. The authors give their results of the performed study comparing different types of approaches. PMID- 25272725 TI - [Magnetic resonance imaging in the staging of malignant lymphomas]. AB - Computed tomography, 18FDG-PET and the hybrid FDG-PET/CT are the most commonly used diagnostic tools for the initial staging and treatment response assessment of malignant lymphomas. MRI techniques such as whole-body MRI and diffusion weighted imaging may become good radiation-free alternatives to FDG-PET/CT. Diffusion-weighted imaging is characterized by high sensitivity for the detection of lesions and allows quantitative assessment of diffusion that may aid in the evaluation of malignant lymphomas. This article will review the value of these emerging MRI techniques for the staging and response assessment of malignant lymphoma. PMID- 25272726 TI - [Professor Era Arsen'evna BERESNEVA: on the occasion of the 85th anniversary of her birth]. PMID- 25272727 TI - [Professor Anatoliy Petrovich SAVCHENKO: on the occasion of the 75th anniversary of his birth]. PMID- 25272728 TI - [Melanin pigments of fungi under extreme environmental conditions (review)]. AB - This review is dedicated to the research on the functions of melanin pigments in fungi. The participation of melanin pigments in protection from environmental factors is considered. Data on the biosynthetic pathways and types of melanin pigments in fungi are presented. PMID- 25272729 TI - Regioselective hydrolysis of acetates in the presence of different yeast strains. AB - The model compound, hexane-1,2-diol diacetate, was hydrolyzed in the presence of supernatant obtained after cultivation of 4 yeast strains: Pichia jadinii, Rhodotorula glutinis and Yarrowia lipolytica KKP 379 and Saccharomyces cerevisiae 102 to evaluate the type of catalysis. The regioselectivity of extracellular enzymes as a function of hydrolysis towards primary and secondary acetic acid ester groups was monitored. The enzymes secreted by P. jadinii, R. glutinis and Y. lipolytica KKP 379 exhibited high regioselectivity towards primary position, while those from S. cerevisiae showed practically no discrimination between the ester groups. PMID- 25272730 TI - [Introduction of additional thiol groups into glucoamylase in Aspergillus awamori and their effect on the thermal stability and catalytic activity of the enzyme]. AB - Five mutant forms of glucoamylase (GA) from the filamentous fungus Aspergillus awamori with artificial disulfide bonds (4D-G137A?A14C, 6D-A14C?Y419C?G137A, 10D V13C?G396C, 11D-V13C?G396C?A14C?Y419C?G137A, and 20D-G137A?A246C?A14C) were constructed using computer simulation and experimentally tested for thermostability. The introduction of two additional disulfide bonds between its first and thirteenth alpha-helices and that of the loop located close to a catalytic residue--E400--made it possible to assess the effects of disulfide bridges on protein thermostability. The mutant proteins with combined amino acid substitutions G137A?A14C, V13C?G396C?A14C?Y419C?G137A, and G137A?A246C?A14C showed higher thermal stability as compared to the wild-type protein. At the same time, new disulfide bridges in the mutant A14C?Y419C?G137A and V13C?G396C proteins led to the destabilization of their structure and the loss of thermal stability. PMID- 25272731 TI - Microbial degradation of chitin waste for production of chitosanase and food related bioactive compounds. AB - Ecological samples rich in microbial diversity like cow dung, legume rhizosphere, fish waste and garden soil were used for isolation of chitosan-degrading microorganisms. Selected isolates were used for production of chitosanase and food related bioactive compounds by conversion of biowaste. Production of glucosamine (Gln), N-acetylglucosamine (NAG), chitooligosaccharides (COS), antioxidants, antibacterial compounds and prebiotics was carried out by microbial fermentation of biowaste. The highest chitosanase activity (8 U/mL) was observed in Aspergillus sp. isolated from fish market waste and it could produce Gln and NAG while Streptomyces sp. isolated from garden soil was able to produce COS along with Gln and NAG. Radical scavenging activity was observed in culture supernatants of 35% of studied isolates, and 20% isolates secreted compounds which showed positive effect on growth of Bifidobacterium. Antibacterial compounds were produced by 40% of selected isolates and culture supernatants of two microbial isolates, Streptomyces zaomyceticus C6 and one of garden soil isolates, were effective against both gram positive and negative bacteria. PMID- 25272732 TI - [Export of an invertase by yeast cells (Candida utilis)]. AB - Export and accumulation of various forms of invertase (EC 3.2.1.26) in the cell wall and culture liquid of the yeast Candida utilis was investigated. It was found that the high-molecular-weight CW-form of invertase is present in the cell wall. This form is not exported into the culture liquid, and it is by a third more glycosylated than the previously described exported S-form. It was shown that one of the two liquid forms of invertase exported into the culture-the glycosylated S-form--is retained in the cell wall, while the other one--the nonglycosylated F-form--was not detected in the cell wall. Based on these results, as well as data on the distribution dynamics of the enzyme in the culture liquid and in the cell wall during different growth stages of a yeast culture, we suggested that the nonglycosylated form was exported into the culture liquid via the zone of abnormal cell wall permeability and the glycosylated forms of this enzyme (both exported and nonexported) did not use this pathway (the degree of N-glycosylation is an important factor determining the final localization of the enzyme). PMID- 25272733 TI - Overexpression and characterization of laccase from Trametes versicolor in Pichia pastoris. AB - A laccase-encoding gene of Trametes versicolor, lccA, was cloned and expressed in Pichia pastoris X33. The lccA gene consists ofa 1560 bp open reading frame encoding 519 amino acids, which was classified into family copper blue oxidase. To improve the expression level of recombinant laccase in P. pastoris, conditions of the fermentation were optimized by the single factor experiments. The optimal fermentation conditions for the laccase production in shake flask cultivation using BMGY medium were obtained: the optimal initial pH 7.0, the presence of 0.5 mM Cu2+, 0.6% methanol added into the culture every 24 h. The laccase activity was up to 11.972 U/L under optimal conditions after 16 days of induction in a medium with 4% peptone. After 100 h of large scale production in 5 L fermenter the enzyme activity reached 18.123 U/L. The recombinant laccase was purified by ultrafiltration and (NH4)2SO4 precipitation showing a single band on SDS-PAGE, which had a molecular mass of 58 kDa. The optimum pH and temperature for the laccase were pH 2.0 and 50 degrees C with 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS) as a substrate. The recombinant laccase was stable over a pH range of 2.0-7.0. The K(m) and the V(max) value of LccA were 0.43 mM and 82.3 U/mg for ABTS, respectively. PMID- 25272734 TI - [Xylanase and cellulase of fungus Cerrena unicolor VKM F-3196: production, properties, and applications for the saccharification of plant material]. AB - Under the conditions of submerged cultivation in a medium containing microcrystalline cellulose, the Cerrena unicolor VKM F-3196 basidiomycete is capable of producing xylanase and cellulase. Electrophoretically homogeneous cellulase and xylanase were obtained using ion exchange and hydrophobic chromatography. The molecular weight of both cellulase and xylanase was -44 kDa. It was shown that xylanase catalyzed the hydrolysis of xylan with the production of xylose, xylobiose, and xylotetrose and it exhibited properties of endoxylanases. Cellulase hydrolyzed carboxymethylcellulose, xylan, and microcrystalline cellulose with the formation of cellotriose and cellotetraose. For both enzymes, the pH optimum was -4.0. The enzymes exhibited moderate thermostability: xylanase retained 35% of the initial activity for an hour at 60 degrees C; cellulase, 10% under the same conditions. Xylanase, cellulose, and a mixture of these enzymes saccharified plant material (wheat, rye, wheat middling, and oat), indicating the possible use of these enzymes in biotechnology. PMID- 25272735 TI - [Peptide-containing fraction from a culture medium of Fusarium sambucinum: composition and biological effects]. AB - The culture fluid of the fungus Fusarium sambucinum was investigated for the presence of new peptide-containing bioregulators, previously identified in various mammalian and plant tissues. A fraction containing peptides with molecular weights from 1000 to 2000 Da, which exhibited specific membranotropic activity and a number of physical and chemical properties characteristic of this group of bioregulators, was obtained. The effects of this fraction on the model roller organotypic cultivation of liver tissue of the Pleurodeles waltl newt in vitro were investigated for the first time. This fraction caused the additional activation of pigmented liver cells of newt (analogues to Kupffer cells of the liver of mammals) and provided the maintenance of cell-cell adhesive interactions in tissues. The results show that a new group of peptide bioregulators was present in the culture medium of the fungus F. sambucinum. PMID- 25272736 TI - Mass spectrometry identification of antifungal lipopeptides from Bacillus sp. BCLRB2 against Rhizoctonia solani and Sclerotinia sclerotiorum. AB - This work aims to characterize the bioactive molecules produced by an antagonistic Bacillus sp. strain BCLRB2 isolated from healthy leaves of olive tree against Rhizoctonia solani and Sclerotinia sclerotiorum. The bacterial strain isolated showed a high and persistent antifungal activity against the two pathogens. The free-cell supernatant showed also a high antifungal activity against R. solani and at a lower extent against S. sclerotiorum. The partial purification of the antifungal substances with methanol gradient applied to C18 column binding the Bacillus BCLRB2 culture supernatant showed that the 20% and 60% methanol fractions had a high and specific activity against S. sclerotiorum and R. solani, respectively. The mass spectrometry identification of the compounds in the fraction specifically active against S. sclerotiorum revealed the presence of bacillomycin D C16 as a major lipopeptide. The fraction specifically active against R. solani contained bacillomycin D C15 and 2 unknown lipopeptides. The 80% methanol fraction had a moderate and a broad spectrum activity against the two pathogens and consisted from two iturin D (C13 and C14) as a major lipopeptides. PMID- 25272737 TI - [Probiotics for plants: NO-producing lactobacilli protect plants from drought]. AB - After the inoculation of wheat roots with a suspension of the bacterium Lactobacillus plantarum, leveling of oxidative stress detected by the accumulation of H2O2 and MDA was found in leaves. Activation of catalase and increased integral antioxidant capacity in seedlings treated with NO-producing lactobacilli were detected during the determination of the contribution of bacterial NO to the plant stress reaction. Thus, for the first time, we have demonstrated that lactobacilli affect plant adaptive responses to stress by the involvement of nitric oxide. PMID- 25272738 TI - [Bioregeneration of the solutions obtained during the leaching of nonferrous metals from waste slag by acidophilic microorganisms]. AB - The bioregeneration of the solutions obtained after the leaching of copper and zinc from waste slag by sulfuric solutions of ferric sulfate is examined. For bioregeneration, associations of mesophilic and moderately thermqophilic acidophilic chemolithotrophic microorganisms were made. It has been shown that the complete oxidation of iron ions in solutions obtained after the leaching of nonferrous metals from waste slag is possible at a dilution of the pregnant solution with a nutrient medium. It has been found that the maximal rate of oxidation of iron ions is observed at the use of a mesophilic association of microorganisms at a threefold dilution of the pregnant solution with a nutrient medium. The application ofbioregeneration during the production of nonferrous metals from both waste and converter slags would make it possible to approach the technology of their processing using the closed cycle of workflows. PMID- 25272739 TI - [Regulation of peroxidase activity under the influence of signaling molecules and Bacillus subtilis 26D in potato plants infected with Phytophthora infestans]. AB - The influence of sequential exposure of 5 x 10(-5) M salicylic acid (SA) or 1 x 10(-7) M jasmonic acid (JA) and endophytic bacterium Bacillus subtilis strain 26D on peroxidase activity, transcription of the M21334 isoperoxidase gene from potato (Solarium tuberosum L.), and the formation of resistance to the infective agent of potato blight Phytophthora infestans (Mont.) de Bary was studied. It was found that individual application of JA or Bacillus subtilis 26D and sequential application of SA and B. subtilis 26D were the most effective in protecting plants against pathogens, while sequential application of JA and B. subtilis 26D drastically suppressed plant resistance. The results suggest the need for strict compliance with regulations when using SA and JA, as well as biological products based on living bacteria as modern plant protection products with immunomodulatory properties that trigger specific signaling pathways, which often interfere with each other. PMID- 25272740 TI - [Study of Yersinia pseudotuberculosis surface antigen epitopes using monoclonal antibodies]. AB - A study of the influence of exogenous factors on the immunochemical activity of the bacterium Yersinia pseudotuberculosis and lipopolysaccharide preparations isolated from bacteria was performed using monoclonal antibodies. It was shown that the hybridomas that were obtained in this work produce antibodies against different and, most likely, species-specific epitopes associated with lipopolysaccharide O side chains. The antibody concentrations produced increased with a decrease in the temperature, at which the bacteria were cultivated. An inhibitory effect of proteinase K, pepsin, and trypsin on the immunochemical activity of bacterial cells, determined using a solid-phase enzyme immunoassay, was demonstrated. Treatment with sodium periodate showed no uniform effect on the reactions between monoclonal antibodies and antigens (lipopolysaccharides and microbial cells), as adjudged by an immunoassay, which is most likely a consequence of the different localization of lipopolysaccharide epitopes recognized by the antibodies from four hybridomas. PMID- 25272741 TI - [Development and testing of an enzyme immunoassay-based monoclonal test system for the detection of the Yersinia pestis V antigen]. AB - An enzyme immunoassay-based test system for Y. pestis V antigen detection was developed. The specificity and sensitivity of this system met the requirements for medical immunobiological preparations for the identification of causative agents of highly fatal diseases. The sensitivity of the test system was assessed, and its high specificity was also demonstrated: the test system did not detect bacterial cells of closely related (four Y. pseudotuberculosis strains) and heterologous microorganism strains. The test system developed was able to detect the V antigen at concentrations as low as 2.0 ng/mL in cells of nine experimental Y. pestis cultures. The obtained preparation can be recommended for use in laboratory diagnostics of plaque. PMID- 25272742 TI - [Cellular test systems for the search for transcription factor activity modulators]. AB - Test systems for monitoring activities and the search for substances activating or inhibiting transcription factors as biotargets have been designed on the basis of luciferase constructs containing binding sites for transcription factors CREB, NFAT, NF-kB, p53, STAT1, GAS, VDR, HSF1, and HIF1alpha. An assessment of the functional activity of reporter constructs has been carried out using their transient transfection into HEK293 cells followed by treatment with specific inducers. The functional activity of all reporter constructs was observed based on the increased luciferase expression. In order to evaluate the efficiency of the suggested test systems, aspirin was used. Incubation of cells transfected with the above-mentioned constructs treated with aspirin was accompanied by the suppression of NF-kB, HIF1alpha, GAS, VDR, and HSF binding activity. The findings revealed for NF-kB, NFAT, and STAT1 confirm the published data concerning the mechanisms of aspirin action. The detected effects of this drug on the HIF1alpha, GAS, VDR, and CREB activity have been demonstrated for the first time. PMID- 25272743 TI - [Regulation of the binding of the BMP-2 growth factor with collagen by blood plasma fibronectin]. AB - The release kinetics of recombinant human bone morphogenic factor 2 (rhBMP-2) from collageneous hydrogel in the presence of human blood plasma have been studied. The expulsion of rhBMP-2 from the collagen-BMP-2 complex by the competitive adhesion of collagen-binding proteins penetrating from plasma was firstly recognized. It was experimentally proven that that blood plasma fibronectin is the main collagen-binding protein, which is responsible for the controlled release of rhBMP-2. As a result, a new collageneous hydrogel with the incorporation of fibronectin was created which retained rhBMP-2 for a twice longer period as compared to the ordinary collageneous hydrogel. A distinctive feature of this new collagen-fibronectin matrix is the slow release of rhBMP-2 in the first three days which allows for the avoiding of adverse effects in clinics caused by the rapid release of large amounts of rhBMP-2 from collageneous hydrogel. PMID- 25272745 TI - [Journal of Applied Biochemistry and Microbiology is 50 years old]. PMID- 25272744 TI - [Polyelectrolyte complexes of lactoferrin and pH-sensitive microparticles on their basis]. AB - Suspensions of insoluble polyelectrolyte complexes of dextran sulfate? (DS) of different molecular masses with lactoferrin (LF) have been fabricated and characterized. The encapsulation efficiency of LF and DS in a complex at pH 3.0 and 4.0 was assessed, and particles were characterized by their sizes and zeta potential. The complexes formed at pH 3.0 differed by a higher stability level. The interaction with DS resulted in a twofold decrease in the antioxidant activity of LF, although the formation of complexes was not accompanied by conformational changes in LF molecules according to IR-spectrometry data. Microencapsulation was carried out by treating the suspensions with negatively charged LF-DS complexes with protamine and chitosane solutions with different molecular masses. The composition, size, and the zeta-potential of interaction products were assessed which allowed us to select the conditions for the preparation of pH-sensitive polyelectrolyte microparticles loaded with LF which would be able to gradually release glycoprotein under conditions that model the passage through the gastrointestinal tract of humans. These data indicate that this approach is promising for the creation of pH-sensitive biopolyelectrolytes suitable for oral administration of LF to target cells. PMID- 25272746 TI - [Methods of microorganism immobilization for dynamic atomic-force studies (review)]. AB - Atomic-force microscopy (AFM) is an efficient method for studying the surface ultrastructure and nanomechanical properties of biological objects (including microorganisms). A correctly selected method of microorganism immobilization (that provides a strong attachment of cells on the surface of a biologically inert substrate and the preservation of their native properties) is an important condition of AFM scanning in a liquid medium. Comparative characteristics of methods of microorganism immobilization (that are applied in dynamic AFM studies) are given in the review. Technologies of mechanical retention and chemical binding of cells to a substrate, as well as protein and immunospecific adsorption, are considered. PMID- 25272747 TI - [Inulinases from various producers: the features of their permolecular organization]. AB - The structural organization of inulinases from yeasts, fungi, and plants are researched. For studying their sizes, molecular weight, and permolecular organization, an approach consisting of a combination of atomic force microscopy with methods of dynamic light scattering, gel chromatography, and electrophoresis was used. It is shown that inulinases from Kluyveromyces marxianus and Aspergillus niger form geterodimers and inulinases from tubers of Helianthus tuberosus are present as both dimers and monomers. The role of various forms in the functional activity of inulinase molecules is discussed. PMID- 25272748 TI - [Direct cloning of gene encoding a novel amylomaltase from soil bacterial DNA for large-ring cyclodextrin production]. AB - The aim of this study was to isolate a novel amylomaltase gene from community DNA of soil samples collected from Ban Nong Khrok hot spring in Thailand without bacterial cultivation. Using PCR, a 1.5 kb full-length gene was amplified and ligated with pGEM-T easy vector to transform into Escherichia coli DH5 alpha for sequencing. The obtained gene encoding an amylomaltase consisted of 1.503 bp that translated into 500 amino acids. Amino acid sequence deduced from this gene was highly homologous with that of amylomaltase from Thermus thermophillus ATCC 33923. In order to express the enzyme, the cloned gene was subcloned into plasmid pET-17b and introduced into E. coli BL21 (DE3). The maximum expression was observed when the cloned cells were cultured at 37 degrees C for 6 h with 0.5 mM IPTG induction. By 10% SDS-PAGE, the relative molecular mass of the purified amylomaltase was approximately 58 kDa. This enzyme was optimally active at 70 degrees C and pH 9.0. In addition, the enzyme could hydrolyze pea starch to yield the large-ring cyclodextrins with degrees of polymerization of 23 and higher. It is noted that CD29 was the product in the largest quantity under all tested conditions. PMID- 25272749 TI - Purification and characterization of an extremely stable glucose isomerase from Geobacillus thermodenitrificans TH2. AB - The D-glucose/D-xylose isomerase was purified from a thermophilic bacterium, Geobacillus thermodenitrificans TH2, by precipitating with heat shock and using Q Sepharose ion exchange column chromatography, and then characterized. The purified enzyme had a single band having molecular weight of 49 kDa on SDS-PAGE. In the presence of D-glucose as a substrate, the optimum temperature and pH of the enzyme were found to be 80 degrees C and 7.5, respectively. The purified xylose isomerase of G. thermodenitrificans TH2 was extremely stable at pH 7.5 after 96 h incubation at 4 degrees C and 50 degrees C. When the thermal stability profile was analyzed, it was determined that the purified enzyme was extremely stable during incubation periods of 4 months and 4 days at 4 degrees C and 50 degrees C, respectively. The K(m) and V(max) values of the purified xylose isomerase from G. thermodenitrificans TH2 were calculated as 32 mM and 4.68 micromol/min per mg of protein, respectively. Additionally, it was detected that some metal ions affected the enzyme activity at different ratios. The enzyme was active and stable at high temperatures and nearly neutral pHs which are desirable for the usage in the food and ethanol industry. PMID- 25272750 TI - Purification and cloning of nicosulfuron-degrading enzymes from Bacillus subtilis YB1. AB - The nicosulfuron-degrading enzymes from Bacillus subtilis strain YB1 were purified and their genes were cloned. The proteins of bacterial culture filtrate were precipitated with ammonium sulfate or acetone. The extracellular proteins concentrated by acetone were purified from DEAE-Sepharose Fast Flow chromatography. The four protein peaks eluted from DEAE-column were separated and purified by native PAGE. Three components (P1-1, P3-2, P4-3) had nicosulfuron degrading activity, and component P4-3 degradated 57.5% of this compound. The molecular weights of the components were 33.5, 54.8 and 37.0 kDa, respectively. The amino acid sequences of nicosulfuron-degrading enzymes from B. subtilis YB1 were determined by MALDI-TOF-MS, indicating these enzymes as manganese ABC transporter, vegetative catalase 1 and acetoin dehydrogenase E1, respectively. Using PCR amplification, genes 918, 1428, 1026 bp in size were detected for the enzymes studied. PMID- 25272751 TI - An increase of curdlan productivity by integration of carbon/nitrogen sources control and sequencing dual fed-batch fermentors operation. AB - Curdlan is produced by Agrobacterium sp. ATCC 31749 under nitrogen-limited conditions not associated with cell growth. A novel curdlan production process was developed based on the different nutrient requirements for microbial cell growth and its efficiency was increased by integrating carbon/nitrogen sources control and sequencing dual fed-batch fermentors operation. By feeding ammonium solution to supply abundant nitrogen source and controlling pH in Fermentor I, cell growth was accelerated. High cell density of 29 g/L was attained. The culture broth in Fermentor I was then inoculated into sequencing Fermentor II which alleviated the high requirement for dissolved oxygen and accumulation of inhibitory metabolic by-products during curdlan production. Fermentor I promoted cell growth. Curdlan production started instantaneously in Fermentor II. By feeding nutrient solution with high carbon/nitrogen ratio and NaOH solution for pH adjustment, a feasible and optimal curdlan production process was formulated. The productivity, conversion efficiency and curdlan yield were achieved of 0.98 g/(L h), 57% (w) and 67 g/L, respectively. Such novel process can be scaled up for significant cost reduction at the industrial level. PMID- 25272752 TI - [Novel immobilization of arginase I via cellulose-binding domain and its application in producing of L-ornitine]. AB - The recombinant Escherichia coli strain pET35b-ARG, which overexpresses arginase I fused to a cellulose-binding domain (CBD), was developed. After preparing cellulose microspheres, arginase I was immobilized via the CBD of the fusion protein. Under optimal reaction conditions (40 degrees C, pH 9.5, 1 mM of Mn2+, 30 microl/ml of immobilized enzyme, 30 g/l of L-Arg, and for I h), the conversion rate of L-Arg was 98.7%. After 7 reuses of 30 microl of immobilized enzyme in 1 ml of catalytic solution, 153 mg of L-Orn with 97.3% purity was obtained. This indicated that the immobilization method was effective, feasible and could be used for the industrial production of L-Orn in the future. PMID- 25272753 TI - Bioflocculant production by Bacillus sp. Gilbert isolated from a marine environment in South Africa. AB - In our previous study we reported on the bioflocculant production by a Bacillus species isolated from sediment samples of Algoa Bay in the Eastern Cape Province of South Africa. In current study we carried out further evaluation on the effect of different culture conditions on the bioflocculant production, as well as characterised the bioflocculant produced in detail. The bacteria produced bioflocculant optimally under the following conditions: using sodium carbonate (95.2% flocculating activity) and potassium nitrate (76.6% flocculating activity) as carbon and nitrogen sources, respectively; inoculum size of 3% (v/v); initial pH 9.0; and Al3+ as coagulant aid. The crude bioflocculant retained 44.2% residual flocculating activity after heating at 100 degrees C for 15 min. Chemical analysis of the Bacillus sp. Gilbert purified bioflocculant demonstrated that it was composed mainly of polysaccharide. Fourier transform infrared spectroscopy analysis revealed the presence of hydroxyl, carboxyl and methylene groups in the bioflocculant and energy-dispersive X-ray analysis detected the elemental composition in mass proportion (% w/w) of C, N, O, S and P as 4.12 : 7.40: 39.92: 3.00: 13.91. Scanning electron micrograph image of the bioflocculant revealed an amorphous compound. PMID- 25272754 TI - Highly stable laccase from repeated-batch culture of Funalia trogii ATCC 200800. AB - The effect of temperature, pH, different inhibitors and additives on activity and stability of crude laccase obtained from repeated-batch culture of white rot fungus Funalia trogii ATCC 200800 was studied. The crude enzyme showed high activity at 55-90 degrees C, which was maximal at 80-95 degrees C. It was highly stable within the temperature intervals 20-50 degrees C. The half life of the enzyme was about 2 h and 5 min at 60 degrees C and 70 degrees C, respectively. pH optimum of fungal laccase activity was revealed at pH 2.5. The enzyme from F. trogii ATCC 200800 was very stable between pH values of 3.0-9.0. NaN3 and KCN were detected as the most effective potent enzyme inhibitors among different compounds tested. The fungal enzyme was highly resistant to the various metal ions, inorganic salts, and organic solvents except propanol, at least for 5 min. Because of its high stability and efficient decolorization activity, the use of the crude F. trogii ATCC 200800 laccase instead of pure enzyme form may be a considerably cheaper solution for biotechnological applications. PMID- 25272755 TI - [Chromatographic and spectroscopic characterization of phycocyanin and its subunits purified from Anabaena variabilis CCC421]. AB - Phycocyanin, a high value pigment was purified from diazotrophic cyanobacteria Anabaena variabilis CCC421 using a strategy involving ammonium sulfate precipitation, dialysis and anion exchange chromatography using DEAE-cellulose column. 36% phycocyanin with a purity of 2.75 was recovered finally after anion exchange chromatography. Purified phycocyanin was found to contain 2 subunits of 17 and 18 kDa which were identified as a-and (3 subunits by SDS-PAGE and MALDI TOE HPLC method using a C5 column coupled with fluorescence or photodiode-based detection was also developed to separate and detect the A. variabilis CCC421 phycocyanin subunits. The fluorescence method was more sensitive than photodiode one. The purified phycocyanin from A. variabilis CCC421 as well as its subunits was characterized with respect to absorption and IR spectra. Spectral characterization of the subunits revealed that alpha and beta subunits contained one and two phycocyanobilin groups as chromophores, respectively. PMID- 25272756 TI - [Comparative assessment of Cladophora, Spirogyra and Oedogonium biomass for the production of fatty acid methyl esters]. AB - The use of alternative fuels for the mitigation of ecological impacts by use of diesel has been focus of intensive research. In the present work, algal oils extracted from cultivated biomass of Cladophora sp., Spirogyra sp. and Oedogonium sp. were evaluated for the lipase-mediated synthesis of fatty acid monoalkyl esters (FAME, biodiesel). To optimize the transesterification of these oils, different parameters such as the alkyl group donor, reaction temperature, stirring time and oil to alcohol ratio were investigated. Four different alcohols i.e. methanol, ethanol, n-propanol and n-butanol were tested as alkyl group donor for the biosynthesis FAME and methanol was found to be the best. Similarly, temperature 50 C and stirring time of 6 h were optimized for the transesterification of oils with methanol. The maximum biodiesel conversions from Cladophora (75.0%), Spirogyra (87.5%) and Oedogonium (92.0%) were obtained when oil to alcohol ratio was 1 : 8. PMID- 25272757 TI - [Biological activity of lipids and photosynthetic pigments of Sargassum pallidum C. Agardh]. AB - The biological activity of lipids and photosynthetic pigments of the kelp Sargassum pallidum (Turner) C. Agardh has been studied. Free fatty acids and their esters demonstrated considerable antimicrobial activity against bacteria (Staphylococcus aureus[ital] and Escherichia coli), yeast-like fungi (Candida albicans), and opportunistic pathogenic (Aspergilius niger) and phytopathogenic (Fusarium oxysporum, and Septoria glycines) fungi. Glyceroglycolipids and neutral lipids demonstrated moderate activity. Fucoxanthin and chlorophylls weakly suppressed the growth of microorganisms. None of the studied substances demonstrated activity against Ehrlich's carcinoma. It was shown that the season of weed harvesting affected both antimicrobial and hemolytic activities of different lipids due to changes in their fatty acid composition. PMID- 25272758 TI - [Effect of chitooligosaccharides with different degrees of acetylation on the activity of wheat pathogen-inducible anionic peroxidase]. AB - The effect of chitooligosaccharides (CHOSs) with a molecular weight of 5-10 kDa and a degree of acetylation (DA) of 65 and 13% at a concentration of 1.0 mg/L on the expression of the TC151917 gene, which encodes wheat anionic peroxidase, and the activity of "anionic" isoperoxidases in common wheat plants infected with Septoria nodorum Berk.--the causative agent of septoriosis. Treatment with CHOSs with a 65% DA and infection promoted the transcription of the anionic peroxidase gene and increased the enzymatic activity of the anionic peroxidase with an isoelectric point of 3.5 in soluble and ion-bound to cell walls protein fractions. Chitooligosaccharides with a 13% DA change these parameters to a lesser extent. These data suggest the importance of the degree of acetylation of CHOSs in the development of immune responses of wheat with the involvement of peroxidases. PMID- 25272759 TI - [Effects of low doses of essential oil on the antioxidant state of the erythrocytes, liver, and the brains of mice]. AB - We studied the effects of essential oil from oregano and clove and a mixture of lemon essential oil and a ginger extract on the antioxidant state of organs in intact and three experimental groups of Bulb mice. We found that the essential oil was an efficient in vivo bioantioxidant when mice were treated with it for 6 months even at very low doses, such as 300 ng/day. All essential oil studied inhibited lipid peroxidation (LPO) in the membranes of erythrocytes that resulted in increased membrane resistance to spontaneous hemolysis, decreased membrane microviscosity, maintenance of their structural integrity, and functional activity. The essential oil substantially decreased the LPO intensity in the liver and the brains of mice and increased the resistance of liver and brain lipids to oxidation and the activity of antioxidant enzymes in the liver. The most expressed bioantioxidant effect on erythrocytes was observed after clove oil treatment, whereas on the liver and brain, after treatment with a mixture of lemon essential oil and a ginger extract. PMID- 25272760 TI - [Novel antiproteinase hemosorbent]. AB - A method has been developed for producing a biospecific hydrogel hemosorbent by the radical copolymerization of an unsaturated derivative of ovomucoid from duck egg white with acrylamide and N,N'-methylene bisacrylamide in an aqueous solution in the presence of mercaptoacetic acid serving as a chain transfer agent. The use of a chain transfer agent has been shown to result in changes in the structure of the hydrogel formed, namely, an increase in the degree of swelling in aqueous solutions and a decrease in the number of large pores. This creates favorable conditions for the functioning of immobilized ovomucoid and allows for an increase in the serine proteinase absorption capacity of the hemosorbent. PMID- 25272762 TI - [We congratulate Aleksei Mikhailovich Bezborodov on his jubilee]. PMID- 25272761 TI - [Inducible specific lux-biosensors for the detection of antibiotics: construction and main parameters]. AB - Based on Escherichia coli, highly sensitive specific lux-biosensors for the detection of tetracycline and beta-lactam antibiotics, quinolones, and aminoglycosides have been obtained. To make biosensors, bacteria were used that contained fungal plasmids pTetA'::lux, pAmpC'::lux, pColD'::lux, and plbpA'::lux, in which transcription of the reporter Photorhabdus luminescens luxCDABE genes occurred from the inducible promoters of the tetA, ampC, cda, and ibpA genes, respectively. The main parameters (threshold sensitivity and response time) of lux-biosensors were measured. The high specificity of biosensors responding only to antibiotics of a certain type was demonstrated. PMID- 25272763 TI - [Significance of local synchronization and oscillatory processes of thalamic neurons in goal-directed human behavior]. AB - The time-frequency characteristics and interneuron interaction in the cell ensembles of non-specific (CM-Pf) and motor (Voi) thalamus were analyzed. Neuronal activity was registered by microelectrode technique during 18 stereotactic neurosurgery operations in spasmodic torticollis patients. The presentation of functionally significant verbal stimuli was accompanied by the emergence of short-term (0.5-1.5 s) local synchronization and stabilization of the oscillatory (3-6 Hz) activity in nearby neurons of nonspecific (CM-Pf) thalamus. These focuses of synchronized oscillatory neuronal activity were correlated with the moment of the greatest concentration of selective attention. Similar phenomenon of short-term synchronization was observed in the motor (Voi) and nonspecific (CM-Pf) thalamus of the human brain during the voluntary movements. Synchronization of neuronal activity occurred at the height of the motor act implementation, correlating with the maximum muscle tension, as well as in aftereffect of the voluntary movement. Overall, the findings suggest an important role of the local oscillations (3-6 Hz) and synchronization ofthalamic neurons in the mechanisms of relevant information transmission during goal directed human behavior. PMID- 25272764 TI - [Changes of the alpha-rhythm after introducing stimuli Go/NoGo in the context of experiments with a set to an angry face]. AB - At healthy adults is (n = 35) in the middle of 16 second pauses between target (faces) and starting stimuli conditioning signals Go/NoGo. Lack of essential changes of flexibility of the set after introduction of an additional cognitive task is explained by enhansment of the induced synchronization of an alpha rhythm in time intervals between target, conditioning and starting stimuli. The increase of alpha potentials synchronization reflect the top-down inhibitory control suppressing effect of irrelevant factors, and that facilitating processing of significant information. In the range of time between NoGo and starting stimuli locally in a motor zone of cortex of only the left hemisphere (C3, FC3) the induced synchronization of low-frequency and especially high-frequency alpha rhythm is registered. One more experimental confirmation of the theory on the brake nature of this electrophysiological phenomenon is obtained. Used in physiology of the highest nervous activity of concept about internal or conditional inhibition is considered within the theory of top-down inhibitory control from prefrontal cortex. PMID- 25272765 TI - [Age differences of event-related potentials in the perception of successive and spacial components of auditory information]. AB - The perception of spatial and successive contexts of auditory information develops during human ontogeny. We compared event-related potentials (ERPs) recorded in 5- to 6-year-old children (N = 15) and adults (N = 15) in response to a digital series with omitted digits to explore age differences in the perception of successive auditory information. In addition, ERPs in response to the sound of falling drops delivered binaurally were obtained to examine the spatial context of auditory information. The ERPs obtained from the omitted digits significantly differed in the amplitude and latency of the N200 and P300 components between adults and children, which supports the hypothesis that the perception of a successive auditory structure is less automated in children compared with adults. Although no significant differences were found in adults, the sound of falling drops presented to the left ears of children elicited ERPs with earlier latencies and higher amplitudes of P300 and N400 components in the right temporal area. Stimulation of the right ear caused increasing amplitude of the N100 component in children. Thus, the observed differences in auditory ERPs of children and adults reflect developmental changes in the perception of spatial and successive auditory information. PMID- 25272766 TI - [Comparative MRI morphometric study of the corpus callosum at term and preterm infants]. AB - A comparative morphometric analysis of MRI brain tomograms of term ant preterm born children was conducted. Common morphometric indexes and a novel quantitative parameter, a coefficient of corpus callosum (kCC), developed with regard to prenatal cortex ontogenesis pattern were applied to the study in order to get objective structural characteristics of the brain. All these quantitative indexes display anatomical features of the preterm brain. Reduced values of corpus callosum coefficient at preterm born children are known to associate with altered proportion between its rostral and caudal segments. A threshold coefficient value was established to differentiate preterm brain from the term one and it has proven its statistical significance. PMID- 25272767 TI - [The frequency-contrast sensitivity of visual stimulus perception in patients with schizophrenia with the therapy of atypical and typical antipsychotic drugs]. AB - We studied the effect of typical and atypical antipsychotics drag treatment on the perception of visual stimulus which activates preferentially different visual channels. We recorded contrast sensitivity in normal and schizophrenic patients. Elements presented with Gabor-like gratings with sinusoidal distribution of brightness, spatial frequency: 0.4 cycles/degree, 3.6 and 17.9 cycles/degree. Patients were divided into two groups. One group--patients treated with atypical antipsychotics, and the second group--patients treated with typical antipsychotics drags. Registered a decline compared with the normal contrast sensitivity for low and medium spatial frequencies. We observed significant difference between two groups of patients in the range of low spatial frequencies. PMID- 25272768 TI - [EEG markers of spontaneous recovery of vertical posture in patients with consequences of severe traumatic brain injury]. AB - 9 patients (mean age 23.6 +/- 3.15 y.o.) with severe traumatic brain injury (TBI) and impairment of vertical posture were included in complex clinical and EEG study during spontaneous recovery of vertical posture (VP). Patients were included in three different groups according to severity of deficit according to MPAI, FIM and MMSE scales. EEG data have been compared to those of 10 healthy volunteers (mean age 22.8 +/- 0.67 yo.). In patients with moderate brain impairment and fast recovery of VP (over 2 weeks) change of posture from sitting to standup has been accompanied by EEG-signs similar to those of healthy people. These included predominant increase of coherence in right hemisphere for majority of frequency bands, although in more complex conditions EEG of these patients showed pathological signs. In patients with more severe deficit spontaneous recovery of VP has been accompanied by "hyper-reactive" change of EEG for all frequency bands without local specificity. This finding didn't depend on side ofbrain impairment and could be considered as marker of positive dynamics of VP restoration. In patients with most severe brain impairment and deficit of functions VP didn't recover after 3 month of observation. EEG-investigation has revealed absence of reactive change of EEG during passive verticalisation. This finding can be used as marker of negative prognosis. PMID- 25272769 TI - [Oscillatory processes in microlymphatic bed of human skin]. AB - Laser Doppler flowmetry with wavelet-analysis of oscillations in microlymphocirculation was used for the first time at 30 persons with (n = 17) and without edema (n = 13) of the upper extremities distal parts. Human skin microlymphatic flow is characterized by well-defined predomination of pacemaker phasic oscillations in frequency range from 0.021 Hz to 0.042 Hz (palmar surface of finger distal phalange) or from 0.016 Hz to 0.035 Hz (forearm skin). Edema was accompanied by increase of average peak frequencies and normalized maximum amplitudes of phasic oscillations (A(l)/M(l), where A(l)--average maximum amplitude of phasic oscillations, M(l)--value of average lymphatic flow, both in perfusion units). Myogenic, endothelial and respiratory low amplitude oscillations were registered rarely. Heart rate rhythms were not revealed in lymphatic flow. Intercommunications were not found between values of A(l)/M(l) and skin temperature. Only in physiologic conditions without edema negative correlation was revealed between values of A(l)/M(l) and amplitudes of myogenic oscillations in blood flow; the latter reflect the number of open capillaries and the activity of oxidative metabolism. Intercommunications were not found between lymphatic and blood flow oscillations in edema availability. Normalized amplitudes and frequencies of phasic oscillations may serve as effective diagnostic indices in micro-lymphocirculation study. PMID- 25272770 TI - [The significance of sympathovagal balance in the forming of respiration dependent oscillations in cardiovascular system in human]. AB - The effect of deep breathing controlled in both rate and amplitude on the heart rate variability (HRV) and respiration-dependent blood flow oscillations of forearm and finger-pad skin has been studied in 29 young healthy volunteers from 18 to 25 years old. To reveal the effect of the segments of the vegetative autonomic nervous system on the amplitudes of HRV and respiration-dependent oscillations of skin blood flow we estimated the parameters of the cardiovascular system into two groups of participants: with formally high and low sympathovagal balance values. The sympathovagal balance value was judged by the magnitude of LF/HF power ratio calculated for each participant using the spontaneous breathing rhythmogram. It was found what the participants with predominant parasympathetic tonus had statistically significant higher amplitudes of H R V and skin blood flow oscillations in the breathing rate less than 4 cycles per min than the subjects with predominant sympathetic tonus. In the forearm skin, where the density of sympathetic innervations is low comparatively to that in the finger skin, no statistically significant differences in the amplitude of respiratory skin blood flow oscillations was found between the two groups of participants. PMID- 25272771 TI - [Muscular strength development by electromagnetic stimulation]. AB - A new tool for muscular strength development by electromagnetic stimulation (MS) of muscular during voluntary contraction has been described. 18 healthy subjects (men) took part in the research. They were devided into two groups--control (CG) and experimental (EG). Subjects of CG and EG have equal muscular strength parameters. M. gastrocnemius of subjects in EG was exposed to MS (1.8 T, 5 Hz) during training exercises (plantar foot flection). The subjects of CG did not receive MS. The torque of plantar foot flection of EG subjects increased significantly (24%) during 10 days training. The torque of plantar foot flection of CG subjects did not change significantly. We hypothesize increasing of muscular strength of EG subjects was result of high-threshold motor units activation under MS. PMID- 25272772 TI - [Influence of Achilles tendon vibration on the human vertical posture during standing with asymmetrical leg loading]. AB - The shift of center of pressure (CP) of body and CP of each leg was studied during Achilles tendon vibration of one or both legs while subject was standing with symmetrical load on the legs or with the load transferred on one leg. The CP shift of standing subject during unilateral Achilles tendon vibration depended both on the side of the tendon vibration and on the leg load. When standing with a load transferred on one leg the shift of common CP was larger than when the vibration was applied to the loaded leg. The CP shift of one leg was greater if the vibration, and the load was applied to it. Vibration of unloaded leg caused a CP shift in the contralateral loaded leg. In this case, the vibration of left unloaded leg caused no noticeable CP shift of left leg, while the vibration of the unloaded right leg caused CP shift of right foot. In the same conditions of load and vibration the CP displacement of right leg was larger than the CP shift of left foot. It can be assumed that the change in the load on the leg and unilateral vibration of leg muscles change of the internal representation of the vertical body axis, which affects the CP position of one leg during the muscles vibration. PMID- 25272773 TI - [Assessment of influence of breath holding and hyperventilation on human postural stability with spectral analysis of stabilographic signal]. AB - The influence of breath holding and voluntary hyperventilation on the classic stabilometric parameters and the frequency characteristic of stabilographic signal were studied. We measured the stabilometric parameters on the force platform ("Ritm", Russia) on the healthy volunteers (n = 107) during quiet breath, voluntary hyperventilation (20 seconds) and maximal inspiratory breath holding (20 seconds). Respiratory frequency, respiratory amplitude and ventilation were estimated with strain gauge. We found that antero-posterior and medio-lateral sway amplitude and velocity as well as sway surface at breath holding and at quiet breathing were the same, so breath holding didn't influence the postural stability. However the spectral parameters shifted to the high frequency range due to alteration of the respiratory muscles contractions during breath-holding versus quiet breath. Voluntary hyperventilation caused significant increase of all stabilographic indices that implied an impairment of postural stability, which was due to the increase of respiration frequency and amplitude. We also found that the spectral indices moved toward the high-frequency range with more pronounced degree of this shift versus breath holding. Besides, amplitudes of spectral peaks also increased. Perhaps such change of spectral indices was due to distortion of proprioceptive information because of increased excitability of nerve fibers during hyperventilation. Maximal inspiration breath holding causes strain of the postural control mechanisms that is reflected as elevation of postural sway frequency with no postural stability changes. Hyperventilation leads to the most prominent strain of balance function and decrease of steadiness that is manifested as increase of center of pressure oscillations amplitude and frequency. PMID- 25272774 TI - [Dynamics of duration of tracheal forced expiratory noises during long-term isolation in the "Mars-500" experiment]. AB - Dynamics of duration of tracheal forced expiratory noises in a group of volunteers was studied before, during and after 520-days confinement. The duration did not change in most volunteers. Two volunteers demonstrated significant changes of tracheal sounds duration and some spirometric parameters. Increase in duration of tracheal forced expiratory noises and decrease in spirometric parameters reveal ventilatory impairment of obstructive type. Analysis of duration of tracheal forced expiratory noises dynamics during prolonged confinement proves to be a sensitive technique to test ventilatory function changes. PMID- 25272775 TI - [Effects of additional breathing resistance on oxygen consumption in healthy subjects]. AB - Decrease of oxygen delivery is common in hypoxia. This is the reason of decrease of consumption (VO2) at Mammalia including human. Previously, we have described a hypoxic hypometabolism at 1/3 health persons breathing 17% O2 oxygen air. This light hypoxic (latent hypoxic) condition didn't issue hypoxia because of SpO2 had dropped from 97-98% to 95-96%. We hypothesized the existence of another reason for VO2 decrease. This is the ability of tissue to decrease oxygen consumption in human organism. Thus the hypometabolism maintains delivery/consumption O2 balance when respiratory center is informed by afferent receptors about potential threat of tissue hypoxia. The aim of this study was to investigate parameters of gas exchange in light mixed resistive load 0.4 cmH2O s L(-1). For compare it was used date obtained at ordinary mouthpiece with resistance less 0.1 cmH2O s L(-1). During the study 14 health subjects (6 men and 8 women) with the age ranging from 23 to 48 years were observed. Date showed a significant decrease in mean (SD) of VO2 at 9% and CO2 release (VCO2) at 10%. Value of SpO2 didn't change and remain 97.5%. The results suggest that hypometabolism may be a reaction prevented by disturbance O2 delivery/consumption for tissue of human organism. PMID- 25272776 TI - [Changes in functional organization of the respiratory system among residents of West Siberia in the winter season]. AB - The study examines respiratory parameters in healthy young males from Western Siberia. The correlations between the parameters are analyzed and the functional structure of the respiratory system in the summer and in the winter is identified. It was discovered that different regulatory programs operate depending on the temperature of inhaled air. The study shows that the changes in the oxygen request of the body in the summer are achieved through the changes in the volume of pulmonary ventilation ("ventilation" or "summer program"). In the winter, when maintaining the level of energy processes in the body is in conflict with maintaining thermal homeostasis in the respiratory regions of the lungs, pulmonary ventilation becomes limited and the number of functioning lung units is reduced. At the same time, for providing compensation, lung diffusion capacity increases ("diffusion" or "winter program"). This means that the functioning of the apparatus of external respiration is optimized in the winter. PMID- 25272777 TI - [EMG characteristics of women in respect with phase of the menstrual cycle, season and type of vegetative regulation]. AB - Here we report on the electromyographic (EMG) characteristics of young females (n = 23, 19.9 +/- 1.4 years) under varied environmental and physical conditions: 4 phases of menstrual cycle phase (early and late follicular, ovulation, and luteal), spring and autumn seasons, and type of the vegetative nervous system (VNS) regulation based on the linear and novel non-linear parameters of interference EMG (iEMG) in m. biceps br. Additionally, we characterize activity of motor units of m. triceps br. The major finding was that most of the variables of iEMG and MU activity significantly decreased in the ovulation phase in the spring season. Among types of VNS regulation, the vagotonic type exerted influence on the neuromuscular status of young women. PMID- 25272778 TI - [To the potential use of alcoholic cardiomyopathy echocardiography assessment of forming]. AB - Chronic alcohol abuse leads not only to a significant human psychic and social degradation, but also promotes the alcoholic cardiomyopathy formation, that is one of the leading causes of high mortality of alcoholics. However, to date in clinic there are no unified approaches in the prevention and treatment of alcoholic cardiomyopathy, first of all, due to the lack of the adequate model in the experimental pharmacology, which can assess the stages of formation of alcoholic cardiomyopathy objective and in real time, and thus create the basis for the search and study the mechanisms of action of drugs for the treatment of this serious disease. Studing the possibility of echocardiography using in experiments with rats exposed to prolonged forced alcoholism is one of the approaches to solve this problem. It was shown that the significant changes of intracardiac echocardiography hemodynamics corresponding to the known from the clinic, begining to form from the 20th week of systematic consumption of alcohol by rats. At this time interval the reduction in inotropic function of the heart in alcoholized rats compared to control is observed: fraction shortening (FS) is 41.9% (40.3-42.2) and 51.3% (48.8-59.1) respectively, and ejection fraction (EF) 78.8 (77.4-79.2) and 87.5% (84.6-92.4) respectively, p = 0.0215. The dilated heart failure develops in the rats from the 24 week of regular alcohol consumption, as evidenced not only by dynamic reducing of FS and FV, but also by the dilatation ofthe heart. For example, the end-systolic size of the left ventricle in animals consuming alcohol compared with control increased more than 2 times (4.31 mm (3.80-4.41) and 2.0 mm (1.85-2.36); p = 0.0008, and the end diastolic dimension was 5.95 mm (5.13-6.37) and 4.52 mm (3.85-4.90) respectively; p = 0.0171. Thus, the echocardiographic picture characteristic for alcoholic dilated cardiomyopathy is formed by the end of the 24th week of chronic alcoholiation. PMID- 25272779 TI - [Molecular-physiological aspects of peptide regulation of function of the retina in retinitis pigmentosa]. AB - Peptide's bioregulators promotes restoration of the physiological activity of the retina in retinitis pigmentosa in older adults and in animal models. The molecular mechanism of physiological activity of peptides is connected with its ability to regulate synthesis of protein markers of differentiation of neurons and retinal pigment epithelium epigenetically. PMID- 25272780 TI - [Work aggravated asthma]. AB - One out of five working persons with asthma has work-related respiratory symptoms. When exploring the symptoms of a working-age patient it is essential to survey the job description and working conditions. Early intervention in the factors aggravating the respiratory symptoms will decrease morbidity, maintain working capacity and improve the quality of life. Occupational health service and the employer play a central role in identifying and decreasing the exposure factors in the working environment as well as in patient guidance for asthma therapy and protecting from the stimuli. The working capacity of an asthmatic person can be improved by applying vocational rehabilitation. PMID- 25272781 TI - [Thrombophilia and pregnancy]. AB - Owing to the physiologic changes associated with pregnancy there is a considerably elevated risk of thrombosis during pregnancy and immediately after childbirth. Familial or acquired thrombophilia, i.e. tendency for thrombosis, increases the risk of pregnancy-related thrombosis. Recommendations for the prevention of pregnancy-related venous thromboses are not uniform - the risk of thrombosis must thus be evaluated on an individual basis. Critical clinical consideration should be undertaken when exploring familial thrombophilia in connection with pregnancy complications. Investigation of antiphospholipid antibodies is recommended in connection with certain pregnancy complications. PMID- 25272782 TI - [The use of direct oral anticoagulants (DOAC) in the treatment atrial fibrillation (AF) patients]. AB - AF is associated with the risk of stroke, and this risk is exceedingly high in elderly patients (> or = 75 years) and in patients after a stroke. DOACs are appropriate anticoagulants for AF patients without mechanical heart valves or mitral stenosis. Patients on DOACs do not require routine monitoring of coagulation, but need regular follow-up visits including an assessment of therapy adherence, thromboembolic and bleeding events and measurements of hemoglobin and platelets values as well as renal and liver function. PMID- 25272784 TI - [Simulation training for better patient safety-learning from team work]. AB - At work, healthcare personnel will encounter various emergency situations and patients who are in poor physical condition and require urgent care. A multidisciplinary team of experts must be able to carry out seamless collaboration, even when working together for the first time. Described in this review is how systematically arranged simulation rehearsals help form a united expert group from a group of individual experts. PMID- 25272783 TI - [Investments of research and treatment of brain diseases will pay of time]. AB - In 2010, a quarter of direct healthcare cost in Europe were spent on brain diseases. The importance of preventing and treating brain diseases and maintaining of functional capacity of the brain will increase in our society with ageing population and with increasing cognitive requirements of modern working life. Public funding of basic and clinical neuroscience has, however, frozen to levels achieved years ago, clinical research of brain diseases being at a particular risk. Research projects directed to prevention, treatment, and rehabilitation of brain diseases will pay off, also when assessed by economic measures. PMID- 25272785 TI - [Information technology and the riddle of household remedy]. AB - I Adverse effects associated with medication are one of the most common reported problems related to patient care. Problems arise especially when the patient is transferred from one unit to another or when treatment responsibility is changed within a unit. Information technology was expected to solve these problems, but the expectations have not fully become fulfilled. The legislation and functionalities of electronic prescription have brought new problems to be solved. While part of the problems can be solved by computer-based applications, training is required in order to change the operational culture and improve patient safety. PMID- 25272786 TI - [Hand hygiene--part of patient safety from Semmelweis to the present]. AB - Hand disinfection is one of the most important part of patient safety. By adequate hand disinfection healthcare workers can prevent about 40 per cent of healthcare-associated infections and about 50 per cent of patients' MRSA contaminations in hospitals. Adherence to hand disinfection has been observed in an average of 40 per cent of patient contacts. One of the risk factors leading to poor adherence is the "doctor" status of a healthcare worker. Introduction of an alcohol-based hand rub close to the patient is one of the most significant factors for improved hand hygiene. PMID- 25272787 TI - [Respiratory depression caused by a fentanyl patch applied as a topical analgesic]. AB - Intoxications caused by fentanyl patches are fairly common in emergency departments. Fentanyl extracted from patches may cause intoxications and even deaths in drug abusers due to very high amount of fentanyl in the patches. In the case described by us the cause of intoxication was exceptional, as the patient had placed the patch as topical treatment for shoulder pain. Due to the small and unobtrusive size of the patch and lack of anamnestic information (patient was unconscious) it took five days before the patch was noticed on the patient's skin. PMID- 25272788 TI - [Central venous catheter with a poor flow]. AB - Insertion of a central venous catheter is a quite common procedure; for instance in USA it is done for approx. five million patients per year. At the operating department of Meilahti hospital, central venous catheters have been placed as a main or side procedure for approx. 2000 patients per year. In addition, central venous catheters are placed in emergency departments and in some operational units, such as dialysis catheters in dialysis units. Although the application of ultrasound imaging has now resulted in improved patient safety, complications continue to occur. To exclude complications, a chest X-ray is often taken after the procedure. The control image may reveal even unexpected issues. PMID- 25272789 TI - [Update on current care guideline: acute coronary syndrome--unstable angina and myocardial infarction without ST elevation]. AB - Diagnosis, risk assessment, and treatment of acute coronary syndrome should be done promptly, beginning from the first medical contact. Treatment is based on risk assessment. Antithrombotic treatment contains aspirin, LMWH, and clopidogrel, prasugrel or ticagrelor, according to local practice. High risk patients benefit from early invasive treatment. Bleeding complications should be avoided especially in patients with kidney disease or in elderly patients. Effective secondary prevention begins during the hospital stay. All patients should have an individual rehabilitation and follow-up plan after acute treatment. PMID- 25272790 TI - [Update on current care guidelines: acute respiratory failure--preoperative evaluation]. AB - Concomitant diseases, the patient's general condition, exercise capacity and the extent of surgery are determinants of the operative risk. Increasing number of patients with endovascular stents and antithrombotic medication need special perioperative precautions as well as the eventual endocarditis prophylaxis. The risk of perioperative complications can probably be decreased by respiratory physiotherapy, correction of anaemia and smoking cessation. Severe liver or kidney insufficiency need be evaluated. Principles of preoperative fasting and perioperative strategies with concomitant medication are described, and use of preoperative carbohydrate drinks are encouraged. PMID- 25272791 TI - [Update on current care guideline: chronic obstructive pulmonary disease (COPD)]. AB - Clinical serverity of COPD is based not only on the grade of obstruction in spirometry, but also on symptoms and risk of exacerbations. Symptoms can be defined by questionnaires, such as CAT-test (COPD assessment -test) or mMRC (modified Medical Research Council -test). Smoking cessation and physical activity are important treatment options. Pharmacological treatment is selected by symptoms, risk of exacerbations and co-occurrence of asthma and COPD. Non invasive ventilation (NIV) is recommended in the treatment of severe hypercapnic exacerbations. Palliative treatment of end stage COPD is included in the guidelines. PMID- 25272792 TI - Conflicting interests in medicine. Foreword. PMID- 25272793 TI - [The notion of conflict of interest in the field of health and environment: philosophical and legal approaches]. AB - This paper considers the conflict of interest in philosophical and legal perspective. The philosophical approach comes from two perspectives: political philosophy focuses on the role of the link of interest in the city considered in the light of a broader reflection on the conditions of living together. Antiquity philosophers have enhanced the interest link as privileged vector of humanization and socialization of individuals. In the eighteenth century, Adam Smith considers the pursuit of individual interests a stronger social base that love of neighbor advocated by Christians. Moral philosophy focuses specifically on the passage of interest linked to the conflict of interest. It wondered if we should be impartial in all circumstances or whether it's right to give priority to our friends and loved ones. Thus, it poses the question of whether introspection is sufficient to detect conflicts of interest or if the look of an external third party is still required. The legal process differs from the philosophical approach at two levels; on the one hand, its scope is more limited: the law doesn't envisage the benefits of links of interest on social life even though it may protect some of them (in the context of the family, for example) and is intended to prevent bias that may taint the decision public. On the other hand, the lawyer doesn't enter the interiority of individuals but stands by what appears on the outside: it tracks the suspicion of bias can have serious impacts, such as health and the environment. Somehow, it is more radical. It's noteworthy that despite its many developments, the law can't to stop conflicts of interest in research. Several reasons account for this impasse: scientists receive mission to partner with industry to develop products but they must remain independent in order to assess the risks; there is a tendency to always choose the same experts; there are conflicts of interest intellectuals which are not easy to detect. PMID- 25272794 TI - [Conflict of interest and bioethics]. AB - "Conflicts of interests" is a multi-meaning expression. To give a juridical concept is not easy because this concept is applied in public and private law. Maybe this is the reason of not having a law giving a valid definition in any case In health area, a conflict of interests is present many times, i.e. at the beginning of a research, when informing its results, etc. This conflict of interests may affect different aspects of the research work, economic or not; sometimes totally or partially. The economic resources is one of the most common reasons of the conflict of interests. The mass media often cause conflicts of interests informing the general public about new scientific discovery in a simple way to be understood but without been quite assertive. Other times, great enterprises hide information about new and better medicines due to the fact that they have many old medicines that should be sold before introducing in the market the new ones. From the academic point of view, conflicts may arise when the public funds are wrongly used to support unworthy researches. PMID- 25272795 TI - [The whistleblowers]. AB - To alert consists in informing about a danger in order to avoid any aggravation. When health or environment public authorities submit such an alert, it isn't questioned nor subject to a problem of legitimacy. However, the State does not have the exclusive right to watch, and whistleblower alerts are more and more often submitted by citizens who attempt to disclose public interest information. The legal protection of these alerts by citizens is not clear so these unusual denunciations need to be legally framed. The issue is very important since human body infringement is at stake. Thus, it is necessary to acknowledge whistleblowers an individual right to alert, depending on who the information is addressed to. Individuals have a right to alert the population on behalf of the freedom of expression which gives everyone the chance to enrich public debates within the limits of abuse. But, sometimes, they have to do it, so that the alert can be regarded as the fulfillment of a duty of citizens that allows them to participate in the defense of public interest. PMID- 25272796 TI - [Health agencies and the every day management of bioethics]. AB - Taking into account their acquired experience, would not health agencies become the place where biomedical practices will be managed on an every day basis? Would in a near future these agencies have the role to interprete the principles of the bioethics law to adapt them to concrete issues? PMID- 25272797 TI - [Health agencies and biomedicine: a new technocratic legitimity and a strategy to share power]. AB - The role of health agencies in the field of biomedicine does not appear today anymore as a question of systemic approach but much more as a question of implementing the bioethical principles acknowledged in the legislation and by the different stake-holders of the biomedical techniques. PMID- 25272798 TI - [Kairos. Decision-making in medical ethics]. AB - This paper assesses the decision making patterns in medical ethics: the formalized pattern of decision science, the meditative pattern of an art of judgement and lastly the still-to-be-elaborated pattern of kairology or sense of the right time. The ethical decision is to be thought out in the conditions of medical action while resorting to the philosophical concepts that shed light on the issue. And it is precisely where medicine and philosophy of human action meet that the Greek notion of kairos, or "propitious moment", evokes the critical point where decision has to do with what is vital. Reflection shows that this kairos can be thought out outside the sacrificial pattern (deciding comes down to killing a possibility) by understanding the opportune moment as a sign of ethical action, as the condition for the formation of the subject (making a decision) and finally as a new relationship to time, including in the context of medical urgency. Thus with an approach to clinical ethics centred on the relation to the individual, the focus is less on the probabilistic knowledge of the decidable than on the meaning of the decision, and the undecidable comes to be accepted as an infinite dimension going beyond the limits of our acts, which makes the contingency and the grandeur of human responsibility. PMID- 25272799 TI - [The solidarity of the human body]. AB - The legal and bioethical regulation of the uses of the elements of the human body can be described by means of the concept of solidarity. From the French example, we can so show that the State tries to frame solidarities which already exist, for example between people who share the same genome, in the family, or, on the contrary, tent to impose or to direct the sharing of the human biological resources (organs, tissues, gametes, stem cell...). PMID- 25272800 TI - [Actors and tools of predictive genetics: ethics at the heart of governance]. AB - Genetic prediction is at the cross road of the various meanings of the concept of personalized medicine or medicine 4P: Personalized, Preventive, predictive and participative, also called precision medicine or prevision medicine. This entire frame questions i) the place of data in medicine and its consequences on the relation between patients and doctors; ii) the empowerment of people in the management of their own health; iii) the access to health related data outside the health system (tests directly provided to the consumer over the counter). These various dimensions are analyzed through the phenomenon of massive data and large-scale genetic tests, in particular DNA sequencing in the clinical frame, the blurred limits between categories previously clearly distinct (e.g. research versus clinical care), the recommendations of professional societies of human genetics. The analysis conducted shows that the technological development and the tools of personalized medicine cannot occur in a responsible way without a concomitant analysis of the underlying values at stake. PMID- 25272801 TI - Front and centre--our values, our voice, our power. PMID- 25272802 TI - Am I entitled to overtime if I don't get to have a lunch break? PMID- 25272803 TI - Does repositioning prevent pressure ulcers? Show me the evidence! PMID- 25272804 TI - Injuries and impairments--your obligations in job application and registration. PMID- 25272805 TI - Maternity Choices Australia: women working with midwives to improve birth care. PMID- 25272806 TI - Peter Greste just doing his job. PMID- 25272808 TI - [ATP-binding cassette transporters and transmembrane transport in Mycobacterium tuberculosis--a review]. AB - Mycobacterium tuberculosis, an intracellular bacterium, mainly lives in the phagosome of the macrophage. It utilizes competitive uptake of nutrients as well as active efflux of noxious compounds to maintain its survival. Thus, the ATP binding cassette transporters involved in either process mentioned above are essential for its pathogenicity. There are 38 ATP-binding cassette transporters identified in the genome of M. tuberculosis. This sort of proteins facilitate the transport of various substrates ranging from ions, sugars, amino acids, oligopeptides and drugs. In this review, we summarized the substrate specificity and transport mechanism of these transporters and their relationship with virulence in M. tuberculosis. PMID- 25272807 TI - [Application of levansucrase in levan synthesis--a review]. AB - Levan is a fructan mainly linked by beta-(2,6)-glycosidic bonds with some beta (2,1)-linked branch chains. Some microbial levan exhibit biological activities such as antitumor, antidiabetic and immunostimulating activities. hypolipidemic effect, and function as prebiotics, which has a wide and potential application in the pharmaceutical and food industry. Because of low extraction yields from microbial fermentation and a very complex process for chemical synthesis of levan, enzymatic synthesis of levan has attracted tremendous interest. Levansucrase (EC 2. 4. 1. 10), a beta-propeller protein belonging to the glycoside hydrolase family 68 (GH68) with reaction mechanism of non-Leloir glycosyltransferase, catalyzes the synthesis of levan by transferring the fructosyl group of non-activated sucrose into the fructan chain. The molecular structure and regulation of gene expression of some microbial levansucrases have been elucidated. Meanwhile, the enzymatic synthesis of levan by levansucrase is widely studied. In this review, catalytic mechanism of levansucrase, molecular structure and regulation of gene expression of some microbial levansucrases, and the application of levansucrases in enzymatic synthesis of levan were summarized. PMID- 25272809 TI - [Genetic diversity and phylogeny of soybean rhizobia isolated from the Hilly area of Central Sichuan in China]. AB - OBJECTIVE: We investigated the genetic diversity and phylogeny of 28 rhizobial isolates from root nodules of soybean growing in the Hilly Area of Central Sichuan in China. METHODS: We used 16S rDNA PCR-RFLP and phylogenetic analyses of the 16S rDNA, glnII and symbiotic genes (nodC). RESULTS: Five 16S rDNA genotypes among the isolates were distinguished with restriction endonucleases Hae III, Hinf I, Msp I and Taq I. In the 16S rDNA PCR-RFLP analysis, all the isolates are divided into Bradyrhizobium group and Sinonrhizobium group at the 83% level, and Sinonrhizobium strains accounted for 75% of the isolates. The phylogenetic analyses of 16S rDNA, glnII and nodC show that 4 representative strains SCAUs1, SCAUs2, SCAUs7 and SCAUs4 were closely related to S. fredii USDA205(T) while the other 2 representative strains SCAUs3 and SCAUs5 were closely related to B. yuanmingense CCBAU10071(T) and B. diazoefficiens USDA110(T). The 16S rDNA, glnII and nodC sequence similarity of 4 Sinonrhizobium representative strains were 98.3% - 99.9%, 98.2% - 100% and 100%, respectively. CONCLUSION: Soybean rhizobia isolated from the Hilly Area of Central Sichuan in China has rich genetic diversity, S. fredii was the predominant genus. PMID- 25272810 TI - [Isolation, identification of TJ430 strain and characterization of its antifungal metabolite]. AB - OBJECTIVE: To screen new agro-antibiotics, rare actinomycetes were isolated by improved separation methods from soil samples and the chemical structure of the antifungal active product was elucidated. METHODS: Dry heating method was used for soil samples pretreatment and the improved HV separation medium for rare actinomycetes separation; agar block rapid screening was used for the rapid evaluation of rare actinomycetes biological activity. For the identification of a strain numbered TJ430, morphology observation, cell chemical composition analysis, physiological and biochemical analysis, enzymology characteristics analysis, 16 S rDNA sequence analysis, and DNA hybridization method were used. Bioactive crude extract from fermentation was purified by column chromatography and preparative chromatography; infrared spectroscopy and high resolution mass spectrometry was used for structure elucidation of bioactive ingredient. RESULTS: A total of 570 rare actinomycetes strains were isolated. Antibacterial activity of rapid screen showed that the numbed TJ430 strain showed excellent anti oomycetes and broad-spectrum antifungal activity. Strain identification results show that the strain is a S. cavourensis. The molecular formulas of the effective ingredient is C40H66N3O11, molecular weight is 765. Amino, methyl, methylene, carbonyl, covalent bond, isopropyl and other chemical groups should contained in the molecular. CONCLUSION: The characterized antibacterial active ingredient has good development prospect. PMID- 25272811 TI - [Effect of FarR on transcriptional levels of arginine biosynthetic genes in Corynebacterium crenatum AS 1.542 and its relationship with ArgR]. AB - OBJECTIVE: The FarR protein was involved in the regulation of arginine biosynthetic pathway in corynebacterium, but the regulation mechanism of FarR protein and its relationship with the negative regulator ArgR have never been reported. In this work, we constructed two deletion mutants: C. crenatum delta farR and C. crenatum delta argR delta farR, and investigated the FarR function and its relationship with ArgR through the determination of transcriptional levels of arginine biosynthetic genes in four strains, including C. crenatum delta argR constructed in previous work. METHODS: We used marker-less knockout technology to construct C. crenatum delta farR and C. crenatum delta argR delta farR, and compared the transcriptional levels of the arginine biosynthetic genes in three mutant strains with those of the wild type strain using real-time fluorescence quantitative PCR. RESULTS: The results of RT-qPCR indicate that, in the absence of ArgR, FarR acted as a positive regulator. When farR gene was knockout alone, the transcriptional levels of arginine biosynthetic genes appeared up-regulated, down-regulated or no influence. CONCLUSION: FarR and ArgR are involved together in the regulation of arginine biosynthetic pathway of C. crenatum. PMID- 25272812 TI - [Modification in de novo purine pathway for adenosine accumulation by Bacillus subtilis]. AB - OBJECTIVE: To study the effects of co-overexpression of purF, purM, purN, purH and purD genes on adenosine production in Bacillus subtilis. METHODS: First, an extra purF gene under control of the P43 promoter was integrated into the B. subtilis chromosome at the native purF locus by single crossover, resulting in simultaneous expression of purF, purM, purN, purH and purD. Then the transcriptional levels of the five genes in the engineering strain were tested by Realtime Quantitative PCR. The activity of PRPP amidotransferase was also detected. Finally, cell growth, glucose consumption and adenosine production in engineering strain along with original strain were examined. RESULTS: The transcriptional analysis showed that purF and its downstream genes purM, purN, purH and purD were simultaneously upregulated at different level. The PRPP amidotransferase activity of engineering strain was about 2.4-fold that of original strain. Shake flask fermentation showed the improvement in adenosine yield and conversion ratio from glucose to adenosine (17.5% and 26.1%, respectively). Fed-batch fermentation by the engineering strain was conducted. Compared with the original strain, adenosine accumulation of engineering strain increased within the same fermentation time. However, the cell growth of engineering strain was retarded. CONCLUSION: The co-overexpression of purF and its downstream genes purM, purN, purH and purD could enhance the adenosine yield in the culture broth. This paper could facilitate future research by providing theoretical evidence and method of metabolic engineering. PMID- 25272813 TI - [Identification of Pantoea agglomeran XM2 with biocontrol activity against postharvest pear black spot]. AB - OBJECTIVE: We isolated the bacterial strain XM2 from prunes (Prunus domestica L.) fruit surface. XM2 was identified and tested as an antagonist for postharvest biological control of black spot disease (Alternaria alternata) on pear fruits. METHODS: Strain XM2 was identified according to its morphological, physiological and biochemical characteristics and 16S rDNA sequence analysis. Inhibition tests were performed in wounds of pear fruits using different types of XM2 inocula, different concentration and inoculation time of XM2 and A. alternata. Effect of XM2 on mycelia morphology of A. alternata was observed under microscope. RESULTS: Strain XM2 was identified as Pantoea agglomeran. Biological control of XM2 against black spot disease was significantly better than the control, and the best inhibitory was observed when inoculated with suspension (97.73% of control effect). Higher XM2 concentration and lower A. alternata concentration showed better inhibitory effect. Similarly, the earlier inoculation of XM2 than A. Alternata, the better inhibitory effect on disease development. Microscopic observation found that XM2 broke part of the mycelia, making cell contents spilled and hyphae distorted. CONCLUSION: Pantoea agglomeran XM2 has the potential as an effective antagonist against postharvest pear blank spot disease. PMID- 25272814 TI - [Comparison of monosaccharide composition of capsular polysaccharides in Streptococcus suis serotype 1, 2, 14 and 1/2]. AB - OBJECTIVE: There are one-way or two-way cross-reactions among Streptococcus suis serotype 1, 2, 1/2 and 14, the reason to which was unknown. METHODS: The capsular polysaccharides of serotype 14 and 1/2 were purified on Sephacryl S-300 column and identified by phenol-sulphuric acid method and dot-ELISA. The molecular weight of the serotype 14 and 1/2 capsular polysaccharides was revealed as 487.38 kDa and 512.72 kDa by high performance gel permeation chromatography, respectively. RESULTS: The monosaccharide composition of serotype 14 and 1/2 capsular polysaccharides was determined as Glc/Gal/GlcNAc/Rha/Neu5Ac (1: 2.94 : 1.35 : 0.24 : 0.37) and Glc/Gal/GlcNAc/GalNAc/Rha/Neu5Ac (1 : 1.67 : 1.05 : 0.93: 0.72 : 0.7) by pre-column derivatization high performance liquid chromatography, fluorescent labeling HPLC and NMR, respectively. These were compared with the composition of serotype 1 and 2 capsular polysaccharides. Glc, GlcN, Gal and Neu5Ac was contained in the capsular polysaccharides of serotype 1, 2 14 and 1/2. But there is no prominent correlation between the monosaccharide composition and cross-reactions. The cross-reactions among them could be induced by the structure of the capsular polysaccharides and/or the other components on the cell wall. PMID- 25272815 TI - [Construction and characterization of R169H mutant of aspartokinase from Corynebacterium pekinense]. AB - OBJECTIVE: Increasing the activity of aspartokinase (AK) from Corynebacterium pekinense. METHODS: The gene of AK was constructed and mutated by site-specific mutagenesis. The mutational recombinant plasmid was heterologously expressed in Escherichia coli BL21. The mutational AK was purified by Ni(2+)-NTA column after ultrasonicating of the recombinant bacteria, and then identified by SDS-PAGE and Western blot. We compared the kinetic difference between R169H AK and WT AK by determining the enzymatic activities. Some other characteristics of R169H AK and WTAK were also studied. RESULTS: The mutant R169H was successfully constructed. The molecular weight of AK was 48kDa. V(max) of R169H AK was 226.3 U/mg x s(-1), which was 2.3 times higher than that of WT AK. The optimum reaction temperature of R169H AK was 26 degrees C, the same as that of WT AK. The optimum reaction pH of R169H AK was 9.0, slightly higher than that of WT AK. The half-life period of R169H AK under optimum temperature and pH were 5.5h, much higher than that of WT AK. Lysine, threonine and methionine had an active effect on the activity of R169H AK when they were in low concentration. CONCLUSION: The hydrogen bond between R169 and E92 was broken down in R169H AK, which could affect the degree of polymerization and further lowered the affinity of mutant AK with substrates and then decreased the inhibition inducing by the metabolites. Thus, the V(max) of mutant AK from R169H had increased by 2.3 times compared with that of WT AK. PMID- 25272816 TI - [Isolation and characterization of a non-pathogenic Marek's disease virus with a naturally inserted REV LTR sequence]. AB - OBJECTIVE: Marek's disease virus (MDV), GD06 strain, was isolated from healthy Three-Yellow chickens without MD vaccine. In this study, we characterized GD06 strain. METHODS: Meq gene and repeat short region of GD06 strain were amplified and analyzed, and the serotype was determined by indirect immunofluorescence assay. The growth characteristics of GD06 stain were evaluated in Specific Pathogen Free (SPF) chickens and chicken embryo fibroblasts. The pathogenicity of GD06 strain was assessed by challenge test using SPF chickens. RESULTS: GD06 strain was MDV-1 serotype with a naturally inserted reticuloendotheliosis virus long terminal repeat sequence. Similar to the vaccinated strains CVI988/Rispens and 814, the Meq gene of strain GD06 contained a 59-aa insertion in the proline rich domain compared with very virulent strain Md5. On 96, 120, 144, 168 and 192 hours post infection, the virus titers of GD06 were higher than that of CVI988/Rispens in vitro (P < 0.05), and the viremia levels in GD06-infected group were significantly higher than that of CVI988/Rispens group on 21 and 42 days post inoculation (P < 0.05). The result of challenge test demonstrated that GD06 remained nonpathogenic for chickens and induced little immunosuppressive effects. CONCLUSION: GD06 is an MDV-1 non-pathogenic strain naturally integrated with reticuloendotheliosis virus and long terminal repeat sequence. PMID- 25272817 TI - [MiR432* regulate the replication of coxsackievirus A16 in rhabdomyosarcoma cells]. AB - OBJECTIVE: MicroRNAs (miRNAs) play an important role in infection and replication of virus in host cells. In this study, we examined miRNAs' effects on the replication of Coxsackievirus A16 (CA16) in rhabdomyosarcoma cells. METHODS: We constructed target gene of miRNAs screening system. We used 3'untranslated region (UTR) dual luciferase reporter analysis to identify putative miRNA targets in the CA16 virus genome. First, 12 segments of CA16 virus genome were inserted to the pMIR vector and the luciferase expression were assayed to identify the target gene of putative miRNA. The reporter gene expression of the cells transfected with the vector containing 5'-UTR was significantly downregulated. Then, using online analysis programs we screened the miRNAs that may target to 5'-UTR. Furthermore, Western blot and real-time PCR test were used to study the effect of miRNAs on viral replication. RESULTS: The study showed that miR432 * could stimulate the replication of CA16 virus. On the contrary, miR432 * inhibitor could suppress CA16 virus replication. CONCLUSION: Cellular miRNAs could regulate the replication of CA16 virus in host cells. Our findings support the notion that the cellular miRNAs play an important role in the host and virus infection. PMID- 25272818 TI - [Construction of recombinant baculovirus vectors started by EF1alpha]. AB - OBJECTIVE: To improve the transduction efficiency of baculovirus and exogenous gene expression level, we chose a mammalian cell-specific promoter-human extension factor 1alpha promoter (EF1-alpha), used virus pseudotyped tools- truncated vessicular stomatitis virus protein G (VSV-GED), added woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) and adenovirus inverted terminal repeats (ITRs). METHOD: We constructed two improved recombinant baculoviruses transfer vectors named pWK and pWK-ITR with the pFB-VSV-GED-WPRE. The recombinant transfer vectors pWK-eGFP, pWK-ITR-eGFP and pWK (-)-eGFP were constructed by inserting the Enhanced Green Fluorescent Protein (eGFP) reporter gene into the downstream of EF1alpha promoter. Constructed recombinant plasmid transfected Sf9 insect cells, and observed the expression of green fluorescent protein by using the inverted fluorescence microscope. RESULTS: The fluorescence expression rate of BV-WK-eGFP, BV-WK-ITR-eGFP containing WPRE and ITRs was significantly higher than the negative control, ITRs can effectively extend the expression time of eGFP, the expression time of eGFP in BV-WK-eGFP and BV-WK-ITR eGFP increased 72 hours compared to the negative control BV-WK (-) -eGFP. The transduction time of VSV-GED pseudotyped baculovirus BV-WK-eGFP, BV-WK-ITR-eGFP was obviously shorten in OL cells, and reduced 24 hours compared to the negative control BV-WK (-) -eGFP, transduction efficiency were higher 25.7% and 36.5% than the negative control BV-WK (-) -eGFP, respectively. CONCLUSION: The experiments proved that the VSV-GED could effectively improve the transduction efficiency of baculovirus, WPRE could enhance the expression efficiency of the exogenous gene significantly, and ITRs extend the expression time. The research will lay a foundation to explore improved recombinant baculovirus express exogenous genes in vertebrate cells and research the new recombinant live vector vaccine. PMID- 25272819 TI - [Multiplex PCR assay for detection of virulence genes in avian pathogenic Escherichia coli]. AB - OBJECTIVE: To efficiently study the virulence genes distribution of Avian pathogenic Escherichia coli (APEC), we developed four multiplex PCR to detect adhesin-associated genes, invasin and toxin-associated genes, serum resistance associated genes and iron acquisition-associated genes. METHODS: According to gene sequences published in GenBank, we designed and synthesized 18 specific primer pairs, which were used in the four multiplex PCR. Then, we determined the sensitivity of multiplex PCR using diluted bacterial or DNA templates. To verify the feasibility of these multiplex PCR, we determined the distribution of virulence genes in 100 APEC isolates using these multiplex PCR. RESULTS: According to the results of PCR, we can conclude that each of the 18 genes was exactly and effectively amplified in the four multiplex PCR. The sensitivities of these four multiplex PCR were 10(3) Colony forming units (CFU), 10(3) CFU, 10(5) CFU, 10(5) CFU bacteria and 1ng, 1ng, 10ng and 10ng DNA, respectively. Furthermore, the results multiplex PCR for virulence genes distribution in 100 APEC were same as the single PCR. CONCLUSION: These results suggest that multiplex PCR developed in this study could efficiently detect the virulence genes of APEC, which was a useful and rapid technique for epidemiological investigation. PMID- 25272820 TI - [Cloning and analysis of a halogenase gene of Streptomyces sp. 604F from the Arctic Ocean]. AB - OBJECTIVE: To clone a halogenase gene from halometabolite-producing Streptomyces sp. 604F to facilitate identification of potential halometabolites and its biosynthetic gene cluster. METHODS: We used agar block method to detect the antimicrobial activity of Streptomyces sp. 604F. We further amplified the conserved regions of type I polyketide synthase (PKS I), type II polyketide synthase (PKS II) and nonribosomal peptide synthetase (NRPS) encoding genes by degenerative PCR. We detected halometabolites in fermentation extracts of Streptomyces sp. 604F analyzed by liquid chromatography-time of flight mass spectrometry (LC-Tof MS). Next, we amplified halogenase gene fragment from Streptomyces sp. 604F by using degenerative primers targeting reduced flavin adenine dinucleotide (FADH2) -dependent halogenase genes. Finally, we cloned the full halogenase gene and its flanking sequences through high-efficiency thermal asymmetric interlaced PCR (hiTAIL-PCR). RESULTS: Streptomyces sp. 604F showed promising antifungal activity against Candida albicans ATCC 10231, and its genome contained genes encoding PKS I, PKS II, NRPS and a halogenase with 1443 bp. The halogenase is a new non-tryptophan halogenase, and most closely related to halogenases catalyzing the chlorination of glycopeptides. CONCLUSION: Streptomyces sp. 604F possessed a new non-tryptophan halogenase, which may be involved in halogenation of glycopeptide-like metabolites. The cloning and analysis of this halogenase have provided guidance for searching target halometabolites, and laid the foundation for obtaining the biosynthetic gene cluster. PMID- 25272821 TI - [Application of CADD on multi-target drug R&D in natural products]. AB - Multi-target drugs can simultaneously adjust multiple links of the disease network. Despite the higher efficacy and lower toxicity caused by single targets, multi-target drugs become ideal drugs for treating complicated diseases as well the main direction of drug R & D. By virtue of their structural diversity, higher multi-target activity and lower toxicity, natural products become an important source for developing multi-target drugs. Computer-aided drug design (CADD) is a commonly used multi-target drug R&D method, which mainly includes virtual screening and pharmacophore design. In this paper, the authors made a systematical analysis and discussed the prospects and advantages of various methods for multi-target drug R&D with natural products. PMID- 25272822 TI - [Medicinal plant hairy roots generating and their applications]. AB - As a kind of the plant tissue cultures, hairy root culture is characterized by rapid growth without exogenous hormones source and high yield of secondary metabolites, which attracted the attention of scholars in resent years. This work systematically summarized the research of medicinal plant hairy roots, including the mechanism, current situation of medicinal plant hairy roots, and their applications. PMID- 25272823 TI - [Research progress of chemical composition of taxane in Taxus canadensis and medicine source crisis solution]. AB - Taxus canadensis distributed mainly in North America, such as northern Minnesota, Newfoundland, south to Wisconsin and Pennsylvania. Its composition has been shown to be very different from other species, and in recent years, some new skeletons also have been found in Canada yew. Through analysis of the taxanes content on various Taxus plants containing taxanes, the results showed a higher content of taxol in T. canadensis. Based on the current research on T. canadensis (from the research results of the author in recent years, as well as from studies of scholars in the field), the paper outlined the research progress in recent years on the chemical constituents of taxane of T. canadensis and the spectral characteristics of various types of compounds. Besides, this paper analyzed the present research about solutions for the taxol drug source crisis. PMID- 25272824 TI - [Advance in studies on Aconitum traditional Chinese medicines in toxicokinetics and metabonomics]. AB - Aconitum, as a kind of common traditional Chinese medicine, contains multiple biological active substances, with a very high medicinal value but high toxicity. Its major toxic ingredients are aconitine, mesaconitine and hypaconitine, which are also efficient ingredients. Therefore, the safety of its clinical application has aroused wide attention. With the constant deepening of drug development studies, people want to learn about its toxic mechanism and the regularity of its emergence and development of its toxicology, so as to make a scientific and rational assessment for its safety. Therefore, toxicokinetics and metabonomics have gradually become important content in the new drug assessment. During the development of drug performance, it is crucial to establish a scientific, objective and standardized Aconitum safety evaluation system and correctly assess and utilize its toxicity. Having summarized studies on metabonomics and toxicokinetics of Aconitum drugs in recent years, authors proposed to strengthen the studies on Aconitum drug safety assessment and establish a scientific and standardized safety evaluation system as soon as possible, in order to make the national treasure more useful. PMID- 25272825 TI - [Research progress of emodin anti-gallbladder carcinoma]. AB - Emodin is an effective active ingredient extracted from Chinese herbal medicine, which has the function of antimicrobial, anti-inflammatory, antioxidant and scavenging oxygen free radicals, inhibiting platelet aggregation, improving microcirculation, protecting various organs and tissues as well as a wide range of anti-tumor effect. Primary biliary gallbladder is a common malignant tumor resection rate and lack of effective adjuvant treatment. It has been confirmed that emodin has broad spectrum antitumor effect, whereas, whether it has curative effect in the treatment of gallbladder carcinoma there is no reliable clinical trials confirmed that its resistance to gallbladder carcinoma function needs further experimental research. In this review, we report the research progress of emodin anti-gallbladder carcinoma. PMID- 25272826 TI - [Investigation of production status in major wolfberry producing areas of China and some suggestions]. AB - To investigate the production status and the safety influence factors of wolfberry in China. We investigated the detailed factors which affect the quality safe of wolfberry in the periods of July-August 2013 and July-September 2009. The factors include fertilizing patterns, the used pesticide and preliminary process wolfberry. The factors were discussed according to the results of investigation, and suggestions were proposed for the management and production departments of wolfberry. PMID- 25272827 TI - [Roles of reactive oxygen species in Streptomyces pactum Act12-induced tanshinone production in Salvia miltiorrhiza hairy roots]. AB - Our previous research indicated that the Streptomyces pactum Act12 (Act12) had a certain promotional effect on tanshinone accumulation and up-regulated the expression of genes 3-hydroxy-3-methyglutaryl-CoA reductase (HMGR) and 1-deoxy-d xylulose-5-phosphate reductoisomerase (DXR) in Salvia miltiorrhiza hairy roots. This study focuses on the roles of reactive oxygen species in S. pactum Act12 induced tanshinone production in S. miltiorrhiza hairy roots. The 4% Act12, 4% Act12 + CAT and 4% Act12 + SOD were added to S. miltiorrhiza hairy root and subcultured for 21 days, the dry weight, contents of reactive oxygen species, contents of tanshinones and expression of HMGR and DXR were determined at different harvest-time. The generation of reactive oxygen species (ROS) in S. miltiorrhiza hairy roots was triggered by 4% Act12 treatment. The relative expressions of genes HMGR and DXR in 4% Act12 treatment were 32.4 and 4.8-fold higher than those in the control. And the total tanshinone in the hairy roots was 10.2 times higher than that of the control. The CAT and SOD could significantly inhibit the ROS accumulation and relative expressions of genes HMGR and DXR in 4% Act12 treatment, which induced the total tanshinone content was decreased by 74.6% comparing with the 4% Act12 treatment. ROS mediated Act12-induced tanshinone production. The Act12 may be via the ROS signal channel to activate the tanshinone biosynthesis pathways. Thereby the tanshinon content in hairy roots was increased. PMID- 25272828 TI - [Influence of plant growth regulater on yield and quality of Salvia miltiorrhiza]. AB - The study is aimed to investigate the effect of plant growth regulators on yield and quality of the Salvia miltiorrhiza. The plant growth regulators was spraying on Salvia plants in July or August in field experiment, then the yield, ingredient content and the antioxidant activity were determined. The results showed that plant growth regulator 'Zhuanggenling' could increase the yield of Salvia with root-planting by 38.45%. Plant growth regulator 'Duoxiaozuo' could increase the yield of Salvia with seedling planting by 14.19%. Both plant growth regulator significantly reduced the antioxidant activity of Salvia in vitro, but they had no significant effect on active ingredient contents. PMID- 25272829 TI - [Effect of drought stress on growth and physiological-biochemical characteristics of Stellaria dichotoma]. AB - A pot experiment was conducted to study effect of drought stress on leaf physiological characteristics and growth of one year old Stellaria dichotoma seedlings. The result showed that plant height and shoot dry weight significantly decreased with decrease in soil water content; however, root length and root dry weight increased at light drought stress and decreased at severe drought stress. The result also showed that with the decrease of soil water content, proline content in S. dichotoma leaves decreased then increase, while solube protein content decreased. Activities of SOD and POD in S. dichotoma leaves significantly decreased as soil water content decreased, while activity of CAT significantly decreased at severe drought stress. Membrane permeability in S. dichotoma leaves increased, while MDA content decreased then increased as soil water decreased. These results suggest that S. dichotoma had osmotic stress resistance ability and reactive oxygen scavenging capacity at light drought stress, which caused S. dichotoma growth was no inhibited at a certain extent drought stress. PMID- 25272830 TI - [Dynamic accumulation regulation of curcumin, demethoxycurcumin and bisdemethoxyeurcumin in three strains of curcuma longae rhizome]. AB - The paper is aimed to study the dynamic accumulation regulation of curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxyeurcumin (BDMC) in three strains of Curcuma longa, and provide scientific references for formalized cultivation, timely harvesting, quality control and breeding cultivation of C. longa. The accumulation regulation of the three curcumin derivatives was basically the same in rhizome of three strains. The relative contents decreased along with plant development growing, while the accumulation per hectare increased with plant development growing. The accumulation of curcuminoids per hectare could be taken as the assessment standard for the best harvest time of C. longa. A3 was the best strain in terms of Cur and BDMC content. PMID- 25272831 TI - [Establishment of culture system of Silybum marianum hairy roots and determination of silybin]. AB - This research uses six Agrobacterium rhizogenes R1601, R15384, R1000, A4, R1025 and R1 to infect silymarin explants to induce hairy roots and silibin. All of the six A. rhizogenes can induce Silybum marianum to generate hairy roots and the A. rhizogene A4 shows comparatively high infection on the plant. This research determines the condition to induce silymarin hairy roots by the factors of infection time, pre-culturing, co-culturing and pH value. The fact that MS liquid medium fits the proliferation of silymarin hairy roots is determined. Through PCR molecular identification, it can be seen that the DNA plasmids in the A. rhizogenes are successfully integrated into the genome of transformed roots. Using liquid chromatography, it is determined that the silibin content in silymarin hairy roots is 2.5 times that in the plant In this research, the silymarin hairy roots culturing system is established, which lays a foundation for the study of culturing silymarin hairy roots and producing silibin. PMID- 25272832 TI - [Identification of Schisandra chinensis with white fruits based on ITS2 sequences]. AB - OBJECTIVE: To analyse a special kind of Schisandra chinensis with the white fruit using ITS2 barcode at molecular levels. METHOD: ITS2 regions were sequenced bidirectionally. Sequence assembly and consensus sequence generation were performed using the CodonCode Aligner, MEGA 5.0 software was used to align the sequences. The ITS2 secondary structure was predicted using ITS2 web server, BLAST 1 method was used to identify the S. chinensis with the white fruit. RESULT: The length of the ITS2 sequence was 231 bp. And the sample was identified as S. chinensis using the method of BLAST 1. Their mean interspecific genetic distance (K2P distance) among the populations of the S. chinensis with the white fruit and S. chinensis was far lower than the mean interspecific genetic distance between the S. chinensis and S. sphenanthera. CONCLUSION: By using ITS2 the S. chinensis with the white fruit was identified as S. chinensis, and the ITS2 barcode could be used to identify S. chinensis and S. sphenanthera. PMID- 25272833 TI - [Effects of flower bud removal and artificial pollination on growth and yield of Tulipa edulis]. AB - The study was conducted to explore the response of growth and yield of Tulipa edulis to flower bud removal and artificial pollination. And flower bud removal and artificial pollination were carried out in the squaring period and bloom stage respectively. The morphological index and biomass indicators were determined and the yield was counted in harvest time. Result showed that flower bud removal was beneficial to the growth of T. edulis, resulting in increasing growth index, biomass as well as the yield of bulb. The diameter and dry weight of T. edulis fruit by artificial pollination were increased significantly compared with the control. Seed setting percentage increased to 100%, and the number of seed as well as the single grain weight increased by 69.03% and 16.48%, respectively, which did not significantly affect the bulb production. In conclusion, Flower bud removal treatment accelerates bulb biomass increase, so as to improve its yield. Artificial pollination raised significantly seed setting percentage, seed number as well as the single grain weight. PMID- 25272834 TI - [Mechanism exploration on synthesis of secondary metabolites in Sorbus aucuparia cell cultures treated with yeast extract]. AB - Suspension cultures cell of Sorbus aucuparia (SASC) was used as materials, the changes of physiological and biochemical indexes of SASC after treatment with yeast extract (YE) were detected, and the synthetic mechanism of secondary metabolites in SASC treated with YE was preliminarily explored. The results were as follows: under the assay conditions, SASC was induced to synthesize five biphenyl compounds, and these compounds content changed differently with induction time prolonging; YE treatment inhibited cell growth, the culture medium pH was gradually reduced after treatment; water-soluble protein content showed a trend of slow decline, which was significantly increased in YE treatment group (YE group) compared with the control group (CK group), the maximum relative content was 147.76% in contrast with CK group; both YE group and CK group were extracellular Ca2+ flow influx, but the YE group flow was significantly slow than CK group. The results indicate that YE induced the cells in a stress state, which was not conducive to the growth of cells and forced the cells to synthesize biphenyl compounds against external stress; water-soluble protein may serve as intracellular enzymes involved in the synthesis of compounds regulation; Ca2+ may as signal molecule mediate cell signal transduction respond to YE stress. PMID- 25272835 TI - Chemical of Vitex trifolia. AB - A new steroidal ester, beta-rosaterol palmitate (1) along with ten known compounds, uvaol(2), 3-epi-ursolic acid (3), 2alpha, 3beta, 24-trihydroxyolean-12 en-28-oic acid (4), 2alpha, 3alpha, 24-trihydroxyurs-12-en-28-oic acid (5), 2alpha, 3alpha, 24-trihydroxyolean-12-en-28-oic acid (6), 2alpha, 3alpha, 24 trihydroxyolean-12-en-28-oic acid-28-O-beta-D-glucopyranosyl ester (7), (Z)-9 hexadecenoic acid (8), octacosyl alcohol (9), beta-sitosterol (10) and beta daucosterol (11), has been isolated from the stems and leaves of Vitex trifolia. Their structures were elucidated using a combination of 1D and 2D NMR techniques (COSY, HMQC, and HMBC)and HR-ESI-MS analyses. Compounds 2-7 were isolated from this plant for the first time. PMID- 25272836 TI - [Chemical constituents of Jasminum giraldii and their antioxidant activity]. AB - Ten compounds were isolated from the barks of Jasminum giraldii by means of various of chromatographic techniques such as silica gel, Sephadex LH-20 and Rp HPLC. Their structures were identified by spectroscopic data analysis as (+) medioresinol (1), (+) -syringaresinol (2), syringaresinol-4'-O-beta-D glucopyranoside (3), oleanic acid (4), 3-methoxy-4-hydroxy-trans-cinnamaldehyde (5), trans-sinapaldehyde (6), syringaldehyde (7), 1-(4-methoxy -phenyl) -ethanol (8), trans-cinnamic acid (9), and 4-(1-methoxyethyl) -phenol (10). Among them, compounds 1-3, 5-8 and 10 were isolated from the J. genus for the first time and compounds 4 and 9 were obtained from J. giraldii for the first time. In the DPPH free radical scavenging assay, compound 1 exhibited significant activity (IC50 55.1 micromol x L(-1)), compared with vitamin C(IC50 59.9 micromol x L(-1)); and compound 2 showed moderate activity (IC50 79.0 micromol x L(-1)), compared with 2, 6-di-tert-butyl4-methylphenol (IC50 236 micromol x L(-1)). PMID- 25272837 TI - [Chemical constituents from Solanum rostratum]. AB - Ten compounds were isolated from the aerial part of Solanum rostratum by means of various chromatographic techniques such as silica gel, Sephadex LH-20, ODS and preparative HPLC. Their structures were identified as dioscin (1), hypoglaucin H (2), hyperin (3), isoquercitrin (4), isorhamnetin-3-O-beta-D-galactopyranoside (5), kaempferol-3-O-beta-D-glucoside (6), smilaxchinoside A (7), 26-O-beta-D glucopyranosyl-3beta, 20alpha,26-triol-25 (R) -delta5,22-dienofurostan-3-O-alpha L-rhamnopyranosyl (1 --> 2) -[ alpha-L-rhamnopyranosyl (1 --> 4)] -beta-D glucopyranoside (8), beta-sitosterol (9), and daucosterol (10), on the basis of physicochemical properties and spectroscopic data analysis. Among them ,compounds 7 and 8 were isolated from the genus Solanum for the first time, and the remaining compounds were obtained from this plant for the first time. PMID- 25272838 TI - [Sulfation of naringenin by Mucor sp]. AB - Naringenin (1) was transformed to three metabolites (2-4) by Mucor sp. Based on LCMS(n)-IT-TOF and NMR spectroscopic data, 2-4 were identified as naringenin-7-O sulphate, naringenin-4'-O-sulphate, and naringenin-5-O-sulphate, respectively. These results might provide hints to the mammalian/human metabolism of naringenin. PMID- 25272839 TI - [Synthesis and identification of artificial antigens of paneoniflorin]. AB - Oxidation method with sodium iodide was used to synthesize immunogenic antigen (PF-BSA) and coating antigen (PF-OVA) of paeoniflorin. UV spectroscopy showed that paeoniflorin was successfully conjugated with BSA and OVA. After immunized by PF-BSA, the mice can produce anti-paeoniflorin antibodies specifically. The ELISA test results showed the high titer (1:12 800) and specificity (IC50 = 0.791 mg x L(-1)) of the antiserum from mice injected with PF-BSA. Also, the antiserum showed low cross activities against nine traditional Chinese medicine (TCM) of small molecules. These artificial antigens were successfully synthesized and the anti-paeoniflorin antibody well prepared, which provides the experimental basis for the further study of ELISA and its kit. PMID- 25272840 TI - [Phenolic compounds in branches of Tamarix rasissima]. AB - To study the chemical constituents of the branches of Tamarix rasissima, repeated silica gel column chromatography, Sephadex LH-20 chromatography and recrystallization were applied for chemical constituents isolation and purification. Ten phenolic compounds were isolated from the n-BuOH fraction and their structures were elucidated by physical properties and spectra analysis such as UV, ESI-MS and NMR as monodecarboxyellagic acid (1), ellagic acid (2), 3, 3' di-O-methylellagic acid (3), 3, 3'-di-O-methylellagic acid-4-O-beta-D glucopyranoside (4), 3, 3'-di-O-methylellagic acid-4'-O-alpha-D-arabinfuranoside (5), ferulic acid (6), isoferulic acid (7), caffeic acid (8), 4-O-acetyl-caffeic acid (9), and 4-methyl-1, 2-benzenediol (10). All compounds except for isoferulic acid were isolated firstly from this plant except for isoferulic acid, and compounds 5, 9 and 10 were obtained from Tamarix genus for the first time. PMID- 25272841 TI - [Simultaneous determination of nine chemical markers of bletillae rhizoma by ultra performance liquid chromatography]. AB - A UPLC method has been developed in the current investigation for simultaneous determination of nine chemical markers of Bletilla striata, 4-hydroxymethylphenyl beta-D-glucoside, blestroside, dactylorhin A, militarine, dihydrophenanthrene 5, gymnoside V, dihydrophenanthrene 1, benzylphenanthrene 3 and gymnosides IX. Separation was performed at 45 degrees C on an ACQUITY UPLC BEH C18 column (2.1 mm x 150 mm, 1.7 microm) with a gradient solvent system of acetonitrile-water as the mobile phase. The flow rate was 0.3 mL x min(-1), the detection wavelength was 280 nm. The results showed that the nine chemical markers could be well resolved and that in the selected linear range, all calibration curves of the nine chemical markers showed good linearity (r > or = 0.999 3). The recoveries (n = 6) were in the range of 98.15% - 102.2% and RSDs were between 2.1% - 3.6%. The data suggested that the developed UPLC-UV method had good reproducibility, robustness, and accuracy, which was suitable for the quality control of Bletilla striata. Applications of the method showed that the nine chemical markers had higher contents in the wild B. striata than in the cultivated ones. PMID- 25272842 TI - [HPLC fingerprint of glycyrrhizea radix et rhizoma praeparata cum melle]. AB - The chromatographic fingerprint was established by eluting with the mobile phase consisted of acetonitrile and 0.2% formic acid water on an Agilent TC-C18 (2) column (4.6 mm x 250 mm, 5 microm). Six chromatographic peaks were identified by HPLC-MS/MS method. Ten batches of Glycyrrhizea Radix et Rhizoma Praeparata Cum Melle were determined, and the similarity was arranged from 0.72 to 0.99. Good precision, stability and repeatability were obtained, and this study provides a reference for the quality control of Glycyrrhizea Radix et Rhizoma Praeparata Cum Melle. PMID- 25272843 TI - [Optimization of hydrolysis process of linarin using response surface methodology and research about ARI activity of glycosylation-acacetin]. AB - OBJECTIVE: To optimize the hydrolysis process of linarin by response surface methodology, and to use the model of aldose reductase to study the acacetin's activity of aldose reductase inhibitory. METHOD: The model of acacetin enzyme in vitro was established by the determination of fluorescence absorption of NADPH, the inhibition rate of acacetin aldose reductase was calculated, and then the IC50 of hydrolysis was obtained. The hydrolysis process of linarin hydrolysis condition was optimized by using response surface method. RESULT: The results indicated that the IC50 of acacetin (2.74 mg x L(-1)) was less than the IC50 of linarin (3.53 mg x L(-1)). Hydrolyzation time of 7.4 h, sulphuric acid concentration of 0.54 mol x L(-1) and the ratio of material to liquid of 3 : 1 were the optimum conditions. CONCLUSION: Hydrolyzate acacetin has preferable inhibitory activity of aldose reductase. The optimized hydrolysis condition of linarin is convenient to use with good predictability. PMID- 25272844 TI - [In vitro studies of Raf-CREB, Akt-CREB, and CaMK II -CREB signal transduction pathway regulated by ginsenosides Rb1, Rg1 and Re]. AB - OBJECTIVE: Effects of ginsenoside Rb1, Rg1 and Re on neurotrophic factor signal transduction pathway using liposome-mediated transfection of eukaryotic cells approach. METHOD: The injury model was established by treating SH-SY5Y cells with 0.6 mmol x L(-1) of corticosterone (CORT) by 24 h. SH-SY5Y cell were pretreated with CORT for 30 min followed by co-treated with 120,60 and 20 micromol x L(-1) of Rb1, 120, 80 and 40 micromol x L(-1) of Rg1 and 120, 80 and 40 micromol x L( 1) of Re for 24 h. Cells viability was determined by Cell Counting Kit (CCK) assay. CREB expressing Luciferase reporter gene was constructed and transfected with plasmid containing hRaf, hcAMP, hAkt, hCaMK gene into human embryonic kidney (HEK293) cells using liposornal transfection reagent lipofection 2000. The expression of CREB before and after it addion of Rb1, Rg1 and Re was examined by Luc assay system and Western blotting. RESULT: Compared with normal control group, CORT significantly decreased the viability of SH-SY5Y cells to 67.21% (P < 0.01). CCK results show that Rb1 (60 micromol x L(-1)), Rg1 (80 micromol x L(-1)) and Re (80 micromol x L(-1)) on SH-SY5Y cells have significant protective effect (P < 0.01). Lucassay and Western blotting results show that the gene and protein levels of CREB increased significantly through the pathway of Raf and Akt with Rb1 and Rg1 (P < 0.01), Re can increase significantly the gene and protein levels of CREB through the pathway of Raf and CaMK II. CONCLUSION: Rb1, Rg1 and Re protects SH-SY5Y cells from CORT-induced damage and the neuroprotective mechanism may be associated with the Raf-CREB, Akt-CREB and CaMK II -CREB pathways. PMID- 25272845 TI - [Study on effect of astragali radix polysaccharides in improving learning and memory functions in aged rats and its mechanism]. AB - To observe the effect of Astragali Radix polysaccharides (APS) on the learning and memory functions of aged rats, in order to explore its mechanism for improving the learning and memory functions. Natural aging female SD rats were selected in the animal model and randomly divided into the control group, the APS low-dose group (50 mg x kg(-1)), the APS high-dose group (150 mg x kg(-1)) and the piracetam-treated group (560 mg x kg(-1)). They were orally administered with the corresponding drugs for consecutively 60 days. Besides, a young control group was set. The learning and memory functions of the rats were tested by the open field test and the Morris water maze task. The Western-blot method was used to observe the levels of relevant neural plasticity protein N-methyl-D-aspartate receptor (NMDA receptor) in hippocampus, calcium/calmodulin dependent protein kinase II (CaMK II), protein kinase (PKA), the phosphorylation level of CAMP response element binding protein (CREB) and the protein expression of brain derived neurotrophic factor(BDNF). In this study, the authors found that the learning and memory functions and the hippocampus neural plasticity protein expression of the aged rat group were much lower than that of the young control group (P < 0.01). Compared with the aged rat group, the APS group showed the significant improvement in the impaired learning and memory functions of aged rats and the up-regulation in the hippocampus neural plasticity protein expression. The results showed that APS may improve the learning and memory functions of aged rats by increasing the expressions of relevant neural plasticity proteins. PMID- 25272846 TI - [Study on protective effect of total saponins of Panax japonicus on LPS-induced RAW264. 7 cell inflammation through NF-kappaB pathway]. AB - OBJECTIVE: To observe the anti-inflammatory effect of total saponins of Panax japonicus on LPS-induced RAW264. 7 macrophages. METHOD: The effect of total saponins of P. japonicus of different concentrations on RAW264. 7 cell viability was determined with the MTT method. The NO kit assay was adopted to detect the NO release of total saponins of P. japonicus to LPS-induced RAW264. 7 cells. The enzyme linked immunosorbent assay (ELISA) was used to detect the secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1beta). The reverse transeriptase-polymerase chain reaction (RT-PCR) was used to determine the expression of inducible nitric oxide synthase (iNOS) ,TNF-alpha,IL-1beta. The protein expression of nuclear transcription factor-kappaB p65 (NF-kappaB p65) was tested by Western blot. RESULT: The safe medication range of total saponins of P. japonicus was less than 80 mg x L(-1). Compared with the LPS model group, total saponins of P. japonicus high, middle and low dose groups (0.1, 1, 10, 40 mg x L( 1)) could significantly reduce the secretion of NO, TNF-alpha, IL-1beta of LPS induced RAW264. 7 cells, and inhibit the expressions of iNOS, TNF-alpha and IL 1beta mRNA and the protein expression of NF-kappaB p65. CONCLUSION: This study preliminarily proves the protective effect of total saponins of P. japonicus on LPS-induced RAW264.7 macrophages. Its action mechanism may be related to NF kappaB signal pathway. PMID- 25272847 TI - [Chicory extract's influence on gut bacteria of abdominal obesity rat]. AB - OBJECTIVE: To investigate the efficacy mechanisme of chicory extract interventing abdominal obesity rat from the aspect of gut bacteria. METHOD: Male SD rats were randomly divided into five groups, namely the normal group, model group, large and small dose group of chicory and the fenofibrate group. Normal group was given deionized water, the other group was given fructose water and give the medical treatment of chicory and fenofibrate. Assay triglycerides, total cholesterol, LDL and HDL by biochemical methods and measure body weight and abdominal circumference and microscopicly observe the count changes of gut bacteria through real-time PCR method. RESULT: Compared with normal group, the triglyceride level and abdominal circumference were significantly higher (P < 0.05), weight and high density lipoprotein increased but no significant changes and E. coli, lactobacillus increased significantly. Compared with model group, chicory extract large and small dose group and the fenofibrate group can significantly reduce triglyceride levels (P < 0.05), reduce the number of E. coli and Lactobacillus and increase the number of bifidobacteria. The fenofibrate group can significantly reduce total cholesterol and high-density lipoprotein levels. CONCLUSION: The chicory's treatment effect on abdominal obesity is significant. The efficacy mechanisme intervention abdominal obesity may be related to the reduction of the number of lactic acid bacteria and E. coli and the increase of bifidobacteria. PMID- 25272848 TI - [Effect on M1 macrophages of shenlian extracts]. AB - This study discusses the effects of Shenlian extracts (SL) on M1 macrophages in atherosclerosis. The MTT assay was used to detect the growth inhibition rates of RAW264.7 cells. RAW264.7 cells were stimulated with murine interferon-gamma (IFN gamma) plus lipopolysaccharide (LPS) to induce M1 macrophages. The different concentrations of SL extracts (high-dose 50 mg x L(-1), moderate-dose 25 mg x L( 1), low-dose 12.5 mg x L(-1)) were added. The CD86 of M1 macrophages in cell membrane was measured by flow cytometry. The mRNA expression of iNOS and TNF alpha gene was detected by reverse transcription PCR (RT-PCR). And the supernatants were collected, the content of IL-6 and TNF-alpha were detected with ELISA kits. The results of this experiment show that the expression of the cell membrane molecule CD86, iNOS and TNF-alpha gene, the content of IL-6 and TNF alpha was obviously increased in M1 macrophages by IFN-gamma and LPS. The different doses of SL extract could reduce the expression of the above indicators. The above experimental results demonstrate that IFN-gamma combined LPS can induce RAW264.7 cell to type into M1 macrophages, and SL extracts can inhibit M1 macrophages. PMID- 25272849 TI - [Study of effect of tongsaimai tablets on experimental diabetic foot model rats]. AB - OBJECTIVE: To observe the effect of Tongsaimai (TSM) tablets in treating foot trauma of diabetic foot (DF) model rats, and discuss its potential mechanism. METHOD: Male SD rats were selected to duplicate the diabetic foot ulcer model and randomly divided into the blank control group, the model group, the metformin treatment group, and TSM 12.44, 6.22, 3.11 g x kg(-1) groups (n = 10). The healing of ulcer wounds were observed on day 1, 4, 8, 13 and 18. After 18 days, a histopathologic examination was conducted for ulcer tissues. The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) were detected by hydroxylamine and TBA methods. The content of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined with the radioimmunoassay. The immunohistochemical method was used to observe the expression of vascular endothelial growth factor (VEGF) in ulcer tissues and the number of capillary vessels. RESULT: TSM could alleviate the pathological changes of diabetic foot rats, accelerate the ulcer healing on 4, 8, 13, 18 d, reduce MDA, IL-6, TNF alpha, VEGF content in rat serum at 18 d (after the rehabilitation period), and enhance the SOD content. Specifically, the TSM 12.44 g x kg(-1) group showed significant differences compared with the model group (P < 0.05, P < 0.01). At 18 d after the treatment (the late rehabilitation period), the VEGF expression of TSM 12.44, 6.22 g x kg(-1) groups and the number of blood capillaries of the TSM 12.44 g x kg(-1) group were significantly lower than that of the model group (P < 0.05, P < 0.01). CONCLUSION: TSM could promote the foot wound healing of DF model rats, reduce MDA, IL-6 and TNF-alpha levels in serum, increase the SOD content and decrease the VEGF expression and the number of blood capillaries in the late rehabilitation period. Its action mechanism may be related to the inhibition of oxidative stress injury and the inflammatory cell infiltration. PMID- 25272850 TI - [Protein interaction network analysis of Panax notoginseng saponins]. AB - Panax notoginseng (PN) is one of the commonly used clinical medicines for cardiovascular diseases and possesses a variety of pharmacological effects. P. notoginseng saponins (PNS) are the most important bioactive components in PN. The purpose of this study was to explain the mechanism of PNS on molecular network level. 18 targets of the main medicinal ingredients of PNS were gained by virtual screening based on pharmacophores and data mining. A protein interaction network of PNS was constructed with 189 nodes and 721 interactions. By a graph theoretic clustering algorithm Molecular Complex Detection (MCODE), 14 modules were detected. Gene ontology (GO) enrichment analysis of the modules demonstrated that the roles of PNS played in cardiovascular disease related to multiple biological processes, which could represent the characteristics of traditional Chinese medicine (TCM) as a whole to regulate the disease. The results showed that the blood circulation and hemostasis efficacy of PN related with the biological processes such as positive regulation of cAMP metabolic and biosynthetic process, platelet activation and regulation of blood vessel size, regulation of T cell proliferation and differentiation and so on. Therefore, the module-based network analysis will be an effective method for better understanding TCM. PMID- 25272851 TI - [Effects of alkaloids from coptidis rhizoma on blood lipid metabolism and low denstity lipoprotein receptor mRNA in golden hamsters]. AB - To study the effects of alkaloids from Coptidis Rhizoma on low-density lipoprotein receptor (LDLR) mRNA expression and antihyperlipedemic levels. The LDLR mRNA expression were detected by real time fluorescence quantitative PCR, and the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-c) and high-density lipoprotein cholesterol (HDL-c) in serum were measured at the first and last examination. The results show that, after the drug treatment, compared with the model group, each drug group showed a lipid lowering effect. Especially, coptisine, palmatine, jatrorrhinze were significantly reduced TC, TG, LDL-c (P < 0.05, P < 0.01), and increased HDL-c (P < 0.01). In addition, they also increased mRNA expression of the LDLR in liver and HepG2 cells. The results showed that alkaloids from Coptidis Rhizoma can regulate lipid metabolism disorder, and coptisine have the best lipid-lowering effect. PMID- 25272852 TI - [Effect of jiaotai pill on pancreatic fat accumulation and islet cell apoptosis in rats with type 2 diabetes]. AB - In this study, the rat type 2 diabetes mellitus (T2DM) model was established through tail vein injection with low dose of streptozotocin (STZ) and high fat diet for 8 weeks, and then treated with Jiaotai Pill. The oral glucose tolerance test (OGTT), fasting serum insulin (FINS), free fatty acid(FFA) levels and blood lipid were assayed. HOMA-IR was calculated. Pancreatic pathology was performed. And pancreatic triglyceride (TG) content was examined by the lipid extraction method. Pancreatic islet cell apoptosis were detected by terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL). According to the results, the model group showed abnormal OGTT, increased FINS, HOMA-IR, FFA, lipid disorder, obvious fat accumulation and significantly increased TG content in pancreatic tissues, and enhanced pancreatic islet cell apoptosis. Compared with the model group, the Jiaotai Pill group displayed improved OGTT, reduced FINS, HOMA-IR, FFA, recovered lipid disorder, decreased fat accumulation and significantly declined TG content in pancreatic tissues, and lowered pancreatic islet cell apoptosis. In summary, Jiaotai pill could effectively treat type 2 diabetes in rats. Its mechanism may be related to the reduction in pancreatic fat accumulation and islet cell apoptosis. PMID- 25272853 TI - [Research of mechanism jinxueyuan granules increased saliva secretion of xerostomia model rats]. AB - To analyze the specific mechanism of Jinxueyuan granules, the relationship between the Jinxueyuan granules increased the saliva secretion of xerostomia model SD rats and excitement of receptors were studied in this experiment. In the study, three groups of xerostomia model rats were successfully established by using M-receptor blockers-4-diphenyl-acetoxy-N-methyl-piperidine (4-DAMP) and atropine, or adrenergic receptor blocker phentolamine; after the modeling, the medicine Jinxueyuan granules were gavaged. According to the clinical dose of Jinxueyuan granules and SD rats body surface area, the rats in atropine group were divided three dose groups respectively, namely low, medium and high dose of Jinxueyuan granules groups. The 4-DAMP group and phentolamine group were gavaged medium dose of Jinxueyuan granules. And the amount of salivary secretion for 150 minutes in all groups continuously were measured, and the effect of Jinxueyuan granules increased salivation and the relationship between characteristics and the receptors were observed; and submandibular gland tissue of the rats was isolated, then the effect of Jinxueyuan Granules for expression of the water channel protein aquaporin-5 (AQP5) in submandibular gland cells was analyzed by the Western blot technology. It was found that the saliva secretion of Jinxueyuan Granules groups was increased significantly, and compared with the saline control group, phentolamine group, 4-DAMP group and atropine group, difference was significant, P < 0.05. There was no significant difference between the low-dose of Jinxueyuan granules group and the saline group, but the medium dose of Jinxueyuan granules group had a significant difference, compared with the saline group (P < 0.05). In the time distribution of increasing saliva secretion, there was a significant difference between the saline and Jinxueyuan granules group in the saliva secretion (P < 0.05). After administration of Jinxueyuan granules, the expression of AQP5 protein in the submandibular gland cells expressing of treatment groups was increased, and compared with the blocker groups, there was a significant difference, P < 0.05. Except the atropine group, there was no significant difference in Jinxueyuan granules relieving the inhibition induced by blocks in phentolamine group and 4-DAMP group, compared with the saline group. Compared the AQP5 expression in three blockers groups, there was no significant difference in the efficacy of Jinxueyuan granules between phentolamine group and 4-DAMP group; but there was a significant difference between the atropine group and other groups (P < 0.05). Therefore, it was considered that the mechanism of Jinxueyuan granules increasing saliva secretion (effectiveness of nourishing Yin and generating body fluid ) possibly through the pathway mediated by muscarinic M receptor, especially M3 receptor, or adrenergic receptor, and increased expression of salivary gland AQP5 membrane, and then stimulate saliva production. PMID- 25272854 TI - [Spectroscopic studies on binding of beta-elemene to human serum albumin]. AB - Beta-Elemene is an antitumor drug which is isolated from the traditional Chinese medicinal herb Curcumae Phaeocaulis Rhizoma, it is the main component of elemene which is extracted from the plant and delivered via blood circulation after intravenous injection. The antitumor effect of beta-elemene in vitro and in vivo was definite, and beta-elemene could improve the patient immunity and no sever side effect, drug resistance or bone marrow suppression were found during the clinical studies. And human serum albumin (HSA) is a primary extracellular protein which has a high concentration distribution in blood plasma and has many characteristic physiological functions. Therefore, the binding of beta-elemene to protein may be very important for absorption, distribution, metabolism and elimination. Therefore, the study on the interaction of beta-elemene with drug carrying protein is very important. In this work, molecular binding of beta elemene to human serum albumin (HSA) was investigated by using spectrofluorometer. the binding constants suggested that a strong interaction and the formation of a complex between beta-elemene and HSA. This clearly implies that beta-elemene can be stored and removed by the proteins in the body. Furthermore, the fluorescence quenching results showed that the HSA fluorescence was quenched by beta-elemene through static quenching mechanism. Thermodynamic parameters showed that hydrophobic interactions play a role in the binding of beta-elemene to HSA. The negative deltaH(0) and positive deltaS(0) in case of beta-elemene therefore showed that electrostatic attraction play a role in the binding of beta-elemene to HSA. PMID- 25272855 TI - [Absorption of extractive Polygonum orientale in rat everted gut sacs]. AB - Using in vitro everted gut to investigate the intestinal absorption of the extracts from Polygonum orientale at different concentration. UPLC-MS/MS was used to detect the content of protocatechuic acid, isoorientin, orientin, vitexin, cynaroside, quercitrin, kaempferol-rhamnoside in different intestinal segments, then compared the results with the absorption of chemical components of extractive P. orientale in each intestinal segments, and calculated the absorption parameter. We took the statistic analysis with SPSS statistic software. The influence significance of each factors were analyzed to describe the character of absorption. The absorption of each component is linearity in different intestinal segments and different dose, and the square of coeficient correlation exceed 0.95, which consistent with zero order rate process. The K(a) increase along with the raised dosage of the extractive P. orientale (R2 > 0.95), indicated it is the passive absorption; different intestinal segments have different absorption. And the absorption trend in intestinal is duodenum, jejunum, ileum are greater than the colon. As ingredients are selectively absorbed in intestinal sac, the everted intestinal sac method is selected to assess the intestinal absorption charcteristics of ingredients of extractive P. orientale. PMID- 25272856 TI - [Study on in vivo pharmacokinetics of cucurbitacin injection in rats]. AB - To establish a method for the determination of cucurbitacin in plasma samples, in order to study the in vivo pharmacokinetic characteristics of cucurbitacin in rats. Rats were intravenously injected with cucurbitacin. With diphenhydramine as the internal standard (IS), the plasma concentrations of cucurbitacin in rat plasma at different time points were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). With electrospray ionization source, the positive ion detection in the multiple reaction monitoring mode was conducted to determine the ion-pairs for target compound and IS were m/z 503.2/113.1 and m/z 256.0/167.2, respectively. Agilent ZOBAX SB-C18 column (2.1 mm x 50 mm, 1.8 microm) was adopted and eluted with methanol and 0.1% formic acid (55:45), and the flow rate was 0.2 mL x min(-1). DAS 2.0 software was applied to fit the blood concentration and calculate corresponding pharmacokinetic parameters. The rats were intravenously injected with cucurbitacin at the concentration of 3.0 mg x kg(-1). The target blood quality concentration show good linear relations within the range of 10.5-3 150 microg x L(-1) (R2 = 0.996), the lower limit of the standard curve was 10.5 microg x L(-1), and the signal to noise ratio S/N = 12. Intra- and inter-day precisions RSD was less than 6.9% and 14%, respectively; The accuracy RE ranged between 0.20% and 3.7%; The extraction recoveries ranged between 92.7% and 97.1%. Regarding the pharmacokinetic parameters of tail intravenous injection of cucurbitacin, AUC (0-t) was (811.615 +/- 111.578) microg x h x L(-1), (t1/2) was (1.285 +/- 1.390) h, CL was (3.627 +/- 0.487) L x h x kg( 1), and V(d) was (6.721 +/- 7.429) L x kg(-1). In this study, researchers established a simple, accurate, sensitive and highly specific method for determining the blood concentration of cucurbitacin, and reported the in vivo pharmacokinetic characteristics of cucurbitacin in rats for the first time. PMID- 25272857 TI - [Preparation of paeonol transdermal delivery systems based on proniosomes-based ointment and its pharmacokinetics characters]. AB - The paeonol proniosomes ointment and ordinary ointment were administered to rats. Physiological saline served as perfused solution. The perfusion rate was 5 mL x L(-1) and the microdialysis samples were collected every 20 min intervals. The paeonol concentration in perfused solution was determined by HPLC. Investigation of the pharmacokinetics of paeonol proniosomes ointment and ordinary ointment by the skin-blood synchronous microdialysis coupled with HPLC is reported in this study. The results show that the recovery was (54.80 +/- 1.50)% in vitro and (54.58 +/- 4.61)% in vivo. The results showed that paeonol proniosomes ointment significantly raised the drug concentrations in skin more than the paeonol ordinary ointment. The paeono proniosomes ointment has less drugs into the blood as the ordinary ointments in blood, but its blood drug concentrations were steadier. The paeonol proniosomes ointment may be developed into a new preparation. PMID- 25272858 TI - [Proteomic study on effect of tangcao pill on microsome CYP450]. AB - Tangcao pill is commonly applied in adjuvant and even alternative therapy for patients with AIDS. However, the herb contains complex ingredients, but with unknown effect against anti-HIV drug and unknown function. Because CYP450 emzyme is the main metabolic enzymes of the drug, it is of important significance to study the regulation of CYP450 enzymes before and after the combined administration of Tangcao pill and EFV. Proteomics, due to its high throughout and high sensitivity, has been widely applied in CYP450 enzyme study. In this paper, liver microsomes were separated through differential centrifugation. Their proteins were separated through SDS-PAGE. The three protein bands that CYP450 enzymes were located were cut and identified by liquid chromatography tandem mass spectrometry. Totally 16 CYP450 isoenzymes were identified. Furthermore, in order to make a quantitative analysis on the effect of tang herb on CYP450 emzyme, the multiple reaction monitoring (MRM) technology based on MS was adopted. The CYP2C11 was selected based on the results of the mass spectrum identification of proteins. The characteristic polypeptides were obtained through searching Expasy blast database. The m/z of the fragment ions was less than 800. In the paper, the m/z of ion pairs of CYP2C11 were 711.5/232.1, 711.5/319.2, 711.5/466.2 and 711.5/595.3, and the m/z of ESAT-6 (internal standard, IS) were 735.5/215.3, 735.5/389.3, 735.5/460.3 and 735.5/524.3. The relative peak (analyte/IS) area was adopted for the relative quantitative analysis. Compared with the EFV single administration group, the EFV and Tangcao pill combined administration group showed a 1.6-fold increase in CYP2C11. The results of the paper indicated that Tangcao pill may affect drug metabolism by regulating metabolic enzymes such as CYP2C11, but the specific mechanism still unknown. PMID- 25272859 TI - [Pharmacokinetics behavior of raltitrexed in rats after repeatedly injected with Huangqi injection]. AB - In this study, the variation of pharmacokinetics behavior of raltitrexed (RTX) in rats after repeatedly injected with Huangqi injection was investigated. Twelve SD rats were divided into two groups: the multidose group and the RTX group. Rats in multidose group were iv. injected with Huangqi injection (dose of 1.575 mL x kg( 1)) everyday at 8 am for a week, and had free accesses for food and water. The rats were fasted for food but not water since 8 h before the eighth day. At the eighth morning, firstly, rats were injected with Huangqi injection (dose of 1.575 mL x kg(-1)), and 5 min later, were injected with RTX (dose of 0.467 mg x kg( 1)); rats in RTX group were not disposed in the previous seven days, also had free accesses for food and water, and were iv. injected with raltitrexed at the same time as Multidose group at the eighth day morning. Rat plasma was collected at different time and processed with methanol to precipitate the protein before HPLC assays. The pharmacokinetics parameters for two groups were calculated by software 3P97. Through the observation of drug concentration in plasma and time curve, we found that at almost every time point the concentration of RTX in plasma in multidose group was lower than the RTX group. When comparing the pharmacokinetics parameters between the multidose group and the RTX group, the average of AUC(0-t) and half-life(t1/2) of multidose group were decreased from 56 080 microg x min x L(-1) and 15.07 min to 35 834 microg x min x L(-1) and 8.95 min, respectively, while the clearance (CL) was increased from 0.51 to 0.83 mL x h(-1). Therefore, it could be deduced that repeatedly injected with AR injection may influence the renal excretion and glycometabolism of RTX, thus change pharmacokinetics behavior of raltitrexed in rats plasma. This result may give us a hint to prudantly manage the drug combination of RTX and Huangqi injection. PMID- 25272860 TI - [Analysis on composition regularity of carthami flos-containing traditional Chinese medicines]. AB - To analyze the composition regularity of Carthami Flos-containing prescriptions of the Drug Standards of Ministry of Health of People's Republic of China Traditional Chinese Medicine Preparations (the ministerial standards for Traditional Chinese Medicine) based on the traditional Chinese medicine inheritance support system (TCMISS, RZDZ No. 0389952). Efforts were made to identify 331 prescriptions containing Carthami Flos and summarize 16 attending functions and 10 commonly used drug combinations. Three commonly used drug combinations were selected for an in-depth analysis on Carthami Flos's combined administration regularity. Based on Carthami Flos's attending functions, its effects in paralysis, traumatic injuries and dysmenorrheal were compared to analyze Carthami Flos's core drug combinations for treating different diseases. The regularity of clinical administration and the characteristics of commonly used drug combinations were summarized to provide reference for Carthami Flos's clinical application and new ideas for new drug R&D. Carthami Flos prescriptions was mainly used to treat blood stasis and pain and mostly combined with drugs that could activate blood, promote the circulation of qi and dispel pathogenic wind to treat Qi-stagnation and blood stasis caused by various pathogenic factors such as wind, cold and dampness. PMID- 25272861 TI - [A cold/heat property classification strategy based on bio-effects of herbal medicines]. AB - The property theory of Chinese herbal medicine (CHM) is regarded as the core and basic of Chinese medical theory, however, the underlying mechanism of the properties in CHMs remains unclear, which impedes a barrier for the modernization of Chinese herbal medicine. The properties of CHM are often categorized into cold and heat according to the theory of Chinese medicine, which are essential to guide the clinical application of CHMs. There is an urgent demand to build a cold/heat property classification model to facilitate the property theory of Chinese herbal medicine, as well as to clarify the controversial properties of some herbs. Based on previous studies on the cold/heat properties of CHM, in this paper, we described a novel strategy on building a cold/heat property classification model based on herbal bio-effect. The interdisciplinary cooperation of systems biology, pharmacological network, and pattern recognition technique might lighten the study on cold/heat property theory, provide a scientific model for determination the cold/heat property of herbal medicines, and a new strategy for expanding the Chinese herbal medicine resources as well. PMID- 25272862 TI - Remarks by Melvin D. Wolfberg, O.D., on recognition of J. Harold Bailey before the AOA House of Delegates scheduled for 8:45 AM, June 23, 1991, Dallas, Texas. PMID- 25272863 TI - Harold R. Barnes (1895-1972), optometric practitioner and instructor and boxing official turned boxing opponent. PMID- 25272864 TI - Numbers of optometry school graduates since 1925. PMID- 25272865 TI - A historical survey of books on myopia. AB - This paper describes books with content solely on myopia or with titles that imply that they were entirely on myopia. Thirty such books were found, published from 1912 to 2010. For the purpose of organization, they are classified as textbooks, treatises on treatment, treatises on etiology, and conference proceedings. Changing contents of the books through the years reflect increasing sophistication of myopia research and clinical care. PMID- 25272867 TI - [Correlation between percentages of PMN, MNC, FBC and wound age after skeletal muscle injury in rats]. AB - OBJECTIVE: To study the percentages of polymorphonuclear leukocytes (PMN), mononuclear cells (MNC) and fibroblastic cells (FBC) in different post-traumatic intervals after skeletal muscle mechanical injury in rats. METHODS: The rat model of skeletal muscle mechanical injury was established. The rats were divided into injured groups (6 h, 12 h, 1 d, 3 d, 7 d, 10 d and 14 d after injury) and control group. The percentages of PMN, MNC and FBC in different post-traumatic intervals after skeletal muscle mechanical injury were assessed with HE staining and image analysis. RESULTS: At post-injury 6-12h, the percentages of PMN and MNC infiltration appeared in injured sites and that of PMN reached peak. At 1 d, the percentage of MNC infiltration appeared and reached peak, while that of PMN decreased. At 3-7 d, the percentage of FBC gradually increased, while that of PMN and MNC decreased. At 10-14d, the percentage of FBC reached peak. CONCLUSION: The percentages of PMN, MNC and FBC in injured zones showed time-dependent changes, which might be used as reference index for determination of age of skeletal muscle injury. PMID- 25272866 TI - Negative modulation of NO for diaphragmatic contractile reduction induced by sepsis and restraint position. AB - In practice of forensic medicine, potential disease can be associated with fatal asphyxia in restraint position. Research has demonstrated that nitric oxide (NO) and nitric oxide synthase (NOS) are plentifully distributed in skeletal muscle, contributing to the regulation of contractile and relaxation. In the current study, respiratory functions, indices of diaphragmatic biomechanical functions ex vivo, as well as NO levels in serum, the expressions of diaphragmatic inducible NOS (iNOS) mRNA, and the effects of L-NNA on contractility of the diaphragm were observed in sepsis induced by cecal ligation and puncture (CLP) under the condition of restraint position. The results showed that in the CLP12-18h rats, respiratory dysfunctions; indices of diaphragmatic biomechanical functions (Pt, +dT/dt(max), -dT/dt(max), CT, Po, force over the full range of the force frequency relationship and fatigue resistance) declined progressively; the NO level in serum, and iNOS mRNA expression in the diaphragm increased progressively; force increased significantly at all stimulation frequencies after L-NNA pre-incubation. Restraint position 1 h in CLP12 h rats resulted in severe respiratory dysfunctions after relative stable respiratory functions, almost all the indices of diaphragmatic biomechanical functions declined further, whereas little change took place in NO level in serum and diaphragmatic iNOS mRNA expression; and the effects of L-NNA were lack of statistical significance compared with those of CLP12 h, but differed from CLP18 h group. These results suggest that restraint position and sepsis act together in a synergistic manner to aggravate the great reduction of diaphragmatic contractility via, at least in part, the negative modulation of NO, which may contribute to the pathogenesis of positional asphyxia. PMID- 25272868 TI - [Expression of CaMK II delta in cerebral cortex following traumatic brain injury]. AB - OBJECTIVE: To observe the time-course expression of calcium-calmodulin dependent protein kinase II delta (CaMK II delta) in cerebral cortex after traumatic brain injury (TBI). METHODS: The TBI rat model was established. The expression of CaMK II delta in cerebral cortex around injured area was tested by Western blotting and immunohistochemical staining. RESULTS: Western blotting revealed expression of CaMK II delta in normal rat brain cortex. It gradually increased after TBI, peaked after 3 days, and then returned to normal level. The result of immunohistochemical staining was consistent with that of Western blotting. CONCLUSION: The expression of CaMK II delta around injured area after TBI increased initially and then decreased. It could be used as a new indicator for wound age determination following TBI. PMID- 25272869 TI - [The community succession of sarcosaphagous insects on pig carcasses in summer indoor and outdoor environment in Shenzhen area]. AB - OBJECTIVE: To explore the growing development and community succession of main sarcosaphagous insects on pig carcasses in summer indoor and outdoor environment in Shenzhen area and to estimate the postmortem interval (PMI). METHODS: From early May to August in 2013, in Forensic Medical Examination Center of Shenzhen Public Security Bureau, the main insect species and the decomposition process were observed in two adult pig carcasses of simulative indoor and outdoor environment. The different decomposition stages and the community succession of insects were recorded. RESULTS: The indoor and outdoor pig carcasses showed skeleton 412.5 and 325 hours after death, respectively. The main species of flies on pig carcasses were Chrysomya megacephala, Chrysomya rufifacies and Chrysomya chani. The main species of beetles were Crecphilus maxillosus, Necrobia ruficollis, Saprinus splendens and Dermestes maculatu. The dominant species of flies in the outdoor pig carcasses obviously produced the second generations due to the effect of mass rainfall, nor in the indoor pig carcasses. CONCLUSION: There are regular patterns on the community succession of insects on pig carcasses in summer indoor and outdoor environment in Shenzhen area. The activity patterns of seven typical insects and their larva show important value for estimating PMI. PMID- 25272870 TI - [Changes of oscillatory potentials of electroretinogram after methanol intoxication in rats]. AB - OBJECTIVE: To study the characters of oscillatory potentials (OPs) of electroretinogram (ERG) after methanol intoxication in rats. METHOD: The SD rat models of methanol intoxication were established and divided into control group, 3-day intoxication group, 7-day intoxication group. The changes of OPs of ERG were recorded in a dark room. RESULTS: The total amplitudes of 3-day and 7-day intoxication groups decreased approximately 50% compared with that of the control group, while the schedule delayed approximately 16% and 61%, respectively. CONCLUSION: The characters of methanol intoxication in rats included delay in schedule and decline in the total amplitude of OPs. PMID- 25272871 TI - [Isokinetic muscle test of normal people's knees in different postures]. AB - OBJECTIVE: To study the influence of different positions in the isokinetic muscle test of knees by CON-TREX Biomechanical Test and Training System, so as to select the suitable conditions for forensic identification of muscle strength test. METHODS: Fifty-two healthy volunteers joined the isokinetic muscle strength test in unfixed and fixed position, respectively and in two kinds of angular speed (60 degrees/s and 30 degrees/s). The differences of peak torque (PT) and peak torque angle (PTA) between bilateral knee flexor and extensor were statistically analyzed. RESULTS: In the unfixed position, under the two speed, there was statistically significant difference in PT between bilateral knee flexor and extensor (P < 0.05); while in the fixed position, under the two speed, there was no statistically significant difference (P > 0.05). In any kind of conditions, the PTA of bilateral knee flexor and extensor did not have statistically significant difference (P > 0.05). CONCLUSION: The position of the subject influences the results of PT. So the position of subject in knees isokinetic muscle test should be regulated. PMID- 25272872 TI - [The subtle anatomical structures of normal nasal bone in MSCT image and forensic identification]. AB - OBJECTIVE: To summarize the subtle anatomical structures of the normal nasal bone in multi-slice spiral CT (MSCT) image through the observation of the three dimensional images. METHODS: One hundred and twenty volunteers who had no nasal trauma and disease history were collected. The nasal was scanned using MSCT. Raw data was reconstructed into bone window images (slice thickness 0.6 mm, slice interval 0.5 mm), and then the images were imported into Syngo Imaging XS software to reconstruct three-dimensional images and to summarize the nasal bone's subtle anatomical structures. RESULTS: The subtle anatomy of normal nasal bone generally included four seams, two holes and one edge. The four seams were left and right nasal-maxillary suture, nasal-frontal seam, and internasal suture. The two holes were left and right nasal aperture. The edge of the nasal was the lower edge of the nasal bone. In addition, there was suture bone in internasal suture in some normal nose. The nasal aperture mostly was hole-like, but some nasal apertures were line shape. The nasal edge can be divided into flat type, wave-shaped type, inverted spike type, hook-shaped type and others. CONCLUSION: The anatomy diversity and individual differences in nasal bone are large. MSCT and three-dimensional image reconstruction techniques, combined with the history of trauma could distinguish between the normal anatomy and fractures. PMID- 25272873 TI - [DNA quantification of blood samples pre-treated with pyramidon]. AB - OBJECTIVE: To study DNA quantification and STR typing of samples pre-treated with pyramidon. METHODS: The blood samples of ten unrelated individuals were anticoagulated in EDTA. The blood stains were made on the filter paper. The experimental groups were divided into six groups in accordance with the storage time, 30 min, 1 h, 3 h, 6 h, 12 h and 24h after pre-treated with pyramidon. DNA was extracted by three methods: magnetic bead-based extraction, QIAcube DNA purification method and Chelex-100 method. The quantification of DNA was made by fluorescent quantitative PCR. STR typing was detected by PCR-STR fluorescent technology. RESULTS: In the same DNA extraction method, the sample DNA decreased gradually with times after pre-treatment with pyramidon. In the same storage time, the DNA quantification in different extraction methods had significant differences. Sixteen loci DNA typing were detected in 90.56% of samples. CONCLUSION: Pyramidon pre-treatment could cause DNA degradation, but effective STR typing can be achieved within 24 h. The magnetic bead-based extraction is the best method for STR profiling and DNA extraction. PMID- 25272875 TI - [Application of microperimeter in the visual function evaluation]. AB - In condition of direct vision on hindus of eye, microperimeter can quantitatively detect the retinal light sensitivity of macular area, and record real time tracking of the eye, automatically analyze the location and stability of fixation. Microperimeter matches hindus image with micro cyclogram point-to point, thus it achieves the combination of visual function and structure. The characteristics of microperimeter have good relations with subjective vision, so it can be a new method for the accurate vision evaluation and has application potential to assess the visual function in legal medicine. In this article, we summarize the principle, method and parameters of microperimeter. Also, the applications of microperimeter in vision assessment are focused in order to provide a reference for the assessment of visual function in the legal medicine. PMID- 25272874 TI - [Consistency study of PowerPlex 21 kit and Goldeneye 20A kit and forensic application]. AB - To ensure the consistency of genotype results for PowerPlex 21 kit and Goldeneye 20A kit. METHODS: The STR loci were amplified in DNA samples from 205 unrelated individuals in Beijing Han population. And consistency of 19 overlap STR loci typing were observed. The genetic polymorphism of D1S1656 locus was obtained. RESULTS: All 19 overlap loci typing showed consistent. The proportion of peak height of heterozygous loci in two kits showed no statistical difference (P > 0.05). The observed heterozygosis of D1S1656 was 0.878. The discrimination power was 0.949. The excluding probability of paternity of triplet was 0.751. The excluding probability of paternity of diploid was 0.506. The polymorphism information content was 0.810. CONCLUSION: PowerPlex 21 kit and Goldeneye 20A kit present a good consistency. The primer design is reasonable. The polymorphism of D1S1656 is good. The two kits can be used for human genetic analysis, paternity test, and individual identification in forensic practice. PMID- 25272876 TI - [Progress on association between COMT gene and violence behavior in patients with schizophrenia]. AB - The prevalence of violence behavior in patients with schizophrenia is higher than that in common population. Data suggest that genetic factors may play a substantial role for the etiology of the behavior. Among the particular gene polymorphisms that have been considered to be involved in violence behavior, the catechol-O-methyltransferase (COMT) gene had been the focus of recent research. This article reviews the association research between COMT gene and violence behavior in patients with schizophrenia in several aspects: SNP polymorphism of COMT Val158Met and COMT Ala72Ser, haplotype of COMT gene and DNA methylation of promoter region of COMT gene. The genetic research direction is presented for patients with schizophrenia. PMID- 25272877 TI - [Relationship between genetic polymorphism of dopamine receptor and schizophrenia and its forensic significance]. AB - Schizophrenia is a common but complex mental disorder affected by multiple factors. Forensic psychiatric assessment of schizophrenia involves evaluations on many aspects, but there is no effective biological identification index for schizophrenia. Researches indicate that dysfunction of dopaminergic neurotransmission plays an important role in the pathogenesis of schizophrenia. Our study reviews the classification, genetic structure of dopamine receptors and the recent pertinent studies between the dopamine receptors and schizophrenia and its forensic significance. PMID- 25272878 TI - New trends in the treatment of nicotine addiction. AB - The aim of this study was to discuss the therapeutic substances used to treat nicotine addiction, not registered in Poland. This paper presents the results of the latest clinical trials and the possibility of their use in the treatment of nicotine addiction. The first two discussed drugs clonidine and nortriptyline are recommended by clinical practice guidelines AHRQ (Agency for Healthcare Research and Quality) as the substance of the second line in the fight against addiction. Nortriptyline belongs to tricyclic antidepressants. Its mechanism of action is the inhibition of the reuptake of norepinephrine. It is suggested as the antagonist of activity of nicotinic receptors. The results confirm its efficacy in the treatment of nicotine addiction, but many side effects limit its use. Clonidine acts presumably by inhibition of sympathetic hyperactivity characteristic of symptoms associated with nicotine rehab. The remaining compounds under discussion, such as: venlafaxine, fluoxetine, moclobemide and rimonabant, are not registered in any country with an indication to use in the treatment of nicotine addiction, however, due to the mechanism in which they act, the possibility of their use in the treatment of this disease is considered. The possibility of using anxiolytics such as: buspirone, diazepam, meprobamate and beta-blockers: metoprolol and oxprenolol is also considered in order to treat the anxiety appearing as one of the symptoms of abstinence. An interesting proposal to combat nicotine addiction are vaccines--NicVAX, CYT002-NicQb and TA-NIC. Currently, they are in clinical phase I and II of their development. Their operation would be based on the induction of specific antibodies that bind nicotine in the plasma, thus prevent it reaching the nicotinic receptors. Preliminary results confirm the possible positive effects in the prevention and treatment of nicotine addiction. PMID- 25272879 TI - Recent pharmacological advancements in schiff bases: a review. AB - Schiff bases are the biologically privileged scaffolds in organic chemistry, commonly synthesized from the condensation reaction of carbonyl functional group with amines. Naturally occurring and synthetically prepared Schiff bases are active molecules with many pharmacological activities like antibacterial, anti cancer, anti-fungal, anti-malarial, antioxidant and many more. This review article summarizes pharmacological developments in the recent few years and gives a brief overview of their therapeutic potential. PMID- 25272880 TI - Functions and application of exosomes. AB - The cells continuously secrete a large number of different types of microvesicles including macro-and micro-molecules into the extracellular fluids. One of them are exosomes, which are nano-sized vesicles capable of transferring the DNAs, microRNAs, non-coding RNAs and lipids with or without direct cell to cell contact, so representing the novel way of intracellular communication. In this review, we tried to summarize the exosomal structure, composition, formation, and isolation. We also discussed their active role in pathogenesis. The potential use of exosomes for diagnostic and therapeutic purposes in various diseases is also discussed. Exosomes are perceived to be used as carriers between different locations of body. Exosomes are secreted by all types of cells and are also found abundantly in the body fluids such as: saliva, blood, urine and breast milk. The major role of exosomes is to carry the information by delivering various effectors or signaling molecules between specific cells. This review summarizes current knowledge about the exosomes, their functions, biological and therapeutic use as well as emerging exosomes based therapies that could not be applied before. PMID- 25272881 TI - New renin inhibitors--stability and activity determination. Part I. AB - A series of new six potential renin inhibitors containing pseudodipeptides were synthesized. Stability for all compounds (1-6) in homogenates of liver, kidney, lung and in serum, gastric, intestinal juice and in the presence of alpha chymotrypsin was determined. Compound 5 was unstable, compound 6 was stable, other compounds were partly unstable, compound 2 was stable except kidney homogenate and compound 4 was stable except liver homogenate. Inhibitory activity of the compounds was measured in vitro by HPLC determination of lowering concentration of substrate (angiotensinogen) in the presence of renin and the potential renin inhibitor (compounds 1-6). Compound 2, 4 and 6 showed inhibitory activity (1.4 x 10(-6), 5.2 x 10(-6), 1.5 x 10(-7) M, respectively). Other compounds (1, 3, 5) showed no inhibitory activity up to 10(-5) M. PMID- 25272882 TI - New renin inhibitors--stability and activity determination. Part II. AB - A series of new six pseudodipeptic potential renin inhibitors were synthesized. Enzymatic stability for all compounds (1-6) in homogenates (liver, kidney, lung) and body fluids (serum, gastric, intestinal juice) and alpha-chymotrypsin was determined. Compounds 4 was stable, compound 5 was unstable and compounds 1, 2, 3, 6 were partly unstable. Inhibitory activity of the compounds was measured in vitro by HPLC determination of lowering concentration of substrate (angiotensinogen) in the presence of renin and the potential renin inhibitor (compounds 1-6). Compound 4, 5, 6 showed inhibitory activity (0.9 x 10(-6), 1.3 x 10(-8), 2.2 x 10(-6) M, respectively). Other compounds showed no inhibitory activity up to 10(-5) M. PMID- 25272883 TI - Development studies on determination of preservatives decomposition products. AB - Preservatives are chemical substances whose role is to protect medicinal products against harmful changes caused by microorganisms. They are added to sterile medicinal products, such as eye drops and multidose solutions for injections, as well as to non-sterile products, such as water oral solutions, creams, gels, suppositories and capsules with liquid content. The most commonly used preservatives include: benzyl alcohol, butyl, ethyl, methyl and propyl p hydroxybenzoates and their sodium salts. In medicinal products benzyl alcohol slowly oxidizes to benzaldehyde and benzoic acid while esters of p-hydroxybenzoic acid hydrolyze to p-hydroxybenzoic acid. HPLC methods were elaborated for identification and quantitative determination of the parabens, benzyl alcohol, active substances as well as their impurities in pharmaceuticals: oral solutions Amertil and Efforil (contain cetirizine hydrochloride or etilefrine hydrochloride and parabens), eye drops Difadol (contains diclofenac sodium and benzyl alcohol) and cream Tenasil (contains terbinafine hydrochloride and benzyl alcohol). The HPLC systems consisted of columns: Supelcosil LC-DP, Inertsil ODS-3 or Discovery HS F5 and three mobile phases mixtures of acetonitrile with buffers of various pH (3, 5 and 7) in proportions 45 : 55 (v/v). These systems have been characterized with appropriate selectivity (all the Rs values > 2) and sensitivity (LOD approx. 0.01 microg/mL). They also demonstrated satisfactory precision and a linear dependence between the analyte content and the peak area. PMID- 25272884 TI - Identification of similarities in metallic content of herbal infusions using non linear approach. AB - The content of Cd, Cr, Cu, Fe, Pb, Mn, Ni and Zn was determined, using flame atomic absorption spectrometry in infusions made from commercial herbal mixtures readily available in herbal stores. ANOVA test revealed that the metal contents did not differ considerably in most of infusions. The scatter plot of principal component analysis (PCA) designated infusions characterized by similar contents of trace elements. It was possible to indicate distinctive metal concentrations in Pyrosan, Septosan and Urosan infusions as they vastly contrasted with others. The levels of Mn, Zn, Cd were characteristic for Pyrosan infusions, while Cr, Fe, Cd were specific to Septosan, and Mn, Zn, Fe to Urosan. Self-organizing maps did not fully correspond with PCA results because PCA classified samples relying mainly on apparent similarities in metal contents. PMID- 25272885 TI - Synthesis of some new carbonitriles and pyrazole coumarin derivatives with potent antitumor and antimicrobial activities. AB - 3-Acetyl-4-hydroxycoumarin (2) was reacted with some aldehydes (4 chlorobenzaldehyde, 4-bromobenzaldehyde, 5-methylfurfural) to afford the chalcones (3a-c). Cyclization of these chalcones with malononitrile in the presence of ammonium acetate afforded pyridine carbonitriles (4a-c), while the cyclization reaction of chalcones (3a-c) with ethyl cyanoacetate afforded the oxopyridine carbonitriles (5a-c). On the other hand, the chalcones (3a-c) reacted with hydrazine hydrate in alcohol to yield pyrazoles (6a-c), but when the same reaction is carried out in the presence of acetic acid, the acetyl pyrazole derivatives (7a-c) were obtained. Finally, the reaction of the chalcones (3a-c) with phenylhydrazine afforded phenylpyrazole derivatives (8a-c). The structures of synthesized compounds were confirmed by their micro analysis and spectral data (IR, NMR and MS). Twelve samples were evaluated for the human breast adenocarcinoma cytotoxicity, three of them showed moderate activity, the rest of the samples showed weak cytotoxic activity (very high IC50), but for the hepatocarcinoma cell lines four samples showed weak cytotoxic effect, while the rest of the compounds showed very weak effect. For antimicrobial study, three compounds proved to be the most promising against tested bacterial organisms. PMID- 25272886 TI - Synthesis and molecular docking of some novel anticancer sulfonamides carrying a biologically active pyrrole and pyrrolopyrimidine moieties. AB - Abstract: A novel series of pyrroles and pyrrolopyrimdines carrying a biologically active sulfonamide moiety have been synthesized. The structures were confirmed by elemental analyses and spectral data. All the target compounds were subjected to in vitro cytotoxic screening on breast cancer cell line (MCF-7). Most of the synthesized compounds showed good activity as cytotoxic agents with better IC50 than doxorubicin as a reference drug. In order to suggest a mechanism of action for their activity, molecular docking on the active site of human c-Src was performed for all synthesized compounds. PMID- 25272887 TI - Utility of L-norephedrine in the semisynthesis of novel thiourea and thiazolidine derivatives as a new class of anticancer agents. AB - The natural alkaloid 1-norephedrine 1 was utlized in the synthesis of some novel thiourea derivatives 2, 5 and thiazolidinones 4a,b and 6, 7. Structures of the synthesized compounds were confirmed by analytical and spectral data. The synthesized compounds were evaluated in vitro for anticancer activity against the human breast (MCF-7), human liver (HEPG2) and human colon (HCT116) cancer cell lines. Thiazolidinone derivative 7 was the most active against all the cell lines with values IC50 = 2.60, 2.80 and 2.60 microg/mL compared with doxorubicin (IC50 = 5.40, 2.97 and 5.26 microg/mL). Thiazolidinone derivative 6 exhibited higher activity with IC50 value (3.20 microg/mL) against HCT116 when compared with doxorubicin with IC50 value (5.26 microg/mL) as positive control. PMID- 25272889 TI - Antioxidant and hypoglycemic effect of Otostegia aucheri methanolic extract in streptozotocin-induced diabetic male long-Evans rats. AB - Present study is based on the investigation of antioxidant and antihyperglycemic effect of methanolic extract from areal parts of Otostigea aucheri (OA). 2,2 Diphenyl-1 -picrylhydrazyl (DPPH) method was used to measure the antioxidant activity of extract of the species Otostigea aucheri. The observed scavenging activity for the free radicals was significant and it was compared with the standard BHT inhibition method. The IC50 value obtained of methanolic extract was 2.23 microg/mL. The methanolic extract of OA on the blood glucose level was further studied in normal (non-diabetic), streptozotocin (STZ)-induced type I and type II diabetic male Long-Evans rats at postprandial glucose load state. The results revealed that the oral administration of methanolic extract (1.25 g/kg) of OA showed no remarkable hypoglycemic effect in normal and type 1 (IDDM) diabetic rats. However, the methanolic extract significantly lowered (p < 0.005) serum glucose level in type II diabetic (NIDDM) models when simultaneous glucose was administered. This screening for antioxidant activity interprets the pernicious effects of diabetes that have been associated with mediation through the oxidation stress. The study also suggests to introduce natural source of the potential orally active antioxidant and active antihyperglycemic phytochemicals for the future. It may also improve the impaired antioxidant defense system. PMID- 25272888 TI - Phospholipases A2: enzymatic assay for snake venom (Naja naja karachiensis) with their neutralization by medicinal plants of Pakistan. AB - Phospholipases A2 (PLA2) are the most lethal and noxious component of Naja naja karachiensis venom. They are engaged to induce severe toxicities after their penetration in victims. Present study was designed to highlight hydrolytic actions of PLA. in an egg yolk mixture and to encounter their deleterious effects via medicinal plants of Pakistan. PLA2 were found to produce free fatty acids in a dose dependent manner. Venom at concentration of 0.1 mg was found to liberate 26.6 pmoles of fatty acids with a decline in pH1 of 0.2 owing to the presence of PLA2 (133 Unit/mg). When quantity of venom was increased up to 8 mg, it caused to release 133 pmoles of free fatty acids with a decrease in 1.0 pH due to abundance in PLA, (665 Unit/mg). The rest of other doses of venom (0.3-4.0 mg) was found to liberate fatty acids between these two upper and lower limits. Twenty eight medicinal plants (0.1-0.6 mg) were tried to abort PLA, hydrolytic action, however, all were found useful (50-100%) against PLA,. Bauhinia variegate L., Citrus limon (L.). Burm.f. Enicostemnma hyssopifolium (Willd.) Verdoorn, Ocimum sanctum. Psoralea corylifolia L. and Stenolobium stans (L.) D. Don were found excellent in switching off 100% phospholipases A, at their lowest concentration (0.1 mg). Three plants extract were found useful only at lower concentration (0.1 mg), however, their higher doses were seemed to aggravate venom response. Eight medicinal plants failed to neutralize PLA, rather their higher doses were found effective. Standard antidote and rest of other plants extract were able to show maximum of 50% efficiencies. Therefore, it is necessary to identify and isolate bioactive constituent(s) from above cited six medicinal plants to eradicate the problem of snake bite in the future. PMID- 25272890 TI - Usefulness of Rosen's postulate for studying the relationship between the structure of cholic acid oxyethylation products and the process of solubilization of lipophilic therapeutic agents (BCS class II and IV) in aqueous solutions in equilibrium. AB - We verified the usefulness of "Rosen's postulate", i.e., the logarithm of reciprocal concentration of surfactant--log(1/cPi=20) by which the surface tension of a solution can be decreased by 20 mJ/m2 in relation to water (physiological value gamma25 = 48-52 mJ/m2) in the evaluation of the applicatory properties of cholic acid oxyethylation products. Moreover, the values of deltaG0m for solubilizers and their micellar adducts with diclofenac, naproxen, and loratadine constituted the basis for estimating the thermodynamic value of "Rebinder's effect", associated with change in the state of matter of therapeutic agent. We determined critical micellar concentration for the aqueous products of oxyethylation and for micellar adducts with diclofenac, naproxen, and loratadine, and used these values to calculate (thermodynamic potential of micelle formation). PMID- 25272891 TI - Tenoxicam-kollicoat IR binary systems: physicochemical and biological evaluation. AB - Tenoxicam (TNX) binary systems in Kollicoat IR (KL) matrix were prepared in different drug: polymer ratios using kneading and spray-drying method. The prepared binary systems were characterized for drug dissolution rate, differential scanning calorimetry (DSC), IR spectroscopy and x-ray diffractometry. The results showed that the drug dissolution rate was remarkably enhanced by incorporating it in the KL matrix either by kneading or spray-drying, and the dissolution rate was increased by decreasing the drug weight ratio. The DSc and x-ray studies revealed the presence of TNX in less crystalline or amorphous state in its-KL binary systems. Moreover, the spray-dried TNX-KL system in 1:4 ratio, that exhibited the faster dissolution rate, was formulated in oral disintegrating tablets (ODTs). The data indicated that a fast disintegration and higher drug dissolution rate was achieved in case of the ODTs containing the spray-dried form compared to the ODTS containing untreated drug or the commercial tablet (Epicotil). Also, the drug exhibited significantly (p < 0.01) faster onset of the anti-inflammatory analgesic activities in case of the ODTs containing the spray-dried form, that was superior to that observed with both the commercial tablet product and the ODTS containing untreated drug. PMID- 25272892 TI - Stability of cilazapril in pediatric oral suspensions prepared from commercially available tablet dosage forms. AB - Abstract: Cilazapril is a drug commonly used in management of heart failure in pediatric population. On pharmaceutical market it is available only in inconvenient for pediatric use tablet dosage forms. Until now, no oral liquid formulation containing cilazapril has been evaluated. Therefore, the aim of this study was to prepare easy to made and palatable 1 mg/mL oral liquid formulation with cilazapril (with consideration of original and generic cilazapril tablet and different packages) and subsequent investigation of physicochemical stability of these suspensions. Formulations were compounded using cilazapril obtained from original or generic cilazapril marketed tablet formulations and Ora-Blend" suspending agent. Stability of prepared suspensions stored in closed amber glass or amber plastic PET bottles in the temperature of 298 K was estimated throughout 28 day shelf-life period. Chemical stability was assessed by HPLC cilazapril stability indicating method. Physical stability was evaluated by appearance, taste, smell, pH and theological assessments. Cilazapril oral suspensions at concentration of 1 mg/mL demonstrated satisfactory stability over 28 day long storage at room temperature. Cilazapril concentrations remained within acceptable limit (+/- 10%) stored in closed amber bottles made of glass or PET material. Moreover, suspensions physical properties remained unaffected. Cilazapril - Ora Blend* pediatric oral liquid is easy to made, palatable and stable when stored at room temperature for 28 days. Stability of cilazapril oral liquid remains unchanged while using cilazapril tablets produced by different manufacturers and bottles made of amber glass or PET material. PMID- 25272893 TI - Possible mechanism of cardiac depressant activity of Berberis orthobotrys roots in isolated rabbit heart. AB - Berberis orhob, otrvs Bien. ex Aitch. (B.o.) has been reported to have antihypertensive effect in different experimental models. The aim of present study was to evaluate the possible antihypertensive mechanism. Aqueous methanolic extract of B.o. roots and its various fractions namely (ethyl acetate, n-butanol or aqueous) in different concentrations (10 ng/mL, 100 ng/mL, I pg/mL, 10 pg/mL, 100 pg/mL ) were evaluated in isolated perfused rabbit heart to assess their effect on force of contraction, HR and perfusion pressure. The crude extract of B.o. and its fractions exhibited a significant decrease in heart rate, contractility and perfusion pressure of isolated rabbit heart, however, butanolic fraction produced more prominent effect and was selected for further study. The effects of butanol fraction were not blocked by atropine (10' M) in isolated perfused heart. However, butanol fraction significantly blocked the effects of adrenaline (10' M). It is therefore conceivable that cardiac depressant activity of B.o. butanol fraction might be due to the presence of certain 3-blocking agents which might be responsible for antihypertensive effect However, further experiments are required to isolate the active compound(s) and elucidate exact mechanism of action. PMID- 25272894 TI - Pharmacological evaluation of antihypertensive effect of aerial parts of Thymus linearis benth. AB - Traditionally Thymus linearis Benth. have been used for treatment of various diseases including hypertension. The present study was conducted to evaluate the hypotensive and antihypertensive effect of aqueous methanolic extract of aerial parts of Thymus linearis Benth. in normotensive and hypertensive rats. Acute and subchronic studies were also conducted. The aqueous methanolic extract produced a significant decrease in SBP, DBP, MBP and heart rate of both normotensive and hypertensive rats. LDv, of the extract was found to be 3000 mg/kg. The extract also exhibited a reduction in serum ALT, AST, ALP, cholesterol, triglycerides and LDL levels, while a significant increase in HDL level was observed. It is conceivable therefore, that Thymus linearis Benth. contains certain active compound(s) that are possibly responsible for the observed antihypertensive activity. Moreover, these findings further authenticate the traditional use of this plant in folklore medicine. PMID- 25272895 TI - Safety and efficacy of bone wax in patients on oral anticoagulant therapy. AB - Cardiovascular conditions, apart from neoplastic diseases, remain the major cause of death in developed countries; therefore, the number of patients receiving oral anticoagulants is constantly increasing. Anticoagulant therapy considerably reduced mortality in patients with history of myocardial infarction among others. Although many interventions may be performed without withdrawal of the anticoagulant and tooth extraction was qualified as a procedure of low hemorrhage risk, a majority of dentists refer the patient to a cardiologist several days before the elective tooth extraction to withdraw anticoagulants. The aim of the study was to evaluate the efficacy and safety of bone wax used to stop bleeding after dental procedures in a group of patients on chronic anticoagulant therapy and find an answer to a question, whether it is justified to temporarily withdraw anticoagulants for this type of procedures. The study involved 176 patients on chronic anticoagulant therapy undergoing tooth extraction (154 subjects) or surgical extraction of a retained tooth (48 subjects). After the procedure, in each case the alveolus was filled with bone wax to stop bleeding. In all patients involved in the study bleeding from the alveolus was successfully stopped during the procedure. None of the subjects reported increased bleeding from the operational site after coming back home. Bone wax is a good, efficient, and safe material to block bleeding from the alveolus following tooth extractions, also in patients on chronic anticoagulant therapy. The study demonstrated that withdrawal or adjustment of anticoagulant therapy is not necessary before an elective tooth extraction. PMID- 25272896 TI - Safety of oral ibuprofen--analysis of data from the spontaneous reporting system in Poland. AB - Ibuprofen is a popular over-the-counter, non-steroidal anti-inflammatory medication, frequently used for the relief of fever, headaches, menstrual and other minor pains as well as a major active ingredient in numerous cold preparations. We analyzed sales volume and data obtained from the monitoring of spontaneous reports on the adverse effects of IBUM soft capsules, IBUM Forte soft capsules, and IBUM oral suspension 100 mg/5 mL collected by the manufacturer (PPF HASCO-LEK S.A. Wroclaw, Poland) and National Monitoring Center in Warszawa in the period between October 2002 and June 2012. A total of 19,644,797 units of IBUM soft capsules 200 mg, 5,678,164 units of IBUM Forte soft capsules 400 mg and 4,333,325 units of IBUM oral suspension 100 mg/5 mL (29,656,286 units altogether) produced by PPF HASCO-LEK S.A. Wrodcaw, P'oland were marketed during the period analyzed. There were 5 spontaneous reports regarding these medications registered in Poland in the period analyzed. Forms of oral ibuprofen are very safe medication rarely causing adverse effects; nevertheless, the existing spontaneous monitoring system of adverse effects in Poland is not sensitive enough to detect all adverse effects and needs improvement. PMID- 25272898 TI - [Animal welfare and antibiotic use reduction]. PMID- 25272897 TI - The penetration of sunitinib through the blood-brain barrier after the administration of ciprofloxacin. PMID- 25272900 TI - [Court for owners]. PMID- 25272899 TI - [Perception of animal welfare changes constantly]. PMID- 25272901 TI - [Surveillance]. PMID- 25272902 TI - [Postvaccinal fatal Streptococcus zooepidemicus necrotizing fasciitis in a young dog: a case report]. AB - A 2.5-years-old female mongrel dog was routinely subcutaneously vaccinated. A few hours later mental dullness was noticed by the owner progressing into stupor the next day and resulting in a comatose state and death within 48 hours after vaccination. At post mortem examination, which was extended with histology and bacteriology, a necrotizing fasciitis and bacteremia caused by Streptococcus equi subsp. zooepidemicus were established. In the isolated Streptococcus strain four different superantigens were demonstrated that appeared to be able to produce exotoxins in vitro. Therefore, it is concluded that the minor skin trauma caused by vaccination enabled this strain to gain access to the subcutaneous tissue and to induce a necrotizing fasciitis. This process was complicated with a bacterial septicemia leading to death of the dog within 48 hours. PMID- 25272903 TI - [Horse importation from developing countries and the risk of importing zoonoses]. PMID- 25272904 TI - [Half of the pigs for food consumption are Actinobacillus pleuropneumoniae carriers when slaughtered]. PMID- 25272905 TI - [Dog unfriendly community management touches veterinarian]. PMID- 25272906 TI - [Antibiotics: an easy upgrade for small animal practice]. PMID- 25272907 TI - [Feed management in horse husbandry]. PMID- 25272908 TI - [Prevention of inherited diseases]. PMID- 25272909 TI - [Veterinarian cooperation Dactari: ready for the future]. PMID- 25272910 TI - [Bovine virus diarrhea: unclear vision but lots of damage]. PMID- 25272911 TI - [The Screech owl has it difficult]. PMID- 25272912 TI - Report offers lessons from the Oso landslide. PMID- 25272913 TI - It's personal. PMID- 25272914 TI - Taking a second look at training. PMID- 25272915 TI - Moving beyond reactive safety. PMID- 25272917 TI - Enough already with the preaching! PMID- 25272916 TI - Vacuuming up to prevent dust explosions. PMID- 25272918 TI - New alliance helps with clearing the air. PMID- 25272919 TI - Eliminating the controversy over safety incentive programs. PMID- 25272920 TI - Wellness incentives encourage participation and engagement. PMID- 25272921 TI - The importance of CPR &AED safety training. PMID- 25272922 TI - CPR/AED training isn't enough: we must teach 'response'. PMID- 25272923 TI - What are the costs associated with marijuana legalization? PMID- 25272924 TI - Drug testing & safety: what's the connection? PMID- 25272925 TI - Choosing the right protective footwear. PMID- 25272926 TI - Understanding head protection. PMID- 25272927 TI - Opportunity knocks. PMID- 25272928 TI - Cut costs, not fingers, with an injury & illness prevention program. PMID- 25272929 TI - Keep infections out. PMID- 25272930 TI - Leading the way to leading indicators. PMID- 25272931 TI - Becoming a rising star in safety. PMID- 25272932 TI - Sherlocking safety. PMID- 25272933 TI - Roles of microRNA in vascular diseases in cardiac and pulmonary systems. AB - Coronary artery disease (CAD) and pulmonary arterial hypertension (PAH) are two of the most dangerous vascular diseases. Their etiology and pathogenesis are not yet fully understood, thus it remains difficult to achive great advance in the diagnose, therapy and prognosis techniques. microRNAs (miRNAs), a class of highly conserved, small, noncoding RNAs, critically mediate the post-transcriptional gene modulation, which regulates an array of important physiopathological processes including those occurring in cardiac and pulmonary systems. Thereby manipulation of miRNA expression could potentially be applied therapeutically. In this review, we summarize the current knowledge on the roles of miRNAs in the development of vascular diseases, especially in CAD and PAH, providing a theoretical basis for potential uses of miRNA in diagnosis, prognosis, and therapy in these cardiovascular diseases. PMID- 25272934 TI - Electrochemistry of moexipril: experimental and computational approach and voltammetric determination. AB - The electrochemistry of moexipril (MOE) was studied by electrochemical methods with theoretical calculations performed at B3LYP/6-31 + G (d)//AM1. Cyclic voltammetric studies were carried out based on a reversible and adsorption controlled reduction peak at -1.35 V on a hanging mercury drop electrode (HMDE). Concurrently irreversible diffusion-controlled oxidation peak at 1.15 V on glassy carbon electrode (GCE) was also employed. Potential values are according to Ag/AgCI, (3.0 M KCI) and measurements were performed in Britton-Robinson buffer of pH 5.5. Tentative electrode mechanisms were proposed according to experimental results and ab-initio calculations. Square-wave adsorptive stripping voltammetric methods have been developed and validated for quantification of MOE in pharmaceutical preparations. Linear working range was established as 0.03-1.35 microM for HMDE and 0.2-20.0 microM for GCE. Limit of quantification (LOQ) was calculated to be 0.032 and 0.47 microM for HMDE and GCE, respectively. Methods were successfully applied to assay the drug in tablets by calibration and standard addition methods with good recoveries between 97.1% and 106.2% having relative standard deviation less than 10%. PMID- 25272935 TI - Determination of log P values of new cyclen based antimalarial drug leads using RP-HPLC. AB - Lipophilicity, expressed by log P, is an important physicochemical property of drugs that affects many biological processes, including drug absorption and distribution. The main purpose of this study to determine the log P values of newly discovered drug leads using reversed-phase high-performance liquid chromatography (RP-HPLC). The reference standards, with varying polarity ranges, were dissolved in methanol and analyzed by RP-HPLC using a C18 column. The mobile phase consisted of a mixture of acetonitrile, methanol and water in a gradient elution mode. A calibration curve was plotted between the experimental log P values and obtained log k values of the reference standard compounds and a best fit line was obtained. The log k values of the new drug leads were determined in the same solvent system and were used to calculate the respective log P values by using the best fit equation. The log P vs. log k data gave a best fit linear curve that had an R2 of 0.9786 with Pvalues of the intercept and slope of 1.19 x 10(-6) and 1.56 x 10(-10), respectively, at 0.05 level of significance. Log P values of 15 new drug leads and related compounds, all of which are derivatives of macrocyclic polyamines and their metal complexes, were determined. The values obtained are closely related to the calculated log P (Clog P) values using ChemDraw Ultra 12.0. This experiment provided efficient, fast and reasonable estimates of log P values of the new drug leads by using RP-HPLC. PMID- 25272936 TI - Simultaneous analysis of vitamins B in pharmaceuticals and dietary supplements by capillary electrophoresis hyphenated with triple quadrupole mass spectrometry. AB - The advanced hyphenated method based on capillary electrophoresis (CE) on-line combined with electrospray ionization (ESI) and tandem mass spectrometry (MS/MS, here triple quadrupole, QqQ) was developed and applied in pharmaceutical analysis in this work. Under the optimized CE separation (background electrolyte: 50 mmol/L formic acid with pH 2.05), ESI ionization (sheath liquid: 0.1% v/v formic acid in 50% v/v aq methanol) and QqQ detection (100-160V fragmentor voltage, 15 25eV collision energy, depending on the type of analyte) conditions, highly efficient, reproducible, accurate, sensitive (sub microg/mL LODs) and selective (each analyte was unequivocally specified by two characteristic MS signals, i.e. qualifier, quantifier) determination of vitamins B was achieved. All vitamins B, namely thiamine, riboflavin, nicotinamide, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid and cyanocobalamine, were simultaneously determined in various dosage forms (injection solution, tablets, and effervescent tablets) within ca. 16 min. The main benefits of the proposed CE-ESI-QqQ method in comparison with the CE-UV ones are considerably enhanced sensitivity and selectivity. Other benefits are low cost, simplicity, flexibility and environmental aspects when comparing CE-ESI-QqQ with HPLC-MS. Successful validation and application of the proposed CE-ESI-QqQ method suggest its routine use in highly effective and reliable multi-drug quality control. PMID- 25272937 TI - Oral delivery of insulin using a lipoamino acid nanocarrier system. AB - Lipoamino acid nanocarriers based on the interactions between L-arginine and oleic acid were formulated with the aid of Tween 80 and explored as a novel carrier for the oral administration of insulin. The interaction between oleic acid and L-arginine was confirmed by FTIR, DSC/TGA, viscosity and surface tension measurements. The pharmacological activity of orally administered insulin-loaded nanocarriers (10, 25 and 50 IU/kg) was evaluated in healthy rabbits. Insulin loaded in lipoamino acid nanocarriers was therapeutically active as demonstrated by the remarkable reduction in blood glucose levels after oral administration of the preparation. A blood glucose lowering of 80% was achieved 4 h after administration of the oral insulin preparation. In addition, insulin-loaded nanocarriers decreased glycemia in a dose dependent manner, with the maximum effect noticed with 50 IU/kg. Moreover, a significant effect observed 1 h after administration suggested that these nanocarriers could be considered as a fast acting preparation. These results clearly show that these lipoamino acid nanocarriers hold promising potential for oral delivery of insulin. PMID- 25272938 TI - Toxicity of 50-nm polystyrene particles co-administered to mice with acetaminophen, 5-aminosalicylic acid or tetracycline. AB - We investigated whether nano-sized polystyrene particles affect drug-induced toxicity. The particles, which are widely used industrially, had diameters of 50 (NPP50), 200 (NPP200) or 1000 (NPP1000) nm. The toxic chemicals tested were acetaminophen (APAP), 5-aminosalicylic acid (5-ASA), tetracycline (TC), and sodium valproate (VPA). All treatments in the absence of the nanoparticles were non-lethal and did not result in severe toxicity. However, when mice were injected with APAP, 5-ASA or TC together with polystyrene particles, synergistic, enhanced toxicity was observed in mice injected with NPP50. These synergic effects were not observed in mice co-injected with NPP200 or NPP1000. On the other hand, co-administration of VPA and NPP50, NPP200 or NPP1000 did not elevate toxicity. The results show that NPP50 differs in hepatotoxicity depending on the drug co-administered. These findings suggest that further evaluation of the interactions between polystyrene nanoparticles and drugs is a critical prerequisite to the pharmaceutical application of nanotechnology. PMID- 25272939 TI - Losartan inhibits LPS + ATP-induced IL-1beta secretion from mouse primary macrophages by suppressing NALP3 inflammasome. AB - OBJECTIVES: IL-1beta is a potent proinflammatory, pro-fibrogenetic and pro athrosclerosis cytokine which has been shown to play an important role in an expanding number of noninfectious, chronic inflammatory conditions including cardiovascular disease, renal fibrosis, rheumatoid arthritis and even type 2 diabetes. Losartan is an angiotensin II receptor antagonist widely used for the treatment of hypertension, diabetic nephropathy and congestive heart failure. In this study, we attempted to clarify whether losartan has an inhibitory effect on IL-1beta. To further elucidate the molecular mechanism underlying the anti-IL 1beta property of losartan, we studied the LPS+ATP-induced activation of NALP3 inflammasome which controls the muturation and secretion of IL-1beta. METHODS: LPS and ATP were used to stimulate the release of IL-1beta from thioglycollate elicited macrophages from BALB/c mice. The production of IL-1beta was evaluated by ELISA assay and NALP3, caspase-1, IL-beta mRNA levels were determined by reverse transcription-polymerase chain reaction. RESULTS: In cultured thioglycollate-elicited macrophages, we observed that LPS + ATP greatly enhanced IL-1 beta secretion (6938.00 +/- 83.45; P < 0.05) and the mRNA levels of NALP3, caspase-1 which are two main components of NALP3 inflammasome (60.88 +/- 8.28; 1.31 +/- 0.04, P < 0.05 for both). The macrophages co-cultured with losartan showed low production of IL-1beta (3907.50 +/- 143.61; P < 0.05) and low production of NALP3, caspase-1mRNA (29.82 +/- 6.92; 1.12 +/- 0.05, P < 0.05 for both). Losartan did not reduce IL-1beta mRNA(P > 0.05). CONCLUSIONS: Our results show that the NALP3 inflammasome is up-regulated and activated in the mouse macrophage in response to LPS + ATP stimulation. Losartan is able to suppress the LPS + ATP-induced production of IL-1beta protein. In addition, this effectmay be partially mediated by suppressing NALP3 inflammasome activation. PMID- 25272940 TI - Local anesthetic activity of mixtures of cis- and trans-(2 dimethylaminomethylcycloheptyl)-2-alkoxyphenylcarbamates. AB - In a previous study, we synthesized two homologous series of racemic stereoisomeric cis- and trans-(2-dimethylaminomethylcycloheptyl)-2 alkoxyphenylcarbamates with alkyl chain lengths ranging from C1 to C8 and analyzed their local anesthetic activity. Here, we show that the local anesthetic activities of mixtures of cis-1 and trans-1 stereoisomers are higher than the sum of activities calculated for the individual stereoisomers at all molar fractions. We conclude that an appropriate ratio of cis- and trans-stereoisomers is necessary to achieve the maximum anesthetic activity of the studied stereoisomeric carbamates. PMID- 25272941 TI - Catalpol regulates function of hypothalamic-pituitary-adrenocortical-axis in an Alzheimer's disease rat model. AB - AIMS: To investigate the regulating effects of catalpol on the hypothalamic pituitary- adrenocortical-axis (HPA) in an Alzheimer's disease (AD) rat model. METHODS: Healthy male Wistar Rats were selected. The AD model was generated by orthotopic injection of beta-amyloid 25-35 (Abeta25-35) into the right lateral ventricle. The animals were divided into five study groups: Catalpol at low dose (5 mg/kg), Catalpol at high dose (10 mg/kg), model control group and sham surgery control group, n = 9 respectively. The serum concentration of hydrocortisone (HYD), adrenocorticotropin (ACTH) and corticotropin releasing hormone (CRH) determined by Enzyme-Linked Immunosorbent Assay (ELISA). Structural alterations of the hypothalamus were examined by H&E stain and electron microscope. The CRH receptor 1 (CRHR1) positive neurons were detected with immunohistochemistry. RESULTS: Serum HYD level was significantly increased (p < 0.01), and both ACTH and CRH were dramatically decreased (p < 0.01) in the AD model group rats compared with normal control rats at day 7. Catalpol treatment was able to improve the hormone secretion disorder in AD model group rats compared with the model group (p < 0.01 or p < 0.05) in particular at 21 days. Structure damage of hypothalamus in the AD rat as evidenced less CRHR1 positive neurons, rough endoplasmic reticulum dilation and degranulation, and mitochondrial swelling under electron microscope. Catalpol treatment at both high and low doses was able to alleviate the structure damage of the hypothalamus in the AD rats. CONCLUSIONS: Catalpol could improve the endocrine function of the HPA and alleviate the structural damage of hypothalamus in AD rats. PMID- 25272942 TI - The cytokines (IFN-gamma, IL-2, IL-4, IL-10, IL-17) and Treg cytokine (TGF-beta1) levels in adults with immune thrombocytopenia. AB - Previous studies have indicated that autoimmune diseases might be caused by an imbalance of T helper cells (Th), cytokines, and regulatory T cells (Treg) cytokines. We measured the plasma concentrations of Th1-associated cytokines (IFN gamma, IL-2), Th2 -associated cytokines (IL-4, IL-10), Th17-associated cytokine (IL-17) and Treg -associated cytokine (TGF-beta1) in adult patients with immune thrombocytopenia (ITP) and evaluated their clinical relevance. Plasma IFN-gamma, IL-2, IL-4, IL-10, IL-17 and TGF-beta1 concentrations of 52 ITP patients and 30 age- and sex-matched healthy controls were measured by enzyme-linked immunosorbent assay method (ELISA). Concentration of Th2 cytokines (IL-4 and IL 10) were significantly higher in ITP patients compared to controls (P < 0.05). However, concentrations of Th1 cytokines (IFN-gamma, IL-2), Th17 cytokine (IL-17) and Treg cytokine (TGF-beta1) were lower in ITP patients (P < 0.05). Concentration of IL-17 was significantly higher in chronic ITP patients compared to severe ITP patients (P < 0.05), and no significant difference of cytokine concentration among the other subgroups in ITP patients was found. Among the ITP patients, concentration of IFN-gamma correlated positively and significantly with PAIgG (r = 0.48, P = 0.02). A significant correlation was neither found between other cytokine levels and platelet count, nor between cytokine levels and megakaryocytes number, nor between cytokines levels and PAIgG or GPIIb/IIIa and/or GPIb/IX autoantibodies. The present study demonstrates that an imbalance of Th and Treg cytokines may mediate the pathogenesis of ITP. PMID- 25272943 TI - Inhibitory effect of reinioside C on vascular smooth muscle cells proliferation induced by angiotensin II via inhibiting NADPH oxidase-ROS-ENK1/2-NF-kappaB-AP-1 pathway. AB - The proliferation of vascular smooth muscle cells (VSMCs) induced by angiotensin II (Ang II) plays a vital role in the pathogenesis of arteriosclerosis and restenosis. In the present study, the effect of reinioside C, a main active ingredient of Polygala fallax Hemsl, on proliferation of VSMCs induced by Ang II was investigated. It was found that Ang II (1 microM) markedly stimulated proliferation of VSMCs. Pretreatment of reinioside C (3, 10 or 30 microM) concentration-dependently inhibited the proliferative effect of Ang II. To determine the possible mechanism, NADPH oxidase subunits (Nox-1, Nox-4) mRNA expression, intracellular ROS level, phosphorylation of ERK1/2, NF-kappaB activity, and mRNA expression of AP-1 subunits (c-fos, c-jun) and c-myc were measured. The results demonstrated that reinioside C attenuated Ang II-induced NADPH oxidase mRNA expression, generation of ROS, ERK1/2 phosphorylation, activation of NF-kappaB, and mRNA expression of AP-1 and c-myc in VSMCs in a concentration-dependent manner. The effects of Ang II were also inhibited by diphenyleneiodonium (DPI, the NADPH oxidase inhibitor), PD98059 (the ERK1/2 inhibitor) and pyrrolidine dithiocarbamate (PDTC, the NF-kappaB inhibitor). These results suggest reinioside C attenuates Ang II-induced proliferation of VSMCs by inhibiting NADPH oxidase-ROS-ERK1/2-NF-kappaB-AP-1 pathway. PMID- 25272944 TI - Cardioprotective effects of low-dose combination therapy with rosuvastatin and fasudil in the isolated rat heart. AB - The cardiovascular pleiotropic effects of statins and a Rho-kinase inhibitor (fasudil) could be of interest to prevent myocardial ischemia reperfusion injury (MIRI). In the present study, we investigated whether low-dose rosuvastatin and fasudil, separately not possessing cardioprotection, express cardioprotective effects when combined. The isolated rat hearts underwent 30 min global ischemia and 120 min reperfusion. Rosuvastatin (3 microM) and fasudil (1 microM) were administered 15 min before ischemia. NG-nitro-L-arginine methylester (30 microM) (L-NAME) was given at the onset of reperfusion. Myocardial infarct size, apoptosis, myocardial nitric oxide (NO) content and endothelial nitric oxide synthase (eNOS) expression were evaluated. The combination treatment significantly decreased infarct size and percentage of apoptosis and increased the content of NO and eNOS expression, whereas treatment with rosuvastatin and fasudil alone at the same doses did not lead to cardioprotection. Furthermore, L NAME reversed the cardioprotective effect of rosuvastatin/fasudil combination treatment. In summary, rosuvastatin combined with fasudil treatment had synergistic protective effects against MIRI, which were mediated by increasing eNOS and NO production. This new concept could be valuable in MIRI prevention. PMID- 25272945 TI - Involvement of dopamine D1 receptors of the hippocampal dentate gyrus in spatial learning and memory deficits in a rat model of vascular dementia. AB - We investigated the involvement of dopamine (DA) and its D1 receptors of the hippocampal dentate gyrus (DG) in spatial learning and memory deficits in a rat model of vascular dementia (VD) established by permanent bilateral carotid occlusion. Spatial learning and memory abilities of rats were measured by Morris water maze, and extracellular concentrations of DA in the DG were determined by in vivo microdialysis. The DA concentrations in the DG decreased in the VD rats compared with sham-operated group. Microinjection of SFK38393 (D1 receptor agonist) into the DG attenuates spatial learning and memory deficits in the VD rats. PMID- 25272946 TI - Bioassay-guided isolation of the antinociceptive compounds motiol and beta sitosterol from Scorzonera latifolia root extract. AB - Scorzonera latifolia (Asteraceae) is a plant widely distributed in Central and East Anatolia. A mastic, named yaki sakizi, is prepared from the latex and roots of S. latifolia and similar species. This latex is used in Turkish folk medicine for its analgesic activity, as anthelmintic and against infertility. The aim of this study was to isolate the compounds responsible for the antinociceptive activity of S. latifolia using bioassay-guided fractionation. The methanolic extract of the S. latifolia roots was prepared and subjected to chromatographic purification. Isolated active compounds were identified by means of MS and NMR techniques. Writhing and tail-flick tests were used to determine antinociceptive activity. Motiol and beta-sitosterol were isolated as compounds with promising antinociceptive activity. It is suggested that antinociceptive activity of the plant extract is probably caused by the synergic interaction of the isolated compounds. PMID- 25272947 TI - Plant germination and production of callus from the yellow hornpoppy (Glaucium flavum): the first stage of micropropagation. AB - The yellow hornpoppy, Glaucium flavum Cr. (Fam. Papaveraceae) is a perennial herb, distributed in the Mediterranean region, including Egypt. The plant contains many benzyl isoquinoline alkaloids from the aporphine type such as glaucine, isoboldine, 1-chelidonine, 1-norchelidonine and 3-O-methylarterenol, making it to display various medicinal activities including antitussive, anticancer, antioxidant, antimicrobial, antiviral, hypoglycemic, analgesic, antipyretic, bronchodilator and anti-inflammatory effects. The plant is now rare and endangered in the Egyptian flora due to urban sprawl. The present study looks into Glaucium flavum seeds' in vitro germination as well as the ability of the explants taken from the growing seedlings to form stable callus lines in order to enable micropropagation as a way to save the rare plant. The study also scans the production of different medicinally valuable alkaloids, particularly glaucine, in produced callus. PMID- 25272948 TI - Bis(amino)cyclopropenylidene (BAC) catalyzed aza-benzoin reaction. AB - A bis(amino)cyclopropenylidene (BAC) catalyzed aza-benzoin reaction between aldehydes and phosphinoyl imines has been developed. The reaction is general with a wide range of aromatic aldehydes and aromatic imines. The reaction displays excellent chemoselectivity favoring aza-benzoin products over homobenzoin products. PMID- 25272950 TI - Mammography equipment design: impact on radiographers' practice. AB - OBJECTIVES: Identify radiographers' postures during frequent mammography procedures related to the mammography equipment and patient characteristics. METHODS: A postural task analysis was performed using images acquired during the simulation of mammography positioning procedures. Simulations included craniocaudal/(CC) and mediolateral-oblique/(MLO) positioning in three different settings: radiographers and patients with similar statures, radiographers smaller than the patients and radiographers taller than the patients. Measurements of postural angles were performed by two raters using adequate software and classified according to the European Standard EN1005-4:2005 + A1:2008. RESULTS: The simulations revealed that the most awkward posture in mammography is during the positioning of MLO projection in short-stature patients. Postures identified as causing work-related musculoskeletal disorder (WRMSD) risk were neck extension, arms elevated and the back stooped, presenting angles of 87.2, 118.6 and 63.6, respectively. If radiographers were taller than patients, then the trunk and arm postures were not acceptable. CONCLUSIONS: Working in a mammography room leads to awkward postures that can have an impact on radiographers' health, namely WRMSDs. The results in this study showed that there are non-acceptable postures associated with frequent working procedures in mammography. MLO is the most demanding procedure for radiographer postures and may be related to WRMSDs. Mammography devices should be redesigned considering adjustability for radiographers. MAIN MESSAGES: * Mammography constraints for radiographers in mammography procedures have not been well studied. * Performing mammography leads to awkward postures that can impact radiographers' health. * MLO, the most demanding procedure for radiographers, is possibly related to WRMSDs. PMID- 25272949 TI - Prediction of uridine modifications in tRNA sequences. AB - BACKGROUND: In past number of methods have been developed for predicting post translational modifications in proteins. In contrast, limited attempt has been made to understand post-transcriptional modifications. Recently it has been shown that tRNA modifications play direct role in the genome structure and codon usage. This study is an attempt to understand kingdom-wise tRNA modifications particularly uridine modifications (UMs), as majority of modifications are uridine-derived. RESULTS: A three-steps strategy has been applied to develop an efficient method for the prediction of UMs. In the first step, we developed a common prediction model for all the kingdoms using a dataset from MODOMICS-2008. Support Vector Machine (SVM) based prediction models were developed and evaluated by five-fold cross-validation technique. Different approaches were applied and found that a hybrid approach of binary and structural information achieved highest Area under the curve (AUC) of 0.936. In the second step, we used newly added tRNA sequences (as independent dataset) of MODOMICS-2012 for the kingdom wise prediction performance evaluation of previously developed (in the first step) common model and achieved performances between the AUC of 0.910 to 0.949. In the third and last step, we used different datasets from MODOMICS-2012 for the kingdom-wise individual prediction models development and achieved performances between the AUC of 0.915 to 0.987. CONCLUSIONS: The hybrid approach is efficient not only to predict kingdom-wise modifications but also to classify them into two most prominent UMs: Pseudouridine (Y) and Dihydrouridine (D). A webserver called tRNAmod (http://crdd.osdd.net/raghava/trnamod/) has been developed, which predicts UMs from both tRNA sequences and whole genome. PMID- 25272951 TI - A new muscle glycogen storage disease associated with glycogenin-1 deficiency. AB - We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin 1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1. PMID- 25272955 TI - ReaxFF reactive molecular dynamics on silicon pentaerythritol tetranitrate crystal validates the mechanism for the colossal sensitivity. AB - Recently quantum mechanical (QM) calculations on a single Si-PETN (silicon pentaerythritol tetranitrate) molecule were used to explain its colossal sensitivity observed experimentally in terms of a unique Liu carbon-silyl nitro ester rearrangement (R3Si-CH2-O-R2-> R3Si-O-CH2-R2). In this paper we expanded the study of Si-PETN from a single molecule to a bulk system by extending the ReaxFF reactive force field to describe similar Si-C-H-O-N systems with parameters optimized to reproduce QM results. The reaction mechanisms and kinetics of thermal decomposition of solid Si-PETN were investigated using ReaxFF reactive molecular dynamics (ReaxFF-RMD) simulations at various temperatures to explore the origin of the high sensitivity. We find that at lower temperatures, the decomposition of Si-PETN is initiated by the Liu carbon-silyl nitro-ester rearrangement forming Si-O bonds which is not observed in PETN. As the reaction proceeds, the exothermicity of Si-O bond formation promotes the onset of NO2 formation from N-OC bond cleavage which does not occur in PETN. At higher temperatures PETN starts to react by the usual mechanisms of NO2 dissociation and HONO elimination; however, Si-PETN remains far more reactive. These results validate the predictions from QM that the significantly increased sensitivity of Si-PETN arises from a unimolecular process involving the unusual Liu rearrangement but not from multi-molecular collisions. It is the very low energy barrier and the high exothermicity of the Si-O bond formation providing energy early in the decomposition process that is responsible. PMID- 25272953 TI - A review of peer-mediated social interaction interventions for students with autism in inclusive settings. AB - This review addresses the use of peer-mediated interventions (PMI) to improve the social interaction skills of students with autism spectrum disorder (ASD) in inclusive settings. The purpose of this review is to (a) identify the characteristics and components of peer-mediated social interaction interventions, (b) evaluate the effectiveness of PMI by offering an analysis of intervention results and research design, and (c) suggest directions for future research. Overall, results suggest that PMI is a promising treatment for increasing social interaction in children, adolescents, and young adults with ASD in inclusive settings, with positive generalization, maintenance, and social validity outcomes. Findings also suggest that participant characteristics and the type of social deficit an individual exhibits are important considerations when choosing the optimal configuration of PMI strategies. PMID- 25272952 TI - "Where Does the Circle End?": Representation as a Critical Aspect of Reflection in Teaching Social and Behavioral Sciences in Medicine. AB - OBJECTIVE: This paper describes a reflective learning program within a larger curriculum on behavioral and social science that makes use of close reading, written representation of experience, discussion, and textual response. This response may in turn lead to further reflection, representation, and response in a circular pattern. A unique feature of this program is that it pays attention to the representation itself as the pivotal activity within reflective learning. Using the narrative methods that are the hallmark of this program, faculty writings were analyzed to characterize the essential benefits that derive from these practices. METHODS: In the context of a faculty development seminar on the teaching of behavioral and social sciences in medical curricula, a group of 15 faculty members wrote brief narratives of reflective learning experiences in which they had made use of the methods described above. Their responses were submitted to iterative close reading and discussion, and potential themes were identified. RESULTS: Four themes emerged: writing as attention to self, writing as attention to other, writing as reader/writer contract, and writing as discovery. In each instance, writing provides a new or deepened perspective, and in each case, the dividends for the writer are amplified by the narrative skills of those who read, listen, and respond. CONCLUSIONS: The narrative pedagogy described and modeled herein provides a potentially promising approach to teaching the social, cultural, behavioral, and interpersonal aspects of medical education and practice. Future research will deepen our understanding of the benefits and limitations of this pedagogy and expand our appreciation of its applications. PMID- 25272956 TI - Painful erythematous plaque with vesicles and pustules. PMID- 25272958 TI - Development of a specific immunomagnetic capture-PCR for rapid detection of viable Mycoplasma agalactiae in sheep milk samples. AB - AIMS: To develop an immunomagnetic capture (IMC) to detect viable Mycoplasma agalactiae in routine ovine milk samples. METHODS AND RESULTS: Polyclonal antibodies against two M. agalactiae membrane surface proteins (P80 and P55) were covalently conjugated to magnetic beads (MBs) to form MB-Ab80 and MB-Ab55. Mycoplasma agalactiae cells were captured by a specific antigen-antibody reaction and magnetic separation. Immunomagnetic capture (IMC) was used to isolate and concentrate M. agalactiae in serial decimal dilutions and in artificially contaminated milk to facilitate subsequent detection by PCR. A 375-bp fragment of M. agalactiae was amplified using a pair of M. agalactiae-specific primers in PCR. The limit of detection of IMC-PCR method ranged from 10 to 10(2) CCU ml(-1) when mycoplasmas were resuspended in PBS and from 10(2) to 10(3) CCU ml(-1) when mycoplasmas were resuspended in uncontaminated ovine milk. This study also describes the application of IMC-PCR method to test for M. agalactiae in 516 milk samples collected from sheep with suspected contagious agalactia. Its performance was evaluated relative to culture. CONCLUSIONS: This report has demonstrated for the first time, the effective use of rapid and reliable IMC combined with PCR assay for the detection of viable M. agalactiae. SIGNIFICANCE AND IMPACT OF THE STUDY: The method IMC-PCR provides an alternative to conventional microbiological detection, method and it could be applied to quick detection of M. agalactiae in routine sheep milk samples. PMID- 25272957 TI - Proteins of the VEGFR and EGFR pathway as predictive markers for adjuvant treatment in patients with stage II/III colorectal cancer: results of the FOGT-4 trial. AB - BACKGROUND: Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients. METHODS: The patients' data examined in this study were from the collective of the 5-FU/FA versus 5 FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 alpha, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. RESULTS: Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5 FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5 FU/FA (p=0.106). Patients who were negative for Hif-1 alpha, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 alpha (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination. CONCLUSIONS: The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 alpha negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/- irinotecan in stage II/III colorectal cancer. PMID- 25272959 TI - Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema. AB - We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1*105), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-beta levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2. PMID- 25272960 TI - Complete genomic characterization of a porcine reproductive and respiratory syndrome virus isolate in Xinjiang province of China. AB - Porcine reproductive and respiratory syndrome (PRRS) is a swine disease of major economic importance that causes reproductive and respiratory problems in pigs. In the present study, one strain of porcine reproductive and respiratory syndrome virus (PRRSV) was isolated in Xinjiang province, Northwest China, designated XJu 1. The full-length genome of XJu-1 was found to be 14,987 nucleotides in length, including the poly(A) tail. Comparative analysis with the genomic sequences of type 2 isolates revealed that XJu-1 shared 87.2-99.2 % identity with these isolates, but only 60.4 % with the type 1 virus-Lelystad Virus, indicating that this new Chinese isolate was closely related to the North American PRRSV genotype. XJu-1 was a novel strain with unique deletions in NSP2 region, namely that 150-amino acid deletion in NSP2. The genomic variations of XJu-1 strain provided the basis for further studies of virulence determinants and evolution for PRRSVs. PMID- 25272961 TI - Sesavirus: prototype of a new parvovirus genus in feces of a sea lion. AB - We describe the nearly complete genome of a highly divergent parvovirus, we tentatively name Sesavirus, from the feces of a California sea lion pup (Zalophus californianus) suffering from malnutrition and pneumonia. The 5,049-base-long genome contained two major ORFs encoding a 553-aa nonstructural protein and a 965 aa structural protein which shared closest amino acid identities of 25 and 28 %, respectively, with members of the copiparvovirus genus known to infect pigs and cows. Given the low degree of similarity, Sesavirus might be considered as prototype for a new genus with a proposed name of Marinoparvovirus in the subfamily Parvovirinae. PMID- 25272962 TI - Catalytic oxidation of biorefinery lignin to value-added chemicals to support sustainable biofuel production. AB - Transforming plant biomass to biofuel is one of the few solutions that can truly sustain mankind's long-term needs for liquid transportation fuel with minimized environmental impact. However, despite decades of effort, commercial development of biomass-to-biofuel conversion processes is still not an economically viable proposition. Identifying value-added co-products along with the production of biofuel provides a key solution to overcoming this economic barrier. Lignin is the second most abundant component next to cellulose in almost all plant biomass; the emerging biomass refinery industry will inevitably generate an enormous amount of lignin. Development of selective biorefinery lignin-to-bioproducts conversion processes will play a pivotal role in significantly improving the economic feasibility and sustainability of biofuel production from renewable biomass. The urgency and importance of this endeavor has been increasingly recognized in the last few years. This paper reviews state-of-the-art oxidative lignin depolymerization chemistries employed in the papermaking process and oxidative catalysts that can be applied to biorefinery lignin to produce platform chemicals including phenolic compounds, dicarboxylic acids, and quinones in high selectivity and yield. The potential synergies of integrating new catalysts with commercial delignification chemistries are discussed. We hope the information will build on the existing body of knowledge to provide new insights towards developing practical and commercially viable lignin conversion technologies, enabling sustainable biofuel production from lignocellulosic biomass to be competitive with fossil fuel. PMID- 25272963 TI - A single amino acid substitution affects the substrate specificity of the seryl tRNA synthetase homologue. AB - Recently described and characterized Bradyrhizobium japonicum glycine:[carrier protein] ligase 1 (Bj Gly:CP ligase 1), a homologue of methanogenic type seryl tRNA synthetase (SerRS) is an intriguing enzyme whose physiological role is not yet known. While aminoacyl-tRNA synthetases supply ribosome with amino acids for protein biosynthesis, this homologue transfers the activated amino acid to a specific carrier protein. Despite remarkable structural similarity between the Bj Gly:CP ligase 1 and the catalytic core domain of methanogenic type SerRS, the ligase displays altered and relaxed substrate specificity. In contrast to methanogenic SerRS which exclusively activates serine, the Bj Gly:CP ligase 1 predominantly activates glycine. Besides, it shows low activity in the presence of alanine, but it is incapable of activating serine. The detailed computational study aiming to address this unexpected substrate specificity toward the small aliphatic amino acids revealed the A281G Bj Gly:CP ligase 1 mutant as the most promising candidate with reconstituted catalytic activity toward the larger substrates. The A281G mutation is predicted to increase the active site volume, allowing alanine and serine to establish important hydrogen bonds within the active site, and to adopt an optimal orientation for the reaction. The results were tested by the site-directed mutagenesis experiments coupled with in vitro kinetic assays. It was found that the A281G substitution greatly affects the enzyme specificity and allows efficient activation of both polar and small aliphatic amino acids (serine, glycine and alanine), confirming predictions and conclusions based on molecular dynamics simulations. PMID- 25272964 TI - Temporal changes in soil bacterial diversity and humic substances degradation in subarctic tundra soil. AB - Humic substances (HS), primarily humic acids (HA) and fulvic acids (FA), are the largest constituent of soil organic matter. In microcosm systems with subarctic HS-rich tundra soil (site AK 1-75; approximately 5.6 degrees C during the thawing period) from Council, Alaska, the HA content significantly decreased to 48% after a 99-day incubation at 5 degrees C as part of a biologically mediated process. Accordingly, levels of FA, a putative byproduct of HA degradation, consistently increased to 172% during an identical incubation process. Culture independent microbial community analysis showed that during the microcosm experiments, the relative abundance of phyla Proteobacteria (bacteria) and Euryarchaeota (archaea) largely increased, indicating their involvement in HS degradation. When the indigenous bacteria in AK 1-75 were enriched in an artificial mineral medium spiked with HA, the changes in relative abundance were most conspicuous in Proteobacteria (from 60.2 to 79.0%), specifically Betaproteobacteria-related bacteria. One hundred twenty-two HA-degrading bacterial strains, primarily from the genera Paenibacillus (phylum Firmicutes) and Pseudomonas (class Gammaproteobacteria), were cultivated from AK 1-75 and nearby sites. Through culture-dependent analysis with these bacterial isolates, we observed increasing HS-degradation rates in parallel with rising temperatures in a range of 0 degrees C to 20 degrees C, with the most notable increase occurring at 8 degrees C compared to 6 degrees C. Our results indicate that, although microbial-mediated HS degradation occurs at temperature as low as 5 degrees C in tundra ecosystems, increasing soil temperature caused by global climate change could enhance HS degradation rates. Extending the thawing period could also increase degradation activity, thereby directly affecting nearby microbial communities and rhizosphere environments. PMID- 25272966 TI - Polarisation charge switching through the motion of metal atoms trapped in fullerene cages. AB - The formation of an endohedral fullerene can lead to charge transfer and the generation of a trapped positively charged metal ion. Using Ca@C60 and [Ca@C60](+) endohedral fullerenes as models, density functional theory calculations predict that the motion of a calcium ion within a fullerene is accompanied by large changes in electron density on the surrounding carbon cage. In the case of [Ca@C60](+), partial atomic charge distribution on the carbon cage is split between hemispheres into regions of positive and negative charge as Ca(n+) moves inside the fullerene cage (non-integer n strongly depends on position of the ion). It is proposed that within tethered fullerene cages the movement of partial atomic charge could form the bases of a molecular polarisation storage bit, and that adopted in the form of [Ca@C60](+) the presence of an overall charge may offer a route to either optical or electronic control. PMID- 25272967 TI - Relational victimization, friendship, and adolescents' hypothalamic-pituitary adrenal axis responses to an in vivo social stressor-ERRATUM. PMID- 25272968 TI - Superconductivity of lanthanum revisited: enhanced critical temperature in the clean limit. AB - The thickness dependence of the superconducting energy gap DeltaLa of double hexagonally close packed (dhcp) lanthanum islands grown on W(110) is studied by scanning tunneling spectroscopy, from the bulk to the thin-film limit. Superconductivity is suppressed by the boundary conditions for the superconducting wavefunction on the surface and W/La interface, leading to a linear decrease of the critical temperature Tc as a function of the inverse film thickness. For the thick, bulk-like films, DeltaLa and Tc are 40% larger compared to the literature values of dhcp La as measured by other techniques. This finding is reconciled by examining the effects of surface contamination as probed by modifications of the surface state, suggesting that the large Tc originates in the superior purity of the samples investigated here. PMID- 25272965 TI - An examination of the bidirectional relationship between functioning and symptom levels in patients with anxiety disorders in the CALM study. AB - BACKGROUND: Patients with anxiety disorders suffer marked functional impairment in their activities of daily living. Many studies have documented that improvements in anxiety symptom severity predict functioning improvements. However, no studies have investigated how improvements in functioning simultaneously predict symptom reduction. We hypothesized that symptom levels at a given time point will predict functioning at the subsequent time point, and simultaneously that functioning at a given time point will predict symptom levels at a subsequent time point. METHOD: Patients were recruited from primary-care centers for the Coordinated Anxiety Learning and Management (CALM) study and were randomized to receive either computer-assisted cognitive-behavioral therapy and/or medication management (ITV) or usual care (UC). A cross-lagged panel design examined the relationship between functional impairment and anxiety and depression symptom severity at baseline, 6-, 12-, and 18-month follow-up assessments. RESULTS: Prospective prediction of functioning from symptoms and symptoms from functioning were both important in modeling these associations. Anxiety and depression predicted functioning as strongly as functioning predicted anxiety and depression. There were some differences in these associations between UC and ITV. Where differences emerged, the UC group was best modeled with prospective paths predicting functioning from symptoms, whereas symptoms and functioning were both important predictors in the ITV group. CONCLUSIONS: Treatment outcome is best captured by measures of functional impairment as well as symptom severity. Implications for treatment are discussed, as well as future directions of research. PMID- 25272969 TI - Homologues of insecticidal toxin complex genes within a genomic island in the marine bacterium Vibrio parahaemolyticus. AB - Three insecticidal toxin complex (tc)-like genes were identified in Vibrio parahaemolyticus 13-028/A3, which can cause acute hepatopancreatic necrosis disease in penaeid shrimp. The three genes are a tcdA-like gene (7710 bp), predicted to code for a 284-kDa protein; a tcdB-like gene (4272 bp), predicted to code for a 158-kDa protein; and a tccC3-like gene (2916 bp), predicted to encode a 107-kDa protein. All three predicted proteins contain conserved domains that are characteristic of their respective Tc proteins. By RT-PCR, all three tc-like genes were found to be expressed in this bacterium. Through genome walking and the use of PCR to join contigs surrounding these three genes, a genomic island (87 712 bp, named tc-GIvp) was found on chromosome II localized next to the tRNA Gly. The GC content of this island, which is not found in other Vibrio species, is 40%. The tc-GIvp is characterized to have 60 ORFs encoding regulatory or virulence factors. These include a type 6 secretion protein VgrG, EAL domain containing proteins, fimbriae subunits and assembly proteins, invasin-like proteins, peptidoglycan-binding proteins, and Tc proteins. The tc-GIvp also contains 21 transposase genes, suggesting that it was acquired through horizontal transfer from other organisms. PMID- 25272970 TI - Acute cardiovascular autonomic responses to inhaled particulates. AB - PURPOSE: Harmful effects of inhaled particulates have been established in epidemiologic studies of ambient air pollution. In particular, heart rate variability responses to high levels of environmental tobacco smoke (ETS), similar to responses observed during direct smoking, have been reported. We sought to determine whether such responses could be observed at lower particulate concentrations. METHODS: We monitored cardiovascular responses of non-smoking 21 women and 19 men to work-place-relevant levels of: ETS, cooking oil fumes (Coil), wood smoke (WS), and water vapor as sham control. Responses, tested on three consecutive days (random order of aerosol presentation), were averaged for each subject. RESULTS: Low frequency spectral powers of heart rate and blood pressure rose during recovery from exposure to particulate, but not to sham exposures. At breathing frequencies, spectral power of men's systolic pressure doubled, and baroreflex effectiveness increased, following ETS exposure. An index of sympathetic control of heart rate was more pronounced in men than women, in response to ETS and Coil, compared to WS and sham. CONCLUSIONS: When measured under controlled conditions, autonomic activities in non-smoking men and women exposed to low level, short term, particulate concentrations were similar to those observed during longer term, higher level exposures to ETS and to direct smoking. These increased indexes of sympathetic control of heart rate and peripheral vasomotion followed introduction of particulates by about 15 min. Finally, coupling of heart rate and systolic pressure indicated an increase in baroreflex activity in the response to breathing ETS that was less effective in men than women. PMID- 25272971 TI - Calf venous compliance measured by venous occlusion plethysmography: methodological aspects. AB - PURPOSE: Calf venous compliance (C calf) is commonly evaluated with venous occlusion plethysmography (VOP) during a standard cuff deflation protocol. However, the technique relies on two not previously validated assumptions concerning thigh cuff pressure (P cuff) transmission and the impact of net fluid filtration (F filt) on C calf. The aim was to validate VOP in the lower limb and to develop a model to correct for F filt during VOP. METHODS: Strain-gauge technique was used to study calf volume changes in 15 women and 10 age-matched men. A thigh cuff was inflated to 60 mmHg for 4 and 8 min with a subsequent decrease of 1 mmHg s(-1). Intravenous pressure (P iv) was measured simultaneously. C calf was determined with the commonly used equation [Compliance = beta 1 + 2beta 2 * P cuff] describing the pressure-compliance relationship. A model was developed to identify and correct for F filt. RESULTS: Transmission of P cuff to P iv was 100 %. The decrease in P cuff correlated well with P iv reduction (r = 0.99, P < 0.001). Overall, our model showed that C calf was underestimated when F filt was not accounted for (all P < 0.01). F filt was higher in women (P < 0.01) and showed a more pronounced effect on C calf compared to men (P < 0.05). The impact of F filt was similar during 4- and 8-min VOP. CONCLUSIONS: P cuff is an adequate substitute for P iv in the lower limb. F filt is associated with an underestimation of C calf and differences in the effect of F filt during VOP can be accounted for with the correction model. Thus, our model seems to be a valuable tool in future studies of venous wall function. PMID- 25272972 TI - Cardiorespiratory fitness, respiratory function and hemodynamic responses to maximal cycle ergometer exercise test in girls and boys aged 9-11 years: the PANIC Study. AB - PURPOSE: We aimed to provide comprehensive data on and reference values for cardiorespiratory fitness, respiratory function and hemodynamic responses during and after maximal cycle ergometer test in children. METHODS: The participants were a population sample of 140 children (69 girls) aged 9-11 years. Heart rate (HR) and systolic blood pressure (SBP) were measured from pre-exercise rest to the end of recovery. Respiratory gases were measured directly by the breath-by breath method. Peak workload, HR changes, peak oxygen uptake (VO2), peak oxygen pulse (O2 pulse), peak respiratory exchange ratio (RER) and the lowest ratio of ventilation and carbon dioxide output (VE/VCO2) during the exercise test in girls and boys were presented according to their distributions in 5 categories. RESULTS: HR decreased more during 4-min recovery in boys than in girls (76 vs. 67 beats/min, p < 0.001), whereas SBP decrease was similar in boys and girls (30 vs. 22 mmHg, p = 0.66). Boys had a higher peak VO2 per weight [51.9 vs. 47.6 ml/kg/min, p < 0.001] and per lean mass [67.3 vs. 63.0 ml/kg/min, p < 0.001] than girls. Peak O2 pulse per lean mass was higher in boys than in girls (0.34 vs. 0.31 ml/kg/beat, p < 0.001). There was no difference in the lowest VE/VCO2 during the test between boys and girls (28 vs. 29, p = 0.18). CONCLUSIONS: The indicators of cardiorespiratory fitness were better in boys than in girls. These data enable the evaluation of cardiorespiratory function during and after maximal exercise test and the detection of children with abnormal values. PMID- 25272974 TI - Flawed assumptions used to defend screening mammography. PMID- 25272973 TI - Changing epidemiology of malaria in Sabah, Malaysia: increasing incidence of Plasmodium knowlesi. AB - BACKGROUND: While Malaysia has had great success in controlling Plasmodium falciparum and Plasmodium vivax, notifications of Plasmodium malariae and the microscopically near-identical Plasmodium knowlesi increased substantially over the past decade. However, whether this represents microscopic misdiagnosis or increased recognition of P. knowlesi has remained uncertain. METHODS: To describe the changing epidemiology of malaria in Sabah, in particular the increasing incidence of P. knowlesi, a retrospective descriptive study was undertaken involving a review of Department of Health malaria notification data from 2012 2013, extending a previous review of these data from 1992-2011. In addition, malaria PCR and microscopy data from the State Public Health Laboratory were reviewed to estimate the accuracy of the microscopy-based notification data. RESULTS: Notifications of P. malariae/P. knowlesi increased from 703 in 2011 to 815 in 2012 and 996 in 2013. Notifications of P. vivax and P. falciparum decreased from 605 and 628, respectively, in 2011, to 297 and 263 in 2013. In 2013, P. malariae/P. knowlesi accounted for 62% of all malaria notifications compared to 35% in 2011. Among 1,082 P. malariae/P. knowlesi blood slides referred for PCR testing during 2011-2013, there were 924 (85%) P. knowlesi mono infections, 30 (2.8%) P. falciparum, 43 (4.0%) P. vivax, seven (0.6%) P. malariae, six (0.6%) mixed infections, 31 (2.9%) positive only for Plasmodium genus, and 41 (3.8%) Plasmodium-negative. Plasmodium knowlesi mono-infection accounted for 32/156 (21%) and 33/87 (38%) blood slides diagnosed by microscopy as P. falciparum and P. vivax, respectively. Twenty-six malaria deaths were reported during 2010-2013, including 12 with 'P. malariae/P. knowlesi' (all adults), 12 with P. falciparum (seven adults), and two adults with P. vivax. CONCLUSIONS: Notifications of P. malariae/P. knowlesi in Sabah are increasing, with this trend likely reflecting a true increase in incidence of P. knowlesi and presenting a major threat to malaria control and elimination in Malaysia. With the decline of P. falciparum and P. vivax, control programmes need to incorporate measures to protect against P. knowlesi, with further research required to determine effective interventions. PMID- 25272975 TI - A comparison of three clustering methods for finding subgroups in MRI, SMS or clinical data: SPSS TwoStep Cluster analysis, Latent Gold and SNOB. AB - BACKGROUND: There are various methodological approaches to identifying clinically important subgroups and one method is to identify clusters of characteristics that differentiate people in cross-sectional and/or longitudinal data using Cluster Analysis (CA) or Latent Class Analysis (LCA). There is a scarcity of head to-head comparisons that can inform the choice of which clustering method might be suitable for particular clinical datasets and research questions. Therefore, the aim of this study was to perform a head-to-head comparison of three commonly available methods (SPSS TwoStep CA, Latent Gold LCA and SNOB LCA). METHODS: The performance of these three methods was compared: (i) quantitatively using the number of subgroups detected, the classification probability of individuals into subgroups, the reproducibility of results, and (ii) qualitatively using subjective judgments about each program's ease of use and interpretability of the presentation of results.We analysed five real datasets of varying complexity in a secondary analysis of data from other research projects. Three datasets contained only MRI findings (n = 2,060 to 20,810 vertebral disc levels), one dataset contained only pain intensity data collected for 52 weeks by text (SMS) messaging (n = 1,121 people), and the last dataset contained a range of clinical variables measured in low back pain patients (n = 543 people). Four artificial datasets (n = 1,000 each) containing subgroups of varying complexity were also analysed testing the ability of these clustering methods to detect subgroups and correctly classify individuals when subgroup membership was known. RESULTS: The results from the real clinical datasets indicated that the number of subgroups detected varied, the certainty of classifying individuals into those subgroups varied, the findings had perfect reproducibility, some programs were easier to use and the interpretability of the presentation of their findings also varied. The results from the artificial datasets indicated that all three clustering methods showed a near-perfect ability to detect known subgroups and correctly classify individuals into those subgroups. CONCLUSIONS: Our subjective judgement was that Latent Gold offered the best balance of sensitivity to subgroups, ease of use and presentation of results with these datasets but we recognise that different clustering methods may suit other types of data and clinical research questions. PMID- 25272976 TI - Very preterm birth and foetal growth restriction are associated with specific cognitive deficits in children attending mainstream school. AB - AIM: This study investigated the association of prenatal and neonatal factors with cognitive outcomes in schoolchildren born very preterm without impairments at the age of nine. METHODS: We recruited a prospective regional cohort of 154 very low gestational age (VLGA) children of <32 weeks and 90 term-born comparison children born between November 1998 and November 2002 at Oulu University Hospital, Finland. Cognitive outcome was assessed using an inclusive neuropsychological test repertoire at the age of nine. RESULTS: The final study group comprised 77 VLGA children without cerebral palsy or any cognitive impairment and 27 term-born children. VLGA was associated with a 1.5-point [95% confidence interval (CI) 0.6-2.3] reduction in visuospatial-sensorimotor processing and a 1.2-point (95% CI 0.5-1.9) reduction in attention-executive functions scores. Foetal growth restriction (FGR) was the only clinical risk factor that was associated with cognitive outcome. Children with FGR had a significant decrease in language (1.7 points, 95% CI 0.50-3.0) and memory learning (1.6 points, 95% CI 0.4-2.8) scores. CONCLUSION: Children born very preterm without impairments had poorer performance in specific neurocognitive skills than term-born children. FGR was an independent risk factor for compromised neurocognitive outcome in VLGA children and predicted difficulties in language, memory and learning. PMID- 25272977 TI - Long-term evaluation of periodontal parameters and implant outcomes in periodontally compromised patients: a systematic review. AB - BACKGROUND: The aim of this systematic review is to evaluate the long-term outcomes of patients with periodontitis submitted to periodontal therapy/maintenance and implant placement. METHODS: Studies reporting clinical and/or long-term implant outcomes from partially edentulous patients with periodontitis who were treated and followed periodontal maintenance for >=5 years were considered eligible for the review. Screening of the articles, data extraction, and quality assessment were conducted independently and in duplicate. RESULTS: Search of MEDLINE, EMBASE, and CENTRAL databases resulted in 959 papers, and of them 931 were excluded after title/abstract assessment. The full texts of 28 potentially eligible publications were screened, but only 10 studies met inclusion criteria. Most of the included studies (77.8%) presented a medium/high methodologic quality. The results demonstrated that patients with a diagnosis of periodontitis had satisfactory implant outcomes. Implant survival was high (92.1%) within studies reporting 10 years of follow-up. Parameters related to probing depth, clinical attachment level, and bone loss around teeth increased the occurrence of peri-implantitis and implant loss. Non-attendance to periodontal maintenance and smoking habits were also associated with less favorable implant outcomes. CONCLUSIONS: This systematic review confirmed that implant therapy can be successfully used in patients with a diagnosis of periodontitis who underwent proper therapy and regular periodontal maintenance. Residual pockets, non-attendance to the periodontal maintenance program, and smoking were considered to be negative factors for the long-term implant outcomes. PMID- 25272978 TI - Role of transforming growth factor-beta1 in cyclosporine-induced epithelial-to mesenchymal transition in gingival epithelium. AB - BACKGROUND: It has been proposed that cyclosporin A (CsA) may induce epithelial to-mesenchymal transition (EMT) in gingiva. The aims of the present study are to confirm the notion that EMT occurs in human gingival epithelial (hGE) cells after CsA treatment and to investigate the role of transforming growth factor beta1 (TGF-beta1) on this CsA-induced EMT. METHODS: The effects of CsA, with and without TGF-beta1 inhibitor, on the morphologic changes of primary culture of hGE cells were examined in vitro. The changes of protein and messenger RNA (mRNA) expressions of two EMT markers (E-cadherin and alpha-smooth muscle actin) in the hGE cells after CsA treatment with and without TGF-beta1 inhibitor were evaluated with immunocytochemistry and real-time polymerase chain reaction. RESULTS: The epithelial cells became spindle-like, elongated, and disassociated from neighboring cells and lost their original cobblestone monolayer pattern when CsA was added. However, the epithelial cells stayed in their original cobblestone morphology with treatment of TGF-beta1 inhibitor on top of the CsA treatment. When CsA was given, the protein and mRNA expressions of E-cadherin and alpha-SMA were significantly altered, and these alterations were significantly reversed with pretreatment of TGF-beta1 inhibitor. CONCLUSIONS: CsA could induce Type 2 EMT in gingiva by changing the morphology of epithelial cells and altering the EMT markers/effectors. The CsA-induced gingival EMT is dependent or at least partially dependent on TGF-beta1. PMID- 25272979 TI - Immediate loading of mandibular overdentures supported by one-piece, direct metal laser sintering mini-implants: a short-term prospective clinical study. AB - BACKGROUND: Only a few studies have dealt with immediately loaded, unsplinted mini-implants supporting ball attachment-retained mandibular overdentures (ODs). The aim of this study is to evaluate treatment outcomes of ball attachment retained mandibular ODs supported by one-piece, unsplinted, immediately loaded, direct metal laser sintering (DMLS) mini-implants. METHODS: Over a 4-year period (2009 to 2012), all patients referred to the Dental Clinic, University of Varese, and to a private practice for treatment with mandibular ODs were considered for inclusion in this study. Each patient received three or four DMLS mini-implants. Immediately after implant placement, a mandibular OD was connected to the implants. At each annual follow-up session, clinical and radiographic parameters were assessed, including the following outcome measures: 1) implant failures; 2) peri-implant marginal bone loss; and 3) complications. Statistical analysis was conducted using a life-table analysis. RESULTS: A total of 231 one-piece DMLS mini-implants were inserted in 62 patients. After 4 years of loading, six implants failed, giving an overall cumulative survival rate of 96.9%. The mean distance between the implant shoulder and the first visible bone-to-implant contact was 0.38 +/- 0.25 and 0.62 +/- 0.20 mm at the 1- and 4-year follow-up examinations, respectively. An incidence of 6.0% of biologic complications was reported; prosthetic complications were more frequent (12.9%). CONCLUSIONS: Within the limits of this study, it can be concluded that the immediate loading of one-piece, unsplinted, DMLS titanium mini-implants by means of ball attachment supported mandibular ODs is a successful treatment procedure. Long-term follow-up studies are needed to confirm these results. PMID- 25272980 TI - Bone demineralization with citric acid enhances adhesion and spreading of preosteoblasts. AB - BACKGROUND: Previous studies have demonstrated that bone demineralization can improve consolidation in bone grafts. The biologic mechanisms underlying this phenomenon remain unclear. METHODS: Twelve adult male guinea pigs were used in this experiment. Forty-five bone samples removed from the calvaria of nine animals were divided in groups (n = 9) according to the time of demineralization with citric acid (50%, pH 1): 15, 30, 90, and 180 seconds and non-demineralized samples (control). Preosteoblasts (MC3T3-E1) were cultured on the bone samples for 24, 48, and 72 hours (n = 3). Fifteen samples removed from the remaining three animals were analyzed by scanning electron microscopy/energy dispersive spectrometry (SEM/EDS) after demineralization (n = 3). RESULTS: The number of preosteoblasts increased significantly with time in all groups. The bone surface area covered by these cells increased with time, except in the control group. Intragroup differences occurred between 24 and 72 hours (P < 0.05). Samples demineralized for 30 seconds showed greater area covered by preosteoblast cells than for the other times of demineralization in all periods of cell culture (P < 0.05) without a statistically significant difference compared with 15 seconds. SEM/EDS showed diminished content of calcium (Ca) after 15 seconds of demineralization, but the Ca content increased after 180 seconds of demineralization (P < 0.05). The phosphorus (P) amount increased significantly only after 30 seconds of demineralization (P < 0.5). The sulfur (S) content was increased in demineralized samples in relation to non-demineralized ones, reaching the highest level after 90 seconds, when the difference became significant in relation to all the other times of demineralization (P < 0.05). Magnesium (Mg) content did not differ significantly between demineralized and non demineralized samples. CONCLUSIONS: Bone surfaces demineralized for 30 seconds increased the spreading of preosteoblasts as well as the surface area covered by these cells. Bone demineralization deserves to be studied in periodontal and maxillofacial regenerative procedures. PMID- 25272981 TI - Evaluation of the osteogenic potential of growth factor-rich demineralized bone matrix in vivo. AB - BACKGROUND: The study evaluates the osteogenic properties and biocompatibility of growth factor-rich demineralized bone matrix (GDBM) by comparing with cancellous mineralized bone matrix (CMBM) and anorganic bovine bone matrix (ABBM). METHODS: Thirty-six Sprague-Dawley rats were used (n = 6/group/time point). To assess biocompatibility and osteoinductivity, the respective bone matrices were randomly placed in subcutaneous pouches for 7 and 28 days and evaluated by histology and osteopontin expression. Osteoconductivity was assessed by randomly implanting respective bone matrices in osteotomies on femurs for 14 and 28 days and evaluated by microcomputed tomography and histology. RESULTS: Neither acute inflammation nor mineralized tissue was noted in any of the subcutaneous specimens, whereas expression of osteopontin was more prominent in the GDBM group. Among the femoral specimens, the greatest relative bone volume (bone volume [BV] divided by trabecular volume [TV]) and trabecular thickness was noted in the ABBM group at both time points, whereas less BV/TV was noted in GDBM group at day 14. Residual matrix particles were noted in all examined groups at both time points, without significant differences regarding defect fill between groups. The GDBM group presented similar levels of newly formed bone compartment and marrow space to those of the ABBM group. CONCLUSIONS: GDBM demonstrated acceptable biocompatibility and osteogenic potential comparable to ABBM in vivo. Further investigations in a more clinically relevant model are warranted. PMID- 25272982 TI - Increased expression of interleukin (IL)-35 and IL-17, but not IL-27, in gingival tissues with chronic periodontitis. AB - BACKGROUND: Interleukin (IL)-35 plays an important role in immune regulation through the suppression of effector T-cell populations, including T-helper 17 (Th17) cells. Although Th17 cells and IL-17 are involved in the pathogenesis of periodontitis, the level of IL-35 in inflamed periodontal tissues is unclear. Here, IL-35, IL-17, and IL-27 production/expression in gingival crevicular fluid (GCF) and human gingival tissue were investigated. METHODS: GCF samples were collected from buccal (mesial, center, and distal) sites of teeth from patients with chronic periodontitis (CP) and healthy controls and were analyzed by enzyme linked immunosorbent assay for IL-35 (periodontitis, n = 36; healthy, n = 30) and IL-17 (periodontitis, n = 16; healthy, n = 13). Gingival tissue, including sulcus/pocket epithelium and underlying connective tissue, was collected from an additional 10 healthy participants and 10 patients with CP and were analyzed by quantitative polymerase chain reaction (qPCR) for Epstein Barr virus-induced gene 3 (EBI3), IL12A, and IL17A. IL27p28 was also tested by qPCR. RESULTS: IL-35 and IL-17 were significantly higher in GCF from patients with periodontitis than healthy participants (P <0.01, P <0.05, respectively). In both healthy participants and those with periodontitis, positive correlations were found among IL-35 and probing depth and clinical attachment level (CAL) as well as between IL 17 and CAL. EBI3, IL12A (components of IL-35), and IL17A messenger RNA expression levels were significantly higher in inflamed gingival tissue than in healthy control tissues (P <0.05). IL27p28 was not detected in any sample, suggesting that IL-27 is not produced in large quantities in periodontal tissue. CONCLUSION: IL-35 and IL-17, but not IL-27, may play important roles in the pathogenesis of periodontitis. PMID- 25272984 TI - Diversity of nematodes in the yellow-necked field mouse Apodemus flavicollis from the Peripannonic region of Serbia. AB - Up to six nematode species were identified from 86 specimens of the yellow-necked field mouse Apodemus flavicollis from three mountainous localities known as Avala, Cer and Liskovac in Serbia. The highest prevalence of infection of 97% was recorded from Mt. Avala. Only one nematode species, Syphacia frederici, occurred in all three localities. There was complete overlap in nematode species from Mts. Avala and Liskovac, whereas the taxonomic distinctness of Mt. Cer was seen in the presence of the insect-transmitted species Rictularia proni. Locality was a statistically significant factor in all the best-fitted generalized linear models of variation in abundances. The highest level of both species richness and parasite alpha diversity (Shannon's H= 1.47) was found in the easternmost Mt. Liskovac, whereas the diversity indices were lowest for the westernmost Mt. Cer (Shannon's H= 0.48). In view of this geographical difference, the beta diversity indices were calculated along a west to east longitudinal gradient. PMID- 25272983 TI - Assisted reproductive outcomes of male cancer survivors. AB - PURPOSE: The objective of our study was to evaluate the reproductive outcome of male cancer survivors treated with intracytoplasmic sperm injection (ICSI) using cryopreserved sperm and compare it with the same treatment in non-cancer males. METHODS: We retrospectively analyzed database derived from cancer and non-cancer patients undergoing sperm cryopreservation from August 2008 to August 2012 at a university-based center. We evaluated the reproductive outcome of those cancer and non-cancer patients that had frozen sperm and returned subsequently to the clinic for assisted reproduction. RESULTS: We studied 272 males with cancer and 296 infertile males. The most prevalent types of cancer in our cohort were lymphoma (25.3 %), testicular cancer (19.2 %), leukemia (7.3 %), and other malignancies including sarcoma, gastrointestinal, and central nervous system malignancies (48.2 %). The use rate of cryopreserved sperm was 10.7 % for cancer patients and 30.7 % for non-cancer patients. The mean age of males with cancer who returned to the clinic for fertility treatment was 36.7 +/- 6 years, and the diagnoses were testis cancer (43.4 %), lymphoma (36.9 %), leukemia (13 %), and other malignancies (6.7 %). Live birth rate of the cancer cohort was 62.1 %, which was higher than that of the normospermic non-cancer population (p < 0.0047). CONCLUSIONS: The use rate of cryopreserved sperm from oncofertility preservation cases is at around 10 %. The live birth rate using assisted reproductive technologies among these patients is at least comparable to that of the non-cancer population. IMPLICATIONS FOR CANCER SURVIVORS: To our knowledge, this was the first comparative study of male cancer survivors treated with ICSI using cryopreserved sperm, which were compared to non-cancer males undergoing the same treatment. Male fertility preservation is a highly valued service that should be strongly encouraged prior to beginning cytotoxic cancer treatment. These results can help healthcare professionals in oncology to improve the quality of counseling on fertility preservation when managing young men with newly diagnosed cancer that require gonadotoxic treatment. PMID- 25272985 TI - Relationship between serum symmetric dimethylarginine concentration and glomerular filtration rate in cats. AB - BACKGROUND: Direct measurement of glomerular filtration rate (GFR) is the preferred method to assess renal function in cats, but it is not widely used in the diagnosis of chronic kidney disease (CKD). In cats with CKD, symmetric dimethylarginine (SDMA) has been shown to increase and to correlate with plasma creatinine concentrations. HYPOTHESIS: In cats, reduced GFR corresponds with increased serum SDMA concentration. ANIMALS: The study group consisted of ten client-owned cats whose GFR had been measured previously. Cats ranged in age from 11.1 to 16.9 years; both azotemic and nonazotemic animals were included. METHODS: Glomerular filtration rate was determined for each cat by plasma iohexol clearance using the three sample slope-intercept method, and serum SDMA concentration was measured by liquid chromatography-mass spectrometry. RESULTS: A linear relationship was observed between GFR and the reciprocal of serum SDMA concentration (R(2) = 0.82, P < .001). A similar relationship was found between GFR and the reciprocal of plasma creatinine concentration (R(2) = 0.81, P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Increased serum SDMA concentrations were observed in cats with reduced renal function as determined by direct measurement of GFR. This finding indicates that SDMA could have clinical applications in the diagnosis of CKD in cats. PMID- 25272986 TI - [Penis-preserving surgery in patients with primary penile urethral cancer]. AB - BACKGROUND: Primary urethral cancer in males is a rare entity with only approximately 800 cases described, which is why it is difficult to formulate evidence-based guidelines for treatment. For tumors in the pT2 stage with a localization distal to the membranous urethra, a penis-preserving operation can be carried out. METHODS: In the period from November 2006 to February 2014 a total of 4 patients with primary urethral cancer underwent a penis-preserving urethral resection. The tumor characteristics and treatment results were collated retrospectively. RESULTS: Of the four patients one had a transitional cell carcinoma of the mid-penile urethra in stage pT2 G2. In two out of the four patients a squamous cell carcinoma (PEC) was present in the mid-penile urethra in stages pT2 G2 and pT2 G3, respectively, with concomitant carcinoma in situ (CIS). The fourth patient had a PEC of the fossa terminalis in stage pT2 G2. Initially all patients underwent a penis-preserving resection. In one case, despite an initial R0 resection a local recurrence occurred and a complete penectomy was performed. Irradiation and lymphadenectomy were not carried out. At a mean follow up of 37 months all patients are currently in complete remission. CONCLUSION: Primary penile urethral cancer can be treated by a penis-preserving operation. Close follow-up is essential because recurrence can arise despite an initial R0 resection. PMID- 25272987 TI - [Documentation quality of histopathology reports of prostate needle biopsies: a snapshot]. AB - BACKGROUND: A standardized assessment of findings from prostate needle biopsies in pathology is of great importance for the individual recommendations for therapy of patients with prostate cancer. To this end criteria were developed which are formulated as recommendations in the S3 guidelines for prostate cancer and in joint instructions of the Bundesverband Deutscher Pathologen (BDP, "National Association of German Pathologists") and the Deutsche Gesellschaft fur Pathologie (DGP, "German Society of Pathology"). In this article the findings from tumor positive prostate needle biopsies taken from various institutes in Germany, were investigated exclusively to determine to what extent the recommended parameters were followed. MATERIAL AND METHODS: The study encompassed the findings from 91 patients with a mean age of 65.3 years from whom an average of 9.3 biopsy samples from different regions of the prostate were submitted. All diagnosed tumors corresponded to a standard type adenocarcinoma according to the classification of the World Health Organization (WHO) which was detected in an average of 2.5 biopsy regions per patient. The assessment was made from H & E stained serial sections which was supplemented in 11 (12.1%) cases by special staining methods and in 40 (44%) cases by immunohistochemical staining techniques. The length of the needle biopsy was documented in 88 (96.7%) cases and the tumor spread also in 88 cases. The tumor stage was reported in 16 cases (17.6%). RESULTS: The Gleason grading score (GS) was reported in all 91 cases whereby the old GS was explicitly used in 1 case and the modified GS in all other cases. The allocated GS ranged from 4 to 10 whereby 8 cases were graded as <=5, 46 as GS grade 6, 27 as GS grade 7 and 10 as GS >7. Out of 45 cases with several positive biopsy samples, 38 were uniformly graded (84.4%), 6 out of the 7 samples which were not uniformly graded were allocated a GS of 6 or 7 and 1 sample was graded as GS 6-9. In 64 cases (70.3%) the conventional 3-stage WHO grading (n=42) and the Helpap grading (n=22) were additionally used. The WHO and Helpap grading scores were found to be highly correlated with the GS grading scores and the Union for International Cancer Control (UICC) grading scores derived from it (chi2-test, p<0.001), although surprising allocations were selected in isolated cases. CONCLUSION: In total, the only serious deficits were that in three cases (3.3%) no information was supplied on the estimated spread of the tumor in the tumor positive biopsies because this information can be decisive for therapy decisions, particularly for the selection of an active surveillance strategy. Also a relatively large number of cases were assigned a GS score <= 5 which is not recommended in the modified Gleason grading. Furthermore, translation of the GS into the other grading forms used revealed that the biological assessment of the GS showed clear differences between the various participating institutes. In conclusion, the findings of the pathologists as a rule incorporated all the parameters necessary for a therapy decision in accordance with the guidelines so that they can be considered comprehensive and completely valid apart from a few exceptions. PMID- 25272988 TI - [Complex residual tumors after chemotherapy of nonseminomatous germ cell tumors. Laparoscopic management - limits and chances]. AB - PURPOSE: Laparoscopic retroperitoneal lymph node dissection (L-RPLND) is often required in patients with metastatic nonseminomatous germ cell tumors (NSGCT) and residual tumors after chemotherapy. Laparoscopy has become established as a safe procedure in the surgical management of these tumors. Due to the rapid development of laparoscopy, complex retroperitoneal and even intrathoracic residuals can also be treated in high volume centers. PATIENTS AND METHODS: This study included 21 retrospectively identified NSGCT and seminoma patients (mean age 29 years) with metastatic disease and clinical stage (CS) IIA-IIIB. A bilateral L-RPLND was performed in all male patients between 2009 and 2014. In 19 patients an infiltration of the great vessels was detected during surgery and vascular reconstruction was necessary. In 2 patients an intrathoracic residual 5.4 cm and 7 cm in size, respectively, was diagnosed during follow-up. Exclusion criteria for L-RPLND were positive tumor markers after chemotherapy, patients with local recurrence after previous open L-RPLND and patients with excessive vascular involvement. RESULTS: In this series no conversions to open surgery were necessary. The mean tumor size post-chemotherapy was 3.6 cm (range 1.5-9.7 cm). The mean measured blood loss was 294 ml (range 50-1000 ml). The mean hospitalization time was 6 days (range 3-9 days) and mean follow-up was 16 months (range 1-37 months). No complications higher than grade II (Clavien-Dindo classification) were registered in the immediate postoperative course. During the follow-up period no in-field recurrences were registered. CONCLUSION: The L-RPLND seems to be a safe alternative surgical procedure for certain complex residuals with vascular involvement after chemotherapy of testicular cancer. Bilateral L RPLND is technically feasible and reproducible under guaranteed oncological principles. An infiltration of the great vessels and also intrathoracic residuals can be managed in selected patients without compromising the clinical and oncological course. PMID- 25272989 TI - In vitro oxidative metabolism of cajaninstilbene Acid by human liver microsomes and hepatocytes: involvement of cytochrome p450 reaction phenotyping, inhibition, and induction studies. AB - Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid), an active constituent of pigeonpea leaves, an important tropical crop, is known for its clinical effects in the treatment of diabetes, hepatitis, and measles and its potential antitumor effect. In this study, the effect of the cytochrome P450 isozymes on the activity of CSA was investigated. Two hydroxylation metabolites were identified in the study. The reaction phenotype study showed that CYP3A4, CYP2C9, and CYP1A2 were the major cytochrome P450 isozymes in the metabolism of CSA. The metabolic food-drug interaction potential was also evaluated in vitro. The effect of CSA inhibition/induction of enzymatic activities of seven drug-metabolizing CYP450 isozymes in vitro was estimated by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques. CSA showed different inhibitory effects on different isozymes. CSA reversibly inhibited CYP3A4 and CYP2C9 activities in human liver microsomes with IC50 values of 28.3 and 31.3 MUM, respectively, but exhibited no inhibition activities to CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP2E1. CSA showed a weak effect on CYP450 enzymes in a time-dependent manner. CSA did not substantially induce CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations up to 30 MUM in primary human hepatocytes. The results of our experiments may be helpful to predict clinically significant food-drug interactions when other drugs are administered in combination with CSA. PMID- 25272990 TI - Cytological cycles and fates in Psidium myrtoides are altered towards new cell metabolism and functionalities by the galling activity of Nothotrioza myrtoidis. AB - The morphogenesis of galls occurs by the redifferentiation of cells that assume new functions in the modified host plant organs. The redifferentiated cells in the galls of Nothotrioza myrtoidis on Psidium myrtoides have low complexity metabolism and are photosynthesis-deficient. These galls were studied in search for evidences of the establishment of new cell cycles and fates and cytological gradients that corroborate their metabolic profile. Young and mature leaves of P. myrtoides and leaf galls induced by N. myrtoidis at different developmental stages were collected along 24 months and analyzed under light and transmission electron microscopy. The leaves of P. myrtoides are long-lasting and did not senesce within the analyzed period, while the galls have a shorter cycle, and senesce within 1 year. A homogenous parenchyma is established by a "standby redifferentiation" of the chlorophyllous tissues, and sclerenchyma cells redifferentiate from parenchyma cells in the outer cortex of the mature galls. The lack of organelles, the underdeveloped lamellation of chloroplasts, and the occurrence of few plastoglobules are related to the photosynthetic deficiency of the galls. No cytological gradients were observed, but the organelle-rich cells of the vascular and perivascular parenchymas are similar to those of the nutritive tissues of galls induced by other insect taxa. These cells nearest to the feeding sites of N. myrtoidis present higher metabolism and well-developed apparatus for the prevention of oxidative stress. The features herein described corroborate the low metabolic profile of the galls as the cell cycles and fates of P. myrtoides are manipulated for completely new functionalities. PMID- 25272991 TI - A quantitative assessment of the association between 1425G/A polymorphism in PRKCH and risk of stroke. AB - Previous studies suggested an association between 1425G/A polymorphism in PRKCH and stroke risk, but the results were inconsistent. To obtain a more precise estimation, we carried out a meta-analysis to analyze the effect of 1425G/A SNP in PRKCH on stroke risk. We searched PubMed, ISI Web of Science, Chinese Biomedical Database, China National Knowledge Infrastructure and WANFANG Data for all eligible case-control studies through April 2014. The odds ratios (ORs), together with the 95% confidence intervals (CIs), were calculated to evaluate the strength of association between 1425G/A SNP and stroke risk. Overall, seven eligible studies involving a total of 4,574 cases and 5,471 controls were included in our meta-analysis. The results showed that the variant genotypes of 1425G/A polymorphism in PRKCH were significantly associated with a higher risk of stroke in all genetic models (GA vs. GG: OR 1.35, 95% CI 1.24-1.47, P < 0.001; AA vs. GG: OR 1.50, 95% CI 1.24-1.82, P < 0.001; GA/AA vs. GG: OR 1.37, 95% CI 1.26 1.49, P < 0.001; AA vs. GA/GG: OR 1.35, 95% CI 1.12-1.62, P = 0.002; A vs. G: OR 1.29, 95% CI 1.21-1.39, P < 0.001). In the subgroup analysis, significantly increased risks were also observed for ischemic stroke, larger sample size (>1,000) and population-based studies. The result of our meta-analysis indicated that the 1425G/A SNP in PRKCH may contribute to susceptibility of stroke, especially for ischemic stroke. PMID- 25272993 TI - Doctor who prescribed Viagra for himself is struck off. PMID- 25272995 TI - The relationship between parents' poor emotional health status and childhood mood and anxiety disorder in Florida children, national survey of children's health, 2011-2012. AB - The purpose of this study was to examine how parents' emotional health relates to childhood mood and anxiety disorder among Florida children in the 2011-2012 National Survey of Children's Health. Analyses were restricted to 1,241 Florida children 6-17 years of age. Childhood mood and anxiety disorder was defined as a parent-reported diagnosis of current depression or anxiety. Parents' emotional health status was a composite measure of the lowest reported emotional health of any parent in the household. To assess the association between parents' emotional health and childhood mood and anxiety disorder, bivariate and multivariate logistic regression analyses were performed. Nearly 5 % of Florida children had a mood or anxiety disorder in 2011-2012. Children living with a parent in poor emotional health were significantly more likely to have a mood or anxiety disorder compared to children living with a parent in good emotional health (OR 5.01; 95 % CI 1.89, 13.29). After adjusting for covariates, this association remained substantial and significant (aOR 4.33; 95 % CI 1.49, 12.57). Findings presented here are consistent with national findings and emphasize the strong link between parents' emotional health status and childhood mood and anxiety disorders. To address the mental health of children in the state of Florida, Florida public health initiatives should consider family processes and child level characteristics. PMID- 25272994 TI - Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study. AB - Venous thromboembolism [TE] is a multifactorial disease, and protein S deficiency [PSD] constitutes a major risk factor. In the present study the prevalence of PSD and the clinical presentation at TE onset in a cohort of children is reported. In 367 unselected paediatric patients with TE (age 0.1-18 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Thirty of 367 paediatric patients (8.2 %) derived from 27 families had PSD. Mean age at first TE onset was 14.5 years (range 0.1 to 18). Thrombotic locations were cerebral veins (n=8), calf vein TE (n=3) deep veins (DVT) of the leg (n=12), DVT & pulmonary embolism (n=5) and intra-cardiac veins (n=1) or purpura fulminans (n=1). PSD co-occurred with the factor 5 mutation at rs6025 or the homozygous factor 2 susceptibility variant at rs1799963 in one case each. The Heerlen polymorphism detected in five children presented with milder PSD. In 18 patients (60 %) a concomitant risk factor for TE was identified. A second TE event within primarily healthy siblings occurred in three of 27 PSD families (11.0 %). In this cohort of children with symptomatic TE, the prevalence of PSD adjusted for family status was 7.4 %. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population. PMID- 25272992 TI - Air pollution exposure and lung function in highly exposed subjects in Beijing, China: a repeated-measure study. AB - BACKGROUND: Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM(2.5) and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China. METHODS: The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM(2.5), and nine elemental components of PM(2.5) during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM(2.5) as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase. RESULTS: The two groups had high and overlapping exposure distributions with mean personal PM(2.5) of 94.6 MUg/m3 (IQR: 48.5 126.6) in office workers and 126.8 MUg/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM(2.5). However, FEV1 showed negative associations with concentrations of four elements: Si (-3.07%, 95% CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95% CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95% CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95% CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative associations with concentrations of three elements: Si (-3.23%, 95% CI: -5.61; 0.79), Al (-3.26%, 95% CI: -5.73; -0.72), and Ca (-1.86%, 95% CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workers. CONCLUSION: Selected elemental components of PM(2.5) showed effects on lung function that were not found in analyses of particle levels alone. PMID- 25272996 TI - Induction rates and delivery outcomes after a policy limiting elective inductions. AB - The purpose of this study was to assess induction rates, maternal, and neonatal outcomes following adoption of a policy prohibiting elective inductions at less than 39 weeks gestation and inductions between 39 and 41 weeks with an unfavorable cervix. A retrospective cohort study of all deliveries greater than or equal to 37 weeks gestation was conducted 1 year prior to through 1 year after implementation of the induction policy. Induction rates before and after the policy were calculated as the primary outcome while maternal and neonatal conditions were assessed as secondary outcomes. Elective inductions (p = 0.016), elective inductions less than 39 weeks gestation (p = 0.020), and elective inductions 39-40 weeks and 6 days gestation with an unfavorable cervix (p = 0.031) decreased significantly following adoption of the policy. Maternal and neonatal outcomes, including rates of cesarean deliveries, postpartum hemorrhage, chorioamnionitis, and neonatal intensive care unit admissions remained unchanged, though this study was not adequately powered to detect differences in these outcomes. An institutional induction policy was associated with a reduction in elective inductions prior to 39 weeks and up to 40 weeks and 6 days with an unfavorable cervix. These reductions were not accompanied by change in maternal or neonatal outcomes at our institution. PMID- 25272998 TI - The 125th regional meeting (kinki area). PMID- 25272997 TI - Restoration of singularities in reconstructed phase of crystal image in electron holography. AB - Off-axis electron holography can be used to measure the inner potential of a specimen from its reconstructed phase image and is thus a powerful technique for materials scientists. However, abrupt reversals of contrast from white to black may sometimes occur in a digitally reconstructed phase image, which results in inaccurate information. Such phase distortion is mainly due to the digital reconstruction process and weak electron wave amplitude in some areas of the specimen. Therefore, digital image processing can be applied to the reconstruction and restoration of phase images. In this paper, fringe reconnection processing is applied to phase image restoration of a crystal structure image. The disconnection and wrong connection of interference fringes in the hologram that directly cause a 2pi phase jump imperfection are correctly reconnected. Experimental results show that the phase distortion is significantly reduced after the processing. The quality of the reconstructed phase image was improved by the removal of imperfections in the final phase. PMID- 25272999 TI - The 130th regional meeting (kanto area). PMID- 25273000 TI - Historical analysis in pediatric psychology: the influence of societal and professional conditions on two early pediatric psychology articles and the field's subsequent development. AB - The field of pediatric psychology arose in the 1960s in response to a variety of societal and professional needs. 2 seminal articles written during this time, by Jerome Kagan (1965) and Logan Wright (1967), played key roles in the field's development. However, their efficacy in galvanizing a response from medical professionals and psychologists had much to do with broad-ranging developments in pediatric public health, intraprofessional changes among medical specialties, and a growing preoccupation with "psychosocial" and parenting issues. The purpose of this paper is to situate Kagan's (1965) and Wright's (1967) contributions within their social and historical contexts, and thereby to elicit reflection on the field's subsequent and continued development. PMID- 25273001 TI - Constructing one-dimensional silver nanowire-doped reduced graphene oxide integrated with CdS nanowire network hybrid structures toward artificial photosynthesis. AB - A ternary hybrid structure of one-dimensional (1D) silver nanowire-doped reduced graphene oxide (RGO) integrated with a CdS nanowire (NW) network has been fabricated via a simple electrostatic self-assembly method followed by a hydrothermal reduction process. The electrical conductivity of RGO can be significantly enhanced by opening up new conduction channels by bridging the high resistance grain-boundaries (HGBs) with 1D Ag nanowires, which results in a prolonged lifetime of photo-generated charge carriers excited from the CdS NW network, thus making Ag NW-RGO an efficient co-catalyst with the CdS NW network toward artificial photosynthesis. PMID- 25273003 TI - Technology and health care - official journal of the European society for engineering and medicine: a new journal. PMID- 25273004 TI - The European Society for Engineering and Medicine (ESEM) fills a need in Europe. PMID- 25273002 TI - Proteome of Geobacter sulfurreducens in the presence of U(VI). AB - Geobacter species often play an important role in the in situ bioremediation of uranium-contaminated groundwater, but little is known about how these microbes avoid uranium toxicity. To evaluate this further, the proteome of Geobacter sulfurreducens exposed to 100 uM U(VI) acetate was compared to control cells not exposed to U(VI). Of the 1363 proteins detected from these cultures, 203 proteins had higher abundance during exposure to U(VI) compared with the control cells and 148 proteins had lower abundance. U(VI)-exposed cultures expressed lower levels of proteins involved in growth, protein and amino acid biosynthesis, as well as key central metabolism enzymes as a result of the deleterious effect of U(VI) on the growth of G. sulfurreducens. In contrast, proteins involved in detoxification, such as several efflux pumps belonging to the RND (resistance nodulation-cell division) family, and membrane protection, and other proteins, such as chaperones and proteins involved in secretion systems, were found in higher abundance in cells exposed to U(VI). Exposing G. sulfurreducens to U(VI) resulted in a higher abundance of many proteins associated with the oxidative stress response, such as superoxide dismutase and superoxide reductase. A strain in which the gene for superoxide dismutase was deleted grew more slowly than the WT strain in the presence of U(VI), but not in its absence. The results suggested that there is no specific mechanism for uranium detoxification. Rather, multiple general stress responses are induced, which presumably enable Geobacter species to tolerate high uranium concentrations. PMID- 25273005 TI - Ageing and brain: clinical perspectives of PET. PMID- 25273006 TI - Micro-computers in the assessment and rehabilitation of brain-damaged patients. AB - This paper provides an overview of the computerized assessment and rehabilitation of patients with cognitive disorders caused by focal brain damage. The characteristics of computer-based rehabilitation systems are discussed in general and questions as to their efficacy addressed. Diagnostic but in particular rehabilitation systems for the following areas are examined more closely: attention disorders, visual-perceptual disorders, memory and language disorders. The development of hard and software is followed back to its beginnings. Typical examples of modern systems are given. The focus is on systems evaluated in the course of a European Concerted Research Action.Supported by the European Commission, Project No. MR4*-0231-D). PMID- 25273007 TI - Diseases of the circulatory system: mechanical assistance. AB - Patients in cardiogenic shock may benefit from treatment with mechanical circulatory support systems. These systems permit either bridging to the recovery of native heart function (bridge to weaning) or bridging to a natural cardiac graft (bridging to transplantation). The present world experience includes 965 implants for bridging to weaning and 544 implants for bridging to transplantation. From this experience it has become clear that patients about to die have the possibility for survival after or with mechanical circulatory support. The risks of the procedures have also been clearly shown. Based on current experience new orientations for clinical research and developments in bioengineering are indicated. PMID- 25273008 TI - Early detection of osteoarthritis by 3D computed tomography. AB - Osteoarthritis is a common disease that constitutes a considerable socioeconomic burden. So far no radiological procedure was available that allowed the disease to be detected in an early stage. Monitoring disease progression and efficacy of therapeutic procedures was also not possible.We present a measuring procedure and describe evaluation tools that are based on 3D computed tomography. The procedure provides quantitative data on pathological features known to be associated with osteoarthritis such as subchondral sclerosis, osteophytes, joint space narrowing, and bone lesions. It is fully three dimensional, the results are operator independent and describe global as well as local parameters. Changes in these parameters are evaluated from differential images. For that purpose a 3D matching procedure based on translation and rotation-specific correlation techniques is used that allows a repositioning of the bone objects with a mismatch of less than 0.3 mm with regard to translations and 0.250 with regard to rotations.The use of the new tools for measurement, repositioning and evaluation is illustrated with the results from a clinical study. Patients with mild osteoarthritis of the knee joint, healthy controls and osteoporotic patients, all in the same age range of 60 to 75 years, were examined during three years. The cortical to trabecular bone ratio describing subchondral sclerosis proved to be especially helpful to distinguish early osteoarthritic cases from age matched controls. Disease progression is best shown by the increase in the number of detected bone lesions, a reduction of the mean distance between femur and tibia and an increase in the cortical to trabecular bone ratio. Hence the presented procedure appears to have a great potential in diagnosis and treatment monitoring of osteoarthritis. PMID- 25273010 TI - Towards objective medical decisions with the aid of knowledge based systems. PMID- 25273009 TI - The scope of minimally invasive pediatric surgery (MIPS) and its influence on reduced length of hospitalization. AB - Minimally invasive pediatric surgery (MIPS) is a new dimension in pediatric surgery. The scope of methods replacing large operations in children by smaller endo- or laparoscopic interventions is presented.Electromagnetic double-segmental elongation has achieved auto anastomosis in 16 out of 22 children with long gap esophageal atresias since 1975. A new radial laser-applicator with entirely lateral radiation has led to a method for endoscopic occlusion of esophagotracheal and other fistulas with a 100% success rate in a minipig-model. Our experience with 54 laparoscopic interventions including large bowel resections, hiatus hernia, and a new technique for pyloromyotomy documents that laparoscopy halves hospitalisation-periods and may well become the most rapidly growing branch of pediatric surgery. PMID- 25273011 TI - Background and current state-of-the-art. PMID- 25273012 TI - Clinicians' requirements. 1. A pragmatic operational viewpoint. PMID- 25273013 TI - Clinicians' needs and requirements. 2. Conceptual comments. PMID- 25273015 TI - Safety and security. PMID- 25273014 TI - Current relevant developments in information technology. PMID- 25273016 TI - Quality and its evaluation. PMID- 25273017 TI - Discussion and conclusions. PMID- 25273018 TI - THE EC Biomedical and health research programme BIOMED (1991-1994). PMID- 25273019 TI - Elections could rekindle health debate in Brazil. PMID- 25273021 TI - Facilitating a transparent and tailored scientific discussion about the added value of animal feeding trials as well as in vitro and in silico approaches with whole food/feed for the risk assessment of genetically modified plants. PMID- 25273020 TI - Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-Ceria. AB - Two Ceria nanomaterials (NM-211 and NM-212) were tested for inhalation toxicity and organ burdens in order to design a chronic and carcinogenicity inhalation study (OECD TG No. 453). Rats inhaled aerosol concentrations of 0.5, 5, and 25 mg/m(3) by whole-body exposure for 6 h/day on 5 consecutive days for 1 or 4 weeks with a post-exposure period of 24 or 129 days, respectively. Lungs were examined by bronchoalveolar lavage and histopathology. Inhaled Ceria is deposited in the lung and cleared with a half-time of 40 days; at aerosol concentrations higher than 0.5 mg/m(3), this clearance was impaired resulting in a half-time above 200 days (25 mg/m(3)). After 5 days, Ceria (>0.5 mg/m(3)) induced an early inflammatory reaction by increases of neutrophils in the lung which decreased with time, with sustained exposure, and also after the exposure was terminated (during the post-exposure period). The neutrophil number observed in bronchoalveolar lavage fluid (BALF) was decreasing and supplemented by mononuclear cells, especially macrophages which were visible in histopathology but not in BALF. Further progression to granulomatous inflammation was observed 4 weeks post-exposure. The surface area of the particles provided a dose metrics with the best correlation of the two Ceria's inflammatory responses; hence, the inflammation appears to be directed by the particle surface rather than mass or volume in the lung. Observing the time course of lung burden and inflammation, it appears that the dose rate of particle deposition drove an initial inflammatory reaction by neutrophils. The later phase (after 4 weeks) was dominated by mononuclear cells, especially macrophages. The progression toward the subsequent granulomatous reaction was driven by the duration and amount of the particles in the lung. The further progression of the biological response will be determined in the ongoing long-term study. PMID- 25273022 TI - Toxicity of single-walled carbon nanotubes. AB - Carbon nanotubes (CNTs) are an important class of nanomaterials, which have numerous novel properties that make them useful in technology and industry. Generally, there are two types of CNTs: single-walled nanotubes (SWNTs) and multi walled nanotubes. SWNTs, in particular, possess unique electrical, mechanical, and thermal properties, allowing for a wide range of applications in various fields, including the electronic, computer, aerospace, and biomedical industries. However, the use of SWNTs has come under scrutiny, not only due to their peculiar nanotoxicological profile, but also due to the forecasted increase in SWNT production in the near future. As such, the risk of human exposure is likely to be increased substantially. Yet, our understanding of the toxicological risk of SWNTs in human biology remains limited. This review seeks to examine representative data on the nanotoxicity of SWNTs by first considering how SWNTs are absorbed, distributed, accumulated and excreted in a biological system, and how SWNTs induce organ-specific toxicity in the body. The contradictory findings of numerous studies with regards to the potential hazards of SWNT exposure are discussed in this review. The possible mechanisms and molecular pathways associated with SWNT nanotoxicity in target organs and specific cell types are presented. We hope that this review will stimulate further research into the fundamental aspects of CNTs, especially the biological interactions which arise due to the unique intrinsic characteristics of CNTs. PMID- 25273023 TI - Transcriptional regulation, stabilization, and subcellular redistribution of multidrug resistance-associated protein 1 (MRP1) by glycogen synthase kinase 3alphabeta: novel insights on modes of cadmium-induced cell death stimulated by MRP1. AB - Cadmium (Cd) resistance is associated with the suppression of autophagy in H460 lung cancer cells, which is regulated by phospho(p)serine-glycogen synthase kinase (GSK) 3alphabeta. However, the involvement of multidrug resistance (MDR) in this signaling pathway and its underlying mechanisms remain to be elucidated. In this study, we used Cd-resistant cells (RH460), developed from H460 lung cancer cells, to demonstrate that the induction of MDR-associated protein (MRP1) in response to Cd is enhanced in H460 cells compared to RH460. Treating RH460 cells with Cd induced large cytoplasmic vacuoles, which was inhibited by the autophagy inhibitor 3-methyladenine. MRP1 was detected in the nuclear-rich membrane fractions and redistributed from the perinuclear to the cytoplasmic compartment following exposure to Cd. Cd-induced MRP1, p-Ser/p-Tyr GSK3alphabeta, and LC3-II were all suppressed by the GSK3 inhibitor SB216763, but increased by lithium. Furthermore, MRP1 was upregulated by the Ser/Thr phosphatase inhibitor okadaic acid and downregulated by the tyrosine phosphatase inhibitor vanadate, suggesting that MRP1 protein was stabilized by p-Ser GSK3alphabeta. In addition, co-immunoprecipitation and co-localization analyzes revealed a physical interaction between MRP1 and p-Ser GSK3alphabeta. Genetic knockdown of GSK3beta decreased Cd-induced MRP1 mRNA and protein levels, whereas its overexpression upregulated MRP1 protein expression. MRP1 also co-localized with lysosomal membrane protein-2, which may cause lysosomal membrane permeabilization and the subsequent release of cathepsins into the cytosol. In mice chronically injected with Cd, MRP1 localized to the perinuclear region of bronchial and alveolar epithelial cells. Collectively, these data suggest that Cd toxicity is regulated by the transcriptional regulation, stabilization, and subcellular redistribution of MRP1 via the posttranslational modification of GSK3alphabeta. Therefore, the serine phosphorylation of GSK3alphabeta plays a critical role in MRP1-induced cell death. PMID- 25273024 TI - Preparation of polyamide nanocapsules of Aloe vera L. delivery with in vivo studies. AB - Aloe vera is the oldest medicinal plant ever known and the most applied medicinal plant worldwide. The purpose of this study was to prepare polyamide nanocapsules containing A. vera L. by an emulsion diffusion technique with in vivo studies. Diethyletriamine (DETA) was used as the encapsulating polymer with acetone ethyl acetate and dimethyl sulfoxide (DMSO) as the organic solvents and Tween and gelatin in water as the stabilizers. Sebacoyl chloride (SC) monomer, A. vera L. extract, and olive oil were mixed with the acetone and then water containing DETA monomer was added to the solution using a magnetic stirrer. Finally, the acetone was removed under vacuum, and nanocapsules were obtained using a freeze drier. This study showed that the size of the nanocapsule depends on a variety of factors such as the ratio of polymer to oil, the concentration of polymers, and the plant extract. The first sample is without surfactant and the size of nanocapsules in the sample is 115 nm. By adding surfactant, nanocapsules size was reduced to 96 nm. Nanocapsules containing A. vera were administered to rats and the effects were compared with a normal control group. The results showed that in the A. vera group, the effect is higher. The nanocapsules were identified by scanning electron microscopy (SEM), zeta potential sizer (ZPS), and Fourier transform infrared spectroscopy (FT-IR). PMID- 25273025 TI - Comparative pharmacokinetic study of mangiferin after oral administration of pure mangiferin and US patented polyherbal formulation to rats. AB - The US patented polyherbal formulation for the prevention and management of type II diabetes and its vascular complications was used for the present study. The xanthone glycoside mangiferin is one of the major effector constituents in the Salacia species with potential anti-diabetic activity. The pharmacokinetic differences of mangiferin following oral administration of pure mangiferin and polyherbal formulation containing Salacia species were studied with approximately the same dose 30 mg/kg mangiferin and its distribution among the major tissue in Wistar rats. Plasma samples were collected at different time points (15, 30, 60, 120, 180, 240, 360, 480, 600, 1,440, 2,160, and 2880 min) and subsequently analyzed using a validated simple and rapid LC-MS method. Plasma concentration versus time profiles were explored by non-compartmental analysis. Mangiferin plasma exposure was significantly increased when administered from formulation compared to the standard mangiferin. Mangiferin resided significantly longer in the body (last mean residence time (MRTlast)) when given in the form of the formulation (3.65 h). Cmax values of formulation (44.16 MUg/mL) administration were elevated when compared to equivalent dose of the pure mangiferin (15.23 MUg/mL). Tissue distribution study of mangiferin from polyherbal formulation was also studied. In conclusion, the exposure of mangiferin is enhanced after formulation and administration and could result in superior efficacy of polyherbal formulation when compared to an equivalent dose of mangiferin. The results indicate that the reason which delays the elimination of mangiferin and enhances its bioavailability might the interactions of the some other constituents present in the polyherbal formulation. Distribution study results indicate that mangiferin was extensively bound to the various tissues like the small intestine, heart, kidney, spleen, and liver except brain tissue. PMID- 25273026 TI - Factors influencing aerodynamic particle size distribution of suspension pressurized metered dose inhalers. AB - Pressurized metered dose inhalers (pMDIs) are frequently used for the treatment of asthma and chronic obstructive pulmonary disease. The aerodynamic particle size distribution (APSD) of the residual particles delivered from a pMDI plays a key role in determining the amount and region of drug deposition in the lung and thereby the efficacy of the inhaler. In this study, a simulation model that predicts the APSD of residual particles from suspension pMDIs was utilized to identify the primary determinants for APSD. These findings were then applied to better understand the effect of changing drug concentration and micronized drug size on experimentally observed APSDs determined through Andersen Cascade Impactor testing. The experimental formulations evaluated had micronized drug mass median aerodynamic diameters (MMAD) between 1.2 and 2.6 MUm and drug concentrations ranging from 0.01 to 1% (w/w) with 8.5% (w/w) ethanol in 1,1,1,2 tetrafluoroethane (HFA-134a). It was determined that the drug concentration, micronized drug size, and initially atomized droplet distribution have a significant impact in modulating the proportion of atomized droplets that contain multiple suspended drug particles, which in turn increases the residual APSD. These factors were found to be predictive of the residual particle MMAD for experimental suspension HFA-134a formulations containing ethanol. The empirical algebraic model allows predicting the residual particle size for a variety of suspension formulations with an average error of 0.096 MUm (standard deviation of 0.1 MUm). PMID- 25273027 TI - Antitumor activity of DMAKO-05, a novel shikonin derivative, and its metabolism in rat liver microsome. AB - The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8 dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug. PMID- 25273028 TI - Roller compaction of hydrophilic extended release tablets-combined effects of processing variables and drug/matrix former particle size. AB - The present study shows that roller compaction (RC) can successfully be used as a granulation method to prepare hydroxypropyl methylcellulose (HPMC)-based extended release matrix tablets containing a high drug load, both for materials deforming mainly by fragmentation (paracetamol) as for those having mainly plastic deformation (ibuprofen). The combined effect of RC process variables and composition on the manufacturability of HPMC tablets was investigated. Standard wet granulation grade HPMC was compared with a larger particle size direct compressible HPMC grade. Higher roll pressure was found to result in larger paracetamol granules and narrower granule particle size distributions, especially for formulations containing smaller size HPMC. However, for ibuprofen, no clear effect of roll pressure was observed. High roll pressure also resulted in denser ribbon and less bypass fines during RC. Loss of compactibility was observed for granules compared to powder blends, which was found to be related to differences in granule porosity and morphology. Using the large-sized HPMC grade did in some cases result in lower tensile strength tablets but had the advantage to improve the powder flow into the roller compactor. This work also indicates that when the HPMC level lies near the percolation threshold, significant changes can occur in the drug release rate due to changes in other factors (raw material characteristics and processing). PMID- 25273029 TI - Biopolymer-based transdermal films of donepezil as an alternative delivery approach in Alzheimer's disease treatment. AB - Matrix type transdermal films of donepezil (DNP) as an alternative delivery approach was designed to improve patient compliance to Alzheimer disease treatment. Sodium alginate, a natural polysaccharide, was used as matrix-forming agent in the optimization of transdermal films. Propylene glycol and dl-limonene was added into films as a plasticizer and permeation enhancer, respectively. As well as mechanical strength and bioadhesiveness of optimized transdermal films of DNP, the impact of dl-limonene concentration in films on DNP in vitro permeation across pig skin was assessed. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) measurements were carried out to examine the effects of enhancer on in vitro conformational order of the stratum corneum intercellular lipids following permeation study. Results showed that transdermal formulations of DNP were suitable due to both mechanical and bioadhesive features of the films. In vitro skin permeation study indicated that dl-limonene at a concentration of 3% was optimum with high drug flux. ATR-FTIR results confirmed a more fluidized stratum corneum lipid state in the presence of dl-limonene, indicating its permeation enhancement effect. Regarding to achieve therapeutic levels of DNP, it seems to be feasible deliver DNP with transdermal films for the management of Alzheimer disease. PMID- 25273030 TI - A novel approach in distinguishing between role of hydrodynamics and mechanical stresses similar to contraction forces of GI tract on drug release from modified release dosage forms. AB - The objective of this study was to determine the influence of mechanical stresses simulating gastrointestinal contraction forces of 2.0 N (stomach) and 1.2 N (intestine) on the gel properties and drug release characteristics from sustained release swelling and eroding hydrophilic matrices during dissolution studies. Two batches of tetracycline-sustained release tablets containing hydroxypropyl methyl cellulose (HPMC) were manufactured and subjected to USP apparatus II (pH 2.2 buffer) dissolution studies. Hydrated tablets were periodically removed, placed in a petri dish, and multiple times (six cycle) compressed with a flat-ended probe (diameter 1.3 cm) on a texture analyzer at preprogrammed force of either 2.0 or 1.2 N to determine force-distance profiles and changes in drug release rate. The calculated similarity factor values showed dissimilar dissolution profiles using standard dissolution profile as a reference. The similarity factor (f2) values were especially lower than 50 at 2.0 N and, when profiles between the two batches compressed at 1.2 and 2.0 N, were compared with each other. The changes in dissolution pattern and release rate were significantly different after 4 h of dissolution. At 8 h, tablets were fully hydrated and no force could be detected by the probe, indicating a very soft gel matrix. It appears that the contraction forces in the stomach and intestine are capable of altering drug release from modified release hydrophilic matrices during transit in the human GI tract. Accounting for these forces during dissolution can enhance predictions of in vivo drug release, achieve better in vitro and in vivo correlation, introduce improvement in dissolution methods, and better understand the critical quality attributes (CQAs) and factors in quality by design (QbD) during the product development process. PMID- 25273031 TI - In-depth oral presentations and oral communications. PMID- 25273032 TI - In-depth oral presentations and oral communications. PMID- 25273034 TI - Attitudes, beliefs, and perceptions of caregivers and rehabilitation providers about disabled children's sleep health: a qualitative study. AB - BACKGROUND: Children with disabilities are more likely to have sleep disturbances than children without disabilities. Identifying attitudes, beliefs, knowledge, and perceptions of caregivers and health professionals is essential in developing effective intervention programs to improve disabled children's sleep health. However, no such qualitative data about adults who have key roles in the life and daytime activities of children with disabilities are available. This qualitative study aimed to understand attitudes, beliefs, knowledge, and perceptions about disabled children's sleep hygiene among caregivers and rehabilitation providers of children with disabilities. METHODS: Twenty seven adults, including nine primary caregivers and eighteen rehabilitation providers, participated in five focus group discussions between September and December 2012 at the Rehabilitation Center in Punta Arenas, Chile. A trained facilitator guided focus group discussions using a semi-structured script. Audiotapes and transcripts of focus group discussions were reviewed and analyzed for recurrent themes. RESULTS: Participants identified seven themes related to children's sleep hygiene: lifestyle behaviors, family factors, children's disabilities and/or comorbidities, environmental factors, adults' responsibilities for children's sleep, perception of good sleep, and parental distress about children's sleep problems. While both caregivers and rehabilitation providers recognized the importance of sleep for children's health and functioning, they differed in their understanding of how sleep hygiene practices influence sleep. Rehabilitation providers recognized the negative influence of electronics on sleep and the positive influence of sleep routines. In contrast, caregivers reported use of television/movie watching and stimulants as coping strategies for managing children's sleep problems. CONCLUSIONS: Caregivers may benefit from better understanding the influence of electronics and stimulant use on child sleep health. Rehabilitation providers are well positioned to provide educational messages to both children and caregivers in order to change their attitudes, perceptions, and practices surrounding sleep. These qualitative data are valuable in developing intervention programs aimed at improving sleep health among children with disabilities. PMID- 25273035 TI - American Society of Clinical Oncology position statement on obesity and cancer. AB - Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team--the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis--is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer. PMID- 25273036 TI - Preoperative atrial fibrillation and outcome in patients undergoing on-pump or off-pump coronary bypass surgery: lessons learned from the GOPCABE trial. AB - OBJECTIVES: Patients undergoing coronary bypass grafting (CABG) are at higher risk if they suffer from atrial fibrillation (AF). It was suggested that performing CABG without the use of cardiopulmonary bypass (off-pump) would reduce perioperative risk. We assessed the influence of preoperative AF on outcome in a randomized cohort of patients above the age of 75 undergoing either on-pump or off-pump CABG. METHODS: The German Off-Pump Coronary Artery Bypass grafting in the Elderly trial, a randomized, controlled multicentre trial conducted at 12 German institutions, enrolled 2303 patients between 2008 and 2011. The presence of AF was recorded at admission and discharge. There was no record on the rhythm status during hospital stay. RESULTS: AF at admission was present in 5% in the on pump (121/1158) and 5% in the off-pump (112/1145) group. The number of patients with AF at discharge was not different between these two groups (10% on pump, 10% off pump). As expected, AF patients had worse preoperative conditions, which had a negative impact on outcome: The combined end-point of death, infarction, stroke, dialysis and revascularization occurred more often (13 vs 8%, P = 0.008) and 30-day mortality was significantly higher (6 vs 2%, P = 0.003) in AF patients. However, the operative technique used for CABG did not affect these outcome parameters. CONCLUSIONS: AF at admission is a significant risk factor for elderly patients undergoing coronary bypass grafting. However, this risk is not altered by performing bypass grafting off pump. PMID- 25273037 TI - Response to leptin and nitric oxide in blood pressure regulation in humans. PMID- 25273038 TI - Polishing and toothbrushing alters the surface roughness and gloss of composite resins. AB - This study aimed to investigate the surface roughness and gloss of composite resins after using two polishing systems and toothbrushing. Six composite resins (Durafill VS, Filtek Z250, Filtek Z350 XT, Kalore, Venus Diamond, and Venus Pearl) were evaluated after polishing with two polishing systems (Sof-Lex, Venus Supra) and after toothbrushing up to 40,000 cycles. Surface roughness (Ra) and gloss were determined for each composite resin group (n=6) after silicon carbide paper grinding, polishing, and toothbrushing. Two-way ANOVA indicated significant differences in both Ra and gloss between measuring stages for the composite resins tested, except Venus Pearl, which showed significant differences only in gloss. After polishing, the Filtek Z350 XT, Kalore, and Venus Diamond showed significant increases in Ra, while all composite resin groups except the Filtek Z350 XT and Durafill VS with Sof-Lex showed increases in gloss. After toothbrushing, all composite resin demonstrated increases in Ra and decreases in gloss. PMID- 25273039 TI - In vitro comparison of fracture load of implant-supported, zirconia-based, porcelain- and composite-layered restorations after artificial aging. AB - This study evaluated fracture load of single-tooth, implant-supported, zirconia based, porcelain- and indirect composite-layered restorations after artificial aging. Forty-four zirconia-based molar restorations were fabricated on implant abutments and divided into four groups, namely, zirconia-based all-ceramic restorations (ZAC group) and three types of zirconia-based composite-layered restorations (ZIC-P, ZIC-E, and ZIC groups). Before layering an indirect composite material, the zirconia copings in the ZIC-P and ZIC-E groups were primed with Clearfil Photo Bond and Estenia Opaque Primer, respectively. All restorations were cemented on the abutments with glass-ionomer cement and then subjected to thermal cycling and cyclic loading. All specimens survived thermal cycling and cyclic loading. The fracture load of the ZIC-P group (2.72 kN) was not significantly different from that of the ZAC group (3.05 kN). The fracture load of the zirconia-based composite-layered restoration primed with Clearfil Photo Bond (ZIC-P) was comparable to that of the zirconia-based all-ceramic restoration (ZAC) after artificial aging. PMID- 25273040 TI - Effects of degree of dissociation of acid used on hydrolytic durability of ceramic primer. AB - In this study, effects of the degree of dissociation of acids on the hydrolysis rate of methoxy group in gamma-methacryloxypropyltrimethoxysilane (gamma-MPS) and the adsorption characteristics of gamma-MPS on ceramic surfaces were studied using acetic, phosphoric, and hydrochloric acids. Hydrolytic stability of gamma MPS adsorption layer at the resin-ceramic interface was thus examined. (29)Si NMR observations of acidactivated gamma-MPS and contact angle measurements following ceramic surface silanization were performed. Bond strengths of resin to the silanized ceramic surfaces were measured. Statistical analyses of shear bond strength and contact angle data were performed. Increase in the degree of dissociation of the acid used increased the hydrolysis rate of methoxy group in gamma-MPS, but lowered the contact angle to the silanized ceramic surface. Decrease in the contact angle increased the hydrolytic stability of gamma-MPS adsorption layer. PMID- 25273041 TI - Effect of composition of experimental fluorinated soft lining materials on bond strength to denture base resin. AB - The purpose of the present study was to investigate the effect of the composition of experimental fluorinated soft lining materials on bond strength to denture base resin. Vinylidene fluoride/hexafluoro propylene copolymer (2-6F), tridecafluorooctyl methacrylate (13FMA), methoxy diethylene glycol methacrylate (MDGMA), and silica (as filler) were used for fabrication of the experimental soft lining materials. Nine experimental soft lining materials having various compositions of 2-6F, 13FMA, and MDGMA were prepared. Shear and tensile bond strength tests were performed before and after immersion in water. The water sorption for the materials was also measured. An increase in the content of acrylic monomer, MDGMA, in the experimental materials increased the bond strength before immersion in water but reduced the bond strength after immersion in water as compared to that before immersion in water. The inclusion of fluorinated monomer (13FMA) in the materials appeared to affect water sorption. PMID- 25273042 TI - Surface characteristics and castability of Zr-14Nb alloy dental castings. AB - The purpose of this study was to evaluate mechanical properties, surface characteristics and castability of Zr-14Nb dental castings. The mean 0.2% proof and ultimate tensile strengths of Zr-14Nb were approximately 68% and 76% those of Ti-6Al-7Nb, respectively, while they were comparable to Co-29Cr-6Mo. Elongation of Zr-14Nb was the highest of all alloys tested. The hardened reaction layer was formed on the surfaces of the Zr-14Nb castings. The layer consisted of oxygen and aluminum originating form investment. The castability of Zr-14Nb was comparable to that of Ti-6Al-7Nb. Dental castings of Zr-14Nb reveal mechanical properties that were within the range of the other dental alloys. Further improvements in castability and minimization of the surface reaction layer are needed for applications in dental prostheses. PMID- 25273043 TI - Evaluation of biofilm formation in the presence of saliva on poly(ethylene glycol)deposited titanium. AB - Titanium (Ti) is widely used for oral cavity biomedical devices. However, because it penetrates the mucosa and exists partially external to the tissue, it sometimes induces tissue inflammation, minor infection, or peri-implantitis due to oral bacteria after implantation and causes serious consequences. We have previously shown that poly(ethylene glycol) (PEG)- electrodeposited Ti inhibits bacterial adhesion and biofilm formation. However, the effect of the PEG coating in body fluid is still unclear. In this study, we investigated bacterial colony morphology and biofilm formation on PEG-electrodeposited Ti in comparison with untreated Ti in the presence of saliva. After 48 h incubation, Streptococcus mutans biofilms adhered on the untreated Ti were rigid and cohesive, while those on the PEG-electrodeposited were loose and were easily washed off. These results indicate electrodeposited-PEG layers inhibit the biofilm formation on Ti in the presence of saliva. PMID- 25273044 TI - Evaluation of the effects of fluoride-releasing varnish on dentin demineralization using optical coherence tomography. AB - Effects of a fluoride-releasing varnish containing surface reaction-type prereacted glass ionomer (S-PRG) filler on dentin demineralization were examined using optical coherence tomography. Bovine incisors that were sliced and treated with undersaturated 0.1 M lactic acid buffer solution (DE group). A thin film of varnish-containing S-PRG filler was applied before demineralization (PRG group). Control was maintained in artificial saliva. Using optical coherence tomography of selected locations on the dentin surface, peak intensity (dB) and width (MUm) at 1/e(2) were obtained and integrated values calculated. Although alterations in integrated values were different in each group, there was a slight but not significant increase in those for the control group and a slight but significant increase for the De group. For the PRG group, integrated values were doubled seven days after experiment initiation, followed by a significant increase. Fluoride-releasing varnish containing S-PRG fillers prevented dentin demineralization as detected by optical coherence tomography. PMID- 25273045 TI - Dental pulp cells that express adeno-associated virus serotype 2-mediated BMP-7 gene enhanced odontoblastic differentiation. AB - This present study investigated the potential of adeno-associated virus serotype 2 (AAV2) mediated BMP-7 (AAV2-BMP-7) to induce odontoblastic differentiation of human dental pulp cells (DPCs) in vitro. AAV2-BMP-7 was constructed to overexpress BMP-7, and the biologic effects of BMP-7 on DPCs were investigated by the evaluation of the activity of alkaline phosphatase (ALPase), the detection of the expression of dentin sialophosphoprotein (DSPP) and osteocalcin (OCN) expression and the analysis of the proliferative ability of the cells. DPCs that were infected with AAV2-BMP-7 displayed significantly upregulated ALP activity and formed mineralized nodules. Moreover, AAV2-BMP-7 promoted the expression of mineralization-related genes, which included DSPP and OCN. In addition, there was no significant difference between the proliferative ability of AAV2-BMP-7 and the control group. In conclusion, AAV2-BMP-7 promoted the odontoblastic differentiation in DPCs, a clear indication of the therapeutic potential of AAV2 BMP-7 in dental tissue regeneration. PMID- 25273046 TI - Chemical alteration by tooth bleaching of human salivary proteins that infiltrated subsurface enamel lesions--experimental study with bovine lesion model systems. AB - Salivary macromolecules infiltrate white and brown spot enamel lesions and adsorb onto hydroxyapatite. Calcium-binding salivary proteins such as statherin hinder remineralization of these lesions. We assessed whether bleaching agents can remove salivary components that have infiltrated and bound to experimental subsurface lesions in bovine enamel prepared by immersing specimens in acid and then human saliva. Transversal microradiography showed that such demineralized lesions mimicked incipient carious lesions. Bound proteins to the experimental and untreated control specimens were eluted in a stepwise manner with phosphatebuffered saline, 0.4 M phosphate buffer, and 1 M HCl. SDS-PAGE of dialyzed extracts showed that specific salivary proteins bound to the lesions, while virtually no protein bands were detected if the specimens were bleached. Western blotting showed that even statherin, which was more firmly bound than other proteins, was removed. In-office bleaching agent may be useful in treating enamel lesions for removing proteins bound to these lesions. PMID- 25273047 TI - A three-dimensional finite element evaluation of magnetic attachment attractive force and the influence of the magnetic circuit. AB - The finite element method has been considered to be excellent evaluative technique to study magnetic circuit optimization. The present study analyzed and quantitatively evaluated the different effects of magnetic circuit on attractive force and magnetic flux density using a three-dimensional finite element method for comparative evaluation. The diameter of a non-magnetic material in the shield disk of a magnetic assembly was variably increased by 0.1 mm to a maximum 2.0 mm in this study design. The analysis results demonstrate that attractive force increases until the diameter of the non-magnetic spacing material reaches a diameter of 0.5 mm where it peaks and then decreases as the overall diameter increases over 0.5 mm. The present analysis suggested that the attractive force for a magnetic attachment is optimized with an appropriate magnetic assembly shield disk diameter using a non-magnetic material to effectively change the magnetic circuit efficiency and resulting retention. PMID- 25273048 TI - Use of a gelatin hydrogel membrane containing beta-tricalcium phosphate for guided bone regeneration enhances rapid bone formation. AB - The purpose of this study was to evaluate a thin gelatin hydrogel membrane containing beta-tricalcium phosphate (G-TCP) for use in guided bone regeneration, a technique that we developed. G-TCP membranes were fabricated from gelatin and beta-TCP powder, freezedried, and cross-linked by heating. The resulting G-TCP membranes were as thin as collagen membranes, with high mechanical integrity. Proliferation and differentiation of rat bone marrow stromal cells (BMSCs) on G TCP and collagen membranes were examined. On both membranes, BMSCs proliferated well and expressed alkaline phosphatase. However, more bone-like mineralized tissue formed on G-TCP membranes than on collagen membranes at 4 weeks. The effects of G-TCP and collagen membranes on bone regeneration in rat parietal bone defects were histologically examined. Bone bridges with mature uniform bone were observed under G-TCP membranes as early as 2 weeks. These results indicate that G TCP is a GBR membrane that is comparable or superior to collagen membrane. PMID- 25273049 TI - Effect of thione primers on adhesive bonding between an indirect composite material and Ag-Pd-Cu-Au alloy. AB - The current study evaluated the effect of primers on the shear bond strength of an indirect composite material joined to a silverpalladium-copper-gold (Ag-Pd-Cu Au) alloy (Castwell). Disk specimens were cast from the alloy and were air abraded with alumina. Eight metal primers were applied to the alloy surface. A light-polymerized indirect composite material (Solidex) was bonded to the alloy. Shear bond strength was determined both before and after the application of thermocycling. Two groups primed with Metaltite (thione) and M. L. Primer (sulfide) showed the greatest post-thermocycling bond strength (8.8 and 6.5 MPa). The results of the X-ray photoelectron spectroscopic (XPS) analysis suggested that the thione monomer (MTU-6) in the Metaltite primer was strongly adsorbed onto the Ag-Pd-Cu-Au alloy surface even after repeated cleaning with acetone. The application of either the thione (MTU-6) or sulfide primer is effective for enhancing the bonding between a composite material and Ag-Pd-Cu-Au alloy. PMID- 25273050 TI - Analysis of fracture surface of titanium-porcelain bonding by electron spectroscopy for chemical analysis. AB - Three commercially available porcelains bonded to titanium were evaluated to determine the weakest zone of the titanium-porcelain bonding structures. Tensile bond tests were performed for these specimens (NO, DU, and VI) and for Ni-Cr alloy-porcelain bonding samples that served as controls. The maximum bond strengths between porcelain and titanium and the Ni-Cr alloy subjected to different metal surface treatments were compared. Sand blasting effectively increased bond strengths in titanium-porcelain bonding materials. No statistically significant differences in the maximum bond strengths were found between the NO sample and a control; however, sample NO exhibited greater maximum bond strength than DU and VI samples. The bond strengths increased with increasing area fractions of porcelain failure on fracture surfaces. The weakest zones were investigated based on the oxygen chemical states determined by electron spectroscopy for chemical analysis, which include bridging oxygen (Si-O Si), nonbridging oxygen (Si-O(-) M(+)), and titanium oxide (O(2-)) states. We concluded that the titanium oxide layer is the weakest zone of titanium-porcelain bonding structures. PMID- 25273051 TI - Influence of plasma and ultraviolet treatment of zirconia on initial attachment of human oral keratinocytes: expressions of laminin gamma2 and integrin beta4. AB - Initial attachment of human oral keratinocytes cultured on yttria-stabilized tetragonal zirconia polycrystal (TZP) surfaces that were subjected to UV or oxygen plasma (O2-plasma) treatment was investigated. The viability of the attached cells, mRNA expression of laminin gamma2 and integrin beta4, distribution of laminin gamma2 and integrin beta4, cell area, and cell morphology were assessed. The results showed that no differences in the viability of attached cells were recognized among the conditions. However, expression of laminin gamma2 and integrin beta4 as well as cell morphology were promoted only in O2-plasma specimens even though superhydrophilicity was obtained in both the UV and O2-plasma specimens compared with the untreated control specimen. The photocatalytic activity was believed to be closely involved in the above mentioned differences. The results of this study suggest that TZP surface treated with oxygen plasma promotes the initial attachment capability of human oral keratinocytes with enhancing the extracellular matrix such as laminin gamma2. PMID- 25273052 TI - Mechanical properties of composite resin blocks for CAD/CAM. AB - This study compared commercial composite resin blocks with one ceramic block for use in computer-aided design/computer aided manufacturing (CAD/CAM). Four composite resins, one composite ceramic, and one feldspar-ceramic block were investigated. Flexural strength (FS), flexural modulus (FM), and Vickers hardness (VH) were determined under three conditions: dry storage; immersion in water at 37 degrees C for 7 days; and immersion in water at 37 degrees C for 7 days followed by 10,000 thermocycles. After dry storage, FS ranged from 127 to 242 MPa, FM from 9.6 to 51.5 GPa, and VH from 64 to 455. Two-way ANOVA was performed for FS, FM and VH followed by Tukey's multiple comparison (alpha<0.05). Results demonstrated that the materials degraded after water immersion and thermocycling, but their properties were within the acceptable range for fabrication of single restorations according to the ISO standard for ceramics (ISO 6872:2008). PMID- 25273053 TI - Dengue envelope domain III-peptide binding analysis via tryptophan fluorescence quenching assay. AB - In the efforts to find an anti-viral treatment for dengue, a simple tryptophan fluorescence-screening assay aimed at identifying dengue domain III envelope (EIII) protein inhibitors was developed. Residue Trp391 of EIII was used as an intrinsic probe to monitor the change in fluorescence of the tryptophan residue upon binding to a peptide. The analysis was based on the electron excitation at 280 nm and fluorescence emission at 300-400 nm of EIII, followed by quenching of fluorescence in the presence of potential peptidic inhibitors coded DS36wt, DS36opt, DN58wt and DN58opt. The present study found that the fluorescence of the recombinant EIII was quenched following the binding of DS36opt, DN58wt and DN58opt in a concentration-dependent manner. Since the lambdamax for emission remained unchanged, the effect was not due to a change in the environment of the tryptophan side chain. In contrast, a minimal fluorescence-quenching effect of DS36wt at 20 and 40 uM suggested that the DS36wt does not have any binding ability to EIII. This was supported by a simple native-page gel retardation assay that showed a band shift of EIII domain when incubated with DS36opt, DN58wt and DN58opt but not with DS36wt. We thus developed a low-cost and convenient spectrophotometric binding assay for the analysis of EIII-peptide interactions in a drug screening application. PMID- 25273054 TI - Asymmetric reductive aldol-type reaction with carbonyl compounds using dialkyl tartrate as a chiral ligand. AB - An asymmetric reductive aldol-type reaction of alpha,beta-unsaturated esters with carbonyl compounds using Rh catalyst and Et2Zn was investigated. A chiral zinc complex from alpha,beta-unsaturated ester was easily generated as the key intermediate from Et2Zn and Wilkinson's catalyst with diisopropyl L-(+)-tartrate to give a variety of enantioenriched beta-hydroxy esters. The reaction was also applied to the intramolecular reductive aldol cyclization. PMID- 25273055 TI - Preparation of polypseudorotaxanes composed of cyclodextrin and polymers in microspheres. AB - We prepared polypseudorotaxanes (PPRXs) composed of cyclodextrin (CyD) and polyethylene glycol (PEG) inside microspheres (MSs) by an emulsifying process using polypropylene glycol (PPG) that shows temperature-dependent hydrophilicity changes; PPG is hydrophobic at high temperatures but hydrophilic at low temperatures. An aqueous solution of CyD and PEG was dispersed as droplets in PPG at 60 degrees C then cooled to 0 degrees C to allow water of droplets to transfer into PPG. On removal of water in the droplets, CyD and PEG were left behind as a CyD/PEG PPRX inside the solid-state MSs. Examination of alpha-, beta-, and gamma CyD revealed that alpha-CyD was suitable for the formation of PPRX containing PEG in this MS preparation procedure. Interestingly, a new PPRX composed of alpha-CyD and PPG was formed in the alpha-CyD MSs when they were prepared in the absence of PEG from the aqueous solution of alpha-CyD. This MS fabrication procedure can control the size and shape of PPRX particles, and will contribute to the production of new types of CyD inclusion complexes. PMID- 25273057 TI - Contribution of glucose to crystallization of phenytoin in injectable dosage form by dilution with infusion fluids. AB - The crystallization of phenytoin occurring after its dilution with infusion fluid is a major concern in the clinical use of injectable phenytoin. To gain further understanding of the crystallization, this study assessed details of the involvement of glucose in this action. For sample preparation, phenytoin crystals were created by diluting the injectable phenytoin with infusion fluids with different glucose concentrations at different temperature, and then the characteristics of the crystallization (e.g., crystal size in the long direction, accumulated amount over 24 h, and crystallization rate constant) were measured. Results of the analysis of variance indicated that the glucose concentration and temperature had significant impacts on the crystallization. The mode of action of the glucose concentration was suggested to be different from that of the incubation temperature. This study also examined the molecular mobility of components (i.e., glucose, propylene glycol, phenytoin) in the admixtures using diffusion NMR techniques. The findings will provide valuable information for the clinical use of injectable phenytoin. PMID- 25273056 TI - Development of 2-thioxoquinazoline-4-one derivatives as dual and selective inhibitors of dynamin-related protein 1 (Drp1) and puromycin-sensitive aminopeptidase (PSA). AB - An established inhibitor of dynamin-related protein 1 (Drp1), 3-(2,4-dichloro-5 methoxyphenyl)-2-thioxoquinazoline-4-one (mdivi-1), was recently reported also to show potent puromycin-sensitive aminopeptidase (PSA)-inhibitory activity. Herein, we report structural development of mdivi-1 derivatives and structure-activity relationship (SAR) analysis of the synthesized compounds, as well as the structurally related PSA-specific inhibitor 3-(2,6-diethylphenyl)quinazoline-2,4 dione (PAQ-22), with the aim of identifying key structural features for inhibitory activity in order to develop selective inhibitors of Drp1, which is a potential target for treatment of Huntington's disease. Among the synthesized compounds, 3-(4-chloro-3-methoxyphenyl)-2-thioxoquinazoline-4-one (10g) exhibited more potent Drp1-inhibitory activity than mdivi-1 with high selectivity for Drp1 over PSA. PMID- 25273058 TI - A novel selenadiazole derivative induces apoptosis in human glioma cells by dephosphorylation of AKT. AB - Selenadiazole derivatives are synthetic organoselenium compounds with improved anticancer activity and greater selectivity than inorganic selenium. In this study, 4-(benzo[c][1,2,5]selenadiazol-6-yl)-benzene-1,2-diamine (BSBD) was shown to induce time- and dose-dependent apoptosis in SWO-38 human glioma cells by accumulation of a sub-G1 cell population, DNA fragmentation, nuclear condensation, caspase activation and poly(ADP-ribose) polymerase (PARP) cleavage. Further mechanistic investigation showed that BSBD treatment induced dephosphorylation of AKT and DNA damage-mediated activation of p53, leading to extensive apoptosis through the mitochondrial pathway. Our findings suggest that BSBD represents a potential human glioma therapeutic. PMID- 25273059 TI - Sesquiterpenoids and lignans from the roots of Syringa pinnatifolia. AB - Two new sesquiterpenoids, pinnatifone A (1) and pinnatifone B (2), and two new lignans, pinnatifolin (3) and isopinnatifolin (4), along with six known lignans (5-10), were isolated from the roots of Syringa pinnatifolia. The structures of the new compounds were elucidated by extensive spectroscopic methods, including NMR, MS, UV, and IR spectra. The lignans were screened for their anti-oxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH) assay). Most of them showed potent anti-oxidant activity, especially compound 5, whose potent anti-oxidant activity had an SC50 value higher than that of the positive control vitamin C. PMID- 25273060 TI - Taxiphyllin 6'-O-gallate, actinidioionoside 6'-O-gallate and myricetrin 2"-O sulfate from the leaves of Syzygium samarangense and their biological activities. AB - Three new compounds were isolated from a MeOH extract of the leaves of Syzygium samarangense, one new cyanogenic glucoside, taxiphyllin 6'-O-gallate (1), one new megastigmane glucoside, actinidioionoside 6'-O-gallate (2), and one new sulfated flavonoid rhamnoside, myricetrin 2"-O-sulfate (3), together with 14 known compounds, lupeol (4), demethoxymatteucinol (5), cryptostrobin (6), betulinic acid (7), beta-sitosterol glucoside (8), 2R-prunasin (9), myrciaphenone A (10), 1 feruloyl-beta-D-glucopyranoside (11), (3S,5R,6R,7E,9S)-3,5,6,9 tetrahydroxymegastigman-7-ene (12), guaijaverin (13), myricetin 4'-methyl ether 3 O-alpha-L-rhamnopyranoside (14), myricetrin (15), gallic acid (16) and actinidioionoside (17). The structures of the new compounds were determined through a combination of spectroscopic, HPLC and chemical analyses. PMID- 25273061 TI - Chemical structures and hepatoprotective effects of constituents from Cassia auriculata leaves. AB - An 80% aqueous acetone extract of Cassia auriculata leaves was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the 80% aqueous acetone extract, we isolated a new benzocoumarin glycoside, avaraoside I (1), and a new flavanol dimer, avaraol I (2), together with 29 known constituents. The structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. In addition, three isolated compounds, pseudosemiglabrin (15, 0.0011%), (2S)-7,4' dihydroxyflavan(4beta->8)-catechin (22, 0.00075%), and (2S)-7,4' dihydroxyflavan(4beta->8)-gallocatechin (23, 0.092%), displayed hepatoprotective effects equivalent to that of the hepatoprotective agent, silybin. PMID- 25273062 TI - Synthesis and antiviral activities of some 2,4,6-trisubstituted 1,3,5-triazines. AB - We describe the synthesis and results of biological evaluation of newly designed 2,4,6-trisubstituted symmetrical 1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted TAZ derivatives, some CS-symmetrical alkoxy-amino substituted TAZ derivatives, including 7ggp and 6dpp, showed significant antiviral activity against herpes simplex virus type 1 (HSV-1). The compound with the highest level of antiviral activity was C3-symmetrical trialkoxy-TAZ derivative 4bbb, which showed a considerably high selectivity index (IC50/EC50=256.6). The structure-activity relationships for anti-HSV-1 activity of the tested 2,4,6-trisubstituted TAZ derivatives are also described. PMID- 25273063 TI - Enantioselective desymmetrization of FTY720. AB - A method for enantioselective desymmetrization of N-Ac and N-Boc-FTY720 by nonenzymatic asymmetric acylation was developed. Effective enantioselective monobenzoylation using benzoyl chloride in the presence of the tetraphenylbisoxazoline (L2)-CuCl2 complex gave the desired products 3a and 3b in 52-62% yield with 64% ee. PMID- 25273064 TI - Ticks and rickettsial infection in the wildlife of two regions of the Brazilian Amazon. AB - During 2009-2012, wild animals and their ticks were sampled in two areas within the Amazon biome of Brazil, in the states of Mato Grosso and Para. Animal tissues, blood, and ticks were molecularly tested for Rickettsia and Coxiella DNA. A total of 182 wild animals were sampled, comprising 28 mammalian, five avian, and three reptilian species. Animal tissues or blood were all negative for Rickettsia or Coxiella DNA. A total of 454 ticks (22 larvae, 226 nymphs, 127 males, 79 females) were collected from 52 (28.6%) animals, and identified into 15 species: Amblyomma cajennense, A. naponense, A. humerale, A. nodosum, A. goeldii, A. oblongoguttatum, A. longirostre, A. calcaratum, A. coelebs, A. pacae, A. geayii, A. rotundatum, A. auricularium, A. ovale, and Haemaphysalis juxtakochi. While no Coxiella DNA was identified in ticks, six Rickettsia species were detected in the ticks. "Candidatus Rickettsia amblyommii" was the most common agent, detected in four tick species, A. cajennense, A. auricularium, A. longirostre, and A. humerale. The second most common agent, R. bellii, was detected in A. humerale and A. naponense. Rickettsia rhipicephali was detected in H. juxtakochi, and R. felis in A. humerale. Two possible new Rickettsia species were detected in A. naponense ticks, namely, a novel spotted fever group agent close-related to R. africae in Para, and a novel Canadensis group agent in Mato Grosso. Results of the present study expand our knowledge on the tick fauna, and on the yet infantile knowledge of tick-borne rickettsiae in the Amazon biome. PMID- 25273065 TI - RNAi-mediated knockdown of transformer-2 in the predatory mite Metaseiulus occidentalis via oral delivery of double-stranded RNA. AB - Little is known about the process of sex determination at the molecular level in Metaseiulus occidentalis, a parahaploid species and natural enemy of phytophagous pest mites. Detailed knowledge of the sex-determination pathway could allow genetic manipulation of M. occidentalis to produce more female offspring, which could improve its effectiveness as a biological control agent. RNA interference is useful for assessing the function of putative sex-determination genes by reducing or eliminating gene expression. In many insect species the transformer-2 (tra-2) gene is an upstream regulatory element in the sex-determination cascade, and knockdown of tra-2 expression can alter the sex ratio. We assessed whether oral delivery of tra-2 double-stranded RNA to M. occidentalis virgin females would affect the sex of her progeny. Females that ingested tra-2 dsRNA produced significantly fewer eggs compared to control females suggesting that tra-2 is somehow involved in reproduction by females. However, the sex ratio of the few progeny that were laid was not altered, so it is unclear whether tra-2 is involved in sex determination. This is an initial step towards elucidating the molecular components of sex determination in M. occidentalis. PMID- 25273066 TI - A descriptive study of adrenal crises in adults with adrenal insufficiency: increased risk with age and in those with bacterial infections. AB - BACKGROUND: An adrenal crisis (AC) is a major cause of morbidity in hypoadrenal patients. However, there is little information available on the incidence and underlying causes of AC. METHODS: The aim of the present study was to describe the incidence of AC in New South Wales (NSW), Australia. Using a health department database, we selected de-identified data on all adults aged 20 years and over who were treated in any hospital in NSW between July1, 2000-June 30, 2011, with either a principal or secondary diagnosis of an AC. AC admission rates were calculated overall and within age categories. Frequencies of co-morbid diagnoses were analysed by age and sex groups. Poisson regression was used to assess the significance of the observed change in AC related admissions with age, while controlling for any secular trends by including year in the model. Chi sq tests were used to assess the differences in frequencies of categorical variables between groups. RESULTS: 824 patients received treatment for an AC in hospital, corresponding to 74.9 admissions/year. The majority (62.5%) of the patients were women and 52.8% were aged 60 years and over. Admission rates were significantly associated with increasing age (p < 0.0001). Patients in the 60-69, 70-79 and 80+ age groups had the highest average admission rates (24.3, 35.2 and 45.8 per million/year). A principal or secondary diagnosis of an infection was reported in 317 (38.5%) patients and infection was significantly associated with age (p < 0.0001) with older patients having the highest proportion of cases. The most frequent infections were pneumonia/lower respiratory tract infection in 85 (10.3%) cases and urinary tract infection (UTI) in 82 (10.0%) patients. Women experienced 78.0% of the reported UTIs. There were 125 patients (15.2%) with an AC and a record of gastroenteritis. Twenty-six (3.2%) patients died in hospital but, of these, only 4 deaths (0.9%) were recorded among the 467 patients with a principal diagnosis of an AC. CONCLUSIONS: The incidence of AC increases with age. Infections, especially bacterial infections, are associated with the incidence of ACs and this increases with age. PMID- 25273067 TI - Identification of the novel HLA-A*11:192 allele by HLA typing of a Caucasian individual. AB - We report the new HLA-A*11:192 allele differing from A*11:01 by one nucleotide in exon 2. PMID- 25273076 TI - Coordinating the clinical management of imported human cases suspected of being infected with a highly pathogenic virus such as Ebola. PMID- 25273068 TI - Alignathon: a competitive assessment of whole-genome alignment methods. AB - Multiple sequence alignments (MSAs) are a prerequisite for a wide variety of evolutionary analyses. Published assessments and benchmark data sets for protein and, to a lesser extent, global nucleotide MSAs are available, but less effort has been made to establish benchmarks in the more general problem of whole-genome alignment (WGA). Using the same model as the successful Assemblathon competitions, we organized a competitive evaluation in which teams submitted their alignments and then assessments were performed collectively after all the submissions were received. Three data sets were used: Two were simulated and based on primate and mammalian phylogenies, and one was comprised of 20 real fly genomes. In total, 35 submissions were assessed, submitted by 10 teams using 12 different alignment pipelines. We found agreement between independent simulation based and statistical assessments, indicating that there are substantial accuracy differences between contemporary alignment tools. We saw considerable differences in the alignment quality of differently annotated regions and found that few tools aligned the duplications analyzed. We found that many tools worked well at shorter evolutionary distances, but fewer performed competitively at longer distances. We provide all data sets, submissions, and assessment programs for further study and provide, as a resource for future benchmarking, a convenient repository of code and data for reproducing the simulation assessments. PMID- 25273070 TI - Parente2: a fast and accurate method for detecting identity by descent. AB - Identity-by-descent (IBD) inference is the problem of establishing a genetic connection between two individuals through a genomic segment that is inherited by both individuals from a recent common ancestor. IBD inference is an important preceding step in a variety of population genomic studies, ranging from demographic studies to linking genomic variation with phenotype and disease. The problem of accurate IBD detection has become increasingly challenging with the availability of large collections of human genotypes and genomes: Given a cohort's size, a quadratic number of pairwise genome comparisons must be performed. Therefore, computation time and the false discovery rate can also scale quadratically. To enable accurate and efficient large-scale IBD detection, we present Parente2, a novel method for detecting IBD segments. Parente2 is based on an embedded log-likelihood ratio and uses a model that accounts for linkage disequilibrium by explicitly modeling haplotype frequencies. Parente2 operates directly on genotype data without the need to phase data prior to IBD inference. We evaluate Parente2's performance through extensive simulations using real data, and we show that it provides substantially higher accuracy compared to previous state-of-the-art methods while maintaining high computational efficiency. PMID- 25273069 TI - Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity. AB - Genome-wide association studies (GWAS) identify regions of the genome correlated with disease risk but are restricted in their ability to identify the underlying causative mechanism(s). Thus, GWAS are useful "roadmaps" that require functional analysis to establish the genetic and mechanistic structure of a particular locus. Unfortunately, direct functional testing in humans is limited, demonstrating the need for complementary approaches. Here we used an integrated approach combining zebrafish, rat, and human data to interrogate the function of an established GWAS locus (SHROOM3) lacking prior functional support for chronic kidney disease (CKD). Congenic mapping and sequence analysis in rats suggested Shroom3 was a strong positional candidate gene. Transferring a 6.1-Mb region containing the wild-type Shroom3 gene significantly improved the kidney glomerular function in FHH (fawn-hooded hypertensive) rat. The wild-type Shroom3 allele, but not the FHH Shroom3 allele, rescued glomerular defects induced by knockdown of endogenous shroom3 in zebrafish, suggesting that the FHH Shroom3 allele is defective and likely contributes to renal injury in the FHH rat. We also show for the first time that variants disrupting the actin-binding domain of SHROOM3 may cause podocyte effacement and impairment of the glomerular filtration barrier. PMID- 25273077 TI - S-1 as monotherapy or in combination with leucovorin as second-line treatment in gemcitabine-refractory advanced pancreatic cancer: a randomized, open-label, multicenter, phase II study. AB - BACKGROUND: In this study, we compared the efficacy and safety of the oral fluoropyrimidine S-1 as monotherapy or in combination with leucovorin as the second-line treatment for patients with metastatic pancreatic cancer whose disease had progressed on gemcitabine treatment. METHODS: The study was a randomized, open-label, controlled study. Patients randomly received S-1 or S-1 in combination with leucovorin (SL arm) in 21-day cycles. The primary endpoint was the 6-month survival rate. RESULTS: A total of 92 patients were randomized to S-1 (n = 47) and SL (n = 45). No statistically significant differences were observed between the two arms with regard to 6-month survival rates (40% vs. 49%), median overall survival (5.5 vs. 6.3 months), median progression-free survival (1.9 vs. 3.0 months), and overall response rate (4.7% vs. 8.3%). The rate of major grade 3-4 adverse events of digestive toxicity was significantly higher in the SL arm than in the S-1 arm. CONCLUSION: Compared with S-1, SL did not improve the survival of patients with metastatic pancreatic cancer who had failed to benefit from prior gemcitabine treatment, but SL had a higher adverse event rate. PMID- 25273078 TI - Patient experience and attitudes toward addressing the cost of breast cancer care. AB - BACKGROUND: The American Society of Clinical Oncology views patient-physician discussion of costs as a component of high-quality care. Few data exist on patients' views regarding how cost should be addressed in the clinic. METHODS: We distributed a self-administered, anonymous, paper survey to consecutive patients with breast cancer presenting for a routine visit within 5 years of diagnosis at an academic cancer center. Survey questions addressed experience and preferences concerning discussions of cost and views on cost control. Results are primarily descriptive, with comparison among participants on the basis of disease stage, using chi-square and Fisher's exact tests. All p values are two-sided. RESULTS: We surveyed 134 participants (response rate 86%). Median age was 61 years, and 28% had stage IV disease. Although 44% of participants reported at least a moderate level of financial distress, only 14% discussed costs with their doctor; 94% agreed doctors should talk to patients about costs of care. Regarding the impact of costs on decision making, 53% felt doctors should consider direct costs to the patient, but only 38% felt doctors should consider costs to society. Moreover, 88% reported concern about costs of care, but there was no consensus on how to control costs. CONCLUSION: Most breast cancer patients want to discuss costs of care, but there is little consensus on the desired content or goal of these discussions. Further research is needed to define the role of cost discussions at the bedside and how they will contribute to the goal of high quality and sustainable cancer care. PMID- 25273079 TI - Sleep-related breathing disorders in patients with tumors in the head and neck region. AB - BACKGROUND: Sleep disturbance is a prominent complaint of cancer patients. Most studies have focused on insomnia and cancer-related fatigue. Obstructive sleep apnea (OSA) has been reported in small studies and case reports. METHODS: In a retrospective review of patients who underwent formal sleep evaluation and polysomnography (PSG) from 2006 to 2011, 56 patients with tumors in the head and neck region were identified. Clinical characteristics, sleep-related history, and PSG data were reviewed. RESULTS: Most patients had active cancer (80%), and the majority had squamous pathology (68%). Prominent symptoms included daytime fatigue (93%), daytime sleepiness (89%), and snoring (82%). Comorbid conditions primarily included hypertension (46%) and hypothyroidism (34%). Significant sleep related breathing disorder was noted in 93% of patients, and 84% met clinical criteria for OSA. A male predominance (77%) was noted, and patients were not obese (body mass index <30 kg/m(2) in 52%). The majority of patients (79%) underwent radiation prior to sleep study, of which 88% had OSA, and in the group without prior radiation, 67% had OSA. Adherence to positive airway pressure (PAP) therapy was slightly better when compared with the general population. A subset of patients with persistent hypoxia despite advanced forms of PAP required tracheostomy. Multivariate analysis revealed that patients with active disease and radiation prior to PSG were more likely to have OSA. CONCLUSION: Sleep related breathing disorder was common in patients with tumors in the head and neck region referred for evaluation of sleep disruption, and most met clinical criteria for OSA. Daytime fatigue and sleepiness were the most common complaints. OSA was prevalent in male patients, and most with OSA were not obese. Architectural distortion from the malignancy and/or treatment may predispose these patients to OSA by altering anatomic and neural factors. A heightened clinical suspicion for sleep-related breathing disorder and referral to a sleep specialist would be beneficial for patients with these complaints. PMID- 25273081 TI - Progress toward curing HIV infections with hematopoietic stem cell transplantation. AB - Combination antiretroviral therapy can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate the virus. A major obstacle in the quest for a cure is the difficulty in targeting and measuring latently infected cells. To date, a single person seems to have been cured of HIV. Hematopoietic stem cell transplantation (HSCT) preceded this cancer patient's long-term sustained HIV remission, but researchers have been unable to replicate this cure, and the mechanisms that led to HIV remission remain to be established. In February 2014, the National Institute of Allergy and Infectious Diseases sponsored a workshop that provided a venue for in-depth discussion of whether HSCT could be exploited to cure HIV in cancer patients requiring such procedures. Participants also discussed how HSCT might be applied to a broader community of HIV-infected persons in whom the risks of HSCT currently outweigh the likelihood and benefits of HIV cure. PMID- 25273082 TI - The role of antiviral therapy in immunocompromised patients with herpes simplex virus meningitis. AB - BACKGROUND: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are important causes of acute neurologic illness. Although the role of acyclovir in treating HSV encephalitis is clear, the role of antiviral therapy in HSV meningitis remains controversial. METHODS: In this retrospective observational study, we reviewed the charts of all patients with cerebrospinal fluid specimens positive for HSV-1 or HSV-2 by polymerase chain reaction between July 2000 and November 2012. Patients' charts were reviewed for demographic data, clinical presentation, treatment, and clinical outcomes. RESULTS: Forty-two patient-episodes were clinically classified as meningitis. In 6 episodes (14.3%), patients with meningitis received no antivirals, whereas the remaining episodes were treated with an oral antiviral (n = 11 [26.2%]), combination intravenous and oral therapy (n = 22 [52.4%]), or intravenous acyclovir alone (n = 3 [7.1%]). Six patients had recurrent episodes of meningitis and all recovered without any neurologic sequelae. Neurologic outcomes were significantly improved with antiviral therapy in immunocompromised patients with herpes meningitis (P < .05), but not in the 27 patient-episodes among immunocompetent patients (P = 1.0), as no neurologic sequelae were noted in this group. CONCLUSIONS: Most patients with HSV meningitis rapidly improve, but immunocompromised hosts have more neurologic sequelae and may benefit from antiviral therapy. Our data suggest symptomatic treatment alone for immunocompetent patients with HSV meningitis, avoiding the cost and side effects of prolonged intravenous acyclovir therapy; in contrast, immunocompromised patients had improved outcomes and would therefore benefit from antiviral therapy. PMID- 25273083 TI - Editorial commentary: Comparative efficacy of lamivudine and emtricitabine: comparing the results of randomized trials and cohorts. PMID- 25273080 TI - Increased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort. AB - BACKGROUND: Guidelines for treatment of human immunodeficiency virus type 1 (HIV 1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART. METHODS: This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. RESULTS: Therapy naive HIV-1-infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11-2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25-3.52) in on-treatment analysis. Propensity score-adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61-3.42) with efavirenz and 2.01 (95% CI, 1.36-2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression. CONCLUSIONS: The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available. PMID- 25273084 TI - Reciprocal myocardial-endocardial interactions pattern the delay in atrioventricular junction conduction. AB - Efficient blood flow depends on two developmental processes that occur within the atrioventricular junction (AVJ) of the heart: conduction delay, which entrains sequential chamber contraction; and valve formation, which prevents retrograde fluid movement. Defects in either result in severe congenital heart disease; however, little is known about the interplay between these two crucial developmental processes. Here, we show that AVJ conduction delay is locally assigned by the morphogenetic events that initiate valve formation. Our data demonstrate that physical separation from endocardial-derived factors prevents AVJ myocardium from becoming fast conducting. Mechanistically, this physical separation is induced by myocardial-derived factors that support cardiac jelly deposition at the onset of valve formation. These data offer a novel paradigm for conduction patterning, whereby reciprocal myocardial-endocardial interactions coordinate the processes of valve formation with establishment of conduction delay. This, in turn, synchronizes the electrophysiological and structural events necessary for the optimization of blood flow through the developing heart. PMID- 25273085 TI - mTOR regulates brain morphogenesis by mediating GSK3 signaling. AB - Balanced control of neural progenitor maintenance and neuron production is crucial in establishing functional neural circuits during brain development, and abnormalities in this process are implicated in many neurological diseases. However, the regulatory mechanisms of neural progenitor homeostasis remain poorly understood. Here, we show that mammalian target of rapamycin (mTOR) is required for maintaining neural progenitor pools and plays a key role in mediating glycogen synthase kinase 3 (GSK3) signaling during brain development. First, we generated and characterized conditional mutant mice exhibiting deletion of mTOR in neural progenitors and neurons in the developing brain using Nestin-cre and Nex-cre lines, respectively. The elimination of mTOR resulted in abnormal cell cycle progression of neural progenitors in the developing brain and thereby disruption of progenitor self-renewal. Accordingly, production of intermediate progenitors and postmitotic neurons were markedly suppressed. Next, we discovered that GSK3, a master regulator of neural progenitors, interacts with mTOR and controls its activity in cortical progenitors. Finally, we found that inactivation of mTOR activity suppresses the abnormal proliferation of neural progenitors induced by GSK3 deletion. Our findings reveal that the interaction between mTOR and GSK3 signaling plays an essential role in dynamic homeostasis of neural progenitors during brain development. PMID- 25273086 TI - A conserved role for non-neural ectoderm cells in early neural development. AB - During the early steps of head development, ectodermal patterning leads to the emergence of distinct non-neural and neural progenitor cells. The induction of the preplacodal ectoderm and the neural crest depends on well-studied signalling interactions between the non-neural ectoderm fated to become epidermis and the prospective neural plate. By contrast, the involvement of the non-neural ectoderm in the morphogenetic events leading to the development and patterning of the central nervous system has been studied less extensively. Here, we show that the removal of the rostral non-neural ectoderm abutting the prospective neural plate at late gastrulation stage leads, in mouse and chick embryos, to morphological defects in forebrain and craniofacial tissues. In particular, this ablation compromises the development of the telencephalon without affecting that of the diencephalon. Further investigations of ablated mouse embryos established that signalling centres crucial for forebrain regionalization, namely the axial mesendoderm and the anterior neural ridge, form normally. Moreover, changes in cell death or cell proliferation could not explain the specific loss of telencephalic tissue. Finally, we provide evidence that the removal of rostral tissues triggers misregulation of the BMP, WNT and FGF signalling pathways that may affect telencephalon development. This study opens new perspectives on the role of the neural/non-neural interface and reveals its functional relevance across higher vertebrates. PMID- 25273087 TI - Genome-wide identification of signaling center enhancers in the developing limb. AB - The limb is widely used as a model developmental system and changes to gene expression patterns in its signaling centers, notably the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER), are known to cause limb malformations and evolutionary differences in limb morphology. Although several genes that define these limb signaling centers have been described, the identification of regulatory elements that are active within these centers has been limited. By dissecting mouse E11.5 limbs that fluorescently mark the ZPA or AER, followed by fluorescence-activated cell sorting and low-cell H3K27ac ChIP seq, we identified thousands of specific signaling-center enhancers. Our ChIP-seq datasets show strong correlation with ZPA- and AER-expressed genes, previously characterized functional ZPA and AER enhancers and enrichment for relevant biological terms related to limb development and malformation for the neighboring genes. Using transgenic assays, we show that several of these sequences function as ZPA and AER enhancers. Our results identify novel ZPA and AER enhancers that could be important regulators of genes involved in the establishment of these specialized regions and the patterning of tetrapod limbs. PMID- 25273088 TI - IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress. AB - Osteosarcoma is a malignant bone tumor in children and adolescents characterized by intrinsic therapeutic resistance. The IGF2 is expressed at elevated levels in osteosarcoma after treatment with chemotherapy, prompting an examination of its functional contributions to resistance. We found that continuous exposure to IGF2 or insulin in the absence of serum created a dormant growth state in osteosarcoma cells that conferred resistance to various chemotherapeutic drugs in vitro. Mechanistic investigations revealed that this dormant state correlated with downregulation of downstream signaling by the IGF1 receptor, heightened cell survival, enhanced autophagy, and the presence of extracellular glutamine. Notably, inhibiting autophagy or depleting glutamine was sufficient to increase chemotherapeutic sensitivity in osteosarcoma xenografts in mice. Clinically, we confirmed that IGF expression levels were elevated in human osteosarcoma specimens from patients who received chemotherapy. Together, our results suggest that activation of IGF or insulin signaling preserves the survival of osteosarcoma cells under chemotherapeutic stress, providing a drug-resistant population that may engender minimal residual disease. Attenuating this survival mechanism may help overcome therapeutic resistance in osteosarcoma. PMID- 25273090 TI - Tumor-derived osteopontin suppresses antitumor immunity by promoting extramedullary myelopoiesis. AB - Extramedullary myelopoiesis occurs commonly in tumor-bearing animals and is known to lead to accumulation of peripheral myeloid-derived suppressor cells (MDSC), which play an important role in immune escape. However, the cellular and molecular mechanisms by which tumors induce extramedullary myelopoiesis are poorly understood. In this study, we found that osteopontin expressed by tumor cells enhances extramedullary myelopoiesis in a CD44-dependent manner through the Erk1/2-MAPK pathway. Osteopontin-mediated extramedullary myelopoiesis was directly associated with increased MDSCs in tumor-bearing hosts. More importantly, osteopontin silencing in tumor cells delayed both tumor growth and extramedullary myelopoiesis, while the same treatment did not affect tumor growth in vitro. Finally, treatment with an antibody against osteopontin inhibited tumor growth and synergized with cell-based immunotherapeutic vaccines in mediating antitumor immunity. Our findings unveil a novel immunosuppressive role for tumor derived osteopontin and offer a rationale for its therapeutic targeting in cancer treatment. PMID- 25273089 TI - RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner. AB - Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients. PMID- 25273092 TI - Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. AB - A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs. In this study, we defined parameters that maximize the antitumor activity of a nanoliposomal formulation of irinotecan (nal IRI). In a mouse xenograft model of human colon carcinoma, nal-IRI dosing could achieve higher intratumoral levels of the prodrug irinotecan and its active metabolite SN-38 compared with free irinotecan. For example, nal-IRI administered at doses 5-fold lower than free irinotecan achieved similar intratumoral exposure of SN-38 but with superior antitumor activity. Tumor response and pharmacokinetic modeling identified the duration for which concentrations of SN-38 persisted above a critical intratumoral threshold of 120 nmol/L as determinant for antitumor activity. We identified tumor permeability and carboxylesterase activity needed for prodrug activation as critical factors in achieving longer duration of SN-38 in tumors. Simulations varying tumor permeability and carboxylesterase activity predicted a concave increase in tumor SN-38 duration, which was confirmed experimentally in 13 tumor xenograft models. Tumors in which higher SN-38 duration was achieved displayed more robust growth inhibition compared with tumors with lower SN-38 duration, confirming the importance of this factor in drug response. Overall, our work shows how liposomal encapsulation of irinotecan can safely improve its antitumor activity in preclinical models by enhancing accumulation of its active metabolite within the tumor microenvironment. PMID- 25273093 TI - Opening up clinical study design to the long tail. PMID- 25273091 TI - TGFbeta receptor 1: an immune susceptibility gene in HPV-associated cancer. AB - Only a minority of those exposed to human papillomavirus (HPV) develop HPV related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFbetaR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFbetaR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFbetaR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFbetaR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFbetaR1/TGFbeta signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID- 25273094 TI - IL-25: the missing link between allergy, viral infection, and asthma? AB - Interleukin 25 boosts proinflammatory and proasthmatic responses in the allergic lung and emerges as a key determinant of virally induced asthma exacerbations and as a therapeutic target for asthma (Beale et al., this issue). PMID- 25273095 TI - Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. AB - Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation. PMID- 25273096 TI - Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. AB - Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/betaGeo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/betaGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome. PMID- 25273098 TI - Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans. AB - Spinal cord injury (SCI) is a devastating disorder for which the identification of exacerbating factors is urgently needed. We demonstrate that transient hyperglycemia during acute SCI is a detrimental factor that impairs functional improvement in mice and human patients after acute SCI. Under hyperglycemic conditions, both in vivo and in vitro, inflammation was enhanced through promotion of the nuclear translocation of the nuclear factor kappaB (NF-kappaB) transcription factor in microglial cells. During acute SCI, hyperglycemic mice exhibited progressive neural damage, with more severe motor deficits than those observed in normoglycemic mice. Consistent with the animal study findings, a Pearson chi(2) analysis of data for 528 patients with SCI indicated that hyperglycemia on admission (glucose concentration >=126 mg/dl) was a significant risk predictor of poor functional outcome. Moreover, a multiple linear regression analysis showed hyperglycemia at admission to be a powerful independent risk factor for a poor motor outcome, even after excluding patients with diabetes mellitus with chronic hyperglycemia (regression coefficient, -1.37; 95% confidence interval, -2.65 to -0.10; P < 0.05). Manipulating blood glucose during acute SCI in hyperglycemic mice rescued the exacerbation of pathophysiology and improved motor functional outcomes. Our findings suggest that hyperglycemia during acute SCI may be a useful prognostic factor with a negative impact on motor function, highlighting the importance of achieving tight glycemic control after central nervous system injury. PMID- 25273099 TI - Miles to go: the prison expressway, health research, and health activism. PMID- 25273097 TI - A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. AB - Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation is a cause of accelerated graft loss. To evaluate pathogenic antibodies (Abs) in rFSGS, we processed 141 serum samples from 64 patients with and without primary rFSGS and 34 non-FSGS control patients transplanted at four hospitals. We screened about 9000 antigens in pretransplant sera and selected 10 Abs targeting glomerular antigens for enzyme-linked immunosorbent assay (ELISA) validation. A panel of seven Abs (CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and APOL2) could predict posttransplant FSGS recurrence with 92% accuracy. Pretransplant elevation of anti-CD40 Ab alone had the best correlation (78% accuracy) with rFSGS risk after transplantation. Epitope mapping of CD40 with customized peptide arrays and rFSGS sera demonstrated altered immunogenicity of the extracellular CD40 domain in rFSGS. Immunohistochemistry of CD40 demonstrated a differential expression in FSGS compared to non-FSGS controls. Anti-CD40 Abs purified from rFSGS patients were particularly pathogenic in human podocyte cultures. Injection of anti-CD40/rFSGS Ab enhanced suPAR (soluble urokinase receptor)-mediated proteinuria in wild-type mice, yet no sensitizing effect was noted in mice deficient in CD40 or in wild-type mice that received blocking Ab to CD40. In conclusion, a panel of seven Abs can help identify primary FSGS patients at high risk of recurrence before transplantation. Intrarenal CD40 (and possibly other specific glomerular antigens) is an important contributor to FSGS disease pathogenesis. Human trials of anti-CD40 therapies are warranted to evaluate their efficacy for preventing rFSGS and improving graft survival. PMID- 25273102 TI - A Python package for parsing, validating, mapping and formatting sequence variants using HGVS nomenclature. AB - Biological sequence variants are commonly represented in scientific literature, clinical reports and databases of variation using the mutation nomenclature guidelines endorsed by the Human Genome Variation Society (HGVS). Despite the widespread use of the standard, no freely available and comprehensive programming libraries are available. Here we report an open-source and easy-to-use Python library that facilitates the parsing, manipulation, formatting and validation of variants according to the HGVS specification. The current implementation focuses on the subset of the HGVS recommendations that precisely describe sequence-level variation relevant to the application of high-throughput sequencing to clinical diagnostics. AVAILABILITY AND IMPLEMENTATION: The package is released under the Apache 2.0 open-source license. Source code, documentation and issue tracking are available at http://bitbucket.org/hgvs/hgvs/. Python packages are available at PyPI (https://pypi.python.org/pypi/hgvs). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273103 TI - The RNA shapes studio. AB - MOTIVATION: Abstract shape analysis, first proposed in 2004, allows one to extract several relevant structures from the folding space of an RNA sequence, preferable to focusing in a single structure of minimal free energy. We report recent extensions to this approach. RESULTS: We have rebuilt the original RNAshapes as a repository of components that allows us to integrate several established tools for RNA structure analysis: RNAshapes, RNAalishapes and pknotsRG, including its recent extension pKiss. As a spin-off, we obtain heretofore unavailable functionality: e. g. with pKiss, we can now perform abstract shape analysis for structures holding pseudoknots up to the complexity of kissing hairpin motifs. The new tool pAliKiss can predict kissing hairpin motifs from aligned sequences. Along with the integration, the functionality of the tools was also extended in manifold ways. AVAILABILITY AND IMPLEMENTATION: As before, the tool is available on the Bielefeld Bioinformatics server at http://bibiserv.cebitec.uni-bielefeld.de/rnashapesstudio. CONTACT: bibi help@cebitec.uni-bielefeld.de. PMID- 25273104 TI - WhopGenome: high-speed access to whole-genome variation and sequence data in R. AB - SUMMARY: The statistical programming language R has become a de facto standard for the analysis of many types of biological data, and is well suited for the rapid development of new algorithms. However, variant call data from population scale resequencing projects are typically too large to be read and processed efficiently with R's built-in I/O capabilities. WhopGenome can efficiently read whole-genome variation data stored in the widely used variant call format (VCF) file format into several R data types. VCF files can be accessed either on local hard drives or on remote servers. WhopGenome can associate variants with annotations such as those available from the UCSC genome browser, and can accelerate the reading process by filtering loci according to user-defined criteria. WhopGenome can also read other Tabix-indexed files and create indices to allow fast selective access to FASTA-formatted sequence files. AVAILABILITY AND IMPLEMENTATION: The WhopGenome R package is available on CRAN at http://cran.r-project.org/web/packages/WhopGenome/. A Bioconductor package has been submitted. CONTACT: lercher@cs.uni-duesseldorf.de. PMID- 25273105 TI - OrthoInspector 2.0: Software and database updates. AB - SUMMARY: We previously developed OrthoInspector, a package incorporating an original algorithm for the detection of orthology and inparalogy relations between different species. We have added new functionalities to the package. While its original algorithm was not modified, performing similar orthology predictions, we facilitated the prediction of very large databases (thousands of proteomes), refurbished its graphical interface, added new visualization tools for comparative genomics/protein family analysis and facilitated its deployment in a network environment. Finally, we have released three online databases of precomputed orthology relationships. AVAILABILITY: Package and databases are freely available at http://lbgi.fr/orthoinspector with all major browsers supported. CONTACT: odile.lecompte@unistra.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273107 TI - ExportAid: database of RNA elements regulating nuclear RNA export in mammals. AB - MOTIVATION: Regulation of nuclear mRNA export or retention is carried out by RNA elements but the mechanism is not yet well understood. To understand the mRNA export process, it is important to collect all the involved RNA elements and their trans-acting factors. RESULTS: By hand-curated literature screening we collected, in ExportAid database, experimentally assessed data about RNA elements regulating nuclear export or retention of endogenous, heterologous or artificial RNAs in mammalian cells. This database could help to understand the RNA export language and to study the possible export efficiency alterations owing to mutations or polymorphisms. Currently, ExportAid stores 235 and 96 RNA elements, respectively, increasing and decreasing export efficiency, and 98 neutral assessed sequences. AVAILABILITY AND IMPLEMENTATION: Freely accessible without registration at http://www.introni.it/ExportAid/ExportAid.html. Database and web interface are implemented in Perl, MySQL, Apache and JavaScript with all major browsers supported. PMID- 25273106 TI - Curation, integration and visualization of bacterial virulence factors in PATRIC. AB - MOTIVATION: We've developed a highly curated bacterial virulence factor (VF) library in PATRIC (Pathosystems Resource Integration Center, www.patricbrc.org) to support infectious disease research. Although several VF databases are available, there is still a need to incorporate new knowledge found in published experimental evidence and integrate these data with other information known for these specific VF genes, including genomic and other omics data. This integration supports the identification of VFs, comparative studies and hypothesis generation, which facilitates the understanding of virulence and pathogenicity. RESULTS: We have manually curated VFs from six prioritized NIAID (National Institute of Allergy and Infectious Diseases) category A-C bacterial pathogen genera, Mycobacterium, Salmonella, Escherichia, Shigella, Listeria and Bartonella, using published literature. This curated information on virulence has been integrated with data from genomic functional annotations, trancriptomic experiments, protein-protein interactions and disease information already present in PATRIC. Such integration gives researchers access to a broad array of information about these individual genes, and also to a suite of tools to perform comparative genomic and transcriptomics analysis that are available at PATRIC. AVAILABILITY AND IMPLEMENTATION: All tools and data are freely available at PATRIC (http://patricbrc.org). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273108 TI - Inference of protein kinetics by stochastic modeling and simulation of fluorescence recovery after photobleaching experiments. AB - MOTIVATION: Fluorescence recovery after photobleaching (FRAP) is a functional live cell imaging technique that permits the exploration of protein dynamics in living cells. To extract kinetic parameters from FRAP data, a number of analytical models have been developed. Simplifications are inherent in these models, which may lead to inexhaustive or inaccurate exploitation of the experimental data. An appealing alternative is offered by the simulation of biological processes in realistic environments at a particle level. However, inference of kinetic parameters using simulation-based models is still limited. RESULTS: We introduce and demonstrate a new method for the inference of kinetic parameter values from FRAP data. A small number of in silico FRAP experiments is used to construct a mapping from FRAP recovery curves to the parameters of the underlying protein kinetics. Parameter estimates from experimental data can then be computed by applying the mapping to the observed recovery curves. A bootstrap process is used to investigate identifiability of the physical parameters and determine confidence regions for their estimates. Our method circumvents the computational burden of seeking the best-fitting parameters via iterative simulation. After validation on synthetic data, the method is applied to the analysis of the nuclear proteins Cdt1, PCNA and GFPnls. Parameter estimation results from several experimental samples are in accordance with previous findings, but also allow us to discuss identifiability issues as well as cell-to cell variability of the protein kinetics. IMPLEMENTATION: All methods were implemented in MATLAB R2011b. Monte Carlo simulations were run on the HPC cluster Brutus of ETH Zurich. CONTACT: lygeros@control.ee.ethz.ch or lygerou@med.upatras.gr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273109 TI - KDDN: an open-source Cytoscape app for constructing differential dependency networks with significant rewiring. AB - We have developed an integrated molecular network learning method, within a well grounded mathematical framework, to construct differential dependency networks with significant rewiring. This knowledge-fused differential dependency networks (KDDN) method, implemented as a Java Cytoscape app, can be used to optimally integrate prior biological knowledge with measured data to simultaneously construct both common and differential networks, to quantitatively assign model parameters and significant rewiring p-values and to provide user-friendly graphical results. The KDDN algorithm is computationally efficient and provides users with parallel computing capability using ubiquitous multi-core machines. We demonstrate the performance of KDDN on various simulations and real gene expression datasets, and further compare the results with those obtained by the most relevant peer methods. The acquired biologically plausible results provide new insights into network rewiring as a mechanistic principle and illustrate KDDN's ability to detect them efficiently and correctly. Although the principal application here involves microarray gene expressions, our methodology can be readily applied to other types of quantitative molecular profiling data. AVAILABILITY: Source code and compiled package are freely available for download at http://apps.cytoscape.org/apps/kddn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273110 TI - PROPER: comprehensive power evaluation for differential expression using RNA-seq. AB - MOTIVATION: RNA-seq has become a routine technique in differential expression (DE) identification. Scientists face a number of experimental design decisions, including the sample size. The power for detecting differential expression is affected by several factors, including the fraction of DE genes, distribution of the magnitude of DE, distribution of gene expression level, sequencing coverage and the choice of type I error control. The complexity and flexibility of RNA-seq experiments, the high-throughput nature of transcriptome-wide expression measurements and the unique characteristics of RNA-seq data make the power assessment particularly challenging. RESULTS: We propose prospective power assessment instead of a direct sample size calculation by making assumptions on all of these factors. Our power assessment tool includes two components: (i) a semi-parametric simulation that generates data based on actual RNA-seq experiments with flexible choices on baseline expressions, biological variations and patterns of DE; and (ii) a power assessment component that provides a comprehensive view of power. We introduce the concepts of stratified power and false discovery cost, and demonstrate the usefulness of our method in experimental design (such as sample size and sequencing depth), as well as analysis plan (gene filtering). AVAILABILITY: The proposed method is implemented in a freely available R software package PROPER. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273111 TI - PFP/ESG: automated protein function prediction servers enhanced with Gene Ontology visualization tool. AB - Protein function prediction (PFP) is an automated function prediction method that predicts Gene Ontology (GO) annotations for a protein sequence using distantly related sequences and contextual associations of GO terms. Extended similarity group (ESG) is another GO prediction algorithm that makes predictions based on iterative sequence database searches. Here, we provide interactive web servers for the PFP and ESG algorithms that are equipped with an effective visualization of the GO predictions in a hierarchical topology. AVAILABILITY: PFP/ESG servers are freely available at http://kiharalab.org/web/pfp.php and http://kiharalab.org/web/esg.php, or access both at http://kiharalab.org/pfp_esg.php. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273112 TI - MulRF: a software package for phylogenetic analysis using multi-copy gene trees. AB - SUMMARY: MulRF is a platform-independent software package for phylogenetic analysis using multi-copy gene trees. It seeks the species tree that minimizes the Robinson-Foulds (RF) distance to the input trees using a generalization of the RF distance to multi-labeled trees. The underlying generic tree distance measure and fast running time make MulRF useful for inferring phylogenies from large collections of gene trees, in which multiple evolutionary processes as well as phylogenetic error may contribute to gene tree discord. MulRF implements several features for customizing the species tree search and assessing the results, and it provides a user-friendly graphical user interface (GUI) with tree visualization. The species tree search is implemented in C++ and the GUI in Java Swing. AVAILABILITY: MulRF's executable as well as sample datasets and manual are available at http://genome.cs.iastate.edu/CBL/MulRF/, and the source code is available at https://github.com/ruchiherself/MulRFRepo. CONTACT: ruchic@ufl.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25273113 TI - Impedance pH Guided Approach to Proton Pump Inhibitor-refractory Non-erosive Reflux Disease. PMID- 25273114 TI - Is "how are you doing"enough? Need for tailored questions to the patients with functional dyspepsia. PMID- 25273116 TI - Effect of Prucalopride in the Treatment of Chronic Constipation in Asian and Non Asian Women: A Pooled Analysis of 4 Randomized, Placebo-controlled Studies. AB - BACKGROUND/AIMS: To compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC). METHODS: Data of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of >= 3 spontaneous complete bowel movements (SCBMs)/week; average increases of >= 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). RESULTS: Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of >= 3 SCBMs/week in Asian (34% vs. 11%, P < 0.001) and non-Asian (24.6% vs. 10.6%, P < 0.001) subgroups. The number of patients reporting an increase of>= 1 SCBMs/week from baseline was significantly higher in the prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups. CONCLUSIONS: Prucalopride 2-mg once-daily treatment over 12 weeks was more efficacious than placebo in promoting SCBMs and improve-ment of CC associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non Asian patients.(J Neurogastroenterol Motil 2014;20:458-468). PMID- 25273117 TI - Effects of GC7101, a Novel Prokinetic Agent on Gastric Motor Function: Ex Vivo Study. AB - BACKGROUND/AIMS: GC7101, an extract of Lonicera Flos, is a novel developing drug for reflux esophagitis and functional dyspepsia. However, the drug's exact pharmacological mechanism of action remains unclear. This study assessed the effects of GC7101 on gastro-intestinal (GI) motor function. METHODS: We used male guinea pigs to evaluate the effects of GC7101 on GI motility. The contraction of antral circular muscle in the presence of different doses of GC7101 was measured in a tissue bath. The prokinetic effects of GC7101 were tested using the charcoal transit assay from the pylorus to the most distal point of migration of charcoal mixture. To clarify the mechanism of action of GC7101, atropine, dopamine and the selective 5-hydroxytryptamine 4 receptor antagonist, GR113808 were used. RESULTS: The maximal amplitude of circular muscle contraction was induced by 5 mg mL(-1) GC7101. The area under the curve of con-traction was significantly increased at 5 mg mL(-1) GC7101. Addition of 10(-6) M atropine, 10(-8) M dopamine or 10(-7) M GR 113808 to GC7101 5 mg mL(-1) decreased the amplitude and area under curve compared to GC7101 5 mg mL(-1) alone. GC7101 accelerated GI transit in a dose dependent manner except 100 mg kg(-1). Delayed GI transit caused by atropine, dop amine and GR 113808 was restored by GC7101 50 mg kg(-1). CONCLUSIONS: GC7101, an extract of Lonicera Flos, exerts a gastric prokinetic effect in guinea pig through cholinergic, antidopaminergic and serotonergic mechanisms. Therefore, GC7101 might be a novel drug for the treatment of functional dyspepsia.(J Neurogastroenterol Motil 2014;20:469-474). PMID- 25273118 TI - Validation and diagnostic usefulness of gastroesophageal reflux disease questionnaire in a primary care level in Mexico. AB - BACKGROUND/AIMS: Different non-invasive diagnostics strategies have been used to assess patients with gastroesophageal reflux. Gastroesophageal reflux disease (GERD) questionnaire (GerdQ) is a 6-item, easy to use questionnaire that was developed primarily as a diagnostic tool for GERD in primary care. Our aim was to validate and assess diagnostic utility of GerdQ questionnaire in Mexican patients in the primary care setting. METHODS: The study was performed in 3 phases: (1) a questionnaire translation and comprehension study (n = 20), (2) are a reproduci bility and validation study (50 patients and 50 controls) and (3) a study to assess the clinical utility in 252 subjects with GERD symptoms. Diagnostic accuracy was calculated using endoscopy and/or pH-metry as the gold standard. RESULTS: Internal consistency measured by the Cronbach's alpha coefficient was 0.81 for patients and 0.90 for healthy controls, with a mixed coefficient of 0.93. Reproducibility for GerdQ was very good and its discriminating validity was 88%. Most of the pa-tients with erosive reflux and non-erosive reflux with abnormal pH-metry had scores > 8, meanwhile most of the patients with functional heartburn and hypersensitive esophagus had < 8. Sensitivity, specificity and positive predictive value of GerdQ com-pared to the gold standard were 72%, 72% and 87%, respectively. CONCLUSIONS: In Mexico, the GerdQ questionnaire Spanish validated version is useful for GERD diagnosis in the primary care setting.(J Neurogastroenterol Motil 2014;20:475-482). PMID- 25273115 TI - Colonic migrating motor complexes, high amplitude propagating contractions, neural reflexes and the importance of neuronal and mucosal serotonin. AB - The colonic migrating motor complex (CMMC) is a critical neurally mediated rhythmic propulsive contraction observed in the large intestine of many mammals. It seems to be equivalent to the high amplitude propagating contractions (HAPCs) in humans. This review focuses on the probable neural mechanisms involved in producing the CMMC or HAPC, their likely de-pendence on mucosal and neuronal serotonin and pacemaker insterstitial cells of Cajal networks and how intrinsic neural re-flexes affect them. Discussed is the possibility that myenteric 5 hydroxytryptamine (5-HT) neurons are not only involved in tonic inhibition of the colon, but are also involved in generating the CMMC and modulation of the entire enteric nervous system, including coupling motility to secretion and blood flow. Mucosal 5-HT appears to be important for the initiation and effective propagation of CMMCs, although this mechanism is a longstanding controversy since the 1950s, which we will address. We argue that the slow apparent propagation of the CMMC/HAPC down the colon is unlikely to result from a slowly conducting wave front of neural activity, but more likely because of an interaction between ascending excitatory and descending (serotonergic) inhibitory neural pathways interacting both within the myenteric plexus and at the level of the muscle. That is, CMMC/HAPC propagation appears to be similar to esophageal peristalsis. The suppression of inhibitory (neuronal nitric oxide synthase) motor neurons and mucosal 5-HT release by an upregulation of prostaglandins has important implications in a num-ber of gastrointestinal disorders, especially slow transit constipation.(J Neurogastroenterol Motil 2014;20:423-446). PMID- 25273119 TI - High-resolution Impedance Manometry Criteria in the Sitting Position Indicative of Incomplete Bolus Clearance. AB - BACKGROUND/AIMS: We used high-resolution impedance manometry (HRIM) to determine the length of breaks on the isobaric contour which would predict incomplete bolus clearance in patients in the sitting position. METHODS: In total, 651 swallows in 71 patients with esophageal symptoms were studied using a solid-state HRIM system in the sitting position. Each swallow was classified as complete or incomplete bolus clearance by impedance criteria and peristaltic integrity was evaluated using 20- and 30-mmHg pressure topography isobaric contours. Correlations between the lengths of the breaks for 20- and 30-mmHg were analyzed. RESULTS: Complete bolus clearance was observed in 83.3% (542/651) of swallows. Breaks of 3 and 7 cm or less were associated with a bolus clearance of 96.8% on the 20-mmHg and 94.7% on the 30-mmHg isobaric contour, respectively (P < 0.001). The areas under the ROC curves for the 20 and 30 mmHg isobaric contours were 0.900 and 0.950, respectively. The sensitivity and specificity for complete bolus clearance were 75.6% and 89.3% for breaks 3 cm or less on the 20-mmHg isobaric contour and 87.9% and 78.7% for breaks 7 cm or less on the 30-mmHg contour (P < 0.001). CONCLUSIONS: Breaks of < 3 cm in the 20-mmHg isobaric contour or < 7 cm in the 30 mmHg isobaric contour were associated with com-plete bolus clearance. The threshold for breaks in the sitting position was greater than previous reports using the supine posi-tion and longer breaks predicted incomplete bolus clearance.(J Neurogastroenterol Motil 2014;20:491-496). PMID- 25273120 TI - Diagnostic Utility of Impedance-pH Monitoring in Refractory Non-erosive Reflux Disease. AB - BACKGROUND/AIMS: Approximately one-third of non-erosive reflux disease (NERD) patients are refractory to proton pump inhibitors (PPI) and face a therapeutic challenge. Therefore, it is important to differentiate between pathological and non-pathological reflux utilizing multichannel intraluminal impedance-pH (MII-pH) to analyze symptom-reflux association and diagnose true NERD versus hyper sensitive esophagus (HE) and functional heartburn (FH). Herein, we evaluated the diagnostic yield of MII-pH in refractory NERD and sub-classified it based on quantity and quality of acid/non-acid reflux and reflux-symptom association. METHODS: Sixty symptomatic NERD patients on twice daily PPI for > 2 months were prospectively evaluated by MII-pH. Distal and prox-imal refluxes, bolus exposure time (BET), esophageal acid exposure time, symptom index (SI) and symptom association proba-bility (SAP) were measured. RESULTS: Thirty-two (53%) patients had BET > 1.4% (MII-pH positive-true NERD), while 28 (47%) had BET < 1.4% (MII-pH negative NERD) where SI and SAP were negative in 15/60 (25%; categorized as FH) and SI or SAP were positive in 13/60 (22%; identi-fied as HE). Thirty-eight (63%) patients reported significant SI or SAP parameters where > 80% of symptoms were associated with non-acid reflux. The number of distal refluxes in true NERD versus FH or HE were significantly different, but not between FH and HE. CONCLUSIONS: Approximately 60% of refractory PPI NERD patients had positive reflux-symptom association, primarily due to non-acid reflux. Nearly half of NERD patients on PPI had normal MII-pH monitoring, sub-divided further into FH and HE equally.(J Neurogastroenterol Motil 2014;20:497-505). PMID- 25273121 TI - Impact of eating attitude and impairment of physical quality of life between tertiary clinic and primary clinic functional dyspepsia outpatients in Japan. AB - BACKGROUND/AIMS: There is no available data on factors associated with healthcare seeking behavior for functional dyspepsia (FD) symptoms at ei-ther tertiary or primary clinics in Japan. Therefore, we aimed to compare clinical symptoms and life styles such as sleep dis-orders and eating attitude in FD patients visiting general practitioners at primary clinics with those consulting gastro enterologists at tertiary clinics to clarify healthcare-seeking patterns in Japanese patients. METHODS: Fifty-one FD outpatients in a tertiary clinic (college hospital), 50 FD outpatients visiting primary clinics and 50 healthy volunteers were enrolled. Clinical symptoms, quality of life, sleep disorders, eating attitude and anxiety were estimated using the Gastroin-testinal Symptom Rating Scale (GSRS), Social Functioning-8 (SF-8) test, Pittsburg Sleep Quality Index (PSQI) test and State-Trait Anxiety Inventory (STAI) for FD outpatients and healthy volunteers. RESULTS: FD outpatients exhibited higher mean scores of GSRS than healthy volunteers. The SF-8 physical component summary scores in the tertiary clinic group were significantly lower than those in the primary clinic group. GSRS scores were significantly (P < 0.001, P = 0.002) associated with global PSQI scores in FD outpatients as well as with STAI-trait scores (P = 0.006, P = 0.001) compared to healthy volunteers. The frequency of eating between meals in the primary clinic group was significantly (P < 0.05) higher than that in the tertiary clinic group. CONCLUSIONS: It may be important for clarification of healthcare-seeking behavior to determine the difference in both impairment of physical quality of life and eating attitudes between tertiary clinic and primary clinic FD outpatients in Japan.(J Neurogastroenterol Motil 2014;20:506-515). PMID- 25273122 TI - Post-traumatic Stress Disorder Is Associated With Irritable Bowel Syndrome in African Americans. AB - BACKGROUND/AIMS: Psychosocial stressors likely play an important role in irritable bowel syndrome (IBS). The association between IBS and post-trau-matic stress disorder (PTSD) in non-minorities has been described. Our aim was to investigate the potential association between IBS and PTSD in an urban African American population. METHODS: Our institution maintains a longitudinal population based survey of African Americans (AA). The survey utilizes a complex, stratified sampling design. The study group consisted of adult AA meeting Rome III criteria for IBS of any subtype. The 4-item Primary Care PTSD screener was administered; score of>= 3 (range, 0-4) was considered positive for PTSD. Depression (Public Health Questionnaire-9 depression) and anxiety (generalized anxiety disorder-7) levels were measured using standardized scales. To assess quality of life, norm based physical and mental component summary scores from the short-form 36 health survey ver-sion 2 were obtained. Descriptive and inferential statistics were calculated using Complex Sample Module of SPSS after weight-ing of the study sample. RESULTS: Four hundred nineteen subjects included corresponded to a weighted 21,264 (95% CI, 19,777-22,751) individuals. The preva-lence of IBS in our sample of urban AA was 8.2%. In multivariate regression analysis, female gender, age > 40, higher educa-tional attainment and divorce were independently associated with IBS. Those with IBS were considerably more likely to suffer from PTSD (OR, 4.54; 95% CI, 4.07-5.06). PTSD was independently associated with depression, anxiety, harmful drinking and substance abuse. CONCLUSIONS: In AA, PTSD is independently associated with IBS. PTSD has a significantly negative impact on physical and mental self-assess-ment of quality of life. Evaluation of minorities presenting with functional gastrointestinal disorders should include screening for PTSD.(J Neurogastroenterol Motil 2014;20:523-530). PMID- 25273123 TI - Fecal Evacuation Disorder Among Patients With Solitary Rectal Ulcer Syndrome: A Case-control Study. AB - BACKGROUND/AIMS: Data on frequency of fecal evacuation disorder (FED) among patients with solitary rectal ulcer syndrome (SRUS), hitherto an enigmatic condition, are scanty. Moreover, most such studies had limitations due to small sample size and lack of inclusion of healthy controls (HC). METHODS: Forty patients with SRUS underwent symptom assessments, sigmoidoscopy, anorectal manometry, defecography, balloon ex-pulsion test (BET); endoscopic ultrasound (EUS) of anal sphincter complex was performed in a subgroup. Physiological tests (anorectal manometry and BET) were also performed in 19 HC. RESULTS: Patients with SRUS (26/40 male, age 37 [18-80] years) more often had FED than HC (10/19 male, age 43 [25-72] years) as shown by weight needed to expel the balloon (300 [0-700] g vs. 100 [0-400] g; P = 0.006), a trend towards abnormal BET (need of > 200 g weight for expulsion) (21/40 [53%] vs. 5/19 [26%], P = 0.058) and impaired anal relaxation (14/40 [35%] vs 2/19 [10.5%]; P = 0.048). Using Rome III criteria, most patients with SRUS reported having chronic constipation (36/40 [90%]) in spite of having normal (Bristol stool type IV, 21/40 [53%]) and diarrheal (types V, VI, VII, 6/40 [20%]) stool forms (Asian classification). SRUS patients more often (17/40 [43%]) had functional defecation disorder (Rome III criteria). Patients with SRUS with abnormal BET had thicker internal anal sphincter than those without (3.9 [3.4-7.0] mm vs 2.8 [2.0-4.0] mm; P = 0.01). CONCLUSIONS: FED was commoner among patients with SRUS as evidenced by abnormal BET and sphincter relaxation. Those with abnormal BET had thicker internal sphincter on EUS than those without.(J Neurogastroenterol Motil 2014;20:531-538). PMID- 25273125 TI - What is the therapeutic mechanism of the probiotics in irritable bowel syndrome patients with visceral hypersensitivity? PMID- 25273124 TI - Length tension function of puborectalis muscle: implications for the treatment of fecal incontinence and pelvic floor disorders. AB - BACKGROUND/AIMS: External anal sphincter (EAS) and puborectalis muscle (PRM) play important role in anal continence function. Based on length-tension measurement, we recently reported that the human EAS muscle operates at short sarcomere length under phys-iological conditions. Goal of our study was to determine if PRM also operates at the short sarcomere length. METHODS: Length-tension relationship of the PRM muscle was studied in vivo in 10 healthy nullipara women. Length was altered by vagi-nal distension using custom-designed probes of 5, 10, 15, 20, 25 and 30 mm diameters as well as by distending a poly-ethylene bag with different volumes of water. Probes were equipped with a reverse perfuse sleeve sensor to measure vaginal pressure (surrogate of PRM tension). PRM electromyogram (EMG) was recorded using wire electrodes. Three-dimensional ultra-sound images were obtained to determine effect of vaginal distension on PRM length. RESULTS: Ultrasound images demonstrate distension volume dependent increase in PRM length. Rest and squeeze pressures of vaginal bag increased with the increase in bag volume. Similarly, the change in vaginal pressure, which represents the PRM contraction increased with the increase in the probe size. Increase in probe size was not associated with an increase in EMG activity (a marker of neural drive) of the PRM. CONCLUSIONS: Probe size dependent increase in PRM contraction pressure, in the presence of constant EMG (neural input) proves that the hu-man PRM operates at short sarcomere length. Surgically adjusting the PRM length may represent a novel strategy to improve treat anal continence and possibly other pelvic floor disorders.(J Neurogastroenterol Motil 2014;20:539-546). PMID- 25273126 TI - Circulating Inflammatory Cytokines Are Associated With the Risk of Barrett's Esophagus in Western Persons. PMID- 25273127 TI - Optimal Testing for Diagnosis of Fructose Intolerance: Over-dosage Leads to False Positive Intolerance Test. PMID- 25273128 TI - A Case of Post-fundoplication Dysphagia: Another Possible Interpretation of the Manometric Findings. PMID- 25273130 TI - A comparative analysis of characteristic floral scent compounds in Prunus mume and related species. AB - In order to investigate the difference in their characteristic floral scents between Prunus mume Siebold & Zucc. and the related Prunus species, their headspace volatiles and endogenous extraction were analyzed by gas chromatography mass spectrometry. The efficiency of substrate utilization of the flowers was studied by incubating them with different alcohol substrates. Our results indicated that benzyl acetate is a dominant compound influencing the characteristic floral scent of P. mume. An alcohol substrate concentration of 4 mmol L(-1) and a reaction time of 2 h were constituted the reaction condition for catalysis of exogenous alcohol substrates by the flowers. Under these conditions, Prunus sibirica exhibited the highest utilization efficiency for benzyl alcohol substrate while the utilization efficiency of Prunus persica was the lowest. Comparative analysis of several alcohol substrates indicated that the flowers of the tested species had selective specificity for benzyl alcohol substrates. PMID- 25273129 TI - Applying association mapping and genomic selection to the dissection of key traits in elite European wheat. AB - KEY MESSAGE: We show the application of association mapping and genomic selection for key breeding targets using a large panel of elite winter wheat varieties and a large volume of agronomic data. The heightening urgency to increase wheat production in line with the needs of a growing population, and in the face of climatic uncertainty, mean new approaches, including association mapping (AM) and genomic selection (GS) need to be validated and applied in wheat breeding. Key adaptive responses are the cornerstone of regional breeding. There is evidence that new ideotypes for long-standing traits such as flowering time may be required. In order to detect targets for future marker-assisted improvement and validate the practical application of GS for wheat breeding we genotyped 376 elite wheat varieties with 3,046 DArT, single nucleotide polymorphism and gene markers and measured seven traits in replicated yield trials over 2 years in France, Germany and the UK. The scale of the phenotyping exceeds the breadth of previous AM and GS studies in these key economic wheat production regions of Northern Europe. Mixed-linear modelling (MLM) detected significant marker-trait associations across and within regions. Genomic prediction using elastic net gave low to high prediction accuracies depending on the trait, and could be experimentally increased by modifying the constituents of the training population (TP). We also tested the use of differentially penalised regression to integrate candidate gene and genome-wide markers to predict traits, demonstrating the validity and simplicity of this approach. Overall, our results suggest that whilst AM offers potential for application in both research and breeding, GS represents an exciting opportunity to select key traits, and that optimisation of the TP is crucial to its successful implementation. PMID- 25273131 TI - Prophylactic effect of the oral administration of transgenic rice seeds containing altered peptide ligands of type II collagen on rheumatoid arthritis. AB - Rheumatoid arthritis is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We generated transgenic rice seeds expressing three types of altered peptide ligands (APL) and the T cell epitope of type II collagen (CII256-271). When these transgenic rice and non-transgenic rice seeds were orally administrated to DBA/1 J mice once a day for 14 days, followed by immunization with CII, the clinical score of collagen-induced arthritis (CIA) was reduced and inflammation and erosion in the joints were prevented in mice fed APL7 transgenic rice only. IL-10 production against the CII antigen significantly increased in the splenocytes and iLN of CIA mice immunized with the CII antigen, whereas IFN-gamma, IL-17, and IL-2 levels were not altered. These results suggest that IL-10-mediated immune suppression is involved in the prophylactic effects caused by transgenic rice expressing APL7. PMID- 25273132 TI - Commensal bacteria directly suppress in vitro degranulation of mast cells in a MyD88-independent manner. AB - The intestine harbors a substantial number of commensal bacteria that provide considerable benefits to the host. Epidemiologic studies have identified associations between alterations in the composition of the intestinal microbiota and the development of allergic disease. However, the cellular and molecular mechanisms underlying these effects remain to be determined. Here, we show that heat-killed commensal bacteria suppressed degranulation of mast cells in vitro in a MyD88-independent manner. In particular, Enterococcus faecalis showed the strongest suppression of degranulation through partial inhibition of Ca(2+) signaling upon the high affinity IgE receptor (FcepsilonRI) cross-linking. PMID- 25273133 TI - Involvement of hydrophobic amino acid residues in C7-C8 loop of Aspergillus oryzae hydrophobin RolA in hydrophobic interaction between RolA and a polyester. AB - Hydrophobins are amphipathic secretory proteins with eight conserved cysteine residues and are ubiquitous among filamentous fungi. The Cys3-Cys4 and Cys7-Cys8 loops of hydrophobins are thought to form hydrophobic segments involved in adsorption of hydrophobins on hydrophobic surfaces. When the fungus Aspergillus oryzae is grown in a liquid medium containing the polyester polybutylene succinate-co-adipate (PBSA), A. oryzae produces hydrophobin RolA, which attaches to PBSA. Here, we analyzed the kinetics of RolA adsorption on PBSA by using a PBSA pull-down assay and a quartz crystal microbalance (QCM) with PBSA-coated electrodes. We constructed RolA mutants in which hydrophobic amino acids in the two loops were replaced with serine, and we examined the kinetics of mutant adsorption on PBSA. QCM analysis revealed that mutants with replacements in the Cys7-Cys8 loop had lower affinity than wild-type RolA for PBSA, suggesting that this loop is involved in RolA adsorption on PBSA. PMID- 25273134 TI - Enhancement of RNA annealing and strand displacement found in archaeal ribonuclease P proteins is conserved in Escherichia coli protein C5 and yeast protein Rpr2. AB - We analyzed modes of action of ribonuclease P (RNase P) proteins, C5 in Escherichia coli and Rpr2 in Saccharomyces cerevisiae, using a pair of complementary fluorescence-labeled oligoribonucleotides. Fluorescence resonance energy transfer-based assays revealed that RNA annealing and strand displacement activities found in archaeal RNase P proteins are prevalent in eubacterial (C5) and eukaryotic (Rpr2) RNase P proteins. PMID- 25273135 TI - Effects of deer bone extract on the expression of pro-inflammatory cytokine and cartilage-related genes in monosodium iodoacetate-induced osteoarthritic rats. AB - Deer bone extract has the potential to relieve the discomfort or the articular cartilaginous damage associated with osteoarthritic (OA) and may be useful as a natural supplement for OA treatment without serious side effects. We analyzed the expression of pro-inflammatory cytokine and cartilage-related genes in monosodium iodoacetate-induced OA rats. Increases in the levels of serum pro-inflammatory cytokines, such as interleukin-1beta, interleukin-6, and tumor necrosis factor alpha were significantly inhibited by the administration of deer bone extract (p<0.05). Decreases in the expression of collagen type II (COL2) and tissue inhibitors of metalloproteinases (TIMPs) mRNAs in the cartilage were significantly inhibited by deer bone extract treatment (p<0.05). The deer bone extract significantly suppressed the expression of matrix metalloproteinases (MMPs) mRNAs in the cartilage. The deer bone extract induced the up-regulation of COL2 and TIMP mRNAs and the down-regulation of MMP mRNAs by suppressing the expression of pro-inflammatory cytokine mRNAs. PMID- 25273136 TI - The multi-herbal formula Chong-Myung-Tang improves spatial memory and increases cell genesis in the dentate gyrus of aged mice. AB - Chong-Myung-Tang (CMT) is a multi-herbal formula that has been used to improve memory. However, the potential mechanism remains unknown. The present study investigated the effects of CMT (50, 100, and 200 mg/kg) on spatial memory of aged mice. The behavioral training tests indicated that 200 mg/kg CMT treatment can significantly improve spatial memory of aged mice in the Morris water maze. Moreover, cell survival was examined by injecting bromodeoxyuridine (BrdU) on the first three days. The result showed that 200 mg/kg CMT treatment significantly increased cell survival in the dentate gyrus. Cell proliferation was determined by injecting BrdU 2 h before the mice were killed. The result suggested that CMT treatments had no influence on cell proliferation in the dentate gyrus. Thus, an increase in cell survival in the dentate gyrus stimulated by CMT may be involved in the effect of CMT on spatial memory improvement. PMID- 25273137 TI - Enhancement of exercise endurance capacity by fermented deer antler in BALB/c mice. AB - To investigate the activity of fermented deer antler on exercise endurance capacity, we evaluated endurance capacity in five-week-old male BALB/c mice by administering the fermented deer antler extract (FA) or the non-fermented deer antler extract (NFA) and then subjected the mice to exercise in the form of swimming. The mice administered 500 mg/kg/day of FA showed a significant increase in swimming time compared with mice administered placebo (16.55 min vs. 21.64 min, P<0.05). Serum lactate dehydrogenase (LDH), the marker of the liver and muscle damage, was significantly lower in FA groups. However, NFA groups did not show significantly different swimming time or serum LDH from that of the control group. Moreover, the FA-500 group had significantly higher hepatic superoxide dismutase (SOD) activity after forced swimming than the control and NFA groups (P<0.05). These findings suggest that fermentation may increase the exercise endurance capacity of the deer antler. PMID- 25273138 TI - Antioxidative properties of ascorbigen in using multiple antioxidant assays. AB - The antioxidative properties of ascorbigen, one of the major indole-derived compounds of Brassica vegetables, were systematically evaluated using multiple assay systems with comparison to the well-known antioxidants ascorbic acid and Trolox. We first performed assays using model radicals, DPPH radical, galvinoxyl radical, and ABTS radical cation (ABTS(*+)). Ascorbigen showed stronger activity than that of ascorbic acid in the ABTS(*+)-scavenging assay but showed no activity in the DPPH radical- and galvinoxyl radical-scavenging assays. In the ABTS(*+)-scavenging assay, the indole moiety of ascorbigen contributed to scavenging of the radicals to produce indole-3-aldehyde as one of the final reaction products. The activity of ascorbigen was then evaluated by an oxygen radical absorbance capacity assay and an oxidative hemolysis inhibition assay using physiologically relevant peroxyl radicals, AAPH-derived radicals. Ascorbigen showed much stronger antioxidant activity than did ascorbic acid and Trolox. Therefore, antioxidant activity of ascorbigen might be more beneficial than has been thought for daily health care. PMID- 25273139 TI - Pollen Typhae total flavone improves insulin resistance in high-fat diet and low dose streptozotocin-induced type 2 diabetic rats. AB - Pollen Typhae total flavone (PTF), the extract from Pollen Typhae, is reported to enhance glucose uptake in C2C12 myotubes in vitro, but the convincing evidence is lacking in vivo. In this study, PTF ameliorated insulin resistance and dyslipidemia, but failed to significantly increase body weight in type 2 diabetic rats induced by high-fat diet and low-dose streptozotocin. PMID- 25273140 TI - The enhancing effect of fucoidan derived from Undaria pinnatifida on immunoglobulin production by mouse spleen lymphocytes. AB - In this study, we revealed that a Mekabu (Udaria pinnantifida) extract enhanced immunoglobulin (Ig) production of mouse spleen lymphocytes. Furthermore, it was suggested that water-soluble and high molecular weight ingredients in the Mekabu extract have significant enhancing effect on Ig production. Therefore, fucoidan was estimated as the active component. PMID- 25273141 TI - Practical application of flavonoid-poor menu meals to the study of the bioavailability of bilberry anthocyanins in human subjects. AB - Practical application of flavonoid-poor menus was evaluated on the bioavailability of anthocyanins as model flavonoids. Detectable amounts of flavonoids were not found in plasma and urine collected from 13 participants, who took the menus. After ingesting bilberry anthocyanins (919 MUmol), average plasma AUC0-6h, Cmax, Tmax values and urinary recovery were 386.0 nmol h/mL, 139.1 nM, 1.31 h and 0.21%, respectively. PMID- 25273142 TI - The human bitter taste receptor hTAS2R39 is the primary receptor for the bitterness of theaflavins. AB - We purified several hundred mgs of four major theaflavins (theaflavin, theaflavin 3-O-gallate, theaflavin-3'-O-gallate, and theaflavin-3,3'-O-digallate). Among the 25 hTAS2Rs expressed in HEK293T cells, hTAS2R39 and hTAS2R14 were activated by theaflavins. Both hTAS2R39 and hTAS2R14 responded to theaflavin-3'-O-gallate. In addition, hTAS2R39 was activated by theaflavin and theaflavin-3,3'-O-gallate, but not by theaflavin-3-O-gallate. In contrast, hTAS2R14 responded to theaflavin-3-O gallate. PMID- 25273143 TI - Urine 3-hydroxykynurenine is higher during the postovulatory phase than in the preovulatory phase indicating a higher vitamin B6 requirement. AB - The relationship between l-tryptophan to nicotinamide metabolism and the menstrual cycle of Japanese women was investigated. Nine metabolism intermediates from urine samples collected during the preovulatory and postovulatory phases were measured. Only urine 3-hydroxykynurenine was higher in the postovulatory phase than in the preovulatory phase. This increase in 3-hydroxykynurenine suggests a decreased reaction of 3-hydroxykynurenine -> 3-hydroxyanthranilic acid catalyzed by kynureninase, a vitamin B6 enzyme. PMID- 25273144 TI - Production of a pharmaceutical intermediate via biohydroxylation using whole cells of Rhodococcus rubropertinctus N82. AB - Rhodococcus rubropertinctus N82 possesses unique regiospecific hydroxylation activity in biotransformation of compounds. In this study, the ability of whole cells of the strain R. rubropertinctus N82 in biotransformation was studied. The hydroxylation activity resulted in transforming 6,7-dihydro-4H-thieno[3,2-c] pyridine-5-carboxylic acid tert-butyl ester (LS1) into 2-hydroxy-6,7-dihydro-4H thieno[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (LP1), a pharmaceutical intermediate. By optimizing conditions for the hydroxylating biotransformation using whole cells of R. rubropertinctus N82 as biocatalyst, 3.3 mM LP1 was successfully produced from 4 mM LS1 with a molar yield of 83%. Thus, effective method was newly developed to produce LP1, which is a synthetic intermediate of a platelet inhibitor active pharmaceutical ingredient drug, prasugrel. PMID- 25273146 TI - Metabolically driven equilibrium shift of asymmetric amination of ketones by omega-transaminase using alanine as an amino donor. AB - Removal of a side product to overcome unfavorable equilibrium is a prerequisite for the asymmetric amination of ketones using omega-transaminase (omega-TA). Alanine has been preferred as an amino donor because its deamination product (i.e. pyruvate) is easily removable by several enzymatic methods. Here, we demonstrated that the removal of pyruvate by an innate metabolic pathway could afford equilibrium shift of the omega-TA reactions. PMID- 25273145 TI - Identification and characterization of Aeromonas hydrophila genes encoding the outer membrane receptor of ferrioxamine B and an AraC-type transcriptional regulator. AB - We found that, under iron-limiting conditions, Aeromonas hydrophila ATCC 7966(T) could utilize the xenosiderophore desferrioxamine B (DFOB) for growth by inducing the expression of its own outer membrane receptor. Two consecutive genes, desR and desA, were selected as candidates involved in DFOB utilization. The presence of the ferric-uptake regulator boxes in their promoters suggested that these genes are under iron-dependent regulation. Mutation of desA, a gene that encodes the outer membrane receptor of ferrioxamine B, disrupted the growth of the amonabactin-deficient mutant in the presence of DFOB. beta-Galactosidase reporter assays and reverse transcriptase-quantitative PCR demonstrated that desR, a gene that encodes an AraC-like regulator homolog is required for the induction of desA transcription in the presence of DFOB and under iron-limiting conditions. The functions of desA and desR were analyzed using complementation experiments. Our data provided evidence that DesA is powered primarily by the TonB2 system. PMID- 25273147 TI - Screening micro-organisms for cadmium absorption from aqueous solution and cadmium absorption properties of Arthrobacter nicotianae. AB - To obtain basic information on how microbial cells absorb cadmium from aqueous solution, we examined cadmium absorption in various micro-organisms. Of 51 micro organism strains tested, we found that some Gram-positive bacteria, such as, Arthrobacter nicotianae and Bacillus subtilis, and some actinomycetes, such as, Streptomyces flavoviridis and S. levoris were highly capable of absorbing cadmium from an aqueous solution. A. nicotianae absorbed the largest amount of cadmium, over 800 MUmol cadmium per gram of dry wt. cells. However, cadmium absorption by A. nicotianae was affected by the solution pH, cadmium concentration, and cell density. The absorption of cadmium was very rapid. Some factors that affected cadmium absorption by A. nicotianae cells were also discussed. PMID- 25273148 TI - Fungal colonization and enzyme-mediated metabolism of waste coal by Neosartorya fischeri strain ECCN 84. AB - Colonization and oxidative metabolism of South African low-rank discard coal by the fungal strain ECCN 84 previously isolated from a coal environment and identified as Neosartorya fischeri was investigated. Results show that waste coal supported fungal growth. Colonization of waste coal particles by N. fischeri ECCN 84 was associated with the formation of compact spherical pellets or sclerotia like structures. Dissection of the pellets from liquid cultures revealed a nucleus of "engulfed" coal which when analyzed by energy dispersive X-ray spectroscopy showed a time-dependent decline in weight percentage of elemental carbon and an increase in elemental oxygen. Proliferation of peroxisomes in hyphae attached to coal particles and increased extracellular laccase activity occurred after addition of waste coal to cultures of N. fischeri ECCN 84. These results support a role for oxidative enzyme action in the biodegradation of coal and suggest that extracellular laccase is a key component in this process. PMID- 25273152 TI - Dynamical conductivity of boron carbide: heavily damped plasma vibrations. AB - The FIR reflectivity spectra of boron carbide, measured down to omega~10 cm(-1) between 100 and 800 K, are essentially determined by heavily damped plasma vibrations. The spectra are fitted applying the classical Drude-Lorentz theory of free carriers. The fitting Parameter Pi=omegap/omegatau yields the carrier densities, which are immediately correlated with the concentration of structural defects in the homogeneity range. This correlation is proved for band-type and hopping conductivity. The effective mass of free holes in the valence band is estimated at m*/me~2.5. The mean free path of the free holes has the order of the cell parameters. PMID- 25273150 TI - Validation of the Chinese version of the Canadian Haemophilia Outcomes-Kids' Life Assessment Tool (the CHO-KLAT). AB - It is important to assess the health-related quality of life outcomes of boys in China, but there are no tools validated for this purpose. The objective of the study was to assess the validity of the Simplified Chinese version of the CHO KLAT2.0 . We recruited 60 boys with either haemophilia A (HA) or haemophilia B (HB) and their parents from four regions in China, and assessed the validity of CHO-KLAT compared to the PedsQL. All participants complete the CHO-KLAT a second time 1-2 weeks later to assess reliability. The boys ranged in age from 7 to 18 (mean = 12.4; SD = 3.03) years. The severity distribution was: mild (9), moderate (10) and severe (41). On-demand therapy was received by 26 boys, while 18 received low-dose prophylaxis (HA: 10 IU kg(-1) 2-3 times/week(-1) , and HB: 20 IU kg(-1) 1 time/week(-1) ). The mean CHO-KLAT scores were 63.7 (SD = 10.6) for child-report and 58.3 (SD = 11.4) for parent-report. Validity was supported by a correlation of 0.67 (P < 0.0001) with the PedsQL for child-report and 0.64 (P < 0.0001) for parent-report. The test-retest reliability was 0.88 (95% CI: 0.82 0.94) for child-report, and 0.90 (95% CI: 0.86-0.95) for parent-report. Inter rater reliability was 0.46 (95% CI: 0.26-0.66). CHO-KLAT scores were 11 points higher among patients who had been on prophylaxis 3 times per week for >=24 weeks. These results confirm the reliability and validity of the Chinese version of the CHO-KLAT. This measure is suitable for use in prospective clinical trials in boys with haemophilia in China. PMID- 25273151 TI - Childhood trauma and schizotypy: a systematic literature review. AB - BACKGROUND: Schizotypy is a complex concept, commonly defined as a genetic vulnerability to schizophrenia that falls on a continuum between healthy variation and severe mental illness. There is a growing body of evidence supporting an association between childhood trauma and increased psychotic experiences and disorders. However, the evidence as to whether there is a similar association with schizotypy has yet to be systematically synthesized and assessed. METHOD: We conducted a systematic search of published articles on the association between childhood trauma and schizotypy in four major databases. The search covered articles from 1806 to 1 March 2013 and resulted in 17,003 articles in total. Twenty-five original research studies met the eligibility criteria and were included in this review. RESULTS: All 25 studies supported the association between at least one type of trauma and schizotypy, with odds ratios (ORs) ranging between 2.01 and 4.15. There was evidence supporting the association for all types of trauma, with no differential effects. However, there was some variability in the quality of the studies, with most using cross-sectional designs. Individuals who reported adverse experiences in childhood scored significantly higher on positive and negative/disorganized schizotypy compared to those who did not report such experiences. CONCLUSIONS: All forms of childhood trauma and other stressful events (e.g. bullying) were found to be associated with schizotypy, with especially strong associations with positive schizotypy. However, because of the methodological limitations of several studies and a lack of further exploration of different possible mechanistic pathways underlying this association, more research is required. PMID- 25273153 TI - A multifaceted intervention package to improve the diagnosis and management of delirium. AB - ABSTRACT Background: Delirium is a major cause of morbidity and mortality amongst hospital patients. Previous studies have shown that it is often poorly recognized and managed. We wanted to assess the impact of a multifaceted intervention on delirium management. Methods: A pre/post-intervention design was used. The local hospital delirium guideline was adapted into A7 sized cards and A3/A2 posters. Cards were distributed to junior doctors and teaching sessions were held. Computer screen savers were displayed and delirium promotion days held. The pre/post-intervention data were used to audit the following: delirium knowledge through questionnaires, documented use of the confusion assessment method (CAM) and identification and management of eight common precipitating factors. Re-audit was four months post baseline with interventions within this period. chi2 tests were used for statistical analysis. Results: A convenience sample of randomly selected doctors in postgraduate training posts completed 100 questionnaires and 25 clinical notes were selected via retrospective identification of delirium. Results from questionnaires demonstrated significant improvements in: recognizing CAM as the diagnostic tool for delirium (24% vs. 71%, p < 0.01); identifying haloperidol as first line in pharmacological management (55% vs. 98%, p <0.01) and its correct dose (40% vs. 67%, p <0.01). In clinical practice, there was significant improvement in documentation of CAM for inpatient delirium assessments (0% vs. 77%, p <0.01). Trainees found the delirium card "very helpful" (82%) and carried it with them at all times (70%). Conclusion: This multifaceted intervention increased CAM use in delirium recognition and improved the knowledge of pharmacological management. The delirium card was highly popular. PMID- 25273154 TI - Colorectal Cancer Incidence Rates in the Louisiana Acadian Parishes Demonstrated to be Among the Highest in the United States. AB - OBJECTIVES: Determine whether colorectal cancer (CRC) rates are disproportionately high in the French-Acadian region (population 1.2 million) of Louisiana, home of the Cajuns, a founder population. METHODS: 2005-2009 cancer incidence rates were stratified by age/race/gender in the 18 Acadian parish region and 9-parish subgroup with higher proportions of French speakers and compared with Louisiana and United States rates. Parishes were identified through language census data. A total of 3,288 CRC cases were identified in the Acadian region and 11,737 in Louisiana. RESULTS: CRC rates in whites and white males in the 18 parishes were statistically significantly higher than both Louisiana and US rates. In the 9 parishes, rates increased further; whites had an incidence of 56.1/100,000, 13% higher than Louisiana (P<0.0003) and 23% higher than US rates (P<0.0001). In white males, incidence was 72.6/100,000, 19% higher than Louisiana (P<0.0002) and 37% higher than US rates (P<0.0001). If the 9-parish regions were considered a "state," white males would have the highest CRC incidence in the United States by 11% (P<0.0175) compared with other white male populations. CONCLUSIONS: CRC rates are among the highest in the United States, increasing with the proportion of French speakers, a marker for the Cajun population. This appears to be the first study identifying a high rate of cancer in a large, regional, US founder population, raising the possibility of a genetic predisposition. Alternatively, an unidentified, robust environmental risk factor may be present. Future studies are needed to identify genetic and/or other risk factors in this population. PMID- 25273156 TI - Aggregation-induced chiral symmetry breaking of a naphthalimide-cyanostilbene dyad. AB - Spontaneously emerged supramolecular chirality and chiral symmetry breaking from achiral/racemic constituents remain poorly understood. We here report that supramolecular chirality may emerge from the structural flexibility of achiral aryl nitrogen centres which provide instantaneous chirality. Employing a naphthalimide-cyanostilbene dyad as a model, we explored the underlying mechanism of aggregation-induced chiral symmetry breaking and found that the conformations of the N-naphthylpiperazine and the N,N-dimethylaniline units facilitate the formation of ordered supramolecular structures and offer opposite handedness. Furthermore, chiral symmetry breaking of the monomers was amplified by the formation of dimers. The microscopic and the macroscopic observations from the theoretical simulations and experimental measurements are thus rationalized by connecting the population of the dihedral angles of the aryl nitrogen centres, the morphology of the self-assemblies, and the observed circular dichroism spectra. PMID- 25273155 TI - Coil-Assisted Retrograde Transvenous Obliteration (CARTO) for the Treatment of Portal Hypertensive Variceal Bleeding: Preliminary Results. AB - OBJECTIVES: To describe the technical feasibility, safety, and clinical outcomes of coil-assisted retrograde transvenous obliteration (CARTO) in treating portal hypertensive non-esophageal variceal hemorrhage. METHODS: From October 2012 to December 2013, 20 patients who received CARTO for the treatment of portal hypertensive non-esophageal variceal bleeding were retrospectively evaluated. All 20 patients had at least 6-month follow-up. All patients had detachable coils placed to occlude the efferent shunt and retrograde gelfoam embolization to achieve complete thrombosis/obliteration of varices. Technical success, clinical success, rebleeding, and complications were evaluated at follow-up. RESULTS: A 100% technical success rate (defined as achieving complete occlusion of efferent shunt with complete thrombosis/obliteration of bleeding varices and/or stopping variceal bleeding) was demonstrated in all 20 patients. Clinical success rate (defined as no variceal rebleeding) was 100%. Follow-up computed tomography after CARTO demonstrated decrease in size with complete thrombosis and disappearance of the varices in all 20 patients. Thirteen out of the 20 had endoscopic confirmation of resolution of varices. Minor post-CARTO complications, including worsening of esophageal varices (not bleeding) and worsening of ascites/hydrothorax, were noted in 5 patients (25%). One patient passed away at 24 days after the CARTO due to systemic and portal venous thrombosis and multi organ failure. Otherwise, no major complication was noted. No variceal rebleeding was noted in all 20 patients during mean follow-up of 384+/-154 days. CONCLUSIONS: CARTO appears to be a technically feasible and safe alternative to traditional balloon-occluded retrograde transvenous obliteration or transjugular intrahepatic portosystemic shunt, with excellent clinical outcomes in treating portal hypertensive non-esophageal variceal bleeding. PMID- 25273158 TI - Economic and social impact of medical technology: Opening Lecture Second European Conference on Engineering and Medicine, Stuttgart, April 25-28, 1993. PMID- 25273159 TI - Multicentre European COMAC-BME study on the standardisation of bone densitometry procedures. AB - 26 European centres participated in a concerted research action Biomedical Engineering: Quantitative Assessment of Osteoporosis. With a newly designed European spine and forearm phantom, the stability, accuracy, precision of dual energy absorption (DXA) and quantitative computer tomography (QCT) densitometry machines have been evaluated. Marked and clinically significant differences were found between brands and between techniques. Cross-calibration formulae have been made and normative data evaluated for different regions (spine, femoral neck, femoral trochanteric and forearm). A general fit for all data obtained from different machines was established.The cross-calibration formulae will allow a sensitivity analysis to assist the choice of equipment for clinical management of different categories of patients with bone disease. The present results obtained with an internationally accepted European spine and forearm phantom can now serve to stimulate the manufacturers to improve the comparability of bone measurements between machines. PMID- 25273160 TI - Mechanism of muscle contraction. AB - This work is the first attempt to propose a complex model of muscle contraction in which different aspects of the sarcomere shortening are collected into a logical entity. Proposed are some suggestions to answer some fundamental questions concerning the molecular mechanism of muscle contraction, such as the following: "of which part of the myosin molecule does the crossbridge consist?", "how does the crossbridge act?", "what are two heads of the myosin molecule needed for?", "in what way is the metabolic energy of ATP converted into the mechanical work of muscle contraction?", "does the actin filament influence have a passive or active role in the process of muscle contraction?", "what is the role of the third filament - a connecting one?", "in what way is muscle relaxation generated?". PMID- 25273157 TI - Levosimendan exerts anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. AB - Levosimendan is a positive inotropic drug for the treatment of acute decompensated heart failure (HF). Clinical trials showed that levosimendan was particularly effective in HF due to myocardial infarction. Myocardial necrosis induces a strong inflammatory response, involving chemoattractants guiding polymorphonuclear neutrophils (PMN) into the infarcted myocardial tissue. Our aim was to examine whether levosimendan exhibits anti-inflammatory effects on human adult cardiac myocytes (HACM) and human heart microvascular endothelial cells (HHMEC). Cardiac myocytes and endothelial cells were stimulated with interleukin 1beta (IL)-1beta (200 U/ml) and treated with levosimendan (0.1-10 uM) for 2-48 hours. IL-1beta strongly induced expression of IL-6 and IL-8 in HACM and E selectin and intercellular adhesion molecule-1 (ICAM-1) in HHMEC and human umbilical vein endothelial cells (HUVEC). Treatment with levosimendan strongly attenuated IL-1beta-induced expression of IL-6 and IL-8 in HACM as well as E selectin and ICAM-1 in ECs. Levosimendan treatment further reduced adhesion of PMN to activated endothelial cells under both static and flow conditions by approximately 50 %. Incubation with 5-hydroxydecanoic acid, a selective blocker of mitochondrial ATP-dependent potassium channels, partly abolished the above seen anti-inflammatory effects. Additionally, levosimendan strongly diminished IL 1beta-induced reactive oxygen species and nuclear factor-kappaB (NF-kappaB) activity through inhibition of S536 phosphorylation. In conclusion, levosimendan exhibits anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. These findings could explain, at least in part, the beneficial effects of levosimendan after myocardial infarction. PMID- 25273161 TI - High resolution CT of the lungs: Proper mA s settings for clinical use. AB - Fifty-five patients undergoing routine chest CT were examined with four additional high resolution computed tomography (HRCT) slices to determine the proper milliampere-second settings for clinical HRCT of the lungs. The following technical factors were used: 1-mm collimation, 2-s scan time, 120 kVp and different milliampere settings (160 mA, 100 mA, 60 mA, 30 mA). On 47 out of 54 patients all the four HRCT cuts were at exactly the same level. These images were independently reviewed and assessed by three radiologists. The body mass index was calculated in order to determine the effect of the size of the patient on the milliamperage setting needed. The standard deviation of CT values of 1 mm and 10 mm slice was measured in a Plexiglas phantom with different mA settings. The slice thickness was measured with thermoluminescence dosimeter. In the phantom study the change of milliamperage from 160 mA to 30 mA at 120 kVp and 2 s increased standard deviation in CT units from about 4.6 to 8.9 in 1 mm slice and from about 2.9 to 4.3 in 10 mm slice. The Computed Tomography Dose Index (CTDI) values of both 1 mm and 10 mm slices at 160 mA-30 mA were approximately from 9 to 2 cGy (rad). In the patient study 1 mm HRCT scans with 120 kVp/100 mA/2 s showed the same diagnostic information as 120 kVp/160 mA/2 s scans for all patients regardless of size. If only the normal weight patients are considered, all the details were also well seen with 120 kVp/60 mA/2 s settings. In our study contrary to earlier reports 30 mA/2s was inadequate for diagnosis. We conclude that at 120 kVp medium-dose settings 60-100 mA/2 s or 120-200 mA s are in clinical practice appropriate for HRCT studies of the lungs in most patients. PMID- 25273162 TI - Design of spherical carbon adsorbent for extracorporeal detoxification. AB - A special carbon adsorbent (CA), designed for use in extracorporeal detoxification by hemoperfusion, was produced from a spherical synthetic polymer by our own technolique and tested at a preclinical level. Comparison of mechanical properties, sorption and biocompatibility between CA and medical hemosorbents was made. The carbon adsorbent is hard, has a smooth surface, shows good sorption properties and has acceptable biocompatibility. These features qualify the carbon adsorbent for use in clinical hemoperfusion without any additional membrane coating. PMID- 25273163 TI - Application of gel-integrated macroporous hydroxyapatite in the treatment of marginal periodontitis. PMID- 25273164 TI - Hemolysis in fresh human blood with a new hemoperfusion pump to prevent myocardial ischemia during coronary angioplasty. AB - A new, 5 ml, piston type hemoperfusion pump, designed to prevent myocardial ischemia during coronary angioplasty, was evaluated in vitro at different flow rates. The driving pressures necessary to achieve the different flow rates and biochemical indicators of hemolysis, were assessed. Fresh human blood was perfused through 2 angioplasty catheter types, one with distal side holes and another catheter type without side holes but with a tapered distal segment. Despite high driving pressures, shear stress > 200 Pa, turbulent flow and the presence of occlusive valves in the pump, hemolysis proved to be minimal. This is most readily explained by the short period of time during which the blood was subjected to mechanical factors that cause hemolysis. Additionally, the volume of the pump, and hence the amount of blood subjected to mechanical hemolysis, was small. The side holes in the catheter caused obstruction by promoting the formation of clots. PMID- 25273165 TI - "Chromosome": a knowledge-based system for the chromosome classification. AB - Chromosome, a knowledge-based analysis system has been designed for the classification of human chromosomes. Its aim is to perform an optimal classification by driving a tool box containing the procedures of image processing, pattern recognition and classification. This paper presents the general architecture of Chromosome, based on a multiagent system generator. The image processing tool box is described from the met aphasic enhancement to the fine classification. Emphasis is then put on the knowledge base intended for the chromosome recognition. The global classification process is also presented, showing how Chromosome proceeds to classify a given chromosome. Finally, we discuss further extensions of the system for the karyotype building. PMID- 25273167 TI - Calendar: international symposium on new epidemics in occupational health, 16-19 may, 1994, helsinki, Finland. PMID- 25273166 TI - A 3-D moment based approach for blood vessel detection and quantification in MRA. AB - This paper describes a new method for the three-dimensional (3-D) tracking and the quantification of blood vessels from magnetic resonance angiography (MRA). The approach is based on 3-D geometrical moments and consists of the following steps: (1) interactive selection of 3-D seed points; (2) automatic tracking of the vessels; (3) local computation of both diameter and orientation; (4) rendering of the vessels. This detection and estimation scheme has been validated on simulated and real data. PMID- 25273168 TI - Influence of gold-bipyridyl derivants on aggregation and disaggregation of the prion neuropeptide PrP106-126. AB - Metal complexes can effectively inhibit the aggregation of amyloid peptides, such as Abeta, human islet amyloid polypeptide, and prion neuropeptide PrP106-126. Gold (Au) complexes exhibited better inhibition against PrP106-126 aggregation, particularly the Au-bipyridyl (bpy) complex; however, the role of different ligand configurations remains unclear. In the present study, three derivants of Au-bpy complexes, namely, [Au(Me2bpy)Cl2]Cl, [Au(t-Bu2bpy)Cl2]Cl, and [Au(Ph2bpy)Cl2]Cl, were investigated to determine their influence on the aggregation and disaggregation of PrP106-126. The steric and aromatic effects of the ligand resulted in enhanced binding affinity. Inhibition was significantly affected by a large ligand. The neurotoxicity of the SH-SY5Y cells induced by PrP106-126 was reduced by the three Au-bpy derivants. However, the disaggregation ability was not in accordance with the results obtained for selected complexes during inhibition, suggesting a different mechanism of interaction between gold complexes and PrP106-126. The key peptide residues contributed to both the inhibition and disaggregation capabilities through the metal coordination and the hydrophobic interaction with the metal complexes. Thus, understanding the aggregation mechanism of the prion peptide would be helpful in designing novel metal-based drugs against amyloid fibril formation. PMID- 25273169 TI - Upregulation of mediator MED23 in non-small-cell lung cancer promotes the growth, migration, and metastasis of cancer cells. AB - Mediator complex subunit MED23 has been reported to facilitate the transformation induced by oncogenic Ras in non-small-cell lung carcinoma (NSCLC). However, the expression pattern and biological functions of MED23 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of MED23 was significantly upregulated in NSCLC samples compared to their adjacent normal tissues. Moreover, in the biological function studies, overexpression of MED23 was further validated to promote the growth, migration, and metastasis of NSCLC cells, while knockdown of the expression of MED23 inhibited the growth, migration, and metastasis of NSCLC cells in vitro and in vivo. Mechanistically, MED23 was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that MED23 played an oncogenic role in the progression of NSCLC and that MED23 might be a promising target for the treatment of NSCLC. PMID- 25273170 TI - Downregulation of MLL3 in esophageal squamous cell carcinoma is required for the growth and metastasis of cancer cells. AB - The mixed lineage leukemia 3 (MLL3), a member of the mixed lineage leukemia (MLL) family, has been reported to be mutated in multiple cancer types. However, its function in esophageal squamous cell carcinoma (ESCC) remains poorly understood. Here, we found that the expression of MLL3 was downregulated in ESCC tissues. Moreover, over-expression of MLL3 in ESCC cells inhibited cell proliferation and migration, while the knockdown expression of MLL3 promoted the tumorigenicity of ESCC cells. Mechanistically, MLL3 regulated the expression of multiple growth related and migration-related genes. Taken together, our study suggested that downregulation of MLL3 was very important in the progression of ESCC. PMID- 25273171 TI - GDC-0152 induces apoptosis through down-regulation of IAPs in human leukemia cells and inhibition of PI3K/Akt signaling pathway. AB - The inhibitor of apoptosis proteins (IAPs) is closely related to leukemia apoptosis. The present study was undertaken to determine the molecular mechanisms by which GDC-0152, an IAP inhibitor, induces apoptosis in human leukemia cells (K562 and HL60 cells). GDC-0152 inhibited the proliferation of K562 and HL60 cells in a dose- and time-dependent manner, which was largely attributed to intrinsic apoptosis. GDC-0152 down-regulated the IAPs including X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP1), and cellular inhibitor of apoptosis protein-2 (cIAP2) expression and induced the activation of caspase-9 and caspase-3. GDC-0152-induced cell proliferation inhibition in K562 cells was prevented by pan-caspase inhibitor. GDC-0152 also inhibited PI3K and Akt expression in K562 and HL60 cells. Taken together, these findings suggest that GDC-0152 results in human leukemia apoptosis through caspase-dependent mechanisms involving down-regulation of IAPs and inhibition of PI3K/Akt signaling. PMID- 25273172 TI - Causal relevance of circulating adiponectin with cancer: a meta-analysis implementing Mendelian randomization. AB - Some studies have observed a lower circulating level of adiponectin in cancer patients, but whether this observation is causal remains unresolved. We therefore undertook a meta-analysis implementing Mendelian randomization to exploit the causal relevance of circulating adiponectin with cancer by using multiple polymorphisms in adiponectin encoded gene ADIPOQ as instrumental variables. Eligible articles were identified from PubMed and Embase. Data and study quality were assessed in duplicate. Total 26 articles including 31 study groups were analyzed. Overall allelic association with cancer was significant for rs822396 (odds ratio (OR) = 0.91; P = 0.045) and rs1501299 (OR = 0.89; P = 0.051), with low or moderate heterogeneity. Carriers of rs2241766 GG genotype (weighted mean difference (WMD) = 0.86; P = 0.037) or G allele (WMD = 0.68; P = 0.047) had significantly higher circulating adiponectin than the TT genotype carriers, without heterogeneity. Using rs2241766 as an instrument in Mendelian randomization analysis, an increment of 1 mg/L in circulating adiponectin was significantly associated with a 43-50% reduced risk for lung cancer, but with a 20-40% increased risk of colorectal cancer, respectively. There was no observable publication bias. Genetically elevated circulating adiponectin might confer a protective effect against lung cancer, yet a risky effect for colorectal cancer. Further validation is urgently required. PMID- 25273173 TI - Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O. AB - Riboflavin (vitamin B2) is a precursor for coenzymes involved in energy production, biosynthesis, detoxification, and electron scavenging. Previously, we demonstrated that irradiated riboflavin (IR) has potential antitumoral effects against human leukemia cells (HL60), human prostate cancer cells (PC3), and mouse melanoma cells (B16F10) through a common mechanism that leads to apoptosis. Hence, we here investigated the effect of IR on 786-O cells, a known model cell line for clear cell renal cell carcinoma (CCRCC), which is characterized by high risk metastasis and chemotherapy resistance. IR also induced cell death in 786-O cells by apoptosis, which was not prevented by antioxidant agents. IR treatment was characterized by downregulation of Fas ligand (TNF superfamily, member 6)/Fas (TNF receptor superfamily member 6) (FasL/Fas) and tumor necrosis factor receptor superfamily, member 1a (TNFR1)/TNFRSF1A-associated via death domain (TRADD)/TNF receptor-associated factor 2 (TRAF) signaling pathways (the extrinsic apoptosis pathway), while the intrinsic apoptotic pathway was upregulated, as observed by an elevated Bcl-2 associated x protein/B-cell CLL/lymphoma 2 (Bax/Bcl-2) ratio, reduced cellular inhibitor of apoptosis 1 (c-IAP1) expression, and increased expression of apoptosis-inducing factor (AIF). The observed cell death was caspase-dependent as proven by caspase 3 activation and poly(ADP-ribose) polymerase-1 (PARP) cleavage. IR-induced cell death was also associated with downregulation of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue (avian)/protein serine/threonine kinase B/extracellular signal-regulated protein kinase 1/2 (Src/AKT/ERK1/2) pathway and activation of p38 MAP kinase (p38) and Jun-amino-terminal kinase (JNK). Interestingly, IR treatment leads to inhibition of matrix metalloproteinase-2 (MMP-2) activity and reduced expression of renal cancer aggressiveness markers caveolin-1, low molecular weight phosphotyrosine protein phosphatase (LMWPTP), and kinase insert domain receptor (a type III receptor tyrosine kinase) (VEGFR-2). Together, these results show the potential of IR for treating cancer. PMID- 25273174 TI - delta-catenin promotes the malignant phenotype in breast cancer. AB - delta-Catenin is a member of the p120 catenin family. Similar to p120ctn, delta catenin contains nine central Armadillo repeats and binds to the juxtamembrane domain (JMD) of E-cadherin. We used immunohistochemistry to detect delta-catenin expression in breast carcinoma (128 cases), and delta-catenin mRNA and protein expression was detected by reverse transcription-polymerase chain reaction and Western blotting (45 cases). The effects of delta-catenin on the activity of small GTPases and the biological behavior of breast cancer cells were explored by pulldown, flow cytometry, methyl thiazolyl tetrazolium, and Matrigel invasion assays. The results showed that delta-catenin expression increased in breast cancer tissues and was associated with a higher degree of malignancy (invasive lobular breast cancer, high tumor-node-metastasis stage, lymph node metastasis, and C-erbB-2+) and poor prognosis. Postoperative survival was shorter in patients with delta-catenin-positive expression than in patients with negative expression. delta-Catenin may regulate Cdc42/Rac1 activity, promote proliferation and invasion of breast cancer cells, and alter cell cycle progression. We conclude that delta-catenin tends to overexpress in breast carcinoma and promotes the malignant phenotype. PMID- 25273176 TI - Genome sequence of Vibrio diabolicus and identification of the exopolysaccharide HE800 biosynthesis locus. AB - Vibrio diabolicus, a marine bacterium originating from deep-sea hydrothermal vents, produces the HE800 exopolysaccharide with high value for biotechnological purposes, especially for human health. Its genome was sequenced and analyzed; phylogenetic analysis using the core genome revealed V. diabolicus is close to another deep-sea Vibrio sp. (Ex25) within the Harveyi clade and Alginolyticus group. A genetic locus homologous to the syp cluster from Vibrio fischeri was demonstrated to be involved in the HE800 production. However, few genetic particularities suggest that the regulation of syp expression may be different in V. diabolicus. The presence of several types of glycosyltransferases within the locus indicates a capacity to generate diversity in the glycosidic structure, which may confer an adaptability to environmental conditions. These results contribute to better understanding exopolysaccharide biosynthesis and for developing new efficient processes to produce this molecule for biotechnological applications. PMID- 25273175 TI - Rotundarpene prevents TRAIL-induced apoptosis in human keratinocytes by suppressing the caspase-8- and Bid-pathways and the mitochondrial pathway. AB - The extract and hemiterpene glycosides of Ilex rotunda Thunb have demonstrated antioxidant and anti-inflammatory effects. Nevertheless, the effect of rotundarpene on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of rotundarpene on TRAIL-induced apoptosis in human keratinocytes. TRAIL triggers apoptosis by inducing a decrease in the cytosolic levels of Bid, Bcl-2, Bcl-xL, and survivin proteins, increase in the cytosolic levels of Bax, and increase in the mitochondrial levels of VDAC1, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9, and -3), cleavage of PARP-1, and an increase in the tumor suppressor p53 levels. Treatment with rotundarpene prevented TRAIL-induced changes in the levels of apoptosis-related proteins, formations of reactive oxygen species and nitric oxide, nuclear damage, and cell death. These results suggest that rotundarpene may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8- and Bid-pathways and the mitochondria-mediated cell death pathway, which is associated with the formation of reactive oxygen species and reactive nitrogen species. These data suggest that rotundarpene appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases. PMID- 25273177 TI - Extracellular biogenic nanomaterials inhibit pyoverdine production in Pseudomonas aeruginosa: a novel insight into impacts of metal(loid)s on environmental bacteria. AB - Anthropogenic activities such as mining, smelting, and industrial use have caused serious problems of metal(loid) pollution in nearly every country in the world. A wide range of environmental microorganisms are capable of transforming metal(loid)s into nanomaterials, i.e., biogenic nanomaterials (bio-NMs), in the environment. Although the impacts of various metal(loid)s on the ecosystems have been extensively studied, the potential influence of the bio-NMs generated in the environment to environmental organisms is largely unexplored. Using tellurium nanomaterials transformed from tellurite by a metal-reducing bacterium as model bio-NMs, we demonstrated that the bio-NMs significantly decreased siderophore production in an environmental bacterium Pseudomonas aeruginosa in both planktonic cultures and biofilms. Transcriptomic analysis revealed that the bio NMs inhibited the expression of genes involved in biosynthesis and transport of siderophores. Siderophores secreted by certain bacteria in microbial communities can be considered as public goods that can be exploited by local communities, playing an important role in shaping microbial communities. The inhibition of siderophore production by the bio-NMs implies that bio-NMs may have an important influence on the ecosystems through altering specific functions of environmental bacteria. Taken together, this study provides a novel insight into the environmental impacts of metal(loid)s. PMID- 25273178 TI - Elevated level of the second messenger c-di-GMP in Comamonas testosteroni enhances biofilm formation and biofilm-based biodegradation of 3-chloroaniline. AB - The bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a ubiquitous second messenger that determines bacterial lifestyle between the planktonic and biofilm modes of life. Although the role of c-di-GMP signaling in biofilm development and dispersal has been extensively studied, how c-di-GMP signaling influences environmental bioprocess activities such as biodegradation remains unexplored. To elucidate the impacts of elevating c-di-GMP level on environmental bioprocesses, we constructed a Comamonas testosteroni strain constitutively expressing a c-di-GMP synthase YedQ from Escherichia coli and examined its capability in biofilm formation and biodegradation of 3-chloroaniline (3-CA). The high c-di-GMP strain exhibited an increased binding to Congo red dye, a decreased motility, and an enhanced biofilm formation capability. In planktonic cultures, the strain with an elevated c-di-GMP concentration and the wild type could degrade 3-CA comparably well. However, under batch growth conditions with a high surface to volume ratio, an elevated c-di-GMP concentration in C. testosteroni significantly increased the contribution of biofilms in 3-CA biodegradation. In continuous submerged biofilm reactors, C. testosteroni with an elevated c-di-GMP level exhibited an enhanced 3-CA biodegradation and a decreased cell detachment rate. Taken together, this study provides a novel strategy to enhance biofilm based biodegradation of toxic xenobiotic compounds through manipulating bacterial c-di-GMP signaling. PMID- 25273179 TI - Asymmetric multiscale detrended cross-correlation analysis of financial time series. AB - We propose the asymmetric multiscale detrended cross-correlation analysis (MS ADCCA) method and apply MS-ADCCA method to explore the existence of asymmetric cross-correlation for daily price returns in US and Chinese stock markets and to assess the properties of these asymmetric cross-correlations. The results all show the existences of asymmetric cross-correlations, while small asymmetries at small scales and larger asymmetries at larger scales are also displayed. There is a strong similarity between S&P500 and DJI, and we reveal that the asymmetries depend more on the cross-correlations of S&P500 vs. DJI, S&P500 vs. NQCI, DJI vs. NQCI, and ShangZheng vs. ShenCheng when the market is falling than rising, respectively. By comparing the spectra of S&P500 vs. NQCI and DJI vs. NQCI with uptrends and downtrends, we detect some new characteristics which lead to some new conclusions. Likewise, some new conclusions also can be drawn by the new characteristics displayed through the comparison between the spectra of ShangZheng vs. HSI and ShenCheng vs. HSI. Obviously, we conclude that although the overall spectra are similar and one market has the same effect when it is rising and falling in the study of asymmetric cross-correlations between it and different markets, the cross-correlations and asymmetries on the trends of the different markets are all different. MS-ADCCA method can detect the differences on the asymmetric cross-correlations by different trends of markets. Moreover, the uniqueness of cross-correlation between NQCI and HSI can be detected in the study of the asymmetric cross-correlations, which confirms that HSI is unique in the Chinese stock markets and NQCI is unique in the US stock markets further. PMID- 25273180 TI - Traffic time series analysis by using multiscale time irreversibility and entropy. AB - Traffic systems, especially urban traffic systems, are regulated by different kinds of interacting mechanisms which operate across multiple spatial and temporal scales. Traditional approaches fail to account for the multiple time scales inherent in time series, such as empirical probability distribution function and detrended fluctuation analysis, which have lead to different results. The role of multiscale analytical method in traffic time series is a frontier area of investigation. In this paper, our main purpose is to introduce a new method-multiscale time irreversibility, which is helpful to extract information from traffic time series we studied. In addition, to analyse the complexity of traffic volume time series of Beijing Ring 2, 3, 4 roads between workdays and weekends, which are from August 18, 2012 to October 26, 2012, we also compare the results by this new method and multiscale entropy method we have known well. The results show that the higher asymmetry index we get, the higher traffic congestion level will be, and accord with those which are obtained by multiscale entropy. PMID- 25273181 TI - Chaotic motion of charged particles in toroidal magnetic configurations. AB - We study the motion of a charged particle in a tokamak magnetic field and discuss its chaotic nature. Contrary to most of recent studies, we do not make any assumption on any constant of the motion and solve numerically the cyclotron gyration using Hamiltonian formalism. We take advantage of a symplectic integrator allowing us to make long-time simulations. First considering an idealized magnetic configuration, we add a nongeneric perturbation corresponding to a magnetic ripple, breaking one of the invariant of the motion. Chaotic motion is then observed and opens questions about the link between chaos of magnetic field lines and chaos of particle trajectories. Second, we return to an axisymmetric configuration and tune the safety factor (magnetic configuration) in order to recover chaotic motion. In this last setting with two constants of the motion, the presence of chaos implies that no third global constant exists, we highlight this fact by looking at variations of the first order of the magnetic moment in this chaotic setting. We are facing a mixed phase space with both regular and chaotic regions and point out the difficulties in performing a global reduction such as gyrokinetics. PMID- 25273182 TI - Pinning synchronization of hybrid-coupled directed delayed dynamical network via intermittent control. AB - This paper concerns the problem of exponential synchronization for a class of general delayed dynamical networks with hybrid coupling via pinning periodically intermittent control. Both the internal delay and coupling delay are taken into account in the network model. Meanwhile, the transmission delay and self-feedback delay are involved in the delayed coupling term. By establishing a new differential inequality, several simple and useful exponential synchronization criteria are derived analytically. It is shown that the controlled synchronization state can vary in comparison with the conventional synchronized solution, and the degree of the node and the inner delayed coupling matrix play important roles in the controlled synchronization state. By choosing different inner delayed coupling matrices and the degrees of the node, different controlled synchronization states can be obtained. Furthermore, the detail pinning schemes deciding what nodes should be chosen as pinned candidates and how many nodes are needed to be pinned for a fixed coupling strength are provided. The simple procedures illuminating how to design suitable intermittent controllers in real application are also given. Numerical simulations, including an undirected scale free network and a directed small-world network, are finally presented to demonstrate the effectiveness of the theoretical results. PMID- 25273183 TI - Influences of periodic mechanical deformation on pinned spiral waves. AB - In a generic model of excitable media, we study the behavior of spiral waves interacting with obstacles and their dynamics under the influences of simple periodic mechanical deformation (PMD). Depending on the characteristics of the obstacles, i.e., size and excitability, the rotation of a pinned spiral wave shows different scenarios, e.g., embedding into or anchoring on an obstacle. Three different drift phenomena induced by PMD are observed: scattering on small partial-excitable obstacles, meander-induced unpinning on big partial-excitable obstacles, and drifting around small unexcitable obstacles. Their underlying mechanisms are discussed. The dependence of the threshold amplitude of PMD on the characteristics of the obstacles to successfully remove pinned spiral waves on big partial-excitable obstacles is studied. PMID- 25273184 TI - Clustering dynamics of complex discrete-time networks and its application in community detection. AB - The clustering phenomenon is common in real world networks. A discrete-time network model is proposed firstly in this paper, and then the phase clustering dynamics of the networks are studied carefully. The proposed model acts as a bridge between the dynamic phenomenon and the topology of a modular network. On one hand, phase clustering phenomenon will occur for a modular network by the proposed model; on the other hand, the communities can be identified from the clustering phenomenon. Beyond the phases' information, it is found that the frequencies of phases can be applied to community detection also with the proposed model. In specific, communities are identified from the information of phases and their frequencies of the nodes. Detailed algorithm for community detection is provided. Experiments show that the performance and efficiency of the dynamics based algorithm are competitive with recent modularity based algorithms in large scale networks. PMID- 25273185 TI - Synchronization and an application of a novel fractional order King Cobra chaotic system. AB - In this paper, we design a new three dimensional King Cobra face shaped fractional order chaotic system. The multi-scale synchronization scheme of two fractional order chaotic systems is described. The necessary conditions for the multi-scale synchronization of two identical fractional order King Cobra chaotic systems are derived through feedback control. A new cryptosystem is proposed for an image encryption and decryption by using synchronized fractional order King Cobra chaotic systems with the supports of multiple cryptographic assumptions. The security of the proposed cryptosystem is analyzed by the well known algebraic attacks. Numerical simulations are given to show the effectiveness of the proposed theoretical results. PMID- 25273186 TI - Fractal dimension computation from equal mass partitions. AB - Numerical methods which utilize partitions of equal-size, including the box counting method, remain the most popular choice for computing the generalized dimension of multifractal sets. However, it is known that mass-oriented methods generate relatively good results for computing generalized dimensions for important cases where the box-counting method is known to fail. Here, we revisit two mass-oriented methods and discuss their strengths and limitations. PMID- 25273187 TI - Controlling systems that drift through a tipping point. AB - Slow parameter drift is common in many systems (e.g., the amount of greenhouse gases in the terrestrial atmosphere is increasing). In such situations, the attractor on which the system trajectory lies can be destroyed, and the trajectory will then go to another attractor of the system. We consider the case where there are more than one of these possible final attractors, and we ask whether we can control the outcome (i.e., the attractor that ultimately captures the trajectory) using only small controlling perturbations. Specifically, we consider the problem of controlling a noisy system whose parameter slowly drifts through a saddle-node bifurcation taking place on a fractal boundary between the basins of multiple attractors. We show that, when the noise level is low, a small perturbation of size comparable to the noise amplitude applied at a single point in time can ensure that the system will evolve toward a target attracting state with high probability. For a range of noise levels, we find that the minimum size of perturbation required for control is much smaller within a time period that starts some time after the bifurcation, providing a "window of opportunity" for driving the system toward a desirable state. We refer to this procedure as tipping point control. PMID- 25273188 TI - Controllability of asynchronous Boolean multiplex control networks. AB - In this article, the controllability of asynchronous Boolean multiplex control networks (ABMCNs) is studied. First, the model of Boolean multiplex control networks under Harvey' asynchronous update is presented. By means of semi-tensor product approach, the logical dynamics is converted into linear representation, and a generalized formula of control-depending network transition matrices is achieved. Second, a necessary and sufficient condition is proposed to verify that only control-depending fixed points of ABMCNs can be controlled with probability one. Third, using two types of controls, the controllability of system is studied and formulae are given to show: (a) when an initial state is given, the reachable set at time s under a group of specified controls; (b) the reachable set at time s under arbitrary controls; (c) the specific probability values from a given initial state to destination states. Based on the above formulae, an algorithm to calculate overall reachable states from a specified initial state is presented. Moreover, we also discuss an approach to find the particular control sequence which steers the system between two states with maximum probability. Examples are shown to illustrate the feasibility of the proposed scheme. PMID- 25273189 TI - Terahertz radiation induced chaotic electron transport in semiconductor superlattices with a tilted magnetic field. AB - Chaotic electron transport in semiconductor superlattice induced by terahertz electric field that is superimposed on a dc electric field along the superlattice axis are studied using the semiclassical motion equations including the effect of dissipation. A magnetic field that is tilted relative to the superlattice axis is also applied to the system. Numerical simulation shows that electrons in superlattice miniband exhibit complicate nonlinear oscillating modes with the influence of terahertz radiation. Transitions between frequency-locking and chaos via pattern forming bifurcations are observed with the varying of terahertz amplitude. It is found that the chaotic regions gradually contract as the dissipation increases. We attribute the appearance of complicate nonlinear oscillation in superlattice to the interaction between terahertz radiation and internal cooperative oscillating mode relative to Bloch oscillation and cyclotron oscillation. PMID- 25273190 TI - Experimental dynamical characterization of five autonomous chaotic oscillators with tunable series resistance. AB - In this paper, an experimental characterization of the dynamical properties of five autonomous chaotic oscillators, based on bipolar-junction transistors and obtained de-novo through a genetic algorithm in a previous study, is presented. In these circuits, a variable resistor connected in series to the DC voltage source acts as control parameter, for a range of which the largest Lyapunov exponent, correlation dimension, approximate entropy, and amplitude variance asymmetry are calculated, alongside bifurcation diagrams and spectrograms. Numerical simulations are compared to experimental measurements. The oscillators can generate a considerable variety of regular and chaotic sine-like and spike like signals. PMID- 25273191 TI - Synchronous rotations in parametrically excited pendula. AB - In this work, we provide an analytic justification for the existence of a synchronously rotating state in a Kapitsa pendulum, i.e., a pendulum where the base is subjected to vibration. Qualitative arguments as well as mathematical calculations are presented to demonstrate the existence of this state. An approximate recipe for determining the basin of attraction is also given. This theory is used to explain the motion of a popular but intriguing toy called devil's stick. PMID- 25273192 TI - Can spurious indications for phase synchronization due to superimposed signals be avoided? AB - We investigate the relative merit of phase-based methods-mean phase coherence, unweighted and weighted phase lag index-for estimating the strength of interactions between dynamical systems from empirical time series which are affected by common sources and noise. By numerically analyzing the interaction dynamics of coupled model systems, we compare these methods to each other with respect to their ability to distinguish between different levels of coupling for various simulated experimental situations. We complement our numerical studies by investigating consistency and temporal variations of the strength of interactions within and between brain regions using intracranial electroencephalographic recordings from an epilepsy patient. Our findings indicate that the unweighted and weighted phase lag index are less prone to the influence of common sources but that this advantage may lead to constrictions limiting the applicability of these methods. PMID- 25273193 TI - Efficient allocation of heterogeneous response times in information spreading process. AB - Recently, the impacts of spatiotemporal heterogeneities of human activities on spreading dynamics have attracted extensive attention. In this paper, we intend to understand how the heterogeneous distribution of response times at the individual level influences information spreading. Based on the uncorrelated scale-free networks without degree-degree correlation, we study the susceptible infected spreading dynamics with adjustable power-law response time distribution, and find that the stronger the heterogeneity of response times is, the faster the information spreading is in the early and middle stages. Following a given heterogeneity, the procedure of reducing the correlation between the response times and degrees of individuals can also accelerate the spreading dynamics in the early and middle stages. However, the dynamics in the late stage is slightly more complicated, and there is an optimal value of the full prevalence time (i.e., the time for full infection on a network) changing with the heterogeneity of response times and the response time-degree correlation, respectively. The optimal phenomena result from the efficient allocation of heterogeneous response times. PMID- 25273194 TI - Bifurcation and chaos in the simple passive dynamic walking model with upper body. AB - We present some rich new complex gaits in the simple walking model with upper body by Wisse et al. in [Robotica 22, 681 (2004)]. We first show that the stable gait found by Wisse et al. may become chaotic via period-doubling bifurcations. Such period-doubling routes to chaos exist for all parameters, such as foot mass, upper body mass, body length, hip spring stiffness, and slope angle. Then, we report three new gaits with period 3, 4, and 6; for each gait, there is also a period-doubling route to chaos. Finally, we show a practical method for finding a topological horseshoe in 3D Poincare map, and present a rigorous verification of chaos from these gaits. PMID- 25273195 TI - Structured chaos in a devil's staircase of the Josephson junction. AB - The phase dynamics of Josephson junctions (JJs) under external electromagnetic radiation is studied through numerical simulations. Current-voltage characteristics, Lyapunov exponents, and Poincare sections are analyzed in detail. It is found that the subharmonic Shapiro steps at certain parameters are separated by structured chaotic windows. By performing a linear regression on the linear part of the data, a fractal dimension of D = 0.868 is obtained, with an uncertainty of +/-0.012. The chaotic regions exhibit scaling similarity, and it is shown that the devil's staircase of the system can form a backbone that unifies and explains the highly correlated and structured chaotic behavior. These features suggest a system possessing multiple complete devil's staircases. The onset of chaos for subharmonic steps occurs through the Feigenbaum period doubling scenario. Universality in the sequence of periodic windows is also demonstrated. Finally, the influence of the radiation and JJ parameters on the structured chaos is investigated, and it is concluded that the structured chaos is a stable formation over a wide range of parameter values. PMID- 25273196 TI - Discriminating chaotic and stochastic dynamics through the permutation spectrum test. AB - In this paper, we propose a new heuristic symbolic tool for unveiling chaotic and stochastic dynamics: the permutation spectrum test. Several numerical examples allow us to confirm the usefulness of the introduced methodology. Indeed, we show that it is robust in situations in which other techniques fail (intermittent chaos, hyperchaotic dynamics, stochastic linear and nonlinear correlated dynamics, and deterministic non-chaotic noise-driven dynamics). We illustrate the applicability and reliability of this pragmatic method by examining real complex time series from diverse scientific fields. Taking into account that the proposed test has the advantages of being conceptually simple and computationally fast, we think that it can be of practical utility as an alternative test for determinism. PMID- 25273197 TI - A feedback control strategy for the airfoil system under non-Gaussian colored noise excitation. AB - The stability of a binary airfoil with feedback control under stochastic disturbances, a non-Gaussian colored noise, is studied in this paper. First, based on some approximated theories and methods the non-Gaussian colored noise is simplified to an Ornstein-Uhlenbeck process. Furthermore, via the stochastic averaging method and the logarithmic polar transformation, one dimensional diffusion process can be obtained. At last by applying the boundary conditions, the largest Lyapunov exponent which can determine the almost-sure stability of the system and the effective region of control parameters is calculated. PMID- 25273198 TI - How to estimate the correlation dimension of high-dimensional signals? AB - The paper presents improvements to the Takens-Ellner (TE) algorithm estimating the correlation dimension (d) of high-dimensional signals. The signal being the sum of 4 Lorenz signals and possessing the correlation dimension d approximately equal to 8 was analyzed. The conversion of TE to the classic Grassberger Proccacia (GP) algorithm is presented that shows the advantage of TE over the GP algorithm. The maximal d estimated for the given number of points in phase space is significantly higher for the TE algorithm than for the GP algorithm. The formula for the precision of individual d estimation is presented. The paper shows, how to estimate the distance corresponding to the end of the Linear Scaling Region in the correlation integral function, even before starting the procedure of d estimation. It makes it possible to reject the majority of longer distances from the analysis reducing the computation time considerably. PMID- 25273199 TI - Brownian transport of finite size particles in a periodic channel coexisting with an energetic potential. AB - Transport of particles with different sizes moving in a two-dimensional periodic channel is studied in the presence of an unbiased external force and a periodic energetic potential. While particles are going through entropic barrier resulting from the geometric restraints, the transport is also influenced by the energetic potential. For the case of an unbiased external force, the competition between the energetic potential and entropic barrier leads to different transport direction of particles, which sensitively depends on the particles radius. Particles move to the left when smaller than a critical radius and larger than another critical radius, whereas particles move to the right in the range of two critical radii. Therefore, the results we have presented can contribute further to the invention of machines for particle separation. PMID- 25273200 TI - Scale-invariant entropy-based theory for dynamic ordering. AB - Dynamically Ordered self-organized dissipative structure exists in various forms and at different scales. This investigation first introduces the concept of an isolated embedding system, which embeds an open system, e.g., dissipative structure and its mass and/or energy exchange with its surroundings. Thereafter, scale-invariant theoretical analysis is presented using thermodynamic principles for Order creation, existence, and destruction. The sustainability criterion for Order existence based on its structured mass and/or energy interactions with the surroundings is mathematically defined. This criterion forms the basis for the interrelationship of physical parameters during sustained existence of dynamic Order. It is shown that the sufficient condition for dynamic Order existence is approached if its sustainability criterion is met, i.e., its destruction path is blocked. This scale-invariant approach has the potential to unify the physical understanding of universal dynamic ordering based on entropy considerations. PMID- 25273201 TI - Radiating subdispersive fractional optical solitons. AB - It was recently found [Fujioka et al., Phys. Lett. A 374, 1126 (2010)] that the propagation of solitary waves can be described by a fractional extension of the nonlinear Schrodinger (NLS) equation which involves a temporal fractional derivative (TFD) of order alpha > 2. In the present paper, we show that there is also another fractional extension of the NLS equation which contains a TFD with alpha < 2, and in this case, the new equation describes the propagation of radiating solitons. We show that the emission of the radiation (when alpha < 2) is explained by resonances at various frequencies between the pulses and the linear modes of the system. It is found that the new fractional NLS equation can be derived from a suitable Lagrangian density, and a fractional Noether's theorem can be applied to it, thus predicting the conservation of the Hamiltonian, momentum and energy. PMID- 25273202 TI - Effect of autaptic activity on the response of a Hodgkin-Huxley neuron. AB - An autapse is a special synapse that connects a neuron to itself. In this study, we investigated the effect of an autapse on the responses of a Hodgkin-Huxley neuron to different forms of external stimuli. When the neuron was subjected to a DC stimulus, the firing frequencies and the interspike interval distributions of the output spike trains showed periodic behaviors as the autaptic delay time increased. When the input was a synaptic pulse-like train with random interspike intervals, we observed low-pass and band-pass filtering behaviors. Moreover, the region over which the output ISIs are distributed and the mean firing frequency display periodic behaviors with increasing autaptic delay time. When specific autaptic parameters were chosen, most of the input ISIs could be filtered, and the response spike trains were nearly regular, even with a highly random input. The background mechanism of these observed dynamics has been analyzed based on the phase response curve method. We also found that the information entropy of the output spike train could be modified by the autapse. These results also suggest that the autapse can serve as a regulator of information response in the nervous system. PMID- 25273203 TI - Polynomial law for controlling the generation of n-scroll chaotic attractors in an optoelectronic delayed oscillator. AB - Controlled transitions between a hierarchy of n-scroll attractors are investigated in a nonlinear optoelectronic oscillator. Using the system's feedback strength as a control parameter, it is shown experimentally the transition from Van der Pol-like attractors to 6-scroll, but in general, this scheme can produce an arbitrary number of scrolls. The complexity of every state is characterized by Lyapunov exponents and autocorrelation coefficients. PMID- 25273204 TI - Continuous-time control of alternans in long Purkinje fibers. AB - Alternans-an arrhythmic response of cardiac tissue to periodic pacing-often serves as a precursor to a more dangerous, and potentially lethal, state of fibrillation. Suppression of alternans using feedback control may be a plausible method to prevent fibrillation. Several approaches based on impulsive control have been proposed previously, where feedback is applied for a brief instance of time during each pacing interval. This paper presents a continuous-time approach, where feedback current is applied at all times, which is capable of suppressing alternans in fibers of significantly greater length (up to at least 4 cm), compared with impulsive control (less than 1 cm), and for a wide range of pacing cycle lengths. PMID- 25273205 TI - Effects of spike-time-dependent plasticity on the stochastic resonance of small world neuronal networks. AB - The phenomenon of stochastic resonance in Newman-Watts small-world neuronal networks is investigated when the strength of synaptic connections between neurons is adaptively adjusted by spike-time-dependent plasticity (STDP). It is shown that irrespective of the synaptic connectivity is fixed or adaptive, the phenomenon of stochastic resonance occurs. The efficiency of network stochastic resonance can be largely enhanced by STDP in the coupling process. Particularly, the resonance for adaptive coupling can reach a much larger value than that for fixed one when the noise intensity is small or intermediate. STDP with dominant depression and small temporal window ratio is more efficient for the transmission of weak external signal in small-world neuronal networks. In addition, we demonstrate that the effect of stochastic resonance can be further improved via fine-tuning of the average coupling strength of the adaptive network. Furthermore, the small-world topology can significantly affect stochastic resonance of excitable neuronal networks. It is found that there exists an optimal probability of adding links by which the noise-induced transmission of weak periodic signal peaks. PMID- 25273206 TI - How well-connected is the surface of the global ocean? AB - The Ekman dynamics of the ocean surface circulation is known to contain attracting regions such as the great oceanic gyres and the associated garbage patches. Less well-known are the extents of the basins of attractions of these regions and how strongly attracting they are. Understanding the shape and extent of the basins of attraction sheds light on the question of the strength of connectivity of different regions of the ocean, which helps in understanding the flow of buoyant material like plastic litter. Using short flow time trajectory data from a global ocean model, we create a Markov chain model of the surface ocean dynamics. The surface ocean is not a conservative dynamical system as water in the ocean follows three-dimensional pathways, with upwelling and downwelling in certain regions. Using our Markov chain model, we easily compute net surface upwelling and downwelling, and verify that it matches observed patterns of upwelling and downwelling in the real ocean. We analyze the Markov chain to determine multiple attracting regions. Finally, using an eigenvector approach, we (i) identify the five major ocean garbage patches, (ii) partition the ocean into basins of attraction for each of the garbage patches, and (iii) partition the ocean into regions that demonstrate transient dynamics modulo the attracting garbage patches. PMID- 25273207 TI - Multifractal detrended moving average analysis for texture representation. AB - Multifractal detrended moving average analysis (MF-DMA) is recently employed to detect long-range correlation and multifractal nature in stationary and non stationary time series. In this paper, we propose a method to calculate the generalized Hurst exponent for each pixel of a surface based on MF-DMA, which we call the MF-DMA-based local generalized Hurst exponent. These exponents form a matrix, which we denote by LHq. These exponents are similar to the multifractal detrended fluctuation analysis (MF-DFA)-based local generalized Hurst exponent. The performance of the calculated LHq is tested for two synthetic multifractal surfaces and ten randomly chosen natural textures with analytical solutions under three cases, namely, backward (theta = 0), centered (theta = 0.5), and forward (theta = 1) with different q values and different sub-image sizes. Two sets of comparison segmentation experiments between the three cases of the MF-DMA-based LHq and the MF-DFA-based LHq show that the MF-DMA-based LHq is superior to the MF DFA-based LHq. In addition, the backward MF-DMA algorithm is more efficient than the centered and forward algorithms. An interest finding is that the LHq with q < 0 outperforms the LHq with q > 0 in characterizing the image features of natural textures for both the MF-DMA and MF-DFA algorithms. PMID- 25273208 TI - Community structure revealed by phase locking. AB - Community structure can naturally emerge in paths to synchronization, and scratching it from the paths is a tough issue that accounts for the diverse dynamics of synchronization. In this paper, with assumption that the synchronization on complex networks is made up of local and collective processes, we proposed a scheme to lock the local synchronization (phase locking) at a stable state, meanwhile, suppress the collective synchronization based on Kuramoto model. Through this scheme, the network dynamics only contains the local synchronization, which suggests that the nodes in the same community synchronize together and these synchronization clusters well reveal the community structure of network. Furthermore, by analyzing the paths to synchronization, the relations or overlaps among different communities are also obtained. Thus, the community detection based on the scheme is performed on five real networks and the observed community structures are much more apparent than modularity-based fast algorithm. Our results not only provide a deep insight to understand the synchronization dynamics on complex network but also enlarge the research scope of community detection. PMID- 25273209 TI - Stationary spots and stationary arcs induced by advection in a one-activator, two inhibitor reactive system. AB - This paper studies the spatiotemporal dynamics of a reaction-diffusion-advection system corresponding to an extension of the Oregonator model, which includes two inhibitors instead of one. We show that when the reaction-diffusion, two dimensional problem displays stationary patterns the addition of a plug flow can induce the emergence of new types of stationary structures. These patterns take the form of spots or arcs, the size and the spacing of which can be controlled by the flow. PMID- 25273210 TI - Roles of superthermal electrons and positrons on positron-acoustic solitary waves and double layers in electron-positron-ion plasmas. AB - Positron-acoustic (PA) solitary waves (SWs) and double layers (DLs) in four component plasmas consisting of immobile positive ions, mobile cold positrons, and superthermal (kappa distributed) hot positrons and electrons are investigated both numerically and analytically by deriving Korteweg-de Vries (K-dV), modified K-dV (mK-dV), and Gardner equations along with their DLs solutions using the reductive perturbation method. It is examined that depending on the plasma parameters, the K-dV SWs, Gardner SWs, and DLs support either compressive or rarefactive structures, whereas mK-dV SWs support only compressive structure. It is also found that the presence of superthermal (kappa distributed) hot positrons and hot electrons significantly modify the basic features of PA SWs as well as PA DLs. Besides, the critical number density ratio of hot positrons and cold positrons play an important role in the polarity of PA SWs and DLs. The implications of our results in different space as well as laboratory plasma environments are briefly discussed. PMID- 25273211 TI - Synchronization and array-enhanced resonances in delayed coupled neuronal network with channel noise. AB - This paper studies the combined effect of transmission delay and channel fluctuations on population behaviors of an excitatory Erdos-Renyi neuronal network. First, it is found that the network reaches a perfect spatial temporal coherence at a suitable membrane size. Such a coherence resonance is stimulus free and is array-enhanced. Second, the presence of transmission delay can induce intermittent changes of the population dynamics. Besides, two resonant peaks of the population firing rate are observed as delay changes: one is at taud~7ms for all membrane areas, which reflects the resonance between the delayed interaction and the intrinsic period of channel kinetics; the other occurs when the transmission delay equals to the mean inter-spike intervals of the population firings in the absence of delay, which reflects the resonance between the delayed interaction and the firing period of the non-delayed system. Third, concerning the impact of network topology and population size, it is found that decreasing the connection probability does not change the range of transmission delay but broadens the range of synaptic coupling that supports population neurons to generate action potentials synchronously and temporally coherently. Furthermore, there exists a critical connection probability that distinguishes the population dynamics into an asynchronous and synchronous state. All the results we obtained are based on networks of size N = 500, which are shown to be robust to further increasing the population size. PMID- 25273212 TI - Metrics for evaluation of the author's writing styles: who is the best? AB - Studying the complexity of language has attracted the physicist's attention recently. The methods borrowed from the statistical mechanics; namely, the complex network theory, can be used for exploring the regularities as a characteristic of complexity of language. In this paper, we focus on the authorship identification by using the complex network approach. We introduce three metrics which enable us for comparison the author's writing styles. This approach was previously used by us for finding the author of unknown book among collection of thirty six books written by five Persian poets. Here, we select a collection of one hundred and one books of nine English writers and quantify their writing styles according to our metrics. In our experiment, Shakespeare appears as the best author who follows a unique writing style in all of his works. PMID- 25273213 TI - Geometrical measurement of cardiac wavelength in reaction-diffusion models. AB - The dynamics of reentrant arrhythmias often consists in multiple wavelets propagating throughout an excitable medium. An arrhythmia can be sustained only if these reentrant waves have a sufficiently short wavelength defined as the distance traveled by the excitation wave during its refractory period. In a uniform medium, wavelength may be estimated as the product of propagation velocity and refractory period (electrophysiological wavelength). In order to accurately measure wavelength in more general substrates relevant to atrial arrhythmias (heterogeneous and anisotropic), we developed a mathematical framework to define geometrical wavelength at each time instant based on the length of streamlines following the propagation velocity field within refractory regions. Two computational methods were implemented: a Lagrangian approach in which a set of streamlines were integrated, and an Eulerian approach in which wavelength was the solution of a partial differential equation. These methods were compared in 1D/2D tissues and in a model of the left atrium. An advantage of geometrical definition of wavelength is that the wavelength of a wavelet can be tracked over time with high temporal resolution and smaller temporal variability in an anisotropic and heterogeneous medium. The results showed that the average electrophysiological wavelength was consistent with geometrical measurements of wavelength. Wavelets were however often shorter than the electrophysiological wavelength due to interactions with boundaries and other wavelets. These tools may help to assess more accurately the relation between substrate properties and wavelet dynamics in computer models. PMID- 25273214 TI - Control effects of stimulus paradigms on characteristic firings of parkinsonism. AB - Experimental studies have shown that neuron population located in the basal ganglia of parkinsonian primates can exhibit characteristic firings with certain firing rates differing from normal brain activities. Motivated by recent experimental findings, we investigate the effects of various stimulation paradigms on the firing rates of parkinsonism based on the proposed dynamical models. Our results show that the closed-loop deep brain stimulation is superior in ameliorating the firing behaviors of the parkinsonism, and other control strategies have similar effects according to the observation of electrophysiological experiments. In addition, in conformity to physiological experiments, we found that there exists optimal delay of input in the closed-loop GPtrain|M1 paradigm, where more normal behaviors can be obtained. More interestingly, we observed that W-shaped curves of the firing rates always appear as stimulus delay varies. We furthermore verify the robustness of the obtained results by studying three pallidal discharge rates of the parkinsonism based on the conductance-based model, as well as the integrate-and-fire-or-burst model. Finally, we show that short-term plasticity can improve the firing rates and optimize the control effects on parkinsonism. Our conclusions may give more theoretical insight into Parkinson's disease studies. PMID- 25273215 TI - Adaptive fuzzy dynamic surface control for the chaotic permanent magnet synchronous motor using Nussbaum gain. AB - This paper is concerned with the problem of adaptive fuzzy dynamic surface control (DSC) for the permanent magnet synchronous motor (PMSM) system with chaotic behavior, disturbance and unknown control gain and parameters. Nussbaum gain is adopted to cope with the situation that the control gain is unknown. And the unknown items can be estimated by fuzzy logic system. The proposed controller guarantees that all the signals in the closed-loop system are bounded and the system output eventually converges to a small neighborhood of the desired reference signal. Finally, the numerical simulations indicate that the proposed scheme can suppress the chaos of PMSM and show the effectiveness and robustness of the proposed method. PMID- 25273216 TI - Decreased coherence and functional connectivity of electroencephalograph in Alzheimer's disease. AB - In this paper, we investigate the abnormalities of electroencephalograph (EEG) signals in the Alzheimer's disease (AD) by analyzing 16-scalp electrodes EEG signals and make a comparison with the normal controls. Coherence is introduced to measure the pair-wise normalized linear synchrony and functional correlations between two EEG signals in different frequency domains, and graph analysis is further used to investigate the influence of AD on the functional connectivity of human brain. Data analysis results show that, compared with the control group, the pair-wise coherence of AD group is significantly decreased, especially for the theta and alpha frequency bands in the frontal and parieto-occipital regions. Furthermore, functional connectivity among different brain regions is reconstructed based on EEG, which exhibit obvious small-world properties. Graph analysis demonstrates that the local functional connections between regions for AD decrease. In addition, it is found that small-world properties of AD networks are largely weakened, by calculating its average path lengths, clustering coefficients, global efficiency, local efficiency, and small-worldness. The obtained results show that both pair-wise coherence and functional network can be taken as effective measures to distinguish AD patients from the normal, which may benefit our understanding of the disease. PMID- 25273217 TI - Delayed feedback control and phase reduction of unstable quasi-periodic orbits. AB - The delayed feedback control (DFC) is applied to stabilize unstable quasi periodic orbits (QPOs) in discrete-time systems. The feedback input is given by the difference between the current state and a time-delayed state in the DFC. However, there is an inevitable time-delay mismatch in QPOs. To evaluate the influence of the time-delay mismatch on the DFC, we propose a phase reduction method for QPOs and construct a phase response curve (PRC) from unstable QPOs directly. Using the PRC, we estimate the rotation number of QPO stabilized by the DFC. We show that the orbit of the DFC is consistent with the unstable QPO perturbed by a small state difference resulting from the time-delay mismatch, implying that the DFC can certainly stabilize the unstable QPO. PMID- 25273218 TI - Controlling chaos faster. AB - Predictive feedback control is an easy-to-implement method to stabilize unknown unstable periodic orbits in chaotic dynamical systems. Predictive feedback control is severely limited because asymptotic convergence speed decreases with stronger instabilities which in turn are typical for larger target periods, rendering it harder to effectively stabilize periodic orbits of large period. Here, we study stalled chaos control, where the application of control is stalled to make use of the chaotic, uncontrolled dynamics, and introduce an adaptation paradigm to overcome this limitation and speed up convergence. This modified control scheme is not only capable of stabilizing more periodic orbits than the original predictive feedback control but also speeds up convergence for typical chaotic maps, as illustrated in both theory and application. The proposed adaptation scheme provides a way to tune parameters online, yielding a broadly applicable, fast chaos control that converges reliably, even for periodic orbits of large period. PMID- 25273220 TI - Synthesis of Cr and La-codoped SrTiO3 nanoparticles for enhanced photocatalytic performance under sunlight irradiation. AB - In this study, we report a facile polymeric citrate strategy for the synthesis of Cr,La-codoped SrTiO3 nanoparticles. The synthesized samples were well characterized by various analytical techniques. The UV-vis DRS studies reveal that the absorption edge shifts towards the visible light region after doping with Cr, which is highly beneficial for absorbing the visible light in the solar spectrum. More attractively, codoping with La exhibits greatly enhanced photocatalytic activity for the degradation of Rhodamine B under sunlight irradiation. The optimum photocatalytic activity at 1 atom% of Cr,La-codoped SrTiO3 nanoparticles is almost 6 times higher than that of pure SrTiO3 nanoparticles and 3 times higher than that of Cr-doped SrTiO3 nanoparticles. The high photocatalytic performance in the present photocatalytic system is due to codoping with La, which acts as a most effective donor for stabilizing Cr(3+) in Cr,La-codoped SrTiO3 nanoparticles. More importantly, the synthesized photocatalysts possess high reusability. A proposed mechanism for the enhanced photocatalytic activity of Cr,La-codoped SrTiO3 nanoparticles was also investigated by trapping experiments. Therefore, our results not only demonstrate the highly efficient visible light photocatalytic activity of the Cr,La-codoped SrTiO3 photocatalyst, but also enlighten the codoping strategy in the design and development of advanced photocatalytic materials for energy and environmental applications. PMID- 25273219 TI - Dynamical glucometry: use of multiscale entropy analysis in diabetes. AB - Diabetes mellitus (DM) is one of the world's most prevalent medical conditions. Contemporary management focuses on lowering mean blood glucose values toward a normal range, but largely ignores the dynamics of glucose fluctuations. We probed analyte time series obtained from continuous glucose monitor (CGM) sensors. We show that the fluctuations in CGM values sampled every 5 min are not uncorrelated noise. Next, using multiscale entropy analysis, we quantified the complexity of the temporal structure of the CGM time series from a group of elderly subjects with type 2 DM and age-matched controls. We further probed the structure of these CGM time series using detrended fluctuation analysis. Our findings indicate that the dynamics of glucose fluctuations from control subjects are more complex than those of subjects with type 2 DM over time scales ranging from about 5 min to 5 h. These findings support consideration of a new framework, dynamical glucometry, to guide mechanistic research and to help assess and compare therapeutic interventions, which should enhance complexity of glucose fluctuations and not just lower mean and variance of blood glucose levels. PMID- 25273221 TI - Registered nurses' experiences of their decision-making at an Emergency Medical Dispatch Centre. AB - AIMS AND OBJECTIVES: To describe registered nurses' experiences at an Emergency Medical Dispatch Centre. BACKGROUND: It is important that ambulances are urgently directed to patients who are in need of immediate help and of quick transportation to a hospital. Because resources are limited, Emergency Medical Dispatch centres cannot send ambulances with high priority to all callers. The efficiency of the system is therefore dependent on triage. Nurses worldwide are involved in patient triage, both before the patient's arrival to the hospital and in the subsequent emergency care. Ambulance dispatching is traditionally a duty for operators at Emergency Medical Dispatch centres, and in Sweden this duty has become increasingly performed by registered nurses. DESIGN: A qualitative design was used for this study. METHODS: Fifteen registered nurses with experience at Emergency Medical Dispatch centres were interviewed. The participants were asked to describe the content of their work and their experiences. They also described the most challenging and difficult situations according to the critical incidence technique. Content analysis was used. RESULTS: Two themes emerged during the analysis: 'Having a profession with opportunities and obstacles' and 'Meeting serious and difficult situations', with eight sub-themes. The results showed that the decisions to dispatch ambulances were both challenging and difficult. Difficulties included conveying medical advice without seeing the patient, teaching cardio-pulmonary resuscitation via telephone and dealing with intoxicated and aggressive callers. Conflicts with colleagues and ambulance crews as well as fear of making wrong decisions were also mentioned. CONCLUSIONS: Work at Emergency Medical Dispatch centres is a demanding but stimulating duty for registered nurses. RELEVANCE TO CLINICAL PRACTICE: Great benefits can be achieved using experienced triage nurses, including increased patient safety and better use of medical resources. Improved internal support systems at Emergency Medical Dispatch centres and striving for a blame-free culture are important factors to attract and retain employees. PMID- 25273223 TI - Urticaria. AB - Urticaria is a very common skin disease which was already described in the ancient world. Questions still remain about its pathogenesis and management remain open. Compared to other common skin diseases, the published evidence is rather low. The clinical symptoms with pruritic transient wheals and/or angioedema are caused by mediators (particularly histamine) released by activated mast cells and basophils. The mechanism of target cell activation has not been clarified in detail for most urticaria subtypes. Different urticaria subtypes should be distinguished. Spontaneous forms are more common than inducible forms. Chronic urticaria and urticaria in certain age groups (children, pregnancy) can be difficult to manage. Therefore, international consensus resulting in the regular update of urticaria guidelines can be very helpful. Currently, these updated guidelines include a three-step treatment algorithm for chronic spontaneous urticaria. Only the first step of this algorithm, second generation H1-antihistamine in standard dose, utilized approved drugs. However after omalizumab was established as a third line choice in the guideline algorithm, it has approved in many countries for chronic spontaneous urticaria without response to H1-antihistamines. The exact mechanism of action of omalizumab in urticaria has not been fully elucidated. Unrevealing this mechanism might result in a deeper understanding of urticaria pathogenesis and the development of further therapeutic strategies. PMID- 25273222 TI - Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC). AB - Ionizing radiation alone or in combination with chemotherapy is the main treatment modality for brain tumors including glioblastoma. Adult neurons and astrocytes demonstrate substantial radioresistance; in contrast, human neural stem cells (NSC) are highly sensitive to radiation via induction of apoptosis. Irradiation of tumor cells has the potential risk of affecting the viability and function of NSC. In this study, we have evaluated the effects of irradiated glioblastoma cells on viability, proliferation and differentiation potential of non-irradiated (bystander) NSC through radiation-induced signaling cascades. Using media transfer experiments, we demonstrated significant effects of the U87MG glioblastoma secretome after gamma-irradiation on apoptosis in non irradiated NSC. Addition of anti-TRAIL antibody to the transferred media partially suppressed apoptosis in NSC. Furthermore, we observed a dramatic increase in the production and secretion of IL8, TGFbeta1 and IL6 by irradiated glioblastoma cells, which could promote glioblastoma cell survival and modify the effects of death factors in bystander NSC. While differentiation of NSC into neurons and astrocytes occurred efficiently with the corresponding differentiation media, pretreatment of NSC for 8 h with medium from irradiated glioblastoma cells selectively suppressed the differentiation of NSC into neurons, but not into astrocytes. Exogenous IL8 and TGFbeta1 increased NSC/NPC survival, but also suppressed neuronal differentiation. On the other hand, IL6 was known to positively affect survival and differentiation of astrocyte progenitors. We established a U87MG neurosphere culture that was substantially enriched by SOX2(+) and CD133(+) glioma stem-like cells (GSC). Gamma-irradiation up-regulated apoptotic death in GSC via the FasL/Fas pathway. Media transfer experiments from irradiated GSC to non-targeted NSC again demonstrated induction of apoptosis and suppression of neuronal differentiation of NSC. In summary, intercellular communication between glioblastoma cells and bystander NSC/NPC could be involved in the amplification of cancer pathology in the brain. PMID- 25273225 TI - "Tell me, how bright your hypomania is, and I tell you, if you are happily in love!"--among young adults in love, bright side hypomania is related to reduced depression and anxiety, and better sleep quality. AB - BACKGROUND: Studies on adolescents and adults show that romantic love (RL) is associated with favorable emotional states. However, data on these associations are scarce for adults. The aim of the present study was, therefore, to explore the associations between RL, symptoms of depression, anxiety, hypomania (bright side and dark side), and sleep in a sample of adults. METHOD: A total of 844 participants currently in love (M = 24.79 years, 75.8% females) took part in the study. They completed a series of questionnaires related to RL, symptoms of depression, anxiety, hypomania (bright side and dark side), and sleep. RESULTS: An increased state of RL was associated both with the bright and the dark side of hypomania (BRHYP and DAHYP). Relative to participants with BRHYP, participants with DAHYP reported stronger symptoms of depression and state anxiety, and poor sleep quality. CONCLUSIONS: The pattern of results adds to our knowledge that in adults RL is not entirely a joyful and happy period of life. Rather, data suggest that for young adults in love, bright versus dark side of hypomania was associated with a different quality of psychological functioning and sleep. We conclude that experiencing RL might be a critical life event associated with symptoms of depression and anxiety, and poor sleep. PMID- 25273224 TI - Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. AB - BACKGROUND: The advent of effective targeted therapy for BRAF(V600E) -mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced-stage BRAF-mutant lung adenocarcinomas. METHODS: Data were reviewed for patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), human epidermal growth factor receptor 2 (HER2), AKT1, BRAF, dual specificity mitogen-activated protein kinase kinase 1 (MEK1), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA); for anaplastic lymphoma kinase (ALK) translocations; and for MET amplification. RESULTS: Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%; 95% confidence interval [CI], 1.4%-3.4%): 17 (81%; 95% CI, 60%-92%) were BRAF(V600E) mutations, and 4 were non-BRAF(V600E) mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur than most other genotypic abnormalities in current or former smokers (BRAF vs sensitizing EGFR, 82% vs 36%, mid-P < .001; BRAF vs ALK, 39%, mid-P = .003; BRAF vs other mutations, 49%, mid-P = .02; BRAF vs patients with more than 1 oncogenic driver [doubleton], 46%, mid-P = .04.) The double-mutation rate was 16% among patients with BRAF mutations but 5% among patients with other genomic abnormalities (mid-P = .045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P > .20). CONCLUSIONS: BRAF mutations occurred in 2.2% of advanced-stage lung adenocarcinomas, were most commonly V600E, and were associated with distinct clinicopathologic features in comparison with other genomic subtypes and with a high mutation rate in more than 1 gene. These findings underscore the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas. PMID- 25273227 TI - Excitation of nucleobases from a computational perspective II: dynamics. AB - This chapter is devoted to unravel the relaxation processes taking place after photoexcitation of isolated DNA/RNA nucleobases in gas phase from a time dependent perspective. To this aim, several methods are at hand, ranging from full quantum dynamics to various flavours of semiclassical or ab initio molecular dynamics, each with its advantages and its limitations. As this contribution shows, the most common approach employed up to date to learn about the deactivation of nucleobases in gas phase is a combination of the Tully surface hopping algorithm with on-the-fly CASSCF calculations. Different dynamics methods or, even more dramatically, different electronic structure methods can provide different dynamics. A comprehensive review of the different mechanisms suggested for each nucleobase is provided and compared to available experimental time scales. The results are discussed in a general context involving the effects of the different applied electronic structure and dynamics methods. Mechanistic similarities and differences between the two groups of nucleobases - the purine derivatives (adenine and guanine) and the pyrimidine derivatives (thymine, uracil, and cytosine) - are elucidated. Finally, a perspective on the future of dynamics simulations in the context of nucleobase relaxation is given. PMID- 25273226 TI - Strong genetic structure corresponds to small-scale geographic breaks in the Australian alpine grasshopper Kosciuscola tristis. AB - BACKGROUND: Mountain landscapes are topographically complex, creating discontinuous 'islands' of alpine and sub-alpine habitat with a dynamic history. Changing climatic conditions drive their expansion and contraction, leaving signatures on the genetic structure of their flora and fauna. Australia's high country covers a small, highly fragmented area. Although the area is thought to have experienced periods of relative continuity during Pleistocene glacial periods, small-scale studies suggest deep lineage divergence across low-elevation gaps. Using both DNA sequence data and microsatellite markers, we tested the hypothesis that genetic partitioning reflects observable geographic structuring across Australia's mainland high country, in the widespread alpine grasshopper Kosciuscola tristis (Sjosted). RESULTS: We found broadly congruent patterns of regional structure between the DNA sequence and microsatellite datasets, corresponding to strong divergence among isolated mountain regions. Small and isolated mountains in the south of the range were particularly distinct, with well-supported divergence corresponding to climate cycles during the late Pliocene and Pleistocene. We found mixed support, however, for divergence among other mountain regions. Interestingly, within areas of largely contiguous alpine and sub-alpine habitat around Mt Kosciuszko, microsatellite data suggested significant population structure, accompanied by a strong signature of isolation by-distance. CONCLUSIONS: Consistent patterns of strong lineage divergence among different molecular datasets indicate genetic breaks between populations inhabiting geographically distinct mountain regions. Three primary phylogeographic groups were evident in the highly fragmented Victorian high country, while within-region structure detected with microsatellites may reflect more recent population isolation. Despite the small area of Australia's alpine and sub-alpine habitats, their low topographic relief and lack of extensive glaciation, divergence among populations was on the same scale as that detected in much more extensive Northern hemisphere mountain systems. The processes driving divergence in the Australian mountains might therefore differ from their Northern hemisphere counterparts. PMID- 25273228 TI - Stress response and virulence of heat-stressed Campylobacter jejuni. AB - Thermotolerant Campylobacter spp. frequently cause bacterial gastroenteritis in humans commonly infected through the consumption of undercooked poultry meat. We examined Campylobacter jejuni heat-stress responses in vitro after exposure to 48 degrees C and 55 degrees C. The in vivo modulation of its pathogenicity was also investigated using BALB/c mice intravenously infected with stressed C. jejuni. Regardless of the bacterial growth phase, the culturability and viability of C. jejuni in vitro was reduced after exposure to 55 degrees C. This correlated with the altered protein profile and decreased virulence properties observed in vivo. Heat stress at 48 degrees C elicited the transition to more resistant bacterial forms, independent of morphological changes or the appearance of shorter spiral and coccoid cells. This treatment did not cause marked changes in bacterial virulence properties in vivo. These results indicated that the characteristics and pathogenicity of C. jejuni in response to heat stress are temperature dependent. Further studies on the responses of C. jejuni to stresses used during food processing, as well as the modulation of its virulence, are important for a better understanding of its contamination and infective cycle, and will, thus, contribute to improved safety in the food production chain. PMID- 25273231 TI - British Association of Dermatologists' guidelines for the management of cutaneous warts 2014. PMID- 25273232 TI - Does Presumed Consent Save Lives? Evidence from Europe. AB - One policy tool that could affect organ donation rates is legislative defaults. In this study, we examine how presumed consent impacts cadaveric donations and kidney transplantations, using a panel dataset from the EU-27 countries plus Croatia in the period 2000-2010. We find that presumed consent countries have 28% to 32% higher cadaveric donation and 27% to 31% higher kidney transplant rates in comparison to informed consent countries, after accounting for potential confounding factors. After studying willingness to donate one's organs and registering preferences for organ donation, we find that presumed consent could increase cadaveric donation rates, because people fail to register their preferences and many have no preference for organ donation. PMID- 25273229 TI - Impact of hydraulic well restoration on native bacterial communities in drinking water wells. AB - The microbial monitoring of drinking water production systems is essential to assure water quality and minimize possible risks. However, the comparative impact of microbes from the surrounding aquifer and of those established within drinking water wells on water parameters remains poorly understood. High pressure jetting is a routine method to impede well clogging by fine sediments and also biofilms. In the present study, bacterial communities were investigated in a drinking water production system before, during, and after hydraulic purging. Variations were observed in bacterial communities between different wells of the same production system before maintenance, despite them having practically identical water chemistries. This may have reflected the distinct usage practices of the different wells, and also local aquifer heterogeneity. Hydraulic jetting of one well preferentially purged a subset of the dominating taxa, including lineages related to Diaphorobacter, Nitrospira, Sphingobium, Ralstonia, Alkanindiges, Janthinobacterium, and Pseudomonas spp, suggesting their tendency for growth in well-associated biofilms. Lineages of potential drinking water concern (i.e. Legionellaceae, Pseudomonadaceae, and Acinetobacter spp.) reacted distinctly to hydraulic jetting. Bacterial diversity was markedly reduced in drinking water 2 weeks after the cleaning procedure. The results of the present study provide a better understanding of drinking water wells as a microbial habitat, as well as their role in the microbiology of drinking water systems. PMID- 25273233 TI - Interferon regulatory factor 8 expressed in microglia contributes to tactile allodynia induced by repeated cold stress in rodents. AB - We investigated the role of interferon regulatory factor 8 (IRF8) in a model of chronic pain in which repeated cold stress (RCS) exposure produces tactile allodynia. RCS exposure produced a decrease in paw withdrawal threshold (PWT) to mechanical stimulation. Spinal microglia of RCS-exposed mice were morphologically activated. Expression of IRF8 was significantly increased in the spinal cord of RCS-exposed mice and was localized in microglia. IRF8-knockout mice failed to show the RCS-induced decrease in PWT. Thus, RCS exposure activates spinal microglia and upregulation of IRF8 in these cells is involved in the development of tactile allodynia after RCS exposure. PMID- 25273230 TI - Temperature-dependent variations in sulfate-reducing communities associated with a terrestrial hydrocarbon seep. AB - Terrestrial hydrocarbon seeps are an important source of naturally emitted methane over geological time. The exact community compositions responsible for carbon cycling beneath these surface features remain obscure. As sulfate reduction represents an essential process for anoxic organic mineralization, this study collected muddy fluids from a high-temperature hydrocarbon seep in Taiwan and analyzed community structures of sulfate-supplemented sediment slurries incubated anoxically at elevated temperatures. The results obtained demonstrated that sulfate consumption occurred between 40 degrees C and 80 degrees C. Dominant potential sulfate reducers included Desulfovibrio spp., Desulfonatronum spp., Desulforhabdus spp., and Desulfotomaculum spp. at 40 degrees C, Thermodesulfovibrio spp. at 50 degrees C, Thermodesulfovibrio spp. and Thermacetogenium spp. at 60 degrees C, Thermacetogenium spp. and Archaeoglobus spp. at 70 degrees C, and Archaeoglobus spp. at 80 degrees C. None of these potential sulfate reducers exceeded 7% of the community in the untreated sample. Since no exogenous electron donor was provided during incubation, these sulfate reducers appeared to rely on the degradation of organic matter inherited from porewater and sediments. Aqueous chemistry indicated that fluids discharged in the region represented a mixture of saline formation water and low-salinity surface water; therefore, these lines of evidence suggest that deeply-sourced, thermophilic and surface-input, mesophilic sulfate-reducing populations entrapped along the subsurface fluid transport could respond rapidly once the ambient temperature is adjusted to a range close to their individual optima. PMID- 25273234 TI - Molecular basis for the high CO2 adsorption capacity of chabazite zeolites. AB - CO2 adsorption in Li-, Na-, K-CHA (Si/Al=6,=12), and silica chabazite zeolites was investigated by powder diffraction. Two CO2 adsorption sites were found in all chabazites with CO2 locating in the 8-membered ring (8MR) pore opening being the dominant site. Electric quadrupole-electric field gradient and dispersion interactions drive CO2 adsorption at the middle of the 8 MRs, while CO2 polarization due to interaction with cation sites controls the secondary CO2 site. In Si-CHA, adsorption is dominated by dispersion interactions with CO2 observed on the pore walls and in 8 MRs. CO2 adsorption complexes on dual cation sites were observed on K-CHA, important for K-CHA-6 samples due to a higher probability of two K(+) cations bridging CO2. Trends in isosteric heats of CO2 adsorption based on cation type and concentration can be correlated with adsorption sites and CO2 quantity. A decrease in the hardness of metal cations results in a decrease in the direct interaction of these cations with CO2. PMID- 25273235 TI - Irksome students. PMID- 25273236 TI - [Physical activity--never too late!]. PMID- 25273237 TI - [An evidence-based collaboration reform?]. PMID- 25273238 TI - Re: When the patient refuses blood transfusion. PMID- 25273244 TI - [Outdoor spaces in psychiatry--a gust of the past or a humane patient right?]. PMID- 25273245 TI - [Advice for people who have forgotten to take their epilepsy medicine]. PMID- 25273247 TI - [Physical activity, smoking and mortality among men who participated in the Oslo studies of 1972 and 2000]. AB - BACKGROUND: Few Norwegian data are available on the importance of physical activity with regard to mortality. Our objective was to study mortality in light of leisure time physical activity and smoking. MATERIAL AND METHOD: Men born in the period 1923-1932 were included in the Oslo Study in 1972-1973 and then investigated again in 2000. A total of 5738 men were included in the analyses. Physical activity was registered as self-reported number of hours at low and high intensity, as well by the Gothenburg question on the degree of leisure activity (sedentary, low, moderate, high). Cox regression analysis was used for statistical computation. RESULTS: After 12 years, men who reported a moderate amount of activity (approximately 30 minutes per day six times per week of low or high activity) in the year 2000 had a 40% lower mortality rate than the physically inactive (the reference group). A change in activity level in older age was independently associated with a risk of death. The Gothenburg question on amount of activity gave the same predictive information value as smoking. INTERPRETATION: Our data indicate that there is a dose-response relationship between the degree of physical activity and early death. An increase in activity was just as strongly associated with reduced mortality as quitting smoking. Based on these data, physical activity should be recommended as a daily habit. PMID- 25273248 TI - [Pre-hospital observation as an alternative to emergency hospitalisation]. AB - BACKGROUND: Pre-hospital observation beds in community care centres have for many years served as an alternative to hospitalisation in rural districts of Norway. The article presents the use of observation beds associated with the Fosen A&E centre. MATERIAL AND METHOD: A retrospective review of records of patients who had contacted Fosen A&E centre during the period 21 August 2006-21 August 2009 was undertaken. Patient characteristics and clinical pathways were registered, including admissions to hospital or to an observation bed, as well as re admissions. Ever since observation beds were first introduced, clear inclusion and exclusion criteria have been applied with regard to the allocation of patients to observation beds. RESULTS: Altogether 8027 patients had been in direct contact with an A&E doctor, and 2342 were admitted, of whom 77% to hospital and 23% to an observation bed. Of the 530 patients admitted to an observation bed, 55% were 70 years or older. Of these, 68% were discharged to their homes within 36 hours, 17% were transferred to hospital, and the remainder received further treatment in a local rehabilitation unit or nursing home. The rate of readmission to observation beds or hospital amounted to 4% among those who had been discharged after no more than three days, and 18% among those discharged after 3-28 days. INTERPRETATION: A low number of readmissions may indicate that the use of observation beds is an alternative to hospitalisation. PMID- 25273249 TI - Deep brain stimulation in essential tremor. PMID- 25273251 TI - [What should forensic psychiatry contribute with?]. PMID- 25273250 TI - [A woman in her 50s with heavy breathing and hypotension]. PMID- 25273252 TI - Urine microscopy--an important diagnostic tool. PMID- 25273253 TI - Cancer--life, death and love. PMID- 25273254 TI - [Field cancerization of skin and mucous membranes]. PMID- 25273259 TI - ["Blood is a very special juice"--introduction of serum therapy for diphtheria in Norway]. PMID- 25273267 TI - Integrated analysis of miRNA and mRNA expression profiles in response to Cd exposure in rice seedlings. AB - BACKGROUND: Independent transcriptome profile analyses of miRNAs or mRNAs under conditions of cadmium (Cd) stress have been widely reported in plants. However, a combined analysis of sRNA sequencing expression data with miRNA target expression data to infer the relative activities of miRNAs that regulate gene expression changes resulting from Cd stress has not been reported in rice. To elucidate the roles played by miRNAs in the regulation of changes in gene expression in response to Cd stress in rice (Oryza sativa L.), we simultaneously characterized changes in the miRNA and mRNA profiles following treatment with Cd. RESULTS: A total of 163 miRNAs and 2,574 mRNAs were identified to be differentially expressed under Cd stress, and the changes in the gene expression profile in the shoot were distinct from those in the root. At the miRNA level, 141 known miRNAs belonging to 48 families, and 39 known miRNAs in 23 families were identified to be differentially expressed in the root and shoot, respectively. In addition, we identified eight new miRNA candidates from the root and five from the shoot that were differentially expressed in response to Cd treatment. For the mRNAs, we identified 1,044 genes in the root and 448 genes in the shoot that were up regulated, while 572 and 645 genes were down-regulated in the root and shoot, respectively. GO and KEGG enrichment analyses showed that genes encoding secondary, metabolite synthases, signaling molecules, and ABC transporters were significantly enriched in the root, while only ribosomal protein and carotenoid biosynthesis genes were significantly enriched in the shoot. Then 10 known miRNA mRNA interaction pairs and six new candidate ones, that showed the opposite expression patterns, were identified by aligning our two datasets against online databases and by using the UEA sRNA toolkit respectively. CONCLUSIONS: This study is the first to use high throughput DNA sequencing to simultaneously detect changes in miRNA and mRNA expression patterns in the root and shoot in response to Cd treatment. These integrated high-throughput expression data provide a valuable resource to examine global genome expression changes in response to Cd treatment and how these are regulated by miRNAs. PMID- 25273268 TI - Multifocal ischemic brain infarctions secondary to spontaneous basilar artery occlusion in a dog with systemic thromboembolic disease. PMID- 25273270 TI - Host genetics and parasitic infections. AB - Parasites still impose a high death and disability burden on human populations, and are therefore likely to act as selective factors for genetic adaptations. Genetic epidemiological investigation of parasitic diseases is aimed at disentangling the mechanisms underlying immunity and pathogenesis by looking for associations or linkages between loci and susceptibility phenotypes. Until recently, most studies used a candidate gene approach and were relatively underpowered, with few attempts at replicating findings in different populations. However, in the last 5 years, genome-wide and/or multicentre studies have been conducted for severe malaria, visceral leishmaniasis, and cardiac Chagas disease, providing some novel important insights. Furthermore, studies of helminth infections have repeatedly shown the involvement of common loci in regulating susceptibility to distinct diseases such as schistosomiasis, ascariasis, trichuriasis, and onchocherciasis. As more studies are conducted, evidence is increasing that at least some of the identified susceptibility loci are shared not only among parasitic diseases but also with immunological disorders such as allergy or autoimmune disease, suggesting that parasites may have played a role in driving the evolution of the immune system. PMID- 25273269 TI - Genetic basis of age-dependent synaptic abnormalities in the retina. AB - Understanding the normal aging process will help us determine the mechanisms of how age-related diseases are caused and progress. A/J inbred mice have been shown to exhibit accelerated aging phenotypes in the retina including increased inflammation and photoreceptor cell degeneration, which resemble human aging symptoms. C57BL/6J (B6) inbred mice are less susceptible for these abnormalities, indicating the existence of genetic factor(s) that affect their severity. In this study, we determined that another age-dependent phenotype, ectopic synapse formation, is also accelerated in the A/J retina compared to the B6 retina. Through genetic mapping utilizing recombinant inbred strains, we identified quantitative trait loci (QTLs) on chromosome 7 and 19, which contribute to abnormal retinal synapses as well as other age-dependent phenotypes. Using consomic single chromosome substitution lines where a single chromosome is from A/J and the rest of the genome is B6, we investigated the individual effect of each QTL on retinal aging phenotypes. We observed that both QTLs independently contribute to abnormal retinal synapses, reduction in the number of cone cells, and an up-regulation of retinal stress marker, glial fibrillary acidic protein (GFAP). Mice with a single chromosome substitution on chromosome 19 also exhibited an increase in inflammatory cells, which is characteristic of aging and age-related macular degeneration. Thus, we identified QTLs that are independently capable of affecting the severity and progression of age-dependent retinal abnormalities in mice. PMID- 25273271 TI - Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. AB - OBJECTIVE: The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti-JC virus (JCV) antibodies. We analyzed whether anti-JCV antibody levels, measured as index, may further define PML risk in seropositive patients. METHODS: The association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JCV antibody-positive multiple sclerosis (MS) patients from natalizumab clinical studies and postmarketing sources. For PML and non-PML patients, the probabilities of having an index below and above a range of anti-JCV antibody index thresholds were calculated using all available data and applied to the PML risk stratification algorithm. Longitudinal stability of anti-JCV antibody index was also evaluated. RESULTS: Anti-JCV antibody index data were available for serum/plasma samples collected >6 months prior to PML diagnosis from 71 natalizumab-treated PML patients and 2,522 non-PML anti-JCV antibody-positive patients. In patients with no prior immunosuppressant use, anti-JCV antibody index distribution was significantly higher in PML patients than in non-PML patients (p < 0.0001). Among patients who were anti-JCV antibody negative at baseline in the AFFIRM and STRATIFY-1 trials, 97% remained consistently negative or below an index threshold of 1.5 over 18 months. Retrospective analyses of pre PML samples collected longitudinally from PML patients displayed sustained higher anti-JCV antibody index over time. INTERPRETATION: Anti-JCV antibody levels in serum/plasma, measured as index, may differentiate PML risk in anti-JCV antibody positive MS patients with no prior immunosuppressant use. Continued evaluation of anti-JCV antibody index and PML risk is warranted. PMID- 25273272 TI - Sequential stenting for extensive malignant airway stenosis. AB - PURPOSE: Malignant airway stenosis extending from the bronchial bifurcation to the lower lobar orifice was treated with airway stenting. We herein examine the effectiveness of airway stenting for extensive malignant airway stenosis. METHODS: Twelve patients with extensive malignant airway stenosis underwent placement of a silicone Dumon Y stent (Novatech, La Ciotat, France) at the tracheal bifurcation and a metallic Spiral Z-stent (Medico's Hirata, Osaka, Japan) at either distal side of the Y stent. We retrospectively analyzed the therapeutic efficacy of the sequential placement of these silicone and metallic stents in these 12 patients. RESULTS: The primary disease was lung cancer in eight patients, breast cancer in two patients, tracheal cancer in one patient, and thyroid cancer in one patient. The median survival period after airway stent placement was 46 days. The Hugh-Jones classification and performance status improved in nine patients after airway stenting. One patient had prolonged hemoptysis and died of respiratory tract hemorrhage 15 days after the treatment. CONCLUSION: Because the initial disease was advanced and aggressive, the prognosis after sequential airway stent placement was significantly poor. However, because respiratory distress decreased after the treatment in most patients, this treatment may be acceptable for selected patients with extensive malignant airway stenosis. PMID- 25273273 TI - Vasodilation Responses to Non-Selective alpha-Adrenergic Blockage of Coronary Bypass Grafts in Diabetic and Non-Diabetic Patients: In Vitro Study. AB - BACKGROUND: Adrenergic tonus is increased in atherosclerotic coronary arteries. In this study, we aimed to demonstrate in vitro effects of phentolamine, a reversible nonselective alpha (alpha) adrenergic blocker, on coronary artery bypass grafts (CABG) and compare its effects in diabetic and nondiabetic patients. METHODS: A total number of 30 patients (15 diabetic and 15 nondiabetic) who were assigned to elective CABG surgery were enrolled into the study. For both groups of patients, 16 internal mammarian artery (IMA) samples, 16 saphenous vein (SV) samples and 16 radial artery (RA) samples were collected and studied in the tissue bath system. The vasodilatation responses to increasing doses of phentolamine were recorded. RESULTS: When grafts were compared in terms of amount of vasodilatation to phentolamine, IMA had the most prominent vasodilatation followed by RA and SV respectively. Although the vasodilatation responses in nondiabetic patients were numerically higher than diabetic patients, there was no statistically difference between the groups. CONCLUSION: Phentolamine, a nonselective alpha adrenergic blocker, is proven to have equal vasodilatory effects in diabetic and nondiabetic CABG grafts and can safely be used both intravenously and topically in the perioperative period. PMID- 25273274 TI - Stray animal and human defecation as sources of soil-transmitted helminth eggs in playgrounds of Peninsular Malaysia. AB - Soil contaminated with helminth eggs and protozoan cysts is a potential source of infection and poses a threat to the public, especially to young children frequenting playgrounds. The present study determines the levels of infection of helminth eggs in soil samples from urban and suburban playgrounds in five states in Peninsular Malaysia and identifies one source of contamination via faecal screening from stray animals. Three hundred soil samples from 60 playgrounds in five states in Peninsular Malaysia were screened using the centrifugal flotation technique to identify and determine egg/cyst counts per gram (EPG) for each parasite. All playgrounds, especially those in Penang, were found to be contaminated with eggs from four nematode genera, with Toxocara eggs (95.7%) the highest, followed by Ascaris (93.3%), Ancylostoma (88.3%) and Trichuris (77.0%). In addition, faeces from animal shelters were found to contain both helminth eggs and protozoan cysts, with overall infection rates being 54% and 57% for feline and canine samples, respectively. The most frequently occurring parasite in feline samples was Toxocara cati (37%; EPG, 42.47 +/- 156.08), while in dog faeces it was Ancylostoma sp. (54%; EPG, 197.16 +/- 383.28). Infection levels also tended to be influenced by season, type of park/playground and the texture of soil/faeces. The occurrence of Toxocara, Ancylostoma and Trichuris eggs in soil samples highlights the risk of transmission to the human population, especially children, while the presence of Ascaris eggs suggests a human source of contamination and raises the issue of hygiene standards and public health risks at sites under investigation. PMID- 25273275 TI - Rapid and sensitive detection of Listeria monocytogenes by cross-priming amplification of lmo0733 gene. AB - Listeria monocytogenes is a food-borne pathogen that causes severe opportunistic infection in humans and animals. This study reports the development of single cross-priming amplification (S-CPA) and double CPA (D-CPA) assays targeting species-specific gene lmo0733 for identifying L. monocytogenes strains. The CPA assays were performed at a constant temperature 64 degrees C using seven specific primers and evaluated for specificity and sensitivity. The color change of positive amplification was directly observed by Loopamp(r) Fluorescent Detection Reagent (FD), and the DNA products were visualized as a ladder-like banding pattern on 2.5% gel electrophoresis. Moreover, the positive reactions were also detected by real-time measurement of turbidity. 50 L. monocytogenes and 46 non-L. monocytogenes strains were used for the method verification, and the specificity was 100%. The limit of detection (LoD) of the S-CPA and D-CPA assays was 2.5 pg DNA per reaction and 10-fold more sensitive than PCR. A total of 60 pork samples were tested for L. monocytogenes using the S-CPA assay developed in the study, and the accuracy of the S-CPA and the culture-biotechnical method was 100% identical. The results suggested that the S-CPA assay was a rapid, sensitive, and valuable tool for detection of L. monocytogenes in food products. PMID- 25273276 TI - No evidence for histamine H4 receptor in human monocytes. AB - The histamine H4 receptor (H4R) is a classic pertussis toxin-sensitive Gi protein coupled receptor that mediates increases in intracellular calcium concentration ([Ca(2+)]i). The presence of H4R in human eosinophils has been rigorously documented by several independent groups. It has also been suggested that H4R is expressed in human monocytes, but this suggestion hinges in part on H4R antibodies with questionable specificity. This situation prompted us to reinvestigate H4R expression in human monocytes. As positive control, we studied human embryonic kidney 293T cells stably expressing the human H4R (hH4R). In these cells, histamine (HA) and the H4R agonist UR-PI376 (2-cyano-1-[4-(1H imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine) induced pertussis toxin sensitive [Ca(2+)]i increases. However, in quantitative real-time polymerase chain reaction studies we failed to detect hH4R mRNA in human monocytes and U937 promonocytes. In human monocytes, ATP and N-formyl-l-methionyl-l-leucyl-l phenylalanine increased [Ca(2+)]i, but HA, UR-PI376, and 5-methylhistamine (a dual H4R/H2 receptor agonist) did not. In U937 promonocytes and differentiated U937 cells, HA increased [Ca(2+)]i, but this increase was mediated via HA H1 receptor. In conclusion, there is no evidence for the presence of H4R in human monocytes. PMID- 25273277 TI - Effects of neutral red assisted viability assessment on the cryotolerance of isolated bovine preantral follicles. AB - PURPOSE: Fertility preservation strategies warrant non-invasive viability assessment of preantral follicles (PAF) such as staining with Neutral Red (NR) that is incorporated by viable follicles. To optimize the procedure, we firstly determined the lowest concentration and shortest exposure time needed for optimal viability screening of isolated bovine PAF. Secondly, we combined this protocol to a vitrification procedure to assess cryotolerance of the stained follicles. METHODS: Isolated PAF (900, divided over 6 replicates) were cultured in DMEM/Ham's F12 (Culture Medium - Cm) for 4 days (38.5 degrees C, 5% CO2). On D0, D2 and D4, follicles were stained, by adding NR medium (NRm = Cm with different concentrations NR) after which viability was assessed by counting stained/non stained PAF every 30 min for a period of 2 h. RESULTS: Following a binary logistic regression analysis with staining as a result (yes/no) versus log concentration, a probability model could be fitted, indicating that the proportion of stained follicles remained stable after 30 min when 15 MUg/ml NR was used, without compromising follicular health and viability. Consequently, using this protocol, no significant effect of staining prior to vitrification, was found on PAF viability immediately after warming or following 4 days of culture. CONCLUSIONS: In conclusion, we propose NR staining as a non-invasive, non-detrimental viability assessment tool for PAF, when applied at 15 MUg/ml for 30 min, being perfectly compatible with PAF vitrification. PMID- 25273278 TI - Cardiomyocyte subdomain contractility arising from microenvironmental stiffness and topography. AB - Cellular structure and function are interdependent. To understand this relationship in beating heart cells, individual neonatal rat ventricular myocytes (NRVMs) were analyzed one and 3 days after plating when cultured on different stiffness (100, 400 kPa) and surface structures (flat or [Formula: see text] high, [Formula: see text] diameter, microposts spaced [Formula: see text] apart) manufactured from polydimethylsiloxane. Myofibril structure seen by immunohistochemistry was organized in three dimensions when NRVMs were attached to microposts. On day three, paxillin distribution near the post serving as cellular anchorage was quantified on both soft posts (12.04 % of total voxel count) and stiff posts (8.16 %). Living NRVMs were analyzed using line scans for sarcomeric shortening and shortening velocity, and traction force microscopy for surface stress and surface tension. One day after plating, NRVMs shortened more on soft posts ([Formula: see text] at [Formula: see text]) compared to either soft flat ([Formula: see text] at [Formula: see text]), stiff posts ([Formula: see text] at [Formula: see text]) or stiff flat ([Formula: see text] at [Formula: see text]). NRVMs have decreased shortening and shortening velocity on soft posts ([Formula: see text] at [Formula: see text]) compared to soft flat ([Formula: see text] at [Formula: see text]) substrates. The surface stress and surface tension increased over time for both soft post ([Formula: see text] and [Formula: see text] to [Formula: see text] and [Formula: see text]) and flat ([Formula: see text] and [Formula: see text] to [Formula: see text] and [Formula: see text]) substrates. Paxillin displacement during contraction on day three was significantly greater in NRVMs attached to soft posts [Formula: see text] compared to flat [Formula: see text] substrates. The volume and time creating four-dimensional data, interpreted by structural engineering theory, demonstrate subdomain structure is maintained by the counterbalance between the external load acting upon and the internal forces generated by the cardiomyocyte. These findings provide further insight into localized regulation of cellular mechanical function. PMID- 25273279 TI - Give me a sign: decoding four complex hand gestures based on high-density ECoG. AB - The increasing understanding of human brain functions makes it possible to directly interact with the brain for therapeutic purposes. Implantable brain computer interfaces promise to replace or restore motor functions in patients with partial or complete paralysis. We postulate that neuronal states associated with gestures, as they are used in the finger spelling alphabet of sign languages, provide an excellent signal for implantable brain computer interfaces to restore communication. To test this, we evaluated decodability of four gestures using high-density electrocorticography in two participants. The electrode grids were located subdurally on the hand knob area of the sensorimotor cortex covering a surface of 2.5-5.2 cm(2). Using a pattern-matching classification approach four types of hand gestures were classified based on their pattern of neuronal activity. In the two participants the gestures were classified with 97 and 74% accuracy. The high frequencies (>65 Hz) allowed for the best classification results. This proof-of-principle study indicates that the four gestures are associated with a reliable and discriminable spatial representation on a confined area of the sensorimotor cortex. This robust representation on a small area makes hand gestures an interesting control feature for an implantable BCI to restore communication for severely paralyzed people. PMID- 25273281 TI - Cannabinoid CB1 receptor signaling dichotomously modulates inhibitory and excitatory synaptic transmission in rat inner retina. AB - In the inner retina, ganglion cells (RGCs) integrate and process excitatory signal from bipolar cells (BCs) and inhibitory signal from amacrine cells (ACs). Using multiple labeling immunohistochemistry, we first revealed the expression of the cannabinoid CB1 receptor (CB1R) at the terminals of ACs and BCs in rat retina. By patch-clamp techniques, we then showed how the activation of this receptor dichotomously regulated miniature inhibitory postsynaptic currents (mIPSCs), mediated by GABAA receptors and glycine receptors, and miniature excitatory postsynaptic currents (mEPSCs), mediated by AMPA receptors, of RGCs in rat retinal slices. WIN55212-2 (WIN), a CB1R agonist, reduced the mIPSC frequency due to an inhibition of L-type Ca(2+) channels no matter whether AMPA receptors were blocked. In contrast, WIN reduced the mEPSC frequency by suppressing T-type Ca(2+) channels only when inhibitory inputs to RGCs were present, which could be in part due to less T-type Ca(2+) channels of cone BCs, presynaptic to RGCs, being in an inactivation state under such condition. This unique feature of CB1R mediated retrograde regulation provides a novel mechanism for modulating excitatory synaptic transmission in the inner retina. Moreover, depolarization of RGCs suppressed mIPSCs of these cells, an effect that was eliminated by the CB1R antagonist SR141716, suggesting that endocannabinoid is indeed released from RGCs. PMID- 25273282 TI - PNPLA3 in end-stage liver disease: alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival. AB - BACKGROUND AND AIMS: The rs738409 variant (I148M) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end-stage liver disease has not been addressed yet. METHODS: The I148M polymorphism was genotyped in a well characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant. RESULTS: The G allele of the I148M variant was significantly overrepresented in patients with alcoholic liver disease (ALD, P < 0.001) and associated with hepatocellular carcinoma (HCC) development (odds ratio [OR] = 2.399; 95% confidence interval [CI]: 1.292-4.455; P = 0.008) while not affecting the other liver disease entities. Time until hydropic decompensation (P = 0.04) and hepatic encephalopathy (P = 0.043) was significantly impaired for ALD patients carrying either one or two mutated G alleles. Actuarial survival free of liver transplantation was further reduced for ALD carriers of the I148M variant (CC = 30.7 months +/- 7.9, 95% CI: 15.1-46.2 vs CG/GG: 17.1 months +/- 3.3, 95% CI: 3.3-10.6; P = 0.012) compared with wild-type patients. Cox multivariate analysis identified the PNPLA3 I148M genotype as an independent predictor actuarial survival free of liver transplantation (OR = 1.77; 95% CI: 1.27-2.47; P = 0.001). CONCLUSIONS: In end-stage liver disease patients, we identified ALD to be predominantly affected by the PNPLA3 I148M variant resulting in an increased risk of HCC and reduced transplantation free survival. Genetic testing of the I148M genotype in ALD patients awaiting liver transplantation might be beneficial for these patients. PMID- 25273283 TI - Advances in targeting strategies for nanoparticles in cancer imaging and therapy. AB - In the last decade, nanoparticles have offered great advances in diagnostic imaging and targeted drug delivery. In particular, nanoparticles have provided remarkable progress in cancer imaging and therapy based on materials science and biochemical engineering technology. Researchers constantly attempted to develop the nanoparticles which can deliver drugs more specifically to cancer cells, and these efforts brought the advances in the targeting strategy of nanoparticles. This minireview will discuss the progress in targeting strategies for nanoparticles focused on the recent innovative work for nanomedicine. PMID- 25273280 TI - Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. AB - Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug-cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05 mg/kg, 6 h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for 3 weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings also suggest that wheel running may be preventing certain allostatic changes in the brain reward and stress systems contributing to the negative reinforcement and perpetuation of the addiction cycle. PMID- 25273284 TI - Technical and non-technical aspects of psychiatric care: the need for a balanced view. PMID- 25273287 TI - A social neuroscience perspective on clinical empathy. PMID- 25273288 TI - Harnessing the potential of the therapeutic alliance. PMID- 25273289 TI - Towards a hermeneutic shift in psychiatry. PMID- 25273285 TI - Biomarkers and clinical staging in psychiatry. AB - Personalized medicine is rapidly becoming a reality in today's physical medicine. However, as yet this is largely an aspirational goal in psychiatry, despite significant advances in our understanding of the biochemical, genetic and neurobiological processes underlying major mental disorders. Preventive medicine relies on the availability of predictive tools; in psychiatry we still largely lack these. Furthermore, our current diagnostic systems, with their focus on well established, largely chronic illness, do not support a pre-emptive, let alone a preventive, approach, since it is during the early stages of a disorder that interventions have the potential to offer the greatest benefit. Here, we present a clinical staging model for severe mental disorders and discuss examples of biological markers that have already undergone some systematic evaluation and that could be integrated into such a framework. The advantage of this model is that it explicitly considers the evolution of psychopathology during the development of a mental illness and emphasizes that progression of illness is by no means inevitable, but can be altered by providing appropriate interventions that target individual modifiable risk and protective factors. The specific goals of therapeutic intervention are therefore broadened to include the prevention of illness onset or progression, and to minimize the risk of harm associated with more complex treatment regimens. The staging model also facilitates the integration of new data on the biological, social and environmental factors that influence mental illness into our clinical and diagnostic infrastructure, which will provide a major step forward in the development of a truly pre-emptive psychiatry. PMID- 25273286 TI - Cognitive impairments in psychotic disorders: common mechanisms and measurement. AB - Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a "generalized deficit", in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM-5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders. PMID- 25273291 TI - Off label CBT: a promising therapy or an adjunctive pluralistic therapeutic ingredient? PMID- 25273290 TI - The promise of cognitive behavior therapy for treatment of severe mental disorders: a review of recent developments. AB - Cognitive behavior therapy (CBT), as exemplified by the model of psychotherapy developed and refined over the past 40 years by A.T. Beck and colleagues, is one of the treatments of first choice for ambulatory depressive and anxiety disorders. Over the past several decades, there have been vigorous efforts to adapt CBT for treatment of more severe mental disorders, including schizophrenia and the more chronic and/or treatment refractory mood disorders. These efforts have primarily studied CBT as an adjunctive therapy, i.e., in combination with pharmacotherapy. Given the several limitations of state-of-the-art pharmacotherapies for these severe mental disorders, demonstration of clinically meaningful additive effects for CBT would have important implications for improving public health. This paper reviews the key developments in this important area of therapeutics, providing a summary of the current state of the art and suggesting directions for future research. PMID- 25273292 TI - CBT for severe mental disorder: a good product that is in danger of being over extended. PMID- 25273294 TI - CBT for psychosis: effectiveness, diversity, dissemination, politics, the future and technology. PMID- 25273293 TI - Have the potential benefits of CBT for severe mental disorders been undersold? PMID- 25273295 TI - The efficacy of CBT for severe mental illness and the challenge of dissemination in routine care. PMID- 25273296 TI - The usefulness for indicated prevention of severe mental disorders should play a central part in the further development of CBT. PMID- 25273297 TI - CBT for psychotic disorders: beyond meta-analyses and guidelines - it is time to implement! PMID- 25273298 TI - Expand the applicability and acceptability of CBT approaches in mood disorders. PMID- 25273299 TI - Non-pharmacological and pharmacological treatments act on the same brain. PMID- 25273300 TI - How well can post-traumatic stress disorder be predicted from pre-trauma risk factors? An exploratory study in the WHO World Mental Health Surveys. AB - Post-traumatic stress disorder (PTSD) should be one of the most preventable mental disorders, since many people exposed to traumatic experiences (TEs) could be targeted in first response settings in the immediate aftermath of exposure for preventive intervention. However, these interventions are costly and the proportion of TE-exposed people who develop PTSD is small. To be cost-effective, risk prediction rules are needed to target high-risk people in the immediate aftermath of a TE. Although a number of studies have been carried out to examine prospective predictors of PTSD among people recently exposed to TEs, most were either small or focused on a narrow sample, making it unclear how well PTSD can be predicted in the total population of people exposed to TEs. The current report investigates this issue in a large sample based on the World Health Organization (WHO)'s World Mental Health Surveys. Retrospective reports were obtained on the predictors of PTSD associated with 47,466 TE exposures in representative community surveys carried out in 24 countries. Machine learning methods (random forests, penalized regression, super learner) were used to develop a model predicting PTSD from information about TE type, socio-demographics, and prior histories of cumulative TE exposure and DSM-IV disorders. DSM-IV PTSD prevalence was 4.0% across the 47,466 TE exposures. 95.6% of these PTSD cases were associated with the 10.0% of exposures (i.e., 4,747) classified by machine learning algorithm as having highest predicted PTSD risk. The 47,466 exposures were divided into 20 ventiles (20 groups of equal size) ranked by predicted PTSD risk. PTSD occurred after 56.3% of the TEs in the highest-risk ventile, 20.0% of the TEs in the second highest ventile, and 0.0-1.3% of the TEs in the 18 remaining ventiles. These patterns of differential risk were quite stable across demographic-geographic sub-samples. These results demonstrate that a sensitive risk algorithm can be created using data collected in the immediate aftermath of TE exposure to target people at highest risk of PTSD. However, validation of the algorithm is needed in prospective samples, and additional work is warranted to refine the algorithm both in terms of determining a minimum required predictor set and developing a practical administration and scoring protocol that can be used in routine clinical practice. PMID- 25273302 TI - Guided Internet-based vs. face-to-face cognitive behavior therapy for psychiatric and somatic disorders: a systematic review and meta-analysis. AB - Internet-delivered cognitive behavior therapy (ICBT) has been tested in many research trials, but to a lesser extent directly compared to face-to-face delivered cognitive behavior therapy (CBT). We conducted a systematic review and meta-analysis of trials in which guided ICBT was directly compared to face-to face CBT. Studies on psychiatric and somatic conditions were included. Systematic searches resulted in 13 studies (total N=1053) that met all criteria and were included in the review. There were three studies on social anxiety disorder, three on panic disorder, two on depressive symptoms, two on body dissatisfaction, one on tinnitus, one on male sexual dysfunction, and one on spider phobia. Face to-face CBT was either in the individual format (n=6) or in the group format (n=7). We also assessed quality and risk of bias. Results showed a pooled effect size (Hedges' g) at post-treatment of -0.01 (95% CI: -0.13 to 0.12), indicating that guided ICBT and face-to-face treatment produce equivalent overall effects. Study quality did not affect outcomes. While the overall results indicate equivalence, there are still few studies for each psychiatric and somatic condition and many conditions for which guided ICBT has not been compared to face to-face treatment. Thus, more research is needed to establish equivalence of the two treatment formats. PMID- 25273304 TI - Definition, assessment and rate of psychotherapy side effects. PMID- 25273303 TI - The psychosis spectrum in a young U.S. community sample: findings from the Philadelphia Neurodevelopmental Cohort. AB - Little is known about the occurrence and predictors of the psychosis spectrum in large non-clinical community samples of U.S. youths. We aimed to bridge this gap through assessment of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort, a collaborative investigation of clinical and neurobehavioral phenotypes in a prospectively accrued cohort of youths, funded by the National Institute of Mental Health. Youths (age 11-21; N=7,054) and collateral informants (caregiver/legal guardian) were recruited through the Children's Hospital of Philadelphia and administered structured screens of psychosis spectrum symptoms, other major psychopathology domains, and substance use. Youths were also administered a computerized neurocognitive battery assessing five neurobehavioral domains. Predictors of psychosis spectrum status in physically healthy participants (N=4,848) were examined using logistic regression. Among medically healthy youths, 3.7% reported threshold psychotic symptoms (delusions and/or hallucinations). An additional 12.3% reported significant sub-psychotic positive symptoms, with odd/unusual thoughts and auditory perceptions, followed by reality confusion, being the most discriminating and widely endorsed attenuated symptoms. A minority of youths (2.3%) endorsed subclinical negative/disorganized symptoms in the absence of positive symptoms. Caregivers reported lower symptom levels than their children. Male gender, younger age, and non-European American ethnicity were significant predictors of spectrum status. Youths with spectrum symptoms had reduced accuracy across neurocognitive domains, reduced global functioning, and increased odds of depression, anxiety, behavioral disorders, substance use and suicidal ideation. These findings have public health relevance for prevention and early intervention. PMID- 25273305 TI - Cultural inroads in DSM-5. PMID- 25273306 TI - DSM-5 cross-cutting symptom measures: a step towards the future of psychiatric care? PMID- 25273307 TI - Uncomplicated depression is normal sadness, not depressive disorder: further evidence from the NESARC. PMID- 25273301 TI - The influence of illness-related variables, personal resources and context related factors on real-life functioning of people with schizophrenia. AB - In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real-life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness-related variables, personal resources and context-related factors. Some of these variables were never investigated before in relationship with real-life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real-life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real-life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real-life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real-life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia. PMID- 25273308 TI - Public attitudes towards psychiatric medication: a comparison between United States and Germany. PMID- 25273309 TI - The impact of adolescent cannabis use, mood disorder and lack of education on attempted suicide in young adulthood. PMID- 25273310 TI - Gambling and the enduring financial recession in Greece. PMID- 25273311 TI - Depression: a silent driver of the global tuberculosis epidemic. PMID- 25273313 TI - The WPA Action Plan 2014-2017. PMID- 25273312 TI - A plea to change the misnomer ECT. PMID- 25273314 TI - Synergetic effect of combined fumaric acid and slightly acidic electrolysed water on the inactivation of food-borne pathogens and extending the shelf life of fresh beef. AB - AIMS: To evaluate synergetic effect of slight acidic electrolysed water (SAEW) and fumaric acid (FA) on inactivation of total viable count (TVC) and Staphylococcus aureus, Listeria monocytogenes, Escherichia coli O157:H7 and Salmonella Typhimurium in fresh beef and to study shelf life and sensory quality of beef. METHODS AND RESULTS: Inoculated samples was dipped for 1, 3 and 5 min and immersed at 25, 40 and 60 degrees C in SAEW, strong acidic electrolysed water (StAEW) and SAWE + FA. Treated meat was air-packaged and stored at 4 or 10 degrees C. During storage, sampling was performed at 2-day intervals for microbiological and sensory changes. TVC was decontaminated at 40 degrees C for 3 min by more than 3.70 log CFU g(-1) , and examined pathogens were reduced by more than 2.60 log CFU g(-1) with SAEW + FA treatment. This treatment prolonged shelf life of beef meat up to 9 and 7 days when stored at 4 and 10 degrees C, respectively. CONCLUSION: The combined treatment of SAEW + FA showed greater bactericidal effect and prolonged shelf life compared with individual treatments. SIGNIFICANCE AND IMPACT OF THE STUDY: Combined treatment of SAEW and FA can be a suitable hurdle technology reducing bacteria in fresh beef, substantially enhancing their microbial safety and decreasing pathogens growth during storage. PMID- 25273315 TI - Association between mobile phone use and inattention in 7102 Chinese adolescents: a population-based cross-sectional study. AB - BACKGROUND: The dramatic growth of mobile phone (MP) use among young people has increased interest in its possible health hazards in this age group. The aim of this cross-sectional study was to investigate the association between MP use and inattention in adolescents. METHODS: A total of 7720 middle school students were involved in this cross-sectional study. Inattention was assessed as defined for the Attention Deficit component of Attention deficit/Hyperactivity disorder (ADHD) by the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev. [DSM-IV-TR]). The demographic characteristics and information on MP use were included in the questionnaire. Chi-square tests and logistic regression models were used to analyze the data. RESULTS: In total, 7102 (91.99%) valid questionnaires were obtained. After adjusted for confounders, inattention in adolescents was significantly associated with MP ownership, the time spent on entertainment on MP per day, the position of the MP during the day and the mode of the MP at night. The strongest association between inattention and the time spent on the MP was among students who spent more than 60 minutes per day playing on their MP. CONCLUSIONS: Our study shows some associations between MP use and inattention in Chinese adolescents. Decreasing MP usage to less than 60 minutes per day may help adolescents to stay focused and centered. PMID- 25273316 TI - Hypogonadotropic hypogonadism in a female patient previously diagnosed as having waardenburg syndrome due to a sox10 mutation. PMID- 25273318 TI - Diagnostic performance of elastography in cytologically indeterminate thyroid nodules. AB - Cytological examination of material from fine-needle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4-20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p < 0.0001) with a OR of 21.9 (95 % CI 7.1-76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7-106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up. PMID- 25273317 TI - Inflammation in diabetic nephropathy: moving toward clinical biomarkers and targets for treatment. AB - Diabetic nephropathy (DN) is a leading cause of end stage renal failure and there is an urgent need to identify new clinical biomarkers and targets for treatment to effectively prevent and slow the progression of the complication. Many lines of evidence show that inflammation is a cardinal pathogenetic mechanism in DN. Studies in animal models of experimental diabetes have demonstrated that there is a low-grade inflammation in the diabetic kidney. Both pharmacological and genetic strategies targeting inflammatory molecules have been shown to be beneficial in experimental DN. In vitro studies have cast light on the cellular mechanisms whereby diabetes triggers inflammation and in turn inflammation magnifies the kidney injury. Translation of this basic science knowledge into potential practical clinical applications is matter of great interest for researchers today. This review focuses on key pro-inflammatory systems implicated in the development of DN: the tumor necrosis factor(TNF)-alpha/TNF-alpha receptor system, the monocyte chemoattractant protein-1/CC-chemokine receptor-2 system, and the Endocannabinoid system that have been selected as they appear particularly promising for future clinical applications. PMID- 25273319 TI - Pulsed electromagnetic fields inhibit bone loss in streptozotocin-induced diabetic rats. AB - Evidences have shown that pulsed electromagnetic fields (PEMFs) can partially prevent bone loss in streptozotocin (STZ)-induced diabetic rats. However, the precise mechanisms accounting for these favorable effects are unclear. This study aimed to investigate the effects of PEMFs on bone mass and receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) and Wnt/beta-catenin signaling pathway in STZ rats. Thirty 3-month-old Sprague Dawley rats were randomly divided into the following three groups (n = 10): control group (injection of saline vehicle), DM group (injection of STZ), and PEMFs group (injection of STZ + PEMFs exposure). One week following injection of STZ, rats in the PEMFs group were subject to PEMFs stimulus for 40 min/day, 5 days/week, and lasted for 12 weeks. After 12 week intervention, the results showed that PEMFs increased serum bone-specific alkaline phosphatase level and bone mineral density, and inhibited deterioration of bone microarchitecture and strength in STZ rats. Furthermore, PEMFs up-regulated the mRNA expressions of low-density lipoprotein receptor-related protein 5, beta-catenin and runt-related gene 2 (Runx2), and down-regulated dickkopf1 in STZ rats. However, mRNA expressions of RANKL and OPG were not affected by PEMFs. PEMFs can prevent the diabetes-induced bone loss and reverse the deterioration of bone microarchitecture and strength by restoring Runx2 expression through regulation of Wnt/beta-catenin signaling, regardless of its no glucose lowering effect. PMID- 25273321 TI - Altered sigma-1 receptor expression in two animal models of cognitive impairment. AB - PURPOSE: Sigma-1 receptors are involved in learning and memory processes. We assessed sigma-1 receptor expression and memory function in two animal models of cognitive impairment. PROCEDURES: Male Wistar-Hannover rats were either lesioned by unilateral injection of N-methyl-D-aspartic acid in the nucleus basalis, or deprived of rapid eye movement sleep for 48 h, using the modified multiple platform method. Sigma-1 receptor expression was examined with the positron emission tomography radiotracer [(11)C]SA4503, immunohistochemistry, and Western blotting. RESULTS: Cortical tracer uptake after 1 week was not significantly affected by lesioning. Immunohistochemistry revealed moderate increases of sigma 1 receptors at bregma level -2.8, in parietal cortex layer V of the lesioned hemisphere. Sleep deprivation lowered passive avoidance test scores and reduced [(11)C]SA4503 accumulation and sigma-1 receptor expression in pons. CONCLUSIONS: Cholinergic lesioning causes an increase of sigma-1 receptor expression in a small cortical area which may be neuroprotective. Sleep deprivation decreases receptor expression in midbrain and pons. PMID- 25273322 TI - Synthesis and preclinical evaluation of [18F]FCHC for neuroimaging of fatty acid amide hydrolase. AB - PURPOSE: Fatty acid amide hydrolase (FAAH), a catabolic enzyme which regulates lipid transmitters in the endocannabinoid system, is an avidly sought therapeutic and positron emission tomography (PET) imaging target for studies involving addiction and neurological disorders. We report the synthesis of a new fluorine 18-labeled FAAH inhibitor, trans-3-(4, 5-dihydrooxazol-2-yl)phenyl-4 [(18)F]fluorocyclohexylcarbamate ([(18)F]FCHC), and its evaluation in rat brain. PROCEDURES: The synthesis of [(18)F]FCHC was conducted via a 3-step, 1-pot reaction, resulting in uncorrected radiochemical yields between 10 and 20% (n = 5) relative to [(18)F]fluoride, with specific activities of >5 Ci/MUmol at the end of the synthesis. The radiosynthesis was seamlessly automated using a commercial radiofluorination apparatus. Ex vivo biodistribution and preliminary PET imaging studies were carried out in male Sprague-Dawley rats. RESULTS: Rat brain biodistribution at 2 min post-injection showed a standard uptake value of 4.6 +/- 0.1 in the cortex, which increased to 7.8 +/- 0.1 at 40 min. Pretreatment with the selective FAAH inhibitor URB597 reduced uptake of radioactivity in all brain regions by >90%, with 98 % blockade in the FAAH-rich cortex. PET imaging was consistent with biodistribution studies. CONCLUSIONS: [(18)F]FCHC appears to be a highly sensitive (18)F-labeled radiotracer for imaging FAAH in the central nervous system, and these results warrant further imaging in nonhuman primates. PMID- 25273323 TI - Optimization of mesenchymal stem cells (MSCs) delivery dose and route in mice with acute liver injury by bioluminescence imaging. AB - PURPOSE: Both experimental and initial clinical studies have shown the therapeutic potential of mesenchymal stem cells (MSCs) in liver disease. Noninvasive tracking of MSCs could facilitate its clinical translation. The purpose of this study was to optimize MSCs delivery dose and route in mice with acute liver injury using bioluminescence imaging (BLI) to track the cells. PROCEDURES: MSCs were labeled with the Luc2-mKate2 dual-fusion reporter gene (MSCs-R). The fate of MSCs-R was tracked through in vivo BLI after administration of different doses or delivery through different routes. RESULTS: When delivered via the superior mesenteric vein (SMV), the high-dose (1.0 * 10(6) and 5.0 * 10(5)) group mice demonstrated high liver BLI signal but also had lethal portal vein embolization (PVE). By contrast, no PVE and its related death occurred in the low-dose (2.5 * 10(5)) group mice. Thus, 2.5 * 10(5) is the optimal delivery dose. Three delivery routes, i.e., inferior vena cava (IVC), SMV, and intrahepatic (IH) injection, were also systematically compared. After IVC infusion, MSCs-R were quickly trapped inside the lungs, and no detectable homing to the liver and other organs was observed. By IH injection, lung entrapment was bypassed, but MSCs-R distribution was only localized in the injection region of the liver. By contrast, after SMV infusion, MSCs-R were dispersedly distributed and stayed as long as 7-day posttransplantation in the liver. The in vivo imaging results were further validated by ex vivo imaging, digital subtraction angiography (DSA), and tissue analysis. Therefore, SMV is the optimal MSCs delivery route for liver disease. CONCLUSIONS: Collectively, BLI, which could dynamically and quantitatively track cellular location and survival, is useful in determining MSCs transplantation parameters. PMID- 25273320 TI - Metabolic and anatomic characteristics of benign and malignant adrenal masses on positron emission tomography/computed tomography: a review of literature. AB - PET/CT with (18)F-fluorodeoxyglucose (FDG) or using different radiocompounds has proven accuracy for detection of adrenal metastases in patients undergoing cancer staging. It can assist the diagnostic work-up in oncology patients by identifying distant metastases to the adrenal(s) and defining oligometastatic disease that may benefit from targeted intervention. In patients with incidentally discovered adrenal nodules, so-called adrenal "incidentaloma" FDG PET/CT is emerging as a useful test to distinguish benign from malignant etiology. Current published evidence suggests a role for FDG PET/CT in assessing the malignant potential of an adrenal lesion that has been 'indeterminately' categorized with unenhanced CT, adrenal protocol contrast-enhanced CT, or chemical-shift MRI. FDG PET/CT could be used to stratify patients with higher risk of malignancy for surgical intervention, while recommending surveillance for adrenal masses with low malignant potential. There are caveats for interpretation of the metabolic activity of an adrenal nodule on PET/CT that may lead to false-positive and false negative interpretation. Adrenal lesions represent a wide spectrum of etiologies, and the typical appearances on PET/CT are still being described, therefore our goal was to summarize the current diagnostic strategies for evaluation of adrenal lesions and present metabolic and anatomic appearances of common and uncommon adrenal lesions. In spite of the emerging role of PET/CT to differentiate benign from malignant adrenal mass, especially in difficult cases, it should be emphasized that PET/CT is not needed for most patients and that many diagnostic problems can be resolved by CT and/or MR imaging. PMID- 25273324 TI - Using ionic liquids in whole-cell biocatalysis for the nucleoside acylation. AB - BACKGROUND: The use of biocatalysts has become an increasingly attractive alternative to traditional chemical methods, due to the high selectivity, mild reaction conditions and environmentally-friendly processes in nonaqueous catalysis of nucleosids. However, the extensive use of organic solvents may generally suffer from sever drawbacks such as volatileness and toxicity to the environment and lower activity of the biocatalyst. Recently, ionic liquids are considered promising solvents for nonaqueous biocatalysis of polyhydroxyl compounds as ILs are environmental-friendly. RESULTS: In this research, we developed new IL-containing reaction systems for synthesis of long chain nucleoside ester catalyzed by Pseudomonas fluorescens whole-cells. Various ILs exerted significant but different effects on the bio-reaction. And their effects were closely related with both the anions and cations of the ILs. Use of 10% [BMI][PF6]/THF gave high reaction efficiency of arabinocytosine laurate synthesis, in which the initial rate, product yield and 5'-regioselectivity reached 2.34 mmol/L.h, 81.1% and >99%, respectively. Furthermore, SEM analysis revealed that ILs can alter the cell surface morphology, improve the permeability of cell envelopes and thus facilitate the mass transfer of substrates to the active sites of cell-bound enzymes. CONCLUSION: Our research demonstrated the potential of ILs as promising reaction medium for achieving highly efficient and regioselective whole-cell catalysis. PMID- 25273326 TI - Substrate phonon-mediated plasmon hybridization in coplanar graphene nanostructures for broadband plasmonic circuits. AB - The mode hybridization between adjacent graphene nanoribbons determines the integration density of graphene-based plasmonic devices. Here, plasmon hybridization in graphene nanostructures is demonstrated through the characterization of the coupling strength of plasmons in graphene nanoribbons as a function of charge density and inter-ribbon spacing using Fourier transform infrared microscopy. In combination with numerical simulations, it is shown that the plasmon coupling is strongly mediated by the substrate phonons. For polar substrates, the plasmon coupling strength is limited by the plasmon-phonon interactions. In contrast, a nonpolar substrate affects neither the energy distribution of the original plasmon modes in graphene nanostructures nor their plasmon interactions, which increases exponentially as the inter-ribbon spacing decreases. To further explore the potential of graphene broadband plasmonics on nonpolar substrates, a scheme is proposed that uses a metal-dielectric heterostructure to prevent the overlap of plasmons between neighboring graphene nanoribbons. The device structures retain the plasmon resonance frequency of the graphene ribbons and maximally isolate the plasmonic components from the surrounding electromagnetic environment, allowing modular design in integrated plasmonic circuits. PMID- 25273325 TI - The prevalence of malocclusion and its association with dental caries among 12-18 year-old disabled adolescents. AB - BACKGROUND: To assess the prevalence of malocclusion among 12-18-year-old disabled adolescents in Chennai, Tamil Nadu, India, by using the Dental Aesthetic Index (DAI) and to determine the association of malocclusion with dental caries. METHODS: This cross-sectional study included 243 children with various mental disabilities with or without physical infirmities. The Dental Aesthetic Index (DAI) and the dentition status were recorded using the World Health Organization Oral Health Surveys - Basic Methods (1997) Pro-forma. The Decayed (D), Missing (M) and Filled (F) components of the DMF index were calculated using the Dentition Status and Treatment Need (DSTN). A Chi-square test, ANOVA, and t-test were used to derive inferential statistics. RESULTS: The mean DAI score +/- standard deviation was 39.0 +/- 12.3. A total of 123 (50.6%) participants (74 males and 49 females) had DAI scores of 36 and above, which indicated a handicapping malocclusion requiring mandatory orthodontic treatment. Sixty-nine (28.4%) adolescents (36 males and 33 females) had DAI scores between 31 and 35, which indicated severe malocclusion, for which orthodontic intervention was desirable. Incisal segment crowding (84.8%) was the most common aspect of the malocclusion. The mean DMFT score was 4.36 +/- 3.81, and 82.8% of the participants had a DMFT score > 0. There was no statistically significant correlation between the mean DAI and DMFT scores (r = 0.090, p = 0.15). Only 16 (6.6%) of the adolescents had minor or no anomaly not needing orthodontic treatment. CONCLUSIONS: The prevalence of malocclusion and dental caries was found to be high. However, there was no positive correlation between the severity of malocclusion and dental caries among the surveyed disabled adolescents. PMID- 25273327 TI - Influence of protein tyrosine phosphatase gene (PTPN22) polymorphisms on rheumatic heart disease susceptibility in North Indian population. AB - This study was aimed to assess the association of Protein tyrosine phosphatase non-receptor22 (PTPN22) gene single nucleotide polymorphisms (SNPs) with rheumatic heart disease (RHD) susceptibility in 400 RHD patients and 300 controls. The PTPN22 polymorphisms (rs2476601, rs1217406 and rs3789609) were genotyped using Taqman probes (Applied Biosystems, Foster City, CA). Statistical analysis was performed by spss and haplotype analysis by snpstat. The frequencies of variant alleles were not different between controls and cases (rs2476601: 2.00% & 1.05%; rs1217406: 36.33% & 34.75%; and rs3789609: 38.17% & 40.00%, respectively]. However, G rs2476601 A rs1217406 T rs3789609 haplotype turned out to be a low risk factor for RHD (P = 0.0042) predisposition in females and adult patients. This study suggests PTPN22 haplotype may modulate the risk to RHD in North Indians. PMID- 25273328 TI - Breast pathology second review identifies clinically significant discrepancies in over 10% of patients. AB - BACKGROUND: Patients seeking a second opinion or continuation of care at our hospital will routinely have their pathology reviewed prior to initiating treatment. To assess the relevance of this review in patients with breast cancer, we compared original pathology reports submitted during the referral with second review reports issued at our institution. We also assessed compliance with College of American Pathologists (CAP) requirements regarding inclusion of scientifically validated data elements (SVDE) in these pathology reports. METHODS: We retrospectively studied all 1,970 breast pathology referral cases reviewed during one calendar year. The variables studied were histologic classification; tumor grade, necrosis, size, margin status, lymphatic/vascular invasion, dermal involvement, and biomarker profile (ER, PR, and Her-2). Each variable was rated as "agree," "disagree," "missing information," or "not applicable." RESULTS: A significant discrepancy, defined as a disagreement that affected patient care, was found in 226 cases (11.47%). Additionally, in 418 resection cases (31.6%), some CAP-checklist specific required information was missing. The most common areas of significant discrepancy were histologic category (66 cases; 33%) and biomarker reporting (50 cases; 25%). The most problematic diagnostic categories were intraductal lesions, lobular carcinoma, metaplastic carcinomas, and phyllodes tumors. Most disagreements in the biomarker profile category were interpretive, but in 20% of discrepant cases, findings were supported by repeat immunohistochemical analysis. CONCLUSIONS: Our results confirm the value and utility of obtaining a second opinion to optimize patient care. Changes in diagnoses obtained after second review should be interpreted and reported in a collaborative fashion, noting the benefit of a review from second pair of experienced eyes. Our results support the use of second review to ensure inclusion of CAP-required data elements in pathology reports. PMID- 25273330 TI - Ricoeur and the ethics of care. AB - This introduction to the special issue on 'Ricoeur and the ethics of care' is not a standard editorial. It provides not only an explanation of the central questions and a first impression of the articles, but also a critical discussion of them by an expert in the field of care ethics, Joan Tronto. After explaining the reasons to bring Ricoeur into dialogue with the ethics of care (I), and analyzing how the four articles of this special issue shape this dialogue (II), the authors give the floor to Tronto (III). She focuses on the central issue at stake: what may be the value of a more abstract, conceptual approach for the ethics of care as a radically practice-oriented way of thinking? She argues that the four contributions too easily frame this value in terms of Ricoeur's relational anthropology. Instead she points out that if the ethics of care is a kind of practice, it makes sense to think of such practices as necessarily building upon one another, expanding constantly the context and relationships upon which practices are built. In the final section (IV) the authors respond to Tronto's framing of 'practices all the way up' by arguing that this approach need not be at odds with one inspired by Ricoeur's conceptual thinking. Rather the two can be seen as different movements-upwards and downwards-that both contribute constructively to the shaping of the important intermediary zone between the practices and the abstract ideals. PMID- 25273329 TI - ARIZONA study: is the risk of post-herpetic neuralgia and its burden increased in the most elderly patients? AB - BACKGROUND: In a context of change in the demographic profile of the older population, to identify an age threshold for increased risk and burden of herpes zoster (HZ) in 70+ patients. METHODS: Post hoc analysis of the 12-month French nationwide prospective observational ARIZONA cohort study. HZ was assessed by means of the following validated questionnaires: Neuropathic Pain Symptom Inventory (NPSI), Zoster Brief Pain Inventory (ZBPI), Short-Form health survey (SF-12), and Hospital Anxiety and Depression Scale (HADS). RESULTS: 644 general practitioners included 1,358 volunteer patients with acute HZ in the ARIZONA study; 609 patients (45%) were 70+. In 70+ patients, age did not increase rash severity or HZ-related pain intensity at diagnosis, but increased by 64% the frequency of ophthalmic zoster (from 5.5% in 70-74 years age-group to 9.0% in 85+ patients, p = NS). Age was significantly associated with low physical health as assessed by the SF-12 Physical Component Summary (SF-12 PCS) score and bad mood as assessed by the HADS depression score (p < 0.001). Within the year following HZ, post-herpetic neuralgia (PHN) was systematically but not significantly more frequent in 85+ patients than in the 70-74, 75-79, or 80-84 years age-groups (19.0% vs. 13.3%/15.3%/11.6% at month 3; 15.1% vs. 7.3%/11.0%/12.2% at month 6; 15.2% vs. 6.0%/8.0%/6.0% at month12, respectively). SF-12 PCS and HADS depression scores improved from day 0 to month 12 in all patients (p < 0.001). 85+ patients were more impaired than younger patients (p < 0.001), but without clear difference according to PHN. CONCLUSIONS: This study did not show in 70+ patients a clear and significant age threshold at which disease burden increased, although for some domains the impact seemed higher among the oldest patients; the cut-off of 70 years remains thus relevant for clinical and epidemiological studies. However, at individual level, assessment of the burden of HZ and HZ-related pain appears necessary to improve management and prevent functional decline in the most vulnerable 70+ patients. PMID- 25273331 TI - Autonomy and its vulnerability: Ricoeur's view on justice as a contribution to care ethics. AB - We examine an article of Paul Ricoeur on autonomy and vulnerability. Ricoeur presents the two notions in the field of justice as intricately woven into each other. He analyzes their interdependence on three levels of human agency. Ricoeur's exposition has a focus on judicial judgment. After presenting Ricoeur's argument and an analysis of his main points, the author argues that Ricoeur's reflection lines up with some essential intentions of care ethics. Ricoeur's contribution to care ethics is given in a delicate balance of autonomy and its vulnerability. PMID- 25273332 TI - Love and justice's dialectical relationship: Ricoeur's contribution on the relationship between care and justice within care ethics. AB - The relationship between love/care and justice was one of the key tensions from which care ethics originated; to this very day it is subject of debate between various streams of thought within care ethics. With some exceptions (e.g. Christa Schnabl) most approaches have in common the belief that care and justice are mutually exclusive concepts, or at least as so different that their application is situated on different levels. Hence, both are complementary, but distinct, so that there is no real interaction. This paper aims to investigate whether, and if so, how, a deeper understanding of Ricoeur's thoughts on this matter enriches the relationship between care and justice with respect to care ethics. This connection suggests itself from Ricoeur's interpretation of the relationship as a dialectical one in which the logic of superabundance (love) and the logic of equivalence (justice) meet. Care enables people to see the face and individuality of the one, 'le chacun,' within the anonymous structures of justice that tend to reduce all human beings to the anonymous each, 'le on'; justice in its turn is the precondition for love to become incarnated and made real. What may this view- of care and justice standing in close connection, in which they correct and strengthen each other--add to the understanding of concrete practices of care? PMID- 25273333 TI - Affirming Life in the Face of Death: Ricoeur's Living Up to Death as a modern ars moriendi and a lesson for palliative care. AB - In his posthumously published Living Up to Death Paul Ricoeur left an impressive testimony on what it means to live at a high old age with death approaching. In this article I present him as a teacher who reminds us of valuable lessons taught by patients in palliative care and their caretakers who accompany them on their way to death, and also as a guide in our search for a modern ars moriendi, after- what many at least experience as--the breakdown of traditional religious belief in a personal afterlife. These lessons can be summarized in the following theses. 'Living up to death, one cannot experience one's own death. Therefore, never consider someone dying as moribund'. 'Though everybody is alone in dying, nobody should die alone.' 'The preparation for death is an affirmation of life'. 'Life experienced as a gift can be given up'. The plausibility of the last thesis, however, may go beyond the confines of austere philosophical thinking. PMID- 25273334 TI - Self-sacrifice and self-affirmation within care-giving. AB - According to the ethics of care, practices of care are sources of moral knowledge that take human relatedness into account. However, caregivers may also find themselves in situations that demand sacrifices, even to the point where their own self is at stake. This may not only be cause for concern about the risks of caregivers, the result of an unequal distribution of power, but it may as well be a chance for affirmation of one's identity, of self-attestation. As Ricoeur argues, giving of the self or even giving one's life may be the ultimate expression of one's belonging, in friendship, devotion or loyalty. Ricoeur also considers the meaning of giving a gift, which to him does not lie in any return gift, but rather in the gift as offering, as generosity. Giving is first of all a risk, a sacrifice, with only the hope that it will be received. In this article I aim to extend his argument to the realm of caregiving, thereby supporting my claim that some sort of self-sacrifice is implied in the very act of caring for others. PMID- 25273335 TI - Three amino acid residues in the envelope of human immunodeficiency virus type 1 CRF07_BC regulate viral neutralization susceptibility to the human monoclonal neutralizing antibody IgG1b12. AB - The CD4 binding site (CD4bs) of envelope glycoprotein (Env) is an important conserved target for anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies. Neutralizing monoclonal antibodies IgG1 b12 (b12) could recognize conformational epitopes that overlap the CD4bs of Env. Different virus strains, even derived from the same individual, showed distinct neutralization susceptibility to b12. We examined the key amino acid residues affecting b12 neutralization susceptibility using single genome amplification and pseudovirus neutralization assay. Eleven amino acid residues were identified that affect the sensitivity of Env to b12. Through site-directed mutagenesis, an amino acid substitution at position 182 in the V2 region of Env was confirmed to play a key role in regulating the b12 neutralization susceptibility. The introduction of V182L to a resistant strain enhanced its sensitivity to b12 more than twofold. Correspondingly, the introduction of L182V to a sensitive strain reduced its sensitivity to b12 more than tenfold. Amino acid substitution at positions 267 and 346 could both enhance the sensitivity to b12 more than twofold. However, no additive effect was observed when the three site mutageneses were introduced into the same strain, and the sensitivity was equivalent to the single V182L mutation. CRF07_BC is a major circulating recombinant form of HIV-1 prevalent in China. Our data may provide important information for understanding the molecular mechanism regulating the neutralization susceptibility of CRF07_BC viruses to b12 and may be helpful for a vaccine design targeting the CD4bs epitopes. PMID- 25273337 TI - New quantitative aPTT waveform analysis and its application in laboratory management of haemophilia A patients. AB - Diagnosis of haemophilia A is usually made by the measurement of factor VIII (FVIII) activity that allows categorization of the disease severity. However, tests that assess global haemostasis may better reflect clinical features and give additional clinically relevant information. The aim of this study was to develop a new quantitative activated partial thromboplastin time (aPTT) waveform analysis and compare it with FVIII activities to find out whether waveform parameters are superior determinants of clinical phenotype. A total of 81 haemophilia A patients divided into two groups (37 severe, 44 non-severe) were included in the study. The control group comprised 101 healthy male volunteers. Quantitative aPTT waveform analysis was performed with Actin FS on BCS (Siemens Healthcare Diagnostics, Marburg, Germany) using three parameters (DELTA, RATIO-1, RATIO-2) obtained from a single aPTT measurement with two evaluation modes. FVIII activities were measured by one-stage clotting and two-stage chromogenic assay. Statistically significant difference (P < 0.001) between control group and all haemophilia A patients, as well as between severe and non-severe haemophilia A patients was obtained for all quantitative waveform parameters. Our study revealed parameter DELTA as the best waveform parameter, showing significant correlation with FVIII activities and clinical parameters, and excellent performance for distinguishing between severe and non-severe haemophilia A patients (ROC analysis: sensitivity 97.3%, specificity 93.2%). The results obtained by new quantitative aPTT waveform analysis were superior to those obtained by standard laboratory methods. The simplicity and cost-benefit of the method make this approach a reasonable and promising tool for assessing coagulation in haemophilia A patients. PMID- 25273336 TI - Reduction in insulin sensitivity and inadequate beta-cell capacity to counteract the increase in insulin resistance in children with idiopathic growth hormone deficiency during 12 months of growth hormone treatment. AB - PURPOSE: To evaluate the performance of various indexes of insulin sensitivity and secretion and to identify the most useful indicator of deterioration of glucose metabolism in a cohort of children with growth hormone (GH) deficiency (GHD) during GH treatment. METHODS: In 73 GHD children (55 M, 18 F; mean age 10.5 years) at baseline and after 12 months of treatment, we evaluated a number of surrogate indexes of insulin secretion and sensitivity. In a subgroup of 11 children we also performed an euglycemic hyperinsulinemic clamp. RESULTS: After 12 months, a significant increase in fasting glucose (p < 0.001) and HbA1c levels (p < 0.001) was documented, despite all children remained with a normal glucose tolerance. With regard the insulin secretion, Homa-beta did not show any significant change (p = 0.073), while oral disposition index (DIo) showed a significant decrease (p = 0.031). With regard the insulin sensitivity, Homa-IR significantly increased (p < 0.001) with a concomitant decrease in QUICKI (p < 0.001). ISI Matsuda showed a decrease, although not statistically significant (p = 0.069). In the subgroup of 11 children, the M value derived from clamp showed a significant decrease (p = 0.011) and a significant positive correlation was found between M value and ISI Matsuda both at baseline (rho 0.950; p = 0.001) and after 12 months (rho 0.980; p = 0.001) but not with Homa-IR and QUICKI. CONCLUSIONS: 12 months of GH treatment lead to a decrease in insulin sensitivity and impairment in insulin secretion relative to insulin sensitivity even without evident changes in glucose tolerance. DIo has proven to be the most useful indicator of deterioration of glucose metabolism even in cases in which the overt glucose abnormalities have not yet appeared. PMID- 25273338 TI - Do Bolivian small holder farmers improve and retain knowledge to reduce occupational pesticide poisonings after training on Integrated Pest Management? AB - BACKGROUND: Pesticide consumption is increasing in Bolivia as well as pest resistance, pesticide poisonings and pollution of the environment. This survey evaluates the training of small holder farmers on pesticide handling and ecological alternatives to reduce the negative pesticide effects. METHOD: A baseline survey was performed in 2002 and follow-up surveys in 2004 and 2009. Farmers were selected and trained on Integrated Pest Management (IPM) from 2002 to 2004 in Farmer Field Schools (FFS). After exclusions and drop outs, 23 FFS trained farmers could be compared to 47 neighbor farmers for changes in 'knowledge, attitude and practice' (KAP) on IPM and symptoms of poisoning when handling pesticides. Statistical analysis was performed with SPSS version 21.0 using chi2-test, Cochran's Q test and Student's T-test. RESULTS: Improvements were seen in both groups but most significant among the FFS farmers. At baseline no difference were seen between the two groups apart from a more frequent use of personal protection among the FFS farmers. After the training was finished significant differences were seen between FFS farmers and neighbor farmers on all KAP variables, a difference reduced to six of the KAP variables in 2009. No difference was seen in self-reported poisonings after pesticide handling. FFS farmers improved their KAP scores markedly during training and there after retained their knowledge, while neighbor farmers improved during the entire period. Ecological farming without the use of pesticides increased most among the FFS farmers. CONCLUSION: The study showed a sustained improvement among Farmers Field School trained farmers on personal protection and hygiene when handling pesticides, knowledge and use of IPM and ecological alternatives and a reduction in self-reported symptoms after pesticide handling. Similar though less pronounced improvements was seen among neighbor farmers having had less training and information on pesticide handling and alternatives than the FFS trained farmers. Training of farmers on IPM and good agricultural practices has positive effects, but is scarce in Bolivia as in most low-income countries and must be encouraged to support an improved and sustainable food production and to protect the health of farmers and consumers as well as the environment. PMID- 25273339 TI - Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibition. AB - BACKGROUND: One of the leading causes of death and illness within the agriculture industry is through unintentionally ingesting or inhaling organophosphate pesticides. OP intoxication directly inhibits acetylcholinesterase, resulting in an excitatory signaling cascade leading to fasciculation, loss of control of bodily fluids, and seizures. METHODS: Our model was developed using a discrete, rules-based modeling approach in NetLogo. This model includes acetylcholinesterase, the nicotinic acetylcholine receptor responsible for signal transduction, a single release of acetylcholine, organophosphate inhibitors, and a theoretical novel medical countermeasure. We have parameterized the system considering the molecular reaction rate constants in an agent-based approach, as opposed to apparent macroscopic rates used in differential equation models. RESULTS: Our model demonstrates how the cholinergic crisis can be mitigated by therapeutic intervention with an acetylcholinesterase activator. Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors. It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors. CONCLUSION: We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication. PMID- 25273340 TI - Comparative study of the interaction of meso-tetrakis (N-para-trimethyl-anilium) porphyrin (TMAP) in its free base and Fe derivative form with oligo(dA.dT)15 and oligo(dG.dC)15. AB - Interaction between a cationic porphyrin and its ferric derivative with oligo(dA.dT)15 and oligo(dG.dC)15 was studied by UV-vis spectroscopy, resonance light scattering (RLS), and circular dichroism (CD) at different ionic strengths; molecular docking and molecular dynamics simulation were also used for completion. Followings are the observed changes in the spectral properties of meso-tetrakis (N-para-trimethyl-anilium) porphyrin (TMAP), as a free-base porphyrin with no axial ligand, and its Fe derivative (FeTMAP) upon interaction with oligo(dA.dT)15 and oligo(dG.dC)15: (1) the substantial red shift and hypochromicity at the Soret maximum in the UV-vis spectra; (2) the increased RLS intensity by increasing the ionic strength; and (3) an intense bisignate excitonic CD signal. All of them are the reasons for TMAP and FeTMAP binding to oligo(dA.dT)15 and oligo(dG.dC)15 with the outside binding mode, accompanied by the self-stacking of the ligands along the oligonucleotide helix. The CD results demonstrated a drastic change from excitonic in monomeric behavior at higher ionic strengths, which indicates the groove binding of the ligands with oligonucleotides. Molecular docking also confirmed the groove binding mode of the ligands and estimated the binding constants and energies of the interactions. Their interaction trend was further confirmed by molecular dynamics technique and structure parameters obtained from simulation. It showed that TMAP reduced the number of intermolecular hydrogen bonds and increased the solvent accessible surface area in the oligonucleotide. The self-aggregation of ligands at lower concentrations was also confirmed. PMID- 25273341 TI - Bevacizumab beyond progression in breast cancer. PMID- 25273342 TI - Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open label, randomised phase 3 trial. AB - BACKGROUND: Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. METHODS: In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. FINDINGS: Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow up at the time of this prespecified primary progression-free survival analysis was 15.9 months (IQR 9.1-21.7) in the chemotherapy-alone group and 16.1 months (10.6-22.7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6.3 months [95% CI 5.4-7.2] vs 4.2 months [3.9-4.7], respectively, stratified hazard ratio [HR] 0.75 [95% CI 0.61-0.93], two-sided stratified log-rank p=0.0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. INTERPRETATION: These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. FUNDING: F Hoffmann-La Roche. PMID- 25273343 TI - Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. AB - BACKGROUND: Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. METHODS: We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75-100 mg/m(2)) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m(2) twice per day on days 1-14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (<=1.5 vs >1.5 * upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00929240. FINDINGS: Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11.9 months [95% CI 9.8-15.4] vs 4.3 months [3.9-6.8]; stratified hazard ratio 0.38 [95% CI 0.27-0.55]; two-sided log-rank p<0.0001), as was overall survival (median 39.0 months [95% CI 32.3-not reached] vs 23.7 months [18.5-31.7]; stratified HR 0.43 [95% CI 0.26-0.69]; two-sided log-rank p=0.0003). Results for time to progression were consistent with those for progression-free survival. 78 (86%) patients in the bevacizumab and capecitabine group and 72 (77%) in the bevacizumab only group had an objective response. Clinical benefit was recorded in 92 (98%) patients in the bevacizumab alone group and 90 (99%) in the bevacizumab and capecitabine group. Mean change from baseline in global health score did not differ significantly between groups. Grade 3 or worse adverse events during the maintenance phase were more common with bevacizumab and capecitabine than with bevacizumab only (45 [49%] of 91 patients vs 25 [27%] of 92 patients). The most common grade 3 or worse events were hand-foot syndrome (28 [31%] in the bevacizumab and capecitabine group vs none in the bevacizumab alone group), hypertension (eight [9%] vs three [3%]), and proteinuria (three [3%] vs four [4%]). Serious adverse events were reported by ten (11%) patients in the bevacizumab and capecitabine group and seven (8%) patients in the bevacizumab only group. INTERPRETATION: Despite prematurely terminated accrual and the lack of information about post-progression treatment, both progression-free survival and overall survival were significantly improved with bevacizumab and capecitabine compared with bevacizumab alone as maintenance treatment. These results might inform future maintenance trials and current first-line treatment strategies for HER2-negative metastatic breast cancer. FUNDING: F Hoffmann-La Roche. PMID- 25273344 TI - Association of physical activity with lower type 2 diabetes incidence is weaker among individuals at high genetic risk. AB - AIMS/HYPOTHESIS: We examined whether or not the association of physical activity with type 2 diabetes incidence differs according to several types of genetic susceptibility. METHODS: In a large prospective cohort with 821 incident cases of type 2 diabetes, we examined interactions of physical activity with: (1) each of 65 type 2 diabetes-associated single nucleotide polymorphisms (SNPs); (2) a genetic risk score (GRS) comprising all 65 SNPs; (3) two GRSs comprised of SNPs implicated in insulin resistance (IR) and insulin secretion; (4) GRSs for fasting insulin (FI) and fasting glucose. RESULTS: We found a significant interaction of physical activity and the type 2 diabetes GRS (p interaction = 0.016), suggesting a weaker protective effect of physical activity in those at high genetic risk. Based on the interactions observed with the IR GRS (p interaction = 0.046) and the FI GRS (p interaction = 0.042), it appears that the overall type 2 diabetes GRS interaction most likely occurs through genetic susceptibility to IR as opposed to insulin secretion. Furthermore, this interaction was more pronounced in women (p interaction = 0.0025) than in men (p interaction = 0.46). No single SNP stood out as displaying a strong interaction with physical activity. CONCLUSIONS/INTERPRETATION: We conclude that although physical activity appears to have an overall protective effect on type 2 diabetes, this putative effect is weakest among individuals with high genetic risk for type 2 diabetes and IR. PMID- 25273345 TI - Pregnancy glycaemia and cord-blood levels of insulin and leptin in Pakistani and white British mother-offspring pairs: findings from a prospective pregnancy cohort. AB - AIMS/HYPOTHESIS: To determine the extent to which gestational fasting and postload levels of glucose explain differences in infant fat mass between UK-born Pakistani and white British infants. METHODS: Analyses were undertaken in a prospective pregnancy cohort study of 1,415 women and their singleton live-born infants (629 white British and 786 Pakistani). Infant fat mass was assessed by cord-blood leptin levels and fetal insulin secretion by cord-blood insulin levels. Maternal OGTTs were completed at 26-28 weeks of gestation. RESULTS: Pakistani women had higher fasting and postload glucose levels and greater incidence of gestational diabetes than white British women. Higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin in all participants, irrespective of ethnicity. Cord-blood leptin levels were 16% (95% CI 6, 26) higher in Pakistani than in white British infants. After adjustment for fasting glucose levels, this difference attenuated to 7% ( 3, 16), and with additional adjustment for cord-blood insulin levels it attenuated further to 5% (-4, 14). Path analyses supported the hypothesis that fasting glucose levels mediate the relationship of Pakistani ethnicity to greater fat mass at birth, as measured by cord-blood leptin levels; on average, 19% of this mediation involved fetal insulin secretion. Postload glucose levels did not act as an important mediator of ethnic differences in cord-blood leptin levels. Results were very similar when 130 women with gestational diabetes were removed. CONCLUSIONS/INTERPRETATION: These novel findings suggest a role of maternal pregnancy glycaemia in mediating differences in fat mass between Pakistani and white British infants. PMID- 25273348 TI - Relation between spin and orbital magnetism in excited states of ferromagnetic materials. AB - We report the first-principles study of the orbital magnetism, the magnetic anisotropy energy, the ratio of the spin, and the orbital moments in nano-sized systems perturbed from their magnetic ground state. We investigate one monolayer thick films of Co, Fe, and FePt. Two types of the perturbation are studied. First, the collinear spin structure is rotated continuously between the easy and hard axes. Second, the non-collinear spin structures are considered varying in both the angles between spin moments and the direction of the net magnetization. In agreement with the experiment we obtain a variety of behaviours. We show that the magnetic anisotropy energy can both increase and decrease with increasing magnetic disorder. The type of behaviour depends on the variation of the electronic structure with increasing angles between atomic moments. We obtain the effect of band narrowing accompanying the spin disorder that correlates with the band narrowing obtained experimentally in a laser irradiated system. In agreement with this experiment we show that the ratio of the spin and orbital moments can both remain unchanged and vary strongly. We analyse the applicability of Bruno's picture, which suggests proportionality between magnetic-anisotropy energy and orbital moment anisotropy for non-collinear spin configurations. We study the non collinearity of the atomic spin and orbital moments and demonstrate that the response of the orbital moments to the variation of the spin structure can be unexpected and spectacular. PMID- 25273347 TI - The influence of negative life events on hippocampal and amygdala volumes in old age: a life-course perspective. AB - BACKGROUND: Psychosocial stress has been related to changes in the nervous system, with both adaptive and maladaptive consequences. The aim of this study was to examine the relationship of negative events experienced throughout the entire lifespan and hippocampal and amygdala volumes in older adults. METHOD: In 466 non-demented old adults (age range 60-96 years, 58% female), hippocampal and amygdala volumes were segmented using Freesurfer. Negative life events and the age at which these events occurred were assessed by means of a structured questionnaire. Using generalized linear models, hippocampal and amygdala volumes were estimated with life events as independent variables. The statistical analyses were adjusted for age, gender, intracranial volume, lifestyle factors, cardiovascular risk factors, depressive symptoms, and cognitive functioning. RESULTS: Total number of negative life events and of late-life events, but not of early-life, early-adulthood, or middle-adulthood events, was related to larger amygdala volume. There were interactions of early-life events with age and gender. Participants who reported two or more early-life events had significantly smaller amygdala and hippocampal volumes with increasing age. Furthermore, smaller hippocampal volume was found in men who reported two or more early-life events, but not in women. CONCLUSIONS: These results suggest that the effect of negative life events on the brain depends on the time when the events occurred, with the strongest effects observed during the critical time periods of early and late life. PMID- 25273346 TI - Cord blood insulinoma-associated protein 2 autoantibodies are associated with increased risk of type 1 diabetes in the population-based Diabetes Prediction in Skane study. AB - AIMS/HYPOTHESIS: The aim of this study was to examine the effect of cord blood autoantibodies on the risk for type 1 diabetes in children followed prospectively from birth. METHODS: The Diabetes Prediction in Skane (DiPiS) study consists of 35,853 children from the general population born during 2000-2004. Samples were collected at birth and analysed for HLA genotypes and autoantibodies to glutamate decarboxylase 65 (GAD65), insulin and insulinoma-associated protein 2 (IA-2). After adjusting for HLA, sex, maternal age and parental type 1 diabetes, independent associations with risk of diabetes were assessed using multivariate Cox proportional hazards models. RESULTS: In total, 151 children (0.4%) had developed type 1 diabetes by the end of 2013 at a median age of 5.8 years (0.8 12.2 years). In the multivariate analysis, the presence of IA-2 autoantibodies (IA-2A) in cord blood (HR 6.88, 95% CI 1.46,32.4; p = 0.003), but not maternal diabetes (HR 1.38, 95% CI 0.24,7.84; p = 0.71), was associated with risk of developing type 1 diabetes. No increased risk could be seen for the presence of autoantibodies to GAD65 or insulin. CONCLUSIONS/INTERPRETATION: Our study indicates that the presence of cord blood IA-2A superimposes maternal diabetes and other cord blood islet autoantibodies as a predictor of type 1 diabetes development in the child. These findings may be of significance for future screening and study protocols on type 1 diabetes prediction. PMID- 25273349 TI - Professional training in the context of food and nutrition security. AB - BACKGROUND: Primary care is an important area in which to confront situations of food and nutrition insecurity. To undertake action in this area, well-prepared professionals are necessary. Courses of health training are not yet, however, equipped to offer the necessary preparation. Aim To analyse the topics taught in nutrition graduation courses related to the abilities and competencies demanded by professional work in this area. METHODS: The curricula of the nutrition courses offered in the municipality of Sao Paulo, Brazil were analysed. Nutritionists and teachers were interviewed. The triangulation of the data obtained was undertaken by means of a qualitative approach taking the theory of social representations as the frame of reference. RESULTS: The concepts necessary to act within the context of food and nutrition security are related to a humanistic approach, the unity of theory and practice, the nutritionist's role as educator, teamwork and reflection on public health. PMID- 25273350 TI - Open Payments goes live with pharma to doctor fee data: first analysis. PMID- 25273352 TI - Anti-idiotypic nanobody-phage based real-time immuno-PCR for detection of hepatocarcinogen aflatoxin in grains and feedstuffs. AB - Aflatoxins are a group of extremely toxic small molecules that have been involved in human hepatic and extrahepatic carcinogenesis as causative agents. Herein, we developed a real-time immuno polymerase chain reaction (IPCR) assay for the accurately quantitative detection of aflatoxins in agri-products base on a M13 phage containing aflatoxin anti-idiotypic nanobody and its encoding DNA which was used to design the specific primers. The limit of detection (LOD) of the assay is 0.02 ng/mL, which exhibits a 4-fold improvement over traditional phage ELISA. The developed method was successfully validated with the samples of corn, rice, peanut, and feedstuff, which are major aflatoxin-contaminated agri-products. And the recoveries were from 77.05 to 122.16%. For further validation, the developed assay was also compared with a reference HPLC method for the analysis of aflatoxins in corn and peanuts, and concordant results (R(2) = 0.991) were obtained. In this context, this study provides a novel opportunity to analyze aflatoxins in agri-products. PMID- 25273351 TI - Protein biomarkers identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillators: findings from the Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSE-ICD). AB - BACKGROUND: Primary prevention implantable cardioverter defibrillators (ICDs) reduce all-cause mortality, but the benefits are heterogeneous. Current risk stratification based on left ventricular ejection fraction has limited discrimination power. We hypothesize that biomarkers for inflammation, neurohumoral activation, and cardiac injury can predict appropriate shocks and all-cause mortality in patients with primary prevention ICDs. METHODS AND RESULTS: The Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSe-ICD) enrolled 1189 patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end point was an ICD shock for adjudicated ventricular tachyarrhythmia. The secondary end point was all-cause mortality. After a median follow-up of 4.0 years, 137 subjects experienced an appropriate ICD shock and 343 participants died (incidence rates of 3.2 and 5.8 per 100 person-years, respectively). In multivariable-adjusted models, higher interleukin-6 levels increased the risk of appropriate ICD shocks. In contrast, C-reactive protein, interleukin-6, tumor necrosis factor-alpha receptor II, pro-brain natriuretic peptide (pro-BNP), and cardiac troponin T showed significant linear trends for increased risk of all cause mortality across quartiles. A score combining these 5 biomarkers identified patients who were much more likely to die than to receive an appropriate shock from the ICD. CONCLUSIONS: An increase in serum biomarkers of inflammation, neurohumoral activation, and myocardial injury increased the risk for death but poorly predicted the likelihood of an ICD shock. These findings highlight the potential importance of serum-based biomarkers in identifying patients who are unlikely to benefit from primary prevention ICDs. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov; Unique Identifier: NCT00733590. PMID- 25273354 TI - Gene therapy approach to FAP: in vivo influence of T119M in TTR deposition in a transgenic V30M mouse model. AB - Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of amyloid fibrils composed by mutated transthyretin (TTR) mainly in the peripheral nervous system. At present, liver transplantation is still the standard treatment to halt the progression of clinical symptoms in FAP, but new therapeutic strategies are emerging, including the use of TTR stabilizers. Here we propose to establish a new gene therapy approach using adeno-associated virus (AAV) vectors to deliver the trans suppressor TTR T119M variant to the liver of transgenic TTR V30M mice at different ages. This TTR variant is known for its ability to stabilize the tetrameric protein. Analysis of the gastrointestinal tract of AAV-treated animals revealed a significant reduction in deposition of TTR non-fibrillar aggregates in as much as 34% in stomach and 30% in colon, as well as decreased levels of biomarkers associated with TTR deposition, namely the endoplasmic reticulum stress marker BiP and the extracellular matrix protein MMP-9. Moreover, we showed with different studies that our approach leads to an increase in tetrameric and more stable forms of TTR, in favor of destabilized monomers. Altogether our data suggest the possibility to use this gene therapy approach in a prophylactic manner to prevent FAP pathology. PMID- 25273353 TI - Intramuscular delivery of heterodimeric IL-15 DNA in macaques produces systemic levels of bioactive cytokine inducing proliferation of NK and T cells. AB - Interleukin-15 (IL-15) is a common gamma-chain cytokine that has a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha (IL-15Ralpha) chain, which together form the IL-15 heterodimer. We have generated DNA vectors expressing the heterodimeric IL-15 by optimizing mRNA expression and protein trafficking. Repeated administration of these DNA plasmids by intramuscular injection followed by in vivo electroporation in rhesus macaques resulted in sustained high levels of IL 15 in plasma, with no significant toxicity. Administration of DNAs expressing heterodimeric IL-15 also resulted in an increased frequency of NK and T cells undergoing proliferation in peripheral blood. Heterodimeric IL-15 led to preferential expansion of CD8(+)NK cells, all memory CD8(+) T-cell subsets and effector memory CD4(+) T cells. Expression of heterodimeric IL-15 by DNA delivery to the muscle is an efficient procedure to obtain high systemic levels of bioactive cytokine, without the toxicity linked to the high transient cytokine peak associated with protein injection. PMID- 25273355 TI - Rapid outer-surface protein C DNA tattoo vaccination protects against Borrelia afzelii infection. AB - Borrelia afzelii is the predominant Borrelia species causing Lyme borreliosis in Europe. Currently there is no human vaccine against Lyme borreliosis, and most research focuses on recombinant protein vaccines against Borrelia burgdorferi sensu stricto. DNA tattooing is a novel vaccination method that can be applied in a rapid vaccination schedule. We vaccinated C3H/HeN mice with B. afzelii strain PKo OspC (outer-surface protein C) using a codon-optimized DNA vaccine tattoo and compared this with recombinant protein vaccination in a 0-2-4 week vaccination schedule. We also assessed protection by DNA tattoo in a 0-3-6 day schedule. DNA tattoo and recombinant OspC vaccination induced comparable total IgG responses, with a lower IgG1/IgG2a ratio after DNA tattoo. Two weeks after syringe-challenge with 5 * 10(5) B. afzelii spirochetes most vaccinated mice had negative B. afzelii tissue DNA loads and all were culture negative. Furthermore, DNA tattoo vaccination in a 0-3-6 day regimen also resulted in negative Borrelia loads and cultures after challenge. To conclude, DNA vaccination by tattoo was fully protective against B. afzelii challenge in mice in a rapid vaccination protocol, and induces a favorable humoral immunity compared to recombinant protein vaccination. Rapid DNA tattoo is a promising vaccination strategy against spirochetes. PMID- 25273356 TI - Mechanism-based inactivation of human cytochrome P450 3A4 by two piperazine containing compounds. AB - Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of more than half of pharmaceutic drugs, and inactivation of CYP3A4 can lead to adverse drug drug interactions. The substituted imidazole compounds 5-fluoro-2-[4-[(2-phenyl 1H-imidazol-5-yl)methyl]-1-piperazinyl]pyrimidine (SCH 66712) and 1-[(2-ethyl-4 methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP) have been previously identified as mechanism-based inactivators (MBI) of CYP2D6. The present study shows that both SCH 66712 and EMTPP are also MBIs of CYP3A4. Inhibition of CYP3A4 by SCH 66712 and EMTPP was determined to be concentration, time, and NADPH dependent. In addition, inactivation of CYP3A4 by SCH 66712 was shown to be unaffected by the presence of electrophile scavengers. SCH 66712 displays type I binding to CYP3A4 with a spectral binding constant (Ks) of 42.9 +/- 2.9 uM. The partition ratios for SCH 66712 and EMTPP were 11 and 94, respectively. Whole protein mass spectrum analysis revealed 1:1 binding stoichiometry of SCH 66712 and EMTPP to CYP3A4 and a mass increase consistent with adduction by the inactivators without addition of oxygen. Heme adduction was not apparent. Multiple mono-oxygenation products with each inactivator were observed; no other products were apparent. These are the first MBIs to be shown to be potent inactivators of both CYP2D6 and CYP3A4. PMID- 25273358 TI - Long-term consequences of alcohol misuse in Scottish military veterans. AB - OBJECTIVE: Serving military personnel are more likely to drink heavily than civilians. The aim of our study was to examine whether veterans have an increased risk of alcoholic liver disease and alcohol-related death compared with non veterans. DESIGN: Retrospective cohort study of 57 000 veterans resident in Scotland and 173 000 age, sex and area of residence-matched civilians, using Cox proportional hazard models to compare the risk of alcoholic liver disease and alcohol-related death overall, by sex, birth cohort, length of service and year of recruitment, adjusting for socioeconomic status. RESULTS: Over mean 29 years follow-up, 677 (1.20%) veterans developed alcoholic liver disease compared with 2175 (1.26%) non-veterans (adjusted HR=0.91, 95% CIs 0.84 to 0.99, p=0.035). Only the 1945-1949 veterans' birth cohort was at higher risk, unadjusted HR=1.25, 95% CIs 1.07 to 1.47, p=0.004, although their difference in risk became non significant after adjusting for socioeconomic status, p=0.052. The pattern was similar for alcohol-related death. Veterans were less likely than non-veterans to have comorbid hepatitis C. Older age at recruitment at a time of high operational activity in the early 1970s was associated with increased risk, but longer service was not. CONCLUSIONS: Overall, veterans in Scotland had a significantly reduced risk of alcoholic liver disease or alcohol-related death compared with non-veterans, although the risk was higher in those born before 1950. Reasons for the changing pattern are likely to be complex and may reflect operational exposure, social attitudes to alcohol and the impact of recent military health promotion. PMID- 25273357 TI - Individual differences in cognitive ability at age 20 predict pulmonary function 35 years later. AB - BACKGROUND: Poor pulmonary function is associated with mortality and age-related diseases, and can affect cognitive performance. However, extant longitudinal studies indicate that early cognitive ability also affects later pulmonary function. Despite the multifaceted nature of pulmonary function, most longitudinal studies were limited to a single index of pulmonary function: forced expiratory volume in 1 s (FEV1). In this study, we examined whether early adult cognitive ability predicted five different indices of pulmonary function in mid life. METHODS: Mixed modelling tested the association between young adult general cognitive ability (mean age=20), measured by the Armed Forces Qualification Test (AFQT), and mid-life pulmonary function (mean age=55), in 1019 men from the Vietnam Era Twin Study of Aging. Pulmonary function was indexed by per cent predicted values for forced vital capacity (FVC%p), FEV1%p, maximum forced expiratory flow (FEFmax%p), and maximal voluntary ventilation (MVV%p), and by the ratio of FEV1 to FVC (FEV1/FVC), an index of lung obstruction. RESULTS: After adjusting for smoking, pulmonary disease, occupation, income and education, age 20 AFQT was significantly (p<0.05) associated with mid-life FVC%p (beta=0.10), FEV1%p (beta=0.13), FEFmax%p (beta=0.13), and MVV%p (beta=0.13), but was not significantly associated with FEV1/FVC (beta=0.03, p=0.34). CONCLUSIONS: Early adult cognitive ability is a predictor of multiple indices of aging-related pulmonary function 35 years later, including lung volume, airflow and ventilator capacity. Cognitive deficits associated with impaired aging-related lung function may, thus, be partly pre-existing. However, results also highlight that early life risk factors may be differentially related to different metrics of later life pulmonary health. PMID- 25273360 TI - Less is not always more: embracing (appropriate) medical intensity. PMID- 25273361 TI - Mesoporous BN and BCN nanocages with high surface area and spherical morphology. AB - Novel mesoporous BN and BCN materials with cage type porous structure and spherical morphology have been synthesized using carbon nanocages with 3D porous structure as a template via an elemental substitution method at a low synthesis temperature. The obtained materials exhibit a large specific pore volume with uniform pore size distribution and the specific surface area ranging from 945 to 1023 m(2) g(-1). PMID- 25273362 TI - Acupuncture does not improve chronic knee pain, study finds. PMID- 25273359 TI - Machine-Based, Self-guided Home Therapy for Individuals With Severe Arm Impairment After Stroke: A Randomized Controlled Trial. AB - BACKGROUND: Few therapeutic options exist for the millions of persons living with severe arm impairment after stroke to increase their dose of arm rehabilitation. This study compared self-guided, high-repetition home therapy with a mechanical device (the resonating arm exerciser [RAE]) to conventional therapy in patients with chronic stroke and explored RAE use for patients with subacute stroke. METHODS: A total of 16 participants with severe upper-extremity impairment (mean Fugl-Meyer [FM] score = 21.4 +/- 8.8 out of 66) >6 months poststroke were randomized to 3 weeks of exercise with the RAE or conventional exercises. The primary outcome measure was FM score 1 month posttherapy. Secondary outcome measures included Motor Activity Log, Visual Analog Pain Scale, and Ashworth Spasticity Scale. After a 1-month break, individuals in the conventional group also received a 3-week course of RAE therapy. RESULTS: The change in FM score was significant in both the RAE and conventional groups after training (2.6 +/- 1.4 and 3.4 +/- 2.4, P = .008 and .016, respectively). These improvements were not significant at 1 month. Exercise with the RAE led to significantly greater improvements in distal FM score than conventional therapy at the 1-month follow up (P = .02). In a separate cohort of patients with subacute stroke, the RAE was found feasible for exercise. DISCUSSION: In those with severe arm impairment after chronic stroke, home-based training with the RAE was feasible and significantly reduced impairment without increasing pain or spasticity. Gains with the RAE were comparable to those found with conventional training and also included distal arm improvement. PMID- 25273363 TI - Increased requirement for central venous catheter replacement in paediatric oncology patients with deep venous thrombosis: a multicentre study. PMID- 25273364 TI - Nonanatomic anterior cruciate ligament reconstruction with double-stranded semitendinosus grafts in children with open physes: minimum 15-year follow-up. AB - BACKGROUND: Nonanatomic anterior cruciate ligament (ACL) reconstruction (ACLR) with double-stranded semitendinosus grafts in children with open physes has been described as a successful surgical technique in short-term follow-up clinical reports. PURPOSE: To evaluate the clinical outcomes of nonanatomic ACLR in children with open physes and a minimum of 15 years' follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twelve patients with an average age of 10.7 years (range, 8.3-12.4 years) underwent ACLR between 1991 and 1998. All patients were classified as Tanner development stage 2 or lower. The surgical technique involved transphyseal tibial tunnel drilling and over-the-top (OTT) femoral fixation using a double-stranded graft for all patients. Clinical outcomes were evaluated in terms of the manual Lachman test, pivot-shift test, return to sports activity, and International Knee Documentation Committee (IKDC) score at the end of growth and at a minimum 15-year follow-up (range, 15-22 years). RESULTS: No clinically significant growth disturbance was observed. Ten patients had a grade A IKDC score, and 2 patients had a grade B IKDC score at the end of growth. There was no progression of laxity or modification of knee stability with growth. Three patients (25%) had ACL reruptures during sports activities after growth plate closure. All patients with reruptured ACLs underwent additional reconstructive surgery. CONCLUSION: Anterior cruciate ligament reconstruction using the OTT technique in the femur and the transphyseal technique in the tibia produces good results with regard to growth plate closure but a high failure rate in adulthood. PMID- 25273366 TI - Conference on "Science Policy in the Service of a Greater Europe", Organised by the OstWest-Wirtschafts Academie Postdam, Schlobeta Celilienhof, 28-31 January 1993: What is the European Community doing with Eastern Europe in the field of Science and Technology? PMID- 25273365 TI - Role of comorbidities as limiting factors to the effect of hyperbaric oxygen in diabetic foot patients: a retrospective analysis. AB - INTRODUCTION: The effectiveness of hyperbaric oxygen therapy (HBOT) on selected diabetic foot wounds continues to be controversial. A holistic approach to diabetes and its comorbidities may be beneficial in the discussion of the proper application of this treatment modality. The aim of the current study is to evaluate the efficacy of HBOT on diabetic foot wounds and provide clinical data that may support this knowledge. METHODS: The present study was a retrospective analysis of the effect of HBOT on diabetic foot lesions ranging 3-5 on the Wagner Grading System. Patients had been treated with HBOT and monitored for 12 months. The results were analyzed in relation to age, gender, diabetes duration and type, microangiopathic complications, peripheral arterial disease (PAD), history of coronary artery disease, stroke, hypertension, smoking habits, glycated hemoglobin, blood sedimentation rate, C-reactive protein, and number of HBOT sessions. Microangiopathies were evaluated as retinopathy, nephropathy, and neuropathy. PAD was determined by available color Doppler ultrasonography and/or angiographic data depending on a modified scoring system. The data of arteries from the aorta to the dorsal pedal artery were scored singly. Average scores of aorto-iliac, femoral, popliteal and pedal levels were also evaluated with this system to compare the healing results in relation to PAD. RESULTS: One hundred and seventeen patients with 126 diabetic foot wounds were treated. Histories of coronary artery disease, stroke, and non-proliferative or proliferative retinopathy had negative effects on HBOT (P = 0.002, P = 0.015, P = 0.022, respectively). Depending on the scorings of PAD, the single arterial scores and average scores of aorto-iliac, popliteal and pedal levels had no relation to outcomes, while the average scores of the femoral arterial level affected the results (P = 0.048). CONCLUSIONS: Diabetic foot patients with histories of coronary artery diseases or stroke and non-proliferative or proliferative retinopathy might resist HBOT. PAD at the femoral arterial level has been shown to have a significant negative effect on HBOT outcomes that should be first considered for surgery. In contrast, PAD below the knee does not seem to be an obstacle to the efficacy of HBOT. PMID- 25273367 TI - Flow dynamic effect of the anastomotic angle: a numerical study of pulsatile flow in vascular graft anastomoses models. AB - Pulsatile non-Newtonian blood flow in three distal end-to-side anastomoses models of prosthetic grafts has been analysed applying computer simulation. The anastomotic angles of the three-dimensional geometric models vary over 30 degrees , 45 degrees and 60 degrees . The pulsatile inflow conditions in the graft remain unchanged. Numerical results are presented for the axial and the secondary flow velocity and the wall shear stress distribution. Further, the paths of fluid particles and the particle residence times are demonstrated by means of numerical flow visualization. The quantitative study shows complex flow and wall shear stress patterns with flow separation and strong secondary motion in the host vessel and a weakly migrating flow stagnation point on the arterial floor during the entire pulse cycle in the models under consideration. The flow dynamic effects, which seem to be important in the development of intimal hyperplasia, are dependent on the anastomotic angle and increase with increasing angle. PMID- 25273368 TI - Performance assessment of a range of commercial jet nebulisers. AB - The performance of 14 jet nebulisers was assessed using 4 ml of 0.9% w/v saline and a flow-rate of 10 l/min. Nebulisation time (T), percentage mass of drug released as aerosol (P), rate of emission of aerosol (R) and mass median diameter of aerosol distribution (mmd) were recorded. The Side-Stream (Medic-Aid Ltd.), Sure-Mist (Unimed (UK) Ltd.) and Up-Draft (Hudson Inc.) had the lowest T (561 s, 618 s, 637 s respectively) and the Micro-Cirrus (Intersurgical Ltd.) and Up-Draft II (Hudson Inc.) had the highest T (2466 s, 1659 s respectively). The Micro-Neb III (Lifecare Ltd.), Side-Stream and Respirgard (Marquest Ltd.) produced the highest P (68%, 67%, 66% respectively), the Sure-Mist and Up-draft had the lowest P (46.5%, 39% respectively). The Micro-Cirrus, Up-Draft II (Hudson Inc.) and Venticaire (S and W Vickers) had low R values (0.49, 0.801, 0.905 mg/min respectively), the Side-Stream had the highest R (4.08 mg/min). The Micro-Cirrus had a low mmd (1.04 m). The Pulmo-Neb (DeVilbiss Ltd.), Unineb (Unimed (UK) Ltd.) and Up-Draft had relatively high mmd (4.97 MUm, 4.34 MUm, 4.24 MUm). PMID- 25273369 TI - Miniaturized integrated biosensors. AB - Miniaturized integrated thin-film biosensors were developed for use in clinical analyzers and for in vivo applications. A glucose and a lactate sensor were integrated with a pH-sensor on a flexible substrate. Both enzyme sensors are based on the electrochemical measurement of H2O2 produced by the enzymes glucoseoxidase and lactateoxidase respectively. The solid state pH-sensor uses a neutral carrier membrane. The intended application of this device is the monitoring of metabolic parameters in the intensive care unit and the operation theater and the use as a sensor module in clinical analyzers. The glucose-, lactate- and pH-sensor was tested in buffer solutions and undiluted serum showing excellent performance. PMID- 25273370 TI - Laser diode coupled with optical fiber for applications in photodynamic therapy. AB - A diode laser with roughly 480 mW/cm2 emission at 776 nm was developed and engineered to obtain a uniform illumination of tumour cells deposited on Petri dishes having an external diameter of 5 cm. The efficacy of the apparatus in inducing photocytotoxic effects was successfully checked by irradiation of pigmented melanoma cells in the presence of a photosensitizer, Si(IV) naphthalocyanine, having intense absorption bands at 776 nm. Our results open interesting prospects for extending photodynamic therapy to highly pigmented tumours. PMID- 25273371 TI - Computer-supported device for histomorphometric investigations on laser-surgery. AB - A device for quantitative morphometric analysis of tissue alterations caused by laser or electrosurgery was developed. The unit was designed for interactive evaluation of histological specimens obtained by experimental surgery. It consists of a microscope, a stepper-motor driven scanning stage, a digitizing tablet and a PC with software developed for this purpose. The depth of the incision, the width and the area of the coagulation zone can be measured independent of the microscopic magnification. Graphs and data can be exported in standard data-formats (ASCII, HPGL, DXF) for further processing. The application is demonstrated on experimental incisions with a CO2-laser in the oral mucosa of pigs; quantitative data are presented. PMID- 25273372 TI - An ARX model for light propagation in biological tissue. AB - For many applications in biomedical engineering, and especially for precise dosimetry in photodynamic therapy, it is essential to determine the absorption and scattering of light in biological tissue very precisely. At present it is not possible to measure the absorption and scattering coefficient separately by using an endoscopic sensor based upon the backscattering phenomenon. In this paper, we propose a solution to this problem. We present a new model derived from Kubelka and Munk's theory, which is known to be suitable for the description of optical phenomena in tissue. Then we apply an algorithm often used in signal processing, the Auto Regressive with eXternal input or ARX model, which allows us to determine both optical coefficients separately. A first validation is done by numerical simulation, then measurements with phantoms were done. The results of both tests prove the model to be reliable and effective. PMID- 25273373 TI - VentEx: an on-line knowledge-based system to support ventilator management. AB - This paper will demonstrate the clinical application of a knowledge-based decision-support system called VentEx for ventilator management. VentEx has been implemented using a knowledge-based development tool on a PC under the Microsoft Windows multitasking environment. It is integrated into a computer aided ventilator system including the Siemens Elema Servo Ventilator 900 C equipped with a Servo Computer Module 990 and the CO2 analyser 930. The system provides advanced ventilator monitoring with expert advice concerning ventilator strategy and settings based on data from on-line monitoring. The knowledge base has been primarily validated and the system has been clinically tested by the intensive care unit staff. Different approaches such as knowledge acquisition, representation and system integration have been outlined and discussed. PMID- 25273374 TI - Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics. AB - The ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed. PMID- 25273376 TI - Psychomotor vigilance performance predicted by Epworth Sleepiness Scale scores in an operational setting with the United States Navy. AB - It is critical in operational environments to identify individuals who are at higher risk of psychomotor performance impairments. This study assesses the utility of the Epworth Sleepiness Scale for predicting degraded psychomotor vigilance performance in an operational environment. Active duty crewmembers of a USA Navy destroyer (N = 69, age 21-54 years) completed the Epworth Sleepiness Scale at the beginning of the data collection period. Participants wore actigraphs and completed sleep diaries for 11 days. Psychomotor vigilance tests were administered throughout the data collection period using a 3-min version of the psychomotor vigilance test on the actigraphs. Crewmembers with elevated scores on the Epworth Sleepiness Scale (i.e. Epworth Sleepiness Scale >10) had 60% slower reaction times on average, and experienced at least 60% more lapses and false starts compared with individuals with normal Epworth Sleepiness Scale scores (i.e. Epworth Sleepiness Scale <= 10). Epworth Sleepiness Scale scores were correlated with daily time in bed (P < 0.01), sleep (P < 0.05), mean reaction time (P < 0.001), response speed 1/reaction time (P < 0.05), slowest 10% of response speed (P < 0.001), lapses (P < 0.01), and the sum of lapses and false starts (P < 0.001). In this chronically sleep-deprived population, elevated Epworth Sleepiness Scale scores identified that subset of the population who experienced degraded psychomotor vigilance performance. We theorize that Epworth Sleepiness Scale scores are an indication of personal sleep debt that varies depending on one's individual sleep requirement. In the absence of direct performance metrics, we also advocate that the Epworth Sleepiness Scale can be used to determine the prevalence of excessive sleepiness (and thereby assess the risk of performance decrements). PMID- 25273375 TI - NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence. AB - RATIONALE: Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences. The use of intermediate ND phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives (WISDM) represent heavy, pervasive smoking, which is a core feature of nicotine dependence, making these motives strong candidates as intermediate phenotypes. OBJECTIVE: This study examines the WISDM PDM as a novel intermediate phenotype of nicotine dependence. METHODS: The study used data from 734 European Americans who smoked at least 5 cigs/day [M = 16.2 (SD = 9.5) cigs/day], completed a phenotypic assessment, and provided a sample of DNA. Based on prior evidence of the role of genetic variation in the NCAM1-TTC12-ANKK1-DRD2 region on chromosome 11q23 in smoking behavior, associations among 12 region loci with nicotine dependence and PDM phenotypes were examined using haplotype and individual loci approaches. In addition, mediational analysis tested the indirect pathway from genetic variation to smoking motives to nicotine dependence. RESULTS: NCAM1-TTC12-ANKK1-DRD2 region loci and haplotypes were significantly associated with the motive of Automaticity and, further, Automaticity significantly mediated associations among NCAM1-TTC12 ANKK1-DRD2 cluster variants and nicotine dependence. CONCLUSIONS: These results suggest that motives related to automaticity are a viable intermediate phenotype for understanding genetic contributions to nicotine dependence. Further, NCAM1 TTC12-ANKK1-DRD2 variants may increase the likelihood that a person will become dependent via a highly automatic smoking ritual that can be elicited with little awareness. PMID- 25273377 TI - Experiences in the military may impact dual-axis neuroendocrine processes in veterans. AB - Military stressors such as survival training can affect endocrine functioning in the short term, and combat has been associated with endocrine changes linked to psychopathology. However, studies with military samples examining whether there are individual differences in these changes as part of normal development, or as an adaptive mechanism in adulthood are lacking. This study examined whether exposure to combat in a sample of veterans was associated with differential endocrine activity to a laboratory frustration task. Results indicated that Army veterans demonstrated significant testosterone reactivity to frustration and negative coupling between cortisol and testosterone. Alternatively, Navy and Marine veterans demonstrated little testosterone reactivity to frustration and positive coupling between cortisol and testosterone. Positive cortisol testosterone coupling was stronger among individuals who had more dangerous combat experiences. This latter pattern may better prepare individuals for stressful life experiences and supports the contention that adulthood stressors may calibrate endocrine systems. Results are explained in the context of the Adaptive Calibration Model (Ellis et al., 2012, Developmental Psychology, 48(3), 598-623) which proposes that exposure to key environmental dimensions during endocrinologically malleable life stages (e.g., puberty) can change stress responsivity, resulting in a faster life history trajectory (e.g., increased risk taking and aggression). PMID- 25273378 TI - Americans' attitudes toward premarital sex and pornography consumption: a national panel analysis. AB - National panel data gathered in 2008 (T1) and 2010 (T2) from 420 Black and White US adults aged 18-89 years (M = 45.37, SD = 15.85) were employed to assess prospective associations between pornography consumption and premarital sex attitudes. Premarital sex attitudes were indexed via a composite measure of perceptions of the appropriateness of adults and teenagers having premarital sex. Wright's (2011) sexual script acquisition, activation, application model (3AM) of media sexual socialization was used as the guiding theoretical framework. The 3AM maintains that sexual media may be used by consumers to inform their sexual scripts but that attitude change from exposure to sexual media is less likely when media scripts are incongruent with consumers' preexisting scripts. Consistent with these postulates, the association between pornography consumption at T1 and more positive attitudes toward premarital sex at T2 was strongest for younger adults, who are less oppositional to premarital sex than older adults. Contrary to the position that associations between pornography consumption and premarital sex attitudes are due to individuals who already have positive attitudes toward premarital sex selecting content congruent with their attitudes, premarital sex attitudes at T1 did not predict pornography consumption at T2. PMID- 25273381 TI - Polymorphic transformations and optical properties of graphene-based Ag-doped titania nanostructures. AB - TiO2 is the most studied semiconductor material for photovoltaics and photocatalyst applications, but due to a very large electron hole recombination process it is difficult to use it as a photovoltaics material. In this context graphene-decorated Ag-doped TiO2 nanostructures have been synthesized by a simple, cost effective chemical method. In this paper, we have studied the structural transformations and electronic band structure of Ag-doped TiO2 due to the incorporation of graphene oxide. Pure rutile and anatase-rutile mixed phases of TiO2 nanoparticles were obtained by Ag doping and annealing at 400 degrees C. A large red shift was observed in most of the graphene-decorated, doped TiO2 hybrid nanostructures, which is because of the electron transfer between the conduction bands of the doped TiO2 and the multilayer graphene. The Ag-doped TiO2 nanoparticles appear in the shape of a bunch of bananas (or rice-like) because of the jumbled collection of particles, which remain unaltered even after graphene decoration. The strong electrical coupling of Ag-doped TiO2 with reduced graphene oxide produces an advanced hybrid material useful for superior photovoltaics, photocatalytic activity and other applications. PMID- 25273382 TI - A new vetulicolian from Australia and its bearing on the chordate affinities of an enigmatic Cambrian group. AB - BACKGROUND: Vetulicolians are one of the most problematic and controversial Cambrian fossil groups, having been considered as arthropods, chordates, kinorhynchs, or their own phylum. Mounting evidence suggests that vetulicolians are deuterostomes, but affinities to crown-group phyla are unresolved. RESULTS: A new vetulicolian from the Emu Bay Shale Konservat-Lagerstatte, South Australia, Nesonektris aldridgei gen. et sp. nov., preserves an axial, rod-like structure in the posterior body region that resembles a notochord in its morphology and taphonomy, with notable similarity to early decay stages of the notochord of extant cephalochordates and vertebrates. Some of its features are also consistent with other structures, such as a gut or a coelomic cavity. CONCLUSIONS: Phylogenetic analyses resolve a monophyletic Vetulicolia as sister-group to tunicates (Urochordata) within crown Chordata, and this holds even if they are scored as unknown for all notochord characters. The hypothesis that the free swimming vetulicolians are the nearest relatives of tunicates suggests that a perpetual free-living life cycle was primitive for tunicates. Characters of the common ancestor of Vetulicolia + Tunicata include distinct anterior and posterior body regions - the former being non-fusiform and used for filter feeding and the latter originally segmented - plus a terminal mouth, absence of pharyngeal bars, the notochord restricted to the posterior body region, and the gut extending to the end of the tail. PMID- 25273383 TI - Electro-optical study of the exposure of Azospirillum brasilense carbohydrate epitopes. AB - The exposure of Azospirillum brasilense carbohydrate epitopes was investigated by electro-optical analysis of bacterial cell suspensions. To study changes in the electro-optical (EO) properties of the suspensions, we used antibodies generated to the complete lipopolysaccharide of A. brasilense type strain Sp7 and also antibodies to the smooth and rough O polysaccharides of Sp7. After 18 hr of culture growth, the EO signal of the suspension treated with antibodies to smooth O polysaccharide was approximately 20% lower than that of the suspension treated with antibodies to complete lipopolysaccharide (control). After 72 hr of culture growth, the strongest EO signal was observed for the cells treated with antibodies to rough O polysaccharide (approximately 46% greater than the control), whereas for the cells treated with antibodies to smooth O polysaccharide, it was much lower (approximately 23% of the control). These data were confirmed by electron microscopy. The results of the study may have importance for the rapid evaluation of changes in lipopolysaccharide form in microbial biotechnology, when the antigenic composition of the bacterial surface requires close control. PMID- 25273384 TI - Bioengineered acellular dermal matrices for the repair of abdominal wall defects in rats. AB - PURPOSE: Acellular grafts can be used as a better substitute for the prosthetic meshes in reconstruction of abdominal wall defect. The purpose of study was to develop bioengineered scaffolds by seeding primary mouse embryo fibroblast cells (p-MEF) on decellularized rabbit skin and to test the efficacy of these scaffolds for the repair of abdominal wall defects in rats. METHODS: The study was conducted on 18 clinically healthy adult Wistar rats of either sex. The animals were randomly divided into two equal groups having nine animals in each group. In both the groups a 20 * 20 mm(2) size full thickness muscle defect was created under xylazine and ketamine anaesthesia in the mid-ventral abdominal wall. In group I the defect was repaired with acellular dermal matrix alone and in group II it was repaired with p-MEF seeded dermal matrix. Matrices were implanted by synthetic absorbable suture material (polyglycolic acid) in continuous suture pattern. The efficacy of the bioengineered matrices in the reconstruction of full thickness abdominal wall defects was evaluated. RESULTS: Macroscopic observations revealed that adhesions with skin and abdominal viscera were found to be less in group II as compared to group I. Immunological reactions were reduced in group II. Histopathological observations also revealed that fibroplasia and collagen fiber arrangement was found to be better in group II. No recurrence of hernia was found in both the groups. CONCLUSION: On the basis of the results bioengineered cell seeded scaffolds were found to be better than non-cell seeded scaffolds for the repair of abdominal wall defects in rats. PMID- 25273386 TI - Tryptanthrin protects hepatocytes against oxidative stress via activation of the extracellular signal-regulated kinase/NF-E2-related factor 2 pathway. AB - Tryptanthrin [6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline], originally isolated from Isatidis radix, has been characterized as having anti-microbial and anti-tumor activities. It is well-known that excess oxidative stress is one of the major factors causing cell damage in the liver. This study investigated the cytoprotective effects and molecular mechanism of tryptanthrin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress in human hepatocyte-derived HepG2 cells. Tryptanthrin pre-treatment blocked the reactive oxygen species production, mitochondrial dysfunction, and cell death induced by tBHP. Moreover, tryptanthrin reversed tBHP-induced GSH reduction. This study also confirmed the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by tryptanthrin as a plausible molecular mechanism for its cytoprotective effects. Specifically, tryptanthrin treatment induced nuclear translocation and transactivation of Nrf2 as well as phosphorylation of extracellular signal-regulated kinase (ERK), a potential upstream kinase of Nrf2. Tryptanthrin also up-regulated the expression of the heme oxygenase 1 and glutamate-cysteine ligase catalytic subunits, which are representative target genes of Nrf2. Moreover, inhibitor of ERK was used to verify the important role of the ERK-Nrf2 pathway in the hepatoprotective effects of tryptanthrin. In conclusion, this study demonstrated that tryptanthrin protects hepatocytes against oxidative stress through the activation of the ERK/Nrf2 pathway in HepG2 cells. PMID- 25273385 TI - Polyphenol extracts from Punica granatum and Terminalia chebula are anti inflammatory and increase the survival rate of chickens challenged with Escherichia coli. AB - Avian pathogenic Escherichia coli (APEC) causes inflammation in multiple organs of chickens called avian colibacillosis, and results in serious economic loss to the chicken industry. Polyphenolic compounds possess a wide range of physiological activities that may contribute to their beneficial effects against inflammation-related diseases. In this study, the curative effect and mechanism of action of the polyphenolic extracts from Punica granatum L. and Terminalia chebula Retz. in chickens challenged with APEC were studied. Specific-pathogen free white Leghorn chickens (males, 21-d old) were challenged with APEC and then given oral administration of extracts of P. granatum and T. chebula. The extracts decreased the morbidity and inflammation induced by APEC. Data from quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay showed that the extracts of P. granatum and T. chebula polyphenols (GCP) reversed the over-expression genes of the Toll-like receptor (TLR) 2, 4, and 5, down-regulated the activation of nuclear factor-kappa B signal transduction pathways, and inhibited the production of pro-inflammatory cytokines. Naturally occurring GCP may be a potential alternative medicine for the prevention or treatment of avian colibacillosis. PMID- 25273387 TI - Chondroitin sulfate-glycyl-prednisolone conjugate as arthritis targeting system: localization and drug release in inflammatory joints. AB - Chondroitin sulfate-glycyl-prednisolone conjugate (CS-GP) was previously demonstrated to exhibit superior anti-arthritic effects compared to prednisolone (PD) alone. In this study, CS-GP was examined for its pharmacokinetic features and tropism for inflammatory joints using rats with adjuvant-induced arthritis in order to identify the mechanism of the potential enhancement. After intravenous injection (2.5 mg PD eq./kg), CS-GP yielded an area under the curve (AUC) of the total (free+conjugated) drug much higher than that of PD alone. After intravenous administration at the same dose, the drug distribution to the hind paw inflammatory joints was investigated. For PD alone, the PD concentration was 1.2 1.7 ug/g at 1 h and fell to 0.12-0.14 ug/g at 24 h. In contrast, CS-GP maintained the total concentration in the range of 0.55-0.97 ug/g for 1-24 h, and maintained the free PD concentration at 0.06-0.16 ug/g for 1-24 h. Furthermore, at 24 h after intravenous administration (2.5 mg PD eq./kg), CS-GP exhibited a higher total drug concentration in arthritic rats than in healthy rats. These findings suggested that CS-GP may have the ability to target inflammatory joints. As the apparent molecular weight of CS-GP became greater in plasma, it might interact with blood components and cause high plasma retention and good tropism to the inflammatory sites. Enhancement of the anti-inflammatory potential of CS-GP was found to be due to good maintenance of drug levels in the inflamed area. PMID- 25273388 TI - ORI2 inhibits coxsackievirus replication and myocardial inflammation in experimental murine myocarditis. AB - We purified ORI2 [3-(3,4-dihydroxyphenyl)acrylic acid 1-(3,4-dihydroxyphenyl)-2 methoxycarbonylethyl ester] from an extract of the plant Isodon excisus. We tested the antiviral effect of ORI2 in a coxsackievirus-induced myocarditis model. Coxsackievirus B3 (CVB3) is a common cause of myocarditis and dilated cardiomyopathy. Activation of extracellular signal-regulated kinase (ERK) and Akt signaling in virus-infected cells is essential for CVB3 replication. Antiviral compounds were screened by HeLa cell survival assay. Several purified natural compounds were added to HeLa cells cultured in 96-well plates for 30 min after 1 multiplicity of infection (m.o.i) CVB3 infection. ORI2 significantly improved HeLa cell survival in a dose-dependent manner. For in vivo studies, BALB/c mice (n=20) were infected with CVB3, then 10 of the mice were treated by daily intraperitoneal injections of ORI2 (100 mM) for 3 consecutive days. ORI2 treatment significantly improved early survival in the treated mice compared to untreated mice (85% vs. 50%, respectively). Organ virus titers and myocardial damage were significantly lower in the ORI2-treated mice than in untreated mice. These results demonstrate that ORI2, delivered by intraperitoneal injection after CVB3 infection, has a significant antiviral effect by markedly inhibiting virus replication, resulting in a decrease in organ virus titer and myocardial damage. ORI2 may be developed as a potential therapeutic agent for the treatment of CVB3 infections. PMID- 25273389 TI - In vitro and in vivo evaluation under finite conditions of a transdermal oil-in water type emulsified formulation of propiverine hydrochloride. AB - A transdermal oil-in-water type emulsified formulation containing propiverine hydrochloride, used for treatment of an overactive bladder (OAB), was evaluated for in vitro skin permeation under finite conditions and in vivo transdermal absorption. Propiverine hydrochloride solubility was determined using 1,3 butyleneglycol, polyoxyethylene (2) oleylether, isostearyl alcohol, and lauryl alcohol. The solubility increased as the solubility parameter value increased. In vitro skin permeation in hairless mouse skin and in vivo transdermal absorption in rats were measured using propiverine hydrochloride dissolved in a simple solution containing these solvents. Dependent on the increase in in vitro flux, the in vivo area under the curve up to 72 h (AUC0-72) was increased. Therefore, the emulsified formulation was prepared containing these ingredients using polyoxyethylene (20) stearylether for optimization. The emulsified formulation was used to conduct in vivo single- and repeated-dose absorption studies in rats. After single-dose transdermal administration of the emulsified formulation, the AUC0-72 was equivalent to that of the simple solution. Furthermore, results using the emulsified formulation indicated an increase in AUC0-72 and significant extension of the elimination half-life, in comparison with oral administration. After repeated-dose administration, a significant minimum plasma concentration was observed compared with oral administration. These results demonstrate that the emulsified formulation is a good option for transdermal delivery of propiverine hydrochloride. PMID- 25273390 TI - Hydrogel-based ultra-moisturizing cream formulation for skin hydration and enhanced dermal drug delivery. AB - To develop an external vehicle for skin hydration and enhanced dermal drug delivery, a hydrogel-based ultra-moisturizing cream (HUMC) was successfully formulated with carbopol 934P, urea, Tinocare GL, grape seed oil, and other excipients. The HUMC showed plastic flow behavior due to a gel structure with a cream base. Different types of drug-free vehicles such as a hydrogel, conventional cream (CC), and three HUMCs were prepared and subjected to an in vivo skin hydration test on a hairless mouse using a corneometer. Hydration effect (?AU) was in the order of HUMC2>HUMC1 >= CC>HUMC3>hydrogel. Using nile red (NR) and 5-carboxyfluorescein (5-CF) as lipophilic and hydrophilic fluorescent probes, respectively, in vitro skin permeation and accumulation studies were conducted using Franz diffusion cells. The values of steady-state flux (Jss, ng/h/cm(2)) were obtained: 74.8 (CC), 145.6 (HUMC1), and 161.9 (HUMC2) for NR delivery; 6.8 (CC), 8.3 (HUMC1), and 10.9 (HUMC2) for 5-CF delivery. The amounts retained in the skin at 12 h (Qr, ng/cm(2)) were determined: 86.4 (CC) and 102.0 (HUMC2) for NR; and 70.1 (CC) and 195.6 (HUMC2) for 5-CF. Confocal microscopy was used to visualize the distribution of the fluorescent probes. NR tended to be localized into the deeper part of the skin with adipose tissue whereas 5-CF localized in the upper layer of the skin. Thus we propose that HUMC2 is an efficacious vehicle for skin hydration and enhances dermal delivery of lipophilic and hydrophilic drugs. PMID- 25273391 TI - Anti-adipogenic constituents from Dioscorea opposita in 3T3-L1 cells. AB - We previously reported the lipase inhibitory activity of the n-BuOH fraction of Dioscorea opposita (DOB) and its isolates. This study sought to evaluate their anti-adipogenic activity in terms of their effects on the adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha) as well as phosphorylated AMP-activated protein kinase (p-AMPK) and carnitine palmitoyl transferase-1 (CPT-1). DOB apparently attenuated 3T3-L1 adipocyte differentiation (33.6% decrease at 20 ug/mL). In addition, a marked decrease (90.4%) in the expression of PPARgamma was observed in the DOB-treated 3T3-L1 cells. Four isolates from DOB: (4E,6E)-1,7-bis(4-hydroxyphenyl)-4,6-heptadien-3-one (1), (3R,5R)-1,7-bis(4-hydroxy-3-methoxyphenyl)-3,5-heptanediol (2), batatasin I (3), and (1E,4E,6E)-1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (4), suppressed adipocyte differentiation by inhibiting PPARgamma at 20 uM (85.9%, 68.6%, 76.2%, and 90.2% decrease, respectively) and C/EBPalpha (51.7%, 3.1%, 20.9%, and 59.8% decrease, respectively). Batatasin I was found to increase p-AMPK and CPT-1 at a concentration of 20 uM in 3T3-L1 adipocytes, resulting in inhibiting adipogenesis. Taken together, batatasin I might be responsible for the anti adipogenic effect of DOB via inhibition of PPARgamma and C/EBPalpha and activation of p-AMPK and CPT-1. PMID- 25273392 TI - Discovery of novel adenylyl cyclase inhibitor by cell-based screening. AB - We screened 2400 compounds to find novel inhibitors of the adenylyl cyclase (AC) protein kinase A (PKA)-cAMP response-element-binding protein (CREB) signaling pathway (AC/PKA/CREB pathway). Using a multistep cell-based screening system employing split luciferase technique, we narrowed down the candidates effectively from 2400 chemical compounds and identified a novel AC inhibitor (compound 1). Since dysregulation of the AC/PKA/CREB pathway is known to cause diseases not only in the nervous system but also in other organs, compound 1 is expected to be developed as a medicine for these diseases. PMID- 25273393 TI - Possible involvement of caspases in proliferation of neocortical neural stem/progenitor cells in the developing mouse brain. AB - Caspases are well-known enzymes that work as initiators and effectors of apoptosis. To elucidate the role of caspases in neurodevelopment, we sought to determine if caspases are involved in the proliferation of neural stem/progenitor cells (NPCs) in the developing mouse brain. Labeling with 5-bromo-2'-deoxyuridine (BrdU) from days 14 to 18 of pregnant mice revealed that the 18-d old fetus had many BudU-positive cells in its brain. Double-labeling revealed that active caspase-3 was co-localized with these BrdU-positive cells in the neocortex, hippocampus, and subventricular zone of the fetal brain. Active caspase-3 was detected in cultures of NPCs derived from the neocortex of 15-d old fetuses during culture periods. Importantly, the pan-caspase inhibitor z-VAD-FMK was effective at completely inhibiting neurosphere formation by the NPCs. These results suggest the possibility that the caspase cascade is essential for the proliferation of neocortical NPCs in the developing mouse brain. PMID- 25273394 TI - Multidimensional Poverty and Health Status as a Predictor of Chronic Income Poverty. AB - Longitudinal analysis of Wave 5 to 10 of the nationally representative Household, Income and Labour Dynamics in Australia dataset was undertaken to assess whether multidimensional poverty status can predict chronic income poverty. Of those who were multidimensionally poor (low income plus poor health or poor health and insufficient education attainment) in 2007, and those who were in income poverty only (no other forms of disadvantage) in 2007, a greater proportion of those in multidimensional poverty continued to be in income poverty for the subsequent 5 years through to 2012. People who were multidimensionally poor in 2007 had 2.17 times the odds of being in income poverty each year through to 2012 than those who were in income poverty only in 2005 (95% CI: 1.23-3.83). Multidimensional poverty measures are a useful tool for policymakers to identify target populations for policies aiming to improve equity and reduce chronic disadvantage. PMID- 25273395 TI - Short-term preoperative octreotide treatment for TSH-secreting pituitary adenoma. AB - Preoperative control of hyperthyroidism in patients with TSH-secreting pituitary adenomas (TSHoma) may avoid perioperative thyroid storm. Perioperative administration of octreotide may control hyperthyroidism, as well as shrink tumor size. The effects of preoperative octreotide treatment were assessed in a large number of patients with TSHomas. Of 81 patients who underwent surgery for TSHoma at Toranomon Hospital between January 2001 and May 2013, 44 received preoperative short-term octreotide. After excluding one patient because of side effects, 19 received octreotide as a subcutaneous injection, and 24 as a long-acting release (LAR) injection. Median duration between initiation of octreotide treatment and surgery was 33.5 days. Octreotide normalized free T4 in 36 of 43 patients (84%) and shrank tumors in 23 of 38 (61%). Length of octreotide treatment did not differ significantly in patients with and without hormonal normalization (p=0.09) and with and without tumor shrinkage (p=0.84). Serum TSH and free T4 concentrations, duration of treatment, incidence of growth hormone (GH) co secretion, results of octreotide loading tests, form of administration (subcutaneous injection or LAR), tumor volume, and tumor consistency did not differ significantly in patients with and without hormonal normalization and with and without tumor shrinkage. Short-term preoperative octreotide administration was highly effective for TSHoma shrinkage and normalization of excess hormone concentrations, with tolerable side effects. PMID- 25273396 TI - Induction of thyroid remission using rituximab in a patient with type 3 autoimmune polyglandular syndrome including Graves' disease and type 1 diabetes mellitus: a case report. AB - Rituximab (RTX) is a monoclonal antibody that targets the B-cell-specific CD20 antigen. Recent reports indicate that RTX is effective against type 1 diabetes mellitus (T1DM) and hematologic as well as autoimmune diseases. Other studies have indicated that RTX therapy leads to the remission of recurrent or active Graves' disease (GD). However, the efficacy of RTX in Japanese patients with autoimmune polyglandular syndrome (APS) has not been reported to date. Herein, we report the case of a patient with GD and T1DM with sustained endogenous insulin secretion capacity. To protect pancreatic beta cells, we administered RTX at a dose of 500 mg (approximately 300 mg/m2) on 2 occasions 1 week apart. After treatment, no adverse effects were observed, and thyroid stimulating hormone receptor antibody (TRAb) was no longer detectable 4 months after RTX administration. In addition, the reduction in TRAb level improved thyroid function. Notably, the treatment induced remission over a period of 1 year after the diagnosis of GD. PMID- 25273397 TI - Generation and characterization of MafA-Kusabira Orange mice. AB - MafA and MafB are basic leucine zipper transcription factors expressed in mature pancreatic beta- and alpha-cells, respectively. MafA is not only an insulin gene transcription factor but is also critical for the maturation and maintenance of beta-cell function, whereas MafB is expressed in immature beta-cells during development and in compromised beta-cells in diabetes. In this study, we developed a mouse model to easily trace the promoter activity of MafA in beta cells as a tool for studying beta-cell differentiation, maturation, regeneration and function using the expression of the fluorescent protein Kusabira Orange (KOr) driven by the BAC-mafA promoter. The expression of KOr was highly restricted to beta-cells in the transgenic pancreas. By crossing MafA-KOr mice with MafB(GFP/+) reporter mice, simultaneous monitoring of MafA and MafB expressions in the isolated islets was successfully performed. This system can be a useful tool for examining dynamic changes in the differentiation and function of pancreatic islets by visualizing the expressions of MafA and MafB. PMID- 25273398 TI - Inaugural Christianson Syndrome Association conference: families meeting for the first time. AB - Christianson syndrome (CS) is an X-linked neurodevelopmental disorder caused by deleterious mutations in SLC9A6. Affected families organized the inaugural Christianson Syndrome Association conference to advance CS knowledge and develop questions that may be prioritized in future research. PMID- 25273401 TI - Communication: Thermodynamics of stacking disorder in ice nuclei. AB - A simple Ising-like model for the stacking thermodynamics of ice 1 is constructed for nuclei in supercooled water, and combined with classical nucleation theory. For relative stabilities of cubic and hexagonal ice I within the range of experimental estimates, this predicts critical nuclei are stacking disordered at strong sub-cooling, consistent with recent experiments. At higher temperatures nucleation of pure hexagonal ice is recovered. Lattice-switching Monte-Carlo is applied to accurately compute the relative stability of cubic and hexagonal ice for the popular mW model of water. Results demonstrate that this model fails to adequately capture the relative energetics of the two polytypes, leading to stacking disorder at all temperatures. PMID- 25273402 TI - Communication: Charge-transfer rate constants in zinc-porphyrin-porphyrin-derived dyads: a Fermi golden rule first-principles-based study. AB - We investigate photoinduced charge transfer (CT) processes within dyads consisting of porphyrin derivatives in which one ring ligates a Zn metal center and where the rings vary by their degree of conjugation. Using a first-principles approach, we show that molecular-scale means can tune CT rates through stabilization affected by the polar environment. Such means of CT tuning are important for achieving high efficiency optoelectronic applications using organic semiconducting materials. Our fully quantum mechanical scheme is necessary for reliably modeling the CT process across different regimes, in contrast to the pervading semi-classical Marcus picture that grossly underestimates transfer in the far-inverted regime. PMID- 25273400 TI - Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3. AB - BACKGROUND: Pituitary dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian wolfdogs. OBJECTIVES: To investigate whether Saarloos and Czechoslovakian wolfdog dwarfs have the same LHX3 mutation as do Germans Shepherd Dog dwarfs. A specific aim was to determine the carrier frequency among Saarloos and Czechoslovakian wolfdogs used for breeding. ANIMALS: Two client-owned Saarloos wolfdogs and 4 client-owned Czechoslovakian wolfdogs with pituitary dwarfism, 239 clinically healthy client owned Saarloos wolfdogs, and 200 client-owned clinically healthy Czechoslovakian wolfdogs. METHODS: Genomic DNA was amplified using polymerase chain reaction (PCR). In the Saarloos and Czechoslovakian wolfdog dwarfs, PCR products were analyzed by sequencing. DNA fragment length analysis was performed on the samples from the clinically healthy dogs. RESULTS: Saarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs. The frequency of carriers of this mutation among clinically healthy Saarloos and Czechoslovakian wolfdogs used for breeding was 31% and 21%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: An LHX3 mutation is associated with pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs. The rather high frequency of carriers of the mutated gene in the 2 breeds emphasizes the need for screening before breeding. If all breeding animals were genetically tested for the presence of the LHX3 mutation and a correct breeding policy would be implemented, this disease could be eradicated completely. PMID- 25273399 TI - Comparative analysis of the Geobacillus hemicellulose utilization locus reveals a highly variable target for improved hemicellulolysis. AB - BACKGROUND: Members of the thermophilic genus Geobacillus can grow at high temperatures and produce a battery of thermostable hemicellulose hydrolytic enzymes, making them ideal candidates for the bioconversion of biomass to value added products. To date the molecular determinants for hemicellulose degradation and utilization have only been identified and partially characterized in one strain, namely Geobacillus stearothermophilus T-6, where they are clustered in a single genetic locus. RESULTS: Using the G. stearothermophilus T-6 hemicellulose utilization locus as genetic marker, orthologous hemicellulose utilization (HUS) loci were identified in the complete and partial genomes of 17/24 Geobacillus strains. These HUS loci are localized on a common genomic island. Comparative analyses of these loci revealed extensive variability among the Geobacillus hemicellulose utilization systems, with only seven out of 41-68 proteins encoded on these loci conserved among the HUS+ strains. This translates into extensive differences in the hydrolytic enzymes, transport systems and metabolic pathways employed by Geobacillus spp. to degrade and utilize hemicellulose polymers. CONCLUSIONS: The genetic variability among the Geobacillus HUS loci implies that they have variable capacities to degrade hemicellulose polymers, or that they may degrade distinct polymers, as are found in different plant species and tissues. The data from this study can serve as a basis for the genetic engineering of a Geobacillus strain(s) with an improved capacity to degrade and utilize hemicellulose. PMID- 25273403 TI - Communication: Molecular-level insights into asymmetric triblock copolymers: network and phase development. AB - Molecularly asymmetric triblock copolymers progressively grown from a parent diblock copolymer can be used to elucidate the phase and property transformation from diblock to network-forming triblock copolymer. In this study, we use several theoretical formalisms and simulation methods to examine the molecular-level characteristics accompanying this transformation, and show that reported macroscopic-level transitions correspond to the onset of an equilibrium network. Midblock conformational fractions and copolymer morphologies are provided as functions of copolymer composition and temperature. PMID- 25273404 TI - Communication: Newton homotopies for sampling stationary points of potential energy landscapes. AB - One of the most challenging and frequently arising problems in many areas of science is to find solutions of a system of multivariate nonlinear equations. There are several numerical methods that can find many (or all if the system is small enough) solutions but they all exhibit characteristic problems. Moreover, traditional methods can break down if the system contains singular solutions. Here, we propose an efficient implementation of Newton homotopies, which can sample a large number of the stationary points of complicated many-body potentials. We demonstrate how the procedure works by applying it to the nearest neighbor phi(4) model and atomic clusters. PMID- 25273405 TI - Communication: Two-step explosion processes of highly charged fullerene cations C60(q+) (q = 20-60). AB - To establish the fundamental understanding of the fragmentation dynamics of highly positive charged nano- and bio-materials, we carried out on-the-fly classical trajectory calculations on the fragmentation dynamics of C60(q+) (q = 20-60). We used the UB3LYP/3-21G level of density functional theory and the self consistent charge density-functional based tight-binding theory. For q >= 20, we found that a two-step explosion mechanism governs the fragmentation dynamics: C60(q+) first ejects singly and multiply charged fast atomic cations C(z+) (z >= 1) via Coulomb explosions on a timescale of 10 fs to stabilize the remaining core cluster. Thermal evaporations of slow atomic and molecular fragments from the core cluster subsequently occur on a timescale of 100 fs to 1 ps. Increasing the charge q makes the fragments smaller. This two-step mechanism governs the fragmentation dynamics in the most likely case that the initial kinetic energy accumulated upon ionization to C60(q+) by ion impact or X-ray free electron laser is larger than 100 eV. PMID- 25273406 TI - Generalized trajectory surface-hopping method for internal conversion and intersystem crossing. AB - Trajectory-based fewest-switches surface-hopping (FSSH) dynamics simulations have become a popular and reliable theoretical tool to simulate nonadiabatic photophysical and photochemical processes. Most available FSSH methods model internal conversion. We present a generalized trajectory surface-hopping (GTSH) method for simulating both internal conversion and intersystem crossing processes on an equal footing. We consider hops between adiabatic eigenstates of the non relativistic electronic Hamiltonian (pure spin states), which is appropriate for sufficiently small spin-orbit coupling. This choice allows us to make maximum use of existing electronic structure programs and to minimize the changes to available implementations of the traditional FSSH method. The GTSH method is formulated within the quantum mechanics (QM)/molecular mechanics framework, but can of course also be applied at the pure QM level. The algorithm implemented in the GTSH code is specified step by step. As an initial GTSH application, we report simulations of the nonadiabatic processes in the lowest four electronic states (S0, S1, T1, and T2) of acrolein both in vacuo and in acetonitrile solution, in which the acrolein molecule is treated at the ab initio complete active-space self-consistent-field level. These dynamics simulations provide detailed mechanistic insight by identifying and characterizing two nonadiabatic routes to the lowest triplet state, namely, direct S1 -> T1 hopping as major pathway and sequential S1 -> T2 -> T1 hopping as minor pathway, with the T2 state acting as a relay state. They illustrate the potential of the GTSH approach to explore photoinduced processes in complex systems, in which intersystem crossing plays an important role. PMID- 25273407 TI - Nonlinear coupled equations for electrochemical cells as developed by the general equation for nonequilibrium reversible-irreversible coupling. AB - We show how the Butler-Volmer and Nernst equations, as well as Peltier effects, are contained in the general equation for nonequilibrium reversible and irreversible coupling, GENERIC, with a unique definition of the overpotential. Linear flux-force relations are used to describe the transport in the homogeneous parts of the electrochemical system. For the electrode interface, we choose nonlinear flux-force relationships. We give the general thermodynamic basis for an example cell with oxygen electrodes and electrolyte from the solid oxide fuel cell. In the example cell, there are two activated chemical steps coupled also to thermal driving forces at the surface. The equilibrium exchange current density obtains contributions from both rate-limiting steps. The measured overpotential is identified at constant temperature and stationary states, in terms of the difference in electrochemical potential of products and reactants. Away from these conditions, new terms appear. The accompanying energy flux out of the surface, as well as the heat generation at the surface are formulated, adding to the general thermodynamic basis. PMID- 25273408 TI - Path induced coherent energy transfer in light-harvesting complexes in purple bacteria. AB - Features of path dependent energy transfer in a dual-ring light-harvesting (LH2) complexes (B850) system have been examined in detail systematically. The Frenkel Dirac time dependent variational method with the Davydov D1 Ansatz is employed with detailed evolution of polaron dynamics in real space readily obtained. It is found that the phase of the transmission amplitude through the LH2 complexes plays an important role in constructing the coherent excitonic energy transfer. It is also found that the symmetry breaking caused by the dimerization of bacteriochlorophylls and coherence or correlation between two rings will be conducive in enhancing the exciton transfer efficiency. PMID- 25273409 TI - Excitation energies from particle-particle random phase approximation: Davidson algorithm and benchmark studies. AB - The particle-particle random phase approximation (pp-RPA) has been used to investigate excitation problems in our recent paper [Y. Yang, H. van Aggelen, and W. Yang, J. Chem. Phys. 139, 224105 (2013)]. It has been shown to be capable of describing double, Rydberg, and charge transfer excitations, which are challenging for conventional time-dependent density functional theory (TDDFT). However, its performance on larger molecules is unknown as a result of its expensive O(N(6)) scaling. In this article, we derive and implement a Davidson iterative algorithm for the pp-RPA to calculate the lowest few excitations for large systems. The formal scaling is reduced to O(N(4)), which is comparable with the commonly used configuration interaction singles (CIS) and TDDFT methods. With this iterative algorithm, we carried out benchmark tests on molecules that are significantly larger than the molecules in our previous paper with a reasonably large basis set. Despite some self-consistent field convergence problems with ground state calculations of (N - 2)-electron systems, we are able to accurately capture lowest few excitations for systems with converged calculations. Compared to CIS and TDDFT, there is no systematic bias for the pp-RPA with the mean signed error close to zero. The mean absolute error of pp-RPA with B3LYP or PBE references is similar to that of TDDFT, which suggests that the pp-RPA is a comparable method to TDDFT for large molecules. Moreover, excitations with relatively large non-HOMO excitation contributions are also well described in terms of excitation energies, as long as there is also a relatively large HOMO excitation contribution. These findings, in conjunction with the capability of pp RPA for describing challenging excitations shown earlier, further demonstrate the potential of pp-RPA as a reliable and general method to describe excitations, and to be a good alternative to TDDFT methods. PMID- 25273410 TI - Diffusion on a rugged energy landscape with spatial correlations. AB - Rugged energy landscapes find wide applications in diverse fields ranging from astrophysics to protein folding. We study the dependence of diffusion coefficient (D) of a Brownian particle on the distribution width (E) of randomness in a Gaussian random landscape by simulations and theoretical analysis. We first show that the elegant expression of Zwanzig [Proc. Natl. Acad. Sci. U.S.A. 85, 2029 (1988)] for D(E) can be reproduced exactly by using the Rosenfeld diffusion entropy scaling relation. Our simulations show that Zwanzig's expression overestimates D in an uncorrelated Gaussian random lattice - differing by almost an order of magnitude at moderately high ruggedness. The disparity originates from the presence of "three-site traps" (TST) on the landscape - which are formed by the presence of deep minima flanked by high barriers on either side. Using mean first passage time formalism, we derive a general expression for the effective diffusion coefficient in the presence of TST, that quantitatively reproduces the simulation results and which reduces to Zwanzig's form only in the limit of infinite spatial correlation. We construct a continuous Gaussian field with inherent correlation to establish the effect of spatial correlation on random walk. The presence of TSTs at large ruggedness (E ? k(B)T) gives rise to an apparent breakdown of ergodicity of the type often encountered in glassy liquids. PMID- 25273411 TI - Nanoscale Turing structures. AB - Formation of Turing patterns of nanoscopic length scale is simulated using molecular dynamics. Based on Fourier spectra of the concentrations of species, we compare stabilities of the structures of different wavelengths and for different intermolecular potentials. Long range attraction is shown to oppose the formation of structures. Our simulations suggest that Turing patterns can be a method of self-organization at a length scale of down to 20 molecular diameters. PMID- 25273412 TI - Improving long time behavior of Poisson bracket mapping equation: a mapping variable scaling approach. AB - Semiclassical approaches are widely employed for understanding nonadiabatic processes in complex systems. However, many semiclassical approaches may suffer from various unphysical behaviors especially in the long time limit. For example, the Poisson bracket mapping equation (PBME), an example of semiclassical approaches that can be usefully adopted in simulating large systems, sometimes displays negative populations in long simulations. Here, to reduce the error in such population dynamics, we present a mapping variable scaling approach for PBME. We demonstrate that our approach yields the equilibrium population reliably in the long time limit by simulating energy transfers in a series of model systems. Based on error analyses of the system density matrices, we determine conditions for reliable dynamics in model two-state systems. We then apply our scheme to following the energy transfer dynamics in a more realistic seven state model with parameters that reflect experimental situations. With this, we confirm that the modified PBME provides correct equilibrium populations in the long time limit, with acceptable deterioration in the short time dynamics. We also test how the initial bath energy distribution changes in time depending on the schemes of sampling the initial bath modes, and try to see its effect on the system dynamics. Finally, we discuss the applicability of our scaling scheme to all-atom style semiclassical simulations of complex systems. PMID- 25273413 TI - Derivation of general analytic gradient expressions for density-fitted post Hartree-Fock methods: an efficient implementation for the density-fitted second order Moller-Plesset perturbation theory. AB - General analytic gradient expressions (with the frozen-core approximation) are presented for density-fitted post-HF methods. An efficient implementation of frozen-core analytic gradients for the second-order Moller-Plesset perturbation theory (MP2) with the density-fitting (DF) approximation (applying to both reference and correlation energies), which is denoted as DF-MP2, is reported. The DF-MP2 method is applied to a set of alkanes, conjugated dienes, and noncovalent interaction complexes to compare the computational cost of single point analytic gradients with MP2 with the resolution of the identity approach (RI-MP2) [F. Weigend and M. Haser, Theor. Chem. Acc. 97, 331 (1997); R. A. Distasio, R. P. Steele, Y. M. Rhee, Y. Shao, and M. Head-Gordon, J. Comput. Chem. 28, 839 (2007)]. In the RI-MP2 method, the DF approach is used only for the correlation energy. Our results demonstrate that the DF-MP2 method substantially accelerate the RI-MP2 method for analytic gradient computations due to the reduced input/output (I/O) time. Because in the DF-MP2 method the DF approach is used for both reference and correlation energies, the storage of 4-index electron repulsion integrals (ERIs) are avoided, 3-index ERI tensors are employed instead. Further, as in case of integrals, our gradient equation is completely avoid construction or storage of the 4-index two-particle density matrix (TPDM), instead we use 2- and 3-index TPDMs. Hence, the I/O bottleneck of a gradient computation is significantly overcome. Therefore, the cost of the generalized Fock matrix (GFM), TPDM, solution of Z-vector equations, the back transformation of TPDM, and integral derivatives are substantially reduced when the DF approach is used for the entire energy expression. Further application results show that the DF approach introduce negligible errors for closed-shell reaction energies and equilibrium bond lengths. PMID- 25273414 TI - Transition properties from the Hermitian formulation of the coupled cluster polarization propagator. AB - Theory of one-electron transition density matrices has been formulated within the time-independent coupled cluster method for the polarization propagator [R. Moszynski, P. S. Zuchowski, and B. Jeziorski, Coll. Czech. Chem. Commun. 70, 1109 (2005)]. Working expressions have been obtained and implemented with the coupled cluster method limited to single, double, and linear triple excitations (CC3). Selected dipole and quadrupole transition probabilities of the alkali earth atoms, computed with the new transition density matrices are compared to the experimental data. Good agreement between theory and experiment is found. The results obtained with the new approach are of the same quality as the results obtained with the linear response coupled cluster theory. The one-electron density matrices for the ground state in the CC3 approximation have also been implemented. The dipole moments for a few representative diatomic molecules have been computed with several variants of the new approach, and the results are discussed to choose the approximation with the best balance between the accuracy and computational efficiency. PMID- 25273415 TI - Fast optimization of binary clusters using a novel dynamic lattice searching method. AB - Global optimization of binary clusters has been a difficult task despite of much effort and many efficient methods. Directing toward two types of elements (i.e., homotop problem) in binary clusters, two classes of virtual dynamic lattices are constructed and a modified dynamic lattice searching (DLS) method, i.e., binary DLS (BDLS) method, is developed. However, it was found that the BDLS can only be utilized for the optimization of binary clusters with small sizes because homotop problem is hard to be solved without atomic exchange operation. Therefore, the iterated local search (ILS) method is adopted to solve homotop problem and an efficient method based on the BDLS method and ILS, named as BDLS-ILS, is presented for global optimization of binary clusters. In order to assess the efficiency of the proposed method, binary Lennard-Jones clusters with up to 100 atoms are investigated. Results show that the method is proved to be efficient. Furthermore, the BDLS-ILS method is also adopted to study the geometrical structures of (AuPd)79 clusters with DFT-fit parameters of Gupta potential. PMID- 25273416 TI - A new dipolar potential for numerical simulations of polar fluids on the 4D hypersphere. AB - We present a new method for Monte Carlo or Molecular Dynamics numerical simulations of three-dimensional polar fluids. The simulation cell is defined to be the surface of the northern hemisphere of a four-dimensional (hyper)sphere. The point dipoles are constrained to remain tangent to the sphere and their interactions are derived from the basic laws of electrostatics in this geometry. The dipole-dipole potential has two singularities which correspond to the following boundary conditions: when a dipole leaves the northern hemisphere at some point of the equator, it reappears at the antipodal point bearing the same dipole moment. We derive all the formal expressions needed to obtain the thermodynamic and structural properties of a polar liquid at thermal equilibrium in actual numerical simulation. We notably establish the expression of the static dielectric constant of the fluid as well as the behavior of the pair correlation at large distances. We report and discuss the results of extensive numerical Monte Carlo simulations for two reference states of a fluid of dipolar hard spheres and compare these results with previous methods with a special emphasis on finite size effects. PMID- 25273417 TI - Driven translocation of a polymer: role of pore friction and crowding. AB - Force-driven translocation of a macromolecule through a nanopore is investigated systematically by taking into account the monomer-pore friction as well as the "crowding" of monomers on the trans-side of the membrane which counterbalance the driving force acting in the pore. The problem is treated self-consistently, so that the resulting force in the pore and the dynamics on the cis and trans sides mutually influence each other. The set of governing differential-algebraic equations for the translocation dynamics is derived and solved numerically. The analysis of this solution shows that the crowding of monomers on the trans side hardly affects the dynamics, but the monomer-pore friction can substantially slow down the translocation process. Moreover, the translocation exponent alpha in the translocation time-vs.-chain length scaling law, tau ? N(alpha), becomes smaller for relatively small chain lengths as the monomer-pore friction coefficient increases. This is most noticeable for relatively strong forces. Our findings show that the variety of values for alpha reported in experiments and computer simulations, may be attributed to different pore frictions, whereas crowding effects can generally be neglected. PMID- 25273418 TI - Most spin-1/2 transition-metal ions do have single ion anisotropy. AB - The cause for the preferred spin orientation in magnetic systems containing spin 1/2 transition-metal ions was explored by studying the origin of the easy-plane anisotropy of the spin-1/2 Cu(2+) ions in CuCl2.2H2O, LiCuVO4, CuCl2, and CuBr2 on the basis of density functional theory and magnetic dipole-dipole energy calculations as well as a perturbation theory treatment of the spin-orbit coupling. We find that the spin orientation observed for these spin-1/2 ions is not caused by their anisotropic spin exchange interactions, nor by their magnetic dipole-dipole interactions, but by the spin-orbit coupling associated with their crystal-field split d-states. Our study also predicts in-plane anisotropy for the Cu(2+) ions of Bi2CuO4 and Li2CuO2. The results of our investigations dispel the mistaken belief that magnetic systems with spin-1/2 ions have no magnetic anisotropy induced by spin-orbit coupling. PMID- 25273419 TI - Robust and efficient variational fitting of Fock exchange. AB - We propose a new variational fitting approach for Fock exchange that requires only the calculation of analytical three-center electron repulsion integrals. It relies on localized molecular orbitals and Hermite Gaussian auxiliary functions. The working equations along with a detailed description of the implementation are presented. The computational performance of the new algorithm is analyzed by benchmark calculations on systems with different dimensionality. Comparison with standard four-center and three-center electron repulsion integral Hartree-Fock calculations shows an excellent accuracy-performance relation. PMID- 25273420 TI - On combining temperature and pressure effects on structural properties of crystals with standard ab initio techniques. AB - A general-purpose, fully automated, computationally efficient implementation is presented of a series of techniques for the simultaneous description of pressure and temperature effects on structural properties of materials, by means of standard ab initio simulations. Equilibrium volume, bulk modulus, thermal expansion coefficient, equation-of-state, Gruneisen parameter, constant-pressure and constant-volume specific heats are computed as a function of temperature and pressure for the simple crystal of diamond and compared with accurate experimental data. Convergence of computed properties with respect to super-cell size is critically discussed. The effect on such properties of the adopted exchange-correlation functional of the density-functional-theory is discussed by considering three different levels of approximation (including hybrids): it is found to be rather small for the temperature dependence of equilibrium volume and bulk modulus, whereas it is quite large as regards their absolute values. PMID- 25273422 TI - Extensions of the interfacial pinning method and application to hard core systems. AB - The precise estimation of the location of phase transitions is an essential task in the study of many condensed matter systems. A recently developed technique denoted interface pinning (IP) [U. R. Pedersen, F. Hummel, G. Kresse, G. Kahl, and C. Dellago, Phys. Rev. B. 88, 094101 (2013); U. R. Pedersen, J. Chem. Phys. 139, 104102 (2013)] can accurately estimate the location of fluid-solid transition using the NP(z)T ensemble for single-component systems by computing the free energy difference between a solid and a fluid. The IP method is extended here to be applicable to different ensembles for both single-component systems and binary mixtures. A more general scheme is also proposed for the extrapolation of properties targeting coexistence conditions. This framework is used to estimate the coexistence pressure for the isotropic-rotator phase transition for three single-component polyhedral systems and to estimate isotropic-crystal coexistence compositions for a binary mixture of hard cubes and spheres. In addition, by exploring various choices for the order parameter used to distinguish between the isotropic and ordered phases, it is found that volume provides a reasonable alternative to translational order parameters which can be either more expensive to calculate or unable to pin a two-phase interfacial state. PMID- 25273421 TI - Restricted active space calculations of L-edge X-ray absorption spectra: from molecular orbitals to multiplet states. AB - The metal L-edge (2p -> 3d) X-ray absorption spectra are affected by a number of different interactions: electron-electron repulsion, spin-orbit coupling, and charge transfer between metal and ligands, which makes the simulation of spectra challenging. The core restricted active space (RAS) method is an accurate and flexible approach that can be used to calculate X-ray spectra of a wide range of medium-sized systems without any symmetry constraints. Here, the applicability of the method is tested in detail by simulating three ferric (3d(5)) model systems with well-known electronic structure, viz., atomic Fe(3+), high-spin [FeCl6](3-) with ligand donor bonding, and low-spin [Fe(CN)6](3-) that also has metal backbonding. For these systems, the performance of the core RAS method, which does not require any system-dependent parameters, is comparable to that of the commonly used semi-empirical charge-transfer multiplet model. It handles orbitally degenerate ground states, accurately describes metal-ligand interactions, and includes both single and multiple excitations. The results are sensitive to the choice of orbitals in the active space and this sensitivity can be used to assign spectral features. A method has also been developed to analyze the calculated X-ray spectra using a chemically intuitive molecular orbital picture. PMID- 25273423 TI - Approaching exact hyperpolarizabilities via sum-over-states Monte Carlo configuration interaction. AB - We propose using sum-over-states calculations with the compact wavefunctions of Monte Carlo configuration interaction to approach accurate values for higher order dipole properties up to second hyperpolarizabilities in a controlled way. We apply the approach to small systems that can generally be compared with full configuration interaction (FCI) results. We consider hydrogen fluoride with a 6 31g basis and then look at results, including frequency dependent properties, in an aug-cc-pVDZ basis. We extend one calculation beyond FCI by using an aug-cc pVTZ basis. The properties of an H4 molecule with multireference character are calculated in an aug-cc-pVDZ basis. We then investigate this method on a strongly multireference system with a larger FCI space by modelling the properties of carbon monoxide with a stretched geometry. The behavior of the approach with increasing basis size is considered by calculating results for the neon atom using aug-cc-pVDZ to aug-cc-pVQZ. We finally test if the unusual change in polarizability between the first two states of molecular oxygen can be reproduced by this method in a 6-31g basis. PMID- 25273425 TI - Local-hybrid functional based on the correlation length. AB - Local-hybrid functionals involve position-dependent mixing of Hartree-Fock and density-functional exchange, which should allow improved performance relative to conventional hybrids by reducing the inherent delocalization error and improving the long-range behaviour. Herein, the same-spin correlation length, obtained from the Fermi-hole radius, is used as the mixing parameter. The performance of the resulting local-hybrid functional is assessed for standard thermochemical and kinetics benchmarks. The local hybrid is shown to perform significantly better than the corresponding global hybrid in almost all cases. PMID- 25273424 TI - IETS and quantum interference: propensity rules in the presence of an interference feature. AB - Destructive quantum interference in single molecule electronics is an intriguing phenomenon; however, distinguishing quantum interference effects from generically low transmission is not trivial. In this paper, we discuss how quantum interference effects in the transmission lead to either low current or a particular line shape in current-voltage curves, depending on the position of the interference feature. Second, we consider how inelastic electron tunneling spectroscopy can be used to probe the presence of an interference feature by identifying vibrational modes that are selectively suppressed when quantum interference effects dominate. That is, we expand the understanding of propensity rules in inelastic electron tunneling spectroscopy to molecules with destructive quantum interference. PMID- 25273426 TI - Surface plasmon modes of a nanoegg above a substrate. AB - An analytical approach describing the surface plasmon modes of a nanoegg (a nanoshell with a nonconcentric core) above a substrate is presented. The bispherical coordinate system is used for mathematical convenience. A general dispersion relation for the coupled modes as function of geometrical characteristics of the system is obtained. In the special case (in the limit of a very large separation between the nanoegg and substrate) dispersion relation of the plasmon modes of an isolated nanoegg is derived. It is shown that the coupled plasmon modes exhibit excellent numerical convergence. PMID- 25273428 TI - Description of electron transfer in the ground and excited states of organic donor-acceptor systems by single-reference and multi-reference density functional methods. AB - Electron transfer in the ground and excited states of a model donor-acceptor (D A) system is investigated using the single-reference and multi-reference density functional theory (DFT) methods. To analyze the results of the calculations, a simple two-site multi-reference model was derived that predicts a stepwise electron transfer in the S0 state and a wave-like dependence of the S1 electron transfer on the external stimulus. The standard single-reference Kohn-Sham (KS) DFT approach and the time-dependent DFT (TDDFT) method failed to describe the correct dependence of the S0 and S1 electron transfer on the external electric field applied along the donor-acceptor system. The multi-reference DFT approach, the spin-restricted ensemble-referenced KS (REKS) method, was able to successfully reproduce the correct behavior of the S0 and S1 electron transfer on the applied field. The REKS method was benchmarked against experimentally measured gas phase charge transfer excitations in a series of organic donor acceptor complexes and displayed its ability to describe this type of electronic transitions with a very high accuracy, mean absolute error of 0.05 eV with the use of the standard range separated density functionals. On the basis of the calculations undertaken in this work, it is suggested that the non-adiabatic coupling between the S0 and S1 states may interfere with the electron transfer in a weakly coupled donor-acceptor system. It is also suggested that the electronic excitation of a D(+)-A(-) system may play a dual role by assisting the further electron transfer at certain magnitudes of the applied electric field and causing the backward transfer at lower electric field strengths. PMID- 25273429 TI - Theoretical approach for optical response in electrochemical systems: application to electrode potential dependence of surface-enhanced Raman scattering. AB - We propose a theoretical approach for optical response in electrochemical systems. The fundamental equation to be solved is based on a time-dependent density functional theory in real-time and real-space in combination with its finite temperature formula treating an electrode potential. Solvation effects are evaluated by a dielectric continuum theory. The approach allows us to treat optical response in electrochemical systems at the atomistic level of theory. We have applied the method to surface-enhanced Raman scattering (SERS) of 4 mercaptopyridine on an Ag electrode surface. It is shown that the SERS intensity has a peak as a function of the electrode potential. Furthermore, the real-space computational approach facilitates visualization of variation of the SERS intensity depending on an electrode potential. PMID- 25273427 TI - Assessment of approximate computational methods for conical intersections and branching plane vectors in organic molecules. AB - Quantum-chemical computational methods are benchmarked for their ability to describe conical intersections in a series of organic molecules and models of biological chromophores. Reference results for the geometries, relative energies, and branching planes of conical intersections are obtained using ab initio multireference configuration interaction with single and double excitations (MRCISD). They are compared with the results from more approximate methods, namely, the state-interaction state-averaged restricted ensemble-referenced Kohn Sham method, spin-flip time-dependent density functional theory, and a semiempirical MRCISD approach using an orthogonalization-corrected model. It is demonstrated that these approximate methods reproduce the ab initio reference data very well, with root-mean-square deviations in the optimized geometries of the order of 0.1 A or less and with reasonable agreement in the computed relative energies. A detailed analysis of the branching plane vectors shows that all currently applied methods yield similar nuclear displacements for escaping the strong non-adiabatic coupling region near the conical intersections. Our comparisons support the use of the tested quantum-chemical methods for modeling the photochemistry of large organic and biological systems. PMID- 25273430 TI - Thermodynamics, compressibility, and phase diagram: shock compression of supercritical fluid xenon. AB - Supercritical fluids have intriguing behaviors at extreme pressure and temperature conditions, prompting the need for thermodynamic properties of supercritical fluid xenon (SCF) under shock compression. Double-shock experimental data on SCF xenon in the 140 GPa pressure range were directly measured by means of a multi-channel pyrometer and a Doppler-pins-system. It entered the so-called warm dense region. We found that the shock compressed SCF Xe had higher dynamic compression and higher number density than that of liquid Xe at same shock pressure. The larger compressibility of SCF Xe in our experiments could be explained that the increase of electronic excitations and ionizations leaded to a large drop of thermal pressure and a softening of Hugoniot. The high pressure phase diagram of xenon was depicted with the aid of the degeneracy, coupling parameter, and current available experiments on the pressure-temperature plane. PMID- 25273431 TI - Double aromaticity in transition metal centered double-ring boron clusters M@B2n (M = Ti, Cr, Fe, Ni, Zn; n = 6, 7, 8). AB - It is well known that double-ring boron clusters have got the special double aromaticity with delocalized pi orbitals in two directions (tangential and radial), which are potential ligands centered by a transition metal. In this article, the transition metal centered double-ring boron clusters M@B2n (M = Ti, Cr, Fe, Ni, Zn; n = 6, 7, 8) are theoretically investigated by density functional theory calculations. These endohedral compounds have also got double aromaticity in both tangential and radial directions. Interestingly, the tangential delocalized pi orbitals of boron ligands following the Huckle's (4n + 2) rule do not interact with the central metal, while the radial pi orbitals of boron ligands are bonded with the central mental to form spd-pi endohedral bonding. The spd-pi endohedral bonding follows the 18e-principle in Ni@B14 and Fe@B16. However, due to the flat shape of the compounds, 14e (Cr@B14) and 16e (Ni@B12) can also be electronically very stable where the energy levels of the spd-pi orbitals delocalized in z-direction rise up. This intriguing bonding model makes sense in further study of the boron chemistry. PMID- 25273432 TI - Elastic differential cross sections for C4F6 isomers in the 1.5-200 eV energy electron impact: similarities with six fluorine containing molecules and evidence of F-atom like scattering. AB - We report absolute elastic differential cross sections for electron interactions with the C4F6 isomers, hexafluoro-1,3-butadiene (1,3-C4F6), hexafluoro-2-butyne (2-C4F6), and hexafluorocyclobutene (c-C4F6). The incident electron energy range is 1.5-200 eV, and the scattered electron angular range for the differential measurements varies from 15 degrees to 150 degrees . In all cases the absolute scale of the differential cross section was set using the relative flow technique, with helium as the reference species. Atomic-like behaviour in these scattering systems is shown here for the first time, and is further investigated by comparing the elastic cross sections for the C4F6 isomers with other fluorinated molecules, such as SF6 and CnF6 (n = 2, 3, and 6). We note that for all the six-F containing molecules, the scattering process for electron energies above 30 eV is indistinguishable. Finally, we report results for calculations of elastic differential cross sections for electron scattering from each of these isomers, within an optical potential method and assuming a screened corrected independent atom representation. The level of agreement between these calculations and our measurements is found to be quite remarkable in all cases. PMID- 25273433 TI - Free base tetraazaporphine isolated in inert gas hosts: matrix influence on its spectroscopic and photochemical properties. AB - The absorption, fluorescence, and excitation spectra of free base tetraazaporphine (H2TAP) trapped in Ne, N2, and Ar matrices have been recorded at cryogenic temperatures. Normal Raman spectra of H2TAP were recorded in KBr discs and predicted with density functional theory (DFT) using large basis sets calculations. The vibrational frequencies observed in the Raman Spectrum exhibit reasonable agreement with those deduced from the emission spectra, as well as with frequencies predicted from large basis set DFT computations. The upper state vibrational frequencies, obtained from highly resolved, site selected excitation spectra, are consistently lower than the ground state frequencies. This contrasts with the situation in free base phthalocyanine, where the upper state shows little changes in vibrational frequencies and geometry when compared with the ground state. Investigations of the photochemical properties of H2TAP isolated in the three matrices have been performed using the method of persistent spectral hole-burning (PSHB). This technique has been used to reveal sites corresponding to distinct N-H tautomers which were not evident in the absorption spectra. An analysis of the holes and antiholes produced with PSHB in the Qx (0-0) absorption band made it possible to identify inter-conversion of distinct host sites. PMID- 25273434 TI - Influence of Duschinsky and Herzberg-Teller effects on S0-> S1 vibrationally resolved absorption spectra of several porphyrin-like compounds. AB - The S0 -> S1 (Q band) high-resolved absorption spectra of three porphyrin-like compounds, porphycene, magnesium porphyrin, and zinc tetraazaporphyrin, were simulated in the framework of the Franck-Condon approximation including the Duschinsky and Herzberg-Teller (HT) contributions. Substitution of meso-aza on porphyrin macrocycle framework could change severely the absorption energy, vibrational intensity, and spectral profile of Q band. Therefore, we focused attention on the spectral similarities and contrasts among the three compounds based on the density functional theory and its time-dependent extension calculations. The simulated spectra agreed well with the experimental ones and further confirmed that the HT and Duschinsky effects have significant influence on the weakly allowed or forbidden transition of sizable organic molecules. The pure HT and Duschinsky effects were explored separately to clarify their contributions on changing vibrational intensities of different modes. Moreover, we tentatively assigned most of the vibrational modes which appeared in the experimental spectra but corresponding assignments were not given. The present work provided a useful method to simulate and interpret the absorption spectra of porphyrin-like compounds. PMID- 25273436 TI - Critical nucleus composition in a multicomponent system. AB - The properties of a critical nucleus are derived using the capillarity theory in the framework of classical nucleation. An analytical solution for the composition of a critical nucleus is given for low supersaturation. The theory is valid for any multicomponent systems. It is found that the deviation in nucleus composition from the equilibrium tie-line is mainly due to the difference in the Hessian of the Gibbs energy of the phases and the magnitude of the deviation in composition from equilibrium is order of the supersaturation. Despite our analysis strictly holds for low supersaturation, this suggests strong deviations near the spinodal line. PMID- 25273435 TI - Simulation of resonance hyper-Rayleigh scattering of molecules and metal clusters using a time-dependent density functional theory approach. AB - Resonance hyper-Rayleigh scattering (HRS) of molecules and metal clusters have been simulated based on a time-dependent density functional theory approach. The resonance first-order hyperpolarizability (beta) is obtained by implementing damped quadratic response theory using the (2n + 1) rule. To test this implementation, the prototypical dipolar molecule para-nitroaniline (p-NA) and the octupolar molecule crystal violet are used as benchmark systems. Moreover, small silver clusters Ag 8 and Ag 20 are tested with a focus on determining the two-photon resonant enhancement arising from the strong metal transition. Our results show that, on a per atom basis, the small silver clusters possess two photon enhanced HRS comparable to that of larger nanoparticles. This finding indicates the potential interest of using small metal clusters for designing new nonlinear optical materials. PMID- 25273437 TI - Triply differential (e,2e) studies of phenol. AB - We have measured (e,2e) triple differential cross sections (TDCS) for the electron-impact ionisation of phenol with coplanar asymmetrical kinematics for an incident electron energy of 250 eV. Experimental measurements of the angular distribution of the slow outgoing electrons at 20 eV are obtained when the incident electron scatters through angles of -5 degrees , -10 degrees , and -15 degrees , respectively. The TDCS data are compared with calculations performed within the molecular 3-body distorted wave model. In this case, a mixed level of agreement, that was dependent on the kinematical condition being probed, was observed between the theoretical and experimental results in the binary peak region. The experimental intensity of the recoil features under all kinematical conditions was relatively small, but was still largely underestimated by the theoretical calculations. PMID- 25273438 TI - An ab initio study of the electronic structure of the boron oxide neutral (BO), cationic (BO+), and anionic (BO-) species. AB - The BO neutral, cationic, and anionic molecular species have been painstakingly studied through multireference configuration interaction and single reference coupled cluster methods employing basis sets of quintuple cardinality. Potential energy curves have been constructed for 38 (BO), 37 (BO(+)), and 12 (BO(-)) states and the usual molecular parameters have been extracted most of which are in very good agreement with the scarce experimental data. Numerous avoided crossings appear on more or less all of the studied states of the neutral and cationic species challenging the validity of the Born Oppenheimer approximation. Finally, all excited states of the anionic system lie above the ground state of the neutral BO system and are therefore resonances. PMID- 25273439 TI - A full-dimensional multilayer multiconfiguration time-dependent Hartree study on the ultraviolet absorption spectrum of formaldehyde oxide. AB - Employing the multilayer multiconfiguration time-dependent Hartree (ML-MCTDH) method in conjunction with the multistate multimode vibronic coupling Hamiltonian (MMVCH) model, we perform a full dimensional (9D) quantum dynamical study on the simplest Criegee intermediate, formaldehyde oxide, in five lower-lying singlet electronic states. The ultraviolet (UV) spectrum is then simulated by a Fourier transform of the auto-correlation function. The MMVCH model is built based on extensive MRCI(8e,8o)/aug-cc-pVTZ calculations. To ensure a fast convergence of the final calculations, a large number of ML-MCTDH test calculations is performed to find an appropriate multilayer separations (ML-trees) of the ML-MCTDH nuclear wave functions, and the dynamical calculations are carefully checked to ensure that the calculations are well converged. To compare the computational efficiency, standard MCTDH simulations using the same Hamiltonian are also performed. A comparison of the MCTDH and ML-MCTDH calculations shows that even for the present not-too-large system (9D here) the ML-MCTDH calculations can save a considerable amount of computational resources while producing identical spectra as the MCTDH calculations. Furthermore, the present theoretical B(1)A'< X(1)A' UV spectral band and the corresponding experimental measurements [J. M. Beames, F. Liu, L. Lu, and M. I. Lester, J. Am. Chem. Soc. 134, 20045-20048 (2012); L. Sheps, J. Phys. Chem. Lett. 4, 4201-4205 (2013); W.-L. Ting, Y.-H. Chen, W. Chao, M. C. Smith, and J. J.-M. Lin, Phys. Chem. Chem. Phys. 16, 10438 10443 (2014)] are discussed. To the best of our knowledge, this is the first theoretical UV spectrum simulated for this molecule including nuclear motion beyond an adiabatic harmonic approximation. PMID- 25273440 TI - Photoelectron spectroscopy and ab initio calculations of small SinSm- (n = 1,2; m = 1-4) clusters. AB - Binary cluster anions composed of silicon and sulfur elements, SinSm(-) (n = 1,2; m = 1-4), were investigated by using photoelectron spectroscopy and ab initio calculations. The vertical detachment energies and the adiabatic detachment energies of these clusters were obtained from their photoelectron spectra. The electron affinity of SiS molecule is determined to be 0.477 +/- 0.040 eV. The results show that the most stable structures of the anionic and neutral SinSm (n = 1,2; m = 1-4) clusters prefer to adopt planar configurations except that the structures of Si2S4(-) and Si2S2 are slightly bent. PMID- 25273441 TI - MULTIMODE quantum calculations of vibrational energies and IR spectrum of the NO+(H2O) cluster using accurate potential energy and dipole moment surfaces. AB - A new, full (nine)-dimensional potential energy surface and dipole moment surface to describe the NO(+)(H2O) cluster is reported. The PES is based on fitting of roughly 32,000 CCSD(T)-F12/aug-cc-pVTZ electronic energies. The surface is a linear least-squares fit using a permutationally invariant basis with Morse-type variables. The PES is used in a Diffusion Monte Carlo study of the zero-point energy and wavefunction of the NO(+)(H2O) and NO(+)(D2O) complexes. Using the calculated ZPE the dissociation energies of the clusters are reported. Vibrational configuration interaction calculations of NO(+)(H2O) and NO(+)(D2O) using the MULTIMODE program are performed. The fundamental, a number of overtone, and combination states of the clusters are reported. The IR spectrum of the NO(+)(H2O) cluster is calculated using 4, 5, 7, and 8 modes VSCF/CI calculations. The anharmonic, coupled vibrational calculations, and IR spectrum show very good agreement with experiment. Mode coupling of the water "antisymmetric" stretching mode with the low-frequency intermolecular modes results in intensity borrowing. PMID- 25273442 TI - Photoelectron angular distributions for states of any mixed character: an experiment-friendly model for atomic, molecular, and cluster anions. AB - We present a model for laboratory-frame photoelectron angular distributions in direct photodetachment from (in principle) any molecular orbital using linearly polarized light. A transparent mathematical approach is used to generalize the Cooper-Zare central-potential model to anionic states of any mixed character. In the limit of atomic-anion photodetachment, the model reproduces the Cooper-Zare formula. In the case of an initial orbital described as a superposition of s and p-type functions, the model yields the previously obtained s-p mixing formula. The formalism is further advanced using the Hanstorp approximation, whereas the relative scaling of the partial-wave cross-sections is assumed to follow the Wigner threshold law. The resulting model describes the energy dependence of photoelectron anisotropy for any atomic, molecular, or cluster anions, usually without requiring a direct calculation of the transition dipole matrix elements. As a benchmark case, we apply the p-d variant of the model to the experimental results for NO(-) photodetachment and show that the observed anisotropy trend is described well using physically meaningful values of the model parameters. Overall, the presented formalism delivers insight into the photodetachment process and affords a new quantitative strategy for analyzing the photoelectron angular distributions and characterizing mixed-character molecular orbitals using photoelectron imaging spectroscopy of negative ions. PMID- 25273443 TI - First-principles binary diffusion coefficients for H, H2, and four normal alkanes + N2. AB - Collision integrals related to binary (dilute gas) diffusion are calculated classically for six species colliding with N2. The most detailed calculations make no assumptions regarding the complexity of the potential energy surface, and the resulting classical collision integrals are in excellent agreement with previous semiclassical results for H + N2 and H2 + N2 and with recent experimental results for CnH(2n+2) + N2, n = 2-4. The detailed classical results are used to test the accuracy of three simplifying assumptions typically made when calculating collision integrals: (1) approximating the intermolecular potential as isotropic, (2) neglecting the internal structure of the colliders (i.e., neglecting inelasticity), and (3) employing unphysical R(-12) repulsive interactions. The effect of anisotropy is found to be negligible for H + N2 and H2 + N2 (in agreement with previous quantum mechanical and semiclassical results for systems involving atomic and diatomic species) but is more significant for larger species at low temperatures. For example, the neglect of anisotropy decreases the diffusion coefficient for butane + N2 by 15% at 300 K. The neglect of inelasticity, in contrast, introduces only very small errors. Approximating the repulsive wall as an unphysical R(-12) interaction is a significant source of error at all temperatures for the weakly interacting systems H + N2 and H2 + N2, with errors as large as 40%. For the normal alkanes in N2, which feature stronger interactions, the 12/6 Lennard-Jones approximation is found to be accurate, particularly at temperatures above ~700 K where it predicts the full-dimensional result to within 5% (although with somewhat different temperature dependence). Overall, the typical practical approach of assuming isotropic 12/6 Lennard-Jones interactions is confirmed to be suitable for combustion applications except for weakly interacting systems, such as H + N2. For these systems, anisotropy and inelasticity can safely be neglected but a more detailed description of the repulsive wall is required for quantitative predictions. A straightforward approach for calculating effective isotropic potentials with realistic repulsive walls is described. An analytic expression for the calculated diffusion coefficient for H + N2 is presented and is estimated to have a 2-sigma error bar of only 0.7%. PMID- 25273444 TI - Dynamics of the reaction of C3(a3Piu) radicals with C2H2: a new source for the formation of C5H. AB - The reaction C3(a(3)Piu) + C2H2 -> C5H + H was investigated at collision energy 10.9 kcal mol(-1) that is less than the enthalpy of ground-state reaction C3(X(1)Sigmag (+)) + C2H2 -> C5H + H. C3(a(3)Piu) radicals were synthesized from 1% C4F6/He by pulsed high-voltage discharge. The title reaction was conducted in a crossed molecular-beam apparatus equipped with a quadrupole-mass filter. Product C5H was interrogated with time-of-flight spectroscopy and synchrotron vacuum-ultraviolet ionization. Reactant C3(a(3)Piu) and product C5H were identified using photoionization spectroscopy. The ionization thresholds of C3(X(1)Sigmag(+)) and C3(a(3)Piu) are determined as 11.6 +/- 0.2 eV and 10.0 +/- 0.2 eV, respectively. The C5H product is identified as linear pentynylidyne that has an ionization energy 8.4 +/- 0.2 eV. The title reaction releases translational energy 10.6 kcal mol(-1) in average and has an isotropic product angular distribution. The quantum-chemical calculation indicates that the C3(a(3)Piu) radical attacks one of the carbon atoms of C2H2 and subsequently a hydrogen atom is ejected to form C5H + H, in good agreement with the experimental observation. As far as we are aware, the C3(a(3)Piu) + C2H2 reaction is investigated for the first time. This work gives an implication for the formation of C5H from the C3(a(3)Piu) + C2H2 reaction occurring in a combustion or discharge process of C2H2. PMID- 25273445 TI - Nesting of thermodynamic, structural, and dynamic anomalies in liquid silicon. AB - Anomalous behaviour in density, diffusivity, and structural order is investigated for silicon modeled by the Stillinger-Weber potential by performing molecular dynamics simulations. As previously reported in the case of water [J. R. Errington and P. G. Debenedetti, Nature (London) 409, 318 (2001)] and silica [M. S. Shell, P. G. Debenedetti, and A. Z. Panagiotopoulos, Phys. Rev. E 66, 011202 (2002)], a cascading of thermodynamic, dynamic, and structural anomalous regions is also observed in liquid silicon. The region of structural anomaly includes the region of diffusivity anomaly, which in turn encompasses the region of density anomaly (which is unlike water but similar to silica). In the region of structural anomaly, a tight correlation between the translational and tetrahedrality order parameter is found, but the correlation is weaker when a local orientational order parameter (q3) is used as a measure of tetrahedrality. The total excess entropy and the pair correlation entropy are computed across the phase diagram and the correlation between the excess entropy and the regions of anomalies in the phase diagram of liquid silicon is examined. Scaling relations associating the excess entropy with the diffusion coefficient show considerable deviation from the quasi-universal behaviour observed in hard-sphere and Lennard Jones liquids and some liquid metals. Excess entropy based criteria for diffusivity and structural anomalies fail to capture the observed regions of anomaly. PMID- 25273446 TI - Dependence of the atomic level Green-Kubo stress correlation function on wavevector and frequency: molecular dynamics results from a model liquid. AB - We report on a further investigation of a new method that can be used to address vibrational dynamics and propagation of stress waves in liquids. The method is based on the decomposition of the macroscopic Green-Kubo stress correlation function into the atomic level stress correlation functions. This decomposition, as was demonstrated previously for a model liquid studied in molecular dynamics simulations, reveals the presence of stress waves propagating over large distances and a structure that resembles the pair density function. In this paper, by performing the Fourier transforms of the atomic level stress correlation functions, we elucidate how the lifetimes of the stress waves and the ranges of their propagation depend on their frequency, wavevector, and temperature. These results relate frequency and wavevector dependence of the generalized viscosity to the character of propagation of the shear stress waves. In particular, the results suggest that an increase in the value of the frequency dependent viscosity at low frequencies with decrease of temperature is related to the increase in the ranges of propagation of the stress waves of the corresponding low frequencies. We found that the ranges of propagation of the shear stress waves of frequencies less than half of the Einstein frequency extend well beyond the nearest neighbor shell even above the melting temperature. The results also show that the crossover from quasilocalized to propagating behavior occurs at frequencies usually associated with the Boson peak. PMID- 25273447 TI - Calculating two-dimensional THz-Raman-THz and Raman-THz-THz signals for various molecular liquids: the samplers. AB - Recently, two-dimensional (2D) THz-Raman spectroscopy has been used to investigate the intermolecular modes of liquid water. We examine such 2D spectroscopy signals by means of full molecular dynamics (MD) simulations. In this way, we carry out a detailed analysis of intermolecular interactions that play an essential role in many important chemical processes. We calculate 2D Raman-THz-THz (RTT), THz-Raman-THz (TRT), and 2D Raman signals for liquid water, methanol, formamide, acetonitrile, formaldehyde, and dimethyl sulfoxide using an equilibrium-non-equilibrium hybrid MD simulation algorithm originally developed for 2D Raman spectroscopy. These signals are briefly analyzed in terms of anharmonicity and nonlinear polarizability of vibrational modes on the basis of the 2D Raman signals calculated from a Brownian oscillator model with a nonlinear system-bath interaction. We find that the anharmonic contribution is dominant in the RTT case, while the nonlinear polarizability contribution is dominant in the TRT case. For water and methanol, we observed vibrational echo peaks of librational motion in the 2D TRT signals. The predicted signal profiles and intensities that we obtained provide valuable information that can be applied to 2D spectroscopy experiments, allowing them to be carried out more efficiently. PMID- 25273448 TI - Frequency analysis of stress relaxation dynamics in model asphalts. AB - Asphalt is an amorphous or semi-crystalline material whose mechanical performance relies on viscoelastic responses to applied strain or stress. Chemical composition and its effect on the viscoelastic properties of model asphalts have been investigated here by computing complex modulus from molecular dynamics simulation results for two different model asphalts whose compositions each resemble the Strategic Highway Research Program AAA-1 asphalt in different ways. For a model system that contains smaller molecules, simulation results for storage and loss modulus at 443 K reach both the low and high frequency scaling limits of the Maxwell model. Results for a model system composed of larger molecules (molecular weights 300-900 g/mol) with longer branches show a quantitatively higher complex modulus that decreases significantly as temperature increases over 400-533 K. Simulation results for its loss modulus approach the low frequency scaling limit of the Maxwell model at only the highest temperature simulated. A Black plot or van Gurp-Palman plot of complex modulus vs. phase angle for the system of larger molecules suggests some overlap among results at different temperatures for less high frequencies, with an interdependence consistent with the empirical Christensen-Anderson-Marasteanu model. Both model asphalts are thermorheologically complex at very high frequencies, where they show a loss peak that appears to be independent of temperature and density. PMID- 25273449 TI - Freezing lines of colloidal Yukawa spheres. II. Local structure and characteristic lengths. AB - Using the Rogers-Young (RY) integral equation scheme for the static pair correlation functions combined with the liquid-phase Hansen-Verlet freezing rule, we study the generic behavior of the radial distribution function and static structure factor of monodisperse charge-stabilized suspensions with Yukawa-type repulsive particle interactions at freezing. In a related article, labeled Paper I [J. Gapinski, G. Nagele, and A. Patkowski, J. Chem. Phys. 136, 024507 (2012)], this hybrid method was used to determine two-parameter freezing lines for experimentally controllable parameters, characteristic of suspensions of charged silica spheres in dimethylformamide. A universal scaling of the RY radial distribution function maximum is shown to apply to the liquid-bcc and liquid-fcc segments of the universal freezing line. A thorough analysis is made of the behavior of characteristic distances and wavenumbers, next-neighbor particle coordination numbers, osmotic compressibility factor, and the Ravache-Mountain Streett minimum-maximum radial distribution function ratio. PMID- 25273450 TI - Tailoring sodium silicophosphate glasses containing SiO6-octahedra through structural rules and topological principles. AB - SiO4 tetrahedra in certain sodium silicophosphate glasses can be transformed into SiO6 octahedra that determine the macroscopic properties of silicophosphate glasses to a large extent. In this study, we develop the quantitative evolution rule of each network former. In addition, based on the underlying structure and topology, temperature-dependent topological constrain theory is used to elucidate the composition dependence of glass transition temperature and hardness. The properties of sodium silicophosphate glasses have been accurately predicted. These understandings will help us design new type of silicophosphate glasses containing unique SiO6 octahedra. PMID- 25273451 TI - Experiments on tracer diffusion in aqueous and non-aqueous solvent combinations. AB - Forced Rayleigh scattering is used to study the tracer diffusion of an azobenzene in binary combinations of polar solvents, including water. In the absence of water, the tracer diffusion coefficient D in the mixture lies between the diffusion coefficients within the pure solvents, on a curve that is reasonably close to the prediction of free-volume theory. If water is present, on the other hand, the diffusion coefficient displays a minimum that is less than the smaller of the two pure-solvent values. We attempt to understand the different behavior in water by concentrating on the fairly hydrophobic nature of the solute, leading to a first solvent shell that is hydrophobic on the inside and hydrophilic on the outside. We also believe that clusters of amphiphiles explain the observation that, in aqueous combinations, D is nearly constant above a certain amphiphile mole fraction. PMID- 25273452 TI - Structure and transport of aqueous electrolytes: from simple halides to radionuclide ions. AB - Molecular simulations are used to compare the structure and dynamics of conventional and radioactive aqueous electrolytes: chloride solutions with sodium, potassium, cesium, calcium, and strontium. The study of Cs(+) and Sr(2+) is important because these radioactive ions can be extremely harmful and are often confused by living organisms for K(+) and Ca(2+), respectively. Na(+), Ca(2+), and Sr(2+) are strongly bonded to their hydration shell because of their large charge density. We find that the water molecules in the first hydration shell around Na(+) form hydrogen bonds between each other, whereas molecules in the first hydration shell around Ca(2+) and Sr(2+) predominantly form hydrogen bonds with water molecules in the second shell. In contrast to these three ions, K(+) and Cs(+) have low charge densities so that they are weakly bonded to their hydration shell. Overall, the structural differences between Ca(2+) and Sr(2+) are small, but the difference between their coordination numbers relative to their surface areas could potentially be used to separate these ions. Moreover, the different decays of the velocity-autocorrelation functions corresponding to these ions indicates that the difference in mass could be used to separate these cations. In this work, we also propose a new definition of the pairing time that is easy to calculate and of physical significance regardless of the problem at hand. PMID- 25273453 TI - Hydrodynamic anomalies in supercritical fluid. AB - Using the molecular dynamics simulations we investigate properties of velocity autocorrelation function of Lennard-Jones fluid at long and intermediate time scales in wide ranges of temperature and density. We show that the amplitudes of both the leading and the subleading time asymptotic terms of velocity autocorrelation function, a1 and a2, show essentially non-monotonic temperature and density dependence. There are two lines on temperature-density plain corresponding to maxima of a1 (a2) along isochors and isotherms situated in the supercritical fluid (hydrodynamic anomalies). These lines give insight into the stages of the fluid evolution into gas. PMID- 25273455 TI - Theory of adhesion: role of surface roughness. AB - We discuss how surface roughness influences the adhesion between elastic solids. We introduce a Tabor number which depends on the length scale or magnification, and which gives information about the nature of the adhesion at different length scales. We consider two limiting cases relevant for (a) elastically hard solids with weak (or long ranged) adhesive interaction (DMT-limit) and (b) elastically soft solids with strong (or short ranged) adhesive interaction (JKR-limit). For the former cases we study the nature of the adhesion using different adhesive force laws (F ~ u(-n), n = 1.5-4, where u is the wall-wall separation). In general, adhesion may switch from DMT-like at short length scales to JKR-like at large (macroscopic) length scale. We compare the theory predictions to results of exact numerical simulations and find good agreement between theory and simulation results. PMID- 25273454 TI - Ion aggregation in high salt solutions: ion network versus ion cluster. AB - The critical aggregation phenomena are ubiquitous in many self-assembling systems. Ions in high salt solutions could also spontaneously form larger ion aggregates, but their effects on hydrogen-bond structures in water have long been controversial. Here, carrying out molecular dynamics (MD) simulation studies of high salt solutions and comparing the MD simulation results with infrared absorption and pump-probe spectroscopy of O-D stretch mode of HDO in highly concentrated salt solutions and (13)C-NMR chemical shift of S(13)CN(-) in KSCN solutions, we find evidence on the onset of ion aggregate and large-scale ion-ion network formation that concomitantly breaks water hydrogen-bond structure in certain salt solutions. Despite that these experimental results cannot provide direct evidence on the three-dimensional morphological structures of ion aggregates, they serve as reference data for verifying MD simulation methods. The MD results suggest that disrupted water hydrogen-bond network is intricately intertwined with ion-ion network. This further shows morphological variation of ion aggregate structures from ion cluster to ion network in high salt solutions that are interrelated to the onset of macroscopic aggregate formation and the water hydrogen-bond structure making and breaking processes induced by Hofmeister ions. PMID- 25273457 TI - Light-driven electron transport through a molecular junction based on cross conjugated systems. AB - This work explores light-driven electron transport through cross-conjugated molecules with different numbers of alkenyl groups. In the framework of coherent quantum transport, the analysis uses single-particle Green's functions together with non-Hermitian Floquet theory. With realistic parameters stemming from spectroscopy, the simulations show that measurable current (~10(-11) A) caused by photon-assisted tunneling should be observed in a weak driving field (~2 * 10(5) V/cm). Current-field intensity characteristics give one-photon and two-photon field amplitude power laws. The gap between the molecular orbital and the Fermi level of the electrodes is revealed by current-field frequency characteristics. Due to generalized parity symmetry, the cross-conjugated molecules with odd and even numbers of alkenyl groups exhibit completely different current-polarization characteristics, which may provide an advantageous feature in nanoelectronic applications. PMID- 25273456 TI - Thermodynamics of surface defects at the aspirin/water interface. AB - We present a simulation scheme to calculate defect formation free energies at a molecular crystal/water interface based on force-field molecular dynamics simulations. To this end, we adopt and modify existing approaches to calculate binding free energies of biological ligand/receptor complexes to be applicable to common surface defects, such as step edges and kink sites. We obtain statistically accurate and reliable free energy values for the aspirin/water interface, which can be applied to estimate the distribution of defects using well-established thermodynamic relations. As a show case we calculate the free energy upon dissolving molecules from kink sites at the interface. This free energy can be related to the solubility concentration and we obtain solubility values in excellent agreement with experimental results. PMID- 25273458 TI - Electron hole pair mediated vibrational excitation in CO scattering from Au(111): incidence energy and surface temperature dependence. AB - We investigated the translational incidence energy (Ei) and surface temperature (Ts) dependence of CO vibrational excitation upon scattering from a clean Au(111) surface. We report absolute v = 0 -> 1 excitation probabilities for Ei between 0.16 and 0.84 eV and Ts between 473 and 973 K. This is now only the second collision system where such comprehensive measurements are available - the first is NO on Au(111). For CO on Au(111), vibrational excitation occurs via direct inelastic scattering through electron hole pair mediated energy transfer - it is enhanced by incidence translation and the electronically non-adiabatic coupling is about 5 times weaker than in NO scattering from Au(111). Vibrational excitation via the trapping desorption channel dominates at Ei = 0.16 eV and quickly disappears at higher Ei. PMID- 25273459 TI - Dissociation and recombination of D2 on Cu(111): ab initio molecular dynamics calculations and improved analysis of desorption experiments. AB - Obtaining quantitative agreement between theory and experiment for dissociative adsorption of hydrogen on and associative desorption of hydrogen from Cu(111) remains challenging. Particularly troubling is the fact that theory gives values for the high energy limit to the dissociative adsorption probability that is as much as two times larger than experiment. In the present work we approach this discrepancy in three ways. First, we carry out a new analysis of the raw experimental data for D2 associatively desorbing from Cu(111). We also perform new ab initio molecular dynamics (AIMD) calculations that include effects of surface atom motion. Finally, we simulate time-of-flight (TOF) spectra from the theoretical reaction probability curves and we directly compare them to the raw experimental data. The results show that the use of more flexible functional forms for fitting the raw TOF spectra gives fits that are in slightly better agreement with the raw data and in considerably better agreement with theory, even though the theoretical reaction probabilities still achieve higher values at high energies. The mean absolute error (MAE) for the energy E0 at which the reaction probability equals half the experimental saturation value is now lower than 1 kcal/mol, the limit that defines chemical accuracy, while a MAE of 1.5 kcal/mol was previously obtained. The new AIMD results are only slightly different from the previous static surface results and in slightly better agreement with experiment. PMID- 25273460 TI - Effect of the asymmetry of the coupling of the redox molecule to the electrodes in the one-level electrochemical bridged tunneling contact on the Coulomb blockade and the operation of molecular transistor. AB - Effect of the asymmetry of the redox molecule (RM) coupling to the working electrodes on the Coulomb blockade and the operation of molecular transistor is considered under ambient conditions for the case of the non-adiabatic tunneling through the electrochemical contact having a one-level RM. The expressions for the tunnel current, the positions of the peaks of the tunnel current/overpotential dependencies, and their full widths at the half maximum are obtained for arbitrary values of the parameter d describing the coupling asymmetry of the tunneling contact and the effect of d on the different characteristics of the tunneling contact is studied. The tunnel current/overpotential and the differential conductance/bias voltage dependencies are calculated and interpreted. In particular, it is shown that the effect of the Coulomb blockade on the tunnel current and the differential conductance has a number of new features in the case of the large coupling asymmetry. It is also shown that, for rather large values of the solvent reorganization energy, the coupling asymmetry enhanced strongly amplification and rectification of the tunnel current in the most of the regions of the parameter space specifying the tunneling contact. The regions of the parameter space where both strong amplification and strong rectification take place are also revealed. The obtained results allow us to prove the possibility of the realization of the effective electrochemical transistor based on the one-level RM. PMID- 25273461 TI - Method of increments for the halogen molecular crystals: Cl, Br, and I. AB - Method of increments (MI) calculations reveal the n-body correlation contributions to binding in solid chlorine, bromine, and iodine. Secondary binding contributions as well as d-correlation energies are estimated and compared between each solid halogen. We illustrate that binding is entirely determined by two-body correlation effects, which account for >80% of the total correlation energy. One-body, three-body, and exchange contributions are repulsive. Using density-fitting (DF) local coupled-cluster singles, doubles, and perturbative triples for incremental calculations, we obtain excellent agreement with the experimental cohesive energies. MI results from DF local second-order Moller-Plesset perturbation (LMP2) yield considerably over-bound cohesive energies. Comparative calculations with density functional theory and periodic LMP2 method are also shown to be less accurate for the solid halogens. PMID- 25273462 TI - Knudsen diffusion and surface trapping rates in slit, capillary, and spherical pores. AB - De Gennes model for Knudsen diffusion and strong surface trapping kinetics is applied to slit, capillary, and spherical pores. The exact analytical survival probability-time expressions obtained for each case, which scale with the average pore diameter, are compared with numerical simulation curves for a densely packed hard sphere model porous bed. PMID- 25273463 TI - Impact of surface nanostructure on ice nucleation. AB - Nucleation of water on solid surface can be promoted noticeably when the lattice parameter of a surface matches well with the ice structure. However, the characteristic length of the surface lattice reported is generally less than 0.5 nm and is hardly tunable. In this paper, we show that a surface with nanoscale roughness can also remarkably promote ice nucleation if the characteristic length of the surface structure matches well with the ice crystal. A series of surfaces composed of periodic grooves with same depth but different widths are constructed in molecular dynamics simulations. Water cylinders are placed on the constructed surfaces and frozen at constant undercooling. The nucleation rates of the water cylinders are calculated in the simulation using the mean first-passage time method and then used to measure the nucleation promotion ability of the surfaces. Results suggest that the nucleation behavior of the supercooled water is significantly sensitive to the width of the groove. When the width of the groove matches well with the specific lengths of the ice crystal structure, the nucleation can be promoted remarkably. If the width does not match with the ice crystal, this kind of promotion disappears and the nucleation rate is even smaller than that on the smooth surface. Simulations also indicate that even when water molecules are adsorbed onto the surface structure in high-humidity environment, the solid surface can provide promising anti-icing ability as long as the characteristic length of the surface structure is carefully designed to avoid geometric match. PMID- 25273464 TI - Methanol synthesis on ZnO(0001-). IV. Reaction mechanisms and electronic structure. AB - Methanol synthesis from CO and H2 over ZnO, which requires high temperatures and high pressures giving rise to a complex interplay of physical and chemical processes over this heterogeneous catalyst surface, is investigated using ab initio simulations. The redox properties of the surrounding gas phase are known to directly impact on the catalyst properties and thus, set the overall catalytic reactivity of this easily reducible oxide material. In Paper III of our series [J. Kiss, J. Frenzel, N. N. Nair, B. Meyer, and D. Marx, J. Chem. Phys. 134, 064710 (2011)] we have qualitatively shown that for the partially hydroxylated and defective ZnO(0001-) surface there exists an intricate network of surface chemical reactions. In the present study, we employ advanced molecular dynamics techniques to resolve in detail this reaction network in terms of elementary steps on the defective surface, which is in stepwise equilibrium with the gas phase. The two individual reduction steps were investigated by ab initio metadynamics sampling of free energy landscapes in three-dimensional reaction subspaces. By also sampling adsorption and desorption processes and thus molecular species that are in the gas phase but close to the surface, our approach successfully generated several alternative pathways of methanol synthesis. The obtained results suggest an Eley-Rideal mechanism for both reduction steps, thus involving "near-surface" molecules from the gas phase, to give methanol preferentially over a strongly reduced catalyst surface, while important side reactions are of Langmuir-Hinshelwood type. Catalyst re-reduction by H2 stemming from the gas phase is a crucial process after each reduction step in order to maintain the catalyst's activity toward methanol formation and to close the catalytic cycle in some reaction channels. Furthermore, the role of oxygen vacancies, side reactions, and spectator species is investigated and mechanistic details are discussed based on extensive electronic structure analysis. PMID- 25273465 TI - Calculating hydrodynamic interactions for membrane-embedded objects. AB - A recently introduced numerical scheme for calculating self-diffusion coefficients of solid objects embedded in lipid bilayer membranes is extended to enable calculation of hydrodynamic interactions between multiple objects. The method is used to validate recent analytical predictions by Oppenheimer and Diamant [Biophys. J. 96, 3041 2009] related to the coupled diffusion of membrane embedded proteins and is shown to converge to known near-field lubrication results as objects closely approach one another; however, the present methodology also applies outside of the limiting regimes where analytical results are available. Multiple different examples involving pairs of disk-like objects with various constraints imposed on their relative motions demonstrate the importance of hydrodynamic interactions in the dynamics of proteins and lipid domains on membrane surfaces. It is demonstrated that the relative change in self-diffusion of a membrane embedded object upon perturbation by a similar proximal solid object displays a maximum for object sizes comparable to the Saffman-Delbruck length of the membrane. PMID- 25273466 TI - On the separability of the extended molecule: Constructing the best localized molecular orbitals for an organic molecule bridging two model electrodes. AB - Based on a quantum chemical valence formalism that allows the rigorous construction of best-localized molecular orbitals on specific parts of an extended system, we examined the separability of individual components of model systems relevant to the description of electron transport in molecular devices. We started by examining how to construct the maximally localized electronic density at the tip of a realistic model of a gold electrode. By varying the number of gold atoms included in the local region where to project the total electronic density, we quantitatively assess how many molecular orbitals are entirely localized in that region. We then considered a 1,4-benzene-di-thiol molecule connected to two model gold electrodes and examined how to localize the electronic density of the total system in the extended molecule, a fractional entity comprising the organic molecule plus an increasing number of the closest metal atoms. We were able to identify in a rigorous manner the existence of three physically different electronic populations, each one corresponding to a distinct set of molecular orbitals. First, there are those entirely localized in the extended molecule, then there is a second group of those completely distributed in the gold atoms external to that region, and, finally, there are those delocalized over the entire system. This latter group can be associated to the shared electronic population between the extended molecule and the rest of the system. We suggest that the treatment here presented could be useful in the theoretical analysis of the electronic transport in nanodevices whenever the use of localized molecular states are required by the physics of the specific problem, such as in cases of weak coupling and super-exchange limits. PMID- 25273467 TI - Beneficial compressive strain for oxygen reduction reaction on Pt (111) surface. AB - We investigated the influence of compressive surface strain on the progression of oxygen reduction reaction (ORR) on Pt(111) surface using the density functional theory (DFT) calculation method. Specifically, we calculated the binding energies of all the chemical species possibly involved in ORR and the reaction energies (heat of reaction and activation energy) of all the possible ORR elementary reactions on the Pt(111) surfaces with -2% and -3% strain. Our DFT results indicate that all the ORR species bind more weakly on the compressively strained surfaces than on an unstrained surface owing to strain-induced d-electron band broadening. Our DFT calculations further predict that both OOH dissociation and HOOH dissociation pathways could be active for ORR on the Pt(111) surface with compressive strain between -2% and -3%. Moreover, the activation energies of the ORR rate-determining steps on the compressively strained Pt(111) surfaces were found to be lower than that on the unstrained Pt(111) surface. It was thus inferred that a -2% to -3% surface strain could lead to enhanced ORR activity on the Pt(111) catalysts. Consequently, our study suggests that tuning surface strain is an effective way to improve the performance of Pt-based electrocatalysts for ORR. PMID- 25273468 TI - Effect of bending flexibility on the phase behavior and dynamics of rods. AB - We study by means of molecular and Brownian dynamics simulations the influence of bending flexibility on the phase behavior and dynamics of monodisperse hard filamentous particles with an aspect ratio of 8 and persistence lengths equal to 3 and 11 times the particle length. Although our particles are much shorter, the latter corresponds to the values for wild-type and mutant fd virus particles that have been subject of a recent experimental study, where the diffusion of these particles in the nematic and smectic-A phase was investigated by means of video fluorescence microscopy [E. Pouget, E. Grelet, and M. P. Lettinga, Phys. Rev. E 84, 041704 (2011)]. In agreement with theoretical predictions and simulations, we find that for the more flexible particles (shorter persistence length) the nematic (N) to smectic-A (Sm-A) phase transition shifts to larger values of the particle density. Interestingly, we find that for the more rigid particles (larger persistence length), the smectic layer-to-layer distance decreases monotonically with increasing density, whereas for the more flexible ones, it first increases, reaches a maximum and then decreases. For our more flexible particles, we find a smectic-B phase at sufficiently high densities. Moreover, in line with experimental observations and theoretical predictions, we find heterogeneous dynamics in the Sm-A phase, in which particles hop between the smectic layers. We compare the diffusion of our two types of particle at identical values of smectic order parameter, and find that flexibility does not change the diffusive behavior of particles along the director yet significantly slows down the diffusion perpendicular to it. In our simulations, the ratio of diffusion constants along and perpendicular to the director decreases just beyond the N-Sm-A phase transition for both our stiff and more flexible particles. PMID- 25273469 TI - Optical extinction, refractive index, and multiple scattering for suspensions of interacting colloidal particles. AB - We provide a general microscopic theory of the scattering cross-section and of the refractive index for a system of interacting colloidal particles, exact at second order in the molecular polarizabilities. In particular: (a) we show that the structural features of the suspension are encoded into the forward scattered field by multiple scattering effects, whose contribution is essential for the so called "optical theorem" to hold in the presence of interactions; (b) we investigate the role of radiation reaction on light extinction; (c) we discuss our results in the framework of effective medium theories, presenting a general result for the effective refractive index valid, whatever the structural properties of the suspension, in the limit of particles much larger than the wavelength; (d) by discussing strongly-interacting suspensions, we unravel subtle anomalous dispersion effects for the suspension refractive index. PMID- 25273470 TI - Temperature-sensitive nanogels in the presence of salt: explicit coarse-grained simulations. AB - In this work, coarse-grained simulations of two charged thermo-shrinking nanogels (with degrees of ionization of 0.125 and 0.250) in the presence of 1:1 and 3:1 electrolytes have been explicitly performed through the bead-spring model of polyelectrolyte. In a first set of simulations, salt concentrations for 1:1 and 3:1 electrolytes ranged from 1 to 100 mM and from 0.167 to 16.7 mM, respectively, whereas temperature remained fixed at a value for which hydrophobic forces were negligible in our case (288 K). The sizes of swollen nanogels are smaller when trivalent cations are present, but they do not change significantly in the range of concentrations of 3:1 electrolyte studied here. It should be also stressed that trivalent cations neutralize the nanogel charge more efficiently. According to these results the electrostatic repulsion plays an important role. In a second set of simulations, the temperature varied from 288 to 333 K to study the effect of salt on the thermal response when hydrophobic forces are not negligible. For the nanogels with the lowest degree of ionization, the behavior of the radius with increasing the temperature can be described by a sigmoid function, which shifts towards lower temperatures in the presence of salt. This shift is more clearly observed for trivalent cations, even at low concentrations. For the nanogels with the highest degree of ionization, the effect of additional electrolyte is also noticeable. In this case, hydrophobic forces are not the only responsible for their shrinkage in the presence of trivalent cations. The surface electrostatic potential and the concentration of salt cations inside the nanogel have been computed from simulations and a modified Poisson-Boltzmann (PB) cell model. The thermosensitivity in size have certain influence on the sensitivity of these properties to temperature changes. The rich behavior of the surface electrostatic potential and the uptake of salt cations are successfully predicted by the modified PB cell model proposed (at least qualitatively). Particularly, the model is able to predict how the retention of salt cations depends on their charge and the ionic valence when nanogels shrink. PMID- 25273471 TI - Structural control of elastic moduli in ferrogels and the importance of non affine deformations. AB - One of the central appealing properties of magnetic gels and elastomers is that their elastic moduli can reversibly be adjusted from outside by applying magnetic fields. The impact of the internal magnetic particle distribution on this effect has been outlined and analyzed theoretically. In most cases, however, affine sample deformations are studied and often regular particle arrangements are considered. Here we challenge these two major simplifications by a systematic approach using a minimal dipole-spring model. Starting from different regular lattices, we take into account increasingly randomized structures, until we finally investigate an irregular texture taken from a real experimental sample. On the one hand, we find that the elastic tunability qualitatively depends on the structural properties, here in two spatial dimensions. On the other hand, we demonstrate that the assumption of affine deformations leads to increasingly erroneous results the more realistic the particle distribution becomes. Understanding the consequences of the assumptions made in the modeling process is important on our way to support an improved design of these fascinating materials. PMID- 25273472 TI - Mean properties and free energy of a few hard spheres confined in a spherical cavity. AB - We use analytical calculations and event-driven molecular dynamics simulations to study a small number of hard sphere particles in a spherical cavity. The cavity is also taken as the thermal bath so that the system thermalizes by collisions with the wall. In that way, these systems of two, three, and four particles, are considered in the canonical ensemble. We characterize various mean and thermal properties for a wide range of number densities. We study the density profiles, the components of the local pressure tensor, the interface tension, and the adsorption at the wall. This spans from the ideal gas limit at low densities to the high-packing limit in which there are significant regions of the cavity for which the particles have no access, due the conjunction of excluded volume and confinement. The contact density and the pressure on the wall are obtained by simulations and compared to exact analytical results. We also obtain the excess free energy for N = 4, by using a simulated-assisted approach in which we combine simulation results with the knowledge of the exact partition function for two and three particles in a spherical cavity. PMID- 25273473 TI - Phase behaviors and membrane properties of model liposomes: temperature effect. AB - The phase behaviors and membrane properties of small unilamellar vesicles have been explored at different temperatures by dissipative particle dynamics simulations. The vesicles spontaneously formed by model lipids exhibit pre transition from gel to ripple phase and main transition from ripple to liquid phase. The vesicle shape exhibits the faceted feature at low temperature, becomes more sphere-like with increasing temperature, but loses its sphericity at high temperature. As the temperature rises, the vesicle size grows but the membrane thickness declines. The main transition (Tm) can be identified by the inflection point. The membrane structural characteristics are analyzed. The inner and outer leaflets are asymmetric. The length of the lipid tail and area density of the lipid head in both leaflets decrease with increasing temperature. However, the mean lipid volume grows at low temperature but declines at high temperature. The membrane mechanical properties are also investigated. The water permeability grows exponentially with increasing T but the membrane tension peaks at Tm. Both the bending and stretching moduli have their minima near Tm. Those results are consistent with the experimental observations, indicating that the main signatures associated with phase transition are clearly observed in small unilamellar vesicles. PMID- 25273474 TI - Temperature dependent micro-rheology of a glass-forming polymer melt studied by molecular dynamics simulation. AB - We present a Molecular Dynamics simulation study of a micro-rheological probing of the glass transition in a polymer melt. Our model system consists of short bead-spring chains and the temperature ranges from well above the glass transition temperature to about 10% above it. The nano-particle clearly couples to the slowing down of the polymer segments and the calculated storage and loss moduli reveal the approach to the glass transition. At temperatures close to the mode coupling Tc of the polymer melt, the micro-rheological moduli measure the local viscoelastic response of the cage of monomers surrounding the nano-particle and no longer reveal the true melt moduli. The incoherent scattering function of the nano-particle exhibits a stretched exponential decay, typical for the alpha process in glass forming systems. We find no indication of a strong superdiffusive regime as has been deduced from a recent experiment in the same temperature range but for smaller momentum transfers. PMID- 25273475 TI - Merging and hopping processes in systems of ultrasoft, cluster forming particles under compression. AB - We have exposed a two-dimensional nanodrop of particles interacting via an ultrasoft (i.e., bounded), purely repulsive potential to a combined thermo- and barostat. While increasing the pressure steadily via a suitable pressure increment the temperature of the system is kept at a fixed target temperature. Once the hexagonal crystal composed of clusters of overlapping particles has formed, we investigate the system's reaction on the non-equilibrium conditions. Recording the trajectories of the particles in molecular dynamics simulations, we can identify how particle hopping and cluster merging events are realized. We find that the number of particles involved in these processes is of comparable size and that under-populated clusters (with ~70% of the average cluster size) are prone for merging processes. Theoretical predictions about the density dependence of the average cluster size and of the nearest cluster-distance are confirmed within good accuracy. PMID- 25273476 TI - Non-monotonic swelling of surface grafted hydrogels induced by pH and/or salt concentration. AB - We use a molecular theory to study the thermodynamics of a weak-polyacid hydrogel film that is chemically grafted to a solid surface. We investigate the response of the material to changes in the pH and salt concentration of the buffer solution. Our results show that the pH-triggered swelling of the hydrogel film has a non-monotonic dependence on the acidity of the bath solution. At most salt concentrations, the thickness of the hydrogel film presents a maximum when the pH of the solution is increased from acidic values. The quantitative details of such swelling behavior, which is not observed when the film is physically deposited on the surface, depend on the molecular architecture of the polymer network. This swelling-deswelling transition is the consequence of the complex interplay between the chemical free energy (acid-base equilibrium), the electrostatic repulsions between charged monomers, which are both modulated by the absorption of ions, and the ability of the polymer network to regulate charge and control its volume (molecular organization). In the absence of such competition, for example, for high salt concentrations, the film swells monotonically with increasing pH. A deswelling-swelling transition is similarly predicted as a function of the salt concentration at intermediate pH values. This reentrant behavior, which is due to the coupling between charge regulation and the two opposing effects triggered by salt concentration (screening electrostatic interactions and charging/discharging the acid groups), is similar to that found in end-grafted weak polyelectrolyte layers. Understanding how to control the response of the material to different stimuli, in terms of its molecular structure and local chemical composition, can help the targeted design of applications with extended functionality. We describe the response of the material to an applied pressure and an electric potential. We present profiles that outline the local chemical composition of the hydrogel, which can be useful information when designing applications that pursue or require the absorption of biomolecules or pH-sensitive molecules within different regions of the film. PMID- 25273477 TI - Crystal nucleation mechanism in melts of short polymer chains under quiescent conditions and under shear flow. AB - We present a molecular dynamics simulation study of crystal nucleation from undercooled melts of n-alkanes, and we identify the molecular mechanism of homogeneous crystal nucleation under quiescent conditions and under shear flow. We compare results for n-eicosane (C20) and n-pentacontahectane (C150), i.e., one system below the entanglement length and one above, at 20%-30% undercooling. Under quiescent conditions, we observe that entanglement does not have an effect on the nucleation mechanism. For both chain lengths, the chains first align and then straighten locally, then the local density increases and finally positional ordering sets in. At low shear rates the nucleation mechanism is the same as under quiescent conditions, while at high shear rates the chains align and straighten at the same time. We report on the effects of shear rate and temperature on the nucleation rates and estimate the critical shear rates, beyond which the nucleation rates increase with the shear rate. In agreement with previous experimental observation and theoretical work, we find that the critical shear rate corresponds to a Weissenberg number of order 1. Finally, we show that the viscosity of the system is not affected by the crystalline nuclei. PMID- 25273478 TI - Constriction model of actomyosin ring for cytokinesis by fission yeast using a two-state sliding filament mechanism. AB - We developed a model describing the structure and contractile mechanism of the actomyosin ring in fission yeast, Schizosaccharomyces pombe. The proposed ring includes actin, myosin, and alpha-actinin, and is organized into a structure similar to that of muscle sarcomeres. This structure justifies the use of the sliding-filament mechanism developed by Huxley and Hill, but it is probably less organized relative to that of muscle sarcomeres. Ring contraction tension was generated via the same fundamental mechanism used to generate muscle tension, but some physicochemical parameters were adjusted to be consistent with the proposed ring structure. Simulations allowed an estimate of ring constriction tension that reproduced the observed ring constriction velocity using a physiologically possible, self-consistent set of parameters. Proposed molecular-level properties responsible for the thousand-fold slower constriction velocity of the ring relative to that of muscle sarcomeres include fewer myosin molecules involved, a less organized contractile configuration, a low alpha-actinin concentration, and a high resistance membrane tension. Ring constriction velocity is demonstrated as an exponential function of time despite a near linear appearance. We proposed a hypothesis to explain why excess myosin heads inhibit constriction velocity rather than enhance it. The model revealed how myosin concentration and elastic resistance tension are balanced during cytokinesis in S. pombe. PMID- 25273479 TI - Edward Flatau (1868-1932) and his eponym. PMID- 25273480 TI - Faecal microbiota transplantation: from practice to legislation before considering industrialization. AB - Recurrent Clostridium difficile infections constitute an important medical concern. Evidence has been provided showing that faecal microbiota transplantation is a more efficient treatment than antibiotics. Serious side effects are unusual, and acceptability is not an obstacle. Nevertheless, protocols are heterogeneous with respect to the selection of donors and the methodology used for the faecal transplantation. Regulations by both the Food and Drug Administration and the French authorities consider stool samples to be drugs, and suggest strict supervision in clinical trials. Donor screening by questionnaire or by blood and stool analysis, which is essential in eliminating pathogens or viruses before transplantation, is similar in different countries, with a few exceptions. The traceability of the faecal transplant and long-term follow-up of the patients in clinical trials are issues that may be difficult to organize. The use of frozen microbiota facilitates transplantation, and the nasogastric route seems to be at least as effective as other invasive methods and avoids the risk of anaesthesia. Synthetic microbiota is an approach that selects a mixture of bacteria, thereby eliminating the risk of transmissible disease; however, this approach is not yet evidence-based. The use of pills, which is currently being tested in clinical trials, will certainly be the starting point for the extensive use and wide industrialization of faecal microbiota transplantation. PMID- 25273481 TI - Characterization of a pancreatic islet cell tumor in a polar bear (Ursus maritimus). AB - Herein, we report a 25-year-old male polar bear suffering from a pancreatic islet cell tumor. The aim of this report is to present a case of this rare tumor in a captive polar bear. The implication of potential risk factors such as high carbohydrate diet or the presence of amyloid fibril deposits was assessed. Necropsy examination revealed several other changes, including nodules observed in the liver, spleen, pancreas, intestine, and thyroid glands that were submitted for histopathologic analysis. Interestingly, the multiple neoplastic nodules were unrelated and included a pancreatic islet cell tumor. Immunohistochemistry of the pancreas confirmed the presence of insulin and islet amyloid polypeptide (IAPP) within the pancreatic islet cells. The IAPP gene was extracted from the paraffin embedded liver tissue and sequenced. IAPP cDNA from the polar bear exhibits some differences as compared to the sequence published for several other species. Different factors responsible for neoplasms in bears such as diet, infectious agents, and industrial chemical exposure are reviewed. This case report raised several issues that further studies may address by evaluating the prevalence of cancers in captive or wild animals. PMID- 25273483 TI - The eminent anatomists who discovered the upper oesophageal sphincter. AB - OBJECTIVE: To discover the anatomist who first identified the upper oesophageal sphincter. METHOD: The authors searched dozens of antique anatomy textbooks kept in the old section of the 'Vincenzo Pinali' Medical Library of Padua University, looking for descriptions of the upper oesophageal sphincter. RESULTS: The oesophageal sphincter was drawn correctly only in 1601, by Julius Casserius, in the book De vocis auditusque organis historia anatomica... (which translates as 'An Anatomical History on the Organs of Voice and Hearing ...'), and was properly described by Antonio Maria Valsalva in 1704 in the book De aure humana tractatus... ('Treatise on the Human Ear ...'). CONCLUSION: Anatomists Casserius and Valsalva can be considered the discoverers of the 'oesophageal sphincter'. PMID- 25273482 TI - Assessing premorbid cognitive ability in adults with type 2 diabetes mellitus--a review with implications for future intervention studies. AB - Associations between type 2 diabetes mellitus (T2DM) and accelerated cognitive decline are well established. However, the sensitivity of neuropsychological tests to detect early deficits in cognitively normal adults with T2DM is unknown. This review examined cognitive domains and specific neuropsychological tests that are impaired in T2DM, based on clinically significant differences (effect sizes >0.5) between T2DM and groups without T2DM. Nine cross-sectional studies were identified which reported means and standard deviations for individual tests. Tests of executive function, working memory and psychomotor and attentional functions were found to be impaired in T2DM. Impairments of executive function and choice reaction time may have consequences for everyday functioning, in particular the risk of falls in older adults. More research on cognitive deficits in dual-task situations and how they impact everyday functioning is needed; the Trail Making Task, Symbol Digit Modalities Test, Verbal Fluency Task and tests of reaction time and processing speed could be included as core components of test batteries in future intervention studies. They could also be assessed in newly diagnosed T2DM and used to monitor progressive deterioration of cognitive function and the efficacy of therapeutic interventions on cognitive function. PMID- 25273484 TI - Before Charcot. AB - From the time of Greco-Roman Medicine, the uncertain nature of hysterical illness was a fertile source of controversy. Because there were no testable objective signs of disease, the diverse ideas relating hysteria to the uterus and to psychological and physiological causes generated persisting polemics. Theories fluctuated chaotically, influenced by social changes of prosperity or deprivation, current attitudes, and issues of gender. Faced with a large number of patients with such illnesses as well as many with epilepsy, mental illnesses, and organic nervous disorders, Charcot set about investigating hysterics to determine what neurological abnormalities might explain them. His many predecessors, from Sydenham and Willis in the 17th century to Briquet and Bourneville in the 19th century, whose views are outlined in this chapter, both conditioned and influenced his efforts. Charcot succeeded in promoting his work at Salpetriere, which for a time was respected throughout the world. PMID- 25273485 TI - Socioeconomic background of hysteria's metamorphosis from the 18th Century to World War I. AB - The many changes in the etiopathogenic theories of hysteria, developed from the end of the 18th century to the end of World War I, can only be understood by studying the social, political, economic, and cultural transformations of the Western world during the same period. These transformations, presented below along with concurrent medical discoveries, make it possible to explain the ongoing metamorphosis of both hysteria and the image of the hysteric patient. PMID- 25273486 TI - 'Fin-de-Siecle' epidemiology of hysteria. AB - An 'explanatory epidemiology' of disorders labelled 'hysteria' towards the end of the 19th century provides precious information--through the numerous statistical works of the period - about the conceptions of practitioners and the various cultural factors which made this era, in France, 'the golden age' of hysteria. The heyday of hysteria at the end of the century appears to be closely linked to the prestige of Charcot and the promotion of his ideas through the circle of his pupils. The disappearance after his death of hysteria, as he had described it in a defined and systematical manner, is a strong argument for considering it to be a transient mental illness, according to the definition of this concept by Ian Hacking. The regular appearance since then of new nonorganic diseases, avatars of hysteria, with a strong potential for contagiousness and whose causality is exterior to the person, as well as the persistence of the older, more characteristic forms, is evocative of the existence of an ancestral reactional mode taking on various clinical forms according to time and place. PMID- 25273487 TI - Clinical manifestations of hysteria: an epistemological perspective or how historical dynamics illuminate current practice. AB - Hysteria has generated the most heated debates among physicians, from antiquity to the present day. It has been long confused with neuroses and neurological pathologies such as Parkinson's disease and epilepsy, principally associated with women and sexual disorders. The clinical manifestations must first be seen in their historical context, as interpretation varies according to the time period. Recently, the Diagnostic and Statistical Manual of Mental Disorders by the American Psychiatric Association marked a break in the consensus that previously seemed to apply to the concept of hysteria and approach to the clinical manifestations. The clinical manifestations of hysteria are numerous and multifaceted, comprising 3 main classifications: paroxysms, attacks, and acute manifestations; long-lasting functional syndromes, and visceral events. Each main classification can be subdivided into several subgroups. The first main group of paroxysms, attacks, and acute manifestations includes major hysterical attacks, such as prodrome, trance and epileptic states, minor hysterical attacks such as syncope and tetany, twilight states, paroxysmal amnesia, and cataleptic attacks. The second group includes focal hysterical symptoms, paralyses, contractures and spasms, anesthesia, and sensory disorders. Visceral manifestations can be subdivided into spasms, pain, and general and trophic disorders. The diversity of the symptoms of hysteria and its changing clinical presentation calls into question the same hysterical attacks and the same symptoms, which have had only a few differences for over 2,000 years. A new definition of hysteria should be proposed, in that it is a phenomenon that is not pathological, but physiological and expressional. PMID- 25273488 TI - Jean-Martin Charcot and his legacy. AB - Jean-Martin Charcot (1825-1893) rightly is considered the father of both modern neurology and psychiatry in France and much beyond. While he never was interested in mental disease and what was called 'alienism' at the time, his career at La Salpetriere Hospital over 30 years was mainly marked by the development of a huge group of students which focused on the study and management of hysteria. When Charcot took office at the beginning of 1862, hysteria was a 'no-man's land', medically speaking, since neither the alienists nor the internists had much interest in this condition. At La Salpetriere, these chronic patients were largely left to themselves before Desire Bourneville, one of Charcot's first students, convinced his chief to care for them. Subsequently, the studies of Charcot with Paul Richer, Joseph Babinski, Georges Gilles de la Tourette, Paul Sollier, Pierre Janet, and many others allowed the condition to be addressed in detail. During his stay with Charcot in 1885-1866, Sigmund Freud, a young neuropathologist at the time, became fascinated by hysteria, an interest which probably was the main start of his interest in psychology. Charcot emphasized the concept of mental factors in hysteria, along with that of a 'dynamic' lesion, which accounted for the lack of neuropathological findings in the patients. While his ideas on hysteria and hypnotism were criticized after his death even by former pupils, such as Babinski, recent findings from functional studies using magnetic resonance imaging show how accurate and often visionary Charcot's thinking was in this field. PMID- 25273489 TI - Hypnosis and the Nancy quarrel. AB - The theme of hysteria and hypnotism has been attracting the attention of medics, psychologists, writers, and the broad lay public. The role of hypnotism in the context of societal functioning, especially in crime, was a subject of research and significant debates between different neurology and psychology schools. One of these debates was between the Nancy and Salpetriere schools of neurology at the end of the 19th century, and it was focused around a few cases of crime committed allegedly under hypnosis. In order to understand this particular quarrel, this chapter examines the history of mesmerism, hysteria, hypnosis, and fin-de-siecle neurology represented by both the Nancy and Salpetriere schools. PMID- 25273490 TI - The girls of La Salpetriere. AB - It was only by chance that French hospital authorities assigned Jean-Martin Charcot to the care of hysterics and epileptics, starting in 1870, at La Salpetriere Hospital. The famous clinical work that resulted has been the subject of much discussion and, in many cases, misinterpretation. By referring to original sources, i.e., the medical observations written at the time by the department's staff, our aim is to bring the hospitalized patients to life. Many of these observations contain intimate details and reveal the painful experiences that led these young women to La Salpetriere. To understand the gradual, 20-year evolution of Charcot's neurological thinking about hysteria, from organicity to psychology, in both clinical and therapeutic terms, it is more revealing to analyze all the physical and psychological miseries that make up this forgotten 'human material' than it is to examine the neurologist's famous lessons. PMID- 25273491 TI - Public medical shows. AB - In the second half of the 19th century, Jean-Martin Charcot (1825-1893) became famous for the quality of his teaching and his innovative neurological discoveries, bringing many French and foreign students to Paris. A hunger for recognition, together with progressive and anticlerical ideals, led Charcot to invite writers, journalists, and politicians to his lessons, during which he presented the results of his work on hysteria. These events became public performances, for which physicians and patients were transformed into actors. Major newspapers ran accounts of these consultations, more like theatrical shows in some respects. The resultant enthusiasm prompted other physicians in Paris and throughout France to try and imitate them. We will compare the form and substance of Charcot's lessons with those given by Jules-Bernard Luys (1828-1897), Victor Dumontpallier (1826-1899), Ambroise-Auguste Liebault (1823-1904), Hippolyte Bernheim (1840-1919), Joseph Grasset (1849-1918), and Albert Pitres (1848-1928). We will also note their impact on contemporary cinema and theatre. PMID- 25273492 TI - Emma Bovary, Hedda Gabler, and Harold Brodkey would not have lived without Charcot: hysteria in novels. AB - Medical humanities is the interdisciplinary field of humanities (literature, philosophy, ethics, history, and religion), social science (anthropology, cultural studies, psychology, and sociology), and the arts (literature, theater, film, and visual arts), and their application to medical education and practice. In this chapter, the concept of 'hysteria' is put into a medical humanities perspective. We review the concept of hysteria concisely. Two novels and one autobiographical story are used as material in order to study how 'hysteria' is represented in literary work. Madame Bovary (Gustave Flaubert), Hedda Gabler (Henrik Ibsen), and A Story in an Almost Classical Mode (Harold Brodkey) were searched for elements that are characteristic of hysteria. Excessive emotion, dramatics, attention-seeking behavior, physical symptoms of unknown and unidentifiable organic causes, self-centered behavior, and flirtatious behavior are the six elements used to operationalize hysteria. It was found that these elements were present in both a quantitative and qualitative manner in the literary works examined. Acknowledging some limitations and suggesting some research areas and clinical implications, we conclude that literary works are useful in analyzing concepts in medicine. Also, more generally, using literary works seems to have a positive impact on readers, healthcare providers, and researchers in the healthcare domain. Studying novels and related literary work contributes to the body of knowledge of medical humanities. PMID- 25273493 TI - Traces of hysteria in novels. AB - There have been many descriptions of presumed 'hysterics' in fiction, many appearing in French literature, but also in a number of other languages. It is clear that contemporary medical ideas and insights about hysteria had a major influence on its depiction in novels. This is particularly true for naturalistic literature, which has been the subject of previous reviews. Here, we focus on a more recent novel: Human Traces by Sebastian Faulks (2005). What is special about the depiction of hysteria in this work is that the presumed 'hysteric' turns out not to be hysteric at all. In the novel, as well as in this chapter, the diagnosis of hysteria is discussed in the light of theories about hysteria of around 1900. For comparison, we present some examples of true 'hysterics' as they occur in fiction. Since it has become clear that severe nonpsychiatric diseases such as an ovarian teratoma can lead to bizarre phenotypes, the association of 'hysteria' with the womb has to be seen in another light. PMID- 25273494 TI - Sigmund Freud and hysteria: the etiology of psychoanalysis? AB - Sigmund Freud developed a specific interest in hysteria after his stay with Professor Jean-Martin Charcot during the winter of 1885-1886, although his previous activity mainly consisted of neuropathology and general medical practice. Most of his initial studies on hysteria (hysteria in men, influence of subconscious ideas, role of traumas, and psychological and sexual factors) were indeed 'borrowed' from Charcot and his immediate followers, such as Pierre Janet and Paul Richer. Subsequently, Freud developed with Breuer a theory of hysteria which encompassed a mixture of Janet's 'fixed subconscious ideas' with the 'pathological secret' concept of Moriz Benedikt. After their book Studies on Hysteria (1895), Freud interrupted his collaboration with Breuer and developed the concept of conversion of psychological problems into somatic manifestations, with a strong 'sexualization' of hysteria. Firstly, he believed that actual abuses had occurred in these patients (the 'seduction' theory), but then blamed them for having deceived him on that issue, so that he subsequently launched a 'fantasy' theory to explain the development of hysterical symptoms without the necessity of actual abuses. Like many of his contemporaries, and contrary to his claims, Freud did not follow a scientific process of verified experiments, but rather adapted his theories to the evolution of his own beliefs on psychological conditions, selectively emphasizing the aspects of his 'therapies' with patients which supported his emerging ideas, with often abrupt changes in theoretical interpretations. While it remains difficult to get a clear, synthetic vision of what was Freud's definite theory of hysteria, it is obvious that hysteria really was the origin of what would become Freud's psychoanalytical theory. Indeed, psychoanalysis appears to have been initially developed by him largely in order to absorb and explain his many changes in the interpretation of hysterical manifestations. PMID- 25273495 TI - Paul Sollier, Pierre Janet, and their vicinity. AB - Paul Sollier (1861-1933) and Pierre Janet (1859-1947) shared the same fate: achieving fame during their lives, then slipping into obscurity. However, their work is highly relevant for describing and explaining hysteria in the tradition of Jean-Martin Charcot (1825-1893). Both men had their teacher's clinical perspicacity, which enabled them to accumulate detailed clinical and psychological descriptions. These were published in books that achieved success in their day. From his descriptions, Sollier deduced a pathophysiology of hysteria in which a psychic inhibition led to a functional deficit in sensory motor areas. This is partially confirmed by current functional brain imaging techniques. As for Janet, he developed concepts which are still valid today, involving personality dissociation, what he referred to as 'fixed ideas', and the subconscious. Sollier and Janet both saw hysteria as a response to the trigger of an emotional shock, specific to certain personalities. While the fundamental work by Joseph Babinski (1857-1932) on hysterical paralysis did much to enrich neurological semiology, Sollier contributed a novel description of the pathophysiology of hysteria, and Janet elucidated its psychopathological mechanisms. PMID- 25273496 TI - Criticism of pithiatism: eulogy of Babinski. AB - Babinski, 'Chef de Clinique' of Charcot from 1885 to 1887, fully supported the ideas of his teacher on hysteria and thought that a dynamic brain cortical lesion is the cause of the disease. After Charcot's death in 1893, Babinski gradually revised his position. In a first step, he described many neurological signs in order to clearly distinguish hysterical manifestations from the organic disorders of the central nervous system. The most famous one bears his name, the Babinski sign, an inversion of the plantar cutaneous reflex, testifying to a lesion of the pyramidal tract. In a second step, he defined what remained of hysteria and proposed in 1901 to abandon the term 'hysteria' in favor of the neologism 'pithiatism', defined as a pathologic state resulting in disorders which can be very accurately reproduced by suggestion, and can disappear by persuasion. Babinski therefore retained the exclusive etiological role of suggestion and refuted, unlike Dejerine, the role of emotion. He also sought to separate pithiatism from simulation, but ambiguously he made pithiatics 'semi malingerers'. During the Great War, with Froment, he described physiopathic disorders and separated them from pithiatic disorders and simulation. After being accepted by many French neurologists, pithiatism, the word as well as the concept, gently died out. There remained little more than a few philosophical uses (especially by Jean-Paul Sartre and Maurice Merleau-Ponty) or metaphorical ones. What remains of the work of Babinski in the field of hysteria is not so much the creation of pithiatism as the masterly description of neurological signs to formally exclude an organic lesion of the nervous system or simulation before looking like hysteria disorders. PMID- 25273497 TI - The borderland with neurasthenia ('functional syndromes'). AB - At the end of the 19th century, neurasthenia and hysteria were considered distinct diseases. Specifically, neurasthenia was regarded as a disease of the body, whereas hysteria was regarded as a disease of the psyche. However, immediately before World War I, due to their common characteristics, both hysteria and neurasthenia were thought to be 'functional diseases'. Moreover, it was suggested that heredity and the presence in both of the predisposing condition called 'nervous weakness' were other shared factors. Nervous weakness was considered essential for the definition of neurasthenia, but it was also considered a precondition for the development of hysteria. Because of this, it is still difficult to demarcate a line between neurasthenia and hysteria; therefore, the two diseases should be considered as sharing a common borderland with each other. PMID- 25273498 TI - World War I psychoneuroses: hysteria goes to war. AB - During the First World War, military physicians from the belligerent countries were faced with soldiers suffering from psychotrauma with often unheard of clinical signs, such as camptocormia. These varied clinical presentations took the form of abnormal movements, deaf-mutism, mental confusion, and delusional disorders. In Anglo-Saxon countries, the term 'shell shock' was used to define these disorders. The debate on whether the war was responsible for these disorders divided mobilized neuropsychiatrists. In psychological theories, war is seen as the principal causal factor. In hystero-pithiatism, developed by Joseph Babinski (1857-1932), trauma was not directly caused by the war. It was rather due to the unwillingness of the soldier to take part in the war. Permanent suspicion of malingering resulted in the establishment of a wide range of medical experiments. Many doctors used aggressive treatment methods to force the soldiers exhibiting war neuroses to return to the front as quickly as possible. Medicomilitary collusion ensued. Electrotherapy became the basis of repressive psychotherapy, such as 'torpillage', which was developed by Clovis Vincent (1879 1947), or psychofaradism, which was established by Gustave Roussy (1874-1948). Some soldiers refused such treatments, considering them a form of torture, and were brought before courts-martial. Famous cases, such as that of Baptiste Deschamps (1881-1953), raised the question of the rights of the wounded. Soldiers suffering from psychotrauma, ignored and regarded as malingerers or deserters, were sentenced to death by the courts-martial. Trials of soldiers or doctors were also held in Germany and Austria. After the war, psychoneurotics long haunted asylums and rehabilitation centers. Abuses related to the treatment of the Great War psychoneuroses nevertheless significantly changed medical concepts, leading to the modern definition of 'posttraumatic stress disorder'. PMID- 25273499 TI - Hysteria around the world. AB - In the 20th century the term hysteria declined and the interest in the hysteria related diseases decreased in comparison to the florid period of studies that was inspired by Charcot's legacy in the second half of the 19th century. Scientific interest has once again increased in the 21st century, and dissociative and somatoform disorders (previously indicated as hysteria or hysterical neurosis) have come to be regarded as conditions that are known to be much more prevalent than formerly estimated. Available current epidemiological data from several countries on different continents (adopting DSM criteria for diagnosis) suggest not only that the prevalence is probably similar, but also that there is a consistency in their clinical manifestation around the world and across different cultures, social classes, and institutional settings. In line with this uniformity, and also with Charcot's concept of hysteria as a functional disorder, neuroimaging studies suggest that for some of these disorders, there might be some changes of neural connectivity in specific pathways at the origin of the behavioral aspects. Only large-scale multidisciplinary transcultural studies can improve the research and the development of therapeutic interventions for these disorders. PMID- 25273500 TI - History of physical and 'moral' treatment of hysteria. AB - This historical review presents the advances made mostly during the last 200 years on the description, concepts, theories, and (more specifically) cure of patients suffering from hysteria, a still obscure entity. The denomination of the syndrome has changed over time, from hysteria (reinvestigated by Paul Briquet and Jean-Martin Charcot) to pithiatism (Joseph Babinski), then to conversion neurosis (Sigmund Freud), and today functional neurological disorders according to the 2013 American Neurological Association DSM-5 classification. The treatment was renewed in the second half of the 19th century in Paris by Paul Briquet and then by Jean-Martin Charcot. Hysterical women, who represented the great majority of cases, were cured by physical therapy (notably physio-, hydro-, and electrotherapy, and in some cases ovary compression) and 'moral' therapies (general, causal therapy, rest, isolation, hypnosis, and suggestion). At the turn of the 19th and 20th centuries, psychotherapy, psychoanalysis, and persuasion were established respectively by Pierre Janet, Sigmund Freud, and Joseph Babinski. During World War I, military forces faced a large number of posttrauma neurosis cases among soldiers (named the 'Babinski-Froment war neurosis' and Myers 'shell shock', in the French and English literature, respectively). This led to the use of more brutal therapies in military hospitals, combining electrical shock and persuasion, particularly in France with Clovis Vincent and Gustave Roussy, but also in Great Britain and Germany. After World War I, this method was abandoned and there was a marked decrease in interest in hysteria for a long period of time. Today, the current treatment comprises (if possible intensive) physiotherapy, together with psychotherapy, and in some cases psychoanalysis. Antidepressants and anxiolytics may be required, and more recently cognitive and behavioral therapy. Repetitive transcranial magnetic stimulation is a new technique under investigation which may be promising in patients presenting with motor conversion syndrome (motor deficit or movement disorder). Functional neurological disorders remain a difficult problem to manage with frequent failures and chronic handicapping evolution. This emphasizes the need for therapeutic innovations in the future. PMID- 25273501 TI - 'Hysteria' today and tomorrow. AB - 'Hysteria' (conversion disorder) remains in modern humanity and across cultures, as it has for millennia. Advances today in tools and criteria have afforded more accurate diagnosis, and advances in treatments have empowered patients and providers, resulting in a renewed interest in somatoform disorders. Future progress in understanding mechanisms may be influenced by developments in functional neuroimaging and neurophysiology. No animal model exists for somatoform symptoms or conversion disorder. Despite the absence of a known molecular mechanism, psychotherapy is helping patients with conversion disorder to take control of their symptoms and have improved quality of life, shedding light on what was once an enigma. PMID- 25273502 TI - Involvement of a novel fermentative bacterium in acidification in a thermophilic anaerobic digester. AB - Acidification results from the excessive accumulation of volatile fatty acids and the breakthrough of buffering capacity in anaerobic digesters. However, little is known about the identity of the acidogenic bacteria involved. Here, we identified an active fermentative bacterium during acidification in a thermophilic anaerobic digester by sequencing and phylogenetic analysis of isotopically labeled rRNA. The digestion sludge retrieved from the beginning of pH drop in the laboratory scale anaerobic digester was incubated anaerobically at 55 degrees C for 4 h during which 13C-labeled glucose was supplemented repeatedly. 13CH4 and 13CO2 were produced after substrate addition. RNA extracts from the incubated sludge was density-separated by ultracentrifugation, and then bacterial communities in the density fractions were screened by terminal restriction fragment length polymorphism and clone library analyses based on 16S rRNA transcripts. Remarkably, a novel lineage within the genus Thermoanaerobacterium became abundant with increasing the buoyant density and predominated in the heaviest fraction of RNA. The results in this study indicate that a thermoacidophilic bacterium exclusively fermented the simple carbohydrate glucose, thereby playing key roles in acidification in the thermophilic anaerobic digester. PMID- 25273504 TI - Foreign exam management in practice: seamless access to foreign images and results in a regional environment. AB - A challenge for many clinical users is that a patient may receive a diagnostic imaging (DI) service at a number of hospitals or private imaging clinics. The DI services that patients receive at other locations could be clinically relevant to current treatments, but typically, there is no seamless method for a clinical user to access longitudinal DI results for their patient. Radiologists, and other specialists that are intensive users of image data, require seamless ingestion of foreign exams into the picture archiving and communication system (PACS) to achieve full clinical value. Most commonly, a clinical user will depend on the patient to bring in a CD that contains imaging from another location. However, a number of issues can arise when using this type of solution. Firstly, a CD will not provide the clinical user with the full longitudinal record of the patient. Secondly, a CD often will not contain the report associated with the images. Finally, a CD is not seamless, due to the need to manually import the contents of the CD into the local PACS. In order to overcome these limitations, and provide clinical users with a greater benefit related to a patient's longitudinal DI history, the implementation of foreign exam management (FEM) at the local site level is required. This paper presents the experiences of FEM in practice. By leveraging industry standards and edge devices to support FEM, multiple sites with disparate PACS and radiology information system (RIS) vendors are able to seamlessly ingest foreign exams within their local PACS as if they are local exams. PMID- 25273503 TI - CSI 2.0: a significantly improved version of the Chemical Shift Index. AB - Protein chemical shifts have long been used by NMR spectroscopists to assist with secondary structure assignment and to provide useful distance and torsion angle constraint data for structure determination. One of the most widely used methods for secondary structure identification is called the Chemical Shift Index (CSI). The CSI method uses a simple digital chemical shift filter to locate secondary structures along the protein chain using backbone (13)C and (1)H chemical shifts. While the CSI method is simple to use and easy to implement, it is only about 75 80% accurate. Here we describe a significantly improved version of the CSI (2.0) that uses machine-learning techniques to combine all six backbone chemical shifts ((13)Calpha, (13)Cbeta, (13)C, (15)N, (1)HN, (1)Halpha) with sequence-derived features to perform far more accurate secondary structure identification. Our tests indicate that CSI 2.0 achieved an average identification accuracy (Q3) of 90.56% for a training set of 181 proteins in a repeated tenfold cross-validation and 89.35% for a test set of 59 proteins. This represents a significant improvement over other state-of-the-art chemical shift-based methods. In particular, the level of performance of CSI 2.0 is equal to that of standard methods, such as DSSP and STRIDE, used to identify secondary structures via 3D coordinate data. This suggests that CSI 2.0 could be used both in providing accurate NMR constraint data in the early stages of protein structure determination as well as in defining secondary structure locations in the final protein model(s). A CSI 2.0 web server (http://csi.wishartlab.com) is available for submitting the input queries for secondary structure identification. PMID- 25273505 TI - Computer aided preoperative evaluation of the residual liver volume using computed tomography images. AB - Major hepatectomy causes a risk of postoperative liver dysfunction, failure, and infections like surgical site infection. Preoperative assessment of the liver volume and function of the remnant liver is a mandatory prerequisite before performing such surgery. The aim of this work is to develop and test a software application for evaluation of the residual function of the liver prior to the intervention of the surgeons. For this purpose, a technique for evaluation of liver volume from computed tomography (CT) images has been developed. Furthermore, the methodology algorithms were implemented and incorporated within a software tool with three basic functionalities: volume determination based on segmentation of liver from CT images, virtual tumour resection and estimation of the residual liver function and 3D visualisation. Forty-one sets of abdominal CT images consisting of different number of tomographic slice images were used to test and evaluate the proposed approach. Volumes that were obtained after manual tracing by two surgeon experts showed a relative difference of 3.5 %. The suggested methodology was encapsulated within an application with user-friendly interface that allows surgeons interactively to perform virtual tumour resection, to evaluate the relative residual liver and render the final result. Thereby, it is a tool in the surgeons' hands that significantly facilitates their duties, saves time, and allows them to objectively evaluate the situation and take the right decisions. At the same time, the tool appears to be appropriate educational instrument for virtual training of young surgeon specialists. PMID- 25273506 TI - Preventing errors in laterality. AB - An error in laterality is the reporting of a finding that is present on the right side as on the left or vice versa. While different medical and surgical specialties have implemented protocols to help prevent such errors, very few studies have been published that describe these errors in radiology reports and ways to prevent them. We devised a system that allows the radiologist to view reports in a separate window, displayed in a simple font and with all terms of laterality highlighted in separate colors. This allows the radiologist to correlate all detected laterality terms of the report with the images open in PACS and correct them before the report is finalized. The system is monitored every time an error in laterality was detected. The system detected 32 errors in laterality over a 7-month period (rate of 0.0007 %), with CT containing the highest error detection rate of all modalities. Significantly, more errors were detected in male patients compared with female patients. In conclusion, our study demonstrated that with our system, laterality errors can be detected and corrected prior to finalizing reports. PMID- 25273509 TI - Convective polymer assembly for the deposition of nanostructures and polymer thin films on immobilized particles. AB - We report the preparation of polymer particles via convective polymer assembly (CPA). Convection is used to move polymer solutions and cargo through an agarose gel that contains immobilized template particles. This method both coats and washes the particles in a process that is amenable to automation, and does not depend on passive diffusion or electrical currents, thus facilitating incorporation of fragile and nanoscale objects, such as liposomes and gold nanoparticles, into the thin polymer films. Template dissolution leads to the formation of stable polymer particles and capsules. PMID- 25273508 TI - Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study. AB - BACKGROUND AND AIM: Sorafenib is recommended as a standard treatment for advanced hepatocellular carcinoma (HCC). The efficacy and safety of sorafenib as a first line therapy in Korean patients with advanced HCC were investigated. METHODS: From 2007 to 2012, 86 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) treated with sorafenib as a first-line therapy were enrolled from five tertiary hospitals. Predictors of overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: The median age was 59.5 years, and 71 (82.6%) were males; 57 (66.3%) patients were in Child-Pugh class A. The median OS and PFS were 5.0 (range 4.0-5.9) and 3.2 (range 2.6-3.7) months, respectively. Regarding OS, Child-Pugh class A (6.0 vs 2.8 months), tumor diameter < 5 cm (6.0 vs 4.3 months), baseline alpha-fetoprotein < 200 ng/mL (5.8 vs 4.1 months), and the advent of hand-foot-skin reaction of >= grade 2 (5.9 vs 4.0 months) were independent favorable predictors (all P < 0.05). Similarly, regarding PFS, Child Pugh class A (4.3 vs 2.1 months), tumor diameter < 5 cm (3.9 vs 2.8 months), baseline alpha-fetoprotein < 200 ng/mL (5.6 vs 2.8 months), and the advent of hand-foot-skin reaction of >= grade 2 (4.5 vs 2.6 months) were independent favorable predictors (all P < 0.05). All toxicities during sorafenib treatment were manageable. CONCLUSIONS: Because the efficacy of sorafenib seems marginal in Korean patients with treatment-naive HCC, how to select candidates with favorable outcomes should be further investigated. PMID- 25273507 TI - ZNF695 methylation predicts a response of esophageal squamous cell carcinoma to definitive chemoradiotherapy. AB - PURPOSE: Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT. METHODS: A total of 104 patients were divided into screening (n = 43) and validation (n = 61) sets. A genome-wide DNA methylation analysis was performed using an Infinium HumanMethylation450 BeadChip array. Methylation levels were measured by quantitative methylation-specific PCR and normalized by the fraction of cancer cells in a sample. RESULTS: The genome-wide methylation analysis of seven responders and eight non-responders identified 18 genomic regions specifically (un)methylated in the responders. Among these, methylation of the promoter CpG island of ZNF695 was significantly associated with the response to dCRT in the screening set (P = 0.004), and a cutoff value was determined. In the validation set, the association was successfully validated (P = 0.021), and a high specificity (90 %) for the prediction of responders was obtained using the prefixed cutoff value. In addition, a multivariate analysis showed that ZNF695 methylation was an independent predictive factor for the response to dCRT (OR 7.55, 95 % CI 2.12-26.9, P = 0.002). CONCLUSION: ZNF695 methylation was significantly associated with the response to dCRT and is a promising predictive marker for the response to dCRT. PMID- 25273510 TI - Effects of short-term oral administration of trimethoprim-sulfamethoxazole on tear production in clinically normal Syrian hamsters. AB - OBJECTIVE: To determine effects of 14 days of oral administration of trimethoprim sulfamethoxazole on aqueous tear production in clinically normal Syrian hamsters. ANIMAL STUDIED: Fifteen healthy adult Syrian hamsters. PROCEDURE: Baseline phenol red thread test (PRTT) values were recorded 1 day prior to treatment. Eight hamsters in treated group received 15 mg/kg trimethoprim-sulfamethoxazole orally twice a day for 14 days. The remaining seven hamsters were used as untreated controls and received a placebo. All ophthalmic tests were performed without chemical restraint. PRTT values were evaluated in both eyes of all Syrian hamsters using a commercial PRTT strip of a single lot number. RESULTS: The mean +/- SD baseline PRTT values for treatment group and control group were 7.25 +/- 1.3 mm/15 s and 5.42 +/- 1.13 mm/15 s, respectively. After 14 days of drug administration, the mean +/- SD PRTT values for treatment group and control group were 5.62 +/- 1.5 and 5.64 +/- 0.74, respectively. Significant decreases in the PRTT values, compared with baseline values, were observed in the treatment group on day 15 (P = 0.042). CONCLUSIONS: Trimethoprim-sulfamethoxazole decreased tear production in the hamster in this study. PMID- 25273511 TI - Prospective evaluation of a complex public health intervention: lessons from an initial and follow-up cross-sectional survey of the tuberculosis strain typing service in England. AB - BACKGROUND: The national tuberculosis strain typing service (TB-STS) was introduced in England in 2010. The TB-STS involves MIRU-VNTR typing of isolates from all TB patients for the prospective identification, reporting and investigation of TB strain typing clusters. As part of a mixed-method evaluation, we report on a repeated cross-sectional survey to illustrate the challenges surrounding the evaluation of a complex national public health intervention. METHODS: An online initial and follow-up questionnaire survey assessed the knowledge, attitudes and practices of public health staff, physicians and nurses working in TB control in November 2010 and March 2012. It included questions on the implementation, experience and uptake of the TB-STS. Participants that responded to both surveys were included in the analysis. RESULTS: 248 participants responded to the initial survey and 137 of these responded to the follow-up survey (56% retention). Knowledge: A significant increase in knowledge was observed, including a rise in the proportion of respondents who had received training (28.6% to 67.9%, p = 0.003), and the self-rated knowledge of how to use strain typing had improved ('no knowledge' decreased from 43.2% to 27.4%). Attitudes: The majority of respondents found strain typing useful; the proportion that reported strain typing to be useful was similar across the two surveys (95.7% to 94.7%, p = 0.67). Practices: There were significant increases between the initial and follow-up surveys in the number of respondents who reported using strain typing (57.0% to 80.5%, p < 0.001) and the proportion of time health protection staff spent on investigating TB (2.74% to 7.08%, p = 0.04). CONCLUSIONS: Evaluation of a complex public health intervention is challenging. In this example, the immediate national roll-out of the TB-STS meant that a controlled survey design was not possible. This study informs the future development of the TB-STS by identifying the need for training to reach wider professional groups, and argues for its continuation based on service users' perception that it is useful. By highlighting the importance of a well-defined sampling frame, collecting baseline information, and including all stakeholders, it provides lessons for the implementation of similar services in other countries and future evaluations of public health interventions. PMID- 25273512 TI - Chryseobacterium takakiae sp. nov., a member of the phylum Bacteroidetes isolated from Takakia lepidozioides. AB - A Gram-stain-negative, rod-shaped and non-endospore-forming bacterium, designated strain AG1-2(T), was isolated from Takakia lepidozioides collected from the Gawalong glacier in Tibet, China and characterized using a polyphasic taxonomic approach. The predominant fatty acids of strain AG1-2(T) were iso-C15 : 0 (36.0 %), iso-C17:0 3-OH (20.2 %), summed feature 9 (iso-C17:1omega9c and/or C16:0 10 methyl, 16.4%) and summed feature 3 (C16:1omega7c and/or C16:1omega6c, 11.1%). The major polar lipids were phosphatidylethanolamine, three unidentified aminolipids and two unidentified lipids. Strain AG1-2(T) contained MK-6 as the dominant menaquinone, and the genomic DNA G+C content was 37.3 mol%. The phylogenetic analysis based on the 16S rRNA gene sequences showed that strain AG1 2(T) was affiliated to species of the genus Chryseobacterium, and its closest related species were Chryseobacterium taiwanense Soil-3-27(T), Chryseobacterium hispalense AG13(T), Chryseobacterium camelliae THG C4-1(T) and Chryseobacterium taeanense PHA3-4(T) with a sequence similarity of 98.0, 97.8, 97.3 and 97.1%, respectively. However, the DNA-DNA relatedness values between these strains and strain AG1-2(T) were 29, 21, 21 and 45%, respectively. Based on phylogenetic inference and phenotypic data, strain AG1-2(T) is considered to represent a novel species of the genus Chryseobacterium, for which the name Chryseobacterium takakiae sp. nov. is proposed. The type strain is AG1-2(T) ( = CGMCC 1.12488(T) = DSM 26898(T)). PMID- 25273513 TI - Acidiphilium iwatense sp. nov., isolated from an acid mine drainage treatment plant, and emendation of the genus Acidiphilium. AB - Several strains of aerobic, acidophilic, chemo-organotrophic bacteria belonging to the genus Acidiphilium were isolated from an acid mine drainage (AMD) (pH 2.2) treatment plant. 16S rRNA gene sequence comparisons showed that most of the novel isolates formed a phylogenetically coherent group (designated Group Ia) distinguishable from any of the previously established species of the genus Acidiphilium at <98% similarity. This was supported by genomic DNA-DNA hybridization assays. The Group Ia isolates were characterized phenotypically by an oval cell morphology, non-motility, growth in the range pH 2.0-5.5 (optimum pH 3.5), lack of photosynthetic pigment and the presence of C19:0 cyclo omega8c as the main component of the cellular fatty acids and ubiquinone-10 as the major quinone. On the basis of these data, the name Acidiphilium iwatense sp. nov. is proposed to accommodate the Group Ia isolates, and the description of the genus Acidiphilium is emended. The type strain of Acidiphilium iwatense sp. nov. is MS8(T) ( =NBRC 107608(T)=KCTC 23505(T)). PMID- 25273514 TI - Massilia norwichensis sp. nov., isolated from an air sample. AB - A Gram-negative, rod-shaped and motile bacterial isolate, designated strain NS9(T), isolated from air of the Sainsbury Centre for Visual Arts in Norwich, UK, was subjected to a polyphasic taxonomic study including phylogenetic analyses based on partial 16S rRNA, gyrB and lepA gene sequences and phenotypic characterization. The 16S rRNA gene sequence of NS9(T) identified Massilia haematophila CCUG 38318(T), M. niastensis 5516S-1(T) (both 97.7% similarity), M. aerilata 5516S-11(T) (97.4%) and M. tieshanensis TS3(T) (97.4%) as the next closest relatives. In partial gyrB and lepA sequences, NS9(T) shared the highest similarities with M. haematophila CCUG 38318(T) (94.5%) and M. aerilata 5516 11(T) (94.3%), respectively. These sequence data demonstrate the affiliation of NS9(T) to the genus Massilia. The detection of the predominant ubiquinone Q-8, a polar lipid profile consisting of the major compounds diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol and a polyamine pattern containing 2-hydroxyputrescine and putrescine were in agreement with the assignment of strain NS9(T) to the genus Massilia. Major fatty acids were summed feature 3 (C16:1omega7c and/or iso-C15 : 0 2-OH), C16:0, C18: 1omega7c and C10:0 3-OH. Dissimilarities in partial lepA and gyrB gene sequences as well as results from DNA-DNA hybridizations demonstrate that strain NS9(T) is a representative of an as-yet undescribed species of the genus Massilia that is also distinguished from its close relatives based on physiological and biochemical traits. Hence, we describe a novel species, for which we propose the name Massilia norwichensis sp. nov., with the type strain NS9(T) ( = CCUG 65457(T) =LMG 28164(T)). PMID- 25273515 TI - Kidney-brain link in traumatic brain injury patients? A preliminary report. AB - BACKGROUND: Kidney hyperfiltration with augmented renal clearance is frequently observed in patients with traumatic brain injury. The aim of this study is to report preliminary findings about the relationship between brain autoregulation impairment, estimated kidney glomerular filtration rate and outcome in critically ill patients after severe traumatic brain injury. METHODS: Data collected from a cohort of 18 consecutive patients with severe traumatic brain injury managed with ICP monitoring in a Neurocritical Care Unit, were retrospectively analyzed. Early morning blood tests were performed for routine chemistry assessments and we analyzed creatinine and estimated creatinine clearance, osmolarity, and sodium. Daily norepinephrine dose, protein intake, and water balance were documented. Time average of brain monitoring data (intracranial pressure, cerebral perfusion pressure, and cerebrovascular reactivity pressure index--PRx) were calculated for 6 h before blood sample tests. Patient outcome was evaluated using Glasgow outcome scale at 6-month follow-up, considering nonfatal outcome if GOS >= 3 and fatal outcome if GOS < 3. Multiple linear regression models were used to study the crude and adjusted effects of the above variables on PRx throughout time. RESULTS: A total of 199 complete daily observations from 18 adult consecutive multiple trauma patients with severe traumatic brain injury were analyzed. At hospital admission, the median post-resuscitation Glasgow coma score was 6 (range 3-12), mean SAPSII score was 44.65 with predicted mortality of 36 %. Hospital mortality rate was 27 % and median GOS at 6 month after discharge was 3. Creatinine clearance (CrCl) was found to have a negative correlation with PRx (Pearson correlation--0.82), with statistically significant crude (p < 0.001) and adjusted (p = 0.001) effects. For each increase of 10 ml/min in CrCl (estimated either by the Cockcroft-Gault or by Modification of Diet in Renal Disease Study equations) a mean decrease in PRx of approximately 0.01 was expected. Amongst possible confounders only norepinephrine was shown to have a significant effect. Mean PRx value for outcome fatal status was greater than mean PRx for nonfatal status (p < 0.05), regardless of the model used for the CrCl estimation. CONCLUSIONS: Better cerebral autoregulation evaluated with cerebrovascular PRx is significantly correlated with augmented renal clearance in TBI patients and associates with better outcome. PMID- 25273516 TI - Arsenic removal from water employing a combined system: photooxidation and adsorption. AB - A combined system employing photochemical oxidation (UV/H2O2) and adsorption for arsenic removal from water was designed and evaluated. In this work, a bench scale photochemical annular reactor was developed being connected alternately to a pair of adsorption columns filled with titanium dioxide (TiO2) and granular ferric hydroxide (GFH). The experiences were performed by varying the relation of As concentration (As (III)/As (V) weight ratio) at constant hydrogen peroxide concentration and incident radiation. Experimental oxidation results were compared with theoretical predictions using an intrinsic kinetic model previously obtained. In addition, the effectiveness of the process was evaluated using a groundwater sample. The mathematical model of the entire system was developed. It could be used as an effective tool for the design and prediction of the behaviour of these types of systems. The combined technology is efficient and promising for arsenic removal to small and medium scale. PMID- 25273517 TI - Alternatives to neonicotinoid insecticides for pest control: case studies in agriculture and forestry. AB - Neonicotinoid insecticides are widely used for control of insect pests around the world and are especially pervasive in agricultural pest management. There is a growing body of evidence indicating that the broad-scale and prophylactic uses of neonicotinoids pose serious risks of harm to beneficial organisms and their ecological function. This provides the impetus for exploring alternatives to neonicotinoid insecticides for controlling insect pests. We draw from examples of alternative pest control options in Italian maize production and Canadian forestry to illustrate the principles of applying alternatives to neonicotinoids under an integrated pest management (IPM) strategy. An IPM approach considers all relevant and available information to make informed management decisions, providing pest control options based on actual need. We explore the benefits and challenges of several options for management of three insect pests in maize crops and an invasive insect pest in forests, including diversifying crop rotations, altering the timing of planting, tillage and irrigation, using less sensitive crops in infested areas, applying biological control agents, and turning to alternative reduced risk insecticides. Continued research into alternatives is warranted, but equally pressing is the need for information transfer and training for farmers and pest managers and the need for policies and regulations to encourage the adoption of IPM strategies and their alternative pest control options. PMID- 25273518 TI - Acidophilic denitrifiers dominate the N2O production in a 100-year-old tea orchard soil. AB - Aerobic denitrification is the main process for high N2O production in acid tea field soil. However, the biological mechanisms for the high emission are not fully understood. In this study, we examined N2O emission and denitrifier communities in 100-year-old tea soils with four pH levels (3.71, 5.11, 6.19, and 7.41) and four nitrate concentration (0, 50, 200, and 1000 mg kg(-1) of NO3 (-) N) addition. Results showed the highest N2O emission (10.1 mg kg(-1) over 21 days) from the soil at pH 3.71 with 1000 mg kg(-1) NO3 (-) addition. The N2O reduction and denitrification enzyme activity in the acid soils (pH <7.0) were significantly higher than that of soils at pH 7.41. Moreover, TRF 78 of nirS and TRF 187 of nosZ dominated in soils of pH 3.71, suggesting an important role of acidophilic denitrifiers in N2O production and reduction. CCA analysis also showed a negative correlation between the dominant denitrifier ecotypes (nirS TRF 78, nosZ TRF 187) and soil pH. The representative sequences were identical to those of cultivated denitrifiers from acidic soils via phylogenetic tree analysis. Our results showed that the acidophilic denitrifier adaptation to the acid environment results in high N2O emission in this highly acidic tea soil. PMID- 25273519 TI - Surfactant-modified bentonite clays: preparation, characterization, and atrazine removal. AB - Bentonite clay was modified using quaternary ammonium cations, viz. phenyltrimethylammonium (PTMA), hexadecyltrimethylammonium (HDTMA), trioctylmethylammonium (TOMA) [100 % of cation exchange capacity of clay], and stearylkonium (SK) [100 % (SK-I) and 250 % (SK-II) of cation exchange capacity of clay]. The organoclays were characterized using X-ray diffraction (XRD), infrared (IR) spectroscopy, and scanning electron microscopy (SEM). Atrazine adsorption on modified clays was studied using a batch method. Bentonite clay was a poor adsorbent of atrazine as 9.4 % adsorption was observed at 1 MUg mL(-1) atrazine concentration. Modification of clay by PTMA cation did not improve atrazine adsorption capacity. However, atrazine adsorption in HDTMA-, TOMA-, and SK bentonites varied between 49 and 72.4 % and data fitted well to the Freundlich adsorption isotherm (R > 0.96). Adsorption of atrazine in organoclays was nonlinear and slope (1/n) values were <1. The product of Freundlich adsorption constants, K f(1/n) in HDTMA-, TOMA-, and SK-I-bentonites was 239.2, 302.4, and 256.6, respectively, while increasing the SK cation loading in the clay (SK-II) decreased atrazine adsorption [K f(1/n) - 196.4]. Desorption of atrazine from organoclays showed hysteresis and TOMA- and SK-I-bentonites were the best organoclays to retain the adsorbed atrazine. Organoclays showed better atrazine removal from wastewater than an aqueous solution. The synthesized organoclays may find application in soil and water decontamination and as a carrier for atrazine controlled released formulations. PMID- 25273520 TI - Enhanced green fluorescent protein-mediated synthesis of biocompatible graphene. AB - BACKGROUND: Graphene is the 2D form of carbon that exists as a single layer of atoms arranged in a honeycomb lattice and has attracted great interest in the last decade in view of its physical, chemical, electrical, elastic, thermal, and biocompatible properties. The objective of this study was to synthesize an environmentally friendly and simple methodology for the preparation of graphene using a recombinant enhanced green fluorescent protein (EGFP). RESULTS: The successful reduction of GO to graphene was confirmed using UV-vis spectroscopy, and FT-IR. DLS and SEM were employed to demonstrate the particle size and surface morphology of GO and EGFP-rGO. The results from Raman spectroscopy suggest the removal of oxygen-containing functional groups from the surface of GO and formation of graphene with defects. The biocompatibility analysis of GO and EGFP rGO in human embryonic kidney (HEK) 293 cells suggests that GO induces significant concentration-dependent cell toxicity in HEK cells, whereas graphene exerts no adverse effects on HEK cells even at a higher concentration (100 MUg/mL). CONCLUSIONS: Altogether, our findings suggest that recombinant EGFP can be used as a reducing and stabilizing agent for the preparation of biocompatible graphene. The novelty and originality of this work is that it describes a safe, simple, and environmentally friendly method for the production of graphene using recombinant enhanced green fluorescent protein. Furthermore, the synthesized graphene shows excellent biocompatibility with HEK cells; therefore, biologically synthesized graphene can be used for biomedical applications. To the best of our knowledge, this is the first and novel report describing the synthesis of graphene using recombinant EGFP. PMID- 25273521 TI - Diagnosis of primary pulmonary T- cell/histiocyte-rich large B cell lymphoma with tissue eosinophilia via clinicopathological observation and molecular assay. AB - BACKGROUND: Primary pulmonary lymphoma (PPL) is rare and easily misdiagnosed because of the lack of typical clinical features. It most commonly involves elderly patients aged between 60 and 70 years, and pathological diagnosis depends mainly on chest surgery rather than bronchial mucosal biopsy. Via percutaneous needle aspiration biopsy of the lung of a 33-year-old woman, which had distinct tissue eosinophilia, we diagnosed a rare case of rapidly growing large B cell lymphoma. METHODS: Bronchial mucosal biopsy and computed tomography-guided percutaneous needle aspiration biopsy were performed to determine the nature of the lesion, and we identified its immunophenotype using immunohistochemistry. We used BIOMED-2 gene rearrangement PCR to determine lymphocyte clonality; laser microdissection was used to confirm the clonality of suspicious malignant lymphocytes. RESULTS: Morphologically, the lesion was composed of a large number of eosinophilic cells and a few lymphoid cells. Immunohistochemical staining revealed a few CD1alpha-positive cells, but they were S-100-negative. The small lymphoid cells predominantly expressed CD3; the large lymphoid cells expressed CD20 and some scattered large lymphoid cells expressed Pax5. However, molecular studies confirmed clonal immunoglobulin heavy chain (IGH)-D gene rearrangement in Pax5-positive large B lymphocytes. CONCLUSIONS: This is the first recorded case of T- cell/histiocyte-rich large B cell lymphoma with tissue eosinophilia of the lung. It highlights the unusual morphological features of PPL that might be mistaken for eosinophilic granuloma or parasitic infection. In addition, IGH and T cell receptor gene rearrangement play important roles in differentiating rare B cell lymphoma from lung space-occupying lesions with abundant eosinophils or T cell infiltration. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://med.motic.com/MoticGallery/Slides/AC5C9A6F-46EC-4C71-A448 1312F6900C65?user=2C69F0D6-A478-4A2B-ABF0-BB36763E8025. PMID- 25273523 TI - Controllable synthesis of 3D Ni(OH)2 and NiO nanowalls on various substrates for high-performance nanosensors. AB - Large-area and uniform three-dimensional (3D) beta-Ni(OH)2 and NiO nanowalls were synthesized on a variety of rigid and flexible substrates via a simple aqueous chemical deposition process. The beta-Ni(OH)2 nanowalls consist of single-crystal Ni(OH)2 nanosheets that were vertically grown on different substrates. The height, crystallinity, and morphology of the Ni(OH)2 nanowalls can be readily modified by adjusting the reaction time and concentration of the NiCl2 solution. The synthesis mechanism of the Ni(OH)2 nanowalls was determined through heterogeneous nucleation and subsequent oriented crystal growth. 3D NiO nanowalls were obtained by thermal decomposition of the Ni(OH)2 nanowalls at 400 degrees C in Ar atmosphere. Highly sensitive, selective gas sensors and electrochemical sensors based on these NiO nanowalls were developed. The chemiresistive gas sensors based on the NiO nanowalls grown on ceramic substrates exhibited an excellent performance with low detection limit for formaldehyde (8 ppb) and NO2 (15 ppb). The electrochemical sensor based on the NiO nanowalls grown on an FTO glass substrate had a superior selectivity to non-enzymatic glucose with a detection limit of 200 nm. PMID- 25273522 TI - Reproductive health and burn-out among female physicians: nationwide, representative study from Hungary. AB - BACKGROUND: There is a worldwide rising tendency of women deciding to become physicians; hence, one of the most remarkable fields of investigation is the wellbeing of female doctors. The aim of this study was to describe female physicians' reproductive health in Hungary and to explore the potential correlation between their reproductive disorders and burnout symptoms. Up to our present knowledge, there have not been any studies investigating the correlation between reproductive disorders and burnout of female physicians; therefore, our study represents a unique approach. METHODS: Data in this representative cross sectional epidemiological study were obtained from online questionnaires completed by 3039 female physicians. Participants in a representative nationwide survey (Hungarostudy, 2013) served as controls (n = 1069). Differences between physicians and the control group were disclosed by chi-square test. Correlations between certain factors of reproductive health and the three dimensions of burnout were detected by Pearson correlations and X2 test. Binary logistic regression analysis was used to determine the association between burnout and reproductive health. RESULTS: Female physicians were more often characterised by time-to-pregnancy interval longer than one year (18.4% vs. 9.8%), were bearing more high-risk pregnancies (26.3% vs.16.3%), and were more likely to be undergoing infertility therapy (8.5% vs. 3.4%) and experiencing miscarriage (20.8% vs. 14.6%) during their reproductive years, compared with the general female population. With the exception of miscarriages, the difference remained significant in all comparisons with the professional control group. Both high risk pregnancies and miscarriages of doctors were associated with depersonalisation (p = 0.028 and p = 0.012 respectively) and personal accomplishment (p = 0.016 and p = 0.008 respectively) dimensions of burnout. Results of the multivariate analysis showed that, beside traditional risk factors, depersonalisation acted as an important explanatory factor in case of high-risk pregnancies (OR = 1.086). CONCLUSIONS: There is a circulatory causality between burnout and the development of reproductive disorders. Burnout is an important risk factor for high-risk pregnancies and miscarriages, and it has a negative effect on the outcome of pregnancies. At the same time, women suffering from reproductive disorders are more likely to develop burnout syndrome. Improvement of working conditions and prevention of burnout in female doctors are equally important tasks. PMID- 25273524 TI - Education-corrected CERAD identifies MCI and dementia in Parkinson's disease. AB - OBJECTIVES: This study examined whether controlling for educational background in the CERAD cognitive screening battery would affect the likelihood of patients with Parkinson's disease to fulfill criteria for mild cognitive impairment (PD MCI) and dementia (PDD). MATERIALS & METHODS: One-hundred seventeen patients with PD were studied. Cognitive impairment was determined as two subtest scores falling below either the standard cutoff scores or education-corrected cutoff scores. The presence of dementia was determined by clinical interview or Clinical Dementia Rating. Patients were then classified as PD-MCI and PDD according to cognitive test performance and presence/absence of dementia. RESULTS: The number of cognitively impaired patients (PD-MCI or PDD) was significantly higher when education-controlled cutoff scores were used (62.5% vs 38%). Correspondingly, the number of false negatives (demented PD patients performing normally in CERAD) was significantly lower when education-corrected cutoff scores were used (4% vs 10%). CONCLUSIONS: Controlling for education increases the sensitivity of the CERAD for PD-MCI and PDD. PMID- 25273525 TI - Adjuvant chemoradiotherapy versus chemotherapy for gastric cancer: a meta analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of adjuvant chemoradiotherapy (CRT) versus chemotherapy (CT) for patients with gastric cancer. METHODS: Electronic databases including PUBMED, EMBASE, and Cochrane Library were retrieved for original studies from their inception to April 2014. Two reviewers independently evaluated the quality of the included studies and extracted the data. All Statistical analyses were performed using RevMan Version 5.2 software. RESULTS: Six randomized controlled trials involving 1,171 patients were included. The meta-analysis showed that there were statistical significances between chemoradiotherapy group and chemotherapy group in 5-year disease free survival rate (OR = 1.56, 95% CI: 1.09-2.24), local regional recurrence rate (OR = 0.46, 95% CI: 0.32-0.67) and neutropenia (OR = 1.47, 95% CI: 1.11-1.96). While treatment efficacy did not differ significantly by the 5-year overall survival rate (OR = 1.32, 95% CI: 0.92-1.88), 3-year disease free survival rate (OR = 1.28, 95% CI: 0.92-1.80), and new metastases (OR = 0.76, 95% CI: 0.57-1.03). Toxicities were not significantly different between two groups for nausea/vomiting, diarrhea, anemia, and thrombocytopenia. CONCLUSIONS: For patients with gastric cancer, adjuvant chemoradiotherapy could significantly improve 5-year disease free survival rate and reduce local-regional recurrence rate compared with chemotherapy and, can be well accepted and tolerated. PMID- 25273527 TI - Two ultrastructural distribution patterns of immunoglobulin G in human placenta and functional implications. AB - The placenta is known to protect the fetus from infection and maternal rejection. In a previous study, we demonstrated that placental trophoblasts can synthesize immunoglobulin G (IgG). In this study, we investigated the distribution of immunoglobulins (IgG, IgM, and IgA), IgG receptors (FcRn and FcgammaRIII), and complement proteins in placental trophoblasts at the ultrastructural level. In addition, we studied the mRNA expression of IgG1 heavy chain (IGHG1), recombination activating gene 1 (RAG1), RAG2, and activation-induced cytidine deaminase (AID) with nested RT-PCR in primary cultured trophoblasts. The mRNA transcripts of IGHG1, RAG1, RAG2, and AID were all identified in primary trophoblasts, further establishing the IgG-producing capacity of trophoblasts. At the ultrastructural level with colloidal gold-labeled antibodies, IgG was found to be distributed in two distinct locations in syncytiotrophoblasts. For one, it was colocalized with FcRn in endosome displaying low electron density, and for the other it was colocalized with complement C1q in medium-electron density irregular structures that have not been reported previously. This characteristic distribution suggests that IgG is likely processed through two molecular mechanisms in syncytiotrophoblasts: receptor-bound transportation across the syncytiotrophoblast and formation of immune complexes with locally produced IgG. The latter mechanism is probably aimed at neutralizing detrimental maternal anti paternal major histocompatibility complex antibodies. Our findings support the hypothesis that placenta-produced IgG can selectively react with maternal anti fetus antibodies and provide a mechanism of fetomaternal tolerance to protect the fetus from maternal immune rejection. PMID- 25273526 TI - The relationship between asymptomatic organ damage, and serum soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and Interleukin-17A (IL 17A) levels in non-diabetic hypertensive patients. AB - BACKGROUND: This study aimed to measure the serum soluble tumor necrosis factor like weak inducer of apoptosis (sTWEAK) and interleukin-17A (IL-17A) levels in hypertensive patients with/without asymptomatic organ damage (AOD), as well as to determine the relationship between the serum sTWEAK and IL17-A levels, and carotid intima media thickness (CIMT), proteinuria, retinopathy, and the left ventricle mass index (LVMI). METHODS: The study included 159 patients diagnosed with and followed-up for primary hypertension (HT); 79 of the patients had AOD (61 female and 18 male) and 80 did not (52 female and 28 male). sTWEAK and IL-17A levels were measured in all patients. RESULTS: The sTWEAK level was significantly lower in the patients with AOD than in those without AOD (858.4 pg/mL vs. 1151.58 pg/mL, P = 0.001). The sTWEAK level was negatively correlated with the mean microalbuminuria level and LVMI. The median IL-17A level was significantly higher in the patients with AOD than in those without AOD (2.34 pg/mL vs. 1.80 pg/mL, P = 0.001). There was a positive correlation between mean IL-17A level, and mean microalbuminuria level, CIMT, and LVMI. Multivariate logistic regression analysis showed that patient age, sTWEAK level, and mean 24-h systolic blood pressure were predictors of AOD. CONCLUSIONS: The sTWEAK level was lower and IL-17A level was higher in the patients with AOD. It remains unknown if sTWEAK and IL-17A play a role in the pathophysiology of AOD. Prospective observational studies are needed to determine the precise role of sTWEAK and IL-17A in the development of target organ damage. PMID- 25273528 TI - Functional analysis of miR-34c as a putative tumor suppressor in high-grade serous ovarian cancer. AB - Altered microRNA expression patterns are implicated in the formation of many human diseases, including ovarian cancer. Our laboratory previously created Dicer(fl/fl)/Pten(fl/fl)/Amhr2(cre/+) mice, which developed high-grade serous carcinomas originating from mouse fallopian tubes, while neither Dicer(fl/fl)/Amhr2(cre/+) nor Pten(fl/fl)/Amhr2(cre/+) mice developed tumors. To explore miRNAs involved in the tumorigenesis in the double-knockout (DKO) mice, tumor cell lines were established from mouse primary tumors, and the most abundant miRNAs present in mouse normal fallopian tubes, let-7b and miR-34c, were expressed in these cell lines. We found that miR-34c had a more dramatic effect on inhibiting tumor cell viability than let-7b. The action of miR-34c induced tumor cell cycle arrest in G1 phase and apoptosis, and was accompanied with the regulation of key genes involved in cell proliferation and cell cycle G1/S transition. miR-34c suppressed the expression of Ezh2 and Mybl2, which may transcriptionally and functionally activate Cdkn1c. Furthermore, miR-34c levels are extremely low in human serous adenocarcinomas compared with human normal fallopian tubes. Expression of miR-34c in human ovarian cancer cells phenocopied its effects in DKO mouse tumor cells. However, miR-34b/c(-/ )/Pten(fl/fl)/Amhr2(cre/+) mice failed to develop high-grade serous carcinomas, implicating a combination of miRNAs in the tumorigenesis process. Thus, while miR 34c is a putative tumor suppressor in high-grade serous ovarian carcinoma with potential therapeutic advantages, screening of additional miRNAs for their effects alone and in combination with miR-34c is highly warranted to uncover miRNAs that synergize with miR-34c against cancer. PMID- 25273529 TI - Interferon gamma-mediated BoHV-4 replication restriction in bovine endometrial stromal cells is host IDO1 gene expression independent and BoHV-4 IE2 gene expression dependent. AB - In the present work the interaction between bovine herpesvirus 4 (BoHV-4) infected bovine endometrial stromal cells (BESCs) and interferon gamma (IFNG) was investigated. Starting from the particular tropism of BoHV-4 toward BESCs, a pure population of these cells, free of CD45-positive cells, was prepared and proven to have a bona fide mesenchymal derivation as shown by vimentin-positive and cytokeratin-negative staining. BESCs expressed functional IFNG receptors (IFNGR) 1 and 2 but not IFNG ligand. BESCs transfected with a new reporter construct made by cloning the bovine indoleamine 2, 3-dioxygenase 1 (IDO1) promoter in front of the luciferase reporter gene responded to exogenous IFNG treatment. Further, IFNG treated or constitutively secreting IFNG BESCs strongly restricted BoHV-4 replication and consequent cytopathic effect. IDO1 expression in BESCs was tightly induced by IFNG and IDO1 was previously shown to be the mediator for some of the IFNG pathogenostatic effects. However, IDO1 inhibitors and IDO1 constitutive expression could not respectively abrogate or recapitulate IFNG effect on BoHV-4-infected BESCs, whereas BoHV-4 immediate early (IE2) gene expression was transcriptionally depressed by IFNG axis activation independently from IDO1 expression; this was further confirmed by revealing a BoHV-4 IE2 gene promoter area containing potential responsive elements interacting with inhibitory transcription factors induced by IFNG in BESCs. The data achieved in this work highlight at least two issues: first, the role of BESCs as target/effector cells for the IFNG; second, the importance of uterine IFNG integrity to control BoHV-4 infection recrudescence from a persistent/latent state to a chronic disease, endometritis. PMID- 25273530 TI - Human exosomal placenta-associated miR-517a-3p modulates the expression of PRKG1 mRNA in Jurkat cells. AB - During pregnancy, human placenta-associated microRNAs (miRNAs) derived from the miRNA cluster in human chromosome 19 are expressed in villous trophoblasts and secreted into maternal circulation via exosomes; however, little is known about whether circulating placenta-associated miRNAs are transferred into maternal immune cells via exosomes, and modulate expression of target genes in the recipient cells. We employed an in vitro model of trophoblast-immune cell communication using BeWo cells (a human trophoblast cell line) and Jurkat cells (a human leukemic T-cell line) and investigated whether BeWo exosomal placenta associated miRNAs can suppress expression of target genes in the recipient Jurkat cells. Using this system, we identified PRKG1 as a target gene of placenta associated miRNA miR-517a-3p. Moreover, we demonstrated that BeWo exosomal miR 517a-3p was internalized into Jurkat cells and subsequently suppressed the expression of PRKG1 in recipient Jurkat cells. Furthermore, using peripheral blood natural killer (NK) cells in vivo, we confirmed that circulating miR-517a 3p was delivered into maternal NK cells as it was into Jurkat cells in vitro. Placenta-associated miR-517a-3p was incorporated into maternal NK cells in the third trimester, and it was rapidly cleared after delivery. Expression levels of miR-517a-3p and its target mRNA PRKG1 were inversely correlated in NK cells before and after delivery. These in vitro and in vivo results suggest that exosome-mediated transfer of placenta-associated miRNAs and subsequent modulation of their target genes occur in maternal NK cells. The present study provides novel insight into our understanding of placenta-maternal communication. PMID- 25273531 TI - Non-Hodgkin lymphoma and hepatitis C: where we are and what next? AB - The association between hepatitis C virus and certain B-cell non-Hodgkin lymphomas, such as marginal zone lymphomas, is supported by epidemiological studies. The exact pathogenetic mechanism is still unknown but both chronic antigenic stimulation and viral lymphotropism may contribute to the evolution of the malignant clone. Furthermore, the hematologic response following hepatitis C antiviral treatment suggests that the virus may have an etiologic role. Interferon and ribavirin based treatment proved to be successful in small case series of hepatitis C virus associated splenic lymphoma with villous lymphocytes, therefore, it is suggested that antiviral treatment could be an alternative to chemo-immunotherapy. In the near future new more potent direct acting antivirals will make interferon free treatments possible. It is still an open question whether these new short-course regimens are also effective in the treatment of associated lymphomas and what is the importance of the lymphoid reservoir in eliminating HCV. PMID- 25273533 TI - Social Media in Medical Education. PMID- 25273532 TI - Association of cerebrospinal fluid anti-Sm antibodies with acute confusional state in systemic lupus erythematosus. AB - INTRODUCTION: Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. Previous studies revealed the strong association between serum anti-Sm and organic brain syndrome, consisting mainly of acute confusional state (ACS) of diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE). However, the precise mechanism by which anti-Sm causes diffuse NPSLE remains unclear. Of note, recent studies demonstrated that anti-U1 RNP antibodies (anti-RNP) in cerebrospinal fluid (CSF) are associated with NPSLE. The present study was designed to explore the association of anti-Sm antibodies in CSF with NPSLE. METHODS: Paired serum and CSF specimens were obtained from 72 patients with NPSLE (49 with diffuse NPSLE, 23 with neurological syndromes or peripheral neuropathy (focal NPSLE) and from 22 control patients with non-SLE neurological diseases. Sera were also obtained from 41 patients with active SLE without neuropsychiatric manifestations (non-NPSLE). Anti-Sm and anti-RNP were measured by enzyme-linked immunosorbent assay (ELISA). Blood-brain barrier (BBB) function and intrathecal anti-Sm production were evaluated by Q albumin and CSF anti-Sm index, respectively. Binding of anti-Sm to neuroblastoma cell lines SK-N-MC and Neuro2a was examined by flow cytometry and by cell ELISA. RESULTS: Anti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control. CSF anti-Sm, but not CSF anti-RNP, was significantly elevated in ACS compared with non-ACS diffuse NPSLE or with focal NPSLE. By contrast, there were no significant differences in serum anti-Sm or anti-RNP among subsets of NPSLE and non-NPSLE. Whereas there were no significant differences in CSF anti-Sm index, Q albumin was elevated in ACS compared with non-ACS or with focal NPSLE. Notably, CSF anti-Sm was correlated with Q albumin (r = 0.2373, P = 0.0447) or with serum anti-Sm (r = 0.7185, P <0.0001) in 72 patients with NPSLE. Finally, monoclonal anti-Sm and purified human anti-Sm bound to the surface of SK-N-MC and Neuro2a. CONCLUSIONS: These results demonstrate that the elevation of CSF anti-Sm through transudation from systemic circulation due to damaged BBB plays a critical role in the pathogenesis of ACS. More importantly, the data indicate that anti-Sm is yet another autoantibody with presumed neural toxicity, but might not be the last. PMID- 25273535 TI - Patient selection for stroke endovascular therapy--DWI-ASPECTS thresholds should vary among age groups: insights from the RECOST study. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the benefits of endovascular intervention in large-vessel occlusion strokes, depending on age class. MATERIALS AND METHODS: A clinical management protocol including intravenous treatment and mechanical thrombectomy was instigated in our center in 2009 (Prognostic Factors Related to Clinical Outcome Following Thrombectomy in Ischemic Stroke [RECOST] study). All patients with acute ischemic stroke with an anterior circulation major-vessel occlusion who presented within 6 hours were evaluated with an initial MR imaging examination and were analyzed according to age subgroups (younger than 50 years, 50-59 years, 60-69 years, 70-79 years; 80 years or older). The mRS score at 3 months was the study end point. RESULTS: One hundred sixty-five patients were included in the analysis. The mean age was 67.4 years (range, 29-90 years). The mean baseline NIHSS score was 17.24 (range, 3 27). The mean DWI-derived ASPECTS was 6.4. Recanalization of TICI 2b/3 was achieved in 80%. At 3 months, 41.72% of patients had a good outcome, with a gradation of prognosis depending on the age subgroup and a clear cutoff at 70 years. Only 19% of patients older than 80 years had a good outcome at 3 months (mean ASPECTS = 7.4) with 28% for 70-79 years (mean ASPECTS = 6.8), but 58% for 60-69 years (mean ASPECTS = 6), 52% for 50-59 years (mean ASPECTS = 5.91), and 72% for younger than 50 years (mean ASPECTS = 6.31). In contrast, the mortality rate was 35% for 80 years and older, and 26% for 70-79 versus 5%-9% for younger than 70 years. CONCLUSIONS: The elderly may benefit from thrombectomy when their ischemic core volume is low in comparison with younger patients who still benefit from acute recanalization despite larger infarcts. Stroke volume thresholds should, therefore, be related and adjusted to the patient's age group. PMID- 25273534 TI - MR imaging of myeloperoxidase activity in a model of the inflamed aneurysm wall. AB - BACKGROUND AND PURPOSE: Although myeloperoxidase activity in vivo can be visualized by using noninvasive imaging, successful clinical translation requires further optimization of the imaging approach. We report a motion-sensitized driven-equilibrium MR imaging approach for the detection of a myeloperoxidase activity-specific gadolinium-containing imaging agent in experimental aneurysm models, which compensates for irregular blood flow, enabling vascular wall imaging in the aneurysm. MATERIALS AND METHODS: A phantom was built from rotational angiography of a rabbit elastase aneurysm model and was connected to a cardiac pulse duplicator mimicking rabbit-specific flow conditions. A T1-weighted turbo spin-echo-based motion-sensitized driven-equilibrium pulse sequence was optimized in vitro, including the addition of fat suppression and the selection of the velocity-encoding gradient parameter. The optimized sequence was applied in vivo to rabbit aneurysm models with and without inflammation in the aneurysmal wall. Under each condition, the aneurysms were imaged before and after intravenous administration of the imaging agent. The signal-to-noise ratio of each MR imaging section through the aneurysm was calculated. RESULTS: The motion sensitized driven-equilibrium sequence was optimized to reduce flow signal, enabling detection of the myeloperoxidase imaging agent in the phantom. The optimized imaging protocol in the rabbit model of saccular aneurysms revealed a significant increase in the change of SNR from pre- to post-contrast MR imaging in the inflamed aneurysms compared with naive aneurysms and the adjacent carotid artery (P < .0001). CONCLUSIONS: A diagnostic MR imaging protocol was optimized for molecular imaging of a myeloperoxidase-specific molecular imaging agent in an animal model of inflamed brain aneurysms. PMID- 25273536 TI - Effects of agmatine on blood-brain barrier stabilization assessed by permeability MRI in a rat model of transient cerebral ischemia. AB - BACKGROUND AND PURPOSE: BBB disruption after acute ischemic stroke and subsequent permeability increase may be enhanced by reperfusion. Agmatine has been reported to attenuate BBB disruption. Our aim was to evaluate the effects of agmatine on BBB stabilization in a rat model of transient cerebral ischemia by using permeability dynamic contrast-enhanced MR imaging at early stages and subsequently to demonstrate the feasibility of dynamic contrast-enhanced MR imaging for the investigation of new therapies. MATERIALS AND METHODS: Thirty four male Sprague-Dawley rats were subjected to transient MCA occlusion for 90 minutes. Immediately after reperfusion, agmatine (100 mg/kg) or normal saline was injected intraperitoneally into the agmatine-treated group (n = 17) or the control group, respectively. MR imaging was performed after reperfusion. For quantitative analysis, regions of interest were defined within the infarct area, and values for volume transfer constant, rate transfer coefficient, volume fraction of extravascular extracellular space, and volume fraction of blood plasma were obtained. Infarct volume, infarct growth, quantitative imaging parameters, and numbers of factor VIII-positive cells after immunohistochemical staining were compared between control and agmatine-treated groups. RESULTS: Among the permeability parameters, volume transfer constant and volume fraction of extravascular extracellular space were significantly lower in the agmatine treated group compared with the control group (0.05 +/- 0.02 minutes(-1) versus 0.08 +/- 0.03 minute(-1), P = .012, for volume transfer constant and 0.12 +/- 0.06 versus 0.22 +/- 0.15, P = .02 for volume fraction of extravascular extracellular space). Other permeability parameters were not significantly different between the groups. The number of factor VIII-positive cells was less in the agmatine-treated group than in the control group (3-fold versus 4-fold, P = .037). CONCLUSIONS: In ischemic stroke, agmatine protects the BBB, which can be monitored in vivo by quantification of permeability by using dynamic contrast enhanced MR imaging. Therefore, dynamic contrast-enhanced MR imaging may serve as a potential imaging biomarker for assessing the BBB stabilization properties of pharmacologic agents. PMID- 25273537 TI - Differences in neuroradiology training programs around the world. AB - BACKGROUND AND PURPOSE: No previous study compares neuroradiology training programs and teaching schedules across the globe, to our knowledge. This study was conducted to better understand international program requisites. MATERIALS AND METHODS: Data from 43 countries were collected by an e-mail-based questionnaire (response rate, 84.0%). Radiologists across the world were surveyed regarding the neuroradiology training schemes in their institutions. Answers were verified by officers of the national neuroradiology societies. RESULTS: While many countries do not provide fellowship training in neuroradiology (n = 16), others have formal postresidency curricula (n = 27). Many programs have few fellows and didactic sessions, but the 1- or 2-year duration of fellowship training is relatively consistent (n = 23/27, 85%). CONCLUSIONS: There is a wide variety of fellowship offerings, lessons provided, and ratios of teachers to learners in neuroradiology training programs globally. PMID- 25273539 TI - Very late antigen-5 facilitates stromal progenitor cell differentiation into myofibroblast. AB - Fibrotic disease is associated with abrogated stromal cell proliferation and activity. The precise identity of the cells that drive fibrosis remains obscure, in part because of a lack of information on their lineage development. To investigate the role of an early stromal progenitor cell (SPC) on the fibrotic process, we selected for, and monitored the stages of, fibroblast development from a previously reported free-floating anchorage-independent cell (AIC) progenitor population. Our findings demonstrate that organotypic pulmonary, cardiac, and renal fibroblast commitment follows a two-step process of attachment and remodeling in culture. Cell differentiation was confirmed by the inability of SPCs to revert to the free-floating state and functional mesenchymal stem/stromal cell (MSC) differentiation into osteoblast, adipocyte, chondrocyte, and fibroblastic lineages. The myofibroblastic phenotype was reflected by actin stress-fiber formation, alpha-smooth muscle production, and a greater than threefold increase in proliferative activity compared with that of the progenitors. SPC-derived pulmonary myofibroblasts demonstrated a more than 300 fold increase in fibronectin-1 (Fn1), collagen, type 1, alpha1, integrin alpha-5 (Itga5), and integrin beta-1 (Itgb1) transcript levels. Very late antigen-5 (ITGA5/ITGB1) protein cluster formations were also prevalent on the differentiated cells. Normalized SPC-derived myofibroblast expression patterns reflected those of primary cultured lung myofibroblasts. Intratracheal implantation of pulmonary AICs into recipient mouse lungs resulted in donor cell FN1 production and evidence of epithelial derivation. SPC derivation into stromal tissue in vitro and in vivo and the observation that MSC and fibroblast lineages share a common ancestor could potentially lead to personalized antifibrotic therapies. PMID- 25273538 TI - The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery. AB - The autism spectrum disorders (ASDs) comprise a set of neurodevelopmental disorders that are, at best, poorly understood but are the fastest growing developmental disorders in the United States. Because animal models of polygenic disorders such as the ASDs are difficult to validate, the derivation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming offers an alternative strategy for identifying the cellular mechanisms contributing to ASDs and the development of new treatment options. Access to statistically relevant numbers of ASD patient cell lines, however, is still a limiting factor for the field. We describe a new resource with more than 200 cell lines (fibroblasts, iPSC clones, neural stem cells, glia) from unaffected volunteers and patients with a wide range of clinical ASD diagnoses, including fragile X syndrome. We have shown that both normal and ASD-specific iPSCs can be differentiated toward a neural stem cell phenotype and terminally differentiated into action-potential firing neurons and glia. The ability to evaluate and compare data from a number of different cell lines will facilitate greater insight into the cause or causes and biology of the ASDs and will be extremely useful for uncovering new therapeutic and diagnostic targets. Some drug treatments have already shown promise in reversing the neurobiological abnormalities in iPSC-based models of ASD-associated diseases. The ASD Stem Cell Resource at the Children's Hospital of Orange County will continue expanding its collection and make all lines available on request with the goal of advancing the use of ASD patient cells as disease models by the scientific community. PMID- 25273540 TI - Cartilage repair using human embryonic stem cell-derived chondroprogenitors. AB - In initial work, we developed a 14-day culture protocol under potential GMP, chemically defined conditions to generate chondroprogenitors from human embryonic stem cells (hESCs). The present study was undertaken to investigate the cartilage repair capacity of these cells. The chondrogenic protocol was optimized and validated with gene expression profiling. The protocol was also applied successfully to two lines of induced pluripotent stem cells (iPSCs). Chondrogenic cells derived from hESCs were encapsulated in fibrin gel and implanted in osteochondral defects in the patella groove of nude rats, and cartilage repair was evaluated by histomorphology and immunocytochemistry. Genes associated with chondrogenesis were upregulated during the protocol, and pluripotency-related genes were downregulated. Aggregation of chondrogenic cells was accompanied by high expression of SOX9 and strong staining with Safranin O. Culture with PluriSln1 was lethal for hESCs but was tolerated by hESC chondrogenic cells, and no OCT4-positive cells were detected in hESC chondrogenic cells. iPSCs were also shown to generate chondroprogenitors in this protocol. Repaired tissue in the defect area implanted with hESC-derived chondrogenic cells was stained for collagen II with little collagen I, but negligible collagen II was observed in the fibrin-only controls. Viable human cells were detected in the repair tissue at 12 weeks. The results show that chondrogenic cells derived from hESCs, using a chemically defined culture system, when implanted in focal defects were able to promote cartilage repair. This is a first step in evaluating these cells for clinical application for the treatment of cartilage lesions. PMID- 25273541 TI - Engineering efficient retinal pigment epithelium differentiation from human pluripotent stem cells. AB - Human embryonic stem cells (hESCs) are a promising source of retinal pigment epithelium (RPE) cells: cells that can be used for the treatment of common and incurable forms of blindness, such as age-related macular degeneration. Although most hESC lines will produce a number of clusters of pigmented RPE cells within 30-50 days when allowed to spontaneously differentiate, the timing and efficiency of differentiation is highly variable. This could prove problematic in the design of robust processes for the large scale production of RPE cells for cell therapy. In this study we sought to identify, quantify, and reduce the sources of variability in hESC-RPE differentiation. By monitoring the emergence of pigmented cells over time, we show how the cell line, passaging method, passage number, and seeding density have a significant and reproducible effect on the RPE yield. To counter this variability, we describe the production of RPE cells from two cell lines in feeder-free, density controlled conditions using single cell dissociation and seeding that is more amenable to scaled up production. The efficacy of small molecules in directing differentiation toward the RPE lineage was tested in two hESC lines with divergent RPE differentiation capacities. Neural induction by treatment with a bone morphogenetic protein inhibitor, dorsomorphin, significantly enhanced the RPE yield in one cell line but significantly reduce it in another, generating instead a Chx10 positive neural progenitor phenotype. This result underlines the necessity to tailor differentiation protocols to suit the innate properties of different cell lines. PMID- 25273542 TI - Clinical implication of allogenic implantation of adipogenic differentiated adipose-derived stem cells. AB - We recently reported that autologous adipogenic differentiated adipose-derived stem cells (ASCs) can potentially be used as an effective and safe therapy for soft-tissue regeneration. In the present study, we investigated whether adipogenic differentiated ASCs can be used for allogenic applications to enlarge their therapeutic use. The allogenic immune response of adipogenic differentiated ASCs was investigated by flow cytometry and mixed lymphocyte culture. To determine whether adipogenic differentiated ASCs can form new adipose tissue without immune rejection, these cells were implanted subcutaneously into allo- or xenogenic recipient mice. In addition, the safety of the allogenic implantation of adipogenic differentiated ASCs was explored in a phase I clinical study. Adipogenic differentiated ASCs do not express major histocompatibility complex (MHC) class II molecules and costimulatory molecules, and the expression levels of MHC class I decreased after differentiation. In addition, these cells do not elicit an immune response against MHC-mismatched allogenic lymphocytes and formed new adipose tissue without immune rejection in the subcutaneous region of MHC mismatched mice. Moreover, these cells did not induce clinically significant local and systemic immune responses or adverse events in the subcutaneous region of donor-independent healthy subjects. These results suggest that adipogenic differentiated ASCs can be used as a "universal donor" for soft-tissue engineering in MHC-mismatched recipients. PMID- 25273543 TI - Preconception care: it's never too early. AB - The preconception window has been recognized as one of the earliest sensitive windows of human development, and interventions that focus on this period have the potential to affect not only pregnancy but long term outcomes as well. The journal Reproductive Health has published a supplement entitled 'Preconception Interventions' which includes a series of systematic reviews regarding the impact of public health interventions during the preconception period on maternal and child health. These articles describe the role that poor preconception health plays in creating health disparities across the globe. The reviews highlight our current understanding (or lack thereof) regarding how both maternal and paternal preconception health and knowledge shapes the long-term health of not only children, but of families, communities, and nations. Researchers and healthcare workers should take particular note of these interventions, as the preconception time period may be as important as the pregnancy and post-pregnancy periods, and is critical in terms of bridging the gap in the continuum of care, particularly for adolescents. PMID- 25273544 TI - Developing a two-sided intervention to facilitate shared decision-making in haemophilia: decision boxes for clinicians and patient decision aids for patients. AB - BACKGROUND: People with haemophilia face many treatment decisions, which are largely informed by evidence from observational studies. Without evidence-based 'best' treatment options, patient preferences play a large role in decisions regarding therapy. The shared decision-making (SDM) process allows patients and health care providers to make decisions collaboratively based on available evidence, and patient preferences. Decision tools can help the SDM process. The objective of this project was to develop two-sided decision tools, decision boxes for physicians and patient decision aids for patients, to facilitate SDM for treatment decisions in haemophilia. METHODS: Development of the decision tools comprised three phases: topic selection, prototype development and usability testing with targeted end-users. Topics were selected using a Delphi survey. Tool prototypes were based on a previously validated framework and were informed by systematic literature reviews. Patients, through focus groups, and physicians, through interviews, reviewed the prototypes iteratively for comprehensibility and usability. RESULTS: The chosen topics were: (i) prophylactic treatment: when to start and dosing, (ii) choosing factor source and (iii) immunotolerance induction: when to start and dosing. Intended end users (both health care providers and haemophilia patients and caregivers) were engaged in the development process. Overall perception of the decision tools was positive, and the purpose of using the tools was well received. CONCLUSIONS: This study demonstrates the feasibility of developing decision tools for haemophilia treatment decisions. It also provides anecdotal evidence of positive perceptions of such tools. Future directions include assessment of the tools' practical value and impact on clinical practice. PMID- 25273545 TI - Effects of temperature and heat waves on emergency department visits and emergency ambulance dispatches in Pudong New Area, China: a time series analysis. AB - BACKGROUND: In July 2013, an extended heat episode with extreme high temperature covered Pudong New Area, the largest district in Shanghai. The current study estimates the impacts of temperature and heat waves on emergency department visits (EDV) and emergency ambulance dispatches (EAD) using time-series approaches in Pudong, from 2011 to 2013. METHODS: An over-dispersed Poisson generalized additive model was used to examine the association between temperature and EDV and EAD. Heat wave effects with different heat wave definitions considering both the intensity and durations were also estimated. RESULTS: Immediate effects of temperature on EDV and EAD were detected, after controlling for trends of time and day of week. The exposure-response relationships showed J-shaped curves with higher threshold temperature of EDV than that of EAD visually. When estimating risk changes on heat days compared with non-heat days using different percentiles of daily mean temperature in definition, EAD showed significant increases while non-significant or even negative associations were found for EDV. Heat wave with intensity above the 90th percentile had 2.62% (95% CI: 1.78%, 3.46%) and 0.95% (95% CI: 0.22%, 1.69%) increases in EDV for a duration of at least 2 days and 3 days respectively. The relative increase of EAD were 4.85% (95% CI: 1.42%, 8.39%) and 3.94% (95% CI: 0.88%, 7.10%). CONCLUSIONS: Varied effects of temperature and heat waves on emergency department visits and emergency ambulance dispatches were investigated. This wider view of the health effect of temperature indicated that interventions for both public health education and health services management should be considered in the study region. PMID- 25273548 TI - Contribution of microbiota to the intestinal physicochemical barrier. AB - The large number of intestinal microorganisms, which exceeds the total number of human cells by ten folds, alludes to a significant contribution to human health. This is vivid in enteric and some systemic diseases emanating from disruption of the microbiota. As life style keeps shifting towards disruption of the microbiota in most societies worldwide, interest in the contribution of the microbiota to gut health has grown enormously. Many studies have been conducted to elucidate the exact contribution of the microbiota to human health. The knowledge gained from these studies indicates that the microbiota interacts with the intestinal milieu to maintain gut health. In this review, the crosstalk of microbiota with the intestinal physicochemical barrier pivotal to the gut innate immunity is highlighted. In particular, the review focuses on the role of the microbiota on competitive exclusion of pathogens, intestinal pH, epithelial mechanical barrier integrity, apical actin cytoskeleton, antimicrobial peptides, and the mucus layer. Understanding this microbe-host relationship will provide useful insight into overcoming some diseases related to the disruption of the host microbiota. PMID- 25273547 TI - The effect of Lactobacillus paracasei subsp. paracasei L. casei W8(r) on blood levels of triacylglycerol is independent of colonisation. AB - Gut microbiota (GM) dysbiosis has been linked to obesity and its metabolic complications such as cardiovascular disease (CVD). The risk of developing CVD increases with elevated concentration of serum triacylglycerol (TAG). In a blinded, randomised two-arm parallel human intervention study we have previously found that four weeks of supplementation with Lactobacillus paracasei subsp. paracasei L. casei W8(r) (L. casei W8) compared to placebo reduced the concentration of TAG in 64 young healthy adults, an effect, likely mediated by a decreased stearoyl- CoA desaturase-1 (SCD1) activity. In the present study we analysed faecal samples obtained during the intervention study to investigate whether this effect was related to the ability of L. casei W8 to colonise the human gut after supplementation of L. casei W8 (1010 cfu daily) as determined by qPCR specific for L. paracasei and L. casei (L. casei group); whether L. casei W8 consumption affected GM composition as determined by 16S rRNA gene targeted 454/FLX amplicon sequencing; and whether these changes were associated with changes in TAG concentration and SCD1 activity. Faecal samples were collected at baseline, after four weeks supplementation and two weeks after the supplementation was ended, and fasting blood samples were collected at baseline and after 4 weeks. Four weeks supplementation with L. casei W8 did not affect the overall composition of the GM; however, an increase in the relative abundance of the L. casei group from 8.48*10-6% of the total GM compared to 2.83*10-3% at baseline (P<0.001) was observed. Two weeks after supplementation ended, the relative abundance of the L. casei group was still increased 14 times compared to before the intervention (P<0.01). However, neither the increase in the abundance of the L. casei group nor overall GM composition correlated with changes in blood lipids or SCD1 activity. PMID- 25273546 TI - Promoting the recovery of injured liver with poly (3-hydroxybutyrate-co-3 hydroxyvalerate-co-3-hydroxyhexanoate) scaffolds loaded with umbilical cord derived mesenchymal stem cells. AB - Cell-based therapies are major focus of current research for treatment of liver diseases. In this study, mesenchymal stem cells were isolated from human umbilical cord Wharton's jelly (WJ-MSCs). Results confirmed that WJ-MSCs isolated in this study could express the typical MSC-specific markers and be induced to differentiate into adipocytes, osteoblasts, and chondrocytes. They could also be induced to differentiate into hepatocyte-like cells. Poly (3-hydroxybutyrate-co-3 hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx) is a new member of polyhydroxyalkanoate family and biodegradable polyester produced by bacteria. PHBVHHx scaffolds showed much higher cell attachment and viability than the other polymers tested. PHBVHHx scaffolds loaded with WJ-MSCs were transplanted into liver-injured mice. Liver morphology improved after 30 days of transplantation and looked similar to normal liver. Concentrations of serum alanine aminotransferase and total bilirubin were significantly lower, and albumin was significantly higher on days 14 and 30 in the WJ-MSCs+scaffold group than in the carbon tetrachloride (CCl4) group. Hematoxylin-eosin staining showed that liver had similar structure of normal liver lobules and similar size and shape of normal hepatic cells, and Masson staining demonstrated that liver had less blue staining for collagen after 30 days of transplantation. Real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that the expression of the bile duct epithelial cell gene CK-19 in mouse liver is significantly lower on days 14 and 30 in the WJ-MSCs+scaffold group than in the CCl4 group. Real-time RT PCR, immunocytochemistry, and periodic acid-Schiff staining showed that WJ-MSCs in scaffolds differentiated into hepatocyte-like cells on days 14 and 30 in the WJ-MSCs+scaffold group. Real-time RT-PCR also demonstrated that WJ-MSCs in scaffolds expressed endothelial cell genes Flk-1, vWF, and VE-cadherin on days 14 and 30 in the WJ-MSCs+scaffold group, indicating that WJ-MSCs also differentiated into endothelial-like cells. These results demonstrated that PHBVHHx scaffolds loaded with WJ-MSCs significantly promoted the recovery of injured liver and could be further studied for liver tissue engineering. PMID- 25273549 TI - Half-Heusler thermoelectrics: a complex class of materials. AB - Half-Heusler thermoelectrics first attracted interest in the late-1990s and are currently undergoing a renaissance. This has been driven by improved synthesis, processing and characterisation methods, leading to increases in the thermoelectric figure of merit and the observation of novel phenomena such as carrier filtering in nanocomposite samples. The difficulty in extracting good thermoelectric performance is at first glance surprising given the relative simplicity of the ideal crystal structure with only site occupancies and lattice parameter as crystallographic variables. However, the observed thermoelectric properties are found to depend sensitively on sample processing. Recent work has shown that prepared ingots can contain a range of inhomogeneities, including interstitials, nano- and micron sized Heusler inclusions and multiple half Heusler phases. For this reason, the prepared materials are far more complex than initially appreciated and this may offer opportunities to enhance the thermoelectric figure of merit. PMID- 25273550 TI - Childhood trauma is associated with a specific admixture of affective, anxiety, and psychosis symptoms cutting across traditional diagnostic boundaries. AB - BACKGROUND: Meta-analyses link childhood trauma to depression, mania, anxiety disorders, and psychosis. It is unclear, however, whether these outcomes truly represent distinct disorders following childhood trauma, or that childhood trauma is associated with admixtures of affective, psychotic, anxiety and manic psychopathology throughout life. METHOD: We used data from a representative general population sample (NEMESIS-2, n = 6646), of whom respectively 1577 and 1120 had a lifetime diagnosis of mood or anxiety disorder, as well as from a sample of patients with a diagnosis of schizophrenia (GROUP, n = 825). Multinomial logistic regression was used to assess whether childhood trauma was more strongly associated with isolated affective/psychotic/anxiety/manic symptoms than with their admixture. RESULTS: In NEMESIS-2, largely comparable associations were found between childhood trauma and depression, mania, anxiety and psychosis. However, childhood trauma was considerably more strongly associated with their lifetime admixture. These results were confirmed in the patient samples, in which it was consistently found that patients with a history of childhood trauma were more likely to have a combination of multiple symptom domains compared to their non-traumatized counterparts. This pattern was also found in exposed individuals who did not meet criteria for a psychotic, affective or anxiety disorder and who did not seek help for subclinical psychopathology. CONCLUSIONS: Childhood trauma increases the likelihood of a specific admixture of affective, anxiety and psychotic symptoms cutting across traditional diagnostic boundaries, and this admixture may already be present in the earliest stages of psychopathology. These findings may have significant aetiological, pathophysiological, diagnostic and clinical repercussions. PMID- 25273552 TI - Prevalence of female urinary incontinence and its impact on quality of life in a cluster population in the United Kingdom (UK): a community survey. AB - AIM: To ascertain the prevalence of urinary incontinence and lower urinary tract symptoms, impact on quality of life and help-seeking behaviour. BACKGROUND: Urinary incontinence is common and will affect more individuals as the population ages. Estimates of the prevalence of urinary incontinence vary hugely. Additional information is required to inform resource allocation. METHODS: Population-based cross-sectional postal evaluation of all female patients over 21 years registered at a single medical practice in the United Kingdom. FINDINGS: A total of 40% of respondents suffered urinary incontinence, which caused significant problems in 8.5%. Stress urinary incontinence was the most common type of incontinence while 10% had symptoms of voiding dysfunction. A total of 17% of women had sought professional help. Patients perceived that urinary incontinence was part of the natural ageing process and that there was a low expectation of successful treatment. PMID- 25273551 TI - Common mental disorders in primary health care: differences between Latin American-born and Spanish-born residents in Madrid, Spain. AB - PURPOSE: Our main objective was to estimate and compare the prevalence of the most common mental disorders between Latin American-born and Spanish-born patients in Madrid, Spain. We also analyzed sociodemographic factors associated with these disorders and the role of the length of residency for Latin American born patients. METHODS: We performed a cross-sectional study to compare Latin American-born (n = 691) and Spanish-born outpatients (n = 903) from 15 primary health care centers in Madrid, Spain. The Primary Care Evaluation of Mental Disorders was used to diagnose common mental disorders. Sociodemographic, psychosocial, and migration data were collected. RESULTS: We detected common mental disorders in 49.9 % (95 % CI = 47.4-52.3 %) of the total sample. Values were higher in Latin American-born patients than in Spanish-born patients for any disorder (57.8 % vs. 43.9 %, p < 0.001), mood disorders (40.1 % vs. 34.8 %, p = 0.030), anxiety disorders (20.5 % vs. 15.3 %, p = 0.006), and somatoform disorders (18.1 % vs. 6.6 %, p < 0.001). There were no statistically significant differences in prevalence between Latin American-born patients with less than 5 years of residency and Latin American-born residents with 5 or more years of residency. Finally, multivariate analysis shows that gender, having/not having children, monthly income, geographic origin, and social support were significantly associated with several disorders. LIMITATIONS: The sample was neither population-based nor representative of the general immigrant or autochthonous populations. CONCLUSIONS: The study provides further evidence of the high prevalence of common mental disorders in Latin American-born patients in Spain compared with Spanish-born patients. PMID- 25273553 TI - Zinc and smoking habits in the setting of hypertension in a Spanish populations. AB - The objective of this study was to evaluate the relationship between trace and toxic amounts of zinc (Zn) in biological samples (blood and urine) and the smoking habits of hypertensive patients and healthy control subjects in Valladolid (Spain). In order to compare biological samples, the concentrations of these samples were measured using inductively coupled plasma mass spectrometry. The limits of detection for Zn in blood plasma ranged between 4.22 and 17.34 MUmol l(-1) and were <0.08 MUmol g(-1) creatinine in urine. The results of this study indicate that the highest mean values of serum Zn were found in non hypertensive nonsmokers (13.39+/-4.35 MUmol l(-1)), whereas the highest urine Zn values were observed in hypertensive nonsmokers (2.78+/-2.13 MUmol l(-1)). Higher Zn serum/urine quotient levels were observed in non-hypertensive and nonsmoking women, whereas lower levels were noted in non-hypertensive and smoking women (P=0.012). This study identified a correlation between Zn serum/urine quotients and cotinine levels (a marker of smoking), a correlation that suggests that smoking lowers the Zn serum/urine quotient, which was lower in hypertensive subjects than in control subjects. PMID- 25273554 TI - Prevention of metabolic disorders with telmisartan and indapamide in a Chinese population with high-normal blood pressure. AB - High-normal blood pressure is considered a precursor of stage 1 hypertension that is associated with metabolic disorders. This study aims to investigate whether the pharmacologic treatment of high-normal blood pressure affects metabolism, especially in abdominally obese individuals, and the pharmacoeconomics of two antihypertensive agents, telmisartan and indapamide. Subjects with high-normal blood pressure were randomly assigned to receive telmisartan, indapamide or placebo for 3 years. All the subjects were instructed to modify their lifestyle to reduce blood pressure throughout the study. A total of 221 subjects were randomly assigned to telmisartan, 213 to indapamide and 230 to placebo. After the 3-year intervention, blood pressure was lower in the telmisartan and indapamide groups (P<0.05), FPG in the telmisartan group was lower during the first 2 years (P<0.05) and no characteristic differences were found in those with abdominal obesity among the three groups (P>0.05). The percentage of subjects with metabolic syndrome was significantly decreased in the telmisartan and indapamide groups (P<0.05), but was only significantly decreased in the telmisartan group for subjects with abdominal obesity (P<0.05). The acquisition cost for telmisartan was ~1.86 times higher than for indapamide for a similar antihypertensive effect. The intervention for high-normal blood pressure with telmisartan and indapamide appeared to be feasible and reduced the risk of metabolic syndrome. Telmisartan was more effective, whereas indapamide had better pharmacoeconomic benefits. PMID- 25273555 TI - Induction of focal adhesions and motility in Drosophila S2 cells. AB - Focal adhesions are dynamic structures that interact with the extracellular matrix on the cell exterior and actin filaments on the cell interior, enabling cells to adhere and crawl along surfaces. We describe a system for inducing the formation of focal adhesions in normally non-ECM-adherent, nonmotile Drosophila S2 cells. These focal adhesions contain the expected molecular markers such as talin, vinculin, and p130Cas, and they require talin for their formation. The S2 cells with induced focal adhesions also display a nonpolarized form of motility on vitronectin-coated substrates. Consistent with findings in mammalian cells, the degree of motility can be tuned by changing the stiffness of the substrate and was increased after the depletion of PAK3, a p21-activated kinase. A subset of nonmotile, nonpolarized cells also exhibited focal adhesions that rapidly assembled and disassembled around the cell perimeter. Such cooperative and dynamic fluctuations of focal adhesions were decreased by RNA interference (RNAi) depletion of myosin II and focal adhesion kinase, suggesting that this behavior requires force and focal adhesion maturation. These results demonstrate that S2 cells, a cell line that is well studied for cytoskeletal dynamics and readily amenable to protein manipulation by RNAi, can be used to study the assembly and dynamics of focal adhesions and mechanosensitive cell motility. PMID- 25273556 TI - Loss of the Sec1/Munc18-family proteins VPS-33.2 and VPS-33.1 bypasses a block in endosome maturation in Caenorhabditis elegans. AB - The end of the life of a transport vesicle requires a complex series of tethering, docking, and fusion events. Tethering complexes play a crucial role in the recognition of membrane entities and bringing them into close opposition, thereby coordinating and controlling cellular trafficking events. Here we provide a comprehensive RNA interference analysis of the CORVET and HOPS tethering complexes in metazoans. Knockdown of CORVET components promoted RAB-7 recruitment to subapical membranes, whereas in HOPS knockdowns, RAB-5 was found also on membrane structures close to the cell center, indicating the RAB conversion might be impaired in the absence of these tethering complexes. Unlike in yeast, metazoans have two VPS33 homologues, which are Sec1/Munc18 (SM)-family proteins involved in the regulation of membrane fusion. We assume that in wild type, each tethering complex contains a specific SM protein but that they may be able to substitute for each other in case of absence of the other. Of importance, knockdown of both SM proteins allowed bypass of the endosome maturation block in sand-1 mutants. We propose a model in which the SM proteins in tethering complexes are required for coordinated flux of material through the endosomal system. PMID- 25273560 TI - Standardising outcome measures using z scores. PMID- 25273559 TI - Lanthionine synthetase C-like protein 2 (LanCL2) is a novel regulator of Akt. AB - The serine/threonine protein kinase Akt controls a wide range of biochemical and cellular processes under the modulation of a variety of regulators. In this study, we identify the lanthionine synthetase C-like 2 (LanCL2) protein as a positive regulator of Akt activation in human liver cells. LanCL2 knockdown dampens serum- and insulin-stimulated Akt phosphorylation, whereas LanCL2 overexpression enhances these processes. Neither insulin receptor phosphorylation nor the interaction between insulin receptor substrate and phosphatidylinositide 3-kinase (PI3K) is affected by LanCL2 knockdown. LanCL2 also does not function through PP2A, a phosphatase of Akt. Instead, LanCL2 directly interacts with Akt, with a preference for inactive Akt. Moreover, we show that LanCL2 also binds to the Akt kinase mTORC2, but not phosphoinositide-dependent kinase 1. Whereas LanCL2 is not required for the Akt-mTORC2 interaction, recombinant LanCL2 enhances Akt phosphorylation by target of rapamycin complex 2 (mTORC2) in vitro. Finally, consistent with a function of Akt in regulating cell survival, LanCL2 knockdown increases the rate of apoptosis, which is reversed by the expression of a constitutively active Akt. Taken together, our findings reveal LanCL2 as a novel regulator of Akt and suggest that LanCL2 facilitates optimal phosphorylation of Akt by mTORC2 via direct physical interactions with both the kinase and the substrate. PMID- 25273557 TI - Acute increase of alpha-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation. AB - Parkinson's disease is associated with multiplication of the alpha-synuclein gene and abnormal accumulation of the protein. In animal models, alpha-synuclein overexpression broadly impairs synaptic vesicle trafficking. However, the exact steps of the vesicle trafficking pathway affected by excess alpha-synuclein and the underlying molecular mechanisms remain unknown. Therefore we acutely increased synuclein levels at a vertebrate synapse and performed a detailed ultrastructural analysis of the effects on presynaptic membranes. At stimulated synapses (20 Hz), excess synuclein caused a loss of synaptic vesicles and an expansion of the plasma membrane, indicating an impairment of vesicle recycling. The N-terminal domain (NTD) of synuclein, which folds into an alpha-helix, was sufficient to reproduce these effects. In contrast, alpha-synuclein mutants with a disrupted N-terminal alpha-helix (T6K and A30P) had little effect under identical conditions. Further supporting this model, another alpha-synuclein mutant (A53T) with a properly folded NTD phenocopied the synaptic vesicle recycling defects observed with wild type. Interestingly, the vesicle recycling defects were not observed when the stimulation frequency was reduced (5 Hz). Thus excess alpha-synuclein impairs synaptic vesicle recycling evoked during intense stimulation via a mechanism that requires a properly folded N-terminal alpha helix. PMID- 25273558 TI - Predicting interactome network perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia. AB - Genomic variations such as point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and therapeutic targets. However, predicting the functional effect of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes are likely dependent of complex molecular interaction networks. Using as models three different chromosomal translocations ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and TCF3-PBX1 (E2A-PBX1)-frequently found in precursor-B-cell acute lymphoblastic leukemia (preB-ALL), we develop an approach to extract perturbed molecular interactions from gene expression changes. We show that the MYC and JunD transcriptional circuits are specifically deregulated after ETV6-RUNX1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and ETV6-RUNX1 acute lymphoblastic leukemia. PMID- 25273562 TI - Predicting dual-targeting anti-influenza agents using multi-models. AB - Influenza is an acute respiratory infectious disease caused by influenza viruses. Its subtype can be distinguished based on the antigenicity of two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). One of the main challenges in anti-influenza drug development is the quick evolution of drug resistance due to virus mutations. One solution to this problem is to develop dual-targeting anti-influenza agents. In this paper, a new rationally designed virtual screening protocol that combines structure-based approaches (molecular docking and molecular dynamic simulations) and ligand-based approaches (support vector machines and 3D shape & electrostatic similarity algorithms) is reported for the virtual screening of dual-targeting agents against HA and NA. The final hits came from the consensus of the ligand- and receptor-based knowledge of HA and NA and were tested using ADMET predictions. Evidence from the binding energy calculations and binding mode analyses suggested that several of the hits are promising as dual-targeting anti-influenza agents. The virtual screening protocol may also lead to the identification of innovative drugs in other fields. PMID- 25273564 TI - Virus-like particles as vaccine. AB - This review presents data on commercial and experimental virus-like particle (VLP) vaccines, including description of VLP vaccines against influenza. Virus like particles are multimeric, sometimes multiprotein nanostructures assembled from viral structural proteins and are devoid of any genetic material. VLPs present repetitive high-density displays of viral surface proteins. Importantly, they contain functional viral proteins responsible for cell penetration by the virus, ensuring efficient cell entry and thus tissue-specific targeting, determined by the origin of the virus. The foremost application of VLPs is in vaccinology, where they provide delivery systems that combine good safety profiles with strong immunogenicity and constitute a safe alternative to inactivated infectious viruses. These stable and versatile nanoparticles display excellent adjuvant properties capable of inducing innate and cognate immune responses. They present both, high-density B-cell epitopes, for antibody production and intracellular T-cell epitopes, thus inducing, respectively, potent humoral and cellular immune responses. Uptake of VLPs by antigen-presenting cells leads to efficient immune responses resulting in control of pathogenic microorganisms. PMID- 25273563 TI - A review of syntheses of 1,5-disubstituted tetrazole derivatives. AB - This report provides a brief overview of the various representative literature procedures for the synthesis of 1,5-disubstituted tetrazoles (1,5-DSTs) and fused 1,5-disubstituted tetrazoles with more than 120 references. Most of the published methods for the synthesis of 1,5-DSTs include the use of nitriles, amides, thioamides, imidoyl chlorides, heterocumulenes, isocyanates, isothiocyanates, carbodiimides, ketenimines, ketones, amines, and alkenes as the starting materials. The transformation of 1- and 5-substituted tetrazoles into 1,5-DSTs is also covered in this report. PMID- 25273565 TI - Expression of avian influenza haemagglutinin (H5) and chicken interleukin 2 (chIL 2) under control of the ptcB promoter in Lactococcus lactis. AB - Gram-positive and nonpathogenic lactic acid bacteria (LAB) are considered to be promising candidates for the development of new, safe systems of heterologous protein expression. Recombinant LAB has been shown to induce specific local and systemic immune response against selected pathogens, and could be a good alternative to classical attenuated carriers. The main goal of our study was to express the avian influenza haemagglutinin (H5) and chicken interleukin 2 (chIL 2) in Lactococcus lactis. Results of this study were anticipated to lead to construction of lactococcal strain(s) with potential vaccine properties against the avian influenza A (H5N1) virus. Expression of the cloned H5 gene, its His tagged variant and chIL-2 gene, under the control of the ptcB gene promoter was attested by RT-PCR on transcriptional level and Western or dot blot analysis on translational level, demonstrating that system can be an attractive solution for production of heterologous proteins. The results of the preliminary animal trial conducted in mice are a promising step toward development of a vaccine against avian bird flu using Lactococcus lactis cells as antigen carriers. PMID- 25273566 TI - Silencing KRAS overexpression in arsenic-transformed prostate epithelial and stem cells partially mitigates malignant phenotype. AB - Inorganic arsenic is a human carcinogen that likely targets the prostate. Chronic arsenic exposure malignantly transforms the RWPE-1 human prostate epithelial line to chronic arsenic exposed-prostate epithelial (CAsE-PE) cells, and a derivative normal prostate stem cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs). The KRAS oncogene is highly overexpressed in CAsE-PE cells and activation precedes transformation, inferring mechanistic significance. As-CSCs also highly overexpress KRAS. Thus, we hypothesize KRAS activation is key in causing and maintaining an arsenic-induced malignant phenotype, and hence, KRAS knockdown (KD) may reverse this malignant phenotype. RNA interference using shRNAmirs to obtain KRAS KD was used in CAsE-PE and As-CSC cells. Cells analyzed 2 weeks post transduction showed KRAS protein decreased to 5% of control after KD, confirming stable KD. KRAS KD decreased phosphorylated ERK, indicating inhibition of RAS/ERK signaling, a proliferation/survival pathway activated with arsenic transformation. Secreted metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but KRAS KD from 4 weeks on decreased secreted MMP-9 activity by 50% in As-CSCs. Colony formation, a characteristic of cancer cells, was decreased in both KRAS KD transformants. KRAS KD also decreased the invasive capacity of both cell types. KRAS KD decreased proliferation in As CSCs, consistent with loss of rapid tumor growth. Genes predicted to impact cell proliferation (eg, Cyclin D1, p16, and p21) changed accordingly in both KD cell types. Thus, KRAS silencing impacts aspects of arsenic-induced malignant phenotype, inducing loss of many typical cancer characteristics particularly in As-CSCs. PMID- 25273567 TI - Genetic deletion of LXRalpha prevents arsenic-enhanced atherosclerosis, but not arsenic-altered plaque composition. AB - Arsenic exposure has been linked to an increased incidence of atherosclerosis. Previously, we have shown in vitro and in vivo that arsenic inhibits transcriptional activation of the liver X receptors (LXRs), key regulators of lipid homeostasis. Therefore, we evaluated the role of LXRalpha in arsenic induced atherosclerosis using the apoE(-/-) mouse model. Indeed, deletion of LXRalpha protected apoE(-/-) mice against the proatherogenic effects of arsenic. We have previously shown that arsenic changes the plaque composition in apoE(-/-) mice. Arsenic decreased collagen content in the apoE(-/-) model, and we have observed the same diminution in LXRalpha(-/-)apoE(-/-) mice. However, the collagen-producing smooth muscle cells (SMCs) were decreased in apoE(-/-), but increased in LXRalpha(-/-)apoE(-/-). Although transcriptional activation of collagen remained the same in SMC from both genotypes, arsenic-exposed LXRalpha( /-)apoE(-/-) plaques had increased matrix metalloproteinase activity compared with both control LXRalpha(-/-)apoE(-/-) and apoE(-/-), which could be responsible for both the decrease in plaque collagen and the SMC invasion. In addition, arsenic increased plaque lipid accumulation in both genotypes. However, macrophages, the cells known to retain lipid within the plaque, were unchanged in arsenic-exposed apoE(-/-) mice, but decreased in LXRalpha(-/-)apoE(-/-). We confirmed in vitro that these cells retained more lipid following arsenic exposure and are more sensitive to apoptosis than apoE(-/-). Mice lacking LXRalpha are resistant to arsenic-enhanced atherosclerosis, but arsenic-exposed LXRalpha(-/-)apoE(-/-) mice still present a different plaque composition pattern than the arsenic-exposed apoE(-/-) mice. PMID- 25273575 TI - Safe European home. PMID- 25273569 TI - Myocardial perfusion imaging in emergency department patients with negative cardiac biomarkers: yield for detecting ischemia, short-term events, and impact of downstream revascularization on mortality. AB - BACKGROUND: In patients with possible acute coronary syndromes, guidelines recommend routine provocative testing after negative cardiac biomarkers. We hypothesized that myocardial perfusion imaging would be low yield with limited short-term value and that early revascularization would not affect mortality. METHODS AND RESULTS: We identified consecutive patients referred from our emergency department between October 2004 and September 2011 who had myocardial perfusion imaging after negative troponin T tests and nondiagnostic ECGs. We assessed the incidence of abnormal myocardial perfusion imaging, coronary angiography, revascularization, and mortality. In a cohort of 5354 patients (58.7% female, age 59 +/- 13, 78.6% thrombolysis in myocardial infarction [TIMI] <=2), 9% had >5% and 3.6% had >10% ischemic myocardium. Among patients with TIMI scores <=2, 6.1% had >5% ischemic myocardium compared with 19.6% of patients with TIMI scores >=3 (P<0.001). At 30 days, 7 patients were deceased, 187 had revascularization, and 6 had revascularization for an acute myocardial infarction. Over 3.4 +/- 1.9 years of follow-up, 347 patients died. In propensity matched groups of patients with ischemia, there was no association between early revascularization and mortality (hazard ratio, 1.00; 95% confidence interval, 0.49-2.07). CONCLUSIONS: Routine provocative testing to detect ischemia before emergency department discharge is low yield in patients with negative troponins and TIMI scores <=2 and modest yield in patients with TIMI scores >=3. In all patients, 30 days events are rare. Finally, in patients with ischemia, we are unable to demonstrate a mortality benefit with early revascularization. PMID- 25273577 TI - Ultrafast spectroscopy and structural characterization of a photochromic isomerizing ruthenium bis-sulfoxide complex. AB - Irradiation of [Ru(bpy)2(bpSOp)](PF6)2 (where bpy is 2,2'-bipyridine and bpSOp is 1,3-bis(phenylsulfinyl)propane) results in the formation of two new isomers, namely the S,O- and O,O-bonded species. The crystal structure of the bis thioether and bis-sulfoxide complexes are reported. NMR spectroscopy of the bis thioether complex in solution is consistent with the molecular structure determined by diffraction methods. Further, NMR spectroscopy of the bis-sulfoxide complex reveals two conformers in solution, one that is consistent with the solid state structure and a second conformer showing distortion in the aliphatic portion of the chelate ring. Time-resolved visible absorption spectroscopy reveals isomerization time constants of 91 ps in dichloroethane (DCE) and 229 ps in propylene carbonate (PC). Aggregate isomerization quantum yields of 0.57 and 0.42 have been determined in DCE and in PC, respectively. The kinetics of the thermal reversion from the O,O- to S,O-bonded isomer are strongly solvent dependent, occurring with rates of 2.41 * 10(-3) and 4.39 * 10(-5) s(-1) in DCE, and 4.68 * 10(-4) and 9.79 * 10(-6) s(-1) in PC. The two kinetic components are assigned to the two isomers identified in solution. PMID- 25273568 TI - Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance. AB - BACKGROUND: In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. METHODS AND RESULTS: In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51 +/- 12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57 +/- 6% to 54 +/- 7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1 +/- 5.1 to 15.9 +/- 6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). CONCLUSIONS: Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects. PMID- 25273578 TI - Coagulation proteases and cardiovascular disease. PMID- 25273579 TI - Adding decision support to a clinical information system. AB - Methods and tools were developed and designed to give assistance when creating and maintaining decision support systems in which the knowledge part is represented as rules written according to the Arden Syntax. Methods have also been designed and developed to support the process of adding decision support systems to clinical systems. PMID- 25273580 TI - Computer supported patient management. AB - Both a prototype medical record system and a protocol information system are presented. Both systems are used for research purposes. The philosophy behind the medical record system is that the system should provide both freedom of vocabulary and freedom of level of detail. The freedom of vocabulary is guaranteed by allowing free text entry. Freedom of level of detail is obtained by structuring the medical record in a hierarchical way and to allow the physician to enter data at the level of detail that suits him best. The protocol information system supports the physician in managing the patient. It guides the user through the protocol and allows him to obtain background information about the protocol. Both flowcharts and images are included. After each session a summary of the steps taken can be printed. A first evaluation indicates that physicians like to use the system and learn from it. PMID- 25273581 TI - Clinical information process units (CIPUs) - a system ergonomic approach to medical information systems. AB - This article constitutes an introduction to the basic tools necessary to understand Systems Ergonomics applied to the development of clinical systems. A basic description of clinical patient care in the system ergonomics language is provided, and the current situation found in hospital information management is criticized from an ergonomic point of view. We have laid out a model of the information flow in the clinical environment, which breaks the complex process of patient care in clearly defined elements: the Clinical Information Process Units. Presented here as an example of the application of Systems Ergonomics to the clinical working processes, the Clinical Information Process Units constitute the central element in the system ergonomic model of the information flow in the clinical environment. PMID- 25273582 TI - Problem-oriented data presentation and navigation in an ICU information system: a system ergonomic approach. PMID- 25273583 TI - Automatic compensation of endotracheal tube resistance in spontaneously breathing patients. AB - The considerable additional ventilatory work needed to overcome the resistance of the endotracheal tube (ETT) is flow-dependent. In spontaneously breathing intubated patients this additional ventilatory work is therefore dependent on the flow pattern and cannot be adequately compensated for by support with a constant pressure. We propose a method to fully compensate for the ETT resistance during inspiration and expiration by regulating tracheal pressure (Ptrach),Ptrach is calculated at a rate of 500 Hz by measurement of flow and pressure at the outer end of the ETT and from coefficients describing the flow-dependent ETT resistance. The calculated tracheal pressure is fed into a modified demand-flow ventilator which can then control tracheal pressure to a target value (Ptrach,targ). Tracheal pressure can either be kept constant (automatic tube compensation, ATC), or changed in any chosen fashion. We tested our system on a laboratory lung model simulating a spontaneously breathing patient. Even under the simulation of extreme conditions the maximum deviation of Ptrach from Ptrach,targ was smaller than 2.5 mbar. We evaluated our system in 10 spontaneously breathing intubated patients breathing at ATC with or without volume proportional pressure support (VPPS) by measuring Ptrach. The mean maximum deviation of Ptrach from Ptrach,targ was 2.9 mbar. The rms-deviation was 1.1 mbar (inspiration and expiration considered) and 1.7 mbar (inspiration alone). The accuracy of the control of Ptrach is thus comparable to the control of airway pressure afforded by the unmodified demand-flow ventilator. PMID- 25273584 TI - Editorial introduction. PMID- 25273586 TI - Medical technology and research: an engineer's view. AB - Medical Technology and Research are discussed here from the particular viewpoint of a university engineering department active in a specific area of biomedical engineering research (biomechanics and rehabilitation engineering) and in charge of a postgraduate programme in Biomedical and Clinical Engineering. Hence the focus of this paper is on medical technology. Medical technology is discussed within two distinct - but interrelated - contexts: health care practice on the one hand (1) and medical research on the other hand (2). European cooperation in Biomedical Engineering research is reviewed, together with the relevant EC programmes (3). Finally, our own conclusions are added to those of the EC-IRDAC report (4). PMID- 25273589 TI - Contents of technology and health care volume 1. PMID- 25273590 TI - In Situ characterization of proteins using laserspray ionization on a high performance MALDI-LTQ-Orbitrap mass spectrometer. AB - The MALDI-LTQ-Orbitrap XL mass spectrometer is a high performance instrument capable of high resolution and accurate mass (HRAM) measurements. The maximum m/z of 4000 precludes the MALDI analysis of proteins without generating multiply charged ions. Herein, we present the study of HRAM laserspray ionization mass spectrometry (MS) with MS/MS and MS imaging capabilities using 2 nitrophloroglucinol (2-NPG) as matrix on a MALDI-LTQ-Orbitrap XL mass spectrometer. The optimized conditions for multiply charged ion production have been determined and applied to tissue profiling and imaging. Biomolecules as large as 15 kDa have been detected with up to five positive charges at 100 K mass resolution (at m/z 400). More importantly, MS/MS and protein identification on multiply charged precursor ions from both standards and tissue samples have been achieved for the first time with an intermediate-pressure source. The initial results reported in this study highlight potential utilities of laserspray ionization MS analysis for simultaneous in situ protein identification, visualization, and characterization from complex tissue samples on a commercially available HRAM MALDI MS system. PMID- 25273591 TI - Partially Edentulous Arches: A 5-Year Survey of Patients Treated at the Fluminense Federal University Removable Prosthodontics Clinics in Brazil. AB - PURPOSE: This study investigated the number and Kennedy Classification of the edentulous arches in patients treated at the Removable Partial Denture (RPD) Clinics of the Fluminense Federal University School of Dentistry (FO-UFF) in Rio de Janeiro, Brazil, from 2005 to 2010. MATERIALS AND METHODS: A cross-sectional retrospective survey was conducted on patient record charts to identify gender, age, number, and location of the edentulous arches, and Kennedy Class type. RESULTS: One hundred and forty-six patients were analyzed for this study (96 [65.8%] women and 50 [34.2%] men). Two hundred and ninety-two arches were analyzed: 74 arches (25%) were found with intact dentitions, 18 (6.1%) were edentulous arches, and 200 (68.8%) were partially edentulous arches. Ninety-one patients (62.3%) needed oral rehabilitation with RPDs on one arch and 55 (37.7%) in both arches. One hundred and eight (53.2%) partially edentulous mandibles and 92 (46.8%) partially edentulous maxillae were found. Kennedy Class I was more frequent in the mandibular arch (58 patients; 29%) whereas Kennedy Class III was more frequent in the maxillary arch (40 patients; 20%). Patients aged between 51 and 60 years presented the highest percentage of partially edentulous arches (33.6%). CONCLUSION: Mandibular Kennedy Class I and maxillary Kennedy Class III presented the highest frequency in patients treated at the FO-UFF. These results are in agreement with previous studies that evaluated the different Kennedy classes in partially edentulous arches. PMID- 25273592 TI - Roll up polymer/oxide/polymer nanomembranes as a hybrid optical microcavity for humidity sensing. AB - A hybrid optical microcavity from rolled-up polymer/oxide/polymer nanomembranes presents its excellent capability for environmental relative humidity detection. When exposed to a moist surrounding, poly(acrylic acid)/poly(ethylenimine) polymers swell greatly due to the absorption of water molecules, which thus leads to an increased wall thickness of the tubular optical microcavity and therefore presents a profound wavelength redshift of its whispering-gallery mode resonance. These experiments fit well with the calculation based on the Mie-scattering theory. Theoretical calculation also demonstrates that the thin walls of our tubular microcavities contribute to a high detection sensitivity compared to other microcavities. Our work could lead to new designs and applications of optical microcavities. PMID- 25273593 TI - Uncertainty measurement for automated macro program-processed quantitative proton NMR spectra. AB - The evaluation of a fully automated quantitative proton nuclear magnetic resonance spectroscopy (qNMR) processing program, including the determination of its processing uncertainty, and the calculations of the combined uncertainty of the qNMR result, is presented with details on the use of a trimmed purity average. Quantitative NMR spectra (1359) were collected over a 4-month period on various concentrations of pseudoephedrine HCl dissolved in D2O (0.0610 to 93.60 mg/mL) containing maleic acid (the internal standard) to yield signal-to-noise ratios ranging from 3 to 72,000 for analyte integral regions. The resulting 5436 purities exhibited a normal distribution about the best estimate of the true value. The median absolute deviation (MAD) statistical method was used to obtain a model of uncertainty relative to the signal-to-noise of the analyte's integral peaks. The model was then tested using different concentrations of known purity chloroquine diphosphate. qNMR results of numerous illicit heroin HCl samples were compared to those obtained by capillary electrophoresis. PMID- 25273594 TI - Distributed computing strategies for processing of FT-ICR MS imaging datasets for continuous mode data visualization. AB - High-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging enables the spatial mapping and identification of biomolecules from complex surfaces. The need for long time-domain transients, and thus large raw file sizes, results in a large amount of raw data ("big data") that must be processed efficiently and rapidly. This can be compounded by large area imaging and/or high spatial resolution imaging. For FT-ICR, data processing and data reduction must not compromise the high mass resolution afforded by the mass spectrometer. The continuous mode "Mosaic Datacube" approach allows high mass resolution visualization (0.001 Da) of mass spectrometry imaging data, but requires additional processing as compared to feature-based processing. We describe the use of distributed computing for processing of FT-ICR MS imaging datasets with generation of continuous mode Mosaic Datacubes for high mass resolution visualization. An eight-fold improvement in processing time is demonstrated using a Dutch nationally available cloud service. PMID- 25273596 TI - Abstracts for the XXVII Congress of the Spanish Society for Clinical Pharmacology, 2-4 October 2014, Seville, Spain. PMID- 25273595 TI - JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner. AB - Tumors characterized by an intense ribosome biogenesis often display a more aggressive behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, including the epigenetic regulation of the condensation of chromatin portions containing rRNA genes. JHDM1B (Jumonji C histone demethylase 1B) is a histone demethylase able to regulate the accessibility of rRNA genes. In this study, we aimed to define the contribution of JHDM1B expression to the features of breast cancer, a tumor type whose behavior is related to the rate of ribosome biogenesis. We show that, in breast cancer-derived cell lines, the increase in rRNA transcription that follows JHDM1B knock-down is mirrored by an augmented cell proliferation only in p53 compromised cells, while p53 competent cells undergo cellular senescence and death. The latter effect appears to be mediated by a p38-dependent phosphorylation of p53, inducing the expression of p15(Ink4b) and p21(Waf1). In breast cancers, lower JHDM1B expression correlates with an increased size of specifically stained nucleolar organized regions, a morphological parameter directly related to the rate of ribosome biogenesis and with a poorer prognosis. In addition, in tumors lacking the controller function of p53, a lower expression of JHDM1B is associated with an increased tumor size at diagnosis. Altogether, our data indicate that epigenetic activation of rDNA genes induced by JHDM1B depletion is associated with a p53-dependent growth arrest, but may promote cancer cell growth when p53 is lacking. PMID- 25273597 TI - Evaluation of serum procalcitonin and C-reactive protein levels as biomarkers of Henoch-Schonlein purpura in pediatric patients. AB - Henoch-Schonlein purpura (HSP) is a vasculitic disorder resulting from autoinflammatory-mediated tissue injury. Procalcitonin (PCT) and C-reactive protein (CRP) are two biomarkers of the immune response that recognize bacterial infection and inflammation, respectively. This study tested whether levels of PCT and CRP were associated with selected clinical features, disease severity, and organ damage in HSP. Eighty-nine pediatric patients with HSP were analyzed for clinical manifestations and organ damage. Serum CRP, PCT, and occult blood in the urine and stool (prior to steroid therapy) were measured. Disease severity was classified according to previously established clinical classifications. Sixty patients (67.4 %) had a low clinical score (LCS) of <4 (group A) while 29 patients (32.5 %) had a high clinical score (HCS) of >=4 (group B). When patients were then classified by the presence of gastrointestinal bleeding, 66 (74.2 %) cases lacked alimentary tract hemorrhage (group C) while 23 (25.8 %) cases presented with gastrointestinal bleeding (group D). There were no significant differences in CRP (group A: median = 5.26, range = 1.00-77.60 vs. group B: median = 8.59, range = 1.00-144.00 mg/l; u = 1.397) or PCT levels (group A: median = 0.05, range = 0.05-0.24 vs. group B: median = 0.08, range = 0.05-1.02 ng/ml; u = 1.709) between groups A and B. When serum PCT levels were examined in relation to gastrointestinal bleeding, the levels of serum PCT were higher in group D than group C patients (group D: median = 0.09, range = 0.05-1.02 vs. group C: median = 0.05, range = 0.05-0.32 ng/ml; u = 2.849). It is important to note that the average PCT level was below the threshold for a systemic bacterial infection (0.5 ng/ml). We did not observe a correlation between CRP levels and the absence or presence of GI bleeding in groups C or D (group C: median = 4.66, range = 1.00-144.00 vs. group D: median = 9.44, range = 1.06-124.00 mg/l; u = 1.783), respectively. In all patients, there was a significant correlation between the concentrations of PCT and CRP (r = 0.721, p = 0.002). In patients with HSP, inflammatory markers are not uniformly associated with the disease and instead, show variable association depending on the clinical severity and level of organ damage. In patients with severe HSP, elevated serum PCT was significantly associated with gastrointestinal bleeding. In contrast, CRP was not a specific predictor for different clinical classifications of HSP, despite a similar pattern of concentration changes to PCT. PMID- 25273602 TI - Polymer nanofibers: preserving nanomorphology in ternary blend organic photovoltaics. AB - The morphology of donor-acceptor blends holds the key to good performance through the balancing of good exciton dissociation efficiency and interconnectivity for good charge collection. In this work, the good morphology is preserved in ternary blend systems through the use of poly(3-hexylthiophene) (P3HT) nanofibers. The iridium(III)-based metal complex is incorporated in P3HT-PCBM blends as a triplet exciton sensitizer in the bulk heterojunction (BHJ) organic photovoltaics (OPV). The devices using triplet-sensitized ternary blends of P3HT experience a significant degradation in performance, a tendency further aggravated by thermal treatment. This is due to disruption in the morphology thus affecting charge generation and collection. In order to overcome these morphological issues and to circumvent the restriction due to the crystallization of the polymers, here we demonstrate the use of pre-assembled nanofibers in these ternary blends. The concept of stabilizing the nanomorphology of the blend material through the use of nanofibers can also be applied to other ternary systems. PMID- 25273598 TI - The effects of the natural enzyme, Pectinex Ultra SP-L, on human cell cultures and bacterial biofilms in vitro. AB - BACKGROUND: Pectinex Ultra SP-L (Pectinex) is a microbial-derived enzyme that is used in the food industry and that has been shown to inhibit bacterial biofilms. It has been suggested that Pectinex may be useful in the management of biofilm related bacterial infections and therefore warrants further investigation in this regard. The aim of this study was to investigate the cytotoxicity of Pectinex on cervical adenocarcinoma cells (HeLa), lymphocytes and neutrophils. Cell viability and morphology were assessed using an in vitro spectrophotometric MTT (3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay and polarization optical transmitted light differential interference contrast microscopy. This study also investigated the antibacterial and antibiofilm actions of Pectinex, alone and in combination with antibiotics, on standard and clinical cultures of Staphylococcus aureus and Pseudomonas aeruginosa. Minimum inhibitory (MIC) and bactericidal (MBC) concentrations were determined using p-iodo-nitrotetrazolium violet staining of bacterial cultures and regrowth of subcultures. Biofilm biomass and cell viability were quantified spectrophotometrically after staining with crystal violet and MTT. RESULTS: The IC50 (+/-SEM) of Pectinex was 193.9 (+/ 22.2) PGU/ml for HeLa cells, 383.4 (+/-81.5) and 629.6 (+/-62.8) PGU/ml for fMLP stimulated and non-stimulated lymphocytes respectively, and 245.9 (+/-9.4) and 529.7 (+/-40.7) PGU/ml for fMLP-stimulated and non-stimulated neutrophils, respectively. Induced morphological features characteristic of apoptosis and necrosis included cell membrane blebs and vacuolization in HeLa cells, clumping in lymphocytes, as well as shrunken rounded cells, apoptotic bodies and debris in all cultures. Pectinex (7.42 - 950 PGU/ml-1) was not bactericidal. In clinical cultures of Staphylococcus aureus, co-administration of Pectinex was associated with a 28.0% increase in both the MIC and MBC of amoxicillin-clavulanate. In clinical cultures of P. aeruginosa, there was an 89.0% and 92.8% increase in the MIC and MBC of ciprofloxacin, respectively. Pectinex <= 118.75 PGU/ml-1 and incubation periods >= 6 h were associated with increased biomass and cell viability in S. aureus or P. aeruginosa biofilms. CONCLUSIONS: Pectinex appeared to antagonize the antibacterial effects of amoxicillin-clavulanate and ciprofloxacin and furthermore demonstrated significant cytotoxicity. It was therefore deemed unsuitable for the management of either planktonic or biofilm phenotypes of S. aureus or P. aeruginosa. PMID- 25273604 TI - Challenges with effective nutrient supplementation for amphibians: A review of cricket studies. AB - Over the last 25 years, numerous studies have investigated the impact of insect supplementation on insect nutrient content. In light of recent nutrition related challenges with regards to zoo amphibians fed an insect based diet, this review attempts to comprehensively compile both anecdotal and published data in the context of practical application on this topic. Insects, primarily crickets, used for amphibian diets historically demonstrate low concentrations of key nutrients including calcium and vitamin A. Commonly used practices for supplementation involving powder dusting or gut loading have been shown to improve delivery of calcium and vitamin A, though often not reaching desired nutrient concentrations. The large variety of factors influencing insect nutrient content are difficult to control, making study design, and results often inconsistent. Formulation and availability of more effective gut loading diets, combined with a standardized protocol for insect husbandry and dietary management may be the most effective way to supplement insects for use in amphibian feeding programs. Ideally, the nutritional improvement of feeder insects would begin at the breeder level; however, until this becomes a viable choice, we confirm that supplementation of crickets through both gut-loading and dusting appear necessary to support the nutritional health of amphibians and other insectivores in managed collections. PMID- 25273603 TI - Serum lipoprotein changes in dogs with renal disease. AB - BACKGROUND: People with renal disease develop a dyslipidemia that contributes to progression of renal injury and development of cardiovascular disease. Lipoproteins in dogs with renal disease have not been investigated. HYPOTHESIS: Dogs with chronic kidney disease (CKD) have dyslipidemia characterized by increased lower density lipoproteins and decreased high-density lipoproteins (HDLs). The degree of dyslipidemia is positively correlated with severity of disease, as reflected by serum creatinine concentration. ANIMALS: Prospective study of client-owned dogs presented to the Cornell University Hospital for Animals: 29 dogs with confirmed CKD, 5 dogs with nephrotic syndrome (NS), and 12 healthy control dogs presented for routine vaccinations, dental cleaning, or owned by students. METHODS: Lipoprotein electrophoresis was used to quantify relative proportions of the 3 main classes of lipoproteins in canine serum: low density lipoproteins (LDL), very low-density lipoproteins (VLDL), and HDL. Serum cholesterol and creatinine concentrations; urinalysis and urine protein-to creatinine ratio were measured by standard methods. RESULTS: Dyslipidemia was consistently found in dogs with CKD and NS and was characterized by a decrease in HDL and variable increases in LDL and VLDL. Dogs with NS had a proportionately greater increase in the VLDL fraction, as compared with dogs with CKD. CONCLUSION AND CLINICAL IMPORTANCE: Dyslipidemia similar to that documented in people with renal disease occurs in dogs with CKD, despite serum cholesterol concentrations often being within the reference interval. The contribution of altered lipoproteins to the pathogenesis of renal disease in dogs warrants additional study. PMID- 25273605 TI - Therapeutic designing for urethral obstruction by virtual urethra and flow dynamics simulation. AB - INTRODUCTION: Transurethral surgery is widely accepted as standard therapy for male urethral obstruction. The present study was undertaken to identify and select lesions to be managed by processing endoscopic images of the urethra for assisting less invasive therapy in patients with voiding dysfunction. MATERIAL AND METHODS: Cystourethroscopic video files of 25 patients with lower urinary tract symptoms were recorded before and after administration of alpha-1 adrenoceptor antagonists. Each video frame was restored and tagged with information indicating the position in the panoramic image of the urethra. A three-dimensional virtual urethra was created to indicate critical lesions for voiding dysfunction, together with fluid dynamics simulation of urine flow. RESULTS: The urine stream was depicted in the virtual urethras in 19 patients. Before therapy, 17 patients showed vortex formation that was diminished after therapy in nine patients with a significant relationship in improvement of relative energy loss of flow (p=0.025). The narrowing points proximal to the vortex, candidate of lesions, were identified in the panoramic image and linked to the endoscopic image. DISCUSSION: Therapeutic designing for endoscopic management was possible in patients with voiding dysfunction based on computational fluid dynamics, and would be promising as "focal" therapy for aging males. PMID- 25273606 TI - Hydrogeology: Objectives, Methods, Applications. PMID- 25273609 TI - Cardiac wall motion abnormality after bleeding from vertebral artery aneurysms. AB - OBJECTIVE: Lesions in the medulla oblongata may be causally associated with cardiac wall motion abnormality (WMA). Although subarachnoid hemorrhage (SAH) patients occasionally develop WMA, the relationship between aneurysmal locations and the frequency of WMA has rarely been investigated. The objective of this study was to evaluate whether the frequency of WMA was higher after the rupture of vertebral artery (VA) aneurysms than that of non-VA aneurysms. METHODS: We performed a retrospective chart analysis of 244 SAH patients who underwent transthoracic echocardiography and plasma catecholamine measurements. The frequencies of WMA and electrocardiographic (ECG) abnormalities were compared among patients classified by the location of aneurysms. Multivariate regression analysis was conducted to identify variables correlated with WMA. Furthermore, the relationship between plasma catecholamine levels and aneurysmal locations was evaluated. RESULTS: The frequency of WMA was significantly higher in patients with VA aneurysms than in those with non-VA aneurysms (45 vs. 22 %, p = 0.01). However, there was no significant difference in the frequency of ECG abnormalities. Multivariate regression analysis showed that VA aneurysms (OR, 3.317; 95 % CI, 1.129-9.745), poor-grade SAH (OR, 2.733; 95 % CI, 1.320-5.658) and concomitant hydrocephalus (OR, 3.658; 95 % CI, 1.690-7.917) correlated with WMA. There were no significant intergroup differences in plasma catecholamine levels. CONCLUSION: VA aneurysms are close to several medullary nuclei that integrate autonomic inputs. A transient deformation and ischemia of the medulla oblongata caused by the mechanical stress related to the rupture of a VA aneurysm and/or a concomitant hydrocephalus may be responsible for the disproportionately high frequency of WMA. PMID- 25273610 TI - A pedigree analysis of two homozygous mutant Gitelman syndrome cases. AB - Gitelman syndrome (GS) is a salt-wasting tubulointerstitial disease of autosomal recessive inheritance (OMIM613395) caused by genic mutation of SLC12A3, which codes thiazide-sensitive Na-Cl cotransporter (NCCT) gene. The gene mutation of the majority of GS patients is compound heterozygous. This study analyzes two cases of GS gene mutation and the clinical phenotype. Twenty patients of two GS pedigrees underwent direct sequence alignment of 26 exons of SLC12A3 to spot and locate mutant site. Proband A of Pedigree I had three mutant sites: Arg928Cys, a homozygote, missense mutation, and two homozygous silent mutations, Ala122Ala and Thr465Thr, and 8 members of Pedigree I carried Arg928Cy heterozygous mutation. Proband B of Pedigree II had a homozygote, Ser710X, and a termination codon was spotted, which would inevitably be translated into abridged and defective protein, and 7 members had Ser710X heterozygous mutation. The heterozygous mutation carriers of the two pedigrees often have stimulus-controlled hypokalemia after strenuous exercise. The parents of Proband A are cousins, a case of intermarriage. Both probands show hypokalemia, hypochloraemia, hypocalcinuria, hyperreninemia, and hyperaldosteronemia; Proband A has normal serum magnesium and increased urinary sodium excretion, while Proband B has hypomagnesemia and increased urinary magnesium ion excretion. Both probands have normal or lower blood pressure, weakness and numbness of lower extremities, muscular soreness, and occasional palpitations and chest discomfort. Proband A wearies easily and Proband B has occasional joint numbness and pain. These two homozygous mutations are responsible for the morbidity of two GS families and they show heterogenicity of clinical phenotype. PMID- 25273611 TI - The regulation of circulating ghrelin - with recent updates from cell-based assays. AB - Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels. PMID- 25273612 TI - Depressive rumination and experiential avoidance: a task based exploration. AB - Depressive rumination has been conceptualized as being closely connected with experiential avoidance. Evidence supporting this hypothesis derives primarily from studies using self-report measures. The present study explores this idea using a task-based assessment of avoidance. College students (N = 100) rated their emotional responses to 60 computer-presented images (positive, negative and neutral). Response times for the image-rating task were surreptitiously recorded, along with Ruminative Response Scale and Beck Depression Inventory II scores. Rumination was correlated with faster response times for negative, but not positive or neutral images. These findings are interpreted as lending support to the experiential avoidance conceptualization of rumination; however, consideration is also given to a potentially synergistic interpretation implicating heightened threat monitoring. PMID- 25273613 TI - Selected ophthalmic diagnostic tests, bony orbit anatomy, and ocular histology in sambar deer (Rusa unicolor). AB - PURPOSE: The purpose of this study was to establish reference values for diagnostic ophthalmic tests in sambar deer (Rusa unicolor) as well as to describe the most relevant features of the bony orbital anatomy and ocular histology. METHOD: Twenty healthy animals, free living in a forest reserve, that were captured for clinical evaluation as part of a health survey were evaluated. Schirmer tear test-1 (STT1), conjunctival microbiota, intraocular pressure (IOP), conjunctival cytology, anatomy of the bony orbit, and ocular histology were studied. RESULTS: Mean +/- SD STT1 and IOP values were 18.8 +/- 4.7 mm and 11.4 +/- 2.8 mmHg, respectively. IOP was significantly higher in adult (4-8 years) animals (P = 0.04). Bacterial growth was present in 100% of the samples, with a prevalence for Staphylococcus sp. and Bacillus sp. The conjunctival cytology revealed predominance of columnar epithelial cells with mild pigmentation. The sambar deer orbit is completely encompassed by bone. The ocular histology was very similar to most mammalians. CONCLUSIONS: The findings in this study will be useful in the diagnosis of ocular diseases in Rusa unicolor. PMID- 25273614 TI - Practical implementation of faecal transplantation. AB - Clostridium difficile infection is a leading cause of antibiotic-related and healthcare-related diarrhoea. In the past decade, faecal microbiota transplantation or transfer has attracted increasing interest as an effective treatment strategy for severe recurrent C. difficile infection, with a global success rate of >80%. However, experience with this procedure is limited by a lack of randomized trials supporting its efficacy and the lack of standardization of the procedure. This review will address the practical aspects of the protocol. PMID- 25273615 TI - Bio-inspired smart single asymmetric hourglass nanochannels for continuous shape and ion transport control. AB - Inspired by biological asymmetric ion channels, new shape-tunable and pH responsive asymmetric hourglass single nanochannel systems demonstrate unique ion transport properties. It is found that the change in shape and pH cooperatively control the ion transport within the nanochannel ranging from asymmetric shape with asymmetric ion transport, to asymmetric shape with symmetric ion transport and symmetric shape with symmetric ion transport. PMID- 25273616 TI - Coronal plane fracture of the femoral condyles: anatomy, injury patterns, and approach to management of the Hoffa fragment. AB - OBJECTIVE: The purpose of this article is to provide a review of coronal fractures of the femoral condyles, known as Hoffa fractures. This includes a review of the normal anatomy of the femoral condyles, examples of the injury, and postoperative imaging findings after surgical treatments. CONCLUSIONS: Knowledge of anatomy with related pathology, orthopedic trends, imaging findings, and complications, is important in assessing Hoffa fractures. PMID- 25273617 TI - A database system for the registration of complications and failures in cochlear implant surgery applied to over 1000 implantations performed in Nijmegen, The Netherlands. AB - OBJECTIVE: To create a system for the uniform registration and classification of complications and failures in cochlear implant surgery, and apply it to all the patients who underwent implantation in our clinic. METHOD: The definition of a medical complication was established, and data for all cochlear implantations performed between 1987 and 2012 were entered into a custom-made database system. RESULTS: One or more medical complications were registered in 19.0 per cent of 1003 cochlear implantations. The incidence of 'hard failure' was 2.3 per cent. Findings revealed a decrease in device failures over the years; the rate of medical complications remained constant. CONCLUSION: Our database system, which is available free of charge, enables fast and accurate data entry. There were a relatively high number of (minor) complications in our series, but comparison with the relevant literature is difficult. This emphasises the need for a uniform definition of 'complication' as it relates to cochlear implant surgery, and an appropriate classification system for such complications. PMID- 25273618 TI - Venovenous extracorporeal life support for posttraumatic respiratory distress syndrome in adults: the risk of major hemorrhages. AB - BACKGROUND: The aim of this retrospective study is to investigate the therapeutic benefits and the bleeding risks of venovenous extracorporeal life support (VV ECLS) when used for adult posttraumatic respiratory distress syndrome (posttraumatic ARDS). MATERIALS AND METHODS: Twenty adult trauma patients (median age: 38 years, median injury severity score: 35) treated with VV-ECLS in a level I trauma center between January 2004 and June 2013 were enrolled in this study. The indication of VV-ECLS for posttraumatic ARDS was refractory hypoxemia (PaO2/FiO2 ratio <= 70 mmHg) under advanced mechanical ventilation. To minimize potential complications, a protocol-guided VV-ECLS was adopted. RESULTS: Sixteen patients were weaned off VV-ECLS, and of these patients fourteen survived. Medians of the trauma-to-ECLS time, the pre-ECLS mechanical ventilation, and the ECLS duration in all patients were 64, 45, and 144 hours respectively. The median PaO2/FiO2 ratio was improved significantly soon after VV-ECLS, from 56 to 106 mmHg (p < 0.001). However, seven major hemorrhages occurred during VV-ECLS, of which three were lethal. The multivariate analysis revealed that the occurrence of major hemorrhages during VV-ECLS was independently related to the trauma-to ECLS time < 24 hours (OR: 20; p = 0.02; 95% CI: 2-239; c-index: 0.81). CONCLUSIONS: Despite an effective respiratory support, VV-ECLS should be cautiously administered to patients who develop advanced ARDS soon after major trauma. PMID- 25273620 TI - One-step transfistula large versus conventional balloon dilation following precut fistulotomy in difficult biliary cannulation for the removal of biliary stones: a multicenter retrospective study. AB - BACKGROUND AND AIM: After selective biliary access following precut fistulotomy in difficult biliary cannulations (DBC), there are several methods of completely opening the remaining papillary roof for the removal of biliary stones. We evaluated the efficacy of one-step transfistula balloon dilation following fistulotomy in DBC for the removal of biliary stones. METHODS: This retrospective multicenter study was performed in four tertiary referral centers. Patients who underwent fistulotomy due to DBC were enrolled. Precut fistulotomy followed by conventional (<= 10 mm) or large balloon (>= 12 mm) dilation through the fistulotomy tract was performed to remove biliary stones. The main outcome measures were technical success and transfistula balloon dilation-related complications. RESULTS: A total of 154 patients were enrolled. Large balloon and conventional balloon dilation were performed in 57 and 97 patients, respectively. The primary technical success of stone removal was 100% (57/57) for large balloon dilation and 96.9% (94/97) for conventional balloon dilation (P = 0.296). The mean procedure time from biliary access to removal of stones was 29.3 min in large balloon and 22.2 min in conventional balloon dilation (P = 0.042), and the mean numbers of endoscopic retrograde cholangiopancreatography sessions were 1.4 and 1.3, respectively (P = 0.175). Transfistula balloon dilation-related complications were not different between the two groups (10.5% in large balloon dilation vs 16.5% in conventional balloon dilation, P = 0.307). CONCLUSIONS: One step transfistula balloon dilation following precut fistulotomy in DBC may be safe and effective for the removal of biliary stones. There were no differences in therapeutic outcomes and complications between large and conventional balloon dilation. PMID- 25273619 TI - Plasma cytokine levels are related to brain volumes in HIV-infected individuals. AB - HIV-infected individuals frequently exhibit brain dysfunction despite antiretroviral treatment. The neuropathological mechanisms underlying these abnormalities remain unclear, pointing to the importance of identifying biomarkers sensitive to brain dysfunction. We examined 74 medically stable HIV infected individuals using T1-weighted MRI. Volumes of the cortical grey matter (GM), white matter (WM), caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala, and ventricles were derived using automated parcellation. A panel of plasma cytokines was measured using multiplexed bead array immunoassay. A model selection algorithm was used to select the combination of clinical and cytokine markers that best predicted each brain volumetric measure in a series of linear regression models. Higher CD4 nadir, shorter HIV infection duration, and antiretroviral treatment were significantly related to higher volumes of the putamen, thalamus, hippocampus, and WM. Older age was related to lower volumes in most brain regions and higher ventricular volume. Higher IFN gamma, MCP-1, and TNF-alpha were related to higher volumes of the putamen, pallidum, amygdala, GM, and WM. Higher IL-1beta, IL-6, IL-16, IL-18, IP-10, MIP 1beta, and SDF-1alpha were related to lower volumes of the putamen, pallidum, thalamus, hippocampus, amygdala, GM, and WM; and higher ventricular volume. The current findings provide evidence linking smaller brain volumes to HIV disease history, antiretroviral treatment, and advanced age. Cytokine markers, especially IL-6 and IL-16, showed robust association with brain volumes even after accounting for other clinical variables, demonstrating their utility in examining the mechanisms of HIV-associated brain abnormalities. PMID- 25273622 TI - Circulating levels of maternal plasma cell-free miR-21 are associated with maternal body mass index and neonatal birth weight. PMID- 25273621 TI - The impact of preoperative patient characteristics on health states after total hip replacement and related satisfaction thresholds: a cohort study. AB - BACKGROUND: The aim of the study was to analyze the effect of preoperative patient characteristics on health outcomes 6 months after total hip replacement (THR), to support patient's decision making in daily practice with predicted health states and satisfaction thresholds. By giving incremental effects for different patient subgroups, we support comparative effectiveness research (CER) on osteoarthritis interventions. METHODS: In 2012, 321 patients participated in health state evaluation before and 6 months after THR. Health-related quality of life (HRQoL) was measured with the EQ-5D questionnaire. Hip-specific pain, function, and mobility were measured with the WOMAC in a prospective observation of a cohort. The predictive capability of preoperative patient characteristics - classified according to socio-demographic factors, medical factors, and health state variables - for changes in health outcomes is tested by correlation analysis and multivariate linear regressions. Related satisfaction thresholds were calculated with the patient acceptable symptom state (PASS) concept. RESULTS: The mean WOMAC and EQ-5D scores before operation were 52 and 60 respectively (0 worst, 100 best). At the 6-month follow-up, scores improved by 35 and 19 units. On average, patients reported satisfaction with the operation if postoperative (change) WOMAC scores were higher than 85 (32) and postoperative (change) EQ-5D scores were higher than 79 (14). CONCLUSIONS: Changes in WOMAC and EQ-5D scores can mainly be explained by preoperative scores. The lower the preoperative WOMAC or EQ-5D scores, the higher the change in the scores. Very good or very poor preoperative scores lower the probability of patient satisfaction with THR. Shared decision making using a personalized risk assessment approach provides predicted health states and satisfaction thresholds. PMID- 25273623 TI - Impact of medical training and clinical experience on the assessment of oxygenation and hypoxaemia after general anaesthesia: an observational study. AB - In Germany it is common practice to use pulse oximetry and supplementary oxygen only on request in patients breathing spontaneously transferred to the post anaesthesia care unit (PACU) following surgery under general anaesthesia. The main aim was to study the influence of medical training and clinical experience on assessing SpO(2) and detecting hypoxaemia in these patients. The second aim was to do a preliminary assessment whether this practice can be found in countries other than Germany. Anaesthetists, nurses and medical students estimated SpO(2) in patients breathing room air at the end of transfer to the PACU following surgery (including all major surgical fields) under general anaesthesia. Estimated SpO(2) was compared to SpO(2) measured by pulse oximetry. A survey was carried out among European anaesthesists concerning the use of pulse oximetry and supplementary oxygen during patient transfer to the PACU. Hypoxaemia (SpO(2) < 90 %) occurred in 154 (13.5 %) out of 1,138 patients. Anaesthetists, nurses, and medical students identified only 25, 23, and 21 patients of those as being hypoxaemic, respectively. Clinical experience did not improve detection of hypoxaemia both in anaesthetists (p = 0.63) and nurses (p = 0.18). Use of pulse oximetry and supplemental oxygen during patient transfer to the PACU in European countries differs to a large extent. It seems to be applied only on request in many hospitals. Considering the uncertainty about deleterious effects of transient, short lasting hypoxaemia routine use of pulse oximetry is advocated for patient transfer to the PACU. PMID- 25273624 TI - The accuracy of respiratory rate assessment by doctors in a London teaching hospital: a cross-sectional study. AB - Respiratory rate (RR) is one of the most sensitive markers of a patient condition and a core aspect of multiple clinical assessment tools. Doctors use a number of methods to assess RR, including formal measurement, and 'spot' assessments, although this is not recommended. This study aimed to assess the accuracy of the methods of RR measurement being used by doctors. A cross-sectional study assessing the accuracy (range, bias, and imprecision) of doctors' 'spot' and 'formal' respiratory rate assessments, using videos of mock patients. 54 doctors in a London teaching hospital participated. Both methods showed high levels of inaccuracy, though formal methods were more accurate than 'spot' assessments. 52 and 19% of doctors did not identify the respiratory rates shown as abnormal, using 'spot' and formal assessment methods respectively. We observed a trend towards decreasing accuracy of 'spot' assessments with increasing clinical experience (p = 0.0490). Current methods of RR assessment by doctors are inaccurate. This may be significantly delaying appropriate clinical care, or even misguiding treatment. PMID- 25273625 TI - Measuring gas exchange with step changes in inspired oxygen: an analysis of the assumption of oxygen steady state in patients suffering from COPD. AB - Bedside estimation of pulmonary gas exchange efficiency may be possible from step changes in FIO2 and subsequent measurement of arterial oxygenation at steady state conditions. However, a steady state may not be achieved quickly after a change in FIO2, especially in patients with lung disease such as COPD, rendering this approach cumbersome. This paper investigates whether breath by breath measurement of respiratory gas and arterial oxygen levels as FIO2 is changed can be used as a much more rapid alternative to collecting data from steady state conditions for measuring pulmonary gas exchange efficiency. Fourteen patients with COPD were studied using 4-5 step changes in FIO2 in the range of 0.15-0.35. Values of expired respiratory gas and arterial oxygenation were used to calculate and compare the parameters of a mathematical model of pulmonary gas exchange in two cases: from data at steady state; and from breath by breath data prior to achievement of a steady state. For each patient, the breath by breath data were corrected for the delay in arterial oxygen saturation changes following each change in FIO2. Calculated model parameters were shown to be similar for the two data sets, with Bland-Altman bias and limits of agreement of -0.4 and -3.0 to 2.2 % for calculation of pulmonary shunt and 0.17 and -0.47 to 0.81 kPa for alveolar to end-capillary PO2, a measure of oxygen abnormality due to shunting plus regions of low [Formula: see text] A/[Formula: see text] ratio. This study shows that steady state oxygen levels may not be necessary when estimating pulmonary gas exchange using changes in FIO2. As such this technique may be applicable in patients with lung disease such as COPD. PMID- 25273626 TI - Pulse perfusion value predicts eye opening after sevoflurane anaesthesia: an explorative study. AB - The variables measured in modern pulse oximetry apparatuses include a graphical pulse curve and a specified perfusion value (PV) that could be a sensitive marker for detecting differences in sympathetic activity. We hypothesized that there is a correlation between a reduction of PV and the time to eye opening after general anaesthesia. The objective was to investigate whether PV can predict eye opening after sevoflurane anaesthesia. Prospective, explorative clinical study included 20 patients, ASA physical status 1 or 2, at Skane University Hospital, Lund, Sweden, from November 2012 to January 2013 scheduled for elective breast tumour surgery. A general anaesthesia was delivered with inhalation of oxygen, nitrous oxide and sevoflurane anaesthesia to a depth of 1.2 minimal alveolar concentration. Sevoflurane inspiratory and expiratory concentrations were measured. Bispectral index monitoring, PV as measured by pulse oximeter, heart rate and carbon dioxide were registered at before anaesthesia, 15 min after induction (at 1.2 minimal alveolar concentration), at end of surgery and at eye opening at the end of anaesthesia. PV values were lower before anaesthesia and at eye opening compared to at 15 min after induction and at end of surgery (P < 0.05). The reduction of PV between end of surgery and eye opening was 0.76. We conclude that the pulse oximeter PV could be a useful variable to assess the timing of recovery, in terms of eye opening after a general anaesthesia. PMID- 25273627 TI - Utilization of organophosphate:phosphate antiporter for isotope-labeling experiments in E. coli. AB - The transport of organophosphates across the cytoplasma membrane is mediated by organophosphate:phosphate antiporter proteins. In this work, we present the application of a recombinant phosphoenolpyruvate:phosphate antiporter for isotopic labeling experiments in E. coli strains. The antiporters UhpT, UhpT D388C, and PgtP were investigated regarding transport activity and growth on phosphoenolpyruvate as sole carbon source. The expression of the protein variant UhpT-D388C in a shikimic acid producing E. coli strain was used to show the successful isotopic labeling of shikimic acid from extracellular phosphoenolpyruvate. The results demonstrate the possibility of a direct incorporation of exogenously applicated glycolysis intermediates into E. coli cells for 13C-labeling experiments. PMID- 25273629 TI - Haemonchus longistipes Railliet & Henry, 1909 (Nematoda, Trichostrongylidae) from the Egyptian dromedary, Camelus dromedarius (Artiodactyla: Camelidae), first identification on the basis of light and ultrastructural data. AB - Haemonchus longistipes is a gastrointestinal abomasal nematode which is one of the most prevalent and pathogenic parasites infesting the stomach of ruminants. On the basis of light and ultrastructural data, the objective of the present study was to introduce a first identification of the cameline haemonchosis caused by H. longistipes. Abomasa of 42 Egyptian camels Camelus dromedarius (Artiodactyla: Camelidae) were collected monthly from September 2013 to April 2014 from the main slaughter house of Cairo, Egypt. Adult male and female nematode worms were recovered from 26 (62%) specimens of the examined abomasa. The parasites were of yellow color; the body was filiform (slender) tapered towards the anterior end in male and towards both ends in female. Buccal capsules absent, the buccal cavity was small with a conspicuous dorsal lancet extended from dorsal wall. The cervical papillae were prominent and spine-like. The body length of the female worm was 16.6-20.5 (18.5 +/- 0.3) mm. The anterior end to the cervical papillae was 3.19-4.30 (4.12 +/- 0.5) mm. The vulva of the female had a linguiform process or flap, the tail is without a spine, and the anal pore at the posterior end of the body had a simple dorsal rim. The body of male was 10.4-14.7 (13.9 +/- 2.0) mm in length. The male bursa had elongated lobes supported by long, slender rays. The small dorsal lobe was asymmetrical with Y shaped dorsal rays. The spicules were long with a length of 0.52-0.54 (0.53 +/- 0.05) mm, each provided with a small barb and pore near its extremity. Synlophe was bilaterally and dorsoventrally symmetrical; it extended from cephalic expansion over anterior 50% of prebursal or prevulvar body and consisted of a maximum of 42 ridges. The described species herein was compared with the three morphologically similar species Haemonchus mitchelli, Haemonchus okapiae, and H. longistipes with their synlophes consist of 42 ridges distributed over the anterior half of the body. These species can be separated by unique structural characteristics of their synlophes, spicules, and copulatory bursa. The most morphologically similar species to the recovered worm was H. longistipes. Also, some of the parameters with regard to morphology and morphometry of this parasite were described for the first time. PMID- 25273628 TI - Whole genome association study identifies regions of the bovine genome and biological pathways involved in carcass trait performance in Holstein-Friesian cattle. AB - BACKGROUND: Four traits related to carcass performance have been identified as economically important in beef production: carcass weight, carcass fat, carcass conformation of progeny and cull cow carcass weight. Although Holstein-Friesian cattle are primarily utilized for milk production, they are also an important source of meat for beef production and export. Because of this, there is great interest in understanding the underlying genomic structure influencing these traits. Several genome-wide association studies have identified regions of the bovine genome associated with growth or carcass traits, however, little is known about the mechanisms or underlying biological pathways involved. This study aims to detect regions of the bovine genome associated with carcass performance traits (employing a panel of 54,001 SNPs) using measures of genetic merit (as predicted transmitting abilities) for 5,705 Irish Holstein-Friesian animals. Candidate genes and biological pathways were then identified for each trait under investigation. RESULTS: Following adjustment for false discovery (q-value < 0.05), 479 quantitative trait loci (QTL) were associated with at least one of the four carcass traits using a single SNP regression approach. Using a Bayesian approach, 46 QTL were associated (posterior probability > 0.5) with at least one of the four traits. In total, 557 unique bovine genes, which mapped to 426 human orthologs, were within 500kbs of QTL found associated with a trait using the Bayesian approach. Using this information, 24 significantly over-represented pathways were identified across all traits. The most significantly over represented biological pathway was the peroxisome proliferator-activated receptor (PPAR) signaling pathway. CONCLUSIONS: A large number of genomic regions putatively associated with bovine carcass traits were detected using two different statistical approaches. Notably, several significant associations were detected in close proximity to genes with a known role in animal growth such as glucagon and leptin. Several biological pathways, including PPAR signaling, were shown to be involved in various aspects of bovine carcass performance. These core genes and biological processes may form the foundation for further investigation to identify causative mutations involved in each trait. Results reported here support previous findings suggesting conservation of key biological processes involved in growth and metabolism. PMID- 25273630 TI - Contrasting patterns of structural host specificity of two species of Heligmosomoides nematodes in sympatric rodents. AB - Host specificity is a fundamental property of parasites. Whereas most studies focus on measures of specificity on host range, only few studies have considered quantitative aspects such as infection intensity or prevalence. The relative importance of these quantitative aspects is still unclear, mainly because of methodological constraints, yet central to a precise assessment of host specificity. Here, we assessed simultaneously two quantitative measures of host specificity of Heligmosomoides glareoli and Heligmosomoides polygyrus polygyrus infections in sympatric rodent hosts. We used standard morphological techniques as well as real-time quantitative PCR and sequencing of the rDNA ITS2 fragment to analyse parasite infection via faecal sample remains. Although both parasite species are thought to be strictly species-specific, we found morphologically and molecularly validated co- and cross-infections. We also detected contrasting patterns within and between host species with regard to specificity for prevalence and intensity of infection. H. glareoli intensities were twofold higher in bank voles than in yellow-necked mice, but prevalence did not differ significantly between species (33 vs. 18%). We found the opposite pattern in H. polygyrus infections with similar intensity levels between host species but significantly higher prevalence in mouse hosts (56 vs. 10%). Detection rates were higher with molecular tools than morphological methods. Our results emphasize the necessity to consider quantitative aspects of specificity for a full view of a parasites' capacity to replicate and transmit in hosts and present a worked example of how modern molecular tools help to advance our understanding of selective forces in host-parasite ecology and evolution. PMID- 25273631 TI - Triosephosphate isomerase of Taenia solium (TTPI): phage display and antibodies as tools for finding target regions to inhibit catalytic activity. AB - Previous studies demonstrated that antibodies against triosephosphate isomerase of Taenia solium (TTPI) can alter its enzymatic catalysis. In the present study, we used antibodies produced against the NH2-terminal region of TTPI (1/3NH2TTPI) and the phage display technology to find target regions to inhibit TTPI activity. As a first step, we obtained polyclonal antibodies against non-conserved regions from the 1/3NH2TTPI, which had an inhibitory effect of about 74 % on catalytic activity. Afterward, they were used to screen a library of phage-displayed dodecapeptides; as a result, 41 phage mimotope clones were isolated and grouped according to their amino acid sequence, finding the consensus A1 (VPTXPI), A2 (VPTXXI), B (LTPGQ), and D (DPLPR). Antibodies against selected phage mimotope clones were obtained by rabbit's immunization; these ones clearly recognized TTPI by both Western blot and ELISA. However, only the mimotope PDTS16 (DSVTPTSVMAVA) clone, which belongs to the VPTXXI consensus, raised antibodies capable of inhibiting the TTPI catalytic activity in 45 %. Anti-PDTS16 antibodies were confronted to several synthetic peptides that encompass the 1/3NH2TTPI, and they only recognized three, which share the motif FDTLQK belonging to the helix-alpha1 in TTPI. This suggests that this motif is the main part of the epitope recognized by anti-PDTS16 antibodies and revealed its importance for TTPI catalysis. PMID- 25273632 TI - Trichomonas gypaetinii n. sp., a new trichomonad from the upper gastrointestinal tract of scavenging birds of prey. AB - In the context of an epidemiological study carried out by several wildlife recovery centers in Spain, trichomonads resembling Trichomonas gallinae were found in the oropharyngeal cavity of 2 Egyptian vultures (Neophron percnopterus) and 14 cinereous vultures (Aegypius monachus) which did not show any symptoms of trichomonosis. In order to characterize them, these isolates along with seven other T. gallinae isolates obtained from different hosts and from different geographical origin were analyzed. Genetic analyses were performed by sequencing the small subunit ribosomal RNA (SSU-rRNA) and the internal transcribed spacers (ITS1 and ITS2) and the 5.8S rRNA regions. The morphological study of the isolates in both light and scanning electron microscopy was also performed. The sequences obtained in the genetic analysis coincide with previously published sequences of an isolate named as Trichomonas sp., obtained from a bearded vulture (Gypaetus barbatus), and showed clear differences to the T. gallinae sequences (97 and 90-91% homology, respectively, for SSU-rRNA and ITS regions) and display higher similarity with Trichomonas vaginalis and Trichomonas stableri than with T. gallinae. Multivariate statistical analysis of the morphometric study also reveals significant differences between the trichomonads of vultures and the isolates of T. gallinae. The isolates from vultures presented smaller values for each variable except for the length of axostyle projection, which was higher. These results together with the different nature of their hosts suggest the possibility of a new species of trichomonad which we hereby name Trichomonas gypaetinii, whose main host are birds of the subfamily Gypaetinae. PMID- 25273633 TI - Novel lipase purification methods - a review of the latest developments. AB - Microbial lipases are popular biocatalysts due to their ability to catalyse diverse reactions such as hydrolysis, esterification, and acidolysis. Lipases function efficiently on various substrates in aqueous and non-aqueous media. Lipases are chemo-, regio-, and enantio-specific, and are useful in various industries, including those manufacturing food, detergents, and pharmaceuticals. A large number of lipases from fungal and bacterial sources have been isolated and purified to homogeneity. This success is attributed to the development of both conventional and novel purification techniques. This review highlights the use of these techniques in lipase purification, including conventional techniques such as: (i) ammonium sulphate fractionation; (ii) ion-exchange; (iii) gel filtration and affinity chromatography; as well as novel techniques such as (iv) reverse micellar system; (v) membrane processes; (vi) immunopurification; (vi) aqueous two-phase system; and (vii) aqueous two-phase floatation. A summary of the purification schemes for various bacterial and fungal lipases are also provided. PMID- 25273635 TI - [Epidemiological studies on the environmental pollutants and allergies: focused on indoor air quality]. PMID- 25273634 TI - Palm kernel cake extract exerts hepatoprotective activity in heat-induced oxidative stress in chicken hepatocytes. AB - BACKGROUND: Palm kernel cake (PKC), the most abundant by-product of oil palm industry is believed to contain bioactive compounds with hepatoprotective potential. These compounds may serve as hepatoprotective agents which could help the poultry industry to alleviate adverse effects of heat stress on liver function in chickens. METHODS: This study was performed to evaluate the hepatoprotective potential of PKC extract in heat-induced oxidative stress in chicken hepatocytes. The nature of the active metabolites and elucidation of the possible mechanism involved were also investigated. RESULTS: The PKC extract possessed free radical scavenging activity with values significantly (p < 0.05) lower than silymarin as the reference antioxidant. Heat-induced oxidative stress in chicken hepatocyte impaired the total protein, lipid peroxidation and antioxidant enzymes activity significantly (p < 0.05). Treatment of heat-induced hepatocytes with PKC extract (125 MUg/ml) and silymarin as positive control increased these values significantly (p < 0.05). The real time PCR and western blot analyses revealed the significant (p < 0.05) up-regulation of oxidative stress biomarkers including TNF-like, IFN-gamma and IL-1beta genes; NF-kappaB, COX-2, iNOS and Hsp70 proteins expression upon heat stress in chicken hepatocytes. The PKC extract and silymarin were able to alleviate the expression of all of these biomarkers in heat-induced chicken hepatocytes. The gas chromatography-mass spectrometry analysis of PKC extract showed the presence of fatty acids, phenolic compounds, sugar derivatives and other organic compounds such as furfural which could be responsible for the observed hepatoprotective activity. CONCLUSION: Palm kernel cake extract could be a potential agent to protect hepatocytes function under heat induced oxidative stress. PMID- 25273636 TI - [Progress of the research on air pollution (PM2.5, Asian sand dust, etc) and allergy]. PMID- 25273637 TI - [Air pollution, climate and upper respiratory allergic disease]. PMID- 25273638 TI - [Guidelines for the clinical management of allergic conjunctival disease (2nd edition): the point of the management with using eye drops]. PMID- 25273639 TI - [Roles of runx transcription factor family in inflammation]. PMID- 25273640 TI - [Association between fungi and asthma]. PMID- 25273641 TI - [The role of IL-33 in allergic rhinitis]. PMID- 25273642 TI - [Dynamic characteristics of flow trainer for dpi and its clinical relevance]. AB - BACKGROUND: Trainer devices are widely employed for flow instruction in the use of dry powder inhalers (DPI). However, their aerodynamic characteristics in actual use have yet to be investigated. METHODS: We recorded inhalation flow signals and sounds produced from trainers for Diskus(r), Symbicort(r), Pulmicort(r) and Twisthaler(r) while five volunteers inhaled from the trainers with various inhalation patterns. RESULTS: Inhalation flow was classified into four patterns; the best, trapezoid, delayed peak and others. All the trainers exhibited flow-thresholds with appropriate precision for instruction. Sound intensity from the Diskus(r) trainer was almost proportional to inhaled flow rate, and it may be useful for flow pattern estimation. In other trainers, when flow exceeded some thresholds, sounds abruptly developed and continued with high intensity. Thus, they may be convenient for recognizing appropriate flow rates. In all trainers, when the subjects inhaled rapidly and forcefully, sound developed at 0.19-0.24 s after the onset of inhalation. Thus, with this flow pattern, trainers may indicate a flow rate approaching the peak of drug dispersion from the DPI. When the subject inhaled less rapidly, the threshold for sound development decreased by 10%. CONCLUSION: The instructor in DPI use should be aware of the aerodynamic characteristics of each individual trainer. Rapid inhalation should also be encouraged. PMID- 25273644 TI - The role of phonons for exciton and biexciton generation in an optically driven quantum dot. AB - For many applications of semiconductor quantum dots in quantum technology, well controlled state preparation of the quantum dot states is mandatory. Since quantum dots are embedded in the semiconductor matrix, their interaction with phonons often plays a major role in the preparation process. In this review, we discuss the influence of phonons on three basically different optical excitation schemes that can be used for the preparation of exciton, biexciton and superposition states: a resonant excitation leading to Rabi rotations in the excitonic system, an excitation with chirped pulses exploiting the effect of adiabatic rapid passage and an off-resonant excitation giving rise to a phonon assisted state preparation. We give an overview of experimental and theoretical results, showing the role of phonons and compare the performance of the schemes for state preparation. PMID- 25273643 TI - [Sensitization to laboratory animal allergens among students and researchers exposed to laboratory rodents in Hokkaido university]. AB - BACKGROUND: Based on a case who developed anaphylaxis after mouse bite which occurred at Hokkaido University, we studied on allergic sensitization prevalence for laboratory animals among students and researchers who are exposed to laboratory rodents and rabbit, for the purpose of allergy prevention, particularly anaphylaxis. METHODS: We carried out the health check-up on laboratory animal allergy (LAA) by questionnaires and specific-IgE antibody test for 555 rodents and/or rabbit handlers from whom informed consent was obtained. RESULT: Prevalence of positive IgE antibody higher than class 1 to mice, rats, hamsters, guinea pigs, and/or rabbits in the examinees was 14.1% (62/441) , 17.9% (50/279) , 18.8% (6/32) , 17.4% (4/23) , and 11.3% (12/106) , respectively. Moreover, among users of mouse, those who had allergic symptoms during contact with animals resulted in significantly higher positive rate for anti-mouse IgE antibody test than the other (38.1% vs 8.8%, p<0.01) . CONCLUSION: Health check up including measurement of specific-IgE antibody against laboratory animals is useful for understanding allergic sensitization. PMID- 25273645 TI - Impact of haemophilia with inhibitors on caregiver burden in the United States. AB - Inhibitor development complicates haemophilia treatment and may impact caregiver burden. Compare overall burden of caregivers of children with/without inhibitors in the United States using a novel disease-specific questionnaire and the previously validated CarerQol. An on-line questionnaire with six burden domains (i.e. emotional stress, personal sacrifice, financial burden, medical management, child's pain, and transportation) and three visual analogue scales (VAS) was developed based upon a targeted literature review and previous survey findings. The study sample consisted of caregivers of children with haemophilia. The total burden score was calculated by summing the six individual burden domain scores. Higher scores represented greater burden. Descriptive statistics was performed to examine the sample characteristics. The Wilcoxon rank-sum test was performed to compare burden by inhibitor status. All variables were considered significant at P < 0.001. A total of 310 caregivers completed the survey; 30 of them reported caring for a child with an inhibitor. A majority of caregivers of children with inhibitors were mothers (80.0%) and between 35 and 44 years of age (56.7%). Caregivers of children with inhibitors reported significantly higher median total burden scores (99.0 vs. 76.5, P < 0.0001) and median burden-VAS scores (5.5 vs. 3.0, P < 0.0001), as compared to those caring for children without inhibitors. A similar trend was seen across all the six burden domains, with greatest difference in the median burden scores observed in the 'personal sacrifice' (3.2 vs. 2.0) and 'transportation' (3.3 vs. 2.3) domains. Burden of caregivers should be considered when assessing the psychosocial aspects of managing patients with inhibitors. PMID- 25273647 TI - [Esophageal reconstruction--using gastric tube instead of whole stomach]. AB - Stomach is the first choice for esophageal reconstruction following esophagectomy. In the earlier days, however, whole stomach pulling-up was the major surgery, which had some shortcomings. Recently, gastric tube has gained wide acceptance for esophageal reconstruction. This paper summarized the anatomical and physiological advantage of stomach, the disadvantage of whole stomach, and benefits of gastric tube for esophageal reconstruction. PMID- 25273646 TI - Use of varenicline for smoking cessation treatment in UK primary care: an association rule mining analysis. AB - BACKGROUND: Varenicline is probably the most effective smoking cessation pharmacotherapy, but is less widely used than nicotine replacement therapy. We therefore set out to identify the characteristics of numerically important groups of patients who typically do, or do not, receive varenicline in the UK. METHODS: We used association rule mining to analyse data on prescribing of smoking cessation pharmacotherapy in relation to age, sex, comorbidity and other variables from 477,620 people aged 16 years and over, registered as patients throughout 2011 with one of 559 UK general practices in The Health Improvement Network (THIN) database, and recorded to be current smokers. RESULTS: 46,685 participants (9.8% of all current smokers) were prescribed any smoking cessation treatment during 2011, and 19,316 of these (4% of current smokers, 41% of those who received any therapy) were prescribed varenicline. Prescription of varenicline was most common among heavy smokers aged 31-60, and in those with a diagnosis of COPD. Varenicline was rarely used among smokers who were otherwise in good health, or were aged over 60, were lighter smokers, or had psychotic disorders or dementia. CONCLUSIONS: Varenicline is being underused in healthy smokers, or in older smokers, and in those with psychotic disorders or dementia. Since varenicline is probably the most effective available single cessation therapy, this study identifies under-treatment of substantial public health significance. PMID- 25273648 TI - [Colon interposition for esophageal reconstruction]. AB - Although the stomach is the first choice for esophageal reconstruction following esophagectomy, the colon interposition would be the best one when stomach removed or diseased. The colon reconstruction for esophagus, therefore, is the inevitable procedure in esophageal surgery. This paper focused on the colon interposition in terms of history, anatomy point, critical skills, and future prospect. PMID- 25273649 TI - [Free jejunum for circumferential hypopharynx and cervical esophagus reconstruction]. AB - Free jejunum has always been a good choice for circumferential hypopharynx and cervical esophagus reconstruction with a low complication rate. Although more and more flaps were used in recent years, free jejunum is still considered as the first choice for such defect. PMID- 25273650 TI - [Applicability of skin flaps and myocutaneous flaps for esophageal surgery]. AB - Stomach and colon are always used to reconstruct esophagus after esophagectomy. However, alternative procedures to reconstruct or repair esophagus are required if the patients suffered from gastric or colonic diseases, underwent gastric colonic operations or had severe local esophageal stricture. More than ten kinds of skin flaps and myocutaneous flaps, which are classified into free or pedicled ones, are used to reconstruct or repair esophagus. Microvascular anastomosis is required while using free flaps. Necrosis of the free flaps is prone to developing once the vascular occlusion occurs. The pectoralis major myocutaneous and latissimus dorsi pedicled flaps have sufficient blood supplies. However, both are bulky and difficult to reconstruct a circumferential esophagus through contouring a tube. Platysma myocutaneous flaps have a large surface area and are supplied from multiple vessels. Single lateral and bilateral platysma myocutaenous flap can be applied to repair the cervical esophageal defect and circumferential cervical esophagus, respectively. The use of platysma myocutaneous to repair and reconstruct cervical esophagus is a procedure easy to perform and confer excellent outcomes. There is no development of ulcer and hair growth after long-term follow-up and resistance to radiotherapy. PMID- 25273651 TI - [Fast track surgery in esophagectomy for esophageal cancer]. AB - In the past decade, fast track surgery protocols have been implemented in several fields of surgery. With these protocols, a faster recovery and shorter hospital stay can be accomplished. Fast track surgery may improve patients' satisfaction while reducing the hospitalization expenses. Through literature review combined with our clinical practice, this article aims to evaluate practical measures of a fast track surgery protocol in esophagectomy for esophageal cancer and their clinical application. PMID- 25273652 TI - [Application of cervical triangulating stapled anastomosis in minimally invasive esophagectomy]. AB - OBJECTIVE: To explore the safety and feasibility of cervical triangulating stapled anastomosis(TSA) for esophagogastric anastomosis(EGA) after minimally invasive esophagectomy (MIE). METHODS: Clinical data of 137 patients undergoing MIE for esophageal cancer(EC) in our department from January 2013 to March 2014 using end to side circular stapled anastomosis (CSA, 60 cases) or end-to-end triangulating stapled anastomosis (TSA, 77 cases) in the neck were retrospectively analyzed. The short-term outcomes between the two groups were evaluated and compared. RESULTS: Cervical anastomotic leakage occurred in 3 patients(3.9%) of TSA group, but in six(10.0%) of CSA group (P=0.152). The incidence of anastomotic stenosis was 1.3%(1/77) and 15.0%(9/60) in TSA and CSA group respectively(P=0.002). The median hospital stay and perioperative mortality were not significantly different between the two groups as well as postoperative respiratory and cardiovascular complications. CONCLUSIONS: TSA is a safely and effectively alternative method for EGA with lower incidence of postoperative gastrointestinal complications, especially in anastomotic stricture. PMID- 25273653 TI - [Two types of digestive tract reconstruction after proximal gastrectomy for early gastroesophageal junction adenocarcinoma: a randomized controlled study]. AB - OBJECTIVE: To investigate the better method of digestive tract reconstruction in proximal gastrectomy for early gastroesophageal junction adenocarcinoma. METHODS: A total of 153 cases of early gastroesophageal junction adenocarcinoma who were planned to receive radical proximal gastrectomy from January 2003 to December 2011 were prospectively enrolled and randomly divided into two groups by table of random number according to methods of digestive tract reconstruction, including 3S anastomosis group (80 cases, 3S jejunal interposition) and traditional anastomosis group (73 cases, esophageal remnant gastric posterior wall anastomosis). Postoperative complications, operative time, mortality, nutritional parameters and postoperative quality of life were compared between these two groups. RESULTS: There were no significant differences between two groups in postoperative complications, operative time and mortality (all P>0.05). 3S anastomosis group was better in nutritional parameters than traditional group six months after operation (P<0.05). As compared to traditional group, incidence of reflux esophagitis decreased [20.0%(16/80) vs. 46.6%(34/73), P<0.01] and gastric emptying time prolonged obviously [(160.8+/-8.1) min vs. (61.1+/-10.8) min, P<0.01] in 3S anastomosis group 18 months after operation. Postoperative QLQ-C30 rating scale revealed quality of life was significantly higher in 3S anastomosis group as compared to traditional group. CONCLUSION: Jejunal interposition is a better method of digestive tract reconstruction in proximal gastrectomy for early gastroesophageal junction carcinoma. PMID- 25273654 TI - [Risk factors of benign anastomostic strictures after esophagectomy with cervical reconstruction]. AB - OBJECTIVE: To identify the risk factors of benign cervical anastomotic strictures after esophagectomy. METHODS: Clinical data of 946 esophageal cancer patients undergoing esophagectomy with cervical anastomosis between 2003 and 2012 were analyzed retrospectively. Benign stricture was defined as dysphagia for which endoscopic dilation of the anastomosis was needed. Histologically proven malignant stricture was not regarded as benign stricture. chi(2) test and logistic regression model were used for univariate and multivariate analysis respectively. RESULTS: A total of 146 patients(16.5%) developed benign stricture during follow-up. Univariate analysis showed that the patients with cardiovascular disease (P=0.001), diabetes mellitus(P=0.041), gastric tube reconstruction(P=0.050), end-to-end anastomosis (P=0.013), or postoperative anastomotic leakage(P=0.008) had higher stricture rate. Multivariate analysis revealed that cardiovascular disease(P=0.004), gastric tube reconstruction (P=0.026), end-to-end anastomosis(P=0.043), and postoperative anastomotic leakage(P=0.001) were independently predictive factors for development of benign stricture. CONCLUSIONS: The benign cervical stricture rate after esophagetomy with cervical gastric anastomosis is quite high. In order to prevent benign stricture formation, end-to-end anastomosis should be avoid. Blood pressure should be controlled for those with cardiovascular disease. Endoscopic dilation in an earlier stage postoperatively should be considered for those who develop anastomotic leakage. PMID- 25273655 TI - [Comparison of the stapled suture with the manual suture in the application of minimally invasive esophagectomy]. AB - OBJECTIVE: To compare the associated anastomotic complication of cervical esophagogastric anastomosis between stapled and hand-sewn anastomosis in minimally invasive esophagectomy(MIE). METHODS: Clinical data of 203 patients with esophageal cancer receiving combined thoracoscopic and laparoscopic esophagectomy with anastomosis in the neck in our hospital from January 2010 to November 2013 were retrospectively analyzed. All the patients were divided into stapled group(104 patients) and hand-sewn group(99 patients). The incidence of anastomotic leakage and anastomotic stricture between these two groups were compared. RESULTS: There were no significant differences between two groups in gender, age, body mass index, total protein, albumin, and neoadjuvant chemotherapy(all P>0.05). There was no significant difference between the two groups in the incidence of anastomotic leakage [6/104(5.77%) vs. 3/99(3.03%), P>0.05], while the difference in the incidence of anastomotic stricture was significant [10/104(9.62%) vs. 2/99(2.02%), P<0.05]. The time of anastomosis, dieting and hospital stay was (15.5+/-5.0) min, (5.0+/-2.8) d and (18.3+/-5.9) d in stapled group, which was significantly shorter than (28.0+/-4.5) min, (5.9+/ 1.2) d and (21.8+/-4.2) d in hand-sewn group(all P<0.05). CONCLUSION: In the minimally invasive esophagectomy, stapled cervical esophagogastric anastomosis is simple and precise, but it is associated with increased risk of anastomotic stricture, therefore the type of anastomosis should be chosen based on the conditions of the patient. PMID- 25273656 TI - [Analysis of early lymph node metastasis pattern and prognosis in thoracic esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the pattern of early lymph node metastasis of thoracic esophageal squamous cell carcinoma and its prognostic value. METHODS: Clinical and follow-up data of 126 patients with pathological stage pN1 of esophageal squamous cell carcinoma undergoing radical esophagectomy in our department from January 2005 to December 2008 were analyzed retrospectively. Impact of lymph node metastasis pattern on prognosis was investigated. RESULTS: The relatively common sites of lymph node metastasis were upper mediastinum(53.8%), middle and lower thoracic paraesophageal(38.3%), right and left cardiac(34.4%) and the left gastric artery(36.8%). Univariate analysis showed that the lymph node metastasis of subcarinal, middle and lower thoracic paraesophageal and the left gastric artery was associated with 5-year survival rate. Multivariate analysis revealed that the presence of subcarinal and middle and lower thoracic paraesophagea lymph node metastasis was an independent risk factor of survival. CONCLUSIONS: Upper mediastinal, middle and lower thoracic paraesophageal, right and left cardiac and the left gastric artery are the earliest lymph node metastasis sites of esophageal squamous cell carcinoma. The presence of subcarinal and middle and lower thoracic paraesophagea lymph node metastasis is an independent risk factor of survival. Patient prognosis should be analyzed with lymph node metastasis pattern based on the 7th edition UICC-AJCC TNM classification system. PMID- 25273657 TI - [Short-term efficacy comparison between Ivor-Lewis approach and McKeown approach in minimally invasive esophagectomy]. AB - OBJECTIVE: To compare the perioperative complications between Ivor-Lewis approach and McKeown approach in minimally invasive esophagectomy and gastric tube reconstruction for the treatment of middle and lower thoracic esophageal cancer. METHODS: Retrospective analysis of clinical data was performed on 288 patients with middle and lower thoracic esophageal cancer who underwent completely minimally invasive esophagectomy by one surgical team in Fujian Medical University Union Hospital from December 2010 to March 2014. Among the 288 patients, 103 patients underwent combined laparoscopic and thoracoscopic esophagectomy and intrathoracic esophagogastric anastomosis using a transoral anvil(Orvil)(Ivor-Lewis group, 2-incision) and 185 patients underwent combined laparoscopic and thoracoscopic esophagectomy and cervical anastomosis(McKeown group, 3-incision). Patients were stratified by surgical approach and perioperative outcomes were compared between the two groups. RESULTS: There were no statistical differences between two groups in intra-operative blood loss, conversion to open, extubation time, time to resume oral intake, postoperative hospital stay, the median number of lymph nodes resected. The operation time of Ivor-Lewis group was significantly shorter than that of McKeown group [(283.4+/ 32.0) min vs. (303.6+/-43.7) min, P=0.003). The hospital cost of Ivor-Lewis group was significantly higher than that of McKeown group [(76 492+/-18 553) yuan vs. (68 923+/-17 331) yuan, P<0.01]. There were no statistical differences between two groups in chylothorax, delayed gastric emptying, atrial fibrillation, postoperative bleeding, admission to ICU, short-term postoperative mortality (P>0.05). The total postoperative complication morbidity of Ivor-Lewis group was significantly lower than that of McKeown group(16.5% vs. 31.4%, P<0.01). Ivor Lewis group had lower pulmonary complication(8.7% vs. 25.9%, P<0.01), anastomotic leakage(1.9% vs. 13.0%, P<0.01), anastomotic stricture (0% vs. 4.9%, P<0.05), recurrent laryngeal nerve injury(1.0% vs. 7.0%, P<0.05). CONCLUSION: Ivor-Lewis approach is associated with less postoperative complications, but higher cost as compared to McKeown approach in the treatment of middle and lower thoracic esophageal cancer. PMID- 25273658 TI - [A meta-analysis of esophagectomy: the comparative study of Ivor-Lewis operation and Sweet operation]. AB - OBJECTIVE: Investigate the best surgical resection of esophageal cancer by comparing the efficacy and safety between Ivor-Lewis esophagectomy and Sweet esophagectomy. METHODS: The relevant literatures comparing Ivor-Lewis esophagectomy with Sweet esophagectomy were searched through PubMed, Embase, the Cochrane Library, Google scholar, CNKI, CBM, VIP, WanFang Data. RevMan 5.2 software was used for data analysis. RESULTS: A total of 4106 patients in 15 studies were reviewed and the data were pooled for analysis. Meta-analysis showed that, compared with the Sweet group, Ivor-Lewis operative time was significantly longer(pooled mean difference=57.40; 95%CI:42.43 to 72.38; P=0.000), operative bleeding was significantly higher(pooled mean difference=28.39, 95%CI:4.06 to 52.72, P=0.02); the number of lymph node dissection significantly more(pooled mean difference=4.19, 95%CI:3.06 to 5.32, P=0.000); No significant difference was present in hospital stay, vocal cord paralysis, chylous leakage, pulmonary complications, anastomotic leakage(all P>0.05). The 5-year survival between the two groups showed no significant difference(P=0.52). CONCLUSIONS: The two kinds of operation have the same long term effect. Compared with Ivor-Lewis operation, Sweet operation is easier to perform, less time consuming and more tolerable. Ivor-Lewis operation can dissect more lymph nodes than Sweet operation, without increased complications. PMID- 25273659 TI - [Feasibility of "no tube no fasting" therapy in thoracolaparoscopic oesophagectomy for patients with oesophageal cancer]. AB - OBJECTIVE: To investigate the feasibility of no nasogastric intubation and early oral feeding at will after thoracolaparoscopic esophagectomy for patients with esophageal cancer. METHODS: Between January 2013 and January 2014, the feasibility of no nasogastric intubation and early oral feeding at postoperative day(POD) 1 after thoracolaparoscopic esophagectomy was prospectively investigated in 156 patients (trial group) with esophageal cancer in the Henan Cancer Hospital. One hundred and sixty patients previously managed in the same unit who were treated routinely after thoracolaparoscopic esophagectomy were served as control group. RESULTS: Of 156 patients of trial group, 6(3.8%) patients could not take food early as planned because of postoperative complications. The overall complication rate in trial group was 19.2%(30/156), which was 25.0%(30/160) in control group (P=0.217). The anastomotic leakage in trial group and control group was 2.6%(4/156) and 4.3%(7/160) respectively (P=0.380). Compared with control group, time to first flatus [(2.1+/-0.9) d vs. (3.3+/-1.1) d, P<0.001], bowel movement [(4.4+/-1.3) d vs. (6.6+/-1.0) d, P<0.001] and postoperative hospital stay [(8.3+/-3.2) d vs. (10.4+/-3.6) d, P<0.001] were significantly shorter in trial group. CONCLUSIONS: No nasogastric intubation and early oral feeding postoperatively in patients with thoracolaparoscopic esophagectomy is feasible and safe. This management can shorten postoperative hospital stay and fasten postoperative bowel function recovery. PMID- 25273661 TI - [Omental transposition to mediastinum improves the outcome of postoperative intra thoracic infections of Ivor-Lewis surgery]. AB - OBJECTIVE: To study the efficacy of pedicled greater omentum transposed to mediastinum in prevention against postoperative in-hospital intrathoracic complications after esophagectomy. METHODS: Clinical data of 148 consecutive patients with esophageal cancer undergoing Ivor-Lewis surgery in our department from January 2010 to May 2014 were retrospectively reviewed. Among them, 84 patients with omental transposition(transposition group) and 64 patients without omental transposition(non-transposition group) were compared. RESULTS: Postoperative hospital stay was shorter in patients with omental transposition compared to those without omental transposition(P<0.05). Intrathoracic infection rate was significantly lower in transposition group(33/84, 39.3%) than that in non-transposition group(36/64, 56.2%), and as was the combined sepsis rate[19/33, 57.6% vs. 31/36, 86.1%, P<0.05]. No significant differences were found in the morbidity of anastomotic leakage, wound infection, cardiac complication and mortality during hospitalization. The median postoperative hospital stay was significantly shorter in transposition group than that in non-transposition group(13.0 vs. 16.5 days, P<0.05). CONCLUSION: Omental transposition to mediastinum can reduce the development and severity of intrathoracic infection and shorten hospital stay in patients undergoing esophagectomy. PMID- 25273660 TI - [Clinical value of thoracoscopic extensive mediastinal lymphadenectomy in the surgical treatment of esophageal carcinoma]. AB - OBJECTIVE: To explore the safety and feasibility of extensive mediastinal lymphadenectomy during thoracoscopic esophagectomy in the treatment of esophageal carcinoma. METHODS: Clinical data of 125 patients with esophageal carcinoma undergoing thoracoscopic and laparoscopic esophagectomy(TLE) in West China Hospital of Sichuan University between May 2009 and December 2011 were retrospectively analyzed. Patients were divided into 2 groups: non-extensive mediastinal lymphadenectomy group(non-extensive group, n=53) and extensive mediastinal lymphadenectomy group(extensive group, n=72). Perioperative outcomes of these two groups were compared. RESULTS: No significant differences were found in the time of thoracic operation, length of intensive care unit stay and postoperative hospital stay, postoperative complication and the overall mortality between the two groups. Compared with non-extensive group, extensive group showed less blood loss during thoracic operation [(140.6+/-62.1) ml vs. (167.7+/-69.2) ml, P=0.023], more thoracic lymph nodes harvested (12.2+/-4.2 vs. 9.0+/-4.1, P<0.01). Seventeen patients (23.6%) in extensive group were found to have positive recurrent laryngeal nerve lymph nodes, which resulted in upstaging of TNM in 7 patients(9.7%). The incidence of recurrent laryngeal nerve palsy was higher in extensive group as compared to non-extensive group, but the difference was not statistically significant (6.9% vs. 1.9%, P=0.240). CONCLUSION: Extensive mediastinal lymphadenectomy during thoracoscopic esophagectomy is a feasible and safe procedure for esophageal carcinoma patients, which can increase the number of harvested lymph node and the accuracy of tumor staging. PMID- 25273662 TI - [Comparison of thoracoscopic esophagectomy and traditional esophagectomy in radical mediastinal lymphadenectomy for esophageal cancer]. AB - OBJECTIVE: To compare thoracoscopic esophagectomy with traditional esophagectomy in radical mediastinal lymphadenectomy for esophageal cancer, and to explore the feasibility and safety of thoracoscopic mediastinal lymphadenectomy for esophagectomy. METHODS: Clinical data associated with perioperation and mediastinal lymph nodes clearance of 304 patients undergoing radical operation of esophageal cancer via left neck-right chest-upper abdomen in our department from June 2009 to June 2011 were analyzed retrospectively. Among 304 cases, 199 received traditional open radical resection and 105 thoracoscopic esophagectomy. The intrathoracic mediastinal lymph node metastasis rate, extent of metastasis, time of operation, blood loss and complications between two groups were compared. RESULTS: All the 304 cases completed their operations successfully. A total of 3724 mediastinal lymph nodes were removed, mean 12.3+/-7.0 per case, including 1065 in thoracoscopic group, mean 10.1+/-5.5 per case, and 2659 in open group, mean 13.3+/-7.5 per case, whose difference was significant. But further analysis according to the postoperative pathologic staging showed no significant difference of above lymph nodes removed between two groups. Mediastinal lymph node metastasis was found in 126 patients with a rate of 41.4%, which was 35.6% and 44.7% in thoracoscopic and open groups respectively without significant difference(P>0.05). The left laryngeal recurrent nerve lymph node metastasis rate in open group and thoracoscopic group was 16.1% and 6.7% respectively, and the difference was significant(P<0.05). Differences of lymph node metastasis rate in other regions were not significant between the two groups. There were 365 positive lymph nodes, and the lymph node metastasis degree was 9.8%. which was 8.2% and 10.5% in thoracoscopic group and open group respectively(P<0.05), besides metastasis degree of open group was much higher in right laryngeal recurrent nerve and subcarinal lymph node region. The overall complication rate was 36.8%, which was 28.6% in thoracoscopic group and 41.2% in open group respectively with significant difference(P<0.05). There were no significant differences in operative time and blood loss between the two groups(both P>0.05). CONCLUSION: Radical mediastinal lymphadenectomy with thoracoscopic esophagectomy is technically safe and feasible for early to moderate stage esophageal cancer with similar lymph nodes removed and lower complication morbidity. In the early period of carrying out thoracoscopic radical mediastinal lymphadenectomy, laryngeal recurrent nerve and subcarinal lymph node region should be identified to prevent incidental injury. PMID- 25273663 TI - [Analysis of postoperative quality of life in patients with middle thoracic esophageal carcinoma undergoing minimally invasive Ivor-Lewis esophagectomy]. AB - OBJECTIVE: To compare the effect of minimally invasive Ivor-Lewis esophagectomy with traditional Ivor-Lewis esophagectomy on the quality of life in patients with middle thoracic esophageal carcinoma. METHODS: Retrospective analysis was performed on 121 patients with middle thoracic esophageal carcinoma, of whom sixty patients underwent minimally invasive Ivor-Lewis esophagectomy(endoscopic group) and sixty-one patients underwent traditional Ivor-Lewis esophagectomy (open group). All the items of EORTC questionnaire QLQ-C30, seven items of QLQ OES18 and two additional items(right upper limbs activity obstacle and numbness of right chest wall) were used to evaluate the quality of life. RESULTS: The scores of global quality of life, physical functioning, role functioning, social functioning, fatigue, pain, dyspnea and troublesome coughing were more favourable in endoscopy group than those in open group at 4-week and 12-week after operation(P<0.05). However, the advantage of endoscopy group only sustained in global quality of life, physical functioning and fatigue at 24-week after operation(P<0.05). Furthermore, the scores of pain, right upper limbs activity obstacle and numbness of right chest wall were less in endoscopy group than those in open group at 4-week, 12-week and 24-week after operation. CONCLUSION: Minimally invasive Ivor-Lewis esophagectomy is associated with less trauma, shorter time of recovery and better postoperative quality of life. PMID- 25273664 TI - [Study on safety and feasibility of minimally invasive esophagectomy without the use of postoperative nasogastric tube decompression]. AB - OBJECTIVE: To investigate the safety and feasibility of forgoing postoperative nasogastric tube decompression in minimally invasive esophagectomy for patients with esophagus carcinoma. METHODS: Clinical data of 90 eligible patients who underwent elective minimally invasive esophagectomy in our department from January 2012 to May 2013 by the same surgical team were retrospectively analyzed. Among them, 45 patients did not receive the use of postoperative nasogastric tube decompression and 45 patients received nasogastric tube decompression after operation. The observation parameters included the time to first flatus, the time to intake of fluid diet, the duration of postoperative hospitalization, pharyngalgia, vomiting, and postoperative complications, as well as the need for placing or replacing the nasogastric tube. RESULTS: The incidence of pharyngalgia was significantly higher in nasogastric tube group (100% vs 44.4%, P<0.001). The time to intake of fluid diet [median 2 d(2-4 d) vs. median 9 d(7-20 d), P<0.001] and the time to first flatus [median 3 d(3-8 d) vs. median 6 d(3-9 d), P<0.001] were all significantly shorter in non-nasogastric tube group as compared to nasogastric tube group. Compared with the nasogastric tube group, the non nasogastric tube group had shorter postoperative hospital stay (P<0.001). There were no significant differences in the incidence of postoperative complications and vomiting between two groups. CONCLUSION: Minimally invasive esophagectomy without the use of postoperative nasogastric tube decompression is safe and feasible, which can improve recovery and shorten postoperative hospital stay. PMID- 25273665 TI - [Choice of surgical approach for Siewert II and III adenocarcinomas of the esophagogastric junction]. AB - OBJECTIVE: To explore the optimal surgical approach for Siewert II and III adenocarcinoma of esophagogastric junction (AEG). METHODS: Clinical data of 135 patients with Siewert II and III AEG treated in our hospital from August 2007 to August 2012 were analyzed retrospectively. Of 135 patients, 57 received transthoracic path for the stomach and proximal gastrectomy, second station lymph node resection (transthoracic group), and 78 cases received transabdominal hiatal approach (transabdominal group). The intraoperative lymph node harvested, postoperative complications and 5-year survival rate were compared between the two groups. RESULTS: There were no significant differences in the residual tumor positive margin and anastomotic leakage rate between the two groups (both P>0.05). Compared with transthoracic group, transabdominal group had more lymph node dissected (11.1+/-0.2 vs. 10.4+/-0.3, P=0.033], less postoperative cardiac [2.6% (2/78) vs. 19.3% (11/57), P<0.01] and pulmonary [7.7% (6/78) vs. 21.1% (12/57), P<0.05] morbidity, and short postoperative hospital stay [(13.4+/-0.1) d vs. (16.4+/-0.3) d, P<0.01]. A total of 128 cases were followed up for median 38 months (6 to 72 months). The 5-year survival rate in transthoracic group and transabdominal group was 29.8% and 34.6% respectively, without significant difference (P>0.05). CONCLUSION: For the treatment of patients with Siewert II and III AEG, transabdominal hiatal approach can remove more lymph nodes, reduce postoperative cardiopulmonary morbidity and shorten hospital stay. PMID- 25273666 TI - [Strategies of surgery treatment for cervical esophageal cancer]. AB - OBJECTIVE: To explore the methods and means of surgical treatment for cervical esophageal cancer in order to get the best efficacy. METHODS: Retrospective investigation and analysis were carried out in 137 patients with cervical esophageal cancer undergoing operation in our hospital from January 2005 to December 2013. According to lesion locations, these cases were divided into two groups: larynx preservation group(Group A) and laryngectomy group(Group B). Surgery options of Group A included inversion esophagectomy without thoracotomy, three-incision esophagectomy, end to end anastomosis of cervical esophagus after local resection. Group B included gastric-pharyngeal anastomosis, pharyn esophagus plasty, colon replacement of the esophagus or jejunal interposition. All the patients received postoperative adjuvant therapy. RESULTS: There were no perioperative deaths. The main postoperative complications included anastomotic fistula in 20 cases(14.6%), postoperative massive bleeding after inversion esophagectomy in 3 cases, chylothorax in 1 case, anastomotic stenosis in 9 cases, severe gastroesophageal reflux in 6 cases and serious aspiration pneumonia in 2 cases. All these patients had complete resolution of disease with good postoperative quality of life. The 1-year, 3-year and 5-year survival were 73.7%, 48.4% and 26.8% respectively. The most important causes of postoperative death included local recurrence, cervical or mediastinal lymph node metastases, cachexia and multiple organic metastasis. CONCLUSION: It is critical to select reasonable methods of operations to reduce postoperative complications and to receive proper adjuvant therapy. PMID- 25273667 TI - [Anesthesia for esophagectomy]. AB - Esophagectomy is one of the most complicated procedures. Satisfactory anesthesia not only ensures the safety in terms of low morbidity and mortality postoperatively, but also one of the potential factors relevant to long-term survival. Most of physicians, however, ignore the significance of anesthesia. This article focuses on the recent advances of anesthesia for esophagectomy in preoperative preparation for induction, rapid-sequence induction, one-lung ventilation, fluid management during surgery and postoperative early extubation and analgesia. PMID- 25273668 TI - Online groups and patient forums. AB - Online mental health support forums are becoming increasingly popular and there is evidence that they are useful: particularly for providing anonymous support and filling information gaps. However, there are also very real concerns about negative outcomes for users. One online mental health service, Big White Wall, manages these risks and supports its members through the provision of 24 hour professional moderation. Comparison of Big White Wall's member population with the population of one London borough shows a diverse user group, but members are more likely to be female, and aged 25 to 34, or unemployed. PMID- 25273670 TI - The importance of a correct positioning of the heart using IQ-SPECT system with multifocal collimators in myocardial perfusion imaging: a phantom study. AB - BACKGROUND: We have recently validated a quarter-time protocol in Myocardial Perfusion Imaging named IQ-SPECT, whose basic principle is to implement a multifocal collimator; However, in clinical practice, it may sometimes be difficult to center the heart in the region of highest magnification of the multifocal collimators (the so-called sweet spot). We therefore aimed to evaluate whether a heart mispositioning may affect results in MPI. METHODS: We simulated a rest study with an anthropomorphic phantom with an in vivo distribution of 400 MBq [(99m)Tc]tetrofosmin, with and without a transmural defect (TD). For each set of images, we performed 5 acquisitions, one with a correct centering and with other 4 degrees of mispositioning. Raw data and reconstructed images were evaluated qualitatively and quantitatively, including no corrections, correction for attenuation, for scatter or for both. We assessed polar plot uniformity, LV wall thickness, and TD and cavity contrast. RESULTS: Images obtained either with a correct heart centering or with mild misposition showed no differences, both qualitatively and quantitatively. Those obtained with major mispositioning differed in uniformity and TD contrast depending on correction parameters. CONCLUSION: This is the first study investigating how a heart mispositioning can affect diagnostic accuracy with IQ-SPECT system. Mild-to-moderate mispositioning (<=2.5 cm) is unlikely to significantly affect results. PMID- 25273673 TI - Thermal conductivity of twisted bilayer graphene. AB - We have investigated experimentally the thermal conductivity of suspended twisted bilayer graphene. The measurements were performed using an optothermal Raman technique. It was found that the thermal conductivity of twisted bilayer graphene is lower than that of monolayer graphene and the reference, Bernal stacked bilayer graphene in the entire temperature range examined (~300-700 K). This finding indicates that the heat carriers - phonons - in twisted bilayer graphene do not behave in the same manner as that observed in individual graphene layers. The decrease in the thermal conductivity found in twisted bilayer graphene was explained by the modification of the Brillouin zone due to plane rotation and the emergence of numerous folded phonon branches that enhance the phonon Umklapp and normal scattering. The results obtained are important for understanding thermal transport in two-dimensional systems. PMID- 25273669 TI - Second trimester amniotic fluid cytokine concentrations, Ureaplasma sp. colonisation status and sexual activity as predictors of preterm birth in Chinese and Australian women. AB - BACKGROUND: This study tested if second trimester amniotic fluid cytokine levels, Ureaplasma sp. colonisation and sexual activity predict preterm birth and explain the differential preterm birth rates in Chinese compared to Australian women. METHODS: Amniotic fluid was collected by amniocentesis (Chinese 480, Australian 492). Cytokines were measured by multiplex assay and Ureaplasma sp. DNA was detected by PCR analysis. Lifestyle factors, including history of smoking and sexual activity during pregnancy, were obtained through completion of questionnaires upon recruitment to the study. RESULTS: Inflammatory cytokine concentrations were poorly predictive of preterm birth. Ureaplasma sp. was detected in two of the Chinese pregnancies and none from Australia. Sexual activity was less frequent in Chinese, and was not associated with preterm birth or amniotic fluid findings in either population. DISCUSSION: Second trimester amniocentesis for measurement of inflammatory markers and Ureaplasma sp. DNA was not indicative of risk of preterm birth, at least in these populations. The lower rate of preterm birth in China was not explained by differences in amniotic fluid inflammatory markers, Ureaplasma sp. colonisation, or sexual activity. PMID- 25273671 TI - Myocardial perfusion imaging determination using an appropriate use smartphone application. AB - BACKGROUND: Inappropriate cardiac imaging has been a significant cost concern and cause of radiation burden to patients. OBJECTIVE: To assess if a smartphone application (app) based on 2009 Appropriate Use Criteria (AUC) for Cardiac Radionuclide Imaging published by American College of Cardiology would be feasible at the point of order. METHODS: We evaluated stress myocardial perfusion imaging (MPI) (N = 403) (mean age = 62.23 years; 47.89% males) over a 4 month period using a smartphone app to determine whether the study ordered was Appropriate, Inappropriate, or Uncertain per 2009 AUC. We also monitored the time needed to use the app to determine the level of appropriateness of each stress MPI. The results of the stress MPI were noted. RESULTS: Of the 403 stress MPIs evaluated, 267 (66.25%) were noted to be Appropriate, 118 (29.28%) were Inappropriate, and 13 (3.23%) were Uncertain, per AUC; 5 (1.25%) remained unclassified. Average time needed to use the app to assess each stress MPI for appropriateness was noted to be 44 (+/-9) seconds. Non-teaching physicians ordered 70 (38.89%) inappropriate stress MPIs as compared to 20 (23.53%) ordered by physicians on resident teaching service, and 28 (23.33%) by cardiologists (P = .0045). Among inappropriately ordered stress MPIs, 87 (42.65%) were ordered in females as compared to 31 (17.13%) in males (P < .0001). 70 (26.22%) stress MPIs among appropriately ordered were abnormal (reversible ischemia or fixed perfusion defect) as compared to 15 (12.17%) among inappropriately ordered stress MPIs (P = .0032). CONCLUSION: A free and convenient smartphone app provides an easy-to-use tool to assist physicians in determining the level of appropriateness of stress MPI in a time- and cost-effective manner at the point of order. The smartphone app may have potential to promote the usage of the AUC and possibly aid reduction of healthcare cost and ionizing radiation burden. PMID- 25273674 TI - Functional characterisation of a novel mutation affecting the catalytic domain of MMP2 in siblings with multicentric osteolysis, nodulosis and arthropathy. AB - Multicentric osteolysis, nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder. To date, 13 mutations of the matrix metalloproteinase 2 (MMP2) gene have been detected in 26 patients with MONA and other osteolytic syndromes. Here, we describe the molecular and functional analysis of a novel MMP2 mutation in two adult Italian siblings with MONA. Both siblings displayed palmar-plantar subcutaneous nodules, tendon retractions, limb arthropathies, osteolysis in the toes and pigmented fibrous skin lesions. Molecular analysis identified a homozygous MMP2 missense mutation in exon 8 c.1228G>C (p.G410R), not detected in 260 controls and predicted by several bioinformatic tools to be pathogenic. By protein modelling, the mutant residue was predicted to affect the main chain conformation of the catalytic domain. Gelatin zymography, the gold standard test for MMP2 function, of serum-free conditioned medium from G410R-MMP2 expressing human embryonic kidney (HEK) cells, showed a complete loss of gelatinolytic activity. The novel mutation is located in the catalytic domain, as are 3 (p.E404K, p.V400del and p.G406D) of the other 13 MMP2 mutations described to date; however, p.G410R underlies a phenotype that is only partially overlapping that of other MMP2 exon 8 mutation carriers. Our results further delineate the complexity of genotype-phenotype correlations in MONA, broaden the repertoire of reported MMP2 mutation and enhance the comprehension of the protein motifs crucial for MMP2 catalytic activity. PMID- 25273675 TI - "I should have discharged him but I felt guilty": a qualitative investigation of clinicians' emotions in the context of implementing occupational therapy. AB - BACKGROUND: Clinicians' emotions about practice are a potentially powerful yet largely overlooked factor in implementation of good-quality care. The present paper expands the current, limited evidence about clinicians' emotions by (i) describing clinician-reported examples of emotions about practice and (ii) identifying the clinical situations in which, according to clinicians, emotions emerge and influence practice. METHODS: Semi-structured, face-to-face interviews with 25 clinicians (children's occupational therapists) were conducted across six health care organisations. Participants were asked to reflect on their practice in two recent patient cases, one that they perceived 'successful' and another 'unsuccessful'. Interviews were transcribed verbatim, and the transcripts were analysed for emerging themes. A proportion of transcripts were independently read and coded, and the themes were validated through critical discussion. RESULTS: A key theme was clinicians' emotions, especially negative emotions including guilt, anger, worry, frustration and inadequacy. These were described in connection with situations where the clinicians perceived that (i) they failed to provide good quality care, (ii) they were unable to achieve positive health outcomes or engage the patient or (iii) there was conflict between what they were asked to do and the norms they held important. CONCLUSIONS: Clinicians experience a range of negative emotions about practice. These are particularly likely to emerge in situations where clinicians perceive that their actions and practice fall short of the standards, norms or outcomes that they hold as important. The results inform the specification of emotions and emotion-triggering situations for future investigations of health care implementation. PMID- 25273676 TI - Activation of fibroblast-like synoviocytes derived from rheumatoid arthritis via lysophosphatidic acid-lysophosphatidic acid receptor 1 cascade. AB - INTRODUCTION: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to G protein-coupled receptors (LPA1-6). Recently, we reported that abrogation of LPA receptor 1 (LPA1) ameliorated murine collagen-induced arthritis, probably via inhibition of inflammatory cell migration, Th17 differentiation and osteoclastogenesis. In this study, we examined the importance of the LPA-LPA1 axis in cell proliferation, cytokine/chemokine production and lymphocyte transmigration in fibroblast-like synoviocytes (FLSs) obtained from the synovial tissues of rheumatoid arthritis (RA) patients. METHODS: FLSs were prepared from synovial tissues of RA patients. Expression of LPA1-6 was examined by quantitative real-time RT-PCR. Cell surface LPA1 expression was analyzed by flow cytometry. Cell proliferation was analyzed using a cell-counting kit. Production of interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), chemokine (C C motif) ligand 2 (CCL2), metalloproteinase 3 (MMP-3) and chemokine (C-X-C motif) ligand 12 (CXCL12) was measured by enzyme-linked immunosorbent assay. Pseudoemperipolesis was evaluated using a coculture of RA FLSs and T or B cells. Cell motility was examined by scrape motility assay. Expression of adhesion molecules was determined by flow cytometry. RESULTS: The expression of LPA1 mRNA and cell surface LPA1 was higher in RA FLSs than in FLSs from osteoarthritis tissue. Stimulation with LPA enhanced the proliferation of RA FLSs and the production of IL-6, VEGF, CCL2 and MMP-3 by FLSs, which were suppressed by an LPA1 inhibitor (LA-01). Ki16425, another LPA1 antagonist, also suppressed IL-6 production by LPA-stimulated RA FLSs. However, the production of CXCL12 was not altered by stimulation with LPA. LPA induced the pseudoemperipolesis of T and B cells cocultured with RA FLSs, which was suppressed by LPA1 inhibition. In addition, LPA enhanced the migration of RA FLSs and expression of vascular cell adhesion molecule and intercellular adhesion molecule on RA FLSs, which were also inhibited by an LPA1 antagonist. CONCLUSIONS: Collectively, these results indicate that LPA-LPA1 signaling contributes to the activation of RA FLSs. PMID- 25273678 TI - ABCB1 C3435T polymorphism influences the risk for Alzheimer's disease. AB - To evaluate the association of ATP-binding cassette subfamily B member 1 (ABCB1) genetic variants with the susceptibility to Alzheimer's disease (AD), we genotyped the rs1128503 (C1236T), rs2032582 (G2677T/A), and rs1045642 (C3435T) polymorphisms in a case-control sample (234 AD patients, 225 controls). Single marker analyses revealed a significant association solely for the rs1045642 polymorphism (C/C genotype carriers had increased risk for AD), which remains significant after correction for multiple testing. Haplotype analyses indicated three nominally significant associations which were lost after applying multiple test correction. PMID- 25273679 TI - A legacy of loss: stories of replacement dynamics and the subsequent child. AB - This article, a qualitative exploration of the experiences of subsequent children, endeavors to clarify common issues and experiences of this population. Subsequent children, also known as subsequent siblings, are children born after the death of a brother or sister. For this study, 25 adult subsequent siblings participated in semi-structured interviews. Few researchers have written about this population, and much of what has been documented was researched from single case studies, or from very small samples. This study aims to explore the commonalities of the unique experience of being a subsequent child. Themes which emerged include various replacement child dynamics, impaired bonding with parents or altered parenting as a result of the loss, family grief and its repercussions, meaning making and spiritual questioning, fantasies about the lost sibling, disenfranchised and unresolved grief, taking on a caregiver role, and survivor guilt. The implications for clinical practice are presented. PMID- 25273677 TI - Patients' priorities for treatment decision making during periods of incapacity: quantitative survey. AB - OBJECTIVE: Clinical practice aims to respect patient autonomy by basing treatment decisions for incapacitated patients on their own preferences. Yet many patients do not complete an advance directive, and those who do frequently just designate a family member to make decisions for them. This finding raises the concern that clinical practice may be based on a mistaken understanding of patient priorities. The present study aimed to collect systematic data on how patients prioritize the goals of treatment decision making. METHOD: We employed a self-administered, quantitative survey of patients in a tertiary care center. RESULTS: Some 80% or more of the 1169 respondents (response rate = 59.8%) ranked six of eight listed goals for treatment decision making as important. When asked which goal was most important, 38.8% identified obtaining desired or avoiding unwanted treatments, 20.0% identified minimizing stress or financial burden on their family, and 14.6% identified having their family help to make treatment decisions. No single goal was designated as most important by 25.0% of participants. SIGNIFICANCE OF RESULTS: Patients endorsed three primary goals with respect to decision making during periods of incapacity: being treated consistent with their own preferences; minimizing the burden on their family; and involving their family in the decision-making process. However, no single goal was prioritized by a clear majority of patients. These findings suggest that advance care planning should not be limited to documenting patients' treatment preferences. Clinicians should also discuss and document patients' priorities for how decisions are to be made. Moreover, future research should evaluate ways to modify current practice to promote all three of patients primary goals for treatment decision making. PMID- 25273680 TI - Probabilistic thinking and death anxiety: a terror management based study. AB - Terror Management Theory has been utilized to understand how death can change behavioral outcomes and social dynamics. One area that is not well researched is why individuals willingly engage in risky behavior that could accelerate their mortality. One method of distancing a potential life threatening outcome when engaging in risky behaviors is through stacking probability in favor of the event not occurring, termed probabilistic thinking. The present study examines the creation and psychometric properties of the Probabilistic Thinking scale in a sample of young, middle aged, and older adults (n = 472). The scale demonstrated adequate internal consistency reliability for each of the four subscales, excellent overall internal consistency, and good construct validity regarding relationships with measures of death anxiety. Reliable age and gender effects in probabilistic thinking were also observed. The relationship of probabilistic thinking as part of a cultural buffer against death anxiety is discussed, as well as its implications for Terror Management research. PMID- 25273681 TI - End-of-life preferences in Afro-Caribbean older adults: a systematic literature review. AB - Research suggests that older Blacks tend to prefer more aggressive treatment as they transition toward the end of life. African and Afro-Caribbean immigrants and their offspring are the fastest growing segments of the Black population in the United States. With the increasing population of Black older adults, the cost of end-of-life care is rising. This article presents a review of the literature on the end-of-life preferences of Afro-Caribbean older adults. Findings suggest that Afro-Caribbean older adults make end-of-life decisions with a significant emphasis on family structure, religion/spirituality, cultural identity, migration, and communication. Concerns regarding the meaning of end-of-life preparation and hospice are often viewed in ways that differ from that of healthcare providers. Future research is needed to investigate this process in the Afro-Caribbean older adult subset. PMID- 25273682 TI - Death on the digital landscape: a preliminary investigation into the grief process and motivations behind participation in the online memoriam. AB - Increasingly, individuals are bonding and maintaining relationships online. These digital representations of ourselves allow us to connect with others in ways previously not possible. One behavior that is growing in online presentations of self is grieving after the death of an individual in our social network. This work investigates the outcomes of online grieving from a transcorporeal communication model perspective, and draws conclusions on the outcomes of online grief behaviors. PMID- 25273683 TI - Suicide around anniversary times. AB - The anniversary of the loss of a loved one is known to induce negative emotions, which for some can be significant. The present study examined the incidence of suicide around the time of such anniversaries using data from the Queensland Suicide Register for the years 1998 to 2008. There were statistically significant increases in suicide events immediately after the loss of a loved one and around the anniversary of the loss. Limitations of the study are noted. PMID- 25273684 TI - Attribution of mental disorders in suicide occurrence. AB - The present study aimed to determine attribution of mental disorders in suicide occurrence. By a cross-sectional study, all suicide records (n = 5188), between 1993 and 2009 in Ilam province, were investigated. Multiple logistic regression analysis was adopted. Totally, 27.5% of the suicides occurred due to mental disorders. This was significantly higher in males (29.3%), individuals born in 1996 (44%) and 1990s (30.3%), those aged 30 years and above (33.2%) and suicide attempters (28.3%), respectively and separately. The risk of suicide due to mental disorders was observed for females (OR = 0.85, CI = 0.74-0.97), those born in 1994 (OR = 2.82, CI = 1.27-6.24), completed suicides (OR = 0.81, CI = 0.68 0.97) and the age group 25 to 29 years old (OR = 0.82, CI = 0.66-1.01). Suicide due to mental disorders was higher among males compared to females, the rate of which was directly proportional to attempted suicide and age. It is therefore recommended that health educations be seriously carried on targeted groups. PMID- 25273687 TI - Ipilimumab and whole brain radiation therapy for melanoma brain metastases. AB - Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans post-treatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatment-related toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3-4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity. PMID- 25273688 TI - The prognosis of refractory epilepsy patients rejected from epilepsy surgery. AB - OBJECTIVE: Up to one-third of individuals diagnosed as having epilepsy continue to have seizures despite appropriate anti-epileptic drug treatment. These patients are often referred for presurgical evaluation, and many are rejected from focal resective surgery due to medical reasons or, alternatively, they choose not to undergo it. We compared the outcomes and characteristics of the non operated patients who continued on medical therapy alone with those who underwent vagus nerve stimulator (VNS) implantation in addition to medical therapy. METHODS: The medical records of consecutive adult patients referred for presurgical evaluation for suitability for epilepsy surgery in the Tel-Aviv Sourasky Medical Center between 2007 and 2011 and were rejected from or decided against surgery were reviewed. Updated information on seizure frequency was supplemented by telephone interviews between April and July, 2013. RESULTS: Fifty two patients who continued solely on medical therapy and 35 patients who additionally underwent VNS implantation were included in the study. Forty-seven of the former and 33 of the latter agreed to be interviewed. There was a significant improvement in the seizure frequency between the time of the presurgical evaluation and the time of the interview in both groups. Eight medically treated patients (17%) and 2 patients who also underwent VNS implantation (6%) reported being seizure-free during the preceding 3 months. CONCLUSIONS: A considerable minority of patients with refractory epilepsy who were rejected or chose not to undergo epilepsy surgery may improve over time and even become seizure-free following adjustment of anti-epileptic drugs with or without concomitant VNS. PMID- 25273690 TI - [Near knee osteotomies. New trends and new techniques]. PMID- 25273689 TI - High pathogenicity and low genetic evolution of avian paramyxovirus type I (Newcastle disease virus) isolated from live bird markets in Uganda. AB - BACKGROUND: Newcastle disease is still a serious disease of poultry especially in backyard free-range production systems despite the availability of cross protective vaccines. Healthy-looking poultry from live bird markets have been suspected as a major source of disease spread although limited studies have been conducted to ascertain the presence of the virulent strains in the markets and to understand how they are related to outbreak strains. METHODS: This study evaluated the occurrence of Newcastle disease virus in samples collected from poultry in live bird markets across Uganda. The isolates were pathoyped using standard methods (mean death time (MDT), intracelebral pathogenicity index (ICPI), and sequencing of the fusion protein cleavage site motif) and also phylogenetically analysed after sequencing of the full fusion and hemagglutin neuraminidase genes. The isolates were classified into genotypes and subgenotypes based on the full fusion protein gene classification system and compared with other strains in the region and world-wide. RESULTS: Virulent avian paramyxovirus type I (APMV-1) (Newcastle disease virus) was isolated in healthy-looking poultry in live bird markets. The viruses belonged to a new subgenotype, Vd, in genotype V, and clustered together with Tanzania and Kenya strains. They harbored low genetic diversity. CONCLUSION: The occurrence of virulent AMPV-1 strains in live bird markets may serve as sources of Newcastle disease outbreaks in non commercial farms. PMID- 25273691 TI - Establishment and characterization of mesenchymal stem cell-like clonal stem cells from mouse salivary glands. AB - Successful therapy for radiation-induced salivary gland (SG) hypofunction is currently unavailable; however, tissue-specific stem cells are expected to be promising candidates for SG regeneration. Here, we present our method for the establishment of single cell-derived clonal stem cells from mouse SGs and describe their characteristics. Salivary gland-derived clonal stem cells (SGSCs) were isolated and expanded in vitro by a modified subfractionation culture method. The properties of SGSCs were examined with respect to their marker expression, gene expression, differentiation potential, and in vitro immunosuppressive activity relative to bone marrow-derived mesenchymal stem cells (BM-MSCs). SGSCs appeared to largely share the characteristics of BM-MSCs based on their marker expression, whereas they differentially expressed some genes, including AQP5, E-Cadherin, Laminin, ZO-1, and COL4. SGSCs showed the ability to differentiate into fat, bone, and cartilage cell types, as well as into alpha amylase-producing and hepatocyte-like cells after appropriate induction. The in vitro immunosuppressive activity of SGSCs was found to be more potent than that of BM-MSCs. These results showed that SGSCs possess the properties of MSCs with some differential gene expression and they are salivary-specific stem cells with both epithelial and mesenchymal properties. The biological functions of SGSCs and their relevance to SG epithelial progenitor cells require further investigation. PMID- 25273692 TI - Educating caregivers about the natural history of infantile hemangiomas. PMID- 25273695 TI - Solute effect on basal and prismatic slip systems of Mg. AB - In an effort to design novel magnesium (Mg) alloys with high ductility, we present a first principles data based on the Density Functional Theory (DFT). The DFT was employed to calculate the generalized stacking fault energy curves, which can be used in the generalized Peierls-Nabarro (PN) model to study the energetics of basal slip and prismatic slip in Mg with and without solutes to calculate continuum scale dislocation core widths, stacking fault widths and Peierls stresses. The generalized stacking fault energy curves for pure Mg agreed well with other DFT calculations. Solute effects on these curves were calculated for nine alloying elements, namely Al, Ca, Ce, Gd, Li, Si, Sn, Zn and Zr, which allowed the strength and ductility to be qualitatively estimated based on the basal dislocation properties. Based on our multiscale methodology, a suggestion has been made to improve Mg formability. PMID- 25273694 TI - Altered performance in attention tasks in patients with seasonal allergic rhinitis: seasonal dependency and association with disease characteristics. AB - BACKGROUND: Seasonal allergic rhinitis (SAR) is a chronic disease affecting about 23% of the European population with increasing prevalence rates. Beside classical symptoms (i.e., sneezing, nasal congestion), patients frequently complain about subjective impairments in cognitive functioning during periods of acute allergic inflammation. However, objective evidence for such deficits or the role of potential modulators and underlying mechanisms is limited. The present study aimed to investigate the effect of SAR on attention-related cognitive processes. In addition, relationships between attention performance, sleep and mood disturbances as well as specific disease characteristics as potential modulators of this link were explored. METHOD: SAR patients (n = 41) and non-allergic healthy controls (n = 42) completed a set of attention tasks during a symptomatic allergy period and during a non-symptomatic period. Influences of sleep, mood, total immunoglobulin E (IgE) levels and individual allergy characteristics on cognitive performance were evaluated. RESULTS: Compared to healthy controls, SAR patients had a slower processing speed during both symptomatic and non symptomatic allergy periods. Additionally, they showed a more flexible adjustment in attention control, which may serve as a compensatory strategy. Reduction in processing speed was positively associated with total IgE levels whereas flexible adjustment of attention was linked with anxious mood. No association was found between SAR-related attention deficits and allergy characteristics or sleep. CONCLUSIONS: SAR represents a state that is crucially linked to impairments in information processing and changes in attentional control adjustments. These cognitive alterations are more likely to be influenced by mood and basal inflammatory processes than sleep impairments or subjective symptom severity. PMID- 25273693 TI - Long-term dizziness handicap in patients with vestibular schwannoma: a multicenter cross-sectional study. AB - OBJECTIVE: (1) To characterize long-term dizziness following observation, microsurgery, and stereotactic radiosurgery (SRS) for small to medium-sized vestibular schwannoma (VS) using a validated self-assessment inventory; and (2) to identify clinical variables associated with long-term dizziness handicap. STUDY DESIGN: Cross-sectional observational study. SETTING: Two independent tertiary academic referral centers: one located in the United States and one in Norway. SUBJECTS AND METHODS: All patients with sporadic VS of less than 3 cm who underwent primary microsurgery, SRS, or observation between 1998 and 2008 were identified. Subjects were surveyed via a postal questionnaire using the Dizziness Handicap Inventory (DHI) and a VS symptom questionnaire. RESULTS: The overall survey response rate was 79%. A total of 538 respondents (mean age, 64 years; 56% female) were analyzed, and the mean time interval between treatment and survey was 7.7 years. Pretreatment variables associated with greater dizziness handicap included female sex, older age, larger tumor size, preexisting diagnosis of headache or migraine, and symptoms of dizziness predating treatment. Significant posttreatment features strongly associated with poor long-term DHI scores included frequency and severity of ongoing headache. On multivariable analysis, treatment modality did not influence long-term dizziness handicap. CONCLUSION: At a mean of approximately 8 years following treatment, over half of patients with VS reported ongoing dizziness. The authors have identified several baseline features that may help predict the risk of lasting dizziness. Treatment modality does not appear to influence long-term DHI score. We found a strong association between posttreatment headache and poor dizziness handicap. Future study is needed to further define this relationship. PMID- 25273696 TI - A family of novel Mn3Ln4 clusters displaying single-molecule magnet behavior. AB - Using 3-methyloxysalicylaldoxime (mosaoH2) and N-methyl diethanolamine (N-mdeaH2) as coligands, a family of heptanuclear Mn/Ln heterometallic compounds [Mn(II)Mn(III)2Ln(III)4(mosao)2(mosaoH)4(piv)4(N-mdea)4].xMeCN [Ln = Dy(1), Tb(2) and Y(3), pivH = pivalic acid] have been prepared. The crystal structures of 1-3 were obtained, and their core consists of two Mn(III)Ln2(MU3-OR)2 (RO(2-) = N mdea(2-)) triangles linked to a central Mn(II) atom. A dc magnetic susceptibility study reveals that single-ion effects of the Ln ions are dominant in compounds 1 and 2. As for compound 3, which contains diamagnetic Y ions, the magnetic interactions between Mn ions via oximate NO bridges are revealed to be ferromagnetic. Fitting of the chi(m)T vs. T data gives g = 1.96 and J = 1.12 cm( 1), affording a S = 13/2 ground state. All of the three compounds exhibit frequency-dependent out-of-phase ac susceptibility signals indicative of slow magnetization relaxation and potential SMM behavior. Among them, 1 and 3 display the out-of-phase chi"(m) peak maximum above 2.0 K. Fitting of the ac susceptibility data to the Arrhenius law gives an energy barrier U(eff) = 9.27/13.83 K for 1 and 3, respectively. PMID- 25273697 TI - [Actively offering the evaluation and containment of cardiovascular risks (CCM Project, 2009]. AB - The cardiovascular diseases (CVD) are the most cause of death globally, and represent a problem of public health,both in terms of morbidity and disability. The Regional Centre for disease prevention and Control of Veneto Region (CCMR- Veneto) proposed a structured model operating in ways similar to cancer screening: active recall of healthy subjects, offers to intervene in selected subjects. Subjects of both gender aged between 45-59 years, after pre evaluation/exclusion by the general practitioner, were recalled and evaluated by a trained health assistant using anthropometric measurements, screening blood pressure, fasting blood glucose, and evaluation of lifestyle. 17.000 subjects were invited to the project, with an adhesion of 61%. 56,5% of them present unhealthy lifestyles and normal blood values (lipids, glucose and blood pressure); 14% were detected new hyperglycemic and/or hypertensive and 24% have healthy lifestyles and normal blood values. Regarding to the lifestyles, it results that 31, 3% had a sedentary lifestyles, 20% smokes and 50% is overweight. The subjects with unhealthy lifestyles were invited from health assistant to participate, and counseled them on some initiatives to make changes, and reassessed after 6 months/1 year. The proposed model seems to be a good both because using previously tested structured models, and because it placed up front strategic actions of the Prevention Departments. PMID- 25273698 TI - The relative attractiveness of distractors and targets affects the coming and going of item-specific control: evidence from flanker tasks. AB - The item-specific proportion congruence (ISPC) effect refers to the attenuation of interference for mostly incongruent relative to mostly congruent items. In the present study, qualitatively different ISPC effects were observed in letter- and arrow-based flanker tasks despite their common use of the original two-item set design. Consistent with the predictions of the dual item-specific mechanisms account, contingency-driven ISPC effects were observed when stimuli were used that attracted attention to the irrelevant dimension (Experiments 1, 3, and 6), whereas control-driven ISPC effects were observed when attention was attracted to the relevant dimension (Experiments 2, 4, and 5). The evidence for control-driven ISPC effects in the two-item set design (1) challenges the contingency account, which claims that ISPC effects are solely contingency-driven, and (2) supports an expanded definition of cognitive control that includes fast and flexible adjustments that minimize attention to distractors upon encountering stimuli that have previously been associated with a history of conflict. PMID- 25273700 TI - Invited article: Characterization of background sources in space-based time-of flight mass spectrometers. AB - For instruments that use time-of-flight techniques to measure space plasma, there are common sources of background signals that evidence themselves in the data. The background from these sources may increase the complexity of data analysis and reduce the signal-to-noise response of the instrument, thereby diminishing the science value or usefulness of the data. This paper reviews several sources of background commonly found in time-of-flight mass spectrometers and illustrates their effect in actual data using examples from ACE-SWICS and MESSENGER-FIPS. Sources include penetrating particles and radiation, UV photons, energy straggling and angular scattering, electron stimulated desorption of ions, ion induced electron emission, accidental coincidence events, and noise signatures from instrument electronics. Data signatures of these sources are shown, as well as mitigation strategies and design considerations for future instruments. PMID- 25273699 TI - Elevated autocrine EDIL3 protects hepatocellular carcinoma from anoikis through RGD-mediated integrin activation. AB - BACKGROUND: A remolded microenvironment in hepatocellular carcinoma (HCC) caused by abnormally expressed matricellular proteins could promote HCC progression. The cell-matrix interactions mediated by integrins play an important role in tumor microenvironment. Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein with angiogenic and anti inflammatory effects, is abnormally highly expressed in HCC. Here we aim to analyze its expression in liver and HCC tissues, investigate the underlined mechanisms accounted for HCC progression. METHODS: EDIL3 expression level is examined in normal liver, cirrhotic liver and HCC at both mRNA and protein level. The association between EDIL3 and clinical outcomes is analyzed. The pattern of EDIL3 expression and location is examined using Immunofluorescence and ELISA. Overexpression or knock-down of EDIL3 in a panel of cell lines are subjected to assays related to proliferation, invasion, and anoikis to investigate the mechanisms of this matrix protein in HCC progression. Recombinant EDIL3 treatment is applied to confirm the results. RESULTS: Compared with normal liver and cirrhotic liver, EDIL3 is elevated in HCC. High level of EDIL3 protein is much more commonly in patients with larger tumor or portal vein tumor thrombus (PVTT) formation, associated with poor prognosis. EDIL3 is abundantly expressed in HCC cells and secreted by cancer cells. In vitro and in vivo studies indicate that EDIL3, probably in an autocrine manner, inhibits anoikis and promotes anchorage independent growth of HCC cells. Further mechanistic studies suggest integrin ligation by EDIL3 and thus that the sustained activation of the FAK-Src-AKT signal is responsible for the anoikis resistance and anchorage independence. Both the administration of cilengitide, a RGD-containing integrin antagonist, and silencing of integrin alphaV, an important RGD-binding integrin, results in the blockade of anoikis-resistance induced by EDIL3. CONCLUSION: Our study suggests that high levels of autocrine EDIL3 may contribute to a receptive microenvironment for the survival of detached HCC cells and may involve in cancer cell spreading. We also highlight the importance of interaction between EDIL3 and integrin alphaV and suggest disrupting the ligation of EDIL3 to integrins via RGD blocking in selected patients may bear potential therapeutic value. PMID- 25273701 TI - Optical re-injection in cavity-enhanced absorption spectroscopy. AB - Non-mode-matched cavity-enhanced absorption spectrometry (e.g., cavity ringdown spectroscopy and integrated cavity output spectroscopy) is commonly used for the ultrasensitive detection of trace gases. These techniques are attractive for their simplicity and robustness, but their performance may be limited by the reflection of light from the front mirror and the resulting low optical transmission. Although this low transmitted power can sometimes be overcome with higher power lasers and lower noise detectors (e.g., in the near-infrared), many regimes exist where the available light intensity or photodetector sensitivity limits instrument performance (e.g., in the mid-infrared). In this article, we describe a method of repeatedly re-injecting light reflected off the front mirror of the optical cavity to boost the cavity's circulating power and deliver more light to the photodetector and thus increase the signal-to-noise ratio of the absorption measurement. We model and experimentally demonstrate the method's performance using off-axis cavity ringdown spectroscopy (OA-CRDS) with a broadly tunable external cavity quantum cascade laser. The power coupled through the cavity to the detector is increased by a factor of 22.5. The cavity loss is measured with a precision of 2 * 10(-10) cm(-1)/?Hz; an increase of 12 times over the standard off-axis configuration without reinjection and comparable to the best reported sensitivities in the mid-infrared. Finally, the re-injected CRDS system is used to measure the spectrum of several volatile organic compounds, demonstrating the improved ability to resolve weakly absorbing spectroscopic features. PMID- 25273703 TI - A quantum cascade laser-based water vapor isotope analyzer for environmental monitoring. AB - A field-deployable mid-infrared quantum cascade laser-based spectrometer was designed and developed for measurements of H2(16)O and H2(18)O at 7.12 MUm. H2(16)O and H2(18)O absorption features at 1390.52 cm(-1) and 1389.91 cm(-1), respectively, accessible within current tuning range of the laser, were targeted. The target lines were carefully selected to assure similar absorption levels and similar temperature sensitivities of the line strength due to comparable lower state energies. A real-time spectral fitting algorithm was implemented for isotopic concentration retrieval. Detection limits for H2(16)O and H2(18)O of 2.2 ppm and 7.0 ppb, respectively, were achieved at a dew point of 14 degrees C (volume mixing ratio of 15,766 ppm) in 1 s integration time, which resulted in a delta(18)O isotopic ratio measurement precision of 0.250/00. The ultimate minimum detection limits obtained after 160 s integration time for H2(16)O and H2(18)O, and delta(18)O measurements were 0.6 ppm, 1.7 ppb, and 0.050/00, respectively. PMID- 25273702 TI - Sub-nanosecond time-resolved ambient-pressure X-ray photoelectron spectroscopy setup for pulsed and constant wave X-ray light sources. AB - An apparatus for sub-nanosecond time-resolved ambient-pressure X-ray photoelectron spectroscopy studies with pulsed and constant wave X-ray light sources is presented. A differentially pumped hemispherical electron analyzer is equipped with a delay-line detector that simultaneously records the position and arrival time of every single electron at the exit aperture of the hemisphere with ~0.1 mm spatial resolution and ~150 ps temporal accuracy. The kinetic energies of the photoelectrons are encoded in the hit positions along the dispersive axis of the two-dimensional detector. Pump-probe time-delays are provided by the electron arrival times relative to the pump pulse timing. An average time-resolution of (780 +/- 20) ps (FWHM) is demonstrated for a hemisphere pass energy E(p) = 150 eV and an electron kinetic energy range KE = 503-508 eV. The time-resolution of the setup is limited by the electron time-of-flight (TOF) spread related to the electron trajectory distribution within the analyzer hemisphere and within the electrostatic lens system that images the interaction volume onto the hemisphere entrance slit. The TOF spread for electrons with KE = 430 eV varies between ~9 ns at a pass energy of 50 eV and ~1 ns at pass energies between 200 eV and 400 eV. The correlation between the retarding ratio and the TOF spread is evaluated by means of both analytical descriptions of the electron trajectories within the analyzer hemisphere and computer simulations of the entire trajectories including the electrostatic lens system. In agreement with previous studies, we find that the by far dominant contribution to the TOF spread is acquired within the hemisphere. However, both experiment and computer simulations show that the lens system indirectly affects the time resolution of the setup to a significant extent by inducing a strong dependence of the angular spread of electron trajectories entering the hemisphere on the retarding ratio. The scaling of the angular spread with the retarding ratio can be well approximated by applying Liouville's theorem of constant emittance to the electron trajectories inside the lens system. The performance of the setup is demonstrated by characterizing the laser fluence-dependent transient surface photovoltage response of a laser excited Si(100) sample. PMID- 25273704 TI - Field programmable gate array-assigned complex-valued computation and its limits. AB - We discuss how leveraging Field Programmable Gate Array (FPGA) technology as part of a high performance computing platform reduces latency to meet the demanding real time constraints of a quantum optics simulation. Implementations of complex valued operations using fixed point numeric on a Virtex-5 FPGA compare favorably to more conventional solutions on a central processing unit. Our investigation explores the performance of multiple fixed point options along with a traditional 64 bits floating point version. With this information, the lowest execution times can be estimated. Relative error is examined to ensure simulation accuracy is maintained. PMID- 25273705 TI - Device and method of optically orienting biaxial crystals for sample preparation. AB - An optical instrument we refer to as the "biaxial orientation device" has been developed for finding the optical plane, acute bisectrix, and obtuse bisectrix in biaxial crystals by means of optically aligning conoscopically formed melatopes and measuring the angular coordinates of the melatopes, where the angular values allow for determination of the optical plane containing the optical axes using a vector algebra approach. After determination of the optical plane, the instrument allows for the sample to be aligned in the acute bisectrix or obtuse bisectrix orientations and to be transferred to a simple mechanical component for subsequent grinding and polishing, while preserving the orientation of the polished faces relative to the optical plane, acute bisectrix, and obtuse bisectrix during the grinding and polishing process. Biaxial crystalline material samples prepared in the manner are suitable for accurate spectroscopic absorption measurements in the acute bisectrix and obtuse bisectrix directions as well as perpendicular to the optical plane. PMID- 25273706 TI - Bent crystal spectrometer for both frequency and wavenumber resolved x-ray scattering at a seeded free-electron laser. AB - We present a cylindrically curved GaAs x-ray spectrometer with energy resolution DeltaE/E = 1.1 * 10(-4) and wave-number resolution of Deltak/k = 3 * 10(-3), allowing plasmon scattering at the resolution limits of the Linac Coherent Light Source (LCLS) x-ray free-electron laser. It spans scattering wavenumbers of 3.6 to 5.2/A in 100 separate bins, with only 0.34% wavenumber blurring. The dispersion of 0.418 eV/13.5 MUm agrees with predictions within 1.3%. The reflection homogeneity over the entire wavenumber range was measured and used to normalize the amplitude of scattering spectra. The proposed spectrometer is superior to a mosaic highly annealed pyrolytic graphite spectrometer when the energy resolution needs to be comparable to the LCLS seeded bandwidth of 1 eV and a significant range of wavenumbers must be covered in one exposure. PMID- 25273708 TI - A broadband microwave Corbino spectrometer at 3He temperatures and high magnetic fields. AB - We present the technical details of a broadband microwave spectrometer for measuring the complex conductance of thin films covering the range from 50 MHz up to 16 GHz in the temperature range 300 mK-6 K and at applied magnetic fields up to 8 T. We measure the complex reflection from a sample terminating a coaxial transmission line and calibrate the signals with three standards with known reflection coefficients. Thermal isolation of the heat load from the inner conductor is accomplished by including a section of NbTi superconducting cable (transition temperature around 8-9 K) and hermetic seal glass bead adapters. This enables us to stabilize the base temperature of the sample stage at 300 mK. However, the inclusion of this superconducting cable complicates the calibration procedure. We document the effects of the superconducting cable on our calibration procedure and the effects of applied magnetic fields and how we control the temperature with great repeatability for each measurement. We have successfully extracted reliable data in this frequency, temperature, and field range for thin superconducting films and highly resistive graphene samples. PMID- 25273707 TI - Design and analysis of a spectro-angular surface plasmon resonance biosensor operating in the visible spectrum. AB - Surface plasmon resonance (SPR) sensing is one of the most widely used methods to implement biosensing due to its sensitivity and capacity for label-free detection. Whilst most commercial SPR sensors operate in the angular regime, it has recently been shown that an increase in sensitivity and a greater robustness against noise can be achieved by measuring the reflectivity when varying both the angle and wavelength simultaneously, in a so-called spectro-angular SPR biosensor. A single value decomposition method is used to project the two dimensional spectro-angular reflection signal onto a basis set and allow the image obtained from an unknown refractive index sample to be compared very accurately with a pre-calculated reference set. Herein we demonstrate that a previously reported system operated in the near infra-red has a lower detection limit when operating in the visible spectrum due to the improved spatial resolution and numerical precision of the image sensor. The SPR biosensor presented here has an experimental detection limit of 9.8 * 10(-7) refractive index unit. To validate the system as a biosensor, we also performed the detection of synthetic RNA from pathogenic Legionella pneumophila with the developed biosensing platform. PMID- 25273709 TI - A programmable broadband low frequency active vibration isolation system for atom interferometry. AB - Vibration isolation at low frequency is important for some precision measurement experiments that use atom interferometry. To decrease the vibrational noise caused by the reflecting mirror of Raman beams in atom interferometry, we designed and demonstrated a compact stable active low frequency vibration isolation system. In this system, a digital control subsystem is used to process and feedback the vibration measured by a seismometer. A voice coil actuator is used to control and cancel the motion of a commercial passive vibration isolation platform. With the help of field programmable gate array-based control subsystem, the vibration isolation system performed flexibly and accurately. When the feedback is on, the intrinsic resonance frequency of the system will change from 0.8 Hz to about 0.015 Hz. The vertical vibration (0.01-10 Hz) measured by the in loop seismometer is reduced by an additional factor of up to 500 on the basis of a passive vibration isolation platform, and we have proved the performance by adding an additional seismometer as well as applying it in the atom interferometry experiment. PMID- 25273710 TI - A mirror for lab-based quasi-monochromatic parallel x-rays. AB - A multilayered parabolic mirror with six W/Al bilayers was designed and fabricated to generate monochromatic parallel x-rays using a lab-based x-ray source. Using this mirror, curved bright bands were obtained in x-ray images as reflected x-rays. The parallelism of the reflected x-rays was investigated using the shape of the bands. The intensity and monochromatic characteristics of the reflected x-rays were evaluated through measurements of the x-ray spectra in the band. High intensity, nearly monochromatic, and parallel x-rays, which can be used for high resolution x-ray microscopes and local radiation therapy systems, were obtained. PMID- 25273711 TI - Narrow band wavelength selective filter using grating assisted single ring resonator. AB - This paper illustrates a filter configuration which uses a single ring resonator of larger radius connected to a grating resonator at its drop port to achieve single wavelength selectivity and switching property with spectral features suitable for on-chip wavelength selection applications. The proposed configuration is expected to find applications in silicon photonics devices such as, on-chip external cavity lasers and multi analytic label-free biosensors. The grating resonator has been designed for a high Q-factor, high transmittivity, and minimum loss so that the wavelength selectivity of the device is improved. The proof-of-concept device has been demonstrated on a Silicon-on-Insulator (SOI) platform through electron beam lithography and Reactive Ion Etching (RIE) process. The transmission spectrum shows narrow band single wavelength selection and switching property with a high Free Spectral Range (FSR) ~60 nm and side band rejection ratio >15 dB. PMID- 25273712 TI - Quantitative measurement of phase variation amplitude of ultrasonic diffraction grating based on diffraction spectral analysis. AB - A new method based on diffraction spectral analysis is proposed for the quantitative measurement of the phase variation amplitude of an ultrasonic diffraction grating. For a traveling wave, the phase variation amplitude of the grating depends on the intensity of the zeroth- and first-order diffraction waves. By contrast, for a standing wave, this amplitude depends on the intensity of the zeroth-, first-, and second-order diffraction waves. The proposed method is verified experimentally. The measured phase variation amplitude ranges from 0 to 2pi, with a relative error of approximately 5%. A nearly linear relation exists between the phase variation amplitude and driving voltage. Our proposed method can also be applied to ordinary sinusoidal phase grating. PMID- 25273713 TI - Upgrade of the electron beam ion trap in Shanghai. AB - Over the last few years the Shanghai electron beam ion trap (EBIT) has been successfully redesigned and rebuilt. The original machine, developed under collaboration with the Shanghai Institute of Applied Physics, first produced an electron beam in 2005. It could be tuned with electron energies between 1 and 130 keV and beam current up to 160 mA. After several years of operation, it was found that several modifications for improvements were necessary to reach the goals of better electron optics, higher photon detection, and ion injection efficiencies, and more economical running costs. The upgraded Shanghai-EBIT is made almost entirely from Ti instead of stainless steel and achieves a vacuum of less than 10(-10) Torr, which helps to minimize the loss of highly changed ions through charge exchange. Meanwhile, a more compact structure and efficient cryogenic system, and excellent optical alignment have been of satisfactory. The magnetic field in the central trap region can reach up till 4.8 T with a uniformity of 2.77 * 10(-4). So far the upgraded Shanghai-EBIT has been operated up to an electron energy of 151 keV and a beam current of up to 218 mA, although promotion to even higher energy is still in progress. Radiation from ions as highly charged as Xe(53+, 54+) has been produced and the characterization of current density is estimated from the measured electron beam width. PMID- 25273714 TI - A hemispherical Langmuir probe array detector for angular resolved measurements on droplet-based laser-produced plasmas. AB - In this work, a new diagnostic tool for laser-produced plasmas (LPPs) is presented. The detector is based on a multiple array of six motorized Langmuir probes. It allows to measure the dynamics of a LPP in terms of charged particles detection with particular attention to droplet-based LPP sources for EUV lithography. The system design permits to temporally resolve the angular and radial plasma charge distribution and to obtain a hemispherical mapping of the ions and electrons around the droplet plasma. The understanding of these dynamics is fundamental to improve the debris mitigation techniques for droplet-based LPP sources. The device has been developed, built, and employed at the Laboratory for Energy Conversion, ETH Zurich. The experimental results have been obtained on the droplet-based LPP source ALPS II. For the first time, 2D mappings of the ion kinetic energy distribution around the droplet plasma have been obtained with an array of multiple Langmuir probes. These measurements show an anisotropic expansion of the ions in terms of kinetic energy and amount of ion charge around the droplet target. First estimations of the plasma density and electron temperature were also obtained from the analysis of the probe current signals. PMID- 25273715 TI - Characterisation of deuterium spectra from laser driven multi-species sources by employing differentially filtered image plate detectors in Thomson spectrometers. AB - A novel method for characterising the full spectrum of deuteron ions emitted by laser driven multi-species ion sources is discussed. The procedure is based on using differential filtering over the detector of a Thompson parabola ion spectrometer, which enables discrimination of deuterium ions from heavier ion species with the same charge-to-mass ratio (such as C(6+), O(8+), etc.). Commonly used Fuji Image plates were used as detectors in the spectrometer, whose absolute response to deuterium ions over a wide range of energies was calibrated by using slotted CR-39 nuclear track detectors. A typical deuterium ion spectrum diagnosed in a recent experimental campaign is presented, which was produced from a thin deuterated plastic foil target irradiated by a high power laser. PMID- 25273716 TI - Study on the steady operating state of a micro-pulse electron gun. AB - Micro-pulse electron gun (MPG) employs the basic concept of multipacting to produce high-current and short-pulse electron beams from a radio-frequency (RF) cavity. The concept of MPG has been proposed for more than two decades. However, the unstable operating state of MPG vastly obstructs its practical applications. This paper presents a study on the steady operating state of a micro-pulse electron gun with theory and experiments. The requirements for the steady operating state are proposed through the analysis of the interaction between the RF cavity and the beam load. Accordingly, a MPG cavity with the frequency of 2856 MHz has been designed, constructed, and tested. Some primary experiments have been finished. Both the unstable and stable operating states of the MPG have been observed. The stable output beam current has been detected at about 3.8 mA. Further experimental study is under way now. PMID- 25273717 TI - Hybrid monitor for both beam position and tilt of pulsed high-current beams. AB - A Hybrid beam monitor, integrated with both azimuthal and axial B-dot probes, was designed for simultaneous measurement of both beam position and beam angle for pulsed high-current beams at the same location in beam pipe. The output signals of axial B-dot probes were found to be mixed with signals caused by transverse position deviation. In order to eliminate the unwanted signals, an elimination method was developed and its feasibility tested on a 50-Omega coaxial line test stand. By this method, a waveform, shape-like to that of input current and proportional to the tilt angle, was simulated and processed by following integration step to achieve the tilt angle. The tests showed that the measurement error of displacement and tilt angle less than 0.3 mm and 1.5 mrad, respectively. The latter error could be reduced with improved probes by reducing the inductance of the axial B-dot probe, but the improvement reached a limit due to some unknown systemic mechanism. PMID- 25273718 TI - Design, conditioning, and performance of a high voltage, high brightness dc photoelectron gun with variable gap. AB - A new high voltage photoemission gun has been constructed at Cornell University which features a segmented insulator and a movable anode, allowing the cathode anode gap to be adjusted. In this work, we describe the gun's overall mechanical and high voltage design, the surface preparation of components, as well as the clean construction methods. We present high voltage conditioning data using a 50 mm cathode-anode gap, in which the conditioning voltage exceeds 500 kV, as well as at smaller gaps. Finally, we present simulated emittance results obtained from a genetic optimization scheme using voltage values based on the conditioning data. These results indicate that for charges up to 100 pC, a 30 mm gap at 400 kV has equal or smaller 100% emittance than a 50 mm gap at 450 kV, and also a smaller core emittance, when placed as the source for the Cornell energy recovery linac photoinjector with bunch length constrained to be <3 ps rms. For 100 pC up to 0.5 nC charges, the 50 mm gap has larger core emittance than the 30 mm gap, but conversely smaller 100% emittance. PMID- 25273719 TI - Development of all-solid-state flash x-ray generator with photoconductive semiconductor switches. AB - A compact, low-jitter, and high repetitive rate all-solid-state flash x-ray generator making use of photo conductive semiconductor switches was developed recently for the diagnostic purpose of some hydrokinetical experiments. The generator consisted of twelve stages of Blumlein pulse forming networks, and an industrial cold cathode diode was used to generate intense x-ray radiations with photon energy up to 220 keV. Test experiments showed that the generator could produce >1 kA electron beam currents and x-ray pulses with ~40 ns duration under 100 Hz repetitive rates at least (limited by the triggering laser on hand), also found was that the delay time of the cathode explosive emission is crucial to the energy transfer efficiency of the whole system. In addition, factors affecting the diode impedance, how the switching synchronization and diode impedance determining the allowable operation voltage were discussed. PMID- 25273720 TI - Development of a Big Area BackLighter for high energy density experiments. AB - A very large area (7.5 mm(2)) laser-driven x-ray backlighter, termed the Big Area BackLighter (BABL) has been developed for the National Ignition Facility (NIF) to support high energy density experiments. The BABL provides an alternative to Pinhole-Apertured point-projection Backlighting (PABL) for a large field of view. This bypasses the challenges for PABL in the equatorial plane of the NIF target chamber where space is limited because of the unconverted laser light that threatens the diagnostic aperture, the backlighter foil, and the pinhole substrate. A transmission experiment using 132 kJ of NIF laser energy at a maximum intensity of 8.52 * 10(14) W/cm(2) illuminating the BABL demonstrated good conversion efficiency of >3.5% into K-shell emission producing ~4.6 kJ of high energy x rays, while yielding high contrast images with a highly uniform background that agree well with 2D simulated spectra and spatial profiles. PMID- 25273721 TI - Hall probe measurements of the poloidal magnetic field in Compact Toroidal Hybrid plasmas. AB - A linear array of 16 Hall effect sensors has been developed to directly measure the poloidal magnetic field inside the boundary of a non-axisymmetric hybrid torsatron/tokamak plasma. The array consists of miniature gallium arsenide Hall sensor elements mounted 8 mm apart on a narrow, rotatable printed circuit board inserted into a re-entrant stainless steel tube sheathed in boron nitride. The sensors are calibrated on the bench and in situ to provide accurate local measurements of the magnetic field to aid in reconstructing the equilibrium plasma current density profiles in fully three-dimensional plasmas. Calibrations show that the sensor sensitivities agree with the nominal manufacturers specifications of 1.46 V/T. Poloidal fields measured with the Hall sensor array are found to be within 5% of poloidal fields modeled with a Biot-Savart code. PMID- 25273722 TI - A field programmable gate array-based time-resolved scaler for collinear laser spectroscopy with bunched radioactive potassium beams. AB - A new data acquisition system including a Field Programmable Gate Array (FPGA) based time-resolved scaler was developed for laser-induced fluorescence and beam bunch coincidence measurements. The FPGA scaler was tested in a collinear laser spectroscopy experiment on radioactive (37)K at the BEam COoler and LAser spectroscopy (BECOLA) facility at the National Superconducting Cyclotron Laboratory at Michigan State University. A 1.29 MUs bunch width from the buncher and a bunch repetition rate of 2.5 Hz led to a background suppression factor of 3.1 * 10(5) in resonant photon detection measurements. The hyperfine structure of (37)K and its isotope shift relative to the stable (39)K were determined using 5 * 10(4) s(-1) (37)K ions injected into the BECOLA beam line. The obtained hyperfine coupling constants A((2)S(1/2)) = 120.3(1.4) MHz, A((2)P(1/2)) = 15.2(1.1) MHz, and A((2)P(3/2)) = 1.4(8) MHz, and the isotope shift deltanu(39, 37) = -264(3) MHz are consistent with the previously determined values, where available. PMID- 25273723 TI - Resolving the bulk ion region of millimeter-wave collective Thomson scattering spectra at ASDEX Upgrade. AB - Collective Thomson scattering (CTS) measurements provide information about the composition and velocity distribution of confined ion populations in fusion plasmas. The bulk ion part of the CTS spectrum is dominated by scattering off fluctuations driven by the motion of thermalized ion populations. It thus contains information about the ion temperature, rotation velocity, and plasma composition. To resolve the bulk ion region and access this information, we installed a fast acquisition system capable of sampling rates up to 12.5 GS/s in the CTS system at ASDEX Upgrade. CTS spectra with frequency resolution in the range of 1 MHz are then obtained through direct digitization and Fourier analysis of the CTS signal. We here describe the design, calibration, and operation of the fast receiver system and give examples of measured bulk ion CTS spectra showing the effects of changing ion temperature, rotation velocity, and plasma composition. PMID- 25273724 TI - Flush-mounted probe diagnostics for argon glow discharge plasma. AB - A comparison is made between plasma parameters measured by a flush-mounted probe (FP) and a cylindrical probe (CP) in argon glow discharge plasma. Parameters compared include the space potential, the plasma density, and the effective electron temperature. It is found that the ion density determined by the FP agrees well with the electron density determined by the CP in the quasi-neutral plasma to better than 10%. Moreover, the space potential and effective electron temperature calculated from electron energy distribution function measured by the FP is consistent with that measured by the CP over the operated discharge current and pressure ranges. These results present the FP can be used as a reliable diagnostic tool in the stable laboratory plasma and also be anticipated to be applied in other complicated plasmas, such as tokamaks, the region of boundary layer, and so on. PMID- 25273725 TI - Measurements of the electron temperature fluctuations with a retarding field analyzer on the tokamak ISTTOK. AB - Measurements of the ion temperature fluctuations by retarding field energy analyzed (RFA) based on two point measurements on the exponentially decaying region of the I-V characteristic with two differently DC biased RFA electrodes have been tested and proved in the experiments on the tokamak ISTTOK. In this paper, a DC operation of an RFA has been applied to give direct instantaneous measurements of the electron temperature and electron temperature fluctuations. The results are in good agreement with conventional swept measurements from the RFA. The observed electron temperature fluctuations, 3 mm outside the leading edge of the limiter, have a typical normalized amplitude (standard deviation divided by the average value) of ~13% (T(eav) = 6 eV) and are in opposition to the fluctuations of the floating potential simultaneously measured on the RFA slit. PMID- 25273726 TI - Slightly uneven electric field trigatron employed in tens of microseconds charging time. AB - To solve the issue of operation instability for the trigatron switch in the application of tens of microseconds or even less charging time, a novel trigatron spark gap with slightly uneven electric field was presented. Compared with the conventional trigatron, the novel trigatron was constructed with an obvious field enhancement on the edge of the opposite electrode. The selection of the field enhancement was analyzed based on the theory introduced by Martin. A low voltage trigatron model was constructed and tested on the tens of microseconds charging time platform. The results show that the character of relative range was improved while the trigger character still held a high level. This slightly uneven electric field typed trigatron is willing to be employed in the Tesla transformer - pulse forming line system. PMID- 25273727 TI - Absolute intensity calibration of the 32-channel heterodyne radiometer on experimental advanced superconducting tokamak. AB - This paper presents the results of the in situ absolute intensity calibration for the 32-channel heterodyne radiometer on the experimental advanced superconducting tokamak. The hot/cold load method is adopted, and the coherent averaging technique is employed to improve the signal to noise ratio. Measured spectra and electron temperature profiles are compared with those from an independent calibrated Michelson interferometer, and there is a relatively good agreement between the results from the two different systems. PMID- 25273728 TI - A segmented multi-loop antenna for selective excitation of azimuthal mode number in a helicon plasma source. AB - A flat type, segmented multi-loop antenna was developed in the Tokai Helicon Device, built for producing high-density helicon plasma, with a diameter of 20 cm and an axial length of 100 cm. This antenna, composed of azimuthally splitting segments located on four different radial positions, i.e., r = 2.8, 4.8, 6.8, and 8.8 cm, can excite the azimuthal mode number m of 0, +/-1, and +/-2 by a proper choice of antenna feeder parts just on the rear side of the antenna. Power dependencies of the electron density ne were investigated with a radio frequency (rf) power less than 3 kW (excitation frequency ranged from 8 to 20 MHz) by the use of various types of antenna segments, and n(e) up to ~5 * 10(12) cm(-3) was obtained after the density jump from inductively coupled plasma to helicon discharges. Radial density profiles of m = 0 and +/-1 modes with low and high rf powers were measured. For the cases of these modes after the density jump, the excited mode structures derived from the magnetic probe measurements were consistent with those expected from theory on helicon waves excited in the plasma. PMID- 25273729 TI - Compact and high-particle-flux thermal-lithium-beam probe system for measurement of two-dimensional electron density profile. AB - A compact and high-particle-flux thermal-lithium-beam source for two-dimensional measurement of electron density profiles has been developed. The thermal-lithium beam oven is heated by a carbon heater. In this system, the maximum particle flux of the thermal lithium beam was ~4 * 10(19) m(-2) s(-1) when the temperature of the thermal-lithium-beam oven was 900 K. The electron density profile was evaluated in the small tokamak device HYBTOK-II. The electron density profile was reconstructed using the thermal-lithium-beam probe data and this profile was consistent with the electron density profile measured with a Langmuir electrostatic probe. We confirm that the developed thermal-lithium-beam probe can be used to measure the two-dimensional electron density profile with high time and spatial resolutions. PMID- 25273730 TI - Laboratory-size three-dimensional x-ray microscope with Wolter type I mirror optics and an electron-impact water window x-ray source. AB - We constructed a laboratory-size three-dimensional water window x-ray microscope that combines wide-field transmission x-ray microscopy with tomographic reconstruction techniques, and observed bio-medical samples to evaluate its applicability to life science research fields. It consists of a condenser and an objective grazing incidence Wolter type I mirror, an electron-impact type oxygen Kalpha x-ray source, and a back-illuminated CCD for x-ray imaging. A spatial resolution limit of around 1.0 line pairs per micrometer was obtained for two dimensional transmission images, and 1-MUm scale three-dimensional fine structures were resolved. PMID- 25273731 TI - High-speed imaging upgrade for a standard sample scanning atomic force microscope using small cantilevers. AB - We present an atomic force microscope (AFM) head for optical beam deflection on small cantilevers. Our AFM head is designed to be small in size, easily integrated into a commercial AFM system, and has a modular architecture facilitating exchange of the optical and electronic assemblies. We present two different designs for both the optical beam deflection and the electronic readout systems, and evaluate their performance. Using small cantilevers with our AFM head on an otherwise unmodified commercial AFM system, we are able to take tapping mode images approximately 5-10 times faster compared to the same AFM system using large cantilevers. By using additional scanner turnaround resonance compensation and a controller designed for high-speed AFM imaging, we show tapping mode imaging of lipid bilayers at line scan rates of 100-500 Hz for scan areas of several micrometers in size. PMID- 25273732 TI - Frequency domain approach for time-resolved pump-probe microscopy using intensity modulated laser diodes. AB - We present a scheme for time-resolved pump-probe microscopy using intensity modulated laser diodes. The modulation frequencies of the pump and probe beams are varied up to 500 MHz with fixed frequency detuning typically set at 15 kHz. The frequency response of the pump-probe signal is detected using a lock-in amplifier referenced at the beat frequency. This frequency domain method is capable of characterizing the nanosecond to picosecond relaxation dynamics of sample species without the use of a high speed detector or a high frequency lock in amplifier. Furthermore, as the pump-probe signal is based on the nonlinear interaction between the two laser beams and the sample, our scheme provides better spatial resolution than the conventional diffraction-limited optical microscopes. Time-resolved pump-probe imaging of fluorescence beads and aggregates of quantum dots demonstrates that this method is useful for the microscopic analysis of optoelectronic devices. The system is implemented using compact and low-cost laser diodes, and thus has a broad range of applications in the fields of photochemistry, optical physics, and biological imaging. PMID- 25273734 TI - An unload-induced direct-shear model for granular gouge friction in rock discontinuities. AB - The experimental study introduces an unload-induced direct-shear model to investigate the frictional slip of a layer of simulated granular gouges induced by the combination of a decreasing normal stress and a constant shear stress. A frictional equilibrium state of the gouge layer is initially established under fixed normal and shear stresses. The normal stress is proposed to decrease at a constant unloading rate to induce the frictional slip of the gouge layer, and the shear stress is proposed to keep a constant value during the test. A displacement meter and load cells synchronously measure the slip displacement and the applied normal and shear stresses, respectively. The normal and shear stresses sharply decrease with the frictional slip, owing to damage of gouge contacts. The frictional slip is then gradually arrested with new formation of gouge contacts. A greater initial shear stress induces larger normal and shear stress reductions and a smaller slip displacement. The strain energy stored in the discontinuous system before the frictional slip is found to affect the slip displacement. The advantages and the limitations of this model are discussed at the end. PMID- 25273733 TI - Time-resolved x-ray diffraction techniques for bulk polycrystalline materials under dynamic loading. AB - We have developed two techniques for time-resolved x-ray diffraction from bulk polycrystalline materials during dynamic loading. In the first technique, we synchronize a fast detector with loading of samples at strain rates of ~10(3) 10(4) s(-1) in a compression Kolsky bar (split Hopkinson pressure bar) apparatus to obtain in situ diffraction patterns with exposures as short as 70 ns. This approach employs moderate x-ray energies (10-20 keV) and is well suited to weakly absorbing materials such as magnesium alloys. The second technique is useful for more strongly absorbing materials, and uses high-energy x-rays (86 keV) and a fast shutter synchronized with the Kolsky bar to produce short (~40 MUs) pulses timed with the arrival of the strain pulse at the specimen, recording the diffraction pattern on a large-format amorphous silicon detector. For both techniques we present sample data demonstrating the ability of these techniques to characterize elastic strains and polycrystalline texture as a function of time during high-rate deformation. PMID- 25273735 TI - Adapting a commercial shear rheometer for applications in cartilage research. AB - Cartilage research typically requires a broad range of experimental characterization techniques and thus various testing setups. Here, we describe how several of those tests can be performed with a single experimental platform, i.e. a commercial shear rheometer. Although primarily designed for shear experiments, such a rheometer can be equipped with different adapters to perform indentation and creep measurements, quantify alterations in the sample thickness, and conduct friction measurements in addition to shear rheology. Beyond combining four distinct experimental methods into one setup, the modified rheometer allows for performing material characterizations over a broad range of time scales, frequencies, and normal loads. PMID- 25273736 TI - An air-cooled Litz wire coil for measuring the high frequency hysteresis loops of magnetic samples--a useful setup for magnetic hyperthermia applications. AB - A setup for measuring the high-frequency hysteresis loops of magnetic samples is described. An alternating magnetic field in the range 6-100 kHz with amplitude up to 80 mT is produced by a Litz wire coil. The latter is air-cooled using a forced air approach so no water flow is required to run the setup. High-frequency hysteresis loops are measured using a system of pick-up coils and numerical integration of signals. Reproducible measurements are obtained in the frequency range of 6-56 kHz. Measurement examples on ferrite cylinders and on iron oxide nanoparticle ferrofluids are shown. Comparison with other measurement methods of the hysteresis loop area (complex susceptibility, quasi-static hysteresis loops, and calorific measurements) is provided and shows the coherency of the results obtained with this setup. This setup is well adapted to the magnetic characterization of colloidal solutions of magnetic nanoparticles for magnetic hyperthermia applications. PMID- 25273737 TI - A high pressure cell for supercritical CO2 on-line chemical reactions studied with X-ray techniques. AB - A versatile high pressure X-ray sample cell has been developed for conducting in situ time-resolved X-ray scattering experiments in the pressure and temperature regime required (pressures up to 210 bars and temperatures up to 120 degrees C) for chemical reactions in supercritical fluids. The large exit opening angle of the cell allows simultaneous performance of SAXS-WAXS experiments. Diamond windows are used in order to benefit from the combination of maximum strength, minimal X-ray absorption and chemical inertia. The sample cell can also be utilised for X-ray spectroscopy experiments over a wide range of photon energies. Results of the online synthesis of a block copolymer, poly(methyl methacrylate block-poly(benzyl methacrylate), by Reversible Addition-Fragmentation Chain Transfer (RAFT) in a supercritical CO2 dispersion polymerisation will be discussed. The contribution of the density fluctuations, as function of temperature, to the X-ray scattering signal has been quantified in order to allow appropriate background subtractions. PMID- 25273738 TI - A firmware-defined digital direct-sampling NMR spectrometer for condensed matter physics. AB - We report on the design and implementation of a new digital, broad-band nuclear magnetic resonance (NMR) spectrometer suitable for probing condensed matter. The spectrometer uses direct sampling in both transmission and reception. It relies on a single, commercially-available signal processing device with a user accessible field-programmable gate array (FPGA). Its functions are defined exclusively by the FPGA firmware and the application software. Besides allowing for fast replication, flexibility, and extensibility, our software-based solution preserves the option to reuse the components for other projects. The device operates up to 400 MHz without, and up to 800 MHz with undersampling, respectively. Digital down-conversion with +/-10 MHz passband is provided on the receiver side. The system supports high repetition rates and has virtually no intrinsic dead time. We describe briefly how the spectrometer integrates into the experimental setup and present test data which demonstrates that its performance is competitive with that of conventional designs. PMID- 25273739 TI - Integrated-fin gasket for palm cubic-anvil high pressure apparatus. AB - We described an integrated-fin gasket technique for the palm cubic-anvil apparatus specialized for the high-pressure and low-temperature measurements. By using such a gasket made from the semi-sintered MgO ceramics and the tungsten carbide anvils of 2.5 mm square top, we successfully generate pressures over 16 GPa at both room and cryogenic temperatures down to 0.5 K. We observed a pressure self-increment for this specific configuration and further characterized the thermally induced pressure variation by monitoring the antiferromagnetic transition temperature of chromium up to 12 GPa. In addition to enlarge the pressure capacity, such a modified gasket also improves greatly the surviving rate of electrical leads hanging the sample inside a Teflon capsule filled with the liquid pressure-transmitting medium. These improvements should be attributed to the reduced extrusion of gasket materials during the initial compression. PMID- 25273740 TI - Variable density turbulence tunnel facility. AB - The Variable Density Turbulence Tunnel at the Max Planck Institute for Dynamics and Self-Organization in Gottingen, Germany, produces very high turbulence levels at moderate flow velocities, low power consumption, and adjustable kinematic viscosity between 10(-4) m(2)/s and 10(-7) m(2)/s. The Reynolds number can be varied by changing the pressure or flow rate of the gas or by using different non flammable gases including air. The highest kinematic viscosities, and hence lowest Reynolds numbers, are reached with air or nitrogen at 0.1 bar. To reach the highest Reynolds numbers the tunnel is pressurized to 15 bars with the dense gas sulfur hexafluoride (SF6). Turbulence is generated at the upstream ends of two measurement sections with grids, and the evolution of this turbulence is observed as it moves down the length of the sections. We describe the instrumentation presently in operation, which consists of the tunnel itself, classical grid turbulence generators, and state-of-the-art nano-fabricated hot wire anemometers provided by Princeton University [M. Vallikivi, M. Hultmark, S. C. C. Bailey, and A. J. Smits, Exp. Fluids 51, 1521 (2011)]. We report measurements of the characteristic scales of the flow and of turbulent spectra up to Taylor Reynolds number R(lambda) ~ 1600, higher than any other grid-turbulence experiment. We also describe instrumentation under development, which includes an active grid and a Lagrangian particle tracking system that moves down the length of the tunnel with the mean flow. In this configuration, the properties of the turbulence are adjustable and its structure is resolvable up to R(lambda) ~ 8000. PMID- 25273741 TI - The application of the barrier-type anodic oxidation method to thickness testing of aluminum films. AB - The thickness of the active metal oxide film formed from a barrier-type anodizing process is directly proportional to its formation voltage. The thickness of the consumed portion of the metal film is also corresponding to the formation voltage. This principle can be applied to the thickness test of the metal films. If the metal film is growing on a dielectric substrate, when the metal film is exhausted in an anodizing process, because of the high electrical resistance of the formed oxide film, a sudden increase of the recorded voltage during the anodizing process would occur. Then, the thickness of the metal film can be determined from this voltage. As an example, aluminum films are tested and discussed in this work. This method is quite simple and is easy to perform with high precision. PMID- 25273742 TI - Helium droplet calorimetry of strongly bound species: carbon clusters from C2 to C12. AB - Helium droplet beam methods are a versatile technique that can be used to assemble a wide variety of atomic and molecular clusters. In recent years, methods have been developed to utilize helium droplets as nano-calorimeters to measure the binding energies of weakly bound complexes assembled within the droplet. In the current investigation we extend the helium droplet calorimetry approach to the study of a very strongly bound system: carbon clusters which are bound by several eV per atom. We utilize laser heating of bulk carbon samples to dope the helium droplets with evaporated carbon species. Depending on the laser target, the vaporization plume is found to consist primarily of C3 alone or C2 and C3. These species are sequentially captured by the droplet and assembled into larger carbon clusters in a stepwise manner. The assembled C(n) clusters are detected via mass spectrometry of the doped droplets and the droplet sizes required to detect the various carbon clusters observed are used to estimate the reaction energies of the associated assembly pathways. The helium droplet data qualitatively reflect the trends in assembly energetics, but at first glance appear to yield energies that differ dramatically from theoretical values. Statistical modeling of the helium droplet calorimetry experiment reconciles the differences quantitatively. Our modeling also generates a calibration curve that relates the assembly/reaction energy and threshold mean droplet size over a range of energies from van der Waals interactions to chemical bonding, enabling helium droplet calorimetry methods to be applied quantitatively to a large number of systems. PMID- 25273743 TI - Characterization of buried metal-molecule-metal junctions using Fourier transform infrared microspectroscopy. AB - We have devised an infrared spectromicroscopy based experimental configuration to enable structural characterization of buried molecular junctions. Our design utilizes a small mercury drop at the focal point of an infrared microscope to act as a mirror in studying metal-molecule-metal (MmM) junctions. An organic molecular monolayer is formed either directly on the mercury drop or on a thin, infrared (IR) semi-transparent layer of Au deposited onto an IR transparent, undoped silicon substrate. Following the formation of the monolayer, films on either metal can be examined independently using specular reflection spectroscopy. Furthermore, by bringing together the two monolayers, a buried molecular bilayer within the MmM junction can be characterized. Independent examination of each half of the junction prior to junction formation also allows probing any structural and/or conformational changes that occur as a result of forming the bilayer. Because our approach allows assembling and disassembling microscopic junctions by forming and withdrawing Hg drops onto the monolayer covered metal, spatial mapping of junctions can be performed simply by translating the location of the derivatized silicon wafer. Finally, the applicability of this technique for the longer-term studies of changes in molecular structure in the presence of electrical bias is discussed. PMID- 25273744 TI - Intraoperative cerebral blood flow imaging of rodents. AB - Intraoperative monitoring of cerebral blood flow (CBF) is of interest to neuroscience researchers, which offers the assessment of hemodynamic responses throughout the process of neurosurgery and provides an early biomarker for surgical guidance. However, intraoperative CBF imaging has been challenging due to animal's motion and position change during the surgery. In this paper, we presented a design of an operation bench integrated with laser speckle contrast imager which enables monitoring of the CBF intraoperatively. With a specially designed stereotaxic frame and imager, we were able to monitor the CBF changes in both hemispheres during the rodent surgery. The rotatable design of the operation plate and implementation of online image registration allow the technician to move the animal without disturbing the CBF imaging during surgery. The performance of the system was tested by middle cerebral artery occlusion model of rats. PMID- 25273745 TI - A cryogen-free ultralow-field superconducting quantum interference device magnetic resonance imaging system. AB - Magnetic resonance imaging (MRI) at microtesla fields using superconducting quantum interference device (SQUID) detection has previously been demonstrated, and advantages have been noted. Although the ultralow-field SQUID MRI technique would not need the heavy superconducting magnet of conventional MRI systems, liquid helium required to cool the low-temperature detector still places a significant burden on its operation. We have built a prototype cryocooler-based SQUID MRI system that does not require a cryogen. The SQUID detector and the superconducting gradiometer were cooled down to 3.7 K and 4.3 K, respectively. We describe the prototype design, characterization, a phantom image, and areas of further improvements needed to bring the imaging performance to parity with conventional MRI systems. PMID- 25273746 TI - A technique for measuring dynamic friction coefficient under impact loading. AB - We develop a novel setup based on the split Hopkinson pressure bar technique to test the dynamic friction coefficient under impact loading. In the setup, the major improvement is that the end of the incident bar near the specimen is wedge shaped, which results in a combined compressive and shear loading applied to the specimen. In fact, the shear loading is caused by the interfacial friction between specimen and bars. Therefore, when the two loading force histories are measured, the friction coefficient histories can be calculated without any assumptions and theoretical derivations. The geometry of the friction pairs is simple, and can be either cuboid or cylindrical. Regarding the measurements, two quartz transducers are used to directly record the force histories, and an optical apparatus is designed to test the interfacial slip movement. By using the setup, the dynamic friction coefficient of PTFE/aluminum 7075 friction pairs was tested. The time resolved dynamic friction coefficient and slip movement histories were achieved. The results show that the friction coefficient changes during the loading process, the average data of the relatively stable flat plateau section of the friction coefficient curves is 0.137, the maximum normal pressure is 52 MPa, the maximum relative slip velocity is 1.5 m/s, and the acceleration is 8400 m(2)/s. Furthermore, the friction test was simulated using an explicit FEM code LS-DYNA. The simulation results showed that the constant pressure and slip velocity can both be obtained with a wide flat plateau incident pulse. For some special friction pairs, normal pressure up to a few hundred MPa, interfacial slip velocities up to 10 m/s, and slip movement up to centimeter level can be expected. PMID- 25273747 TI - Pressurized subsampling system for pressured gas-hydrate-bearing sediment: microscale imaging using X-ray computed tomography. AB - A pressurized subsampling system was developed for pressured gas hydrate (GH) bearing sediments, which have been stored under pressure. The system subsamples small amounts of GH sediments from cores (approximately 50 mm in diameter and 300 mm in height) without pressure release to atmospheric conditions. The maximum size of the subsamples is 12.5 mm in diameter and 20 mm in height. Moreover, our system transfers the subsample into a pressure vessel, and seals the pressure vessel by screwing in a plug under hydraulic pressure conditions. In this study, we demonstrated pressurized subsampling from artificial xenon-hydrate sediments and nondestructive microscale imaging of the subsample, using a microfocus X-ray computed tomography (CT) system. In addition, we estimated porosity and hydrate saturation from two-dimensional X-ray CT images of the subsamples. PMID- 25273748 TI - Investigation of thermal and electrical stabilities of a GdBCO coil using grease as an insulation material for practical superconducting applications. AB - This paper presents the effects of thermal grease on the electrical and thermal characteristics of GdBCO pancake coils, observed through charge-discharge, sudden discharge, over-current, and thermal quench testing. In charge-discharge and sudden discharge tests, a coil using thermal grease as an insulation material demonstrated faster charging/discharging rates compared to a coil without turn-to turn insulation. In the case of over-current tests, the coil using thermal grease exhibited the highest electrical stability. Furthermore, thermal quench testing showed the coil employing thermal grease to possess superior thermal characteristics, with rapid cooling and low temperature rise. Overall, the use of thermal grease as an insulation material may be a potential solution to the problems observed with the existing insulation materials, possessing fast charging/discharging rates with superior thermal and electrical stabilities. PMID- 25273749 TI - An estimate of the error caused by the elongation of the wavelength in a focused beam in free-space electromagnetic parameters measurement. AB - A pair of spot-focusing horn lens antenna is the key component in a free-space measurement system. The electromagnetic constitutive parameters of a planar sample are determined using transmitted and reflected electromagnetic beams. These parameters are obtained from the measured scattering parameters by the microwave network analyzer, thickness of the sample, and wavelength of a focused beam on the sample. Free-space techniques introduced by most papers consider the focused wavelength as the free-space wavelength. But in fact, the incident wave projected by a lens into the sample approximates a Gaussian beam, thus, there has an elongation of the wavelength in the focused beam and this elongation should be taken into consideration in dielectric and magnetic measurement. In this paper, elongation of the wavelength has been analyzed and measured. Measurement results show that the focused wavelength in the vicinity of the focus has an elongation of 1%-5% relative to the free-space wavelength. Elongation's influence on the measurement result of the permittivity and permeability has been investigated. Numerical analyses show that the elongation of the focused wavelength can cause the increase of the measured value of the permeability relative to traditionally measured value, but for the permittivity, it is affected by several parameters and may increase or decrease relative to traditionally measured value. PMID- 25273750 TI - Design of pulsed guiding magnetic field for high power microwave generators. AB - In this paper, we present a comprehensive study on designing solenoid together with the corresponding power supply system to excite pulsed magnetic field required for high power microwave generators. Particularly, a solenoid is designed and the excited magnetic field is applied to a Ku-band overmoded Cerenkov generator. It is found in experiment that the electron beam is properly guided by the magnetic field and a 1.1 GW high power microwave is achieved at a central frequency of 13.76 GHz. Pulsed solenoid system has the advantages of compactness and low energy consumption, which are of great interest for repetitive operation. The reported studies and results can be generalized to other applications which require magnetic fields. PMID- 25273751 TI - Probing a dielectric resonator acting as passive sensor through a wireless microwave link. AB - Dielectric resonators, generally used for frequency filtering in oscillator loops, can be used as passive cooperative targets for wireless sensor applications. In the present work, we demonstrate such an approach by probing their spectral characteristics using a microwave RADAR system. The unique spectral response and energy storage capability of resonators provide unique responses allowing to separate the sensor response from clutter. Although the dielectric resonator is not designed for high temperature sensitivity, the accurate determination of the resonance frequency allows for a remote estimate of the temperature with Kelvin resolution. PMID- 25273752 TI - A high-field magnetic resonance imaging spectrometer using an oven-controlled crystal oscillator as the local oscillator of its radio frequency transceiver. AB - A home-made high-field magnetic resonance imaging (MRI) spectrometer with multiple receiving channels is described. The radio frequency (RF) transceiver of the spectrometer consists of digital intermediate frequency (IF) circuits and corresponding mixing circuits. A direct digital synthesis device is employed to generate the IF pulse; the IF signal from a down-conversion circuit is sampled and followed by digital quadrature detection. Both the IF generation and the IF sampling use a 50 MHz clock. An oven-controlled crystal oscillator, which has outstanding spectral purity and a compact circuit, is used as the local oscillator of the RF transceiver. A digital signal processor works as the pulse programmer of the spectrometer, as a result, 32 control lines can be generated simultaneously while an event is triggered. Field programmable gate array devices are utilized as the auxiliary controllers of the IF generation, IF receiving, and gradient control. High performance, including 1 MUs time resolution of the soft pulse, 1 MHz receiving bandwidth, and 1 MUs time resolution of the gradient waveform, is achieved. High-quality images on a 1.5 T MRI system using the spectrometer are obtained. PMID- 25273754 TI - A spatial sampling based 13.3 Gs/s sample-and-hold circuit. AB - This paper presents a high-speed sample-and-hold circuit (SHC) for very fast signal analysis. Spatial sampling techniques are exploited with CMOS transmission lines in a 0.13 MUm standard CMOS process. The SHC includes on chip coplanar waveguides for signal and clock pulse transmission, a clock pulse generator, and three elementary samplers periodically (L = 7.2 mm) placed along the signal propagation line. The SHC samples at 13.3 Gs/s. The circuit occupies an area of 1660 MUm * 820 MUm and consumes ~6 mW at a supply voltage of 1.2 V. The obtained input bandwidth is ~11.5 GHz. PMID- 25273753 TI - A 800 kV compact peaking capacitor for nanosecond generator. AB - An extremely compact high voltage peaking capacitor is developed. The capacitor has a pancake structure with a diameter of 315 mm, a thickness of 59 mm, and a mass of 6.1 kg. The novel structural design endows the capacitor with a better mechanical stability and reliability under hundreds of kilovolts pulse voltage and an inner gas pressure of more than 1.5 MPa. The theoretical value of the capacitor self-inductance is near to 17 nH. Proved by series of electrical experiments, the capacitor can endure a high-voltage pulse with a rise time of about 20 ns, a half-width duration of around 25 ns, and an amplitude of up to 800 kV in a single shot model. When the capacitor was used in an electromagnetic pulse simulator as a peaking capacitor, the rise time of the voltage pulse can be reduced from 20 ns to less than 3 ns. The practical value of the capacitor's inductance deduced from the experimental date is no more than 25 nH. PMID- 25273755 TI - Analysis of folded pulse forming line operation. AB - A compact pulse forming line (CPFL) concept based on a folded transmission line and high-breakdown strength dielectric was explored through an effort combining proof-of-principle experiments with electromagnetic modeling. A small-scale folded CPFL was fabricated using surface-mount ceramic multilayer capacitors. The line consisted of 150 capacitors close-packed in parallel and delivered a 300 ns flat-top pulse. The concept was carried to a 10 kV class device using a polymer ceramic nanocomposite dielectric with a permittivity of 37.6. The line was designed for a 161 ns FWHM length pulse into a matched load. The line delivered a 110 ns FWHM pulse, and the pulse peak amplitude exceeded the matched load ideal. Transient electromagnetic analysis using the particle-in-cell code ICEPIC was conducted to examine the nature of the unexpected pulse shortening and distortion. Two-dimensional analysis failed to capture the anomalous behavior. Three-dimensional analysis replicated the pulse shape and revealed that the bends were largely responsible for the pulse shortening. The bends not only create the expected reflection of the incident TEM wave but also produce a non-zero component of the Poynting vector perpendicular to the propagation direction of the dominant electromagnetic wave, resulting in power flow largely external to the PFL. This analysis explains both the pulse shortening and the amplitude of the pulse. PMID- 25273756 TI - A low phase noise microwave frequency synthesis for a high-performance cesium vapor cell atomic clock. AB - We report the development, absolute phase noise, and residual phase noise characterization of a 9.192 GHz microwave frequency synthesis chain devoted to be used as a local oscillator in a high-performance cesium vapor cell atomic clock based on coherent population trapping (CPT). It is based on frequency multiplication of an ultra-low phase noise 100 MHz oven-controlled quartz crystal oscillator using a nonlinear transmission line-based chain. Absolute phase noise performances of the 9.192 GHz output signal are measured to be -42, -100, -117 dB rad(2)/Hz and -129 dB rad(2)/Hz at 1 Hz, 100 Hz, 1 kHz, and 10 kHz offset frequencies, respectively. Compared to current results obtained in a state-of-the art CPT-based frequency standard developed at LNE-SYRTE, this represents an improvement of 8 dB and 10 dB at f = 166 Hz and f = 10 kHz, respectively. With such performances, the expected Dick effect contribution to the atomic clock short term frequency stability is reported at a level of 6.2 * 10(-14) at 1 s integration time, that is a factor 3 higher than the atomic clock shot noise limit. Main limitations are pointed out. PMID- 25273757 TI - Improved repetition rate mixed isotope CO2 TEA laser. AB - A compact CO2 TEA laser has been developed for remote chemical detection that operates at a repetition rate of 250 Hz. It emits 700 mJ/pulse at 10.6 MUm in a multimode beam with the (12)C(16)O2 isotope. With mixed (12)C(16)O2 plus (13)C(16)O2 isotopes it emits multiple lines in both isotope manifolds to improve detection of a broad range of chemicals. In particular, output pulse energies are 110 mJ/pulse at 9.77 MUm, 250 mJ/pulse at 10 MUm, and 550 mJ/pulse at 11.15 MUm, useful for detection of the chemical agents Sarin, Tabun, and VX. Related work shows capability for long term sealed operation with a catalyst and an agile tuner at a wavelength shift rate of 200 Hz. PMID- 25273758 TI - Determination of the multiple local properties of thin layer with high lateral resolution by scanning acoustic microscopy. AB - Simultaneous determination of the multiple local acoustic and geometrical properties of the thin layer with a high lateral resolution is of great interest in ultrasonic non-destructive evaluation. In this paper, we propose a technique based on the V(z, t) data to simultaneously determine the four local properties of the thin layer, namely, the thickness, the sound velocity, the acoustic impedance, and the density. First, the V(z, t) data are collected from both the thin layer and the reference material. Then the sound velocity and the thickness are calculated by focusing the point-focusing transducer on the front and back surfaces of the thin layer, with the confocal positions determined by averaging the peak positions in the V(z) curves at different frequencies. Second, the acoustic impedance of the thin layer is obtained based on the experimental and theoretical two-dimensional reflection spectrum using the echo from the front surface of the layer. Finally, the density can be obtained by dividing the acoustic impedance by the sound velocity. The four local properties of an aluminum layer are accurately obtained using our method. The largest relative error of determining the four properties is around 1%. This technique opens a new way of simultaneously measuring the multiple local acoustic and geometrical properties of thin layers. PMID- 25273759 TI - Measurements of acoustic particle velocity in a coaxial duct and its application to a traveling-wave thermoacoustic heat engine. AB - We present theoretical solutions, based on linear acoustic theory, for axial acoustic particle velocity in an annular region of a coaxial duct. The solutions are expressed in terms of two non-dimensional parameters h/delta(nu) and R; h and delta(nu), respectively, represent the half of the spacing between two concentric ducts and the characteristic length given by kinematic viscosity of the gas and angular frequency of acoustic oscillations, and R is the radius ratio of the ducts. The validity of the solutions was verified by direct measurements using a laser Doppler velocimeter. The present results are applied to measurements of the acoustic power distribution in a traveling wave thermoacoustic engine with a coaxial duct, which provides experimental evidence for acoustic power feedback in the coaxial duct. PMID- 25273760 TI - Sub-picowatt resolution calorimetry with niobium nitride thin-film thermometer. AB - High-resolution calorimetry has many important applications such as probing nanoscale thermal transport and studying the thermodynamics of biological and chemical systems. In this work, we demonstrated a calorimeter with an unprecedentedly high resolution at room temperature using a high-performance resistive thermometry material, niobium nitride (NbN(x)). Based on a theoretical analysis, we first showed that the heat flux resolution of a resistive thermometry based calorimeter depends on the parasitic thermal conductance of the device and the temperature coefficient of resistance (TCR) of the thermometer, when the noise is limited by the Johnson noise. Based on this analysis, we then developed a calorimeter using NbNx as the thermometry material because it possesses both high TCR (~0.67%/K) and a low thermal conductivity (k ~ 1.1 W/m K). This calorimeter, when used with the modulated heating scheme, demonstrated an unprecedentedly high power resolution of 0.26 pW at room temperature. In addition, NbNx based resistive thermometry can also be extended to cryogenic temperature, where the TCR is shown to be significantly higher. PMID- 25273761 TI - Nanometer-scale temperature imaging for independent observation of Joule and Peltier effects in phase change memory devices. AB - This paper reports a technique for independent observation of nanometer-scale Joule heating and thermoelectric effects, using atomic force microscopy (AFM) based measurements of nanometer-scale temperature fields. When electrical current flows through nanoscale devices and contacts the temperature distribution is governed by both Joule and thermoelectric effects. When the device is driven by an electrical current that is both periodic and bipolar, the temperature rise due to the Joule effect is at a different harmonic than the temperature rise due to the Peltier effect. An AFM tip scanning over the device can simultaneously measure all of the relevant harmonic responses, such that the Joule effect and the Peltier effect can be independently measured. Here we demonstrate the efficacy of the technique by measuring Joule and Peltier effects in phase change memory devices. By comparing the observed temperature responses of these working devices, we measure the device thermopower, which is in the range of 30 +/- 3 to 250 +/- 10 MUV K(-1). This technique could facilitate improved measurements of thermoelectric phenomena and properties at the nanometer-scale. PMID- 25273762 TI - Real-time magnetic nanothermometry: the use of magnetization of magnetic nanoparticles assessed under low frequency triangle-wave magnetic fields. AB - In this study, we propose and demonstrate the usefulness of employing time varying magnetization of a magnetic nanoparticle (MNP) based sample, induced by low frequency (f = 25 Hz) triangular-wave magnetic field, to achieve the approach of real-time recording of magnetization curve, which allows precise and noninvasive temperature probing with real-time performance. Moreover, the present report introduces the design and performed the test of a detection system for accurate and real-time recording of the magnetization curve of MNP-based samples. We found that by employing the magnetization curve of a magnetic fluid sample containing magnetite nanoparticles of about 30 nm in diameter the accuracy of the temperature probing is about 0.32 K (0.1% relative accuracy), with response time of 1 s. Furthermore, an increase in response time from 1 to 8 s improves the accuracy of temperature probing from 0.32 to 0.20 K. Finally, we envisage that breakthroughs in clinical hyperthermia, targeted drug delivery and basic cell research can be accomplished while using the approach reported in this study. PMID- 25273763 TI - Miniature quartz crystal-resonator-based thermogravimetric detector. AB - In this work, a new design for a microheater combined with a quartz crystal microbalance (QCM) array for thermogravimetric analysis is presented. Each QCM consists of two electrodes to excite thickness-shear-mode vibrations and one microheater to increase the temperature on the crystal backside. In addition, all the electrode pads are patterned on the crystal backside, making the design of the QCM compact and user-friendly. Finally, the proposed QCM array was employed to separate ethanol from methanol. This was successfully achieved via thermal desorption spectra calculated by differentiating the frequency changes. PMID- 25273764 TI - Geometry optimization for micro-pressure sensor considering dynamic interference. AB - Presented is the geometry optimization for piezoresistive absolute micro-pressure sensor. A figure of merit called the performance factor (PF) is defined as a quantitative index to describe the comprehensive performances of a sensor including sensitivity, resonant frequency, and acceleration interference. Three geometries are proposed through introducing islands and sensitive beams into typical flat diaphragm. The stress distributions of sensitive elements are analyzed by finite element method. Multivariate fittings based on ANSYS simulation results are performed to establish the equations about surface stress, deflection, and resonant frequency. Optimization by MATLAB is carried out to determine the dimensions of the geometries. Convex corner undercutting is evaluated. Each PF of the three geometries with the determined dimensions is calculated and compared. Silicon bulk micromachining is utilized to fabricate the prototypes of the sensors. The outputs of the sensors under both static and dynamic conditions are tested. Experimental results demonstrate the rationality of the defined performance factor and reveal that the geometry with quad islands presents the highest PF of 210.947 Hz(1/4). The favorable overall performances enable the sensor more suitable for altimetry. PMID- 25273765 TI - An improved filter-u least mean square vibration control algorithm for aircraft framework. AB - Active vibration control of aerospace vehicle structures is very a hot spot and in which filter-u least mean square (FULMS) algorithm is one of the key methods. But for practical reasons and technical limitations, vibration reference signal extraction is always a difficult problem for FULMS algorithm. To solve the vibration reference signal extraction problem, an improved FULMS vibration control algorithm is proposed in this paper. Reference signal is constructed based on the controller structure and the data in the algorithm process, using a vibration response residual signal extracted directly from the vibration structure. To test the proposed algorithm, an aircraft frame model is built and an experimental platform is constructed. The simulation and experimental results show that the proposed algorithm is more practical with a good vibration suppression performance. PMID- 25273766 TI - Enhanced method to reconstruct mode shapes of continuous scanning measurements using the Hilbert Huang transform and the modal analysis method. AB - Generally, it is time consuming to experimentally identify the operating deflection shape or mode shape of a structure. To overcome this problem, the Hilbert Huang transform (HHT) technique has been recently proposed. This technique is used to extract the mode shape from measurements that continuously measure the vibration of a region of interest within a structure using a non contact laser sensor. In previous research regarding the HHT, two technical processes were needed to obtain the mode shape for each mode. The purpose of this study is to improve and complement our previous research, and for this purpose, a modal analysis approach is adapted without using the two technical processes to obtain an accurate un-damped impulse response of each mode for continuous scanning measurements. In addition, frequency response functions for each type of beam are derived, making it possible to make continuously scanned measurements along a straight profile. In this paper, the technical limitations and drawbacks of the damping compensation technique used in previous research are identified. In addition, the separation of resonant frequency (the Doppler effect) that occurs in continuous scanning measurements and the separation of damping phenomenon are also observed. The proposed method is quantitatively verified by comparing it with the results obtained from a conventional approach to estimate the mode shape with an impulse response. PMID- 25273767 TI - Real-time calibration of a feedback trap. AB - Feedback traps use closed-loop control to trap or manipulate small particles and molecules in solution. They have been applied to the measurement of physical and chemical properties of particles and to explore fundamental questions in the non equilibrium statistical mechanics of small systems. These applications have been hampered by drifts in the electric forces used to manipulate the particles. Although the drifts are small for measurements on the order of seconds, they dominate on time scales of minutes or slower. Here, we show that a recursive maximum likelihood (RML) algorithm can allow real-time measurement and control of electric and stochastic forces over time scales of hours. Simulations show that the RML algorithm recovers known parameters accurately. Experimental estimates of diffusion coefficients are also consistent with expected physical properties. PMID- 25273768 TI - Decentralized diagnostics based on a distributed micro-genetic algorithm for transducer networks monitoring large experimental systems. AB - Evolutionary approach to centralized multiple-faults diagnostics is extended to distributed transducer networks monitoring large experimental systems. Given a set of anomalies detected by the transducers, each instance of the multiple-fault problem is formulated as several parallel communicating sub-tasks running on different transducers, and thus solved one-by-one on spatially separated parallel processes. A micro-genetic algorithm merges evaluation time efficiency, arising from a small-size population distributed on parallel-synchronized processors, with the effectiveness of centralized evolutionary techniques due to optimal mix of exploitation and exploration. In this way, holistic view and effectiveness advantages of evolutionary global diagnostics are combined with reliability and efficiency benefits of distributed parallel architectures. The proposed approach was validated both (i) by simulation at CERN, on a case study of a cold box for enhancing the cryogeny diagnostics of the Large Hadron Collider, and (ii) by experiments, under the framework of the industrial research project MONDIEVOB (Building Remote Monitoring and Evolutionary Diagnostics), co-funded by EU and the company Del Bo srl, Napoli, Italy. PMID- 25273769 TI - Development of an aerosol chamber for calibration of 220Rn progeny detectors. AB - This paper describes an aerosol chamber system that can be used for calibrations and performance experiments of passive (220)Rn progeny detectors. For the purpose of this study, an aerosol generation system using carnauba wax as the aerosol material was mounted into the (220)Rn chamber. We used the chamber to measure characteristics of the equilibrium factor (F) of (220)Rn and unattached fraction (f(p)) of (220)Rn progeny, which are important parameters for dose estimation. The first experiment showed that continuous and stable generation of the unattached and aerosol-attached (220)Rn progeny concentrations was obtained. We observed that the spatial distributions in the chamber of the vertical profiles of the unattached and aerosol-attached (220)Rn progeny concentrations were homogeneous, as were the particle number concentration and count median diameter. The values of F and f(p) and their characteristics observed in this study were in the same range as the values reported from indoor measurements. We found that the characteristics of F and f(p) were dependent on the aerosol conditions (particle diameter and particle number concentration). PMID- 25273770 TI - Design, construction, and performance testing of an isothermal naphthalene heat pipe furnace. AB - In this work, an isothermal naphthalene heat pipe furnace was developed to achieve uniformly radiant heating at temperature up to 300 degrees C. The startup, stability, and thermography tests were carried out to evaluate the uniform temperature zone of the furnace. The temperature variance of the uniform temperature zone was observed to be within +/-1 degrees C along the axis of the furnace. To illustrate its capabilities, the furnace was used to successfully sinter thin layers of copper nanoparticle on microporous copper wicks and form biporous wicks, materials of high interest to advanced heat pipe technologies. PMID- 25273771 TI - A novel torsion testing technique for micro-scale specimens based on electromagnetism. AB - A novel torsion apparatus for micro-scale specimens is developed based on electromagnetism, in which a coil-magnet component is used for actuating and torque measuring. When the current gets through the coil, the torque, produced by Ampere force, can be easily measured by recording the current. A laser displacement sensor is applied to measure the rotation angle. The torque is calibrated using Sartorius BP211D balance. The calibration results demonstrate there is a perfect linear relationship between the torque and the current. The torque capacity is 4.0 * 10(-4) N m with noise-floor of less than 10(-8) N m. The rotation angle capacity is 60 degrees with noise-floor of less than 0.02 degrees . Two sets of copper wire specimens, with diameter of 100 MUm and 140 MUm, are tested using this apparatus. Experimental results, with good resolution and repeatability, successfully demonstrate the effectiveness of the torsion testing technique for micro-scale specimens. PMID- 25273772 TI - Low-temperature Bessel beam trap for single submicrometer aerosol particle studies. AB - We report on a new instrument for single aerosol particle studies at low temperatures that combines an optical trap consisting of two counter-propagating Bessel beams (CPBBs) and temperature control down to 223 K (-50 degrees C). The apparatus is capable of capturing and stably trapping individual submicrometer- to micrometer-sized aerosol particles for up to several hours. First results from studies of hexadecane, dodecane, and water aerosols reveal that we can trap and freeze supercooled droplets ranging in size from ~450 nm to 5500 nm (radius). We have conducted homogeneous and heterogeneous freezing experiments, freezing melting cycles, and evaporation studies. To our knowledge, this is the first reported observation of the freezing process for levitated single submicrometer sized droplets in air using optical trapping techniques. These results show that a temperature-controlled CPBB trap is an attractive new method for studying phase transitions of individual submicrometer aerosol particles. PMID- 25273773 TI - Implementation of the scale factor balance on two pairs of quartz-flexure capacitive accelerometers by trimming bias voltage. AB - Gravity gradient measurement makes use of the difference between the outputs of pairs of linear accelerometers, which results in cancelling out the common mode accelerations caused by mounting platform and external environment. One of the key technologies is to match the acceleration-to-voltage or acceleration-to current transfer functions of the pairs of the accelerometers to an extremely high degree of accuracy. The differential signals then make the gravity gradients observable. By using two pairs of the quartz-flexure accelerometers with a capacitive sensing and electrostatic closed-loop control, the electrostatic control bias voltages were trimming remotely and automatically in real time. Each pair of accelerometers was matched individually and then all four accelerometers were finally re-balanced. The experimental results show that the consistency of five digits is achieved at a noise level of ~5*10(-8) g/?Hz (1 g ~ 9.8 m/s(2)) and the scale factors ranging from 0.25 to 0.32 V/mg. Further improvement to the achieved level of matching is limited by the intrinsic noise of the accelerometers used. PMID- 25273774 TI - Novel electrochemical method of fast and reproducible fabrication of metallic nanoelectrodes. AB - A novel electrochemical wire etching method of fabrication of ultrasharp nanoelectrodes is reported. Tungsten wires can be sharpened to less than 10 nm tip radius in a reproducible manner in less than 1 min by using controllable hydrodynamic electrolyte flow combined with optimized electrochemical etching parameters. The method relies on the variations of the electric field at the surface of a metal wire, while the electrolyte solution is in motion, rather than on the ionic gradient generated in a static solution. PMID- 25273775 TI - Low-field nuclear magnetic resonance for the in vivo study of water content in trees. AB - Nuclear magnetic resonance (NMR) and magnetic resonance imaging have long been used to study water content in plants. Approaches have been primarily based on systems using large magnetic fields (~1 T) to obtain NMR signals with good signal to-noise. This is because the NMR signal scales approximately with the magnetic field strength squared. However, there are also limits to this approach in terms of realistic physiological configuration or those imposed by the size and cost of the magnet. Here we have taken a different approach--keeping the magnetic field low to produce a very light and inexpensive system, suitable for bulk water measurements on trees less than 5 cm in diameter, which could easily be duplicated to measure on many trees or from multiple parts of the same tree. Using this system we have shown sensitivity to water content in trees and their cuttings and observed a diurnal signal variation in tree water content in a greenhouse. We also demonstrate that, with calibration and modeling of the thermal polarization, the system is reliable under significant temperature variation. PMID- 25273776 TI - Physical apparatus parameters and model for vibrating tube densimeters at pressures to 140 MPa and temperatures to 473 K. AB - Vibrating tube densimeters are well-established tools for measuring fluid densities precisely at elevated temperatures and pressures. However, the conventional method of calibrating them utilises a model in which the apparatus parameters are represented as polynomials of temperature and pressure that contain a variable number of terms. Here a robust, physically-based model is presented and demonstrated for six different instruments at temperatures from (273 to 473) K, pressures from (0 to 140) MPa, and densities from (0 to 1050) kg m(-3). The model's physical basis ensures that only seven apparatus parameters are required to relate the measured resonant period to fluid mass density with an average r.m.s. deviation of +/-0.23 kg m(-3) across all six densimeters. Estimates for each of the apparatus parameters were made based on the geometry and material properties of the vibrating tubes, and these estimates were consistent with the parameter values determined by calibration with reference fluids. Three of the apparatus parameters describe the temperature dependence of the resonant period: for the six vibrating tubes tested, the relative standard deviations of these parameters were all within the range of values estimated from the thermoelastic properties of the Hastelloy tubes. Two distinct parameters are required to describe the pressure dependence of the vibrating tube's volume and effective spring constant, both of which are estimable from equations describing the elastic deformation of thick-walled tubes. The extensive calibrations conducted demonstrate that, for these densimeters, the variations with pressure of the tube's spring constant and its volume have a ratio that is neither 0 nor 1, as has been assumed previously. The model's physical basis allows vibrating tube densimeters to be calibrated accurately using fewer reference fluid measurements than required by the conventional method. Furthermore, use of the physically-based model reduces the uncertainty of measurements made at densities, temperatures, or pressures beyond the range of the calibration. PMID- 25273777 TI - A parallelogram-based compliant remote-center-of-motion stage for active parallel alignment. AB - Parallel alignment stage with remote-center-of-motion (RCM) is of key importance in precision out-of-plane aligning since it can eliminate the harmful lateral displacement generated at the output platform. This paper presents the development of a parallelogram-based compliant RCM stage for active parallel alignment. Different from conventional parallelogram-based RCM mechanism, the proposed stage is designed with compliant mechanisms, which endows the stage with many attractive merits when used in precision micro-/nanomanipulations. A symmetric double-parallelogram mechanism (SDPM) based on flexure hinges is developed as the rotary guiding component to realize desired RCM function. Due to the geometrical constraint of the SDPM, the operating space of the stage can be easily adjusted by bending the input links without loss of rotational precision. The stage is driven by a piezoelectric actuator and its output motion is measured by non-contact displacement sensors. Based on pseudo-rigid-body simplification method, the analytical models predicting kinematics, statics, and dynamics of the RCM stage have been established. Besides, the dimensional optimization is conducted in order to maximize the first resonance frequency of the stage. After that, finite element analysis is conducted to validate the established models and the prototype of the stage is fabricated for performance tests. The experimental results show that the developed RCM stage has a rotational range of 1.45 mrad while the maximum center shift of the RCM point is as low as 1 MUm, which validate the effectiveness of the proposed scheme. PMID- 25273778 TI - Novel design and sensitivity analysis of displacement measurement system utilizing knife edge diffraction for nanopositioning stages. AB - This paper presents a novel design and sensitivity analysis of a knife edge-based optical displacement sensor that can be embedded with nanopositioning stages. The measurement system consists of a laser, two knife edge locations, two photodetectors, and axillary optics components in a simple configuration. The knife edge is installed on the stage parallel to its moving direction and two separated laser beams are incident on knife edges. While the stage is in motion, the direct transverse and diffracted light at each knife edge is superposed producing interference at the detector. The interference is measured with two photodetectors in a differential amplification configuration. The performance of the proposed sensor was mathematically modeled, and the effect of the optical and mechanical parameters, wavelength, beam diameter, distances from laser to knife edge to photodetector, and knife edge topography, on sensor outputs was investigated to obtain a novel analytical method to predict linearity and sensitivity. From the model, all parameters except for the beam diameter have a significant influence on measurement range and sensitivity of the proposed sensing system. To validate the model, two types of knife edges with different edge topography were used for the experiment. By utilizing a shorter wavelength, smaller sensor distance and higher edge quality increased measurement sensitivity can be obtained. The model was experimentally validated and the results showed a good agreement with the theoretically estimated results. This sensor is expected to be easily implemented into nanopositioning stage applications at a low cost and mathematical model introduced here can be used for design and performance estimation of the knife edge-based sensor as a tool. PMID- 25273780 TI - Development of a steel ball center alignment device based on Michelson interference concept. AB - This study presents a ball center alignment method based on the Michelson interferometer where one of the reflecting mirrors is replaced by a lens and steel ball. By locating the ball away from the focal length of the lens, the beam is reflected as a spherical wave. The interference ring formed by the planar and spherical waves can be clearly observed using a camera without a lens. The distance of the offset of the ball center can be enhanced by more than 140% using this method. A fast ring profile fitting method can reduce circle fitting time to around a third of that needed for Hough transformation. PMID- 25273781 TI - In situ biaxial rotation at low-temperatures in high magnetic fields. AB - We report the design, construction, and characterization of a biaxial sample rotation stage for use in a cryogenic system for orientation-dependent studies of anisotropic electronic transport phenomena at low temperatures and high magnetic fields. Our apparatus allows for continuous rotation of a sample about two axes, both independently and simultaneously. PMID- 25273782 TI - Transmission line transformer for reliable and low-jitter triggering of a railgap switch. AB - The performance of railgap switch critically relies upon multichannel breakdown between the extended electrodes (rails) in order to ensure distributed current transfer along electrode length and to minimize the switch inductance. The initiation of several simultaneous arc channels along the switch length depends on the gap triggering technique and on the rate at which the electric field changes within the gap. This paper presents design, construction, and output characteristics of a coaxial cable based three-stage transmission line transformer (TLT) that is capable of initiating multichannel breakdown in a high voltage, low inductance railgap switch. In each stage three identical lengths of URM67 coaxial cables have been used in parallel and they have been wounded in separate cassettes to enhance the isolation of the output of transformer from the input. The cascaded output impedance of TLT is ~50 Omega. Along with multi channel formation over the complete length of electrode rails, significant reduction in jitter (<=2 ns) and conduction delay (<=60 ns) has been observed by the realization of large amplitude (~80 kV), high dV/dt (~6 kV/ns) pulse produced by the indigenously developed TLT based trigger generator. The superior performance of TLT over conventional pulse transformer for railgap triggering application has been compared and demonstrated experimentally. PMID- 25273779 TI - An apparatus to manipulate and identify individual Ba ions from bulk liquid Xe. AB - We describe a system to transport and identify barium ions produced in liquid xenon, as part of R&D towards the second phase of a double beta decay experiment, nEXO. The goal is to identify the Ba ion resulting from an extremely rare nuclear decay of the isotope (136)Xe, hence providing a confirmation of the occurrence of the decay. This is achieved through Resonance Ionization Spectroscopy (RIS). In the test setup described here, Ba ions can be produced in liquid xenon or vacuum and collected on a clean substrate. This substrate is then removed to an analysis chamber under vacuum, where laser-induced thermal desorption and RIS are used with time-of-flight mass spectroscopy for positive identification of the barium decay product. PMID- 25273783 TI - Direct measurement of shear properties of microfibers. AB - As novel fibers with enhanced mechanical properties continue to be synthesized and developed, the ability to easily and accurately characterize these materials becomes increasingly important. Here we present a design for an inexpensive tabletop instrument to measure shear modulus (G) and other longitudinal shear properties of a micrometer-sized monofilament fiber sample, such as nonlinearities and hysteresis. This automated system applies twist to the sample and measures the resulting torque using a sensitive optical detector that tracks a torsion reference. The accuracy of the instrument was verified by measuring G for high purity copper and tungsten fibers, for which G is well known. Two industrially important fibers, IM7 carbon fiber and Kevlar((r)) 119, were also characterized with this system and were found to have G = 16.5 +/- 2.1 and 2.42 +/- 0.32 GPa, respectively. PMID- 25273784 TI - A geophysical shock and air blast simulator at the National Ignition Facility. AB - The energy partitioning energy coupling experiments at the National Ignition Facility (NIF) have been designed to measure simultaneously the coupling of energy from a laser-driven target into both ground shock and air blast overpressure to nearby media. The source target for the experiment is positioned at a known height above the ground-surface simulant and is heated by four beams from the NIF. The resulting target energy density and specific energy are equal to those of a low-yield nuclear device. The ground-shock stress waves and atmospheric overpressure waveforms that result in our test system are hydrodynamically scaled analogs of full-scale seismic and air blast phenomena. This report summarizes the development of the platform, the simulations, and calculations that underpin the physics measurements that are being made, and finally the data that were measured. Agreement between the data and simulation of the order of a factor of two to three is seen for air blast quantities such as peak overpressure. Historical underground test data for seismic phenomena measured sensor displacements; we measure the stresses generated in our ground surrogate medium. We find factors-of-a-few agreement between our measured peak stresses and predictions with modern geophysical computer codes. PMID- 25273785 TI - Development of a high pressure micromechanical force apparatus. AB - The formation of gas hydrates and subsequent plugging of pipelines are risks that need to be well understood during the production and transportation of oil and gas in subsea flowlines. These flowlines are typically operating at low temperature and high pressure conditions, which are well within the hydrate formation stability region. One of the key processes for hydrate plugs to develop is the agglomeration of hydrates. To obtain a more comprehensive understanding on this problem, we have developed a high-pressure micromechanical force (MMF) apparatus to directly measure cohesive forces between gas hydrate particles. The MMF system is housed in a stainless steel vessel that can withstand pressures of up to 10 MPa, thereby facilitating studies on a broad spectrum of hydrate formers and conditions. The MMF apparatus comprises of two cantilever fibers: one is stationary and another is manipulated via a nano-manipulator. Water droplets (~500 MUm in diameter) are placed at the end of the each cantilever fiber so that they can be converted to hydrate. In order to demonstrate the stability of this apparatus, CH4/C2H6 (74.7 mol. %/25.3 mol. %) mixed hydrates were prepared at 2 MPa and -5 degrees C and annealed at 0 degrees C for 15 h. Subsequently, the hydrate particle cohesive force was measured at 2 degrees C. Compared with the cohesive force of cyclopentane hydrates in cyclopentane liquid (~4.3 mN/m), the average cohesive force of gas hydrates was about 10 times higher, ~43 mN/m. Studies using this new high pressure MMF apparatus will be central to better understand the agglomeration of hydrates in multiphase flowlines. PMID- 25273786 TI - New experimental methodology, setup and LabView program for accurate absolute thermoelectric power and electrical resistivity measurements between 25 and 1600 K: application to pure copper, platinum, tungsten, and nickel at very high temperatures. AB - In this paper we describe an experimental setup designed to measure simultaneously and very accurately the resistivity and the absolute thermoelectric power, also called absolute thermopower or absolute Seebeck coefficient, of solid and liquid conductors/semiconductors over a wide range of temperatures (room temperature to 1600 K in present work). A careful analysis of the existing experimental data allowed us to extend the absolute thermoelectric power scale of platinum to the range 0-1800 K with two new polynomial expressions. The experimental device is controlled by a LabView program. A detailed description of the accurate dynamic measurement methodology is given in this paper. We measure the absolute thermoelectric power and the electrical resistivity and deduce with a good accuracy the thermal conductivity using the relations between the three electronic transport coefficients, going beyond the classical Wiedemann-Franz law. We use this experimental setup and methodology to give new very accurate results for pure copper, platinum, and nickel especially at very high temperatures. But resistivity and absolute thermopower measurement can be more than an objective in itself. Resistivity characterizes the bulk of a material while absolute thermoelectric power characterizes the material at the point where the electrical contact is established with a couple of metallic elements (forming a thermocouple). In a forthcoming paper we will show that the measurement of resistivity and absolute thermoelectric power characterizes advantageously the (change of) phase, probably as well as DSC (if not better), since the change of phases can be easily followed during several hours/days at constant temperature. PMID- 25273787 TI - Note: Reliable low-vibration piezo-mechanical shutter. AB - We present a mechanical shutter based on a bending piezo-actuator. The shutter features an active aperture of about 2 mm, allowing for full extinction and lossless transmission of a beam. Acoustic noise and mechanical vibrations produced are very low and the shutter is outstandingly long-lived; a test device has undergone 20 * 10(6) cycles without breaking. A reflector makes the shutter capable of reliably interrupting a beam with at least 2 W of cw power at 780 nm. The shutter is well suited to create pulses as short as 16 ms, while pulse lengths down to 1 ms are possible. The rise and fall times are approximately 120 us, with a delay of 2 ms. Jitter stays below 10 us, while long-term drifts stay well below 500 us. PMID- 25273788 TI - Note: Enhancement of the extreme ultraviolet emission from a potassium plasma by dual laser irradiation. AB - Emission spectra from multiply charged potassium ions ranging from K(3+) to K(5+) have been obtained in the extreme ultraviolet (EUV) spectral region. A strong emission feature peaking around 38 nm, corresponding to a photon energy of 32.6 eV, is the dominant spectral feature at time-averaged electron temperatures in the range of 8-12 eV. The variation of this emission with laser intensity and the effects of pre-pulses on the relative conversion efficiency (CE) have been explored experimentally and indicate that an enhancement of about 30% in EUV CE is readily attainable. PMID- 25273789 TI - Note: A quartz cell with Pt single crystal bead electrode for electrochemical scanning tunneling microscope measurements. AB - In this paper, we provide and demonstrate a design of a unique cell with Pt single crystal bead electrode for electrochemical scanning tunneling microscope (ECSTM) measurements. The active metal Pt electrode can be protected from air contamination during the preparation process. The transparency of the cell allows the tip and bead to be aligned by direct observation. Based on this, a new and effective alignment method is introduced. The high-quality bead preparations through this new cell have been confirmed by the ECSTM images of Pt (111). PMID- 25273790 TI - Note: Differential amplified high-resolution tilt angle measurement system. AB - A high-resolution tilt angle measurement system is presented in this paper. In this system, the measurement signal is amplified by two steps: (1) amplified by operational amplifier and (2) differential amplified by two MEMS-based inclinometers. The novel application not only amplifies the signal but, more importantly, substantially reduces the electrical interference and common-mode noise among the same circuit design. Thus, both the extremely high resolution and great long-term stability are achieved in this system. Calibrated by an autocollimator, the system shows a resolution of 2 arc sec. The accuracy is better than +/-1.5 arc sec. The zero-drift error is below +/-1 arc sec and +/-2 arc sec in the short and long term, respectively. PMID- 25273791 TI - Note: Effect of photodiode aluminum cathode frame on spectral sensitivity in the soft x-ray energy band. AB - Silicon photodiodes used for soft x-ray detection typically have a thin metal electrode partially covering the active area of the photodiode, which subtly alters the spectral sensitivity of the photodiode. As a specific example, AXUV4BST photodiodes from International Radiation Detectors have a 1.0 MUm thick aluminum frame covering 19% of the active area of the photodiode, which attenuates the measured x-ray signal below ~6 keV. This effect has a small systematic impact on the electron temperature calculated from measurements of soft x-ray bremsstrahlung emission from a high-temperature plasma. Although the systematic error introduced by the aluminum frame is only a few percent in typical experimental conditions on the Madison Symmetric Torus, it may be more significant for other instruments that use similar detectors. PMID- 25273792 TI - Note: A method for minimizing oxide formation during elevated temperature nanoindentation. AB - A standardized method to protect metallic samples and minimize oxide formation during elevated-temperature nanoindentation was adapted to a commercial instrument. Nanoindentation was performed on Al (100), Cu (100), and W (100) single crystals submerged in vacuum oil at 200 degrees C, while the surface morphology and oxidation was carefully monitored using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The results were compared to room temperature and 200 degrees C nanoindentation tests performed without oil, in order to evaluate the feasibility of using the oil as a protective medium. Extensive surface characterization demonstrated that this methodology is effective for nanoscale testing. PMID- 25273793 TI - Note: On the generation of sub-300 keV flash-X-rays using rod-pinch diode: an experimental investigation. AB - Generation of flash X-rays (FXRs) at less than 500 keV is described with emphasis on experimental investigation. The pulser is a Tesla transformer-Water transmission line based pulsed power generator operating in double resonance mode to power a rod-pinch diode. The configuration of aspect ratio reported here falls much below the normally reported ratios for the rod-pinch diode operation. Experimental investigation at such low pulsed voltage has revealed "flowering" of the anode tip and "pitting" of the perspex window. A possible explanation in terms of Lorentz body force is discussed rather than the pinch mechanism generally suggested in literature. The experimental investigation for the FXR generation is corroborated by measuring the radiation dose using CaSO4 (Dy) thermo luminescent dosimeters. PMID- 25273794 TI - Note: Longitudinally excited N2 laser with low beam divergence. AB - We developed a longitudinally excited N2 laser (337 nm) with low beam divergence without collimator lenses. The N2 laser consisted of a 30 cm long Pyrex glass tube with an inner diameter of 2.5 mm, a normal stable resonator formed by flat mirrors, and a simple, novel driver circuit. At a N2 gas pressure of 0.4 kPa and a repetition rate of 40 Hz, the N2 laser produced a circular beam with an output energy of 2.6 MUJ and a low full-angle beam divergence of 0.29 mrad due to the uniform discharge formed by the longitudinal excitation scheme, the long cavity with the small aperture, and the low-input energy oscillation. PMID- 25273795 TI - Note: Enhanced production of He+ from the Versatile Ion Source (VIS) in off resonance configuration. AB - The Versatile Ion Source (VIS) is a microwave discharge ion source installed at INFN-LNS and here used as test-bench for the production of high intensity low emittance proton beams and for studies on plasma physics. A series of measurements have been carried out with VIS in order to test the source with light ions. In particular a He(+) beam has been characterized in terms of plasma discharge parameters. The experiment has been triggered by the observation of X radiation emission from the plasma for some configuration of the magnetic field profile. The plasma electron energy distribution function is in fact modified when in some regions of the plasma chamber under-resonance discharge takes place, fulfilling the condition that allows the electromagnetic wave to electrostatic wave conversion. These tests allowed obtaining more than 50 mA of He(+) beams. PMID- 25273796 TI - Note: A novel normalization scheme for laser-based plasma x-ray sources. AB - A kHz repetition rate laser pump-X-ray probe system for ultrafast X-ray diffraction is set up based on a laser-driven plasma X-ray source. A simple and reliable normalization approach has been developed to minimize the impact of large X-ray pulse intensity fluctuation on data quality. It utilizes one single X ray area detector to record both sample and reference signals simultaneously. Performance of this novel normalization method is demonstrated in reflectivity oscillation measurement of a superlattice sample at sub-ps resolution. PMID- 25273797 TI - Note: An online testing method for lifetime projection of high power light emitting diode under accelerated reliability test. AB - In recent years, due to the fast development of high power light-emitting diode (LED), its lifetime prediction and assessment have become a crucial issue. Although the in situ measurement has been widely used for reliability testing in laser diode community, it has not been applied commonly in LED community. In this paper, an online testing method for LED life projection under accelerated reliability test was proposed and the prototype was built. The optical parametric data were collected. The systematic error and the measuring uncertainty were calculated to be within 0.2% and within 2%, respectively. With this online testing method, experimental data can be acquired continuously and sufficient amount of data can be gathered. Thus, the projection fitting accuracy can be improved (r(2) = 0.954) and testing duration can be shortened. PMID- 25273800 TI - Short-Term Assessment of the OHIP-14 Scale on Denture Wearers Using Adhesives. AB - PURPOSE: The purpose of this study was to assess differences of the Oral Health Implant Profile-14 (OHIP-14) scale over a month and determine association with gender, supporting tissues (KIS), and denture base (KID) among patients wearing complete dentures using denture adhesives. MATERIALS AND METHODS: Sixteen denture wearers, candidates for a new set of complete dentures, were selected. OHIP-14 scores were recorded at the beginning of the study, 6 weeks after fitting of the new set (T0 ), 15 days (T1 ), and finally 30 days (T2 ) after daily use of a denture adhesive as instructed. The KIS and KID were clinically examined and rated according to the Kapur Index. Statistical analyses were based on repeated measures ANOVA, Mann-Whitney test, regression analysis, and Friedman test at a = 0.05. RESULTS: The OHIP-14 scale was found to have a high reliability (alpha = 0.847) and a high test-retest consistency (ICC = 0.889); however, domain 1 had the lowest item-total correlation (rho = 0.144) and item 7 a negative one (rho = 0.414). Trend analysis indicated a significant negative linear trend over time (slope = -3.156, p = 0.002), while repeated-measures ANOVA showed differences in OHIP-14 between T2 and T1 (p = 0.003) or T0 (p = 0.005) intervals. OHIP-14 groups were found to be positively associated with KIS (p = 0.010) and negatively with KID (p = 0.047) groups, but not with gender (p = 0.272). CONCLUSIONS: The study shows that OHIP-14 has a high internal reliability and consistency when applied to new denture wearers, and its score decreases if denture adhesives are used for at least 15 days. Low KIS and high KID contributes to this trend. Some OHIP-14 items are more associated than others with the total score trend over time. PMID- 25273801 TI - Taking the hype out of hypertension. PMID- 25273802 TI - Medical diagnostic systems: a case for neural networks. AB - Recent advances in computer technology offer to the medical profession specialized tools for gathering medical data, processing power, as well as fast storing and retrieving capabilities. Artificial intelligence (AI), an emerging field of computer science is studying the issues of human problem solving and decision making. Furthermore, rule-based systems and knowledge-based systems that are other fields of AI have been adopted by many scientists in an effort to develop intelligent medical diagnostic systems. In this study artificial neural networks (ANN) are introduced as a tool for building an intelligent diagnostic system; the system does not attempt to replace the physician from being the decision maker but to enhance ones facilities for reaching a correct decision. An integrated diagnostic system for assessing certain neuromuscular disorders is used in this study as an example for demonstrating the proposed methodology. The diagnostic system is composed of modules that independently provide numerical data to the system from the clinical examination of a patient, and from various laboratory tests that are performed. The examination procedure has been standardized by developing protocols for each specialized area, in cooperation with experts in the area. At the conclusion of the clinical examination and laboratory tests, data in the form of a numerical vector represents a medical examination snapshot of the subject. Artificial neural network (ANN) models were developed using the unsupervised self-organizing feature maps algorithm. Data from 71 subjects were collected. The ANN models were trained with the data from 41 subjects, and tested with the data from the remaining 30 subjects. Two sets of models were developed; those trained with the data from only the clinical examinations; and those trained by combining the clinical and the laboratory test data. The diagnostic yield that was obtained for the unknown cases is in the region of 73 to 93% for the models trained with only the clinical data, and in the region of 73 to 100% for those trained by combining both the clinical and laboratory data. The pictorial representation of the diagnostic models through the self organized two dimensional feature maps provide the physician with a friendly human-computer interface and a comprehensive tool that can be used for further observations, for example in monitoring disease progression of a subject. PMID- 25273803 TI - A protocol for testing expert-system reliability. AB - We set out a protocol for giving a computerised medical decision system the label of expert-system meaning that its responses are of the same standard as those of an expert. We apply it to the validation of an expert-system, MENINGE, which is applied to diagnosis of meningitis in children. The proposed protocol can be widely used since it doesn't refer to the existence of correct responses for therapy or diagnosis, and since it involves simple statistical computations. First this validation rests on a comparison of agreement among experts and among physicians new to medical practice. Secondly, the agreement of the system with the experts is compared to the agreement of the system with physicians new to medical practice. In order to perform this comparison we recommend a standard agreement measure, the choice of which is an important issue in this paper. PMID- 25273804 TI - Pen-based computing: is it good for health? AB - One of the major factors for the resistance of physicians to the use of computers in their workplace is the computer keyboard. Many physicians cannot type and do not want to type. Furthermore, working on a computer keyboard does not allow them to maintain eye contact with patients, an important success factor for any physician-patient encounter. One possible solution to the problem is to tap the friendly data input interface that is provided by pen-based computers. These devices facilitate data entry with the support of stylus-based touch screen entries, handwriting recognition and use of gestures for word and character editing. They are also unobtrusive and should serve as an excellent data entry interface tool for a clinic-based electronic medical record system. This paper reviews the current pen-based technology and describes two proven applications in healthcare. PMID- 25273805 TI - Performance characteristics of pressure infusors. AB - Pressure infusion devices (PID) are used in trauma hospitals and in military applications to enhance rapid fluid replacement of hypovolemic shocked patients. This work presents a simple inexpensive technique for evaluation of the performance characteristics of pressure infusors. Pressure-volume and volume-time curves of pneumatic and spring-activated infusors have been derived for pressurized infusion with various output resistances. Three indices of performance are suggested for evaluation of pressure infusors: the energy to discharge fluid from the bag, efficiency index and time required to empty 50% of the bag. PMID- 25273806 TI - Analysis of coil parameters for magnetic stimulation. AB - For magnetic stimulation the desired electromagnetic field is produced by a magnetic coil to affect biological tissue and thereby to stimulate it for neurological diagnosis. The coil geometry determines the strength and the duration of the induced electric field in the volume of interest for a given stimulator: The aim of our work is to establish a relationship between the coil geometry and the strength as well as duration of the induced electric field. The calculated results show that there exists an optimal coil geometry for stimulating a given volume of the biological tissues. Our numerical calculation is restricted to an excitable tissue 15 mm below the lower plane of the coil. PMID- 25273807 TI - Computer aided densitometric image analysis of bone remodelling after total hip arthroplasty. AB - By means of a simple and inexpensive system, the computer aided densitometric image analysis (CADIA), we can now evaluate on X-ray film the effect of long term bone remodelling after total hip arthroplasties (THA). The results of CADIA system applied to the historical archive are burdened by a not always acceptable significance. The main source of error is the variance of radiological parameters. An attempt to retrieve the historical archive, that is of every X-ray film obtained out of any radiological control protocol, can be carried out with the bone density ratio representation. We have evaluated three different specimens with bone density ratio analysis: cementless group (96 cases), cemented group (59 cases) and non prosthetized femurs group (51 cases) as a control, all groups were followed up for more than 24 months. Ratios showed up different behaviour among the three specimens, confirming clinical evidence of a lower bone remodelling for cemented THA. PMID- 25273808 TI - Education and training of health informatics in Europe. PMID- 25273810 TI - International Conference on Theoretical and High-Performance Computational Chemistry. PMID- 25273809 TI - Metformin, cancer and glucose metabolism. AB - Metformin is the first-line treatment for type 2 diabetes. Results from several clinical studies have indicated that type 2 diabetic patients treated with metformin might have a lower cancer risk. One of the primary metabolic changes observed in malignant cell transformation is an increased catabolic glucose metabolism. In this context, once it has entered the cell through organic cation transporters, metformin decreases mitochondrial respiration chain activity and ATP production that, in turn, activates AMP-activated protein kinase, which regulates energy homeostasis. In addition, metformin reduces cellular energy availability and glucose entrapment by inhibiting hexokinase-II, which catalyses the glucose phosphorylation reaction. In this review, we discuss recent findings on molecular mechanisms that sustain the anticancer effect of metformin through regulation of glucose metabolism. In particular, we have focused on the emerging action of metformin on glycolysis in normal and cancer cells, with a drug discovery perspective. PMID- 25273811 TI - Aneez Esmail: Almost got expelled from university. PMID- 25273812 TI - Protocol for an exploration of knowledge sharing for improved discharge from a mental health ward. AB - INTRODUCTION: Strategies to reduce hospital admissions for mental health service users have received vast amounts of attention, yet the transfer of care from hospital to the community has been ignored. The discharge process is complex, messy, disjointed and inefficient, relying on cross-agency and organisational working. Focusing on one acute mental health admission ward, we will investigate whether the discharge process for people with severe mental health problems can be enhanced through the creation, implementation and utilisation of a knowledge sharing proforma that is used on their admission to the ward. METHODS AND ANALYSIS: The project uses qualitative interviews to understand the complex processes associated with being admitted and discharged from inpatient mental health wards. Practitioners will be asked to identify and map the relevant stakeholders involved in admission and discharge, and discuss any problems with the process. The study team will work with clinicians to develop a knowledge collection proforma, which will be piloted for 2 months. Qualitative interviews will be carried out to collect reflections on the experiences of using the tool, with data used for further refinement of the intervention. Baseline and repeat quantitative measures will be taken to illustrate any changes to length of stay and readmission rates achieved as a result of the study. ETHICS AND DISSEMINATION: A key issue is that participants are able to comment frankly on something that is a core part of their work, without fear or reprise. It is equally important that all participants are offered the opportunity to develop and coproduce the knowledge collection proforma, in order that the intervention produced is fit for purpose and usable in the real world, away from a research environment. The study has received ethical approval from Nottingham University Business School ethics committee, and has all appropriate National Health Service research governance clearances. PMID- 25273813 TI - Prevalence, nature and predictors of prescribing errors in mental health hospitals: a prospective multicentre study. AB - OBJECTIVE: To determine the prevalence, nature and predictors of prescribing errors (PEs) in three mental health hospitals. SETTING: Inpatient units in three National Health Service (NHS) mental health hospitals in the North West of England. PARTICIPANTS: Trained clinical pharmacists prospectively recorded the number of PEs in newly written or omitted prescription items screened during their routine work on 10 data collection days. A multidisciplinary panel reviewed PE data using established methods to confirm (1) the presence of a PE, (2) the type of PE and (3) whether errors were clinically relevant and likely to cause harm. PRIMARY OUTCOME MEASURES: Frequency, nature and predictors of PEs. RESULTS: Of 4427 screened prescription items, 281 were found to have one or more PEs (error rate 6.3% (95% CI 5.6 to 7.1%)). Multivariate analysis revealed that specialty trainees (OR 1.23 (1.01 to 1.51)) and staff grade psychiatrists (OR 1.50 (1.05 to 2.13)) were more likely to make PEs when compared to foundation year (FY) one doctors, and that specialty trainees and consultant psychiatrists were twice as likely to make clinically relevant PEs (OR 2.61 (2.11 to 3.22) and 2.03 (1.66 to 2.50), respectively) compared to FY one staff. Prescription items screened during the prescription chart rewrite (OR 0.52 (0.33 to 0.82)) or at discharge (OR 0.87 (0.79 to 0.97)) were less likely to be associated with PEs than items assessed during inpatient stay, although they were more likely to be associated with clinically relevant PEs (OR 2.27 (1.72 to 2.99) and 4.23 (3.68 to 4.87), respectively). Prescription items screened at hospital admission were five times more likely (OR 5.39 (2.72 to 10.69)) to be associated with clinically relevant errors than those screened during patient stay. CONCLUSIONS: PEs may be more common in mental health hospitals than previously reported and important targets to minimise these errors have been identified. PMID- 25273814 TI - Gadolinium oxide nanoplates with high longitudinal relaxivity for magnetic resonance imaging. AB - Molecular-based contrast agents for magnetic resonance imaging (MRI) are often characterized by insufficient relaxivity, thus requiring the systemic injection of high doses to induce sufficient contrast enhancement at the target site. In this work, gadolinium oxide (Gd2O3) nanoplates are produced via a thermal decomposition method. The nanoplates have a core diameter varying from 2 to 22 nm, a thickness of 1 to 2 nm and are coated with either an oleic acid bilayer or an octylamine modified poly(acrylic acid) (PAA-OA) polymer layer. For the smaller nanoplates, longitudinal relaxivities (r1) of 7.96 and 47.2 (mM s)(-1) were measured at 1.41 T for the oleic acid bilayer and PAA-OA coating, respectively. These values moderately reduce as the size of the Gd2O3 nanoplates increases, and are always larger for the PAA-OA coating. Cytotoxicity studies on human dermal fibroblast cells documented no significant toxicity, with 100% cell viability preserved up to 250 MUM for the PAA-OA coated Gd2O3 nanoplates. Given the 10 times increase in longitudinal relaxivity over the commercially available Gd based molecular agents and the favorable toxicity profile, the 2 nm PAA-OA coated Gd2O3 nanoplates could represent a new class of highly effective T1 MRI contrast agents. PMID- 25273815 TI - Variable hydraulic resistances and their impact on plant drought response modelling. AB - Plant drought responses are still not fully understood. Improved knowledge on drought responses is, however, crucial to better predict their impact on individual plant and ecosystem functioning. Mechanistic models in combination with plant measurements are promising for obtaining information on plant water status and can assist us in understanding the effect of limiting soil water availability and drought stress. While existing models are reliable under sufficient soil water availability, they generally fail under dry conditions as not all appropriate mechanisms seem yet to have been implemented. We therefore aimed at identifying mechanisms underlying plant drought responses, and in particular investigated the behaviour of hydraulic resistances encountered in the soil and xylem for grapevine (Vitis vinifera L.) and oak (Quercus robur L.). A variable hydraulic soil-to-stem resistance was necessary to describe plant drought responses. In addition, implementation of a variable soil-to-stem hydraulic resistance enabled us to generate an in situ soil-to-stem vulnerability curve, which might be an alternative to the conventionally used vulnerability curves. Furthermore, a daily recalibration of the model revealed a drought induced increase in radial hydraulic resistance between xylem and elastic living tissues. Accurate information on plant hydraulic resistances and simulation of plant drought responses can foster important discussions regarding the functioning of plants and ecosystems during droughts. PMID- 25273816 TI - Gene cloning and enzymatic characterization of alkali-tolerant type I pullulanase from Exiguobacterium acetylicum. AB - A pullulanase gene (Pul3YH5) of 2568 bp, which encodes a protein containing 855 amino acid residues, was cloned from the alkaliphilic bacterium Exiguobacterium acetylicum YH5. The pullulanase (Pul3YH5) contains the YNWGYDP motif of type I pullulanase as well as four conserved glycoside hydrolase sequences of the GH13 (alpha-amylase) family. When the pullulanase gene was cloned and expressed in Escherichia coli BL21 (DE3) plysS, the recombinant pullulanase had a molecular mass of ~100.0 kDa. It was optimally active at 50 degrees C and pH 6.0, alkali tolerant and displayed excellent stability (>93.0%) over a broad pH range (4.0 10.0) when incubated for 30 min without substrate. The enzyme activity of Pul3YH5 was significantly enhanced in the presence of Co(2+) , Fe(2+) and Mn(2+) and was inhibited by Cu(2+) , SDS, beta-mercaptoethanol and EDTA. The enzyme displayed the highest specificity for pullulan (Km = 0.12 +/- 0.02 mg ml(-1) ), followed by soluble starch (Km = 0.69 +/- 0.04 mg ml(-1) ). Substrate hydrolysis demonstrated that pullulanase from E. acetylicum liberated maltotriose from pullulan, although hydrolytic activity was also detected with soluble starch, amylopectin, beta-limited dextrin and glycogen. These enzymatic properties indicate that Pul3YH5 is alkali-tolerant pullulanase and that Pul3YH5 could be useful in the detergent industry. SIGNIFICANCE AND IMPACT OF THE STUDY: Pullulanases have great potential in various industries, ranging from food (high fructose and glucose syrups) to washing detergent industries. In this study, the gene encoding the novel pullulanase from E. acetylicum YH5 was cloned and sequenced, then expressed in E. coli. The properties of the recombinant enzyme in E. coli were also determined. The pullulanase from E. acetylicum YH5 is alkaline tolerant and has a high optimum temperature, making it a candidate for applications in the detergent industry. PMID- 25273817 TI - Molecular cloning, phylogenetic analysis, and expression profiling of endoplasmic reticulum molecular chaperone BiP genes from bread wheat (Triticum aestivum L.). AB - BACKGROUND: The endoplasmic reticulum chaperone binding protein (BiP) is an important functional protein, which is involved in protein synthesis, folding assembly, and secretion. In order to study the role of BiP in the process of wheat seed development, we cloned three BiP homologous cDNA sequences in bread wheat (Triticum aestivum), completed by rapid amplification of cDNA ends (RACE), and examined the expression of wheat BiP in wheat tissues, particularly the relationship between BiP expression and the subunit types of HMW-GS using near isogenic lines (NILs) of HMW-GS silencing, and under abiotic stress. RESULTS: Sequence analysis demonstrated that all BiPs contained three highly conserved domains present in plants, animals, and microorganisms, indicating their evolutionary conservation among different biological species. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that TaBiP (Triticum aestivum BiP) expression was not organ-specific, but was predominantly localized to seed endosperm. Furthermore, immunolocalization confirmed that TaBiP was primarily located within the protein bodies (PBs) in wheat endosperm. Three TaBiP genes exhibited significantly down-regulated expression following high molecular weight-glutenin subunit (HMW-GS) silencing. Drought stress induced significantly up-regulated expression of TaBiPs in wheat roots, leaves, and developing grains. CONCLUSIONS: The high conservation of BiP sequences suggests that BiP plays the same role, or has common mechanisms, in the folding and assembly of nascent polypeptides and protein synthesis across species. The expression of TaBiPs in different wheat tissue and under abiotic stress indicated that TaBiP is most abundant in tissues with high secretory activity and with high proportions of cells undergoing division, and that the expression level of BiP is associated with the subunit types of HMW-GS and synthesis. The expression of TaBiPs is developmentally regulated during seed development and early seedling growth, and under various abiotic stresses. PMID- 25273819 TI - Investigation of metal sorption behavior of Slp1 from Lysinibacillus sphaericus JG-B53: a combined study using QCM-D, ICP-MS and AFM. AB - Surface layer proteins (S-layer) of Lysinibacillus sphaericus JG-B53 are biological compounds with several bio-based technical applications such as biosorptive materials for metal removal or rare metals recovery from the environment. Despite their well-described applications, a deeper understanding of their metal sorption behavior still remains challenging. The metal sorption ability of Au(3+), Pd(2+), Pt(2+) and Eu(3+) was investigated by ICP-MS, AFM and QCM-D which enables the sorption detection in real-time during in situ experiments. Results indicate a high binding of Pd, followed by Au, Eu and Pt to the proteins. The comparison between different methods allowed a deeper understanding of the metal sorption of isolated S-layer either frees in liquid, adsorbed forming a protein layer or as the bacteria surface. PMID- 25273818 TI - Investigating the link between particulate exposure and airway inflammation in the horse. AB - Inhalant exposure to airborne irritants commonly encountered in horse stables is implicated in the pathogenesis of inflammatory airway disease (IAD) and recurrent airway obstruction (RAO), non-infectious, inflammatory pulmonary disorders that impact the health and performance of horses across all equine disciplines. IAD and RAO have overlapping clinical, cytological, and functional manifestations of the pulmonary response to organic dust and noxious gases encountered in the barn environment. Study of these diseases has provided important but incomplete understanding of the effect of air quality upon the respiratory health of horses. In this review, the principles of particulate exposure assessment, including health-related aerosol size fractions and size-selective sampling, the factors influencing air quality in equine environments, and the effect of air quality on the equine respiratory tract are discussed. The objective of this review is to provide the reader with a summary of the most common chronic inflammatory airway diseases in the horse and the principles of air sampling that are essential to the planning, interpretation, and assessment of equine respiratory health-related exposure studies. PMID- 25273821 TI - Confirmation of genetic variants associated with lethal prostate cancer in a cohort of men from hereditary prostate cancer families. AB - Germline genetic variants have been suggested as prognostic biomarkers for identifying patients at high risk for lethal prostate cancer (PCa). Validation studies have confirmed the association of several single nucleotide polymorphisms (SNPs) with fatal PCa, but whether these variants affect PCa-specific mortality (PCSM) in patients with an inherited predisposition to PCa, based on familial history, is unknown. For this study, a cohort of 957 PCa patients from 270 hereditary prostate cancer families of European ancestry was genotyped for a panel of 22 PCSM-associated SNPs. Death certificates were reviewed to confirm cause of death. Mixed-effect Cox proportional hazards models were used to assess survival according to genotypes, accounting for relatedness and clinicopathological factors. Within this cohort, 98 PCa deaths were confirmed over an average follow-up period of 12.7 years after diagnosis. Variant allele carriers for three SNPs had significantly altered risk for PCSM [rs635261 at RNASEL, hazard ratio (HR), 0.35, 95% CI, 0.18-0.66; p = 0.002; rs915927 in XRCC1, HR, 1.91, 95% CI, 1.21-3.02; p = 0.009; and rs2494750 at AKT1, HR, 0.45, 95% CI, 0.23-0.90; p = 0.016). These results confirm the association of genetic variation in three genes with PCa lethality in a cohort of men with an inherited susceptibility to the disease and provide validation evidence that germline SNPs provide prognostic information for PCa patients. Development of a panel of germline biomarkers with clinical utility for distinguishing patients at detection who have an increased risk for fatal PCa is warranted. PMID- 25273822 TI - Accuracy of a hexapod parallel robot kinematics based external fixator. AB - BACKGROUND: Different hexapod-based external fixators are increasingly used to treat bone deformities and fractures. Accuracy has not been measured sufficiently for all models. METHODS: An infrared tracking system was applied to measure positioning maneuvers with a motorized Precision Hexapod(r) fixator, detecting three-dimensional positions of reflective balls mounted in an L-arrangement on the fixator, simulating bone directions. By omitting one dimension of the coordinates, projections were simulated as if measured on standard radiographs. Accuracy was calculated as the absolute difference between targeted and measured positioning values. RESULTS: In 149 positioning maneuvers, the median values for positioning accuracy of translations and rotations (torsions/angulations) were below 0.3 mm and 0.2 degrees with quartiles ranging from -0.5 mm to 0.5 mm and 1.0 degrees to 0.9 degrees , respectively. CONCLUSIONS: The experimental setup was found to be precise and reliable. It can be applied to compare different hexapod-based fixators. Accuracy of the investigated hexapod system was high. PMID- 25273823 TI - Discrimination of familiarity and sex from chemical cues in the dung by wild southern white rhinoceros. AB - Communication in rhinos is primarily mediated by the vocal and olfactory signals as they have relatively poor eyesight. White rhinos are the most social of all the rhinoceros species, they defecate at common dungheaps and the adult bulls use dung and urine to mark their territory. Chemical communication may therefore be particularly important in the social interactions of white rhinos, and its knowledge could be very helpful in their management and conservation. However, no studies have investigated up until now the olfactory discrimination in any rhinoceros species in the wild. We have experimentally studied the reactions of the wild southern white rhinos (Ceratotherium simum) to the dung of familiar and unfamiliar adult females and adult territorial males. We registered the number of sniffing events, the duration of sniffing and the latency of the vigilance posture from the onset of sniffing. The dung of unfamiliar rhinos was sniffed longer than that of familiar rhinos. The rhinos showed a shorter latency of vigilance posture to the familiar dung of males than that of females. For unfamiliar dung, they displayed a shorter latency of vigilance posture to female than male dung. Our results indicate that the rhinos are able to discriminate the familiarity and sex of conspecifics from the smell of their dung. Olfactory cues could therefore play an important role in the social relationships and spatial organization of the southern white rhinoceros. PMID- 25273824 TI - Photochemistry of aldehyde clusters: cross-molecular versus unimolecular reaction dynamics. AB - The unimolecular photochemistry of aldehydes has been extensively studied, both experimentally and computationally. However, less is known about the role of cross-molecular photochemical processes in the condensed-phase photolysis of aldehydes. The triplet-state photochemistry of pentanal in its pentameric (n = 5) cluster was investigated as a model for photochemical reactions of aliphatic aldehydes in atmospheric aerosols. This study employs "on the fly" dynamics simulations using a semi-empirical MRCI electronic code for the singlet and triplet states involved. Previous studies have shown that the triplet-state photochemistry of an isolated pentanal molecule is dominated by Norrish I and II reactions. The main findings for the cluster are: (1) 55% of the trajectories lead to a unimolecular or cross-molecular reaction within a timescale of 100 ps; (2) cross-molecular reactions occur in over 70% of the reactive trajectories; (3) the main cross-molecular processes involve an H-atom transfer from the CHO group of the excited pentanal to an O atom of a nearby pentanal; and (4) the unimolecular Norrish II reaction is suppressed by the cluster environment. The predictions are qualitatively supported by experimental results on the condensed phase photolysis of an aliphatic aldehyde, undecanal. The computational approach should be useful for predicting the mechanisms of other condensed-phase organic photochemical reactions. These results demonstrate a major role of cross molecular processes in the condensed-phase photolysis of carbonyls. The cross molecular reactions discussed in this work are relevant to photolysis-driven processes in atmospheric organic aerosols. It is expected that the condensed phase environment of an organic aerosol particle should support a multitude of similar cross-molecular photochemical processes. PMID- 25273825 TI - Oxygen bubble-templated hierarchical porous epsilon-MnO2 as a superior catalyst for rechargeable Li-O2 batteries. AB - Nickel foam-supported epsilon-MnO2 is synthesized through an oxygen-bubble template-assisted electrodeposition route and is applied as a new cathode catalyst for Li-O2 batteries. Owing to the 3D macro/micro/nano (multiscale) porous architecture, the prepared electrode exhibits low overpotential, high rate capability, and superior cycling durability. PMID- 25273826 TI - Addressing unmet clinical needs: FISHing for bile duct cancer. PMID- 25273827 TI - Why is the General Ophthalmic Services (GOS) Contract that underpins primary eye care in the U.K. contrary to the public health interest? AB - The model for delivery of primary eye care in Europe varies from country to country with differing reliance on ophthalmologists, optometrists and dispensing opticians. Comparative analysis of models has tended to focus on interprofessional working arrangements, training and regulatory issues, rather than on whether a particular model is effective for delivering public health goals for that country. National Health Service (NHS) primary eye care services in the UK are predominantly provided under a General Ophthalmic Services (GOS) Contract between the NHS and practice owners (Contractors). Over two-thirds of sight tests conducted in England, Wales and Northern Ireland and all in Scotland are performed under a GOS Contract, however many people entitled to a GOS sight test do not take up their entitlement. The fee paid for sight tests conducted under a GOS Contract in England, Wales and Northern Ireland does not cover the full cost of conducting the examination. The shortfall must be made up through profits of sale of optical appliances but this business model can be a deterrent to establishing practices within socioeconomically deprived communities, and can also be a barrier to uptake of sight tests, even though many people are entitled to a NHS optical voucher towards the cost of spectacles or contact lenses. This paper critiques the GOS Contracts within the UK. We argue that aspects of the way the GOS Contract is implemented are contrary to the public health interest and that different approaches are needed to address eye health inequalities and to reduce preventable sight loss. PMID- 25273828 TI - Comparison of choroidal thicknesses using swept source and spectral domain optical coherence tomography in diseased and normal eyes. AB - BACKGROUND/AIMS: Choroidal thickness measurements are reported to differ between swept source optical coherence tomography (SS-OCT) and spectral domain OCT (SD OCT). This study aimed to assess the comparability of choroidal thickness measurements using SS-OCT and SD-OCT devices among patients with retinal diseases and normal participants. METHODS: In a prospective cohort study of 100 subjects, comprising patients with retinal disease and normal volunteers, OCT scans were performed sequentially with the DRI OCT-1 and Spectralis OCT using standardised imaging protocols. Subfoveal choroidal thicknesses were independently measured by masked reading-centre certified graders. Paired t tests and intraclass correlation coefficients (ICCs) were used to compare the measurements. RESULTS: Among all 100 participants, mean subfoveal choroidal thickness was 264.3 um and 272.4 um for DRI OCT-1 and Spectralis OCT respectively (p=0.001), with ICC of 0.989. The mean difference in choroidal thickness between OCT devices was larger among eyes with retinal diseases compared with normal eyes (8.4 um vs 7.3 um). Eyes with choroidal thickness <=200 um had smaller differences between OCT devices compared with those with thicker choroids (mean 3.6 um vs 10.0 um, p=0.021). CONCLUSIONS: Subfoveal choroidal thickness measurements are comparable between DRI OCT-1 and Spectralis OCT. The presence of retinal disease increases the variability of choroidal thickness measurements between OCT devices. PMID- 25273829 TI - Men with lower HDL cholesterol levels have significant increment of soluble CD40 ligand and high-sensitivity CRP levels following the cessation of long-term clopidogrel therapy. AB - AIM: The aim of this study was to examine whether the termination of long-term clopidogrel therapy results in a proinflammatory state and whether lipid parameters influence the inflammatory response after stopping the drug. METHODS: A prospective, multicenter study was conducted among 200 patients with implanted coronary stents who received dual antiplatelet therapy for one year, without ischemic or bleeding events. According to the guidelines, clopidogrel was discontinued after one year. In all patients, the high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand (sCD40L) and lipid [total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] levels were measured twice: on the day of cessation of clopidogrel and 45 days after the termination of clopidogrel treatment. RESULTS: In men (n=151), the sCD40L serum levels were significantly higher 45 days after the discontinuation of clopidogrel (p=0.007), while the hsCRP levels were not significantly different (p=0.407). Furthermore, when analyzed across the HDL-C quartiles, the hsCRP and sCD40L values were found to be associated with the levels of HDL-C after the discontinuation of clopidogrel in men. In addition, the men in the first HDL-C quartile exhibited the most pronounced increase in the sCD40L levels (p=0.001) and had significantly higher hsCRP levels (p=0.001) compared to the subjects in the other quartiles. Other lipid parameters did not show any associations with the sCD40L or hsCRP levels. CONCLUSIONS: The discontinuation of clopidogrel is associated with higher increments in the sCD40L level, and a pronounced proinflammatory response is associated with a lower HDL-C concentration. PMID- 25273830 TI - Mechanism of proanthocyanidins-induced alcoholic fermentation enhancement in Saccharomyces cerevisiae. AB - Our previous work revealed proanthocyanidins (PAs) could pose significant enhancement on the activity of H(+)-ATPase and fermentation efficiency after a transient initial inhibition (Li et al in Am J Enol Vitic 62(4):512-518, 2011). The aim of the present work was to understand the possible mechanism for this regulation. At Day 0.5 the gene expression level of PMA1 in AWRI R2 strain supplemented with 1.0 mg/mL PAs was decreased by around 54 % with a 50 % and a 56.5 % increase in the concentration of intracellular ATP and NADH/NAD(+) ratio, respectively, compared to that of control. After the transient adaptation, the gene expression levels of PMA1 and HXT7 in PAs-treated cells were enhanced significantly accompanied by the decrease of ATP contents and NADH/NAD(+) ratio, which resulted in the high level of the activities of rate-limiting enzymes. PAs could pose significant effects on the fermentation via glucose transport, the energy and redox homeostasis as well as the activities of rate-limiting enzymes in glycolysis. PMID- 25273831 TI - Population average T2 MRI maps reveal quantitative regional transformations in the degenerating rabbit intervertebral disc that vary by lumbar level. AB - Magnetic resonance imaging (MRI) with T2-weighting is routinely performed to assess intervertebral disc degeneration. Standard clinical evaluations of MR images are qualitative, however, and do not focus on region-specific alterations in the disc. Utilizing a rabbit needle puncture model, T2 mapping was performed on injured discs to develop a quantitative description of the degenerative process following puncture. To do so, an 18G needle was inserted into four discs per rabbit (L3/L4 to L6/L7) and T2 maps were generated pre- and 4 weeks post injury. Individual T2 maps were normalized to a disc-specific coordinate system and then averaged for pre- and post-injury population composite T2 maps. We also developed a method to automatically segment the nucleus pulposus by fitting the NP region of the T2 maps with modified 2-D and 3-D Gaussian distribution functions. Puncture injury produced alterations in MR signal intensity in a region-specific manner mirroring human degeneration. Population average T2 maps provided a quantitative representation of the injury response, and identified deviations of individual degenerate discs from the pre-injury population. We found that the response to standardized injury was modest at lower lumbar levels, likely as a result of increased disc dimensions. These tools will be valuable for the quantitative characterization of disc degeneration in future clinical and pre clinical studies. PMID- 25273833 TI - Coimmobilization of l-methioninase and glutamate dehydrogenase: Novel approach for L-homoalanine synthesis. AB - L-Homoalanine, a nonnatural amino acid that is rarely found in human and microorganisms, is used in the synthesis of various medically pivotal antiepileptic drugs and antituberculosis compounds. l-Homoalanine can be synthesized by different enzymatic approaches. In this article, the synthesis of l-homoalanine from l-methionine was explored by coimmobilization of Aspergillus flavipes l-methioninase (AfMETase) and glutamate dehydrogenase (GDH) on polyacrylamide and chitosan. Polyacrylamide coimmobilized AfMETase and GDH displayed a maximum reactivity for the synthesis of homoalanine from l methionine. The chitosan-coimmobilized AfMETase and GDH retain about 70% of their initial activity of l-homoalanine production by the fifth catalytic reusability cycle as compared with 50% for polyacrylamide coimmobilizate. Catalytic conditions were optimized for the maximum yield of homoalanine. Homoalanine was purified by cationic and anionic chromatographs and the proton nuclear magnetic resonance (H-NMR) analysis of the lyophilized sample displayed a unique chemical structure identical to the authentic homoalanine. Using dependable dual action of AfMETase and GDH immobilized on a solid support is a novel approach for in vitro enzymatic synthesis of l-homoalanine from l-methionine, and the immobilized enzymes can be reused many times without any significant loss of their activities. PMID- 25273832 TI - Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. AB - PURPOSE: Peptide receptor radionuclide therapy (PRRT) with (90)Y and (177)Lu provides objective responses in neuroendocrine tumours, and is well tolerated with moderate toxicity. We aimed to identify clinical parameters predictive of long-term renal and haematological toxicity (myelodysplastic syndrome and acute leukaemia). METHODS: Of 807 patients studied at IEO-Milan (1997-2013), 793 (98 %) received (177)Lu (278, 34.4 %), (90)Y (358, 44.4 %) or (177)Lu and (90)Y combined (157. 19.5 %), and 14 (2 %) received combinations of PRRT and other agents. Follow-up was 30 months (1-180 months). The parameters evaluated included renal risk factors, bone marrow toxicity and PRRT features. Data analysis included multiple regression, random forest feature selection, and recursive partitioning and regression trees. RESULTS: Treatment with (90)Y and (90)Y + (177)Lu was more likely to result in nephrotoxicity than treatment with (177)Lu alone (33.6 %, 25.5 % and 13.4 % of patients, respectively; p < 0.0001). Nephrotoxicity (any grade), transient and persistent, occurred in 279 patients (34.6 %) and was severe (grade 3 + 4) in 12 (1.5 %). In only 20-27 % of any nephrotoxicity was the disease modelled by risk factors and codependent associations (p < 0.0001). Hypertension and haemoglobin toxicity were the most relevant factors. Persistent toxicity occurred in 197 patients (24.3 %). In only 22-34 % of affected patients was the disease modelled by the clinical data (p < 0.0001). Hypertension (regression coefficient 0.14, p < 0.0001) and haemoglobin toxicity (regression coefficient 0.21, p < 0.0001) were pertinent factors. Persistent toxicity was associated with shorter PRRT duration from the first to the last cycle (mean 387 vs. 658 days, p < 0.004). Myelodysplastic syndrome occurred in 2.35 % of patients (modelled by the clinical data in 30 %, p < 0.0001). Platelet toxicity grade (2.05 +/- 1.2 vs. 0.58 +/- 0.8, p < 0.0001) and longer PRRT duration (22.6 +/- 24 vs. 15.5 +/- 9 months, p = 0.01) were relevant. Acute leukaemia occurred in 1.1 % of patients (modelled by the clinical data in 18 %, p < 0.0001). CONCLUSION: Identified risk factors provide a limited (<30 %) risk estimate even with target tissue dosimetry. These data strongly suggest the existence of unidentified individual susceptibilities to radiation-associated disease. PMID- 25273834 TI - Hepatitis C virus and interferon type III (interferon-lambda3/interleukin-28B and interferon-lambda4): genetic basis of susceptibility to infection and response to antiviral treatment. AB - There has been a significant increase in our understanding of the host genetic determinants of susceptibility to viral infections in recent years. Recently, two single-nucleotide polymorphisms (SNPs), rs12979860 T/C and rs8099917 T/G, upstream of the interleukin (IL)-28B/interferon (IFN)-lambda3 gene have been clearly associated with spontaneous and treatment-induced viral clearance in hepatitis C virus (HCV) infection. Because of their power in predicting the response to IFN/ribavirin therapy, the above SNPs have been used as a diagnostic tool, even though their relevance in the management of HCV infection will be blunt in the era of IFN-free regimens. The recent discovery of a new genetic variant, ss469415590 TT/DeltaG, upstream of the IL-28B gene, which generates the novel IFN-lambda4 protein, has opened up a new and alternative scenario to understand the functional architecture of type III IFN genomic regions and to improve our knowledge of the pathogenetic mechanism of HCV infection. A role of ss469415590 in predicting responsiveness to antiviral therapy has also been observed in HCV-infected patients receiving direct antiviral agents. The underlying biological mechanism that links the above IL-28B polymorphisms (in both IFN-lambda3 and IFN-lambda4) to spontaneous and treatment-induced clearance of HCV infection remains to be discovered. Despite this, shedding some light on this issue, which is the main aim of this review, may provide new insights into the general topic of 'host genetics and viral infections'. PMID- 25273835 TI - Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency. AB - Mutations in the co-chaperone Bcl2-associated athanogene 3 (BAG3) can cause myofibrillar myopathy (MFM), a childhood-onset progressive muscle disease, characterized by the formation of protein aggregates and myofibrillar disintegration. In contrast to other MFM-causing proteins, BAG3 has no direct structural role, but regulates autophagy and the degradation of misfolded proteins. To investigate the mechanism of disease in BAG3-related MFM, we expressed wild-type BAG3 or the dominant MFM-causing BAG3 (BAG3(P209L)) in zebrafish. Expression of the mutant protein results in the formation of aggregates that contain wild-type BAG3. Through the stimulation and inhibition of autophagy, we tested the prevailing hypothesis that impaired autophagic function is responsible for the formation of protein aggregates. Contrary to the existing theory, our studies reveal that inhibition of autophagy is not sufficient to induce protein aggregation. Expression of the mutant protein, however, did not induce myofibrillar disintegration and we therefore examined the effect of knocking down Bag3 function. Loss of Bag3 resulted in myofibrillar disintegration, but not in the formation of protein aggregates. Remarkably, BAG3(P209L) is able to rescue the myofibrillar disintegration phenotype, further demonstrating that its function is not impaired. Together, our knockdown and overexpression experiments identify a mechanism whereby BAG3(P209L) aggregates form, gradually reducing the pool of available BAG3, which eventually results in BAG3 insufficiency and myofibrillar disintegration. This mechanism is consistent with the childhood onset and progressive nature of MFM and suggests that reducing aggregation through enhanced degradation or inhibition of nucleation would be an effective therapy for this disease. PMID- 25273836 TI - Difficulties with emotion regulation in multiple sclerosis: Links to executive function, mood, and quality of life. AB - INTRODUCTION: Little is known about the influence of multiple sclerosis (MS) on the regulation of emotion. The current study tested whether people with MS report more emotion regulation difficulties than healthy controls. The relationship between emotion regulation and other important variables (mood, quality of life, and executive function) was explored. Mediation models were used to further understand the links between emotion regulation, depressed mood, and executive function in MS. METHOD: A total of 31 people with MS and 31 controls completed the Difficulties in Emotion Regulation Scales and measures of executive function (fluency and a go/no-go task), mood (Hospital Anxiety and Depression Scales), and a multidimensional assessment of quality of life (World Health Organization Quality of Life, brief version). RESULTS: People with MS reported experiencing more difficulties in emotion regulation than controls. Mediation analyses indicated that depression mediated the emotion regulation difficulties in MS, while executive dysfunction did not. Difficulties in emotion regulation predicted poorer psychological and social quality of life in MS, independent of problems with executive function. CONCLUSIONS: People with MS experience difficulties in emotion regulation, which predict poorer quality of life. These results indicate that emotional control skills should be investigated in further detail when considering interventions to enhance well-being in MS. PMID- 25273838 TI - A cost-effectiveness analysis of cell free DNA as a replacement for serum screening for Down syndrome. AB - OBJECTIVE: The aim of this article is to determine the cost effectiveness of cell free DNA (cfDNA) as a replacement for integrated screening using a societal cost perspective. METHOD: This study used Monte-Carlo simulation with one-way and probabilistic sensitivity analysis. RESULTS: Cell free DNA is more effective and less costly than integrated screening. The incremental cost-effectiveness ratio for cfDNA relative to the integrated test was -$277 955 per case detected (95th percent confidence interval -$881 882 to $532 785). CONCLUSION: Cell free DNA screening is a cost-effective replacement for maternal serum screening when the lifetime costs of Down syndrome live births are considered. The adoption of cfDNA screening would save approximately $277 955 for each additional case detected over integrated screening. PMID- 25273837 TI - Bleeding following coblation tonsillectomy: a 10-year, single-surgeon audit and modified grading system. AB - OBJECTIVE: Coblation tonsillectomy can be controversial. This study assessed post tonsillectomy haemorrhage outcomes for patients operated on by a single experienced coblation-trained ENT surgeon. STUDY DESIGN: A retrospective audit of coblation tonsillectomies was performed using the Flinders modification of Stammberger criteria for post-tonsillectomy haemorrhage. METHOD: Case note review, interview and database interrogation were utilised to obtain the dataset. Haemorrhage results were compared to reports in the current literature. RESULTS: Of those who underwent coblation tonsillectomy, 3.4 per cent were readmitted to hospital with haemorrhage and 1.3 per cent returned to the operating theatre (0.4 per cent primary haemorrhage and 0.9 per cent secondary haemorrhage). Younger children had a lower risk of returning to the operating theatre than older children or adults (0.3 per cent under the age of 12 years vs 2.0 per cent aged 12 years or older). CONCLUSION: Coblation can be a safe method for tonsillectomy with low complication rates when performed by an experienced ENT surgeon. The Flinders modification of the Stammberger criteria for post-tonsillectomy haemorrhage provides a simple system for data comparison. PMID- 25273839 TI - Adaptive motion artefact reduction in respiration and ECG signals for wearable healthcare monitoring systems. AB - Wearable healthcare monitoring systems (WHMSs) have received significant interest from both academia and industry with the advantage of non-intrusive and ambulatory monitoring. The aim of this paper is to investigate the use of an adaptive filter to reduce motion artefact (MA) in physiological signals acquired by WHMSs. In our study, a WHMS is used to acquire ECG, respiration and triaxial accelerometer (ACC) signals during incremental treadmill and cycle ergometry exercises. With these signals, performances of adaptive MA cancellation are evaluated in both respiration and ECG signals. To achieve effective and robust MA cancellation, three axial outputs of the ACC are employed to estimate the MA by a bank of gradient adaptive Laguerre lattice (GALL) filter, and the outputs of the GALL filters are further combined with time-varying weights determined by a Kalman filter. The results show that for the respiratory signals, MA component can be reduced and signal quality can be improved effectively (the power ratio between the MA-corrupted respiratory signal and the adaptive filtered signal was 1.31 in running condition, and the corresponding signal quality was improved from 0.77 to 0.96). Combination of the GALL and Kalman filters can achieve robust MA cancellation without supervised selection of the reference axis from the ACC. For ECG, the MA component can also be reduced by adaptive filtering. The signal quality, however, could not be improved substantially just by the adaptive filter with the ACC outputs as the reference signals. PMID- 25273841 TI - Localized and bound excitons in type-II ZnMnSe/ZnSSe quantum wells. AB - Photoluminescence of ZnMnSe/ZnSSe multiple quantum wells under a bandgap continuous wave and fs-pulsed excitations is measured in magnetic fields up to 10 T in Faraday geometry at temperatures within the range of 1.6-20 K. The measurements reveal two dominant lines in the spectra and LO-phonon replicas of the lower-energy line. The photoluminescence and time-resolved studies show dramatically different behaviour of the lines. Analysis of their properties reveals that they correspond to recombination of indirect localized excitons and indirect acceptor-bound excitons (A0X). Crossing of exciton and A0X lines because of the difference in magnitudes of their Zeeman shifts is observed. Analysis of LO-phonon replicas of photoluminescence lines provides additional evidence for strong carrier localization bound to A0X. A model of phonon-assisted recombination of indirect acceptor-bound excitons is proposed. The fitting of photoluminescence lines with this model gives the Huang-Rhys factor S?0.25 for A0X and the hole localization size ah?30 A. Contrary to expectations the exciton magnetic polaron effect is hardly observed in these structures. PMID- 25273840 TI - Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. AB - BACKGROUND: Protein synthesis is tightly regulated and alterations to translation are characteristic of many cancers.Translation regulation is largely exerted at initiation through the eukaryotic translation initiation factor 4 F (eIF4F). eIF4F is pivotal for oncogenic signaling as it integrates mitogenic signals to amplify production of pro-growth and pro-survival factors. Convergence of these signals on eIF4F positions this factor as a gatekeeper of malignant fate. While the oncogenic properties of eIF4F have been characterized, genome-wide evaluation of eIF4F translational output is incomplete yet critical for developing novel translation-targeted therapies. RESULTS: To understand the impact of eIF4F on malignancy, we utilized a genome-wide ribosome profiling approach to identify eIF4F-driven mRNAs in MDA-MB-231 breast cancer cells. Using Silvestrol, a selective eIF4A inhibitor, we identify 284 genes that rely on eIF4A for efficient translation. Our screen confirmed several known eIF4F-dependent genes and identified many unrecognized targets of translation regulation. We show that 5'UTR complexity determines Silvestrol-sensitivity and altering 5'UTR structure modifies translational output. We highlight physiological implications of eIF4A inhibition, providing mechanistic insight into eIF4F pro-oncogenic activity. CONCLUSIONS: Here we describe the transcriptome-wide consequence of eIF4A inhibition in malignant cells, define mRNA features that confer eIF4A dependence, and provide genetic support for Silvestrol's anti-oncogenic properties. Importantly, our results show that eIF4A inhibition alters translation of an mRNA subset distinct from those affected by mTOR-mediated eIF4E inhibition. These results have significant implications for therapeutically targeting translation and underscore a dynamic role for eIF4F in remodeling the proteome toward malignancy. PMID- 25273843 TI - SNP characteristics predict replication success in association studies. AB - Successful independent replication is the most direct approach for distinguishing real genotype-disease associations from false discoveries in genome-wide association studies (GWAS). Selecting SNPs for replication has been primarily based on P values from the discovery stage, although additional characteristics of SNPs may be used to improve replication success. We used disease-associated SNPs from more than 2,000 published GWASs to identify predictors of SNP reproducibility. SNP reproducibility was defined as a proportion of successful replications among all replication attempts. The study reporting association for the first time was considered to be discovery and all consequent studies targeting the same phenotype replications. We found that -Log(P), where P is a P value from the discovery study, is the strongest predictor of the SNP reproducibility. Other significant predictors include type of the SNP (e.g., missense vs intronic SNPs) and minor allele frequency. Features of the genes linked to the disease-associated SNP also predict SNP reproducibility. Based on empirically defined rules, we developed a reproducibility score (RS) to predict SNP reproducibility independently of -Log(P). We used data from two lung cancer GWAS studies as well as recently reported disease-associated SNPs to validate RS. Minus Log(P) outperforms RS when the very top SNPs are selected, while RS works better with relaxed selection criteria. In conclusion, we propose an empirical model to predict SNP reproducibility, which can be used to select SNPs for validation and prioritization. PMID- 25273842 TI - A comparison of type 2 diabetes risk allele load between African Americans and European Americans. AB - The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 +/- 4.0, mean +/- SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 +/- 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 * 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility. PMID- 25273844 TI - Epistemological beliefs and therapeutic health concepts of physiotherapy students and professionals. AB - BACKGROUND: Health knowledge develops fast and includes a lot of ambiguous or tentative information. In their daily routine, both health care students and professionals continuously have to make judgments about the viability of health knowledge. People's epistemological beliefs (EBs) and their therapeutic health concepts are factors that influence how they deal with health knowledge. However, very little is known about the occurrence of these factors at different stages of people's career. The present study examines the EBs and therapeutic health concepts of physiotherapy students in their vocational training and the EBs and therapeutic health concepts of professionals. METHODS: In a cross-sectional study physiotherapy students and professional physiotherapists filled in a questionnaire that measured their personal EBs about physiotherapy and medicine, as well as their biomedical and biopsychosocial therapeutic health concepts. We compared the participants' EBs regarding both knowledge domains, and their therapeutic health concepts using paired samples t-tests. We also examined the differences between first-year students, advanced students, and professionals regarding their EBs and their therapeutic health concepts using ANOVAs. RESULTS: Eighty-three students and 84 professionals participated in this study, 114/167 (68%) participants were female. EBs as well as therapeutic health concepts differed depending upon the participants' training status. Professionals had more sophisticated EBs than students regarding both knowledge in physiotherapy (F(2, 164) = 6.74, P = 0.002, eta(2)(p) = 0.08) and knowledge in medicine (F(2, 164) = 5.93, P = 0.003, eta(2)(p) = 0.07). In addition, high values in a biopsychosocial therapeutic health concept already occurred in an early phase of training (F(2, 164) = 5.39, P = 0.005, eta(2)(p) = 0.06), whereas increased values in a biomedical concept did not occur until people's professional life (F(2, 164) = 10.99, P < 0.001, eta(2)(p) = 0.12). CONCLUSIONS: The specificities of personal EBs and therapeutic health concepts in different stages of health care training have so far been insufficiently considered in medical education research. The current study has aimed to shed light on the occurrence of these concepts in students as compared to professionals. We point out implications of our findings for educational practice and make suggestions for future research. PMID- 25273846 TI - Elevated atmospheric CO2 impairs aphid escape responses to predators and conspecific alarm signals. AB - Research into the impact of atmospheric change on predator-prey interactions has mainly focused on density dependent responses and trophic linkages. As yet, the chemical ecology underpinning predator-prey interactions has received little attention in environmental change research. Group living animals have evolved behavioral mechanisms to escape predation, including chemical alarm signalling. Chemical alarm signalling between conspecific prey could be susceptible to environmental change if the physiology and behavior of these organisms are affected by changes in dietary quality resulting from environmental change. Using Rubus idaeus plants, we show that elevated concentrations of atmospheric CO2 (eCO2) severely impaired escape responses of the aphid Amphorophora idaei to predation by ladybird larvae (Harmonia axyridis). Escape responses to ladybirds was reduced by >50% after aphids had been reared on plants grown under eCO2. This behavioral response was rapidly induced, occurring within 24 h of being transferred to plants grown at eCO2 and, once induced, persisted even after aphids were transferred to plants grown at ambient CO2. Escape responses were impaired due to reduced sensitivity to aphid alarm pheromone, (E)-beta-farnesene, via an undefined plant-mediated mechanism. Aphid abundance often increases under eCO2, however, reduced efficacy of conspecific signalling may increase aphid vulnerability to predation, highlighting the need to study the chemical ecology of predator-prey interactions under environmental change. PMID- 25273845 TI - Cotton fiber elongation network revealed by expression profiling of longer fiber lines introgressed with different Gossypium barbadense chromosome segments. AB - BACKGROUND: Cotton fiber, a highly elongated, thickened single cell of the seed epidermis, is a powerful cell wall research model. Fiber length, largely determined during the elongation stage, is a key property of fiber quality. Several studies using expressed sequence tags and microarray analysis have identified transcripts that accumulate preferentially during fiber elongation. To further show the mechanism of fiber elongation, we used Digital Gene Expression Tag Profiling to compare transcriptome data from longer fiber chromosome introgressed lines (CSILs) containing segments of various Gossypium barbadense chromosomes with data from its recurrent parent TM-1 during fiber elongation (from 5 DPA to 20 DPA). RESULTS: A large number of differentially expressed genes (DEGs) involved in carbohydrate, fatty acid and secondary metabolism, particularly cell wall biosynthesis, were highly upregulated during the fiber elongation stage, as determined by functional enrichment and pathway analysis. Furthermore, DEGs related to hormone responses and transcription factors showed upregulated expression levels in the CSILs. Moreover, metabolic and regulatory network analysis indicated that the same pathways were differentially altered, and distinct pathways exhibited altered gene expression, in the CSILs. Interestingly, mining of upregulated DEGs in the introgressed segments of these CSILs based on D-genome sequence data showed that these lines were enriched in glucuronosyltransferase, inositol-1, 4, 5-trisphosphate 3-kinase and desulfoglucosinolate sulfotransferase activity. These results were similar to the results of transcriptome analysis. CONCLUSIONS: This report provides an integrative network about the molecular mechanisms controlling fiber length, which are mainly tied to carbohydrate metabolism, cell wall biosynthesis, fatty acid metabolism, secondary metabolism, hormone responses and Transcription factors. The results of this study provide new insights into the critical factors associated with cell elongation and will facilitate further research aimed at understanding the mechanisms underlying cotton fiber elongation. PMID- 25273847 TI - Prenatal diagnosis of haemophilia in Sweden now more commonly used for psychological preparation than termination of pregnancy. AB - The aims of the study were to define the frequency, outcome and reasons for prenatal diagnosis (PND) in Sweden during a 30-year period in order to study trends and changes. The study population, from the Swedish nationwide registry of PND of haemophilia, consisted of 54 women, compromising >95% of all, who underwent PND (n = 90) of haemophilia during 1977-2013. PND was performed by amniocentesis (n = 10), chorionic villus sampling (n = 64) or by analysis of foetal blood (n = 16). A total of 27/90 foetuses were found to have haemophilia. Sixteen went to termination and the remaining 11 were born during the end of the study period (2000-2013). Three of 90 pregnancies were terminated due to findings other than haemophilia and 3/90 PNDs led to miscarriage. In the 30 families with known haemophilia, PNDs (n = 55) were used in 27/55 cases for 'psychological preparation' and in 23/55 cases with the aim to terminate the pregnancy. A subgroup of women (n = 17) who consecutively underwent PND in the years 1997-2010 were further interviewed. For 11/17, being a carrier had a negative effect on the decision to become pregnant, and in 11 cases PND had influenced their decision to conceive. Our study show that PND of haemophilia is stable over time but increasingly used during the last decade as a psychological preparation for having a child with haemophilia as compared to earlier where more terminations of pregnancies were conducted. PMID- 25273848 TI - Health literacy and obesity among native Hawaiian and Pacific Islanders in the United States. AB - OBJECTIVES: Our purpose was to describe relationships between demographic characteristics, body mass index (BMI), and health literacy among Native Hawaiians and other Pacific Islanders (NHPIs). DESIGN AND SAMPLE: In this cross sectional survey, we interviewed 364 NHPI adults. MEASURES: We used Newest Vital Sign (NVS), a health literacy tool; measured heights and weights; and demographic questions. RESULTS: According to participants' NVS scores, 45.3% had at least a possibility of low health literacy. Lower NVS scores were associated with increased BMI (r = -0.12, p = .027) and increased age (r = -0.26, p < .001). Higher NVS scores were associated with higher incomes (r = 0.21, p = .001) and higher education (r = 0.27, p < .001). Women scored significantly better than men (t = -2.0, p = .05). Participants' NVS scores in Hawaii versus Utah were not significantly different (t = .26, p = .80). CONCLUSIONS: Pathways to health literacy are complex; however, age, income, education, and BMI explained a modest 19.95% of the combined variance in NVS scores. Public health nurses working to improve health literacy could include review of critical information on nutrition facts labels, frequently used calculations, and application of this information when making food choices. PMID- 25273849 TI - Copper(II)-mediated transformation of a tridentate non-innocent ligand into a tetradentate salen-type innocent ligand. AB - A non-innocent ligand, H4L(CH2NH2), was synthesized by introducing a -CH2NH2 group at the ortho carbon atom to the aniline moiety of 2-anilino-4,6-di-tert butylphenol. The new ligand was characterized by IR and NMR spectroscopy and mass spectrometry techniques. Upon treatment with CuCl2?2H2O, this non-innocent ligand provided a mononuclear four-coordinate salen-type Cu(II) complex by complete modification of the ligand backbone. The complex was characterized by IR spectroscopy, mass spectrometry, X-ray single-crystal diffraction, electron paramagnetic resonance (EPR) spectroscopy, and UV/Vis/near-IR spectroscopy techniques. X-ray crystallographic analysis showed an asymmetric environment around the Cu(II) center with a small (~12 degrees ) twist between the two biting planes. Analysis of the X-band EPR spectrum also supported the asymmetric environment and also indicated the presence of an unpaired electron on the dx2-y2 orbital. The UV/Vis/near-IR spectrum showed strong absorption bands for metal-to ligand charge transfer and ligand-to-metal charge transfer along with a Cu(II) centered d-d transition. Mechanistic investigation of the formation of complex 1 indicated that modification of the ligand backbone proceeded through ligand centered amine to imine oxidation as well as through C-N bond-breaking processes. During these processes, 3,5-di-tert-butyl-1,2-benzoquinone and 2-aminobenzylidene were produced. Ammonia, generated in situ through hydrolysis of the imine to the aldehyde, reacted with 3,5-di-tert-butyl-1,2-benzoquinone to form the corresponding 3,5-di-tert-butyl-1,2-iminobenzoquinone moiety, which upon two electron reduction in the reaction medium formed 3,5-di-tert-butyl-1,2 aminophenol. This aminophenol underwent condensation with the H2L5 ligand that was formed by self-condensation of two molecules of 2-aminobenzaldehyde and provided the modified ligand backbone. PMID- 25273850 TI - Individual social capital and survival: a population study with 5-year follow-up. AB - BACKGROUND: The concept of social capital has received increasing attention as a determinant of population survival, but its significance is uncertain. We examined the importance of social capital on survival in a population study while focusing on gender differences. METHODS: We used data from a Danish regional health survey with a five-year follow-up period, 2007-2012 (n = 9288, 53.5% men, 46.5% women). We investigated the association between social capital and all cause mortality, performing separate analyses on a composite measure as well as four specific dimensions of social capital while controlling for covariates. Analyses were performed with Cox proportional hazard models by which hazard ratios and 95% confidence intervals were calculated. RESULTS: For women, higher levels of social capital were associated with lower all-cause mortality regardless of age, socioeconomic status, health, and health behaviour (HR = 0.586, 95% CI = 0.421-0.816) while no such association was found for men (HR = 0.949, 95% CI = 0.816-1.104). Analysing the specific dimensions of social capital, higher levels of trust and social network were significantly associated with lower all-cause mortality in women (HR = 0.827, 95% CI = 0.750-0.913 and HR = 0.832, 95% CI = 0.729-0.949, respectively). For men, strong social networks were associated with a higher risk of all-cause mortality (HR = 1.132, 95% CI = 1.017-1.260). Civic engagement had a similar effect for both men (HR = 0.848, 95% CI = 0.722-0.997) and women (HR = 0.848, 95% CI = 0.630-1.140). CONCLUSIONS: We found differential effects of social capital in men compared to women. The predictive effects on all-cause mortality of four specific dimensions of social capital varied. Gender stratified analysis and the use of multiple indicators to measure social capital are thus warranted in future research. PMID- 25273852 TI - Automatische Impedantie Manometrie (AIM): objectieve diagnostiek van oro faryngale dysfagie. AB - AUTOMATED IMPEDANCE MANOMETRY (AIM): OBJECTIVE DIAGNOSIS OF OROPHARYNGEAL DYSPHAGIA: This review article aims to demonstrate the clinical potential of Automated Impedance Manometry (AIM) as a new, non-radiological technique for screening and diagnosis of oro-pharyngeal dysphagia. An integrated - rather than separate - analysis of pressure and impedance patterns generated in the pharynx when swallowing a food bolus, can be a useful complement to the radiological investigations considered as gold standard today. Major advantages are the objective nature of this technique and the fully automated calculation of various swallow parameters. A global measure of swallowing function can be derived (a Swallow Risk Index, SRI) and is related to (the severity of) the risk of aspiration and the presence of pharyngeal post-swallow residue. It was shown that aspiration on videofluoroscopy was accurately detected by using AIM with a sensitivity of 0.88 and a specificity of 0.96. AIM analysis can be performed quickly and is reliable in the hands of different end users. Various parameters are sufficiently sensitive to detect changes in bolus consistency and - as was recently found - are influenced by swallowing manoeuvers. Furthermore, different patterns of deviant swallow parameters can be found in different patient populations. Whether this observation can provide specific diagnoses and - as a consequence - more targeted treatments is currently under investigation. PMID- 25273853 TI - Teaching methods in community health nursing clerkships: experiences of healthcare staff in Iran. AB - PURPOSE: Healthcare staff educate nursing students during their clerkships at community health nursing programs. Their teaching methods play an important role in nursing students' acquisition of competencies; however, these methods have not been studied thoroughly. Thus, this study aims to describe, interpret, and understand the experiences of healthcare staff's teaching methods in clerkships at a community health nursing program. METHODS: This study was conducted using purposeful sampling and semi-structured interviews with 13 members of the staff of three urban healthcare centers in Iran. The data were analyzed through qualitative content analysis and thematic analysis. RESULTS: Multiplicity of teaching was identified as the main category of teaching method, and the five subcategories were teaching through lecture, demonstration, doing, visits and field trips, and readiness. The most common method used by the healthcare staff was lecturing. CONCLUSION: The healthcare staff used multiple methods to teach students in the nursing clerkship of the community health program, which was the strength of the course. However, they should be familiar with, and utilize additional methods, such as discussion rather than lecture. PMID- 25273855 TI - The unexpected flexibility of natural cellulose at a single-chain level and its implications to the design of nano materials. AB - At crystal or larger scales, natural cellulose was generally recognized to be a rigid material. Our single-chain mechanical measurements, however, reveal that the natural cellulose is as flexible as common synthetic polymers at the single chain level, creating new opportunities in the designing of nano materials. PMID- 25273851 TI - Ethnic differences translate to inadequacy of high-risk screening for gestational diabetes mellitus in an Asian population: a cohort study. AB - BACKGROUND: Universal and high-risk screening for gestational diabetes mellitus (GDM) has been widely studied and debated. Few studies have assessed GDM screening in Asian populations and even fewer have compared Asian ethnic groups in a single multi-ethnic population. METHODS: 1136 pregnant women (56.7% Chinese, 25.5% Malay and 17.8% Indian) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study were screened for GDM by 75-g oral glucose tolerance test (OGTT) at 26-28 weeks of gestation. GDM was defined using the World Health Organization (WHO) criteria. High-risk screening is based on the guidelines of the UK National Institute for Health and Clinical Excellence. RESULTS: Universal screening detected significantly more cases than high-risk screening [crude OR 2.2 (95% CI 1.7-2.8)], particularly for Chinese women [crude OR = 3.5 (95% CI 2.5-5.0)]. Pre-pregnancy BMI > 30 kg/m2 (adjusted OR = 3.4, 95% CI 1.5-7.9) and previous GDM history (adjusted OR = 6.6, 95% CI 1.2-37.3) were associated with increased risk of GDM in Malay women while GDM history was the only significant risk factor for GDM in Chinese women (adjusted OR = 4.7, 95% CI 2.0-11.0). CONCLUSION: Risk factors used in high-risk screening do not sufficiently predict GDM risk and failed to detect half the GDM cases in Asian women. Asian women, particularly Chinese, should be screened to avoid under diagnosis of GDM and thereby optimize maternal and fetal outcomes. PMID- 25273854 TI - Improvement of care for ICU patients with delirium by early screening and treatment: study protocol of iDECePTIvE study. AB - BACKGROUND: Delirium in critically ill patients has a strong adverse impact on prognosis. In spite of its recognized importance, however, delirium screening and treatment procedures are often not in accordance with current guidelines. This implementation study is designed to assess barriers and facilitators for guideline adherence and next to develop a multifaceted tailored implementation strategy. Effects of this strategy on guideline adherence as well as important clinical outcomes will be described. METHODS: Current practices and guideline deviations will be assessed in a prospective baseline measurement. Barriers and facilitators will be identified from a survey among intensive care health care professionals (intensivists and nurses) and focus group interviews with selected health care professionals (n=60). Findings will serve as a foundation for a tailored guideline implementation strategy. Adherence to the guideline and effects of the implementation strategies on relevant clinical outcomes will be piloted in a before-after study in six intensive care units (ICUs) in the southwest Netherlands. The primary outcomes are adherence to screening and treatment in line with the Dutch ICU delirium guideline. Secondary outcomes are process measures (e.g. attendance to training and knowledge) and clinical outcomes (e.g. incidence of delirium, hospital-mortality changes, and length of stay). Primary and secondary outcome data will be collected at four time points including at least 924 patients. Furthermore, a process evaluation will be done, including an economical evaluation. DISCUSSION: Little is known on effective implementation of delirium management in the critically ill. The proposed multifaceted implementation strategy is expected to improve process measures such as screening adherence in line with the guideline and may improve clinical outcomes, such as mortality and length of stay. This ICU Delirium in Clinical Practice Implementation Evaluation study (iDECePTIvE-study) will generate important knowledge for ICU health care providers on how to improve their clinical practice to establish optimum care for delirious patients. TRIALS REGISTRATION: Clinical Trials NCT01952899. PMID- 25273856 TI - Dose-response associations between cycling activity and risk of hypertension in regular cyclists: The UK Cycling for Health Study. AB - Most population studies on physical activity and health have involved largely inactive men and women, thus making it difficult to infer if health benefits occur at exercise levels above the current minimum guidelines. The aim was to examine associations between cycling volume and classical cardiovascular risk markers, including hypertension and hypercholesterolemia, in a population sample of habitual cyclists. A nationwide sample comprising 6949 men and women (aged 47.6 years on average) completed questions about their cycling levels, demographics and health. Nearly the entire sample (96.3%) achieved the current minimum physical activity recommendation through cycling alone. There was a dose response association between cycling volume and risk of diagnosed hypertension (P trend =0.001), with odds ratios of 0.98 (95% confidence interval (CI), 0.80 1.21), 0.86 (0.70, 1.06), 0.67 (95% CI, 0.53-0.83) across categories of 23-40, 40 61 and >61 metabolic equivalent hours/week (MET-h/week) compared with <23 MET h/week. These associations persisted in models adjusted for age, sex, smoking, alcohol, body mass index (BMI) and other moderatevigorous physical activities. We also observed inverse associations between cycling volume and other risk factors including BMI and hypercholesterolemia. In summary, results from a population sample of cyclists suggest that additional cardiovascular health benefits can be achieved beyond the current minimum physical activity recommendation. PMID- 25273857 TI - The impact of age on the benefits and risks of aliskiren treatment: analyses of the 3A registry. AB - We aimed to analyze benefits and risks of aliskiren treatment in older adults (? 65 years) in clinical practice. Patients (n = 14,986) were assigned to either aliskiren (ALIS), an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB), or an agent not blocking the renin-angiotensin system (non-RAS). Older adults (n = 7396) had a longer history of hypertension (8.7 vs 4.7 years; P < 0.0001), lower mean diastolic blood pressure (DBP; 87.7 +/ 11.0 vs 92.1 +/- 11.0 mm Hg) and more renal (12.0 vs 5.6%; P < 0.0001) or cardiovascular disease (44.0 vs 18.9%; P < 0.0001); 4548 received aliskiren (68.8%), 1215 ACEi/ARBs (18.4%) and 850 non-RAS treatments (12.9%). Office BP at 1 year was reduced by 18.4 +/- 21.5/7.2 +/- 12.0 mm Hg. BP reductions were greater (19.5 +/- 21.7/7.6 +/- 12.1 mm Hg) in the aliskiren group than in the ACEi/ARB (15.6 +/- 20.9/6.4 +/- 11.9) and non-RAS groups (16.1 +/- 20.7/6.5 +/- 11.7 mm Hg), respectively (P<0.0001 for systolic BP (SBP) and <0.01 for DBP). After multivariable adjustment, differences in SBP reductions were clinically irrelevant and no differences were noted for DBP. Adverse effects were higher in older adults with no differences between treatment groups. In conclusion, the present analysis of a large, unselected cohort of patients in clinical practice from the 3A study, offers real-life evidence of the effectiveness and safety of aliskiren for the treatment of hypertension in older adults. PMID- 25273858 TI - Hypertension prevalence, awareness, treatment and control in Germany 1998 and 2008-11. AB - Germany was reported to have higher blood pressure (BP) and lower awareness, treatment and control of BP than other western countries based on 1998 data. BP distribution and hypertension management were examined for 1998 and 2008-11 in 7108 adult participants of the German National Health Interview and Examination Survey 1998 (GNHIES98) and in 7095 adult participants the German Health Interview and Examination Survey for Adults 2008-11 (DEGS1) aged 18-79 years. Age- and sex standardized mean systolic BP (SBP) dropped from 129.0 to 124.1 mm Hg (women 127.3-120.8, men 130.7-127.4), mean diastolic BP (DBP) from 78.3 to 73.2 mm Hg (women 78.0-71.2, men 78.5-75.3). Mean SBP and DBP decreased most in treated hypertensives but were also lower in participants without hypertension. The overall prevalence of hypertension, including controlled hypertension, remained almost unchanged (30% vs 32%). Uncontrolled hypertension (BP?140/90 mm Hg) decreased from 23% to 15% (women 22-13%, men 24-18%). Among hypertensives, awareness increased from 69% to 82% (women 74-87%, men 65-78%), treatment increased from 55% to 72% (women 62-79%, men 48-65%) and control increased from 23% to 51% (women 25-58%, men 20-45%). However, men aged 18-29 years had an opposite trend with 1.5 mm Hg higher SBP and increased prevalence of hypertension, which was mostly uncontrolled. These findings suggest that BP has decreased substantially in Germany, while leaving a persistent gender gap in management and room for further improvement of prevention and treatment, particularly in men. PMID- 25273859 TI - Exercise blood pressure: clinical relevance and correct measurement. AB - Blood pressure (BP) is a mandatory safety measure during graded intensity clinical exercise stress testing. While it is generally accepted that exercise hypotension is a poor prognostic sign linked to severe cardiac dysfunction, recent meta-analysis data also implicate excessive rises in submaximal exercise BP with adverse cardiovascular events and mortality, irrespective of resting BP. Although more data is needed to derive submaximal normative BP thresholds, the association of a hypertensive response to exercise with increased cardiovascular risk may be due to underlying hypertension that has gone unnoticed by conventional resting BP screening methods. Delayed BP decline during recovery is also associated with adverse clinical outcomes. Thus, above and beyond being used as a routine safety measure during stress testing, exercise (and recovery) BP may be useful for identifying high-risk individuals and also as an aid to optimise care through appropriate follow-up after exercise stress testing. Accordingly, careful attention should be paid to correct measurement of exercise stress test BP (before, during and after exercise) using a standardised approach with trained operators and validated BP monitoring equipment (manual or automated). Recommendations for exercise BP measurement based on consolidated international guidelines and expert consensus are presented in this review. PMID- 25273860 TI - Uncontrolled hypertension is associated with coronary artery calcification and electrocardiographic left ventricular hypertrophy: a case-control study. AB - We conducted a 1:2 matched case-control study in order to evaluate whether the prevalence of coronary artery calcium (CAC) and electrocardiographic left ventricular hypertrophy (LVH) or strain was higher in patients with uncontrolled hypertension than in subjects from the general population, and evaluate the association between CAC and LVH in patients with uncontrolled hypertension. Cases were patients with uncontrolled hypertension, whereas the controls were random individuals from the general population without cardiovascular disease. CAC score was assessed using a non-contrast computed tomographic scan. LVH was evaluated using the Sokolow-Lyon voltage combination and Cornell voltage-duration product, respectively. Associations between CAC, LVH and traditional cardiovascular risk factors were tested by means of ordinal, conditional and classic binary logistic regression models. We found that uncontrolled hypertension was independently associated with both an ordinal CAC score category (odds ratio (OR) 3.9 (95% CI, 1.6-9.1), P = 0.002), the presence of CAC score>99 (OR 4.5 (95% CI, 1.4-14.7), P = 0.01) and electrocardiographic LVH (OR 10.1 (95% CI, 3.4-30.2), P < 0.001) on both univariate and multivariable analyses. There was, however, no correlation between CAC and LVH. The lack of an association between CAC and LVH suggests that they are markers of different complications of hypertension and may have independent predictive values. Patients with both CAC and LVH may be at higher risk than those in whom only one of these markers is present. PMID- 25273861 TI - Assessment of toxic elements in the samples of different cigarettes and their effect on the essential elemental status in the biological samples of Irish hypertensive consumers. AB - Cigarette smoking causes an acute increase in blood pressure and heart rate and has been found to be associated with malignant hypertension (HT). A significant flux of toxic metals among other toxins reaches the lungs through smoking. In the present study, the relationship between essential (zinc and selenium) and toxic element (TE; cadmium and mercury) and HT incidence in smoker and nonsmoker population living in Dublin, Ireland was investigated. The zinc (Zn), selenium (Se), cadmium (Cd) and mercury (Hg) were determined in biological (scalp hair and blood) samples of smoker and nonsmoker hypertensive patients. For comparison purposes, healthy age- and sex-matched subjects as referents residing in the same city were also selected. The different brands of cigarette consumed by the studied population were also analyzed for Cd and Hg. The concentrations of essential trace and TEs in all studied samples were measured by inductively coupled plasma atomic emission spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology was checked using certified reference materials (CRMs). The recovery of all the studied elements was found to be in the range of 96.4-99.7% of certified values of CRMs. The filler tobacco of different branded cigarettes contains Hg and Cd concentrations in the range of 9.55-12.4 ng and 1.70-2.12 MUg per cigarette, respectively. The results of this study showed that the mean values of Cd and Hg were significantly higher in scalp hair and blood samples of hypertensive patients as compared with healthy controls, whereas Zn and Se concentrations were found to be lower in hypertensive patients, the difference was significant in the case of smoker patients (P < 0.001). The levels of both TEs were 2-3-folds higher in scalp hair and blood samples of nonhypertensive smoker subjects as compared with nonsmoker controls. It was observed that exposure of TEs via cigarette smoking may be synergistic with other risk factors associated with HT. PMID- 25273862 TI - Influence of outliers on accuracy estimation in genomic prediction in plant breeding. AB - Outliers often pose problems in analyses of data in plant breeding, but their influence on the performance of methods for estimating predictive accuracy in genomic prediction studies has not yet been evaluated. Here, we evaluate the influence of outliers on the performance of methods for accuracy estimation in genomic prediction studies using simulation. We simulated 1000 datasets for each of 10 scenarios to evaluate the influence of outliers on the performance of seven methods for estimating accuracy. These scenarios are defined by the number of genotypes, marker effect variance, and magnitude of outliers. To mimic outliers, we added to one observation in each simulated dataset, in turn, 5-, 8-, and 10 times the error SD used to simulate small and large phenotypic datasets. The effect of outliers on accuracy estimation was evaluated by comparing deviations in the estimated and true accuracies for datasets with and without outliers. Outliers adversely influenced accuracy estimation, more so at small values of genetic variance or number of genotypes. A method for estimating heritability and predictive accuracy in plant breeding and another used to estimate accuracy in animal breeding were the most accurate and resistant to outliers across all scenarios and are therefore preferable for accuracy estimation in genomic prediction studies. The performances of the other five methods that use cross validation were less consistent and varied widely across scenarios. The computing time for the methods increased as the size of outliers and sample size increased and the genetic variance decreased. PMID- 25273864 TI - Validation of triaxial accelerometers to measure the lying behaviour of adult domestic horses. AB - Examining the characteristics of an animal's lying behaviour, such as frequency and duration of lying bouts, has become increasingly relevant for animal welfare research. Triaxial accelerometers have the advantage of being able to continuously monitor an animal's standing and lying behaviour without relying on live observations or video recordings. Multiple models of accelerometers have been validated for use in monitoring dairy cattle; however, no units have been validated for use in equines. This study tested Onset Pendant G data loggers attached to the hind limb of each of two mature Standardbred horses for a period of 5 days. Data loggers were set to record their position every 20 s. Horses were monitored via live observations during the day and by video recordings during the night to compare activity against accelerometer data. All lying events occurred overnight (three to five lying bouts per horse per night). Data collected from the loggers was converted and edited using a macro program to calculate the number of bouts and the length of time each animal spent lying down by hour and by day. A paired t-test showed no significant difference between the video observations and the output from the data loggers (P=0.301). The data loggers did not distinguish standing hipshot from standing square. Predictability, sensitivity, and specificity were all >99%. This study has validated the use of Onset Pendant G data loggers to determine the frequency and duration of standing and lying bouts in adult horses when set to sample and register readings at 20 s intervals. PMID- 25273863 TI - Revised annotations, sex-biased expression, and lineage-specific genes in the Drosophila melanogaster group. AB - Here, we provide revised gene models for D. ananassae, D. yakuba, and D. simulans, which include untranslated regions and empirically verified intron-exon boundaries, as well as ortholog groups identified using a fuzzy reciprocal-best hit blast comparison. Using these revised annotations, we perform differential expression testing using the cufflinks suite to provide a broad overview of differential expression between reproductive tissues and the carcass. We identify thousands of genes that are differentially expressed across tissues in D. yakuba and D. simulans, with roughly 60% agreement in expression patterns of orthologs in D. yakuba and D. simulans. We identify several cases of putative polycistronic transcripts, pointing to a combination of transcriptional read-through in the genome as well as putative gene fusion and fission events across taxa. We furthermore identify hundreds of lineage specific genes in each species with no blast hits among transcripts of any other Drosophila species, which are candidates for neofunctionalized proteins and a potential source of genetic novelty. PMID- 25273865 TI - Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases' occurrence. AB - Germ line deleterious mutations of BRCA1 gene are not the unique factor that could inactivate BRCA1 protein which leads to familial breast cancer onset with distant metastases' occurrence. The present research explores the role that could be assigned to BRCA1 SNPs to inactivate BRCA1 protein and therefore to the occurrence of familial breast cancer with an increased risk of distant metastases' occurrence. The presence or the absence of BRCA1 protein was first analyzed by applying the immunohistochemistry technique to the tumors with sporadic and familial breast cancer. Then, a case-control study was conducted including 40 patients with familial breast cancer, 46 ones with sporadic breast cancer and 34 healthy controls based on the genotyping of nine BRCA1 SNPs (c.442.58delT, c.2082C>T, c.2311T>C, c.2612C>T, c.3113A>G, c.3119G>A, c.3548A>G, c.4308T>C and 4837A>G) via direct sequencing. Finally, the functional role that could be assigned to these SNPs was focused upon. miRbase site was used as a bioinformatics tool to predict potential micro-RNAs (miRs) targeting SNPs that are associated with familial breast cancer according to the results of this research. These predicted miRs were confirmed by Q-PCR analysis and correlated with BRCA1 protein expression among patients along with potential distant metastases. Clinical outcome showed that distant metastasis concerned 45 % of familial breast cancer patients and 19.5 % with sporadic breast cancer. Analysis of BRCA1 protein expression revealed a negative staining among 46.6 % of familial breast cancer patients and only 16.6 % within sporadic breast cancer ones. The association of four variants was identified within BRCA1 gene (c.442.58 delT, c.2311T>C, c.2612C>T and c.4308T>C) to familial breast cancer across their wild genotypes. miR-1179 was selected as potential miR that targets the region of BRCA1 mRNA containing the c.2311T>C variant within the TT genotype. The expression of miR-1179 was significantly associated with familial breast cancer patients without BRCA1 deleterious mutations compared to those with sporadic breast cancer according to TT genotype along with BRCA1 negative staining and according to the occurrence of distant metastases. Combination between TT genotype of c.2311T>C and miR-1179 over-expression could generate a lack of BRCA1 protein leading to a high risk of familial breast cancer with distant metastases. PMID- 25273867 TI - [Alumni-what is it then?]. PMID- 25273866 TI - Pre-treatment neutrophil-to-lymphocyte ratio affects survival in patients with advanced hepatocellular carcinoma treated with sorafenib. AB - Sorafenib is the first systemic therapy to demonstrate survival benefit in advanced hepatocellular carcinoma (HCC) in randomized controlled trials with rigorous patient selection. Neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with poor survival in various solid tumors. Our aim is to evaluate the prognostic role of NLR in HCC patients treated with sorafenib. A total of 105 advanced HCC patients treated with sorafenib were retrospectively reviewed, and relevant data from the clinical records were collected. Univariate and multivariate analysis were carried out to identify factors associated with survival. The median age of the cohort was 59.7 years, and 84.8 % were Child-Pugh class A, and 86.7 % had ECOG performance status 0 or 1. Median duration of sorafenib treatment was 100 days. Median overall survival (OS) of the entire cohort was 8.03 months. Median OS was 5.23 months (95 % CI 2.96-7.50 months) and 10.05 months (95 % IC 2.52-18.47 months) for patients with NLR > 3.5 and NLR <= 3.5, respectively (p = 0.002). Alpha-fetoprotein >1,030 ng/mL and serum albumin <=3.8 g/dL were also associated with worse prognosis (p = 0.006 and p = 0.042, respectively). The subgroup of patients with high alpha-fetoprotein, low albumin and NLR > 3.5 had median OS of 1.7 months, whereas the subgroup with none of these parameters had median OS of 16.5 months (p < 0.001). NLR affects survival in advanced HCC patients treated with sorafenib. Selecting HCC patients based on the laboratorial features may improve the therapeutic effectiveness of sorafenib. PMID- 25273868 TI - [Cost-benefit analysis of an intervention to improve udder health in Swiss dairy farms]. AB - The objective of this study was to calculate the national costs associated with udder health in Switzerland and to estimate the cost effectiveness of an udder health intervention program. In 49 farms, yearly mastitis associated costs before and during an intervention were collected at herd level. Costs were calculated for each lactating cow being present in the herd. At the beginning of the intervention, 24 farms received a report with recommendations to improve the udder health. In the following year, those herds were followed-up by their veterinarian at a monthly basis. The other 25 farms were used as a negative control group and neither received any recommendations nor any follow-up. In the first year of analysis (2010), the median udder health associated costs were 209. Swiss Francs for each lactating cow, regardless of the intervention group. During the intervention period (2012), mastitis associated costs were 191.- Swiss Francs for control farms and 396.- Swiss Francs for farms with veterinary intervention on a monthly basis. The median additional costs for herds with intervention were 159.- Swiss Francs per lactating cow. At the national level, mastitis associated costs were estimated at 129.4 millions of Swiss Francs per year. The cost effectiveness of future mastitis control programs can be evaluated with the help of the deterministic model developed during this study. PMID- 25273869 TI - Antimicrobial susceptibility of mastitis pathogens of dairy cows in Switzerland. AB - This study evaluates the antimicrobial resistance of pathogens cultured from 3'954 quarter milk samples from dairy cows in Switzerland. A total of 1'228 Streptococcus (Strep.) uberis, 1'107 Staphylococcus (Staph.) spp. other than Staph. aureus, 598 coliform, 490 Staph. aureus, 270 Enterococcus spp. and 213 Strep. dysgalactiae isolates were tested for susceptibility to 9 antimicrobial drugs using agar diffusion. Streptococcus uberis, Strep. dysgalactiae and Staph. aureus had the highest antimicrobial sensitivities to amoxicillin clavulanic acid (99.6 %, 100 % and 98.8 %, respectively). Of all isolated pathogens, only 2.6 % were resistant to amoxicillin clavulanic acid and 8.0 % to cefoperazone. The overall resistance level to gentamicin was 45.5 %, to penicillin 39.2 %, and to ampicillin 26.7 %. The highest resistance levels occurred with polymyxin (86.0 %), oxacillin (64.7 %) and lincomycin (53.7 %). Our results showed that at least one resistance exists to one antimicrobial agent examined in this study. Ideally the selection of the antibacterial drug for the treatment of intramammary infection should be based on antibiotic susceptibility testing. PMID- 25273870 TI - Computed tomography of the thorax in calves from birth to 105 days of age. AB - The present study was undertaken to provide computed tomographic (CT) reference values for structures in the thorax of the calf. Six clinically healthy Holstein Friesian calves were anaesthetized. Transverse pre- and postcontrast images with a reconstructed 1.5-mm slice thickness were obtained using a multislice-CT scanner at 6 different time points from birth to 105 days of age. Absolute and relative measurements of the trachea, heart, cranial and caudal vena cava, thoracic aorta, right and left principal bronchi, right and left caudal lobar bronchi and the accompanying branches of the right and left pulmonary artery and vein, thoracic lymph nodes and lung density were taken for every time point. All animals were euthanized after the last CT scan, and 4 calves were frozen to generate an atlas comparing gross anatomy with CT. During the study, 4 animals temporarily showed coughing and mucopurulent nasal discharge, and mild to moderate bronchopneumonia and pleuritis were diagnosed using CT. Animals recovered with treatment; however, mild to moderate CT changes remained throughout the study. Even in the 2 clinically normal animals, mild bronchopneumonia was diagnosed on CT. PMID- 25273871 TI - Pneumonia associated with Salmonella spp. infection in a cat receiving cyclosporine. AB - Salmonellosis is uncommon in cats, usually affects the gastrointestinal tract or skin, and can be fatal. This report describes a domestic shorthair cat with severe pneumonia caused by Salmonella spp. without accompanying gastrointestinal or skin manifestations, in which previous administration of cyclosporine may have played a permissive role in its development. Clinical and laboratory findings as well as follow-up are described from diagnosis until complete recovery. This unusual presentation serves to alert practitioners to consider Salmonella spp. as a possible cause of lung disease in cats, especially if immunocompromised. PMID- 25273875 TI - Rapid, highly sensitive detection of herpes simplex virus-1 using multiple antigenic peptide-coated superparamagnetic beads. AB - A sensitive, rapid, and label free magnetic bead aggregation (MBA) assay has been developed that employs superparamagnetic (SPM) beads to capture, purify, and detect model proteins and the herpes simplex virus (HSV). The MBA assay is based on monitoring the aggregation state of a population of SPM beads using light scattering of individual aggregates. A biotin-streptavidin MBA assay had a femtomolar (fM) level sensitivity for analysis times less than 10 minutes, but the response of the assay becomes nonlinear at high analyte concentrations. A MBA assay for the detection of HSV-1 based on a novel peptide probe resulted in the selective detection of the virus at concentrations as low as 200 viral particles (vp) per mL in less than 30 min. We define the parameters that determine the sensitivity and response of the MBA assay, and the mechanism of enhanced sensitivity of the assay for HSV. The speed, relatively low cost, and ease of application of the MBA assay promise to make it useful for the identification of viral load in resource-limited and point-of-care settings where molecular diagnostics cannot be easily implemented. PMID- 25273877 TI - [Efficacy of intra-articular injection of PRP]. PMID- 25273876 TI - Alteration in chondroitin sulfate proteoglycan expression at the epicenter of spinal cord is associated with the loss of behavioral function in Tiptoe walking Yoshimura mice. AB - The objective of this study was to explore the correlation between the alteration in chondroitin sulfate proteoglycan (CSPG) expression at the epicenter of spinal cord and the loss of behavioral function in tiptoe walking Yoshimura mice. The tiptoe walking Yoshimura mice (twy) and Institute of Cancer Research (ICR) mice, aged 20 and 26 weeks, were used in the present study. The behavior assessment, micro-computed tomography and immunofluorescent staining were performed. The compressed spinal cord was histologically analyzed. The results showed that the expression of CSPG was statistically higher at the compressed spinal cord for twy mice compared with that at the normal spinal cord for ICR mice. At the 26th week, a large ossification block at the posterior longitudinal ligament of C1-3 was obviously observed at the micro-CT image We observed the BMS Score was significantly correlated with the expression of glial fibrillary acidic protein, CSPG and hyaluronan (P < 0.05). These findings suggest that compression injury induces the higher CSPG expression at the compressed spinal cord in the twy mice. Furthermore, the alteration in CSPG expression at the epicenter of spinal cord is associated with the loss of behavioral function in twy mice. PMID- 25273878 TI - Clinical practice guideline: tinnitus. AB - OBJECTIVE: Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient's quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. PURPOSE: The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. ACTION STATEMENTS: The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (>= 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (>= 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus. PMID- 25273879 TI - Antibodies reacting with JCPyV_VP2 _167-15mer as a novel serological marker for JC polyomavirus infection. AB - BACKGROUND: JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host, but can be reactivated under immune compromised conditions potentially causing Progressive Multifocal Leukoencephalopathy (PML). Detection of antibodies against the major capsid protein VP1 currently is the main marker for assessment of infection with JCPyV. METHODS: Based on a peptide microarray, peptide JCPyV_VP2_167-15mer was selected and a peptide ELISA was developed for detection of antibodies directed against this peptide. Epitope mapping and computational modelling was performed to further characterize this peptide. In a cohort of 204 healthy subjects it was investigated whether antibodies against JCPyV_VP2_167-15mer were correlated with VP1 serology or urinary viral load. RESULTS: Epitope mapping of peptide JCPyV_VP2_167-15mer showed that the minimal epitope consisted of L173PALTSQEI181 with amino acids P174, L176 and E180 being essential for antibody recognition. Computational analysis was used to predict that this epitope is located at an exposed domain of the VP2 capsid protein, readily accessible for immune recognition upon infection. No correlation could be observed with JCPyV VP1 antibody levels, or urinary viral load. CONCLUSION: This work indicates that specific antibodies against JCPyV_VP2_167-15mer might be considered as a novel serological marker for infection with JCPyV. PMID- 25273881 TI - In cerebrovascular circadian rhythms, EETs keep the beat. Focus on "Rhythmic expression of cytochrome P450 epoxygenases CYP4x1 and CYP2c11 in the rat brain and vasculature". PMID- 25273882 TI - A blood-bud barrier. Focus on "A permeability barrier surrounds taste buds in lingual epithelia". PMID- 25273880 TI - Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes. AB - Dysfunction of macrophages (MPhis) in diabetic wounds impairs the healing. MPhis produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by MPhis and the actions of NPD1 on diabetic MPhi functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, MPhi depletion, MPhis isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of MPhis in NPD1 biosynthesis, and NPD1 action on diabetic MPhi inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated MPhis from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by MPhis. NPD1 enhanced wound healing and innervation in diabetic mice and promoted MPhis functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated MPhis involved 1) attenuating MPhi inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing MPhi production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a MPhis-produced factor that accelerates diabetic wound healing and promotes MPhi pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic MPhis for treatment of diabetic wounds. PMID- 25273883 TI - Induction of angiotensin-converting enzyme after miR-143/145 deletion is critical for impaired smooth muscle contractility. AB - MicroRNAs have emerged as regulators of smooth muscle cell phenotype with a role in smooth muscle-related disease. Studies have shown that miR-143 and miR-145 are the most highly expressed microRNAs in smooth muscle cells, controlling differentiation and function. The effect of miR-143/145 knockout has been established in the vasculature but not in smooth muscle from other organs. Using knockout mice we found that maximal contraction induced by either depolarization or phosphatase inhibition was reduced in vascular and airway smooth muscle but maintained in the urinary bladder. Furthermore, a reduction of media thickness and reduced expression of differentiation markers was seen in the aorta but not in the bladder. Supporting the view that phenotype switching depends on a tissue specific target of miR-143/145, we found induction of angiotensin-converting enzyme in the aorta but not in the bladder where angiotensin-converting enzyme was expressed at a low level. Chronic treatment with angiotensin type-1 receptor antagonist restored contractility in miR-143/145-deficient aorta while leaving bladder contractility unaffected. This shows that tissue-specific targets are critical for the effects of miR-143/145 on smooth muscle differentiation and that angiotensin converting enzyme is one such target. PMID- 25273885 TI - Risk factors for mortality in patients with non-traumatic pontine hemorrhage. AB - OBJECTIVES: For patients with non-traumatic pontine hemorrhage (PH) who will survive, determining prognosis is vital for appropriate therapeutic planning in the acute stage. This study aimed to determine reliable prognostic factors of mortality in patients with PH. MATERIALS AND METHODS: The cases of a total of 118 consecutive PH patients were reviewed. We compared clinical and radiological characteristics between patients who died and survivors by the log-rank test and performed multivariate analysis by the Cox proportional hazards model using variables that were marginally or significantly associated with PH-related death on the log-rank test (P < 0.20). RESULTS: The median length of follow-up was 51 days (interquartile range: 7-742 days). Sixty-six patients (56%) died and 52 (44%) survived during follow-up period. Multivariate analysis showed that Glasgow Coma Scale score <9, hyperthermia (a core temperature of >=39 degrees C), maximum hematoma diameter more than 27 mm, and hematoma extension to midbrain and/or thalamus were significantly related to PH-related death. The Kaplan-Meier method showed that patients without these four factors had successively longer period at PH-related death (21 patients without factors: mean 2900 days; 97 patients with at least one of four factors: mean 820 days). CONCLUSIONS: Promptly identifying PH patients who are most likely die is important. The decision to stop life support in patients with PH is difficult, but factors, which are shown in this study, may be used to determine the level of care. PMID- 25273884 TI - From microbe to man: the role of microbial short chain fatty acid metabolites in host cell biology. AB - Recent studies have highlighted a myriad of ways in which the activity and composition of the gut microbiota can affect the host organism. A primary way in which the gut microbiota affect host physiology is by the production of metabolites, such as short-chain fatty acids (SCFAs), which are subsequently absorbed into the bloodstream of the host. Although recent studies have begun to unravel the ways in which gut microbial SCFAs affect host physiology, less is understood regarding the underlying cell biological mechanisms. In this review, we will outline the known receptors and transporters for SCFAs, and review what is known about the cell biological effects of microbial SCFAs. PMID- 25273887 TI - Safeguarding children: a challenge to doctors. PMID- 25273886 TI - Paravalvular regurgitation after transcatheter aortic valve replacement with the Edwards sapien valve in the PARTNER trial: characterizing patients and impact on outcomes. AB - AIM: The impact of paravalvular regurgitation (PVR) following transcatheter aortic valve replacement (TAVR) remains uncertain. In this analysis, we sought to evaluate the impact of varying degrees of PVR on both mortality and changes in ventricular geometry and function. METHODS AND RESULTS: Clinical and echocardiographic outcomes of patients who underwent TAVR from the randomized cohorts and continued access registries in the PARTNER trial were analysed after stratifying by severity of post-implant PVR, which was graded as none/trace in 52.9% (n = 1288), mild in 38.0% (n = 925), and moderate/severe in 9.1% (n = 221). There were significant differences in baseline clinical and echocardiographic characteristics. After TAVR, all the patients demonstrated increase in left ventricular (LV) function and reduction in the LV mass index, although the magnitude of mass regression was lower in the moderate/severe PVR group. The 30 day mortality (3.1 vs. 3.4 vs. 4.5%, P = 0.56) and stroke (3.4 vs. 3.7 vs. 2.3%, P = 0.59) were similar in all groups (none/trace, mild, and moderate/severe). At 1 year, there was increased all-cause mortality (15.9 vs. 22.2 vs. 35.1%, P < 0.0001), cardiac mortality (6.1 vs. 7.4% vs. 16.3%, P < 0.0001) and re hospitalization (14.4 vs. 23.0 vs. 31.3%, P < 0.0001) with worsening PVR. A multivariable analysis indicated that the presence of moderate/severe PVR (HR: 2.18, 95% CI: 1.57-3.02, P < 0.0001) or mild PVR (HR: 1.37, 95% CI: 1.14-1.90, P = 0.012) was associated with higher late mortality. CONCLUSION: Differences in baseline characteristics in patients with increasing severities of PVR may increase the risk of this complication. Despite these differences, multivariable analysis demonstrated that both mild and moderate/severe PVR predicted higher 1 year mortality. PMID- 25273889 TI - Prevalence of energy intake misreporting in Malay children varies based on application of different cut points. AB - This study aimed to identify the prevalence of energy misreporting amongst a sample of Malay children aged 9-11 years (n = 14) using a range of commonly used cut points. Participants were interviewed using repeated 24 h dietary recalls over three occasions. The Goldberg equations (1991 and 2000), Torun cut points and the Black and Cole method were applied to the data. Up to 11 of 14 children were classified as misreporters, with more under-reporters (between seven and eight children) than over-reporters (four or less children). There were significant differences in the proportion of children classified as energy misreporters when applying basal metabolic rate calculated using FAO/UNU/WHO (1985) and Malaysian-specific equations (p < 0.05). The results show that energy misreporting is common amongst Malay children, varying according to cut point chosen. Objective evaluation of total energy expenditure would help identify which cut point is appropriate for use in Malay paediatric populations. PMID- 25273888 TI - Toward eradication: the effect of Mycobacterium bovis infection in wildlife on the evolution and future direction of bovine tuberculosis management in New Zealand. AB - New Zealand's bovine tuberculosis (TB) control programme has greatly reduced the burden of tuberculosis on the farming industry, from 11% of mature cattle found with TB at slaughter in 1905 to <0.003% in 2012/13. New Zealand implemented TB control measures in cattle from the mid-twentieth century, and later in farmed deer. Control was based on established methods of tuberculin testing of herds, slaughter of suspect cases, and livestock movement control. Unexplained regional control failures and serious disease outbreaks were eventually linked to wildlife vectored infection from the introduced Australian brushtail possum (Trichosurus vulpecula), which also triggered a wildlife disease complex involving a range of introduced species. This paper reviews the progressive elucidation of the epidemiology of Mycobacterium bovis in New Zealand's wildlife and farmed livestock, and the parallel development of research-led, multi-faceted TB control strategies required to protect New Zealand's livestock industries from damaging infection levels. The adoption of coordinated national pest management strategies, with increasingly ambitious objectives agreed between government and industry funders, has driven a costly but very successful management regime targeted at controlling TB in the possum maintenance host. This success has led to initiation of a strategy designed to eradicate TB from New Zealand's livestock and wildlife, which is considered a realistic long-term prospect. PMID- 25273890 TI - Is a foetus developing in a sterile environment? AB - Novel findings in microbiology question the long-standing paradigm that a healthy pregnancy implies a sterile uterus. It now seems that the placenta is frequently colonized with bacteria, and a placental microbiome has been identified. Recent literature findings are summarized here, and an attempt is made to separate pathological bacterial presence from a naturally occurring microbiome. PMID- 25273891 TI - Copper suppresses abscisic acid catabolism and catalase activity, and inhibits seed germination of rice. AB - Although copper (Cu) is an essential micronutrient for plants, a slight excess of Cu in soil can be harmful to plants. Unfortunately, Cu contamination is a growing problem all over the world due to human activities, and poses a soil stress to plant development. As one of the most important biological processes, seed germination is sensitive to Cu stress. However, little is known about the mechanism of Cu-induced inhibition of seed germination. In the present study, we investigated the relationship between Cu and ABA which is the predominant regulator of seed germination. Cu at a concentration of 30 uM effectively inhibited germination of rice caryopsis. ABA content in germinating seeds under copper stress was also higher than that under control conditions. Quantitative real-time PCR (qRT-PCR) revealed that Cu treatment reduced the expression of OsABA8ox2, a key gene of ABA catabolism in rice seeds. In addition, both malondialdehyde (MDA) and H2O2 contents were increased by Cu stress in the germinating seeds. Antioxidant enzyme assays revealed that only catalase activity was reduced by excess Cu, which was consistent with the mRNA profile of OsCATa during seed germination under Cu stress. Together, our results demonstrate that suppression of ABA catabolism and catalase (CAT) activity by excess Cu leads to the inhibition of seed germination of rice. PMID- 25273892 TI - Global transcriptome analysis of Al-induced genes in an Al-accumulating species, common buckwheat (Fagopyrum esculentum Moench). AB - Buckwheat (Fagopyrum esculentum Moench) is a species with high aluminum (Al) tolerance and accumulation. Although the physiological mechanisms for external and internal detoxification of Al have been well studied, the molecular mechanisms responsible are poorly understood. Here, we conducted a genome-wide transcriptome analysis of Al-responsive genes in the roots and leaves using RNA sequencing (RNA-Seq) technology. RNA-Seq generated reads ranging from 56*10(6) to 93*10(6). A total of 148,734 transcript contigs with an average length of 1,014 bp were assembled, generating 84,516 unigenes. Among them, 31,730 and 23,853 unigenes were annotated, respectively, in the NCBI plant database and TAIR database for Arabidopsis. Of the annotated genes, 4,067 genes in the roots and 2,663 genes in the leaves were up-regulated (>2-fold) by Al exposure, while 2,456 genes in the roots and 2,426 genes in the leaves were down-regulated (<2-fold) A few STOP1/ART1 (SENSITIVE TO PROTON RHIZOTOXICITY1/AL RESISTANCE TRANSCRIPTION FACTOR1)-regulated gene homologs including FeSTAR1, FeALS3 (ALUMINUM SENSITIVE3), FeALS1 (ALUMINUM SENSITIVE1), FeMATE1 and FeMATE2 (MULTIDRUG AND TOXIC COMPOUND EXTRUSION1 and 2) were also up-regulated in buckwheat, indicating some common Al tolerance mechanism across the species, although most STOP1/ART1-regulated gene homologs were not changed. Most genes involved in citric and oxalic acid biosynthesis were not significantly altered. Some transporter genes were highly expressed in the roots and leaves and responded to Al stress, implicating their role in Al tolerance and accumulation. Overall, our data provide a platform for further characterizing the functions of genes involved in Al tolerance and accumulation in buckwheat. PMID- 25273893 TI - The Diagnostic Apathia Scale predicts a dose-remission relationship of T-PEMF in treatment-resistant depression. AB - OBJECTIVE: The aim of this study was to evaluate the predictive validity of the apathy subsyndrome in patients with therapy-resistant depression in the dose remission study with transcranial pulsating electromagnetic fields (T-PEMF). METHODS: The apathy subsyndrome consists of the symptoms of fatigue, concentration and memory problems, lack of interests, difficulties in making decisions, and sleep problems. We evaluated 65 patients with therapy-resistant depression. In total, 34 of these patients received placebo T-PEMF in the afternoon and active T-PEMF in the morning, that is, one daily dose. The remaining 31 patients received active T-PEMF twice daily. Duration of treatment was 8 weeks in both groups. The Hamilton Depression Scale (HAM-D17) and the Bech Rafaelsen Melancholia Scale (MES) were used to measure remission. We also focused on the Diagnostic Apathia Scale, which is based on a mixture of items from the MINI and the HAM-D17/MES. RESULTS: In patients without apathy, the remission rate after T-PEMF was 83.9% versus 58.8% in patients with apathy (p<=0.05). In patients without apathy receiving one active dose daily 94.4% remitted versus 50% for patients with apathy (p<=0.05). In patients without apathy who received two active doses 69.9% remitted versus 66.7% for patients with apathy (p<=0.05). CONCLUSION: Taking the baseline diagnosis of the apathy syndrome into consideration, we found that in patients without apathy one daily dose of T-PEMF is sufficient, but in patients with apathy two daily doses are necessary. Including the apathy syndrome as predictor in future studies would seem to be clinically relevant. PMID- 25273894 TI - The effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminosilicate (NSAS) on the expression and activity of P-glycoprotein within Caco-2 cells. AB - BACKGROUND: Many drugs are substrates for P-glycoprotein (P-gp) and interactions involving P-gp may be relevant to clinical practice. Co-administration with P-gp inhibitors or inducers changes the absorption profile as well as the risk for drug toxicity, therefore it is important to evaluate possible P-gp alterations. The purpose of this study was to investigate the effect of two novel cholesterol lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminium silicate (NSAS), a protonated montmorillonite clay, on mdr-1 gene expression and its protein, P-glycoprotein (P-gp) within Caco-2 cells. METHODS: The effects of DAPP and NSAS on the regulation of mdr-1 gene, P-gp protein expression and activity within Caco-2 cells, were determined using cell viability and cytotoxicity tests, RT-PCR, Western Blot analysis and bi directional transport studies. RESULTS: We observed a significant down-regulation of mdr-1 mRNA (e.g. 38.5 +/- 17% decrease vs. control at 5 MUM DAPP and 61.2 +/- 25% versus control at 10 MUM DAPP; n = 6, P* < 0.05) within Caco-2 cells. Western Blot analysis of P-gp expression showed that changes in mdr-1 gene expression lead to correlating changes in P-gp protein expression. This down-regulation of P glycoprotein also resulted in decreased activity of P-glycoprotein compared to untreated control. In contrast, when Caco-2 cells were treated with NSAS, no changes in mdr-1 gene expression, P-gp protein expression nor P-gp activity were observed. CONCLUSIONS: DAPP but not NSAS decreases P-gp mediated drug efflux through decreased mdr-1 gene expression and consequently decreased P-gp protein expression. These findings have to be taken into consideration when DAPP is concurrently given with other drugs that are substrates for P-gp since drug-drug interactions harbour a safety issue and alter bioavailability profiles.NSAS does not have any P-gp altering properties and therefore might not affect drug-drug interactions. We conclude from this study that NSAS might make a safer drug candidate compared to DAPP for lowering LDL-cholesterol. PMID- 25273895 TI - Double Full-Arch Versus Single Full-Arch, Four Implant-Supported Rehabilitations: A Retrospective, 5-Year Cohort Study. AB - PURPOSE: To report the 5-year outcome of the All-on-4 treatment concept comparing double full-arch (G1) and single-arch (G2) groups. MATERIALS AND METHODS: This retrospective cohort study included 110 patients (68 women and 42 men, average age of 55.5 years) with 440 NobelSpeedy groovy implants. One hundred sixty-five full-arch, fixed, immediately loaded prostheses in both jaws were followed for 5 years. G1 consisted of 55 patients with double-arch rehabilitations occluded with implant-supported fixed prostheses, and G2 consisted of 55 patients with maxillary single-arch rehabilitations or mandibular single-arch rehabilitations occluded with natural teeth or removable prostheses. The groups were matched for age (+/-6 years) and gender. Primary outcome measures were cumulative prosthetic (both interim and definitive) and implant survival (Kaplan-Meier product limit estimator). Secondary outcome measures were marginal bone levels at 5 years (through periapical radiographs and using the patient as unit of analysis) and the incidence of mechanical and biological complications. Differences in survival curves (log-rank test), marginal bone level (Mann-Whitney U test), and complications (chi-square test) were compared inferentially between the two groups using the patient as unit of analysis with significance level set at p <= 0.05. RESULTS: No dropouts occurred. Prosthetic survival was 100%. Five patients lost 5 implants (G1: n = 3; G2: n = 2) before 1 year, rendering an estimated cumulative survival rate of 95.5% (G1: 94.5%; G2: 96.4%; Kaplan-Meier, p = 0.645, nonsignificant). The average (SD) marginal bone level was 1.56 mm (0.89) at 5 years [G1: 1.45 mm (0.77); G2: 1.67 mm (0.99); p = 0.414]. The incidence rate of mechanical complications (in both interim and definitive prostheses) was 0.16 and 0.13 for G1 and G2, respectively (p = 0.032). The incidence rate of biological complications was 0.06 and 0.05 for G1 and G2, respectively (p = 0.669). CONCLUSIONS: Based on the results, rehabilitating double- or single-arch edentulous patients did not yield significant differences on survival curves. The incidence of mechanical complications was significantly higher for double-arch rehabilitated patients but nevertheless, these mechanical complications did not affect the long-term survival of either the prostheses or the implants. PMID- 25273896 TI - Quantitative analysis of spiny neurons in the adult human caudate nucleus: can it confirm the current qualitative cell classification? AB - The caudate nucleus, as a part of the striatum (neostriatum or dorsal striatum), is involved in the control of cognitive, motor and limbic functions. The majority of the caudate nucleus cells are projection spiny neurons, whose activity is determined by excitatory inputs from the cortex, thalamus, globus pallidus and brainstem. A qualitative analysis of human caudate nucleus neurons involves the description of the structure and features of cells, and accordingly, their classification into an appropriate type. The aim of this study is to determine the justification of the current qualitative classification of spiny neurons in the precommissural head of the human caudate nucleus by quantifying morphological properties of neurons. After the qualitative analysis of microscopic images of the Golgi-impregnated caudate nucleus neurons, five morphological properties of cells were measured/quantified. In terms of the dendritic field area, caudate nucleus neurons were divided into two subgroups: small and large neurons. In our sample of 251 projection nerve cells, 58.17 % (146) were small and 41.83 % (105) were large neurons. These data show that suggested groups of spiny neurons in the human caudate nucleus differ in their morphology. Since the structure and function of cells are closely correlated, it is possible that these morphologically different types of neurons may represent different functional groups. PMID- 25273897 TI - [Dy(acac)3(dppn)].C2H5OH: construction of a single-ion magnet based on the square antiprism dysprosium(III) ion. AB - The present work reports a new mononuclear Dy(III) complex [Dy(acac)3(dppn)].C2H5OH (1) (acac = acetylacetone, dppn = benzo[i]dipyrido-[3, 2 a:2',3'-c]phenazine). X-ray crystallography analysis reveals that compound 1 is a discrete molecular complex and the Dy(III) center lies in a square-antiprism coordination environment. Furthermore, complex 1 shows single-ion magnet (SIM) behavior. Compared to the reported complexes [Dy(dppz)(acac)3].CH3OH, [Dy(dpq)(acac)3] and [Dy(phen)(acac)3], complex 1 exhibits a different energy barrier, which might be raised from the different coordination environment caused by the different auxiliary co-ligand dppn. The energy barrier variations of these Dy(III)-complexes are consistent with their square antiprism structural features. PMID- 25273899 TI - Hierarchical regulation of wound healing by NOD-like receptors in cardiovascular disease. AB - SIGNIFICANCE: Persistent nonmicrobial tissue injury leads to the nonlinear activation of integrated wound-healing pathways. In chronic cardiovascular diseases, local tissue undergoes dynamic remodeling involving both structural cells and professional innate immune cells in attempts to limit burden of injury. While the final effector mechanisms by which these different cellular populations participate in wound healing are functionally distinct, their upstream molecular signaling pathways can often be shared. RECENT ADVANCES: The NOD-like receptors (NLRs) are intracellular pattern recognition receptors that have been well characterized as key regulators of pro-inflammatory cytokine production in innate immune cells. However, recent evidence has shown that some NLR proteins are additionally expressed by resident structural cells despite negligible cytokine production. These results indicate the potential for noncanonical routes of innate immune signaling by NLRs within solid organ systems. CRITICAL ISSUES: Here, we review the emerging functions of NLR proteins in professional immune and tissue-resident cells, and discuss the implications in wound healing during chronic cardiovascular diseases. Emphasis is placed on NLRP3 and its regulation of cardiac structure and function in response to injury. Specific cellular and subcellular signaling paradigms are also discussed. FUTURE DIRECTIONS: The characterization of how NLRs participate in homeostasis during cellular injury is essential to develop their potential utility for therapeutic intervention in cardiovascular disease. PMID- 25273900 TI - Evidence for ASD recurrence rates and reproductive stoppage from large UK ASD research family databases. AB - Following a diagnosis of a developmental disorder such as autism spectrum disorder (ASD) in early childhood, parents may decide to have fewer children than previously planned. The tendency for families to halt reproduction after receiving a diagnosis for one child is known as reproductive stoppage. Stoppage may lead to an underestimate of recurrence risk estimates of parents having more than one child with ASD. Using two large UK ASD family databases, we investigated recurrence rates for ASD and evidence for reproductive stoppage for both ASD and undiagnosed ASD/broader autism phenotype in a subgroup of families. Reproductive stoppage was tested for using the Mann-Whitney U-test to disprove the null hypothesis that affected and nonaffected children were distributed randomly by birth order. Dahlberg's later-sib method was used to estimate recurrence risk and take stoppage into account. Data were available from 299 families (660 children) including 327 with ASD. Ten percent of the complete families had more than one child with an ASD. Using Dahlberg's later-sib method, the recurrence risk for ASD was 24.7% overall and 50.0% in families with two or more older siblings with ASD. Children with ASD were born significantly later in families than those without ASD in all sibship combinations. This study shows strong evidence that ASD is associated with reproductive stoppage. These data have important implications for family planning and genetic counseling. PMID- 25273901 TI - Photoemission studies of the near EF spectral weight shifts in FeSe1-xTex superconductor. AB - Our valence band photoelectron spectroscopic studies show a temperature dependent spectral weight transfer near the Fermi level in the Fe-based superconductor FeSe1-xTex. Using theoretical band structure calculations we have shown that the weight transfer is due to the temperature induced changes in the Fe(Se,Te)4 tetrahedra. These structural changes lead to shifts in the electron occupancy from the xz/yz and x2-y2 orbitals to the 3z2-r2 orbitals indicating a temperature induced crossover from a metallic state to an Orbital Selective Mott (OSM) Phase. Our study presents an observation of a temperature induced crossover to a low temperature OSM phase in the family of Fe chalcogenides. PMID- 25273902 TI - Editorial Introduction - EC relevant programmes for research and exploitation of results. PMID- 25273903 TI - Venture-capital companies and the Eurotech Capital Programme of the Commission of the European Communities. PMID- 25273904 TI - Eurotech Innvest service. PMID- 25273905 TI - Medical technology research, a case study of five years of government involvement. PMID- 25273906 TI - New trends in electrophysiological signal parametrization and feature extraction. AB - New trends in physiological time series analysis are described. The discussed topics concern: parametric methods including their multi-channel version, non linear formalism, artificial neural networks and wavelet analysis. The parametric methods which have been used mainly in EEG analysis are making their way into other fields. In their multi-channel version autoregressive models furnish information about the intrinsic relationship between signals. The chaotic formalism have brought new insight into the mechanisms of physiological processes. Nevertheless, in the description of physiological time series parameters estimated by means of non-linear formalism should be used with care. Artificial neural networks are becoming a popular method of time series classification. They are especially suitable in case of noisy and incomplete data. Interesting application of neural networks can be foreseen in the problems where not only classification but also control are involved. Wavelet analysis is a new method which makes possible the simultaneous estimation of signal frequency and localization in time with the accuracy superior to any previously known method. The method is especially suitable for the analysis of fast-varying non stationary signals. PMID- 25273907 TI - Performance characteristics of pressure infusors. AB - Pressure infusion devices (PID) are used in trauma hospitals and in military applications to enhance rapid fluid replacement of hypovolemic shocked patients. This work presents a simple inexpensive technique for evaluation of the performance characteristics of pressure infusors. Pressure-volume and volume-time curves of pneumatic and spring-activated infusors have been derived for pressurized infusion with various output resistances. Three indices of performance are suggested for evaluation of pressure infusors: the energy of discharge fluid from the bag, efficiency index and time required to empty 50% of the bag. PMID- 25273908 TI - Cardiovascular responses to intrathoracic pressure variations in coronary disease patients: a computer simulation. AB - Several studies have suggested that the Valsalva maneuver may predispose potential lethal arrhythmias in patients with coronary artery disease, since this maneuver induces diminished coronary flow. On the other hand some studies have suggested that the Valsalva maneuver abruptly reduces determinants of cardiac oxygen demand, relieving angina pectoris. In order to study the variations of the myocardial oxygen supply-demand relation, during different applications of the maneuver, a mathematical model of the human cardiovascular system is presented. The model has been submitted to an evaluation process allowing the inclusion of a number of additional refinements to the mathematical model structures, and the obtaining of a reduced model in order to improve the computer time and parameter estimation of the simulation. The simulated output variables of the model correlate well with in vivo data obtained from ten patients with typical exertional angina pectoris studied during cardiac catheterization. The evaluation of the cardiac catheterization data has allowed the differentiation of two subsets of patients by the identification of two different coronary controllers. Computer simulation has permitted the analysis of the relative influences of the intrathoracic and intraabdominal pressure variations on the cardiovascular variables. Depending on the coronary control of the patients, the simulation results have shown that the myocardial oxygen supply-demand relation, calculated during the simulation of high intrathoracic pressures, long duration Valsalva maneuvers, or two consecutive maneuvers, gets values higher or lower than unity. These results suggest, respectively, beneficial or detrimental cardiac effects on the patients. PMID- 25273909 TI - Analysis of the chest X-ray conference in an intensive care unit. AB - Bed chest X-rays carried out in an Intensive Care Unit (ICU) are an important means of patient monitoring. To get the starting points for standardization of the documentation of X-ray findings, we examined course and contents of the daily X-ray conference in an ICU. We video-taped the conferences and registered its vocabulary.Mean entire duration to comment on the X-rays of one patient was 150 s. On an average, discussion between radiologist and anaesthetist lasted 40 s, dictation of findings 50 s. Sorting and viewing the X-rays took 60 s. Main disruptions were related to non-availability of X-rays and clinical patient data. Clinical information reported during the discussion is rarely mentioned in the dictated findings. PMID- 25273910 TI - Cough-induced electrostimulation in incontinence. AB - A new method for treatment of urinary stress incontinence is described. Through a vaginal plug the pelvic floor muscles receive a series of electric stimulations which are triggered by an increase of abdominal pressure, detected by an inbuilt pressure sensor. In this study the best parameters for the stimuli are determined during three successive coughs, which are the most common course of urine loss. PMID- 25273912 TI - Regression of Electrocardiographic Signs of Left Ventricular Hypertrophy by Combined Treatment With Thiazide Diuretic and Angiotensin-II Receptor Blocker. AB - BACKGROUND: In hypertensive patients, left ventricular hypertrophy (LVH) may persist despite satisfactory blood pressure (BP) control. The efficacy of thiazide diuretics in Western countries has been reported, but whether this applies to hypertensive Japanese patients is uncertain. METHODS AND RESULTS: We randomly assigned 94 patients whose BP was poorly controlled with usual doses of angiotensin-II receptor blockers (ARB), to losartan/hydrochlorothiazide (HCTZ) fixed-dose combination vs. maximum doses of ARB. After 6 months follow-up, decrease in BP, regression of electrocardiographic LVH, and changes in laboratory measurements were examined. Although a similar decrease in BP was observed in both groups, the decrease in LV Sokolow-Lyon voltage, from 34.4+/-9.2 to 29.4+/ 8.8 mm in the losartan/HCTZ vs. from 29.9+/-10.2 to 29.1+/-8.4 mm in the ARB group (P=0.0003), and the decrease in serum B-type natriuretic peptide (BNP) level, from 30.1+/-28.5 to 26.8+/-28.0 pg/ml vs. from 23.7+/-14.8 to 29.8+/-29.3 pg/ml (P=0.045) were greater in the losartan/HCTZ group. By single variable logistic regression analysis, ?BNP (P=0.012) and treatment with losartan/HCTZ (P<0.0001) correlated with the regression of LVH. By multiple variable logistic regression analysis, both ?BNP (P=0.035) and treatment with losartan/HCTZ (P=0.0003) remained significant. No major adverse effects were observed. CONCLUSIONS: Greater regression of LVH was safely achieved with losartan/HCTZ in patients whose BP was poorly controlled with an ARB. PMID- 25273913 TI - Prognostic value of global longitudinal strain in paradoxical low-flow, low gradient severe aortic stenosis with preserved ejection fraction. AB - BACKGROUND : To assess whether global longitudinal strain (GLS) can discriminate high-risk patients with adverse outcome in paradoxical low-flow, low-gradient (LFLPG) severe aortic stenosis (AS). METHODS AND RESULTS: We enrolled 204 patients with severe AS (indexed aortic valve area [iAVA] <0.6 cm(2)/m(2)) and preserved left ventricular ejection fraction (LVEF >50%). Patients were divided into 4 groups according to flow state (stroke volume index < or > 35 ml/m(2)) and mean pressure gradient (< or > 40 mmHg). LV GLS was measured by 2-dimensional speckle-tracking analysis. The primary endpoint consisted of major cardiovascular events, including aortic valve replacement. During a mean 399-day follow-up, 51 (25%) patients met the primary endpoint. Among the 98 LFLPG AS patients, GLS was significantly reduced in patients with any event (-15.6+/-4.5% vs. -19.4+/-3.6%, P=0.002). Using receiver-operating characteristic analysis, we classified LFLPG AS patients as impaired GLS (GLS >=-17%, n=24) or preserved GLS (GLS <-17%, n=74). The impaired GLS group had smaller iAVA, higher LV mass index, higher E/E', and lower overall 2-year event-free survival (57% vs. 97%; P<0.001) than the preserved GLS group. CONCLUSIONS: Longitudinal function was severely impaired in patients with LFLPG AS and they had poor prognosis. GLS could stratify the high-risk group for future adverse outcomes. Patients with paradoxical LFLPG AS comprised a mixed group with different LV mechanical properties associated with different prognoses. PMID- 25273914 TI - Visualization of pulmonary vein-left atrium reconduction site on delayed enhancement magnetic resonance imaging in the second atrial fibrillation catheter ablation. PMID- 25273915 TI - Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013). PMID- 25273916 TI - Electronic and magnetic properties at the edges of nanostructures in an electric field: ab initio study. AB - State of the art ab initio calculations of the electronic and magnetic properties at the edges of magnetic nanostructures in an external electric field are presented in this paper. Our results for the Fe stripes on Fe(0 0 1) reveal the existence of spin-polarized edge states. A spatially inhomogeneous electronic structure is found at the edge. We demonstrate that the spin-dependent screening density varies greatly at the atomic scale. Tuning of the spin-polarization by the external electric field is demonstrated. PMID- 25273918 TI - A comparison of tissue prolapse with optical coherence tomography and intravascular ultrasound after drug-eluting stent implantation. AB - The aim of this study was to compare the detection rate of tissue prolapse (TP) in optical coherence tomography (OCT) and intravascular ultrasound (IVUS) after drug-eluting stent (DES) implantation and evaluate clinical implication of TP at 2 years after percutaneous coronary intervention. In spite of the superiority of OCT in the aspect of resolution when it was compared to IVUS, there was little data about the superiority of OCT in detecting TP. And there has been controversy about the clinical significance of TP. We enrolled 38 patients who treated with DES implantation. OCT and IVUS measurements were performed in stented segments immediately after percutaneous coronary intervention. We matched OCT and IVUS images one by one, and analyzed TP quantitatively in both measurements. Thirty patients (78.9 %) were followed-up for 2 years to evaluate clinical outcome of TP. TP was detected in 95 % of stented lesions by OCT and 45 % of stented lesions by IVUS among 40 stented lesions in 38 patients. The best cut-off values of the area, depth and burden of TP on OCT for the detection of TP on IVUS were 0.17 mm(2), 0.17 mm and 1.98 %, respectively. There was no statistically significant relation between TP and major adverse cardiac event during hospitalization and 2 year follow-up. PMID- 25273917 TI - Magnetic resonance imaging of ionic currents in solution: the effect of magnetohydrodynamic flow. AB - PURPOSE: Reliably detecting MRI signals in the brain that are more tightly coupled to neural activity than blood-oxygen-level-dependent fMRI signals could not only prove valuable for basic scientific research but could also enhance clinical applications such as epilepsy presurgical mapping. This endeavor will likely benefit from an improved understanding of the behavior of ionic currents, the mediators of neural activity, in the presence of the strong magnetic fields that are typical of modern-day MRI scanners. THEORY: Of the various mechanisms that have been proposed to explain the behavior of ionic volume currents in a magnetic field, only one-magnetohydrodynamic flow-predicts a slow evolution of signals, on the order of a minute for normal saline in a typical MRI scanner. METHODS: This prediction was tested by scanning a volume-current phantom containing normal saline with gradient-echo-planar imaging at 3 T. RESULTS: Greater signal changes were observed in the phase of the images than in the magnitude, with the changes evolving on the order of a minute. CONCLUSION: These results provide experimental support for the MHD flow hypothesis. Furthermore, MHD-driven cerebrospinal fluid flow could provide a novel fMRI contrast mechanism. PMID- 25273920 TI - The influence of residential distance on time to treatment in ST-elevation myocardial infarction patients. AB - AIMS: To evaluate the relation between residential distance and total ischaemic time in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: STEMI patients were transported to the Isala Hospital Zwolle with the intention to perform primary percutaneous coronary intervention PCI (pPCI) from 2004 until 2010 (n = 4149). Of these, 1424 patients (34 %) were referred via a non-PCI 'spoke' centre ('spoke' patients) and 2725 patients (66 %) were referred via field triage in the ambulance (ambulance patients). RESULTS: A longer residential distance increased median total ischaemic time in 'spoke' patients (0-30 km: 228 min, >30-60 km: 235 min, >60-90 km: 264 min, p < 0.001), however not in ambulance patients (0-30 km: 179 min, >30-60 km: 175 min, >60-90 km: 186 min, p = 0.225). After multivariable linear regression analysis, in 'spoke' patients residential distance of >30-60 km compared with 0-30 km was not independently associated with ischaemic time; however, a residential distance of >60-90 km (exp (B) = 1.11, 95 % CI 1.01-1.12) compared with 0-30 km was independently related with ischaemic time. In ambulance patients, residential distance of >30-60 and >60-90 km compared with 0-30 km was not independently associated with ischaemic time. CONCLUSION: A longer distance from the patient's residence to a PCI centre was associated with a small but significant increase in time to treatment in 'spoke' patients, however not in ambulance patients. Therefore, referral via field triage in the ambulance did not lead to a significant increase in time to treatment, especially at long distances (up to 90 km). PMID- 25273919 TI - Methionine restriction slows down senescence in human diploid fibroblasts. AB - Methionine restriction (MetR) extends lifespan in animal models including rodents. Using human diploid fibroblasts (HDF), we report here that MetR significantly extends their replicative lifespan, thereby postponing cellular senescence. MetR significantly decreased activity of mitochondrial complex IV and diminished the accumulation of reactive oxygen species. Lifespan extension was accompanied by a significant decrease in the levels of subunits of mitochondrial complex IV, but also complex I, which was due to a decreased translation rate of several mtDNA-encoded subunits. Together, these findings indicate that MetR slows down aging in human cells by modulating mitochondrial protein synthesis and respiratory chain assembly. PMID- 25273921 TI - Left ventricular assist device for end-stage heart failure: results of the first LVAD destination program in the Netherlands. AB - PURPOSE: Mechanical circulatory support with a continuous-flow left ventricular assist device (LVAD) may be a valuable treatment in end-stage heart failure patients for an extended period of time. The purpose of this study was to evaluate the safety and efficacy of implantation of a continuous-flow LVAD in end stage heart failure patients within the first destination program in the Netherlands. METHODS: A third-generation LVAD was implanted in 16 heart failure patients (age 61 +/- 8; 81 % male; left ventricular ejection fraction 20 +/- 6 %) as destination therapy. All patients were ineligible for heart transplant. At baseline, 3 and 6 months, New York Heart Association (NYHA) functional class, quality-of-life and exercise capacity were assessed. Clinical adverse events were registered. RESULTS: Survival at 30 days and 6 months was 88 and 75 %, respectively. In the postoperative phase, 6 (38 %) patients required continuous veno-venous haemofiltration for renal failure and 2 (13 %) patients required extracorporeal membrane oxygenation because of severe right ventricular failure. During follow-up, NYHA functional class and quality-of-life improved from 3.7 +/- 0.1 to 2.3 +/- 0.1 and 57 +/- 5 to 23 +/- 3 at 6 months (P < 0.001), respectively. The 6 min walking distance improved from 168 +/- 42 m to 291 +/- 29 m at 6 months (P = 0.001). CONCLUSION: Continuous-flow LVAD therapy is a promising treatment for patients with end-stage heart failure ineligible for heart transplant. PMID- 25273922 TI - The reduction of post-cardiac surgery infections by statins: solid evidence? PMID- 25273923 TI - Walking without optic flow reduces subsequent vection. AB - This experiment investigated the effect of walking without optic flow on subsequent vection induction and strength. Two groups of participants walked for 5 min (either wearing Ganzfeld goggles or with normal vision) prior to exposure to a vection-inducing stimulus. We then measured the onset latency and strength of vection induced by a radially expanding pattern of optic flow. The results showed that walking without optic flow transiently yielded later vection onsets and reduced vection strength. We propose that walking without optic flow triggered a sensory readjustment, which reduced the ability of optic flow to induce self-motion perception. PMID- 25273925 TI - Biodiversity of yeast mycobiota in "sucuk," a traditional Turkish fermented dry sausage: phenotypic and genotypic identification, functional and technological properties. AB - In this study, yeasts from Turkish fermented sucuks were identified and their functional and technological properties were evaluated. Two hundred fifty-five yeast isolates were obtained from 35 different sucuk samples from different regions of Turkey. The yeast isolates were determined as genotypic using 2 different polymerase chain reaction (PCR) methods (rep-PCR and RAPD-PCR). Functional and technological properties of including proteolytic, lipolytic, and catalase activities, tolerance to NaCl and bile, as well as growing rates at different temperature and pH conditions selected yeast strains were also evaluated. Candida zeylanoides and Debaryomyces hansenii were dominant strains in sucuk samples. All C. zeylanoides and D. hansenii tested could grow at the condition of 15% NaCl and 0.3% bile salt. However, none of the strains were able to grow at 37 degrees C, even though catalase activity, weak proteolytic and lipolytic activities was still observed. D. hansenii were able to grow only at pH 3, while some of C. zeylanoides could grow at lower pH levels (pH 2). Three and 4 strains of C. zeylanoides showed beta-hemolysis activity and nitrate reduction ability to nitrite, respectively. D. hansenii did not have properties, which are beta-hemolysis, nitrate reduction, or hydrogen sulfide production. Overall, diverse yeast mycobiota present in Turkish fermented sucuk and their functional and technological properties were revealed with this study. PMID- 25273924 TI - EEG measures reveal dual-task interference in postural performance in young adults. AB - The study used a dual-task (DT) postural paradigm (two tasks performed at once) that included electroencephalography (EEG) to examine cortical interference when a visual working memory (VWM) task was paired with a postural task. The change detection task was used, as it requires storage of information without updating or manipulation and predicts VWM capacity. Ground reaction forces (GRFs) (horizontal and vertical), EMG, and EEG elements, time locked to support surface perturbations, were used to infer the active neural processes underlying the automatic control of balance in 14 young adults. A significant reduction was seen between single task (ST) and DT conditions in VWM capacity (F(1,13) = 6.175, p < 0.05, r = 06) and event-related potential (ERP) N1 component amplitude over the L motor (p < 0.001) and R sensory (p < 0.05) cortical areas. In addition, a significant increase in the COP trajectory peak (pkcopx) was seen in the DT versus ST condition. Modulation of VWM capacity as well as ERP amplitude and pkcopx in DT conditions provided evidence of an interference pattern, suggesting that the two modalities shared a similar set of attentional resources. The results provide direct evidence of the competition for central processing attentional resources between the two modalities, through the reduction in amplitude of the ERP evoked by the postural perturbation. PMID- 25273926 TI - Fetal diagnosis of testicular torsion: what shall we tell the parents? AB - OBJECTIVES: The objectives of this study are to present our collective experience with the prenatal diagnosis of testicular torsion and to propose a possible prenatal management scheme. METHODS: We retrospectively collected and reviewed all medical records of cases that were diagnosed with perinatal testicular torsion in our medical center between the years 2002 and 2013. Prenatal torsion was categorized as torsion diagnosed in utero or on immediate newborn examination. RESULTS: A total of five unilateral prenatal torsions were diagnosed. Two fetuses were diagnosed in the third trimester of pregnancy. In both cases, cesarean section was performed immediately upon diagnosis. One newborn underwent immediate orchiectomy with contralateral orchiopexy. Torsion was confirmed by pathological examination. The other was managed conservatively, just as the three newborns who were diagnosed immediately after birth. On follow up scan, the affected testicle was found atrophied with lack of blood flow on color Doppler examination. The unaffected contralateral testicle remained within the normal size with good blood flow. CONCLUSIONS: Prenatal diagnosis of unilateral testicular torsion is a coincidental rare finding. Because the twisted testicle cannot be salvaged, induced delivery and prompt surgery are not recommended. PMID- 25273927 TI - Electrocardiography series. Narrow QRS-complex tachycardia: part 2. AB - We discuss two cases of incessant atrial tachycardia (AT), including the presentation and clinical course. It is important to differentiate AT from other causes of supraventricular tachycardia, such as atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT), as it would have implications on clinical management. Electrocardiographic features of AT, especially the presence of an AV Wenckebach phenomenon with 'grouped beating', are critical for differentiating AT from AVRT and AVNRT. It is also vital to identify the P waves and their relations to QRS on electrocardiography, as this would aid in the differentiation of various supraventricular tachycardias. PMID- 25273928 TI - The potential for a controlled human infection platform in Singapore. AB - For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies. PMID- 25273929 TI - Clinics in diagnostic imaging (155). Incidental PDA with secondary pulmonary arterial hypertension. AB - We report the case of a 70-year-old man with an asymptomatic large patent ductus arteriosus (PDA) incidentally detected on triple-rule-out computed tomography (CT). CT clearly demonstrated a vascular structure connecting the descending thoracic aorta to the roof of the proximal left pulmonary artery, consistent with a PDA. Secondary pulmonary arterial hypertension was also evident on CT. The patient was eventually diagnosed with acute coronary syndrome and was successfully treated with coronary artery bypass graft surgery and concomitant patch closure of the PDA. This article aims to outline the imaging features of PDA and highlight the information provided by CT, which is crucial to treatment planning. The pathophysiology, clinical manifestations and closure options of PDA are also briefly discussed. PMID- 25273930 TI - Syndecan-1 is a potential biomarker for triple-positive breast carcinomas in Asian women with correlation to survival. AB - INTRODUCTION: While overexpression of syndecan-1 has been associated with aggressive breast cancer in the Caucasian population, the expression pattern of syndecan-1 in Asian women remains unclear. Triple-positive breast carcinoma, in particular, is a unique subtype that has not been extensively studied. We aimed to evaluate the role of syndecan-1 as a potential biomarker and prognostic factor for triple-positive breast carcinoma in Asian women. METHODS: Using immunohistochemistry, staining scores of 61 triple-positive breast carcinoma specimens were correlated with patients' clinicopathological variables such as age, ethnicity, tumour size, histological grade, lymph node status, lymphovascular invasion, associated ductal carcinoma in situ grade, recurrence and overall survival. RESULTS: Syndecan-1 had intense staining scores in triple positive invasive ductal breast carcinomas when compared to normal breast tissue. On multivariate analysis, syndecan-1 epithelial total percentage and immunoreactivity score showed statistical correlation with survival (p = 0.02). CONCLUSION: The intense staining scores of syndecan-1 and their correlation with overall survival in patients with triple-positive breast carcinoma suggest that syndecan-1 may have a role as a biological and prognostic marker in patients with this specific subtype of breast cancer. PMID- 25273931 TI - Incipient non-arteritic anterior ischaemic optic neuropathy: a distinct clinical entity, the Singapore scene 3. AB - We report five cases of non-arteritic anterior ischaemic optic neuropathy (NA AION) where spontaneous resolution of the optic disc swelling occurred, and all relevant visual modalities were normal at presentation and remained so until resolution of the process after a median time of 9.6 weeks. This condition, which can be termed 'incipient NA-AION' or 'threatened NA-AION', should be recognised so that unnecessary investigations for other and more serious causes of optic disc swelling can be prevented. PMID- 25273932 TI - Preliminary study of an exercise programme for reducing fatigue and improving sleep among long-term haemodialysis patients. AB - INTRODUCTION: Fatigue and quality of sleep are the main factors that contribute to a poor quality of life among patients on long-term haemodialysis. Studies have also emphasised the importance of exercise for improving the wellbeing of dialysis patients. This study aimed to determine the effectiveness of a predialysis low-to-moderate-intensity exercise programme for reducing fatigue and improving sleep disorders among long-term haemodialysis patients. METHODS: In this quasi-experimental study, an exercise programme was conducted three times a week for 12 weeks before long-term haemodialysis patients underwent dialysis at two centres. The patients were categorised into either the exercise group (n = 28) or control group (n = 27). The latter was asked to maintain their current lifestyles. Assessments of fatigue and sleep disorder levels were performed for both groups using self-reported questionnaires at baseline and after intervention. The patients' perception of the exercise programme was also determined using self-reported questionnaires. RESULTS: Paired sample t-test indicated improvements in fatigue level in the exercise group (mean fatigue score: post-treatment 40.5 +/- 7.9 vs. pre-treatment 30.0 +/- 10.9). Improvements in sleep disorders were also observed in the exercise group (mean score: post treatment 7.6 +/- 3.3 vs. pre-treatment 10.1 +/- 3.8). However, sleep quality deteriorated in the control group (mean score: post-treatment 10.7 +/- 2.9 vs. pre-treatment 9.3 +/- 2.9). CONCLUSION: Simple low-to-moderate-intensity exercise is effective for improving fatigue, sleep disorders and the overall quality of life among haemodialysis patients. PMID- 25273933 TI - Severe hypoxaemia can predict unfavourable clinical outcomes in individuals with pulmonary embolism aged over 40 years. AB - INTRODUCTION: Acute pulmonary embolism (APE) is an urgent clinical condition that can progress in a wide variety of ways. Therefore, we sought to develop an easy to-apply algorithm, to be based on readily available clinical indicators, effective in predicting unfavourable outcomes. METHODS: This was a retrospective cohort study based on systematically collected data in a database. The study included 102 patients with APE who were admitted to a tertiary care hospital. The following outcomes were defined as unfavourable: shock, the need for mechanical ventilation, the use of thrombolytics, and death. Logistic regression analysis was used to explore variables significantly associated with outcome and to calculate post-test probabilities. RESULTS: The prevalence of unfavourable outcomes was 25.5% (26 of the 102 patients with APE). The risk of an unfavourable outcome was reduced to 7.0% for patients with APE who were aged <= 40 years. In patients with APE who were aged > 40 years, the presence of hypoxaemia (i.e. peripheral oxygen saturation < 90%) alone increased the risk of an unfavourable outcome to 57.0%. A recent history of trauma and the presence of pre-existing lung or heart disease were significantly associated with unfavourable outcomes. The inclusion of those variables in the logistic regression model increased the post-test risk of an unfavourable outcome to 65.0%-86.0%. CONCLUSION: Advanced age (i.e. > 40 years), the presence of hypoxaemia, a recent history of trauma and the presence of pre-existing lung or heart disease are risk factors for unfavourable outcome in patients with APE. PMID- 25273934 TI - Overlap syndrome between chronic obstructive pulmonary disease and obstructive sleep apnoea in a Southeast Asian teaching hospital. AB - INTRODUCTION: Overlap syndrome between obstructive sleep apnoea (OSA) and chronic obstructive pulmonary disease (COPD) is important but under-recognised. We aimed to determine the prevalence of overlap syndrome and the predictors of OSA in patients with COPD. METHODS: Patients aged >= 40 years were recruited from a dedicated COPD clinic and underwent overnight polysomnography. A diagnosis of OSA was made when apnoea-hypopnoea index (AHI) was >= 5. RESULTS: In all, 22 patients (aged 71 +/- 9 years), predominantly men, were recruited. Mean values recorded were: predicted forced expiratory volume in the first second percentage 55 +/- 15; body mass index 23.7 +/- 6.5 kg/m2; Epworth Sleepiness Scale score 5.6 +/- 5.8; and AHI 15.8 +/- 18.6. Among the 14 patients with OSA (prevalence of overlap syndrome at 63.6%), the mean number of hospital visits for COPD exacerbations in the preceding one year was 0.5 +/- 0.7. Patients with overlap syndrome had worse modified Medical Research Council dyspnoea scale scores and a lower percentage of rapid eye movement (REM) sleep than patients without. There were no other statistical differences in lung function or sleep study indices between the two patient groups. CONCLUSION: The majority of our patients had overlap syndrome and minimal exacerbations, and were not obese or sleepy. Significant differences between patients with and without overlap syndrome were seen in two aspects - the former was more dyspnoeic and had less REM sleep. Our findings suggest that standard clinical predictors cannot be used for patients with overlap syndrome, and therefore, a high index of suspicion is needed. PMID- 25273935 TI - Back pain in patients with severe osteoporosis on teriparatide or antiresorptives: a prospective observational study in a multiethnic population. AB - INTRODUCTION: We evaluated reduced back pain in a multiethnic population treated with teriparatide and/or antiresorptives in real-life clinical settings over 12 months. METHODS: This prospective observational study comprised 562 men and postmenopausal women (mean age 68.8 years) receiving either teriparatide (n = 230), antiresorptives (raloxifene or bisphosphonates; n = 322), or both (n = 10) for severe osteoporosis. The primary endpoint was the relative risk of new/worsening back pain at six months. RESULTS: At baseline, a higher proportion of teriparatide-treated than antiresorptive-treated patients had severe back pain (30.9% vs. 17.7%), extreme pain/discomfort (25.3% vs. 16.8%), extreme anxiety/depression (16.6% vs. 7.8%) and were confined to bed (10.0% vs. 5.3%). Teriparatide-treated patients had higher visual analog scale (VAS) scores for pain (5.8 +/- 2.42 vs. 5.1 +/- 2.58) and lower mean European Quality of Life-5 Dimensions (EQ-5D) scores (37.7 +/- 29.15 vs. 45.5 +/- 31.42) than antiresorptive treated patients. The incidence of new/worsening back pain at six months for patients on teriparatide and antiresorptives was 9.8% and 10.3% (relative risk 0.99, 95% confidence interval 0.80-1.23), respectively. The incidence of severe back pain at 12 months was 1.3% and 1.6% in the teriparatide and antiresorptive treatment groups, respectively. Teriparatide-treated patients had lower mean VAS (2.71 +/- 2.21 vs. 3.30 +/- 2.37) and EQ-5D (46.1 +/- 33.18 vs. 55.4 +/- 32.65) scores at 12 months. More teriparatide-treated patients felt better (82.7% vs. 71.0%) and were very satisfied with treatment (49.4% vs. 36.8%) compared to antiresorptive-treated patients. CONCLUSION: Patients treated with either teriparatide or antiresorptives had similar risk of new/worsening back pain at six months. PMID- 25273936 TI - Comparative assessment of students' performance and perceptions on objective structured practical models in undergraduate pathology teaching. AB - INTRODUCTION: Assessment is an important factor that drives student learning, as students tend to mainly focus on the material to be assessed. The current practice in teaching pathology extensively applies objective-structured practical examination for the assessment of students. As students will have to deal with real patients during clinical years, it is preferred that students learn and practise via potted specimens and slides instead of picture plates. This study aimed to assess the preferred assesment method of pathology practical exercises. METHODS: This was a cross-sectional survey carried out in two consecutive batches of Phase 2 medical students. Student competency was assessed using both the traditional (TD) (i.e. use of potted specimens and slides) and picture plate (PP) methods. To compare the two assessment methods, we compared the mean scores obtained by the students and examined student perception of the two methods. RESULTS: The mean scores obtained via the PP method were significantly higher than those obtained via the TD method for almost all the components tested. CONCLUSION: We found that students performed significantly better (p < 0.05) when assessed using the PP method instead of the TD method. PP preparations might provide better visuals, thus aiding understanding, than the TD method. The findings of this study are valuable in identifying and improving our current teaching and assessment methods of medical students, in line with advancements in information technology. PMID- 25273937 TI - A different viewpoint on pneumococcal glomerulonephritis in a healthy child. PMID- 25273938 TI - Authors' Reply. A different viewpoint on pneumococcal glomerulonephritis in a healthy child. PMID- 25273939 TI - MERS-CoV, surgical mask and N95 respirators. PMID- 25273940 TI - Authors' Reply. MERS-CoV, surgical mask and N95 respirators. PMID- 25273941 TI - Bilateral discoid medial menisci: a rare phenomenon. AB - Discoid medial meniscus is a relatively rare pathology of the knee joint, with bilateral cases even rarer. Herein, we report the case of a 25-year-old man diagnosed with discoid medial meniscus in the right knee with a horizontal tear. Increased cupping of the medial condyle of the tibia, widening of the medial joint space and the presence of discoid meniscus in the right knee prompted investigation of the asymptomatic left knee with magnetic resonance imaging. The contralateral asymptomatic knee also showed evidence of discoid medial meniscus. The symptomatic knee was successfully treated by arthroscopic partial meniscectomy, with excellent functional outcome. PMID- 25273942 TI - Carotidynia after anticancer chemotherapy. AB - Carotidynia is characterised by inflammation limited to the common carotid artery, which has been recognised as a distinct disease entity by advanced vascular imaging. Although most cases of carotidynia are idiopathic, we herein present a case of carotidynia after anticancer chemotherapy. A 64-year-old male patient received docetaxel followed by granulocyte-colony stimulating factor (G CSF) for the treatment of lung squamous carcinoma. After the treatment, bilateral cervical pain developed. Vascular imaging, including magnetic resonance imaging, computed tomography and ultrasonography, showed characteristics specific for carotidynia. Although there was no strong confirmation using tests such as a challenge test, our observations suggest that docetaxel or G-CSF could be a causative drug triggering carotidynia. PMID- 25273943 TI - Acute myocardial infarction and subclavian artery occlusion in a 41-year-old woman with Behcet's disease: coronary and large vessel arteritis. AB - We report the case of a 41-year-old Chinese woman with Behcet's disease (BD) complicated by acute myocardial infarction, requiring inotropic and ventilatory support. Angiography showed critical left anterior descending coronary artery stenosis, a blocked left subclavian artery and left carotid artery stenosis. The patient was successfully treated with a high dose of immunosuppressants, standard anti-ischaemic therapy and percutaneous coronary intervention. Although life threatening, coronary arteritis is a treatable manifestation of BD. We suggest that the diagnosis of coronary arteritis be considered in patients with BD who present with chest pain. Involvement of other arteries should also be looked out for in these patients. PMID- 25273944 TI - Mediastinal impalement with a fibreglass sheet. AB - Mediastinal impalement injuries are uncommon and often fatal. There have been very few reported cases of survival following mediastinal impalement. Patients who present with these injuries always undergo operative intervention regardless of their underlying haemodynamic status or associated injuries. We herein present a case of mediastinal impalement injury, where a sheet of fibreglass had fractured the manubrium and entered the anterior mediastinum with no associated great vessel injury. The fibreglass sheet was removed via a partial sternotomy and the patient made an uneventful postoperative recovery. PMID- 25273945 TI - Coronary artery bypass grafting in a patient with pituitary adenoma: can alertness prevent tragedy? AB - Pituitary apoplexy is a rare, life-threatening complication that may occur after coronary artery bypass graft surgery for patients with pituitary adenomas. The dynamics of cardiopulmonary bypass may contribute to a sudden expansion of silent pituitary adenomas and result in the compression of surrounding structures. A range of clinical features have been described, and the condition requires prompt diagnosis and treatment to prevent further complications. Herein, we present an uncomplicated case highlighting the importance of diagnosing pituitary apoplexy, ensuring high alertness to the condition, so as to prevent life-threatening tragedy due to missed diagnosis. PMID- 25273946 TI - Primary sarcomatoid carcinoma of the mandibular gingiva: clinicopathological and radiological findings. AB - Sarcomatoid carcinoma is a rare, malignant biphasic neoplasm with an epithelial and a spindle cell component. Primary sarcomatoid carcinomas arising from mandibular gingiva are known to be extremely rare, with only one case reported to date. Herein, we discuss the radiographic and computed tomographic appearances and pathological features of primary mandibular sarcomatoid carcinoma, which was confirmed by clinicopathology, in a 72-year-old man. In addition, we present a brief review of the relevant literature. PMID- 25273947 TI - A preoperative serum signature of CEA+/CA125+/CA19-9 >= 1000 U/mL indicates poor outcome to pancreatectomy for pancreatic cancer. AB - Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high-volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19-9 independently indicated surgical response in pancreatic cancer. Patients with CA19-9 >=1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19-9 levels decreased postoperatively. CEA and CA125 in the presence of CA19-9 >=1000 U/mL could independently predict the non-decrease of CA19-9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p < 0.001) for the training cohort and 7.0 months vs. 18.2 months (p < 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA(+)/CA125(+)/CA19-9 >=1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy. PMID- 25273949 TI - Magnetic resonance imaging features of ovarian fibroma, fibrothecoma, and thecoma. AB - OBJECTIVE: To retrospectively evaluate the conventional and functional (diffusion or perfusion-weighted) magnetic resonance (MR) imaging features of ovarian fibroma, fibrothecoma, and thecoma. MATERIALS AND METHODS: Histologically proven ovarian fibromas (n = 19), fibrothecomas (n = 7), and thecomas (n = 2) were reviewed (26 patients). The morphologic and signal intensity (SI) characteristics on conventional MR imaging (n = 28, all cases) were analyzed. The b 1000 signal intensity on diffusion-weighted image (DWI) (n = 22) and the time-to-signal intensity curve on perfusion-weighted image (PWI) (n = 7) were also analyzed. The presence and shape of the ipsilateral ovarian tissue surrounding the lesions were evaluated on T2-weighted image. RESULTS: Twenty-two cases (79%) were predominantly solid tumor. Majority of the detected lesions exhibited the characteristic homogeneous low SI on T1- (24/28, 86%) and T2- (19/28, 68%) weighted image. Conversely, a number of lesions exhibited high SI (9/28, 32%) on T2-weighted image. Most lesions presented with a detectable ipsilateral ovary on T2-weighted image (24/28, 86%). Tumors larger than 6 cm more likely showed atypical morphology (mixed solid and cystic, cystic), atypical SI (high on T1- and T2-weighted image), and large amount ascites. Larger tumor group (>6 cm) was more likely diagnosed as fibrothecoma or thecoma than fibroma by pathology. On DWI, 16 lesions showed low b 1000 signal intensity (16/22, 73%). On PWI, all lesions showed curve type 1 or 2 (7/7, 100%), which tends to characterize benign lesions. All (16/16, 100%) pre-menopausal women had a detectable ipsilateral ovary, and six (60%) out of 10 post-menopausal women had a detectable ipsilateral ovary (p < 0.05). CONCLUSIONS: Combining conventional morphologic and signal intensity characteristics with the findings from DWI or PWI might help differentiate ovarian fibroma, fibrothecoma, and thecoma from ovarian malignancy, although further prospective larger scale study using DWI and PWI is needed. PMID- 25273948 TI - Genetic polymorphisms at SIRT1 and FOXO1 are associated with carotid atherosclerosis in the SAPHIR cohort. AB - BACKGROUND: SIRT1 and FOXO1 interact with each other in multiple pathways regulating aging, metabolism and resistance to oxidative stress and control different pathways involved in atherosclerotic process. It is not known, if genetic polymorphisms (SNPs) at the SIRT1 and FOXO1 have an influence on carotid atherosclerosis. METHODS: Intima-media thickness (IMT) was measured on the common and internal carotid arteries. Morphological alterations of the carotid arteries and size of these alterations were included in the B-score grading on a five point scale. Eleven SNPs at SIRT1 and FOXO1 gene loci were genotyped in the SAPHIR cohort (n = 1742). The association of each SNP with common carotid IMT, internal carotid IMT and B-score was analyzed using linear regression models. RESULTS: A significant association was found between common carotid IMT and two SNPs at FOXO1 - rs10507486, rs2297627 (beta = -0.00168, p = 0.0007 and beta = 0.00144, p = 0.0008 respectively) and at least a trend for rs12413112 at SIRT1 (beta = 0.00177, p = 0.0157) using an additive model adjusting for age and sex. Additional adjustment for traditional cardiovascular risk factors and markers (BMI, smoking status, hypertension, total cholesterol, HDL-cholesterol, hsCRP) even improved the strength of this association (p = 0.0037 for SIRT1 and p = 0.0002 for both SNPs at FOXO1). Analysis for internal carotis IMT and B-score did not reveal any significant association. One haplotype in FOXO1 showed a moderate effect on common carotid IMT and B-score in comparison to the reference haplotype of this gene. Several SNPs within SIRT1 showed differential effects for men and women with higher effect sizes for women: rs3740051 on all three investigated phenotypes (interaction p-value < 0.0069); rs2236319 on common and internal carotid IMT (interaction p-value < 0.0083), rs10823108, rs2273773 on common carotid IMT and rs1467568 on B-score (interaction p-value = 0.0007). The latter was significant in women only (betawomen = 0.111, pwomen = 0.00008; betamen = 0.009, pmen = 0.6464). CONCLUSIONS: This study demonstrated associations of genetic variations at the SIRT1 and FOXO1 loci with carotid atherosclerosis and highlighted the need for further investigation by functional studies. PMID- 25273950 TI - A qualitative evaluation of the psychosocial impact of family history screening in Australian primary care. AB - Whilst the family history is perceived as a routine part of the medical family history it is not used in a systematic way to tailor disease prevention in primary care. Family history questionnaires (FHQs) may have an important role in primary care as a screening tool to support tailored disease prevention. The potential harms and benefits of family history screening in primary care require investigation before routine adoption. This study aimed: first to explore the experience and impact of family history collection via a novel family history questionnaire and subsequent familial risk assessment, and secondly, to assess the acceptability and feasibility of using the questionnaire in Australian primary care. Twenty-eight semi-structured telephone interviews were conducted with patients already enrolled in a family history screening study through their family physician. Qualitative constant comparative analysis was undertaken of transcript data. Common themes included the way in which the family unit, individual stage of life and a number of external triggers interact and contribute to how an individual comes to terms with familial disease risk. Unique findings emerged relating to the Australian perspective of participants. Living in Australia created a barrier to effective communication amongst family members about family health, and family history collection. In addition to the vast geographical distance both within Australia, and between Australia and other countries, there was an additional sense of isolation described within an historical context. The family history screening questionnaire was considered user-friendly and a worthwhile approach to supporting disease prevention in primary care, although some participants did not retain an accurate understanding of their familial cancer risk. In conclusion, a person's response to family history screening is reliant on a complex interplay of family, personal and external factors, which in turn are driven by their stage of life. The impact of immigration and geographic isolation from family members may further complicate a person's response to undertaking family history screening. PMID- 25273951 TI - Patient expectations and attitudes towards specialist genetic eye services. AB - Little research has explored the views of patients referred to specialist genetic eye clinics. Future service development must be informed by the perspectives of patients to ensure services are accessible and meet their needs. Semi-structured telephone interviews were undertaken with patients referred to the Genetic Eye Clinic in Manchester, UK. Participants were interviewed before their first appointment. The interview transcripts were analysed using Interpretative Phenomenological Analysis (IPA). Nine interviews took place. Five participants were adults with sight loss and 4 were the parent/carer of a child patient. The major themes identified were: expectations of a medical-genetic focus to the clinic, psychological adjustment to the diagnosis of an eye condition impacting on counselling and support needs, lack of preparation and restricted expectations due to unfamiliarity with the service and positive attitudes towards genetic research and testing. Key motivating factors for patients attending specialist ophthalmic genetic services are medical-genetic orientated, including accurate diagnostic and prognostic information, participation in research and clarification of recurrence risks. Some barriers to patients accessing and fully engaging with services were identified. There is a need to raise awareness of the specialist service amongst the public, patient organisations and professionals. Facilitating patient preparation for clinic could improve patient outcomes, and the need for integrated services is reinforced. The results feed into the development of a best practice model for the delivery of specialist ophthalmic genetic services. PMID- 25273952 TI - Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome. AB - The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score >=3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p = 0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotype-negative (1.7 vs. 3.1, p = 0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p = 0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted. PMID- 25273953 TI - No shift to a deeper water uptake depth in response to summer drought of two lowland and sub-alpine C3-grasslands in Switzerland. AB - Temperate C3-grasslands are of high agricultural and ecological importance in Central Europe. Plant growth and consequently grassland yields depend strongly on water supply during the growing season, which is projected to change in the future. We therefore investigated the effect of summer drought on the water uptake of an intensively managed lowland and an extensively managed sub-alpine grassland in Switzerland. Summer drought was simulated by using transparent shelters. Standing above- and belowground biomass was sampled during three growing seasons. Soil and plant xylem waters were analyzed for oxygen (and hydrogen) stable isotope ratios, and the depths of plant water uptake were estimated by two different approaches: (1) linear interpolation method and (2) Bayesian calibrated mixing model. Relative to the control, aboveground biomass was reduced under drought conditions. In contrast to our expectations, lowland grassland plants subjected to summer drought were more likely (43-68%) to rely on water in the topsoil (0-10 cm), whereas control plants relied less on the topsoil (4-37%) and shifted to deeper soil layers (20-35 cm) during the drought period (29-48%). Sub-alpine grassland plants did not differ significantly in uptake depth between drought and control plots during the drought period. Both approaches yielded similar results and showed that the drought treatment in the two grasslands did not induce a shift to deeper uptake depths, but rather continued or shifted water uptake to even more shallower soil depths. These findings illustrate the importance of shallow soil depths for plant performance under drought conditions. PMID- 25273954 TI - Immune benefits from alternative host plants could maintain polyphagy in a phytophagous insect. AB - The tritrophic interactions hypothesis, integrating bottom-up (plant-herbivore) and top-down (herbivore-natural enemies) effects, predicts that specialist herbivores should outcompete generalists. However, some phytophagous insects have generalist diets, suggesting that maintenance of a diverse diet may confer certain fitness advantages that outweigh diet specialization. In field conditions, the European grapevine moth, Lobesia botrana, feeds on diverse locally rare alternative host plants (AHPs) although grapevines are a highly abundant and predictable food source. The laboratory studies presented here show that survival, growth, and constitutive levels of immune defences (concentration of haemocytes and phenoloxidase activity) of L. botrana larvae were significantly enhanced when they were fed AHPs rather than grape. These results indicated a strong positive effect of AHPs on life history traits and immune defences of L. botrana. Such positive effects of AHPs should be advantageous to the moth under heavy selective pressure by natural enemies and, as a consequence, favour the maintenance of a broad diet preference in this species. We therefore believe that our results account for the role of immunity in the maintenance of polyphagy in phytophagous insects. PMID- 25273955 TI - To be in time: egg deposition enhances plant-mediated detection of young caterpillars by parasitoids. AB - Animals use information from their environment while foraging for food or prey. When parasitic wasps forage for hosts, they use plant volatiles induced by herbivore activities such as feeding and oviposition. Little information is available on how wasps exploit specific plant volatiles over time, and which compounds indicate changes in host quality. In experiments investigating the role of herbivore-induced plant volatiles in wasp foraging, induction of plant response is usually achieved by placing larvae on clean plants instead of allowing the natural sequence of events: to let eggs deposited by the herbivore develop into larvae. We compared the attraction of the parasitoid Cotesia glomerata to volatiles emitted by black mustard (Brassica nigra) plants induced by eggs and successive larval stages of the Large Cabbage White butterfly (Pieris brassicae) to the attraction of this parasitoid to black mustard plant volatiles induced only by larval feeding in a wind tunnel setup. We show that wasps are attracted to plants infested with eggs just before and shortly after larval hatching. However, wasp preference changed at later time points towards plants induced only by larval feeding. These temporal changes in parasitoid attraction matched with changes in the chemical compositions of the blends of plant volatiles. Previous studies have shown that host quality/suitability decreases with caterpillar age and that P. brassicae oviposition induces plant defences that negatively affect subsequently feeding caterpillars. We investigated parasitoid performance in hosts of different ages. Wasp performance was positively correlated with preference. Moreover, parasitism success decreased with time and host stage. In conclusion, the behaviour of Cotesia glomerata is fine-tuned to exploit volatiles induced by eggs and early host stages that benefit parasitoid fitness. PMID- 25273957 TI - Tungsten oxide@polypyrrole core-shell nanowire arrays as novel negative electrodes for asymmetric supercapacitors. AB - Among active pseudocapacitive materials, polypyrrole (PPy) is a promising electrode material in electrochemical capacitors. PPy-based materials research has thus far focused on its electrochemical performance as a positive electrode rather than as a negative electrode for asymmetric supercapacitors (ASCs). Here high-performance electrochemical supercapacitors are designed with tungsten oxide@PPy (WO3 @PPy) core-shell nanowire arrays and Co(OH)2 nanowires grown on carbon fibers. The WO3 @PPy core-shell nanowire electrode exhibits a high capacitance (253 mF/cm2) in negative potentials (-1.0-0.0 V). The ASCs packaged with CF-Co(OH)2 as a positive electrode and CF-WO3 @PPy as a negative electrode display a high volumetric capacitance up to 2.865 F/cm3 based on volume of the device, an energy density of 1.02 mWh/cm3 , and very good stability performance. These findings promote the application of PPy-based nanostructures as advanced negative electrodes for ASCs. PMID- 25273956 TI - Computed tomographic angiography under sedation in the diagnosis of suspected canine pancreatitis: a pilot study. AB - BACKGROUND: Computed tomography (CT) is highly accurate for diagnosing pancreatitis in humans. The diagnosis of pancreatitis in dogs is based on clinical signs, laboratory findings, and ultrasonographic (US) changes. There are, however, inherent limitations in relying on laboratory and ultrasound findings for the clinical diagnosis of pancreatitis in dogs. HYPOTHESIS/OBJECTIVES: We hypothesized that CT angiography would be a rapid and reliable method to confirm pancreatitis in dogs compared to ultrasonography. The aim was to describe the CT characteristics and compare them to ultrasound findings and correlate the CT appearance to the severity of the patients' clinical course. ANIMALS: A prospective pilot case series; 10 dogs with pancreatitis were enrolled if the history, clinical signs, laboratory, and ultrasonographic findings were indicative of pancreatitis. METHODS: A 3-phase angiographic CT was performed under sedation. Afterward, each dog had US-guided aspirates of the pancreas collected and blood drawn for cPLi assay. Images were evaluated for portion of visible pancreas, pancreatic size and margin, pancreatic parenchyma, presence of peripancreatic changes and contrast enhancement pattern. The results were compared with outcome. RESULTS: An enlarged, homogeneously to heterogeneously attenuating and contrast-enhancing pancreas with ill-defined borders was identified in all dogs. CT identified more features characterizing pancreatic abnormalities compared to US. Thrombi were found in 3/10 dogs. Three dogs with heterogeneous contrast enhancement had an overall poorer outcome than those with homogenous enhancement. CONCLUSIONS AND CLINICAL IMPORTANCE: CT angiography under sedation was used in dogs to confirm clinically suspected pancreatitis and identified clinically relevant and potentially prognostic features of pancreatitis in dogs. PMID- 25273958 TI - From risk analysis to risk governance - Adapting to an ever more complex future. AB - Risk analysis is now widely accepted amongst veterinary authorities and other stakeholders around the world as a conceptual framework for integrating scientific evidence into animal health decision making. The resulting risk management for most diseases primarily involves linking epidemiological understanding with diagnostics and/or vaccines. Recent disease outbreaks such as Nipah virus, SARS, avian influenza H5N1, bluetongue serotype 8 and Schmallenberg virus have led to realising that we need to explicitly take into account the underlying complex interactions between environmental, epidemiological and social factors which are often also spatially and temporally heterogeneous as well as interconnected across affected regions and beyond. A particular challenge is to obtain adequate understanding of the influence of human behaviour and to translate this into effective mechanisms leading to appropriate behaviour change where necessary. Both, the One Health and the ecohealth approaches reflect the need for such a holistic systems perspective, however the current implementation of risk analysis frameworks for animal health and food safety is still dominated by a natural or biomedical perspective of science as is the implementation of control and prevention policies. This article proposes to integrate the risk analysis approach with a risk governance framework which explicitly adds the socio-economic context to policy development and emphasizes the need for organisational change and stakeholder engagement. PMID- 25273959 TI - Detection of Listeria monocytogenes in food samples in Avezzano, Sulmona and Castel di Sangro (province of L'Aquila, Abruzzo, Italy) between 2000-2009. AB - The retrospective study of the results of the analysed samples is a fundamental tool for the identification of major risk related to food and for planning future monitoring activities. The evaluation of the quality of data collected may also allow for estimating the effectiveness of the controls so to improve their efficacy. In this article, the authors evaluated the results of tests for the detection of Listeria monocytogenes performed by the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale' (IZSAM) on food samples collected during the years 2000-2009 in the territory of Avezzano, Sulmona and Castel di Sangro (province of L'Aquila, Abruzzo, Italy). The comparison of the data examined with those from studies conducted in Italy and in other countries shows that the categories with higher percentages of positivity for Listeria monocytogenes are meat and fish products. Data collected do not indicate cheese as a vehicle of contamination in the sampled areas, in contrast to what reported in the national and international literature. It would therefore be necessary to promote an ad hoc sampling in the areas covered by this study to verify this aspect in more depth. PMID- 25273960 TI - Shiga toxin-producing Escherichia coli O157:H7 in milk and milk products in Ogun State, Nigeria. AB - Shiga toxin producing Escherichia coli (STEC) O157 is a major cause of food-borne illnesses in humans. This study investigated the presence of STEC O157 in milk and milk products in Ogun State, Nigeria. Of a total of 202 samples 10 (5%) were positive for STEC O157 including 1 (2%) of 50 raw milk samples, 3 (6%) of 50 samples of fresh local cheese, 1 (2%) of 50 samples of fried local cheese and 5 (9.6%) of 52 fermented milk samples. There was no significant difference (p>0.05) in the prevalence of STEC O157 among the sample types. Of 10 isolates, shiga toxin 1 gene (stx1) was detected only in 2 samples (20%), shiga toxin 2 (stx2) was extracted only in 6 samples (60%), stx1 /stx2 in 2 samples (20.0%), intimin gene (eaeA) in 5 samples (50%), and enterohaemolysin (E-hlyA) gene was isolated in 7 (70%) samples. Rates of resistance of the STEC O157 isolates were: amoxicillin/clavulanic acid 100%, ampicillin 100%, chloramphenicol 60%, nalidixic acid 20%, norfloxacin 10%, streptomycin 30%, sulphamethoxazole/trimethprim 20%, and tetracycline 90%. The isolates were all susceptible to ciprofloxacin and neomycin. The presence of virulent multidrug resistant E. coli O157 strains in milk and milk products as revealed by this study unveils a risk of human exposure to these potentially fatal pathogens following consumption of contaminated products. PMID- 25273961 TI - Analysis of the 227 bp short interspersed nuclear element (SINE) insertion of the promoter of the myostatin (MSTN) gene in different horse breeds. AB - The myostatin (MSTN) gene encodes a protein known to be a negative regulator of muscle mass in mammalian species. Different polymorphisms of the horse (Equus caballus) MSTN gene have been identified, including single nucleotide polymorphisms and a short interspersed nuclear element (SINE) insertion of 227 bp within the promoter of the gene. The SINE insertion has been associated with performance traits in Thoroughbred racehorses and it was proposed as a predictor of optimum racing distance. The aims of this study were to perform in silico analysis to identify putative gains or abrogation of transcription-factor binding sites (TFBSs) generated by the SINE allele of the promoter and to analyse the frequency of the SINE insertion in horses used for racing (gallop and trot) and other purposes. The SINE insertion was genotyped in 227 horses from 10 breeds belonging to different morphological types (brachimorphic, mesomorphic, meso dolichomorphic and dolichomorphic). The presence of the insertion was confirmed in the Quarter Horse (SINE allele frequency of 0.81) and in the Thoroughbred (0.51), whereas the SINE allele did not segregate in any of the other analysed breeds. As the SINE MSTN gene polymorphism may be population or breed specific, it is not a useful marker for association studies in all breeds. PMID- 25273962 TI - First description of adiaspiromycosis in an Eurasian otter (Lutra lutra) in Italy. AB - Adiaspiromycosis is a pulmonary disease caused by the inhalation of the ubiquitous fungus Emmonsia spp., a common soil inhabitant. Information about the replication and dissemination of the fungus from the primary site is lacking. Members of the Family Mustelidae seem to be highly susceptible to this infection, which has been previously reported in otters (Lutra lutra) in Czech Republic/Slovakia, Finland and in the UK. In many cases, Emmonsia-associated lesions have also been reported as incidental findings during necropsies of otherwise healthy animals. A road-killed male Eurasian otter was submitted for the post-mortem examination on 21st December 2009 at the Veterinary Pathology Unit of the Faculty of Veterinary Medicine of Teramo, as part of the RECAL [RECovery and post-mortem Analysis of Eurasian otters (Lutra lutra) in the National Park of Cilento, Vallo di Diano and Alburni (Salerno, Italy), and surrounding areas] project. Histologically, multifocal round structures with a PAS-positive thick tri-laminar wall and a central basophilic granular mass were observed within the alveoli. The adiaspores were surrounded by a severe granulomatous reaction with high number of macrophages, multinucleated giant cells, eosinophils, neutrophils and fibroblasts. Numerous multifocal cholesterol granulomas were observed close to those fungal-induced. To the best of our knowledge, this is the first description of adiaspiromycosis in an Eurasian otter in Italy. PMID- 25273963 TI - Culicoides midges (diptera: ceratopogonidae) as vectors of orbiviruses in Slovakia. AB - In recent years, rapid spread of Culicoides-borne pathogens such as bluetongue (BT) and Schmallenberg viruses have been reported in Europe. In this study we examined the Culicoides populations in farms with wild and domestic ruminants in Eastern Slovakia with the aim to confirm the presence of biting midges serving as potential vectors of important pathogens. The main vector complexes were the Obsoletus complex (54%; n=4,209) and the Pulicaris complex (23%; n=1,796). To estimate the relative abundance of the cryptic species of the Obsoletus complex (Culicoides obsoletus, Culicoides scoticus and Culicoides montanus), we performed the multiplex polymerase chain reaction (PCR) based on ITS-2 and ITS-1 segments, on 125 midges randomly sampled. The relative abundance of C. obsoletus ranged from 5.26% in the farm with wild ruminants to 85.71% in another farm with cattle and sheep. A total of 112 pools of parous and gravid females belonging to the Obsoletus and Pulicaris complexes were tested for virus detection by the real time reverse transcription polymerase chain reaction (RT-PCR) for BT virus, as well as for the Epizootic Hemorrhagic Disease Virus (EHDV), with negative results. PMID- 25273964 TI - Phylogenetic study on the 5'-untranslated region of bovine viral diarrhoea virus isolates from Iran. AB - Bovine viral diarrhoea virus is a pathogen of bovids associated with reproduction system, causing in infected animals a range of ailments, from abortion to congenital defects. In this article, the nucleotide structure of the 5' untranslated region (5-UTR) from 7 Iranian bovine diarrhoea virus (BVDV) isolates was characterized and subjected to comparative analysis against a panel of BVDV isolates from different sources. To this end, a 288 bp-long stretch of the internal ribosome entry site was amplified by RT-PCR. The PCR products subsequently cloned into PTZ57T vector and sequenced using T7 promoter primers. This resulted in detection of 3 new point mutations G -> A and G -> T in 2 isolates. When these findings were phylogenetically assessed, all the examined Iranian isolates were deemed to belong to the type1 of BVDV. Besides, 2 subtypes were identified among these isolates. In group A, a high level of similarity (99.2%) between Iranian isolates with a cytopathic Australian strain of BVDV-1c was detected; while in group B, the 4 Iranian isolates proved to be very similar to NADL-like BVDV-1a strains. We believe that the surprisingly high level of similarity between group A Iranian isolates and their corresponding Australian strain is likely to be an indication of a shared common ancestor. If correct, the most likely explanation of this observation is the introduction of such strains from Australia to Iran, possibly through exportation of infected live animals or animal productions (e.g. semen and meat) at some points in the past. Nevertheless, this hypothesis remains to be proved as further epidemiological work at genomic level is required to understand population of BVDV in Iran. PMID- 25273965 TI - First report of a variant bovine papillomavirus type 2 (BPV-2) in cattle in the Iberian Peninsula. AB - Infections caused by bovine papillomavirus (BPV) have been described worldwide. Some types, like BPV-1 and BPV-2, have been reported in association with skin warts and fibropapillomas in cattle and sarcoids in equids. In this study we have investigated the presence of BPV in cutaneous warts isolated from a steer in Spain. Cutaneous fibropapillomatosis was confirmed by histopathological analysis. Complete genome was amplified by multiple-primed rolling circle and the L1, E5 and E6 genes were sequenced. The isolate was classified as a variant of BPV-2 on the basis of the L1 gene sequences. Genetic variability of L1, E5 and E6 genes was compared with BPV-2 isolates from different hosts in several continents. Some mutations involved non-synonymous substitutions when compared to the prototype strain. One of these non-conservative mutations was located in the jelly roll beta-barrel of the EF loop of the capsid protein (encoded by L1). This study presents the first report of a variant of BPV-2 infection in the Iberian Peninsula and contributes to extend the knowledge of the spreading and circulation of BPV. PMID- 25273966 TI - Occurrence of different Canine distemper virus lineages in Italian dogs. AB - This study describes the sequence analysis of the H gene of 7 Canine distemper virus (CDV) strains identified in dogs in Italy between years 2002-2012. The phylogenetic analysis showed that the CDV strains belonged to 2 clusters: 6 viruses were identified as Arctic-like lineage and 1 as Europe 1 lineage. These data show a considerable prevalence of Arctic-like-CDVs in the analysed dogs. The dogs and the 3 viruses more recently identified showed 4 distinctive amino acid mutations compared to all other Arctic CDVs. PMID- 25273967 TI - Serological evidence for Parapoxvirus infection in chamois from the Tyrol regions of Austria and Italy. AB - Orf-virus (ORFV) is a parapoxvirus that infects small ruminants worldwide causing sporadic zoonotic infections, mainly transmitted by direct contact with sheep and goats. Following an ORFV case in a hunter of Alpine chamois (Rupicapra rupicapra), who did not report previous contact to domestic animals, a serological survey in Western Austria was conducted to assess the seroprevalence of ORFV in this species. In addition, this study also tested blood/tissue samples of chamois from different areas of the adjacent province of Bolzano/Northern Italy for antibodies against ORFV using immunofluorescence and ELISA. The observed seropositivity rates in the chamois tested on the Austrian and Italian side of the Alps were 23.5% and 9.5%, respectively, with a combined 95% confidence interval ranging from 0.0678 to 0.238. Although the prevalence was significantly lower than the one observed in Austrian sheep flocks, this study provided the first evidence that parapoxviruses have spilled over into chamois populations to a significant degree in the Tyrol regions of Austria and Italy. PMID- 25273968 TI - Economic burden of antibiotic resistance: how much do we really know? AB - The declining effectiveness of antibiotics imposes potentially large health and economic burdens on societies. Quantifying the economic outcomes of antibiotic resistance effectively can help policy-makers and healthcare professionals to set priorities, but determining the actual effect of antibiotic resistance on clinical outcomes is a necessary first step. In this article, we review and discuss the contributions and limitations of studies that estimate the disease burden attributable to antibiotic resistance and studies that estimate the economic burden of resistance. We also consider other factors that are important in a comprehensive approach to evaluating the economic burden of antibiotic resistance. PMID- 25273969 TI - Scytalidium dimidiatum associated invasive fungal sinusitis in an immunocompetent patient. AB - BACKGROUND: Scytalidium dimidiatum is a soil and plant pathogen that frequently affects fruit trees, but can also cause human infection. There are only two reported cases of invasive fungal sinusitis involving this rare micro-organism. OBJECTIVE: This paper reports the first case of invasive fungal sinusitis caused by Scytalidium dimidiatum occurring in a young immunocompetent patient from a non endemic region, and discusses potential sources of exposure and relevance of local factors. METHOD: Case report. RESULTS: The patient was treated successfully with a combination of functional endoscopic sinus surgery, and antifungal and corticosteroid treatment. CONCLUSION: This paper describes the first reported case of invasive fungal sinusitis secondary to Scytalidium dimidiatum in a young immunocompetent patient from a non-endemic region. Importance is placed on following a systematic process of investigation and management, and adhering to well-defined basic surgical principles. PMID- 25273970 TI - How prevalent are hazardous attitudes among orthopaedic surgeons? AB - BACKGROUND: So-called "hazardous attitudes" (macho, impulsive, antiauthority, resignation, invulnerable, and confident) were identified by the Federal Aviation Administration and the Canadian Air Transport Administration as contributing to road traffic incidents among college-aged drivers and felt to be useful for the prevention of aviation accidents. The concept of hazardous attitudes may also be useful in understanding adverse events in surgery, but it has not been widely studied. QUESTIONS/PURPOSES: We surveyed a cohort of orthopaedic surgeons to determine the following: (1) What is the prevalence of hazardous attitudes in a large cohort of orthopaedic surgeons? (2) Do practice setting and/or demographics influence variation in hazardous attitudes in our cohort of surgeons? (3) Do surgeons feel they work in a climate that promotes patient safety? METHODS: We asked the members of the Science of Variation Group-fully trained, practicing orthopaedic and trauma surgeons from around the world-to complete a questionnaire validated in college-aged drivers measuring six attitudes associated with a greater likelihood of collision and used by pilots to assess and teach aviation safety. We accepted this validation as applicable to surgeons and modified the questionnaire accordingly. We also asked them to complete the Modified Safety Climate Questionnaire, a questionnaire assessing the absence of a safety climate that is based on the patient safety cultures in healthcare organizations instrument. Three hundred sixty-four orthopaedic surgeons participated, representing a 47% response rate of those with correct email addresses who were invited. RESULTS: Thirty-eight percent (137 of 364 surgeons) had at least one score that would have been considered dangerously high in pilots (> 20), including 102 with dangerous levels of macho (28%) and 41 with dangerous levels of self-confidence (11%). After accounting for possible confounding variables, the variables most closely associated with a macho attitude deemed hazardous in pilots were supervision of surgical trainees in the operating room (p = 0.003); location of practice in Canada (p = 0.059), Europe (p = 0.021), and the United States (p = 0.005); and being an orthopaedic trauma surgeon (p = 0.046) (when compared with general orthopaedic surgeons), but accounted for only 5.3% of the variance (p < 0.001). On average, 19% of surgeon responses to the Modified Safety Climate Questionnaire implied absence of a safety climate. CONCLUSIONS: Hazardous attitudes are common among orthopaedic surgeons and relate in small part to demographics and practice setting. Future studies should further validate the measure of hazardous attitudes among surgeons and determine if they are associated with preventable adverse events. We agree with aviation safety experts that awareness of amelioration of such attitudes might improve safety in all complex, high-risk endeavors, including surgery-a line of thinking that merits additional research. PMID- 25273971 TI - Can high-friction intraannular material increase screw pullout strength in osteoporotic bone? AB - BACKGROUND: Osteoporotic bone brings unique challenges to orthopaedic surgery, including a higher likelihood of problematic screw stripping in cancellous bone. Currently, there are limited options to satisfactorily repair stripped screws. Additionally, nonstripped screws hold with less purchase in osteoporotic bone. QUESTIONS/PURPOSES: This study attempts to answer the following questions: (1) Does high-friction intraannular (HFIA) augmentation increase pullout strength in osteoporotic and in severely osteoporotic bone; and (2) can HFIA repair stripped bone thread in osteoporotic and severely osteoporotic bone? METHODS: We measured screw pullout strength using a synthetic bone model in three groups: (1) predrilled nonstripped control holes as controls; (2) predrilled nonstripped augmented with HFIA; and (3) predrilled stripped holes repaired with HFIA. We tested this in osteoporotic and severely osteoporotic synthetic bone for a total of six test groups. We measured screw pullout force using an electromechanical tensile-testing machine comparing pullout force between the test groups and controls. RESULTS: HFIA augmentation did not increase pullout force compared with the control group in the osteoporotic bone model (489 +/- 175 versus 607 +/- 76, respectively; effect size = 0.94 [95% confidence interval {CI}, -1.75 to 0.08], p = 0.06). However, in severely osteoporotic cancellous bone that was augmented, the HFIA material generated more pullout force than the control (51 +/- 18 versus 35 +/- 16, respectively; effect size = 0.94 [95% CI, -0.02 to 1.82], p = 0.05). In stripped holes, HFIA partially restored pullout strength but remained weaker than controls in both osteoporotic and severely osteoporotic bone models (osteoporotic: 320 +/- 59 versus 607 +/- 76, respectively; effect size = -4.28 [95% CI, -5.57 to -2.51], p < 0.001; severely osteoporotic: 21 +/- 8 versus 35 +/ 16, respectively; effect size = -1.13 [95% CI, -2.0 to 0.12], p = 0.027). CONCLUSIONS: HFIA effectively augmented severely osteoporotic bone for screw purchase, but this effect was not seen for osteoporotic bone. In a model simulating both osteoporotic and severely osteoporotic bone, we found that HFIA can be used to repair stripped screw holes, but the resulting construct remains weaker than nonstripped controls. CLINICAL RELEVANCE: The HFIA material looks promising as a potential solution to stripped screws in osteoporotic bone. However, this material has yet to be tested in human bone. Furthermore, the fine mesh material could be damaged by autoclaving and could break off in vivo causing unknown tissue reactions. We recommend additional testing in a living animal model to better understand how living bone will react to the HFIA material. PMID- 25273972 TI - The myths of femoroacetabular impingement. PMID- 25273973 TI - Statistics-based electron Moire technique: a novel method applied to the characterization of mesoporous structures. AB - We report a statistics-based electron Moire method in this study, for the first time, to cope with the highly distorted fringes and to realize the measurement of disordered mesoporous structures. A grey-level co-occurrence matrix is employed to determine the predominant period and the orientation of a randomly distributed Moire fringe pattern and consequently to obtain the corresponding period/orientation of the test structures. The basic principles, the method descriptions, and the relevant experiments are discussed in detail. Mesoporous alumina films are investigated with the proposed method. PMID- 25273974 TI - FunSeq2: a framework for prioritizing noncoding regulatory variants in cancer. AB - Identification of noncoding drivers from thousands of somatic alterations in a typical tumor is a difficult and unsolved problem. We report a computational framework, FunSeq2, to annotate and prioritize these mutations. The framework combines an adjustable data context integrating large-scale genomics and cancer resources with a streamlined variant-prioritization pipeline. The pipeline has a weighted scoring system combining: inter- and intra-species conservation;loss- and gain-of-function events for transcription-factor binding; enhancer-gene linkages and network centrality; and per-element recurrence across samples. We further highlight putative drivers with information specific to a particular sample, such as differential expression. FunSeq2 is available from funseq2.gersteinlab.org. PMID- 25273976 TI - Research on protein thermal condensation detection based on phase modulation SPR imaging. AB - This article presents a novel SPR imaging biomolecular interaction detection method based on time domain phase modulation. An experimental apparatus of SPR imaging biomolecular interaction detection based on TDPM is established to detect biomolecular interaction. During the experimental pretreatment process, we prepared the 2*2 lysozyme array chip and detected lysozyme thermal condensation state with the experimental apparatus. Using the Stoilov algorithm, we were able to extract the changed phase information as well as obtain the interactive SPR curves and calculate kinetic parameters. This method can sensitively acquire real time phase change caused by biomolecular interaction based on interference imaging and resolve the related bioinformation, which is a potential tool for proteomics research. PMID- 25273975 TI - Community-acquired pneumonia: impact of empirical antibiotic therapy without respiratory fluoroquinolones nor third-generation cephalosporins. AB - Guidelines for inpatients with community-acquired pneumonia (CAP) propose to use respiratory fluoroquinolone (RFQ) and/or third-generation cephalosporins (Ceph 3). However, broad-spectrum antibiotic therapy is associated with the emergence of drug-resistant bacteria. We established a guideline in which RFQ and Ceph-3 were excluded as a first course. Our aim was to evaluate the impact of our therapeutic choices for CAP on the length of hospital stay (LOS) and patient outcome. This was a cohort study of patients with CAP from July 2005 to June 2014. We compared patients benefiting from our guideline established in 2008 to those receiving non-consensual antibiotics. Disease severity was evaluated through the Pneumonia Severity Index (PSI). The empirical treatment for PSI III to V was a combination therapy of amoxicillin-clavulanic acid (AMX-C) + roxithromycin (RX) or AMX + ofloxacin. Adherence to guidelines was defined by the prescription of one of these antibiotic agents. Requirement for intensive care or death defined unfavorable outcome. Among 1,370 patients, 847 were treated according to our guideline (61.8 %, group 1) and 523 without concordant therapy (38.2 %, group 2). The mean PSI was similar: 82 vs. 83, p > 0.5. The mean LOS was lower in group 1: 7.6 days vs. 9.1 days, p < 0.001. An unfavorable outcome was less frequent in group 1: 5.4 % vs. 9.9 %, p = 0.001. In logistic regression models, concordant therapy was associated with a favorable outcome: adjusted odds ratio (AOR) [95 % confidence interval (CI)] 1.85 [1.20-2.88], p = 0.005. CAP therapy without RFQ and Ceph-3 use was associated with a shorter LOS and fewer unfavorable outcomes. PMID- 25273977 TI - The growth of charged platelets. AB - Growth models of charged nanoplatelets are investigated with Monte Carlo simulations and simple theory. In a first model, 2-dimensional simulations in the canonical ensemble are used to demonstrate that the growth of a single weakly charged platelet could be limited by its own internal repulsion. The short range attractive interaction in the crystal is modeled with a square well potential while the electrostatic interactions are described with a screened Coulomb potential. The qualitative behavior of this case can also be described by simply balancing the attractive crystal energy with the screened Coulomb repulsion between the crystal sites. This repulsion is a free energy term dominated by counterion entropy and of course reduced by added salt. For a strongly coupled system, that is with high charge density and divalent counterions as in calcium silicate hydrate, the main product of cement hydration, the screened Coulomb approximation becomes inadequate and the growth behavior has to be described with the full primitive model. In this case, the energetic interactions become relatively more important and the entropy of the system plays a minor role. As a consequence, the electrostatic interactions gradually become less of a hindrance for aggregation and in extreme cases electrostatics actually promote the growth. This is manifested as an increased aggregation with, for example, increasing surface charge density. In the presence of divalent calcium ions and at the high negative surface charge density typical for calcium silicate hydrate, electrostatic interactions are not a hindrance for an infinite growth of the particles. By combining experimental and simulated data we can show that the limited sized platelets found in cement paste is due to a very fast nucleation rate compared to the growth rate. PMID- 25273978 TI - Could clinical experience during clerkship enhance students' clinical performance? AB - BACKGROUND: Medical students learn and practice various clinical skills during clinical clerkship. Patient encounters are important for developing clinical thinking, communication skills, and professional attitude. We investigated whether the amount of clinical experience during clerkship correlated with students' clinical competency and students' perception of effectiveness of their clerkship on it. METHODS: Fourth year medical students undertook the Objective Structured Clinical Examinations (OSCE) in August 2012. Students provided the number of patients for whom they took medical histories or performed physical examinations during clerkship and provided feedback as to whether or not the clinical clerkship was helpful in preparing OSCE. The correlation between the OSCE score and number of patients was analyzed. RESULTS: One hundred thirty students completed the questionnaire (86.6%). OSCE scores correlated with the total number of patients encountered for physical examinations (correlation coefficient, 0.274; p = 0.0105). Cumulative 3-year GPAs were positively correlated with OSCE scores (correlation coefficient, 0.330; p = 0.0001). Most (92.3%) answered that their clinical clerkship was helpful in preparing them for the OSCE; however, only 20% felt that their clinical clerkship was most helpful. Others felt that role playing (38.46%) or the guide book (33.84%) was most helpful. CONCLUSIONS: The amount of clinical experience during the students' clerkship had a small but positive relationship with students' clinical performance. Further research to elucidate the influence of clinical experience on clinical competency is needed. PMID- 25273979 TI - Targeted isometric force impulses in patients with traumatic brain injury reveal delayed motor programming and change of strategy. AB - The capability of quickly (as soon as possible) producing fast uncorrected and accurate isometric force impulses was examined to assess the motor efficiency of patients with moderate to severe traumatic brain injury (TBI) and good motor recovery at a clinical evaluation. Twenty male right-handed patients with moderate to severe TBI and 24 age-matched healthy male right-handed controls participated in the study. The experimental task required subjects to aim brief and uncorrected isometric force impulses to targets visually presented along with subjects' force displays. Both TBI patients and controls were able to produce force impulses whose mean peak amplitudes varied proportionally to the target load with no detectable group difference. Patients with TBI, however, were slower than controls in initiating their responses (reaction times [RTs] were longer by 125 msec) and were also slower during the execution of their motor responses, reaching the peak forces requested 23 msec later than controls (time to peak force: 35% delay). Further, their mean dF/dt (35 kg/sec) was slower than that of controls (53 kg/sec), again indicating a 34% impairment with respect to controls. Overall, patients with TBI showed accurate but delayed and slower isometric force impulses. Thus, an evaluation taking into account also response time features is more effective in picking up motor impairments than the standard clinical scales focusing on accuracy of movement only. PMID- 25273980 TI - Diindolo[2,3-b:2',3'-f]pyrrolo[3,2-b]pyrroles as electron-rich, ladder-type fluorophores: synthesis and optical properties. AB - Previously unknown ladder-type heteroacenes were synthesized in just two steps from aromatic amines, 2-nitrobenzaldehydes, and biacetyl. A recently discovered multicomponent process affording 1,4-dihydropyrrolo[3,2-b]pyrroles was followed by the Cadogan reaction, which resulted in simultaneous closure of two additional pyrrole rings. Rod-like compounds synthesized in this way were stable in the absence of light, and they were transformed into bis(tert-butoxycarbonyl) derivatives. The rigid herringbone-like structure resulted in a strong absorption in the lambda=350-410 nm region and very strong violet and blue emission, which was bathochromically shifted relative to the emission of the parent 1,4 dihydropyrrolo[3,2-b]pyrroles. The optical properties of these compounds strongly suggest that the conjugation spanned the entire pi system. The HOMO energy level was located at -4.6 to -5.1 eV. PMID- 25273981 TI - Risk factors for cancer of cervix, status of screening and methods for its detection. AB - INTRODUCTION: Cervical cancer is a major health problem of Indian women. It is the second most cancer after breast cancer. In India, every year many women suffer from this cancer because they are illiterate and ignored about cervix cancer severity. As India is a socio-economically backward country of the world, most of the women visiting doctor are from rural areas, they have poor hygienic conditions and many more cervical cancer risk factors. RESULT: So this review is an attempt to discuss about all of the major risk factors for cervical cancer, screening factors and detection methods for cervical cancer. CONCLUSION: It aims to keep women of India keeping aside in rural areas informed about cervical cancer severity and its method of detection. PMID- 25273982 TI - Early postoperative bladder training in patients submitted to radical hysterectomy: is it still necessary? A randomized trial. AB - OBJECTIVES: To evaluate the role of bladder training during postoperative hospital stay in patients submitted to nerve-sparing radical hysterectomy, and to identify any clinical or surgical factor associated with postoperative bladder dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Parallel group randomized single institution trial, on gynaecologic malignancies patients conducted in Catholic University of Sacred Heart Rome, between April 2009 and November 2011. Randomization was on 1:1, using a block randomized computer-generated list. INTERVENTIONS: Patients underwent Querleu-Morrow type B2 or C1 radical hysterectomy. After 2 days from surgery, patients were randomized to perform or not bladder training (scheduled clamping and unclamping of the trans-urethral catheter every three hours). Main outcome measures Necessity and duration of clean intermittent self catheterization. RESULTS: Randomized participants were 111 women (bladder training arm n = 55; control arm n = 56). A total of 22 women (19.8%) required clean intermittent self catheterization, equally distributed in the two arms. At univariate analysis, only the type of radical hysterectomy was significantly associated with need of clean intermittent self catheterization (type C1 vs. type B2; p = 0.013). At univariate analysis, duration of clean intermittent self-catheterization was not associated with age, BMI, type of hysterectomy and of neo-adjuvant treatment. CONCLUSIONS: Functional bladder disfunctions are the most common long-term complications following radical hysterectomy. Systematic postoperative bladder training following nerve-sparing radical hysterectomy does not influence the rate of urinary retention or re admission for bladder catheterization. PMID- 25273984 TI - Safety and efficacy of turoctocog alfa (NovoEight(r)) during surgery in patients with haemophilia A: results from the multinational guardianTM clinical trials. AB - Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open-label guardian(TM) clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight((r))), a rFVIII product, in patients with severe haemophilia A (FVIII <= 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4-59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as 'excellent' or 'good' haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg(-1). The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery. PMID- 25273983 TI - iTRAQ-proteomics and bioinformatics analyses of mammary tissue from cows with clinical mastitis due to natural infection with Staphylococci aureus. AB - BACKGROUND: Proteomics and bioinformatics may help us better understand the biological adaptations occurring during bovine mastitis. This systems approach also could help identify biomarkers for monitoring clinical and subclinical mastitis. The aim of the present study was to use isobaric tags for relative and absolute quantification (iTRAQ) to screen potential proteins associated with mastitis at late infectious stage. RESULTS: Healthy and mastitic cows' mammary gland tissues were analyzed using iTRAQ combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS). Bioinformatics analyses of differentially expressed proteins were performed by means of Gene Ontology, metabolic pathways, transcriptional regulation networks using Blast2GO software, the Dynamic Impact Approach and Ingenuity Pathway Analysis. At a false discovery rate of 5%, a total of 768 proteins were identified from 6,499 peptides, which were matched with 15,879 spectra. Compared with healthy mammary gland tissue, 36 proteins were significantly up-regulated (>1.5-fold) while 19 were significantly down-regulated (<0.67-fold) in response to mastitis due to natural infections with Staphylococci aureus. Up-regulation of collagen, type I, alpha 1 (COL1A1) and inter-alpha (Globulin) inhibitor H4 (ITIH4) in the mastitis-infected tissue was confirmed by Western blotting and Immunohistochemistry. CONCLUSION: This paper is the first to show the protein expression in the late response to a mastitic pathogen, thus, revealing mechanisms associated with host tissue damage. The bioinformatics analyses highlighted the effects of mastitis on proteins such as collagen, fibrinogen, fibronectin, casein alpha and heparan sulfate proteoglycan 2. Our findings provide additional clues for further studies of candidate genes for mastitis susceptibility. The up-regulated expression of COL1A1 and ITIH4 in the mastitic mammary gland may be associated with tissue damage and repair during late stages of infection. PMID- 25273985 TI - Molecular typing, antibiotic resistance, virulence gene and biofilm formation of different Salmonella enterica serotypes. AB - Salmonella enterica isolates representing commonly isolated serotypes in Tunisia were analyzed using genotyping and phenotyping methods. ERIC and ITS-PCR applied to 48 Salmonella spp. isolates revealed the presence of 12 and 10 different profiles, respectively. The distribution of profiles among serotypes demonstrated the presence of strains showing an identical fingerprinting pattern. All Salmonella strains used in this study were positive for the sdiA gene. Three Salmonella isolates belonging to serotypes Anatum, Enteritidis and Amsterdam were negative for the invA gene. The spvC gene was detected in thirteen isolates belonging to serotypes Anatum, Typhimurium, Enteritidis, Gallinarum and Montevideo. Antibiotic resistance was frequent among the recovered Salmonella isolates belonging to serotypes Anatum, Typhimurium, Enteritidis, Zanzibar and Derby. The majority of these isolates exhibited resistance to at least two antibiotic families. Four multidrug-resistant isolates were recovered from food animals and poultry products. These isolates exhibited not only resistance to tetracycline, sulphonamides, and ampicillin, but also have shown resistance to fluoroquinolones. Common resistance to nalidixic acid, ciprofloxacin and ofloxacin in two S. Anatum and S. Zanzibar strains isolated from raw meat and poultry was also obtained. Furthermore, wastewater and human isolates exhibited frequent resistance to nalidixic acid and tetracycline. Of all isolates, 33.5% were able to form biofilm. PMID- 25273986 TI - Suppressor mutants from MotB-D24E and MotS-D30E in the flagellar stator complex of Bacillus subtilis. AB - The bacterial flagellar motor is mainly energized by either a proton (H(+)) or sodium ion (Na(+)) motive force and the motor torque is generated by interaction at the rotor-stator interface. MotA/MotB-type stators use H(+) as the coupling ion, whereas MotP/MotS- and PomA/PomB-type stators use Na(+). Bacillus subtilis employs both H(+)-coupled MotA/MotB and Na(+)-coupled MotP/MotS stators, which contribute to the torque required for flagellar rotation. In Escherichia coli, there is a universally conserved Asp-32 residue of MotB that is critical for motility and is a predicted H(+)-binding site. In B. subtilis, the conserved aspartic acid residue corresponds to Asp-24 of MotB (MotB-D24) and Asp-30 of MotS (MotS-D30). Here we report the isolation of two mutants, MotB-D24E and MotS-D30E, which showed a non-motile and poorly motile phenotype, respectively. Up-motile mutants were spontaneously isolated from each mutant. We identified a suppressor mutation at MotB-T181A and MotP-L172P, respectively. Mutants MotB-T181A and MotP L172P showed about 50% motility and a poorly motile phenotype compared to each wild type strain. These suppressor sites were suggested to indirectly affect the structure of the ion influx pathway. PMID- 25273987 TI - Assessment of fecal bacterial diversity among healthy piglets during the weaning transition. AB - The high level of genetic diversity in the microflora of the gastrointestinal tract has the potential to provide numerous beneficial functions to the host. Thus it is now acknowledged that the complexity in animal functioning is linked to the interacting microbiome in the gut. Despite the importance of gut microbiome, there is a lack of information concerning the microbial communities in the pig gut during the weaning transition. This study describes the fecal microbial shifts of healthy piglets during the weaning transition using barcoded pyrosequencing of the prokaryotic 16S rRNA gene. Fecal samples were obtained from 15 piglets during the pre-weaning period (fourth week after birth) and post weaning (sixth week after birth) and were subjected to community genomic DNA extraction for pyrosequencing analysis. As the piglets underwent the weaning transition a trend toward increased bacterial diversity was observed, based on species abundance as measured by the Shannon-Weaver index. Firmicutes (54.0%) and Bacteroidetes (59.6%) were the most dominant phyla during pre-weaning and post weaning, respectively. During the weaning transition a distinct shift from Bacteroides to Prevotella as the most abundant genus was observed. Additionally, we detected a number of abundant gut bacterial species that have not been reported previously. Clostridium rectum, C. clostridioforme, C. lactatifermentans and Butyricimonas virosa were uniquely detected prior to weaning while Roseburia cecicola and Blautia wexlerae were detected during the post-weaning period only. PMID- 25273988 TI - Mechanism of high trehalose accumulation in a spore clone isolated from Shirakami kodama yeast. AB - The intracellular trehalose levels in Shirakami kodama yeast, a strain of Saccharomyces cerevisiae, isolated in 1997 from leaf mold in the Shirakami Mountains and since used as a commercial baker's yeast, are remarkably high, which presumably is related to its tolerance of freezing and drought conditions. We isolated a spore clone from Shirakami kodama yeast with about 1.7-fold higher intracellular trehalose levels than the parental strain and set out to elucidate how this spore clone can accumulate intracellular trehalose to such a high concentration. The gene for trehalose 6-phosphate synthase, TPS1, was duplicated in this spore clone. Both TPS1 genes contributed to the high level of intracellular trehalose as a 3.4-fold decrease resulted from the disruption of one of the two TPS1 genes. Both Msn2 and Msn4, which bind to stress responsive elements in the promoter region of TPS1, were required for production of high levels of trehalose. Furthermore, the neutral trehalase activity of this spore clone is about 3-fold less than that of the laboratory strain although the gene for neutral trehalase, NTH1, functioned normally. These findings indicate that two TPS1 genes and the low trehalase activity are associated with high trehalose accumulation in this spore clone. The wide range of stresses of which we found the spore clone to be tolerant makes this yeast very attractive for commercial application and for further research into the mechanisms underlying stress responses and trehalose metabolism. PMID- 25273989 TI - Optimization of polyethylene glycol (PEG)-mediated DNA introduction conditions for transient gene expression in the unicellular red alga Cyanidioschyzon merolae. PMID- 25273990 TI - Construction of a genetic analysis-available multidrug sensitive yeast strain by disruption of the drug efflux system and conditional repression of the membrane barrier system. PMID- 25273992 TI - Preparing for electronic health records. PMID- 25273991 TI - A comparative effectiveness trial of postoperative management for lumbar spine surgery: changing behavior through physical therapy (CBPT) study protocol. AB - BACKGROUND: The United States has the highest rate of lumbar spine surgery in the world, with rates increasing over 200% since 1990. Medicare spends over $1 billion annually on lumbar spine surgery. Despite surgical advances, up to 40% of patients report chronic pain and disability following surgery. Our work has demonstrated that fear of movement is a risk factor for increased pain and disability and decreased physical function in patients following lumbar spine surgery for degenerative conditions. Cognitive-behavioral therapy and self management treatments have the potential to address psychosocial risk factors and improve outcomes after spine surgery, but are unavailable or insufficiently adapted for postoperative care. Our research team developed a cognitive behavioral based self-management approach to postoperative rehabilitation (Changing Behavior through Physical Therapy (CBPT)). Pilot testing of the CBPT program demonstrated greater improvement in pain, disability, physical and mental health, and physical performance compared to education. The current study compares which of two treatments provided by telephone - a CBPT Program or an Education Program about postoperative recovery - are more effective for improving patient-centered outcomes in adults following lumbar spine surgery for degenerative conditions. METHODS/DESIGN: A multi-center, comparative effectiveness trial will be conducted. Two hundred and sixty patients undergoing lumbar spine surgery for degenerative conditions will be recruited from two medical centers and community surgical practices. Participants will be randomly assigned to CBPT or Education at 6 weeks following surgery. Treatments consist of six weekly telephone sessions with a trained physical therapist. The primary outcome will be disability and secondary outcomes include pain, general health, and physical activity. Outcomes will be assessed preoperatively and at 6 weeks, 6 months and 12 months after surgery by an assessor masked to group allocation. DISCUSSION: Effective rehabilitation treatments that can guide clinicians in their recommendations, and patients in their actions will have the potential to effect change in current clinical practice. TRIAL REGISTRATION: NCT02184143. PMID- 25273994 TI - Differential methylation within the major histocompatibility complex region in rheumatoid arthritis: a replication study. PMID- 25273993 TI - Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of beta2-glycoprotein I in a mouse model of anti phospholipid antibody-induced thrombosis. AB - OBJECTIVE: IgG aPL against domain I of beta2-glycoprotein I (beta2GPI) [anti-DI (aDI)] is associated with the pathogenesis of APS, an autoimmune disease defined by thrombosis and pregnancy morbidity. To date, however, no study has demonstrated direct pathogenicity of IgG aDI in vivo. In this proof-of-concept study, we designed a novel system to affinity purify polyclonal aDI aPL in order to assess its prothrombotic ability in a well-characterized mouse microcirculation model for APS. METHODS: Two polyclonal IgG fractions were isolated from serum of a patient with APS, both with high aPL activity but differing in aDI activity (aDI-rich and aDI-poor). These IgG fractions were tested for their pathogenic ability in an in vivo mouse model of thrombosis. Male CD1 mice were injected intraperitoneally with either aDI-rich or aDI-poor IgG; as a control, IgG isolated from healthy serum was used. A pinch injury was applied to the right femoral vein and thrombus dynamics and tissue factor activity in isolated tissue were evaluated. RESULTS: Both aDI-rich and aDI-poor IgG retained aCL and anti-beta2GPI activity, while only aDI-rich IgG displayed high aDI activity, as defined by our in-house cut-offs for positivity in each assay. aDI rich IgG induced significantly larger thrombi in vivo compared with aDI-poor IgG (P < 0.0001). Similarly, aDI-rich IgG significantly enhanced the procoagulant activity of carotid artery endothelium and peritoneal macrophages isolated from experimental animals (P < 0.01). CONCLUSION: These data directly demonstrate that the ability to cause thrombosis in vivo is concentrated in the aDI fraction of aPL. PMID- 25273995 TI - Dorsal striatum is necessary for stimulus-value but not action-value learning in humans. AB - Several lines of evidence implicate the striatum in learning from experience on the basis of positive and negative feedback. However, the necessity of the striatum for such learning has been difficult to demonstrate in humans, because brain damage is rarely restricted to this structure. Here we test a rare individual with widespread bilateral damage restricted to the dorsal striatum. His performance was impaired and not significantly different from chance on several classic learning tasks, consistent with current theories regarding the role of the striatum. However, he also exhibited remarkably intact performance on a different subset of learning paradigms. The tasks he could perform can all be solved by learning the value of actions, while those he could not perform can only be solved by learning the value of stimuli. Although dorsal striatum is often thought to play a specific role in action-value learning, we find surprisingly that dorsal striatum is necessary for stimulus-value but not action value learning in humans. PMID- 25273996 TI - Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. AB - Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 +/- 7.7 years, four females) and 14 non-carriers (age 60.8 +/- 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants. PMID- 25273997 TI - Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. AB - Structural changes in Purkinje cells have been identified in the essential tremor cerebellum, although the mechanisms that underlie these changes remain poorly understood. Climbing fibres provide one of the major excitatory inputs to Purkinje cells, and climbing fibre-Purkinje cell connections are essential for normal cerebellar-mediated motor control. The distribution of climbing fibre Purkinje cell synapses on Purkinje cell dendrites is dynamically regulated and may be altered in disease states. The aim of the present study was to examine the density and distribution of climbing fibre-Purkinje cell synapses using post mortem cerebellar tissue of essential tremor cases and controls. Using vesicular glutamate transporter type 2 immunohistochemistry, we labelled climbing fibre Purkinje cell synapses of 12 essential tremor cases and 13 age-matched controls from the New York Brain Bank. Normally, climbing fibres form synapses mainly on the thick, proximal Purkinje cell dendrites in the inner portion of the molecular layer, whereas parallel fibres form synapses on the thin, distal Purkinje cell spiny branchlets. We observed that, compared with controls, essential tremor cases had decreased climbing fibre-Purkinje cell synaptic density, more climbing fibres extending to the outer portion of the molecular layer, and more climbing fibre-Purkinje cell synapses on the thin Purkinje cell spiny branchlets. Interestingly, in essential tremor, the increased distribution of climbing fibre Purkinje cell synapses on the thin Purkinje cell branchlets was inversely associated with clinical tremor severity, indicating a close relationship between the altered distribution of climbing fibre-Purkinje cell connections and tremor. These findings suggest that abnormal climbing fibre-Purkinje cell connections could be of importance in the pathogenesis of essential tremor. PMID- 25273999 TI - Cardiovascular health and protection against CVD: more than the sum of the parts? PMID- 25273998 TI - Unconscious relational encoding depends on hippocampus. AB - Textbooks divide between human memory systems based on consciousness. Hippocampus is thought to support only conscious encoding, while neocortex supports both conscious and unconscious encoding. We tested whether processing modes, not consciousness, divide between memory systems in three neuroimaging experiments with 11 amnesic patients (mean age=45.55 years, standard deviation=8.74, range=23 60) and 11 matched healthy control subjects. Examined processing modes were single item versus relational encoding with only relational encoding hypothesized to depend on hippocampus. Participants encoded and later retrieved either single words or new relations between words. Consciousness of encoding was excluded by subliminal (invisible) word presentation. Amnesic patients and controls performed equally well on the single item task activating prefrontal cortex. But only the controls succeeded on the relational task activating the hippocampus, while amnesic patients failed as a group. Hence, unconscious relational encoding, but not unconscious single item encoding, depended on hippocampus. Yet, three patients performed normally on unconscious relational encoding in spite of amnesia capitalizing on spared hippocampal tissue and connections to language cortex. This pattern of results suggests that processing modes divide between memory systems, while consciousness divides between levels of function within a memory system. PMID- 25274000 TI - Ideal cardiovascular health: associations with biomarkers and subclinical disease and impact on incidence of cardiovascular disease in the Framingham Offspring Study. AB - BACKGROUND: The American Heart Association Cardiovascular Health score (CVH score) is inversely associated with cardiovascular disease (CVD) incidence, but the mechanisms underlying this association warrant exploration. METHODS AND RESULTS: We related the CVH score to circulating biomarkers and prevalent subclinical CVD (defined as >=1 of the following: increased carotid intima-media thickness or stenosis, left ventricular hypertrophy [by ECG or echocardiography], left ventricular systolic dysfunction, microalbuminuria, and a reduced ankle brachial index) in 2680 Framingham Study participants (mean age, 58 years; 55% women). After adjustment for age and sex, an ideal CVH score (nonsmoking status, ideal body mass index, regular physical activity, healthy diet, and an optimal profile of serum cholesterol, blood pressure, and glucose; 1 point for each) was associated with higher circulating concentrations of natriuretic peptides (N terminal pro-atrial natriuretic peptide and B-type natriuretic peptide) and lower blood concentrations of plasminogen activator inhibitor-1, aldosterone, C reactive protein, D-dimer, fibrinogen, homocysteine, and growth differentiation factor-15 levels (P<0.001 for all), as well as lower odds of subclinical disease (odds ratio, 0.74 per 1-unit increase in CVH score; 95% confidence interval, 0.68 0.80). The incidence of CVD (267 events over 16 years) was inversely associated with the CVH score in age- and sex-adjusted models (hazard ratio, 0.77 per 1-unit increase in CVH score; 95% confidence interval, 0.70-0.86), which was slightly attenuated upon adjustment for biomarkers and subclinical disease (hazard ratio, 0.87; 95% confidence interval, 0.78-0.97). CONCLUSION: In our prospective community-based study, the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and subclinical disease. PMID- 25274001 TI - Initiatives for improving out-of-hospital cardiac arrest outcomes. PMID- 25274002 TI - Temporal trends in coverage of historical cardiac arrests using a volunteer-based network of automated external defibrillators accessible to laypersons and emergency dispatch centers. AB - BACKGROUND: Although increased dissemination of automated external defibrillators (AEDs) has been associated with more frequent AED use, the trade-off between the number of deployed AEDs and coverage of cardiac arrests remains unclear. We investigated how volunteer-based AED dissemination affected public cardiac arrest coverage in high- and low-risk areas. METHODS AND RESULTS: All public cardiac arrests (1994-2011) and all registered AEDs (2007-2011) in Copenhagen, Denmark, were identified and geocoded. AED coverage of cardiac arrests was defined as historical arrests <=100 m from an AED. High-risk areas were defined as those with >=1 arrest every 2 years and accounted for 1.0% of the total city area. Of 1864 cardiac arrests, 18.0% (n=335) occurred in high-risk areas throughout the study period. From 2007 to 2011, the number of AEDs and the corresponding coverage of cardiac arrests increased from 36 to 552 and from 2.7% to 32.6%, respectively. The corresponding increase for high-risk areas was from 1 to 30 AEDs and coverage from 5.7% to 51.3%, respectively. Since the establishment of the AED network (2007-2011), few arrests (n=55) have occurred <=100 m from an AED with only 14.5% (n=8) being defibrillated before the arrival of emergency medical services. CONCLUSIONS: Despite the lack of a coordinated public access defibrillation program, the number of AEDs increased 15-fold with a corresponding increase in cardiac arrest coverage from 2.7% to 32.6% over a 5-year period. The highest increase in coverage was observed in high-risk areas (from 5.7% to 51.3%). AED networks can be used as useful tools to optimize AED placement in community settings. PMID- 25274003 TI - Incidence of and factors for self-reported fragility fractures among middle-aged and elderly women in rural Korea: an 11-year follow-up study. AB - OBJECTIVES: This community-based cohort study was performed to investigate the incidence of and factors related to self-reported fragility fractures among middle-aged and elderly women living in rural Korea. METHODS: The osteoporosis cohort recruited 430 women 40 to 69 years old in 1999, and 396 of these women were followed over 11 years. In 1999, questionnaires from all participants assessed general characteristics, medical history, lifestyle, menstrual and reproductive characteristics, and bone mineral density. In 2010, self-reported fractures and the date, site, and cause of these fractures were recorded. Cox proportional hazards models were used to calculate hazard ratios (HRs). RESULTS: Seventy-six participants among 3949.7 person-years experienced fragility fractures during the 11-year follow-up. The incidence of fragility fractures was 1924.2 per 100 000 person-years (95% confidence interval [CI], 1491.6 to 2356.8). In the multivariate model, low body mass index (HR, 2.66; 95% CI, 1.13 to 6.24), a parental history of osteoporosis (HR, 2.03; 95% CI, 1.18 to 3.49), and postmenopausal status (HR, 3.50; 95% CI, 1.05 to 11.67) were significantly related to fragility fracture. CONCLUSIONS: Fracture prevention programs are needed among postmenopausal, rural, Korean women with a low body mass index and parental history of osteoporosis Korea. PMID- 25274004 TI - The need for cognitive neuropsychological assessments for estimating risk factors for obesity in adolescents. PMID- 25274006 TI - Lemierre's syndrome: when a contralateral thrombosis stirs the debate. PMID- 25274005 TI - Ventriculo-atrial defect after bioprosthetic aortic valve replacement. AB - We present a case of a 71-year-old Caucasian male with a ventriculo-atrial defect due to infective endocarditis, originating from his aortic root near a bioprosthetic aortic valve, implanted 4 years earlier. Ventriculo-atrial defects are rare and can occur after endocarditis with abscess formation, usually in native tissue. We report a ventriculo-atrial defect due to a paravalvular aortic prosthetic defect, secondary to inflammation, a novel third type of a Gerbode defect. Case presentation, clinical decision making and surgical approach are discusses in this report. PMID- 25274007 TI - Successful use of ceftaroline for the treatment of MRSA meningitis secondary to an infectious complication of lumbar spine surgery. PMID- 25274008 TI - alpha9-nicotinic acetylcholine receptors contribute to the maintenance of chronic mechanical hyperalgesia, but not thermal or mechanical allodynia. AB - BACKGROUND: The current pharmacological treatments for chronic pain are limited. The first analgesic drug approved for clinical use in decades that has a novel molecular target is the synthetic version of a naturally occurring conotoxin. Several conotoxins that target ion channels have progressed to clinical trials for the relief of pain. Vc1.1 and RgIA are analgesic alpha-conotoxins that target alpha9-subunit-containing nicotinic acetylcholine receptors (alpha9-nAChR) as well as GABAB receptor mechanisms. However, the evidence for the involvement of alpha9-nAChRs in pain is controversial. In the present study, the role of the alpha9-nAChR in pain was assessed using a battery of behavioural pain tests and pain models in alpha9-nAChR knockout (KO) mice. RESULTS: alpha9-nAChR KO mice showed normal responses to acute noxious thermal and mechanical stimuli, and developed normal chronic cold and mechanical allodynia in inflammatory and nerve injury pain models. However, KO animals developed mechanical hyperalgesia to a lesser extent than their wild type (WT) counterparts in both inflammatory and neuropathic pain models. Chronic neuropathic pain is sustained in WT mice for at least 21 days post injury, while KO mice show significant recovery by 14 days post injury. KO sham mice were also resistant to the repeated-measures effect of the noxious pain test that caused a gradual onset of mild mechanical hyperalgesia in WT sham animals. CONCLUSIONS: The alpha9-nAChR is not involved in acute pain perception or chronic thermal or mechanical allodynia or thermal hyperalgesia but does contribute to the intensity and duration of chronic mechanical hyperalgesia, suggesting that pain-relieving actions of antagonists that target this site may be restricted to high threshold mechanosensation. The alpha9-nAChR appears to be a valid target for pharmacological compounds that alleviate long-term mechanical hyperalgesia and may be of use as a prophylactic drug to prevent the development of some symptoms of chronic pain. PMID- 25274009 TI - Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis. AB - OBJECTIVE: To examine the safety, effectiveness, and cost effectiveness of long acting insulin for type 1 diabetes. DESIGN: Systematic review and network meta analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, and grey literature were searched through January 2013. STUDY SELECTION: Randomized controlled trials or non-randomized studies of long acting (glargine, detemir) and intermediate acting (neutral protamine Hagedorn (NPH), lente) insulin for adults with type 1 diabetes were included. RESULTS: 39 studies (27 randomized controlled trials including 7496 patients) were included after screening of 6501 titles/abstracts and 190 full text articles. Glargine once daily, detemir once daily, and detemir once/twice daily significantly reduced hemoglobin A1c compared with NPH once daily in network meta-analysis (26 randomized controlled trials, mean difference -0.39%, 95% confidence interval 0.59% to -0.19%; -0.26%, -0.48% to -0.03%; and -0.36%, -0.65% to -0.08%; respectively). Differences in network meta-analysis were observed between long acting and intermediate acting insulin for severe hypoglycemia (16 randomized controlled trials; detemir once/twice daily versus NPH once/twice daily: odds ratio 0.62, 95% confidence interval 0.42 to 0.91) and weight gain (13 randomized controlled trials; detemir once daily versus NPH once/twice daily: mean difference 4.04 kg, 3.06 to 5.02 kg; detemir once/twice daily versus NPH once daily: -5.51 kg, -6.56 to -4.46 kg; glargine once daily versus NPH once daily: 5.14 kg, -6.07 to -4.21). Compared with NPH, detemir was less costly and more effective in 3/14 cost effectiveness analyses and glargine was less costly and more effective in 2/8 cost effectiveness analyses. The remaining cost effectiveness analyses found that detemir and glargine were more costly but more effective than NPH. Glargine was not cost effective compared with detemir in 2/2 cost effectiveness analyses. CONCLUSIONS: Long acting insulin analogs are probably superior to intermediate acting insulin analogs, although the difference is small for hemoglobin A1c. Patients and their physicians should tailor their choice of insulin according to preference, cost, and accessibility. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013003610. PMID- 25274010 TI - Abundant kif21b is associated with accelerated progression in neurodegenerative diseases. AB - Kinesin family member 21b (kif21b) is one of the few multiple sclerosis (MS) risk genes with a presumed central nervous system function. Kif21b belongs to the kinesin family, proteins involved in intracellular transport of proteins and organelles. We hypothesised that kif21b is involved in the neurodegenerative component of MS and Alzheimer's (AD) disease. Post-mortem kinesin expression was assessed in 50 MS, 58 age and gender matched non-demented controls (NDC) and 50 AD. Kif21b expression was five-fold increased in AD compared to MS and NDC aged below 62 years (p = 8*10(-5)), three-fold between 62-72 years (p = 0.005) and not different above 72 years. No significant differences were observed between MS and NDC. In AD, kif21b expression was two-fold increased in Braak stage 6 (scoring for density of neurofibrillary tangles) compared with stage 5 (p = 0.003). In MS patients, kif21b correlated with the extent of grey matter demyelination (Spearman's rho = 0.31, p = 0.03). Abundant kif21b, defined as expression above the median, was associated with a two-fold accelerated development of the Kurtzke Expanded Disability Status Scale (EDSS) 6.0 (median time in low kif21b group 16 years vs. high kif21b 7.5 years, log-rank test p = 0.04) in MS. Given the genetic association of kif21b with MS, the results were stratified according to rs12122721[A] single nucleotide polymorphism (SNP). No association was found between kif21b expression or the time to EDSS 6 in kif21b risk SNP carriers compared to non-risk carriers. Kif21b was expressed in astrocytes in addition to neurons. Upon astrocyte activation, kif21b increased nine-fold. Abundant kif21b expression is associated with severe MS and AD pathology and with accelerated neurodegeneration independent of the kif21b risk SNP. PMID- 25274012 TI - Photoinduced transformation of UVR8 monitored by vibrational and fluorescence spectroscopy. AB - Tryptophan residues at the dimer interface of the plant photoreceptor UVR8 promote monomerisation after UV-B absorption via a so far unknown mechanism. Using FTIR spectroscopy we assign light-induced structural transitions of UVR8 mainly to amino acid side chains without major transformations of the secondary structure of the physiologically relevant C-terminal extension. Additionally, we assign the monomerisation associated increase and red shift of the UVR8 tryptophan emission to a photoinduced rearrangement of tryptophan side chains and a relocation of the aspartic acid residues D96 and D107, respectively. By illumination dependent emission spectroscopy we furthermore determined the quantum yield of photoinduced monomerisation to 20 +/- 8%. PMID- 25274011 TI - Relapsing advanced metatypical basal cell carcinomas (MTBCC) of the face: surgical modalities. AB - Metatypical basal cell carcinoma (MTBCC) represents a high-risk type of cutaneous tumour. We report about three different patients with relapsing advanced large MTBCC: one of the scalp and two of the cheek region. Such patients required in most of the cases a complex surgical approach to achieve a stable and complete remission. In the first presented patient a combination of flaps and grafts has been performed. We describe tailored surgical approaches. By this contrivance it is possible to treat even elderly patients with exposed bone after complete excision effectively and safe. Interdisciplinary team work is for the benefit of these patients. PMID- 25274013 TI - Infrared thermography detects febrile and behavioural responses to vaccination of weaned piglets. AB - An automated, non-invasive system for monitoring of thermoregulation has the potential to mitigate swine diseases through earlier detection. Measurement of radiated temperature of groups of animals by infrared thermography (IRT) is an essential component of such a system. This study reports on the feasibility of monitoring the radiated temperature of groups of animals as a biomarker of immune response using vaccination as a model for febrile disease. In Study A, weaned pigs were either treated with an intramuscular vaccine (FarrowSure Gold), a sham injection of 0.9% saline or left as untreated controls. An infrared thermal camera (FLIR A320) was fixed to the ceiling directly above the pen of animals, and recorded infrared images of the treatment groups at 5 min intervals. The effect on temperature of the spatial distribution of pigs within the pen was significant, with higher temperatures recorded when pigs were grouped together into a single cluster. A higher frequency of clustering behaviour was observed in vaccinated animals compared with controls during a period of the afternoon ~4 to 7 h post-vaccination. The daily mean of the maximum image temperature was significantly higher in vaccinated animals compared with control and sham-treated animals. In the vaccination treated group, the 24 h mean of the maximum temperature was significantly higher during the post-vaccination period compared with the 24 h period before vaccination. Increased temperature in the vaccinated animals occurred from ~3 h, peaked at ~10 h, and remained elevated for up to 20 h post-vaccination. In Study B, the effect of prevalence was tested in terms of the difference in maximum temperature between control and vaccination days. A thermal response to vaccination was detected in a pen of 24 to 26 animals when <10% of the animals were vaccinated. The results support the concept of radiated temperature measurements of groups of animals by IRT as a screening tool for febrile diseases in pig barns. PMID- 25274014 TI - Recent Trends in Sinus Lift Surgery and Their Clinical Implications. AB - BACKGROUND: Sinus lift procedures are used to allow residual bone to accommodate functional implants in atrophic posterior maxilla. Numerous anatomical and surgical advancements in sinus lift surgery are still inspiring clinicians. PURPOSE: The purpose of this study was to describe the recent trends in sinus lift surgery focusing on implant survival, bone grafting, anatomical and surgical considerations, and their clinical implications on the practice of implant dentistry in atrophic posterior maxilla. MATERIALS AND METHODS: We performed an extensive search in MEDLINE, Embase, Scopus, Web of Science, Trip, Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials, and ProQuest Dissertations & Theses. Articles were critically reviewed to determine the level of evidence as per the Canadian Task Force on Preventive Health Care. RESULTS: Comprehensive assessment of sinus septa, sinus pathology, and bone quality and quantity using three-dimensional cone beam computed tomography radiographs is important before placing implants in posterior maxilla. With a residual bone height of less than 5 mm, the survival rate of implant decreases substantially. Lateral window approach can increase the vertical bone height to greater than 9 mm, while osteotome approach can increase this height from 3 to 9 mm. The perforation of Schneiderian membrane doubles the risk for the incidence of sinusitis or infection. The use of piezoelectric surgery allows adequate sinus lift while protecting soft tissues and minimizing patient discomfort. CONCLUSIONS: Although both osteotome and lateral window procedures can help clinicians in overcoming the challenges of placing implants in atrophic posterior maxilla, pre-implant residual bone height is crucial in determining the survival of these implants. Future research directions should consider study designs grounded on longitudinal randomized controlled trials of large sample size. PMID- 25274015 TI - A web-based dietary intervention for people with type 2 diabetes: development, implementation, and evaluation. AB - BACKGROUND: Diabetes is becoming a very important health issue in rapidly developing nations and there is an urgent need to improve overall diabetes self management education in these countries. Although e-health is an emerging theme, only a few successful web-based studies on diabetes self-management have been reported. PURPOSE: We describe the development, implementation, and process evaluation of an Internet-delivered dietary intervention program (myDIDeA) for diabetic patients in a developing country. METHOD: Specific dietary components to be included in the intervention module were first identified through a comprehensive review of literature and guidelines. The lesson plans and the study website were then developed based on the evidence, Transtheoretical Model's Stages of Change and user-centered design approach. Finally, the effectiveness of the website was tested through a randomized-controlled trial to promote dietary change in patients with type 2 diabetes. The participants in the intervention group (n = 66) were given access to myDIDeA for 6 months. Process evaluation in form of intervention adherence and program reception were conducted at post intervention. RESULTS: The response rate for the process evaluation was 89%. On average, each participant logged in at least once for each lesson plan and spent almost 12 min on the site. The participants' content satisfaction, acceptability, and usability scores were satisfactory. The primary outcome of the trial, Dietary Knowledge, Attitude, and Behavior score was strongly correlated with content satisfaction (r = 0.826, p < 0.001), acceptability (r = 0.793, p < 0.001) and usability of the website (r = 0.724, p < 0.001), and moderately correlated with frequency of log-in (r = 0.501, p < 0.05) and duration spent in the website (r = 0.399, p < 0.05). CONCLUSION: The process evaluation of myDIDeA demonstrates its feasibility, and future studies should identify the possibility of extending the use of Internet-based intervention programs to other health behaviors and issues related to self-management of chronic conditions. In addition, interactivity, peer support via social media, and other means to stimulate the interest of participants can be explored. PMID- 25274016 TI - Dynamics of the Plasma Membrane Proton Pump. AB - Proton transfer over distances longer than that of a hydrogen bond often requires water molecules and protein motions. Following transfer of the proton from the donor to the acceptor, the change in the charge distribution may alter the dynamics of protein and water. To begin to understand how protonation dynamics couple to protein and water dynamics, here we explore how changes in the protonation state affect water and protein dynamics in the AHA2 proton pump. We find that the protonation state of the proton donor and acceptor groups largely affects the dynamics of internal waters and of specific hydrogen bonds, and the orientation of transmembrane helical segments that couple remote regions of the protein. The primary proton donor/acceptor group D684, can interact with water molecules from the cytoplasmic bulk and/or other protein groups. PMID- 25274017 TI - A Japanese patient with Lofgren's syndrome with an HLA-DR12 allele and review of literature on Japanese patients. AB - Sarcoidosis is a granulomatous disorder of unknown etiology, with several clinical manifestations. Lofgren's syndrome is an acute type of sarcoidosis, characterized by the triad of arthritis, erythema nodosum, and bilateral hilar lymphadenopathy (BHL), which spontaneously resolve within about 2 years. Lofgren's syndrome is common among young white women from Nordic countries and Ireland, but it is very rare in Japan. Because the incidence of Lofgren's syndrome varies according to race, most studies on Lofgren's syndrome, including HLA typing, have been reported in Western countries. Indeed, HLA-DR3 has been reported to be associated with Lofgren's syndrome in Western countries, although the association between HLA typing and Japanese Lofgren's syndrome remains unclear. Here we present a Japanese patient with Lofgren's syndrome. A 34-year old female patient was hospitalized with arthritis and erythema nodosum. Chest computed tomography revealed mediastinal and BHL. Endobronchial ultrasound-guided transbronchial needle aspiration showed non-caseating epithelioid cell granulomas. Lofgren's syndrome was thus diagnosed. Her ankle arthralgia and bilateral ankle swelling recovered without steroid treatment within two months, and the BHL almost completely diminished one year after admission. Her HLA genotype contains DR12. We also reviewed the literature on 11 Japanese patients with Lofgren's syndrome, showing that HLA-DR12 is present in five out of nine patients (55.6%). The relevant data were unavailable in the remaining three patients. Importantly, only 5.4% of registered donors in the Japan Marrow Donor Program are positive for this allele. We suggest the potential link between HLA DR12 and the pathogenesis of Lofgren's syndrome in Japanese patients. PMID- 25274018 TI - First evidence of fish larvae producing sounds. AB - The acoustic ecology of marine fishes has traditionally focused on adults, while overlooking the early life-history stages. Here, we document the first acoustic recordings of pre-settlement stage grey snapper larvae (Lutjanus griseus). Through a combination of in situ and unprovoked laboratory recordings, we found that L. griseus larvae are acoustically active during the night, producing 'knock' and 'growl' sounds that are spectrally and temporally similar to those of adults. While the exact function and physiological mechanisms of sound production in fish larvae are unknown, we suggest that these sounds may enable snapper larvae to maintain group cohesion at night when visual cues are reduced. PMID- 25274019 TI - Novel glutaminase free L-asparaginase from Nocardiopsis alba NIOT-VKMA08: production, optimization, functional and molecular characterization. AB - Studies were carried out for the optimization and production of novel extracellular glutaminase-free L-asparaginase from Nocardiopsis alba NIOT-VKMA08. Among the tested carbon and nitrogen sources, maximum L-asparaginase production was observed with a combination of L-asparagine and maltose (1.5%) and twofold increase in yield (18.47 IU mL(-1)) was observed with newly optimized NIOT asparaginase medium. Activity of the purified enzyme was moderately inhibited by various divalent cations and thiol group blocking reagents, with K(m) and V(max) of 0.127 mM and 5.50 U ug(-1). Optimum pH and temperature of purified L asparaginase for the hydrolysis of L-asparagine was 8.0 and 37 degrees C, respectively. The enzyme inhibited polyacrylamide formation in 10% solution and it was very specific for its natural substrate L-asparagine. Partial glutaminase activity was not detected, which could reduce the possibility of side effects during cancer therapy. L-Asparaginase biosynthesis gene (ansA) was cloned and transformed in E. coli JM109. The ansA gene sequence reported in this study contains several base substitutions with that of reported sequences in GenBank, resulting in altered amino acid sequences of the translated protein. PMID- 25274021 TI - Erratum to: Social Determinants of Physical Activity Among Adult Asian-Americans: Results from a Population-Based Survey in California. PMID- 25274020 TI - Automatic evidence retrieval for systematic reviews. AB - BACKGROUND: Snowballing involves recursively pursuing relevant references cited in the retrieved literature and adding them to the search results. Snowballing is an alternative approach to discover additional evidence that was not retrieved through conventional search. Snowballing's effectiveness makes it best practice in systematic reviews despite being time-consuming and tedious. OBJECTIVE: Our goal was to evaluate an automatic method for citation snowballing's capacity to identify and retrieve the full text and/or abstracts of cited articles. METHODS: Using 20 review articles that contained 949 citations to journal or conference articles, we manually searched Microsoft Academic Search (MAS) and identified 78.0% (740/949) of the cited articles that were present in the database. We compared the performance of the automatic citation snowballing method against the results of this manual search, measuring precision, recall, and F1 score. RESULTS: The automatic method was able to correctly identify 633 (as proportion of included citations: recall=66.7%, F1 score=79.3%; as proportion of citations in MAS: recall=85.5%, F1 score=91.2%) of citations with high precision (97.7%), and retrieved the full text or abstract for 490 (recall=82.9%, precision=92.1%, F1 score=87.3%) of the 633 correctly retrieved citations. CONCLUSIONS: The proposed method for automatic citation snowballing is accurate and is capable of obtaining the full texts or abstracts for a substantial proportion of the scholarly citations in review articles. By automating the process of citation snowballing, it may be possible to reduce the time and effort of common evidence surveillance tasks such as keeping trial registries up to date and conducting systematic reviews. PMID- 25274022 TI - Evaluating the Effectiveness of an Illustrated Permission/Assent Form. AB - Issues of language and literacy represent a significant barrier to participation in clinical research. This study was designed to explore whether illustrating the permission/assent (P/A) document offers an alternative strategy for communicating study related information to underserved populations. Participants were verbally introduced to a mock study and asked to review the corresponding P/A form with companion pictorials. Questionnaires were used to examine whether the form addressed essential elements of a P/A (as defined under the Code of Federal Regulations) and evaluate the effectiveness of the companion pictures. Over 93% of participants agreed that the form addressed the required basic elements of a P/A. Pictures depicting study procedures were highly effective while images depicting nebulous concepts such as research and voluntariness were deemed less effective. The medical research community can expand enrollment opportunities to underserved populations by using visual aids to complement the informed consent process. PMID- 25274024 TI - Synthesis and structures of doubly-bridged dicyclopentadienyl dinuclear rhenium complexes, and their photochemical reactions with aromatic halides in benzene. AB - Reaction of the doubly-bridged biscyclopentadienes (C5H4(EMe2))(C5H4(SiMe2)) (E = Si(1a), or C(1b)) with Re2(CO)10 in refluxing mesitylene gave the corresponding dirhenium carbonyl complexes [(eta(5)-C5H3)2(EMe2)(SiMe2)][Re(CO)3]2 (trans-2a,b and cis-2a,b), and the desilylated products [(eta(5)-C5H4)2(EMe2)][Re(CO)3]2 (3a,b). Photolysis of trans-2a,b with a series of aryl halides in benzene results in the formation of biphenyl, together with the corresponding rhenium dihalide complexes trans-[(eta(5)-C5H3)2(EMe2)(SiMe2)][Re(CO)3][Re(CO)2X2] (X = Cl, Br, I) (4, 6, 8, or 10) and trans-[(eta(5)-C5H3)2(EMe2)(SiMe2)][Re(CO)2X2]2 (5, 7, or 9). Additional experiments indicate that one phenyl ring in the resulting biphenyl comes from aryl halides and the other phenyl ring comes from the solvent benzene. However, photolysis of trans-2a with benzyl chloride and n-hexyl chloride in benzene afforded the corresponding bibenzyl and n-dodecane, as well as the rhenium dichlorides 8 and 9. In addition, complex trans-2a can also activate the C-F bond on C6F6 to form the pentafluorophenyl rhenium fluoride trans-[(eta(5)-C5H3)2(SiMe2)2][Re(CO)3][Re(CO)2(C6F5)F] (11). Molecular structures of cis-2a, cis-2b, trans-2b, 3b, 6, 7, 8, 11, and 12 determined by X ray diffraction are also presented. PMID- 25274023 TI - Cultural beliefs and understandings of cervical cancer among Mexican immigrant women in Southeast Georgia. AB - Rural Mexican immigrant women in the U.S. are infrequently screened and experience health disparities from cervical cancer. We explored cancer-related cultural beliefs in this population. We administered a cross-sectional survey to 39 Mexican immigrant women due for screening. We conducted univariate and bivariate analyses of participants' characteristics, Pap test history, cancer related knowledge and beliefs, and cultural consensus analysis about causes of cervical cancer and barriers to screening. For all the cultural consensus tasks, there was consensus (Eigenratios >3:1) among survey participants. Comparing the rankings of risk factor clusters, clusters related to sexual behaviors were ranked more severely than clusters related to genetic or other behavioral factors. There was agreement on ideas of cervical cancer causation and barriers to screening among these women. Hence, improved methods of disseminating important health information and greater access to care are needed, particularly in relationship to stigma about sex and birth control practices. PMID- 25274025 TI - So, if I travel to "Venezuela", can I get coccidioidomycosis? PMID- 25274026 TI - Monounsaturated fatty acids, olive oil and health status: a systematic review and meta-analysis of cohort studies. AB - BACKGROUND: The aim of the present meta-analysis of cohort studies was to focus on monounsaturated fat (MUFA) and cardiovascular disease, cardiovascular mortality as well as all-cause mortality, and to distinguish between the different dietary sources of MUFA. METHODS: Literature search was performed using the electronic databases PUBMED, and EMBASE until June 2nd, 2014. Study specific risk ratios and hazard ratios were pooled using a inverse variance random effect model. RESULTS: Thirty-two cohort studies (42 reports) including 841,211 subjects met the objectives and were included. The comparison of the top versus bottom third of the distribution of a combination of MUFA (of both plant and animal origin), olive oil, oleic acid, and MUFA:SFA ratio in each study resulted in a significant risk reduction for: all-cause mortality (RR: 0.89, 95% CI 0.83, 0.96, p = 0.001; I2 = 64%), cardiovascular mortality (RR: 0.88, 95% CI 0.80, 0.96, p = 0.004; I2 = 50%), cardiovascular events (RR: 0.91, 95% CI 0.86, 0.96, p = 0.001; I2 = 58%), and stroke (RR: 0.83, 95% CI 0.71, 0.97, p = 0.02; I2 = 70%). Following subgroup analyses, significant associations could only be found between higher intakes of olive oil and reduced risk of all-cause mortality, cardiovascular events, and stroke, respectively. The MUFA subgroup analyses did not reveal any significant risk reduction. CONCLUSION: The results indicate an overall risk reduction of all-cause mortality (11%), cardiovascular mortality (12%), cardiovascular events (9%), and stroke (17%) when comparing the top versus bottom third of MUFA, olive oil, oleic acid, and MUFA:SFA ratio. MUFA of mixed animal and vegetable sources per se did not yield any significant effects on these outcome parameters. However, only olive oil seems to be associated with reduced risk. Further research is necessary to evaluate specific sources of MUFA (i.e. plant vs. animal) and cardiovascular risk. PMID- 25274028 TI - Interaction of beta-cyclodextrin with nile red in a single live CHO cell: an initiative towards developing a prospective strategy for the excretion of adsorbed drugs from the cell membrane. AB - A successful endeavour has been made to develop a prospective strategy to oust the drug molecules adsorbed on the cell membranes by simply using the non-toxic beta-cyclodextrin (beta-CD). For this purpose, fluorescent probes of different geometries and charge characteristics, namely phenosafranin (PSF) and nile red (NR), were exploited for the in vitro studies using different lipids as model membranes. Considering the success of the in vitro study, the present work is extended to a live Chinese Hamster Ovary (CHO) cell using the dye NR acting as a model drug system. Steady state and time resolved confocal microscopic studies reveal that with the introduction of beta-CD, some of the adsorbed dye molecules are dislodged from the CHO cell membrane to the nanocavity of beta-CD resulting in the formation of dye-beta-CD inclusion complex. This study promises the development of a prospective strategy for the removal of the adsorbed drugs from the cell membranes. PMID- 25274027 TI - Transient partial permeabilization with saponin enables cellular barcoding prior to surface marker staining. AB - Fluorescent cellular barcoding and mass-tag cellular barcoding are cytometric methods that enable high sample throughput, minimize inter-sample variation, and reduce reagent consumption. Previously employed barcoding protocols require that barcoding be performed after surface marker staining, complicating combining the technique with measurement of alcohol-sensitive surface epitopes. This report describes a method of barcoding fixed cells after a transient partial permeabilization with 0.02% saponin that results in efficient and consistent barcode staining with fluorescent or mass-tagged reagents while preserving surface marker staining. This approach simplifies barcoding protocols and allows direct comparison of surface marker staining of multiple samples without concern for variations in the antibody cocktail volume, antigen-antibody ratio, or machine sensitivity. Using this protocol, cellular barcoding can be used to reliably detect subtle differences in surface marker expression. PMID- 25274029 TI - Priority for EU commissioner is implementing tighter rules on tobacco. PMID- 25274032 TI - Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD L1 blockade. AB - Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with alphaPD 1 or alphaPD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFNgamma produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes. PMID- 25274031 TI - Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. AB - Emerging evidence suggests that cytotoxic therapy may actually promote drug resistance and metastasis while inhibiting the growth of primary tumors. Work in preclinical models of breast cancer has shown that acquired chemoresistance to the widely used drug paclitaxel can be mediated by activation of the Toll-like receptor TLR4 in cancer cells. In this study, we determined the prometastatic effects of tumor-expressed TLR4 and paclitaxel therapy and investigated the mechanisms mediating these effects. While paclitaxel treatment was largely efficacious in inhibiting TLR4-negative tumors, it significantly increased the incidence and burden of pulmonary and lymphatic metastasis by TLR4-positive tumors. TLR4 activation by paclitaxel strongly increased the expression of inflammatory mediators, not only locally in the primary tumor microenvironment but also systemically in the blood, lymph nodes, spleen, bone marrow, and lungs. These proinflammatory changes promoted the outgrowth of Ly6C(+) and Ly6G(+) myeloid progenitor cells and their mobilization to tumors, where they increased blood vessel formation but not invasion of these vessels. In contrast, paclitaxel mediated activation of TLR4-positive tumors induced de novo generation of deep intratumoral lymphatic vessels that were highly permissive to invasion by malignant cells. These results suggest that paclitaxel therapy of patients with TLR4-expressing tumors may activate systemic inflammatory circuits that promote angiogenesis, lymphangiogenesis, and metastasis, both at local sites and premetastatic niches where invasion occurs in distal organs. Taken together, our findings suggest that efforts to target TLR4 on tumor cells may simultaneously quell local and systemic inflammatory pathways that promote malignant progression, with implications for how to prevent tumor recurrence and the establishment of metastatic lesions, either during chemotherapy or after it is completed. PMID- 25274033 TI - Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer. AB - Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3 mediated effects, SPOP also exerts SRC-3-independent effects that are AR mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP. PMID- 25274035 TI - The potential beneficial role of faecal microbiota transplantation in diseases other than Clostridium difficile infection. AB - This review gives an outline of the indications for faecal microbiota transplantation (FMT) for diseases other than Clostridium difficile (C. difficile) infection. The remarkable efficacy of FMT against C. difficile infection has already been demonstrated. The use of FMT for other diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and metabolic syndrome, is now being evaluated. The currently available data suggest that FMT might be beneficial for IBD (including ulcerative colitis and, to some extent, Crohn's disease), IBS, and insulin resistance. Several randomized clinical trials are currently being performed, and data are eagerly awaited. A new field of research for the implementation of FMT is the eradication of pathogenic and multiresistant enteric microorganisms. A few animal studies have been performed within this field, but hardly any research data from human studies are available at present. PMID- 25274034 TI - Malignant stroma increases luminal breast cancer cell proliferation and angiogenesis through platelet-derived growth factor signaling. AB - BACKGROUND: Luminal, estrogen receptor-positive breast cancers represent more than 70% of cases. Despite initial good prognoses one third of Luminal cancers eventually recur locally or at distant sites and exhibit hormone resistance. Here we demonstrate that factors elaborated by malignant stromal cells can induce Luminal tumor cells proliferation and promote angiogenesis and hormone independence. We recently isolated a malignant mouse mammary gland stromal cell line named BJ3Z that increases proliferation and angiogenesis in estrogen-free xenografted Luminal MCF-7 breast cancer cells. METHODS: BJ3Z and Normal mouse mammary Fibroblasts (NMFs) were expression profiled using microarray assays. Messenger RNA levels were confirmed by RT-PCR and by immunohistochemistry (IHC). Breast cancer MCF-7, BT-474, BT-20 and MDA-MB-231cell lines and stromal BJ3Z and NMFs were grown for in vitro assays: breast cancer cell lines were treated with stromal cells conditioned media, for three-dimensional (3D) mono and co-cultures in Matrigel, proliferation was measured by Bromo-deoxyuridine (BrdU) incorporation using IHC. Tubule formation in vitro, a proxy for angiogenesis, was assessed using 3D cultured Human Umbilical cord Vascular Endothelial Cells (HUVEC). RESULTS: We show that under estrogen-free conditions, BJ3Z cells but not NMFs increase proliferation of co-cultured Luminal but not basal-like human breast cancer cells in 2D or as 3D Matrigel colonies. Gene expression profiling, RT-PCR analysis and IHC of colony-derived BJ3Z cells and NMFs shows that Platelet Derived Growth Factor ligands (PDGF-A and -B) are elaborated by BJ3Z cells but not NMFs; while PDGF receptors are present on NMFs but not BJ3Z cells. As a result, in colony co-culture assays, BJ3Z cells but not NMFs increase MCF-7 cell proliferation. This can be mimicked by direct addition of PDGF-BB, and blocked by the PDGF receptor inhibitor Imatinib Mesylate. Both normal and malignant stromal cells enhance angiogenesis in an in vitro model. This effect is also due to PDGF and is suppressed by Imatinib. CONCLUSIONS: We provide evidence that Luminal breast cancer cells can be targeted by the PDGF signaling pathway leading to estrogen-independent proliferation and angiogenesis. We speculate that stroma directed therapies, including anti-PDGFR agents like Imatinib, may be useful in combination with other therapies for treatment of luminal cancers. PMID- 25274036 TI - Vitamin D status and incidence of tuberculosis infection conversion in contacts of pulmonary tuberculosis patients: a prospective cohort study. AB - The objective of this study was to estimate the relationship between serum vitamin D (VitD) status and tuberculosis (TB) infection conversion (TBIC), measured by the tuberculin skin test (TST) and an interferon-gamma release assay, the QuantiFERON-TB Gold In-Tube (QFT-GIT) test, in the contacts of pulmonary TB patients in Castellon (Spain) in a prospective cohort study from 2010 to 2012. Initially, the participants were negative to latent TB infection after a screening that included TST and QFT-GIT tests, and other examinations. A baseline determination of 25-hydroxyvitamin D [25(OH)D] was obtained by chemiluminescence immunoassay. After 8-10 weeks, participants were screened for a second time to determine TB infection conversion (TBIC). Poisson regression models were used in the statistical analysis. Of the 247 participants in the cohort, 198 (80.2%) were screened twice and 18 (9.1%) were TBIC cases. The means of VitD concentration in the TBIC cases and the non-cases were 20.7+/-11.9 and 27.2+/-11.4 ng/ml (P = 0.028), respectively. Adjusted for high exposure and TB sputum acid-fast bacilli (AFB)-positive index case, higher serum VitD concentration was associated with low incidence of TBIC (P trend = 0.005), and an increase of 1 ng/ml VitD concentration decreased the incidence of TBIC by 6% (relative risk 0.94, 95% confidence interval 0.90-0.99, P = 0.015). The results suggest that sufficient VitD level could be a protective factor of TBIC. PMID- 25274037 TI - Supervisor variance in psychotherapy outcome in routine practice. AB - OBJECTIVE: Although supervision has long been considered as a means for helping trainees develop competencies in their clinical work, little empirical research has been conducted examining the influence of supervision on client treatment outcomes. Specifically, one might ask whether differences in supervisors can predict/explain whether clients will make a positive or negative change through psychotherapy. METHOD: In this naturalistic study, we used a large (6521 clients seen by 175 trainee therapists who were supervised by 23 supervisors) 5-year archival data-set of psychotherapy outcomes from a private nonprofit mental health center to test whether client treatment outcomes (as measured by the OQ 45.2) differed depending on who was providing the supervision. Hierarchical linear modeling was used with clients (Level 1) nested within therapists (Level 2) who were nested within supervisors (Level 3). RESULTS: In the main analysis, supervisors explained less than 1% of the variance in client psychotherapy outcomes. CONCLUSIONS: Possible reasons for the lack of variability between supervisors are discussed. PMID- 25274038 TI - Family history in the Finnish Prostate Cancer Screening Trial. AB - Family history (FH) is one of the few known risk factors for prostate cancer (PC). There is also new evidence about mortality reduction in screening of PC with prostate-specific antigen (PSA). Therefore, we conducted a prospective study in the Finnish Prostate Cancer Screening Trial to evaluate the impact of FH on outcomes of PC screening. Of the 80,144 men enrolled, 31,866 men were randomized to the screening arm and were invited for screening with PSA test (cut-off 4 ng/ml) every 4 years. At the time of each invitation, FH of PC (FH) was assessed through a questionnaire. The analysis covered a follow-up of 12 years from randomization for all men with data on FH. Of the 23,702 (74.3%) invited men attending screening, 22,756 (96.0%) provided information of their FH. Altogether 1,723 (7.3%) men reported at least one first-degree relative diagnosed with PC and of them 235 (13.6%) were diagnosed with PC. Men with a first-degree FH had increased risk for PC (risk ratio (RR) 1.31, p < 0.001) and the risk was especially elevated for interval cancer (RR 1.65, 95% CI 1.27-2.15). Risk for low grade (Gleason 2-6) tumors was increased (RR 1.46, 95% CI 1.15-1.69), but it was decreased for Gleason 8-10 tumors (RR 0.48, 95% CI 0.25-0.95). PSA test performance (sensitivity and specificity) was slightly inferior for FH positives. No difference in PC mortality was observed in terms of FH. Our findings provide no support for selective PSA screening targeting men with FH of PC. PMID- 25274040 TI - Universals versus historical contingencies in lexical evolution. AB - The frequency with which we use different words changes all the time, and every so often, a new lexical item is invented or another one ceases to be used. Beyond a small sample of lexical items whose properties are well studied, little is known about the dynamics of lexical evolution. How do the lexical inventories of languages, viewed as entire systems, evolve? Is the rate of evolution of the lexicon contingent upon historical factors or is it driven by regularities, perhaps to do with universals of cognition and social interaction? We address these questions using the Google Books N-Gram Corpus as a source of data and relative entropy as a measure of changes in the frequency distributions of words. It turns out that there are both universals and historical contingencies at work. Across several languages, we observe similar rates of change, but only at timescales of at least around five decades. At shorter timescales, the rate of change is highly variable and differs between languages. Major societal transformations as well as catastrophic events such as wars lead to increased change in frequency distributions, whereas stability in society has a dampening effect on lexical evolution. PMID- 25274041 TI - In Vitro Comparison of Marginal and Internal Fit of Press-on-Metal Ceramic (PoM) Restorations with Zirconium-Supported and Conventional Metal Ceramic Fixed Partial Dentures Before and After Veneering. AB - PURPOSE: To compare marginal and internal fit between 3- and 4-unit press-on metal (PoM) ceramic, zirconia-supported, and conventional metal ceramic fixed partial dentures (FPDs) before and after veneering. MATERIALS AND METHODS: Ten pieces for each 3- and 4-unit MC, IPS InLine PoM, and IPS e.max ZirCAD/Zir Press FPDs were produced. Cross-sections from silicone replicas were examined and measured with a light microscope. Occlusal, axial, intermarginal, and marginal mean adaptation scores of cross-sectioned replicas and means of measurements obtained from 4 sites were calculated independently. RESULTS: Mean values for molars were 78.44 +/- 32.01 MUm (MC), 89.84 +/- 29.20 MUm (PoM), and 85.17 +/- 28.49 MUm (Zir). Premolar values were 76.08 +/- 27.92 MUm (MC), 89.94 +/- 23.49 MUm (PoM), and 87.18 +/- 28.25 MUm (Zir). No difference existed between the means of 3- and 4-unit FPDs except the molar-intermarginal region. The mean value of 4 unit FPDs (93.88 +/- 25.41 MUm) was less than the 3-unit FPDs (103.68 +/- 24.55 MUm) at the molar-inter marginal region. A gap increase was observed in all sites except the molar-axio-occlusal region after veneering. According to the mean difference, gap increases at the molar-marginal, molar-intermarginal, and premolar-intermarginal regions were statistically significant. A statistical difference was found at the molar-marginal region for 4-unit MCR (p = 0.041) and 4-unit PoM FPDs (p = 0.042) before and after veneering. Gap increase after veneering of 4-unit metal ceramics at molar-intermarginal, premolar-marginal, and premolar-intermarginal regions (p = 0.020; p = 0.015; p = 0.004) was significant. CONCLUSION: The gap measurements of the IPS InLine PoM and IPS e.max ZirCAD/Zir Press groups were all clinically acceptable. No studies on marginal and internal fit in the IPS InLine PoM system have been published to date. This study should be supported with future studies. No significant increase was observed after press-veneering the IPS e.max ZirCAD frameworks with an IPS e.max ZirPress material; therefore, we recommend the use of this combination. PMID- 25274039 TI - A systematic genetic screen identifies new factors influencing centromeric heterochromatin integrity in fission yeast. AB - BACKGROUND: Heterochromatin plays important roles in the regulation and stability of eukaryotic genomes. Both heterochromatin components and pathways that promote heterochromatin assembly, including RNA interference, RNAi, are broadly conserved between the fission yeast Schizosaccharomyces pombe and humans. As a result, fission yeast has emerged as an important model system for dissecting mechanisms governing heterochromatin integrity. Thus far, over 50 proteins have been found to contribute to heterochromatin assembly at fission yeast centromeres. However, previous studies have not been exhaustive, and it is therefore likely that further factors remain to be identified. RESULTS: To gain a more complete understanding of heterochromatin assembly pathways, we have performed a systematic genetic screen for factors required for centromeric heterochromatin integrity. In addition to known RNAi and chromatin modification components, we identified several proteins with previously undescribed roles in heterochromatin regulation. These included both known and newly characterised splicing-associated proteins,which are required for proper processing of centromeric transcripts by the RNAi pathway, and COP9 signalosome components Csn1 and Csn2, whose role in heterochromatin assembly can be explained at least in part by a role in the Ddb1 dependent degradation of the heterochromatin regulator Epe1. CONCLUSIONS: This work has revealed new factors involved in RNAi-directed heterochromatin assembly in fission yeast. Our findings support and extend previous observations that implicate components of the splicing machinery as a platform for RNAi, and demonstrate a novel role for the COP9 signalosome in heterochromatin regulation. PMID- 25274042 TI - Selective gas adsorption in a pair of robust isostructural MOFs differing in framework charge and anion loading. AB - Activation of the secondary assembly instructions in the mononuclear pyrazine imide complexes [Co(III)(dpzca)2](BF4) or [Co(II)(dpzca)2] and [Ni(II)(dpzca)2] has facilitated the construction of two robust nanoporous three-dimensional coordination polymers, [Co(III)(dpzca)2Ag](BF4)2.2(H2O) [1.2(H2O)] and [Ni(II)(dpzca)2Ag]BF4.0.5(acetone) [2.0.5(acetone)]. Despite the difference in charge distribution and anion loading, the framework structures of 1.2(H2O) and 2.0.5(acetone) are isostructural. One dimensional channels along the b-axis permeate the structures and contain the tetrafluoroborate counterions (the Co(III)-based MOF has twice as many BF4(-) anions as the Ni(II)-based MOF) and guest solvent molecules. These anions are not readily exchanged whereas the solvent molecules can be reversibly removed and replaced. The H2, N2, CO2, CH4, H2O, CH3OH, and CH3CN sorption behaviors of the evacuated frameworks 1 and 2 at 298 K have been studied, and modeled, and both show very high selectivity for CO2 over N2. The increased anion loading in the channels of Co(III)-based MOF 1 relative to Ni(II)-based MOF 2 results in increased selectivity for CO2 over N2 but a decrease in the sorption kinetics and storage capacity of the framework. PMID- 25274043 TI - Enantioselective radical alkynylation of C(sp(3) )-H bonds using sulfoximine as a traceless chiral auxiliary. AB - Enantioselective alkynylation of C(sp(3) )?H bonds adjacent to a nitrogen atom has been achieved using only chiral p-tolyl tert-butyldimethylsilylethynyl sulfoximine and benzophenone under photo-irradiation conditions. A two-carbon alkyne unit was chemo- and enantioselectively transferred at the nitrogen substituted methylene to produce the optically active propargylic amines of various structures. Remarkably, the NH-unprotected sulfoximine group efficiently transmits its stereochemical information to the product and functions as a traceless chiral auxiliary. PMID- 25274044 TI - Mortality after tonsil surgery, a population study, covering eight years and 82,527 operations in Sweden. AB - The objective of this retrospective cohort study was to evaluate mortality rate and cause of death after tonsil surgery in Sweden. Two national registries were used, both run by The Swedish National Board of Health and Welfare, an agency of the Ministry of Health and Social Affairs. In the National Patient register all tonsil surgeries performed in Sweden from 2004 through 2011 were identified. The result from this search was matched with the National Cause of Death Register to identify all deaths that occurred within 30 days of tonsil surgery. Personal identity numbers were used to do the matching of registers. Details on the cause of death were obtained from the Swedish National Board of Health and Welfare. Two deaths were identified in 82,527 operations. Both patients were male, otherwise healthy, children under the age of five, operated due to tonsil-related upper airway obstruction/snoring with coblation technique. Cause of death was bleeding related airway obstruction in both cases and hemodynamic failure caused by blood loss. Both deaths occurred after discharge from the hospital within the first postoperative week. No abnormal levels of analgesics were found in the postmortal investigations. Two deaths related to tonsil surgery (performed on benign indications) were identified in 82,527 operations (2004-2011) in a well-defined national population. Both deaths were due to postoperative bleeding. Based on our findings, the frequency of post-tonsil-surgery mortality in Sweden was 1/41,263, 2004-2011. Level of evidence 2b retrospective cohort study. PMID- 25274045 TI - RhoGDI2 expression in astrocytes after an excitotoxic lesion in the mouse hippocampus. AB - The Rho GDP-dissociation inhibitor (RhoGDI) originally downregulates Rho family GTPases by preventing nucleotide exchange and membrane association. Although RhoGDI2 functions as a metastasis regulator, little is known in glial cells under neuropathological conditions. We monitored RhoGDI2 expression in the mouse brain after administering a kainic acid(KA)-induced excitotoxic lesion. In control, RhoGDI2 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus. However, RhoGDI2 IR was increased in astrocytes markedly throughout the hippocampus at day 3 post-treatment with KA. To further investigate the molecular mechanism of RhoGDI2-induced cellular migration, primary astrocytes were transfected with the flag-tagged RhoGDI2 cDNA. Cell migration assay revealed that RhoGDI2 cDNA transfection inhibits astrocyte migration. Overexpression of RhoGDI2 leads to inhibit protein kinase B (PKB) activation and cdc42 and cAMP responsive element-binding protein (CREB) phosphorylation. In conclusion, our results suggested for the first time that RhoGDI2 is required for PKB and CREB activation and cdc42 expression in astrocyte migration after KA-mediated excitotoxic lesion in mouse brain. PMID- 25274046 TI - Age-associated changes of nitric oxide concentration dynamics in the central nervous system of Fisher 344 rats. AB - The increase in life expectancy is accompanied by an increased risk of developing neurodegenerative disorders and age is the most relevant risk factor for the appearance of cognitive decline. While decreased neuronal count has been proposed to be a major contributing factor to the appearance of age-associated cognitive decline, it appears to be insufficient to fully account for the decay in mental function in aged individuals. Nitric oxide ((*)NO) is a ubiquitous signaling molecule in the mammalian central nervous system. Closely linked to the activation of glutamatergic transmission in several structures of the brain, neuron-derived (*)NO can act as a neuromodulator in synaptic plasticity but has also been linked to neuronal toxicity and degenerative processes. Many studies have proposed that changes in the glutamate-(*)NO signaling pathway may be implicated in age-dependent cognitive decline and that the exact effect of such changes may be region specific. Due to its peculiar physical-chemical properties, namely hydrophobicity, small size, and rapid diffusion properties, the rate and pattern of (*)NO concentration changes are critical determinants for the understanding of its bioactivity in the brain. Here we show a detailed study of how (*)NO concentration dynamics change in the different regions of the brain of Fisher 344 rats (F344) during aging. Using microelectrodes inserted into the living brain of anesthetized F344 rats, we show here that glutamate-induced (*)NO concentration dynamics decrease in the hippocampus, striatum, and cerebral cortex as animals age. performance in behavior testing of short-term and spatial memory, suggesting that the impairment in the glutamate:nNOS pathway represents a functional critical event in cognitive decline during aging. PMID- 25274047 TI - The (Na(+)/K (+))-ATPase activity in the developing rat retina: the role of insulin-like growth factor-I (IGF-I). AB - In this work, the (Na(+)/K(+))-ATPase activity was evaluated during the early stages of the postnatal development of rat retina and showed an almost three-time increase from P0 to P14. Expression of the three catalytic subunit isoforms (alpha1, alpha2, and alpha3) of the (Na(+)/K(+))-ATPase was also evaluated by immunoblot in the same period, but no correlation to the catalytic activity increment was observed. On the other hand, immunolocalization of these three alpha-catalytic isoforms in the developing retina showed an age-related pattern. Involvement of IGF-I in the stimulation of the (Na(+)/K(+))-ATPase was investigated. Our results demonstrate that the exogenous IGF-I (10 ng/mL) stimulates enzyme activity at the age of P7 only. Incubation of retinas with 10 MUM I-OMe-AG 538 (inhibitor of the IGF-I receptor) indicates that the basal (Na(+)/K(+))-ATPase activity is sustained by endogenous IGF-I in P7 animals. These data were corroborated by an age-dependent decrease in the immunodetection of endogenous IGF-I as well as in the phosphorylation level of its cognate receptor in rat retina homogenates. The signaling pathway involved in IGF-I induced modulation of the (Na(+)/K(+))-ATPase was also investigated. Our data show that the inhibitory effects induced by I-OMe-AG 538 and the PI 3-kinase inhibitor Ly 294002 on the basal (Na(+)/K(+))-ATPase activity were non cumulative. Furthermore, IGF-I induced phosphorylation of PKB in a Ly 294002 sensitive manner. Together, these data demonstrate that the PI 3-kinase/PKB signaling pathway is involved in the IGF-I-sustained basal (Na(+)/K(+))-ATPase activity during the first 7 days of the postnatal development of rat retina. PMID- 25274048 TI - Impact of adding therapeutic recommendations to risk assessments from a prediction model for postoperative nausea and vomiting. AB - BACKGROUND: In a large cluster-randomized trial on the impact of a prediction model, presenting the calculated risk of postoperative nausea and vomiting (PONV) on-screen (assistive approach) increased the administration of risk-dependent PONV prophylaxis by anaesthetists. This change in therapeutic decision-making did not improve the patient outcome; that is, the incidence of PONV. The present study aimed to quantify the effects of adding a specific therapeutic recommendation to the predicted risk (directive approach) on PONV prophylaxis decision-making and the incidence of PONV. METHODS: A prospective before-after study was conducted in 1483 elective surgical inpatients. The before-period included care-as-usual and the after-period included the directive risk-based (intervention) strategy. Risk-dependent effects on the administered number of prophylactic antiemetics and incidence of PONV were analysed by mixed-effects regression analysis. RESULTS: During the intervention period anaesthetists administered 0.5 [95% confidence intervals (CIs): 0.4-0.6] more antiemetics for patients identified as being at greater risk of PONV. This directive approach led to a reduction in PONV [odds ratio (OR): 0.60, 95% CI: 0.43-0.83], with an even greater reduction in PONV in high-risk patients (OR: 0.45, 95% CI: 0.28-0.72). CONCLUSIONS: Anaesthetists administered more prophylactic antiemetics when a directive approach was used for risk-tailored intervention compared with care-as usual. In contrast to the previously studied assistive approach, the increase in PONV prophylaxis now resulted in a lower PONV incidence, particularly in high risk patients. When one aims for a truly 'PONV-free hospital', a more liberal use of prophylactic antiemetics must be accepted and lower-risk thresholds should be set for the actionable recommendations. PMID- 25274050 TI - The 65th annual meeting of the american association for the study of liver diseases: the liver meeting 2014. PMID- 25274051 TI - Meeting-at-a-Glance. PMID- 25274053 TI - Continuing medical education and disclosures. PMID- 25274049 TI - Effect of prehabilitation on objectively measured physical fitness after neoadjuvant treatment in preoperative rectal cancer patients: a blinded interventional pilot study. AB - BACKGROUND: Patients requiring surgery for locally advanced rectal cancer often additionally undergo neoadjuvant chemoradiotherapy (NACRT), of which the effects on physical fitness are unknown. The aim of this feasibility and pilot study was to investigate the effects of NACRT and a 6 week structured responsive exercise training programme (SRETP) on oxygen uptake [Formula: see text] at lactate threshold ([Formula: see text]) in such patients. METHODS: We prospectively studied 39 consecutive subjects (27 males) with T3-4/N+ resection margin threatened rectal cancer who completed standardized NACRT. Subjects underwent cardiopulmonary exercise testing at baseline (pre-NACRT), at week 0 (post-NACRT), and week 6 (post-SRETP). Twenty-two subjects undertook a 6 week SRETP on a training bike (three sessions per week) between week 0 and week 6 (exercise group). These were compared with 17 contemporaneous non-randomized subjects (control group). Changes in [Formula: see text] at [Formula: see text] over time and between the groups were compared using a compound symmetry covariance linear mixed model. RESULTS: Of 39 recruited subjects, 22 out of 22 (exercise) and 13 out of 17 (control) completed the study. There were differences between the exercise and control groups at baseline [age, ASA score physical status, World Health Organisation performance status, and Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity (CR-POSSUM) predicted mortality]. In all subjects, [Formula: see text] at [Formula: see text] significantly reduced between baseline and week 0 [-1.9 ml kg(-1) min(-1); 95% confidence interval (CI) -1.3, -2.6; P<0.0001]. In the exercise group, [Formula: see text] at [Formula: see text] significantly improved between week 0 and week 6 (+2.1 ml kg(-1) min(-1); 95% CI +1.3, +2.9; P<0.0001), whereas the control group values were unchanged (-0.7 ml kg(-1) min(-1); 95% CI -1.66, +0.37; P=0.204). CONCLUSIONS: NACRT before rectal cancer surgery reduces physical fitness. A structured exercise intervention is feasible post-NACRT and returns fitness to baseline levels within 6 weeks. CLINICAL TRIAL REGISTRATION NCT: 01325909. PMID- 25274054 TI - Poster sessions. PMID- 25274055 TI - Future meetings 2015. PMID- 25274056 TI - Community and hospital acquired Clostridium difficile in South Australia - ribotyping of isolates and a comparison of laboratory detection methods. AB - A total of 274 samples were screened for toxigenic Clostridium difficile using a combination of several commercially available assays, and positive isolates ribotyped. A two-step algorithm assisted in demonstrating an increased prevalence of C. difficile infection in South Australia of 9.8%, most of which were ribotypes 014 and 052. A glutamate dehydrogenase assay followed by the detection of genes associated with toxin production was the most sensitive and specific algorithm for screening for toxigenic C. difficile. SIGNIFICANCE AND IMPACT OF THE STUDY: Rapid and accurate detection of toxigenic Clostridium difficile is important for the diagnosis of C. difficile colitis and the management of patients in healthcare institutions to minimize the spread of disease. A critical review of currently available commercial methods supports a recommendation for a 2-step algorithm that is relatively inexpensive and amenable to the routine pathology laboratory. It is anticipated that the detection of C. difficile will increase with improved detection methods, and the ribotype prevalence presented in this manuscript will be useful for any current and future source tracking purposes. PMID- 25274057 TI - Genetic and clinical advances in congenital long QT syndrome. AB - Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome characterized by a prolonged QT interval on the 12-lead ECG, torsades de pointes and a higher chance of sudden cardiac death. LQTS segregates in a Mendelian fashion, which includes Romano-Ward syndrome with an autosomal dominant pattern as well as a rare autosomal recessive pattern (Jervell and Lange-Nielsen syndrome). Since 1957 when Jervell and Lange-Nielsen reported the first familial LQTS with congenital deafness, progress in understanding the genetic and electrophysiological mechanisms of LQTS has tremendously improved diagnostic methods and treatments. In the meantime, it has become evident that LQTS may not always be explained by a single gene mutation, but seems to follow a more complex genetic model intertwined with genetic common polymorphisms that have a mild to moderate effect on disease expression. In this review, we summarize the characteristics of LQTS (mainly LQT1-3) and briefly describe the most recent advances in LQTS clinical diagnostics as well as genetics. PMID- 25274058 TI - Persistent tricuspid regurgitation after tricuspid annuloplasty during redo valve surgery affects late survival and valve-related events. AB - BACKGROUND: Long-term survival and incidence of late tricuspid regurgitation (TR) were studied in patients who underwent tricuspid annuloplasty (TAP) during redo valve surgery. METHODS AND RESULTS: We retrospectively analyzed 125 patients (mean age, 64.5+/-10.4 years) who underwent TAP using suture (n=54, group S) or ring (n=71, group R) implantation during redo surgery in a 20-year period. There was a significant difference in prevalence of preoperative atrial fibrillation (P=0.0199). More group S patients were in New York Heart Association functional class III or IV than group R patients (P=0.0066). Mean follow-up was 6.6+/-5.3 years. Mortality rate for group S was 9.3%, and for group R, 7.0% (P=0.6508). Survival at 5 and 10 years was 72.2+/-6.6% vs. 88.1+/-4.0%, and 66.4+/-7.3% vs. 61.0+/-7.2%, respectively (log-rank, P=0.7235). Less than moderate TR (hazard ratio [HR], 0.113; P=0.0198) before discharge was a predictor of late survival. There was no statistically significant difference in freedom from valve-related events (log-rank, P=0.5196). A predictor of freedom from valve-related events was less than moderate TR before discharge (HR 0.428; P=0.0100). It was also a positive predictor of freedom from late TR more than mild (HR 0.070; P<0.0001). CONCLUSIONS: Less than moderate TR before discharge after TAP during redo valve surgery was an independent risk factor for better long-term outcome. PMID- 25274060 TI - Erratum to: Adherence and Delivery: Implementation Quality and Program Outcomes for the Seventh-Grade keepin' it REAL Program. PMID- 25274059 TI - Delivering enhanced testosterone replacement therapy through nanochannels. AB - Primary or secondary hypogonadism results in a range of signs and symptoms that compromise quality of life and requires life-long testosterone replacement therapy. In this study, an implantable nanochannel system is investigated as an alternative delivery strategy for the long-term sustained and constant release of testosterone. In vitro release tests are performed using a dissolution set up, with testosterone and testosterone:2-hydroxypropyl-beta-cyclodextrin (TES:HPCD) 1:1 and 1:2 molar ratio complexes release from the implantable nanochannel system and quantify by HPLC. 1:2 TES:HPCD complex stably achieve 10-15 times higher testosterone solubility with 25-30 times higher in vitro release. Bioactivity of delivered testosterone is verified by LNCaP/LUC cell luminescence. In vivo evaluation of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels by liquid chromatography mass spectrometry (LC/MS) and multiplex assay is performed in castrated Sprague-Dawley rats over 30 d. Animals are treated with the nanochannel implants or degradable testosterone pellets. The 1:2 TES:HPCD nanochannel implant exhibits sustained and clinically relevant in vivo release kinetics and attains physiologically stable plasma levels of testosterone, LH, and FSH. In conclusion, it is demonstrated that by providing long-term steady release 1:2 TES:HPCD nanochannel implants may represent a major breakthrough for the treatment of male hypogonadism. PMID- 25274061 TI - Microscale screening systems for 3D cellular microenvironments: platforms, advances, and challenges. AB - The increasing interest in studying cells using more in vivo-like three dimensional (3D) microenvironments has created a need for advanced 3D screening platforms with enhanced functionalities and increased throughput. 3D screening platforms that better mimic in vivo microenvironments with enhanced throughput would provide more in-depth understanding of the complexity and heterogeneity of microenvironments. The platforms would also better predict the toxicity and efficacy of potential drugs in physiologically relevant conditions. Traditional 3D culture models (e.g., spinner flasks, gyratory rotation devices, non-adhesive surfaces, polymers) were developed to create 3D multicellular structures. However, these traditional systems require large volumes of reagents and cells, and are not compatible with high-throughput screening (HTS) systems. Microscale technology offers the miniaturization of 3D cultures and allows efficient screening of various conditions. This review will discuss the development, most influential works, and current advantages and challenges of microscale culture systems for screening cells in 3D microenvironments. PMID- 25274063 TI - Generation of CRISPR/Cas9-mediated gene-targeted pigs via somatic cell nuclear transfer. AB - The domestic pig has been widely used as an important large animal model. Precise and efficient genetic modification in pig provides a great promise in biomedical research. Recently, clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system has been successfully used to produce many gene-targeted animals. However, these animals have been generated by co injection of Cas9 mRNA and single-guide RNA (sgRNA) into one-cell stage embryos, which mostly resulted in mosaicism of the modification. One or two rounds of further breeding should be performed to obtain homozygotes with identical genotype and phenotype. To address this issue, gene-targeted somatic cells can be used as donor for somatic cell nuclear transfer (SCNT) to produce gene-targeted animals with single and identical mutations. In this study, we applied Cas9/sgRNAs to effectively direct gene editing in porcine fetal fibroblasts and then mutant cell colonies were used as donor to generate homozygous gene-targeted pigs through single round of SCNT. As a result, we successfully obtained 15 tyrosinase (TYR) biallelic mutant pigs and 20 PARK2 and PINK1 double-gene knockout (KO) pigs. They were all homozygous and no off-target mutagenesis was detected by comprehensive analysis. TYR (-/-) pigs showed typical albinism and the expression of parkin and PINK1 were depleted in PARK2 (-/-)/PINK1 (-/-) pigs. The results demonstrated that single- or double-gene targeted pigs can be effectively achieved by using the CRISPR/Cas9 system combined with SCNT without mosaic mutation and detectable off-target effects. This gene-editing system provides an efficient, rapid, and less costly manner to generate genetically modified pigs or other large animals. PMID- 25274062 TI - Immunogenicity of necrotic cell death. AB - The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity. PMID- 25274065 TI - Researcher threatens to seek out and sue anonymous peer reviewers. PMID- 25274064 TI - Functional and pharmacological induced structural changes of the cystic fibrosis transmembrane conductance regulator in the membrane solved using SAXS. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is a membrane-integral protein that belongs to the ATP-binding cassette superfamily. Mutations in the CFTR gene cause cystic fibrosis in which salt, water, and protein transports are defective in various tissues. To investigate the conformation of the CFTR in the membrane, we applied the small-angle x-ray scattering (SAXS) technique on microsomal membranes extracted from NIH/3T3 cells permanentely transfected with wild-type (WT) CFTR and with CFTR carrying the DeltaF508 mutation. The electronic density profile of the membranes was calculated from the SAXS data, assuming the lipid bilayer electronic density to be composed by a series of Gaussian shells. The data indicate that membranes in the microsome vesicles, that contain mostly endoplasmic reticulum membranes, are oriented in the outside-out conformation. Phosphorylation does not change significantly the electronic density profile, while dephosphorylation produces a significant modification in the inner side of the profile. Thus, we conclude that the CFTR and its associated protein complex in microsomes are mostly phosphorylated. The electronic density profile of the DeltaF508-CFTR microsomes is completely different from WT, suggesting a different assemblage of the proteins in the membranes. Low-temperature treatment of cells rescues the DeltaF508-CFTR protein, resulting in a conformation that resembles the WT. Differently, treatment with the corrector VX-809 modifies the electronic profile of DeltaF508-CFTR membrane, but does not recover completely the WT conformation. To our knowledge, this is the first report of a direct physical measurement of the structure of membranes containing CFTR in its native environment and in different functional and pharmacological conditions. PMID- 25274066 TI - Size and shape differences in the distal femur and proximal tibia between normal weight and obese American Whites. AB - This study tests for differences in articular and diaphyseal size and shape of the distal femur and proximal tibia between normal weight and obese individuals, and discusses the effects of obesity on the patterns of sexual dimorphism and secular change in the skeletal morphology of the knee. Measurements of the femur and tibia were recorded for 143 American White adult males and females born in the 20th century. The sample was divided into normal and obese weight categories based on the body mass index. Results show differences between normal weight and obese individuals in the size and shape of the femoral shaft and the medial side of the knee joint, none of which affect the pattern of sexual dimorphism. While changes in skeletal morphology associated with obesity may be observed in recent secular changes, its role is still unclear because of the relatively recent increase in obesity prevalence. PMID- 25274067 TI - Touching points in the energy band structure of bilayer graphene superlattices. AB - The energy band structure of the bilayer graphene superlattices with zero averaged periodic delta-function potentials are studied within the four-band continuum model. Using the transfer matrix method, the study is mainly focused on examining the touching points between adjacent minibands. For the zero-energy touching points the dispersion relation derived shows a Dirac-like double-cone shape with the group velocity which is periodic in the potential strength P with the period of pi and becomes anisotropic at relatively large P. From the finite energy touching points we have identified those located at zero wave-number. It was shown that for these finite-energy touching points the dispersion is direction-dependent in the sense that it is linear or parabolic in the direction parallel or perpendicular to the superlattice direction, respectively. We have also calculated the density of states and the conductivity which demonstrates a manifestation of the touching points examined. PMID- 25274068 TI - Biosynthesis of higher alcohol flavour compounds by the yeast Saccharomyces cerevisiae: impact of oxygen availability and responses to glucose pulse in minimal growth medium with leucine as sole nitrogen source. AB - Higher alcohol formation by yeast is of great interest in the field of fermented beverages. Among them, medium-chain alcohols impact greatly the final flavour profile of alcoholic beverages, even at low concentrations. It is widely accepted that amino acid metabolism in yeasts directly influences higher alcohol formation, especially the catabolism of aromatic and branched-chain amino acids. However, it is not clear how the availability of oxygen and glucose metabolism influence the final higher alcohol levels in fermented beverages. Here, using an industrial Brazilian cachaca strain of Saccharomyces cerevisiae, we investigated the effect of oxygen limitation and glucose pulse on the accumulation of higher alcohol compounds in batch cultures, with glucose (20 g/l) and leucine (9.8 g/l) as the carbon and nitrogen sources, respectively. Fermentative metabolites and CO2 /O2 balance were analysed in order to correlate the results with physiological data. Our results show that the accumulation of isoamyl alcohol by yeast is independent of oxygen availability in the medium, depending mainly on leucine, alpha-keto-acids and/or NADH pools. High-availability leucine experiments showed a novel and unexpected accumulation of isobutanol, active amyl alcohol and 2-phenylethanol, which could be attributed to de novo biosynthesis of valine, isoleucine and phenylalanine and subsequent outflow of these pathways. In carbon-exhausted conditions, our results also describe, for the first time, the metabolization of isoamyl alcohol, isobutanol, active amyl alcohol but not of 2 phenylethanol, by yeast strains in stationary phase, suggesting a role for these higher alcohols as carbon source for cell maintenance and/or redox homeostasis during this physiological phase. PMID- 25274069 TI - Pancreaticoduodenectomy with major vascular resection: a comparison of laparoscopic versus open approaches. AB - BACKGROUND: Major vascular resection when necessary for margin control during pancreaticoduodenectomy is relatively universal with perioperative and oncological outcomes that are similar to those of patients undergoing a PD without venous involvement. The present study compares total laparoscopic pancreaticoduodenectomy (TLPD) versus open pancreaticoduodenectomy (OPD) with major vascular resection. METHODS: We reviewed data for all patients undergoing TLPD or OPD with vascular resection at Mayo Clinic Rochester, between the dates of July 2007 and July 2013. RESULTS: A total of 31 patients undergoing TLPD and 58 patients undergoing OPD with major vascular resection were identified. Mean operative blood loss was significantly less in the laparoscopic (842 cc) compared to the open group (1,452 cc) (p < 0.001), as was median hospital stay, 6 (4-118) versus 9 (6-73) days, respectively (p = 0.006). There was no significant difference in the total number of complications (lap 35%, open 48%) (p = 0.24) or severe complications (>=III) (lap 6.4%, open 3.4%) (p = 0.51) in the two groups. In-hospital mortality or 30-day mortality was not statistically different between the laparoscopic and open groups, 3.2 and 3.4%, respectively (p = 0.96). Patency of the reconstructed vessels on postoperative imaging was not significantly different between the TLPD (93%) and OPD groups (91%) (p = 0.76). In patients with a diagnosis of adenocarcinoma, there was no significant difference in overall survival between the two groups (p = 0.22). CONCLUSION: The present study clearly demonstrates that not only is TLPD with major vascular resection feasible and safe but that it can achieve results that are similar in morbidity and mortality as well as oncologic outcome compared to patients undergoing OPD with major vascular resection. PMID- 25274070 TI - Environmental exposures and the risk of multiple sclerosis investigated in a Norwegian case-control study. AB - BACKGROUND: Several environmental exposures, including infection with Epstein Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis. METHODS: A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated. RESULTS: Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR = 1.79, 95% CI: 1.12-2.87, p = 0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR = 0.56, 95% CI: 0.40-0.78, p = 0.001). More patients than controls reported smoking and fewer patients reported snuff use. CONCLUSIONS: In this Norwegian MS case-control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard. PMID- 25274072 TI - Linearly polarized emission from self-assembled microstructures of mesogenic polythiophenes. AB - This work reports on linearly polarized photoluminescence and electroluminescence through spontaneous self-assembly of mesogenic polythiophenes under ambient conditions. A systematic structural variation and different alkyl chain lengths lead to three series of closely related mesogenic polythiophenes viz.; TPn, TNn and TVn. Polarized light emitting diodes fabricated from TV12 by solution processing with the configuration of ITO/PEDOT:PSS/Polymer/Al show linearly polarized electroluminescence with a dichroic ratio of 14.32. Spun thin films of TV12 elicited a dichroic ratio of 15.02 in photoluminescence. Studies using a range of techniques such as; atomic force microscopy, grazing incidence X-ray diffraction, fluorescence anisotropy, linear dichroism, fluorescence lifetime and dynamic light scattering reveal that the presence of highly ordered self-assembly was responsible for the dimensional confinement of optoelectronic properties. The ordering in the thin films originates from vinyl groups in the side chains of the TV12 polymer. Further studies on device characteristics show higher charge carrier mobility in polymers with vinyl side chains. Solution processed PLEDs show a maximum brightness of 863 cd m(-2) for the TP12 polymer and TV12 based LEDs show a maximum brightness of 524 cd m(-2). PMID- 25274071 TI - Sex-related differences in the association between waist circumference and bone mineral density in a Korean population. AB - BACKGROUND: Large waist circumference is linked to poor health. Investigations of the relationship between waist circumference, as an index of abdominal fat, and bone mineral density (BMD) have yielded inconsistent results. We investigated the association between abdominal obesity measured using waist circumference and BMD in a large-scale population-based study. METHODS: We enrolled 8981 Korean (3592 males and 5389 females) community-dwelling individuals aged >=50 years from 2007 to 2010. BMD was measured using dual-energy X-ray absorptiometry at lumbar spine and femoral neck skeletal sites. A multiple linear regression analysis was used to evaluate the relationship between waist circumference quartiles and BMD after adjusting for age, height, weight, and regular exercise. RESULTS: The adjustment for age, height, weight, and regular exercise revealed a negative linear association between quartile of waist circumference and BMD at the femoral neck and lumbar spine sites in males and females. Waist circumference was more strongly correlated with BMD in males than in females. Although the correlations were slightly attenuated following further adjustment for percent body fat, they remained statistically significant. CONCLUSIONS: Our results revealed that waist circumference is independently and inversely associated with BMD after adjusting for age, weight, height, regular exercise and percent body fat, suggesting that waist circumference is a potential predictor of osteoporosis in middle-aged and older Korean males and females. PMID- 25274074 TI - Enhanced plasmonic properties of gold-catalysed semiconductor nanowires. AB - A key challenge for the development of plasmonic nanodevices is their integration into active semiconducting structures. Gold-catalysed semiconductor nanowires are promising candidates for their bottom-up growth process that aligns a single gold nanoparticle at each nanowire apex. Unfortunately these show extremely poor plasmonic properties. In this work, we propose a way to enhance their plasmonic resonance up to those of ideal and isolated gold nanoparticles. A suitable purification protocol compatible with GaAs and ZnSe molecular beam epitaxy of nanowires is used to produce plasmonic active nanowires, which were used to enhance the Raman signal of pentacene and graphene oxide. Enhancement factors up to three orders of magnitude are demonstrated. PMID- 25274073 TI - Expanding the potential of standard flow cytometry by extracting fluorescence lifetimes from cytometric pulse shifts. AB - Fluorescence lifetime measurements provide information about the fluorescence relaxation, or intensity decay, of organic fluorophores, fluorescent proteins, and other inorganic molecules that fluoresce. The fluorescence lifetime is emerging in flow cytometry and is helpful in a variety of multiparametric, single cell measurements because it is not impacted by nonlinearity that can occur with fluorescence intensity measurements. Yet time-resolved cytometry systems rely on major hardware modifications making the methodology difficult to reproduce. The motivation of this work is, by taking advantage of the dynamic nature of flow cytometry sample detection and applying digital signal processing methods, to measure fluorescence lifetimes using an unmodified flow cytometer. We collect a new lifetime-dependent parameter, referred to herein as the fluorescence-pulse delay (FPD), and prove it is a valid representation of the average fluorescence lifetime. To verify we generated cytometric pulses in simulation, with light emitting diode (LED) pulsation, and with true fluorescence measurements of cells and microspheres. Each pulse is digitized and used in algorithms to extract an average fluorescence lifetime inherent in the signal. A range of fluorescence lifetimes is measurable with this approach including standard organic fluorophore lifetimes (~1 to 22 ns) as well as small, simulated shifts (0.1 ns) under standard conditions (reported herein). This contribution demonstrates how digital data acquisition and signal processing can reveal time-dependent information foreshadowing the exploitation of full waveform analysis for quantification of similar photo-physical events within single cells. PMID- 25274075 TI - Managing chronic pain in adults with haemophilia: current status and call to action. AB - Haemophilic arthroses are associated with acute pain during bleeding episodes and with chronic pain caused by arthritic complications of repeated bleeding into joints. Unlike other conditions (e.g. osteoarthritis, rheumatoid arthritis, sickle cell disease), there are limited data on pain management in haemophilia. Management of arthritic individuals and those with sickle cell disease relies heavily on administration of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics. In haemophilia, acetaminophen often has limited efficacy at therapeutic doses, offering a narrow dosing range in those with liver disease due to chronic hepatitis C. NSAIDs can effectively manage pain in patients with haemophilia, but these agents are potentially associated with a significant risk of precipitating or exacerbating bleeding complications in an already coagulopathic population. Opioids have proven effective in osteoarthritis and sickle cell disease, but outcomes data in those with haemophilia are virtually non-existent. Patients with haemophilia are at least as vulnerable as other chronic pain populations to opioid-related adverse events and to developing abusive behaviours and addiction. Despite pain management strategies for patients with haemophilia being far from optimal, the predominant precept of haemophilia management still applies. As such, it is critically important to aggressively reverse or prevent acute symptomatic bleeding in a timely and effective manner to at least minimize pain and progressive joint damage. This review should serve as a call to action to prioritize pain management in haemophilia care and spur interest in the development, improvement and standardization of tools to assess and manage acute and chronic pain in haemophilia. PMID- 25274076 TI - Serotonergic antidepressant drugs and L-dopa-induced dyskinesias in Parkinson's disease. AB - BACKGROUND: Serotonergic system is believed to play a role in levodopa-induced dyskinesias pathogenesis, and serotonin transporter has been evaluated as potential target. AIM OF THE STUDY: To retrospectively investigate the potential effect of selective serotonin reuptake inhibitors (SSRIs) during dopaminergic treatment, in the development of dyskinesias in patients with Parkinson's disease (PD). METHODS: One hundred and thirty-five consecutive patients with PD, with 10 year follow-up since diagnosis. Age at PD onset, duration of levodopa treatment, maximum daily dose, and SSRIs exposure were collected. Risk, latency, and severity of dyskinesias were evaluated comparing patients with and without SSRIs exposure. RESULTS: Forty-nine patients received SSRIs for a variable period, 86 were never treated; no significant difference between the groups was observed (P = 0.897) in the prevalence of dyskinesias. Considering latency between PD diagnosis and dyskinesias onset, patients exposed to SSRIs developed dyskinesias later (6.48 +/- 1.99 vs 5.70 +/- 1.89 years, P = 0.020). The median dyskinesia severity score was 0 in the exposed group vs 1 in non-exposed patients (P = 0.025). Multivariate analysis demonstrated SSRIs exposure as the only independent predictor, protecting from severe dyskinesia. CONCLUSIONS: Use of SSRIs in patients with PD did not protect from dyskinesias; however, exposure may delay the onset and reduce the severity, confirming modulation of the serotonergic system as possible antidyskinetic strategy. PMID- 25274077 TI - The marginal division of the striatum and hippocampus has different role and mechanism in learning and memory. AB - The memory function of the hippocampal formation (Hip) and the marginal division (MrD) of neostriatum was compared. Rats with bilateral lesions of the MrD either immediate or 24 h after training in Y-maze were found to have decrease in correct runs in both groups. However, animals with transected afferent and efferent nerve bundles to isolate the Hip immediately or 24 h after training in Y-maze were found to show a decrease in correct runs only in the group injured immediately after Y-maze training but not in the 24 h group suggesting that MrD is likely involved in the entire process of long-term memory consolidation whereas the Hip only contributes to memory in the early stage. In addition, animals treated with a NMDA receptor (NMDAR) blocker, e.g. MK-801, showed decreased correct runs in Y maze test and in expression level of phosphorylated CREB (pCREB) in neurons of the MrD but not in the Hip. Furthermore, animals treated with okadaic acid (OA), a potent protein phosphatase 1 inhibitor, showed increased correct runs in the Y maze test. The expression level of pCREB and c-Fos and c-Jun was found increased in neurons of the MrD and the Hip in response to OA treatment. In conclusion, NMDAR and pCREB are involved in memory functions of both the Hip and the MrD. NMDAR might regulate pCREB level in neurons of the MrD but not in the Hip. Hence, the processes and mechanism of learning and memory involved in the MrD and the Hip may be different. PMID- 25274080 TI - Reflectance anisotropy of the anatase Tio2(0 0 1)-(4 * 1) surface. AB - The dielectric functions of bulk anatase TiO(2) and its (4 * 1) reconstructed (0 0 1) surface were calculated using a hybrid density functional theory method. The bulk dielectric function is compared to data obtained from synchrotron radiation reflectivity measurements in the energy range 0-20 eV and to dielectric functions from two Bethe-Salpeter calculations. There is agreement between predictions of the two theoretical methods, except at the absorption threshold, where there is some shift of spectral weight to lower energy in the Bethe-Salpeter calculations. All features observed in the dielectric function derived from synchrotron reflectivity data are reproduced in calculations. There are some differences in relative peak intensities for dielectric functions derived from experiment and theory. A dispersionless surface state is found which is localised on the topmost oxygen ion in the reconstructed surface. The reflectance anisotropy spectrum of the TiO(2)(0 0 1)-(4 * 1) surface shows strong features in the energy range to 12 eV but does not show any features caused by sub-bandgap surface state transitions. PMID- 25274079 TI - Spinal cord compression by B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma in a patient seropositive for human immunodeficiency virus: a case report. AB - INTRODUCTION: Although non-Hodgkin's lymphoma is one of the most common and frequently fatal of the acquired immune deficiency syndrome-defining illnesses, survival has improved significantly since the introduction of antiretroviral therapy. Patients with spinal cord compression resulting from non-Hodgkin's lymphoma present with clinically acute or rapidly progressive neurologic deficits. The purpose of this case report is to present a case of a patient seropositive for human immunodeficiency virus with spinal cord compression due to B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. CASE PRESENTATION: A 40-year-old Asian man, who was seropositive for human immunodeficiency virus, presented with progressive neurological deficits. Magnetic resonance images of his thoracic spine showed an epidural mass from T2 to T4, resulting in severe cord compression. Emergent surgical decompression and biopsy were performed, followed by palliative radiation therapy. The pathologic findings showed that the specimen was compatible with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Palliative radiation therapy was performed; however, leptomeningeal seeding and pulmonary embolism led to his death. CONCLUSIONS: When a patient infected with human immunodeficiency virus presents with a rapidly progressive spinal tumor accompanying paraplegia, non-Hodgkin's lymphoma should be considered, and surgical decompression should be weighed with respect to the patient's general condition and the subtype/prognosis of the lymphoma. PMID- 25274078 TI - Human urine-derived stem cells in combination with polycaprolactone/gelatin nanofibrous membranes enhance wound healing by promoting angiogenesis. AB - BACKGROUND: Despite advancements in wound healing techniques and devices, new treatments are needed to improve therapeutic outcomes. This study aimed to evaluate the potential use of a new biomaterial engineered from human urine derived stem cells (USCs) and polycaprolactone/gelatin (PCL/GT) for wound healing. METHODS: USCs were isolated from healthy individuals. To fabricate PCL/GT composite meshes, twin-nozzle electrospinning were used to spin the PCL and gelatin solutions in normal organic solvents. The morphologies and hydrophilicity properties of PCL/GT membranes were investigated. After USCs were seeded onto a PCL/GT, cell adhesion, morphology, proliferation, and cytotoxicity were examined. Then, USCs were seeded on a PCL/GT blend nanofibrous membrane and transplanted into rabbit full-thickness skin defects for wound repair. Finally, the effect of USCs condition medium on proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) were performed in vitro. RESULTS: USCs were successfully isolated from urine samples and expressed specific mesenchymal stem cells markers and could differentiate into osteoblasts, adipocytes, and chondrocytes. PCL/GT membrane has suitable mechanical properties similar with skin tissue and has good biocompatibility. USCs-PCL/GT significantly enhanced the healing of full-thickness skin wounds in rabbits compared to wounds treated with PCL/GT membrane alone or untreated wounds. USCs-PCL/GT-treated wounds closed much faster, with increased re-epithelialization, collagen formation, and angiogenesis. Moreover, USCs could secrete VEGF and TGF-beta1, and USC-conditioned medium enhanced the migration, proliferation, and tube formation of endothelial cells. CONCLUSION: USCs in combination with PCL/GT significantly prompted the healing of full-thickness skin wounds in rabbits. USCs based therapy provides a novel strategy for accelerating wound closure and promoting angiogenesis. PMID- 25274081 TI - The difficult access to morphology of the heart: clinical implications. AB - The literature on the morphology of the heart is reviewed within the context of recent histological findings. There is strong evidence for a dualistic myocardial function, whereby both ventricular constricting and expanding forces are supposed to act synchronously although with variable effect over the heart cycle.The morphological basis of this dualistic myocardial function is the contorted rope like structure worn into the bulk of the heart muscle. Opinions are divided about the invasiveness of blunt preparation on the heat denatured heart by which the fascicular architecture is carved out of the muscle. Histology confirms the existence of a fascicular substructure. It results from an inhomogeneous repartition of myocardial fibre branchings and the arrangement of the delicate connective tissue netting by which myocardial strands are bundled and wrapped. One important feature of the fascicular structure of the heart muscle is an oblique transmurally arranged element which yields a force vector opposing systolic wall thickening. This structural element which acts in the direction of ventricular dilation probably gains pathological import in some cases of architectural remodelling, namely in myocardial fibrosis and hypertrophy. PMID- 25274082 TI - Determination of volume-dependent respiratory system mechanics in mechanically ventilated patients using the new SLICE method. AB - In patients mechanically ventilated for severe respiratory failure, respiratory system mechanics are non-linear, i.e., volume-dependent. We present a new computer-based multipoint method for simultaneously determining volume-dependent dynamic compliance and resistance. Our method is based on continuously determined tracheal pressure (Ptrach). Tidal volume is subdivided into six volume slices of equal size. One compliance value (intrinsic PEEP considered) and one resistance value are determined for each volume slice by applying of the least-squares-fit (LSF) analysis based on the linear RC-model; we therefore call this the SLICE method. The method gives the course of dynamic compliance and resistance within the tidal volume. The method was evaluated using physical models of the respiratory system with linear and non-linear passive mechanical properties. The relative error of the method is smaller than +/-5%. The method needs no special ventilatory pattern. Using data from 14 patients mechanically ventilated for adult respiratory distress syndrome (ARDS) we found a very good correspondence between the measured end-inspiratory airway pressure (Paw,Ie) and the end inspiratory alveolar pressure (Palv,Ie) calculated from the dynamic compliance values determined with the SLICE method (Palv,Ie = 1.02 * Paw,Ie + 0.097; r2 = 0.977). The SLICE method allows continuous monitoring of non-linear pulmonary mechanics on a breath-by-breath basis at the bedside. PMID- 25274083 TI - Three-dimensional animation of the temporomandibular joint. AB - The aim of this investigation was to develop a method to reconstruct three dimensionally the temporomandibular joint (TMJ) by means of magnetic resonance (MR) tomograms and to combine this reconstruction with jaw motion data, recorded with six degrees of freedom by means of the opto-electronic system Jaws-3D, in order to analyse the movement of the whole condyle within the fossa during opening and closing, protrusive and laterotrusive movements. The three dimensional reconstruction of the TMJ was calculated and animated on a graphics workstation. The condyle - fossa distance during jaw movements was computed for every condylar point and visualized by shading the surface of the condyle with pseudo colors. Furthermore, the location of the minimum condyle-fossa distance was calculated and displayed in a plane graph representing the condylar surface. For five subjects without any past or present history of myoarthropathies of the masticatory system the resulting patterns were analyzed and compared. PMID- 25274084 TI - Eye pupil diameter measurement and assessment via a novel pupilometer system. AB - The latest progress in the area of psychophysiology and psychopathology has urged the need for new tools, being able to perform special, non-invasive measurements. By measuring the eye pupil diameter and its variations, new and interesting conclusions can be reached, concerning the effect of specific drugs on humans or the process of reaction to certain stimuli with psychophysiological significance.We present the design, the development, the integration and the evaluation of a new system for the measurement of the eye pupil diameter and its variations as a function of time. The main advantages are a low cost system based on a personal computer and the introduction of some new algorithmic techniques on manipulating eye images. PMID- 25274085 TI - Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment? AB - BACKGROUND: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers. Our aim was to determine whether validated susceptibility SNP scores improve the predictive ability of risk models in comparison/conjunction to other clinical/demographic information. METHODS: Female BRCA1/2 carriers were identified from the Manchester genetic database, and included in the study regardless of breast cancer status or age. DNA was extracted from blood samples provided by these women and used for gene and SNP profiling. Estimates of survival were examined with Kaplan-Meier curves. Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables. Nonlinear random survival forests were also fit to identify relevant interactions. Models were compared using Harrell's concordance index (1 - c-index). RESULTS: 548 female BRCA1 mutation carriers and 523 BRCA2 carriers were identified from the database. Median Kaplan-Meier estimate of survival was 46.0 years (44.9-48.1) for BRCA1 carriers and 48.9 (47.3 50.4) for BRCA2. By fitting Cox models and random survival forests, including both a genetic SNP score and clinical/demographic variables, average 1 - c-index values were 0.221 (st.dev. 0.019) for BRCA1 carriers and 0.215 (st.dev. 0.018) for BRCA2 carriers. CONCLUSIONS: Random survival forests did not yield higher performance compared to Cox proportional hazards. We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation. PMID- 25274086 TI - Preparation of volatile fatty acid (VFA) calcium salts by anaerobic digestion of glucose. AB - Many potentially useful intermediates such as hydrogen and volatile fatty acids (VFAs) are formed during the complex anaerobic digestion processes that produce methane from biomass. This study recovers VFAs from an anaerobic digester by a combination of gas stripping and absorption with calcium carbonate slurry. Glucose was used as the model substrate because it is readily available, inexpensive, and easily digested. Sludge from a meatworks anaerobic digester produced methane and carbon dioxide (and sometimes a small amount of hydrogen) when batch-fed with glucose. Conditioning the neutral anaerobic sludge to an acidic pH (below 4.8) was achieved using repeated 1 g L(-1) doses of glucose. After conditioning, mainly VFAs and hydrogen were produced. The intermediate VFAs could be stripped using headspace gas. In subsequent fed-batch digestion/stripping cycles, the pH decreased when glucose was added and then increased when the VFA was gas stripped. The predominant acids formed at low pH values were lactic, butyric, and acetic acids. Lactic acid was converted to VFAs during stripping. The VFA calcium salts recovered were 80% butyrate and 20% acetate with minor quantities of propionate and valerate. PMID- 25274087 TI - Tibiofemoral loss of contact area but no changes in peak pressures after meniscectomy in a Lapine in vivo quadriceps force transfer model. AB - PURPOSE: The menisci are thought to modulate load transfer and to absorb shocks in the knee joint. No study has experimentally measured the meniscal functions in the intact, in vivo joint loaded by physiologically relevant muscular contractions. METHODS: Right knee joints of seven New Zealand white rabbits were loaded using isometric contractions of the quadriceps femoris muscles controlled by femoral nerve stimulation. Isometric knee extensor torques at the maximal and two submaximal force levels were performed at knee angles of 70 degrees , 90 degrees , 110 degrees , and 130 degrees . Patellofemoral and tibiofemoral contact areas and pressure distributions were measured using Fuji Presensor film inserted above and below the menisci and also with the menisci removed. RESULTS: Meniscectomy was associated with a decrease in tibiofemoral contact area ranging from 30 to 70% and a corresponding increase in average contact pressures. Contact areas measured below the menisci were consistently larger than those measured on top of the menisci. Contact areas in the patellofemoral joint (PFJ), and peak pressures in tibiofemoral and PFJs, were not affected by meniscectomy. Contact areas and peak pressures in all joints depended crucially on knee joint angle and quadriceps force: The more flexed the knee joint was, the larger were the contact areas and the higher were the peak pressures. CONCLUSIONS: In agreement with the literature, removal of the menisci was associated with significant decreases in tibiofemoral contact area and corresponding increases in average contact pressures, but surprisingly, peak pressures remained unaffected, indicating that the function of the menisci is to distribute loads across a greater contact area. PMID- 25274088 TI - Femoral and tibial insert downsizing increases the laxity envelope in TKA. AB - PURPOSE: This study examines the effect of component downsizing in a modern total knee arthroplasty (TKA) system on the laxity envelope of the knee throughout flexion. METHODS: A robotic testing system was utilized to measure laxity envelopes in the implanted knee by in the anterior-posterior (AP), medial-lateral (ML), internal-external (IE) and varus-valgus (VV) directions. Five fresh-frozen cadavers were tested with a modern cruciate retaining TKA implantation, a 1-mm thinner polyethylene insert and a femoral component 2 mm smaller in the AP dimension. RESULTS: The downsized tibial insert was more lax throughout the flexion arc with up to 2.0 mm more laxity in the AP direction at full extension, a 43.8% increase over the original implantation. A thinner insert consistently increased laxity throughout the arc of flexion in all degrees of freedom. Downsizing the femoral component resulted in 8.5 mm increase in AP laxity at 90 degrees , a 73.9% increase. In mid-flexion, downsizing the femur produced similar laxity values to the downsized insert in AP, ML, IE and VV directions. CONCLUSION: Downsizing the TKA components had significant effects on laxity throughout flexion. Downsizing a femoral component 2 mm had an equivalent increase in laxity in mid-flexion as downsizing the tibial insert 1 mm. This study quantifies the importance of choosing the appropriate implant component size, having the appropriate size available and the effect of downsizing. The laxity of the implanted knee contributes to how the implant feels to the patient and ultimately the patient's satisfaction with their new knee. PMID- 25274089 TI - Strong correlation between the morphology of the proximal femur and the geometry of the distal femoral trochlea. AB - PURPOSE: Previous investigations suggested that the geometry of the proximal femur may be related to osteoarthritis of the tibiofemoral joint and various patellofemoral joint conditions. This study aims to investigate the correlation between proximal and distal femoral geometry. Such a correlation could aid our understanding of patient complications after total knee arthroplasty (TKA) and be of benefit for further development of kinematic approaches in TKA. METHODS: CT scans of 60 subjects (30 males, 30 females) were used to identify anatomical landmarks to calculate anatomical parameters of the femur, including the femoral neck anteversion angle, neck-shaft angle (NSA), mediolateral offset (ML-offset), condylar twist angle (CTA), trochlear sulcus angle (TSA) and medial/lateral trochlear inclination angles (MTIA/LTIA). Correlation analyses were carried out to assess the relationship between these parameters, and the effect of gender was investigated. RESULTS: The CTA, TSA and LTIA showed no correlation with any proximal parameter. The MTIA was correlated with all three proximal parameters, mostly with the NSA and ML-offset. Per 5 degrees increase in NSA, the MTIA was 2.1 degrees lower (p < 0.01), and for every 5 mm increase in ML-offset, there was a 2.6 degrees increase in MTIA (p < 0.01). These results were strongest and statistically significant in females and not in males and were independent of length and weight. CONCLUSIONS: Proximal femoral geometry is distinctively linked with trochlear morphology. In order to improve knowledge on the physiological kinematics of the knee joint and to improve the concept of kinematic knee replacement, the proximal femur seems to be a factor of clinical importance. LEVEL OF EVIDENCE: III. PMID- 25274090 TI - Recovery of gait pattern after medial patellofemoral ligament reconstruction for objective patellar instability. AB - Gait pattern alterations were previously reported in association with objective patellar instability (OPI). Gait pattern comparison between a series of patients having undergone medial patellofemoral ligament (MPFL) reconstruction and a sample of control subjects. Thirty patients at 6 months postoperatively after MPFL reconstruction and thirty control subjects were enrolled in the study for a clinical and biomechanical assessment including gait analysis at three selected walking rates using the GAITRite((r)) system. The mean raw IKDC score was 73 (+/- 19), and the mean Kujala knee function was 84 (+/- 17.5). The study of gait did not demonstrate any significant difference between the two groups at a normal and fast walking rate. At a 10 km/h running speed, the single-support phase was significantly shortened by a mean 2.33% (p < 0.05), the swing phase by a mean 2.64% (p < 0.05) and the double-support phase by a mean 3.49% (p < 0.05) on the operated side. MPFL reconstruction reported good midterm functional and clinical results in the management of OPI. At 6 months postoperatively, the patient gait pattern was similar to that observed in healthy subjects at a normal and fast walking speed. However, our study revealed persistent gait abnormalities at a 10 km/h running speed. These gait alterations seemed to be related to the ligament reconstruction in itself due to the higher strain applied on the reconstructed MPFL during running cycle (10 km/h). Level of evidence IV. PMID- 25274091 TI - Subpectoral biceps tenodesis: a new technique using an all-suture anchor fixation. AB - There are several options for LHB tenodesis; yet, there is no standard of care. This technical note describes an extramedullary all-suture anchor technique for LHB tenodesis that is similar to the extramedullary cortical button technique. The LHB tenodesis is performed by using the Y-Knot (1.3-mm; ConMed Linvatec, Largo, FL).The biceps tenotomy is completed arthroscopically, and a standard subpectoral approach is used for the tenodesis. A reamer is first used to drill through the anterior cortex of the humerus; subsequently, a 1.3-mm drill bit is used to drill through the posterior cortex. The Y-Knot anchor is passed through the bone tunnel and secured on the posterior cortical bone. A modified rolling hitch suture is placed 10 mm distal to the end of the LHB tendon by using one suture limb of the Y-Knot anchor. The other suture limb is pulled to shuttle the LHB tendon into the humerus, and the construct is fixed by tying down one limb to the other. This technical note describes an alternative method for subpectoral biceps tenodesis and uses a small drill hole, conserves bone, and minimizes trauma to the tendon. LEVEL OF EVIDENCE: V. PMID- 25274092 TI - External rotation and active supination CT arthrography for the postoperative evaluation of type II superior labral anterior to posterior lesions. AB - PURPOSE: To evaluate the effectiveness of external rotation and active supination CT arthrography in postoperative evaluation by comparing it with neutral CT arthrography and analyzing its agreement with postoperative clinical results after the repair of type II superior labral anterior to posterior (SLAP) lesions. MATERIALS AND METHODS: A total of 25 patients who had undergone CT arthrography in neutral, external rotation and active supination position at least 1 year after the arthroscopic repair of SLAP lesions were enrolled. Two radiologists independently evaluated the status of the repaired SLAP lesions with neutral CT arthrography and then with external rotation and active supination CT arthrography. RESULTS: Five patients had residual symptoms and positive findings upon SLAP-specific examinations. Agreements between the presence of symptoms and radiologic diagnoses based on neutral CT arthrography were insignificant for reader 1 (kappa = 0.138, p = n.s.) and significant for reader 2 (kappa = 0.328, p = 0.027). However, agreements were highly significant in the analysis following the evaluation of external rotation and active supination CT arthrography for both readers (kappa = 0.694, p < 0.001 in reader 1; kappa = 0.783, p < 0.001 in reader 2). CONCLUSIONS: The presence of contrast-filled gaps between the labrum and glenoid on neutral CT arthrography after SLAP repair is frequent with satisfactory clinical outcomes. Gaps without additional widening upon external rotation and active supination CT arthrography may suggest postoperatively stable biceps anchors, so this new method could minimize the overdiagnosis of recurrent SLAP lesions. Additional gap widening on external rotation and active supination CT arthrography could be related to a true recurrent SLAP lesion and the symptoms of the patients. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 25274093 TI - No difference in clinical outcomes after total knee arthroplasty between patellar eversion and non-eversion. AB - PURPOSE: Multiple surgical techniques in minimally invasive total knee arthroplasty (TKA) are associated with clinical differences. However, whether patellar eversion impairs clinical outcomes remains controversial. We conducted a systematic review of randomized controlled trials (RCTs) to provide current understanding on this topic. METHODS: A literature search of the PubMed, Embase, and Cochrane library databases was performed to identify RCTs comparing patellar eversion with patellar non-eversion (PN). Two authors independently selected the studies, assessed methodological quality, and extracted data. RESULTS: Five RCTs involving 379 knees were included. The results revealed no significant differences in functional scores, pain, quality of life, quadriceps strength, patellar height, alignment, or complication rate between patellar eversion and PN. Power analysis showed that the power of the individual study and meta analysis ranged from 5.0 to 70.8%, with the exception of the power of alignment and patellar height in two of the individual studies, which was 100.0 and 99.9%, respectively. CONCLUSIONS: Based on the current evidence, patellar eversion during TKA could not definitely lead to inferior postoperative outcomes. Patellar eversion and patellar non-eversion could achieve similar clinical outcomes. LEVEL OF EVIDENCE: Systematic review and meta-analysis, Level I. PMID- 25274095 TI - The effect of feedback from post-operative 3D CT on placement of femoral tunnels in single-bundle anatomic ACL reconstruction. AB - PURPOSE: To evaluate the effect of feedback from post-operative 3D CT in the learning process of placing the femoral graft tunnel anatomically using the anteromedial (AM)-portal technique in single-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: An experienced knee surgeon converting from transtibial to AM-portal technique was offered post-operative feedback on tunnel placement. Three groups of patients were included: transtibial drilling, (AM1) anteromedial drilling without feedback and (AM2) anteromedial drilling with post operative CT feedback. Intra-articular landmarks were used as the only guidance for tunnel placement. Tunnel position was compared to an ideal anatomical ACL position using the Bernard and Hertel grid and visual feedback was given on tunnel placements. The effect of feedback was measured as the distance from the anatomical centre, and spread of tunnel placements on post-operative CT performed feedback was initiated. RESULTS: When comparing the femoral tunnel placement to an ideal anatomical centre, there was an improvement in the mean tunnel position after (A) changing from a transtibial to an anatomical technique and a further improvement after (B) initializing the radiological feedback. There was a great variation of femoral tunnel localizations when initially only using intra articular landmarks as guidance for tunnel placement--this variation, however, converged towards the anatomical centre throughout the feedback period and the AM2 group had a femoral tunnel closer (P = 0.001) to the anatomical centre than the AM1 group. CONCLUSIONS: Post-operative 3D CT is effective in the learning process of placing femoral tunnels anatomically by giving post-operative feedback on tunnel placement. Bony landmarks and ACL remnants were found unreliable as the only guidance for femoral tunnel placement in the AM-portal technique-therefore, the use of an aid is recommended to reduce unwanted tunnel variations in a learning phase. LEVEL OF EVIDENCE: Cohort Study, Level III. PMID- 25274096 TI - The clinical symptom profile of early radiographic knee arthritis: a pain and function comparison with advanced disease. AB - PURPOSE: Early knee OA is a significant problem that can be disabling. The purpose of this study was to understand the symptomatic profile of patients with early knee OA when compared to those with end-stage knee OA. METHODS: A cross sectional case control study design was used to compare those with early structural change to those with advanced structural change. In total, 100 consecutive patients with early radiographic knee OA presenting to the knee service outpatient clinic from December 2010 to August 2011 were prospectively identified on the basis of their radiographic changes. All met the symptomatic and radiological diagnostic criteria of early knee OA as defined by Luyten et al. They were compared with 200 knees with full thickness anteromedial knee OA and 200 knees with full thickness tricompartmental knee OA for their demographic, pain and functional profile. RESULTS: Patients with early knee OA were younger than those with full thickness disease. However, 78% of individual patients with early radiographic OA had pain and function scores equal to individual patients presenting for UKA, whilst 74% of individual patients with early radiographic OA had pain and function scores that are equal to or worse than individual patients presenting for TKA. CONCLUSIONS: Patients with early radiographic knee OA demonstrate considerable overlap in the severity of their symptoms with those demonstrating end-stage structural changes within the knee. Patients with early structural changes of arthritis should not be assumed by clinicians to have mild disease. In many cases, their symptoms are as bad as those with end-stage structural changes. This work will help clinicians to identify and categorise those with early arthritis and thereby assist in guiding appropriate treatments. PMID- 25274097 TI - Correlation between varus knee malalignment and patellofemoral osteoarthritis. AB - PURPOSE: To evaluate the relationship between patellofemoral osteoarthritis (OA) and varus OA of the knee with a focus on the location of joint space narrowing. METHODS: Eighty-five patients scheduled to undergo total knee arthroplasty caused by varus OA were enrolled in this study. The relationship between patellofemoral OA and varus knee malalignment was elucidated. To determine the alignment of the patellofemoral joint in varus knees, patellar tilt, and the tibial tuberosity trochlear groove (TT-TG) distance were measured, and patellofemoral OA was classified using computed tomography. RESULTS: The femorotibial angles in patients with stage II-IV patellofemoral OA were significantly larger than those in patients with stage I patellofemoral OA, and the patellar tilt in patients with stage II-IV patellofemoral OA and the TT-TG distance in patients with stage IV patellofemoral OA were significantly larger than those in patients with stage I patellofemoral OA. The TT-TG distance was strongly correlated with patellar tilt (R(2) = 0.41, P < 0.001). Patellofemoral joint space narrowing was mainly noted at the lateral facet, and it was found on both sides as patellofemoral OA worsened. CONCLUSION: Varus knee malalignment was induced by patellofemoral OA, especially at the lateral facet. Patellar tilt and the TT-TG distance are considered critical factors for the severity of patellofemoral OA. Understanding the critical factors for patellofemoral OA in varus knees such as the TT-TG distance and patellar will facilitate the prevention of patellofemoral OA using procedures such as high tibial osteotomy and total knee arthroplasty to correct knee malalignment. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 25274098 TI - Patient expectations of primary and revision anterior cruciate ligament reconstruction. AB - PURPOSE: Unrealistic patient expectations have been shown to negatively influence patient-reported outcomes in orthopaedic surgery. Knowledge about patient expectations is important to associate preoperative expectations with the reasonable outcome of a specific procedure. The purpose of this study was to prospectively analyse and to compare patient expectations of primary and revision anterior cruciate ligament reconstruction (ACLR) and to assess the factors associated with patient expectations. METHODS: Preoperative expectations of 181 consecutive patients undergoing ACLR were assessed prospectively using a 5-item questionnaire. Primary ACLR (P-ACLR) was performed in 133 patients (73%), whereas 48 patients (27%) underwent revision ACLR (R-ACLR). The questionnaire assessed the expectation of the overall condition of the knee joint, return to sports, instability, pain, and risk of osteoarthritis. RESULTS: All patients expected a normal (38%) or nearly normal (62%) condition of the knee joint. Return to sports at the same level was expected by 91%. With regard to instability (pain), no instability (pain) independent of the activity level was expected by 77% (58%). No or only a slightly increased risk of the development of osteoarthritis was expected by 98%. The R-ACLR group showed a significantly lower expectation of the overall condition (p = 0.001), return to sports (p < 0.001), and pain (p = 0.002). No statistically significant difference was found between female and male patients (n.s.). In the P-ACLR group, patients with a history of previous knee surgery showed inferior expectations of return to sports (p = 0.015) and risk of osteoarthritis (p = 0.011). Age, number of previous knee surgeries, and pre injury sports level significantly influenced patient expectations. CONCLUSIONS: Overall, patient expectations of ACL reconstruction are high. Patients undergoing revision ACL reconstruction have lower but still demanding expectations. Younger patients, patients without a history of knee surgery, and highly active patients have higher expectations. Explicit patient information about realistic goals of ACL reconstruction seems to be necessary in order to prevent postoperative dissatisfaction despite a successful operation in the surgeons' point of view. LEVEL OF EVIDENCE: Prospective case series, Level IV. PMID- 25274099 TI - No difference in anterior knee pain after medial unicompartmental knee arthroplasty in patients with or without patellofemoral osteoarthritis. AB - PURPOSE: The purpose of the present study was to compare functional outcomes of medial unicompartmental knee arthroplasty (UKA) in patients with patellofemoral osteoarthritis (PF OA) and those without PF OA and to evaluate the effect of PF OA on functional outcomes after UKA. METHODS: The outcomes of 48 knees in patients without PF OA who underwent medial UKA (non-PF OA group) were compared to the outcomes of 57 knees in patients with PF OA [Kellgren-Lawrence (K-L) grade <= 2] who underwent medial UKA (PF OA group) with a median follow-up of 5.4 years (range 3.1-10.2 years). Clinical outcomes including anterior knee pain, HSS scores, radiological parameters, and the progression of patellofemoral osteoarthritis were compared, and their effects on functional outcomes were evaluated at the final follow-up visits. RESULTS: At final follow-up visits, no significant inter-group difference was found in terms of anterior knee pain (1.9 vs. 1.9 in non-PF OA and PF OA groups, respectively), HSS score, or range of motion. Preoperative anterior knee pain and patellofemoral joint degeneration were found to be unrelated to poor outcome in patients that underwent medial UKA. Furthermore, no correlation was found between any functional outcome variable and chondral lesion pattern. CONCLUSIONS: The result of UKA for medial unicompartmental knee osteoarthritis was excellent regardless of PF OA (K-L grade <= 2). Hence, the patients with medial unicompartmental OA combined with a moderate degree of anterior knee pain or patellofemoral arthritis should be viewed as appropriate candidates for medial UKA. LEVEL OF EVIDENCE: III. PMID- 25274101 TI - Non-alcoholic fatty liver disease: need for a balanced nutritional source. AB - Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are an increasingly common chronic liver disease closely associated with diabetes and obesity that have reached epidemic proportions. Reports on the prevalence of NAFLD have suggested that 27-34% of the general population in the USA and 40-90% of the obese population worldwide have this disease. Increasing urbanisation rate and associated inappropriate lifestyle changes are not only the risk factors of diabetes, but also unmask genetic predisposition in various populations for the metabolic syndrome and its manifestations including NAFLD and NASH. Lifestyle modifications and balanced nutrition are among the foremost management strategies along with ursodeoxycholic acid, metformin, vitamin E and pentoxifylline. Although weight reduction associated with current therapeutic strategies has shown some promise, maintaining it in the long run is largely unsuccessful. With the safety of pharmacotherapy still being uncertain and can be started only after confirmation, other reasonable interventions such as nutrition hold promise in preventing disease progression. The role of dietary components including branched-chain amino acids, methionine, choline and folic acid is currently being evaluated in various clinical trials. Nutritional approaches sought to overcome the limitations of pharmacotherapy also include evaluating the effects of natural ingredients, such as silymarin and spirulina, on liver disease. Understanding the specific interaction between nutrients and dietary needs in NAFLD and maintaining this balance through either a diet or a nutritional product thus becomes extremely important in providing a more realistic and feasible alternative to treat NAFLD. A planned complete nutritional combination addressing specific needs and helping to prevent the progression of NAFLD is the need of the hour to avert people from ending up with complications. PMID- 25274102 TI - Ebola is diagnosed in traveler to US. PMID- 25274100 TI - Metachronous isolated breast metastasis from pulmonary adenocarcinoma with micropapillary component causing diagnostic challenges. AB - BACKGROUND: Breast metastasis from extramammary malignancy is uncommon and often presents diagnostic challenges. Herein, we report a case of a patient with metachronous isolated breast metastasis from pulmonary adenocarcinoma with micropapillary component. CASE PRESENTATION: A 47-year-old woman presented with left breast nodule detected on a screening breast ultrasonography. She had surgery for pulmonary adenocarcinoma 3 years ago, and was disease-free state in the follow up studies. The patient was diagnosed with invasive micropapillary carcinoma of the breast by core needle biopsy. She underwent left breast lumpectomy and sentinel lymph node biopsy, and the histologic findings revealed micropapillary carcinoma. Based on the immunohistochemical study, the final diagnosis was solitary breast metastasis from pulmonary adenocarcinoma with micropapillary component. CONCLUSIONS: The diagnosis of metastasis to the breast from extramammary malignancies is difficult but important for proper management and prediction of prognosis. A careful clinical history with a thorough clinical examination is needed to make the correct diagnosis. PMID- 25274103 TI - A new algorithm for identification of components in a mixture: application to Raman spectra of solid amino acids. AB - The procedure for identifying components in a mixture was developed and tested on Raman spectra of mixtures of solid amino acids, using the spectra of single amino acids as templates. The method is based on finding the optimum scaling coefficients of the linear combination of template spectra that minimize the Canberra distance between measured and reconstructed spectra. The Canberra distance, used here as a measure of dissimilarity between spectra, defines the non-convex objective function in the related optimization process. In view of the possibility of the presence of local minima, differential evolution, which is a non-gradient stochastic method for finding the global minimum, was chosen for optimization. The method was tested on twenty measured spectra of mixtures of solid powders containing one to eight amino acids taken from the collection of twenty that are coded in living organisms. The results show that the procedure can successfully identify several amino acids, and, in general, several components in a mixture. The method was shown to compare favorably against the least squares and partial least squares methods, the procedures used in commercially available chemometrics packages. PMID- 25274104 TI - The Effect of an Electronic SBAR Communication Tool on Documentation of Acute Events in the Pediatric Intensive Care Unit. AB - The Situation, Background, Assessment, Recommendation (SBAR) handoff tool is designed to improve communication. The effects of integrating an electronic medical record (EMR) with a SBAR template are unclear. The research team hypothesizes that an electronic SBAR template improves documentation and communication between nurses and physicians. In all, 84 patient events were recorded from 542 admissions to the pediatric intensive care unit. Three time periods were studied: (a) paper documentation only, (b) electronic documentation, and (c) electronic documentation with an SBAR template. Documentation quality was assessed using a 4-point scoring system. The frequency of event notes increased progressively during the 3 study periods. Mean quality scores improved significantly from paper documentation to EMR free-text notes and to electronic SBAR-template notes, as did nurse and attending physician notification. The implementation of an electronic SBAR note is associated with more complete documentation and increased frequency of documentation of communication among nurses and physicians. PMID- 25274105 TI - House staff perceptions of how handoff quality influences code blue and rapid response team events. PMID- 25274107 TI - Synovial sarcoma of the ethmoidal sinus. AB - BACKGROUND: Synovial sarcoma is a high-grade, soft tissue, malignant disease associated with poor outcome. Typically, synovial sarcoma involves the extremities, with less than 10 per cent of cases occurring in the head and neck region. Synovial sarcoma of the paranasal sinuses is a rare entity. This paper presents a case of an elderly patient with synovial sarcoma of the ethmoidal sinus. CASE REPORT: An 80-year-old woman who had right epistaxis underwent nasal endoscopy and biopsy. The pathology indicated synovial sarcoma and the patient underwent endoscopic excision of the tumour. CONCLUSION: Synovial sarcoma of the ethmoidal sinus is very rare. Patients should undergo excision of the tumour with post-operative radiotherapy. However, the prognosis remains poor and usually the patient succumbs to death within a year. PMID- 25274109 TI - MicroRNA expression analysis of adult-onset Drosophila Alzheimer's disease model. AB - Alzheimer's disease (AD) is the most common reason for dementia in elderly population. Its neuropathological features include senile plaques, neurofibril tangles and neuronal death. Scientists have established many AD animal models, including yeast, Caenorhabditis elegans, Drosophila melanogaster, mice, rats and non-human primates. Drosophila AD models are much more efficient for genetic manipulation and screening assay than mammals. microRNAs (miRNAs) are ~22nt small RNA molecules that fine-tune gene expression at posttranscriptional level. The dysregulation of miRNAs could participate in AD progression by influencing targets' expression and functions. However, miRNA expression profile of AD flies has not yet been investigated. Using the latest uParafloTM miRNA microarray assay, we found that 17 miRNAs that were consistently dysregulated in adult-onset AD Drosophila brains: eight of which were upregulated (miR- 8, miR-13b, miR-277, miR-279, miR-981, miR-995, miR-998, miR-1017) and nine were downregulated (let-7, miR-1, miR-9a, miR-184, miR-193, miR-263b, miR-276a, miR-285, miR-289). KEGG pathway annotations using DIANA miRPath or targets predicted by Targetscan identified 7 pathways (Valine, leucine and isoleucine degradation; MAPK signaling pathway; Dorso-ventral axis formation; Propanoate metabolism; Sphingolipid metabolism; Lysine degradation; Jak- STAT signaling pathway) which might be influenced by these miRNAs. Integrative miRNA/mRNA regulatory network analysis revealed functional cluster with transaminase activity to be potentially regulated by miRNAs in AD. Taken together, our profiling assay identified miRNAs as markers for adult onset AD Drosophila. Dysregulation of miRNA profile may participate in AD pathogenesis by interrupting the metabolism of amino acids in the brain. PMID- 25274108 TI - Association of smoking and alcohol drinking with dementia risk among elderly men in China. AB - BACKGROUND: Previous studies relating smoking and alcohol drinking with the incidence of dementia have been inconsistent. OBJECTIVES: We assessed whether smoking and alcohol drinking was associated with the risk of dementia, including Alzheimer disease (AD) and vascular dementia (VaD) after seven years of follow up. DESIGN: We prospectively analysed the incidence of dementia from 2004 to 2011 among 2959 elderly men, according to their smoking and alcohol drinking status. SETTING: six neighbourhoods from three districts mentioned in Chongqing city. PARTICIPANTS: A total of 3170 men were followed up annually for 7 years. MEASUREMENTS: Cox proportional hazards models were established to evaluate the association between smoking, alcohol drinking and the risk of dementia. RESULTS: The incidences of AD and VaD were higher respectively in current smoking than never smoking, daily drinking than never drinking over 7 years of follow-up (p<0.01). After adjusting for age and other potential confounders, current smoking was associated with increased risk of AD (HR= 2.14, 95% CI 1.20-4.46) and VaD (HR= 3.28, 95% CI 1.14-4.52), meanwhile, daily drinking was related to increased risk of AD (HR= 2.25, 95% CI 1.43-3.97) and VaD (HR= 3.42, 95% CI 1.18 4.51). In addition, co-smoking and drinking were related to with a significantly higher risk of AD and VaD than non-smoking and drinking (HR= 3.03, 95% CI 1.65 4.19) and VaD (HR= 3.96, 95% CI 1.64-4.71). Moreover, co-smoking and drinking had higher risk of AD and VaD compared with current smoking and daily drinking. CONCLUSIONS: Current smoking and daily drinking were found to be significantly associated with dementia in elderly men. PMID- 25274110 TI - Everyday cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment. AB - BACKGROUND: Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to determine which of the IADL-related Everyday Cognition (ECog) scale items are most sensitive for detection of early functional changes. METHODS: We assessed 290 CN and 495 MCI participants from the Alzheimer's Disease Neuroimaging Initiative. We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using only the 17 participant-based and 17 informant based ECog items related to IADL. We then performed Cox regression analyses to predict progression from CN to MCI. All analyses were adjusted for demographic characteristics. RESULTS: We found that worse performance on "remembering a few shopping items" (participant and informant-based p<0.0001), "remembering appointments" (participant and informant-based p<0.0001), "developing a schedule in advance of anticipated events" (participant-based p=0.007), "balancing checkbook" (participant-based p=0.02), and "keeping mail and papers organized" (informant-based p=0.002) best discriminated MCI from CN. We found that worse performance on "keeping mail and papers organized" (participant-based Hazard Ratio (HR)=2.27, p=0.07) marginally predicted greater hazard of progressing from CN to MCI. CONCLUSIONS: Our results indicate that a few simple questions targeting early functional changes, addressed either to the individual or informant, can effectively distinguish between CN elderly and individuals with MCI. Additionally, one of the above questions related to organization suggested which CN individuals are likely to progress to MCI. PMID- 25274111 TI - Pomegranate extract modulates processing of amyloid-beta precursor protein in an aged Alzheimer's disease animal model. AB - Accumulating research supports the neuroprotective effects of pomegranate (Punica granatum) juice and extracts against Alzheimer's disease (AD) but there is limited data available in animal models. Here we investigated the effects of a standardized pomegranate extract (PE) on AD pathology in an aged transgenic AD animal model (R1.40).The mice (age 24-30 months) received either PE (at 100 and 200 mg/kg) or a control solution daily for three weeks, and were evaluated in the Morris water maze and the Y-maze for improvements in spatial long-term and working memory functions. Cortical amyloid-beta precursor protein (APP) and amyloid-beta (Abeta) levels, along with other relevant biomarkers for AD, were measured in brain tissues. PE did not improve cognitive performance of the mice, but altered levels and ratio of the Abeta42 and Abeta40 peptides which would favor a diminution in AD pathogenesis. Further analysis revealed that this reversal could be the product of the modification of gamma-secretase enzyme activity, the enzyme involved in the generation of these Abeta isoforms. Our findings support a specific anti-amyloidogenic mechanism of a pomegranate extract in this aged AD animal model. PMID- 25274112 TI - The complex actions of statins in brain and their relevance for Alzheimer's disease treatment: an analytical review. AB - In view that several studies have shown a positive correlation between high cholesterol and an increase in the risk for developing Alzheimer's disease (AD) statins have been proposed as alternative drugs for its treatment and/or prevention. However, the potential benefits of statins remain controversial. Although they have lipid-lowering properties, statins also have pleiotropic effects that are unrelated to cholesterol reduction and have a wide range of biological implications whose consequences in brain function have not been fully characterized. In this work we analyze different studies that have reported both, beneficial and toxic effects for statins in the central nervous system (CNS), and we revise the literature that claims their potential for treating AD. First, we present an overview of the cholesterol metabolism and its regulation in the brain in order to provide the framework for understanding the pathological association between altered cholesterol and AD. Then, we describe the cholesterol-lowering and pleiotropic properties of statins that have been reported in vivo and in in vitro models. We conclude that the effects of statins in the brain are broad and complex and that their use for treating several diseases including AD should be carefully analyzed given their multiple and broad effects. PMID- 25274113 TI - Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. AB - Despite B vitamin supplementation playing an important role in cognitive function, the exact effect remains unknown. The aim of this study was to systematically review and quantitatively synthesize the efficacy of treatment with vitamins B supplementation in slowing the rate of cognitive, behavioral, functional and global decline in individuals with MCI or AD. A systematic literature search in PubMed, EMBASE, International Pharmaceutical Abstracts, clinicaltrials. gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry was conducted on April 2014, with no limit of date. Five trials met the eligibility criteria and were selected for this meta-analysis. Meta-analysis showed moderate beneficial effects of vitamins B supplementation on memory (SMD 0.60, 95% CI 0.20, 1.00), whereas no significant difference on general cognitive function (WMD -0.10, 95% CI -0.80, 0.59), executive function (SMD 0.05, 95% CI -0.11, 0.21) and attention (WMD -0.03, 95% CI -1.20, 1.14) were found in MCI patients. In addition, no significantly cognitive benefits on the Alzheimer's Disease Assessment Scale (ADAS-cog) (WMD 1.01, 95% CI -0.68, 2.70) and Mini Mental State Examination (MMSE) (WMD -0.22, 95% CI -1.00, 0.57), functional (SMD 0.13, 95% CI -0.05, 0.31), behavioral (SMD 0.04, 95% CI -0.16, 0.25) or global (WMD 0.07, 95% CI -0.48, 0.62) change were observed in AD patients. Collectively, weak evidence of benefits was observed for the domains of memory in patients with MCI. Nevertheless, future standard RCTs are still needed to determine whether it was still significant in larger populations. However, the data does not yet provide adequate evidence of an effect of vitamins B on general cognitive function, executive function and attention in people with MCI. Similarly, folic acid alone or vitamins B in combination are unable to stabilize or slow decline in cognition, function, behavior, and global change of AD patients. PMID- 25274114 TI - Ameliorative effects of baicalein on an amyloid-beta induced Alzheimer's disease rat model: a proteomics study. AB - BACKGROUND: Alzheimer's disease (AD) is the most common type of age-related dementia. Effective anti-AD drugs against amyloid-beta-protein-induced cognitive impairment are still lacking. Baicalein is the main component of Radix Scutellariae and has neuroprotective properties. In this study, we provide further insights into pharmacotherapy mechanisms and potential targets of baicalein in AD. OBJECTIVE: To investigate the therapeutic effects and mechanism of action of baicalein in an AD rat model. METHODS: Male rats were intracerebroventricularly injected with amyloid-beta(Abeta) 1-40, and baicalein was orally administered. The therapeutic effect was evaluated with the Morris water maze test, and the mechanism of action was studied using a proteomics approach and western blotting. RESULTS: Baicalein treatment significantly attenuated Abeta1-40-induced abnormalities in cognitive function. Additionally, the expression levels of 24 proteins in the cerebral cortex and hippocampus were significantly influenced by baicalein; approximately 50% of these proteins are related to energy metabolism and neurotransmission, whereas others are related to anti-apoptosis, anti-oxidation, the stress response, protein phosphorylation, the cytoskeleton, phospholipid metabolism and cell signaling. The expression of these proteins was increased, except for the proteins related to the cytoskeleton. The changes in the expression of 2 proteins were confirmed by western blotting. CONCLUSIONS: Baicalein ameliorates the Abeta1-40-induced dementia in rats and may be a novel and promising drug for the treatment of AD. The therapeutic mechanism may be related to modulation of a number of processes, mainly through the promotion of energy metabolism and neurotransmission, with the additional promotion of anti-apoptosis, anti-oxidation, protein phosphorylation, etc. PMID- 25274116 TI - Characterization of Bacillus spp. from the gastrointestinal tract of Labeo rohita -towards to identify novel probiotics against fish pathogens. AB - The aim of the present study is to screen and characterize endogenous microbiota Bacillus spp. from the gastrointestinal (GI) tract of Labeo rohita in order to evaluate their probiotic attributes. A total of 74 isolates from the GI of L. rohita were evaluated for their antimicrobial properties by agar well-diffusion method against fish pathogens. Based on the better antibacterial features, three isolates (KADR1, KADR3, and KADR4) were selected for further delineation. The three selected isolates exhibited higher tolerance to bile salt, moderate tolerance to low pH, high surface hydrophobicity to solvents, and capable to autoaggregate. All three isolates demonstrated notable proteolytic, catalase activity and susceptibility to various antibiotics. Partial 16S rRNA sequencing revealed that the isolates exhibited 99 % sequence homology with Bacillus subtilis, Bacillus aerophilus, and Bacillus firmus of the database substantiating morphological and physiological characterization. Survivability in low pH and bile salt ensures their adaptability in the fish intestinal microenvironment. The ability to autoaggregate reveals colonization potential in the GI of the fish. Absence of hemolytic activity, antibiotic susceptibility to certain antibiotics, presence of protease and catalase activity, and non-pathogenic caliber of the above-mentioned isolates could be feasible characteristics when considering them as probiotics in the aquaculture industry. PMID- 25274117 TI - Lipid production by pure and mixed cultures of Chlorella pyrenoidosa and Rhodotorula mucilaginosa isolated in Nuevo Leon, Mexico. AB - Given the well-known environmental drawbacks of using fossil fuels, advances in the field of alternative energy have become a worldwide technological priority. Special interest has been focused on the production of biodiesel obtained from oleaginous microorganisms. In the present research, lipid production by two species, microalgae Chlorella pyrenoidosa and yeast Rhodotorula mucilaginosa was assessed, independently and in mixed culture to evaluate a possible synergy. Fatty acid analysis was performed by gas chromatography. Among pure and mixed cultures of both strains and several culturing conditions, the highest biomass and lipid productivity was obtained by C. pyrenoidosa (8.05 and 1.62 g/L, respectively). The results of this study showed that both strains used are in fact oleaginous strains as they were found to reach up to 20 % of lipids, in addition, lipids in both pure and mixed cultures were mainly of triglycerides (>90 %), composed of fatty acid chains between 16 and 18 carbons. PMID- 25274115 TI - Increased susceptibility to oxidative death of lymphocytes from Alzheimer patients correlates with dementia severity. AB - We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer's disease (AD) patients when exposed to hydrogen peroxide (H2O2) induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer's disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to moderate dementia (CDR 1- 2, n=13), and 15 healthy controls (HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and propidium iodide staining. The greatest susceptibility to H2O2-induced death was observed for lymphocytes from severe dementia patients, whereas those with mild-to-moderate dementia exhibited intermediate values, compared to healthy controls. A significant increase in the apoptosis/necrosis ratio was found in AD patients. Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibition significantly protected from H2O2-induced death of lymphocytes, whereby a lower degree of protection was observed in severe AD patients. Moreover, inhibition of PARP-1 abolished the differences in apoptosis/necrosis ratios observed between the three groups of patients. These results support the notion that AD is a systemic disorder, whereby enhanced susceptibility to H2O2-induced death in peripheral lymphocytes correlates with dementia severity and enhanced death in AD patients is attributable to a PARP-dependent increase in the apoptosis/necrosis ratio. PMID- 25274118 TI - Induction therapy, tacrolimus plasma concentration, and duration if intensive care unit stay are risk factors for peripheral leucopenia following heart transplantation. AB - BACKGROUND: Although survival among heart recipients has increased, a limiting factor is chronic adverse effects of immunosuppression therapy. MATERIAL AND METHODS: We performed a retrospective analysis of 22 patients (19 men and 3 women) with a mean age of 48 +/- 12 years who underwent orthotropic heart transplantation. There were 20 (91%) patients who received induction therapy (basiliximab, Simulect, Novartis Europharm Limited). All patients were treated with standard triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). RESULTS: Patients were divided into 2 groups according to postoperative peripheral cytopenia diagnosis. There were 16 (73%) in the cytopenic group and 6 (27%) in the non-cytopenic group. Mean time of peripheral leucopenia detection was 65 +/- 13 days following surgery. The blood leucocyte count was 0.98 +/- 0.2 * 10(3)/mm(3) vs. 5.85 +/- 0.9 * 10(3)/mm(3) in patients with peripheral cytopenia compared to non-cytopenic patients (p<0.01). There was a statistically important difference in duration of intensive care unit stay between the 2 groups (p<0.01). A correlation between tacrolimus serum concentration and risk for leucopenia was also detected (p<0.05). CONCLUSIONS: Basiliximab administration as induction therapy, tacrolimus serum concentration, and duration of intensive care unit stay are risk factors for leucopenia. PMID- 25274121 TI - Vibrational signatures of S-nitrosoglutathione as gaseous, protonated species. AB - Gas-phase ions of protonated l-glutathione as native species, [GSH + H](+), and S nitroso derivative, [GSNO + H](+), have been generated by electrospray ionization and probed via infrared multiple photon dissociation (IRMPD) action spectroscopy. Insight into the conformational landscape is gained from interpretation of the IR spectra aided by high-level theoretical calculations, which enables structural assignment disclosing both the site of protonation and the intramolecular hydrogen-bond network. Calculations yield the low-energy structures of [GSNO + H](+). A admixture of the four most stable ones (SN1, AN1, SN2, and AN2) is apt to account for the experimental IRMPD spectra obtained in both the 1000-2000 and the 3100-3700 cm(-1) spectral ranges. The most stable form of [GSNO + H](+), SN1, protonated at the amino group, presents a syn conformation at the S-N (partial) double bond and all peptidic carbonyls involved in (strong) C?O...H-N hydrogen bonds, so allowing closure of a C5 (beta-strand), two C7 (gamma-turn), and one C9 membered rings. An appreciable barrier to rotation of 43 kJ mol(-1) about the S-N bond is found to separate SN1 from the analogous anti isomer AN1, which lies only 0.70 kJ mol(-1) higher in free energy. Conformers obtained for [GSH + H](+) are very similar to the [GSNO + H](+) counterparts, indicating that the S-nitrosation motif does not affect significantly the geometry of the peptide. The observed nu(NO) signatures at 1622 and 1690 cm(-1), merged with other absorptions, are revealed by their sensitivity to (15)NO isotope labeling and by comparison with the IRMPD spectrum of native [GSH + H](+), providing a diagnostic probe for the S nitrosation feature in natural peptides. PMID- 25274120 TI - A comparison of the Caulobacter NA1000 and K31 genomes reveals extensive genome rearrangements and differences in metabolic potential. AB - The genus Caulobacter is found in a variety of habitats and is known for its ability to thrive in low-nutrient conditions. K31 is a novel Caulobacter isolate that has the ability to tolerate copper and chlorophenols, and can grow at 4 degrees C with a doubling time of 40 h. K31 contains a 5.5 Mb chromosome that codes for more than 5500 proteins and two large plasmids (234 and 178 kb) that code for 438 additional proteins. A comparison of the K31 and the Caulobacter crescentus NA1000 genomes revealed extensive rearrangements of gene order, suggesting that the genomes had been randomly scrambled. However, a careful analysis revealed that the distance from the origin of replication was conserved for the majority of the genes and that many of the rearrangements involved inversions that included the origin of replication. On a finer scale, numerous small indels were observed. K31 proteins involved in essential functions shared 80-95% amino acid sequence identity with their C. crescentus homologues, while other homologue pairs tended to have lower levels of identity. In addition, the K31 chromosome contains more than 1600 genes with no homologue in NA1000. PMID- 25274119 TI - Deciphering the complex three-way interaction between the non-integrin laminin receptor, galectin-3 and Neisseria meningitidis. AB - The non-integrin laminin receptor (LAMR1/RPSA) and galectin-3 (Gal-3) are multi functional host molecules with roles in diverse pathological processes, particularly of infectious or oncogenic origins. Using bimolecular fluorescence complementation and confocal imaging, we demonstrate that the two proteins homo- and heterodimerize, and that each isotype forms a distinct cell surface population. We present evidence that the 37 kDa form of LAMR1 (37LRP) is the precursor of the previously described 67 kDa laminin receptor (67LR), whereas the heterodimer represents an entity that is distinct from this molecule. Site directed mutagenesis confirmed that the single cysteine (C(173)) of Gal-3 or lysine (K(166)) of LAMR1 are critical for heterodimerization. Recombinant Gal-3, expressed in normally Gal-3-deficient N2a cells, dimerized with endogenous LAMR1 and led to a significantly increased number of internalized bacteria (Neisseria meningitidis), confirming the role of Gal-3 in bacterial invasion. Contact dependent cross-linking determined that, in common with LAMR1, Gal-3 binds the meningococcal secretin PilQ, in addition to the major pilin PilE. This study adds significant new mechanistic insights into the bacterial-host cell interaction by clarifying the nature, role and bacterial ligands of LAMR1 and Gal-3 isotypes during colonization. PMID- 25274122 TI - A bedside clinical and ultrasound-based approach to hemodynamic instability - Part II: bedside ultrasound in hemodynamic shock: continuing professional development. AB - Shock is defined as a situation where oxygen transport and delivery is inadequate to meet oxygen demand. The patient in shock is evaluated through medical history, physical examination, and careful observation of the hemodynamic and respiratory monitors. The patient is initially managed with basic resuscitation measures, however bedside ultrasound should be performed if hemodynamic instability persists. We propose to use ultrasound of the inferior vena cava (IVC), and the concept of venous return, as the initial step in order to identify the mechanism of shock. Doppler examination of the hepatic venous flow can also be added. Further ultrasound examination of the patient's heart, thorax, and abdomen can then be performed in order to determine the etiology of shock. In patients with reduced mean systemic venous pressure, an examination of the patient's thoracic and abdominal cavities to detect free fluid, pneumonia, or empyema can be considered. In patients with increased right atrial pressure, transthoracic echocardiography will allow identification of left or right ventricular dysfunction. Finally, in the presence of increased resistance to venous return, thoracic examination for pneumothorax or cardiac tamponade and abdominal examination for signs of abdominal compartment syndrome or IVC occlusion can be considered. Subsequent treatment can then be tailored to the etiology of shock. Elements of bedside ultrasound examination are currently taught in many anesthesia training programs. PURPOSE: To develop an approach to the patient in shock that incorporates bedside ultrasound examination. PMID- 25274123 TI - A reappraisal of the unemployment-mortality relationship: transitory and permanent effects. AB - Using US state-level data for 1974 to 2003, this article estimates a relationship that describes both the transitory and permanent effects of unemployment rates on mortality. It shows that the transitory effect of increasing unemployment rates is to decrease mortality. The permanent effect of increasing unemployment rates is to increase mortality. The detrimental effects of higher unemployment rates on health take a long time to become visible. The permanent scars of unemployment on population health are detrimental and overwhelming. They dwarf any opposite and transitory effects. PMID- 25274124 TI - Viewpoint: Prevention is missing: is China's health reform reform for health? AB - Ancient China emphasized disease prevention. As a Chinese saying goes, 'it is more important to prevent the disease than to cure it'. Traditional Chinese medicine posits that diseases can be understood, thus, prevented. In today's China, the state of people's health seems worse than in the past. Thus the Chinese government undertook the creation of a new health system. Alas, we believe the results are not very satisfactory. The government seems to have overlooked rational allocation between resources for treatment and prevention. Public investment has been gradually limited to the domain of treatment. We respond to this trend, highlighting the importance of prevention and call for government and policymakers to adjust health policy and work out a solution suitable for improving the health of China's people. PMID- 25274125 TI - Enhanced attention capture by emotional stimuli in mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) may be associated with compromised executive functioning and altered emotional reactivity. Despite frequent affective and cognitive symptoms in mTBI, objective evidence for brain dysfunction is often lacking. Previously we have reported compromised performance in symptomatic mTBI patients in an executive reaction time (RT) test, a computer-based RT test engaging several executive functions simultaneously. Here, we investigated the cognitive control processes in mTBI in context of threat-related stimuli. We used behavioral measures and event-related potentials (ERP) to investigate attentional capture by task-relevant and task-irrelevant emotional stimuli during a Go-NoGo task requiring cognitive control. We also assessed subjective cognitive, somatic, and emotional symptoms with questionnaires. Twenty-seven subjects with previous mTBI and 17 controls with previous ankle injury participated in the study over 9 months post-injury. Electroencephalogram (EEG) was recorded while patients performed a modified executive RT-test. N2-P3 ERP component was used as a general measure of allocated attentional and executive processing resources. Although at the time of the testing, the mTBI and the control groups did not differ in symptom endorsement, mTBI patients reported having had more emotional symptoms overall since the injury than controls. The overall RT-test performance levels did not differ between groups. However, when threat-related emotional stimuli were used as Go-signals, the mTBI group was faster than the control group. In comparison to neutral stimuli, threat-related stimuli were associated with increased N2-P3 amplitude in all conditions. This threat-related enhancement of the N2-P3 complex was greater in mTBI patients than in controls in response to Go signals and NoGo signals, independent of relevance. We conclude that mTBI may be associated with enhanced attentional and executive resource allocation to threat related stimuli. Along with behavioral evidence for enhanced attention allocation to threat stimuli, increased brain responses to threat were observed in mTBI. Enhanced attention capture by threat-related emotional stimuli may reflect inefficient top-down control of bottom-up influences of emotion, and might contribute to affective symptoms in mTBI. PMID- 25274127 TI - Method for monitoring deletions in the aflatoxin biosynthesis gene cluster of Aspergillus flavus with multiplex PCR. AB - The report presents a rapid, inexpensive and simple method for monitoring indels with influence on aflatoxin biosynthesis within Aspergillus flavus populations. PCR primers were developed for 32 markers spaced approximately every 5 kb from 20 kb proximal to the aflatoxin biosynthesis gene cluster to the telomere repeat. This region includes gene clusters required for biosynthesis of aflatoxins and cyclopiazonic acid; the resulting data were named cluster amplification patterns (CAPs). CAP markers are amplified in four multiplex PCRs, greatly reducing the cost and time to monitor indels within this region across populations. The method also provides a practical tool for characterizing intraspecific variability in A. flavus not captured with other methods. SIGNIFICANCE AND IMPACT OF THE STUDY: Aflatoxins, potent naturally-occurring carcinogens, cause significant agricultural problems. The most effective method for preventing contamination of crops with aflatoxins is through use of atoxigenic strains of Aspergillus flavus to alter the population structure of this species and reduce incidences of aflatoxin producers. Cluster amplification pattern (CAP) is a rapid multiplex PCR method for identifying and monitoring indels associated with atoxigenicity in A. flavus. Compared to previous techniques, the reported method allows for increased resolution, reduced cost, and greater speed in monitoring the stability of atoxigenic strains, incidences of indel mediated atoxigenicity and the structure of A. flavus populations. PMID- 25274128 TI - [Prof. Dr. med. Thomas G. Wendt Director of the Department of Radiation Oncology at the University Hospital Jena on his 65th birthday]. PMID- 25274126 TI - [Recommendations of the Austrian Society of Rheumatology/Austrian Radiology Rheumatology Initiative for Musculoskeletal Ultrasound for the application of ultrasound in rheumatology]. AB - It is the current goal in rheumatology to diagnose and treat inflammatory rheumatic diseases early in order to avoid structural damage. Functional imaging methods such as musculoskeletal sonography are increasingly used to support the clinical diagnosis. To ascertain the quality of ultrasound assessments performed by rheumatologists in Austria, the Austrian Radiology-Rheumatology Initiative for Musculoskeletal Ultrasound (ARRIMUS) proposed recommendations for a training curriculum, technical standards for ultrasound equipment, minimum requirements for documentation, indications for sonography and the use of ultrasound for interventions. These recommendations have been endorsed by the Austrian Society of Rheumatology and should aid rheumatologists to perform high quality ultrasound assessment in clinical practice. PMID- 25274129 TI - Sagittal gap balancing with the concept of a single radius femoral component in posterior cruciate sacrificing total knee arthroplasty with patient-specific instrumentation. AB - PURPOSE: Sagittal gap balancing (relation between flexion and extension gaps) with placement of trial femoral components and reduction of the patella in total knee arthroplasty (TKA) is important, but it is not easy. The purpose of this study was to investigate whether (1) the flexion and extension gaps were equal when a previously suggested three-dimensional planning for a single-radius femoral component (its sagittal centre is matched with flexion-extension axis of knee movement) is executed with patient-specific instrumentation (PSI) and whether (2) PSI was done with good accuracy, which did not affect the first purpose. METHODS: Posterior cruciate ligament sacrificed (PS) TKA was performed on 12 joints. Using the patients' pre-operative computed tomography (CT) images, PSI was manufactured to fit on the bony surface of the knee joint and to simultaneously transfer pre-operative planning to the operating room. After osteotomy with PSI, gap measurements were calculated with the knee in flexion and extension. Angle deviations of both components were investigated with postoperative CT images. RESULTS: The flexion gap (mean, 19.1 mm) was larger than the extension gap (mean, 12.3 mm) in all cases. Angle differences between pre- and postoperative alignments were within 3 degrees in all cases. CONCLUSIONS: Although PSI executed the pre-operative planning with good accuracy, the flexion gap is always larger than the extension gap. This finding suggests that surgeons may not aim for equal gaps of flexion and extension in PS-TKA. PMID- 25274130 TI - Effects of Different Demineralization-Inhibiting Methods on the Shear Bond Strength of Glass-Ceramics. AB - PURPOSE: This in vitro study was undertaken to evaluate the effects of different demineralization-inhibiting methods on the shear bond strength (SBS) of glass ceramics. MATERIALS AND METHODS: Ninety extracted intact human mandibular lateral insicors were randomly divided into six equal groups. Group C was left untreated, while enamel subsurface demineralization was induced in the other groups. In group D, porcelain discs (3 mm in diameter) were cemented to demineralized enamel by using total-etch photopolymerizing luting composite resin without pretreatment. Demineralized specimens in groups F, CA, M, and I were pretreated with fluoride gel, CPP-ACP paste, microabrasion, and resin infiltration, respectively, and then porcelain discs were cemented. SBS (MPa) was calculated from the failure load (N) per bonded area (mm(2)). Fracture types were examined by optical microscopy (40* magnification). Data were analyzed with ANOVA, Tukey's test, and G-test. RESULTS: ANOVA revealed significant intergroup differences (p < 0.01). No significant differences in SBS (MPa) were found between groups C (19.48 +/- 2.0) and I (20.02 +/- 1.6). Lower SBS values were recorded in groups D (7.93 +/- 0.8), F (12.51 +/- 1.5), CA (17.08 +/- 1.3), and M (14.84 +/- 1.4). Mixed and cohesive failures were the most prevalent in groups M and I, respectively. CONCLUSION: Resin infiltration enhanced the SBS of porcelain discs bonded to demineralized enamel when compared with the other demineralization-inhibiting methods. CLINICAL RELEVANCE: Resin infiltration could be useful to enhance adhesion of glass-ceramics to teeth with white spot lesions. PMID- 25274131 TI - The management of acute adverse effects of breast cancer treatment in general practice: a video-vignette study. AB - BACKGROUND: There has been a focus recently on the use of the Internet and email to deliver education interventions to general practitioners (GPs). The treatment of breast cancer may include surgery, radiotherapy, chemotherapy, and/or hormone treatment. These treatments may have acute adverse effects. GPs need more information on the diagnosis and management of specific adverse effects encountered immediately after cancer treatment. OBJECTIVE: The goal was to evaluate an Internet-based educational program developed for GPs to advise patients with acute adverse effects following breast cancer treatment. METHODS: During phase 1, participants viewed 6 video vignettes of actor-patients reporting 1 of 6 acute symptoms following surgery and chemotherapy and/or radiotherapy treatment. GPs indicated their diagnosis and proposed management through an online survey program. They received feedback about each scenario in the form of a specialist clinic letter, as if the patient had been seen at a specialist clinic after they had attended the GP. This letter incorporated extracts from local guidelines on the management of the symptoms presented. This feedback was sent to the GPs electronically on the same survey platform. In phase 2, all GPs were invited to manage similar cases as phase 1. Their proposed management was compared to the guidelines. McNemar test was used to compare data from phases 1 and 2, and logistic regression was used to explore the GP characteristics that were associated with inappropriate case management. RESULTS: A total of 50 GPs participated. Participants were younger and more likely to be female than other GPs in Australia. For 5 of 6 vignettes in phase 1, management was consistent with expert opinion in the minority of cases (6%-46%). Participant demographic characteristics had a variable effect on different management decisions in phase 1. The variables modeled explained 15%-28% of the differences observed. Diagnosis and management improved significantly in phase 2, especially for diarrhea, neutropenia, and seroma sample cases. The proportion of incorrect management responses was reduced to a minimum (25.3%-49.3%) in phase 2. CONCLUSIONS: There was evidence that providing feedback by experts on specific cases had an impact on GPs' knowledge about how to appropriately manage acute treatment adverse effects. This educational intervention could be targeted to support the implementation of shared care during cancer treatment. PMID- 25274132 TI - Extracorporeal low-energy shock-wave therapy exerts anti-inflammatory effects in a rat model of acute myocardial infarction. AB - BACKGROUND: It has been previously demonstrated that extracorporeal low-energy shock-wave (SW) therapy ameliorates left ventricular (LV) remodeling through enhanced angiogenesis after acute myocardial infarction (AMI) in pigs in vivo. However, it remains to be examined whether SW therapy also exerts anti inflammatory effects on AMI. METHODS AND RESULTS: AMI was created by ligating the proximal left anterior descending coronary artery in rats. They were randomly assigned to 2 groups: with (SW group) or without (control group) SW therapy (0.1 mJ/mm(2), 200 shots, 1 Hz to the whole heart at 1, 3 and 5 days after AMI). Four weeks after AMI, SW therapy significantly ameliorated LV remodeling and fibrosis. Histological examinations showed that SW therapy significantly suppressed the infiltration of neutrophils and macrophages at days 3 and 6, in addition to enhanced capillary density in the border area. Molecular examinations demonstrated that SW therapy enhanced the expression of endothelial nitric oxide synthase and suppressed the infiltration of transforming growth factor-beta1 positive cells early after AMI. SW therapy also upregulated anti-inflammatory cytokines and downregulated pro-inflammatory cytokines in general. CONCLUSIONS: These results suggest that low-energy SW therapy suppressed post-MI LV remodeling in rats in vivo, which was associated with anti-inflammatory effects in addition to its angiogenic effects, and demonstrated a novel aspect of the therapy for AMI. PMID- 25274133 TI - Impact of cardiac magnetic resonance imaging - cardiac contusion with intramural hemorrhage. PMID- 25274134 TI - Omentoplasty for oesophagogastrostomy after oesophagectomy. AB - BACKGROUND: Oesophagectomy followed by oesophagogastrostomy is the preferred treatment for early-stage oesophageal cancer. It carries the risk of anastomotic leakage after oesophagogastric anastomosis, which causes considerable morbidity and mortality and is one of the most dangerous complications. Omentoplasty has been recommended by some researchers to prevent anastomotic leaks associated with oesophagogastrostomy. However, the value of omentoplasty for oesophagogastrostomy after oesophagectomy has not been systematically reviewed. OBJECTIVES: To assess the effects of omentoplasty for oesophagogastrostomy after oesophagectomy in patients with oesophageal cancer. SEARCH METHODS: A comprehensive search to identify eligible studies for inclusion was conducted using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PubMed and other reliable resources. SELECTION CRITERIA: Randomised controlled trials comparing omentoplasty versus no omentoplasty for oesophagogastrostomy after oesophagectomy in patients with oesophageal cancer were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors (Yong Yuan and Xiaoxi Zeng) independently assessed the quality of included studies and extracted data; disagreements were resolved through arbitration by another review author. Results of dichotomous outcomes were expressed as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes were expressed as mean differences (MDs) with 95% CIs. Meta-analysis was performed when available data were sufficiently similar. Subgroup analysis was carried out on the basis of different approaches to surgery. MAIN RESULTS: Three randomised controlled trials (633 participants) were included in this updated review. No significant differences in hospital mortality were noted between the study group (with omentoplasty) and the control group (without omentoplasty) (RR 1.28, 95% CI 0.49 to 3.39). None of the included studies reported differences in long-term survival between the two groups. The incidence of postoperative anastomotic leakage was significantly less among study participants treated with omentoplasty than among those treated without (RR 0.25, 95% CI 0.11 to 0.55), but the additional benefit was seen in the subgroup analysis only for participants undergoing a transhiatal oesophagogastrectomy (THE) procedure (RR 0.23, 95% CI 0.07 to 0.79); transthoracic oesophagogastrectomy (TTE) (RR 0.19, 95% CI 0.03 to 1.03); or three-field oesophagectomy (RR 0.33, 95% CI 0.09 to 1.19 ). Omentoplasty did not significantly improve other surgery-related complications, such as anastomotic stricture (RR 0.91, 95% CI 0.33 to 2.57). However, participants treated with omentoplasty could reduce the duration of hospitalisation compared with that seen in the control group (MD -2.13, 95% CI -3.57 to -0.69). AUTHORS' CONCLUSIONS: Omentoplasty may provide additional benefit in decreasing the incidence of anastomotic leakage after oesophagectomy and oesophagogastrostomy for patients with oesophageal cancer without increasing or decreasing other complications, especially among those treated with THE. It also has the potential to reduce the duration of hospital stay after operation. Further randomised controlled trials are needed to investigate the influences of omentoplasty on the incidence of anastomotic leakage and anastomotic stricture, long-term survival, duration of hospital stay and quality of life after oesophagectomy and oesophagogastrostomy when different surgical approaches are used. PMID- 25274135 TI - Ammonia-mediated, large-scale synthesis of ammonia borane. AB - A simple, large-scale synthesis of ammonia borane from NaBH4 and (NH4)2SO4 at 0 degrees C-rt in THF containing 5% NH3 is described. The presence of ammonia is critical for the reaction to proceed and allows the reaction at high concentrations and ambient temperature without the need for anhydrous solvent or inert atmosphere. PMID- 25274136 TI - Antioxidant and anti-inflammatory effects of Ruta chalepensis L. extracts on LPS stimulated RAW 264.7 cells. AB - Ruta chalepensis L. is used in the traditional herbal treatment of various diseases. The aim of this work is to investigate the effect of different extracts of R. chalepensis L. on inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) gene expressions and their antioxidant capacity on murine RAW 264.7 macrophage challenged with lipopolysaccharide (LPS). In fact, this study shows that the ethanol and ethyl acetate extracts of R. chalepensis L. considerably decreased the nitric oxide (NO) production in murine RAW 264.7 macrophages stimulated with lipopolysaccharide. Thus, the treatment with both extracts significantly suppressed the levels of iNOS and COX-2 gene expressions through the inhibition of the nuclear factor-kappaB (NF-kappaB) activation. The preincubation of RAW 264.7 cells with various concentrations of ethanol and ethyl acetate extracts decreased the production of thiobarbituric acid-reactive substances (TBARS) in a dose-dependent manner. It also increased the activities of antioxidative enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in LPS-stimulated macrophages, compared to those in the cells treated only with LPS. Besides, the (1)H NMR spectra of both extracts have demonstrated the presence of aromatic signals, thus confirming the existence of phenolic compounds such as flavonoids and polyphenols. So, the ethanol and ethyl acetate extracts of R. chalepensis L. have been shown to possess enough antioxidant and anti-inflammatory activities to prevent LPS induced oxidative stress and inflammation in RAW 264.7 macrophages. PMID- 25274137 TI - Sensitivity of visual and quantitative detection of middle cerebral artery occlusion on non-contrast-enhanced computed tomography. AB - INTRODUCTION: This study aims to investigate diagnostic sensitivity and reliability for the detection of middle cerebral artery occlusion (MCAO) on non contrast-enhanced computed tomography (NECT) by visual assessment (VA), Hounsfield unit (HU) measurement, calculation of the Hounsfield unit/hematocrit (HU/Hct) ratio, and combination of visual assessment and attenuation measurement (VA + HU). METHODS: NECT of 18 patients with angiographically proven MCAO and 18 patients without MCAO were reviewed by two blinded observers. Visual assessment of presence or absence of a hyperdense sign was followed by HU measurement of both middle cerebral arteries (MCA). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for VA, HU measurement, HU/Hct ratio, and VA + HU measurement. Receiver operating characteristic curve analysis (ROC) was performed to determine the optimal cut off values for MCAO using attenuation measurements or HU/Hct ratio. RESULTS: Diagnostic sensitivity/specificity was 63%/91% for VA, 56%/88% for attenuation measurement, 68 %/81 % for HU/Hct ratio, and 75%/78% for VA + HU. ROC curve analysis revealed cut-off values of >42.5 HU for attenuation measurements and >1.12 HU/Hct for HU/Hct ratio. CONCLUSION: Combination of visual assessment with additional attenuation measurement with a cut-off value of 42.5 HU is recommended for most sensitive and reliable detection of MCAO on NECT. PMID- 25274139 TI - Synthesis, self-assembly and photophysical properties of oligo(2,5-dihexyloxy-1,4 phenylene vinylene)-block-poly(ethylene glycol). AB - We describe the synthesis and characterization of a family of diblock copolymers with 5 units of a dihexyloxy-phenylenevinylene block (OHPV) connected to a series of poly(ethylene glycol) (PEG) chains of different average lengths (12, 45 and 115 PEG units: OHPV5-b-PEG12, OHPV5-b-PEG45, OHPV5-b-PEG115). All three polymers underwent self-assembly in ethanol, a good solvent for the PEG units, but poor for the OHPV segment. The nature of the structures formed depends sensitively on the length of the PEG block. OHPV5-b-PEG115 formed long fiber-like micelles of uniform width, whereas OHPV5-b-PEG45 formed fragile broad ribbons. We also obtained thin ribbons with OHPV5-b-PEG12 but they tend to fold and twist upon themselves. The structures obtained were characterized by transmission electron microscopy (TEM) and atomic force microscopy (AFM), as well as by wide-angle X ray scattering (WAXS) and differential scanning calorimetry (DSC). In addition, their photophysical properties were examined by UV-vis, steady state fluorescence and fluorescence decay measurements. The results of these experiments indicate that the OHPV groups pack differently in the fiber-like micelles of OHPV5-b PEG115 than in the lamellar structures formed by OHPV5-b-PEG45. PMID- 25274138 TI - Smoking aggravates the impaired pulmonary function of officially acknowledged female victims of air pollution of 40 years ago. AB - Air pollution due to industrial waste and tobacco smoke is detrimental to pulmonary function. However, the combined effects of air pollution and smoking on pulmonary function have not been investigated. We examined the combined effect of air pollution of 40 years ago and concurrent smoking on the pulmonary function of officially acknowledged female victims in Japan, because females are more susceptible to the adverse effects of both irritants than males. The subjects comprised 655 female victims living in one of two areas with air pollution of 40 years ago and 572 females living in an area without air pollution. All victims have been prescribed standard respiratory medications. Pulmonary function was measured in 2000 for air-pollution groups (130 smokers and 525 non-smokers; mean age, 68.4 years) and during the period of 2004 to 2013 for non-air-pollution groups (113 smokers and 459 non-smokers; mean age, 69.0 years). The smokers included both current smokers and ex-smokers. The victims with a history of smoking had significantly lower forced expiratory volume in 1 second (FEV1 % predicted) (mean, 74%) and significantly lower FEV1/forced vital capacity (FVC) (mean, 70%) than the other groups (P<0.001). Thus, smoking aggravates the pulmonary function in officially acknowledged female victims, despite the improved air pollution and the continuous medical care provided by the government. In conclusion, exposure to air pollution of 40 years ago and cigarette smoking are associated with reduced pulmonary function. These results highlight the importance of measures aimed at smoking cessation and limiting air pollution. PMID- 25274140 TI - Detection of Mycobacterium avium subspecies paratuberculosis in environmental samples by faecal culture and real-time PCR in relation to apparent within-herd prevalence as determined by individual faecal culture. AB - SUMMARY Environmental samples are a cost-saving and easy-to-use approach to diagnose paratuberculosis at the herd level. Detailed knowledge concerning its uncertainties in herds with a low prevalence of Mycobacterium avium spp. paratuberculosis (MAP) is required to design sampling strategies in control programmes. This study aimed to calculate a threshold level of the apparent within-herd prevalence (WHPapp) as determined by individual mycobacterial cultivation (faecal culture; FC) of all cows thus allowing the detection of a herd as MAP-positive at a certain probability level (P d). Out of 200 environmental samples taken twice from five predefined locations in a barn, 25 were positive by FC and 60 were positive by a quantitative real-time PCR method (qPCR). A logistic regression model was used to calculate the WHPapp threshold of detection. For 50% P d, a WHPapp threshold of 2.9% was calculated for the combination of three samples (milking area, main cow alleyways, holding pen) tested simultaneously both by FC and qPCR. The threshold increased to 6.2% for 90% P d. Repeated environmental sampling did not reduce the WHPapp threshold. Depending on the particular needs for prevalence estimation or in control programmes (single or repeated sampling) the provided WHPapp thresholds at different P d will enable decisions to be made about various sampling strategies. PMID- 25274142 TI - Host genetics and opportunistic fungal infections. AB - Current knowledge on the human pathophysiology of fungal infections highlights the crucial role of genetic pitfalls in specific immunity pathways that determine, together with other risk factors, the predisposition to and clinical outcome of fungal disease. In several studies, associations between gene polymorphisms and genetic errors have been implicated in an immunodeficiency phenotype and an increased incidence of opportunistic fungal diseases. The major challenge is to fully understand the complex interactions between genetic variations and multiple factors, and their relative contributions to the final clinical fungal disease phenotype. The aim of this review is to present updated knowledge on immunity genetics and susceptibility to medically relevant fungal diseases, such as those caused by Candida, Aspergillus, and certain other more rare fungi. PMID- 25274141 TI - EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma. AB - Soft tissue sarcomas (STS) are heterogeneous malignant tumors of mesenchymal origin. Due to low incidence and high number of different histological subtypes, their pathogenesis and thus potential targets for their therapy remain barely investigated. Several studies revealed significant higher EPHB4 expression in malignancies such as prostate and colorectal cancer showing survival advantages for these tumor cells. Therefore we studied the expression of EPHB4 in a total of 46 clinical human specimens of different STS and human fibroblasts. EPHB4 mRNA and protein expression were significantly increased in synovial sarcoma. After targeting EPHB4 in fibrosarcoma, synovial sarcoma, liposarcoma and MFH sarcoma cell lines by siRNA or by inhibition of autophosphorylation using the specific EPHB4 kinase inhibitor NVP-BHG712 a decreased proliferation rate/vitality of synovial- and fibrosarcoma cells was observed. Silencing of EPHB4 significantly reduced the transmigration of synovial sarcoma cells towards fibroblasts and endothelial cells. In addition, we assessed the anti-metastatic effect of EPHB4 inhibition in vivo by intraperitoneal administration of the EPHB4 inhibitor in an appropriate sarcoma lung metastasis xenograft model. As result 43% of NVP-BHG712 treated mice (n = 3/7) developed pulmonary metastases whereas all control mice (n = 5) revealed lung metastases. The residual 57% of mice (n = 4/7) showed only small local tumor cell spots. Size measurements of the Vimentin positive area explained significant decrease in lung metastasis formation (p < 0.05) after EPHB4 kinase inhibition. In summary, these data provide first evidence of the importance of EPHB4 in the tumorigenesis of synovial sarcoma and present EPHB4 as a potential target in the therapy of this malignancy. PMID- 25274143 TI - Ankle-foot orthoses in children with cerebral palsy: a cross sectional population based study of 2200 children. AB - BACKGROUND: Ankle-foot orthosis (AFO) is the most frequently used type of orthosis in children with cerebral palsy (CP). AFOs are designed either to improve function or to prevent or treat muscle contractures. The purpose of the present study was to analyse the use of, the indications for, and the outcome of using AFO, relative to age and gross motor function in a total population of children with cerebral palsy. METHODS: A cross-sectional study was performed of 2200 children (58% boys, 42% girls), 0-19 years old (median age 7 years), based on data from the national Swedish follow-up programme and registry for CP. To analyse the outcome of passive ankle dorsiflexion, data was compared between 2011 and 2012. The Gross motor classification system (GMFCS) levels of included children was as follows: I (n = 879), II (n = 357), III (n = 230), IV (n = 374) and V (n = 355). RESULTS: AFOs were used by 1127 (51%) of the children. In 215 children (10%), the indication was to improve function, in 251 (11%) to maintain or increase range of motion, and 661 of the children (30%) used AFOs for both purposes. The use of AFOs was highest in 5-year-olds (67%) and was more frequent at lower levels of motor function with 70% at GMFCS IV-V. Physiotherapists reported achievement of functional goals in 73% of the children using AFOs and maintenance or improvement in range of ankle dorsiflexion in 70%. CONCLUSIONS: AFOs were used by half of the children with CP in Sweden. The treatment goals were attained in almost three quarters of the children, equally at all GMFCS levels. AFOs to improve range of motion were more effective in children with a more significant decrease in dorsiflexion at baseline. PMID- 25274144 TI - A clinical study of thoracoscopy-assisted mitral valve replacement concomitant with tricuspid valvuloplasty, with domestically manufactured pipeline products for cardiopulmonary bypass. AB - OBJECTIVE: To discuss the feasibility and experience of treating valvular heart diseases with thoracoscopy-assisted mitral valve replacement concomitant with tricuspid valvuloplasty, with domestically manufactured pipeline products for cardiopulmonary bypass. METHODS: A total of 135 patients with valvular heart disease were admitted to our hospital between January 2011 and January 2013. They received thoracoscopy-assisted mitral valve replacement concomitant with tricuspid valvuloplasty, with domestically manufactured pipeline products. A cardiopulmonary bypass with domestically-manufactured pipeline products was established during the surgery. The procedure was accomplished with the assistance of thoracoscopy through a small incision in the right chest wall. RESULTS: All 135 patients underwent a successful surgery, and were followed up for the duration of half a year to two years. None of them displayed any evidence of complications. Our procedure had the advantage of fewer complications and a significantly shortened time period for the patient care and hospitalization. As opposed to imported pipeline products for cardiopulmonary bypass, our procedure had the advantage of similar clinical results at a lower cost. CONCLUSIONS: Thoracoscopy-assisted mitral valve replacement concomitant with tricuspid valvuloplasty was proved to be a safe and effective method for cardiopulmonary bypass, with the use of domestically manufactured pipeline products. PMID- 25274145 TI - Experimental hut and bioassay evaluation of the residual activity of a polymer enhanced suspension concentrate (SC-PE) formulation of deltamethrin for IRS use in the control of Anopheles arabiensis. AB - BACKGROUND: The Stockholm Convention on Persistent Organic Pollutants (POPs) came into effect in 2004; the use of DDT for malaria control has been allowed to continue under exemption since then due to a perceived absence of equally effective and efficient alternatives. Alternative classes of insecticide for indoor residual spraying (IRS) have a relatively short residual duration of action (2-6 months according to WHO). In areas of year-round transmission multiple spray cycles are required, resulting in significantly higher costs for malaria control programs and user fatigue. This study evaluated performance of a new formulation of deltamethrin (pyrethroid) with polymer (SC-PE) to prolong the effective residual action to >6 months. METHODS: Deltamethrin SC-PE was evaluated alongside an existing water dispersible granule (WG) formulation and DDT water dispersible powder (WP) in laboratory and hut bioassays on mud, concrete, palm thatch and plywood substrates. An experimental hut trial was conducted in Lower Moshi Rice Irrigation Zone, Tanzania from 2008-2009 against wild, free-flying, pyrethroid susceptible An. arabiensis. Performance was measured in terms of insecticide-induced mortality, and blood-feeding inhibition. Bioassays were carried out monthly on sprayed substrates to assess residual activity. RESULTS: Bioassays in simple huts (designed for bioassay testing only) and experimental huts (designed for testing free flying mosquitoes) showed evidence that SC-PE improved longevity on mud and concrete over the WG formulation. Both deltamethrin SC-PE and WG outperformed DDT in bioassays on all substrates tested in the laboratory and simple huts. In experimental hut trials SC-PE, WG and DDT produced high levels of An. arabiensis mortality and the treatments were equivalent over nine months' duration. Marked seasonal changes in mortality were recorded for DDT and deltamethrin treatments, and may have been partly influenced by outdoor temperature affecting indoor resting duration of mosquitoes on sprayed surfaces, although no clear correlation was demonstrated. CONCLUSIONS: There is a limited range of alternative insecticides for IRS, and deltamethrin SC-PE is likely to have an important role as part of a rotation strategy with one or more different insecticide classes rotated annually, particularly in areas that currently have low levels of pyrethroid resistance or low LLIN coverage and year-round malaria transmission. PMID- 25274146 TI - Trauma and posttraumatic stress disorder in transcultural patients with chronic pain. AB - BACKGROUND: Traumatic events are commonly experienced in the general population and can lead to both psychological and physical consequences. While some may process the experienced event without developing trauma related symptoms in the long term, others develop persistent symptomatology in the form of chronic pain depending on the type of trauma as well as various other risk factors. OBJECTIVE: The aim of this study was to examine the relationship of the number of lifetime traumas and chronic pain in a sample of transcultural patients to further develop existing research highlighting an association between the number of traumas and chronic pain that may be independent of a categorical diagnosis of PTSD. METHODS: Using a case-control design, this study compared 29 chronic pain patients (Gerbershagen II/III) born in former Yugoslavia (21 female; age: 52.5 years, SD 7.3) to 21 patients of a general psychiatric sample who were matched by age- (+/ 5 years), migratory-background, and gender. The number of traumas and PTSD symptomatology were assessed using the Harvard Trauma Questionnaire (HTQ). Somatisation, social dysfunction and anxiety were assessed by the General Health Questionnaire 28 (GHQ-28). The Beck Depression Inventory (BDI) was used to determine the presence of depression. RESULTS: 96.9 % of the chronic pain patients reported at least one traumatic event compared to 76.2 % within the control group (p = 0.029). Likewise, the mean number of reported traumas was significantly higher among the chronic pain group at 12 vs. 7 respectively (p = 0.024). Regarding anxiety, depression and social dysfunction, no significant difference between the two groups was found. CONCLUSIONS: Chronic pain patients with migratory background report an unusually high number of traumatic events. Clinicians should carefully screen for trauma history in this group of patients. The present study supports prior research suggesting a cumulative effect of trauma on chronic pain. PMID- 25274148 TI - Animal models for translational proteomics. PMID- 25274147 TI - Mental health system historians: adults with schizophrenia describe changes in community mental health care over time. AB - This qualitative study examined changes in community mental health care as described by adults diagnosed with schizophrenia with long-term involvement in the mental health system to situate their experiences within the context of mental health reform movements in the United States. A sample of 14 adults with schizophrenia who had been consumers of mental health services from 12 to 40 years completed interviews about their hospital and outpatient experiences over time and factors that contributed most to their mental health. Overall, adults noted gradual changes in mental health care over time that included higher quality of care, more humane treatment, increased partnership with providers, shorter hospital stays, and better conditions in inpatient settings. Regardless of the mental health reform era in which they were hospitalized, participants described negative hospitalization experiences resulting in considerable personal distress, powerlessness, and trauma. Adults with less than 27 years involvement in the system reported relationships with friends and family as most important to their mental health, while adults with more than 27 years involvement reported mental health services and relationships with professionals as the most important factors in their mental health. The sample did not differ in self-reported use of services during their initial and most recent hospitalization experiences, but differences were found in participants' reported use of outpatient services over time. Findings underscore the importance of the lived experience of adults with schizophrenia in grounding current discourse on mental health care reform. PMID- 25274154 TI - Flexible, thorn-like ZnO-multiwalled carbon nanotube hybrid paper for efficient ultraviolet sensing and photocatalyst applications. AB - We report fabrication of a flexible, thorn-like ZnO-multiwalled carbon nanotube (MWCNT) hybrid paper with high aspect ratio for efficient ultraviolet (UV) sensing and photocatalyst applications. The thorn-like ZnO-MWCNT hybrid paper was synthesized via atomic layer deposition (ALD) of a uniform ZnO thin film on the outside surface of the MWCNT followed by hydrothermal growth of ZnO branches. The hybrid paper achieved very high surface to volume ratio, which is favorable for photodetector and photocatalyst applications. A photodetector fabricated from the hybrid paper demonstrates a high sensitivity to UV light with a maximum photoresponsivity of 45.1 A W(-1) at 375 nm, corresponding to an external quantum efficiency as high as 14927%. The rise time and fall time of the UV photodetector are 29 ms and 33 ms, respectively, indicating fast transient response characteristics for the device. The high photoresponsivity and fast transient response are attributed to efficient carrier transport and collection efficiency of the hybrid paper. Besides, the thorn-like ZnO-MWCNT hybrid paper demonstrates excellent photocatalytic performance under UV irradiation, enabling photo degradation of organic dyes such as Rhodamine B (RhB) within 90 minutes, with good recyclability. PMID- 25274153 TI - Evaluation of circulating YKL-40 levels in idiopathic interstitial pneumonias. AB - INTRODUCTION: YKL-40 is a novel biomarker in diseases with inflammation, fibrosis and tissue remodelling. Previously, circulating YKL-40 was shown to be elevated in patients with idiopathic pulmonary fibrosis (IPF) and was associated with survival. OBJECTIVE: To compare YKL-40 serum levels between IPF and other interstitial pneumonias such as non-specific interstitial pneumonia (NSIP), smoking-related interstitial lung disease (SR-ILD) and cryptogenic organising pneumonia (COP). MATERIALS AND METHODS: Serum YKL-40 levels were measured in 124 healthy controls and 315 patients. Serial measurements were available in 36 patients with IPF and 6 patients with COP. RESULTS: Serum YKL-40 levels were elevated in all patient groups compared to controls (p < 0.0001), and highest levels were found in the most fibrotic diseases, which showed worst prognosis. CONCLUSION: YKL-40 is highly elevated in fibrotic interstitial pneumonias and may reflect the degree of activity of the fibrogenic process. Remarkably, levels remain high in IPF, but can decrease in other interstitial pneumonias, which appears to be related to a better prognosis. PMID- 25274152 TI - Day occupation is associated with psychopathology for adolescents and young adults with Down syndrome. AB - BACKGROUND: Young adults with Down syndrome experience increased rates of emotional and behavioural problems compared with the general population. Most adolescents with Down syndrome living in Western Australia participate in sheltered employment as their main day occupation. Relationship between day occupation and changes in behaviour has not been examined. Therefore, the aim of this research was to explore any relationship between post school day occupations and changes in the young person's behaviour. METHODS: The Down syndrome Needs Opinion Wishes database was used for case ascertainment of young adults aged 15 to 32 years with Down syndrome. Families of 118 young people in this population based database completed questionnaires in 2004, 2009 and 2011. The questionnaires addressed both young person characteristics such as age, gender, presence of impairments, behaviour, functioning in activities of daily living, and family characteristics such as income and family functioning. Post-school day occupations in which the young people were participating included open and sheltered employment, training and day recreation programs. Change in behaviour of young adults who remained in the same post-school day occupation from 2009 to 2011 (n = 103) were examined in a linear regression model adjusting for confounding variables including age, gender, prior functioning and behaviour in 2004 and family income. RESULTS: In comparison to those young adults attending open employment from 2009 to 2011, those attending day recreation programs were reported to experience worsening in behaviour both in the unadjusted (effect size -0.14, 95% CI -0.24, -0.05) and adjusted models (effect size -0.15, 95% CI -0.29, -0.01). CONCLUSIONS: We found that the behaviour of those participating in open employment improved compared to those attending other day occupations. Further examination of the direction of this association is required. PMID- 25274155 TI - Pharmacokinetics of plasma-derived vs. recombinant FVIII concentrates: a comparative study. AB - Only very few pharmacokinetic (PK) studies comparing plasma derived FVIII (pd FVIII) against recombinant FVIII (rFVIII) concentrates are available. The studies have been generally conducted to demonstrate the bioequivalence of a new product with an old one. The switch from a plasma-derived FVIII (pd-FVIII) to a rFVIII concentrate is a good moment to enrol the patients in a comparative PK study. To achieve information on the PK characteristics of two different classes of FVIII concentrates, according to two different designs: a 10 FVIII concentration/time point design and a reduced 4-point design. A single dose PK comparing pd- and rFVIII concentrates has been performed in four Haemophilia Centres of Italy. Seventeen haemophilia A patients underwent two subsequent single dose PK studies at the moment of switching. Two-compartment- and Non-compartment-analysis did not show significant differences between the outcomes of PK of pd-FVIII and rFVIII, due to inter-patient variability. In vivo recovery (IVR) of rFVIII was slightly higher than that of pd-FVIII and rFVIII/pd-FVIII AUC ratio was 1.37 in 11/17 patients. The difference is only due to the initial distribution phase because after the first 10 h from the end of the infusion, the two decay curves are overlapping. The elimination half-life of the concentrates was very similar even though a complete bioequivalence was not demonstrated because of a higher AUC of rFVIII concentrates, limited to the distribution phase. The higher Cmax and IVR of rFVIII may be due to the presence of heterodimers activated forms of the recombinant molecules. PMID- 25274156 TI - Upper gastrointestinal bleeding caused by severe esophagitis: a unique clinical syndrome. AB - BACKGROUND: We have recognized a unique clinical syndrome in patients with upper gastrointestinal bleeding who are found to have severe esophagitis. AIM: We aimed to more clearly describe the clinical entity of upper gastrointestinal bleeding in patients with severe esophagitis. METHODS: We conducted a retrospective matched case-control study designed to investigate clinical features in patients with carefully defined upper gastrointestinal bleeding and severe esophagitis. Patient data were captured prospectively via a Gastrointestinal Bleeding Healthcare Registry, which collects data on all patients admitted with gastrointestinal bleeding. Patients with endoscopically documented esophagitis (cases) were matched with randomly selected controls that had upper gastrointestinal bleeding caused by other lesions. RESULTS: Epidemiologic features in patients with esophagitis were similar to those with other causes of upper gastrointestinal bleeding. However, hematemesis was more common in patients with esophagitis 86% (102/119) than in controls 55% (196/357) (p < 0.0001), while melena was less common in patients with esophagitis 38% (45/119) than in controls 68% (244/357) (p < 0.0001). Additionally, the more severe the esophagitis, the more frequent was melena. Patients with esophagitis had less abnormal vital signs, lesser decreases in hematocrit, and lesser increases in BUN. Both pre- and postRockall scores were lower in patients with esophagitis compared with controls (p = 0.01, and p < 0.0001, respectively). Length of hospital stay (p = 0.002), rebleeding rate at 42 days (p = 0.0007), and mortality were less in patients with esophagitis than controls. Finally, analysis of patients with esophagitis and cirrhosis suggested that this group of patients had more severe bleeding than those without cirrhosis. CONCLUSIONS: We have described a unique clinical syndrome in patients with upper gastrointestinal bleeding who have erosive esophagitis. This syndrome is manifest by typical clinical features and is associated with favorable outcomes. PMID- 25274157 TI - Age, period, and cohort effects on gastric cancer mortality. AB - BACKGROUND: The incidence of gastric cancer varies both within and among populations and can change rapidly without a corresponding decline in Helicobacter pylori prevalence. Here, we describe the changes in gastric cancer mortality in Japan in relation to age-period-cohort effects as well as the decline in H. pylori prevalence. METHODS: We used data from Japanese for men and women aged 30-94 for birth years 1875-1970 (calendar time 1950-2000) to observe the age, period and cohort effects on gastric cancer mortality rates. Additionally, we used Poisson regression to simultaneously adjust for concurrent age, period and cohort effects as well as for declining H. pylori prevalence in the Japanese population. RESULTS: There was an approximate 60 % decline in gastric cancer mortality between 1965 and 1995. Detailed age, period and cohort analyses and Poisson regression analysis showed these factors interact in complex ways, analyses focused on one or two of these effects, such as birth cohort without considering concurrent age and period would obscure important interactions that affected different age groups at different times to produce this composite effect. CONCLUSION: The underlying complexity in population disease dynamics requires population-specific descriptions of trends using multiple methods to provide an in-depth analysis while simultaneously allowing for necessary statistical adjustments as well as identification of interactions. More thorough descriptions of the population-specific general trends in relation to changes in the population structure (age-period-cohort) enable better prevention and health care policy planning, and further, the descriptions enable hypothesis generation regarding causes of population-specific disease patterns. PMID- 25274158 TI - Treatment with immunosuppressive therapy may improve depressive symptoms in patients with inflammatory bowel disease. AB - INTRODUCTION: Recent research suggests a relationship of inflammatory bowel disease (IBD) and depression. Our objective was to evaluate for improvement of depressive symptoms with treatment of IBD using immunosuppressive medications. METHODS: A retrospective study of consecutive patients with IBD started on immunosuppressive agents [anti-tumor necrosis factor (anti-TNF) or immunomodulator therapy] was conducted. Patients were evaluated if disease activity indices using Harvey Bradshaw Index for Crohn's disease (CD) and Simple Clinical Colitis Disease Activity Index for ulcerative colitis (UC) and depressive indices using Patient Health Questionnaire-9 (PHQ-9) scores were obtained before and at least 30 days after initiation of therapy. RESULTS: Sixteen patients with UC and 53 patients with CD (all with active disease symptoms) were evaluated over a 60 day median follow-up evaluation (range 30, 140 days). Twenty-two patients started on immunomodulator therapy, and 47 patients started on anti-TNF therapy. Crohn's disease patients had significantly decreased PHQ-9 scores at follow-up [median 9 (range 3, 14) to 4 (1, 8)], with significant decreases only in those started on anti-TNF therapy. Changes in PHQ-9 and CRP were correlated (rho = 0.38, p < 0.05). In patients with UC, PHQ-9 scores [5 (3, 9) to 2 (0, 5)] were significantly decreased. Percentage at risk of moderate to severe depression (PHQ-9 scores >=10) was lower after treatment [Crohn's disease 51-18 % (p < 0.05), ulcerative colitis 18-0 %]. CONCLUSION: Depressive scores decreased significantly in patients with IBD treated with immunosuppressive therapy and the number at risk for moderate to severe depression improved significantly. PMID- 25274160 TI - Central pharmacokinetics of levodopa: Lessons from imaging studies. AB - Functional imaging may be particularly helpful for the assessment of levodopa (l dopa) response and long-term complications of therapy in Parkinson's disease. Radiotracer imaging allows the quantitative determination of regional changes in blood flow and glucose metabolism, as well as alterations in brain connectivity and network activation and changes in dopamine receptors, non-dopaminergic neurotransmitter systems, and to a lesser extent, signaling pathways downstream to dopamine receptors. The focus of the present article, however, is the application of positron emission tomography (PET) to study the central pharmacokinetics of l-dopa. Radioligands with limited affinity for the dopamine D2 receptor are sensitive to changes in the levels of synaptic dopamine and can accordingly provide helpful insights into the magnitude and time course of dopamine release after l-dopa. Prolonged fluorodopa PET scans can be used to estimate the rate of dopamine turnover. Studies performed with these techniques have demonstrated increased dopamine turnover and increased but shorter duration release of dopamine after l-dopa as Parkinson's disease (PD) progresses, increased release of dopamine in patients with l-dopa-induced dyskinesia, and that aberrant patterns of dopamine release may actually predict the future development of motor fluctuations. Taken together, the studies provide in vivo validation for the hypothesis that pulsatile stimulation of dopamine receptors plays a critical role in the emergence of long-term motor complications of therapy. Similar approaches can be used to study the non-motor complications of PD and its treatment. Society. PMID- 25274161 TI - Feasibility and analysis of bipolar concentric recording of electrohysterogram with flexible active electrode. AB - The conduction velocity and propagation patterns of the electrohysterogram (EHG) provide fundamental information on the electrophysiological condition of the uterus. However, the accuracy of these measurements can be impaired by both the poor spatial selectivity and sensitivity to the relative direction of the contraction propagation associated with conventional disc electrodes. Concentric ring electrodes could overcome these limitations. The aim of this study was to examine the feasibility of picking up surface EHG signals using a new flexible tripolar concentric ring electrode (TCRE), and to compare these signals with conventional bipolar recordings. Simultaneous recording of conventional bipolar signals and bipolar concentric EHG (BC-EHG) were carried out on 22 pregnant women. Signal bursts were characterized and compared. No significant differences were found between the channels in either duration or dominant frequency in the Fast Wave High frequency range. Nonetheless, the high pass filtering effect of the BC-EHG recordings gave lower frequency content between 0.1 and 0.2 Hz. Although the BC-EHG signal amplitude was about 5-7 times smaller than that of bipolar recordings, a similar signal-to-noise ratio was obtained. These results suggest that the flexible TCRE is able to pick up uterine electrical activity and could provide additional information for deducing the uterine electrophysiological condition. PMID- 25274159 TI - Sex-determination gene SRY potentially associates with poor prognosis but not sex bias in hepatocellular carcinoma. AB - BACKGROUND: Gender disparity is well known in hepatocellular carcinoma (HCC). SRY is a critical sex-determination gene involved in embryonic development. AIM: The potential relevance of SRY to HCC progression was evaluated. METHODS: SRY expression in HCC cell lines and tissues was evaluated. Invasion and wound healing assays were used to evaluate the role of SRY in HCC cell migration. The prognostic value of SRY for HCC patient survival was evaluated. RESULTS: SRY was highly expressed in HCC cell lines and tumor tissues. Downregulation of SRY expression decreased migration and invasion potential of HCC cells. High SRY levels correlated with poor HCC patient survival. Additionally, neither spatial position nor expression intensity of SRY was correlated with HCC gender disparity. CONCLUSIONS: High levels of SRY expression correlated with cancer progression and poor HCC patient survival. However, high SRY levels are not significantly correlated with HCC sex bias. PMID- 25274162 TI - Development of an integrated surface stimulation device for systematic evaluation of wound electrotherapy. AB - Ideally, all chronic wounds would be prevented as they can become life threatening complications. The concept that a wound produces a 'current of injury' due to the discontinuity in the electrical field of intact skin provides the basis for the concept that electrical stimulation (ES) may provide an effective treatment for chronic wounds. The optimal stimulation waveform parameters are unknown, limiting the reliability of achieving a successful clinical therapeutic outcome. In order to gain a more thorough understanding of ES for chronic wound therapy, systematic evaluation using a valid in vivo model is required. The focus of the current paper is development of the flexible modular surface stimulation (MSS) device by our group. This device can be programed to deliver a variety of clinically relevant stimulation paradigms and is essential to facilitate systematic in vivo studies. The MSS version 2.0 for small animal use provides all components of a single-channel, programmable current-controlled ES system within a lightweight, flexible, independently powered portable device. Benchtop testing and validation indicates that custom electronics and control algorithms support the generation of high-voltage, low duty-cycle current pulses in a power-efficient manner, extending battery life and allowing ES therapy to be delivered for up to 7 days without needing to replace or disturb the wound dressing. PMID- 25274164 TI - Hydrogen bonded multilayer films based on poly(2-oxazoline)s and tannic acid. AB - In recent years, the layer-by-layer (LbL) assembly based on hydrogen bonding interactions is gaining popularity for the preparation of thin film coatings, especially for biomedical purposes, based on the use of neutral, non-toxic building blocks. The use of tannic acid (TA) as hydrogen bonding donor is especially interesting as it results in LbL films that are stable under physiological conditions. In this work, investigations on the LbL thin film preparation of TA with poly(2-oxazoline)s with varying hydrophilicity, namely poly(2-methyl-2-oxazoline) (PMeOx), poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2 n-propyl-2-oxazoline) (PnPropOx), are reported. The LbL assembly process is investigated by quartz crystal microbalance and UV-vis spectroscopy revealing linear growth of the film thickness. Furthermore, isothermal titration calorimetry demonstrates the LbL assembly of TA, and PMeOx is found to be mostly enthalpy driven while the LbL assembly of TA with PEtOx and PnPropOx is mostly entropy driven. Finally, scanning electron microscopy and ellipsometry demonstrate the formation of smooth thin films for LbL assembly of TA with all three polymers. Such poly(2-oxazoline) coatings have high potential for use as anti-biofouling coatings. PMID- 25274163 TI - Role of three-dimensional matrix stiffness in regulating the chemoresistance of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) was the most common primary liver cancer, and its resistance to anti-tumor drugs often caused the death of patients suffering with HCC. Matrix stiffness was reported to be closely related to tumor chemoresistance; however, the relationship between HCC drug resistance and three dimensional (3D) matrix stiffness is still unclear at present. In this study, alginate gel (ALG) beads with controllable matrix stiffness were used to mimic tumor tissue rigidity, and the role of 3D matrix stiffness in regulating the chemoresistance of HCC cells was investigated by using these ALG beads. It was found that HCC cells in ALG beads with 105 kPa stiffness had highest resistance to paclitaxel, 5-FU, and cisplatin. Although the mechanism was still uncovered, ABC transporters and endoplasmic reticulum stress-related molecules were highly expressed in ALG bead-encapsulated HCC cells compared with two-dimensional cultured cells, which suggested a very complex mechanism underlying HCC drug resistance in 3D culture conditions. In addition, to mimic the specific stiffness of HCC tumor tissue, or other tumor tissues in vivo, response surface methodology (RSM) was used to build up a prediction mathematical model so that ALG beads with desired matrix stiffness could be prepared by simply changing three factors: molecular weight, G content, and alginate concentration. PMID- 25274165 TI - Algorithm for analysis of administrative pediatric cancer hospitalization data according to indication for admission. AB - BACKGROUND: Childhood cancer relies heavily on inpatient hospital services to deliver tumor-directed therapy and manage toxicities. Hospitalizations have increased over the past decade, though not uniformly across childhood cancer diagnoses. Analysis of the reasons for admission of children with cancer could enhance comparison of resource use between cancers, and allow clinical practice data to be interpreted more readily. Such comparisons using nationwide data sources are difficult because of numerous subdivisions in the International Classification of Diseases Clinical Modification (ICD-9) system and inherent complexities of treatments. This study aimed to develop a systematic approach to classifying cancer-related admissions in administrative data into categories that reflected clinical practice and predicted resource use. METHODS: We developed a multistep algorithm to stratify indications for childhood cancer admissions in the Kids Inpatient Databases from 2003, 2006 and 2009 into clinically meaningful categories. This algorithm assumed that primary discharge diagnoses of cancer or cytopenia were insufficient, and relied on procedure codes and secondary diagnoses in these scenarios. Clinical Classification Software developed by the Healthcare Cost and Utilization Project was first used to sort thousands of ICD-9 codes into 5 mutually exclusive diagnosis categories and 3 mutually exclusive procedure categories, and validation was performed by comparison with the ICD-9 codes in the final admission indication. Mean cost, length of stay, and costs per day were compared between categories of indication for admission. RESULTS: A cohort of 202,995 cancer-related admissions was grouped into four categories of indication for admission: chemotherapy (N=77,791, 38%), to undergo a procedure (N=30,858, 15%), treatment for infection (N=30,380, 15%), or treatment for other toxicities (N=43,408, 21.4%). The positive predictive value for the algorithm was >95% for each category. Admissions for procedures had higher mean hospital costs, longer hospital stays, and higher costs per day compared with other admission reasons (p<0.001). CONCLUSIONS: This is the first description of a method for grouping indications for childhood cancer admission within an administrative dataset into clinically relevant categories. This algorithm provides a framework for more detailed analyses of pediatric hospitalization data by cancer type. PMID- 25274166 TI - Genotoxicity assessment of magnetic iron oxide nanoparticles with different particle sizes and surface coatings. AB - Magnetic iron oxide nanoparticles (IONPs) have been widely used for various biomedical applications such as magnetic resonance imaging and drug delivery. However, their potential toxic effects, including genotoxicity, need to be thoroughly understood. In the present study, the genotoxicity of IONPs with different particle sizes (10, 30 nm) and surface coatings (PEG, PEI) were assessed using three standard genotoxicity assays, the Salmonella typhimurium reverse mutation assay (Ames test), the in vitro mammalian chromosome aberration test, and the in vivo micronucleus assay. In the Ames test, SMG-10 (PEG coating, 10 nm) showed a positive mutagenic response in all the five test bacterial strains with and without metabolic activation, whereas SEI-10 (PEI coating, 10 nm) showed no mutagenesis in all tester strains regardless of metabolic activation. SMG-30 (PEG coating, 30 nm) was not mutagenic in the absence of metabolic activation, and became mutagenic in the presence of metabolic activation. In the chromosomal aberration test, no increase in the incidence of chromosomal aberrations was observed for all three IONPs. In the in vivo micronucleus test, there was no evidence of increased micronuclei frequencies for all three IONPs, indicating that they were not clastogenic in vivo. Taken together, our results demonstrated that IONPs with PEG coating exhibited mutagenic activity without chromosomal and clastogenic abnormalities, and smaller IONPs (SMG-10) had stronger mutagenic potential than larger ones (SMG-30); whereas, IONPs with SEI coating (SEI-10) were not genotoxic in all three standard genotoxicity assays. This suggests that the mutagenicity of IONPs depends on their particle size and surface coating. PMID- 25274167 TI - Challenges in and strategies for the surveillance of school health policies and practices: a commentary. PMID- 25274168 TI - Contribution of organized and nonorganized activity to children's motor skills and fitness. AB - BACKGROUND: To examine the associations between children's organized physical activity (OPA), nonorganized physical activity (NOPA), and health-related outcomes (fundamental movement skill [FMS] fitness). METHODS: Cross-sectional survey of children aged 10-16 years (N = 4273). Organized physical activity and NOPA were assessed by self-report, FMS by process-orientated criteria, and fitness by 20-m shuttle run test. RESULTS: Boys spent 97.5 minutes and girls 86.6 minutes in daily physical activity with the majority spent in OPA (boys, 56.3%; girls 60.5%). Organized physical activity increased with grade, whereas NOPA decreased. Organized physical activity and NOPA were associated with fitness, and OPA was consistently associated with FMS competency. Boys' fitness was associated with OPA and NOPA (adjusted odds ratio [AOR] 1.42, 95% confidence interval [CI]: 1.04, 1.94; AOR 1.26, 95% CI: 1.03, 1.54, respectively), FMS competency (side gallop leap, kick) with OPA and catch, and over-arm throw with both OPA and NOPA. Girls' fitness (AOR 2.62, 95% CI: 1.88, 3.66) and FMS competency were consistently associated with OPA. CONCLUSIONS: Both OPA and NOPA are important contributors to children's physical activity; however, for girls, OPA was more strongly associated with fitness and FMS competency. Our findings support the importance of providing children with opportunities to engage in daily OPA. School physical education programs are an ideal delivery vehicle for OPA and need to be central to education policy. PMID- 25274169 TI - Physical activity breaks and facilities in US secondary schools. AB - BACKGROUND: Research on physical activity breaks and facilities (indoor and outdoor) in secondary schools is relatively limited. METHODS: School administrators and students in nationally representative samples of 8th (middle school) and 10th/12th grade (high school) students were surveyed annually from 2008-2009 to 2011-2012. School administrators reported information about physical activity breaks and facilities. Students self-reported height, weight, and physical activity. RESULTS: The prevalence of physical activity breaks and indoor and outdoor facilities (dichotomized by median split) differed significantly by region of the country, school size, student race/ethnicity, and school socioeconomic status (SES). Breaks were associated with lower odds of overweight (adjusted odds ratio [AOR] = 0.91, 95% confidence interval [CI]: 0.83-1.00) and obesity (AOR = 0.86, 95% CI: 0.75-0.99) among middle school students. Among low SES middle school students and schools, higher indoor facilities were associated with lower rates of overweight and obesity. Among high school students, higher indoor and outdoor facilities were associated with 19-42% higher odds of moderate to-vigorous physical activity. CONCLUSIONS: Physical activity breaks and school facilities may help to address high rates of overweight/obesity and low physical activity levels among secondary students, especially lower-SES students. Students in all schools should have equal access to these resources. PMID- 25274170 TI - Effects of early adolescent alcohol use on mid-adolescent school performance and connection: a longitudinal study of students in Victoria, Australia and Washington State, United States. AB - BACKGROUND: This article examines the effect of early adolescent alcohol use on mid-adolescent school suspension, truancy, commitment, and academic failure in Washington State, United States, and Victoria, Australia. Also of interest was whether associations remain after statistically controlling for other factors known to predict school outcomes. METHODS: State-representative student samples were surveyed in 2002 (grade 7; N = 1858) and followed up annually to 2004 (grade 9) in both sites. Students completed a modified version of the Communities That Care survey to report alcohol use, school outcomes, and risk and protective factors. Response rates were above 74% and retention rates exceeded 98% in both places. RESULTS: Controlling for grade 7 risk factors, grade 7 current alcohol use, and heavy episodic drinking were associated with grade 8 school suspension. Grade 7 current and frequent alcohol use and heavy episodic drinking were linked to grade 9 truancy. In fully adjusted analyses, associations between early alcohol use and academic failure and low school commitment did not remain. CONCLUSIONS: Although alcohol use is one factor influencing school performance and connection, there are other risk factors that need to be targeted to improve school outcomes. PMID- 25274171 TI - Physical activity in preschool children: comparison between Montessori and traditional preschools. AB - BACKGROUND: Little is known about the influence of Montessori methods on children's physical activity (PA). This cross-sectional study compared PA of children attending Montessori and traditional preschools. METHODS: We enrolled 301 children in 9 Montessori and 8 traditional preschools in Columbia, South Carolina. PA was measured by accelerometry on weekdays during preschool (In School), non-school (Non-School), and all day (All Day). Minutes/hour of light, moderate-to-vigorous (MVPA), and total PA (light + MVPA) were calculated. RESULTS: Children attending Montessori preschools accumulated more In-School light (7.7 vs. 6.5 minute/hour), MVPA (7.7 versus 6.5 minute/hour), and total PA (15.4 versus 13.0 minute/hour) than children attending traditional preschools, after adjusting for sex, race/ethnicity, body mass index, parent education and neighborhood poverty index. For Non-School (8.5 versus 6.2 minute/hour) and All Day (8.5 versus 7.6 minute/hour), children in Montessori preschools accumulated more MVPA than children in traditional preschools. In-School PA was higher for children in private Montessori than public Montessori preschools (8.1 versus 7.0 minute/hour; 8.1 versus 6.7 minute/hour; 16.1 versus 13.6 minute/hour, for light, MVPA, and total PA, respectively). CONCLUSIONS: Children attending Montessori preschools were more active than children attending traditional preschools. Adopting the Montessori system may be an important strategy for promoting PA in children. PMID- 25274172 TI - Promoting teacher adoption of physical activity breaks in the classroom: findings of the Central Texas CATCH Middle School Project. AB - BACKGROUND: Research suggests that physical activity breaks (ABs) during class increase students' physical activity levels and provide an academic benefit. This study evaluates a 3-year intervention aimed at encouraging teacher AB use. METHODS: Thirty central Texas middle schools were assigned to 1 of 3 conditions: training-only (Basic), training plus facilitator support (Basic Plus), and training/facilitator support and a social marketing campaign (Basic Plus SM). Teachers completed surveys at end of years 2 (N = 1039) and 3 (N = 831) to assess exposure to program, self-efficacy, and frequency of AB use. RESULTS: At end of year 3, teachers in facilitator-supported conditions reported increased exposure, self-efficacy, and use compared to Basic condition. Only 43.2% of teachers in the Basic condition reported receiving training in ABs compared to 84.2% and 90.6% in the Basic Plus and Basic Plus SM conditions, respectively. Additionally, a greater percentage of teachers in the facilitator-support conditions reported conducting ABs weekly (Basic = 23.3%, Basic Plus = 34.4%, Basic Plus SM = 38.7%, at year 3; p < .001). CONCLUSIONS: Despite perceived barriers, including fear that ABs will detract from instructional time, the intervention was successful in having a core group of teachers implement them weekly. More research is needed to increase the percentage of teachers implementing ABs regularly. PMID- 25274173 TI - Association of being bullied in school with suicide ideation and planning among rural middle school adolescents. AB - BACKGROUND: This study examined the association of ever being bullied in school with suicide ideation (ever thinking about killing oneself) and ever seriously making a plan to kill oneself (suicide planning) among rural middle school adolescents. METHODS: Using the US Centers for Disease Control and Prevention's Middle School Youth Risk Behavior Survey instrument, 2 cross-sectional surveys were conducted among middle school adolescents (N = 1082) in a rural Appalachian county in Ohio in 2009 and 2012. Multivariable logistic regression models assessed the relationship of ever being bullied in school with suicide ideation and planning. RESULTS: Overall, a total of 468 participants (43.1%) reported ever being bullied in school, and 22.3% and 13.2% of the adolescents surveyed reported suicide ideation and planning, respectively. In the multivariable analyses, ever being bullied in school was significantly associated with both suicide ideation (odds ratio [OR] = 2.4; 95% confidence interval [CI]: 1.7-3.5) and planning (OR = 2.5; 95% CI: 1.6-3.8). CONCLUSIONS: The results show a strong association between being bullied in school and suicide ideation and planning among rural middle school adolescents. Prevention of bullying in school as early as in middle school should be a strategy for reducing suicide ideation and planning among adolescents. PMID- 25274175 TI - Alcohol, tobacco, and other drug misuse prevention and cessation programming for alternative high school youth: a review. AB - BACKGROUND: Relative to youth in regular high schools, alternative high school (AHS) youth are at high risk for alcohol, tobacco, and other drug (ATOD) misuse. Prevention and cessation efforts are needed for this population. METHODS: A systematic, exhaustive literature search was completed to identify ATOD misuse prevention and cessation research studies with AHS youth. RESULTS: For the AHS population, 23 ATOD misuse prevention or cessation program evaluations were located. This review indicated that successful efforts have focused on instruction in motivation enhancement, life coping skills, and decision making. CONCLUSIONS: Alcohol, tobacco, and other drug misuse prevention and cessation programming for AHSs is effective, delivered in the classroom or as a school based clinic. There is little evidence, though, that this programming is effective when delivered through other modalities such as via computer or bridging beyond the school setting. More research and application of evidence based programming are recommended for youth in AHS settings. PMID- 25274176 TI - Crossover between Fermi liquid and non-Fermi liquid behavior in the non centrosymmetric compound Yb2Ni12P7. AB - A crossover from a non-Fermi liquid to a Fermi liquid phase in Yb2Ni12P7 is observed by analyzing electrical resistivity rho(T), magnetic susceptibility chi(T), specific heat C(T), and thermoelectric power S(T) measurements. The electronic contribution to specific heat, Ce(T), behaves as Ce(T)/T~-ln(T) for 5 K4 K. A crossover between Fermi-liquid and non-Fermi liquid behavior suggests that Yb2Ni12P7 is in close proximity to a quantum critical point, in agreement with results from recent measurements of this compound under applied pressure. PMID- 25274174 TI - Protective effects of middle school comprehensive sex education with family involvement. AB - BACKGROUND: School-based comprehensive sex education programs can reduce early adolescents' risky sexual behavior. The purpose of this study was to assess the effectiveness of a 3-year comprehensive sex education program in delaying vaginal sex for middle school students and whether the family component of the intervention contributes to its effectiveness. METHODS: This longitudinal evaluation followed a cohort of 6th graders (N = 2453) through the end of 8th grade. The design used random assignment of 24 schools into treatment and comparison conditions. The analysis included multiple-group logistic regression to assess differences in delay of sex between intervention and comparison groups. RESULTS: In schools where the program was taught, 16% fewer boys and 15% fewer girls had had sex by the end of 8th grade compared to boys and girls at comparison schools. Completing family activities during the first year of the program predicted delayed sexual debut for boys. CONCLUSIONS: Theory-based, developmentally appropriate, comprehensive sex education programs that include parent involvement can be effective in delaying vaginal sex for middle school students. Parent involvement is particularly important for boys, as family activities may encourage parents to talk with their sons earlier and more frequently. PMID- 25274177 TI - High-efficiency inverted polymer solar cells controlled by the thickness of polyethylenimine ethoxylated (PEIE) interfacial layers. AB - In this work, we investigate the effect of the thickness of the polyethylenimine ethoxylated (PEIE) interface layer on the performance of two types of polymer solar cells based on inverted poly(3-hexylthiophene) (P3HT):phenyl C61-butryric acid methyl ester (PCBM) and thieno[3,4-b]thiophene/benzodithiophene (PTB7):[6,6] phenyl C71-butyric acid methyl ester (PC71BM). Maximum power conversion efficiencies of 4.18% and 7.40% were achieved at a 5.02 nm thick PEIE interface layer, for the above-mentioned solar cell types, respectively. The optimized PEIE layer provides a strong enough dipole for the best charge collection while maintaining charge tunneling ability. Optical transmittance and atomic force microscopy measurements indicate that all PEIE films have the same high transmittance and smooth surface morphology, ruling out the influence of the PEIE layer on these two parameters. The measured external quantum efficiencies for the devices with thick PEIE layers are quite similar to those of the optimized devices, indicating the poor charge collection ability of thick PEIE layers. The relatively low performance of devices with a PEIE layer of thickness less than 5 nm is the result of a weak dipole and partial coverage of the PEIE layer on ITO. PMID- 25274179 TI - "Listening to the silence quietly": investigating the value of cultural immersion and remote experiential learning in preparing midwifery students for clinical practice. AB - BACKGROUND: Cultural immersion programs are increasingly offered to medical and health science students in an effort to provide experiential learning opportunities that focus on 'the self' as well as 'the other'. Immersion programs encourage self-reflection on attitudes towards cultural differences, provide opportunities to build relationships and work with community members, and allow students to apply knowledge and skills learned in training programs in a supervised practice setting. The aim of this paper is to describe midwifery students' reflections on a remote Aboriginal clinical placement that has been offered at a Western Australian university since 2010. METHODS: Interviews were conducted over a period of 15 months with the first seven participants who completed the program. At the time of interview, four participants were in the final year of their undergraduate degree and three were practicing midwives. In addition, access was given to a detailed journal kept by one participant during the placement. Interviews also were conducted with midwifery staff at the university and practice setting, although the focus of this paper is upon the student experience. RESULTS: Student selection, preparation and learning experiences as well as implications of the placement for midwifery practice are described. The remote clinical placement was highly valued by all students and recommended to others as a profound learning experience. Highlights centred on connections made with community members and cultural knowledge learned experientially, while challenges included geographic and professional isolation and the complexities of health care delivery in remote settings, especially to pregnant and birthing Aboriginal women. All students recognised the transferability of the knowledge and skills acquired to urban settings, and some had already incorporated these learnings into clinical practice. CONCLUSIONS: Cultural immersion programs have the potential to provide students with rich learning experiences that cannot be acquired in classroom settings. In Aboriginal communities on the Ngaanyatjarra Lands students gained valuable insights into the impact of isolation on health service delivery, the extent and strength of cultural traditions in the region, and a heightened awareness of the difficulties encountered by pregnant and birthing Aboriginal women in remote locations. PMID- 25274178 TI - A systematic review and meta-analysis of the impact of native tissue repair for pelvic organ prolapse on sexual function. AB - INTRODUCTION AND HYPOTHESIS: The aim of this review was to investigate the impact of native tissue repair for pelvic organ prolapse (POP) on overall sexual function and dyspareunia. METHODS: Cochrane Incontinence Group Specialized Register of Controlled Trials, The Cochrane Central Register of Controlled Trials, MEDLINE, and Embase were searched for trials of prolapse surgery assessing sexual function and dyspareunia before and after surgery. We assessed observational studies and randomized controlled trials investigating the impact of surgical correction of POP on sexual function. Surgical interventions assessed were anterior and/or posterior repair with or without a vaginal hysterectomy. Studies including patients undergoing concurrent incontinence surgery or vaginal mesh insertion were excluded from the analysis. Dyspareunia was analyzed separately. RESULTS: We identified 674 potential citations, of which 14 articles assessed sexual function and/or dyspareunia before and after traditional prolapse surgery. The results suggest evidence for significant improvement in sexual function postsurgery, with a standardized mean difference of -0.55, 95 % confidence interval (CI) -0.68 to -0.43 in favor of surgical correction. Dyspareunia rates were also significantly improved postoperatively, with overall odds ratio of at least 2.5 times as likely as the chances of deterioration. DISCUSSION: Sexual function is significantly improved and dyspareunia significantly reduced following native tissue prolapse surgery. There were several methodological problems with the quality of the primary research, particularly related to study heterogeneity, use of different outcome measures, and absence of well-designed randomized controlled trials. PMID- 25274180 TI - Munchausen syndrome by adult proxy: a review of the literature. AB - BACKGROUND: Munchausen syndrome by proxy (MSBP), more formally known as factitious disorder imposed on another, is a form of abuse in which a caregiver deliberately produces or feigns illness in a person under his or her care so that the proxy will receive medical care that gratifies the caregiver. Although well documented in the pediatric literature, few cases of MSBP with adult proxies (MSB AP) have been reported. This study reviews existing literature on MSB-AP to provide a framework for clinicians to recognize this disorder. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, PubMed, Web of Knowledge, and PsychINFO, supplemented by bibliographic examination. RESULTS: We identified 13 cases of MSB AP. Perpetrators were caregivers, most (62%) were women, and many worked in healthcare. The age range of the victims was 21 to 82 years. Most were unaware of the abuse, although in 2 cases the victim may have colluded with the perpetrator. Disease fabrication most often resulted from poisoning. CONCLUSIONS: MSB-AP should be included in the differential diagnosis of patients presenting with a complex constellation of symptoms without a unifying etiology and an overly involved caregiver with suspected psychological gain. Early identification is necessary so that healthcare providers do not unknowingly perpetuate harm through treatments that satisfy the perpetrator's psychological needs at the proxy's expense. PMID- 25274181 TI - Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study. AB - BACKGROUND: Dose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC). METHODS: 49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited. RESULTS: Over 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred. CONCLUSIONS: Dose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended. TRIAL REGISTRATION: ISRCTN41540878. PMID- 25274182 TI - Combining one-sample confidence procedures for inference in the two-sample case. AB - We present a simple general method for combining two one-sample confidence procedures to obtain inferences in the two-sample problem. Some applications give striking connections to established methods; for example, combining exact binomial confidence procedures gives new confidence intervals on the difference or ratio of proportions that match inferences using Fisher's exact test, and numeric studies show the associated confidence intervals bound the type I error rate. Combining exact one-sample Poisson confidence procedures recreates standard confidence intervals on the ratio, and introduces new ones for the difference. Combining confidence procedures associated with one-sample t-tests recreates the Behrens-Fisher intervals. Other applications provide new confidence intervals with fewer assumptions than previously needed. For example, the method creates new confidence intervals on the difference in medians that do not require shift and continuity assumptions. We create a new confidence interval for the difference between two survival distributions at a fixed time point when there is independent censoring by combining the recently developed beta product confidence procedure for each single sample. The resulting interval is designed to guarantee coverage regardless of sample size or censoring distribution, and produces equivalent inferences to Fisher's exact test when there is no censoring. We show theoretically that when combining intervals asymptotically equivalent to normal intervals, our method has asymptotically accurate coverage. Importantly, all situations studied suggest guaranteed nominal coverage for our new interval whenever the original confidence procedures themselves guarantee coverage. PMID- 25274183 TI - Cold neutron diffraction contrast tomography of polycrystalline material. AB - Traditional neutron imaging is based on the attenuation of a neutron beam through scattering and absorption upon traversing a sample of interest. It offers insight into the sample's material distribution at high spatial resolution in a non destructive way. In this work, it is expanded to include the diffracted neutrons that were ignored so far and obtain a crystallographic distribution (grain mapping). Samples are rotated in a cold neutron beam of limited wavelength band. Projections of the crystallites formed by the neutrons they diffract are captured on a two dimensional imaging detector. Their positions on the detector reveal their orientation whereas the projections themselves are used to reconstruct the shape of the grains. Indebted to established synchrotron diffraction contrast tomography, this 'cold neutron diffraction contrast tomography' is performed on recrystallized aluminium for experimental comparison between both. Differences between set-up and method are discussed, followed by the application range in terms of sample properties (crystallite size and number, mosaicity and typical materials). Neutron diffraction contrast tomography allows to study large grains in bulky metallic structures. PMID- 25274184 TI - Epidemiology of lysosomal storage diseases in Sweden. AB - AIM: There are more than 50 inherited lysosomal storage diseases (LSDs), and this study examined the incidence of clinically diagnosed LSDs in Sweden. METHODS: The number of patients diagnosed during 1980-2009 was compiled from the registries of the two Swedish diagnostic laboratories that cover the whole country. RESULTS: We identified 433 patients during the 30-year period, with a total incidence of one in every 6100 births and identified fairly constant annual diagnoses during the last 20 years. Krabbe disease was the most common (one in 39 000) followed by Gaucher disease (one in 47 000), metachromatic leukodystrophy and Salla disease. Gaucher disease was more frequent in Sweden than other European countries, due to a founder effect of the mutation (p.L444P) in northern Sweden. Metachromatic leukodystrophy was one of the most common LSDs, in common with other countries. Salla disease, which is very rare elsewhere, was the fourth most common, stemming from a founder mutation in the Salla region of northern Finland brought to Sweden by immigration. CONCLUSION: The collective incidence of LSDs in Sweden was essentially equal to other European countries, but with a somewhat different disease pattern. Our findings have implications for diagnostic algorithms and treatment strategies. PMID- 25274185 TI - The psychosocial impact of hearing aids in children with otitis media with effusion. AB - BACKGROUND: In children, otitis media with effusion is treated using grommets or hearing aids. Parents considering treatment options express concerns regarding the psychosocial impact of hearing aids in terms of self-esteem and bullying. This study assessed the psychosocial impact of hearing aid use. METHODS: A cross sectional study was undertaken comparing hearing aid users to non hearing aid users with regard to their attitudes towards hearing aids. All subjects, who had been diagnosed with otitis media with effusion, were aged less than 16 years, were without disability and attended mainstream schools. A questionnaire was designed and utilised. RESULTS: The study comprised 47 children with hearing aids and 50 with grommets. Significant between-group differences (p < 0.05) were noted with regard to perceptions related to bullying, feelings of inadequacy and embarrassment. The overall negative perceptions of non hearing aid users were not reported by hearing aid users. CONCLUSION: Children with hearing aids do not suffer from bullying or low self-esteem to the extent perceived by parents. This information is useful for informed decisions regarding treatment of otitis media with effusion. PMID- 25274189 TI - Contents of technology and health care volume 2. PMID- 25274186 TI - Diffusion tensor imaging of spinocerebellar ataxia type 12. AB - BACKGROUND: Spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative diseases that are clinically and genetically heterogeneous. SCAs are characterized by a range of neurological symptoms. SCA12 is an autosomal dominant (AD) ataxia caused by a CAG repeat expansion mutation in a presumed promoter region of the gene PPP2R2B in a non-coding region on chromosome 5q32. This study sought to determine changes in different positions in a single Uyghur SCA12 pedigree by measuring the apparent diffusion coefficient (ADC) and fractional anisotropy (FA). MATERIAL AND METHODS: A single Uyghur pedigree was collected and was confirmed to possess SCA12 by genetic diagnosis, among which 13 cases were patients and 54 cases were "healthy" individuals. Five patients were presymptomatic and 15 individuals selected as a control group were examination in the same time. DTI was performed on a 1.5T scanner, with b=1000 s/mm2 and 15 directions. ADC and FA were measured by regions of interest positioned in the corticospinal tract at the level of the pons (pons), superior peduncle (SCP), middle cerebellar peduncle (MCP), cerebellar cortex (CeC), cerebral cortex (CC), and cerebellar vermis (CV) white matter. RESULTS: Compared with the controls, the ADC was significantly elevated in the CeC, SCP, CC, and CV regions in SCA12 patients. The FA significantly decreased in the CC region in SCA12 patients and the CC and CV regions in SCA12 presymptomatic patients. The course of the disease, SARA score, and ADC values in CV showed highly positive correlations. CONCLUSIONS: SCA12 pedigree patients exhibited microstructural damage in the brain white matter. The damage in white matter fiber may first occur in the CC and CV regions in SCA12 presymptomatic patients. The ADC values in the CV region could reflect disease severity in SCA12 patients. PMID- 25274191 TI - Protective role of selenium on aflatoxin b1-induced hepatic dysfunction and apoptosis of liver in ducklings. AB - Aflatoxin B1 (AFB1) is a mycotoxin which causes toxicity through oxidative damage. Selenium (Se), an antioxidative agent, can antagonize some toxicity induced by oxidative stress. The aim of this work was to investigate the toxicity of AFB1 and the protective effects of Se on duckling liver in vivo. The study consisted of three groups: AFB1, AFB1Tx, and a control group. AFB1 group was administered aflatoxin intragastrically (0.1 mg/kg body weight). AFB1Tx group was administered AFB1 intragastrically (0.1 mg/kg body weight) plus sodium selenite (1 mg/kg body weight). The control group was given the same volume of dimethyl sulfoxide (DMSO) via intragastric intubation. All three groups received daily administrations for 28 days. Blood samples were obtained on the 14th, 21st, and 28th days of post-administration, and the serum alanine aminotransferase (ALT) and aspartate transaminase (AST) were evaluated. A high level of serum ALT and AST was observed in AFB1 group. The activity of ALT and AST was significantly lower in Se treatment group than those in AFB1 group. Liver samples were collected on the 14th, 21st, and 28th days of post-administration, and concentrations of Bcl-2, Bax, caspase-3, and p53 were measured. Increased expression level of Bax, caspase-3, and p53 and decreased Bcl-2 expression level and Bcl-2/Bax ratio were observed in AFB1 group. Se diminished hepatic dysfunction, or damage and modulated the expression of apoptotic related proteins, in a time-dependent manner. In conclusion, concurrent treatment with Se reduced the AFB1-induced hepatic dysfunction and apoptosis. PMID- 25274192 TI - Acute and 3-month effects of microcrystalline hydroxyapatite, calcium citrate and calcium carbonate on serum calcium and markers of bone turnover: a randomised controlled trial in postmenopausal women. AB - Ca supplements are used for bone health; however, they have been associated with increased cardiovascular risk, which may relate to their acute effects on serum Ca concentrations. Microcrystalline hydroxyapatite (MCH) could affect serum Ca concentrations less than conventional Ca supplements, but its effects on bone turnover are unclear. In the present study, we compared the acute and 3-month effects of MCH with conventional Ca supplements on concentrations of serum Ca, phosphate, parathyroid hormone and bone turnover markers. We randomised 100 women (mean age 71 years) to 1 g/d of Ca as citrate or carbonate (citrate-carbonate), one of two MCH preparations, or a placebo. Blood was sampled for 8 h after the first dose, and after 3 months of daily supplementation. To determine whether the acute effects changed over time, eight participants assigned to the citrate dose repeated 8 h of blood sampling at 3 months. There were no differences between the citrate and carbonate groups, or between the two MCH groups, so their results were pooled. The citrate-carbonate dose increased ionised and total Ca concentrations for up to 8 h, and this was not diminished after 3 months. MCH increased ionised Ca concentrations less than the citrate-carbonate dose; however, it raised the concentrations of phosphate and the Ca-phosphate product. The citrate-carbonate and MCH doses produced comparable decreases in bone resorption (measured as serum C-telopeptide (CTX)) over 8 h and bone turnover (CTX and procollagen type-I N-terminal propeptide) at 3 months. These findings suggest that Ca preparations, in general, produce repeated sustained increases in serum Ca concentrations after ingestion of each dose and that Ca supplements with smaller effects on serum Ca concentrations may have equivalent efficacy in suppressing bone turnover. PMID- 25274195 TI - 180-W XPS GreenLight laser vaporization for benign prostate hyperplasia: 12-month safety and efficacy results for glands larger than 80 mL. AB - The purpose of the current study was to evaluate the efficacy and safety of laser prostatectomy by using the latest 180-W XPS GreenLight laser with the new MoXy fiber in the surgical treatment of glands larger than 80 mL in a prospective study. From December 2011 to May 2013, 68 consecutive patients with a mean age of 71.1 +/- 9.8 years (range 49 to 85) underwent 180-W XPS laser prostatectomy at our institution. The baseline characteristics, perioperative data, and complications were recorded. Evaluation of outcomes was assessed at 3, 6, and 12 months postoperatively comparing subjective (International Prostate Symptom Score [IPSS], International Index of Erectile Function-5 [IIEF-5]) and objective (Maximal flow rate [Qmax], postvoid residual urine [PVR], transrectal ultrasound [TRUS] volume) parameters to the preoperative data. Mean preoperative prostate volume was 104.3 +/- 29.7 mL (range 81 to 185). Mean operation time was 65.5 +/- 29.6 min (range 38 to 124), with a mean energy delivery of 398 +/- 169 kJ (range 39 to 523). The catheterization time was 20.8 +/- 1.9 h (range 6 to 92) and the hospital stay was 27.3 +/- 8.7 h (range 12 to 80). No major intraoperative complications were observed. Improvement in IPSS, Qmax, and PVR was statistically significant (p < 0.001) at 3, 6, and 12 months. Urethral strictures were observed in two patients (2.9%). No patients required reintervention due to residual adenoma. The average volume reduction was 40.5% at 12 months. Photoselective vaporization of the prostate (PVP) using the new 180-W XPS GreenLight laser system seems to be a safe and effective procedure and could play an important role in the surgical treatment of symptomatic benign prostatic hyperplasia (BPH) patients with larger prostate volumes. PMID- 25274193 TI - 3,4-dihydroxyphenylethanol attenuates spatio-cognitive deficits in an Alzheimer's disease mouse model: modulation of the molecular signals in neuronal survival apoptotic programs. AB - Alzheimer's disease (AD), the most common type of dementia, is a devastating neurodegenerative disease characterized by progressive neuro-cognitive dysfunction. In our study, we investigated the potential of 3,4 dihydroxyphenylethanol (DOPET), a dopamine metabolite, and also a polyphenol from olive oil, in ameliorating soluble oligomeric amyloid beta1-42 plus ibotenic acid (oA42i)-induced neuro-behavioral dysfunction in C57BL/6 mice. The results depicted that intracerebroventricular injection of oA42i negatively altered the spatial reference and working memories in mice, whereas DOPET treatment significantly augmented the spatio-cognitive abilities against oA42i. Upon investigation of the underlying mechanisms, oA42i-intoxicated mice displayed significantly activated death kinases including JNK- and p38-MAPKs with concomitantly inhibited ERK-MAPK/RSK2, PI3K/Akt1, and JAK2/STAT3 survival signaling pathways in the hippocampal neurons. Conversely, DOPET treatment reversed these dysregulated signaling mechanisms comparable to the sham-operated mice. Notably, oA42i administration altered the Bcl-2/Bad levels and activated the caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, apoptotic protease activating factor-1, and caspase-9/3. In contrary, DOPET administration stabilized the dysregulated activities of these apoptotic/anti-apoptotic markers and preserved the mitochondrial ultra architecture. Besides, we observed that oA42i intoxication substantially down regulated the expression of genes involved in the regulation of survival and memory functions including sirtuin-1, cyclic AMP response element-binding protein (CREB), CREB-target genes (BDNF, c-Fos, Nurr1, and Egr1) and a disintegrin and metalloprotease 10. Fascinatingly, DOPET treatment significantly diminished these aberrations when compared to the oA42i group. Taken together, these results accentuate that DOPET may be a multipotent agent to combat AD. PMID- 25274196 TI - Effects of light-emitting diode (LED) therapy on skeletal muscle ischemia reperfusion in rats. AB - Low-level laser therapy has been shown to decrease ischemia-reperfusion injuries in the skeletal muscle by induction of synthesis of antioxidants and other cytoprotective proteins. Recently, the light-emitting diode (LED) has been used instead of laser for the treatment of various diseases because of its low operational cost compared to the use of a laser. The objective of this work was to analyze the effects of LED therapy at 904 nm on skeletal muscle ischemia reperfusion injury in rats. Thirty healthy male Wistar rats were allocated into three groups of ten rats each as follows: normal (N), ischemia-reperfusion (IR), and ischemia-reperfusion + LED (IR + LED) therapy. Ischemia was induced by right femoral artery clipping for 2 h followed by 2 h of reperfusion. The IR + LED group received LED irradiation on the right gastrocnemius muscle (4 J/cm(2)) immediately and 1 h following blood supply occlusion for 10 min. At the end of trial, the animals were euthanized and the right gastrocnemius muscles were submitted to histological and histochemical analysis. The extent of muscle damage in the IR + LED group was significantly lower than that in the IR group (P < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in the IR group were significantly increased (P < 0.05). The muscle tissue glutathione (GSH), superoxide dismutases (SOD), and catalase (CAT) levels in the IR group were significantly lower than those in the subjects in other groups. From the histological and histochemical perspective, the LED therapy has alleviated the metabolic injuries in the skeletal muscle ischemia reperfusion in this experimental model. PMID- 25274197 TI - Effect of high-intensity laser therapy in the management of myofascial pain syndrome of the trapezius: a double-blind, placebo-controlled study. AB - Myofascial pain syndrome (MPS) of the trapezius muscle is one of the main causes of neck pain. In this randomized, double-blind study, we evaluated the effects of high-intensity laser therapy (HILT) in female patients with chronic MPS of the trapezius muscle. The patients were assigned to two groups. The HILT group was treated with HILT and exercise, and the sham therapy group was treated with placebo HILT and exercise. The patients were assessed for pain, cervical active range of motion, disability, and quality of life. Evaluations were performed before treatment (week 0) and after treatment (weeks 4 and 12). Both groups showed significant improvement in all parameters at weeks 4 and 12. However, in a comparison of the percentage changes in the parameters at weeks 4 and 12 relative to pretreatment values, the HILT group showed greater improvement in pain scores, the neck disability index, and several subparts of the short-form 36 health survey (SF-36) (physical functioning, role limitations due to physical functioning, bodily pain, general health perceptions, social functioning, and role limitations due to emotional problems) than did the sham therapy group. We conclude that HILT is an effective therapeutic method in the treatment of patients with chronic MPS of the trapezius muscle. PMID- 25274198 TI - Low power laser stimulation of the bone consolidation in tibial fractures of rats: a radiologic and histopathological analysis. AB - The objective of this study is to analyze the effectiveness of low power laser irradiation in the bone consolidation of tibial fractures in rats. An experimental, comparative, prospective study with control group was designed. Twenty Wistar rats were grouped into control (n = 10) and experimental groups (n = 10). A tibial fracture, with a mechanical drill, was inflicted in all rats. The experimental group received ten days of low power arsenide-gallium laser irradiation of 850 nm (KLD, Sao Paulo, Brasil)-100 mW, 8 J/cm(2), 64 s. Before and after the laser treatment, a radiologic analysis was carried out in both groups, in which the rats were graded from 0 to IV according the Montoya scale of bone consolidation. Also, we histopathologically analyzed the bone to estimate the proliferation of fibroblasts, bone matrix, and angiogenesis with a microscopy, which were graded as I (thin layer of fibroblasts and osteoid matrix), II (thick layer of fibroblasts and osteoid matrix), or III (thick layer of fibroblasts and osteoid matrix and new blood vessels). Radiologic data showed that the experimental group had a higher bone consolidation of Montoya scale after ten days of laser irradiation compared to control group (P < 0.004). Histopathologic data showed more fibroblasts and angiogenesis presence in the group receiving laser irradiation, compared to control group (P < .002). The low power laser radiation therapy may expedite the bone repair after tibial fractures in rats, according to radiologic and histopathologic analysis. PMID- 25274199 TI - Proper name anomia in poststroke aphasics: evidence from a multiple-case study. AB - We aimed to characterize difficulties in famous face naming in three poststroke aphasic patients with a lesion limited to the left mid-posterior temporal language regions, sparing the anterior temporal lobe. The patients did not present semantic deficits specific to known people. Nonetheless, they showed difficulties naming famous buildings in addition to famous faces, but they were comparable to healthy controls in generating proper names. Our results support the critical role of the mid-posterior temporal language regions in the lexical retrieval of proper names, namely from pictorial stimuli, in absence of semantic impairments. PMID- 25274200 TI - Efficacy of tamoxifen and l-carnitine on sperm ultrastructure and seminal oxidative stress in patients with idiopathic oligoasthenoteratozoospermia. AB - Idiopathic oligoathenoteratozoospermia (iOAT) is a common finding in the evaluation of male infertility. Oxidative stress (OS) may underlie its pathology. Tamoxifen and l-carnitine are used to treat idiopathic male infertility. The aim of this work was to detect the efficacy of tamoxifen and l-carnitine on sperm parameters, sperm ultrastructure and seminal OS in iOAT patients. Sixty patients were recruited for this study and divided into three groups; the 1st was treated with tamoxifen, 2nd with l-carnitine and 3rd with both drugs. Semen analysis, malondialdehye (MDA) level and transmission electron microscopy were performed before and after three months treatment. The first group showed significant improvement in MDA levels, sperm concentration, sperm morphology, ultrastructural head, acrosomal and mitochondrial anomalies (P < 0.01). Other parameters were not significantly improved. In the 2nd group, significant improvements in MDA, sperm motility, sperm morphology, ultrastructural mitochondrial and tail anomalies were detected (P < 0.01). No significant improvement in the other parameters. Third group showed improvement in MDA, all semen parameters and all ultrastructural anomalies (P < 0.01). In conclusion, tamoxifen and l-carnitine are effective in improving seminal OS, semen parameters and sperm ultrastructure. Combination of both drugs is superior to monotherapy. PMID- 25274202 TI - Occurrence of Arcobacter in Iranian poultry and slaughterhouse samples implicates contamination by processing equipment and procedures. AB - 1. The occurrence of Arcobacter spp. and three pathogenic species of Arcobacter from Iranian poultry carcasses was investigated at different steps of broiler processing to determine critical control points for reducing carcass contamination. 2. Samples were collected from (a) cloaca immediately before processing, (b) different points during processing and (c) at different stations in a processing plant of a slaughterhouse in southern Iran. 3. After enrichment steps in Arcobacter selective broth, DNA of the samples was extracted and three significant pathogen species of Arcobacter were identified based on polymerase chain reaction (PCR) detection of 16S rRNA and specific species PCR. 4. Out of a total of 540 samples, 244 (45%) were positive for Arcobacter spp. Arcobacter butzleri was more frequently detected (73% +/- 13.9%) than A. cryaeophilus (9% +/ 13.9%) and A. skirrowii (4.1%). In addition, co-colonisation (A. butzleri and A. cryaerophilus) occurred in 13.9% of the positive samples. 5. The results indicate a high prevalence of Arcobacter in the investigated slaughterhouse and broiler carcasses and that Arcobacter is not a normal flora of the broilers. Evidence for the presence of Arcobacter in the environment and water of processing plants suggests that these are sources of contamination of poultry carcasses. In addition, contamination of the poultry carcasses can spread between poultry meats in different parts and processes of the slaughterhouse (pre-scalding to after evisceration). PMID- 25274201 TI - [Main results of studies on primary therapy of head and neck squamous cell carcinoma : highlights of the ASCO Meeting 2014]. AB - The two available options for primary radiochemotherapy (RCT) of locally advanced head and neck squamous cell carcinoma are discussed in the current study: concomitant and sequential RCT. At the annual meeting of the American Society of Clinical Oncology (ASCO) 2014, results of current trials on the primary nonsurgical therapy of locally advanced head and neck tumors were presented. A selection of the most important trials will be summarized in this article. Studies including cisplatin-based RCT as standard therapy for locally advanced head and neck tumors, alternatives for cisplatin, combination with targeted therapy, application of the epidermal growth factor receptor (EGFR) antibody cetuximab and the comparison of concomitant and sequential RCT are discussed. The first completely recruited phase III trial comparing concomitant and sequential RCT will also be presented. PMID- 25274203 TI - Host genetics: deciphering the variability in susceptibility to infections. PMID- 25274204 TI - Reconstruction of dorsal hand and finger defects with reverse radial fasciocutaneous forearm flaps. AB - OBJECTIVES: To evaluate the midterm outcome and the degree of satisfaction of patients who underwent reconstruction of dorsal hand and finger defects with reverse flow radial fasciocutaneous forearm flaps and to test whether or not this is a reliable method which can be applied without the need for microsurgery. PATIENTS AND METHODS: Eleven patients were admitted with post-traumatic complex hand defects and treated by reconstruction with reverse flow radial fasciocutaneous forearm flaps from January 2010 to May 2013. The patient demographics, size of the hand and finger defects, and complications were recorded. The functional status of each of the patients was evaluated using the quick disabilities of the arm, shoulder and hand (DASH) scoring system, and patient satisfaction was assessed using Likert scores. RESULTS: The patients comprised nine males and two females with a mean age of 30.7 +/- 9.7 years. The mean follow-up period was 18.4 +/- 5.2 months. The average defect size was 41 +/- 14.3 cm2. None of the patients had circulation defects caused by the sacrifice of the radial artery. The mean quick DASH score was determined as 30.2 +/- 15.3. The Likert patient satisfaction evaluation was good in one patient, and very good in ten patients. All flaps survived well with only two complications; superficial skin necrosis occurred at the suture site in one patient and venous insufficiency occurred in the other patient. Both complications recovered with secondary healing following wound debridement. CONCLUSIONS: The reverse-flow radial forearm flap is a reliable method in the management of dorsal defects of the hand and does not require micro-surgical techniques. PMID- 25274205 TI - Shoulder arthroscopy remains superior to direct MR arthrography for diagnosis of subtle rotator interval lesions. AB - PURPOSE: To assess the sensitivity, specificity and accuracy of MR arthrography, as opposed to shoulder arthroscopy, in diagnosing individual rotator interval (RI) structures lesions at different levels of severity. MATERIALS AND METHODS: Seventy-five patients were enrolled in a prospective study. All the patients were diagnosed with full-thickness rotator cuff tendon tears on unenhanced MRI and had complimentary MR arthrography to search for obscure RI lesions. All the patients then underwent shoulder arthroscopy. The arthroscopist was blinded about the MR arthrography results. RESULTS: At arthroscopy, 42 patients (56 %) were found to have RI lesion(s) and represented the study group. The remaining 33 patients represented the control group. The sensitivity, specificity and accuracy of MR arthrography for detecting individual RI lesions varied widely depending on the location and severity of the lesions. MR arthrography showed intermediate sensitivity of 67-80 %, specificity of 83-89 % and accuracy of 89-92 % for diagnosing subtle RI lesions; and perfect (100 %) sensitivity, specificity and accuracy for diagnosing biceps long head tendon dislocation. For the rest of RI lesions, MR arthrography showed high sensitivity, specificity and accuracy. Inter observer agreement was found to be almost perfect (K = 0.81-1.0). CONCLUSION: Shoulder arthroscopy remains the gold standard for diagnosing subtle RI lesions. Although MR arthrography has proved to be a valuable tool for diagnosing established RI lesions, it is of intermediate sensitivity for diagnosing subtle RI lesions resulting in early insufficiency of the biceps pulley system. PMID- 25274207 TI - A Trend Toward the Improvement of Survival After TIPS by the Use of Covered Stents: A Meta-Analysis of Two Randomized Controlled Trials. PMID- 25274206 TI - Plate fixation of distal radius fracture and related complications. AB - INTRODUCTION: Distal radius fractures are common. In cases where surgical treatment is needed, volar plates can be used to obtain stable, long-lasting fixation. The design of these plates has continually improved over the years, but complications remain a problem. PURPOSE: The goal of this study was to evaluate the types of complications that occur with different types of volar plates with a view towards preventing them. MATERIALS AND METHODS: The emergency department at our hospital saw 524 patients with distal radius fractures between 2006 and 2008. Some of these were treated surgically with a volar plate. All of the post operative complications were documented. RESULTS: With a minimum follow-up of 6 months, 152 patients who had undergone plate fixation were reviewed: 31 had received plates with non-locking screws or uniaxial locking screws and 121 had received plates with polyaxial locking screws. The complication rate was similar in these two groups (16.1 and 16.5%, respectively). The main complications were tendon ruptures and problems related to the plate itself. DISCUSSION: Plate related complications have been described in published studies, but few of these studies link them to the plate design or surgical technique. Manufacturers must continue to refine these plates to minimise their thickness while keeping their strength. Surgeons must be sure to use a highly exacting technique. PMID- 25274208 TI - [Easing human pain: challenges to a novel therapeutic drug in neuropathic pain]. AB - Pain control is very important since, even today, 20 million people suffer from neuropathic pain. Although many basic science and clinical researchers have made efforts to control pain, the mechanism of neuropathic pain is unfortunately still not fully understood. Morphine, a prototypical opioid, is a useful medicine to relieve severe pain. However, repeated or continuous use of morphine and other opioids are associated with a potential risk of analgesic tolerance, which requires an increase in dosage to maintain the same efficacy. In addition, morphine is not always effective in neuropathic pain. In this review we focus on: (1) the role of muscarinic receptors in the spinal cord and anterior cingulate cortex (ACC) in neuropathic pain, (2) how chemokine (C-C motif) ligand 1 (CCL-1) is involved in neuropathic pain, and (3) the novel mechanism of morphine tolerance. The findings in this study may cast new light on novel mechanism of neuropathic pain and development of novel clinical medicines in the future. PMID- 25274209 TI - [Development of new therapeutic strategy for transporter-related diseases]. AB - Significant technological advances in gene sequence analysis and construction of genetically-modified animals during the last two decades made it possible to reveal that many transporters are associated with diseases. The bile salt export pump (BSEP/ABCB11), a member of the family of ATP-binding cassette transporters, is localized on the canalicular membrane of hepatocytes and predominantly mediates the biliary excretion of bile salts. A hereditary defect of BSEP results in severe cholestasis called progressive familial intrahepatic cholestasis type 2 (PFIC2). Without liver transplantation, this disease progresses to liver failure and death before adulthood; therefore the development of new, less invasive medical therapy for PFIC2 is of the highest priority. We have previously shown that in many cases of PFIC2 patients, the dysfunction of BSEP is attributable to decreased BSEP expression on the hepatocanalicular membrane and that 4 phenylbutyrate (4PB), an approved drug for urea cycle disorder, may be a compound with potential to restore BSEP expression. This drug inhibits ubiquitination of cell surface-resident BSEP and thereby its clathrin-mediated endocytosis through the AP2 adaptor complex, leading to increase in BSEP expression on the canalicular membrane. Clinical studies to investigate the efficacy of 4PB in the treatment of PFIC2 revealed that 4PB therapy biochemically and histologically improved liver function without any side effect. Therefore, 4PB therapy may become the preferred choice, instead of liver transplantation, for PFIC2 patients. The strategy employed and findings in this study would be valuable for the drug development of transporter-related disorders. PMID- 25274210 TI - [Structure analysis of disease-related proteins using vibrational spectroscopy]. AB - Analyses of the structure and properties of identified pathogenic proteins are important for elucidating the molecular basis of diseases and in drug discovery research. Vibrational spectroscopy has advantages over other techniques in terms of sensitivity of detection of structural changes. Spectral analysis, however, is complicated because the spectrum involves a substantial amount of information. This article includes examples of structural analysis of disease-related proteins using vibrational spectroscopy in combination with additional techniques that facilitate data acquisition and analysis. Residue-specific conformation analysis of an amyloid fibril was conducted using IR absorption spectroscopy in combination with (13)C-isotope labeling, linear dichroism measurement, and analysis of amide I band features. We reveal a pH-dependent property of the interacting segment of an amyloidogenic protein, beta2-microglobulin, which causes dialysis-related amyloidosis. We also reveal the molecular mechanisms underlying pH-dependent sugar-binding activity of human galectin-1, which is involved in cell adhesion, using spectroscopic techniques including UV resonance Raman spectroscopy. The decreased activity at acidic pH was attributed to a conformational change in the sugar-binding pocket caused by protonation of His52 (pKa 6.3) and the cation-pi interaction between Trp68 and the protonated His44 (pKa 5.7). In addition, we show that the peak positions of the Raman bands of the C4=C5 stretching mode at approximately 1600 cm(-1) and the Npi-C2-Ntau bending mode at approximately 1405 cm(-1) serve as markers of the His side-chain structure. The Raman signal was enhanced 12 fold using a vertical flow apparatus. PMID- 25274211 TI - [Extracellular adenosine is a therapeutic target for limiting graft-versus-host disease and enhancing the graft-versus-tumor effect against hematopoietic malignancy]. AB - Allogeneic hematopoietic stem cell transplantation is performed in patients with hematologic malignancies refractory to chemotherapy. However, its efficacy is often limited by the development of graft-versus-host disease (GVHD) secondary to the allogeneic interaction of donor T cells with host dendritic cells. On the other hand, the antihost cytotoxicity of donor T cells enhances the graft-versus tumor (GVT) effect. Extracellular adenosine generated by CD73/ecto-5' nucleotidase from ATP via AMP plays pleiotropic roles under physiological and pathological conditions by engaging four adenosine receptors. One study recently demonstrated that ATP released from damaged cells exacerbates GVHD by activating the P2X7 receptor on host dendritic cells. In this review, we summarize our recent findings on the immunosuppressive role of extracellular adenosine in GVHD and the GVT effect. We have shown that in MHC-mismatched bone marrow transplantation, CD73 deficiency, particularly in the recipient, enhanced GVHD severity because of excessive donor T-cell expansion. Severe GVHD was enhanced by repeated administration of a CD73 inhibitor or an adenosine receptor antagonist. A competitive engraftment assay identified endogenous A2AAR signaling in donor T cells as part of a regulatory mechanism by CD73-generated adenosine. Pharmacological inhibition of CD73 enhanced the GVT effect against B-cell lymphoma and improved survival in tumor-relapsing mice after transplantation. Along with our findings, we herein introduce a novel concept that CD73-generated adenosine counteracts the ATP-evoked allogeneic immune reaction as a negative regulatory mechanism in GVHD. Pharmacological manipulation of CD73 activity could be a therapeutic strategy to limit GVHD and to preserve the GVT effect against hematopoietic malignancy. PMID- 25274212 TI - [Effects of genetic and environmental factors on neuropsychological development]. AB - Abnormalities in early brain development contribute to the etiology of many neurological disorders in later life. Recent advances in genome analysis indicate that large numbers of common gene variants shape any individual's disease risk, including that for major mental illnesses. Polyriboinosinic-polyribocytidilic acid (polyI:C) is known to induce strong innate immune responses that mimic immune activation by viral infections. Our previous findings suggest that activation of the innate immune system in astrocytes results in impairments of neurite outgrowth and spine formation, which lead to behavioral abnormalities in adulthood. Although glial cells are classically thought to provide structural and metabolic support to neurons, they are now widely recognized as essential regulators of neuronal development including neuronal migration, axon and dendrite growth, formation of synapses, and synaptic plasticity. Astrocytes also play critical roles in regulating CNS immune function by responding to inflammatory mediators and producing additional cytokines and chemokines. Most of the functions of astrocytes are mediated by the release of humoral factors through a close interaction with neurons. However, the mechanism by which innate immune activation of astrocytes affects neuronal development remains to be determined. To explore the alteration in proteins secreted from murine astrocytes after polyI:C stimulation, astrocyte-conditioned medium (ACM) was analyzed by 2 dimensional fluorescence difference gel electrophoresis (2D-DIGE). We identified matrix metalloproteinase-3 (Mmp3) as a potential mediator of polyI:C/ACM-induced neurodevelopmental impairment. Here, we provide an overview of the mechanism of neurodevelopmental impairment following polyI:C-induced innate immune activation of astrocytes. PMID- 25274213 TI - [Host energy regulation via SCFAs receptors, as dietary nutrition sensors, by gut microbiota]. AB - Food intake regulates energy balance, and its dysregulation leads to metabolic disorders such as obesity and diabetes. Free fatty acids are not only essential nutrients but also act as signaling molecules in various cellular processes. Recent studies have shown that the receptors GPR40, GPR41, GPR43, and GPR120 are new drug targets for treating metabolic disorders because they are activated by free fatty acids. Two of these receptors, GPR41 and GPR43, are activated by short chain fatty acids (SCFAs: acetate, propionate, and butyrate), which are important energy sources for the host. During feeding, SCFAs are produced by the microbial fermentation of dietary fiber in the gut. The gut microbiota affect nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. Hence, GPR41 and GPR43 are also a focus of research into energy regulation via SCFAs. We report that these SCFA receptors are involved in energy homeostasis: GPR41 regulates sympathetic activity, and GPR43 regulates adipose-insulin signaling by sensing SCFAs produced by gut microbiota. We believe that these results will provide valuable insight into therapeutic targets for treating metabolic disorders and diabetes, as well as in the use of probiotics to control gut microbiota. PMID- 25274214 TI - [Adverse effects of nanomaterials on biological defense mechanisms]. AB - Nanomaterials are defined as substances that have at least one dimension <100 nm. They have unique physicochemical properties and innovative functions compared with conventional materials of submicron size. As such, they have many applications in nanomedicine, such as in drug delivery or diagnostic and imaging systems. However, there are a number of safety concerns regarding the use of nanomaterials. Therefore it is essential not only to obtain more information about nanomaterials to ensure their safety, but also to identify novel biomarkers that may predict adverse biological effects induced by nanomaterials. In this regard, neutrophil activation is thought to be involved in some biological responses that are induced after exposure to nanomaterials. However, the detailed mechanisms involved in these events are poorly understood. Here, we examine neutrophil activation induced by nanomaterials. In addition, to develop a safe and effective form of a nanomaterial, we attempted to develop potential biomarkers of silica nanoparticles by proteomics analysis. We believe that our data could provide information of value in nanomaterial risk management and in the establishment of guidelines for assessment of their use. PMID- 25274215 TI - [Development of a novel nanocarrier focusing on the physicochemical properties of an anti-cancer therapy drug--development of anti-cancer nanoparticles containing vitamin E derivative with mulitifaceted anti-cancer effect]. AB - Successful cancer gene therapy is dependent upon the development of nanocarriers that exhibit anti-cancer effects via delivery of nucleic acids to the target site in tumor tissue. The effectiveness of such systems has typically relied on the potency of the anti-cancer nucleic acids, as conventional carriers do not exhibit inherent anti-cancer activity, serving only as vehicles for delivery. Ideal nanocarriers for effective cancer gene therapy should not only serve as delivery systems for transporting anti-cancer nucleic acids to the target tumor tissue, but should also exhibit their own inherent anti-cancer activity. alpha-tocopheryl succinate (TS) has attracted attention as a unique anti-cancer agent for its ability to induce apoptosis in various cancer cells; moreover, TS readily forms nanovesicles (TS-NVs). Thus, vesicles comprised of TS represent prospective tools for use as drug delivery systems (DDS) for cancer therapy. Owing to the low vesicle stability in the presence of divalent cations or serum, however, TS-NVs are not suitable for encapsulating nucleic acids, and require passive targeting delivery to tumor tissue via an enhanced permeability and retention effect. To improve the stability of TS-NVs, we developed novel nanovesicles comprised of TS and egg phosphatidylcholine (EPC), which can form a stable lamellar structure (TS EPC-NVs). In this review, we introduce the development of nanovesicles comprised of TS as a novel DDS carrier and demonstrate the anti-cancer activity of both the encapsulated nucleic acids and the carrier itself. PMID- 25274216 TI - [Role of orexin-A-mediated communication system between brain and peripheral tissues on the development of post-ischemic glucose intolerance-induced neuronal damage]. AB - I recently found that cerebral ischemic stress per se causes hyperglycemia (i.e., post-ischemic glucose intolerance) and suppression of post-ischemic glucose intolerance might be important to improve prognosis. Here, I analyzed the efficacy of suppression of post-ischemic glucose intolerance using orexin-A (OXA) endogenous neuropeptide as a novel therapeutic strategy against cerebral ischemic neuronal damage. OXA in hypothalamus plays a role in many physiological functions including regulation of glucose metabolism. I previously found that the development of post-ischemic glucose intolerance is suppressed by OXA. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic OXA-mediated suppression of post-ischemic glucose intolerance and neuronal damage. Intrahypothalamic administration of OXA significantly suppressed the development of post-ischemic glucose intolerance on day 1 and of neuronal damage on day 3 after middle cerebral artery occlusion (MCAO). In the liver, MCAO-induced decrease in insulin receptors and increase in gluconeogenic enzymes on day 1 was recovered to control levels by OXA; these effects were reversed by hepatic vagotomy. In the medulla oblongata, OXA induced co-localization of the cholinergic neuronal marker choline acetyltransferase with orexin-1 receptor and c-Fos. These results suggest that the vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates neuroprotection by hypothalamic OXA. PMID- 25274217 TI - [Functional analysis of bioactive natural compounds using monoclonal antibodies against natural compounds]. AB - Herbal medicines have recently attracted much importance owing to the rising interest in their health benefits. Hence, further elucidation of the functions and mechanisms of these natural compounds is necessary. Our laboratory has established more than 30 kinds of monoclonal antibodies (MAbs) against bioactive natural compounds. Moreover, we have developed highly sensitive measurement systems for natural compounds, such as enzyme-linked immunosorbent assay (ELISA) and eastern blotting using MAbs. To expand the application of these MAbs to the functional analysis of natural compounds, we established a new approach for the isolation of the target compound from plant extracts using an immunoaffinity column conjugated with an anti-natural compound MAb. Through one-step purification using a MAb-conjugated immunoaffinity column, we have succeeded in preparing a knockout (KO) extract containing all components except the target compound, used as a hapten. Furthermore, we examined the pharmacological effects of the KO extract to identify the precise roles of the bioactive compound in the plant extract. To confirm another beneficial use of MAbs, we investigated the cellular localization and target molecules of natural compounds by immunocytochemistry (ICC) and Western blotting using MAbs. Our results demonstrated that MAbs clearly determined the cellular localization and target molecules of the natural compounds. These approaches may make it possible to determine the potential functions and target molecules of bioactive natural compounds in herbal medicines. PMID- 25274218 TI - [Visualization and analysis of adverse reactions of molecularly targeted anticancer agents using the self-organizing map (SOM)]. AB - Molecularly targeted anticancer agents cause a variety of adverse reactions compared with conventional anticancer agents because of their unique mechanisms of action. Sources of drug information such as package inserts (PIs) provide primarily document-based and numerical information. Therefore it is not easy to obtain a complete picture of drugs with similar effects, or to understand differences among drugs. In this study we used the self-organizing map (SOM) technique to visualize the adverse reactions indicated on PIs of 23 molecularly targeted anticancer agents as of March 2013. In both the presence/absence version and the frequency version, SOM was divided into domains according to mechanism of action, antibody drug or low-molecular weight drug, and molecular target. The component planes of the 753 adverse reaction items in the frequency version enabled us to grasp all available information and differences among the drugs. In some component planes in the presence/absence version, an adverse reaction that had not been reported for a drug but had already been reported for its proximally positioned drug(s) as of March 2013, was found to be reported thereafter by the Drug Safety Update (DSU) or the Adverse Event Report Search System "CzeekV," which is based on FDA Adverse Event Reporting System (FAERS). Our results suggest that visualization of the adverse reactions of molecularly targeted anticancer agents by the SOM technique is useful not only to acquire all available information and differences among drugs, but also to predict the appearance of adverse reactions. PMID- 25274219 TI - [Establishment of background color to discriminate among tablets: sharper and more feasible with color-weak simulation as access to safe medication]. AB - Color-weak persons, who in Japan represent approximately 5% of male and 0.2% of female population, may not be able to discriminate among colors of tablets. Thus using color-weak simulation by VariantorTM we evaluated the effects of background colors (light, medium, and dark gray, purple, blue, and blue green) on discrimination among yellow, yellow red, red, and mixed group tablets by our established method. In addition, the influence of white 10-mm ruled squares on background sheets was examined, and the change in color of the tablets and background sheets through the simulation measured. Variance analysis of the data obtained from 42 volunteers demonstrated that with color-weak vision, the best discrimination among yellow, yellow red, or mixed group tablets was achieved on a dark gray background sheet, and a blue background sheet was useful to discriminate among each tablet group in all colors including red. These results were compared with those previously obtained with healthy and cataractous vision, suggesting that gap in color hue and chroma as well as value between background sheets and tablets affects discrimination with color-weak vision. The observed positive effects of white ruled squares, in contrast to those observed on healthy and cataractous vision, demonstrate that a background sheet arranged by two colors allows color-weak persons to discriminate among all sets of tablets in a sharp and feasible manner. PMID- 25274220 TI - Cost-effectiveness of ultrasound-guided foam sclerotherapy, endovenous laser ablation or surgery as treatment for primary varicose veins from the randomized CLASS trial. AB - BACKGROUND: The treatment of patients with varicose veins constitutes a considerable workload and financial burden to the National Health Service. This study aimed to assess the cost-effectiveness of ultrasound-guided foam sclerotherapy (UGFS) and endovenous laser ablation (EVLA) compared with conventional surgery as treatment for primary varicose veins. METHODS: Participant cost and utility data were collected alongside the UK CLASS multicentre randomized clinical trial, which compared EVLA, surgery and UGFS. Regression methods were used to estimate the effects of the alternative treatments on costs to the health service and quality-adjusted life-years (QALYs) at 6 months. A Markov model, incorporating available evidence on clinical recurrence rates, was developed to extrapolate the trial data over a 5-year time horizon. RESULTS: Compared with surgery at 6 months, UGFS and EVLA reduced mean costs to the health service by L655 and L160 respectively. When additional overhead costs associated with theatre use were included, these cost savings increased to L902 and L392 respectively. UGFS produced 0.005 fewer QALYs, whereas EVLA produced 0.011 additional QALYs. Extrapolating to 5 years, EVLA was associated with increased costs and QALYs compared with UGFS (costing L3640 per QALY gained), and generated a cost saving (L206-439) and QALY gain (0.078) compared with surgery. Applying a ceiling willingness-to-pay ratio of L20 000 per QALY gained, EVLA had the highest probability (78.7 per cent) of being cost effective. CONCLUSION: The results suggest, for patients considered eligible for all three treatment options, that EVLA has the highest probability of being cost effective at accepted thresholds of willingness to pay per QALY. PMID- 25274221 TI - Impact of mechanical bowel preparation on survival after colonic cancer resection (Br J Surg 2014: 101: 1594-1600). PMID- 25274224 TI - System Level spatial-frequency EEG changes coincident with a 90-day cognitive behavioral therapy program for couples in relationship distress. AB - Evaluating relationship intervention programs traditionally involves the use of self-report surveys or observational studies to assess changes in behavior. Instead, to investigate intervention-related changes in behavior, our study evaluates spatial-frequency electroencephalography (EEG) patterns from the brains of couples participating in an Imago Relationship workshop and 12 weeks of group counseling sessions lasting approximately 90 days. This explorative study recorded 32-channel EEGs from nine committed distressed couples prior to, during and immediately following the Imago Relationship Therapy program. A repeated measures t-Test approach was applied to investigate if significant group level brain pattern changes could be identified in key resting state networks in the brains of the participants that could be correlated with changes in relationship outcome. The study results show that significant reductions in EEG power in the alpha2, beta3 and gamma bands were evident in the averaged brain activity in the pre-frontal, frontal and temporal-parietal cortices that are anatomically associated with the frontal executive, default mode and salience networks of the human brain. Our current understanding of system level neural connectivity and network dynamics strongly indicates that each of these systems is integrally required in learning and implementing a complex communication process taught in the Imago intervention. Thus, a high degree of hemispheric lateralization is consistent with our understanding of language function and mood regulation in the brain and is consistent with recent research into the use of resting frontal EEG asymmetry as an indicator of behavioral changes in distressed couples undergoing a program for relationship improvement. Although preliminary, these results further indicate that the EEG is an inexpensive and easily quantifiable measure, and possibly predictor, of behavioral changes in response to a cognitive behavioral intervention. PMID- 25274227 TI - ALK inhibition for the treatment of refractory epithelioid inflammatory myofibroblastic sarcoma. PMID- 25274226 TI - How do the residual fragments after SWL affect the health-related quality of life? A critical analysis in a size-based manner. AB - This study aimed at evaluating the possible effects of residual fragments (RF) after shockwave lithotripsy (SWL) on the health-related quality of life (QOL) of the patients on a size-related basis. Eighty six patients with RF after SWL were divided into three groups: Group 1 (n:30 with fragments <= 2 mm), Group 2 (n:21 2 <= 4 mm) and Group 3 (n:35 > 4 mm). During a 3-month follow-up, spontaneous passage rates, emergency department visits, mean analgesic required, additional procedures and the QOL were all evaluated. QOL was evaluated using the Short Form 36 survey. Of the 30 patients with fragments <= 2 mm all cases passed the fragments spontaneously. Of the 21 cases with fragments 2-<= 4, however, 76% were stone free. Last, of the 35 cases with fragments >4 mm, 52% passed them spontaneously in 3 months. While no patient with fragments <= 2 mm required emergency department visit, 19% of the cases with fragments 2-<= 4 mm and 51.4 % with fragments >4 mm did require this visit. Mean analgesic need (mg) values were higher in cases with larger fragments. Evaluation of the QOL score data in a subgroup comparison base showed that cases with larger fragments had prominently lower scores during both 1- and 3-month evaluation. RF after SWL could pose an impact on the QOL of the cases in a size-related basis. While fragments <= 2 mm had nearly no impact on this aspect larger fragments could significantly affect the QOL. PMID- 25274228 TI - Association between sleep disturbances and abdominal symptoms. AB - OBJECTIVE: Although gastroesophageal reflux disease (GERD) is known to cause sleep disturbances, the relationships between other abdominal symptoms and sleep disorders have not been clarified. In the present study, we examined the relationships between daytime sleepiness and various abdominal symptoms in a non clinical population. METHODS: We enrolled 2,936 subjects who visited Matsue Red Cross Hospital for an annual health check examination during a 10-month consecutive period after excluding those with organic gastrointestinal diseases. The Izumo scale abdominal symptom and Epworth Sleepiness Scale (ESS) questionnaires were employed to evaluate the presence of abdominal symptoms and daytime sleepiness. RESULTS: Among the 2,936 subjects, 233 (7.9%), 254 (8.6%) and 528 (18%) had GERD-like, functional dyspepsia (FD)-like and irritable bowel syndrome (IBS)-like symptoms, respectively. The ESS scores in the subjects with GERD-, FD- and IBS-like symptoms were significantly higher than those observed in the asymptomatic subjects. The subjects with multiple abdominal symptoms tended to have higher ESS scores than those with single symptoms. A multiple logistic regression analysis revealed a younger age and the presence of FD- and IBS-like symptoms to be significant influencing factors for sleep disturbances. CONCLUSION: The presence of FD and IBS symptoms in addition to GERD symptoms exhibits a strong relationship with sleep disturbances from the viewpoint of daytime sleepiness. PMID- 25274229 TI - Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine. AB - OBJECTIVE: To investigate the causes of neurological manifestations in girls immunized with the human papillomavirus (HPV) vaccine. METHODS: During the past nine months, 44 girls visited us complaining of several symptoms after HPV vaccination. Four patients with other proven disorders were excluded, and the remaining forty subjects were enrolled in this study. RESULTS: The age at initial vaccination ranged from 11 to 17 years, and the average incubation period after the first dose of the vaccine was 5.47+/-5.00 months. Frequent manifestations included headaches, general fatigue, coldness of the legs, limb pain and weakness. The skin temperature examined in 28 girls with limb symptoms exhibited a slight decrease in the fingers (30.4+/-2.6 degrees C) and a moderate decrease in the toes (27.1+/-3.7 degrees C). Digital plethysmograms revealed a reduced height of the waves, especially in the toes. The limb symptoms of four girls were compatible with the Japanese clinical diagnostic criteria for complex regional pain syndrome (CRPS), while those in the other 14 girls were consistent with foreign diagnostic criteria for CRPS. The Schellong test identified eight patients with orthostatic hypotension and four patients with postural orthostatic tachycardia syndrome. The girls with orthostatic intolerance and CRPS commonly experienced transient violent tremors and persistent asthenia. Electron microscopic examinations of the intradermal nerves showed an abnormal pathology in the unmyelinated fibers in two of the three girls examined. CONCLUSION: The symptoms observed in this study can be explained by abnormal peripheral sympathetic responses. The most common previous diagnosis in the studied girls was psychosomatic disease. The social problems of the study participants remained unresolved in that the severely disabled girls stopped going to school. PMID- 25274230 TI - Comparison of probe disinfection procedures in routine ultrasonography: hot water versus antiseptic wiping. AB - OBJECTIVE: It is commonly known that ultrasonography (US) transducers function as both a reservoir and means of transfer for hospital infections. The current study aimed to compare the antimicrobial effectiveness of using >80 degrees C water versus antiseptic wipes to disinfect US transducers. METHODS: Subsequent to abdominal inspections in three groups of 20 patients, a swab culture was taken from the transducer in each case. Neither a mechanical nor chemical disinfection was applied to the transducer in the first group. As for the second group, the transducer was placed in >80 degrees C hot water for five minutes. In the third group, the transducer was wiped clean using antiseptic wipes. RESULTS: Of the 60 swab samples collected, 40 did not produce any growth. The number of samples exhibiting growth in the first group involved 18 cases of coagulase-negative staphylococcus (CNS), as well as 15 cases of Listeria spp., one case of Corynebacterium spp. and one case of Bacillus spp., while only one case of CNS was observed in the second and third groups, respectively. The culture growth and colony forming units rate were significantly higher in the samples obtained from the first group than in those obtained from the other groups (p<0.01). As for the second and third groups, no significant differences were found in terms of the amount of colonization and growth (p=1.00). CONCLUSION: Being a practical and a simple method for particular use in developing and underdeveloped countries, where it is hard to access relatively costly transducer disinfection materials, such as antiseptic wipes, hot water disinfection may play an active role in fighting hospital infections. PMID- 25274231 TI - Effectiveness of early ureteric stenting for urosepsis associated with urinary tract calculi. AB - OBJECTIVE: Patients with urosepsis associated with urinary tract calculi occasionally require drainage, primarily via ureteric stenting. Such patients require longer hospitalization. However, the indications for early ureteric stenting for this condition have not been clearly defined. To compare the length of stay (LOS) in the hospital between patients treated with earlier ureteric stenting versus those with delayed ureteric stenting. METHODS: Design: Retrospective cohort study. Setting: An acute care teaching hospital in Japan. MEASUREMENT: Length of hospital stay in days. Patients Patients with urosepsis associated with urinary tract calculi. RESULTS: Among a total of 30 patients (mean age, 72; 13 men), the mean number of days from emergency room admission to ureteric stenting was 3.5 days (range, 1-14 days), and the overall mean LOS was 36 days (range, 8-102 days). The early stenting group (mean LOS, 21 days) had a significantly shorter LOS than the delayed stenting group (mean LOS, 50 days), with an adjusted beta coefficient of -26 days [95% confidence interval (CI), -46, -6]. CONCLUSION: In patients with urosepsis associated with urinary tract calculi, performing early stenting within two days of admission may reduce the LOS in the hospital. PMID- 25274232 TI - Epithelioid inflammatory myofibroblastic sarcoma responsive to surgery and an ALK inhibitor in a patient with panhypopituitarism. AB - We encountered a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) originating from an abdominal organ that rapidly regrew twice. The patient underwent two surgeries. Large tumors grew within three months after the second surgery. The patient subsequently received chemotherapy with an anaplastic lymphoma kinase (ALK) inhibitor. Although EIMS has a poor prognosis, the patient continues to be alive with disease 14 months after surgical treatment and the administration of the ALK inhibitor. PMID- 25274233 TI - Hepatic infarction complicated with acute pancreatitis precisely diagnosed with gadoxetate disodium-enhanced magnetic resonance imaging. AB - Pancreatitis may induce a spectrum of venous and arterial vascular complications. However, hepatic infarction complicated with acute pancreatitis seldom occurs because of the unique vascular configuration of the liver. We herein describe an extremely rare and unique case in which simultaneous portal vein and hepatic vein thrombosis were present. We precisely assessed both hepatic hemodynamics and hepatocellular function using sequential multidetector computed tomography and gadoxetate disodium-enhanced magnetic resonance imaging, which may provide useful information on the pathophysiological state and diagnosis of hepatic infarction. PMID- 25274234 TI - Renal artery stenting crucial to the recovery from acute worsening of chronic renal failure. AB - Recent randomized studies have failed to note any benefits to adding renal artery stenting to optimal medical therapy in patients with atherosclerotic renal artery stenosis (ARAS). We herein present the case of a 75-year-old woman with acute worsening of chronic renal failure in whom renal stenting was essential to saving the patient's life and avoiding dialysis. Although the long-term usefulness of renal artery stenting for ARAS remains controversial, this procedure should be kept in mind as a viable option for treating acute critical cases such as this. PMID- 25274235 TI - Prolonged disturbance of consciousness caused by severe hypophosphatemia: a report of two cases. AB - We herein describe two patients with a prolonged disturbance of consciousness due to severe hypophosphatemia. Case one presented with pneumococcal infection and acute exacerbation of chronic obstructive pulmonary disease and asthma. Case two presented with diabetic foot infections and diabetic ketoacidosis. Both patients responded to initial therapy for their primary diseases, but consciousness became worse in both cases. Their test results for impaired consciousness revealed severe hypophosphatemia; therefore, phosphate replacement therapy was administered, thus resulting in complete alertness. These cases demonstrate that we should consider the possibility of hypophosphatemia in critically ill patients with an altered consciousness. PMID- 25274236 TI - Secondary focal segmental glomerulosclerosis in an adolescent born with a very low birth weight. AB - A 17-year-old man presented with a decreased renal function (creatinine clearance 66.0 ml/min/1.73 m2) and proteinuria (1.25 g/24 hrs). He was born weighing 1,065 g 26 weeks of pregnancy. He was mildly overweight (BMI 26.9 kg/m2) due to an increased weight gain (10 kg) over the past year. Renal biopsy showed perihilar sclerosing lesions in three of eleven glomeruli, low glomerular density, enlarged glomeruli, and limited fusions of foot processes, thus indicating secondary focal segmental glomerulosclerosis (FSGS). We speculated that the patient's overweight status may have caused a worsening of glomerular hyperfiltration due to the fewer number of nephrons leading to the development of secondary FSGS. PMID- 25274237 TI - Withdrawal of epoprostenol therapy in a patient with pulmonary hypertension associated with Sjogren's syndrome. AB - Pulmonary arterial hypertension (PAH) is a rare complication, but a significant prognostic factor in patients with Sjogren's syndrome (SjS). Despite its efficacy, the long-term use of intravenous epoprostenol is sometimes complicated by adverse effects, such as catheter-related infection. This case involves a 38 year-old woman with PAH associated with SjS (PAH-SjS) who was transitioned from treatment with long-term intravenous epoprostenol therapy to combination oral therapy containing bosentan and tadalafil. She has remained in stable condition for more than two years following epoprostenol discontinuation. The details of this report suggest that long-term epoprostenol therapy can be safely tapered off and replaced with combination oral therapy in carefully selected patients with PAH-SjS. PMID- 25274238 TI - Late hematological improvement of myelodysplastic syndrome following treatment with 5-azacitidine therapy. AB - Recently, 5-azacitidine has been reported to improve the survival of patients with high-risk myelodysplastic syndrome (MDS) and was approved for the treatment of MDS in Japan. We herein report a case of high-risk MDS in which the patient exhibited a hematological improvement three months after the first cycle of 5 azacitidine therapy. The second cycle of 5-azacitidine was not administered due to a severe pulmonary infection. Bone marrow aspiration revealed a decrease in the level of blast cells from 7.0% to 0.7%, and the subclassification of MDS improved from refractory anemia with excess blasts (RAEB)-1 to refractory cytopenia with unilineage dysplasia. This case demonstrates a possible late effect of 5-azacitidine treatment. PMID- 25274239 TI - Repeated encephalopathy and hemicerebral atrophy in a patient with familial hemiplegic migraine type 1. AB - We herein describe a case of a 38-year-old man with familial hemiplegic migraine with a T666M mutation in the electrical potential-dependent calcium ion channel (CACNA1A) gene. His migraine was accompanied by hemiparesis and impaired consciousness. Brain magnetic resonance imaging revealed abnormalities in the right cortical hemisphere. Single-photon emission computed tomography demonstrated a decrease in iomazenil uptake and an increase in (99m)Tc-ethyl cysteinate dimer uptake at the ipsilateral site. Positron emission tomography showed a decrease in 18F-fluorodeoxyglucose uptake in the same area, which later showed atrophic changes. The patient's brain atrophy ceased after treatment with sodium valproate. This case suggests that the progression of brain atrophy can be prevented with adequate prophylaxis. PMID- 25274240 TI - Ocular tilt reaction due to a cerebellar hemorrhage. AB - A 78-year-old man with essential hypertension abruptly developed complete ocular tilt reaction (OTR) which consisted of concomitant skew deviation with left hypertropia, extorsion of the right eye and intorsion of the left, and rightward head tilt. Cranial computed tomography demonstrated a localized cerebellar hemorrhage involving the left nodulus. The patient became asymptomatic within two weeks. This is a first reported case of complete OTR due to a cerebellar hemorrhage. Concomitant skew deviation is a common symptom of cerebellar lesions. Moreover, unilateral damage to the utricular pathway due to involvement of the left nodulus might cause rightward conjugate ocular torsion and rightward head tilt. PMID- 25274241 TI - Successful treatment with tocilizumab in a case of intralymphatic histiocytosis associated with rheumatoid arthritis. AB - A 75-year-old woman with rheumatoid arthritis (RA) presented with long-term painful erythema on the right upper arm and left elbow. The patient was diagnosed with intralymphatic histiocytosis (ILH) based on the biopsy findings. Because the patient was unresponsive to single-agent treatment with methotrexate, infliximab and etanercept, we switched to tocilizumab (TCZ) treatment, which induced remission of the ILH. Our case suggests that TCZ may be a treatment option for ILH in patients with RA. PMID- 25274242 TI - Haloed centrilobular sign: early diagnosis of airway-invasive aspergillosis. PMID- 25274243 TI - Alpha-synuclein accumulation in a patient with Auerbach's plexus of pure autonomic failure. PMID- 25274244 TI - Voltage-gated potassium channel antibody-associated encephalitis with claustrum lesions. PMID- 25274245 TI - Evaluation and guidelines for using polyurethane foam (PUF) passive air samplers in double-dome chambers to assess semi-volatile organic compounds (SVOCs) in non industrial indoor environments. AB - Indoor air pollution has been recognized as an important risk factor for human health, especially in areas where people tend to spend most of their time indoors. Many semi-volatile organic compounds (SVOCs) have primarily indoor sources and are present in orders of magnitude higher concentrations indoors than outdoors. Despite this, awareness of SVOCs in indoor air and assessment of the link between indoor concentrations and human health have lagged behind those of outdoor air. This is partially related to challenges associated with indoor sampling of SVOCs. Passive air samplers (PASs), which are widely accepted in established outdoor air monitoring networks, have been used to fill the knowledge gaps on indoor SVOCs distribution. However, their applicability for indoor environments and the assessment of human health risks lack sufficient experimental data. To address this issue, we performed an indoor calibration study of polyurethane foam (PUF) PAS deployed in a double-dome chamber, covering both legacy and new SVOC classes. PUF-PAS and a continuous low-volume active air sampler (AAS) were co-deployed for a calibration period of twelve weeks. Based on the results from this evaluation, PUF-PAS in a double-bowl chamber is recommended for indoor sampling and health risk assessment of gas phase SVOCs, including novel brominated flame retardants (nBFR) providing sufficient exposure time is applied. Data for particle associated SVOCs suffered from significant uncertainties caused by low level of detection and low precision in this study. A more open chamber design for indoor studies may allow for higher sampling rates (RS) and better performance for the particle associated SVOCs. PMID- 25274246 TI - Id proteins in the vasculature: from molecular biology to cardiopulmonary medicine. AB - The inhibitors of differentiation (Id) proteins belong to the helix-loop-helix group of transcription factors and regulate cell differentiation and proliferation. Recent studies have reported that Id proteins play important roles in cardiogenesis and formation of the vasculature. We have also demonstrated that heritable pulmonary arterial hypertension (HPAH) patients have dysregulated Id gene expression in pulmonary artery smooth muscle cells. The interaction between bone morphogenetic proteins and other growth factors or cytokines regulates Id gene expression, which impacts on pulmonary vascular cell differentiation and proliferation. Exploration of the roles of Id proteins in vascular remodelling that occurs in PAH and atherosclerosis might provide new insights into the molecular basis of these diseases. In addition, current progress in identification of the interactors of Id proteins will further the understanding of the function of Ids in vascular cells and enable the identification of novel targets for therapy in PAH and other cardiovascular diseases. PMID- 25274248 TI - Genomic profile of pseudomyxoma peritonei analyzed using next-generation sequencing and immunohistochemistry. AB - Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under-investigated disease. We extracted DNA from 19 appendix-derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer-related genes by amplicon-based next-generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low-grade and high-grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high-grade tumors as compared with low-grade ones (31.3 vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high-grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high-grade histology and reduced survival. PMID- 25274247 TI - Gene/cell therapy approaches for Immune Dysregulation Polyendocrinopathy Enteropathy X-linked syndrome. AB - Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare autoimmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of devastating autoimmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3 mutated stem cells. Potentials and hurdles of both strategies will be highlighted here. PMID- 25274249 TI - Thrombin generation in the presence of platelets is sensitive to the activation status of von Willebrand factor. PMID- 25274250 TI - Assessing the use of antiviral treatment to control influenza. AB - Vaccines are the cornerstone of influenza control policy, but can suffer from several drawbacks. Seasonal influenza vaccines are prone to production problems and low efficacies, while pandemic vaccines are unlikely to be available in time to slow a rapidly spreading global outbreak. Antiviral therapy was found to be beneficial during the influenza A(H1N1)pdm09 pandemic even with limited use; however, antiviral use has decreased further since then. We sought to determine the role antiviral therapy can play in pandemic and seasonal influenza control using conservative estimates of antiviral efficacy, and to assess if conservative but targeted strategies could be employed to optimize the use of antivirals. Using an age-structured contact network model for an urban population, we compared the transmission-blocking ability of a conservative antiviral therapy strategy to the susceptibility-reducing effects of a robust influenza vaccine. Our results show that while antiviral therapy cannot replace a robust influenza vaccine, it can play a role in reducing attack rates and eliminating outbreaks, and could significantly reduce public health burden when vaccine is either unavailable or ineffective. We also found that antiviral therapy, by treating those who are infected, is naturally a highly optimized strategy, and need not be improved upon with expensive targeted campaigns. PMID- 25274251 TI - Faecal microbiota transplantation--the Austrian approach. AB - The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Faecal microbiota transplantation (FMT) is aimed at correcting these alterations by delivering faecal microorganisms from a healthy person to the intestines of a patient. At present, recurrent Clostridium difficile infection is the only indication supported by solid scientific evidence, but many ongoing studies are investigating FMT in other dysbiosis-related diseases, such as inflammatory bowel disease. As there are no systematic methodological investigations, several questions about techniques, donor screening and safety issues remain. This shortage of evidence, especially on long-term safety concerns, is leading to worldwide controversy regarding the use of FMT. Regulations by healthcare authorities vary among different countries. This review reflects the Austrian situation and its FMT guidelines concerning indications, techniques and donor screening, recently developed by local scientific societies. PMID- 25274253 TI - A new human heart vessel identification, segmentation and 3D reconstruction mechanism. AB - BACKGROUND: The identification and segmentation of inhomogeneous image regions is one of the most challenging issues nowadays. The surface vessels of the human heart are important for the surgeons to locate the region where to perform the surgery and to avoid surgical injuries. In addition, such identification, segmentation, and visualisation helps novice surgeons in the training phase of cardiac surgery. METHODS: This article introduces a new mechanism for identifying the position of vessels leading to the performance of surgery by enhancement of the input image. In addition, develop a 3D vessel reconstruction out of a single view of a real human heart colour image obtained during open-heart surgery. RESULTS: Reduces the time required for locating the vessel region of interest (ROI). The vessel ROI must appear clearly for the surgeons. Furthermore, reduces the time required for training cardiac surgery of the novice surgeons. The 94.42% accuracy rate of the proposed vessel segmentation method using RGB colour space compares to other colour spaces. CONCLUSIONS: The advantage of this mechanism is to help the surgeons to perform surgery in less time, avoid surgical errors, and to reduce surgical effort. Moreover, the proposed technique can reconstruct the 3D vessel model from a single image to facilitate learning of the heart anatomy as well as training of cardiac surgery for the novice surgeons. Furthermore, extensive experiments have been conducted which reveal the superior performance of the proposed mechanism compared to the state of the art methods. PMID- 25274252 TI - A comparison of rigid tape and exercise, elastic tape and exercise and exercise alone on pain and lower limb function in individuals with exercise related leg pain: a randomised controlled trial. AB - BACKGROUND: Exercise related leg pain (ERLP) is a common lower limb overuse injury characterised by pain located between the knee and ankle that occurs during activity. The high incidence of the condition, subsequent interference with participation in physical activity and substantial recovery time, highlights a need for effective interventions. Whilst many interventions have been described for the management of ERLP, currently there is a lack of high quality evidence for an effective intervention for the condition. METHODS/DESIGN: A single-blinded randomised controlled clinical trial will be conducted in a community setting. Forty-five female volunteers aged between 18 and 40 years with a history of insidious onset of pain located between the knee and ankle of at least one month duration that is aggravated by weight bearing activities will be recruited for the study. Suitable participants will be randomly allocated to one of three treatment groups for the 6 week intervention period: (i) exercise only, (ii) rigid anti-pronation tape and exercise, (iii) elastic anti-pronation tape and exercise. Outcomes will be measured at baseline, 1, 2 and 6 weeks using primary outcome measures of usual and worst pain visual analogue scale and global perceived improvement. Secondary outcome measures will include Foot and Ankle Ability Measure, Patient Specific Functional Scale and amount of activity in the previous week. In addition, participants will be contacted by phone to obtain primary and secondary outcome measures at 12, 18, 24 and 30 weeks. DISCUSSION: This article describes a single-blinded randomised controlled clinical trial that will utilise high quality methodologies in accordance with CONSORT guidelines. The results of this study will contribute to the limited knowledge regarding effective interventions for the management of ERLP. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12613000914763). PMID- 25274254 TI - Proteomics in chromatin biology and epigenetics. PMID- 25274258 TI - Health technology assessment of cancer drugs in Canada, the United Kingdom and Australia: should the United States take notice? AB - Cancer remains a global problem, with 7.5 million deaths annually, making it responsible for approximately 13% of deaths from all causes. Cancer also becomes more prevalent as the population ages, making it a major health policy challenge for many countries around the world. However, the encouraging news is that the number of cancer-related deaths has stabilized in many countries. At least part of this success may be attributed to improved diagnosis, early intervention strategies and the development of a newer class of anticancer agents, collectively called "targeted therapies", that are more specific in inhibiting key pathways in tumour genesis. However, these newer drugs are associated with a higher cost. As a result, expenditures for agents and cancer in general have been rising rapidly, far beyond the rate of inflation. Some view this as threatening the very health care systems themselves, which are integral to the modern social contract. Different countries have adopted unique mechanisms to facilitate patient access to these newer agents, with the intent of ensuring value for money and sustainability. In this review, cancer care policies and mechanisms for patient access to new drugs will be discussed and compared between select countries. Given its position as a country that allows free pharmaceutical pricing and multi-payer health insurance, the USA will be the reference country and will be compared with the UK, Canada and Australia, three countries with socialized health care systems and active health technology assessment programmes. PMID- 25274260 TI - Two new ectoparasitic species of Aulacothrips Hood, 1952 (Thysanoptera: Heterothripidae) associated with ant-tended treehoppers (Hemiptera). AB - Aulacothrips Hood, 1952 is a remarkable South American genus of ectoparasitic thrips which feed on gregarious ant-tended hemipterans (Hemiptera: Auchenorrhyncha). Here we describe two new species of this genus infesting membracid treehoppers in Colombia and Brazilian Amazon, and provide a key to the five Aulacothrips spp. now recognised. Aulacothrips levinotus n. sp. is unique in having pronotum with only two pairs of major setae; and Aulacothrips tenuis n. sp. has unusually long abdominal tergite IX. These findings will be helpful for understanding the species diversification in this genus, bringing a new perspective on the diversity of Aulacothrips spp. and their myrmecophilous hemipteran hosts. PMID- 25274259 TI - Comparison of PCR methods for detection of Leishmania siamensis infection. AB - BACKGROUND: Leishmania siamensis, a newly identified species, has been reported as a causative agent of leishmaniasis in Thailand. This organism has been identified and genetically characterized using PCR techniques based on several target genes. However, the sensitivities and specificities of these methods for the diagnosis of L. siamensis infection have never been evaluated. METHODS: To evaluate the sensitivities and specificities of PCR methods to detect L. siamensis infection, PCR for different genetic markers, i.e., the small subunit ribosomal RNA region (SSU-rRNA), the internal transcribed spacer 1 region (ITS1), cysteine protease B (cpb), cytochrome b (cyt b), heat shock protein 70 (hsp70), the spliced leader mini-exon, and the triose-phosphate isomerase (tim) genes were compared. RESULTS: Both the ITS1-PCR and the SSU rRNA-PCR could detect promastigote of L. siamensis at concentrations as low as 0.05 parasites/MUl or the DNA concentration at 2.3 pg/MUl. Though the ITS1-PCR method only recognized 8 samples as positive, all of these could be assessed as true positive according to microscopic diagnosis and/or amplifying the results of the PCR and their sequencing, while other methods also produced false positive results. Compared with the ITS1-PCR method, the PCR amplified SSU-rRNA and cpb gene showed 100% sensitivity for the detection of L. siamensis in clinical specimens. The PCR amplified mini-exon and hsp70 gene also gave a high sensitivity of 87.5%. In contrast, the PCR methods for cyt b and tim gene showed low sensitivity. The PCR methods for cyt b, mini-exon and tim gene showed 100% specificity compared with the ITS1-PCR. CONCLUSION: As a result, the ITS1-PCR method is a suitable target for PCR-based detection of L. siamensis infection in clinical specimens due to its high sensitivity and specificity. The results of this study can be used for molecular diagnosis as well as in epidemiological studies of L. siamensis in affected areas. PMID- 25274261 TI - Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. AB - BACKGROUND: The aim of the current study was to estimate sex- and age-specific incidence rates of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using population-based registry data. CFS/ME is a debilitating condition with large impact on patients and their families. The etiology is unknown, and the distribution of the disease in the general population has not been well described. METHODS: Cases of CFS/ME were identified in the Norwegian Patient Register (NPR) for the years 2008 to 2012. The NPR is nationwide and contains diagnoses assigned by specialist health care services (hospitals and outpatient clinics). We estimated sex- and age-specific incidence rates by dividing the number of new cases of CFS/ME in each category by the number of person years at risk. Incidence rate ratios were estimated by Poisson regression with sex, age categories, and year of diagnosis as covariates. RESULTS: A total of 5,809 patients were registered with CFS/ME during 2008 to 2012. The overall incidence rate was 25.8 per 100,000 person years (95% confidence interval (CI): 25.2 to 26.5). The female to male incidence rate ratio of CFS/ME was 3.2 (95% CI: 3.0 to 3.4). The incidence rate varied strongly with age for both sexes, with a first peak in the age group 10 to 19 years and a second peak in the age group 30 to 39 years. CONCLUSIONS: Early etiological clues can sometimes be gained from examination of disease patterns. The strong female preponderance and the two age peaks suggest that sex- and age-specific factors may modulate the risk of CFS/ME. PMID- 25274267 TI - Dual core quantum dots for highly quantitative ratiometric detection of trypsin activity in cystic fibrosis patients. AB - We present herein two colour encoded silica nanospheres (2nanoSi) for the fluorescence quantitative ratiometric determination of trypsin in humans. Current detection methods for cystic fibrosis diagnosis are slow, costly and suffer from false positives. The 2nanoSi proved to be a highly sensitive, fast (minutes), and single-step approach nanosensor for the screening and diagnosis of cystic fibrosis, allowing the quantification of trypsin concentrations in a wide range relevant for clinical applications (25-350 MUg L(-1)). Furthermore, as trypsin is directly related to the development of cystic fibrosis (CF), different human genotypes, i.e. CF homozygotic, CF heterozygotic, and unaffected, respectively, can be determined using our 2nanoSi nanospheres. We anticipate the 2nanoSi system to be a starting point for non-invasive, easy-to-use and cost effective ratiometric fluorescent biomarkers for recessive genetic diseases like human cystic fibrosis. In a screening program in which the goal is to detect disease and also the carrier status, early diagnosis could be of great help. PMID- 25274268 TI - Total elbow arthroplasty in patient with severe von Willebrand disease. PMID- 25274266 TI - Radon balneotherapy and physical activity for osteoporosis prevention: a randomized, placebo-controlled intervention study. AB - Low-dose radon hyperthermia balneo treatment (LDRnHBT) is applied as a traditional measure in the non-pharmacological treatment of rheumatic diseases in Europe. During the last decades, the main approach of LDRnHBT was focused on the treatment of musculoskeletal disorders, but scientific evidence for the biological background of LDRnHBT is weak. Recently, evidence emerged that LDRnHBT influences bone metabolism. We investigated, whether combined LDRnHBT and exercise treatment has an impact on bone metabolism and quality of life in a study population in an age group at risk for developing osteoporosis. This randomized, double-blind, placebo-controlled trial comprised guided hiking tours and hyperthermia treatment in either radon thermal water (LDRnHBT) or radon-free thermal water (PlaceboHBT). Markers of bone metabolism, quality of life and somatic complaints were evaluated. Statistics was performed by linear regression and a linear mixed model analysis. Significant changes over time were observed for most analytes investigated as well as an improvement in self-assessed health in both groups. No significant impact from the LDRnHBT could be observed. After 6 months, the LDRnHBT group showed a slightly stronger reduction of the osteoclast stimulating protein receptor activator of nuclear kB-ligand compared to the PlaceboHBT group, indicating a possible trend. A combined hyperthermia balneo and exercise treatment has significant immediate and long-term effects on regulators of bone metabolism as well as somatic complaints. LDRnHBT and placeboHBT yielded statistically equal outcomes. PMID- 25274270 TI - A latent class method for diagnostic tests: the new, reference, gold standard problem. PMID- 25274269 TI - Intravitreal dexamethasone implant [Ozurdex] for the treatment of nonarteritic anterior ischaemic optic neuropathy. AB - PURPOSE: To evaluate structural and functional outcomes of intravitreal dexamethasone implant (IDI) in three patients presenting with nonarteritic anterior ischaemic optic neuropathy. METHODS: IDI was administered once in three patients. Best-corrected visual acuity (BCVA), perimetry, volume spectral-domain optical coherence tomography scan of the optic disc (ODV), retinal nerve fibre layer (RNFL) scan and visually evoked potential (VEP) measurements were assessed at baseline and after one and 3 months. RESULTS: Mean BCVA was 20/100 in patient 1 (patient 2: 20/100; patient 3: 20/50) at baseline, 20/60 (patient 2: 20/400) at 1 month and 20/80 (20/400; 20/60) at 3 months. Mean deviation in perimetry developed from -4.90 dB (-22.09 dB; -8.68 dB) to -7.60 dB (-30.75 dB) and -14.23 dB (-30.59 dB; -7.17 dB). ODV and RNFL decreased during follow-up. VEP measurements showed a reduction in amplitudes during the entire observation period. CONCLUSIONS: All patients showed a reduction in papilla oedema over time. A functional improvement was not observed. PMID- 25274271 TI - How well do clinicians and patients agree on depression treatment outcomes? Implications for personalized medicine. AB - OBJECTIVE: In order to inform outcomes assessments in personalized medicine research, we evaluated the level of agreement between self-reported (SR) and clinician-rated (CR) measures of depression severity before and after treatment with an antidepressant medication. METHODS: We pooled data from three trials (totaling 2075 patients) assessing the efficacy of antidepressant monotherapy in major depressive disorder. Differences between CR (17-item Hamilton Rating Scale for Depression [HAM-D17]) and SR (30-item Inventory of Depressive Symptomatology Self-Rated) scale scores were used to determine concordance between CR-SR ratings. The effect of anxiety (HAMD17 anxiety-somatization subscale score >=7) on SR-CR agreement was also assessed. RESULTS: The CR-SR scale agreement was good for response (kappa = 0.64) and moderate for remission (kappa = 0.57). Patients who rated their depression as less severe than the clinician were significantly more likely to respond to treatment than over-reporters (odds ratio = 1.62; 95% confidence interval: 1.17-2.25). Although anxiety did not impact the level of agreement, among patients with SR-CR discordance, high anxiety was associated with over-reporting of depression severity. CONCLUSION: The levels of disagreement for response and remission were too high for CR and SR scales to be considered interchangeable for research on patient-level outcomes. Anxiety does not meaningfully impact SR-CR agreement. PMID- 25274272 TI - The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy. AB - Anti-VEGF-A therapy has become a mainstay of treatment for ocular neovascularisation and in cancer; however, their effectiveness is not universal, in some cases only benefiting a minority of patients. Anti-VEGF-A therapies bind and block both pro-angiogenic VEGF-Axxx and the partial agonist VEGF-Axxxb isoforms, but their anti-angiogenic benefit only comes about from targeting the pro-angiogenic isoforms. Therefore, antibodies that exclusively target the pro angiogenic isoforms may be more effective. To determine whether C-terminal targeted antibodies could inhibit angiogenesis, we generated a polyclonal antibody to the last nine amino acids of VEGF-A165 and tested it in vitro and in vivo. The exon8a polyclonal antibody (Exon8apab) did not bind VEGF-A165b even at greater than 100-fold excess concentration, and dose dependently inhibited VEGF A165 induced endothelial migration in vitro at concentrations similar to the VEGF A antibody fragment ranibizumab. Exon8apab can inhibit tumour growth of LS174t cells implanted in vivo and blood vessel growth in the eye in models of age related macular degeneration, with equal efficacy to non-selective anti-VEGF-A antibodies. It also showed that it was the VEGF-Axxx levels specifically that were upregulated in plasma from patients with proliferative diabetic retinopathy. These results suggest that VEGF-A165-specific antibodies can be therapeutically useful. PMID- 25274273 TI - Unguided species delimitation using DNA sequence data from multiple Loci. AB - A method was developed for simultaneous Bayesian inference of species delimitation and species phylogeny using the multispecies coalescent model. The method eliminates the need for a user-specified guide tree in species delimitation and incorporates phylogenetic uncertainty in a Bayesian framework. The nearest-neighbor interchange algorithm was adapted to propose changes to the species tree, with the gene trees for multiple loci altered in the proposal to avoid conflicts with the newly proposed species tree. We also modify our previous scheme for specifying priors for species delimitation models to construct joint priors for models of species delimitation and species phylogeny. As in our earlier method, the modified algorithm integrates over gene trees, taking account of the uncertainty of gene tree topology and branch lengths given the sequence data. We conducted a simulation study to examine the statistical properties of the method using six populations (two sequences each) and a true number of three species, with values of divergence times and ancestral population sizes that are realistic for recently diverged species. The results suggest that the method tends to be conservative with high posterior probabilities being a confident indicator of species status. Simulation results also indicate that the power of the method to delimit species increases with an increase of the divergence times in the species tree, and with an increased number of gene loci. Reanalyses of two data sets of cavefish and coast horned lizards suggest considerable phylogenetic uncertainty even though the data are informative about species delimitation. We discuss the impact of the prior on models of species delimitation and species phylogeny and of the prior on population size parameters (theta) on Bayesian species delimitation. PMID- 25274274 TI - Giant pandas are not an evolutionary cul-de-sac: evidence from multidisciplinary research. AB - The giant panda (Ailuropoda melanoleuca) is one of the world's most endangered mammals and remains threatened by environmental and anthropogenic pressure. It is commonly argued that giant pandas are an evolutionary cul-de-sac because of their specialized bamboo diet, phylogenetic changes in body size, small population, low genetic diversity, and low reproductive rate. This notion is incorrect, arose from a poor understanding or appreciation of giant panda biology, and is in need of correction. In this review, we summarize research across morphology, ecology, and genetics to dispel the idea, once and for all, that giant pandas are evolutionary dead-end. The latest and most advanced research shows that giant pandas are successful animals highly adapted to a specialized bamboo diet via morphological, ecological, and genetic adaptations and coadaptation of gut microbiota. We also debunk misconceptions around population size, population growth rate, and genetic variation. During their evolutionary history spanning 8 My, giant pandas have survived diet specialization, massive bamboo flowering and die off, and rapid climate oscillations. Now, they are suffering from enormous human interference. Fortunately, continued conservation effort is greatly reducing impacts from anthropogenic interference and allowing giant panda populations and habitat to recover. Previous ideas of a giant panda evolutionary cul-de-sac resulted from an unsystematic and unsophisticated understanding of their biology and it is time to shed this baggage and focus on the survival and maintenance of this high-profile species. PMID- 25274275 TI - Women's secure hospital care pathways in practice: a qualitative analysis of clinicians views in England and Wales. AB - BACKGROUND: In England and Wales women form a small but significant group within the wider, largely male, secure hospital population. Secure hospitals are designed to assess and treat individuals with both mental health problems and significant criminal behaviour. The theoretical approach to the care of secure hospital women is increasingly informed by a grasp of gender-specific issues. However, there is a lack of evidence on the adequacy of current structures and processes of care delivery. METHODS: This qualitative study explores the nature and quality of care pathways for women in low and medium secure hospital beds by eliciting participants' views of factors enhancing or impeding care. Beds are publicly funded and provided either by the National Health Service (NHS) or the Independent Sector (IS). Participants from both sectors were local experts (40 Consultant Psychiatrists, 7 Service Managers) who were well placed to describe their immediate health environment. RESULTS: Evidence from the study indicates that participants were focused on the physical relocation of women to less secure conditions, even though many women do not readily achieve this.Participants were alert to potential conflicts between ideal care and affordable care. Ideal care was compromised by the absence of suitable local services (beds or community placements), curtailed episodes of care and changes of care team. It was promoted by an awareness of the specific needs of women, continuity of care and support for teams unfamiliar with women's needs. CONCLUSION: Future service design must address these challenges in care delivery, incorporating a better understanding of and response to the ways the system can echo women's experiences of trauma and their negative attachment histories. Specifically, critical transitions in care must not be allowed to further reinforce the discontinuity, failure and rejection experienced by individual women earlier in their lives. PMID- 25274276 TI - SEOM clinical guidelines for the treatment of renal cell carcinoma. AB - The purpose of this article was to provide updated recommendations for the diagnosis and treatment of renal cell carcinoma. Pathological confirmation is mandatory before treatment with ablative or focal therapies before any type of systemic therapy. Renal cell cancer should be staged according to the TNM classification system. A laparoscopic nephron-sparing surgery should be the approach for tumors <4 cm if technically feasible. Otherwise, radical (or partial in selected cases) nephrectomy is the treatment of choice, with lymph node dissection only performed in patients with clinically detected lymph node involvement. Some retrospective evidence for a cytoreductive nephrectomy in the postimmunotherapy era suggests a benefit in patients with good or intermediate risk or for patients with a symptomatic primary lesion. Adjuvant treatment with chemotherapy or with targeted agents is not recommended and studies are ongoing today. Patients with metastatic disease should be staged by computed tomography scans of the chest, abdomen and pelvis. The efficacy of sunitinib, bevacizumab plus interferon-alpha, and pazopanib is well established in patients with good and intermediate risk as well for temsirolimus in poor-risk patients. These four agents are considered standard of care in first-line treatment. Sorafenib, axitinib and everolimus are standard of care in second line in different settings based on their benefit in PFS. Besides some benefit described for IL-2 in highly selected patients in first line, there is a promising and emerging role for the new immunotherapeutic approaches in metastatic renal cell carcinoma. PMID- 25274278 TI - Intrinsic and interfacial effect of electrode metals on the resistive switching behaviors of zinc oxide films. AB - Exploring the role of electrode metals on the resistive switching properties of metal electrode/oxide/metal electrode sandwiched structures provides not only essential information to understand the underlying switching mechanism of the devices, but also useful guidelines for the optimization of the switching performance. A systematic study has been performed to investigate the influence of electrodes on the resistive switching characteristics of zinc oxide (ZnO) films in this contribution, in terms of both the intrinsic and interfacial effects. It has been found that the low-resistance state resistances (Omega(LRS)) of all the investigated devices are below 50 Omega, which can be attributed to the formation of highly conductive channels throughout the ZnO films. On the other hand, the high-resistance state resistances (Omega(HRS)) depend on the electronegativity and ionic size of the employed electrode metals. Devices with electrode metals of high electronegativity and large ionic size possess high Omega(HRS) values, while those with electrode metals of low electronegativity and small ionic size carry low Omega(HRS) values. A similar trend of the set voltages has also been observed, while the reset voltages are all distributed in a narrow range close to +/-0.5 V. Moreover, the forming voltages of the switching devices strongly depend on the roughness of the metal/ZnO and/or ZnO/metal interface. The present work provides essential information for better understanding the switching mechanism of zinc oxide based devices, and benefits the rational selection of proper electrode metals for the device performance optimization. PMID- 25274277 TI - The kynurenine pathway is involved in bacterial meningitis. AB - BACKGROUND: Bacterial meningitis (BM) is characterized by an intense host inflammatory reaction, which contributes to the development of brain damage and neuronal sequelae. Activation of the kynurenine (KYN) pathway (KP) has been reported in various neurological diseases as a consequence of inflammation. Previously, the KP was shown to be activated in animal models of BM, and the association of the SNP AADAT + 401C/T (kynurenine aminotransferase II - KAT II) with the host immune response to BM has been described. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups. METHODS: The concentrations of tryptophan (TRP), KYN, kynurenic acid (KYNA) and anthranilic acid (AA) were assessed by HPLC from CSF samples of patients hospitalized in the Giselda Trigueiro Hospital in Natal (Rio Grande do Norte, Brazil). The KYN/TRP ratio was used as an index of indoleamine 2,3-dioxygenase (IDO) activity, and cytokines were measured using a multiplex cytokine assay. The KYNA level was also analyzed in relation to AADAT + 401C/T genotypes. RESULTS: In CSF from patients with BM, elevated levels of KYN, KYNA, AA, IDO activity and cytokines were observed. The cytokines INF-gamma and IL-1Ra showed a positive correlation with IDO activity, and TNF-alpha and IL-10 were positively correlated with KYN and KYNA, respectively. Furthermore, the highest levels of KYNA were associated with the AADAT + 401 C/T variant allele. CONCLUSION: This study suggests a downward modulatory effect of the KP on CSF inflammation during BM. PMID- 25274279 TI - Exotic pets - are we serving them well? PMID- 25274280 TI - Dynamics of energy transfer and soft-landing in collisions of protonated dialanine with perfluorinated self-assembled monolayer surfaces. AB - Chemical dynamics simulations are reported which provide atomistic details of collisions of protonated dialanine, ala2-H(+), with a perfluorinated octanethiolate self-assembled monolayer (F-SAM) surface. The simulations are performed at collision energies Ei of 5.0, 13.5, 22.5, 30.00, and 70 eV, and incident angles 0 degrees (normal) and 45 degrees (grazing). Excellent agreement with experiment (J. Am. Chem. Soc., 2000, 122, 9703-9714) is found for both the average fraction and distribution of the collision energy transferred to the ala2-H(+) internal degrees of freedom. The dominant pathway for this energy transfer is to ala2-H(+) vibration, but for Ei = 5.0 eV ~20% of the energy transfer is to ala2-H(+) rotation. Energy transfer to ala2-H(+) rotation decreases with increase in Ei and becomes negligible at high Ei. Three types of collisions are observed in the simulations: i.e. those for which ala2-H(+) (1) directly scatters off the F-SAM surface; (2) sticks/physisorbs on/in the surface, but desorbs within the 10 ps numerical integration of the simulations; and (3) remains trapped (i.e. soft-landed) on/in the surface when the simulations are terminated. Penetration of the F-SAM by ala2-H(+) is important for the latter two types of events. The trapped trajectories are expected to have relatively long residence times on the surface, since a previous molecular dynamics simulation (J. Phys. Chem. B, 2014, 118, 5577-5588) shows that thermally accommodated ala2 H(+) ions have an binding energy with the F-SAM surface of at least ~15 kcal mol( 1). PMID- 25274281 TI - Effect of ibandronate therapy on serum homocysteine and leptin in postmenopausal osteoporotic females. AB - A significant change in serum leptin level and no change in homocysteine were observed with ibandronate treatment. No correlation of homocysteine and leptin was found with bone mass density (BMD). Results indicate that ibandronate reduces serum leptin levels but how does it help in reducing the osteoporosis. It needs to be explored. INTRODUCTION: The current study was planned to determine the effects of ibandronate on serum homocysteine and leptin levels in postmenopausal osteoporotic females and to correlate these with BMD. METHODS: Forty-two newly diagnosed and untreated postmenopausal osteoporotic females were selected on the basis of their BMD (BMD < -2.5) from Orthopaedic Out Patient Department of Shaikh Zayed Hospital, Lahore, Pakistan, and 36, age and BMI matched non-osteoporotic postmenopausal females, were also selected as a control group. Baseline physical and biochemical parameters were compared. In osteoporotic patients, changes in circulating leptin and homocysteine levels were studied after 6 months of therapy with ibandronate (150 mg). The collected data were analyzed on SPSS 16. RESULTS: There was no significant difference observed in the mean value of all baseline parameters except BMD in both groups. After 6 months of treatment with ibandronate (150 mg), a significant change was observed in serum leptin levels (19.48 +/- 1.60 ng/ml vs. 14.09 +/- 0.85 ng/ml, p < 0.002), while no considerable change observed in serum homocysteine levels (16.22 +/- 0.95 MUmol/l vs. 16.80 +/ 1.03 MUmol/l, p < 0.63). Serum leptin was found significantly correlated with anthropometric parameters. No correlation of serum leptin and homocysteine was found with BMD (r = 0.09, p value = 0.54; r = -0.17, p value = 0.27). CONCLUSION: Our results show that ibandronate reduces serum leptin levels while it has no effect on serum homocysteine levels. Further studies are needed to explain how the decrease in serum leptin level may help in reducing the progression of osteoporosis. PMID- 25274282 TI - A quantum fidelity study of the anisotropic next-nearest-neighbour triangular lattice Heisenberg model. AB - Ground- and excited-state quantum fidelities in combination with generalized quantum fidelity susceptibilites, obtained from exact diagonalizations, are used to explore the phase diagram of the anisotropic next-nearest-neighbour triangular Heisenberg model. Specifically, the J'-J2 plane of this model, which connects the J1-J2 chain and the anisotropic triangular lattice Heisenberg model, is explored using these quantities. Through the use of a quantum fidelity associated with the first excited-state, in addition to the conventional ground-state fidelity, the BKT-type transition and Majumdar-Ghosh point of the J1-J2 chain (J'=0) are found to extend into the J'-J2 plane and connect with points on the J2=0 axis thereby forming bounded regions in the phase diagram. These bounded regions are then explored through the generalized quantum fidelity susceptibilities chirho, chi120 degrees , chiD and chiCAF which are associated with the spin stiffness, 120 degrees spiral order parameter, dimer order parameter and collinear antiferromagnetic order parameter respectively. These quantities are believed to be extremely sensitive to the underlying phase and are thus well suited for finite-size studies. Analysis of the fidelity susceptibilities suggests that the J', J2?J phase of the anisotropic triangular model is either a collinear antiferromagnet or possibly a gapless disordered phase that is directly connected to the Luttinger phase of the J1-J2 chain. Furthermore, the outer region is dominated by incommensurate spiral physics as well as dimer order. PMID- 25274284 TI - On the relationship between the causal-inference and meta-analytic paradigms for the validation of surrogate endpoints. AB - The increasing cost of drug development has raised the demand for surrogate endpoints when evaluating new drugs in clinical trials. However, over the years, it has become clear that surrogate endpoints need to be statistically evaluated and deemed valid, before they can be used as substitutes of "true" endpoints in clinical studies. Nowadays, two paradigms, based on causal-inference and meta analysis, dominate the scene. Nonetheless, although the literature emanating from these paradigms is wide, till now the relationship between them has largely been left unexplored. In the present work, we discuss the conceptual framework underlying both approaches and study the relationship between them using theoretical elements and the analysis of a real case study. Furthermore, we show that the meta-analytic approach can be embedded within a causal-inference framework on the one hand and that it can be heuristically justified why surrogate endpoints successfully evaluated using this approach will often be appealing from a causal-inference perspective as well, on the other. A newly developed and user friendly R package Surrogate is provided to carry out the evaluation exercise. PMID- 25274283 TI - Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction. AB - BACKGROUND: Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors. METHODS: NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software. RESULTS: Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-alpha and IFN-gamma); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function. CONCLUSIONS: Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer. PMID- 25274289 TI - Sensitization of ZnO single crystal electrodes with CdSe quantum dots. AB - CdSe quantum dots (QDs) were attached to single crystal ZnO(0001) and ZnO(1100) substrates using capping groups, 4-mercaptobenzoic acid, 2-mercaptoacetic acid, 3 mercaptopropionic acid, 8-mercaptooctanoic acid, and 11-mercaptoundecanoic acid, as bifunctional linker molecules. The spectral response and photosensitization yields of the adsorbed QDs were studied with photocurrent spectroscopy. Atomic force microscopy (AFM) was used to verify the surface structure of the ZnO crystals and to examine the coverage and arrangement of the QDs on the single crystal surface. The inner-sphere aqueous redox couple Sx(2-)/S(2-), often used as a regenerator for chalcogenide-based QDs, as well as outer-sphere redox couples such as ferrocene, were able to regenerate the photoexcited CdSe QDs and suppress their photocorrosion. Differences in the binding of the QDs to different ZnO crystal faces are also reported. PMID- 25274285 TI - The Effects of Linguistic Context on Word Recognition in Noise by Elderly Listeners Using Spanish Sentence Lists (SSL). AB - This study evaluated the effects of the linguistic context on the recognition of words in noise in older listeners using the Spanish Sentence Lists. These sentences were developed based on the approach of the SPIN test for the English language, which contains high and low predictability (HP and LP) sentences. In addition, the relative contribution of peripheral hearing sensitivity, measured by pure-tone hearing thresholds (PTA), to the performance on both types of sentences was assessed in a regression analysis. The results showed that older listeners obtained benefits on word recognition from the linguistic context. PTA contributed significantly to explaining the variance in performance on both HP and LP sentences. PMID- 25274290 TI - Cerebral oxygenation measurement in preterm neonates by various devices. PMID- 25274292 TI - Editorial introduction. PMID- 25274291 TI - Nebulised N-acetylcysteine used in acute tracheostoma obstruction. AB - BACKGROUND: Patients with laryngectomy tracheostomas are at risk of developing acute airway obstruction due to mucous crusting. Current management relies on saline nebulisers, followed by suction and manual evacuation to remove the obstruction. This paper describes the first reported case of using N acetylcysteine nebulisers in addition to saline to adequately soften the mucous plugs in order to facilitate removal. CASE REPORT: A 68-year-old female attended the emergency department with a partial obstruction of her laryngectomy tracheostoma as a result of mucous crusting. Saline nebulisers did not provide adequate softening to allow the obstructing mucous plugs to be removed. N acetylcysteine nebulisers were used to further soften the mucous plugs which successfully resulted in their removal. CONCLUSION: N-acetylcysteine nebulisers can be used to assist in the removal of mucous plugs in saline-resistant cases. PMID- 25274295 TI - Acid-fast bacilli culture positivity and drug resistance in abdominal tuberculosis. PMID- 25274294 TI - Iodine intake and status of UK women of childbearing age recruited at the University of Surrey in the winter. AB - As intra-thyroidal iodine stores should be maximised before conception to facilitate the increased thyroid hormone production during pregnancy, women who are planning to become pregnant should ideally consume 150 MUg iodine/d (US RDA). As few UK data exist for this population group, a cross-sectional study was carried out at the University of Surrey to assess the iodine intake and status of women of childbearing age. Total iodine excretion was measured from 24 h urine samples in fifty-seven women; iodine intake was estimated by assuming that 90 % of ingested iodine was excreted. The average iodine intake was also estimated from 48 h food diaries that the participants completed. The median urinary iodine concentration value (63.1 MUg/l) indicated the group to be mildly iodine deficient by WHO criteria. By contrast, the median 24 h urinary iodine excretion value (149.8 MUg/24 h) indicated a relatively low risk of iodine deficiency. The median estimated iodine intake, extrapolated from urinary excretion, was 167 MUg/d, whereas it was lower, at 123 MUg/d, when estimated from the 48 h food diaries. Iodine intake estimated from the food diaries and 24 h urinary iodine excretion were strongly correlated (r 0.75, P< 0.001). The intake of milk, eggs and dairy products was positively associated with iodine status. The iodine status of this UK cohort is probably a best-case scenario as the women were mostly nutrition students and were recruited in the winter when milk-iodine content is at its highest; further study in more representative cohorts of UK women is required. The present study highlights the need for revised cut-off values for iodine deficiency that are method- and age group-specific. PMID- 25274296 TI - Gut-liver axis and disease infidelity: a subject worth exploring. PMID- 25274298 TI - Immunology: Starve a fever, feed the microbiota. PMID- 25274299 TI - Evolutionary biology: Survival of the fittest group. PMID- 25274297 TI - Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. AB - Systemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid alpha(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host-microbial interactions during pathogen-induced stress. PMID- 25274300 TI - The genetics of monarch butterfly migration and warning colouration. AB - The monarch butterfly, Danaus plexippus, is famous for its spectacular annual migration across North America, recent worldwide dispersal, and orange warning colouration. Despite decades of study and broad public interest, we know little about the genetic basis of these hallmark traits. Here we uncover the history of the monarch's evolutionary origin and global dispersal, characterize the genes and pathways associated with migratory behaviour, and identify the discrete genetic basis of warning colouration by sequencing 101 Danaus genomes from around the globe. The results rewrite our understanding of this classic system, showing that D. plexippus was ancestrally migratory and dispersed out of North America to occupy its broad distribution. We find the strongest signatures of selection associated with migration centre on flight muscle function, resulting in greater flight efficiency among migratory monarchs, and that variation in monarch warning colouration is controlled by a single myosin gene not previously implicated in insect pigmentation. PMID- 25274301 TI - Pulmonary macrophage transplantation therapy. AB - Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ targeted, cell-specific therapy. Here, using granulocyte-macrophage colony stimulating factor (GM-CSF) receptor-beta-deficient (Csf2rb(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP. PMID- 25274303 TI - Lung disease: Treatment by cell transplant. PMID- 25274302 TI - Programmable RNA recognition and cleavage by CRISPR/Cas9. AB - The CRISPR-associated protein Cas9 is an RNA-guided DNA endonuclease that uses RNA-DNA complementarity to identify target sites for sequence-specific double stranded DNA (dsDNA) cleavage. In its native context, Cas9 acts on DNA substrates exclusively because both binding and catalysis require recognition of a short DNA sequence, known as the protospacer adjacent motif (PAM), next to and on the strand opposite the twenty-nucleotide target site in dsDNA. Cas9 has proven to be a versatile tool for genome engineering and gene regulation in a large range of prokaryotic and eukaryotic cell types, and in whole organisms, but it has been thought to be incapable of targeting RNA. Here we show that Cas9 binds with high affinity to single-stranded RNA (ssRNA) targets matching the Cas9-associated guide RNA sequence when the PAM is presented in trans as a separate DNA oligonucleotide. Furthermore, PAM-presenting oligonucleotides (PAMmers) stimulate site-specific endonucleolytic cleavage of ssRNA targets, similar to PAM-mediated stimulation of Cas9-catalysed DNA cleavage. Using specially designed PAMmers, Cas9 can be specifically directed to bind or cut RNA targets while avoiding corresponding DNA sequences, and we demonstrate that this strategy enables the isolation of a specific endogenous messenger RNA from cells. These results reveal a fundamental connection between PAM binding and substrate selection by Cas9, and highlight the utility of Cas9 for programmable transcript recognition without the need for tags. PMID- 25274304 TI - Animal behaviour: Incipient tradition in wild chimpanzees. PMID- 25274305 TI - An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. AB - Throughout evolution primate genomes have been modified by waves of retrotransposon insertions. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. In mouse embryonic stem cells, transcriptional silencing of retrotransposons requires KAP1 (also known as TRIM28) and its repressive complex, which can be recruited to target sites by KRAB zinc-finger (KZNF) proteins such as murine-specific ZFP809 which binds to integrated murine leukaemia virus DNA elements and recruits KAP1 to repress them. KZNF genes are one of the fastest growing gene families in primates and this expansion is hypothesized to enable primates to respond to newly emerged retrotransposons. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA) and long interspersed nuclear element 1 (L1), is unknown. Here we show that two primate-specific KZNF genes rapidly evolved to repress these two distinct retrotransposon families shortly after they began to spread in our ancestral genome. ZNF91 underwent a series of structural changes 8-12 million years ago that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until ~12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93's restriction through the removal of the ZNF93 binding site. Our data support a model where KZNF gene expansion limits the activity of newly emerged retrotransposon classes, and this is followed by mutations in these retrotransposons to evade repression, a cycle of events that could explain the rapid expansion of lineage-specific KZNF genes. PMID- 25274306 TI - Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. AB - Metazoans identify and eliminate bacterial pathogens in microbe-rich environments such as the intestinal lumen; however, the mechanisms are unclear. Host cells could potentially use intracellular surveillance or stress response programs to detect pathogens that target monitored cellular activities and then initiate innate immune responses. Mitochondrial function is evaluated by monitoring mitochondrial protein import efficiency of the transcription factor ATFS-1, which mediates the mitochondrial unfolded protein response (UPR(mt)). During mitochondrial stress, mitochondrial import is impaired, allowing ATFS-1 to traffic to the nucleus where it mediates a transcriptional response to re establish mitochondrial homeostasis. Here we examined the role of ATFS-1 in Caenorhabditis elegans during pathogen exposure, because during mitochondrial stress ATFS-1 induced not only mitochondrial protective genes but also innate immune genes that included a secreted lysozyme and anti-microbial peptides. Exposure to the pathogen Pseudomonas aeruginosa caused mitochondrial dysfunction and activation of the UPR(mt). C. elegans lacking atfs-1 were susceptible to P. aeruginosa, whereas hyper-activation of ATFS-1 and the UPR(mt) improved clearance of P. aeruginosa from the intestine and prolonged C. elegans survival in a manner mainly independent of known innate immune pathways. We propose that ATFS-1 import efficiency and the UPR(mt) is a means to detect pathogens that target mitochondria and initiate a protective innate immune response. PMID- 25274308 TI - Genomics: Of monarchs and migration. PMID- 25274307 TI - Loss of signalling via Galpha13 in germinal centre B-cell-derived lymphoma. AB - Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Galpha12 and Galpha13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Galpha13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Galpha13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Galpha13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Galpha13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Galpha13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Galpha13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Galpha13. These findings identify a Galpha13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma. PMID- 25274310 TI - Site-specific group selection drives locally adapted group compositions. AB - Group selection may be defined as selection caused by the differential extinction or proliferation of groups. The socially polymorphic spider Anelosimus studiosus exhibits a behavioural polymorphism in which females exhibit either a 'docile' or 'aggressive' behavioural phenotype. Natural colonies are composed of a mixture of related docile and aggressive individuals, and populations differ in colonies' characteristic docile:aggressive ratios. Using experimentally constructed colonies of known composition, here we demonstrate that population-level divergence in docile:aggressive ratios is driven by site-specific selection at the group level--certain ratios yield high survivorship at some sites but not others. Our data also indicate that colonies responded to the risk of extinction: perturbed colonies tended to adjust their composition over two generations to match the ratio characteristic of their native site, thus promoting their long term survival in their natal habitat. However, colonies of displaced individuals continued to shift their compositions towards mixtures that would have promoted their survival had they remained at their home sites, regardless of their contemporary environment. Thus, the regulatory mechanisms that colonies use to adjust their composition appear to be locally adapted. Our data provide experimental evidence of group selection driving collective traits in wild populations. PMID- 25274309 TI - Dietary modulation of the microbiome affects autoinflammatory disease. AB - The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1beta (IL 1beta) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1beta production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL 1beta-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1beta expression in distant neutrophils. Furthermore, pro-IL-1beta expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1beta-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1beta and osteomyelitis in Pstpip2(cmo) mice. PMID- 25274313 TI - Does the stigma of mental illness contribute to suicidality? AB - Mental disorders are associated with suicidality and with stigma. Many consequences of stigma, such as social isolation, unemployment, hopelessness or stress, are risk factors for suicidality. Research is needed on the link between stigma and suicidality as well as on anti-stigma interventions and their effects on suicidality. PMID- 25274311 TI - High winter ozone pollution from carbonyl photolysis in an oil and gas basin. AB - The United States is now experiencing the most rapid expansion in oil and gas production in four decades, owing in large part to implementation of new extraction technologies such as horizontal drilling combined with hydraulic fracturing. The environmental impacts of this development, from its effect on water quality to the influence of increased methane leakage on climate, have been a matter of intense debate. Air quality impacts are associated with emissions of nitrogen oxides (NOx = NO + NO2) and volatile organic compounds (VOCs), whose photochemistry leads to production of ozone, a secondary pollutant with negative health effects. Recent observations in oil- and gas-producing basins in the western United States have identified ozone mixing ratios well in excess of present air quality standards, but only during winter. Understanding winter ozone production in these regions is scientifically challenging. It occurs during cold periods of snow cover when meteorological inversions concentrate air pollutants from oil and gas activities, but when solar irradiance and absolute humidity, which are both required to initiate conventional photochemistry essential for ozone production, are at a minimum. Here, using data from a remote location in the oil and gas basin of northeastern Utah and a box model, we provide a quantitative assessment of the photochemistry that leads to these extreme winter ozone pollution events, and identify key factors that control ozone production in this unique environment. We find that ozone production occurs at lower NOx and much larger VOC concentrations than does its summertime urban counterpart, leading to carbonyl (oxygenated VOCs with a C = O moiety) photolysis as a dominant oxidant source. Extreme VOC concentrations optimize the ozone production efficiency of NOx. There is considerable potential for global growth in oil and gas extraction from shale. This analysis could help inform strategies to monitor and mitigate air quality impacts and provide broader insight into the response of winter ozone to primary pollutants. PMID- 25274312 TI - The CarERF genes in chickpea (Cicer arietinum L.) and the identification of CarERF116 as abiotic stress responsive transcription factor. AB - The AP2/ERF family is one of the largest transcription factor gene families that are involved in various plant processes, especially in response to biotic and abiotic stresses. Complete genome sequences of one of the world's most important pulse crops chickpea (Cicer arietinum L.), has provided an important opportunity to identify and characterize genome-wide ERF genes. In this study, we identified 120 putative ERF genes from chickpea. The genomic organization of the chickpea ERF genes suggested that the gene family might have been expanded through the segmental duplications. The 120 member ERF family was classified into eleven distinct groups (I-X and VI-L). Transcriptional factor CarERF116, which is differentially expressed between drought tolerant and susceptible chickpea cultivar under terminal drought stress has been identified and functionally characterized. The CarERF116 encodes a putative protein of 241 amino acids and classified into group IX of ERF family. An in vitro CarERF116 protein-DNA binding assay demonstrated that CarERF116 protein specifically interacts with GCC box. We demonstrate that CarERF116 is capable of transactivation activity of and show that the functional transcriptional domain lies at the C-terminal region of the CarERF116. In transgenic Arabidopsis plants overexpressing CarERF116, significant up-regulation of several stress related genes were observed. These plants also exhibit resistance to osmotic stress and reduced sensitivity to ABA during seed germination. Based on these findings, we conclude that CarERF116 is an abiotic stress responsive gene, which plays an important role in stress tolerance. In addition, the present study leads to genome-wide identification and evolutionary analyses of chickpea ERF gene family, which will facilitate further research on this important group of genes and provides valuable resources for comparative genomics among the grain legumes. PMID- 25274314 TI - Excess of non-right-handedness in schizophrenia: meta-analysis of gender effects and potential biases in handedness assessment. AB - BACKGROUND: The notion that schizophrenia is characterised by increased non-right handedness is a cornerstone of the theory that schizophrenia arises from, and is genetically linked to, abnormal brain lateralisation. Reviews and meta-analyses have reported higher rates of non-right-handers in patients with schizophrenia. However, this was suggested to be the result of a gender artefact or a hidden bias in self-report handedness questionnaires. AIMS: To investigate using a meta analytical approach whether the excess of non-right-handedness is seen in both females and males, and also when handedness is assessed behaviourally. METHOD: Electronic databases were searched for studies that reported (a) the rate of female and male non-right-handers in schizophrenia compared with controls and (b) the rate of non-right-handers in schizophrenia (regardless of gender) based on behavioural handedness assessment. RESULTS: The odds ratios (ORs) for females (OR = 1.63; based on 621 patients, 3747 controls) and males (OR = 1.50; based on 1213 patients, 3800 controls) differed significantly from 1.0, indicating both female and male patients were more often non-right-handed than controls. Moreover, there was an excess of non-right-handedness in patients with schizophrenia when handedness was assessed behaviourally: OR = 1.84 (1255 patients, 6260 controls). Even when both gender and behavioural handedness assessment were controlled for simultaneously, the excess of non-right-handedness persisted. CONCLUSIONS: The findings clearly demonstrate that the excess of non-right-handedness in schizophrenia does not result from a gender artefact or from biased handedness questionnaires. It is a true empirical effect and may indeed reflect a genetic link between schizophrenia and brain lateralisation. PMID- 25274315 TI - Psychotherapy for subclinical depression: meta-analysis. AB - BACKGROUND: There is controversy about whether psychotherapies are effective in the treatment of subclinical depression, defined by clinically relevant depressive symptoms in the absence of a major depressive disorder. AIMS: To examine whether psychotherapies are effective in reducing depressive symptoms, reduce the risk of developing major depressive disorder and have comparable effects to psychological treatment of major depression. METHOD: We conducted a meta-analysis of 18 studies comparing a psychological treatment of subclinical depression with a control group. RESULTS: The target groups, therapies and characteristics of the included studies differed considerably from each other, and the quality of many studies was not optimal. Psychotherapies did have a small to moderate effect on depressive symptoms against care as usual at the post-test assessment (g = 0.35, 95% CI 0.23-0.47; NNT = 5, 95% CI 4-8) and significantly reduced the incidence of major depressive episodes at 6 months (RR = 0.61) and possibly at 12 months (RR = 0.74). The effects were significantly smaller than those of psychotherapy for major depressive disorder and could be accounted for by non-specific effects of treatment. CONCLUSIONS: Psychotherapy may be effective in the treatment of subclinical depression and reduce the incidence of major depression, but more high-quality research is needed. PMID- 25274316 TI - Invited commentary on . . . Psychiatric resilience: longitudinal twin study. AB - The study of resilience may lead to the identification of new targets for prevention and intervention, yet there has been little research on why some people, but not others, show resilience after facing stressful life events. New research in this issue shows that resilience is equally explained by genetic and environmental influences, and that individual experiences and situational factors are both important in shaping resilient responses to stress. These findings could inform the development of interventions that enhance psychiatric resilience after exposure to adversity. PMID- 25274317 TI - A nuanced perspective? PMID- 25274318 TI - Authors' reply. PMID- 25274321 TI - Profile: Frans Van de Werf, MD, PhD, FESC, FACC, FAHA. PMID- 25274320 TI - Kaleidoscope. PMID- 25274322 TI - Tactile localization training for pain, sensory disturbance, and distorted body image: a case study of complex regional pain syndrome. AB - This report presents a case of complex regional pain syndrome. The patient presented with severe pain, sensory disturbance, and distorted body image at the site of initial injury and other body sites. Tactile localization training (TLT) at only the site of initial injury decreased severe pain at the site of initial injury and the secondary affected sites, whereas TLT at secondary affected sites had no effect. These results highlighted the importance of assessing changes in patients' pain processes to determine the part of the body where TLT should be applied. PMID- 25274323 TI - High or low dietary carbohydrate:protein ratios during first-feeding affect glucose metabolism and intestinal microbiota in juvenile rainbow trout. AB - Based on the concept of nutritional programming in mammals, we tested whether an acute hyperglucidic-hypoproteic stimulus during first feeding could induce long term changes in nutrient metabolism in rainbow trout. Trout alevins received during the five first days of exogenous feeding either a hyperglucidic (40% gelatinized starch + 20% glucose) and hypoproteic (20%) diet (VLP diet) or a high protein (60%) glucose-free diet (HP diet, control). Following a common 105-day period on a commercial diet, both groups were then challenged (65 days) with a carbohydrate-rich diet (28%). Short- and long-term effects of the early stimuli were evaluated in terms of metabolic marker gene expressions and intestinal microbiota as initial gut colonisation is essential for regulating the development of the digestive system. In whole alevins (short term), diet VLP relative to HP rapidly increased gene expressions of glycolytic enzymes, while those involved in gluconeogenesis and amino acid catabolism decreased. However, none of these genes showed persistent molecular adaptation in the liver of challenged juveniles (long term). By contrast, muscle of challenged juveniles subjected previously to the VLP stimulus displayed downregulated expression of markers of glycolysis and glucose transport (not seen in the short term). These fish also had higher plasma glucose (9 h postprandial), suggesting impaired glucose homeostasis induced by the early stimulus. The early stimulus did not modify the expression of the analysed metabolism-related microRNAs, but had short and long-term effects on intestinal fungi (not bacteria) profiles. In summary, our data show that a short hyperglucidic-hypoproteic stimulus during early life may have a long-term influence on muscle glucose metabolism and intestinal microbiota in trout. PMID- 25274324 TI - Food searching behaviour of a Lepidoptera pest species is modulated by the foraging gene polymorphism. AB - The extent of damage to crop plants from pest insects depends on the foraging behaviour of the insect's feeding stage. Little is known, however, about the genetic and molecular bases of foraging behaviour in phytophagous pest insects. The foraging gene (for), a candidate gene encoding a PKG-I, has an evolutionarily conserved function in feeding strategies. Until now, for had never been studied in Lepidoptera, which includes major pest species. The cereal stem borer Sesamia nonagrioides is therefore a relevant species within this order with which to study conservation of and polymorphism in the for gene, and its role in foraging a behavioural trait that is directly associated with plant injuries. Full sequencing of for cDNA in S. nonagrioides revealed a high degree of conservation with other insect taxa. Activation of PKG by a cGMP analogue increased larval foraging activity, measured by how frequently larvae moved between food patches in an actimeter. We found one non-synonymous allelic variation in a natural population that defined two allelic variants. These variants presented significantly different levels of foraging activity, and the behaviour was positively correlated to gene expression levels. Our results show that for gene function is conserved in this species of Lepidoptera, and describe an original case of a single nucleotide polymorphism associated with foraging behaviour variation in a pest insect. By illustrating how variation in this single gene can predict phenotype, this work opens new perspectives into the evolutionary context of insect adaptation to plants, as well as pest management. PMID- 25274325 TI - Gluing the 'unwettable': soil-dwelling harvestmen use viscoelastic fluids for capturing springtails. AB - Gluing can be a highly efficient mechanism of prey capture, as it should require less complex sensory-muscular feedback. Whereas it is well known in insects, this mechanism is much less studied in arachnids, except spiders. Soil-dwelling harvestmen (Opiliones, Nemastomatidae) bear drumstick-like glandular hairs (clavate setae) at their pedipalps, which were previously hypothesized to be sticky and used in prey capture. However, clear evidence for this was lacking to date. Using high-speed videography, we found that the harvestman Mitostoma chrysomelas was able to capture fast-moving springtails (Collembola) just by a slight touch of the pedipalp. Adhesion of single clavate setae increased proportionally with pull-off velocity, from 1 MUN at 1 MUm s(-1) up to 7 MUN at 1 mm s(-1), which corresponds to the typical weight of springtails. Stretched glue droplets exhibited characteristics of a viscoelastic fluid forming beads-on-a string morphology over time, similar to spider capture threads and the sticky tentacles of carnivorous plants. These analogies indicate that viscoelasticity is a highly efficient mechanism for prey capture, as it holds stronger the faster the struggling prey moves. Cryo-scanning electron microscopy of snap-frozen harvestmen with glued springtails revealed that the gluey secretions have a high affinity to wet the microstructured cuticle of collembolans, which was previously reported to be barely wettable for both polar and non-polar liquids. Glue droplets can be contaminated with the detached scaly setae of collembolans, which may represent a counter-adaptation against entrapment by the glue, similar to the scaly surfaces of Lepidoptera and Trichoptera (Insecta) facilitating escape from spider webs. PMID- 25274326 TI - Looking upstream for influences on socioeconomic inequalities in health. PMID- 25274327 TI - Alcohol and public health: heavy drinking is a heavy price to pay for populations. PMID- 25274328 TI - miR-183 potentially inhibits NF-kappaB1 expression by directly targeting its 3' untranslated region. AB - Nuclear factor-kappaB (NF-kappaB) is an important transcription factor. While the NF-kappaB signaling pathway is modulated by many microRNAs (miRNAs), very few have been reported to target NF-kappaB1 gene directly. In this study, we used multiple miRNA target prediction programs to predict miRNAs with putative NF kappaB1 3'-untranslated region (UTR) binding sites. miR-183 was strongly implicated and experimentally validated by reporter assays. The results showed a reduced expression of the NF-kappaB1 3'UTR containing luciferase vector by ~30%, which was comparable to the reduction by miR-9 (the only known miRNA targeting the NF-kappaB1 3'UTR). Mutagenesis of the miR-183 seed region binding sequence in the NF-kappaB1 3'UTR abolished the inhibitory effect of miR-183, as noted by the NF-kappaB1 3'UTR-containing reporter. Moreover, similar to miR-9, miR-183 could down-regulate the expression of the reporter driven by NF-kappaB promoter to some degree, suggesting that miR-183 might negatively regulate the endogenous NF kappaB1. Overall, our data provide computational and experimental evidence that NF-kappaB1 is a potential target of miR-183. PMID- 25274329 TI - Methylglyoxal increases dopamine level and leads to oxidative stress in SH-SY5Y cells. AB - More and more studies have suggested that methylglyoxal (MGO) induced by type-2 diabetes is related to Parkinson's disease (PD). However, little is known about the molecular mechanism. In this study, we explored the MGO toxicity in neuroblastoma SH-SY5Y cells. Neurotoxicity of MGO was measured by mitochondrial membrane potential, malondialdehyde, and methylthiazoletetrazolium assays. The levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and 1-methyl-4-phenyl 1,2,3,4-tetrahydroisoquinoline (salsolinol) were detected by liquid chromatography-mass spectrometry/mass spectrometry. The expressions of tyrosine hydroxylase (TH) and dopamine transporter (DAT) were detected by reverse transcriptase polymerase chain reaction and western blot analysis. The results showed that MGO induced an increase in TH and DAT expressions in SH-SY5Y neuroblastoma cells, while the levels of dopamine, DOPAC, and endogenous neurotoxin salsolinol also increased. Aminoguanidine (AG) is an inhibitor of MGO. It was found that AG could decrease the reactive oxygen species (ROS) level induced by MGO, but could not inhibit an increase of TH, DAT and dopamine. The increase of dopamine, DOPAC and salsolinol levels could lead to high ROS and mitochondrial damage. This study suggests that ROS caused by dopamine could contribute to the damage of dopaminergic neurons when MGO is increased during the course of diabetes. PMID- 25274330 TI - Circulating microRNA expression profile: a novel potential predictor for chronic nervous lesions. AB - The mechanisms of chronic neuropathic pain are not clear. Serum microRNAs (miRNAs) might show a special feature for chronic nervous lesions. However, little is known about the changes in circulating miRNAs for the neuropathic pain. Therefore, changes in the circulating miRNAs expression profile for the neuropathic pain were investigated. Serum was collected from rats before and after spinal nerve ligation (SNL) surgery, and a microarray analysis was performed to determine the changes in miRNA expression profile. The expression of inflammatory cytokines in serum from the same individuals, including interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and monocyte chemotactic protein-1 (MCP-1), was also measured. The results showed that the expression levels of IL-6, TNF-alpha, and MCP-1 were significantly elevated in SNL rats which were significantly correlated with pain levels. Nine miRNAs with significantly different expression levels before and after SNL surgery were identified by microarray analysis, which were further validated by quantitative real-time polymerase chain reaction analyses. Compared with naive rats without SNL surgery, the expression of five miRNAs (hsa-miR-221, hsa-miR-34c, hsa-miR-21, hsa-miR-30a-5p, and hsa-miR-206) in the serum of rats after SNL surgery was decreased and four miRNAs (hsa-miR-31-5p, hsa-miR-133b, hsa-miR-22, and hsa miRPlus-A1087) were increased, suggesting that miRNA changes may involve in the regulation of neuropathic pain. TargetScan was used to predict mRNA targets for these miRNAs, and the results showed that the transcripts with multiple predicted target sites belonged to neurologically important pathways. Bioinformatics analysis revealed that several target genes are related to the activation of cell signaling associated with nervous lesions. In this study, the changes to miRNA profiles in serum under neuropathic pain conditions were shown for the first time, suggesting that circulating miRNAs profile in serum is a potential predictor for neuropathic pain. PMID- 25274331 TI - Let-7b-5p regulates proliferation and apoptosis in multiple myeloma by targeting IGF1R. AB - Multiple myeloma (MM) is the most common cause of death from hematological malignancy worldwide, and recent studies have revealed that let-7b-5p can play an inhibitory role in tumorigenesis. However, the role of let-7b-5p in MM still remains unclear. The aim of this study was to elucidate the molecular mechanisms by which let-7b-5p acts as a tumor suppressor in MM. Here, quantitative real-time polymerase chain reaction results showed that the expression of let-7b-5p was remarkably reduced in MM tissues and MM cell lines (RPMI-8226 and U266 cells). Furthermore, over-expression of let-7b-5p significantly suppressed RPMI-8226 cell proliferation and induced S/G2 cell cycle arrest and apoptosis. Luciferase reporter assay results demonstrated that insulin-like growth factor receptor 1 (IGF1R) was negatively regulated by let-7b-5p at the post-transcriptional level. The mRNA and protein levels of IGF1R in RPMI-8226 cells were down-regulated by let-7b-5p. Furthermore, the cell phenotype altered by let-7b-5p inhibitor can be rescued by IGF1R silencing (si-IGF1R). Taken together, our results demonstrated that let-7b-5p functions as a tumor suppressor in MM, suggesting that let-7b-5p may be a potential therapeutic target for MM. PMID- 25274337 TI - Unravelling the true influences of fitness and sex on sweating during exercise. PMID- 25274332 TI - Recombinant Clostridium difficile toxin B induces endoplasmic reticulum stress in mouse colonal carcinoma cells. AB - Clostridium difficile is the main cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans and animals. Its pathogenicity is primarily linked to the secretion of two exotoxins (TcdA and TcdB). Although great progress in the toxic mechanism of TcdA and TcdB has been achieved, there are many conflicting reports about the apoptotic mechanism. More importantly, apoptotic endoplasmic reticulum (ER) stress has been reported in cells treated with Shiga toxins-another kind of cytotoxins that can cause diarrhea and colitis. Herein we checked whether TcdB can induce ER stress. The results showed that recombinant TcdB (rTcdB) activated molecular markers of unfolded protein response, suggesting that rTcdB induced ER stress in CT26 cells. However, rTcdB did not induce the up regulation of C/EBP homologous protein (CHOP), a classic mediator of apoptotic ER stress, but it activated the precursor of cysteine aspartic acid-specific protease 12 (caspase-12), a controversial mediator of apoptotic ER stress. Besides, glucosyltransferase activity-deficient mutant recombinant TcdB induced ER stress, though it has no cytotoxic or cytopathic effect on CT26 cells. Altogether, these data demonstrated that ER stress induced by rTcdB is glucosyltransferase-independent, indicating that ER stress induced by rTcdB is non-apoptotic. This work also offers us a new insight into the molecular mechanism of CHOP protein expression regulation and the role of CHOP expression in ER stress. PMID- 25274338 TI - Getting jittery about the mechanism of hypertension in sleep apnoea. PMID- 25274339 TI - Inhale your blood volume! PMID- 25274340 TI - Development of hypertension in chronic intermittent hypoxia: is it driven by cardiac output rather than by peripheral resistance? PMID- 25274342 TI - Context-dependent inhibition of unloaded muscles during the long-latency epoch. AB - A number of studies have highlighted the sophistication of corrective responses in lengthened muscles during the long-latency epoch. However, in various contexts, unloading can occur, which requires corrective actions from a shortened muscle. Here, we investigate the sophistication of inhibitory responses in shortened muscles due to unloading. Our first experiment quantified the inhibitory responses following an unloading torque that displaced the hand either into or away from a peripheral target. We observed larger long-latency inhibitory responses when perturbed into the peripheral target compared with away from the target. In our second experiment, we characterized the degree of inhibition following unloading with respect to different levels of preperturbation muscle activity. We initially observed that the inhibitory activity during the short latency epoch scaled with increased levels of preperturbation muscle activity. However, this scaling peaked early in the R2 epoch (~ 50 ms) but then quickly diminished through the rest of the long-latency epoch. Finally, in experiment 3, we investigated whether inhibitory perturbation responses consider intersegmental dynamics of the limb. We quantified unloading responses for either pure shoulder or pure elbow torques that evoked similar motion at the shoulder but different elbow motion. The long-latency inhibitory response in the shoulder, unlike the short-latency, was greater for the shoulder torque compared with the response following an elbow torque, as previously observed for a loading response. Taken together, these results illustrate that the long-latency unloading response is capable of a similar level of complexity as observed when loads are applied to the limb. PMID- 25274343 TI - Influence of common synaptic input to motor neurons on the neural drive to muscle in essential tremor. AB - Tremor in essential tremor (ET) is generated by pathological oscillations at 4-12 Hz, likely originating at cerebello-thalamo-cortical pathways. However, the way in which tremor is represented in the output of the spinal cord circuitries is largely unknown because of the difficulties in identifying the behavior of individual motor units from tremulous muscles. By using novel methods for the decomposition of multichannel surface EMG, we provide a systematic analysis of the discharge properties of motor units in nine ET patients, with concurrent recordings of EEG activity. This analysis allowed us to infer the contribution of common synaptic inputs to motor neurons in ET. Motor unit short-term synchronization was significantly greater in ET patients than in healthy subjects. Furthermore, the strong association between the degree of synchronization and the peak in coherence between motor unit spike trains at the tremor frequency indicated that the high synchronization levels were generated mainly by common synaptic inputs specifically at the tremor frequency. The coherence between EEG and motor unit spike trains demonstrated the presence of common cortical input to the motor neurons at the tremor frequency. Nonetheless, the strength of this input was uncorrelated to the net common synaptic input at the tremor frequency, suggesting a contribution of spinal afferents or secondary supraspinal pathways in projecting common input at the tremor frequency. These results provide the first systematic analysis of the neural drive to the muscle in ET and elucidate some of its characteristics that determine pathological tremulous muscle activity. PMID- 25274344 TI - Background complexity affects response of a looming-sensitive neuron to object motion. AB - An increasing number of studies show how stimulus complexity affects the responses of looming-sensitive neurons across multiple animal taxa. Locusts contain a well-described, descending motion-sensitive pathway that is preferentially looming sensitive. However, the lobula giant movement detector/descending contralateral movement detector (LGMD/DCMD) pathway responds to more than simple objects approaching at constant, predictable trajectories. In this study, we presented Locusta migratoria with a series of complex three dimensional visual stimuli presented while simultaneously recording DCMD activity extracellularly. In addition to a frontal looming stimulus, we used a combination of compound trajectories (nonlooming transitioning to looming) presented at different velocities and onto a simple, scattered, or progressive flow field background. Regardless of stimulus background, DCMD responses to looming were characteristic and related to previously described effects of azimuthal approach angle and velocity of object expansion. However, increasing background complexity caused reduced firing rates, delayed peaks, shorter rise phases, and longer fall phases. DCMD responded to transitions to looming with a characteristic drop in a firing rate that was relatively invariant across most stimulus combinations and occurred regardless of stimulus background. Spike numbers were higher in the presence of the scattered background and reduced in the flow field background. We show that DCMD response time to a transition depends on unique expansion parameters of the moving stimulus irrespective of background complexity. Our results show how background complexity shapes DCMD responses to looming stimuli, which is explained within a behavioral context. PMID- 25274345 TI - The power of the mind: the cortex as a critical determinant of muscle strength/weakness. AB - We tested the hypothesis that the nervous system, and the cortex in particular, is a critical determinant of muscle strength/weakness and that a high level of corticospinal inhibition is an important neurophysiological factor regulating force generation. A group of healthy individuals underwent 4 wk of wrist-hand immobilization to induce weakness. Another group also underwent 4 wk of immobilization, but they also performed mental imagery of strong muscle contractions 5 days/wk. Mental imagery has been shown to activate several cortical areas that are involved with actual motor behaviors, including premotor and M1 regions. A control group, who underwent no interventions, also participated in this study. Before, immediately after, and 1 wk following immobilization, we measured wrist flexor strength, voluntary activation (VA), and the cortical silent period (SP; a measure that reflect corticospinal inhibition quantified via transcranial magnetic stimulation). Immobilization decreased strength 45.1 +/- 5.0%, impaired VA 23.2 +/- 5.8%, and prolonged the SP 13.5 +/- 2.6%. Mental imagery training, however, attenuated the loss of strength and VA by ~50% (23.8 +/- 5.6% and 12.9 +/- 3.2% reductions, respectively) and eliminated prolongation of the SP (4.8 +/- 2.8% reduction). Significant associations were observed between the changes in muscle strength and VA (r = 0.56) and SP (r = 0.39). These findings suggest neurological mechanisms, most likely at the cortical level, contribute significantly to disuse-induced weakness, and that regular activation of the cortical regions via imagery attenuates weakness and VA by maintaining normal levels of inhibition. PMID- 25274346 TI - Differential effects of static and dynamic inputs on neuronal excitability. AB - The intrinsic excitability of neurons is known to be dynamically regulated by activity-dependent plasticity and homeostatic mechanisms. Such processes are commonly analyzed in the context of input-output functions that describe how neurons fire in response to constant levels of current. However, it is not well understood how changes of excitability as observed under static inputs translate to the function of the same neurons in their natural synaptic environment. Here we performed a computational study and hybrid experiments on rat bed nucleus of stria terminalis neurons to compare the two scenarios. The inward rectifying Kir current (IKir) and the hyperpolarization-activated cation current (Ih) were found to be considerably more effective in regulating the firing under synaptic inputs than under static stimuli. This prediction was experimentally confirmed by dynamic-clamp insertion of a synthetic inwardly rectifying Kir current into the biological neurons. At the same time, ionic currents that activate with depolarization were more effective regulating the firing under static inputs. When two intrinsic currents are concurrently altered such as those under homeostatic regulation, the effects in firing responses under static vs. dynamic inputs can be even more contrasting. Our results show that plastic or homeostatic changes of intrinsic membrane currents can shape the current step responses of neurons and their firing under synaptic inputs in a differential manner. PMID- 25274347 TI - Time-sensitive reorganization of the somatosensory cortex poststroke depends on interaction between Hebbian and homeoplasticity: a simulation study. AB - Together with Hebbian plasticity, homeoplasticity presumably plays a significant, yet unclear, role in recovery postlesion. Here, we undertake a simulation study addressing the role of homeoplasticity and rehabilitation timing poststroke. We first hypothesize that homeoplasticity is essential for recovery and second that rehabilitation training delivered too early, before homeoplasticity has compensated for activity disturbances postlesion, is less effective for recovery than training delivered after a delay. We developed a neural network model of the sensory cortex driven by muscle spindle inputs arising from a six-muscle arm. All synapses underwent Hebbian plasticity, while homeoplasticity adjusted cell excitability to maintain a desired firing distribution. After initial training, the network was lesioned, leading to areas of hyper- and hypoactivity due to the loss of lateral synaptic connections. The network was then retrained through rehabilitative arm movements. We found that network recovery was unsuccessful in the absence of homeoplasticity, as measured by reestablishment of lesion-affected inputs. We also found that a delay preceding rehabilitation led to faster network recovery during the rehabilitation training than no delay. Our simulation results thus suggest that homeoplastic restoration of prelesion activity patterns is essential to functional network recovery via Hebbian plasticity. PMID- 25274349 TI - Retention and interference of learned dexterous manipulation: interaction between multiple sensorimotor processes. AB - An object can be used in multiple contexts, each requiring different hand actions. How the central nervous system builds and maintains memory of such dexterous manipulations remains unclear. We conducted experiments in which human subjects had to learn and recall manipulations performed in two contexts, A and B. Both contexts involved lifting the same L-shaped object whose geometry cued its asymmetrical mass distribution. Correct performance required producing a torque on the vertical handle at object lift onset to prevent it from tilting. The torque direction depended on the context, i.e., object orientation, which was changed by 180 degrees object rotation about a vertical axis. With an A1B1A2 context switching paradigm, subjects learned A1 in the first block of eight trials as indicated by a torque approaching the required one. However, subjects made large errors in anticipating the required torque when switching to B1 immediately after A1 (negative transfer), as well as when they had to recall A1 when switching to A2 after learning B through another block of eight lifts (retrieval interference). Classic sensorimotor learning theories attribute such interferences to multi-rate, multi-state error-driven updates of internal models. However, by systematically changing the interblock break duration and within block number of trials, our results suggest an alternative explanation underlying interference and retention of dexterous manipulation. Specifically, we identified and quantified through a novel computational model the nonlinear interaction between two sensorimotor mechanisms: a short-lived, context-independent, use dependent sensorimotor memory and a context-sensitive, error-based learning process. PMID- 25274348 TI - Generation of field potentials and modulation of their dynamics through volume integration of cortical activity. AB - Field potentials (FPs) recorded within the brain, often called "local field potentials" (LFPs), are useful measures of net synaptic activity in a neuronal ensemble. However, due to volume conduction, FPs spread beyond regions of underlying synaptic activity, and thus an "LFP" signal may not accurately reflect the temporal patterns of synaptic activity in the immediately surrounding neuron population. To better understand the physiological processes reflected in FPs, we explored the relationship between the FP and its membrane current generators using current source density (CSD) analysis in conjunction with a volume conductor model. The model provides a quantitative description of the spatiotemporal summation of immediate local and more distant membrane currents to produce the FP. By applying the model to FPs in the macaque auditory cortex, we have investigated a critical issue that has broad implications for FP research. We have shown that FP responses in particular cortical layers are differentially susceptible to activity in other layers. Activity in the supragranular layers has the strongest contribution to FPs in other cortical layers, and infragranular FPs are most susceptible to contributions from other layers. To define the physiological processes generating FPs recorded in loci of relatively weak synaptic activity, strong effects produced by synaptic events in the vicinity have to be taken into account. While outlining limitations and caveats inherent to FP measurements, our results also suggest specific peak and frequency band components of FPs can be related to activity in specific cortical layers. These results may help improving the interpretability of FPs. PMID- 25274351 TI - The importance of being vivax. PMID- 25274352 TI - A modern Prometheus. PMID- 25274350 TI - Nerve injury induces a new profile of tactile and mechanical nociceptor input from undamaged peripheral afferents. AB - Chronic pain after nerve injury is often accompanied by hypersensitivity to mechanical stimuli, yet whether this reflects altered input, altered processing, or both remains unclear. Spinal nerve ligation or transection results in hypersensitivity to mechanical stimuli in skin innervated by adjacent dorsal root ganglia, but no previous study has quantified the changes in receptive field properties of these neurons in vivo. To address this, we recorded intracellularly from L4 dorsal root ganglion neurons of anesthetized young adult rats, 1 wk after L5 partial spinal nerve ligation (pSNL) or sham surgery. One week after pSNL, hindpaw mechanical withdrawal threshold in awake, freely behaving animals was decreased in the L4 distribution on the nerve-injured side compared with sham controls. Electrophysiology revealed that high-threshold mechanoreceptive cells of A-fiber conduction velocity in L4 were sensitized, with a seven-fold reduction in mechanical threshold, a seven-fold increase in receptive field area, and doubling of maximum instantaneous frequency in response to peripheral stimuli, accompanied by reductions in after-hyperpolarization amplitude and duration. Only a reduction in mechanical threshold (minimum von Frey hair producing neuronal activity) was observed in C-fiber conduction velocity high-threshold mechanoreceptive cells. In contrast, low-threshold mechanoreceptive cells were desensitized, with a 13-fold increase in mechanical threshold, a 60% reduction in receptive field area, and a 40% reduction in instantaneous frequency to stimulation. No spontaneous activity was observed in L4 ganglia, and the likelihood of recording from neurons without a mechanical receptive field was increased after pSNL. These data suggest massively altered input from undamaged sensory afferents innervating areas of hypersensitivity after nerve injury, with reduced tactile and increased nociceptive afferent response. These findings differ importantly from previous preclinical studies, but are consistent with clinical findings in most patients with chronic neuropathic pain. PMID- 25274354 TI - Results of arthroscopic labral reconstruction of the hip in elite athletes: letter to the editor. PMID- 25274355 TI - Results of arthroscopic labral reconstruction of the hip in elite athletes: response. PMID- 25274353 TI - Effect of graft choice on the outcome of revision anterior cruciate ligament reconstruction in the Multicenter ACL Revision Study (MARS) Cohort. AB - BACKGROUND: Most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome; however, graft choice for revision may be limited due to previously used grafts. HYPOTHESES: Autograft use would result in increased sports function, increased activity level, and decreased osteoarthritis symptoms (as measured by validated patient-reported outcome instruments). Autograft use would result in decreased graft failure and reoperation rate 2 years after revision ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients undergoing revision ACL reconstruction were identified and prospectively enrolled by 83 surgeons at 52 sites. Data collected included baseline demographics, surgical technique, pathologic abnormalities, and the results of a series of validated, patient-reported outcome instruments (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC], and Marx activity rating score). Patients were followed up at 2 years and asked to complete the identical set of outcome instruments. Incidences of additional surgery and reoperation due to graft failure were also recorded. Multivariate regression models were used to determine the predictors (risk factors) of IKDC, KOOS, WOMAC, Marx scores, graft rerupture, and reoperation rate at 2 years after revision surgery. RESULTS: A total of 1205 patients (697 [58%] males) were enrolled. The median age was 26 years. In 88% of patients, this was their first revision, and 341 patients (28%) were undergoing revision by the surgeon who had performed the previous reconstruction. The median time since last ACL reconstruction was 3.4 years. Revision using an autograft was performed in 583 patients (48%), allograft was used in 590 (49%), and both types were used in 32 (3%). Questionnaire follow-up was obtained for 989 subjects (82%), while telephone follow-up was obtained for 1112 (92%). The IKDC, KOOS, and WOMAC scores (with the exception of the WOMAC stiffness subscale) all significantly improved at 2-year follow-up (P < .001). In contrast, the 2-year Marx activity score demonstrated a significant decrease from the initial score at enrollment (P < .001). Graft choice proved to be a significant predictor of 2-year IKDC scores (P = .017). Specifically, the use of an autograft for revision reconstruction predicted improved score on the IKDC (P = .045; odds ratio [OR] = 1.31; 95% CI, 1.01-1.70). The use of an autograft predicted an improved score on the KOOS sports and recreation subscale (P = .037; OR = 1.33; 95% CI, 1.02-1.73). Use of an autograft also predicted improved scores on the KOOS quality of life subscale (P = .031; OR = 1.33; 95% CI, 1.03-1.73). For the KOOS symptoms and KOOS activities of daily living subscales, graft choice did not predict outcome score. Graft choice was a significant predictor of 2-year Marx activity level scores (P = .012). Graft rerupture was reported in 37 of 1112 patients (3.3%) by their 2-year follow-up: 24 allografts, 12 autografts, and 1 allograft and autograft. Use of an autograft for revision resulted in patients being 2.78 times less likely to sustain a subsequent graft rupture compared with allograft (P = .047; 95% CI, 1.01-7.69). CONCLUSION: Improved sports function and patient-reported outcome measures are obtained when an autograft is used. Additionally, use of an autograft shows a decreased risk in graft rerupture at 2 year follow-up. No differences were noted in rerupture or patient-reported outcomes between soft tissue and bone-patellar tendon-bone grafts. Surgeon education regarding the findings of this study has the potential to improve the results of revision ACL reconstruction. PMID- 25274358 TI - Microbial community dynamics in the forefield of glaciers. AB - Retreating ice fronts (as a result of a warming climate) expose large expanses of deglaciated forefield, which become colonized by microbes and plants. There has been increasing interest in characterizing the biogeochemical development of these ecosystems using a chronosequence approach. Prior to the establishment of plants, microbes use autochthonously produced and allochthonously delivered nutrients for growth. The microbial community composition is largely made up of heterotrophic microbes (both bacteria and fungi), autotrophic microbes and nitrogen-fixing diazotrophs. Microbial activity is thought to be responsible for the initial build-up of labile nutrient pools, facilitating the growth of higher order plant life in developed soils. However, it is unclear to what extent these ecosystems rely on external sources of nutrients such as ancient carbon pools and periodic nitrogen deposition. Furthermore, the seasonal variation of chronosequence dynamics and the effect of winter are largely unexplored. Modelling this ecosystem will provide a quantitative evaluation of the key processes and could guide the focus of future research. Year-round datasets combined with novel metagenomic techniques will help answer some of the pressing questions in this relatively new but rapidly expanding field, which is of growing interest in the context of future large-scale ice retreat. PMID- 25274359 TI - Large variation among photoreceptors as the basis of visual flexibility in the common backswimmer. AB - The common backswimmer, Notonecta glauca, uses vision by day and night for functions such as underwater prey animal capture and flight in search of new habitats. Although previous studies have identified some of the physiological mechanisms facilitating such flexibility in the animal's vision, neither the biophysics of Notonecta photoreceptors nor possible cellular adaptations are known. Here, we studied Notonecta photoreceptors using patch-clamp and intracellular recording methods. Photoreceptor size (approximated by capacitance) was positively correlated with absolute sensitivity and acceptance angles. Information rate measurements indicated that large and more sensitive photoreceptors performed better than small ones. Our results suggest that backswimmers are adapted for vision in both dim and well-illuminated environments by having open-rhabdom eyes with large intrinsic variation in absolute sensitivity among photoreceptors, exceeding those found in purely diurnal or nocturnal species. Both electrophysiology and microscopic analysis of retinal structure suggest two retinal subsystems: the largest peripheral photoreceptors provide vision in dim light and the smaller peripheral and central photoreceptors function primarily in sunlight, with light-dependent pigment screening further contributing to adaptation in this system by dynamically recruiting photoreceptors with varying sensitivity into the operational pool. PMID- 25274360 TI - Intraspecific divergence and convergence of floral tube length in specialized pollination interactions. AB - Floral tubes are often thought to be a consequence of adaptive specialization towards pollinator morphology. We explore floral tube length evolution within Tritoniopsis revoluta (Iridaceae), a species with considerable geographical tube length variation. We ask whether tube lengths of T. revoluta populations are associated with pollinator proboscis lengths, whether floral divergence occurs in the presence of different pollinators and whether floral convergence occurs between distantly related populations pollinated by the same pollinator. Finally, we ask whether tube length evolution is directional. Shifts between morphologically different pollinators were always associated with shifts in floral morphology, even when populations were very closely related. Distantly related populations had similar tube lengths when they were pollinated by the same pollinator. Shifts in tube length tended to be from short to long, although reversals were not infrequent. After correcting for the population-level phylogeny, there was a strong positive, linear relationship between floral tube length and pollinator proboscis length, suggesting that plants are functionally specialized on different pollinators at different sites. However, because tube length evolution in this system can be a bidirectional process, specialization to the local pollinator fauna is unlikely to result in evolutionary or ecological dead-ends such as canalization or range limitation. PMID- 25274361 TI - What is the primary function of the early teleost gill? Evidence for Na+/NH+4 exchange in developing rainbow trout (Oncorhynchus mykiss). AB - Post-hatch fishes lack a functional gill and use cutaneous surfaces for exchange with the surrounding environment. The ionoregulatory hypothesis posits that ionoregulation is the first physiological process to be limited by cutaneous exchange, necessitating its shift to the gills. We hypothesized that the ontogeny of branchial ammonia excretion (J amm) is coupled to Na(+) uptake (J Na in) in accordance with the current model for Na+/NH4+ in exchange in freshwater. Using divided chambers, branchial and cutaneous J amm, J Na in and oxygen consumption (MO2) by larval rainbow trout were assessed. Following hatch, the skin accounted for 97% and 86% of total J amm and J Na in, respectively. J amm and J Na in shifted to the gills simultaneously at 15 days post-hatch (dph) and were highly correlated (R(2) = 0.951) at the gills, but not the skin, over development. Contrastingly, MO2 shifted significantly later at 27 dph, in agreement with the ionoregulatory hypothesis. Moreover, the mRNA expression and/or enzymatic activity of Rhesus proteins, Na(+)/H(+)-exchanger, H(+)-ATPase, Na(+)/K(+)-ATPase and carbonic anhydrase, all key components of the Na+/NH4+-exchange system, increased in the gills over larval development. We propose that the ontogeny of branchial J Na in occurs as Na+/NH4+ exchange and provide evidence for a novel element to the ionoregulatory hypothesis, the excretion of potentially lethal metabolic ammonia. PMID- 25274362 TI - Listening to the environment: hearing differences from an epigenetic effect in solitarious and gregarious locusts. AB - Locusts display a striking form of phenotypic plasticity, developing into either a lone-living solitarious phase or a swarming gregarious phase depending on population density. The two phases differ extensively in appearance, behaviour and physiology. We found that solitarious and gregarious locusts have clear differences in their hearing, both in their tympanal and neuronal responses. We identified significant differences in the shape of the tympana that may be responsible for the variations in hearing between locust phases. We measured the nanometre mechanical responses of the ear's tympanal membrane to sound, finding that solitarious animals exhibit greater displacement. Finally, neural experiments signified that solitarious locusts have a relatively stronger response to high frequencies. The enhanced response to high-frequency sounds in the nocturnally flying solitarious locusts suggests greater investment in detecting the ultrasonic echolocation calls of bats, to which they are more vulnerable than diurnally active gregarious locusts. This study highlights the importance of epigenetic effects set forth during development and begins to identify how animals are equipped to match their immediate environmental needs. PMID- 25274363 TI - Road networks predict human influence on Amazonian bird communities. AB - Road building can lead to significant deleterious impacts on biodiversity, varying from direct road-kill mortality and direct habitat loss associated with road construction, to more subtle indirect impacts from edge effects and fragmentation. However, little work has been done to evaluate the specific effects of road networks and biodiversity loss beyond the more generalized effects of habitat loss. Here, we compared forest bird species richness and composition in the municipalities of Santarem and Belterra in Para state, eastern Brazilian Amazon, with a road network metric called 'roadless volume (RV)' at the scale of small hydrological catchments (averaging 3721 ha). We found a significant positive relationship between RV and both forest bird richness and the average number of unique species (species represented by a single record) recorded at each site. Forest bird community composition was also significantly affected by RV. Moreover, there was no significant correlation between RV and forest cover, suggesting that road networks may impact biodiversity independently of changes in forest cover. However, variance partitioning analysis indicated that RV has partially independent and therefore additive effects, suggesting that RV and forest cover are best used in a complementary manner to investigate changes in biodiversity. Road impacts on avian species richness and composition independent of habitat loss may result from road-dependent habitat disturbance and fragmentation effects that are not captured by total percentage habitat cover, such as selective logging, fire, hunting, traffic disturbance, edge effects and road-induced fragmentation. PMID- 25274364 TI - Real-time modulation of perceptual eye dominance in humans. AB - Ocular dominance (OD) has long served as the model for neural plasticity. The shift of OD has been demonstrated by monocular deprivation in animals only during early visual development. Here, for the first time, we show that perceptual eye dominance can be modulated in real time in normal human adults by varying the spatial image content of movies seen dichoptically by the two eyes over a period as short as 2.5 h. Unlike OD shifts seen in early visual development, this modulation in human eye dominance is not simply a consequence of reduced interocular correlation (e.g. synchronicity) or overall contrast energy, but due to the amplitude reductions of specific image components in one eye's view. The spatial properties driving this eye dominance change suggest that the underlying mechanism is binocular but not orientationally selective, therefore uniquely locating it to layer 4 B of area V1. PMID- 25274365 TI - Fatal attraction: vegetation responses to nutrient inputs attract herbivores to infectious anthrax carcass sites. AB - Parasites can shape the foraging behaviour of their hosts through cues indicating risk of infection. When cues for risk co-occur with desired traits such as forage quality, individuals face a trade-off between nutrient acquisition and parasite exposure. We evaluated how this trade-off may influence disease transmission in a 3-year experimental study of anthrax in a guild of mammalian herbivores in Etosha National Park, Namibia. At plains zebra (Equus quagga) carcass sites we assessed (i) carcass nutrient effects on soils and grasses, (ii) concentrations of Bacillus anthracis (BA) on grasses and in soils, and (iii) herbivore grazing behaviour, compared with control sites, using motion-sensing camera traps. We found that carcass-mediated nutrient pulses improved soil and vegetation, and that BA is found on grasses up to 2 years after death. Host foraging responses to carcass sites shifted from avoidance to attraction, and ultimately to no preference, with the strength and duration of these behavioural responses varying among herbivore species. Our results demonstrate that animal carcasses alter the environment and attract grazing hosts to parasite aggregations. This attraction may enhance transmission rates, suggesting that hosts are limited in their ability to trade off nutrient intake with parasite avoidance when relying on indirect cues. PMID- 25274366 TI - Biogeographic patterns in below-ground diversity in New York City's Central Park are similar to those observed globally. AB - Soil biota play key roles in the functioning of terrestrial ecosystems, however, compared to our knowledge of above-ground plant and animal diversity, the biodiversity found in soils remains largely uncharacterized. Here, we present an assessment of soil biodiversity and biogeographic patterns across Central Park in New York City that spanned all three domains of life, demonstrating that even an urban, managed system harbours large amounts of undescribed soil biodiversity. Despite high variability across the Park, below-ground diversity patterns were predictable based on soil characteristics, with prokaryotic and eukaryotic communities exhibiting overlapping biogeographic patterns. Further, Central Park soils harboured nearly as many distinct soil microbial phylotypes and types of soil communities as we found in biomes across the globe (including arctic, tropical and desert soils). This integrated cross-domain investigation highlights that the amount and patterning of novel and uncharacterized diversity at a single urban location matches that observed across natural ecosystems spanning multiple biomes and continents. PMID- 25274367 TI - Evolutionary ecology of specialization: insights from phylogenetic analysis. AB - In this Special feature, we assemble studies that illustrate phylogenetic approaches to studying salient questions regarding the effect of specialization on lineage diversification. The studies use an array of techniques involving a wide-ranging collection of biological systems (plants, butterflies, fish and amphibians are all represented). Their results reveal that macroevolutionary examination of specialization provides insight into the patterns of trade-offs in specialized systems; in particular, the genetic mechanisms of trade-offs appear to extend to very different aspects of life history in different groups. In turn, because a species may be a specialist from one perspective and a generalist in others, these trade-offs influence whether we perceive specialization to have effects on the evolutionary success of a lineage when we examine specialization only along a single axis. Finally, how geographical range influences speciation and extinction of specialist lineages remains a question offering much potential for further insight. PMID- 25274368 TI - Specialization and generalization in the diversification of phytophagous insects: tests of the musical chairs and oscillation hypotheses. AB - Evolutionary biologists have often assumed that ecological generalism comes at the expense of less intense exploitation of specific resources and that this trade-off will promote the evolution of ecologically specialized daughter species. Using a phylogenetic comparative approach with butterflies as a model system, we test hypotheses that incorporate changes in niche breadth and location into explanations of the taxonomic diversification of insect herbivores. Specifically, we compare the oscillation hypothesis, where speciation is driven by host-plant generalists giving rise to specialist daughter species, to the musical chairs hypothesis, where speciation is driven by host-plant switching, without changes in niche breadth. Contrary to the predictions of the oscillation hypothesis, we recover a negative relationship between host-plant breadth and diversification rate and find that changes in host breadth are seldom coupled to speciation events. By contrast, we present evidence for a positive relationship between rates of host switching and butterfly diversification, consonant with the musical chairs hypothesis. These results suggest that the costs of trophic generalism in plant-feeding insects may have been overvalued and that transitions from generalists to ecological specialists may not be an important driver of speciation in general. PMID- 25274369 TI - Evolution of climatic niche specialization: a phylogenetic analysis in amphibians. AB - The evolution of climatic niche specialization has important implications for many topics in ecology, evolution and conservation. The climatic niche reflects the set of temperature and precipitation conditions where a species can occur. Thus, specialization to a limited set of climatic conditions can be important for understanding patterns of biogeography, species richness, community structure, allopatric speciation, spread of invasive species and responses to climate change. Nevertheless, the factors that determine climatic niche width (level of specialization) remain poorly explored. Here, we test whether species that occur in more extreme climates are more highly specialized for those conditions, and whether there are trade-offs between niche widths on different climatic niche axes (e.g. do species that tolerate a broad range of temperatures tolerate only a limited range of precipitation regimes?). We test these hypotheses in amphibians, using phylogenetic comparative methods and global-scale datasets, including 2712 species with both climatic and phylogenetic data. Our results do not support either hypothesis. Rather than finding narrower niches in more extreme environments, niches tend to be narrower on one end of a climatic gradient but wider on the other. We also find that temperature and precipitation niche breadths are positively related, rather than showing trade-offs. Finally, our results suggest that most amphibian species occur in relatively warm and dry environments and have relatively narrow climatic niche widths on both of these axes. Thus, they may be especially imperilled by anthropogenic climate change. PMID- 25274370 TI - Host specialist clownfishes are environmental niche generalists. AB - Why generalist and specialist species coexist in nature is a question that has interested evolutionary biologists for a long time. While the coexistence of specialists and generalists exploiting resources on a single ecological dimension has been theoretically and empirically explored, biological systems with multiple resource dimensions (e.g. trophic, ecological) are less well understood. Yet, such systems may provide an alternative to the classical theory of stable evolutionary coexistence of generalist and specialist species on a single resource dimension. We explore such systems and the potential trade-offs between different resource dimensions in clownfishes. All species of this iconic clade are obligate mutualists with sea anemones yet show interspecific variation in anemone host specificity. Moreover, clownfishes developed variable environmental specialization across their distribution. In this study, we test for the existence of a relationship between host-specificity (number of anemones associated with a clownfish species) and environmental-specificity (expressed as the size of the ecological niche breadth across climatic gradients). We find a negative correlation between host range and environmental specificities in temperature, salinity and pH, probably indicating a trade-off between both types of specialization forcing species to specialize only in a single direction. Trade offs in a multi-dimensional resource space could be a novel way of explaining the coexistence of generalist and specialists. PMID- 25274371 TI - Testing the stages model in the adaptive radiation of cichlid fishes in East African Lake Tanganyika. AB - Adaptive radiation (AR) is a key process in the origin of organismal diversity. However, the evolution of trait disparity in connection with ecological specialization is still poorly understood. Available models for vertebrate ARs predict that diversification occurs in the form of temporal stages driven by different selective forces. Here, we investigate the AR of cichlid fishes in East African Lake Tanganyika and use macroevolutionary model fitting to evaluate whether diversification happened in temporal stages. Six trait complexes, for which we also provide evidence of their adaptiveness, are analysed with comparative methods: body shape, pharyngeal jaw shape, gill raker traits, gut length, brain weight and body coloration. Overall, we do not find strong evidence for the 'stages model' of AR. However, our results suggest that trophic traits diversify earlier than traits implicated in macrohabitat adaptation and that sexual communication traits (i.e. coloration) diversify late in the radiation. PMID- 25274373 TI - New beginnings. PMID- 25274372 TI - Escape from extreme specialization: passionflowers, bats and the sword-billed hummingbird. AB - A striking example of plant/pollinator trait matching is found between Andean species of Passiflora with 6-14-cm-long nectar tubes and the sword-billed hummingbird, Ensifera ensifera, with up to 11-cm-long bills. Because of the position of their anthers and stigmas, and self-incompatibility, these passionflower species depend on E. ensifera for pollination. Field observations show that the bird and plant distribution match completely and that scarcity of Ensifera results in reduced passionflower seed set. We here use nuclear and plastid DNA sequences to investigate how often and when these mutualisms evolved and under which conditions, if ever, they were lost. The phylogeny includes 26 (70%) of the 37 extremely long-tubed species, 13 (68%) of the 19 species with tubes too short for Ensifera and four of the seven bat-pollinated species for a total of 43 (69%) of all species in Passiflora supersection Tacsonia (plus 11 outgroups). We time-calibrated the phylogeny to infer the speed of any pollinator switching. Results show that Tacsonia is monophyletic and that its stem group dates to 10.7 Ma, matching the divergence at 11.6 Ma of E. ensifera from its short-billed sister species. Whether pollination by short-billed hummingbirds or by Ensifera is the ancestral condition cannot be securely inferred, but extremely long-tubed flowers exclusively pollinated by Ensifera evolved early during the radiation of the Tacsonia clade. There is also evidence of several losses of Ensifera dependence, involving shifts to bat pollination and shorter billed birds. Besides being extremely asymmetric-a single bird species coevolving with a speciose plant clade-the Ensifera/Passiflora system is a prime example of a specialized pollinator not driving plant speciation, but instead being the precondition for the maintenance of isolated populations (through reliable seed set) that then underwent allopatric speciation. PMID- 25274374 TI - Clinical practice guideline: tinnitus executive summary. AB - The American Academy of Otolaryngology--Head and Neck Surgery Foundation (AAO HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Tinnitus. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 13 recommendations developed address the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the impact of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. PMID- 25274375 TI - Clinical consensus statement: pediatric chronic rhinosinusitis. AB - OBJECTIVE: To develop a clinical consensus statement on the optimal diagnosis and management of pediatric chronic rhinosinusitis (PCRS). METHODS: A representative 9-member panel of otolaryngologists with no relevant conflicts of interest was assembled to consider opportunities to optimize the diagnosis and management of PCRS. A working definition of PCRS and the scope of pertinent otolaryngologic practice were first established. Patients of ages 6 months to 18 years without craniofacial syndromes or immunodeficiency were defined as the targeted population of interest. A modified Delphi method was then used to distill expert opinion into clinical statements that met a standardized definition of consensus. RESULTS: After 2 iterative Delphi method surveys, 22 statements met the standardized definition of consensus while 12 statements did not. Four statements were omitted due to redundancy. The clinical statements were grouped into 4 categories for presentation and discussion: (1) definition and diagnosis of PCRS, (2) medical treatment of PCRS, (3) adenoiditis/adenoidectomy, and (4) endoscopic sinus surgery (ESS)/turbinoplasty. CONCLUSION: Expert panel consensus may provide helpful information for the otolaryngologist in the diagnosis and management of PCRS in uncomplicated pediatric patients. PMID- 25274377 TI - New strategies in acute promyelocytic leukemia: moving to an entirely oral, chemotherapy-free upfront management approach. AB - Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the management paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA-ATO combination was proved noninferior to a standard ATRA-chemotherapy regimen in patients with non-high risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapy-free regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality. Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO. PMID- 25274379 TI - Tumor stromal phenotypes define VEGF sensitivity--letter. PMID- 25274378 TI - The prostate cancer susceptibility variant rs2735839 near KLK3 gene is associated with aggressive prostate cancer and can stratify gleason score 7 patients. AB - PURPOSE: Gleason score (GS) 7 prostate cancer is a heterogeneous disease with different clinical behavior. We sought to identify genetic biomarkers that may predict the aggressiveness of GS 7 diseases. EXPERIMENTAL DESIGN: We genotyped 72 prostate cancer susceptibility SNPs identified in genome-wide association studies in 1,827 white men with histologically confirmed prostate adenocarcinoma. SNPs associated with disease aggressiveness were identified by comparing high aggressive (GS >=8) and low-aggressive (GS <=6) cases. The significant SNPs were then tested to see whether they could further stratify GS 7 prostate cancer. RESULTS: Three SNPs-rs2735839, rs10486567, and rs103294-were associated with biopsy-proven high-aggressive (GS >=8) prostate cancer (P < 0.05). Furthermore, the frequency of the variant allele (A) at rs2735839 was significantly higher in patients with biopsy-proven GS 4+3 disease than in those with GS 3 + 4 disease (P = 0.003). In multivariate logistic regression analysis, patients carrying the A allele at rs2735839 exhibited a 1.85-fold (95% confidence interval, 1.31-2.61) increased risk of being GS 4 + 3 compared with those with GS 3 + 4. The rs2735839 is located 600 base pair downstream of the KLK3 gene (encoding PSA) on 19q13.33 and has been shown to modulate PSA level, providing strong biologic plausibility for its association with prostate cancer aggressiveness. CONCLUSIONS: We confirmed the association of the rs2735839 with high-aggressive prostate cancer (GS >=8). Moreover, we reported for the first time that rs2735839 can stratify GS 7 patients, which would be clinically important for more accurately assessing the clinical behavior of the intermediate-grade prostate cancer and for tailoring personalized treatment and posttreatment management. PMID- 25274380 TI - Tumor stromal phenotypes define VEGF sensitivity--response. PMID- 25274382 TI - HTRA3 is reduced in ovarian cancers regardless of stage. AB - Ovarian cancer is the leading cause of death in gynaecological cancers. The high temperature requirement factor A3 (HtrA3) is involved in the pathogenesis of ovarian cancer. In this study we investigated whetherHtrA3 protein levels were altered in subtypes of ovarian cancer and whether HtrA3 down-regulation was associated with peritoneal metastasis. Ovarian cancer tissues from 89 patients were analyzed by immunohistochemistry. The levels of HtrA3 protein were lower in all subtypes of ovarian cancer and the lowest levels of HtrA3 were in epithelial ovarian cancer. The down-regulation of HtrA3 levels was not correlated with peritoneal metastasis of epithelial ovarian cancer. PMID- 25274383 TI - [Benign bone tumors]. PMID- 25274384 TI - [Benign bone tumors and tumor-like lesions. What must clinicians know about imaging?]. AB - PURPOSE: Benign bone tumors are relatively seldom compared to degenerative and inflammatory skeletal diseases. There are usually diagnostic difficulties because of their markedly high differential diagnostic potential. This leads to problems regarding the further procedure. PROBLEM: Evaluation of the significance of radiology in the management of benign skeletal lesions. MATERIAL AND METHODS: Significant diagnostic elements of benign bone tumors are presented by means of data from the well-known literature and personal experiences. RESULTS: The tasks in radiology when diagnosing primary bone tumors or tumor-like lesions are firstly, detection or exclusion of a lesion, secondly, limiting the differential diagnostic possibilities or reaching a certain diagnosis and thirdly, staging of bone tumors in cases where the disease needs further diagnostic measures. In particular circumstances the diagnostics of disease recurrence can additionally be necessary. CONCLUSION: The diagnostics of primary and secondary benign (and malignant) bone tumors requires a specialized osteoradiological expertise because of their rarity and the differential diagnostic and differential therapeutic potential. Radiology and pathology are the basis of diagnosing bone tumors and tumor-like lesions. Benign bone tumors and tumor-like lesions can often be diagnosed radiologically; therefore, the choice between a conservative (surveillance) or interventional (surgery) procedure will be correct in most cases. PMID- 25274385 TI - [Benign bone tumors. General principles]. AB - BACKGROUND: Benign bone tumors and tumor-like lesions are much more frequent than malignant bone tumors among the total number of tumors of the skeleton. OBJECTIVE: This article gives a presentation of the characteristics and treatment modalities of benign bone tumors. MATERIAL AND METHODS: In this article in-house treatment principles are compared with those in the currently available literature. RESULTS: Benign bone tumors are frequently found incidentally; however, the term benign does not always signify that a purely observational role is needed. Benign bone tumors differ in their biological behavior and can be latent, active or aggressive which determines the treatment approach. Some benign bone tumors are just as aggressive locally as malignant tumors. The most important diagnostic feature is still conventional radiography and a thorough systematic analysis is necessary. Therapy options range from ignore, wait and see up to wide resection. In contrast to malignant tumors the radicalism of resection can be weighed against the accompanying local control and loss of function. CONCLUSION: The treatment of benign bone tumors depends on the histological type and the biological activity. Most benign bone tumors are diagnosed incidentally and do not necessitate any treatment. PMID- 25274386 TI - [New therapy approaches for giant cell tumors]. AB - BACKGROUND: Giant cell bone tumors (GCT) are benign but partially locally aggressive osteolytic tumors which typically occur around the knee joint in the epiphysis and metaphysis of long bones after maturation of the skeleton is completed. Due to the locally aggressive growth behavior with destruction of the bone structure, the rare possibility of pulmonary metastases in recurrent cases and a very rare possibility of malignancy, GCTs were previously also described as semimalignant bone tumors. THERAPY: The established therapy of these tumors at the typical locations consists of intralesional curettage, extension of resection margins using a high speed trephine and defect reconstruction with bone cement. The local recurrence rate is high (10-40 %) and lowest after using thermal extension of resection margins with a high speed trephine and defect reconstruction with bone cement. For uncommon localizations, such as the spinal column and the sacrum as well as in cases of recurrence, surgical treatment is more complicated. HISTOLOGY: Histologically, GCTs consist of osteoclastic giant and oval-shaped stromal cells which show a high expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and decisively contribute to the osteolytic activity of the tumor. Novel pharmaceutical therapy approaches with human monoclonal RANKL antibodies interfere in this osteodestructive process in an inhibitory manner and can represent alternative treatment options just as the osteosupportive therapy with bisphosphonates. CONCLUSION: After unsatisfactory attempts at surgical treatment of GCT patients, the new treatment option with denosumab is a promising alternative due to its effect as a monoclonal RANKL inhibitor. PMID- 25274387 TI - [Benign cystic bone lesions]. AB - BACKGROUND: Bone cysts are benign tumor-like lesions which often present as a fluid-containing cavity in the bone. They can occur in the skeletal bone as solitary or sometimes multiple bone lesions. OBJECTIVES: This review discusses the diagnostics, radiological appearance and therapeutic strategies of the most important benign cystic bone lesions, such as simple bone cysts, aneurysmal bone cysts, intraosseous ganglia, epidermoid cysts and subchondral cysts. The differential diagnoses with respect to cystoid formations and tumors with cystic components are discussed. METHOD: A selective literature search was performed taking own experiences into consideration. RESULTS: These tumor-like lesions can have the radiological appearance of bone tumors but show no autonomic, stimulus independent growth and can resolve spontaneously. In the majority of cases open biopsy is necessary to confirm the diagnosis. In some cases no surgical intervention is necessary (e.g. do not touch and leave me alone lesions), whereas in other cases the focus of treatment is on the prevention and therapy of pathological fractures as well as prevention of recurrence. CONCLUSION: Cystic bone formations are among the most commonly occurring non-traumatic bone lesions. To eliminate differential diagnostic unclarity, histological investigation of biopsy material is essential. In terms of surgical intervention there exists a trend towards multimodal therapy mostly based on a meticulous curretage. PMID- 25274388 TI - [Benign cartilage tumors. What should I do with incidental findings?]. AB - BACKGROUND: The majority of benign bone tumors are cartilage tumors. Most common are enchondroma and osteochondroma. Often they represent incidental findings in radiological diagnostics. Thus, the incidence of cartilage tumors is unknown, as most of them are never diagnosed due to the absence of any symptoms. OBJECTIVES: This article describes the diagnostic and therapeutic approach of benign cartilage tumors, focusing on incidental findings. METHODS: The current knowledge and our own experience in the diagnostics and treatment of benign condroid tumors are presented. RESULTS: As enchondroma represent most often the classic incidental finding without any symptoms or clinical findings, osteochondroma are often diagnosed in young patients by clinical examination showing a painless swelling that can increase in size according to skeletal growth. Most of these asymptomatic enchondroma and osteochondroma are so called "leave me alone lesions" and do not need any treatment, while other benign tumors (e.g., atypical cartilage tumors, chondroblastoma, chondromyxoidfibroma or osteochondroma with a cartilage cap of over 2 cm) need surgical treatment. These active or local aggressive tumors must be differentiated from the "leave me alone lesions". Additionally, patients with syndromes like Ollier disease (enchondromatosis), Maffucci syndrome or hereditary multiple exostosis must be examined and checked carefully as malignant degradation is possible. CONCLUSION: As most cartilage tumors are benign and remain benign, inappropriate diagnostics or operative treatment just to provide security is obsolete. Plain X-ray is often enough for follow-up and other modalities only become necessary when symptoms occur. PMID- 25274390 TI - [Positioning and approaches for primary and reconstructive interventions of Achilles tendon ruptures]. PMID- 25274389 TI - [Rupture of the Achilles tendon]. AB - The rupture of the Achilles tendon is the most frequent tendon rupture in humans and it is associated with increasing incidence. The main risk factor is intrinsic degeneration of the tendon. During the rupture the person feels a whiplash or dagger thrust-like pain, followed by restricted walking ability and decreased plantar flexion of the ankle. The positive Simmond/Thompson test and a palpable dent above the tendon rupture are pathognomical. Diagnostically, ultrasound of the tendon and lateral x-ray of the calcaneus (bony pull-out of the tendon insertion) are necessary. Regarding correct indication and treatment modalities, most established conservative and surgical therapies realize optimal functional results. Surgical treatment promises better primary stability and slightly earlier better functional results, but there is the potential for surgical complications. Conservative therapy is associated with higher rates of re-rupture and healing of the tendon under elongation. Therefore, therapy planning in Achilles tendon rupture should be determined based on each patient. We recommend surgical treatment in patients with higher sporting demands and in younger patients (< 50 years). PMID- 25274391 TI - [Quality of case allocation of orthopedics and trauma surgery in the 2004 and 2014 versions of the German DRG system. An interim assessment of the development process]. AB - BACKGROUND: Since 2004 the German diagnosis-related groups (DRG) system has been applied nationwide in all German somatic hospitals. The G-DRG system is updated annually in order to increase the quality of case allocation. What developments have occurred since 2004 from the perspective of orthopedics and trauma surgery? This article takes stock of the developments between 2004 and 2014. METHODS: Analysis of relevant diagnoses, medical procedures and G-DRGs in the versions 2004 and 2014 based on the publications of the German DRG Institute (InEK) and the German Institute of Medical Documentation and Information (DIMDI). RESULTS: The number of G-DRGs in the whole system increased by 45.1 % between 2004 and 2014. The number of G-DRGs in the major diagnostic category (MDC) 08 that contains the majority of orthopedic and trauma surgery categories increased in the same period by 61.6 %. The reduction of variance of inlier costs in the MDC 08 category, a statistical measure of the performance of the G-DRG system, was below the corresponding value of the total system in 2004 as well in 2014. However, the reduction of variance of inlier costs in MDC 08 (+ 30.0 %) rose more from 2004 to 2014 than the corresponding value of the overall system (+ 21.5 %). CONCLUSION: Many modifications of the classification systems of diagnoses (ICD-10 GM) and medical procedures (OPS) and the structures of the G-DRG system could significantly improve the quality of case allocation from the perspective of orthopedics and trauma surgery between 2004 and 2014. Th assignment of cases could be differentiated so that complex cases with more utilization of resources were allocated to higher rated G-DRGs and vice versa. However, further improvements of the G-DRG system are necessary. Only correct and complete documentation and coding can provide a high quality of calculation of costs as a basis for a correct case allocation in future G-DRG systems. PMID- 25274392 TI - [Bone resorption in posttraumatic dystrophy. Root cause analysis based on the literature]. AB - BACKGROUND: In posttraumatic dystrophy the resorption of cancellous bone remains an unsolved phenomenon. OBJECTIVES: The possible effects of arteriovenous (av) anastomoses, hypoxia and acidosis in posttraumatic dystrophy on cancellous bone structures should be elucidated. MATERIAL AND METHODS: In posttraumatic dystrophy of the hand after distal radius fracture, hand fractures and elective hand surgery [20] the results suggest that persistent av anastomoses could be the reason for this syndrome. Possible pathways for the occurrence of cancellous bone resorption are discussed in context with the literature. RESULTS AND CONCLUSION: Intraosseous av anastomoses with acidosis and hypoxia of the tissues are probably responsible for the excessive activity of osteoclasts in acute posttraumatic dystrophy. Even enhancements in the late static phase of the three phase bone scan (TPBS) are in agreement with this hypothesis. In cancellous bone these enhancements are induced by the bone seeking tracers. The nomenclature for these tracer molecules is in line with the recommendations of International Union of Pure and Applied Chemistry (IUPAC) as methylene bisphosphonate and hydroxymethylene bisphosphonate. From this, therapeutic recommendations for posttraumatic dystrophy can be derived. The term diphosphonates should be changed to bisphosphonates. PMID- 25274393 TI - Treatment with continuous subcutaneous insulin infusion is associated with lower arterial stiffness. AB - AIMS: To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. METHODS: Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1 diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA1c, heart rate, mean arterial pressure, P creatinine, urinary albumin excretion rate (UAER), smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease (CVD), total cholesterol and statin treatment. Albuminuria was UAER >=30 mg/24-h, and CVD included myocardial infarction, revascularization, peripheral arterial disease and stroke. RESULTS: CSII- versus MDI-treated patients were 48 versus 57 % men, 51 +/- 11 versus 54 +/- 13 years old (mean +/- SD), had 33 +/- 12 versus 32 +/- 16 years diabetes duration and HbA1c 7.8 +/- 0.9 % (62 +/- 10 mmol/mol) versus 8.0 +/- 1.2 % (64 +/- 13 mmol/mol) (P >= 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 +/- 2.8 vs. 10.4 +/- 3.4 m/s; P = 0.016). In fully adjusted analysis, CSII treatment was significantly (P = 0.038) associated with lower PWV, whereas HbA1c-level was not (P = 0.93). CONCLUSIONS: In type 1 diabetes patients, CSII treatment was associated with lower arterial stiffness independent of other risk factors, while HbA1c was not. Although glucose variability was not assessed, our results suggest that glucose variability and not HbA1c-level affect arterial stiffness. This needs confirmation in randomised prospective studies. PMID- 25274394 TI - Pulse wave reflection is associated with diabetes duration, albuminuria and cardiovascular disease in type 1 diabetes. AB - AIMS: We investigate associations between the pulse-wave-derived measures augmentation pressure (AP) and augmentation index, and diabetic complications in type 1 diabetes. METHODS: This cross-sectional study from 2009-2011 included 676 type 1 diabetes patients. SphygmoCor (Atcor Medical, Australia) measured AP and heart rate-adjusted augmentation index (AI75). Diabetic complications were micro- or macroalbuminuria [urinary albumin excretion rate (UAER) 30-299 or >=300 mg/24 h], cardiovascular disease (CVD) (previous revascularization, myocardial infarction, peripheral arterial disease or stroke), autonomic dysfunction (heart rate variability <11 beats/min), or retinopathy (simple, proliferative or blindness). Adjustments included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication, and smoking. RESULTS: AP and AI75 measurements were available in 636 (94.1 %) patients and were 9.9 +/- 7.6 mmHg and 16.9 +/- 12.0, respectively. After adjustment, AP and AI75 were independently associated with diabetes duration and albuminuria (p <= 0.001). Furthermore, higher AP and AI75 were associated with previous CVD [adjusted odds ratios (95 % confidence interval) (per 1 SD increase) 1.9 (1.3-2.7) and 1.5 (1.0-2.2) (p <= 0.039)], but not with autonomic dysfunction or retinopathy (p >= 0.12). CONCLUSIONS: In type 1 diabetes, augmentation pressure and heart rate-adjusted augmentation index were associated with diabetes duration, albuminuria, and CVD, independently of conventional risk factors. ClinicalTrials.gov:NCT01171248. PMID- 25274395 TI - Left ventricular diastolic function in diabetes mellitus type 2 patients: correlation with heart rate and its variability. AB - AIMS: To assess the prevalence of left ventricular diastolic dysfunction in a population of patients with type 2 diabetes mellitus; to determine correlation of diastolic dysfunction with heart rate and its variability. METHODS: The study included 202 patients with type 2 diabetes mellitus. Echocardiography was performed with special reference to diastolic function, and heart rate variability was analysed using standard deviation of normal RR intervals, root mean square of successive differences and percentage of successive R-R intervals greater than 50 ms (pNN 50 %) in a 24-h electrocardiogram recording. RESULTS: Diastolic dysfunction is present in 79 % of type 2 diabetes mellitus patients: grade 1 in 52 %, grade 2 in 26 % and grade 3 in 1 % of patients. The subjects with grade 1 diastolic dysfunction had a statistically significantly higher heart rate variability compared with those with grade 2 diastolic dysfunction (LSD, post hoc test, p = 0.001). In the group with diastolic dysfunction, grade 2 reduced heart rate variability was recorded in 83 % of patients (37 and 7 % for grade 1 and normal diastolic function). An increase in the severity of diastolic dysfunction was associated with decreased heart rate variability and increased heart rate. CONCLUSION: Progression of diastolic dysfunction is associated with a significantly greater prevalence of reduced heart rate variability, which is accompanied by increased heart rate. PMID- 25274396 TI - Atrial fibrillation detection after cryptogenic stroke. PMID- 25274397 TI - Faecal transplantation and infectious diseases practitioners. PMID- 25274398 TI - Novel TBX5 duplication in a Japanese family with Holt-Oram syndrome. AB - Holt-Oram syndrome is an autosomal dominant disorder characterized by upper limb malformations in the preaxial radial ray and cardiac septation and/or a conduction abnormality. It has been demonstrated that Holt-Oram syndrome is caused by mutations in the T-box transcription factor gene TBX5. Numerous germline mutations (more than 90) of this gene have been reported; however, TBX5 mutations are only identified in up to 74% of typical Holt-Oram syndrome patients. We report a Japanese family with 2 affected individuals with the typical Holt-Oram syndrome phenotype, namely bilateral asymmetrical radial ray deformities and an atrial septal defect. An array-based comparative genomic hybridization study revealed an 11-kb duplication at 12q24.1. Moreover, a multiplex ligation-dependent probe amplification study confirmed the duplication of exons 1-6 of TBX5. Although a small duplication in TBX5 (6 bases) has been reported, a large duplication of this gene has not been described previously in typical Holt-Oram syndrome patients. All typical Holt-Oram syndrome cases in which a mutation is not identified should be screened for TBX5 exon duplications. PMID- 25274399 TI - Intrinsic obstruction in pulmonary venous drainage pathway is associated with poor surgical outcomes in patients with total anomalous pulmonary venous connection. AB - The aim of this study was to review the surgical outcomes of conventional repair in patients with total anomalous pulmonary venous connection (TAPVC). Between 1999 and 2012, 46 patients underwent conventional TAPVC repair; of those, 14 required emergent surgery within the first 24 h after their birth for coexisting intrinsic obstruction in pulmonary venous drainage pathway (Group 1). The remaining 32 were operated on after the first day of life and were divided into two groups: with (Group 2, n = 10) and without (Group 3, n = 22) subsequently progressed pulmonary venous obstruction (PVO) after birth. A follow-up was completed on all patients, and the mean follow-up period was 7 +/- 4 years (range 0.9-14). Group 1 required a significantly prolonged nitric oxide inhalation (12 +/- 11 days) and mechanical ventilation support (29 +/- 36 days) compared to Group 2 and Group 3. The actuarial survival rate at 10 years was 69% in Group 1, 88% in Group 2, and 96% in Group 3 (Group 1 vs. Group 3: p = 0.05). Freedom from postoperative pulmonary vein stenosis at 10 years was 39% in Group 1, 70% in Group 2, and 86% in Group 3 (Group 1 vs. Group 3: p = 0.002). However, all the ten survivors in Group 1 showed an NYHA functional status of I or II, and 60% of survivors were free from medication. Outcomes of patients with TAPVC requiring surgical repair at the day of birth for coexisting intrinsic PVO were still dismal; however, the acceptable status of current survivors has encouraged us to treat this challenging group surgically. PMID- 25274400 TI - Outcomes of combined liver-kidney transplantation in children: analysis of the scientific registry of transplant recipients. AB - Combined liver-kidney transplantation (CLKT) in children is uncommon and outcomes have not been well defined. Using the Scientific Registry of Transplant Recipients, data were analyzed on 152 primary pediatric CLKTs performed from October 1987 to February 2011, to determine their outcome in the largest series reported to date. Patient survival was 86.8%, 82.1% and 78.9% at 1, 5 and 10 years, liver graft survival was 81.9%, 76.5% and 72.6%, and kidney graft survival was 83.4%, 76.5% and 66.8%. By way of comparison, the Registry was queried for pediatric patient survival following isolated liver transplantation (LT) during the same time frame: 86.7%, 81.2% and 77.4% and following isolated kidney transplant (KT): 98.2%, 95.4% and 90% at 1, 5 and 10 years. In patients having undergone CLKT, primary hyperoxaluria was associated with reduced patient (p = 0.01), liver graft (p = 0.01) and kidney graft survival (p = 0.01). Furthermore, graft outcome following CLKT improved over the past decade (p = 0.04 for liver, p = 0.02 for kidney), but this did not translate into improved patient outcome (p = 0.2). All in all, our results confirmed that survival following LT was less than following KT, and that CLKT offered similar patient survival to isolated LT. PMID- 25274401 TI - Therapeutic strategies for neuroendocrine liver metastases. AB - Patients who have neuroendocrine tumors frequently present with liver metastases. A wide panel of treatment options exists for these patients. Liver resection with curative intent achieves the best long-term results. Highly selected patients may be considered for liver transplantation. Substantial recurrence rates reported after surgical approaches call for neoadjuvant and adjuvant concepts. Liver directed, locally ablative procedures are recommended for patients with limited, nonresectable tumor burden. Angiographic liver-directed techniques, such as transarterial embolization, transarterial chemoembolization, and selective internal radiotherapy, offer excellent palliation for patients with liver predominant disease. Peptide receptor radionuclide therapy is a promising palliative procedure for patients with hepatic and/or extrahepatic metastases. The efficacy of these treatment options needs to be evaluated in randomized trials. Somatostatin analogues have demonstrated effectiveness not only for symptomatic relief in patients with secreting tumors but also for the control of proliferation in small intestinal neuroendocrine tumors and most recently also in those originating from the pancreas. Chemotherapy is an option mainly for those with pancreatic neuroendocrine tumors and high-grade tumors irrespective of the origin. Novel drugs targeting specific pathways within the tumor cell have produced improved progression-free survival compared with placebo in patients with pancreatic neuroendocrine tumors. Despite such a diverse armamentarium, there is uncertainty with regard to the optimal treatment regimens. Newly introduced molecular-based markers, along with the conduction of clinical trials comparing the efficacy of treatment modalities, offer a chance to move the treatment of neuroendocrine tumor disease toward personalized patient care. In this report, the authors review the approaches for treatment of neuroendocrine liver metastases, identify shortcomings, and anticipate future perspectives. Furthermore, clinical practice recommendations are provided for currently available treatment options. Although multiple modalities are available for the treatment of neuroendocrine liver metastases, optimal management is unclear. The current knowledge pertaining to these treatment options is analyzed. PMID- 25274402 TI - Crucial factor causing collapse and aggregation of cultured cells in epon resin. AB - Ultrastructural artifacts regarding collapse and aggregation of cultured cells have been problematic, especially when investigated apoptotic cells. The infiltration process during sample preparation is considered to be the most crucial factor for this problem. This study was conducted using two culture systems: a suspension culture system of human T-lymphocyte Jurkat cells and rabbit mature dendritic cells and a monolayer culture system of human lung macrophages, human breast cancer cells (A-546 cells) and cat bone-invasive gingival cancer cells (sccf3 cells). Fixation was conducted prior to removing or detaching the cells from the culture dishes. Initial infiltration with a 1 : 3 volume ratio of epon resin : propylene oxide was found to be the most crucial step among these cultured cells. The improved epon-resin infiltration method could eliminate the artifacts. Thus, differentiation between artifactual images and true images is highly possible. PMID- 25274403 TI - Human fetal topographical anatomy of the femoral triangle in relation with change in the hip joint position. AB - Fetal hip joint is characterized by its highly flexion and lateral rotation although adult anatomy of the femoral nerve and iliofemoral ligament suggested the medial rotation. To investigate topographical anatomy of the femoral nerve, artery and vein in the femoral triangle, we histologically examined 11 fetuses (15-37 weeks). The nerve-vessel topographical relation was basically similar to that in adults, but the fan-like nerve division was seen in the horizontal plane in the smaller specimens in contrast to that included in the sagittal plane in the larger specimens. The medial or internal rotation of the nerve division seemed to occur in late stage fetuses, at birth and at infancy. Blood supply to the head of the femur might be also accelerated by changes in the hip joint position. PMID- 25274404 TI - Morphology of the lingual papillae of Egyptian buffalo (Bubalus bubalis). AB - The mammalian tongue has different functions for feeding. We investigated the morphological characteristics of the surface of the tongue of Egyptian buffalo (Bubalus bubalis) using scanning electron microscopy. The lingual surface exhibited different degrees of specialization. The tongue can be divided into the apex, body, and root. The lingual prominence was observed on the posterior area of the lingual body. The lenticular, conical, and vallate papillae were observed on the caudal part of the tongue. The filiform papillae were lingual papillae covering the entire dorsal and ventral surface of the tongue at the lingual apex; they consisted of a main process that functions to transport food materials towards the pharynx. The fungiform papillae were dispersed between the filiform papillae. Large lenticular papillae were found at the lingual prominence. The highly keratinized lenticular papillae aid the physical mastication of plant materials. Twelve vallate papillae were arranged in V shape on the lingual root. These anatomical characteristics of the lingual surface of Egyptian buffalo may enhance understanding of its feeding behavior adaptations. PMID- 25274405 TI - Morphology of the lingual papillae of the black-backed jackal (Canis mesomelas). AB - We examined the dorsal lingual surface of an adult black-backed jackal (Canis mesomelas) by using scanning electron microscopy. The filiform papilla on the lingual apex exhibited a crown-like shape with several pointed processes. The connective tissue core of the filiform papilla was U-shaped. The filiform papillae on the lingual body had several pointed processes. The connective tissue core of the filiform papillae consisted of one large and several small conical papillae. The fungiform papillae on the lingual apex and body had a smooth surface. The connective tissue core of the fungiform papillae was not hollow and did not have processes. The vallate papillae were surrounded by a groove and pad with many processes on the surface. The connective tissue core of the vallate papillae had many ditches. Thus, the tongue of the black-backed jackal more closely resembles that of the bush dog than those of the raccoon dog or fox. PMID- 25274406 TI - Dynamic classification using case-specific training cohorts outperforms static gene expression signatures in breast cancer. AB - The molecular diversity of breast cancer makes it impossible to identify prognostic markers that are applicable to all breast cancers. To overcome limitations of previous multigene prognostic classifiers, we propose a new dynamic predictor: instead of using a single universal training cohort and an identical list of informative genes to predict the prognosis of new cases, a case specific predictor is developed for each test case. Gene expression data from 3,534 breast cancers with clinical annotation including relapse-free survival is analyzed. For each test case, we select a case-specific training subset including only molecularly similar cases and a case-specific predictor is generated. This method yields different training sets and different predictors for each new patient. The model performance was assessed in leave-one-out validation and also in 325 independent cases. Prognostic discrimination was high for all cases (n = 3,534, HR = 3.68, p = 1.67 E-56). The dynamic predictor showed higher overall accuracy (0.68) than genomic surrogates for Oncotype DX (0.64), Genomic Grade Index (0.61) or MammaPrint (0.47). The dynamic predictor was also effective in triple-negative cancers (n = 427, HR = 3.08, p = 0.0093) where the above classifiers all failed. Validation in independent patients yielded similar classification power (HR = 3.57). The dynamic classifier is available online at http://www.recurrenceonline.com/?q=Re_training. In summary, we developed a new method to make personalized prognostic prediction using case-specific training cohorts. The dynamic predictors outperform static models developed from single historical training cohorts and they also predict well in triple-negative cancers. PMID- 25274407 TI - Smoking status and survival: impact on mortality of continuing to smoke one year after the angiographic diagnosis of coronary artery disease, a prospective cohort study. AB - BACKGROUND: Smoking is an undertreated risk factor for coronary artery disease (CAD) and is associated with adverse outcomes after myocardial infarction. Aims of our study were to determine if management of CAD by medical therapy (MT) alone or with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) influence smoking status at one year following angiography and if a change in smoking status at one year influences long term survival. METHODS: Prospective cohort study using the APPROACH registry. Two cohorts were examined: (1) 11,334 patients who returned a one year follow-up questionnaire; (2) 4,246 patients propensity-matched based on their post-angiography treatment - MT or revascularization (RV). Multivariate modeling and survival analysis were used. RESULTS: In the propensity-matched cohort, quit rates at one year were greater among CABG patients (68%) than PCI (37%) or MT patients (47%). Smokers in the RV group, who self-reported quitting at one year, had a significantly reduced mortality compared to those who continued to smoke. CONCLUSIONS: CABG patients were more likely to quit smoking than those treated with MT alone or PCI. Quitting smoking was associated with improved long-term survival; smoking remains a key risk factor for mortality in patients with CAD. These data underscore the importance of nicotine addiction management in patients with CAD and the need to emphasize cessation particularly in those patients undergoing MT or PCI. PMID- 25274408 TI - Very late recurrence of sinus of Valsalva aneurysm rupture after patch repair. AB - BACKGROUND: Sinus of Valsalva aneurysm (SVA) is an uncommon cardiac defect accounting for only 1% of congenital cardiac anomalies and the most common complication is ruptured into the atrium or ventricle. Very late recurrence of ruptured SVA after patch repair is extremely rare. CASE PRESENTATION: We present a case of 57-year-old man had received repair for ruptured Sinus of Valsalva aneurysm at 19 ages. In the clinics, he presented with exertional dyspnea and leg swelling. The serial examination disclosed he had bicuspid aortic valve and very late rupture of SVA connecting to right atrium. After surgical repair again, he was discharged smoothly. CONCLUSION: A very late recurrence of ruptured SVA after surgical repair was rare. We reported a case with unique echocardiographic presentation and a successful repair. PMID- 25274410 TI - Dissecting the molecular pathways of primary aldosteronism. AB - The great majority of the cases clinically diagnosed as primary aldosteronism (PA) have been caused by aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). The differential diagnosis of both subtypes of PA is important due to the different therapeutic modes but clinically it is sometimes difficult. It is also important to understand the morphological features of these two subtypes with special emphasis upon differences of the status for aldosterone biosynthesis. In the last decade, molecular mechanisms of PA including the aberrant expression of G-protein coupled receptors (GPCRs), key regulators of the intracellular calcium signaling pathway and somatic mutations of ion channels, have been revealed and our understanding of the molecular pathways involved in excessive aldosterone production has been markedly advanced. In addition, newly developed monoclonal antibodies specific to the isoform of adrenal steroidogenic enzymes have demonstrated the novel profiles of adrenal steroidogenesis in PA. These novel findings indicate that the molecular mechanisms on the onset and pathophysiology of PA are more complicated than previously considered and further clarification of clinical relevance of these findings is required at this juncture. PMID- 25274409 TI - Schistosoma japonicum in Samar, the Philippines: infection in dogs and rats as a possible risk factor for human infection. AB - The role that animals play in the transmission of Schistosoma japonicum to humans in the Philippines remains uncertain and prior studies have not included several species, adjustment for misclassification error and clustering, or used a cohort design. A cohort study of 2468 people providing stool samples at 12 months following praziquantel treatment in 50 villages of Western Samar, the Philippines, was conducted. Stool samples from dogs, cats, rats, and water buffaloes were collected at baseline (2003-2004) and follow-up (2005). Latent class hierarchical Bayesian log-binomial models adjusting for misclassification errors in diagnostic tests were used. The village-level baseline and follow-up prevalences of cat, dog, and rat S. japonicum infection were associated with the 12-month cumulative incidence of human S. japonicum infection, with similar magnitude and precision of effect, but correlation between infection levels made it difficult to divide their respective effects. The cumulative incidence ratios associated with a 1% increase in the prevalence of infection in dogs at baseline and in rats at follow-up were 1.04 [95% Bayesian credible interval (BCI) 1.02 1.07] and 1.02 (95% BCI 1.01-1.04), respectively, when both species were entered in the model. Dogs appear to play a role in human schistosomiasis infection while rats could be used as schistosomiasis sentinels. PMID- 25274411 TI - Isolation and characterization of a furfural-degrading bacterium Bacillus cereus sp. strain DS1. AB - Furfural was found to be the main organic pollutant in the wastewater coming from the Diosgenin factory. This substance is derived from acidic pentosan in Dioscorea zingiberensis and is also found in a variety of agricultural byproducts, including corncobs, oat, wheat bran, and sawdust. It is regarded as a toxicant and an inhibitor to the growth of microorganism in both sewage disposal and biological fermentation. A furfural-degrading strain (DS1) was isolated from activated sludge of wastewater treatment plant in a diosgenin factory by continuous enrichment culture. The strain was identified as Bacillus cereus based on morphological, physiological tests, as well as on 16S rDNA sequence and Biolog analyses. The capacity of this strain to grow on a mineral salt medium, utilizing furfural as the sole carbon and energy source to degrade furfural, was investigated in this study. Under the condition of pH 9.0, temperature 35 degrees C, with rotating speed of 150 rpm, and an inoculum of 6 %, the strain showed that the furfural degradation capacity reaches 35 % in 7 days, as measured by high-performance liquid chromatography. The addition of inorganic carbon sources could bring down the biodegradation efficiency of the furfural. The strain DS1 showed better furfural removal capacity, as compared to other inorganic carbon sources in the media. Furthermore, a furfural concentration of as high as 4,000 mg L(-1) was tolerated by the culture. The capacity to degrade furfural was demonstrated for the first time by using the genus B. cereus. This study suggests the possible application in biodegradation strategies. PMID- 25274412 TI - Molecular analysis of pbp2b in Streptococcus pneumonia isolated from clinical and normal flora samples. AB - Streptococcus pneumoniae is an important bacterial pathogen responsible for respiratory infections, bacteraemia, and meningitis remains an important cause of disease and mortality in infants and younger children around the world, with penicillin being considered the drug of choice for the treatment of infections. However, penicillin-resistant S. pneumonia is now becoming endemic worldwide. In this study, a total of 80 pneumococcal isolates were collected from different clinical sources as well as normal flora. These isolates were subjected to antimicrobial susceptibility testing and MIC determination. The penicillin binding proteins, pbp2b, were amplified by PCR, and they were sequenced. The genetic relationship of the penicillin-resistant isolates was performed by BOX PCR. Overall, 36 pneumococcal (45 %) isolates were found to be resistant to penicillin with different MICs. The majority of them (80 %) were intermediately resistant with MIC of 0.12-1 ug/ml, whereas 20 % of isolates were penicillin resistant with MICs of >2 ug/ml. The results identified seven groups which were based on the amino acid substitutions of pbp2b. Sequencing analysis revealed that the most prevalent mutation was the substitution of Adenine for Thymine at the position 445 which is next to the second PBP2b-conserved motif (SSN). This study indicates that resistance to penicillin appears to be dependent on specific mutations in pbp2b, and the substitution in S620 -> T near to the third PBP2b conserved motif appears to be important in developing highly antibiotic-resistant isolates. Moreover, there was a positive correlation between the mutations in pbp2b gene and MIC. PMID- 25274413 TI - Mycobacterium genotypes in pulmonary tuberculosis infections and their detection by trained African giant pouched rats. AB - Tuberculosis (TB) diagnosis in low-income countries is mainly done by microscopy. Hence, little is known about the diversity of Mycobacterium spp. in TB infections. Different genotypes or lineages of Mycobacterium tuberculosis vary in virulence and induce different inflammatory and immune responses. Trained Cricetomys rats show a potential for rapid diagnosis of TB. They detect over 28 % of smear-negative, culture-positive TB. However, it is unknown whether these rats can equally detect sputa from patients infected with different genotypes of M. tuberculosis. A 4-month prospective study on diversity of Mycobacterium spp. was conducted in Dar es Salaam, Tanzania. 252 sputa from 161 subjects were cultured on Lowenstein-Jensen medium and thereafter tested by rats. Mycobacterial isolates were subjected to molecular identification and multispacer sequence typing (MST) to determine species and genotypes. A total of 34 Mycobacterium spp. isolates consisting of 32 M. tuberculosis, 1 M. avium subsp. hominissuis and 1 M. intracellulare were obtained. MST analyses of 26 M. tuberculosis isolates yielded 10 distinct MST genotypes, including 3 new genotypes with two clusters of related patterns not grouped by geographic areas. Genotype MST-67, shared by one-third of M. tuberculosis isolates, was associated with the Mwananyamala clinic. This study shows that diverse M. tuberculosis genotypes (n = 10) occur in Dar es Salaam and trained rats detect 80 % of the genotypes. Sputa with two M. tuberculosis genotypes (20 %), M. avium hominissuis and M. intracellulare were not detected. Therefore, rats detect sputa with different M. tuberculosis genotypes and can be used to detect TB in resource-poor countries. PMID- 25274414 TI - Half-life extension technologies for haemostatic agents. AB - The use of plasma-derived and recombinant coagulation factors for the treatment of haemophilia A and B is well established and permits patients to live a relatively normal life. In order to improve treatment options, several products are in development, which have a prolonged duration of action, thus enabling less frequent prophylactic dosing and aiming to reduce the burden of treatment. Several innovative approaches are being pursued to extend the half-life of factor VIIa, factor VIII and factor IX, utilising technologies such as Fc fusion, recombinant albumin fusion and addition of polyethyleneglycol (PEG) (PEGylation). These methods prolong the time in the circulation by reducing degradation and elimination. This review summarises the technologies and products in development and their stages of development, and also discusses their pros and cons. PMID- 25274415 TI - Safety and efficacy of in-hospital clopidogrel-to-prasugrel switching in patients with acute coronary syndrome. An analysis from the 'real world'. AB - Antiplatelet switching in the management of acute coronary syndrome (ACS) seems to be safe, but prospective data are limited. This retrospective study assessed the safety and efficacy of in-hospital clopidogrel-to-prasugrel switching in patients with ACS. We analysed 525 consecutive patients with ACS admitted to our coronary care unit. We assessed the prevalence and the short-term outcomes of in hospital clopidogrel-to-prasugrel switching. Bleeding and thrombotic events were assessed using propensity score matching analysis. A total of 468 patients received acetylsalicylic acid and a P2Y12 ADP receptor inhibitor. Medication switching occurred in 117 patients (25 %). Compared with the clopidogrel group, the switching group consisted preferentially of younger males with STEMI, exhibited fewer comorbidities, and had lower ischaemic risk. We found no differences between the switching group and the clopidogrel group in the bleeding rate [3.6 vs. 2.3 %, odds ratio (OR):1.59 95 % confidence interval (CI): 0.26 9.7, p NS], and in adverse cardiac or cerebrovascular events (MACCE) (5 vs. 8.4 %, OR: 0.57 95 % CI 0.16-2, p NS). In-hospital switching from clopidogrel to prasugrel in a selected high-risk ACS population resulted in a similar incidence of in-hospital haemorrhagic and thrombotic events. This strategy should be clarified in further randomised studies. PMID- 25274416 TI - Seroprevalence, risk factors and genotyping of Toxoplasma gondii in domestic geese (Anser domestica) in tropical China. AB - BACKGROUND: Little information is available about the seroprevalence of Toxoplasma gondii infection in geese (Anser domestica) in China. In the present investigation, the seroprevalence, risk factors and genotyping of T. gondii in geese were investigated in Hainan province, tropical China. FINDINGS: A total of 600 serum samples and 150 brain tissue samples were collected from six administrative regions in tropical China, and assayed for T. gondii antibodies by Indirect Haemagglutination (IHA) test. Genomic DNA was extracted from the 30 brain tissues of seropositive geese and T. gondii B1 gene was amplified using a semi-nested PCR. DNA samples giving positive B1 amplification were then genetically characterized using multi-locus PCR-RFLP. Overall, 17% (95% CI: 14 20) of the animals were positive for T. gondii antibodies. Presence of cats in the household (odds ratio, OR 3), hygiene (OR 2.3) and presence of stray cat around the house (OR 2.3) were considered as main risk factors associated with T. gondii infection. Of 30 DNA samples, three were positive for the T. gondii B1 gene, two showed complete genotyping results. Only one genotype (type II) was identified. CONCLUSIONS: The results of the present survey indicated the presence of T. gondii infection in geese in tropical China. Therefore, it is imperative that improved integrated measures be carried out to prevent and control T. gondii infection in geese in this province. This is the first report documenting the occurrence of T. gondii genotype in geese in China. PMID- 25274417 TI - A mentor training program improves mentoring competency for researchers working with early-career investigators from underrepresented backgrounds. AB - Mentoring is increasingly recognized as a critical element in supporting successful careers in academic research in medicine and related disciplines, particularly for trainees and early career investigators from underrepresented backgrounds. Mentoring is often executed ad hoc; there are limited programs to train faculty to become more effective mentors, and the few that exist have a dearth of empirical support of their impact. In 2013, we recruited 34 faculty from across the US engaged in HIV-related clinical research to participate in a 2 day Mentoring the Mentors workshop. The workshop included didactic and interactive content focused on a range of topics, such as mentor-mentee communication, leadership styles, emotional intelligence, understanding the impact of diversity (unconscious bias, microaggressions, discrimination, tokenism) for mentees, and specific tools and techniques for effective mentoring. Pre- and post-workshop online evaluations documented high rates of satisfaction with the program and statistically significant improvements in self-appraised mentoring skills (e.g. addressing diversity in mentoring, communication with mentees, aligning mentor-mentee expectations), as assessed via a validated mentoring competency tool. This is the first mentoring training program focused on enhancing mentors' abilities to nurture investigators of diversity, filling an important gap, and evaluation results offer support for its effectiveness. Results suggest a need for refinement and expansion of the program and for more comprehensive, long-term evaluation of distal mentoring outcomes for those who participate in the program. PMID- 25274418 TI - Validity of self-measured waist circumference in adults at risk of type 2 diabetes and cardiovascular disease. AB - BACKGROUND: Waist circumference (WC) is used to indirectly measure abdominal adipose tissue and the associated risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Because of its easy implementation and low cost, self-measured WC is commonly used as a screening tool. However, discrepancies between self-measured and objectively measured WC may result in misclassification of individuals when using established cut-off values. The aim of this study was to determine the accuracy of self-measured WC in adults at risk of T2DM and/or CVD, and to determine the anthropometric, demographic and behavioural characteristics associated with bias in self-measured WC. METHODS: Self-measured and objectively measured WC was obtained from 622 participants (58.4% female; mean age 43.4 +/- 5.3 years) in the Hoorn Prevention Study. The associations of gender, age, educational level, body mass index, smoking status, dietary habits, physical activity and sedentary behaviour with the discrepancies between self measured and objectively measured WC were analysed using independents t-test and one-way ANOVA. Bland-Altman plots were used to plot the agreement between the two measures. RESULTS: On average, self-measured WC was overestimated by 5.98 +/- 4.82 cm (P < 0.001). Overestimation was consistent across all subgroups, but was more pronounced in those who were younger and those with lower educational attainment. CONCLUSIONS: The results support self-measured WC as a useful tool for large-scale populations and epidemiological studies when objective measurement is not feasible, but overestimation should be taken into account when screening adults at risk of T2DM and/or CVD. PMID- 25274419 TI - Sequence analysis and expression regulation of rbp4 by 9-cis-RA in Megalobrama amblycephala. AB - Retinol-binding protein 4 (rbp4) is mainly synthesized in the liver, where it binds retinol and then enters the bloodstream, delivering retinol to cells. The full-length cDNA coding rbp4 was cloned from Megalobrama amblycephala. The amino acid sequence showed strong homology with the homologues of other vertebrates, and all structural and functional domains were highly conserved. The mRNA levels in different tissues and development stages detected by quantitative real-time PCR revealed that M. amblycephala rbp4 was highly expressed in liver (P < 0.001), but the lower levels were also detected in eyes, kidney, intestine, and spleen. During the different development stages, the rbp4 mRNA appeared until 28 hours post-fertilization (hpf), underwent a slight drop, and then gradually increased after 50 hpf. In addition, the promoter sequence of M. amblycephala rbp4 was obtained using thermal asymmetric interlaced PCR. Two single nucleotide polymorphism sites (-385A>G and -329C>T) were found in the promoter. Transfection with recombinant plasmids of two different haplotypes (GT, AC) showed that 9-cis retinoic acid (RA) increased the promoter activity, but the AC haplotype was more sensitive to RA. PMID- 25274421 TI - Laser-scribed graphene presents an opportunity to print a new generation of disposable electrochemical sensors. AB - Graphene application within electrochemical sensing has been widely reported, but mainly as a composite, which adds summative effects to an underlying electrode. In this work we report the use of laser-scribed graphene as a distinct electrode patterned on a non-conducting flexible substrate. The laser-scribed graphene electrode compared favourably to established carbon macroelectrodes when evaluating both inner sphere and outer sphere redox probes, providing promise of extensive utility as an electrochemical sensor. The laser-scribed graphene electrode demonstrated the fastest heterogeneous electron transfer rate of all the electrodes evaluated with a k(0) of 0.02373 cm s(-1) for potassium ferricyanide, which exceeds commercially available edge plane pyrolytic graphite at 0.00260 cm s(-1), basal plane pyrolytic graphite at 0.00033 cm s(-1) and the very slow and effectively irreversible electrochemistry observed using single layer graphene. Finally and most significantly, a proof of principle system was fabricated using the laser-scribed graphene as working electrode, counter electrode and underlying base for the Ag/AgCl reference electrode, all in situ on the same planar flexible substrate, removing the requirement of macroscale external electrodes. The planar three electrode format operated with the same optimal electrode characteristics. Furthermore, the fabrication is inexpensive, scalable and compatible with a disposable biosensor format, considerably widening the potential applications in electrochemical bio-sensing for laser-scribed graphene. PMID- 25274420 TI - Hematological, morphological, biochemical and hydromineral responses in Rhamdia quelen sedated with propofol. AB - Rhamdia quelen morphophysiological responses to propofol sedation were examined. The purpose was to investigate whether propofol would be a suitable drug to be used in fish transport procedures. Fish were exposed to 0, 0.4 or 0.8 mg L(-1) propofol for 1, 6 or 12 h in 40 L tanks, simulating open transport systems. Propofol was able to prevent the peak of cortisol levels experienced by the group exposed to 0 mg L(-1) propofol at 1 h. At 0.4 mg L(-1), propofol also preserved the stability of hematological (hematocrit, red blood cell count, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration), morphological (red blood cell area), biochemical (cortisol, glucose, lactate, total protein, ammonia, urea, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase) and hydromineral (Na(+), Cl(-) and K(+) plasma levels) indicators of stress. Such results suggest that sedation with propofol at 0.4 mg L(-1) is suitable for R. quelen transport. PMID- 25274422 TI - The elastin peptide (VGVAPG)3 induces the 3D reorganisation of PML-NBs and SC35 speckles architecture, and accelerates proliferation of fibroblasts and melanoma cells. AB - During melanoma tumour growth, cancerous cells are exposed to the immediate surrounding the micro- and macro environment, which is largely modified through the degradation of the extracellular matrix by fibroblast-derived metalloproteinases. Among the degradation products, (VGVAPG)3, an elastin peptide is known to stimulate the proliferation of both fibroblasts and cancerous cells by binding to the elastin-binding receptor and activating the MEK/ERK signal transduction pathway. As this process strongly modifies mRNA synthesis, we investigated its effect on the relative three-dimensional organisation of the major partners of the mRNA splicing machinery: promyelocytic nuclear bodies (PML NBs ) and splicing component 35 speckles (SC35) of normal fibroblasts and melanoma SK-MEL-28 cells. SC35 and PML-NBs proteins were immunolabeled and imaged by confocal microscopy within these cells cultured with (VGVAPG)3. Three dimensional reconstruction was performed to elucidate the organisation of PML-NBs and SC35 speckles and their spatial relationship. In G0 cells, SC35 speckles were sequestered in PML-NBs. Shortly after (VGVAPG)3 stimulation, the three dimensional organisation of PML-NBs and SC35 speckles changed markedly. In particular, SC35 speckles gradually enlarged and adopted a heterogeneous organisation, intermingled with PML-NBs. Conversely, inhibition of the elastin binding protein or MEK/ERK pathway induced a remarkable early sequestration of condensed SC35 speckles in PML-NBs, the hallmark of splicing inhibition. The 3D architecture of speckles/PML-NBs highlights the modulation in their spatial relationship, the multiple roles of PML-NBs in activation, inhibition and sequestration, and provides the first demonstration of the dependence of PML-NBs and SC35 speckles on the elastin peptide for these functions. PMID- 25274423 TI - Cardiac arrhythmias and electrolyte disturbances in colic horses. AB - BACKGROUND: Despite increased focus on cardiac arrhythmias in horses, the nature and prevalence is still poorly described. Case reports suggest that arrhythmias occurring secondary to systemic disease are seen more commonly in the clinic than arrhythmias caused by cardiac disease. The aim of this study was to investigate the prevalence of arrhythmias in colic horses referred for hospital treatment. Associations between electrolyte disturbances and arrhythmias were also investigated. RESULTS: Heart rate was 37.4 +/- 3.7 bpm in the control group, and 51.6 +/- 11.8 bpm, in the colic group, which was significantly different (P < 0.0001). AV blocks and SVPCs were found in both groups, however only colic horses showed VPCs. No significant difference between the two groups was found for AV blocks, SVPCs, and VPCs (P = 0.08 - 0.76). The mean levels of potassium, sodium, ionized calcium, and chloride were significantly lower in the colic group compared to the control group at admission. Mean levels of glucose and L-lactate were significantly elevated in the colic group (P < 0.05). CONCLUSIONS: This study describes prevalence of cardiac arrhythmias and electrolytes concentrations in colic horses compared to healthy controls. Although we only observed VPCs in the colic horses, no significant differences between colic horses and controls were found. Despite the colic horses having electrolyte changes at admission no correlation was found between the electrolyte disturbances and cardiac arrhythmias. Although no clear conclusions can be drawn from the present study, the results indicate that relatively mild colic per se is not pro-arrhythmogenic, whereas severe colic probably are more likely to result in ventricular arrhythmia. PMID- 25274424 TI - Nanostructured tungsten trioxide thin films synthesized for photoelectrocatalytic water oxidation: a review. AB - The recent developments of nanostructured WO3 thin films synthesized through the electrochemical route of electrochemical anodization and cathodic electrodeposition for the application in photoelectrochemical (PEC) water splitting are reviewed. The key fundamental reaction mechanisms of electrochemical anodization and cathodic electrodeposition methods for synthesizing nanostructured WO3 thin films are explained. In addition, the effects of metal oxide precursors, electrode substrates, applied potentials and current densities, and annealing temperatures on size, composition, and thickness of the electrochemically synthesized nanostructured WO3 thin films are elucidated in detail. Finally, a summary is given for the general evaluation practices used to calculate the energy conversion efficiency of nanostructured WO3 thin films and a recommendation is provided to standardize the presentation of research results in the field to allow for easy comparison of reported PEC efficiencies in the near future. PMID- 25274425 TI - Bacteria of the genus Erwinia found in the spermatheca of the laurel psyllid Trioza alacris. AB - Psylloidea are economically important insects causing serious damage to plants by direct feeding and/or vectoring bacterial pathogens. Results reported here indicate the presence of extracellular bacteria in the spermatheca of egg-laying Trioza alacris females. One phylotype, sharing 99 % identity with the non phytopathogenic bacterium Erwinia tasmaniensis, was identified regardless of methods applied or insect sampling year and location. This is the first study, achieved by ultrastructural, cultural, and 16S rRNA gene-based analysis, of an insect spermatheca microbiota. PMID- 25274426 TI - Dynamics in next-generation solar cells: time-resolved surface photovoltage measurements of quantum dots chemically linked to ZnO (101[combining macron]0). AB - The charge dynamics at the surface of the transparent conducting oxide and photoanode material ZnO are investigated in the presence and absence of light harvesting colloidal quantum dots (QDs). The time-resolved change in surface potential upon photoexcitation has been measured in the m-plane ZnO (101[combining macron]0) using a laser pump-synchrotron X-ray probe methodology. By varying the oxygen annealing conditions, and hence the oxygen vacancy concentration of the sample, we find that dark carrier lifetimes at the ZnO surface vary from hundreds of MUs to ms timescales, i.e. a persistent photoconductivity (PPC) is observed. The highly-controlled nature of our experiments under ultra-high vacuum (UHV), and the use of band-gap and sub-band gap photoexcitation, allow us to demonstrate that defect states ca. 340 meV above the valence band edge are directly associated with the PPC, and that the PPC mediated by these defects dominates over the oxygen photodesorption mechanism. These observations are consistent with the hypothesis that ionized oxygen vacancy states are responsible for the PPC in ZnO. The effect of chemically linking two colloidal QD systems (type I PbS and type II CdS-ZnSe) to the surface has also been investigated. Upon deposition of the QDs onto the surface, the dark carrier lifetime and the surface photovoltage are reduced, suggesting a direct injection of charge carriers into the ZnO conduction band. The results are discussed in the context of the development of next-generation solar cells. PMID- 25274427 TI - Long-term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide-naive chronic hepatitis B patients. AB - Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long-term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide-naive patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12-243 000 IU/mL), and median follow-up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was -0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87-55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80-333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event. PMID- 25274429 TI - A review of the receptor binding and pharmacological effects of N-methyltyramine. AB - N-methyltyramine (NMT) is a protoalkaloid isolated from various plant species. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an alpha-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis). Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown to fats to energy. PMID- 25274428 TI - Steady-state bioavailability of extended-release methylphenidate (MPH-MLR) capsule vs. immediate-release methylphenidate tablets in healthy adult volunteers. AB - OBJECTIVES: The objective of the study was to determine the relative bioavailability of an extended-release multilayer bead formulation of methylphenidate hydrochloride (MPH-MLR) 80 mg vs. methylphenidate immediate release (IR; Ritalin((r))) tablets as single and multiple doses in the fed state. METHODS: A single-center, multiple-dose, randomized, open-label, two-period crossover study conducted in 26 healthy adults assigned to 4 days of once-daily MPH-MLR 80 mg or IR methylphenidate 25 mg three times daily. RESULTS: MPH-MLR 80 mg produced reproducible biphasic profiles of plasma methylphenidate concentrations characterized by a rapid initial peak, followed by a moderate decline reaching a plateau ~5 h post dose, then a gradual increase culminating in an attenuated second peak ~7 h post dose. Maximum concentration was lower for MPH MLR 80 mg than IR methylphenidate 25 mg three times daily on day 1 (23.70 vs. 31.47 ng/mL); exposure was similar. The geometric mean ratios (MPH-MLR/IR methylphenidate [90 % CI]) of log-transformed area under the plasma drug concentration-time curve to the last measurable observation (day 1: 0.88 [84.75 91.80]; day 4: 0.84 [81.16-86.94]), and area under the plasma drug concentration extrapolated to infinity (day 1: 0.93 [88.57-97.28]; day 4: 0.88 [84.48-91.17]) were within the 80-125 % bioequivalence range. The mean +/- SD MPH-MLR 80-mg capsule day 4 area under the plasma drug concentration vs. time curve from 0 to 4 h (74.5 +/- 15.2 ng.h/mL) was greater than IR methylphenidate 25 mg three times daily (66.0 +/- 17.4 ng.h/mL), confirming steady-state levels during the study period. All treatment regimens were safe and well tolerated. CONCLUSION: MPH-MLR 80-mg capsule once daily or IR methylphenidate 25 mg three times daily provides comparable maximum methylphenidate concentrations and systemic exposure in the fed state. PMID- 25274430 TI - Irrepressible MONOPTEROS/ARF5 promotes de novo shoot formation. AB - In vitro regeneration of complete organisms from diverse cell types is a spectacular property of plant cells. Despite the great importance of plant regeneration for plant breeding and biotechnology, its molecular basis is still largely unclear and many important crop plants have remained recalcitrant to regeneration. Hormone-exposure protocols to trigger the de novo formation of either roots or shoots from callus tissue demonstrate the importance of auxin and cytokinin signaling pathways, and genetic differences in these pathways may contribute to the highly divergent responsiveness of plant species to regeneration protocols. In this study, we show that signaling through MONOPTEROS (MP)/AUXIN RESPONSE FACTOR 5 is necessary for the formation of shoots from Arabidopsis calli. Most strikingly, an irrepressible variant of MP, MPDelta, is sufficient for promoting de novo shoot formation through pathways involving the genetically downstream functions of SHOOT MERISTEMLESS (STM) and CYTOKININ RESPONSE FACTOR2 (CRF2). We conclude that the MPDelta genotype can promote de novo shoot formation and can be used to probe corresponding signaling pathways. PMID- 25274431 TI - Enhanced thermoelectric performance in CdO by nano-SiO2 inclusions. AB - We report enhanced thermoelectric (TE) performance in CdO by using thermally insulating nano-particles to mimic nano pores in the composite. Through simply mechanical alloying, we fabricated CdO-SiO2 composites with varying nano-SiO2 concentration from 0.1 to 3 at%. Due to the very low thermal conductivity of nano SiO2 distributed in the CdO matrix, the thermal conductivity of the composite was substantially reduced by about 80%, which lead to the dimensionless figure of merit (ZT) value increment about 28% (from 0.32 to 0.41) at 1000 K. TEM shows the nano inclusions formed within the CdO matrix and grain boundaries as well, which is thought to contribute to the reduction of thermal conductivity of the composite by additional scattering mechanism for the mid- to long-wavelength phonons. This facile and low-cost approach might be widely adopted and synergized to other TE materials systems to further improve their performance. PMID- 25274432 TI - Investigations into the nature of spontelectrics: nitrous oxide diluted in xenon. AB - The recent discovery of a new class of solids displaying bulk spontaneous electric fields as high as 10(8) V m(-1), so-called 'spontelectrics', poses fundamental and unresolved problems in solid state physics. The purpose of the present work is to delve more deeply into the nature of the interactions which give rise to the spontelectric effect in films of nitrous oxide (N2O), by observing the variation of the spontaneous field as the N2O molecules are physically removed from one another by dilution in Xe. Data, obtained using the ASTRID storage ring, are presented for films diluted by factors xi = Xe/N2O of 0.9 to 67, at deposition temperatures of 38 K, 44 K and 48 K, where films are laid down by deposition from a gas mixture. Results show that the spontelectric field decreases as xi increases and that at xi = 67 for 44 K deposition, the spontelectric effect is absent. Reflection-absorption infrared spectroscopy (RAIRS) data are also reported, providing insight into the structure of Xe/N2O films and specifically showing that N2O remains dispersed in the Xe/N2O films prepared here. A simplified theoretical model is developed which illustrates that electric fields can be understood in terms of dilution-dependent dipole orientation. This model is used to reproduce experimental data up to an average molecular separation, s, of >=1.25 nm apart, ~4 times that associated with pure solid N2O. The disappearance of the spontelectric effect at larger average distances of separation, between s = 1.25 nm and s = 1.75 nm, is a phenomenon which cannot be described by any existing model but which shows that dipole dipole interactions are an essential ingredient for the creation of the spontelectric state. PMID- 25274433 TI - Concurrent diseases and conditions in cats with renal infarcts. PMID- 25274434 TI - Letter to the editor. PMID- 25274435 TI - Interpretation of odds and risk ratios. PMID- 25274436 TI - Letter to the editor. PMID- 25274437 TI - A retrospective study of 1,098 blood samples with anemia from adult cats: frequency, classification, and association with serum creatinine concentration. AB - BACKGROUND: Frequency and classification of anemia in terms of regeneration status and erythrocyte indices are not well described in cats. OBJECTIVE: To determine frequency and regenerative status of anemia in samples from adult cats, to assess the sensitivity and specificity of macrocytosis and hypochromasia for detecting regenerative anemia (RA), and to evaluate the association of anemia with increased serum creatinine concentration (SC). STUDY POPULATION: Laboratory records from 30,503 blood samples from cats (2003-2011). METHODS: Clinicopathologic data reviewed retrospectively. Anemia defined as hematocrit (Ht) <=27%, red blood cell count (RBC) <=5.5 * 10(6)/MUL and hemoglobin (Hb) <=9.0 g/dL. RA defined by manual absolute reticulocyte count >50 * 10(3)/MUL. Macrocytosis was defined as mean corpuscular volume (MCV) >55 fL and hypochromasia as mean corpuscular hemoglobin concentration (MCHC) <31 g/dL. Cutoff for increased serum creatinine concentration was 1.6 mg/dL. RESULTS: Overall, 1,098 of 30,503 blood samples (3.6%) from cats fulfilled criteria for anemia, 633 of 1,098 (57.7%) classified as nonregenerative (NRA) and 465 of 1,098 (42.3%) as regenerative. RBC, Ht, and Hb were significantly lower in the RA compared to NRA group (P < .05). Sensitivity and specificity of the combined high MCV and low MCHC to detect samples with RA were 19.5 and 90.7%. SC was increased in 572 of the 1,098 anemic samples (52.1%) and in 11,121 of 29,405 of nonanemic samples (37.8%). CONCLUSIONS AND CLINICAL IMPORTANCE: Majority of anemic samples were classified as NRA. Anemia was more severe in cats with RA. Erythrocyte indices were not sensitive indicators of RA. PMID- 25274438 TI - Endoscopic assessment of the duodenum in dogs with inflammatory bowel disease. AB - BACKGROUND: Endoscopy is performed for direct inspection of the mucosa and acquisition of biopsies in dogs with inflammatory bowel disease (IBD). AIM: To evaluate the interobserver agreement in the endoscopic assessment of duodenal mucosa in dogs with IBD. METHODS: Thirty-five archived endoscopic images of grossly normal (n = 6) and inflamed (n = 29) duodenal mucosa were displayed to 3 expert and 5 trainee endoscopists. Each image was assessed independently by endoscopists for mucosal abnormalities using established indices (of hyperemia, granularity, friability, lymphatic dilatation, and erosions) or interpreted as normal mucosa (trial 1). A repeated trial (trial 2) was performed with the same images presented in random order 1 month later, and accompanied by a visual template. RESULTS: There was slight interobserver agreement in initial mucosal assessment for expert and trainee endoscopists in trial 1 (kappa <= 0.02, P > .05). Interobserver agreement improved in trial 2 for both expert and trainee endoscopists (kappa = 0.2, P > .05) for experts and (P < .05) for trainees. There was a significant (P < .01) improvement in trainee endoscopy scores of lesions from trial 1 to trial 2. Regression analysis showed a significant (P < .01) difference between expert versus trainee endoscopy scores in trial 1. Repeat lesion assessment aided by use of a visual template (trial 2) improved the overall scores of trainee endoscopists to near that of expert endoscopists (P = .06). CONCLUSIONS AND CLINICAL IMPORTANCE: Interobserver agreement of IBD mucosal appearance from endoscopic findings benefitted from operator experience. PMID- 25274439 TI - Characterization of kidney injury molecule-1 in cats. AB - BACKGROUND: Kidney disease (KD) is common in older cats and presumed to arise from subclinical kidney injuries throughout life. Sensitive markers for detecting kidney injury are lacking. Kidney injury molecule 1 (KIM-1) is a useful biomarker of kidney injury in humans and rodents. HYPOTHESIS/OBJECTIVES: Feline KIM-1 is conserved across species, expressed in kidney, and shed into urine of cats with acute kidney injury (AKI). The objectives were to characterize the feline KIM-1 gene and protein, assess available immunoassays for detecting KIM-1 in urine of cats, and identify KIM-1 expression in kidney sections. ANIMALS: Samples from 36 hospitalized and 7 clinically healthy cats were evaluated. Hospitalized cats were divided into 2 groups based on absence (n = 20) or presence (n = 16) of historical KD. METHODS: Feline KIM-1 genomic and complementary DNA sequences were amplified, sequenced and analyzed to determine the presence of isoforms, exon intron organization and similarity with orthologous sequences. Presence in urine was evaluated by immunoassay and expression in kidney by immunohistochemistry. RESULTS: Three expressed feline KIM-1 transcript variants comprising 894, 810, and 705 bp were identified in renal tissue. KIM-1 immunoassays yielded positive results in urine of cats with conditions associated with AKI, but not chronic KD. Immunohistochemistry of kidney sections identified KIM-1 in proximal tubular cells of cats with positive urine immunoassay results. CONCLUSIONS AND CLINICAL IMPORTANCE: Kidney injury molecule 1 was expressed in specific segments of the nephron and detected in urine of cats at risk of AKI. Urine KIM-1 immunoassay may be a useful indicator of tubular injury. PMID- 25274440 TI - Use of plasma renin activity to monitor mineralocorticoid treatment in dogs with primary hypoadrenocorticism: desoxycorticosterone versus fludrocortisone. AB - BACKGROUND: Measurement of plasma renin activity (PRA) is the gold standard for monitoring mineralocorticoid treatment in humans with primary hypoadrenocorticism (PH). OBJECTIVES: To compare PRA in dogs with newly diagnosed PH, dogs with diseases mimicking PH, and healthy dogs, and evaluate measurement of PRA to monitor therapeutic effects in dogs with PH treated with different mineralocorticoids. ANIMALS: Eleven dogs with newly diagnosed PH (group 1), 10 dogs with diseases mimicking PH (group 2), 21 healthy dogs (group 3), 17 dogs with treated PH (group 4). METHODS: In group 1, PRA was measured before treatment and at different times after initiating treatment. In groups 2 and 3, PRA was measured at initial presentation only. In group 4, no baseline PRA was obtained but PRA was measured once or every 1-6 months during treatment. Mineralocorticoid treatment consisted of fludrocortisone acetate (FC) or desoxycorticosterone pivalate (DOCP). RESULTS: Plasma renin activity before treatment was increased in dogs with PH compared to normal dogs and dogs with diseases mimicking PH with median activity of 27, 0.8, and 1.0 ng/mL/h, respectively. In dogs with PH, PRA decreased and normalized with mineralocorticoid treatment using DOCP but not with FC. In dogs treated with DOCP, PRA was lower than in dogs treated with FC. Plasma sodium concentrations were higher and potassium concentrations were lower with DOCP treatment compared to FC treatment. CONCLUSION AND CLINICAL IMPORTANCE: Plasma renin activity is a reliable tool for monitoring mineralocorticoid treatment. DOCP treatment more effectively suppresses PRA compared to FC in dogs with PH. PMID- 25274441 TI - Development and evaluation of an ELISA for the quantitation of anti-Lagenidium giganteum forma caninum antibodies in dogs. AB - BACKGROUND: Lagenidium giganteum forma caninum infection causes severe cutaneous and disseminated disease in dogs. Currently, diagnosis requires culture and rRNA gene sequencing. OBJECTIVE: To develop and evaluate an ELISA for quantitation of anti-L. giganteum f. caninum IgG in canine serum. ANIMALS: Sera were evaluated from 22 dogs infected with L. giganteum f. caninum, 12 dogs infected with Paralagenidium karlingii, 18 dogs infected with Pythium insidiosum, 26 dogs with nonoomycotic fungal infections or other cutaneous or systemic diseases, and 10 healthy dogs. METHODS: Antigen was prepared from a soluble mycelial extract of L. giganteum f. caninum. Optimal antigen and antibody concentrations were determined by checkerboard titration. Results were expressed as percent positivity (PP) relative to a strongly positive control serum. RESULTS: Medians and ranges for PP for each group were: L. giganteum f. caninum (73.9%, 27.9-108.9%), P. karlingii (55.0%, 21.0-90.6%), P. insidiosum (31.3%, 15.8-87.5%), nonoomycotic fungal infection or other cutaneous or systemic diseases (19.2%, 3.2-61.0%), and healthy dogs (9.9%, 7.6-24.6%). Using a PP cutoff value of 40%, sensitivity and specificity (with 95% CI) of the ELISA for detecting L. giganteum f. caninum infection in clinically affected dogs were 90.9% (72.2-97.5%) and 73.2% (60.4 83.0%), respectively. Specificity in dogs infected with P. karlingii was 41.7% (19.3-68.1%) and with P. insidiosum was 66.7% (43.8-83.7%). CONCLUSIONS AND CLINICAL IMPORTANCE: Quantitation of anti-L. giganteum f. caninum antibodies for detection of this infection in dogs has moderately high sensitivity but poor specificity, the latter because of substantial cross-reactivity with anti-P. karlingii and anti-P. insidiosum antibodies. PMID- 25274442 TI - Biopterin status in dogs with myxomatous mitral valve disease is associated with disease severity and cardiovascular risk factors. AB - BACKGROUND: Endothelial dysfunction (ED) has been suggested to be associated with myxomatous mitral valve disease (MMVD) in dogs. Tetrahydrobiopterin (BH4) is an important cofactor for production of the endothelium-derived vasodilator nitric oxide (NO). Under conditions of oxidative stress, BH4 is oxidized to the biologically inactive form dihydrobiopterin (BH2). Thus, plasma concentrations of BH2 and BH4 may reflect ED and oxidative stress. OBJECTIVE: To determine plasma concentrations of BH2 and BH4 in dogs with different degrees of MMVD. ANIMALS: Eighty-four privately owned dogs grouped according to ACVIM guidelines (37 healthy control dogs including 13 Beagles and 24 Cavalier King Charles Spaniels [CKCSs], 33 CKCSs with MMVD of differing severity including 18 CKCSs [group B1] and 15 CKCSs [group B2], and 14 dogs of different breeds with clinical signs of congestive heart failure [CHF] because of MMVD [group C]). METHODS: Dogs underwent clinical examination including echocardiography. Plasma concentrations of BH2 and BH4 were measured using high-performance liquid chromatography with fluorescence detection. RESULTS: Higher plasma BH4 and BH2 concentrations were found with dogs in CHF compared with all other groups (control, B1 and B2; P <= .001). Females had higher concentrations of BH4 and BH4/BH2 (P <= .0003). BH4/BH2 was found to decrease with age (P < .0001). Cardiovascular risk factors in humans such as passive smoking (P <= .01) and increased body weight (P <= .009) were associated with lower BH4 concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: Age, sex, body weight, passive smoking, and cardiac status are associated with plasma biopterin concentration in dogs. Additional studies should clarify the clinical implications of the findings. PMID- 25274443 TI - Phase II evaluation of VDC-1101 in canine cutaneous T-cell lymphoma. AB - BACKGROUND: Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC-1101 (formerly known as GS-9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC-1101 to the skin. HYPOTHESIS/OBJECTIVES: The primary study objective was to identify the objective response rate (ORR) to VDC-1101 in canine CTCL; secondary objectives included characterization of progression-free survival (PFS) and adverse events (AEs). ANIMALS: Twelve dogs with chemotherapy-naive or relapsed, histologically and immunohistochemically confirmed CTCL. METHODS: Dogs received VDC-1101 as a 30-minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently. RESULTS: In 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE. CONCLUSIONS AND CLINICAL IMPORTANCE: VDC-1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis. PMID- 25274444 TI - Outcome in neuroblastoma. AB - OBJECTIVE: To determine outcome of neuroblastoma (NBL) in children under 18 mo of age who had been treated with national protocols. METHODS: The characteristics and treatment outcomes of 27 children were evaluated retrospectively. RESULTS: The event-free survival (EFS) at 60 and 108 mo were 84.7 % +/- 7.7 and 72.6 % +/- 7.7, respectively. The overall survival (OS) was 91.7 % +/- 8 at 108 mo. The only significant risk factor for OS in children with neuroblastoma was the treatment response at the end of therapy (p = 0.001). "Wait and see" policy was applied to two infants with low risk NBL and one infant with stage 4S neuroblastoma and all 3 of these infants have been in remission at last followup. Four of the five patients with MYCN-amplified neuroblastoma were alive at a median follow-up time of 54 mo (range: 5-108 mo). CONCLUSIONS: The EFS and OS of the present group were similar to that of the previous series which included children under 18 mo of age with neuroblastoma. Well known prognostic factors did not affect EFS and OS significantly; this may be related to the retrospective design of the present study and the small number of patients reviewed. High survival rate in infants with MYCN-amplified tumors suggests the difference in the biology of infant neuroblastoma. PMID- 25274445 TI - Bayesian approach for flexible modeling of semicompeting risks data. AB - Semicompeting risks data arise when two types of events, non-terminal and terminal, are observed. When the terminal event occurs first, it censors the non terminal event, but not vice versa. To account for possible dependent censoring of the non-terminal event by the terminal event and to improve prediction of the terminal event using the non-terminal event information, it is crucial to model their association properly. Motivated by a breast cancer clinical trial data analysis, we extend the well-known illness-death models to allow flexible random effects to capture heterogeneous association structures in the data. Our extension also represents a generalization of the popular shared frailty models that usually assume that the non-terminal event does not affect the hazards of the terminal event beyond a frailty term. We propose a unified Bayesian modeling approach that can utilize existing software packages for both model fitting and individual-specific event prediction. The approach is demonstrated via both simulation studies and a breast cancer data set analysis. PMID- 25274448 TI - Entanglement entropy and entanglement spectrum of triplet topological superconductors. AB - We analyze the entanglement entropy properties of a 2D p-wave superconductor with Rashba spin-orbit coupling, which displays a rich phase-space that supports non trivial topological phases, as the chemical potential and the Zeeman term are varied. We show that the entanglement entropy and its derivatives clearly signal the topological transitions and we find numerical evidence that for this model the derivative with respect to the magnetization provides a sensible signature of each topological phase. Following the area law for the entanglement entropy, we systematically analyze the contributions that are proportional to or independent of the perimeter of the system, as a function of the Hamiltonian coupling constants and the geometry of the finite subsystem. For this model, we show that even though the topological entanglement entropy vanishes, it signals the topological phase transitions in a finite system. We also observe a relationship between a topological contribution to the entanglement entropy in a half-cylinder geometry and the number of edge states, and that the entanglement spectrum has robust modes associated with each edge state, as in other topological systems. PMID- 25274446 TI - Aggregate complexes of HIV-1 induced by multimeric antibodies. AB - BACKGROUND: Antibody mediated viral aggregation may impede viral transfer across mucosal surfaces by hindering viral movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible mucosal CD4 T cells and dendritic cells. These functions may work together to provide effective immune exclusion of virus from mucosal tissue; however little is known about the antibody characteristics required to induce HIV aggregation. Such knowledge may be critical to the design of successful immunization strategies to facilitate viral immune exclusion at the mucosal portals of entry. RESULTS: The potential of neutralizing and non-neutralizing IgG and IgA monoclonals (mAbs) to induce HIV-1 aggregation was assessed by Dynamic light scattering (DLS). Although neutralizing and non-neutralizing IgG mAbs and polyclonal HIV-Ig efficiently aggregated soluble Env trimers, they were not capable of forming viral aggregates. In contrast, dimeric (but not monomeric) IgA mAbs induced stable viral aggregate populations that could be separated from uncomplexed virions. Epitope specificity influenced both the degree of aggregation and formation of higher order complexes by dIgA. IgA purified from serum of uninfected RV144 vaccine trial responders were able to efficiently opsonize viral particles in the absence of significant aggregation, reflective of monomeric IgA. CONCLUSIONS: These results collectively demonstrate that dIgA is capable of forming stable viral aggregates providing a plausible basis for testing the effectiveness of aggregation as a potential protection mechanism at the mucosal portals of viral entry. PMID- 25274447 TI - Non communicable disease multimorbidity and associated health care utilization and expenditures in India: cross-sectional study. AB - BACKGROUND: Non communicable disease (NCD) multimorbidity is increasingly becoming common in high income settings but little is known about its epidemiology and associated impacts on citizens and health systems in low and middle-income countries (LMICs). We aim to examine the socio-demographic distribution of NCD multimorbidity (>=2 diseases) and its implications for health care utilization and out-of-pocket expenditure (OOPE) in India. METHODS: We analyzed cross-sectional nationally representative data from the World Health Organisaion Study on Global Ageing and Adult Health (WHO-SAGE), conducted in India during 2007. Multiple logistic regression was used to determine socio demographic predictors of self-reported multimorbidity. A two part model was used to assess the relationship between number of NCDs and health care utilization including OOPE. RESULTS: 28.5% of the sample population had at least one NCD and 8.9% had NCD multimorbidity. The prevalence of multimorbidity increased from 1.3% in 18-29 year olds to 30.6% in those aged 70 years and above. Mean outpatient visits in the preceding 12 months increased from 2.2 to 6.2 and the percentage reporting an overnight hospital stay in the past 3 years increased from 9% to 29% in those with no NCD and >=2 NCDs respectively (p <0.001).OOPE incurred during the last outpatient visit increased from INR 272.1 (95% CI = 249.0-295.2) in respondents with no NCDs to INR 454.1 (95% CI = 407.8-500.4) in respondents with >=2 NCDs. However, we did not find an increase in OOPE during the last inpatient visit with number of NCDs (7865.9 INR for those with zero NCDs compared with 7301.3 for those with >=2 NCDs). For both outpatient and inpatient OOPE, medicine constitutes the largest proportion of spending (70.7% for outpatient, 53.6% for inpatient visit), followed by spending for health care provider (14.0% for outpatient, 12.2% for inpatient visit). CONCLUSION: NCD multimorbidity is common in the Indian adult population and is associated with substantially higher healthcare utilization and OOPE. Strategies to address the growing burden of NCDs in LMICs should include efforts to improve the management of patients with multimorbidity and reduce associated financial burden to individuals and households. PMID- 25274449 TI - Association between visual impairment and sleep duration: analysis of the 2009 National Health Interview Survey (NHIS). AB - BACKGROUND: Visual impairment (VI) is associated with increased mortality and health factors such as depression and cardiovascular disease. Epidemiologic studies consistently show associations between sleep duration with adverse health outcomes, but these have not systematically considered the influence of VI. The aim of this study was to ascertain the independent association between VI and sleep duration using the National Health Interview Survey (NHIS) data. We also examined whether race/ethnicity influenced these associations independently of sociodemographic and medical characteristics. METHODS: Our analysis was based on the 2009 NHIS, providing valid sleep and vision data for 29,815 participants. The NHIS is a cross-sectional household interview survey utilizing a multistage area probability design. Trained personnel from the US census bureau gathered data during face-to-face interview and obtained socio-demographic, self-reported habitual sleep duration and physician-diagnosed chronic conditions. RESULTS: The mean age of the sample was 48 years and 56% were female. Short sleep and long sleep durations were reported by 49% and 23% of the participants, respectively. Visual impairment was observed in 10%. Multivariate-adjusted logistic regression models showed significant associations between VI and short sleep (OR = 1.6, 95% CI = 1.5-1.9 and long sleep durations (OR = 1.6, 95% CI = 1.3-1.9). These associations persisted in multivariate models stratified by race-ethnic groups. CONCLUSION: Visual impairment was associated with both short and long sleep durations. Analysis of epidemiologic sleep data should consider visual impairment as an important factor likely to influence the amount of sleep experienced habitually. PMID- 25274452 TI - Longitudinal relationships between individual and class norms supporting dating violence and perpetration of dating violence. AB - Dating violence is commonly perpetrated in adolescence, making it imperative to understand risk factors in order to inform prevention efforts. Although individual norms supporting dating violence are strongly related to its perpetration, few studies have examined their longitudinal impact. Moreover, the influence of class norms (i.e., norms for students in the same grade, cohort, and school) supporting dating violence on perpetration has rarely been studied. The current study examined longitudinal relationships between individual and class norms supporting dating violence and perpetration of physical and psychological dating violence. Participants were two cohorts of sixth graders from 37 schools who were in dating relationships at Wave 1 and 6 months later at Wave 2 (N = 2,022; 43% female; 52% African American, 21% Latino/a, 20% White, and 7% other). The analyses used a multilevel approach, with students represented at Level 1 and classes (n = 74) at Level 2. The models tested direct effects of Wave 1 individual and class norms supporting dating violence on subsequent changes in perpetration of dating violence at Wave 2 and the extent to which gender moderated these relationships. The findings indicated that greater individual norms supporting male dating violence predicted greater change in perpetration of physical and psychological dating violence and greater individual norms supporting female dating violence predicted greater change in perpetration of psychological dating violence. Greater class norms supporting male dating violence predicted greater change in perpetration of physical dating violence; whereas greater class norms supporting female dating violence predicted less change in perpetration of physical dating violence. These findings highlight the need to address norms in early adolescence. PMID- 25274451 TI - Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review. AB - Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities. In systemic autoimmune conditions, a quantitative and qualitative impairment of regulatory T cells has been shown previously, and in parallel, a relative dominance of pro-inflammatory Th17 cells has been introduced. Moreover, the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD. Additionally, we depict a cytokine imbalance, which give raise to a biased T cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of interleukin (IL)-6, IL-12, IL-17, IL-23, and interferon (IFN)-gamma were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression toward serious systemic autoimmune diseases. Moreover, the early targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage. PMID- 25274454 TI - Sudden deafness as an initial presenting symptom of posterior inferior cerebellar artery infarction: two case reports. AB - OBJECTIVE: This paper reports on two patients with posterior inferior cerebellar artery infarction whose only presenting complaint was acute unilateral hearing loss. CASE REPORTS: In the two cases reported, sudden hearing loss was an initial symptom, with no other neurological signs. Infarction in the territory of the posterior inferior cerebellar artery was diagnosed using brain magnetic resolution imaging. The patients had some degree of hearing improvement 3 or 4 days after initial treatment. CONCLUSION: In this article, new cases of posterior inferior cerebellar artery infarction presenting as sudden deafness, without prominent neurological signs, are described. Otologists should be aware that hearing loss can sometimes appear as a warning sign of impending posterior inferior cerebellar artery infarction. PMID- 25274453 TI - Impact of multiple-dose versus single-dose inhaler devices on COPD patients' persistence with long-acting beta2-agonists: a dispensing database analysis. AB - BACKGROUND: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients' persistence with long-acting beta2-agonists (LABAs). AIMS: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. METHODS: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. RESULTS were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. RESULTS: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76-1.26, P=0.99). Over 80% re-started or switched medication. CONCLUSIONS: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients' persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID- 25274455 TI - The gene polymorphisms of UCP1 but not PPAR gamma and TCF7L2 are associated with diabetic retinopathy in Chinese type 2 diabetes mellitus cases. AB - PURPOSE: This study was designed to investigate the association between the polymorphisms in three insulin resistance-related genes, uncoupling protein-1 (UCP1), peroxisome proliferator-activated receptor gamma (PPARgamma) and transcription factor 7-like 2 (TCF7L2) and the susceptibility to diabetic retinopathy (DR) in a Chinese type 2 diabetes mellitus (T2DM) cohort. METHODS: A total of 792 patients with T2DM were enrolled and categorized into two groups: (1) the DR group consisted of 448 patients, which was further subclassified into a proliferative DR (PDR) group with 220 patients and a non-proliferative DR (NPDR) group with 228 patients; (2) the diabetes without retinopathy (DNR) group, comprised 344 patients who had no signs of DR. Single-nucleotide polymorphisms (SNPs), rs1800592 in the UCP1 gene, rs1801282, rs3856806 and rs1249719 in the PPARgamma gene and rs11196205 in the TCF7L2 gene were genotyped in this study. RESULTS: For SNP rs1800592 of the UCP1 gene, the frequency of allele G and genotype GG was significantly higher in the PDR group than in the DNR group (allele OR: 1.32, 95% CI: 1.03-1.68, p = 0.03; genotype OR: 1.72, 95%CI: 1.06 2.79, p = 0.03). No evident association was found between the allele frequencies and genotype distributions of any individual SNP in the PPARgamma or TCF7L2 genes and DR, PDR or NPDR. Haplotype analyses of the PPARgamma gene did not provide any evidence for an association with DR, PDR or NPDR in this Chinese T2DM cohort. CONCLUSIONS: This study suggests that the SNP rs1800592 in the UCP1 gene is associated with increased risk of PDR in the Chinese T2DM population. PMID- 25274457 TI - Experimental and numerical analysis of mass transfer in a binary mixture with Soret effect in the presence of weak convection. AB - One of the targets of the experiment IVIDIL (Influence Vibrations on Diffusion in Liquids) conducted on-board ISS was to study the response of binary mixtures to vibrational forcing when the density gradient results from thermal and compositional variations. Compositional variations were created by the Soret effect and can strengthen or weaken the overall density gradient and, consequently, the response to vibrational forcing. We present the results of two experimental runs conducted on-board ISS in the frame of the experiment IVIDIL for low and strong vibrational forcing. The experimental observations revealed that a significant mean flow is set within 2 minutes after imposing vibrations and later in time it varies weakly and slowly due to the Soret effect. A mathematical model has been developed to compute the thermal and concentration fields in the experiment IVIDIL and verify the accuracy of picture processing based on the classical approach used in non-convective systems with the Soret effect. The effect of temperature and concentrations perturbations by joint action of vibrational convection and Soret effect on long time scale are carefully examined. The model demonstrates that image processing used for non convective systems is suitable for the systems with vibration-affected thermodiffusion experiment. PMID- 25274456 TI - Identification of the 2-tridecanone responsive region in the promoter of cytochrome P450 CYP6B6 of the cotton bollworm, Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Eukaryote transcription is controlled by regulatory DNA sequences and transcription factors, so transcriptional control of gene plays a pivotal role in gene expression. In this study, we identified the region of the CYP6B6 gene promoter of Helicoverpa armigera which responds to the plant secondary toxicant 2 tridecanone. Transient transfection assay results from five of stepwise deletion fragments linked to the luciferase reporter gene revealed that the promoter activity of each CYP6B6 fragment was significantly higher than that of their basal activity after the Sf9 cells were treated with 2-tridecanone. Among all, the fragment spanning -373 to +405 bp of the CYP6B6 promoter showed an obviously 2-tridecanone inducibility (P<0.0001), which might have the 2-tridecanone responsive element based on promoter activity. Electrophoretic mobility shift assays revealed that the nuclear protein extracted from midgut of the 6th instar larva of H. armigera, reared on 10 mg 2-tridecanone per gram artificial diet for 48 h, could specifically bind to the active region from -373 to 21 bp of the CYP6B6 promoter. The combination feature also appeared when using a shorter fragment from -292 to -154 bp of the CYP6B6 promoter. Taken together, we found a 2-tridecanone core responsive region between -292 and -154 bp of the CYP6B6 promoter. This may lead us to a better understanding of transcriptional mechanism of P450 gene and provide very useful information for the pest control. PMID- 25274450 TI - The Clinical Features of Sarcoidosis: A Comprehensive Review. AB - Sarcoidosis has innumerable clinical manifestations, as the disease may affect every body organ. Furthermore, the severity of sarcoidosis involvement may range from an asymptomatic state to a life-threatening condition. This manuscript reviews a wide variety of common and less common clinical characteristics of sarcoidosis. These manifestations are presented organ by organ, although additional sections describe systemic and multiorgan presentations of sarcoidosis. The lung is the organ most commonly involved with sarcoidosis with at least 90 % of sarcoidosis patients demonstrating lung involvement in most series. The skin, eye, liver, and peripheral lymph node are the next most commonly clinically involved organs in most series, with the frequency of involvement ranging from 10 to 30 %. The actual frequency of sarcoidosis organ involvement is probably much higher as it is frequently asymptomatic and may avoid detection. This is particularly common with lung, liver, cardiac, and bone involvement. Cardiac sarcoidosis is present in 25 % of all sarcoidosis but only causes clinical problems in 5 % of them. Nevertheless, unlike sarcoidosis involvement of most other organs, it may be suddenly fatal. Therefore, it is important to screen for cardiac sarcoidosis in all sarcoidosis patients. All sarcoidosis patients should also be screened for eye involvement as asymptomatic patients may have eye involvement that may cause permanent vision impairment. Pulmonary fibrosis from sarcoidosis is usually slowly progressive but may be life threatening because of the development of respiratory failure, pulmonary hypertension, or hemoptysis related to a mycetoma or bronchiectasis. Some manifestations of sarcoidosis are not organ-specific and probably are the result of a release of mediators from the sarcoid granuloma. Two such manifestations include small fiber neuropathy and fatigue syndromes, and they are observed in a large percentage of patients. PMID- 25274458 TI - Soret separation in a binary liquid mixture near its critical temperature. AB - The values of transport coefficients near a critical point are typically enhanced compared to the values in the classical region far away from a critical point. We report on the impact of the asymptotic behavior of the mass diffusion near the critical region on the Soret separation of the components in a model binary mixture. Concentration patterns are numerically investigated in the case of a spatially varying temperature. The Soret separation in ordinary mixture leads to the establishing of a linear concentration distribution in a steady state. The presence of the critical point redistributes the concentration field, it creates a thin layer with sharp concentration change at the critical region which can be seen as a horizontal plateau on vertical profiles. Large concentration gradients are established across this layer. The analysis showed that the kinetic of the separation significantly depends on whether the critical temperature is inside or outside of the applied temperature region, which is T(cold) <= T <= T(hot). Critical separation road is suggested for the case when T(cr) is located inside this region, T(cold) <= T(cr) <= T(hot). PMID- 25274459 TI - Stability of parent-reported food allergy in six and 7-year-old children: the first 5 years of the Finnish allergy programme. AB - AIM: The Finnish national allergy programme was introduced in 2008 to decrease the burden of allergy in the population. This study, carried out in 2013, evaluated the prevalence of parent-reported food allergies, treated with an avoidance diet until early school age, and discussed the rates in relation to those found in an identical study in 2009. METHODS: School health nurses used a structured questionnaire to interview the parents of 1653 children aged of six or seven in the first year of elementary school. The criterion for a parent-reported food allergy was that the parents considered it necessary for their child to follow an avoidance diet at school. RESULTS: In 2013, 6.1% of the children were allergic to at least one food and 2.5% of the children were allergic to basic foods, such as cows' milk, eggs and wheat, compared with 2.7% in 2009. A significant decrease was seen in allergies to nuts, fruits and vegetables. CONCLUSION: Parent-reported allergies to basic foods, such as cow's milk, eggs and wheat, remained rather stable in first graders of elementary schools during the first 5 years of the Finnish national allergy programme, but allergies to nuts, fruits and vegetables decreased. PMID- 25274460 TI - Effects of exercise on ankle proprioception in adult women during 16 weeks of training and eight weeks of detraining. AB - This study evaluates the effects of training and detraining on ankle proprioception in terms of kinesthesia in adult women. Sixty participants were randomly assigned to three groups. Tai Chi and Brisk Walking Groups went through a 16-week training period followed by an eight-week detraining period. The ankle plantar-flexion, dorsal-flexion, inversion, and eversion kinesthesia were measured every four weeks. The ankle kinesthesia in plantar/dorsal flexion of both exercise groups decreased, but the Tai Chi Group decreased more and sooner than the Brisk Walking Group. The training effects of Tai Chi exercise were retained but diminished during the detraining. The training effects of Brisk Walking exercise were not retained. The kinesthesia of ankle inversion and eversion remained unchanged after training. The results suggest that Tai Chi exercise is more effective in training ankle proprioception in plantar and dorsal flexion and in retaining the training effects compared with Brisk Walking exercise. PMID- 25274461 TI - Coronary revascularization and TAVI: before, during, after or never? AB - Aortic valve stenosis and coronary artery disease (CAD) frequently coexist in elderly patients selected for transcatheter aortic valve implantation (TAVI). Therapeutic strategies to manage concomitant obstructive CAD are therefore an important consideration in the overall management of patients with severe aortic stenosis (AS) undergoing TAVI. Conventional surgical aortic valve replacement and coronary artery bypass grafting is the treatment of choice for low and intermediate risk patients with symptomatic severe AS and concomitant obstructive CAD. However, TAVI and percutaneous coronary intervention (PCI) are viable alternative options for high-risk or inoperable patients presenting with symptomatic severe AS. PCI has been shown to be feasible and safe in selected high-risk or inoperable patients with symptomatic severe AS. However, the optimal timing of PCI relative to the TAVI procedure has been a subject of debate. The most frequent approch is staged PCI typically performed a few weeks prior to TAVI. However, concomitant PCI has also been shown to be a feasible and safe approach, particularly in patients with a low level of CAD complexity and an absence of severe renal impairment. Conversely, staged PCI should be considered in patients with higher degrees of CAD complexity, particularly in the presence of severe renal impairment. The aim of the present review is to discuss the safety and feasibility of performing PCI in elderly patients with severe AS and the optimal timing of PCI relative to the TAVI procedure using the most up-to date available evidence. PMID- 25274462 TI - Is TAVI superior to surgery in high-risk patients? Insight into the concept of individual risk assessment. AB - The prevalence of aortic valve stenosis (AS) is growing in developed countries because its prevalence increases with age. A growing number of elderly patients are currently referred to specialized centres to be evaluated for potential therapeutic strategies. Indeed, two techniques are nowadays able to treat high risk AS patients: TAVI and surgical replacement (AVR). It is the purpose of the present review to summarize current knowledge on safety and efficacy of AVR and TAVI in high-risk patients; to focus on some aspects of recently published guidelines; to emphasize the growing importance of pre-operative individual risk assessment, which is considered the real crucial point for patient selection and trial's comparisons. Indeed, it is worth of noting that currently adopted risk scores do not show satisfactory performances. Accordingly, it becomes of utmost importance to investigate several baseline but still neglected patients' characteristics (e.g. frailty, functional status, co-morbid conditions, etc.), as well as their pathogenetic relationships with interventional results and follow up prognosis. All these items are emphasized in the present review. Finally, we have tried to anticipate future scenarios in terms of both ongoing clinical trials and improvements of risk-scores. PMID- 25274463 TI - [Isolated capitate fractures in the frontal plane]. AB - Isolated fractures of the capitate in the frontal plane are both very rare and most of the time very discreet. There is a great risk to miss such fractures with potential longterm consequences. The following report of two independent patients highlights the importance of computed tomography in order to verify fractures and initiate adequate treatment. PMID- 25274464 TI - The new kidney allocation system (KAS) and the highly sensitized patient: expect the unexpected. PMID- 25274465 TI - Antimicrobial stewardship: an international emergency. PMID- 25274466 TI - Reply to flawed assumptions used to defend screening mammography. PMID- 25274467 TI - Ultra-minimally invasive cardiac surgery: robotic surgery and awake CABG. AB - The recognition of the significant advantages of minimizing surgical trauma has resulted in the development of minimally invasive surgical procedures. Endoscopic surgery confers the benefits of minimally invasive surgery upon patients, and surgical robots have enhanced the ability and precision of surgeons. Consequently, technological advances have facilitated totally endoscopic robotic cardiac surgery, which has allowed surgeons to operate endoscopically, rather than through a median sternotomy, during cardiac surgery. Thus, repairs for structural heart conditions, including mitral valve plasty, atrial septal defect closure, multivessel minimally invasive direct coronary artery bypass grafting and totally endoscopic coronary artery bypass graft surgery (CABG), can be totally endoscopic. On the other hand, general anesthesia remains a risk in patients who have severe carotid artery stenosis before surgery, as well as in those with a history of severe cerebral infarction or respiratory failure. In this study, the potential of a new awake CABG protocol using only epidural anesthesia was investigated for realizing day surgery and was found to be a promising modality for ultra-minimally invasive cardiac surgery. We herein review robot-assisted cardiac surgery and awake off-pump coronary artery bypass grafting as ultra-minimally invasive cardiac surgeries. PMID- 25274469 TI - Estimated risk of radiation-induced cancer from paediatric chest CT: two-year cohort study. AB - BACKGROUND: The increasing absolute number of paediatric CT scans raises concern about the safety and efficacy and the effects of consecutive diagnostic ionising radiation. OBJECTIVE: To demonstrate a method to evaluate the lifetime attributable risk of cancer incidence/mortality due to a single low-dose helical chest CT in a two-year patient cohort. MATERIALS AND METHODS: A two-year cohort of 522 paediatric helical chest CT scans acquired using a dedicated low-dose protocol were analysed retrospectively. Patient-specific estimations of radiation doses were modelled using three different mathematical phantoms. Per-organ attributable cancer risk was then estimated using epidemiological models. Additional comparison was provided for naturally occurring risks. RESULTS: Total lifetime attributable risk of cancer incidence remains low for all age and sex categories, being highest in female neonates (0.34%). Summation of all cancer sites analysed raised the relative lifetime attributable risk of organ cancer incidence up to 3.6% in female neonates and 2.1% in male neonates. CONCLUSION: Using dedicated scan protocols, total lifetime attributable risk of cancer incidence and mortality for chest CT is estimated low for paediatric chest CT, being highest for female neonates. PMID- 25274468 TI - Indications, advantages and limitations of perinatal postmortem imaging in clinical practice. AB - Just as there is a range of paediatric imaging techniques available during life, a similar repertoire is available as part of the foetal and perinatal postmortem examination. In this article, we review the literature regarding the diagnostic utility of postmortem radiography, US, CT and MRI in this clinical setting. There is limited direct evidence on the diagnostic utility of any of these techniques, apart from postmortem MRI, which when combined with other noninvasive investigations, has been shown to be highly sensitive and specific for many foetal postmortem diagnoses. The main disadvantages of postmortem MRI include the longer duration of imaging, the need for appropriate training in the interpretation of normal postmortem changes, and possible non-diagnostic imaging examinations in early gestation foetuses. As less-invasive autopsy becomes increasingly available, the true utility of these techniques will evolve, and clinical guidelines for maximal diagnostic yield can be developed. PMID- 25274470 TI - Seasonal foreign bodies: the dangers of winter holiday ornamentation. AB - Foreign bodies, whether ingested, aspirated or retained in the soft tissues, are a particular hazard to pediatric patients. Ornamentation associated with the winter holidays is an uncommon source of foreign bodies in children, and many of these foreign bodies have a distinct appearance on imaging. Knowledge of these appearances and the unusual features of winter holiday foreign bodies might facilitate their identification. PMID- 25274471 TI - Characteristic odor components of volatile oil from the cultivation medium of Lactobacillus acidophilus. AB - Volatile oils obtained from both the liquid medium after incubation (MAI) and liquid medium before incubation (MBI) in the cultivation process of Lactobacillus acidophilus were isolated by hydrodistillation (HD) and analyzed to investigate the utility of the liquid waste. The composition of the volatile oils was analyzed by capillary gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). In total, 46 and 19 compounds were detected in the volatile oils from MAI (MAI oil) and MBI (MBI oil), respectively. The principle components of MAI oil were fatty acids, including pentanoic acid (12.75%), heptanoic acid (14.05%), and nonanoic acid (14.04%). The important aroma-active compounds in the oils were detected by GC-MS/Olfactometry (GC-O), and their intensity of aroma were measured by aroma extraction dilution analysis (AEDA). Pyrazines were determined as key aroma components; in particular, 2-ethyl-5-methylpyrazine was the most primary aroma-active compound in MAI oil. In addition, as the characteristic aroma-active compounds, 3-(methylthio)-propanal, trimethylpyrazine, and pentanoic acid were also detected in MAI oil. These results imply that the waste medium after incubation of L. acidophilus may be utilized as a source of volatile oils. PMID- 25274472 TI - Study on the effect of polydimethylsiloxane from the viewpoint of oxygen content in oil. AB - It has been reported that polydimethylsiloxane (PDMS) inhibits oxygen dissolution into oil by forming a monolayer on the surface of the oil, thereby reducing thermal oxidation. In the present study, the distribution of PDMS was determined by the inductively coupled plasma atomic emission spectroscopy in standing PDMS containing canola oil. PDMS did not disperse in the oil uniformly, but there was a tendency that the PDMS concentration decreased as the depth of oil increased, and the concentration of the bottom part was the lowest. When canola oil was covered with PDMS by dropping it gently on the surface of the oil and kept at 60 degrees C, the oxygen content and oxidation of the oil were lower than those of the control canola oil. PDMS-containing canola oil and canola oil were heated with stirring from room temperature to 180 degrees C, and then allowed to stand while cooling. Oxygen contents of both oils increased up to 120 degrees C then dropped abruptly. While cooling, oxygen contents sharply increased at 100 degrees C and approached the saturation content, although the increase for PDMS containing canola oil was a little slow. Likewise, the thermal treatment of PDMS containing canola oil and canola oil at 180 degrees C for 1 h under stirring was repeated 5 times with standing intervals for 2-3 days at room temperature. Oxidation of the former was less than that of the latter in spite of its high oxygen content. In conclusion, the oxygen content of oil with/without PDMS addition increased, but oxidation of PDMS-containing canola oil was inhibited both during heating and standing with intermittent heating. It was suggested that PDMS exerted its antioxidative effect regardless of whether it covered the oil or was dispersed in it. PMID- 25274473 TI - Study on Cinnamomum oils: compositional pattern of seven species grown in Vietnam. AB - The leaf essential oils of seven Vietnamese species of the genus Cinnamomum were analyzed by gas chromatography-flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC/MS). The results showed that the species fall into three groups in which one group contains aromatic components, while the second group contains both terpenes and aromatic constituents and the third group contains only terpene constituents. The first group had only Cinnamomum curvifolium as its member and produced oil rich in benzyl cinnamate and benzyl benzoate. The second group producing mixture of phenylpropanoids and oxygenated monoterpene components includes leaves of Cinnamomum kunstleri (methyl eugenol, terpinen-4-ol and 1,8-cineole) and Cinnamomum mairei (eugenol, 1, 8-cineole, neryl acetate and eugenol acetate). The third group rich in terpene constituents could also be divided into two classes. The first class produced oils rich in monoterpene components and includes Cinnamomum damhaensis (linalool, alpha pinene, beta-pinene and 1,8-cineole), Cinnamomum cambodianum (linalool and terpinen-4-ol) and Cinnamomum caryophyllus (1,8-cineole, alpha-pinene and camphene). The second class contains oil with abundance of sesquiterpene compounds and peculiar to Cinnamomum rigidifolium (alpha-selinene, beta caryophyllene and alpha-copaene). This paper discusses further the chemotaxonomic importance of these results and previous data on essential oils of Cinnamomum species analysed from Vietnam. PMID- 25274474 TI - Conference report: 9th International Summer School of Neurology. PMID- 25274476 TI - Presidential Lecture / Special Lecture / ASH Special Lecture / EHA Special Lecture / JSH Award Lecture. PMID- 25274475 TI - Editorial: Linkage of neurodegenerative disorders with other health issues- volume I. PMID- 25274477 TI - Presidential Symposium / JSH-ASH Joint Symposium / JSH-EHA Joint Symposium / Asian Joint Panel Discussion. PMID- 25274478 TI - Symposium. PMID- 25274479 TI - Plenary session / oral session. PMID- 25274480 TI - Poster / Publication Only (SH). PMID- 25274482 TI - Tpl2 induces castration resistant prostate cancer progression and metastasis. AB - Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC. PMID- 25274484 TI - Computer-assisted reproductive surgery: why it matters to reproductive endocrinology and infertility subspecialists. AB - Trained fertility specialists possess a unique clinical perspective and an extensive medical and technological armamentarium to overcome reproductive dysfunction: it is their privilege and ethical duty to lead the field of reproductive surgery. However, modern reproductive surgery can no longer exist outside of the realm of advanced laparoscopy. This has been a major hurdle to the thriving of surgery within our subspecialty, owing to the time and effort required to achieve and maintain proficiency in the anti-ergonomic environment of conventional laparoscopy. Computer-assisted surgery minimizes aptitudinal restrictions to the adoption of advanced laparoscopy. As such, it promotes strategy over technique and may hold the key to the continued success of high specialty reproductive surgery. PMID- 25274483 TI - A review of valve surgery for rheumatic heart disease in Australia. AB - BACKGROUND: Globally, rheumatic heart disease (RHD) remains an important cause of heart disease. In Australia it particularly affects older non-Indigenous Australians and Aboriginal Australians and/or Torres Strait Islander peoples. Factors associated with the choice of treatment for advanced RHD remain variable and poorly understood. METHODS: The Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database was analysed. Demographics, co morbidities, pre-operative status and valve(s) affected were collated and associations with management assessed. RESULTS: Surgical management of 1384 RHD and 15843 non-RHD valve procedures was analysed. RHD patients were younger, more likely to be female and Indigenous Australian, to have atrial fibrillation (AF) and previous percutaneous balloon valvuloplasty (PBV). Surgery was performed on one valve in 64.5%, two valves in 30.0% and three valves in 5.5%. Factors associated with receipt of mechanical valves in RHD were AF (OR 2.69) and previous PBV (OR 1.98) and valve surgery (OR 3.12). Predictors of valve repair included being Indigenous (OR 3.84) and having fewer valves requiring surgery (OR 0.10). Overall there was a significant increase in the use of mitral bioprosthetic valves over time. CONCLUSIONS: RHD valve surgery is more common in young, female and Indigenous patients. The use of bioprosthetic valves in RHD is increasing. Given many patients are female and younger, the choice of valve surgery and need for anticoagulation has implications for future management of RHD and related morbidity, pregnancy and lifestyle plans. PMID- 25274486 TI - Robotic-assisted laparoscopic surgery for hysterectomy and pelvic organ prolapse repair. AB - The robotic platform is a tool that has enabled many gynecologic surgeons to perform procedures by minimally invasive route that would have otherwise been performed by laparotomy. Before the widespread use of this technology, a larger percentage of hysterectomies and sacrocolpopexies were completed via the open route because of the lack of training in traditional laparoscopic suturing, knot tying, and retroperitoneal dissection. Additional deterrents of traditional laparoscopic surgery adoption have included the lengthy learning curve associated with development of advanced laparoscopic skills; and surgeon preference for the open route because of surgical ergonomics, decreased operative time, and more experience with laparotomy. Level I evidence regarding robotic-assisted laparoscopy in benign gynecology is sparse, with most of the data supporting robotic surgery comprised of retrospective cohorts. The literature demonstrates the safety and efficacy of robotic-assisted laparoscopy for hysterectomy and pelvic organ prolapse repair; however, most level I data show increased operative time and cost. The true indications for robotic-assisted laparoscopy in benign gynecology have yet to be discerned. A review of the best available evidence is summarized. PMID- 25274485 TI - Robotic-assisted surgery in gynecologic oncology. AB - The quest for improved patient outcomes has been a driving force for adoption of novel surgical innovations across surgical subspecialties. Gynecologic oncology is one such surgical discipline in which minimally invasive surgery has had a robust and evolving role in defining standards of care. Robotic-assisted surgery has developed during the past two decades as a more technologically advanced form of minimally invasive surgery in an effort to mitigate the limitations of conventional laparoscopy and improved patient outcomes. Robotically assisted technology offers potential advantages that include improved three-dimensional stereoscopic vision, wristed instruments that improve surgeon dexterity, and tremor canceling software that improves surgical precision. These technological advances may allow the gynecologic oncology surgeon to perform increasingly radical oncologic surgeries in complex patients. However, the platform is not without limitations, including high cost, lack of haptic feedback, and the requirement for additional training to achieve competence. This review describes the role of robotic-assisted surgery in the management of endometrial, cervical, and ovarian cancer, with an emphasis on comparison with laparotomy and conventional laparoscopy. The literature on novel robotic innovations, special patient populations, cost effectiveness, and fellowship training is also appraised critically in this regard. PMID- 25274487 TI - Cloning and characterization of a new beta-glucosidase from a metagenomic library of rumen of cattle feeding with Miscanthus sinensis. AB - BACKGROUND: The study on the second generation bio-fuel is a hot area of current research of renewable energy. Among series of key points in this area, the role of beta-glucosidase in the degradation of intermediate gluco-oligosaccharides limits the rate of the complete saccharification of lignocellulose. RESULTS: In this study, a new beta-glucosidase gene, unglu135B12, which was isolated from a metagenomic library of rumen of cattle feeding with Miscanthus sinensis by the function-based screening, encodes a 779 amino acid polypeptide that contains a catalytic domain belonging to glycoside hydrolase family 3 (GH3). It was recombinantly expressed, purified and biochemically characterized. The recombinant beta-glucosidase, unglu135B12, displayed optimum enzymatic activity at pH 5.0 at 38 degrees C, and showed the highest specific activity of 2.5 * 10(3) U/mg under this optimal condition to p-nitrophenyl-beta-D-glucopyranoside (pNPG), and its Km and Vmax values were 0.309 mmol/L and 7.292 MUmol/min, respectively. In addition, the presence of Ca2+, K+, Na+ slightly improved beta glucosidase activity of unglu135B12 by about 5%, while about 10~85% loss of beta glucosidase activity was induced by addition of Mn2+, Fe3+, Zn2+, Cu2+. Interestingly, unglu135B12 was activated by glucose at the concentration lower than 40 mM. CONCLUSIONS: Our findings indicate that unglu135B12 is a new beta glucosidase derived from rumen of cattle, and it might be a potent candidate for saccharification of lignocellulose in industrial application. PMID- 25274488 TI - Q fever in China: a systematic review, 1989-2013. AB - Q fever, first described in 1937, is a worldwide zoonosis caused by Coxiella burnetii that has long been considered an under-reported and under-diagnosed illness. In China, the disease was initially reported in 1950 and in the last 25 years (1989-2013) there have been 29 reports on Q fever in China, nearly half of which were in the last 5 years. These publications have largely been in Chinese and in this review we summarize their findings to enable a better understanding of Q fever in China. The overall prevalence of C. burnetii infections in the reports is 10% (1139/11 209) in people, 15% (288/1918) in cattle and 12% (176/1440) in goats. These infections occurred widely in China with positive people and/or animals reported in 64 cities/municipalities from 19 provinces, particularly those in the eastern, western and northern areas. Cattle and goats had the highest seroprevalences of all the domestic animals studied and a wide variety of ticks were found to be infected. Mice were also commonly infected and had high copy numbers of C. burnetii DNA, suggesting they might be important in the epidemiology of Q fever in China. PMID- 25274490 TI - Label-free visualization of acetaminophen-induced liver injury by high-speed stimulated Raman scattering spectral microscopy and multivariate image analysis. AB - We recently established a high-speed, label-free, spectral imaging method based on stimulated Raman scattering (SRS). This method enables examination of cellular features within relatively short periods, thus enabling new imaging applications in pathology. Previously, we reported on label-free visualization of mouse tissue using SRS spectral microscopy combined with multivariate image analysis, but the feasibility of applying this approach to diseased tissues with diverse morphology and irregular chemical species has not been examined. We, therefore, assessed acetaminophen-induced liver injury to evaluate the potential use of Raman spectral microscopy for visualizing histopathologic specimens. Acetaminophen overdosed mouse liver was prepared and the pathologic changes including centrilobular necrosis were confirmed. Multi-colored images were reconstructed through principal component analysis (PCA) of a multi-band SRS dataset, which provided rich information compared with a monochrome single-band SRS dataset. A wide view of the multi-colored principal component (PC) images showed the distribution of cellular constituents, which was similar to that observed by fat staining. In addition, different types of cells in liver parenchyma were also demonstrated. In conclusion, the combination of SRS spectral microscopy and PCA has the potential to reveal both the morphological and chemical features of specimens and therefore has potential utility in diagnostic pathology. PMID- 25274489 TI - Transcriptome-wide landscape of pre-mRNA alternative splicing associated with metastatic colonization. AB - Metastatic colonization is an ominous feature of cancer progression. Recent studies have established the importance of pre-mRNA alternative splicing (AS) in cancer biology. However, little is known about the transcriptome-wide landscape of AS associated with metastatic colonization. Both in vitro and in vivo models of metastatic colonization were utilized to study AS regulation associated with cancer metastasis. Transcriptome profiling of prostate cancer cells and derivatives crossing in vitro or in vivo barriers of metastasis revealed splicing factors with significant gene expression changes associated with metastatic colonization. These include splicing factors known to be differentially regulated in epithelial-mesenchymal transition (ESRP1, ESRP2, and RBFOX2), a cellular process critical for cancer metastasis, as well as novel findings (NOVA1 and MBNL3). Finally, RNA-seq indicated a large network of AS events regulated by multiple splicing factors with altered gene expression or protein activity. These AS events are enriched for pathways important for cell motility and signaling, and affect key regulators of the invasive phenotype such as CD44 and GRHL1. IMPLICATIONS: Transcriptome-wide remodeling of AS is an integral regulatory process underlying metastatic colonization, and AS events affect the metastatic behavior of cancer cells. PMID- 25274492 TI - Red cell distribution width is associated with incident venous thromboembolism (VTE) and case-fatality after VTE in a general population. AB - Recent studies suggest an association between red cell distribution width (RDW) and incident venous thromboembolism (VTE). We aimed to investigate the impact of RDW on risk of incident and recurrent VTE, and case-fatality, in a general population. RDW was measured in 26,223 participants enrolled in the Tromso Study in 1994-1995. Incident and recurrent VTE events and deaths during follow-up were registered until January 1, 2012. Multivariate Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). There were 647 incident VTE events during a median of 16.8 years of follow-up. Individuals with RDW in the highest quartile (RDW>=13.3%) had 50% higher risk of an incident VTE than those in the lowest quartile (RDW<=12.3%). The association was strongest for unprovoked deep-vein thrombosis (HR highest vs lowest quartile of RDW: 1.8, 95% CI 1.1-3.1). VTE patients with baseline RDW>=13.3% had 30% higher risk of all-cause mortality after the initial VTE event than VTE patients with RDW<13.3%. There were no association between RDW and risk of recurrent VTE. Our findings suggest that high RDW is a risk factor of incident VTE, and that RDW is a predictor of all-cause mortality in VTE patients. PMID- 25274491 TI - Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology. AB - BACKGROUND: Greater degrees of terminal duct lobular unit (TDLU) involution have been linked to lower breast cancer risk; however, factors that influence this process are poorly characterized. METHODS: To study this question, we developed three reproducible measures that are inversely associated with TDLU involution: TDLU counts, median TDLU span, and median acini counts/TDLU. We determined factors associated with TDLU involution using normal breast tissues from 1938 participants (1369 premenopausal and 569 postmenopausal) ages 18 to 75 years in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Multivariable zero-inflated Poisson models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) for factors associated with TDLU counts, and multivariable ordinal logistic regression models were used to estimate odds ratios (ORs) and 95% CIs for factors associated with categories of median TDLU span and acini counts/TDLU. RESULTS: All TDLU measures started declining in the third age decade (all measures, two-sided P trend <= .001); and all metrics were statistically significantly lower among postmenopausal women. Nulliparous women demonstrated lower TDLU counts compared with uniparous women (among premenopausal women, RR = 0.79, 95% CI = 0.73 to 0.85; among postmenopausal, RR = 0.67, 95% CI = 0.56 to 0.79); however, rates of age-related TDLU decline were faster among parous women. Other factors were related to specific measures of TDLU involution. CONCLUSION: Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies. PMID- 25274493 TI - Oxidative stress in entomopathogenic fungi grown on insect-like hydrocarbons. AB - Entomopathogenic fungi mostly attack their insect hosts by penetration through the cuticle. The outermost insect surface is covered by a lipid-rich layer, usually composed of very long chain hydrocarbons. These fungi are apt to grow on straight chain hydrocarbons (alkanes) as the sole carbon source. Insect-like hydrocarbons are first hydroxylated by a microsomal P450 monooxygenase system, and then fully catabolized by peroxisomal beta-oxidation reactions in Beauveria bassiana. In this review, we will discuss lipid metabolism adaptations in alkane grown fungi, and how an oxidative stress scenario is established under these conditions. Fungi have to pay a high cost for hydrocarbon utilization; high levels of reactive oxygen species are produced and a concomitant antioxidant response is triggered in fungal cells to cope with this drawback. PMID- 25274495 TI - Impact of the grinding process on the quantification of ethyl glucuronide in hair using a validated UPLC-ESI-MS-MS method. AB - The Society of Hair Testing (SoHT) has provided cutoffs for the quantification of ethyl glucuronide (EtG) in hair to indicate occasional or chronic/excessive alcohol consumption. Although several sensitive methods have been reported, past proficiency test results show a lack of reproducibility. An ultra-performance liquid chromatographic mass spectrometric method (LLOQ of 10 pg EtG/mg hair) has been validated according to the international guidelines, including the successful participation in five proficiency tests. This method was subsequently used to evaluate the impact of different grinding conditions (cut, weakly or extensively pulverized hair samples) on the final measured EtG concentration. Hair from alcohol consumers (n = 2) and commercially available quality control samples (QCs) (n = 2) was used. For the QCs, extensive pulverization led to a significantly higher amount of measured EtG. In the hair samples obtained from volunteers, cut or weakly pulverized hair resulted in EtG concentrations below the LLOQ, while the mean concentrations of 14 and 40 pg EtG/mg hair were determined after extensive pulverization. Differences in sample preparation could partially explain inter-laboratory variability. As the differences in results can lead to a different interpretation even when applying the SoHT cutoffs, it is of interest to standardize sample preparation techniques in the field of EtG hair testing. PMID- 25274496 TI - Transapical myectomy and surgical cryoablation for refractory ventricular tachycardia due to hypertrophic cardiomyopathy with apical aneurysm. AB - Ventricular tachycardia (VT) associated with midventricular hypertrophic cardiomyopathy and apical aneurysm is rare, but is frequently refractory to medical therapy. We report a case of a 44-year old man with incessant VT despite undergoing catheter ablation in the neck of a left ventricular apical aneurysm. Resection of a hypertrophied midventricular muscle through an apical incision and surgical cryoablation of the aneurysm border from the epicardial and endocardial surface were performed successfully. The patient was well without ventricular arrhythmic events at 2 years postoperatively. PMID- 25274494 TI - Residential proximity to major roadways and prevalent hypertension among postmenopausal women: results from the Women's Health Initiative San Diego Cohort. AB - BACKGROUND: Living near major roadways has been linked with increased risk of cardiovascular events and worse prognosis. Residential proximity to major roadways may also be associated with increased risk of hypertension, but few studies have evaluated this hypothesis. METHODS AND RESULTS: We examined the cross-sectional association between residential proximity to major roadways and prevalent hypertension among 5401 postmenopausal women enrolled into the San Diego cohort of the Women's Health Initiative. We used modified Poisson regression with robust error variance to estimate the association between prevalence of hypertension and residential distance to nearest major roadway, adjusting for participant demographics, medical history, indicators of individual and neighborhood socioeconomic status, and for local supermarket/grocery and fast food/convenience store density. The adjusted prevalence ratios for hypertension were 1.22 (95% CI: 1.07, 1.39), 1.13 (1.00, 1.27), and 1.05 (0.99, 1.12) for women living <=100, >100 to 200, and >200 to 1000 versus >1000 m from a major roadway (P for trend=0.006). In a model treating the natural log of distance to major roadway as a continuous variable, a shift in distance from 1000 to 100 m from a major roadway was associated with a 9% (3%, 16%) higher prevalence of hypertension. CONCLUSIONS: In this cohort of postmenopausal women, residential proximity to major roadways was positively associated with the prevalence of hypertension. If causal, these results suggest that living close to major roadways may be an important novel risk factor for hypertension. PMID- 25274497 TI - Enteral Nutrition in Patients Receiving Mechanical Ventilation in a Prone Position. AB - BACKGROUND: Patients treated with mechanical ventilation in the prone position (PP) could have an increased risk for feeding intolerance. However, the available evidence supporting this hypothesis is limited and contradictory. OBJECTIVE: To examine the feasibility and efficacy of enteral nutrition (EN) support and its associated complications in patients receiving mechanical ventilation in PP. METHODS: Prospective observational study including 34 mechanically ventilated intensive care patients who were turned to the prone position over a 3-year period. End points related to efficacy and safety of EN support were studied. RESULTS: In total, more than 1200 patients were admitted to the intensive care unit over a period of 3 years. Of these, 34 received mechanical ventilation in PP. The mean days under EN were 24.7 +/- 12.3. Mean days under EN in the supine position were significantly higher than in PP (21.1 vs 3.6; P < .001), but there were no significant differences in gastric residual volume adjusted per day of EN (126.6 vs 189.2; P = .054) as well as diet volume ratio (94.1% vs 92.8%; P = .21). No significant differences in high gastric residual events per day of EN (0.06 vs 0.09; P = .39), vomiting per day of EN (0.016 vs 0.03; P = .53), or diet regurgitation per day of EN (0 vs 0.04; P = .051) were found. CONCLUSIONS: EN in critically ill patients with severe hypoxemia receiving mechanical ventilation in PP is feasible, safe, and not associated with an increased risk of gastrointestinal complications. Larger studies are needed to confirm these findings. PMID- 25274498 TI - Suitability of internal transcribed spacers (ITS) as markers for the population genetic structure of Blastocystis spp. AB - BACKGROUND: The purpose of this study was to assess the genetic variation and differentiation of Blastocystis subtypes (STs) recovered from symptomatic children by analysing partial sequences of the small subunit rDNA gene region (SSUrDNA) and internal transcribed spacers (1 and 2) plus the 5.8S region (ITS, ITS1 + 5.8S + ITS2) and comparing with isolates from other countries. FINDINGS: Faecal samples from 47 Blastocystis-infected children with gastrointestinal symptoms and negative for pathogenic enterobacteria were analysed. PCR was performed on DNA from all the samples to identify Blastocystis STs, amplifying a fragment of SSUrDNA and the ITS region. The amplicons were purified and sequenced, and consensus sequences were submitted to GenBank; afterwards, SSUrDNA sequences were analysed for genetic diversity according to geographic area. Regarding the Blastocystis STs found, 51% were ST1, 23% ST2, 19% ST3 and 2% ST7. For ITS, a haplotype network tree and Bayesian inference revealed the presence of two novel variants of ST1, clustering some sequences into ST1A and ST1B. The values of nucleotide diversity (pi) and haplotype polymorphism (theta) for ST1, ST2 and ST3 ranged from 0 to 1, whereas the ratio of genetic differentiation (FST)/migration index (Nm) showed the highest differentiation between Libya and Thailand-Philippines for ST2 (0.282/0.63). In contrast, a high flow gene was observed between Czech Republic-Denmark-Holland-Spain and USA-Mexico-Colombia for ST1 (0.003/84). CONCLUSION: Our data on genetic differentiation and gene flow might explain the differences for the prevalence of Blastocystis STs. Moreover, the ITS region could be used as a genetic marker to assess genetic variation in this parasite. PMID- 25274500 TI - Heart coherence training combined with back school in patients with chronic non specific low back pain: first pragmatic clinical results. AB - The aim of this study was to explore on which variables a stress reduction program based on heart coherence can enhance the effects of a back school (BS) in patients with chronic non-specific low back pain and to explore possible moderators for treatment success. A retrospective explorative design was carried out with 170 patients with chronic non-specific low back pain. 89 Patients were admitted to BS and 81 patients were selected for BS and heart coherence training (BS-HCT). Six sessions of heart coherence were provided. At T0 (baseline) and T1 (discharge), the Numeric Rating Scale for pain (NRS pain), Roland Morris Disability Questionnaire (RMDQ), Pain Disability Index (PDI) and Rand-36 were administered in both groups. Both groups improved significantly on NRS pain, RMDQ, PDI and most of the Rand-36 subscales. On physical functioning, the BS-HCT group improved significantly more than the BS group (p = 0.02) but not after Bonferroni correction. Significant moderate correlations (r = 0.39 and r = 0.48) were found between the change of heart coherence and change of PDI and RMDQ respectively, but not with other variables. Baseline characteristics were not related to change on heart coherence. Providing HCT was more effective on physical functioning compared to a BS program. Change in heart coherence was related significantly to 2 out of 12 analyses. Placebo controlled and blinded studies are needed to confirm this. Characteristics of individuals who might benefit remain unknown. Evidence of this study is considered a level C, because of its pragmatic clinical character. PMID- 25274501 TI - HRV biofeedback for pediatric irritable bowel syndrome and functional abdominal pain: a clinical replication series. AB - Irritable bowel syndrome (IBS) and Functional Abdominal Pain (FAP) are among the most commonly reported Functional Gastrointestinal Disorders. Both have been associated with varying autonomic dysregulation. Heart Rate Variability Biofeedback (HRVB) has recently begun to show efficacy in the treatment of both IBS and FAP. The purpose of this multiple clinical replication series was to analyze the clinical outcomes of utilizing HRVB in a clinical setting. Archival data of twenty-seven consecutive pediatric outpatients diagnosed with IBS or FAP who received HRVB were analyzed. Clinical outcomes were self-report and categorized as full or remission with patient satisfaction, or no improvement. Qualitative reports of patient experiences were also noted. Full remission was achieved by 69.2 % and partial remission was achieved by 30.8 % of IBS patients. Full remission was achieved by 63.6 % and partial remission was achieved by 36.4 % of FAP patients. No patients in either group did not improve to a level of patient satisfaction or >50 %. Patient's commonly reported feeling validated in their discomfort as a result of psychophysiological education. Results suggest that HRVB is a promising intervention for pediatric outpatients with IBS or FAP. Randomized controlled trials are necessary to accurately determine clinical efficacy of HRVB in the treatment of IBS and FAP. PMID- 25274499 TI - Refractory gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is a condition that develops when the reflux of stomach contents into the esophagus causes troublesome symptoms, esophageal injury, and/or complications. Use of proton pump inhibitors (PPI) remains the standard therapy for GERD and is effective in most patients. Those whose symptoms are refractory to PPIs should be evaluated further and other treatment options should be considered, according to individual patient characteristics. Response to PPIs could be total (no symptoms), partial (residual breakthrough symptoms), or absent (no change in symptoms). Patients experiencing complete response do not usually need further management. Patients with partial response can be treated surgically or by using emerging endoscopic therapies. Patients who exhibit no response to PPI need further evaluation to rule out other causes. PMID- 25274503 TI - "Systematizing" ethics consultation services. AB - While valuable work has been done addressing clinical ethics within established healthcare systems, we anticipate that the projected growth in acquisitions of community hospitals and facilities by large tertiary hospitals will impact the field of clinical ethics and the day-to-day responsibilities of clinical ethicists in ways that have yet to be explored. Toward the goal of providing clinical ethicists guidance on a range of issues that they may encounter in the systematization process, we discuss key considerations and potential challenges in implementing system-wide ethics consultation services. Specifically, we identify four models for organizing, developing, and enhancing ethics consultation activities within a system created through acquisitions: (1) train the-trainer, (2) local capacity-building, (3) circuit-riding, and (4) consolidated accountability. We note each model's benefits and challenges. To our knowledge, this is the first paper to consider the broader landscape of issues affected by consolidation. We anticipate that clinical ethicists, volunteer consultants, and hospital administrators will benefit from our recommendations. PMID- 25274504 TI - Nanotube Li2MoO4: a novel and high-capacity material as a lithium-ion battery anode. AB - Carbon-coated Li2MoO4 hexagonal hollow nanotubes were fabricated via a facile sol gel method involving the solution synthesis of Li2MoO4 with subsequent annealing under an inert atmosphere to decompose the organic carbon source. To the best of our knowledge, this is the first report on the synthesis of Li2MoO4 nanotubes. More significantly, we have found that Li2MoO4 can be used as an anode material for lithium-ion batteries (LIBs). When evaluated as an anode material, the carbon coated Li2MoO4 hollow nanotubes show an excellent electrochemical performance with a high reversible capacity (~550 mA h g(-1)) after 23 cycles, good rate capability and cycling stability. Meanwhile, carbon-free Li2MoO4 sample, fabricated via a solid state reaction, was also prepared for comparison. The Li storage mechanism has been investigated in-detail by advanced XPS, in situ XRD and HRTEM. PMID- 25274502 TI - The pathological and molecular but not clinical phenotypes are maintained after second passage of experimental atypical bovine spongiform encephalopathy in cattle. AB - BACKGROUND: Atypical bovine spongiform encephalopathies (BSEs), classified as H type and L-type BSE based on the Western immunoblot profiles, are naturally occurring diseases in cattle, which are phenotypically different to classical BSE. Transmission studies in cattle using the intracerebral route resulted in disease where the phenotypes were maintained irrespective of BSE type but clinically affected cattle with a shorter survival time displayed a nervous form whereas cattle with a longer survival time displayed a dull form. A second transmission study is reported here where four cattle were intracerebrally inoculated with brain tissue from experimentally infected cattle presenting with either the nervous or dull form of H- or L-type BSE to determine whether the phenotype is maintained. RESULTS: The four inoculated cattle were culled at 16.5 19.5 months post inoculation after presenting with difficulty getting up, a positive scratch response (all) and dullness (three cattle), which was not observed in two non-inoculated control cattle, each housed with either group of inoculated cattle. Only the inoculated cattle had detectable prion protein in the brain based on immunohistochemical examination, and the Western immunoblot profile was consistent with the H-type or L-type BSE of the respective donor cattle. CONCLUSIONS: Second passage of H-type and L-type BSE in cattle produced a TSE where the majority of cattle displayed the dull form regardless of clinical disease form of the donor cattle. The pathological and molecular phenotypes of H- and L-type BSE were maintained. PMID- 25274505 TI - Exposure to formaldehyde, nitrogen dioxide, ozone, and terpenes among office workers and associations with reported symptoms. AB - PURPOSE: To compare exposure to formaldehyde, nitrogen dioxide, ozone and terpenes among office workers with and without sick building syndrome and the odds ratio for exposure. Are there significant differences? METHODS: In this cross-sectional study of office workers, we investigated the associations between exposure to formaldehyde, nitrogen dioxide, ozone, alpha-pinene, and D-limonene using a case-control analysis. Data on perceived general, mucosal, and skin symptoms were obtained by questionnaires. Personal exposure measurements of the compounds were performed among cases and controls, and the odds ratios for exposures to the substances, both singly and in combination, were investigated. RESULTS: Exposures varied for formaldehyde between 0.23 and 45 ug/m(3), nitrogen dioxide between 0.26 and 110 ug/m(3), ozone between <16 and 165 ug/m(3), alpha pinene between 0.2 and 170 ug/m(3), and D-limonene between 0.8 and 1,400 ug/m(3). No consistent differences in exposure odds ratios were found between cases and controls or for individual symptoms. PMID- 25274506 TI - Rationalization of dye uptake on titania slides for dye-sensitized solar cells by a combined chemometric and structural approach. AB - A model photosensitizer (D5) for application in dye-sensitized solar cells has been studied by a combination of XRD, theoretical calculations, and spectroscopic/chemometric methods. The conformational stability and flexibility of D5 and molecular interactions between adjacent molecules were characterized to obtain the driving forces that govern D5 uptake and grafting and to infer the most likely arrangement of the molecules on the surface of TiO2. A spectroscopic/chemometric approach was then used to yield information about the correlations between three variables that govern the uptake itself: D5 concentration, dispersant (chenodeoxycholic acid; CDCA) concentration, and contact time. The obtained regression model shows that large uptakes can be obtained at high D5 concentrations in the presence of CDCA with a long contact time, or in absence of CDCA if the contact time is short, which suggests how dye uptake and photovoltaic device preparation can be optimized. PMID- 25274507 TI - Growth hormone receptor signaling is dispensable for HSC function and aging. AB - Growth hormone receptor (Ghr) signaling is important in a wide variety of cellular processes including aging; however, the role of Ghr signaling in hematopoietic stem cell (HSC) biology remains unexplored. Within the hematopoietic system, Ghr is expressed in a highly HSC-specific manner and is significantly upregulated during aging. Exposure of young and old HSCs to recombinant growth hormone ex vivo led to diminished short-term reconstitution and restored B-cell output from old HSCs. Hematopoietic-specific genetic deletion of Ghr neither impacted steady-state hematopoiesis nor serial transplantation potential. Repeat challenge with 5-fluorouracil showed that Ghr was dispensable for HSC activation and homeostatic recovery in vivo and, after challenge, Ghr deficient HSCs functioned normally through serial transplantation. Although exogenous Gh induces age-dependent HSC effects, these results indicate that Ghr signaling appears largely dispensable for HSC function and aging. PMID- 25274509 TI - Disruptive photon technologies for chemical dynamics. AB - A perspective of new and emerging technologies for chemical dynamics is given, with an emphasis on the use of X-ray sources that generate sub-picosecond pulses. The two classes of experimental techniques used for time-resolved measurements of chemical processes and their effects are spectroscopy and imaging, where the latter includes microscopy, diffractive imaging, and crystallography. X-Ray free electron lasers have brought new impetus to the field, allowing not only temporal and spatial resolution at atomic time and length scales, but also bringing a new way to overcome limitations due to perturbation of the sample by the X-ray probe by out-running radiation damage. Associated instrumentation and methods are being developed to take advantage of the new opportunities of these sources. Once these methods of observational science have been mastered it should be possible to use the new tools to directly control those chemical processes. PMID- 25274510 TI - A hybrid pixel detector at an in-house device generating stunning charge density quality data. PMID- 25274508 TI - Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. AB - ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. PMID- 25274511 TI - XPAD X-ray hybrid pixel detector for charge density quality diffracted intensities on laboratory equipment. AB - The new generation of X-ray detectors, the hybrid pixel area detectors or 'pixel detectors', is based on direct detection and single-photon counting processes. A large linearity range, high dynamic and extremely low noise leading to an unprecedented high signal-to-noise ratio, fast readout time (high frame rates) and an electronic shutter are among their intrinsic characteristics which render them very attractive. First used on synchrotron beamlines, these detectors are also promising in the laboratory, in particular for pump-probe or quasi-static experiments and accurate electron density measurements, as explained in this paper. An original laboratory diffractometer made from a Nonius Mach3 goniometer equipped with an Incoatec Mo microsource and an XPAD pixel area detector has been developed at the CRM2 laboratory. Mo Kalpha accurate charge density quality data up to 1.21 A(-1) resolution have been collected on a sodium nitroprusside crystal using this home-made diffractometer. Data quality for charge density analysis based on multipolar modelling are discussed in this paper. Deformation electron densities are compared to those already published (based on data collected with CCD APEXII and CAD4 diffractometers). PMID- 25274512 TI - The trimorphic structure of N,N'-bis(5-methylsalicylidene)-4-methyl-1,3 phenylenediamine. AB - The new Schiff base ligand, N,N'-bis(5-methylsalicylidene)-4-methyl-1,3 phenylenediamine (H2L), has been prepared by condensation of 5 methylsalicylaldehyde with 4-methyl-1,3-phenylenediamine. It was found that this ligand crystallizes in the monoclinic space group P21/c, with Z' = 1. Further studies showed that - as a result of the one-pot metal-promoted reactions - three different polymorphic forms of H2L were obtained, with different numbers (1, 3 or 4) of symmetry-independent molecules depending on the lanthanide metal ion present in the reaction media: La (Z' = 3), Nd (Z' = 4), Sm, Tb, Ho and Yb (all Z' = 1); the last form is identical with that obtained by crystallization of the ligand itself. The geometrical features of all eight independent molecules of H2L are very similar. The relatively strong intramolecular O-H...N hydrogen bonds stabilize almost co-planar conformations of terminal rings and C-C=N-C linkers, at the same time strong hydrogen-bond donors and acceptors involved in these interactions cannot take part in the determination of supramolecular architecture. Therefore, weak intermolecular interactions are important and this can be regarded as one of the reasons for packing conflicts that lead to the presence of polymorphic forms and multiple molecules. The pseudosymmetries are observed in both forms with Z' > 1 and the degree of pseudosymmetry is described by the values of appropriate combinations of the coordinates. In order to elucidate the differences in crystal structures the Hirshfeld surface method was applied. It shows that there are only small differences in the surface shape and in the fingerprint plots; however, the volumes of voids in three structures are significantly different. PMID- 25274513 TI - Experimental and theoretical investigation on the compression mechanism of FeF3 up to 62.0 GPa. AB - VF3-type FeF3 is generally considered as a perovskite with a completely vacant A site. The high-pressure structural evolution of FeF3 has been studied by both X ray diffraction and theoretical simulation up to 62.0 GPa. Experimental and theoretical results demonstrate that VF3-type FeF3 is stable up to 50 GPa. The structural evolution presents three features at different pressure ranges. At P < 10 GPa, the volume reduction is dominated by the FeF6 octahedral rotation, and a small octahedral strain develops upon compression, which represents an elongation of FeF6 octahedra along the c axis. Between 10 and 25 GPa, the volume reduction is mainly attributed to the Fe-F bond length decreasing, and the octahedral strain gradually disappears. Between 25 and 50 GPa, an octahedral elongation along the a axis quickly develops, resulting in a substantial structural distortion. Structural instability is predicted at P > 51 GPa on the basis of a soft mode occurring in phonon calculations. The pressure-volume relationship is described by a third-order Birch-Murnaghan equation-of-state with B0 = 14 (1) GPa, B0' = 17 (1) by experiment and B0 = 10.45 (1) GPa, B'10 = 12.13 (1) by calculation. PMID- 25274514 TI - Prediction of possible CaMnO3 modifications using an ab initio minimization data mining approach. AB - We have performed a crystal structure prediction study of CaMnO3 focusing on structures generated by octahedral tilting according to group-subgroup relations from the ideal perovskite type (Pm?overline 3 m), which is the aristotype of the experimentally known CaMnO3 compound in the Pnma space group. Furthermore, additional structure candidates have been obtained using data mining. For each of the structure candidates, a local optimization on the ab initio level using density-functional theory (LDA, hybrid B3LYP) and the Hartree--Fock (HF) method was performed, and we find that several of the modifications may be experimentally accessible. In the high-pressure regime, we identify a post perovskite phase in the CaIrO3 type, not previously observed in CaMnO3. Similarly, calculations at effective negative pressure predict a phase transition from the orthorhombic perovskite to an ilmenite-type (FeTiO3) modification of CaMnO3. PMID- 25274515 TI - Structural aspects of intermolecular interactions in the solid state of 1,4 dibenzylpiperazines bearing nitrile or amidine groups. AB - The crystal structures of the title 1,4-bis(4-cyanobenzyl)piperazine (1) and 1,4 bis(4-amidinobenzyl)piperazine tetrahydrochloride tetrahydrate (2) are reported. Compound (1) crystallizes in the triclinic space group P?bar 1 and compound (2) in the monoclinic space group P21/n. In both (1) and (2) the asymmetric unit contains one half of the molecule because the central piperazine rings were located across a symmetry center. The packing of both molecules was dominated by hydrogen bonds. The crystal lattice of (1) was formed by weak C-H...N and C H...pi interactions. The crystal structure of (2) was completely different, with cations as well as chloride anions and water molecules taking part in intermolecular interactions. Single-crystal X-ray diffraction studies combined with density functional theory (DFT) calculations allowed the characterization of the intermolecular interactions in those two systems having different types of very strong electrophilic groups: non-ionic nitrile and ionic amidine. Chemical shift data from (13)C CP/MAS (Cross Polarization Magic Angle Spinning) NMR spectra were analyzed using the different procedures for the theoretical computation of shielding constants. PMID- 25274516 TI - Solid-state transformation of nanocrystalline phyllomanganate into tectomanganate: influence of initial layer and interlayer structure. AB - In surficial environments, the fate of many elements is influenced by their interactions with the phyllomanganate vernadite, a nano-sized and turbostratic variety of birnessite. To advance our understanding of the surface reactivity of vernadite as a function of pH, synthetic vernadite (delta-MnO2) was equilibrated at pH ranging from 3 to 10 and characterized structurally using chemical methods, thermogravimetry and modelling of powder X-ray diffraction (XRD) patterns. With decreasing pH, the number of vacant layer sites increases in the octahedral layers of delta-MnO2 (from 0.14 per layer octahedron at pH 10 to 0.17 at pH 3), whereas the number of layer Mn(3+) is, within errors, equal to 0.12 per layer octahedron over the whole pH range. Vacant layer sites are capped by interlayer Mn(3+) sorbed as triple corner-sharing surface complexes (TC sites). The increasing number of interlayer Mn(3+) with decreasing pH (from 0.075 per layer octahedron at pH 10 to 0.175 at pH 3) results in the decrease of the average Mn oxidation degree (from 3.80 +/- 0.01 at pH 10 to 3.70 +/- 0.01 at pH 3) and in the lowering of the Na/Mn ratio (from 27.66 +/- 0.20 at pH 10 to 6.99 +/- 0.16 at pH 3). In addition, in-plane unit-cell parameters are negatively correlated to the number of interlayer Mn at TC sites and decrease with decreasing pH (from b = 2.842 A at pH 10 to b = 2.834 A at pH 3), layer symmetry being systematically hexagonal with a = b * 3(1/2). Finally, modelling of X-ray diffraction (XRD) patterns indicates that crystallite size in the ab plane and along the c* axis decreases with decreasing pH, ranging respectively from 7 nm to 6 nm, and from 1.2 nm to 1.0 nm (pH 10 and 3, respectively). Following their characterization, dry samples were sealed in polystyrene vials, kept in the dark, and re-analysed 4 and 8 years later. With ageing time and despite the dry state, layer Mn(3+) extensively migrates to the interlayer most likely to minimize steric strains resulting from the Jahn-Teller distortion of Mn(3+) octahedra. When the number of interlayer Mn(3+) at TC sites resulting from this migration reaches the maximum value of ~ 1/3 per layer octahedron, interlayer species from adjacent layers share their coordination sphere, resulting in cryptomelane-like tunnel structure fragments (with a 2 * 2 tunnel size) with a significantly improved layer stacking order. PMID- 25274517 TI - Succinate esters: odd-even effects in melting points. AB - Dialkyl succinates show a pattern of alternating behavior in their melting points, as the number of C atoms in the alkane side chain increases, unlike in the dialkyl oxalates [Joseph et al. (2011). Acta Cryst. B67, 525-534]. Dialkyl succinates with odd numbers of C atoms in the alkyl side chain show higher melting points than the immediately adjacent analogues with even numbers. The crystal structures and their molecular packing have been analyzed for a series of dialkyl succinates with 1-4 C atoms in the alkyl side chain. The energy difference (DeltaE) between the optimized and observed molecular conformations, density, Kitaigorodskii packing index (KPI) and C-H...O interactions are considered to rationalize this behavior. In contrast to the dialkyl oxalates where a larger number of moderately strong C-H...O interactions were characteristic of oxalates with elevated melting points, here the molecular packing and the density play a major role in raising the melting point. On moving from oxalate to succinate esters the introduction of the C2 spacer adds two activated H atoms to the asymmetric unit, resulting in the formation of stronger C-H...O hydrogen bonds in all succinates. As a result the crystallinity of long chain alkyl substituted esters improves enormously in the presence of hydrogen bonds from activated donors. PMID- 25274519 TI - Adsorption structure of dimethyl ether on silicalite-1 zeolite determined using single-crystal X-ray diffraction. AB - The adsorption structures of dimethyl ether (DME) on silicalite-1 zeolite (MFI type) are determined using single-crystal X-ray diffraction. The structure of low loaded DME-silicalite-1 indicates that all DME molecules are located in the sinusoidal channel, which is the most stable sorption site based on the van der Waals interaction between DME and the framework. The configuration of guest molecules (linear or bent) plays an important role in determining where the stable sorption site is in the pore system of MFI-type zeolites. Bent molecules favor the sinusoidal channel, while linear molecules favor the straight channel. The contribution of DME-DME interactions is considerable in the high-loaded DME silicalite-1 structure. PMID- 25274518 TI - First experimental charge density study using a Bruker CMOS-type PHOTON 100 detector: the case of ammonium tetraoxalate dihydrate. AB - The aim of this study was to test the applicability of a Bruker AXS CMOS-type PHOTON 100 detector for the purpose of a fine charge density quality data collection. A complex crystal containing oxalic acid, ammonium oxalate and two water molecules was chosen as a test case. The data was collected up to a resolution of 1.31 A(-1) with high completeness (89.1%; Rmrg = 0.0274). The multipolar refinement and subsequent quantum theory of atoms in molecules (QTAIM) analysis resulted in a comprehensive description of the charge density distribution in the crystal studied. The residual density maps are flat and almost featureless. It was possible to derive reliable information on intermolecular interactions to model the anharmonic motion of a water molecule, and also to observe the fine details of the charge density distribution, such as polarization on O and H atoms involved in the strongest hydrogen bonds. When compared with our previous statistical study on oxalic acid data collected with the aid of CCD cameras, the complementary metal-oxide semiconductor (CMOS) detector can certainly be classified as a promising alternative in advanced X-ray diffraction studies. PMID- 25274520 TI - Bond valence at mixed occupancy sites. I. Regular polyhedra. AB - Bond valence sum calculations at mixed occupancy sites show the occurrence of systematic errors leading to apparent violations of the Valence Sum Rule (bond valence theory) in regular and unstrained bonding environments. The systematic deviation of the bond valence from the expected value is observed in the long range structure, and is discussed from geometric and algebraic viewpoints. In the valence-length diagram, such a deviation arises from discrepancies between the intersection points of the long-range bond valences and the theoretical bond valences with the valence-length curves of involved cations. Three factors cause systematic errors in the bond valences: difference in atomic valences, bond valence parameters Ri (the length of a bond of unit valence) and bond valence parameters bi (the bond softness) between the involved cations over the same crystallographic site. One important consequence strictly related to the systematic errors is that they lead to erroneous bond strain values for mixed occupancy sites indicating underbonding or overbonding that actually does not exist. PMID- 25274521 TI - Role of the Li(+) node in the Li-BH4 substructure of double-cation tetrahydroborates. AB - The phase diagram LiBH4-ABH4 (A = Rb,Cs) has been screened and revealed ten new compounds LiiAj(BH4)i+j (A = Rb, Cs), with i, j ranging between 1 and 3, representing eight new structure types amongst homoleptic borohydrides. An approach based on synchrotron X-ray powder diffraction to solve crystal structures and solid-state first principles calculations to refine atomic positions allows characterizing multi-phase ball-milled samples. The Li-BH4 substructure adopts various topologies as a function of the compound's Li content, ranging from one-dimensional isolated chains to three-dimensional networks. It is revealed that the Li(+) ion has potential as a surprisingly versatile cation participating in framework building with the tetrahydroborate anion BH4 as a linker, if the framework is stabilized by large electropositive counter-cations. This utility can be of interest when designing novel hydridic frameworks based on alkaline metals and will be of use when exploring the structural and coordination chemistry of light-metal systems otherwise subject to eutectic melting. PMID- 25274522 TI - Cu3Sn - understanding the systematic absences. AB - The intermetallic compound Cu3Sn has previously been described as a long-period antiphase boundary superstructure of the Cu3Ti structure type. While the compound itself has been reported as a tenfold and an eightfold superstructure, ternary doped alloys show shorter repetitions. Interestingly, the diffraction patterns of these compounds show non-crystallographic absences that cannot be explained using the superstructure models. Since the compound exhibits phase broadening, these models are not satisfactory because the paucity of observed data does not allow for a refinement of the composition. Here, an alternative, superspace model in the orthorhombic space group Xmcm(0beta0)000 is proposed, with the centering vectors (0,0,0,0) and (1/2,0,0,1/2). The presence of the non-crystallographic absences is explained as a result of a dominating occupational modulation that is accompanied by a weaker displacive modulation. In consistency with the EDXS results, the composition has been refined to Cu3 + xSn from single-crystal X-ray diffraction data. It is further demonstrated that by varying the length and the direction of the modulation wavevector in the superspace model, the ternary Cu3Sn compounds and other colored hexagonal close packing (h.c.p.) structures can be produced. PMID- 25274523 TI - Mackay icosahedron explaining orientation relationship of dispersoids in aluminium alloys. AB - The orientation relations (ORs) of the cubic icosahedral quasicrystal approximant phase alpha-Al(Fe,Mn)Si have been studied after low temperature annealing of a 3xxx wrought aluminium alloy by transmission electron microscopy. From diffraction studies it was verified that the most commonly observed OR for the alpha-Al(Fe,Mn)Si dispersoids is [1?bar 11]alpha // [1?bar 11]Al, (5?bar 2?bar 7)alpha // (011)Al. This orientation could be explained by assuming that the internal Mackay icosahedron (MI) in the alpha-phase has a fixed orientation in relation to Al, similar to that of the icosahedral quasi-crystals existing in this alloy system. It is shown that mirroring of the normal-to-high-symmetry icosahedral directions of the MI explains the alternative orientations, which are therefore likely to be caused by twinning of the fixed MI. Only one exception was found, which was related to the Bergman icosahedron internal to the T-phase of the Al-Mg-Zn system. PMID- 25274524 TI - Structure of a new chloroauric acid. AB - The new tetrachloroaurate ethanol hydrate HAuCl4.0.65C2H5OH.1.35H2O was prepared from chloroauric acid trihydrate in ethanol. The compound crystallizes in the triclinic space group P ?bar 1 (No. 2). The [AuCl4](-) units in the structure have approximately square-planar symmetry, forming chains parallel to the crystallographic b-axis direction. PMID- 25274525 TI - Two-dimensionally stacked heterometallic layers hosting a discrete chair dodecameric ring of water clusters: synthesis and structural study. AB - The stacked two-dimensional supramolecular compound catena-{Co(amp)3Cr(ox)3.6H2O} (amp = 2-picolylamine, ox = oxalate) has been synthesized from the bimolecular approach using hydrogen bonds. It is built from layers in which both Co(amp)(3+) (D) and Cr(ox)(3-) (A) ions are bonded in a repeating DADADA... pattern along the a and c axes by multiple hydrogen bonds. These layers host a well resolved R12 dodecameric discrete ring of water clusters built by six independent molecules located around the 2c centrosymmetric Wyckoff positions of the P21/n space group in which the compound crystallizes. These clusters are ranged along the [001] direction, occupy 733.5 A(3) (22.0%) of the unit cell and have a chair conformation via 12 hydrogen bonds. The water molecules of the cluster are linked with stronger hydrogen bonds than those between the cluster and its host, which explains the single continuous step of the dehydration process of the compound. PMID- 25274526 TI - Platelet and other hemostatic characteristics in patients with chronic urticaria. AB - Several publications have pointed out the importance of coagulation and fibrinolysis in the occurrence of chronic urticaria (CU), but only a few indicated the direct role of platelets. We assessed platelet aggregation and evaluated parameters of coagulation and fibrinolysis in patients with CU. Patients (n = 34) diagnosed as having CU and 36 healthy controls were enrolled. Platelet aggregation was assayed using an impedance aggregometer and adenosine diphosphate, arachidonic acid, thrombin receptor-activating peptide (TRAP), and ristocetin as agonists. In patients with CU, significantly decreased platelet aggregation to some agonists (ristocetin and TRAP) was observed. The D-dimer levels were elevated, mean platelet volume was decreased, but no alteration was observed in other coagulation assays. Elevated D-dimer levels indicated that coagulation and fibrinolysis are activated in the patients with CU. Evaluation of platelet function may contribute to identify the role of these cells in the pathogenesis of CU. PMID- 25274527 TI - Is Arterial Hypertension Control Enough to Improve Aortic Stiffness in Untreated Patients With Hypertension? A 3-Year Follow-Up Study. AB - Aortic stiffness is an important determinant of cardiovascular risk. We studied the long-term influence of successful antihypertensive treatment after a 3-year follow-up, regarding aortic stiffness improvement from baseline evaluation in never treated middle-aged patients with mild to moderate essential hypertension. In 132 patients with hypertension, aortic stiffness was evaluated by carotid femoral artery pulse wave velocity (PWV). Patients with 24-hour mean systolic and diastolic blood pressure <=130/80 mm Hg after treatment at reevaluation were considered as well controlled. The PWV after treatment was significantly increased in all patients with hypertension (P < .01) and uncontrolled patients with hypertension (P < .001), remained unchanged in controlled patients with hypertension, and decreased in controlled patients with hypertension with baseline PWV >=12.4 m/s (P = .004), independent of the corresponding blood pressure (BP) decrease. Our study provides evidence that successful antihypertensive treatment leads to PWV improvement when baseline aortic stiffness level is at least moderately increased. The magnitude of observed PWV decrease is independent of the corresponding BP decrease. PMID- 25274528 TI - Renal Stenting for Kidney Salvage in the Management of Renal Artery Atherosclerotic Stenosis. AB - We studied the usefulness of preoperative resistance index to select patients who will benefit most from renal stenting. Sixty-two patients underwent renal stenting. All had chronic renal insufficiency with serum creatinine values ranging from 1.5 to 2.5 mg/dL and blood urea nitrogen between 80 and 107 mg/dL. All treated renal artery stenosis were >70%. Reduction in blood pressure in the early stages was observed in 39 (62.9%) patients; 31 (79.4%) patients returned to preoperative values within 12 months. A progressive reduction in creatinine values and blood urea nitrogen was reached in 43 (69.4%) patients, 12 (19.4%) patients remained unchanged, and the remaining 7 (11.2%) patients worsened. The best improvement in renal function was obtained in patients with a resistance index of <=0.75 A preoperative resistance index up to 0.75 could be used as an indicator to predict which candidates will have improved renal function after stenting. PMID- 25274530 TI - B cell lymphogenesis in swine is located in the bone marrow. AB - A course and a site of B cell development in swine are not firmly known. In this study, we show that B cell lymphogenesis is located in the bone marrow (BM). According to expression of MHC class II (MHC-II), CD2, CD21, CD25, CD45RC, CD172a, swine workshop cluster (identification number) (SWC) 7, and MUHC, porcine BM cells were resolved into seven subsets representing sequential stages of development. Profile of rearrangement-specific products and transcripts from sorted BM cells confirmed the proposed developmental pathway. The same developmental pathway was further proven by analysis of selection for productive rearrangements in Ig H chains and also by cultivation studies. Cultivation also showed that earliest precursors with incomplete DJ rearrangements can still revert their B cell differentiation and develop along myeloid lineage, whereas this is impossible for later developmental stages. Proliferation and the apoptotic potential of individual developmental stages as well as critical checkpoints were also identified. Colocalization experiments showed early colocalization of MHC-II/CD2/CD172a is replaced by colocalization of MHC II/CD2/CD21/SWC7/IgM in immature cells, whereas CD25 and CD45RC did not colocalize with any other studied molecules. In this study, we also finally prove that the BM in pigs is fully functional in adult animals and that B lymphogenesis occurs there throughout life. To our knowledge, this is the first study showing a course and a direct site of B cell lymphogenesis in swine. PMID- 25274531 TI - Regulatory T cells dynamically regulate selectin ligand function during multiple challenge contact hypersensitivity. AB - Regulatory T cells (Tregs) play critical roles in restricting T cell-mediated inflammation. In the skin, this is dependent on expression of selectin ligands required for leukocyte rolling in dermal microvessels. However, whether there are differences in the molecules used by Tregs and proinflammatory T cells to undergo rolling in the skin remains unclear. In this study, we used spinning disk confocal microscopy in Foxp3-GFP mice to visualize rolling of endogenous Tregs in dermal postcapillary venules. Tregs underwent consistent but low-frequency rolling interactions under resting and inflamed conditions. At the early stage of the response, Treg adhesion was minimal. However, at the peak of inflammation, Tregs made up 40% of the adherent CD4(+) T cell population. In a multiple challenge model of contact hypersensitivity, rolling of Tregs and conventional CD4(+) T cells was mostly dependent on overlapping contributions of P- and E selectin. However, after a second challenge, rolling of Tregs but not conventional CD4(+) T cells became P-selectin independent, and Tregs showed reduced capacity to bind P-selectin. Moreover, inhibition of E-selectin at this time point resulted in exacerbation of inflammation. These findings demonstrate that in this multiple challenge model of inflammation, Treg selectin binding capacity and the molecular basis of Treg rolling can be regulated dynamically. PMID- 25274532 TI - Operational guidance for radiation emergency response organisations in Europe for using biodosimetric tools developed in EU MULTIBIODOSE project. AB - In the event of a large-scale radiological emergency, the triage of individuals according to their degree of exposure forms an important initial step of the accident management. Although clinical signs and symptoms of a serious exposure may be used for radiological triage, they are not necessarily radiation specific and can lead to a false diagnosis. Biodosimetry is a method based on the analysis of radiation-induced changes in cells of the human body or in portable electronic devices and enables the unequivocal identification of exposed people who should receive medical treatment. The MULTIBIODOSE (MBD) consortium developed and validated several biodosimetric assays and adapted and tested them as tools for biological dose assessment in a mass-casualty event. Different biodosimetric assays were validated against the 'gold standard' of biological dosimetry-the dicentric assay. The assays were harmonised in such a way that, in an emergency situation, they can be run in parallel in a network of European laboratories. The aim of this guidance is to give a concise overview of the developed biodosimetric tools as well as how and when they can be used in an emergency situation. PMID- 25274529 TI - Differential efficacy of human mesenchymal stem cells based on source of origin. AB - Mesenchymal stem cells (MSCs) are useful in tissue repair but also possess immunomodulatory properties. Murine and uncontrolled human trials suggest efficacy of MSCs in treating lupus. Autologous cells are preferable; however, recent studies suggest that lupus-derived MSCs lack efficacy in treating disease. Thus, the optimum derivation of MSCs for use in lupus is unknown. It is also unknown which in vitro assays of MSC function predict in vivo efficacy. The objectives for this study were to provide insight into the optimum source of MSCs and to identify in vitro assays that predict in vivo efficacy. We derived MSCs from four umbilical cords, four healthy bone marrows (BMs), and four lupus BMs. In diseased MRL/lpr mice, MSCs from healthy BM and umbilical cords significantly decreased renal disease, whereas lupus BM MSCs only delayed disease. Current in vitro assays did not differentiate efficacy of the different MSCs. However, differences in MSC efficacy were observed in B cell proliferation assays. Our results suggest that autologous MSCs from lupus patients are not effective in treating disease. Furthermore, standard in vitro assays for MSC licensing are not predictive of in vivo efficacy, whereas inhibiting B cell proliferation appears to differentiate effective MSCs from ineffective MSCs. PMID- 25274534 TI - Lessons learned from events notified to the French Nuclear Safety Authority during the period 2007-13 in the medical field. AB - The analysis of events is crucial for accident prevention. In 2007, ASN set up a system for the notification of radiation protection events. The majority of them concern the exposure of patients undergoing therapeutic or diagnostic procedures and, to a lesser extent, occupational exposures and the management of radioactive effluents. The most significant events concern interventional radiological procedures and nuclear medicine, in which there are exceedances of mandatory dose limits and staff contaminations, respectively. Deterministic effects in patients were observed following interventional procedures and in nuclear medicine. Many events involve leakage of radioactive effluents and highlight the need to improve the monitoring and maintenance of radioactive effluent facilities. The causes are mainly of organisational and human origin. The lessons learned emphasise the importance of the role of medical physicists and radiation protection officers and the need to implement quality and risk management measures and to conduct clinical audits. PMID- 25274535 TI - The role of roughness-induced damping in the oscillatory motion of bilayer graphene. AB - A multi-scale theoretical model is presented that is the first to offer quantitative agreement with experimental measurements of self-retraction and oscillation of bilayer graphene. The model integrates density-functional theory calculations of the energetics driving flake retraction and molecular-dynamics simulations capturing the dynamic response of laterally-offset rough surfaces. We demonstrate that nanoscale roughness explains self-retraction motion and propose a recipe for tuning that motion by controlling friction. PMID- 25274533 TI - Telomere shortening: a new prognostic factor for cardiovascular disease post radiation exposure. AB - Telomere length has been proposed as a marker of mitotic cell age and as a general index of human organism aging. Telomere shortening in peripheral blood lymphocytes has been linked to cardiovascular-related morbidity and mortality. The authors investigated the potential correlation of conventional risk factors, radiation dose and telomere shortening with the development of coronary artery disease (CAD) following radiation therapy in a large cohort of Hodgkin lymphoma (HL) patients. Multivariate analysis demonstrated that hypertension and telomere length were the only independent risk factors. This is the first study in a large cohort of patients that demonstrates significant telomere shortening in patients treated by radiation therapy who developed cardiovascular disease. Telomere length appears to be an independent prognostic factor that could help determine patients at high risk of developing CAD after exposure in order to implement early detection and prevention. PMID- 25274537 TI - Empagliflozin: a review of its use in patients with type 2 diabetes mellitus. AB - Oral empagliflozin (Jardiance((r))), a sodium glucose cotransporter-2 (SGLT2) inhibitor, is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus. By inhibiting reabsorption of glucose from the proximal tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel insulin-independent mechanism of lowering blood glucose. In several phase III trials (<=104 weeks' duration; typically 24 weeks' duration) and extension studies (typically >=76 weeks' treatment), empagliflozin monotherapy or add-on therapy to other antihyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. In a large phase III trial, as add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. Empagliflozin treatment appeared to have no intrinsic risk of hypoglycaemia, although hypoglycaemia occurred more frequently when empagliflozin was coadministered with insulin and/or a sulfonylurea. With its insulin-independent mechanism of action, empagliflozin monotherapy or combination therapy with other antidiabetic drugs, including insulin, provides a useful addition to the therapeutic options for the management of type 2 diabetes. This article reviews the pharmacological properties and clinical use of empagliflozin in patients with type 2 diabetes. PMID- 25274538 TI - A non-fullerene electron acceptor based on fluorene and diketopyrrolopyrrole building blocks for solution-processable organic solar cells with an impressive open-circuit voltage. AB - A novel solution-processable non-fullerene electron acceptor 6,6'-(5,5'-(9,9 dioctyl-9H-fluorene-2,7-diyl)bis(thiophene-5,2-diyl))bis(2,5-bis(2-ethylhexyl)-3 (thiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione) (DPP1) based on fluorene and diketopyrrolopyrrole conjugated moieties was designed, synthesized and fully characterized. DPP1 exhibited excellent solubility and high thermal stability which are essential for easy processing. Upon using DPP1 as an acceptor with the classical electron donor poly(3-hexylthiophene), solution processable bulk heterojunction solar cells afforded a power conversion efficiency of 1.2% with a high open-circuit voltage (1.1 V). As per our knowledge, this value of open circuit voltage is one of the highest values reported so far for a bulk heterojunction device using DPP1 as a non-fullerene acceptor. PMID- 25274539 TI - A mixture model for the analysis of data derived from record linkage. AB - Combining information from two data sources depends on finding records that belong to the same individual (matches). Sometimes, unique identifiers per individual are not available, and we have to rely on partially identifying variables that are registered in both data sources. A risk of relying on these variables is that some records from both datasets are wrongly linked to each other, which introduces bias in further regression analyses. In this paper, we propose a mixture model where we treat the indicator whether records belong to the same individual as missing. Each pair of records from both datasets contributes independently to a pairwise pseudo-likelihood, which we maximize with an expectation-maximization algorithm. Each part of the pseudo-likelihood is parameterized by the appropriate (parametric) density function. Moreover, some structures of the data allow for simplifying assumptions, which makes the pseudo likelihood considerably easier to parameterize. Because the optimization requires a product over all combinations of records from both datasets, we suggest a procedure that summarizes information from highly unlikely matches. With simulations, we showed that the new approach produces accurate estimates in different linkage scenarios. Moreover, the estimator remained accurate in scenarios where previously proposed analysis approaches give biased results. We applied the method to estimation of the association between pregnancy duration of the first and second born children from the same mother from a register without mother identifier. PMID- 25274540 TI - Beliefs and environmental behavior: the moderating effect of emotional intelligence. AB - Recent decades have seen a proliferation of studies aiming to explain how pro environmental behavior is shaped by attitudes, values and beliefs. In this study, we have included an aspect in our analysis that has been rarely touched upon until now, that is, the intelligent use of emotions as a possible component of pro-environmental behavior. We applied the Trait Meta Mood Scale-24 (TMMS-24) and the New Environmental Paradigm scale to a sample of 184 male and female undergraduate students. We also carried out correlation and hierarchical regression analyses of blocks. The results show the interaction effects of the system of environmental beliefs and the dimensions of emotional intelligence on glass recycling attitudes, intentions and behavior. The results are discussed from the perspective of research on how the management of emotions guides thought and behavior. PMID- 25274536 TI - Patient-centred pharmaceutical design to improve acceptability of medicines: similarities and differences in paediatric and geriatric populations. AB - Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populations. PMID- 25274541 TI - Comparison of the performance of HPV tests in women with abnormal cytology: results of a study within the NHS cervical screening programme. AB - OBJECTIVE: The use of testing for human papillomavirus (HPV) is now recognized as an efficient means of triaging women with low-grade cytological abnormalities to either immediate referral to colposcopy or return to routine recall. We aimed to determine the sensitivity and specificity of each of four newer tests for HPV relative to the Qiagen Hybrid Capture 2 (HC2) assay in order to determine whether they could be approved for use in triage in the NHS cervical screening programme. METHODS: We compared the performance of each of four different HPV assays (Abbott M2000, Roche Cobas, Hologic Cervista and Gen-Probe APTIMA) with that of HC2 in order to determine the sensitivity and specificity of each test relative to HC2 for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse, using routine cytology samples reported as borderline (atypical squamous cells) or mild dyskaryosis (low-grade squamous intraepithelial lesion) from six laboratories in England. All women who were found to be HPV positive on any test were referred to colposcopy. RESULTS: Between 2072 and 4217 tests were performed with each assay. All four assays were shown to have a relative sensitivity of no worse than 95% compared with HC2 when a cut-off of 2 relative light units (RLU) was used. All assays had higher relative specificity than HC2 for both borderline and mild cytology referrals (1.06-1.61). CONCLUSIONS: All assays tested met the criteria required. Consequently, all have now been approved for use in HPV triage in the NHS cervical screening programme. PMID- 25274542 TI - A fast, non-invasive, quantitative staining protocol provides insights in Plasmodium falciparum gamete egress and in the role of osmiophilic bodies. AB - BACKGROUND: Ability of Plasmodium falciparum gametocytes to become extracellular during gametogenesis in the mosquito midgut is a key step of the parasite life cycle. Reliable and quantitative measurement of the efficiency of gamete egress is currently constrained by the fact that this phenomenon is usually observed and quantified in vitro either by live microscopy, by statistically limited ultrastructural analysis or by surface antibody-based protocols which can interfere with this fast and complex cellular process. METHODS: A protocol was developed based on fluorescent wheat germ agglutinin (WGA) surface staining of erythrocytes containing mature P. falciparum gametocytes. After a single centrifugation step and within minutes from the induction of gametogenesis, the activated gametes can be inspected for presence or absence of the fluorescent WGA staining of the host erythrocyte membrane and scored respectively as intracellular or emerged from the erythrocyte. RESULTS: Gametogenesis and gamete egress from WGA surface stained, infected erythrocytes occur with normal kinetics and efficiencies. Quantitative measurements of gamete egress can be obtained in live and in paraformaldehyde-fixed cells, which validates this protocol as a suitable tool both for live imaging studies and for higher throughput applications. The protocol was used here to provide functional information on the ability of gametes to egress through a single exit point induced in the host red blood cell membrane, and to re-analyse the phenotype of Pfg377- and osmiophilic body-defective gametes, suggesting that such parasite components are not directly involved in disruption and shedding of the erythrocyte membrane in female gamete egress. CONCLUSIONS: The development of a reliable, fast, non-invasive and quantitative protocol to finely describe and to measure efficiency of P. falciparum gamete egress is a significant improvement in the tools for functional studies on this key process of the parasite life cycle. This protocol can be used to investigate the molecular mechanisms underlying gamete egress and its adaptation to high throughput applications will enable identification of transmission blocking inhibitors. PMID- 25274543 TI - Re: Longitudinal changes in maternal soluble endoglin and angiopoietin-2 in women at risk for pre-eclampsia. A. Khalil, N. Maiz, R. Garcia-Mandujano, M. Elkhouli and K. H. Nicolaides. Ultrasound Obstet Gynecol 2014; 44: 402-410. PMID- 25274544 TI - Re: Fetal cardiac parameters for prediction of twin-to-twin transfusion syndrome. C. Zanardini, F. Prefumo, A. Fichera, E. Botteri and T. Frusca. Ultrasound Obstet Gynecol 2014; 44: 434-440. PMID- 25274546 TI - The challenge of stimulus control: a comment on Poelman et al. PMID- 25274545 TI - Resistance to N-peptide fusion inhibitors correlates with thermodynamic stability of the gp41 six-helix bundle but not HIV entry kinetics. AB - BACKGROUND: The HIV-1 envelope glycoprotein (Env) undergoes conformational changes that mediate fusion between virus and host cell membranes. These changes involve transient exposure of two heptad-repeat domains (HR1 and HR2) in the gp41 subunit and their subsequent self-assembly into a six-helix bundle (6HB) that drives fusion. Env residues and features that influence conformational changes and the rate of virus entry, however, are poorly understood. Peptides corresponding to HR1 and HR2 (N and C peptides, respectively) interrupt formation of the 6HB by binding to the heptad repeats of a fusion-intermediate conformation of Env, making the peptides valuable probes for studying Env conformational changes. RESULTS: Using a panel of Envs that are resistant to N-peptide fusion inhibitors, we investigated relationships between virus entry kinetics, 6HB stability, and resistance to peptide fusion inhibitors to elucidate how HR1 and HR2 mutations affect Env conformational changes and virus entry. We found that gp41 resistance mutations increased 6HB stability without increasing entry kinetics. Similarly, we show that increased 6HB thermodynamic stability does not correlate with increased entry kinetics. Thus, N-peptide fusion inhibitors do not necessarily select for Envs with faster entry kinetics, nor does faster entry kinetics predict decreased potency of peptide fusion inhibitors. CONCLUSIONS: These findings provide new insights into the relationship between 6HB stability and viral entry kinetics and mechanisms of resistance to inhibitors targeting fusion-intermediate conformations of Env. These studies further highlight how residues in HR1 and HR2 can influence virus entry by altering stability of the 6HB and possibly other conformations of Env that affect rate-limiting steps in HIV entry. PMID- 25274547 TI - Intraoperative bleeding in dogs from Grenada seroreactive to Anaplasma platys and Ehrlichia canis. AB - BACKGROUND: Frequent exposure of Grenadian dogs to Rhipicephalus sanguineus results in Anaplasma platys, and Ehrlichia canis seroreactivity. During elective surgeries, substantial intraoperative hemorrhage occurs in some seroreactive dogs. OBJECTIVES: To assess hemostatic parameters and bleeding tendencies as well as prevalence of PCR positivity in apparently healthy A. platys and E. canis seroreactive and seronegative free-roaming dogs from Grenada. ANIMALS: Forty seven elective surgery dogs allocated to 4 groups: Seronegative control (n = 12), A. platys (n = 10), E. canis (n = 14) and A. platys, and E. canis (n = 11) seroreactive. METHODS: Preoperatively, hemostasis was assessed by platelet count, prothrombin time, activated partial thromboplastin time, and buccal mucosal bleeding time. Intra- and postoperative bleeding scores were subjectively assigned. Blood, spleen, bone marrow, and lymph node aspirates were tested by PCR. RESULTS: Bleeding scores in dogs coseroreactive for A. platys and E. canis were higher (P = .015) than those of seronegative dogs. A. platys DNA was amplified from 7/21 (33%) A. platys seroreactive dogs and from 1 E. canis seroreactive dog; E. canis DNA was amplified from 21/25 (84%) E. canis seroreactive dogs. E. canis DNA was amplified most often from blood, whereas A. platys DNA was amplified most often from bone marrow. CONCLUSIONS AND CLINICAL IMPORTANCE: Apparently healthy, free-roaming dogs coseropositive for A. platys and E. canis may have increased intraoperative bleeding tendencies despite normal hemostatic parameters. Future investigations should explore the potential for vascular injury as a cause for bleeding in these dogs. Improved tick control is needed for dogs in Grenada. PMID- 25274548 TI - Five-year incidence of Nd:YAG laser capsulotomy and association with in vitro proliferation of lens epithelial cells from individual specimens: a case control study. AB - BACKGROUND: The aims of this study were to determine the 5-year incidence of posterior capsule opacification (PCO) requiring Nd:YAG laser capsulotomy in a representative mixed cohort of cataract patients, to determine risk factors for PCO and to investigate possible association with growth of human lens epithelial cells (HLEC) in vitro. METHODS: Pieces of the anterior lens capsule and adhering HLEC were obtained at cataract surgery and cultured individually. After one and two weeks respectively, cultured cells were stained with carboxy-fluorescein diacetate succinimidyl ester (CFDA SE), after which image processing software was used to determine the area of the confluent cell layer. The 5-year incidence of Nd:YAG laser capsulotomy in this cohort was determined through medical records and by mail or telephone interviews. For statistic analyses Mann-Whitney U-test, Fisher's exact test and binary logistic regression were used. RESULTS: Data on treatment/no treatment for PCO was obtained from 270 patients with a median follow-up time of 57 months (range 50-64 months). The three-year cumulative incidence of PCO was 5.2% and the cumulative 5-year incidence was 11.9%. Patients who had undergone Nd:YAG laser capsulotomy were significantly younger (median 71 years) than patients who did not receive treatment for PCO (median 75 years, p = 0.022). Logistic regression demonstrated that apart from younger age, follow-up time and type of intraocular lens (IOL) were associated with risk of PCO, with hydrophilic 1-piece IOLs conferring a higher risk than hydrophobic acrylic 1 piece or 3-piece IOLs (adjusted OR = 9.4, 95% CI 2.5-35.7, p = 0.001). Of the 270 patients from whom information could be retrieved regarding PCO treatment, in vitro cell culture could be established and quantified from 185 patients. No significant difference in cell growth in vitro was shown between patients subsequently requiring/not requiring Nd:YAG laser capsulotomy. CONCLUSIONS: The cumulative 5-year incidence of 11.9% is comparable or slightly higher than reported in other recent studies. The type of IOL was the most important risk factor for PCO in this study, whereas intrinsic proliferative capacity of the individual's lens epithelial cells seems to be less important for subsequent PCO development. PMID- 25274549 TI - Evolution of genome size and chromosome number in the carnivorous plant genus Genlisea (Lentibulariaceae), with a new estimate of the minimum genome size in angiosperms. AB - BACKGROUND AND AIMS: Some species of Genlisea possess ultrasmall nuclear genomes, the smallest known among angiosperms, and some have been found to have chromosomes of diminutive size, which may explain why chromosome numbers and karyotypes are not known for the majority of species of the genus. However, other members of the genus do not possess ultrasmall genomes, nor do most taxa studied in related genera of the family or order. This study therefore examined the evolution of genome sizes and chromosome numbers in Genlisea in a phylogenetic context. The correlations of genome size with chromosome number and size, with the phylogeny of the group and with growth forms and habitats were also examined. METHODS: Nuclear genome sizes were measured from cultivated plant material for a comprehensive sampling of taxa, including nearly half of all species of Genlisea and representing all major lineages. Flow cytometric measurements were conducted in parallel in two laboratories in order to compare the consistency of different methods and controls. Chromosome counts were performed for the majority of taxa, comparing different staining techniques for the ultrasmall chromosomes. KEY RESULTS: Genome sizes of 15 taxa of Genlisea are presented and interpreted in a phylogenetic context. A high degree of congruence was found between genome size distribution and the major phylogenetic lineages. Ultrasmall genomes with 1C values of <100 Mbp were almost exclusively found in a derived lineage of South American species. The ancestral haploid chromosome number was inferred to be n = 8. Chromosome numbers in Genlisea ranged from 2n = 2x = 16 to 2n = 4x = 32. Ascendant dysploid series (2n = 36, 38) are documented for three derived taxa. The different ploidy levels corresponded to the two subgenera, but were not directly correlated to differences in genome size; the three different karyotype ranges mirrored the different sections of the genus. The smallest known plant genomes were not found in G. margaretae, as previously reported, but in G. tuberosa (1C ~ 61 Mbp) and some strains of G. aurea (1C ~ 64 Mbp). CONCLUSIONS: Genlisea is an ideal candidate model organism for the understanding of genome reduction as the genus includes species with both relatively large (~1700 Mbp) and ultrasmall (~61 Mbp) genomes. This comparative, phylogeny-based analysis of genome sizes and karyotypes in Genlisea provides essential data for selection of suitable species for comparative whole-genome analyses, as well as for further studies on both the molecular and cytogenetic basis of genome reduction in plants. PMID- 25274550 TI - Buzz pollination in eight bumblebee-pollinated Pedicularis species: does it involve vibration-induced triboelectric charging of pollen grains? AB - BACKGROUND AND AIMS: Buzz pollination involves explosive pollen release in response to vibration, usually by bees. The mechanism of pollen release is poorly understood, and it is not clear which component of vibration (acceleration, frequency, displacement or velocity) is critical; the role of buzz frequency has been particularly controversial. This study proposes a novel hypothesis that explosive pollen release results from vibration-induced triboelectric charging. If it does, pollen release is expected to depend on achievement of a critical threshold velocity. METHODS: Eight sympatric buzz-pollinated species of Pedicularis that share bumblebee pollinator species were studied, giving a rare opportunity to compare sonication behaviour of a shared pollinator on different plant species. KEY RESULTS: Reconsidering previous experimental studies, it is argued that they establish the critical role of the velocity component of vibration in pollen release, and that when displacement is constrained by body size bees can achieve the critical velocity by adjusting frequency. It was shown that workers of Bombus friseanus assorted themselves among Pedicularis species by body size, and that bees adjusted their buzz/wingbeat frequency ratio, which is taken as an index of the velocity component, to a value that corresponds with the galea length and pollen grain volume of each species of Pedicularis. CONCLUSIONS: Sonication behaviour of B. friseanus differs among Pedicularis species, not only because worker bees assort themselves among plant species by body size, but also because bees of a given size adjust the buzz frequency to achieve a vibration velocity corresponding to the floral traits of each plant species. These findings, and the floral traits that characterize these and other buzz-pollinated species, are compatible with the hypothesis of vibration-induced triboelectric charging of pollen grains. PMID- 25274552 TI - Noninvasive prenatal diagnosis: from dream to reality. PMID- 25274551 TI - Root foraging elicits niche complementarity-dependent yield advantage in the ancient 'three sisters' (maize/bean/squash) polyculture. AB - BACKGROUND AND AIMS: Since ancient times in the Americas, maize, bean and squash have been grown together in a polyculture known as the 'three sisters'. This polyculture and its maize/bean variant have greater yield than component monocultures on a land-equivalent basis. This study shows that below-ground niche complementarity may contribute to this yield advantage. METHODS: Monocultures and polycultures of maize, bean and squash were grown in two seasons in field plots differing in nitrogen (N) and phosphorus (P) availability. Root growth patterns of individual crops and entire polycultures were determined using a modified DNA based technique to discriminate roots of different species. KEY RESULTS: The maize/bean/squash and maize/bean polycultures had greater yield and biomass production on a land-equivalent basis than the monocultures. Increased biomass production was largely caused by a complementarity effect rather than a selection effect. The differences in root crown architecture and vertical root distribution among the components of the 'three sisters' suggest that these species have different, possibly complementary, nutrient foraging strategies. Maize foraged relatively shallower, common bean explored the vertical soil profile more equally, while the root placement of squash depended on P availability. The density of lateral root branching was significantly greater for all species in the polycultures than in the monocultures. CONCLUSIONS: It is concluded that species differences in root foraging strategies increase total soil exploration, with consequent positive effects on the growth and yield of these ancient polycultures. PMID- 25274554 TI - Animal olfactory detection of disease: promises and pitfalls. PMID- 25274553 TI - Translating sanger-based routine DNA diagnostics into generic massive parallel ion semiconductor sequencing. AB - BACKGROUND: Dideoxy-based chain termination sequencing developed by Sanger is the gold standard sequencing approach and allows clinical diagnostics of disorders with relatively low genetic heterogeneity. Recently, new next generation sequencing (NGS) technologies have found their way into diagnostic laboratories, enabling the sequencing of large targeted gene panels or exomes. The development of benchtop NGS instruments now allows the analysis of single genes or small gene panels, making these platforms increasingly competitive with Sanger sequencing. METHODS: We developed a generic automated ion semiconductor sequencing work flow that can be used in a clinical setting and can serve as a substitute for Sanger sequencing. Standard amplicon-based enrichment remained identical to PCR for Sanger sequencing. A novel postenrichment pooling strategy was developed, limiting the number of library preparations and reducing sequencing costs up to 70% compared to Sanger sequencing. RESULTS: A total of 1224 known pathogenic variants were analyzed, yielding an analytical sensitivity of 99.92% and specificity of 99.99%. In a second experiment, a total of 100 patient-derived DNA samples were analyzed using a blind analysis. The results showed an analytical sensitivity of 99.60% and specificity of 99.98%, comparable to Sanger sequencing. CONCLUSIONS: Ion semiconductor sequencing can be a first choice mutation scanning technique, independent of the genes analyzed. PMID- 25274555 TI - DNA ligase-based strategy for quantifying heterogeneous DNA methylation without sequencing. AB - BACKGROUND: DNA methylation is a potential source of disease biomarkers. Typically, methylation levels are measured at individual cytosine/guanine (CpG) sites or over a short region of interest. However, regions of interest often show heterogeneous methylation comprising multiple patterns of methylation (epialleles) on individual DNA strands. Heterogeneous methylation is largely ignored because digital methods are required to deconvolute these usually complex patterns of epialleles. Currently, only single-molecule approaches, such as next generation sequencing (NGS), can provide detailed epiallele information. Because NGS is not yet feasible for routine practice, we developed a single-molecule-like approach, named for epiallele quantification (EpiQ). METHODS: EpiQ uses DNA ligases and the enhanced thermal instability of short (<=19 bases) mismatched DNA probes for the relative quantification of epialleles. The assay was developed using fluorescent detection on a gel and then adapted for electrochemical detection on a microfabricated device. NGS was used to validate the analytical accuracy of EpiQ. RESULTS: In this proof of principle study, EpiQ detected with 90%-95% specificity each of the 8 possible epialleles for a 3-CpG cluster at the promoter region of the CDKN2B (p15) tumor suppressor gene. EpiQ successfully profiled heterogeneous methylation patterns in clinically derived samples, and the results were cross-validated with NGS. CONCLUSIONS: EpiQ is a potential alternative tool for characterizing heterogeneous methylation, thus facilitating its use as a biomarker. EpiQ was developed on a gel-based assay but can also easily be adapted for miniaturized chip-based platforms. PMID- 25274556 TI - Comparative effectiveness research and demonstrating clinical utility for molecular diagnostic tests. PMID- 25274557 TI - From hypomagnesaemia to Zollinger-Ellison syndrome: an adverse effect of a proton pump inhibitor. AB - We describe the case of a 53-year-old man who presented with abdominal pain, diarrhoea and hypomagnesaemia. The hypomagnesaemia proved to be due to gastrointestinal loss as urinary fractional excretion was very low, suggesting non-renal loss. Common causes were discarded and the hypomagnesaemia was attributed to chronic use of the proton pump inhibitor, omeprazole. As such, omeprazole was discontinued and an H2 blocker was given. Several days later the patient presented with upper gastrointestinal bleeding. CT scan demonstrated marked enlargement of the duodenum and proximal jejunum, and abnormal thickening and enhancement of the bowel wall. Urgent oesophagogastroduodenoscopy revealed coffee-ground and bloody contents in the distal oesophagus and stomach, and numerous ulcers along the duodenum and jejunum. A positron emission tomography-CT scan using GA 68-DOTANOC demonstrated increased uptake in the gastroduodenum junction, suggesting a neuroendocrine tumour. Pancreaticoduodenectomy was performed and tumour cells stained positive for gastrin, confirming the tentative diagnosis of Zollinger-Ellison syndrome. PMID- 25274558 TI - Potential involvement of Campylobacter curvus and Haemophilus parainfluenzae in preterm birth. AB - A woman presented with prelabour premature preterm rupture of membranes and delivered extremely preterm at 26 weeks by caesarean section. Histopathology of the placenta indicated moderately severe histological chorioamnionitis with dense infiltration of the chorionic plate by neutrophils. Two sets of low and high vaginal swabs were taken from the mother. A set sent for microbiological analysis at the hospital yielded negative results. The second set was analysed employing culture-independent high-throughput sequencing methods and revealed significant infections with Campylobacter curvus and Haemophilus parainfluenzae. This is the first report of C. curvus infection in the female genital tract that has been identified in a woman who delivered preterm. The case supports the need to review the standard culture methods employed for microbial analyses in hospitals. PMID- 25274559 TI - Challenges in the implantation of a Boston type 1 keratoprosthesis and a glaucoma drainage device in a nanophthalmic eye. AB - A 67-year-old man presented with hand motions vision, a decompensated vascularised cornea and a flat anterior chamber in the right eye 5 years following cataract and glaucoma surgery. He lost the left eye several years ago following a similar intervention. The intraocular pressure (IOP) was 19 mm Hg on four antiglaucoma medications and the axial length was 19 mm. In view of the high risk for graft failure, a Boston type 1 keratoprosthesis (Kpro) was planned for visual rehabilitation, and a glaucoma drainage device (GDD) for IOP control. Although a combined GDD with Kpro was indicated, we performed sequential surgeries to avoid vision threatening hypotony-related complications. He underwent parsplana vitrectomy, prophylactic lamellar sclerectomies and Kpro at the first stage, followed by a paediatric Ahmed glaucoma valve implantation 3 months later. Despite precautions, postoperative uveal effusion occurred but could be managed conservatively. His IOP was controlled; visual acuity improved to 20/50 and remained stable at 2 years. PMID- 25274560 TI - Postpartum pericarditis. PMID- 25274561 TI - Kissing carotid arteries: an unusual cause of prevertebral swelling. PMID- 25274562 TI - Multiple intestinal haemangiomas presenting as intussusception and bleeding. PMID- 25274563 TI - Dental Stem Cell in Tooth Development and Advances of Adult Dental Stem Cell in Regenerative Therapies. AB - Stem cell-based therapies are considered as a promising treatment for many clinical usage such as tooth regeneration, bone repairation, spinal cord injury, and so on. However, the ideal stem cell for stem cell-based therapy still remains to be elucidated. In the past decades, several types of stem cells have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs) and stem cells from apical papilla (SCAP), which may be a good source for stem cell-based therapy in certain disease, especially when they origin from neural crest is considered. In this review, the specific characteristics and advantages of the adult dental stem cell population will be summarized and the molecular mechanisms of the differentiation of dental stem cell during tooth development will be also discussed. PMID- 25274564 TI - Ligament and tendon repair through regeneration using mesenchymal stem cells. AB - One of Nature's gifts to mankind is mesenchymal stem cells (MSC's). They are multipotent in nature and are present literally in every tissue. Since, they possess certain characteristics of stem cells such as self-renewal and differentiation they are known to be one of the key players in normal tissue homeostasis. This novel function of mesenchymal stem cells has been explored by scientists in the field of regenerative medicine. This review gives an insight of the various sources of mesenchymal stem cells available for tissue engineering with regard to tendon and ligament and the mechanism involved during regeneration. PMID- 25274565 TI - Senile scleral plaques imaged with enhanced depth optical coherence tomography. AB - PURPOSE: Senile scleral plaques (SSP) are sharply demarcated greyish areas located just anterior to the insertions of the horizontal rectus muscles and thus are frequently encountered during transscleral intravitreal injections. The aim of this study was to characterize SSP using enhanced depth imaging spectral domain anterior segment optical coherence tomography (OCT) in a cohort of patients attending intravitreal injection clinics. METHODS: Prospective cross sectional study of 380 patients attending the clinic for intravitreal injections at the Department of Ophthalmology at the Bern University Hospital. Thirty-two patients with SSP were identified and the anatomical features were assessed using anterior segment OCT. RESULTS: In our patient cohort, we found a SSP prevalence of 8.2%. Senile scleral plaques were easily identifiable using anterior segment OCT and were found at the insertion sites of the horizontal recti muscles. The mean horizontal diameter was 2.2 mm (+/-760 MUm SD), the mean vertical diameter was 3.3 mm (+/-144 MUm SD), and the average surface area was 5.3 mm(2) (+/-0.4 mm(2) SD). The mean senile scleral plaque thickness was 0.6 mm (+/-149 MUm SD). The mean distance from the limbus was 2.24 mm for nasally located SSP and 3.22 mm for temporally located SSP. CONCLUSION: SSP are frequently encountered during intravitreal injections as they are located just anterior to the insertion sites of the horizontal recti muscles. Because the scleral stroma is rarefied and due to calcifications within SSP, these areas should be avoided when performing multiple intravitreal injections as this may result in rupture of the sclera. PMID- 25274567 TI - Copper-catalyzed intramolecular oxytrifluoromethylthiolation of unactivated alkenes. AB - A mild, versatile, and convenient method for efficient intramolecular oxytrifluoromethylthiolation of unactivated alkenes catalyzed by Cu(OAc)2 has been developed. The reactions were carried out under aerobic conditions and formed a variety of isoxazolines bearing a -SCF3 substituent. PMID- 25274568 TI - Bitter taste causes hostility. AB - The present research tested the novel hypothesis that bitter taste increases hostility. Theoretical background formed the intimate link of the taste-sensory system to the visceral system, with bitter intake typically eliciting a strong aversion response. Three experiments using differential bitter and control stimuli showed that hostile affect and behavior is increased by bitter taste experiences. Specifically, participants who consumed a bitter (vs. control) drink showed an increase in self-reported current hostility (Experiment 1), in hypothetical aggressive affect and hypothetical aggressive behavior (Experiment 2) and in actual hostile behavior assessed using a well-established method for non-physical laboratory aggression (Experiment 3). Furthermore, the effect occurred not only when participants were previously provoked (Experiments 2 and 3) but also when no provocation preceded (Experiment 1 and 3). Importantly, stimulus aversiveness and intensity did not influence the effects observed, ruling them out as explanations. Alternative interpretative frameworks and limitations are discussed. PMID- 25274566 TI - Evolution and functional implications of the tricarboxylic acid cycle as revealed by phylogenetic analysis. AB - The tricarboxylic acid (TCA) cycle, a crucial component of respiratory metabolism, is composed of a set of eight enzymes present in the mitochondrial matrix. However, most of the TCA cycle enzymes are encoded in the nucleus in higher eukaryotes. In addition, evidence has accumulated demonstrating that nuclear genes were acquired from the mitochondrial genome during the course of evolution. For this reason, we here analyzed the evolutionary history of all TCA cycle enzymes in attempt to better understand the origin of these nuclear-encoded proteins. Our results indicate that prior to endosymbiotic events the TCA cycle seemed to operate only as isolated steps in both the host (eubacterial cell) and mitochondria (alphaproteobacteria). The origin of isoforms present in different cell compartments might be associated either with gene-transfer events which did not result in proper targeting of the protein to mitochondrion or with duplication events. Further in silico analyses allow us to suggest new insights into the possible roles of TCA cycle enzymes in different tissues. Finally, we performed coexpression analysis using mitochondrial TCA cycle genes revealing close connections among these genes most likely related to the higher efficiency of oxidative phosphorylation in this specialized organelle. Moreover, these analyses allowed us to identify further candidate genes which might be used for metabolic engineering purposes given the importance of the TCA cycle during development and/or stress situations. PMID- 25274569 TI - Interleukin 17A acts synergistically with interferon gamma to promote protection against Leishmania infantum infection. AB - Interleukin 17 (IL-17) is an inflammatory cytokine that plays a protective role against intracellular parasites. The role of IL-17 during Leishmania infection remains controversial and poorly defined. We evaluated whether IL-17 participates in the host immune response to Leishmania infantum. IL-17A is present in sera from patients with visceral leishmaniasis and decreases after successful treatment. In C57BL/6 infected mice, higher production of IL-17A coincided with the peak of parasitism. Il17ra(-/-) mice were more susceptible to infection and also exhibited reduced inflammatory infiltration and interferon gamma (IFN-gamma) expressing CD4+ T-cell frequencies than wild-type mice. The frequencies of FoxP3+ CD4+ T cells and interleukin 10 (IL-10)-expressing CD4+ T cells were increased in Il17ra(-/-) mice. We also demonstrated that IL-17A acts synergistically with IFN gamma to potentiate NO production and leishmanicidal activity in infected macrophages. Therefore, our results indicate that L. infantum induces IL-17A production, which promotes the control of parasite replication by strengthening T helper type 1 responses and NO production and prevents regulatory T-cell and IL 10-expressing T-cell expansion. PMID- 25274570 TI - Construction and evaluation of a chimeric protein made from Fasciola hepatica leucine aminopeptidase and cathepsin L1. AB - Leucine aminopeptidase (LAP) and cathepsin L1 (CL1) are important enzymes for the pathogenesis and physiology of Fasciola hepatica. These enzymes were analysed in silico to design a chimeric protein containing the most antigenic sequences of LAP (GenBank; AAV59016.1; amino acids 192-281) and CL1 (GenBank CAC12806.1; amino acids 173-309). The cloned 681-bp chimeric fragment (rFhLAP-CL1) contains 270 bp from LAP and 411 bp from CL1, comprising three epitopes, DGRVVHLKY (amino acids 54-62) from LAP, VTGYYTVHSGSEVELKNLV (amino acids 119-137) and YQSQTCLPF (amino acids 161-169) from CL1. The ~25 kDa rFhLAP-CL1 chimeric protein was expressed from the pET15b plasmid in the Rosetta (DE3) Escherichia coli strain. The chimeric protein rFhLAP-CL1, which showed antigenic and immunogenic properties, was recognized in Western blot assays using F. hepatica-positive bovine sera, and induced strong, specific antibody responses following immunization in rabbits. The newly generated chimeric protein may be used as a diagnostic tool for detection of antibodies against F. hepatica in bovine sera and as an immunogen to induce protection against bovine fasciolosis. PMID- 25274571 TI - Memory difficulties are not always a sign of incipient dementia: a review of the possible causes of loss of memory efficiency. AB - INTRODUCTION OR BACKGROUND: Memory problems are a very common reason for presenting to primary care. There is a need for better treatments for dementia. Increased government and media interest may result in greater number seeking help for memory problems, which may not reduce the dementia gap but rather increase numbers seen who do not have dementia. This review highlights the issues around the diagnostic criteria and terminology used for people with memory complaints. SOURCES OF DATA: A comprehensive literature search using PubMed using keywords for articles on subjective memory decline (SMD)/impairment/complaints, subjective cognitive decline (SCD), mild cognitive impairment (MCI) and functional memory disorder (FMD). AREAS OF AGREEMENT: There is a need for early accurate detection of dementia syndromes so that trials of new treatments can begin earlier on the disease process. AREAS OF CONTROVERSY: Diagnostic criteria and terminology used for disorders of memory including SCD, MCI and FMD. GROWING POINTS: This article reviews SCD and whether this can be used to predict Alzheimer's disease. The review also discusses the terminology used for non-progressive memory problems and the long-term outcomes for this patient group. AREAS TIMELY FOR DEVELOPING RESEARCH: The accurate distinction of premorbid dementia syndromes from benign non-progressive memory problems. Studies of treatment options for people with benign non-progressive memory problems and longer-term follow-up to determine which patients develop chronic problems. PMID- 25274572 TI - New methods for identifying infectious diseases. AB - BACKGROUND: The goal of clinical microbiology is to identify the cause of infection, aiding rapid treatment initiation or altering empirically chosen anti microbial regimens. Automation and molecular techniques have brought about a revolution in the clinical laboratory, ensuring ever faster and more accurate diagnoses. In the last few years however, there have been a number of developments that radically alter the way that microbiology and other diagnostic laboratories are advancing. In particular, clinical microbiology will have the opportunity to intervene at the public health level as well as at the individual patient. SOURCES OF DATA, AREAS OF AGREEMENT AND CONTROVERSY: Experts in the new technologies discuss the advances and some of the key literature that has been published to-date. They touch upon both the potential benefits and some of the hurdles that must be overcome before the technologies are embraced fully into the clinical laboratory. GROWING POINTS: This review discusses a number of technologies that may alter the way in which clinical microbiology is used to investigate infectious disease. Diagnostic services in the UK are currently undergoing a process of rationalization, which involves a shift towards laboratory amalgamation, adoption of 24/7 working patterns and greater automation in order to reduce costs. This review explores technologies that are already or are expected to be important in this on-going transition because they simplify or accelerate the complex workflows that are required for pathogen identification. PMID- 25274573 TI - Longitudinal study of thinness from birth to early childhood: the association with parental thinness. AB - AIM: Epidemiological research on thinness, particularly in early childhood, is limited. This study tracked thin children aged 5 years back to birth, compared them with normal-weight children and investigated the relationship with parental thinness. METHODS: We enrolled 2678 children (50.5% boys) aged 5 years and attending kindergarten or nursery in the Nara Prefecture of Japan. The children's height and weight at birth, 1.5 years and 3.5 years, were obtained from mother child health records. Child thinness was defined as having a body mass index (BMI) of less than the fifth percentile of the reference values for Japanese children, and parental thinness was defined as a BMI of <18.5. RESULTS: The overall prevalence of thinness at 5 years of age was 4%, with no significant difference between genders. At every age, weight z-scores and BMI percentiles were significantly lower in thin children than normal-weight children. The increment in weight z-scores between birth and the age of 1.5 years was significantly lower in thin children. The only parental link was paternal thinness and thinness in boys. CONCLUSION: Careful observation of body weight from birth is important to reduce thinness at 5 years of age. Paternal thinness may be a risk factor for thinness in boys. PMID- 25274574 TI - 8th international conference on oncolytic virus therapeutics. AB - The 8th International Conference on Oncolytic Virus Therapeutics meeting was held from April 10-13, 2014, in Oxford, United Kingdom. It brought together experts in the field of oncolytics from Europe, Asia, Australasia, and the Americas and provided a unique opportunity to hear the latest research findings in oncolytic virotherapy. Presentations of recent work were delivered in an informal and intimate setting afforded by a small group of attendees and an exquisitely focused conference topic. Here we describe the oral presentations and enable the reader to share in the benefits of bringing together experts to share their findings. PMID- 25274575 TI - Reptile-associated ticks from Dominica and the Bahamas with notes on hyperparasitic erythraeid mites. AB - Ticks were collected or recorded from 522 individual reptiles on Dominica and from 658 reptiles from the Bahamas. Two species of ticks were collected on Dominica: Amblyomma antillorum and Amblyomma rotundatum. Similarly, 2 species were collected in the Bahamas: Amblyomma albopictum and Amblyomma torrei. On Dominica, A. antillorum was recorded from 517 Lesser Antillean iguanas (Iguana delicatissima), 2 boa constrictors (Boa nebulosa), 1 Antilles snake (Alsophis sibonius), and 1 Dominican ground lizard (Ameiva fuscata), whereas A. rotundatum was recorded from 1 Lesser Antillean skink (Mabuya mabouya). In the Bahamas, A. albopictum was recorded from 131 Andros iguanas (Cyclura cychlura cychlura), 271 Exuma Island iguanas (Cyclura cychlura figginsi), and 1 Andros curlytail lizard (Leiocephalus carinatus coryi), whereas A. torrei was recorded from 255 Exuma Island iguanas. In the Bahamas, A. albopictum parasitized iguanas on Andros Island and the central Exuma Islands, and A. torrei parasitized iguanas in the southern Exumas. An exception to this trend was that A. torrei was collected from iguanas on Pasture Cay in the central Exumas, an anomaly that is explained by the fact that iguanas (with attached ticks) on Pasture Cay were introduced by humans in the past from islands further south. External hyperparasitic larval erythraeid mites ( Leptus sp.) were recorded from A. torrei in the Bahamas. PMID- 25274576 TI - Imbalance of default mode and regulatory networks during externally focused processing in depression. AB - Attentional control difficulties likely underlie rumination, a core cognitive vulnerability in major depressive disorder (MDD). Abnormalities in the default mode, executive and salience networks are implicated in both rumination and attentional control difficulties in MDD. In the current study, individuals with MDD (n = 16) and healthy controls (n = 16) completed tasks designed to elicit self-focused (ruminative) and externally-focused thinking during fMRI scanning. The MDD group showed greater default mode network connectivity and less executive and salience network connectivity during the external-focus condition. Contrary to our predictions, there were no differences in connectivity between the groups during the self-focus condition. Thus, it appears that when directed to engage in self-referential thinking, both depressed and non-depressed individuals similarly recruit networks supporting this process. In contrast, when instructed to engage in non-self-focused thought, non-depressed individuals show a pattern of network connectivity indicative of minimized self-referential processing, whereas depressed individuals fail to reallocate neural resources in a manner consistent with effective down regulation of self-focused thought. This is consistent with difficulties in regulating self-focused thinking in order to engage in more goal directed behavior that is seen in individuals with MDD. PMID- 25274577 TI - How to trust a perfect stranger: predicting initial trust behavior from resting state brain-electrical connectivity. AB - Reciprocal exchanges can be understood as the updating of an initial belief about a partner. This initial level of trust is essential when it comes to establishing cooperation with an unknown partner, as cooperation cannot arise without a minimum of trust not justified by previous successful exchanges with this partner. Here we demonstrate the existence of a representation of the initial trust level before an exchange with a partner has occurred. Specifically, we can predict the Investor's initial investment--i.e. his initial level of trust toward the unknown trustee in Round 1 of a standard 10-round Trust Game-from resting state functional connectivity data acquired several minutes before the start of the Trust Game. Resting-state functional connectivity is, however, not significantly associated with the level of trust in later rounds, potentially mirroring the updating of the initial belief about the partner. Our results shed light on how the initial level of trust is represented. In particular, we show that a person's initial level of trust is, at least in part, determined by brain electrical activity acquired well before the beginning of an exchange. PMID- 25274578 TI - Pan-Canadian study of mammography screening and mortality from breast cancer. AB - BACKGROUND: Screening with mammography has been shown by randomized controlled trials to reduce breast cancer mortality in women aged 40 to 74 years. Estimates from observational studies following screening implementation in different countries have produced varyied findings. We report findings for seven Canadian breast screening programs. METHODS: Canadian breast screening programs were invited to participate in a study aimed at comparing breast cancer mortality in participants and nonparticipants. Seven of 12 programs, representing 85% of the Canadian population, participated in the study. Data were obtained from the screening programs and corresponding cancer registries on screening mammograms and breast cancer diagnoses and deaths for the period between 1990 and 2009. Standardized mortality ratios were calculated comparing observed mortality in participants to that expected based upon nonparticipant rates. A substudy using data from British Columbia women aged 35 to 44 years was conducted to assess the potential effect of self-selection participation bias. All statistical tests were two-sided. RESULTS: Data were obtained on 2796472 screening participants. The average breast cancer mortality among participants was 40% (95% confidence interval [CI] = 33% to 48%) lower than expected, with a range across provinces of 27% to 59%. Age at entry into screening did not greatly affect the magnitude of the average reduction in mortality, which varied between 35% and 44% overall. The substudy found no evidence that self-selection biased the reported mortality results, although the confidence intervals of this assessment were wide. CONCLUSION: Participation in mammography screening programs in Canada was associated with substantially reduced breast cancer mortality. PMID- 25274580 TI - How best to determine the mortality benefit from screening mammography: dueling results and methodologies from Canada. PMID- 25274581 TI - GMC will develop single exam for all medical graduates wishing to practise in UK. PMID- 25274579 TI - Cigarette smoking and variations in systemic immune and inflammation markers. AB - BACKGROUND: A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease. METHODS: Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models. RESULTS: Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1beta, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1beta, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking. CONCLUSIONS: Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time. PMID- 25274582 TI - The unforeseen costs of extraordinary experience. AB - People seek extraordinary experiences--from drinking rare wines and taking exotic vacations to jumping from airplanes and shaking hands with celebrities. But are such experiences worth having? We found that participants thoroughly enjoyed having experiences that were superior to those had by their peers, but that having had such experiences spoiled their subsequent social interactions and ultimately left them feeling worse than they would have felt if they had had an ordinary experience instead. Participants were able to predict the benefits of having an extraordinary experience but were unable to predict the costs. These studies suggest that people may pay a surprising price for the experiences they covet most. PMID- 25274583 TI - Shared experiences are amplified. AB - In two studies, we found that sharing an experience with another person, without communicating, amplifies one's experience. Both pleasant and unpleasant experiences were more intense when shared. In Study 1, participants tasted pleasant chocolate. They judged the chocolate to be more likeable and flavorful when they tasted it at the same time that another person did than when that other person was present but engaged in a different activity. Although these results were consistent with our hypothesis that shared experiences are amplified compared with unshared experiences, it could also be the case that shared experiences are more enjoyable in general. We designed Study 2 to distinguish between these two explanations. In this study, participants tasted unpleasantly bitter chocolate and judged it to be less likeable when they tasted it simultaneously with another person than when that other person was present but doing something else. These results support the amplification hypothesis. PMID- 25274584 TI - Flexible designs for phase II comparative clinical trials involving two response variables. AB - The aim of phase II clinical trials is to determine whether an experimental treatment is sufficiently promising and safe to justify further testing. The need for reduced sample size arises naturally in phase II clinical trials owing to both technical and ethical reasons, motivating a significant part of research in the field during recent years, while another significant part of the research effort is aimed at more complex therapeutic schemes that demand the consideration of multiple endpoints to make decisions. In this paper, our attention is restricted to phase II clinical trials in which two treatments are compared with respect to two dependent dichotomous responses proposing some flexible designs. These designs permit the researcher to terminate the clinical trial when high rates of favorable or unfavorable outcomes are observed early enough requiring in this way a small number of patients. From the mathematical point of view, the proposed designs are defined on bivariate sequences of multi-state trials, and the corresponding stopping rules are based on various distributions related to the waiting time until a certain number of events appear in these sequences. The exact distributions of interest, under a unified framework, are studied using the Markov chain embedding technique, which appears to be very useful in clinical trials for the sample size determination. Tables of expected sample size and power are presented. The numerical illustration showed a very good performance for these new designs. PMID- 25274585 TI - Retinal phototransduction. AB - Vision is perhaps the most important of all our senses, and gives us an immense amount of information regarding the outside world. The initial format in which this information reaches the retina are photons; particles of energy radiation of a given wavelength emitted or reflected from our surroundings. The brain itself however, perceives information in electrical signals via action potentials and changes in electrochemical gradients. The processes involved in the transduction of photons into electrical potentials will be the focus of this article. This review article summarizes the recent advances in understanding these complex pathways and provides an overview of the main molecules involved in the neurobiology of vision. PMID- 25274586 TI - Dermatoglyphic features in patients with multiple sclerosis. AB - OBJECTIVE: To examine dermatoglyphic features to clarify implicated genetic predisposition in the etiology of multiple sclerosis (MS). METHODS: The study was conducted between January and December 2013 in the Departments of Anatomy, and Neurology, Cumhuriyet University School of Medicine, Sivas, Turkey. The dermatoglyphic data of 61 patients, and a control group consisting of 62 healthy adults obtained with a digital scanner were transferred to a computer environment. The ImageJ program was used, and atd, dat, adt angles, a-b ridge count, sample types of all fingers, and ridge counts were calculated. RESULTS: In both hands of the patients with MS, the a-b ridge count and ridge counts in all fingers increased, and the differences in these values were statistically significant. There was also a statistically significant increase in the dat angle in both hands of the MS patients. On the contrary, there was no statistically significant difference between the groups in terms of dermal ridge samples, and the most frequent sample in both groups was the ulnar loop. CONCLUSION: Aberrations in the distribution of dermatoglyphic samples support the genetic predisposition in MS etiology. Multiple sclerosis susceptible individuals may be determined by analyzing dermatoglyphic samples. PMID- 25274587 TI - Prevalence of factors associated with poor outcomes of hospitalized myasthenia gravis patients in Thailand. AB - OBJECTIVE: To examine the prevalence of hospitalized myasthenia gravis (MG), and to determine the factors associated with poor outcomes of hospitalized MG patients at a national level. METHODS: This study was based on a retrospective design. We collected data of hospitalized MG adults recorded by the National Health Security Office, Bangkok, Thailand between October 2009 and September 2010. Clinical data and treatment outcomes were examined. RESULTS: The total number of hospitalized MG patients was 936 cases. The prevalence rate of hospitalized MG patients was 2.17/100,000 population. The average age (SD) was 44.93 (14.16) years. Regarding the discharge status of MG patients, 845 cases (90.3%) had improved. The total hospital charge of MG patients was 64,332,806 baht (USD 2,144,426.87) or an average of 68,731.63 baht/admission (USD 2,291.05), with an average length of stay of 10.45 days. There were 3 significant factors associated with poor outcomes in hospitalized MG patients; namely, hospital category, pneumonia, and respiratory failure. CONCLUSION: The prevalence of admission in MG patients was 2.17 persons/100,000 population. Hospital category, pneumonia, and respiratory failure were significant factors associated with poor outcomes. PMID- 25274588 TI - Systemic review of the epidemiology of autism in Arab Gulf countries. AB - OBJECTIVE: To assess the current state of knowledge on the epidemiology of autism in Arab Gulf countries, and identify gaps for future research. METHODS: PubMed and ScienceDirect databases were used to identify relevant articles published until the 3rd of April 2013 (date of search). The search was conducted using the electronic library of King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Studies were eligible for inclusion if they concerned the epidemiology of autism, conducted in any Arab Gulf country, and published in English. RESULTS: Twelve articles met the inclusion criteria. Studies showed a prevalence ranging from 1.4 to 29 per 10,000 persons. Identified risk factors were metabolic, autoimmune, and environmental in nature. The following determinants were found as possible contributing factors for autism: suboptimal breast-feeding, advanced maternal and paternal age, cesarean section, and prenatal complications. CONCLUSION: Only a few studies explored the epidemiology of autism in Arab Gulf countries and none have investigated the burden of the disease on the child, family, or society. More research is needed to better identify the burden and risk factors of autism in Gulf countries. PMID- 25274589 TI - Predicting factors and prevalence of meningitis in patients with first seizure and fever aged 6 to 18 months. AB - OBJECTIVE: To evaluate predicting factors and prevalence of meningitis in patients with first seizure and fever aged 6-18 months old. METHODS: This cross sectional study was performed on 800 patients aged 6-18 months old who had first attack of seizure with fever between March 2005 and March 2012 in the pediatric ward of Ghaem Hospital, Mashhad, Iran. RESULTS: Among 800 patients, lumbar puncture (LP) was performed in 453 (56.6%) patients, of whom 80 cases had meningitis (17.6% of LP patients). Postictal drowsiness (p=0.003), neurologic deficit (p=0.000), and body temperature >/=38.5˚C (p=0.035) were among the clinical signs, which were statistically significant predicting factors for meningitis. Laboratory tests including white blood count (WBC) >/=15000 mm3 (p=0.004), and hemoglobin (Hb) <10.5 gr/dl (p=0.020) also had statistical significance in predicting meningitis. CONCLUSION: Postictal drowsiness, neurological deficit, body temperature >/=38.5˚C, WBC >/=15000 mm3, and Hb <10.5 gr/dl were clinical and laboratory factors predictive of meningitis in cases with first attack of seizure and fever. PMID- 25274591 TI - Surgical treatment of traumatic multiple intracranial hematomas. AB - OBJECTIVE: To summarize our experience with the surgical treatment of traumatic multiple intracranial hematomas (TMIHs) and discuss the surgical indications. METHODS: We analyzed the clinical data of 118 patients with TMIHs who were treated at the West China Hospital in Sichuan University, Chengdu, China between October 2008 and October 2011, including age, gender, cause of injury, diagnosis, treatment, and outcomes. RESULTS: Among the 118 patients, there were 12 patients with different types of hematomas at the same site, 69 with one hematoma type in different compartments, and 37 with different types of hematomas in different compartments. In total, 106 patients had obliteration of basal cisterns, and 34 had a simultaneous midline shift >/=5 mm. Eighty-nine patients underwent single site surgery, 19 had 2-site surgeries, and 10 patients did not undergo surgery. Based on the Glasgow Outcome Scale 6 months post-injury, 41 patients had favorable outcomes, and 77 had unfavorable outcomes. Basal cisterns obliteration was a strong indicator for surgical treatment. Single- or 2-site surgery was not related to outcome (p=0.234). CONCLUSION: Obliteration of the basal cisterns is a strong indication for surgical treatment of TMIHs. After evacuation of the major hematomas, the remaining hematomas can be treated conservatively. Most patients only require single-site surgical treatment. PMID- 25274590 TI - Association between human leukocyte antigen-DR and demylinating Guillain-Barre syndrome. AB - OBJECTIVE: To find an association between human leukocyte antigen (HLA) class II DRB1, DRB3, DRB4, and DRB5 alleles frequencies in a sample of Iraqi patients with Guillain-Barre syndrome (GBS) and compare with a healthy control group. METHODS: We performed a cross-sectional study consisting of 30 Iraqi Arab patients with GBS attending the Neurological Department in the Neuroscience Hospital, Baghdad, Iraq between September 2012 and June 2013. The control group comprised 42 apparently healthy volunteers. Human leukocyte antigen genotyping for HLA DRB1, DRB3, DRB4, and DRB5 was performed using the polymerase chain reaction-sequence specific primers method. The allele frequencies were compared across both groups. Major histocompatibility complex (MHC)-class II HLA-DR genotyping and serotyping were performed by software analysis. RESULTS: We found increased frequencies of HLA genotype DRB1*03:01 (p=0.0009), DRB1*07:01 (p=0.0015), and DRB4*01:01 (p<0.0001) in patients with GBS compared with healthy controls. The HLA DR6 was increased in the control group (p<0.0001). CONCLUSION: Our results suggest an association between HLA-DRB1*03:01, DRB1*07:01, DRB4*01:01, and HLA DR3, DR7 and a susceptibility to GBS. PMID- 25274593 TI - Ictal asystole in epilepsy patients undergoing inpatient video-EEG monitoring. AB - Ictal asystole (IA) is uncommonly diagnosed and has been implicated as a potential cause of sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy is an increasingly recognizable condition and is more likely to occur in patients with medically intractable epilepsy and those suffering from convulsive epilepsy. We report 2 cases of recent onset of prolonged syncope and unrevealing cardiac work up. The inpatient video-EEG monitoring recorded left temporal ictal discharges followed by IA. Although the role of cardiac pacing is controversial in these patients, both patients had favorable outcome following cardiac pacemaker insertion. This report demonstrates the variability in IA pathophysiology and clinical manifestations. It also advocates that cardiac pacing might have a role in the management of IA. PMID- 25274592 TI - Diagnosis and management of cerebral folate deficiency. A form of folinic acid responsive seizures. AB - Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests. PMID- 25274594 TI - Chronic bilateral hearing loss in an immunocompetent patient. An atypical course of tuberculous meningitis. AB - Congenital, infectious, toxic, and demyelinating disorders are common etiological causes of deafness. Tuberculous meningitis, as one of the infectious causes, should be considered in the differential diagnosis since tuberculosis represents an endemic public health problem in developing countries. Multiple cranial nerve palsies can be expected due to basal meningitis; however, presentation with bilateral hearing loss is quite rare. Early diagnosis and treatment are crucial to prevent mortality and residual neurologic deficits. The focus of this discussion is a 42-year-old female presenting with bilateral hearing loss and nonspecific complaints who was finally diagnosed with chronic tuberculous meningitis. We also demonstrate the characteristic radiological and histopathological findings. PMID- 25274595 TI - Spinal cord ischemia following cervical transforaminal epidural steroid injection. PMID- 25274596 TI - Recurrent episodic vertigo secondary to hyponatremic encephalopathy from water intoxication. PMID- 25274597 TI - Electroencephalography findings in patients with acute post coronary artery bypass graft encephalopathy. AB - OBJECTIVE: To determine the EEG findings associated with acute post coronary artery bypass graft encephalopathy (aPCE), and to study the demographics and neuroimaging findings. METHODS: We reviewed the EEG in all patients with the diagnosis of PCE between February 2006 and December 2011. RESULTS: We identified 21 (20 males, and one female) patients with aPCE. The mean age (+/-SD) was 64 (+/ 11.2) years. Thirteen patients had altered level of consciousness, and 8 presented with confusion out of which 3 had acute seizures. The EEG patterns observed were: a) generalized theta plus intermixed diffuse delta in 7 (33%); b) generalized theta with focal epileptiform discharges in 5 (24%); c) generalized triphasic pattern in 3 (14%); d) generalized theta with lateralized delta in 3 (14%); e) generalized theta with periodic lateralized epileptiform discharges (PLEDs), and bilateral synchronous periodic epileptiform discharges (BIPLEDs) in 2 (10%); and f) one patient (5%) with electrographic seizures. On EEG/neuroimaging correlation, the EEGs that showed generalized slowing and generalized triphasic patterns had no acute changes on imaging, while the EEGs that showed lateralized slowing, focal epileptiform discharges, electrographic seizures and PLEDs had fresh infarcts. Patients with BIPLEDs had unremarkable imaging. CONCLUSION: The EEG features such as lateralized slowing, PLEDs, and electrographic seizure were associated with acute cerebral insults. An altered level of consciousness was the most common symptomatology in our cohort, and could possibly be related to hypoxic/toxic-metabolic etiology. Electrographic seizure detected by EEG may clinically present as aPCE. PMID- 25274598 TI - Level of evidence of clinical neurosurgery research in Saudi Arabia. PMID- 25274599 TI - Acute paraplegia caused by Schistosoma mansoni. PMID- 25274600 TI - Cerebral sinus venous thrombosis in a child with nephrotic syndrome. PMID- 25274601 TI - Five-year relative survival rate of larynx cancer in the USA, Europe and Japan. PMID- 25274602 TI - Characterization of ritonavir-mediated inactivation of cytochrome P450 3A4. AB - Ritonavir is a human immunodeficiency virus (HIV) protease inhibitor and an inhibitor of cytochrome P450 3A4, the major human hepatic drug-metabolizing enzyme. Given the potent inhibition of CYP3A4 by ritonavir, subtherapeutic doses of ritonavir are used to increase plasma concentrations of other HIV drugs oxidized by CYP3A4, thereby extending their clinical efficacy. However, the mechanism of inhibition of CYP3A4 by ritonavir remains unclear. To date, data suggests multiple types of inhibition by ritonavir, including mechanism-based inactivation by metabolic-intermediate complex formation, competitive inhibition, irreversible type II coordination to the heme iron, and more recently heme destruction. The results presented here demonstrate that inhibition of CYP3A4 by ritonavir occurs by CYP3A4-mediated activation and subsequent formation of a covalent bond to the apoprotein. Incubations of [(3)H]ritonavir with reconstituted CYP3A4 and human liver microsomes resulted in a covalent binding stoichiometry equal to 0.93 +/- 0.04 moles of ritonavir bound per mole of inactivated CYP3A4. The metabolism of [(3)H]ritonavir by CYP3A4 leads to the formation of a covalent adduct specifically to CYP3A4, confirmed by radiometric liquid chromatography-trace and whole-protein mass spectrometry. Tryptic digestion of the CYP3A4-[(3)H]ritonavir incubations exhibited an adducted peptide (255-RM K: ESRLEDTQKHR-268) associated with a radiochromatic peak and a mass consistent with ritonavir plus 16 Da, in agreement with the whole-protein mass spectrometry. Additionally, nucleophilic trapping agents and scavengers of free oxygen species did not prevent inactivation of CYP3A4 by ritonavir. In conclusion, ritonavir exhibited potent time-dependent inactivation of CYP3A, with the mechanism of inactivation occurring though a covalent bond to Lys257 of the CYP3A4 apoprotein. PMID- 25274604 TI - Introduction to the proposals from the global bioanalysis consortium harmonization team. PMID- 25274603 TI - Multiple modes of ryanodine receptor 2 inhibition by flecainide. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) causes sudden cardiac death due to mutations in cardiac ryanodine receptors (RyR2), calsequestrin, or calmodulin. Flecainide, a class I antiarrhythmic drug, inhibits Na(+) and RyR2 channels and prevents CPVT. The purpose of this study is to identify inhibitory mechanisms of flecainide on RyR2. RyR2 were isolated from sheep heart, incorporated into lipid bilayers, and investigated by single-channel recording under various activating conditions, including the presence of cytoplasmic ATP (2 mM) and a range of cytoplasmic [Ca(2+)], [Mg(2+)], pH, and [caffeine]. Flecainide applied to either the cytoplasmic or luminal sides of the membrane inhibited RyR2 by two distinct modes: 1) a fast block consisting of brief substate and closed events with a mean duration of ~1 ms, and 2) a slow block consisting of closed events with a mean duration of ~1 second. Both inhibition modes were alleviated by increasing cytoplasmic pH from 7.4 to 9.5 but were unaffected by luminal pH. The slow block was potentiated in RyR2 channels that had relatively low open probability, whereas the fast block was unaffected by RyR2 activation. These results show that these two modes are independent mechanisms for RyR2 inhibition, both having a cytoplasmic site of action. The slow mode is a closed-channel block, whereas the fast mode blocks RyR2 in the open state. At diastolic cytoplasmic [Ca(2+)] (100 nM), flecainide possesses an additional inhibitory mechanism that reduces RyR2 burst duration. Hence, multiple modes of action underlie RyR2 inhibition by flecainide. PMID- 25274605 TI - Reliability and extension of quantitative prediction of CYP3A4-mediated drug interactions based on clinical data. AB - An approach was proposed in 2007 for quantitative predictions of cytochrome P450 (CYP)3A4-mediated drug-drug interactions. It is based on two characteristic parameters: the contribution ratio (CR; i.e., the fraction of victim drug clearance by CYP) and the inhibition ratio (IR) of the inhibitor. Knowledge of these parameters allows forecasting of the ratio between the area under the plasma concentration-time curve (AUC) of the victim drug when given with the inhibitor and the AUC of the victim drug when it is given alone. So far, these parameters were established for 21 substrates and 17 inhibitors. The goals of our study were to test the assumption of substrate independence of the potency of inhibitors in vivo and to estimate the CR and IR for an extended list of substrates and inhibitors of CYP3A4. The assumption of independence of IRs from the substrate was evaluated on a set of eight victim drugs and eight inhibitors. Forty-four AUC ratios were available. This assumption was rejected in four cases, but it did not result in more than a twofold error in AUC ratio predictions. The extended list of substrates and inhibitors was defined by a thorough literature search. Fifty-nine AUC ratios were available for the global analysis. Final estimates of CRs and IRs were obtained for 37 substrates and 25 inhibitors, respectively. The mean prediction error of the ratios was 0.02, while the mean absolute prediction error was 0.58. Predictive distributions for 917 possible interactions were obtained, giving detailed information on some drugs or inhibitors that have been poorly studied so far. PMID- 25274606 TI - Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi mechanistic pharmacokinetic modeling. AB - Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 +/- 3.4 nmol/min/mg, 204 +/- 22 MUM, and 233 +/- 9 MUl/min/mg with intestinal microsomes and 2.92 +/- 0.07 nmol/min/mg, 22.7 +/- 1.2 MUM, and 129 +/ 4 MUl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses. PMID- 25274607 TI - Blocking of JB6 cell transformation by tanshinone IIA: epigenetic reactivation of Nrf2 antioxidative stress pathway. AB - Increasing numbers of natural products have been found to possess anticancer effects. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a master regulator of the antioxidative stress response, and our previous studies found that epigenetic modification of the Nrf2 gene appears to be a critical mechanism. Salvia miltiorrhiza, a Chinese herbal medicine widely used in Asian countries, has been shown to possess anticancer and antioxidant effects. Tanshinone IIA (TIIA), an active component in S. miltiorrhiza, has been reported to activate Nrf2 pathway. The objective of this study was to investigate the epigenetic regulation of Nrf2 by TIIA in mouse skin epidermal JB6 cells and the functional consequences for cell transformation. TIIA was found to induce antioxidant response element-luciferase and upregulate the mRNA and protein levels of Nrf2 and Nrf2 downstream target genes HO-1 and NQO-1. TIIA decreased the colony formation of JB6 cells by approximately 80%. TIIA decreased the protein levels of DNMT1, DNMT3a, DNMT3b, and HDAC3 and inhibited the enzymatic activity of HDACs. Bisulfite genomic sequencing indicated that TIIA demethylated the first five CpGs in the promoter region of the Nrf2 gene. Chromatin immunoprecipitation assays showed that TIIA treatment increased the recruitment of RNA polymerase II at Nrf2 transcription start site but had limited effects on enrichment of Ac-H3 in Nrf2 promoter. Taken together, our results show that TIIA activates the Nrf2 signaling pathway and induces epigenetic demethylation of the CpGs of Nrf2. The epigenetic reactivation of the Nrf2 signaling pathway by TIIA could potentially contribute to the attenuation of JB6 cellular transformation and anticancer effects. PMID- 25274608 TI - Prediction of drug clearance in children: an evaluation of the predictive performance of several models. AB - The objective of this study is to evaluate the predictive performance of several models to predict drug clearance in children <=5 years of age. Six models (allometric model (data-dependent exponent), fixed exponent of 0.75 model, maturation model, body weight-dependent model, segmented allometric model, and age-dependent exponent model) were evaluated in this study. From the literature, the clearance values for six drugs from neonates to adults were obtained. External data were used to evaluate the predictive performance of these models in children <=5 years of age. With the exception of a fixed exponent of 0.75, the mean predicted clearance in most of the age groups was within <=50% prediction error. Individual clearance prediction was erratic by all models and cannot be used reliably to predict individual clearance. Maturation, body weight-dependent, and segmented allometric models to predict clearances of drugs in children <=5 years of age are of limited practical value during drug development due to the lack of availability of data. Age-dependent exponent model can be used for the selection of first-in-children dose during drug development. PMID- 25274609 TI - Toward the establishment of standardized in vitro tests for lipid-based formulations, part 6: effects of varying pancreatin and calcium levels. AB - The impact of pancreatin and calcium addition on a wide array of lipid-based formulations (LBFs) during in vitro lipolysis, with regard to digestion rates and distribution of the model drug danazol, was investigated. Pancreatin primarily affected the extent of digestion, leaving drug distribution somewhat unaffected. Calcium only affected the extent of digestion slightly but had a major influence on drug distribution, with more drug precipitating at higher calcium levels. This is likely to be caused by a combination of removal of lipolysis products from solution by the formation of calcium soaps and calcium precipitating with bile acids, events known to reduce the solubilizing capacity of LBFs dispersed in biorelevant media. Further, during the digestion of hydrophilic LBFs, like IIIA LC, the un-ionized-ionized ratio of free fatty acids (FFA) remained unchanged at physiological calcium levels. This makes the titration curves at pH 6.5 representable for digestion. However, caution should be taken when interpreting lipolysis curves of lipophilic LBFs, like I-LC, at pH 6.5, at physiological levels of calcium (1.4 mM); un-ionized-ionized ratio of FFA might change during digestion, rendering the lipolysis curve at pH 6.5 non-representable for the total digestion. The ratio of un-ionized-ionized FFAs can be maintained during digestion by applying non-physiological levels of calcium, resulting in a modified drug distribution with increased drug precipitation. However, as the main objective of the in vitro digestion model is to evaluate drug distribution, which is believed to have an impact on bioavailability in vivo, a physiological level (1.4 mM) of calcium is preferred. PMID- 25274612 TI - How to tackle the NHS funding crisis? Levy charges. PMID- 25274610 TI - The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria. AB - Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-infinity by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-infinity by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions. PMID- 25274611 TI - T cell immune abnormalities in immune thrombocytopenia. AB - Immune thrombocytopenia is an autoimmune disease with abnormal T cell immunity. Cytotoxic T cells, abnormal T regulatory cells, helper T cell imbalance, megakaryocyte maturation abnormalities and abnormal T cell anergy are involved in the pathogenesis of this condition. The loss of T cell-mediated immune tolerance to platelet auto-antigens plays a crucial role in immune thrombocytopenia. The induction of T cell tolerance is an important mechanism by which the pathogenesis and treatment of immune thrombocytopenia can be studied. Studies regarding the roles of the new inducible costimulator signal transduction pathway, the ubiquitin proteasome pathway, and the nuclear factor kappa B signal transduction pathway in the induction of T cell tolerance can help improve our understanding of immune theory and may provide a new theoretical basis for studying the pathogenesis and treatment of immune thrombocytopenia. PMID- 25274613 TI - Quantitative imaging mass spectrometry of renal sulfatides: validation by classical mass spectrometric methods. AB - Owing to its capability of discriminating subtle mass-altering structural differences such as double bonds or elongated acyl chains, MALDI-based imaging MS (IMS) has emerged as a powerful technique for analysis of lipid distribution in tissue at moderate spatial resolution of about 50 MUm. However, it is still unknown if MS(1)-signals and ion intensity images correlate with the corresponding apparent lipid concentrations. Analyzing renal sulfated glycosphingolipids, sulfatides, we validate for the first time IMS-signal identities using corresponding sulfatide-deficient kidneys. To evaluate the extent of signal quenching effects interfering with lipid quantification, we surgically dissected the three major renal regions (papillae, medulla, and cortex) and systematically compared MALDI IMS of renal sulfatides with quantitative analyses of corresponding lipid extracts by on-target MALDI TOF-MS and by ultra-performance LC-ESI-(triple-quadrupole)tandem MS. Our results demonstrate a generally strong correlation (R(2) > 0.9) between the local relative sulfatide signal intensity in MALDI IMS and absolute sulfatide quantities determined by the other two methods. However, high concentrations of sulfatides in the papillae and medulla result in an up to 4-fold signal suppression. In conclusion, our study suggests that MALDI IMS is useful for semi quantitative dissection of relative local changes of sulfatides and possibly other lipids in tissue. PMID- 25274614 TI - A diachronic-comparative analysis for the identification of the most powerful prognostic index for localized diffuse large B-cell lymphoma. AB - BACKGROUND: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria. RESULTS: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases. CONCLUSIONS: The NCCN IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab. PMID- 25274615 TI - REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours. AB - BACKGROUND: Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data. PATIENTS AND METHODS: In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT. RESULTS: Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1 2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression. CONCLUSION: Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. ClinicalTrials.gov Identifier: NCT01332929. PMID- 25274617 TI - US website details $3.5bn in industry payments to doctors. PMID- 25274616 TI - Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. AB - While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers. PMID- 25274618 TI - Pulmonary adenocarcinomas appearing as part-solid ground-glass nodules: is measuring solid component size a better prognostic indicator? AB - OBJECTIVE: To assess whether measuring the solid portion of adenocarcinomas appearing as part-solid ground-glass nodules (GGNs) can predict a patient's prognosis accurately and how the prognosis corresponds to that of solid nodules. METHODS: 501 patients (solid nodule group, 304; part-solid GGN group, 197) underwent curative surgery for stage I adenocarcinomas. Maximal diameters of the whole lesion including ground-glass opacities (D whole ) and solid components only (D solid ) were measured on CT. Disease-free survival (DFS) and overall survival (OS) were calculated from the date of surgery. RESULTS: D solid was a significant prognostic factor in the part-solid GGN group, while D whole was not. Part-solid GGNs with D solid <=2 cm showed significantly better DFS (P = 0.016) and OS (P = 0.004) than solid nodules; however, those with D solid >2 cm did not show a significant difference. Hazard ratio (HR) for increase in D solid was significantly greater in part-solid GGNs than in solid nodules (P = 0.009). For OS, HR for increase in D solid was greater in part-solid GGNs than in solid nodule, which was marginally not significant (P = 0.060). CONCLUSION: D solid was better than D whole for prognosis prediction of adenocarcinomas appearing as part solid GGNs. In addition, the influence of D solid on prognosis in the part-solid GGN group was greater than in the solid nodule group. KEY POINTS: * Dsolid is a better prognosis indicator than Dsolid in part-solid GGN adenocarcinomas * Part solid GGN adenocarcinoma show better prognosis than solid adenocarcinomas when Dsolid <=2 cm * Dsolid has greater prognostic influence in part-solid GGN adenocarcinomas than solid adenocarcinomas. PMID- 25274619 TI - Imaging of bridging vein thrombosis in infants with abusive head trauma: the "Tadpole Sign". AB - OBJECTIVES: Abusive head trauma (AHT) in infants is usually diagnosed using a multi-disciplinary approach by investigating the circumstances and identifying morphological indicators, for example, subdural hematomas (SDHs), subdural hygromas (SDHys), retinal haemorrhages and encephalopathy. The present morphological study investigates the incidence, radiological characteristics and non-radiological co-factors of bridging vein thrombosis (BVT) in infants with AHT. METHODS: From 2002 to 2013, computed tomography (CT) and magnetic resonance imaging (MRI) material of 628 infants aged 0-2 years were analysed retrospectively. If available, medicolegal expert opinions were additionally considered. Cases with SDHs and/or SDHys were identified and systematically evaluated as to the presence and characteristics of BVT. RESULTS: SDHs and/or SDHys were present in 29 of the 81 cases exhibiting morphological abnormalities in the initial CT. Among these, 11 cases (40%) had BVT (mean age = 5.0 months). BVT could be best depicted in the T1-weighted spin echo and T2*/susceptibility weighted MRI. In one case, BVT could be depicted indirectly using time-of-flight MR venography. The predominant (73%) BVT shape was found to be tadpole-like ("Tadpole Sign"). CONCLUSIONS: In the absence of appropriate accidental trauma, BVT appears to be a strong indicator of AHT. Therefore, the BVT/Tadpole Sign represents compelling cause to search for other signs of AHT. KEY POINTS: * BVT is an excellent indicator of AHT in SDH/SDHy cases. * Accidental trauma must be ruled out before diagnosing AHT. * The Tadpole Sign appears to be the most characteristic shape of BVT. * BVT can be depicted using CT, MRI and MR venography. * The Tadpole Sign suggests searching for other signs of AHT. PMID- 25274620 TI - Perioperative management of oral antiplatelet therapy and clinical outcomes in coronary stent patients undergoing surgery. Results of a multicentre registry. AB - The aim was to investigate the perioperative risk of ischaemic and bleeding events in patients with coronary stents undergoing cardiac and non-cardiac surgery and how these outcomes are affected by the perioperative use of oral antiplatelet therapy. This was a multicentre, retrospective, observational study conducted in patients with coronary stent(s) undergoing cardiac or non-cardiac surgery. The primary efficacy endpoint was the 30-day incidence of major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction (MI) or stroke. The primary safety endpoint was the 30-day incidence of Bleeding Academic Research Consortium (BARC) bleeding >= 2. A total of 666 patients were included. Of these, 371 (55.7 %) discontinued their antiplatelet medication(s) (all or partly) before undergoing surgery. At 30 days, patients with perioperative discontinuation of antiplatelet therapy experienced a significantly higher incidence of MACE (7.5 % vs 0.3 %, p< 0.001), cardiac death (2.7 % vs 0.3 %, p=0.027), and MI (4.0 % vs 0 %, p< 0.001). After adjustment, peri-operative antiplatelet discontinuation was the strongest independent predictor of 30-day MACE (odds ratio [OR]=25.8, confidence interval [CI]=3.37 198, p=0.002). Perioperative aspirin (adjusted OR 0.27, 95 % CI 0.11-0.71, p=0.008) was significantly associated with a lower risk of MACE. The overall incidence of BARC >= 2 bleeding events at 30-days was significantly higher in patients who discontinued oral antiplatelet therapy (25.6 % vs 13.9 %, p< 0.001). However, after adjustment, antiplatelet discontinuation was not independently associated with BARC >= 2 bleeding. In conclusion antiplatelet discontinuation increases the 30-day risk of MACE, in patients with coronary stents undergoing cardiac and non-cardiac surgery, while not offering significant protection from BARC>= 2 bleeding. PMID- 25274621 TI - Vaccination of adult animals with a reduced dose of Brucella abortus S19 vaccine to control brucellosis on dairy farms in endemic areas of India. AB - Bovine brucellosis is an economically important disease which seriously affects dairy farming by causing colossal losses. It can be controlled by practicing vaccination of animals with Brucella abortus S19 vaccine (S19 vaccine). In the present study, adult bovines were vaccinated on seven dairy farms with a reduced dose of S19 vaccine to control brucellosis. Serological screening of adult animals (N = 1,082) by Rose Bengal test (RBT) and ELISA prior to vaccination revealed the presence and absence of brucellosis on five and two farms, respectively. The positive animals (N = 171) were segregated and those which tested negative (N = 911) were vaccinated by conjunctival route with a booster after 4 months. The conjunctival vaccination induced weak antibody response in animals, which vanished within a period of 9 to 12 weeks. Abortion in 12 animals at various stages of pregnancy and post-vaccination was recorded, but none was attributed to S19 vaccine. However, virulent B. abortus was incriminated in six heifers, and the cause of abortion could not be established in six animals. The six aborted heifers perhaps acquired infection through in utero transmission or from the environment which remained undetected until abortion. These findings suggested that vaccination of adult animals with a reduced dose of S19 vaccine by conjunctival route did not produce adverse effects like abortion in pregnant animals and persistent vaccinal antibody titers, which are the major disadvantages of subcutaneous vaccination of adult animals. PMID- 25274622 TI - Risk factors to incidental leptospirosis and its role on the reproduction of ewes and goats of Espirito Santo state, Brazil. AB - Ovine and caprine stockbreeding have been gaining attention in developing countries as an attractive investment. On these animals, infectious diseases of the reproductive tract, such as leptospirosis, can compromise the production leading to economic losses. The present study aimed to determine the risk factors associated with incidental leptospirosis and its influence on the reproductive parameters of ewes and goats of Espirito Santo state, Brazil. A total of 737 animals distributed on 24 herds/flocks were studied, and an overall prevalence of 10.9% seroreactive animals was observed. Serogroup Icterohaemorrhagiae was the most frequent in goats (97.0%) as well as in ewes (78.3%). Regarding risk factors related to leptospirosis, the presence of waterholes and the semi-intensive breeding system were the most important associated to seroreactivity. Besides, there was an observed association between seroreactivity and reproductive failures (P < 0.05). Moreover, seroreactive ewes (relative risk (RR) = 1.3) and goats (RR = 1.9) presented more chances to have abortions than seronegative animals. Furthermore, seroreactive ewes presented 11.6 more chances of having premature births when compared to the seronegative ones. It can be concluded that Leptospira infection, mainly those caused incidental strains (such as Icterohaemorrhagiae serogroup), is a significant factor to reduce the productivity of small ruminants' herds/flocks in the studied region, and environmental measures must be considered on control programs. PMID- 25274623 TI - Climate change. PMID- 25274624 TI - Multiple meanings of "gift" and its value for organ donation. AB - The "gift of life" metaphor is used to promote organ donation where commercialization is prohibited. In this article, we explore how multiple parties involved in organ transfer procedures think of gift terminology by drawing on interview data with transplantation specialists, organ transplant recipients, living directed donors and living nondirected donors. The interviews took place across New Zealand between October 2008 and May 2012, in participants' homes and hospital workplaces. The interviews were transcribed verbatim, coded manually, and thematically analyzed. Although gift language is often viewed as clear-cut, the gift trope has multiple meanings for different constituent and cultural groups, ranging from positive descriptors to obscuring and romanticizing the complexities of transplantation processes. To account for these multiple perspectives, we suggest new ethical models to capture the nuanced phenomenon of organ transfer in ways that recognize the full range of donation and reception experiences. PMID- 25274625 TI - How fatigue influences exercise participation in men with multiple sclerosis. AB - Researchers have suggested that men with multiple sclerosis (MS) experience lower self-efficacy than women with MS and have linked women's self-efficacy with a sense of perceived control over symptoms and activities. Self-efficacy-the belief in one's own ability to achieve an outcome-has also been linked to engagement in healthy behaviors such as exercise. We sampled men with MS to better understand how MS-related fatigue influences exercise participation. Guided by the interpretive description method, we interviewed 18 men about their fatigue and exercise experiences. One overarching theme and three subthemes were developed through multiple readings, author comparisons, and participant reflections. The men described a process of goal readjustment with regard to exercise that helped them stay engaged in meaningful physical activity despite fatigue. Health care professionals might consider introducing goal readjustment strategies to help men with MS-related fatigue retain perceived control over exercise engagement and achieve greater self-efficacy. PMID- 25274626 TI - Health care employee perceptions of patient-centered care. AB - Given the importance of health care employees in the delivery of patient-centered care, understanding their unique perspectives is essential for quality improvement. The purpose of this study was to use photovoice to evaluate perceptions and experiences around patient-centered care among U.S. Veterans Affairs (VA) health care employees. We asked participants to take photographs of salient features in their environment related to patient-centered care. We used the photographs to facilitate dialogue during follow-up interviews. Twelve VA health care employees across two VA sites participated in the project. Although most participants felt satisfied with their work environment and experiences at the VA, they identified several areas for improvement. These included a need for more employee health and wellness initiatives and a need for enhanced opportunities for training and professional growth. Application of photovoice enabled us to learn about employees' unique perspectives around patient-centered care while engaging them in an evaluation of care delivery. PMID- 25274627 TI - Post-translational glycoprotein modifications regulate colon cancer stem cells and colon adenoma progression in Apc(min/+) mice through altered Wnt receptor signaling. AB - Deletion of GnT-V (MGAT5), which synthesizes N-glycans with beta(1,6)-branched glycans, reduced the compartment of cancer stem cells (CSC) in the her-2 mouse model of breast cancer, leading to delay of tumor onset. Because GnT-V levels are also commonly up-regulated in colon cancer, we investigated their regulation of colon CSC and adenoma development. Anchorage-independent cell growth and tumor formation induced by injection of colon tumor cells into NOD/SCID mice were positively associated with GnT-V levels, indicating regulation of proliferation and tumorigenicity. Using Apc(min/+) mice with different GnT-V backgrounds, knock out of GnT-V had no significant effect on the number of adenoma/mouse, but adenoma size was significantly reduced and accompanied increased survival of Apc(min/+) mice with GnT-V deletion (p < 0.01), suggesting an inhibition in the progression of colon adenoma caused by deletion of GnT-V. Decreased expression levels of GnT-V down-regulated the population of colon (intestine) CSC, affecting their ability for self-renewal and tumorigenicity in NOD/SCID mice. Furthermore, altered nuclear translocation of beta-catenin and expression of Wnt target genes were positively associated with expression levels of GnT-V, indicating the regulation of canonical Wnt/beta-catenin signaling. By overexpressing the Wnt receptor, FZD-7, in colon cancer cells, we found that FZD-7 receptors expressed N linked beta(1,6) branching, indicating that FZD-7 can be modified by GnT-V. The aberrant Wnt signaling observed after modulating GnT-V levels is likely to result from altered N-linked beta(1,6) branching on FZD-7, thereby affecting Wnt signaling, the compartment of CSC, and tumor progression. PMID- 25274629 TI - Biochemical and biophysical characterization of the selenium-binding and reducing site in Arabidopsis thaliana homologue to mammals selenium-binding protein 1. AB - The function of selenium-binding protein 1 (SBP1), present in almost all organisms, has not yet been established. In mammals, SBP1 is known to bind the essential element selenium but the binding site has not been identified. In addition, the SBP family has numerous potential metal-binding sites that may play a role in detoxification pathways in plants. In Arabidopsis thaliana, AtSBP1 over expression increases tolerance to two toxic compounds for plants, selenium and cadmium, often found as soil pollutants. For a better understanding of AtSBP1 function in detoxification mechanisms, we investigated the chelating properties of the protein toward different ligands with a focus on selenium using biochemical and biophysical techniques. Thermal shift assays together with inductively coupled plasma mass spectrometry revealed that AtSBP1 binds selenium after incubation with selenite (SeO3(2-)) with a ligand to protein molar ratio of 1:1. Isothermal titration calorimetry confirmed the 1:1 stoichiometry and revealed an unexpectedly large value of binding enthalpy suggesting a covalent bond between selenium and AtSBP1. Titration of reduced Cys residues and comparative mass spectrometry on AtSBP1 and the purified selenium-AtSBP1 complex identified Cys(21) and Cys(22) as being responsible for the binding of one selenium. These results were validated by site-directed mutagenesis. Selenium K edge x-ray absorption near edge spectroscopy performed on the selenium-AtSBP1 complex demonstrated that AtSBP1 reduced SeO3(2-) to form a R-S-Se(II)-S-R-type complex. The capacity of AtSBP1 to bind different metals and selenium is discussed with respect to the potential function of AtSBP1 in detoxification mechanisms and selenium metabolism. PMID- 25274628 TI - An atypical canonical bone morphogenetic protein (BMP) signaling pathway regulates Msh homeobox 1 (Msx1) expression during odontogenesis. AB - Bone morphogenetic protein (BMP) signaling plays an essential role in early tooth development, evidenced by disruption of BMP signaling leading to an early arrested tooth development. Despite being a central mediator of BMP canonical signaling pathway, inactivation of Smad4 in dental mesenchyme does not result in early developmental defects. In the current study, we investigated the mechanism of receptor-activated Smads (R-Smads) and Smad4 in the regulation of the odontogenic gene Msx1 expression in the dental mesenchyme. We showed that the canonical BMP signaling is not operating in the early developing tooth, as assessed by failed activation of the BRE-Gal transgenic allele and the absence of phospho-(p)Smad1/5/8-Smad4 complexes. The absence of pSmad1/5/8-Smad4 complex appeared to be the consequence of saturation of Smad4 by pSmad2/3 in the dental mesenchyme as knockdown of Smad2/3 or overexpression of Smad4 led to the formation of pSmad1/5/8-Smad4 complexes and activation of canonical BMP signaling in dental mesenchymal cells. We showed that Smad1/5 but not Smad4 are required for BMP-induced expression of Msx1 in dental mesenchymal cells. We further presented evidence that in the absence of Smad4, BMPs are still able to induce pSmad1/5/8 nuclear translocation and their binding to the Msx1 promoter directly in dental mesenchymal cells. Our results demonstrate the functional operation of an atypical canonical BMP signaling (Smad4-independent and Smad1/5/8-dependent) pathway in the dental mesenchyme during early odontogenesis, which may have general implication in the development of other organs. PMID- 25274630 TI - Yeast importin-alpha (Srp1) performs distinct roles in the import of nuclear proteins and in targeting proteasomes to the nucleus. AB - Srp1 (importin-alpha) can translocate proteins that contain a nuclear localization signal (NLS) into the nucleus. The loss of Srp1 is lethal, although several temperature-sensitive mutants have been described. Among these mutants, srp1-31 displays the characteristic nuclear import defect of importin-alpha mutants, whereas srp1-49 shows a defect in protein degradation. We characterized these and additional srp1 mutants to determine whether distinct mechanisms were required for intracellular proteolysis and the import of NLS-containing proteins. We determined that srp1 mutants that failed to import NLS-containing proteins (srp1-31 and srp1-55) successfully localized proteasomes to the nucleus. In contrast, srp1 mutants that did not target proteasomes to the nucleus (srp1-49 and srp1-E402Q) were able to import NLS-containing proteins. The proteasome targeting defect of specific srp1 mutants caused stabilization of nuclear substrates and overall accumulation of multiubiquitylated proteins. Co-expression of a member of each class of srp1 mutants corrected both the proteasome localization defect and the import of NLS-containing proteins. These findings indicate that the targeting of proteasomes to the nucleus occurs by a mechanism distinct from the Srp1-mediated import of nuclear proteins. PMID- 25274634 TI - Explorations on people centredness in health systems. PMID- 25274632 TI - Catabolism of (2E)-4-hydroxy-2-nonenal via omega- and omega-1-oxidation stimulated by ketogenic diet. AB - Oxidative stress triggers the peroxidation of omega-6-polyunsaturated fatty acids to reactive lipid fragments, including (2E)-4-hydroxy-2-nonenal (HNE). We previously reported two parallel catabolic pathways of HNE. In this study, we report a novel metabolite that accumulates in rat liver perfused with HNE or 4 hydroxynonanoic acid (HNA), identified as 3-(5-oxotetrahydro-2-furanyl)propanoyl CoA. In experiments using a combination of isotopic analysis and metabolomics studies, three catabolic pathways of HNE were delineated following HNE conversion to HNA. (i) HNA is omega-hydroxylated to 4,9-dihydroxynonanoic acid, which is subsequently oxidized to 4-hydroxynonanedioic acid. This is followed by the degradation of 4-hydroxynonanedioic acid via beta-oxidation originating from C-9 of HNA breaking down to 4-hydroxynonanedioyl-CoA, 4-hydroxyheptanedioyl-CoA, or its lactone, 2-hydroxyglutaryl-CoA, and 2-ketoglutaric acid entering the citric acid cycle. (ii) omega-1-hydroxylation of HNA leads to 4,8-dihydroxynonanoic acid (4,8-DHNA), which is subsequently catabolized via two parallel pathways we previously reported. In catabolic pathway A, 4,8-DHNA is catabolized to 4-phospho 8-hydroxynonanoyl-CoA, 3,8-dihydroxynonanoyl-CoA, 6-hydroxyheptanoyl-CoA, 4 hydroxypentanoyl-CoA, propionyl-CoA, and acetyl-CoA. (iii) The catabolic pathway B of 4,8-DHNA leads to 2,6-dihydroxyheptanoyl-CoA, 5-hydroxyhexanoyl-CoA, 3 hydroxybutyryl-CoA, and acetyl-CoA. Both in vivo and in vitro experiments showed that HNE can be catabolically disposed via omega- and omega-1-oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed that omega- and omega-1-hydroxylation of HNA in rat liver were dramatically up-regulated by a ketogenic diet, which lowered HNE basal level. HET0016 inhibition and mRNA expression level suggested that the cytochrome P450 4A are main enzymes responsible for the NADPH-dependent omega- and omega-1 hydroxylation of HNA/HNE. PMID- 25274631 TI - How periplasmic thioredoxin TlpA reduces bacterial copper chaperone ScoI and cytochrome oxidase subunit II (CoxB) prior to metallation. AB - Two critical cysteine residues in the copper-A site (Cu(A)) on subunit II (CoxB) of bacterial cytochrome c oxidase lie on the periplasmic side of the cytoplasmic membrane. As the periplasm is an oxidizing environment as compared with the reducing cytoplasm, the prediction was that a disulfide bond formed between these cysteines must be eliminated by reduction prior to copper insertion. We show here that a periplasmic thioredoxin (TlpA) acts as a specific reductant not only for the Cu(2+) transfer chaperone ScoI but also for CoxB. The dual role of TlpA was documented best with high-resolution crystal structures of the kinetically trapped TlpA-ScoI and TlpA-CoxB mixed disulfide intermediates. They uncovered surprisingly disparate contact sites on TlpA for each of the two protein substrates. The equilibrium of CoxB reduction by TlpA revealed a thermodynamically favorable reaction, with a less negative redox potential of CoxB (E'0 = -231 mV) as compared with that of TlpA (E'0 = -256 mV). The reduction of CoxB by TlpA via disulfide exchange proved to be very fast, with a rate constant of 8.4 * 10(4) M(-1) s(-1) that is similar to that found previously for ScoI reduction. Hence, TlpA is a physiologically relevant reductase for both ScoI and CoxB. Although the requirement of ScoI for assembly of the Cu(A)-CoxB complex may be bypassed in vivo by high environmental Cu(2+) concentrations, TlpA is essential in this process because only reduced CoxB can bind copper ions. PMID- 25274633 TI - Choline kinase inhibition in rheumatoid arthritis. AB - OBJECTIVES: Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKalpha), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage. METHODS: Choline metabolic profile of FLS cells was determined by (1)H magnetic resonance spectroscopy ((1)HMRS) under conditions of ChoKalpha inhibition. FLS function was evaluated using the ChoKalpha inhibitor MN58b (IC50=4.2 MUM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration. RESULTS: The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKalpha expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKalpha inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKalpha inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. CONCLUSIONS: These data suggest that ChoKalpha inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions. PMID- 25274635 TI - The effects of a people-centred model on longitudinality of care and utilization pattern of healthcare services--Brazilian evidence. AB - Brazil is experiencing a time of change in pattern of care: from 'traditional' to Family Health Strategy (FHS), a model guided by the principles of people, family and community-centred medicine. The heterogeneity in care currently offered affects the primary care impact. This study aims to evaluate the longitudinality of care and correlate this primary care principle to the utilization pattern of care among patients hospitalized due to preventable conditions, comparing the two care models currently offered in Brazil. It is a cross-sectional, analytical and descriptive study with a quantitative approach. The sample consisted of 501 patients from 0 to 14 years old. Data was collected in 2011 and the Primary Care Assessment Tool (PCATool-Brazil) child version was used. Bivariate and multivariate analyses were performed including patient-related variables (age, maternal education, income and type of diagnosis) and care model. From the hospitalizations occurred during the period, 65.2% were Ambulatory Care Sensitive Conditions. Patients evaluated 'longitudinality' as regular. Both the care continuity dimension and the utilization pattern of care services showed a link with the care model offered. Findings suggest that the FHS care model, based on the assumptions of people-centred medicine, was associated with better ratings of care continuity, which was reflected in a more appropriate utilization pattern of care services. PMID- 25274637 TI - 'Your health our concern, our health whose concern?': perceptions of injustice in organizational relationships and processes and frontline health worker motivation in Ghana. AB - Taking a perspective of frontline health workers as internal clients within health systems, this study explored how perceived injustice in policy and organizational matters influence frontline health worker motivation and the consequent effect on workers' attitudes and performance in delivering maternal and neonatal health care in public hospitals. It consisted of an ethnographic study in two public hospitals in Southern Ghana. Participant observation, conversation and in-depth interviews were conducted over a 16-month period. Ethical approval and consent were obtained from relevant persons and authorities. Qualitative analysis software Nvivo 8 was used for coding and analysis of data. Main themes identified in the analysis form the basis for interpreting and reporting study findings. Findings showed that most workers perceived injustice in distributive, procedural and interactional dimensions at various levels in the health system. At the national policy level this included poor conditions of service. At the hospital level, it included perceived inequity in distribution of incentives, lack of protection and respect for workers. These influenced frontline worker motivation negatively and sometimes led to poor response to client needs. However, intrinsically motivated workers overcame these challenges and responded positively to clients' health care needs. It is important to recognize and conceptualize frontline workers in health systems as internal clients of the facilities and organizations within which they work. Their quality needs must be adequately met if they are to be highly motivated and supported to provide quality and responsive care to their clients. Meeting these quality needs of internal clients and creating a sense of fairness in governance arrangements between frontline workers, facilities and health system managers is crucial. Consequently, intervention measures such as creating more open door policies, involving frontline workers in decision making, recognizing their needs and challenges and working together to address them are critical. PMID- 25274638 TI - Towards people-centred health systems: a multi-level framework for analysing primary health care governance in low- and middle-income countries. AB - Although there is evidence that non-government health system actors can individually or collectively develop practical strategies to address primary health care (PHC) challenges in the community, existing frameworks for analysing health system governance largely focus on the role of governments, and do not sufficiently account for the broad range of contribution to PHC governance. This is important because of the tendency for weak governments in low- and middle income countries (LMICs). We present a multi-level governance framework for use as a thinking guide in analysing PHC governance in LMICs. This framework has previously been used to analyse the governance of common-pool resources such as community fisheries and irrigation systems. We apply the framework to PHC because, like common-pool resources, PHC facilities in LMICs tend to be commonly owned by the community such that individual and collective action is often required to avoid the 'tragedy of the commons'-destruction and degradation of the resource resulting from lack of concern for its continuous supply. In the multi level framework, PHC governance is conceptualized at three levels, depending on who influences the supply and demand of PHC services in a community and how: operational governance (individuals and providers within the local health market), collective governance (community coalitions) and constitutional governance (governments at different levels and other distant but influential actors). Using the example of PHC governance in Nigeria, we illustrate how the multi-level governance framework offers a people-centred lens on the governance of PHC in LMICs, with a focus on relations among health system actors within and between levels of governance. We demonstrate the potential impact of health system actors functioning at different levels of governance on PHC delivery, and how governance failure at one level can be assuaged by governance at another level. PMID- 25274636 TI - Evaluating the implementation of community volunteer assessment and referral of sick babies: lessons learned from the Ghana Newhints home visits cluster randomized controlled trial. AB - A World Health Organization (WHO)/United Nations Children's Fund (UNICEF) (2009) joint statement recommended home visits by community-based agents as a strategy to improve newborn survival, based on promising results from Asia. This article presents detailed evaluation of community volunteer assessment and referral implemented within the Ghana Newhints home visits cluster-Randomized Controlled Trial (RCT). It highlights the lessons learned to inform implementation/scale-up of this model in similar settings. The evaluation used a conceptual framework adopted for increasing access to care for sick newborns and involves three main steps, each with a specific goal and key requirements to achieving this. These steps are: sick newborns are identified within communities and referred; families comply with referrals and referred babies receive appropriate management at health facilities. Evaluation data included interviews with 4006 recently delivered mothers; records on 759 directly observed volunteer assessments and 52 validation of supervisors' assessments; newborn care quality assessment in 86 health facilities and in-depth interviews (IDIs) with 55 mothers, 21 volunteers and 15 health professionals. Assessment accuracy of volunteers against supervisors and physician was assessed using Kappa (agreement coefficient). IDIs were analysed by generating and indexing into themes, and exploring relationships between themes and their contextual interpretations. This evaluation demonstrated that identifying, understanding and implementing the key requirements for success in each step of volunteer assessment and referrals was pivotal to success. In Newhints, volunteers (CBSVs) were trusted by families, their visits were acceptable and they engaged mothers/families in decisions, resulting in unprecedented 86% referral compliance and increased (55-77%) care seeking for sick newborns. Poor facility care quality, characterized by poor health worker attitudes, limited the mortality reduction. The important implication for future implementation of home visits in similar settings is that, with 100% specificity but 80% sensitivity of referral decisions, volunteers might miss some danger signs but if successful implementation must translate into mortality reductions, concurrent improvement in facility newborn care quality is imperative. PMID- 25274639 TI - Exploring health researchers' perceptions of policymaking in Argentina: a qualitative study. AB - Much of the published research on evidence-informed health policymaking in low- and middle-income countries has focused on policymakers, overlooking the role of health researchers in the research-to-policy process. Through 20 semi-structured, in-depth qualitative interviews conducted with researchers in Argentina's rural northwest and the capital of Buenos Aires, we explore the perspectives, experiences and attitudes of Argentine health researchers regarding the use and impact of health research in policymaking in Argentina. We find that the researcher, and the researcher's function of generating evidence, is nested within a broader complex system that influences the researcher's interaction with policymaking. This system comprises communities of practice, government departments/civil society organizations, bureaucratic processes and political governance and executive leadership. At the individual level, researcher capacity and determinants of research availability also play a role in contributing to evidence-informed policymaking. In addition, we find a recurrent theme around 'lack of trust' and explore the role of trust within a research system, finding that researchers' distrust towards policymakers and even other researchers are linked inextricably to the sociopolitical history of Argentina, which contributes to shaping researchers' identities in opposition to policymakers. For policymakers, national research councils and funders of national health research systems, this article provides a deeper understanding of researchers' perceptions which can help inform and improve programme design when developing interventions to enhance research utilization and develop equitable and rational health policies. For donors and development agencies interested in health research capacity building and achieving development goals, this research demonstrates a need for investment in building research capacity and training health researchers to interact with the public policy 'world' and enhancing research communications and transferability to decision makers. It also highlights an opportunity to invest in implementation research platforms, such as health policy research and analysis institutions. PMID- 25274640 TI - Patient satisfaction with task shifting of antiretroviral services in Ethiopia: implications for universal health coverage. AB - Formalized task shifting structures have been used to rapidly scale up antiretroviral service delivery to underserved populations in several countries, and may be a promising mechanism for accomplishing universal health coverage. However, studies evaluating the quality of service delivery through task shifting have largely ignored the patient perspective, focusing on health outcomes and acceptability to health care providers and regulatory bodies, despite studies worldwide that have shown the significance of patient satisfaction as an indicator of quality. This study aimed to measure patient satisfaction with task shifting of antiretroviral services in hospitals and health centres in four regions of Ethiopia. This cross-sectional study used data collected from a time motion study of patient services paired with 665 patient exit interviews in a stratified random sample of antiretroviral therapy clinics in 21 hospitals and 40 health centres in 2012. Data were analyzed using f-tests across provider types, and multivariate logistic regression to identify determinants of patient satisfaction. Most (528 of 665) patients were satisfied or somewhat satisfied with the services received, but patients who received services from nurses and health officers were significantly more likely to report satisfaction than those who received services from doctors [odds ratio (OR) 0.26, P < 0.01]. Investments in the health facility were associated with higher satisfaction (OR 1.07, P < 0.01), while costs to patients of over 120 birr were associated with lower satisfaction (OR 0.14, P < 0.05). This study showed high levels of patient satisfaction with task shifting in Ethiopia. The evidence generated by this study complements previous biomedical and health care provider/regulatory acceptability studies to support the inclusion of task shifting as a mechanism for scaling-up health services to achieve universal health coverage, particularly for underserved areas facing severe health worker shortages. PMID- 25274641 TI - Exploring the nature of governance at the level of implementation for health system strengthening: the DIALHS experience. AB - Health system governance has been recognized as a critical element of the health system strengthening agenda. To date, health governance research often focuses at national or global levels, adopting a macro-perspective that deals with governance structures, forms and principles. Little attention has been given to a micro-perspective which recognizes the role of health system actors in governance, or to considering the operational level of the health system. This article presents a South African case study of an intervention to address conflict in roles and responsibilities between multiple actors supporting service delivery at the local level, and explores the broader insights this experience generates about the nature of local health system governance. In an embedded case study, action learning and reflection theory were used to design and implement the intervention. Data in this article were drawn from minutes, observations and recorded reflections of the meetings and workshops that comprised the intervention. A theoretical governance framework was used both to understand the context of the intervention and to analyse the dimensions of governance relevant in the experience. The study shows how, through action learning and reflection, local managers in two organizations came to understand how the higher level misalignment of organizational structures and processes imposed governance constraints on them, and to see the impact this had on their organizational relationships. By re-framing the conflict as organizational, they were then able to create opportunities for staff to understand their context and participate in negotiating principles for communication and collaborative work. The result reduced conflict between staff in the two organizations, leading to improved implementation of programme support. Strengthening relationships among those working at local level by building collaborative norms and values is an important part of local health system governance for improved service delivery by multiple actors. PMID- 25274642 TI - Living through conflict and post-conflict: experiences of health workers in northern Uganda and lessons for people-centred health systems. AB - Providing people-centred health systems--or any systems at all--requires specific measures to protect and retain healthcare workers during and after the conflict. This is particularly important when health staff are themselves the target of violence and abduction, as is often the case. This article presents the perspective of health workers who lived through conflict in four districts of northern Uganda--Pader, Gulu, Amuru, and Kitgum. These contained more than 90% of the people displaced by the decades of conflict, which ended in 2006. The article is based on 26 in-depth interviews, using a life history approach. This participatory tool encouraged participants to record key events and decisions in their lives, and to explore areas such as their decision to become a health worker, their employment history, and their experiences of conflict and coping strategies. These were analyzed thematically to develop an understanding of how to protect and retain staff in these challenging contexts. During the conflict, many health workers lost their lives or witnessed the death of their friends and colleagues. They also experienced abduction, ambush and injury. Other challenges included disconnection from social and professional support systems, displacement, limited supplies and equipment, increased workload and long working days and lack of pay. Health workers were not passive in the face of these challenges, however. They adopted a range of safety measures, such as mingling with community members, sleeping in the bush, and frequent change of sleeping place, in addition to psychological and practical coping strategies. Understanding their motivation and their views provides an important insight how to maintain staffing and so to continue to offer essential health care during difficult times and in marginalized areas. PMID- 25274643 TI - Addressing the social determinants of health: a case study from the Mitanin (community health worker) programme in India. AB - The Mitanin Programme, a government community health worker (CHW) programme, was started in Chhattisgarh State of India in 2002. The CHWs (Mitanins) have consistently adopted roles that go beyond health programme-specific interventions to embrace community mobilization and action on local priorities. The aim of this research was to document how and why the Mitanins have been able to act on the social determinants of health, describing the catalysts and processes involved and the enabling programmatic and organizational factors. A qualitative comparative case study of successful action by Mitanin was conducted in two 'blocks', purposefully selected as positive exemplars in two districts of Chhattisgarh. One case focused on malnutrition and the other on gender-based violence. Data collection involved 17 in-depth interviews and 10 group interviews with the full range of stakeholders in both blocks, including community members and programme team. Thematic analysis was done using a broad conceptual framework that was further refined. Action on social determinants involved raising awareness on rights, mobilizing women's collectives, revitalizing local political structures and social action targeting both the community and government service providers. Through these processes, the Mitanins developed identities as agents of change and advocates for the community, both with respect to local cultural and gender norms and in ensuring accountability of service providers. The factors underpinning successful action on social determinants were identified as the significance of the original intent and vision of the programme, and how this was carried through into all aspects of programme design, the role of the Mitanins and their identification with village women, ongoing training and support, and the relative autonomy of the programme. Although the results are not narrowly generalizable and do not necessarily represent the situation of the Mitanin Programme as a whole, the explanatory framework may provide general lessons for programmes in similar contexts. PMID- 25274644 TI - Does identity shape leadership and management practice? Experiences of PHC facility managers in Cape Town, South Africa. AB - In South Africa, as elsewhere, Primary Health Care (PHC) facilities are managed by professional nurses. Little is known about the dimensions and challenges of their job, or what influences their managerial practice. Drawing on leadership and organizational theory, this study explored what the job of being a PHC manager entails, and what factors influence their managerial practice. We specifically considered whether the appointment of professional nurses as facility managers leads to an identity transition, from nurse to manager. The overall intention was to generate ideas about how to support leadership development among PHC facility managers. Adopting case study methodology, the primary researcher facilitated in-depth discussions (about their personal history and managerial experiences) with eight participating facility managers from one geographical area. Other data were collected through in-depth interviews with key informants, document review and researcher field notes/journaling. Analysis involved data triangulation, respondent and peer review and cross-case analysis. The experiences show that the PHC facility manager's job is dominated by a range of tasks and procedures focused on clinical service management, but is expected to encompass action to address the population and public health needs of the surrounding community. Managing with and through others, and in a complex system, requiring self-management, are critical aspects of the job. A range of personal, professional and contextual factors influence managerial practice, including professional identity. The current largely facility-focused management practice reflects the strong nursing identity of managers and broader organizational influences. However, three of the eight managers appear to self-identify an emerging leadership identity and demonstrate related managerial practices. Nonetheless, there is currently limited support for an identity transition towards leadership in this context. Better support for leadership development could include talent-spotting and nurturing, induction and peer-mentoring for newly appointed facility managers, ongoing peer-support once in post and continuous reflective practice. PMID- 25274645 TI - Examining the links between community participation and health outcomes: a review of the literature. AB - As a key principle of Primary Health Care (PHC) and Health Systems Reform, community participation has a prominent place in the current global dialogue. Participation is not only promoted in the context of provision and utilization of health services. Advocates also highlight participation as a key factor in the wider context of the importance of social determinants of health and health as a human right. However, the evidence that directly links community participation to improved health status is not strong. Its absence continues to be a barrier for governments, funding agencies and health professionals to promote community participation. The purpose of this article is to review research seeking to link community participation with improved health status outcomes programmes. It updates a review undertaken by the author in 2009. The search includes published articles in the English language and examines the evidence of in the context of health care delivery including services and promotion where health professionals have defined the community's role. The results show that in most studies community participation is defined as the intervention seeking to identify a direct causal link between participation and improved health status modeled on Randomized Control studies (RCT). The majority of studies show it is not possible to examine the link because there is no standard definition of 'community' and 'participation'. Where links are found, they are situation-specific and are unpredictable and not generalizable. In the discussion, an alternative research framework is proposed arguing that community participation is better understood as a process. Once concrete interventions are identified (i.e. improved birth outcomes) then the processes producing improved health status outcomes can be examined. These processes may include and can lead to community uptake, ownership and sustainability for health improvements. However, more research is needed to ensure their validity. PMID- 25274646 TI - Leptin and nitric oxide in blood pressure regulation in humans. PMID- 25274647 TI - Health insurance, or particularly its lack, and healthcare consequences among hypertensive Americans. PMID- 25274648 TI - To dream the maybe possible dream: a breast cancer vaccine. PMID- 25274649 TI - Why is metformin contraindicated in chronic kidney disease? (May 2014). PMID- 25274650 TI - In reply. PMID- 25274651 TI - Should all patients have a resting 12-lead ECG before elective noncardiac surgery? PMID- 25274652 TI - Terry nails in a patient with chronic alcoholic liver disease. PMID- 25274653 TI - Bench-to-bedside challenges in developing immune protection against breast cancer. AB - Despite the success of childhood vaccination against infectious diseases, vaccines are lacking against diseases that occur with age. We are developing a vaccine to prevent breast cancer. This article explains the vaccine strategy, how we think the vaccine will work, and how we plan to move forward through clinical trials. PMID- 25274654 TI - Keeping up with immunizations for adults. AB - This paper discusses recommendations from the US Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices for vaccinating adults against influenza, tetanus, measles, mumps, rubella, varicella, hepatitis A and B, human papillomavirus, shingles (zoster), pneumonia, and meningitis. PMID- 25274655 TI - Managing snoring: when to consider surgery. AB - Snoring can range in significance from merely annoying the patient's bed partner to being a symptom of obstructive sleep apnea, a risk factor for heart disease and stroke. If conservative measures do not help, primary care physicians can refer patients for consideration of a variety of surgical procedures to keep the airway open during sleep. PMID- 25274656 TI - Diabetes therapy and cancer risk: where do we stand when treating patients? AB - The pathophysiology of type 2 diabetes mellitus conveys increased cancer risk, and any antidiabetic drug may alter that risk in a favorable or unfavorable way. This article discusses the links between diabetes and cancer, the different agents available for treating diabetes, and the cancer risk associated with these therapies. PMID- 25274657 TI - When patients on target-specific oral anticoagulants need surgery. AB - The target-specific oral anticoagulants (TSOACs), eg, dabigatran, rivaroxaban, and apixaban, are changing the way we manage thromboembolic disease. At the same time, many clinicians wonder how best to manage TSOAC therapy when patients need surgery. An in-depth understanding of these drugs is essential to minimize the risk of bleeding and thrombosis perioperatively. PMID- 25274658 TI - Incidences and Range of Spontaneous Lesions in the Eye of Crl:CD-1(ICR)BR Mice Used in Toxicity Studies. AB - The incidence and range of spontaneous pathology findings were determined in the eyes of male and female control Crl:CD-1(ICR)BR mice. Data were collected from 250, 430, 510, and 2,266 mice from control dose groups of 4-, 13-, 80- and 104 week studies, respectively, carried out between 2005 and 2013. Lesions of the eye were very rare in 4- and 13-week studies, uncommon in 80-week studies, and were of relatively higher incidence in 104-week studies. No sex predilection in the incidence of eye lesions was apparent. No neoplastic lesions were observed, and congenital lesions were very rare. The most common findings were cataracts, retinal degeneration, mineral deposits in the iris, keratitis, anterior uveitis, and mineral deposits in the corneal stroma. These lesions were observed only in animals from 80- and 104-week studies, except retinal degeneration which was observed in animals from all age-groups. There are no previous reports of mineral deposits in the iris in this strain of mice. It is hoped that reference to the incidences reported here will facilitate the differentiation of spontaneous lesions from compound-induced lesions in toxicology studies in this strain of mouse. PMID- 25274660 TI - Development of a computational high-throughput tool for the quantitative examination of dose-dependent histological features. AB - High-resolution digitalizing of histology slides facilitates the development of computational alternatives to manual quantitation of features of interest. We developed a MATLAB-based quantitative histological analysis tool (QuHAnT) for the high-throughput assessment of distinguishable histological features. QuHAnT validation was demonstrated by comparison with manual quantitation using liver sections from mice orally gavaged with sesame oil vehicle or 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD; 0.001-30 MUg/kg) every 4 days for 28 days, which elicits hepatic steatosis with mild fibrosis. A quality control module of QuHAnT reduced the number of quantifiable Oil Red O (ORO)-stained images from 3,123 to 2,756. Increased ORO staining was measured at 10 and 30 MUg/kg TCDD with a high correlation between manual and computational volume densities (Vv ), although the dynamic range of QuHAnT was 10-fold greater. Additionally, QuHAnT determined the size of each ORO vacuole, which could not be accurately quantitated by visual examination or manual point counting. PicroSirius Red quantitation demonstrated superior collagen deposition detection due to the ability to consider all images within each section. QuHAnT dramatically reduced analysis time and facilitated the comprehensive assessment of features improving accuracy and sensitivity and represents a complementary tool for tissue/cellular features that are difficult and tedious to assess via subjective or semiquantitative methods. PMID- 25274664 TI - Four subtypes of gastric cancer identified. PMID- 25274659 TI - Characterization of Batracylin-induced Renal and Bladder Toxicity in Rats. AB - Batracylin (NSC-320846) is a dual inhibitor of DNA topoisomerases I and II. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed. To further investigate batracylin's mechanism of toxicity, studies were conducted in Fischer 344 rats. Once daily oral administration of 16 or 32 mg/kg batracylin to rats for 4 days caused overt toxicity. Abnormal clinical observations and adverse effects on clinical pathology, urinalysis, and histology indicated acute renal damage and urothelial damage and bone marrow dysfunction. Scanning electron microscopy revealed sloughing of the superficial and intermediate urothelial layers. DNA damage was evident in kidney and bone marrow as indicated by histone gamma-H2AX immunofluorescence. After a single oral administration of 16 or 32 mg/kg, the majority of batracylin was converted to N-acetylbatracylin (NAB) with a half-life of 4 hr to 11 hr. Mesna (MesnexTM), a drug known to reduce the incidence of hemorrhagic cystitis induced by ifosfamide or cyclophosphamide, was administered to rats prior to batracylin, but did not alleviate batracylin induced bladder and renal toxicity. These findings suggest that batracylin results in DNA damage-based mechanisms of toxicity and not an acrolein-based mechanism of toxicity as occurs after ifosfamide or cyclophosphamide administration. PMID- 25274663 TI - Proteogenomics sheds light on tumors. PMID- 25274665 TI - Avastin approved for some cervical cancers. PMID- 25274666 TI - Minor clone may drive cancer growth. PMID- 25274667 TI - Regulation may stifle research in Europe. PMID- 25274668 TI - New grants to boost genome sequencing. PMID- 25274669 TI - HPV testing more reassuring than Pap. PMID- 25274671 TI - A new era in CLL treatment. PMID- 25274682 TI - Testing the metal of ERCC2 in predicting the response to platinum-based therapy. AB - DNA repair has been shown to affect the cellular response to platinum-based therapy in a variety of cancers; however, translating this knowledge to the clinic has proven difficult and yielded mixed results. In this issue of Cancer Discovery, Van Allen and colleagues have analyzed responders and nonresponders to neoadjuvant platinum-based therapy with locally advanced urothelial cancer and identified a series of mutations in the nucleotide excision repair (NER) gene ERCC2 that correlate with the response to platinum-based therapy. This work provides evidence that defects in NER can be exploited to maximize the efficacy of conventional platinum-based chemotherapy. PMID- 25274684 TI - A CREB1-TGFbeta2 self-sustaining loop in glioblastoma. AB - A subset of glioblastomas (GBM) has high levels of TGFbeta signaling, and anti TGFbeta therapies are being pursued as treatments for GBM. The work presented here identifies CREB1 as a potential biomarker for TGFbeta-dependent GBM. CREB1 integrates signaling from TGFbeta and the PI3K pathway and nucleates a self sustaining signaling loop that maintains TGFbeta2 expression in GBM with high CREB1 levels. PMID- 25274683 TI - Understanding and targeting alkylator resistance in glioblastoma. AB - Alkylating chemotherapy is the mainstay in the treatment of pediatric and adult glioblastoma despite primary and acquired resistance and scientific efforts to precisely define therapies for individual patients. A focus on non-MGMT-mediated temozolomide resistance for pediatric glioblastoma suggests options for new drug combinations. PMID- 25274685 TI - Noncoding DNA drives cancer, too. PMID- 25274693 TI - FDA guidance on informed consent updated. PMID- 25274694 TI - Lanreotide slows growth of neuroendocrine cancer. PMID- 25274696 TI - NIH funds studies on implications of genetic research. PMID- 25274695 TI - NCI funds community-based trial network. PMID- 25274697 TI - Idelalisib approved for trio of blood cancers. PMID- 25274701 TI - Missing pieces of an ancient puzzle: evolution of the eukaryotic membrane trafficking system. AB - The membrane-trafficking system underpins cellular trafficking of material in eukaryotes and its evolution would have been a watershed in eukaryogenesis. Evolutionary cell biological studies have been unraveling the history of proteins responsible for vesicle transport and organelle identity revealing both highly conserved components and lineage-specific innovations. Recently, endomembrane components with a broad, but patchy, distribution have been observed as well, pieces that are missing from our cell biological and evolutionary models of membrane trafficking. These data together allow for new insights into the history and forces that shape the evolution of this critical cell biological system. PMID- 25274703 TI - Paradox of mother's curse and the maternally provisioned offspring microbiome. AB - Strict maternal transmission creates an "asymmetric sieve" favoring the spread of mutations in organelle genomes that increase female fitness, but diminish male fitness. This phenomenon, called "Mother's Curse," can be viewed as an asymmetrical case of intralocus sexual conflict. The evolutionary logic of Mother's Curse applies to each member of the offspring microbiome, the community of maternally provisioned microbes, believed to number in the hundreds, if not thousands, of species for host vertebrates, including humans. Taken together, these observations pose a compelling evolutionary paradox: How has maternal transmission of an offspring microbiome become a near universal characteristic of the animal kingdom when the genome of each member of that community poses a potential evolutionary threat to the fitness of host males? I review features that limit or reverse Mother's Curse and contribute to resolving this paradox. I suggest that the evolution of vertical symbiont transmission requires conditions that mitigate the evolutionary threat to host males. PMID- 25274704 TI - Expanding the epigenetic landscape: novel modifications of cytosine in genomic DNA. AB - Methylation of the base cytosine in DNA is critical for silencing endogenous retroviruses, regulating gene expression, and establishing cellular identity, and has long been regarded as an indelible epigenetic mark. The recent discovery that the ten eleven translocation (TET) proteins can oxidize 5-methylcytosine (5mC) resulting in the formation of 5-hydroxymethylcytosine (5hmC) and other oxidized cytosine variants in the genome has triggered a paradigm shift in our understanding of how dynamic changes in DNA methylation regulate transcription and cellular differentiation, thus influencing normal development and disease. PMID- 25274702 TI - The meiotic checkpoint network: step-by-step through meiotic prophase. AB - The generation of haploid gametes by meiosis is a highly conserved process for sexually reproducing organisms that, in almost all cases, involves the extensive breakage of chromosomes. These chromosome breaks occur during meiotic prophase and are essential for meiotic recombination as well as the subsequent segregation of homologous chromosomes. However, their formation and repair must be carefully monitored and choreographed with nuclear dynamics and the cell division program to avoid the creation of aberrant chromosomes and defective gametes. It is becoming increasingly clear that an intricate checkpoint-signaling network related to the canonical DNA damage response is deeply interwoven with the meiotic program and preserves order during meiotic prophase. This meiotic checkpoint network (MCN) creates a wide range of dependent relationships controlling chromosome movement, chromosome pairing, chromatin structure, and double-strand break (DSB) repair. In this review, we summarize our current understanding of the MCN. We discuss commonalities and differences in different experimental systems, with a particular emphasis on the emerging design principles that control and limit cross talk between signals to ultimately ensure the faithful inheritance of chromosomes by the next generation. PMID- 25274707 TI - Preparing the workforce for healthy aging programs: the Skills for Healthy Aging Resources and Programs (SHARP) model. AB - Current public health and aging service agency personnel have little training in gerontology, and virtually no training in evidence-based health promotion and disease management programs for older adults. These programs are rapidly becoming the future of our community-based long-term care support system. The purpose of this project was to develop and test a model community college career technical education program, Skills for Healthy Aging Resources and Programs (SHARP), for undergraduate college students, current personnel in aging service and community organizations, and others interested in retraining. A multidisciplinary cross sector team from disciplines of public health, sociology, gerontology and nursing developed four competency-based courses that focus on healthy aging, behavior change strategies, program management, an internship, and an option for leader training in the Chronic Disease Self-Management Program. To enhance implementation and fidelity, intensive faculty development training was provided to all instructors and community agency partners. Baseline and postprogram evaluation of competencies for faculty and students was conducted. Process evaluation for both groups focused on satisfaction with the curricula and suggestions for program improvement. SHARP has been piloted five times at two community colleges. Trainees (n = 113) were primarily community college students (n = 108) and current aging service personnel (n = 5). Statistically significant improvements in all competencies were found for both faculty and students. Process evaluation outcomes identified the needed logical and component adaptations to enhance the feasibility of program implementation, dissemination, and student satisfaction. The SHARP program provides a well-tested, evidence based effective model for addressing workforce preparation in support of healthy aging service program expansion and delivery. PMID- 25274705 TI - Transcriptional regulation by trithorax-group proteins. AB - The trithorax group of genes (trxG) was identified in mutational screens that examined developmental phenotypes and suppression of Polycomb mutant phenotypes. The protein products of these genes are primarily involved in gene activation, although some can also have repressive effects. There is no central function for these proteins. Some move nucleosomes about on the genome in an ATP-dependent manner, some covalently modify histones such as methylating lysine 4 of histone H3, and some directly interact with the transcription machinery or are a part of that machinery. It is interesting to consider why these specific members of large families of functionally related proteins have strong developmental phenotypes. PMID- 25274708 TI - Examining strategies to build and sustain healthy aging programming collaboratives. AB - BACKGROUND: Community collaboratives provide a means to build local capacity, reduce service fragmentation and duplication, maximize efficiency, and create synergies for systems change. But what are the collaborative practices that aging services providers and other stakeholders employ for system change and impact in evidence-based programming for older adults? PURPOSE: The aim of this study was to learn how aging and health collaborations created strategic partnerships to foster multisector systems change and pursue long-term goals and near-term activities to sustain and expand evidence-based health programming. METHODS: Via a multiphase process, we identified eight geographically diverse, exemplar agencies that serve as the coordinators for various community collaborations. Using an interview protocol culled from the literature, we conducted on-site, in depth interviews with leadership and partners. RESULTS: Four creative strategies emerged across sites as contributing to the growth and sustainability of evidence based health programming including engagement of nontraditional partners, development of new relationships with health care, building of innovative systems of structures and tools, and systematically working with vulnerable populations. Opportunities for future initiatives include enhancing linkages with health care, advocating for the value of evidence-based programming, supporting local program development and adaptation, and developing marketing strategies and business models. CONCLUSION: These eight organizations are leveraging their historic strengths and newly acquired expertise to extend health programming beyond established partners and funding silos. The four strategies and specific activities reflected in their work have laid a solid foundation for expanding and embedding future initiatives and positively impacting the health of older adults. PMID- 25274706 TI - Developing a framework and priorities to promote mobility among older adults. AB - Mobility, broadly defined as movement in all of its forms from ambulation to transportation, is critical to supporting optimal aging. This article describes two projects to develop a framework and a set of priority actions designed to promote mobility among community-dwelling older adults. Project 1 involved a concept-mapping process to solicit and organize action items into domains from a broad group of stakeholders to create the framework. Concept mapping uses qualitative group processes with multivariate statistical analysis to represent the ideas visually through maps. A snowball technique was used to identify stakeholders (n = 211). A 12-member steering committee developed a focus prompt, "One specific action that can lead to positive change in mobility for older adults in the United States is..." Project 2 included a Delphi technique (n = 43) with three iterations to prioritize four to six items using results from the concept mapping rating process. Project 1 resulted in 102 items across nine domains (Research to Practice, Independence and Engagement, Built Environment and Safety, Transportation, Policy, Housing and Accessibility, Community Supports, Training, and Coordinated Action). The number of items ranged from 6 to 18 per domain. Project 2 resulted in agreement on four items that reflect the importance of promoting environmental strategies through collaborative initiatives aimed at planning and best practices focusing on environmental enhancements or transit, training of professionals, and integration of mobility into state and local public health plans. These findings can be applied to support coordinated, multidisciplinary research and practice to promote mobility among older adults. PMID- 25274709 TI - National study of chronic disease self-management: age comparison of outcome findings. AB - INTRODUCTION: The adult population is increasingly experiencing one or more chronic illnesses and living with such conditions longer. The Chronic Disease Self-Management Program (CDSMP) helps participants cope with chronic disease related symptomatology and improve their health-related quality of life. Nevertheless, the long-term effectiveness of this evidence-based program on older adults as compared to the middle-aged populations has not been examined in a large-scale, national rollout. METHOD: We identified baseline characteristics of CDSMP participants aged 65 years or older (n = 687, M = 74.8 years) in the National Study of CDSMP from 2010 to 2012. Comparisons were made to middle-aged participants aged 50 to 64 (n = 325, M = 58.3 years). Assessments were conducted at baseline and 12-month follow-up. Linear and generalized linear mixed models were performed to assess changes in primary and secondary outcomes, controlling the key sociodemographics and number of chronic conditions. RESULTS: All primary outcomes (i.e., social/role activities limitation, depression, communication with doctors) significantly improved in both the older and middle-aged cohorts. Although improvements in illness symptomatology (e.g., fatigue, pain, shortness of breath, and sleep problems) were similar across both cohorts, only the middle aged cohort benefitted significantly in terms of overall quality of life and unhealthy mental health days. Effect sizes were larger among the middle-aged population who were also more likely to enter the program in poorer health and be from minority backgrounds. CONCLUSIONS: The current study documented improved health outcomes but more so among the middle-aged population. Findings suggest the importance of examining how age and interacting life circumstances may affect chronic disease self-management. PMID- 25274710 TI - A mixed-methods randomized controlled trial of financial incentives and peer networks to promote walking among older adults. AB - BACKGROUND: Financial incentives and peer networks could be delivered through eHealth technologies to encourage older adults to walk more. METHODS: We conducted a 24-week randomized trial in which 92 older adults with a computer and Internet access received a pedometer, daily walking goals, and weekly feedback on goal achievement. Participants were randomized to weekly feedback only (Comparison), entry into a lottery with potential to earn up to $200 each week walking goals were met (Financial Incentive), linkage to four other participants through an online message board (Peer Network), or both interventions (Combined). Main outcomes were the proportion of days walking goals were met during the 16 week intervention and 8-week follow-up. We conducted a content analysis of messages posted by Peer Network and Combined arm participants. RESULTS: During the 16-week intervention, there were no differences in the proportion of days walking goals were met in the Financial Incentive (39.7%; p = .78), Peer Network (24.9%; p = .08), and Combined (36.0%; p = .77) arms compared with the Comparison arm (36.0%). During 8 weeks of follow-up, the proportion of days walking goals were met was lower in the Peer Network arm (18.7%; p = .025) but not in the Financial Incentive (29.3%; p = .50) or Combined (24.8%; p = .37) arms, relative to the Comparison arm (34.5%). Messages posted by participants focused on barriers to walking and provision of social support. CONCLUSIONS: Financial incentives and peer networks delivered through eHealth technologies did not result in older adults walking more. PMID- 25274711 TI - A systematic review of the use of technology for reminiscence therapy. AB - As the segment of the population 65 years of age or older continues to grow, the number of individuals with dementia increases proportionally, highlighting the need to design therapies that meet the social and emotional needs of people with dementia. Information and communication technologies (ICT) are potential venues for supporting the delivery of such therapies, including reminiscence therapy (RT), which is a non-pharmacological intervention involving the prompting of past memories, often with artifacts such as old photographs or music for therapeutic benefits such as the facilitation of social interactions or the increase of self esteem. This paper systematically examines the scientific literature on the use of ICT for facilitating RT to assess the current state of the evidence and identify future trends. We searched the PubMed (1966-2013), ACM (1954-2013), and PsycINFO (1908-2013) repositories using the keywords dementia and reminiscence. Three hundred eighty-six articles were retrieved, 44 of which met the inclusion and exclusion criteria. Findings of the systematic review include that there are benefits to using ICT for RT interventions. Some of these benefits are access to rich and engaging multimedia reminiscence materials, opportunities for people with dementia to participate in social interactions and take ownership of conversations, and a reduction of barriers due to motor deficits during interactions with media. Future studies should explore the types and content of media beneficial to individuals at different stages of dementia. PMID- 25274712 TI - Fostering engagement and independence: opportunities and challenges for an aging society. PMID- 25274713 TI - A randomized trial to measure the impact of a community-based cognitive training intervention on balance and gait in cognitively intact Black older adults. AB - INTRODUCTION: Fall prevention is important for maintaining mobility and independence into old age. Approaches for reducing falls include exercise, tai chi, and home modifications; however, causes of falling are multifactorial and include not just physical but cognitive factors. Cognitive decline occurs with age, but older adults with the greatest declines in executive function experience more falls. The purpose of this study was twofold: to demonstrate the feasibility of a community-based cognitive training program for cognitively intact Black older adults and to analyze its impact on gait and balance in this population. METHOD: This pilot study used a pretest/posttest randomized trial design with assignment to an intervention or control group. Participants assigned to the intervention completed a computer-based cognitive training class that met 2 days a week for 60 min over 10 weeks. Classes were held at senior/community centers. Primary outcomes included balance as measured by the Berg Balance Scale (BBS), 10 meter gait speed, and 10-meter gait speed under visuospatial dual-task condition. All measures were assessed at baseline and immediately post-intervention. RESULTS: Participants were community-dwelling Black adults with a mean age of 72.5 and history of falls (N = 45). Compared to controls, intervention participants experienced statistically significant improvements in BBS and gait speed. Mean performance on distracted gait speed also improved more for intervention participants compared to controls. CONCLUSION: Findings from this pilot randomized trial demonstrate the feasibility of a community-based cognitive training intervention. They provide initial evidence that cognitive training may be an efficacious approach toward improving balance and gait in older adults known to have a history of falls. PMID- 25274715 TI - Volunteering as a pathway to productive and social engagement among older adults. AB - INTRODUCTION: Research on outcomes of volunteering in later life largely focuses on the health of volunteers. This is in contrast to studies of youth, where attention is directed toward the effects of volunteering on subsequent productive and citizen behaviors. In this study, we examined the effects of volunteering on subsequent social and civic activity of older adults. METHOD: This study was conducted with volunteers from Experience Corps(r) (EC), a national program that brings older adults into schools to work with students. Data were derived from a baseline survey of older adults who were new EC volunteers in fall of 2006 and 2007. Follow-up interviews were conducted with 338 volunteers in fall 2010 to capture work, education, and community activities undertaken subsequent to joining EC. RESULTS: Subsequent to joining EC, 16% of volunteers reported that they started a new job, 53% started another volunteer position, 40% started a community activity, and 39% took a class/started educational program. When asked if and how EC participation played a role in their new involvements, 71% said it increased confidence, 76% said it increased realization of the importance of organized activities/daily structure, and more than 40% said they made social connections that led to new involvements. Most reported they were more likely to be involved in advocacy efforts for public education. DISCUSSION: Volunteering among older adults is a means as well as an end--just as it is for young people. Programs can do more to attract and serve older adults by promoting volunteering as a pathway to other engagements, including work, social, and civic activities. PMID- 25274714 TI - A systematic review of strategies to foster activity engagement in persons with dementia. AB - Dementia is a growing public health issue. Activity, a positive therapeutic modality, has potential to enhance quality of life and reduce behavioral symptoms in persons with dementia--outcomes eluding pharmacological treatments. However, it is unclear how to effectively engage persons with dementia in activities for them to derive desired benefits. We present a systematic review of 28 studies involving 50 tests of different ways of modifying activities to enhance engagement and reduce behavioral and psychological symptoms for this group. Of 50 tests, 22 (44%) evaluated changes to objects and properties (e.g., introducing activities with intrinsic interest), 6 (12%) evaluated changes to space demands (e.g., lighting, noise levels), 8 (16%) evaluated changes to social demands (e.g., prompts, praise), and 14 (28%) combined two or more activity modifications. No modifications were made to the sequence and timing of activities. Although modifications to objects and properties were the most common, outcomes for engagement and behaviors were mixed. Modifications to space and social demands were less frequently tested, but consistently yielded positive outcomes. No modifications resulted in negative behavioral outcomes or decreased engagement. Methodological strengths of studies included direct observation of outcomes and fidelity assessments. Few studies however involved persons with dementia at home. Our review revealed a growing evidentiary base for different modifications to foster engagement in activities and reduce behavioral and psychological symptoms. Future studies should evaluate how contextual factors (e.g., physical environment, activity type) and caregiver ability to employ activity modifications affect engagement. PMID- 25274717 TI - Patient communication self-efficacy, self-reported illness symptoms, physician communication style and mental health and illness in hospital outpatients. AB - In this cross-sectional study, we investigated the associations between patient communication self-efficacy and self-reported symptoms in doctor-patient communication, as perceived by patients, and the mental health and illness of hospital outpatients. Using data from a sample of 74 outpatients (mean age = 37.58 years, standard deviation = 12.54), a structural equation model was calculated. The results showed that communication self-efficacy and respectful behaviour were associated with mental health and illness. Furthermore, self reported symptoms were correlated with mental illness. Gender and educational differences also occurred. The findings suggest that enhancing patients' communication skills could benefit outpatients in general, but female and less educated patients in particular. PMID- 25274718 TI - The role of obstetric knowledge in utilization of delivery service in Nepal. AB - Birth Preparedness and Complication Readiness (BP/CR) program has been promoted in Nepal to equip pregnant women with obstetric knowledge so as to motivate them to seek professional care. Using a prospective design of 701 pregnant women of more than 5 months gestation in a central hills district of Nepal, we evaluated if having obstetric knowledge could make a difference in maternal delivery behaviour. The results suggested that BP/CR program was effective in raising women's obstetric knowledge, which was significantly associated with facility delivery according to logistic regression analysis. In particular, women who acknowledged that unexpected problems could occur during pregnancy and childbirth were more likely (odds ratio [OR] 5.83, 95% confidence interval [CI] 2.95-11.52) to deliver at a health facility than others unaware of the possible consequences. Similarly, women who knew any antepartum danger sign (OR 2.16, 95% CI: 1.17 3.98), any intrapartum danger sign (OR 3.80, 95% CI: 2.07-6.96) and any postpartum danger sign (OR 3.47 95% CI: 1.93-6.25), tended to deliver at a health facility. Convincing and counselling the pregnant women of the health consequences of pregnancy and childbirth would increase their utilization of delivery service. PMID- 25274716 TI - Health-related quality of life and health behaviors in a population-based sample of older, foreign-born, Chinese American adults living in New York City. AB - Although the New York City Chinese population aged >= 65 years increased by 50% between 2000 and 2010, the health needs of this population are poorly understood. Approximately 3,001 Chinese individuals from high-density Asian American New York City areas were included in the REACH U.S. Risk Factor Survey; 805 (26.8%) were aged >= 65 years and foreign-born. Four health-related quality of life and three behavioral risk factor outcome variables were examined. Descriptive statistics were conducted by gender, and logistic regression models assessed sociodemographic and health factors associated with each outcome. Few women were current smokers (1.3% vs. 14.8% of men), 19% of respondents ate fruits and vegetables more than or equal to five times daily, and one-third of individuals received sufficient weekly physical activity. Days of poor health were similar to the national population aged >= 65 years, while self-reported fair or poor health was much greater among our Chinese sample; over 60% of respondents rated their health as fair or poor. Lower education and lower obesity were significantly associated with cigarette smoking among men, and older age was significantly associated with insufficient physical activity overall. Female gender was significantly associated with all poor health days; older age was significantly associated with poor days of physical health, and lower income was significantly associated with poor days of physical health and fair or poor self-reported health. This study provides important health-related information on a rapidly growing older population and highlights future research areas to inform culturally appropriate health promotion and disease prevention strategies and policies within community-based settings. PMID- 25274719 TI - Short- and long-term theory-based predictors of physical activity in women who participated in a weight-management program. AB - This study analyzed psychosocial predictors of the Theory of Planned Behavior (TPB) and Self-Determination Theory (SDT) and evaluated their associations with short- and long-term moderate plus vigorous physical activity (MVPA) and lifestyle physical activity (PA) outcomes in women who underwent a weight management program. 221 participants (age 37.6 +/- 7.02 years) completed a 12 month SDT-based lifestyle intervention and were followed-up for 24 months. Multiple linear regression analyses tested associations between psychosocial variables and self-reported short- and long-term PA outcomes. Regression analyses showed that control constructs of both theories were significant determinants of short- and long-term MVPA, whereas affective and self-determination variables were strong predictors of short- and long-term lifestyle PA. Regarding short-term prediction models, TPB constructs were stronger in predicting MVPA, whereas SDT was more effective in predicting lifestyle PA. For long-term models, both forms of PA were better predicted by SDT in comparison to TPB. These results highlight the importance of comparing health behavior theories to identify the mechanisms involved in the behavior change process. Control and competence constructs are crucial during early adoption of structured PA behaviors, whereas affective and intrinsic sources of motivation are more involved in incidental types of PA, particularly in relation to behavioral maintenance. PMID- 25274720 TI - Gender norms, poverty and armed conflict in Cote D'Ivoire: engaging men in women's social and economic empowerment programming. AB - Engaging men is a critical component in efforts to reduce intimate partner violence (IPV). Little is known regarding men's perspectives of approaches that challenge inequitable gender norms, particularly in settings impacted by armed conflict. This article describes men's experiences with a women's empowerment program and highlights men's perceptions of gender norms, poverty and armed conflict, as they relate to achieving programmatic goals. Data are from 32 Ivorian men who participated in indepth interviews in 2012. Interviews were undertaken as part of an intervention that combined gender dialogue groups for both women and their male partners with women's only village savings and loans programs to reduce IPV against women. Findings suggested that in the context of armed conflict, traditional gender norms and economic stressors experienced by men challenged fulfillment of gender roles and threatened men's sense of masculinity. Men who participated in gender dialogue groups discussed their acceptance of programming and identified improvements in their relationships with their female partners. These men further discussed increased financial planning along with their partners, and attributed such increases to the intervention. Addressing men's perceptions of masculinity, poverty and armed conflict may be key components to reduce men's violence against women in conflict-affected settings. PMID- 25274721 TI - Typology of delivery quality: latent profile analysis of teacher engagement and delivery techniques in a school-based prevention intervention, keepin' it REAL curriculum. AB - Enhancing the delivery quality of school-based, evidence-based prevention programs is one key to ensuring uniform program effects on student outcomes. Program evaluations often focus on content dosage when implementing prevention curricula, however, less is known about implementation quality of prevention content, especially among teachers who may or may not have a prevention background. The goal of the current study is to add to the scholarly literature on implementation quality for a school-based substance use prevention intervention. Twenty-five schools in Ohio and Pennsylvania implemented the original keepin' REAL (kiR) substance use prevention curriculum. Each of the 10, 40-45 min lessons of the kiR curriculum was video recorded. Coders observed and rated a random sample of 276 videos reflecting 78 classes taught by 31 teachers. Codes included teachers' delivery techniques (e.g., lecture, discussion, demonstration and role play) and engagement with students (e.g. attentiveness, enthusiasm and positivity). Based on the video ratings, a latent profile analysis was run to identify typology of delivery quality. Five profiles were identified: holistic approach, attentive teacher-orientated approach, enthusiastic lecture approach, engaged interactive learning approach and skill practice-only approach. This study provides a descriptive typology of delivery quality while implementing a school-based substance use prevention intervention. PMID- 25274722 TI - Effect of a school-based intervention on physical activity and quality of life through serial mediation of social support and exercise motivation: the PESSOA program. AB - The aim of this study was to explore the effects of social support and behavioral regulation of exercise on physical activity (PA) and quality of life (QoL), in a Portuguese school-based intervention. We hypothesized that serial mediation effects would be present leading to greater levels of PA and QoL. The sample comprised 1042 students (549 boys), aged 10-16 years, BMI = 19.31 +/- 3.51, allocated to two groups of schools: control (n = 207) and intervention (n = 835). This study will report the 24 months results of the program, which aimed to develop healthy lifestyles. Questionnaires were used to measure PA, QoL, motivation to exercise and social support. There was no direct impact of the intervention on QoL or PA. Serial mediation analyses were conducted. Social support (P < 0.019) and intrinsic motivation (P = 0.085) increased more on intervention group. Indirect effects were observed in all serial mediation models. The positive indirect effects on PA and QoL were explained by the increase on peer/parent support in serial with the increase in intrinsic motivation (P < 0.01). Parental support led to an increase on external motivation (P < 0.05), which buffered the effects of the intervention. This school-based intervention promoted the development of social support and motivational mechanisms that explained higher levels of PA and QoL. PMID- 25274723 TI - Personal and environmental predictors of the intention to use maternal healthcare services in Kalomo, Zambia. AB - Low maternal healthcare service utilization contributes to poor maternal and new born health outcomes in rural Zambia. The purpose of this study was to identify important factors influencing women's intention to use these services in Kalomo, Zambia. An interviewer-administered questionnaire was used to collect data from 1007 women of reproductive age (15-45 years) from 13 rural health centres with the lowest service utilization rates in the district. Questions included measures of (past) healthcare seeking behaviour, psychosocial variables (attitude, perceived social norms, perceived behavioural control), logistical barriers (e.g., distance to the clinic) and sociodemographic variables (e.g., age, income and education level). Overall, our findings showed that most respondents had high intention to use healthcare services. Intention was positively associated with attitude, personal norms, behavioural control, education and income levels. Conversely, intention was negatively related to perceived social norms, age and distance. Multivariate regression analysis showed that, together, these variables accounted for 41.8% of the variance in intention, with perceived behavioural control being the strongest predictor of intention, followed by geographical distance and perceived social norms. These findings suggest that public health programmes mitigating these important factors are likely to motivate pregnant women to use maternal healthcare services. PMID- 25274724 TI - TRF2 and the evolution of the bilateria. AB - The development of a complex body plan requires a diversity of regulatory networks. Here we consider the concept of TATA-box-binding protein (TBP) family proteins as "system factors" that each supports a distinct set of transcriptional programs. For instance, TBP activates TATA-box-dependent core promoters, whereas TBP-related factor 2 (TRF2) activates TATA-less core promoters that are dependent on a TCT or downstream core promoter element (DPE) motif. These findings led us to investigate the evolution of TRF2. TBP occurs in Archaea and eukaryotes, but TRF2 evolved prior to the emergence of the bilateria and subsequent to the evolutionary split between bilaterians and nonbilaterian animals. Unlike TBP, TRF2 does not bind to the TATA box and could thus function as a new system factor that is largely independent of TBP. We postulate that this TRF2-based system served as the foundation for new transcriptional programs, such as those involved in triploblasty and body plan development, that facilitated the evolution of bilateria. PMID- 25274725 TI - Network dynamics determine the autocrine and paracrine signaling functions of TNF. AB - A hallmark of the inflammatory response to pathogen exposure is the production of tumor necrosis factor (TNF) that coordinates innate and adaptive immune responses by functioning in an autocrine or paracrine manner. Numerous molecular mechanisms contributing to TNF production have been identified, but how they function together in macrophages remains unclear. Here, we pursued an iterative systems biology approach to develop a quantitative understanding of the regulatory modules that control TNF mRNA synthesis and processing, mRNA half-life and translation, and protein processing and secretion. By linking the resulting model of TNF production to models of the TLR-, the TNFR-, and the NFkappaB signaling modules, we were able to study TNF's functions during the inflammatory response to diverse TLR agonists. Contrary to expectation, we predicted and then experimentally confirmed that in response to lipopolysaccaride, TNF does not have an autocrine function in amplifying the NFkappaB response, although it plays a potent paracrine role in neighboring cells. However, in response to CpG DNA, autocrine TNF extends the duration of NFkappaB activity and shapes CpG-induced gene expression programs. Our systems biology approach revealed that network dynamics of MyD88 and TRIF signaling and of cytokine production and response govern the stimulus-specific autocrine and paracrine functions of TNF. PMID- 25274726 TI - Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix. AB - During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg-Gly-Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function. PMID- 25274727 TI - Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation. AB - The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ~ 2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as "regulons" to enable spatially proximal genes to be coordinately transcribed in response to hormones. PMID- 25274728 TI - The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. AB - The mammalian lymphatic vasculature is important for returning fluids from the extracellular tissue milieu back to the blood circulation. We showed previously that Prox1 dosage is important for the development of the mammalian lymphatic vasculature. The lack of Prox1 activity results in the complete absence of lymphatic endothelial cells (LECs). In Prox1 heterozygous embryos, the number of LECs is reduced because of a decrease in the progenitor pool in the cardinal vein. This reduction is caused by some progenitor cells being unable to maintain Prox1 expression. In this study, we identified Vegfr3, the cognate receptor of the lymphangiogenic growth factor Vegfc, as a dosage-dependent, direct in vivo target of Prox1. Using various mouse models, we also determined that Vegfr3 regulates Prox1 by establishing a feedback loop necessary to maintain the identity of LEC progenitors and that Vegfc-mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors. We propose that this feedback loop is the main sensing mechanism controlling the number of LEC progenitors and, as a consequence, the number of budding LECs that will form the embryonic lymphatic vasculature. PMID- 25274730 TI - A dsRNA-binding protein of a complex invertebrate DNA virus suppresses the Drosophila RNAi response. AB - Invertebrate RNA viruses are targets of the host RNA interference (RNAi) pathway, which limits virus infection by degrading viral RNA substrates. Several insect RNA viruses encode suppressor proteins to counteract this antiviral response. We recently demonstrated that the dsDNA virus Invertebrate iridescent virus 6 (IIV 6) induces an RNAi response in Drosophila. Here, we show that RNAi is suppressed in IIV-6-infected cells and we mapped RNAi suppressor activity to the viral protein 340R. Using biochemical assays, we reveal that 340R binds long dsRNA and prevents Dicer-2-mediated processing of long dsRNA into small interfering RNAs (siRNAs). We demonstrate that 340R additionally binds siRNAs and inhibits siRNA loading into the RNA-induced silencing complex. Finally, we show that 340R is able to rescue a Flock House virus replicon that lacks its viral suppressor of RNAi. Together, our findings indicate that, in analogy to RNA viruses, DNA viruses antagonize the antiviral RNAi response. PMID- 25274731 TI - Highly potent dUTPase inhibition by a bacterial repressor protein reveals a novel mechanism for gene expression control. AB - Transfer of phage-related pathogenicity islands of Staphylococcus aureus (SaPI-s) was recently reported to be activated by helper phage dUTPases. This is a novel function for dUTPases otherwise involved in preservation of genomic integrity by sanitizing the dNTP pool. Here we investigated the molecular mechanism of the dUTPase-induced gene expression control using direct techniques. The expression of SaPI transfer initiating proteins is repressed by proteins called Stl. We found that Phi11 helper phage dUTPase eliminates SaPIbov1 Stl binding to its cognate DNA by binding tightly to Stl protein. We also show that dUTPase enzymatic activity is strongly inhibited in the dUTPase:Stl complex and that the dUTPase:dUTP complex is inaccessible to the Stl repressor. Our results disprove the previously proposed G-protein-like mechanism of SaPI transfer activation. We propose that the transfer only occurs if dUTP is cleared from the nucleotide pool, a condition promoting genomic stability of the virulence elements. PMID- 25274732 TI - A biomechanical mechanism for initiating DNA packaging. AB - The bacterial chromosome is under varying levels of mechanical stress due to a high degree of crowding and dynamic protein-DNA interactions experienced within the nucleoid. DNA tension is difficult to measure in cells and its functional significance remains unclear although in vitro experiments have implicated a range of biomechanical phenomena. Using single-molecule tools, we have uncovered a novel protein-DNA interaction that responds to fluctuations in mechanical tension by condensing DNA. We combined tethered particle motion (TPM) and optical tweezers experiments to probe the effects of tension on DNA in the presence of the Hha/H-NS complex. The nucleoid structuring protein H-NS is a key regulator of DNA condensation and gene expression in enterobacteria and its activity in vivo is affected by the accessory factor Hha. We find that tension, induced by optical tweezers, causes the rapid compaction of DNA in the presence of the Hha/H-NS complex, but not in the presence of H-NS alone. Our results imply that H-NS requires Hha to condense bacterial DNA and that this condensation could be triggered by the level of mechanical tension experienced along different regions of the chromosome. PMID- 25274733 TI - Telomere stability and development of ctc1 mutants are rescued by inhibition of EJ recombination pathways in a telomerase-dependent manner. AB - The telomeres of linear eukaryotic chromosomes are protected by caps consisting of evolutionarily conserved nucleoprotein complexes. Telomere dysfunction leads to recombination of chromosome ends and this can result in fusions which initiate chromosomal breakage-fusion-bridge cycles, causing genomic instability and potentially cell death or cancer. We hypothesize that in the absence of the recombination pathways implicated in these fusions, deprotected chromosome ends will instead be eroded by nucleases, also leading to the loss of genes and cell death. In this work, we set out to specifically test this hypothesis in the plant, Arabidopsis. Telomere protection in Arabidopsis implicates KU and CST and their absence leads to chromosome fusions, severe genomic instability and dramatic developmental defects. We have analysed the involvement of end-joining recombination pathways in telomere fusions and the consequences of this on genomic instability and growth. Strikingly, the absence of the multiple end joining pathways eliminates chromosome fusion and restores normal growth and development to cst ku80 mutant plants. It is thus the chromosomal fusions, per se, which are the underlying cause of the severe developmental defects. This rescue is mediated by telomerase-dependent telomere extension, revealing a competition between telomerase and end-joining recombination proteins for access to deprotected telomeres. PMID- 25274734 TI - Protein-responsive ribozyme switches in eukaryotic cells. AB - Genetic devices that directly detect and respond to intracellular concentrations of proteins are important synthetic biology tools, supporting the design of biological systems that target, respond to or alter specific cellular states. Here, we develop ribozyme-based devices that respond to protein ligands in two eukaryotic hosts, yeast and mammalian cells, to regulate the expression of a gene of interest. Our devices allow for both gene-ON and gene-OFF response upon sensing the protein ligand. As part of our design process, we describe an in vitro characterization pipeline for prescreening device designs to identify promising candidates for in vivo testing. The in vivo gene-regulatory activities in the two types of eukaryotic cells correlate with in vitro cleavage activities determined at different physiologically relevant magnesium concentrations. Finally, localization studies with the ligand demonstrate that ribozyme switches respond to ligands present in the nucleus and/or cytoplasm, providing new insight into their mechanism of action. By extending the sensing capabilities of this important class of gene-regulatory device, our work supports the implementation of ribozyme-based devices in applications requiring the detection of protein biomarkers. PMID- 25274735 TI - Ribosome-controlled transcription termination is essential for the production of antibiotic microcin C. AB - Microcin C (McC) is a peptide-nucleotide antibiotic produced by Escherichia coli cells harboring a plasmid-borne operon mccABCDE. The heptapeptide MccA is converted into McC by adenylation catalyzed by the MccB enzyme. Since MccA is a substrate for MccB, a mechanism that regulates the MccA/MccB ratio likely exists. Here, we show that transcription from a promoter located upstream of mccA directs the synthesis of two transcripts: a short highly abundant transcript containing the mccA ORF and a longer minor transcript containing mccA and downstream ORFs. The short transcript is generated when RNA polymerase terminates transcription at an intrinsic terminator located in the intergenic region between the mccA and mccB genes. The function of this terminator is strongly attenuated by upstream mcc sequences. Attenuation is relieved and transcription termination is induced when ribosome binds to the mccA ORF. Ribosome binding also makes the mccA RNA exceptionally stable. Together, these two effects-ribosome-induced transcription termination and stabilization of the message-account for very high abundance of the mccA transcript that is essential for McC production. The general scheme appears to be evolutionary conserved as ribosome-induced transcription termination also occurs in a homologous operon from Helicobacter pylori. PMID- 25274736 TI - ViRBase: a resource for virus-host ncRNA-associated interactions. AB - Increasing evidence reveals that diverse non-coding RNAs (ncRNAs) play critically important roles in viral infection. Viruses can use diverse ncRNAs to manipulate both cellular and viral gene expression to establish a host environment conducive to the completion of the viral life cycle. Many host cellular ncRNAs can also directly or indirectly influence viral replication and even target virus genomes. ViRBase (http://www.rna-society.org/virbase) aims to provide the scientific community with a resource for efficient browsing and visualization of virus-host ncRNA-associated interactions and interaction networks in viral infection. The current version of ViRBase documents more than 12,000 viral and cellular ncRNA associated virus-virus, virus-host, host-virus and host-host interactions involving more than 460 non-redundant ncRNAs and 4400 protein-coding genes from between more than 60 viruses and 20 hosts. Users can query, browse and manipulate these virus-host ncRNA-associated interactions. ViRBase will be of help in uncovering the generic organizing principles of cellular virus-host ncRNA associated interaction networks in viral infection. PMID- 25274737 TI - RiceVarMap: a comprehensive database of rice genomic variations. AB - Rice Variation Map (RiceVarMap, http:/ricevarmap.ncpgr.cn) is a database of rice genomic variations. The database provides comprehensive information of 6,551,358 single nucleotide polymorphisms (SNPs) and 1,214,627 insertions/deletions (INDELs) identified from sequencing data of 1479 rice accessions. The SNP genotypes of all accessions were imputed and evaluated, resulting in an overall missing data rate of 0.42% and an estimated accuracy greater than 99%. The SNP/INDEL genotypes of all accessions are available for online query and download. Users can search SNPs/INDELs by identifiers of the SNPs/INDELs, genomic regions, gene identifiers and keywords of gene annotation. Allele frequencies within various subpopulations and the effects of the variation that may alter the protein sequence of a gene are also listed for each SNP/INDEL. The database also provides geographical details and phenotype images for various rice accessions. In particular, the database provides tools to construct haplotype networks and design PCR-primers by taking into account surrounding known genomic variations. These data and tools are highly useful for exploring genetic variations and evolution studies of rice and other species. PMID- 25274739 TI - The non-canonical hydroxylase structure of YfcM reveals a metal ion-coordination motif required for EF-P hydroxylation. AB - EF-P is a bacterial tRNA-mimic protein, which accelerates the ribosome-catalyzed polymerization of poly-prolines. In Escherichia coli, EF-P is post translationally modified on a conserved lysine residue. The post-translational modification is performed in a two-step reaction involving the addition of a beta lysine moiety and the subsequent hydroxylation, catalyzed by PoxA and YfcM, respectively. The beta-lysine moiety was previously shown to enhance the rate of poly-proline synthesis, but the role of the hydroxylation is poorly understood. We solved the crystal structure of YfcM and performed functional analyses to determine the hydroxylation mechanism. In addition, YfcM appears to be structurally distinct from any other hydroxylase structures reported so far. The structure of YfcM is similar to that of the ribonuclease YbeY, even though they do not share sequence homology. Furthermore, YfcM has a metal ion-coordinating motif, similar to YbeY. The metal ion-coordinating motif of YfcM resembles a 2 His-1-carboxylate motif, which coordinates an Fe(II) ion and forms the catalytic site of non-heme iron enzymes. Our findings showed that the metal ion coordinating motif of YfcM plays an essential role in the hydroxylation of the beta-lysylated lysine residue of EF-P. Taken together, our results suggested the potential catalytic mechanism of hydroxylation by YfcM. PMID- 25274738 TI - THOC5 controls 3'end-processing of immediate early genes via interaction with polyadenylation specific factor 100 (CPSF100). AB - Transcription of immediate early genes (IEGs) in response to extrinsic and intrinsic signals is tightly regulated at multiple stages. It is known that untranslated regions of the RNA can play a role in these processes. Here we show that THOC5, a member of the TREX (transcription/export) complex, plays a role in expression of only a subset of constitutively active genes, however transcriptome analysis reveals that more than 90% of IEG were not induced by serum in THOC5 depleted cells. Furthermore, THOC5 depletion does not influence the expression of the most rapidly induced IEGs, e.g. Fos and Jun. One group of THOC5 target genes, including Id1, Id3 and Wnt11 transcripts, were not released from chromatin in THOC5 depleted cells. Genes in another group, including Myc and Smad7 transcripts, were released with shortening of 3'UTR by alternative cleavage, and were spliced but export was impaired in THOC5 depleted cells. By interactome analysis using THOC5 as bait, we show that upon stimulation with serum THOC5 forms a complex with polyadenylation-specific factor 100 (CPSF100). THOC5 is required for recruitment of CPSF100 to 3'UTR of THOC5 target genes. These data suggest the presence of a novel mechanism for the control of IEG response by THOC5 via 3'end-processing. PMID- 25274741 TI - Cholecystic adenocarcinoma and pancreatic insulinomas in a goat. AB - A 13-year-old female Boer goat with a history of chronic arthritis and recurrent episodes of recumbency, increased serum gamma-glutamyl transferase, and complete inability to stand was submitted for necropsy. Gross changes included the presence of a white, firm, smooth, 6 cm * 4 cm * 3 cm mass that diffusely expanded and partially effaced the gall bladder and infiltrated the adjacent hepatic parenchyma. On cut surface, the mass was pale yellow and had small, irregular, dark yellow areas. Scattered through the pancreas were 2 gray, well demarcated, soft, homogeneous, 1 cm in diameter nodules that bulged out from the capsular surface. The right femoral head had a locally extensive area of cartilage erosion. Histological and immunohistochemical evaluation of the gall bladder and pancreatic nodules revealed a primary cholecystic adenocarcinoma and multifocal insulinomas, respectively. A metastatic focus from the gall bladder neoplasm was observed infiltrating the right adrenal gland medulla. The goat also had mild pulmonary infestation by Muellerius capillaris. Primary hepatobiliary and pancreatic neoplasia is rare in goats, and to the authors' knowledge, neither cholecystic adenocarcinoma nor pancreatic insulinomas have been previously reported in this species. PMID- 25274740 TI - Capping of vesicular stomatitis virus pre-mRNA is required for accurate selection of transcription stop-start sites and virus propagation. AB - The multifunctional RNA-dependent RNA polymerase L protein of vesicular stomatitis virus catalyzes unconventional pre-mRNA capping via the covalent enzyme-pRNA intermediate formation, which requires the histidine-arginine (HR) motif in the polyribonucleotidyltransferase domain. Here, the effects of cap defective mutations in the HR motif on transcription were analyzed using an in vitro reconstituted transcription system. The wild-type L protein synthesized the leader RNA from the 3'-end of the genome followed by 5'-capped and 3' polyadenylated mRNAs from internal genes by a stop-start transcription mechanism. Cap-defective mutants efficiently produced the leader RNA, but displayed aberrant stop-start transcription using cryptic termination and initiation signals within the first gene, resulting in sequential generation of ~40-nucleotide transcripts with 5'-ATP from a correct mRNA-start site followed by a 28-nucleotide transcript and long 3'-polyadenylated transcript initiated with non-canonical GTP from atypical start sites. Frequent transcription termination and re-initiation within the first gene significantly attenuated the production of downstream mRNAs. Consistent with the inability of these mutants in in vitro mRNA synthesis and capping, these mutations were lethal to virus replication in cultured cells. These findings indicate that viral mRNA capping is required for accurate stop start transcription as well as mRNA stability and translation and, therefore, for virus replication in host cells. PMID- 25274742 TI - Flavobacterium columnare: an important contributing factor to fish die-offs in southern lakes of Saskatchewan, Canada. AB - During June and July 2012, Buffalo Pound Lake and Blackstrap Lake in Saskatchewan, Canada were visited biweekly and surveyed for sick and dying fish. During this investigation, 2 fish kills were identified. Buffalo Pound experienced a large die-off of yellow perch (Perca flavascens) in June, while Blackstrap experienced a die-off of lake whitefish (Coregonus clupeaformis) in July. In excess of 50 fish were examined for gross lesions at each lake, and dead and moribund fish consistently had 1 or more of the following lesions: multifocal petechial cutaneous hemorrhage, skin ulceration, or branchial necrosis. Of these, 17 fish were collected for necropsy, and major tissues were submitted for histology. Aerobic bacterial culture was performed on 16 out of 17 fish. In 7 out of 8 (88%) yellow perch, the body wall had multiple areas of pale discoloration that corresponded to erosion and ulceration of the skin. Seven out of 8 (88%) whitefish had severe necrotizing branchiitis, and 8 out of 8 (100%) had severe epicardial parasitism, consistent with Ichthyocotylurus erraticus. Wet mounts of skin and gill lesions demonstrated filamentous bacteria with gliding motility, which often formed haystack-like arrangements. Flavobacterium columnare and Aeromonas hydrophila were cultured from skin and gill lesions of all fish. Based on the characteristic appearance and distribution of lesions, mortality was attributed to columnaris disease with secondary infection with A. hydrophila. The current study demonstrates that columnaris disease is an important contributor to fish kills in southern Saskatchewan lakes. However, further research is needed to determine what role environmental factors play in outbreaks of columnaris disease in prairie lakes. PMID- 25274743 TI - Retrospective study of central nervous system lesions and association with Parelaphostrongylus species by histology and specific nested polymerase chain reaction in domestic camelids and wild ungulates. AB - Formalin-fixed, paraffin-embedded tissues from elk (Cervus elaphus), goats, and camelids with case histories and lesions suggestive of Parelaphostrongylus tenuis were examined by histology to characterize lesions that could aid in definitively diagnosing P. tenuis infection. Additionally, sections of paraffin-embedded tissue were used in a nested polymerase chain reaction (nPCR) using Parelaphostrongylus-specific primers to determine how PCR results corresponded with histological findings. Histological changes in brain and spinal cord consisted of linear tracks of hemorrhage; tracks or perivascular accumulations of hemosiderin-laden macrophages; acute foci of axonal degeneration and/or linear glial scars; and perivascular, parenchymal, or meningeal accumulations of eosinophils and/or lymphocytes and plasma cells. Of the 43 samples with histologic lesions consistent with neural larval migrans, 19 were PCR positive; however, only 8 were confirmed Parelaphostrongylus by DNA sequencing. Additionally, 1 goat was identified with a protostrongylid that had a 97% identity to both Parelaphostrongylus odocoilei and a protostrongylid nematode from pampas deer (Ozotoceros bezoarticus celer) from Argentina. None of the histologic lesions individually or in combination correlated statistically to positive molecular tests for the nematode. The results indicate that it is possible to extract Parelaphostrongylus DNA from formalin-fixed, paraffin embedded tissue, but extended fixation presumably can cause DNA crosslinking. Nested PCR provides another diagnostic tool to identify the cause of neurologic disease in camelids and elk with histologic lesions consistent with neural larval migrans. Furthermore, potential novel protostrongylid DNA was detected from a goat with lesions consistent with P. tenuis infection, suggesting that other neurotropic Parelaphostrongylus species may occur locally. PMID- 25274744 TI - Outbreaks of Vesicular stomatitis Alagoas virus in horses and cattle in northeastern Brazil. AB - The current article describes outbreaks of vesicular stomatitis (VS) in horses and cattle in Paraiba and Rio Grande do Norte states, northeastern Brazil, between June and August 2013. The reported cases affected 15-20 horses and 6 cattle distributed over 6 small farms in 4 municipalities, but additional data indicated the involvement of a large number of animals on several farms. The disease was characterized by blisters; eruptive lesions in coronary bands, lips, mouth, and muzzle; salivation; claudication and loss of condition. Swollen lower limbs and lips, and ulcerated and erosive areas in the lips and muzzle were observed in some horses. A necrotizing vesiculopustular dermatitis and stomatitis was observed histologically. Vesicular stomatitis virus was isolated from the vesicular fluid of a horse lesion and shown to be serologically related to the VS Indiana serogroup (VSIV) by virus neutralization. Convalescent sera of affected horses and cattle, and from healthy contacts, harbored high levels of neutralizing antibodies against the isolated virus (named VSIV-3 2013SaoBento/ParaibaE). Genomic sequences of VSIV subtype 3 (Vesicular stomatitis Alagoas virus) were amplified by reverse transcription polymerase chain reaction out of clinical specimens from a cow and a horse from different farms. Nucleotide sequencing and phylogenetic analysis of the phosphoprotein gene indicated that the 2 isolates were derived from the same virus and clustered them in VSIV-3, along with VS viruses identified in southeastern and northeastern Brazil in the last decades. Thus, the present report demonstrates the circulation of VSIV-3 in northeastern Brazil and urges for more effective diagnosis and surveillance. PMID- 25274745 TI - Diagnostic features in 10 naturally occurring cases of acute fatal canine leptospirosis. AB - The current report describes the diagnostic features in 10 cases of acute fatal canine leptospirosis with minimal renal and hepatic changes that may present a diagnostic challenge for the pathologist. Most affected dogs were less than 6 months of age and had a biochemical profile consistent with hepatorenal dysfunction. Clinical signs consisted of vomiting, depression, icterus, dehydration, diarrhea, and anorexia. All dogs died or were humanely euthanized within 3-7 days after the onset of clinical disease. Necropsy findings included pulmonary edema with hemorrhages, icterus, renal and hepatic pallor and swelling, and gastric edema with hemorrhage. Despite severe azotemia, histological changes in the kidneys were subtle in all dogs, and included mild renal tubular simplification, with single-cell necrosis and attenuation, along with minimal interstitial lymphoplasmacytic inflammation, edema, and hemorrhage. Hepatic lesions included scattered hepatocellular single-cell necrosis and hepatocellular dissociation. Prominent extrarenal lesions typically associated with uremia including vascular fibrinoid necrosis in multiple organs, pulmonary mineralization with occasional fibrinosuppurative exudation, and gastric mineralization were also present. Postmortem diagnostic confirmation was based on the detection of leptospiral antigen on fresh renal samples by fluorescent antibody test and on the demonstration of intact spirochetes in sections of kidneys using immunohistochemical staining. Acute fatal canine leptospirosis occurred as a fulminant hepatorenal disease affecting mainly young dogs, and the diagnosis was dependent on the recognition of the subtle renal changes with confirmation via fluorescent antibody testing or immunohistochemical staining. PMID- 25274746 TI - Validation of the Inventory of Callous-Unemotional Traits Among a Portuguese Sample of Detained Juvenile Offenders. AB - The main aim of the present study was to examine the psychometric properties of the Inventory of Callous-Unemotional Traits (ICU) among a sample of incarcerated male Portuguese juvenile offenders (N = 221). Based on this sample, the Portuguese version of the ICU demonstrated promising psychometric properties, namely, in terms of factor structure, internal consistency, convergent validity, discriminant validity, and concurrent validity that generally justifies its use among this population. Statistically significant associations were found with conduct disorder, age of criminal onset, crime seriousness, physical violence use in committing crimes, alcohol use, cannabis use, and cocaine/heroin use. PMID- 25274747 TI - Couples Counseling for Aboriginal Clients Following Intimate Partner Violence: Service Providers' Perceptions of Risk. AB - Interventions for family violence in Aboriginal communities should take a culture based approach and focus on healing for the whole family. The purpose of this research was to identify risk issues from the perspective of service providers for couples counseling with Aboriginal clients following intimate partner violence. A total of 25 service providers participated in over the phone interviews concerning risk with Aboriginal men in couple counseling. Five concepts emerged including (a) collaterals, (b) commitment to change, (c) violence, (d) mind-set, and (e) mental health. It was concluded that culturally competent interventions should involve the entire community and have a restorative approach. The concepts were compared and contrasted with the available literature. PMID- 25274749 TI - Descending controls: how to harness for the relief of pain? PMID- 25274748 TI - Predictors of response and relapse in patients with idiopathic membranous nephropathy treated with tacrolimus. AB - BACKGROUND: Although tacrolimus is recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of idiopathic membranous nephropathy (MN), little is known about factors that influence response and relapse of the disease after tacrolimus therapy. METHODS: Multicentre study that collected 122 MN patients with nephrotic syndrome and stable renal function treated with tacrolimus. Duration of treatment was 17.6 +/- 7.2 months, including a full-dose and a tapering period. RESULTS: The percentage of remission was 60, 78 and 84% after 6, 12 and 18 months of treatment, respectively. The amount of proteinuria at baseline significantly predicted remission, the lower the baseline proteinuria the higher the probability of remission. Only 10 patients (8%) received concomitantly corticosteroids, and their rate of remission was similar (80% at 18 months). Among responders, 42% achieved complete remission (CR) and 58% partial remission (PR). Almost half (44%) of the responder patients relapsed. The amount of proteinuria at the onset of tacrolimus tapering was significantly higher in relapsing patients. By multivariable analysis, the presence of a PR versus CR at the onset of tacrolimus tapering and a shorter duration of the tapering period significantly predicted relapses. Tolerance was good and the number of adverse events low. CONCLUSIONS: Tacrolimus monotherapy is an effective and safe option for the treatment of MN with stable renal function. Relapses are frequent in patients with PR and can be partially prevented by a longer tapering period. PMID- 25274750 TI - Synaptic properties and functional consequences of cholinergic signalling in the mammalian CNS. PMID- 25274751 TI - Emerging ceramic-based materials for dentistry. AB - Our goal is to give an overview of a selection of emerging ceramics and issues for dental or biomedical applications, with emphasis on specific challenges associated with full-contour zirconia ceramics, and a brief synopsis on new machinable glass-ceramics and ceramic-based interpenetrating phase composites. Selected fabrication techniques relevant to dental or biomedical applications such as microwave sintering, spark plasma sintering, and additive manufacturing are also reviewed. Where appropriate, the authors have added their opinions and guidance. PMID- 25274753 TI - Clinical trial registration in oral health journals. AB - Prospective registration of randomized controlled trials (RCTs) represents the best solution to reporting bias. The extent to which oral health journals have endorsed and complied with RCT registration is unknown. We identified journals publishing RCTs in dentistry, oral surgery, and medicine in the Journal Citation Reports. We classified journals into 3 groups: journals requiring or recommending trial registration, journals referring indirectly to registration, and journals providing no reference to registration. For the 5 journals with the highest 2012 impact factors in each group, we assessed whether RCTs with results published in 2013 had been registered. Of 78 journals examined, 32 (41%) required or recommended trial registration, 19 (24%) referred indirectly to registration, and 27 (35%) provided no reference to registration. We identified 317 RCTs with results published in the 15 selected journals in 2013. Overall, 73 (23%) were registered in a trial registry. Among those, 91% were registered retrospectively and 32% did not report trial registration in the published article. The proportion of trials registered was not significantly associated with editorial policies: 29% with results in journals that required or recommended registration, 15% in those that referred indirectly to registration, and 21% in those providing no reference to registration (P = 0.05). Less than one-quarter of RCTs with results published in a sample of oral health journals were registered with a public registry. Improvements are needed with respect to how journals inform and require their authors to register their trials. PMID- 25274752 TI - CCL7 is a protective factor secreted by mechanically loaded osteocytes. AB - In a search for factors up-regulated by mechanical strain in osteocytes, we discovered that chemokine (C-C motif) ligand 7 (CCL7), a chemotactic myokine, was highly expressed in MLO-Y4 osteocyte-like cells. Although MLO-Y4 cells secrete potent chemotactic factors for osteoclast precursors, CCL7 was not responsible for this activity. CCL7 was increased in osteocytes in response to tooth movement in vivo. Since mechanical loading plays a crucial role in maintaining osteocyte viability, CCL7 was tested for protective activity and found to be protective against cell death induced by dexamethasone and etoposide. CCL7 specific antibody partially, but in combination with indomethacin, completely abrogated the protective effects of fluid flow shear stress against dexamethasone-induced cell death. CCL7 activated the beta-catenin pathway through phosphorylation of glycogen synthase kinase 3 (GSK-3), suggesting that this pathway is responsible for the observed protective effects. A related cytokine, CCL2, also produced by MLO-Y4 cells but not regulated by mechanical loading, proved to be more potent and protected against cell death induced by not only dexamethasone, but also by Tumor Necrosis Factor alpha (TNFalpha). Whereas osteocytes may produce CCL2 in constitutively low levels, a major function of mechanically induced CCL7 may be to selectively protect osteocytes in an autocrine manner against glucocorticoid induced cell death. PMID- 25274754 TI - Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders. AB - Study of monogenic congenital heart disease (CHD) has provided entry points to gain new understanding of heart development and the molecular pathogenesis of CHD. In this review, we discuss monogenic CHD caused by mutations of the cardiac transcription factor genes NKX2-5 and GATA4. Detailed investigation of these genes in mice and humans has expanded our understanding of heart development, shedding light on the complex genetic and environmental factors that influence expression and penetrance of CHD gene mutations. PMID- 25274755 TI - Therapeutic strategies to inhibit MYC. AB - MYC is a master regulator of stem cell state, embryogenesis, tissue homeostasis, and aging. As in health, in disease MYC figures prominently. Decades of biological research have identified a central role for MYC in the pathophysiology of cancer, inflammation, and heart disease. The centrality of MYC to such a vast breadth of disease biology has attracted significant attention to the historic challenge of developing inhibitors of MYC. This review will discuss therapeutic strategies toward the development of inhibitors of MYC-dependent transcriptional signaling, efforts to modulate MYC stability, and the elusive goal of developing potent, direct-acting inhibitors of MYC. PMID- 25274757 TI - Heart fields and cardiac morphogenesis. AB - In this review, we focus on two important steps in the formation of the embryonic heart: (i) the progressive addition of late differentiating progenitor cells from the second heart field that drives heart tube extension during looping morphogenesis, and (ii) the emergence of patterned proliferation within the embryonic myocardium that generates distinct cardiac chambers. During the transition between these steps, the major site of proliferation switches from progenitor cells outside the early heart to proliferation within the embryonic myocardium. The second heart field and ballooning morphogenesis concepts have major repercussions on our understanding of human heart development and disease. In particular, they provide a framework to dissect the origin of congenital heart defects and the regulation of myocardial proliferation and differentiation of relevance for cardiac repair. PMID- 25274760 TI - A case of plagiarism: lessons for editors, authors, reviewers, readers, and plagiarists. PMID- 25274761 TI - Chlorhexidine gluconate bathing to reduce methicillin-resistant Staphylococcus aureus acquisition. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a virulent organism causing substantial morbidity and mortality in intensive care units. Chlorhexidine gluconate, a topical antiseptic solution, is effective against a wide spectrum of gram-positive and gram-negative bacteria, including MRSA. Objectives To examine the impact of a bathing protocol using chlorhexidine gluconate and bath basin management on MRSA acquisition in 5 adult intensive care units and to examine the cost differences between chlorhexidine bathing by using the bath-basin method versus using prepackaged chlorhexidine-impregnated washcloths. METHODS: The protocol used a 4-oz bottle of 4% chlorhexidine gluconate soap in a bath basin of warm water. Patients in 3 intensive care units underwent active surveillance for MRSA acquisition; patients in 2 other units were monitored for a new positive culture for MRSA at any site 48 hours after admission. RESULTS: Before the protocol, 132 patients acquired MRSA in 34333 patient days (rate ratio, 3.84). Afterwards, 109 patients acquired MRSA in 41376 patient days (rate ratio, 2.63). The rate ratio difference is 1.46 (95% CI, 1.12 1.90; P = .003). The chlorhexidine soap and bath basin method cost $3.18 as compared with $5.52 for chlorhexidine-impregnated wipes (74% higher). CONCLUSIONS: The chlorhexidine bathing protocol is easy to implement, cost effective, and led to decreased unit-acquired MRSA rates in a variety of adult intensive care units. PMID- 25274756 TI - The genetics of human skin disease. AB - The skin is composed of a variety of cell types expressing specific molecules and possessing different properties that facilitate the complex interactions and intercellular communication essential for maintaining the structural integrity of the skin. Importantly, a single mutation in one of these molecules can disrupt the entire organization and function of these essential networks, leading to cell separation, blistering, and other striking phenotypes observed in inherited skin diseases. Over the past several decades, the genetic basis of many monogenic skin diseases has been elucidated using classical genetic techniques. Importantly, the findings from these studies has shed light onto the many classes of molecules and essential genetic as well as molecular interactions that lend the skin its rigid, yet flexible properties. With the advent of the human genome project, next generation sequencing techniques, as well as several other recently developed methods, tremendous progress has been made in dissecting the genetic architecture of complex, non-Mendelian skin diseases. PMID- 25274762 TI - Activated partial thromboplastin times from venipuncture versus central venous catheter specimens in adults receiving continuous heparin infusions. AB - BACKGROUND: In patients receiving heparin infusions, variations in specimen collection technique may contribute to inaccurate measurements of activated partial thromboplastin time (aPTT). OBJECTIVES: To determine if there is a difference in aPTT results between specimens collected from a central venous access device (CVAD) compared with venipuncture in patients receiving heparin infusions. METHODS: Simultaneous blood samples (CVAD vs venipuncture) from 66 patients receiving continuous heparin infusions were compared. RESULTS: The mean aPTT difference (peripheral aPTT minus CVAD aPTT) was -7.3 seconds (P=.07). Neither length of time heparin was turned off (P=.18) nor waste volume (P=.32) was significantly associated with the difference in aPTT. The median aPTT difference when the CVAD specimen was obtained from the heparin infusion port was -20.5 seconds, compared with -0.1, -3.0, and -0.2 seconds for specimens from a port proximal to, distal to, or coterminal with the heparin infusion, respectively (P=.008). CONCLUSIONS: Use of this protocol resulted in similar aPTTs when the CVAD specimen was not obtained from the heparin infusion port. However, obtaining the specimen from the heparin infusion port resulted in significantly higher aPTT values. PMID- 25274763 TI - Carbapenem-resistant enterobacteriaceae: occult threat in the intensive care unit. AB - Carbapenem-resistant Enterobacteriaceae are a group of virulent, drug-resistant gram-negative bacteria that are increasingly the cause of infection. Such infections are associated with a high morbidity and mortality and increased health care costs. Management of these infections requires recognition of patients at risk for multidrug-resistant microbial colonization and infections, identification of the causative organism, and rapid, appropriate treatment. Lack of awareness of proper isolation of patients harboring these organisms and delay in prescribing antibiotics such as tigecycline and polymyxins contribute to the spread of infection in intensive care units. Surveillance and infection control measures are paramount in preventing outbreaks of infection caused by carbapenem resistant Enterobacteriaceae. Critical care nurses are in a vital position to monitor patients at risk for such infections and to promote infection prevention measures. PMID- 25274758 TI - Fungal biofilms, drug resistance, and recurrent infection. AB - A biofilm is a surface-associated microbial community. Diverse fungi are capable of biofilm growth. The significance of this growth form for infection biology is that biofilm formation on implanted devices is a major cause of recurrent infection. Biofilms also have limited drug susceptibility, making device associated infection extremely difficult to treat. Biofilm-like growth can occur during many kinds of infection, even when an implanted device is not present. Here we summarize the current understanding of fungal biofilm formation, its genetic control, and the basis for biofilm drug resistance. PMID- 25274764 TI - Closed blood conservation device for reducing catheter-related infections in children after cardiac surgery. AB - BACKGROUND: Arterial catheters are potential sources of nosocomial infection. OBJECTIVE: To investigate use of a closed blood conservation device in preventing catheter-related bloodstream infections in children after cardiac surgery. METHODS: Children with an indwelling arterial catheter after cardiac surgery were randomly assigned to 2 groups: a control group with a conventional 3-way stopcock in the catheter system and an interventional group with the conservation device in the catheter system. Catheter tips, catheter intraluminal fluid, and blood samples obtained from the catheter and peripherally were cultured for microbiological analysis. RESULTS Intraluminal fluid contamination was significantly lower (P = .03) in the interventional group (3 of 147 catheters) than in the control group (10 of 137 catheters). The 2 groups did not differ significantly in the rate of tip colonization (9 of 147 vs 12 of 137; P = .40) or in the number of catheter-related bloodstream infections (0 of 147 vs 2 of 137; P = .21). CONCLUSION: Use of a closed blood conservation device could decrease the incidence of catheter-related contamination of intraluminal fluid. PMID- 25274765 TI - Intravenous lipids: antidotal therapy for drug overdose and toxic effects of local anesthetics. AB - Intravenous lipid emulsion is an accepted therapy for the treatment of severe cardiac toxic effects caused by local anesthetics. Lipid emulsion therapy has also been used successfully to treat cardiac arrest and intractable arrhythmias caused by overdoses of antiepileptic drugs, cardiovascular drugs, and psychotropic medications, but experience with intravenous lipids as antidotal therapy in these clinical situations is limited. However, intravenous lipids are relatively safe, widely available, and easy to administer, and many published case reports document their dramatic effectiveness. Patients who have not responded to standard therapies have been quickly revived by administration of intravenous lipids. Use of lipids most likely will increase, and critical care nurses should be familiar with lipid therapy. PMID- 25274766 TI - Navigating the 7 cs of certified practice. PMID- 25274767 TI - Oxygen and oxygenation. PMID- 25274768 TI - Prevention of falls: applying AACN's healthy work environment standards to a fall campaign. PMID- 25274770 TI - I am a critical care nurse. PMID- 25274771 TI - The pathogenesis of Kirner's deformity: A clinical, radiological and histological study. AB - The distal phalanx in Kirner's disease is abnormal and recognizable both clinically and radiologically. Despite previous investigation, the cause of these abnormalities is not clear. The current study seeks to evaluate the abnormal physis in Kirner's deformity using radiological investigation, intraoperative observation and histopathological assessment in three clinical cases. Similarities with clinodactyly are described. Three patients with Kirner's deformity underwent plain-film radiography and magnetic resonance imaging. Intraoperative observations were recorded, and histologic assessment of anatomically abnormal tissue was performed in all three cases. All three modalities of investigation (plain-film X-rays, magnetic resonance imaging and histological findings) were consistent and supported the intraoperative observation of cartilage abnormally situated anterior to the diaphysis and deep to the flexor tendon. There is thus evidence for the presence of an incomplete volar bracket or L-shaped physis in Kirner's deformity, analogous with the C shaped bracket found in clinodactyly. LEVEL OF EVIDENCE: Aetiological Study; Level 4. PMID- 25274772 TI - Modified anterograde pedicle advancement flap in fingertip injury. AB - Soft tissue reconstruction is needed to maintain the maximum length of the fingers in fingertip injury. The purpose of this study was to present an anterograde pedicle advancement flap technique, for the treatment of fingertip injuries, which involved a modification to the anterograde advancement flap by the dissection of the digital nerve and artery with a pedicle to advance the flap. This technique was used in 12 fingers in patients who had undergone soft tissue reconstruction of fingertip injuries between January 2012 and October 2013. The sizes of the flaps ranged from 8 * 7 mm to 14 * 10 mm. The mean length of advancement was 9.7 mm (range 7-13). The mean value of the static two-point discrimination test of the healed flaps was 5.1 mm (range 4-6) and the flaps survived in all the 12 cases. The modified anterograde pedicle advancement flap provides a reliable coverage of sensate soft tissue without bone shortening in fingertip injuries.Level II. PMID- 25274774 TI - Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. AB - In some neurological diseases caused by repeat expansions such as myotonic dystrophy, the RNA-binding protein muscleblind-like 1 (MBNL1) accumulates in intranuclear inclusions containing mutant repeat RNA. The interaction between MBNL1 and mutant RNA in the nucleus is a key event leading to loss of MBNL function, yet the details of this effect have been elusive. Here, we investigated the mechanism and significance of MBNL1 nuclear localization. We found that MBNL1 contains two classes of nuclear localization signal (NLS), a classical bipartite NLS and a novel conformational NLS. Alternative splicing of exon 7 acts as a switch between these NLS types and couples MBNL1 activity and intracellular localization. Depending on its nuclear localization, MBNL1 promoted nuclear accumulation of mutant RNA containing a CUG or CAG repeat, some of which produced proteins containing homopolymeric tracts such as polyglutamine. Furthermore, MBNL1 repressed the expression of these homopolymeric proteins including those presumably produced through repeat-associated non-ATG (RAN) translation. These results suggest that nuclear retention of expanded RNA reflects a novel role of MBNL proteins in repressing aberrant protein expression and may provide pathological and therapeutic implications for a wide range of repeat expansion diseases associated with nuclear RNA retention and/or RAN translation. PMID- 25274773 TI - Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression. AB - Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that is involved in the regulation of the unfolded protein response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production and regulation of insulin biosynthesis and secretion. In this study, single cell Ca(2+) imaging with fura-2 and direct measurements of free cytosolic ATP concentration ([ATP]CYT) with adenovirally expressed luciferase confirmed a reduced and delayed rise in cytosolic free Ca(2+) concentration ([Ca(2+)]CYT), and additionally, diminished [ATP]CYT rises in response to elevated glucose concentrations in WFS1-depleted MIN6 cells. We also observed that sarco(endo)plasmic reticulum ATPase (SERCA) expression was elevated in several WFS1-depleted cell models and primary islets. We demonstrated a novel interaction between WFS1 and SERCA by co-immunoprecipitation in Cos7 cells and with endogenous proteins in human neuroblastoma cells. This interaction was reduced when cells were treated with the ER stress inducer dithiothreitol. Treatment of WFS1-depleted neuroblastoma cells with the proteasome inhibitor MG132 resulted in reduced accumulation of SERCA levels compared with wild-type cells. Together these results reveal a role for WFS1 in the negative regulation of SERCA and provide further insights into the function of WFS1 in calcium homeostasis. PMID- 25274775 TI - Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing. AB - Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed population doubling and accelerated senescence in Aptx-/- primary mouse fibroblasts, which is not due to detectable telomere instability or cell cycle deregulation but is associated with a reduction in transcription recovery following oxidative stress. Expression of SOD1(G93A) uncovers a survival defect ex vivo in cultured cells and in vivo in tissues lacking Aptx. The surviving neurons feature numerous and deep nuclear envelope invaginations, a hallmark of cellular stress. Furthermore, they possess an elevated number of high-density nuclear regions and a concomitant increase in histone H3 K9 trimethylation, hallmarks of silenced chromatin. Finally, the accelerated cellular senescence was also observed at the organismal level as shown by down-regulation of insulin-like growth factor 1 (IGF-1), a hallmark of premature ageing. Together, this study demonstrates a protective role of Aptx in vivo and suggests that its loss results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of premature ageing, systemically. PMID- 25274776 TI - Fhl1 W122S causes loss of protein function and late-onset mild myopathy. AB - A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice. PMID- 25274778 TI - Attenuation of Wnt/beta-catenin activity reverses enhanced generation of cardiomyocytes and cardiac defects caused by the loss of emerin. AB - Mutations in EMD, encoding emerin cause skeletal muscle and heart defects in patients with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) but the underlying mechanisms leading to cardiac defects are poorly understood. Here, we investigated the role of emerin in controlling cardiomyocyte proliferation and cardiac remodeling and explored its function in regulation of the Wnt/beta catenin pathway. We observed a remarkable increase of cardiomyocytes in emerin null adult mice accompanied with decreased numbers of multinucleated cells. Depletion of emerin in mouse ES cell-derived cardiomyocytes by shRNA caused hyperactivation of Wnt/beta-catenin signaling, increased proliferation and abrogated timely cardiac differentiation. Likewise, emerin-null mice exhibited increased Wnt/beta-catenin signaling, cardiac dysfunction and perturbed hypertrophic remodeling following pressure overload. Pharmacological inhibition of beta-catenin normalized proliferation and differentiation of ES cell-derived cardiomyocytes while inactivation of a single allele of beta-catenin efficiently rescued cardiac dysfunction in emerin-null mice. We conclude that emerin constrains beta-catenin signaling in the heart providing tight control of cardiomyocyte numbers. Enhanced Wnt/beta-catenin signaling seems to contribute to cardiac defects observed in X-EDMD. Hence, therapeutic inhibition of Wnt/beta catenin signaling might be beneficial for X-EDMD patients. PMID- 25274779 TI - CFTR mRNA expression is regulated by an upstream open reading frame and RNA secondary structure in its 5' untranslated region. AB - Post-transcriptional regulation of gene expression through 5' untranslated region (5'UTR)-encoded cis-acting elements is an important mechanism for the control of protein expression levels. Through controlling specific aspects of translation initiation, expression can be tightly regulated while remaining responsive to cellular requirements. With respect to cystic fibrosis (CF), the overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking mutants, such as delta-F508, is of great biological and clinical interest. By understanding the post-transcriptional mechanisms that regulate CFTR expression, new procedures can be developed to enhance CFTR expression in homozygous delta F508 CF patients. We have identified the key elements of a complex negative regulatory mechanism that is encoded within the human CFTR 5'UTR and show how these elements act in combination to restrict CFTR gene expression to a consistently low level in a transcript-specific manner. This study shows, for the first time, that endogenous human CFTR expression is post-transcriptionally regulated through a 5'UTR-mediated mechanism. We show that the very low levels of endogenous CFTR expression, compared with other low expression genes, are maintained through the co-operative inhibitory effects of an upstream open reading frame and a thermodynamically stable RNA secondary structure. PMID- 25274777 TI - Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model. AB - Defects in aryl hydrocarbon receptor interacting protein-like1 (AIPL1) are associated with blinding diseases with a wide range of severity in humans. We examined the mechanism behind autosomal dominant cone-rod dystrophy (adCORD) caused by 12 base pair (bp) deletion at proline 351 of hAIPL1 (P351Delta12) mutation in the primate-specific region of human AIPL1. Mutant P351Delta12 human isoform, aryl hydrocarbon receptor interacting protein-like 1 (hAIPL1) mice demonstrated a CORD phenotype with early defects in cone-mediated vision and subsequent photoreceptor degeneration. A dominant CORD phenotype was observed in double transgenic animals expressing both mutant P351Delta12 and normal hAIPL1, but not with co-expression of P351Delta12 hAIPL1 and the mouse isoform, aryl hydrocarbon receptor interacting protein-like 1 (mAipl1). Despite a dominant effect of the mutation, we successfully rescued cone-mediated vision in P351Delta12 hAIPL1 mice following high over-expression of WT hAIPL1 by adeno associated virus-mediated gene delivery, which was stable up to 6 months after treatment. Our transgenic P351Delta12 hAIPL1 mouse offers a novel model of AIPL1 CORD, with distinct defects from both the Aipl1-null mouse mimicking LCA and the Aipl1-hypomorphic mice mimicking a slow progressing RP. PMID- 25274780 TI - Zebrafish cul4a, but not cul4b, modulates cardiac and forelimb development by upregulating tbx5a expression. AB - CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disrupted in mammals. We here investigated the roles of cul4a and cul4b during zebrafish embryogenesis by using the morpholino knockdown approach. We found that cul4a is essential for cardiac development as well as for pectoral fin development. Whereas cul4a morphants appeared to be unperturbed in chamber specification, they failed to undergo heart looping. The failures in heart looping and pectoral fin formation in cul4a morphants were accompanied by greatly reduced proliferation of cardiac cells and pectoral fin-forming cells. We demonstrated that tbx5a, a transcription factor essential for heart and limb development, is transcriptionally upregulated by cul4a and mediates the function of cul4a in cardiac and pectoral fin development. In contrast to the critical importance of cul4a, cul4b appeared to be dispensable for zebrafish development and was incapable of compensating for the loss of cul4a. This work provides the first demonstration of an essential role of cul4a, but not cul4b, in cardiac development and in the regulation of tbx5a in zebrafish. These findings justify exploring the functional role of CUL4A in human cardiac development. PMID- 25274781 TI - Reduction of hRNase H2 activity in Aicardi-Goutieres syndrome cells leads to replication stress and genome instability. AB - Aicardi-Goutieres syndrome (AGS) is an inflammatory encephalopathy caused by defective nucleic acids metabolism. Over 50% of AGS mutations affect RNase H2 the only enzyme able to remove single ribonucleotide-monophosphates (rNMPs) embedded in DNA. Ribonucleotide triphosphates (rNTPs) are incorporated into genomic DNA with relatively high frequency during normal replication making DNA more susceptible to strand breakage and mutations. Here we demonstrate that human cells depleted of RNase H2 show impaired cell cycle progression associated with chronic activation of post-replication repair (PRR) and genome instability. We identify a similar phenotype in cells derived from AGS patients, which indeed accumulate rNMPs in genomic DNA and exhibit markers of constitutive PRR and checkpoint activation. Our data indicate that in human cells RNase H2 plays a crucial role in correcting rNMPs misincorporation, preventing DNA damage. Such protective function is compromised in AGS patients and may be linked to unscheduled immune responses. These findings may be relevant to shed further light on the mechanisms involved in AGS pathogenesis. PMID- 25274783 TI - Proximal opening wedge osteotomy with wedge-plate fixation compared with proximal chevron osteotomy for the treatment of hallux valgus: a prospective, randomized study. AB - BACKGROUND: Hallux valgus with an increased intermetatarsal angle is usually treated with a proximal metatarsal osteotomy. The proximal chevron osteotomy is commonly used but is technically difficult. This study compares the proximal opening wedge osteotomy of the first metatarsal with the proximal chevron osteotomy for the treatment of hallux valgus with an increased intermetatarsal angle. METHODS: This prospective, randomized multicenter (three-center) study was based on the clinical outcome scores of the Short Form-36, the American Orthopaedic Foot & Ankle Society forefoot questionnaire, and the visual analog scale for pain, activity, and patient satisfaction. Subjects were assessed prior to surgery and at three, six, and twelve months postoperatively. Surgeon preference was evaluated based on questionnaires and the operative times required for each procedure. RESULTS: No significant differences were found for any of the patients' clinical outcome measurements between the two procedures. The proximal opening wedge osteotomy was found to lengthen, and the proximal chevron osteotomy was found to shorten, the first metatarsal. The intermetatarsal angles improved (decreased) significantly, from 14.8 degrees +/- 3.2 degrees to 9.1 degrees +/ 2.9 (mean and standard deviation) after a proximal opening wedge osteotomy and from 14.6 degrees +/- 3.9 degrees to 11.3 degrees +/- 4.0 degrees after a proximal chevron osteotomy (p < 0.05 for both). Operative time required for performing a proximal opening wedge osteotomy is similar to that required for performing a proximal chevron osteotomy (mean and standard deviation, 67.1 +/- 16.5 minutes compared with 69.9 +/- 18.6 minutes; p = 0.510). CONCLUSIONS: Opening wedge and proximal chevron osteotomies have comparable radiographic outcomes and comparable clinical outcomes for pain, satisfaction, and function. The proximal opening wedge osteotomy lengthens, and the proximal chevron osteotomy shortens, the first metatarsal. The proximal opening wedge osteotomy was subjectively less technically demanding and was preferred by the orthopaedic surgeons in this study. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274782 TI - Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. AB - Mutations in the RNA-binding protein FUS/TLS (FUS) have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Although predominantly nuclear, this heterogenous nuclear ribonuclear protein (hnRNP) has multiple functions in RNA processing including intracellular trafficking. In ALS, mutant or wild-type (WT) FUS can form neuronal cytoplasmic inclusions. Asymmetric arginine methylation of FUS by the class 1 arginine methyltransferase, protein arginine methyltransferase 1 (PRMT1), regulates nucleocytoplasmic shuttling of FUS. In motor neurons of primary spinal cord cultures, redistribution of endogenous mouse and that of ectopically expressed WT or mutant human FUS to the cytoplasm led to nuclear depletion of PRMT1, abrogating methylation of its nuclear substrates. Specifically, hypomethylation of arginine 3 of histone 4 resulted in decreased acetylation of lysine 9/14 of histone 3 and transcriptional repression. Distribution of neuronal PRMT1 coincident with FUS also was detected in vivo in the spinal cord of FUS(R495X) transgenic mice. However, nuclear PRMT1 was not stable postmortem obviating meaningful evaluation of ALS autopsy cases. This study provides evidence for loss of PRMT1 function as a consequence of cytoplasmic accumulation of FUS in the pathogenesis of ALS, including changes in the histone code regulating gene transcription. PMID- 25274784 TI - Results of gait analysis including the Oxford foot model in children with clubfoot treated with the Ponseti method. AB - BACKGROUND: The aim of the study was to evaluate how clubfeet treated with the Ponseti method compare with control feet in gait analysis and whether additional information can be provided by the Oxford foot model. METHODS: All patients with a minimum age of three years in our prospective database of clubfeet treated with the Ponseti method were considered for inclusion. Exclusion criteria were an associated syndrome or neurological disease, positional (slight) clubfoot, and presentation at an age of more than three months. Of the 125 patients with 199 clubfeet who satisfied the criteria, thirty-six (29%) agreed to participate in the study. Four of these were excluded because of insufficient gait analysis data, leaving thirty-two patients with fifty clubfeet for evaluation. Clinical examination and three-dimensional gait analysis including the Oxford foot model were performed, and a disease-specific questionnaire was administered. Kinetic and kinematic results were compared with those of an age-matched control group (n = 15). RESULTS: The mean score on the disease-specific questionnaire was 83.5. Gait analysis showed significantly decreased range of motion, plantar flexion, and power of the ankle compared with controls. The mean external foot progression angle of 5.7 degrees in the Ponseti group was slightly less than that in the controls. Slight intoeing occurred in 24%, and 12% did not achieve a neutral position during swing phase. Slight compensation was observed, including external rotation of the hip in 28%. The Oxford foot model revealed differences in foot motion between the groups. CONCLUSIONS: Clubfoot treatment with the Ponseti method yielded good clinical results with high functional scores. Three dimensional gait analysis demonstrated distinctive but slight deviations. Intoeing was less frequent and less severe compared with groups in the literature. We recommend the use of three-dimensional gait analysis, including a foot model, as an objective tool for evaluation of the results of clubfoot treatment. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274785 TI - Effects of the combination of microfracture and self-assembling Peptide filling on the repair of a clinically relevant trochlear defect in an equine model. AB - BACKGROUND: The goal of this study was to test the ability of an injectable self assembling peptide (KLD) hydrogel, with or without microfracture, to augment articular cartilage defect repair in an equine cartilage defect model involving strenuous exercise. METHODS: Defects 15 mm in diameter were created on the medial trochlear ridge and debrided down to the subchondral bone. Four treatment groups (n = 8 each) were tested: no treatment (empty defect), only defect filling with KLD, only microfracture, and microfracture followed by filling with KLD. Horses were given strenuous exercise throughout the one-year study. Evaluations included lameness, arthroscopy, radiography, and gross, histologic, immunohistochemical, biochemical, and biomechanical analyses. RESULTS: Overall, KLD-only treatment of defects provided improvement in clinical symptoms and improved filling compared with no treatment, and KLD-only treatment protected against radiographic changes compared with microfracture treatment. Defect treatment with only microfracture also resulted in improved clinical symptoms compared with no treatment, and microfracture treatment resulted in repair tissue containing greater amounts of aggrecan and type-II collagen compared with KLD-only treatment. Microfracture treatment also protected against synovial fibrosis compared with no treatment and KLD-only treatment. Treatment with the self-assembling KLD peptide in combination with microfracture resulted in no additional improvements over microfracture-only treatment. In general, the nature of the predominant tissue in the defects was a mix of noncartilaginous and fibrocartilage tissue, with no significant differences among the treatments. CONCLUSIONS: Treatment of defects with only KLD or with only microfracture resulted in an improvement in clinical symptoms compared with no treatment; the improvement likely resulted from different causes depending on the treatment. Whereas microfracture improved the quality of repair tissue, KLD improved the amount of filling and protected against radiographic changes. CLINICAL RELEVANCE: Treatment of defects with only microfracture and with KLD only resulted in clinical improvements compared with untreated defects, despite differing with respect to the structural improvements that they induced. PMID- 25274786 TI - Cost-effectiveness analysis of fixation options for intertrochanteric hip fractures. AB - BACKGROUND: Intertrochanteric hip fractures are a major source of morbidity and financial burden, accounting for 7% of osteoporotic fractures and costing nearly $6 billion annually in the United States. Traditionally, "stable" fracture patterns have been treated with an extramedullary sliding hip screw whereas "unstable" patterns have been treated with the more expensive intramedullary nail. The purpose of this study was to identify parameters to guide cost effective implant choices with use of decision-analysis techniques to model these common clinical scenarios. METHODS: An expected-value decision-analysis model was constructed to estimate the total costs and health utility based on the choice of a sliding hip screw or an intramedullary nail for fixation of an intertrochanteric hip fracture. Values for critical parameters, such as fixation failure rate, were derived from the literature. Three scenarios were evaluated: (1) a clearly stable fracture (AO type 31-A1), (2) a clearly unstable fracture (A3), or (3) a fracture with questionable stability (A2). Sensitivity analysis was performed to test the validity of the model. RESULTS: The fixation failure rate and implant cost were the most important factors in determining implant choice. When the incremental cost for the intramedullary nail was set at the median value ($1200), intramedullary nailing had an incremental cost effectiveness ratio of $50,000/quality-adjusted life year when the incremental failure rate of sliding hip screws was 1.9%. When the incremental failure rate of sliding hip screws was >5.0%, intramedullary nails dominated with lower cost and better health outcomes. The sliding hip screw was always more cost-effective for A1 fractures, and the intramedullary nail always dominated for A3 fractures. As for A2 fractures, the sliding hip screw was cost-effective in 70% of the cases, although this was highly sensitive to the failure rate. CONCLUSIONS: Sliding hip screw fixation is likely more cost-effective for stable intertrochanteric fractures (A1) or those with questionable stability (A2), whereas intramedullary nail fixation is more cost-effective for reverse obliquity fractures (A3). These conclusions are highly sensitive to the fixation failure rate, which was the major influence on the model results. PMID- 25274787 TI - Accelerated rehabilitation compared with a standard protocol after distal radial fractures treated with volar open reduction and internal fixation: a prospective, randomized, controlled study. AB - BACKGROUND: There are relatively few studies in the literature that specifically evaluate accelerated rehabilitation protocols for distal radial fractures treated with open reduction and internal fixation (ORIF). The purpose of this study was to compare the early postoperative outcomes (at zero to twelve weeks postoperatively) of patients enrolled in an accelerated rehabilitation protocol with those of patients enrolled in a standard rehabilitation protocol following ORIF for a distal radial fracture. We hypothesized that patients with accelerated rehabilitation after volar ORIF for a distal radial fracture would have an earlier return to function compared with patients who followed a standard protocol. METHODS: From November 2007 to November 2010, eighty-one patients with an unstable distal radial fracture were prospectively randomized to follow either an accelerated or a standard rehabilitation protocol after undergoing ORIF with a volar plate for a distal radial fracture. Both groups began with gentle active range of motion at three to five days postoperatively. At two weeks, the accelerated group initiated wrist/forearm passive range of motion and strengthening exercises, whereas the standard group initiated passive range of motion and strengthening at six weeks postoperatively. Patients were assessed at three to five days, two weeks, three weeks, four weeks, six weeks, eight weeks, twelve weeks, and six months postoperatively. Outcomes included Disabilities of the Arm, Shoulder and Hand (DASH) scores (primary outcome) and measurements of wrist flexion/extension, supination, pronation, grip strength, and palmar pinch. RESULTS: The patients in the accelerated group had better mobility, strength, and DASH scores at the early postoperative time points (zero to eight weeks postoperatively) compared with the patients in the standard rehabilitation group. The difference between the groups was both clinically relevant and statistically significant. CONCLUSIONS: Patients who follow an accelerated rehabilitation protocol that emphasizes motion immediately postoperatively and initiates strengthening at two weeks after volar ORIF of a distal radial fracture have an earlier return to function than patients who follow a more standard rehabilitation protocol. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274788 TI - TheT1 pelvic angle, a novel radiographic measure of global sagittal deformity, accounts for both spinal inclination and pelvic tilt and correlates with health related quality of life. AB - BACKGROUND: Adult spinal deformity is a prevalent cause of pain and disability. Established measures of sagittal spinopelvic alignment such as sagittal vertical axis and pelvic tilt can be modified by postural compensation, including pelvic retroversion, knee flexion, and the use of assistive devices for standing. We introduce the T1 pelvic angle, a novel measure of sagittal alignment that simultaneously accounts for both spinal inclination and pelvic retroversion. The purpose of this study was to investigate the relationship of the T1 pelvic angle and other established sagittal alignment measures and to correlate these parameters with health-related quality-of-life measures. METHODS: This is a multicenter, prospective, cross-sectional analysis of consecutive patients with adult spinal deformity. Inclusion criteria were adult spinal deformity, an age of greater than eighteen years, and any of the following: scoliosis, a Cobb angle of >= 20 degrees , sagittal vertical axis of >= 5 cm, thoracic kyphosis of >= 60 degrees , and pelvic tilt of >= 25 degrees . Clinical measures of disability included the Oswestry Disability Index (ODI), Scoliosis Research Society (SRS) 22, and Short Form-36 (SF-36) questionnaires. RESULTS: Five hundred and fifty nine consecutive patients with adult spinal deformity (mean age, 52.5 years) were enrolled. The T1 pelvic angle correlated with the sagittal vertical axis (r = 0.837), pelvic incidence minus lumbar lordosis (r = 0.889), and pelvic tilt (0.933). Categorizing the patients by increasing T1 pelvic angle (<10 degrees , 10 degrees to 20 degrees , 21 degrees to 30 degrees , and > 30 degrees ) revealed a significant and progressive worsening in health-related quality of life (p < 0.001 for all). The T1 pelvic angle and sagittal vertical axis correlated with the ODI (0.435 and 0.455), SF-36 Physical Component Summary ( 0.445 and -0.458), and SRS (-0.358 and -0.383) (p < 0.001 for all). Utilizing a linear regression analysis, a T1 pelvic angle of 20 degrees corresponded to a severe disability (an ODI of >40), and the meaningful change in T1 pelvic angle corresponding to one minimal clinically important difference was 4.1 degrees on the ODI. CONCLUSIONS: The T1 pelvic angle correlates with health-related quality of life in patients with adult spinal deformity. The T1 pelvic angle is related to both pelvic tilt and sagittal vertical axis; however, unlike sagittal vertical axis, it does not vary on the basis of the extent of pelvic retroversion or patient support in standing. Since the T1 pelvic angle is an angular and not a linear measure, it does not require calibration of the radiograph. Thus, the T1 pelvic angle measures sagittal deformity independent of many postural compensatory mechanisms, and it can be useful as a preoperative planning tool, with a target T1 pelvic angle of < 14 degrees . LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274789 TI - Comparison of gait after Syme and transtibial amputation in children: factors that may play a role in function. AB - BACKGROUND: Preservation of maximal limb length during amputation is often recommended to maximize the efficiency and symmetry of gait. The goals of this study were to determine (1) whether there are gait differences between children with a Syme (or Boyd) amputation and those with a transtibial-level amputation, and (2) whether the type of prosthetic foot affects gait and PODCI (Pediatric Outcomes Data Collection Instrument) outcomes. METHODS: Sixty-four patients (age range, 4.7 to 19.2 years) with unilateral below-the-knee prosthesis use (forty one in the Syme group and twenty-three in the transtibial group) underwent gait analysis and review of data for the involved limb. The twelve prosthetic foot types were categorized as designed for a high, medium, or low activity level (e.g., Flex foot, dynamic response foot, or SACH). Statistical analyses were conducted. RESULTS: Kinematic differences of <4 degrees in total prosthetic ankle motion and 8 degrees in external hip rotation were seen between the Syme and transtibial groups. Ankle power was greater in the transtibial group, whereas the Syme group had greater coronal-plane hip power (p < 0.05). Prosthetic ankle motion was significantly greater in the high compared with the medium and low performance feet. However, the PODCI happiness score was higher in patients with low compared with medium-performance feet (p < 0.05). CONCLUSIONS: Small differences in prosthetic ankle motion and power were found between children with Syme and transtibial amputations. Ankle motion was greater in patients using high performance feet (9% of the total cohort) compared with medium-performance (59%) and low-performance (31%) feet. Despite the increased ankle motion achieved with high-performance dynamic feet, this advantage was not reflected in peak power of the prosthetic ankle or the PODCI sports/physical functioning subscale. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274790 TI - Injury type and emergency department management of orthopaedic patients influences follow-up rates. AB - BACKGROUND: Orthopaedic clinic follow-up is required to ensure optimal management and outcome for many patients who present to the emergency department (ED) with an orthopaedic injury. While several studies have shown that demographic variables influence patient follow-up after discharge from the ED, the objective of this study was to examine orthopaedic-related and other factors associated with the failure to return for orthopaedic outpatient management, so-called "no show," after an ED visit. METHODS: A chart review was conducted at a large academic public hospital. Four hundred and sixty-four consecutive adult patients who received an orthopaedic consult in the ED with subsequent referral to the orthopaedic clinic from January through June, 2011, were included. With use of chi-square and Mann-Whitney univariate tests, data regarding injury type and management were analyzed for association with no-show. Variables with p < 0.25 were included in a multivariate stepwise forward logistic regression analysis. RESULTS: The overall no-show rate was 26.1%. Logistic regression modeling revealed significant differences in no-show rates based on cause of injury (odds ratio [OR] 7.51; 95% confidence interval [CI], 2.27 to 25.1), with assault victims having the highest no-show rate. Anatomic region of injury significantly influenced no-show rates (OR 6.61; 95% CI, 1.45 to 30.5), with patients with a spine or back complaint having the highest no-show rate. Follow-up rates were influenced by the orthopaedic resident provider consulted (OR 10.8; 95% CI, 4.11 to 31.1), and this was not related to level of training (p = 0.25). The type of bracing applied influenced the no-show rate (OR 2.46; 95% CI, 1.58 to 3.96), and the easier it was to remove the brace (splint), the worse the follow-up (p = 0.0001). Several demographic variables were also predictive of clinic nonattendance, including morbid obesity (OR 15.0; 95% CI, 4.83 to 51.6) and current tobacco use (OR 5.56; 95% CI, 2.19 to 15.4). CONCLUSIONS: This study supports previous evidence of high no-show rates with scheduled orthopaedic follow-up among patients treated in the ED. The data highlight distinct orthopaedic-related factors associated with nonattendance. These findings are useful in identifying patients at high risk for no-show to scheduled orthopaedic follow-up appointments and may influence disposition and management decisions for these patients. PMID- 25274792 TI - Walking age of infants with idiopathic clubfoot treated using the ponseti method. AB - BACKGROUND: The Ponseti method is an established approach to treating idiopathic clubfoot in infants. The method involves a period of cast immobilization and postcorrective bracing that potentially interferes with normal movements of the lower extremities. In the present study, we investigated the age at which infants who had idiopathic clubfoot treated using the Ponseti method achieved independent walking. METHODS: We prospectively evaluated patients of a single surgeon. Included in the study were all patients with idiopathic clubfoot who were full term at birth, were no more than twelve weeks of age at the start of treatment, had received no prior outside treatment, and were followed for a minimum of twenty-four months. RESULTS: Ninety-four patients were included. The mean age at which patients began walking independently was 14.5 +/- 2.6 months (range, ten to twenty-two months). By eighteen months, 90% of the patients were walking without assistance. Patients with moderate or severe clubfoot deformity began walking earlier than did patients with very severe deformity (a mean of 14.2 months compared with 15.8 months; p = 0.03). Patients who experienced a relapse before learning to walk began walking later than those who did not relapse (a mean of 15.9 months compared with 14.2 months; p = 0.04). Other patient and treatment related variables had no significant influence on the onset of walking. CONCLUSIONS: On the basis of our findings, parents of infants with idiopathic clubfoot treated using the Ponseti method may expect their child to achieve independent walking approximately two months later than infants without clubfoot deformity. A greater delay may be expected for those patients who have a very severe deformity or those who experience a deformity relapse. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274791 TI - A review of osteocyte function and the emerging importance of sclerostin. AB - ? Osteocytes, derived from osteoblasts, reside within bone and communicate extensively with other bone cell populations to regulate bone metabolism. The mature osteocyte expresses the protein sclerostin, a negative regulator of bone mass.? In normal physiologic states, the protein sclerostin acts on osteoblasts at the surface of bone and is differentially expressed in response to mechanical loading, inflammatory molecules such as prostaglandin E2, and hormones such as parathyroid hormone and estrogen.? Pathologically, sclerostin dysregulation has been observed in osteoporosis-related fractures, failure of implant osseous integration, metastatic bone disease, and select genetic diseases of bone mass.? An antibody that targets sclerostin, decreasing endogenous levels of sclerostin while increasing bone mineral density, is currently in phase-III clinical trials.? The osteocyte has emerged as a versatile, indispensable bone cell. Its location within bone, extensive dendritic network, and close communication with systemic circulation and other bone cells produce many opportunities to treat a variety of orthopaedic conditions. PMID- 25274793 TI - Associations between preoperative physical therapy and post-acute care utilization patterns and cost in total joint replacement. AB - BACKGROUND: Health-care costs following acute hospital care have been identified as a major contributor to regional variation in Medicare spending. This study investigated the associations of preoperative physical therapy and post-acute care resource use and its effect on the total cost of care during primary hip or knee arthroplasty. METHODS: Historical claims data were analyzed using the Centers for Medicare & Medicaid Services Limited Data Set files for Diagnosis Related Group 470. Analysis included descriptive statistics of patient demographic characteristics, comorbidities, procedures, and post-acute care utilization patterns, which included skilled nursing facility, home health agency, or inpatient rehabilitation facility, during the ninety-day period after a surgical hospitalization. To evaluate the associations, we used bivariate and multivariate techniques focused on post-acute care use and total episode-of-care costs. RESULTS: The Limited Data Set provided 4733 index hip or knee replacement cases for analysis within the thirty-nine-county Medicare hospital referral cluster. Post-acute care utilization was a significant variable in the total cost of care for the ninety-day episode. Overall, 77.0% of patients used post-acute care services after surgery. Post-acute care utilization decreased if preoperative physical therapy was used, with only 54.2% of the preoperative physical therapy cohort using post-acute care services. However, 79.7% of the non preoperative physical therapy cohort used post-acute care services. After adjusting for demographic characteristics and comorbidities, the use of preoperative physical therapy was associated with a significant 29% reduction in post-acute care use, including an $871 reduction of episode payment driven largely by a reduction in payments for skilled nursing facility ($1093), home health agency ($527), and inpatient rehabilitation ($172). CONCLUSIONS: The use of preoperative physical therapy was associated with a 29% decrease in the use of any post-acute care services. This association was sustained after adjusting for comorbidities, demographic characteristics, and procedural variables. CLINICAL RELEVANCE: Health-care providers can use this methodology to achieve an integrative, cost-effective, patient care pathway using preoperative physical therapy. PMID- 25274794 TI - Surgical anatomy of the sternoclavicular joint: a qualitative and quantitative anatomical study. AB - BACKGROUND: The quantitative anatomical relationships of the main ligamentous, tendinous, and osseous structures of the sternoclavicular joint have not been widely investigated. The purpose of this study was to provide a quantitative description of the sternoclavicular joint in relation to relevant surgical landmarks. METHODS: We dissected eleven nonpaired, fresh-frozen cadaveric sternoclavicular joints from four men and seven women (mean age at death, fifty three years; range, thirty-three to sixty-four years) and measured the ligaments, musculature, and osseous landmarks with use of a three-dimensional coordinate measuring device. RESULTS: The clavicular pectoralis ridge, located at the 9:30 clock-face position on a right clavicle, served as a reliable osseous landmark for reference to the soft-tissue attachments around the sternoclavicular joint. The costoclavicular ligament was the largest ligament of the sternoclavicular joint, with 80% greater footprint area than that of the posterior sternoclavicular ligament. Articular cartilage covered 67% of the medial end of the clavicle and was located anteroinferiorly. The sternohyoid muscle inserted directly over the posterior sternoclavicular joint and the medial end of the clavicle, whereas the sternothyroid muscle inserted 9.5 mm inferior to the posterior-superior articular margin of the manubrium and coursed 19.8 mm laterally along the first rib. An avascular plane that can serve as a "safe zone" for posterior dissection was observed in each specimen, posterior to the sternoclavicular joint and anterior to the sternohyoid and sternothyroid muscles. CONCLUSIONS: The clavicular pectoralis ridge can be used as an intraoperative guide for clavicle orientation and tunnel placement in sternoclavicular ligament reconstruction. Sternoclavicular joint resection arthroplasty should avoid injuring the costoclavicular ligament, which is the largest sternoclavicular joint ligament. Resection of only the anteroinferior aspect of the medial end of the clavicle may provide adequate decompression while preserving the stability of the clavicle. The location of the sternohyoid and sternothyroid musculotendinous insertions appear to provide a "safe zone" for posterior clavicle and manubrial dissection. PMID- 25274795 TI - Periprosthetic femoral fracture within two years after total hip replacement: analysis of 437,629 operations in the nordic arthroplasty register association database. AB - BACKGROUND: We used the Nordic Arthroplasty Register Association database to evaluate whether age, sex, preoperative diagnosis, fixation, and implant design influence the risk of revision arthroplasty due to periprosthetic fracture within two years from operation of a primary total hip replacement. METHODS: Included in the study were 325,730 cemented femoral stems and 111,899 uncemented femoral stems inserted from 1995 to 2009. Seven frequently used stems (two cemented stems [Exeter and Lubinus SP II] and five uncemented stems [Bi-Metric, Corail, CLS Spotorno, ABG I, and ABG II]) were specifically studied. RESULTS: The incidence of revision at two years was low: 0.47% for uncemented stems and 0.07% for cemented stems. Uncemented stems were much more likely to have this complication (relative risk, 8.72 [95% confidence interval, 7.37 to 10.32]; p < 0.0005). Age had no consistent influence on the risk for revision of cemented stems, but revision in the uncemented group increased with increasing age. A cemented stem was associated with a higher risk in male patients compared with female patients (hazard ratio, 1.95 [95% confidence interval, 1.51 to 2.53]; p < 0.0005), whereas an uncemented stem was associated with a reduced risk in male patients compared with female patients (hazard ratio, 0.74 [95% confidence interval, 0.62 to 0.89]; p = 0.001). The risk for revision due to early periprosthetic fracture increased during the 2003 to 2009 period compared with the 1995 to 2002 period both before and after adjustment for demographic factors and fixation (relative risk, 1.44 [95% confidence interval, 1.18 to 1.69]; p < 0.0005). The hazard ratio for the Exeter stem was about five times higher than that for the Lubinus SP II stem (hazard ratio, 5.03 [95% confidence interval, 3.29 to 7.70]; p < 0.0005). Of the five uncemented stems, the ABG II stem showed an increased hazard ratio of 1.63 (95% confidence interval, 1.16 to 2.28) (p = 0.005), whereas the Corail stem showed a decreased hazard ratio of 0.47 (95% confidence interval, 0.34 to 0.65) (p < 0.0005) compared with the reference Bi-Metric design. CONCLUSIONS: The shape and surface finish of the femoral stem and its fixation could be related to the increased risk of some prosthetic designs. Even if the incidence of early periprosthetic fracture in general is low and other reasons for revision must be considered, specific attention should be given to the choice of fixation and stem design in risk groups. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274797 TI - The renewal of excellence. AB - Excellence in orthopaedic surgery has been a long time in the making. What we currently enjoy reflects over a century of innovation, leadership, and consummate professionalism. Today, our practice faces monumental challenges that have never been more demanding, and our commitment to the preservation and advancement of excellence has never been more pressing. Away from the scientific tone but without romanticizing our proud heritage, this article seeks to revitalize the values that have defined our practice, drawing on the wisdom and experiences of leaders in our field. Collectively, it aims to stimulate our enlightened understanding, to reignite our hopes, and to reaffirm our commitment to the highest standards of excellence. PMID- 25274796 TI - Long-term clinical outcomes and survivorship of press-fit condylar sigma fixed bearing and mobile-bearing total knee prostheses in the same patients. AB - BACKGROUND: We are aware of no study that has compared press-fit condylar Sigma fixed-bearing and mobile-bearing total knee prostheses in the same patients after more than ten years of follow-up. The purpose of the current study was to compare these two implants with respect to the functional and radiographic results, prevalence of osteolysis, and overall revision rates at a mean of 12.1 years of follow-up. METHODS: The study consisted of a consecutive series of 444 patients (mean age [and standard deviation], 66.5 +/- 7.4 years) who underwent simultaneous bilateral total knee arthroplasty, with one side treated immediately after the other. All of the patients received a press-fit condylar Sigma mobile bearing prosthesis on one side and a press-fit condylar Sigma fixed-bearing prosthesis on the contralateral side. The minimum duration of follow-up was ten years (mean, 12.1 years; range, ten to thirteen years). At the time of each follow-up visit, the patients were assessed clinically and radiographically. RESULTS: Postoperative total knee scores (95 and 94 points), Western Ontario and McMaster Universities Osteoarthritis Index (19 and 18 points), University of California, Los Angeles activity score (both prostheses, 5 points), range of motion (129 degrees +/- 6.3 degrees and 127 degrees +/- 6.8 degrees ), and radiographic findings did not differ significantly between the press-fit condylar Sigma mobile and fixed-bearing designs at the final follow-up. The prevalence of aseptic loosening (1.4% and 1.8%) did not differ significantly between the mobile and fixed-bearing implant designs. No knee in either group had osteolysis. The estimated survival rate with revision as the end point was 98.2% (95% confidence interval, 91% to 99%) and 97.5% (95% confidence interval, 91% to 99%) at 12.1 years for the mobile and fixed-bearing implant groups, respectively. CONCLUSIONS: The results of the present long-term clinical study suggest that excellent clinical and radiographic results were achieved with both the press-fit condylar Sigma mobile and fixed-bearing cruciate-retaining total knee designs. We found no significant clinical advantage for a mobile-bearing over a fixed-bearing total knee prosthesis. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25274798 TI - Myth busters: an AOA symposium: AOA critical issues. AB - One of the goals of the annual American Orthopaedic Association (AOA) meeting is to address controversy, both in leadership and clinical practice. A panel of experts in their respective fields presented the background and literature behind three "myths" in orthopaedic management and made conclusions as to their validity. First, Dr. Kocher took on the myth of prophylactic pinning on the contralateral "normal" side for a patient with a slipped capital femoral epiphysis. Second, Dr. Probe evaluated the myth that all intertrochanteric fractures are best treated with intramedullary devices. Last, Dr. Foster and Dr. Silvestri tackled the myth that autograft is always the best choice for anterior cruciate ligament (ACL) reconstruction. All three of these topics are subjects of current debate. The panel's careful examination of the available data along with their expertise in the management of these problems is presented in this thought provoking JBJS Critical Issues article. PMID- 25274799 TI - The effect of focused instruction on orthopaedic surgery residents' ability to objectively measure intracompartmental pressures in a compartment syndrome model. PMID- 25274800 TI - T1 pelvic angle (TPA): another acronym to add to the pile, or the missing link for assessing sagittal plane alignment in adult spinal deformity? PMID- 25274801 TI - See you in the Paralympics in 2022: commentary on an article by Kelly A. Jeans, MS, et al.: "comparison of gait after syme and transtibial amputation in children. factors that may play a role in function". PMID- 25274802 TI - Effectiveness of the E2-classical swine fever virus recombinant vaccine produced and formulated within whey from genetically transformed goats. AB - Subunit recombinant vaccines against classical swine fever virus (CSFV) are a promising alternative to overcome practical and biosafety issues with inactivated vaccines. One of the strategies in evaluation under field conditions is the use of a new marker E2-based vaccine produced in the milk of adenovirally transduced goats. Previously we had demonstrated the efficacy of this antigen, which conferred early protection and long-lasting immunity in swine against CSFV infection. Here, we have used a simpler downstream process to obtain and formulate the recombinant E2 glycoprotein expressed in the mammary gland. The expression levels reached approximately 1.7 mg/ml, and instead of chromatographic separation of the antigen, we utilized a clarification process that eliminates the fat content, retains a minor amount of caseins, and includes an adenoviral inactivation step that improves the biosafety of the final formulation. In a vaccination and challenge experiment in swine, different doses of the E2 antigen contained within the clarified whey generated an effective immune response of neutralizing antibodies that protected all of the animals against a lethal challenge with CSFV. During the immunization and after challenge, the swine were monitored for adverse reactions related to the vaccine or symptoms of CSF, respectively. No adverse reactions or clinical signs of disease were observed in vaccinated animals, in which no replication of CSFV could be detected after challenge. Overall, we consider that the simplicity of the procedures proposed here is a further step toward the introduction and implementation of a commercial subunit vaccine against CSF. PMID- 25274803 TI - IP-10 and MIG are compartmentalized at the site of disease during pleural and meningeal tuberculosis and are decreased after antituberculosis treatment. AB - The diagnosis of active tuberculosis (TB) disease remains a challenge, especially in high-burden settings. Cytokines and chemokines are important in the pathogenesis of TB. Here we investigate the usefulness of circulating and compartmentalized cytokines/chemokines for diagnosis of TB. The levels of multiple cytokines/chemokines in plasma, pleural fluid (PF), and cerebrospinal fluid (CSF) were determined by Luminex liquid array-based multiplexed immunoassays. Three of 26 cytokines/chemokines in plasma were significantly different between TB and latent tuberculosis infection (LTBI). Among them, IP-10 and MIG had the highest diagnostic values, with an area under the receiver operating characteristic curve (ROC AUC) of 0.92 for IP-10 and 0.86 for MIG for distinguishing TB from LTBI. However, IP-10 and MIG levels in plasma were not different between TB and non-TB lung disease. In contrast, compartmentalized IP 10 and MIG in the PF and CSF showed promising diagnostic values in discriminating TB and non-TB pleural effusion (AUC = 0.87 for IP-10 and 0.93 for MIG), as well as TB meningitis and non-TB meningitis (AUC = 0.9 for IP-10 and 0.95 for MIG). A longitudinal study showed that the plasma levels of IP-10, MIG, granulocyte colony-stimulating factor (G-CSF), and gamma interferon (IFN-gamma) decreased, while the levels of MCP-1/CCL2 and eotaxin-1/CCL11 increased, after successful treatment of TB. Our findings provide a practical methodology for discriminating active TB from LTBI by sequential IFN-gamma release assays (IGRAs) and plasma IP 10 testing, while increased IP-10 and MIG at the site of infection (PF or CSF) can be used as a marker for distinguishing pleural effusion and meningitis caused by TB from those of non-TB origins. PMID- 25274804 TI - Field evaluation of the InBios Chagas detect plus rapid test in serum and whole blood specimens in Bolivia. AB - Trypanosoma cruzi causes Chagas disease, which affects an estimated 7 million to 8 million people. Chagas disease is endemic throughout Latin America, with the highest prevalence in Bolivia. Conventional diagnosis requires a well-equipped laboratory with experienced personnel. We evaluated the Chagas Detect Plus (CDP) (InBios, Seattle, WA), a rapid immunochromatographic assay for IgG antibodies to T. cruzi. CDP performance was compared to infection status based on results obtained by indirect hemagglutination assay, immunofluorescent-antibody test, and enzyme-linked immunosorbent assay. Confirmed infection required positive results by at least 2 conventional assays. We used specimens from adults of both sexes in a general hospital in the city of Santa Cruz and from pregnant women in a hospital and children in villages in the Bolivian Chaco, an area of hyperendemicity. CDP was performed in paired whole-blood and serum specimens from 385 individuals in the two hospital studies and in 200 serum specimens from the community study. CDP showed sensitivities/specificities of 96.2% (95% confidence interval, 92.7 to 98.4)/98.8% (95.9 to 99.9) in whole blood and 99.3% (97.5 to 99.9)/96.9% (94.2 to 98.6) in serum, with no differences by sex, age group, or study site. CDP showed excellent sensitivity and specificity in our study population, comparable to those of conventional serology. The test is reliable for field surveys, requires no laboratory equipment, and performed well in serum and whole blood. The CDP could also be used for accurate maternal screening to identify neonates at risk of congenital transmission. CDP performance data in diverse geographic areas are needed to strengthen the evidence base for its use. PMID- 25274806 TI - Towards a reconceptualization of the temporoparietal junction in stimulus-driven attention. PMID- 25274807 TI - Neurodevelopmental constraints of syntax rule transfer effects as landmarks for sensitive periods of language acquisition. PMID- 25274805 TI - Multiple low-dose challenges in a rhesus macaque AIDS vaccine trial result in an evolving host response that affects protective outcome. AB - Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV. PMID- 25274808 TI - Hippocampal dysregulation of neurofibromin-dependent pathways is associated with impaired spatial learning in engrailed 2 knock-out mice. AB - Genome-wide association studies indicated the homeobox-containing transcription factor Engrailed-2 (En2) as a candidate gene for autism spectrum disorders (ASD). Accordingly, En2 knock-out (En2(-/-)) mice show anatomical and behavioral "ASD like" features, including decreased sociability and learning deficits. The molecular pathways underlying these deficits in En2(-/-) mice are not known. Deficits in signaling pathways involving neurofibromin and extracellular regulated kinase (ERK) have been associated with impaired learning. Here we investigated the neurofibromin-ERK cascade in the hippocampus of wild-type (WT) and En2(-/-) mice before and after spatial learning testing. When compared with WT littermates, En2(-/-) mice showed impaired performance in the Morris water maze (MWM), which was accompanied by lower expression of the activity-dependent gene Arc. Quantitative RT-PCR, immunoblotting, and immunohistochemistry experiments showed a marked downregulation of neurofibromin expression in the dentate gyrus of both naive and MWM-treated En2(-/-) mice. ERK phosphorylation, known to be induced in the presence of neurofibromin deficiency, was increased in the dentate gyrus of En2(-/-) mice after MWM. Treatment of En2(-/-) mice with lovastatin, an indirect inhibitor of ERK phosphorylation, markedly reduced ERK phosphorylation in the dentate gyrus, but was unable to rescue learning deficits in MWM-trained mutant mice. Further investigation is needed to unravel the complex molecular mechanisms linking dysregulation of neurofibromin-dependent pathways to spatial learning deficits in the En2 mouse model of ASD. PMID- 25274809 TI - Doxorubicin attenuates serotonin-induced long-term synaptic facilitation by phosphorylation of p38 mitogen-activated protein kinase. AB - Doxorubicin (DOX) is an anthracycline used widely for cancer chemotherapy. Its primary mode of action appears to be topoisomerase II inhibition, DNA cleavage, and free radical generation. However, in non-neuronal cells, DOX also inhibits the expression of dual-specificity phosphatases (also referred to as MAPK phosphatases) and thereby inhibits the dephosphorylation of extracellular signal regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK), two MAPK isoforms important for long-term memory (LTM) formation. Activation of these kinases by DOX in neurons, if present, could have secondary effects on cognitive functions, such as learning and memory. The present study used cultures of rat cortical neurons and sensory neurons (SNs) of Aplysia to examine the effects of DOX on levels of phosphorylated ERK (pERK) and phosphorylated p38 (p-p38) MAPK. In addition, Aplysia neurons were used to examine the effects of DOX on long-term enhanced excitability, long-term synaptic facilitation (LTF), and long-term synaptic depression (LTD). DOX treatment led to elevated levels of pERK and p-p38 MAPK in SNs and cortical neurons. In addition, it increased phosphorylation of the downstream transcriptional repressor cAMP response element-binding protein 2 in SNs. DOX treatment blocked serotonin-induced LTF and enhanced LTD induced by the neuropeptide Phe-Met-Arg-Phe-NH2. The block of LTF appeared to be attributable to overriding inhibitory effects of p-p38 MAPK, because LTF was rescued in the presence of an inhibitor (SB203580 [4-(4-fluorophenyl)-2-(4 methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]) of p38 MAPK. These results suggest that acute application of DOX might impair the formation of LTM via the p38 MAPK pathway. PMID- 25274810 TI - Dissociated signals in human dentate gyrus and CA3 predict different facets of recognition memory. AB - A wealth of evidence has implicated the hippocampus and surrounding medial temporal lobe cortices in support of recognition memory. However, the roles of the various subfields of the hippocampus are poorly understood. In this study, we concurrently varied stimulus familiarization and repetition to engage different facets of recognition memory. Using high-resolution fMRI (1.5 mm isotropic), we observed distinct familiarity and repetition-related recognition signal profiles in the dentate gyrus (DG)/CA3 subfield in human subjects. The DG/CA3 demonstrated robust response suppression with repetition and familiarity-related facilitation. Both of these discrete responses were predictive of different aspects of behavioral performance. Consistent with previous work, we observed novelty responses in CA1 consistent with "match/mismatch detection," as well as mixed recognition signaling distributed across medial temporal lobe cortices. Additional analyses indicated that the repetition and familiarity-related signals in the DG/CA3 were strikingly dissociated along the hippocampal longitudinal axis and that activity in the posterior hippocampus was strongly correlated with the retrosplenial cortex. These data provide novel insight into the roles of hippocampal subfields in support of recognition memory and further provide evidence of a functional heterogeneity in the human DG/CA3, particularly along the longitudinal axis. PMID- 25274811 TI - The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. AB - Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD. PMID- 25274812 TI - Altered activity in the central medial thalamus precedes changes in the neocortex during transitions into both sleep and propofol anesthesia. AB - How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing "top-down" inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20-40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1-4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated. PMID- 25274814 TI - Plasticity in developing brain: active auditory exposure impacts prelinguistic acoustic mapping. AB - A major task across infancy is the creation and tuning of the acoustic maps that allow efficient native language processing. This process crucially depends on ongoing neural plasticity and keen sensitivity to environmental cues. Development of sensory mapping has been widely studied in animal models, demonstrating that cortical representations of the sensory environment are continuously modified by experience. One critical period for optimizing human language mapping is early in the first year; however, the neural processes involved and the influence of passive compared with active experience are as yet incompletely understood. Here we demonstrate that, while both active and passive acoustic experience from 4 to 7 months of age, using temporally modulated nonspeech stimuli, impacts acoustic mapping, active experience confers a significant advantage. Using event-related potentials (ERPs), we show that active experience increases perceptual vigilance/attention to environmental acoustic stimuli (e.g., larger and faster P2 peaks) when compared with passive experience or maturation alone. Faster latencies are also seen for the change discrimination peak (N2*) that has been shown to be a robust infant predictor of later language through age 4 years. Sharpening is evident for both trained and untrained stimuli over and above that seen for maturation alone. Effects were also seen on ERP morphology for the active experience group with development of more complex waveforms more often seen in typically developing 12- to 24-month-old children. The promise of selectively "fine-tuning" acoustic mapping as it emerges has far-reaching implications for the amelioration and/or prevention of developmental language disorders. PMID- 25274813 TI - Photoactivation-induced instability of rhodopsin mutants T4K and T17M in rod outer segments underlies retinal degeneration in X. laevis transgenic models of retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is an inherited neurodegenerative disease involving progressive vision loss, and is often linked to mutations in the rhodopsin gene. Mutations that abolish N-terminal glycosylation of rhodopsin (T4K and T17M) cause sector RP in which the inferior retina preferentially degenerates, possibly due to greater light exposure of this region. Transgenic animal models expressing rhodopsin glycosylation mutants also exhibit light exacerbated retinal degeneration (RD). In this study, we used transgenic Xenopus laevis to investigate the pathogenic mechanism connecting light exposure and RD in photoreceptors expressing T4K or T17M rhodopsin. We demonstrate that increasing the thermal stability of these rhodopsins via a novel disulfide bond resulted in significantly less RD. Furthermore, T4K or T17M rhodopsins that were constitutively inactive (due to lack of the chromophore-binding site or dietary deprivation of the chromophore precursor vitamin A) induced less toxicity. In contrast, variants in the active conformation accumulated in the ER and caused RD even in the absence of light. In vitro, T4K and T17M rhodopsins showed reduced ability to regenerate pigment after light exposure. Finally, although multiple amino acid substitutions of T4 abolished glycosylation at N2 but were not toxic, similar substitutions of T17 were not tolerated, suggesting that the carbohydrate moiety at N15 is critical for cell viability. Our results identify a novel pathogenic mechanism in which the glycosylation-deficient rhodopsins are destabilized by light activation. These results have important implications for proposed RP therapies, such as vitamin A supplementation, which may be ineffective or even detrimental for certain RP genotypes. PMID- 25274815 TI - EOL-1, the homolog of the mammalian Dom3Z, regulates olfactory learning in C. elegans. AB - Learning is an essential function of the nervous system. However, our understanding of molecular underpinnings of learning remains incomplete. Here, we characterize a conserved protein EOL-1 that regulates olfactory learning in Caenorhabditis elegans. A recessive allele of eol-1 (enhanced olfactory learning) learns better to adjust its olfactory preference for bacteria foods and eol-1 acts in the URX sensory neurons to regulate learning. The mammalian homolog of EOL-1, Dom3Z, which regulates quality control of pre-mRNAs, can substitute the function of EOL-1 in learning regulation, demonstrating functional conservation between these homologs. Mutating the residues of Dom3Z that are critical for its enzymatic activity, and the equivalent residues in EOL-1, abolishes the function of these proteins in learning. Together, our results provide insights into the function of EOL-1/Dom3Z and suggest that its activity in pre-mRNA quality control is involved in neural plasticity. PMID- 25274816 TI - PKA reduces the rat and human KCa3.1 current, CaM binding, and Ca2+ signaling, which requires Ser332/334 in the CaM-binding C terminus. AB - The Ca(2+)-dependent K(+) channel, KCa3.1 (KCNN4/IK/SK4), is widely expressed and contributes to cell functions that include volume regulation, migration, membrane potential, and excitability. KCa3.1 is now considered a therapeutic target for several diseases, including CNS disorders involving microglial activation; thus, we need to understand how KCa3.1 function is regulated. KCa3.1 gating and trafficking require calmodulin binding to the two ends of the CaM-binding domain (CaMBD), which also contains three conserved sites for Ser/Thr kinases. Although cAMP protein kinase (PKA) signaling is important in many cells that use KCa3.1, reports of channel regulation by PKA are inconsistent. We first compared regulation by PKA of native rat KCa3.1 channels in microglia (and the microglia cell line, MLS-9) with human KCa3.1 expressed in HEK293 cells. In all three cells, PKA activation with Sp-8-Br-cAMPS decreased the current, and this was prevented by the PKA inhibitor, PKI14-22. Inhibiting PKA with Rp-8-Br-cAMPS increased the current in microglia. Mutating the single PKA site (S334A) in human KCa3.1 abolished the PKA-dependent regulation. CaM-affinity chromatography showed that CaM binding to KCa3.1 was decreased by PKA-dependent phosphorylation of S334, and this regulation was absent in the S334A mutant. Single-channel analysis showed that PKA decreased the open probability in wild-type but not S334A mutant channels. The same decrease in current for native and wild-type expressed KCa3.1 channels (but not S334A) occurred when PKA was activated through the adenosine A2a receptor. Finally, by decreasing the KCa3.1 current, PKA activation reduced Ca(2+)-release-activated Ca(2+) entry following activation of metabotropic purinergic receptors in microglia. PMID- 25274818 TI - Bridging the gap: a reticulo-propriospinal detour bypassing an incomplete spinal cord injury. AB - Anatomically incomplete spinal cord injuries are often followed by considerable functional recovery in patients and animal models, largely because of processes of neuronal plasticity. In contrast to the corticospinal system, where sprouting of fibers and rearrangements of circuits in response to lesions have been well studied, structural adaptations within descending brainstem pathways and intraspinal networks are poorly investigated, despite the recognized physiological significance of these systems across species. In the present study, spontaneous neuroanatomical plasticity of severed bulbospinal systems and propriospinal neurons was investigated following unilateral C4 spinal hemisection in adult rats. Injection of retrograde tracer into the ipsilesional segments C3 C4 revealed a specific increase in the projection from the ipsilesional gigantocellular reticular nucleus in response to the injury. Substantial regenerative fiber sprouting of reticulospinal axons above the injury site was demonstrated by anterograde tracing. Regrowing reticulospinal fibers exhibited excitatory, vGLUT2-positive varicosities, indicating their synaptic integration into spinal networks. Reticulospinal fibers formed close appositions onto descending, double-midline crossing C3-C4 propriospinal neurons, which crossed the lesion site in the intact half of the spinal cord and recrossed to the denervated cervical hemicord below the injury. These propriospinal projections around the lesion were significantly enhanced after injury. Our results suggest that severed reticulospinal fibers, which are part of the phylogenetically oldest motor command system, spontaneously arborize and form contacts onto a plastic propriospinal relay, thereby bypassing the lesion. These rearrangements were accompanied by substantial locomotor recovery, implying a potential physiological relevance of the detour in restoration of motor function after spinal injury. PMID- 25274817 TI - Sensory gain outperforms efficient readout mechanisms in predicting attention related improvements in behavior. AB - Spatial attention has been postulated to facilitate perceptual processing via several different mechanisms. For instance, attention can amplify neural responses in sensory areas (sensory gain), mediate neural variability (noise modulation), or alter the manner in which sensory signals are selectively read out by postsensory decision mechanisms (efficient readout). Even in the context of simple behavioral tasks, it is unclear how well each of these mechanisms can account for the relationship between attention-modulated changes in behavior and neural activity because few studies have systematically mapped changes between stimulus intensity, attentional focus, neural activity, and behavioral performance. Here, we used a combination of psychophysics, event-related potentials (ERPs), and quantitative modeling to explicitly link attention-related changes in perceptual sensitivity with changes in the ERP amplitudes recorded from human observers. Spatial attention led to a multiplicative increase in the amplitude of an early sensory ERP component (the P1, peaking ~80-130 ms poststimulus) and in the amplitude of the late positive deflection component (peaking ~230-330 ms poststimulus). A simple model based on signal detection theory demonstrates that these multiplicative gain changes were sufficient to account for attention-related improvements in perceptual sensitivity, without a need to invoke noise modulation. Moreover, combining the observed multiplicative gain with a postsensory readout mechanism resulted in a significantly poorer description of the observed behavioral data. We conclude that, at least in the context of relatively simple visual discrimination tasks, spatial attention modulates perceptual sensitivity primarily by modulating the gain of neural responses during early sensory processing. PMID- 25274819 TI - Fast but fleeting: adaptive motor learning processes associated with aging and cognitive decline. AB - Motor learning has been shown to depend on multiple interacting learning processes. For example, learning to adapt when moving grasped objects with novel dynamics involves a fast process that adapts and decays quickly-and that has been linked to explicit memory-and a slower process that adapts and decays more gradually. Each process is characterized by a learning rate that controls how strongly motor memory is updated based on experienced errors and a retention factor determining the movement-to-movement decay in motor memory. Here we examined whether fast and slow motor learning processes involved in learning novel dynamics differ between younger and older adults. In addition, we investigated how age-related decline in explicit memory performance influences learning and retention parameters. Although the groups adapted equally well, they did so with markedly different underlying processes. Whereas the groups had similar fast processes, they had different slow processes. Specifically, the older adults exhibited decreased retention in their slow process compared with younger adults. Within the older group, who exhibited considerable variation in explicit memory performance, we found that poor explicit memory was associated with reduced retention in the fast process, as well as the slow process. These findings suggest that explicit memory resources are a determining factor in impairments in the both the fast and slow processes for motor learning but that aging effects on the slow process are independent of explicit memory declines. PMID- 25274820 TI - FAK is required for Schwann cell spreading on immature basal lamina to coordinate the radial sorting of peripheral axons with myelination. AB - Without Focal Adhesion Kinase (FAK), developing murine Schwann cells (SCs) proliferate poorly, sort axons inefficiently, and cannot myelinate peripheral nerves. Here we show that FAK is required for the development of SCs when their basal lamina (BL) is fragmentary, but not when it is mature in vivo. Mutant SCs fail to spread on fragmentary BL during development in vivo, and this is phenocopied by SCs lacking functional FAK on low laminin (LN) in vitro. Furthermore, SCs without functional FAK initiate differentiation prematurely, both in vivo and in vitro. In contrast to their behavior on high levels of LN, SCs lacking functional FAK grown on low LN display reduced spreading, proliferation, and indicators of contractility (i.e., stress fibers, arcs, and focal adhesions) and are primed to differentiate. Growth of SCs lacking functional FAK on increasing LN concentrations in vitro revealed that differentiation is not regulated by G1 arrest but rather by cell spreading and the level of contractile actomyosin. The importance of FAK as a critical regulator of the specific response of developing SCs to fragmentary BL was supported by the ability of adult FAK mutant SCs to remyelinate demyelinated adult nerves on mature BL in vivo. We conclude that FAK promotes the spreading and actomyosin contractility of immature SCs on fragmentary BL, thus maintaining their proliferation, and preventing differentiation until they reach high density, thereby promoting radial sorting. Hence, FAK has a critical role in the response of SCs to limiting BL by promoting proliferation and preventing premature SC differentiation. PMID- 25274822 TI - Structured synaptic inhibition has a critical role in multiple-choice motion discrimination tasks. AB - Neural network models have been constructed to explore the underlying neural mechanisms for decision-making in multiple-choice motion-discrimination tasks. Despite great progress made, several key experimental observations have not been interpreted. In contrast to homogeneous connectivity between pyramidal cells and interneurons in previous models, here their connectivity is totally structured in a continuous recurrent network model. Specifically, we assume two types of inhibitory connectivity: opposite-feature and similar-feature inhibition, representing that the connectivity strength has a maximum between neural pairs with opposite and identical preferred directions, respectively. With a common parameter set, the model accounted for a wide variety of physiological and behavioral data from monkey experiments, including those that previous models failed to reproduce. We found that the opposite-feature inhibition endows the decision-making circuit with an elimination strategy, which effectively reduces the number of choice alternatives for inspection to speed up the decision process at the cost of decision accuracy. Conversely, the similar-feature inhibition markedly enhances the ability of the network to make a choice among multiple options and improves the accuracy of decisions, while slowing down the decision process. A simplified mean-field model was also presented to analytically characterize the effect of structured inhibition on fine discrimination. We made a testable prediction: only the combination of cross-feature and similar-feature inhibition enables the circuit to make a categorical choice among 12 alternatives. Together, the current work highlights the importance of structured synaptic inhibition in multiple-choice decision-making processes and sheds light on the neural mechanisms for visual motion perception. PMID- 25274821 TI - Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. AB - Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression. PMID- 25274823 TI - Distinct representation and distribution of visual information by specific cell types in mouse superficial superior colliculus. AB - The superficial superior colliculus (sSC) occupies a critical node in the mammalian visual system; it is one of two major retinorecipient areas, receives visual cortical input, and innervates visual thalamocortical circuits. Nonetheless, the contribution of sSC neurons to downstream neural activity and visually guided behavior is unknown and frequently neglected. Here we identified the visual stimuli to which specific classes of sSC neurons respond, the downstream regions they target, and transgenic mice enabling class-specific manipulations. One class responds to small, slowly moving stimuli and projects exclusively to lateral posterior thalamus; another, comprising GABAergic neurons, responds to the sudden appearance or rapid movement of large stimuli and projects to multiple areas, including the lateral geniculate nucleus. A third class exhibits direction-selective responses and targets deeper SC layers. Together, our results show how specific sSC neurons represent and distribute diverse information and enable direct tests of their functional role. PMID- 25274825 TI - Loss of Smarc proteins impairs cerebellar development. AB - SMARCA4 (BRG1) and SMARCB1 (INI1) are tumor suppressor genes that are crucially involved in the formation of malignant rhabdoid tumors, such as atypical teratoid/rhabdoid tumor (AT/RT). AT/RTs typically affect infants and occur at various sites of the CNS with a particular frequency in the cerebellum. Here, granule neurons and their progenitors represent the most abundant cell type and are known to give rise to a subset of medulloblastoma, a histologically similar embryonal brain tumor. To test how Smarc proteins influence the development of granule neurons and whether this population may serve as cellular origin for AT/RTs, we specifically deleted Smarca4 and Smarcb1 in cerebellar granule cell precursors. Respective mutant mice displayed severe ataxia and motor coordination deficits, but did not develop any tumors. In fact, they suffered from a severely hypoplastic cerebellum due to a significant inhibition of granule neuron precursor proliferation. Molecularly, this was accompanied by an enhanced activity of Wnt/beta-catenin signaling that, by itself, is known to cause a nearly identical phenotype. We further used an hGFAP-cre allele, which deleted Smarcb1 much earlier and in a wider neural precursor population, but we still did not detect any tumor formation in the CNS. In summary, our results emphasize cell type-dependent roles of Smarc proteins and argue against cerebellar granule cells and other progeny of hGFAP-positive neural precursors as the cellular origin for AT/RTs. PMID- 25274824 TI - EAAT2 (GLT-1; slc1a2) glutamate transporters reconstituted in liposomes argues against heteroexchange being substantially faster than net uptake. AB - The EAAT2 glutamate transporter, accounts for >90% of hippocampal glutamate uptake. Although EAAT2 is predominantly expressed in astrocytes, ~10% of EAAT2 molecules are found in axon terminals. Despite the lower level of EAAT2 expression in glutamatergic terminals, when hippocampal slices are incubated with low concentration of d-aspartate (an EAAT2 substrate), axon terminals accumulate d-aspartate as quickly as astroglia. This implies an unexplained mismatch between the distribution of EAAT2 protein and of EAAT2-mediated transport activity. One hypothesis is that (1) heteroexchange of internal substrate with external substrate is considerably faster than net uptake and (2) terminals favor heteroexchange because of high levels of internal glutamate. However, it is currently unknown whether heteroexchange and uptake have similar or different rates. To address this issue, we used a reconstituted system to compare the relative rates of the two processes in rat and mice. Net uptake was sensitive to changes in the membrane potential and was stimulated by external permeable anions in agreement with the existence of an uncoupled anion conductance. By using the latter, we also demonstrate that the rate of heteroexchange also depends on the membrane potential. Additionally, our data further suggest the presence of a sodium leak in EAAT2. By incorporating the new findings in our previous model of glutamate uptake by EAAT2, we predict that the voltage sensitivity of exchange is caused by the voltage-dependent third Na(+) binding. Further, both our experiments and simulations suggest that the relative rates of net uptake and heteroexchange are comparable in EAAT2. PMID- 25274826 TI - Long-term seizure suppression and optogenetic analyses of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. AB - Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior studies have not explicitly examined cell types and synaptic mechanisms for long-term seizure suppression. To address this gap, we transplanted medial ganglionic eminence (MGE) cells from embryonic day 13.5 VGAT-Venus or VGAT-ChR2-EYFP transgenic embryos into the dentate gyrus (DG) of adult mice 2 weeks after induction of TLE with pilocarpine. Beginning 3-4 weeks after status epilepticus, we conducted continuous video-electroencephalographic recording until 90-100 d. TLE mice with bilateral MGE cell grafts in the DG had significantly fewer and milder electrographic seizures, compared with TLE controls. Immunohistochemical studies showed that the transplants contained multiple neuropeptide or calcium-binding protein-expressing interneuron types and these cells established dense terminal arborizations onto the somas, apical dendrites, and axon initial segments of dentate granule cells (GCs). A majority of the synaptic terminals formed by the transplanted cells were apposed to large postsynaptic clusters of gephyrin, indicative of mature inhibitory synaptic complexes. Functionality of these new inhibitory synapses was demonstrated by optogenetically activating VGAT-ChR2-EYFP expressing transplanted neurons, which generated robust hyperpolarizations in GCs. These findings suggest that fetal GABAergic interneuron grafts may suppress pharmacoresistant seizures by enhancing synaptic inhibition in DG neural circuits. PMID- 25274828 TI - Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors. AB - GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses. PMID- 25274827 TI - GluA1 phosphorylation contributes to postsynaptic amplification of neuropathic pain in the insular cortex. AB - Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices. PMID- 25274831 TI - Tuberculosis abscess of the chest wall. AB - A 42-year-old male presented in June of 2011 with nocturnal fevers, night sweats, an 8-kg weight loss, and a cutaneous right chest wall mass. In March of 2013, a computed tomographic scan of the thorax showed a 54 * 18 * 26-mm right lower lobe mass with peripheral calcifications, and in May of 2013, he was admitted for a segmental lobectomy, in which histologic examination of the pulmonary tissue revealed granulomas with multinucleated giant cells. The tissue was negative for acid-fast bacillae on Ziehl-Neelsen stain, and culture grew Mycobacterium tuberculosis. Therefore, he was started on four first-line antituberculosis medications and showed rapid symptomatic improvement. PMID- 25274829 TI - Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke. AB - Stroke is a major public health concern. The lack of effective therapies heightens the need for new therapeutic targets. Mammalian brain has the ability to rewire itself to restore lost functionalities. Promoting regenerative repair, including neurogenesis and dendritic remodeling, may offer a new therapeutic strategy for the treatment of stroke. Here, we report that interaction of neuronal nitric oxide synthase (nNOS) with the protein postsynaptic density-95 (PSD-95) negatively controls regenerative repair after stroke in rats. Dissociating nNOS-PSD-95 coupling in neurons promotes neuronal differentiation of neural stem cells (NSCs), facilitates the migration of newborn cells into the injured area, and enhances neurite growth of newborn neurons and dendritic spine formation of mature neurons in the ischemic brain of rats. More importantly, blocking nNOS-PSD-95 binding during the recovery stage improves stroke outcome via the promotion of regenerative repair in rats. Histone deacetylase 2 in NSCs may mediate the role of nNOS-PSD-95 association. Thus, nNOS-PSD-95 can serve as a target for regenerative repair after stroke. PMID- 25274832 TI - Prototheca wickerhamii cutaneous and systemic infections. AB - Prototheca wickerhamii, an environmental alga, rarely causes human infections. We present a case of Prototheca wickerhamii cutaneous and systemic infections in an 85-year-old male with adrenal insufficiency. This organism was identified by morphological features and microbiological tests. The patient was successfully treated with ketoconazole. PMID- 25274830 TI - Genetic labeling reveals novel cellular targets of schizophrenia susceptibility gene: distribution of GABA and non-GABA ErbB4-positive cells in adult mouse brain. AB - Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1 ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. Nevertheless, its cellular targets remain controversial. ErbB4 was thought to express in excitatory neurons, although recent studies disputed this view. Using mice that express a fluorescent protein under the promoter of the ErbB4 gene, we determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain, and hindbrain. In particular, ErbB4 is expressed in serotoninergic neurons of raphe nuclei but not in norepinephrinergic neurons of the locus ceruleus. In hypothalamus, ErbB4 is present in neurons that express oxytocin. Finally, ErbB4 is expressed in a group of cells in the subcortical areas that are positive for S100 calcium binding protein beta. These results identify novel cellular targets of NRG1-ErbB4 signaling. PMID- 25274837 TI - AAP recommendations on iodine nutrition during pregnancy and lactation. PMID- 25274838 TI - Author's Response. PMID- 25274839 TI - An embarrassment of riches. PMID- 25274840 TI - In reply. PMID- 25274842 TI - HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum. AB - OBJECTIVES: To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. METHODS: Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. RESULTS: We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. CONCLUSIONS: Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies. PMID- 25274844 TI - Vascular risk, depression, and stroke: post hoc ergo propter hoc ... or not. PMID- 25274843 TI - The entity of parkinsonism and associated lipomatosis. PMID- 25274841 TI - LMNA-associated myopathies: the Italian experience in a large cohort of patients. AB - OBJECTIVES: Our aim was to conduct a comparative study in a large cohort of myopathic patients carrying LMNA gene mutations to evaluate clinical and molecular features associated with different phenotypes. METHODS: We performed a retrospective cohort study of 78 myopathic patients with LMNA mutation and 30 familial cases with LMNA mutation without muscle involvement. We analyzed features characterizing the various forms of LMNA-related myopathy through correlation statistics. RESULTS: Of the 78 patients, 37 (47%) had limb-girdle muscular dystrophy 1B (LGMD1B), 18 (23%) congenital muscular dystrophy (MDCL), 17 (22%) autosomal dominant Emery-Dreifuss muscular dystrophy 2 (EDMD2), and 6 (8%) an atypical myopathy. The myopathic phenotypes shared a similar cardiac impairment. Cardioverter defibrillator or pacemaker was implanted in 41 (53%) myopathic patients compared to 7 (23%) familial cases without muscle involvement (p = 0.005). Heart transplantation was performed in 8 (10.3%) myopathic patients and in none of the familial cases. Ten (12.8%) myopathic patients died; there were no deaths among the familial cases (p = 0.032). Missense mutations were found in 14 patients (82%) with EDMD2 and 14 patients (78%) with MDCL compared to 17 patients (45%) with LGMD1B and 4 (67%) atypical patients. Frameshift mutations were detected in 17 (45%) LGMD1B compared to 3 (18%) EDMD2, 1 (6%) MDCL, and 2 (33%) with atypical myopathy (p = 0.021). Furthermore, frameshift mutations were found in 30 of 73 patients (41%) with heart involvement compared to 4 of 35 (11%) without heart involvement (p = 0.004). CONCLUSIONS: Our data provided new insights in LMNA-related myopathies, whose natural history appears to be dominated by cardiac involvement and related complications. PMID- 25274846 TI - Biopsy-negative PET-positive giant-cell arteritis. PMID- 25274845 TI - Cerebrovascular regulation, exercise, and mild traumatic brain injury. AB - A substantial number of people who sustain a mild traumatic brain injury report persistent symptoms. Most common among these symptoms are headache, dizziness, and cognitive difficulties. One possible contributor to sustained symptoms may be compromised cerebrovascular regulation. In addition to injury-related cerebrovascular dysfunction, it is possible that prolonged rest after mild traumatic brain injury leads to deconditioning that may induce physiologic changes in cerebral blood flow control that contributes to persistent symptoms in some people. There is some evidence that exercise training may reduce symptoms perhaps because it engages an array of cerebrovascular regulatory mechanisms. Unfortunately, there is very little work on the degree of impairment in cerebrovascular control that may exist in patients with mild traumatic brain injury, and there are no published studies on the subacute phase of recovery from this injury. This review aims to integrate the current knowledge of cerebrovascular mechanisms that might underlie persistent symptoms and seeks to synthesize these data in the context of exploring aerobic exercise as a feasible intervention to treat the underlying pathophysiology. PMID- 25274847 TI - Comment: How personal is Alzheimer disease? PMID- 25274848 TI - Pseudo-dominant inheritance of a novel CTSF mutation associated with type B Kufs disease. PMID- 25274849 TI - Midlife personality and risk of Alzheimer disease and distress: a 38-year follow up. AB - OBJECTIVE: To study the association between midlife neuroticism and extraversion and development of late-life dementia and long-standing distress in a sample of women followed for 38 years. METHODS: A population-based sample of 800 women, aged 38 to 54 years, was examined in 1968, with subsequent examinations in 1974, 1980, 1992, 2000, and 2005. Neuroticism and extraversion were assessed using the Eysenck Personality Inventory at baseline. Distress was measured according to a standardized question at each study wave. Dementia was diagnosed according to DSM III-R criteria based on information from neuropsychiatric examinations, informant interviews, hospital records, and registry data. RESULTS: During the 38-year follow-up, 153 women developed dementia; Alzheimer disease (AD) dementia was diagnosed in 104 of these. A higher degree of neuroticism in midlife was associated with increased risk of AD dementia and long-standing distress over 38 years. The association between neuroticism and AD dementia diminished after adjusting for long-standing distress. Extraversion was associated with a lower degree of long-standing distress, but had no impact on AD dementia. When the 2 personality dimensions were combined, high neuroticism/low extraversion showed the highest risk of AD dementia. CONCLUSIONS: Our study suggests that midlife neuroticism is associated with increased risk of AD dementia, and that distress mediates this association. The results have clinical implications because a group of women at risk of AD dementia is identified. PMID- 25274850 TI - Residential exposure to extremely low frequency electromagnetic fields and the risk of ALS. PMID- 25274851 TI - Predicting quality of life outcomes after subthalamic nucleus deep brain stimulation. AB - OBJECTIVES: To examine disease, treatment, cognitive, and psychological factors associated with quality of life (QoL) before and after surgery and assess the ability to predict QoL outcomes. METHODS: We identified a retrospective, cross sectional sample of 85 patients with Parkinson disease who underwent subthalamic deep brain stimulation (DBS). Patients' QoL was categorized as "improved" and "stable/worsened" using reliable change indices. Univariate correlational analyses identified relationships between Parkinson's Disease Questionnaire-39 ratings and disease (Unified Parkinson's Disease Rating Scale-III [UPDRS-III] motor scores on and off medications, disease duration), treatment (medication burden, unilateral vs bilateral DBS), cognitive (neuropsychological battery), and psychological (depression) variables. Step-wise multiple linear regression and logistic regression models included selected preoperative variables to predict change in QoL ratings and QoL outcome after surgery. RESULTS: Fifty-one percent of patients reported clinically significant improvements in QoL while 47% reported stable QoL and 2% worsened. Motor scores (UPDRS-III) were not relevant to QoL changes, potentially because of the rarity of poor motor outcomes, while single-trial learning and depression scores were the most important variables in predicting QoL changes. There was a subtle additional benefit to undergoing bilateral subthalamic nucleus DBS. CONCLUSIONS: The findings provide greater insight into the nonmotor features that contribute to the success of subthalamic nucleus DBS procedures from the patient's perspective and raise questions about the treatment focus and emphasis on symptom profiles in DBS candidacy evaluations. PMID- 25274852 TI - Depression in context of low neuroticism is a risk factor for stroke: a 9-year cohort study. AB - OBJECTIVE: Depression predicts stroke; however, meta-analyses show significant heterogeneity. We hypothesize that the risk of depression on incident stroke is conditional upon the relative contribution of vascular disease and of neuroticism in the underlying pathways to depression in a specific patient. We examined whether depression increases stroke in persons with low neuroticism and without preexisting cardiac disease. METHODS: This was a population-based cohort study with 9-year follow-up (n = 2,050; >=55 years, 52% female). The incidence of stroke was determined by self-report data as well as data from general practitioners and death certificates. Neuroticism was measured using the Dutch Personality Questionnaire and depression using the Center for Epidemiologic Studies-Depression scale. All data were analysed by Cox proportional hazards regression. RESULTS: A total of 117 incident cases of stroke occurred during follow-up. Among persons with a history of cardiac disease (n = 401), depression predicted incident stroke independent of neuroticism level with a hazard ratio (HR) of 1.05 (95% confidence interval [CI] 1.01-1.10) (p = 0.02). In persons without cardiac disease (n = 1,649), depression and neuroticism interacted significantly in predicting incident stroke (p = 0.028). Stratified analyses showed that depression predicted incident stroke in those with low neuroticism, HR 1.05 (95% CI 1.00-1.09) (p = 0.033), but not in those with high neuroticism, HR 1.01 (95% CI 0.96-1.05) (p = 0.82). CONCLUSIONS: In persons without preexistent cardiac disease, depression is only predictive for future stroke in absence of high neuroticism. This might be explained by the hypothesis that late life depression in context of low neuroticism is a marker of subclinical vascular disease. PMID- 25274853 TI - Detection of modified-live equine intranasal vaccine pathogens in adult horses using quantitative PCR. PMID- 25274854 TI - Combinations of oseltamivir and fibrates prolong the mean survival time of mice infected with the lethal H7N9 influenza virus. AB - The outbreak of human infections caused by the novel avian-origin H7N9 influenza viruses in China since March 2013 underscores the urgent need to find an effective treatment strategy against H7N9 infection in humans. In this study, we assessed the effectiveness of combinations of oseltamivir and two immunomodulators (simvastatin and fenofibrate) against H7N9 infection in a mouse model. Mice treated with oseltamivir plus fenofibrate exhibited the longest mean survival time, the largest reduction of viral titre in lung tissue, the highest levels of CD4(+) and CD8(+) T-lymphocytes, and the greatest decrease in pulmonary inflammation. Thus, the combination of oseltamivir plus fenofibrate improved the outcomes of mice infected with H7N9 virus by simultaneously reducing viral replication and normalizing the aberrant immune response. This drug combination should be considered in randomized controlled trials of treatments for H7N9 patients. PMID- 25274855 TI - Combinatorial library-based profiling of the antibody response against hepatitis C virus in humans. AB - The antibody response plays a crucial role against hepatitis C virus (HCV) infection, and our understanding of this intricate progress in vivo is far from complete. We previously reported a novel and robust technique based on a large combinatorial viral antigen library displayed on the surface of the yeast Saccharomyces cerevisiae, allowing comprehensive profiling of polyclonal antibody responses in vivo in both qualitative and quantitative terms. Here, we report the generation and application of a combinatorial library of HCV strain JFH1 envelope glycoprotein to profile the antibody response in four HCV chronically infected individuals. By systematic analysis of the location and frequency of antigenic fragments along the JFH1 envelope glycoprotein, we showed that the major binding antibody response was targeted to E2 (80.9-99.8 %), whilst that against E1 was relatively small (0.3-19.0 %). A total of five major antigenic domains (D1-D5) were identified: one was within E1 and an additional four within E2, despite substantial variability among the different individuals. However, serum absorption with the yeast clones containing the antigenic domain D1 resulted in more reduction in neutralizing antibody activity against pseudotyped HCV than those in E2, suggesting that E1 contains additional neutralizing epitopes. Our results have provided additional insights into the HCV-specific antibody response in humans and should assist in a better understanding of protective antibody immunity and in guiding the development of effective vaccines and therapeutics against HCV infection. PMID- 25274856 TI - Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus. AB - Biopsies from patients show that hepadnaviral core proteins and capsids - collectively called core - are found in the nucleus and cytoplasm of infected hepatocytes. In the majority of studies, cytoplasmic core localization is related to low viraemia while nuclear core localization is associated with high viral loads. In order to better understand the molecular interactions leading to core localization, we analysed transfected hepatoma cells using immune fluorescence microscopy. We observed that expression of core protein in the absence of other viral proteins led to nuclear localization of core protein and capsids, while expression of core in the context of the other viral proteins resulted in a predominantly cytoplasmic localization. Analysis of which viral partner was responsible for cytoplasmic retention indicated that the HBx, surface proteins and HBeAg had no impact but that the viral polymerase was the major determinant. Further analysis revealed that epsilon, an RNA structure to which the viral polymerase binds, was essential for cytoplasmic retention. Furthermore, we showed that core protein phosphorylation at Ser 164 was essential for the cytoplasmic core localization phenotype, which is likely to explain differences observed between individual cells. PMID- 25274857 TI - An avian leukosis virus subgroup J isolate with a Rous sarcoma virus-like 5'-LTR shows enhanced replication capability. AB - Avian leukosis virus subgroup J (ALV-J) was first isolated from meat-producing chickens that had developed myeloid leukosis. However, ALV-J infections associated with hemangiomas have occurred in egg-producing (layer) flocks in China. In this study, we identified an ALV-J layer isolate (HLJ13SH01) as a recombinant of ALV-J and a Rous sarcoma virus Schmidt-Ruppin B strain (RSV-SRB), which contained the RSV-SRB 5'-LTR and the other genes of ALV-J. Replication kinetic testing indicated that the HLJ13SH01 strain replicated faster than other ALV-J layer isolates in vitro. Sequence analysis indicated that the main difference between the two isolates was the 5'-LTR sequences, particularly the U3 sequences. A 19 nt insertion was uniquely found in the U3 region of the HLJ13SH01 strain. The results of a Dual-Glo luciferase assay revealed that the 19 nt insertion in the HLJ13SH01 strain increased the enhancer activity of the U3 region. Moreover, an additional CCAAT/enhancer element was found in the 19 nt insertion and the luciferase assay indicated that this element played a key role in increasing the enhancer activity of the 5'-U3 region. To confirm the potentiation effect of the 19 nt insertion and the CCAAT/enhancer element on virus replication, three infectious clones with 5'-U3 region variations were constructed and rescued. Replication kinetic testing of the rescued viruses demonstrated that the CCAAT/enhancer element in the 19 nt insertion enhanced the replication capacity of the ALV-J recombinant in vitro. PMID- 25274858 TI - P and M gene junction is the optimal insertion site in Newcastle disease virus vaccine vector for foreign gene expression. AB - Newcastle disease virus (NDV) has been developed as a vector for vaccine and gene therapy purposes. However, the optimal insertion site for foreign gene expression remained to be determined. In the present study, we inserted the green fluorescence protein (GFP) gene into five different intergenic regions of the enterotropic NDV VG/GA vaccine strain using reverse genetics technology. The rescued recombinant viruses retained lentogenic pathotype and displayed delayed growth dynamics, particularly when the GFP gene was inserted between the NP and P genes of the virus. The GFP mRNA level was most abundant when the gene was inserted closer to the 3' end and gradually decreased as the gene was inserted closer to the 5' end. Measurement of the GFP fluorescence intensity in recombinant virus-infected cells demonstrated that the non-coding region between the P and M genes is the optimal insertion site for foreign gene expression in the VG/GA vaccine vector. PMID- 25274859 TI - Recanalization of infrainguinal chronic total occlusions with the crosser system: results of the PATRIOT trial. AB - PURPOSE: To evaluate the angiographic and functional outcomes of the Crosser chronic total occlusion (CTO) recanalization system used to facilitate crossing of infrainguinal occlusions resistant to conventional guidewire techniques. METHODS: Eighty-five patients with a previous or concurrent failed attempt to cross a CTO using conventional guidewire techniques were enrolled at eight United States centers. Occlusions were at least 30 days old and <=30 cm in length. Primary endpoints included advancement of the recanalization system into or through the occlusion gaining guidewire access in the distal vessel beyond the lesion, and 30-day freedom from clinical perforation requiring treatment. RESULTS: The average age of occlusion was 16 months, the mean occlusion length was 117.5 +/- 84.0 mm, 55.7% had unfavorable morphology for crossing, and 75% were moderately to severely calcified. Superficial femoral artery (SFA) occlusions were most commonly treated (61.2%), followed by popliteal artery (20%), and tibioperoneal (16.5%) occlusions. The CTO was crossed and the guidewire successfully advanced into the distal true lumen in 83.5% of cases. Following adjunctive therapy, 81.2% achieved a satisfactory angiographic result (<=50% residual stenosis). At 30 days post procedure, 98.8% of patients were free from clinical perforation. CONCLUSION: Use of the Crosser CTO recanalization system facilitated crossing of guidewire-resistant, chronic, infrainguinal occlusions with minimal risk of clinically significant vessel perforation. PMID- 25274860 TI - Serial intravascular ultrasound analysis of stent strut distribution and fracture: an integrated analysis of the taxus IV, V, and VI trials. AB - AIMS: Non-uniform distribution of drug-eluting stent struts may cause uneven drug deposition associated with an adverse neointimal response and clinical events. This study assesses circumferential stent strut distribution in bare-metal (BMS) and paclitaxel-eluting (Taxus) stents post implantation and at 9-month follow-up, as well as its impact on intimal hyperplasia (IH). METHODS AND RESULTS: In the current analysis, intravascular ultrasound (IVUS) substudies of the Taxus IV, V, and VI trials were combined. Among them, 242 stents (117 BMS and 125 Taxus) had paired IVUS images post procedure and at 9-month follow-up that were reassessed at 1 mm intervals. Post implantation, the maximum interstrut angle (71.5 +/- 17.7 degrees vs 70.0 +/- 19.6 degrees ; P=.53) and minimum number of stent struts (7.1 +/- 1.0 vs 7.2 +/- 0.8; P=.32) were similar in Taxus vs BMS subgroups, respectively. At 9-month follow-up, the maximum angle increased (92.8 +/- 22.1 degrees and 81.7 +/- 20.6 degrees ) and stent strut numbers decreased (6.1 +/- 0.9 and 6.5 +/- 1.0) for both Taxus and BMS, respectively, as compared to immediately post implantation (all P<.001). The increased stent angle was more pronounced for Taxus compared with BMS (P<.01). Non-uniform strut distribution did not affect IH pattern or clinical outcomes in either stent population. No complete stent fractures were identified. CONCLUSION: Stent strut distribution changed from implantation to follow-up with an increased interstrut angle and fewer visible stent struts. These changes were more pronounced for Taxus as compared to BMS; however, non-uniform strut distribution was unrelated to increased IH or clinical outcomes. PMID- 25274861 TI - Comparison of the novel vasodilator uridine triphosphate and adenosine for the measurement of fractional flow reserve. AB - AIM: Examination of the fractional flow reserve (FFR) responses of intravenous (IV) adenosine with increasing doses of intracoronary (IC) adenosine versus IC uridine triphosphate (UTP) in patients with coronary artery disease. METHODS AND RESULTS: We measured FFR in 25 patients during continuous IV and IC infusion (using a microcatheter in the coronary ostium). Standard IV adenosine infusion (140 MUg/kg/min) was compared to 8 equimolar incremental doses of IC UTP and IC adenosine (20, 40, 60, 80, 160, 240, 320 and 640 MUg/min) in a randomized order. Across all doses, DeltaFFR[IC UTP - IC adenosine] was -0.038 +/- 0.008, P<.001. At the highest dose of IC UTP, FFR was significantly lower (FFR[IC UTP] = 0.62 +/ 0.04) than during IV adenosine (FFR[IV adenosine] = 0.72 +/- 0.05; P=.02) and IC adenosine (FFR[IC adenosine] = 0.68 +/- 0.05; P=.03). Furthermore, UTP had significantly fewer side effects compared to IV (P<.001) and IC adenosine (P<.05). CONCLUSION: IC UTP lowered FFR significantly more than both IV and IC adenosine and with fewer side effects, and could be a more precise alternative to adenosine. PMID- 25274862 TI - Transcoronary mapping of ventricular asynchrony due to left bundle branch block in a porcine model. AB - BACKGROUND: Optimal positioning of the left ventricular (LV) lead at the latest activated part of the left ventricle is one of the major challenges in implantation of cardiac resynchronization therapy (CRT) devices with respect to ascertaining an optimal resynchronization effect resulting in a high responder rate. In the present study, we evaluated the feasibility of transcoronary measurement of LV electrical activation by a coated guidewire in a porcine model. METHODS AND RESULTS: Transcoronary measurement of ventricular activation was performed in 16 pigs under general anesthesia. Left bundle branch block (LBBB) was induced by transvenous pacing in the right ventricular apex (RVA). A specially coated guidewire (Vision Wire; Biotronik) serving as the different electrode was positioned subsequently in the proximal and distal part of each coronary main vessel. A cutaneous skin patch electrode was placed at the back of the thorax of the animal to act as the indifferent electrode. Both electrodes were connected to a portable electrophysiology lab system (EP Tracer 38; CardioTek). Mean QRS width during transvenous right ventricular pacing was 83 +/- 5 ms with a typical LBBB pattern. The measured time interval between the beginning of the QRS complex in the surface electrocardiogram (ECG) and the local signal derived from the tip of the guidewire (QRS-EGM) was 32 +/- 9 ms in the distal ramus circumflex (RCX) coronary artery and 51 +/- 6 ms in the proximal RCX, yielding a mean delay of 18 +/- 8 ms within this vessel. In the left anterior descending (LAD) coronary artery, the local signal was 23 +/- 10 ms in the distal part and 41 +/- 10 ms in the proximal part of the vessel, with an identical mean delay of 18 +/- 8 ms. The QRS-EGM interval within the right coronary artery (RCA) was 14 +/- 8 ms in the distal part and 40 +/- 9 ms in the proximal part of the vessel, resulting in a mean delay of 25 +/- 7 ms. The delay between the activation of the distal RCA and the activation of the distal LAD and RCX was statistically significant (P<.001). Within the proximal guidewire positions, the latest electrical activation of the left ventricle during pacing induced LBBB could be observed in the RCX with 51.4 +/- 6.3 ms (P<.01). CONCLUSION: Transcoronary measurement of LV excitation by a specially coated guidewire is feasible and could confirm the electrical asynchrony induced by LBBB. Since coronary angiography is a mandatory part of the evaluation of patients for CRT implantation, a "transcoronary mapping procedure" can be easily performed, thereby evaluating the latest activated part of the left ventricle in advance of the implantation procedure, aiming to improve the responder rate in CRT therapy. PMID- 25274863 TI - Decrease of vascular and bleeding complications after balloon aortic valvuloplasty performed without heparin. AB - OBJECTIVES: To determine whether vascular and bleeding complications may be reduced with balloon aortic valvuloplasty (BAV) performed without heparin. BACKGROUND: Vascular and bleeding complications are currently the main adverse events occurring after BAV. METHODS: This registry included 162 consecutive patients with severe aortic stenosis who underwent BAV by femoral approach in our center between 2008 and 2012. Eighty-five patients had unfractionated heparin (UH) 50 IU/kg bolus IV during the procedure, whereas 77 patients did not have heparin. Our primary combined endpoint included severe vascular or bleeding complications (BARC score >=3), severe ischemic events (acute limb ischemia or systemic embolism) or death at 1-month follow-up. RESULTS: The primary composite endpoint was achieved in 25 patients overall (15.4%) and was significantly lower in the heparin-free group (10.3% vs 20.0%; P=.03). Vascular, bleeding, or ischemic events were dramatically lower in the heparin-free group (6.5%) compared with the heparin group (18.8%; P=.01). UH use was associated with an increased risk of vascular and bleeding complications (relative risk, 2.92; 95% confidence interval, 1.35-7.94), but not with a decreased risk of ischemic events (relative risk, 1.81, 95% confidence interval, 0.34-9.61). After adjustment for patient and procedure characteristics, including the sheath size, heparin use was the only significant predictor of the primary endpoint (adjusted odds ratio, 2.94; 95% confidence interval, 1.75-14.74). CONCLUSION: BAV performed without heparin is associated with a reduction of severe vascular events or death without increased ischemic risk. This marked difference is difficult to explain by confounding factors, but should be confirmed in a randomized controlled trial. PMID- 25274864 TI - Switching from transfemoral to transradial access for PCI: a single-center learning curve over 5 years. AB - BACKGROUND: Percutaneous coronary intervention (PCI) via the transradial (TR) route is an increasingly popular alternative to the transfemoral (TF) route. However, there are limiting factors to its adoption. We report the learning curve over 5 years in a high-volume PCI center during the crossover from TF to TR access for PCI. OBJECTIVE: To evaluate clinical characteristics, radiation doses, screening times, and subsequent clinical outcomes in subjects with femoral and radial access sites for PCI. DESIGN: We retrospectively analyzed our databases for PCI procedures/outcomes of all patients from 2006-2010. SETTING: A university teaching hospital PCI center performing cases predominantly femorally at the beginning of the study period, and transitioning to a predominantly radial access center at the end of the study period. PATIENTS: All patients undergoing PCI via either femoral or radial approach over a 5-year period. RESULTS: In year 1, TR access was used in 31.4% of cases; this rate increased to 90.1% in year 5. The switch from TF to TR access was observed among all operators and all groups of patients regardless of presentation, gender, age, and lesion complexity. In year 1, fluoroscopy times and radiation doses were higher in the TR group, but equalized in years 2 and 3 and reversed during years 4 and 5 when the TR rate was >90%. Over 5 years, the rates of vascular complications and major bleeding were higher in the TF cohort and were associated with longer hospital stay. In hospital mortality was lower in the TR group. CONCLUSION: The change from TF to TR approach for PCI in a high-volume center is achievable within 5 years, and results in marked clinical benefits. There was an initial learning curve for fluoroscopy time and radiation dose, but this improved once an operator performed >60% of cases radially. PMID- 25274865 TI - Transcatheter aortic valve-in-valve implantation: clinical outcome as defined by VARC-2 and postprocedural valve dysfunction according to the primary mode of bioprosthesis failure. AB - OBJECTIVES: The objectives of this study were to investigate: (1) the clinical outcome of transcatheter aortic valve-in-valve (VIV) implantation according to Valve Academic Research Consortium (VARC)-2 criteria; and (2) to determine whether postprocedural transvalvular gradients differ in patients with bioprosthesis regurgitation or stenosis as primary mode of failure. BACKGROUND: Transcatheter aortic VIV implantation has become a feasible option for selected high-risk patients with failed aortic surgical bioprostheses. METHODS: Transcatheter aortic VIV implantation was performed in 14 high-risk individuals at the University of Zurich and University College London. RESULTS: The prosthesis was successfully implanted in 13 patients (93%). In 1 patient, a second transcatheter valve needed to be implanted due to valve malpositioning. Thirty-day all-cause mortality was 7% (1/14). Prosthetic valve dysfunction according to VARC-2 at 30 days was observed in 7/14 patients (50%) due to an increased postprocedural transvalvular gradient >20 mm Hg. Preprocedural transaortic gradients correlated significantly with postprocedural gradients (r=0.91; P<.001). At 30-day follow-up, postprocedural gradients were higher in patients with aortic stenosis as primary mode of failure as compared to those with aortic regurgitation (36 +/- 6 mm Hg vs 16 +/- 4 mm Hg; P=.01). None of the patients exhibited prosthetic valve regurgitation of more than mild degree. CONCLUSION: The feasibility and safety of VIV implantation in failed aortic bioprostheses is demonstrated. A higher postprocedural gradient was observed after VIV implantation in patients with aortic stenosis as compared to regurgitation as primary mode of failure. PMID- 25274866 TI - Perioperative duplex ultrasound following endothermal ablation of the saphenous vein: is it worthless? AB - Fifteen years ago, radiofrequency ablation of the saphenous vein was introduced as a new and minimally invasive modality for the treatment of superficial venous insufficiency. Three years later, it was followed by endovenous laser ablation. These procedures have revolutionized the treatment of superficial venous insufficiency and have caused a dramatic shift from a highly invasive and morbid inpatient procedure, to a minimally invasive and ambulatory office procedure. Soon after their introduction, a new clinical entity was identified: endothermal heat-induced thrombosis (EHIT). This terminology, a classification system, and treatment strategies were introduced by Kabnick in 2005. Subsequently, advances in technique, along with the discovery of associated risk factors and a better understanding of the pathophysiologic process of endothermal coagulum formation, have reduced the current incidence of EHIT classes 2-4 to between 1%-2%. Still, a paucity of data exists regarding the true incidence of clinically significant pulmonary embolism secondary to EHIT. The authors believe that the rate is less than 0.01%. Furthermore, successful thermal saphenous ablation efficacy in the perioperative period approaches 99%. Despite these excellent numbers, the standard of care is to obtain a duplex ultrasound to evaluate for the presence of EHIT within the first 1-2 weeks post endovenous thermal ablation. Given this information, the authors believe that performing duplex ultrasound in the perioperative period is wasteful and an inefficacious use of limited health-care resources. Thus, the authors advocate against routine duplex to evaluate treatment efficacy and EHIT presence during the perioperative period in asymptomatic patients. PMID- 25274867 TI - Usefulness of enhanced stent visualization imaging technique in simple and complex PCI cases. AB - Stent underexpansion and underdeployment are associated with unfavorable outcomes including stent thrombosis, in-stent restenosis, and geographical miss. Visualization of coronary stents is increasingly difficult due to the reduction in stent strut thickness to improve deliverability. The gold standard evaluation method for stent expansion is intravascular ultrasound (IVUS), but its routine use is costly, time-consuming, and not without risk. Enhanced stent visualization is a novel fluoroscopy-based technique that improves visualization of deployed stents in the coronary arteries. We present a case series highlighting the use of this technique in percutaneous coronary intervention. PMID- 25274868 TI - Inappropriate use of the appropriate use criteria (AUC) as a guide for reimbursement. PMID- 25274869 TI - Subintimal space plaque modification for "balloon-uncrossable" chronic total occlusions. AB - Novel techniques for percutaneous revascularization of chronic total occlusions or other complex coronary lesions utilize the subintimal space to safely and efficiently traverse the occluded coronary segment. Antegrade and retrograde dissection reentry is gaining popularity, and is an elegant method to successfully cross coronary chronic total occlusions. We describe a "subintimal space plaque modification" that involves use of antegrade and retrograde dissection reentry techniques to treat "balloon-uncrossable" coronary lesions. PMID- 25274870 TI - Successful percutaneous management of partial avulsion of the native aortic valve complex complicating transcatheter aortic valve replacement. AB - This is the first reported case of partial aortic valve and annulus rupture during transcatheter aortic valve replacement, and its successful management through percutaneous means. It stresses the fact that even severe procedural complications can often be treated by a heart team endovascularly, without requiring sternotomy. PMID- 25274871 TI - CT-reconstructed three-dimensional printed models of the right subclavian artery and aorta define age-related changes and facilitate benchtop catheter testing. AB - BACKGROUND: Severe tortuosity of the right subclavian artery (RSCA) encountered during transradial cardiac catheterization can lead to longer procedures, increased fluoroscopy time, inability to engage the coronary artery ostia, and potentially procedural failure. Increasing age is strongly correlated with subclavian tortuosity; however, the magnitude and direction of age-related changes in aortic and subclavian artery anatomy have not been defined. METHODS: Chest computed tomography (CT) angiograms of 14 patients (6 age <45 years and 8 age >=75 years) were evaluated for RSCA tortuosity. Measurements were taken along the midline of the vessel and compared to the straight distance traveled (index of tortuosity = straight distance/midline length). One normal and one tortuous subclavian were selected for three-dimensional printing and various catheters were benchtop tested on both models. RESULTS: The older group had longer (11.95 cm vs 9.6 cm; P<.01) and more tortuous subclavian arteries (lower index of tortuosity, 0.65 vs 0.76; P<.01) with more posterior unfolding (distance to most posterior aspect, 3.74 +/- 0.77 cm vs 1.76 +/- 0.58 cm; P<.001). Engagement of the coronary arteries of the normal model was significantly easier, with successful engagement of one or both coronaries with every catheter (n=7). Only 2 of 7 catheters (Radial Brachial and Extra Backup 3.0) were able to engage the coronary arteries in the tortuous model. CONCLUSION: Age is associated with elongation, tortuosity, and posterior unfolding of the RSCA. Three-dimensional printing of normal and tortuous arteries is feasible and shows potential to test differences between catheters. PMID- 25274872 TI - Is there an effect of contrast media on multifrequency transcranial Doppler classification of cerebral microemboli during coronary angiogram? PMID- 25274876 TI - Legal applications of the "best interest of the child" standard: judicial rationalization or a measure of institutional competence? AB - This article explores the use of the best interest standard in the context of third-party interventions in ongoing parent-child relationships. I start by examining the history of the best interest standard and show that it has had different meanings in different eras. I then address the nature of the family and the question of whether interests beyond those addressed in the child's best interest standard are a legitimate part of family decision-making. I conclude that ongoing families are entitled to at least a measure of deference in their decisions about their children. Third-party interventions, such as those of doctors or judges, should require something more than simply a difference of opinion about where the child's interests lie. PMID- 25274875 TI - Genetic testing of children for diseases that have onset in adulthood: the limits of family interests. AB - Two recent policy statements, one from the American Academy of Pediatrics and one from the American College of Medical Genetics, reach very different conclusions about the question of whether children should be tested for adult-onset genetic conditions. The American Academy of Pediatrics policy begins with the presumption that genetic testing for children should be driven by the best interest of the child. It recognizes the importance of preserving the child's open future, recommending that genetic testing for adult-onset diseases be deferred. The American College of Medical Genetics, by contrast, recommended testing children for at least some adult conditions, although it should be noted they have recently modified this recommendation. They justified this recommendation by arguing that it, in fact, was in the best interests of the child and family to receive this information. In this article, we analyze these 2 different positions and suggest ways that the seeming conflicts between them might be reconciled. PMID- 25274877 TI - Is the best interest standard good for pediatrics? AB - We argue that the "best interest standard" for surrogate decision-making is problematic for a number of reasons. First, reliance on the best interest standard is subjective. Second, it leads to behavior that is intolerant and polarizing. Third, appeals to the best interest standard are often vague and indeterminate. After all, cases are usually controversial precisely because reasonable people disagree about what is or is not in a child's best interest. We then recommend that, instead of the best interest standard, parents should be held to a standard that we call the "not unreasonable" standard. By that standard, parents' decisions would be respected unless they were deemed unreasonable. This recommendation would allow a greater range for parental discretion than the best interest standard. PMID- 25274878 TI - Whose interests count? AB - Whose interests should count and how should various interests be balanced at the pediatric patient's bedside? The interests of the child patient clearly count. Recently, however, many authors have argued that the family's interests also count. But how should we think about the interests of others? What does it mean to talk about "the family" in this context? Does it really just mean the interests of each individual family member? Or is the family itself a moral entity that has interests of its own independent of the interests of each of its members? Are such interests important only as they affect the patient's interest or also for their own sake? In this special supplement to Pediatrics, a group of pediatricians, philosophers, and lawyers grapple with these questions. They examine these issues from different angles and reach different conclusions. Jointly, they demonstrate the ethical importance and, above all, the ethical complexity of the family's role at the bedside. PMID- 25274879 TI - Four models of family interests. AB - In this article, I distinguish between 4 models for thinking about how to balance the interests of parents, families, and a sick child: (1) the oxygen mask model; (2) the wide interests model; (3) the family interests model; and (4) the direct model. The oxygen mask model - which takes its name from flight attendants' directives to parents to put on their own oxygen mask before putting on their child's - says that parents should consider their own interests only insofar as doing so is, ultimately, good for the sick child. The wide interests model suggests that in doing well by my child I am at the very same time doing well by myself. My interests can, and plausibly do, encompass the interests of others; they are, to that extent, wide. There is, then, no sharp separation between the interests of the sick child and the interests of other family members. In the family interests model, families themselves are seen as having interests that are neither identical to the sum, nor a simple function, of the interests of individual family members. The family has goals, values, and aspirations that are essentially corporate rather than individual. According to this model, these family interests can explain why sacrifices can sometimes be demanded of some family members for the sake of others in a medical setting. Finally, the direct model takes a simpler view of family members' interests; it claims that these interests matter simply on their own and should be taken into account in making treatment decisions for a sick child. This model openly considers the competing interests that parents and other family members often have when caring for a sick child, and advocates for weighing those interests when making decisions for and about the sick child. While there is room for all four models at the bedside, I argue that the direct model should be highlighted in clinical decision-making. PMID- 25274880 TI - Deception and the death of Ilyusha: truth and the best interest of a dying child in The Brothers Karamazov. AB - For centuries, many physicians and parents assumed that it was ethically justifiable to lie to a dying child. The reasoning was clear. Because the lie would likely eliminate or prevent a concrete harm (the child's fear), and the lie is about a harm that is unavoidable anyway, a lie appeared to be the morally desirable thing to do. Today, the ethical consensus has shifted. Many doctors and other health professionals now argue that we have an obligation to tell children the cold, hard truth. In this article, I argue that "the cold, hard truth" (assuming we can know it with certainty) might not always be in the best interest of the patient. To illustrate the point, I analyze an episode in Dostoevsky's novel, The Brothers Karamazov, in which a child is dying, his father lies to him about it, and 2 doctors take very different approaches to the truth. Each of these individuals has a particular interest when it comes to the question of "the truth" about the death of Ilyusha. I use this story to ask whether it is ethically permissible to lie to a dying child and, if so, who has the moral authority to tell that lie. PMID- 25274881 TI - Why families matter. AB - Serious illness puts pressure not only on individual family members but also on the family itself. The care of an acutely ill child requires the family to channel many of its resources toward a single member--an arrangement that can usually be sustained for a while but that cannot continue indefinitely while the other members do without. Illness disrupts ordinary familial functions and, if it is serious enough, threatens to break the family altogether. In this article, I argue that there are situations in which the threat to family integrity is so real and serious that the interests of parents or siblings or sometimes grandparents may override the interests of the pediatric patient. PMID- 25274882 TI - Description of active joint count trajectories in juvenile idiopathic arthritis. AB - OBJECTIVE: To describe the trajectories of longitudinal joint disease activity in juvenile idiopathic arthritis (JIA), and to examine associations of clinical and laboratory characteristics with the identified trajectories. METHODS: A retrospective cohort study at 2 Canadian centers was performed. The longitudinal trajectories of active joint counts were described in a proof-of-concept study using a latent growth curve analysis. Baseline patient characteristics were compared across trajectory groups. RESULTS: Data were analyzed on 659 children diagnosed with JIA between March 1980 and September 2009. The median age at diagnosis was 10.0 years (interquartile range 3.7-13.4) and 61% (402/659) were female. The International League of Associations for Rheumatology (ILAR) diagnoses were as follows: oligoarthritis (36%), enthesitis-related arthritis (20%), rheumatoid factor (RF)-negative polyarthritis (13%), undifferentiated arthritis (12%), psoriatic arthritis (8%), systemic arthritis (7%), and RF positive polyarthritis (4%). Based on the trajectories of their active joint counts, the 659 patients were each classified in 1 of 5 latent classes (which can be described as high decreasing, moderate increasing, persistent moderate, persistent low, and minimal joint activity). These latent classes were clinically and statistically distinct from the ILAR categories. CONCLUSION: In this proof-of concept study, in which we used an analytic methodology in a novel way, we identified 5 clinically and statistically distinct trajectories of disease course. The subsets of patients within each class were different from those described by the ILAR classification criteria. This successful application of this method supports its use in a chronic disease with a fluctuating course such as JIA. These methods should be expanded for the purposes of predictive modeling. PMID- 25274883 TI - Genome wide gene expression analysis of the posterior capsule in patients with osteoarthritis and knee flexion contracture. AB - OBJECTIVE: Knee flexion contractures (KFC) are limitations in the ability to fully extend the knee joint. In people with knee osteoarthritis (OA), KFC are common, impair function, and worsen outcomes after arthroplasty. In KFC, the posterior knee capsule is believed to play a key role, but the pathophysiology remains poorly understood. We sought to identify gene expression differences in the posterior knee capsule of patients with OA with and without KFC. METHODS: Capsule tissue was obtained from the knees of 12 subjects diagnosed with advanced stage OA at the time of knee arthroplasty surgery. The presence or absence of KFC allocated patients into 2 groups using a case-control design. Genomewide capsular gene expression was compared between the 2 patient groups. Confirmation of differential expression of the corresponding proteins was performed by immunohistochemistry on tissue sections. RESULTS: There were no significant demographic differences between the patients with OA with KFC and without KFC save for reduced extension in their surgical knee (p<0.01). KFC patients showed a 6.4-fold decrease in CSN1S1 (p=0.017) gene expression and a 3.7-, 2.0-, and 2.6 fold increase in CHAD, Sox9, and Cyr61 gene expression, respectively (p=0.001, 0.004, 0.001, respectively). There were corresponding increases in protein levels for chondroadherin, sex determining region Y-box 9, and casein alphaS1 (all p<0.05). Functional analysis of the differentially expressed genes indicated a strong association with pathways related to the extracellular matrix and to tissue fibrosis. CONCLUSION: Posterior capsules in endstage OA knees with KFC exhibited differential expression of 4 genes all previously documented to be associated with tissue fibrosis. PMID- 25274884 TI - Prognosis of seronegative patients in a large prospective cohort of patients with early inflammatory arthritis. AB - OBJECTIVE: Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are believed to be associated with more severe rheumatoid arthritis; however, studies in early inflammatory arthritis (EIA) have yielded conflicting results. Our study determined the prognosis of baseline ACPA-negative and RF-negative patients. METHODS: Patients enrolled in the Canadian Early Arthritis Cohort had IgM RF and IgG anticyclic citrullinated peptide antibodies 2 (anti-CCP2) measured at baseline. Remission was defined as a Disease Activity Score of 28 joints (DAS28) < 2.6 using logistic regression accounting for confounders at 12-month and 24-month followup. RESULTS: Of the 841 patients, 216 (26%) were negative for both RF and anti-CCP2. Compared to seropositive subjects, seronegative subjects were older (57 +/- 15 vs 51 +/- 14 yrs), more males proportionately (31% vs 23%), and had shorter length of symptoms (166 +/- 87 vs 192 +/- 98 days), and at baseline had higher mean swollen joint count (SJC; 8.8 +/- 6.8 vs 6.5 +/- 5.6), DAS28 (5.0 +/- 1.6 vs 4.8 +/- 1.5), and erosive disease (32% vs 24%, p < 0.05). Treatment was similar between the 2 groups. At 24-month followup, seronegative compared to seropositive subjects had greater mean change (Delta +/- SD) in disease activity measures: DeltaSJC counts (-6.9 +/- 7.0 vs -5.1 +/- 5.9), DeltaDAS28 (-2.4 +/- 2.0 vs -1.8 +/- 1.8), and DeltaC-reactive protein (-11.0 +/- 17.9 vs -6.4 +/- 17.5, p < 0.05). Accounting for confounders, antibody status was not significantly associated with remission. However, at 12-month followup, ACPA positive subjects were independently more likely to have new erosive disease (OR 2.94, 95% CI 1.45-5.94). CONCLUSION: Although seronegative subjects with EIA have higher baseline DAS28 compared to seropositive subjects, they have a good response to treatment and are less likely to develop erosive disease during followup. PMID- 25274885 TI - Systemic sclerosis sine scleroderma: a multicenter study of 1417 subjects. AB - OBJECTIVE: To describe the clinical and serological features of systemic sclerosis sine scleroderma (ssSSc) in a multicentered SSc cohort. METHODS: Data from 1417 subjects in the Canadian Scleroderma Research Group registry were extracted to identify subjects with ssSSc, defined as SSc diagnosed by an expert rheumatologist, but without any sclerodactyly or skin involvement prior to baseline study visit or during followup. Clinical and serological features of ssSSc subjects were compared to limited (lcSSc) and diffuse cutaneous SSc (dcSSc) subjects. RESULTS: At the first registry visit, only 57 subjects (4.0%) were identified as having ssSSc. Of these, 30 (2.1%) were reclassified as lcSSc within 1.9 years. Thus, only 27 ssSSc subjects (1.9%) remained, with mean followup of 2.4 years. Clinical profiles of ssSSc were generally similar or milder compared to lcSSc, and milder than dcSSc, including rates of interstitial lung disease (25.9% ssSSc, 25.4% lcSSc, 40.3% dcSSc). Patients with ssSSc had serological profiles similar to those with lcSSc, including high rates of anticentromere antibodies (50.0% ssSSc, 47.5% lcSSc, 12.1% dcSSc), and low rates of antitopoisomerase I (16.7% ssSSc, 7.0% lcSSc, 21.8% dcSSc) and anti-RNA polymerase III (0 ssSSc, 11.1% lcSSc, 34.9% dcSSc). CONCLUSION: The condition ssSSc is rare and resembles lcSSc. These observations suggest that ssSSc is most likely a forme fruste of lcSSc, and that the absence of skin involvement may in part be related to misclassification arising from early or subtle skin involvement. There is little evidence to consider ssSSc as a distinct clinical or serological subset of SSc. PMID- 25274886 TI - Clinical manifestations and longterm outcome for patients with Takayasu arteritis in China. AB - OBJECTIVE: To describe a large cohort of patients with Takayasu arteritis in China. METHODS: We retrospectively analyzed 566 patients hospitalized in Fuwai Hospital between 2002 and 2013. Data collected were clinical characteristics, laboratory findings, angiographic features, treatment, and longterm outcome. RESULTS: The female to male ratio was 3.8 to 1, and the mean age of onset was 28.9 +/- 12.0 years. The most common inflammatory symptom, initial symptom, and coexisting disease were fever (52, 9.2%), dizziness (214, 37.8%), and hypertension (HTN; 392, 69.3%), respectively. Pulmonary artery, coronary artery involvement, and aortic regurgitation were found in 83 (14.7%), 66 (11.7%), and 181 (36.7%) patients, respectively. Elevation of the erythrocyte sedimentation rate was observed in 131 patients (23.1%). Treatment included drugs, interventional therapy, autologous blood vessel transplant, artificial blood vessel transplant, and aortic valve replacement. During a mean followup of 5.0 +/ 0.2 years, 32 patients died, including 1 patient who died suddenly during coronary angiography. HTN, major complications, and a progressive disease course were significant prognostic markers. CONCLUSION: HTN, rather than fever, is the leading reason for patients with Takayasu arteritis to see a doctor in China. HTN, major complications, and a progressive disease course are statistically significant predictors of survival. Because of cardiovascular events associated with the disease, early diagnosis and treatment are urgent to improve prognosis. PMID- 25274887 TI - Transitioning to employment with a rheumatic disease: the role of independence, overprotection, and social support. AB - OBJECTIVE: To examine perceived independence, overprotection, and support, and their association with the employment participation of young adults with rheumatic disease. METHODS: One hundred and forty-three young adults, ages 18 to 30 years, with systemic lupus erythematosus (54.5%) and juvenile arthritis (45.5%) completed a 30-min online questionnaire of their work and education experiences. Information collected was demographic, health (e.g., pain, fatigue, disease activity), work context (e.g., career satisfaction, helpfulness of job accommodation/benefits, and workplace activity limitations), and psychosocial (e.g., independence, social support, and overprotection). Log-Poisson regression analysis examined factors associated with employment status. RESULTS: Over half of respondents were employed (59%) and 26% were enrolled in school. Respondents reported moderate to high perceptions of independence and social support. However, 27% reported that "quite a bit" to "a great deal" of overprotection characterized their relationships with those closest to them. At the bivariate level, employed participants and those indicating greater perceived independence reported greater social support and less overprotection. Multivariable analysis revealed that being employed was associated with older age, more job accommodations/benefits perceived as being helpful, and greater perceived independence. CONCLUSION: This is one of the first studies examining the employment of young adults with rheumatic diseases. Findings highlight the importance of psychosocial perceptions such as independence and overprotection, in addition to support related to working. Additional research is needed to better understand the role of those close to young adults with rheumatic diseases in supporting independence and encouraging employment. PMID- 25274888 TI - Detection of subclinical synovitis with macrophage targeting and positron emission tomography in patients with rheumatoid arthritis without clinical arthritis. AB - OBJECTIVE: To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure. METHODS: (R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0-3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0-66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (>1) were summed to obtain a cumulative MRI score (range 0-288). Occurrence of flare was determined during 3-year followup. RESULTS: Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (>6, n=3) corresponded with highest cumulative MRI scores (>39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0-4.5) vs 0 (0-1), p<0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare. CONCLUSION: (R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R) 11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years. PMID- 25274889 TI - Development of a modified hand mobility in scleroderma (HAMIS) test and its potential as an outcome measure in systemic sclerosis. AB - OBJECTIVE: To modify the hand mobility in scleroderma (HAMIS) test by reducing the number of items and amount of equipment needed, and to evaluate the construct validity of this modified HAMIS (mHAMIS). METHODS: Our retrospective study is based on 266 patients previously examined using the original HAMIS test. Data were divided into 3 groups depending on disease duration after onset: (1) 0-3 years, (2) 3.1-5 years, and (3) 5.1-9 years. Disease variables included were skin involvement using the disease subset and the modified Rodnan skin score (mRSS), and digital lesions. Cronbach's alpha coefficient was calculated separately for limited (lcSSc) and diffuse systemic sclerosis (dcSSc) for the right and left hand, and for the groups with different disease duration. The construct validity of the mHAMIS was assessed by searching for a correlation with hand skin score. RESULTS: An mHAMIS test consisting of finger flexion, finger extension, finger abduction, and dorsal extension was developed. The internal consistency of this test was 0.78, 0.83, and 0.73 in the 3 groups with different disease duration. In the whole study group, mHAMIS showed a significant correlation with mRSS and hand skin score (rs=0.39 and 0.43, respectively), and was able to discriminate between lcSSc and dcSSc (p=0.001), and between patients with and without ulcers (p=0.015). CONCLUSION: The mHAMIS involves 4 easily measurable items and has the potential to be a relevant clinical measure of outcome in the evaluation of fibrotic skin involvement in SSc. PMID- 25274890 TI - Performance of the 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis (SSc) in large, well defined cohorts of SSc and mixed connective tissue disease. AB - OBJECTIVE: To assess the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for Systemic Sclerosis (SSc) on defined subgroups of SSc and in mixed connective tissue disease (MCTD) as an SSc-related disease. METHODS: The 2013 ACR/EULAR criteria were assessed in 425 consecutive patients suspected to have SSc and seen at Oslo University Hospital, and in the nationwide Norwegian MCTD cohort (n = 178). In the SSc group, 239/425 patients had disease duration < 3 years (in 82 of these, duration was < 1 yr). Patients were subgrouped as limited SSc (n = 294), diffuse SSc (n = 97), SSc sine scleroderma (n = 10), and early SSc (prescleroderma; n = 24). Item data were complete, except nailfold capillaroscopy and telangiectasia results, missing in the MCTD cohort. RESULTS: The 2013 ACR/EULAR SSc criteria were met by 409/425 patients (96%) in the SSc group. For comparison, only 75% (293/391) met the 1980 ACR SSc classification criteria. All the novel items in the 2013 ACR/EULAR criteria were frequent in the SSc cohort. Considering that there were missing data on 2 items, 10% (18/178) of the MCTD cohort met the 2013 ACR/EULAR criteria, giving an estimated specificity of 90% toward this SSc-like disorder. CONCLUSION: In our large and representative group of consecutive patients with SSc, the 2013 ACR/EULAR SSc criteria were more sensitive than the ACR 1980 criteria. However, the new criteria did not completely segregate SSc from MCTD, making specificity a potential issue. PMID- 25274891 TI - Coronary and abdominal aorta calcification in rheumatoid arthritis: relationships with traditional cardiovascular risk factors, disease characteristics, and concomitant treatments. AB - OBJECTIVE: To assess the influence of traditional cardiovascular (CV) risk factors, disease characteristics, and concomitant treatments in patients with rheumatoid arthritis (RA) on coronary artery calcification (CAC) and abdominal aorta calcification (AAC). METHODS: In our cross-sectional study, 75 patients with RA were compared with 75 age-matched and sex-matched control participants. The CAC and AAC scores were measured by computed tomography in patients with no clinical evidence of coronary artery disease. The relationships between the presence or absence of CAC and AAC and traditional CV risk factors, disease characteristics, and concomitant treatments in patients with RA were assessed in a multiple logistic regression analysis. RESULTS: The RA and control groups did not differ significantly in terms of age, sex composition, or the prevalence of traditional CV risk factors. AAC and CAC were more prevalent and severe in patients with RA than in controls. Older age (OR=1.15, p<0.01) and hypertension (OR=3.77, p=0.04) were found to be independently associated with CAC, whereas current use of methotrexate (MTX; OR=0.12, p=0.01) was found to be associated with the absence of CAC. Older age (OR per yr=1.17, p<0.001) and erosive arthritis (OR=3.78, p=0.03) were found to be independently associated with AAC. CONCLUSION: Our study demonstrates that in patients with RA, (1) CAC and AAC are more prevalent and more severe compared with age-matched and sex-matched control participants, (2) current use of MTX is a major determinant of the absence of CAC, and (3) erosive arthritis is a major determinant of AAC. PMID- 25274893 TI - The effect of antiestrogen agents on risk of autoimmune disorders in patients with breast cancer. AB - OBJECTIVE: To investigate the relationship between antiestrogen therapy in women with breast cancer and risk of autoimmune disease. METHODS: We used a national database to assess the incidence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) following treatment with selective estrogen receptor modulators (SERM) or aromatase inhibitors (AI) in women with breast cancer. The total number of patients in our study was 190,620. RESULTS: We observed highly significant, cumulative dose-dependent increased OR of incidence of both SLE and RA following treatment with SERM (p < 0.0001). The odds of developing RA were also increased following AI therapy (p < 0.001), but there was a trend for reduced odds of SLE, though this trend did not attain statistical significance (p = 0.070 for 2-11 months of treatment and p = 0.254 for 12+ months of treatment). CONCLUSION: Antiestrogen agents may have an important effect on risk of autoimmune disease. PMID- 25274892 TI - Failure in longterm treatment is rare in actively treated patients with rheumatoid arthritis, but may be predicted by high health assessment score at baseline and by residual disease activity at 3 and 6 months: the 5-year followup results of the randomized clinical NEO-RACo trial. AB - OBJECTIVE: With modern initial aggressive combination treatments with synthetic disease-modifying antirheumatic drugs (sDMARD), most patients with rheumatoid arthritis (RA) achieve remission, have marginal radiographic progression, and sustain normal function. Here we aim to identify the patients failing these targets even after aggressive treatment. METHODS: Ninety-nine patients with early, active RA were treated with a combination of 3 sDMARD and prednisolone (PRD), and either infliximab or placebo infusions during the first 6 months, aiming at strict remission. After 24 months, the treatments became unrestricted. At 60 months, 4 evident clinical features of treatment failure were defined: area under curve (AUC) between 6-60 months for disease activity score assessing 28 joints > 2.6; AUC 6-60 for health assessment questionnaire > 0.5; progression in total Sharp/van der Heijde score 0-60 months > 3 units; and need of PRD or biologic DMARD treatment at 60 months. RESULTS: A total of 93 patients were followed up for 60 months. Of them, 45 had no features of treatment failure, 30 had 1, 10 had 2, 7 had 3, and 1 patient had all 4 features. Having 2-4 features of treatment failure at 5 years was predicted by the health assessment score at baseline, and by even low residual disease activity at 3 and 6 months. CONCLUSIONS: Only 20% of the patients with RA treated early with combination sDMARD and PRD have more than 1 clinical feature of treatment failure at 60 months. Residual clinical disease activity at 3-6 months was the most important predictor for identifying these patients. The study was registered at www.clintrials.gov (NCT00908089). PMID- 25274895 TI - Evaluation of germinal center-like structures and B cell clonality in patients with primary Sjogren syndrome with and without lymphoma. AB - OBJECTIVE: Germinal center (GC)-like structures have previously been observed in minor salivary glands (MSG) of patients with primary Sjogren syndrome (pSS). The aim of our study was to explore the prevalence and features of GC-like structures and B cell clonality in patients with pSS with and without lymphoma. METHODS: Based on a nationwide survey in Norway, we included 21 patients with pSS and with a concomitant lymphoma from whom MSG and/or lymphoma biopsies were available. Tonsil biopsies and MSG from 28 patients with pSS without lymphoma were used as controls. The presence of GC-like structures was investigated with H&E staining and double staining for CD21/IgD and CD38/IgD. B cell clonality in MSG and tumors were investigated with analysis of immunoglobulin gene rearrangements. RESULTS: H&E labeling of MSG revealed GC-like structures in 17/40 (43%) of the patients: 4/12 (33%) with and 13/28 (46%) without lymphoma. Staining for CD21/CD38/IgD demonstrated CD21+ networks in 27/40 (68%) of the patients. CD21+/CD38- infiltrates were seen in 25/40 (63%) of the patients, and 16 of these were IgD+ within the infiltrate. Five percent (2/40) of the patients presented with CD21+/CD38+ infiltrates resembling tonsillar GC. Monoclonal B cell infiltration in MSG was present in 5/12 patients (42%) with and 5/28 patients (18%) without lymphoma (p=0.12). In 2/10 (20%) of cases where both MSG and lymphoma biopsies were available, identical clonal rearrangements were detected. CONCLUSION: GC like structures seen in H&E-stained MSG may represent various subtypes of CD21+ infiltrates. We were unable to detect a clear association between cellular infiltrates, B cell clonality, and lymphoma development. PMID- 25274894 TI - Which factors influence radiographic progression during treatment with tumor necrosis factor inhibitors in clinical practice? Results from 930 patients with rheumatoid arthritis in the nationwide Danish DANBIO registry. AB - OBJECTIVE: To investigate baseline characteristics associated with radiographic progression and the effect of disease activity, drug, switching, and withdrawal on radiographic progression in tumor necrosis factor (TNF) inhibitor-naive patients with rheumatoid arthritis (RA) followed for about 2 years after anti-TNF initiation in clinical practice. METHODS: DANBIO-registered patients with RA who had available radiographs (anti-TNF initiation and ~2 yrs followup) were included. Radiographs were scored, blinded to chronology with the Sharp/van der Heijde method and linked with DANBIO data. Baseline characteristics were investigated with univariate regression and significant variables included in a multivariable logistic regression analysis with +/- radiographic progression [Delta total Sharp score (TSS) > 0] as dependent variable. Effect of time averaged C-reactive protein (CRP), 28-joint Disease Activity Score with CRP (DAS28-CRP), and treatment status at followup were investigated with univariate regression analysis. RESULTS: The study included 930 patients. They were 75% women, 79% positive for IgM-rheumatoid factor (IgM-RF), median age was 57 yrs (range 19-88), disease duration 9 yrs (1-59), DAS28-CRP 5.0 (1.4-7.8), TSS median 15 [3-45 interquartile range (IQR)] and mean 31 (SD 40). Patients started treatment with infliximab (59%), etanercept (18%), or adalimumab (23%). At followup (median 526 days, IQR 392-735), 61% were treated with the initial anti TNF, 29% had switched TNF inhibitor, and 10% had withdrawn. Twenty-seven percent of patients had progressed radiographically. DeltaTSS was median 0.0 [0.0-0.5 IQR/mean 0.6 (SD 2.4)] units/year. Higher TSS, older age, positive IgM-RF, and concomitant prednisolone at baseline were associated with radiographic progression. Time-averaged DAS28-CRP and time-averaged CRP, but not type of TNF inhibitor, were associated with radiographic progression. Patients who stopped/switched during followup progressed more than patients who continued treatment. CONCLUSION: High TSS, older age, IgM-RF positivity, and concomitant prednisolone were associated with radiographic progression during 2 years of followup of 930 anti-TNF-treated patients with RA in clinical practice. High disease activity and switching/stopping anti-TNF treatment were associated with radiographic progression. PMID- 25274896 TI - The effect of male sex on survival in systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) has a female predominance, however, little is understood about the effect of sex on SSc manifestations and survival. The objectives of our study were to evaluate differences in disease manifestations, and survival rates between males and females with SSc. METHODS: A retrospective cohort study of the Toronto Scleroderma Program was conducted to evaluate sex based differences in disease manifestations and survival. A relative survival analysis compared SSc survival to the general population. RESULTS: There were 959 patients (791 females, 168 males) identified, with a female:male ratio of 4.7:1. Males more frequently had diffuse SSc [45% vs 30%, relative risk (RR) 1.44, 95% CI 1.18-1.75] and interstitial lung disease (ILD; 41% vs 33%, RR 1.24, 95% CI 1.01-1.52). There were 324 deaths (65 males, 259 females). Males had increased unadjusted mortality compared to females (HR 1.57, 95% CI 1.19-2.06). In an adjusted model including immunosuppressive use, male sex (HR 1.40, 95% CI 1.06 1.85), ILD (HR 1.58, 95% CI 1.26-1.98), and older age at diagnosis (HR 1.05, 95% CI 1.04-1.06) were independently associated with increased mortality, whereas the limited subtype (HR 0.70, 95% CI 0.49-0.77) and anticentromere antibodies (HR 0.70, 95% CI 0.49-0.98) were independently associated with decreased mortality. Male sex was associated with increased risk of mortality (HR 1.16, p=0.003) in patients with SSc above that observed for males in the general population. CONCLUSION: The differential effect of disease between sexes is small, yet males have decreased survival compared to females with SSc. PMID- 25274897 TI - Naproxen effects on brain response to painful pressure stimulation in patients with knee osteoarthritis: a double-blind, randomized, placebo-controlled, single dose study. AB - OBJECTIVE: The aim of our study was to investigate the effects of naproxen, an antiinflammatory analgesic drug, on brain response to painful stimulation on the affected knee in chronic osteoarthritis (OA) using functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled study. METHODS: A sample of 25 patients with knee OA received naproxen (500 mg), placebo, or no treatment in 3 separate sessions in a randomized manner. Pressure stimulation was applied to the medial articular interline of the knee during the fMRI pain sequence. We evaluated subjective pain ratings at every session and their association with brain responses to pain. An fMRI control paradigm was included to discard global brain vascular effects of naproxen. RESULTS: We found brain activation reductions under naproxen compared to no treatment in different cortical and subcortical core pain processing regions (p<=0.001). Compared to placebo, naproxen triggered an attenuation of amygdala activation (p=0.001). Placebo extended its attenuation effects beyond the classical pain processing network (p<=0.001). Subjective pain scores during the fMRI painful task differed between naproxen and no treatment (p=0.037). Activation attenuation under naproxen in different regions (i.e., ventral brain, cingulate gyrus) was accompanied by an improvement in the subjective pain complaints (p<=0.002). CONCLUSION: Naproxen effectively reduces pain-related brain responses involving different regions and the attenuation is related to subjective pain changes. Our current work yields further support to the utility of fMRI to objectify the acute analgesic effects of a single naproxen dose in patients affected by knee OA. The trial was registered at the EuropeanClinicalTrials Database, "EudraCT Number 2008-004501-33". PMID- 25274898 TI - Anticyclic citrullinated peptide antibodies in rheumatoid and nonrheumatoid rheumatic disorders: experience with 1162 patients. AB - OBJECTIVE: Anticyclic citrullinated peptide antibodies (anti-CCP) are considered specific markers of rheumatoid arthritis (RA) and have been included in the revised classification criteria for RA diagnosis. However, these antibodies have also been detected in patients with other types of chronic inflammatory rheumatism. Our objectives were to identify the prevalence of positive anti-CCP patients in non-RA diseases, to determine the diagnostic value of anti-CCP for the diagnosis of RA, to specify the clinical characteristics of non-RA patients positive for anti-CCP, and to determine the discriminatory value of the levels of anti-CCP in patients among the various diseases. METHODS: We carried out an observational and descriptive study. All the determinations of anti-CCP requested by the 2 rheumatology departments at Cochin Hospital over a period of 18 months were analyzed. Such determinations were requested for 1162 patients in total. Anti-CCP levels were determined with the Euro Diagnostica ELISA kit, with values >= 25 U for this test being considered positive. The diagnosis of rheumatic conditions was the responsibility of the treating physician. RESULTS: Anti-CCP antibodies were detected in 357 (30.7%) of the 1162 patients. The prevalence of anti-CCP was 292/417 (70.0%) in RA, 13/122 (10.6%) in patients with psoriatic arthritis, 13/62 (20.9%) in patients with unclassified rheumatism, 11/33 (33.3%) in patients with primary Sjogren syndrome, 5/30 (16.6%) in patients with systemic lupus erythematosus, 3/28 (10.7%) in patients with mixed connective tissue disorder, 3/36 (8.3%) in patients with systemic sclerosis, 7/44 (15.9%) in patients with juvenile arthritis, and 6/220 (2.7%) in patients with noninflammatory diseases. In the population of patients positive for anti-CCP, mean anti-CCP levels were 869.4 (+/- 978.4) U/ml, with no significant difference between RA [854.8 (+/- 959.8) U/ml] and any of the non-RA conditions [922.7 (+/- 1070.0) U/ml]. CONCLUSION: Anti-CCP are a hallmark of RA, but may be observed in other inflammatory, systemic, or mechanical diseases. In this large cohort of patients, the presence of second-generation anti-CCP (anti-CCP2) antibodies is useful in diagnosing RA (70% sensitivity, 91.3% specificity), but examining the levels of these antibodies does not appear to offer further discriminatory power among patients who are anti-CCP2-positive. PMID- 25274899 TI - Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen. AB - OBJECTIVE: Two studies evaluated efficacy and safety of tanezumab versus naproxen for treatment of knee or hip osteoarthritis (OA). METHODS: Randomized controlled studies [NCT00830063 (Study 1015, n=828) and NCT00863304 (Study 1018, n=840)] of subjects with hip or knee OA compared intravenous tanezumab (5 mg or 10 mg) to placebo and naproxen (500 mg twice daily). Coprimary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function (0-10 numerical rating scale), and patient's global assessment of OA at Week 16. RESULTS: In both studies, tanezumab reduced pain versus placebo [least squares mean differences, 95% CI, tanezumab 5 mg: -1.21 (-1.72, -0.70); 1.13 (-1.65, -0.62); tanezumab 10 mg: -0.91 (-1.42, -0.40); -0.80 (-1.32, 0.29)], and improved function and global scores. Tanezumab 5 mg produced greater pain reduction [-0.76 (-1.28, -0.25); -0.69 (-1.21, -0.17)], and favorable functional and global outcomes versus naproxen. Pain reductions with tanezumab 10 mg versus naproxen did not reach significance, unlike functional (both studies) and global (1 study) outcomes; thus, tanezumab 10 mg was not superior to naproxen, and predefined statistical testing procedures were not met, allowing for conclusion of superiority of tanezumab 5 mg over naproxen despite replicated favorable coprimary outcomes. Tanezumab was associated with greater incidence of peripheral sensory adverse events (paresthesia, hyperesthesia, hypoesthesia, burning sensation), pain in extremity, peripheral edema, and arthralgia. Overall frequency and discontinuations as a result of adverse events were similar to placebo and naproxen. CONCLUSION: Tanezumab provides efficacious treatment of knee or hip OA and may have therapeutic utility in patients with OA who experience inadequate analgesia with nonsteroidal antiinflammatory drugs. PMID- 25274900 TI - Patients with rheumatoid arthritis in clinical remission manifest persistent joint inflammation on histology and imaging studies. AB - OBJECTIVE: The purpose of our study was to test the hypothesis that synovitis on magnetic resonance imaging (MRI) and ultrasound (US) observed in patients with rheumatoid arthritis (RA) who meet remission criteria reflects active inflammation on histopathology. METHODS: We analyzed 15 synovial specimens obtained during surgical procedures from 14 patients with RA in clinical remission as defined by the American College of Rheumatology criteria. Histological specimens were scored for hyperplasia of synovial lining and synovial stroma, inflammation, lymphoid follicles, and vascularity. The histology scores were classified as minimal, mild, moderate, or severe disease activity. US and MRI performed within a 4-month period of surgery were scored for disease activity. The correlation between histology and imaging scores was examined. RESULTS: Four of 14 patients were receiving anti-tumor necrosis factor (TNF) therapy, 4 were receiving methotrexate (MTX) alone, 4 were taking MTX and hydroxychloroquine (HCQ), and 1 was taking HCQ and sulfasalazine. Four specimens had severe, 6 moderate, 3 mild, and 2 minimal disease activity on histology. Three of 4 specimens with minimal and mild histology were observed in subjects receiving anti-TNF therapy. Synovitis was noted on greyscale in 80% of joints and Doppler signal in 60%. MRI demonstrated synovitis and bone marrow edema in 86% of images. Positive but not significant correlations were noted between histology and synovitis scores on US. CONCLUSION: Despite clinical remission, histology and imaging studies documented a persistently active disease state that may explain the mechanism for radiographic progression. PMID- 25274901 TI - Serum S100A12 may be a useful biomarker of disease activity in adult-onset Still's disease. AB - OBJECTIVE: S100A12 and soluble receptor for advanced glycation endproducts (sRAGE) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis. We investigated the clinical significance of these markers in adult-onset Still's disease (AOSD). METHODS: Blood samples were collected from 37 patients with active AOSD and 38 healthy controls (HC). Of the patients with AOSD, followup samples were collected from 19 patients after resolution of disease activity. RESULTS: Serum S100A12 (547.9 +/- 148.4 ng/ml) in patients with AOSD was higher than those of HC (272.3 +/- 133 ng/ml, p < 0.001). The sRAGE levels of AOSD (514.1 +/- 273.6 pg/ml) were lower than those of HC (850.3 +/- 405.8 pg/ml, p < 0.001). Serum S100A12 correlated with serum sRAGE (r = -0.228, p = 0.049). Serum S100A12 correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, and systemic score, whereas sRAGE did not correlate with any disease activity markers. In addition, the level of S100A12 was decreased after disease activity was resolved in followed-up patients with AOSD (505.7 +/- 161.3 ng/ml vs 361.3 +/- 162.5 ng/ml, p = 0.01). Further, the change of S100A12 was well correlated with that of ESR, CRP, and systemic score. CONCLUSION: S100A12 levels showed strong correlations with known disease activity markers such as ESR, CRP, ferritin, and systemic score. In the followup patients with AOSD, most patients showed decreased S100A12 levels after resolution of disease activity. These results suggest that serum S100A12 can be a reliable clinical marker for monitoring disease activity and treatment response. PMID- 25274902 TI - Earlier time to remission predicts sustained clinical remission in early rheumatoid arthritis--results from the Canadian Early Arthritis Cohort (CATCH). AB - OBJECTIVE: To evaluate the prevalence and predictive factors of sustained remission in an early rheumatoid arthritis (ERA) population. Predictive factors of sustained remission in ERA are unknown. We hypothesized that a short time to remission is an important predictor of sustained clinical remission. METHODS: Patients in the Canadian Early Arthritis Cohort were included. Remission was defined by Boolean-based American College of Rheumatology/European League Against Rheumatism clinical trial and clinical practice definitions and Simplified Disease Activity Index (SDAI). Logistic regression analysis identified predictors of sustained remission and influence of time to remission. RESULTS: Of 1840 patients, 633 (34%) achieved clinical trial remission, 759 (41%) clinical practice remission, and 727 (39%) SDAI remission. Over half of those meeting remission criteria achieved sustained remission based on clinical trial (55%), clinical practice (60%), and/or SDAI (58%). Corticosteroid use and lack of initial disease-modifying antirheumatic drug (DMARD) were associated with decreased probability of sustained remission, while initial combination DMARD increased this probability. Female sex, greater pain, and longer time to first remission made sustained remission less likely. CONCLUSION: Female sex, greater pain, and lack of initial DMARD therapy reduced the probability of sustained remission. A shorter time to remission is related to sustainability and supports striving for early remission. PMID- 25274905 TI - Inhibitory control of the cough reflex by galanin receptors in the caudal nucleus tractus solitarii of the rabbit. AB - The caudal nucleus tractus solitarii (NTS) is the main central station of cough related afferents and a strategic site for the modulation of the cough reflex. The similarities between the characteristics of central processing of nociceptive and cough-related inputs led us to hypothesize that galanin, a neuropeptide implicated in the control of pain, could also be involved in the regulation of the cough reflex at the level of the NTS, where galanin receptors have been found. We investigated the effects of galanin and galnon, a nonpeptide agonist at galanin receptors, on cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30-50 nl) into the caudal NTS of pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Galnon antitussive effects on cough responses to the mechanical stimulation of the airway mucosa via a custom-built device were also investigated. Bilateral microinjections of 1 mM galanin markedly decreased cough number, peak abdominal activity, and increased cough-related total cycle duration. Bilateral microinjections of 1 mM galnon induced mild depressant effects on cough, whereas bilateral microinjections of 10 mM galnon caused marked antitussive effects consistent with those produced by galanin. Galnon effects were confirmed by using the cough-inducing device. The results indicate that galanin receptors play a role in the inhibitory control of the cough reflex at the level of the caudal NTS and provide hints for the development of novel antitussive strategies. PMID- 25274906 TI - Optogenetics, the intersection between physics and neuroscience: light stimulation of neurons in physiological conditions. AB - Neuronal stimulation by light is a novel approach in the emerging field of optogenetics, where genetic engineering is used to introduce light-activated channels. However, light is also capable of stimulating neurons even in the absence of genetic modifications through a range of physical and biological mechanisms. As a result, rigorous design of optogenetic experiments needs to take note of alternative and parallel effects of light illumination of neuronal tissues. Thus all matters relating to light penetration are critical to the development of studies using light-activated proteins. This paper discusses ways to quantify light, light penetration in tissue, as well as light stimulation of neurons in physiological conditions. We also describe the direct effect of light on neurons investigated at different sites. PMID- 25274907 TI - Contribution of the autophagy-lysosomal and ubiquitin-proteasomal proteolytic systems to total proteolysis in rainbow trout (Oncorhynchus mykiss) myotubes. AB - The ubiquitin-proteasome system (UPS) is recognized as the major contributor to total proteolysis in mammalian skeletal muscle, responsible for 50% or more of total protein degradation in skeletal muscle, whereas the autophagic-lysosome system (ALS) plays a more minor role. While the relative contribution of these systems to muscle loss is well documented in mammals, little is known in fish species. The current study uses myotubes derived from rainbow trout myogenic precursor cells as an in vitro model of white muscle tissue. Cells were incubated in complete or serum-deprived media or media supplemented with insulin-like growth factor-1 (IGF-1) and exposed to selective proteolytic inhibitors to determine the relative contribution of the ALS and UPS to total protein degradation in myotubes in different culture conditions. Results indicate that the ALS is responsible for 30-34% and 50% of total protein degradation in myotubes in complete and serum-deprived media, respectively. The UPS appears to contribute much less to total protein degradation at almost 4% in cells in complete media to nearly 17% in serum-deprived cells. IGF-1 decreases activity of both systems, as it inhibited the upregulation of both proteolytic systems induced by serum deprivation. The combined inhibition of both the ALS and UPS reduced degradation by a maximum of 55% in serum-deprived cells, suggesting an important contribution of other proteolytic systems to total protein degradation. Collectively, these data identify the ALS as a potential target for strategies aimed at improving muscle protein retention and fillet yield through reductions in protein degradation. PMID- 25274908 TI - The repeated sit-to-stand maneuver is a superior method for cardiac baroreflex assessment: a comparison with the modified Oxford method and Valsalva maneuver. AB - Baroreflex assessment has diagnostic and prognostic utility in the clinical and research environments, and there is a need for a reliable, simple, noninvasive method of assessment. The repeated sit-to-stand method induces oscillatory changes in blood pressure (BP) at a desired frequency and is suitable for assessing dynamic baroreflex sensitivity (BRS). However, little is known about the reliability of this method and its ability to discern fundamental properties of the baroreflex. In this study we sought to: 1) evaluate the reliability of the sit-to-stand method for assessing BRS and compare its performance against two established methods (Oxford method and Valsalva maneuver), and 2) examine whether the frequency of the sit-to-stand method influences hysteresis. Sixteen healthy participants underwent three trials of each method. For the sit-to-stand method, which was performed at 0.1 and 0.05 Hz, BRS was quantified as an integrated response (BRSINT) and in response to falling and rising BP (BRSDOWN and BRSUP, respectively). Test retest reliability was assessed using the intraclass correlation coefficient (ICC). Irrespective of frequency, the ICC for BRSINT during the sit-to-stand method was >=0.88. The ICC for a rising BP evoked by phenylephrine (PEGAIN) in the Oxford method was 0.78 and <=0.5 for the remaining measures. During the sit-to-stand method, hysteresis was apparent in all participants at 0.1 Hz but was absent at 0.05 Hz. These findings indicate the sit to-stand method is a statistically reliable BRS assessment tool and suitable for the examination of baroreflex hysteresis. Using this approach we showed that baroreflex hysteresis is a frequency-dependent phenomenon. PMID- 25274909 TI - Patient satisfaction after total knee replacement: new inroads. PMID- 25274910 TI - The surgical treatment of rheumatoid arthritis: a new era? AB - There has been an in increase in the availability of effective biological agents for the treatment of rheumatoid arthritis as well as a shift towards early diagnosis and management of the inflammatory process. This article explores the impact this may have on the place of orthopaedic surgery in the management of patients with rheumatoid arthritis. PMID- 25274912 TI - Results of Birmingham hip resurfacing at 12 to 15 years: a single-surgeon series. AB - We report a 12- to 15-year implant survival assessment of a prospective single surgeon series of Birmingham Hip Resurfacings (BHRs). The earliest 1000 consecutive BHRs including 288 women (335 hips) and 598 men (665 hips) of all ages and diagnoses with no exclusions were prospectively followed-up with postal questionnaires, of whom the first 402 BHRs (350 patients) also had clinical and radiological review. Mean follow-up was 13.7 years (12.3 to 15.3). In total, 59 patients (68 hips) died 0.7 to 12.6 years following surgery from unrelated causes. There were 38 revisions, 0.1 to 13.9 years (median 8.7) following operation, including 17 femoral failures (1.7%) and seven each of infections, soft-tissue reactions and other causes. With revision for any reason as the end point Kaplan-Meier survival analysis showed 97.4% (95% confidence interval (CI) 96.9 to 97.9) and 95.8% (95% CI 95.1 to 96.5) survival at ten and 15 years, respectively. Radiological assessment showed 11 (3.5%) femoral and 13 (4.1%) acetabular radiolucencies which were not deemed failures and one radiological femoral failure (0.3%). Our study shows that the performance of the BHR continues to be good at 12- to 15-year follow-up. Men have better implant survival (98.0%; 95% CI 97.4 to 98.6) at 15 years than women (91.5%; 95% CI 89.8 to 93.2), and women < 60 years (90.5%; 95% CI 88.3 to 92.7) fare worse than others. Hip dysplasia and osteonecrosis are risk factors for failure. Patients under 50 years with osteoarthritis fare best (99.4%; 95% CI 98.8 to 100 survival at 15 years), with no failures in men in this group. PMID- 25274911 TI - The relationship between operative and radiographic acetabular component orientation: which factors influence resultant cup orientation? AB - There is great variability in acetabular component orientation following hip replacement. The aims of this study were to compare the component orientation at impaction with the orientation measured on post-operative radiographs and identify factors that influence the difference between the two. A total of 67 hip replacements (52 total hip replacements and 15 hip resurfacings) were prospectively studied. Intra-operatively, the orientation of the acetabular component after impaction relative to the operating table was measured using a validated stereo-photogrammetry protocol. Post-operatively, the radiographic orientation was measured; the mean inclination/anteversion was 43 degrees (sd 6 degrees )/ 19 degrees (sd 7 degrees ). A simulated radiographic orientation was calculated based on how the orientation would have appeared had an on-table radiograph been taken intra-operatively. The mean difference between radiographic and intra-operative inclination/anteversion was 5 degrees (sd 5 degrees )/ -8 degrees (sd 8 degrees ). The mean difference between simulated radiographic and intra-operative inclination/anteversion, which quantifies the effect of the different way acetabular orientation is measured, was 3 degrees /-6 degrees (sd 2 degrees ). The mean difference between radiographic and simulated radiographic orientation inclination/anteversion, which is a manifestation of the change in pelvic position between component impaction and radiograph, was 1 degrees /-2 degrees (sd 7 degrees ). This study demonstrated that in order to achieve a specific radiographic orientation target, surgeons should implant the acetabular component 5 degrees less inclined and 8 degrees more anteverted than their target. Great variability (2 sd about +/- 15 degrees ) in the post-operative radiographic cup orientation was seen. The two equally contributing causes for this are variability in the orientation at which the cup is implanted, and the change in pelvic position between impaction and post-operative radiograph. PMID- 25274913 TI - Cost analysis of fresh-frozen femoral head allografts: is it worthwhile to run a bone bank? AB - To assess the sustainability of our institutional bone bank, we calculated the final product cost of fresh-frozen femoral head allografts and compared these costs with the use of commercial alternatives. Between 2007 and 2010 all quantifiable costs associated with allograft donor screening, harvesting, storage, and administration of femoral head allografts retrieved from patients undergoing elective hip replacement were analysed. From 290 femoral head allografts harvested and stored as full (complete) head specimens or as two halves, 101 had to be withdrawn. In total, 104 full and 75 half heads were implanted in 152 recipients. The calculated final product costs were ?1367 per full head. Compared with the use of commercially available processed allografts, a saving of at least ?43 119 was realised over four-years (?10 780 per year) resulting in a cost-effective intervention at our institution. Assuming a price of between ?1672 and ?2149 per commercially purchased allograft, breakeven analysis revealed that implanting between 34 and 63 allografts per year equated to the total cost of bone banking. PMID- 25274914 TI - A multidisciplinary team approach to two-stage revision for the infected hip replacement: a minimum five-year follow-up study. AB - We report the five year outcomes of a two-stage approach for infected total hip replacement. This is a single-surgeon experience at a tertiary centre where the more straightforward cases are treated using single-stage exchange. This study highlights the vital role of the multidisciplinary team in managing these cases. A total of 125 patients (51 male, 74 female) with a mean age of 68 years (42 to 78) were reviewed prospectively. Functional status was assessed using the Harris hip score (HHS). The mean HHS improved from 38 (6 to 78.5) pre-operatively to 81.2 (33 to 98) post-operatively. Staphylococcus species were isolated in 85 patients (68%). The rate of control of infection was 96% at five years. In all, 19 patients died during the period of the study. This represented a one year mortality of 0.8% and an overall mortality of 15.2% at five years. No patients were lost to follow-up. We report excellent control of infection in a series of complex patients and infections using a two-stage revision protocol supported by a multidisciplinary approach. The reason for the high rate of mortality in these patients is not known. PMID- 25274915 TI - The expression of vascular endothelial growth factor and Syndecan-4 in cartilage from osteoarthritic knees. AB - Previous studies support the important role of vascular endothelial growth factor (VEGF) and syndecan-4 in the pathogenesis of osteoarthritis (OA). Both VEGF and syndecan-4 are expressed by chondrocytes and both are involved in the regulation of matrix metalloproteinase-3, resulting in the activation of aggrecanase II (ADAMTS-5), which is essential in the pathogenesis of OA. However, the relationship between VEGF and syndecan-4 has not been established. As a pilot study, we assayed the expression of VEGF and syndecan-4 in cartilage samples and cultured chondrocytes from osteoarthritic knee joints and analysed the relationship between these two factors. Specimens were collected from 21 female patients (29 knees) who underwent total knee replacement due to severe medial OA of the knee (Kellgren-Lawrence grade 4). Articular cartilage samples, obtained from bone and cartilage excised during surgery, were analysed and used for chondrocyte culture. We found that the levels of expression of VEGF and syndecan 4 mRNA did not differ significantly between medial femoral cartilage with severe degenerative changes and lateral femoral cartilage that appeared grossly normal (p = 0.443 and 0.622, respectively). Likewise, the levels of expression of VEGF and syndecan-4 mRNA were similar in cultured chondrocytes from medial and lateral femoral cartilage. The levels of expression of VEGF and syndecan-4 mRNAs were significantly and positively correlated in cartilage explant (r = 0.601, p = 0.003) but not in cultured chondrocytes. These results suggest that there is a close relationship between VEGF and syndecan-4 in the cartilage of patients with OA. Further studies are needed to determine the exact pathway by which these two factors interact in the pathogenesis of OA. PMID- 25274916 TI - Clinical outcomes of second-look arthroscopic evaluation after anterior cruciate ligament augmentation: comparison with single- and double-bundle reconstruction. AB - We report the clinical outcome and findings at second-look arthroscopy of 216 patients (mean age 25 years (11 to 58)) who underwent anterior cruciate ligament (ACL) reconstruction or augmentation. There were 73 single-bundle ACL augmentations (44 female, 29 male), 82 double-bundle ACL reconstructions (35 female, 47 male), and 61 single-bundle ACL reconstructions (34 female, 27 male). In 94 of the 216 patients, proprioceptive function of the knee was evaluated before and 12 months after surgery using the threshold to detect passive motion test. Second-look arthroscopy showed significantly better synovial coverage of the graft in the augmentation group (good: 60 (82%), fair: 10 (14%), poor: 3 (4%)) than in the other groups (p = 0.039). The mean side-to-side difference measured with a KT-2000 arthrometer was 0.4 mm (-3.3 to 2.9) in the augmentation group, 0.9 mm (-3.2 to 3.5) in the double-bundle group, and 1.3 mm (-2.7 to 3.9) in the single-bundle group: the result differed significantly between the augmentation and single-bundle groups (p = 0 .013). No significant difference in the Lysholm score or pivot-shift test was seen between the three groups (p = 0.09 and 0.65, respectively). In patients with good synovial coverage, three of the four measurements used revealed significant improvement in proprioceptive function (p = 0.177, 0.020, 0.034, and 0.026). We conclude that ACL augmentation is a reasonable treatment option for patients with favourable ACL remnants. PMID- 25274917 TI - Increased satisfaction after total knee replacement using sensor-guided technology. AB - The aim of this prospective multicentre study was to report the patient satisfaction after total knee replacement (TKR), undertaken with the aid of intra operative sensors, and to compare these results with previous studies. A total of 135 patients undergoing TKR were included in the study. The soft-tissue balance of each TKR was quantified intra-operatively by the sensor, and 18 (13%) were found to be unbalanced. A total of 113 patients (96.7%) in the balanced group and 15 (82.1%) in the unbalanced group were satisfied or very satisfied one year post operatively (p = 0.043). A review of the literature identified no previous study with a mean level of satisfaction that was greater than the reported level of satisfaction of the balanced TKR group in this study. Ensuring soft-tissue balance by using intra-operative sensors during TKR may improve satisfaction. PMID- 25274918 TI - The identification and quantification of instability in a primary total knee replacement prior to revision. AB - Instability is the reason for revision of a primary total knee replacement (TKR) in 20% of patients. To date, the diagnosis of instability has been based on the patient's symptoms and a subjective clinical assessment. We assessed whether a measured standardised forced leg extension could be used to quantify instability. A total of 25 patients (11 male/14 female, mean age 70 years; 49 to 85) who were to undergo a revision TKR for instability of a primary implant were assessed with a Nottingham rig pre-operatively and then at six and 26 weeks post-operatively. Output was quantified (in revolutions per minute (rpm)) by accelerating a stationary flywheel. A control group of 183 patients (71 male/112 female, mean age 69 years) who had undergone primary TKR were evaluated for comparison. Pre operatively, all 25 patients with instability exhibited a distinctive pattern of reduction in 'mid-push' speed. The mean reduction was 55 rpm (sd 33.2). Post operatively, no patient exhibited this pattern and the reduction in 'mid-push' speed was 0 rpm. The change between pre- and post-operative assessment was significant (p < 0.001). No patients in the control group exhibited this pattern at any of the intervals assessed. The between-groups difference was also significant (p < 0.001). This suggests that a quantitative diagnostic test to assess the unstable primary TKR could be developed. PMID- 25274919 TI - The anatomical footprint of the Achilles tendon: a cadaveric study. AB - We dissected 12 fresh-frozen leg specimens to identify the insertional footprint of each fascicle of the Achilles tendon on the calcaneum in relation to their corresponding muscles. A further ten embalmed specimens were examined to confirm an observation on the retrocalcaneal bursa. The superficial part of the insertion of the Achilles tendon is represented by fascicles from the medial head of the gastrocnemius muscle, which is inserted over the entire width of the inferior facet of the calcaneal tuberosity. In three specimens this insertion was in continuity with the plantar fascia in the form of periosteum. The deep part of the insertion of the Achilles tendon is made of fascicles from the soleus tendon, which insert on the medial aspect of the middle facet of the calcaneal tuberosity, while the fascicles of the lateral head of the gastrocnemius tendon insert on the lateral aspect of the middle facet of the calcaneal tuberosity. A bicameral retrocalcaneal bursa was present in 15 of the 22 examined specimens. This new observation and description of the insertional footprint of the Achilles tendon and the retrocalcaneal bursa may allow a better understanding of the function of each muscular part of the gastrosoleus complex. This may have clinical relevance in the treatment of Achilles tendinopathies. PMID- 25274920 TI - Antibiotic cement-coated rods: an effective treatment for infected long bones and prosthetic joint nonunions. AB - The treatment of infected nonunions is difficult. Antibiotic cement-coated (ACC) rods provide stability as well as delivering antibiotics. We conducted a review of 110 infected nonunions treated with ACC rods. Patients were divided into two groups: group A (67 patients) with an infected arthrodesis, and group B (43 patients) with an infected nonunion in a long bone. In group A, infected arthrodesis, the success rate after the first procedure was 38/67 (57%), 29/67 (43%) required further surgery for either control of infection or non-union. At last follow-up, five patients required amputation, representing a limb salvage rate of 62/67 (93%) overall. In all, 29/67 (43%) presented with a bone defect with a mean size of 6.78 cm (2 to 25). Of those with a bone defect, 13/29 (45%) required further surgery and had a mean size of defect of 7.2 cm (3.5 to 25). The cultures were negative in 17/67 (26%) and the most common organism cultured was methicillin-resistant staphylococcus aureus (MRSA) (23/67, (35%)). In group B, long bones nonunion, the success rate after the first procedure was 26/43 (60%), 17/43 (40%) required further surgery for either control of infection or nonunion. The limb salvage rate at last follow-up was 43/43 (100%). A total of 22/43 (51%) had bone defect with a mean size of 4.7 cm (1.5 to 11.5). Of those patients with a bone defect, 93% required further surgery with a mean size of defect of 5.4 cm (3 to 8.5). The cultures were negative in 10/43 (24%) and the most common organism cultured was MRSA, 15/43 (35%). ACC rods are an effective form of treatment for an infected nonunion, with an acceptable rate of complications. PMID- 25274921 TI - Comparative outcome of arthroscopic release for frozen shoulder in patients with and without diabetes. AB - Our aim was to compare the outcome of arthroscopic release for frozen shoulder in patients with and without diabetes. We prospectively compared the outcome in 21 patients with and 21 patients without diabetes, two years post-operatively. The modified Constant score was used as the outcome measure. The mean age of the patients was 54.5 years (48 to 65; male:female ratio: 18:24), the mean pre operative duration of symptoms was 8.3 months (6 to 13) and the mean pre operative modified Constant scores were 36.6 (standard deviation (sd) 4.6) and 38.4 (sd 5.7) in the diabetic and non-diabetic groups, respectively. The mean modified Constant scores at six weeks, six months and two years post-operatively in the diabetics were 55. 6 (sd 4.7), 67. 4 (sd 5.6) and 84. 4 (sd 6.8), respectively; and in the non-diabetics 66.8 (sd 4.5), 79.6 (sd 3.8) and 88.6 (sd 4.2), respectively. A total of 15 (71%) of diabetic patients recovered a full range of movement as opposed to 19 (90%) in the non-diabetics. There was significant improvement (p < 0.01) in the modified Constant scores following arthroscopic release for frozen shoulder in both groups. The results in diabetics were significantly worse than those in non-diabetics six months post-operatively (p < 0.01) with a tendency towards persistent limitation of movement two years after operation. These results may be used when counselling diabetic patients for the outcome after arthroscopic treatment of frozen shoulder. PMID- 25274922 TI - Medium-term clinical results of a linked total elbow replacement system. AB - Medium-term results of the Discovery elbow replacement are presented. We reviewed 51 consecutive primary Discovery total elbow replacements (TERs) implanted in 48 patients. The mean age of the patients was 69.2 years (49 to 92), there were 19 males and 32 females (37%:63%) The mean follow-up was 40.6 months (24 to 69). A total of six patients were lost to follow-up. Statistically significant improvements in range movement and Oxford Elbow Score were found (p < 0.001). Radiolucent lines were much more common in, and aseptic loosening was exclusive to, the humeral component. Kaplan-Meier survivorship at five years was 92.2% (95% CI 74.5% to 96.4%) for aseptic loosening. In four TERs, periprosthetic infection occurred resulting in failure. A statistically significant association between infection and increased BMI was found (p = 0.0268). Triceps failure was more frequent after the Mayo surgical approach and TER performed after previous trauma surgery. No failures of the implant were noted. Our comparison shows that the Discovery has early clinical results that are similar to other semi-constrained TERs. We found continued radiological surveillance with particular focus on humeral lucency is warranted and has not previously been reported. Despite advances in the design of total elbow replacement prostheses, rates of complication remain high. PMID- 25274923 TI - GeneXpert polymerase chain reaction for spinal tuberculosis: an accurate and rapid diagnostic test. AB - The lack of an accurate, rapid diagnostic test for mycobacterium tuberculosis (TB) is a major handicap in the management of spinal TB. GeneXpert, a new, rapid molecular diagnostic test is recommended as the first line investigation for suspected pulmonary TB in areas with a high prevalence of HIV or drug resistance, yet it has not been validated for the diagnosis of musculoskeletal TB. The aim of this study was to assess the accuracy of GeneXpert in diagnosing spinal TB. A prospective clinical study of 69 consecutive adults with suspected spinal TB was conducted at a tertiary hospital in an area with the highest incidence and prevalence of TB in the world. GeneXpert was used on tissue samples of the enrolled patients and its diagnostic accuracy compared with a reference standard of tissue in liquid culture. A total of 71 spine samples from 69 patients (two re biopsies) were included in the study. The GeneXpert test showed a sensitivity of 95.6% and specificity of 96.2% for spinal TB. The results of the GeneXpert test were available within 48 hours compared with a median of 35 days (IQR 15 to 43) for cultures. All cases of multi-drug resistant TB (MDR TB) were diagnosed accurately with the GeneXpert test. The MDR TB rate was 5.8%. PMID- 25274924 TI - Outcome at 12 to 22 years of 1502 tibial shaft fractures. AB - Fractures of the tibial shaft are common injuries, but there are no long-term outcome data in the era of increased surgical management. The aim of this prospective study was to assess the clinical and functional outcome of this injury at 12 to 22 years. Secondary aims were to determine the short- and long term mortality, and if there were any predictors of clinical or functional outcome or mortality. From a prospective trauma database of 1502 tibial shaft fractures in 1474 consecutive adult patients, we identified a cohort of 1431 tibial diaphyseal fractures in 1403 patients, who fitted our inclusion criteria. There were 1024 men, and mean age at injury was 40.6 years. Fractures were classified according to the AO system, and open fractures graded after Gustilo and Anderson. Requirement of fasciotomy, time to fracture union, complications, incidence of knee and ankle pain at long-term follow-up, changes in employment and the patients' social deprivation status were recorded. Function was assessed at 12 to 22 years post-injury using the Short Musculoskeletal Function Assessment and short form-12 questionnaires. Long-term functional outcome data was available for 568 of the surviving patients, 389 were deceased and 346 were lost to follow up. Most fractures (90.7%, n = 1363) united without further intervention. Fasciotomies were performed in 11.5% of patients; this did not correlate with poorer functional outcome in the long term. Social deprivation was associated with a higher incidence of injury but had no impact on long-term function. The one-year mortality in those over 75 years of age was 29 (42%). At long-term follow-up, pain and function scores were good. However, 147 (26%) reported ongoing knee pain, 62 (10%) reported ankle pain and 97 (17%) reported both. Such joint pain correlated with poorer functional outcome. PMID- 25274925 TI - The role of inter-prosthetic distance, cortical thickness and bone mineral density in the development of inter-prosthetic fractures of the femur: a biomechanical cadaver study. AB - It is becoming increasingly common for a patient to have ipsilateral hip and knee replacements. The inter-prosthetic (IP) distance, the distance between the tips of hip and knee prostheses, has been thought to be associated with an increased risk of IP fracture. Small gap distances are generally assumed to act as stress risers, although there is no real biomechanical evidence to support this. The purpose of this study was to evaluate the influence of IP distance, cortical thickness and bone mineral density on the likelihood of an IP femoral fracture. A total of 18 human femur specimens were randomised into three groups by bone density and cortical thickness. For each group, a defined IP distance of 35 mm, 80 mm or 160 mm was created by choosing the appropriate lengths of component. The maximum fracture strength was determined using a four-point bending test. The fracture force of all three groups was similar (p = 0.498). There was a highly significant correlation between the cortical area and the fracture strength (r = 0.804, p < 0.001), whereas bone density showed no influence. This study suggests that the IP distance has little influence on fracture strength in IP femoral fractures: the thickness of the cortex seems to be the decisive factor. PMID- 25274926 TI - The treatment of the acute Essex-Lopresti injury. AB - The Essex-Lopresti injury (ELI) of the forearm is a rare and serious condition which is often overlooked, leading to a poor outcome. The purpose of this retrospective case study was to establish whether early surgery can give good medium-term results. From a group of 295 patients with a fracture of the radial head, 12 patients were diagnosed with ELI on MRI which confirmed injury to the interosseous membrane (IOM) and ligament (IOL). They were treated by reduction and temporary Kirschner (K)-wire stabilisation of the distal radioulnar joint (DRUJ). In addition, eight patients had a radial head replacement, and two a radial head reconstruction. All patients were examined clinically and radiologically 59 months (25 to 90) after surgery when the mean Mayo Modified Wrist Score (MMWS) was 88.4 (78 to 94), the mean Mayo Elbow Performance Scores (MEPS) 86.7 (77 to 95) and the mean disabilities of arm, shoulder and hand (DASH) score 20.5 (16 to 31): all of these indicate a good outcome. In case of a high index of suspicion for ELI in patients with a radial head fracture, we recommend the following: confirmation of IOM and IOL injury with an early MRI scan; early surgery with reduction and temporary K-wire stabilisation of the DRUJ; preservation of the radial head if at all possible or replacement if not, and functional bracing in supination. This will increase the prospect of a good result, and avoid the complications of a missed diagnosis and the difficulties of late treatment. PMID- 25274927 TI - The outcome of resection of the distal ulna for tumour without soft-tissue or prosthetic reconstruction. AB - In patients with a tumour affecting the distal ulna it is difficult to preserve the function of the wrist following extensive local resection. We report the outcome of 12 patients (nine female, three male) who underwent excision of the distal ulna without local soft-tissue reconstruction. In six patients, an aggressive benign tumour was present and six had a malignant tumour. At a mean follow-up of 64 months (15 to 132) the mean Musculoskeletal Tumour score was 64% (40% to 93%) and the mean DASH score was 35 (10 to 80). The radiological appearances were satisfactory in most patients. Local recurrence occurred in one patient with benign disease and two with malignant disease. The functional outcome was thus satisfactory at a mean follow-up in excess of five years, with a relatively low rate of complications. The authors conclude that complex reconstructive soft-tissue procedures may not be needed in these patients. PMID- 25274928 TI - Does a pathological fracture affect the prognosis in patients with osteosarcoma of the extremities? : a systematic review and meta-analysis. AB - Opinion remains divided as to whether the development of pathological fracture affects the prognosis of patients with an osteosarcoma of the extremities. We conducted a comprehensive systematic review and meta-analysis of papers which reported the outcomes of osteosarcoma patients with and without a pathological fracture. There were eight eligible papers for final analysis which reported on 1713 patients, of whom 303 (17.7%) had a pathological fracture. The mean age for 1464 patients in six studies was 23.2 years old (2 to 82). The mean follow-up for 1481 patients in seven studies was 90.1 months (6 to 240). The pooled estimates of local recurrence rates in osteosarcoma patients with and without pathological fractures were 14.4% (8.7 to 20.0) versus 11.4% (8.0 to 14.8). The pooled estimate of relative risk was 1.39 (0.89 to 2.20). The pooled estimates of five year event-free survival rates in osteosarcoma patients with and without a pathological fracture were 49.3% (95% CI 43.6 to 54.9) versus 66.8% (95% CI 60.7 to 72.8). The pooled estimate of relative risk was 1.33 (1.12 to 1.59). There was no significant difference in the rate of local recurrence between patients who were treated by amputation or limb salvage. The development of a pathological fracture is a negative prognostic indicator in osteosarcoma and is associated with a reduced five-year event-free survival and a possibly higher rate of local recurrence. Our findings suggest that there is no absolute indication for amputation, as similar rates of local recurrence can be achieved in patients who are carefully selected for limb salvage. PMID- 25274929 TI - The use of extracorporeally irradiated autografts in pelvic reconstruction following tumour resection. AB - The aim of this study was to evaluate the functional and oncological outcome of extracorporeally irradiated autografts used to reconstruct the pelvis after a P1/2 internal hemipelvectomy. The study included 18 patients with a primary malignant bone tumour of the pelvis. There were 13 males and five females with a mean age of 24.8 years (8 to 62). Of these, seven had an osteogenic sarcoma, six a Ewing's sarcoma, and five a chondrosarcoma. At a mean follow-up of 51.6 months (4 to 185), nine patients had died with metastatic disease while nine were free from disease. Local recurrence occurred in three patients all of whom eventually died of their disease. Deep infection occurred in three patients and required removal of their graft in two while the third underwent a hindquarter amputation for extensive flap necrosis. The mean Musculoskeletal Tumor Society functional score of the 16 patients who could be followed-up for at least 12 months was 77% (50 to 90). Those 15 patients who completed the Toronto Extremity Salvage Score questionnaire had a mean score of 71% (53 to 85). Extracorporeal irradiation and re-implantation of bone is a valid method of reconstruction after an internal hemipelvectomy. It has an acceptable morbidity and a functional outcome that compares favourably with other available reconstructive techniques. PMID- 25274930 TI - Surgical correction of shoulder rotation deformity in brachial plexus birth palsy: long-term results in 118 patients. AB - We present the long-term results of open surgery for internal shoulder rotational deformity in brachial plexus birth palsy (BPBP). From 1997 to 2005, 207 patients (107 females, 100 males, mean age 6.2 (0.6 to 34)) were operated on with subscapularis elongation and/or latissimus dorsi to infraspinatus transfer. Incongruent shoulder joints were relocated. The early results of these patients has been reported previously. We analysed 118 (64 females, 54 males, mean age 15.1 (7.6 to 34)) of the original patient cohort at a mean of 10.4 years (7.0 to 15.1) post-operatively. A third of patients with relocated joints had undergone secondary internal rotational osteotomy of the humerus. A mixed effects models approach was used to evaluate the effects of surgery on shoulder rotation, abduction, and the Mallet score. Independent factors were time (pre-and post surgery), gender, age, joint category (congruent, relocated, relocated plus osteotomy) and whether or not a transfer had been performed. Data from a previously published short-term evaluation were reworked in order to obtain pre operative values. The mean improvement in external rotation from pre-surgery to the long-term follow-up was 66.5 degrees (95% confidence interval (CI) 61.5 to 71.6). The internal rotation had decreased by a mean of 22.6 degrees (95% CI 18.7 to -26.5). The mean improvement in the three-grade aggregate Mallet score was 3.1 (95% CI 2.7 to 3.4), from 8.7 (95% CI 8.4 to 9.0) to 11.8 (11.5 to 12.1). Our results show that open subscapularis elongation achieves good long-term results for patients with BPBP and an internal rotation contracture, providing lasting joint congruency and resolution of the trumpet sign, but with a moderate mean loss of internal rotation. PMID- 25274931 TI - Factors associated with an unfavourable outcome after Salter innominate osteotomy in patients with unilateral developmental dysplasia of the hip: does occult dysplasia of the contralateral hip affect the outcome? AB - Salter innominate osteotomy is an effective reconstructive procedure for the treatment of developmental dysplasia of the hip (DDH), but some children have a poor outcome at skeletal maturity. In order to investigate factors associated with an unfavourable outcome, we assessed the development of the contralateral hip. We retrospectively reviewed 46 patients who underwent a unilateral Salter osteotomy at between five and seven years of age, with a mean follow-up of 10.3 years (7 to 20). The patients were divided into three groups according to the centre-edge angle (CEA) of the contralateral hip at skeletal maturity: normal (> 25 degrees , 22 patients), borderline (20 degrees to 25 degrees , 17 patients) and dysplastic (< 20 degrees , 7 patients). The CEA of the affected hip was measured pre-operatively, at eight to nine years of age, at 11 to 12 years of age and at skeletal maturity. The CEA of the affected hip was significantly smaller in the borderline and dysplastic groups at 11 and 12 years of age (p = 0.012) and at skeletal maturity (p = 0.017) than in the normal group. Severin group III was seen in two (11.8%) and four hips (57.1%) of the borderline and dysplastic groups, respectively (p < 0.001). Limited individual development of the acetabulum was associated with an unfavourable outcome following Salter osteotomy. PMID- 25274932 TI - The effect of a dedicated Ponseti service on the outcome of idiopathic clubfoot treatment. AB - We report the effect of introducing a dedicated Ponseti service on the five-year treatment outcomes of children with idiopathic clubfoot. Between 2002 and 2004, 100 feet (66 children; 50 boys and 16 girls) were treated in a general paediatric orthopaedic clinic. Of these, 96 feet (96%) responded to initial casting, 85 requiring a tenotomy of the tendo-Achillis. Recurrent deformity occurred in 38 feet and was successfully treated in 22 by repeat casting and/or tenotomy and/or transfer of the tendon of tibialis anterior, The remaining 16 required an extensive surgical release. Between 2005 and 2006, 72 feet (53 children; 33 boys and 20 girls) were treated in a dedicated multidisciplinary Ponseti clinic. All responded to initial casting: 60 feet (83.3%) required a tenotomy of the tendo Achillis. Recurrent deformity developed in 14, 11 of which were successfully treated by repeat casting and/or tenotomy and/or transfer of the tendon of tibialis anterior. The other three required an extensive surgical release. Statistical analysis showed that children treated in the dedicated Ponseti clinic had a lower rate of recurrence (p = 0.068) and a lower rate of surgical release (p = 0.01) than those treated in the general clinic. This study shows that a dedicated Ponseti clinic, run by a well-trained multidisciplinary team, can improve the outcome of idiopathic clubfoot deformity. PMID- 25274934 TI - Occupational exposure to blood among hospital workers in montenegro. AB - This cross-sectional study was performed in nine Montenegrin hospitals to estimate the burden of occupational exposure to blood among hospital workers in Montenegro in 2010 using a modified Croatian self-reporting questionnaire on exposure to blood-borne infections. Of the 1043 respondents, 517 (49.6 %) reported exposure to blood. Variations between the hospitals were not significant, except for the hospital in Kotor, which stands out with the high percentage of exposed hospital workers (p<0.05). More than 77 % of exposures were not reported through standard hospital protocols at the time of the incident. The most exposed group to blood were nurses (357 of 517; 69.1 %), but the percentage of exposed nurses within the group did not stand out compared to other occupations and was close to that reported by physicians (50.57 % vs. 57.49 %, respectively). The number of hospital workers with appropriate HBV vaccination was surprisingly low (35.7 %) and significantly below the recommended best practice (at least two consecutive doses of HBV vaccine documented for 100 % of employees) (p<0.001). Even with its limitations, our study fills a gap in knowledge about the actual number of sharps incidents and other occupational exposure to blood among hospital workers in Montenegro as well as about the issue of underreporting, which is very common. It also confirms the urgent need for active implementation of special, comprehensive measures to prevent needle-stick and other sharps injuries. Constant staff training, life-long learning, and standardising post-exposure procedures are also recommended. PMID- 25274935 TI - Different enzymatic activities in carp (cyprinus carpio L.) as potential biomarkers of exposure to the pesticide methomyl. AB - This study investigated the influence of the pesticide methomyl on different enzymatic activities in carp. The fish were exposed to a sub-lethal concentration (0.34 mg L-1) of methomyl for 15 days. On days 4 and 15, catalase (CAT) and glutathione-S-transferase (GST) activities were measured in the liver and gills. Acetylcholinesterase (AChE) activity in brain and muscle was also determined. Liver catalase activity slightly increased in exposed fish when compared to controls, but it was statistically significant only at the beginning of the experiment. No changes in CAT activity in the gills of exposed and control animals were observed (mean values were in the range 10.7-11.7 nmol min-1 per mg of protein). Liver GST activity was slightly inhibited in the exposed animals at the beginning of the study; however, it was significantly inhibited in the gills. Brain AChE activity was diminished throughout the experiment and significantly decreased after 96 h of exposure compared to controls (0.041 vs. 0.075 nmol min1 per mg of protein; p<0.001). Our findings suggest that CAT, GST, and AChE are reliable biomarkers of effect after exposure to methomyl. PMID- 25274936 TI - Dissolved heavy metal determination and ecotoxicological assessment: a case study of the corumbatai river (sao paulo, Brazil). AB - The aim of this one-year study (August 2009 to July 2010) was to evaluate the Corumbatai River water polluted by anthropogenic sources and see how it affects the reproduction of the microcrustacean Ceriodaphnia dubia (Richard, 1984) in laboratory conditions over seven days of exposure to water samples collected monthly at six different locations. We determined the concentrations of zinc (Zn), copper (Cu), nickel (Ni), lead (Pb), and cadmium (Cd), as well as physicochemical parameters such as dissolved oxygen, conductivity, water temperature, and pH. Dissolved oxygen and conductivity demonstrated anthropogenic influence, as dissolved oxygen concentration decreased and conductivity increased from the upstream to the downstream stretch of the river. The effects on C. dubia were observed in the months with high precipitation, but the toxicity cannot be associated with any particular contaminant. Heavy metal levels kept well below the limit values. Zn and Pb had the highest concentrations in the water during the sampling period, probably due to the industrial and agricultural influence. However, these levels do not seem to be associated with precipitation, which suggests that their primary source was industry. Physicochemical parameters, the ecotoxicological assay, and determination of heavy metals proved to be efficient tools to evaluate aquatic environments. PMID- 25274937 TI - Skin and the environment. PMID- 25274938 TI - Sampling the stratum corneum for toxic chemicals. AB - Dermal exposure is an important pathway in environmental health. Exposure comes from contaminated water, soil, treated surfaces, textiles, aerosolized chemicals, and agricultural products. It can occur in homes, schools, play areas, and work settings in the form of industrial sources, consumer products, or hazardous wastes. Dermal exposure is most likely to occur through contact with liquids, water, soil, sediment, and contaminated surfaces. The ability to detect and measure exposure to toxic materials on the skin is an important environmental health issue. The stratum corneum is the skin's first and principal barrier layer of protection from the outside world. It has a complex structure that can effectively protect against a wide variety of physical, chemical, and biological contaminants. However, there are a variety of chemical agents that can damage the stratum corneum and the underlying epidermis, dermis and subcutis, and/or enter systemic circulation through the skin. There are numerous ways of sampling the stratum corneum for these toxic materials like abrasion techniques, biopsy, suction blistering, imaging, washing, wipe sampling, tape stripping, and spot testing. Selecting a method likely depends on the particular needs of the situation. Hence, there is a need to review practical considerations for their use in sampling the stratum corneum for toxins. PMID- 25274939 TI - Irritant contact dermatitis. AB - Irritant contact dermatitis (ICD) is the most common form of contact dermatitis. It represents the cutaneous response to the toxic/physical effects of a wide variety of environmental agents. Nowadays, it is recognized that irritancy does not represent a single monomorphous entity but rather a complex biologic syndrome with diverse pathophysiology and clinical manifestations. The clinical presentation is highly variable depending on several factors, including properties and strength of the irritant, dose, duration and frequency of exposure, environmental factors, and skin susceptibility. The pathophysiological mechanism depends on activation of the innate immune system and involves skin barrier disruption, cellular changes, and release of proinflammatory mediators that directly recruit and activate T lymphocytes. The diagnosis of irritant contact dermatitis is often clinical, and involves a comprehensive history and examination, as well as the exclusion of allergic contact dermatitis with patch testing. Recent advances in understanding the pathogenesis as well as better awareness of the clinical significance of ICD will lead to a improved care for our patients. PMID- 25274940 TI - Cutaneous irritancy of water. AB - Abstract Water is an ubiquitous irritant that exerts its irritancy through different mechanisms. Water passage and optimal water content is a highly controlled process of human skin and changes in the water gradient may lead to skin diseases. The pH, osmolarity, and temperature of water can all be attributes of water irritancy. In addition, the irritancy of water is also determined by individual susceptibility. PMID- 25274941 TI - Photoallergy. AB - Abstract Photoallergic contact dermatitis (PACD) is a hypersensitivity reaction mounting from skin exposure to generally harmless amounts of ultraviolet and/or visible light in the presence of a photoreactive allergen. These reactions are typically delayed type (Gell and Coombs type IV) reactions and require pre sensitization to photoallergens. Phototoxic reactions are clinically similar and often difficult to differentiate from photoallergies, but they are caused by interaction of light with photoirritants and do not require sensitization. The main investigative technique to diagnose PACD is photopatch testing, which is not commonly used; therefore, PACD may be overlooked in many patients. Currently, leading contact photosensitizers are sunscreens and topical non-steroidal anti inflammatory drugs. This article provides an overview on photocontact allergies. PMID- 25274942 TI - No effect of CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) on lipid-lowering response to statins in Greek patients with primary hypercholesterolemia. AB - BACKGROUND: Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. CYP3A4 intron 6 C>T polymorphism (CYP3A4*22 allele, rs35599367) has been recently identified and was associated with reduced CYP3A4 expression. We analyzed the association of CYP3A4*22 allele with response to atorvastatin and simvastatin. METHODS: A total of 416 statin treated (207 atorvastatin- and 209 simvastatin-treated) adults with primary hypercholesterolemia were included in the study. Total cholesterol and low density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. CYP3A4*22 allele was analyzed with TaqMan assay. RESULTS: In the entire cohort population, 41 individuals carried CYP3A4*22 allele (18 in atorvastatin and 23 in simvastatin treatment). CYP3A4*22 allele was not associated with lipid-lowering response to atorvastatin or simvastatin. No sex gene or statin dose-gene interaction was observed in either statin-treated patient cohort. CONCLUSIONS: The effect of CYP3A4*22 allele on lipid-lowering response to CYP3A metabolized statins, if present, can potentially be masked by relevant confounding or uncontrolled factors; therefore, further population driven studies are required. PMID- 25274943 TI - Experience with the first fully automated chemiluminescence immunoassay for the quantification of 1alpha, 25-dihydroxy-vitamin D. AB - BACKGROUND: Previous studies have shown that the measurement of vitamin D and its derivatives, especially its active metabolite 1alpha, 25-dihydroxy-vitamin D [1,25(OH)2D], is highly complex and prone to analytical error. We have evaluated a new immunological method for detecting and quantifying of 1,25(OH)2D. This assay is fully automated, sensitive and uses a specific recombinant fusion protein for capturing of 1,25(OH)2D. The assay was originally developed by DiaSorin for the immunoassay analyzer LIAISON XL. METHODS: Performance data of this assay were determined including intra- and inter-assay precision, recovery, linearity, and limit of detection of the DiaSorin 1,25(OH)2D immunoassay on the LIAISON XL analyzer. Respective data were compared from two different liquid chromatography tandem mass spectrometry (LC-MS/MS) assays and a common radioimmunoassay (RIA) using clinical samples taken from patients suffering from vitamin D deficiency, chronic renal failure, biliary atresia, hyperparathyroidism, vitamin D-dependent rickets or sarcoidosis, as well as from pregnant women and high-level athletes. RESULTS: The performance evaluation of 1,25(OH)2D resulted in an intra-assay and total imprecision correlation variant between 1.4% and 5.2% and 3.8%-7.1% with the new immunoassay and 3.5%-5.8% or 3.8%-7.5% with the LC-MS/MS method, respectively. Limits of detection and quantification of the immunoassay were 0.7 ng/L and 5.0 ng/L for the LIAISON XL immunoassay and 1.8 ng/L and 5.4 ng/L for the LC-MS/MS assay, respectively. Pearson's coefficients of correlation were 0.998 and 0.952 for method comparison to different established LC-MS/MS methods. Linear regression according to Passing and Bablok showed larger deviations to the RIA (slopes 0.64-0.97, coefficients of correlation 0.822-0.823). CONCLUSIONS: The DiaSorin LIAISON XL 1,25(OH)2D immunoassay appears to have improved comparability to LC-MS/MS with low imprecision and limits of detection. The assay time of 65 min, the small sample volume required (75 MUL) and the throughput of 90 tests/hour without manually handling time for extraction and purification procedures is superior to the LC MS/MS method. PMID- 25274944 TI - Urinary thiosulfate as failed prostate cancer biomarker - an exemplary multicenter re-evaluation study. AB - BACKGROUND: In 2013, thiosulfate in urine has been proposed as promising prostate cancer (PCa) biomarker. However, a missing comparison with other proven PCa markers suggested a re-evaluation study. Therefore, together with the authors from the initial study, the diagnostic accuracy of thiosulfate was compared with that of urinary prostate cancer associated 3 (PCA3), serum prostate health index (Phi), and percent free prostate-specific antigen (%fPSA). Thiosulfate was further measured in a multicenter approach to exclude center-related biases. METHODS: Thiosulfate, calculated as ratio of thiosulfate to urinary creatinine (TS/Crea ratio), was measured in two cohorts in a total of 269 patients. In the retrospective study (n=160) PCA3, Phi, PSA, and %fPSA were compared with the TS/Crea ratio between patients with and without PCa according to the prostate needle biopsy results. The second prospective cohort included 109 patients from four centers. RESULTS: The median TS/Crea ratio was not statistically different between the patients with and without PCa. The receiver-operating characteristics showed that the TS/Crea ratio was unable to discriminate between patients with and without PCa in contrast to %fPSA, Phi, and PCA3. In all four centers, the low median TS/Crea ratios (<1 mmol/mol) in both patient cohorts were confirmed and thiosulfate was again not able to distinguish between them (p-values, 0.13-0.90). CONCLUSIONS: This study could not confirm the previously observed high median TS/Crea ratio in PCa patients in comparison to non-PCa patients. Thiosulfate subsequently failed as PCa biomarker while PCA3 and Phi showed the expected diagnostic improvement. PMID- 25274945 TI - Does creatinine analytical performance support robust identification of acute kidney injury within individual laboratories in a region. PMID- 25274946 TI - The stability of select biomarkers in frozen plasma over time: an evaluation of a low-volume sample analyzer. PMID- 25274947 TI - Clinical utility of determining tumor markers in patients with signs and symptoms of cancer. AB - BACKGROUND: Diagnosing patients with signs or symptoms suggestive of cancer is difficult. Serum tumor markers (TM) may be useful, but it is known that a range of pathologies other than cancer can increase their concentrations and so TM data must be interpreted with caution. The aim of this study is to determine the diagnostic accuracy of TMs in patients with signs or symptoms of cancer. METHODS: We prospectively studied 234 patients seen at rapid diagnostic units who presented signs or symptoms suggestive of cancer. Ninety patients had wasting syndrome, 74 had pulmonary symptoms and 70 other presentations. CYFRA21-1, CEA, CA19-9, total bilirubin and creatinine were determined. The final diagnosis was obtained after 6 months' follow-up. Patients were classified according to the absence (group A) or presence (group B) of abnormal bilirubin or creatinine. RESULTS: Of the 234 patients studied, 103 (44.0%) had tumors diagnosed. Cut-off points for each TM were calculated for a specificity of 100%. For the total group, the values were CYFRA21-1, 15 MUg/L, CEA, 43.8 MUg/L and CA19-9, 7428 KU/L, with an overall sensitivity of 46.6%. For group A (n=142), the following cut-off points were established: CYFRA21-1, 7.8 MUg/L, CEA, 13.8 MUg/L and CA19 9, 101 KU/L, obtaining a sensitivity of 68.6%. For group B (n=92), the values were the same as for the whole group, and a sensitivity of 42.4% was achieved. CONCLUSIONS: We conclude that TMs can aid diagnosis in these patients with signs or symptoms suggestive of cancer. Their sensitivity can be improved by using different cut-off points in the presence and absence of renal and hepatic dysfunction. PMID- 25274948 TI - Role of cerebrospinal fluid biomarkers to predict conversion to dementia in patients with mild cognitive impairment: a clinical cohort study. AB - BACKGROUND: Cerebrospinal fluid (CSF) levels assessment of Abeta1-42 and Tau proteins may be accurate diagnostic biomarkers for the differentiation of preclinical Alzheimer's disease (AD) from age-associated memory impairment, depression and other forms of dementia in patients with mild cognitive impairment (MCI). The aim of our study was to explore the utility of CSF biomarkers in combination with common cognitive markers as predictors for the risk of AD development, and other forms of dementia, and the time to conversion in community patients with MCI. METHODS: A group of 71 MCI patients underwent neurological assessment, extended neuropsychological evaluation, routine blood tests, ApoE determination, and lumbar puncture to dose t-tau, p-tau181, Abeta1-42. We investigated baseline CSF and neuropsychological biomarker patterns according to groups stratified with later diagnoses of AD conversion (MCI-AD), other dementia (MCI-NAD) conversion, or clinical stability (sMCI). RESULTS: Baseline Abeta1-42 CSF levels were significantly lower in MCI-AD patients compared to both sMCI and MCI-NAD. Additionally, p-tau181 was higher in the MCI-AD group compared to sMCI. The MCI-AD subgroup analysis confirmed the role of Abeta1-42 in its predictive role of time to conversion: rapid converters had lower Abeta1-42 levels compared to slow converters. Logistic regression and survival analysis further supported the key predictive role of baseline Abeta1-42 for incipient AD and dementia-free survival. CONCLUSIONS: Our results confirm the key role of CSF biomarkers in predicting patient conversion from MCI to dementia. The study suggests that CSF biomarkers may also be reliable in a real world clinical setting. PMID- 25274949 TI - Non-invasive prenatal diagnosis of monogenic disorders: an optimized protocol using MEMO qPCR with miniSTR as internal control. AB - BACKGROUND: Analysis of circulating cell-free fetal DNA (cffDNA) in maternal plasma is very promising for early diagnosis of monogenic diseases. However, this approach is not yet available for routine use and remains technically challenging because of the low concentration of cffDNA, which is swamped by the overwhelming maternal DNA. METHODS: To make clinical applications more readily accessible, we propose a new approach based on mutant enrichment with 3'-modified oligonucleotides (MEMO) PCR along with real-time PCR to selectively amplify from the maternal blood the paternally inherited fetal allele that is not present in the maternal genome. RESULTS: The first proof of concept of this strategy was displayed for cystic fibrosis by the accuracy of our detection of the p.Gly542* mutation used as the initial developmental model. Subsequently, a retrospective study of plasmas originating from two pregnant women carrying a fetus with private mutation confirmed the effectiveness of our method. We confirmed the presence of cffDNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit. CONCLUSIONS: This new non-invasive prenatal diagnosis test offers numerous advantages over current methods: it is simple, cost effective, time efficient and does not require complex equipment or bioinformatics settings. Moreover, our assays for different private mutations demonstrate the viability of this approach in clinical settings for monogenic disorders. PMID- 25274950 TI - The tumor necrosis factor-alpha -238G/A and IL-6 -572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls. AB - BACKGROUND: Inflammation plays an imperative role in the etiology of cardiovascular diseases (CVD). The role of cytokines in the development and progression of idiopathic dilated cardiomyopathy (IDCM) is still uncertain. The current study was conducted to evaluate the association of tumor necrosis factor alpha (TNF-alpha) -238G/A and IL-6 -572G/C gene polymorphism with IDCM in a Pakistani population. METHODS: IDCM cases (n=250) and healthy controls (n=300) were genotyped using PCR-RFLP. RESULTS: The variant genotypes of both the loci showed significant differences between patients and controls (p<0.05). However, 238G/A polymorphism did not show association with the disease in the presence of covariates. We also conducted a meta-analysis of both the loci with regards to CVD in accordance with the Prisma checklist. No significant relation of the TNF alpha -238G/A polymorphism with CVD was found; however, this single nucleotide polymorphism (SNP) showed an association with the disease in the Asian population after subgroup analysis (p=0.01). Whereas, the IL-6 -572G/C polymorphism showed that the variant genotype (GC+CC) was associated with higher risk of CVD in contrast to the GG genotype. Furthermore, subgroup meta-analysis demonstrated a significant association of the -572 polymorphism with CVD in Asians, but no association was observed among Western populations with this SNP. CONCLUSIONS: Our findings support an association between the IL-6 -572G/C polymorphism and IDCM risk. The role of the TNF-alpha -238G/A polymorphism in IDCM is still unclear. Further studies are warranted to determine the serum cytokine levels in relation to the cytokines' SNP in diverse ethnic groups to ascertain the molecular basis of the disease pathology. PMID- 25274951 TI - Immunoassay of thyroid peroxidase autoantibodies: diagnostic performance in automated third generation methods. A multicentre evaluation. AB - BACKGROUND: The use of automated immunometric methods for the detection of anti thyroid peroxidase antibodies (TPOAb), the main serological marker of autoimmune thyroid diseases (AITD), has expanded in recent years. However, it is not known whether these new automated platforms have improved the diagnostic performance of TPOAb assays. The aim of this study was to evaluate the potential improvement of the inter-method agreement of current automated third generation systems, 12 years after a previous study, which had assessed the analytical variability between semi-automated second generation methods of TPOAb detection. METHODS: Eight pools of sera from patients with chronic lymphocytic thyroiditis, exhibiting different TPOAb concentrations, were collected from routine laboratory diagnostics and distributed to seven companies throughout Italy. All automated third generation methods were calibrated against the Medical Research Council (MRC) reference preparation 66/387. RESULTS: The overall mean variability (CV) was 93.6% when results were expressed in part as arbitrary Units (U/mL) and in part as International Units (IU/mL). The conversion of all values in IU/mL resulted in a significant decrease of CV (49.8%). The CV expressed as COM (cut off concentration multiples) was 64.0%. Agreement of qualitative results was 95.3% with a pronounced difference in the threshold values proposed by manufacturers (range 3.2-35.0 IU/mL). CONCLUSIONS: These findings confirm the improvement of harmonisation between different methods of automated third generation TPOAb assays. Nevertheless, further efforts should be made in the definition of the positive cut-off concentration to avoid misclassification of AITD patients as well as in a new international reference preparation and in the autoantigen purification modality. PMID- 25274953 TI - Plasma visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) concentration is not related to kidney function in elderly subjects. AB - BACKGROUND: Studies assessing plasma visfatin/nicotinamide phosphoribosyltransferase (NAMPT) concentrations in chronic kidney disease with the ELISA method are restricted mainly to subjects with end-stage kidney disease. Therefore, little is known about to what extent glomerular filtration rate (GFR) affects the plasma levels of visfatin/NAMPT. The aim of this study was to assess the relations between circulating visfatin/NAMPT levels and estimated GFR (eGFR), independently of potential confounders such as inflammation, nutritional status, and insulin resistance in the elderly population. METHODS: The analysis included 3023 elderly subjects (1076 with impaired kidney excretory function - eGFR <60 mL/min/1.73 m2) who were participants of the PolSenior study. Serum insulin, glucose, creatinine, C-reactive protein, interleukin-6, and plasma visfatin/NAMPT concentrations were measured by a highly specific ELISA method. Insulin resistance was assessed on the basis of homeostasis model assessment for insulin resistance, and kidney excretory function was assessed using the full MDRD formula. RESULTS: Similar plasma visfatin/NAMPT levels were found in subjects with eGFR >=60 and <60 mL/min/1.73 m2 (0.96 ng/mL in both groups), and even in those subjects with eGFR 15-30 mL/min/1.73 m2 (0.83 ng/mL). Additionally, there was no association between plasma visfatin/NAMPT concentrations and eGFR values in models of regression analysis including confounding factors. CONCLUSIONS: The results of our study suggest that plasma visfatin/NAMPT levels are not affected by impaired kidney excretory function in elderly subjects. PMID- 25274952 TI - Diagnostic performance study of an antigen microarray for the detection of antiphospholipid antibodies in human serum. AB - BACKGROUND: The parallelization of clinically relevant antigens in a microarray format is of growing importance due to the ability to measure multiple antigen antibody interactions. With the development of a microarray for the detection of antiphospholipid antibodies we focussed on one important autoimmune disease that is still diagnostically challenging. Reasons are the heterogeneity of the autoantibodies and the unspecific clinical symptoms. METHODS: For the covalent immobilization of antigenic structures, glass transducers were coated with 11 aminoundecyltrimethoxysilane (11-AUTMS). In total 35 antiphospholipid syndrome (APS) patients, six patients with lupus erythematosus and 24 healthy controls were investigated on a microarray format using polarized imaging reflectometric interference spectroscopy. RESULTS: The novel surface modification based on the short derivative 11-AUTMS resulted in a selective biosensor allowing a clear differentiation of patient and control samples. It combined proteinogenic as well as phospholipid-derived antigens, namely beta2-glycoprotein I (beta2-GPI), prothrombin, cardiolipin (CL) and a beta2-GPI/CL complex. With optimized regeneration conditions, up to 20 consecutive measurements could be performed on one chip. Sensitivity was determined to be 0.800-0.929, specificity was between 0.733 and 0.969, depending on the respective antigen. CONCLUSIONS: Multiplexed determination of serological parameters has a great potential. We have shown that our biosensor is capable of detecting four different APS relevant antibodies in parallel exhibiting a sensitivity and specificity comparable to existing ELISA methods. PMID- 25274954 TI - Preanalytical errors: a preliminary approach to the point of view of primary health care givers. AB - BACKGROUND: The presence of errors in the preanalytical phase is a widely studied topic. However, information regarding the perspective of those professionals involved is rather scant. METHODS: Two focus groups of professionals from Primary Care involved in the preanalytical phase (general practitioners [GP], community nurses [CN], and other auxiliary health workers, including administrative personnel [AHW]) were convened. A qualitative analysis with a phenomenological approach was performed by using the structure of SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis as a guide, and results were categorized by grouping the resultant dimensions according to this structure. RESULTS: Overall, 12 professionals (3 GP, 6 CN, and 3 AHW) were distributed in two groups. Age and gender distribution were similar between groups. The most commented strengths were organizational capability and teamwork. The main weakness was the workload increase (compared to the short time spent on sample collection). Opportunities were related to workload optimization through on-line analytical requests. Threats were related to the long time elapsed between sample drawing at Primary Care and delivery to the Central Laboratory. CONCLUSIONS: The phenomenological approach allows revealing those aspects that cannot be entirely elucidated by objective data measurement. Attitudes considered as positive can be exploited by the institution, whereas those considered as negative alert us to possible future problems. Primary Care professionals offered a different point of view to laboratory staff, but both recognized high workload as the main threat and on line analytical request as the best opportunity. These perspectives may help to improve detection and decrease the number of errors. PMID- 25274955 TI - Accuracy of GFR estimating equations combining standardized cystatin C and creatinine assays: a cross-sectional study in Sweden. AB - BACKGROUND: The recently established international cystatin C calibrator makes it possible to develop non-laboratory specific glomerular filtration rate (GFR) estimating (eGFR) equations. This study compares the performance of the arithmetic mean of the revised Lund-Malmo creatinine and CAPA cystatin C equations (MEANLM-REV+CAPA), the arithmetic mean of the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) creatinine and cystatin C equations (MEANCKD-EPI), and the composite CKD-EPI equation (CKD-EPICREA+CYSC) with the corresponding single marker equations using internationally standardized calibrators for both cystatin C and creatinine. METHODS: The study included 1200 examinations in 1112 adult Swedish patients referred for measurement of GFR (mGFR) 2008-2010 by plasma clearance of iohexol (median 51 mL/min/1.73 m2). Bias, precision (interquartile range, IQR) and accuracy (percentage of estimates +/-30% of mGFR; P30) were compared. RESULTS: Combined marker equations were unbiased and had higher precision and accuracy than single marker equations. Overall results of MEANLM-REV+CAPA/MEANCKD-EPI/CKD-EPICREA+CYSC were: median bias -2.2%/-0.5%/ 1.6%, IQR 9.2/9.2/8.8 mL/min/1.73 m2, and P30 91.3%/91.0%/91.1%. The P30 figures were about 7-14 percentage points higher than the single marker equations. The combined equations also had a more stable performance across mGFR, age and BMI intervals, generally with P30 >=90% and never <80%. Combined equations reached P30 of 95% when the difference between eGFRCREA and eGFRCYSC was <10% but decreased to 82% at a difference of >=40%. CONCLUSIONS: Combining cystatin C and creatinine assays improves GFR estimations with P30 >=90% in adults. Reporting estimates of both single and combined marker equations in clinical settings makes it possible to assess the validity of the combined equation based on the agreement between the single marker equations. PMID- 25274956 TI - Multicentre evaluation of the Premier Hb9210 HbA1c analyser. AB - BACKGROUND: The accurate and precise quantification of HbA1c is essential for the diagnosis and routine monitoring of patients with diabetes. We report an evaluation of the Trinity Biotech Premier Hb9210 analyser (Bray, Ireland/Kansas City, MO, USA), a boronate affinity chromatography-based high performance liquid chromatography (HPLC) system for the measurement of glycated haemoglobin. METHODS: We evaluated the analytical performance of the Hb9210 as part of a multicentre evaluation. The effect of haemoglobin variants, other potential interferences and the performance in comparison to both the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and National Glycohemoglobin Standardization Program (NGSP) reference systems, was assessed. Most of the centres participating also act as reference laboratories for both the IFCC standardisation network for HbA1c and the NGSP. RESULTS: The combined data from all centres showed total coefficients of variation (CV) of 2.71%, 2.32% and 2.14% at low, medium and high values, respectively, for mmol/mol (SI units) and 1.62%, 1.59% and 1.68% for % (NGSP units), which are well below the recommended upper limits of 3% CV for mmol/mol (SI units) and 2% CV for % (NGSP). The analyser showed a good correlation to HbA1c methods currently used in clinical practice and the IFCC reference method procedure. Haemoglobin variants AC, AS, AE and AD do not affect the measurement of HbA1c. Overall the Hb9210 performs well across the whole analytical range. CONCLUSIONS: The Hb9210 performs well and is suitable for clinical application in the analysis of HbA1c. PMID- 25274957 TI - Diagnosis and evaluation of severity of sepsis via the use of biomarkers and profiles of 13 cytokines: a multiplex analysis. AB - BACKGROUND: The object of this study was to evaluate biomarkers for diagnosis of sepsis, hematologic parameters, and cytokine profiles for use in the diagnosis and evaluation of severity of sepsis. METHODS: We enrolled 127 consecutive patients with systemic inflammatory response syndrome (SIRS), 97 of whom were diagnosed with sepsis. The following biomarkers were evaluated: procalcitonin (PCT); C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); white blood cell count, immature granulocyte (IG) count; and multiplex cytokines, including interleukin (IL)1-beta (IL1beta), IL2, IL4, IL5, IL6, IL9, IL10, IL12p70, IL13, IL17, IL22, tumor necrosis factor-alpha (TNFalpha), and interferon gamma (IFNgamma). A cytokine bead immunoassay was used to perform simultaneous measurements. RESULTS: The disease involving urinary and respiratory tract constituted 57.5% of all patients. The severity of infection was classified as follows: SIRS patients, n=30; sepsis patients, n=81; and septic shock/severe sepsis patients, n=16. PCT, IL6, and CRP had high area under receiver operation characteristic curve (AUCs) and accuracy, which is as follows: PCT: 0.841, 80.5%; IL6: 0.811, 77.1%; CRP: 0.784, 73.8%, respectively. Severity of sepsis could be discriminated by PCT, IL6, and IL5. Unlike other cytokines, IFNgamma had an inverse relation with severity of sepsis. The relationship between cytokine profiles and clinical diagnosis of sepsis was unclear. CONCLUSIONS: PCT, IL6, and CRP values could assist diagnosis, and PCT, IL6, and IL5 had discriminative properties for determination of severity of sepsis. IFNgamma revealed a distinct inverse relationship with severity of sepsis. As there was no relationship between cytokine profiles and sepsis, further studies are required to develop clinical applications. PMID- 25274958 TI - Comparison of analytical sensitivity and women's interpretation of home pregnancy tests. AB - BACKGROUND: Internationally there are no defined standards for expressing the performance of home-based pregnancy tests, nor any pre-defined accuracy standard requirements. The aim of this study was to evaluate the accuracy of a selection of home-based pregnancy tests relative to their packaging/product insert claims. METHODS: Eight home-based pregnancy tests were evaluated using human chorionic gonadotrophin (hCG) urine standards (0, 15, 25 mlU/mL). Testing was performed by a technician and results were read by a technician and a panel of consumer volunteers (each blinded to the expected result) and compared with the expected result based on the manufacturer's claimed accuracy. Volunteers also completed questionnaires relating to various device attributes. RESULTS: The overall agreement between the technician reading and expected reading from the hCG concentration was >90% for the Clearblue(r) DIGITAL, Clearblue(r) PLUS, Confirme(r) Plus, David(r) and HausTM tests, and approximately 80% for Predictor(r) Early; agreement was <50% for Femitest(r) Jet Ultra and Cyclotest(r) Early tests. RESULTS were available from 72 volunteers (aged 18-45 years). Overall the percentage agreement between volunteer result and expected result was >95% for Clearblue DIGITAL and Clearblue PLUS tests; agreement for all other tests was <75% (lowest were Cyclotest Early and Femitest Jet Ultra, 33.0% and 39.4%, respectively). The Clearblue DIGITAL test was scored most highly by volunteers in the questionnaires. CONCLUSIONS: Many home-based pregnancy tests commonly used by women are not as accurate as their packaging information claims. International test standards which define appropriate performance characteristics for home pregnancy tests are urgently required. PMID- 25274960 TI - Laboratory medicine as the science that underpins medicine: the "high sensitivity" troponin paradigm. AB - The availability of so-called high-sensitivity troponin assays (hsTn) has scored a compelling goal for laboratory medicine, allowing the safe clinical application of international recommendations for the definition of acute myocardial infarction (AMI). However, the introduction of hsTn has not been welcomed by clinicians, claiming an increase in false-positive results. Here we critically trace back the steps following the introduction of hsTn by referring to the 5 year practical experience in our academic hospital and to suitable information available in the literature. In agreement with published data, we found that hsTn introduction was associated with an increased number of AMI diagnoses, whereas the test volume, the revascularization rate, and the proportion of cases with negative angiography findings remained virtually unchanged. Fast-track protocols for ruling out AMI have been further optimized to recommend sampling at presentation and after 3 h only. We focus on a cost-effective use of hsTn that can account for all clinical variables increasing the pre-test probability in order to ensure that tests are ordered only for patients at medium to high risk for acute coronary syndrome (ACS). To guide interpretation of results, hsTn typical release patterns suggestive for AMI should be identified by evaluating the significance of concentration changes. hsTn have markedly shortened the time to rule out or rule in AMI and has the potential to improve the prognostic assessment of critical patients in clinical contexts different from ACS. PMID- 25274959 TI - A novel biosensor-based microarray assay for the visualized detection of CYP2C19 *2, *3, *4 and *5 polymorphisms. AB - BACKGROUND: A number of studies have indicated that the conversion of clopidogrel to its active metabolite is reduced in patients who carry the CYP2C19 *2, *3, *4 or *5 loss-of-function allele, resulting in decreased response of platelet to clopidogrel treatment and worse cardiovascular outcome. The aim of this study was to develop a novel biosensor-based microarray to visually detect CYP2C19 polymorphisms. METHODS: The target DNA was amplified from regions flanking the respective alleles using 5'-biotinylated reverse primer, and plasmids were prepared for the respective alleles. High stringency reversed hybridization, horseradish peroxidase-labeled streptavidin reaction, and color development, with multiple washes in different steps, were carried out and the results were recorded with an optical camera. The gene chips were tested for specificity, detection limit, intra- and inter-batch variations using the constructed plasmids. Finally, 88 clinical samples were assayed with this microarray as well as direct sequencing. RESULTS: The results could be seen with the naked eye. Concordance tests indicated that for alleles *2, *3, *4, and *5, the kappa values between this assay and plasmids all reached 1.000. The detection limit was 5*102 cells/mL. Concordance test between direct sequencing and the microarray assay using 88 clinical samples gave rise to the kappa value of 0.983, and p<0.01, indicating very high concordance. CONCLUSIONS: This novel biosensor-based microarray assay can amplify the signal in situ so that it can be detected by simple instruments or even the naked eyes. It is promising for clinical application in hospital laboratories. PMID- 25274961 TI - The baseline serum value of alpha-amylase is a significant predictor of distance running performance. AB - BACKGROUND: This study was planned to investigate whether serum alpha-amylase concentration may be associated with running performance, physiological characteristics and other clinical chemistry analytes in a large sample of recreational athletes undergoing distance running. METHODS: Forty-three amateur runners successfully concluded a 21.1 km half-marathon at 75%-85% of their maximal oxygen uptake (VO2max). Blood was drawn during warm up and 15 min after conclusion of the run. RESULTS: After correction for body weight change, significant post-run increases were observed for serum values of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatine kinase (CK), iron, lactate dehydrogenase (LDH), triglycerides, urea and uric acid, whereas the values of body weight, glomerular filtration rate, total and low density lipoprotein-cholesterol were significantly decreased. The concentration of serum alpha-amylase was unchanged. In univariate analysis, significant associations with running performance were found for gender, VO2max, training regimen and pre-run serum values of alpha-amylase, CK, glucose, high density lipoprotein-cholesterol, LDH, urea and uric acid. In multivariate analysis, only VO2max (p=0.042) and baseline alpha-amylase (p=0.021) remained significant predictors of running performance. The combination of these two variables predicted 71% of variance in running performance. The baseline concentration of serum alpha-amylase was positively correlated with variation of serum glucose during the trial (r=0.345; p=0.025) and negatively with capillary blood lactate at the end of the run (r=-0.352; p=0.021). CONCLUSIONS: We showed that the baseline serum alpha-amylase concentration significantly and independently predicts distance running performance in recreational runners. PMID- 25274962 TI - From symptoms to biomarkers: a change of paradigm. PMID- 25274964 TI - Should we search for linear correlations between global strain parameters and ejection fraction? Reply. PMID- 25274965 TI - Association of pulmonary sling and atypical tracheal tree arrangement in a young girl. PMID- 25274966 TI - Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation. AB - AIMS: Little is known about the impact of left-ventricular (LV) diastolic dysfunction on risk of atrial fibrillation (AF) recurrence in patients with left atrial (LA) dilation. To evaluate, in patients with symptomatic persistent AF and LA dilation, the incremental role of LV diastolic dysfunction in predicting early AF recurrence after cardioversion (CV). METHODS AND RESULTS: From July 2011 to July 2013, 175 patients with persistent AF referred to our centre for CV were screened. Inclusion criteria were: European Heart Rhythm Association (EHRA) class >=2 despite optimal medical treatment and heart rate at rest <=80 bpm, LA volume >=34 mL/m(2), EF > 35%, absence of untreated ischaemic disease and significant valvular disease, successful CV. Finally, 127 patients (age 64 +/- 10 years, 60% EHRA >=3, LA volume 42 +/- 15 mL/m(2)) were enrolled. At 3 months, 37 (29%) patients presented AF recurrence. At univariate analysis, AF duration >90 days before CV (P < 0.01), septal e' <8 cm/s (P 0.03), and septal E/e' ratio >=11 (P < 0.001) but no LA dimensions significantly correlated with AF recurrence. Logistic regression analysis confirmed septal E/e' ratio >=11 as the best predictor of recurrence (OR 3.25 95% CI 1.19-8.86 P 0.001) together with an AF duration >90 days before the CV (OR 2.69 95% CI 1.01-7.53 P 0.04). At ROC curve analysis, the septal E/e' ratio >=11 showed the best diagnostic accuracy (AUC 0.66, 95% CI 0.55 0.76, P 0.007). CONCLUSION: In this population with symptomatic persistent AF and LA enlargement, septal E/e' ratio >=11 and AF duration >90 days predicted AF recurrence at 3 months. PMID- 25274967 TI - DUBs counteract parkin for efficient mitophagy. PMID- 25274968 TI - Celiac disease. AB - On the basis of strong evidence, gastrointestinal symptoms and failure to thrive are classic presentations of celiac disease, but atypical, nongastrointestinal symptoms are also extremely common, particularly in the older child and adolescent. (3)(4)(8). On the basis of some research evidence and consensus, guidelines recommend celiac testing in symptomatic children with typical and atypical symptoms and consideration of testing in those with associated conditions and first-degree relatives of those with celiac disease. (3)(9). On the basis of strong research evidence, measurement of tTG IgA and total serum IgA level has been reported to be the most cost-effective and accurate means of serologic testing for celiac disease and is the test of choice unless the child is younger than 2 years or IgA deficient. (9). On the basis of strong research evidence, children with elevated titers of celiac antibodies or strong clinical suspicion for celiac disease should be referred to a gastroenterologist for upper endoscopy and biopsy. Until this procedure is performed, the child should continue on a diet with ingestion of gluten. (3)(9). On the basis of strong research evidence, all those with a confirmed diagnosis of celiac disease should follow a strict gluten-free diet for life, with avoidance of all foods that contain wheat, barley, and rye ingredients. (3)(4). Referral to a health care professional with specialized knowledge of celiac disease and the gluten-free diet is critical because of the numerous ways, often hidden, in which gluten may be present in the diet and environment. PMID- 25274970 TI - Evaluation and treatment of nonmonosymptomatic enuresis. AB - On the basis of some research evidence and consensus, up to one-third of patients with enuresis will have daytime urinary symptoms indicative of lower urinary tract (LUT) dysfunction. (8)(9) On the basis of international consensus, children with enuresis and LUT dysfunction are correctly identified as having nonmonosymptomatic enuresis (NMSE) (formerly termed diurnal enuresis). (1)(2) On the basis of some research evidence and consensus, an adequate voiding and elimination history is the primary tool in differentiating between MSE and NMSE. (2)(7)(8). On the basis of some research evidence and consensus, therapy for NMSE is based on addressing underlying LUT dysfunction, constipation, and comorbid behavioral conditions before addressing enuresis. (2)(8)(9)(12) On the basis of some research evidence and consensus, treatment of underlying BBD and comorbid conditions will often result in improvement or resolution of enuresis. (2)(8)(9)(12). On the basis of international consensus, if enuresis is still present and a concern after treatment of underlying LUT, specific medical or behavioral therapy for enuresis should be offered to the family.(2)(8). PMID- 25274969 TI - Respiratory distress in the newborn. AB - Respiratory distress presents as tachypnea, nasal flaring, retractions, and grunting and may progress to respiratory failure if not readily recognized and managed. Causes of respiratory distress vary and may not lie within the lung. A thorough history, physical examination, and radiographic and laboratory findings will aid in the differential diagnosis. Common causes include transient tachypnea of the newborn, neonatal pneumonia, respiratory distress syndrome (RDS), and meconium aspiration syndrome (MAS). Strong evidence reveals an inverse relationship between gestational age and respiratory morbidity. (1)(2)(9)(25)(26) Expert opinion recommends careful consideration about elective delivery without labor at less than 39 weeks' gestation. Extensive evidence, including randomized control trials, cohort studies, and expert opinion, supports maternal group B streptococcus screening, intrapartum antibiotic prophylaxis, and appropriate followup of high-risk newborns according to guidelines established by the Centers for Disease Control and Prevention. (4)(29)(31)(32)(34) Following these best practice strategies is effective in preventing neonatal pneumonia and its complications. (31)(32)(34). On the basis of strong evidence, including randomized control trials and Cochrane Reviews, administration of antenatal corticosteroids (5) and postnatal surfactant (6) decrease respiratory morbidity associated with RDS. Trends in perinatal management strategies to prevent MAS have changed. There is strong evidence that amnioinfusion, (49) oropharyngeal and nasopharyngeal suctioning at the perineum, (45) or intubation and endotracheal suctioning of vigorous infants (46)(47) do not decrease MAS or its complications. Some research and expert opinion supports endotracheal suctioning of nonvigorous meconium-stained infants (8) and induction of labor at 41 weeks' gestation (7) to prevent MAS. PMID- 25274973 TI - Henoch-Schonlein purpura. PMID- 25274971 TI - Index of suspicion. PMID- 25274974 TI - Testicular and scrotal masses. PMID- 25274975 TI - Visual diagnosis: 12-month-old boy with persistent rash and lymphadenopathy. AB - Gianotti-Crosti syndrome (GCS) is a self-limiting, papular or papulovesicular, symmetric, acral exanthem that typically presents subsequent to viral infection, bacterial infection, or immunization in a child 1 to 4 years old. The rash can persist for 2 to 10 weeks. Recent infection with Epstein-Barr virus is the most common serologic finding in patients who have developed GCS. The diagnosis is often made after the child has been unsuccessfully treated for a more common cause of an acral rash (eg, scabies). There are no pathognomonic laboratory or histopathologic findings. GCS, therefore, is still a clinical diagnosis of exclusion. The rash is self-limited, and treatment is usually not necessary. However, topical corticosteroids are anecdotally reported to reduce duration of rash. Oral antihistamines can be used to treat pruritus. Parents should be assured that resolution is almost always complete, scarring seldom occurs, and recurrence is rare. PMID- 25274976 TI - Visual diagnosis: newborn with absence of skin. AB - ACC is a rare condition that has to be approached by a multidisciplinary team, including a pediatrician, dermatologist, and plastic surgeon. Associated malformations should be ruled out in a patient with ACC, and conservative management is usually the mainstay of treatment. Antibiotic therapy is not used routinely unless lesions are infected. PMID- 25274984 TI - 2014 SNMMI Highlights Lecture: Cardiovascular Imaging. PMID- 25274978 TI - Attribution of 12 high-risk human papillomavirus genotypes to infection and cervical disease. AB - BACKGROUND: We estimated the prevalence and incidence of 14 human papillomavirus (HPV) types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS), using predefined algorithms that adjusted for multiple-type infected lesions. METHODS: A total of 10,656 women ages 15 to 26 years and 1,858 women ages 24 to 45 years were enrolled in the placebo arms of one of three clinical trials of a quadrivalent HPV vaccine. We estimated the cumulative incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by a prophylactic 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine. RESULTS: The cumulative incidence of persistent infection with >=1 of the seven high-risk types included in the 9 valent vaccine was 29%, 12%, and 6% for women ages 15 to 26, 24 to 34, and 35 to 45 years, respectively. A total of 2,507 lesions were diagnosed as CIN or AIS by an expert pathology panel. After adjusting for multiple-type infected lesions, among women ages 15 to 45 years, these seven high-risk types were attributed to 43% to 55% of CIN1, 70% to 78% of CIN2, 85% to 91% of CIN3, and 95% to 100% of AIS lesions, respectively. The other tested types (HPV35/39/51/56/59) were attributed to 23% to 30% of CIN1, 7% to 14% of CIN2, 3% to 4% of CIN3, and 0% of AIS lesions, respectively. CONCLUSIONS: Approximately 85% or more of CIN3/AIS, >70% CIN2, and approximately 50% of CIN1 lesions worldwide are attributed to HPV6/11/16/18/31/33/45/52/58. IMPACT: If 9-valent HPV vaccination programs are effectively implemented, the majority of CIN2 and CIN3 lesions worldwide could be prevented, in addition to approximately one-half of CIN1. PMID- 25274985 TI - The receptor kinase IMPAIRED OOMYCETE SUSCEPTIBILITY1 attenuates abscisic acid responses in Arabidopsis. AB - In plants, membrane-bound receptor kinases are essential for developmental processes, immune responses to pathogens and the establishment of symbiosis. We previously identified the Arabidopsis (Arabidopsis thaliana) receptor kinase IMPAIRED OOMYCETE SUSCEPTIBILITY1 (IOS1) as required for successful infection with the downy mildew pathogen Hyaloperonospora arabidopsidis. We report here that IOS1 is also required for full susceptibility of Arabidopsis to unrelated (hemi)biotrophic filamentous oomycete and fungal pathogens. Impaired susceptibility in the absence of IOS1 appeared to be independent of plant defense mechanism. Instead, we found that ios1-1 plants were hypersensitive to the plant hormone abscisic acid (ABA), displaying enhanced ABA-mediated inhibition of seed germination, root elongation, and stomatal opening. These findings suggest that IOS1 negatively regulates ABA signaling in Arabidopsis. The expression of ABA sensitive COLD REGULATED and RESISTANCE TO DESICCATION genes was diminished in Arabidopsis during infection. This effect on ABA signaling was alleviated in the ios1-1 mutant background. Accordingly, ABA-insensitive and ABA-hypersensitive mutants were more susceptible and resistant to oomycete infection, respectively, showing that the intensity of ABA signaling affects the outcome of downy mildew disease. Taken together, our findings suggest that filamentous (hemi)biotrophs attenuate ABA signaling in Arabidopsis during the infection process and that IOS1 participates in this pathogen-mediated reprogramming of the host. PMID- 25274987 TI - Dissociating Contributions of the Motor Cortex to Speech Perception and Response Bias by Using Transcranial Magnetic Stimulation. AB - Recent studies using repetitive transcranial magnetic stimulation (TMS) have demonstrated that disruptions of the articulatory motor cortex impair performance in demanding speech perception tasks. These findings have been interpreted as support for the idea that the motor cortex is critically involved in speech perception. However, the validity of this interpretation has been called into question, because it is unknown whether the TMS-induced disruptions in the motor cortex affect speech perception or rather response bias. In the present TMS study, we addressed this question by using signal detection theory to calculate sensitivity (i.e., d') and response bias (i.e., criterion c). We used repetitive TMS to temporarily disrupt the lip or hand representation in the left motor cortex. Participants discriminated pairs of sounds from a "ba"-"da" continuum before TMS, immediately after TMS (i.e., during the period of motor disruption), and after a 30-min break. We found that the sensitivity for between-category pairs was reduced during the disruption of the lip representation. In contrast, disruption of the hand representation temporarily reduced response bias. This double dissociation indicates that the hand motor cortex contributes to response bias during demanding discrimination tasks, whereas the articulatory motor cortex contributes to perception of speech sounds. PMID- 25274986 TI - Synaptic Basis for Cross-modal Plasticity: Enhanced Supragranular Dendritic Spine Density in Anterior Ectosylvian Auditory Cortex of the Early Deaf Cat. AB - In the cat, the auditory field of the anterior ectosylvian sulcus (FAES) is sensitive to auditory cues and its deactivation leads to orienting deficits toward acoustic, but not visual, stimuli. However, in early deaf cats, FAES activity shifts to the visual modality and its deactivation blocks orienting toward visual stimuli. Thus, as in other auditory cortices, hearing loss leads to cross-modal plasticity in the FAES. However, the synaptic basis for cross-modal plasticity is unknown. Therefore, the present study examined the effect of early deafness on the density, distribution, and size of dendritic spines in the FAES. Young cats were ototoxically deafened and raised until adulthood when they (and hearing controls) were euthanized, the cortex stained using Golgi-Cox, and FAES neurons examined using light microscopy. FAES dendritic spine density averaged 0.85 spines/MUm in hearing animals, but was significantly higher (0.95 spines/MUm) in the early deaf. Size distributions and increased spine density were evident specifically on apical dendrites of supragranular neurons. In separate tracer experiments, cross-modal cortical projections were shown to terminate predominantly within the supragranular layers of the FAES. This distributional correspondence between projection terminals and dendritic spine changes indicates that cross-modal plasticity is synaptically based within the supragranular layers of the early deaf FAES. PMID- 25274988 TI - Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets. AB - The Src homology-2 domain containing protein B (SHB) has previously been shown to function as a pleiotropic adapter protein, conveying signals from receptor tyrosine kinases to intracellular signaling intermediates. The overexpression of Shb in beta-cells promotes beta-cell proliferation by increased insulin receptor substrate (IRS) and focal adhesion kinase (FAK) activity, whereas Shb deficiency causes moderate glucose intolerance and impaired first-peak insulin secretion. Using an array of techniques, including live-cell imaging, patch-clamping, immunoblotting, and semi-quantitative PCR, we presently investigated the causes of the abnormal insulin secretory characteristics in Shb-knockout mice. Shb knockout islets displayed an abnormal signaling signature with increased activities of FAK, IRS, and AKT. beta-catenin protein expression was elevated and it showed increased nuclear localization. However, there were no major alterations in the gene expression of various proteins involved in the beta-cell secretory machinery. Nor was Shb deficiency associated with changes in glucose induced ATP generation or cytoplasmic Ca(2+) handling. In contrast, the glucose induced rise in cAMP, known to be important for the insulin secretory response, was delayed in the Shb-knockout compared with WT control. Inhibition of FAK increased the submembrane cAMP concentration, implicating FAK activity in the regulation of insulin exocytosis. In conclusion, Shb deficiency causes a chronic increase in beta-cell FAK activity that perturbs the normal insulin secretory characteristics of beta-cells, suggesting multi-faceted effects of FAK on insulin secretion depending on the mechanism of FAK activation. PMID- 25274989 TI - Glucagon secretion after metabolic surgery in diabetic rodents. AB - Excessive or inadequate glucagon secretion promoting hepatic gluconeogenesis and glycogenolysis is believed to contribute to hyperglycemia in patients with type 2 diabetes. Currently, metabolic surgery is an accepted treatment for obese patients with type 2 diabetes and has been shown to improve glycemic control in Goto-Kakizaki (GK) rats, a lean animal model for type 2 diabetes. However, the effects of surgery on glucagon secretion are not yet well established. In this study, we randomly assigned forty 12- to 14-week-old GK rats to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Ten age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control was assessed before and 4 weeks after surgery. Fasting- and mixed-meal-induced plasma levels of insulin and glucagon were measured. Overall glycemic control improved in GKSG and GKGB rats. Fasting insulin levels in WIC rats were similar to those for GKC or GKSS rats. Fasting glucagon levels were highest in GKGB rats. Whereas WIC, GKC, and GKSS rats showed similar glucagon levels, without any significant meal-induced variation, a significant rise occurred in GKSG and GKGB rats, 30 min after a mixed meal, which was maintained at 60 min. Both GKSG and GKGB rats showed an elevated glucagon:insulin ratio at 60 min in comparison with all other groups. Surprisingly, the augmented post-procedural glucagon secretion was accompanied by an improved overall glucose metabolism in GKSG and GKGB rats. Understanding the role of glucagon in the pathophysiology of type 2 diabetes requires further research. PMID- 25274991 TI - Significant difference in drug susceptibility distribution between Mycobacterium avium and Mycobacterium intracellulare. PMID- 25274990 TI - Effects of target typicality on categorical search. AB - The role of target typicality in a categorical visual search task was investigated by cueing observers with a target name, followed by a five-item target present/absent search array in which the target images were rated in a pretest to be high, medium, or low in typicality with respect to the basic-level target cue. Contrary to previous work, we found that search guidance was better for high-typicality targets compared to low-typicality targets, as measured by both the proportion of immediate target fixations and the time to fixate the target. Consistent with previous work, we also found an effect of typicality on target verification times, the time between target fixation and the search judgment; as target typicality decreased, verification times increased. To model these typicality effects, we trained Support Vector Machine (SVM) classifiers on the target categories, and tested these on the corresponding specific targets used in the search task. This analysis revealed significant differences in classifier confidence between the high-, medium-, and low-typicality groups, paralleling the behavioral results. Collectively, these findings suggest that target typicality broadly affects both search guidance and verification, and that differences in typicality can be predicted by distance from an SVM classification boundary. PMID- 25274992 TI - Rapid and direct detection of herpes simplex virus in cerebrospinal fluid by use of a commercial real-time PCR assay. AB - Central nervous system infection due to herpes simplex virus (HSV) is a medical emergency and requires rapid diagnosis and initiation of therapy. In this study, we compared a routine real-time PCR assay for HSV types 1 (HSV-1) and 2 (HSV-2) to a recently FDA-approved direct PCR assay (Simplexa HSV-1/2 Direct; Focus Diagnostics, Cypress, CA) using cerebrospinal fluid samples (n = 100). The Simplexa HSV-1/2 assays demonstrated a combined sensitivity and specificity of 96.2% (50/52) and 97.9% (47/48), respectively. In addition, the Simplexa assay does not require nucleic acid extraction, and the results are available in 60 min. PMID- 25274993 TI - Identification of primary drug resistance to rifampin in Mycobacterium leprae strains from leprosy patients in Amazonas State, Brazil. AB - The aim of this study was to identify polymorphisms in the folp1, gyrA, and rpoB genes in leprosy patients treated in Amazonas State, Brazil. Among 197 slit-skin smear samples from untreated or relapsed patients, we found three cases of primary resistance to rifampin and one confirmed case of multidrug resistance. PMID- 25274994 TI - Enterocytozoon bieneusi genotypes in children in Northeast China and assessment of risk of zoonotic transmission. AB - The prevalence (7.5%, 19/255) and genotypes of Enterocytozoon bieneusi in children of various age categories and clinical presentations were determined herein. The co-occurrence of the known genotypes (CS-4, EbpC, and Henan-IV) in children and pigs in the same study area, the phylogenetic characterization of novel genotypes (NEC1 to NEC5), and the assessment of potential risk factors associated with zoonotic transmission robustly suggested that pigs could be a significant source of human E. bieneusi infections in northeast China. PMID- 25274995 TI - Direct detection and prediction of all pneumococcal serogroups by target enrichment-based next-generation sequencing. AB - Despite the availability of standard methods for pneumococcal serotyping, there is room for improvement in the available methods, in terms of throughput, multiplexing capacity, and the number of serotypes identified. We describe a target enrichment-based next-generation sequencing method applied to nasopharyngeal samples for direct detection and serogroup prediction of all known serotypes of Streptococcus pneumoniae, 32 to the serotype level and the rest to the closely related serogroup level. The method was applied to detect and to predict the serogroups of pneumococci directly in clinical samples and from sweeps of primary culture DNA, with increased detection rates versus culture based identification and agreement with the serotypes/serogroups determined by conventional serotyping methods. We propose this method, in conjunction with traditional serotyping methods, as an alternative to rapid detection and serotyping of pneumococci. PMID- 25274996 TI - Pattern of circulation of norovirus GII strains during natural infection. AB - Norovirus (NoV) is considered a major cause of nonbacterial gastroenteritis among people of all ages worldwide, but the natural course of infection is incompletely known. In this study, the pattern of circulation of NoVs was studied among 146 children and 137 adults in a small community in southwestern Cameroon. The participants provided monthly fecal samples during a year. NoV RNA was detected in at least one sample from 82 (29%) of the participants. The partial VP1 region could be sequenced in 36 NoV GII-positive samples. Three different genotypes were identified (GII.1, GII.4, and GII.17), with each genotype circulating within 2 to 3 months and reappearing after a relapse period of 2 to 3 months. Most infections occurred once, and 2 episodes at most within a year were detected. No difference in the frequency of NoV infection between children and adults was recorded. The same genotype was detected for a maximum of 2 consecutive months in 3 children only, suggesting that a less than 30-day duration of viral shedding in natural infection was common. Reinfection within a year with the same genotype was not observed, consistent with short-term homotypic immune protection. The study revealed that NoV strains are circulating with a limited duration of viral shedding both in the individuals and the population as part of their natural infection. The results also provide evidence of cross-protective immunity of limited duration between genotypes of the same genogroup. PMID- 25274997 TI - Evaluation of the BD GeneOhm methicillin-resistant Staphylococcus aureus (MRSA) assay as a method for detection of MRSA isolates, using a large collection of European and North African isolates. AB - Using a large collection of European and North African methicillin-resistant Staphylococcus aureus (MRSA) isolates with a variety of genetic backgrounds and staphylococcal cassette chromosome mec (SCCmec) types, we evaluated the reliability of the BD GeneOhm MRSA assay. Results revealed high performance of this test for detecting MRSA strains provided from Europe and North Africa (98.3%). PMID- 25274998 TI - Rapid identification of pathogens from pediatric blood cultures by use of the FilmArray blood culture identification panel. AB - The performance of the FilmArray blood culture identification (BCID) panel has been studied in adult patients. We describe here an evaluation of this assay for the rapid identification of pathogens in Bactec Peds Plus/F and Bactec standard anaerobic/F bottles that contained blood samples from pediatric patients at a tertiary care children's hospital. PMID- 25274999 TI - Can newly developed, rapid immunochromatographic antigen detection tests be reliably used for the laboratory diagnosis of influenza virus infections? AB - Five years ago, the Point-Counterpoint series was launched. The initial article asked about the role of rapid immunochromatographic antigen testing in the diagnosis of influenza A virus 2009 H1N1 infection (D. F. Welch and C. C. Ginocchio, J Clin Microbiol 48:22-25, 2010, http://dx.doi.org/10.1128/JCM.02268 09). Since that article, not only have major changes been made in immunochromatographic antigen detection (IAD) testing for the influenza viruses, but there has also been rapid development of commercially available nucleic acid amplification tests (NAATs) for influenza virus detection. Further, a novel variant of influenza A, H7N9, has emerged in Asia, and H5N1 is also reemergent. In that initial article, the editor of this series, Peter Gilligan, identified two issues that required further consideration. One was how well IAD tests worked in clinical settings, especially in times of antigen drift and shift. The other was the role of future iterations of influenza NAATs and whether this testing would be available in a community hospital setting. James Dunn, who is Director of Medical Microbiology and Virology at Texas Children's Hospital, has extensive experience using IAD tests for diagnosing influenza. He will discuss the application and value of these tests in influenza diagnosis. Christine Ginocchio, who recently retired as the Senior Medical Director, Division of Infectious Disease Diagnostics, North Shore-LIJ Health System, and now is Vice President for Global Microbiology Affairs at bioMerieux, Durham, NC, wrote the initial counterpoint in this series, where she advocated the use of NAATs for influenza diagnosis. She will update us on the commercially available NAAT systems and explain what their role should be in the diagnosis of influenza infection. PMID- 25275001 TI - Efficient diagnosis and treatment follow-up of human brucellosis by a novel quantitative TaqMan real-time PCR assay: a human clinical survey. AB - Rapid and effective diagnosis of brucellosis is a challenge for clinicians. Even when diagnosis is on time and therapy is initiated, meticulous follow-up appointments are crucial for ensuring the efficacy of the treatment. Due to shortcomings of serological methods, molecular diagnosis, especially real-time PCR, is becoming a main approach in laboratory diagnostics. Thus, the development of efficient procedures and standardization of the PCR tests will have a great impact on the precise detection and quantification of bacterial DNA loads, which is valuable for the medical management of brucellosis patients. We developed a new TaqMan real-time PCR directed to bcsp31, a shared gene of the brucellae. The bcsp31 gene fragment was cloned into pJET1.2. Recombinant pJET1.2-bcsp31 was linearized by HindIII digestion, and the product was used for the preparation of a standard curve. A panel of Brucella spp. and non-Brucella pathogens was tested. No bacterial genomes other than those of the brucellae were detected. According to the results, specificity of the method was 100%. In a clinical assessment, the positive-control group comprised 37 patients with microbiologically confirmed brucellosis, and 25 healthy individuals served as the negative-control group. By the end of the treatment period, there was a significant decrease in the DNA load of the 37 brucellosis patients, which persisted for the 4 weeks of monitoring after treatment, suggesting that our proposed method is an efficient monitoring tool. Serum samples prior to any treatment were collected from the 25 serologically suspicious patients and assessed by our method; 72% of these patients tested positive for brucellosis. PMID- 25275002 TI - Development and optimization of a real-time PCR assay for detection of herpes simplex and varicella-zoster viruses in skin and mucosal lesions by use of the BD Max open system. AB - We transitioned laboratory-developed PCR assays for herpes simplex virus 1 (HSV 1), HSV-2, and varicella-zoster virus (VZV) to the BD Max system by using BD Max open system reagents. After optimization, the agreement with the reference PCR assay was 100% (123/123) for HSV-1, 96.7% (119/123) for HSV-2, and 100% (60/60) for VZV using retrospective clinical samples. PMID- 25275000 TI - Multiplex PCR for detection of seven virulence factors and K1/K2 capsular serotypes of Klebsiella pneumoniae. AB - A single multiplex PCR assay targeting seven virulence factors and the wzi gene specific for the K1 and K2 capsular serotypes of Klebsiella pneumoniae was developed and tested on 65 clinical isolates, which included 45 isolates responsible for community-acquired severe human infections. The assay is useful for the surveillance of emerging highly virulent strains. PMID- 25275003 TI - Comparison of the IMDx influenza A virus, influenza B virus, and respiratory syncytial virus A/B assay on the m2000 platform with real-time reverse transcriptase PCR assays. PMID- 25275004 TI - Chronic hepatitis E virus infection in a pediatric female liver transplant recipient. AB - We describe a case of chronic hepatitis E virus (HEV) infection in a 13-year-old female liver transplant recipient with recurrent increased aminotransferase levels and acute cellular rejection. This finding demonstrates that chronic HEV infection can occur and should be further investigated in immunocompromised patients in Latin America. PMID- 25275006 TI - Acidovorax oryzae catheter-associated bloodstream infection. AB - Acidovorax oryzae is a bacterium that has never before been reported as pathogenic in human subjects. Here we describe the first case of a successfully treated A. oryzae catheter-associated bloodstream infection in an immunocompetent patient prior to heart transplantation. PMID- 25275005 TI - Phenotypic and genotypic analysis of Clostridium difficile isolates: a single center study. AB - Clostridium difficile infections (CDI) are a growing concern in North America, because of their increasing incidence and severity. Using integrated approaches, we correlated pathogen genotypes and host clinical characteristics for 46 C. difficile infections in a tertiary care medical center during a 6-month interval from January to June 2010. Multilocus sequence typing (MLST) demonstrated 21 known and 2 novel sequence types (STs), suggesting that the institution's C. difficile strains are genetically diverse. ST-1 (which corresponds to pulsed field gel electrophoresis strain type NAP1/ribotype 027) was the most prevalent (32.6%); 43.5% of the isolates were binary toxin gene positive, of which 75% were ST-1. All strains were ciprofloxacin resistant and metronidazole susceptible, and 8.3% and 13.0% of the isolates were resistant to clindamycin and tetracycline, respectively. The corresponding resistance loci, including potential novel mutations, were identified from the whole-genome sequencing (WGS) of the resistant strains. Core genome single nucleotide polymorphisms (SNPs) determining the phylogenetic relatedness of the 46 strains recapitulated MLST types and provided greater interstrain differentiation. The disease severity was greatest in patients infected with ST-1 and/or binary gene-positive strains, but genome wide SNP analysis failed to provide additional associations with CDI severity within the same STs. We conclude that MLST and core genome SNP typing result in the same phylogenetic grouping of the 46 C. difficile strains collected in a single hospital. WGS also has the capacity to differentiate those strains within STs and allows the comparison of strains at the individual gene level and at the whole-genome level. PMID- 25275007 TI - Investigating the role of a backbone to substrate hydrogen bond in OMP decarboxylase using a site-specific amide to ester substitution. AB - Hydrogen bonds between backbone amide groups of enzymes and their substrates are often observed, but their importance in substrate binding and/or catalysis is not easy to investigate experimentally. We describe the generation and kinetic characterization of a backbone amide to ester substitution in the orotidine 5' monophosphate (OMP) decarboxylase from Methanobacter thermoautotrophicum (MtOMPDC) to determine the importance of a backbone amide-substrate hydrogen bond. The MtOMPDC-catalyzed reaction is characterized by a rate enhancement (~10(17)) that is among the largest for enzyme-catalyzed reactions. The reaction proceeds through a vinyl anion intermediate that may be stabilized by hydrogen bonding interaction between the backbone amide of a conserved active site serine residue (Ser-127) and oxygen (O4) of the pyrimidine moiety and/or electrostatic interactions with the conserved general acidic lysine (Lys-72). In vitro translation in conjunction with amber suppression using an orthogonal amber tRNA charged with L-glycerate ((HO)S) was used to generate the ester backbone substitution (S127(HO)S). With 5-fluoro OMP (FOMP) as substrate, the amide to ester substitution increased the value of Km by ~1.5-fold and decreased the value of kcat by ~50-fold. We conclude that (i) the hydrogen bond between the backbone amide of Ser-127 and O4 of the pyrimidine moiety contributes a modest factor (~10(2)) to the 10(17) rate enhancement and (ii) the stabilization of the anionic intermediate is accomplished by electrostatic interactions, including its proximity of Lys-72. These conclusions are in good agreement with predictions obtained from hybrid quantum mechanical/molecular mechanical calculations. PMID- 25275010 TI - Network histograms and universality of blockmodel approximation. AB - In this paper we introduce the network histogram, a statistical summary of network interactions to be used as a tool for exploratory data analysis. A network histogram is obtained by fitting a stochastic blockmodel to a single observation of a network dataset. Blocks of edges play the role of histogram bins and community sizes that of histogram bandwidths or bin sizes. Just as standard histograms allow for varying bandwidths, different blockmodel estimates can all be considered valid representations of an underlying probability model, subject to bandwidth constraints. Here we provide methods for automatic bandwidth selection, by which the network histogram approximates the generating mechanism that gives rise to exchangeable random graphs. This makes the blockmodel a universal network representation for unlabeled graphs. With this insight, we discuss the interpretation of network communities in light of the fact that many different community assignments can all give an equally valid representation of such a network. To demonstrate the fidelity-versus-interpretability tradeoff inherent in considering different numbers and sizes of communities, we analyze two publicly available networks--political weblogs and student friendships--and discuss how to interpret the network histogram when additional information related to node and edge labeling is present. PMID- 25275009 TI - Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis. AB - Intrinsic apoptotic stimuli initiate mammalian cells' apoptotic program by first activating the proteins that have only Bcl-2 homology domain 3 (BH3), such as Bcl 2 interacting mediator of cell death (Bim) and truncated BH3 interacting death domain agonist (tBid), which in turn trigger conformational changes in BCL2 associated X (Bax) and BCL2-antagonist/killer (Bak) proteins that enable oligomer formation on the mitochondria, causing cytochrome c and other apoptogenic proteins in the intermembrane space to leak out. Leaked cytochrome c then initiates apoptotic caspase activation through a well-defined biochemical pathway. However, how oligomerized Bax and Bak cause cytochrome c release from mitochondria remains unknown. We report here the establishment of cell lines in which Bim or tBid can be inducibly expressed to initiate apoptosis in a controlled, quantitative manner. We used these cell lines to examine apoptotic events after Bax and Bak oligomerization but before cytochrome c release. The mitochondrial metalloprotease OMA1 was activated in this system in a Bax- and Bak dependent fashion. Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. Thus it is clear that oligomerized Bax and Bak trigger apoptosis by causing both the permeabilization of the mitochondrial outer membrane and activation OMA1. PMID- 25275008 TI - Delayed Ras/PKA signaling augments the unfolded protein response. AB - During environmental, developmental, or genetic stress, the cell's folding capacity can become overwhelmed, and misfolded proteins can accumulate in all cell compartments. Eukaryotes evolved the unfolded protein response (UPR) to counteract proteotoxic stress in the endoplasmic reticulum (ER). Although the UPR is vital to restoring homeostasis to protein folding in the ER, it has become evident that the response to ER stress is not limited to the UPR. Here, we used engineered orthogonal UPR induction, deep mRNA sequencing, and dynamic flow cytometry to dissect the cell's response to ER stress comprehensively. We show that budding yeast augments the UPR with time-delayed Ras/PKA signaling. This second wave of transcriptional dynamics is independent of the UPR and is necessary for fitness in the presence of ER stress, partially due to a reduction in general protein synthesis. This Ras/PKA-mediated effect functionally mimics other mechanisms, such as translational control by PKR-like ER kinase (PERK) and regulated inositol-requiring enzyme 1 (IRE1)-dependent mRNA decay (RIDD), which reduce the load of proteins entering the ER in response to ER stress in metazoan cells. PMID- 25275011 TI - Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion. AB - Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed "type VII." How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE-PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways. PMID- 25275012 TI - Ca2+ and cAMP signaling pathways interact to increase the diuretic effect of serotonin in Malpighian tubules of the kissing bug. Focus on "Serotonin triggers cAMP- and PKA-1-mediated intracellular calcium waves in Malpighian tubules of Rhodnius prolixus". PMID- 25275013 TI - Endothelial cells but not platelets are the major source of Toll-like receptor 4 in the arterial thrombosis and tissue factor expression in mice. AB - It is known that Toll-like receptor (TLR)-4 plays an important role in myocardial infarction and atherothrombosis. The role of TLR-4 in arterial thrombosis is undefined. Both TLR-4-deficient (TLR-4(-/-)) and wild-type (WT) mice were subjected to FeCl3 carotid artery injury, and the time required to form an occlusive thrombus was measured. The mean time to occlusion in TLR-4(-/-) mice was significantly greater than that in WT mice after injury (303 +/- 32 vs. 165 +/- 34 s, P < 0.05). Furthermore, when we used a WT or TLR-4(-/-)-derived platelet reinfusion in a platelet depletion/reinfusion procedure, there was no significant change in the occlusion time and tissue factor (TF) activity in injured arteries between WT mice and platelet-depleted WT mice. Similarly, no significant difference was observed between TLR-4(-/-) mice and platelet-depleted TLR-4(-/-) mice for the WT or TLR-4(-/-)-derived platelet reinfusion. However, TF expression and activity were significantly reduced in the vascular wall of TLR-4( /-) mice compared with WT mice. In vivo, lipopolysaccharide accelerated the occlusion time in WT mice but not TLR-4(-/-) mice. In vitro, LPS-induced TF activity was reduced in endothelial cells of TLR-4(-/-) mice relative to WT mice. The data demonstrate that TLR-4 contributes to arterial thrombosis formation in vivo and causes increased TF expression and activity in vitro. The results further suggest that the stimulation is mainly derived by endothelial cells but is not due to platelet-derived TLR-4. PMID- 25275014 TI - Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension. AB - Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (Po2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney Qo2, cortical Po2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 +/- 3.3 vs. 0.9 +/- 0.4 pmol O2 . s(-1). mg protein(-1), P < 0.05) and increased whole kidney Qo2 (55 +/- 16 vs. 33 +/- 10 MUmol O2/min, P < 0.05). Corticomedullary Po2 was lower in TX compared with 1K-CON (30 +/- 13 vs. 47 +/- 4 MUM, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Qo2, Po2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage. PMID- 25275015 TI - Genes associated with succeptibility to lung adenocarcinoma among never smokers suggest the mechanism of disease. AB - Global statistics estimate that 15% of all cases of lung cancer in men and 53% in women are not attributable to smoking, and these data indicate that worldwide, approximately 25% of patients with lung cancer are never smokers. The etiology of lung cancer is disputed. The present study reviews the genes associated with susceptibility to lung cancer among never smokers and suggests possibilities for the involvement of metabolic syndrome. The environment appears to have changed the genes susceptible to lung cancer. Classical genes associated with lung cancer are decreasing and novel emerging genes may reflect changes in lifestyle. We provide evidence that the genes associated with susceptibility to lung cancer in never smokers are very similar to those reported in patients with metabolic syndrome, and that simply quitting smoking is not sufficient as the primary means of preventing lung cancer. PMID- 25275016 TI - Pharmacogenomics in lung cancer chemotherapy: a review of what the oncologist should know. AB - Lung cancer is the leading cause of cancer-related death around the world; the addition of chemotherapy to treatment of this disease has been shown to significantly increase progression-free survival and overall survival. Despite newer chemotherapies, it is important to personalize the care (treatment and dose) upon each single patient's susceptibility for controlling and reducing adverse side-effects, at best. The present review describes the current status of pharmacogenomics studies regarding germline DNA variants that may alter response and tolerability to chemotherapeutic agents used to treat lung cancer, including perspective studies. PMID- 25275017 TI - Soft tissue limb and trunk sarcomas: diagnosis, treatment and follow-up. AB - This review focuses on epidemiology, aetiology, clinical presentation, diagnosis, management, prognosis and follow-up of soft tissue sarcomas (STS) involving limbs and trunk. Any patient with a suspected STS should be referred to a specialized sarcoma centre and managed by a multidisciplinary group. The standard treatment is surgical excision followed by adjuvant radiotherapy (RT). Radiotherapy is recommended in patients with intermediate-or high-grade tumors, >5 cm of diameter or <5 cm. RT may be indicated in low grade, deep and large-size STS and/or in absence of adequate margins, after discussion within a multidisciplinary group. Neoadjuvant radiotherapy and chemotherapy should be taken into consideration for patients with borderline resectable tumors. In selected cases, amputation may be the only curative option. Isolated limb perfusion is a pre-operative treatment that may allow for amputation to be avoided. Adjuvant chemotherapy should be considered only in selected cases. Regular follow-up with clinical examination, ultrasound (US) or magnetic resonance imaging (MRI) to exclude local recurrences and chest-X-ray or chest computed tomography (CT) to exclude metastatic disease is recommended. For metastatic disease, doxorubicin is the first-line standard therapy. Second-line agents include trabectedin, ifosfamide, dacarbazine and the combination of gemcitabine-plus-docetaxel. Surgical resection of local recurrences or lung metastases should be evaluated in selected cases. PMID- 25275018 TI - Chemotherapy of rare skin adnexal tumors: a review of literature. AB - Malignant skin adnexal tumors are rare neoplasms which are derived from adnexal epithelial structures of the skin: hair follicle, or sebaceous, apocrine or eccrine glands. Among them, eccrine porocarcinoma is the most frequent, with an aggressive behavior compared to other more common forms of non-melanoma skin cancer. Only few reports describe the treatment of metastatic adnexal tumors, and there is no consensus about the better strategy of chemotherapy. Given the few cases and the absence of randomized clinical trials, it is important to collect clinical experiences on these tumors. Most of these adenocarcinomas are very aggressive and also chemoresistant, and only a targeted-therapy could have an impact on patient survival. Therefore, further studies on the biology of these diseases are necessary. The purpose of the present review is to discuss the treatment of malignant neoplasms of cutaneous adnexae and to suggest some future therapeutic options based on targeted-therapy. PMID- 25275019 TI - Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression. AB - BACKGROUND/AIM: Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells. The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment. MATERIALS AND METHODS: A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression. RESULTS: Apicidin, a histone deacetylase inhibitor, showed the greatest anti-proliferative activity with a lethal dose 50 (LD50) value of 5.17 MUM. Apicidin significantly reduced the expression of MUC4 and its transcription factor hepatocyte nuclear factor 4alpha. Combined treatment with a sub therapeutic concentration of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells. CONCLUSION: Apicidin appears to be a novel anti proliferative agent against pancreatic cancer cells that may reverse chemoresistance by epigenetically regulating MUC4 expression. PMID- 25275020 TI - STAT3 activation and infiltration of eosinophil granulocytes in mycosis fungoides. AB - Eosinophil granulocytes have been implicated in anticancer immunity but recent data indicate that eosinophils can also promote cancer. Herein, we studied eosinophils in skin lesions from 43 patients with mycosis fungoides (MF). The presence of eosinophils correlated with disease stage: 78% of patients with advanced disease displayed eosinophil infiltration, whereas this was only seen in 11% of patients with patches (p<0.01), and in 48% of those with plaque disease. Importantly, 72% of patients with positive staining for phospho-signal-transducer and-activator-of-transcription (pY-STAT3) in malignant T-cells also stained positively for eosinophils, whereas this was only observed in 28% of pY-STAT3 negative patients (p<0.01). Notably, malignant T-cells expressed eosinophilic activation and trafficking factors: High-mobility group BOX-1 protein (HMGB1) and interleukin 5 (IL5). STAT3 siRNA profoundly inhibited IL5 but not HMGB1 expression. In conclusion, these data suggest that malignant T-cells orchestrate accumulation and activation of eosinophils supporting the notion of STAT3 being a putative target for therapy. PMID- 25275021 TI - Promise of combining a Bcl-2 family inhibitor with bortezomib or SAHA for adult T cell leukemia/lymphoma. AB - BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes and its prognosis still remains very poor. MATERIALS AND METHODS: The potential of combining the Bcl-2 homology 3 mimetic ABT-737, which blocks Bcl-2, Bcl-XL, and Bcl-w, with either the proteasome inhibitor bortezomib or histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) to inhibit the growth of human T-lymphotropic virus type-I (HTLV-1) infected T-cell lines and its mechanism was further evaluated. RESULTS: ABT-737 synergistically induced apoptosis when combined with either bortezomib or SAHA in HTLV-1 infected T-cell lines and fresh ATL cells. Bortezomib increased the expression of Noxa, which subsequently enhanced the formation of Mcl-1-Noxa complexes, resulting in the functional neutralization of Mcl-1, an inducer of resistance to ABT-737. On the other hand, SAHA reduced the expression of survivin, an anti-apoptotic molecule that confers drug resistance on ATL cells. CONCLUSION: The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL. PMID- 25275022 TI - Differential expression of VEGF and IL-1alpha after photodynamic treatment in combination with doxorubicin or taxotere. AB - AIM: To show the impact of chemotherapeutic drugs doxorubicin and taxotere on the molecular pattern of cell response to photodynamic treatment (PDT). MATERIALS AND METHODS: Human squamous cell carcinoma cells A-431 were studied. Apoptosis was investigated by recording caspase-3 activity. Expression of IL-1alpha and VEGF on mRNA and protein levels was measured by qPCR and ELISA. RESULTS: PDT in combination with either doxorubicin or taxotere was found to be more cytotoxic in comparison to either single-treatment. The expression of IL-1alpha and VEGF was up-regulated in PDT-treated cells, either alone or in combination with doxorubicin or taxotere. Addition of doxorubicin to the cytokine induction after PDT was not detected, however, taxotere promoted significant over-expression of IL-1alpha and VEGF on the protein level. CONCLUSION: Contribution of chemotherapeutic drugs to IL-1 alpha and VEGF release from cells which received dual treatment involving PDT could be significantly different, despite the same level of cytotoxicity. PMID- 25275023 TI - New therapeutic possibilities of combined treatment of radiotherapy with oxaliplatin and its liposomal formulation, LipoxalTM, in rectal cancer using xenograft in nude mice. AB - AIM: To determine the benefits of irradiation at the time of maximum linking of oxaliplatin to the DNA of tumor cells, and evaluate the potential of its liposomal formulation, LipoxalTM, for chemoradiation therapy. MATERIALS AND METHODS: Nude mice implanted with human colorectal carcinoma HCT116 cells were injected with oxaliplatin or LipoxalTM. The amount of platinum in tumor, tumoral DNA, normal tissues and blood was measured 4, 24, 48, 72 and 96 h later by inductively coupled plasma mass spectrometry. The effect of concomitant radiotherapy was assessed as tumor growth delay resulting from irradiation 4, 24 and 48 h after drug administration. RESULTS: While the amount of platinum in the tumor reached a peak at 4 h after injection and declined over time, the concentration of oxaliplatin-DNA adducts reached two maxima observed at 4 h and 48 h after drug administration, a behavior not observed with LipoxalTM. The greatest combined effect was obtained when radiation was given at 48 h after drug injection, resulting in an increase of tumor growth delay by factors of 3.71 and 3.33 for treatments with oxaliplatin and LipoxalTM, respectively. CONCLUSION: Our results confirm the importance of irradiating a tumor when the concentration of oxaliplatin bound to tumor DNA is maximal. This finding should have a significant impact on the design of more efficient chemoradiation treatment protocols and should be further explored in clinical studies. PMID- 25275024 TI - The apelin-APJ system induces tumor arteriogenesis in hepatocellular carcinoma. AB - AIM: The apelin-APJ system regulates angiogenesis, and is overexpressed in several types of cancer. The aim of this study was to clarify the role of the apelin-APJ system in the angiogenesis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Expressions of angiogenic factors and vascular markers were investigated in specimens from 90 HCC patients. A subcutaneous HCC tumor mouse model was treated with the APJ antagonist, F13A, and tumor growth and vascular development were assessed. RESULTS: APJ expression was observed in arteriole-smooth muscle. Higher amounts of APJ(+)-arteriole and apelin were detected in tumors (p<0.001 for both). APJ(+)-arteriole and apelin expression were more commonly observed in moderately- and poorly-differentiated than in well differentiated HCC (p <= 0.003). HCC with irregular dilated arteries expressed higher levels of apelin (p=0.012). Tumor growth was inhibited by treatment with F13A (p<0.001), and arterioles were decreased in the treated group (p=0.047), in vivo. CONCLUSION: Apelin-APJ is overexpressed, and works as a signal for arteriogenesis in HCC. PMID- 25275025 TI - Vasohibin-1 increases the malignant potential of colorectal cancer and is a biomarker of poor prognosis. AB - BACKGROUND: Vasohibin-1 (VASH1) is related to angiogenesis and poor prognosis in several types of cancers. However, the biological function and clinical significance of VASH1 in colorectal cancer (CRC) are not fully known. MATERIALS AND METHODS: The associations between VASH1 expression and clinicopathological features were investigated by immunohistochemistry in 429 CRC tissues. To evaluate the function of VASH1 in vitro, small-interfering VASH1-targeting RNA was transfected into human CRC cell lines. RESULTS: We found that VASH1 was highly expressed in the cytoplasm of CRC tissues. High VASH1 expression in the cytoplasm was significantly associated with tumor progression, such as larger tumor size, advanced T-stage, lymph node metastasis, distant metastasis and poor prognosis. Moreover, a significant positive correlation was detected between VASH1 expression and microvessel density. VASH1 siRNA inhibited CRC cell proliferation, migration, and invasion, and promoted anoikis. CONCLUSION: Overexpression of VASH1 in CRC cells increased malignant potential and promoted metastasis. PMID- 25275027 TI - Synergistic effects between catalase inhibitors and modulators of nitric oxide metabolism on tumor cell apoptosis. AB - Inhibitors of catalase (such as ascorbate, methyldopa, salicylic acid and neutralizing antibodies) synergize with modulators of nitric oxide (NO) metabolism (such as arginine, arginase inhibitor, NO synthase-inducing interferons and NO dioxygenase inhibitors) in the singlet oxygen-mediated inactivation of tumor cell protective catalase. This is followed by reactive oxygen species (ROS)-dependent apoptosis induction. TGF-beta, NADPH oxidase-1, NO synthase, dual oxidase-1 and caspase-9 are characterized as essential catalysts in this process. The FAS receptor and caspase-8 are required for amplification of ROS signaling triggered by individual compounds, but are dispensable when the synergistic effect is established. Our findings explain the antitumor effects of catalase inhibitors and of compounds that target NO metabolism, as well as their synergy. These data may have an impact on epidemiological studies related to secondary plant compounds and open new perspectives for the establishment of novel antitumor drugs and for the improvement of established chemotherapeutics. PMID- 25275026 TI - Expression of chemokine ligand 18 in stage IA low-grade endometrial cancer. AB - BACKGROUND/AIM: The identification of novel molecules associated with endometrial cancer (EC) development might offer less invasive surgery, better fertility preservation, and avoidance of unnecessary adjuvant therapy. MATERIALS AND METHODS: Microarray analysis was conducted using fresh surgically-obtained specimens from five EC patients and five cases with benign tumours. Additionally, immunohistochemical studies of the most highly expressed molecules were performed on paraffin-embedded tissues from these patients and others with stage IA, grade 1-2 EC (n=3) with or without (n=7) recurrent disease. RESULTS: The most highly expressed gene in EC was chemokine ligand 18 (CCL18), with a 35.6-fold change compared to benign tumors. CCL18 expression was observed in tumor cells at the myometrial invasive front in 9 out of 11 tested samples. CONCLUSION: CCL18 expression was positively correlated with malignancy in EC. Further investigation with a larger number of samples or examination of serum CCL18 levels is warranted. PMID- 25275028 TI - Synchrotron-based photon activation therapy effect on cisplatin pre-treated human glioma stem cells. AB - BACKGROUND: Glioblastoma multiforme (GBM) is one of the deadliest cancers characterized by very limited sensitivity to chemo- and/or radiotherapy. The presence of GBM stem-like cells in the tumor might be relevant for GBM treatment resistance. AIM: To provide a proof-of-concept of the efficacy of photon activation therapy (PAT) using monochromatic synchrotron radiation (SR), in killing GBM stem cells pre-treated with cisplatin. MATERIALS AND METHODS: Irradiation was performed using a 1-8 Gy dose range and energies just above or below the platinum K-shell edge (78.39 keV) or with a conventional X-ray source. Cells were exposed to drug concentrations allowing 90% cell survival, mimicking the unfavourable tissue distribution generally achieved in GMB patients. RESULTS: a significant enhancement in cell lethality was observed using SR compared to conventional X-ray irradiation. CONCLUSION: PAT deserved to be further explored in in vivo models based on GBM stem-like cells. PMID- 25275029 TI - Prognostic significance of high mobility group box 1 (HMGB1) expression in patients with colorectal cancer. AB - BACKGROUND: High mobility group 1 (HMGB1) is a highly conserved non-histone nucleosomal protein in mammals. We investigated the clinical significance of HMGB1 expression in colorectal cancer (CRC). PATIENTS AND METHODS: The expression of HMGB1 mRNA in 140 tumor and normal tissues from CRC patients was examined by quantitative real-time polymerase chain reaction (PCR). We immunohistochemically investigated HMGB1 expression in tumor and metastatic lymph nodes in CRC. RESULTS: HMGB1 expression was significantly higher in tumor than in normal tissues. High HMGB1 expression was associated with larger tumor volumes, higher rates of lymphatic invasion, more frequent lymph node metastases and poorer prognoses for overall survival. Multivariate analyses showed that HMGB1 expression was an independent prognostic indicator of overall survival. Immunocytochemical analysis revealed that HMGB1 was overexpressed in both CRC tissues and regional lymph node metastases. CONCLUSION: Investigating HMGB1 expression may be a predictor of postoperative lymph node metastasis and prognosis in CRC. PMID- 25275030 TI - Resveratrol augments paclitaxel treatment in MDA-MB-231 and paclitaxel-resistant MDA-MB-231 breast cancer cells. AB - BACKGROUND: Resveratrol (RES) inhibits cell growth, induces apoptosis and augments chemotherapeutics in multiple cancer types, although its effects on drug resistant cancer cells are unknown. MATERIALS AND METHODS: To study the effects of resveratrol in triple-negative breast cancer cells that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the MDA-MB-231 cell line. RESULTS: The resistant MDA-MB-231/PacR cells exhibited a 12-fold increased resistance to paclitaxel. RES treatment reduced cell proliferation and colony formation and increased senescence and apoptosis in both parental and resistant cells. Importantly, RES augmented the effects of paclitaxel in both cell lines. Up-regulation of the MDR1 and CYP2C8 genes were shown to be potential mechanisms of paclitaxel resistance in the resistant cells. CONCLUSION: RES, both alone and in combination with paclitaxel, may be useful in the treatment of paclitaxel-sensitive and paclitaxel-resistant triple-negative breast cancer cells. PMID- 25275031 TI - Effect of Wnt inhibitors in pancreatic cancer. AB - BACKGROUND/AIM: Activated Wnt signaling in cancer cells leads to cell proliferation. It has been shown that the Wnt pathway is activated in pancreatic adenocarcinoma cells. Therefore, we tested the effect of Wnt inhibitors in human and murine pancreatic cancer cell lines. MATERIALS AND METHODS: The Wnt inhibitors ethacrynic acid (EA), ciclopirox olamine (CIC), piroctone olamine (PO) and griseofulvin (GF) were tested in murine and human pancreatic cancer cell lines with the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: We showed that the Wnt inhibitors significantly reduced cell viability in murine, as well as human pancreatic cancer cell lines. CONCLUSION: These results may lead to a new therapeutic option with Wnt inhibitors for patients with pancreatic adenocarcinoma. PMID- 25275032 TI - DNA methylation at selected CpG sites in peripheral blood leukocytes is predictive of gastric cancer. AB - BACKGROUND/AIM: Recently, a set of studies addressed the question of the prevalence of aberrant methylation in surrogate tissues, such as peripheral blood leukocytes. Toward this aim, we conducted a case-control pilot study to investigate aberrant methylation in leukocytes of gastric cancer patients. MATERIALS AND METHODS: The SNuPE combined with ion pair reverse phase HPLC (SIRPH method) was used to examine site-specific methylation status at selected CpG sites of the promoter regions of APC, ACIN1, BCL2, CD44, DAPK1, CDKN2A, RARB, TNFRSF10C HS3ST2 and of LINE-1, Alu repeats. RESULTS: We observed that in the patients, tumor suppressor genes were slightly but significantly higher methylated at several CpG sites, while DNA repetitive elements were slightly less methylated compared to controls. This was found to be significantly associated with higher prevalence for gastric cancer. CONCLUSION: These results suggest that larger studies must be carried-out to explore the biological significance and clinical usefulness of leukocyte DNA as non-invasive detection tool for gastric cancer. PMID- 25275033 TI - Optimization of ultrasmall superparamagnetic iron oxide (P904)-enhanced magnetic resonance imaging of lymph nodes: initial experience in a mouse model. AB - BACKGROUND: P904 is a novel ultra-small superparamagnetic iron oxide (USPIO) contrast agent. This study was conducted to investigate the optimal dose of P904 for magnetic resonance imaging (MRI) of lymph nodes. MATERIALS AND METHODS: T2* weighted 3T MRI was performed in 14 normal mice before and 24 h after P904 injection at varying doses. Normalized signal intensity (nSI), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and contrast ratio (CR) were calculated to determine the optimal dose. MRI of the metastatic lymph node models (n=5) was acquired using the optimal dose and correlated with pathological results to calculate sensitivity and specificity. The mean SI ratio between pre- and postcontrast MRI was also calculated for each lymph node. RESULTS: The mean nSI and SNR values on postcontrast images were significantly lower at 300 MUmol Fe/kg than at 75 MUmol Fe/kg (p<0.001). The mean CNR and CR values were significantly higher at 300 MUmol Fe/kg than at the other two doses (p<0.05). At the optimal dose of 300 MUmol Fe/kg, the mean SI ratio of benign lymph nodes was significantly lower than that of metastatic lymph nodes (p<0.001). The Az (areas under the receiver operating characteristic curves) value for diagnosing lymph node metastasis at the optimal dose was 0.97. CONCLUSION: The optimal dose for P904-enhanced MRI of the lymph nodes was 300 MUmol Fe/kg, which could be used for the diagnosis of lymph node metastasis. PMID- 25275034 TI - Effects of digoxin and Na, K-ATPase immunoexpression on human oral squamous carcinomas. AB - AIM: The present study evaluated the expression of alpha1 and beta1 Na,K-ATPase, as well as the effects of digoxin (DGX) on oral squamous cell carcinomas (OSCCs). PATIENTS AND METHODS: Immunohistochemical expression of alpha1 and beta1 Na,K ATPase were evaluated in 60 patients who underwent treatment at the Sao Joao de Deus Hospital. SCC-25 viability was assessed by the colorimetric assay. Chi square or Fisher's exact tests were used to analyze the association of alpha1 and beta1 Na,K-ATPase expression with the variables. RESULTS: Immunoexpression of alpha1 and beta1 Na,K-ATPase were observed in 28% and 55% of the tumors, however these proteins were not significant prognostic factors. Tobacco was significantly associated with alpha1 expression. SCC-25 viability decreased significantly after treatment with 1 MUM DGX at 24 h. CONCLUSION: The smoking status of OSCC patients was significantly associated with alpha1 expression and DGX affected the SCC-25 viability in a dose- and duration-dependent manner. PMID- 25275035 TI - Quantitative structure-cytotoxicity relationship of 3-styrylchromones. AB - BACKGROUND: Fifteen 3-styrylchromones were subjected to quantitative structure activity relationship (QSAR) analysis based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to explore their biological activities. MATERIALS AND METHODS: Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor-selectivity was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal human oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of CC50 to EC50 (50% cytoprotective concentration from HIV infection). Physicochemical, structural and quantum chemical parameters were calculated based on the conformations optimized by the LowModeMD method followed by the density functional theory (DFT) method. RESULTS: All 3-styrylchromone derivatives showed moderate-to-high tumor selectivity. Especially, compounds that have a methoxy group at 6-position of the chromone ring and hydroxyl group at 4'-position of phenyl group in styryl moiety [ 11: ] showed the highest tumor-selectivity. On the other hand, their cytotoxicity against normal cells showed good correlation to the descriptors that reflect hydrophobic interaction and molecular shapes. CONCLUSION: Multivariate statistics with chemical descriptors for the location of substituted group, molecular shape and electrostatic interaction may be useful for designing the most favorable compound with higher tumor selectivity. PMID- 25275036 TI - Crosstalk between tumor blood vessels heterogeneity and hormonal profile of pituitary adenomas: evidence and controversies. AB - AIM: Pituitary adenomas are intracranial tumors with controversial histopathology and heterogeneous clinical behaviour. Angiogenesis and tumor blood vessels' role in pathogenesis, remain one of the great pituitary tumor mysteries. No connection between tumor vessel heterogeneity, hormonal profile and biological behaviour has been reported. We aimed to study pituitary adenomas blood vessels concerning their immature, intermediate or mature phenotype and microvessel density, correlated with immunohistochemical hormonal profile and hormone values in serum and cerebrospinal fluid. MATERIALS AND METHODS: We classified pituitary adenomas according to hormone profile and we applied a double immunostaining highlighting both endothelial and perivascular cells for a more accurate assessment of blood vessel types. RESULTS: Overall microvessel density was found to be highest in growth hormone-secreting adenomas (48.51 +/- 12.15) and lowest in prolactinomas (29.15 +/- 18.78). When we differentially counted tumor blood vessels we observed a predominance of immature and intermediate blood vessels compared to mature ones. A significant correlation was found between immature tumor blood vessels and tissue prolactin expression, as assessed by immunhistochemistry (p=0.044). A partial correlation was found between serum (p=0.036) and cerebrospinal prolactin values (p=0.006) with immature and intermediate blood vessels. Also, a partial correlation has been reported only between mature blood vessels and cerebrospinal fluid prolactin values (p=0.008). No correlation was obtained for other types of pituitary adenomas. CONCLUSION: Our results suggest a strong involvement of prolactin with a dual role in pituitary adenomas vasculature remodelling by acting both on endothelial and perivascular cells, a finding that could partially explain discrepancies between clinical diagnosis and hormonal profile. PMID- 25275037 TI - Aberrations of BUBR1 and TP53 gene mutually associated with chromosomal instability in human colorectal cancer. AB - BACKGROUND/AIM: Defects in mitotic checkpoint and p53-dependent pathways associate with chromosomal instability. In the present study, we investigated the interplay between BUBR1 and p53 and their association with genetic instability in colorectal cancer. PATIENTS AND METHODS: 139 colorectal cases were examined for BUBR1, p53 and genetic instability indicators. BUBR1 expression was evaluated by immunohistochemistry and TP53 gene was directly sequenced. DNA ploidy was studied by laser scanning cytometry; MSI and TP53 loss of heterozygosity was also examined. RESULTS: 64% of cases had high BUBR1 expression and were associated with the TP53 mutation. High BUBR1 expression and TP53 mutation associated with DNA aneuploidy and showed an inverse association with MSI. Cases with high BUBR1 expression and TP53 mutation had profound aneuploidy phenotypes and less frequent MSI compared to cases with one or neither aberration. CONCLUSION: Our findings indicated an interplay between BUBR1 and p53 in colorectal cancer. Altered expression of both molecules was associated with chromosomal instability. PMID- 25275038 TI - Impact of sodium butyrate on the network of adhesion/growth-regulatory galectins in human colon cancer in vitro. AB - BACKGROUND/AIM: The physiological compound sodium butyrate can induce differentiation in colon cancer cells in vitro. Due to the role of galectins in growth control we explored its effect on this network beyond galectins-1 and -3, with deliberate consideration of the status of microsatellite stability, for nine cell lines. MATERIALS AND METHODS: Microscopical monitoring and measurement of alkaline phosphatase activity ascertained butyrate's impact on cells. Monitoring by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting with galectin-type-specific probes characterized galectin expression. RESULTS: Controlled by expectable strong up-regulation of galectin-1 and comparatively small effects on galectin-3 regulation for galectins-4, -7, -8 and -9 were reported with no obvious association to microsatellite stability status. Neoexpression of the GAL-12 gene was observed in eight out of nine tested lines. CONCLUSION: Butyrate affects the galectin network beyond galectins-1 and -3, warranting further cell biological and histochemical studies. PMID- 25275039 TI - Resveratrol enhances mitomycin C-mediated suppression of human colorectal cancer cell proliferation by up-regulation of p21WAF1/CIP1. AB - BACKGROUND/AIM: Studies have shown that natural products could potentially be employed in combination therapies to decrease toxicity to healthy tissues by chemotherapy drugs. No studies however, have investigated the potential modulatory role of resveratrol (RV) on mitomycin C (MMC)-mediated effects on colorectal cancer. The aim of the present study was to investigate the impact of RV on MMC-mediated inhibition of colorectal cancer cell proliferation and to assess the potential mechanisms for such effects. MATERIALS AND METHODS: Primary cell lines generated from resected colorectal tumor specimens were treated with RV, MMC or RV+MMC and cell proliferation and gene expression analyses were performed. RESULTS: Suppression of cell proliferation by RV+MMC was significantly greater than individual treatments. RV+MMC synergistically modulated several genes but the up-regulation of p21(WAF1/CIP1) was several-fold greater. CONCLUSION: The up-regulation of p21(WAF1/CIP1), which inhibits the cell cycle at G0/G1 and G2/M phases, may represent the predominant mechanism for enhancement of MMC-mediated anti-cancer effects by resveratrol. PMID- 25275040 TI - Selective anticancer activity of neurotoxin 1-methyl-4-phenylpyridinium on non small cell lung adenocarcinoma A549 cells. AB - BACKGROUND: Lung cancer is the second leading cause of mortality among men and women in the U.S. Among different varieties of lung cancer, the non-small cell lung cancer (NSCLC) has the highest frequency comprising about 85% of cases. We evaluated 1-methyl-4-phenylpyridinium ion (MPP(+)) for cytotoxicity against human lung adenocarcinoma A549, human normal lung and rat normal liver cells after a 48 h treatment. MATERIALS AND METHODS: In vitro cytotoxicity was evaluated by the crystal-violet method, mitochondrial respiratory status by calorimetric reduction of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, mitochondrial membrane potential by rhodamine 123 fluorometric assay and glutathione levels by 5,5-dithiobis-2-nitrobenzoic acid. RESULTS: MPP(+) caused a significant dose-dependent death of A549 cells. In human normal lung and rat normal liver cells, MPP(+) did not cause severe cytotoxicity, which was reflected with a selectivity index (SI) of greater than 7. Further studies revealed that, in addition to its interaction with mitochondria, MPP(+) significantly depleted total glutathione levels in A549 cells. CONCLUSION: MPP(+) possesses highly selective, potent anticancer activity against lung adenocarcinoma. PMID- 25275041 TI - Synergism from combinations of tris(benzimidazole) monochloroplatinum(II) chloride with capsaicin, quercetin, curcumin and cisplatin in human ovarian cancer cell lines. AB - In the present study, synergism in activity from the sequenced combinations of monofunctional platinum tris(benzimidazole)monochloroplatinum(II) chloride (coded as LH4) with capsaicin, quercetin, curcumin and cisplatin was investigated as a function of sequence of administration in a number of human ovarian tumor models. Cellular accumulations of platinum and the levels of platinum-DNA binding were also determined for the 0/0 h and 4/0 sequences of administration. LH4 was found to be more active against the resistant A2780(cisR) and A2780(ZD0473R) cell lines than the parent A2780 cell line. As applied to combinations of LH4 with phytochemicals capsaicin, quercetin and curcumin, bolus administration was found to be most synergistic in both the parent A2780 and the resistant A2780(cisR) cell lines. For the combinations of LH4 with cisplatin, additiveness was observed in both the resistant cell lines but mild synergism was observed in the parent cell line. Greater activity of designed monofunctional platinum LH4 against resistant tumor models and synergism from combinations with phytochemicals indicate that the compound has the potential for development as a novel platinum based anticancer drug. PMID- 25275042 TI - Lysophosphatidylserine stimulates chemotactic migration of colorectal cancer cells through GPR34 and PI3K/Akt pathway. AB - BACKGROUND: Lysophosphatidylserine (lysoPS) is a type of lysophospholipid mediator, which is involved in allergic conditions and tumor progression. We investigated the physiological function of lysoPS on colorectal cancer (CRC) cell lines, as well as the involved receptor and signaling pathways. MATERIALS AND METHODS: Expression of lysoPS receptors on six cell lines was examined by reverse transcription-polymerase chain reaction (RT-PCR). The physiological functions of lysoPS were investigated, and experiments using small interfering RNA (siRNA) or inhibitors of the signaling pathways were conducted. RESULTS: Among the three lysoPS receptors, GPR34 was highly expressed on all cell lines. LysoPS stimulated the chemotactic migratory ability. Wortmannin inhibited the migratory ability, as well as the GPR34 knock-down, strongly suggestive of the involvement of this receptor in the PI3K/Akt pathway. CONCLUSION: The involved receptor and pathways in the migratory ability in response to lysoPS was demonstrated, which opens premises for targeting as a new strategy for prevention and treatment of colorectal cancer. PMID- 25275043 TI - Synergistic combinations of tanshinone IIA and trans-resveratrol toward cisplatin comparable cytotoxicity in HepG2 human hepatocellular carcinoma cells. AB - AIM: To determine the combinative effects of tanshinone IIA (Tan IIA) and trans resveratrol (Resv) on cytotoxicity, apoptosis, cell-cycle arrest and DNA fragmentation in HepG2 human liver cancer cells. MATERIALS AND METHODS: Cytotoxicity was detected by the cell proliferation and cytotoxicity WST-1 assay. Cell-cycle arrest and apoptosis were determined using flow cytometry analysis. DNA fragments were separated by gel electrophoresis. RESULTS: Tan IIA and Resv at mixture ratios of 1/2:1/2 and 1/3:2/3 exerted synergistic cytotoxicity comparable to that of cisplatin. Elevated proportions of sub-G1 and apoptotic cells were respectively found in the combinative treatments in comparison with hypothetic values of additive effects. Moreover, a more intensive pattern of apoptotic DNA fragmentation was visualized in combined treatments than in individual ones. CONCLUSION: Combining Tan IIA and Resv causes synergistic cisplatin-comparable, cytotoxicity and robustly induces apoptosis, sub-G1 cell cycle arrest and DNA fragmentation. This study provides evidence supporting further pre-clinical investigations of the combinational synergism. PMID- 25275044 TI - The role of functional polymorphisms of cyclooxygenase 2 in renal cell carcinoma. AB - Renal cell carcinoma (RCC) accounts for about 3% of all cancer-related mortalities worldwide and the risk factors for the development of RCC have not yet been fully elucidated. Mounting evidence shows that overexpression of cyclo oxygenase 2 (COX2) is commonly found in malignant tumors, including RCC. However, the contribution of genotypic variations of COX2 to RCC has not been studied. We hypothesized that variants of the COX2 gene are associated with risk of susceptibility to RCC in Taiwan. In this hospital-based case-control study, 92 patients with RCC and 580 age- and gender-matched cancer-free controls were recruited and the associations of COX2 A-1195G, G-765C, T+8473C, intron 1, intron 5, and intron 6 polymorphisms with RCC risk were examined in this Taiwanese population. The results showed that compared to the wild-type GG genotype, the CG genotype for COX2 G-765C was significantly associated with a lower risk of RCC (odds ratio=0.34, 95% confidence interval=0.15-0.80, p=0.0082). For other polymorphic sites, no obvious associations were found. There was also an obvious association of COX2 G765C genotype with reduced RCC risk among those without family cancer history (p=0.0331). These evidence indicated that COX2 G-765C genotype involved in the etiology of RCC and may serve as a novel genetic marker for susceptibility of RCC. PMID- 25275045 TI - Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33 positive HL-60 myeloid leukemia cells. AB - BACKGROUND/AIM: Gemtuzumab ozogamicin (GO) consists of the cluster of differentiation 33 (CD33) antibody linked to calicheamicin. The binding of GO to the CD33 antigen on leukemic cells results in internalization and subsequent release of calicheamicin, thereby inducing DNA strand breaks. We hypothesized that the poly (ADP-ribose) polymerase inhibitor olaparib might inhibit DNA repair initiated by GO-induced DNA strand breaks, thereby increasing cytotoxicity. MATERIALS AND METHODS: The human myeloid leukemia cell line HL-60 and a GO resistant variant (HL/GO20) were used. RESULTS: The 50% growth-inhibitory concentrations (IC50) were 24 ng/ml for HL-60 cells and 550 ng/ml for GO resistant variant HL/GO20 cells. HL/GO20 cells were also refractory to GO-induced apoptosis. CD33 positivity was reduced in HL/GO20 cells. Olaparib-alone did not inhibit the cell growth and did not induce apoptosis in either HL-60 cells or HL/GO20 cells at concentrations of up to 10 MUM. When cells were treated with different concentrations of GO in the presence of 10 MUM olaparib, the IC50 of GO for HL-60 cells was 13 ng/ml. The combination index was 0.86, indicating synergistic cytotoxicity of GO and olaparib in combination. Such a combination was ineffective for HL/GO20 cells. CONCLUSION: GO and olaparib exerted synergistic cytotoxicity in CD33-positive myeloid leukemia cells in vitro. PMID- 25275046 TI - Ouabain mediates integrin switch in human lung cancer cells. AB - BACKGROUND: Physiological effects of ouabain, an endogenous human hormone, are being intensively investigated. However, its role in regulation of integrin pattern in lung cancer is largely unknown. The switching in the expression pattern of integrins is recognized as an important factor facilitating metastasis of several cancers. MATERIALS AND METHODS: Cytotoxicity and proliferative effects of ouabain on H460 lung cancer cells were evaluated by the MTT assay. The levels of integrin proteins in response to ouabain were determined by western blotting. Anchorage-independent growth and migration behaviors were performed by the wound healing assay and colony formation assay, respectively. RESULTS: Herein, the results suggested that exposure of the lung cancer cells to physiological concentrations of ouabain significantly altered the level of integrins. Ouabain suppressed integrin alpha4, alpha5, alphav, beta3 and beta4, whereas it had no significant effect on integrin beta1 and beta4. According to the switch patterns of integrins, ouabain treatment resulted in a dramatic reduction of cell colony size and inhibition of cancer cell migration. However, ouabain-induced integrin switch had only a slight effect on chemotherapeutic drug susceptibility. CONCLUSION: Ouabain may have a role in suppressing cancer metastasis via integrin regulation. PMID- 25275047 TI - Activating mutations affecting the NF-kappa B pathway and EZH2-mediated epigenetic regulation are rare events in primary mediastinal large B-cell lymphoma. AB - BACKGROUND: Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) frequently observed in young patients. High-dose immunochemotherapy constitutes the current therapeutic gold standard, despite significant toxicity and serious late effects. Several hotspots harboring oncogenic gain-of-function mutations were recently shown to pose vital hallmarks in activated B-cell like (ABC-) (CD79B, CARD11 and MYD88) and germinal center like (GCB-) DLBCL (EZH2), respectively. Several promising targeted-therapy approaches, derived from these findings, are currently under development. MATERIALS AND METHODS: We thoroughly characterized a cohort of 25 untreated patients with de novo PMBL by immunohistochemical and cytogenetic means and assessed the prevalence of activating mutations affecting EZH2, CD79B and CARD11 utilizing a polymerase chain reaction (PCR)-based capillary sequencing approach. Moreover, the MYD88 p. L265P status was assessed by employing a pyrosequencing approach. RESULTS: PMBLs included in this study did not harbor any of the reported hotspot mutations activating the nuclear factor (NF)-kappa B signaling cascade or the EZH2-mediated epigenetic deregulation of gene expression. Immunohistochemical characterization revealed an ABC phenotype in 44% (n=11) of cases. CONCLUSION: We report that genetic alterations of these genes are rare events in PMBL unlike other subtypes of DLBCL. Our findings suggest that a substantial subset of PMBL patients may benefit from treatment approaches targeting BCR-mediated activation of NF-kappa B. PMID- 25275048 TI - Inhibition of JNK potentiates temozolomide-induced cytotoxicity in U87MG glioblastoma cells via suppression of Akt phosphorylation. AB - Glioblastoma (formally glioblastoma multiforme, GBM) represents both the most common and most malignant variant among numerous of primary brain tumors. Temozolomide (TMZ) has been used for the treatment of glioblastoma. However, less than 1/3 of glioblastomas respond to TMZ-based therapies. Therefore, strategies to enhance the effect of TMZ are needed for more effective targeted therapeutics. Stress-activated protein kinases (SAPKs) JNK and p38 MAPK have been known to have apoptotic or anti-apoptotic effects depending on cell type and condition. On the other hand, Akt is a key regulator of cellular survival and has direct effects on the apoptosis machinery. In addition, it was discovered that Akt activation is primed by the activity of JNK. We, therefore, examined whether inhibition of JNK or p38 potentiates TMZ-induced apoptosis in U87MG cells via inhibition of Akt activation. TMZ significantly induced Akt activation as well as JNK or p38 activation. Inhibition of JNK suppressed Akt activation and potentiated TMZ induced cytotoxicity. The phosphorylation of GSK-3beta and Bad, the downstream mediators of Akt, was also suppressed by the inhibition of JNK. The present data strongly suggest that there may be a crosstalk between JNK pathway and Akt pathway in glioblastoma and that further investigation based on the present data may provide a valuable approach for enhancing TMZ-induced cytotoxicity in glioblastoma. PMID- 25275049 TI - Mixed adenoneuroendocrine carcinoma of the colon: molecular pathogenesis and treatment. AB - BACKGROUND/AIM: We report a case of a mixed adenoneuroendocrine carcinoma developed in a colorectal adenocarcinoma with lymph node and liver metastases exclusively emanating from the neuroendocrine carcinoma component. The patient underwent right hemicolectomy and postoperatively received chemotherapy with cisplatin and etoposide and subsequent high-dose induction chemotherapy, followed by autologous stem cell transplantation. Following this treatment, there was a complete remission. Currently, thirty months after treatment, the patient is in unmaintained complete remission. Comparative exome sequencing of germline DNA and DNA from the two separate malignant components revealed six somatic changes in cancer consensus genes. Both components shared somatic mutations in Adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog (KRAS), B-cell CLL/lymphoma 9 (BCL9) and Forkhead Box P1 (FOXP1) genes. Mutation in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) was only found in the neuroendocrine carcinoma component. The finding of several identical somatic mutations in both components supports a clonal relationship between the neuroendocrine carcinoma and the adenocarcinoma. We suggest that a mutation in SMARCA4 could be responsible for the transformation of the adenocarcinoma component into the neuroendocrine phenotype. PMID- 25275050 TI - Intrapelvic fat makes robot-assisted radical prostatectomy difficult. AB - AIM: We investigated the relationship between a new index considering the estimated working space and difficulty of robot-assisted radical prostatectomy (RARP) using our database. PATIENTS AND METHODS: Working height was calculated by the obstetric conjugate diameter minus the bladder and rectal wall thicknesses minus the thickness of postvesical fat minus the rectal fat thicknesses measured using preoperative magnetic resonance imaging (MRI). The proportion of working height was calculated by dividing the working height by the obstetric conjugate diameter. RESULTS: A total of 112 RARP cases were enrolled. The mean obstetric conjugate was 105 mm and the mean proportion of working height was 72.5%. Multivariate linear regression analysis indicated that the proportion of working height was an independent predictive factor for both console time and estimated blood loss. CONCLUSION: The difficulty of RARP can be predicted by measuring the fat thicknesses around the rectum and bladder by MRI before surgery. PMID- 25275051 TI - Carcinoembryonic antigen half-life is an early predictor of therapeutic effects in induction chemotherapy for liver metastases from colorectal cancer. AB - AIM: We evaluated the relationship between carcinoembryonic antigen half-life (CEA-HL) in the early period of induction chemotherapy for patients with liver metastases from colorectal cancer (CRLM) and their clinicopathological response. PATIENTS AND METHODS: Seventy-four patients with initially unresectable CRLM received FOLFOX with or without bevacizumab and 30 patients underwent hepatic resection. The CEA-HL in the early postoperative period was investigated, and the pathological response was classified according to tumor regression grade (TRG). RESULTS: The CEA-HL after the third chemotherapeutic course (CEA-HL3) was significantly shorter in responders compared to non-responders. In the 30 patients who underwent hepatectomy, the CEA-HL3 was significantly shorter in the major or complete-pathological-response group for the TRGs than in the the partial-pathological-response group. If the patients were divided into two groups according to the median value of 20 days, progression-free survival and overall survival were significantly better in those with CEA-HL3 below the cut-off. CONCLUSION: The CEA-HL is an early predictor of the pathological response and prognosis after induction chemotherapy for CRLM. PMID- 25275052 TI - Features related to breast cancer in an entire Argentine rural population. AB - AIM: A descriptive study was developed in an entire Argentine rural community considering breast cancer risk factors, preventive strategies and breast cancer incidence. PATIENTS AND METHODS: the study comprised of 83 women. A questionnaire of 34 items was employed; a mammogram and a breast ultrasound were performed. ANOVA and Pearson correlation were employed. RESULTS: Mean age was 54.5 years; 69% of women were postmenopausal; 96% had children; breastfeeding was X=10 months/child; Body Mass Index (BMI) was X=27.8 kg/m(2); 13% had first-degree relatives with breast cancer; 90% of women considered mammographic screening a necessary study. One woman had presented breast cancer. Argentine screening guidelines were not followed and an inverse relationship between education level and age of first mammogram was found (p<0.05). Mammographic and ultrasound studies did not reveal potential abnormalities. CONCLUSION: Peculiar social and cultural characteristics may be relevant to evaluate breast cancer risk factors in Argentina. PMID- 25275053 TI - Impact of comorbidity on initial treatment and overall survival in elderly head and neck cancer patients. AB - BACKGROUND: Comorbidity is a determinant of treatment selection and survival in various cancers including head and neck cancer (HNC) and is often associated with a higher utilization of non-curative intent treatment. PATIENTS AND METHODS: In this retrospective study we analyzed 182 consecutively treated HNC patients >65 years old at the Dallas Veterans Affairs Medical Center from January 2000-June 2007. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). Treatment was classified as curative vs. non-curative intent. RESULTS: Median overall survival was 883 days. Patients with a CCI score 0-2 had non-significant higher rate of curative intent treatment than patients with CCI score >2 (83.8% vs. 74.6%, p=0.13). In multivariate analysis, only stage had significant prognostic importance (hazard ratio (HR) 1.66; 95% confidence interval (CI) 1.29 2.14; p<0.0005). In separate multivariate analyses of patients treated with surgery or chemoradiation, CCI was not a significant predictor of survival with HR of 0.88 (95% CI 0.69-1.11; p=0.29) and 1.13 (95% CI 0.83-1.53; p=0.44), respectively. CONCLUSION: In our elderly HNC population, CCI was not an independent predictor of selection of curative intent treatment or overall survival. PMID- 25275054 TI - Maximal debulking liver resection as a beneficial treatment strategy for advanced and aggressive colorectal liver metastases. AB - BACKGROUND: A survival benefit is generally considered unobtainable following incomplete hepatic resection in patients with colorectal liver metastases. However, this question should be readdressed considering recent chemotherapy, often combining a monoclonal antibody directed against colorectal cancer with various classic and improved strategies. We examined whether a survival benefit could be obtained from maximal reduction surgery for colorectal liver metastases. PATIENTS AND METHODS: We retrospectively analyzed data from 165 patients with liver recurrence after hepatectomy for colorectal metastases. RESULTS: We hypothesized that recurrence soon after surgery, frequently involved metastases left behind during liver resection, resembling the situation after debulking hepatectomy. When patients were divided according to time of liver recurrence, patients with early recurrence had significantly poorer overall survival than those with later recurrence (p<0.01). However, patients with multiple bilobar metastases (n=77), having a greater likelihood of metastases left behind at hepatectomy, had similar survival whether recurrence was early or late (p=0.13). Response to chemotherapy before first hepatectomy was prognostically important (relative risk of 0.107; p=0.02) for patients with early liver recurrence, as were number of recurrent tumors and status of extrahepatic disease. CONCLUSION: Debulking surgery for multiple bilobar metastases may represent a treatment strategy with potential survival benefit, especially when initial metastases respond well to pre-hepatectomy chemotherapy. PMID- 25275056 TI - Role of surgical treatment in breast cancer liver metastases: a single center experience. AB - BACKGROUND/AIM: The aim of the present study was to review a single hepatobiliary center experience, the benefit of hepatic metastasectomy in breast cancer liver metastases (BCLM) patients and to identify predictors of survival. PATIENTS AND METHODS: Fifty-two female patients underwent surgery for BCLM between 2002 and 2013. Only patients with liver resections (n=43) were included in the analysis. RESULTS: The median survival of the 43 patients with liver resection was 32.2 months. The factors significantly associated with overall post-hepatectomy survival were estrogen/progesteron receptor (ER/PR) status (p=0.002), node involvement of the primary tumor (p=0.049), size (p=0.005) and number (p=0.006) of the metastatic lesions. The 1-, 3- and 5-year survival rates after curative liver resection were 93.02%, 74.42%, 58.14%, respectively. CONCLUSION: BCLM resection is a safe procedure and offers survival benefit, especially in patients with reduced liver metastatic burden (solitary metastases, diameter of the metastases <5 cm) and positive ER/PR status. PMID- 25275055 TI - Prognostic significance of CD3+ tumor-infiltrating lymphocytes in patients with endometrial carcinoma. AB - AIM: The aim of the present study was to investigate tumor-infiltrating leukocytes in patients with endometrial carcinoma. PATIENTS AND METHODS: Cluster of differentiation (CD)3(+), CD8(+) and C20(+) tumor-infiltrating lymphocytes (TILs) and CD68(+) tumor-associated macrophages (TAMs) were evaluated retrospectively by immunohistochemistry in tumor specimen from 124 patients with endometrial carcinoma. RESULTS: A significant decrease of CD3(+) TILs and an increase of CD68(+) TAM count was associated with higher tumor stage. In patients with early-stage, high-risk tumors, low intraepithelial CD3(+) TIL counts were associated with significantly inferior survival. In multivariate analysis of patients with early-stage tumors, intraepithelial CD3(+) TIL counts were an independent predictor of survival. CONCLUSION: In patients with endometrial carcinoma a decrease of intraepithelial CD3(+) TIL counts is associated with advanced stage and high risk group. Intraepithelial CD3(+) TIL counts are an independent predictor of survival in patients with early tumors. PMID- 25275057 TI - Outcomes and complications of reconstruction using tumor-bearing frozen autografts in patients with metastatic bone tumors. AB - BACKGROUND: Tumor-bearing frozen autografts have been used for reconstruction of bone defects after resection of bone tumors. In the present study, outcomes and complications of reconstruction using frozen autografts were assessed to determine indications for this procedure in patients with metastatic bone lesions. PATIENTS AND METHODS: Twenty-two patients were treated with reconstruction using frozen autografts. The surgical technique involved excision of the bone lesion, curettage, freezing in liquid nitrogen, thawing and reconstruction. RESULTS: Limb function was evaluated in 11 patients; wa found excellent in 10 patients and good in 1 patient. Five-year overall survival and disease-free survival rates were 46.7% and 26.3%, respectively. Five-year fracture-free survival and recurrence-free survival rates were 79.9% and 100%, respectively. Complications were observed in 6 patients and included fractures (4), deep infection (1) and osteoarthritis (1). CONCLUSION: Reconstruction using frozen autografts is a beneficial treatment option in patients with long expected survival or complete cure of the primary cancer. PMID- 25275058 TI - Beef consumption and fatty acids serum concentration: relationship with salivary gland tumors in Cordoba, Argentina. AB - AIM: The objective of the present study was to analyze beef consumption, conjugated linoleic acid (CLA) and n-3 fatty acid (FA) serum concentration and their relation to salivary gland tumors (SGT). A questionnaire on non-nutritional risk factors and a validated food frequency questionnaire were applied in 20 SGT and 20 control (Co) patients. MATERIALS AND METHODS: Food data were processed by the Interfood v.1.3 software. Serum CLA was analyzed by chromatography. RESULTS: Non-significant differences were found between SGT and Co regarding lean and fatty BC and serum CLA. Serum n-3 linolenic acid concentration was higher in Co than in SGT (p=0.004). No associations between BC and CLA serum concentration were found, but a strong-positive association between total energy intake and total fat intake and SGT were observed. A significant inverse association between oleic and linoleic FA intake and SGT was recorded. CONCLUSION: Serum oleic and linolenic FAs showed a significant negative association with SGT. PMID- 25275059 TI - Concordance between biopsy and radical prostatectomy specimen Gleason score in internal and external pathology facilities. AB - BACKGROUND: Biopsy Gleason score (bGS) is an important tool for staging and decision making in patients with prostate cancer. Therefore, the data from biopsy should be both reproducible across different pathologists and predictive of the true underlying tumour. We evaluated the agreement between bGS with prostatectomy Gleason score (pGS) comparing patients who underwent prostate biopsy at our hospital with those who did it at an outside facility. MATERIALS AND METHODS: We retrospectively analyzed patients who underwent robot-assisted radical prostatectomy at our Hospital in 2011 and 2012. Patients were divided depending on the site of prostate biopsy. We calculated a weighted kappa statistic to evaluate the concordance from bGS and pGS in the two groups and to evaluate the Gleason score (GS) concordance comparing the proportion of positive cores at biopsy. RESULTS: A total of 124 patients with completed data were identified (70 patients performed biopsy at our institution and 54 at an outside facility). The weighted kappa score for GS agreement was 0.40 for our Institution and 0.27 for other facilities. The weighted kappa score stratified by biopsy hospital for patients with at least 30% of positive cores was 0.46 for our hospital and 0.42 for other facilities. CONCLUSION: Internal prostate biopsy predicted better pGS than outside facility biopsy reports. When the percentage of biopsy-positive cores increases, the agreement between bGS and pGS is similar between the two groups. For certain cases in which an outside laboratory biopsy results in equivocal clinical decision, biopsy re-evaluation by internal pathologists can help reveal the true underlying tumor architecture and extension. PMID- 25275060 TI - Identifying melanoma patients with 1-3 brain metastases who may benefit from whole-brain irradiation in addition to radiosurgery. AB - BACKGROUND/AIM: To develop a tool for estimating the risk of developing new cerebral lesions in 69 melanoma patients receiving radiosurgery for 1-3 cerebral metastases. PATIENTS AND METHODS: Ten factors were investigated: lactate dehydrogenase (LDH), radiosurgery dose, age, gender, performance status, maximum diameter, location and number of cerebral lesions, extra-cranial spread, time between melanoma diagnosis and radiosurgery. Two factors, number of lesions and extra-cranial spread, were included in the tool. Scoring points were achieved by dividing the 6-month rate of freedom from new cerebral lesions by 10. RESULTS: Sum scores were 9, 11, 12 or 14 points. Six-month rates of freedom from new brain metastases were 28%, 63%, 59% and 92% (p=0.002). Three prognostic groups were designed: A (9 points), B (11-12 points) and C (14 points). Freedom from new cerebral lesion rates were 28%, 60% and 92% (p<0.001). CONCLUSION: Group A and B patients should be considered for additional whole-brain radiotherapy (WBRT). PMID- 25275061 TI - Protein expression differences between lung adenocarcinoma and squamous cell carcinoma with brain metastasis. AB - AIM: We investigated tissue biomarkers in non-small cell lung cancer (NSCLC) to find indicators of brain metastasis and peritumoral brain edema. PATIENTS AND METHODS: Fifty-two cases were studied out of which 26 had corresponding brain metastatic tissue. Clinicopathological characteristics of tumors were correlated with biomarkers of cell adhesion, cell growth, cell cycle and apoptosis regulation that were previously immunohistochemically studied but never analyzed separately according to histological subgroups, gender and smoking history. RESULTS: Increased collagen XVII in adenocarcinoma (ADC) and increased caspase-9, CD44v6, and decreased cellular apoptosis susceptibility protein (CAS) and Ki-67 in squamous cell carcinoma (SCC) correlated significantly with brain metastasis. Increased beta-catenin, E-cadherin and decreased caspase-9 expression in primary SCC, and decreased CD44v6 expression in brain metastatic SCC tissues showed a significant correlation with the extent of peritumoral brain edema. Positive correlation between smoking and biomarker expression could be observed in metastatic ADCs with p16 and caspase-8, while-negative correlation was found in SCC without brain metastasis with caspase-3, and in SCC with brain metastasis with p27. CONCLUSION: Our results highlight the importance of separate analysis of biomarker expression in histological subtypes of NSCLC. PMID- 25275062 TI - Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer. AB - BACKGROUND/AIM: The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. We evaluated the relationship between the expression of SPARC, ITGAV, THBS1 and VCAM 1 genes of extracellular matrix in the progression and dissemination of colorectal cancer (CRC). PATIENTS AND METHODS: Adult patients (N=114) underwent resection of CRC. Gene expression in CRC was determined by quantitative real-time polymerase chain reaction (PCR). Protein expression was analyzed by immunohistochemistry (IHC). Correlation with pathway-related molecules (p53, Bcl 2, Ki-67, EGFR and VEGF) was assessed. RESULTS: Tumors with perineural invasion showed overexpression (p=0.028) of the ITGAV gene with regard to cancers without perineural invasion and validation of the result through IHC expression of the corresponding proteins, was significant for the expression of ITGAV protein (p=0.001). CONCLUSION: The overexpression of ITGAV gene was associated with higher progression and spread of CRC via perineural invasion. PMID- 25275063 TI - Neurofibromatosis type 1 and GIST: is there a correlation? AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by neurologic, dermatologic and orthopedic manifestations. There is a spectrum of tumors that affects individuals with NF1 at an increased incidence compared to the general population, such as neurofibromas, malignant peripheral nerve sheath tumors (MPNST) and gliomas. There has been a growing number of literature reporting an association between NF1 and gastrointestinal stromal tumors (GIST). CASE REPORT: We herein report a case of recurrent asymptomatic GIST in a 50-year-old woman with a history of neurofibromatosis type 1. DISCUSSION: NF1-associated GIST has been described to comprise a minority of cases, in which there is an alternative molecular pathogenesis. This difference between NF1-related GISTs and that of the general population has important therapeutic implications. The presence of kinase mutations has been shown to be predictive of clinical response to imatinib, a tyrosine kinase inhibitor. PMID- 25275064 TI - Versican expression in tumor epithelial cells is correlated with a good prognosis in gastric cancer. AB - BACKGROUND/AIM: Versican expression has been reported to have prognostic value in several cancers. The aim of the present study was to investigate the prognostic significance of versican expression in gastric cancer. MATERIALS AND METHODS: In total, 105 gastric cancer patients who received gastrectomy were included in the study. Versican expression in the epithelial and stromal components of the tumors was determined by immunohistochemistry. RESULTS: Versican was expressed in 21.0% of tumor epithelial cells and 44.8% of stromal cells. Patients with versican expression in tumor epithelial cells had significantly better 5-year disease-free (p=0.021) and overall (p=0.034) survival rates, whereas versican expression in stromal cells was not associated with disease-free (p=0.532) and overall (p=0.876) survival. Multivariate analysis showed that versican expression in tumor epithelial cells was an independent prognostic indicator for better clinical outcome in disease-free and overall survival. CONCLUSION: Versican expression in tumor epithelial cells predicts a good prognosis for gastric cancer patients. PMID- 25275065 TI - Postoperative radiotherapy for gallbladder cancer. AB - AIM: To evaluate the results of postoperative radiotherapy (PORT) and to identify prognostic factors for gallbladder cancer (GBC). PATIENTS AND METHODS: We retrospectively analyzed 86 patients with GBC who underwent potentially curative surgical resection and PORT between November 1993 and December 2009. All patients received three-dimensional conformal radiotherapy and 61 patients (71%) had concurrent chemotherapy. Survival outcomes including locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) rates were analyzed. RESULTS: The median follow-up period was 83 months for surviving patients. The 5 year OS, DFS and LRC rates were 42%, 36% and 73%, respectively. Isolated locoregional recurrence as first failure occurred in seven patients (8%). On multivariate analysis, the postoperative carbohydrate antigen 19-9 (CA 19-9) level was a significant prognostic factor for LRC, DFS and OS. CONCLUSION: Adjuvant radiotherapy might be an effective treatment in terms of LRC in GBC. Postoperative CA 19-9 might be useful as a surrogate marker for survival. PMID- 25275066 TI - The response to induction therapy is crucial for the treatment outcomes of elderly patients with acute myeloid leukemia: single-institution experience. AB - BACKGROUND/AIM: The prognosis of acute myeloid leukemia (AML) in elderly patients remains poor due to their poor general condition and the intrinsic chemotherapy resistant nature of their leukemia cells. The present retrospective study evaluated the clinical background as well as the response to treatment, of an unselected group of elderly patients with AML who were admitted to our Institution over a period of six years. PATIENTS AND METHODS: Patients aged 65 years or older with AML admitted to our Institution between January 2005 and May 2011 were evaluated retrospectively. RESULTS: Forty-six patients were admitted to our Institution, among whom 41 received remission induction chemotherapy. Twenty four patients received intensive chemotherapy, while 13 received low-dose cytarabine-based chemotherapy. Other modalities were used in four patients. Complete remission was obtained in 20 patients (48.8%). The complete remission rate (50.0%) tended to be higher in patients receiving intensive chemotherapy than in those receiving low-dose cytarabine-based regimens (30.7%; p=0.25). The median survival time for the whole patient group was 12 months and the 2-year overall survival was 18%. The median survival times for patients with complete remission and for non-responding patients were 14 months and 7 months, respectively. The 2-year overall survival in patients with complete remission was 32%, while that of non-responding patients was 6% (p=0.0025, log-rank test). CONCLUSION: The present study suggests the necessity of achieving complete remission for obtaining better survival for elderly patients with AML. PMID- 25275067 TI - Long-term survival in patients with incurable breast cancer. An analysis of 93 cases. AB - BACKGROUND/AIM: The aim of this study was to elucidate why some patients with incurable breast cancer may survive far beyond our expectation. PATIENTS AND METHODS: The analysis is based on two cohorts of patients with unresectable locoregional recurrences or distant metastases. Survival time, tumor characteristics, disease-free interval, metastasis type, coexistent diseases and a family history for breast cancer were recorded. RESULTS: Among 553 patients, 93 patients were found to have survived >4 years. The following favourable prognostic factors were identified: a disease-free interval of 5.5 years and a high frequency of locoregional and skeletal metastasis. In addition, the patients showed several coexistent disorders and a higher incidence of familial breast cancer. The more coexistent disorders are found in a patient, the longer seems to be the survival. CONCLUSION: Survival in metastatic breast cancer may not only be determined by known prognostic factors but also by a variety of hormonal and complex genetic influences, and possibly by non-cytotoxic drugs. PMID- 25275068 TI - First-line treatment result influence second-line regimen selection in targeted therapy for metastatic renal cell carcinoma. AB - BACKGROUND: Sequential treatments using various targeted-therapies have been recommended for metastatic renal cell carcinoma. However, regimen selection remains difficult when adapting to various clinical situations. PATIENTS AND METHODS: From 2006 to 2012, 29 patients who received sequential targeted-therapy at our hospital were included for analysis of the treatment regimens and outcome. RESULTS: Patients who used sunitinib as first-line and axitinib as second-line treatment experienced a similar second-line treatment duration, as those used the same first-line and everolimus as the second-line regimen. The first-line sunitinib treatment duration was longer in the axitinib group. CONCLUSION: Our data showed a promising sequential treatment result using sunitinib-axitinib and sunitinib-everolimus. In patients whose first-line sunitinib treatment resulted in primary resistance, second-line everolimus was found to still contribute a fair degree of disease control. Patients who responded to first-line sunitinib could also achieved fair disease control using second-line axitinib. PMID- 25275069 TI - Docetaxel and intermittent erlotinib in patients with metastatic Non-Small Cell Lung Cancer; a phase II study from the Hellenic Cooperative Oncology Group. AB - AIM: To determine the more effective dosing sequence of intermittent erlotinib and docetaxel for treating chemotherapy-naive patients with advanced Non-Small Cell Lung Cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized to receive daily erlotinib for 12 consecutive days prior to docetaxel (Arm A) or after docetaxel (Arm B). Progression-free survival (PFS) was the primary end point; secondary end-points were overall survival (OS) and objective response rate (ORR). RESULTS: Fifty eligible patients received a total of 226 treatment cycles (median: 3). Median PFS and OS were 3.6 months and 10.5 months, respectively (differences were not statistically significant between the two arms). Neutropenia grade 3 and 4 occurred in 15 patients, while two patients developed grade 3 diarrhea. There were two treatment-related deaths (pulmonary embolism and non-neutropenic sepsis). CONCLUSION: Intermittent administration of erlotinib does not appear to improve the clinical outcome of single-agent docetaxel chemotherapy in unselected patients with NSCLC in the first-line setting. PMID- 25275070 TI - Activity of a three-drug combination including cisplatin (CLOVER regimen) for poorly differentiated neuroendocrine carcinoma. AB - BACKGROUND/AIM: No standard treatment has been established for poorly differentiated neuroendocrine carcinomas (PDNEC). The aim of this study is to evaluate the response to the combination of three drugs. MATERIAL AND METHODS: We reviewed 21 PDNEC patients treated from 2008 to 2013 in two Institutions. Five patients were initially treated with epirubicin, fluorouracil and temozolomide. Because of toxicity, the regimen was modified into cisplatin, capecitabine and dacarbazine (scheme B-CLOVER regimen). RESULTS: Primary tumor site was: pancreas 7 (33%), lung 5 (24%), colon-rectum 5 (24%), unknown 3 (14%) and stomach 1 (5%). The response rate was 24% (0 complete response, 24% partial responses, 38% stable disease, 9% progression and 19% unassessable). The global overall survival (OS) is 13 months (range=1-29) and progression-free survival (PFS) was 6 months (range=1-11). CONCLUSION: The combination chemotherapy of cisplatinum, capecitabine and dacarbazine is feasible and should be considered as an option for PDNEC. PMID- 25275072 TI - Factors predictive of endometrial carcinoma in patients with atypical endometrial hyperplasia on preoperative histology. AB - AIM: To identify predictive factors of endometrial cancer in patients with atypical endometrial hyperplasia (AEH). PATIENTS AND METHODS: This was a retrospective cohort study of 79 patients diagnosed with AEH. Clinicopathological characteristics of patients and final histology on hysterectomy were reviewed and univariate and multivariate analyses were performed. RESULTS: Nineteen cases of endometrial cancer (24%) were diagnosed at final histology. Most patients had IA (n=15, 79%) grade 1 (n=15, 79%) cancer, but two had FIGO stage IIIC (10.5%). The predictive factors of endometrial cancer on final histology in univariate analysis were: hysteroscopic sampling, older age, post-menopausal status, suspicion of cancer on hysteroscopy and suspicion of cancer at histology. In multivariable analysis, the only predictive factors of endometrial cancer were older age and the suspicion of cancer on hysteroscopy. CONCLUSION: In patients with AEH on biopsy, our results showed that hysteroscopy could be performed both to assess macroscopic features of malignancy and to orient biopsy. PMID- 25275073 TI - The self-rating score (SRS) versus the examiner rating score (ERS) in measuring helplessness in healthy individuals and in patients with benign breast disease and breast cancer: a prospective case-control study in Finland. AB - BACKGROUND: The self-rating score (SRS) versus examiner rating score (ERS) in measuring helplessness in healthy study subjects (HSS) and in patients with benign breast disease (BBD) and breast cancer (BC) has not been yet compared in a prospective study. We, therefore, investigated SRS versus ERS in 115 patients. PATIENTS AND METHODS: In an extension of the Kuopio Breast Cancer Study 115 women with breast symptoms were evaluated for hopelessness versus helplessness before any diagnostic procedures were carried-out. RESULTS: The SRS and the ERS for hopelessness were highly significantly positively correlated in the HSS, BBD and BC groups. The weighted kappa values for hopelessness between the SRS and the ERS in the HSS, BBD and BC groups were also statistically significant. There was also a significant positive correlation between the SRS and the ERS for helplessness in the HSS, BBD and BC groups. The weighted and unweighted kappa-values for hopelessness versus helplessness for the SRS in the HSS, BBD and BC groups were statistically significant. The Spearman correlation coefficients and both weighted and unweighted kappa values for hopelessness versus helplessness in the ERS in the HSS, BBD and BC groups were statistically significant. CONCLUSION: The results of this study support a specific link between hopelessness and helplessness attitude characteristics by SRS and ERS. This finding is of clinical importance, since in the BC and BBD groups, hopelessness/helplessness might be associated with a delay in BC diagnosis and have a negative impact on the adjustment and well-being of patients. PMID- 25275071 TI - Plasma chromogranin A levels predict survival and tumor response in patients with advanced gastroenteropancreatic neuroendocrine tumors. AB - AIM: To correlate the baseline and change of chromogranin A (CgA) levels with patient survival and tumor response in Asian patients with advanced gastro enteropancreatic neuroendocrine tumors (GEP-NETs). PATIENTS AND METHODS: Sixty patients with advanced GEP-NET treated in a medical center between April 2010 and April 2013 were enrolled retrospectively. Plasma CgA level was analyzed for correlation with the patient's clinical outcome and tumor response. RESULTS: Multivariate analysis showed that independent favorable prognostic factors for overall survival were: Eastern Cooperative Oncology Groups performance score 0-1, World Health Organization tumor grade 1-2, single organ metastasis and less than twice the upper normal range of baseline CgA levels. Percentage changes in paired CgA tests (DeltaCgA) of more than 17% can predict partial response or stable disease from progressive disease with 91.2% sensitivity and 82.9% specificity. CONCLUSION: Baseline plasma CgA levels predicted overall survival and DeltaCgA predicted treatment response in Asian patients with GEP-NETs. PMID- 25275074 TI - Bimodal pattern of the impact of body mass index on cancer-specific survival of upper urinary tract urothelial carcinoma patients. AB - AIM: To clarify how body mass index (BMI) affects the risk of death from upper urinary tract urothelial carcinoma (UUTUC) we investigated the impact of BMI on UUTUC using a Japanese multicenter database. PATIENTS AND METHODS: Between January 1995 and December 2010, 1,329 patients with upper urinary tract tumors were treated in 13 institutions in Japan. From this group, a cohort of 1,014 patients treated with radical nephroureterectomy was retrospectively reviewed. BMI was categorized into the following three groups: BMI <22.5, BMI 22.5 to <25 and BMI >= 25. The association between each group and cancer-specific survival (CSS) was analyzed using Cox proportional hazards regression models. RESULTS: The median BMI was 22.4 kg/m(2) (interquartile range, 20.5-24.8). Out of all patients, 213 (21%) died of UUTUC. Hazard ratios of the BMI >= 25 and the BMI <22.5 group were 1.76 and 1.66, respectively. CONCLUSION: Both higher and lower BMI affect the prognosis of UUTUC treated with radical nephroureterectomy. PMID- 25275075 TI - Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: preliminary analysis of a multicentre study. AB - AIM: To assess the incidence of morbidity and mortality of Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy. PATIENTS AND METHODS: A retrospective multicentric study was performed. Six hundred and eighty-three patients were recorded. Predictors of morbidity and mortality were evaluated with univariate and multivariate analysis. RESULTS: In univariate analysis, older age, Eastern Cooperative Oncology Group score, a greater value of Peritoneal Cancer Index (PCI) and sub-optimal cytoreduction were correlated with higher mortality, while older age, presence of ascites, ovarian origin of carcinomatosis, closed technique, a greater value of PCI, longer operative time and sub-optimal cytoreduction were predictors of higher morbidity. In multivariate analysis, older age and a greater value of PCI were correlated with higher mortality; older age, ovarian origin of tumor, presence of ascites, closed technique and longer operative time were predictors of higher morbidity. CONCLUSION: Careful patient selection has to be performed to improve clinical outcomes. PMID- 25275076 TI - Improvement of high-sensitivity inflammation-based Glasgow prognostic score by gastrectomy is a favorable prognostic factor in patients with gastric cancer. AB - AIM: The aim of the present study was to clarify the efficacy of inflammation based Glasgow prognostic score after surgery in patients with gastric cancer and to determine clinicopathological factors affecting score improvement. PATIENTS AND METHODS: Participants in this retrospective study were 236 patients with gastric cancer who underwent gastrectomy at the Fukuoka University Hospital. The high-sensitivity inflammation-based Glasgow prognostic score (HS-GPS) (cut-off values: 0.3 mg/dl for C-reactive protein; 3.5 g/dl for albumin) were calculated before and 1 month after surgery, and correlated to clinicopathological parameters and prognosis after surgery. RESULTS: HS-GPS was classified as normal (score 0) in 162 patients and abnormal (score 1 or 2) in 74 patients. Out of the 162 patients with normal HS-GPS before surgery, 62 showed abnormal HS-GPS after surgery, while 26 of the 74 patients with abnormal HS-GPS before surgery improved to normal HS-GPS postoperatively. Abnormal HS-GPS before (p<0.0001) and after (p=0.0002) surgery were unfavorable prognostic factors in univariate analysis. HS GPS after surgery was an independent prognostic factor (p=0.0324) in multivariate analysis, but HS-GPS before surgery was not. In the sub-group with abnormal HS GPS before surgery (but not normal HS-GPS before surgery), improved HS-GPS after surgery had a favorable prognostic impact in both uni- (p=0.0039) and multivariate analyses (p=0.0032). CONCLUSION: HS-GPS after surgery may be a valuable prognostic factor in patients with gastric cancer. Supplemental therapy represented by adjuvant chemotherapy might be required for gastric cancer patients showing no improvement in HS-GPS after gastrectomy. PMID- 25275077 TI - A prospective case-control study on the impact of neoadjuvant chemotherapy on surgery-related outcomes of laparoscopic radical hysterectomy. AB - AIM: To investigate whether perioperative outcomes of class III/type C laparoscopic radical hysterectomy (LRH) for cervical cancer (CC) are influenced by neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: Data of consecutive patients, affected by locally advanced-stage CC, undergoing NACT plus LRH were matched 1:2 with consecutive patients, affected by early-stage CC who underwent LRH without NACT. RESULTS: Twenty and 40 patients underwent NACT with LRH and LRH aIone, respectively. Demographic characteristics were balanced between groups. Number of lymph nodes yielded, parametrial width and length of vaginal cuff were not influenced by preoperative administration of NACT. Patients undergoing NACT plus LRH experienced slightly higher blood loss (225 vs. 200 ml; p=0.05) than patients in the control group, but had a similar operative time and length of hospital stay. No between-group differences in transfusion and complications rates were observed (p>0.2). CONCLUSION: The administration of NACT does not affect the surgery-related outcomes of LRH. PMID- 25275078 TI - Clinical outcome of induction chemotherapy in locally advanced head and neck squamous cell carcinoma. AB - BACKGROUND AIM: We evaluated the efficacy and toxicities of three induction chemotherapy regimens in locally advanced head and neck cancer and assessed the clinical significance of human papillomavirus (HPV) in induction chemotherapy. PATIENTS AND METHODS: Fifty-two patients were retrospectively evaluated; 12 patients received 5-fluorouracil-plus-cisplatin (FP); 24 patients received docetaxel-plus-cisplatin (DP); 16 patients received docetaxel, cisplatin, and 5 fluorouracil (TPF). RESULTS: The TPF regimen showed a trend towards a higher overall response rate and pathological complete response and led to a significantly higher rate of metabolic complete response. Patients with HPV positive tumors exhibited a significantly higher pathological complete response rate than those with HPV-negative tumors. In univariate analysis, the prognostic factors significantly affecting progression-free survival were lymph node stage, and metabolic and pathological complete response. CONCLUSION: TPF induction chemotherapy tended to improve clinical outcome, with manageable toxicity. Pathological complete response was positively correlated with HPV positivity. PMID- 25275079 TI - Treatment outcome of radiation therapy for intracranial germinoma: adaptive radiation field in relation to response to chemotherapy. AB - AIM: To determine the optimal radiotherapy (RT) target volume in correlation with tumor response to chemotherapy in patients with intracranial germinoma. PATIENTS AND METHODS: Seventy-two patients received chemotherapy followed by RT. The RT field was tailored to chemotherapy response. RESULTS: Five-year recurrence-free survival (RFS) was 87% and overall survival was 97%. RT field was significantly associated with RFS, with 5-year RFS rates of 95%, 91%, and 62% in those who received craniospinal irradiation, whole-brain/whole-ventricle RT, and focal RT, respectively (p=0.01). In the complete-response group after chemotherapy, 5-year RFS rates were 100% after whole-brain RT/whole-ventricle RT and 70% after focal RT (p=0.04). In the partial-response group, 5-year RFS rates after craniospinal irradiation, whole-brain RT, and focal RT were 100%, 85%, and 33%, respectively (p<0.01). CONCLUSION: Regardless of response, those treated with focal RT had an excessively high relapse rate. Whole-brain/whole-ventricle RT could be applied to patients who show a complete response to chemotherapy, but the optimal strategy for patients with partial response needs further investigation. PMID- 25275080 TI - Changes in the diffusion capacity for carbon monoxide and the development of non infectious pneumonitis in patients with metastatic renal cell carcinoma treated with everolimus. AB - AIM: The aim of the present study was to evaluate how treatment with everolimus changes readouts of the pulmonary function test (PFT) in patients with metastatic renal cell carcinoma (mRCC). We also attempted to determine whether changes of PFT or everolimus-associated non-infectious pneumonitis (NIP) might affect the efficacy of everolimus. MATERIALS AND METHODS: The results of PFTs, radiological reports and medical records of 36 mRCC patients treated with everolimus after failure to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) were reviewed. RESULTS: Whereas 9 patients (30%) developed radiological changes consistent with everolimus-associated NIP (pneumonitis group), 27 were included in the non-pneumonitis group. The baseline value of the diffusing capacity for carbon monoxide divided by the alveolar volume (DLco/VA) was 90%. It decreased significantly as the duration of treatment increased (p<0.01). There was no significant difference in DLco/VA values between patients with and without NIP either at baseline (p=0.28) and 6 weeks after the initiation of everolimus therapy (p=0.18). The changes in DLco/VA between baseline and 6 weeks did not differ between the two groups (p=0.55). Time-dependent covariate Cox analysis, indicated that the decrease in DLco/VA was not correlated with the efficacy of everolimus in terms of progression-free survival (PFS; HR=1.0, p=0.94) and overall survival (OS; HR=0.98, p=0.18), whereas development of NIP was associated with worse PFS (HR=4.60, p=0.01). CONCLUSION: Patients with mRCC who are receiving everolimus therapy display a reduction in DLco/VA over time. However, neither the baseline DLco/VA nor the change in DLco/VA over time can help predict either development of NIP or the efficacy of everolimus. PMID- 25275081 TI - Increase of peripheral blood CD57+ T-cells in patients with oral squamous cell carcinoma. AB - BACKGROUND/AIM: The subset of T-cells positive for expression of cluster of differentiation (CD) 57 has been associated with various cancer phenotypes. However, the presence of CD57(+) T-cells in patients with oral squamous cell carcinoma (OSCC) has yet to be confirmed. In the present study, we examined the diagnostic significance of the presence of CD57(+) T-cells in peripheral blood (PB) from patients with OSCC. MATERIALS AND METHODS: The subset of CD57(+) T cells in PB was analyzed in 43 patients with OSCC by fluorescence-activated cell sorting (FACS) analysis. RESULTS: The proportion of CD57(+) T-cells, including both CD8(+) and CD4(+) subsets, significantly increased with clinical stage, especially in parallel with tumor size. CONCLUSION: Our results suggest that an increase in the population of CD57(+) T-cells is a potent prognostic marker and may also influence the systemic immunity of patients with OSCC. PMID- 25275082 TI - Obesity is a risk factor for multifocal disease and recurrence after colorectal cancer surgery: a case-control study. AB - BACKGROUND: Several studies have demonstrated that obesity is a risk factor for colorectal cancer (CRC), but few data are available regarding its role in multifocal disease and postoperative recurrence. The present study aimed to assess the role of obesity as a risk factor for multifocal disease and postoperative recurrence in patients with CRC. PATIENTS AND METHODS: The records of 940 consecutive patients with CRC admitted to three surgical centres between January 2006 and January 2011 were retrospectively analysed. The 595 individuals whose preoperative body mass index (BMI) values were available were included in the study. Following WHO guidelines, the patients were stratified into four groups depending on their BMI values. Age at disease onset, clinical presentation, tumor invasiveness, the presence of multiple foci, and the colon cancer recurrence rate in the four groups were assessed and compared. RESULTS: At multivariate analysis, diagnosis of familial adenomatous polyposis (FAP) and a BMI>30 were found to be independent predictors of synchronous polyps (Odd Ratio [OR]=10.7, 95% Confidence interval (CI)=2-75, p=0.005; and OR=2.2, 95% CI=1.3 3.9, p=0.003, respectively). The cancer recurrence rate in the patients with stage 2 CRC was significantly higher in the obese with respect to the non-obese (p=0.05). At multivariate analysis, BMI>30, FAP, and positivity by the Bethesda criteria were found to be independent predictors of recurrence after CRC surgery. CONCLUSION: Obese patients diagnosed with CRC require thorough colonic exploration prior to surgery and necessitate more frequent postoperative endoscopic examinations with respect to patients without any risk factors. PMID- 25275083 TI - Results of S-1-based chemotherapy for platinum (and antrathycline)-refractory advanced thymic carcinoma. AB - AIM: The aim of the present study was to retrospectively evaluate the role of S-1 based chemotherapy for patients with relapsed advanced thymic carcinoma (TC). PATIENTS AND METHODS: This study was a retrospective review of TC patients who had received S-1-based chemotherapy for patients with platinum- and antrathycline failure TC. Patients received S-1 monotherapy or S-1/gemcitabine combination therapy, that were repeated until disease progression. RESULTS: The patients consisted of 4 males and 4 females with a median age of 59 years (range=41-71); 2 with squamous cell carcinoma, 3 with undifferentiated carcinoma, 1 with poorly differentiated neuroendocrine carcinoma and 2 not otherwise specified. Grade 3 or higher toxicity was only neutropenia (25.0%). No treatment-related death was observed. The response rate was 50.0% (95% confidence interval (CI)=21.5-78.5%). The median progression free-survival (PFS) and overall survival (OS) of S-1-based chemotherapy were 6.0 and 13.5 months, respectively. CONCLUSION: S-1-based chemotherapy was found to be potentially useful for patients with relapsed TC. PMID- 25275084 TI - Prevalence of human papillomavirus infection in Greek patients with squamous cell carcinoma of the larynx. AB - BACKGROUND/AIM: The causal relation between human papillomavirus (HPV) infection and squamous cell carcinoma (SCC) of the larynx has not been yet clarified. The aim of the present study was to investigate HPV infection in 54 SCC of the larynx and correlate it with patients' epidemiological and clinicopathological data. MATERIALS AND METHODS: Fifty-four biopsies were collected from patients with laryngeal SCC and tested for HPV DNA. Local recurrence analysis was performed at the 2- year follow-up. RESULTS: HPV DNA was detected in 18.5% (10/54) of laryngeal SCC; infection from high risk (hr) HPV and low risk (lr) HPV types was found in 16.7% (9/54) and 1.8% (1/54) of the samples, respectively. HPV 16 was the commonest type detected in 7.5% (4/54). The presence of HPV DNA was significantly associated with the absence of tobacco use (p=0.001) and poorly differentiated tumors (p=0.003). CONCLUSION: This study confirms the prevalence of HPV infection among patients with SCC of the larynx. PMID- 25275085 TI - Hypofractionated stereotactic radiotherapy using CyberKnife as a boost treatment for head and neck cancer, a multi-institutional survey: impact of planning target volume. AB - AIM: To evaluate the role of hypofractionated stereotactic radiotherapy (hSRT) as a boost treatment for head and neck cancer. PATIENTS AND METHODS: We conducted a multi-institutional retrospective review for the outcome of boost irradiation using CyberKnife for head and neck cancer patients from the charts of four Institutes. Twenty-five patients were treated with hSRT boost for primary site with a median follow-up of 28 months. Treatment sites were 11 nasopharynx, 7 oropharynx, one hypopharynx, 3 nasal cavity or paranasal sinus and three oral cancers. All patients underwent preceding conventional radiotherapy of 35 to 72 Gy (median, 50 Gy) in 1.2- to 2 Gy-fractions. The dose and fractionation scheme of the Cyberknife SRT boost was individualized and the prescribed dose ranged from 12 Gy to 35 Gy in 1 to 5 fractions (median, 15 Gy in 3 fractions). RESULTS: There were 18 complete responses, 6 partial responses and one progressive disease, resulting in 96% (24/25) response rate. Local control (LC) rates at 2- and 5-years were 89% and 71%, respectively. Progression-free survival (PFS) and overall survival (OS) at 2- and 5-years were 70%/ 83% and 70%/ 70%, respectively. Planning target volume (PTV) at boost treatment planning and initial response were predisposing factors for PFS and OS. Patients with PTV <= 20 cm(3) showed better PFS (92%) and OS (100%) than those with a PTV > 20 cm(3) (PFS, 61% and OS, 47%). Good initial response predicts better outcome in LC, PFS and OS. CONCLUSION: The results of the present study showed potential benefits of the CyberKnife hSRT boost. Smaller PTV and good initial response predict good outcome. PMID- 25275087 TI - Early wound reactions of Japanese maple during winter dormancy: the effect of two contrasting temperature regimes. AB - During winter dormancy, temperate trees are capable of only a restricted response to wounding. Depending on the ambient temperature during winter dormancy, wounded trees may start compartmentalization, e.g. by producing inhibitory compounds, but it is thought that processes involving cell proliferation, such as the formation of callus and wound xylem, are delayed until the next growing season. We investigated the effect of two contrasting temperature regimes on early reactions of Acer palmatum trees to wounding during winter bud dormancy. Stems of A. palmatum trees were wounded and stored under an ambient temperature of 4 or 15 degrees C for 3 weeks during winter bud dormancy. We then studied wound reactions in the living bark, cambial region and xylem. In the 4 degrees C treatment, wound reactions were virtually absent. In the 15 degrees C treatment, however, trees reacted to wounding by dieback of the cortex and phloem and by the formation of ligno-suberized layers. In the cambial zone, cambial dieback occurred and callus tissue and wound xylem were formed locally, close to the wound margins. In the xylem, compartmentalization took place by deposition of inhibitory compounds in fibre cells and vessel elements. We conclude that temperature is an important factor in wound reactions during winter dormancy, and may even induce proliferation of callus and wound xylem within a 3-week period. It therefore seems likely that trees that have been wounded during dormancy in areas with mild or warm winters might cope better with wounding, as unlike trees in cold environments, they may compartmentalize wounds even during winter dormancy. PMID- 25275088 TI - Advance Care Planning: practicalities, legalities, complexities and controversies. AB - Increasing numbers, complexities and technology dependencies of children and young people with life-limiting conditions require paediatricians to be well prepared to meet their changing needs. Paediatric Advance Care Planning provides a framework for paediatricians, families and their multidisciplinary teams to consider, reflect and record the outcome of their conversations about what might happen in the future in order to optimise quality of clinical care and inform decision-making. For some children and young people this will include discussions about the possibility of death in childhood. This may be unexpected and sudden, in the context of an otherwise active management plan or may be expected and necessitate discussions about the process of dying and attention to symptoms. Decision-making about appropriate levels of intervention must take place within a legal and ethical framework, recognising that the UK Equality Act (2010) protects the rights of disabled children and young people and infants and children of all ages to the same high quality healthcare as anyone else. PMID- 25275089 TI - Occipital plagiocephaly: unilateral lambdoid synostosis versus positional plagiocephaly. AB - OBJECTIVE: We defined parameters that could differentiate between positional and synostotic plagiocephaly and defined a diagnostic chart for decision making. DESIGN: Prospective study. SETTING: We examined 411 children with non-syndromic skull abnormalities between January 2011 and December 2012. PARTICIPANTS: A total of 8 infants under 1 year of age with proven unilateral non-syndromic lambdoid synostosis (LS) and 261 children with positional deformity were examined to outline the specific clinical features of both diagnoses. After clinical examination, an ultrasound revealed either a closed suture suggestive of LS or a patent lambdoid suture suggestive of positional deformity. For patients with synostosis, plain radiographs, MR imaging and follow-up examinations were performed. In cases of open sutures, only follow-ups were completed. MAIN OUTCOME MEASURE: Clinical, imaging, genesis and treatment differences between positional plagiocephaly and LS. RESULTS: In all 8 cases of unilateral LS and 258 cases of positional plagiocephaly, the diagnosis was established by clinical examination alone. In three cases of positional plagiocephaly, diagnosis was determined after an additional ultrasonography. MR imaging revealed a unilateral tonsillar herniation in five of the eight children with LS and hydrocephalus in one child. CONCLUSIONS: We have suggested a list of clinical features that specify the underlying cause of posterior plagiocephaly. An additional ultrasound scanning confirmed the diagnosis without any risks of ionising radiation or sedation as in a CT scan. PMID- 25275090 TI - Etanercept versus monoclonal antibodies in axial spondyloarthritis: game over? PMID- 25275091 TI - Trends in medication usage in juvenile idiopathic arthritis: prescribing trends or trends in prescribers? PMID- 25275092 TI - Is visceral fat the missing link in the relationship between inflammation and insulin resistance in RA? PMID- 25275093 TI - Systemic lupus erythematosus, osteoporosis, and fractures. PMID- 25275094 TI - Attrition rupture of ulnar nerve in an elbow of a patient with rheumatoid arthritis. PMID- 25275095 TI - Predictive factors for low ankle brachial index in patients with systemic lupus erythematosus. PMID- 25275096 TI - Dr. Erdozain, et al reply. PMID- 25275097 TI - Effect of traditional cardiovascular risk factors on the independent relationship of leptin with atherosclerosis in rheumatoid arthritis. PMID- 25275100 TI - Myelinating cocultures of rat retinal ganglion cell reaggregates and optic nerve oligodendrocyte precursor cells. AB - This protocol describes the generation of a rapidly myelinating central nervous system coculture for the study of complex neuronal-glial interactions in vitro. Postnatal rat retinal ganglion cells (RGCs) purified by immunopanning are promoted to cluster into reaggregates and then allowed to extend dense beds of radial axons for 10-14 d. Subsequently, rodent oligodendrocyte precursor cells are purified by immunopanning, transfected if desired, and seeded on top of the RGC reaggregates. Under the conditions described here, compact myelin can be observed within 6 d. PMID- 25275099 TI - Functional roles of nucleosome stability and dynamics. AB - Nucleosome is a histone-DNA complex known as the fundamental repeating unit of chromatin. Up to 90% of eukaryotic DNA is wrapped around consecutive octamers made of the core histones H2A, H2B, H3 and H4. Nucleosome positioning affects numerous cellular processes that require robust and timely access to genomic DNA, which is packaged into the tight confines of the cell nucleus. In living cells, nucleosome positions are determined by intrinsic histone-DNA sequence preferences, competition between histones and other DNA-binding proteins for genomic sequence, and ATP-dependent chromatin remodelers. We discuss the major energetic contributions to nucleosome formation and remodeling, focusing especially on partial DNA unwrapping off the histone octamer surface. DNA unwrapping enables efficient access to nucleosome-buried binding sites and mediates rapid nucleosome removal through concerted action of two or more DNA binding factors. High-resolution, genome-scale maps of distances between neighboring nucleosomes have shown that DNA unwrapping and nucleosome crowding (mutual invasion of nucleosome territories) are much more common than previously thought. Ultimately, constraints imposed by nucleosome energetics on the rates of ATP-dependent and spontaneous chromatin remodeling determine nucleosome occupancy genome-wide, and shape pathways of cellular response to environmental stresses. PMID- 25275101 TI - Synthesis of NAADP-AM as a membrane-permeant NAADP analog. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP), like the other major messengers for Ca2+ mobilization, is passively membrane-impermeant. Instead, a cell-permeant acetoxymethyl ester derivative of NAADP (NAADP-AM) can be synthesized as described here and used to study NAADP-mediated Ca2+ release. PMID- 25275102 TI - Measurement of luminal pH of acidic stores as a readout for NAADP action. AB - In addition to mobilizing Ca2+, NAADP plays a role in modulating the luminal pH (pHL) of acidic stores of the endolysosomal system. The effects of NAADP on pHL have been most extensively studied in the sea urchin egg, both in the intact egg and in egg homogenates. Related observations have also been made in mammalian systems (e.g., guinea pig atrial myocytes and pancreatic acinar cells). Although the connection between Ca2+ mobilization and increase in pHL is not understood, pHL can be a useful parameter to measure when studying NAADP-mediated signaling. This protocol describes the fluorescent measurement of pHL of acidic stores. It relies on the use of acridine orange (AO), a standard dye for pHL. AO selectively accumulates to high concentrations in the lumen of organelles as a function of acidity; at these high concentrations it self-quenches. When pHL increases, some AO is lost from the vesicle. As a result, the lower luminal AO concentration relieves the quenching and fluorescence increases in the lumen. PMID- 25275103 TI - Synthesis of caged NAADP. AB - Caged derivatives of Ca2+-mobilizing messengers, such as nicotinic acid adenine dinucleotide phosphate (NAADP), are particularly useful for establishing the effects of these messengers on Ca2+ signaling. Caged NAADP is no longer commercially available but can be synthesized in house, as described here. In brief, a stable precursor of the caging reagent is made and converted to an unstable reactive reagent immediately before addition to the compound to be caged. PMID- 25275104 TI - Isolation of mitochondria from tissue culture cells. AB - The number of mitochondria per cell varies substantially from cell line to cell line. For example, human HeLa cells contain at least twice as many mitochondria as smaller mouse L cells. This protocol starts with a washed cell pellet of 1-2 mL derived from ~109 cells grown in culture. The cells are swollen in a hypotonic buffer and ruptured with a Dounce or Potter-Elvehjem homogenizer using a tight fitting pestle, and mitochondria are isolated by differential centrifugation. PMID- 25275105 TI - Isolation of mitochondria from animal tissue. AB - Rat or mouse liver is the most frequently used tissue for mitochondrial preparations because it is readily available, easy to homogenize, and replete with mitochondria. A motor-driven Teflon and glass Potter-Elvehjem homogenizer is the best choice for homogenizing liver, but if one is not available, this tissue is soft enough that a Dounce homogenizer with a loose (A) pestle can also be used. The yield and purity of the mitochondrial preparation will be influenced by the method and speed of preparation and the age and physiological condition of the animal. PMID- 25275106 TI - Purification of mitochondria by sucrose step density gradient centrifugation. AB - Mitochondrial fractions isolated from tissue culture cells or tissue such as liver after differential centrifugation can be purified further by density gradient centrifugation. Here we describe the use of sucrose for this purpose because it is commonly used and inexpensive and the resulting mitochondria preparations are useful for many purposes. PMID- 25275107 TI - Basic quantitative polymerase chain reaction using real-time fluorescence measurements. AB - This protocol uses quantitative polymerase chain reaction (qPCR) to measure the number of DNA molecules containing a specific contiguous sequence in a sample of interest (e.g., genomic DNA or cDNA generated by reverse transcription). The sample is subjected to fluorescence-based PCR amplification and, theoretically, during each cycle, two new duplex DNA molecules are produced for each duplex DNA molecule present in the sample. The progress of the reaction during PCR is evaluated by measuring the fluorescence of dsDNA-dye complexes in real time. In the early cycles, DNA duplication is not detected because inadequate amounts of DNA are made. At a certain threshold cycle, DNA-dye complexes double each cycle for 8-10 cycles, until the DNA concentration becomes so high and the primer concentration so low that the reassociation of the product strands blocks efficient synthesis of new DNA and the reaction plateaus. There are two types of measurements: (1) the relative change of the target sequence compared to a reference sequence and (2) the determination of molecule number in the starting sample. The first requires a reference sequence, and the second requires a sample of the target sequence with known numbers of the molecules of sequence to generate a standard curve. By identifying the threshold cycle at which a sample first begins to accumulate DNA-dye complexes exponentially, an estimation of the numbers of starting molecules in the sample can be extrapolated. PMID- 25275108 TI - Fluorodeoxyglucose-based positron emission tomography imaging to monitor drug responses in hematological tumors. AB - Positron emission tomography (PET) can be used to monitor the uptake of the labeled glucose analog fluorodeoxyglucose (18F-FDG), a process that is generally believed to reflect viable tumor cell mass. The use of 18F-FDG PET can be helpful in documenting over time the reduction in tumor mass volume in response to anticancer drug therapy in vivo. In this protocol, we describe how to monitor the response of murine B-cell lymphomas to an inducer of apoptosis, the anticancer drug vorinostat (a histone deacetylase inhibitor). B-cell lymphoma cells are injected into recipient mice and, on tumor formation, the mice are treated with vorinostat. The tracer 18F-FDG is then injected into the mice at several time points, and its uptake is monitored using PET. Because the uptake of 18F-FDG is not a direct measure of apoptosis, an additional direct method proving that apoptotic cells are present should also be performed. PMID- 25275109 TI - Fluorodeoxyglucose-based positron emission tomography imaging to monitor drug responses in solid tumors. AB - Positron emission tomography (PET) is used to monitor the uptake of the labeled glucose analogue fluorodeoxyglucose (18F-FDG) by solid tumor cells, a process generally believed to reflect viable tumor cell mass. The use of 18F-FDG exploits the high demand for glucose in tumor cells, and serves to document over time the response of a solid tumor to an inducer of apoptosis. The apoptosis inducer crizotinib is a small-molecule inhibitor of c-Met, a receptor tyrosine kinase that is often dysregulated in human tumors. In this protocol, we describe how to monitor the response of a solid tumor to crizotinib. Human gastric tumor cells (GTL-16 cells) are injected into recipient mice and, on tumor formation, the mice are treated with crizotinib. The tracer 18F-FDG is then injected into the mice at several time points, and its uptake is monitored using PET. Because 18F-FDG uptake varies widely among different tumor models, preliminary experiments should be performed with each new model to determine its basal level of 18F-FDG uptake. Verifying that the basal level of uptake is sufficiently above background levels will assure accurate quantitation. Because 18F-FDG uptake is not a direct measure of apoptosis, it is advisable to carry out an additional direct method to show the presence of apoptotic cells. PMID- 25275110 TI - In vivo calcium recordings and channelrhodopsin-2 activation through an optical fiber. AB - We describe here an approach for the fluorometric monitoring of population activity in neurons in live mice combined with the activation of optogenetic actuators in vivo. In this protocol, a thin multimode fiber, which is used for both delivering excitation light and collecting emitted fluorescence signals, is inserted into the skull of a mouse. When combined with multicell bolus loading of Ca(2+) indicators, this optical fiber and its associated fluorescence detection system can be used for the in vivo recording of brain Ca(2+) signals from a local cluster of coactive neurons. The fiber can also be used for the optogenetic stimulation of light-activated ion channels, such as channelrhodopsin-2, allowing the monitoring of local calcium signals evoked by optogenetic stimulation. PMID- 25275111 TI - Cell-flow technique. AB - Various devices have been used to flow neurotransmitter solutions over cells containing receptors (e.g., ligand-gated ion channels) for whole-cell current recordings. With many of the devices, the orientation between the porthole of the flow device and the cell is not maintained absolutely constant. Orientation is critical for reproducibility in kinetic experiments. To be able to change the composition of the flowing solution during an experiment and still maintain a constant orientation, we use the cell-flow device described here. A peristaltic pump, a stainless steel U-tube, two different sizes of peristaltic tubing, and a solenoid valve are required to create a simple solution exchange system that can rapidly apply and remove solutions over the surface of a cell in tens of milliseconds. This system allows one to test multiple conditions on a cell containing the receptor of interest while constantly "washing" the cell with extracellular buffer solution between experimental applications. The use of the solenoid valve allows for the application of solutions to be precisely timed and controlled by a computer during electrophysiological current recording. PMID- 25275112 TI - Tetracycline-regulated mouse models of cancer. AB - Genetically engineered mouse models (GEMMs) have proven essential to the study of mammalian gene function in both development and disease. However, traditional constitutive transgenic mouse model systems are limited by the temporal and spatial characteristics of the experimental promoter used to drive transgene expression. To address this limitation, considerable effort has been dedicated to developing conditional and inducible mouse model systems. Although a number of approaches to generating inducible GEMMs have been pursued, several have been restricted by toxic or undesired physiological side effects of the compounds used to activate gene expression. The development of tetracycline (tet)-dependent regulatory systems has allowed for circumvention of these issues resulting in the widespread adoption of these systems as an invaluable tool for modeling the complex nature of cancer progression. PMID- 25275113 TI - Myelinating cocultures of purified oligodendrocyte lineage cells and retinal ganglion cells. AB - In this article, we introduce methods for generating rapidly myelinating cocultures with reaggregates of purified retinal ganglion cells and optic nerve oligodendrocyte precursor cells. This coculture system facilitates the study of complex central nervous system neuronal-glial interactions and myelination. It enables control of the extracellular environment and allows the use of transfected, virally infected, mutant, or knockout neurons and/or glial cell types. It is therefore possible to assess the role of various signaling pathways and genes in myelination and node of Ranvier formation. PMID- 25275115 TI - Isolation of mitochondria from cells and tissues. AB - Mitochondria are complex organelles at the center of cellular metabolism, apoptosis, and signaling. They continue to be the subject of intense basic investigation to understand their composition and function, but they have also captivated the attention of clinical researchers because of the growing knowledge of the (sometimes unexpected) roles of mitochondria in human diseases and aging. A full understanding of these intriguing organelles often requires their purification from cells or tissues under specific physiological or pathological conditions. Here we provide some introductory considerations for those interested in purifying mitochondria for subsequent downstream biophysical, structural, and functional analysis. PMID- 25275114 TI - Fluorescence microscopy. AB - Fluorescence microscopy is a major tool with which to monitor cell physiology. Although the concepts of fluorescence and its optical separation using filters remain similar, microscope design varies with the aim of increasing image contrast and spatial resolution. The basics of wide-field microscopy are outlined to emphasize the selection, advantages, and correct use of laser scanning confocal microscopy, two-photon microscopy, scanning disk confocal microscopy, total internal reflection, and super-resolution microscopy. In addition, the principles of how these microscopes form images are reviewed to appreciate their capabilities, limitations, and constraints for operation. PMID- 25275116 TI - Caged neurotransmitters and other caged compounds: design and application. AB - The approaches using caged neurotransmitters described here enable transient kinetic investigations to be made with membrane-bound proteins (receptors) on a cell surface with the same time resolution as was previously possible only with proteins in solution. PMID- 25275117 TI - Differential contribution of adeno-associated virus type 2 Rep protein expression and nucleic acid elements to inhibition of adenoviral replication in cis and in trans. AB - The helper-dependent adeno-associated virus type 2 (AAV-2) exhibits complex interactions with its helper adenovirus. Whereas AAV-2 is dependent on adenoviral functions for productive replication, it conversely inhibits adenoviral replication, both when its genome is present in trans after coinfection with both viruses and when it is present in cis, as in the production of recombinant adenovirus (rAd)/AAV-2 hybrid vectors. The notion that AAV-mediated inhibition of adenoviral replication is due predominantly to the expression of the AAV-2 Rep proteins was recently challenged by successful Rep78 expression in a rAd5 vector through recoding of the Rep open reading frame (ORF). We closely analyzed the relative contributions of AAV-2 nucleic acid elements and Rep protein expression to the inhibition of adenoviral replication in both of the above scenarios. When present in cis, a sequence element in the 3' part of the rep gene, comprising only the AAV-2 p40 promoter and the AAV-2 intron sequence, which we termed the RIS-Ad, completely blocks adenoviral replication. p5/p19 promoter-driven Rep protein expression, on the other hand, only weakly inhibits rAd/AAV-2 vector propagation, and by inactivation of the RIS-Ad, it is feasible to generate first generation rAd vectors expressing functional Rep proteins. The RIS-Ad plays no role in the inhibition of adenoviral replication in trans in a model closely mimicking AAV-2-Ad coinfection. In this case, expression of the Rep proteins is required, as well as the presence of an amplifiable inverted terminal repeat (ITR)-containing template. Thus, very different AAV-2 elements and mechanisms are involved in inhibition of adenoviral replication during rAd/AAV-2 vector propagation and after Ad-AAV coinfection. IMPORTANCE: This is the first study to systematically compare the contributions of AAV-2 protein expression and AAV-2 nucleic acid elements to the inhibition of adenoviral replication in rAd/AAV-2 hybrid vector generation and in AAV-2-adenovirus coinfection. This study shows that the two inhibitory processes are very different with regard to AAV-2 functions and the mechanisms involved. Whereas inhibition of rAd/AAV-2 hybrid vector propagation mostly involves a 3' nucleic acid element in the rep gene, inhibition of an adenoviral genome in trans requires the Rep proteins and the AAV ITRs. These findings have important implications both for a basic understanding of the AAV replication cycle and for generation of rAd/AAV-2 hybrid vectors expressing the nonstructural and structural proteins of AAV-2. PMID- 25275118 TI - Role of the short telomeric repeat region in Marek's disease virus replication, genomic integration, and lymphomagenesis. AB - Marek's disease virus (MDV) is a cell-associated alphaherpesvirus that causes generalized polyneuritis and T-cell lymphomas in chickens. MDV is able to integrate its genome into host telomeres, but the mechanism of integration is poorly understood. The MDV genome harbors two arrays of telomeric repeats (TMR) at the ends of its linear genome: multiple telomeric repeats (mTMR), with a variable number of up to 100 repeats, and short telomeric repeats (sTMR), with a fixed number of 6 repeats. The mTMR have recently been shown to play an important role in MDV integration and tumor formation; however, the functions of the sTMR have remained unknown. In this study, we demonstrate that deletion of the sTMR in the MDV genome abrogates virus replication, while extensive mutation of the sTMR does not, indicating that the presence of the sTMR but not the sTMR sequence itself is important. Furthermore, we generated a panel of truncation mutants to determine the minimal length of the sTMR and observed a direct correlation between sTMR length and MDV replication. To address the role of sTMR in MDV replication, integration, and tumorigenesis, sTMR sequences were replaced by a scrambled repeated sequence (vsTMR_mut). vsTMR_mut replicated comparably to parental and revertant viruses in vitro. In vivo, however, a significant reduction in disease and tumor incidence was observed in chickens infected with vsTMR_mut that also correlated with a reduced number of viral integration sites in tumor cells. Taken together, our data demonstrate that the sTMR play a central role in MDV genome replication, pathogenesis, and MDV-induced tumor formation. IMPORTANCE: Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that infects chickens and causes high economic losses in the poultry industry. MDV integrates its genetic material into host telomeres, a process that is crucial for efficient tumor formation. The MDV genome harbors two arrays of telomeric repeats (TMR) at the ends of its linear genome that are identical to host telomeres and that are termed mTMR and sTMR. mTMR have been recently shown to be involved in MDV integration, while the functions of sTMR remain unknown. Here, we demonstrate that the presence and length of sTMR sequence, but not the exact nucleotide sequence, are crucial for MDV replication. Furthermore, the sTMR contribute to the high integration frequency of MDV and are important for MDV pathogenesis and tumor formation. As a number of herpesviruses harbor arrays of telomeric repeats (TMR), MDV serves as a model to determine the role of the herpesvirus TMR in replication, integration, and pathogenesis. PMID- 25275119 TI - Role of Mason-Pfizer monkey virus CA-NC spacer peptide-like domain in assembly of immature particles. AB - The hexameric lattice of an immature retroviral particle consists of Gag polyprotein, which is the precursor of all viral structural proteins. Lentiviral and alpharetroviral Gag proteins contain a peptide sequence called the spacer peptide (SP), which is localized between the capsid (CA) and nucleocapsid (NC) domains. SP plays a critical role in intermolecular interactions during the assembly of immature particles of several retroviruses. Published models of supramolecular structures of immature particles suggest that in lentiviruses and alpharetroviruses, SP adopts a rod-like six-helix bundle organization. In contrast, Mason-Pfizer monkey virus (M-PMV), a betaretrovirus that assembles in the cytoplasm, does not contain a distinct SP sequence, and the CA-NC connecting region is not organized into a clear rod-like structure. Nevertheless, the CA-NC junction comprises a sequence critical for assembly of immature M-PMV particles. In the present work, we characterized this region, called the SP-like domain, in detail. We provide biochemical data confirming the critical role of the M-PMV SP like domain in immature particle assembly, release, processing, and infectivity. Circular dichroism spectroscopy revealed that, in contrast to the SP regions of other retroviruses, a short SP-like domain-derived peptide (SPLP) does not form a purely helical structure in aqueous or helix-promoting solution. Using 8-A cryo electron microscopy density maps of immature M-PMV particles, we prepared computational models of the SP-like domain and indicate the structural features required for M-PMV immature particle assembly. IMPORTANCE: Retroviruses such as HIV-1 are of great medical importance. Using Mason-Pfizer monkey virus (M-PMV) as a model retrovirus, we provide biochemical and structural data confirming the general relevance of a short segment of the structural polyprotein Gag for retrovirus assembly and infectivity. Although this segment is critical for assembly of immature particles of lentiviruses, alpharetroviruses, and betaretroviruses, the organization of this domain is strikingly different. A previously published electron microscopic structure of an immature M-PMV particle allowed us to model this important region into the electron density map. The data presented here help explain the different packing of the Gag segments of various retroviruses, such as HIV, Rous sarcoma virus (RSV), and M-PMV. Such knowledge contributes to understanding the importance of this region and its structural flexibility among retroviral species. The region might play a key role in Gag-Gag interactions, leading to different morphological pathways of immature particle assembly. PMID- 25275120 TI - RNA populations in immunocompromised patients as reservoirs for novel norovirus variants. AB - Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of norovirus outbreaks are caused by genogroup II.4 (GII.4). Novel GII.4 strains emerge every 2 to 4 years and replace older variants as the dominant norovirus. Novel variants emerge through a combination of recombination, genetic drift, and selection driven by population immunity, but the exact mechanism of how or where is not known. We detected two previously unknown novel GII.4 variants, termed GII.4 UNK1 and GII.4 UNK2, and a diverse norovirus population in fecal specimens from immunocompromised individuals with diarrhea after they had undergone bone marrow transplantation. We hypothesized that immunocompromised individuals can serve as reservoirs for novel norovirus variants. To test our hypothesis, metagenomic analysis of viral RNA populations was combined with a full-genome bioinformatic analysis of publicly available GII.4 norovirus sequences from 1974 to 2014 to identify converging sites. Variable sites were proportionally more likely to be within two amino acids (P < 0.05) of positively selected sites. Further analysis using a hypergeometric distribution indicated that polymorphic site distribution was random and its proximity to positively selected sites was dependent on the size of the norovirus genome and the number of positively selected sites.In conclusion, random mutations may have a positive impact on driving norovirus evolution, and immunocompromised individuals could serve as potential reservoirs for novel GII.4 strains. IMPORTANCE: Norovirus is the most common cause of viral gastroenteritis in the United States. Every 2 to 3 years novel norovirus variants emerge and replace dominant strains. The continual emergence of novel noroviruses is believed to be caused by a combination of genetic drift, population immunity, and recombination, but exactly how this emergence occurs remains unknown. In this study, we identified two novel GII.4 variants in immunocompromised bone marrow transplant patients. Using metagenomic and bioinformatic analysis, we showed that most genetic polymorphisms in the novel variants occur near 0 to 2 amino acids of positively selected sites, but the distribution of mutations was random; clustering of polymorphisms with positively selected sites was a result of genome size and number of mutations and positively selected sites. This study shows that immunocompromised patients can harbor infectious novel norovirus variants, and although mutations in viruses are random, they can have a positive effect on viral evolution. PMID- 25275121 TI - A combination of HA and PA mutations enhances virulence in a mouse-adapted H6N6 influenza A virus. AB - H6N6 viruses are commonly isolated from domestic ducks, and avian-to-swine transmissions of H6N6 viruses have been detected in China. Whether subsequent adaptation of H6N6 viruses in mammals would increase their pathogenicity toward humans is not known. To address this, we generated a mouse-adapted (MA) swine influenza H6N6 virus (A/swine/Guangdong/K6/2010 [GDK6-MA]) which exhibited greater virulence than the wild-type virus (GDK6). Amino acid substitutions in PB2 (E627K), PA (I38M), and hemagglutinin ([HA] L111F, H156N, and S263R) occurred in GDK6-MA. HA with the H156N mutation [HA(H156N)] resulted in enlarged plaque sizes on MDCK cells and enhanced early-stage viral replication in mammalian cells. PA(I38M) raised polymerase activity in vitro but did not change virus replication in either mammalian cells or mice. These single substitutions had only limited effects on virulence; however, a combination of HA(H156N S263R) with PA(I38M) in the GDK6 backbone led to a significantly more virulent variant. This suggests that these substitutions can compensate for the lack of PB2(627K) and modulate virulence, revealing a new determinant of pathogenicity for H6N6 viruses in mice, which might also pose a threat to human health. IMPORTANCE: Avian H6N6 influenza viruses are enzootic in domestic ducks and have been detected in swine in China. Infections of mammals by H6N6 viruses raise the possibility of viral adaptation and increasing pathogenicity in the new hosts. To examine the molecular mechanisms of adaptation, a mouse-adapted avian-origin swine influenza H6N6 virus (GDK6-MA), which had higher virulence than its parental virus, was generated. Specific mutations were found in PB2 (E627K), PA (I38M), and HA (L111F, H156N, and S263R) and were assessed for their virulence in mice. The combination of HA(H156N S263R) and PA(I38M) compensated for the lack of PB2(627K) and showed increased pathogenicity in mice, revealing a novel mechanism that can affect the virulence of influenza viruses. H6N6 viruses should be monitored in the field for more virulent forms that could threaten human health. PMID- 25275122 TI - Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. AB - Many viruses utilize cell adhesion molecules of the immunoglobulin superfamily as receptors. In particular, viruses of different classes exploit nectins. The large DNA viruses, herpes simplex and pseudorabies viruses, use ubiquitous nectins 1 and 2. The negative-strand RNA virus measles virus (MeV) uses tissue-specific nectin-4, and the positive-strand RNA virus poliovirus uses nectin-like 5 (necl 5), also known as poliovirus receptor. These viruses contact the BC, C'C", and FG loops on the upper tip of their receptor's most membrane-distal domain. This location corresponds to the newly defined canonical adhesive interface of nectins, but how viruses utilize this interface has remained unclear. Here we show that the same key residues in the BC and FG loops of nectin-4 govern binding to the MeV attachment protein hemagglutinin (H) and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. On the other hand, residues in the C'C" loop necessary for homo- and heterotypic interactions are dispensable for MeV-induced fusion and cell entry. Remarkably, the C'C" loop governs dissociation of the nectin-4 and H ectodomains. We provide formal proof that H can interfere with the formation of stable nectin-1/nectin-4 heterodimers. Finally, while developing an alternative model to study MeV spread, we observed that polarized primary pig airway epithelial sheets cannot be infected. We show that a single amino acid variant in the BC loop of pig nectin-4 fully accounts for restricted MeV entry. Thus, the three loops forming the adhesive interface of nectin-4 have different roles in supporting MeV H association and dissociation and MeV-induced fusion. IMPORTANCE: Different viruses utilize nectins as receptors. Nectins are immunoglobulin superfamily glycoproteins that mediate cell cell adhesion in vertebrate tissues. They interact through an adhesive interface located at the top of their membrane-distal domain. How viruses utilize the three loops forming this interface has remained unclear. We demonstrate that while nectin-nectin interactions require residues in all three loops, the association of nectin-4 with the measles virus hemagglutinin requires only the BC and FG loops. However, we discovered that residues in the C'C" loop modulate the dissociation of nectin-4 from the viral hemagglutinin. Analogous mechanisms may support cell entry of other viruses that utilize nectins or other cell adhesion molecules of the immunoglobulin superfamily as receptors. PMID- 25275123 TI - Evolution of cocirculating varicella-zoster virus genotypes during a chickenpox outbreak in Guinea-Bissau. AB - Varicella-zoster virus (VZV), a double-stranded DNA alphaherpesvirus, is associated with seasonal outbreaks of varicella in nonimmunized populations. Little is known about whether these outbreaks are associated with a single or multiple viral genotypes and whether new mutations rapidly accumulate during transmission. Here, we take advantage of a well-characterized population cohort in Guinea-Bissau and produce a unique set of 23 full-length genome sequences, collected over 7 months from eight households. Comparative sequence analysis reveals that four distinct genotypes cocirculated among the population, three of which were present during the first week of the outbreak, although no patients were coinfected, which indicates that exposure to infectious virus from multiple sources is common during VZV outbreaks. Transmission of VZV was associated with length polymorphisms in the R1 repeat region and the origin of DNA replication. In two cases, these were associated with the formation of distinct lineages and point to the possible coevolution of these loci, despite the lack of any known functional link in VZV or related herpesviruses. We show that these and all other sequenced clade 5 viruses possess a distinct R1 repeat motif that increases the acidity of an ORF11p protein domain and postulate that this has either arisen or been lost following divergence of the major clades. Thus, sequencing of whole VZV genomes collected during an outbreak has provided novel insights into VZV biology, transmission patterns, and (recent) natural history. IMPORTANCE: VZV is a highly infectious virus and the causative agent of chickenpox and shingles, the latter being particularly associated with the risk of painful complications. Seasonal outbreaks of chickenpox are very common among young children, yet little is known about the dynamics of the virus during person-to-person to transmission or whether multiple distinct viruses seed and/or cocirculate during an outbreak. In this study, we have sequenced chickenpox viruses from an outbreak in Guinea Bissau that are supported by detailed epidemiological data. Our data show that multiple different virus strains seeded and were maintained throughout the 6 month outbreak period and that viruses transmitted between individuals accumulated new mutations in specific genomic regions. Of particular interest is the potential coevolution of two distinct parts of the genomes and our calculations of the rate of viral mutation, both of which increase our understanding of how VZV evolves over short periods of time in human populations. PMID- 25275124 TI - Anterograde glycoprotein-dependent transport of newly generated rabies virus in dorsal root ganglion neurons. AB - Rabies virus (RABV) spread is widely accepted to occur only by retrograde axonal transport. However, examples of anterograde RABV spread in peripheral neurons such as dorsal root ganglion (DRG) neurons indicated a possible bidirectional transport by an uncharacterized mechanism. Here, we analyzed the axonal transport of fluorescence-labeled RABV in DRG neurons by live-cell microscopy. Both entry related retrograde transport of RABV after infection at axon endings and postreplicative transport of newly formed virus were visualized in compartmentalized DRG neuron cultures. Whereas entry-related transport at 1.5 MUm/s occurred only retrogradely, after 2 days of infection, multiple particles were observed in axons moving in both the anterograde and retrograde directions. The dynamics of postreplicative retrograde transport (1.6 MUm/s) were similar to those of entry-related retrograde transport. In contrast, anterograde particle transport at 3.4 MUm/s was faster, indicating active particle transport. Interestingly, RABV missing the glycoproteins did not move anterogradely within the axon. Thus, anterograde RABV particle transport depended on the RABV glycoprotein. Moreover, colocalization of green fluorescent protein (GFP)-labeled ribonucleoproteins (RNPs) and glycoprotein in distal axonal regions as well as cotransport of labeled RNPs with membrane-anchored mCherry reporter confirmed that either complete enveloped virus particles or vesicle associated RNPs were transported. Our data show that anterograde RABV movement in peripheral DRG neurons occurs by active motor protein-dependent transport. We propose two models for postreplicative long-distance transport in peripheral neurons: either transport of complete virus particles or cotransport of RNPs and G-containing vesicles through axons to release virus at distal sites of infected DRG neurons. IMPORTANCE: Rabies virus retrograde axonal transport by dynein motors supports virus spread over long distances and lethal infection of the central nervous system. Though active rabies virus transport has been widely accepted to be unidirectional, evidence for anterograde spread in peripheral neurons supports the hypothesis that in some neurons RABV also enters the anterograde pathway by so-far unknown mechanisms. By live microscopy we visualized fast anterograde axonal transport of rabies virus. The velocities exceeded those of retrograde movements, suggesting that active, most likely kinesin-dependent transport machineries are involved. Dependency of anterograde transport on the expression of virus glycoprotein G and cotransport with vesicles further suggest that complete enveloped virus particles or cotransport of virus ribonucleoprotein and G-containing vesicles occurred. These data provide the first insight in the mechanism of anterograde rabies virus transport and substantially contribute to the understanding of RABV replication and spread of newly formed virus in peripheral neurons. PMID- 25275126 TI - Nipah virion entry kinetics, composition, and conformational changes determined by enzymatic virus-like particles and new flow virometry tools. AB - Virus-cell membrane fusion is essential for enveloped virus infections. However, mechanistic viral membrane fusion studies have predominantly focused on cell-cell fusion models, largely due to the low availability of technologies capable of characterizing actual virus-cell membrane fusion. Although cell-cell fusion assays are valuable, they do not fully recapitulate all the variables of virus cell membrane fusion. Drastic differences between viral and cellular membrane lipid and protein compositions and curvatures exist. For biosafety level 4 (BSL4) pathogens such as the deadly Nipah virus (NiV), virus-cell fusion mechanistic studies are notably cumbersome. To circumvent these limitations, we used enzymatic Nipah virus-like-particles (NiVLPs) and developed new flow virometric tools. NiV's attachment (G) and fusion (F) envelope glycoproteins mediate viral binding to the ephrinB2/ephrinB3 cell receptors and virus-cell membrane fusion, respectively. The NiV matrix protein (M) can autonomously induce NiV assembly and budding. Using a beta-lactamase (betaLa) reporter/NiV-M chimeric protein, we produced NiVLPs expressing NiV-G and wild-type or mutant NiV-F on their surfaces. By preloading target cells with the betaLa fluorescent substrate CCF2-AM, we obtained viral entry kinetic curves that correlated with the NiV-F fusogenic phenotypes, validating NiVLPs as suitable viral entry kinetic tools and suggesting overall relatively slower viral entry than cell-cell fusion kinetics. Additionally, the proportions of F and G on individual NiVLPs and the extent of receptor-induced conformational changes in NiV-G were measured via flow virometry, allowing the proper interpretation of the viral entry kinetic phenotypes. The significance of these findings in the viral entry field extends beyond NiV to other paramyxoviruses and enveloped viruses. IMPORTANCE: Virus-cell membrane fusion is essential for enveloped virus infections. However, mechanistic viral membrane fusion studies have predominantly focused on cell-cell fusion models, largely due to the low availability of technologies capable of characterizing actual virus-cell membrane fusion. Although cell-cell fusion assays are valuable, they do not fully recapitulate all the variables of virus cell membrane fusion. For example, drastic differences between viral and cellular membrane lipid and protein compositions and curvatures exist. For biosafety level 4 (BSL4) pathogens such as the deadly Nipah virus (NiV), virus-cell fusion mechanistic studies are especially cumbersome. To circumvent these limitations, we used enzymatic Nipah virus-like-particles (NiVLPs) and developed new flow virometric tools. Our new tools allowed us the high-throughput measurement of viral entry kinetics, glycoprotein proportions on individual viral particles, and receptor-induced conformational changes in viral glycoproteins on viral surfaces. The significance of these findings extends beyond NiV to other paramyxoviruses and enveloped viruses. PMID- 25275125 TI - Cooperativity among Rev-associated nuclear export signals regulates HIV-1 gene expression and is a determinant of virus species tropism. AB - Murine cells exhibit a profound block to HIV-1 virion production that was recently mapped to a species-specific structural attribute of the murine version of the chromosomal region maintenance 1 (mCRM1) nuclear export receptor and rescued by the expression of human CRM1 (hCRM1). In human cells, the HIV-1 Rev protein recruits hCRM1 to intron-containing viral mRNAs encoding the Rev response element (RRE), thereby facilitating viral late gene expression. Here we exploited murine 3T3 fibroblasts as a gain-of-function system to study hCRM1's species specific role in regulating Rev's effector functions. We show that Rev is rapidly exported from the nucleus by mCRM1 despite only weak contributions to HIV-1's posttranscriptional stages. Indeed, Rev preferentially accumulates in the cytoplasm of murine 3T3 cells with or without hCRM1 expression, in contrast to human HeLa cells, where Rev exhibits striking en masse transitions between the nuclear and cytoplasmic compartments. Efforts to bias Rev's trafficking either into or out of the nucleus revealed that Rev encoding a second CRM1 binding domain (Rev-2xNES) or Rev-dependent viral gag-pol mRNAs bearing tandem RREs (GP 2xRRE), rescue virus particle production in murine cells even in the absence of hCRM1. Combined, these results suggest a model wherein Rev-associated nuclear export signals cooperate to regulate the number or quality of CRM1's interactions with viral Rev/RRE ribonucleoprotein complexes in the nucleus. This mechanism regulates CRM1-dependent viral gene expression and is a determinant of HIV-1's capacity to produce virions in nonhuman cell types. IMPORTANCE: Cells derived from mice and other nonhuman species exhibit profound blocks to HIV-1 replication. Here we elucidate a block to HIV-1 gene expression attributable to the murine version of the CRM1 (mCRM1) nuclear export receptor. In human cells, hCRM1 regulates the nuclear export of viral intron-containing mRNAs through the activity of the viral Rev adapter protein that forms a multimeric complex on these mRNAs prior to recruiting hCRM1. We demonstrate that Rev-dependent gene expression is poor in murine cells despite the finding that, surprisingly, the bulk of Rev interacts efficiently with mCRM1 and is rapidly exported from the nucleus. Instead, we map the mCRM1 defect to the apparent inability of this factor to engage Rev multimers in the context of large viral Rev/RNA ribonucleoprotein complexes. These findings shed new light on HIV-1 gene regulation and could inform the development of novel antiviral strategies that target viral gene expression. PMID- 25275128 TI - The human cytomegalovirus UL26 protein antagonizes NF-kappaB activation. AB - Viral infection frequently triggers activation of host innate immune pathways that attempt to limit viral spread. The NF-kappaB pathway is a critical component that governs this response. We have found that the human cytomegalovirus (HCMV) U(L)26 protein antagonizes NF-kappaB activation. Upon infection, an HCMV strain lacking the U(L)26 gene (DeltaU(L)26) induced the nuclear translocation of the NF kappaB RelB subunit and activated expression and secretion of interleukin-6 (IL 6), an NF-kappaB target gene. The DeltaU(L)26 mutant was also more sensitive to challenge with tumor necrosis factor alpha (TNF-alpha), a canonical NF-kappaB inducer. Further, expression of U(L)26 in the absence of other viral proteins blocked NF-kappaB activation induced by either TNF-alpha treatment or infection with Sendai virus (SeV). Our results indicate that U(L)26 expression is sufficient to block TNF-alpha-induced NF-kappaB nuclear translocation and IkappaB degradation. Last, U(L)26 blocks TNF-alpha-induced IkappaB-kinase (IKK) phosphorylation, a key step in NF-kappaB activation. Combined, our results indicate that U(L)26 is part of a viral program to antagonize innate immunity through modulation of NF-kappaB signaling. IMPORTANCE: The NF-kappaB signaling pathway regulates innate immunity, an integral host process that limits viral pathogenesis. Viruses have evolved mechanisms to modulate NF-kappaB signaling to ensure their replication. HCMV is a major cause of birth defects and disease in immunosuppressed populations. HCMV is known to actively target the NF-kappaB pathway, which is important for HCMV infection. Our results indicate that the HCMV U(L)26 gene is a key modulator of NF-kappaB pathway activity. We find the U(L)26 gene is both necessary and sufficient to block NF-kappaB activation upon challenge with antiviral cytokines. Further, U(L)26 attenuates the phosphorylation and activation of a key NF-kappaB activating kinase complex, IKK. Our study provides new insight into how HCMV targets the NF-kappaB pathway. Given its importance to viral infection, the mechanisms through which viruses target the NF-kappaB pathway highlight areas of vulnerability that could be therapeutically targeted to attenuate viral replication. PMID- 25275127 TI - HIV-1 Nef and Vpu are functionally redundant broad-spectrum modulators of cell surface receptors, including tetraspanins. AB - HIV-1 Nef and Vpu are thought to optimize virus replication in the infected host, at least in part via their ability to interfere with vesicular host cell trafficking. Despite the use of distinct molecular mechanisms, Nef and Vpu share specificity for some molecules such as CD4 and major histocompatibility complex class I (MHC-I), while disruption of intracellular transport of the host cell restriction factor CD317/tetherin represents a specialized activity of Vpu not exerted by HIV-1 Nef. To establish a profile of host cell receptors whose intracellular transport is affected by Nef, Vpu, or both, we comprehensively analyzed the effect of these accessory viral proteins on cell surface receptor levels on A3.01 T lymphocytes. Thirty-six out of 105 detectable receptors were significantly downregulated by HIV-1 Nef, revealing a previously unappreciated scope with which HIV-1 Nef remodels the cell surface of infected cells. Remarkably, the effects of HIV-1 Vpu on host cell receptor exposure largely matched those of HIV-1 Nef in breadth and specificity (32 of 105, all also targeted by Nef), even though the magnitude was generally less pronounced. Of particular note, cell surface exposure of all members of the tetraspanin (TSPAN) protein family analyzed was reduced by both Nef and Vpu, and the viral proteins triggered the enrichment of TSPANs in a perinuclear area of the cell. While Vpu displayed significant colocalization and physical association with TSPANs, interactions of Nef with TSPANs were less robust. TSPANs thus emerge as a major target of deregulation in host cell vesicular transport by HIV-1 Nef and Vpu. The conservation of this activity in two independent accessory proteins suggests its importance for the spread of HIV-1 in the infected host. IMPORTANCE: In this paper, we define that HIV-1 Nef and Vpu display a surprising functional overlap and affect the cell surface exposure of a previously unexpected breadth of cellular receptors. Our analyses furthermore identify the tetraspanin protein family as a previously unrecognized target of Nef and Vpu activity. These findings have implications for the interpretation of effects detected for these accessory gene products on individual host cell receptors and illustrate the coevolution of Nef and Vpu function. PMID- 25275129 TI - The 2'-5'-oligoadenylate synthetase 3 enzyme potently synthesizes the 2'-5' oligoadenylates required for RNase L activation. AB - The members of the oligoadenylate synthetase (OAS) family of proteins are antiviral restriction factors that target a wide range of RNA and DNA viruses. They function as intracellular double-stranded RNA (dsRNA) sensors that, upon binding to dsRNA, undergo a conformational change and are activated to synthesize 2'-5'-linked oligoadenylates (2-5As). 2-5As of sufficient length act as second messengers to activate RNase L and thereby restrict viral replication. We expressed human OAS3 using the baculovirus system and purified it to homogeneity. We show that recombinant OAS3 is activated at a substantially lower concentration of dsRNA than OAS1, making it a potent in vivo sensor of dsRNA. Moreover, we find that OAS3 synthesizes considerably longer 2-5As than previously reported, and that OAS3 can activate RNase L intracellularly. The combined high affinity for dsRNA and the capability to produce 2-5As of sufficient length to activate RNase L suggests that OAS3 is a potent activator of RNase L. In addition, we provide experimental evidence to support one active site of OAS3 located in the C terminal OAS domain and generate a low-resolution structure of OAS3 using SAXS. IMPORTANCE: We are the first to purify the OAS3 enzyme to homogeneity, which allowed us to characterize the mechanism utilized by OAS3 and identify the active site. We provide compelling evidence that OAS3 can produce 2'-5'-oligoadenylates of sufficient length to activate RNase L. This is contrary to what is described in the current literature but agrees with recent in vivo data showing that OAS3 harbors an antiviral activity requiring RNase L. Thus, our work redefines our understanding of the biological role of OAS3. Furthermore, we used a combination of mutagenesis and small-angle X-ray scattering to describe the active site and low-resolution structure of OAS3. PMID- 25275130 TI - HIV-1 envelope glycan moieties modulate HIV-1 transmission. AB - The HIV-1 envelope protein (Env) is heavily glycosylated, with approximately 50% of the Env molecular mass being contributed by N-glycans. HIV-1 Env N-glycans shield the protein backbone and have been shown to play key roles in determining Env structure, surface exposure, and, consequently, antigenicity, infectivity, antibody neutralization, and carbohydrate and receptor binding. Studies of HIV-1 glycosylation have focused mainly on the position of glycosylation, rather than the types of glycans. Also, the role of Env glycan moieties on HIV-1 transmission has not been systematically defined. Using viruses with modified Env glycan content and heterogeneity, we examined the effects of Env glycan moieties on the major events of HIV-1 transmission. Compared to viruses with less oligomannose and more complex Env glycans, viruses with more oligomannose and less complex glycans more efficiently (i) transcytosed across an epithelial cell monolayer, (ii) attached to monocyte-derived macrophages (MDMs), (iii) bound monocyte derived dendritic cells (MoDCs), and (iv) trans-infected primary lymphocytes via MoDCs. However, viruses with more oligomannose and less complex glycans displayed impaired infectivity in TZMbl cells, MDMs, primary lymphocytes, and fresh human intestinal tissue. Thus, N-linked Env glycans display discordant effects on the major events of HIV-1 transmission, with mature oligosaccharide structures on Env playing a crucial role in HIV-1 infection. Env glycosylation should be taken into consideration in the development of vaccine strategies to interdict HIV-1 transmission. IMPORTANCE: HIV-1 Env N-glycans shield the protein backbone and play key roles in determining Env structure and surface exposure, thereby impacting Env antigenicity, infectivity, antibody neutralization, and carbohydrate and receptor binding. Studies of HIV-1 glycosylation have focused mainly on the position of glycosylation, rather than the types of glycans. In the study described in this report, we investigated systematically the role of Env glycan moieties on HIV-1 transmission. We show that N-linked Env glycans display discordant effects on the major events of HIV-1 transmission. These data indicate that Env glycan moieties impact HIV-1 transmission and that modulation of Env glycan moieties offers a potential strategy for the development of therapeutic or prophylactic vaccines against HIV-1. PMID- 25275131 TI - Vaccine-induced CD107a+ CD4+ T cells are resistant to depletion following AIDS virus infection. AB - CD4(+) T-cell responses are crucial for effective antibody and CD8(+) T-cell induction following virus infection. However, virus-specific CD4(+) T cells can be preferential targets for human immunodeficiency virus (HIV) infection. HIV specific CD4(+) T-cell induction by vaccination may thus result in enhancement of virus replication following infection. In the present study, we show that vaccine elicited CD4(+) T cells expressing CD107a are relatively resistant to depletion in a macaque AIDS model. Comparison of virus-specific CD107a, macrophage inflammatory protein-1beta, gamma interferon, tumor necrosis factor alpha, and interleukin-2 responses in CD4(+) T cells of vaccinated macaques prechallenge and 1 week postchallenge showed a significant reduction in the CD107a(-) but not the CD107a(+) subset after virus exposure. Those vaccinees that failed to control viremia showed a more marked reduction and exhibited significantly higher viral loads at week 1 than unvaccinated animals. Our results indicate that vaccine induced CD107a(-) CD4(+) T cells are depleted following virus infection, suggesting a rationale for avoiding virus-specific CD107a(-) CD4(+) T-cell induction in HIV vaccine design. IMPORTANCE: Induction of effective antibody and/or CD8(+) T-cell responses is a principal vaccine strategy against human immunodeficiency virus (HIV) infection. CD4(+) T-cell responses are crucial for effective antibody and CD8(+) T-cell induction. However, virus-specific CD4(+) T cells can be preferential targets for HIV infection. Here, we show that vaccine induced virus-specific CD107a(-) CD4(+) T cells are largely depleted following infection in a macaque AIDS model. While CD4(+) T-cell responses are important in viral control, our results indicate that virus-specific CD107a(-) CD4(+) T-cell induction by vaccination may not lead to efficient CD4(+) T-cell responses following infection but rather be detrimental and accelerate viral replication in the acute phase. This suggests that HIV vaccine design should avoid virus specific CD107a(-) CD4(+) T-cell induction. Conversely, this study found that vaccine-induced CD107a(+) CD4(+) T cells are relatively resistant to depletion following virus challenge, implying that induction of these cells may be an alternative approach toward HIV control. PMID- 25275132 TI - Expression of the human cytomegalovirus UL11 glycoprotein in viral infection and evaluation of its effect on virus-specific CD8 T cells. AB - The human cytomegalovirus (CMV) UL11 open reading frame (ORF) encodes a putative type I transmembrane glycoprotein which displays remarkable amino acid sequence variability among different CMV isolates, suggesting that it represents an important virulence factor. In a previous study, we have shown that UL11 can interact with the cellular receptor tyrosine phosphatase CD45, which has a central role for signal transduction in T cells, and treatment of T cells with large amounts of a soluble UL11 protein inhibited their proliferation. In order to analyze UL11 expression in CMV-infected cells, we constructed CMV recombinants whose genomes either encode tagged UL11 versions or carry a stop mutation in the UL11 ORF. Moreover, we examined whether UL11 affects the function of virus specific cytotoxic T lymphocytes (CTLs). We found that the UL11 ORF gives rise to several proteins due to both posttranslational modification and alternative translation initiation sites. Biotin labeling of surface proteins on infected cells indicated that only highly glycosylated UL11 forms are present at the plasma membrane, whereas less glycosylated UL11 forms were found in the endoplasmic reticulum. We did not find evidence of UL11 cleavage or secretion of a soluble UL11 version. Cocultivation of CTLs recognizing different CMV epitopes with fibroblasts infected with a UL11 deletion mutant or the parental strain revealed that under the conditions applied UL11 did not influence the activation of CMV-specific CD8 T cells. For further studies, we propose to investigate the interaction of UL11 with CD45 and the functional consequences in other immune cells expressing CD45. IMPORTANCE: Human cytomegalovirus (CMV) belongs to those viruses that extensively interfere with the host immune response, yet the precise function of many putative immunomodulatory CMV proteins remains elusive. Previously, we have shown that the CMV UL11 protein interacts with the leukocyte common antigen CD45, a cellular receptor tyrosine phosphatase with a central role for signal transduction in T cells. Here, we examined the proteins expressed by the UL11 gene in CMV-infected cells and found that at least one form of UL11 is present at the cell surface, enabling it to interact with CD45 on immune cells. Surprisingly, CMV-expressed UL11 did not affect the activity of virus-specific CD8 T cells. This finding warrants investigation of the impact of UL11 on CD45 functions in other leukocyte subpopulations. PMID- 25275133 TI - Recombinant hepatitis C virus envelope glycoprotein vaccine elicits antibodies targeting multiple epitopes on the envelope glycoproteins associated with broad cross-neutralization. AB - Although effective hepatitis C virus (HCV) antivirals are on the horizon, a global prophylactic vaccine for HCV remains elusive. The diversity of the virus is a major concern for vaccine development; there are 7 major genotypes of HCV found globally. Therefore, a successful vaccine will need to protect against HCV infection by all genotypes. Despite the diversity, many monoclonal antibodies (MAbs) with broadly cross-neutralizing activity have been described, suggesting the presence of conserved epitopes that can be targeted to prevent infection. Similarly, a vaccine comprising recombinant envelope glycoproteins (rE1E2) derived from the genotype 1a HCV-1 strain has been shown to be capable of eliciting cross-neutralizing antibodies in guinea pigs, chimpanzees, and healthy human volunteers. In order to investigate the basis for this cross neutralization, epitope mapping of anti-E1E2 antibodies present within antisera from goats and humans immunized with HCV-1 rE1E2 was conducted through peptide mapping and competition studies with a panel of cross-neutralizing MAbs targeting various epitopes within E1E2. The immunized-goat antiserum was shown to compete with the binding of all MAbs tested (AP33, HC33.4, HC84.26, 1:7, AR3B, AR4A, AR5A, IGH526, and A4). Antisera showed the best competition against HC84.26 and AR3B and the weakest competition against AR4A. Furthermore, antisera from five immunized human vaccinees were shown to compete with five preselected MAbs (AP33, AR3B, AR4A, AR5A, and IGH526). These data show that immunization with HCV-1 rE1E2 elicits antibodies targeting multiple cross-neutralizing epitopes. Our results further support the use of such a vaccine antigen to induce cross-genotype neutralization. IMPORTANCE: An effective prophylactic vaccine for HCV is needed for optimal control of the disease burden. The high diversity of HCV has posed a challenge for developing vaccines that elicit neutralizing antibodies for protection against infection. Despite this, we have previously shown that a vaccine comprising recombinant envelope glycoproteins derived from a single genotype 1a strain was capable of eliciting a cross-neutralizing antibody response in human volunteers. Here, we have used competition binding assays and peptide binding assays to show that antibodies present in the antisera from vaccinated goats and humans bind epitopes overlapping with those of a variety of well-characterized cross-neutralizing monoclonal antibodies. This provides a mechanism for the cross-neutralizing human antisera: antibodies present in the antisera bind to conserved regions associated with cross-neutralization. Importantly, this work provides further support for a vaccine comprising recombinant envelope glycoproteins, perhaps in a formulation with a vaccine component eliciting strong anti-HCV CD4(+) and CD8(+) T cell responses. PMID- 25275134 TI - Linking pig-tailed macaque major histocompatibility complex class I haplotypes and cytotoxic T lymphocyte escape mutations in simian immunodeficiency virus infection. AB - The influence of major histocompatibility complex class I (MHC-I) alleles on human immunodeficiency virus (HIV) diversity in humans has been well characterized at the population level. MHC-I alleles likely affect viral diversity in the simian immunodeficiency virus (SIV)-infected pig-tailed macaque (Macaca nemestrina) model, but this is poorly characterized. We studied the evolution of SIV in pig-tailed macaques with a range of MHC-I haplotypes. SIV(mac251) genomes were amplified from the plasma of 44 pig-tailed macaques infected with SIV(mac251) at 4 to 10 months after infection and characterized by Illumina deep sequencing. MHC-I typing was performed on cellular RNA using Roche/454 pyrosequencing. MHC-I haplotypes and viral sequence polymorphisms at both individual mutations and groups of mutations spanning 10-amino-acid segments were linked using in-house bioinformatics pipelines, since cytotoxic T lymphocyte (CTL) escape can occur at different amino acids within the same epitope in different animals. The approach successfully identified 6 known CTL escape mutations within 3 Mane-A1*084-restricted epitopes. The approach also identified over 70 new SIV polymorphisms linked to a variety of MHC-I haplotypes. Using functional CD8 T cell assays, we confirmed that one of these associations, a Mane B028 haplotype-linked mutation in Nef, corresponded to a CTL epitope. We also identified mutations associated with the Mane-B017 haplotype that were previously described to be CTL epitopes restricted by Mamu-B*017:01 in rhesus macaques. This detailed study of pig-tailed macaque MHC-I genetics and SIV polymorphisms will enable a refined level of analysis for future vaccine design and strategies for treatment of HIV infection. IMPORTANCE: Cytotoxic T lymphocytes select for virus escape mutants of HIV and SIV, and this limits the effectiveness of vaccines and immunotherapies against these viruses. Patterns of immune escape variants are similar in HIV type 1-infected human subjects that share the same MHC-I genes, but this has not been studied for SIV infection of macaques. By studying SIV sequence diversity in 44 MHC-typed SIV-infected pigtail macaques, we defined over 70 sites within SIV where mutations were common in macaques sharing particular MHC-I genes. Further, pigtail macaques sharing nearly identical MHC-I genes with rhesus macaques responded to the same CTL epitope and forced immune escape. This allows many reagents developed to study rhesus macaques to also be used to study pigtail macaques. Overall, our study defines sites of immune escape in SIV in pigtailed macaques, and this enables a more refined level of analysis of future vaccine design and strategies for treatment of HIV infection. PMID- 25275135 TI - Determinants of efficient degradation of APOBEC3 restriction factors by HIV-1 Vif. AB - The APOBEC3 deoxycytidine deaminases can restrict the replication of HIV-1 in cell culture to differing degrees. The effects of APOBEC3 enzymes are largely suppressed by HIV-1 Vif that interacts with host proteins to form a Cullin5-Ring E3 ubiquitin ligase that induces (48)K-linked polyubiquitination (poly-Ub) and proteasomal degradation of APOBEC3 enzymes. Vif variants have differing abilities to induce degradation of APOBEC3 enzymes and the underlying biochemical mechanisms for these differences is not fully understood. We hypothesized that by characterizing the interaction of multiple APOBEC3 enzymes and Vif variants we could identify common features that resulted in Vif-mediated degradation and further define the determinants required for efficient Vif-mediated degradation of APOBEC3 enzymes. We used Vifs from HIV-1 NL4-3 (IIIB) and HXB2 to characterize their induced degradation of and interaction with APOBEC3G, APOBEC3G D128K, APOBEC3H, and APOBEC3B in 293T cells. We quantified the APOBEC3G-Vif and APOBEC3H Vif interaction strengths in vitro using rotational anisotropy. Our biochemical and cellular analyses of the interactions support a model in which the degradation efficiency of VifIIIB and VifHXB2 correlated with both the binding strength of the APOBEC3-Vif interaction and the APOBEC3-Vif interface, which differs for APOBEC3G and APOBEC3H. Notably, Vif bound to APOBEC3H and APOBEC3B in the natural absence of Vif-induced degradation and the interaction resulted in (63)K-linked poly-Ub of APOBEC3H and APOBEC3B, demonstrating additional functionality of the APOBEC3-Vif interaction apart from induction of proteasomal degradation. IMPORTANCE: APOBEC3 enzymes can potently restrict the replication of HIV-1 in the absence of HIV-1 Vif. Vif suppresses APOBEC3 action by inducing their degradation through a direct interaction with APOBEC3 enzymes and other host proteins. Vif variants from different HIV-1 strains have different effects on APOBEC3 enzymes. We used differing Vif degradation capacities of two Vif variants and various APOBEC3 enzymes with differential sensitivities to Vif to delineate determinants of the APOBEC3-Vif interaction that are required for inducing efficient degradation. Using a combined biochemical and cellular approach we identified that the strength of the APOBEC3-Vif binding interaction and the APOBEC3-Vif interface are determinants for degradation efficiency. Our results highlight the importance of using Vif variants with different degradation potential when delineating mechanisms of Vif-induced APOBEC3 degradation and identify features important for consideration in the development of HIV-1 therapies that disrupt the APOBEC3-Vif interaction. PMID- 25275137 TI - Kaposi's sarcoma-associated herpesvirus downregulates transforming growth factor beta2 to promote enhanced stability of capillary-like tube formation. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), the most common tumor of AIDS patients worldwide. A key characteristic of KS tumors is extremely high levels of vascular slits and extravasated red blood cells, making neoangiogenesis a key component of the tumor. The main KS tumor cell is the spindle cell, a cell of endothelial origin that maintains KSHV predominantly in the latent state. In cultured endothelial cells, latent KSHV infection induces angiogenic phenotypes, including longer-term stabilization of capillary-like tube formation in Matrigel, a basement membrane matrix. The present studies show that KSHV infection of endothelial cells strongly downregulates transforming growth factor beta2 (TGF-beta2). This downregulation allows the stabilization of capillary-like tube formation during latent infection, as the addition of exogenous TGF-beta2 inhibits the KSHV induced stability of these structures. While two KSHV microRNAs are sufficient to downregulate TGF-beta2 in endothelial cells, they are not required during KSHV infection. However, activation of the gp130 cell surface receptor is both necessary and sufficient for downregulation of TGF-beta2 in KSHV-infected cells. IMPORTANCE: Kaposi's sarcoma is a highly vascularized, endothelial cell-based tumor supporting large amounts of angiogenesis. There is evidence that KSHV, the etiologic agent of KS, induces aberrant angiogenesis. For example, KSHV induces stabilization of capillary-like tube formation in cultured endothelial cells. A clearer understanding of how KSHV regulates angiogenesis could provide potential therapeutic targets for KS. We found that KSHV downregulates TGF-beta2, a cytokine related to TGF-beta1 that is known to inhibit angiogenesis. The downregulation of this inhibitor promotes the stability of capillary-like tube formation insofar as adding back TGF-beta2 to infected cells blocks KSHV-induced long-term tubule stability. Therefore, KSHV downregulation of TGF-beta2 may increase aberrant vascularization in KS tumors through increased capillary formation and thereby aid in KS tumor promotion. PMID- 25275136 TI - Viral reprogramming of the Daxx histone H3.3 chaperone during early Epstein-Barr virus infection. AB - Host chromatin assembly can function as a barrier to viral infection. Epstein Barr virus (EBV) establishes latent infection as chromatin-assembled episomes in which all but a few viral genes are transcriptionally silent. The factors that control chromatin assembly and guide transcription regulation during the establishment of latency are not well understood. Here, we demonstrate that the EBV tegument protein BNRF1 binds the histone H3.3 chaperone Daxx to modulate histone mobility and chromatin assembly on the EBV genome during the early stages of primary infection. We demonstrate that BNRF1 substitutes for the repressive cochaperone ATRX to form a ternary complex of BNRF1-Daxx-H3.3-H4, using coimmunoprecipitation and size-exclusion chromatography with highly purified components. FRAP (fluorescence recovery after photobleaching) assays were used to demonstrate that BNRF1 promotes global mobilization of cellular histone H3.3. Mutation of putative nucleotide binding motifs on BNRF1 attenuates the displacement of ATRX from Daxx. We also show by immunofluorescence combined with fluorescence in situ hybridization that BNRF1 is important for the dissociation of ATRX and Daxx from nuclear bodies during de novo infection of primary B lymphocytes. Virion-delivered BNRF1 suppresses Daxx-ATRX-mediated H3.3 loading on viral chromatin as measured by chromatin immunoprecipitation assays and enhances viral gene expression during early infection. We propose that EBV tegument protein BNRF1 replaces ATRX to reprogram Daxx-mediated H3.3 loading, in turn generating chromatin suitable for latent gene expression. IMPORTANCE: Epstein Barr Virus (EBV) is a human herpesvirus that efficiently establishes latent infection in primary B lymphocytes. Cellular chromatin assembly plays an important role in regulating the establishment of EBV latency. We show that the EBV tegument protein BNRF1 functions to regulate chromatin assembly on the viral genome during early infection. BNRF1 alters the host cellular chromatin assembly to prevent antiviral repressive chromatin and establish chromatin structure permissive for viral gene expression and the establishment of latent infection. PMID- 25275140 TI - Retraction: Microstructural brain abnormalities of children of idiopathic generalized epilepsy with generalized tonic-clonic seizure: a voxel-based diffusional kurtosis imaging study by: Junling Gao, Shi-Ting Feng, Bangxian Wu, Nanjie Gong, Minhua Lu, Po-Man Wu, He Wang, Xiaoming He, and Bingsheng Huang. PMID- 25275139 TI - Genome analysis of the first Marseilleviridae representative from Australia indicates that most of its genes contribute to virus fitness. AB - The family Marseilleviridae consists of Acanthamoeba-infecting large DNA viruses with icosahedral particles ~ 0.2 MUm in diameter and genome sizes in the 346- to 380-kb range. Since the isolation of Marseillevirus from a cooling tower in Paris (France) in 2009, the family Marseilleviridae has expanded rapidly, with representatives from Europe and Africa. Five members have been fully sequenced that are distributed among 3 emerging Marseilleviridae lineages. One comprises Marseillevirus and Cannes 8 virus, another one includes Insectomime virus and Tunisvirus, and the third one corresponds to the more distant Lausannevirus. We now report the genomic characterization of Melbournevirus, the first representative of the Marseilleviridae isolated from a freshwater pond in Melbourne, Australia. Despite the large distance separating this sampling point from France, Melbournevirus is remarkably similar to Cannes 8 virus and Marseillevirus, with most orthologous genes exhibiting more than 98% identical nucleotide sequences. We took advantage of this optimal evolutionary distance to evaluate the selection pressure, expressed as the ratio of nonsynonymous to synonymous mutations for various categories of genes. This ratio was found to be less than 1 for all of them, including those shared solely by the closest Melbournevirus and Cannes 8 virus isolates and absent from Lausannevirus. This suggests that most of the 403 protein-coding genes composing the large Melbournevirus genome are under negative/purifying selection and must thus significantly contribute to virus fitness. This conclusion contrasts with the more common view that many of the genes of the usually more diverse large DNA viruses might be (almost) dispensable. IMPORTANCE: A pervasive view is that viruses are fast-evolving parasites and carry the smallest possible amount of genomic information required to highjack the host cell machinery and perform their replication. This notion, probably inherited from the study of RNA viruses, is being gradually undermined by the discovery of DNA viruses with increasingly large gene content. These viruses also encode a variety of DNA repair functions, presumably slowing down their evolution by preserving their genomes from random alterations. On the other hand, these viruses also encode a majority of proteins without cellular homologs, including many shared only between the closest members of the same family. One may thus question the actual contribution of these anonymous and/or quasi-orphan genes to virus fitness. Genomic comparisons of Marseilleviridae, including a new Marseillevirus isolated in Australia, demonstrate that most of their genes, irrespective of their functions and conservation across families, are evolving under negative selection. PMID- 25275138 TI - Exposure of epitope residues on the outer face of the chikungunya virus envelope trimer determines antibody neutralizing efficacy. AB - Chikungunya virus (CHIKV) is a reemerging alphavirus that causes a debilitating arthritic disease and infects millions of people and for which no specific treatment is available. Like many alphaviruses, the structural targets on CHIKV that elicit a protective humoral immune response in humans are poorly defined. Here we used phage display against virus-like particles (VLPs) to isolate seven human monoclonal antibodies (MAbs) against the CHIKV envelope glycoproteins E2 and E1. One MAb, IM-CKV063, was highly neutralizing (50% inhibitory concentration, 7.4 ng/ml), demonstrated high-affinity binding (320 pM), and was capable of therapeutic and prophylactic protection in multiple animal models up to 24 h postexposure. Epitope mapping using a comprehensive shotgun mutagenesis library of 910 mutants with E2/E1 alanine mutations demonstrated that IM-CKV063 binds to an intersubunit conformational epitope on domain A, a functionally important region of E2. MAbs against the highly conserved fusion loop have not previously been reported but were also isolated in our studies. Fusion loop MAbs were broadly cross-reactive against diverse alphaviruses but were nonneutralizing. Fusion loop MAb reactivity was affected by temperature and reactivity conditions, suggesting that the fusion loop is hidden in infectious virions. Visualization of the binding sites of 15 different MAbs on the structure of E2/E1 revealed that all epitopes are located at the membrane-distal region of the E2/E1 spike. Interestingly, epitopes on the exposed topmost and outer surfaces of the E2/E1 trimer structure were neutralizing, whereas epitopes facing the interior of the trimer were not, providing a rationale for vaccine design and therapeutic MAb development using the intact CHIKV E2/E1 trimer. IMPORTANCE: CHIKV is the most important alphavirus affecting humans, resulting in a chronic arthritic condition that can persist for months or years. In recent years, millions of people have been infected globally, and the spread of CHIKV to the Americas is now beginning, with over 100,000 cases occurring in the Caribbean within 6 months of its arrival. Our study reports on seven human MAbs against the CHIKV envelope, including a highly protective MAb and rarely isolated fusion loop MAbs. Epitope mapping of these MAbs demonstrates how some E2/E1 epitopes are exposed or hidden from the human immune system and suggests a structural mechanism by which these MAbs protect (or fail to protect) against CHIKV infection. Our results suggest that the membrane-distal end of CHIKV E2/E1 is the primary target for the humoral immune response to CHIKV, and antibodies targeting the exposed topmost and outer surfaces of the E2/E1 trimer determine the neutralizing efficacy of this response. PMID- 25275141 TI - Andres Carrasco (1946-2014). PMID- 25275142 TI - Reply by the authors of the original article. PMID- 25275143 TI - PedsQL correlates to PODCI in pediatric orthopaedic outpatient clinic. AB - PURPOSE: Quality-of-life (QOL) measures can be a valuable tool to assess the general welfare across a spectrum of patients in a pediatric orthopaedic outpatient clinic and can be a simple way to assess patient-based outcomes particularly for quality initiatives. The Pediatric Outcomes Data Collection Instrument (PODCI) is validated for many orthopaedic conditions but typically takes around 20 minutes to complete (86 questions). The Pediatric Quality of Life Inventory (PedsQL) takes <4 minutes to complete (23 questions) but has not been assessed in an orthopaedic setting. We initiated this study to find the best method for assessing QOL in our outpatient clinic. A short pediatric QOL measure that is correlated to an established orthopaedic-specific QOL measure is needed; therefore, we compared the PedsQL to the PODCI in the outpatient orthopaedic clinic. METHODS: This was a quality initiative project and as such did not require a priori IRB approval. Families of patients 2 to 18 years old who presented for follow-up after upper or lower extremity fractures or brachial plexus injuries in the orthopaedic clinic from October 2010 through August 2011 were asked to fill out both the PODCI and the PedsQL. Patients aged 5 years and older filled out a patient-report PedsQL; patients aged 11 years and older filled out the patient-report PODCI. Parents/guardians completed questionnaires for children of all ages. Most fracture patients (and/or their parent/guardian) repeated the questionnaires after 6 to 12 weeks. Data were then assessed for correlation between the PODCI and PedsQL. RESULTS: A total of 428 parent/guardian reports for 283 patients and 172 self-reports for 104 patients were included. The correlation between the PODCI Global score and the PedsQL Total score for the parent/guardian-reported questionnaires for all injuries was 0.77 (95% confidence interval, 0.72-0.82). When categorized within domains and injuries, parent/guardian-reported correlations ranged from 0.23 to 0.79. In patients aged 11 years and older, the correlation between the PODCI and PedsQL for the patient reported questionnaire for all injuries was 0.85 (95% confidence interval, 0.80 0.89). When categorized within domains and injuries, patient-reported correlations ranged from 0.30 to 0.99. CONCLUSIONS: Utilizing the substantially shorter PedsQL in a high volume orthopaedic clinic as a substitute for the PODCI for quality improvement measures seems reasonable. Correlation between the PedsQL Global score and the PODCI Total score for orthopaedic patients is strong. Utilizing the patient-reported questionnaires when age appropriate is best. In this era of increased outcome reporting, PedsQL may be a valuable tool. PMID- 25275144 TI - Work-life balance: Kid-friendly digs. PMID- 25275145 TI - It's a big world out there. By Caveman. PMID- 25275146 TI - Isopropoxy-carvacrol, a derivative obtained from carvacrol, reduces acute inflammation and nociception in rodents. AB - Monoterpenes, compounds mainly presented in essential oils, have important pharmacological actions. Isopropoxy-carvacrol (IPC) is a derivative of the monoterpene carvacrol, and its pharmacological properties have not yet been investigated. The aim of this study was to analyse the acute anti-inflammatory and antinociceptive properties of IPC. Mice (25-30 g) and rats (150-230 g) were pre-treated (i.p.) with IPC at the doses of 10, 30 or 100 mg/kg or vehicle (Tween 80, 0.5%), 30 min. before injection of the phlogistic agents. Both the first and the second phases of formalin-induced nociception were significantly reduced by IPC (100 mg/kg). Injection of carrageenan in mice paw reduced the threshold of stimulus intensity, applied with an analgesymeter, necessary to cause paw withdrawal, which was significantly reduced by 100 mg/kg of IPC. The area under curve (0-4 hr) of rat paw oedema induced by injection of carrageenan was also significantly diminished by the administration of IPC (100 mg/kg). Administration of 12-O-tetradecanoylphorbol-13-acetate (TPA) markedly increased mice ear oedema and myeloperidase (MPO) activity. Topical co-administration of IPC (0.3-3 mg/ear) during the induction did not affect TPA-induced ear oedema, but significantly decreased MPO activity in the ears, when compared with the vehicle. In in vitro experiments, IPC reduced lipoperoxidation induced by different stimuli, showed nitric oxide scavenger activity and did not interfere with murine macrophage viability in concentrations up to 100 lg/mL. These results demonstrate that IPC exerts acute anti-inflammatory and antinociceptive activities, suggesting that it may represent an alternative in the development of new future therapeutic strategies. PMID- 25275147 TI - Structure-activity relationship of terpenes with anti-inflammatory profile - a systematic review. AB - Inflammation is a complex biological response that in spite of having available treatments, their side effects limit their usefulness. Because of this, natural products have been the subject of incessant studies, among which the class of terpenes stands out. They have been the source of study for the development of anti-inflammatory drugs, once their chemical diversity is well suited to provide skeleton for future anti-inflammatory drugs. This systematic review reports the studies present in the literature that evaluate the anti-inflammatory activity of terpenes suffering any change in their structures, assessing whether these changes also brought changes in their effects. The search terms anti-inflammatory agents, terpenes, and structure-activity relationship were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between January 2002 and August 2013. Twenty-seven papers were found concerning the structural modification of terpenes with the evaluation of antiinflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti-inflammatory drugs. PMID- 25275149 TI - Singapore/world: Trade fairs shunned. PMID- 25275150 TI - New Zealand: Industry spins doubt on plain packs. PMID- 25275151 TI - UK: Lifesaving Quit campaign awarded. PMID- 25275148 TI - Ubiquitination of pattern recognition receptors in plant innate immunity. AB - Lacking an adaptive immune system, plants largely rely on plasma membrane resident pattern recognition receptors (PRRs) to sense pathogen invasion. The activation of PRRs leads to the profound immune responses that coordinately contribute to the restriction of pathogen multiplication. Protein post translational modifications dynamically shape the intensity and duration of the signalling pathways. In this review, we discuss the specific regulation of PRR activation and signalling by protein ubiquitination, endocytosis and degradation, with a particular focus on the bacterial flagellin receptor FLS2 (flagellin sensing 2) in Arabidopsis. PMID- 25275152 TI - Canada: Twisting the legacy name. PMID- 25275153 TI - WHO Alliance for the Global Elimination of Blinding Trachoma by the year 2020. Progress report on elimination of trachoma, 2013. PMID- 25275154 TI - Proceedings of the 22nd Annual Meeting of Intelligent Systems for Molecular Biology (ISMB), July 11-15, 2014, Boston, MA. PMID- 25275156 TI - Proceedings of the Third Asian-Pacific Topic Conference (APTC2012): Nutrition related disorders and digestive system, November 2-3, 2012, Tokyo, Japan. PMID- 25275155 TI - Proceedings of the Workshop on Cancer stem cells: the mechanisms of radioresistance and biomarker discovery, 23-24 September, 2013, Dresden, Germany. PMID- 25275157 TI - Proceedings of the Diagnostic Criteria in Autoimmune Diseases, 9th International Congress on Autoimmunity, March 26-30, 2014, Nice, France. PMID- 25275158 TI - Proceedings of the Eleventh International Symposium on the Maillard reaction, September 16-20, 2012, Nancy, France. PMID- 25275159 TI - Proceedings of Eighth International Hematologic Malignancies 2012 Conference, October 10-14, 2012, Houston, TX. PMID- 25275160 TI - Proceedings of the 44th Annual Meeting of the American Pediatric Surgical Association, 2-5 May, 2013, Marco Island, FL. PMID- 25275161 TI - Proceedings of the 6th Dubrovnik International Conference on Multiple Sclerosis, 10-12 May 2012, Dubrovnik, Croatia. PMID- 25275162 TI - Special issue of Connective Tissue Research dedicated to Arthur Veis. PMID- 25275163 TI - Proceedings of the 4th International Conference on Metallomics, July 8-11, 2013, Oviedo, Spain. PMID- 25275164 TI - Retraction notice to: SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. PMID- 25275165 TI - Investigation of the influence of vanadium compounds treatment in NZO mice model- preliminary study. AB - Abstract: New Zealand obese mice (NZO) are characterized by symptoms similar to human metabolic syndrome. Vanadium in different investigations showed anti diabetic activity but until now an NZO mice model has not been tested with this element. The aim of this study was to investigate anti-diabetic activity of three vanadium compounds (VOSO4, VO(mal)2 and Na(VO(O2)2bpy) x 8H2O) in the NZO model. Metabolic syndrome was induced by special diet (1.5% of cholesterol and 15% of saturated fatty acids) during 8 weeks. In the next 5 weeks, the tested vanadium compounds were administered once daily, in a dose of 0.063 mmol/kg of body mass. At the end of the experiment, glucose, cholesterol, triglycerides and alanine transaminase were measured in the serum. The obtained results showed that the glucose level was decreased nearly to the healthy NZO mice in comparison to the NZO mice with metabolic syndrome. In all groups on the diet with cholesterol, the level of this parameter was statistically higher in comparison to the group without cholesterol addition. Vanadium treatment in a dose 0.063 mmol/kg of body mass does not influence cholesterol, triglycerides and alanine transaminase activity. PMID- 25275166 TI - Education - an important prescription for health. PMID- 25275167 TI - Conclusions. PMID- 25275168 TI - Reply to Reshef et al.: Falsifiability or bust. PMID- 25275169 TI - Reply to Brunet and Doolittle: Both selected effect and causal role elements can influence human biology and disease. PMID- 25275170 TI - Optimization of a Raman microscopy technique to efficiently detect amorphous amorphous phase separation in freeze-dried protein formulations. AB - A confocal Raman microscopic technique was optimized to more efficiently detect amorphous-amorphous phase separation in freeze-dried protein formulations. A Renishaw Raman inVia confocal microscope was used to collect 100-200 MUm line maps (2 MUm step size) of freeze-dried protein-excipient formulations. At each point across the line map, the composition was evaluated from the intensity of the nonoverlapping peaks representative of each component. Collection aperture, scan time, and line map length significantly contributed to the phase-separation analysis, whereas different sample preparation methods did not affect the analysis. Using the optimized parameters (i.e., large aperture 5 s scan time, 200 MUm line map), phase separation was successfully detected in binary polymer formulations and was comparable to the previously developed Raman method. However, the previous method required 2.5 h/sample, whereas the optimized method only requires 0.5 h/sample. Phase separation was detected in the following protein-excipient formulations: lysozyme-trehalose (1:1), lysozyme-isomaltose (1:1), beta-lactoglobulin-dextran (1:1), beta-lactoglobulin-dextran (1:3), and beta-lactoglobulin-trehalose (1:1). Phase separation was not detected in lysozyme sucrose (1:1) and beta-lactoglobulin-sucrose (1:1) formulations. The optimized method successfully detected phase separation in several protein formulations, where phase separation was previously suspected, and promised to be a useful tool for detection of phase separation in amorphous therapeutic formulations. PMID- 25275171 TI - Author response. PMID- 25275173 TI - EAPCI focus on GACI, the French Coronary Atheroma and Interventional Cardiology Group: an interview with the president, Rene Koning. PMID- 25275172 TI - Author response. PMID- 25275174 TI - Systemic pesticide concerns extend beyond the bees. PMID- 25275175 TI - Stephen F. Goodwin. PMID- 25275176 TI - [Age-specific changes in the cerebral cortex capillaries]. AB - The present paper reports an attempt to determine the biological age in man based on the results of the studies of the capillary bed of the cerebral cortex in different periods of postnatal ontogenesis (from 1 month to 83 years). The material was investigated by histological and histochemical methods. It is concluded that the data obtained concerning the structural and functional changes in the capillaries of different regions of the olfactory brain can be used for the personality identification for the purpose of forensic medical expertise. PMID- 25275177 TI - [The new working classification of blood stain patterns]. AB - The results of analysis of the existing classifications of blood stain patterns indicate that systematization of the morphological characteristics of blood stains requires that mechanisms and circumstances of the injury, properties of the surfaces receiving blood stains and the objects leaving them should be taken into consideration. The new working classification of blood stain patterns has been developed for the purposes of forensic medical expertise satisfying the above requirements. It makes it possible to pass to the next stage of research on systematization of the general and specific morphological features of blood stains depending on concrete circumstances of bodily injuries. PMID- 25275178 TI - [The specific mechanism of bruising inflicted by rubber bullets of traumatic weapons]. AB - The objective of the present study was to elucidate the specific features of the injuries inflicted by rubber bullets of traumatic weapons based on the results of real and experimental observations. Morphological characteristics of external lesions are presented as determined by peculiarities of tissue destruction caused by mechanical impact. Metric characteristics of morphological features of contour (circular) bruises and elastic projectiles coincide with the dimensional ratio in the model of interaction of interest, i.e. the action of a dull indenter on the elastoplastic semispace. PMID- 25275179 TI - [Peculiarities of the driver's position in cars of various types influencing biomechanics of body movements in the case of emergency break application]. AB - The objective of the present work was to determine the mean angles between different body segments of the car drivers depending on their position in various types of the vehicles ("sedan", "crossover", "minivan") at the moment immediately preceding emergency break application. The study was based on the experimental data obtained with the participation of volunteers and the results of simulation. These materials were treated with the use of the arithmetic mean, mean square deviation, and mean error. The rank correlation method was employed. The significance of the difference between the quantities of interest was estimated with the use of Student's t-table. The angles between different body segments of the car drivers depending on their position in various types of the vehicles ("sedan", "crossover", "minivan") were measured. The data obtained confirm that peculiarities of the driver's position in the car determine the mechanisms of the injuries related to a car incident. PMID- 25275181 TI - [On the use of the spectral speech characteristics for the determination of biometric parameters of the vocal tract in forensic medical identification of the speaker's personality]. AB - The objective of the present study was to elucidate the relationship between the spectral speech characteristics and the biometric parameters of the speaker's vocal tract. The secondary objective was to consider the theoretical basis behind the medico-criminalistic personality identification from the biometric parameters of the speaker's vocal tract. The article is based on the results of real forensic medical investigations and the literature data. PMID- 25275180 TI - [Forensic medical evaluation of hereditary predisposition to thrombophilia in the case of thrombotic complications of a mechanical injury]. AB - The objective of the present work was to develop the forensic medical criteria for the assessment of the significance of hereditary predisposition to thrombophilia in the case of thrombotic complications of a mechanical injury. The results of analysis of the frequency of genes responsible for hereditary predisposition to thrombogenesis (FII, FV, MTHFR, FGB, PAL-1) among the victims of mechanical injuries are presented. A total of 251 subjects were available for the examination. They were divided into 4 groups as follows: the subjects presenting with deep venous thrombosis in the lower extremities (DVTLE) after the injury (group 1), subjects with DVTLE without the preceding trauma (group 2), those with an injury to the locomotor apparatus without a subsequent thrombotic complication (group 3), and practically healthy persons (group 4). It was shown that the subjects of group I had the highest frequency of mutations and polymorphisms of MTHFR and PAl-1 genes. It is concluded that genetic typing for the detection of mutations in these two genes is indispensable for the subjects presenting with thrombotic complications after mechanical injuries to the locomotor organs. PMID- 25275182 TI - [The morphofunctional changes in the rat lung tissue during simulation of acute fatal poisoning with household gas]. AB - The methods of light microscopy, immunohistochemistry, and electron microscopy were employed to study the morphofunctional changes in epithelium of bronchial and respiratory segments of the rat lungs used as models of acute fatal poisoning with household gas. It was shown that this toxic effect induces the pathological process involving all the elements of the epithelial layer in the bronchial and respiratory segments of the lungs of experimental animals. At the ultrastructural level, mitochondria and endoplasmic reticulum structures are affected, with the death of epithelial cells leading to the damage of the aerohematic barrier. The toxic effect of the gaseous mixture on the membranes causes the destruction of various elements of the epithelial layer. The results of this study help to understand the mechanisms of death in the case of acute fatal poisoning with household gas. PMID- 25275183 TI - [Changes in the biochemical, chemical and toxicological characteristics of pericardial fluid in the case of fatal narcotic intoxication]. AB - This article describes the biochemical and chemical-toxicological investigations into the properties of the pericardial fluid designed to improve the effectiveness of forensic medical examination of the cases of fatal drug poisoning. The objectives of the study were the detection and determination of the type of narcotic substances in the pericardial fluid, evaluation of the quantitative changes in enzyme activities (AST, ALT and CPK) in the pericardial fluid, and the development of the criteria for the forensic medical diagnostics of fatal drug poisoning. The materials used in the study were the pericardial fluid and blood taken during forensic medical examination of 247 corpses of men (87.04%) and women (12.96%) at the age from 13 to 35 years who died from different causes. They were divided into two groups. The study group was comprised of 142 subjects who died from drug poisoning, the control group consisted of 105 subjects who died from other causes. The methods used to study the pericardial fluid included gas-liquid chromatography to detect the presence and the type of the poisonous drugs, as well as biochemical and colorimetric methods to determine the amount of enzymes AST, ALT, and CPK. The study revealed no traces of drugs or their metabolites in the pericardial fluid from the 105 control corpses. Positive results of the forensic drug tests were obtained in all the 142 cases of the study group. The changes in the parameters and the biochemical composition of pericardial fluid and blood in fatal drug poisoning were reliably established including the alteration of the enzyme levels, such as AST, ALT, and CPK. In the control group, the quantitative parameters of the enzyme activities did not exceed the normal values whereas in the study group a significant increase of AST, ALT, and CPK levels in the pericardial fluid and blood in comparison with the normal values was documented. Conclusion: the results obtained in the studies of both groups provide a basis on which to propose the reliable criteria for forensic medical diagnostics of fatal drug poisoning taking into consideration the changes in the chemical, toxicological, and biochemical parameters of the pericardial fluid. PMID- 25275185 TI - [The determination of the natural content of chemical elements in human biological objects (liver, kidney, stomach) by mass spectrometry with inductively coupled plasma]. AB - The objective of the present work was to continue the studies of the sites of concentration of the chemical elements corresponding to normal homeostasis in human biological objects by mass spectrometry with inductively coupled plasma. The study yielded the data on the natural content of 27 elements in the cadaveric liver, kidney, and stomach. It is recommended to use these findings as the reference parameters corresponding to normal homeostasis. PMID- 25275184 TI - [The identification and quantitative measurement of mirtazapine isolated from the biological material by high performance liquid chromatography]. AB - The present study was designed to estimate the effectiveness of isolation of mirtazapine from the liver, blood, and urine. The conditions were developed for the identification and quantitative measurement of the isolated mirtazapine with the use of high performance liquid chromatography and detection from the UV spectrum and mass-spectrometry. The retention time of mirtazapine isolated from the liver was 2.88 +/- 0.08 min. The straight-line equation within the range of mirtazapine concentrations from 1 to 20 mc/ml was characterized by the dependence: Y = 3.25 x 10(4)X - 6.27 x 10(3) (r = 0.9997). The study showed that it is possible to isolate 46.44 +/- 1.89% of mirtazapine present in the liver and 50.4 +/- 1.05% from blood using extraction by acetonitrile acidified with an 1 M hydrochloric acid solution. Chloroform extraction from urine at pH 7.0-8.0 releases 90.22 +/- 1.88% of mirtazapine. PMID- 25275186 TI - [A case of suicide committed with a crossbow]. AB - The paper reports the results of forensic medical expertise of the corpse of a young man who committed suicide by two arrow shots to the head with a MK-80-A4AL crossbow. Both wounds are penetrating brain injuries. PMID- 25275187 TI - [The determination of the ballistics of a hunting rifle loaded with a Poleva-3 bullet]. AB - Various approaches are considered to determine the shooting range of a hunting rifle loaded with a Poleva-3 bullet from the specific features of gunshot injuries inflicted by container-type Poleba-3 bullets for hunting rifles. PMID- 25275188 TI - [The topical issues of road traffic injury emerging from the publications in the journal "Forensic Medical Expertise" for the period from 1958 to 2012]. AB - The results of the sientometric analysis of the publications in the journal Sudebno-meditsinskaya ekspertiza (Forensic Medical Expertise) for the 55 year period (from 1958 to 2012) was used to evaluate the information support of scientific research and practical observations of forensic medical experts concerning the topical issues of road traffic injury in this country. The authors performed the search for the relevant publications which revealed 165 articles that were classified and grouped with a view to their systematic assessment for the enhancement of the effectiveness of research work and practical activities of specialists concerned with forensic medical traumatology with special reference to road traffic injury. The present paper is a preliminary communication to be followed by a series of further publications containing the results of in-depth sientometric analysis of the articles published by specialists in injury cases involving cars, trains, and airplanes in the journal Sudebno-meditsinskaya ekspertiza. PMID- 25275189 TI - [The report on the 7th All-Russian Congress of Forensic Medical Experts and its Resolution (21-24 October 2013, Moscow)]. PMID- 25275190 TI - [The Armenian-Russian Scientific Conference "Topical issues of forensic medical expertise and medical law"]. PMID- 25275191 TI - He's done it again! PMID- 25275192 TI - Code black at Cairns Hospital. PMID- 25275193 TI - QH's left-hand not talking to its right-hand. PMID- 25275194 TI - Policy roundtable creates a long-term plan for asylum seekers. PMID- 25275195 TI - Federal budget update. PMID- 25275196 TI - When the cost outweighs the benefit. PMID- 25275197 TI - Who cares for you night and day? Nurses and midwives! PMID- 25275198 TI - Reflective exercise: Obligation to disclose injury and impairment. PMID- 25275199 TI - Pulse Health nurses step up for industrial action. PMID- 25275200 TI - Workers' compensation changes starting to wash through. PMID- 25275201 TI - Here come the primary health networks. PMID- 25275202 TI - What's good for the goose? Queensland Health and 'prescribed employers'. PMID- 25275203 TI - Blazing a trail from Bathurst to Brussels. PMID- 25275204 TI - Effects of vanadium complexes supplementation on V, Cu, Mn, K, Fe, Zn, and Ca concentration in STZ diabetic rats pancreas. AB - The objective of the study was to assess the effects of Na[V(V)O(O2)2(2,2'-bpy)] x 8 H2O (complex 1), Na[V(V)O(O2)2(1,10'-phen)] x 5 H2O (complex 2), Na[V(V)O(O2)2(4,4'-Me-2,2'-bpy)] x 8 H2O (complex 3), [V(V)O(SO,)(1,10'-phen)] x 2 H2O, (complex 4), [V(IV)O(SO4)(2,2'-bpy)] x H2O (complex 5), where: 2,2'-bpy = 2,2'-bipyridine, 1.10'-phen = 1,10'-phenanthroline, 4,4'-Me-2,2'-bpy = 4,4' dimethyl-2,2'-bipyridine and a small insulin injection on V, Cu, Mn, K, Fe, Zn, and Ca concentration in the STZ (streptozotocin) diabetic rats pancreas during a 5-week treatment with the tested complexes. In all groups of animals metal concentration in the pancreas was investigated by means of Proton Induced X-ray Emission (PIXE) method. Maximum concentration of vanadium was observed in the pancreas for complex 5 (1.69 +/- 0.09 mg/kg dry weight), lower for complex 3 (1.51 +/- 0.10 mg/kg dry weight), and the lowest for complex 1 (1.21 +/- 0.27 mg/kg dry weight) supplementation. The influence of vanadium administration on other metals' concentration in the rats' pancreas was also investigated. All vanadium-tested complexes showed an increase of zinc concentration in the examined pancreas in comparison to the diabetic animals not treated with vanadium. The results were the highest for complex 1 and the lowest for complex 5. The concentration of Fe, Cu, Mn, K and Ca in the pancreas is not evidently influenced by administration of the vanadium complexes. PMID- 25275212 TI - Correction to enantioselective organocatalytic hantzsch synthesis of polyhydroquinolines. PMID- 25275213 TI - iNOS inhibitory activity of sesquiterpenoids and a monoterpenoid from the rhizomes of Curcuma wenyujin. AB - Eleven new sesquiterpenoids, wenyujinins A-K (1-11), and a new monoterpenoid, wenyujinin L (12), were isolated from the rhizomes of Curcuma wenyujin. Their structures and relative configurations were elucidated using 1D and 2D NMR, X-ray crystallographic analysis, and HRESIMS data. The absolute configurations of 1, 2, 3, 4, 6, 8, 9, and 10 were determined by comparison of the experimental and calculated ECD spectra. The absolute configuration of 5 was determined from the ECD data of the [Rh2(OCOCF3)4] complex, whereas those of 7 and 12 were determined from the ECD spectra of the compounds alone. Compounds 7 and 7a strongly inhibited the induction of NO production by LPS, with IC50 values of 7.6 and 8.5 MUM, respectively. Compounds 6 and 10 moderately inhibited NO production with IC50 values of 47.7 and 48.6 MUM, respectively. PMID- 25275214 TI - Fluorescent organic nanoparticles with enhanced fluorescence by self-aggregation and their application to cellular imaging. AB - We report a simple strategy to prepare organic biocompatible fluorescent nanoparticles with enhanced fluorescence. A significant fluorescence enhancement was realized by designing a fluorescent small molecule, 4,4'-(2,7-bis[4-{1,2,2 triphenylvinyl}phenyl]-9H-fluorene-9,9-diyl)bis(N,N,N-trimethylbutan-1 aminum)bromide (TPEFN), with aggregation-induced emission enhancement (AIEE) effect. Nanoparticles of TPEFN can be formed through molecular self-aggregation by gradually increasing the water fraction in TPEFN mixed solution (methanol/water). Fluorescence enhancement by about 120-fold was observed after nanoparticle formation. By addition of the biomolecule adenosine triphosphate (ATP), larger nanoparticles of TPEFN are formed and further fluorescence enhancement can be achieved, yielding a total fluorescence enhancement of 420 fold compared with the TPEFN molecular solution. Both of these nanoparticles show very good biocompatibility. Ultrabright spots present in the confocal laser scanning microscopy image again proved the formation of nanoparticles. Positively charged side chains of TPEFN endow these nanoparticles cationic surfaces. The size of the prepared TPEFN nanoparticles and their cationic surface allow them to be rapidly internalized into cells. Cell viability assays prove that the TPEFN nanoparticles have high biocompatibility. These organic fluorescent nanoparticles show great promise for applications in cellular imaging or biotechnology. PMID- 25275215 TI - Brush/gold nanoparticle hybrids: effect of grafting density on the particle uptake and distribution within weak polyelectrolyte brushes. AB - The effect of the brush grafting density on the loading of 13 nm gold nanoparticles (AuNPs) into stimuli-responsive poly(N,N-(dimethylamino ethyl) methacrylate) (PDMAEMA) brushes anchored to flat impenetrable substrates is reported. Atom-transfer radical polymerization (ATRP) is used to grow polymer brushes via a "grafting from" approach from a 2-bromo-2-methyl-N-(3 (triethoxysilyl) propyl) propanamide (BTPAm)-covered silicon substrate. The grafting density is varied by using mixtures of initiator and a "dummy" molecule that is not able to initiate polymerization. A systematic study is carried out by varying the brush grafting density while keeping all of the other parameters constant. X-ray reflectivity is a suitable tool for investigating the spatial structure of the hybrid, and it is combined with scanning electron microscopy and UV/vis spectroscopy to study the particle loading and interpenetration of the particles within the polymer brush matrix. The particle uptake increases with decreasing grafting density and is highest for an intermediate grafting density because more space between the polymer chains is available. For very low grafting densities of PDMAEMA brushes, the particle uptake decreases because of a lack of the polymer matrix for the attachment of particles. The structure of the surface grafted polymer chains changes after particle attachment. More water is incorporated into the brush matrix after particle immobilization, which leads to a swelling of the polymer chains in the hybrid material. Water can be removed from the brush by decreasing the relative humidity, which leads to brush shrinking and forces the AuNPs to get closer to each other. PMID- 25275216 TI - Ultrastructural characters of the spermatozoa in Digeneans of the genus Lecithochirium Luhe, 1901 (Digenea, Hemiuridae), parasites of fishes: comparative study of L. microstomum and L. musculus. AB - This study provides the first ultrastructural data of spermatozoa in the genus Lecithochirium. The spermatozoa of L. microstomum (from Trichiurus lepturus in Senegal) and L. musculus (from Anguilla anguilla in Corsica) exhibit the general pattern described in the great majority of the Digenea, namely two axonemes with the 9 + "1" pattern typical of the Trepaxonemata, one mitochondrion, a nucleus, parallel cortical microtubules and external ornamentation of the plasma membrane. Spermatozoa of L. microstomum and L. musculus have some specific features such as the presence of a reduced number of cortical microtubules arranged on only one side of the spermatozoon, the lack of spine-like bodies and expansion of the plasma membrane. The external ornamentation of the plasma membrane entirely covers the anterior extremity of the spermatozoa. The ultrastructure of the posterior extremity of the spermatozoa corresponds to the pattern previously described in the Hemiuridae, characterized by only singlets of the second axoneme. A particularity of these spermatozoa is the organization of the microtubule doublets of the second axoneme around the nucleus in the posterior part of the spermatozoon. PMID- 25275217 TI - Probing the effect of ionic strength on the functional robustness of the triheme cytochrome PpcA from Geobacter sulfurreducens: a contribution for optimizing biofuel cell's power density. AB - The increase of conductivity of electrolytes favors the current production in microbial fuel cells (MFCs). Adaptation of cell cultures to higher ionic strength is a promising strategy to increase electricity production. The bacterium Geobacter sulfurreducens is considered a leading candidate for MFCs. Therefore, it is important to evaluate the impact of the ionic strength on the functional properties of key periplasmic proteins that warrants electron transfer to cell exterior. The effect of the ionic strength on the functional properties of triheme cytochrome PpcA, the most abundant periplasmic cytochrome in G. sulfurreducens, was investigated by NMR and potentiometric methods. The redox properties of heme IV are the most affected ones. Chemical shift perturbation measurements on the backbone NMR signals, at increasing ionic strength, also showed that the region close to heme IV is the most affected due to the large number of positively charged residues, which confer a highly positive electrostatic surface around this heme. The shielding of these positive charges at high ionic strength explain the observed decrease in the reduction potential of heme IV and shows that PpcA was designed to maintain its functional mechanistic features even at high ionic strength. PMID- 25275218 TI - Beraprost, a stable analog of prostacyclin, enhances cough reflex sensitivity to capsaicin in bronchitic patients. AB - AIMS: Inflammatory mediators are involved in the pathophysiology of neutrophilic bronchial disorders presenting with chronic productive cough. Accumulating evidence indicates that prostanoids are key elements in the pathophysiology of these disorders. However, little is known about the role of prostacyclin in neutrophilic bronchial inflammation. METHODS: The effect of beraprost, a chemically and biologically stable analog of prostacyclin, on cough response to inhaled capsaicin was examined in 14 patients with chronic bronchitis, a neutrophilic bronchial disorder, in a randomized, placebo-controlled crossover study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of the airway cough reflex sensitivity. RESULTS: After a 2-week treatment with beraprost (80 MUg twice a day orally), the cough threshold was significantly (P < .05) decreased as compared with placebo [12.2 (geometric standard error of the mean [GSEM] 1.5) MUM vs. 24.4 (GSEM 1.3)]. CONCLUSIONS: These findings indicate that prostacyclin is involved in the pathophysiology of cough reflex sensitivity in patients with chronic bronchitis, a frequently encountered neutrophilic bronchial disorder presenting with chronic productive cough. PMID- 25275219 TI - Association of Epstein Barr virus A73 gene polymorphism with nasopharyngeal carcinoma. AB - OBJECTIVE: To study the association between Epstein Barr (EB) virus A73 gene polymorphism and nasopharyngeal carcinoma (NPC) in a Chinese Han population. METHODS: A case-control study was designed, including 510 nasopharyngeal cancer patients and 520 healthy controls, A157154C genotypes of the A73 gene in EB virus were detected, genotype and allele frequency distribution between the two groups were compared. RESULTS: The C allele frequency in the NPC group was significantly higher than that in the control group (68.4% vs. 61.2%; p<0.001). The CC genotype frequency in the NPC group was significantly higher than that in the control group, the difference was significant (47.4% vs. 41.2%; p<0.001). The CC genotype frequency in male patients was significantly higher than that in female patients in the NPC group, the difference was significant (50.3% vs. 34.7%; p<0.001). CONCLUSION: A157154C polymorphism of the A73 gene in EB virus was associated with NPC susceptibility. PMID- 25275220 TI - BCN nanotubes as highly sensitive torsional electromechanical transducers. AB - Owing to their mechanically tunable electronic properties, carbon nanotubes (CNTs) have been widely studied as potential components for nanoelectromechanical systems (NEMS); however, the mechanical properties of multiwall CNTs are often limited by the weak shear interactions between the graphitic layers. Boron nitride nanotubes (BNNTs) exhibit a strong interlayer mechanical coupling, but their high electrical resistance limits their use as electromechanical transducers. Can the outstanding mechanical properties of BNNTs be combined with the electromechanical properties of CNTs in one hybrid structure? Here, we report the first experimental study of boron carbonitride nanotube (BCNNT) mechanics and electromechanics. We found that the hybrid BCNNTs are up to five times torsionally stiffer and stronger than CNTs, thereby retaining to a large extent the ultrahigh torsional stiffness of BNNTs. At the same time, we show that the electrical response of BCNNTs to torsion is 1 to 2 orders of magnitude higher than that of CNTs. These results demonstrate that BCNNTs could be especially attractive building blocks for NEMS. PMID- 25275221 TI - Antioxidant and associated capacities of Camu camu (Myrciaria dubia): a systematic review. AB - An aging population in the United States presents important challenges for patients and physicians. The presence of inflammation can contribute to an accelerated aging process, the increasing presence of comorbidities, oxidative stress, and an increased prevalence of chronic pain. As patient-centered care is embracing a multimodal, integrative approach to the management of disease, patients and physicians are increasingly looking to the potential contribution of natural products. Camu camu, a well-researched and innovative natural product, has the potential to contribute, possibly substantially, to this management paradigm. The key issue is to raise camu camu's visibility through increased emphasis on its robust evidentiary base and its various formulations, as well as making consumers, patients, and physicians more aware of its potential. A program to increase the visibility of camu camu can contribute substantially not only to the management of inflammatory conditions and its positive contribution to overall good health but also to its potential role in many disease states. PMID- 25275223 TI - Religious Coping and Psychological and Behavioral Adjustment After Hurricane Katrina. AB - Positive and negative religious coping are related to positive and negative psychological adjustment, respectively. The current study examined the relation between religious coping and PTSD, major depression, quality of life, and substance use among residents residing in Mississippi at the time of Hurricane Katrina. Results indicated that negative religious coping was positively associated with major depression and poorer quality of life and positive religious coping was negatively associated with PTSD, depression, poorer quality of life, and increased alcohol use. These results suggest that mental health providers should be mindful of the role of religious coping after traumatic events such as natural disasters. PMID- 25275224 TI - Degradation, phytoprotection and phytoremediation of phenanthrene by endophyte Pseudomonas putida, PD1. AB - Endophytes have been isolated from a large diversity of plants and have been shown to enhance the remediation efficiency of plants, but little information is available on the influence of endophytic bacteria on phytoremediation of widespread environmental contaminants such as polycyclic aromatic hydrocarbons (PAHs). In this study we selected a naturally occurring endophyte for its combined ability to colonize plant roots and degrade phenanthrene in vitro. Inoculation of two different willow clones and a grass with Pseudomonas putida PD1 was found to promote root and shoot growth and protect the plants against the phytotoxic effects of phenanthrene. There was an additional 25-40% removal of phenanthrene from soil by the willow and grasses, respectively inoculated with PD1 when compared to the uninoculated controls. Fluorescent microscopy using fluorescent protein tagging of PD1 confirmed the presence of bacteria inside the root tissue. Inoculation of willows with PD1 consistently improved the growth and health when grown in hydroponic systems with high concentrations of phenanthrene. To our knowledge this is the first time that the inoculation of willow plants has been shown to improve the degradation of PAHs and improve the health of the host plants, demonstrating the potential wide benefit to the field of natural endophyte-assisted phytoremediation. PMID- 25275226 TI - Should comparative effectiveness research ignore industry-funded data? PMID- 25275222 TI - Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit. AB - SIGNIFICANCE: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases. RECENT ADVANCES: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome. CRITICAL ISSUES: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke. FUTURE DIRECTIONS: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases. PMID- 25275227 TI - Why are patients uncertain about the human papillomavirus vaccine's effectiveness? PMID- 25275229 TI - Pay for quality: how much pay for how much quality? PMID- 25275225 TI - Foxm1 regulates resolution of hyperoxic lung injury in newborns. AB - Current treatments for inflammation associated with bronchopulmonary dysplasia (BPD) fail to show clinical efficacy. Foxm1, a transcription factor of the Forkhead box family, is a critical mediator of lung development and carcinogenesis, but its role in BPD-associated pulmonary inflammation is unknown. Immunohistochemistry and RNA analysis were used to assess Foxm1 in lung tissue from hyperoxia-treated mice and patients with BPD. LysM-Cre/Foxm1(-/-) mice, in which Foxm1 was deleted from myeloid-derived inflammatory cells, including macrophages, monocytes, and neutrophils, were exposed to neonatal hyperoxia, causing lung injury and remodeling. Measurements of lung function and flow cytometry were used to evaluate the effects of Foxm1 deletion on pulmonary inflammation and repair. Increased Foxm1 expression was observed in pulmonary macrophages of hyperoxia-exposed mice and in lung tissue from patients with BPD. After hyperoxia, deletion of Foxm1 from the myeloid cell lineage decreased numbers of interstitial macrophages (CD45(+)CD11b(+)Ly6C(-)Ly6G(-)F4/80(+)CD68( )) and impaired alveologenesis and lung function. The exaggerated BPD-like phenotype observed in hyperoxia-exposed LysM-Cre/Foxm1(-/-) mice was associated with increased expression of neutrophil-derived myeloperoxidase, proteinase 3, and cathepsin g, all of which are critical for lung remodeling and inflammation. Our data demonstrate that Foxm1 influences pulmonary inflammatory responses to hyperoxia, inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar injury and remodeling in neonatal lungs. PMID- 25275230 TI - Continuous infusion of levodopa-carbidopa intestinal gel in Parkinson's disease. AB - Evaluation of: Olanow CW, Kieburtz K, Odin P et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 13(2), 141-149 (2014). Levodopa-induced motor complications, including motor fluctuations and dyskinesia, can be a major source of disability for Parkinson's disease patients. The development of levodopa-induced motor complications has been attributed to the pulsatile dopaminergic stimulation characteristic of conventional oral levodopa regimens. This is a review of a 12 week, randomized, controlled, double-blind, double-dummy study of continuous jejunal infusion of levodopa-carbidopa intestinal gel to determine if the continuous infusion of levodopa reduces motor complications in Parkinson's disease. Results demonstrated that levodopa-carbidopa intestinal gel significantly reduced off-time without increasing troublesome dyskinesia compared with standard oral levodopa therapy. Adverse effects were common in both the levodopa-carbidopa intestinal gel and placebo groups and were related primarily to the infusion hardware. PMID- 25275231 TI - Impact of extended-release quetiapine fumarate on hospitalization length and cost in schizophrenia and bipolar disorder patients: a retrospective, hospital-based, US-cohort analysis. AB - AIM: The aim was to evaluate the impact of quetiapine extended release (XR) on hospitalization length and cost in schizophrenia or bipolar disorder, versus quetiapine immediate release (IR), using Premier PerspectiveTM inpatient hospital database data. METHODS: Inpatient discharges classified within diagnosis-related group 430 (psychoses), prescribed quetiapine XR or IR, were identified. Patients had International Classification of Disease-9 diagnosis of schizophrenia or bipolar disorder. The impact of the XR formulation on hospitalization length and costs was assessed using generalized linear model analyses. RESULTS: A total of 30,429 discharges between 1 January 2008 and 30 June 2009 were analyzed. Patients who received quetiapine XR had significantly reduced hospitalization length (10.73% estimated reduction; p = 0.001) and cost (9.52% estimated reduction; p < 0.001), versus IR. This corresponds to a 1.0-day reduction in hospitalization (10.73% of 9.2 days) and US$532 reduction in hospitalization cost (9.52% of US$5588) per patient, based on least squares mean estimations. Evaluation of patient subpopulations suggested the reduction in length of hospitalization for quetiapine XR versus IR was driven mainly by patients with bipolar disorder, whereas cost reduction was driven mainly by patients with schizophrenia. CONCLUSION: Inpatient use of quetiapine XR in schizophrenia or bipolar disorder is associated with reduced hospitalization length and cost, possibly due to the faster titration schedule versus quetiapine IR. PMID- 25275232 TI - Using indirect comparisons to compare interventions within a Cochrane review: a tool for comparative effectiveness research. AB - AIM: Assessing relative performance among competing interventions is an important part of comparative effectiveness research. Bayesian indirect comparisons add information to existing Cochrane reviews, such as which intervention is likely to perform best. However, heterogeneity variance priors may influence results and, potentially, clinical guidance. METHODS: We highlight the features of Bayesian indirect comparisons using a case study of a Cochrane review update in asthma care. The probability that one self-management educational intervention outperforms others is estimated. Simulation studies investigate the effect of heterogeneity variance prior distributions. RESULTS: Results suggest a 55% probability that individual education is best, followed by combination (39%) and group (6%). The intervention with few trials was sensitive to prior distributions. CONCLUSION: Bayesian indirect comparisons updates of Cochrane reviews are valuable comparative effectiveness research tools. PMID- 25275233 TI - Implications of different laboratory-based incident diabetic kidney disease definitions on comparative effectiveness studies. AB - BACKGROUND: Comparative effectiveness studies using electronic health records (EHRs) often define chronic kidney disease (CKD) outcomes using laboratory-based definitions. Recommendations for defining CKD require multiple longitudinal measurements. The implications of applying these definitions to EHR data are poorly understood. METHODS: Using a cohort of 36,025 individuals with diabetes from three health systems who initiated a new glucose-lowering medication, we compared concordance and CKD incidence rates and rate ratios for glucose-lowering medication classes for laboratory-based CKD definitions requiring one versus multiple abnormal tests. RESULTS & CONCLUSION: CKD incidence rates differed more than twofold based on the definition. Reassuring for CER, incidence rate ratios for glucose-lowering medication classes on risk of developing CKD were relatively unaffected by CKD definition. PMID- 25275234 TI - Analysis of the influence of recent reforms in China: cardiovascular and cerebrovascular medicines as a case history to provide future direction. AB - BACKGROUND: Pharmaceutical expenditure has grown by 16% per annum in China, enhanced by incentives for physicians and hospitals. Hospital pharmacies dispense 80% of medicines in China, accounting for 46% of total hospital expenditure. Principal measures to moderate drug expenditure growth include pricing initiatives as limited demand-side measures. OBJECTIVE: Assess current utilization and expenditure including traditional Chinese medicines (TCMs) between 2006 and 2012. METHODS: Uncontrolled retrospective study of medicines to treat cardiovascular and cerebrovascular diseases in one of the largest hospitals in southwest China. RESULTS: Utilization increased 3.3-fold for cerebrovascular medicines, greatest for TCMs, with expenditure increasing 4.85-fold. Low prices for generics were seen, similar to Europe. However, there was variable utilization of generics at 29-31% of total product volumes in recent years. There continued to be irrationality in prescribing with high use of TCMs, and the utilization of different medicines dropping significantly once they achieved low prices. CONCLUSION: Prices still have an appreciable impact on utilization in China. Potential measures similar to those implemented among western European countries could improve prescribing rationality and conserve resources. PMID- 25275235 TI - A comparison of outcomes for early oropharyngeal cancers treated with single modality surgery versus radiotherapy. AB - AIMS: We retrospectively compared results of surgery alone (SX) or radiotherapy alone (RT) for early stage tonsil and base of tongue cancers. MATERIALS & METHODS: Outcomes for 386 SX and 362 RT patients from Surveillance, Epidemiology and End RESULTS database were analyzed using propensity covariate adjusted and inverse probability weighting models. RESULTS: With median follow-up of 71 months, unadjusted overall survival at 5 years was 66.1% for SX versus 50.2% for RT (p < 0.001). Unadjusted cancer-specific survival was 80.9% for SX versus 67.3% for RT (p < 0.001). In multivariate analysis, treatment modality maintained association with overall survival and cancer-specific survival. Inverse probability weighting-adjusted 5-year overall survival was 75.2% for SX versus 67.4% for RT (p = 0.002). Inverse probability weighting-adjusted cancer-specific survival was 86.0% for SX versus 77.4% for RT (p < 0.001). CONCLUSION: Explanations for higher survival for SX include comorbidities, superiority of surgery and underascertainment of postoperative radiation in Surveillance, Epidemiology and End Results. PMID- 25275236 TI - Incremental cost per quality-adjusted life year gained? The need for alternative methods to evaluate medical interventions for ultra-rare disorders. AB - Drugs for ultra-rare disorders (URDs) rank prominently among the most expensive medicines on a cost-per-patient basis. Many of them do not meet conventional standards for cost-effectiveness. In light of the high fixed cost of R&D, this challenge is inversely related to the prevalence of URDs. The present paper sets out to explain the rationale underlying a recent expert consensus on these issues, recommending a more rigorous assessment of the clinical effectiveness of URDs, applying established standards of evidence-based medicine. This may include conditional approval and reimbursement policies, which should be combined with a firm expectation of proof of a minimum significant clinical benefit within a reasonable time. In contrast, current health economic evaluation paradigms fail to adequately reflect normative and empirical concerns (i.e., morally defensible 'social preferences') regarding healthcare resource allocation. Hence there is a strong need for alternative economic evaluation models for URDs. PMID- 25275237 TI - Composite scores in comparative effectiveness research: counterbalancing parsimony and dimensionality in patient-reported outcomes. AB - When planning a comparative effectiveness study comparing disease-modifying treatments, competing demands influence choice of outcomes. Current practice emphasizes parsimony, although understanding multidimensional treatment impact can help to personalize medical decision-making. We discuss both sides of this 'tug of war'. We discuss the assumptions, advantages and drawbacks of composite scores and multidimensional outcomes. We describe possible solutions to the multiple comparison problem, including conceptual hierarchy distinctions, statistical approaches, 'real-world' benchmarks of effectiveness and subgroup analysis. We conclude that comparative effectiveness research should consider multiple outcome dimensions and compare different approaches that fit the individual context of study objectives. PMID- 25275238 TI - Impact of Sativex((r)) on quality of life and activities of daily living in patients with multiple sclerosis spasticity. AB - In individuals with multiple sclerosis (MS) spasticity, associated symptoms such as spasms, pain, mobility restrictions and sleep disturbances can interfere with the ability to perform activities of daily living and reduce quality of life (QoL). Recent cross-sectional studies from Europe have confirmed that advancing severity of MS spasticity correlates directly with worsening QoL. The treatment effect of Sativex((r)) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) on QoL has been evaluated in randomized controlled trials, observational studies conducted under everyday clinical practice conditions and a survey in long-term users. Symptomatic relief of MS spasticity in responders to Sativex was associated with quantifiable improvements in QoL and activities of daily living that were maintained over time. Benefits were perceived by both patients and caregivers. PMID- 25275240 TI - Enhancement of phosphorescence and unimolecular behavior in the solid state by perfect insulation of platinum-acetylide polymers. AB - Controlling the thermal fluctuations and molecular environment of a phosphorescent polymer backbone is vital to enhancing its phosphorescence intensity in the solid state. Here, we demonstrate enhanced phosphorescence control through a systematic investigation of cyclodextrin-based insulated platinum-acetylide polymers with well-defined coverage areas. Modification of the coverage areas revealed two unprecedented effects of macrocyclic insulation on phosphorescence behavior. First, the insulation of particular areas suppresses the thermal relaxation processes of the triplet species because of the restriction of structural fluctuations. Cyclic insulation fixes a polymer chain and concomitantly enhances the phosphorescence intensity in both the solution and solid states. Second, complete three-dimensional insulation protects the polymer from interactions with other platinum and acetylide units, and even oxygen molecules. Notably, these polymers display identical phosphorescence behaviors in both the solution and solid states, essentially achieving "unimolecular phosphorescence." PMID- 25275241 TI - Potential risks of excess iodine ingestion and exposure: statement by the american thyroid association public health committee. PMID- 25275242 TI - Evaluation of microvascular structure in humans: a 'state-of-the-art' document of the Working Group on Macrovascular and Microvascular Alterations of the Italian Society of Arterial Hypertension. AB - The evaluation of microvascular structure is, in general, not an easy task. Among the methods that may be applied to humans, plethysmographic evaluation of small arteries and wire or pressure micromyography were extensively used in the last decades. The media-to-lumen ratio of small arteries evaluated by micromyography was demonstrated to possess a strong prognostic significance; however, its extensive evaluation is limited by the local invasiveness of the assessment. Noninvasive approaches were then proposed, including capillaroscopy, which provides information about microvascular rarefaction. Recently, the interest of investigators was focused on the retinal microvascular bed. In particular, a noninvasive measurement of the wall-to-lumen ratio of retinal arterioles using scanning laser Doppler flowmetry has been introduced.Recent data suggest a rather good agreement between this approach and micromyographic measurements, generally considered the gold standard approach. Therefore, the evaluation of microvascular structure is progressively moving from bench to bedside, and it could represent, in the immediate future, an evaluation to be performed in all hypertensive patients, in order to obtain a better stratification of cardiovascular risk. PMID- 25275243 TI - Is there a differential impact of parity on blood pressure by age? AB - OBJECTIVE: In pregnancy, women experience metabolic and hemodynamic changes of potential long-term impact. Conflicting evidence exists on the impact on blood pressure (BP). We investigated the association between parity and BP in the Swiss Study on Air Pollution And Lung and Heart Disease In Adults cohort. METHODS: Multilevel linear and logistic regression analyses were performed in 2837 women aged 30-73 years, with data on parity, number of births, BP, and doctor-diagnosed hypertension adjusting for potential confounders. Hypertension was defined as at least 140/90 mmHg, doctor diagnosed or taking relevant treatment. Stratified analyses were performed by age (<40, 40-59, and >=60 years) and menopausal status. RESULTS: Parous women had a mean of 2.3 pregnancies (SD 0.95, range 1-7). A total of 26% were nulliparous. Mean BP was 119/76 mmHg in nulliparous and 121/76 mmHg in parous women. Parity had a significant adverse effect on BP in women at least 60 years [SBP 5.6 mmHg, 95% confidence interval (CI) 2.3 to 8.9; DBP 1.8 mmHg, 95% CI 0.1 to 3.6] and protective effect in women below 40 years (SBP -3.4 mmHg, 95% CI -5.8 to -1.0; DBP -0.2 mmHg, 95% CI -1.0 to 0.6). With increasing number of births, SBP (mmHg/birth; 95% CI) increased in older (1.2, 95% CI 0.2 to 2.2) and decreased in younger women (-1.6, 95% CI -2.6 to -0.5). Opposite effects of parity were also found for diagnosed hypertension. No interaction by menopausal status was found. CONCLUSION: Our analyses yield differential effects of parity on BP in older vs. younger women. Reductions in BP in younger parous women have been described before; the opposite impact in older women is new. The findings may constitute biological mechanisms in an aging population or reflect birth cohort effects. PMID- 25275244 TI - Nonlinear association between pulse wave velocity and cognitive function: a population-based study. AB - BACKGROUND: Arterial stiffness has been hypothesized to contribute to cognitive decline. However, previous studies have reported inconsistent results. The aim of this cross-sectional study was to investigate the association between carotid femoral pulse wave velocity (cfPWV), a marker of arterial stiffness, and cognitive function. METHODS: The study population comprised 2637 individuals from the population-based Malmo Diet and Cancer Study (mean age 72.1 years, 60.8% women). During the follow-up examinations between 2007 and 2012, cfPWV and results on the a quick test of cognitive speed (AQT) and Mini Mental State Examination (MMSE) cognitive tests were measured. RESULTS: After adjustments for demographics and traditional cardiovascular risk factors, a linear association was found between cfPWV and AQT (B = 0.37; P = 0.039). On the basis of hypothesis that individuals with high cfPWV values have worse cognitive function than can be inferred from a linear association, cfPWV was dichotomized at the 90th percentile (the binary variable denoted cfPWV >13.8). When cfPWV >13.8 was added to the model, the linear association between continuous cfPWV and AQT disappeared (B = 0.08; P = 0.72), but cfPWV >13.8 was highly significant (B = 4.81; P = 0.004). In the adjusted model with MMSE as outcome variable, cfPWV >13.8 also reached a statistically significant effect. CONCLUSION: Arterial stiffness was inversely associated with cognitive function in a nonlinear fashion, with individuals in the top decentile of cfPWV explaining the association. Results from linear regressions should thus be interpreted with caution because, even when statistical significance is reached, they can be explained by pronounced nonlinearity. PMID- 25275245 TI - Amino-terminal-pro-B-type natriuretic peptide levels and low diastolic blood pressure: potential relevance to the diastolic J-curve. AB - BACKGROUND: There is debate whether the J-curve relationship between cardiac event risk and DBP is because of inherent cardiac risk or is a consequence of blood pressure (BP) lowering therapy. METHODS: We examined the association between the cardiovascular risk marker amino-terminal-pro-B-type natriuretic peptide (NT-proBNP) and DBP in 1781 women and 2211 men aged at least 60 years with one or more cardiovascular risk factors; exclusion criteria were known heart failure or cardiac abnormality on a cardiac imaging study. RESULTS: The lowest median serum NT-proBNP levels were for DBP 85-89 mmHg for both women and men. DBP less than 70 mmHg in women and less than 80 mmHg in men was associated with higher NT-proBNP levels than the levels at DBP 85-89 mmHg, and this relationship was present for those with SBP equal to or less than 140 and SBP greater than 140 mmHg. In conditional logistic regression models, the association of elevated NT proBNP levels with low DBP in women was no longer statistically significant after adjustment for age, ischaemic heart disease (IHD), pulse rate, atrial fibrillation, haemoglobin and glomerular filtration rate, whereas the association in men was no longer statistically significant after adjustment for age and IHD. By contrast, the association between elevated NT-proBNP levels and low DBP remained statistically significant after adjustment for the number of antihypertensive drug classes alone or together with all antihypertensive drugs, including beta-blocker therapy. CONCLUSION: There was a J-curve relationship between the cardiovascular risk marker NT-proBNP and DBP that was explained by the clinical variables and not by the BP-lowering therapy. PMID- 25275246 TI - An audit and suggested guidelines for in-patient blood pressure measurement. AB - OBJECTIVE: No universally accepted guideline exists for measurement of blood pressure for patients confined to bed. The aim was to establish areas of technique that might be open to standardization to improve measurement reliability similar to those used for office BP measurements. METHODS: In-patient blood pressure measurement (IPBPM) was closely observed in 100 patients in a variety of medical wards during routine vital signs observation rounds, comparing the methods observed with current office BPM guidelines. RESULTS: IPBPM, always taken initially with automated machines, was measured once only in 96% of patients. Around 7% patients were lying flat, 32% semi-reclined, 24% had their back unsupported, 15% crossed legs, 9% arms unsupported, 65% arm below heart level, 4% above, 36% incorrect cuff size for arm circumference, 43% bladder not centred over brachial artery and 14% had arrhythmia not documented by ward staff during the measurement. Staff and patients were conversing during 41% measurements. CONCLUSION: There is a lack of standardization of automated IPBPM technique including a failure to adhere to principles of measurement already established for office BP in a majority (97%) of patients. This may lead to potentially erroneous BP readings, which are an unreliable basis for clinical interpretation and decision making. There is a need for universal hospital specific guidelines for IPBPM and programmes to train and monitor staff for adherence to these. Particular attention should be given to those factors well known to affect blood pressure measurement, including correct cuff size and placement, arm position and absence of talking during measurement as well as only using validated machines. Additional recommendations might include the routine use of manual BP readings where appropriate (such as with very low or irregular heart rates), BP measured in both arms on admission and the arm with the highest BP used thereafter and recording the side of IPBPM and patient position. We recommend that a task force is commissioned to develop universal guidelines for this important part of clinical assessment. PMID- 25275247 TI - Heritability of blood pressure through latent curve trajectories in families from the Gubbio population study. AB - BACKGROUND AND OBJECTIVES: Prospective investigations on cardiovascular risk factors in populations provide a unique opportunity to dissect time-dependent quantitative complex traits, such as arterial blood pressure (BP), into their polygenic and environmental components. BP heritability analyses were carried out on 2620 patients belonging to 711 nuclear pedigrees that could be followed up throughout 25 years in the Gubbio Population Study. METHODS: Each patient's BP serial measurements were summarized into individual intercepts (expected values at baseline) and slopes (time-related changes), which were predicted through latent curve models. These models considered either age in years or waves (times from the first survey) as time axis and were linked at a family level in the heritability analyses using additive polygenic-common environment-unique error models adjusted for sex, age and clinical variables. RESULTS: The additive genetic effect explained 32-49% of the variance of SBP values at baseline, the wave-dependent analysis with nuclear pedigrees and the sibs-household matrix accounting for higher heritability values. Heritability of DBP baseline value was lower than that of SBP in analyses by age (5-15%), but fell in the same heritability range as SBP on the analysis by waves (36-37%). The BP variation over time (slope) explained by an additive genetic effect ranged from 33 to 43% and from 24 to 25% for SBP and DBP, respectively, in the analysis by age. Shared environment also exerted a significant influence, but explained a smaller portion of the variances (4-17%) for both traits. CONCLUSION: Longitudinal data from the Gubbio population show strong to moderate genetic influences on SBP and DBP baseline values and changes over time with a smaller, though significant, effect of environment. PMID- 25275249 TI - Five-year weight changes associate with blood pressure alterations independent of changes in serum insulin. AB - OBJECTIVE: In overweight-related hypertension, the effect of weight changes on blood pressure (BP) is believed to be mediated by insulin. To test this hypothesis, we studied 5-year changes in weight, BP, and insulin in a general population of Danish adults (n = 3443; mean age 45.7 +/- 7.6 years). METHODS: We assessed the glucose-insulin metabolism by a standard oral glucose tolerance test. We divided the antihypertensive and antidiabetic medication-free participants into three groups: weight loss (n = 515), weight stable (n = 1778), and weight gain (n = 1150). RESULTS: Losing on average 6.5 kg body weight, the weight loss group experienced a 28.2% reduction [(95% confidence interval [CI] 31 to -25); P < 0.001] in fasting insulin and a 23.9% reduction [(95% CI -28 to 19); P < 0.001] in 2-h insulin. Gaining on average 6.4 kg, the weight gain group experienced a 12.5% increase [(95% CI 9 to 16); P < 0.001] in fasting insulin and 32.8% increase [(95% CI 28 to 38); P < 0.001] in 2-h insulin. Using linear regression adjusting for differences in sex, age, family history of hypertension, baseline BMI, SBP and DBP, lifestyle risk factors, and their 5-year changes, weight loss was associated with a decrease in SBP of -1.8 mmHg (95% CI -2.8 to 0.7), whereas weight gain with an increase in SBP of 1.9 mmHg (95% CI 1.2 to 2.6), both with P less than 0.001. Adding fasting insulin, 2-h insulin, Deltafasting insulin, and Delta2-h insulin only marginally attenuated the association, and furthermore, none of the insulin variables was significantly associated with SBP or DBP (P >= 0.08). The results for changes in DBP were similar to SBP. CONCLUSION: Five-year weight changes associate with BP alterations independent of the insulin changes. PMID- 25275248 TI - Rho kinase inhibition mitigates sunitinib-induced rise in arterial pressure and renal vascular resistance but not increased renal sodium reabsorption. AB - OBJECTIVES: The therapeutic use of the vascular endothelial growth factor (VEGF) antagonist sunitinib is limited by sunitinib-induced hypertension. The hypotheses were tested that sunitinib increases renal vascular resistance (RVR) and renal Na+ reabsorption, and that Rho kinase (ROCK) inhibition blunts sunitinib-induced hypertension. METHODS: Sunitinib actions on human and rat resistance arteries were investigated by myography. The effects of sunitinib alone or in combination with a ROCK inhibitor on arterial pressure and renal function were investigated in rats by radiotelemetry, renal function and metabolism studies accompanied by biochemical, molecular and histological analyses. RESULTS: Sunitinib blunted agonist-induced vasoconstriction and facilitated endothelium-dependent vasodilation. Within 4 days, sunitinib treatment caused arterial pressure and RVR to rise by 30 mmHg and 5 mmHg * ml * min * g kidney weight, respectively, accompanied by reduced glomerular filtration rate and fractional Na+ excretion with unaffected fractional Li+ excretion. ROCK inhibition blunted sunitinib induced hypertension and prevented the early rise in RVR, but not the decrease in fractional Na+ excretion, which may explain its modest effect on sunitinib induced hypertension. CONCLUSION: Our data indicate that early sunitinib-induced hypertension is associated with modest alterations in renal vascular function, but markedly increased renal sodium reabsorption, probably due to direct actions of the VEGF antagonist on the collecting duct, suggesting that VEGF receptors regulate renal Na+ absorption. PMID- 25275250 TI - Arterial stiffness in atherosclerotic renovascular hypertension. AB - OBJECTIVE: Arterial stiffness is an independent cardiovascular risk factor. Aging, high blood pressure and increased renin-angiotensin system activity contribute to increased arterial stiffness in patients with atherosclerotic renovascular hypertension (aRVH). A literature search failed to identify any study related to this topic. Therefore, our aim was to determine the arterial stiffness in patients with aRVH and analyze whether stenting in addition to multifactorial drug therapy has beneficial effects on markers of stiffness and the clinical course. METHODS: In this 6-month longitudinal study, 37 patients with refractory hypertension and unilateral aRVH were enrolled. After stenting, all patients received multifactorial dug therapy including 80 mg of telmisartan. Arterial stiffness indices were determined using Arteriograph. The control group consisted of 44 patients with essential hypertension. RESULTS: There were no differences in brachial blood pressure values between the two groups (P > 0.05). At baseline, adjusted pulse wave velocity (PWV) was higher in aRVH patients than that of essential hypertensive patients (12.8 +/- 0.4 vs. 11.6 +/- 0.3 m/s; P = 0.029). In the aRVH group, at the end of the follow-up, a significant decrease in the aortic augmentation index (37.7 +/- 9.9 vs. 33.7 +/- 11.4; P = 0.02) without changes in PWV was observed (P > 0.05). CONCLUSION: This study is the first to show that arterial stiffness is higher in patients with refractory aRVH than in those with essential hypertension. Multifactorial therapy based on stenting and intensive medical treatment reduced central blood pressure and augmentation index. Failure to obtain PWV reduction is likely a consequence of the present irreversible structural vessel changes. Longer follow-up might enable us to resolve whether arterial stiffness indices have better predictive ability in patients with aRVH than brachial blood pressure. PMID- 25275251 TI - Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes. AB - OBJECTIVE: To assess the ability of olmesartan (OLM) to prevent or delay left ventricular remodeling and hypertrophy in patients with type 2 diabetes. METHODS: This prespecified ECG substudy of Randomised OlmesArtan and Diabetes MicroAlbuminuria Prevention (ROADMAP), which compared OLM with placebo, assessed the signs of left ventricular remodeling in patients with a 12-lead ECG at baseline and after at least 2 years. Cornell voltage QRS duration product (primary objective), Cornell voltage index and Sokolow-Lyon index were assessed. RESULTS: In total, 9418 ECG recordings and 1513 patients from ROADMAP were analyzed (placebo, n = 736; OLM, n = 777). Quartiles defined by baseline Cornell voltage QRS duration product were assessed and the proportion of patients in the highest quartile (>=200 mVms) increased from 24.0 to 26.5% in the placebo group and decreased from 25.5 to 22.3% in the OLM group [odds ratio (OR) 0.598 (95% confidence interval [CI] 0.440-0.813); P = 0.0011]. The OR did not change after adjustment for baseline parameters. By the end of study, 38.7% of patients in the placebo group and 34.7% in the OLM group shifted from a lower to a higher quartile or remained in the highest quartile of Cornell voltage QRS duration product [OR 0.797 (95% CI 0.637-0.996); P = 0.0465]. This translated into a 20.3% risk reduction with OLM and suggested OLM attenuated the progression of left ventricular remodeling versus placebo. CONCLUSION: OLM substantially delayed the development of left ventricular remodeling in type 2 diabetes. This effect was not explained by the differences in blood pressure control. Thus, OLM delayed the onset of microalbuminuria, as well as the ECG signs of cardiac structural adaptation in type 2 diabetes. PMID- 25275252 TI - Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. AB - PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. DESIGN: Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005, through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. SETTING: Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. PATIENTS: Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. METHODS: A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. RESULTS: Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every three months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI: 1% - 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. CONCLUSIONS: This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock. PMID- 25275253 TI - Change of junctions between stations 10 and 4 in the new International Association for the Study of Lung Cancer Lymph Node Map: a validation study from a single, tertiary referral hospital experience. AB - BACKGROUND: Some tumors previously staged as N2 disease, using the Mountain Dresler/American Thoracic Society (MD-ATS) map are staged as N1 per the new International Association for the Study of Lung Cancer (IASLC) lymph node (LN) map. We aimed to evaluate the effectiveness of the IASLC LN map in stratifying prognosis in patients with non-small cell lung cancer (NSCLC) and LN metastasis in nodal stations 4 or 10. METHODS: Of 2,086 patients undergoing curative surgical resection for NSCLC, we searched for patients who had LNs harboring cancer cells in nodal stations 10 or 4 (n = 531) and reclassified them into three different subgroups (N1 [N1 according to both the MD-ATS and IASLC maps], in between [N2 according to the MD-ATS map but N1 by the IASLC map], and N2 [N2 according to both maps]) based on histopathologic results. We compared disease free survival (DFS) among the three subgroups by using the Kaplan-Meier method and log-rank analysis. RESULTS: Of 531 patients, 295 belonged to the N1 group, 66 patients belonged to in-between group, and 170 patients belonged to N2 group, according to the IASLC map. The cumulative DFS rates at 5 years for the N1, in between, and N2 groups were 47%, 39%, and 29%, respectively. In multivariate analysis, LN ratio was identified as significant independent prognostic factor (hazard ratio, 2.877; 95% CI, 1.391-5.950; P = .004). CONCLUSIONS: The changed definition between N1 and N2 diseases by the IASLC LN map works well, as expected, in stratifying patient prognosis. Positive LN ratio may be more valuable than the nodal stations involved in predicting patient survival in resectable NSCLC. PMID- 25275254 TI - An unusual case of hypopituitarism and transient thyrotoxicosis following asymptomatic pituitary apoplexy. AB - Although pituitary function is often impaired in pituitary apoplexy, the development of thyrotoxicosis is rare. We describe an unusual case of hypopituitarism due to pituitary apoplexy coexisting with transient hyperthyroidism. A 74-year-old woman presented with severe fatigue, palpitation, appetite loss, hypotension, and hyponatremia. Endocrine studies showed hyperthyroidism and anterior pituitary hormone deficiencies. A magnetic resonance imaging suggested recent-onset pituitary apoplexy in a pituitary tumor, although the patient had no apoplectic symptoms such as headache and visual disturbance. Thyrotoxicosis and adrenal insufficiency worsened her general condition. Glucocorticoid supplementation improved her clinical symptoms and hyponatremia. Serum anti-thyrotropin receptor and thyroid-stimulating antibody titers were negative, and her thyroid function was spontaneously normalized without antithyroid medication, suggesting painless thyroiditis. Thereafter, her thyroid function decreased because of central hypothyroidism and 75 ug of levothyroxine was needed to maintain thyroid function at the euthyroid stage. The pituitary mass was surgically removed and an old hematoma was detected in the specimen. Considering that painless thyroiditis develops as a result of an autoimmune process, an immune rebound mechanism due to adrenal insufficiency probably caused painless thyroiditis. Although the most common type of thyroid disorder in pituitary apoplexy is central hypothyroidism, thyrotoxicosis caused by painless thyroiditis should be considered even if the patient has pituitary deficiencies. Because thyrotoxicosis with adrenal insufficiency poses a high risk for a life threatening adrenal crisis, prompt diagnosis and treatment are critical. PMID- 25275255 TI - Challenges in the diagnosis of pheochromocytoma and paraganglioma syndrome. AB - OBJECTIVES: Adrenal pheochromocytomas are rare neuroendocrine tumours, however their prevalence is probably underestimated - in some series 50% were diagnosed at autopsy. The clinical presentation varies among patients, that is why diagnosis might be difficult to establish. Pheochromocytoma may coexist with paraganglioma and when paraganglioma is diagnosed, the patient should be screened for pheochromocytoma too, especially in people with hypertension. We present a case of woman with pheochromocytoma, but diagnosed after incidence of stroke, who had also paraganglioma in the past. Additionally, a teratoma was diagnosed simultaneously. CASE REPORT: 49-year old woman with hypertension was referred to the Department of Endocrinology, Diabetology and Isotope Therapy in Wroclaw with suspected pheochromocytoma. She was operated twice because of paraganglioma of the right and left carotid artery, second operation was complicated with stroke. After administration of anticoagulants a bleeding from gastrointestinal tract occurred. During diagnostic process CT of the abdomen showed tumour in the right adrenal gland and a tumour in pelvis. Significantly elevated catecholamines and their metabolites in blood and urine confirmed the diagnosis of pheochromocytoma. Both tumours were removed surgically, the second was teratoma maturum. Genetic screening for hereditary pheochromocytoma was proceeded. A mutation in SDHD gene was revealed in patient's DNA and subsequently in blood samples of her sister and daughter. CONCLUSIONS: Occurrence of paraganglioma with hypertension suggest need of screening for pheochromocytoma-paraganglioma syndrome, especially in case of paragangliomas in family history. Early treatment is crucial to avoid life threatening cardiovascular complications. The association between pheochromocytoma and teratoma is unclear. PMID- 25275256 TI - Circulating levels of neurotrophic factors in autism spectrum disorders. AB - OBJECTIVES: Evaluate the levels of a neurotrophic factor and some neurotrophins in the plasma of patients with Autism Spectrum Disorders (ASD). DESIGN: This study enrolled 30 children with ASD and 19 healthy children. Plasma levels of the neurotrophins BDNF, NGF, NT3, NT4 and of the neurotrophic factor GDNF were measured by Enzyme-Linked Immunosorbent Assay. SETTING: The etiopathogenesis of ASD is largely unknown, but it seems to involve dysfunction in several biological systems. One of these systems comprises the neurotrophic factors, which are molecules involved in many processes in the central nervous system, including neuronal survival, synaptogenesis and synaptic plasticity. Recent studies have shown association between neurotrophic factors and ASD. RESULTS: No differences in plasma BDNF, NGF, NT3, NT4 and GDNF were found between ASD and control. Neurotrophic factors are not altered in ASD. CONCLUSIONS: These molecules may play a minor role in ASD. PMID- 25275257 TI - Complex morphological and molecular genetic examination of amelogenesis imperfecta: a case presentation of two Czech siblings with a non-syndrome form of the disease. AB - Amelogenesis imperfecta (AI) is an overarching term for a group of rare inherited disorders of hard tooth tissues. It is characterized by various defects in proper enamel formation. AI is a severe disorder that affects both the aesthetics and function of the dentition, with affected teeth increasingly suffering from dental caries. Therefore, early diagnosis and lifelong stomatological interventions are important. Due to the complex nature of AI family history, stomatological, radiographic, and molecular genetic examinations should be part of the diagnostic portfolio. Additionally, we utilized new visualization methods for the assessment of teeth demineralization. We present a case report of two affected Czech sisters (6 and 8 years old) with clinically defined AI. These are the first Czech cases in which comprehensive clinical and genetic analysis had been carried out and reflect the complex clinical nature, positive treatment options, and limitations of candidate-gene molecular genetic testing. PMID- 25275258 TI - Corticotropin-releasing factor receptor type 1 colocalizes with type 2 in corticotropin-releasing factor-containing cellular profiles in rat brain. AB - OBJECTIVES: To investigate whether CRHR1 and CRHR2 are colocalized in CRH specific neurons in rat brain. METHODS: Double/triple immunofluorescence, and combined in situ hybridization were performed in the PVN, amygdala and hippocampus, and triple immunofluorescence was applied to the median eminence (ME), dorsal raphe (DR) and locus coeruleus (LC). RESULTS: Both CRHR1 and CRHR2 immunoreactivity were highly coexpressed in the PVN, central nucleus of the amygdala (CeA) and hippocampus. Triple immunofluorescence under confocal microscopy confirmed that CRHR1 and CRHR2 are coexpressed in CRH-producing neurons in these regions. The results of in situ hybridization combined with double immunofluorescence further strengthened the finding that CRHR1 and CRHR2 were coexpressed in CRH-specific neurons in the PVN, CeA and hippocampus. In addition, CRH immunoreactivity signals were evidently distributed in the ME, DR and LC, and were coexpressed with both receptors. CONCLUSION: CRH receptors colocalize in CRH-containing neurons in the PVN, CeA and hippocampus, and CRH, CRHR1, and CRHR2 coexist in the DR and LC. Our results implicate CRHR1 and CRHR2 in coordinating the regulation of CRH neuronal activity in stress and behavioral responses. PMID- 25275259 TI - Differing clinical presentations of two unrelated cases of X-linked adrenoleukodystrophy with identical mutation Y296C in the ABCD1 gene. AB - OBJECTIVES: X-linked adrenoleukodystrophy is a genetically determined disorder that causes varying degrees of malfunction of the adrenal cortex and central nervous system. Our aim was to investigate the occurrence of known, or new, mutations in the ABCD1 gene in two unrelated patients with clinical suspicion of the adrenoleukodystrophy. METHODS: Two unrelated patients - the first with behavioral changes, the second with progressive cognitive deficit - underwent a clinical and genetic examination in order to establish a diagnosis and discover a possible mutation. RESULTS: In the first patient, a 47 year old man, the clinical examination showed dementia of the frontal type and spastic quadriparesis. The patient also suffered from adrenal insufficiency for 6 years. An MRI showed confluent hyperintensive lesions in FLAIR images in the frontal lobe of both hemispheres. The second patient, a 16 year old boy, suffered also from Addison's disease since the age of 9, and developed cognitive deficit in the course of one year. The MRI showed posterior atrophy and hyperintensive lesions in parietal and occipital lobes in T2WI. In both cases, genetic analyses showed a missense mutation at the codon 887 (A>G) in exon 1 of the ABCD1 gene, predicting the substitution Y296C in the ALD protein. CONCLUSION: We detected the same mutation of the ABCD1 gene in two unrelated patients with ALD. In the first case there was frontal lobe involvement, in the second case parieto-occipital involvement. Both pathologic involvement and clinical presentation differed in two cases of the same mutation. PMID- 25275260 TI - Dopamine inhibits excitatory neurotransmission in basolateral amygdala during development via pre-synaptic mechanism. AB - OBJECTIVES: Dopaminergic signaling in the basolateral amygdala (BLA) is important for emotion-related activity. However, little is known about the influence of dopamine (DA) on excitatory synaptic transmission of pyramidal neurons in BLA at early developmental stage. Here in this study, we observed the effect of DA on excitatory neurotransmission in the pyramidal cells of BLA in acute slices. METHODS: Acute slices from amygdala of rats at the age of 14-16 days were prepared and maintained in vitro using standard method. Whole-cell patch clamp recordings were performed to examine the evoked excitatory postsynaptic current (eEPSC), spontaneous excitatory postsynaptic current (sEPSC) and miniature excitatory postsynaptic current (mEPSC). Drugs including DA and synaptic blockers were added in recording solution due to different experimental designs. RESULTS: We found that bath application of DA at a concentration of 100 MUM significantly inhibited the amplitude of evoked EPSC. However, the amplitude and frequency of mEPSC were not affected. We also found increased pair pulse facilitation after DA application, indicating DA inhibited excitatory neurotransmission through suppression of release probability at the pre-synaptic terminals. Importantly, DA was also effective in decreasing activity induced upregulation in sEPSCs. Moreover, the DA effects were not affected by either antagonist of dopamine 1 or dopamine 2-like receptors. CONCLUSION: We studied the effects of DA on excitatory neurotransmission and found that DA inhibited glutamatergic synaptic transmission via modulation of pre-synaptic release probability. PMID- 25275261 TI - Effects of maternal vitamin D status on pregnancy outcomes, health of pregnant women and their offspring. AB - OBJECTIVE: Pregnancy increases the demand for vitamins, including vitamin D. Data on effects of vitamin D deficiency for pregnant woman and fetus available in Poland are scarce. The aim of this study was to evaluate vitamin D3 concentration in pregnant women and its influence on pregnancy course, health of pregnant women and their offspring. PATIENTS AND METHODS: The study included 102 healthy pregnant women, aged 21 to 40 years, mean 30.5+/-4.9 years. Women were divided into three groups based on 25(OH)D serum concentration in the third trimester of pregnancy: Group I - with sufficient 25(OH)D serum concentration (>30 ng/ml), Group II - with vitamin D3 insufficiency (20-30 ng/ml), Group III - with serious vitamin D deficiency (<20 ng/ml). RESULTS: Optimal vitamin D concentrations were found only in 31.2% of women, however in winter months only in 16%. Bacterial vaginosis was significantly more common in women with vitamin D deficiency and insufficiency (p<0.05). In contrast, there were no relations between vitamin D status and the incidence of gestational diabetes, preeclampsia, mode of delivery and size of newborns. A relationship between vitamin D deficiency and insufficiency during pregnancy and subsequent incidence of respiratory infections in children (p<0.05) was demonstrated. CONCLUSIONS: 1. The current model of vitamin D supplementation in pregnant women in Poland is insufficient, particularly in winter. 2. Vitamin D deficiency in pregnant women fosters development of bacterial vaginosis during pregnancy and recurrent respiratory infections in children, suggestive of the role of vitamin D in prevention of infections. PMID- 25275262 TI - Identifying distinct candidate genes for early Parkinson's disease by analysis of gene expression in whole blood. AB - OBJECTIVE: Parkinson disease (PD) is a degenerative disorder of the central nervous system, and in the majority of cases, the causes of PD are unknown. Coupled with impressive advances in statistical tools for analyzing large, complex data sets, well-designed microarray experiments are poised to make a big impact in the field of diseases. So we set the study to identify distinct PD associated candidates. METHODS: Candidate genes, with statistical significant changes of expression in PD patients' samples, were extracted from a transcriptome-wide microarray data in 105 individuals, which were downloaded from GEO, NCBI, by using statistical methods; Selected findings were confirmed by principal component analysis (PCA) and functional and pathway enrichment analysis were used to further study about the distinct candidates. RESULTS: A total of 10 distinctly differentially expressed genes were identified in PD patitents' samples. After PCA confirmation, we specifically pointed out 4 genes (PRKAG2, DLG1, DDX3Y, RPS4Y) as the high confidence distinct candidates in PD. Network and functional categories showed that they were most related to translational elongation(GO:0006414) and participated in mTOR signaling pathway(hsa04150). CONCLUSION: Among 10 distinct genes which are identified in PD patients' samples, DLG1, XIST, DDX3Y and RPS4Y1 genes can classify samples into different group clearly, and they are regarded as high confidence distinct gene biomarkers of PD. Our results provide a systematic view of the functional alterations of PD that may help to elucidate the mechanisms of PD and lead to improved treatments for PD patients. PMID- 25275263 TI - Is nocturnal epilepsy cause of disturbed quality of sleep and elevated daytime sleepiness? AB - OBJECTIVES: Authors evaluated quality of sleep and daytime vigilance in patients with nocturnal epilepsy and compared it to those with daytime epilepsy. BACKGROUND: Nocturnal seizures are an important type of epilepsy. They can result in morbidity due to disruption of sleep architecture. Daytime sleepiness, as a serious consequence of nocturnal seizures, has negative influence on quality of life in patients with epilepsy. METHODS: Authors examined 100 patients with epilepsy. The occurrence of epileptic seizures in circadian rhythm, type of epilepsy and epileptic seizures, as well as aetiology of epilepsy were evaluated. Patients were divided in two groups, 17 patients with nocturnal epilepsy and 83 patients with epileptic seizures not related to sleep. All of them underwent overnight video-EEG-polysomnography and they filled in the Epworth Sleepiness Scale questionnaire (ESS) as well as The Pittsburgh Sleep Quality Index questionnaire (PSQI). RESULTS: Overnight video-EEG-polysomnography detected significant changes in the sleep architecture in patients with nocturnal epilepsy. Significant decrease of N3 stage of NREM sleep (14.31%+/-8.07 in the group of nocturnal epilepsy vs. 20.12%+/-9.24 in the group of daytime epilepsy, p=0.01). Concurrently, significantly poorer sleep quality according to PSQI (18.52+/-7.51 in the group of nocturnal epilepsy vs. 6.21+/-3.62 in the group of daytime epilepsy, p=0.01) and tendency to increased daytime sleepiness according to ESS was revealed in these patients. CONCLUSION: Remarkable changes in sleep architecture associated with poor quality of sleep and increased daytime sleepiness were detected in patients with nocturnal epilepsy. In conclusion, we emphasize the importance of sleep history taking in patients with epilepsy and their further evaluation in sleep laboratory. PMID- 25275265 TI - Persistent remission of Graves' disease or evolution from Graves' disease to Hashimoto's thyroiditis in childhood - a report of 6 cases and clinical implications. AB - BACKGROUND: The main clinical manifestations of autoimmune thyroid diseases are Graves' disease (GD) and Hashimoto's thyroiditis (HT). Graves' disease is the cause of most cases of hyperthyroidism in childhood. Indications for radical therapy (surgery or 131I treatment) in children are still a matter of discussion, as sustained (sometimes very long) remission of GD is possible, while the radical therapy almost always leads to hypothyroidism. Spontaneous evolution from GD with hyperthyroidism to HT with hypothyroidism may also be observed. OBJECTIVE: The aim of the study was to analyze the clinical course of 6 cases of hyperthyroid girls with GD in whom a normalization of previously increased autoantibodies against thyrotropin (TSH) receptor (anti-TSHR) was observed together with a significant increase in autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg), with concomitant hypo- or euthyroidism but no recurrence of hyperthyroidism. SUBJECTS: Patients' age at diagnosis ranged from 5.0 to 16.5 years. Two (2) patients had Turner syndrome, another one (1), diabetic, was on insulin therapy. RESULTS: In all the girls, antithyroid drugs were administered and euthyroid state was achieved during the first 2.0-3.5 months of the treatment. Mild side effects were observed in only one case. The therapy was continued up to 1.5-4.0 years. Relapses during the therapy were observed in 2 cases. Up to now, no relapses have been observed for 0.5-7.5 years since the therapy withdrawal in 5 patients (1 patient was lost to follow-up), 2 patients are currently treated with levothyroxine due to hypothyroidism. CONCLUSIONS: It seems that the prolonged pharmacotherapy with antithyroid drugs, followed by observation after remission of hyperthyroidism, may be an appropriate therapeutic option at least in some children with GD as they can be cured without radical therapy and the potential risks of such treatment. PMID- 25275266 TI - Perspectives in genetic prediction of Alzheimer's disease. AB - Alzheimer disease (AD) represents a group of multifactorial disorders characterized by a progressive decline of mental faculties eventually leading to dementia and death. Aging of human populations is behind the rapid worldwide increase in the prevalence of AD in recent decades. AD prevention critically depends on reliable AD-predictive genetic testing but its further development is delicately poised at present. New DNA-analyzing technologies such as the Next Generation Sequencing (NGS) have allowed rapid and comprehensive analysis of the genome and might have aided the research into the genetics of AD. However, discoveries of epigenetic mechanisms and non-coding forms of DNA and RNA - while helping to explain complexities of AD etiologies - have imposed additional challenges onto the AD diagnostics based on DNA analyses. Environmental factors can, via epigenetic mechanisms, modify both coding and non-coding DNA and this has to be respected in DNA testing, including NGS. Risk calculations based on the known odds and risk ratios for selected DNA polymorphisms are viable options at present, while the applications of neural network methodology seems the most promising way forward in the development of predictive AD tests in future. PMID- 25275264 TI - Mechano-transduction effect of shockwaves in the treatment of lumbar facet joint pain: comparative effectiveness evaluation of shockwave therapy, steroid injections and radiofrequency medial branch neurotomy. AB - OBJECTIVE: Lumbar facet joints (FJ) is a common source of low back pain and contributes approximmately on one third of chronic low back pain. Medial branch radiofrequency neurotomy is considered as a gold standard in the treatment of facet joint pain. Corticosteroid injections have also presented effect in FJ pain. As an interventional procedures, they carry not-negligible risk of possible complications including infection, damage to nerve root or medial branch structures. Shockwave therapy (SWT) is a non-invasive method for treatment of various musculoskeletal disorders. Its effect is based on transduction of mechanical energy, transferred to cascade of various biochemical processes in target tissue. Its efficacy was proved in the treatment of different painful conditions. The efficacy of SWT was not yet studied in FJ pain. Aim of our work was to compare the efficacy of SWT against interventional treatment procedures - radiofrequency neurotomy and corticosteroid FJ injections. METHODS: A retrospective study was done on 62 selected patients with unilateral chronic lumbar facet pain. There were 32 women and 30 men, divided into SWT group, corticosteroid injections group radiofrequency group. Nociceptive and neuropathic pain intensity and severity of pain were measured. RESULTS: Shockwave therapy had shown better longterm results compared to FJ injections group and little inferior efficacy compared to RMBN. We did not observe any adverse effects and complications in SWT group. Moreover, in SWT and RMBN groups, significant longterm improvement in daily activities limitation, was observed. CONCLUSIONS: SWT appears to be a safe and perspective option in the treatment of FJ pain with negligible side effects. PMID- 25275267 TI - Sheehan's syndrome with cardiac arrest: a case report and review of the literature. AB - A 62-year-old woman was admitted to our hospital because of unconsciousness and hypoglycaemia. She had a history of weakness and fatigue after postpartum haemorrhage in 1983. Unfortunately, she was not diagnosed with Sheehan's syndrome and did not receive sufficient professional treatment due to the limited medical resources in her hometown. A laboratory examination at the local hospital revealed severe hypoglycaemia (1.8 mmol/L) with relatively low serum potassium (2.9 mmol/L). The woman appeared twice in the hospital with cardiac arrest, and her medical history, and the later laboratory investigations were consistent with Sheehan's syndrome. Empty sella was also found by magnetic resonance imaging (MRI). We conclude that Sheehan's syndrome may lead to cardiac arrest with the complication of hypokalaemia and deserves the vigilance of clinicians. PMID- 25275268 TI - Six months training alone or combined with diet alters HOMA-AD, HOMA-IR and plasma and adipose tissue adiponectin in obese women. AB - OBJECTIVE: We investigate the effect of 6 months aerobic training alone or in combination with diet on adiponectin in circulation and in adipose abdominal tissue (AT) in obese women. METHODS: Twenty obese subjects were randomized into a 24 weeks intervention: 1) training (TR) and 2) training and diet (TRD). Blood samples were collected at baseline, after 12 wk and 24 wk. AT biopsies were obtained only at baseline and after 24 wk. RESULTS: In the TRD group the fat loss was after 12 wk -13.74% (p<0.01) and after 24 wk -21.82% (p<0.01) with no changes in the TR group. After 12 and 24 wk, VO2max was increased by 21.81-39.54% (p<0.05) in the TRD group and 18.09-40.95% in the TR group (p<0.05). After 12 wk, plasma adiponectin was raised only in the TRD group (55.8%, p<0.05). After 24 weeks, circulating adiponectin was elevated by 110.4% (p<0.01) in the TRD group and by 27% (p<0.05) in the TR group. In AT biopsies, subjects in the TRD and TR groups exhibited a significant increase in adiponectin (p<0.05 and p<0.01, respectively). The two indices HOMA-IR and HOMA-AD for assessing insulin resistance were strongly affected by protocols. HOMA-IR decreased (p<0.05) only after 24 wk in the TRD group. HOMA-AD increased in both groups after 12 (p<0.05) and 24 wk (p<0.01). CONCLUSION: Six months chronic aerobic exercise alone or combined with diet result in a significant increase in circulating and adipose tissue adiponectin levels in obese women independent of changes in body composition and/or in HOMA-IR. PMID- 25275269 TI - Eruca sativa might influence the growth, survival under simulated gastrointestinal conditions and some biological features of Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus rhamnosus strains. AB - The growth and viability of three Lactobacillus strains, Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus rhamnosus, after their passage through simulated gastric and pancreatic juices were studied as a function of their presence in the growth medium of rocket salad (Eruca sativa). The presence of E. sativa affected some of the biological properties of the strains. For example, L. acidophilus and L. plantarum worked more efficiently in the presence of E. sativa, increasing not only the antioxidant activity of the medium, but also their own antioxidant power and antimicrobial activity; L. rhamnosus was not affected in the same manner. Overall, the presence of vegetables might help to boost, in specific cases, some of the characteristics of lactobacilli, including antioxidant and antimicrobial power. PMID- 25275272 TI - Ruthenium-catalyzed double-fold C-H tertiary alkoxycarbonylation of arenes using di-tert-butyl dicarbonate. AB - An efficient ruthenium-catalyzed double-fold C-H alkoxycarbonylation of arenes was developed using di-tert-butyl dicarbonate as the tertiary esterification reagent, which leads to a direct route to valuable 2,6-dicarboxylated products. PMID- 25275270 TI - Atrazine affects phosphoprotein and protein expression in MCF-10A human breast epithelial cells. AB - Atrazine, a member of the 2-chloro-s-triazine family of herbicides, is the most widely used pesticide in the world and often detected in agriculture watersheds. Although it was generally considered as an endocrine disruptor, posing a potential threat to human health, the molecular mechanisms of atrazine effects remain unclear. Using two-dimensional gel electrophoresis, we identified a panel of differentially expressed phosphoproteins and total proteins in human breast epithelial MCF-10A cells after being exposed to environmentally relevant concentrations of atrazine. Atrazine treatments for 6 h resulted in differential expression of 4 phosphoproteins and 8 total-proteins as compared to the control cells (>1.5-fold, p<0.05). MALDI-TOF MS/MS analysis revealed that the differentially expressed proteins belong to various cellular compartments (nucleus, cytosol, membrane) and varied in function, including those regulating the stress response such as peroxiredoxin I, HSP70 and HSP27; structural proteins such as tropomyosin and profilin 1; and oncogenesis proteins such as ANP32A. Six of the 12 identified proteins were verified by quantitative PCR for their transcript levels. The most up-regulated phosphoprotein by atrazine treatment, ANP32A, was further analyzed for its expression, distribution and cellular localization using Western blot and immunocytochemical approaches. The results revealed that ANP32 expression after atrazine treatment increased dose and time dependently and was primarily located in the nucleus. This study may provide new evidence on the potential toxicity of atrazine in human cells. PMID- 25275271 TI - LEADER 3--lipase and amylase activity in subjects with type 2 diabetes: baseline data from over 9000 subjects in the LEADER Trial. AB - OBJECTIVES: This report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial describes baseline lipase and amylase activity in type 2 diabetic subjects without acute pancreatitis symptoms before randomization to the glucagonlike peptide analog liraglutide or placebo. METHODS: The LEADER is an international randomized placebo-controlled trial evaluating the cardiovascular safety of liraglutide in 9340 type 2 diabetic patients at high cardiovascular risk. Fasting lipase and amylase activity was assessed at baseline, before receiving liraglutide or placebo, using a commercial assay (Roche) with upper limit of normal values of 63 U/L for lipase and 100 U/L for amylase. RESULTS: Either or both enzymes were above the upper limit of normal in 22.7% of subjects; 16.6% (n = 1540) had an elevated lipase level (including 1.2% >3-fold elevated), and 11.8% (n = 1094) had an elevated amylase level (including 0.2% >3-fold elevated). In multivariable regression models, severely reduced kidney function was associated with the largest effect on increasing activity of both. However, even among subjects with normal kidney function, 12.2% and 7.7% had elevated lipase and amylase levels. CONCLUSIONS: In this large study of type 2 diabetic patients, nearly 25% had elevated lipase or amylase levels without symptoms of acute pancreatitis. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients. PMID- 25275275 TI - Global health as a frame of mind. PMID- 25275274 TI - Mid-infrared laser orbital septal tightening: ex vivo dosimetry study and pilot clinical study. AB - IMPORTANCE: Blepharoplasty is one of the most commonly performed facial aesthetic surgeries. While myriad techniques exist to improve the appearance of the lower eyelids, there is no clear consensus on the optimal management of the orbital septum. OBJECTIVES: To evaluate the safety and feasibility of the use of the holmium:yttrium aluminum garnet (Ho:YAG) laser for orbital septal tightening, and to determine whether modest use of this laser would provide some degree of clinical efficacy. DESIGN, SETTING, AND PARTICIPANTS: Direct laser irradiation of ex vivo bovine tissue was used to determine appropriate laser dosimetry using infrared thermal imaging and optical coherence tomography before conducting a pilot clinical study in 5 patients. Laser irradiation of the lower eyelid orbital septum was performed through a transconjunctival approach. Standardized preoperative and postoperative photographs were taken for each patient and evaluated by 6 unbiased aesthetic surgeons. EXPOSURE: Use of the Ho:YAG laser for orbital septal tightening. MAIN OUTCOME AND MEASURE: To determine appropriate laser dosimetry, infrared thermal imaging and optical coherence tomography were used to monitor temperature and tissue shape changes of ex vivo bovine tissue that was subjected to direct laser irradiation. For the clinical study, preoperative and postoperative photographs were evaluated by 6 surgeons on a 10 point Likert scale. RESULTS: Optical coherence tomography demonstrated that laser irradiation of bovine tissue to a temperature range of 60 degrees C to 80 degrees C resulted in an increase in thickness of up to 2-fold. There were no complications or adverse cosmetic outcomes in the patient study. Patient satisfaction with the results of surgery averaged 7 on a 10-point Likert scale. For 3 patients, 3 (50%) of the evaluators believed there was a mild improvement in appearance of the lower eyelids after surgery. The remaining patients were thought to have no significant changes. CONCLUSIONS AND RELEVANCE: Transconjunctival Ho:YAG laser blepharoplasty is a safe procedure that may ameliorate mild pseudoherniation of lower eyelid orbital fat and is a first step toward the development of percutaneous techniques. PMID- 25275273 TI - Structure-based design and functional studies of novel noroviral 3C protease chimaeras offer insights into substrate specificity. AB - The norovirus NS6 protease is a key target for anti-viral drug development. Noroviruses encode a 2200 amino acid polyprotein which is cleaved by this critical protease at five defined boundary substrates into six mature non structural (NS) proteins. Studies of the human norovirus (HNV) NS6 protease, in the context of a full ORF1 polyprotein, have been severely hampered because HNVs are not culturable. Thus, investigations into the HNV NS6 protease have been largely restricted to in vitro assays using Escherichia coli-expressed, purified enzyme. The NS6 protease is formed of two distinct domains joined by a linking loop. Structural data suggest that domain 2 of the protease possesses substantial substrate binding pockets which form the bulk of the interactions with the NS boundaries and largely dictate boundary specificity and cleavage. We have constructed chimaeric murine norovirus (MNV) genomes carrying individual domains from the HNV protease and demonstrated by cell transfection that chimaeric HNV proteases have functional activity in the context of the full-length ORF1 polyprotein. Although domain 2 primarily confers boundary specificity, our data suggest that an inter-domain interaction exists within HNV NS6 protease which influences cleavage of specific substrates. The present study also shows that chimaeric MNVs provide improved models for studying HNV protein function in the context of a full ORF1 polyprotein. PMID- 25275276 TI - The financial health of global health programs. AB - BACKGROUND AND OBJECTIVES: No studies have examined how established global health (GH) programs have achieved sustainability. The objective of this study was to describe the financial status of GH programs. METHODS: In this cross-sectional survey of the Society of Teachers of Family Medicine's Group on Global Health, we assessed each program's affiliation, years of GH activities, whether or not participation was formalized, time spent on GH, funding, and anticipated funding. RESULTS: We received 31 responses (30% response rate); 55% were affiliated with residencies, 29% were affiliated with medical schools, 16% were affiliated with both, and 68% had formalized programs. Respondents spent 19% full-time equivalent (FTE) on GH and used a mean of 3.3 funding sources to support GH. Given a mean budget of $28,756, parent institutions provided 50% while 15% was from personal funds. Twenty-six percent thought their funding would increase in the next 2 years. Compared to residencies, medical school respondents devoted more time (26% FTE versus 13% FTE), used more funding categories (4.7 versus 2.2), and anticipated funding increases (42.8% versus 12.0%). Compared to younger programs (? 5 years), respondents from older programs (> 5 years) devoted more time (25% FTE versus 16% FTE) and used more funding categories (3.8 versus 2.9). Compared to those lacking formal programs, respondents from formalized programs were less likely to use personal funds (19% versus 60%). CONCLUSIONS: This limited descriptive study offers insight into the financial status of GH programs. Despite institutional support, respondents relied on personal funds and were pessimistic about future funding. PMID- 25275277 TI - Solutions for the global surgical crisis: the role of family medicine in surgery, obstetrics, and anesthesia. PMID- 25275278 TI - The dawn of family medicine in Ethiopia. AB - BACKGROUND AND OBJECTIVES: This article describes the development of the first training program in family medicine in Ethiopia that was launched on February 4, 2013, at Addis Ababa University (AAU). The postgraduate program will prepare highly trained doctors for all parts of the country who choose generalism for their lifelong career. The paper describes a series of strategies that were used from 2008 to 2013 to take the Ethiopian family medicine program from vision to reality. There is no single model for the development of family medicine in a country where it does not yet exist. In this case the strategies included Continuing Medical Education events, discussions with stakeholders, international collaboration, needs assessment, curriculum design, and faculty development. The article also reviews both the potential for a new program in family medicine to contribute to the country's health system plus the challenges that are expected in the early stages of establishing a new specialty. The challenges include the ambiguous roles of the family physician in the Ethiopian health care system, uncertainty about career opportunities, adaptation of the curriculum to address local needs, expansion of the training programs to produce larger numbers of family physicians, development of Ethiopian faculty who will be teachers of family medicine, and internal and external brain drain. Family physicians will need to maintain a respectful relationship with other specialist physicians as well as nonphysician primary care providers. The development of this AAU family medicine residency is an example of a successful inter- institutional relationship between local and international partners to create a sustainable, Ethiopian-led training program. Insights from this article may guide development of similar training programs. PMID- 25275279 TI - Toward a cultural consciousness of self in relationship: from "us and them" to "we". AB - BACKGROUND AND OBJECTIVES: While skills and techniques can help family physicians and other health professionals achieve basic competence in working across cultural and social boundaries, perhaps their most important tasks are those directed inward toward attitudes, beliefs, and capacities for self-exploration. This essay links the practice and teaching of cross-cultural medicine to clinicians' and educators' exploration of their own self- consciousness. The more they are willing to explore the unfamiliar within themselves, the more emotionally and psychologically comfortable they can become in dealing with the joys and challenges inherent in cross-cultural medicine. Several practices can foster this development of a sense of self in relationship with others. As health professionals and medical educators recognize and promote an awareness of self in relationship, they can enhance their personal and professional roles to become more effective advocates of equity and social justice in every clinical encounter. PMID- 25275280 TI - Entry of US medical school graduates into family medicine residencies: 2013- 2014. AB - BACKGROUND AND OBJECTIVES: This is the 33rd annual report prepared by the American Academy of Family Physicians (AAFP) that reports retrospectively the percentage of graduates from US MD and DO-granting medical schools who entered an Accreditation Council for Graduate Medical Education (ACGME)-accredited family medicine residency program and covers the period between July 2013 and June 2014. Approximately 8.5% of the 18,384 graduates of US MD-granting medical schools entered family medicine in 2014. Seventy of the 130 US LCME-accredited medical schools produced 80% of the graduates who entered family medicine. Schools that received public funding and schools with a department or division of family medicine had higher percentages of students selecting family medicine. Schools are ranked based upon a 3-year rolling average for the percentage of their graduates who entered family medicine. The West North Central, Mountain, and Pacific regions reported the highest percentages of medical school graduates who were first-year residents in family medicine programs (13.3%, 11.8%, and 11.8% respectively). PMID- 25275281 TI - Results of the 2014 National Resident Matching Program(r): family medicine. AB - BACKGROUND AND OBJECTIVES: The 2014 National Residency Matching Program(r) results reveal that the number of family medicine positions offered in the Match(r) by programs accredited by the Accreditation Council on Graduate Medical Education has increased compared to 2013 (3,132 versus 3,062), while the total of all other primary care specialties combined has remained unchanged (784). The number of US seniors matching into family medicine also increased in 2014 over the prior year (1,416 versus 1,374). The percentage of US seniors who matched into family medicine programs grew modestly in 2014 compared to 2013 (8.6% versus 8.4%). Approximately four out of five primary care positions offered in the Match are in family medicine residency programs (3,132 versus 784). Similarly, three out of four US seniors matching into a primary care specialty match into a family medicine program (1,416 versus 520). By way of comparison, nearly five times the number of US seniors matched into family medicine as compared to medicine pediatrics, the next largest primary care specialty. PMID- 25275282 TI - Changing first-year medical students' attitudes toward primary care. AB - BACKGROUND AND OBJECTIVES: With the passing of the Patient Protection and Affordable Care Act, an additional 34 million people will gain access to health care. Combined with population growth and aging adults, expanded insurance coverage will dramatically increase the demand for primary care services. To encourage medical students to pursue primary care, medical schools are integrating courses that will expose students to primary care medicine early in their education. METHODS: We used a descriptive, cross-sectional study design to evaluate the impact of a week-long intensive course in primary care on first-year medical students' attitudes toward primary care. We developed a 25-item survey to assess medical students' knowledge, perception, and attitudes about primary care; the survey was administered before and after the course. RESULTS: A total of 125 first-year medical students (mean age=23.7 +/- 2.9 years, 52.4% female, 75.8% Non Hispanic white, 11.2% rural) completed the pre-course survey, and 117 completed the post-course survey. We observed positive improvements in attitudes toward primary care in 20 of the 25 survey questions (with effect sizes ranging from 0.16--0.33). Further, students stated that the course improved their understanding of the scope of primary care and emphasized the importance and complexity of primary care medicine. CONCLUSIONS: A week-long intensive course in primary care can influence medical students' attitudes toward primary care; however, the long-term impact on students' decision to pursue primary care is not known and needs to be evaluated. These findings provide empirical support for the integration of primary care courses into medical school curricula. PMID- 25275283 TI - A rural pathways program for high school students: reinforcing a sense of place. AB - BACKGROUND AND OBJECTIVES: The affinity model predicts that students from rural areas who train in smaller towns will be more likely to choose rural practice. Most pipeline programs based on this model begin in college or medical school. Many rural students first encounter academic and career planning challenges prior to college, and a few programs are focused on high school students. METHODS: We report pre- and post-program opinions and American College Testing (ACT) practice scores from 151 participants in a high school rural scholar program over the first 10 years of the program. RESULTS: After participation, the students showed significantly more positive opinions about their county's health care resources and their knowledge of career options, and they knew more names of the providers in their county. Their practice ACT scores increased slightly, and their assessment that they were well prepared to take the ACT improved. Seventy-five percent have pursued a health career, and 10% have entered medical school. CONCLUSIONS: A summer program that allows high school students to shadow health professionals in their hometown and study in a virtual classroom can accomplish modest academic gains while producing more positive opinions about the health care in their county. They also report better understanding of the career options available to them. PMID- 25275284 TI - Community partnered projects: residents engaging with community health centers to improve care. AB - BACKGROUND: Important residency curricular elements, including scholarship, quality improvement (QI), and community health, often exist as independent components. We developed a curriculum to train residents to become community responsive physicians that included longitudinal care at a community health center (CHC) with a unique community-partnered project (CPP). We evaluated outcomes of one CPP and delineated challenges in implementing the curriculum. METHODS: After performing a needs assessment, the resident-CHC team designed a QI intervention to improve documentation of smoking status and cessation counseling. A chart review of 100 random patients assessed pre- and post-intervention documentation. Patient focus groups were held to guide the development of the final intervention, which included medical assistant (MA) education, appropriate patient education materials, and a visual communication system for MAs and providers. Curriculum evaluation via interviews with residency and community partners was done periodically throughout the 2-year process. RESULTS: Focus group participants saw clinicians as a resource for quitting but did not want to talk about quitting at every visit. We reviewed 317 patient visits pre-QI intervention and 191 post-QI intervention. There were no significant changes in the percent of visits where smoking status was documented (82% versus 79%); however, smoking cessation counseling during office visits increased significantly (19% to 54%). Key challenges included academic-community communication and resident scheduling and availability. CONCLUSIONS: In this CPP curriculum, residents made a difference in practice outcomes, and ongoing attention to challenges assisted with the project's success, possibly enhancing residents' likelihood of incorporating QI and principles of community health into their future careers. PMID- 25275287 TI - Comprehensive GME reform-the time is now. PMID- 25275288 TI - From acquisition to participation: theorizing virtual patient use in family medicine education. PMID- 25275289 TI - Authors' reply to from acquisition to participation: theorizing virtual patient use in family medicine education. PMID- 25275290 TI - Anomalous origin of the right coronary artery from the posterior, non-coronary sinus of Valsalva diagnosed by cardiac magnetic resonance imaging. AB - Anomalous origin of the right coronary artery from the posterior, non-coronary sinus is extremely rare and has never been reported in a paediatric-age competitive athlete. We report this very rare case of the right coronary artery arising from the posterior sinus. In the anomalous right coronary from the posterior sinus, the proximal right coronary artery appears widely patent and has no interarterial course. PMID- 25275291 TI - Three-dimensional reconstruction of skeletal muscle extracellular matrix ultrastructure. AB - The skeletal muscle extracellular matrix (ECM) supports muscle's passive mechanical function and provides a unique environment for extracellular tissues such as nerves, blood vessels, and a cadre of mononuclear cells. Within muscle ECM, collagen is thought to be the primary load-bearing protein, yet its structure and organization with respect to muscle fibers, tendon, and mononuclear cells is unknown. Detailed examination of extracellular collagen morphology requires high-resolution electron microscopy performed over relatively long distances because multinucleated muscle cells are very long and extend from several millimeters to several centimeters. Unfortunately, there is no tool currently available for high resolution ECM analysis that extends over such distances relevant to muscle fibers. Serial block face scanning electron microscopy is reported here to examine skeletal muscle ECM ultrastructure over hundreds of microns. Ruthenium red staining was implemented to enhance contrast and utilization of variable pressure imaging reduced electron charging artifacts, allowing continuous imaging over a large ECM volume. This approach revealed previously unappreciated perimysial collagen structures that were reconstructed via both manual and semi-automated segmentation methods. Perimysial collagen structures in the ECM may provide a target for clinical therapies aimed at reducing skeletal muscle fibrosis and stiffness. PMID- 25275293 TI - Risk for uveitis with oral moxifloxacin: a comparative safety study. AB - IMPORTANCE: Numerous case reports have suggested that the recent use of moxifloxacin may lead to uveitis. This epidemiologic study is, to our knowledge, the first to explore the relationship between oral moxifloxacin hydrochloride use and uveitis. OBSERVATIONS: We conducted a case-control study within a cohort of men aged 40 to 85 years followed up from January 2001 through December 2011. All cases with a new diagnosis of uveitis were identified. For each case, 10 control subjects were matched by age, cohort entry date, and follow-up duration. For identified uveitis cases, current use of moxifloxacin, levofloxacin, or ciprofloxacin hydrochloride was compared with nonuse. Rate ratios were adjusted for potential confounding variables. We identified 13,313 uveitis cases and 133,130 corresponding controls. Compared with nonusers of fluoroquinolones, current first-time users of moxifloxacin demonstrated the highest risk for uveitis (adjusted rate ratio, 2.98 [95% CI, 1.80-4.94]). Current first-time users of ciprofloxacin (adjusted rate ratio, 1.96 [95% CI, 1.56-2.47]) showed an increased risk for uveitis, while current first-time users of levofloxacin (adjusted rate ratio, 1.26 [95% CI, 0.90-1.77]) did not show a significant association with uveitis. CONCLUSION AND RELEVANCE: Current use of moxifloxacin or ciprofloxacin appears to increase the risk for uveitis. A statistically significant association of current first-time use of levofloxacin with uveitis could not be identified. Levofloxacin may pose the least risk for uveitis compared with moxifloxacin and ciprofloxacin. PMID- 25275294 TI - miR-524-5p suppresses the growth of oncogenic BRAF melanoma by targeting BRAF and ERK2. AB - It has been well documented that miRNAs can modulate the effectiveness of cancer associated signaling pathways. Mitogen-activated protein kinase (MAPK/ERK) signaling plays an essential role in the progression of many cancers, including melanoma and colon cancers. However, no single miRNA is reported to directly target multiple components of the MAPK/ERK pathway. We performed a miRNA PCR array screening with various MAPK/ERK signaling activities. The miRNA array data revealed that the expression of miR-524-5p was decreased in cells with an active MAPK/ERK pathway and confirmed that the expression of miR-524-5p is inversely associated with the activity of the MAPK/ERK pathway. We demonstrated that miR 524-5p directly binds to the 3'-untranslated regions of both BRAFandERK2 and suppresses the expression of these proteins. Because BRAF and ERK2 are the main components of MAPK signaling, the overexpression of miR-524-5p effectively inhibits MAPK/ERK signaling, tumor proliferation, and melanoma cell migration. Moreover, tumors overexpressing miR-524-5p were significantly smaller than those of the negative control mice. Our findings provide new insight into the role of miR-524-5p as an important miRNA that negatively regulates the MAPK/ERK signaling pathway, suggesting that miR-524-5p could be a potent therapeutic candidate for melanoma treatment. PMID- 25275295 TI - Chemoradiation provides a physiological selective pressure that increases the expansion of aberrant TP53 tumor variants in residual rectal cancerous regions. AB - Neoadjuvant chemoradiotherapy has been introduced in patients with surgically resected rectal cancer and reduced the local recurrence. Heterogeneity exists in rectal cancer, and we hypothesized that there are subclones resistant to chemoradiotherapy within the cancer mass. We performed DNA-targeted sequencing of pre- and post-treatment tumor tissues obtained from 20 rectal cancer patients who received chemoradiotherapy. The variant frequency of the mutant clones was compared between pre- and post-treatment samples of nine non-responder patients. RNA-targeted sequencing of 57 genes related to sensitivity to chemotherapy and radiotherapy was performed for the paired samples. Immunohistochemical analyses of p53 expression were also performed on the paired samples from the nine non responder patients. DNA-sequencing detected frequent mutations of suppressor genes including TP53, APC and FBXW7 in the post-treatment samples of the nine non responders. The frequency of TP53 mutations showed significant increases after chemoradiotherapy. RNA-targeted sequencing of 29 tumor tissues demonstrated that decreased expression of three genes and increased expression of four genes were detected in the post-treatment samples. Significantly increased expression of TP53 was observed in the post-treatment samples. Immunohistochemical staining for p53 revealed that increased p53 intensity scores were observed after chemoradiotherapy. These results suggest that the tumors with TP53 mutations tend to accumulate through chemoradiotherapy. PMID- 25275296 TI - HAX1 regulates E3 ubiquitin ligase activity of cIAPs by promoting their dimerization. AB - HS-1-associated protein X-1 (HAX1) is a multi-functional protein which was first identified as a Hematopoietic cell specific Lyn Substrate 1 (HS1)-binding protein. Although the roles of HAX1 in apoptosis have been unraveled and HAX1 has been proposed to be involved in several diseases, additional roles of HAX1 are still being identified. Here, we demonstrated that HAX1 directly interacted with cellular Inhibitor of Apoptosis Proteins (cIAPs), ubiquitin E3 ligases which regulate the abundance of cellular proteins, via ubiquitin-dependent proteasomal degradation. We showed that HAX1 promotes auto-ubiquitination and degradation of cIAPs by facilitating the intermolecular homodimerization of RING finger domain. Moreover, HAX1 regulates the non-canonical Nuclear Factor-kappaB (NF-kappaB) signaling pathway by modulating the stability of NF-kappaB-Inducing Kinase (NIK), which is one of the substrates of cIAPs. Taken together, these results unveil a novel role of HAX1 in the non-canonical NF-kappaB pathway, and provide an important clue that HAX1 is a potential therapeutic target for the treatment of cancer. PMID- 25275297 TI - Oncogene addiction: resetting the safety switch? PMID- 25275298 TI - The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies. AB - The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-beta in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration. PMID- 25275299 TI - Heterotrimeric G-protein alpha-12 (Galpha12) subunit promotes oral cancer metastasis. AB - Oral squamous cell carcinoma (OSCC) has a propensity to spread to the cervical lymph nodes (LN). The presence of cervical LN metastases severely impacts patient survival, whereby the two-year survival for oral cancer patients with involved LN is ~30% compared to over 80% in patients with non-involved LN. Elucidation of key molecular mechanisms underlying OSCC metastasis may afford an opportunity to target specific genes, to prevent the spread of OSCC and to improve patient survival. In this study, we demonstrated that expression of the heterotrimeric G protein alpha-12 (Galpha12) is highly up-regulated in primary tumors and LN of OSCC patients, as assessed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). We also found that exogenous expression of the constitutively activated-form of Galpha12 promoted cell migration and invasion in OSCC cell lines. Correspondingly, inhibition of Galpha12 expression by shRNA consistently inhibited OSCC cell migration and invasion in vitro. Further, the inhibition of G12 signaling by regulator of G-protein signaling (RGS) inhibited Galpha12-mediated RhoA activation, which in turn resulted in reduced LN metastases in a tongue-orthotopic xenograft mouse model of oral cancer. This study provides a rationale for future development and evaluation of drug candidates targeting Galpha12-related pathways for metastasis prevention. PMID- 25275302 TI - Live cell off-target identification of lapatinib using ligand-directed tosyl chemistry. AB - We demonstrate that ligand-directed tosyl (LDT) chemistry is applicable to off target identification in live cells. Lapatinib (Lap)-based LDT reagents not only labeled a receptor tyrosine kinase, HER2, target protein, but also the protein disulfide isomerase (PDI) that should be an off-target protein for Lap. PMID- 25275301 TI - Src-dependent phosphorylation at Y406 on the thyroid hormone receptor beta confers the tumor suppressor activity. AB - Association studies suggest that the thyroid hormone receptor beta1 (TRbeta1) could function as a tumor suppressor in cancer cells. However, the underlying molecular mechanisms remain to be elucidated. We explored how TRbeta1 acted as a tumor suppressor in breast cancer MDA cells. Proliferation and invasiveness were markedly inhibited in cells stably expressing TRbeta1 (MDA-TRbeta1 cells). cSrc phosphorylated TRbeta1 at Y406 signaled T3-induced degradation. Mutation of Y406 to Phe (TRbeta1Y406F) did not affect T3 binding affinity, but blocked T3-induced degradation in cells. Importantly, cell-based studies showed that TRbeta1Y406F lost the inhibitory effects by TRbeta1 on cell proliferation and invasion. Consistently, in xenograft models, MDA-TRbeta1 cells exhibited significantly slower tumor growth rates than those of Neo control cells. In contrast, the tumor growth rates of MDA-TRbeta1Y406F cells were indistinguishable from those of Neo control cells. We further showed that markedly more TRbeta1Y406F than TRbeta1 was physically associated with cSrc in cells, leading to constitutive activation of cSrc-FAK-ERK signaling. In contrast, degradation of T3-bound TRbeta1 complexed with cSrc attenuated signaling to decrease cell proliferation and invasiveness, thus confirming TRbeta1 as a tumor suppressor. Thus, the present studies suggested that TRbeta1 could be tested as a novel potential therapeutic target. PMID- 25275300 TI - Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. AB - The therapeutic response and clinical outcome of patients diagnosed with the same cancer type and that receive identical treatment is highly variable to reflect the genetic heterogeneity within tumor cells. Non-coding RNAs (ncRNAs) are recently discovered molecules that regulate eukaryotic gene expression and represent a significant advance towards a better understanding of the mechanisms that govern cellular growth. NcRNAs are essential for the proper regulation of cell proliferation and survival under physiologic conditions and are deregulated in many pathologies, e.g., human cancers. NcRNAs have been associated with cancer diagnosis, staging, treatment response, metastasis and survival and include distinct subtypes, e.g., long ncRNAs (lncRNAs) and microRNAs (miRNAs). LncRNAs have been linked to essential growth-promoting activities and their deregulation contributes to tumor cell survival. A prominent example is the Hox transcript antisense intergenic lncRNA, HOTAIR, that cooperates with the polycomb repressive complex to reprogram chromatin organization. HOTAIR expression is deregulated in a spectrum of cancers and HOTAIR expression correlates with patient survival. Here, we highlight emerging evidence that supports a role for lncRNAs in cancer with implications for the development of novel diagnostics and therapeutics. PMID- 25275303 TI - Temperature governs on-host distribution of the northern fowl mite, Ornithonyssus sylviarum (Acari: Macronyssidae). AB - The northern fowl mite, Ornithonyssus sylviarum (Canestri & Fanzago), is an ectoparasite of more than 70 species of North American wild birds, but it has a particularly significant impact on chickens, where it is a permanent resident of vent feathers. Improved control practices depend on a better understanding of host-mite relationships. ISA Brown hens were inoculated experimentally with northern fowl mite adults, and northern fowl mite populations developed naturally. Using a fast-response microprobe, temperatures of individual vent feathers (n = 15) were recorded at 5-mm increments along the length of the feather shaft. Immediately after temperatures were recorded, the individual feathers were quickly clipped at the skin surface and then flash-frozen between 2 small blocks of dry ice, freezing all northern fowl mite stages in situ. The feathers then were cut into 5-mm sections for careful mite enumeration by life stage. There were no overall differences among life stages in the distributions on the feather. Mite positions on feathers (distance from skin) varied distinctly with feather zone temperatures, as well as with ambient and average temperatures over the prior 24 hr. Ambient temperature at time of sampling affected the positions of the 2 mobile categories, adults and larvae/nymphs, but showed no statistical relationship with egg distribution. In contrast, ambient 24-hr temperature influenced the positions of all life stages. On-host feather temperatures reflected ambient temperatures. Feathers collected on hot days (ambient temperatures of 23-33 C) provided a narrow and quite warm range of temperature conditions for mites (often >30-36 C). Temperatures on cool days (ambient temperatures of <23 C) provided much wider on-host temperature ranges for mites to occupy (13-35 C). Mites were farther from the skin on warmer days. When mites had a broad range of temperatures, the feather temperature zone occupied by all life stages averaged 28-29 C. Mites move to occupy favorable temperature conditions on-host. When further out on feathers in warm weather, and under thermal stress, northern fowl mites either move off host or are dislodged. They then become a human pest, are noticed by farmers, and are more likely to disperse. PMID- 25275304 TI - JAK2/STAT3 inhibition attenuates noise-induced hearing loss. AB - Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor that plays a key role in oxidative stress mediated tissue injury. As reactive oxygen species (ROS) are a known source of damage to tissues of the inner ear following loud sound exposure, we examined the role of the Janus kinase 2 (JAK2)/STAT3 signaling pathway in noise induce hearing loss using the pathway specific inhibitor, JSI-124. Mice were exposed to a moderately damaging level of loud sound revealing the phosphorylation of STAT3 tyrosine 705 residues and nuclear localization in many cell types in the inner ear including the marginal cells of the stria vascularis, type II, III, and IV fibrocytes, spiral ganglion cells, and in the inner hair cells. Treatment of the mice with the JAK2/STAT3 inhibitor before noise exposure reduced levels of phosphorylated STAT3 Y705. We performed auditory brain stem response and distortion product otoacoustic emission measurements and found increased recovery of hearing sensitivity at two weeks after noise exposure with JAK2/STAT3 inhibition. Performance of cytocochleograms revealed improved outer hair cell survival in JSI-124 treated mice relative to control. Finally, JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. Together, these findings demonstrate that inhibiting the JAK2/STAT3 signaling pathway is protective against noise-induced cochlear tissue damage and loss of hearing sensitivity. PMID- 25275305 TI - Mycobacterium bovis in Burkina Faso: epidemiologic and genetic links between human and cattle isolates. AB - BACKGROUND: In sub-Saharan Africa, bovine tuberculosis (bTB) is a potential hazard for animals and humans health. The goal of this study was to improve our understanding of bTB epidemiology in Burkina Faso and especially Mycobacterium bovis transmission within and between the bovine and human populations. METHODOLOGY/PRINCIPAL FINDINGS: Twenty six M. bovis strains were isolated from 101 cattle carcasses with suspected bTB lesions during routine meat inspections at the Bobo Dioulasso and Ouagadougou slaughterhouses. In addition, 7 M. bovis strains were isolated from 576 patients with pulmonary tuberculosis. Spoligotyping, RDAf1 deletion and MIRU-VNTR typing were used for strains genotyping. The isolation of M. bovis strains was confirmed by spoligotyping and 12 spoligotype signatures were detected. Together, the spoligotyping and MIRU VNTR data allowed grouping the 33 M. bovis isolates in seven clusters including isolates exclusively from cattle (5) or humans (1) or from both (1). Moreover, these data (genetic analyses and phenetic tree) showed that the M. bovis isolates belonged to the African 1 (Af1) clonal complex (81.8%) and the putative African 5 (Af5) clonal complex (18.2%), in agreement with the results of RDAf1 deletion typing. CONCLUSIONS/SIGNIFICANCE: This is the first detailed molecular characterization of M. bovis strains from humans and cattle in Burkina Faso. The distribution of the two Af1 and putative Af5 clonal complexes is comparable to what has been reported in neighbouring countries. Furthermore, the strain genetic profiles suggest that M. bovis circulates across the borders and that the Burkina Faso strains originate from different countries, but have a country-specific evolution. The genetic characterization suggests that, currently, M. bovis transmission occurs mainly between cattle, occasionally between cattle and humans and potentially between humans. This study emphasizes the bTB risk in cattle but also in humans and the difficulty to set up proper disease control strategies in Burkina Faso. PMID- 25275306 TI - Natural isotopic signatures of variations in body nitrogen fluxes: a compartmental model analysis. AB - Body tissues are generally 15N-enriched over the diet, with a discrimination factor (Delta15N) that varies among tissues and individuals as a function of their nutritional and physiopathological condition. However, both 15N bioaccumulation and intra- and inter-individual Delta15N variations are still poorly understood, so that theoretical models are required to understand their underlying mechanisms. Using experimental Delta15N measurements in rats, we developed a multi-compartmental model that provides the first detailed representation of the complex functioning of the body's Delta15N system, by explicitly linking the sizes and Delta15N values of 21 nitrogen pools to the rates and isotope effects of 49 nitrogen metabolic fluxes. We have shown that (i) besides urea production, several metabolic pathways (e.g., protein synthesis, amino acid intracellular metabolism, urea recycling and intestinal absorption or secretion) are most probably associated with isotope fractionation and together contribute to 15N accumulation in tissues, (ii) the Delta15N of a tissue at steady-state is not affected by variations of its P turnover rate, but can vary according to the relative orientation of tissue free amino acids towards oxidation vs. protein synthesis, (iii) at the whole-body level, Delta15N variations result from variations in the body partitioning of nitrogen fluxes (e.g., urea production, urea recycling and amino acid exchanges), with or without changes in nitrogen balance, (iv) any deviation from the optimal amino acid intake, in terms of both quality and quantity, causes a global rise in tissue Delta15N, and (v) Delta15N variations differ between tissues depending on the metabolic changes involved, which can therefore be identified using simultaneous multi-tissue Delta15N measurements. This work provides proof of concept that Delta15N measurements constitute a new promising tool to investigate how metabolic fluxes are nutritionally or physiopathologically reorganized or altered. The existence of such natural and interpretable isotopic biomarkers promises interesting applications in nutrition and health. PMID- 25275307 TI - Dynamics of DNA replication during premeiosis and early meiosis in wheat. AB - Meiosis is a specialised cell division that involves chromosome replication, two rounds of chromosome segregation and results in the formation of the gametes. Meiotic DNA replication generally precedes chromosome pairing, recombination and synapsis in sexually developing eukaryotes. In this work, replication has been studied during premeiosis and early meiosis in wheat using flow cytometry, which has allowed the quantification of the amount of DNA in wheat anther in each phase of the cell cycle during premeiosis and each stage of early meiosis. Flow cytometry has been revealed as a suitable and user-friendly tool to detect and quantify DNA replication during early meiosis in wheat. Chromosome replication was detected in wheat during premeiosis and early meiosis until the stage of pachytene, when chromosomes are associated in pairs to further recombine and correctly segregate in the gametes. In addition, the effect of the Ph1 locus, which controls chromosome pairing and affects replication in wheat, was also studied by flow cytometry. Here we showed that the Ph1 locus plays an important role on the length of meiotic DNA replication in wheat, particularly affecting the rate of replication during early meiosis in wheat. PMID- 25275308 TI - Rapid Fishery Assessment by Market Survey (RFAMS)--an improved rapid-assessment approach to characterising fish landings in developing countries. AB - The complex multi-gear, multi-species tropical fisheries in developing countries are poorly understood and characterising the landings from these fisheries is often impossible using conventional approaches. A rapid assessment method for characterising landings at fish markets, using an index of abundance and estimated weight within taxonomic groups, is described. This approach was developed for contexts where there are no detailed data collection protocols, and where consistent data collection across a wide range of fisheries types and geographic areas is required, regardless of the size of the site and scale of the landings. This methodology, which was demonstrated at seven fish landing sites/fish markets in southern Indonesia between July 2008 and January 2011, provides a rapid assessment of the abundance and diversity in the wild catch over a wide variety of taxonomic groups. The approach has wider application for species-rich fisheries in developing countries where there is an urgent need for better data collection protocols, monitoring future changes in market demographics, and evaluating health of fisheries. PMID- 25275309 TI - Synergy between sphingosine 1-phosphate and lipopolysaccharide signaling promotes an inflammatory, angiogenic and osteogenic response in human aortic valve interstitial cells. AB - Given that the bioactive lipid sphingosine 1-phosphate is involved in cardiovascular pathophysiology, and since lipid accumulation and inflammation are hallmarks of calcific aortic stenosis, the role of sphingosine 1-phosphate on the pro-inflammatory/pro-osteogenic pathways in human interstitial cells from aortic and pulmonary valves was investigated. Real-time PCR showed sphingosine 1 phosphate receptor expression in aortic valve interstitial cells. Exposure of cells to sphingosine 1-phosphate induced pro-inflammatory responses characterized by interleukin-6, interleukin-8, and cyclooxygenase-2 up-regulations, as observed by ELISA and Western blot. Strikingly, cell treatment with sphingosine 1 phosphate plus lipopolysaccharide resulted in the synergistic induction of cyclooxygenase-2, and intercellular adhesion molecule 1, as well as the secretion of prostaglandin E2, the soluble form of the intercellular adhesion molecule 1, and the pro-angiogenic factor vascular endothelial growth factor-A. Remarkably, the synergistic effect was significantly higher in aortic valve interstitial cells from stenotic than control valves, and was drastically lower in cells from pulmonary valves, which rarely undergo stenosis. siRNA and pharmacological analysis revealed the involvement of sphingosine 1-phosphate receptors 1/3 and Toll-like receptor-4, and downstream signaling through p38/MAPK, protein kinase C, and NF-kappaB. As regards pro-osteogenic pathways, sphingosine 1-phosphate induced calcium deposition and the expression of the calcification markers bone morphogenetic protein-2 and alkaline phosphatase, and enhanced the effect of lipopolysaccharide, an effect that was partially blocked by inhibition of sphingosine 1-phosphate receptors 3/2 signaling. In conclusion, the interplay between sphingosine 1-phosphate receptors and Toll-like receptor 4 signaling leads to a cooperative up-regulation of inflammatory, angiogenic, and osteogenic pathways in aortic valve interstitial cells that seems relevant to the pathogenesis of aortic stenosis and may allow the inception of new therapeutic approaches. PMID- 25275311 TI - Adenovirus-encoding virus-associated RNAs suppress HDGF gene expression to support efficient viral replication. AB - Non-coding small RNAs are involved in many physiological responses including viral life cycles. Adenovirus-encoding small RNAs, known as virus-associated RNAs (VA RNAs), are transcribed throughout the replication process in the host cells, and their transcript levels depend on the copy numbers of the viral genome. Therefore, VA RNAs are abundant in infected cells after genome replication, i.e. during the late phase of viral infection. Their function during the late phase is the inhibition of interferon-inducible protein kinase R (PKR) activity to prevent antiviral responses; recently, mivaRNAs, the microRNAs processed from VA RNAs, have been reported to inhibit cellular gene expression. Although VA RNA transcription starts during the early phase, little is known about its function. The reason may be because much smaller amount of VA RNAs are transcribed during the early phase than the late phase. In this study, we applied replication deficient adenovirus vectors (AdVs) and novel AdVs lacking VA RNA genes to analyze the expression changes in cellular genes mediated by VA RNAs using microarray analysis. AdVs are suitable to examine the function of VA RNAs during the early phase, since they constitutively express VA RNAs but do not replicate except in 293 cells. We found that the expression level of hepatoma-derived growth factor (HDGF) significantly decreased in response to the VA RNAs under replication-deficient condition, and this suppression was also observed during the early phase under replication-competent conditions. The suppression was independent of mivaRNA-induced downregulation, suggesting that the function of VA RNAs during the early phase differs from that during the late phase. Notably, overexpression of HDGF inhibited AdV growth. This is the first report to show the function, in part, of VA RNAs during the early phase that may be contribute to efficient viral growth. PMID- 25275310 TI - Genome-wide discovery of drug-dependent human liver regulatory elements. AB - Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements. PMID- 25275312 TI - IL-32gamma delays spontaneous apoptosis of human neutrophils through MCL-1, regulated primarily by the p38 MAPK pathway. AB - IL-32gamma is a multifunctional cytokine involved in various inflammatory and auto-immune diseases in which neutrophils can affect the evolution of these diseases. To persist at inflammatory sites, neutrophils require inhibition of their rapid and constitutive apoptosis, an inhibitory effect that phlogogenic cytokines support. To date, the effects of IL-32gamma on neutrophils remain unknown. We demonstrate that IL-32gamma delays, in a dose-dependent manner, the spontaneous apoptosis of human blood neutrophils by activating mainly p38 MAPK through rapid p38 phosphorylation. PI3-K and ERK1/2 MAPK are also involved, but to a lesser extent. Most of cytokines that induce retardation of neutrophil apoptosis activate the expression of MCL-1 at both mRNA and protein levels. IL 32gamma added to human blood neutrophils in vitro is associated with sustained levels of MCL-1 protein. This effect in neutrophils corresponds to a decrease of MCL-1 protein degradation without any effect on MCL-1 mRNA levels. The sustained levels of MCL-1 induced by IL-32gamma are only abrogated by the p38beta MAPK inhibitor SB202190. Additionally, IL-32gamma induces a reduction in caspase 3 activity in neutrophils. In conclusion, IL-32gamma affects human blood neutrophils in vitro by increasing their survival, suggesting that this cytokine could have profound effects on the deleterious functions of neutrophils in several diseases. PMID- 25275313 TI - Cannabinoids alleviate experimentally induced intestinal inflammation by acting at central and peripheral receptors. AB - BACKGROUND AND AIMS: In an attempt to further investigate the role of cannabinoid (CB) system in the pathogenesis of inflammatory bowel diseases, we employed two recently developed ligands, AM841 (a covalently acting CB agonist) and CB13 (a peripherally-restricted CB agonist) to establish whether central and peripheral CB sites are involved in the anti-inflammatory action in the intestine. METHODS AND RESULTS: AM841 (0.01, 0.1 and 1 mg/kg, i.p.) significantly decreased inflammation scores in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-treated mice when administered before induction of colitis or as a treatment of existing intestinal inflammation. The effect was absent in CB1, CB2 and CB(1/2)-deficient mice. A peripherally-restricted agonist CB13 did not alleviate colitis when given i.p. (0.1 mg/kg), but significantly decreased inflammation score after central administration (0.1 ug/animal). CONCLUSIONS: This is the first evidence that central and peripheral CB receptors are responsible for the protective and therapeutic action of cannabinoids in mouse models of colitis. Our observations provide new insight to CB pharmacology and validate the use of novel ligands AM841 and CB13 as potent tools in CB-related research. PMID- 25275314 TI - Study of the affinity between the protein kinase PKA and peptide substrates derived from kemptide using molecular dynamics simulations and MM/GBSA. AB - We have carried out a protocol in computational biochemistry including molecular dynamics (MD) simulations and MM/GBSA free energy calculations on the complex between the protein kinase A (PKA) and the specific peptide substrate Kemptide (LRRASLG). We made the same calculations on other PKA complexes that contain Kemptide derivatives (with mutations of the arginines, and with deletions of N and C-terminal amino acids). We predicted shifts in the free energy changes from the free PKA to PKA-substrate complex (DeltaDeltaG(E->ES)) when Kemptide structure is modified (we consider that the calculated shifts correlate with the experimental shifts of the free energy changes from the free PKA to the transition states (DeltaDeltaG(E->TS)) determined by the catalytic efficiency (k(cat)/K(M)) changes). Our results demonstrate that it is possible to predict the kinetic properties of protein kinases using simple computational biochemistry methods. As an additional benefit, these methods give detailed molecular information that permit the analysis of the atomic forces that contribute to the affinity between protein kinases and their substrates. PMID- 25275315 TI - How are health research priorities set in low and middle income countries? A systematic review of published reports. AB - BACKGROUND: Priority setting is increasingly recognised as essential for directing finite resources to support research that maximizes public health benefits and drives health equity. Priority setting processes have been undertaken in a number of low- and middle-income country (LMIC) settings, using a variety of methods. We undertook a critical review of reports of these processes. METHODS AND FINDINGS: We searched electronic databases and online for peer reviewed and non-peer reviewed literature. We found 91 initiatives that met inclusion criteria. The majority took place at the global level (46%). For regional or national initiatives, most focused on Sub Saharan Africa (49%), followed by East Asia and Pacific (20%) and Latin America and the Caribbean (18%). A quarter of initiatives aimed to cover all areas of health research, with a further 20% covering communicable diseases. The most frequently used process was a conference or workshop to determine priorities (24%), followed by the Child Health and Nutrition Initiative (CHNRI) method (18%). The majority were initiated by an international organization or collaboration (46%). Researchers and government were the most frequently represented stakeholders. There was limited evidence of any implementation or follow-up strategies. Challenges in priority setting included engagement with stakeholders, data availability, and capacity constraints. CONCLUSIONS: Health research priority setting (HRPS) has been undertaken in a variety of LMIC settings. While not consistently used, the application of established methods provides a means of identifying health research priorities in a repeatable and transparent manner. In the absence of published information on implementation or evaluation, it is not possible to assess what the impact and effectiveness of health research priority setting may have been. PMID- 25275316 TI - Dengue viruses are enhanced by distinct populations of serotype cross-reactive antibodies in human immune sera. AB - Dengue viruses (DENV) are mosquito-borne flaviviruses of global importance. DENV exist as four serotypes, DENV1-DENV4. Following a primary infection, individuals produce DENV-specific antibodies that bind only to the serotype of infection and other antibodies that cross-react with two or more serotypes. People exposed to a secondary DENV infection with another serotype are at greater risk of developing more severe forms of dengue disease. The increased risk of severe dengue in people experiencing repeat DENV infections appear to be due, at least in part, to the ability of pre-existing serotype cross-reactive antibodies to form virus antibody complexes that can productively infect Fcgamma receptor-bearing target cells. While the theory of antibody-dependent enhancement (ADE) is supported by several human and small animal model studies, the specific viral antigens and epitopes recognized by enhancing human antibodies after natural infections have not been fully defined. We used antibody-depletion techniques to remove DENV specific antibody sub-populations from primary DENV-immune human sera. The effects of removing specific antibody populations on ADE were tested both in vitro using K562 cells and in vivo using the AG129 mouse model. Removal of serotype cross-reactive antibodies ablated enhancement of heterotypic virus infection in vitro and antibody-enhanced mortality in vivo. Further depletion studies using recombinant viral antigens showed that although the removal of DENV E-specific antibodies using recombinant E (rE) protein resulted in a partial reduction in DENV enhancement, there was a significant residual enhancement remaining. Competition ADE studies using prM-specific Fab fragments in human immune sera showed that both rE-specific and prM-specific antibodies in primary DENV-immune sera significantly contribute to enhancement of heterotypic DENV infection in vitro. Identification of the targets of DENV-enhancing antibodies should contribute to the development of safe, non-enhancing vaccines against dengue. PMID- 25275317 TI - Tracking functional brain changes in patients with depression under psychodynamic psychotherapy using individualized stimuli. AB - OBJECTIVE: Neurobiological models of depression posit limbic hyperactivity that should normalize after successful treatment. For psychotherapy, though, brain changes in patients with depression show substantial variability. Two critical issues in relevant studies concern the use of unspecific stimulation experiments and relatively short treatment protocols. Therefore changes in brain reactions to individualized stimuli were studied in patients with depression after eight months of psychodynamic psychotherapy. METHODS: 18 unmedicated patients with recurrent major depressive disorder were confronted with individualized and clinically derived content in a functional MRI experiment before (T1) and after eight months (T2) of psychodynamic therapy. A control group of 17 healthy subjects was also tested twice without intervention. The experimental stimuli were sentences describing each participant's dysfunctional interpersonal relationship patterns derived from clinical interviews based on Operationalized Psychodynamic Diagnostics (OPD). RESULTS: At T1 patients showed enhanced activation compared to controls in several limbic and subcortical regions, including amygdala and basal ganglia, when confronted with OPD sentences. At T2 the differences in brain activity between patients and controls were no longer apparent. Concurrently, patients had improved significantly in depression scores. CONCLUSIONS: Using ecologically valid stimuli, this study supports the model of limbic hyperactivity in depression that normalizes after treatment. Without a control group of untreated patients measured twice, though, changes in patients' brain activity could also be attributed to other factors than psychodynamic therapy. PMID- 25275318 TI - Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome. AB - Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14(++)CD16(-) monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. PMID- 25275319 TI - Memory maintenance in synapses with calcium-based plasticity in the presence of background activity. AB - Most models of learning and memory assume that memories are maintained in neuronal circuits by persistent synaptic modifications induced by specific patterns of pre- and postsynaptic activity. For this scenario to be viable, synaptic modifications must survive the ubiquitous ongoing activity present in neural circuits in vivo. In this paper, we investigate the time scales of memory maintenance in a calcium-based synaptic plasticity model that has been shown recently to be able to fit different experimental data-sets from hippocampal and neocortical preparations. We find that in the presence of background activity on the order of 1 Hz parameters that fit pyramidal layer 5 neocortical data lead to a very fast decay of synaptic efficacy, with time scales of minutes. We then identify two ways in which this memory time scale can be extended: (i) the extracellular calcium concentration in the experiments used to fit the model are larger than estimated concentrations in vivo. Lowering extracellular calcium concentration to in vivo levels leads to an increase in memory time scales of several orders of magnitude; (ii) adding a bistability mechanism so that each synapse has two stable states at sufficiently low background activity leads to a further boost in memory time scale, since memory decay is no longer described by an exponential decay from an initial state, but by an escape from a potential well. We argue that both features are expected to be present in synapses in vivo. These results are obtained first in a single synapse connecting two independent Poisson neurons, and then in simulations of a large network of excitatory and inhibitory integrate-and-fire neurons. Our results emphasise the need for studying plasticity at physiological extracellular calcium concentration, and highlight the role of synaptic bi- or multistability in the stability of learned synaptic structures. PMID- 25275320 TI - Promoter analysis reveals globally differential regulation of human long non coding RNA and protein-coding genes. AB - Transcriptional regulation of protein-coding genes is increasingly well understood on a global scale, yet no comparable information exists for long non coding RNA (lncRNA) genes, which were recently recognized to be as numerous as protein-coding genes in mammalian genomes. We performed a genome-wide comparative analysis of the promoters of human lncRNA and protein-coding genes, finding global differences in specific genetic and epigenetic features relevant to transcriptional regulation. These two groups of genes are hence subject to separate transcriptional regulatory programs, including distinct transcription factor (TF) proteins that significantly favor lncRNA, rather than coding-gene, promoters. We report a specific signature of promoter-proximal transcriptional regulation of lncRNA genes, including several distinct transcription factor binding sites (TFBS). Experimental DNase I hypersensitive site profiles are consistent with active configurations of these lncRNA TFBS sets in diverse human cell types. TFBS ChIP-seq datasets confirm the binding events that we predicted using computational approaches for a subset of factors. For several TFs known to be directly regulated by lncRNAs, we find that their putative TFBSs are enriched at lncRNA promoters, suggesting that the TFs and the lncRNAs may participate in a bidirectional feedback loop regulatory network. Accordingly, cells may be able to modulate lncRNA expression levels independently of mRNA levels via distinct regulatory pathways. Our results also raise the possibility that, given the historical reliance on protein-coding gene catalogs to define the chromatin states of active promoters, a revision of these chromatin signature profiles to incorporate expressed lncRNA genes is warranted in the future. PMID- 25275321 TI - Analysis of children's perception of triatomine vectors of chagas disease through drawings: opportunities for targeted health education. AB - BACKGROUND: Chagas disease is a tropical parasitic disease affecting about 10 million people, mostly in the Americas, and transmitted mainly by triatomine bugs. Insect vector control with indoor residual insecticides and the promotion of housing improvement is the main control intervention. The success of such interventions relies on their acceptance and appropriation by communities, which depends on their knowledge and perceptions of both the disease and the vector. In this study, we investigated school-aged children's knowledge and perception on triatomine vectors and Chagas disease to further understand how communities view this vector and the disease in Yucatan, Mexico. METHODOLOGY/PRINCIPAL FINDINGS: We performed an analysis of children's drawings on the theme of triatomines and their house in several rural villages, to explore in an open-ended manner their views, understanding and misconceptions. A total of 261 drawings were collected from children ages 6-12 from four villages. We found that children are very familiar with triatomine vectors, and know very well many aspects of their biology and ecology, and in particular their blood-feeding habits. On the other hand, their drawings suggest that the role of triatomines as vectors of a chronic and severe cardiac disease is less understood, and the main perceived health threat appears limited to the bite itself, as previously observed in adults. CONCLUSIONS/SIGNIFICANCE: These results have important implications for the specific design of future education materials and campaigns, and for the promotion of the inclusion of children in raising Chagas disease awareness in these endemic communities. PMID- 25275322 TI - The relationship between brain morphology and polysomnography in healthy good sleepers. AB - BACKGROUND: Normal sleep continuity and architecture show remarkable inter individual variability. Previous studies suggest that brain morphology may explain inter-individual differences in sleep variables. METHOD: Thirty-eight healthy subjects spent two consecutive nights at the sleep laboratory with polysomnographic monitoring. Furthermore, high-resolution T1-weighted MRI datasets were acquired in all participants. EEG sleep recordings were analyzed using standard sleep staging criteria and power spectral analysis. Using the FreeSurfer software for automated segmentation, 174 variables were determined representing the volume and thickness of cortical segments and the volume of subcortical brain areas. Regression analyses were performed to examine the relationship with polysomnographic and spectral EEG power variables. RESULTS: The analysis did not provide any support for the a-priori formulated hypotheses of an association between brain morphology and polysomnographic variables. Exploratory analyses revealed that the thickness of the left caudal anterior cingulate cortex was positively associated with EEG beta2 power (24-32 Hz) during REM sleep. The volume of the left postcentral gyrus was positively associated with periodic leg movements during sleep (PLMS). CONCLUSIONS: The function of the anterior cingulate cortex as well as EEG beta power during REM sleep have been related to dreaming and sleep-related memory consolidation, which may explain the observed correlation. Increased volumes of the postcentral gyrus may be the result of increased sensory input associated with PLMS. However, due to the exploratory nature of the corresponding analyses, these results have to be replicated before drawing firm conclusions. PMID- 25275323 TI - Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling. AB - The Insulin signaling pathway couples growth, development and lifespan to nutritional conditions. Here, we demonstrate a function for the Drosophila lipoprotein LTP in conveying information about dietary lipid composition to the brain to regulate Insulin signaling. When yeast lipids are present in the diet, free calcium levels rise in Blood Brain Barrier glial cells. This induces transport of LTP across the Blood Brain Barrier by two LDL receptor-related proteins: LRP1 and Megalin. LTP accumulates on specific neurons that connect to cells that produce Insulin-like peptides, and induces their release into the circulation. This increases systemic Insulin signaling and the rate of larval development on yeast-containing food compared with a plant-based food of similar nutritional content. PMID- 25275326 TI - Ibarapa programme: half a century of rural health service, training, and international cooperation in Nigeria. PMID- 25275324 TI - Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe and life threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1 domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation. METHODS: Wild-type (WT) mice and Spred-2( /-) mice were exposed to intratracheal LPS (50 ug in 50 uL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/-) mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. RESULTS: LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/-) mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-alpha, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS induced inflammation in Spred-2(-/-) mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE 12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. CONCLUSIONS: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI. PMID- 25275325 TI - Acylation stimulating protein, complement C3 and lipid metabolism in ketosis prone diabetic subjects. AB - BACKGROUND: Ketosis-prone diabetes (KPDM) is new-onset diabetic ketoacidosis without precipitating factors in non-type 1 diabetic patients; after management, some are withdrawn from exogenous insulin, although determining factors remain unclear. METHODS: Twenty KPDM patients and twelve type 1 diabetic patients (T1DM), evaluated at baseline, 12 and 24 months with/without insulin maintenance underwent a standardized mixed-meal tolerance test (MMTT) for 2 h. RESULTS: At baseline, triglyceride and C3 were higher during MMTT in KPDM vs. T1DM (p<0.0001) with no differences in non-esterified fatty acids (NEFA) while Acylation Stimulating Protein (ASP) tended to be higher. Within 12 months, 11 KPDM were withdrawn from insulin treatment (KPDM-ins), while 9 were maintained (KPDM+ins). NEFA was lower in KPDM-ins vs. KPDM+ins at baseline (p = 0.0006), 12 months (p<0.0001) and 24 months (p<0.0001) during MMTT. NEFA in KPDM-ins decreased over 30-120 minutes (p<0.05), but not in KPDM+ins. Overall, C3 was higher in KPDM-ins vs KPDM+ins at 12 months (p = 0.0081) and 24 months (p = 0.0019), while ASP was lower at baseline (p = 0.0024) and 12 months (p = 0.0281), with a decrease in ASP/C3 ratio. CONCLUSIONS: Notwithstanding greater adiposity in KPDM-ins, greater NEFA decreases and lower ASP levels during MMTT suggest better insulin and ASP sensitivity in these patients. PMID- 25275327 TI - Pilot walnut intervention study of urolithin bioavailability in human volunteers. AB - A pilot intervention study was conducted in human volunteers (n = 4) to establish the bioavailability of urolithins, which are the terminal end-products of ellagitannin metabolism by the gastrointestinal microflora. Biospecimens (blood, feces, and urine) along with urolithins purified therefrom were analyzed for their antioxidant capacity in a range of in vitro assays. Urolithin metabolites were identified and quantitated in the biospecimens by negative ion mode HPLC-ESI MS analysis. The data in this pilot study show that the metabolism of ellagitannins in the four volunteers gave rise to a diverse profile and a highly variable concentration of urolithins in urine. The concentration of glucuronidated urolithins in blood and urine did not correlate with antioxidant capacity. However, the antioxidant capacity of urine, but not plasma biospecimens, was highly correlated with uric acid concentration. The antioxidant capacity of fecal extracts correlated positively with the concentration of urolithin D in both the DPPH and FRAP assays, but not in the ORAC assay, which was entirely consistent with the in vitro assays for pure urolithin D. PMID- 25275328 TI - Increases in heroin overdose deaths - 28 States, 2010 to 2012. AB - Nationally, death rates from prescription opioid pain reliever (OPR) overdoses quadrupled during 1999-2010, whereas rates from heroin overdoses increased by <50%. Individual states and cities have reported substantial increases in deaths from heroin overdose since 2010. CDC analyzed recent mortality data from 28 states to determine the scope of the heroin overdose death increase and to determine whether increases were associated with changes in OPR overdose death rates since 2010. This report summarizes the results of that analysis, which found that, from 2010 to 2012, the death rate from heroin overdose for the 28 states increased from 1.0 to 2.1 per 100,000, whereas the death rate from OPR overdose declined from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. OPR overdose mortality declined significantly among males, persons aged <45 years, persons in the South, and non-Hispanic whites. Five states had increases in the OPR death rate, seven states had decreases, and 16 states had no change. Of the 18 states with statistically reliable heroin overdose death rates (i.e., rates based on at least 20 deaths), 15 states reported increases. Decreases in OPR death rates were not associated with increases in heroin death rates. The findings indicate a need for intensified prevention efforts aimed at reducing overdose deaths from all types of opioids while recognizing the demographic differences between the heroin and OPR-using populations. Efforts to prevent expansion of the number of OPR users who might use heroin when it is available should continue. PMID- 25275329 TI - Typhoid Fever surveillance and vaccine use - South-East Asia and Western Pacific regions, 2009-2013. AB - Typhoid fever is a serious, systemic infection resulting in nearly 22 million cases and 216,500 deaths annually, primarily in Asia. Safe water, adequate sanitation, appropriate personal and food hygiene, and vaccination are the most effective strategies for prevention and control. In 2008, the World Health Organization (WHO) recommended use of available typhoid vaccines to control endemic disease and outbreaks and strengthening of typhoid surveillance to improve disease estimates and identify high-risk populations (e.g., persons without access to potable water and adequate sanitation). This report summarizes the status of typhoid surveillance and vaccination programs in the WHO South-East Asia (SEAR) and Western Pacific regions (WPR) during 2009-2013, after the revised WHO recommendations. Data were obtained from the WHO/United Nations Children's Fund (UNICEF) Joint Reporting Form on Immunization, a supplemental survey of surveillance and immunization program managers, and published literature. During 2009-2013, 23 (48%) of 48 countries and areas of SEAR (11) and WPR (37) collected surveillance or notifiable disease data on typhoid cases, with most surveillance activities established before 2008. Nine (19%) countries reported implementation of typhoid vaccination programs or recommended vaccine use during 2009-2013. Despite the high incidence, typhoid surveillance is weak in these two regions, and vaccination efforts have been limited. Further progress toward typhoid fever prevention and control in SEAR and WPR will require country commitment and international support for enhanced surveillance, targeted use of existing vaccines and availability of newer vaccines integrated within routine immunization programs, and integration of vaccination with safe water, sanitation, and hygiene measures. PMID- 25275330 TI - Update: influenza activity -- United States and worldwide, May 18-September 20, 2014. AB - During May 18-September 20, 2014, the United States experienced low levels of seasonal influenza activity overall. Influenza A (H1N1)pdm09 (pH1N1), influenza A (H3N2), and influenza B viruses were detected worldwide and were identified sporadically in the United States. In August, two influenza A (H3N2) variant viruses (H3N2v) were detected in Ohio. This report summarizes influenza activity in the United States and worldwide during May 18-September 20, 2014. PMID- 25275331 TI - Ebola virus disease outbreak - West Africa, September 2014. AB - CDC is assisting ministries of health and working with other organizations to control and end the ongoing outbreak of Ebola virus disease (Ebola) in West Africa. The updated data in this report were compiled from ministry of health situation reports and World Health Organization (WHO) sources. Total case counts include all suspected, probable, and confirmed cases as defined by each country. These data reflect reported cases, which make up an unknown proportion of all actual cases. The data also reflect reporting delays that might vary from country to country. PMID- 25275332 TI - Ebola virus disease outbreak - Nigeria, July-September 2014. AB - On July 20, 2014, an acutely ill traveler from Liberia arrived at the international airport in Lagos, Nigeria, and was confirmed to have Ebola virus disease (Ebola) after being admitted to a private hospital. This index patient potentially exposed 72 persons at the airport and the hospital. The Federal Ministry of Health, with guidance from the Nigeria Centre for Disease Control (NCDC), declared an Ebola emergency. Lagos, (pop. 21 million) is a regional hub for economic, industrial, and travel activities and a setting where communicable diseases can be easily spread and transmission sustained. Therefore, implementing a rapid response using all available public health assets was the highest priority. On July 23, the Federal Ministry of Health, with the Lagos State government and international partners, activated an Ebola Incident Management Center as a precursor to the current Emergency Operations Center (EOC) to rapidly respond to this outbreak. The index patient died on July 25; as of September 24, there were 19 laboratory-confirmed Ebola cases and one probable case in two states, with 894 contacts identified and followed during the response. Eleven patients with laboratory-confirmed Ebola had been discharged, an additional patient was diagnosed at convalescent stage, and eight patients had died (seven with confirmed Ebola; one probable). The isolation wards were empty, and 891 (all but three) contacts had exited follow-up, with the remainder due to exit on October 2. No new cases had occurred since August 31, suggesting that the Ebola outbreak in Nigeria might be contained. The EOC, established quickly and using an Incident Management System (IMS) to coordinate the response and consolidate decision making, is largely credited with helping contain the Nigeria outbreak early. National public health emergency preparedness agencies in the region, including those involved in Ebola responses, should consider including the development of an EOC to improve the ability to rapidly respond to urgent public health threats. PMID- 25275333 TI - Importation and containment of Ebola virus disease - Senegal, August-September 2014. AB - On August 29, 2014, Senegal confirmed its first case of Ebola virus disease (Ebola) in a Guinean man, aged 21 years, who had traveled from Guinea to Dakar, Senegal, in mid-August to visit family. Senegalese medical and public health personnel were alerted about this patient after public health staff in Guinea contacted his family in Senegal on August 27. The patient had been admitted to a referral hospital in Senegal on August 26. He was promptly isolated, and a blood sample was sent for laboratory confirmation; Ebola was confirmed by reverse transcriptase-polymerase chain reaction at Institut Pasteur Dakar on August 29. The patient's mother and sister had been admitted to an Ebola treatment unit in Guinea on August 26, where they had named the patient as a contact and reported his recent travel to Senegal. Ebola was likely transmitted to the family from the brother of the patient, who had traveled by land from Sierra Leone to Guinea in early August seeking treatment from a traditional healer. The brother died in Guinea on August 10; family members, including the patient, participated in preparing the body for burial. PMID- 25275334 TI - Poly(amide-imide)/silica supported PEI hollow fiber sorbents for postcombustion CO(2) capture by RTSA. AB - Amine-loaded poly(amide-imide) (PAI)/silica hollow fiber sorbents are created and used in a rapid temperature swing adsorption (RTSA) system for CO2 capture under simulated postcombustion flue gas conditions. Poly(ethylenimine) (PEI) is infused into the PAI/mesoporous silica hollow fiber sorbents during fiber solvent exchange steps after fiber spinning. A lumen-side barrier layer is also successfully formed on the bore side of PAI/silica hollow fiber sorbents by using a mixture of Neoprene with cross-linking agents in a post-treatment process. The amine loaded fibers are tested in shell-and-tube modules by exposure on the shell side at 1 atm and 35 degrees C to simulated flue gas with an inert tracer (14 mol % CO2, 72 mol % N2, and 14 mol % He, at 100% relative humidity (RH)). The fibers show a breakthrough CO2 capacity of 0.85 mmol/g-fiber and a pseudoequilibrium CO2 uptake of 1.19 mmol/g-fiber. When tested in the temperature range of 35-75 degrees C, the PAI/silica/PEI fiber sorbents show a maximum CO2 capacity at 65 degrees C, owing to a trade-off between thermodynamic and kinetic factors. To overcome mass transfer limitations in rigidified PEI infused in the silica, an alternate PEI infusion method using a glycerol/PEI/methanol mixture is developed, and the CO2 sorption performance is improved significantly, effectively doubling the functional sorption capacity. Specifically, the glycerol plasticized sorbents are found to have a breakthrough and equilibrium CO2 capacity of 1.3 and 2.0 mmol/g of dry fiber sorbent at 35 degrees C, respectively. Thus, this work demonstrates two PAI-based sorbents that are optimized for different sorption conditions with the PAI/silica/PEI sorbents operating effectively at 65 degrees C and the PAI/silica/PEI-glycerol sorbents operating well at 35 degrees C with significantly improved sorption capacity. PMID- 25275335 TI - Viral myocarditis. AB - The term myocarditis describes inflammatory disorders of the heart muscle of varied infectious and non-infectious origins. It can be caused by any kind of infection, drugs, toxic substances, or be associated with autoimmune conditions. Viruses are the main causes at least in developed countries. Acute myocarditis most commonly results from an external inflammatory trigger inducing the host immune response, which may range from minimally transient response to fulminant overwhelming cellular infiltration. If the immune system does not eliminate the infectious pathogen early on, chronic infection develops with or without accompanying inflammation. Post-infectious autoimmunity may persist despite effective virus clearance. Since the pathological conditions take place at the cellular level, viral myocarditis and postinfectious autoimmunity can be suggested but not diagnosed clinically. All clinical methods including imaging techniques are misleading if infectious agents are involved. Accurate diagnosis demands simultaneous histologic, immunohistochemical and molecular biological workup of the tissue. If the primary infectious or immune-mediated causes of the disease are carefully defined by clinical and biopsy based tools, specific antiviral treatment options in addition to basic symptomatic therapy are available under certain conditions. These may allow a tailored cause-specific treatment that improves symptoms and prognosis of patients with acute and chronic disease. PMID- 25275336 TI - New water-soluble carbamate ester derivatives of resveratrol. AB - Low bioavailability severely hinders exploitation of the biomedical potential of resveratrol. Extensive phase-II metabolism and poor water solubility contribute to lowering the concentrations of resveratrol in the bloodstream after oral administration. Prodrugs may provide a solution-protection of the phenolic functions hinders conjugative metabolism and can be exploited to modulate the physicochemical properties of the compound. We report here the synthesis and characterization of carbamate ester derivatives of resveratrol bearing on each nitrogen atom a methyl group and either a methoxy-poly(ethylene glycol)-350 (mPEG 350) or a butyl-glucosyl promoiety conferring high water solubility. Ex vivo absorption studies revealed that the butyl-glucosyl conjugate, unlike the mPEG 350 one, is able to permeate the intestinal wall. In vivo pharmacokinetics confirmed absorption after oral administration and showed that no hydrolysis of the carbamate groups takes place. Thus, sugar groups can be attached to resveratrol to obtain soluble derivatives maintaining to some degree the ability to permeate biomembranes, perhaps by facilitated or active transport. PMID- 25275337 TI - Macular hole from a central retinal artery occlusion. PMID- 25275338 TI - High yield of bronchoscopic transparenchymal nodule access real-time image-guided sampling in a novel model of small pulmonary nodules in canines. AB - BACKGROUND: Bronchoscopic transparenchymal nodule access (BTPNA) is a novel approach to accessing pulmonary nodules. This real-time, image-guided approach was evaluated for safety, accuracy, and yield in the healthy canine model. METHODS: A novel, inorganic model of subcentimeter pulmonary nodules was developed, consisting of 0.25-cc aliquots of calcium hydroxylapatite (Radiesse) implanted via transbronchial access in airways seven generations beyond the main bronchi to represent targets for evaluation of accuracy and yield. Thoracic CT scans were acquired for each subject, and from these CT scans LungPoint Virtual Bronchoscopic Navigation software provided guidance to the region of interest. Novel transparenchymal nodule access software algorithms automatically generated point-of-entry recommendations, registered CT images, and real-time fluoroscopic images and overlaid guidance onto live bronchoscopic and fluoroscopic video to achieve a vessel-free, straight-line path from a central airway through parenchymal tissue for access to peripheral lesions. RESULTS: In a nine-canine cohort, the BTPNA procedure was performed to sample 31 implanted Radiesse targets, implanted to simulate pulmonary nodules, via biopsy forceps through a specially designed sheath. The mean length of the 31 tunnels was 35 mm (20.5-50.3 mm range). Mean tunnel creation time was 16:52 min, and diagnostic yield was 90.3% (28 of 31). No significant adverse events were noted in the status of any of the canine subjects post BTPNA, with no pneumothoraces and minimal bleeding (all bleeding events < 2 mL in volume). CONCLUSIONS: These canine studies demonstrate that BTPNA has the potential to achieve the high yield of transthoracic needle aspiration with the low complication profile associated with traditional bronchoscopy. These results merit further study in humans. PMID- 25275339 TI - Quality-of-life improvement after free gracilis muscle transfer for smile restoration in patients with facial paralysis. AB - IMPORTANCE: Facial paralysis can contribute to disfigurement, psychological difficulties, and an inability to convey emotion via facial expression. In patients unable to perform a meaningful smile, free gracilis muscle transfer (FGMT) can often restore smile function. However, little is known about the impact on disease-specific quality of life. OBJECTIVE: To determine quantitatively whether FGMT improves quality of life in patients with facial paralysis. DESIGN, SETTING, AND PARTICIPANTS: Prospective evaluation of 154 FGMTs performed at a facial nerve center on 148 patients with facial paralysis. The Facial Clinimetric Evaluation (FaCE) survey and Facial Assessment by Computer Evaluation software (FACE-gram) were used to quantify quality-of-life improvement, oral commissure excursion, and symmetry with smile. INTERVENTION: Free gracilis muscle transfer. MAIN OUTCOMES AND MEASURES: Change in FaCE score, oral commissure excursion, and symmetry with smile. RESULTS: There were 127 successful FGMTs on 124 patients and 14 failed procedures on 13 patients. Mean (SD) FaCE score increased significantly after successful FGMT (42.30 [15.9] vs 58.5 [17.60]; paired 2-tailed t test, P < .001). Mean (SD) FACE scores improved significantly in all subgroups (nonflaccid cohort, 37.8 [19.9] vs 52.9 [19.3]; P = .02; flaccid cohort, 43.1 [15.1] vs 59.6 [17.2]; P < .001; trigeminal innervation cohort, 38.9 [14.6] vs 55.2 [18.2]; P < .001; cross-face nerve graft cohort, 47.3 [16.6] vs 61.7 [16.9]; P < .001) except the failure cohort (36.5 [20.8] vs 33.5 [17.9]; Wilcoxon signed-rank test, P = .15). Analysis of 40 patients' photographs revealed a mean (SD) preoperative and postoperative excursion on the affected side of -0.88 (3.79) and 7.68 (3.38), respectively (P < .001); symmetry with smile improved from a mean (SD) of 13.8 (7.46) to 4.88 (3.47) (P < .001). CONCLUSIONS AND RELEVANCE: Free gracilis muscle transfer has become a mainstay in the management armamentarium for patients with severe reduction in oral commissure movement after facial nerve insult and recovery. We found a quantitative improvement in quality of life after FGMT in patients who could not recover a meaningful smile after facial nerve insult. Quality-of-life improvement was not statistically different between donor nerve groups or facial paralysis types. PMID- 25275340 TI - Injection of cardiac stem cells prolongs the survival of cardiac allograft rats. AB - Cardiac c-kit+ cells isolated from cardiac explant-derived cells modestly improve cardiac functions after myocardial infarction; however, their full potential has not yet been realized. The present study was undertaken to determine the isolation and culture of c-kit+ cardiac stem cells (CSCs), and the roles of myocardial injection of CSCs on the survival of rat cardiac allograft. Recipient Sprague-Dawley rats were transplanted with hearts from Wistar rats. In the in vitro experiment, c-kit+ cells were isolated from mouse heart fragment culture by magnetic cell sorting. CSCs expressed of cardiomyocyte specific protein cardiac troponin I, alpha smooth muscle actin and von Willebrand factor in conditioned culture. CSC injection increased graft survival of cardiac allograft rats. The effects of CSCs on increase in graft survival of cardiac allograft rats were blocked by stromal-derived factor-1 (SDF-1) knockdown. The expression of SDF-1 was increased after CSC injection into the cardiac of cardiac allograft rats. These results indicate that CSC injection into the cardiac prolongs graft survival of cardiac allograft rats. SDF-1 plays an important role in the effects of CSCs on the graft survival of cardiac allograft rats. PMID- 25275342 TI - Maternal hyperoxygenation and foetal cardiac MRI in the assessment of the borderline left ventricle. AB - Using phase-contrast MRI in a foetus with borderline left ventricular hypoplasia at 37 weeks' gestation we showed an increase in pulmonary blood flow during maternal hyperoxygenation. The associated increase in venous return to the left atrium, however, resulted in reversal of the atrial shunt, with no improvement in left ventricular output. The child initially underwent single ventricle palliation with a neonatal hybrid procedure, but following postnatal growth of the left ventricle tolerated conversion to a biventricular circulation at 5 months of age. We conclude that when there is significant restriction of filling or outflow obstruction across the left heart, neither prenatal nor postnatal acute pulmonary vasodilation can augment left ventricular output enough to support a biventricular circulation. Chronic pulmonary vasodilation may stimulate the growth of the left-sided structures allowing biventricular repair, raising the intriguing question of whether chronic maternal oxygen therapy might obviate the need for neonatal single ventricle pallation in the setting of borderline left ventricular hypoplasia. PMID- 25275341 TI - Effects of a blend of essential oils and an enzyme combination on nutrient digestibility, ileum histology and expression of inflammatory mediators in weaned piglets. AB - The aim of this study was to test the hypothesis of an improved gut environment of post-weaning piglets when administered a blend of essential oils (EO; thymol and cinnamaldehyde) and an enzyme combination (xylanase and beta-glucanase (XB)) either alone or in combination. To assess the effect of dietary treatments, faecal nutrient digestibility and microbial counts, as well as ileum histology and gene expression of inflammatory mediators were evaluated. One hundred and ninety-two weaned piglets were allocated into four experimental treatments, and fed the basal diet (CTRL) either without or with EO, XB or their combination (EO+XB) for a 42-day period. The experiment concerning digestibility was designed with two periods (period I: days 15 to 21; period II: days 29 to 35) and the faeces were collected on days 20, 21, 34 and 35. On day 42, six piglets from each treatment were slaughtered. It was found that EO, XB and EO+XB supplementation did not affect (P>0.05) the growth performance of the piglets from days 0 to 42. Moreover, no dietary effect on faecal score was observed. Faecal digestibility of dry matter, organic matter, ash, dietary fibre, lipid, CP and NDF were increased from period I to period II (P<0.01 to P=0.06), while no effect (P>0.05) of EO, XB or their combination on the faecal digestibility was observed at both periods. Compared with the CTRL diet, dietary XB reduced the faecal Lactobacillus and Escherichia coli counts but increased the Lactobacillus to Coliforms ratio on day 42 (P=0.02, 0.03 and 0.03, respectively), and all the additives supplementations decreased the counts of faecal Coliforms on day 42 (P<0.01). XB supplementation increased the villus to crypt ratio (P=0.04) and reduced the mucosal macrophages number (P<0.01) in the ileum compared with the CTRL group, and dietary EO or EO+XB decreased the number of lymphatic follicles (P=0.01 and P<0.01, respectively) and mucosal macrophages (P=0.02 and P<0.01, respectively). In addition, the interleukin (IL)-1alpha was downregulated in piglets treated with EO+XB compared with the EO group (P=0.02). In conclusion, the administration of EO, XB or their combination was effective in improving ileum histology, and EO+XB supplementation might benefit the modulation of the expression of ileum inflammatory cytokines in piglets. PMID- 25275343 TI - Differential cytotoxic properties of drugs used for intra-articular injection on human chondrocytes: an experimental in-vitro study. AB - BACKGROUND: Intra-articular injection of local anaesthetics, opioids and corticosteroids is frequently used to obtain perioperative analgesia following joint surgery. Although local anaesthetics were shown to induce chondrotoxicity, the safety profile regarding chondrotoxicity of other injected drugs is less clear. OBJECTIVE: Our objective was to investigate cytotoxicity of drugs used for intra-articular analgesia. DESIGN: An experimental in-vitro study. SETTING: Hannover Medical School, science laboratory, 2013. MATERIAL: Human cartilage cell line T/C 28-a2. INTERVENTION: Incubation of cells with different concentrations of bupivacaine, s-ketamine, morphine and dexamethasone for 1 h. MAIN OUTCOME MEASURES: Fraction of Annexin V positive and Annexin V and propidium iodide double positive cells after 1 h of incubation with tested drug measured by flow cytometry. RESULTS: Both morphine (0.1 to 10 MUmol l) and dexamethasone (10 to 1000 MUmol/l) failed to induce cytotoxicity after 1 h of exposure. The previously reported chondrotoxicity of bupivacaine (10 to 500 MUmol l or 2.8 to 140 MUg ml) was confirmed by a concentration-dependent increased staining with Annexin V and propidium iodide. Exposure to S-ketamine (10 to 500 MUmol l) induced a significant late apoptotic and necrotic cell fraction at 10 MUmol l or 2.4 MUg ml. Concentrations of 100 and 500 MUmol l induced a significant increase in early apoptotic cells. CONCLUSION: Morphine and dexamethasone showed no cytotoxic effects in our study and might thus be better alternatives to the clinically frequently applied bupivacaine. S-ketamine induced an intensive dose-dependent cytotoxic effect and should probably be avoided for intra-articular injection. PMID- 25275344 TI - Knowledge and attitudes toward depression among community members in rural Gujarat, India. AB - Limited data exist regarding community attitudes and knowledge about clinical depression in rural India. We administered 159 questionnaires and 7 focus groups to Gujarati villagers to explore knowledge and beliefs about clinical depression. Quantitative data were analyzed for frequencies, nonparametric correlations, and principal components, whereas qualitative data were coded for prominent themes. Two groups of subjects emerged from our analysis: one "medically oriented" group that viewed depression as a medical condition and expressed optimism regarding its prognosis and one "spiritually oriented" group that expressed pessimism. Correlations emerged between etiological belief, degree of optimism, and associated stigma. The subjects were pessimistic when they attributed depression to a traumatic event, punishment from God, or brain disease but optimistic when depression was attributed to socioeconomic circumstances. Overall, the subjects were knowledgeable and open-minded toward depression and demonstrated curiosity and willingness to learn more. This study will help to inform future clinical and educational outreach in rural Gujarat. PMID- 25275345 TI - Cognitive appraisal vs. exposure-based stress measures: links to perceived mental and physical health in low-income black women. AB - Although stress is linked to mental and physical health, self-reports of stress may be operationalized using measures that emphasize cognitive appraisals of stressors or that simply record stressor exposure. Theory and research suggest that appraisal-based measures may be superior in measuring self-reports of stress. However, use of exposure-based measures persists, especially in ethnic disparities research. This study examined the utility of appraisal-based versus exposure-based stress measures in linking stress to mental and physical health in low-income black women. Measures emphasizing cognitive appraisals were superior in predicting mental and physical health because global stress rating best predicted physical health whereas mental health was best predicted by perceived stress. A checklist of exposure to stressful events was not substantially predictive of either mental or physical health, suggesting that cognitive appraisals of stressors are important in linking stress to health perceptions in blacks. The results also suggest that stress impacts mental health first, which then, in turn, influences physical health. Overall, these results illuminate the importance of cognitive appraisals in linking stress to perceptions of mental and physical health in black women. PMID- 25275347 TI - Young children use shared experience to interpret definite reference. AB - We investigated whether children at the ages of two and three years understand that a speaker's use of the definite article specifies a referent that is in common ground between speaker and listener. An experimenter and a child engaged in joint actions in which the experimenter chose one of three similar objects of the same category to perform an action. In subsequent interactions children were asked to get 'the X' or 'a X'. When children were instructed with the definite article they chose the shared object significantly more often than when they were instructed with the indefinite article in which case children's choice was at chance. The findings show that in their third year children use shared experiences to interpret the speaker's communicative intention underlying her referential choice. The results are discussed with respect to children's representation of linguistic categories and the role of joint action for establishing common ground. PMID- 25275348 TI - A preliminary study of muscular artifact cancellation in single-channel EEG. AB - Electroencephalogram (EEG) recordings are often contaminated with muscular artifacts that strongly obscure the EEG signals and complicates their analysis. For the conventional case, where the EEG recordings are obtained simultaneously over many EEG channels, there exists a considerable range of methods for removing muscular artifacts. In recent years, there has been an increasing trend to use EEG information in ambulatory healthcare and related physiological signal monitoring systems. For practical reasons, a single EEG channel system must be used in these situations. Unfortunately, there exist few studies for muscular artifact cancellation in single-channel EEG recordings. To address this issue, in this preliminary study, we propose a simple, yet effective, method to achieve the muscular artifact cancellation for the single-channel EEG case. This method is a combination of the ensemble empirical mode decomposition (EEMD) and the joint blind source separation (JBSS) techniques. We also conduct a study that compares and investigates all possible single-channel solutions and demonstrate the performance of these methods using numerical simulations and real-life applications. The proposed method is shown to significantly outperform all other methods. It can successfully remove muscular artifacts without altering the underlying EEG activity. It is thus a promising tool for use in ambulatory healthcare systems. PMID- 25275349 TI - Cascading multi-hop reservation and transmission in underwater acoustic sensor networks. AB - The long propagation delay in an underwater acoustic channel makes designing an underwater media access control (MAC) protocol more challenging. In particular, handshaking-based MAC protocols widely used in terrestrial radio channels have been known to be inappropriate in underwater acoustic channels, because of the inordinately large latency involved in exchanging control packets. Furthermore, in the case of multi-hop relaying in a hop-by-hop handshaking manner, the end-to end delay significantly increases. In this paper, we propose a new MAC protocol named cascading multi-hop reservation and transmission (CMRT). In CMRT, intermediate nodes between a source and a destination may start handshaking in advance for the next-hop relaying before handshaking for the previous node is completed. By this concurrent relaying, control packet exchange and data delivery cascade down to the destination. In addition, to improve channel utilization, CMRT adopts a packet-train method where multiple data packets are sent together by handshaking once. Thus, CMRT reduces the time taken for control packet exchange and accordingly increases the throughput. The performance of CMRT is evaluated and compared with that of two conventional MAC protocols (multiple access collision avoidance for underwater (MACA-U) and MACA-U with packet trains (MACA-UPT)). The results show that CMRT outperforms other MAC protocols in terms of both throughput and end-to-end delay. PMID- 25275346 TI - Subtle to severe hepatobiliary morbidity in Opisthorchis viverrini endemic settings in southern Laos. AB - Evidence of severe hepatobiliary morbidity associated with Opisthorchis viverrini liver fluke infection including cholangiocarcinoma (CCA) is scarce in Laos although O. viverrini infection is highly prevalent. We assessed hepatobiliary morbidity using abdominal ultrasonography (US) in O. viverrini adult patients in Saravan province, Southern Laos. A random sample of 431 O. viverrini patients from 10 villages underwent abdominal US. Mild, moderate and markedly advanced periductal fibrosis was diagnosed in 7.0%, 66.5%, and 17.0% of patients, respectively. Normal liver parenchyma was seen in only 9.5% of patients. Presence of gall stones (13.2%), sludge (1.4%), gall wall thickening (1.2%), bile duct dilatation (1.6%), fatty liver (12.0%), kidney stones (8.6%) and cysts (7.9%) were diagnosed in considerable frequencies. In five patients (1.2%) hepatobiliary lesions suggesting CCA were diagnosed. Tumour markers, i.e. Interleukin-6, plasminogen activator inhibitor and carbohydrate antigen 19-9 were within normal range. The number of CCA suspected liver masses and hepatobiliary morbidity diagnosed among clinically asymptomatic adult patients in O. viverrini endemic area presents a major public health concern in Laos. However, definitive diagnosis of Opisthorchis-related severe sequelae including CCA is urgently needed to gauge the burden of this deadly disease in Laos. PMID- 25275350 TI - Distributed RSS-based localization in wireless sensor networks based on second order cone programming. AB - In this paper, we propose a new approach based on convex optimization to address the received signal strength (RSS)-based cooperative localization problem in wireless sensor networks (WSNs). By using iterative procedures and measurements between two adjacent nodes in the network exclusively, each target node determines its own position locally. The localization problem is formulated using the maximum likelihood (ML) criterion, since ML-based solutions have the property of being asymptotically efficient. To overcome the non-convexity of the ML optimization problem, we employ the appropriate convex relaxation technique leading to second-order cone programming (SOCP). Additionally, a simple heuristic approach for improving the convergence of the proposed scheme for the case when the transmit power is known is introduced. Furthermore, we provide details about the computational complexity and energy consumption of the considered approaches. Our simulation results show that the proposed approach outperforms the existing ones in terms of the estimation accuracy for more than 1:5 m. Moreover, the new approach requires a lower number of iterations to converge, and consequently, it is likely to preserve energy in all presented scenarios, in comparison to the state-of-the-art approaches. PMID- 25275351 TI - Recognition and successful treatment of priapism and suspected black widow spider bite with antivenin. AB - Priapism, although uncommon in preadolescent children, is considered a true emergency. Envenomation by a black widow spider bite has been reported to induce priapism as a manifestation of its toxicity. Early recognition and timely administration of antivenin have been reported to be effective in relieving priapism. Clinicians who care for children need to be aware of this unusual presentation. The diagnosis is traditionally from either direct observation of a spider bite or capture of a spider. We report a case of a previously healthy 2 year-old boy who presented with severe irritability, leg cramps, and stomach ache. The diagnosis of a likely black widow spider envenomation was made on the basis of clinical suspicion and suggestive physical findings in absence of demonstrated exposure. This case highlights the importance of early recognition and successful resolution of symptoms with administration of antivenin and supportive care. PMID- 25275352 TI - Splenic injury after blunt abdominal trauma during a soccer (football) game. AB - The spleen is the most commonly injured abdominal organ in children who sustain blunt abdominal trauma, and pediatric splenic injury may result from minor mechanisms of injury, including sports participation. We present 2 cases of splenic injury in soccer goalies because of blunt abdominal trauma sustained during game play. Although abdominal organ injuries are uncommon in soccer, emergency medicine and primary care physicians must be aware of the possibility. A high index of suspicion and careful physical examination are key in making the diagnosis. PMID- 25275353 TI - Ventricular tachycardia after ketamine sedation for fracture reduction. AB - This case report describes a 10-year-old female patient who underwent ketamine sedation for fracture reduction and experienced asymptomatic ventricular tachycardia after the sedation. She had no history of syncope, chest pain, palpations, or light-headedness and had a normal physical examination. This is the first reported case of a patient experiencing ventricular tachycardia after ketamine use for sedation. This case demonstrates a serious and potentially harmful possible adverse effect of ketamine administration. PMID- 25275354 TI - Epiglottitis as a presentation of leukemia in an adolescent. AB - Epiglottitis is a life-threatening entity that can present in children or adults. Although the incidence has declined since the introduction of the Haemophilus influenzae type B vaccine in 1985, cases continue to be identified in high-risk populations. In pediatric oncology patients specifically, epiglottitis has been reported after initiation of chemotherapy. We report the first case of epiglottits as the initial presentation of leukemia in a pediatric patient. PMID- 25275355 TI - A rare cause of severe rectal bleeding: solitary rectal ulcer syndrome. AB - Solitary rectal ulcer syndrome is a rare benign disorder in children which often goes unrecognized or easily misdiagnosed with other common diseases. It usually presents with rectal bleeding, constipation, mucous discharge, prolonged straining, tenesmus, and lower abdominal pain. The rectal bleeding varies from a little fresh blood to severe hemorrhage that requires blood transfusion. We report herein a pediatric case of solitary rectal ulcer syndrome who admitted to pediatric emergency department with severe rectal bleeding for reminding this rare syndrome. PMID- 25275356 TI - Acute obtundation in a 9-month-old patient: ethanol ingestion. AB - Alcohol ingestion in the pediatric patient can be life threatening. Younger patients consume larger volumes per body weight with accidental ingestions, and children have more serious adverse effects at lower blood alcohol levels. Complications of alcohol poisoning can include hypothermia, hypoglycemia, seizures, coma, and death. We present the course of a 9-month-old female infant who became unresponsive at home and presented to the emergency department comatose. When her blood alcohol level registered 489 mg/dL, it was revealed that she had accidentally been given a bottle of formula mixed with vodka rather than water. The infant required intubation for severely depressed level of consciousness and aggressive fluid resuscitation for hemodynamic instability. She had a peak lactate level of 24 mmol/L and a peak blood alcohol level of 524 mg/dL. Based on the severity of her initial presentation, preparations were made for hemodialysis. The infant responded to supportive measures including mechanical ventilation, fluids, and dextrose, and hemodialysis was not necessary. Her alcohol clearance followed zero-order kinetics at an average rate of 28.6 mg/dL per hour over 15.5 hours from her peak level of 524 mg/dL to the lowest measured value of 80 mg/dL. The kinetics of ethanol clearance at this level of toxicity, which is the highest reported in an infant to date, enhance our knowledge of ethanol metabolism and will assist in management decisions in cases of severe intoxication. PMID- 25275357 TI - Management of simple nail bed lacerations and subungual hematomas in the emergency department. AB - Fingertip crush injuries are common hand injuries in children and often are evaluated initially in an emergency department. Nail bed injuries can be classified into subungual hematomas, simple or stellate lacerations, crush injuries, and avulsions. Emergency department physicians with good knowledge of fingertip anatomy can appropriately manage these injuries so as to prevent long term fingertip deformities and functional deficits. The management of simple nail bed lacerations and subungual hematomas has remained somewhat controversial with much debate surrounding the necessity of removing the nail plate for repair of a nail bed laceration versus trephination alone of a large subungual hematoma. This article will discuss the management and evaluation of simple nail bed injuries by emergency department physicians to prevent chronic nail and fingertip deformities. PMID- 25275359 TI - Pediatric emergency medicine legal briefs. PMID- 25275361 TI - ECGs in the ED. PMID- 25275360 TI - Incidental renal mass found on focused assessment with sonography in trauma. AB - We present the case of a 9-year-old female who presented after minor blunt abdominal trauma during a sporting event. On focused assessment with sonography for trauma, she was found to have an incidental renal mass, which was ultimately diagnosed as a renal cell carcinoma. In this report, we focus on the use of bedside ultrasound as a screening test and the management of incidental findings. PMID- 25275362 TI - Regional control of head and neck melanoma with selective neck dissection. AB - IMPORTANCE: Historically, patients with cervical metastases from melanoma of the head and neck were treated with a radical neck dissection. This study evaluates the efficacy of limiting the extent of lymphadenectomy in this high-risk population. OBJECTIVES: To determine whether limiting the extent of lymphadenectomy for patients with biopsy-proven melanoma has a negative effect on regional control. Our hypothesis was that performing a more limited lymphadenectomy does not have a negative impact on regional control. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, single-cohort study was performed using a prospectively collected database of patients with head and neck melanoma with histopathologically positive lymph nodes after modified radical (MRND) or selective neck dissection (SNDs) performed at a high-volume, academic, tertiary care center. INTERVENTIONS: Lymphadenectomy was performed as clinically indicated. MAIN OUTCOMES AND MEASURES: Primary end points were regional recurrence and regional recurrence free survival. Univariable and multivariable analyses were conducted using multiple patient characteristics. RESULTS: Forty one patients underwent SND or MRND from 2001 through 2010. The median number of positive nodes was 1 (range, 1-16). Twenty-six patients (63%) received adjuvant radiation and 23 patients (56%) received adjuvant immunotherapy or chemotherapy. The median follow-up time was 17 months (range, 1-116 months). Regional control was achieved in 29 patients (71%). Median regional recurrence-free survival was 21 months (range, 1-116 months). Age (hazard ratio [HR], 1.13; 95% CI, 1.01 1.26), total number of nodes examined (HR, 1.05; 95% CI, 1.01-1.10), and number of sentinel lymph nodes examined (HR, 1.45; 95% CI, 1.01-2.09) were all significantly associated with increased recurrence-free survival. Tumor depth, extracapsular spread, number of nodes positive, prior SLNB, extent of lymphadenectomy, and adjuvant therapy were not significant. CONCLUSIONS AND RELEVANCE: Limiting the extent of lymphadenectomy with frequent use of adjuvant radiation therapy is effective in achieving regional control of head and neck melanoma with cervical metastases. PMID- 25275364 TI - Asking about adherence - from flipping the coin to strong evidence. AB - In the era of antiretroviral therapy (ART) as prevention for transmission of HIV as well as treatment for HIV-positive individuals irrespective of CD4 cell counts, the importance of adherence has grown. Although adherence is not the only determinant of treatment success, it is one of the only modifiable risk factors. Treatment failure reduces future treatment options and therefore long-term clinical success as well as increases the possibility of developing drug resistant mutations. Drug-resistant strains of HIV can then be transmitted to uninfected or drug-naive individuals limiting their future treatment options, making adherence an important public-health topic, especially in resource-limited settings. Adherence should be monitored as a part of routine clinical care; however, no gold standard for assessment of adherence exists. For use in daily clinical practice, self-report is the most likely candidate for widespread use due to its many advantages over other measurement methods, such as low cost and ease of administration. Asking individuals about their adherence behaviour has been shown to yield valid and predictive data - well beyond the mere flip of a coin. However, there is still work to be done. This article reviews the literature and evidence on self-reported adherence, identifies gaps in adherence research, and makes recommendations for clinicians on how to best utilise self reported adherence data to support patients in daily clinical practice. PMID- 25275363 TI - The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. AB - BACKGROUND: Polymorphisms in the MUC5B promoter, TOLLIP, and nine additional genetic loci have been associated with idiopathic pulmonary fibrosis (IPF) within non-Hispanic white populations. It is unknown whether these variants account for risk of IPF in other racial/ethnic populations. We conducted a candidate single nucleotide polymorphism (SNP) association study in cohorts of Mexican and Korean patients with IPF. METHODS: We chose 12 SNPs from 11 loci that are associated with IPF among non-Hispanic whites and genotyped these SNPs in cohorts of Mexican (83 patients, 111 control subjects) and Korean (239 patients, 87 control subjects) people. Each SNP was tested for association with IPF, after adjusting for age and sex. RESULTS: The MUC5B promoter SNP rs35705950 was associated with IPF in the Mexican (OR = 7.36, P = .0001), but not the Korean (P = .99) cohort. The SNP in IVD (chromosome15, rs2034650) was significantly associated with pulmonary fibrosis in both the Mexican (OR = 0.40, P = .01) and Korean (OR = 0.13, P = .0008) cohorts. In the Korean cohort, there were no other variants associated with disease. In the Mexican cohort, SNPs on chromosomes 3, 4, and 11 were also associated with disease. CONCLUSIONS: The strongest identified genetic risk factor for IPF among the non-Hispanic white population, the MUC5B promoter polymorphism, is also a strong risk factor in a Mexican population, but is very rare in a Korean population. The majority of genetic variants that account for risk of IPF in groups other than non-Hispanic whites are unknown. Hispanic and Asian populations should be studied separately to identify genetic risk loci for IPF. PMID- 25275365 TI - Independent and joint effect of type 2 diabetes and gastric and hepatobiliary diseases on risk of pancreatic cancer risk: 10-year follow-up of population-based cohort. AB - BACKGROUND: Type 2 diabetes mellitus, gastric and hepatobiliary comorbidities, and cancer share common risk factors: for example, tobacco, obesity, physical inactivity, high calorie intake, and metabolic disorders. Prior studies find type 2 diabetes and gastric and hepatobiliary comorbidities heightening risk of pancreatic cancer. Yet joint association of type 2 diabetes mellitus and gastric and hepatobiliary comorbidities on pancreatic cancer risk has not been assessed. METHODS: This study rates independent/joint effects of type 2 diabetes as well as gastric and hepatobiliary comorbidity on pancreatic cancer risk for a retrospective population-based cohort of 166,850 type 2 diabetics identified in 1997-1998 and followed for 10-11 years, comparing their cancer incidence with that of 166,850 non-diabetics matched for age, gender, and locale. Time-dependent Cox's proportional hazards model evaluted joint association of type 2 diabetes and chronic conditions on pancreatic cancer risk. RESULTS: A total of 1178 subjects were newly diagnosed with pancreatic cancer during follow-up, with incidence rates of 0.49 per 1000 person-years in type 2 diabetes and 0.26 per 1000 person-years in the non-diabetics. We observed greater magnitude of hazard ratios (HRs) of pancreatic cancer for patients with type 2 diabetes along with acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer compared with patients without type 2 diabetes or counterpart comorbidity (HR: 1.36, 95% confidence interval (CI): 1.19-1.56; 1.74, 1.23-2.45; 9.18, 7.44-11.33; and 2.31, 1.98-2.70, respectively). Main effects of type 2 diabetes were all statistically with narrow 95% CI and remained similar across risk stratification with various comorbidities: range 1.59-1.80. CONCLUSIONS: Our study demonstrates that pre-existing type 2 diabetes, acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer independently or jointly predict subsequent pancreatic cancer risk. Clinicians must recognise burden of these gastric and hepatobiliary comorbidities and keep clinically vigilant for their diagnosis. PMID- 25275367 TI - We need to be better prepared for hydroxychloroquine retinopathy. PMID- 25275366 TI - Vector competence in West African Aedes aegypti Is Flavivirus species and genotype dependent. AB - BACKGROUND: Vector competence of Aedes aegypti mosquitoes is a quantitative genetic trait that varies among geographic locations and among different flavivirus species and genotypes within species. The subspecies Ae. aegypti formosus, found mostly in sub-Saharan Africa, is considered to be refractory to both dengue (DENV) and yellow fever viruses (YFV) compared to the more globally distributed Ae. aegypti aegypti. Within Senegal, vector competence varies with collection site and DENV-2 viral isolate, but knowledge about the interaction of West African Ae. aegypti with different flaviviruses is lacking. The current study utilizes low passage isolates of dengue-2 (DENV-2-75505 sylvatic genotype) and yellow fever (YFV BA-55 -West African Genotype I, or YFV DAK 1279-West African Genotype II) from West Africa and field derived Ae. aegypti collected throughout Senegal to determine whether vector competence is flavivirus or virus genotype dependent. METHODOLOGY/PRINCIPAL FINDINGS: Eight collections of 20-30 mosquitoes from different sites were fed a bloodmeal containing either DENV-2 or either isolate of YFV. Midgut and disseminated infection phenotypes were determined 14 days post infection. Collections varied significantly in the rate and intensity of midgut and disseminated infection among the three viruses. CONCLUSIONS/SIGNIFICANCE: Overall, vector competence was dependent upon both viral and vector strains. Importantly, contrary to previous studies, sylvatic collections of Ae. aegypti showed high levels of disseminated infection for local isolates of both DENV-2 and YFV. PMID- 25275368 TI - Anesthesia and increased hypercarbic drive impair the coordination between breathing and swallowing. AB - BACKGROUND: Coordination between breathing and swallowing helps prevent aspiration of foreign material into the respiratory tract. The authors examined the effects of anesthesia and hypercapnia on swallowing-breathing coordination. METHODS: In a randomized controlled crossover study, general anesthesia with propofol or sevoflurane was titrated using an up-down method to identify the threshold for suppression of the motor response to electrical stimulation of the forearm. Additional measurements included bispectral index, genioglossus electromyogram, ventilation (pneumotachometer), and hypopharyngeal pressure. During wakefulness and at each level of anesthesia, carbon dioxide was added to increase the end-tidal pressure by 4 and 8 mmHg. A swallow was defined as increased genioglossus activity with deglutition apnea and an increase in hypopharyngeal pressure. Spontaneous swallows were categorized as physiological (during expiration or followed by expiration) or pathological (during inspiration or followed by an inspiration). RESULTS: A total of 224 swallows were analyzed. Anesthesia increased the proportion of pathological swallows (25.9% vs. 4.9%) and decreased the number of swallows per hour (1.7+/-3.3 vs. 28.0+/-22.3) compared to wakefulness. During anesthesia, hypercapnia decreased hypopharyngeal pressure during inspiration (-14.1+/-3.7 vs. -8.7+/-2 mmHg) and increased minute ventilation, the proportion of pathological swallows (19.1% vs. 12.3%), and the number of swallows per hour (5.5+/-17.0. vs. 1.3+/-5.5). CONCLUSIONS: Anesthesia impaired the coordination between swallowing and respiration. Mild hypercapnia increased the frequency of swallowing during anesthesia and the likelihood of pathological swallowing. During anesthesia, the risk for aspiration may be further increased when ventilatory drive is stimulated. PMID- 25275369 TI - Effects of atrazine, metolachlor, carbaryl and chlorothalonil on benthic microbes and their nutrient dynamics. AB - Atrazine, metolachlor, carbaryl, and chlorothalonil are detected in streams throughout the U.S. at concentrations that may have adverse effects on benthic microbes. Sediment samples were exposed to these pesticides to quantify responses of ammonium, nitrate, and phosphate uptake by the benthic microbial community. Control uptake rates of sediments had net remineralization of nitrate (-1.58 NO3 ug gdm-1 h-1), and net assimilation of phosphate (1.34 PO4 ug gdm-1 h-1) and ammonium (0.03 NH4 ug gdm-1 h-1). Metolachlor decreased ammonium and phosphate uptake. Chlorothalonil decreased nitrate remineralization and phosphate uptake. Nitrate, ammonium, and phosphate uptake rates are more pronounced in the presence of these pesticides due to microbial adaptations to toxicants. Our interpretation of pesticide availability based on their water/solid affinities supports no effects for atrazine and carbaryl, decreasing nitrate remineralization, and phosphate assimilation in response to chlorothalonil. Further, decreased ammonium and phosphate uptake in response to metolachlor is likely due to affinity. Because atrazine target autotrophs, and carbaryl synaptic activity, effects on benthic microbes were not hypothesized, consistent with results. Metolachlor and chlorothalonil (non-specific modes of action) had significant effects on sediment microbial nutrient dynamics. Thus, pesticides with a higher affinity to sediments and/or broad modes of action are likely to affect sediment microbes' nutrient dynamics than pesticides dissolved in water or specific modes of action. Predicted nutrient uptake rates were calculated at mean and peak concentrations of metolachlor and chlorothalonil in freshwaters using polynomial equations generated in this experiment. We concluded that in natural ecosystems, peak chlorothalonil and metolachlor concentrations could affect phosphate and ammonium by decreasing net assimilation, and nitrate uptake rates by decreasing remineralization, relative to mean concentrations of metolachlor and chlorothalonil. Our regression equations can complement models of nitrogen and phosphorus availability in streams to predict potential changes in nutrient dynamics in response to pesticides in freshwaters. PMID- 25275370 TI - Radiofrequency catheter ablation of atrial tachyarrhythmias after an atrial switch operation in a patient with univentricular heart combined with transposition of the great arteries. AB - A 31-year-old patient previously underwent a Mustard operation presented with palpitations. Atrial tachycardia and paroxysmal atrial fibrillation were documented on the surface electrocardiogram. Under the guidance of a three dimensional electroanatomic mapping system, ablation of the isolated left-sided pulmonary vein and a cavo-tricuspid isthmus-dependent intra-atrial macro re-entry circuit eliminated atrial tachycardia and paroxysmal atrial fibrillation without the recurrence of atrial tachyarrhythmia. PMID- 25275371 TI - Comprehensive mapping of the Escherichia coli flagellar regulatory network. AB - Flagellar synthesis is a highly regulated process in all motile bacteria. In Escherichia coli and related species, the transcription factor FlhDC is the master regulator of a multi-tiered transcription network. FlhDC activates transcription of a number of genes, including some flagellar genes and the gene encoding the alternative Sigma factor FliA. Genes whose expression is required late in flagellar assembly are primarily transcribed by FliA, imparting temporal regulation of transcription and coupling expression to flagellar assembly. In this study, we use ChIP-seq and RNA-seq to comprehensively map the E. coli FlhDC and FliA regulons. We define a surprisingly restricted FlhDC regulon, including two novel regulated targets and two binding sites not associated with detectable regulation of surrounding genes. In contrast, we greatly expand the known FliA regulon. Surprisingly, 30 of the 52 FliA binding sites are located inside genes. Two of these intragenic promoters are associated with detectable noncoding RNAs, while the others either produce highly unstable RNAs or are inactive under these conditions. Together, our data redefine the E. coli flagellar regulatory network, and provide new insight into the temporal orchestration of gene expression that coordinates the flagellar assembly process. PMID- 25275373 TI - Dip TIPS as a facile and versatile method for fabrication of polymer foams with controlled shape, size and pore architecture for bioengineering applications. AB - The porous polymer foams act as a template for neotissuegenesis in tissue engineering, and, as a reservoir for cell transplants such as pancreatic islets while simultaneously providing a functional interface with the host body. The fabrication of foams with the controlled shape, size and pore structure is of prime importance in various bioengineering applications. To this end, here we demonstrate a thermally induced phase separation (TIPS) based facile process for the fabrication of polymer foams with a controlled architecture. The setup comprises of a metallic template bar (T), a metallic conducting block (C) and a non-metallic reservoir tube (R), connected in sequence T-C-R. The process hereinafter termed as Dip TIPS, involves the dipping of the T-bar into a polymer solution, followed by filling of the R-tube with a freezing mixture to induce the phase separation of a polymer solution in the immediate vicinity of T-bar; Subsequent free-drying or freeze-extraction steps produced the polymer foams. An easy exchange of the T-bar of a spherical or rectangular shape allowed the fabrication of tubular, open- capsular and flat-sheet shaped foams. A mere change in the quenching time produced the foams with a thickness ranging from hundreds of microns to several millimeters. And, the pore size was conveniently controlled by varying either the polymer concentration or the quenching temperature. Subsequent in vivo studies in brown Norway rats for 4-weeks demonstrated the guided cell infiltration and homogenous cell distribution through the polymer matrix, without any fibrous capsule and necrotic core. In conclusion, the results show the "Dip TIPS" as a facile and adaptable process for the fabrication of anisotropic channeled porous polymer foams of various shapes and sizes for potential applications in tissue engineering, cell transplantation and other related fields. PMID- 25275372 TI - Differential pro-inflammatory responses of astrocytes and microglia involve STAT3 activation in response to 1800 MHz radiofrequency fields. AB - Microglia and astrocytes play important role in maintaining the homeostasis of central nervous system (CNS). Several CNS impacts have been postulated to be associated with radiofrequency (RF) electromagnetic fields exposure. Given the important role of inflammation in neural physiopathologic processes, we investigated the pro-inflammatory responses of microglia and astrocytes and the involved mechanism in response to RF fields. Microglial N9 and astroglial C8-D1A cells were exposed to 1800 MHz RF for different time with or without pretreatment with STAT3 inhibitor. Microglia and astrocytes were activated by RF exposure indicated by up-regulated CD11b and glial fibrillary acidic protein (GFAP). However, RF exposure induced differential pro-inflammatory responses in astrocytes and microglia, characterized by different expression and release profiles of IL-1beta, TNF-alpha, IL-6, PGE2, nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Moreover, the RF exposure activated STAT3 in microglia but not in astrocytes. Furthermore, the STAT3 inhibitor Stattic ameliorated the RF-induced release of pro-inflammatory cytokines in microglia but not in astrocytes. Our results demonstrated that RF exposure differentially induced pro-inflammatory responses in microglia and astrocytes, which involved differential activation of STAT3 in microglia and astrocytes. Our data provide novel insights into the potential mechanisms of the reported CNS impacts associated with mobile phone use and present STAT3 as a promising target to protect humans against increasing RF exposure. PMID- 25275375 TI - A novel optical intracellular imaging approach for potassium dynamics in astrocytes. AB - Astrocytes fulfill a central role in regulating K+ and glutamate, both released by neurons into the extracellular space during activity. Glial glutamate uptake is a secondary active process that involves the influx of three Na+ ions and one proton and the efflux of one K+ ion. Thus, intracellular K+ concentration ([K+]i) is potentially influenced both by extracellular K+ concentration ([K+]o) fluctuations and glutamate transport in astrocytes. We evaluated the impact of these K+ ion movements on [K+]i in primary mouse astrocytes by microspectrofluorimetry. We established a new noninvasive and reliable approach to monitor and quantify [K+]i using the recently developed K+ sensitive fluorescent indicator Asante Potassium Green-1 (APG-1). An in situ calibration procedure enabled us to estimate the resting [K+]i at 133+/-1 mM. We first investigated the dependency of [K+]i levels on [K+]o. We found that [K+]i followed [K+]o changes nearly proportionally in the range 3-10 mM, which is consistent with previously reported microelectrode measurements of intracellular K+ concentration changes in astrocytes. We then found that glutamate superfusion caused a reversible drop of [K+]i that depended on the glutamate concentration with an apparent EC50 of 11.1+/-1.4 uM, corresponding to the affinity of astrocyte glutamate transporters. The amplitude of the [K+]i drop was found to be 2.3+/-0.1 mM for 200 uM glutamate applications. Overall, this study shows that the fluorescent K+ indicator APG-1 is a powerful new tool for addressing important questions regarding fine [K+]i regulation with excellent spatial resolution. PMID- 25275376 TI - Tracking the sleep onset process: an empirical model of behavioral and physiological dynamics. AB - The sleep onset process (SOP) is a dynamic process correlated with a multitude of behavioral and physiological markers. A principled analysis of the SOP can serve as a foundation for answering questions of fundamental importance in basic neuroscience and sleep medicine. Unfortunately, current methods for analyzing the SOP fail to account for the overwhelming evidence that the wake/sleep transition is governed by continuous, dynamic physiological processes. Instead, current practices coarsely discretize sleep both in terms of state, where it is viewed as a binary (wake or sleep) process, and in time, where it is viewed as a single time point derived from subjectively scored stages in 30-second epochs, effectively eliminating SOP dynamics from the analysis. These methods also fail to integrate information from both behavioral and physiological data. It is thus imperative to resolve the mismatch between the physiological evidence and analysis methodologies. In this paper, we develop a statistically and physiologically principled dynamic framework and empirical SOP model, combining simultaneously-recorded physiological measurements with behavioral data from a novel breathing task requiring no arousing external sensory stimuli. We fit the model using data from healthy subjects, and estimate the instantaneous probability that a subject is awake during the SOP. The model successfully tracked physiological and behavioral dynamics for individual nights, and significantly outperformed the instantaneous transition models implicit in clinical definitions of sleep onset. Our framework also provides a principled means for cross-subject data alignment as a function of wake probability, allowing us to characterize and compare SOP dynamics across different populations. This analysis enabled us to quantitatively compare the EEG of subjects showing reduced alpha power with the remaining subjects at identical response probabilities. Thus, by incorporating both physiological and behavioral dynamics into our model framework, the dynamics of our analyses can finally match those observed during the SOP. PMID- 25275378 TI - Heterobifunctional PEG ligands for bioconjugation reactions on iron oxide nanoparticles. AB - Ever since iron oxide nanoparticles have been recognized as promising scaffolds for biomedical applications, their surface functionalization has become even more important. We report the synthesis of a novel polyethylene glycol-based ligand that combines multiple advantageous properties for these applications. The ligand is covalently bound to the surface via a siloxane group, while its polyethylene glycol backbone significantly improves the colloidal stability of the particle in complex environments. End-capping the molecule with a carboxylic acid introduces a variety of coupling chemistry possibilities. In this study an antibody targeting plasminogen activator inhibitor-1 was coupled to the surface and its presence and binding activity was assessed by enzyme-linked immunosorbent assay and surface plasmon resonance experiments. The results indicate that the ligand has high potential towards biomedical applications where colloidal stability and advanced functionality is crucial. PMID- 25275377 TI - Coordination of fictive motor activity in the larval zebrafish is generated by non-segmental mechanisms. AB - The cellular and network basis for most vertebrate locomotor central pattern generators (CPGs) is incompletely characterized, but organizational models based on known CPG architectures have been proposed. Segmental models propose that each spinal segment contains a circuit that controls local coordination and sends longer projections to coordinate activity between segments. Unsegmented/continuous models propose that patterned motor output is driven by gradients of neurons and synapses that do not have segmental boundaries. We tested these ideas in the larval zebrafish, an animal that swims in discrete episodes, each of which is composed of coordinated motor bursts that progress rostrocaudally and alternate from side to side. We perturbed the spinal cord using spinal transections or strychnine application and measured the effect on fictive motor output. Spinal transections eliminated episode structure, and reduced both rostrocaudal and side-to-side coordination. Preparations with fewer intact segments were more severely affected, and preparations consisting of midbody and caudal segments were more severely affected than those consisting of rostral segments. In reduced preparations with the same number of intact spinal segments, side-to-side coordination was more severely disrupted than rostrocaudal coordination. Reducing glycine receptor signaling with strychnine reversibly disrupted both rostrocaudal and side-to-side coordination in spinalized larvae without disrupting episodic structure. Both spinal transection and strychnine decreased the stability of the motor rhythm, but this effect was not causal in reducing coordination. These results are inconsistent with a segmented model of the spinal cord and are better explained by a continuous model in which motor neuron coordination is controlled by segment-spanning microcircuits. PMID- 25275380 TI - Melatonin enhances photo-oxidation of 2',7'-dichlorodihydrofluorescein by an antioxidant reaction that renders N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). AB - The indolamine melatonin (MEL) is described as an antioxidant and a free radical scavenger. However occasionally, the indoleamine has been reported to increase free radicals with insufficient mechanistic explanation. In an attempt to find a reason for those controversial results, a potential mechanism that explains MEL prooxidant activity is investigated. The current controversy about redox detection methods has prompted us to search a possible interaction between MEL and dichlorodihydrofluorescein (DCFH2), perhaps the most widely fluorescence probe employed for free radicals detection in cellular models. Here, it is demonstrated that melatonin potentiates the photooxidation of DCFH2 in a cell free system, increasing the production of its fluorescent metabolite. Indeed, MEL works as an antioxidant scavenging hydroxyl radicals in this system. Thus, this reaction between MEL and DCFH2 produces N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), a biogenic amine with antioxidant properties too. This reaction is O2 and light dependent and it is prevented by antioxidants such as N-acetylcysteine or ascorbic acid. Furthermore, when DCFH2 has been employed to evaluate antioxidant or prooxidant activities of MEL in cellular models it is confirmed that it works as an antioxidant but these results can be modulated by light misleading to a prooxidant conclusion. In conclusion, here is demonstrated that DCFH2, light and melatonin interact and results obtained using these fluorescence probes in studies with melatonin have to be carefully interpreted. PMID- 25275379 TI - Cadmium-induced hydrogen sulfide synthesis is involved in cadmium tolerance in Medicago sativa by reestablishment of reduced (homo)glutathione and reactive oxygen species homeostases. AB - Until now, physiological mechanisms and downstream targets responsible for the cadmium (Cd) tolerance mediated by endogenous hydrogen sulfide (H2S) have been elusive. To address this gap, a combination of pharmacological, histochemical, biochemical and molecular approaches was applied. The perturbation of reduced (homo)glutathione homeostasis and increased H2S production as well as the activation of two H2S-synthetic enzymes activities, including L-cysteine desulfhydrase (LCD) and D-cysteine desulfhydrase (DCD), in alfalfa seedling roots were early responses to the exposure of Cd. The application of H2S donor sodium hydrosulfide (NaHS), not only mimicked intracellular H2S production triggered by Cd, but also alleviated Cd toxicity in a H2S-dependent fashion. By contrast, the inhibition of H2S production caused by the application of its synthetic inhibitor blocked NaHS-induced Cd tolerance, and destroyed reduced (homo)glutathione and reactive oxygen species (ROS) homeostases. Above mentioned inhibitory responses were further rescued by exogenously applied glutathione (GSH). Meanwhile, NaHS responses were sensitive to a (homo)glutathione synthetic inhibitor, but reversed by the cotreatment with GSH. The possible involvement of cyclic AMP (cAMP) signaling in NaHS responses was also suggested. In summary, LCD/DCD-mediated H2S might be an important signaling molecule in the enhancement of Cd toxicity in alfalfa seedlings mainly by governing reduced (homo)glutathione and ROS homeostases. PMID- 25275381 TI - The largest subunit of RNA polymerase II as a new marker gene to study assemblages of arbuscular mycorrhizal fungi in the field. AB - Due to the potential of arbuscular mycorrhizal fungi (AMF, Glomeromycota) to improve plant growth and soil quality, the influence of agricultural practice on their diversity continues to be an important research question. Up to now studies of community diversity in AMF have exclusively been based on nuclear ribosomal gene regions, which in AMF show high intra-organism polymorphism, seriously complicating interpretation of these data. We designed specific PCR primers for 454 sequencing of a region of the largest subunit of RNA polymerase II gene, and established a new reference dataset comprising all major AMF lineages. This gene is known to be monomorphic within fungal isolates but shows an excellent barcode gap between species. We designed a primer set to amplify all known lineages of AMF and demonstrated its applicability in combination with high-throughput sequencing in a long-term tillage experiment. The PCR primers showed a specificity of 99.94% for glomeromycotan sequences. We found evidence of significant shifts of the AMF communities caused by soil management and showed that tillage effects on different AMF taxa are clearly more complex than previously thought. The high resolving power of high-throughput sequencing highlights the need for quantitative measurements to efficiently detect these effects. PMID- 25275383 TI - Screening Questions for Nonsteroidal Anti-inflammatory Drug Risk Knowledge. AB - OBJECTIVE: The aim of this study was to evaluate screening questions for estimating nonsteroidal anti-inflammatory drug (NSAID) risk knowledge. METHODS: Cross-sectional data from a telephone interview of NSAID users 50 years or older from 39 physician practices in Alabama were used. Patient-reported awareness of prescription NSAID risk and health literacy were the independent variables, and a cumulative index score of objectively tested knowledge of 4 prominent NSAID risks was the dependent variable. General linearized latent and mixed model ordered logistic regression was used to estimate associations among the independent variables, covariates, and objectively tested NSAID risk knowledge. Population averaged probabilities for levels of objectively tested NSAID risk knowledge were subsequently estimated. RESULTS: Subjective awareness of any prescription NSAID risk (adjusted odds ratio [AOR], 2.40; 95% confidence interval [CI], 1.55-3.74), adequate health literacy (AOR, 1.71; 95% CI, 1.04-2.83), and physician counseling about 1 or more NSAID risks (AOR, 1.69; 95% CI, 1.09-2.61) were significantly and positively associated with NSAID risk knowledge. The probability of correctly answering at least 1 of the 4 NSAID risk knowledge questions was 70% in the absence of any subjective risk awareness and in less than adequate health literacy. Whereas the probability of correctly answering at least 1 of the 4 NSAID risk knowledge questions increased to 86% in the presence of subjective awareness of any prescription NSAID risk and adequate health literacy. CONCLUSIONS: Screening questions for subjective NSAID risk awareness and health literacy are predictive of objectively tested NSAID knowledge and can be used to triage patients as well as subsequently initiate and direct a conversation about NSAID risk. PMID- 25275382 TI - Biomarkers in Trypanosoma cruzi-infected and uninfected individuals with varying severity of cardiomyopathy in Santa Cruz, Bolivia. AB - BACKGROUND: Twenty to thirty percent of persons with Trypanosoma cruzi infection eventually develop cardiomyopathy. If an early indicator were to be identified and validated in longitudinal studies, this could enable treatment to be prioritized for those at highest risk. We evaluated cardiac and extracellular matrix remodeling markers across cardiac stages in T. cruzi infected (Tc+) and uninfected (Tc-) individuals. METHODS: Participants were recruited in a public hospital in Santa Cruz, Bolivia and assigned cardiac severity stages by electrocardiogram and echocardiogram. BNP, NTproBNP, CKMB, troponin I, MMP-2, MMP 9, TIMP-1, TIMP-2, TGFb1, and TGFb2 were measured in specimens from 265 individuals using multiplex bead systems. Biomarker levels were compared between Tc+ and Tc- groups, and across cardiac stages. Receivers operating characteristic (ROC) curves were created; for markers with area under curve>0.60, logistic regression was performed. RESULTS: Analyses stratified by cardiac stage showed no significant differences in biomarker levels by Tc infection status. Among Tc+ individuals, those with cardiac insufficiency had higher levels of BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 than those with normal ejection fraction and left ventricular diameter. No individual marker distinguished between the two earliest Tc+ stages, but in ROC-based analyses, MMP-2/MMP-9 ratio was significantly higher in those with than those without ECG abnormalities. CONCLUSIONS: BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 levels rose with increasing severity stage but did not distinguish between Chagas cardiomyopathy and other cardiomyopathies. Among Tc+ individuals without cardiac insufficiency, only the MMP-2/MMP-9 ratio differed between those with and without ECG changes. PMID- 25275386 TI - Surveyors targeting liquid-concentrated controlled medications. PMID- 25275384 TI - Mesoscopic model and free energy landscape for protein-DNA binding sites: analysis of cyanobacterial promoters. AB - The identification of protein binding sites in promoter sequences is a key problem to understand and control regulation in biochemistry and biotechnological processes. We use a computational method to analyze promoters from a given genome. Our approach is based on a physical model at the mesoscopic level of protein-DNA interaction based on the influence of DNA local conformation on the dynamics of a general particle along the chain. Following the proposed model, the joined dynamics of the protein particle and the DNA portion of interest, only characterized by its base pair sequence, is simulated. The simulation output is analyzed by generating and analyzing the Free Energy Landscape of the system. In order to prove the capacity of prediction of our computational method we have analyzed nine promoters of Anabaena PCC 7120. We are able to identify the transcription starting site of each of the promoters as the most populated macrostate in the dynamics. The developed procedure allows also to characterize promoter macrostates in terms of thermo-statistical magnitudes (free energy and entropy), with valuable biological implications. Our results agree with independent previous experimental results. Thus, our methods appear as a powerful complementary tool for identifying protein binding sites in promoter sequences. PMID- 25275385 TI - A novel weighted total difference based image reconstruction algorithm for few view computed tomography. AB - In practical applications of computed tomography (CT) imaging, due to the risk of high radiation dose imposed on the patients, it is desired that high quality CT images can be accurately reconstructed from limited projection data. While with limited projections, the images reconstructed often suffer severe artifacts and the edges of the objects are blurred. In recent years, the compressed sensing based reconstruction algorithm has attracted major attention for CT reconstruction from a limited number of projections. In this paper, to eliminate the streak artifacts and preserve the edge structure information of the object, we present a novel iterative reconstruction algorithm based on weighted total difference (WTD) minimization, and demonstrate the superior performance of this algorithm. The WTD measure enforces both the sparsity and the directional continuity in the gradient domain, while the conventional total difference (TD) measure simply enforces the gradient sparsity horizontally and vertically. To solve our WTD-based few-view CT reconstruction model, we use the soft-threshold filtering approach. Numerical experiments are performed to validate the efficiency and the feasibility of our algorithm. For a typical slice of FORBILD head phantom, using 40 projections in the experiments, our algorithm outperforms the TD-based algorithm with more than 60% gains in terms of the root-mean-square error (RMSE), normalized root mean square distance (NRMSD) and normalized mean absolute distance (NMAD) measures and with more than 10% gains in terms of the peak signal-to-noise ratio (PSNR) measure. While for the experiments of noisy projections, our algorithm outperforms the TD-based algorithm with more than 15% gains in terms of the RMSE, NRMSD and NMAD measures and with more than 4% gains in terms of the PSNR measure. The experimental results indicate that our algorithm achieves better performance in terms of suppressing streak artifacts and preserving the edge structure information of the object. PMID- 25275387 TI - Thanks for asking. PMID- 25275389 TI - Frank L. Grosso: a pharmacist with the heart of a businessman. PMID- 25275388 TI - Cross-cultural health care for older adults: strategies for pharmacists. AB - The United States population not only is aging, but also becoming more ethnically diverse. Approximately half of elders who take medications find adherence challenging, and cultural diversity is one of the variables that may affect adherence. By better understanding patients' cultural perspectives, senior care pharmacists can more effectively address their medication management needs; failure to recognize these differences may contribute to misunderstanding or miscommunication that may affect treatment. When a patient does not adhere to prescribed medications, explore reasons and feelings. Different ethnic groups have varying communication styles and also seek different degrees of family involvement in diagnosis and treatment. Some mistrust in Western health care, choose to use herbs and nonpharmacologic agents, and have different time orientation that may affect adherence. Senior pharmacists have an active role in screening, evaluation, and counseling elderly, ethnically diverse patients. Applying general trends of cultural values should not be mistaken for stereotyping. PMID- 25275390 TI - Screening for adverse drug events in older adults: the impact of interventions. AB - OBJECTIVE: Primary, to evaluate the usefulness of a comprehensive medication review (CMR) process in screening for adverse drug event (ADE) risk and to measure the impact of pharmacist recommendations; secondary, to evaluate whether screening tools assist in detecting ADEs. DESIGN: Nonrandomized, prospective pre/post pilot study. SETTING: Wisconsin-based community pharmacy affiliated with a two-campus retirement facility serving independently living older adults. PARTICIPANTS: Sixty-nine older adults responded to the initial call for participation in the ADE screening (mean age 84 years, mean daily medications: 13.7). Thirty-nine older adults (mean age 86 years, mean daily medications: 13.8) participated in both pre/post pilot study phases. INTERVENTION: Each participant received a CMR, including self-identified geriatric syndromes and St. Louis University Memory Screen (SLUMS) assessment. Recommendation letters included lifestyle changes to reduce medication use. A three-month follow-up call gathered current medication lists and recommendation acceptance rates. Repeat screenings were also conducted. MAIN OUTCOME MEASURE(S): Number of ADEs identified, recommendation acceptance rates, medication-related changes. Secondary measures: self-reported geriatric syndromes, SLUMS scores associated with ADE identification, screening tools associated with ADE identification. RESULTS: Pharmacist-initiated CMRs resulted in a high rate of discontinued nonsteroidal anti-inflammatory drugs (NSAIDs) and overall reduction in the number of scheduled medications. Participants with a positive ADE history were significantly more likely to report a suspected current ADE. Pharmacists incorporated nonpharmacologic interventions for reported geriatric syndromes, with high participant acceptance rates. In isolated cases, cognition was measurably improved with discontinuation of a targeted medication. CONCLUSIONS: Pharmacist provided CMR services should be comprehensive, including patient's self-report of ADEs and history of ADEs. Pharmacist intervention can minimize prescription medication use, reducing the risk of ADEs. PMID- 25275391 TI - Unnecessary lipid-lowering drugs in an outpatient geriatric clinic. AB - OBJECTIVES: Identify the number of patients in the University of Colorado Seniors Clinic who were prescribed a nonstatin lipid-lowering therapy and describe a pharmacist intervention that can reduce the unnecessary use of these agents. SETTING: Outpatient geriatrics clinic in a university health system. PRACTICE DESCRIPTION: The University of Colorado Seniors Clinic provides outpatient care for ambulatory patients 75 years of age or older. In 2012, there were 2,000 active patients, with 7,000 clinic visits. PRACTICE INNOVATION: All patients prescribed extended-release niacin, ezetimibe, fenofibrate, gemfibrozil, or prescription omega-3-acid ethyl esters were identified. Extended-release niacin, ezetimibe, fenofibrate, and gemfibrozil were deemed necessary if the patient was intolerant to statin therapy or could not attain the cholesterol goal with the maximum tolerated dose of a statin. Fenofibrate, gemfibrozil, and prescription omega-3-acid ethyl esters were considered necessary if the patient had a history of triglycerides above 500 mg/dL. If a pharmacist deemed the medication unnecessary, a note was placed in the medical record and discussed face-to-face with the provider. MAIN OUTCOME MEASURE(S): The number of patients and types of drugs that were prescribed and discontinued; the cost savings to the health system. RESULTS: Fifty-five patients were prescribed a potentially unnecessary lipid-lowering drug. Twenty-three drugs were discontinued, for an estimated $38,660.40 in cost savings. CONCLUSIONS: A low percentage of patients were prescribed a nonstatin lipid-lowering agent in this population. However, more than half were deemed unnecessary and were stopped, resulting in significant savings and health benefits. Applying this on a larger scale could result in significant savings and improved health. PMID- 25275392 TI - Overactive bladder: OTC oxybutynin transdermal patch for women. AB - The prevalence and burden of overactive bladder (OAB) in the population is remarkable. An estimated 20 million adult women in the United States have symptoms of OAB. Despite the negative impact on their health-related quality of life, many do not seek treatment. Antimuscarinic agents for OAB have long been available only with a prescription. However, the Food and Drug Administration approved an over-the-counter (OTC) oxybutynin transdermal patch for use in women in 2013, and the product recently came to market. The availability of an OTC antimuscarinic medication for OAB introduces the opportunity for females to self treat the condition. Prior to the prescription-to-OTC switch, the efficacy and safety data for the prescription product were evaluated. Consumer research studies guided the development of the drug label. PMID- 25275393 TI - Neuroendocrine humoral and vascular components in the pressor pathway for brain angiotensin II: a new axis in long term blood pressure control. AB - Central nervous system (CNS) administration of angiotensin II (Ang II) raises blood pressure (BP). The rise in BP reflects increased sympathetic outflow and a slower neuromodulatory pressor mechanism mediated by CNS mineralocorticoid receptors (MR). We investigated the hypothesis that the sustained phase of hypertension is associated also with elevated circulating levels of endogenous ouabain (EO), and chronic stimulation of arterial calcium transport proteins including the sodium-calcium exchanger (NCX1), the type 6 canonical transient receptor potential protein (TRPC6), and the sarcoplasmic reticulum calcium ATPase (SERCA2). Wistar rats received a chronic intra-cerebroventricular infusion of vehicle (C) or Ang II (A, 2.5 ng/min, for 14 days) alone or combined with the MR blocker, eplerenone (A+E, 5 ug/day), or the aldosterone synthase inhibitor, FAD286 (A+F, 25 ug/day). Conscious mean BP increased (P<0.05) in A (123 +/- 4 mm Hg) vs all other groups. Blood, pituitary and adrenal samples were taken for EO radioimmunoassay (RIA), and aortas for NCX1, TRPC6 and SERCA2 immunoblotting. Central infusion of Ang II raised plasma EO (0.58 +/- 0.08 vs C 0.34 +/- 0.07 nM (P<0.05), but not in A + E and A + F groups as confirmed by off-line liquid chromatography (LC)-RIA and LC-multistage mass spectrometry. Two novel isomers of EO were elevated by Ang II; the second less polar isomer increased >50-fold in the A+F group. Central Ang II increased arterial expression of NCX1, TRPC6 and SERCA2 (2.6, 1.75 and 3.7-fold, respectively; P<0.01)) but not when co-infused with E or F. Adrenal and pituitary EO were unchanged. We conclude that brain Ang II activates a CNS-humoral axis involving plasma EO. The elevated EO reprograms peripheral ion transport pathways known to control arterial Na(+) and Ca(2+) homeostasis; this increases contractility and augments sympathetic effects. The new axis likely contributes to the chronic pressor effect of brain Ang II. PMID- 25275394 TI - Ras GTPase activating protein CoIra1 is involved in infection-related morphogenesis by regulating cAMP and MAPK signaling pathways through CoRas2 in Colletotrichum orbiculare. AB - Colletotrichum orbiculare is the causative agent of anthracnose disease on cucurbitaceous plants. Several signaling pathways, including cAMP-PKA and mitogen activating protein kinase (MAPK) pathways are involved in the infection-related morphogenesis and pathogenicity of C. orbiculare. However, upstream regulators of these pathways for this species remain unidentified. In this study, CoIRA1, encoding RAS GTPase activating protein, was identified by screening the Agrobacterium tumefaciens-mediated transformation (AtMT) mutant, which was defective in the pathogenesis of C. orbiculare. The coira1 disrupted mutant showed an abnormal infection-related morphogenesis and attenuated pathogenesis. In Saccharomyces cerevisiae, Ira1/2 inactivates Ras1/2, which activates adenylate cyclase, leading to the synthesis of cAMP. Increase in the intracellular cAMP levels in coira1 mutants and dominant active forms of CoRAS2 introduced transformants indicated that CoIra1 regulates intracellular cAMP levels through CoRas2. Moreover, the phenotypic analysis of transformants that express dominant active form CoRAS2 in the comekk1 mutant or a dominant active form CoMEKK1 in the coras2 mutant indicated that CoRas2 regulates the MAPK CoMekk1-Cmk1 signaling pathway. The CoRas2 localization pattern in vegetative hyphae of the coira1 mutant was similar to that of the wild-type, expressing a dominant active form of RFP-CoRAS2. Moreover, we demonstrated that bimolecular fluorescence complementation (BiFC) signals between CoIra1 and CoRas2 were detected in the plasma membrane of vegetative hyphae. Therefore, it is likely that CoIra1 negatively regulates CoRas2 in vegetative hyphae. Furthermore, cytological analysis of the localization of CoIraI and CoRas2 revealed the dynamic cellular localization of the proteins that leads to proper assembly of F-actin at appressorial pore required for successful penetration peg formation through the pore. Thus, our results indicated that CoIra1 is involved in infection-related morphogenesis and pathogenicity by proper regulation of cAMP and MAPK signaling pathways through CoRas2. PMID- 25275397 TI - National Farm Medicine Center celebrates 10 years editing Journal of Agromedicine. PMID- 25275396 TI - Insights into Vibrio cholerae intestinal colonization from monitoring fluorescently labeled bacteria. AB - Vibrio cholerae, the agent of cholera, is a motile non-invasive pathogen that colonizes the small intestine (SI). Most of our knowledge of the processes required for V. cholerae intestinal colonization is derived from enumeration of wt and mutant V. cholerae recovered from orogastrically infected infant mice. There is limited knowledge of the distribution of V. cholerae within the SI, particularly its localization along the villous axis, or of the bacterial and host factors that account for this distribution. Here, using confocal and intravital two-photon microscopy to monitor the localization of fluorescently tagged V. cholerae strains, we uncovered unexpected and previously unrecognized features of V. cholerae intestinal colonization. Direct visualization of the pathogen within the intestine revealed that the majority of V. cholerae microcolonies attached to the intestinal epithelium arise from single cells, and that there are notable regiospecific aspects to V. cholerae localization and factors required for colonization. In the proximal SI, V. cholerae reside exclusively within the developing intestinal crypts, but they are not restricted to the crypts in the more distal SI. Unexpectedly, V. cholerae motility proved to be a regiospecific colonization factor that is critical for colonization of the proximal, but not the distal, SI. Furthermore, neither motility nor chemotaxis were required for proper V. cholerae distribution along the villous axis or in crypts, suggesting that yet undefined processes enable the pathogen to find its niches outside the intestinal lumen. Finally, our observations suggest that host mucins are a key factor limiting V. cholerae intestinal colonization, particularly in the proximal SI where there appears to be a more abundant mucus layer. Collectively, our findings demonstrate the potent capacity of direct pathogen visualization during infection to deepen our understanding of host pathogen interactions. PMID- 25275398 TI - Pyrethroid exposure and diabetes? PMID- 25275395 TI - Brugia malayi microfilariae induce a regulatory monocyte/macrophage phenotype that suppresses innate and adaptive immune responses. AB - BACKGROUND: Monocytes and macrophages contribute to the dysfunction of immune responses in human filariasis. During patent infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. AIM: To determine whether blood microfilariae directly act on blood monocytes and in vitro generated macrophages to induce a regulatory phenotype that interferes with innate and adaptive responses. METHODOLOGY AND PRINCIPAL FINDINGS: Monocytes and in vitro generated macrophages from filaria non-endemic normal donors were stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could show that monocytes stimulated with Mf lysate develop a defined regulatory phenotype, characterised by expression of the immunoregulatory markers IL-10 and PD-L1. Significantly, this regulatory phenotype was recapitulated in monocytes from Wuchereria bancrofti asymptomatically infected patients but not patients with pathology or endemic normals. Monocytes from non-endemic donors stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and cytokine production (IFN-gamma, IL-13 and IL-10). IFN-gamma responses were restored by neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate expressed high levels of IL-10 and had suppressed phagocytic abilities. Finally Mf lysate applied during the differentiation of macrophages in vitro interfered with macrophage abilities to respond to subsequent LPS stimulation in a selective manner. CONCLUSIONS AND SIGNIFICANCE: Conclusively, our study demonstrates that Mf lysate stimulation of monocytes from healthy donors in vitro induces a regulatory phenotype, characterized by expression of PD-L1 and IL-10. This phenotype is directly reflected in monocytes from filarial patients with asymptomatic infection but not patients with pathology or endemic normals. We suggest that suppression of T cell functions typically seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in an IL-10-dependent manner. Together with suppression of macrophage innate responses, this may contribute to the overall down-regulation of immune responses observed in asymptomatically infected patients. PMID- 25275399 TI - Factors influencing poisoning symptoms: a case study of vegetable farmers exposed to mixed insecticides in Prek Balatchheng Village, Cambodia. AB - This study aimed to identify factors influencing poisoning symptoms among 153 mixed insecticide-exposed vegetable farmers in one Cambodian village, where 153 factory workers were selected as a comparative nonexposed group. The research instruments were questionnaires and reactive-paper test kits. The majority of vegetable farmers were male, with approximately 87% of the total participants with an average age of 34 years. The personal hygiene scores of most vegetable farmers (108; 70.8%) were moderate, and knowledge scores were at poor level (131; 85.6%). Abnormally low cholinesterase (ChE) levels were detected among 119 (77.8%) farmers. Multiple logistic regression analysis was used to identify factors associated with possible poisoning symptoms. This study found that mixing an average of four to six types of insecticides (odds ratio [OR] = 4.6; P = .03) and abnormal ChE level (OR = 4.09; P = .004) was associated with central nervous system (CNS) symptoms. Age group >45 years (OR = 2.8; P = .04) and type of vegetable "other" (OR = 2.73; P = .02) were associated with gastrointestinal symptoms. Type of insecticide, organophosphates (OPs) and carbamates (CMs) (OR = 3.2; P = .04), was associated with respiratory symptoms. It is recommended that farmers should reduce insecticide spraying times, increase their use of personal protective equipment (PPE), and undergo training on insecticide use. These combined measures should improve the insecticide-related health status of vegetable farmers in this area. PMID- 25275400 TI - Respiratory fit testing for farmworkers in the Black Dirt region of Hudson Valley, New York. AB - Respiratory protection in agriculture has lagged behind other industries. Migrant farmworkers often work in dusty environments yet do not receive appropriate, fitted respiratory protection. During May and June of 2013, researchers pilot tested a respiratory protection program adapted to fit the unique needs of migrant and seasonal farmworkers. It was implemented in Spanish, with literacy support, at convenient times and locations. Additionally, staff was known to workers, and a farmworker medical center provided medical follow-up. Fifty-six farmworkers participated (68%; 82 invited). Of the participants, 88% were male; 20% reported using respiratory protection. One worker had been fit tested previously; 57% reported being exposed to pesticides. All but six farmworkers passed the medical clearance (91%). The mask most commonly fit to the American born population was a good fit for only 41% of Latino farmworkers. The fact that two thirds of invited farmworkers participated in the clearance and over half completed mask fitting indicates that the modified protocol meets farmworker needs. A wide range of mask types should be made available for Latino farmworkers. PMID- 25275401 TI - Safety and injury characteristics of youth farmworkers in North Carolina: a pilot study. AB - Agriculture is a unique US industry in how youth are involved. Youth employed in agriculture experience high rates of injury, and youth migrant and seasonal farmworkers may be extremely vulnerable. The primary aim for this analysis is to describe the personal characteristics, work characteristics, occupational safety behaviors, and occupational injuries of North Carolina youth farmworkers. This pilot study uses data from interviewer-administered questionnaires with 87 youth farmworkers. Participants included males (62.1%) and females (37.9%), with 26.4% aged 10-13 years, 39.1% 14-15 years, and 34.5% 16-17 years. The majority (78.2%) were born in the United States. Most worked in tobacco (46.0%), sweet potatoes (28.7%), and berries (28.7%). They were paid by the hour (54.0%) and piece rate (55.2%); 21.8% reported a problem getting paid the amount earned. Three quarters wore a hat, and 63.2% wore gloves while working. Five (5.7%) had received pesticide use training in the past year. Over half reported a musculoskeletal injury (54.0%), a traumatic injury (60.9%), or a dermatological injury (72.4%) in the last year. Six of the injuries led to medical treatment, and 10 resulted in missed school or work. Farmworker youth in North Carolina are at times not treated fairly when they work, occupational safety behaviors are limited (increasing exposure to pesticides and other environmental hazards), and they commonly experience injuries. Research on the occupational exposures and health experienced by youth farmworkers is needed to inform policy. Changes in policy are warranted to improve the safety of youth farmworkers. PMID- 25275402 TI - Health-risk behaviors in agriculture and related factors, southeastern Anatolian region of Turkey. AB - Human behavior plays a central role in the maintenance of health and the prevention of diseases. This study aimed to determine the risky behaviors of farm operators selected from a province of Turkey's southeastern Anatolian region, as well as the factors related to risky behaviors. In this cross-sectional analysis, 380 farm operators were enrolled through simple random selection method, and the response rate was 85%. Health-risk behavior was measured using the Control List of Occupational Risks in Agriculture. Of 323 farm operators, 85.4% were male. The prevalence of risky behaviors related to measures of environmental risks were higher in animal husbandry, transportation, transportation and maintenance of machinery, pesticide application, child protection, thermal stress, and psychosocial factors in the work place. Education, age, duration of work, and size of agricultural area were associated with risky behaviors in a multiple linear regression (P < .05). Findings showed that a certified training program and a behavior surveillance system for agriculture should be developed. PMID- 25275403 TI - A meta-analytic review of the effectiveness of single-layer clothing in preventing exposure from pesticide handling. AB - This review summarizes available information on the penetration of pesticides through single-layer clothing by pesticide handlers and introduces epidemiological and observational studies on pesticide exposure. The data for this report were taken from peer-reviewed articles, publicly available government reports, and publicly available government reviews of registrant-submitted data and information. The arithmetic mean of calculated clothing penetration was obtained for various parts of the body (upper arm, lower arm, chest/torso, back/torso, upper leg, and lower leg) that were exposed to pesticide. The range of pesticide penetration to the various parts of the body through single-layer clothing during mixing, loading, and application (MLA) activities was found to be 6.2% +/- 5.7% to 21.4% +/- 6.7%, which demonstrates a potential for increased and unintentional pesticide exposures. Based on this evaluation, some accepted default values for protection against pesticide exposure may be overestimated. PMID- 25275404 TI - Employer differences in upper-body musculoskeletal disorders and pain among immigrant Latino poultry processing workers. AB - Between-employer differences in working conditions may lead to variable injury rates. The objective of this paper is to assess the difference in the prevalence of epicondylitis, rotator cuff syndrome, and low back pain among immigrant Latino poultry workers at plants of three different employers. Data were collected from a cross-sectional study among 286 poultry processing workers. Community-based sampling was used to recruit participants in western North Carolina. Rotator cuff syndrome (26.7%) and low back pain (27.9%) were more prevalent among employees of one specific employer. Multivariate analysis showed significant associations of low back pain and rotator cuff syndrome with age, task performed in the processing line, and employer. Employer is a major predictor of musculoskeletal disorders and pain. Line speed and work pace may account for these differences and provide an opportunity for regulation and intervention to protect the health of workers. PMID- 25275405 TI - The association of respiratory symptoms and indoor housing conditions among migrant farmworkers in eastern North Carolina. AB - Farm labor housing has been described as among the worst in the nation, oftentimes with poor and unsanitary indoor living conditions. The objective of this study was to evaluate the association between indoor environmental risk factors and respiratory health among migrant farmworker occupants (N = 352) living in employer-provided housing. A cross-sectional sample of adult Latino male farm laborers were administered a questionnaire to identify the prevalence of major respiratory symptoms. Self-reported and independent observations were made to evaluate environmental respiratory risk factors and indoor housing conditions, including but not limited to, the presence of cockroaches, rodents, pesticides, and visible signs of mold. Spirometry was performed to evaluate lung function using FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity), and FEV1 /FVC ratio. Bivariate analysis was applied to evaluate associations between respiratory symptoms and selected indoor environmental risk factors. Findings for respiratory health included prevalence of wheeze (11.4%), coughing up phlegm (17.3%), tightness of chest (16.8%), and runny or stuffy nose (34.4%). Respiratory risks identified inside the dwellings included the use of pesticides or bug sprays for cockroaches (31.5%), rat or mouse poison (19.5%), visible signs of water damage in the bathroom (22.5%), and mold in the sleeping room (11.1%). Spirometry values were normal for most occupants, although statistically significant associations were found between mold and coughing up phlegm when not having a cold (P = .0262); presence of mold and asthma (P = .0084); pesticides used in the home and tightness of chest (P = .0001); and use of tobacco and coughing up phlegm (P = .0131). Although causal inference can be difficult to establish from a cross-sectional study, findings from this study represents suggestive evidence that indoor environmental risk factors may be contributory factors for respiratory health problems among this vulnerable workgroup population. PMID- 25275406 TI - Organophosphate pesticide exposure in school-aged children living in rice and aquacultural farming regions of Thailand. AB - Organophosphate pesticides (OPs) are widely used in agricultural sectors in Thailand. Previous studies have documented that children residing in agricultural areas have higher exposure to OPs than children living in other residential areas. The objective of this study was to quantify urinary biomarkers of OP exposure and determine the environmental conditions and activities that predict their levels among children living in Central Thailand farming regions. In October 2011, 53 6-8-year-old participants were recruited from Pathum Thani Province, Thailand. Twenty-four lived in rice farming communities at Khlong Luang District where OPs are the pesticides used frequently. Twenty-nine participants, living in aquacultural farming communities at Lum Luk Ka District where OPs are not used, were recruited to serve as controls for pathways of exposure (e.g., residential, dietary) other than occupational/paraoccupational exposures encountered in rice farming. Household environments and participants' activities were assessed using a parental structured interview. Urine samples (first morning voids) were collected from participants for OP urinary metabolite (i.e., dialkylphosphates [DAPs] and 3,5,6-trichloro-2-pyridinol [TCPy]) measurements. The levels of most urinary OP metabolites were significantly higher in participants who lived in a rice farming community than those who lived in an aquacultural farming community (P < .05). The results from linear regression analysis revealed that the frequency of OP application on rice farms (?DAP: P = .001; TCPy: P = .001) and living in a rice farming community (?DAP: P = .009; TCPy: P < .001) were significant predictors of urinary DAP metabolite levels in participants. Increasing TCPy levels were significantly related to proximity to rice farm (P = .03), being with parent while working on a farm (P = .02), playing on a farm (P = .03), and the presence of observable dirt accumulated on the child's body (P = .02). In conclusion, OP metabolite levels among children who live in rice farming communities were strongly influenced by farming activity, household environments, and child behaviors, suggesting that these are the primary pathways in which children living in these agricultural communities in Thailand were exposed to OPs. PMID- 25275407 TI - Is cumulated pyrethroid exposure associated with prediabetes? A cross-sectional study. AB - Pyrethroids are a class of insecticides used widely for vector control programs. Acute pyrethroid poisoning is rare, but well documented, whereas effects of cumulative exposure are insufficiently described, including possible negative effect on glucose regulation. The objective of this study was to investigate an association between exposure to pyrethroids and abnormal glucose regulation (prediabetes or diabetes). A cross-sectional study was performed among 116 pesticide sprayers from public vector control programs in Bolivia and 92 nonexposed controls. Pesticide exposure (duration, intensity, cumulative exposure) was assessed from questionnaire data. Participants were asked about symptoms of diabetes. Blood samples were analyzed for glycosylated hemoglobin (HbA1c), a measure of glucose regulation. No association was found between pyrethroid exposure and diabetes symptoms. The prevalence of abnormal glucose regulation (defined as HbA1c >= 5.6%) was 61.1% among sprayers and 7.9% among nonexposed controls, corresponding to an adjusted odds ratio (OR [95% confidence interval]) for all sprayers of 11.8 [4.2-33.2] and 18.5 [5.5-62.5] for pyrethroid exposed only. Among sprayers who had only used pyrethroids, a significant positive trend was observed between cumulative pesticide exposure (total number of hours sprayed) and adjusted OR of abnormal glucose regulation, with OR 14.7 [0.9-235] in the third exposure quintile. The study found a severely increased prevalence of prediabetes among Bolivian pesticide sprayers compared with a control group, but the relevance of the control group is critical. Within the spraying group, an association between cumulative exposure to pyrethroids and abnormal glucose regulation was seen. Further studies are needed to confirm this association. PMID- 25275408 TI - Agricultural work exposures and pulmonary function among hired farm workers in California (the MICASA study). AB - Despite California's dependence on hired farm labor, scarce research has been conducted on the respiratory health of hired farm workers. Agricultural exposures to inorganic and organic dusts can adversely affect an individual's respiratory health and differ by farm type and job task. The purpose of the present analysis was to examine associations between agricultural work exposures and pulmonary function among 450 California farm workers. Data were collected as part of the Mexican Immigration to California: Agricultural Safety and Acculturation (MICASA) study, a prospective cohort study examining occupational risk factors and health of hired farm worker families in Mendota, California. Time-weighted self-reported average (TWSRA) dust scores were calculated from assessments of past-12-month agricultural work history. Other dust exposure indicator variables included months worked in agriculture in the past 12 months and years worked in agriculture. Multiple linear regression modeled FEV1 (forced expiratory volume in 1 second), FEF(25-75%) (forced midexpiratory flow rate), FVC (forced vital capacity), FEV6, FEV1/FVC, and FEV1/FEV6 separately. Seventy-six percent of participants had worked in agriculture in the past year. In models conducted for crops and tasks separately, high TWSRA dust score was associated with better FEV6. Crop and task models showed associations between greater months worked in agriculture in the past year and better FEV1, FEF(25-75%), and FEV6. Both models also found greater years worked in agriculture to be associated with worse FEV1/FEV6. Results were generally in the opposite direction as expected given past research but not uncommon. Future research should investigate relationships between pulmonary function and agricultural dust exposure over a lifetime and changes in pulmonary function over time. PMID- 25275411 TI - Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma. AB - We investigated the intraocular pressure (IOP) lowering efficacy of preservative free fixed and non-fixed combination of tafluprost 0.0015% and timolol 0.5% in pseudoexfoliative glaucoma (XFG). A per protocol worse eye analysis was made on all XFG patients who participated in a recent 6 month, prospective, randomized, double-masked, parallel group, multicenter phase III study. The mean time-wise IOP decreased by 8.62 to 10.25 mmHg (31.8 to 36.7%) in the fixed dose combination arm (15 patients) and by 5.38 to 11.35 mmHg (21.3 to 41.2%) in the non-fixed combination arm (13 patients), respectively (p < 0.001 for all comparisons). The results show that a preservative-free fixed dose combination of tafluprost and timolol provides a clinically significant IOP reduction in XFG, and may offer an advantage for the XFG patients with dry eye, due to its preservative-free nature. PMID- 25275413 TI - The use of (68)Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177)Lu DOTATATE therapy in pituitary carcinoma. AB - A 68-year-old man, with a history of pituitary surgery and radiation therapy for pituitary macroadenoma 20 years earlier, presented with a pituitary mass and enlarging lesions within the posterior fossa and spinal canal. Biopsy revealed low-grade pituitary carcinoma. PET/CT scan showed multiple foci of increased Ga DOTATATE activity including pituitary and posterior fossa lesions. After 3 fractions of Lu DOTATATE therapy, the tumor remained stable over 4 years on MRI and Ga DOTATATE scans. This case illustrates the benefit of Ga DOTATATE PET/CT in malignant pituitary disease to assess potential for somatostatin receptor therapy with Lu DOTATATE and monitor treatment. PMID- 25275414 TI - 99mTc-MDP SPECT/CT demonstrating extraosseous periarticular amyloid deposits in primary systemic amyloidosis associated with multiple myeloma. AB - Amyloidosis is a rare disorder characterized by variable extracellular accumulation of a complex substance consisting of proteinaceous fibrils (amyloid fibrils) and nonfibrillar glycoprotein or amyloid P component. We present a case of a primary systemic amyloidosis associated with multiple myeloma in a 48-year old woman whose Tc-MDP SPECT/CT study revealed extraosseous periarticular uptake in amyloid deposits with no abnormal focal tracer uptake in the bone. PMID- 25275415 TI - Metastatic poorly differentiated prostatic carcinoma with neuroendocrine differentiation: negative on 68Ga-PSMA PET/CT. AB - Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68(HBED-CC)], abbreviated as Ga-PSMA, is a novel radiotracer undergoing evaluation for PET/CT imaging of prostate carcinoma. Its major advantage is the sensitive detection of lesions even at low prostate specific antigen level and high target-to-background ratios obtained in metastatic lesions, which is better than that obtained with F fluoromethylcholine. We present the case of a 28-year-old man with poorly differentiated prostate carcinoma with neuroendocrine differentiation, whose lesions did not show significant Ga-PSMA localization. As literature on utility of Ga-PSMA PET/CT for imaging prostate carcinoma grows, it is important to be aware of potential false negatives that could influence study results. PMID- 25275416 TI - Diffuse hepatic amebiasis detected by FDG PET/CT. AB - A 39-year-old man presented with sudden decreased visual acuity in his left eye. Orbital CT and MRI revealed a soft tissue lesion in his left orbital apex. FDG PET/CT showed increased FDG uptake by the left orbital lesion, abnormal focal FDG uptake in the soft tissues of the external ears, and abnormal heterogeneous FDG activity throughout the liver. Percutaneous liver biopsy, external auditory canal discharge, and stool specimens revealed amebiasis. The patient responded to antiamebic therapy, and his lesions improved. The case demonstrates that during its early stage, hepatic amebiasis may be associated with a relatively heterogeneous pattern of FDG uptake. PMID- 25275417 TI - Recurrent ureteric transitional cell carcinoma presenting as an isolated brain metastasis: incidental detection with 18F-FDG PET/CT. AB - Brain metastasis from transitional cell carcinoma (TCC) of the ureter is extremely rare. Here we present a case of a 73-year-old woman, a follow-up case of ureteric TCC in whom isolated brain metastasis was incidentally detected at follow-up 18F-FDG PET/CT. This was corroborated with MRI. She underwent excision of the lesion, and histopathology confirmed metastatic TCC. PMID- 25275418 TI - FDG PET findings of the brain in sudden blindness caused by bilateral central retinal artery occlusion revealing giant cell arteritis. AB - We report the case of a 73-year-old woman presenting sudden blindness caused by bilateral simultaneous central retinal artery occlusion revealed by ophthalmoscopy. Temporal artery biopsy confirmed the giant cell arteritis. The patient was treated with a systemic steroid without visual recovery. FDG PET/CT was performed 6 months later in the context of persistent inflammatory syndrome. This case shows the close relationship between functional activity and glucose energy metabolism. We observed both bilateral occipital hypometabolism corresponding to loss of functional activity and bilateral temporal (auditory areas) and orbitofrontal hypermetabolism related to compensatory neuronal plasticity. PMID- 25275419 TI - Giant pulmonary chondroid hamartoma: imaging and pathology correlation of a rare tumor demonstrated with bone scintigraphy and 18F-FDG PET/CT. AB - A 35-year-old man presented to the emergency department with a worsening cough and a history of unintended weight loss. Chest radiograph revealed a giant mass occupying the left hemithorax. On CT scan, the mass measured over 20 cm and shifted the heart into the right hemithorax. Bone scan demonstrated multifocal radiotracer uptake within coarse intratumoral calcifications. Biopsy revealed no malignant cells. However, malignancy was clinically suspected due to size, and FDG PET/CT was performed. Mild FDG uptake was present in the mass. The mass was excised, and pathologic examination revealed the rare diagnosis of a giant pulmonary chondroid hamartoma. PMID- 25275420 TI - Erlotinib-induced cutaneous toxicity: findings on 18F-FDG PET/CT imaging. AB - Erlotinib is a reversible epidermal growth factor receptor tyrosine kinase inhibitor used to treat advanced non-small cell lung carcinoma patients who have shown progression on at least 1 prior chemotherapy regimen. Most of the patients on erlotinib show cutaneous adverse effects. We report the 18F-FDG PET/CT findings in a case of metastatic non-small cell lung carcinoma on erlotinib chemotherapy with developed skin toxicity. PMID- 25275422 TI - The Effects of Cold Pressor-Induced Pain on PASAT Performance. AB - Although clinicians have frequently observed that patients with chronic pain experience cognitive deficits related to memory and concentration, research on these deficits is equivocal, with some studies showing significant impairment and others suggesting minimal deficits. As such, the present study sought to examine the relationship between laboratory-induced pain and performance on the Paced Auditory Serial Addition Test (PASAT) using a mixed factorial design. Seventy-two nonclinical volunteers were randomly assigned to a pain group, who took the PASAT while experiencing cold pressor-induced pain, or a control group, who took the PASAT while experiencing painless room-temperature water immersion. To account for practice effects, all participants were administered 1 practice trial and 3 standard trials of the PASAT, with the final trial administered in cold pressor induced pain or painless water immersion. The results revealed a significant interaction between condition and PASAT performance, F(1, 64) = 23.63, p < .001, partial eta(2) = .27. The control group increased performance by 6 items while the pain group showed no such improvement. The results suggest that because the pain group did not demonstrate the same practice effects relative to the control group, their performance was impaired by cold pressor-induced pain. However, the impairment was relatively mild (about 0.5 standard deviation) and did not occur in all participants. PMID- 25275421 TI - Intrapancreatic accessory spleen detected by 68Ga DOTANOC PET/CT and 99mTc colloid SPECT/CT scintigraphy. AB - A 77-year-old man was referred to our center for a suspected neuroendocrine neoplasm in the pancreatic tail, incidentally detected at CT. Ga DOTANOC PET/CT showed intense tracer uptake in the pancreatic lesion. At MRI, the lesion was similar to the spleen on all sequences, suggesting the presence of intrapancreatic accessory spleen. A Tc-colloid SPECT/CT scan performed to differentiate spleen tissue from neuroendocrine tumor revealed a focal uptake in the pancreatic lesion, thus confirming the presence of ectopic spleen and avoiding unnecessary surgery. PMID- 25275423 TI - The experiences of female athletic trainers in the role of the head athletic trainer. AB - CONTEXT: Very few women have leadership positions in athletic training (ie, head athletic training positions) in intercollegiate athletics. Research exists on the barriers to attaining the role; however, our understanding about the experiences of those currently engaged in the role is limited. OBJECTIVE: To examine the experiences of female head athletic trainers as they worked toward and attained the position of head athletic trainer. DESIGN: Qualitative study. SETTING: National Collegiate Athletic Association Division I setting. PATIENTS OR OTHER PARTICIPANTS: Eight female athletic trainers serving in the role of head athletic trainer participated in our study. The mean age of the participants was 45 +/- 12 years, with 5 +/- 1.5 years of experience in the role of head athletic trainer and 21 +/- 10 years of experience as athletic trainers. DATA COLLECTION AND ANALYSIS: We conducted phone interviews with the 8 participants following a semistructured format. Interviews were transcribed verbatim and analyzed following a general inductive approach as described by Thomas. To establish credibility, we used a peer reviewer, member checks, and multiple-analyst triangulation. RESULTS: Six major themes emerged from our analysis regarding the experiences of female head athletic trainers. Opportunities to become a head athletic trainer, leadership qualities, and unique personal characteristics were discussed as factors leading to the assumption of the role of the head athletic trainer. Where women hold back, family challenges, and organizational barriers speak to the potential obstacles to assuming the role of head athletic trainer. CONCLUSIONS: Female head athletic trainers did not seek the role, but through persistence and encouragement, they find themselves assuming the role. Leadership skills were discussed as important for success in the role of head athletic trainer. Life balancing and parenting were identified as barriers to women seeking the role of head athletic trainer. PMID- 25275425 TI - Pushed beyond the brink: Allee effects, environmental stochasticity, and extinction. AB - To understand the interplay between environmental stochasticity and Allee effects, we analyse persistence, asymptotic extinction, and conditional persistence for stochastic difference equations. Our analysis reveals that persistence requires that the geometric mean of fitness at low densities is greater than one. When this geometric mean is less than one, asymptotic extinction occurs with high probability for low initial population densities. Additionally, if the population only experiences positive density-dependent feedbacks, conditional persistence occurs provided the geometric mean of fitness at high population densities is greater than one. However, if the population experiences both positive and negative density-dependent feedbacks, conditional persistence only occurs if environmental fluctuations are sufficiently small. We illustrate counter-intuitively that environmental fluctuations can increase the probability of persistence when populations are initially at low densities, and can cause asymptotic extinction of populations experiencing intermediate predation rates despite conditional persistence occurring at higher predation rates. PMID- 25275426 TI - The cost-effectiveness of OM-85 in managing respiratory tract infections in China. AB - OBJECTIVES: To demonstrate the health economic impact of OM-85, a bacterial lysates based immunostimulant, for its approved indications in China. METHODS: A cost-effectiveness decision tree model was constructed comparing OM-85 with the best supportive care/placebo therapy for managing the acute exacerbation of chronic bronchitis and rhinosinusitis in the Chinese population. Clinical efficacy and adverse events (AE) data were included in the model based on a thorough literature review. All localized direct treatment costs, including drug cost, AE costs, and medical treatment costs for underlining diseases were included from a Chinese third party payer perspective. A Key Opinion Leaders (KOL) survey was conducted with 20 senior physicians specialized in respiratory, ENT, allergy, and immunology fields from tertiary hospitals in Beijing, Shanghai, Guangzhou, Hangzhou, Shenyang, and Wuhan to validate the local treatment costs. Incremental cost-effectiveness ratio (ICER) was calculated based on the above efficacy and cost information. RESULTS: OM-85 is a cost-effective therapy when compared with placebo (standard care). OM-85 can treat/prevent one additional full episode exacerbation of chronic bronchitis and one additional full episode exacerbation of rhinosinusitis with only additional costs of RMB 653 and RMB 1182.84, respectively. In comparison, each acute exacerbation of chronic bronchitis will cost RMB 4510.10, and each acute exacerbation of rhinosinuisitis will cost RMB 1807.21 in a Chinese clinical management setting. One-way sensitivity analyses were performed and the ICER result was demonstrated to be consistent. CONCLUSIONS: OM 85 reduces acute exacerbations among patients with chronic bronchitis and chronic rhinosinusitis when compared with Placebo (standard care). From a Chinese payer perspective, OM 85 is a cost-effective therapy in the clinical management of both chronic bronchitis and rhinosinusitis in the adult population. PMID- 25275424 TI - Apathy is associated with white matter abnormalities in anterior, medial brain regions in persons with HIV infection. AB - Apathy is a relatively common psychiatric syndrome in HIV infection, but little is known about its neural correlates. In the present study, we examined the associations between apathy and diffusion tensor imaging (DTI) indices in key frontal white matter regions in the thalamocorticostriatal circuit, which has been implicated in the expression of apathy. Nineteen participants with HIV infection and 19 demographically comparable seronegative comparison subjects completed the Apathy subscale of the Frontal Systems Behavioral Scale as a part of a comprehensive neuropsychiatric research evaluation. When compared to the seronegative participants, the HIV+ group had significantly more frontal white matter abnormalities. Within HIV+ persons, and as predicted, higher ratings of apathy were associated with greater white matter alterations in the anterior corona radiata, genu, and orbital medial prefrontal cortex. The associations between white matter alterations and apathy were independent of depression and were stronger among participants with lower current cluster of differentiation 4 (CD4) counts. All told, these findings indicate that apathy is independently associated with white matter abnormalities in anterior, medial brain regions in persons infected with HIV, particularly in the setting of lower current immune functioning, which may have implications for antiretroviral therapy. PMID- 25275427 TI - Chemoprophylaxis for venous thromboembolism in otolaryngology. AB - IMPORTANCE: Venous thromboembolism (VTE) causes significant morbidity and mortality in surgical patients. Despite strong evidence that thromboprophylaxis reduces the incidence VTE, guidelines for prophylaxis in otolaryngology are not well established. Key to the development of VTE prophylaxis recommendations are effective VTE risk stratification and evaluation of the benefits and harms of prophylaxis. OBJECTIVE: To evaluate the effectiveness and safety of VTE chemoprophylaxis among a population of otolaryngology patients stratified by risk. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 3498 adult patients admitted for otolaryngologic surgery at a single-institution academic tertiary care medical center between September 1, 2003, and June 30, 2010. INTERVENTIONS: Patients were stratified into 2 groups based on whether they received VTE chemoprophylaxis. MAIN OUTCOMES AND MEASURES: Incidence of VTE and bleeding-related complications within 30 days after surgery. RESULTS: Of 1482 patients receiving VTE chemoprophylaxis, 18 (1.2%) developed a VTE compared with 27 of 2016 patients (1.3%) who did not receive prophylaxis (P = .75). Patients with Caprini VTE risk scores greater than 7 were less likely to have a VTE with perioperative chemoprophylaxis (5.3% vs 10.4%; P = .06). Of patients with VTE chemoprophylaxis, 3.5% developed a bleeding complication compared with 1.2% of patients without prophylaxis (P < .001). Bleeding complications were associated with concomitant use of antiplatelet medications and chemoprophylaxis. Among patients undergoing free tissue transfer, chemoprophylaxis significantly decreased the incidence of VTE (2.1% vs 7.7%; P = .002) and increased bleeding complications (11.9% vs 4.5%; P = .01). In all other patients, VTE chemoprophylaxis did not significantly influence the likelihood of VTE (1.0% vs 0.6%; P = .12) or bleeding (1.5% vs 0.9%; P = .15). CONCLUSIONS AND RELEVANCE: Effectiveness and safety of VTE chemoprophylaxis differed between patient subgroups, defined by Caprini risk score and by procedure. Effectiveness was most evident in patients with high Caprini risk scores and microvascular free tissue reconstruction. Bleeding complications were associated with VTE chemoprophylaxis administered in close proximity to potent antiplatelet therapy. The Caprini risk assessment model appears to be an effective tool to stratify otolaryngology patients by risk for VTE. Patients undergoing free tissue reconstruction merit further study before developing recommendations for VTE prophylaxis because of their higher risk of both VTE and bleeding. PMID- 25275428 TI - Prion protein-specific antibodies-development, modes of action and therapeutics application. AB - Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are lethal neurodegenerative disorders involving the misfolding of the host encoded cellular prion protein, PrPC. This physiological form of the protein is expressed throughout the body, and it reaches the highest levels in the central nervous system where the pathology occurs. The conversion into the pathogenic isoform denoted as prion or PrPSc is the key event in prion disorders. Prominent candidates for the treatment of prion diseases are antibodies and their derivatives. Anti-PrPC antibodies are able to clear PrPSc from cell culture of infected cells. Furthermore, application of anti-PrPC antibodies suppresses prion replication in experimental animal models. Major drawbacks of immunotherapy are immune tolerance, the risks of neurotoxic side effects, limited ability of compounds to cross the blood-brain barrier and their unfavorable pharmacokinetic. The focus of this review is to recapitulate the current understanding of the molecular mechanisms for antibody mediated anti-prion activity. Although relevant for designing immunotherapeutic tools, the characterization of key antibody parameters shaping the molecular mechanism of the PrPC to PrPSc conversion remains elusive. Moreover, this review illustrates the various attempts towards the development of anti-PrP antibody compounds and discusses therapeutic candidates that modulate PrP expression. PMID- 25275429 TI - Comparison of pharmacodynamics between low dose ticagrelor and clopidogrel after loading and maintenance doses in healthy Korean subjects. AB - The novel antiplatelet agent ticagrelor has been demonstrated to exert a faster and more powerful inhibition of platelet aggregation in comparison to clopidogrel in coronary artery disease patients. However, a ticagrelor dose of 90 mg twice daily might not be suitable for patients of East Asian ethnicity, and has not been fully investigated. The aim of this study was to assess the effects of low loading doses (LD, 90 mg) and maintenance doses (MD, 90 mg daily) of ticagrelor in comparison to clopidogrel (600 mg LD, 75 mg daily MD) in healthy Korean volunteers. Twelve subjects were randomized into two groups, receiving either clopidogrel (600 mg LD, followed by 75 mg MD daily for 5 days) or ticagrelor (90 mg LD, followed by 90 mg MD daily for 5 days). Following a 2-week washout period, the treatments were switched between the groups. Three platelet function assessment methods which included light transmission aggregometry (LTA), the VerifyNow assay and multiple electrode platelet aggregometry (MEA) were then used to serially measure platelet function at various time points (baseline, 0.5, 2, 6, 24, 26, 120 and 122 h). The mean IPA to 10 uM ADP in the ticagrelor group was significantly higher than that for the clopidogrel group at the 0.5, 2, 6, 26 and 122 h time points (p <= 0.001). However, there was no significant difference between the two groups at the 24- and 120-hour time points (p > 0.05). The assay results produced by the other two platelet function tests (VerifyNow and MEA) were similar to those obtained by LTA. The low loading and maintenance doses of ticagrelor (90 mg LD, 90 mg daily MD) cause a more rapid and potent inhibition of platelet function when compared to clopidogrel (600 mg LD and 75 mg MD). Additionally, at the lowest value of platelet inhibition strength, oral once daily administration of ticagrelor was no less efficacious than clopidogrel at the 24- and 120-hour time points. Due to a large diurnal variation occurring with a single daily dose, a lower dose twice-daily could be a better option for patients of East Asian ethnicity. PMID- 25275432 TI - Health literacy, cognitive function, proper use, and adherence to inhaled asthma controller medications among older adults with asthma. AB - BACKGROUND: We sought to investigate the degree to which cognitive skills explain associations between health literacy and asthma-related medication use among older adults with asthma. METHODS: Patients aged >= 60 years receiving care at eight outpatient clinics (primary care, geriatrics, pulmonology, allergy, and immunology) in New York, New York, and Chicago, Illinois, were recruited to participate in structured, in-person interviews as part of the Asthma Beliefs and Literacy in the Elderly (ABLE) study (n = 425). Behaviors related to medication use were investigated, including adherence to prescribed regimens, metered-dose inhaler (MDI) technique, and dry powder inhaler (DPI) technique. Health literacy was measured using the Short Test of Functional Health Literacy in Adults. Cognitive function was assessed in terms of fluid (working memory, processing speed, executive function) and crystallized (verbal) ability. RESULTS: The mean age of participants was 68 years; 40% were Hispanic and 30% non-Hispanic black. More than one-third (38%) were adherent to their controller medication, 53% demonstrated proper DPI technique, and 38% demonstrated correct MDI technique. In multivariable analyses, limited literacy was associated with poorer adherence to controller medication (OR, 2.3; 95% CI, 1.29-4.08) and incorrect DPI (OR, 3.51; 95% CI, 1.81-6.83) and MDI (OR, 1.64; 95% CI, 1.01-2.65) techniques. Fluid and crystallized abilities were independently associated with medication behaviors. However, when fluid abilities were added to the model, literacy associations were reduced. CONCLUSIONS: Among older patients with asthma, interventions to promote proper medication use should simplify tasks and patient roles to overcome cognitive load and suboptimal performance in self-care. PMID- 25275430 TI - Impact of sampling density on the extent of HIV clustering. AB - Identifying and monitoring HIV clusters could be useful in tracking the leading edge of HIV transmission in epidemics. Currently, greater specificity in the definition of HIV clusters is needed to reduce confusion in the interpretation of HIV clustering results. We address sampling density as one of the key aspects of HIV cluster analysis. The proportion of viral sequences in clusters was estimated at sampling densities from 1.0% to 70%. A set of 1,248 HIV-1C env gp120 V1C5 sequences from a single community in Botswana was utilized in simulation studies. Matching numbers of HIV-1C V1C5 sequences from the LANL HIV Database were used as comparators. HIV clusters were identified by phylogenetic inference under bootstrapped maximum likelihood and pairwise distance cut-offs. Sampling density below 10% was associated with stochastic HIV clustering with broad confidence intervals. HIV clustering increased linearly at sampling density >10%, and was accompanied by narrowing confidence intervals. Patterns of HIV clustering were similar at bootstrap thresholds 0.7 to 1.0, but the extent of HIV clustering decreased with higher bootstrap thresholds. The origin of sampling (local concentrated vs. scattered global) had a substantial impact on HIV clustering at sampling densities >=10%. Pairwise distances at 10% were estimated as a threshold for cluster analysis of HIV-1 V1C5 sequences. The node bootstrap support distribution provided additional evidence for 10% sampling density as the threshold for HIV cluster analysis. The detectability of HIV clusters is substantially affected by sampling density. A minimal genotyping density of 10% and sampling density of 50-70% are suggested for HIV-1 V1C5 cluster analysis. PMID- 25275435 TI - Public health measures to control the spread of antimicrobial resistance in Neisseria gonorrhoeae in men who have sex with men. AB - Gonorrhoea is one of the most common sexually transmitted infections. The control of gonorrhoea is extremely challenging because of the repeated development of resistance to the antibiotics used for its treatment. We explored different strategies to control the spread of antimicrobial resistance and prevent increases in gonorrhoea prevalence. We used a mathematical model that describes gonorrhoea transmission among men who have sex with men and distinguishes gonorrhoea strains sensitive or resistant to three antibiotics. We investigated the impact of combination therapy, switching first-line antibiotics according to resistance thresholds, and other control efforts (reduced sexual risk behaviour, increased treatment rate). Combination therapy can delay the spread of resistance better than using the 5% resistance threshold. Increased treatment rates, expected to enhance gonorrhoea control, may reduce gonorrhoea prevalence only in the short term, but could lead to more resistance and higher prevalence in the long term. Re-treatment of resistant cases with alternative antibiotics can substantially delay the spread of resistance. In conclusion, combination therapy and re-treatment of resistant cases with alternative antibiotics could be the most effective strategies to prevent increases in gonorrhoea prevalence due to antimicrobial resistance. PMID- 25275433 TI - New developments of RNAi in Paracoccidioides brasiliensis: prospects for high throughput, genome-wide, functional genomics. AB - BACKGROUND: The Fungal Genome Initiative of the Broad Institute, in partnership with the Paracoccidioides research community, has recently sequenced the genome of representative isolates of this human-pathogen dimorphic fungus: Pb18 (S1), Pb03 (PS2) and Pb01. The accomplishment of future high-throughput, genome-wide, functional genomics will rely upon appropriate molecular tools and straightforward techniques to streamline the generation of stable loss-of function phenotypes. In the past decades, RNAi has emerged as the most robust genetic technique to modulate or to suppress gene expression in diverse eukaryotes, including fungi. These molecular tools and techniques, adapted for RNAi, were up until now unavailable for P. brasiliensis. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we report Agrobacterium tumefaciens mediated transformation of yeast cells for high-throughput applications with which higher transformation frequencies of 150+/-24 yeast cell transformants per 1*106 viable yeast cells were obtained. Our approach is based on a bifunctional selective marker fusion protein consisted of the Streptoalloteichus hindustanus bleomycin resistance gene (Shble) and the intrinsically fluorescent monomeric protein mCherry which was codon-optimized for heterologous expression in P. brasiliensis. We also report successful GP43 gene knock-down through the expression of intron containing hairpin RNA (ihpRNA) from a Gateway-adapted cassette (cALf) which was purpose-built for gene silencing in a high-throughput manner. Gp43 transcript levels were reduced by 73.1+/-22.9% with this approach. CONCLUSIONS/SIGNIFICANCE: We have a firm conviction that the genetic transformation technique and the molecular tools herein described will have a relevant contribution in future Paracoccidioides spp. functional genomics research. PMID- 25275434 TI - Resting energy expenditure prediction in recreational athletes of 18-35 years: confirmation of Cunningham equation and an improved weight-based alternative. AB - INTRODUCTION: Resting energy expenditure (REE) is expected to be higher in athletes because of their relatively high fat free mass (FFM). Therefore, REE predictive equation for recreational athletes may be required. The aim of this study was to validate existing REE predictive equations and to develop a new recreational athlete specific equation. METHODS: 90 (53 M, 37 F) adult athletes, exercising on average 9.1 +/- 5.0 hours a week and 5.0 +/- 1.8 times a week, were included. REE was measured using indirect calorimetry (Vmax Encore n29), FFM and FM were measured using air displacement plethysmography. Multiple linear regression analysis was used to develop a new FFM-based and weight-based REE predictive equation. The percentage accurate predictions (within 10% of measured REE), percentage bias, root mean square error and limits of agreement were calculated. Results: The Cunningham equation and the new weight-based equation REE(kJ / d) = 49.940* weight(kg) + 2459.053* height(m) - 34.014* age(y) + 799.257* sex(M = 1,F = 0) + 122.502 and the new FFM-based equation REE(kJ / d) = 95.272*FFM(kg) + 2026.161 performed equally well. De Lorenzo's equation predicted REE less accurate, but better than the other generally used REE predictive equations. Harris-Benedict, WHO, Schofield, Mifflin and Owen all showed less than 50% accuracy. CONCLUSION: For a population of (Dutch) recreational athletes, the REE can accurately be predicted with the existing Cunningham equation. Since body composition measurement is not always possible, and other generally used equations fail, the new weight-based equation is advised for use in sports nutrition. PMID- 25275436 TI - Subconjunctival indocyanine green identifies lymphatic vessels. PMID- 25275437 TI - On-chip determination of C-reactive protein using magnetic particles in continuous flow. AB - We demonstrate the application of a multilaminar flow platform, in which functionalized magnetic particles are deflected through alternating laminar flow streams of reagents and washing solutions via an external magnet, for the rapid detection of the inflammatory biomarker, C-reactive protein (CRP). The two-step sandwich immunoassay was accomplished in less than 60 s, a vast improvement on the 80-300 min time frame required for enzyme-linked immunosorbent assays (ELISA) and the 50 min necessary for off-chip magnetic particle-based assays. The combination of continuous flow and a stationary magnet enables a degree of autonomy in the system, while a detection limit of 0.87 MUg mL(-1) makes it suitable for the determination of CRP concentrations in clinical diagnostics. Its applicability was further proven by assaying real human serum samples and comparing those results to values obtained using standard ELISA tests. PMID- 25275438 TI - Local markets for global health technologies: lessons learned from advancing 6 new products. AB - Key components to support local institutional and consumer markets are: supply chain, finance, clinical use, and consumer use. Key lessons learned: (1) Build supply and demand simultaneously. (2) Support a lead organization to drive the introduction process. (3) Plan for scale up from the start. (4) Profitability for the private sector is an absolute. PMID- 25275440 TI - Behavioural and physiological effects of finely balanced decision-making in chickens. AB - In humans, more difficult decisions result in behavioural and physiological changes suggestive of increased arousal, but little is known about the effect of decision difficulty in other species. A difficult decision can have a number of characteristics; we aimed to monitor how finely balanced decisions, compared to unbalanced ones, affected the behaviour and physiology of chickens. An unbalanced decision was one in which the two options were of unequal net value (1 (Q1) vs. 6 (Q6) pieces of sweetcorn with no cost associated with either option); a finely balanced decision was one in which the options were of equal net value (i.e. hens were "indifferent" to both options). To identify hens' indifference, a titration procedure was used in which a cost (electromagnetic weight on an access door) was applied to the Q6 option, to find the individual point at which hens chose this option approximately equally to Q1 via a non-weighted door. We then compared behavioural and physiological indicators of arousal (head movements, latency to choose, heart-rate variability and surface body temperature) when chickens made decisions that were unbalanced or finely balanced. Significant physiological (heart-rate variability) and behavioural (latency to pen) differences were found between the finely balanced and balanced conditions, but these were likely to be artefacts of the greater time and effort required to push through the weighted doors. No other behavioural and physiological measures were significantly different between the decision categories. We suggest that more information is needed on when best to monitor likely changes in arousal during decision-making and that future studies should consider decisions defined as difficult in other ways. PMID- 25275441 TI - Thermal and concentration stratifications effects in radiative flow of Jeffrey fluid over a stretching sheet. AB - In this article we investigate the heat and mass transfer analysis in mixed convective radiative flow of Jeffrey fluid over a moving surface. The effects of thermal and concentration stratifications are also taken into consideration. Rosseland's approximations are utilized for thermal radiation. The nonlinear boundary layer partial differential equations are converted into nonlinear ordinary differential equations via suitable dimensionless variables. The solutions of nonlinear ordinary differential equations are developed by homotopic procedure. Convergence of homotopic solutions is examined graphically and numerically. Graphical results of dimensionless velocity, temperature and concentration are presented and discussed in detail. Values of the skin-friction coefficient, the local Nusselt and the local Sherwood numbers are analyzed numerically. Temperature and concentration profiles are decreased when the values of thermal and concentration stratifications parameters increase. Larger values of radiation parameter lead to the higher temperature and thicker thermal boundary layer thickness. PMID- 25275439 TI - Butanol isomers exert distinct effects on voltage-gated calcium channel currents and thus catecholamine secretion in adrenal chromaffin cells. AB - Butanol (C4H10OH) has been used both to dissect the molecular targets of alcohols/general anesthetics and to implicate phospholipase D (PLD) signaling in a variety of cellular functions including neurotransmitter and hormone exocytosis. Like other primary alcohols, 1-butanol is a substrate for PLD and thereby disrupts formation of the intracellular signaling lipid phosphatidic acid. Because secondary and tertiary butanols do not undergo this transphosphatidylation, they have been used as controls for 1-butanol to implicate PLD signaling. Recently, selective pharmacological inhibitors of PLD have been developed and, in some cases, fail to block cellular functions previously ascribed to PLD using primary alcohols. For example, exocytosis of insulin and degranulation of mast cells are blocked by primary alcohols, but not by the PLD inhibitor FIPI. In this study we show that 1-butanol reduces catecholamine secretion from adrenal chromaffin cells to a much greater extent than tert-butanol, and that the PLD inhibitor VU0155056 has no effect. Using fluorescent imaging we show the effect of these drugs on depolarization-evoked calcium entry parallel those on secretion. Patch-clamp electrophysiology confirmed the peak amplitude of voltage-gated calcium channel currents (I(Ca)) is inhibited by 1-butanol, with little or no block by secondary or tert-butanol. Detailed comparison shows for the first time that the different butanol isomers exert distinct, and sometimes opposing, effects on the voltage-dependence and gating kinetics of I(Ca). We discuss these data with regard to PLD signaling in cellular physiology and the molecular targets of general anesthetics. PMID- 25275442 TI - The effects of the shape and size of the clinical target volume on the planning target volume margin. AB - PURPOSE: To investigate the impact of clinical target volume (CTV) shape and size on CTV to planning target volume (PTV) margin expansion. METHODS AND MATERIALS: Using numerical integration methods, margins accounting for random errors and systematic errors were calculated for CTVs of different shapes and sizes. We use k(r-95) and k(s-95) to represent the coefficients, for random errors and systematic errors, respectively, that ensure that every point of the CTV receives >=95% of the prescribed dose. RESULTS: The part of the margin accounting for random errors depends on CTV shape and size; generally, a convex part of a CTV would have a larger margin than a concave part. However, the part of the margin accounting for systematic errors is independent of CTV shape and size. CONCLUSIONS: CTV shape and size should be considered when generating a PTV. For a complex CTV, the margins of the various parts of the CTV are different and related to local forms. PMID- 25275443 TI - De novo assembly of the common bean transcriptome using short reads for the discovery of drought-responsive genes. AB - The common bean (Phaseolus vulgaris L.) is one of the most important food legumes, far ahead of other legumes. The average grain yield of the common bean worldwide is much lower than its potential yields, primarily due to drought in the field. However, the gene network that mediates plant responses to drought stress remains largely unknown in this species. The major goals of our study are to identify a large scale of genes involved in drought stress using RNA-seq. First, we assembled 270 million high-quality trimmed reads into a non-redundant set of 62,828 unigenes, representing approximately 49 Mb of unique transcriptome sequences. Of these unigenes, 26,501 (42.2%) common bean unigenes had significant similarity with unigenes/predicted proteins from other legumes or sequenced plants. All unigenes were functionally annotated within the GO, COG and KEGG pathways. The strategy for de novo assembly of transcriptome data generated here will be useful in other legume plant transcriptome studies. Second, we identified 10,482 SSRs and 4,099 SNPs in transcripts. The large number of genetic markers provides a resource for gene discovery and development of functional molecular markers. Finally, we found differential expression genes (DEGs) between terminal drought and optimal irrigation treatments and between the two different genotypes Long 22-0579 (drought tolerant) and Naihua (drought sensitive). DEGs were confirmed by quantitative real-time PCR assays, which indicated that these genes are functionally associated with the drought-stress response. These resources will be helpful for basic and applied research for genome analysis and crop drought resistance improvement in the common bean. PMID- 25275444 TI - Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. AB - Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone. PMID- 25275445 TI - Evidence of conformational selection driving the formation of ligand binding sites in protein-protein interfaces. AB - Many protein-protein interactions (PPIs) are compelling targets for drug discovery, and in a number of cases can be disrupted by small molecules. The main goal of this study is to examine the mechanism of binding site formation in the interface region of proteins that are PPI targets by comparing ligand-free and ligand-bound structures. To avoid any potential bias, we focus on ensembles of ligand-free protein conformations obtained by nuclear magnetic resonance (NMR) techniques and deposited in the Protein Data Bank, rather than on ensembles specifically generated for this study. The measures used for structure comparison are based on detecting binding hot spots, i.e., protein regions that are major contributors to the binding free energy. The main tool of the analysis is computational solvent mapping, which explores the surface of proteins by docking a large number of small "probe" molecules. Although we consider conformational ensembles obtained by NMR techniques, the analysis is independent of the method used for generating the structures. Finding the energetically most important regions, mapping can identify binding site residues using ligand-free models based on NMR data. In addition, the method selects conformations that are similar to some peptide-bound or ligand-bound structure in terms of the properties of the binding site. This agrees with the conformational selection model of molecular recognition, which assumes such pre-existing conformations. The analysis also shows the maximum level of similarity between unbound and bound states that is achieved without any influence from a ligand. Further shift toward the bound structure assumes protein-peptide or protein-ligand interactions, either selecting higher energy conformations that are not part of the NMR ensemble, or leading to induced fit. Thus, forming the sites in protein-protein interfaces that bind peptides and can be targeted by small ligands always includes conformational selection, although other recognition mechanisms may also be involved. PMID- 25275446 TI - Granulocyte-Colony Stimulating Factor related pathways tested on an endometrial ex-vivo model. AB - INTRODUCTION: Recombinant human Granulocyte-Colony Stimulating Factor (rhG-CSF) supplementation seems to be a promising innovative therapy in reproductive medicine, used in case of recurrent miscarriage, embryo implantation failure or thin endometrium, although its mechanisms of action remain unknown. Our aim was to identify possible endometrial pathways influenced by rhG-CSF. MATERIALS AND METHODS: Hypothetical molecular interactions regulated by G-CSF were designed through a previous large scale endometrial microarray study. The variation of endometrial expression of selected target genes was confirmed in control and infertile patients. G-CSF supplementation influence on these targets was tested on an endometrial ex-vivo culture. Middle luteal phase endometrial biopsies were cultured on collagen sponge with or without rhG-CSF supplementation during 3 consecutive days. Variations of endometrial mRNA expression for the selected targets were studied by RT-PCR. RESULTS: At the highest dose of rhG-CSF stimulation, the mRNA expression of these selected target genes was significantly increased if compared with their expression without addition of rhG-CSF. The selected targets were G-CSF Receptor (G-CSFR), Integrin alpha-V/beta-3 (ITGB3) implicated in cell migration and embryo implantation, Plasminogen Activator Urokinase Receptor (PLAUR) described as interacting with integrins and implicated in cell migration, Thymidine Phosphorylase (TYMP) implicated in local angiogenesis, CD40 and its ligand CD40L involved in cell proliferation control. CONCLUSION: RhG-CSF seems able to influence endometrial expressions crucial for implantation process involving endometrial vascular remodelling, local immune modulation and cellular adhesion pathways. These variations observed in an ex vivo model should be tested in-vivo. The strict indications or counter indication of rhG-CSF supplementation in reproductive field are not yet established, while the safety of its administration in early pregnancy on early embryogenesis still needs to be demonstrated. Nevertheless, rhG-CSF appears as a promising therapy in some difficult and unsolved cases of reproductive failure. Indications of pre conceptual rhG-CSF supplementation may derive from a diagnosed lack of endometrial expression of some target genes. PMID- 25275447 TI - LINE-1 hypomethylation in blood and tissue samples as an epigenetic marker for cancer risk: a systematic review and meta-analysis. AB - OBJECTIVE: A systematic review and a meta-analysis were carried out in order to summarize the current published studies and to evaluate LINE-1 hypomethylation in blood and other tissues as an epigenetic marker for cancer risk. METHODS: A systematic literature search in the Medline database, using PubMed, was conducted for epidemiological studies, published before March 2014. The random-effects model was used to estimate weighted mean differences (MDs) with 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by sample type (tissue or blood samples), cancer types, and by assays used to measure global DNA methylation levels. The Cochrane software package Review Manager 5.2 was used. RESULTS: A total of 19 unique articles on 6107 samples (2554 from cancer patients and 3553 control samples) were included in the meta-analysis. LINE-1 methylation levels were significantly lower in cancer patients than in controls (MD: -6.40, 95% CI: -7.71, -5.09; p<0.001). The significant difference in methylation levels was confirmed in tissue samples (MD -7.55; 95% CI: -9.14, -65.95; p<0.001), but not in blood samples (MD: -0.26, 95% CI: -0.69, 0.17; p = 0.23). LINE-1 methylation levels were significantly lower in colorectal and gastric cancer patients than in controls (MD: -8.33; 95% CI: -10.56, -6.10; p<0.001 and MD: 5.75; 95% CI: -7.75, -3.74; p<0.001) whereas, no significant difference was observed for hepatocellular cancer. CONCLUSIONS: The present meta-analysis adds new evidence to the growing literature on the role of LINE-1 hypomethylation in human cancer and demonstrates that LINE-1 methylation levels were significantly lower in cancer patients than in control samples, especially in certain cancer types. This result was confirmed in tissue samples, both fresh/frozen or FFPE specimens, but not in blood. Further studies are needed to better clarify the role of LINE-1 methylation in specific subgroups, considering both cancer and sample type, and the methods of measurement. PMID- 25275448 TI - Association of serum microRNA expression in hepatocellular carcinomas treated with transarterial chemoembolization and patient survival. AB - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is one of the most deadly tumors. Transarterial chemoembolization (TACE) is effective for unresectable HCC. In recent years, miRNAs have been proposed as novel diagnostic and prognostic tools for HCC. This study aimed to identify whether microRNAs (miRNAs) can serve as biomarkers to reliably predict outcome before HCC patients are treated with TACE. METHODS: Eleven miRNAs (miR-, miR-19a, miR-101-3p, miR-199a-5p, miR-200a, miR-21, miR-214, miR-221, miR-222, miR-223 and miR-, -5p) were quantified by quantitative real-time PCR (qRT-PCR) in 136 HCC patients' serum before they received TACE therapy. Univariate and multivariate analysis were used to identify the prognostic value of clinical parameters and miRNAs. Area under the receiver operating characteristic curve (AUC) was used to evaluate the prediction potency. RESULTS: The levels of some miRNAs were dramatically associated with clinicopathologic features regarding Child-Puge class, AFP, tumor size and satellite nodules. Univariate analysis revealed that miR-200a, miR-21, miR-122 and miR-224-5p were significantly associated with patients' survival. Multivariate analysis demonstrated that AFP, satellite nodules and miR-200a were the independent prognostic factors associated with survival in this cohort (p = 0.000, 0.001, 0.000, respectively). The probability of the prognostic accuracy of miR-200a was 81.64% (74.47% specificity and 88.76% sensitivity), which was higher than the classifier established by combination of AFP and satellite nodules (76.87% probability, 70.21% specificity and 69.66% sensitivity). Furthermore, the combination of AFP, satellite nodules and miR-200a demonstrated as a classifier for HCC prognosis, yielding a ROC curve area of 88.19% (93.62% specificity and 68.54% sensitivity). CONCLUSIONS: Our study indicated that serum miR-200a may prognosticate disease outcome in HCC patients with TACE therapy. Therefore, miR 200a can potentially guide individualized treatment for HCC patients with a high risk of TACE treatment failures. PMID- 25275449 TI - Fibromyalgia patients had normal distraction related pain inhibition but cognitive impairment reflected in caudate nucleus and hippocampus during the Stroop Color Word Test. AB - The mechanisms causing cognitive problems in chronic pain patients are not well understood. We used the Stroop color word task (SCWT) to investigate distraction induced analgesia, cognitive performance, and cerebral activation patterns in 29 fibromyalgia (FM) patients (mean age 49.8 years, range 25-64 years) and 31 healthy controls (HC) (mean age 46.3 years, range 20-63 years). In the first study, SCWT was used to investigate distraction-induced analgesia in FM patients. Two versions of the task were applied, one with only congruent color-word images and one with incongruent images. Pressure pain thresholds were assessed using a pressure algometer before, during, and following SCWT. In the second study, reaction times (RTs) were assessed and functional magnetic resonance imaging (fMRI) was used to investigate cerebral activation patterns in FM patients and HC during the SCWT. An event-related task mixing incongruent and congruent images was used. In study one, we found reduced pressure pain sensitivity during SCWT in both groups alike and no statistically significant differences were seen between the incongruent and congruent conditions. The study two revealed longer RTs during the incongruent compared to the congruent condition in both groups. FM patients had longer RTs than HC in both conditions. Furthermore, we found a significant interaction between group and congruency; that is, the group differences in RTs were more pronounced during the incongruent condition. This was reflected in a reduced activation of the caudate nucleus, lingual gyrus, temporal areas, and the hippocampus in FM patients compared to HC. In conclusion, we found normal pain inhibition during SWTC in FM patients. The cognitive difficulties seen in FM patients, reflected in longer RTs, were related to reduced activation of the caudate nucleus and hippocampus during incongruent SCWT, which most likely affected the mechanisms of cognitive learning in FM patients. PMID- 25275450 TI - Phylogenetic distribution of extant richness suggests metamorphosis is a key innovation driving diversification in insects. AB - Insects and their six-legged relatives (Hexapoda) comprise more than half of all described species and dominate terrestrial and freshwater ecosystems. Understanding the macroevolutionary processes generating this richness requires a historical perspective, but the fossil record of hexapods is patchy and incomplete. Dated molecular phylogenies provide an alternative perspective on divergence times and have been combined with birth-death models to infer patterns of diversification across a range of taxonomic groups. Here we generate a dated phylogeny of hexapod families, based on previously published sequence data and literature derived constraints, in order to identify the broad pattern of macroevolutionary changes responsible for the composition of the extant hexapod fauna. The most prominent increase in diversification identified is associated with the origin of complete metamorphosis, confirming this as a key innovation in promoting insect diversity. Subsequent reductions are recovered for several groups previously identified as having a higher fossil diversity during the Mesozoic. In addition, a number of recently derived taxa are found to have radiated following the development of flowering plant (angiosperm) floras during the mid-Cretaceous. These results reveal that the composition of the modern hexapod fauna is a product of a key developmental innovation, combined with multiple and varied evolutionary responses to environmental changes from the mid Cretaceous floral transition onward. PMID- 25275451 TI - Reduction of the six-minute walk distance in children with sickle cell disease is correlated with silent infarct: results from a cross-sectional evaluation in a single center in Belgium. AB - BACKGROUND: The 6-minute walk test (6 MWT) is used in adults and children affected by a wide range of chronic diseases to evaluate their sub-maximal exercise capacity. It reflects the global response of various physiological systems in a situation simulating a daily life activity. METHODS: We analyzed factors affecting the 6 MWT in 46 Sickle Cell Disease children. Forty-two were treated with hydroxyurea (HU). Patients with normal test (>80% of the age standardized predicted value) were compared to patients with abnormal test (<= 80%). Baseline hematological values, clinical events, cerebrovascular disease, cardio-pulmonary parameters and disease-modifying treatment were compared according to the performance of the test. RESULTS: Among the 46 patients, 14 had an abnormal 6 MWT. In univariate analysis, both groups were similar for biological and clinical data. Six of the 14 patients with an abnormal 6 MWT had silent infarct (SI) compared to 6/32 with a normal test (P = 0.09). When excluding chronically transfused patients, 4 of the 11 patients with an abnormal 6 MWT had SI compared to 1/26 (P = 0.02). Baseline pulse oximetry was normal in both groups but slightly lower in patients with abnormal 6 MWT (P = 0.02). No patient presented exercise-induced desaturation. In multivariate analysis, the only factor associated with abnormal 6 MWT was the presence of SI (P = 0.045). CONCLUSIONS: In our cohort of 46 patients characterized by high exposure rate to HU and by the absence of severe cardiopulmonary disease, the sole factor independently associated with 6 MWT was the presence of SI. The lower exercise capacity of children with SI may reflect some subclinical neurological impairment as they do not differ by hemoglobin level or cardiopulmonary parameters. PMID- 25275453 TI - Echocardiographic assessment of left ventricular dyssynchrony in Egyptian children with congestive heart failure due to dilated cardiomyopathy. AB - OBJECTIVE: To evaluate the presence of cardiac dyssynchrony in Egyptian children with congestive heart failure due to dilated cardiomyopathy. MATERIALS AND METHODS: A total of 30 children with congestive cardiac failure due to dilated cardiomyopathy and 30 healthy age-matched controls were examined with conventional echocardiography, tissue Doppler, and speckle tracking imaging. RESULTS: Conventional Doppler echocardiography demonstrated significant left ventricular systolic and diastolic dysfunction in the patient group. Tissue Doppler showed significant decrease in S-wave velocity and E'/A' ratio, and prolonged isovolumic contraction and relaxation times of mitral annulus as well as significant prolongation in mean difference between time-to-peak systolic strain of the basal septal and basal lateral segments in the patient group compared with the control group (p<0.005). Speckle tracking imaging demonstrated significant prolongation in mean difference between time-to-peak systolic strain of anteroseptal and posterior segments in both circumferential and radial strain analysis in the patient group than in the control group (p<0.005). It also demonstrated significant prolongation in the mean difference between time-to-peak systolic strain of the basal septal and basal lateral segments in longitudinal strain analysis in the patient group than in the control group (p<0.005). A significant increase in the standard deviation of time-to-peak strain, as a marker of increased intra-ventricular dyssynchrony, was present in the patient group compared with the control group (p=0.008). CONCLUSION: Children with congestive heart failure due to dilated cardiomyopathy usually suffer from significant intra-ventricular dyssynchrony. Tissue Doppler imaging and speckle tracking imaging strain analysis are helpful tools to detect the presence of cardiac dyssynchrony. PMID- 25275452 TI - Photosynthetic diffusional constraints affect yield in drought stressed rice cultivars during flowering. AB - Global production of rice (Oryza sativa) grain is limited by water availability and the low 'leaf-level' photosynthetic capacity of many cultivars. Oryza sativa is extremely susceptible to water-deficits; therefore, predicted increases in the frequency and duration of drought events, combined with future rises in global temperatures and food demand, necessitate the development of more productive and drought tolerant cultivars. We investigated the underlying physiological, isotopic and morphological responses to water-deficit in seven common varieties of O. sativa, subjected to prolonged drought of varying intensities, for phenotyping purposes in open field conditions. Significant variation was observed in leaf-level photosynthesis rates (A) under both water treatments. Yield and A were influenced by the conductance of the mesophyll layer to CO2 (g(m)) and not by stomatal conductance (g(s)). Mesophyll conductance declined during drought to differing extents among the cultivars; those varieties that maintained g(m) during water-deficit sustained A and yield to a greater extent. However, the variety with the highest g(m) and yield under well-watered conditions (IR55419 04) was distinct from the most effective cultivar under drought (Vandana). Mesophyll conductance most effectively characterises the photosynthetic capacity and yield of O. sativa cultivars under both well-watered and water-deficit conditions; however, the desired attributes of high g(m) during optimal growth conditions and the capacity for g(m) to remain constant during water-deficit may be mutually exclusive. Nonetheless, future genetic and physiological studies aimed at enhancing O. sativa yield and drought stress tolerance should investigate the biochemistry and morphology of the interface between the sub stomatal pore and mesophyll layer. PMID- 25275455 TI - Enhanced cycle performance of lithium-sulfur batteries using a separator modified with a PVDF-C layer. AB - High energy density Li-S batteries are highly attractive. However, their use in practical applications has been greatly affected by their poor cycle life and low rate performance, which can be partly attributed to the dissolution of polysulfides from the S cathode and their migration to the Li anode through the separator. While much effort has been devoted to designing the structure of the S cathodes for suppressing the dissolution of polysulfides, relatively little emphasis has been placed on modifying the separator. Herein, we demonstrate a new approach for modifying the separator with a polyvinylidene fluoride-carbon (PVDF C) layer, where the polysulfides generated in the Li-S cells can be localized on the cathode side. Li-S batteries based on the novel separator and a cathode prepared by the simple mixing of a S powder and super P have delivered discharge capacities of 918.6 mAh g(-1), 827.2 mAh g(-1), and 669.1 mAh g(-1) after 100, 200, and 500 cycles, respectively, at a discharge rate of 0.5 C. Even under current densities of up to 5 C, the cells were able to retain a discharge capacity of 393 mAh g(-1), thereby demonstrating an excellent high rate performance and stability. The exceptional electrochemical performance could be attributed to the intense adsorption capability of the micropores, presence of C C double bonds, and conductivity of the C network in the PVDF-C layer. This economical and simple strategy to overcome the polysulfide dissolution issues provides a commercially feasible method for the construction of Li-S batteries. PMID- 25275454 TI - A relay network of extracellular heme-binding proteins drives C. albicans iron acquisition from hemoglobin. AB - Iron scavenging constitutes a crucial challenge for survival of pathogenic microorganisms in the iron-poor host environment. Candida albicans, like many microbial pathogens, is able to utilize iron from hemoglobin, the largest iron pool in the host's body. Rbt5 is an extracellular glycosylphosphatidylinositol (GPI)-anchored heme-binding protein of the CFEM family that facilitates heme-iron uptake by an unknown mechanism. Here, we characterize an additional C. albicans CFEM protein gene, PGA7, deletion of which elicits a more severe heme-iron utilization phenotype than deletion of RBT5. The virulence of the pga7-/- mutant is reduced in a mouse model of systemic infection, consistent with a requirement for heme-iron utilization for C. albicans pathogenicity. The Pga7 and Rbt5 proteins exhibit distinct cell wall attachment, and discrete localization within the cell envelope, with Rbt5 being more exposed than Pga7. Both proteins are shown here to efficiently extract heme from hemoglobin. Surprisingly, while Pga7 has a higher affinity for heme in vitro, we find that heme transfer can occur bi directionally between Pga7 and Rbt5, supporting a model in which they cooperate in a heme-acquisition relay. Together, our data delineate the roles of Pga7 and Rbt5 in a cell surface protein network that transfers heme from extracellular hemoglobin to the endocytic pathway, and provide a paradigm for how receptors embedded in the cell wall matrix can mediate nutrient uptake across the fungal cell envelope. PMID- 25275456 TI - Ruthenium complex with benznidazole and nitric oxide as a new candidate for the treatment of chagas disease. AB - BACKGROUND: Chagas disease remains a serious medical and social problem in Latin America and is an emerging concern in nonendemic countries as a result of population movement, transfusion of infected blood or organs and congenital transmission. The current treatment of infected patients is unsatisfactory due to strain-specific drug resistance and the side effects of the current medications. For this reason, the discovery of safer and more effective chemotherapy is mandatory for the successful treatment and future eradication of Chagas disease. METHODS AND FINDINGS: We investigated the effect of a ruthenium complex with benznidazole and nitric oxide (RuBzNO2) against Trypanosoma cruzi both in vitro and in vivo. Our results demonstrated that RuBzNO2 was more effective than the same concentrations of benznidazole (Bz) in eliminating both the extracellular trypomastigote and the intracellular amastigote forms of the parasite, with no cytotoxic effect in mouse cells. In vivo treatment with the compound improved the survival of infected mice, inhibiting heart damage more efficiently than Bz alone. Accordingly, tissue inflammation and parasitism was significantly diminished after treatment with RuBzNO2 in a more effective manner than that with the same concentrations of Bz. CONCLUSIONS: The complexation of Bz with ruthenium and nitric oxide (RuBzNO2) increases its effectiveness against T. cruzi and enables treatment with lower concentrations of the compound, which may reduce the side effects of Bz. Our findings provide a new potential candidate for the treatment of Chagas disease. PMID- 25275457 TI - VE-cadherin-independent cancer cell incorporation into the vascular endothelium precedes transmigration. AB - Metastasis is accountable for 90% of cancer deaths. During metastasis, tumor cells break away from the primary tumor, enter the blood and the lymph vessels, and use them as highways to travel to distant sites in the body to form secondary tumors. Cancer cell migration through the endothelium and into the basement membrane represents a critical step in the metastatic cascade, yet it is not well understood. This process is well characterized for immune cells that routinely transmigrate through the endothelium to sites of infection, inflammation, or injury. Previous studies with leukocytes have demonstrated that this step depends heavily on the activation status of the endothelium and subendothelial substrate stiffness. Here, we used a previously established in vitro model of the endothelium and live cell imaging, in order to observe cancer cell transmigration and compare this process to leukocytes. Interestingly, cancer cell transmigration includes an additional step, which we term 'incorporation', into the endothelial cell (EC) monolayer. During this phase, cancer cells physically displace ECs, leading to the dislocation of EC VE-cadherin away from EC junctions bordering cancer cells, and spread into the monolayer. In some cases, ECs completely detach from the matrix. Furthermore, cancer cell incorporation occurs independently of the activation status and the subendothelial substrate stiffness for breast cancer and melanoma cells, a notable difference from the process by which leukocytes transmigrate. Meanwhile, pancreatic cancer cell incorporation was dependent on the activation status of the endothelium and changed on very stiff subendothelial substrates. Collectively, our results provide mechanistic insights into tumor cell extravasation and demonstrate that incorporation is one of the earliest steps. PMID- 25275458 TI - De novo transcriptome and small RNA analysis of two Chinese willow cultivars reveals stress response genes in Salix matsudana. AB - Salix matsudana Koidz. is a deciduous, rapidly growing, and drought resistant tree and is one of the most widely distributed and commonly cultivated willow species in China. Currently little transcriptomic and small RNAomic data are available to reveal the genes involve in the stress resistant in S. matsudana. Here, we report the RNA-seq analysis results of both transcriptome and small RNAome data using Illumina deep sequencing of shoot tips from two willow variants(Salix. matsudana and Salix matsudana Koidz. cultivar 'Tortuosa'). De novo gene assembly was used to generate the consensus transcriptome and small RNAome, which contained 106,403 unique transcripts with an average length of 944 bp and a total length of 100.45 MB, and 166 known miRNAs representing 35 miRNA families. Comparison of transcriptomes and small RNAomes combined with quantitative real-time PCR from the two Salix libraries revealed a total of 292 different expressed genes(DEGs) and 36 different expressed miRNAs (DEMs). Among the DEGs and DEMs, 196 genes and 24 miRNAs were up regulated, 96 genes and 12 miRNA were down regulated in S. matsudana. Functional analysis of DEGs and miRNA targets showed that many genes were involved in stress resistance in S. matsudana. Our global gene expression profiling presents a comprehensive view of the transcriptome and small RNAome which provide valuable information and sequence resources for uncovering the stress response genes in S. matsudana. Moreover the transcriptome and small RNAome data provide a basis for future study of genetic resistance in Salix. PMID- 25275460 TI - Two BN isosteres of anthracene: synthesis and characterization. AB - The synthesis of two parental BN anthracenes, 1 and 2, was developed, and their electronic structure and reactivity behavior were characterized in direct comparison with all-carbon anthracene. Gas-phase UV-photoelecton spectroscopy studies revealed the following HOMO energy trend: anthracene, -7.4 eV; BN anthracene 1, -7.7 eV; bis-BN anthracene 2, -8.0 eV. The lambdamax of the lower energy band in the UV-vis absorption spectrum is as follows: anthracene, 356 nm; BN anthracene 1, 359 nm; bis-BN anthracene 2, 357 nm. Thus, although the HOMO is stabilized with increasing BN incorporation, the HOMO-LUMO band gap remains unchanged across the anthracene series. The emission lambdamax values for the three investigated anthracene compounds are at 403 nm. The pKa values of the N-H proton for BN anthracene 1 and bis-BN anthracene 2 were determined to be approximately 26. BN anthracenes 1 and 2 do not undergo heat- or light-induced cycloaddition reactions or Friedel-Crafts acylations. Electrophilic bromination of BN anthracene 1 with Br2, however, occurs regioselectively at the 9-position. The reactivity behavior and regioselectivity of bromination of BN anthracenes are consistent with the electronic structure of these compounds; i.e., (1) the lower HOMO energy levels for BN anthracenes stabilize the molecules against cycloaddition and Friedel-Crafts reactions, and (2) the HOMO orbital coefficients are consistent with the observed bromination regioselectivity. Overall, this work demonstrates that BN/CC isosterism can be used as a molecular design strategy to stabilize the HOMO of acene-type structures while the optical band gap is maintained. PMID- 25275459 TI - Fast synchronization of ultradian oscillators controlled by delta-notch signaling with cis-inhibition. AB - While it is known that a large fraction of vertebrate genes are under the control of a gene regulatory network (GRN) forming a clock with circadian periodicity, shorter period oscillatory genes like the Hairy-enhancer-of split (Hes) genes are discussed mostly in connection with the embryonic process of somitogenesis. They form the core of the somitogenesis-clock, which orchestrates the periodic separation of somites from the presomitic mesoderm (PSM). The formation of sharp boundaries between the blocks of many cells works only when the oscillators in the cells forming the boundary are synchronized. It has been shown experimentally that Delta-Notch (D/N) signaling is responsible for this synchronization. This process has to happen rather fast as a cell experiences at most five oscillations from its 'birth' to its incorporation into a somite. Computer simulations describing synchronized oscillators with classical modes of D/N-interaction have difficulties to achieve synchronization in an appropriate time. One approach to solving this problem of modeling fast synchronization in the PSM was the consideration of cell movements. Here we show that fast synchronization of Hes type oscillators can be achieved without cell movements by including D/N cis inhibition, wherein the mutual interaction of DELTA and NOTCH in the same cell leads to a titration of ligand against receptor so that only one sort of molecule prevails. Consequently, the symmetry between sender and receiver is partially broken and one cell becomes preferentially sender or receiver at a given moment, which leads to faster entrainment of oscillators. Although not yet confirmed by experiment, the proposed mechanism of enhanced synchronization of mesenchymal cells in the PSM would be a new distinct developmental mechanism employing D/N cis-inhibition. Consequently, the way in which Delta-Notch signaling was modeled so far should be carefully reconsidered. PMID- 25275461 TI - RAGE, receptor of advanced glycation endoproducts, negatively regulates chondrocytes differentiation. AB - RAGE, receptor for advanced glycation endoproducts (AGE), has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE) demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-kappaB inhibitor I-kappaB SR inhibited RAGE-induced NF-kappaB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-kappaB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA) partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-kappaB-independent and Rho family GTPases-dependent mechanisms. PMID- 25275462 TI - Mechanism and function of mixed-mode oscillations in vibrissa motoneurons. AB - Vibrissa motoneurons in the facial nucleus innervate the intrinsic and extrinsic muscles that move the whiskers. Their intrinsic properties affect the way they process fast synaptic input from the vIRT and Botzinger nuclei together with serotonergic neuromodulation. In response to constant current (I(app)) injection, vibrissa motoneurons may respond with mixed mode oscillations (MMOs), in which sub-threshold oscillations (STOs) are intermittently mixed with spikes. This study investigates the mechanisms involved in generating MMOs in vibrissa motoneurons and their function in motor control. It presents a conductance-based model that includes the M-type K+ conductance, g(M), the persistent Na+ conductance, g(NaP), and the cationic h conductance, g(h). For g(h) = 0 and moderate values of g(M) and g(NaP), the model neuron generates STOs, but not MMOs, in response to I(app) injection. STOs transform abruptly to tonic spiking as the current increases. In addition to STOs, MMOs are generated for g(h)>0 for larger values of I(app); the I(app) range in which MMOs appear increases linearly with g(h). In the MMOs regime, the firing rate increases with I(app) like a Devil's staircase. Stochastic noise disrupts the temporal structure of the MMOs, but for a moderate noise level, the coefficient of variation (CV) is much less than one and varies non-monotonically with I(app). Furthermore, the estimated time period between voltage peaks, based on Bernoulli process statistics, is much higher in the MMOs regime than in the tonic regime. These two phenomena do not appear when moderate noise generates MMOs without an intrinsic MMO mechanism. Therefore, and since STOs do not appear in spinal motoneurons, the analysis can be used to differentiate different MMOs mechanisms. MMO firing activity in vibrissa motoneurons suggests a scenario in which moderate periodic inputs from the vIRT and Botzinger nuclei control whisking frequency, whereas serotonergic neuromodulation controls whisking amplitude. PMID- 25275463 TI - Cysteine transport through excitatory amino acid transporter 3 (EAAT3). AB - Excitatory amino acid transporters (EAATs) limit glutamatergic signaling and maintain extracellular glutamate concentrations below neurotoxic levels. Of the five known EAAT isoforms (EAATs 1-5), only the neuronal isoform, EAAT3 (EAAC1), can efficiently transport the uncharged amino acid L-cysteine. EAAT3-mediated cysteine transport has been proposed to be a primary mechanism used by neurons to obtain cysteine for the synthesis of glutathione, a key molecule in preventing oxidative stress and neuronal toxicity. The molecular mechanisms underlying the selective transport of cysteine by EAAT3 have not been elucidated. Here we propose that the transport of cysteine through EAAT3 requires formation of the thiolate form of cysteine in the binding site. Using Xenopus oocytes and HEK293 cells expressing EAAT2 and EAAT3, we assessed the transport kinetics of different substrates and measured transporter-associated currents electrophysiologically. Our results show that L-selenocysteine, a cysteine analog that forms a negatively charged selenolate ion at physiological pH, is efficiently transported by EAATs 1 3 and has a much higher apparent affinity for transport when compared to cysteine. Using a membrane tethered GFP variant to monitor intracellular pH changes associated with transport activity, we observed that transport of either L-glutamate or L-selenocysteine by EAAT3 decreased intracellular pH, whereas transport of cysteine resulted in cytoplasmic alkalinization. No change in pH was observed when cysteine was applied to cells expressing EAAT2, which displays negligible transport of cysteine. Under conditions that favor release of intracellular substrates through EAAT3 we observed release of labeled intracellular glutamate but did not detect cysteine release. Our results support a model whereby cysteine transport through EAAT3 is facilitated through cysteine de-protonation and that once inside, the thiolate is rapidly re-protonated. Moreover, these findings suggest that cysteine transport is predominantly unidirectional and that reverse transport does not contribute to depletion of intracellular cysteine pools. PMID- 25275465 TI - GIANT: a cytoscape plugin for modular networks. AB - Network analysis provides deep insight into real complex systems. Revealing the link between topological and functional role of network elements can be crucial to understand the mechanisms underlying the system. Here we propose a Cytoscape plugin (GIANT) to perform network clustering and characterize nodes at the light of a modified Guimera-Amaral cartography. This approach results into a vivid picture of the a topological/functional relationship at both local and global level. The plugin has been already approved and uploaded on the Cytoscape APP store. PMID- 25275464 TI - Immune biomarkers predictive of respiratory viral infection in elderly nursing home residents. AB - OBJECTIVE: To determine if immune phenotypes associated with immunosenescence predict risk of respiratory viral infection in elderly nursing home residents. METHODS: Residents >= 65 years from 32 nursing homes in 4 Canadian cities were enrolled in Fall 2009, 2010 and 2011, and followed for one influenza season. Following influenza vaccination, peripheral blood mononuclear cells (PBMCs) were obtained and analysed by flow cytometry for T-regs, CD4+ and CD8+ T-cell subsets (CCR7+CD45RA+, CCR7-CD45RA+ and CD28-CD57+) and CMV-reactive CD4+ and CD8+ T cells. Nasopharyngeal swabs were obtained and tested for viruses in symptomatic residents. A Cox proportional hazards model adjusted for age, sex and frailty, determined the relationship between immune phenotypes and time to viral infection. RESULTS: 1072 residents were enrolled; median age 86 years and 72% female. 269 swabs were obtained, 87 were positive for virus: influenza (24%), RSV (14%), coronavirus (32%), rhinovirus (17%), human metapneumovirus (9%) and parainfluenza (5%). In multivariable analysis, high T-reg% (HR 0.41, 95% CI 0.20 0.81) and high CMV-reactive CD4+ T-cell% (HR 1.69, 95% CI 1.03-2.78) were predictive of respiratory viral infection. CONCLUSIONS: In elderly nursing home residents, high CMV-reactive CD4+ T-cells were associated with an increased risk and high T-regs were associated with a reduced risk of respiratory viral infection. PMID- 25275469 TI - A novel test for independence derived from an exact distribution of ith nearest neighbours. AB - Dependence measures and tests for independence have recently attracted a lot of attention, because they are the cornerstone of algorithms for network inference in probabilistic graphical models. Pearson's product moment correlation coefficient is still by far the most widely used statistic yet it is largely constrained to detecting linear relationships. In this work we provide an exact formula for the [Formula: see text]th nearest neighbor distance distribution of rank-transformed data. Based on that, we propose two novel tests for independence. An implementation of these tests, together with a general benchmark framework for independence testing, are freely available as a CRAN software package (http://cran.r-project.org/web/packages/knnIndep). In this paper we have benchmarked Pearson's correlation, Hoeffding's D, dcor, Kraskov's estimator for mutual information, maximal information criterion and our two tests. We conclude that no particular method is generally superior to all other methods. However, dcor and Hoeffding's D are the most powerful tests for many different types of dependence. PMID- 25275467 TI - Sources and distribution of surface water fecal contamination and prevalence of schistosomiasis in a Brazilian village. AB - BACKGROUND: The relationship between poor sanitation and the parasitic infection schistosomiasis is well-known, but still rarely investigated directly and quantitatively. In a Brazilian village we correlated the spatial concentration of human fecal contamination of its main river and the prevalence of schistosomiasis. METHODS: We validated three bacterial markers of contamination in this population by high throughput sequencing of the 16S rRNA gene and qPCR of feces from local residents. The qPCR of genetic markers from the 16S rRNA gene of Bacteroides-Prevotella group, Bacteroides HF8 cluster, and Lachnospiraceae Lachno2 cluster as well as sequencing was performed on georeferenced samples of river water. Ninety-six percent of residents were examined for schistosomiasis. FINDINGS: Sequence of 16S rRNA DNA from stool samples validated the relative human specificity of the HF8 and Lachno 2 fecal indicators compared to animals. The concentration of fecal contamination increased markedly along the river as it passed an increasing proportion of the population on its way downstream as did the sequence reads from bacterial families associated with human feces. Lachnospiraceae provided the most robust signal of human fecal contamination. The prevalence of schistosomiasis likewise increased downstream. Using a linear regression model, a significant correlation was demonstrated between the prevalence of S. mansoni infection and local concentration of human fecal contamination based on the Lachnospiraceae Lachno2 cluster (r2 0.53) as compared to the correlation with the general fecal marker E. coli (r2 0.28). INTERPRETATION: Fecal contamination in rivers has a downstream cumulative effect. The transmission of schistosomiasis correlates with very local factors probably resulting from the distribution of human fecal contamination, the limited movement of snails, and the frequency of water contact near the home. In endemic regions, the combined use of human associated bacterial markers and GIS analysis can quantitatively identify areas with risk for schistosomiasis as well as assess the efficacy of sanitation and environmental interventions for prevention. PMID- 25275470 TI - Assessing T cell clonal size distribution: a non-parametric approach. AB - Clonal structure of the human peripheral T-cell repertoire is shaped by a number of homeostatic mechanisms, including antigen presentation, cytokine and cell regulation. Its accurate tuning leads to a remarkable ability to combat pathogens in all their variety, while systemic failures may lead to severe consequences like autoimmune diseases. Here we develop and make use of a non-parametric statistical approach to assess T cell clonal size distributions from recent next generation sequencing data. For 41 healthy individuals and a patient with ankylosing spondylitis, who undergone treatment, we invariably find power law scaling over several decades and for the first time calculate quantitatively meaningful values of decay exponent. It has proved to be much the same among healthy donors, significantly different for an autoimmune patient before the therapy, and converging towards a typical value afterwards. We discuss implications of the findings for theoretical understanding and mathematical modeling of adaptive immunity. PMID- 25275466 TI - Analysis of Candida albicans mutants defective in the Cdk8 module of mediator reveal links between metabolism and biofilm formation. AB - Candida albicans biofilm formation is a key virulence trait that involves hyphal growth and adhesin expression. Pyocyanin (PYO), a phenazine secreted by Pseudomonas aeruginosa, inhibits both C. albicans biofilm formation and development of wrinkled colonies. Using a genetic screen, we identified two mutants, ssn3Delta/Delta and ssn8Delta/Delta, which continued to wrinkle in the presence of PYO. Ssn8 is a cyclin-like protein and Ssn3 is similar to cyclin dependent kinases; both proteins are part of the heterotetrameric Cdk8 module that forms a complex with the transcriptional co-regulator, Mediator. Ssn3 kinase activity was also required for PYO sensitivity as a kinase dead mutant maintained a wrinkled colony morphology in the presence of PYO. Furthermore, similar phenotypes were observed in mutants lacking the other two components of the Cdk8 module-Srb8 and Srb9. Through metabolomics analyses and biochemical assays, we showed that a compromised Cdk8 module led to increases in glucose consumption, glycolysis-related transcripts, oxidative metabolism and ATP levels even in the presence of PYO. In the mutant, inhibition of respiration to levels comparable to the PYO-treated wild type inhibited wrinkled colony development. Several lines of evidence suggest that PYO does not act through Cdk8. Lastly, the ssn3 mutant was a hyperbiofilm former, and maintained higher biofilm formation in the presence of PYO than the wild type. Together these data provide novel insights into the role of the Cdk8 module of Mediator in regulation of C. albicans physiology and the links between respiratory activity and both wrinkled colony and biofilm development. PMID- 25275471 TI - Bartsocas-Papas Syndrome: A Case Report and Review of the Literature. AB - Bartsocas-Papas syndrome (BPS) is an autosomal recessively inherited form of the popliteal pterygium syndrome characterized by severe growth retardation, midface hypoplasia, popliteal pterygia, and syndactyly. Almost all affected babies die in utero or infancy. We report the difficulties of reconstruction and ongoing plastic surgical management in an 8-year-old child with BPS. With increasingly sophisticated resuscitation and supportive techniques, it is possible that more patients with BPS will survive beyond the neonatal period. This raises new challenges with reconstruction highlighted by this case with a difficult balance between trying to overcome some of the profound effects of the syndrome versus diminishing quality of life for the child by repeated and often unsuccessful surgical procedures. PMID- 25275468 TI - Mass spectrometry-based metabolite profiling in the mouse liver following exposure to ultraviolet B radiation. AB - Although many studies have been performed on the effects of ultraviolet (UV) radiation on the skin, only a limited number of reports have investigated these effects on non-skin tissue. This study aimed to describe the metabolite changes in the liver of hairless mice following chronic exposure to UVB radiation. We did not observe significant macroscopic changes or alterations in hepatic cholesterol and triglyceride levels in the liver of UVB-irradiated mice, compared with those for normal mice. In this study, we detected hepatic metabolite changes by UVB exposure and identified several amino acids, fatty acids, nucleosides, carbohydrates, phospholipids, lysophospholipids, and taurine-conjugated cholic acids as candidate biomarkers in response to UVB radiation in the mouse liver by using various mass spectrometry (MS)-based metabolite profiling including ultra performance liquid chromatography-quadrupole time-of-flight (TOF)-MS, gas chromatography-TOF-MS and nanomate LTQ-MS. Glutamine exhibited the most dramatic change with a 5-fold increase in quantity. The results from altering several types of metabolites suggest that chronic UVB irradiation may impact significantly on major hepatic metabolism processes, despite the fact that the liver is not directly exposed to UVB radiation. MS-based metabolomic approach for determining regulatory hepatic metabolites following UV irradiation will provide a better understanding of the relationship between internal organs and UV light. PMID- 25275472 TI - Asymptomatic Deep Peroneal Vein Thrombosis During Free Fibula Flap Harvest: A Review of the Literature, Strategies for Preoperative Assessment, and an Algorithm for Reconstruction. AB - The free fibula flap is the preferred reconstructive method for oncologic defects of the mandible. Arterial inflow of the extremity is routinely evaluated with several modalities; however, venous screening is rarely performed. Patients with cancer are at elevated risk of occult deep venous thrombosis (DVT). An asymptomatic thrombus encountered during free fibula reconstruction is a serious concern. Although such cases have been reported, we suspect the incidence of DVT during fibula free flap harvest is underappreciated. This monograph uses a case example to review risk factors for occult DVT, present a strategy for preoperative assessment, and provide a reconstructive algorithm to for mandibular reconstruction in such instances. PMID- 25275473 TI - Volar Stabilization of the Distal Radioulnar Joint for Chronic Instability Using the Pronator Quadratus. AB - In cases of chronic distal radioulnar joint (DRUJ) instability without DRUJ arthritis, reconstruction of the mechanical integrity of the radioulnar ligaments of the triangular fibrocartilage complex has been considered an ideal surgical treatment. However, reconstructive methods have several disadvantages.We evaluated volar stabilization of the DRUJ for chronic instability using the pronator quadratus (PQ) to determine whether it provided (1) proper stability, (2) restored wrist function, (3) was relatively convenient, and (4) was associated with a low complication rate. Altogether, 21 patients with chronic DRUJ instability (12 men, 9 women) with a mean age of 34 years (range, 17-65 years) were enrolled in the study. The diagnostic criteria were as follows: 3 months after the injury, greater than 8 mm of palmar-dorsal translation of the ulna relative to the radius, there was a lack of clear end point resistance compared with the contralateral side, and nonstressed computed tomographic scans provided supporting evidence. Follow-up was at least 12 months (range, 12-38 months). Palmar-dorsal translation of the ulna relative to the radius was decreased significantly from 10 to 4 mm (P = 0.028) and epicenter was increased significantly at the last follow-up [P = 0.015/0.026 (70 degrees of supination/neutral, respectively)]. Wrist range of motion was not significantly different, but grip strength had increased from 72% to 91%. Disabilities of the arm, shoulder, and hand and patient-rated wrist evaluation were also decreased compared with preoperative measurements [34.4 to 12.5/42.7 to 14.7 (disabilities of the arm, shoulder, and hand/patient-rated wrist evaluation, respectively)]. Pronator quadratus advancement volar stabilization provided proper stability, restored wrist function, was relatively convenient, and was associated with few complications. Our experience indicates that it is an acceptable, effective treatment option to reverse DRUJ instability in patients who did not have advanced DRUJ arthritis. PMID- 25275474 TI - Treatment of the Secondary Defect on the First Metatarsophalangeal Joint Using the Medial Plantar Hallucal Artery Dorsal Perforator Flap. AB - Injuries or burns to the dorsum of the first metatarsophalangeal (MTP) joint may develop scar formation, resulting in hyperextension contracture. Surgical correction of the deformity often produces a secondary defect. The purpose of this study is to report on the use of the medial plantar hallucal artery dorsal perforator flap for the treatment of such defect. From February 2010 to June 2011, 16 patients were treated. The mean preoperative hyperextension of the first MTP joint was 48 degrees. The mean size of the defects was 3.6 * 6 cm. The mean flap size was 4 * 6.5 cm. The mean pedicle length was 4 cm. All flaps survived completely. Patient follow-up lasted a mean of 14 months. At the final follow-up, the mean hyperextension of the first MTP joint was 9 degrees. After surgery, the mean Foot Function Index improved from 62 to 7. Almost all patients were satisfied with the results. Transferring the medial plantar hallucal artery dorsal perforator flap is a useful and reliable technique for the reconstruction of the secondary defect on the first MTP joint. PMID- 25275475 TI - Pediatric Facial Fractures: A Review of 2071 Fractures. AB - BACKGROUND: Facial fractures are infrequent in children and adolescents, and there are only few reports that review a significant number of patients. The objective of this study was to analyze the pattern of maxillofacial fractures in pediatric patients of Portugal. STUDY DESIGN: We reviewed the clinical records of a series of 1416 patients 18 years or younger with facial fractures, treated by the Department of Plastic Reconstructive, Aesthetic and of Maxillofacial Surgery of Sao Joao Hospital, Porto, Portugal, between 1993 and 2012. The following parameters were evaluated: age; sex; cause of the accident; hour, day, and month of hospital admission; location and type of fractures; presence and location of associated injuries; treatment methods; length of in-hospital stay; and complications. RESULTS: A total of 2071 fractures were treated. The ratio of boys to girls was 3.1:1. Patients between 16 and 18 years old were the major group (43.9%). Motor vehicle accident was the most common cause of injuries (48.7% of patients). Mandibular fractures were the most common (44.4%). Associated injuries occurred in 1015 patients (71.7%). CONCLUSIONS: Pediatric facial fractures are usually associated with severe trauma. There has been a highly significant decrease (P < 0.001) in pediatric facial fractures in Portugal for the past 20 years. PMID- 25275476 TI - Wound Healing Effect of Conditioned Media Obtained From Adipose Tissue on Human Skin Cells: A Comparative in Vitro Study. AB - BACKGROUND: Split-thickness skin grafting is the gold standard to cover extensive acute and chronic wounds with a well-vascularized wound bed. Although some headway has been made in developing biological agents to speed up healing, there is still no treatment that sufficiently replaces skin grafts to date. The use of secretory factors of adipose tissue may be a feasible approach to developing topical wound applications for faster wound healing. METHODS: In this study, the effect of conditioned media (CMs) of human adipose-derived stem cells (ASCs), adipocytes, or adipose tissue on human skin cells was evaluated for viability, proliferation, and migration in vitro. Differentiation potential of stem cells treated with CM was monitored by AdipoRed staining and qualitative real-time polymerase chain reaction. Angiogenic potential of human endothelial cells treated with CM was tested via sprouting assay. RESULTS: The CM of adipose tissue significantly enhanced ASC proliferation (P < 0.01). Treatment with CM showed no inductive effect on ASC differentiation into adipocytes but, at the same time, significantly induced cell sprouting of endothelial cells (P < 0.001). We show for the first time that CM of adipose tissue is a potent inducer of proliferation of ASCs and angiogenesis, with comparable effects with those of stem cell enriched CM. CONCLUSIONS: We suggest the use of the secretome of adipose tissue to produce CM for topical application on wounds, rather than working with adipose tissue or including the difficult process of enriching the patients' stem cells in vitro. PMID- 25275477 TI - The scope of practice of hand surgery within plastic surgery: the ACAPS national survey to assess current practice and develop educational guidelines. AB - BACKGROUND: There is no consensus among plastic surgeons regarding what constitutes the scope of hand surgery practice. Due to this lack, there is a wide variability in what hand surgery procedures plastic surgery resident will see and participate in during the course of training. We assessed what faculty members of plastic surgery training programs felt were contained within the scope of practice of hand surgery. METHODS: A survey was sent to all members of the American Council of Academic Plastic Surgeons. Respondents reported size of department, faculty fellowship training, hand surgery call coverage, and amount of elective hand surgery within their training program. They also identified what procedures were within the scope of hand surgery. RESULTS: Ninety-three responses were received. Thirty-five respondents were certified or eligible for the surgery of the hand examination. Twenty-five respondents had 0 or 1 surgery-of-the-hand surgeon among their faculty. Thirty-nine departments/divisions performed 10 or fewer elective hand surgeries per week. Seventy-eight percent of groups taking hand call reported that all faculty members took hand call regardless of whether they had hand fellowship training. Although nearly all cover hand and wrist infections, only 49% provide care for distal radius fractures. CONCLUSIONS: In many residency programs, hand surgery exposure is in the setting of trauma and emergencies. The inclusion of complex elective hand surgeries within a plastic surgery practice and residency program allows residents to see the full spectrum of hand surgery. This allows them to make an informed decision regarding whether to seek subspecialty training and continue the participation of plastic surgeons in the full spectrum of hand surgery. PMID- 25275478 TI - Application of C-Shaped Osteotomy and Distraction Osteogenesis for Correction of Radial Angulation Deformities of the Hand in Children With Apert Syndrome: Review of 10 Years of Experience. AB - Apert syndrome is characterized by short, radially deviated thumbs, leading to difficulties in daily life such as holding a fork or a spoon and buttoning up. The main goal of surgery is to achieve thumb to index finger pinch to overcome these difficulties. Seven patients (14 extremities) followed up with Apert syndrome underwent distraction after a C-shaped osteotomy to simultaneously correct the brachydactyly and the angulation deformity of the bilateral thumbs. The patients ranged in age from 4 to 7 years at the distraction operation, with a mean (SD) of 4.7 (1.7) years, and the mean (SD) length of follow-up was 100.6 (14.95) months. The mean (SD) length of the phalanges at the beginning of distraction was 19.1 (3.26) mm, and the mean (SD) length of the distracted phalanx at long-term follow-up visit was 26.2 (5.63) mm. The mean (SD) correction of radial angulation was calculated as 42.6 (9.95) degrees, and the difference was considered as being statistically significant (P < 0.001). Minor complications such as pin loosening were observed in 6 extremities of 4 patients, and 2 patients were treated for pin tract infection. Index-to-thumb pinching was acquired by all the patients after distraction and correction of angulation. The hand features of Apert syndrome are as noteworthy as the craniofacial features and thus may lead to functional impairment and limitations in daily life. Distraction with a C-shaped osteotomy seems to be a promising method to correct both the shortness and the radial angulation of the thumb to achieve functional results. PMID- 25275479 TI - Asymmetric synthesis of (-)-brevipolide H through cyclopropanation of the alpha,beta-unsaturated ketone. AB - Brevipolides are 5,6-dihydro-gamma-pyrone derivatives, first reported in 2004 as the inhibitors of the chemokine receptor CCR5 and exhibiting cytotoxicity against cancer cells. Starting from the C2 symmetric diene-diol 2, ent-brevipolide H was synthesized for the first time in 11 steps. The anti-addition of the sulfur ylide to the alpha,beta-unsaturated enones was developed to give the key cyclopropane moiety. The synthetic (-)-brevipolide H showed an IC50 value of 7.7 MUM against PC-3 cells. PMID- 25275480 TI - Urethral dysfunction in female mice with estrogen receptor beta deficiency. AB - Estrogen has various regulatory functions in the growth, development, and differentiation of the female urogenital system. This study investigated the roles of ERbeta in stress urinary incontinence (SUI). Wild-type (ERbeta(+/+)) and knockout (ERbeta(-/-)) female mice were generated (aged 6-8 weeks, n = 6) and urethral function and protein expression were measured. Leak point pressures (LPP) and maximum urethral closure pressure (MUCP) were assessed in mice under urethane anesthesia. After the measurements, the urethras were removed for proteomic analysis using label-free quantitative proteomics by nano-liquid chromatography-mass spectrometry (LC-MS/MS) analysis. The interaction between these proteins was further analysed using MetaCore. Lastly, Western blot was used to confirm the candidate proteins. Compared with the ERbeta(+/+) group, the LPP and MUCP values of the ERbeta(-/-) group were significantly decreased. Additionally, we identified 85 differentially expressed proteins in the urethra of ERbeta(-/-) female mice; 57 proteins were up-regulated and 28 were down regulated. The majority of the ERbeta knockout-modified proteins were involved in cell-matrix adhesion, metabolism, immune response, signal transduction, nuclear receptor translational regelation, and muscle contraction and development. Western blot confirmed the up-regulation of myosin and collagen in urethra. By contrast, elastin was down-regulated in the ERbeta(-/-) mice. This study is the first study to estimate protein expression changes in urethras from ERbeta(-/-) female mice. These changes could be related to the molecular mechanism of ERbeta in SUI. PMID- 25275481 TI - Transport of eicosapentaenoic acid-derived PGE3, PGF(3alpha), and TXB3 by ABCC4. AB - BACKGROUND: Eicosapentaenoic acid-derived prostaglandin (PG) E3, PGF(3alpha), and thromboxane (TX) B3 are bioactive lipid mediators which have anti-cancer and anti inflammatory effects. To exert their effects, PGE3, PGF(3alpha), and TXB3 must be released to the extracellular space from cells, but the release mechanism has been unclear. We therefore investigated the contribution of ATP-binding cassette transporter C4 (ABCC4), which has been known as a prostanoids efflux transporter, to the release of PGE3, PGF(3alpha), and TXB3. MATERIALS AND METHODS: ATP dependent transport of PGE3, PGF(3alpha), and TXB3 via ABCC4 was investigated by using inside-out membrane vesicles prepared from ABCC4-overexpressing HEK293 cells. To evaluate the contribution of ABCC4 to the release of PGE3, PGF(3alpha), and TXB3, we measured the extracellular and intracellular levels of PGE3, PGF(3alpha), and TXB3 in A549 cells when we used ABCC4 inhibitors (dipyridamole, MK571, and probenecid) or ABCC4 siRNAs. The quantification of PGE3, PGF(3alpha), and TXB3 was performed by using liquid chromatography-tandem mass spectrometry. RESULTS: The apparent Km values for ABCC4-mediated transport were 2.9+/-0.1 uM for PGE3, 12.1+/-1.3 uM for PGF(3alpha), and 11.9+/-1.4 uM for TXB3 and the ATP dependent accumulation of PGE3, PGF(3alpha), and TXB3 into vesicles was decreased by using typical substrates and inhibitors of ABCC4. ABCC4 inhibitors and ABCC4 knockdown showed the reduction of extracellular/intracellular ratio of PGE3 (40 60% of control) and PGF(3alpha) (60-80% of control) in A549 cells. CONCLUSIONS: Our results suggest that PGE3, PGF(3alpha), and TXB3 are substrates of ABCC4 and ABCC4 partially contributes to the release of PGE3 and PGF(3alpha). PMID- 25275482 TI - Hospital disaster preparedness in Switzerland. AB - STUDY OBJECTIVE: Hospital preparedness is an essential component of any developed health care system. However, there is no national legislation in Switzerland. The objective of this inquiry was to establish the geographic distribution, availability and characteristics of hospital preparedness across Switzerland. METHODS: A questionnaire regarding hospital preparedness in 2006 was addressed to all heads responsible for emergency departments (ED). The survey was initiated in 2007 and finalised in 2012. RESULTS: Of the 138 ED, 122 (88%) returned the survey. Eighty nine EDs (82%) had a disaster plan. CONCLUSIONS: Our study identified an insufficient rate of hospitals in which emergency physicians reported a disaster plan. The lack of national or cantonal legislation regulating disaster preparedness may be partially responsible for this. PMID- 25275483 TI - Leishmaniasis in the middle East: incidence and epidemiology. AB - Leishmaniasis is a major health problem worldwide, with several countries reporting cases of leishmaniasis resulting in loss of human life or a lifelong stigma because of bodily scars. The Middle East is endemic for cutaneous leishmaniasis, with countries like Syria reporting very high incidence of the disease. Despite several countries establishing national control programs for containing the sandfly vector and treatment of infection, the disease continues to spread. In addition to the endemicity of the region for leishmaniasis, the Middle East has seen a great deal of human migration either for earning of livelihood or due to political upheaval in the region. These factors contribute to the spread and proliferation of the causative species Leishmania and its sandfly host. This review discusses the current epidemiological scenario in Iraq, Syria, Saudi Arabia, and Jordan, emphasizing the number of cases reported, vector species, Leishmania species, and treatment available. The data is primarily from WHO reports for each country and current and old literature. PMID- 25275484 TI - Species richness and assemblages in landscapes of different farming intensity- time to revise conservation strategies? AB - Worldwide conservation goals to protect biodiversity emphasize the need to rethink which objectives are most suitable for different landscapes. Comparing two different Swedish farming landscapes, we used survey data on birds and vascular plants to test whether landscapes with large, intensively managed farms had lower richness and diversity of the two taxa than landscapes with less intensively managed small farms, and if they differed in species composition. Landscapes with large intensively managed farms did not have lower richness than smaller low intensively managed farms. The landscape types were also similar in that they had few red listed species, normally targeted in conservation. Differences in species composition demonstrate that by having both types of agricultural landscapes regional diversity is increased, which is seldom captured in the objectives for agro-environmental policies. Thus we argue that focus on species richness or red listed species would miss the actual diversity found in the two landscape types. Biodiversity conservation, especially in production landscapes, would therefore benefit from a hierarchy of local to regional objectives with explicit targets in terms of which aspects of biodiversity to focus on. PMID- 25275485 TI - Thermosensitive and mucoadhesive sol-gel composites of paclitaxel/dimethyl-beta cyclodextrin for buccal delivery. AB - The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O methyl)-beta-cyclodextrin (DMbetaCD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4 degrees C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37 degrees C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127 based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel. PMID- 25275487 TI - Triptolide preserves cognitive function and reduces neuropathology in a mouse model of Alzheimer's disease. AB - Triptolide, a major bioactive ingredient of a widely used herbal medicine, has been shown to possess multiple pharmacological functions, including potential neuroprotective effects pertinent to Alzheimer's disease (AD) in vitro. However, the therapeutic potential of triptolide for AD in vivo has not been thoroughly evaluated. In the present study, we investigated the impact of peripherally administered triptolide on AD-related behavior and neuropathology in APPswe/PS1DeltaE9 (APP/PS1) mice, an established model of AD. Our results showed that two-month treatment with triptolide rescued cognitive function in APP/PS1 mice. Immunohistochemical analyses indicated that triptolide treatment led to a significant decrease in amyloid-beta (Abeta) deposition and neuroinflammation in treated mice. In contrast to previous findings in vitro, biochemical analyses showed that triptolide treatment did not significantly affect the production pathway of Abeta in vivo. Intriguingly, further analyses revealed that triptolide treatment upregulated the level of insulin-degrading enzyme, a major Abeta degrading enzyme in the brain, indicating that triptolide treatment reduced Abeta pathology by enhancing the proteolytic degradation of Abeta. Our findings demonstrate that triptolide treatment ameliorates key behavioral and neuropathological changes found in AD, suggesting that triptolide may serve as a potential therapeutic agent for AD. PMID- 25275488 TI - Bioconjugation of gold nanoparticles through the oxidative coupling of ortho aminophenols and anilines. AB - While there are a number of methods for attaching gold nanoparticles (AuNPs) to biomolecules, the existing strategies suffer from nonspecific AuNP adsorption, reagents that are unstable in aqueous solutions, and/or long reaction times. To improve upon existing AuNP bioconjugation strategies, we have adapted a recently reported potassium ferricyanide-mediated oxidative coupling reaction for the attachment of aniline-functionalized AuNPs to o-aminophenol-containing oligonucleotides, peptides, and proteins. The aniline-AuNPs are stable in aqueous solutions, show little-to-no nonspecific adsorption with biomolecules, and react rapidly (30 min) with o-aminophenols under mild conditions (pH 6.5, 1 mM oxidant). PMID- 25275489 TI - Enhancing the functional content of eukaryotic protein interaction networks. AB - Protein interaction networks are a promising type of data for studying complex biological systems. However, despite the rich information embedded in these networks, these networks face important data quality challenges of noise and incompleteness that adversely affect the results obtained from their analysis. Here, we apply a robust measure of local network structure called common neighborhood similarity (CNS) to address these challenges. Although several CNS measures have been proposed in the literature, an understanding of their relative efficacies for the analysis of interaction networks has been lacking. We follow the framework of graph transformation to convert the given interaction network into a transformed network corresponding to a variety of CNS measures evaluated. The effectiveness of each measure is then estimated by comparing the quality of protein function predictions obtained from its corresponding transformed network with those from the original network. Using a large set of human and fly protein interactions, and a set of over 100 GO terms for both, we find that several of the transformed networks produce more accurate predictions than those obtained from the original network. In particular, the HC.cont measure and other continuous CNS measures perform well this task, especially for large networks. Further investigation reveals that the two major factors contributing to this improvement are the abilities of CNS measures to prune out noisy edges and enhance functional coherence in the transformed networks. PMID- 25275486 TI - Epstein-Barr virus nuclear antigen 3A promotes cellular proliferation by repression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. AB - Latent infection by Epstein-Barr virus (EBV) is highly associated with the endemic form of Burkitt lymphoma (eBL), which typically limits expression of EBV proteins to EBNA-1 (Latency I). Interestingly, a subset of eBLs maintain a variant program of EBV latency - Wp-restricted latency (Wp-R) - that includes expression of the EBNA-3 proteins (3A, 3B and 3C), in addition to EBNA-1. In xenograft assays, Wp-R BL cell lines were notably more tumorigenic than their counterparts that maintain Latency I, suggesting that the additional latency associated proteins expressed in Wp-R influence cell proliferation and/or survival. Here, we evaluated the contribution of EBNA-3A. Consistent with the enhanced tumorigenic potential of Wp-R BLs, knockdown of EBNA-3A expression resulted in abrupt cell-cycle arrest in G0/G1 that was concomitant with conversion of retinoblastoma protein (Rb) to its hypophosphorylated state, followed by a loss of Rb protein. Comparable results were seen in EBV immortalized B lymphoblastoid cell lines (LCLs), consistent with the previous observation that EBNA-3A is essential for sustained growth of these cells. In agreement with the known ability of EBNA-3A and EBNA-3C to cooperatively repress p14(ARF) and p16(INK4a) expression, knockdown of EBNA-3A in LCLs resulted in rapid elevation of p14(ARF) and p16I(NK4a). By contrast, p16(INK4a) was not detectably expressed in Wp-R BL and the low-level expression of p14(ARF) was unchanged by EBNA-3A knockdown. Amongst other G1/S regulatory proteins, only p21(WAF1/CIP1), a potent inducer of G1 arrest, was upregulated following knockdown of EBNA-3A in Wp-R BL Sal cells and LCLs, coincident with hypophosphorylation and destabilization of Rb and growth arrest. Furthermore, knockdown of p21(WAF1/CIP1) expression in Wp-R BL correlated with an increase in cellular proliferation. This novel function of EBNA-3A is distinct from the functions previously described that are shared with EBNA-3C, and likely contributes to the proliferation of Wp-R BL cells and LCLs. PMID- 25275490 TI - Complexity and dynamics of HIV-1 chemokine receptor usage in a multidrug resistant adolescent. AB - Maraviroc (MVC) is licensed in clinical practice for patients with R5 virus and virological failure; however, in anecdotal reports, dual/mixed viruses were also inhibited. We retrospectively evaluated the evolution of HIV-1 coreceptor tropism in plasma and peripheral blood mononuclear cells (PBMCs) of an infected adolescent with a CCR5/CXCR4 Trofile profile who experienced an important but temporary immunological and virological response during a 16-month period of MVC based therapy. Coreceptor usage of biological viral clones isolated from PBMCs was investigated in U87.CD4 cells expressing wild-type or chimeric CCR5 and CXCR4. Plasma and PBMC-derived viral clones were sequenced to predict coreceptor tropism using the geno2pheno algorithm from the V3 envelope sequence and pol gene resistant mutations. From start to 8.5 months of MVC treatment only R5X4 viral clones were observed, whereas at 16 months the phenotype enlarged to also include R5 and X4 clones. Chimeric receptor usage suggested the preferential usage of the CXCR4 coreceptor by the R5X4 biological clones. According to phenotypic data, R5 viruses were susceptible, whereas R5X4 and X4 viruses were resistant to RANTES and MVC in vitro. Clones at 16 months, but not at baseline, showed an amino acidic resistance pattern in protease and reverse transcription genes, which, however, did not drive their tropisms. The geno2pheno algorithm predicted at baseline R5 viruses in plasma, and from 5.5 months throughout follow-up only CXCR4-using viruses. An extended methodological approach is needed to unravel the complexity of the phenotype and variation of viruses resident in the different compartments of an infected individual. The accurate evaluation of the proportion of residual R5 viruses may guide therapeutic intervention in highly experienced patients with limited therapeutic options. PMID- 25275491 TI - Birth weight, intrauterine growth retardation and fetal susceptibility to porcine reproductive and respiratory syndrome virus. AB - The severity of porcine reproductive and respiratory syndrome was compared in pregnant gilts originating from high and low birth weight litters. One-hundred and eleven pregnant gilts experimentally infected with porcine reproductive and respiratory syndrome virus on gestation day 85 (+/-1) were necropsied along with their fetuses 21 days later. Ovulation rates and litter size did not differ between groups, but fetuses from low birth weight gilts were shorter, lighter and demonstrated evidence of asymmetric growth with large brain:organ weight ratios (i.e. brain sparing). The number of intrauterine growth retarded fetuses, defined by brain:organ weight ratios greater than 1 standard deviation from the mean, was significantly greater in low, compared to high, birth weight gilts. Although gammadelta T cells significantly decreased over time in high compared to low birth weight gilts, viral load in serum and tissues, gilt serum cytokine levels, and litter outcome, including the percent dead fetuses per litter, did not differ by birth weight group. Thus, this study provided no substantive evidence that the severity of porcine reproductive and respiratory syndrome is affected by dam birth weight. However, intrauterine growth retarded fetuses had lower viral loads in both fetal thymus and in endometrium adjacent to the umbilical stump. Crown rump length did not significantly differ between fetuses that survived and those that died at least one week prior to termination. Taken together, this study clearly demonstrates that birth weight is a transgenerational trait in pigs, and provides evidence that larger fetuses are more susceptible to transplacental PRRSv infection. PMID- 25275492 TI - Molecular pathology of rare bleeding disorders (RBDs) in India: a systematic review. AB - BACKGROUND: Though rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India. OBJECTIVES: To comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs. METHODS: Pubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words "rare bleeding disorders", "mutations", "India", "fibrinogen", "afibrinogenemia", "factor II deficiency", "prothrombin" "factor VII deficiency", "factor V deficiency", "factor X deficiency", "factor XI deficiency", "combined factor V and VIII deficiency", "factor XIII deficiency", "Bernard Soulier syndrome" and "Glanzmanns thrombasthenia" in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org). RESULTS: Taken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs. CONCLUSION: There is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families. PMID- 25275493 TI - Evaluation of a dengue NS1 antigen detection assay sensitivity and specificity for the diagnosis of acute dengue virus infection. AB - BACKGROUND: Currently, no dengue NS1 detection kit has regulatory approval for the diagnosis of acute dengue fever. Here we report the sensitivity and specificity of the InBios DEN Detect NS1 ELISA using a panel of well characterized human acute fever serum specimens. METHODOLOGY/PRINCIPAL FINDINGS: The InBios DENV Detect NS1 ELISA was tested using a panel composed of 334 serum specimens collected from acute febrile patients seeking care in a Bangkok hospital in 2010 and 2011. Of these patients, 314 were found to have acute dengue by either RT-PCR and/or anti-dengue IgM/IgG ELISA. Alongside the InBios NS1 ELISA kit, we compared the performance characteristics of the BioRad Platelia NS1 antigen kit. The InBios NS1 ELISA Ag kit had a higher overall sensitivity (86% vs 72.8%) but equal specificity (100%) compared to the BioRad Platelia kit. The serological status of the patient significantly influenced the outcome. In primary infections, the InBios NS1 kit demonstrated a higher sensitivity (98.8%) than in secondary infections (83.5%). We found significant variation in the sensitivity of the InBios NS1 ELISA kit depending on the serotype of the dengue virus and also found decreasing sensitivity the longer after the onset of illness, showing 100% sensitivity early during illness, but dropping below 50% by Day 7. CONCLUSION/SIGNIFICANCE: The InBios NS1 ELISA kit demonstrated high accuracy when compared to the initial clinical diagnosis with greater than 85% agreement when patients were clinically diagnosed with dengue illness. Results presented here suggest the accurate detection of circulating dengue NS1 by the InBios DENV Detect NS1 ELISA can provide clinicians with a useful tool for diagnosis of early dengue infections. PMID- 25275494 TI - Linking Populus euphratica hydraulic redistribution to diversity assembly in the arid desert zone of Xinjiang, China. AB - The hydraulic redistribution (HR) of deep-rooted plants significantly improves the survival of shallow-rooted shrubs and herbs in arid deserts, which subsequently maintain species diversity. This study was conducted in the Ebinur desert located in the western margin of the Gurbantonggut Desert. Isotope tracing, community investigation and comparison analysis were employed to validate the HR of Populus euphratica and to explore its effects on species richness and abundance. The results showed that, P. euphratica has HR. Shrubs and herbs that grew under the P. euphratica canopy (under community: UC) showed better growth than the ones growing outside (Outside community: OC), exhibiting significantly higher species richness and abundance in UC than OC (p<0.05) along the plant growing season. Species richness and abundance were significantly logarithmically correlated with the P. euphratica crown area in UC (R2 = 0.51 and 0.84, p<0.001). In conclusion, P. euphratica HR significantly ameliorates the water conditions of the shallow soil, which then influences the diversity assembly in arid desert communities. PMID- 25275496 TI - Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio as indicators of potential severity of Plasmodium vivax malaria in patients with thrombocytopenia. AB - INTRODUCTION: Angiogenic factors such as angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) are biomarkers produced during activation and dysfunction of the vascular endothelium in several infectious diseases. The aim of this study was to determine the serum levels of Ang-1 and Ang-2 and to establish their relationship with the main indicators of worst-case prognosis in patients with P. vivax malaria. METHODS: This is a retrospective case-control study nested within a cohort of symptomatic malaria patients. A potentially severe case was defined as a patient that presented at least one of the main indicators of the worst-case prognosis for falciparum malaria, as established by the World Health Organization. Ang-2 and Ang-1 and the Ang-2/Ang-1 ratio were used to analyze the role of angiopoietins as biomarkers in signaling potentially severe vivax malaria. ROC curves were generated to identify a cut-off point discriminating between the angiopoietin concentrations that were most strongly associated with potential infection severity. RESULTS: The serum levels of Ang-2 and the Ang 2/Ang-1 ratio were higher in the case group. In contrast, the serum levels of Ang 1 were lower in the cases than in the control patients. The blood count for platelets showed a positive correlation with Ang-1 and a negative correlation with Ang-2 and with the Ang-2/Ang-1 ratio. The area under the ROC curve (AUC) for serum angiopoietins, as an indicator of worst-case prognosis in a potentially severe P. vivax malarial infection, was larger in the subgroup of patients with platelet counts <75,000/uL. CONCLUSION: This study showed that patients with predictors of worst-case prognoses for P. vivax malaria have lower Ang-1 and higher Ang-2 serum levels (and higher values for the Ang-2/Ang-1 ratio) than controls. Elevated serum levels of Ang-2 and high values for the Ang-2/Ang-1 ratio may potentially be used as predictors of worst-case prognoses for P. vivax malaria, especially in patients with thrombocytopenia. PMID- 25275497 TI - Protospacer adjacent motif (PAM)-distal sequences engage CRISPR Cas9 DNA target cleavage. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)-associated enzyme Cas9 is an RNA-guided nuclease that has been widely adapted for genome editing in eukaryotic cells. However, the in vivo target specificity of Cas9 is poorly understood and most studies rely on in silico predictions to define the potential off-target editing spectrum. Using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we delineate the genome-wide binding panorama of catalytically inactive Cas9 directed by two different single guide (sg) RNAs targeting the Trp53 locus. Cas9:sgRNA complexes are able to load onto multiple sites with short seed regions adjacent to (5')NGG(3') protospacer adjacent motifs (PAM). Yet among 43 ChIP-seq sites harboring seed regions analyzed for mutational status, we find editing only at the intended on-target locus and one off-target site. In vitro analysis of target site recognition revealed that interactions between the 5' end of the guide and PAM-distal target sequences are necessary to efficiently engage Cas9 nucleolytic activity, providing an explanation for why off-target editing is significantly lower than expected from ChIP-seq data. PMID- 25275495 TI - H2B mono-ubiquitylation facilitates fork stalling and recovery during replication stress by coordinating Rad53 activation and chromatin assembly. AB - The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to gammaH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression. PMID- 25275499 TI - Risk factors of developmental defects of enamel--a prospective cohort study. AB - BACKGROUND AND OBJECTIVE: Current studies on the aetiology of developmental defects of enamel (DDE) are subject to recall bias because of the retrospective collection of information. Our objective was to investigate potential risk factors associated with the occurrence of DDE through a prospective cohort study. METHODS: Using a random community sample of Hong Kong children born in 1997, we performed a cohort study in which the subjects' background information, medical and dental records were prospectively collected. A clinical examination to identify DDE was conducted in 2010 when the subjects were 12 years old. The central incisor, lateral incisor and first molar in each quadrant were chosen as the index teeth and were examined 'wet' by two trained and calibrated examiners using the modified FDI (DDE) Index. RESULTS: With a response rate of 74.9%, the 514 examined subjects had matched data for background information. Diffuse opacites were the most common type of DDE. Of the various possible aetiological factors considered, only experience of severe diseases during the period 0-3 years was associated with the occurrence of 'any defect' (p = 0.017) and diffuse opacities (p = 0.044). The children with experience of severe diseases before 3 years of age were 7.89 times more likely to be affected by 'any defect' compared with those who did not have the experience (OR 7.89; 95% CI 1.07, 58.14; p = 0.043). However, after adjusting for confounding factors, the association no longer existed. CONCLUSION: No variables could be identified as risk factors of DDE in this Hong Kong birth cohort. PMID- 25275501 TI - Molecular Co(II) and Co(III) heteroarylalkenolates as efficient precursors for chemical vapor deposition of Co3O4 nanowires. AB - Two new cobalt precursors, Co(II)(PyCHCOCF3)2(DMAP)2 (1) and Co(III)(PyCHCOCF3)3 (2), based on Co(II) and Co(III) centers were synthesized using a redox active ligand system. The different chemical configurations of 1 and 2 and differential valence states of cobalt were confirmed by crystal structure determination and comprehensive analytical studies. Whereas 1 could not be studied by NMR due to the paramagnetic nature of the central atom, 2 was unambiguously characterized by multinuclear 1D and 2D NMR experiments in solution. Both compounds are efficient precursors for catalyst-free growth of Co3O4 nanowires on Si and Al2O3 substrates by a chemical vapor deposition process. The different valence states of cobalt species influenced their chemical decomposition pathways in the gas phase; for instance, 1 was partially oxidized (Co(2+) -> Co(3+)), and 2 underwent reduction (Co(3+) -> Co(2+)) to form pure cobaltite in both cases that verified the metal ligand redox interplay. Co3O4 nanowires with nanometric diameters (50-100 nm) were obtained irrespective of the chosen cobalt precursor. Investigations on the humidity sensing behavior of CVD deposits demonstrated their potential as promising sensor materials. PMID- 25275502 TI - Mechanistic studies of silica polymerization from supersaturated aqueous solutions by means of time-resolved light scattering. AB - Silica polymerization in a supersaturated aqueous solution of sodium silicate is a fundamental mineralization process with broad relevance for technical applications as well as for biological processes. To contribute to a better understanding of the mechanism underlying the polymerization of sodium silicate under ambient conditions, a combined multiangle static and dynamic light scattering study on the evolution of particle mass and size is applied for the first time in a time-resolving manner. The light scattering experiments are complemented by a time-resolved analysis of the decay of the concentration of monomeric silicate by means of the silicomolybdate method. Particle formation was investigated at a variable concentration of silicate at pH 7 and 8. The joint experiments revealed a loss of monomers, which is parallel to the formation of compact, spherical particles growing by a monomer-addition process. An increase in the silicate content of up to 750 ppm increased the extent of nucleation and at the same time decreased the lag time observed between the start of the reaction and the actual onset of the growth of particles. Once the silica content is considerably larger than 1000 ppm, the formation of particles is succeeded by particle-particle agglomeration leading to larger fractal-like particles. By the time agglomeration becomes noticeable with light scattering, the monomer concentration has already reached its equilibrium value. An increase in the pH to 8 again revealed particle formation via a monomer-addition process. However, the extent of nucleation was increased and particle-particle agglomeration was inhibited even at an initial silica content of 2000 ppm. PMID- 25275498 TI - Payoffs, not tradeoffs, in the adaptation of a virus to ostensibly conflicting selective pressures. AB - The genetic architecture of many phenotypic traits is such that genes often contribute to multiple traits, and mutations in these genes can therefore affect multiple phenotypes. These pleiotropic interactions often manifest as tradeoffs between traits where improvement in one property entails a cost in another. The life cycles of many pathogens include periods of growth within a host punctuated with transmission events, such as passage through a digestive tract or a passive stage of exposure in the environment. Populations exposed to such fluctuating selective pressures are expected to acquire mutations showing tradeoffs between reproduction within and survival outside of a host. We selected for individual mutations under fluctuating selective pressures for a ssDNA microvirid bacteriophage by alternating selection for increased growth rate with selection on biophysical properties of the phage capsid in high-temperature or low-pH conditions. Surprisingly, none of the seven unique mutations identified showed a pleiotropic cost; they all improved both growth rate and pH or temperature stability, suggesting that single mutations even in a simple genetic system can simultaneously improve two distinct traits. Selection on growth rate alone revealed tradeoffs, but some mutations still benefited both traits. Tradeoffs were therefore prevalent when selection acted on a single trait, but payoffs resulted when multiple traits were selected for simultaneously. We employed a molecular-dynamics simulation method to determine the mechanisms underlying beneficial effects for three heat-shock mutations. All three mutations significantly enhanced the affinities of protein-protein interfacial bindings, thereby improving capsid stability. The ancestral residues at the mutation sites did not contribute to protein-protein interfacial binding, indicating that these sites acquired a new function. Computational models, such as those used here, may be used in future work not only as predictive tools for mutational effects on protein stability but, ultimately, for evolution. PMID- 25275500 TI - P. berghei telomerase subunit TERT is essential for parasite survival. AB - Telomeres define the ends of chromosomes protecting eukaryotic cells from chromosome instability and eventual cell death. The complex regulation of telomeres involves various proteins including telomerase, which is a specialized ribonucleoprotein responsible for telomere maintenance. Telomeres of chromosomes of malaria parasites are kept at a constant length during blood stage proliferation. The 7-bp telomere repeat sequence is universal across different Plasmodium species (GGGTTT/CA), though the average telomere length varies. The catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), is present in all sequenced Plasmodium species and is approximately three times larger than other eukaryotic TERTs. The Plasmodium RNA component of TERT has recently been identified in silico. A strategy to delete the gene encoding TERT via double cross-over (DXO) homologous recombination was undertaken to study the telomerase function in P. berghei. Expression of both TERT and the RNA component (TR) in P. berghei blood stages was analysed by Western blotting and Northern analysis. Average telomere length was measured in several Plasmodium species using Telomere Restriction Fragment (TRF) analysis. TERT and TR were detected in blood stages and an average telomere length of ~ 950 bp established. Deletion of the tert gene was performed using standard transfection methodologies and we show the presence of tert- mutants in the transfected parasite populations. Cloning of tert- mutants has been attempted multiple times without success. Thorough analysis of the transfected parasite populations and the parasite obtained from extensive parasite cloning from these populations provide evidence for a so called delayed death phenotype as observed in different organisms lacking TERT. The findings indicate that TERT is essential for P. berghei cell survival. The study extends our current knowledge on telomere biology in malaria parasites and validates further investigations to identify telomerase inhibitors to induce parasite cell death. PMID- 25275503 TI - Cutaneous leishmaniasis and sand fly fluctuations are associated with el nino in panama. AB - BACKGROUND: Cutaneous Leishmaniasis (CL) is a neglected tropical vector-borne disease. Sand fly vectors (SF) and Leishmania spp parasites are sensitive to changes in weather conditions, rendering disease transmission susceptible to changes in local and global scale climatic patterns. Nevertheless, it is unclear how SF abundance is impacted by El Nino Southern Oscillation (ENSO) and how these changes might relate to changes in CL transmission. METHODOLOGY AND FINDINGS: We studied association patterns between monthly time series, from January 2000 to December 2010, of: CL cases, rainfall and temperature from Panama, and an ENSO index. We employed autoregressive models and cross wavelet coherence, to quantify the seasonal and interannual impact of local climate and ENSO on CL dynamics. We employed Poisson Rate Generalized Linear Mixed Models to study SF abundance patterns across ENSO phases, seasons and eco-epidemiological settings, employing records from 640 night-trap sampling collections spanning 2000-2011. We found that ENSO, rainfall and temperature were associated with CL cycles at interannual scales, while seasonal patterns were mainly associated with rainfall and temperature. Sand fly (SF) vector abundance, on average, decreased during the hot and cold ENSO phases, when compared with the normal ENSO phase, yet variability in vector abundance was largest during the cold ENSO phase. Our results showed a three month lagged association between SF vector abundance and CL cases. CONCLUSION: Association patterns of CL with ENSO and local climatic factors in Panama indicate that interannual CL cycles might be driven by ENSO, while the CL seasonality was mainly associated with temperature and rainfall variability. CL cases and SF abundance were associated in a fashion suggesting that sudden extraordinary changes in vector abundance might increase the potential for CL epidemic outbreaks, given that CL epidemics occur during the cold ENSO phase, a time when SF abundance shows its highest fluctuations. PMID- 25275504 TI - Further characterization of HDAC and SIRT gene expression patterns in pancreatic cancer and their relation to disease outcome. AB - Ductal adenocarcinoma of the pancreas is ranking 4 for patient' death from malignant disease in Western countries, with no satisfactory treatment. We re examined more precisely the histone deacetylases (HDAC) and Sirtuin (SIRT) gene expression patterns in pancreatic cancer with more pancreatic tumors and normal tissues. We also examined the possible relationship between HDAC gene expression levels and long term disease outcome. Moreover, we have evaluated by using an in vitro model system of human pancreatic tumor cell line whether HDAC7 knockdown may affect the cell behavior. We analyzed 29 pancreatic adenocarcinoma (PA), 9 chronic pancreatitis (CP), 8 benign pancreatic (BP) and 11 normal pancreatic tissues. Concerning pancreatic adenocarcinoma, we were able to collect biopsies at the tumor periphery. To assess the possible involvement of HDAC7 in cell proliferation capacity, we have generated recombinant human Panc-1 tumor which underexpressed or overexpressed HDAC7. The expression of HDAC1,2,3,4,7 and Nur77 increased in PA samples at levels significantly higher than those observed in the CP group (p = 0.0160; 0.0114; 0.0227; 0.0440; 0.0136; 0.0004, respectively). The expression of HDAC7, was significantly greater in the PA compared with BP tissue samples (p = 0.05). Mean mRNA transcription levels of PA for HDAC7 and HDAC2 were higher when compared to their counterpart biopsies taken at the tumor periphery (p = 0.0346, 0.0053, respectively). Moreover, the data obtained using confocal microscopy and a quantitative method of immunofluorescence staining strongly support the HDAC7 overexpression in PA surgical specimens. The number of deaths and recurrences at the end of follow up were significantly greater in patients with overexpression of HDAC7. Interestingly, the rate of growth was significantly reduced in the case of cell carrying shRNA construct targeting HDAC7 encoding gene when compared to the parental Panc-1 tumor cells (p = 0.0015) at 48 h and 96 h (p = 0.0021). This study strongly support the notion that HDAC7play a role in pancreatic adenocarcinoma progression. PMID- 25275505 TI - Synaptic size dynamics as an effectively stochastic process. AB - Long-term, repeated measurements of individual synaptic properties have revealed that synapses can undergo significant directed and spontaneous changes over time scales of minutes to weeks. These changes are presumably driven by a large number of activity-dependent and independent molecular processes, yet how these processes integrate to determine the totality of synaptic size remains unknown. Here we propose, as an alternative to detailed, mechanistic descriptions, a statistical approach to synaptic size dynamics. The basic premise of this approach is that the integrated outcome of the myriad of processes that drive synaptic size dynamics are effectively described as a combination of multiplicative and additive processes, both of which are stochastic and taken from distributions parametrically affected by physiological signals. We show that this seemingly simple model, known in probability theory as the Kesten process, can generate rich dynamics which are qualitatively similar to the dynamics of individual glutamatergic synapses recorded in long-term time-lapse experiments in ex-vivo cortical networks. Moreover, we show that this stochastic model, which is insensitive to many of its underlying details, quantitatively captures the distributions of synaptic sizes measured in these experiments, the long-term stability of such distributions and their scaling in response to pharmacological manipulations. Finally, we show that the average kinetics of new postsynaptic density formation measured in such experiments is also faithfully captured by the same model. The model thus provides a useful framework for characterizing synapse size dynamics at steady state, during initial formation of such steady states, and during their convergence to new steady states following perturbations. These findings show the strength of a simple low dimensional statistical model to quantitatively describe synapse size dynamics as the integrated result of many underlying complex processes. PMID- 25275506 TI - Transport and metabolism behavior of brazilein during its entrance into neural cells. AB - Brazilein, a natural small molecule, shows a variety of pharmacological activities, especially on nervous system and immune system. As a potential multifunctional drug, we studied the distribution and the transport behavior and metabolic behavior of brazilein in vivo and in vitro. Brazilein was found to be able to distribute in the mouse brain and transport into neural cells. A metabolite was found in the brain and in the cells. Positive and negative mode MS/MS and Q-TOF were used to identify the metabolite. MS/MS fragmentation mechanisms showed the methylation occurred at the 10-hydroxyl of brazilein (10-O methylbrazilein). Further, catechol-O- methyltransferase (COMT) was confirmed as a crucial enzyme correlated with the methylated metabolite generation by molecular docking and pharmacological experiment. PMID- 25275507 TI - Selection based on indirect genetic effects for growth, environmental enrichment and coping style affect the immune status of pigs. AB - Pigs living in intensive husbandry systems may experience both acute and chronic stress through standard management procedures and limitations in their physical and social environment, which may have implications for their immune status. Here, the effect of a new breeding method where pigs were selected on their heritable influence on their pen mates' growth, and environmental enrichment on the immune status of pigs was investigated. Hereto, 240 pigs with a relatively positive genetic effect on the growth of their pen mates (+SBV) and 240 pigs with a relatively negative genetic effect on the growth of their pen mates (-SBV) were housed in barren or straw-enriched pens from 4 to 23 weeks of age (n = 80 pens in total). A blood sample was taken from the pigs before, three days after a 24 h regrouping test, and at week 22. In addition, effects of coping style, as assessed in a backtest, and gender were also investigated. Mainly, +SBV were found to have lower leukocyte, lymphocyte and haptoglobin concentrations than SBV pigs. Enriched housed pigs had a lower neutrophil to lymphocyte (N:L) ratio and lower haptoglobin concentrations, but had higher antibody titers specific for Keyhole Limpet Hemocyanin (KLH) than barren housed pigs. No interactions were found between SBV class and housing. Furthermore, pigs with a proactive coping style had higher alternative complement activity and, in the enriched pens, higher antibody titers specific for KLH than pigs with a reactive coping style. Lastly, females tended to have lower leukocyte, but higher haptoglobin concentrations than castrated males. Overall, these results suggest that +SBV pigs and enriched housed pigs were less affected by stress than -SBV and barren housed pigs, respectively. Moreover, immune activation might be differently organized in individuals with different coping styles and to a lesser extent in individuals of opposite genders. PMID- 25275508 TI - In situ mortality experiments with juvenile sea bass (Dicentrarchus labrax) in relation to impulsive sound levels caused by pile driving of windmill foundations. AB - Impact assessments of offshore wind farm installations and operations on the marine fauna are performed in many countries. Yet, only limited quantitative data on the physiological impact of impulsive sounds on (juvenile) fishes during pile driving of offshore wind farm foundations are available. Our current knowledge on fish injury and mortality due to pile driving is mainly based on laboratory experiments, in which high-intensity pile driving sounds are generated inside acoustic chambers. To validate these lab results, an in situ field experiment was carried out on board of a pile driving vessel. Juvenile European sea bass (Dicentrarchus labrax) of 68 and 115 days post hatching were exposed to pile driving sounds as close as 45 m from the actual pile driving activity. Fish were exposed to strikes with a sound exposure level between 181 and 188 dB re 1 uPa2.s. The number of strikes ranged from 1739 to 3067, resulting in a cumulative sound exposure level between 215 and 222 dB re 1 uPa2.s. Control treatments consisted of fish not exposed to pile driving sounds. No differences in immediate mortality were found between exposed and control fish groups. Also no differences were noted in the delayed mortality up to 14 days after exposure between both groups. Our in situ experiments largely confirm the mortality results of the lab experiments found in other studies. PMID- 25275510 TI - Study on the main components interaction from Flos Lonicerae and Fructus Forsythiae and their dissolution in vitro and intestinal absorption in rats. AB - The Flos Lonicerae-Fructus Forsythiae herb couple is the basic components of Chinese herbal preparations (Shuang-Huang-Lian tablet, Yin-Qiao-Jie-Du tablet and Fufang Qin-Lan oral liquid), and its pharmacological effects were significantly higher than that in Flos Lonicerae or Fructus Forsythiae, but the reasons remained unknown. In the present study, pattern recognition analysis (hierarchical cluster analysis (HCA) and principal component analysis (PCA)) combined with UHPLC-ESI/LTQ-Orbitrap MS system were performed to study the chemical constitution difference between co-decoction and mixed decoction in the term of chemistry. Besides, the pharmacokinetics in vivo and intestinal absorption in vitro combined with pattern recognition analysis were used to reveal the discrepancy between herb couple and single herbs in the view of biology. The observation from the chemical view in vitro showed that there was significant difference in quantity between co-decoction and mixed decoction by HCA, and the exposure level of isoforsythoside and 3, 5-dicaffeoylquinic acid in co-decoction, higher than that in mixed decoction, directly resulted in the discrepancy between co-decoction and mixed decoction using both PCA and HCA. The observation from the pharmacokinetics displayed that the exposure level in vivo of neochlorogenic acid, 3, 4-dicaffeoylquinic acid, isoforsythoside and forsythoside A, higher than that in single herbs, was the main factor contributing to the difference by both PCA and HCA, interestingly consistent with the results obtained from Caco-2 cells in vitro, which indicated that it was because of intestinal absorption improvement of neochlorogenic acid, 3, 4 dicaffeoylquinic acid, isoforsythoside and forsythoside A that resulted in a better efficacy of herb couple than that of single herbs from the perspective of biology. The results above illustrated that caffeic acid derivatives in Flos Lonicerae-Fructus Forsythiae herb couple could be considered as chemical markers for quality control of its preparations. PMID- 25275509 TI - Meta-analysis of the effects of insect vector saliva on host immune responses and infection of vector-transmitted pathogens: a focus on leishmaniasis. AB - A meta-analysis of the effects of vector saliva on the immune response and progression of vector-transmitted disease, specifically with regard to pathology, infection level, and host cytokine levels was conducted. Infection in the absence or presence of saliva in naive mice was compared. In addition, infection in mice pre-exposed to uninfected vector saliva was compared to infection in unexposed mice. To control for differences in vector and pathogen species, mouse strain, and experimental design, a random effects model was used to compare the ratio of the natural log of the experimental to the control means of the studies. Saliva was demonstrated to enhance pathology, infection level, and the production of Th2 cytokines (IL-4 and IL-10) in naive mice. This effect was observed across vector/pathogen pairings, whether natural or unnatural, and with single salivary proteins used as a proxy for whole saliva. Saliva pre-exposure was determined to result in less severe leishmaniasis pathology when compared with unexposed mice infected either in the presence or absence of sand fly saliva. The results of further analyses were not significant, but demonstrated trends toward protection and IFN-gamma elevation for pre-exposed mice. PMID- 25275511 TI - Development of glomerulus-, tubule-, and collecting duct-specific mRNA assay in human urinary exosomes and microvesicles. AB - Urinary exosomes and microvesicles (EMV) are promising biomarkers for renal diseases. Although the density of EMV is very low in urine, large quantity of urine can be easily obtained. In order to analyze urinary EMV mRNA, a unique filter device to adsorb urinary EMV from 10 mL urine was developed, which is far more convenient than the standard ultracentrifugation protocol. The filter part of the device is detachable and aligned to a 96-well microplate format, therefore multiple samples can be processed simultaneously in a high throughput manner following the isolation step. For EMV mRNA quantification, the EMV on the filter is lysed directly by adding lysis buffer and transferred to an oligo(dT) immobilized microplate for mRNA isolation followed by cDNA synthesis and real time PCR. Under the optimized assay condition, our method provided comparable or even superior results to the standard ultracentrifugation method in terms of mRNA assay sensitivity, linearity, intra-assay reproducibility, and ease of use. The assay system was applied to quantification of kidney-specific mRNAs such as NPHN and PDCN (glomerular filtration), SLC12A1 (tubular absorption), UMOD and ALB (tubular secretion), and AQP2 (collecting duct water absorption). 12-hour urine samples were collected from four healthy subjects for two weeks, and day-to-day and individual-to-individual variations were investigated. Kidney-specific genes as well as control genes (GAPDH, ACTB, etc.) were successfully detected and confirmed their stable expressions through the two-week study period. In conclusion, this method is readily available to clinical studies of kidney diseases. PMID- 25275512 TI - Site-specific chemoenzymatic labeling of aerolysin enables the identification of new aerolysin receptors. AB - Aerolysin is a secreted bacterial toxin that perforates the plasma membrane of a target cell with lethal consequences. Previously explored native and epitope tagged forms of the toxin do not allow site-specific modification of the mature toxin with a probe of choice. We explore sortase-mediated transpeptidation reactions (sortagging) to install fluorophores and biotin at three distinct sites in aerolysin, without impairing binding of the toxin to the cell membrane and with minimal impact on toxicity. Using a version of aerolysin labeled with different fluorophores at two distinct sites we followed the fate of the C terminal peptide independently from the N-terminal part of the toxin, and show its loss in the course of intoxication. Making use of the biotinylated version of aerolysin, we identify mesothelin, urokinase plasminogen activator surface receptor (uPAR, CD87), glypican-1, and CD59 glycoprotein as aerolysin receptors, all predicted or known to be modified with a glycosylphosphatidylinositol anchor. The sortase-mediated reactions reported here can be readily extended to other pore forming proteins. PMID- 25275513 TI - HIV acquisition is associated with increased antimicrobial peptides and reduced HIV neutralizing IgA in the foreskin prepuce of uncircumcised men. AB - BACKGROUND: The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition. METHODS: To assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda. RESULTS: Participants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted OR = 0.31; 95% CI, 0.16-0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11-0.39). Levels of the alpha-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 log(n) pg/mL, P = 0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 log(n) pg/mL, P = 0.0002 and 0.013). CONCLUSIONS: This prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk. PMID- 25275514 TI - Contribution of the nos-pdt operon to virulence phenotypes in methicillin sensitive Staphylococcus aureus. AB - Nitric oxide (NO) is emerging as an important regulator of bacterial stress resistance, biofilm development, and virulence. One potential source of endogenous NO production in the pathogen Staphylococcus aureus is its NO-synthase (saNOS) enzyme, encoded by the nos gene. Although a role for saNOS in oxidative stress resistance, antibiotic resistance, and virulence has been recently described, insights into the regulation of nos expression and saNOS enzyme activity remain elusive. To this end, transcriptional analysis of the nos gene in S. aureus strain UAMS-1 was performed, which revealed that nos expression increases during low-oxygen growth and is growth-phase dependent. Furthermore, nos is co-transcribed with a downstream gene, designated pdt, which encodes a prephenate dehydratase (PDT) enzyme involved in phenylalanine biosynthesis. Deletion of pdt significantly impaired the ability of UAMS-1 to grow in chemically-defined media lacking phenylalanine, confirming the function of this enzyme. Bioinformatics analysis revealed that the operon organization of nos-pdt appears to be unique to the staphylococci. As described for other S. aureus nos mutants, inactivation of nos in UAMS-1 conferred sensitivity to oxidative stress, while deletion of pdt did not affect this phenotype. The nos mutant also displayed reduced virulence in a murine sepsis infection model, and increased carotenoid pigmentation when cultured on agar plates, both previously-undescribed nos mutant phenotypes. Utilizing the fluorescent stain 4-Amino-5-Methylamino 2',7'-Difluorofluorescein (DAF-FM) diacetate, decreased levels of intracellular NO/reactive nitrogen species (RNS) were detected in the nos mutant on agar plates. These results reinforce the important role of saNOS in S. aureus physiology and virulence, and have identified an in vitro growth condition under which saNOS activity appears to be upregulated. However, the significance of the operon organization of nos-pdt and potential relationship between these two enzymes remains to be elucidated. PMID- 25275515 TI - Mouse activity across time scales: fractal scenarios. AB - In this work we devise a classification of mouse activity patterns based on accelerometer data using Detrended Fluctuation Analysis. We use two characteristic mouse behavioural states as benchmarks in this study: waking in free activity and slowwave sleep (SWS). In both situations we find roughly the same pattern: for short time intervals we observe high correlation in activity--a typical 1/f complex pattern--while for large time intervals there is anti correlation. High correlation of short intervals (0.01 s to 2 s: waking state and 0.01 s to 0.1 s: SWS) is related to highly coordinated muscle activity. In the waking state we associate high correlation both to muscle activity and to mouse stereotyped movements (grooming, waking, etc.). On the other side, the observed anti-correlation over large time scales (30 s to 300 s: waking state and 0.3 s to 5 s: SWS) during SWS appears related to a feedback autonomic response. The transition from correlated regime at short scales to an anti-correlated regime at large scales during SWS is given by the respiratory cycle interval, while during the waking state this transition occurs at the time scale corresponding to the duration of the stereotyped mouse movements. Furthermore, we find that the waking state is characterized by longer time scales than SWS and by a softer transition from correlation to anticorrelation. Moreover, this soft transition in the waking state encompass a behavioural time scale window that gives rise to a multifractal pattern. We believe that the observed multifractality in mouse activity is formed by the integration of several stereotyped movements each one with a characteristic time correlation. Finally, we compare scaling properties of body acceleration fluctuation time series during sleep and wake periods for healthy mice. Interestingly, differences between sleep and wake in the scaling exponents are comparable to previous works regarding human heartbeat. Complementarily, the nature of these sleep-wake dynamics could lead to a better understanding of neuroautonomic regulation mechanisms. PMID- 25275516 TI - Public beliefs on antibiotics and symptoms of respiratory tract infections among rural and urban population in Poland: a questionnaire study. AB - INTRODUCTION: General public views and expectations around the use of antibiotics can influence general practitioners' antibiotic prescribing decisions. We set out to describe the knowledge, attitudes and beliefs about the use of antibiotics for respiratory tract infections in adults in Poland, and explore differences according to where people live in an urban-rural continuum. MATERIAL AND METHODS: Face to face survey among a stratified random sample of adults from the general population. RESULTS: 1,210 adults completed the questionnaire (87% response rate); 44.3% were rural; 57.9% were women. 49.4% of rural respondents and 44.4% of urban respondents had used an antibiotic in the last 2 years. Rural participants were less likely to agree with the statement "usually I know when I need an antibiotic," (53.5% vs. 61.3% respectively; p = 0.015) and reported that they would consult with a physician for a cough with yellow/green phlegm (69.2% vs. 74.9% respectively; p = 0.004), and were more likely to state that they would leave the decision about antibiotic prescribing to their doctor (87.5% vs. 85.6% respectively; p = 0.026). However, rural participants were more likely to believe that antibiotics accelerate recovery from sore throat (45.7% vs. 37.1% respectively; p = 0.017). Use of antibiotic in the last 2 years, level of education, number of children and awareness of the problem of developing antimicrobial resistance predicted accurate knowledge about antibiotic effectiveness. CONCLUSIONS: There were no major differences in beliefs about antibiotics between urban and rural responders, although rural responders were slightly less confident in their knowledge about antibiotics and self-reported greater use of antibiotics. Despite differences in the level of education between rural and urban responders, there were no significant differences in their knowledge about antibiotic effectiveness. PMID- 25275517 TI - Ego depletion impairs implicit learning. AB - Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent. PMID- 25275518 TI - Trainable high resolution melt curve machine learning classifier for large-scale reliable genotyping of sequence variants. AB - High resolution melt (HRM) is gaining considerable popularity as a simple and robust method for genotyping sequence variants. However, accurate genotyping of an unknown sample for which a large number of possible variants may exist will require an automated HRM curve identification method capable of comparing unknowns against a large cohort of known sequence variants. Herein, we describe a new method for automated HRM curve classification based on machine learning methods and learned tolerance for reaction condition deviations. We tested this method in silico through multiple cross-validations using curves generated from 9 different simulated experimental conditions to classify 92 known serotypes of Streptococcus pneumoniae and demonstrated over 99% accuracy with 8 training curves per serotype. In vitro verification of the algorithm was tested using sequence variants of a cancer-related gene and demonstrated 100% accuracy with 3 training curves per sequence variant. The machine learning algorithm enabled reliable, scalable, and automated HRM genotyping analysis with broad potential clinical and epidemiological applications. PMID- 25275519 TI - Cryptosporidium prevalence and risk factors among mothers and infants 0 to 6 months in rural and semi-rural Northwest Tanzania: a prospective cohort study. AB - BACKGROUND: Cryptosporidium epidemiology is poorly understood, but infection is suspected of contributing to childhood malnutrition and diarrhea-related mortality worldwide. METHODS/FINDINGS: A prospective cohort of 108 women and their infants in rural/semi-rural Tanzania were followed from delivery through six months. Cryptosporidium infection was determined in feces using modified Ziehl-Neelsen staining. Breastfeeding/infant feeding practices were queried and anthropometry measured. Maternal Cryptosporidium infection remained high throughout the study (monthly proportion = 44 to 63%). Infection did not differ during lactation or by HIV-serostatus, except that a greater proportion of HIV positive mothers were infected at Month 1. Infant Cryptosporidium infection remained undetected until Month 2 and uncommon through Month 3 however, by Month 6, 33% of infants were infected. There were no differences in infant infection by HIV-exposure. Overall, exclusive breastfeeding (EBF) was limited, but as the proportion of infants exclusively breastfed declined from 32% at Month 1 to 4% at Month 6, infant infection increased from 0% at Month 1 to 33% at Month 6. Maternal Cryptosporidium infection was associated with increased odds of infant infection (unadjusted OR = 3.18, 95% CI 1.01 to 9.99), while maternal hand washing prior to infant feeding was counterintuitively also associated with increased odds of infant infection (adjusted OR = 5.02, 95% CI = 1.11 to 22.78). CONCLUSIONS: Both mothers and infants living in this setting suffer a high burden of Cryptosporidium infection, and the timing of first infant infection coincides with changes in breastfeeding practices. It is unknown whether this is due to breastfeeding practices reducing pathogen exposure through avoidance of contaminated food/water consumption; and/or breast milk providing important protective immune factors. Without a Cryptosporidium vaccine, and facing considerable diagnostic challenges and ineffective treatment in young infants, minimizing the overall environmental burden (e.g. contaminated water) and particularly, maternal Cryptosporidium infection burden as a means to protect against early infant infection needs prioritization. PMID- 25275520 TI - An extract of pomegranate fruit and galangal rhizome increases the numbers of motile sperm: a prospective, randomised, controlled, double-blinded trial. AB - Pomegranate fruit (Punica granatum) and galangal (Alpinia galanga) have separately been shown to stimulate spermatogenesis and to increase sperm counts and motility in rodents. Within traditional medicine, pomegranate fruit has long been used to increase fertility, however studies on the effect on spermatogenesis in humans have never been published. With this study we investigated whether oral intake of tablets containing standardised amounts of extract of pomegranate fruit and powder of greater galangal rhizome (Punalpin) would increase the total number of motile spermatozoa. The study was designed as a prospective, randomized, controlled, double-blinded trial. Enrolment was based on the mean total number of motile spermatozoa of two ejaculates. The participants delivered an ejaculate after 4-8 days of tablet intake and two ejaculates just before they stopped taking the tablets. Seventy adult men with a semen quality not meeting the standards for commercial application at Nordic Cryobank, but without azoospermia, were included in the study. Participants were randomized to take tablets containing extract of pomegranate fruit (standardised with respect to punicalagin A+B, punicalin and ellagic acid) and freeze-dried rhizome of greater galangal (standardised with respect to 1'S-1'-acetoxychavicol acetate) or placebo on a daily basis for three months. Sixty-six participants completed the intervention (active treatment: n = 34; placebo: n = 32). After the intervention the total number of motile spermatozoa was increased in participants treated with plant extracts compared with the placebo group (p = 0.026). After three months of active treatment, the average total number of motile sperm increased by 62% (from 23.4 to 37.8 millions), while for the placebo group, the number of motile sperm increased by 20%. Sperm morphology was not affected by the treatment. Our findings may help subfertile men to gain an improved amount of motile ejaculated sperm by taking tablets containing preparations of pomegranate fruit extract and rhizome of greater galangal. TRIAL REGISTRATION: ClinicalTrials.gov NCT01357044. PMID- 25275522 TI - Social priming increases nonverbal expressive behaviors in schizophrenia. AB - Semantic priming tasks are classically used to influence and implicitly promote target behaviors. Recently, several studies have demonstrated that prosocial semantic priming modulated feelings of social affiliation. The main aim of this study was to determine whether inducing feelings of social affiliation using priming tasks could modulate nonverbal social behaviors in schizophrenia. We used the Scrambled Sentence Task to prime schizophrenia patients according to three priming group conditions: pro-social, non-social or anti-social. Forty-five schizophrenia patients, diagnosed according to DSM-IV-TR, were randomly assigned to one of the three priming groups of 15 participants. We evaluated nonverbal social behaviors using the Motor-Affective subscale of the Motor-Affective-Social Scale. Results showed that schizophrenia patients with pro-social priming had significantly more nonverbal behaviors than schizophrenia patients with anti social and non-social priming conditions. Schizophrenia patient behaviors are affected by social priming. Our results have several clinical implications for the rehabilitation of social skills impairments frequently encountered among individuals with schizophrenia. PMID- 25275521 TI - Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex. AB - Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of beclin 1 causes a disruption of active Rab5 GTPase associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or beclin 1, but not by a coiled-coil domain-truncated beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-beclin 1 interaction underlies beclin 1's function in endocytosis. PMID- 25275523 TI - A reappraisal of how to build modular, reusable models of biological systems. PMID- 25275524 TI - Detection and molecular characterization of Giardia duodenalis in children attending day care centers in Majadahonda, Madrid, Central Spain. AB - Infections by the protozoan enteroparasites Giardia duodenalis and Cryptosporidium spp are a major cause of morbidity in children attending day care facilities in developed countries. In this cross-sectional study, we aimed to estimate the occurrence and genotype frequencies of these pathogens in children attending day care centers in Majadahonda, Central Spain. To do so, single stool samples were obtained from 90 children and tested for the presence of G duodenalis and Cryptosporidium spp by conventional microscopy and immunochromatography. Positive results by these techniques were subsequently confirmed by immunofluorescence microscopy. G duodenalis-positive samples were subjected to molecular characterization studies by multilocus sequence-based genotyping of the glutamate dehydrogenase and beta-giardin genes of the parasite. G duodenalis assemblages were confirmed by restriction fragment length polymorphism analyses and sequencing. A socioepidemiological questionnaire was used to identify variables potentially associated with giardiasis/cryptosporidiosis in the population of children under investigation. Overall, G duodenalis and Cryptosporidium spp were detected in 15.5% and 3.3% of stool samples, respectively. Giardiasis and cryptosporidiosis were found in 3/3 and 2/3 day care centers, respectively, affecting mainly infants aged 13 to 24 months. A total of 8 G duodenalis isolates were confirmed as subassemblage BIV, all of them belonging to asymptomatic children. Attempts to genotype Cryptosporidium isolates failed. None of the variables considered could be associated with higher risk of infection with giardiasis or cryptosporidiosis. These results clearly indicate that asymptomatic infections with G duodenalis and Cryptosporidium spp are frequent in <3-year-old children in Central Spain. PMID- 25275525 TI - Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization. AB - Renal oncocytoma is a benign tumor with characteristic histologic findings. We describe an oncocytoma-like renal tumor with progression to high-grade oncocytic carcinoma and metastasis. A 74-year-old man with no family history of cancer presented with hematuria. Computed tomography showed an 11 cm heterogeneous multilobulated mass in the right kidney lower pole, enlarged aortocaval lymph nodes, and multiple lung nodules. In the nephrectomy specimen, approximately one third of the renal tumor histologically showed regions classic for benign oncocytoma transitioning to regions of high-grade carcinoma without sharp demarcation. With extensive genomic investigation using single nucleotide polymorphism-based array virtual karyotyping, multiregion sequencing, and expression array analysis, we were able to show a common lineage between the benign oncocytoma and high-grade oncocytic carcinoma regions in the tumor. We were also able to show karyotypic differences underlying this progression. The benign oncocytoma showed no chromosomal aberrations, whereas the high-grade oncocytic carcinoma showed loss of the 17p region housing FLCN (folliculin [Birt Hogg-Dube protein]), loss of 8p, and gain of 8q. Gene expression patterns supported dysregulation and activation of phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt), mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathways in the high-grade oncocytic carcinoma regions. This was partly attributable to FLCN underexpression but further accentuated by overexpression of numerous genes on 8q. In the high-grade oncocytic carcinoma region, vascular endothelial growth factor A along with metalloproteinases matrix metallopeptidase 9 and matrix metallopeptidase 12 were overexpressed, facilitating angiogenesis and invasiveness. Genetic molecular testing provided evidence for the development of an aggressive oncocytic carcinoma from an oncocytoma, leading to aggressive targeted treatment but eventual death 39 months after the diagnosis. PMID- 25275526 TI - Imaging diagnosis for left ventricular thrombosis in idiopathic hypereosinophilic syndrome: two case reports. AB - Idiopathic hypereosinophilic syndrome (IHES) is a rare disease that is frequently associated with cardiac thrombosis and endocardial wall thickness. This case report describes 2 patients who had IHES associated with left ventricular (LV) thrombi. The patients' symptoms are atypical. Peripheral blood and bone marrow tests showed markedly elevated eosinophils. Electrocardiography showed ischemic changes in both patients. Negative computed tomography (CT) angiography excluded coronary artery stenosis. Transthoracic echocardiography (TTE), conventional multislice spiral CT, gemstone spectral CT, and cardiac magnetic resonance imaging were used to identify the LV intraluminal thrombus and endocardial thickening, and the diagnostic values of each imaging method were analyzed and compared. These patients were clinically diagnosed as "IHES, LV thrombosis, NYHA heart function classification I." Both patients received oral prednisone and warfarin therapy. At 5 month follow-up, TTE rechecks showed that the size of the LV thrombotic lesion was reduced in the first case but substantially increased in the second case. PMID- 25275527 TI - Comparison of the interferon-gamma release assay with the traditional methods for detecting Mycobacterium tuberculosis infection in children. AB - The purpose of the article is to compare the whole blood interferon-gamma release assay (IGRA) with the traditional methods for detecting Mycobacterium tuberculosis (MTB) infection in children. Fifteen childhood patients with tuberculosis and 15 healthy children were recruited. Sputa samples and venous blood were collected, and according to different procedures, IGRA, sputum smear, colloidal gold assay (CGA), fluorescence quantitation polymerase chain reaction (FQ-PCR), and tuberculosis skin test (TST) were, respectively, performed. Thirty healthy children vaccinated with Bacillus Calmette-Guerin (BCG) were also recruited, and the comparative test was carried out between IGRA and TST. In all of 15 childhood patients with TB, the positive rates were 86.7%, 20.0%, 26.7%, 40%, and 66.7% in IGRA, sputum smear, CGA, FQ-PCR, and TST, respectively. In the children vaccinated with BCG, the positive rate of IGRA was significantly lower than that of TST (6.7% vs 76.7%). From high to low, the specificities of the five methods were sputum smear (100%), IGRA (86.7%), FQ-PCR (86.7%), TST (40%), and CGA (26.7%). Although the specificities of sputum smear and FQ-PCR were more than or equal to that of IGRA, the relative sensitivities limited their applications in populations of children. IGRA is a sensitive and specific method, and could be taken as a first choice for detecting MTB infection in populations of children. PMID- 25275528 TI - Ectopic osteogenesis of macroscopic tissue constructs assembled from human mesenchymal stem cell-laden microcarriers through in vitro perfusion culture. AB - We had previously demonstrated the feasibility of preparing a centimeter-sized bone tissue construct by following a modular approach. In the present study, the objectives were to evaluate osteogenesis and tissue formation of human amniotic mesenchymal stem cells-laden CultiSpher S microcarriers during in vitro perfusion culture and after subcutaneous implantation. Microtissues were prepared in dynamic culture using spinner flasks in 28 days. In comparison with 1-week perfusion culture, microtissues became more obviously fused, demonstrating significantly higher cellularity, metabolic activity, ALP activity and calcium content while maintaining cell viability after 2-week perfusion. After subcutaneous implantation in nude mice for 6 and 12 weeks, all explants showed tight contexture, suggesting profound tissue remodeling in vivo. In addition, 12 week implantation resulted in slightly better tissue properties. However, in vitro perfusion culture time exerted great influence on the properties of corresponding explants. Degradation of microcarriers was more pronounced in the explants of 2-week perfused macrotissues compared to those of 1-week perfusion and directly implanted microtissues. Moreover, more blood vessel infiltration and bone matrix deposition with homogeneous spatial distribution were found in the explants of 2-week perfused macrotissues. Taken together, in vitro perfusion culture time is critical in engineering bone tissue replacements using such a modular approach, which holds great promise for bone regeneration. PMID- 25275530 TI - Glaucoma, Alzheimer's disease, and Parkinson's disease: an 8-year population based follow-up study. AB - BACKGROUND: Glaucoma is the leading cause of irreversible blindness worldwide and primary open-angle glaucoma (POAG) is the most common type of glaucoma. An association between POAG and the subsequent risk of Alzheimer's disease (AD) and Parkinson's disease (PD) was unclear. OBJECTIVE: To investigate the association between POAG (including normal-tension glaucoma) and the subsequent risk of AD or PD 8 years following a diagnosis of POAG. METHODS: We performed a retrospective, propensity-score-matched analysis of a population-based cohort consisting of patients with and without POAG aged 60 years and older. Control patients without POAG were propensity-score matched to POAG patients based on their baseline characteristics. RESULTS: The incidence rates and confidence intervals (CIs) of AD among the patients with and without POAG were 2.85 (95% CI: 2.19-3.70) and 1.98 (95% CI: 1.68-2.31) per 1000 person-years, respectively. The incidence rates of PD among the POAG and non-POAG cohorts were 4.36 (95% CI: 3.52-5.39) and 4.37 (95% CI: 3.92-4.86) per 1000 person-years, respectively. Kaplan-Meier failure curves showed that the POAG patients had a higher risk of AD than the control patients did (log-rank test, P= .0189). However, the cumulative PD hazard ratios for the POAG and non-POAG patients did not differ significantly (log-rank test, P= .9953). CONCLUSION: In elderly patients, POAG is a significant predictor of AD, but POAG is not a predictor of PD. PMID- 25275529 TI - Hyperoxygenation attenuated a murine model of atopic dermatitis through raising skin level of ROS. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from excessive stimulation of immune cells. Traditionally, reactive oxygen species (ROS) have been implicated in the progression of inflammatory diseases, but several opposing observations suggest the protective role of ROS in inflammatory disease. Recently, we demonstrated ROS prevented imiquimod-induced psoriatic dermatitis through enhancing regulatory T cell function. Thus, we hypothesized AD might also be attenuated in elevated levels of ROS through tissue hyperoxygenation, such as by hyperbaric oxygen therapy (HBOT) or applying an oxygen-carrying chemical, perfluorodecalin (PFD). Elevated levels of ROS in the skin have been demonstrated directly by staining with dihydroethidum as well as indirectly by immunohistochemistry (IHC) for indoleamine 2,3-dioxygenase (IDO). A murine model of AD was developed by repeated application of a chemical irritant (1% 2,4-dinitrochlorobenzene) and house dust mite (Dermatophagoide farinae) extract on one ear of BALB/c mice. The results showed treatment with HBOT or PFD significantly attenuated AD, comparably with 0.1% prednicarbate without any signs of side effects, such as telangiectasia. The expressions of interleukin-17A and interferon-gamma were also decreased in the AD lesions by treatment with HBOT or PFD. Enhanced expression of IDO and reduced level of hypoxia-inducible factor 1alpha, in association with increased frequency of FoxP3+ regulatory T cells in the AD lesions, might be involved in the underlying mechanism of oxygen therapy. Taken together, it was suggested that tissue hyperoxygenation, by HBOT or treatment with PFD, might attenuate AD through enhancing skin ROS level. PMID- 25275531 TI - Leishmania specific CD4 T cells release IFNgamma that limits parasite replication in patients with visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is associated with increased circulating levels of multiple pro-inflammatory cytokines and chemokines, including IL-12, IFNgamma, and TNFalpha, and elevated expression of IFNgamma mRNA in lesional tissue such as the spleen and bone marrow. However, an immunological feature of VL patients is that their peripheral blood mononuclear cells (PBMCs) typically fail to respond to stimulation with leishmanial antigen. Unexpectedly, it was recently shown that Leishmania specific IFNgamma, can readily be detected when a whole blood stimulation assay (WBA) is used. We sought to define the conditions that permit whole blood cells to respond to antigen stimulation, and clarify the biological role of the IFNgamma found to be released by cells from VL patients. CD4+ T cells were found to be crucial for and the main source of the IFNgamma production in Leishmania stimulated whole blood (WB) cultures. Complement, antibodies and red blood cells present in whole blood do not play a significant role in the IFNgamma response. The IFNgamma production was reduced by blockade of human leukocyte antigen (HLA)-DR, indicating that the response to leishmanial antigens observed in WB of active VL patients is a classical HLA- T cell receptor (TCR) driven reaction. Most importantly, blockade of IFNgamma in ex-vivo splenic aspirate cultures demonstrated that despite the progressive nature of their disease, the endogenous IFNgamma produced in patients with active VL serves to limit parasite growth. PMID- 25275532 TI - Genetic diversity and evolution of satellite RNAs associated with the bamboo mosaic virus. AB - Satellite RNAs (satRNAs) are subviral agents that depend on cognate helper viruses for genome replication and encapsidation. Their negative impacts on helper viruses have been exploited to control plant viral diseases. SatBaMV is a commonly found satRNA associated with Bamboo mosaic virus (BaMV) that infects diverse bamboo species in the field. To investigate the genetic diversity and evolution of satRNAs, we examined seven satBaMV populations derived from five bamboo species and cultivars from Taiwan, China, and India and one from the greenhouse. We found 3 distinct clades among the seven populations. Clade I is consisted of all satBaMV isolates, except for those from Dendrocalamus latiflorus in Taiwan and Bambusa vulgaris in India, which belong to Clades II and III, respectively. Interestingly, nucleotide diversity was lower for Clade I than II and III. However, the nucleotide diversity did not seem to depend on bamboo species or geographic location. Our population genetic analyses revealed the presence of excessive low-frequency polymorphic sites, which suggests that the satBaMV population was under purifying selection and/or population expansion. Further analysis of P20, the only satBaMV gene that encodes a non-structural protein involved in the long-distance movement of satBaMV, showed evidence of purifying selection. Taken together, our results suggest that purifying selection against defective P20 protein is responsible at least in part for the evolution of the satBaMV genome. PMID- 25275535 TI - Iron bioavailability in two commercial cultivars of wheat: comparison between wholegrain and white flour and the effects of nicotianamine and 2'-deoxymugineic acid on iron uptake into Caco-2 cells. AB - Iron bioavailability in unleavened white and wholegrain bread made from two commercial wheat varieties was assessed by measuring ferritin production in Caco 2 cells. The breads were subjected to simulated gastrointestinal digestion and the digests applied to the Caco-2 cells. Although Riband grain contained a lower iron concentration than Rialto, iron bioavailability was higher. No iron was taken up by the cells from white bread made from Rialto flour or from wholegrain bread from either variety, but Riband white bread produced a small ferritin response. The results probably relate to differences in phytate content of the breads, although iron in soluble monoferric phytate was demonstrated to be bioavailable in the cell model. Nicotianamine, an iron chelator in plants involved in iron transport, was a more potent enhancer of iron uptake into Caco-2 cells than ascorbic acid or 2'-deoxymugineic acid, another metal chelator present in plants. PMID- 25275533 TI - Direct reprogramming of Huntington's disease patient fibroblasts into neuron-like cells leads to abnormal neurite outgrowth, increased cell death, and aggregate formation. AB - Recent advances in trans-differentiation of one type cell to another have made it possible to directly convert Huntington's disease (HD) patient fibroblasts into neurons by modulation of cell-lineage-specific transcription factors or RNA processing. However, this possibility has not been examined. Here, we demonstrate that HD patient-derived fibroblasts can be directly trans-differentiated into neuron-like cells by knockdown of the expression of a single gene encoding the polypyrimidine-tract-binding protein. The directly converted HD neuron-like cells were positive in expression of Tuj1, NeuN, DARPP-32, and gamma-aminobutyric acid and exhibited neuritic breakdown, abnormal neuritic branching, increased cell death, and aggregation of mutant huntingtin. These observations indicate that the neuron-like cells directly converted from HD patient fibroblasts recapitulate the major aspects of neuropathological characteristics of HD and thus provide an additional model for understanding the disorder and validation of therapeutic reagents. PMID- 25275536 TI - Modeling the effect of intra-voxel diffusion of contrast agent on the quantitative analysis of dynamic contrast enhanced magnetic resonance imaging. AB - Quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides estimates of physiologically relevant parameters related to tissue blood flow, vascular permeability, and tissue volume fractions which can then be used for prognostic and diagnostic reasons. However, standard techniques for DCE-MRI analysis ignore intra-voxel diffusion, which may play an important role in contrast agent distribution and voxel signal intensity and, thus, will affect quantification of the aforementioned parameters. To investigate the effect of intra-voxel diffusion on quantitative DCE-MRI, we developed a finite element model of contrast enhancement at the voxel level. For diffusion in the range of that expected for gadolinium chelates in tissue (i.e., 1 * 10(-4) to 4 * 10(-4) mm(2)/s), parameterization errors range from -58% to 12% for K(trans), -9% to 8% for ve, and -60% to 213% for vp over the range of K(trans), v(e), v(p), and temporal resolutions investigated. Thus the results show that diffusion has a significant effect on parameterization using standard techniques. PMID- 25275537 TI - 45 Years of Simultaneous Le Fort III and Le Fort I Osteotomies: A Systematic Literature Review. AB - OBJECTIVE: To review and collectively summarize our knowledge of simultaneous Le Fort III and Le Fort I osteotomies. DESIGN: A PubMed search using "Le Fort III," "simultaneous Le Fort III and Le Fort I," "combined Le Fort III and Le Fort I," "dual midface," and "segmental midface" was performed. Articles with relevant abstracts were obtained for formal review. A new case of simultaneous Le Fort III and Le Fort I is presented to describe and discuss specific operative indications and surgical decisions. RESULTS: There were 14 articles that met inclusion criteria with reports of simultaneous Le Fort III and Le Fort I osteotomies. A total of 20 cases were present in the literature. No major complications were reported. We performed combined Le Fort III with Le Fort I osteotomies in a 25 year-old patient with Crouzon syndrome who had undergone a previous Le Fort III at the age of 4 years. The patient tolerated the procedure well, and postoperatively, her exophthalmos and class III malocclusion were corrected. CONCLUSIONS: Simultaneous Le Fort III and Le Fort I can correct differential upper and lower midface hypoplasia and is a well-tolerated procedure in the mature facial skeleton. This systematic review improves our understanding of the surgical technique and indications for a procedure that can correct complex midfacial deformities. PMID- 25275534 TI - Use of a novel chagas urine nanoparticle test (chunap) for diagnosis of congenital chagas disease. AB - BACKGROUND: Detection of congenital T. cruzi transmission is considered one of the pillars of control programs of Chagas disease. Congenital transmission accounts for 25% of new infections with an estimated 15,000 infected infants per year. Current programs to detect congenital Chagas disease in Latin America utilize microscopy early in life and serology after 6 months. These programs suffer from low sensitivity by microscopy and high loss to follow-up later in infancy. We developed a Chagas urine nanoparticle test (Chunap) to concentrate, preserve and detect T. cruzi antigens in urine for early, non-invasive diagnosis of congenital Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: This is a proof-of concept study of Chunap for the early diagnosis of congenital Chagas disease. Poly N-isopropylacrylamide nano-particles functionalized with trypan blue were synthesized by precipitation polymerization and characterized with photon correlation spectroscopy. We evaluated the ability of the nanoparticles to capture, concentrate and preserve T. cruzi antigens. Urine samples from congenitally infected and uninfected infants were then concentrated using these nanoparticles. The antigens were eluted and detected by Western Blot using a monoclonal antibody against T. cruzi lipophosphoglycan. The nanoparticles concentrate T. cruzi antigens by 100 fold (western blot detection limit decreased from 50 ng/ml to 0.5 ng/ml). The sensitivity of Chunap in a single specimen at one month of age was 91.3% (21/23, 95% CI: 71.92%-98.68%), comparable to PCR in two specimens at 0 and 1 month (91.3%) and significantly higher than microscopy in two specimens (34.8%, 95% CI: 16.42%-57.26%). Chunap specificity was 96.5% (71/74 endemic, 12/12 non-endemic specimens). Particle-sequestered T. cruzi antigens were protected from trypsin digestion. CONCLUSION/SIGNIFICANCE: Chunap has the potential to be developed into a simple and sensitive test for the early diagnosis of congenital Chagas disease. PMID- 25275538 TI - The 100 Most-Cited Human Cleft Lip and Palate-Related Articles Published in Dentistry, Oral Surgery, and Medicine Journals. AB - OBJECTIVE: To identify the 100 most-cited articles pertaining to human cleft lip and palate research published in dentistry, oral surgery, and medicine journals and to identify their principal bibliometric characteristics. DESIGN: Web-based bibliometric analysis. MAIN OUTCOME MEASURE: The Web of Science was searched to identify the 100 most-cited clinical articles related to cleft lip and/or palate. Information was extracted with regard to total number of citations, number of authors, affiliations, year, and journal of publication, Medical Subject Headings, type of study, specific area of study. Trends in citations were assessed. RESULTS: The 100 most-cited articles identified received between 437 and 58 citations. The oldest was published in 1954 and the most recent in 2008. The number of authors ranged from 1 to 12, with an average of three authors per article. Most of the first authors were affiliated with institutions in the United States, with the most prolific institution being the University of Iowa. More than 70% of the studies appeared in The Cleft Palate-Craniofacial Journal. There was a significant negative correlation between average citations per year and time since publication (P < .001); whereas, a significant positive correlation was observed between average citations per year and number of total citations (P < .001). CONCLUSIONS: The 100 most-cited articles in human cleft lip and palate research published in dentistry, oral surgery, and medicine journals are listed and characterized. This can be used as a potential knowledge base for specialists in training or to produce relevant knowledge defining the direction of future research. PMID- 25275539 TI - Abnormal Variations in the Facial Soft Tissues of Individuals With Down Syndrome: Sudan Versus Italy. AB - OBJECTIVE: To provide quantitative information about the facial soft tissue of Italian and Northern Sudanese subjects with Down syndrome by using summary anthropometric measurements. DESIGN, SETTING, AND PATIENTS: The three-dimensional coordinates of soft tissue facial landmarks were obtained using a computerized digitizer in 54 Italian subjects with Down syndrome (20 females and 34 males, 13 to 52 years), in 64 Northern Sudanese subjects with Down syndrome (18 females and 46 males, 5 to 34 years), and in 578 Italian and 653 Northern Sudanese reference subjects, matched for sex and age. From the landmarks, 16 facial dimensions were calculated. Data from subjects with Down syndrome were compared with those collected from control individuals by computing z scores. Two summary anthropometric measurements for quantifying craniofacial variations were obtained: the mean z score (an index of overall facial size) and its standard deviation, the craniofacial variability index (an index of facial harmony). RESULTS: In subjects with Down syndrome, facial size was significantly smaller and craniofacial variability was significantly greater than in typically developed individuals; 93% of Italian and 81% of Northern Sudanese subjects with Down syndrome had one or both values outside the normal interval. Overall, Italian subjects with Down syndrome differed more from the norm than did those from Northern Sudan. In the Northern Sudanese subjects, the mean z scores and the craniofacial variability index were significantly influenced by age: Older Northern Sudanese subjects with Down syndrome had smaller mean z scores and craniofacial variability index values than younger subjects. CONCLUSIONS: The two ethnic groups had different alterations in their soft tissue facial dimensions that were partially influenced by age. PMID- 25275540 TI - Premaxillary Distraction Osteogenesis Using an Intraoral Appliance for Unilateral Cleft Lip and Palate: Case Report. AB - OBJECTIVE: Premaxillary distraction osteogenesis was introduced using intraoral devices to correct maxillary hypoplasia and lengthen the alveolar bone horizontally in a patient with unilateral cleft lip and palate. METHODS: For premaxillary distraction osteogenesis, Le Fort I osteotomy was performed. Vertical osteotomy lines were located distally of the upper right canine and left first premolar to separate the anterior segment of the maxilla. After a 7-day latency period, distraction was allowed to continue for 20 days at a rate of 0.5 mm/d, followed by a 3-month consolidation period. After consolidation, orthodontic treatment and bilateral intraoral vertical ramus osteotomy were performed for the mandibular setback. The implant and prosthodontic treatments were applied to the alveolar ridge area created by the distraction osteogenesis. RESULTS: The A-point moved 8.0 mm forward during the distraction osteogenesis period, and the recurrence rate was 25% after the retention period. The transverse dimension of the upper arch was expanded during orthodontic treatment. The quality of the alveolar bone created by distraction osteogenesis was acceptable for the prosthodontic implant. CONCLUSIONS: Premaxillary distraction osteogenesis and arch expansion is an effective treatment strategy, improving function, aesthetics, and stability for cleft patients with multiple missing teeth. PMID- 25275541 TI - Characterization of uncultivable bat influenza virus using a replicative synthetic virus. AB - Bats harbor many viruses, which are periodically transmitted to humans resulting in outbreaks of disease (e.g., Ebola, SARS-CoV). Recently, influenza virus-like sequences were identified in bats; however, the viruses could not be cultured. This discovery aroused great interest in understanding the evolutionary history and pandemic potential of bat-influenza. Using synthetic genomics, we were unable to rescue the wild type bat virus, but could rescue a modified bat-influenza virus that had the HA and NA coding regions replaced with those of A/PR/8/1934 (H1N1). This modified bat-influenza virus replicated efficiently in vitro and in mice, resulting in severe disease. Additional studies using a bat-influenza virus that had the HA and NA of A/swine/Texas/4199-2/1998 (H3N2) showed that the PR8 HA and NA contributed to the pathogenicity in mice. Unlike other influenza viruses, engineering truncations hypothesized to reduce interferon antagonism into the NS1 protein didn't attenuate bat-influenza. In contrast, substitution of a putative virulence mutation from the bat-influenza PB2 significantly attenuated the virus in mice and introduction of a putative virulence mutation increased its pathogenicity. Mini-genome replication studies and virus reassortment experiments demonstrated that bat-influenza has very limited genetic and protein compatibility with Type A or Type B influenza viruses, yet it readily reassorts with another divergent bat-influenza virus, suggesting that the bat-influenza lineage may represent a new Genus/Species within the Orthomyxoviridae family. Collectively, our data indicate that the bat-influenza viruses recently identified are authentic viruses that pose little, if any, pandemic threat to humans; however, they provide new insights into the evolution and basic biology of influenza viruses. PMID- 25275544 TI - Membrane topology and cellular dynamics of foot-and-mouth disease virus 3A protein. AB - Foot-and-mouth disease virus non-structural protein 3A plays important roles in virus replication, virulence and host-range; nevertheless little is known on the interactions that this protein can establish with different cell components. In this work, we have performed in vivo dynamic studies from cells transiently expressing the green fluorescent protein (GFP) fused to the complete 3A (GFP3A) and versions including different 3A mutations. The results revealed the presence of a mobile fraction of GFP3A, which was found increased in most of the mutants analyzed, and the location of 3A in a continuous compartment in the cytoplasm. A dual behavior was also observed for GFP3A upon cell fractionation, being the protein equally recovered from the cytosolic and membrane fractions, a ratio that was also observed when the insoluble fraction was further fractioned, even in the presence of detergent. Similar results were observed in the fractionation of GFP3ABBB, a 3A protein precursor required for initiating RNA replication. A nonintegral membrane protein topology of FMDV 3A was supported by the lack of glycosylation of versions of 3A in which each of the protein termini was fused to a glycosylation acceptor tag, as well as by their accessibility to degradation by proteases. According to this model 3A would interact with membranes through its central hydrophobic region exposing its N- and C- termini to the cytosol, where interactions between viral and cellular proteins required for virus replication are expected to occur. PMID- 25275546 TI - Testing a better method of predicting postsurgery soft tissue response in Class II patients: A prospective study and validity assessment. AB - OBJECTIVE: (1) To perform a prospective study using a new set of data to test the validity of a new soft tissue prediction method developed for Class II surgery patients and (2) to propose a better validation method that can be applied to a validation study. MATERIALS AND METHODS: Subjects were composed of two subgroups: training subjects and validation subjects. Eighty Class II surgery patients provided the training data set that was used to build the prediction algorithm. The validation data set of 34 new patients was used for evaluating the prospective performance of the prediction algorithm. The validation was conducted using four validation methods: (1) simple validation and (2) fivefold, (3) 10 fold, and (4) leave-one-out cross-validation (LOO). RESULTS: The characteristics between the training and validation subjects did not differ. The multivariate partial least squares regression returned more accurate prediction results than the conventional method did. During the prospective validation, all of the cross validation methods (fivefold, 10-fold, and LOO) demonstrated fewer prediction errors and more stable results than the simple validation method did. No significant difference was noted among the three cross-validation methods themselves. CONCLUSION: After conducting a prospective study using a new data set, this new prediction method again performed well. In addition, a cross validation technique may be considered a better option than simple validation when constructing a prediction algorithm. PMID- 25275545 TI - Adiponectin abates atherosclerosis by reducing oxidative stress. AB - BACKGROUND: We investigated whether the anti-atherosclerosis of adiponectin (APN) relates to the reduction of oxidative stress. We observed the overexpression of adiponectin gene with different titers on atherosclerosis (AS) models of high-fat apolipoprotein E-deficient (ApoE-/-) mice. MATERIAL AND METHODS: We divided 48 male ApoE-/- mice into 4 groups: control group, high-fat diet group, low adiponectin group, and high adiponectin group. The low and high adiponectin group mice were treated with recombinant adenovirus expressing mice adiponectin (Ad APN) with low-dose adiponectin 1.0*108 p.f.u. and high-dose adiponectin 5.0*108 p.f.u. via the tail every 2 weeks and given a high-fat diet for the last 8 weeks. On the 14th day after injection, blood samples were obtained from the vena cava. RESULTS: Along with increased serum adiponectin, serum superoxide dismutase (SOD) activity increased (P<0.05) and concentration of malondialdehyde (MDA) was decreased (P<0.05). Levels of total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) were decreased, especially TC and LDL-C (P<0.05). A real-time fluorescent quantitative polymerase chain reaction test was used to analyze levels of mRNA expression for endothelial nitric oxide synthase (eNOS) and adiponectin in the aorta. Along with increased adiponectin, the mRNA expression of eNOS in the aorta was increased significantly (P<0.05). The lesion formation in the aortic sinus was inhibited by 25% and 31% in the low-APN group and high-APN group, respectively (P<0.05). Along with the increase of adiponectin doses, the damage of atherosclerosis gradually eased. However, the differences between the low-APN group and high-APN group had no statistical significance. CONCLUSIONS: Adiponectin may protect the aorta from atherosclerosis injury by reducing oxidative stress, reducing lesion formation size in the aortic root and reducing TC, TG, and LDL-C in serum. The molecular mechanism may involve preservation of SOD, reducing MDA in serum, and increasing eNOS and adiponectin mRNA expression in the aorta. PMID- 25275548 TI - Glutathione-S-transferase: a minor allergen in birch pollen due to limited release from hydrated pollen. AB - BACKGROUND: Recently, a protein homologous to glutathione-S-transferases (GST) was detected in prominent amounts in birch pollen by proteomic profiling. As members of the GST family are relevant allergens in mites, cockroach and fungi we investigated the allergenic relevance of GST from birch (bGST). METHODOLOGY: bGST was expressed in Escherichia coli, purified and characterized by mass spectrometry. Sera from 217 birch pollen-allergic patients were tested for IgE reactivity to bGST by ELISA. The mediator-releasing activity of bGST was analysed with IgE-loaded rat basophil leukaemia cells (RBL) expressing human FcepsilonRI. BALB/c mice were immunized with bGST or Bet v 1. Antibody and T cell responses to either protein were assessed. IgE-cross-reactivity between bGST with GST from house dust mite, Der p 8, was studied with murine and human sera in ELISA. The release kinetics of bGST and Bet v 1 from birch pollen were assessed in water, simulated lung fluid, 0.9% NaCl and PBS. Eluted proteins were quantified by ELISA and analysed by immunoblotting. PRINCIPLE FINDINGS: Only 13% of 217 birch pollen allergic patients showed IgE-reactivity to bGST. In RBL assays bGST induced mediator release. Immunization of mice with bGST induced specific IgE and a Th2 dominated cellular immune response comparably to immunization with Bet v 1. bGST did not cross-react with Der p 8. In contrast to Bet v 1, only low amounts of bGST were released from pollen grains upon incubation in water and the different physiological solutions. CONCLUSION/SIGNIFICANCE: Although bGST is abundant in birch pollen, immunogenic in mice and able to induce mediator release from effector cells passively loaded with specific IgE, it is a minor allergen for birch pollen-allergic patients. We refer this discrepancy to its limited release from hydrated pollen. Hence, bGST is an example demonstrating that allergenicity depends mainly on rapid elution from airborne particles. PMID- 25275547 TI - Maternal obesity and tobacco use modify the impact of genetic variants on the occurrence of conotruncal heart defects. AB - Conotruncal heart defects (CTDs) are among the most severe birth defects worldwide. Studies of CTDs indicate both lifestyle behaviors and genetic variation contribute to the risk of CTDs. Based on a hybrid design using data from 616 case-parental and 1645 control-parental triads recruited for the National Birth Defects Prevention Study between 1997 and 2008, we investigated whether the occurrence of CTDs is associated with interactions between 921 maternal and/or fetal single nucleotide polymorphisms (SNPs) and maternal obesity and tobacco use. The maternal genotypes of the variants in the glutamate-cysteine ligase, catalytic subunit (GCLC) gene and the fetal genotypes of the variants in the glutathione S-transferase alpha 3 (GSTA3) gene were associated with an elevated risk of CTDs among obese mothers. The risk of delivering infants with CTDs among obese mothers carrying AC genotype for a variant in the GCLC gene (rs6458939) was 2.00 times the risk among those carrying CC genotype (95% confidence interval: 1.41, 2.38). The maternal genotypes of several variants in the glutathione-S-transferase (GST) family of genes and the fetal genotypes of the variants in the GCLC gene interacted with tobacco exposures to increase the risk of CTDs. Our study suggests that the genetic basis underlying susceptibility of the developing heart to the adverse effects of maternal obesity and tobacco use involve both maternal and embryonic genetic variants. These results may provide insights into the underlying pathophysiology of CTDs, and ultimately lead to novel prevention strategies. PMID- 25275549 TI - Lack of a 5.9 kDa peptide C-terminal fragment of fibrinogen alpha chain precedes fibrosis progression in patients with liver disease. AB - Early detection of fibrosis progression is of major relevance for the diagnosis and management of patients with liver disease. This study was designed to find non-invasive biomarkers for fibrosis in a clinical context where this process occurs rapidly, HCV-positive patients who underwent liver transplantation (LT). We analyzed 93 LT patients with HCV recurrence, 41 non-LT patients with liver disease showing a fibrosis stage F>=1 and 9 patients without HCV recurrence who received antiviral treatment before LT, as control group. Blood obtained from 16 healthy subjects was also analyzed. Serum samples were fractionated by ion exchange chromatography and their proteomic profile was analyzed by SELDI-TOF-MS. Characterization of the peptide of interest was performed by ion chromatography and electrophoresis, followed by tandem mass spectrometry identification. Marked differences were observed between the serum proteome profile of LT patients with early fibrosis recurrence and non-recurrent LT patients. A robust peak intensity located at 5905 m/z was the distinguishing feature of non-recurrent LT patients. However, the same peak was barely detected in recurrent LT patients. Similar results were found when comparing samples of healthy subjects with those of non LT fibrotic patients, indicating that our findings were not related to either LT or HCV infection. Using tandem mass-spectrometry, we identified the protein peak as a C-terminal fragment of the fibrinogen alpha chain. Cell culture experiments demonstrated that TGF-beta reduces alpha-fibrinogen mRNA expression and 5905 m/z peak intensity in HepG2 cells, suggesting that TGF-beta activity regulates the circulating levels of this protein fragment. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen alpha chain as an early serum biomarker of fibrogenic processes in patients with liver disease. PMID- 25275550 TI - Monte Carlo study of radiation dose enhancement by gadolinium in megavoltage and high dose rate radiotherapy. AB - MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38+/-0.12, 1.39+/-0.21, 2.51+/-0.34, 3.59+/-0.26, and 4.59+/-0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09+/-0.14, 0.50+/-0.28, 1.19+/-0.29, 1.68+/-0.39, and 2.34+/-0.24. For Ir-192 with direct contact, the enhanced were 0.50+/-0.14, 2.79+/-0.17, 5.49+/-0.12, 8.19+/-0.14, and 10.80+/-0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed. PMID- 25275551 TI - A biological stone from a medieval cemetery in Poland. AB - A review of the literature shows that origination of biological stones as well as their pathogenesis mostly depend on the environmental factors. As a result, the structural spectrum of such calculi and their chemical composition are highly diversified. It is well known that biological stones are formed mostly in the digestive and urinary tracts. However, it has been demonstrated that this kind of stony structure can be also, though rarely, found in circulatory and reproductive systems, skin, mucosa, and tear ducts. Although in palaeopathology, the list of biological stones is enriched by stony tumours and/or discharges, it is very difficult to uncover the small size deposits in excavation material. In the literature such findings, originating from different countries and centuries, are few. The described stone was found among the bones of an adult individual in the medieval cemetery of Gdansk (Poland). The SEM, X-ray spectrometer and chemical evaluation revealed that it was a bladder calculus. PMID- 25275553 TI - Dose-response algorithms for water-borne Pseudomonas aeruginosa folliculitis. AB - We developed two dose-response algorithms for P. aeruginosa pool folliculitis using bacterial and lesion density estimates, associated with undetectable, significant, and almost certain folliculitis. Literature data were fitted to Furumoto & Mickey's equations, developed for plant epidermis-invading pathogens: N l = A ln(1 + BC) (log-linear model); P inf = 1-e(-r c C) (exponential model), where A and B are 2.51644 * 107 lesions/m2 and 2.28011 * 10-11 c.f.u./ml P. aeruginosa, respectively; C = pathogen density (c.f.u./ml), N l = folliculitis lesions/m2, P inf = probability of infection, and r C = 4.3 * 10-7 c.f.u./ml P. aeruginosa. Outbreak data indicates these algorithms apply to exposure durations of 41 +/- 25 min. Typical water quality benchmarks (~10-2 c.f.u./ml) appear conservative but still useful as the literature indicated repeated detection likely implies unstable control barriers and bacterial bloom potential. In future, culture-based outbreak testing should be supplemented with quantitative polymerase chain reaction and organic carbon assays, and quantification of folliculitis aetiology to better understand P. aeruginosa risks. PMID- 25275554 TI - Evaluation of the agronomic performance of atrazine-tolerant transgenic japonica rice parental lines for utilization in hybrid seed production. AB - Currently, the purity of hybrid seed is a crucial limiting factor when developing hybrid japonica rice (Oryza sativa L.). To chemically control hybrid seed purity, we transferred an improved atrazine chlorohydrolase gene (atzA) from Pseudomonas ADP into hybrid japonica parental lines (two maintainers, one restorer), and Nipponbare, by using Agrobacterium-mediated transformation. We subsequently selected several transgenic lines from each genotype by using PCR, RT-PCR, and germination analysis. In the presence of the investigated atrazine concentrations, particularly 150 uM atrazine, almost all of the transgenic lines produced significantly larger seedlings, with similar or higher germination percentages, than did the respective controls. Although the seedlings of transgenic lines were taller and gained more root biomass compared to the respective control plants, their growth was nevertheless inhibited by atrazine treatment compared to that without treatment. When grown in soil containing 2 mg/kg or 5 mg/kg atrazine, the transgenic lines were taller, and had higher total chlorophyll contents than did the respective controls; moreover, three of the strongest transgenic lines completely recovered after 45 days of growth. After treatment with 2 mg/kg or 5 mg/kg of atrazine, the atrazine residue remaining in the soil was 2.9-7.0% or 0.8-8.7% respectively, for transgenic lines, and 44.0 59.2% or 28.1-30.8%, respectively, for control plants. Spraying plants at the vegetative growth stage with 0.15% atrazine effectively killed control plants, but not transgenic lines. Our results indicate that transgenic atzA rice plants show tolerance to atrazine, and may be used as parental lines in future hybrid seed production. PMID- 25275555 TI - Types or modes of malingering? A confirmatory factor analysis of performance and symptom validity tests. AB - Recently, the dichotomy between performance validity tests (PVT) and symptom validity tests (SVT) has been suggested to differentiate between invalid performance and invalid self-report, respectively. PVTs are typically used to identify malingered cognitive impairment, while SVTs identify malingered psychological or somatic symptoms. It is assumed that people can malinger different types of problems, but the impact of modes of reporting invalidly has been largely unexplored. A mixed neurological sample (n = 130) was tested with the Test of Memory Malingering, the Forced Recognition part of the California Verbal Learning Test, and the self-report Structured Inventory of Malingered Symptoms (SIMS). Confirmatory factor analyses testing both method- and content based factor models found best fit for the method-based division. Regression analyses of other self-rating and performance-based tests provided further support for the importance of type of methods used to collect information. While acknowledging the types of symptoms malingered, the clinician is advised also to consider how information is gathered by using both PVTs and SVTs. SIMS is a good candidate for a stand-alone SVT, although the utility of the Low Intelligence subscale is questionable as a validity measure. PMID- 25275556 TI - GPR55 deletion in mice leads to age-related ventricular dysfunction and impaired adrenoceptor-mediated inotropic responses. AB - G protein coupled receptor 55 (GPR55) is expressed throughout the body, and although its exact physiological function is unknown, studies have suggested a role in the cardiovascular system. In particular, GPR55 has been proposed as mediating the haemodynamic effects of a number of atypical cannabinoid ligands; however this data is conflicting. Thus, given the incongruous nature of our understanding of the GPR55 receptor and the relative paucity of literature regarding its role in cardiovascular physiology, this study was carried out to examine the influence of GPR55 on cardiac function. Cardiac function was assessed via pressure volume loop analysis, and cardiac morphology/composition assessed via histological staining, in both wild-type (WT) and GPR55 knockout (GPR55(-/-)) mice. Pressure volume loop analysis revealed that basal cardiac function was similar in young WT and GPR55(-/-) mice. In contrast, mature GPR55(-/-) mice were characterised by both significant ventricular remodelling (reduced left ventricular wall thickness and increased collagen deposition) and systolic dysfunction when compared to age-matched WT mice. In particular, the load dependent parameter, ejection fraction, and the load-independent indices, end systolic pressure-volume relationship (ESPVR) and Emax, were all significantly (P<0.05) attenuated in mature GPR55(-/-) mice. Furthermore, GPR55(-/-) mice at all ages were characterised by a reduced contractile reserve. Our findings demonstrate that mice deficient in GPR55 exhibit maladaptive adrenergic signalling, as evidenced by the reduced contractile reserve. Furthermore, with age these mice are characterised by both significant adverse ventricular remodelling and systolic dysfunction. Taken together, this may suggest a role for GPR55 in the control of adrenergic signalling in the heart and potentially a role for this receptor in the pathogenesis of heart failure. PMID- 25275558 TI - Biothiols as chelators for preparation of N-(aminobutyl)-N (ethylisoluminol)/Cu(2+) complexes bifunctionalized gold nanoparticles and sensitive sensing of pyrophosphate ion. AB - In this work, chemiluminescence (CL) reagent and catalyst metal ion complexes bifunctionalized gold nanoparticles (BF-AuNPs) with high CL efficiency were synthesized via an improved synthesis strategy. Biothiols, such as cysteine (Cys), cysteinyl-glycine (Cys-Gly), homocysteine (Hcy), and glutathione (GSH), instead of 2-[bis[2-[carboxymethyl-[2-oxo-2-(2 sulfanylethylamino)ethyl]amino]ethyl]amino]acetic acid (DTDTPA), were used as new chelators. N-(aminobutyl)-N-(ethylisoluminol) (ABEI) was used as a model of CL reagents and Cu(2+) as a model of metal ion. In this strategy, biothiols were first grafted on the surface of ABEI-AuNPs by Au-S bond. Then, Cu(2+) was captured onto the surface of ABEI-AuNPs by the coordination reaction to form BF AuNPs. The CL intensity of Cu(2+)-Cys/ABEI-AuNPs was 1 order of magnitude higher than that of DTDTPA/Cu(2+)-ABEI-AuNPs synthesized by the previous work. Moreover, strong CL emission of Cu(2+)-Cys/ABEI-AuNPs was also observed in neutral pH conditions. In addition, the present BF-AuNPs synthesis method exhibited advantages over the previous method in CL efficiency, simplicity, and synthetic rate. Finally, by virtue of Cu(2+)-Cys/ABEI-AuNPs as a platform, a simple CL chemosensor for the sensitive and selective detection of pyrophosphate ion (PPi) was established based on the competitive coordination interactions of Cu(2+) between Cys and PPi. The method exhibited a wide detection range from 10 nM to 100 MUM, with a low detection limit of 3.6 nM. The chemosensor was successfully applied to the detection of PPi in human plasma samples. It is of great application potential in clinical analysis. This work reveals that BF-AuNPs could be used as ideal nanointerface for the development of novel analytical methods. PMID- 25275557 TI - Role of microRNA modulation in the interferon-alpha/ribavirin suppression of HIV 1 in vivo. AB - BACKGROUND: Interferon-alpha (IFN-alpha) treatment suppresses HIV-1 viremia and reduces the size of the HIV-1 latent reservoir. Therefore, investigation of the molecular and immunologic effects of IFN-alpha may provide insights that contribute to the development of novel prophylactic, therapeutic and curative strategies for HIV-1 infection. In this study, we hypothesized that microRNAs (miRNAs) contribute to the IFN-alpha-mediated suppression of HIV-1. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-alpha treatment on global miRNA expression profile, HIV 1 viremia, and potential regulatory networks between miRNAs and cell-intrinsic anti-HIV-1 host factors in vivo. METHODS: Global miRNA expression was examined in longitudinal PBMC samples obtained from seven HIV/HCV-coinfected, antiretroviral therapy-naive individuals before, during, and after pegylated interferon alpha/ribavirin therapy (IFN-alpha/RBV). We implemented novel hybrid computational-empirical approaches to characterize regulatory networks between miRNAs and anti-HIV-1 host restriction factors. RESULTS: miR-422a was the only miRNA significantly modulated by IFN-alpha/RBV in vivo (p<0.0001, paired t test; FDR<0.037). Our interactome mapping revealed extensive regulatory involvement of miR-422a in p53-dependent apoptotic and pyroptotic pathways. Based on sequence homology and inverse expression relationships, 29 unique miRNAs may regulate anti HIV-1 restriction factor expression in vivo. CONCLUSIONS: The specific reduction of miR-422a is associated with exogenous IFN-alpha treatment, and likely contributes to the IFN-alpha suppression of HIV-1 through the enhancement of anti HIV-1 restriction factor expression and regulation of genes involved in programmed cell death. Moreover, our regulatory network analysis presents additional candidate miRNAs that may be targeted to enhance anti-HIV-1 restriction factor expression in vivo. PMID- 25275560 TI - Changes in the metabolic profile of pregnant ewes to an acute feed restriction in late gestation. AB - AIM: To detect early changes in the metabolic profile of pregnant ewes subject to acute feed restriction at 130 days of gestation, and to establish indicators of risk for ovine pregnancy toxaemia (OPT) for diagnostic purposes. METHODS: Twenty Corriedale ewes with known mating dates, carrying a single fetus, were used. Ewes were maintained on meadow grasslands and at 130 days of gestation were randomly divided in two groups of 10 ewes. The control group had ad libitum access to pasture. Ewes in the restricted group were subjected to an acute feed restriction for a maximum of 144 hours (6 days), with free access to water. From the start (0 hours) until the end of feed restriction, blood samples were collected from all ewes to monitor concentrations of cortisol, non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BOHB) daily, and glucose in plasma every 6 hours; urinary pH was also measured. Every 6 hours the food restricted ewes were observed to detect clinical signs of OPT e.g. apathy, grinding teeth, empty chewing movements, head leaning against the wall, tachypnea and not drinking water. RESULTS: In food-restricted ewes, concentrations of glucose decreased and differed from control ewes from 54 to 90 hours (p<0.001), and 96 to 102 hours (p<0.05). Concentrations of BOHB, cortisol and NEFA increased following feed restriction and differed from control ewes after 48 to 144 hours (p<0.01). Eight of the 10 restricted ewes showed clinical signs of OPT after 102-132 hours. Mean concentrations of glucose, BOHB and cortisol differed between control and restricted ewes prior to the onset of clinical signs of OPT, after 48-96 hours of feed restriction (p<0.01). Mean gestational length, and time from birth to placental expulsion was not affected by the feed restriction. CONCLUSIONS: Our results suggest that concentrations of glucose, BOHB and cortisol in plasma may provide a precocious diagnosis of subclinical OPT, using values of 1.59 (SD 0.24) mmol/L, 2.26 (SD 1.03) mmol/L and 15.09 (SD 7.75) nmol/L, respectively. The identification of a potentially harmful metabolic imbalance could lead to the improvement of treatment success. PMID- 25275559 TI - The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR. AB - The apelin receptor (AR or APJ) is a class A (rhodopsin-like) G-protein-coupled receptor with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, apelin, induces diverse physiological effects including vasoconstriction and dilation, strengthening of heart muscle contractility, angiogenesis, and regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ELABELA, was identified as having a crucial role in zebrafish (Danio rerio) embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity, and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about the mechanisms of peptide-AR activation. Additional complexity arises from modulation of the AR by 2 endogenous peptide ligands, both with multiple bioactive isoforms of variable length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other G-protein-coupled receptors. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR. PMID- 25275563 TI - The horseshoe crab of the genus Limulus: living fossil or stabilomorph? AB - A new horseshoe crab species, Limulus darwini, is described from the uppermost Jurassic (ca. 148 Ma) near-shore sediments of the Kcynia Formation, central Poland. The only extant species Limulus polyphemus (Linnaeus) inhabits brackish marine, shallow water environments of the east coast of the United States. Here it is shown that there are no important morphological differences between the Kcynia Formation specimens and extant juvenile representatives of the genus Limulus. The palaeoecological setting inhabited by the new species and the trophic relationships of extant horseshoe crabs are discussed in an attempt to determine the potential range of food items ingested by these Mesozoic xiphosurans. In this paper we propose the adoption of a new term stabilomorphism, this being: an effect of a specific formula of adaptative strategy among organisms whose taxonomic status does not exceed genus-level. A high effectiveness of adaptation significantly reduces the need for differentiated phenotypic variants in response to environmental changes and provides for long term evolutionary success. PMID- 25275561 TI - The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells. AB - BACKGROUND: Statins have recently been highlighted for their pleiotropic actions distinct from cholesterol-lowering effects. Despite this interest, it is currently unknown whether statin therapy inhibits peritoneal dialysis (PD) related epithelial-mesenchymal transition (EMT). METHODS: In vitro, human peritoneal mesothelial cells (HPMCs) were exposed to 5.6 mM glucose (NG) or 100 mM glucose (HG) with or without simvastatin (1 uM). In vivo, PD catheters were inserted into 32 Sprague-Dawley rats, and saline (C, n = 16) or 4.25% peritoneal dialysis fluid (PDF) (PD, n = 16) was infused for 4 weeks. Eight rats from each group were treated with 5 mg/kg/day of simvastatin intraperitoneally. Changes in the protein expression of EMT markers such as E-cadherin, alpha-SMA, Snail, and fibronectin in HPMCs and the peritoneum were evaluated by Western blot analysis and immunofluorescence or immunohistochemical staining. We also explored whether activation of the mevalonate pathway and its downstream small GTPases were involved in dialysis-related peritoneal EMT and could be inhibited by statin treatment. RESULTS: Compared to NG cells, E-cadherin expression was significantly decreased, while alpha-SMA, Snail, and fibronectin expression were significantly increased in HPMCs exposed to HG, and these changes were abrogated by simvastatin (p<0.05). In addition, the cobblestone-like appearance of normal HPMCs was converted into a fibroblast-like morphology after HG treatment, which was reversed by simvastatin. These EMT-like changes were also observed in HPMCs treated with geranyl-geranyl pyrophosphate (5 uM). HG significantly increased the protein expression of RhoA and Rac1 in the membrane fractions, and these increases were ameliorated by simvastatin (p<0.05). In PD rats, E-cadherin in the peritoneum was significantly decreased, whereas alpha-SMA, Snail, and fibronectin expression were significantly increased (p<0.05) compared to C rats. The thickness of the mesothelial layer in the peritoneum were also significantly greater in PD rats than in C rats (p<0.05). These changes of the peritoneum in PD rats were significantly attenuated by simvastatin. CONCLUSION: This study demonstrated that PD-related EMT was mediated via the mevalonate pathway, and statin treatment inhibited the EMT changes in HG-treated HPMCs and PDF-stimulated PD rats. These findings suggest that statins may be a promising therapeutic strategy for preservation of peritoneal membrane integrity in long-term PD patients. PMID- 25275562 TI - Contribution of the community health volunteers in the control of Buruli ulcer in Benin. AB - BACKGROUND: Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. Usually BU begins as a painless nodule, plaque or edema, ultimately developing into an ulcer. The high number of patients presenting with ulcers in an advanced stage is striking. Such late presentation will complicate treatment and have long-term disabilities as a consequence. The disease is mainly endemic in West Africa. The primary strategy for control of this disease is early detection using community village volunteers. METHODOLOGY/PRINCIPAL FINDINGS: In this retrospective, observational study, information regarding Buruli ulcer patients that reported to one of the four BU centers in Benin between January 2008 and December 2010 was collected using the WHO/BU01 forms. Information used from these forms included general characteristics of the patient, the results of diagnostic tests, the presence of functional limitations at start of treatment, lesion size, patient delay and the referral system. The role of the different referral systems on the stage of disease at presentation in the hospital was analyzed by a logistic regression analysis. About a quarter of the patients (26.5%) were referred to the hospital by the community health volunteers. In our data set, patients referred to the hospital by community health volunteers appeared to be in an earlier stage of disease than patients referred by other methods, but after adjustment by the regression analysis for the health center, this effect could no longer be seen. The Polymerase Chain Reaction (PCR) for IS2404 positivity rate among patients referred by the community health volunteers was not systematically lower than in patients referred by other systems. CONCLUSIONS/SIGNIFICANCE: This study clarifies the role played by community health volunteers in Benin, and shows that they play an important role in the control of BU. PMID- 25275564 TI - Repair of intermediate-size nasal defects: a working algorithm. AB - IMPORTANCE: "Large" nasal defects are typically classified as larger than 1.5 cm. Within that group, however, there is a subset of patients with smaller nasal defects (1.5-2.5 cm) who are treated differently. This study examines the different methods that we have used in the reconstruction of such "intermediate size" nasal defects. OBJECTIVE: To review the treatment and outcomes of patients who have undergone reconstruction of intermediate-size nasal defects and to share our empirical algorithm. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective review at an academic university practice of all patients who had undergone reconstruction of intermediate-size (1.5-2.5 cm) nasal defects from January 1, 1999, to September 1, 2013. From these data, a working algorithm was derived. INTERVENTIONS: Nasal reconstruction of intermediate-size nasal defects. MAIN OUTCOMES AND MEASURES: Method of reconstruction was correlated with site and size of defects. Postoperative complications were reviewed. RESULTS: A total of 315 patients with nasal defects measuring 1.5 to 2.5 cm were identified. Of these, 199 patients (63.2%) had a defect in a single subunit, and 116 (37.8%) had involvement of a combination of subunits. Ninety-seven patients (30.8%) had local flaps, 94 patients (29.8%) had forehead flaps, 51 patients (16.2%) had full thickness skin grafts (FTSG), 40 (12.7%) had composite grafts, and 33 (10.5%) had melolabial flaps. The defects were categorized according to subunit locations. There was a pattern of reconstruction for each defect according to their site, size, and depth. Alar defects were mainly repaired with melolabial flaps (25 of 85 patients [29.4%]), or by composite grafts (24 of 85 patients [28.2%]). Nasal tip defects were mainly repaired using local flaps (28 of 69 patients [40.5%]), FTSG (19 of 69 patients [27.5%]), and forehead flaps (19 of 69 patients [27.5%]). The reconstruction of choice in dorsal and sidewall defects were local flaps and forehead flaps. There were 28 wound-related complications, such as pincushioning, dehiscence, and infection (incidence rate, 8.9%), and 4 cases of postoperative nasal obstruction (1.3%). CONCLUSIONS AND RELEVANCE: There is a paucity of literature on the subject of reconstruction of intermediate-size nasal defects. This algorithm is derived from our practice and offers the surgeon specific reconstructive options for consideration when facing nasal defects of 1.5 to 2.5 cm. The algorithm is based on subunits. PMID- 25275566 TI - Clinically stable type A aortic dissection: an unusual case. AB - Acute type A aortic dissection is a catastrophic situation, often accompanied by aortic regurgitation. A rarely described cause of aortic regurgitation, in this clinical scenario, is the prolapse of an intimal flap into the left ventricular outflow tract. We present here a case of acute type A aortic dissection with a circumferential intimal flap, prolapsing into the left ventricular outflow tract and causing massive aortic regurgitation. PMID- 25275565 TI - An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. AB - An inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea. We mapped a PN locus in Leonbergers to a 250 kb region on canine chromosome 16 (Praw = 1.16*10-10, Pgenome, corrected = 0.006) utilizing a high-density SNP array. Within this interval is the ARHGEF10 gene, a member of the rho family of GTPases known to be involved in neuronal growth and axonal migration, and implicated in human hypomyelination. ARHGEF10 sequencing identified a 10 bp deletion in affected dogs that removes four nucleotides from the 3'-end of exon 17 and six nucleotides from the 5'-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3'-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs. The overall clinical picture of PN in these breeds, and the effects of sex and heterozygosity of the ARHGEF10 deletion, are less clear due to the likely presence of other forms of PN with variable ages of onset and severity of clinical signs. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species. PMID- 25275568 TI - Support effect in oxide catalysis: methanol oxidation on vanadia/ceria. AB - Density functional theory is used for periodic models of monomeric vanadia species deposited on the CeO2(111) surface to study dissociative adsorption of methanol and its subsequent dehydrogenation to formaldehyde. Dispersion-corrected PBE+U calculations are performed and compared with HSE and B3LYP results. Dissociative adsorption of methanol at different sites on VO2.CeO2(111) is highly exothermic with adsorption energies of 1.8 to 1.9 eV (HSE+D). Two relevant pathways for desorption of formaldehyde are found with intrinsic barriers for the redox step of 1.0 and 1.4 eV (HSE+D). The calculated desorption temperatures (370 and 495 K) explain the peaks observed in temperature-programmed desorption experiments. Different sites of the supported catalyst system are involved in the two pathways: (i) methanol can chemisorb on the CeO2 surface filling a so-called pseudovacancy and the H atom is transferred to an V-O-Ce interphase bond or (ii) CH3OH may chemisorb at the V-O-Ce interphase bond and form a V-OCH3 species from which H is transferred to the ceria surface, providing evidence for true cooperativity. In both cases, ceria is directly involved in the redox process, as two electrons are accommodated in Ce f states forming two Ce(3+) ions whereas vanadium remains fully oxidized (V(5+)). PMID- 25275567 TI - Re-emergence of rabies in the Guangxi province of Southern China. AB - BACKGROUND: Human rabies cases in the Guangxi province of China decreased from 839 in 1982 to 24 in 1995, but subsequently underwent a sharp increase, and has since maintained a high level. METHODOLOGY/PRINCIPAL FINDINGS: 3,040 brain samples from normal dogs and cats were collected from 14 districts of Guangxi and assessed by RT-PCR. The brain samples showed an average rabies virus (RV) positivity rate of 3.26%, but reached 4.71% for the period Apr 2002 to Dec 2003. A total of 30 isolates were obtained from normal dogs and 28 isolates from rabid animals by the mouse inoculation test (MIT). Six representative group I and II RV isolates showed an LD50 of 10-5.35/ml to 10-6.19/ml. The reactivity of monoclonal antibodies (MAbs) to group I and II RV isolates from the Guangxi major epidemic showed that eight anti-G MAbs showed strong reactivity with isolates of group I and II with titers of >=10,000; however, the MAbs 9-6, 13-3 and 12-14 showed lower reactivity. Phylogenetic analysis based on the G gene demonstrated that the Guangxi RV isolates have similar topologies with strong bootstrap values and are closely bonded. Alignment of deduced amino acids revealed that the mature G protein has four substitutions A96S, L132F, N436S, and A447I specific to group I, and 13 substitutions T90M, Y168C, S204G, T249I, P253S, S289T, V332I, Q382H, V427I, L474P, R463K Q486H, and T487N specific to group II, coinciding with the phylogenetic analysis of the isolates. CONCLUSIONS: Re-emergence of human rabies has mainly occurred in rural areas of Guangxi since 1996. The human rabies incidence rate increased is related with RV positive rate of normal dogs. The Guangxi isolates tested showed a similar pathogenicity and antigenicity. The results of phylogenetic analysis coincide with that of alignment of deduced amino acids. PMID- 25275569 TI - Faecalibacterium prausnitzii inhibits interleukin-17 to ameliorate colorectal colitis in rats. AB - BACKGROUND AND AIMS: It has been shown that Faecalibacterium prausnitzii (F. prausnitzii), one of the dominant intestinal bacterial flora, may protect colonic mucosa against the development of inflammation and subsequent inflammatory bowel disease (IBD), with the underlying mechanisms being unclear. METHODS: The impacts of F. prausnitzii and its metabolites on IL-23/Th17/IL-17 pathway markers were determined in human monocytes and a rat model of colitis induced by 2,4,6 trinitrobenzene sulfonic acid. F. prausnitzii and its culture medium (containing complete metabolites) were used to treat the rats in vivo, as well as rat splenocytes and human monocytes in vitro. Inflammatory cytokines were measured in colon tissue, plasma and cell culture medium. RESULTS: The culture supernatant of F. prausnitzii increased plasma anti-Th17 cytokines (IL-10 and IL-12)and suppressed IL-17 levels in both plasma and colonic mucosa, with ameliorated colonic colitis lesions. This inhibition of IL-17 release has also been observed in both rat splenocytes and human venous monocytes in vitro. The culture supernatant of F. prausnitzii also suppressed Th17 cell differentiation induced by cytokines (TGF-beta and IL-6) and bone marrow-derived dendritic cells (BMDCs) in vitro. The metabolites of F. prausnitzii in the culture supernatant exert a stronger anti-inflammatory effect than the bacterium itself. F. prausnitzii protected the colon mucosa against the development of IBD by its metabolites, suggesting a promising potential for the use of F. prausnitzii and its metabolic products in the treatment of IBD. PMID- 25275571 TI - Time at risk and intention-to-treat analyses: parallels and implications for inference. AB - Although the standard recommendation is to exclude person-time not at risk (ie, time during which the outcome could not have occurred) from the denominators of disease rates, there are scenarios where person-time not at risk should be included. In particular, we draw an analogy between including person-time not at risk and intention-to-treat (ITT) analyses of randomized trials, and excluding person-time not at risk and compliance-corrected analysis of these same trials. Excluding person-time not at risk is appropriate when addressing questions of the biologic or mechanistic effects of an exposure, whereas the ITT-type approach typically addresses questions regarding the effect of an exposure under observed compliance patterns. The choice of approach directly affects the causal question being addressed and subsequent inference, with potential implications for public health. When interested in estimating treatment effects that allow and account for potential noncompliance, or where the exposure may be associated with the time at risk, we argue that person-time not at risk should be included. In the case of time to pregnancy, although the ITT-type analysis may underestimate the biological fecundity of the population, it may also yield an answer to a question that is of more interest to couples trying to become pregnant. PMID- 25275570 TI - Expression profile of the Schistosoma japonicum degradome reveals differential protease expression patterns and potential anti-schistosomal intervention targets. AB - Blood fluke proteases play pivotal roles in the processes of invasion, nutrition acquisition, immune evasion, and other host-parasite interactions. Hundreds of genes encoding putative proteases have been identified in the recently published schistosome genomes. However, the expression profiles of these proteases in Schistosoma species have not yet been systematically analyzed. We retrieved and culled the redundant protease sequences of Schistosoma japonicum, Schistosoma mansoni, Echinococcus multilocularis, and Clonorchis sinensis from public databases utilizing bioinformatic approaches. The degradomes of the four parasitic organisms and Homo sapiens were then comparatively analyzed. A total of 262 S. japonicum protease sequences were obtained and the expression profiles generated using whole-genome microarray. Four main clusters of protease genes with different expression patterns were identified: proteases up-regulated in hepatic schistosomula and adult worms, egg-specific or predominantly expressed proteases, cercaria-specific or predominantly expressed proteases, and constantly expressed proteases. A subset of protease genes with different expression patterns were further validated using real-time quantitative PCR. The present study represents the most comprehensive analysis of a degradome in Schistosoma species to date. These results provide a firm foundation for future research on the specific function(s) of individual proteases and may help to refine anti proteolytic strategies in blood flukes. PMID- 25275573 TI - Association between occupational dust exposure and prognosis of idiopathic pulmonary fibrosis: a Korean national survey. AB - BACKGROUND: Previous studies have investigated the relationship between occupational and environmental agents and idiopathic pulmonary fibrosis (IPF). However, there have been few studies regarding the prognosis of patients with IPF according to patient occupation. METHODS: We investigated whether occupational dust exposure was associated with clinically decreased lung function and poor prognosis. The Korean Interstitial Lung Disease Research Group conducted a national survey to evaluate the clinical, physiologic, radiologic, and survival characteristics of patients with IPF. A total of 1,311 patients with IPF were stratified into five groups according to their occupation: (1) unemployed or homemakers (n = 628); (2) farmers, fishers, or ranchers (n = 230); (3) sales or service personnel (n = 131); (4) clerical or professional personnel (n = 151); and (5) specific dust-exposed workers (n = 171). RESULTS: The mean age of subjects at diagnosis, was 67.5 +/- 9.7 years. Current smokers were 336 patients, 435 were exsmokers, and 456 were never smokers. Dust-exposed workers showed early onset of IPF (61.3 +/- 8.6 years; P < .001) and a longer duration of symptoms at diagnosis (17.0 +/- 28.2 months; P = .004). Aging (P = .001; hazard ratio [HR], 1.034; 95% CI, 1.014-1.054), FVC % predicted at diagnosis (P = .004; HR, 0.984; 95% CI, 0.974-0.995), and dust-exposure occupation (P = .033; HR, 1.813; 95% CI, 1.049-3.133) were associated with mortality. CONCLUSIONS: These findings indicate that occupational dust may be an aggravating factor associated with a poor prognosis in IPF. PMID- 25275572 TI - Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the Democratic Republic of the Congo. AB - BACKGROUND: Sleeping sickness caused by Trypanosoma brucei (T.b.) gambiense constitutes a serious health problem in sub-Sahara Africa. In some foci, alarmingly high relapse rates were observed in patients treated with melarsoprol, which used to be the first line treatment for patients in the neurological disease stage. Particularly problematic was the situation in Mbuji-Mayi, East Kasai Province in the Democratic Republic of the Congo with a 57% relapse rate compared to a 5% relapse rate in Masi-Manimba, Bandundu Province. The present study aimed at investigating the mechanisms underlying the high relapse rate in Mbuji-Mayi using an extended collection of recently isolated T.b. gambiense strains from Mbuji-Mayi and from Masi-Manimba. METHODOLOGY/PRINCIPAL FINDINGS: Forty five T.b. gambiense strains were used. Forty one were isolated from patients that were cured or relapsed after melarsoprol treatment in Mbuji-Mayi. In vivo drug sensitivity tests provide evidence of reduced melarsoprol sensitivity in these strains. This reduced melarsoprol sensitivity was not attributable to mutations in TbAT1. However, in all these strains, irrespective of the patient treatment outcome, the two aquaglyceroporin (AQP) 2 and 3 genes are replaced by chimeric AQP2/3 genes that may be associated with resistance to pentamidine and melarsoprol. The 4 T.b. gambiense strains isolated in Masi Manimba contain both wild-type AQP2 and a different chimeric AQP2/3. These findings suggest that the reduced in vivo melarsoprol sensitivity of the Mbuji Mayi strains and the high relapse rates in that sleeping sickness focus are caused by mutations in the AQP2/AQP3 locus and not by mutations in TbAT1. CONCLUSIONS/SIGNIFICANCE: We conclude that mutations in the TbAQP2/3 locus of the local T.b. gambiense strains may explain the high melarsoprol relapse rates in the Mbuji-Mayi focus but other factors must also be involved in the treatment outcome of individual patients. PMID- 25275574 TI - Adjuvant dexamethasone: innovation, farce, or folly? PMID- 25275575 TI - Perineural hematoma may result in nerve inflammation and myelin damage. AB - BACKGROUND AND OBJECTIVES: Perineural hematoma may occur during performance of peripheral nerve blocks. The aim of this study was to test the hypothesis that an iatrogenic hematoma in the immediate vicinity of a peripheral nerve may cause histologic evidence of nerve injury. METHODS: Fifty milliliters of autologous blood was injected adjacent to the right sciatic nerve in 20 anesthetized female pigs. In order to discern between blood-related volume and immune effects, 50 mL of albumin was injected at the same location in an additional 22 pigs. Either blood or albumin was injected in random order. The left sciatic nerve served as a negative control in all animals, that is, either no needle placement or needle placement without injection. After 48 hours, the nerves were resected. The grade of nerve injury was scored from 0 (no injury) to 3 (severe injury) by histologic analysis of myelin tissue and inflammatory cells. RESULTS: Eighty-two nerve specimens were examined. Injury scores were significantly (P < 0.01) higher in the blood injection (n = 20; median [interquartile range] 2 [2-2]) and albumin injection (n = 22, 1 [1-2]) conditions compared with the no needle placement (n = 22, 0 [0-1]) and "dry needle placement" (n = 20, 1 [0-1]) conditions. Widespread inflammatory changes were seen in the blood injection group, in which 15% of nerve specimens showed damage to myelin. CONCLUSIONS: Our data suggest that hematoma adjacent to nerve tissue may result in structural nerve injury and inflammatory changes. PMID- 25275576 TI - Evaluation of epidural and peripheral nerve catheter heating during magnetic resonance imaging. AB - BACKGROUND: Many epidural and peripheral nerve catheters contain conducting wire that could heat during magnetic resonance imaging (MRI), requiring removal for scanning. METHODS: We tested 2 each of 6 brands of regional analgesia catheters (from Arrow International [Reading, Pennsylvania], B. Braun Medical Inc [Bethlehem, Pennsylvania], and Smiths Medical/Portex [Keene, New Hampshire]) for exposure to clinical 1.5- and 3-T MRI. Catheters testing as nonmagnetic were placed in an epidural configuration in a standard human torso-sized phantom, and an MRI pulse sequence applied at the maximum scanner-allowed radiofrequency specific absorption rate (SAR) for 15 minutes. Temperature and SAR exposure were sampled during MRI using multiple fiberoptic temperature sensors. RESULTS: Two catheters (the Arrow StimuCath Peripheral Nerve and B. Braun Medical Perifix FX Epidural) were found to be magnetic and not tested further. At 3 T, exposure of the remaining 3 epidural and 1 peripheral nerve catheter to the scanner's maximum RF exposure elicited anomalous heating of 4 degrees C to 7 degrees C in 2 Arrow Epidural (MultiPort and Flex-Tip Plus) catheters at the entry points. Temperature increases for the other catheters at 3 T, and all catheters at 1.5 T were 1.4 degrees C or less. When normalized to the body-average US Food and Drug Administration guideline SAR of 4 W/kg, maximum projected temperature increases were 0.1 degrees C to 2.5 degrees C at 1.5 T and 0.7 degrees C to 2.7 degrees C at 3 T, except for the Arrow MultiPort Flex-Tip Plus catheter at 3 T whose increase was 14 degrees C. CONCLUSIONS: Most but not all catheters can be left in place during 1.5-T MRI scans. Heating of less than 3 degrees C during MRI for most catheters is not expected to be injurious. While heating was lower at 1.5 T versus 3 T, performance differences between products underscore the need for safety testing before performing MRI. PMID- 25275577 TI - Effect of intravenous lidocaine on postoperative recovery of patients undergoing mastectomy: a double-blind, placebo-controlled randomized trial. AB - BACKGROUND: One of the modalities of treatment for breast cancer surgery pain is opioids, and opioids are associated with adverse effects such as itching and postoperative nausea and vomiting (PONV). Intravenous (IV) lidocaine has been shown to reduce opioid consumption and to improve overall postoperative outcomes in abdominal surgery. In this study, we tested the effect of intraoperative IV lidocaine infusion on the quality of postoperative recovery after breast cancer surgery. METHODS: Seventy-one patients undergoing breast cancer surgery were randomly assigned to receive either placebo (group P; n = 34) or IV lidocaine (group L; n = 37, bolus 1.5 mg/kg at induction, then infusion at 2 mg/kg/h, stopped 2 hours after the end of surgery) in a prospective double-blind design. Intraoperative and postoperative morphine consumption was calculated. Postoperative pain scores, PONV, and fatigue were assessed at 2, 24, and 48 hours after surgery. Duration of postoperative hospital stay was recorded. RESULTS: Demographics were the same between the groups. There was no statistically significant difference in intraoperative or postoperative morphine consumption (P = 0.188 and P = 0.758) between groups. Overall pain scores either at rest or activity (P = 0.348 and P = 0.810, respectively), PONV (P = 0.350), fatigue (P = 0.758), or duration of postoperative hospital stay (P = 0.218) were not statistically different. CONCLUSIONS: Our findings did not show a significant effect of IV lidocaine during breast cancer surgery on opioid consumption, pain score, PONV, or fatigue, indicating that the benefit of this approach does not generalize across all types of surgery. PMID- 25275578 TI - Using an international clinical registry of regional anesthesia to identify targets for quality improvement. AB - BACKGROUND: Despite the widespread use of regional anesthesia, limited information on clinical performance exists. Institutions, therefore, have little knowledge of how they are performing in regard to both safety and effectiveness. In this study, we demonstrate how a medical institution (or physician/physician group) may use data from a multicenter clinical registry of regional anesthesia to inform quality improvement strategies. METHODS: We analyzed data from the International Registry of Regional Anesthesia that includes prospective data on peripheral regional anesthesia procedures from 19 centers located around the world. Using data from the clinical registry, we present summary statistics of the overall safety and effectiveness of regional anesthesia. Furthermore, we demonstrate, using a variety of performance measures, how these data can be used by hospitals to identify areas for quality improvement. To do so, we compare the performance of 1 member institution (a US medical center in New Hampshire) to that of the other 18 member institutions of the clinical registry. RESULTS: The clinical registry contained information on 23,271 blocks that were performed between June 1, 2011, and May 1, 2014, on 16,725 patients. The overall success rate was 96.7%, immediate complication rate was 2.2%, and the all-cause 60-day rate of neurological sequelae was 8.3 (95% confidence interval, 7.2- 9.7) per 10,000. Registry-wide major hospital events included 7 wrong-site blocks, 3 seizures, 1 complete heart block, 1 retroperitoneal hematoma, and 3 pneumothoraces. For our reference medical center, we identified areas meriting quality improvement. Specifically, after accounting for differences in the age, sex, and health status of patient populations, the reference medical center appeared to rely more heavily on opioids for postprocedure management, had higher patient pain scores, and experienced delayed discharge when compared with other member institutions. CONCLUSIONS: To our knowledge, this is the first large-scale effort to use a clinical registry to provide comparative outcome rates representing the safety and effectiveness of regional anesthesia. These results can be used to help inform quality improvement strategies. PMID- 25275579 TI - Brainstem auditory and somatosensory evoked potentials in relation to clinical and neuroimaging findings in Chiari type 1 malformation. AB - PURPOSE: The aim of this study was to describe the abnormalities found in the recordings of evoked potentials (EPs), in particular those of brainstem auditory evoked potentials and somatosensory evoked potentials, in a homogeneous series of patients with Chiari type 1 malformation (CM-1) and study their relationship with clinical symptoms and malformation severity. CM-1 is characterized by cerebellar tonsils that descend below the foramen magnum and may be associated with EP alterations. However, only a small number of authors have described these tests in CM-1, and the patient groups studied to date have been small and heterogeneous. METHODS: The clinical findings, neuroimages, and EP findings were retrospectively studied in a cohort of 50 patients with CM-1. RESULTS: Seventy percent of patients had EP abnormalities (brainstem auditory evoked potential: 52%, posterior tibial nerve somatosensory evoked potential: 42%, and median nerve somatosensory evoked potential: 34%). The most frequent alteration was an increased central conduction time. Morphometric measurements differed between the normal and pathological groups, although no statistical significance was found when comparing these groups. CONCLUSIONS: A high percentage of patients with CM-1 show EP alterations regardless of their clinical or radiological findings, thus highlighting the necessity of performing these tests, especially in patients with few or no symptoms. PMID- 25275580 TI - Dental follicle cells rescue the regenerative capacity of periodontal ligament stem cells in an inflammatory microenvironment. AB - AIMS: Periodontal ligament stem cells (PDLSCs) are one of the best candidates for periodontal regeneration. Their function could be impaired in periodontitis microenvironment. Dental follicle cells (DFCs), serving as precursor cells and mesenchymal stem cells, have intimate connection with PDLSCs. However, it is still unknown whether DFCs could provide a favorable microenvironment to improve the proliferation and differentiation capacity of PDLSCs from healthy subjects (HPDLSCs) and patients diagnosed with periodontitis (PPDLSCs). METHODS: HPDLSCs, PPDLSCs and DFCs were harvested and identified using microscopic and flow cytometric analysis. Then, the coculture systems of DFCs/HPDLSCs and DFCs/PPDLSCs were established with 0.4 um transwell, in which all the detection indexs were obtained from HPDLSCs and PPDLSCs. The expression of stemness-associated genes was detected by real-time PCR, and the proliferation ability was assessed using colony formation and cell cycle assays. The osteogenic differentiation capacity was evaluated by real-time PCR, western blot, ALP activity, Alizarin Red S staining and calcium level analysis, while the adipogenic differentiation capacity was determined by real-time PCR and Oil Red O staining. The cell sheet formation in vitro was observed by HE staining and SEM, and the implantation effect in vivo was evaluated using HE staining and Masson's trichrome staining. RESULTS: PPDLSCs had a greater proliferation capability but lower osteogenic and adipogenic potential than HPDLSCs. DFCs enhanced the proliferation and osteogenic/adipogenic differentiation of HPDLSCs and PPDLSCs to different degrees. Moreover, coculture with DFCs increased cell layers and extracellular matrix of HPDLSCs/PPDLSCs cell sheets in vitro and improved periodontal regeneration by HPDLSCs/PPDLSCs in vivo. CONCLUSIONS: Our data suggest that the function of PPDLSCs could be damaged in the periodontitis microenvironment. DFCs appear to enhance the self-renewal and multi-differentiation capacity of both HPDLSCs and PPDLSCs, which indicates that DFCs could provide a beneficial microenvironment for periodontal regeneration using PDLSCs. PMID- 25275581 TI - Diagnosis as the First Critical Point in the Treatment Trajectory: An Exploration of Operable Lung Cancer Patients' Lived Experiences. AB - BACKGROUND: Significant advances have been made in the surgical treatment of lung cancer while patient experiences with diagnosis, treatment, and rehabilitation remain only sparsely researched. OBJECTIVE: The objective of this study was to investigate how the diagnosis affects the daily lives of patients with operable lung cancer in order to identify their needs for care interventions from the point of diagnosis to hospitalization. METHODS: We investigated patients' lived experiences from a longitudinal perspective at 4 critical time points during the treatment trajectory; we present here the findings from the first time point, diagnosis. Data were collected through interviews conducted 7 to 10 days following diagnosis of lung cancer. Data from 19 patients are included, and the analysis is based on Ricoeur's interpretation theory. The study framework is inspired by Schutz's phenomenological sociology. RESULTS: The findings are presented as themes that summarize and express the ways in which a diagnosis affects patients' daily lives: the cancer diagnosis comes as a shock, it changes everyday awareness; it presents the patient with an unfamiliar body, disturbs social relationships, forces the patient to face a new life situation, and demands one-on-one supportive care. CONCLUSIONS: Diagnosis is the first critical point for patients with operable lung cancer and disrupts their daily life. Patients need psychosocial support during the period from diagnosis to surgical intervention and patient-tailored one-on-one information. IMPLICATIONS FOR PRACTICE: This article contributes to the knowledge base of support needs of lung cancer patients. Interventions aimed at supportive care during the period between diagnosis and surgical intervention should be researched. PMID- 25275582 TI - Comparison of Foot Bathing and Foot Massage in Chemotherapy-Induced Peripheral Neuropathy. AB - BACKGROUND: In a clinical setting, patients have been observed to complain of discomfort and to discontinue treatment because of chemotherapy-induced peripheral neuropathy (CIPN), but few data exist regarding the quality of life in these patients in Korea. OBJECTIVE: The purpose of this quasi-experimental study was to analyze the effects of foot bathing and massage in patients with CIPN. METHODS: Subjects included 48 patients with CIPN, who were hospitalized in C University Hospital. The subjects were alternately assigned to 1 of 2 groups according to their registration order. The interventions consisted of 8 treatments of foot bathing or massage over a period of 2 weeks, at 30 minutes per session, every other day. RESULTS: The foot skin temperature increased significantly in the foot bathing group, whereas it decreased significantly in the massage group. Quality of life was significantly increased in the foot bathing group, whereas it was significantly decreased in the massage group. CONCLUSIONS: Although foot bathing and foot massage are both supportive care techniques for CIPN patients, foot bathing was more effective than foot massage on skin temperature, grade of neurotoxicity, and quality of life. Additional well designed studies are recommended, so that the effectiveness of foot bathing and foot massage is confirmed. IMPLICATIONS FOR PRACTICE: Foot bathing is more useful as supportive care with respect to nonpharmacologic interventions for alleviating CIPN and promoting the quality of life in cancer patients. PMID- 25275583 TI - Exercise: A Path to Wellness During Adjuvant Chemotherapy for Breast Cancer? AB - BACKGROUND: Breast cancer treatment can represent a threat to a patient's wellness. The role of exercise in perceived wellness in women with breast cancer merits further study. OBJECTIVE: The objective of this study was to describe how exercise is perceived by women to influence their physical and psychosocial wellness at the time they were receiving chemotherapy. METHODS: Five focus group interviews with a total of 27 women with early-stage breast cancer were conducted. Prior to the focus groups, the women had participated in an exercise intervention during chemotherapy treatment. RESULTS: Three themes emerged from the analysis: exercise shapes feelings of psychological wellness; exercise stimulates feelings of physical wellness; and exercise influences social wellness. The women reported feeling stronger in a psychological sense after exercising, that the strength exercise improved their upper-limb functioning, and that engaging in exercise triggered social support and interactions. CONCLUSIONS: Exercise during breast cancer treatment is perceived to enhance the patients' wellness on several dimensions and in particular psychological wellness. Exercise might support the patients' efforts to restore their sense of wellness and enhance their level of daily life functioning. IMPLICATIONS FOR PRACTICE: Cancer nurses should promote exercise as a wellness-fostering intervention during chemotherapy treatment. Focusing on how exercise can contribute to feelings of wellness may help women with breast cancer choose exercise as a health-promoting activity that contributes to their recovery. PMID- 25275584 TI - CDCP1 identifies a CD146 negative subset of marrow fibroblasts involved with cytokine production. AB - In vitro expanded bone marrow stromal cells contain at least two populations of fibroblasts, a CD146/MCAM positive population, previously reported to be critical for establishing the stem cell niche and a CD146-negative population that expresses CUB domain-containing protein 1 (CDCP1)/CD318. Immunohistochemistry of marrow biopsies shows that clusters of CDCP1+ cells are present in discrete areas distinct from areas of fibroblasts expressing CD146. Using a stromal cell line, HS5, which approximates primary CDCP1+ stromal cells, we show that binding of an activating antibody against CDCP1 results in tyrosine-phosphorylation of CDCP1, paralleled by phosphorylation of Src Family Kinases (SFKs) Protein Kinase C delta (PKC-delta). When CDCP1 expression is knocked-down by siRNA, the expression and secretion of myelopoietic cytokines is increased. These data suggest CDCP1 expression can be used to identify a subset of marrow fibroblasts functionally distinct from CD146+ fibroblasts. Furthermore the CDCP1 protein may contribute to the defining function of these cells by regulating cytokine expression. PMID- 25275586 TI - Could progressive outer retinal necrosis begin with retinal deep capillary ischemia? PMID- 25275585 TI - Cyclophilin A associates with enterovirus-71 virus capsid and plays an essential role in viral infection as an uncoating regulator. AB - Viruses utilize host factors for their efficient proliferation. By evaluating the inhibitory effects of compounds in our library, we identified inhibitors of cyclophilin A (CypA), a known immunosuppressor with peptidyl-prolyl cis-trans isomerase activity, can significantly attenuate EV71 proliferation. We demonstrated that CypA played an essential role in EV71 entry and that the RNA interference-mediated reduction of endogenous CypA expression led to decreased EV71 multiplication. We further revealed that CypA directly interacted with and modified the conformation of H-I loop of the VP1 protein in EV71 capsid, and thus regulated the uncoating process of EV71 entry step in a pH-dependent manner. Our results aid in the understanding of how host factors influence EV71 life cycle and provide new potential targets for developing antiviral agents against EV71 infection. PMID- 25275587 TI - Association of endothelial nitric oxide synthase gene G894T polymorphism and serum nitric oxide levels in patients with preeclampsia and gestational hypertension. AB - OBJECTIVE: Pregnancy-induced hypertension is one of the most important cause of maternal-fetal morbidity and mortality. Pregnancy-related hypertensive disorders are usually associated with diminished nitric oxide (NO) levels. We aimed to evaluate the role of serum NO levels and eNOS gene G894T polymorphism on hypertensive disorders of pregnancy. METHODS: Eighty patients with gestational hypertension or preeclampsia, and 80 healthy pregnants were enrolled to analyze serum NO levels and G894T polymorphism of the eNOS gene. NO level was analyzed by high-performance liquid chromatography (HPLC) method. The G894T polymorphism of the eNOS gene was determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: There was no significant difference between groups in terms of G894T/eNOS genotype and allele frequencies (p > 0.05). Serum NO levels were significantly lower in the patients group. In the control group, subjects with thymine-thymine (TT) genotype had significantly lower NO levels when compared to subjects with guanine-guanine (GG) or guanine thymine (GT) genotype (p < 0.05). CONCLUSIONS: We failed to demonstrate an association between eNOS gene G894T polymorphism and serum NO levels in patients with pregnancy-induced hypertensive disorders. We established a relation between pregnancy-induced hypertension and low NO levels. PMID- 25275589 TI - The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo. AB - There is an urgent clinical need for safe and effective treatment agents and therapy targets for estrogen receptor negative (ER-) breast cancer. G protein coupled receptor 30 (GPR30), which mediates non-genomic signaling of estrogen to regulate cell growth, is highly expressed in ER--breast cancer cells. We here showed that activation of GPR30 by the receptor-specific agonist G-1 inhibited the growth of ER--breast cancer cells in vitro. Treatment of ER--breast cancer cells with G-1 resulted in G2/M-phase arrest, downregulation of G2-checkpoint regulator cyclin B, and induction of mitochondrial-related apoptosis. The G-1 treatment increased expression of p53 and its phosphorylation levels at Serine 15, promoted its nuclear translocation, and inhibited its ubiquitylation, which mediated the growth arrest effects on cell proliferation. Further, the G-1 induced sustained activation and nuclear translocation of ERK1/2, which was mediated by GPR30/epidermal growth factor receptor (EGFR) signals, also mediated its inhibition effects of G-1. With extensive use of siRNA-knockdown experiments and inhibitors, we found that upregulation of p21 by the cross-talk of GPR30/EGFR and p53 was also involved in G-1-induced cell growth arrest. In vivo experiments showed that G-1 treatment significantly suppressed the growth of SkBr3 xenograft tumors and increased the survival rate, associated with proliferation suppression and upregulation of p53, p21 while downregulation of cyclin B. The discovery of multiple signal pathways mediated the suppression effects of G-1 makes it a promising candidate drug and lays the foundation for future development of GPR30 based therapies for ER- breast cancer treatment. PMID- 25275588 TI - Severe influenza A(H1N1)pdm09 infection induces thymic atrophy through activating innate CD8(+)CD44(hi) T cells by upregulating IFN-gamma. AB - Thymic atrophy has been described as a consequence of infection by several pathogens including highly pathogenic avian influenza virus and is induced through diverse mechanisms. However, whether influenza A(H1N1)pdm09 infection induces thymic atrophy and the mechanisms underlying this process have not been completely elucidated. Our results show that severe infection of influenza A(H1N1)pdm09 led to progressive thymic atrophy and CD4+ CD8+ double-positive (DP) T-cells depletion due to apoptosis. The viruses were present in thymus, where they activated thymic innate CD8(+)CD44(hi) single-positive (SP) thymocytes to secrete a large amount of IFN-gamma. Milder thymic atrophy was observed in innate CD8+ T-cell-deficient mice (C57BL/6J). Neutralization of IFN-gamma could significantly rescue the atrophy, but peramivir treatment did not significantly alleviate thymic atrophy. In this study, we demonstrated that thymic innate CD8(+)CD44(hi) SP T-cells have critical roles in influenza A(H1N1)pdm09 infection induced thymic atrophy through secreting IFN-gamma. This exceptional mechanism might serve as a target for the prevention and treatment of thymic atrophy induced by influenza A(H1N1)pdm09. PMID- 25275592 TI - Transcriptional repression of CDKN2D by PML/RARalpha contributes to the altered proliferation and differentiation block of acute promyelocytic leukemia cells. AB - Cell proliferation and differentiation are highly coordinated processes. These two processes are disrupted during leukemogenesis, resulting in differentiation block and uncontrolled proliferation in leukemia. To understand the mechanisms disrupting the coordination between the two processes in acute promyelocytic leukemia (APL), we investigated the regulatory mechanism of the negative cell cycle regulator CDKN2D by the promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein and the role of CDKN2D in cell differentiation and proliferation. We found that CDKN2D expression in APL cells was significantly lower than that in normal promyelocytes. By chromatin immunoprecipitation and luciferase reporter assays, we showed that PML/RARalpha directly bound to and inhibited the transactivation of the CDKN2D promoter. Further evidence by the truncated and mutated CDKN2D promoters revealed that the everted repeat 8 (ER8) motif on the promoter was the binding site of PML/RARalpha. Forced expression of CDKN2D induced G0/G1 phase arrest and partial granulocytic differentiation in APL derived NB4 cells, suggesting the function of CDKN2D in regulating both cell proliferation and granulocytic differentiation. Furthermore, all-trans retinoic acid (ATRA) significantly induced CDKN2D expression in APL cells and knockdown of CDKN2D expression during ATRA treatment partially blocked the ATRA-induced differentiation and cell cycle arrest. Collectively, our data indicate that CDKN2D repression by PML/RARalpha disrupts both cell proliferation and differentiation in the pathogenesis of APL, and induced expression of CDKN2D by ATRA alleviates the disruption of both processes to ensure treatment efficiency. This study provides a mechanism for coupling proliferation and differentiation in leukemic cells through the action of CDKN2D. PMID- 25275593 TI - Ligand-activated peroxisome proliferator-activated receptor-delta and -gamma inhibit lipopolysaccharide-primed release of high mobility group box 1 through upregulation of SIRT1. AB - Peroxisome proliferator-activated receptors (PPARs) inhibit lipopolysaccharide (LPS)-primed release of high mobility group box 1 (HMGB1), a late proinflammatory mediator, but the underlying molecular mechanism is not completely understood. In this study, we demonstrated that the inhibition of HMGB1 release by PPAR-delta and -gamma is associated with the deacetylase activity of SIRT1. Ligand-activated PPAR-delta and -gamma inhibited LPS-primed release of HMGB1, concomitant with elevation in SIRT1 expression and promoter activity. These effects were significantly reduced in the presence of small interfering (si)RNAs against PPAR, indicating that PPAR-delta and -gamma are involved in both HMGB1 release and SIRT1 expression. In addition, modulation of SIRT1 expression and activity by siRNA or chemicals correspondingly influenced the effects of PPARs on HMGB1 release, suggesting a mechanism in which SIRT1 modulates HMGB1 release. Furthermore, we showed for the first time that HMGB1 acetylated in response to LPS or p300/CBP-associated factor (PCAF) is an effective substrate for SIRT1, and that deacetylation of HMGB1 is responsible for blockade of HMGB1 release in macrophages. Finally, acetylation of HMGB1 was elevated in mouse embryonic fibroblasts from SIRT1-knockout mice, whereas this increase was completely reversed by ectopic expression of SIRT1. These results indicate that PPAR mediated upregulation of SIRT1 modulates the status of HMGB1 acetylation, which, in turn, has a critical role in the cellular response to inflammation through deacetylation-mediated regulation of HMGB1 release. PMID- 25275594 TI - MicroRNA-207 enhances radiation-induced apoptosis by directly targeting Akt3 in cochlea hair cells. AB - MicroRNAs (miRNAs) have important roles in various types of cellular biological processes. Our study aimed to determine whether miRNAs function in the regulation of ionizing radiation (IR)-induced cell death in auditory cells and to determine how they affect the cellular response to IR. Microarray and qRT-PCR were performed to identify and confirm the differential expression of miRNAs in the cochlea hair cell line HEI-OC1 and in vivo after IR. Upregulation or downregulation of miRNAs using miRNA mimics or inhibitor were detected to characterize the biological effects of the indicated miRNAs. Bioinformatic analyses, luciferase reporter assays and mRNA knockdown were performed to identify a miRNA target gene. We determined that miR-207 was significantly upregulated after IR. MiR-207 enhances IR-induced apoptosis and DNA damage in HEI OC1 cells. Furthermore, Akt3 was confirmed to be a direct target of miR-207. Downregulation of Akt3 mimics the effects of miR-207. MiR-207 enhances IR-induced apoptosis by directly targeting Akt3 and anti-miR-207 may have a potential role in protecting cochlea hair cells from IR. PMID- 25275595 TI - Synergistic anti-tumor activity and inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways in human melanoma. AB - Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244-TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244-TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1alpha, VEGFalpha, IL-8 and TGFbeta1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo. PMID- 25275596 TI - Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe. AB - Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe induced apoptosis. PMID- 25275597 TI - CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell derived TECK promotes the growth and invasion of endometriotic lesions. AB - Endometriosis is associated with an abnormal immune response to endometrial cells, which can facilitate the implantation and proliferation of ectopic endometrial tissue. The proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) is significantly increased in the peritoneal fluid of women with endometriosis. The thymus-expressed chemokine TECK/CCL25 directly promotes the invasiveness of endometrial stromal cells (ESCs). The aim of this study was to investigate the effects of ESC-derived TECK on the crosstalk between Tregs and ESCs in the progress of endometriosis. We determined that the percentage of Tregs and the concentration of TECK increased in the peritoneal fluid with the progression of endometriosis. The supernatant from co-cultured human ESCs and macrophages not only induced Treg differentiation and increased Treg expression of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta) and CD73 by activating the AKT/STAT3 signaling pathway but also repressed Treg apoptosis by downregulating Fas and FasL expression and enhanced the Treg-mediated suppression of CD4(+)CD25( ) T cells. In addition, in vitro and in vivo trials confirmed that these effects could be inhibited by anti-TECK neutralizing Abs. The secretion of IL-10 and TGF beta by Tregs increased MMP2 expression and decreased TIMP1 expression and further stimulated the proliferation and invasion of ESCs and the growth of ectopic lesions. These results indicate that TECK derived from ESCs and macrophages upregulates the number and function of Tregs in the ectopic milieu, which contributes to endometriotic immunotolerance and high levels of ESC proliferation and invasion, thereby facilitating the progression of endometriosis. PMID- 25275598 TI - PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. AB - The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance. PMID- 25275599 TI - MUC1 extracellular domain confers resistance of epithelial cancer cells to anoikis. AB - Anoikis, a special apoptotic process occurring in response to loss of cell adhesion to the extracellular matrix, is a fundamental surveillance process for maintaining tissue homeostasis. Resistance to anoikis characterises cancer cells and is a pre-requisite for metastasis. This study shows that overexpression of the transmembrane mucin protein MUC1 prevents initiation of anoikis in epithelial cancer cells in response to loss of adhesion. We show that this effect is largely attributed to the elongated and heavily glycosylated extracellular domain of MUC1 that protrudes high above the cell membrane and hence prevents activation of the cell surface anoikis-initiating molecules such as integrins and death receptors by providing them a mechanically 'homing' microenvironment. As overexpression of MUC1 is a common feature of epithelial cancers and as resistance to anoikis is a hallmark of both oncogenic epithelial-mesenchymal transition and metastasis, MUC1 mediated cell resistance to anoikis may represent one of the fundamental regulatory mechanisms in tumourigenesis and metastasis. PMID- 25275600 TI - Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling. AB - Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for patients with ZAP-70 expression in CLL cells. The tyrosine kinase inhibitor gefitinib has been shown to be effective at induce apoptosis in acute myeloid leukemia through inhibition of Syk. In this study, we sought to test the efficacy of gefitinib in primary human ZAP-70+ CLL cells. We demonstrate that gefitinib preferentially induces cell death in ZAP-70-expressing CLL cells with a median IC50 of 4.5 MUM. In addition, gefitinib decreases the viability of ZAP-70+ Jurkat T leukemia cells but fails to affect T cells from CLL patients. Western blot analysis shows gefitinib reduces both basal and B-cell receptor (BCR)-stimulated phosphorylation of Syk/ZAP-70, ERK, and Akt in ZAP-70+ CLL cells. Moreover, gefitinib inhibits the pro-survival response from BCR stimulation and decreases pro-survival proteins such as Mcl-1. Finally, ZAP-70 expression sensitizes Raji cells to gefitinib treatment. These results demonstrate that gefitinib specifically targets ZAP-70+ CLL cells and inhibits the BCR cell survival pathway leading to apoptosis. This represents the likelihood of tyrosine kinase inhibitors being effective targeted treatments for ZAP-70+ CLL cells. PMID- 25275601 TI - Seizure activity results in calcium- and mitochondria-independent ROS production via NADPH and xanthine oxidase activation. AB - Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), which then contribute to seizure-induced neuronal damage and eventually cell death. Although the mechanisms of seizure-induced ROS generation are unclear, mitochondria and cellular calcium overload have been proposed to have a crucial role. We aim to determine the sources of seizure-induced ROS and their contribution to seizure-induced cell death. Using live cell imaging techniques in glioneuronal cultures, we show that prolonged seizure-like activity increases ROS production in an NMDA receptor-dependent manner. Unexpectedly, however, mitochondria did not contribute to ROS production during seizure-like activity. ROS were generated primarily by NADPH oxidase and later by xanthine oxidase (XO) activity in a calcium-independent manner. This calcium-independent neuronal ROS production was accompanied by an increase in intracellular [Na(+)] through NMDA receptor activation. Inhibition of NADPH or XO markedly reduced seizure-like activity-induced neuronal apoptosis. These findings demonstrate a critical role for ROS in seizure-induced neuronal cell death and identify novel therapeutic targets. PMID- 25275602 TI - TGF-beta is an inducer of ZEB1-dependent mesenchymal transdifferentiation in glioblastoma that is associated with tumor invasion. AB - Different molecular subtypes of glioblastoma (GBM) have been recently identified, of which the mesenchymal subtype is associated with worst prognoses. Here, we report that transforming growth factor-beta (TGF-beta) is able to induce a mesenchymal phenotype in GBM that involves activation of SMAD2 and ZEB1, a known transcriptional inducer of mesenchymal transition in epithelial cancers. TGF-beta exposure of established and newly generated GBM cell lines was associated with morphological changes, enhanced mesenchymal marker expression, migration and invasion in vitro and in an orthotopic mouse model. TGF-beta-induced mesenchymal differentiation and invasive behavior was prevented by chemical inhibition of TGF beta signaling as well as small interfering RNA (siRNA)-dependent silencing of ZEB1. Furthermore, TGF-beta-responding and -nonresponding GBM neurospheres were identified in vitro. Interestingly, nonresponding cells displayed already high levels of pSMAD2 and ZEB1 that could not be suppressed by inhibition of TGF-beta signaling, suggesting the involvement of yet unknown mechanisms. These different GBM neurospheres formed invasive tumors in mice as well as revealed mesenchymal marker expression in immunohistochemical analyses. Moreover, we also detected distinct zones with overlapping pSMAD2, elevated ZEB1 and mesenchymal marker expression in GBM patient material, suggestive of the induction of local, microenvironment-dependent mesenchymal differentiation. Overall, our findings indicate that GBM cells can acquire mesenchymal features associated with enhanced invasive potential following stimulation by secretory cytokines, such as TGF beta. This property of GBM contributes to heterogeneity in this tumor type and may blur the boundaries between the proposed transcriptional subtypes. Targeting TGF-beta or downstream targets like ZEB1 might be of potential benefit in reducing the invasive phenotype of GBM in a subpopulation of patients. PMID- 25275603 TI - Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma. AB - Drug transporters such as P-glycoprotein (ABCB1) have been associated with chemotherapy resistance and are considered unfavorable prognostic factors for survival of cancer patients. Analyzing mRNA expression levels of a subset of drug transporters by quantitative reverse transcription polymerase chain reaction (qRT PCR) or protein expression by tissue microarray (TMA) in tumor samples of therapy naive stage IV head and neck squamous cell carcinoma (HNSCC) (qRT-PCR, n = 40; TMA, n = 61), this in situ study re-examined the significance of transporter expression for progression-free survival (PFS) and overall survival (OS). Data from The Cancer Genome Atlas database was used to externally validate the respective findings (n = 317). In general, HNSCC tended to lower expression of drug transporters compared to normal epithelium. High ABCB1 mRNA tumor expression was associated with both favorable progression-free survival (PFS, p = 0.0357) and overall survival (OS, p = 0.0535). Similar results were obtained for the mRNA of ABCC1 (MRP1, multidrug resistance-associated protein 1; PFS, p = 0.0183; OS, p = 0.038). In contrast, protein expression of ATP7b (copper transporter ATP7b), mRNA expression of ABCG2 (BCRP, breast cancer resistance protein), ABCC2 (MRP2), and SLC31A1 (hCTR1, human copper transporter 1) did not correlate with survival. Cluster analysis however revealed that simultaneous high expression of SLC31A1, ABCC2, and ABCG2 indicates poor survival of HNSCC patients. In conclusion, this study militates against the intuitive dogma where high expression of drug efflux transporters indicates poor survival, but demonstrates that expression of single drug transporters might indicate even improved survival. Prospectively, combined analysis of the 'transportome' should rather be performed as it likely unravels meaningful data on the impact of drug transporters on survival of patients with HNSCC. PMID- 25275604 TI - The actin binding protein adseverin regulates osteoclastogenesis. AB - Adseverin (Ads), a member of the Gelsolin superfamily of actin binding proteins, regulates the actin cytoskeleton architecture by severing and capping existing filamentous actin (F-actin) strands and nucleating the assembly of new F-actin filaments. Ads has been implicated in cellular secretion, exocytosis and has also been shown to regulate chondrogenesis and megakaryoblastic leukemia cell differentiation. Here we report for the first time that Ads is involved in regulating osteoclastogenesis (OCG). Ads is induced during OCG downstream of RANK ligand (RANKL) stimulation and is highly expressed in mature osteoclasts. The D5 isoform of Ads is not involved in regulating OCG, as its expression is not induced in response to RANKL. Three clonal Ads knockdown RAW264.7 (RAW) macrophage cell lines with varying degrees of Ads expression and OCG deficiency were generated. The most drastic OCG defect was noted in the clonal cell line with the greatest degree of Ads knockdown as indicated by a lack of TRAcP staining and multinucleation. RNAi mediated knockdown of Ads in osteoclast precursors resulted in distinct morphological changes characterized by altered F actin distribution and increased filopodia formation. Ads knockdown precursor cells experienced enhanced migration while fusion of knockdown precursors cells was limited. Transient reintroduction of de novo Ads back into the knockdown system was capable of rescuing TRAcP expression but not osteoclast multinucleation most likely due to the transient nature of Ads expression. This preliminary study allows us to conclude that Ads is a RANKL induced early regulator of OCG with a potential role in pre-osteoclast differentiation and fusion. PMID- 25275605 TI - Acetate availability and utilization supports the growth of mutant sub populations on aging bacterial colonies. AB - When bacterial colonies age most cells enter a stationary phase, but sub populations of mutant bacteria can continue to grow and accumulate. These sub populations include bacteria with mutations in rpoB (RNA polymerase beta-subunit) or rpoS (RNA polymerase stress-response sigma factor). Here we have identified acetate as a nutrient present in the aging colonies that is utilized by these mutant subpopulations to support their continued growth. Proteome analysis of aging colonies showed that several proteins involved in acetate conversion and utilization were upregulated during aging. Acetate is known to be excreted during the exponential growth phase but can be imported later during the transition to stationary phase and converted to acetyl-CoA. Acetyl-CoA is used in multiple processes, including feeding into the TCA cycle, generating ATP via the glyoxylate shunt, as a source of acetyl groups for protein modification, and to support fatty acid biosynthesis. We showed that deletion of acs (encodes acetyl CoA synthetase; converts acetate into acetyl-CoA) significantly reduced the accumulation of rpoB and rpoS mutant subpopulations on aging colonies. Measurement of radioactive acetate uptake showed that the rate of conversion decreased in aging wild-type colonies, was maintained at a constant level in the rpoB mutant, and significantly increased in the aging rpoS mutant. Finally, we showed that the growth of subpopulations on aging colonies was greatly enhanced if the aging colony itself was unable to utilize acetate, leaving more acetate available for mutant subpopulations to use. Accordingly, the data show that the accumulation of subpopulations of rpoB and rpoS mutants on aging colonies is supported by the availability in the aging colony of acetate, and by the ability of the subpopulation cells to convert the acetate to acetyl-CoA. PMID- 25275606 TI - Advance directives and the impact of timing. A qualitative study with Swiss general practitioners. AB - PRINCIPLES: Advance directives are seen as an important tool for documenting the wishes of patients who are no longer competent to make decisions in regards to their medical care. Due to their nature, approaching the subject of advance directives with a patient can be difficult for both the medical care provider and the patient. This paper focuses on general practitioners' perspectives regarding the timing at which this discussion should take place, as well as the advantages and disadvantages of the different moments. METHODS: In 2013, 23 semi-structured face-to-face interviews were performed with Swiss general practitioners. Interviews were analysed using qualitative content analysis. RESULTS: In our sample, 23 general practitioners provided different options that they felt were appropriate moments: either (a) when the patient is still healthy, (b) when illness becomes predominant, or (c) when a patient has been transferred to a long term care facility. Furthermore, general practitioners reported uncertainty and discomfort regarding initiating the discussion. CONCLUSION: The distinct approaches, perspectives and rationales show that there is no well-defined or "right" moment. However, participants often associated advance directives with death. This link caused discomfort and uncertainty, which led to hesitation and delay on the part of general practitioners. Therefore we recommend further training on how to professionally initiate a conversation about advance directives. Furthermore, based on our results and experience, we recommend an early approach with healthy patients paired with later regular updates as it seems to be the most effective way to inform patients about their end-of-life care options. PMID- 25275608 TI - Structural characterization of CO-inhibited Mo-nitrogenase by combined application of nuclear resonance vibrational spectroscopy, extended X-ray absorption fine structure, and density functional theory: new insights into the effects of CO binding and the role of the interstitial atom. AB - The properties of CO-inhibited Azotobacter vinelandii (Av) Mo-nitrogenase (N2ase) have been examined by the combined application of nuclear resonance vibrational spectroscopy (NRVS), extended X-ray absorption fine structure (EXAFS), and density functional theory (DFT). Dramatic changes in the NRVS are seen under high CO conditions, especially in a 188 cm(-1) mode associated with symmetric breathing of the central cage of the FeMo-cofactor. Similar changes are reproduced with the alpha-H195Q N2ase variant. In the frequency region above 450 cm(-1), additional features are seen that are assigned to Fe-CO bending and stretching modes (confirmed by (13)CO isotope shifts). The EXAFS for wild-type N2ase shows evidence for a significant cluster distortion under high-CO conditions, most dramatically in the splitting of the interaction between Mo and the shell of Fe atoms originally at 5.08 A in the resting enzyme. A DFT model with both a terminal -CO and a partially reduced -CHO ligand bound to adjacent Fe sites is consistent with both earlier FT-IR experiments, and the present EXAFS and NRVS observations for the wild-type enzyme. Another DFT model with two terminal CO ligands on the adjacent Fe atoms yields Fe-CO bands consistent with the alpha-H195Q variant NRVS. The calculations also shed light on the vibrational "shake" modes of the interstitial atom inside the central cage, and their interaction with the Fe-CO modes. Implications for the CO and N2 reactivity of N2ase are discussed. PMID- 25275609 TI - COMparison of Platelet reactivity following prAsugrel and ticagrelor loading dose in ST-Segment elevation myocardial infarctION patients: The COMPASSION study. AB - Prasugrel and ticagrelor are potent P2Y12-ADP receptor antagonists which are superior to clopidogrel in acute coronary syndromes. To date no clinical trial directly compared these two drugs. Platelet reactivity correlates with ischemic and bleeding events in patients undergoing percutaneous coronary intervention. Recent pharmacological studies have observed a delayed onset of action of these two drugs in ST-segment elevation myocardial infarction (STEMI). We provide the first adequately powered pharmacological study comparing PR following ticagrelor and prasugrel loading dose (LD) in STEMI patients when the maximal biological effect is reached. In the present study, ticagrelor was associated with a lower rate of high on-treatment PR compared to prasugrel. PMID- 25275611 TI - On the two-step mechanism for synthesis of transition-metal nanoparticles. AB - The two-step particle synthesis mechanism, also known as the Finke-Watzky (1997) mechanism, has emerged as a significant development in the field of nanoparticle synthesis. It explains a characteristic feature of the synthesis of transition metal nanoparticles, an induction period in precursor concentration followed by its rapid sigmoidal decrease. The classical LaMer theory (1950) of particle formation fails to capture this behavior. The two-step mechanism considers slow continuous nucleation and autocatalytic growth of particles directly from precursor as its two kinetic steps. In the present work, we test the two-step mechanism rigorously using population balance models. We find that it explains precursor consumption very well, but fails to explain particle synthesis. The effect of continued nucleation on particle synthesis is not suppressed sufficiently by the rapid autocatalytic growth of particles. The nucleation continues to increase breadth of size distributions to unexpectedly large values as compared to those observed experimentally. A number of variations of the original mechanism with additional reaction steps are investigated next. The simulations show that continued nucleation from the beginning of the synthesis leads to formation of highly polydisperse particles in all of the tested cases. A short nucleation window, realized with delayed onset of nucleation and its suppression soon after in one of the variations, appears as one way to explain all of the known experimental observations. The present investigations clearly establish the need to revisit the two-step particle synthesis mechanism. PMID- 25275610 TI - Triglyceride levels are closely associated with mild declines in estimated glomerular filtration rates in middle-aged and elderly Chinese with normal serum lipid levels. AB - OBJECTIVE: To investigate the relationship between lipid profiles [including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] and a mild decline in the estimated glomerular filtration rate (eGFR) in subjects with normal serum lipid levels. DESIGN AND METHODS: In this study, we included 2647 participants who were >= 40 years old and had normal serum lipid levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the GFR. A mildly reduced eGFR was defined as 60-90 mL/min/1.73 m(2). First, multiple linear regression analysis was used to estimate the association of lipid profiles with the eGFR. Then, the levels of each lipid component were divided into four groups, using the 25th, 50th and 75th percentiles as cut-off points. Finally, multiple logistic regression analysis was used to investigate the association of different lipid components with the risk of mildly reduced eGFR. RESULTS: In the group with a mildly reduced eGFR, TG and LDL-C levels were significantly increased, but HDL-C levels were significantly decreased. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), smoking and drinking, only TC and TG were independently related to the eGFR. Additionally, only TG showed a linear relationship with an increased risk of a mildly reduced eGFR, with the highest quartile group (TG: 108 150 mg/dl [1.22-1.70 mmol/L]) having a significantly increased risk after adjusting for the above factors. CONCLUSIONS: Triglyceride levels are closely associated with a mildly reduced eGFR in subjects with normal serum lipid levels. Dyslipidemia with lower TG levels could be used as new diagnostic criteria for subjects with mildly reduced renal function. PMID- 25275612 TI - Maximal voluntary force strengthened by the enhancement of motor system state through barely visible priming words with reward. AB - The topic of unconscious influences on behaviour has long been explored as a means of understanding human performance and the neurobiological correlates of intention, motivation, and action. However, what is relatively unknown is whether subconsciously delivered priming stimuli, with or without rewards, can affect individuals' maximum level of force produced with their best effort. We demonstrated using transcranial magnetic stimulation that barely visible priming of an action concept, when combined with a reward in the form of a consciously visible positive stimulus, could alter the state of the motor system. In accordance with this neurophysiological alteration, the prime-plus-reward stimuli significantly increased the hand-grip force level of maximum voluntary contraction with little conscious awareness. This is the first objective evidence that the barely conscious presence of a behavioral goal can influence the state of the motor system and arouse latent ability for human force exertion. PMID- 25275613 TI - The effect of treatment history on therapeutic outcome: psychological and neurobiological underpinnings. AB - It is increasingly recognized that the efficacy of medical treatments is determined in critical part by the therapeutic context in which it is delivered. An important characteristic of that context is treatment history. We recently reported first evidence for a carry-over of treatment experience to subsequent treatment response across different treatment approaches. Here we expand on these findings by exploring the psychological and neurobiological underpinnings of the effect of treatment experience on future treatment response in an experimental model of placebo analgesia with a conditioning procedure. In a combined behavioral and neuroimaging study we experimentally induced positive or negative experiences with an analgesic treatment in two groups of healthy human subjects. Subsequently we compared responses to a second, different analgesic treatment between both groups. We found that participants with an experimentally induced negative experience with the first treatment showed a substantially reduced response to a second analgesic treatment. Intriguingly, several psychological trait variables including anxiety, depression and locus of control modulate the susceptibility for the effects of prior treatment experiences on future treatment outcome. These behavioral effects were supported by neuroimaging data which showed significant differences in brain regions encoding pain and analgesia between groups. These differences in activation patterns were present not only during the pain phase, but also already prior to painful stimulation and scaled with the individual treatment response. Our data provide behavioral and neurobiological evidence showing that the influence of treatment history transfers over time and over therapeutic approaches. Our experimental findings emphasize the careful consideration of treatment history and a strictly systematic treatment approach to avoid negative carry-over effects. PMID- 25275615 TI - Evaluation of bioaerosol exposures during hospital bronchoscopy examinations. AB - During hospital bronchoscopy examinations, aerosols emitted from the patient's during coughing can be found suspended in the ambient air. The aerosols can contain pathogenic microorganisms. Depending on their size, these microorganisms can remain in the air for a long time. The objective of this study was to measure the sizes and concentrations of the biological and non-biological particles produced during bronchoscopy examinations, and to propose preventive or corrective measures. Two bronchoscopy rooms were studied. An aerodynamic particle sizer (UV-APS) was used to establish the concentrations of the particles present and their size distributions. This instrument determines the aerodynamic diameter of the aerosols and can distinguish fluorescent (bioaerosols) and non-fluorescent particles. Reference concentrations were measured before the start of the examinations (morning background concentrations). They were used as comparison levels for the concentrations measured during and at the end of the bronchoscopies. In parallel, computational fluid dynamics (CFD) made it possible to isolate and understand different factors that can affect the concentration levels in bronchoscopy rooms. The concentrations of the non-fluorescent and fluorescent particles (bioaerosols) were significantly higher (p <= 0.05) during the bronchoscopy examinations than the reference concentrations. For the investigated factors, the bioaerosol concentrations were significantly higher during bronchoscope insertion tasks. The time required at the end of the day for the bioaerosols to reach the morning reference concentrations was about fifteen minutes. The average particle sizes were 2.9 MUm for the fluorescent particles (bioaerosols) and 0.9 MUm for the non-fluorescent particles. Our models based on computational fluid dynamics (CFD) enabled us to observe the behaviour of aerosols for the different rooms. PMID- 25275614 TI - Hybridization capture using short PCR products enriches small genomes by capturing flanking sequences (CapFlank). AB - Solution hybridization capture methods utilize biotinylated oligonucleotides as baits to enrich homologous sequences from next generation sequencing (NGS) libraries. Coupled with NGS, the method generates kilo to gigabases of high confidence consensus targeted sequence. However, in many experiments, a non negligible fraction of the resulting sequence reads are not homologous to the bait. We demonstrate that during capture, the bait-hybridized library molecules add additional flanking library sequences iteratively, such that baits limited to targeting relatively short regions (e.g. few hundred nucleotides) can result in enrichment across entire mitochondrial and bacterial genomes. Our findings suggest that some of the off-target sequences derived in capture experiments are non-randomly enriched, and that CapFlank will facilitate targeted enrichment of large contiguous sequences with minimal prior target sequence information. PMID- 25275616 TI - Colorimetric disposable paper coated with ZnO@ZnS core-shell nanoparticles for detection of copper ions in aqueous solutions. AB - In this study, we have proposed a new nanoparticle-containing test paper sensor that could be used as an inexpensive, easy-to-use, portable, and highly selective sensor to detect Cu(2+) ions in aqueous solutions. This disposable paper sensor is based on ZnO@ZnS core-shell nanoparticles. The core-shell nanoparticles were synthesized using a chemical method and then they were used for coating the paper. The synthesis of the ZnO@ZnS core-shell nanoparticles was performed at a temperature as low as 60 degrees C, and so far this is the lowest temperature for the synthesis of such core-shell nanoparticles. The sensitivity of the paper sensor was investigated for different Cu(2+) ion concentrations in aqueous solutions and the results show a direct linear relation between the Cu(2+) ions concentration and the color intensity of the paper sensor with a visual detection limit as low as 15 MUM (~0.96 ppm). Testing the present paper sensor on real river turbulent water shows a maximum 5% relative error for determining the Cu(2+) ions concentration, which confirms that the presented paper sensor can successfully be used efficiently for detection in complex solutions with high selectivity. Photographs of the paper sensor taken using a regular digital camera were transferred to a computer and analyzed by ImageJ Photoshop software. This finding demonstrates the potential of the present disposable paper sensor for the development of a portable, accurate, and selective heavy metal detection technology. PMID- 25275617 TI - Strain-promoted oxidative annulation of arynes and cyclooctynes with benzamides: palladium-catalyzed C-H/N-H activation for the synthesis of N-heterocycles. AB - Strained alkynes include arynes and cyclooctynes reacted with N-methoxyamides through palladium-catalyzed C-H/N-H activation for the first time. A variety of important N-heterocycles such as phenanthridinones and isoquinolones were constructed in one step with high efficiency. PMID- 25275618 TI - Online detection of reactive oxygen species in ultraviolet (UV)-Irradiated nano TiO2 suspensions by continuous flow chemiluminescence. AB - Reactive oxygen species (ROS) play very important roles in the photocatalytic reactions of semiconductors. Using a continuous flow chemiluminescence (CFCL) system, we developed three methods for the selective, sensitive, and online detection of O2(* -), *OH, and H2O2 generated during ultraviolet (UV) irradiation of nano-TiO2 suspensions. TiO2 nanoparticles were irradiated in a photoreactor and pumped continuously into a detection cell. To detect O2(* -), luminol was mixed with TiO2 before it entered the detection cell. For the detection of short lived *OH, phthalhydrazide was added into the photoreactor to capture *OH, and then mixed with H2O2/K5Cu(HIO6)2 to produce chemiluminescence (CL). To detect H2O2, an irradiated TiO2 suspension was kept in darkness for 30 min, and then mixed with luminol/K3Fe(CN)6 to produce CL. The selectivity of each method for a particular ROS was verified by using specific ROS scavengers. For a given ROS, a comparison between CL and conventional method showed good agreement for a series of TiO2 concentrations. The sensitivity of CL method was approximately 3-, 1200-, and 5-fold higher than the conventional method for O2(* -), *OH, and H2O2, respectively. To demonstrate the utility of the methods, ROS in three different types of TiO2 suspensions was detected by CFCL. It was found that photodegradation efficiency of Rhodamine B correlated the best (R(2) > 0.95) with the amount of photogenerated *OH, implying that *OH was the major oxidant in Rhodamine B photodegradation reaction. CFCL may provide a convenient tool for the studies on the reaction kinetics of ROS-participated decomposition of environmental contaminants. PMID- 25275620 TI - Factors influencing parental consent in a hypothetical pediatric vaccine trial in a developing country setting: a questionnaire study. AB - Clinical vaccine trials have been lacking in the pediatric population due to lower consent rate of the parents. We assessed characteristics of the parents, and motives and barriers underlying the decision process. The results of the questionnaire were evaluated by multivariate analysis. Parents who opted in were younger and more often employed than the parents who opted out. The most important motives were receiving detailed information about trial and benefits to human health. The qualified education of medical community and public about the rationale and benefits of trials is essential for opt-in. PMID- 25275619 TI - Factors influencing sleep disturbances among spouse caregivers of cancer patients in Northeast China. AB - BACKGROUND: In China, spouse caregivers of cancer patients (SCCPs) are involved in all aspects of patient care and experience psychological distress which could result in sleep disturbance and fatigue. However, few studies have explored the differences between SCCPs and the general population, or what factors affect SCCPs' sleep. This study aims to (1) Compare the differences in sleep disturbances and fatigue severity between SCCPs and the age- and gender-matched general population, and (2) Identify selected personal characteristics, including coping style that affect sleep disturbances in SCCPs. METHODOLOGY/PRINCIPAL FINDINGS: The Stress and Coping Model was used to guide this study. Participants were recruited from the northeast part of China and included 600 people from the general population and 300 SCCPs. Participants completed a socio-demographic form, Fatigue Scale-14, trait Coping Style Questionnaire, and Symptom Checklist 90. RESULTS: The majority of the participants were middle age, most of whom (78.7%) spent more than 8 hours each day taking care of their spouses. Compared to the general population, the SCCPs experienced significant sleep disturbances with a mean of 7.30 (SD = 1.27), and fatigue severity with a mean of 8.11 (SD = 3.25). Among the selected SCCPs' personal characteristics, current poor health status (beta = 0.14, P<0.001), having a spouse under mixed treatment (beta = 0.13, p<0.001), and financial burden (beta = 0.14, P<0.001) are the significant predictors for sleep disturbances. Positive coping is the predictor for fewer sleep disturbances (beta = 0.27, P<0.001). Those who reported sleep disturbances also experienced higher physical and mental fatigue severity (P<0.001). CONCLUSION: Intervention to improve coping style in SCCPs is needed. Further research is also needed to explore the other mediators and moderators that regulate sleep disturbance and health outcomes in the SCCPs. PMID- 25275621 TI - Research misconduct definitions adopted by U.S. research institutions. AB - In 2000, the U.S. federal government adopted a uniform definition of research misconduct as fabrication, falsification, or plagiarism (FFP), which became effective in 2001. Institutions must apply this definition of misconduct to federally-funded research to receive funding. While institutions are free to adopt definitions of misconduct that go beyond the federal standard, it is not known how many do. We analyzed misconduct policies from 183 U.S. research institutions and coded them according to thirteen different types of behavior mentioned in the misconduct definition. We also obtained data on the institution's total research funding and public vs. private status, and the year it adopted the definition. We found that more than half (59%) of the institutions in our sample had misconduct policies that went beyond the federal standard. Other than FFP, the most common behaviors included in definitions were "other serious deviations" (45.4%), "significant or material violations of regulations" (23.0%), "misuse of confidential information" (15.8%), "misconduct related to misconduct" (14.8%), "unethical authorship other than plagiarism" (14.2%), "other deception involving data manipulation" (13.1%), and "misappropriation of property/theft" (10.4%). Significantly more definitions adopted in 2001 or later went beyond the federal standard than those adopted before 2001 (73.2% vs. 26.8%), and significantly more definitions adopted by institutions in the lower quartile of total research funding went beyond the federal standard than those adopted by institutions in the upper quartiles. Public vs. private status was not significantly associated with going beyond the federal standard. PMID- 25275622 TI - Problems with traditional science publishing and finding a wider niche for post publication peer review. AB - Science affects multiple basic sectors of society. Therefore, the findings made in science impact what takes place at a commercial level. More specifically, errors in the literature, incorrect findings, fraudulent data, poorly written scientific reports, or studies that cannot be reproduced not only serve as a burden on tax-payers' money, but they also serve to diminish public trust in science and its findings. Therefore, there is every need to fortify the validity of data that exists in the science literature, not only to build trust among peers, and to sustain that trust, but to reestablish trust in the public and private academic sectors that are witnessing a veritable battle-ground in the world of science publishing, in some ways spurred by the rapid evolution of the open access (OA) movement. Even though many science journals, traditional and OA, claim to be peer reviewed, the truth is that different levels of peer review occur, and in some cases no, insufficient, or pseudo-peer review takes place. This ultimately leads to the erosion of quality and importance of science, allowing essentially anything to become published, provided that an outlet can be found. In some cases, predatory OA journals serve this purpose, allowing papers to be published, often without any peer review or quality control. In the light of an explosion of such cases in predatory OA publishing, and in severe inefficiencies and possible bias in the peer review of even respectable science journals, as evidenced by the increasing attention given to retractions, there is an urgent need to reform the way in which authors, editors, and publishers conduct the first line of quality control, the peer review. One way to address the problem is through post-publication peer review (PPPR), an efficient complement to traditional peer-review that allows for the continuous improvement and strengthening of the quality of science publishing. PPPR may also serve as a way to renew trust in scientific findings by correcting the literature. This article explores what is broadly being said about PPPR in the literature, so as to establish awareness and a possible first-tier prototype for the sciences for which such a system is undeveloped or weak. PMID- 25275623 TI - Commentary: flawed science delays smelter cleanup and worsens health. AB - For 6,000 years, humans have known about smelter hazards. Yet these metals threats continue. Why? This commentary provides one preliminary answer. It (1) summarizes the history of smelter pollution and (2) suggests that at least 3 problems-especially flawed smelter-polluter science-allow continuing health threats. It (3) illustrates this flawed science by using one of the most dangerous of U.S. former smelters, in DePue, Illinois. There polluters are avoiding violating the law yet trying to minimize smelter-caused health threats, thus clean-up costs, by using two questionable scientific claims. The causality denial claim denies that smelter metals cause neurodegenerative diseases. The biomagnification-denial claim denies that food-chain biomagnification of smelter metals can put citizens at risk. The commentary shows both claims err, and (4) suggests ways to address flawed smelter science and resulting health harms. PMID- 25275624 TI - Letter to the editor: self-plagiarism, textual recycling, and conceptual plagiarism. PMID- 25275625 TI - Evidence of a bacterial receptor for lysozyme: binding of lysozyme to the anti sigma factor RsiV controls activation of the ecf sigma factor sigmaV. AB - sigma factors endow RNA polymerase with promoter specificity in bacteria. Extra Cytoplasmic Function (ECF) sigma factors represent the largest and most diverse family of sigma factors. Most ECF sigma factors must be activated in response to an external signal. One mechanism of activation is the stepwise proteolytic destruction of an anti-sigma factor via Regulated Intramembrane Proteolysis (RIP). In most cases, the site-1 protease required to initiate the RIP process directly senses the signal. Here we report a new mechanism in which the anti sigma factor rather than the site-1 protease is the sensor. We provide evidence suggesting that the anti-sigma factor RsiV is the bacterial receptor for the innate immune defense enzyme, lysozyme. The site-1 cleavage site is similar to the recognition site of signal peptidase and cleavage at this site is required for sigmaV activation in Bacillus subtilis. We reconstitute site-1 cleavage in vitro and demonstrate that it requires both signal peptidase and lysozyme. We demonstrate that the anti-sigma factor RsiV directly binds to lysozyme and muramidase activity is not required for sigmaV activation. We propose a model in which the binding of lysozyme to RsiV activates RsiV for signal peptidase cleavage at site-1, initiating proteolytic destruction of RsiV and activation of sigmaV. This suggests a novel mechanism in which conformational change in a substrate controls the cleavage susceptibility for signal peptidase. Thus, unlike other ECF sigma factors which require regulated intramembrane proteolysis for activation, the sensor for sigmaV activation is not the site-1 protease but the anti-sigma factor. PMID- 25275627 TI - High fat diet modulates Trypanosoma cruzi infection associated myocarditis. AB - BACKGROUND: Trypanosoma cruzi, the causative agent of Chagas disease, has high affinity for lipoproteins and adipose tissue. Infection results in myocarditis, fat loss and alterations in lipid homeostasis. This study was aimed at analyzing the effect of high fat diet (HFD) on regulating acute T. cruzi infection-induced myocarditis and to evaluate the effect of HFD on lipid metabolism in adipose tissue and heart during acute T. cruzi infection. METHODOLOGY/PRINCIPAL FINDINGS: CD1 mice were infected with T. cruzi (Brazil strain) and fed either a regular control diet (RD) or HFD for 35 days following infection. Serum lipid profile, tissue cholesterol levels, blood parasitemia, and tissue parasite load were analyzed to evaluate the effect of diet on infection. MicroPET and MRI analysis were performed to examine the morphological and functional status of the heart during acute infection. qPCR and immunoblot analysis were carried out to analyze the effect of diet on the genes involved in the host lipid metabolism during infection. Oil red O staining of the adipose tissue demonstrated reduced lipolysis in HFD compared to RD fed mice. HFD reduced mortality, parasitemia and cardiac parasite load, but increased parasite load in adipocytes. HFD decreased lipolysis during acute infection. Both qPCR and protein analysis demonstrated alterations in lipid metabolic pathways in adipose tissue and heart in RD fed mice, which were further modulated by HFD. Both microPET and MRI analyses demonstrated changes in infected RD murine hearts which were ameliorated by HFD. CONCLUSION/SIGNIFICANCE: These studies indicate that Chagasic cardiomyopathy is associated with a cardiac lipidpathy and that both cardiac lipotoxicity and adipose tissue play a role in the pathogenesis of Chagas disease. HFD protected mice from T. cruzi infection-induced myocardial damage most likely due to the effects of HFD on both adipogenesis and T. cruzi infection-induced cardiac lipidopathy. PMID- 25275626 TI - Cell type specific alterations in interchromosomal networks across the cell cycle. AB - The interchromosomal organization of a subset of human chromosomes (#1, 4, 11, 12, 16, 17, and 18) was examined in G1 and S phase of human WI38 lung fibroblast and MCF10A breast epithelial cells. Radial positioning of the chromosome territories (CTs) was independent of gene density, but size dependent. While no changes in radial positioning during the cell cycle were detected, there were stage-specific differences between cell types. Each CT was in close proximity (interaction) with a similar number of other CT except the gene rich CT17 which had significantly more interactions. Furthermore, CT17 was a member of the highest pairwise CT combinations with multiple interactions. Major differences were detected in the pairwise interaction profiles of MCF10A versus WI38 including cell cycle alterations from G1 to S. These alterations in interaction profiles were subdivided into five types: overall increase, overall decrease, switching from 1 to >=2 interactions, vice versa, or no change. A global data mining program termed the chromatic median determined the most probable overall association network for the entire subset of CT. This probabilistic interchromosomal network was nearly completely different between the two cell lines. It was also strikingly altered across the cell cycle in MCF10A, but only slightly in WI38. We conclude that CT undergo multiple and preferred interactions with other CT in the nucleus and form preferred -albeit probabilistic- interchromosomal networks. This network of interactions is altered across the cell cycle and between cell types. It is intriguing to consider the relationship of these alterations to the corresponding changes in the gene expression program across the cell cycle and in different cell types. PMID- 25275628 TI - Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study. AB - BACKGROUND: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). METHODS AND RESULTS: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (>=50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF<=1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r2 = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r2 = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures. CONCLUSION: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample. PMID- 25275629 TI - What goes in must come out: testing for biases in molecular analysis of arbuscular mycorrhizal fungal communities. AB - Arbuscular mycorrhizal (AM) fungi are widely distributed microbes that form obligate symbioses with the majority of terrestrial plants, altering nutrient transfers between soils and plants, thereby profoundly affecting plant growth and ecosystem properties. Molecular methods are commonly used in the study of AM fungal communities. However, the biases associated with PCR amplification of these organisms and their ability to be utilized quantitatively has never been fully tested. We used Terminal Restriction Fragment Length Polymorphism (TRFLP) analysis to characterise artificial community templates containing known quantities of defined AM fungal genotypes. This was compared to a parallel in silico analysis that predicted the results of this experiment in the absence of bias. The data suggest that when used quantitatively the TRFLP protocol tested is a powerful, repeatable method for AM fungal community analysis. However, we suggest some limitations to its use for population-level analyses. We found no evidence of PCR bias, supporting the quantitative use of other PCR-based methods for the study of AM fungi such as next generation amplicon sequencing. This finding greatly improves our confidence in methods that quantitatively examine AM fungal communities, providing a greater understanding of the ecology of these important fungi. PMID- 25275633 TI - Detecting non-bridging oxygens: non-resonant inelastic X-ray scattering in crystalline lithium borates. AB - Probing the local environment of low-Z elements, such as oxygen, is of great interest for understanding the atomic-scale behavior in materials, but it requires experimental techniques allowing it to work with versatile sample environments. In this paper, the local environment of lithium borate crystals is investigated using non-resonant inelastic X-ray scattering (NRIXS) at energy losses corresponding to the oxygen K-edge. Large variations of the spectral features are observed close to the edge onset in the 535-540 eV energy range when varying the Li2O content. Calculations allow identification of contributions associated with bridging oxygen (BO) and non-bridging oxygen (NBO) atoms. The main result resides in the observed core-level shift of about 1.7 eV in the spectral signatures of the BO and NBO. The clear signature at 535 eV in the O K edge NRXIS spectrum is thus an original way to probe the presence of NBOs in borates, with the great advantage of making possible the use of complex environments such as a high-pressure cell or high-temperature device for in situ measurements. PMID- 25275634 TI - Charge-transfer interactions for the fabrication of multifunctional viral nanoparticles. AB - A facile strategy to fabricate multifunctional viral nanoparticles was described by introducing charge-transfer interactions between a pyrenyl motif with dinitrophenyl and pyridinium-contained guest molecules. PMID- 25275631 TI - Prognostic significance of systemic inflammation-based lymphocyte- monocyte ratio in patients with lung cancer: based on a large cohort study. AB - Increasing evidence indicates cancer-related inflammatory biomarkers show great promise for predicting the outcome of cancer patients. The lymphocyte- monocyte ratio (LMR) was demonstrated to be independent prognostic factor mainly in hematologic tumor. The aim of the present study was to investigate the prognostic value of LMR in operable lung cancer. We retrospectively enrolled a large cohort of patients with primary lung cancer who underwent complete resection at our institution from 2006 to 2011. Inflammatory biomarkers including lymphocyte count and monocyte count were collected from routinely performed preoperative blood tests and the LMR was calculated. Survival analyses were calculated for overall survival (OS) and disease-free survival (DFS). A total of 1453 patients were enrolled in the study. The LMR was significantly associated with OS and DFS in multivariate analyses of the whole cohort (HR = 1.522, 95% CI: 1.275-1.816 for OS, and HR = 1.338, 95% CI: 1.152-1.556 for DFS). Univariate subgroup analyses disclosed that the prognostic value was limited to patients with non-small-cell lung cancer (NSCLC) (HR: 1.824, 95% CI: 1.520-2.190), in contrast to patients with small cell lung cancer (HR: 1.718, 95% CI: 0.946-3.122). Multivariate analyses demonstrated that LMR was still an independent prognostic factor in NSCLC. LMR can be considered as a useful independent prognostic marker in patients with NSCLC after complete resection. This will provide a reliable and convenient biomarker to stratify high risk of death in patients with operable NSCLC. PMID- 25275632 TI - Latitudinal variation of a defensive symbiosis in the Bugula neritina (Bryozoa) sibling species complex. AB - Mutualistic relationships are beneficial for both partners and are often studied within a single environment. However, when the range of the partners is large, geographical differences in selective pressure may shift the relationship outcome from positive to negative. The marine bryozoan Bugula neritina is a colonial invertebrate common in temperate waters worldwide. It is the source of bioactive polyketide metabolites, the bryostatins. Evidence suggests that an uncultured vertically transmitted symbiont, "Candidatus Endobugula sertula", hosted by B. neritina produces the bryostatins, which protect the vulnerable larvae from predation. Studies of B. neritina along the North American Atlantic coast revealed a complex of two morphologically similar sibling species separated by an apparent biogeographic barrier: the Type S sibling species was found below Cape Hatteras, North Carolina, while Type N was found above. Interestingly, the Type N colonies lack "Ca. Endobugula sertula" and, subsequently, defensive bryostatins; their documented northern distribution was consistent with traditional biogeographical paradigms of latitudinal variation in predation pressure. Upon further sampling of B. neritina populations, we found that both host types occur in wider distribution, with Type N colonies living south of Cape Hatteras, and Type S to the north. Distribution of the symbiont, however, was not restricted to Type S hosts. Genetic and microscopic evidence demonstrates the presence of the symbiont in some Type N colonies, and larvae from these colonies are endowed with defensive bryostatins and contain "Ca. Endobugula sertula". Molecular analysis of the symbiont from Type N colonies suggests an evolutionarily recent acquisition, which is remarkable for a symbiont thought to be transmitted only vertically. Furthermore, most Type S colonies found at higher latitudes lack the symbiont, suggesting that this host-symbiont relationship is more flexible than previously thought. Our data suggest that the symbiont, but not the host, is restricted by biogeographical boundaries. PMID- 25275630 TI - Identification of cell-binding adhesins of Leptospira interrogans. AB - Leptospirosis is a globally distributed bacterial infectious disease caused by pathogenic members of the genus Leptospira. Infection can lead to illness ranging from mild and non-specific to severe, with jaundice, kidney and liver dysfunction, and widespread endothelial damage. The adhesion of pathogenic Leptospira species (spp.), the causative agent of leptospirosis, to host tissue components is necessary for infection and pathogenesis. While it is well established that extracellular matrix (ECM) components play a role in the interaction of the pathogen with host molecules, we have shown that pathogenic Leptospira interrogans binds to host cells more efficiently than to ECM components. Using in vitro phage display to select for phage clones that bind to EA.hy926 endothelial cells, we identified the putative lipoproteins LIC10508 and LIC13411, and the conserved hypothetical proteins LIC12341 and LIC11574, as candidate L. interrogans sv. Copenhageni st. Fiocruz L1-130 adhesins. Recombinant LIC11574, but not its L. biflexa homologue LBF1629, exhibited dose-dependent binding to both endothelial and epithelial cells. In addition, LIC11574 and LIC13411 bind to VE-cadherin, an endothelial cell receptor for L. interrogans. Extraction of bacteria with the non-ionic detergent Triton X-114 resulted in partitioning of the candidate adhesins to the detergent fraction, a likely indication that these proteins are outer membrane localized. All candidate adhesins were recognized by sera obtained from leptospirosis patients but not by sera from healthy individuals as assessed by western blot. This work has identified bacterial adhesins that are potentially involved in L. interrogans infection of the mammalian host, and through cadherin binding, may contribute to dissemination and vascular damage. Our findings may be of value in leptospirosis control and prevention, with the bacterial adhesins potentially serving as targets for development of diagnostics, therapeutics, and vaccines. PMID- 25275635 TI - Both transmembrane domains of BK beta1 subunits are essential to confer the normal phenotype of beta1-containing BK channels. AB - Voltage/Ca2+(i)-gated, large conductance K+ (BK) channels result from tetrameric association of alpha (slo1) subunits. In most tissues, BK protein complexes include regulatory beta subunits that contain two transmembrane domains (TM1, TM2), an extracellular loop, and two short intracellular termini. Four BK beta types have been identified, each presenting a rather selective tissue-specific expression profile. Thus, BK beta modifies current phenotype to suit physiology in a tissue-specific manner. The smooth muscle-abundant BK beta1 drastically increases the channel's apparent Ca2+(i) sensitivity. The resulting phenotype is critical for BK channel activity to increase in response to Ca2+ levels reached near the channel during depolarization-induced Ca2+ influx and myocyte contraction. The eventual BK channel activation generates outward K+ currents that drive the membrane potential in the negative direction and eventually counteract depolarization-induced Ca2+ influx. The BK beta1 regions responsible for the characteristic phenotype of beta1-containing BK channels remain to be identified. We used patch-clamp electrophysiology on channels resulting from the combination of smooth muscle slo1 (cbv1) subunits with smooth muscle-abundant beta1, neuron-abundant beta4, or chimeras constructed by swapping beta1 and beta4 regions, and determined the contribution of specific beta1 regions to the BK phenotype. At Ca2+ levels found near the channel during myocyte contraction (10 uM), channel complexes that included chimeras having both TMs from beta1 and the remaining regions ("background") from beta4 showed a phenotype (V(half), tau(act), tau(deact)) identical to that of complexes containing wt beta1. This phenotype could not be evoked by complexes that included chimeras combining either beta1 TM1 or beta1 TM2 with a beta4 background. Likewise, beta "halves" (each including beta1 TM1 or beta1 TM2) resulting from interrupting the continuity of the EC loop failed to render the normal phenotype, indicating that physical connection between beta1 TMs via the EC loop is also necessary for proper channel function. PMID- 25275636 TI - Beta-amyloid oligomers induce early loss of presynaptic proteins in primary neurons by caspase-dependent and proteasome-dependent mechanisms. AB - Beta-amyloid is a major pathogenic molecule for Alzheimer's disease (AD) and can be aggregated into a soluble oligomer, which is a toxic intermediate, before amyloid fibril formation. Beta-amyloid oligomers are associated closely with early synaptic loss in AD. However, it is still unknown which synaptic proteins are involved in the synaptotoxicity, and a direct comparison among the synaptic proteins should also be addressed. Here, we investigated changes in the expression of several presynaptic and postsynaptic proteins in primary neurons after treatment with a low-molecular weight and a high-molecular weight beta amyloid oligomer. Both oligomers induced early neuronal dysfunction after 4 h and significantly reduced presynaptic protein (synaptophysin, syntaxin, synapsin, and synaptotagmin) expression. However, the expression of postsynaptic proteins (PSD95, NMDAR2A/B, and GluR2/3), except NMDAR1 was not reduced, and some protein expression levels were increased. Glutamate treatment, which is correlated with postsynaptic activation, showed more postsynaptic-specific protein loss compared with beta-amyloid oligomer treatment. Finally, the caspase inhibitor zVAD and the proteasomal inhibitor MG132 attenuated presynaptic protein loss. Thus, our data showed changes in synaptic proteins by beta-amyloid oligomers, which provides an understanding of early synaptotoxicity and suggests new approaches for AD treatment. PMID- 25275637 TI - Rendaku (Japanese sequential voicing) as rule application: an ERP study. AB - Japanese sequential voicing (rendaku) is a process of voicing the initial obstruent of the second member of a compound word in Japanese (e.g. hon 'book'+tana 'shelf'->hon-dana). We conducted an event-related potential measurement experiment to investigate whether rendaku is a regular process of rule application or an analogical process based on lexical memory. When rendaku was applied wrongly to words lexically specified to resist rendaku, a left anterior negativity component, followed by a P600 was observed, whereas applying rendaku against a phonological constraint known as Lyman's law elicited a P600 component alone. Failure of rendaku application where it should apply yielded an N400. These results suggest that rendaku is a process involving rule application. PMID- 25275638 TI - Neural correlates of executive dysfunction in schizophrenia: failure to modulate brain activity with task demands. AB - In schizophrenia, executive functions are impaired and are associated with altered activation of prefrontal areas. We used H2[15]O PET to examine patients with schizophrenia and matched controls on a random number generation (RNG) task and a control counting (COUNT) task. To assess the effects of increasing task demand, both tasks were performed at three different rates (intervals 1, 2 or 3 s). Both groups showed a significant increase in the nonrandomness of responses at faster rates of RNG. Despite similar performances, patients but not controls showed higher activation of the right dorsolateral prefrontal cortex (DLPFC) and atypically reduced activation of the right anterior cingulate gyrus and the right medial frontal gyrus in RNG compared with COUNT, whereas only for controls, activation of the left DLPFC was increased and activation of the right superior temporal gyrus and the right superior frontal gyrus was reduced in the same comparison. Whereas for the controls several cortical areas including the bilateral superior temporal gyrus and the bilateral DLPFC, together with the right cerebellum, showed significant changes in regional cerebral blood flow with faster or slower rates, patients with schizophrenia showed rate-dependent changes only in the left cerebellum. In conclusion, the patients' failure to modulate cortical activation with changing demands of rate, particularly in prefrontal areas and in the cerebellum, and even when performance is similar to that in healthy controls, is a characteristic of their abnormal pattern of executive processing. PMID- 25275639 TI - Positive correlation between drowsiness and prefrontal activation during a simulated speed-control driving task. AB - The present study aimed to examine the relationship between drowsiness and prefrontal activation during simulated driving tasks using a wireless portable near-infrared spectroscopy device. Participants drove from start to goal along default routes with either intentional control of their driving speed (speed control group) or not (speed-free group). Drowsiness level was assessed using a five-item Likert-type questionnaire. The behavioral data indicated longer driving time in the speed-control group than in the speed-free group, whereas no difference in the number of errors was found between the two groups. Importantly, the speed-control group showed a significant positive correlation between the drowsiness score and left prefrontal activation, whereas the speed-free group did not. The results suggest that drowsy individuals may show increased prefrontal activation as compensatory efforts to maintain the desired level of performance in tasks that require deliberate control of behaviors. Furthermore, the present study shows that near-infrared spectroscopy may provide us with a possibility to examine the state of drowsiness during daily-life operations. PMID- 25275640 TI - Acute exercise increases oxygenated and deoxygenated hemoglobin in the prefrontal cortex. AB - Both acute and chronic exercise is consistently associated with a number of benefits to physical and mental health, including cardiovascular function, body weight, mood, and cognition. Near-infrared spectroscopy is an ideal method to measure changes in oxygenated and deoxygenated hemoglobin (O2Hb and dHb) levels in the prefrontal cortex (PFC) during exercise, to better understand the locus of such changes in affective and cognitive processes. The present study tracked time dependent changes in O2Hb and dHb levels in the PFC as a function of parametrically manipulated target exercise intensity. Near-infrared spectroscopy was conducted as regular exercisers completed a 30-min bout of exercise with one of three target intensities: 52% (low condition), 68% (moderate condition), or 84% (high condition) of age-adjusted maximum heart rate. Heart rate data confirmed that the participants reached their goal intensities immediately, after 10 min, or after 20 min, respectively. Data showed that O2Hb and dHb levels in the PFC increased as a function of both exercise load and duration. An 84%>68%>52% difference was evident after 18 min of cycling for O2Hb and after 23 min of cycling for dHb. The present results add to the growing body of literature showing that at submaximal levels, increasing exercise intensities reliably promote prefrontal cerebral oxygenation. PMID- 25275641 TI - Nonconscious memory for motion activates MT+. AB - Extrastriate region MT+ is widely thought to reflect conscious motion processing. The primary aim of the present functional MRI study was to assess whether MT+ is activated during nonconscious memory for motion. During the encoding phase, moving and stationary abstract shapes were presented to the left or right of fixation. During the retrieval phase, the same shapes were presented at fixation and participants classified each shape as 'moving-left', 'moving-right', 'stationary-left', or 'stationary-right'. The contrast of moving>stationary shapes at encoding was used to identify the location of MT+. Event-related activity was then extracted from MT+ within each hemisphere. MT+ activity was significantly greater for moving-misses than for stationary-misses, which indicates that nonconscious memory for motion activates MT+. Furthermore, nonconscious memory activity (moving-misses) had an earlier temporal onset than conscious memory activity (moving-hits). The present results are the first, to our knowledge, to demonstrate that MT+ is associated with nonconscious motion processing. Therefore, activity in this region or in other visual-sensory regions should not be assumed to reflect conscious processing. PMID- 25275642 TI - Adaptive prediction as a strategy in microbial infections. PMID- 25275643 TI - Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. AB - Antibodies targeting receptor-mediated entry of HCV into hepatocytes confer limited therapeutic benefits. Evidence suggests that exosomes can transfer genetic materials between cells; however, their role in HCV infection remains obscure. Here, we show that exosomes isolated from sera of chronic HCV infected patients or supernatants of J6/JFH1-HCV-infected Huh7.5 cells contained HCV RNA. These exosomes could mediate viral receptor-independent transmission of HCV to hepatocytes. Negative sense HCV RNA, indicative of replication competent viral RNA, was present in exosomes of all HCV infected treatment non-responders and some treatment-naive individuals. Remarkably, HCV RNA was associated with Ago2, HSP90 and miR-122 in exosomes isolated from HCV-infected individuals or HCV infected Huh7.5 cell supernatants. Exosome-loading with a miR-122 inhibitor, or inhibition of HSP90, vacuolar H+-ATPases, and proton pumps, significantly suppressed exosome-mediated HCV transmission to naive cells. Our findings provide mechanistic evidence for HCV transmission by blood-derived exosomes and highlight potential therapeutic strategies. PMID- 25275645 TI - Characterization of fibrillar collagens and extracellular matrix of glandular benign prostatic hyperplasia nodules. AB - OBJECTIVE: Recent studies have associated lower urinary tract symptoms (LUTS) in men with prostatic fibrosis, but a definitive link between collagen deposition and LUTS has yet to be demonstrated. The objective of this study was to evaluate ECM and collagen content within normal glandular prostate tissue and glandular BPH, and to evaluate the association of clinical parameters of LUTS with collagen content. METHODS: Fibrillar collagen and ECM content was assessed in normal prostate (48 patients) and glandular BPH nodules (24 patients) using Masson's trichrome stain and Picrosirius red stain. Second harmonic generation (SHG) imaging was used to evaluate collagen content. Additional BPH tissues (n = 47) were stained with Picrosirius red and the association between clinical parameters of BPH/LUTS and collagen content was assessed. RESULTS: ECM was similar in normal prostate and BPH (p = 0.44). Total collagen content between normal prostate and glandular BPH was similar (p = 0.27), but a significant increase in thicker collagen bundles was observed in BPH (p = 0.045). Using SHG imaging, collagen content in BPH (mean intensity = 62.52; SEM = 2.74) was significantly higher than in normal prostate (51.77+/-3.49; p = 0.02). Total collagen content was not associated with treatment with finasteride (p = 0.47) or alpha-blockers (p = 0.52), pre-TURP AUA symptom index (p = 0.90), prostate-specific antigen (p = 0.86), post-void residual (PVR; p = 0.32), prostate size (p = 0.21), or post-TURP PVR (p = 0.51). Collagen content was not associated with patient age in patients with BPH, however as men aged normal prostatic tissue had a decreased proportion of thick collagen bundles. CONCLUSIONS: The proportion of larger bundles of collagen, but not total collagen, is increased in BPH nodules, suggesting that these large fibers may play a role in BPH/LUTS. Total collagen content is independent of clinical parameters of BPH and LUTS. If fibrosis and overall ECM deposition are associated with BPH/LUTS, this relationship likely exists in regions of the prostate other than glandular hyperplasia. PMID- 25275646 TI - Synergism and antagonism between Bacillus thuringiensis Vip3A and Cry1 proteins in Heliothis virescens, Diatraea saccharalis and Spodoptera frugiperda. AB - Second generation Bt crops (insect resistant crops carrying Bacillus thuringiensis genes) combine more than one gene that codes for insecticidal proteins in the same plant to provide better control of agricultural pests. Some of the new combinations involve co-expression of cry and vip genes. Because Cry and Vip proteins have different midgut targets and possibly different mechanisms of toxicity, it is important to evaluate possible synergistic or antagonistic interactions between these two classes of toxins. Three members of the Cry1 class of proteins and three from the Vip3A class were tested against Heliothis virescens for possible interactions. At the level of LC50, Cry1Ac was the most active protein, whereas the rest of proteins tested were similarly active. However, at the level of LC90, Cry1Aa and Cry1Ca were the least active proteins, and Cry1Ac and Vip3A proteins were not significantly different. Under the experimental conditions used in this study, we found an antagonistic effect of Cry1Ca with the three Vip3A proteins. The interaction between Cry1Ca and Vip3Aa was also tested on two other species of Lepidoptera. Whereas antagonism was observed in Spodoptera frugiperda, synergism was found in Diatraea saccharalis. In all cases, the interaction between Vip3A and Cry1 proteins was more evident at the LC90 level than at the LC50 level. The fact that the same combination of proteins may result in a synergistic or an antagonistic interaction may be an indication that there are different types of interactions within the host, depending on the insect species tested. PMID- 25275647 TI - Two strategies for response to 14 degrees C cold-water immersion: is there a difference in the response of motor, cognitive, immune and stress markers? AB - Here, we address the question of why some people have a greater chance of surviving and/or better resistance to cold-related-injuries in prolonged exposure to acute cold environments than do others, despite similar physical characteristics. The main aim of this study was to compare physiological and psychological reactions between people who exhibited fast cooling (FC; n = 20) or slow cooling (SC; n = 20) responses to cold water immersion. Individuals in whom the T(re) decreased to a set point of 35.5 degrees C before the end of the 170 min cooling time were indicated as the FC group; individuals in whom the T(re) did not decrease to the set point of 35.5 degrees C before the end of the 170 min cooling time were classified as the SC group. Cold stress was induced using intermittent immersion in bath water at 14 degrees C. Motor (spinal and supraspinal reflexes, voluntary and electrically induced skeletal muscle contraction force) and cognitive (executive function, short term memory, short term spatial recognition) performance, immune variables (neutrophils, leucocytes, lymphocytes, monocytes, IL-6, TNF-alpha), markers of hypothalamic-pituitary adrenal axis activity (cortisol, corticosterone) and autonomic nervous system activity (epinephrine, norepinephrine) were monitored. The data obtained in this study suggest that the response of the FC group to cooling vs the SC group response was more likely an insulative-hypothermic response and that the SC vs the FC group displayed a metabolic-insulative response. The observations that an exposure time to 14 degrees C cold water--which was nearly twice as short (96 min vs 170-min) with a greater rectal temperature decrease (35.5 degrees C vs 36.2 degrees C) in the FC group compared with the SC group--induces similar responses of motor, cognitive, and blood stress markers were novel. The most important finding is that subjects with a lower cold-strain-index (SC group) showed stimulation of some markers of innate immunity and suppression of markers of specific immunity. PMID- 25275648 TI - Effects of secondary metabolite extract from Phomopsis occulta on beta-amyloid aggregation. AB - Inhibition of beta-amyloid (Abeta) aggregation is an attractive therapeutic and preventive strategy for the discovery of disease-modifying agents in Alzheimer's disease (AD). Phomopsis occulta is a new, salt-tolerant fungus isolated from mangrove Pongamia pinnata (L.) Pierre. We report here the inhibitory effects of secondary metabolites from Ph. occulta on the aggregation of Abeta42. It was found that mycelia extracts (MEs) from Ph. occulta cultured with 0, 2, and 3 M NaCl exhibited inhibitory activity in an E. coli model of Abeta aggregation. A water-soluble fraction, ME0-W-F1, composed of mainly small peptides, was able to reduce aggregation of an Abeta42-EGFP fusion protein and an early onset familial mutation Abeta42E22G-mCherry fusion protein in transfected HEK293 cells. ME0-W-F1 also antagonized the cytotoxicity of Abeta42 in the neural cell line SH-SY5Y in dose-dependent manner. Moreover, SDS-PAGE and FT-IR analysis confirmed an inhibitory effect of ME0-W-F1 on the aggregation of Abeta42 in vitro. ME0-W-F1 blocked the conformational transition of Abeta42 from alpha-helix/random coil to beta-sheet, and thereby inhibited formation of Abeta42 tetramers and high molecular weight oligomers. ME0-W-F1 and other water-soluble secondary metabolites from Ph. occulta therefore represent new candidate natural products against aggregation of Abeta42, and illustrate the potential of salt tolerant fungi from mangrove as resources for the treatment of AD and other diseases. PMID- 25275649 TI - Confidence sharing: an economic strategy for efficient information flows in animal groups. AB - Social animals may share information to obtain a more complete and accurate picture of their surroundings. However, physical constraints on communication limit the flow of information between interacting individuals in a way that can cause an accumulation of errors and deteriorated collective behaviors. Here, we theoretically study a general model of information sharing within animal groups. We take an algorithmic perspective to identify efficient communication schemes that are, nevertheless, economic in terms of communication, memory and individual internal computation. We present a simple and natural algorithm in which each agent compresses all information it has gathered into a single parameter that represents its confidence in its behavior. Confidence is communicated between agents by means of active signaling. We motivate this model by novel and existing empirical evidences for confidence sharing in animal groups. We rigorously show that this algorithm competes extremely well with the best possible algorithm that operates without any computational constraints. We also show that this algorithm is minimal, in the sense that further reduction in communication may significantly reduce performances. Our proofs rely on the Cramer-Rao bound and on our definition of a Fisher Channel Capacity. We use these concepts to quantify information flows within the group which are then used to obtain lower bounds on collective performance. The abstract nature of our model makes it rigorously solvable and its conclusions highly general. Indeed, our results suggest confidence sharing as a central notion in the context of animal communication. PMID- 25275644 TI - Current and potential treatments for ubiquitous but neglected herpesvirus infections. PMID- 25275650 TI - Trajectories of HbA1c levels in children and youth with type 1 diabetes. AB - PURPOSE: To illustrate the distribution of Hemoglobin A1c (HbA1c) levels according to age and gender among children, adolescents and youth with type 1 diabetes (T1DM). METHODS: Consecutive HbA1c measurements of 349 patients, aged 2 to 30 years with T1DM were obtained from 1995 through 2010. Measurement from patients diagnosed with celiac disease (n = 20), eating disorders (n = 41) and hemoglobinopathy (n = 1) were excluded. The study sample comprised 4815 measurements of HbA1c from 287 patients. Regression percentiles of HbA1c were calculated as a function of age and gender by the quantile regression method using the SAS procedure QUANTREG. RESULTS: Crude percentiles of HbA1c as a function of age and gender, and the modeled curves produced using quantile regression showed good concordance. The curves show a decline in HbA1c levels from age 2 to 4 years at each percentile. Thereafter, there is a gradual increase during the prepubertal years with a peak at ages 12 to 14 years. HbA1c levels subsequently decline to the lowest values in the third decade. Curves of females and males followed closely, with females having HbA1c levels about 0.1% (1.1 mmol/mol) higher in the 25th 50th and 75th percentiles. CONCLUSION: We constructed age-specific distribution curves for HbA1c levels for patients with T1DM. These percentiles may be used to demonstrate the individual patient's measurements longitudinally compared with age-matched patients. PMID- 25275651 TI - Structural basis for inhibition of the MDM2:p53 interaction by an optimized MDM2 binding peptide selected with mRNA display. AB - The oncoprotein MDM2 binds to tumor suppressor protein p53 and inhibits its anticancer activity, which leads to promotion of tumor cell growth and tumor survival. Abrogation of the p53:MDM2 interaction reportedly results in reactivation of the p53 pathway and inhibition of tumor cell proliferation. We recently performed rigorous selection of MDM2-binding peptides by means of mRNA display and identified an optimal 12-mer peptide (PRFWEYWLRLME), named MDM2 Inhibitory Peptide (MIP), which shows higher affinity for MDM2 (and also its homolog, MDMX) and higher tumor cell proliferation suppression activity than known peptides. Here we determined the NMR solution structure of a MIP-MDM2 fusion protein to elucidate the structural basis of the tight binding of MIP to MDM2. A region spanning from Phe3 to Met11 of MIP forms a single alpha-helix, which is longer than those of the other MDM2-binding peptides. MIP shares a conserved Phe3-Trp7-Leu10 triad, whose side chains are oriented towards and fit into the hydrophobic pockets of MDM2. Additionally, hydrophobic surface patches that surround the hydrophobic pockets of MDM2 are covered by solvent-exposed MIP residues, Trp4, Tyr6, and Met11. Their hydrophobic interactions extend the interface of the two molecules and contribute to the strong binding. The potential MDM2 inhibition activity observed for MIP turned out to originate from its enlarged binding interface. The structural information obtained in the present study provides a road map for the rational design of strong inhibitors of MDM2:p53 binding. PMID- 25275652 TI - Molecular epidemiology of Japanese encephalitis virus in mosquitoes in Taiwan during 2005-2012. AB - Japanese encephalitis (JE) is a mosquito-borne zoonotic disease caused by the Japanese encephalitis virus (JEV). Pigs and water birds are the main amplifying and maintenance hosts of the virus. In this study, we conducted a JEV survey in mosquitoes captured in pig farms and water bird wetland habitats in Taiwan during 2005 to 2012. A total of 102,633 mosquitoes were collected. Culex tritaeniorhynchus was the most common mosquito species found in the pig farms and wetlands. Among the 26 mosquito species collected, 11 tested positive for JEV by RT-PCR, including Cx. tritaeniorhynchus, Cx. annulus, Anopheles sinensis, Armigeres subalbatus, and Cx. fuscocephala. Among those testing positive, Cx. tritaeniorhynchus was the predominant vector species for the transmission of JEV genotypes I and III in Taiwan. The JEV infection rate was significantly higher in the mosquitoes from the pig farms than those from the wetlands. A phylogenetic analysis of the JEV envelope gene sequences isolated from the captured mosquitoes demonstrated that the predominant JEV genotype has shifted from genotype III to genotype I (GI), providing evidence for transmission cycle maintenance and multiple introductions of the GI strains in Taiwan during 2008 to 2012. This study demonstrates the intense JEV transmission activity in Taiwan, highlights the importance of JE vaccination for controlling the epidemic, and provides valuable information for the assessment of the vaccine's efficacy. PMID- 25275654 TI - Could progressive outer retinal necrosis begin with retinal deep capillary ischemia?--reply. PMID- 25275653 TI - Assessment of cytotoxic and genotoxic potential of pyracarbolid by Allium test and micronucleus assay. AB - The present study evaluates the cytotoxic and genotoxic potential of pyracarbolid using both micronuleus (MN) assay, in human lymphocytes, and Allium cepa assay, in the root meristem cells. In Allium test, EC50 value was determined in order to selecting the test concentrations for the assay and the root tips were treated with 25 ppm (EC50/2), 50 ppm (EC50) and 100 ppm (EC50 * 2) concentrations of pyracarbolid. One percent of dimethyl sulphoxide (DMSO) and methyl methane sulfonate (MMS) were used as negative and positive controls, respectively. In the micronucleus assay, the cultures were treated with four concentrations (250, 500, 750 and 1000 ug/ml) of pyracarbolid for 24 and 48 h, negative and positive controls were also used in the experiment parallely. The results showed that mitotic index (MI) significantly reduced with increasing the pyracarbolid concentration at each exposure time. It was also obtained that prophase and metaphase index decreased significantly in all concentration at each exposure time. Anaphase index decreased as well and results were found to be statistically significant, except 24 h. A significant increase was observed in MN frequency in all concentrations and both treatment periods when compared with the controls. Pyracarbolid also caused a significant reduction in the cytokinesis block proliferation index (CBPI) in all concentration and both exposure time. PMID- 25275655 TI - Validation study of the European Portuguese version of the Confusion Assessment Method (CAM). AB - BACKGROUND: The Confusion Assessment Method (CAM) is the most widely used delirium screening instrument. The aim of this study was to evaluate the reliability and validity of the European Portuguese version of CAM. METHODS: The sample included elderly patients (>=65 years), admitted for at least 48 h, into two intermediate care units (ICMU) of Intensive Medicine and Surgical Services in a university hospital. Exclusion criteria were: score <=11 on the Glasgow Coma Scale (GCS), blindness/deafness, inability to communicate and to speak Portuguese. For concurrent validity, a blinded assessment was conducted by a psychiatrist (DSM-IV-TR, as a reference standard) and by a trained researcher (CAM). This instrument was also compared with other cognitive measures to evaluate convergent validity. Inter-rater reliability was also assessed. RESULTS: In this sample (n = 208), 25% (n = 53) of the patients had delirium, according to DSM-IV-TR. Using this reference standard, the CAM had a moderate sensitivity of 79% and an excellent specificity of 99%. The positive predictive value was 95%, indicating a strong ability to confirm delirium with a positive test result, and the negative predictive value was lower (93%). Good convergent validity was also found, in particular with Mini-Mental State Examination (MMSE) (rs = -0.676; p <=0.01) and Digit Span Test (DST) forward (rs = -0.605; p <=0.01), as well as a high inter-rater reliability (diagnostic k = 1.00; single items' k between 0.65 and 1.00). CONCLUSION: Robust results on concurrent and convergent validity and good reliability were achieved. This version was shown to be a valid and reliable instrument for delirium detection in elderly patients hospitalized in intermediate care units. PMID- 25275656 TI - Is there a multiplicative adverse effect of cardiovascular and kidney disease on neuropsychological measures? AB - Increasing age is accompanied by increased incidence and comorbidity of various chronic diseases. Many of these conditions, such as cardiovascular and kidney disease, can lead to declines in cognitive functioning. A simple additive effect may be commonly assumed. We here evaluate the hypothesis that such effects may be multiplicative/interactive rather than simply additive, resulting in disproportionate decrements in performance on tests of different cognitive functions. Participants were the 1,782 Canadians aged 65 years and older who completed the clinical assessment of the national Canadian Study of Health and Aging and who were without dementia. Participants were categorized as having either kidney disease, cardiovascular disease, neither, or both. Scores on a measure of verbal fluency showed the predicted interaction effects, but not in the predicted pattern of worst performance in the group with both disorders. Reasons for the relative lack of observed main effects of disease and multiplicative interactions, such as the exclusion of people with dementia and nature of the sample from the community, are discussed. PMID- 25275657 TI - Changes in causes of death among persons with AIDS: San Francisco, California, 1996-2011. AB - The increased life expectancy among HIV-infected persons treated with combination antiretroviral therapy (ART), risk behaviors, and co-morbidities associated with ART place HIV-infected persons at risk for non-HIV-related causes of death. We used the San Francisco HIV/AIDS registry to identify deaths that occurred from January 1996 through December 2011. Temporal trends in AIDS- and non-AIDS-related mortality rates, the proportion of underlying and contributory causes of death, and the ratio of observed deaths in the study population to expected number of deaths among California men aged 20-79 (standardized mortality ratio [SMR]) of underlying causes of death were examined. A total of 5338 deaths were identified. The annual AIDS-related death rate (per 100 deaths) declined from 10.8 in 1996 to 0.9 in 2011 (p<0.0001), while the annual death rate from non-AIDS-related causes declined from 2.1 in 1996 to 0.9 in 2011 (p<0.0001). The proportion of deaths due to all types of heart disease combined, all non-AIDS cancers combined, mental disorders resulting from substance abuse, drug overdose, suicide and chronic obstructive pulmonary disease increased significantly over time. The SMRs for liver diseased decreased significantly over time but remained elevated. Our data highlight the importance of age-related causes of death as well as deaths from causes that are, at least in part, preventable. PMID- 25275659 TI - The impact of body mass index on radiotherapy technique in patients with early stage endometrial cancer: a single-center dosimetric study. AB - OBJECTIVE: We aimed to evaluate the impact of body mass index on radiotherapy (RT) technique in patients with early-stage endometrial cancer. MATERIALS AND METHODS: Twenty-seven consecutive patients were included in the study and divided into 3 groups with respect to their body mass index (normal weight, 18.5-24.9 kg/m; overweight, 25-29.9 kg/m; obese, 30-39.9 kg/m). Treatment plans using field in-field (FIF) and 3-dimensional conformal RT (3D-CRT) were compared for the doses in the planning target volume (PTV), organs-at-risk (OAR) volumes, dose homogeneity index, and monitor unit counts required for the treatment. RESULTS: The FIF technique was superior to 3D-CRT with respect to the maximum and mean doses received by OAR and dose homogeneity index values. The subgroup analyses revealed that the maximum dose received by the right femur and the mean doses received by the rectum and bladder were significantly reduced only in obese patients (Ps = 0.021, 0.008, and 0.008, respectively). The FIF technique significantly reduced the PTV volumes irradiated with greater than 105% of the prescribed dose (P < 0.001). The volumes of bowel and bone marrow receiving more than the prescribed dose of 30 Gy were significantly reduced only in obese patients (Ps = 0.025 and 0.043, respectively). The volumes of bladder, bowel, and bone marrow receiving more than the prescribed dose of 45 Gy were significantly reduced in only obese patients (Ps = 0.011, 0.011, and 0.008, respectively). CONCLUSIONS: Considering the lower maximum doses in OAR and PTV, we demonstrate the FIF technique to be more advantageous than 3D-CRT during adjuvant RT for early-stage endometrial cancer patients. This advantage is more prominent in obese patients. Therefore, FIF technique represents an effective pelvic RT treatment option for obese patients in clinics that do not have access to or prefer an alternative to intensity-modulated RT. PMID- 25275660 TI - Proportion hyperglycosylated hCG: a new test for discriminating gestational trophoblastic diseases. AB - INTRODUCTION: Hyperglycosylated human chorionic gonadotropin (hCG) is a variant of hCG with large oligosaccharide side chains. Although hCG is produced by syncytiotrophoblast cells, hyperglycosylated hCG marks cytotrophoblast cell. Hyperglycosylated hCG signals placental implantation. METHODS: Total hCG in serum and urine is measured by the Siemens Immulite hCG pregnancy test; the result is in milli-international unit per milliliter. Hyperglycosylated hCG is determined by the B152 microtiter plate assay; the result is in nanogram per milliliter. Hyperglycosylated hCG results can be converted to milli-international unit per milliliter equivalents by multiplying by 11. The test measures proportion hyperglycosylated hCG, hyperglycosylated hCG / total hCG. RESULTS: Proportion hyperglycosylated hCG marks cases intent on developing persistent hydatidiform mole (68% detection at 17% false detection). Proportion hyperglycosylated hCG also marks persistent hydatidiform mole (100% detection at 5.1% false detection). Proportion hyperglycosylated hCG distinguishes choriocarcinoma and gestational trophoblastic neoplasm cases, absolutely discriminating aggressive cases and minimally aggressive cases. Proportion hyperglycosylated hCG identifies quiescent gestational trophoblastic disease cases. It recognizes quiescent cases that become persistent disease (100% detection at 0% false positive). DISCUSSION: Proportion hyperglycosylated hCG is an invaluable test for discriminating gestational trophoblastic diseases. PMID- 25275661 TI - Patterns of recurrence and role of pelvic radiotherapy in ovarian clear cell adenocarcinoma. AB - OBJECTIVE(S): The aims of this study were to analyze patterns of recurrence in patients with ovarian clear cell adenocarcinoma (CCA) and to evaluate the role of pelvic radiotherapy (RT). METHODS AND MATERIALS: All patients with ovarian CCA treated at a single institution between 1989 and 2012 were identified, and their medical records were reviewed. Eligibility criteria included histologic diagnosis of pure CCA of the ovary, surgical staging for International Federation of Gynecology and Obstetrics stage I-to-IIIC disease, and adjuvant or neoadjuvant chemotherapy. Selected end points were 3-, 5-, and 8-year cumulative incidence of pelvic recurrence (CIPR). RESULTS: Fifty-six patients met eligibility criteria. Most received intravenous carboplatin and paclitaxel for a median of 6 cycles. Six patients (10.7%) received pelvic RT, and 50 (89.3%) did not. Pelvic RT patients had stage I-to-IIC disease. Median follow-up was 39 months (range, 1-69 months). For the group as a whole, 14 patients (25%) had initial disease recurrence involving the pelvis, whereas 6 (10.7%) had first recurrence outside the pelvis. Three-, 5- and 8-year CIPR were 28.2%, 38.5%, and 43.2%, respectively. There was no significant difference in 3-, 5-, or 8-year CIPR between the group of patients receiving RT (20%, 20%, and 20%) and a group of patients with stages I to IIC who did not receive RT (9.9%, 22.4%, and 30.2%), P = 0.22. During RT, patients developed mild grade 1-to-2 side effects. After RT, 1 patient developed lower extremity lymphedema with recurrent cellulitis. One patient who developed small bowel obstruction before RT developed small bowel radiation enteritis and obstruction after RT, ultimately requiring surgical intervention. CONCLUSIONS: These findings suggest that ovarian CCA exhibits a propensity for pelvic recurrence after surgery and chemotherapy. RT, a local treatment that can effectively sterilize microscopic tumor cells, may benefit patients with this disease. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT. PMID- 25275662 TI - Medical morbidities in endometrial cancer patients. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence and types of medical morbidities in Thai endometrial cancer (EMC) patients and their impact on treatment outcomes. METHODS: The EMC patients treated in the institution from 1995 to 2012 and with available medical history were identified. Data collected were age; medical morbidities; tumor stage, histopathology, and grade; adjuvant therapy; living status; and cause of death. RESULTS: Of the 335 EMC patients included in the study, 77.3% had early-stage diseases, and 46.6% received adjuvant therapy. A total of 220 patients (65.7%) had medical morbidities. Median age of patients with medical morbidities was significantly higher than those without: 59 years (range, 30-84 years) versus 52 years (range, 30-86 years) (P < 0.001). One or more components of metabolic syndrome were the most common: 10.9% had all 4 components, 30.0% had three, and 31.4% had two. Thyroid dysfunction, as the second most common, was found in 8.2%. From a median follow-up of 56.5 months (0.07-234.04 months), 18.5% were dead: 11.6% from EMC, 4.8% from medical conditions, and 2.1% from other causes. Survival of the patients who had or had no medical morbidities was not significantly different: 5-year overall survival and 5-year cancer-specific survival were 84.7% (95% confidence interval [CI], 79.6%-89.8%) versus 84.0% (95% CI, 76.9%-91.0%) (P = 0.918) and 87.3% (95% CI, 82.6%-92.0%) versus 89.3% (95% CI, 83.2%-95.3%) (P = 0.986), respectively. CONCLUSION: This was the first large analysis in South-East Asia showing common incidence of medical morbidities in EMC patients. One or more components of metabolic syndrome were the most common. Some medical illnesses were the causes of death. Comprehensive and continual medical care for EMC patients is important. PMID- 25275663 TI - Association between bone marrow dosimetric parameters and acute hematologic toxicity in cervical cancer patients undergoing concurrent chemoradiotherapy: comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy. AB - OBJECTIVE: We compare different dosimetric parameters in cervical cancer patients receiving concurrent chemotherapy and three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT) and explore the incidence of hematological toxicity (HT) in these patients. METHODS: Twenty patients receiving 3DCRT or IMRT and 4 weekly doses of cisplatin (25 mg/m/w) were studied. The volumes of bone marrow receiving 10, 20, 30, 40 and 50 Gy or greater (V10, V20, V30, V40, and V50, respectively) were calculated. The HT was graded according to the guidelines of the Radiation Therapy Oncology Group system. The associations between dosimetric parameters and HT and chemotherapy delivery were analyzed. RESULTS: The bone marrows V30, V40, and V50 were lower in the IMRT group than in the 3DCRT group (62.93% vs 76.91%, 31.36% vs 39.60%, and 9.79% vs 15.44%, respectively). No statistical difference was observed for both V10 and V20. Acute hematologic toxicity occurred in both groups but was more frequent in the 3DCRT group. The percentage of patients with grade 2 and worse leukopenia and neutropenia was 90% and 80% in the 3DCRT group, whereas it was 80% and 40% in the IMRT group. The median nadir of white blood cells and the absolute neutrophil count were significantly lower in the 3DCRT group than in the IMRT group (1.96 * 10(9) vs 2.72 * 10(9) and 1.09 * 10(9) vs 1.86 * 10(9), respectively). CONCLUSION: The IMRT reduced the volume of bone marrow irradiated at the higher doses and the incidence and severity of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemoradiotherapy. PMID- 25275664 TI - Analyzing simultaneous positive expression of EZH2 and P53 protein to improve predictive value in cervical squamous cell carcinoma. AB - OBJECTIVE: The current study was undertaken to investigate the predictive value of simultaneous enhancer of zeste homolog 2 (EZH2) and P53 expression in lesions of patients with cervical squamous cell carcinoma. METHODS: Quantum dot double fluorescence staining was applied to detect EZH2 and P53 protein in biopsy tissue of 168 patients with cervical squamous cell carcinoma. The expression was classified into double positive (EZH2 and P53 were positively expressed), single positive (either EZH2 or P53 was positively expressed), and double negative (neither was positively expressed). The EZH2 and P53 expression, clinical stages of cervical cancer, lymph node metastasis, progression-free survival, and overall survival were analyzed. RESULTS: A relationship of EZH2 and P53 expression with the clinical stage of cervical cancer and lymph node metastasis was indicated. Simultaneous detection of both proteins could partly predict prognosis, consistent with previous studies' results. The current study demonstrated that the expression levels of EZH2 and P53 in tumor tissue and the proportion of cases with double-positive expression significantly increased with increasing clinical stages of cancer, also confirming up-regulated expression of EZH2 and P53 with increasing stages. These findings may suggest that the 2 proteins were involved in the development of cervical cancer, but the nature of their interaction is undefined. The increase of EZH2 and P53 expression in patients with lymph node metastasis indicated that they may be involved in metastasis of cervical cancer. CONCLUSION: Simultaneous positive EZH2 and P53 expression could improve the predictive value of a poor prognosis in cervical cancer. PMID- 25275665 TI - Chiral alkynylcarbinols from marine sponges: asymmetric synthesis and biological relevance. AB - Covering: up to March 2014. Previous review on the topic: B. W. Gung, C. R. Chim., 2009, 12, 489-505. Chiral alpha-functional lipidic propargylic alcohols extracted from marine sponges, in particular of the pacific genus Petrosia, constitute a class of acetylenic natural products exhibiting remarkable in vitro biological activities, especially anti-tumoral cytotoxicity. These properties, associated to functionalities that are uncommon among natural products, have prompted recent projects on asymmetric total synthesis. On the basis of a three sector structural typology, three main sub-types of secondary alkynylcarbinols (with either alkyl, alkenyl, or alkynyl as the second substituent) can be identified as the minimal pharmacophoric units. Selected natural products containing these functionalities have been targeted using previously known or on purpose-designed procedures, where the stereo-determining step can be: (i) a C-C bond forming reaction (e.g. the Zn-mediated addition of alkynyl nucleophiles to aldehydes in the presence of chiral aminoalcohols), (ii) a functional layout (e.g. the asymmetric organo- or metallo-catalytic reduction of ynones), or (iii) an enantiomeric resolution (e.g. a lipase-mediated kinetic resolution via acetylation). The promising medicinal importance of these targets is finally surveyed, and future investigation prospects are proposed, such as: (i) further total synthesis of known or future extraction products; (ii) the synthesis of non natural analogues, with simpler lipophilic environments of the alkynylcarbinol based pharmacophoric units; (iii) the variation and optimization of both the pharmacophoric units and their lipophilic environment; and (iv) investigations into the biological mode of action of these unique structures. PMID- 25275666 TI - A quantum dynamics study of the ultrafast relaxation in a prototypical Cu(I) phenanthroline. AB - The ultrafast nonadiabatic dynamics of a prototypical Cu(I)-phenanthroline complex, [Cu(dmp)2](+) (dmp = 2,9-dimethyl-1,10-phenanthroline), initiated after photoexcitation into the optically bright metal-to-ligand charge-transfer (MLCT) state (S3) is investigated using quantum nuclear dynamics. In agreement with recent experimental conclusions, we find that the system undergoes rapid (~100 fs) internal conversion from S3 into the S2 and S1 states at or near the Franck Condon (FC) geometry. This is preceded by a dynamic component with a time constant of ~400 fs, which corresponds to the flattening of the ligands associated with the pseudo Jahn-Teller distortion. Importantly, our simulations demonstrate that this latter aspect is in competition with subpicosecond intersystem crossing (ISC). The mechanism for ISC is shown to be a dynamic effect, in the sense that it arises from the system traversing the pseudo Jahn Teller coordinate where the singlet and triplet states become degenerate, leading to efficient crossing. These first-principles quantum dynamics simulations, in conjunction with recent experiments, allow us to clearly resolve the mechanistic details of the ultrafast dynamics within [Cu(dmp)2](+), which have been disputed in the literature. PMID- 25275667 TI - Does the site of platelet sequestration predict the response to splenectomy in adult patients with immune thrombocytopenic purpura? AB - Splenectomy is the only potentially curative treatment for chronic immune thrombocytopenic purpura (ITP) in adults. However, one-third of the patients relapse without predictive factors identified. We evaluate the predictive value of the site of platelet sequestration on the response to splenectomy in patients with ITP. Eighty-two consecutive patients with ITP treated by splenectomy between 1992 and 2013 were retrospectively reviewed. Platelet sequestration site was studied by (111)Indium-oxinate-labeled platelets in 93% of patients. Response to splenectomy was defined at last follow-up as: complete response (CR) for platelet count (PC) >=100 * 10(9)/L, response (R) for PC>=30 * 10(9)/L and <100 * 10(9)/L with absence of bleeding, no response (NR) for PC<30 * 10(3)/L or significant bleeding. Laparoscopic splenectomy was performed in 81 patients (conversion rate of 16%), and open approach in one patient. Median follow-up was 57 months (range, 1-235). Platelet sequestration study was performed in 93% of patients: 50 patients (61%) exhibited splenic sequestration, 9 (11%) hepatic sequestration and 14 patients (17%) mixed sequestration. CR was obtained in 72% of patients, R in 25% and NR in 4% (two with splenic sequestration, one with hepatic sequestration). Preoperative PC, age at diagnosis, hepatic sequestration and male gender were significant for predicting CR in univariate analysis, but only age (HR = 1.025 by one-year increase, 95% CI [1.004-1.047], p = 0.020) and pre operative PC (HR = 0.112 for > 100 versus <=100, 95% CI [0.025-0.493], p = 0.004) were significant predictors of recurrence-free survival in multivariate analysis. Response to splenectomy was independent of the site of platelet sequestration in patients with ITP. Pre-operative platelet sequestration study in these patients cannot be recommended. PMID- 25275668 TI - Total synthesis of (-)-N-methylwelwitindolinone B isothiocyanate via a chlorinative oxabicycle ring-opening strategy. AB - The first total synthesis of N-methylwelwitindolinone B isothiocyanate is reported. The route features several key steps, including a regio- and diastereoselective chlorinative oxabicycle ring-opening reaction to introduce the challenging alkyl chloride motif. PMID- 25275669 TI - Polyethylene glycol formulations show different soft tissue remodeling and angiogenesis features. AB - BACKGROUND: Soft tissue regeneration and remodeling is fundamental in periodontal surgery, thus we investigated the angiogenic response elicited in the subcutaneous tissue of rats by a proprietary, polyethylene glycol hydrogel formulation (PEG) alone or conjugated with specific amelogenins (EMD) or nanobioglass particles (NBG). METHODS: Discs with three different formulations (PEG, PEG-EMD, and PEG-NBG) were inserted into four unconnected subcutaneous pouches, produced on the back of Sprague-Dawley rats (n=56, divided into three groups), and used for blood flow evaluation by Laser Doppler analysis at 1, 2, 4, 8, and 16 weeks or for histological and immunohistochemical analysis at 1, 2, 4, 8, and 16 weeks. RESULTS: All formulations showed tissue integration, absence of inflammatory reaction (as revealed by myeloperoxidase staining), and increased vascularization (by counting microvascular density following CD31 staining). Laser Doppler analysis revealed a statistically significant increase in blood flow after 1 week for PEG-EMD and after 2 weeks for PEG-NBG. The angiogenic response was significantly increased at 1, 2, and 8 weeks for PEG-EMD, but only at 4 weeks for PEG-NBG. CONCLUSIONS: The studied biomaterials revealed equal biocompatibility and tissue integration properties. PEG-EMD showed the most pronounced and consistent angiogenic response in the early phases of wound healing, while the PEG-NBG formulation provided a slower and delayed, but relevant, response. PMID- 25275670 TI - Transoral robotic surgery for obstructive sleep apnea: perioperative management and postoperative complications. AB - IMPORTANCE: Patients who undergo surgery for obstructive sleep apnea (OSA) have acceptable perioperative morbidity that is similar to that seen in other sleep related surgical procedures. OBJECTIVE: To perform the first large-scale evaluation of perioperative management and postoperative complications in patients who undergo transoral robotic surgery (TORS) for OSA. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study from 2010 to 2013 of 166 adult patients with moderate to severe OSA (defined as apnea-hypopnea index, >20) who had experienced failure of conventional therapy with positive airway pressure and underwent TORS at an academic practice with follow-up greater than 3 months. INTERVENTIONS: Transoral robotic surgery with or without additional multilevel airway procedures. MAIN OUTCOMES AND MEASURES: Major and minor complication rates. RESULTS: There were 122 men and 44 women with a mean (SD) age of 54.6 (12.3) years. The mean (SD) American Society of Anesthesiologists (ASA) score was 2.3 (0.5). There were 11 major complications, including secondary bleeding requiring intervention (7 patients), pulmonary embolism requiring anticoagulation therapy (2 patients), aspiration requiring prolonged hospitalization (1 patient), and dysphagia resulting in gastrostomy tube dependence (1 patient). There were 32 minor complications, including dehydration and/or uncontrolled pain (16 patients), globus sensation (8 patients), bleeding (5 patients), lip burn (2 patients), and pharyngeal laceration during intubation (1 patient); the majority resolved without sequelae. Preoperative ASA score (P = .003) and number of procedures performed (P = .004) predicted a postoperative complication. Age (P = .29), body mass index (P = .55), apnea-hypopnea index (P = .67), lowest arterial oxygen saturation (P = .63), number of comorbidities (P = .46), and individual comorbidities did not predict a complication. CONCLUSIONS AND RELEVANCE: Transoral robotic surgery can be safely performed in patients with OSA with an acceptable complication rate. Complications are similar to those seen with other surgical treatments of OSA and were only predicted by ASA score and number of procedures performed. PMID- 25275671 TI - Thrombocytopenia as an inexpensive, valuable predictor for survival in patients with hepatocellular carcinoma. PMID- 25275672 TI - Low-dose topiramate in alcohol dependence: a single-blind, placebo-controlled study. AB - INTRODUCTION: Topiramate (TOP) and anticonvulsants in general are considered safe and effective drugs for the treatment of alcohol dependence, even though TOP induced adverse events are quite common, especially for high initial doses or if titration to 300 mg/d is too rapid. The aim of the present study was to assess the efficacy and tolerability profile of low-dose TOP for relapse prevention. METHODS: After detoxification, 52 patients were randomized into 2 groups as follows: 26 patients received 100 mg of TOP (oral, twice daily), titrated over 2 weeks, and 26 patients received placebo (PLA). Both groups underwent rehabilitation twice a week. RESULTS: After 6 weeks of treatment, compared with the PLA group, patients receiving TOP showed the following: (1) fewer drinking days (P < 0.05); (2) less daily alcohol consumption (P < 0.05); (3) more days of treatment (P < 0.05); (4) reduced levels of craving (Obsessive-Compulsive Drinking Scale) and withdrawal symptoms (Clinical Institute Withdrawal Assessment for Alcohol-Revised); and (5) improvement of anxiety, depression, and obsessive compulsive symptom severity (Symptom Check List 90 Revised). CONCLUSIONS: Despite the small sample size and the short follow-up period, the present PLA-controlled study demonstrated the potential usefulness of TOP, even when administered at a dosage of 100 mg/d, for the treatment of detoxified alcohol-dependent subjects, confirming results from previous studies testing higher doses of TOP. PMID- 25275673 TI - Amisulpride for older patients with long-standing schizophrenia. AB - A large and growing number of older people across the world experience schizophrenia. Recommendations for their treatment are largely based on data extrapolated from studies of the use of antipsychotic medications in younger populations. The present study was designed to evaluate the efficacy and safety of amisulpride monotherapy in a diagnostically homogeneous group of elderly patients without cognitive impairment experiencing schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for schizophrenia). Mortality and rehospitalization for a 5-year period were the predefined outcome measures. We conducted a retrospective chart review of all elderly (60 years and older) schizophrenia patients treated in a large tertiary care center. Of the 527 elderly schizophrenia patients for a 5-year period (2007 2013), 30 patients, mean (SD) age of 67.5 (5.8) years, were treated with amisulpride monotherapy. There were 19 women and 11 men in the analyzed group. Mean duration of disease was 34.4 years. All had been exposed to at least 3 first and second-generation antipsychotics before amisulpride treatment. Amisulpride was very well tolerated by the patients, and mortality rate (10% vs 19%) was significantly lower than that of other first- and second-generation antipsychotics (P < 0.02). Rehospitalization rates with amisulpride were significantly lower than those with other second-generation antipsychotics (P < 0.001). We tentatively conclude that our preliminary results demonstrate that amisulpride is an efficacious and safe atypical antipsychotic for the treatment for elderly schizophrenia patients. PMID- 25275674 TI - Statistics commentary series: Commentary #5--can it work or does it work? The difference between efficacy and effectiveness trials. PMID- 25275676 TI - Fluorescent gold nanoclusters: recent advances in sensing and imaging. PMID- 25275675 TI - Photosensitization by imatinib. A photochemical and photobiological study of the drug and its substructures. AB - Imatinib (IMT) is a promising tyrosine kinase inhibitor used in the treatment of some types of human cancer. It constitutes a successful example of rational drug design based on the optimization of the chemical structure to reach an improved pharmacological activity. Cutaneous reactions, such as increased photosensitivity or pseudoporphyria, are among the most common nonhematological IMT side effects; however, the molecular bases of these clinical observations have not been determined. Thus, to gain insight into the IMT photosensitizing properties, we addressed its photobehavior together with that of its potentially photoactive anilino-pyrimidine and pyridyl-pyrimidine fragments. In this context, steady state and time-resolved fluorescence as well as laser flash photolysis experiments have been conducted, and the DNA photosensitization potential has been investigated by means of single-strand break detection using agarose gel electrophoresis. The obtained results reveal that the drug itself and its anilino pyrimidine fragment are not DNA photosensitizers. By contrast, the pyridyl pyrimidine substructure displays a marked phototoxic potential, which has been associated with the generation of a long-lived triplet excited state. Interestingly, this reactive species is efficiently quenched by benzanilide, another molecular fragment of IMT. Clearly, integration of the photoactive pyridyl-pyrimidine moiety in a more complex structure strongly modifies its photobehavior, which in this case is fortunate as it leads to an improved toxicological profile. Thus, on the bases of the experimental results, direct in vivo photosensitization by IMT seems unlikely. Instead, the reported photosensitivity disorders could be related to indirect processes, such as the previously suggested impairment of melanogenesis or the accumulation of endogenous porphyrins. PMID- 25275677 TI - Maneb-induced dopaminergic neuronal death is not affected by loss of mitochondrial complex I activity: results from primary mesencephalic dopaminergic neurons cultured from individual Ndufs4+/+ and Ndufs4-/- mouse embryos. AB - Primary cultures from embryonic mouse ventral mesencephalon are widely used for investigating the mechanisms of dopaminergic neuronal death in Parkinson's disease models. Specifically, single mouse or embryo cultures from littermates can be very useful for comparative studies involving transgenic mice when the neuron cultures are to be prepared before genotyping. However, preparing single mouse embryo culture is technically challenging because of the small number of cells present in the mesencephalon of each embryo (150 000-300 000), of which only 0.5-5% are tyrosine hydroxylase-positive, dopaminergic neurons. In this study, we optimized the procedure for preparing primary mesencephalic neuron cultures from individual mouse embryos. Mesencephalic neurons were dissociated delicately, plated on Aclar film coverslips, and incubated in DMEM supplemented with fetal bovine serum for 5 days and then N2 supplement was added for 1 day, which resulted in the best survival of dopaminergic neurons from each embryo. Using this optimized method, we prepared mesencephalic neuron cultures from single Ndufs4 or Ndufs4 embryos and investigated the role of mitochondrial complex I in maneb-induced dopamine neuron death. Our results suggest that maneb toxicity to dopamine neurons is not affected by the loss of mitochondrial complex I activity in Ndufs4 cultures. PMID- 25275678 TI - Internetwork dynamic connectivity effectively differentiates schizophrenic patients from healthy controls. AB - Increasingly more neuroimaging studies have shown that the complex symptoms of schizophrenia are linked to disrupted neural circuits and dysconnectivity of intrinsic connectivity networks. Previous studies have assumed temporal stationarity of resting-state functional connectivity, whereas temporal dynamics have rarely been explored. Here, we utilized resting-state functional MRI with a sliding window approach to measure the amplitude of low-frequency fluctuations (ALFFs) in functional connectivity in 24 patients with schizophrenia and 25 healthy controls. We found that there were significant differences in the ALFFs of specific connections, the majority of which were located between the intrinsic connectivity networks. Importantly, the experimental results of a multivariate pattern analysis of these ALFF measures showed that 81.3% (P<0.0009) of the participants were correctly classified as either schizophrenic patients or healthy controls by leave-one-out cross-validation. Our results show significant abnormality in the dynamics of internetwork functional connectivity in schizophrenia, which contributes toward the characterization and differentiation of schizophrenic patients, and may be used as a potential biomarker. PMID- 25275679 TI - [Not Available]. PMID- 25275680 TI - [Not Available]. PMID- 25275681 TI - [Announcement - prize for patient safety]. PMID- 25275682 TI - [Not Available]. PMID- 25275683 TI - [Not Available]. PMID- 25275684 TI - [Not Available]. PMID- 25275685 TI - [66th Congress - urologists expect 20 % more patients]. PMID- 25275686 TI - [Endocrinology - treating only true testosterone deficiency]. PMID- 25275687 TI - [Recruiting participants - study of therapy of CRPC]. PMID- 25275688 TI - [Preventing needlestick injuries]. PMID- 25275689 TI - [Regional conventions: still up-to-date?]. AB - This article poses the question whether regional meetings are still contemporary for continuing medical education using the example of this year's joint meeting of the Vereingung der Mitteldeutschen Urologen e. V. and the Sachsischen Gesellschaft fur Urologie e. V., which took place in Marburg from May 22nd - 24th , 2014. It gives an overview of the most important and interesting topics of the meeting and highlights the advantages of regional meetings in comparison to other kinds of medical education possibilities such as national conventions or internet based courses. The authors conclude that in spite of a significant financial costs and organisational effort, regional meetings contain unique and favourable characteristics and hence should remain a permanent feature of the scientific landscape in Germany. PMID- 25275690 TI - [Health insurance - private or legally mandated? Choosing a suitable insurance group]. PMID- 25275691 TI - [Contract physician rights - physician without partnership status in group practice must bear the tax risk]. PMID- 25275692 TI - [Obituary - Prof. Dr. h. c. Fumihiko Ikoma]. PMID- 25275693 TI - Intra-vaginal prostaglandin E2 versus double-balloon catheter for labor induction in term oligohydramnios. AB - OBJECTIVE: Compare mechanical and pharmacological ripening for patients with oligohydramnios at term. STUDY DESIGN: Fifty-two patients with oligohydramnios ? 5 cm and Bishop score ? 6 were randomized for labor induction with a vaginal insert containing 10 mg timed-release dinoprostone (PGE2) or double-balloon catheter. The primary outcome was time from induction to active labor. Time to labor, neonatal outcomes and maternal satisfaction were also compared. RESULT: Baseline characteristics were similar. Time from induction to active labor (13 with PGE2 vs 19.5 h with double-balloon catheter; P = 0.243) was comparable, with no differences in cesarean rates (15.4 vs 7.7%; P = 0.668) or neonatal outcomes. The PGE2 group had higher incidence of early device removal (76.9 vs 26.9%; P = 0.0001), mostly because of active labor or non-reassuring fetal heart rate. Fewer PGE2 patients required oxytocin augmentation for labor induction (53.8 vs 84.6% P = 0.034). Time to delivery was significantly shorter with PGE2 (16 vs 20.5 h; P = 0. 045). CONCLUSION: Intravaginal PGE2 and double-balloon catheter are comparable methods for cervical ripening in term pregnancies with oligohydramnios. PMID- 25275694 TI - Do thawing and warming affect the integrity of human milk? AB - OBJECTIVE: To evaluate the integrity of the human milk (pH, bacterial counts, host defense factors and nutrients) subjected to thawing, warming, refrigeration and maintenance at room temperature. STUDY DESIGN: Mothers in the neonatal intensive care unit donated freshly expressed milk. A baseline sample was stored at -80 degrees C and the remainder of the milk was divided and stored for 7 days at -20 degrees C. The milk was then subjected to two methods of thawing and warming: tepid water and waterless warmer. Thawed milk also was refrigerated for 24 h prior to warming. Lastly, warmed milk was maintained at room temperature for 4 h to simulate a feeding session. Samples were analyzed for pH, bacterial colony counts, total fat and free fatty acids, and the content of protein, secretory IgA and lactoferrin. Data were analyzed by repeated-measures analysis of variance and paired t test. RESULT: There were no differences between processing methods and no changes in fat, protein, lactoferrin and secretory immunoglobulin A with processing steps. Milk pH and bacterial colony counts declined while free fatty acids rose with processing. Refrigeration of thawed milk resulted in greater declines in pH and bacteria and increases in free fatty acids. Bacterial colony counts and free fatty acids increased with maintenance at room temperature. CONCLUSION: The integrity of the milk was affected similarly by the two thawing and warming methods. Thawing and warming change the integrity of previously frozen human milk, but not adversely. Concerns about maintaining warmed milk at room temperature need to be explored. PMID- 25275695 TI - Race differences in the association between multivitamin exposure and wheezing in preterm infants. AB - OBJECTIVE: We aimed to determine whether vitamin D exposure, as estimated by use of multivitamins, is positively or negatively associated with recurrent wheezing in infants born preterm. STUDY DESIGN: This prospective cohort study enrolled 300 infants, born at 28(0/7) to 34(6/7) weeks gestational age, and conducted follow up at 3-, 6-, 9- and 12-month adjusted age. RESULT: Black (55.9%) and non-black (36.6%) infants experienced recurrent wheezing. Adjusted odds ratios (ORs) for the association between multivitamin exposure at 3 months and recurrent wheezing were 2.15 (95% confidence interval (CI): 0.97, 4.75) for black and 0.43 (95% CI: 0.19, 0.96) for non-black infants with an interaction by race (P=0.003). In lag effect models, ORs were 2.69 (95% CI: 1.41, 5.14) for black and 0.50 (95% CI: 0.27, 0.92) for non-black infants. CONCLUSION: Differences by race were seen in association between multivitamins and wheezing; population heterogeneity should be considered when evaluating vitamin supplementation. PMID- 25275696 TI - A spectrum project: preterm birth and small-for-gestational age among infants with birth defects. AB - OBJECTIVE: The aim of this study is to investigate the association between birth defects (BDs), prematurity and small-for-gestational age (SGA) in a population based sample. STUDY DESIGN: Participants were singleton live births enrolled in the National Birth Defects Prevention Study, including 18 737 case infants with one or more BD and 7999 controls. Logistic regression models to evaluate associations between BDs, prematurity and fetal growth were computed while adjusting for covariates. RESULT: Cases were significantly more likely to be born prematurely than controls, particularly at 24 to 28 weeks of gestation. The highest odds ratios for preterm birth were found for intestinal atresia, anencephaly, gastroschisis and esophageal atresia. Infants with BDs were also significantly more likely to be SGA than controls (17.2 and 7.8%). CONCLUSION: Infants with BDs are more likely than controls to be born prematurely and SGA. Findings from this study present additional evidence demonstrating a complex interaction between the development of BDs, prematurity and intrauterine growth. PMID- 25275697 TI - Maternal hypothyroidism may be associated with CHD in offspring. AB - OBJECTIVES: This study tested whether mothers with maternal hypothyroidism have increased odds of CHD in their offspring, and examined the relationship between CHD, maternal thyroid function, and nausea and vomiting in pregnancy. BACKGROUND: Maternal hypothyroidism increases the risk for foetal demise and prematurity and can have a negative impact on neurodevelopment. Prior studies have postulated a relationship between maternal thyroid function, CHD, and maternal nausea and vomiting in pregnancy. METHODS: A cross-sectional case-control study was conducted over a 17-month period to obtain a history of maternal thyroid status and nausea and vomiting in pregnancy. Paediatric echocardiograms were evaluated for CHD by a blinded paediatric cardiologist. Logistic regression analysis was performed to examine the association between CHD and maternal hypothyroidism. RESULTS: Of the 998 maternal-child pairs, 10% (98/998) of the mothers reported a history of prenatal hypothyroidism. The overall prevalence of CHD in the study sample was 63% (630/998). Mothers with a history of hypothyroidism were significantly more likely to have offspring with CHD compared with mothers without a history of hypothyroidism (72 versus 62%; p=0.04). The adjusted odds ratio (95% confidence interval) of CHD in offspring associated with reported maternal hypothyroidism was 1.68 (1.02-2.78). CONCLUSION: This study suggests that maternal hypothyroidism is a risk factor for the development of CHD. Further prospective investigations are necessary to confirm this association and delineate pathogenic mechanisms. PMID- 25275699 TI - Live-cell real-time imaging of mitochondria in HIV-1-infected cells. PMID- 25275698 TI - Parallel microfluidic chemosensitivity testing on individual slice cultures. AB - There is a critical unmet need to tailor chemotherapies to individual patients. Personalized approaches could lower treatment toxicity, improve the patient's quality of life, and ultimately reduce mortality. However, existing models of drug activity (based on tumor cells in culture or animal models) cannot accurately predict how drugs act in patients in time to inform the best possible treatment. Here we demonstrate a microfluidic device that integrates live slice cultures with an intuitive multiwell platform that allows for exposing the slices to multiple compounds at once or in sequence. We demonstrate the response of live mouse brain slices to a range of drug doses in parallel. Drug response is measured by imaging of markers for cell apoptosis and for cell death. The platform has the potential to allow for identifying the subset of therapies of greatest potential value to individual patients, on a timescale rapid enough to guide therapeutic decision-making. PMID- 25275702 TI - Construction of bicyclo[3.2.1]octanes with four stereogenic centers by organocatalytic domino Michael/Aldol reaction. AB - An enantio- and diastereoselective organocatalytic domino Michael/Aldol reaction for the direct preparation of synthetically and medicinally relevant bicyclo[3.2.1]octane derivatives with four stereogenic centers, including two quaternary carbons, has been described. The reaction tolerates a large variety of substituents on beta,gamma-unsaturated 1,2-ketoesters and cyclic 1,3-ketoesters. It allows for the formation of various bicyclo[3.2.1]octanes in good yields (53 98%), diastereoselectivities (1:1 to 5:1 dr), and enantioselectivities (up to 95:5 ee). PMID- 25275701 TI - Transbronchial vs transesophageal needle aspiration using an ultrasound bronchoscope for the diagnosis of mediastinal lesions: a randomized study. AB - BACKGROUND: The purpose of this study was to compare the tolerance, efficacy, and safety of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) with transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with an endobronchial ultrasound scope for the first pathologic diagnosis of lesions accessible by both procedures. METHODS: Patients who had lesions accessible by both EBUS-TBNA and EUS-FNA were enrolled and were randomized to undergo either procedure. Patients quantified tolerance, and operators charted the quality of examination using a 100-mm visual analog scale (VAS). RESULTS: A specific diagnosis was made in 50 of 55 patients (91%) in the EBUS-TBNA group and in 48 of 55 patients (87%) in the EUS-FNA group (P = .76). Compared with EBUS-TBNA, EUS-FNA was associated with a shorter duration of procedure (median, 15.3 min vs 11.3 min; P < .001), lower doses of IV midazolam (mean, 4.4 mg vs 4 mg; P = .02) and intraairway lidocaine (mean, 303 mg vs 189 mg; P < .001), less frequent oxygen desaturations (23 of 55 vs two of 55, P < .001), and higher operator satisfaction (P < .001). There was no significant difference in patient tolerance according to the patients' VAS. Lymph node infection occurred in one patient in the EBUS-TBNA group and in two patients in the EUS-FNA group. CONCLUSIONS: Both EBUS-TBNA and EUS-FNA provide high accuracy with good tolerance, although the occurrence of infectious complications should be monitored carefully. EUS-FNA has the advantage of comparable tolerance with fewer doses of anesthetics and sedatives, a shorter procedure time, and fewer oxygen desaturations during the procedure. TRIAL REGISTRY: UMIN Clinical Trials Registry; No.: UMIN000005757; URL: http://www.umin.ac.jp/ctr/. PMID- 25275700 TI - Functional interdependence of NHE1 and merlin in human melanoma cells. AB - Upregulation of the Na(+)/H(+) exchanger isoform 1 (NHE1) has been correlated with tumor malignancy. In contrast, moesin-radixin-ezrin-like protein (merlin) is a tumor suppressor that protects from cancerogenesis. Merlin is highly related to the members of the ezrin, radixin, and moesin (ERM) protein family that are directly attached to and functionally linked with NHE1. In addition, merlin inhibits the MAPK cascade and the Rho-GTPases known to activate NHE1 activity. The present study investigates whether NHE1 expression and activity affect merlin or, conversely, whether merlin has an impact on NHE1 in human melanoma (MV3) cells. Indeed, features of merlin-deficient MV3 cells point to a functional link: merlin-deficient cells showed a decreased NHE1 expression and, paradoxically, an increase in NHE1 activity as measured upon cytosolic acidification (NH4Cl prepulse method). Loss of merlin also led to an elevated cell motility that could be further increased by NHE1 overexpression, whereas NHE1 overexpression alone had no effect on migration. In contrast, neither NHE1 expression nor its activity had an impact on merlin expression. These results suggest a novel tumor suppressor function of merlin in melanoma cells: the inhibition of the proto oncogenic NHE1 activity, possibly including its downstream signaling pathways. PMID- 25275703 TI - [70]Fullerenes assist the formation of phospholipid bicelles at low lipid concentrations. AB - The incorporation of neutral [70]fullerenes (C70) led to bicelle formation in a relatively low lipid concentration range from neutral lipid mixtures (DMPC/DHPC). Furthermore, C70 addition resulted in the formation of large bicelles with a radius of ca. 100 nm, in contrast to C70-free bicelles that were formed from anionic lipid mixtures (DMPC/DHPC/DMPG). The stabilization of these bicelles was attributed to C70 incorporation into the membranes. PMID- 25275704 TI - Editorial: HIV-1 infection and the nervous system: a shifting target. PMID- 25275705 TI - HIV neuropathy. AB - PURPOSE OF REVIEW: To present an overview of HIV-associated distal symmetric polyneuropathy (HIV-DSP) and other HIV-related peripheral neuropathies in the post-highly active retroviral therapy era. RECENT FINDINGS: HIV-DSP has become the most common neurologic complication of HIV largely due to the prolonged survival of HIV-positive patients with the advent of highly active retroviral therapy. HIV-DSP can be attributed to the disease itself or to secondary effects of certain HAART agents, and often the two disease entities cannot be distinguished. HIV-DSP can lead to significant morbidity and interfere with daily activities. Diagnosis can be obtained from a detailed history and neurologic exam revealing absent ankle jerks and abnormal, vibratory perception or decreased pinprick or temperature. Supporting studies include nerve conduction studies and skin biopsy. Although there are no United States Food and Drug Administration approved treatments for HIV-DSP, clinicians often use off-label medications, including antidepressants, anticonvulsants, topical agents and other analgesics. SUMMARY: The prevalence of those affected by HIV-DSP will continue to grow with the aging population of HIV-infected individuals. Compared to the diabetic neuropathy drug trials, trials in both symptomatic and disease-modifying agents for HIV-DSP have had little success. Other forms of HIV-related peripheral neuropathies are discussed briefly, and include acute and chronic inflammatory demyelinating polyneuropathy, autonomic neuropathy, polyradiculopathy, mononeuropathies, mononeuritis multiplex, cranial neuropathies, and amyotrophic lateral sclerosis-like motor neuropathy. PMID- 25275707 TI - The brain and HAART: collaborative and combative connections. AB - PURPOSE OF REVIEW: To summarize contemporary observations regarding the effects of highly active antiretroviral therapy (HAART) on the brain. RECENT FINDINGS: The effects of HAART on the structure and function of the brain during HIV/AIDS is currently a subject of intense interest because the brain is one of the most drug-impenetrable organs that is infected by HIV-1 and as such represents an important reservoir for replication-competent virus. The effects of HAART on neurocognitive impairment caused by HIV-1 infection remain uncertain with both beneficial and adverse outcomes reported with different HAART regimens. Similarly, the effects of individual HAART regimens on viral quantity in cerebrospinal fluid as a surrogate indicator of brain virus burden are variable. Indeed, the situation is further complicated by the ranking of antiretroviral therapies (ARTs) by their central nervous system penetration-effectiveness score on the basis of ART concentrations in cerebrospinal fluid. Experimental studies have also yielded equivocal findings depending on the model and individual ART. At the same time, a burgeoning body of experimental data has demonstrated neurotoxic effects of several ARTs, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). SUMMARY: HAART selection strategies are currently guided by efficacy, resistance testing, toxicity, potential drug interactions and theoretical brain penetration. As improved strategies are developed to target the viral reservoir within the brain, greater knowledge of the effects of ARTs on neural tissues will be needed to operationalize their use in a rational manner that maximizes antiretroviral efficacy and minimizes the neurotoxic complications. PMID- 25275708 TI - Conformal atomic layer deposition of alumina on millimeter tall, vertically aligned carbon nanotube arrays. AB - Atomic layer deposition (ALD) can be used to coat high aspect ratio and high surface area substrates with conformal and precisely controlled thin films. Vertically aligned arrays of multiwalled carbon nanotubes (MWCNTs) with lengths up to 1.5 mm were conformally coated with alumina from base to tip. The nucleation and growth behaviors of Al2O3 ALD precursors on the MWCNTs were studied as a function of CNT surface chemistry. CNT surfaces were modified through a series of post-treatments including pyrolytic carbon deposition, high temperature thermal annealing, and oxygen plasma functionalization. Conformal coatings were achieved where post-treatments resulted in increased defect density as well as the extent of functionalization, as characterized by X-ray photoelectron spectroscopy and Raman spectroscopy. Using thermogravimetric analysis, it was determined that MWCNTs treated with pyrolytic carbon and plasma functionalization prior to ALD coating were more stable to thermal oxidation than pristine ALD coated samples. Functionalized and ALD coated arrays had a compressive modulus more than two times higher than a pristine array coated for the same number of cycles. Cross-sectional energy dispersive X-ray spectroscopy confirmed that Al2O3 could be uniformly deposited through the entire thickness of the vertically aligned MWCNT array by manipulating sample orientation and mounting techniques. Following the ALD coating, the MWCNT arrays demonstrated hydrophilic wetting behavior and also exhibited foam-like recovery following compressive strain. PMID- 25275706 TI - New insights into immune reconstitution inflammatory syndrome of the central nervous system. AB - PURPOSE OF REVIEW: To highlight the importance of immune reconstitution inflammatory syndrome affecting the brain in HIV-infected individuals in the absence of opportunistic infections. To describe the varied clinical manifestations, unifying pathophysiological features and discuss the principles of management of this syndrome. RECENT FINDINGS: Immune reconstitution inflammatory syndrome within the brain is commonly seen in patients with HIV infection upon initiation of antiretroviral drugs. The fulminant forms occur in the face of opportunistic infections or uncontrolled viral replication within the brain. In this case, the enhanced immune response is targeted against the microbial agent, and the brain suffers bystander damage. Treatment requires the combination of the antimicrobial agent, continued antiretrovirals and in some cases corticosteroids. It is increasingly being recognized that despite adequate control of viral replication in the brain, some patients develop a chronic form of T cell encephalitis which appears to be driven by continued production of HIV Tat protein. In others, the immune response may be targeted against the host antigens in the brain. SUMMARY: In patients with central nervous system-immune reconstitution inflammatory syndrome, the use of corticosteroids and strategies that prevent T cell migration into the brain may be needed. Extreme caution is necessary if viral eradication strategies are to be employed that involve activation of viral reservoirs, as these patients may be at risk for developing central nervous system-immune reconstitution inflammatory syndrome. PMID- 25275709 TI - Effect of morphology and manganese valence on the voltage fade and capacity retention of Li[Li2/12Ni3/12Mn7/12]O2. AB - We have determined the electrochemical characteristics of the high voltage, high capacity Li-ion battery cathode material Li[Li2/12Ni3/12Mn7/12]O2 prepared using three different synthesis routes: sol-gel, hydroxide coprecipitation, and carbonate coprecipitation. Each route leads to distinct morphologies and surface areas while maintaining the same crystal structures. X-ray photoelectron spectroscopy (XPS) measurements reveal differences in their surface chemistries upon cycling, which correlate with voltage fading. Indeed, we observe the valence state of Mn on the surface to decrease upon lithiation, and this reduction is specifically correlated to discharging below 3.6 V. Furthermore, the data shows a correlation of the formation of Li2CO3 with the Mn oxidation state from the decomposition of electrolyte. These phenomena are related to each material's electrochemistry in order to expand upon the reaction mechanisms taking place specifically in terms of the particle morphology produced by each synthetic approach. PMID- 25275711 TI - Spin-glass behavior and incommensurate modulation in high-pressure perovskite BiCr0.5Ni0.5O3. AB - The BiCr(0.5)Ni(0.5)O(3) perovskite has been obtained at high pressure. Neutron and synchrotron diffraction data show a Pnma orthorhombic structure with a = 5.5947(1) A, b = 7.7613(1) A, and c = 5.3882(1) A at 300 K and random B-site Cr/Ni distribution. Electron diffraction reveals an incommensurate modulation parallel to the b axis. The combination of either Cr-O-Ni (J > 0) or Cr-O-Cr/Ni-O Ni (J < 0) nearest-neighbor spin interactions results in a random-bond spin-glass configuration. Magnetization, neutron diffraction, and muon-spin-relaxation measurements demonstrate that variations in the local bonding and charge states contribute to the magnetic frustration. PMID- 25275710 TI - Influenza-associated hospitalizations, Singapore, 2004-2008 and 2010-2012. AB - Studies of influenza-associated hospitalizations in tropical settings are lacking. To increase understanding of the effect of influenza in Singapore, we estimated the age-specific influenza-associated hospitalizations for pneumonia and influenza during 2004-2008 and 2010-2012. The rate of hospitalization was 28.3/100,000 person-years during 2004-2008 and 29.6/100,000 person-years during 2010-2012. The age-specific influenza-associated hospitalization rates followed a J-shaped pattern: rates in persons >75 years of age and in children <6 months of age were >47 times and >26 times higher, respectively, than those for persons 25 44 years of age. Across all ages during these 2 study periods, ~12% of the hospitalizations for pneumonia and influenza were attributable to influenza. The rates and proportions of hospitalizations for influenza, particularly among the very young and the elderly, are considerable in Singapore and highlight the importance of vaccination in protecting populations at risk. PMID- 25275712 TI - Non-invasive hemodynamic analysis in cardiac resynchronization therapy patients wearing quadripolar left ventricular leads: the importance of pacing electrode selection. AB - AIM: Quadripolar left ventricular (LV) leads offer multiple choices for LV pacing increasing programming flexibility. Aim of this study is to assess the influence of LV pacing vector selection on hemodynamic parameters for patients who underwent cardiac resynchronization therapy (CRT) using quadripolar LV lead chronically evaluated with a non-invasive approach by Nexfin((r)) system provided analysis (BMEYE B.V., Amsterdam, The Netherlands). METHODS AND RESULTS: In 16 CRT patients implanted with a quadripolar LV lead (mean follow-up 8,8 +/-13,4 months after implantation), we measured Cardiac Output (CO), Mean Blood Pressure (MBP), Total Peripheral Resistance (TPR), LV dP/dt max and Stroke volume (SV) from each one of the ten available bipolar pacing configurations. All the recorded parameters showed marked differences among the ten pacing configurations, but dP/dt max, SV and TPR were those showing the wider range, depending of the selected pacing vector. The average delta for the whole group of subjects between the maximum and minimum hemodynamic values for each pacing configuration were 15.9% for SV, 21.1% for dP/dt max and 20.3% for TPR. Inter-individual analysis of data failed to identify a link between a specific pacing vector and the hemodynamic response. CONCLUSION: Our study demonstrates that different bipolar pacing configurations, even if arising from a single CS branch, substantially modify the hemodynamic effect of LV pacing in CRT patients. Moreover, the non invasive hemodynamic analysis suggests the better pacing configuration should be established individually and could represent an important issue in optimizing CRT during follow-up. PMID- 25275713 TI - Early changes in longitudinal deformation indices in young asymptomatic patients with type 1 diabetes mellitus: assessment by speckle-tracking echocardiography. AB - BACKGROUND: We explored early changes in regional left ventricular systolic and diastolic function assessed by speckle-tracking echocardiography (STE) in young asymptomatic patients with type 1 diabetes mellitus (DM), compared with healthy controls. METHODS: We enrolled 30 normotensive asymptomatic patients with type 1 DM, age <=40 years, DM duration >5 years, and left ventricular ejection fraction >=50%; and thirty matched controls. They underwent conventional echocardiography, and tissue Doppler imaging (TDI). Myocardial deformation indices were measured by STE. We measured global longitudinal systolic strain, global longitudinal systolic strain rate, and global longitudinal early diastolic strain rate, as an average of 18 myocardial segments. RESULTS: The mean age was 27.7+/-4.5 years, (41.7% males). The mean duration of diabetes was 14.3+/-5.8 years. The 2-D ejection fraction was lower in diabetic patients versus controls (P=0.03). The trans-mitral A peak was higher, and isovolumetric relaxation time longer in diabetics (P<0.05 for both). Both lateral and septal E values were lower, and E/E ratio higher in diabetics (P<0.05 for all). The global longitudinal systolic strain and strain rate were decreased in diabetics (-17.7+/-2.5% versus -21.2+/ 1.7%, and -1.1+/-0.2 versus -1.3+/-0.2 s-1, P<0.001 and P=0.003, respectively). The global longitudinal early diastolic strain rate was comparable to controls (1.5+/-0.4 versus 1.6+/-0.3 s-1, respectively, P=0.33). CONCLUSIONS: In asymptomatic patients with type 1 DM, global longitudinal systolic function measured by STE was impaired versus controls; diastolic function was impaired by conventional echocardiography and TDI. PMID- 25275714 TI - Prevalence of coronary artery anomalies in patients undergoing coronary artery angiography: a review of 16768 patients. A retrospective, single-center study. AB - AIM: Coronary artery anomalies (CAAs) most of the time are detected at birth. The aim of this study was to report the prevalence of CAAs by investigating coronary artery angiography (CAG) images of patients admitted to the authors' hospital, a tertiary healthcare provider. METHODS: Images of 16,768 patients who underwent CAG in our hospital were evaluated regarding CAAs. RESULTS: CAAs were detected in 120 (0.7%) cases. Anomalous origin and course of arteries were observed in 86 (0.51%) cases. Seven of these cases were diagnosed with acute coronary syndrome and 5 of them were treated with angioplasty without any complication. Absence of LMCA was revealed as the most frequent anomaly in the subgroup analysis of origin and course anomalies by being spotted in 59 (49.9 %) cases of total 120. Myocardial bridge, which constituted all intrinsic coronary anomalies in our study, was determined in 18 (0.1%) patients. All of the anomalies of coronary termination were coronary artery fistulas which were seen in 16 (0.09%) of patients and 2 of them were occluded with coil. CONCLUSION: Absence of LMCA was the most frequently encountered anomaly. Although CAAs are rare cases, they can cause difficulties in CAG interventions and surgical operations. This study presents CAA frequencies of patients who performed CAG. PMID- 25275715 TI - Left ventricular non compaction: epidemiology, clinical findings, diagnosis and therapy. AB - Left ventricular non compaction (LVNC) is a cardiomyopathy due to an arrest of the normal development of myocardium which determines the persistence of fetal myocardium in postnatal life in at least 2/3 of the wall (criterion known as non compacted/ compacted ratio greater than 2). Although in absence of a confirmed prevalence of LVNC, reviewing literature shows an increasing number of reports over the years, though diagnosed cases represent just the tip of a realistically far wider phenomenon. Clinical manifestations are variable, ranging from the absence of any symptom to congestive heart failure, arrhythmias and systemic thromboembolism. Echocardiography is the gold standard for the diagnosis. Tissue Doppler and three-dimensional echocardiography may give further information in the evaluation of patients affected by LVNC. Magnetic resonance could refine diagnosis particularly in those patients with not conclusive echocardiogram: it may help in differential diagnosis and give prognostic information. There is no specific therapy for patients with LVNC but the treatment is aimed at treating heart failure, or other complications such as arrhythmias and thromboembolic events. PMID- 25275716 TI - Beyond PARTNER: appraising the evolving trends and outcomes in transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) has become the preferred treatment in patients with symptomatic severe aortic stenosis deemed to be at prohibitive or high risk for surgical aortic valve replacement. With evolving technology, improving practices and patient selection, outcomes in TAVR have improved. In the not so distant future, TAVR may become an alternative to surgical aortic valve replacement even for patients who are not at high risk for open surgery. However, issues such as stroke, paravalvular leak and pacemaker need remain, and the unknown limitations of TAVR, including durability and undefined options for reintervention for prosthesis dysfunction, must be addressed before this therapy can be extended to younger, lower risk patients. PMID- 25275717 TI - Pulmonary arterial hypertension: a review in pharmacotherapy. AB - Pulmonary arterial hypertension (PAH) is a progressive disease that remains incurable. The past 2 decades have witnessed many advances in PAH-directed therapies. More recently, 3 new oral agents have become available in the United States within the past 2 years. Treprostinil is now available in extended-release oral tablets. Macitentan is the third endothelin receptor antagonist approved for use, demonstrating benefits on morbidity and mortality among patients with PAH in an event-driven study. Riociguat is the first soluble guanylate cyclase stimulator that has been approved for use in the United States. This article reviews the clinical efficacy and safety of these 3 agents and the roles they play in the management of PAH. Additionally, we review the limitations of using surrogate markers such as change in 6-minute walk distance to assess disease progression. PMID- 25275718 TI - Evaluation of a precise and measurable model for learning laparoscopic tissue handling. AB - INTRODUCTION: Laparoscopic tissue handling is quite difficult to measure using virtual-reality laparoscopic simulators and box-trainer exercises, and therefore, completion time is the predominant performance measure for simulation-based laparoscopic training exercises. The purpose of this study was to evaluate the construct validity of a training and assessment model for precise laparoscopic handling of delicate tissue. METHODS: Participants (n = 35) completed 2 progressively challenging laparoscopic tissue translocation exercises using delicate foam pieces and templates. Deidentified performances were scored using objective measures for tissue damage, accuracy, percentage complete, and completion time. Evaluation included multiple analysis of variance with repeated measures among the 3 groups as follows: medical students, residents and faculty who perform laparoscopic surgery less than once per week, and faculty members who perform laparoscopic surgery at least once per week. RESULTS: The model demonstrated significant construct validity by discriminating performances between the types of shapes and templates and across the levels of surgical experience on all dimensions. A significant interaction effect between the level of expertise and the difficulty of the exercise revealed excellent discrimination between experienced laparoscopic surgeons and others. DISCUSSION: This low-cost model provides an alternative or adjunct platform for laparoscopic training and assessment that requires precise and measurable handling of a delicate tissue. PMID- 25275719 TI - Evaluation of the educational value of a virtual reality TURP simulator according to a curriculum-based approach. AB - PURPOSE: This study aimed to evaluate the place of the TURPsim (Simbionix/VirtaMed, Beit Goal, Israel) within a urologic residency training curriculum, including training needs analysis (TNA) and investigating its validity. MATERIALS AND METHODS: Training needs analysis was conducted by an expert panel to identify procedural steps and pitfalls. Performance metrics of the simulator were compared with the TNA results. Participants were distributed according to their level of experience (completed transurethral resection of the prostate [TURP] procedures) as follows: novices (0), intermediates (1-50), and experts (>50). They followed standardized instructions and then performed 2 complete TURP procedures on the TURPsim. RESULTS: Ten of 22 procedural steps (TNA) and 4 of 11 pitfalls were covered by the TURPsim. A total of 66 participants, 22 in each group, were included. Median general judgment (face and content) about the TURPsim was rated 7.3 (median, 7; range, 3-9). Ninety-three percent of all participants qualified the TURPsim as a useful training model. Intermediates and experts had a significant faster resection time and less blood loss compared with novices (construct) (P = 0.001). Novices needed to re-resect previous lobes, and they also resected the prostate in the incorrect order more frequently compared with intermediates and experts. CONCLUSIONS: Training needs analysis is of paramount importance in the evaluation process of a training program. This curriculum-based approach including validity of a simulator seems valuable and may narrow the gap between skills laboratory and clinical practice. This study showed face, content, and construct validity of the TURPsim, and this simulator finds its place in the current urologic curriculum to train basic and procedural TURP skills. PMID- 25275720 TI - Cost savings of performing paracentesis procedures at the bedside after simulation-based education. AB - INTRODUCTION: Paracentesis procedures are increasingly performed in interventional radiology (IR) rather than at the bedside, and there are few comparative effectiveness data on safety or cost. There is also no consensus about the need for blood product transfusions before the procedure. In a previous study, we reported that the selection of procedure location was largely discretionary and that bedside procedures had equal or better outcomes than IR procedures. Therefore, the aim of this study was to evaluate direct hospital costs of IR paracentesis procedures compared with procedures performed at the bedside by simulation-trained clinicians. METHODS: We performed an observational study of paracentesis procedures on a hepatology/liver transplant floor at a tertiary care hospital from July 2008 to December 2011. We modeled hospital costs for IR facility use and transfused blood products and calculated the cost of simulation training to compare costs between IR and bedside procedures. RESULTS: Five hundred eighty-eight patients underwent 764 paracentesis procedures (331 in IR and 433 at bedside). Fifty-one patients (15.4%) with IR procedures received platelet transfusions versus 16 patients (3.7%) with bedside procedures (P < 0.001). Forty-nine patients (14.8%) with IR procedures received fresh frozen plasma transfusions versus 24 patients (5.5%) with bedside procedures (P < 0.001). There were no clinical differences in platelet counts or coagulopathy between groups. In random-effects logistic regression, IR procedures had significantly higher likelihood of platelet (odds ratio, 6.36; 95% confidence interval, 3.28-12.35) and fresh frozen plasma (odds ratio, 3.41; 95% confidence interval, 1.95-5.95) transfusions. Total costs were $663.42 per case for IR and $134.01 per case for bedside procedures. CONCLUSIONS: Training residents to perform bedside paracentesis procedures was highly cost-effective. This approach should be considered as part of national efforts to reduce hospital costs while providing quality care. PMID- 25275721 TI - The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. AB - IMPORTANCE: Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques. OBJECTIVES: To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography. EXPOSURE: Hydroxychloroquine use for at least 5 years. MAIN OUTCOMES AND MEASURES: Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence. RESULTS: Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27). CONCLUSIONS AND RELEVANCE: These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss. PMID- 25275722 TI - Rate of dementia diagnoses according to the degree of aging of the population. AB - BACKGROUND: There is a lack of information regarding geographical differences in the incidence and prevalence of dementia diagnosis according to the degree of aging of the population. The objectives of this study were to analyze the rate of dementia diagnoses, and to compare the dementia subtypes and the clinical characteristics of the patients depending on the degree of aging of their municipalities. METHODS: We used data from the Registry of Dementias of Girona (ReDeGi), containing the cases of dementia diagnosed in the memory clinics of the Health Region of Girona, in Catalonia (Spain), during 2007-2012. The municipalities were classified by a cluster analysis as aged or young municipalities according to their proportion of older people using population ageing indicators. The incidence rates of dementia diagnosis in each type of municipality were compared. RESULTS: The ReDeGi registered 4,314 cases in the municipalities under surveillance. The clinical incidence of dementia was lower in aged municipalities (4.5 vs. 6.1 cases per 1,000 person-years aged 65 and over). Patients from young municipalities had an increased frequency of behavioral and psychological symptoms of dementia. CONCLUSIONS: The environment may influence the clinical manifestations of dementia that predispose people to visit health specialists and obtain a diagnosis. PMID- 25275723 TI - A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-beta cascades with restored caveolin-1 expression. AB - INTRODUCTION: Pulmonary hypertension (PH) is characterized by increased pressure in the pulmonary artery and right ventricular hypertrophy (RVH). Recently, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), was shown to inhibit experimental PH. Here we identified a novel ACE2 activator and investigated how the compound reduced monocrotaline (MCT)-induced PH. METHODS: To induce PH, Sprague-Dawley rats were injected subcutaneously with MCT, followed by the continuous administration of NCP-2454, an ACE2 activator, using osmotic pumps. Pulmonary arterial compliance was monitored every week until 4 weeks post-injection (wpi). RVH and lung remodeling was evaluated using lung tissue at 4 wpi. RESULTS: NCP-2454 upregulated the production of Ang-(1-7) when incubated with ACE2 and Ang II. Notably, a continuous infusion of NCP-2454 significantly improved pulmonary arterial compliance, right ventricular systolic pressure, and RVH in MCT-treated rats. Interestingly, NCP-2454 increased the relative expression of ACE2 and MAS mRNA in lung tissue, especially in MCT treated rats. In addition, the compound inhibited the MCT-induced overexpression of transforming growth factor beta, phosphorylation of signal transducer and activator of transcription-3 (STAT3), and interleukin-6 production. The compound also restored the expression of caveolin-1 (Cav-1), which negatively regulates the Janus kinase-STAT signaling cascade. CONCLUSIONS: NCP-2454 prevented MCT induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression. PMID- 25275725 TI - Diterpenoids of terrestrial origin. AB - Covering: January to December 2013. Previous review, Nat. Prod. Rep., 2013, 30, 1346-1356. This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 179 references. PMID- 25275726 TI - Role of proton hopping in surface charge transport on tin dioxide as revealed by the thermal dependence of conductance. AB - The presence of water on an oxide surface can dramatically alter its electrical properties with important consequences for electrical measurements by scanning probe microscopy, and for the use of semiconducting oxides in sensing applications. Here, the thermal dependence of the conductance of tin dioxide is interpreted by combining semiconductor equilibrium carrier statistics with a proton hopping mechanism. First, the functional form of this charge transport model is fit to experimental conductance data for tin dioxide. Next, the important energy parameters in the model are computed with density functional theory. Comparing the values of the energy parameters obtained by fitting, to the values for the same parameters obtained from electronic structure calculations, yields new insight into the surface charge transport in tin dioxide. In particular, it is found that mobile protons, freed from the dissociative adsorption of water on the [110] surface, are an essential component of the observed thermal dependence of conductance in tin dioxide. PMID- 25275724 TI - Regression of human papillomavirus intraepithelial lesions is induced by MVA E2 therapeutic vaccine. AB - Human papilloma viruses can induce warts, condylomas, and other intraepithelial cervical lesions that can progress to cancer. Cervical cancer is a serious problem in developing countries because early detection is difficult, and thus proper early treatment is many times missing. In this phase III clinical trial, we evaluated the potential use of MVA E2 recombinant vaccinia virus to treat intraepithelial lesions associated with papillomavirus infection. A total of 1176 female and 180 male patients with intraepithelial lesions were studied. They were injected with 10(7) MVA E2 virus particles directly into their uterus, urethra, vulva, or anus. Patients were monitored by colposcopy and cytology. Immune response was determined by measuring the antibody titer against MVA E2 virus and by analyzing the cytotoxic activity against cancer cells bearing papillomavirus DNA. Papillomavirus was determined by the Hybrid Capture method or by polymerase chain reaction analysis. By histology, 1051 (89.3%) female patients showed complete elimination of lesions after treatment with MVA E2. In 28 (2.4%) female patients, the lesion was reduced to CIN 1. Another 97 (8.3%) female patients presented isolated koilocytes after treatment. In men, all lesions were completely eliminated. All MVA E2-treated patients developed antibodies against the MVA E2 vaccine and generated a specific cytotoxic response against papilloma transformed cells. Papillomavirus DNA was not detected after treatment in 83% of total patients treated. MVA E2 did not generate any apparent side effects. These data suggest that therapeutic vaccination with MVA E2 vaccine is an excellent candidate to stimulate the immune system and generate regression in intraepithelial lesions when applied locally. PMID- 25275727 TI - Cation-modulated reactivity of iridium hydride pincer-crown ether complexes. AB - Complexes of a new multidentate ligand combining a rigid, strongly donating pincer scaffold with a flexible, weakly donating aza-crown ether moiety are reported. The pincer-crown ether ligand exhibits tridentate, tetradentate, and pentadentate coordination modes. The coordination mode can be changed by Lewis base displacement of the chelating ethers, with binding equilibria dramatically altered through lithium and sodium cation-macrocycle interactions. Cation promoted hydrogen activation was accomplished by an iridium monohydride cation ligated in a pentadentate fashion by the pincer-crown ether ligand. The rate can be controlled on the basis of the choice of cation (with lithium-containing reactions proceeding about 10 times faster than sodium-containing reactions) or on the basis of the concentration of the cation. Up to 250-fold rate enhancements in H/D exchange rates are observed when catalytic amounts of Li(+) are added. PMID- 25275728 TI - Levels of angiogenic proteins in plasma and platelets are not different between patients with hepatitis B/C-related cirrhosis and patients with cirrhosis and hepatocellular carcinoma. AB - Increasing evidence suggests that levels of angiogenic proteins within blood platelets change at the earliest stages of cancer development and may thus provide a promising diagnostic and prognostic tool. Patients with cirrhosis have increased risk of developing hepatocellular carcinoma (HCC). We aimed to study whether development of HCC in hepatitis-related cirrhosis results in changes in platelet levels of angiogenic proteins. We studied the intraplatelet levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), endostatin, platelet factor 4 (PF4) and thrombospondin type 1 (TSP-1) in 38 consecutive patients with hepatitis B- or C-related liver cirrhosis with or without HCC in addition to plasma levels of the same proteins. Twenty healthy volunteers were included to establish reference values for the various tests. Intraplatelet levels of VEGF, bFGF, HGF and endostatin were significantly higher in patients compared to controls. Intraplatelet levels of PDGF, PF4 and TSP-1 were comparable between patients and controls. Plasma levels of VEGF, bFGF and endostatin were comparable between patients and controls. Plasma levels of PDGF, PF4 and TSP-1 were decreased in patients, but this difference disappeared when levels were corrected for platelet count. Intraplatelet and plasma levels of all proteins assessed were comparable between patients with and without HCC. In conclusion, the intraplatelet levels of some angiogenic proteins are elevated in cirrhosis, but do not discriminate between patients with and without HCC. Thus, intraplatelet levels of angiogenic proteins do not seem useful as diagnostic or prognostic biomarker of HCC in cirrhotic patients. PMID- 25275730 TI - Surgical treatment of the neglected achilles tendon rupture with Hyalonect. AB - BACKGROUND: The purpose of this study was to report the management and outcomes of ten patients with chronic Achilles tendon rupture treated with a turndown gastrocnemius-soleus fascial flap wrapped with a surgical mesh (Hyalonect). METHODS: Ten men with neglected Achilles tendon rupture were treated with a centrally based turndown gastrocnemius fascial flap wrapped with Hyalonect. Hyalonect is a knitted mesh composed of HYAFF, a benzyl ester of hyaluronic acid. The Achilles tendon ruptures were diagnosed more than 1 month after injury. The mean patient age was 41 years. All of the patients had weakness of active plantarflexion. The mean preoperative American Orthopaedic Foot and Ankle Society score was 64.8. RESULTS: The functional outcome was excellent. The mean American Orthopaedic Foot and Ankle Society score was 97.8 at the latest follow-up. There were significant differences between the preoperative and postoperative scores. Ankle range of motion was similar in both ankles. Neither rerupture nor major complication, particularly of wound healing, was observed. CONCLUSIONS : For patients with chronic Achilles tendon rupture with a rupture gap of at least 5 cm, surgical repair using a single turndown fascial flap covered with Hyalonect achieved excellent outcomes. PMID- 25275729 TI - Fracture healing and biomarker expression in a diabetic Zucker rat model. AB - BACKGROUND: Persons with diabetes have a higher incidence of fractures compared with persons without diabetes. However, there is little published information concerning the deleterious effect of late-stage diabetes on fracture healing. There are no studies using animal models that evaluate the effect of advanced diabetes on fracture healing. The purpose of our study was to evaluate cytokine expression, specifically macrophage inflammatory protein 1 (MIP-1) and vascular endothelial growth factor, in fracture healing in a type 2 diabetes rat model. METHODS: We evaluated biomarker expression after femur fracture using a rat model. The two groups consisted of 24 Zucker diabetic rats (study group) and 12 Zucker lean rats (control group). An independent reviewer was used to assess delayed union. We evaluated serum samples 2, 4, 7, and 14 days after surgery for MIP-1, vascular endothelial growth factor, leptin, and other cytokine levels. RESULTS: At 3 weeks, Kaplan-Meier estimates showed that 45.8% of femur fractures in Zucker diabetic rats had healed, whereas 81.8% of those in Zucker lean rats had healed (P = .02). A logistic regression model to predict fast healing that included the three cytokines and diabetes status showed that the only factor achieving significance was MIP-1alpha. Vascular endothelial growth factor was the only biomarker to show significance compared with delayed healing. CONCLUSIONS: These results confirm significant differences in biomarker expression between diabetic and nondiabetic rats during bone healing. The key factors for bone healing may appear early in the healing process, whereas differences in diabetes versus nondiabetes are seen later in the healing process. Increased levels of MIP 1alpha were associated with the likelihood of delayed healing. PMID- 25275731 TI - Effects of shock-absorbing insoles during transition from natural grass to artificial turf in young soccer players: a randomized controlled trial. AB - BACKGROUND: Playing soccer on artificial turf can provoke pain in young players. Using shock-absorbing insoles (SAIs) can result in decreased pain perception. We sought to investigate the pain and comfort intensity experienced during the switch from natural grass to third-generation artificial turf and with the use of SAIs on artificial turf during training in young soccer players. METHODS: In a prospective randomized controlled study, 75 players were included from the youth teams of U15, U17, and U19. Pain intensity and comfort were assessed after training on only grass turf for 3 months. Randomization stratified by team level and age was performed; the intervention group received SAIs, and the control group used their own insoles. Assessments were repeated after 3 weeks on artificial turf (baseline) and 3 more weeks (follow-up) on artificial turf with SAIs/usual insoles. RESULTS: Pain intensity increased and comfort decreased significantly after 3 weeks of training on artificial grass compared with natural grass (P < .05). The addition of SAIs resulted in significantly reduced pain intensity compared with the usual insoles (P < .05). CONCLUSIONS: The switch to artificial turf is associated with less comfort and more pain during training in young soccer players. The use of SAIs led to lower pain intensity, highlighting a protective role of the insoles after 6 weeks of training on artificial turf. PMID- 25275732 TI - Description of total population hospital admissions for Morton's metatarsalgia in Australia. AB - BACKGROUND: Morton's metatarsalgia is a painful perineural fibroma of a plantar nerve, most commonly of the second or third intermetatarsal spaces of the forefoot. The aim of this study was to investigate hospital admissions with a diagnosis of Morton's metatarsalgia in the Australian population from 1998 to 2008. METHODS: Data regarding admissions with a diagnosis code of ICD-10 G57.6 were extracted from the Australian Institute of Health and Welfare databases of hospital morbidity from 1998 to 2008. The event of interest was an admission with ICD-10 G57.6 (Morton's metatarsalgia). The explanatory variables included sex and age group. Rates were calculated using the estimated resident population counts to determine denominators. RESULTS: Morton's metatarsalgia admissions were almost three-fold higher for women in the population compared to men. The rate of admissions for Morton's metatarsalgia was the highest for the total population in the 55- to 59-year-old age group. Among women admitted for Morton's metatarsalgia, the highest rate was in the 50- to 54-year-old age group; among men, the highest rate was in the slightly older 55- to 59-year-old age category. CONCLUSIONS: Population-level information on admissions for Morton's metatarsalgia show that admissions were three times higher among women compared to men. The highest admission rate was in the 50- to 55-year-old age group. PMID- 25275733 TI - Posterior tibial tendinopathy: what are the risk factors? AB - BACKGROUND: Posterior tibial tendinopathy (PTT) is the most common cause of acquired (progressive) flatfoot deformity in adults. To date, PTT research has mainly focused on management rather than on causal mechanisms. The etiology of PTT is likely to be multifactorial because both intrinsic and extrinsic risk factors have been reported. We sought to critically evaluate reported etiologic factors for PTT and consider the concept of genetic risk factors. METHODS: A detailed review of the literature published after 1936 was undertaken using English-language medical databases. RESULTS: No clear consensus exists as to the relative importance of the risk factors reported, and neither has any consideration been given to a possible genetic basis for PTT. CONCLUSIONS: To date, studies have examined various intrinsic and extrinsic risk factors implicated in the etiology of PTT. The interaction of these factors with an individual's genetic background may provide valuable data and help offer a more complete risk profile for PTT. A properly constructed genetic association study to determine the genetic basis of PTT would provide a novel and alternative approach to understanding this condition. PMID- 25275735 TI - The enemy of the feet: blisters in ultraendurance runners. AB - BACKGROUND: Blisters are the most common dermatologic problem in ultraendurance runners. Their incidence, localization, pain scores, and risk factors in field conditions are poorly understood. METHODS: We conducted an observational field based cohort study during the 5-day multistage 2010 and 2011 Al Andalus Ultimate Trail (219 km). Daily postrace data on blister frequency, localization, severity, and preventive measures from 50 ultramarathon runners were collected through the direct interview technique. RESULTS: After 4 days of running (182 km), blisters occurred in 76% of the participants (P < .001 versus stage 1) compared with 34% after day 1, 54% after day 2, and 72% after day 3 (P < .001 versus stage 1). Most of the blisters formed on the toes (65%) (P < .001), followed by blisters on other locations of the foot: the ball of the foot (16%), heel (14%), and sole (5%). Blisters were more painful toward the end of the race, and those on the sole and heel tended to be the most painful, although this did not reach statistical significance. Prophylactic measures studied (type and fabric of socks; application of antiperspirants, talcum powder, or lubricant to feet; and prophylactic taping) did not show any reduction in blister rates. The only predictive marker for reduced blister incidence was previous ultramarathon experience in men (r = -0.44, P < .05). CONCLUSIONS: Blisters are extremely common in multistage ultramarathon races. Race experience in male ultramarathon runners is associated with reduced blister rates. PMID- 25275734 TI - An assessment of hallux limitus in university basketball players compared with noncompetitive individuals. AB - BACKGROUND: Injuries of the first metatarsophalangeal joint have lately been receiving attention from researchers owing to the important functions of this joint. However, most of the studies of turf toe injuries have focused on sports played on artificial turf. METHODS: This study compared the range of motion of the first metatarsophalangeal joint in collegiate basketball players (n = 123) and noncompetitive individuals (n = 123). RESULTS: A statistically significant difference (P < .001) in range of motion was found between the two groups. The difference between the two sample means was 21.35 degrees . CONCLUSIONS : With hallux rigidus being a potential sequela of repeated turf toe injuries, it seems likely that subacute turf toe injuries occur in basketball players, leading to degenerative changes that result in hallux limitus. PMID- 25275736 TI - Efinaconazole 10% solution in the treatment of onychomycosis of the toenails. AB - BACKGROUND: Efinaconazole 10% solution is a new triazole antifungal agent developed for the topical treatment of onychomycosis. This article reviews the pooled results of the two pivotal clinical trials of this drug that have been performed in the United States, Canada, and Japan. METHODS: The two studies of 1,655 patients were both double-blind, vehicle-controlled, parallel-group, randomized, multicenter studies designed to determine the efficacy and safety of efinaconazole 10% solution in the treatment of mild-to-moderate onychomycosis of the toenails caused by dermatophytes. Treatment was provided once daily for 48 weeks, and the primary end point was at week 52. RESULTS: The combined results show a 56% mycologic cure rate compared with 17% for vehicle at week 52. Clinical treatment success was achieved in 43% of patients treated with efinaconazole 10% solution at follow-up (week 52). Clinical treatment success was achieved in 47% of patients. As expected for a topical agent, the use of efinaconazole 10% solution was found to be safe, with mild, transient irritation at the site of application reported as the most common adverse event. CONCLUSIONS: The efficacy and safety profile of efinaconazole 10% solution suggests that it may represent an important advance in the topical treatment of onychomycosis. Further studies will help us better understand the role of this agent for the treatment of this widespread podiatric medical condition. PMID- 25275737 TI - Consequences of repetitive toenail cutting by podiatric physicians on force production, endurance to fatigue, and the electromyogram of the flexor digitorum superficialis muscles. AB - BACKGROUND: We hypothesized that the repetitive use of a toenail clipper by podiatric physicians could induce fatigue of the flexor digitorum superficialis (FDS) muscle, reducing the accuracy of toenail cutting. METHODS: We examined the consequences of cutting a plastic sheet, reproducing the resistance of thick toenails, with a podiatric medical clipper on the maximal handgrip force (Fmax) developed by the FDS muscle and an isometric handgrip sustained at 50% of Fmax, during which endurance to fatigue and changes in the power spectra of the surface FDS muscle electromyogram (root mean square and median frequency) were measured. The same participants randomly performed one or five runs of 30 successive cuttings, each on different days. RESULTS: After the first and fifth cutting runs, Fmax increased, suggesting a post-tetanic potentiation. During the handgrip sustained at 50% of Fmax, we measured a significant reduction in the tension-time index after the first cutting run. Moreover, after the fifth cutting run, the tension-time index decrease was significantly accentuated, and the decrease in FDS muscle median frequency was enhanced. No median frequency decline was measured during the cutting runs. CONCLUSIONS: These results suggest that the efficacy of occupational podiatric medical tasks progressively declines with the repetition of toenail cutting. We propose solutions to remedy this situation. PMID- 25275738 TI - Radiographic anatomy of the foot and ankle-part 2: the greater tarsus. AB - BACKGROUND: Normal radiographic anatomy of the foot and ankle, aside from my previous work, has been addressed only superficially or sparingly in the medical literature. This project correlates detailed radiographic anatomy of the entire adult foot and ankle (two-dimensional) to osteology (three-dimensional). METHODS: Each bone's position was determined after meticulous examination and correlation to an articulated skeleton relative to the image receptor and direction of the x ray beam, with correlation to the radiograph for confirmation. RESULTS: Images of each foot and distal leg bone ("front" and "back" perspectives) are presented alongside a corresponding radiographic image for comparison. The normal gross and radiographic anatomy is correlated and described for each radiographic positioning technique. CONCLUSIONS: Foundational knowledge is provided that future researchers can use as a baseline ("normal") and that students and practitioners can use for comparison when interpreting radiographs and distinguishing abnormal findings. The results of the original project, owing to its broad scope, have been divided into five parts: the lower leg, the greater tarsus (the focus of this article), the lesser tarsus, the metatarsals, and the phalanges. PMID- 25275739 TI - Subungual syringoid eccrine carcinoma of the great toe nail complex: a case report. AB - Syringoid eccrine carcinoma is a very rare skin cancer. We present a case of a 22 year-old woman with a presentation of syringoid eccrine carcinoma in the subungual region of the hallux. This clinical case demonstrates our work-up that led to a proper diagnosis and management of this pathology. We discuss our surgical procedure of choice and the outcome. This report adds valuable information to a limited database of knowledge available on the diagnosis and management of syringoid eccrine carcinomas. PMID- 25275740 TI - Transplantation with allograft for rupture of the flexor hallucis longus tendon with subsequent longitudinal tear of the flexor digitorum longus tendon at the master knot of Henry: a case report. AB - A rare case of closed complete rupture of the flexor hallucis longus tendon with subsequent longitudinal tear of the flexor digitorum longus tendon is reported in a marathon runner. This is also a first case report of flexor hallucis longus transplant with cadaveric posterior tibial tendon allograft. Two minimal incisions distal and proximal to the malleolus allowed for tunneling with urethral dilators to open the tendon sheath for transplantation, avoiding the need for a large incision. Postoperatively, the patient regained active flexion at the interphalangeal joint of the left hallux. Four months after surgery, full range of motion was observed and dynamometric exam revealed 68% of the strength of the contralateral side. The patient was able to resume competitive running after the surgery and performed well in her age bracket. PMID- 25275741 TI - Primary high-grade squamous cell carcinoma of the foot: a case report. AB - Squamous cell carcinoma is the second most common type of skin cancer and may present in the distal extremities including the foot. We present a case in which a primary squamous cell carcinoma of the foot, which presented as a granulomatous ulcerating lesion, was diagnosed and successfully treated with a radical resection. Our case shows an atypical presentation of a very common malignancy and, it is therefore essential for health-care providers to consider malignancy in all suspicious lesions of the foot. PMID- 25275742 TI - Simultaneous bilateral stress fractures in a homemaker: a case report and literature review. AB - Stress fractures commonly occur in athletes and military cadets due to repetitive stress on the bony cortex. Stress fractures of the tibia are commonly localized proximally and occur during aerobic weightbearing exercises. This is an unusual case of bilateral simultaneous distal tibial stress fracture in a young homemaker. PMID- 25275743 TI - The development of a charcot foot after significant weight loss in people with diabetes: three cautionary tales. AB - Medication to aid weight loss and weight loss surgery are becoming more commonly available for people with diabetes. As a result of profound weight loss, diabetes may go into remission and many biochemical and physical parameters improve. However, some of the end organ damage associated with diabetes may not improve, peripheral neuropathy being an example. We present three cases in people with diabetes and pre-existing peripheral neuropathy who had lost significant weight. They became more mobile and developed a Charcot foot despite their diabetes improving significantly. People who have lost significant weight should continue to monitor their feet because the risks of foot disease remain even if diabetes goes into remission. PMID- 25275744 TI - Reconstruction of the one-digit foot with an osteocutaneous fibula flap: a case report. AB - The decision to amputate or reconstruct after high-energy foot injuries is controversial. A 25-year-old male patient was admitted to our clinic with a complex injury to his left foot sustained during a mine explosion, and the second to fifth digits and metatarsals of the left foot had been traumatically amputated before admission to our facility. The complex left foot defect was reconstructed with an osteocutaneous fibula flap during a single session. An osteotomy was performed on the bone segment of the flap, and both lateral longitudinal and transverse arches were repaired. Both aesthetic and functional outcomes were very satisfactory, including independent ambulation, light jogging, and full performance of activities of daily living without limitation. Many factors, including comorbidities, should be considered during the decision-making process of amputating or reconstructing complex foot injuries. PMID- 25275746 TI - Schwannoma of the left foot: a brief overview with focus on associated clinical syndromes. AB - In this article, we present a 25-year-old man who developed an asymptomatic schwannoma on his left lateral heel and review the salient features of this cutaneous condition. A schwannoma is a slowly growing neoplasm of Schwann cell origin. Histology shows high cellularity (Antoni A regions), nuclear palisades (Verocay bodies), and alternating myxoid regions (Antoni B regions). Very few cases have been reported on the foot or ankle. As with this patient, most schwannomas do not cause symptoms, but some result in dysesthesia and nerve dysfunction. Multiple schwannomas may indicate an underlying syndrome such as neurofibromatosis type 1, type 2, and schwannomatosis. The differential diagnosis for schwannoma includes fibrosarcoma, leiomyosarcoma, and neurofibroma. The definitive treatment is surgical excision. This usually results in complete resolution with minimal recurrence, as was the case for this patient. PMID- 25275745 TI - Fibrolipomatous hamartoma of nerve in the great toe. AB - Fibrolipomatous hamartoma is a rare benign tumor characterized by infiltration of fibrous and adipose tissue found within the epineurium and perineurium of the distal peripheral nerves. Most commonly seen in the upper extremities and median nerve, it is rarely involved in the foot and ankle. We report a rare case of fibrolipomatous hamartoma found in the great toe of a 25-year-old patient. Magnetic resonance imaging demonstrated a heterogeneous mass, confirming the mass was solid rather than a fluid collection. Surgical excision revealed a fatty, fibrous, well-demarcated, encapsulated, solid soft-tissue mass. A surgical excision was performed and a pathologic diagnosis of fibrolipomatous hamartoma was made. PMID- 25275747 TI - Schwannoma of the posterior tibial nerve: case study. AB - BACKGROUND: Schwannomas are rare, slow-growing, benign tumors consisting of Schwann cells. They may cause pressure along a bony structure, resulting in increased pain and discomfort. Less than 1% of schwannomas become malignant, and localization in the foot is uncommon (2%-3% of reported cases). METHODS: We present a case of a schwannoma of a branch of the posterior tibial nerve sheath. The goal is to assist in recognition, diagnosis, and treatment of schwannoma in the foot and ankle. This is a case of a 51-year-old male soccer player with a soft-tissue mass along the medial ankle at the tarsal tunnel area with an insidious onset (2 years). Physical examination revealed a 3.0 * 2.5-cm mass; magnetic resonance imaging confirmed location, size, and depth. RESULTS: Surgical resection of the soft-tissue mass was performed under general anesthesia. The mass was found to be superior to the flexor retinaculum and attached by a small nerve branch of the posterior tibial nerve that traveled through the flexor retinaculum. A tissue specimen was sent to the pathology laboratory, and a schwannoma was confirmed histologically. CONCLUSIONS: Schwannomas can occur after trauma, especially if the posterior tibial nerve or its branches are affected intrinsically or extrinsically, leading to discomfort, pain, and numbness along the tarsal tunnel. Also, unique to this case, a schwannoma may occur along the small branches of the posterior tibial nerve and present anatomically superior to the flexor retinaculum. PMID- 25275748 TI - Nodular amyloidosis: clinical recognition of an unusual entity. AB - Nodular amyloidosis is a protein deposition disorder that is important to recognize in the clinical setting. Identification and differentiation from primary systemic amyloidosis, which has an identical cutaneous presentation, but serious systemic implications, is of particular significance. Our case report highlights two patients who presented with isolated involvement of the plantar surface and ungual phalanges, each with concomitant tinea pedis. Recognition and diagnosis of cutaneous amyloidosis enables discrimination from systemic disease, and if found, prompt institution of appropriate treatment. PMID- 25275749 TI - Bilateral ankle clonus as initial manifestation of progressive multifocal leukoencephalopathy: a case report. AB - We report on a rare case of foot and ankle clonus as the initial presentation of progressive multifocal leukoencephalopathy in a young patient with no known history of HIV or AIDS and no significant past medical or social history. The patient came to the emergency department with a chief complaint of muscle spasms in his lower extremities and unsteadiness in gait. The patient was diagnosed as having bilateral ankle clonus. Work-up revealed an absolute lymphocyte CD4+ count of 18, an HIV viral load of 1,690,000, and a positive John Cunningham virus polymerase chain reaction in the cerebral spinal fluid, indicating that the patient had progressive multifocal leukoencephalopathy and AIDS. The diagnosis of progressive multifocal leukoencephalopathy should be in the foot and ankle surgeon's differential diagnosis when a patient presents with neurological symptoms in the lower extremities. PMID- 25275750 TI - Congenital missing tibial sesamoid in a marathon runner: a case report. AB - The absence of the hallucal tibial sesamoid is seldom seen in the clinical setting. We present a case of a symptomatic missing tibial sesamoid in a female marathon runner. PMID- 25275751 TI - Residency development. PMID- 25275755 TI - Computational derivation of structural alerts from large toxicology data sets. AB - Structural alerts have been one of the backbones of computational toxicology and have applications in many areas including cosmetic, environmental, and pharmaceutical toxicology. The development of structural alerts has always involved a manual analysis of existing data related to a relevant end point followed by the determination of substructures that appear to be related to a specific outcome. The substructures are then analyzed for their utility in posterior validation studies, which at times have stretched over years or even decades. With higher throughput methods now being employed in many areas of toxicology, data sets are growing at an unprecedented rate. This growth has made manual analysis of data sets impractical in many cases. This report outlines a fully automatic method that highlights significant substructures for toxicologically important data sets. The method identifies important substructures by computationally breaking chemical structures into fragments and analyzing those fragments for their contribution to the given activity by the calculation of a p-value and a substructure accuracy. The method is intended to aid the expert in locating and analyzing alerts by automatic retrieval of alerts or by enhancing existing alerts. The method has been applied to a data set of AMES mutagenicity results and compared to the substructures generated by manual curation of this same data set as well as another computationally based substructure identification method. The results show that this method can retrieve significant substructures quickly, that the substructures are comparable and in some cases superior to those derived from manual curation, that the substructures found covers all previously known substructures, and that they can be used to make reasonably accurate predictions of AMES activity. PMID- 25275756 TI - Expression and localization of ghrelin and its receptor in ovarian follicles during different stages of development and the modulatory effect of ghrelin on granulosa cells function in buffalo. AB - Ghrelin, a hormone predominantly found in the stomach, was recently described as a factor that controls female reproductive function. The aim of our study was to investigate the expression and localization of ghrelin and its active receptor, growth hormone secretagogue receptor type 1a (GHS-R1a) in buffalo ovarian follicles of different follicular size and to investigate role of ghrelin on estradiol (E2) secretion, aromatase (CYP19A1), proliferating cell nuclear antigen (PCNA) and apoptosis regulator Bax gene expression on granulosa cell culture. Using real time PCR and western blot, we measured gene and protein expression of examined factors. Localization was done with immunofluorescence method. Expression of ghrelin increased with follicle size with significantly highest in dominant or pre-ovulatory follicle (P<0.05). Expression of GHS-R1a was comparable in medium and large follicle but was higher than small follicles (P<0.05). Both the factors were localized in granulosa and theca cells. Pattern of intensity of immunofluorescence was similar with mRNA and protein expression. In the in vitro study granulosa cells (GCs) were cultured and treated with ghrelin each at 1, 10 and 100ng/ml concentrations for two days after obtaining 75-80 per cent confluence. Ghrelin treatment significantly (P<0.05) inhibited E2 secretion, CYP19A1 expression, apoptosis and promoted cell proliferation. In conclusion, this study provides novel evidence for the presence of ghrelin and receptor GHS R1a in ovarian follilcles and modulatory role of ghrelin on granulosa cell function in buffalo. PMID- 25275757 TI - Genetic control of immunity to Turnip mosaic virus (TuMV) pathotype 1 in Brassica rapa (Chinese cabbage). AB - Turnip mosaic virus (TuMV) is the major virus infecting crops of the genus Brassica worldwide. A dominant resistance gene, TuRB01b, that confers immunity to the virus isolate UK 1 (a representative pathotype 1 isolate of TuMV) on Brassica rapa was identified in the Chinese cabbage cultivar Tropical Delight. The TuRB01b locus was mapped to a 2.9-cM interval on B. rapa chromosome 6 (A6) that was flanked by RFLP markers pN101e1 and pW137e1. This mapping used a first backcross (B(1)) population segregating for the resistance gene at TuRB01b and sets of RFLP markers employed in previous mapping experiments in Brassica. Virus-plant interaction phenotypes were assayed in inbred progeny derived from B(1) individuals to allow different virus isolates to be tested. Comparative mapping confirmed that A6 of B. rapa was equivalent to chromosome 6 of Brassica napus (A6) and that the map position of TuRB01b in B. rapa could be identical to that of TuRB01 in B. napus. Detailed evaluation of plant-virus interactions showed that TuRB01 and TuRB01b had indistinguishable specificities to a range of TuMV isolates. The possibility that TuRB01 and TuRB01b represent similar or identical alleles at the same A genome resistance locus suggests that B. napus acquired TuRB01 from the B. rapa gene pool. PMID- 25275758 TI - New-onset nasal obstruction and epistaxis of the left side of the nose. PMID- 25275760 TI - The impact of Ramadan fast on patients with gout. AB - BACKGROUNDS: Ramadan fast is a religious custom in Islam. Increased serum uric acid level during this month had been reported in past studies of nongout patients. OBJECTIVES: The objective of this study was to assess the impact of Ramadan fast on patients with gout. METHODS: All Moslem patients with gout from the registry of Nazareth Hospital, who intended to fast during Ramadan, were asked to participate in our study (group 1). Data regarding age, gender, income, education, duration of gout, meds, adherence to low-purine diet, and gouty attacks were documented. Age- and gender matched Moslem patients from the same registry, but who did not intend to fast during Ramadan, were asked to participate as a control group (group 2). Just prior to and at the end of Ramadan, blood for uric acid, creatinine, and urea levels were obtained as well as body mass index, from all the patients. During Ramadan, patients were monitored for gouty arthritis or renal calculi attacks, as well as low-purine diet and medicine adherence. RESULTS: Twenty-one and 22 patients from groups 1 and 2, respectively, completed the study. Mean serum uric acid, urea, creatinine, and body mass index levels at the end of Ramadan fasts in group 1 patients were 8.11 mg/dL, 26.38 mmol/L, 0.87 mg/dL, and 31.0 kg/m, respectively, as compared with 7.92 mg/dL (P = 0.707), 24.54 mmol/L (P = 0.769), 0.84 mg/dL (P = 0.180), and 30.5 kg/m (P = 0.907) respectively, obtained just prior to the fast. No significant change in any parameter was seen also in group 2 patients. There also was no significant change between the 2 groups in arthritis or renal calculi attacks and also in medication and low-purine diet adherence, during Ramadan. CONCLUSIONS: There was no risk for a significant increase in gouty arthritic/renal calculi attacks or serum uric acid in patients with gout during Ramadan fast. PMID- 25275761 TI - Bisphosphonates and hip and nontraumatic subtrochanteric femoral fractures in the Veterans Health Administration. AB - PURPOSE: Subtrochanteric femoral shaft fractures after little or no trauma have been reported in long-term users of bisphosphonates, but risks relative to hip fracture protective effects and among men are not clear. We examined associations between bisphosphonate use and nontraumatic subtrochanteric (NTST) femoral fractures and hip fractures in the Veterans Health Administration. METHODS: This retrospective cohort study was conducted using 1998-2007 Veterans Health Administration electronic medical records data on 78,155 individuals who had a fragility fracture at age 45 years or older. Time-to-event analysis examined associations of bisphosphonates with risk of NTST femoral fracture and, separately, hip fracture, controlling for sociodemographics, medications, and comorbid medical conditions. RESULTS: The cohort had a mean age 66.5 years (32.5% were >=75 years old) at the time of their first fracture, and 69.3% were observed for 6 or more years; only 11.8% were prescribed bisphosphonates during observation. During follow-up, 408 had an NTST femoral second fracture, and 1584 had a hip second fracture. Compared with those never on bisphosphonates, the adjusted hazard ratio for NTST femoral second fracture among patients on 4 years of therapy or longer was 0.40 (95% confidence interval, 0.16-0.97) and for hip second fracture was 0.38 (95% confidence interval, 0.24-0.61). CONCLUSIONS: Bisphosphonate treatment in this high-risk cohort was infrequent with few long term users, limiting power to assess long-term effects. Nontraumatic subtrochanteric femoral fractures were uncommon, and longer bisphosphonate use was associated with lower (not higher) risk. In men, risks of NTST femoral fractures associated with bisphosphonate treatment may be low in contrast to substantial protective benefits for hip fracture. PMID- 25275762 TI - Short-term total hip replacement outcomes in ankylosing spondylitis. AB - BACKGROUND: While rates of total hip replacement (THR) in spondyloarthritis are increasing, contemporary outcomes are not well described. OBJECTIVES: This study analyzes 2-year outcomes in a contemporary cohort of ankylosing spondylitis (AS) patients undergoing THR. METHODS: A case-control study was performed using data from an institutional arthroplasty registry. Validated AS cases were matched 4:1 by age and procedure to patients with osteoarthritis (OA). Data were obtained prior to surgery and at 2 years. Multiple imputation techniques were performed to avoid systematic bias due to missing data. RESULTS: Thirty eligible AS cases were identified between May 2007 and February 2010. Ankylosing spondylitis cases had worse American Society of Anesthesia class (P < 0.001) and more comorbidities (P = 0.02) compared with OA. Ankylosing spondylitis had worse preoperative lower extremity Western Ontario and McMaster Universities Arthritis Index pain (46.8 vs 55.4; P = 0.03), function (43.0 vs 55.1; P = 0.04), and general health status measured as SF-12 (Short-Form Health Survey) physical component scale (PCS) score (29.6 vs 36.0; P < 0.001), however, there was no difference at two years in pain (89.4 vs 92.5; P = 0.23) or function (83.9 vs 90.1; P = 0.04). Physical component scale score remained significantly worse (41.2 vs 50.1; P < 0.001). Better preoperative SF-12 PCS score significantly decreased the risk of a poor pain outcome (odds ratio, 0.06; 95% confidence interval, 0.01-0.40). Overall satisfaction was high. CONCLUSIONS: Although patients with AS in a contemporary cohort have more comorbidities and worse physical function prior to THR, they achieve similar gains as OA. In a multivariate regression controlling for multiple potential confounders including back pain, only preoperative health status measured as SF-12 PCS score was a significant risk factor for a poor 2 year pain. Among contemporary patients, AS is not an independent risk factor for poor THR outcomes.Take-Home Message Patients with AS have significant improvement in pain and function after THR.Poor preoperative function and low-back pain are not risk factors for poor THR outcomes for patients with AS.Despite improvements, low SF-12 PCS scores indicate persistent limitations due to health. PMID- 25275763 TI - Role of bronchoalveolar lavage for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates. AB - OBJECTIVES: The aims of the study were to evaluate the effectiveness of bronchoalveolar lavage (BAL) for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates and to evaluate factors that affect the diagnostic yield. METHODS: A retrospective study was performed in patients with rheumatic autoimmune diseases and lung infiltrates whose BALs were sent for microbial assays at Peking Union Medical College Hospital from January 2009 to June 2013. Patient characteristics, clinical symptoms, medication history, laboratory parameters, radiographic findings, lung lobe lavaged, and diagnostic yield were retrieved. RESULTS: Seventy BALs were performed in 69 patients. The overall diagnostic yield of BAL for pulmonary infection was 17.1% (12/70), sensitivity was 35.5%, and specificity was 97.4%. Twelve microorganisms were isolated from 12 different BALs conforming to diagnostic criteria, including 4 Aspergillus, 3 Pneumocystis jirovecii, 3 gram-negative bacilli, 1 gram-positive coccus, and 1 mycobacterium. Patients with clinical symptoms of fever, cough, or expectoration had a higher diagnostic yield than patients without either symptom (25.6% vs 3.7%, P = 0.042). Patients with ground-glass opacity, mass, or consolidation radiographically had a higher yield than did patients with reticular or nodular infiltrates (20.3% vs 0, P < 0.001). CONCLUSIONS: Bronchoalveolar lavage is a useful tool for patients with rheumatic autoimmune diseases and lung infiltrates, especially in cases where initial antimicrobial therapy is ineffective. Opportunistic pathogens are important in patients with rheumatic autoimmune diseases and lung infiltrates and should be considered when antibacterial treatment is ineffective. PMID- 25275764 TI - Rheumatic disease in wartime: gouty generals in battles lost or won. AB - Leadership by a commander is an important determinant of military outcomes. This report describes 2 19th-century wars in which the commanding general was afflicted with severe, disabling gout. In the First Afghan War (1839-1942), the result was disastrous, but in the Spanish-American War (1898), subordinates ignored the general's orders and saved the day. PMID- 25275765 TI - Impact of the 2012 London Olympic and Paralympic Games on physical activity of rheumatology patients. AB - BACKGROUND: Lack of physical activity in the general population is one of the biggest health challenges we face. For rheumatology patients, and other patients with chronic disease, exercise is an essential part of disease management. However, very few patients exercise effectively.One of the aspirations of the London 2012 Olympic/Paralympic Games was to catalyze people into long-term physical activity. METHODS: We surveyed our rheumatology patients at 3 high profile times in the year after the Olympics. RESULTS: Two hundred fifty-three patients were enrolled within the study; the largest diagnosis subgroup being rheumatoid arthritis (36%). Ninety-five percent of our patients regard exercise as beneficial; 36% still think it does harm. Most common barriers to exercise were pain (53%), tiredness (44%), and lack of time (36%). Forty-five percent exercise daily, mostly just walking. Twnety-seven patients (16%) were motivated by the 2012 Olympic and Paralympic Games toward physical activity. They were mostly motivated by athletics' individual stories (67%), taking part in a big sports festival (11%) and demonstration of top sporting levels (4%). Eighteen patients in total (7%) increased their amount of exercise in response to the London 2012 Olympic and Paralympic Games. There was no difference between patient diagnostic groups. CONCLUSIONS: Only a small minority of patients increased their amount of exercise in response to the 2012 Olympic and Paralympic Games. The message about the importance of physical exercise to health needs to be clear, unambiguous, and consistent, because a significant number of patients still think that physical activity does harm. Big sporting events such as the London 2012 Olympic and Paralympic Games can be used as an opportunity to remind patients that physical activity does good and is not harmful. Athletes' individual stories could be used in future as part of a strategy to encourage exercise for all patients. PMID- 25275766 TI - Anti-RNA polymerase III antibodies in the diagnosis of scleroderma renal crisis in the absence of skin disease. AB - Scleroderma renal crisis (SRC) occurs in approximately 10% of patients with systemic sclerosis (SSc), particularly in those with diffuse skin disease. Scleroderma renal crisis has rarely been described to occur in patients with SSc without skin involvement. Scleroderma renal crisis without skin disease represents a major diagnostic challenge, particularly in patients without overt SSc involvement of other organ systems. It closely mimics the presentation of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, and treatment is therefore often directed at this entity. Anti-RNA polymerase III antibody testing has been previously reported to be used in 4 patients to diagnose SRC in the absence of sclerotic skin disease.We report 2 patients without skin disease or overt visceral involvement at presentation who presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Both patients eventually developed diffuse and rapidly progressive skin thickening. Anti-RNA polymerase III antibodies were strongly positive, supporting that their renal presentations were secondary to SRC. PMID- 25275767 TI - Pediatric neuropathic arthropathy initially masquerading as inflammatory arthritis. AB - We describe a case of neuropathic arthropathy in the knees of a child eventually diagnosed with a hereditary sensory and autonomic neuropathy. The child was initially treated for rheumatologic disease at an outside institution. History and neurological workup revealed a neuropathy most consistent with hereditary sensory and autonomic neuropathy type II. Hereditary sensory and autonomic neuropathy should be considered in the differential diagnosis of children with joint abnormalities whose workup for an inflammatory arthropathy is negative and who exhibit diminished pain sensation on examination. PMID- 25275769 TI - Takayasu arteritis presenting as new-onset hypertension. PMID- 25275768 TI - Familial aggregation of a Chinese female premenopausal gout: monogenic, polygenic, or clinical coincidence? PMID- 25275771 TI - Fibromyalgia-like illness in 2 girls after human papillomavirus vaccination. PMID- 25275772 TI - Can febuxostat reduce triglyceride and cholesterol serum levels in gouty patients? PMID- 25275773 TI - Central nervous system involvement in relapsing polychondritis. PMID- 25275774 TI - A beneficial long-term and consistent response to rituximab in the treatment of refractory neutropenia and arthritis in a patient with Felty syndrome. PMID- 25275775 TI - Thalidomide-induced orofacial neuropathy. PMID- 25275776 TI - Antisynthetase syndrome with subcutaneous emphysema and pneumomediastinum. PMID- 25275777 TI - Human sulfotransferase 1A1-dependent mutagenicity of 12-hydroxy-nevirapine: the missing link? AB - Nevirapine (NVP) is a frequently used anti-HIV drug. Despite its efficacy, NVP has been associated with serious skin and liver injuries in exposed patients and with increased incidences of hepatoneoplasias in rodents. Current evidence supports the involvement of reactive metabolites in the skin and liver toxicities of NVP, formed by cytochrome P450-mediated oxidations and/or subsequent phase II sulfonation. However, to date, standard in vitro genotoxicity tests have provided no evidence that NVP is either mutagenic or clastogenic. The human sulfotransferase 1A1-dependent mutagenicity of 12-hydroxy-NVP, one of the major metabolites of NVP, is demonstrated here. PMID- 25275779 TI - The 2013 Doris Schwartz Gerontological Nursing Research Award: Eileen M. Sullivan Marx, PhD, CRNP, RN, FAAN. PMID- 25275778 TI - Live fibroblast harvest reveals surface marker shift in vitro. AB - Current methods for the isolation of fibroblasts require extended ex vivo manipulation in cell culture. As a consequence, prior studies investigating fibroblast biology may fail to adequately represent cellular phenotypes in vivo. To overcome this problem, we describe a detailed protocol for the isolation of fibroblasts from the dorsal dermis of adult mice that bypasses the need for cell culture, thereby preserving the physiological, transcriptional, and proteomic profiles of each cell. Using the described protocol we characterized the transcriptional programs and the surface expression of 176 CD markers in cultured versus uncultured fibroblasts. The differential expression patterns we observed highlight the importance of a live harvest for investigations of fibroblast biology. PMID- 25275780 TI - Evaluating the impact of palliative or hospice care provided in nursing homes. AB - Palliative and hospice care are increasingly being provided in nursing home settings. The current article reviews the existing evidence relevant to nursing homes to provide practitioners with a greater understanding of the impact of palliative and hospice care on clinical care outcomes (e.g., pain, symptom management), processes of care outcomes (e.g., hospitalizations, cost of care), and family member or health care proxy perceptions of care. Overall, the provision of hospice or palliative care in nursing facilities can improve the clinical care residents receive, reduce hospitalizations, and improve family members' perception of care. PMID- 25275781 TI - Testing telehealth using technology-enhanced nurse monitoring. AB - Technology-enhanced nurse monitoring is a telehealth solution that helps nurses with assessment, diagnosis, and triage of older adults living in community-based settings. This technology links biometric and nonbiometric sensors to a data management system that is monitored remotely by RNs and unlicensed support staff. Nurses faced a number of challenges related to data interpretation, including making clinical inferences from nonbiometric data, integrating data generated by three different telehealth applications into a clinically meaningful cognitive framework, and figuring out how best to use nursing judgment to make valid inferences from online reporting systems. Nurses developed expertise over the course of the current study. The sponsoring organization achieved a high degree of organizational knowledge about how to use these systems more effectively. Nurses saw tremendous value in the telehealth applications. The challenges, learning curve, and organizational improvements are described. PMID- 25275782 TI - Hydrate for health: listening to older adults' need for information. AB - An interdisciplinary team of faculty and students developed the Hydrate for Health project to provide relevant and evidence-based information to community dwelling older adults. Evidence-based factsheets on bladder health, nighttime urination, medication safety, and physical activity/exercise, as well as a fluid intake self-monitoring tool, were developed. Four focus groups were conducted and included older adults (N = 21) who participated in activities at two local senior centers to obtain their feedback about the relevance of the factsheets. Extensive revisions were required based on the feedback received. Older adults expressed a desire for pragmatic information (i.e., how to determine fluid sources from food, how to measure water, how to determine their own fluid needs). They also wanted information that could be easily incorporated into daily life. Nurses play a central role in listening to and incorporating older adults' voices into consumer education materials. PMID- 25275783 TI - Remaining in the nursing home versus transfer to acute care: resident, family, and staff preferences. AB - Resident and family insistence on transfer is a major factor in the occurrence of potentially avoidable transfers from nursing homes (NHs) to acute care. The purpose of this study was to explore resident, family, and staff preferences regarding transfer to acute care. A sample of 271 NH residents, family members, staff, and medical providers were interviewed. Seventy-seven percent of residents reported that they had not given any thought to the question of whether they would want to be transferred to acute care. Family members wanted more information than residents, but more residents (39%) thought they should be fully involved in the transfer decision than their family members (12%) or staff (12%). Staff preferred keeping residents in the NH. Families were divided between transferring residents and having them remain in the NH. More residents indicated that their desire to transfer would depend on the severity of their condition and their prognosis. Ethnic group differences were noted. Results suggest that discussion of this issue should occur soon after admission and that differences in perspectives may be expected from those involved. PMID- 25275784 TI - Merging person-centered care with translational research to improve the lives of older adults: creating community-based nursing research networks. AB - Translational research is a leading trend in science with the aim of bridging the research-practice gap to significantly speed the implementation of effective interventions in clinical practice. Integrating the values and preferences of older adults and their families into this process is critical to the success of translational research. Engaging communities in meaningful research is an important part of advancing translational science in which older adults are partners in developing solutions to the health needs of individuals within communities. The current article describes one approach to developing an infrastructure (i.e., community-based nursing research network) to support patient-centered care within translational research. Nurses are uniquely poised and prepared to assume leadership roles in community-based research networks to support a true collaboration among stakeholders that prizes the voices of older adults and integrates them into practice efforts. PMID- 25275786 TI - Bilateral lacrimal mucoceles in a setting of congenital arhinia. PMID- 25275785 TI - Kinetic size-exclusion chromatography with mass spectrometry detection: an approach for solution-based label-free kinetic analysis of protein-small molecule interactions. AB - Studying the kinetics of reversible protein-small molecule binding is a major challenge. The available approaches require that either the small molecule or the protein be modified by labeling or immobilization on a surface. Not only can such modifications be difficult to do but also they can drastically affect the kinetic parameters of the interaction. To solve this problem, we present kinetic size exclusion chromatography with mass spectrometry detection (KSEC-MS), a solution based label-free approach. KSEC-MS utilizes the ability of size-exclusion chromatography (SEC) to separate any small molecule from any protein-small molecule complex without immobilization and the ability of mass spectrometry (MS) to detect a small molecule without a label. The rate constants of complex formation and dissociation are deconvoluted from the temporal pattern of small molecule elution measured with MS at the exit from the SEC column. This work describes the concept of KSEC-MS and proves it in principle by measuring the rate constants of interaction between carbonic anhydrase and acetazolamide. PMID- 25275787 TI - Traumatic globe rupture and herniation into the maxillary sinus. PMID- 25275788 TI - Orbital emphysema complicating jones tube placement in a patient treated with continuous positive airway pressure. PMID- 25275789 TI - Removable cranial windows for long-term imaging in awake mice. AB - Cranial window implants in head-fixed rodents are becoming a preparation of choice for stable optical access to large areas of the cortex over extended periods of time. Here we provide a highly detailed and reliable surgical protocol for a cranial window implantation procedure for chronic wide-field and cellular imaging in awake, head-fixed mice, which enables subsequent window removal and replacement in the weeks and months after the initial craniotomy. This protocol has facilitated awake, chronic imaging in adolescent and adult mice over several months from a large number of cortical brain regions; targeted virus and tracer injections from data obtained using prior awake functional mapping; and functionally targeted two-photon imaging across all cortical layers in awake mice using a microprism attachment to the cranial window. Collectively, these procedures extend the reach of chronic imaging of cortical function and dysfunction in behaving animals. PMID- 25275791 TI - [Case control trial on putative factors antagonising the successful project course of MD thesis projects]. AB - INTRODUCTION: Award of the degree MD has special relevance in Germany since the underlying research project can be started during the qualification for admission to doctoral training. This leads to a large number of thesis projects with a not always sufficiently pronounced enthusiasm and thus poor chances of success. Accordingly a case control study was undertaken in the Department of Human Medicine, Witten/Herdecke University to investigate reported drop-outs of thesis projects. MATERIAL AND METHOD: In autumn 2012 all students in the clinical phases of human medicine education were surveyed using a self-conceived questionnaire on previously initiated or terminated thesis projects, "terminated" is defined as the unsuccessful ending of a project after working for at least 3 months. Individually reported thesis terminations were evaluated using defined items in a 4-stage Likert scale regarding thesis plan and project, subsequently, graduate students who successfully completed a project received the same questionnaire. The items possibly corresponding to process determinants were averaged to a total of 7 dimensions prior to the analysis; the resulting scores were normalised in value ranges 0.0 to 1.0 (1.0 = optimal project situation) whereby individual items could be included in several scores. By means of 5 items a primary endpoint from the faculty's perspective on "compliance with formal procedures" was aggregated; by means of a two-sided Wilcoxon test at the 5 % level students with unsuccessful and successful courses were compared along the corresponding scores. RESULTS: 181 of 276 students from 7 study semesters participated in the screening; details of 17 terminations and 23 currently successful courses could be evaluated in the case control study. For significant differences (p < 0.001) between unsuccessful and successful courses in the primary endpoint, median scores of 0.17 (0.07-0.50) versus 0.73 (0.53-0.83) were estimated. CONCLUSION: There were differences between unsuccessful and (as yet) successful courses, especially with regard to the aspects "compliance with formal procedures". Thus a recommendation can be derived in the sense of a stricter and, if necessary, sanctioning demand for formal procedures such as early reporting of thesis projects to the responsible committees. A weakness is the low number of evaluable self-reported drop-outs as well as the overall moderate response rate. PMID- 25275792 TI - [Lid reconstruction for large lower eyelid defects (extending into canthus) with Hughes flap and skin graft - possibilities and limitations]. AB - PURPOSE: The aim of lid reconstruction is restoration of function, comfort and cosmesis. Large defects of the lower eyelid especially with extension into the canthus are a surgical challenge. A Hughes flap combined with a skin graft is a good option not only for central defects of the lower eyelid. METHODS: This article presents the surgical outcome in a series of 45 patients with large full thickness lower eyelid defects partially extended into the canthus after tumour excision. These patients underwent reconstructive eyelid surgery using a Hughes flap, autogenous skin graft, partially combined with other surgical techniques. RESULTS after division, possibilities and limitations are shown in this article. The analysis was based on photo documentation, surgery reports and patient statements. In all cases surgery was performed by the same surgeon. RESULTS: 45 patients were identified during a 3-year interval. The average age at the time of eyelid reconstruction was 70.6 years (range 38-94 years). Lid defects extending into the canthus were observed in 20 patients (9 inner/11 outer canthal region). The average size of lid defect was 17 mm and ranged from 9 to 28 mm horizontally. 26 patients showed defects >= 15 mm; 16 of them were identified with an extension into the canthus (8 inner/8 outer). Flap complications occurred in 14 patients after flap division; 8 with primary canthal involvement. After Hughes procedure, flap division and correction of complications (epilation, debulking, resuturing) 44 patients showed a very good lower lid position with good functional and cosmetic results. Due to incomplete lid closure 1 patient developed severe complications of corneal surface. Follow-up time ranged from 5 to 10 months (on average 6 months). In 6 patients the Hughes procedure was combined with other reconstructive techniques. CONCLUSIONS: In cases of large lower lid defects (even with extension into the canthus) the Hughes flap combined with skin graft and other reconstructive procedures leads to a well tightened lid position, shows a high grade of patient satisfaction although the complete blepharorrhaphy is necessary for 6 weeks and complications occur. For one-eyed patients a one step surgical procedure should be preferred. PMID- 25275793 TI - [Conservative treatment of dry eye]. AB - The use of topic anti-inflammatory drugs has become very important in the treatment of dry eye disease. Besides the basic therapy including tear replacement, use of serum eye drops and mucolytic eye drops, the topical application of corticosteroids and cyclosporin A is more commonly used in moderate to severe forms of dry eye disease. The consistent treatment of Meibomian gland dysfunction as a frequent reason for evaporative dry eye is also of particular importance. Understanding the chronicity of the disease and long term compliance are the essential for successful therapy of this widespread disease. PMID- 25275790 TI - Affinity purification-mass spectrometry and network analysis to understand protein-protein interactions. AB - By determining protein-protein interactions in normal, diseased and infected cells, we can improve our understanding of cellular systems and their reaction to various perturbations. In this protocol, we discuss how to use data obtained in affinity purification-mass spectrometry (AP-MS) experiments to generate meaningful interaction networks and effective figures. We begin with an overview of common epitope tagging, expression and AP practices, followed by liquid chromatography-MS (LC-MS) data collection. We then provide a detailed procedure covering a pipeline approach to (i) pre-processing the data by filtering against contaminant lists such as the Contaminant Repository for Affinity Purification (CRAPome) and normalization using the spectral index (SIN) or normalized spectral abundance factor (NSAF); (ii) scoring via methods such as MiST, SAInt and CompPASS; and (iii) testing the resulting scores. Data formats familiar to MS practitioners are then transformed to those most useful for network-based analyses. The protocol also explores methods available in Cytoscape to visualize and analyze these types of interaction data. The scoring pipeline can take anywhere from 1 d to 1 week, depending on one's familiarity with the tools and data peculiarities. Similarly, the network analysis and visualization protocol in Cytoscape takes 2-4 h to complete with the provided sample data, but we recommend taking days or even weeks to explore one's data and find the right questions. PMID- 25275794 TI - Septum primum malposition defect and inferior sinus venosus defect: a rare association. AB - We present a case of a 2-year-old girl who presented with respiratory distress and umbilical abscess, and was found to have an inferior sinus venosus defect, malposition of the atrial septum primum, absent septum secundum, and anomalous drainage of the right upper and lower pulmonary veins to the right atrium. PMID- 25275795 TI - Interaction between metal cation and unnatural peptide backbone mediated by polarized water molecules: study of infrared spectroscopy and computations. AB - In this work, the interaction between metal cation and a model beta-peptide N ethylpropionamide (NEPA) in aqueous solution is investigated using infrared absorption spectroscopy. Monovalent (Na(+)), divalent (Ca(2+), Mg(2+)), and trivalent (Al(3+)) metal cations added to NEPA/water solution at moderate concentrations split the amide-I frequency into a red- and blue-shifted component. Molecular dynamics simulations of NEPA in moderate cationic strength are conducted to gain insight into the structural details of the peptide-salt water system, particularly in the vicinity of the amide group. Our results do not suggest a direct contact between cation and amide oxygen in the solution phase; otherwise, only a significant red shift in the amide-I frequency would occur due to the vibrational Stark effect, as evidenced by quantum chemistry computations. Instead, our results suggest it is the dynamical interaction between the formed cation/water/anion complexes and the amide group that causes the observed split in the amide-I peak, which indicates the presence of both salting-in (red shifted) and salting-out (blue-shifted) NEPA species. The presence of dynamic and polarized water molecules between the amide oxygen and the cation complex is believed to be the key to the split amide-I peaks in the cation-rich environment. Our results can be useful to better understand the cationic Hofmeister series. PMID- 25275796 TI - Outcomes after early splenectomy for hematological disorders. AB - PURPOSE: Acute splenic sequestration crisis is a devastating complication of sickle cell disease that can require prophylactic splenectomy. Historically, splenectomy before 5 years of age was avoided because of fear of overwhelming postsplenectomy sepsis. Recently, splenectomy has been performed as early as 2 years of age, but the safety of this approach is unknown. This study compared outcomes of splenectomy performed in patients under 5 years of age with those 5 years of age and older. MATERIALS AND METHODS: A retrospective chart review of patients registered in a children's hospital hematology database was performed to examine intraoperative and postoperative outcomes after splenectomy. Statistical data analysis included Fisher's exact tests for categorical variables and the nonparametric median test for continuous variables. RESULTS: From 1997 to 2012, 30 sickle cell patients underwent splenectomy. At surgery, 18 of the 30 patients were under 5 years of age (Group 1), and 12 patients were 5 years of age or older (Group 2). Almost all procedures were laparoscopic. Both group had similar operative times, rates of conversion, and frequencies of complications. Both groups had similar lengths of follow-up (median, 62 months for Group 1 versus 63 months for Group 2). No portal vein thromboses or postsplenectomy sepsis events occurred in either group. CONCLUSIONS: In this study, there was no evidence that the incidence of complications was higher after splenectomy at a younger age. A large, multicenter study is needed to further evaluate the safety of this practice. PMID- 25275797 TI - Identification of a novel lysyl oxidase-like 2 alternative splicing isoform, LOXL2 Deltae13, in esophageal squamous cell carcinoma. AB - Lysyl oxidase-like 2 (LOXL2) participates in every stage of cancer progression and promotes invasion and metastasis. In this study, we identified a novel alternative splicing isoform of LOXL2, namely LOXL2 Deltae13, which lacked exon 13. Deletion of exon 13 caused an open reading frame shift and produced a truncated protein. LOXL2 Deltae13 was expressed ubiquitously in cell lines and tissues and was mainly localized to the cytoplasm. Although it showed impaired deamination enzymatic activity compared with full-length LOXL2, LOXL2 Deltae13 promoted the cell mobility and invasion of esophageal squamous cell carcinoma (ESCC) cells to greater degrees. In further research on the mechanisms, gene expression profiling and signaling pathway analysis revealed that LOXL2 Deltae13 induced the expression of MAPK8 without affecting the FAK, AKT, and ERK signaling pathways. RNAi-mediated knockdown of MAPK8 could block the cell migration promoted by LOXL2De13, but it had little effect on that of full-length LOXL2. Our data suggest that LOXL2 Deltae13 modulates the effects of cancer cell migration and invasion through a different mechanism from that of full-length LOXL2 and that it may play a very important role in tumor carcinogenesis and progression. PMID- 25275798 TI - Endothelial function in children with OSA and the effects of adenotonsillectomy. AB - BACKGROUND: The association between childhood OSA and endothelial function as measured by flow-mediated dilation (FMD) and its response to OSA treatment are uncertain. The objective of this study was to compare FMD in children with OSA with nonsnoring control subjects and to examine its response to treatment. METHODS: Index cases were children aged 6 to 18 years with habitual snoring and polysomnography (PSG)-confirmed OSA (obstructive apnea hypopnea index [OAHI] > 1 events/h). Each case was paired with an age-, sex-, and BMI-matched nonsnoring control subject recruited from our previous community growth survey. All subjects underwent FMD measurement in the morning after overnight PSG. Adenotonsillectomy (AT) was offered to subjects who satisfied predefined AT operation criteria. All cases underwent repeat PSG and FMD assessment 6 months later. RESULTS: A total of 63 case-control pairs were recruited. The OSA group had a significantly higher OAHI (median, 5.3 events/h [interquartile range (IQR), 2.6-11.7] vs 0.2 events/h [IQR, 0-0.5], P < .001) and lower FMD (mean +/- SD, 7.9% +/- 1.3% vs 8.3% +/- 0.8%; P = .04) than the control group. Thirty-two case subjects underwent AT. A significant reduction in OAHI was documented in the AT group (-8.8 events/h [IQR, -13.7 to -4.7]; P < .001) accompanied by a significant increase in FMD (+0.6% [IQR, 0.4-1.4]; P < .001), which was not observed in subjects who did not undergo AT. CONCLUSIONS: Children with OSA had reduced FMD, which was reversible with treatment. PMID- 25275799 TI - Radical based strategy toward the synthesis of 2,3-dihydrofurans from aryl ketones and aromatic olefins. AB - A copper-mediated annulation of aryl ketones with a wide range of aromatic olefins has been developed. This strategy allowed convenient access to 2,3 dihydrofuran derivatives. The versatility of the protocol is shown by synthesizing alpha-methyl dihydrofurans, which serve as an intermediate for the synthesis of vitamin B1. In addition, the applicability of the protocol in conjugated systems is demonstrated. A radical pathway was presumed and supported for annulation of aryl ketones with olefins. PMID- 25275802 TI - Effect of dicarboxylic acid chain length on the self-cleaning property of Nano TiO2-coated cotton fabrics. AB - In this study, the effect of dicarboxylic acid chain length on the amount of TiO2 nanoparticles (TiO2NPs) adsorption-produced self-cleaning property and washing durability on cotton fabrics were investigated. First, cotton fabric samples were treated with three kinds of dicarboxylic acids--oxalic, succinic, and adipic acids--and then dipped in TiO2NP solution with a certain concentration. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) was used to investigate bonds formation between dicarboxylic acid groups and hydroxyl groups of cellulose, and a scanning electron microscope (SEM) was applied for the analysis of surface morphology in specimens. Drop absorbency time was determined for samples using the AATCC TM 79:2000. Washing stability and the amount absorption of TiO2NPs were determined by weighing and absorption spectrophotometry procedures, and the stain removal evaluation was conducted to assess the self-cleaning property. Results showed that all of the dicarboxylic acids used in this experiment improved the amount of TiO2NPs absorbed onto cotton samples and their durability to washing. In addition, color variation of samples treated with oxalic acid after 180 min of UV irradiation and drop absorbency time for samples treated with succinic acid were significantly increased by about 126 and 600%, respectively. The best durability was obtained from adipic acid, while a better self-cleaning property was obtained from oxalic acid. PMID- 25275801 TI - Crystallographic textures and morphologies of solution cast Ibuprofen composite films at solid surfaces. AB - The preparation of thin composite layers has promising advantages in a variety of applications like transdermal, buccal, or sublingual patches. Within this model study the impact of the matrix material on the film forming properties of ibuprofen-matrix composite films is investigated. As matrix materials polystyrene, methyl cellulose, or hydroxyl-ethyl cellulose were used. The film properties were either varied by the preparation route, i.e., spin coating or drop casting, or via changes in the relative ratio of the ibuprofen and the matrix material. The resulting films were investigated via X-ray diffraction and atomic force microscope experiments. The results show that preferred (100) textures can be induced via spin coating with respect to the glass surface, while the drop casting results in a powder-like behavior. The morphologies of the films are strongly impacted by the ibuprofen amount rather than the preparation method. A comparison of the various matrix materials in terms of their impact on the dissolution properties show a two times faster zero order release from methyl cellulose matrix compared to a polystyrene matrix. The slowest rate was observed within the hydroxyl ethyl cellulose as the active pharmaceutical ingredients (APIs) release is limited by diffusion through a swollen matrix. The investigation reveals that the ibuprofen crystallization and film formation is only little effected by the selected matrix material than that compared to the dissolution. A similar experimental approach using other matrix materials may therefore allow to find an optimized composite layer useful for a defined application. PMID- 25275804 TI - In situ study of reaction kinetics using compressed sensing NMR. AB - We demonstrate the application of Compressed Sensing-NMR to decrease the data acquisition time of 2D COSY NMR from >5 h to ~1.5 h such that the kinetics of a reaction are followed, along with identification of intermediate and product species. PMID- 25275805 TI - Institution-to-institution mentoring to build capacity in 24 local US health departments: best practices and lessons learned. AB - INTRODUCTION: Institutional mentoring may be a useful capacity-building model to support local health departments facing public health challenges. The New York City Department of Health and Mental Hygiene conducted a qualitative evaluation of an institutional mentoring program designed to increase capacity of health departments seeking to address chronic disease prevention. The mentoring program included 2 program models, a one-to-one model and a collaborative model, developed and implemented for 24 Communities Putting Prevention to Work grantee communities nationwide. METHODS: We conducted semi-structured telephone interviews to assess grantees' perspectives on the effectiveness of the mentoring program in supporting their work. Two interviews were conducted with key informants from each participating community. Three evaluators coded and analyzed data using ATLAS.ti software and using grounded theory to identify emerging themes. RESULTS: We completed 90 interviews with 44 mentees. We identified 7 key program strengths: learning from the New York City health department's experience, adapting resources to local needs, incorporating new approaches and sharing strategies, developing the mentor-mentee relationship, creating momentum for action, establishing regular communication, and encouraging peer interaction. CONCLUSION: Participants overwhelmingly indicated that the mentoring program's key strengths improved their capacity to address chronic disease prevention in their communities. We recommend dissemination of the results achieved, emphasizing the need to adapt the institutional mentoring model to local needs to achieve successful outcomes. We also recommend future research to consider whether a hybrid programmatic model that includes regular one-on-one communication and in-person conferences could be used as a standard framework for institutional mentoring. PMID- 25275806 TI - Burden of disease, injuries, and risk factors in the Kingdom of Saudi Arabia, 1990-2010. AB - INTRODUCTION: We report the burden of disease and risk factors measured by causes of death, years of life lost attributable to premature mortality (YLLs), years of life lived with disability (YLDs), and disability-adjusted life years (DALYs) for 1990, 2005, and 2010 in the Kingdom of Saudi Arabia (KSA). METHODS: We used the Global Burden of Diseases 2010 (GBD 2010) methodology to estimate the country level burden of disease in KSA. We used data from systematic reviews of the literature, household survey data, antenatal clinic surveillance data, reportable disease notifications, disease registries, hospital admissions data, outpatient visit data, population-based cancer registries, active screening data, and other administrative data. RESULTS: Noncommunicable diseases and road traffic injuries became the leading cause of death and disability in KSA in 2010. Elevated body mass index was the leading risk factor for disease (7.02% for males and 4.61% for females in 2010). High glucose levels were the second leading disease risk factor for females (3.28%) and third for males (6.25%) in 2010. Preterm birth complications were the main cause for DALYs in 1990; however, in 2010, the leading cause of DALYs for males was road traffic injuries (12.40%) and for females it was major depressive disorder (7.88%). CONCLUSION: KSA is facing a rising burden of noncommunicable diseases and road traffic injuries as a result of rapid changes in behaviors. Our results demonstrate the need for major intervention to reduce these burdens and to engage other sectors of the government and the community in these efforts. PMID- 25275807 TI - Promotion and provision of colorectal cancer screening: a comparison of colorectal cancer control program grantees and nongrantees, 2011-2012. AB - INTRODUCTION: Since 2009, the Centers for Disease Control and Prevention (CDC) has awarded nearly $95 million to 29 states and tribes through the Colorectal Cancer Control Program (CRCCP) to fund 2 program components: 1) providing colorectal cancer (CRC) screening to uninsured and underinsured low-income adults and 2) promoting population-wide CRC screening through evidence-based interventions identified in the Guide to Community Preventive Services (Community Guide). CRCCP is a new model for disseminating and promoting use of evidence based interventions. If the program proves successful, CDC may adopt the model for future cancer control programs. The objective of our study was to compare the colorectal cancer screening practices of recipients of CRCCP funding (grantees) with those of nonrecipients (nongrantees). METHODS: We conducted parallel Web based surveys in 2012 with CRCCP grantees (N = 29) and nongrantees (N = 24) to assess promotion and provision of CRC screening, including the use of evidence based interventions. RESULTS: CRCCP grantees were significantly more likely than nongrantees to use Community Guide-recommended evidence-based interventions (mean, 3.14 interventions vs 1.25 interventions, P < .001) and to use patient navigation services (eg, transportion or language translation services) (72% vs 17%, P < .001) for promoting CRC screening. Both groups were equally likely to use other strategies. CRCCP grantees were significantly more likely to provide CRC screening than were nongrantees (100% versus 50%, P < .001). CONCLUSION: Results suggest that CRCCP funding and support increases use of evidence-based interventions to promote CRC screening, indicating the program's potential to increase population-wide CRC screening rates. PMID- 25275808 TI - National and state cost savings associated with prohibiting smoking in subsidized and public housing in the United States. AB - INTRODUCTION: Despite progress in implementing smoke-free laws in indoor public places and workplaces, millions of Americans remain exposed to secondhand smoke at home. The nation's 80 million multiunit housing residents, including the nearly 7 million who live in subsidized or public housing, are especially susceptible to secondhand smoke infiltration between units. METHODS: We calculated national and state costs that could have been averted in 2012 if smoking were prohibited in all US subsidized housing, including public housing: 1) secondhand smoke-related direct health care, 2) renovation of smoking permitted units; and 3) smoking-attributable fires. Annual cost savings were calculated by using residency estimates from the Department of Housing and Urban Development and cost data reported elsewhere. Data were adjusted for inflation and variations in state costs. National and state estimates (excluding Alaska and the District of Columbia) were calculated by cost type. RESULTS: Prohibiting smoking in subsidized housing would yield annual cost savings of $496.82 million (range, $258.96-$843.50 million), including $310.48 million ($154.14-$552.34 million) in secondhand smoke-related health care, $133.77 million ($75.24-$209.01 million) in renovation expenses, and $52.57 million ($29.57-$82.15 million) in smoking-attributable fire losses. By state, cost savings ranged from $0.58 million ($0.31-$0.94 million) in Wyoming to $124.68 million ($63.45-$216.71 million) in New York. Prohibiting smoking in public housing alone would yield cost savings of $152.91 million ($79.81-$259.28 million); by state, total cost savings ranged from $0.13 million ($0.07-$0.22 million) in Wyoming to $57.77 million ($29.41-$100.36 million) in New York. CONCLUSION: Prohibiting smoking in all US subsidized housing, including public housing, would protect health and could generate substantial societal cost savings. PMID- 25275809 TI - Structure and magnetic properties of the spin-1/2-based honeycomb NaNi2BiO(6 delta) and its hydrate NaNi2BiO(6-delta).1.7H2O. AB - We present the structure and magnetic properties of the honeycomb anhydrate NaNi2BiO6-delta and its monolayer hydrate NaNi2BiO6-delta.1.7H2O, synthesized by deintercalation of the layered alpha-NaFeO2-type honeycomb compound Na3Ni2BiO6. The anhydrate adopts ABAB-type oxygen packing and a one-layer hexagonal unit cell, whereas the hydrate adopts an oxygen packing sequence based on a three layer rhombohedral subcell. The metal-oxide layer separations are 5.7 A in the anhydrate and 7.1 A in the hydrate, making the hydrate a quasi 2-D honeycomb system. The compounds were characterized through single crystal diffraction, powder X-ray diffraction, thermogravimetric analysis, and elemental analysis. Temperature-dependent magnetic susceptibility measurements show both to have negative Weiss temperatures (-18.5 and -14.6 K, respectively) and similar magnetic moments (2.21 and 2.26 MUB/Ni, respectively), though the field-dependent magnetization and heat capacity data suggest subtle differences in their magnetic behavior. The magnetic moments per Ni are relatively high, which we suggest is due to the presence of a mixture of Ni(2+) and Ni(3+) caused by oxygen vacancies. PMID- 25275811 TI - Management of Hepatitis B virus infection during pregnancy. AB - Hepatitis B virus (HBV) infects over 2 billion people worldwide, with approximately 360 million chronically infected. It results in substantial morbidity and mortality, with an estimated 600,000 deaths per year. In endemic areas, mother to child transmission (MTCT) is the most important source of new infections, but even in areas with low endemicity, over 1/3 of infections can still be attributed to this route. Although very effective active-passive immunoprophylaxis with hepatitis B immune globulin (HBIG) and HBV vaccine is available, even with full compliance, failure can be seen in highly viremic mothers who are positive for hepatitis B e antigen. Potential means of reducing the risk of MTCT include nucleotide/nucleoside antiviral agents, interferon in very select cases, and mode of delivery. Determining the optimal therapy and its timing, and preventing both obstetric and liver related complications remains a challenge, but is also an important opportunity to reduce chronic hepatitis B infection. In this review, we provide an overview of issues associated with hepatitis B and its treatment during pregnancy, and suggest an algorithm for management. PMID- 25275812 TI - Cancer biomarkers: the role of structured data reporting. AB - CONTEXT: The College of American Pathologists has been producing cancer protocols since 1986 to aid pathologists in the diagnosis and reporting of cancer cases. Many pathologists use the included cancer case summaries as templates for dictation/data entry into the final pathology report. These summaries are now available in a computer-readable format with structured data elements for interoperability, packaged as "electronic cancer checklists." Most major vendors of anatomic pathology reporting software support this model. OBJECTIVES: To outline the development and advantages of structured electronic cancer reporting using the electronic cancer checklist model, and to describe its extension to cancer biomarkers and other aspects of cancer reporting. DATA SOURCES: Peer reviewed literature and internal records of the College of American Pathologists. CONCLUSIONS: Accurate and usable cancer biomarker data reporting will increasingly depend on initial capture of this information as structured data. This process will support the standardization of data elements and biomarker terminology, enabling the meaningful use of these datasets by pathologists, clinicians, tumor registries, and patients. PMID- 25275814 TI - Methodological lessons. PMID- 25275813 TI - Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens From Patients With Adenocarcinoma of the Stomach or Esophagogastric Junction. PMID- 25275815 TI - Endowrist versus wrist: a case-controlled study comparing robotic versus hand assisted laparoscopic surgery for rectal cancer. AB - BACKGROUND: Laparoscopic total mesorectal excision (TME) remains a technically challenging procedure. This study aims to compare the surgical outcomes of the robotic-assisted laparoscopic (RAL) versus hand-assisted laparoscopic (HAL) techniques in performing TME for patients with rectal cancers. METHODS: A retrospective review of all patients who underwent RAL TME for rectal cancers was performed. These cases were matched for age, sex, and stage of malignancy with patients who underwent HAL TME. Data collected included age, sex, American Society of Anesthesiologists scores, comorbid conditions, types of surgical resections and operative times, perioperative complications, length of hospital stays, and histopathologic outcomes were analyzed. RESULTS: From August 2008 to August 2011, 19 patients, with a median age of 62 (range, 47 to 92) years underwent RAL TME. Eight (42.1%) patients received neoadjuvant chemoradiotherapy. The median docking and operative times were 10 (range, 3 to 34) and 390 (range, 289 to 771) minutes, respectively. There was 1 (5.3%) conversion to open surgery. The grade of mesorectal excision was histopathologically reported as complete in all 19 cases. Positive circumferential margin was reported in 1 (5.3%) patient.Comparing the 2 groups, more patients in the RAL group received neoadjuvant chemoradiotherapy (8 vs. 3; P=0.048). The operative times were longer in the RAL group (390 vs. 225 min; P<0.001). A higher proportion of patients in the HAL group required conversion to open surgery (5 vs. 1; P=0.180) and developed perioperative morbidities (3 vs. 7; P=0.269). The median length of hospitalization was comparable between both groups (RAL: 7 vs. HAL: 6 d; P=0.476).The procedural cost was significantly higher in the RAL group (US$12,460 vs. US$8560; P<0.001), whereas the nonprocedural cost remained comparable between the 2 groups (RAL: US$4470 vs. HAL: US$4500; P=0.729). CONCLUSIONS: RAL TME is associated with lower conversion and morbidity rates compared with HAL TME. The longer operating times and higher procedural costs are current limitations to its widespread adoption. PMID- 25275816 TI - Insurance status and outcomes in laparoscopic adjustable gastric banding. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a proven method for achieving long-term weight loss, but there has been controversy regarding how pay status impacts outcomes after surgery. OBJECTIVES: To compare outcomes of LAGB with respect to percentage excess weight loss (%EWL), perioperative complications, and number of band adjustments between insured and self-financed patients. METHODS: Retrospective analysis of data (n=108) including demographics, comorbidities, operative complications, and %EWL for 5 years postsurgery. RESULTS: There were no demographic differences between the Insured Group and the Self-financed Group, except mean preoperative BMI (P=0.049). There were no complications reported and no differences in %EWL between the groups. CONCLUSIONS: This is the first study assessing outcomes and complication rates with respect to pay status in an outpatient surgery center bariatric patient population. These results demonstrate that self-financed patients did not achieve greater weight loss compared with privately insured patients undergoing LAGB. PMID- 25275817 TI - Laparoscopic tension-free abdominal wall repair: impact of mesh size and of different fixation devices in a consecutive series of 120 patients. AB - PURPOSE: To assess the impact of mesh size and fixation devices on short-term outcomes in a consecutive series of tension-free laparoscopic abdominal wall repairs. METHODS: Data for 120 consecutive, unselected patients undergoing tension-free laparoscopic incisional (n=63) or umbilical (n=57) hernia repair were prospectively collected. A multivariate analysis was performed to evaluate variables influencing outcomes. RESULTS: Persistent seromas were observed in 13 patients (10.83%) and 2 recurrences (1.98%) occurred. Mesh size >300 cm was associated with increased hospital stay [odds ratio (OR) 4.83; 95% confidence interval (CI), 1.5-15.53; P=0.008], increased postoperative day 1 (POD1) pain assessed with visual analog scale (OR 5.51; 95% CI, 1.76-17.2; P=0.003), and the presence of complications (OR 10.4; 95% CI, 1.85-58.96; P=0.007). Body mass index >30 resulted in increased hospital stay (OR 3.05; 95% CI, 1.23-7.57; P=0.01) and increased POD1 visual analog scale (OR 2.28; 95% CI, 1-5.18; P=0.04). CONCLUSIONS: Mesh size and obesity were the main factors influencing postoperative outcomes. PMID- 25275818 TI - Dynamics simulations and statistical modeling of thermal decomposition of 1-ethyl 3-methylimidazolium dicyanamide and 1-ethyl-2,3-dimethylimidazolium dicyanamide. AB - Quasi-classical, direct dynamics trajectories were calculated at the B3LYP/6-31G* level of theory, in an attempt to understand decomposition mechanisms of 1-ethyl 3-methylimidazolium dicyanamide (EMIM(+)DCA(-)) and 1-ethyl-2,3 dimethylimidazolium dicyanamide (EMMIM(+)DCA(-)). The trajectories showed many dissociation paths for these two ionic liquids. Using trajectory results as a guide, structures of transition states and products that might be important for decomposition of these two compounds were determined using density functional theory calculations. Rice-Ramsperger-Kassel-Marcus (RRKM) theory was then utilized to examine properties of energized ionic liquids and to determine unimolecular rates for crossing various transition states. On the basis of RRKM modeling, initial decomposition paths for energized EMIM(+)DCA(-) correspond to formation of an N-heterocyclic carbene and acid pair via transfer of the C2 proton of EMIM(+) to DCA(-), and evolution of methylimidazole and ethylimidazole via SN2 alkyl abstraction by DCA(-). Similar decomposition paths were identified for energized EMMIM(+)DCA(-), except that the reactivity of C2 of the imidazolium cation is significantly reduced upon substitution of a methyl group for a hydrogen atom at this position. The present work demonstrates that dynamics simulations, in conjunction with statistical modeling, are able to provide insight into decomposition mechanisms, kinetics, and dynamics for alkylimidazolium-based ionic liquids and to predict product branching ratios and how they vary with decomposition temperatures. PMID- 25275819 TI - Substance P protects against hyperoxic-induced lung injury in neonatal rats. AB - The aim of the study was to investigate the effects of substance P (SP) in hyperoxia-induced lung injury in newborn rats. Thirty-two rat pups were randomly divided into four groups: normoxia/saline, normoxia/SP, hyperoxia/saline and hyperoxia/SP. In a separate set of experiments, the neonatal rat pups were exposed to 21% or >95% O2 for 14 days with or without intraperitoneal administration of SP. On day 14, the animals were sacrificed and the lungs were processed for histology and biochemical analysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used for the detection of apoptosis. Antioxidant capacity was assessed by glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), oxidative stress was assessed by determining the extent of formation of malondialdehyde (MDA), activities of NADPH oxidase activity, and formation of reactive oxygen species (ROS). The activity of phospho p38 (p-p38) and -ERK1/2 (p-ERK1/2) proteins and expression of NF-E2-related factor 2 (NRF2) were detected by Western blot, and the expression of p-p38 was detected by immunofluorescence analysis. Compared with the hyperoxia treatment, the lung damage was significantly ameliorated following the SP treatment. Furthermore, the lungs from the pups exposed to hyperoxia TUNEL-positive nuclei increased markedly and decreased significantly after SP treatment. The levels of MDA decreased and that of GSH-Px and SOD increased following the SP treatment. The SP treatment significantly suppressed the activity of NADPH oxidase and reduced ROS production. SP stimulation may result in blocking p38 MAPK and ERK signaling pathways, and the activities of p-p38 and p-ERK, and expression of NRF2 decreased following the SP treatment. These findings indicate that SP can ameliorate hyperoxic lung injury through decreasing cell apoptosis, elevating antioxidant activities, and attenuating oxidative stress. PMID- 25275820 TI - I2-mediated oxidative cyclization for synthesis of substituted indolizines. AB - A direct method for the synthesis of substituted indolizines by means of I2 mediated oxidative tandem cyclization via C-N/C-C bond formation was developed. Various substituted aromatic/aliphatic enolizable aldehydes and 2 pyridylacetates/acetonitrile/acetone proceeded smoothly in this transformation, and the desired products were generated in moderate to good yields. PMID- 25275821 TI - NIS-mediated oxidative cyclization of N-(2-trifluoromethyl-3-alkynyl) hydroxylamines: a facile access to 4-trifluoromethyl-5-acylisoxazoles. AB - A novel NIS-mediated oxidative cyclization of N-(2-trifluoromethyl-3 alkynyl)hydroxylamines is developed, which provides a facile access to 4 trifluoromethyl-5-acylisoxazoles in 33-91% yields. Various types of commonly used electrophilic halogen source such as ICl, I2, NIS, NBS and NCS at different temperatures in various solvents were investigated. It was found that the NIS acts as both an oxidant and an electrophile for the present sequential transformation. The scope, mechanism and application of this NIS-mediated domino reaction for further synthetic transformation were studied. PMID- 25275823 TI - Elemental fingerprinting of materials with sensitivity at the atomic limit. AB - By using synchrotron X-rays as a probe and a nanofabricated smart tip of a tunneling microscope as a detector, we have achieved chemical fingerprinting of individual nickel clusters on a Cu(111) surface at 2 nm lateral resolution, and at the ultimate single-atomic height sensitivity. Moreover, by varying the photon energy, we have succeeded to locally measure photoionization cross sections of just a single Ni nanocluster, which opens new exciting opportunities for chemical imaging of nanoscale materials. PMID- 25275822 TI - Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material. AB - Abstract Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50*10(11) pt/ml; CI, 4.26*10(11) to 6.75*10(11) pt/ml), vector genomes (mean, 5.75*10(11) vg/ml; CI, 3.05*10(11) to 1.09*10(12) vg/ml), and infectious units (mean, 1.26*10(9) IU/ml; CI, 6.46*10(8) to 2.51*10(9) IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community. PMID- 25275824 TI - Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment based approach. AB - Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of alpha-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration. PMID- 25275825 TI - Grafting influences phenolic profile and carpometric traits of fruits of greenhouse-grown eggplant (Solanum melongena L.). AB - The influence of eggplant grafting on tomato rootstock was evaluated during the two growing seasons. Yield, quality traits, and individual phenolics in fruits were assessed. Three commercial varieties and one landrace were used as scions. Grafting significantly increased eggplant yield and decreased the presence of calyx prickles. The effect of grafting on the accumulation of major phenolic constituents in eggplant fruit was inconsistent: in the year with less solar radiation and lower mean daily air temperatures, grafting decreased phenolic content in commercial variety/rootstock fruit and increased the content in landrace/rootstock fruit. An opposite effect in the latter combination was observed in the year with improved conditions for eggplant cultivation. The browning potential of fruit pulp was highly dependent on variety/landrace and partly also on grafting combination. Differences in correlations between phenolic constituents and browning potential (positive for varieties and negative for landrace) could also be ascribed to the importance of other antioxidants for diminished eggplant pulp browning. PMID- 25275826 TI - Clinical significance of platelet-associated hematological parameters as an early supplementary diagnostic tool for sepsis in thrombocytopenic very-low-birth weight infants. AB - Sepsis is an important cause of death in very-low-birth-weight (VLBW) neonates. Although conventional diagnostic indicator of sepsis has been done by blood cultures, this took much longer time. The measurement of platelet-associated parameters such as mean platelet volume (MPV) and platelet distribution width (PDW) become more reliable and accurate parameters as a non-specific marker for sepsis. Our objective is to examine the usefulness of those platelet hematological parameters as a supplementary diagnostic tool for sepsis in VLBW infants. This study is a retrospective cohort study of neonates subject to the diagnosis of sepsis from October 2006 to July 2010. This study was conducted at Korea University medical center. We studied total 2,336 infants for 32 days from birth (Day 0) to Day 31. We compared three groups of infants to examine differences of platelet parameters according to their age from birth to Day 31: (i) full-terms versus VLBW without sepsis, (ii) VLBW without sepsis versus VLBW with sepsis and (iii) thrombocytopenic VLBW without sepsis versus those with sepsis. The platelet-associated parameters were significantly distinguishable between septic and non-septic groups at their early age (~ 1 week), especially platelet counts (PLT) (p = 0.0091), MPV (p = 0.007) and PDW (p = 0.0372) in thrombocytopenic VLBW infants. The decreased PLT, elevated MPV and PDW were major characteristics of septic group. We suggested maximum cutoff values of the platelet factors by performing receiver operating characteristic curve analysis between septic and non-septic thrombocytopenic VLBW infants, among which MPV was the most promising index (AUCMPV = 0.7044 > AUCPLT = 0.6921 > AUCPDW = 0.6593). Platelet-associated hematological parameters are useful for the early diagnosis of sepsis as a more efficient and supplementary diagnostic method in thrombocytopenic VLBW infants. PMID- 25275827 TI - A novel in vitro whole plant system for analysis of polyphenolics and their antioxidant potential in cultivars of Ocimum basilicum. AB - Plants are an important source for medicinal compounds. Chemical screening and selection is critical for identification of compounds of interest. Ocimum basilicum (Basil) is a rich source of polyphenolics and exhibits high diversity, therefore bioprospecting of a suitable cultivar is a necessity. This study reports on the development of a true to type novel "in vitro system" and its comparison with a conventional system for screening and selection of cultivars for high total phenolics, individual polyphenolics, and antioxidant content. We have shown for the first time using online acidic potassium permanganate chemiluminescence that extracts from Ocimum basilicum showed antioxidant potential. The current study identified the cultivar specific composition of polyphenolics and their antioxidant properties. Further, a distinct relationship between plant morphotype and polyphenolic content was also found. Of the 15 cultivars examined, "Holy Green", "Red Rubin", and "Basil Genovese" were identified as high polyphenolic producing cultivars while "Subja" was determined to be a low producer. The "in vitro system" enabled differentiation of the cultivars in their morphology, polyphenolic content, and antioxidant activity and is a cheap and efficient method for bioprospecting studies. PMID- 25275828 TI - Two-level QSAR network (2L-QSAR) for peptide inhibitor design based on amino acid properties and sequence positions. AB - In the design of peptide inhibitors the huge possible variety of the peptide sequences is of high concern. In collaboration with the fast accumulation of the peptide experimental data and database, a statistical method is suggested for peptide inhibitor design. In the two-level peptide prediction network (2L-QSAR) one level is the physicochemical properties of amino acids and the other level is the peptide sequence position. The activity contributions of amino acids are the functions of physicochemical properties and the sequence positions. In the prediction equation two weight coefficient sets {ak} and {bl} are assigned to the physicochemical properties and to the sequence positions, respectively. After the two coefficient sets are optimized based on the experimental data of known peptide inhibitors using the iterative double least square (IDLS) procedure, the coefficients are used to evaluate the bioactivities of new designed peptide inhibitors. The two-level prediction network can be applied to the peptide inhibitor design that may aim for different target proteins, or different positions of a protein. A notable advantage of the two-level statistical algorithm is that there is no need for host protein structural information. It may also provide useful insight into the amino acid properties and the roles of sequence positions. PMID- 25275829 TI - Recurrent Proliferative Glomerulonephritis With Monoclonal IgG Deposits After a Renal Transplant Which Was Insensitive to Pulse Therapy Remitted by Double Filtration Plasmapheresis. AB - Proliferative glomerulonephritis with monoclonal IgG deposits manifesting as a nephrotic syndrome recently has been described as a renal disease with the pathological features of mesangial and subendothelial deposits of monoclonal IgG. Eight cases of recurrent proliferative glomerulonephritis with monoclonal IgG deposits after a renal transplant have been reported. Almost all of these patients had a certain remission of proteinuria by steroids alone or with cyclophosphamide, and had further remission through other special treatments (ie, rituximab and plasmapheresis). We present a case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits of the IgG3? subtype after a renal transplant, which was insensitive to pulse intravenous methyl-prednisolone and cyclophosphamide remitted by double filtration plasmapheresis. This case report reveals that recurrent proliferative glomerulo-nephritis with monoclonal IgG deposits may be insensitive to intravenous pulse therapy of methylprednisolone and cyclophosphamide. We advocate double filtration plasmapheresis as an effective treatment of proliferative glomerulo-nephritis with monoclonal IgG deposits on remission of proteinuria. PMID- 25275830 TI - Toward complete miniaturisation of flow injection analysis systems: microfluidic enhancement of chemiluminescent detection. AB - Conventional flow injection systems for aquatic environmental analysis typically comprise large laboratory benchscale equipment, which place considerable constraints for portable field use. Here, we demonstrate the use of an integrated acoustically driven microfluidic mixing scheme to enhance detection of a chemiluminescent species tris(2,2'-bipyridyl)dichlororuthenium(II) hexahydrate-a common chemiluminescent reagent widely used for the analysis of a wide range of compounds such as illicit drugs, pharmaceuticals, and pesticides-such that rapid in-line quantification can be carried out with sufficient on-chip sensitivity. Specifically, we employ surface acoustic waves (SAWs) to drive intense chaotic streaming within a 100 MUL chamber cast in polydimethoxylsiloxane (PDMS) atop a microfluidic chip consisting of a single crystal piezoelectric material. By optimizing the power, duration, and orientation of the SAW input, we show that the mixing intensity of the sample and reagent fed into the chamber can be increased by one to two orders of magnitude, leading to a similar enhancement in the detection sensitivity of the chemiluminescent species and thus achieving a theoretical limit of detection of 0.02 ppb (0.2 nM) of l-proline-a decade improvement over the industry gold-standard and two orders of magnitude more sensitive than that achievable with conventional systems-simply using a portable photodetector and without requiring sample preconcentration. This on-chip microfluidic mixing strategy, together with the integrated miniature photodetector and the possibility for chip-scale microfluidic actuation, then alludes to the attractive possibility of a completely miniaturized platform for portable field-use microanalytical systems. PMID- 25275831 TI - Technique of combined glaucoma tube shunt and keratoprosthesis implantation. AB - OBJECTIVE: To describe the surgical technique and outcomes of implantation of a glaucoma drainage device (GDD) at the time of Boston type I keratoprosthesis (KPro) procedure. METHODS: Consecutive cases of combined GDD and KPro surgery performed between January 2005 and January 2011 with at least 6 months of follow up were reviewed. Outcome measures included visual acuity, number of glaucoma medications, and complications. RESULTS: Twenty-nine eyes (29 patients) underwent combined GDD and KPro surgery. 82.8% of KPro were retained at a mean follow-up of 34.4+/-17.7 months. Major complications included corneal necrosis (3 eyes, 10.3%), retinal detachment (3 eyes, 10.3%), endophthalmitis (1 eye, 3.4%), sterile vitritis (1 eye, 3.4%), and loss of light perception (2 eyes, 6.9%). Final corrected distance visual acuity improved in 17 (58.6%), remained unchanged in 7 (24.1%), and worsened in 5 eyes (17.2%). Mean numbers of glaucoma medications required postoperatively from 3 to 36 months were lower than the preoperative number, but the differences were not statistically significant. The tube of the GDD was able to be inserted into the anterior chamber or the ciliary sulcus in 27 eyes (91.3%). In 14 eyes with anterior segment ocular coherence tomographic evaluation, blockage of the ostium of the tube was noted in 2 eyes (14.3%). CONCLUSIONS: Combined GDD and KPro surgery provides the opportunity of additional IOP management and restoring vision in the same setting, saving the patient from additional glaucoma surgery, and is not associated with an increased KPro retention failure rate or other secondary complications. PMID- 25275832 TI - Interocular retinal nerve fiber layer thickness symmetry value in normal young adults. AB - PURPOSE: The aim of this study was to determine the normal range of interocular peripapillary retinal nerve fiber layer (RNFL) thickness symmetry value in young adults. Factors affecting interocular RNFL thickness symmetry were also investigated. MATERIALS AND METHODS: Both eyes of 241 ophthalmologically and neurologically normal subjects were scanned using optical coherence tomography (200*200 optic disc cube protocol). The effect of ocular cyclotorsion on interocular RNFL thickness symmetry was determined and mathematically accounted for. Symmetry value between the right and left RNFL thickness values was calculated. Linear regression analyses were used to identify correlations between the corrected interocular symmetry value and interocular differences in refractive error, axial length, superior and inferior temporal retinal artery and vein location, and optical coherence tomography signal strength. RESULTS: The mean interocular RNFL thickness symmetry value before and after correction of ocular cyclotorsion was 0.8791+/-0.0665 and 0.9044+/-0.0571 (P<0.001), respectively. Interocular differences in axial length, inferior temporal retinal arcade location, and refractive error were weakly and negatively correlated with the ocular cyclotorsion-corrected symmetry value (P<0.05). Anatomic differences between the eyes in the location of the superior temporal retinal artery and vein were strongly correlated with the corrected symmetry value (P<0.01, R=0.208). CONCLUSIONS: On the basis of the data obtained here from normal individuals, a corrected symmetry value of <0.77 might indicate the presence of pathologic conditions affecting the RNFL. Interocular RNFL thickness symmetry was influenced more heavily by interocular superotemporal vessel location than by anisometropia. PMID- 25275834 TI - Dynamic contrast-enhanced ultrasound parametric maps to evaluate intratumoral vascularization. AB - OBJECTIVES: The purposes of this study were to assess the reliability of parametric maps from dynamic contrast-enhanced ultrasound (DCE-US) to reflect the heterogeneous distribution of intratumoral vascularization and to predict the tissue features linked to vasculature. This study was designed to compare DCE-US parametric maps with histologic vascularity measurements. MATERIALS AND METHODS: Dynamic contrast-enhanced ultrasound was performed on 17 melanoma-bearing nude mice after a 0.1-mL bolus injection of SonoVue (Bracco SPA, Milan, Italy). The parametric maps were developed from raw linear data to extract pixelwise 2 semiquantitative parameters related to perfusion and blood volume, namely, area under the curve (AUC) and peak intensity (PI). The mathematical method to fit the time-intensity curve for each pixel was a polynomial model used in clinical routine and patented by the team. Regions of interest (ROIs) were drawn on DCE-US parametric maps for whole tumors and for several local areas of 15 mm within each tumor (iROI), the latter reflecting the heterogeneity of intratumoral blood volume. As the criterion standard correlation, microvessel densities (MVDs) were determined for both ROI categories. In detail, for all iROI of 15 mm, MVD and maturity were divided separately for vessels of 0 to 10 MUm, 10 to 40 MUm, and greater than 40 MUm in diameter, and the results were correlated with the ultrasound findings. RESULTS: Among the 17 studied mice, a total of 64 iROIs were analyzed. For the whole-tumor ROI set, AUC and PI values significantly correlated with MVD (rAUC = 0.52 [P = 0.0408] and rPI = 0.70 [P = 0.0026]). In the case of multiple iROI, a strong linear correlation was observed between the DCE-US parameters and the density of vessels ranging in their diameter from 0 to 10 MUm (rAUC = 0.68 [P < 0.0001]; rPI = 0.63 [P < 0.0001]), 10 to 40 MUm (rAUC = 0.98 [P = 0.0003]; rPI = 0.98 [P = 0.0004]), and greater than 40 MUm (rAUC = 0.86 [P = 0.0120]; rPI = 0.92 [P = 0.0034]), respectively. However, the DCE-US parameter values of perfusion and blood volume were not significantly different according to the diameters (AUC: P = 0.1731; PI: P = 0.2918) and maturity of blood vessels. CONCLUSIONS: Parametric maps of DCE-US can be reliably established from raw linear data and reflect the heterogeneous histological measures of vascularization within tumors. In contrast, the values of DCE-US parametric maps (AUC, PI) do not allow deduction of heterogeneous tissue features such as the diameters and maturity of vascular networks. PMID- 25275836 TI - Growing mass on the right side of the neck. PMID- 25275833 TI - Divergent long-term consequences of chronic treatment with haloperidol, risperidone, and bromocriptine on traumatic brain injury-induced cognitive deficits. AB - Antipsychotic drugs (APDs) are provided in the clinic to manage traumatic brain injury (TBI)-induced agitation and aggression. Experimental TBI studies consistently show that daily administration of the APDs, haloperidol (HAL) and risperidone (RISP), hinder recovery. However, it is unknown how long the adverse effects remain after cessation of treatment. To elucidate this clinically relevant issue, anesthetized male rats were randomly assigned to four TBI (controlled cortical impact) and four sham groups administered HAL (0.5 mg/kg), RISP (0.45 mg/kg), bromocriptine (BRO; 5.0 mg/kg, included as a control for D2 receptor action), or vehicle (VEH; 1 mL/kg) 24 h after surgery and once-daily for 19 days. Motor and cognitive recovery was assessed on days 1-5 and 14-19, respectively, and again at 1 and 3 months after drug withdrawal. No overall group differences were observed for motor function among the TBI groups, although the HAL group showed a greater beam-walk deficit on day 5 versus the VEH and BRO groups. Cognitive recovery was significantly impaired in the HAL and RISP groups during the treatment phase versus VEH and BRO. Further, BRO was superior to VEH (p=0.0042). At 1 month, both groups that received APDs continued to exhibit significant cognitive impairment versus VEH and BRO; at 3 months, only the HAL group was impaired. Moreover, the HAL, RISP, and VEH groups continued to be cognitively deficient versus BRO, which also reduced cortical damage. These data replicate previous reports that HAL and RISP impede cognitive recovery after TBI and expand the literature by revealing that the deleterious effects persist for 3 months after drug discontinuation. BRO conferred cognitive benefits when administered concomitantly with behavioral testing, thus replicating previous findings, and also after cessation demonstrating enduring efficacy. PMID- 25275837 TI - Influence of players' vocalisations on soccer referees' decisions. AB - The influence of a potentially fouled player's vocalisations on the referee's decisions was investigated. Experienced soccer referees watched video clips of real-match situations that were presented either without sound or with sound where a player's vocalisations were clearly audible and made judgements regarding fouls, direction of play and personal penalties. The results revealed that players' vocalisations had no impact on the foul decisions of the referees. However, once a referee made a foul decision, the player's vocalisations led to an increased number of personal penalties (increase in yellow cards) for the foul causing player. In addition to crowd noise, a player's vocalisations during a foul are used as a proximal cue in the referee's decision-making process. PMID- 25275839 TI - Preparation, identfication, and activity assay of lamprey (lampetra japonica) natural intelectins. AB - Intelectins play an important role in innate immune response. In a previous study, lamprey inteletins purified by galactose-Sepharose were inactive and insoluble. Herein, we provided a simple and effective method to purify natural intelectins from the serum of lamprey (Lethenteron japonicum) using proteinG agarose. SDS-PAGE, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), and mass spectrometry (MS) were used to analyze the purified proteins. The purified proteins were identified to be lamprey serum lectin and intelectinB. The activity analysis results indicated that the proteins had certain extent agglutination activity. The effective method will be useful to study their immune functions and molecular mechanisms. PMID- 25275840 TI - [Medicine crisis based on evidences]. PMID- 25275841 TI - [Hepatitis B vaccination coverage and associated factor for vaccine acceptance: a cross-sectional study in health workers of the Acapulco General Hospital, Mexico]. AB - BACKGROUND: Vaccination is a key current prophylactic measure for occupational risk of hepatitis B virus (HBV) infection. This study measures HBV vaccination coverage among health personnel in a Mexican hospital, and identifies factors associated with completion of the vaccination schedule. METHODS: A cross sectional study in workers of the Acapulco General Hospital, Mexico. Interviews documented vaccination history against HBV, number of doses received, and date of vaccination. Health workers with complete vaccination were considered those with at least three doses of vaccine received at intervals of two months between first and second doses, and six months to a year in the third dose. RESULTS: Some 52% of workers (436/834) reported at least one vaccination during their professional life and only 5.5% (46/834) completed the HBV vaccination schedule. Factors associated with completion were academic degree, perception of infection risk at work, and knowledge of vaccine efficacy and the need for a complete schedule. CONCLUSIONS: In line with hospitals in other studies, few hospital workers were fully vaccinated. Evidence from this study can inform efforts to increase HBV vaccination coverage. PMID- 25275843 TI - [Validation of a questionnaire to quantify the risk for skin cancer]. AB - INTRODUCTION: Currently, strategies are needed to identify the population at risk for skin cancer in order to implement prevention and for early diagnosis. There are no validated Spanish language instruments to measure skin cancer risk. OBJECTIVES: To design and validate a self-applied questionnaire to quantify the risk of melanoma and non-melanoma skin cancer in a Mexican population. METHODS: A self-applied questionnaire was designed to measure risk factors for skin cancer. Face and content validity was assessed by five experts in skin cancer. The value of each item was weighted according to the relative risk of the risk factors. The questionnaire was applied to extreme groups in order to measure the construct validity. Reliability was evaluated using test-retest method two weeks after the first application. RESULTS: The questionnaire was applied to patients with (n = 147) and without (n = 249) skin cancer from the Dermatologic Center "Dr. Ladislao de la Pascua". The total score of the questionnaire was different in both groups (U = 2,104.5, p = 0.0001) and ROC curve determined that five points or more equals high risk for skin cancer (area 0.964; 95% CI: 0.946-0.981; p = 0.0001). The reliability of the instrument was 0.971 (95% CI: 0.943-0.986; p = 0.0001). CONCLUSION: This is the first Spanish language questionnaire valid to measure risk of skin cancer, whose application at the population level would be useful to identify high-risk individuals who need preventative interventions. PMID- 25275842 TI - [Epidemiology of glomerular disease in adults: a database review]. AB - INTRODUCTION: Glomerular disease is among the top ten leading causes of death in Mexico. AIM: To assess the frequency of glomerulopathy in western Mexico in a Regional Hospital belonging of the Instituto Mexicano Del Seguro Social. METHODS: Single hospital center retrospective analysis. We reviewed all native kidney biopsies between January 2003 and December 2011, in patients more than 16 years old, to establish clinical features, presentation, and histological report. RESULTS: A total of 163 reports were analyzed; patients with a mean age of 32.6 +/- 13.3 years, 55% female, 24% had systemic arterial hypertension, and 10% with a family history of chronic renal failure. The most frequent types of primary glomerulonephritis were focal segmental glomerulosclerosis (FSGS) in 47% of cases, followed by membranous nephropathy in 15%. The most frequent types of secondary glomerulonephritis were lupus nephritis in 14%, followed by diabetic nephropathy in 4% and amyloidosis in 1.2%. CONCLUSION: Focal segmental glomerulosclerosis is the most frequent type of glomerulopathy in our population; we observed a minor percentage of Inmunoglobulin A (IgA) nephropathy compared with worldwide reports. This information is a contribution to the understanding of the prevalence of glomerulopathy in western Mexico. PMID- 25275844 TI - [Behavioral assessment of the "schizophrenia-like" phenotype in an animal model of neonatal lesion in the ventral hippocampus (NLVH) of young and adult rats]. AB - Schizophrenia is a serious mental disorder that affects one in 100 people worldwide, and is characterized by distorted thoughts and perceptions. Several animal models have been developed, based primarily on the study of the mechanism of action of antipsychotics. In this paper we present a number of classic behavioral tests (memory, social interaction, and pre-pulse inhibition) associated with schizophrenia in young and adult animals with NLVH. The animal model of NLVH is a heuristic model that discriminates, by behavioral testing, the phenotype "schizophrenia-like" from other behavioral paradigms such as depression and anxiety, specifically in adult animals. The genomics study of this model promises to be an important source of candidate genes for schizophrenia in humans. PMID- 25275845 TI - [Analysis of the prevalence of scoliosis and associated factors in a population of Mexican schoolchildren using sifting techniques]. AB - BACKGROUND: It is known that in the last decade, spinal disorders are increasing among children, and this generates high concern in areas of healthcare and educational stakeholders to develop preventative strategies to help curb this trend. This paper intends to go a step further in this direction and to explore factors associated with the presence of scoliosis hump, thus contributing to a better approach in the treatment and prevention of this disease in Mexican schools. OBJECTIVES: The objectives of the study were to analyze the prevalence of scoliosis, posture, laterality, obesity, early plant development, and deformity in schoolchildren aged 9-12 years of Ciudad Carmen (Mexico) and to check the possible relationship of the latter with the presence of hump scoliosis. METHODS: The sample consisted of 295 Mexican schoolchildren, analyzed in 2012, with an average age of 10.36 years (SD: 1,142); valued by Adams Test, Posture Kendall, BMI, Edinburgh inventory test, and plantogram sitting height. For analysis of the data, SPSS 20.0 was used. RESULTS: The number of subjects who had scoliosis was 42 (14.2%), improper posture occurred in 123 (41.7%) cases, 158 (53.5%) subjects were obese, in 63.7% maturational development had not started, most were skilled and had a normal foot type, and after the binary logistic regression analysis, the factors with a significant level of association with the presence of scoliosis were laying hump (Exp [B]: 5.569; 2.746-11.757), the type of foot (Exp [B]: 0151; 0.033-0.652), and age (Exp [B]: 242; 0.192-0.877). CONCLUSIONS: The prevalence of scoliosis among Mexican schoolchildren is similar to that found in other parts of the world. half of the school presented data from obesity and four in ten students had abnormal posture. Furthermore, the model indicated that subjects with correct posture were five-times less likely to develop scoliosis hump, that schoolchildren with normal feet were 14% less likely to have scoliosis, and that the risk increased with age. PMID- 25275846 TI - [Signaling mechanisms involved in resolution of inflammation]. AB - Inflammation is a physiological process, which eliminates pathogens and induces repair of damaged tissue. This process is controlled by negative feedback mechanisms, but if the inflammation persists, it generates a deleterious autoimmune process or can to contribute with diseases such as obesity or cancer. The inflammation resolution involves mechanisms such as decrease of proliferation and maturation of immune cells, phagocytosis and apoptosis of immune cells, and decrease of proinflammatory mediators. Therefore, is relevant to study the physiological effects of specific receptors that participate in inflammation resolution and the design of specific agonists as conventional anti-inflammatory therapeutics, without dramatic collateral effects. In this review, we study some mechanisms associated with inflammation inhibition, particularly the transduction of receptors for ligands with anti-inflammatory effects and that are relevant for their potential therapeutic. PMID- 25275847 TI - [The auditory pathway: levels of integration of information and principal neurotransmitters]. AB - In this paper we studied the central auditory pathway (CAP) from an anatomical, physiological and neurochemical standpoint, from the inner ear, brainstem, thalamus to the temporal auditory cortex. The characteristics of the spiral ganglion of Corti, auditory nerve, cochlear nuclei, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and auditory cortex, including the auditory efferent pathway, are given. CAP is described as the electrical impulses, travelling through axons, allowing ions to enter a neuron and vesicles with neurotransmitters (NT) and then released into synaptic space. The NT changes the functioning of the cells; when attached to specific receptors on the next nerve cell, NT-receiver union causes input of ions through Gap sites, resulting in a postsynaptic potential that is spread over all CAP. In addition, the effects of the NT are not limited to the transmission, but as trophic agents that promote the formation of new neural networks. Even the anatomy, physiology, neurochemical aspects, and the different types of synapses are not fully understood to comprehend the organization of the CAP, but remain under investigation because of the relevance for the treatment of various central auditory disorders. PMID- 25275848 TI - [Laparoscopic management of a congenital diaphragmatic hernia]. AB - Morgagni diaphragmatic hernia is a birth defect whose presentation in adults is rare. Diagnosis is usually made as an incidental finding through image studies; infrequently, patients may present with symptoms such as dyspnea or retrosternal pain. Open surgical repair has been the preferred management method of symptomatic presentation. In this paper we present the case of a 42 year-old-male with symptoms of retrosternal pain and dyspnea. Diaphragmatic hernia diagnosis was made by CT and it was managed by laparoscopic repair of the diaphragmatic hernia. PMID- 25275849 TI - [Thyroid hormone resistance (THR): a case report]. AB - Thyroid hormone resistance is a syndrome characterized by a reduced response to thyroid hormone with different degrees of resistance at target tissues. We present the clinical features, physical findings, and study protocol in a woman with thyroid hormone resistance. An arginine to tryptophan mutation on the beta isoform of the thyroid hormone receptor gene was demonstrated. Thyroid hormone resistance is an uncommon cause of thyroid dysfunction. It is necessary to perform an adequate study and confirmation to avoid an inadequate and ineffective treatment of this condition. PMID- 25275850 TI - [The first mastectomy for breast cancer in America: Aguascalientes, Mexico, 1777]. AB - In this paper we present the first evidence of a mastectomy for breast cancer in America, performed in Aguascalientes, Mexico, in the eighteenth century. This intervention was recorded in an anonymous ex-voto in which Mrs. Josefa Peres Maldonado thanks the Black Christ of Encino and the Immaculate Conception or Virgin of the village for the good results obtained. The French physician and surgeon Peter Maille performed the operation with the help of friars of the convent-hospital San Juan de Dios. We review the history of the surgical treatment of breast cancer, the pictorial structure of the document, the surgical technique proposed by the Royal College of Surgeons (New Spain) at the time, and the association between this event and its time as an example of the impact that the Age of Enlightenment had in New Spain. PMID- 25275851 TI - [The artistic heritage of the Mexican National Academy of Medicine: two important pieces]. PMID- 25275852 TI - Lung-residing myeloid-derived suppressors display dual functionality in murine pulmonary tuberculosis. AB - RATIONALE: Myeloid cells encompass distinct populations with unique functions during homeostasis and disease. Recently, a novel subset of innate cells, myeloid derived suppressor cells (MDSCs), has been described in cancer, which suppresses T-cell responses and fosters disease progression. The role of MDSCs in infection is insufficiently addressed. OBJECTIVES: To examine the presence and function of MDSCs during experimental pulmonary tuberculosis (TB) and further understand the immunologic consequences of direct interactions between MDSCs and lung bacterial pathogens. METHODS: Using cell-based approaches and experimental mouse models for pulmonary TB we characterized MDSCs as novel myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). MEASUREMENTS AND MAIN RESULTS: MDSCs readily phagocytosed Mtb, and released proinflammatory (IL-6, IL-1alpha) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in the lung in disease resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4Ralpha and heightened TB lethality, whereas targeted depletion of MDSCs ameliorated disease. CONCLUSIONS: Our data reveal that MDSCs provide a niche for pathogen survival and tailor immunity in TB. These findings suggest MDSCs as amenable targets for host directed therapies and emphasize them as cellular-immune regulators during chronic inflammatory conditions, including chronic infections and microbial complications of neoplastic disorders. PMID- 25275853 TI - Reliability and validity of the Symptoms of Depression Questionnaire (SDQ). AB - Current measures for major depressive disorder focus primarily on the assessment of depressive symptoms, while often omitting other common features. However, the presence of comorbid features in the anxiety spectrum influences outcome and may effect treatment. More comprehensive measures of depression are needed that include the assessment of symptoms in the anxiety-depression spectrum. This study examines the reliability and validity of the Symptoms of Depression Questionnaire (SDQ), which assesses irritability, anger attacks, and anxiety symptoms together with the commonly considered symptoms of depression. Analysis of the factor structure of the SDQ identified 5 subscales, including one in the anxiety depression spectrum, with adequate internal consistency and concurrent validity. The SDQ may be a valuable new tool to better characterize depression and identify and administer more targeted interventions. PMID- 25275854 TI - Chiral resolution and absolute configuration of a pair of rare racemic spirodienone sesquineolignans from Xanthium sibiricum. AB - A pair of racemic spirodienone neolignan enantiomers, (+/-)-sibiricumin A, were isolated from the extract of the fruits of Xanthium sibiricum. The resolution of (+)- and (-)-sibiricumin A was achieved by chiral HPLC. The absolute configurations of the racemes were assigned by X-ray and by electronic circular dichroism (ECD). This experiment is the first unambiguous determination of the absolute configuration of spirodienone neolignan. PMID- 25275855 TI - Addressing prescription opioid overdose: data support a comprehensive policy approach. PMID- 25275856 TI - The G protein-coupled receptor GPR162 is widely distributed in the CNS and highly expressed in the hypothalamus and in hedonic feeding areas. AB - The Rhodopsin family is a class of integral membrane proteins belonging to G protein-coupled receptors (GPCRs). To date, several orphan GPCRs are still uncharacterized and in this study we present an anatomical characterization of the GPR162 protein and an attempt to describe its functional role. Our results show that GPR162 is widely expressed in GABAergic as well as other neurons within the mouse hippocampus, whereas extensive expression is observed in areas related to energy homeostasis and hedonic feeding such as hypothalamus, amygdala and ventral tegmental area, regions known to be involved in the regulation of palatable food consumption. PMID- 25275857 TI - From bedside to cell biology: a century of history on lysosomal dysfunction. AB - Lysosomal storage disorders (LSDs) are a group of rare genetic diseases, generally caused by a deficiency of specific lysosomal enzymes, which results in abnormal accumulation of undegraded substrates. The first clinical reports describing what were later shown to be LSDs were published more than a hundred years ago. In general, the history and pathophysiology of LSDs has impacted on our current knowledge of lysosomal biology. Classically, depending on the nature of the substrates, LSDs can be divided into different subgroups. The mucopolysaccharidoses (MPSs) are those caused by impaired degradation of glycosaminoglycans (GAGs). Amongst LSDs, the MPSs are a major group of pathologies with crucial historical relevance, since their study has revealed important biological pathways and highlighted interconnecting pathological cascades which are still being unveiled nowadays. Here we review the major historical discoveries in the field of LSDs and their impact on basic cellular knowledge and practical applications. Attention will be focused on the MPSs, with occasional references to other LSDs. We will show as studies on the metabolic basis of this group of diseases have increased our knowledge of the complex degradative pathways associated with the lysosome and established the basis to the development of specific therapeutic approaches aiming at correcting or, at least ameliorating their associated phenotypes. PMID- 25275858 TI - Reference ranges of lymphocyte subsets in healthy Qatari adults. AB - AIM: Determine reference ranges of lymphocyte subsets in healthy Qatari adults. PATIENTS & METHODS: Blood samples (n = 150) were investigated using four colors flow cytometery. RESULTS: The mean percentage and absolute values of the lymphocyte subsets were: CD3: 73.6 +/- 6.1%; 2,072 +/- 644 cells/MUl; CD4: 41.1 +/- 7.9%; 1,167 +/- 396 cells/MUl; CD8: 33.8 +/- 7.1%; 967 +/- 364 cells/MUl; B cells (CD19(+)): 11.3 +/- 3.9%; 318 +/- 144 cells/MUl and natural killer (NK) cells (CD16/56(+)): 16.5 +/- 6.3%, 440 +/- 401 cells/MUl, respectively. The CD4/CD8 ratio was 1.3 +/- 0.5. The ratio, CD3(+) and CD4(+) percentage and CD4(+) cell counts were significantly higher in females; CD8(+) and NK cell count and CD8(+) percentage were significantly higher in males. The impact of age was less certain. CONCLUSION: The reference values of lymphocyte subsets appear to be specific to this population, demonstrating the importance of establishing local reference ranges. PMID- 25275859 TI - Perfluoroalkane force field for lipid membrane environments. AB - In this work, we present atomic parameters of perfluoroalkanes for use within the CHARMM force field. Perfluorinated alkanes represent a special class of molecules. On the one hand, they are considerably more hydrophobic than lipids, but on the other hand, they are not lipophilic either. Instead, they represent an independent class of philicity, enabling a whole portfolio of applications within both materials science and biochemistry. We performed a thorough parametrization of all bonded and nonbonded parameters with a particular focus on van der Waals parameters. Here, the general framework of the CHARMM and CGenFF force fields has been followed. The van der Waals parameters have been fitted to experimental densities over a wide range of temperatures and pressures. This newly parametrized class of molecules will open the gate for a variety of simulations of biologically relevant systems within the CHARMM force field. A particular perspective for the present work is the influence of polyphilic transmembrane molecules on membrane properties, aggregation phenomena, and transmembrane channels. PMID- 25275861 TI - Effects of targeted education for first-year university students on knowledge and attitudes about stem cell transplantation and donation. AB - OBJECTIVES: Hematopoietic stem cell transplantation is a life-saving treatment, but donor numbers are lacking in Turkey and elsewhere. Increased awareness of hematopoietic stem cell transplantation among university students might help expand donation. We evaluated the effect of a brief targeted educational intervention on knowledge and attitudes about hematopoietic stem cell transplantation and donation among first-year university students in Turkey. MATERIALS AND METHODS: There were 301 first-year university students (median age, 18 y) who volunteered: 163 medical students (54%) and 138 law students (46%). Before and after a brief lecture about hematopoietic stem cell transplantation, students answered a 5-item yes-or-no questionnaire regarding (1) knowledge about health benefits of hematopoietic stem cell transplantation; (2) knowledge about stem cell banking and donation in Turkey; (3) knowledge about the transplantation procedure; (4) prior experience and/or willingness to donate blood; and (5) willingness to donate stem cells. Reasons for motivation to donate blood and/or stem cells were categorized. Results before and after the lecture were evaluated with univariate and multivariate analyses. RESULTS: The response rate was 100%. Significantly greater proportions of students had knowledge about hematopoietic stem cell transplantation and willingness to donate blood and stem cells after the lecture. There were no differences between medical and law students before the lecture. After the lecture, a significantly greater proportion of medical students indicated knowledge about health benefits of hematopoietic stem cell transplantation, stem cell banking and donation in Turkey, and the transplantation procedure. CONCLUSIONS: Brief education about hematopoietic stem cell transplantation for university students can increase knowledge and awareness about hematopoietic stem cell transplantation and cause more positive attitudes about stem cell donation. PMID- 25275860 TI - Resolving anatomical and functional structure in human brain organization: identifying mesoscale organization in weighted network representations. AB - Human brain anatomy and function display a combination of modular and hierarchical organization, suggesting the importance of both cohesive structures and variable resolutions in the facilitation of healthy cognitive processes. However, tools to simultaneously probe these features of brain architecture require further development. We propose and apply a set of methods to extract cohesive structures in network representations of brain connectivity using multi resolution techniques. We employ a combination of soft thresholding, windowed thresholding, and resolution in community detection, that enable us to identify and isolate structures associated with different weights. One such mesoscale structure is bipartivity, which quantifies the extent to which the brain is divided into two partitions with high connectivity between partitions and low connectivity within partitions. A second, complementary mesoscale structure is modularity, which quantifies the extent to which the brain is divided into multiple communities with strong connectivity within each community and weak connectivity between communities. Our methods lead to multi-resolution curves of these network diagnostics over a range of spatial, geometric, and structural scales. For statistical comparison, we contrast our results with those obtained for several benchmark null models. Our work demonstrates that multi-resolution diagnostic curves capture complex organizational profiles in weighted graphs. We apply these methods to the identification of resolution-specific characteristics of healthy weighted graph architecture and altered connectivity profiles in psychiatric disease. PMID- 25275862 TI - From hearing with a cochlear implant and a contralateral hearing aid (CI/HA) to hearing with two cochlear implants (CI/CI): a within-subject design comparison. AB - OBJECTIVE: To compare within-subject bilateral-binaural and bimodal complementary abilities between bimodal (cochlear implant and hearing aid; CI/HA) and bilateral CI hearing (CI/CI), thereby enabling better-informed counseling of experienced CI/HA users contemplating contralateral implantation. STUDY DESIGN: Comparative within-subject case review. SETTING: Outpatient hearing clinic. PATIENTS: Ten experienced adult CI/HA users with severe-to-profound hearing loss in the HA ear, who converted to CI/CI between 2 and 11 years after initial implantation. INTERVENTION: Task-specific testing of bilateral-binaural hearing (sound lateralization, binaural summation/redundancy/unmasking, head-shadow effect), bimodal complementary benefit (contribution of low-frequency information), and a self-report Speech, Spatial, and Qualities of Hearing (SSQ) questionnaire, all before and 1 year after contralateral cochlear implantation. MAIN OUTCOME MEASURES: Test result differences between CI/HA and CI/CI conditions. RESULTS: CI/CI hearing was better than CI/HA for speech lateralization and for perception of semantically unpredictable sentences in speech noise with speech at 0 degrees and noise at +90 degrees azimuth on the old CI side. CI/HA was better than CI/CI only for differences between perception of natural prosody speech and of speech with flattened fundamental frequency (F0) contour with speech and noise in front (at 0 degrees azimuth). Total scores on the SSQ questionnaire were higher in CI/CI than in CI/HA users. CONCLUSION: Counseling regarding contralateral implantation for CI/HA users with severe-to-profound hearing loss in the HA ear, though generally positive, should consider individual functional needs, and cover expectations about the expected trade-off between gaining improved understanding and speech lateralization in challenging listening conditions and losing some low frequency cues still available with CI/HA hearing. PMID- 25275863 TI - Clinical and radiological guidance in managing facial nerve schwannomas. AB - OBJECTIVE: To present a review of all patients diagnosed with a facial nerve schwannoma (FNS) managed in our center over almost two decades, and suggest guidelines for their classification and management. STUDY DESIGN: Retrospective case review SETTING: Tertiary referral center PATIENTS: Twenty-eight patients with a facial nerve schwannoma INTERVENTION: Conservative or surgical management depending on clinical and radiological features MAIN OUTCOME MEASURE: Patient demographics, site of tumor, and clinical symptoms, including facial nerve function (House-Brackmann score) at baseline and follow-up. In those managed surgically, operative approach and surgical outcomes were also recorded. RESULTS: Of 28 patients, 16 were male. Mean age at presentation was 46 years. The majority presented with either facial weakness or hearing loss. The internal auditory canal segment of the facial nerve was the most commonly affected (19/28, 68%). Multi-segmental lesions were found in almost half (46%) of patients. Facial weakness was most commonly associated with involvement of the labyrinthine segment (89%). Overall, 16 (57%) patients were managed surgically. CONCLUSION: FNS may be difficult to distinguish on both clinical and imaging grounds from other cerebellopontine pathologies on the basis of audiovestibular symptoms alone. The presence of facial weakness in combination with imaging findings suggestive of FNS is highly suggestive for FNS. In patients with brainstem compression, rapid tumor growth, or House-Brackmann greater than 4, we suggest a surgical approach based on preoperative audiovestibular status, helping optimize long-term facial function and minimize morbidity. Facial nerve reanimation at the time of primary surgery is preferred. PMID- 25275864 TI - Pressure assessment of superior semicircular canal dehiscence repair techniques- a temporal bone study. AB - OBJECTIVE: To develop a cadaveric temporal bone preparation to compare the strength of superior semicircular canal dehiscence (SCD) repair techniques. BACKGROUND: Superior semicircular canal dehiscence syndrome is a clinical condition with a variety of auditory and vestibular symptoms resulting from a mobile third window into the inner ear. Patients with incapacitating symptoms often undergo surgical repair. There have been no previous studies to directly assess the strength of techniques used for repair of SCD. METHODS: The ability of repair techniques to withstand prolonged pressure application was measured in prepared temporal bones (n = 5). Pressure changes were compared with the superior semicircular canal intact and with the dehiscence repaired via three repair techniques (resurfacing, plugging, and combined plugging and resurfacing). RESULTS: Each of the three repair techniques resisted loss of applied pressure as well as the closed system before creation of the dehiscence at pressures comparable to high-normal intracranial pressure (23-25 cm H2O). At supra physiologic pressure levels (45-55 cm H2O), the combined plugging and resurfacing technique showed consistent resistance to loss of pressure as compared to instances of failure with either of the single repair approaches. CONCLUSION: Findings from the cadaveric temporal bone preparations revealed that even immediately after repair, each of the three main techniques are equally resistant to the application of high-normal intracranial pressure levels. However, with consistent resistance to loss of pressure across all trials, the combined plugging and resurfacing technique may offer improved resistance in instances where supra-physiologic pressures are encountered. PMID- 25275865 TI - Vibro-EAS: a proposal for electroacoustic stimulation. AB - HYPOTHESIS: In situ evaluation of the vibration performance of a hybrid system for intracochlear fluid stimulation, constructed from a floating mass transducer (FMT) coupled to an electric acoustic stimulation (EAS) cochlea implant (CI) electrode. BACKGROUND: EAS uses both CI technology to restore severe-to-profound hearing loss at high frequencies and acoustic amplification for mild-to-moderate hearing loss in the low-to-mid frequency range. More patients with residual hearing are becoming candidates for EAS surgery because of the improved techniques for hearing preservation. Most patients with partial deafness fulfill the audiological criteria at low and mid-frequencies for the active middle-ear implant with FMT (VSB). The FMT of the VSB is a potential device for acoustical stimulation in EAS. METHODS: In seven fresh human temporal bones, stapes amplitude responses for fixation of a FMT to the long incus process (standard coupling) was compared with those for FMT fixation to a 20-mm inserted standard cochlea electrode array (31.5 mm) via the round window (Vibro-EAS). Vibration of the stapes footplate was measured by laser Doppler vibrometry. RESULTS: For 0.316 Vrms drive voltage, stimulation of the intracochlear fluid using a FMT-driven CI electrode (Vibro-EAS) yielded stapes amplitude responses comparable to those for acoustic stimulation with 84 dB SPL. These amplitude responses are 30 to 42 dB lower at frequencies up to 4 kHz than those for VSB standard coupling. CONCLUSION: Intracochlear combined electrical and mechanical stimulation may be a viable technique for electroacoustic stimulation. A reliable technique for attachment or integration of the FMT to the cochlea electrode array has yet to be developed. PMID- 25275866 TI - A novel intraoral bone conduction hearing prosthesis: one-year safety and efficacy study. AB - OBJECTIVE: To assess the safety and efficacy of an intraoral bone conduction (IOBC) hearing prosthesis after 12 months of use. STUDY DESIGN: Prospective cohort study. SETTING: Multisite study including private practice, hospital-based practice, tertiary care, and academic medical centers. PATIENTS: Patients aged 18 years or older with single-sided deafness (SSD). MAIN OUTCOME MEASURE(S): At the end of 6 months and 12 months, patients were asked to complete the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire and SSD questionnaire in addition to audiometric testing. RESULTS: Eighty-one patients completed the study. Hearing thresholds remained the same throughout the study. APHAB results showed a significant benefit (p < 0.001) in categories of ease of communication, reverberation, background noise, and global score. The SSD questionnaire showed a high satisfaction among participants, with 93.8% of patients likely to recommend the IOBC. Dissatisfaction was highest with regard to patient's ability to eat with device, with only 55.6% satisfied. No serious adverse events were reported during the study. CONCLUSION: The IOBC is a safe and effective alternative to percutaneous osseointegrated hearing implants for patients with SSD. Patient satisfaction and improved hearing benefit are observed after 1 year of using the device. The IOBC significantly benefitted patients in APHAB categories of ease of communication, reverberation, background noise, and the overall global hearing score. The in-the-mouth transducer is the least-liked feature for some patients, particularly with regard to eating; however, the majority of patients are willing to deal with the size of the device for the hearing benefit gained. PMID- 25275867 TI - Evidence for the expansion of pediatric cochlear implant candidacy. AB - OBJECTIVE: To test the hypothesis that children who are non-traditional cochlear implant candidates, but are not making progress with appropriately fitted hearing aids and intervention, will demonstrate significant benefit from cochlear implantation as defined by improvement in (1) speech perception, (2) auditory skills development, and/or (3) progress on standardized measures of receptive and expressive language. STUDY DESIGN: Retrospective case series. SETTING: Two tertiary academic cochlear implant centers. PATIENTS: All pediatric patients that underwent cochlear implantation were reviewed. Only those meeting one or both of the following criteria were included: (1) less severe hearing loss than specified in the current indications and (2) open-set word and/or sentence recognition scores greater than 30% for children who are able to participate in speech perception testing. Patients with auditory neuropathy were excluded. INTERVENTION(S): Cochlear implantation. MAIN OUTCOME MEASURES: Pre- and postoperative results of age appropriate speech recognition tests, auditory questionnaires, and standardized norm-referenced estimates of speech and language development. RESULTS: A total of 51 patients met study criteria. The mean age at time of surgery was 8.3 years and 24% underwent bilateral sequential implantation. Overall, the mean speech recognition improvement was 63 percentage points in the implanted ear (p < 0.001) and 40 percentage points in the bimodal condition (p < 0.001). Results of auditory and language development measures revealed significant improvement after implantation (p < 0.05). CONCLUSION: Non traditional pediatric implant recipients derive significant benefit from cochlear implantation. A large-scale reassessment of pediatric cochlear implant candidacy, including less severe hearing losses and higher preoperative speech recognition, is warranted to allow more children access to the benefits of cochlear implantation. PMID- 25275868 TI - Sound location modulation of electrocochleographic responses in chinchilla with single-sided deafness and fitted with an osseointegrated bone-conducting hearing prosthesis. AB - HYPOTHESIS: Bone-anchored hearing systems (BAHSs) provide sound location dependent input to the normal ear for reducing the head shadow effect in the case of single-sided deafness (SSD). BACKGROUND: Patients with SSD can be fit with a BAHS positioned on the impaired side. Despite successful outcomes and some reports of spatial hearing capabilities, little data are available regarding the physiologic performance of BAHSs in response to free-field sounds. METHODS: Cochlear microphonics (CMs) were recorded from five chinchillas before and after destruction of one cochlea. A BAHS (Cochlear Baha) was fitted on the deafened side. CM measurements were made in response to tones, with and without the BAHS, to free-field sounds presented ipsilateral to the SSD, on the side of the normal ear, and along the midline. Stimuli were also presented directly through the BAHS and an earphone to generate sounds with interaural time and level differences approximating free-field sounds. RESULTS: With the BAHS, CM thresholds were decreased (re: no BAHS) by approximately 10 dB for sources ipsilateral to the SSD, approximately 14 dB for midline sources, and approximately 5 dB for sources contralateral to the SSD. Changes in CM amplitudes and thresholds were sound location dependent. CM amplitudes were modulated by interaural time and level differences generated by the linear interaction of BAHS and acoustic signals. CONCLUSION: This study suggests that BAHS can provide input to the normal ear that is modulated by sound location, which serves to reduce the head shadow effect and may also offer cues to sound location. PMID- 25275869 TI - Epidemiology of vestibulo-ocular reflex function: data from the Baltimore Longitudinal Study of Aging. AB - OBJECTIVE: To determine age-related changes in vestibulo-ocular reflex (VOR) function in community-dwelling adults, and evaluate these for associations with demographic characteristics and cardiovascular risk factors. STUDY DESIGN: Cross sectional analysis within the Baltimore Longitudinal Study of Aging (BLSA), a longitudinal prospective cohort study. SETTING: Vestibular testing laboratory within an acute care teaching hospital. PATIENTS: Community-dwelling adults enrolled in the BLSA. INTERVENTION(S): Horizontal VOR gain measurement using video head-impulse testing and visual acuity testing. MAIN OUTCOME MEASURE(S): VOR gain was calculated as the ratio of eye velocity to head velocity. Demographic and cardiovascular risk factor data were collected through study questionnaires. RESULTS: One hundred nine subjects were analyzed with mean age (SD) 69.9 years (14.2), with a range from 26 to 92 years. VOR gain remained stable from age 26 to 79 after which it significantly declined at a rate of 0.012/year (p = 0.033) in adjusted analyses. Individuals aged 80 years or older had a nearly 8-fold increased odds of VOR gain less than 0.80 relative to those aged less than 80 years in multivariate models (prevalence of 13.2% vs. 2.8%; OR 7.79, 95% CI: 1.04-58.38). Otherwise, VOR gain did not differ significantly across demographic or cardiovascular risk groups. CONCLUSION: We report age related decline in VOR function in individuals aged 80 years and older. Further analyses are in progress to establish the significance of these VOR abnormalities to functional and mobility outcomes in older individuals. PMID- 25275870 TI - Retinitis pigmentosa: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials and the video head impulse test. AB - OBJECTIVE: Retinitis pigmentosa (RP) represents a group of inherited disorders in which abnormalities of the photoreceptors lead to progressive visual loss. Night blindness, peripheral visual field loss, and eventual total blindness represent typical visual damage of such disease. No study has previously evaluated the presence of a "latent" vestibular deficit in patients with RP. STUDY DESIGN: Prospective study with caloric test, cervical vestibular evoked myogenic potentials (C-VEMPs), ocular vestibular evoked myogenic potentials (O-VEMPs), and video head impulse test (v-HIT). SETTING: Tertiary referral center. PATIENTS: 16 patients suffering from RP. INTERVENTION: Evaluation of vestibular dysfunction with caloric test, C-VEMPs, O-VEMPs, and the measurement of the vestibular-ocular reflex (VOR) using the v-HIT. RESULTS: Only five patients with RP showed normal values in all the vestibular tests performed. Three patients had an evident deficit at the caloric test, whereas eight (50%) of them had a normal caloric test but a pathological response in at least one of the other vestibular tests performed. No patient of the study showed a bilateral otolith or ampullary dysfunction. CONCLUSION: Our patients with RP unexpectedly showed pathological responses in at least one of the vestibular tests performed. Nowadays, in patients affected by RP, a vestibular diagnostic protocol must include VEMPs and v-HIT to confirm the vestibular damage and to identify selective damage of the vestibular nerve. PMID- 25275871 TI - Success of lateral graft technique for closure of tympanic membrane perforations. AB - OBJECTIVE: We wished to determine if the success of lateral graft tympanoplasty was affected by either size of perforation, previous underlay tympanoplasty, or patient age. PATIENTS: A review was performed of patients who underwent lateral graft tympanoplasty by the senior author between March 2010 and July 2013 with patient number based on an a priori power analysis. Patient demographics, baseline clinical data, postoperative findings, and audiologic data were collected. INTERVENTIONS: Lateral graft tympanoplasty. MAIN OUTCOME MEASURES: The primary outcome was closure of perforation. The secondary outcome was change in air-bone gap. RESULTS: Thirty patients were included with a mean follow-up period of 14 months. Closure of tympanic membrane perforation occurred in 93%. Closure was observed in 13 of 15 (87%) patients with perforations 50% or smaller and in all patients (15 of 15) with perforations larger than 50% (p = 0.48, Fisher's exact test). For revision cases, 8 of 9 (89%) were closed compared to 20 of 21 (95%) in primary tympanoplasty (p = 0.52). Perforations in adults and children were equally likely to be closed (10 of 11 children vs. 18 of 19 adults) (p = 1). The mean preoperative to postoperative air-bone gap improved from 24 +/- 12 dB to 14 +/- 8 dB (p = 0.0003, paired t test). CONCLUSIONS: Lateral graft tympanoplasty has a high success rate for the closure of tympanic membrane perforations with a significant improvement in air-bone gap. There were no significant differences in success comparing small versus large perforations, primary versus revision tympanoplasty, or adults versus children. PMID- 25275872 TI - Association between vestibular function and motor performance in hearing-impaired children. AB - OBJECTIVE: The clinical balance performance of normal-hearing (NH) children was compared with the balance performance of hearing-impaired (HI) children with and without vestibular dysfunction to identify an association between vestibular function and motor performance. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Thirty-six children (mean age, 7 yr 5 mo; range, 3 yr 8 mo-12 yr 11 mo) divided into three groups: NH children with normal vestibular responses, HI children with normal vestibular responses, and HI children with abnormal vestibular function. INTERVENTIONS: A vestibular test protocol (rotatory and collic vestibular evoked myogenic potential testing) in combination with three clinical balance tests (balance beam walking, one-leg hopping, one-leg stance). MAIN OUTCOME MEASURES: Clinical balance performance. RESULTS: HI children with abnormal vestibular test results obtained the lowest quotients of motor performance, which were significantly lower compared with the NH group (p < 0.001 for balance beam walking and one-leg stance; p = 0.003 for one-leg hopping). The balance performance of the HI group with normal vestibular responses was better in comparison with the vestibular impaired group but still significantly lower compared with the NH group (p = 0.020 for balance beam walking; p = 0.001 for one-leg stance; not significant for one-leg hopping). CONCLUSION: These results indicate an association between vestibular function and motor performance in HI children, with a more distinct motor deterioration if a vestibular impairment is superimposed to the auditory dysfunction. PMID- 25275873 TI - Barotrauma-induced Pneumolabyrinth and Pneumocephalus Associated With Semicircular Canal Dehiscence. PMID- 25275874 TI - Concomitant spuriously elevated white blood cell count, a previously underestimated phenomenon in EDTA-dependent pseudothrombocytopenia. AB - The proportion and potential risk of concomitant spuriously elevated white blood cell count (SEWC) are underestimated in ethylenediaminetetraacetic acid (EDTA) dependent pseudothrombocytopenia (PTCP). The proportion, kinetics and prevention of SEWC remain poorly understood. A total of 25 patients with EDTA-dependent PTCP were enrolled in this study. With the hematology analyzer Coulter LH 750, we determined the time courses of WBC count, WBC differential and platelet count in EDTA- and sodium citrate-anticoagulated blood, respectively. Blood smears were prepared to inspect the presence of platelet clumps using light microscopy. The effect of automatic instrumental correction on the extent of SEWC was evaluated. The proportion of SEWC was 92% in EDTA-dependent PTCP and 73.9% of SEWCs were within the normal range. The development of SEWC was time-dependent, and neutrophils and lymphocytes were the main subpopulations involved in SEWC. A strong and significant correlation (r = 0.9937, p < 0.001) was found between the increased WBC count and the decreased platelet count. Both corrected and uncorrected WBC counts at 15 minutes or later after blood collection in EDTA were significantly higher than their basal counts, respectively, p < 0.05. Interestingly, in citrated blood, WBC counts after blood collection were not significantly different from its basal counts, p > 0.05. A high proportion of concomitant SEWCs, which are mainly within normal range, are present in patients with EDTA-dependent PTCP. Proper interpretation of SEWC is crucial to avoid clinic errors. SEWC develops in a time-dependent pattern, although the Coulter LH 750 only partly mitigates the extent of SEWC, sodium citrate is able to effectively prevent SEWC. PMID- 25275875 TI - Group medication management for buprenorphine/naloxone in opioid-dependent veterans. AB - OBJECTIVE: Substance use disorders are a key concern among US veterans. Substance use disorder pharmacotherapies with support for effectiveness are limited. Buprenorphine/naloxone (Suboxone) is an effective opioid replacement treatment option for opioid use disorder when used as part of a comprehensive treatment program. In June 2011, the Veterans Affairs San Diego Healthcare System began using a group format to prescribe buprenorphine/naloxone. This study aimed at examining outcomes of retention rates and percentage opioid negative urine samples. Results were compared for veteran patients seen in group versus individual formats. METHODS: This retrospective chart review included data from 32 patients who were prescribed buprenorphine/naloxone between a 3-year window (ie, January 1, 2010, and December 31, 2012). RESULTS: Overall results were 46% retention in treatment after 1 year, and 94% of opioid urine samples were negative. More patients seen in group were retained in treatment at 1 year compared with those seen individually (69% vs 27%, respectively; P < 0.03). CONCLUSIONS: This study found that veterans prescribed buprenorphine/naloxone in a group setting as part of a drug and alcohol treatment program were retained in treatment longer than veterans prescribed this medication individually. Because of inherent limitations in the study design, no causality can be determined; however, given the results found here, group medication management of buprenorphine/naloxone should be explored further. PMID- 25275876 TI - Pain and emotional distress among substance-use patients beginning treatment relative to a representative comparison group. AB - OBJECTIVES: A secondary analysis assessed health-related quality-of-life (HRQOL) characteristics (ie, anxiety, depression, fatigue, and types of pain) among patients entering substance-use treatment and identified characteristics specific to treatment modalities relative to a representative comparison group. METHODS: As part of a larger alcohol bank assessment, substance-use patients (n = 406) beginning methadone treatment (n = 170) or other outpatient treatment (n = 236) and a comparison group representative of the general population (n = 1000) completed a survey measuring anxiety, depression, fatigue, pain interference, and pain in the last 7 days. Previous studies lacked comparable and concurrent assessments across these 3 groups. RESULTS: Patients entering substance-use treatment had relatively high levels of emotional distress and poorer HRQOL relative to the general population. Among treatment modalities, patients beginning methadone treatment reported the highest levels of pain interference and pain behavior and the poorest physical functioning. Before the potentially modifying effects of methadone maintenance, patients beginning agonist therapy reported the greatest levels of compromised quality of life. CONCLUSIONS: These data present the magnitude of differences in HRQOL characteristics between treatment and comparison groups using the same assessment rubric and may help inform the design and timing of treatment modalities, thereby enhancing treatment efficacy for patients. PMID- 25275879 TI - Structural and optical properties of self-assembled chains of plasmonic nanocubes. AB - Solution-based linear self-assembly of metal nanoparticles offers a powerful strategy for creating plasmonic polymers, which, so far, have been formed from spherical nanoparticles and cylindrical nanorods. Here we report linear solution based self-assembly of metal nanocubes (NCs), examine the structural characteristics of the NC chains, and demonstrate their advanced optical characteristics. In comparison with chains of nanospheres with similar dimensions, composition, and surface chemistry, predominant face-to-face assembly of large NCs coated with short polymer ligands led to a larger volume of hot spots in the chains, a nearly uniform E-field enhancement in the gaps between colinear NCs, and a new coupling mode for NC chains due to the formation of a Fabry-Perot resonator structure formed by face-to-face bonded NCs. The NC chains exhibited stronger surface-enhanced Raman scattering in comparison with linear assemblies of nanospheres. The experimental results were in agreement with finite difference time domain simulations. PMID- 25275877 TI - A latent class analysis of pathological-gambling criteria among high school students: associations with gambling, risk and health/functioning characteristics. AB - OBJECTIVES: To identify subtypes of adolescent gamblers based on the 10 Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for pathological gambling and the 9 Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for gambling disorder and to examine associations between identified subtypes with gambling, other risk behaviors, and health/functioning characteristics. METHODS: Using cross-sectional survey data from 10 high schools in Connecticut (N = 3901), we conducted latent class analysis to classify adolescents who reported past-year gambling into gambling groups on the basis of items from the Massachusetts Gambling Screen. Adolescents also completed questions assessing demographic information, substance use (cigarette, marijuana, alcohol, and other drugs), gambling behaviors (relating to gambling formats, locations, motivations, and urges), and health/functioning characteristics (eg, extracurricular activities, mood, aggression, and body mass index). RESULTS: The optimal solution consisted of 4 classes that we termed low risk gambling (86.4%), at-risk chasing gambling (7.6%), at-risk negative consequences gambling (3.7%), and problem gambling (PrG) (2.3%). At-risk and PrG classes were associated with greater negative functioning and more gambling behaviors. Different patterns of associations between at-risk and PrG classes were also identified. CONCLUSIONS: Adolescent gambling classifies into 4 classes, which are differentially associated with demographic, gambling patterns, risk behaviors, and health/functioning characteristics. Early identification and interventions for adolescent gamblers should be sensitive to the heterogeneity of gambling subtypes. PMID- 25275880 TI - Regioselective allene hydroarylation via one-pot allene hydrosilylation/Pd catalyzed cross-coupling. AB - Advances in hydroarylation have been achieved by the development of a one-pot regioselective allene hydrosilylation/Pd(0)-catalyzed cross-coupling protocol. The regioselectivity is primarily governed by N-heterocyclic carbene (NHC) ligand identity in the hydrosilylation step and is preserved in the subsequent cross coupling reaction. This methodology affords streamlined access to functionalized 1,1-disubstituted alkenes with excellent regiocontrol. PMID- 25275882 TI - Molecular structures and solvation of free monomeric and dimeric ferriheme in aqueous solution: insights from molecular dynamics simulations and extended X-ray absorption fine structure spectroscopy. AB - CHARMM force field parameters have been developed to model nonprotein bound five coordinate ferriheme (ferriprotoporphyrin IX) species in aqueous solution. Structures and solvation were determined from molecular dynamics (MD) simulations at 298 K of monomeric [HO-ferriheme](2-), [H2O-ferriheme](-), and [H2O ferriheme](0); pi-pi dimeric [(HO-ferriheme)2](4-), [(H2O-ferriheme)(HO ferriheme)](3-), [(H2O-ferriheme)2](2-), and [(H2O-ferriheme)2](0); and MU-oxo dimeric [MU-(ferriheme)2O](4-). Solvation of monomeric species predominated around the axial ligand, meso-hydrogen atoms of the porphyrin ring (Hmeso), and the unligated face. Existence of pi-pi ferriheme dimers in aqueous solution was supported by MD calculations where such dimers remained associated over the course of the simulation. Porphyrin rings were essentially coplanar. In these dimers major and minor solvation was observed around the axial ligand and Hmeso positions, respectively. In MU-oxo ferriheme, strong solvation of the unligated face and bridging oxide ligand was observed. The solution structure of the MU-oxo dimer was investigated using extended X-ray absorption fine structure (EXAFS) spectroscopy. The EXAFS spectrum obtained from frozen solution was markedly different from that recorded on dried MU-oxo ferriheme solid. Inclusion of five solvent molecules obtained from spatial distribution functions in the structure generated from MD simulation was required to produce acceptable fits to the EXAFS spectra of the dimer in solution, while the solid was suitably fitted using the crystal structure of MU-oxo ferriheme dimethyl ester which included no solvent molecules. PMID- 25275881 TI - Disseminated Mucormycosis With Cerebral Involvement Owing to Rhizopus Microsporus in a Kidney Recipient Treated With Combined Liposomal Amphotericin B and Posaconazole Therapy. AB - Three months after a kidney transplant, a man experienced an internuclear ophthalmoplegia. Magnetic resonance imaging found a punctuate hyperintensity of the brainstem. Afterwards, the patient presented with peripheral facial paralysis. A complete morphologic assessment showed an increase of the brainstem lesion, together with an excavated pulmonary nodule. Combination therapy with high-dose liposomal amphotericin B and voriconazole was begun for the putative aspergillosis. Owing to its atypical clinical presentation and negative detection of Aspergillus galactomannan antigen on sera, a biopsy specimen of the lung lesion was obtained. Histopathological and mycological investigations allowed the diagnosis of mucormycosis owing to Rhizopus microsporus. Accordingly, voriconazole was replaced with posaconazole. After 5 months, regression of the cerebral lesion was noted. Disseminated mucormycosis in solid-organ recipients is uncommon and mycological diagnosis is challenging. Mortality is high and is increased by diagnostic delay. Treating mucormycosis requires surgical debridement and appropriate antifungal therapy (usually intravenous liposomal amphotericin B). This report suggests that a combination of liposomal amphotericin B and posaconazole can be a therapeutic option in patients with a poor prognosis. PMID- 25275883 TI - Cyclic voltammetric determination of free and total sulfite in muscle foods using an acetylferrocene-carbon black-poly(vinyl butyral) modified glassy carbon electrode. AB - A novel method for the selective extraction of free (pH 8.4) and total sulfite (pH 11.0) from muscle foods and the following determination by a voltammetric sensor was reported. The proposed method was based on the eletrocatalytic oxidation of sulfite at modified glassy carbon electrode (GCE) fabricated by immobilizing 9 MUg of acetylferrocene on the surface of GCE along with 35 MUg of carbon black to improve the electron transfer within poly(vinyl butyral) membrane matrix. The external standard calibration curve was linear in the range of 0.03 4.0 mmol L(-1) with a detection limit of 15 MUmol L(-1). This method had been applied to the determination of free and total sulfite in shrimp muscle fortified samples and compared with an ion chromatography method. The proposed electrode and analysis methods were proven to be sensitive, accurate, and rapid and exhibited very good reproducibility and stability under the used conditions. PMID- 25275885 TI - Label-free detection and discrimination of poly-brominated diphenylethers using molecularly imprinted photonic cross-reactive sensor arrays. AB - Molecularly imprinted photonic polymers can serve as ideal sensing elements for efficiently creating cross-reactive sensor arrays. Based on this concept, a new method for sensitive and label-free detection of challenging PBDEs was developed, by which the direct detection and discrimination of trace levels of PBDEs against a high-background of interferents was achieved with 100% accuracy. PMID- 25275886 TI - Activation of BNGR-A24 by direct interaction with tachykinin-related peptides from the silkworm Bombyx mori leads to the Gq- and Gs-coupled signaling cascades. AB - Tachykinins constitute one of the largest peptide families in the animal kingdom and exert their diverse actions via G protein-coupled receptors (GPCRs). In this study, the Bombyx tachykinin-related peptides (TKRPs) were identified as specific endogenous ligands for the Bombyx neuropeptide GPCR A24 (BNGR-A24) and thus designated BNGR-A24 as BmTKRPR. Using both mammalian cell line HEK293 and insect cell line Sf21, further characterization demonstrated that BmTKRPR was activated, thus resulting in intracellular accumulation of cAMP, Ca(2+) mobilization, and ERK1/2 phosphorylation in a Gs and Gq inhibitor-sensitive manner. Moreover, quantitative reverse transcriptase polymerase chain reaction analysis and dsRNA mediated knockdown experiments suggested a possible role for BmTKRPR in the regulation of feeding and growth. Our findings enhance the understanding of the Bombyx TKRP system in the regulation of fundamental physiological processes. PMID- 25275884 TI - In silico models for predicting vector control chemicals targeting Aedes aegypti. AB - Human arboviral diseases have emerged or re-emerged in numerous countries worldwide due to a number of factors including the lack of progress in vaccine development, lack of drugs, insecticide resistance in mosquitoes, climate changes, societal behaviours, and economical constraints. Thus, Aedes aegypti is the main vector of the yellow fever and dengue fever flaviviruses and is also responsible for several recent outbreaks of the chikungunya alphavirus. As for the other mosquito species, the A. aegypti control relies heavily on the use of insecticides. However, because of increasing resistance to the different families of insecticides, reduction of Aedes populations is becoming increasingly difficult. Despite the unquestionable utility of insecticides in fighting mosquito populations, there are very few new insecticides developed and commercialized for vector control. This is because the high cost of the discovery of an insecticide is not counterbalanced by the 'low profitability' of the vector control market. Fortunately, the use of quantitative structure-activity relationship (QSAR) modelling allows the reduction of time and cost in the discovery of new chemical structures potentially active against mosquitoes. In this context, the goal of the present study was to review all the existing QSAR models on A. aegypti. The homology and pharmacophore models were also reviewed. Specific attention was paid to show the variety of targets investigated in Aedes in relation to the physiology and ecology of the mosquito as well as the diversity of the chemical structures which have been proposed, encompassing man made and natural substances. PMID- 25275887 TI - Principal findings of systematic reviews for chronic treatment in childhood asthma. AB - OBJECTIVE: To summarize the principal findings pertaining to most effective long term pharmacologic treatment of childhood asthma. METHODS: Systematic reviews of randomized clinical trials (SRCTs) on pharmacologic chronic treatment in children (1-18 years) with persistent asthma were retrieved through MEDLINE, EMBASE, CINAHL, SCOPUS, and CDSR (up to January2014). RESULTS: One hundred eighty-three SRCTs were searched from databases. Among those, 39 SRCTs were included: two were related to step 1, 24 to step 2, nine to steps 3 and 4, and four to step 5 (according with NAEPP and GINA guidelines). The methodological quality of these SRCTs was determined by using the AMSTAR tool. RESULTS: For step 1: addition of ipatropium bromide to short-acting beta2-agonists does not show any benefit. For step 2: in preschoolers, inhaled corticosteroids (ICSs) reduce severe exacerbations and improve other clinical and lung function parameters. In children, ICSs are superior to leukotriene receptor antagonist (LTRA), cromones, or xantines in reducing severe exacerbations, improving lung function and other clinical outcomes. Fluticasone propionate (FP) is better than beclomethasone dipropionate (BDP) or budesonide only for lung function; but similar to hydrofluoroalkane-BDP or to ciclosenide. Compared to low ICSs doses, moderate doses result in only better lung function, but this is not true for FP. For steps 3 and 4: adding LTRA to ICS confers a small benefit; adding LABA improves lung function but does not reduce exacerbations more than double or higher ICS doses. For step 5: adding omalizumab decreases exacerbations. CONCLUSIONS: SRCTs are useful for guiding decisions in chronic childhood asthma treatment. PMID- 25275888 TI - Caffeine supplementation and peak anaerobic power output. AB - The aim of this study was to investigate the effects of caffeine supplementation on peak anaerobic power output (Wmax). Using a counterbalanced, randomised, double-blind, placebo-controlled design, 14 well-trained men completed three trials of a protocol consisting of a series of 6-s cycle ergometer sprints, separated by 5-min passive recovery periods. Sprints were performed at progressively increasing torque factors to determine the peak power/torque relationship and Wmax. Apart from Trial 1 (familiarisation), participants ingested a capsule containing 5 mg.kg(-1) of caffeine or placebo, one hour before each trial. The effects of caffeine on blood lactate were investigated using capillary samples taken after each sprint. The torque factor which produced Wmax was not significantly different (p >= 0.05) between the caffeine (1.15 +/- 0.08 N.m.kg(-1)) and placebo (1.13 +/- 0.10 N.m.kg(-1)) trials. There was, however, a significant effect (p < 0.05) of supplementation on Wmax, with caffeine producing a higher value (1885 +/- 303 W) than placebo (1835 +/- 290 W). Analysis of the blood lactate data revealed a significant (p < 0.05) torque factor * supplement interaction with values being significantly higher from the sixth sprint (torque factor 1.0 N.m.kg(-1)) onwards following caffeine supplementation. The results of this study confirm previous reports that caffeine supplementation significantly increases blood lactate and Wmax. These findings may explain why the majority of previous studies, which have used fixed-torque factors of around 0.75 N.m.kg(-1) and thereby failing to elicit Wmax, have failed to find an effect of caffeine on sprinting performance. PMID- 25275890 TI - Long-term prospects for the environmental profile of advanced sugar cane ethanol. AB - This work assessed the environmental impacts of the production and use of 1 MJ of hydrous ethanol (E100) in Brazil in prospective scenarios (2020-2030), considering the deployment of technologies currently under development and better agricultural practices. The life cycle assessment technique was employed using the CML method for the life cycle impact assessment and the Monte Carlo method for the uncertainty analysis. Abiotic depletion, global warming, human toxicity, ecotoxicity, photochemical oxidation, acidification, and eutrophication were the environmental impacts categories analyzed. Results indicate that the proposed improvements (especially no-til farming-scenarios s2 and s4) would lead to environmental benefits in prospective scenarios compared to the current ethanol production (scenario s0). Combined first and second generation ethanol production (scenarios s3 and s4) would require less agricultural land but would not perform better than the projected first generation ethanol, although the uncertainties are relatively high. The best use of 1 ha of sugar cane was also assessed, considering the displacement of the conventional products by ethanol and electricity. No-til practices combined with the production of first generation ethanol and electricity (scenario s2) would lead to the largest mitigation effects for global warming and abiotic depletion. For the remaining categories, emissions would not be mitigated with the utilization of the sugar cane products. However, this conclusion is sensitive to the displaced electricity sources. PMID- 25275891 TI - Phenotypic modification of human airway epithelial cells in air-liquid interface culture induced by exposure to the tobacco-specific nitrosamine 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). AB - The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogen. We used an air-liquid interface epithelial cell culture system to model changes associated with NNK exposure relative to pathologies documented in human tobacco-related illnesses. Although in vitro systems exhibit certain limitations, they often offer accentuation of subtle pathologies. While the distribution of cell types in control cultures typically favors the ciliated cell phenotype, NNK-exposed cultures transitioned to non ciliated cell phenotypes as well as reflecting features consistent with squamous metaplasia. We conclude that NNK impacts normal growth and differentiation of human airway epithelium in a short interval of time in vitro. PMID- 25275889 TI - Understanding how organized youth sport maybe harming individual players within the family unit: a literature review. AB - Within the United States, close to 45 million youths between the ages of 6 and 18 participate in some form of organized sports. While recent reviews have shown the positive effects of youth sport participation on youth health, there are also several negative factors surrounding the youth sport environment. To date, a comprehensive review of the negative physical and psychological effects of organized sport on youth has not been done and little to date has documented the effect organized sport has on other players within a family, particularly on parents and siblings. Therefore the purpose of this paper is to conduct a review of papers on the negative effects of organized sport on the youth athlete and their parents and siblings. Articles were found by searching multiple databases (Physical Education Index and Sociology, Psychology databases (Proquest), SPORTDiscus and Health, History, Management databases (EBSCOhost), Science, Social Science, Arts and Humanities on Web of Science (ISI), SCOPUS and Scirus (Elsevier). Results show the darker side of organized sport for actors within the family unit. Ideas for future research are drawn and recommendations are made to optimize the youth sport experience and family health. PMID- 25275892 TI - Synthesis of the putative structure of 15-oxopuupehenoic acid. AB - Synthesis of the putative structure of the marine natural 15-oxopuupehenoic acid has been achieved starting from commercial (-)-sclareol. Key steps of the synthetic sequence are the Robinson annulation of a beta-ketoester and methyl vinyl ketone and an unprecedented cyclization of the resulting alpha,beta-enone, which is mediated by tin(IV) chloride in the presence of N phenylselenophthalimide. The physical properties of the synthetic compound are somewhat different from those reported for the natural product. PMID- 25275893 TI - Time course of skin features and inflammatory biomarkers after liquid sulfur mustard exposure in SKH-1 hairless mice. AB - Sulfur mustard (SM) is a strong bifunctional alkylating agent that produces severe tissue injuries characterized by erythema, edema, subepidermal blisters and a delayed inflammatory response after cutaneous exposure. However, despite its long history, SM remains a threat because of the lack of effective medical countermeasures as the molecular mechanisms of these events remain unclear. This limited number of therapeutic options results in part of an absence of appropriate animal models. We propose here to use SKH-1 hairless mouse as the appropriate model for the design of therapeutic strategies against SM-induced skin toxicity. In the present study particular emphasis was placed on histopathological changes associated with inflammatory responses after topical exposure of dorsal skin to three different doses of SM (0.6, 6 and 60mg/kg) corresponding to a superficial, a second-degree and a third-degree burn. Firstly, clinical evaluation of SM-induced skin lesions using non invasive bioengineering methods showed that erythema and impairment of skin barrier increased in a dose dependent manner. Histological evaluation of skin sections exposed to SM revealed that the time to onset and the severity of symptoms including disorganization of epidermal basal cells, number of pyknotic nuclei, activation of mast cells and neutrophils dermal invasion were dose-dependent. These histopathological changes were associated with a dose- and time-dependent increase in expression of specific mRNA for inflammatory mediators such as interleukins (IL1beta and IL6), tumor necrosis factor (TNF)-alpha, cycloxygenase-2 (COX-2), macrophage inflammatory proteins (MIP-1alpha, MIP-2 and MIP-1alphaR) and keratinocyte chemoattractant (KC also called CXCL1) as well as adhesion molecules (L-selectin and vascular cell adhesion molecule (VCAM)) and growth factor (granulocyte colony stimulating factor (Csf3)). A dose-dependent increase was also noted after SM exposure for mRNA of matrix metalloproteinases (MMP9) and laminin-gamma2 which are associated with SM-induced blisters formation. Taken together, our results show that SM-induced skin histopathological changes related to inflammation is similar in SKH-1 hairless mice and humans. SKH-1 mouse is thus a reliable animal model for investigating the SM-induced skin toxicity and to develop efficient treatment against SM-induced inflammatory skin lesions. PMID- 25275896 TI - Ocular and systemic manifestations of exfoliation syndrome. AB - Exfoliation syndrome is an age-related disease characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues. It leads to the most common identifiable cause of open-angle glaucoma worldwide, comprising the majority of glaucoma in some countries. The material in the eye appears as white deposits on the anterior lens surface and/or pupillary border. During pupillary movement, the iris scrapes exfoliation material from the lens surface, while the material on the lens causes rupture of iris pigment epithelial cells, with concomitant pigment dispersion into the anterior chamber and its deposition on anterior chamber structures. Exfoliation material can be found in many different organs. It is an ischemic disease and is associated with elevated serum homocysteine. Systemic associations include transient ischemic attacks, hypertension, angina, myocardial infarction, cerebrovascular and cardiovascular disease, aortic aneurysm, Alzheimer disease, and hearing loss. The discovery in 2007 of nonsynonymous single nucleotide polymorphisms in the LOXL1 (lysyl oxidase-like 1) gene are expected to make a major impact not only in understanding exfoliation syndrome, but in leading to new avenues of therapy. PMID- 25275897 TI - The composition of exfoliation material and the cells involved in its production. AB - The hallmark of exfoliation syndrome is the pathologic production and stable accumulation of an abnormal, fibrillar, extracellular material (XFM). Although the exact biochemical composition of the pathologic matrix product is still not known, immunohistochemical and biochemical approaches have shown XFM to represent a highly glycosylated, cross-linked, and enzymatically resistant glycoprotein/proteoglycan complex, composed of a protein core surrounded by glycoconjugates. The protein core includes basement membrane components, such as laminin, nidogen, and fibronectin, and components of the elastic fiber system, such as fibrillin-1, elastin, and latent transforming growth factor binding proteins, as well as enzymatically active components, such as metalloproteinases, the extracellular chaperone clusterin, and the cross-linking enzyme lysyl oxidase like 1 (LOXL1). Ultrastructural evidence suggests that XFM is multifocally produced by intraocular cells, such as ciliary epithelial cells, preequatorial epithelial cells of the lens, trabecular and corneal endothelial cells, all cell types of the iris, as well as by extraocular cells, such as fibrocytes, vascular cells, and muscle cells. All cells involved in the exfoliation syndrome process disclosed common ultrastructural signs of active fibrillogenesis and metabolic activation, such as increased vesicular transport to the cell surface, XFM formation within infoldings of cellular surfaces, and a prominent rough endoplasmic reticulum. Finally, cells involved in the production of XFM displayed a gene expression pattern characterized by the upregulation of elastic components, the transient upregulation of LOXL1, and the dysregulated expression of cytoprotective gene products, matrix metalloproteinases, and their inhibitors, possibly leading to the accumulation and stable deposition of XFM. PMID- 25275899 TI - Biology of the extracellular matrix: an overview. AB - The extracellular matrix (ECM) is an intricate network composed of an array of multidomain macromolecules organized in a cell/tissue-specific manner. Components of the ECM link together to form a structurally stable composite, contributing to the mechanical properties of tissues. The ECM is also a reservoir of growth factors and bioactive molecules. It is a highly dynamic entity that is of vital importance, determining and controlling the most fundamental behaviors and characteristics of cells such as proliferation, adhesion, migration, polarity, differentiation, and apoptosis. PMID- 25275898 TI - The trabecular meshwork in normal eyes and in exfoliation glaucoma. AB - Trabecular meshwork (TM) and ciliary muscle contraction and relaxation function together to provide control of outflow. The active role the TM plays in the regulation of intraocular pressure (IOP) is mediated by cytoskeletal and contractility mechanisms as well as signal/transduction factors that mediate its response to stressors. This complex system is altered with age and the glaucomas, and it can be difficult to differentiate between the various etiological effects/agents. Factors such as a compromised antioxidant defense system and altered extracellular matrix metabolism are known to contribute to impaired outflow and may be common to primary open-angle glaucoma, exfoliation syndrome, and exfoliation glaucoma (XFG). Genes differentially expressed in diseased ocular tissue or in cultured HTM cell models, and thus implicated in the disease process, include SOD2, ALDH1A1, MGST1, LOX, and LOXL1, elements of the transforming growth factor-beta/bone morphogenetic protein/SMAD signaling pathways, connective tissue growth factor, matrix metalloproteinase-2, a tissue inhibitor of metalloproteinases also known as TIMP-2, and endothelin-1 (ET-1). In exfoliation syndrome and XFG fibrillar, proteinaceous extracellular material is produced in excess and accumulates in both outflow pathways but does not always lead to elevated IOP. Locally produced material may accumulate in the intertrabecular spaces, juxtacanalicular (JCT) meshwork, and the inner wall of Schlemm's canal as a result of a combination of both excessive synthesis and insufficient degradation. An increase in JCT plaque and decreased cellularity in the TM are thought to contribute to decreased outflow facility in glaucoma patients, but XFG patient specimens show reduced extracellular plaque material in the JCT, and the structural integrity of trabecular endothelial cells is mostly retained and cellularity remains unchanged. The distinctions between causes/effects of structural changes leading to reduced outflow/elevated IOP are important for developing effective, individualized treatment strategies. PMID- 25275900 TI - Glycomics, extracellular matrix, and anti-glycan antibodies in exfoliation syndrome. AB - Exfoliation syndrome (XFS) is considered to be a disease of extracellular matrix. Here we review key experimental evidence of aberrations in structure, expression, and function of glycoproteins, complex carbohydrates, and glycosaminoglycans found in extracellular matrix components forming exfoliation material in patients presenting with XFS. We hypothesize that certain components of the accumulating exfoliation material can become immunogenic, and multiple natural antibodies or autoantibodies are generated. Anti-glycan antibodies (AGAs) can be captured on Printed Glycan Array. Our preliminary results show robust immunoprofiles of AGAs in sera of patients with XFS, and the significant presence of AGAs in aqueous humor of these patients. These findings offer insight into the dynamics of AGAs during the development of XFS that could lead to the identification of the AGA based XFS immuno-signature. PMID- 25275902 TI - Microfibril-associated disorders: fibrillinopathies. PMID- 25275901 TI - Extracellular, stem cells and regenerative ophthalmology. AB - Retinal degenerative diseases, including retinitis pigmentosa, age-related macular degeneration, and glaucoma, still lack effective medical treatments. The stem cell-based regenerative approach has been proposed to treat these degenerative diseases. The major challenge for regenerative ophthalmology is to produce enough desirable retinal neurons in vitro from various stem cell types. Extracellular matrix proteins are important for stem cell self-renewal and differentiation in various systems. They have also been used in combination with various growth factors to expand retinal stem cells and produce desirable retinal neuronal types. This review summarizes our current understanding of how extracellular matrix proteins regulate stem cell function and discusses their application in regenerative ophthalmology. PMID- 25275903 TI - The blood-aqueous barrier in health and disease. AB - The blood-aqueous barrier of the eye is composed by tight junctions in the ciliary process nonpigmented epithelium, the endothelial cells in the iris vasculature, and the inner wall endothelium of Schlemm's canal. Tight junctions are gatekeepers of the paracellular transport limiting the selective diffusion of ions and small solutes through the space between neighboring cells. Tight junctions (ie, junctional adhesion molecules, claudins, occludins, zonula occludens, cingulin) are part of the apical junctional complex that also includes the adherens junctions (ie, cadherin-catenin and nectin-afadin complexes) and the gap junctions (ie, connexins). These junctional complexes respond rapidly to pharmacologic agents and physiological changes. Barrier dysfunction can contribute to the pathophysiology of inflammatory ocular diseases in a passive way by the vascular leakage of blood-borne molecules and inflammatory cells into the anterior segment of the eye. PMID- 25275904 TI - The cellular and molecular biology of the iris, an overlooked tissue: the iris and pseudoexfoliation glaucoma. AB - Located between the cornea and the lens, the Iris is fully immersed in aqueous humor. During exfoliation syndrome, a disorder of the elastic fibers, an abnormal fibrillar material (XFM) is deposited on the anterior lens capsule underneath the pigment epithelium of the Iris. Release of this material to the aqueous humor reaches the trabecular meshwork where its presence is associated with elevated intraocular pressure. Ultrastructural studies suggest that the XFM material is produced by the lens capsule, lens epithelial and iris pigment epithelial cells (IPE). The involvement of the IPE in pseudoexfoliation glaucoma has not been extensively addressed. Immunohistochemistry studies have shown higher levels of LOXL1 and clusterin in the IPE extracellular space of specimens from exfoliation patients. But studies using IPE cells to understand the formation of the XFM in vitro and/or in vivo are scarce. A focus on the Iris and its IPE cells would be key for the elucidation of XFM and the understanding of the development of pseudoexfoliation glaucoma. PMID- 25275905 TI - LOXL1-associated candidate epithelial pathomechanisms in exfoliation glaucoma. AB - Results of the present study support ocular epithelia-specific LOXL1 functions in exfoliation glaucoma that may include both dysregulated extracellular matrix cross-linking activity and cellular mechanisms involving a role for LOXL1, in direct interaction with Snail1, in promoting epithelial to mesenchymal transition and a potential shift towards fibrogenic epithelial cell phenotypes. PMID- 25275907 TI - Metabolomics/Proteomics strategies used to identify biomarkers for exfoliation glaucoma. AB - It is currently estimated that 60 to 70 million people worldwide are affected by open-angle glaucoma and the majority of patients who present to clinic have raised intraocular pressure, visual field loss, and cupping of the optic nerve. Although exfoliation glaucoma (XFG) correlates with age, it is the most common cause of secondary open-angle glaucoma in the world and, with elevated intraocular pressure at onset, this disease runs an aggressive clinical course. XFG differs from primary open-angle glaucoma, in that patients have a diminished response to medication, show accelerated rates of disease progression, and therefore have a higher need for surgery. Here we highlight some major findings in the literature, which relate to the search for biomarkers of XFG by metabolomics and proteomics strategies. PMID- 25275906 TI - Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome. AB - Exfoliation syndrome (XFS) is a complex, late-onset disorder of the elastic fiber system and the most common identifiable cause of open-angle glaucoma. Strong genetic risk is conferred by the lysyl oxidase-like 1 (LOXL1) gene, but additional comodulating factors are necessary for the manifestation of the disease. The aim of this study was to establish a comprehensive expression profile of LOXL1 and elastic proteins in XFS eyes and to analyze their regulation in an in vitro cell culture system. Eyes with XFS with and without glaucoma, and normal control eyes were analyzed for major elastic fiber components (elastin, fibrillin-1, fibulin-4), and lysyl oxidase (LOX) enzymes by real-time PCR, immunohistochemistry, and electron microscopy. Cultured human Tenon's capsule fibroblasts were exposed to transforming growth factor-beta1, IL-6, homocysteine, oxidative stress, hypoxia, or ultraviolet radiation, and changes in the expression of LOXL1 and elastic components of XFS material were assessed by real time PCR, immunohistochemistry, and Western blotting. LOXL1 expression in anterior eye tissues was significantly increased in early XFS stages but was decreased in advanced stages as compared with controls. LOXL1 was also found to be a major component of XFS material and to colocalize with elastin, fibrillin-1, and fibulin-4, which were upregulated in parallel to LOXL1. In contrast, in most posterior segment tissues, LOXL1 and elastic fiber proteins displayed no differential expression. Interestingly, lamina cribrosa specimens of early and late XFS stages without and with glaucoma revealed a selective downregulation of LOXL1 and elastic fiber components on the mRNA and protein level, which was associated with pronounced ultrastructural alterations of the laminar elastic fiber network in XFS eyes. Treatment of cultured cells with XFS-associated pathogenetic stimuli induced a significant increase in the expression of LOXL1 and elastic proteins and resulted in their assembly into XFS-like fibrils in vitro. The findings support the notion that both genetic and nongenetic factors may cooperate in the stable accumulation of XFS aggregates and provide evidence for a XFS-specific elastinopathy of the lamina cribrosa, possibly rendering XFS eyes more vulnerable to pressure-induced optic nerve damage and glaucoma development. PMID- 25275908 TI - Lysyl oxidases in the trabecular meshwork. AB - The mechanical properties of the extracellular matrix (ECM) play an important role in maintaining cellular function and overall tissue homeostasis. Emerging evidence suggests that biomechanical modifications of the ECM may be initiators and/or drivers of disease, exemplified by increased tissue stiffness. Specific ECM cross-linking enzymes (tissue transglutaminase, lysyl oxidase, and lysyl oxidase-like 1) are expressed in the trabecular meshwork and are regulated by transforming growth factor beta (TGF-beta) isoforms. As TGF-beta isoforms are elevated in the aqueous humor of glaucoma patients, trabecular meshwork stiffness mediated by ECM cross-linking may be responsible for increased aqueous humor outflow resistance and elevated intraocular pressure. PMID- 25275909 TI - Immune phenomena in glaucoma and conformational disorders: why is the second eye not involved? AB - Data along several lines of evidence have suggested that a systemic autoimmune response may be provoked in glaucoma and could contribute to retinal ganglion cell loss. If such an autoimmune response exists, one could predict that in cases of unilateral glaucoma, autoantibodies generated would affect both eyes, leading to damage in the unaffected, contralateral eye in an intraocular pressure independent manner. However, such an effect has not yet been reported. There are currently no data to reconcile these contrasting observations but a review of the literature suggests a possible explanation. PMID- 25275910 TI - Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome. AB - Variants in LOXL1 are significantly associated with exfoliation syndrome (XFS), however the impact of the associated variants on disease development is not yet understood. Initially the associated missense changes, R141L and G153D, were considered to be pathogenic alleles. Flipping of the risk allele in certain populations for both missense variants provided strong evidence that these missense changes are not biologically significant and suggest that other LOXL1 variant(s), in linkage disequilibrium with these missense variants, predispose to exfoliation syndrome by affecting gene expression or protein function. Several lines of evidence support dysregulation of LOXL1 gene expression as a contributing factor to disease development. First, in the German population the R141L (rs1048661) risk allele reduced LOXL1 expression by 20%. Second, haplotype analysis identified a risk haplotype that includes including R141L, G153D, as well as a LOXL1 promoter region variant previously shown to reduce gene expression (rs16958477). Third, the LOXL1 risk haplotype influences gene expression induced by disease-associated factors TGF-B1, oxidative stress, UV light and hypoxia. Finally, a LOXL1 null mouse has some features of XFS suggesting that decreased enzyme activity contributes to predisposition to the disease. Collectively, these results suggest that dysregulation of LOXL1 expression is a contributing factor to exfoliation disease development. PMID- 25275911 TI - Prospects for gene-environment interactions in exfoliation syndrome. AB - Complex traits can be triggered by environmental factors in genetically predisposed individuals. The lysyl oxidase-like 1 gene (LOXL1) variants associated with exfoliation syndrome (XFS) are detected in >90% of cases that have been genotyped from sites around the world. Remarkably, roughly 80% of people without XFS also possess these same variants in all populations that have been tested. Nonetheless, the prevalence of XFS varies from <=0.4% to >20%. These data suggest that other genetic variants, epigenetic modifications, or environmental factors also contribute to XFS. Furthermore, it is possible that environmental factors modify the association between LOXL1 and XFS. Interactions between LOXL1 variants and environmental factors could explain the varying prevalence of XFS seen throughout the world. At the very least, the discovery of the association between LOXL1 variants and XFS has opened the door to the discovery of environmental risk factors for this condition. Candidate gene environment interactions in XFS will be discussed. PMID- 25275913 TI - Peptide-based treatment strategies for cataract. AB - Cataract produces vision loss due to opacification of the lens. Two possible reasons for cataract formation are insolubility of crystallin proteins and fibril (aggregate) formation. Currently, the only available treatment is surgical replacement of the lens with a synthetic one. An alternative treatment that is both economically and technologically accessible is needed in developing countries where untreated cataract and coincident blindness is high, access to trained surgeons is limited, and the cost of surgery may be prohibitive. We present current progress toward the development of a nonsurgical treatment strategy focusing on promoting protein solubility and/or dissolving fibrillar aggregates. PMID- 25275912 TI - Animal models of exfoliation syndrome, now and future. AB - At present, no animal models fully embody exfoliation syndrome or exfoliation glaucoma. Both genetic and environmental factors appear critical for disease manifestation, and both must be considered when generating animal models. Because mice provide a powerful mammalian platform for modeling complex disease, this paper focuses on mouse models of exfoliation syndrome and exfoliation glaucoma. PMID- 25275914 TI - Potential drug delivery approaches for XFS-associated and XFS-associated glaucoma. AB - Key tissue targets in treating exfoliation syndrome (XFS) and the associated glaucoma include lens, iris, and ciliary body, which produce the exfoliative material, and the trabecular meshwork, which may be impaired by the exfoliative material. In addition to antiglaucoma drug therapy, strategies for treating the disease include approaches for preventing formation of exfoliative material as well as those aimed at digesting exfoliative material. A variety of drug molecules including small molecules, protein drugs, and nucleic acids are potential candidates for treating XFS. Potential drug classes include antioxidants, lysyl oxidase-like 1 enhancers, antifibrotics, anti-inflammatory agents, proteases, and chaperones. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye. Thus, unique drug delivery approaches are needed for each drug type (small molecules, proteins, and nucleic acids). In addition, there is a need for sustaining drug therapy for treating XFS, which can potentially be addressed by using nanoparticles, microparticles, implants, and contact lens delivery systems. This article provides an overview of drug delivery challenges and opportunities in treating XFS with the focus being on nanomedicines. PMID- 25275915 TI - Noninvasive ocular drug delivery: potential transcorneal and other alternative delivery routes for therapeutic molecules in glaucoma. AB - Drug delivery to the eye is made difficult by multiple barriers (such as the tear film, cornea, and vitreous) between the surface of the eye and the treatment site. These barriers are difficult to surmount for the purposes of drug delivery without causing toxicity. Using nanotechnology tools to control, manipulate, and study delivery systems, new approaches to delivering drugs, genes, and antigens that are effective and safe can be developed. Topical administration to the ocular surface would be the safest method for delivery, as it is noninvasive and painless compared with other delivery methods. However, there is only limited success using topical delivery methods, especially for gene therapy. Current thinking on treatments of the future enabled by nanodelivery systems and the identification of target specificity parameters that require deeper understanding to develop successful topical delivery systems for glaucoma is highlighted. PMID- 25275916 TI - Exfoliation syndrome and systemic cardiovascular diseases. AB - Exfoliation syndrome (XFS) is a systemic condition. Intraocular alterations represent only a part of the exfoliation-related clinical signs. Exfoliation material has been identified in the visceral organs, skin, and vessel walls. This triggered several studies that investigated association between XFS and cardiovascular diseases. In many populations, significant associations between XFS and various systemic vascular diseases including elevated plasma homocysteine level, myocardial dysfunction, stroke, aortic aneurysm, and white matter lesions were found. Some of these XFS-associated vascular diseases are caused by elastosis of the vessel wall, which may be directly related to general extracellular dysfunction in XFS. Another part of the pathologic vascular alterations (reduced cutaneous capillary flow reactions, impaired baroreflex sensitivity, parasympathetic cardiovascular neuropathy, and pathologic heart rate variability indices), however, suggests that vascular dysregulation beyond the age-related normal decline may also play a role both in the development and worsening of the systemic cardiovascular diseases in XFS. The exact mechanism of the development of systemic vascular dysregulation associated with XFS is currently unknown. PMID- 25275918 TI - Lignin cross-links with cysteine- and tyrosine-containing peptides under biomimetic conditions. AB - The work presented here investigates the cross-linking of various nucleophilic amino acids with lignin under aqueous conditions, thus providing insight as to which amino acids might cross-link with lignin in planta. Lignin dehydrogenation polymer (DHP) was prepared in aqueous solutions that contained tripeptides with the general structure XGG, where X represents an amino acid with a nucleophilic side chain. Fourier-transform infrared spectroscopy and energy dispersive X-ray spectroscopy showed that peptides containing cysteine and tyrosine were incorporated into the DHP to form DHP-CGG and DHP-YGG adducts, whereas peptides containing other nucleophilic amino acids were not incorporated. Scanning electron microscopy showed that the physical morphology of DHP was altered by the presence of peptides in the aqueous solution, regardless of peptide incorporation into the DHP. Nuclear magnetic resonance (NMR) spectroscopy showed that cysteine containing peptide cross-linked with lignin at the lignin alpha-position, whereas in the case of the lignin-tyrosine adduct the exact cross-linking pathway could not be determined. This is the first study to use NMR to confirm cross-linking between lignin and peptides under biomimetic conditions. The results of this study may indicate the potential for lignin-protein linkage formation in planta, particularly between lignin and cysteine- and/or tyrosine-rich proteins. PMID- 25275919 TI - Molecular dynamics investigation of the adhesion mechanism acting between dopamine and the surface of dopamine-processed aramid fibers. AB - Dopamine, as a universal material for surface treatment, can effectively improve the surface performance of aramid fibers. However, directly processing the surface of aramid fibers using dopamine currently incurs a high cost. To seek dopamine substitutes, one must first explore the adhesion mechanism responsible for binding the dopamine to the surface of the fiber. In this study, we construct an all-atomic molecular dynamics model of an aramid fiber before and after surface modification using dopamine. A force field based on condensed-phase optimized molecular potentials for atomistic simulation studies (COMPASS) is used. Using it, we analyze the surface adhesion mechanism of polydopamines aggregated by 21 kinds of molecular structures typically found on the surface of aramid fibers. The results show that a clear and smooth interface is formed between the polydopamine nanofilm layer and the surface of the aramid fiber. The high atomic density of the polydopamine in the small interface region is found to be conducive to noncovalent bonds of polydopamines with the surface of the aramid fiber. In addition, we investigate the works of adhesion of the 21 molecular structures typically found on the surface of aramid fibers. The results suggest that the work of adhesion of 5,6-indolequinone is the highest, followed by annular eumelanin molecules with annular planar structure. Straight-chain shaped dimers proved to be the molecules with the highest adhesion ability of the dihydroxyindole chain oligomers. Therefore, there is reason to suppose that more molecular structures (as above) can be formed by processing the surface of aramid fibers using dopamine by controlling the processing conditions. These molecular structures help improve the adhesion ability of the dopamine on the surface of the aramid fiber. Additionally, if these polydopamine molecules with high adhesion ability can be synthesized on a large scale, then new surface-processing materials are possible. PMID- 25275920 TI - Biosynthesis of antimycins with a reconstituted 3-formamidosalicylate pharmacophore in Escherichia coli. AB - Antimycins are a family of natural products generated from a hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line. Although they possess an array of useful biological activities, their structural complexity makes chemical synthesis challenging, and their biosynthesis has thus far been dependent on slow-growing source organisms. Here, we reconstituted the biosynthesis of antimycins in Escherichia coli, a versatile host that is robust and easy to manipulate genetically. Along with Streptomyces genetic studies, the heterologous expression of different combinations of ant genes enabled us to systematically confirm the functions of the modification enzymes, AntHIJKL and AntO, in the biosynthesis of the 3-formamidosalicylate pharmacophore of antimycins. Our E. coli-based antimycin production system can not only be used to engineer the increased production of these bioactive compounds, but it also paves the way for the facile generation of novel and diverse antimycin analogues through combinatorial biosynthesis. PMID- 25275921 TI - Expression kinetics of metalloproteinases and their tissue inhibitors in experimental murine pulmonary tuberculosis. AB - AIM: Explore the temporal expression of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during experimental tuberculosis induced by virulent Mycobacterium tuberculosis strain H37Rv. METHODS: BALB/c mice were infected via endotracheal instillation with H37Rv. Groups of mice were euthanized at different time points during infection. RNA was isolated from the lungs, and the expression of MMP-3, 8, 9, 10, 12, 13 and TIMP-1-4 was determined by quantitative PCR. Immunohistochemical detection of MMP-3, MMP-9, and MMP-10 was done to determine the cell source. RESULTS: The infection with H37Rv-induced inflammation resulted in maximal up-regulation of MMP-3, 8, 9, 10, 12 and 13 at day 21 postinfection. Additionally, MMP-13 showed another expression peak during late disease at day 60. Airway epithelium and macrophages were the most common MMP-3 and MMP-9 immunopositive cells, while for MMP-10, macrophages and endothelial cells were the most common, particularly at days 14 and 21 in well formed granulomas. During late disease, vacuolated macrophages in pneumonic areas and bronchial epithelium showed mild MMP immunostaining. CONCLUSIONS: MMP-3, 8, 9, 10, 12, and 13 are maximally expressed at the peak of granuloma formation in the mouse tuberculosis model, with no compensation in levels or timing of TIMP expression. This data opens the possibility of participation of these molecules in the granuloma process. PMID- 25275922 TI - Egg sampling as a possible alternative to blood sampling when monitoring the exposure of yellow-legged gulls (Larus michahellis) to avian influenza viruses. AB - We explored whether antibody detection in egg yolks could serve as an alternative to antibody detection in plasma samples when monitoring yellow-legged gulls (Larus michahellis) for exposure to avian influenza viruses (AIVs). We tested female plasma and eggs for anti-AIV antibodies and used the data we obtained to check whether the two sample types yielded the same antibody status (positive or negative) and to compare the antibody prevalence estimated from the blood data with that estimated from the yolk data. Our results showed that sampling one egg per clutch, regardless of that egg's position in the laying sequence, is sufficient to provide an unbiased estimate of antibody prevalence across clutches. The results also showed that almost 25% of the clutches laid by positive females contained only antibody-negative eggs, which suggests that yolk samples might underestimate female antibody prevalence. However, this result may stem from differences in the methods used to assess plasma versus yolk antibody status. Further research is needed to clarify this issue; while the number of false negatives could be reduced by adapting antibody detection techniques, it may be that they are an unavoidable consequence of natural avian maternal transfer dynamics. PMID- 25275923 TI - Reversible tuning of chemical structure of Nafion cast film by heat and acid treatment. AB - Effects of annealing have been studied on the chemical structure, water uptake, and acidity of the cast Nafion thin film of thickness ~ 6 MUm using a fluorescent probe, 2-(3'-pyridyl)benzimidazole (3PBI), and attenuated total reflactance infrared (ATR-IR) spectroscopy. Nonannealed films and thick Nafion 117 membrane have been used as reference materials, in order to develop a complete understanding of the effect. Annealing has been found to cause a decrease in acidity of otherwise highly acidic ionomer, as sensed by the fluorescent probe and loss of water, as reflected in the ATR-IR spectrum. This observation is surprising and cannot be explained in the light of previous reports of physical changes. Our ATR-IR study has revealed changes in the chemical structure of the hydrophilic part of the ionomer, leading to the formation of sulfonic acid anhydrides. This phenomenon can rationalize the decreased acidity reported in our fluorescence study. Interestingly, acid treatment of the annealed film restores the acidity of the unannealed films. This cannot be rationalized simply by a greater proton uptake from the solution, as the film has to be electroneutral. It appears that the anhydrides formed during the annealing process undergo acid hydrolysis, leading to an increase in the number of SO3(-) groups and, consequently, an increase in the number of H3O(+) ions in the water channels. Besides, the films can be hydrated to an extent that is much greater than Nafion membranes, but the water uptake of acid treated annealed film is slightly less than that of nonannealed films. Hence, we conclude that, along with annealing, acid treatment, a procedure that is generally not performed on the cast films, is an important pretreatment procedure to improve the acidity and hence the transport properties of the cast film. PMID- 25275924 TI - A liquid contact line receding on a soft gel surface: dip-coating geometry investigation. AB - We studied the dynamics of a liquid contact line receding on a hydrophobic soft gel (SBS-paraffin). In order to realize a well-defined geometry with an accurate control of velocity, a dip-coating setup was implemented. Provided that the elastic modulus is small enough, a significant deformation takes place near the contact line, which in turn drastically influences the wetting behaviour. Depending on the translation velocity of the substrate, the contact line exhibits different regimes of motions. Continuous motions are observed at high and low velocities, meanwhile two types of stick-slip motion - periodic and erratic - appear at intermediate velocities. We suggest that the observed transitions could be explained in terms of the competition between different frequencies, i.e., the frequency of the strain field variation induced by the contact line motion and the crossover frequency of the gel related to the material relaxation. Our results provide systematic views on how the wetting of liquid is modified by the rheological properties of a complex soft substrate. PMID- 25275925 TI - Self-assembly micelles with lipid core of cholesterol for docetaxel delivery to B16F10 melanoma and HepG2 cells. AB - The objective of the present study was to prepare a micellar polymeric carrier for the delivery of Docetaxel (DTX) as a kind of polysorbate free preparation. Pluronic F127 (PF127) was conjugated to cholesterol (Chol) via succinyl linkage and characterized by FTIR and HNMR. DTX-loaded polymeric micelles were prepared via film hydration method. Physicochemical properties of micelles including particle size, zeta potential, drug loading and release efficiency were studied. The critical micelle concentration (CMC) was determined using pyrene as a hydrophobic fluorescent probe. In vitro cytotoxicity of micelles was evaluated in B16F10 melanoma cells and HepG2 cell line. The FTIR and HNMR spectroscopy methods confirmed the conjugation of PF127 to cholesterol via succinyl linkage. The micelles were spherical under scanning electron microscope (SEM) with the mean particle size of 248.2 +/- 8-278.8 +/- 12.3 nm and zeta potential ranging from 17.2 +/- 8.7 to -28.4 +/- 12.7 mV. Drug loading efficiency was higher than 98%. The in vitro release study showed the sustained release behavior of DTX within 144 h. The CMC of the micelles was about 41.67 +/- 0.17 ug/ml, which was significantly lower than the CMC of pure PF127 micelles. Compared with the free drug, DTX-loaded micelles showed higher cytotoxicity against B16F10 melanoma and HepG2 cell lines. PMID- 25275927 TI - Synthesis and characterization of heterobimetallic complexes with direct Cu-M bonds (M = Cr, Mn, Co, Mo, Ru, W) supported by N-heterocyclic carbene ligands: a toolkit for catalytic reaction discovery. AB - Building upon the precedent of catalytically active (NHC)Cu-FeCp(CO)2 complexes, a series of (NHC)Cu-[M] complexes were synthesized via the addition of Na(+)[M]( ) reagents to (NHC)CuCl synthons. The different [M](-) anions used span a range of 7 * 10(7) relative nucleophilicity units, allowing for controlled variation of nucleophile/electrophile pairing in the heterobimetallic species. Direct Cu-M bonds (M = Cr, Mn, Co, Mo, Ru, W) formed readily when the bulky IPr carbene was used as a support. Crystallographic characterization and computational examination of these complexes was conducted. For the smaller IMes carbene, structural isomerism was observed when using the weakest [M](-) nucleophiles, with (IMes)Cu-[M] and {(IMes)2Cu}{Cu[M]2} isomers being observed in equilibrium. Collectively, the series of complexes provides a toolbox for catalytic reaction discovery with precise control of structure-function relationships. PMID- 25275926 TI - Lung Angiogenesis Requires CD4(+) Forkhead Homeobox Protein-3(+) Regulatory T Cells. AB - Angiogenesis in ischemic organs is modulated by immune cells. Systemic neovascularization of the ischemic lung requires macrophages, with chemokines playing a central role in new vessel growth. Because regulatory T (Treg) cells modulate tumor-induced neovascularization, we questioned whether this CD4(+) lymphocyte subset impacts blood vessel growth during ischemia. In a model of left lung ischemia, an increase in CD4(+) CD25(+) forkhead homeobox protein-3 (Foxp3)(+) cells was observed 3-5 days after the onset of ischemia in wild-type C57Bl/6 mice. Using transgenic mice where Foxp3(+) Treg cells can be depleted with diphtheria toxin (DT; Foxp3(DTR)), we unexpectedly found that Foxp3(+) Treg depletion led to markedly reduced lung angiogenesis (90% reduction from Foxp3(gfp) controls). Adoptive transfer studies using CD4(+) CD25(+) splenocytes from congenic CD45.1 mice into Foxp3(+) Treg-depleted mice showed an almost complete recovery of the angiogenic phenotype (80% of Foxp3(gfp) controls). A survey of lung gene expression of angiogenic (lipopolysaccharide-induced CXC chemokine [LIX], IL-6, IL-17) and angiostatic (IFN-gamma, transforming growth factor-beta, IL-10) cytokines showed Treg-dependent differences only in LIX (CXCL5) and IL-6. Protein confirmation demonstrated a significant reduction in LIX in Treg-deficient mice compared with controls 5 days after the onset of ischemia. Phenotyping other inflammatory cells in the lung by multicolor flow cytometry demonstrated a significantly reduced number of macrophages (major histocombatibility complex class II [MHCII](int), CD11C(+)) in Treg-deficient lungs compared with Treg-sufficient lungs. Treg cells are essential for maximal systemic angiogenesis after pulmonary ischemia. One likely mechanism responsible for the decrease in angiogenesis in Treg-depleted mice was the decline in the essential CXC chemokine, LIX. PMID- 25275928 TI - Visible-light-assisted electrocatalytic oxidation of methanol using reduced graphene oxide modified Pt nanoflowers-TiO2 nanotube arrays. AB - In this work, Pt nanoflowers deposited on highly ordered TiO2 nanotube arrays (TNTs) by modification of reduced graphene oxide (RGO) nanostructures have been synthesized. The ternary complex (Pt-TNTs/RGO) displays efficient electrocatalytic performance toward methanol oxidation in alkaline medium. The electrochemical impedance spectroscopy (EIS) and responsive photocurrent results indicate that the presence of graphene could effectively promote charge separation during electrocatalytic process. Interestingly, with assistance of visible light illumination, the electrocatalytic activity and stability of the ternary complex electrode toward methanol oxidation are distinctly improved. Both electro- and photo-catalytic processes for methanol oxidation contribute to the enhanced catalytic performance and stability. Moreover, the ternary electrode also displays efficient photoelectrocatalytic degradation of methylene blue (MB) under visible light illumination. The present work sheds light on developing highly efficient and long-term stability catalysts for methanol oxidation with assistance of visible-light illumination. PMID- 25275929 TI - Utilization of CO2 fixating bacterium Actinobacillus succinogenes 130Z for simultaneous biogas upgrading and biosuccinic acid production. AB - Biogas is an attractive renewable energy carrier. However, it contains CO2 which limits its use for certain applications. Here we report a novel approach for removing CO2 from biogas and capturing it as a biochemical through a biological process. This approach entails converting CO2 into biosuccinic acid using the bacterial strain Actinobacillus succinogenes 130 Z, and simultaneously producing high-purity CH4 (> 95%). Results showed that when pressure during fermentation was increased from 101.325 to 140 kPa, higher CO2 solubility was achieved, thereby positively affecting final succinic acid yield and titer, CO2 consumption rate, and CH4 purity. When using biogas as the only CO2 source at 140 kPa, the CO2 consumption rate corresponded to 2.59 L CO2 L(-1) d(-1) with a final succinic acid titer of 14.4 g L(-1). Under this pressure condition, the highest succinic acid yield and biogas quality reached corresponded to 0.635 g g(-1) and 95.4% (v v(-1)) CH4 content, respectively, after 24 h fermentation. This work represents the first successful attempt to develop a system capable of upgrading biogas to vehicle fuel/gas grid quality and simultaneously produce biosuccinic acid, a valuable building block with large market potential in the near term. PMID- 25275930 TI - Plasmonic nanosnowmen with a conductive junction as highly tunable nanoantenna structures and sensitive, quantitative and multiplexable surface-enhanced Raman scattering probes. AB - The precise design and synthesis of plasmonic nanostructures allow us to manipulate, enhance, and utilize the optical characteristics of metallic materials. Although many multimeric structures (e.g., dimers) with interparticle nanogap have been heavily studied, the plasmonic nanostructures with a conductive junction have not been well studied mostly because of the lack of the reliable synthetic methods that can reproducibly and precisely generate a large number of the plasmonic nanostructures with a controllable conductive nanojunction. Here, we formed various asymmetric Au-Ag head-body nanosnowman structures with a highly controllable conductive nanojunction and studied their plasmon modes that cover from visible to near-infrared range, electromagnetic field enhancement, and surface-enhanced Raman scattering (SERS) properties. It was shown that change in the plasmonic neck region between Au head and Ag body nanoparticles and symmetry breaking using different sizes and compositions within a structure can readily and controllably introduce various plasmon modes and change the electromagnetic field inside and around a nanosnowman structure. The charge-transfer and capacitive coupling plasmon modes at low frequencies are tunable in the snowman structure, and subtle change in the conductive junction area of the nanosnowman dramatically affects the resulting electromagnetic field and optical signal. The relationships between the electromagnetic field distribution and enhancement in the snowman structure, excitation laser wavelength, and Raman dye were also studied, and it was found that the strongest electromagnetic field was observed in the crevice area on the junction and synthesizing a thinner and sharper neck junction is critical to generate the stronger electromagnetic field in the crevice area and to obtain the charge-transfer mode-based near-infrared signal. We have further shown that highly reproducible SERS signals can be generated from these nanosnowman structures with a linear dependence on particle concentration (5 fM to 1 pM) and the SERS-enhancement factor values of >10(8) can be obtained with the aid of the resonance effect in SERS. Finally, a wide range of LSPR bands with high tunability along with high structural reproducibility and high synthetic yield make the nanosnowman structures as very good candidates for practically useful multiple-wavelength-compatible, quantitative and sensitive SERS probes, and highly tunable nanoantenna structures. PMID- 25275932 TI - Suspicion of heparin-induced thrombocytopenia in internal medicine: How appropriate is the ordering of anti-PF4/heparin antibody testing? AB - Thrombocytopenia is frequent in hospitalized patients, and heparin-induced thrombocytopenia (HIT) is often suspected when a decrease in platelet count is concomitant with heparin treatment. ELISA tests used for anti-PF4/heparin antibodies detection usually have high sensitivity but only fair specificity for HIT. Pre-test probability scores (such as 4 Ts or HEP scores) have been validated and a low probability score rules out HIT without anti-PF4/heparin testing. The aims of this study are to evaluate the appropriateness of anti-PF4/heparin testing according to pre-test probabilities of HIT and to compare the abilities of the 4 Ts and HEP scores to avoid inappropriate anti-PF4/heparin testing. This retrospective observational study included 74 consecutive patients hospitalized in a general internal medicine division who had anti-PF4/heparin testing for suspicion of HIT. 4 Ts and HEP scores were computed retrospectively. About 73% of patients who had ordering of an anti-PF4/heparin were at low risk according to the 4 Ts score, and 46% according to the HEP score. Heparin was discontinued in 61% and 62% of low-risk patients according to 4 Ts and HEP scores and switched to alternative anticoagulant in 31% and 32% of them, respectively. No case of HIT was diagnosed in patients with a low-risk score. One major bleeding and no thrombosis were observed. For the 4 Ts score, the sensitivity was 100%, the negative predictive value (NPV) was 100%, the specificity was 77%, and the positive predictive value (PPV) was 20% (95% CI: 7-44). For the HEP score, the sensitivity was 100%, the NPV was 100%, the specificity was 49%, and the PPV was 10%. In conclusion, pre-test probability scores were vastly underused in this internal medicine population despite their ability to rule out HIT without laboratory testing in a large proportion of patients. Appropriate use of those instruments should be actively promoted. PMID- 25275931 TI - Rethinking fat as a fuel for endurance exercise. AB - A key element contributing to deteriorating exercise capacity during physically demanding sport appears to be reduced carbohydrate availability coupled with an inability to effectively utilize alternative lipid fuel sources. Paradoxically, cognitive and physical decline associated with glycogen depletion occurs in the presence of an over-abundance of fuel stored as body fat that the athlete is apparently unable to access effectively. Current fuelling tactics that emphasize high-carbohydrate intakes before and during exercise inhibit fat utilization. The most efficient approach to accelerate the body's ability to oxidize fat is to lower dietary carbohydrate intake to a level that results in nutritional ketosis (i.e., circulating ketone levels >0.5 mmol/L) while increasing fat intake for a period of several weeks. The coordinated set of metabolic adaptations that ensures proper interorgan fuel supply in the face of low-carbohydrate availability is referred to as keto-adaptation. Beyond simply providing a stable source of fuel for the brain, the major circulating ketone body, beta hydroxybutyrate, has recently been shown to act as a signalling molecule capable of altering gene expression, eliciting complementary effects of keto-adaptation that could extend human physical and mental performance beyond current expectation. In this paper, we review these new findings and propose that the shift to fatty acids and ketones as primary fuels when dietary carbohydrate is restricted could be of benefit for some athletes. PMID- 25275934 TI - A pilot study on the Psoriasis Area and Severity Index (PASI) for small areas: Presentation and implications of the Low PASI score. AB - BACKGROUND: The Psoriasis Area and Severity Index (PASI) is not able to measure small affected areas in a body region which is important for assessing the performance of high-effective treatment. OBJECTIVE: To present the Low PASI score, show the difference between the classic PASI and the Low PASI, evaluate the inter-observer agreement of both scores, and compare the two scores within investigators. METHODS: Cross-sectional study. Two investigators independently assessed the classic PASI and the Low PASI in 10 patients with mild-to-moderate plaque psoriasis. Differences in outcome between the two scores were calculated. Intra-class correlation coefficients (ICC) were used to determine the inter observer agreement and to compare measurements of the two scores within both investigators. Prediction limits of 95% for the errors in measurements were provided. RESULTS: In both investigators, Low PASI was mean 1.71 and 1.76, whereas the classic PASI was mean 4.14 and 4.33. The inter-observer agreement (ICC) was excellent for both investigators in both scores (ICC classic PASI = 0.95 and Low PASI = 0.87). CONCLUSION: The Low PASI score allows more possible scores at lower levels of psoriasis extent (affected areas lower than 10% in a body region) compared to the classic PASI. This new score may lead to a more precise analysis of treatment responses and may have important clinical implications. PMID- 25275933 TI - Characterizing self-reported sleep disturbance after mild traumatic brain injury. AB - Sleep disturbance after mild traumatic brain injury (mTBI) is commonly reported as debilitating and persistent. However, the nature of this disturbance is poorly understood. This study sought to characterize sleep after mTBI compared with a control group. A cross-sectional matched case control design was used. Thirty three persons with recent mTBI (1-6 months ago) and 33 age, sex, and ethnicity matched controls completed established questionnaires of sleep quality, quantity, timing, and sleep-related daytime impairment. The mTBI participants were compared with an independent sample of close-matched controls (CMCs; n = 33) to allow partial internal replication. Compared with controls, persons with mTBI reported significantly greater sleep disturbance, more severe insomnia symptoms, a longer duration of wake after sleep onset, and greater sleep-related impairment (all medium to large effects, Cohen's d > 0.5). No differences were found in sleep quantity, timing, sleep onset latency, sleep efficiency, or daytime sleepiness. All findings except a measure of sleep timing (i.e., sleep midpoint) were replicated for CMCs. These results indicate a difference in the magnitude and nature of perceived sleep disturbance after mTBI compared with controls, where persons with mTBI report poorer sleep quality and greater sleep-related impairment. Sleep quantity and timing did not differ between the groups. These preliminary findings should guide the provision of clearer advice to patients about the aspects of their sleep that may change after mTBI and could inform treatment selection. PMID- 25275936 TI - Nanoparticles based on naturally-occurring biopolymers as versatile delivery platforms for delicate bioactive molecules: an application for ocular gene silencing. AB - Nanoparticles based on naturally-occurring biopolymers, most of them endogenous macromolecules, were designed as a versatile generation of delivery platforms for delicate bioactive molecules. The design of these nanosystems was specifically based on our recent finding about the ability of endogenous polyamine spermine (SPM) to interact with anionic biopolymers (ABs) generating ionically cross linked nanosystems. The initial first generation of these delivery platforms, based on glycosaminoglycans and other polysaccharides, showed a very high association capacity for some delicate bioactive proteins such as growth factors, but a limited capacity to associate negatively charged molecules, such as pDNA and siRNA. However, the versatility of these nanosystems in terms of composition allowed us to customise the association of active ingredients and their physicochemical characteristics. Concretely, we prepared and incorporated gelatine cationized with spermine (CGsp) to their composition. The resulting modified formulations were characterised by a nanometric size (150-340 nm) and offer the possibility to modulate their zeta potential (from -35 to 28 mV), providing an efficient association of nucleic acids. The biological evaluation of these optimised nanosystems revealed that they are able to be internalised in vivo into corneal and conjunctival tissues and also to provide a significant siRNA gene silencing effect. PMID- 25275938 TI - Preparation, characteristics and assessment of a novel gelatin-chitosan sponge scaffold as skin tissue engineering material. AB - In order to develop a skin tissue engineering material for wound dressing application, a novel gelatin-chitosan sponge scaffold was designed and studied. The effect of chitosan and gelatin ratio on the morphology, pore size, porosity, water uptake capacity, water retention capacity and the degradation behavior were evaluated. Biocompatibility was investigated by both MTT method and AO/EB staining method. Antibacterial assessment and in vivo pharmacodynamic was also studied to evaluate the potential for wound healing. Results showed the sponge scaffold have uniform porous structure with pore size range between 120 and 140 MUm, high porosity (>90%), high water uptake capacity (>1500%), high water retention capacity (>400%), and degradation percent in 28 days between 38.3 and 53.9%. Biocompatibility results showed that the activity of cells could not be affected by the nature of the sponge and it was suitable for cell adhesion and proliferation for 21 days. In vivo evaluation indicated that the sponge scaffold could offer effective support and attachment to cells for skin wound healing. In conclusion, the developed sponge scaffold was a potential skin tissue engineering material with appropriate physical properties and good biocompatibility. PMID- 25275937 TI - Fused-filament 3D printing (3DP) for fabrication of tablets. AB - The use of fused-filament 3D printing (FF 3DP) to fabricate individual tablets is demonstrated. The technology permits the manufacture of tablets containing drug doses tailored to individual patients, or to fabrication of tablets with specific drug-release profiles. Commercially produced polyvinyl alcohol (PVA) filament was loaded with a model drug (fluorescein) by swelling of the polymer in ethanolic drug solution. A final drug-loading of 0.29% w/w was achieved. Tablets of PVA/fluorescein (10 mm diameter) were printed using a 3D printer. It was found that changing the degree of infill percentage in the printer software varied the weight and volume of the printed tablets. The tablets were mechanically strong and no significant thermal degradation of the active occurred during printing. Dissolution tests were conducted in modified Hank's buffer. The results showed release profiles were dependent on the infill percentage used to print the tablet. The study indicates that FF 3DP has the potential to offer a new solution for fabricating personalized-dose medicines or unit dosage forms with controlled release profiles. In addition, the low cost of FDM printers means the paradigm of extemporaneous or point-of-use manufacture of personalized-dose tablets is both feasible and attainable. PMID- 25275940 TI - Synthesis of highly substituted adamantanones from bicyclo[3.3.1]nonanes. AB - Trifluoromethanesulfonic acid and other electrophiles promote formation of the adamantanone core from the readily accessible 1,5-dimethyl-3,7 dimethylenebicyclo[3.3.1]nonan-9-one 2. Because adamantyl cation 3 can be trapped by a range of nucleophiles, including aromatic and heteroaromatic rings, alcohol, nitriles, and halides, access to a wide variety of functionality at the newly formed tertiary position is provided. PMID- 25275939 TI - Visceral mesh modified with cyclodextrin for the local sustained delivery of ropivacaine. AB - The aim of the study was to develop a polyester visceral implant modified with a cyclodextrin polymer for the local and prolonged delivery of ropivacaine to reduce post operatory pain. Therefore, we applied a coating of an inguinal mesh with a crosslinked polymer of hydroxypropyl-beta-cyclodextrin (HPbetaCD) whose specific host-guest complex forming properties were expected to improve the adsorption capacity of the implant toward anesthetic, and then to release it within a sustained period. The modification reaction of the textile with cyclodextrin was explored through the study of the influence of the pad/dry/cure process parameters and the resulting implant (PET-CD) was characterized by solid state NMR and SEM. Besides, the inclusion complex between ropivacaine and CD was studied by NMR and capillary electrophoresis in PBS medium. Finally, ropivacaine sorption test showed that a maximum of 30 mg/g of ropivacaine could be adsorbed on the functionalized samples. In dynamic batch tests in PBS at pH 7.4, the release could be observed up to 6h. The cytocompatibility of the PET-CD loaded with ropivacaine was also studied and reached 65% cell vitality after 6 days. PMID- 25275942 TI - Apoptotic gene expression in sinecatechins-treated external genital and perianal warts. PMID- 25275941 TI - Single-step plasma synthesis of carbon-coated silicon nanoparticles. AB - We have developed a novel single-step technique based on nonthermal, radio frequency (rf) plasmas to synthesize sub-10 nm, core-shell, carbon-coated crystalline Si (c-Si) nanoparticles (NPs) for potential application in Li(+) batteries and as fluorescent markers. Hydrogen-terminated c-Si NPs nucleate and grow in a SiH4-containing, low-temperature plasma in the upstream section of a tubular quartz reactor. The c-Si NPs are then transported downstream by gas flow, and are coated with amorphous carbon (a-C) in a second C2H2-containing plasma. X ray diffraction (XRD), X-ray photoelectron spectroscopy, and in situ attenuated total reflection Fourier transform infrared spectroscopy show that a thin, < 1 nm, 3C-SiC layer forms at the c-Si/a-C interface. By varying the downstream C2H2 plasma rf power, we can alter the nature of the a-C coating as well as the thickness of the interfacial 3C-SiC layer. The transmission electron microscopy (TEM) analysis is in agreement with the Si NP core size determined by Raman spectroscopy, photoluminescence spectroscopy, and XRD analysis. The size of the c Si NP core, and the corresponding light emission from these NPs, was directly controlled by varying the thickness of the interfacial 3C-SiC layer. This size tunable emission thus also demonstrates the versatility of this technique for synthesizing c-Si NPs for potential applications in light emitting diodes, biological markers, and nanocrystal inks. PMID- 25275943 TI - Two-Dimensional Vibrational Spectroscopy of a Dissipative System with the Optimized Mean-Trajectory Approximation. AB - The optimized mean-trajectory (OMT) approximation is a semiclassical method for computing vibrational response functions from action-quantized classical trajectories connected by discrete transitions representing radiation-matter interactions. Here we apply this method to an anharmonic chromophore coupled to a harmonic bath. A forward-backward trajectory implementation of the OMT method is described that addresses the numerical challenges of applying the OMT to large systems with disparate frequency scales. The OMT is shown to well reproduce line shapes and waiting time dynamics in the pure dephasing limit of weak coupling to an off-resonant bath. The OMT is also shown to describe a case where energy transfer is the predominant source of line broadening. PMID- 25275944 TI - Precursor-directed biosynthesis of 5-hydroxytryptophan using metabolically engineered E. coli. AB - A novel biosynthetic pathway was designed and verified reversely leading to the production of 5-hydroxytryptophan (5-HTP) from glucose. This pathway takes advantage of the relaxed substrate selectivities of relevant enzymes without employing the unstable tryptophan 5-hydroxylase. First, high-titer of 5-HTP was produced from 5-hydroxyanthranilate (5-HI) by the catalysis of E. coli TrpDCBA. Then, a novel salicylate 5-hydroxylase was used to convert the non-natural substrate anthranilate to 5-HI. After that, the production of 5-HI from glucose was achieved and optimized with modular optimization. In the end, we combined the full pathway and adopted a two-stage strategy to realize the de novo production of 5-HTP. This work demonstrated the application of enzyme promiscuity in non natural pathway design. PMID- 25275945 TI - Chemopreventive effect of phosphodieasterase-4 inhibition in benzo(a)pyrene induced murine lung cancer model. AB - PURPOSE: Cigarette smoking increases chronic airway inflammation, oxidative stress, and epithelial mesenchymal transition (EMT), which may result in chronic obstructive pulmonary disease (COPD) and tumor growth in the lung. Phosphodiesterase 4 (PDE4) inhibitors are known to reduce inflammation, and they have recently been introduced for the treatment of COPD. We assessed the impact of rolipram, a selective PDE4 inhibitor, on chemoprevention in benzo(a)pyrene induced lung cancer in mice. MATERIALS AND METHODS: Female A/J mice were given a single dose of benzo(a)pyrene. Intraperitoneal administration of rolipram began 2 weeks post-carcinogen treatment and continued tri-weekly for 28 weeks. Tumor load was determined by averaging the total tumor volume in each group. RESULTS: Benzo(a)pyrene induced an average tumor size of 10.4 +/- 1.7 tumors per mouse, with an average tumor load of 25.9 +/- 3.8 mm(3). Rolipram significantly decreased tumor number, by 45.1%, and tumor load, by 52.9%, compared with the benzo(a)pyrene group. Ki67 staining was reduced in rolipram-treated mice compared with benzo(a)pyrene-treated mice. The increased expression of EMT markers caused by benzo(a)pyrene was inhibited by rolipram. Rolipram significantly attenuated NF kappaB and Nrf2 expression in benzo(a)pyrene-induced lung cancer tissues. CONCLUSIONS: In vivo experiments in the benzo(a)pyrene-induced model of lung cancer show that PDE4 inhibition significant inhibits lung carcinogenesis. Our results provide evidence that PDE4 inhibitors may be suitable for the prevention of the lung cancer in high-risk groups, for example, heavy smokers and patients with COPD. PMID- 25275946 TI - Molecular simulations with solvent competition quantify water displaceability and provide accurate interaction maps of protein binding sites. AB - Binding sites present well-defined interaction patterns that putative ligands must meet. Knowing them is essential to guide structure-based drug discovery projects. However, complex aspects of molecular recognition-such as protein flexibility or the effect of aqueous solvation-hinder accurate predictions. This is particularly true for polar contacts, which are heavily influenced by the local environment and the behavior of discrete water molecules. Here we present and validate MDmix (Molecular Dynamics simulations with mixed solvents) as a method that provides much more accurate interaction maps than ordinary potentials (e.g., GRID). Additionally, MDmix also affords water displaceability predictions, with advantages over methods that use pure water as solvent (e.g., inhomogeneous fluid solvation theory). With current MD software and hardware solutions, predictions can be obtained in a matter of hours and visualized in a very intuitive manner. Thus, MDmix is an ideal complement in everyday structure-based drug discovery projects. PMID- 25275947 TI - Correlation between excited-state intramolecular proton-transfer and singlet oxygen quenching activities in 1-(acylamino)anthraquinones. AB - Excited-state intramolecular proton-transfer (ESIPT) and singlet-oxygen ((1)O2) quenching activities of intramolecularly hydrogen-bonded 1 (acylamino)anthraquinones have been studied by means of static and laser spectroscopies. The ESIPT shows a substituent effect, which can be explained in terms of the nodal-plane model. The ESIPT activity positively and linearly correlates with their (1)O2 quenching activity. The reason for this correlation can be understood by considering ESIPT-induced distortion of their ground-state potential surface and their encounter complex formation with (1)O2. Intramolecularly hydrogen-bonded hydroxyanthraquinones found in aloe also show a similar positive and linear correlation, which can be understood in the same way. PMID- 25275948 TI - The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. AB - BACKGROUND: Current understanding of the clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is poor and based predominantly on small case series. In our clinical experience, we have found that the diagnosis of DIPNECH is frequently delayed because respiratory symptoms are ascribed to other lung conditions. The objectives of this study were to collect and analyze longitudinal clinical data on pulmonary physiology, chest high-resolution CT (HRCT) imaging, and therapies to better delineate the course of disease. METHODS: We established a cohort of patients (N = 30) with DIPNECH seen at our institution. We used descriptive statistics to summarize cohort characteristics and longitudinal analytic techniques to model FEV1 % predicted (FEV1%) over time. RESULTS: All subjects were women who presented with long standing cough and dyspnea. The majority had an FEV1% < 50% at the time of diagnosis. Forty percent were given a diagnosis of asthma as the cause for physiologic obstruction. The mean FEV1% for the entire cohort showed no statistically significant decline over time, but 26% of the subjects experienced a 10% decline in FEV1 within 2 years. Among the pathology samples available for review, 28% (five of 18) had typical carcinoids and 44% had associated constrictive bronchiolitis. We propose clinical diagnostic criteria for DIPNECH that incorporate demographic, pulmonary physiology, HRCT imaging, and transbronchial and surgical lung biopsy data. CONCLUSIONS: DIPNECH is a female predominant lung disease manifested by dyspnea and cough, physiologic obstruction, and nodules on HRCT imaging. Additional research is needed to understand the natural history of this disease and validate the proposed diagnostic criteria. PMID- 25275949 TI - Blood pressure measurement under standardized indoor condition may mask seasonal blood pressure variation in men with mildly elevated blood pressure. AB - BACKGROUND: Blood pressure (BP) is generally higher in cold than in warm seasons. This seasonal BP change is largely attributable to outdoor temperature changes. However, if such a typical seasonal change is observed in BP measured under a standardized indoor condition remains unclear. METHODS: Resting supine BPs and heart rate (HR) were measured under a standardized room temperature during summer and the next winter in 104 untreated men (38.1 +/- 4.4 years). Subjects were classified as having normotension (NT group: n = 79) or mildly elevated BP (ME group: n = 25) according to the summer measurements. Seasonal variation was defined as the difference from winter to summer measurements. We also examined body composition, endocrine parameters, and renal function. RESULTS: Age did not differ in the two groups (37.6 +/- 4.2 versus 39.1 +/- 4.9 years). The mean seasonal change in systolic BP was 2.7 +/- 1.1 mmHg for the NT group and -4.6 +/- 1.9 mmHg for the ME group (p = 0.001). Laboratory and outdoor temperatures did not differ between the two groups in either season. HR, noradrenaline, and estimated glomerular filtration rate were significantly higher during winter in the NT group but not in ME group. CONCLUSIONS: Typical seasonal change in BP may be masked in mildly elevated BP measured under a standardized indoor condition. The mechanisms are multifactorial. Our data suggest that out-of-office BP measurements are necessary for correctly understanding seasonal BP change especially in individuals with mildly elevated BP. PMID- 25275950 TI - Vaccine administration in children with chronic kidney disease. AB - Pediatric patients with severe chronic kidney disease (CKD) on conservative treatment, on dialysis, and those with renal transplantation are at a higher risk for infectious diseases as the result of impaired immune responses against infectious agents. Infections in these patients can have drastic consequences for disease morbidity and mortality. Immunization is a crucial preventive strategy for disease management in this pediatric population. However, vaccination coverage among children with CKD remains low due to safety concerns and doubts about vaccine immunogenicity and efficacy. In this study, we reviewed why children with CKD are at higher risk of infections, the importance of vaccinations among these children, barriers to vaccinations, and recommend the best vaccination schedules. Overall, vaccines have acceptable immunogenicity, efficacy, and safety profiles in children with CKD. However, in some cases, the protective antibody levels induced by vaccines and the benefits and risks of booster vaccine doses must be individually managed. Furthermore, close contacts and household members of these children should complete age-appropriate vaccination schedules to increase the child's indirect protection. PMID- 25275951 TI - OXA-23 carbapenemase in multidrug-resistant Acinetobacter baumannii ST2 type: first identification in L'Aquila Hospital (Italy). AB - In this study 114 extensively drug-resistant Acinetobacter baumannii clinical isolates were characterized. The strains were collected at L'Aquila Hospital after the earthquake in L'Aquila city (central Italy) on the 6th of April 2009. The genes blaOXA-23 and blaOXA-51 were detected in all clinical isolates analyzed, whereas blaTEM-1 allele was detected in 56/114 isolates. The blaOXA-23 gene is located downstream the ISAba region and is under control of a strong promoter. On 42/80 A. baumannii the presence of two class 1 integrons was ascertained on chromosomal DNA. Variable regions show different gene array: (1) aadB and aadA2, (2) aacA4, aac(6')-Ib-cr, and aadA1. Macrorestriction analysis using ApaI restriction endonuclease identifies three clusters (A, B, and C) according to pulsed-field gel electrophoresis profiles. All isolates analyzed belong to the clone A. baumannii sequence type 2. PMID- 25275952 TI - Morphotropy and temperature-driven polymorphism in A2Th(AsO4)2 (A = Li, Na, K, Rb, Cs) series. AB - A new alkaline thorium arsenate family was obtained and systematically investigated. The structures of A2Th(AsO4)2 (A = Li, Na, K, Rb, Cs) were determined from single crystal X-ray diffraction data. Li2Th(AsO4)2 and either isostructural K2Th(AsO4)2 and Rb2Th(AsO4)2 crystallize in the monoclinic crystal system. Na2Th(AsO4)2 and Cs2Th(AsO4)2 crystallize in the orthorhombic and tetragonal crystal systems, respectively. Li2Th(AsO4)2 consists of [Th(AsO4)2](2 ) layers with Li atoms in the interlayer space. The rest of the compounds are based on 3D frameworks. Differences in local environments of ThO8 coordination polyhedra are described in relation to the symmetry. Despite different local environments of ThO8 coordination polyhedra and different structural symmetry, underlying nets of A2Th(AsO4)2 (A = Na, K, Rb, Cs) were shown to be the same. Single-crystal and powder Raman spectra were measured, and bands are assigned. DSC measurements showed phase transitions in K2Th(AsO4)2 and Rb2Th(AsO4)2, which were studied using high-temperature powder X-ray diffraction (HT-PXRD). The data of HT-PXRD demonstrates two high-temperature polymorphic modification of K2Th(AsO4)2 and only one for the isotypic Rb2Th(AsO4)2. The phase transitions in both K and Rb phases are reversible. PMID- 25275954 TI - Lattice Boltzmann modeling of droplet condensation on superhydrophobic nanoarrays. AB - Droplet nucleation and growth on superhydrophobic nanoarrays is simulated by employing a multiphase, multicomponent lattice Boltzmann (LB) model. Three typical preferential nucleation modes of condensate droplets are observed through LB simulations with various geometrical parameters of nanoarrays, which are found to influence the wetting properties of nanostructured surfaces significantly. The droplets nucleated at the top of posts (top nucleation) or in the upside interpost space of nanoarrays (side nucleation) will generate a nonwetting Cassie state, while the ones nucleated at the bottom corners between the posts of nanoarrays (bottom nucleation) produce a wetting Wenzel state. The simulated time evolutions of droplet pressures at different locations are analyzed, which offers insight into the underlying physics governing the motion of droplets growing from different nucleation modes. It is demonstrated that the nanostructures with taller posts and a high ratio of post height to interpost space (H/S) are beneficial to produce the top- and side-nucleation modes. The simulated wetting states of condensate droplets on the nanostructures, having various geometrical configurations, compare reasonably well with experimental observations. The established relationship between the geometrical parameters of nanoarrays and the preferential nucleation modes of condensate droplets provides guidance for the design of nanoarrays with desirable anticondensation superhydrophobic properties. PMID- 25275953 TI - Bioinformatic and biochemical characterizations of C-S bond formation and cleavage enzymes in the fungus Neurospora crassa ergothioneine biosynthetic pathway. AB - Ergothioneine is a histidine thiol derivative. Its mycobacterial biosynthetic pathway has five steps (EgtA-E catalysis) with two novel reactions: a mononuclear nonheme iron enzyme (EgtB) catalyzed oxidative C-S bond formation and a PLP mediated C-S lyase (EgtE) reaction. Our bioinformatic and biochemical analyses indicate that the fungus Neurospora crassa has a more concise ergothioneine biosynthetic pathway because its nonheme iron enzyme, Egt1, makes use of cysteine instead of gamma-Glu-Cys as the substrate. Such a change of substrate preference eliminates the competition between ergothioneine and glutathione biosyntheses. In addition, we have identified the N. crassa C-S lyase (NCU11365) and reconstituted its activity in vitro, which makes the future ergothioneine production through metabolic engineering feasible. PMID- 25275955 TI - Emissions of fine particle fluoride from biomass burning. AB - The burning of biomasses releases fluorine to the atmosphere, representing a major and previously uncharacterized flux of this atmospheric pollutant. Emissions of fine particle (PM2.5) water-soluble fluoride (F-) from biomass burning were evaluated during the fourth Fire Laboratory at Missoula Experiment (FLAME-IV) using scanning electron microscopy energy dispersive X-ray spectroscopy (SEM-EDX) and ion chromatography with conductivity detection. F- was detected in 100% of the PM2.5 emissions from conifers (n=11), 94% of emissions from agricultural residues (n=16), and 36% of the grasses and other perennial plants (n=14). When F- was quantified, it accounted for an average (+/-standard error) of 0.13+/-0.02% of PM2.5. F- was not detected in remaining samples (n=15) collected from peat burning, shredded tire combustion, and cook-stove emissions. Emission factors (EF) of F- emitted per kilogram of biomass burned correlated with emissions of PM2.5 and combustion efficiency, and also varied with the type of biomass burned and the geographic location where it was harvested. Based on recent evaluations of global biomass burning, we estimate that biomass burning releases 76 Gg F- yr(-1) to the atmosphere, with upper and lower bounds of 40-150 Gg F- yr(-1). The estimated F- flux from biomass burning is comparable to total fluorine emissions from coal combustion plus other anthropogenic sources. These data demonstrate that biomass burning represents a major source of fluorine to the atmosphere in the form of fine particles, which have potential to undergo long-range transport. PMID- 25275956 TI - Correlation between nanomechanics and polymorphic conformations in amyloid fibrils. AB - Amyloid fibrils occur in diverse morphologies, but how polymorphism affects the resulting mechanical properties is still not fully appreciated. Using formalisms from the theory of elasticity, we propose an original way of averaging the second area moment of inertia for non-axisymmetric fibrils, which constitutes the great majority of amyloid fibrils. By following this approach, we derive theoretical expressions for the bending properties of the most common polymorphic forms of amyloid fibrils (twisted ribbons, helical ribbons, and nanotubes), and we benchmark the predictions to experimental cases. These results not only allow an accurate estimation of the amyloid fibrils' elastic moduli but also bring insight into the structure-property relationships in the nanomechanics of amyloid systems, such as in the closure of helical ribbons into nanotubes. PMID- 25275957 TI - Effect of water sorption on the electronic conductivity of porous polymer electrolyte membrane fuel cell catalyst layers. AB - A method is described for measuring the effective electronic conductivity of porous fuel cell catalyst layers (CLs) as a function of relative humidity (RH). Four formulations of CLs with different carbon black (CB) contents and ionomer equivalent weights (EWs) were tested. The van der Pauw method was used to measure the sheet resistance (RS), which increased with RH for all samples. The increase was attributed to ionomer swelling upon water uptake, which affects the connectivity of CB aggregates. Greater increases in RS were observed for samples with lower EW, which uptake more water on a mass basis per mass ionomer. Transient RS measurements were taken during absorption and desorption, and the resistance kinetics were fit using a double exponential decay model. No hysteresis was observed, and the absorption and desorption kinetics were virtually symmetric. Thickness measurements were attempted at different RHs, but no discernible changes were observed. This finding led to the conclusion that the conducting Pt/C volume fraction does not change with RH, which suggests that effective medium theory models that depend on volume fraction alone cannot explain the reduction in conductivity with RH. The merits of percolation-based models were discussed. Optical micrographs revealed an extensive network of "mud cracks" in some samples. The influence of water sorption on CL conductivity is primarily explained by ionomer swelling, and its effects on the quantity and quality of interaggregate contacts were discussed. PMID- 25275958 TI - Color Stability Behavior of Methacrylate-based Resin Composites Polymerized with Light-emitting Diodes and Quartz-Tungsten-Halogen. AB - Despite significant developments in improving the optical properties of resin composite materials, their color stability remains a challenge. This study aimed to evaluate the shade stability of light-polymerized, methacrylate-based resin composites with different filler particle composition (microfill, minifill, nanohybrids, and microhybrids) polymerized with quartz-tungsten-halogen (QTH) and light-emitting diodes (LED). METHODS AND MATERIALS: Composite discs were fabricated from Tetric EvoCeram, Premise, Artiste, and Beautifil II (nanohybrids); Filtek Supreme Plus and Vit-l-escence (microhybrids); Heliomolar (microfill); and Estelite Sigma Quick (minifill) using a Teflon mold. The specimens were irradiated either with QTH (Elipar 2500; 600 mW/cm(2)) for 40 seconds or with LED (Bluephase G2; 1200 mW/cm(2)) for 20 seconds. Color parameters were measured with a colorimeter before and after polymerization and at 24 hours, one week, one month, and three months. Color change was calculated among the different storage periods. RESULTS: There was a significant effect of the composite, time, and their interaction (p<0.001) but no effect of the polymerization unit on the color stability. Color changes immediately after polymerization and at 24 hours (4.22 and 3.88 for LED; and 4.08 and 3.82 for QTH) were not significantly different from each other but were both significantly higher than changes after one week (0.96 and 0.78), one month (1.12 and 1.02), and three months (1.27 and 1.11) for LED and QTH, respectively (p<0.001). CONCLUSIONS: Color changes were observed for all the materials that were dependent on the type of composite but not on the polymerization unit. These color shifts took place primarily immediately after polymerization and after 24 hours and were additive in nature. PMID- 25275959 TI - Biological restorations as an alternative to reconstructing posterior teeth: a case report. AB - This article reports on a three-year follow-up of two biological restorations performed on a 15-year-old female patient. After clinical evaluation, tooth fragments from extracted permanent molars were obtained from a Human Teeth Bank and were autoclaved, adjusted to the prepared cavity, and bonded to the remaining tooth structure with dual resin cement. The technical aspects are described and the benefits and disadvantages of biological restorations as an alternative treatment for rehabilitation of severely destroyed permanent molars are discussed. PMID- 25275960 TI - Effect of beverages on color and translucency of new tooth-colored restoratives. AB - This investigation examined the susceptibility to staining and translucency changes of some new tooth-colored restorative materials after immersion in different beverages. The materials studied were 3M Filtek Z350XT (ZT), 3M Filtek 350XT Flowable Restorative (ZF), Shofu Beautifil Flow Plus (BF), Shofu Beautifil II (B2), 3M Ketac Nano (N100), and 3M Photac Fil (PF). Following the manufacturers' instructions, 42 samples were made from each material and placed in an incubator at 100% humidity and 37 degrees Celsius for 24 hours. Baseline L*, a*, b* readings were taken against white and black backgrounds using a photospectrometer. The samples were then randomly assigned to be immersed in seven beverages, namely cola drink, orange juice, red wine, vodka, black coffee, green tea, and distilled water for a period of seven days. Color readings were taken again by recording the L*, a*, b* values. Data was analyzed using t-tests, one-way analysis of variance with Tukey post hoc and Pearson's correlation (p<0.05). BF generally performed as well as the conventional composite resin materials (ZT and ZF) but N100 and B2 did not. PF had the largest staining and translucency changes. Coffee, red wine, and tea resulted in the most staining and negative translucency changes. An inverse correlation between DeltaE and DeltaTP was observed for all materials and beverages with the exception of orange juice. PMID- 25275961 TI - Raman spectroscopic assessment of degree of conversion of bulk-fill resin composites--changes at 24 hours post cure. AB - OBJECTIVE: The aim of this study was to determine degree of conversion (DC) of solid and flowable bulk-fill composites immediately and after 24 hours and investigate the variations of DC at surface and depths up to 4 mm. MATERIALS AND METHODS: Eight bulk-fill composites (Tetric EvoCeram Bulk Fill [shades IVA and IVB], Quixfil, X-tra fil, Venus Bulk Fill, X-tra Base, SDR, Filtek Bulk Fill) were investigated, and two conventional composites (GrandioSO, X-Flow) were used as controls. The samples (n = 5) were cured for 20 seconds with irradiance of 1090 mW/cm(2). Raman spectroscopic measurements were made immediately after curing on sample surfaces and after 24 hours of dark storage at surface and at incremental depths up to 4 mm. Mean DC values were compared using repeated measures analysis of variance (ANOVA) and t-test for dependent samples. RESULTS: Surface DC values immediately after curing ranged from 59.1%-71.8%, while the 24 hour postcure values ranged from 71.3%-86.1%. A significant increase of DC was observed 24 hours post cure for all bulk-fill composites, which amounted from 11.3% to 16.9%. Decrease of DC through depths up to 4 mm varied widely among bulk fill composites and ranged from 2.9% to 19.7%. CONCLUSIONS: All bulk-fill composites presented a considerable 24-hour postcure DC increase and clinically acceptable DC at depths up to 4 mm. Conventional control composites were sufficiently cured only up to 2 mm, despite significant postcure polymerization. PMID- 25275962 TI - Shape-controlled synthesis of gold nanostructures using DNA origami molds. AB - We introduce a new concept that allows the synthesis of inorganic nanoparticles with programmable shape. Three-dimensional DNA origami nanostructures harboring an internal cavity are used as molds. A small gold nanoparticle within the cavity nucleates solution-based gold deposition leading to mold filling. We demonstrate the fabrication of 40 nm long rodlike gold particles with quadratic cross section and the formation of higher order assemblies of the obtained particles, which is mediated by their DNA shell. PMID- 25275963 TI - Rapid exchange between atmospheric CO2 and carbonate anion intercalated within magnesium rich layered double hydroxide. AB - The carbon cycle, by which carbon atoms circulate between atmosphere, oceans, lithosphere, and the biosphere of Earth, is a current hot research topic. The carbon cycle occurring in the lithosphere (e.g., sedimentary carbonates) is based on weathering and metamorphic events so that its processes are considered to occur on the geological time scale (i.e., over millions of years). In contrast, we have recently reported that carbonate anions intercalated within a hydrotalcite (Mg0.75Al0.25(OH)2(CO3)0.125.yH2O), a class of a layered double hydroxide (LDH), are dynamically exchanging on time scale of hours with atmospheric CO2 under ambient conditions. (Ishihara et al., J. Am. Chem. Soc. 2013, 135, 18040-18043). The use of (13)C-labeling enabled monitoring by infrared spectroscopy of the dynamic exchange between the initially intercalated (13)C labeled carbonate anions and carbonate anions derived from atmospheric CO2. In this article, we report the significant influence of Mg/Al ratio of LDH on the carbonate anion exchange dynamics. Of three LDHs of various Mg/Al ratios of 2, 3, or 4, magnesium-rich LDH (i.e., Mg/Al ratio = 4) underwent extremely rapid exchange of carbonate anions, and most of the initially intercalated carbonate anions were replaced with carbonate anions derived from atmospheric CO2 within 30 min. Detailed investigations by using infrared spectroscopy, scanning electron microscopy, powder X-ray diffraction, elemental analysis, adsorption, thermogravimetric analysis, and solid-state NMR revealed that magnesium rich LDH has chemical and structural features that promote the exchange of carbonate anions. Our results indicate that the unique interactions between LDH and CO2 can be optimized simply by varying the chemical composition of LDH, implying that LDH is a promising material for CO2 storage and/or separation. PMID- 25275964 TI - Synthesis and biological evaluation of a novel series of heterobivalent muscarinic ligands based on xanomeline and 1-[3-(4-butylpiperidin-1-yl)propyl] 1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1). AB - Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77 LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for beta-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and beta arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length. PMID- 25275965 TI - Geochemical processes constraining iron uptake in Strategy II Fe acquisition. AB - Phytosiderophores (PS) are natural chelating agents, exuded by graminaceous plants (grasses) for the purpose of Fe acquisition (Strategy II). They can form soluble Fe complexes with soil-Fe that can be readily taken up. PS are exuded in a diurnal pulse release, and with the start of PS release a "window of iron uptake" opens. In the present study we examined how this window is constrained in time and concentration by biogeochemical processes. For this purpose, a series of interaction experiments was done with a calcareous clay soil and the phytosiderophore 2'-deoxymugineic acid (DMA), in which metal and DMA speciation were examined as a function of time and DMA concentration. Various kinetically and thermodynamically controlled processes affected the size of the window of Fe uptake. Adsorption lowered, but did not prevent Fe mobilization by DMA. Microbial activity depleted DMA from solution, but not on time scales jeopardizing Strategy II Fe acquisition. Complexation of competing metals played an important role in constraining the window of Fe uptake, particularly at environmentally relevant PS concentrations. Our study provides a conceptual model that takes into account the chemical kinetics involved with PS-mediated Fe acquisition. The model can help to explain how success or failure of PS-mediated Fe acquisition depends on environmental conditions. PMID- 25275966 TI - Multipurpose ultra and superhydrophobic surfaces based on oligodimethylsiloxane modified nanosilica. AB - Nonfluorinated hydrophobic surfaces are of interest for reduced cost, toxicity, and environmental problems. Searching for such surfaces together with versatile processing, A200 silica nanoparticles are modified with an oligodimethylsiloxane and used by themselves or with a polymer matrix. The goal of the surface modification is controlled aggregate size and stable suspensions. Characterization is done by NMR, microanalysis, nitrogen adsorption, and dynamic light scattering. The feasibility of the concept is then demonstrated. The silica aggregates are sprayed in a scalable process to form ultrahydrophobic and imperceptible coatings with surface topographies of controlled nanoscale roughness onto different supports, including nanofibrillated cellulose. To improve adhesion and wear properties, the organosilica was mixed with polymers. The resulting composite coatings are characterized by FE-SEM, AFM, and contact angle measurements. Depending on the nature of the polymer, different functionalities can be developed. Poly(methyl methacrylate) leads to almost superhydrophobic and highly transparent coatings. Composites based on commercial acrylic car paint show "pearl-bouncing" droplet behavior. A light-emitting polyfluorene is synthesized to prepare luminescent and water repellent coatings on different supports. The interactions between polymers and the organosilica influence coating roughness and are critical for wetting behavior. In summary, the feasibility of a facile, rapid, and fluorine-free hydrophobization concept was successfully demonstrated in multipurpose antiwetting applications. PMID- 25275967 TI - Percutaneous fixation of anterior and posterior column acetabular fractures. AB - Although open reduction and internal fixation (ORIF) has been the standard of care for acetabular fractures, recent advancements in minimally invasive techniques have allowed percutaneous fixation to gain popularity. Percutaneous technique has been described in the literature as an adjuvant to ORIF. However, isolated percutaneous fixation has the advantage of limiting soft tissue disruption, length of surgery, and blood loss when compared with ORIF. The technique also allows for earlier return to activity and better pain control when compared with nonsurgical management. This article reviews both indications and limitations, while highlighting the technique for percutaneous fixation of both anterior and posterior column acetabular fractures. PMID- 25275968 TI - Minimally invasive plating for fresh displaced midshaft fractures of the clavicle. AB - The authors retrospectively reviewed 269 patients treated from September 2006 to August 2011 with the minimally invasive plate osteosynthesis (MIPO) technique using a universal reconstruction ribbon plate for fresh displaced midshaft fracture of the clavicle. Mean follow-up was 40.6 months. All had bony union (average healing time, 14.6 weeks). At 2-month postoperative follow-up, the mean Constant-Murley score was 92 points and the mean Disabilities of the Arm, Shoulder and Hand (DASH) score was 4.6 points. A total of 166 patients underwent hardware removal at an average of 15 months. A total of 258 patients were satisfied with the results of this surgery. This technique appears to be safe, simple, effective, and practical and to lead to rapid recovery, a high rate of union, a favorable cosmetic effect, and excellent function restoration. Thus, it can be considered an alternative to conventional plate osteosynthesis, intramedullary fixation, or non-operative treatment for fresh displaced midshaft clavicle fractures. PMID- 25275969 TI - Improved repair of bone defects with prevascularized tissue-engineered bones constructed in a perfusion bioreactor. AB - Vascularization of tissue-engineered bones is critical to achieving satisfactory repair of bone defects. The authors investigated the use of prevascularized tissue-engineered bone for repairing bone defects. The new bone was greater in the prevascularized group than in the non-vascularized group, indicating that prevascularized tissue-engineered bone improves the repair of bone defects. [Orthopedics. 2014; 37(10):685-690.]. PMID- 25275970 TI - Salvage of failed total hip arthroplasty with proximal femoral replacement. AB - EDUCATIONAL OBJECTIVES: As a result of reading this article, physicians should be able to: 1. Identify the available types of reconstruction for failed total hip arthroplasty. 2. Summarize the preoperative workup of patients with failed total hip arthroplasty and massive proximal femoral bone loss. 3. Assess the surgical technique of proximal femoral replacement for failed total hip arthroplasty. 4. Recognize treatment complications, patient outcomes, and survival of proximal femoral megaprostheses for revision of failed total hip arthroplasty. Despite recent advances in device manufacturing and surgical techniques, the management of proximal femoral bone loss in revision total hip arthroplasty remains challenging. Currently, failed total hip arthroplasty in elderly and less active patients, nonunion of the proximal femur with multiple failed attempts at osteosynthesis, resection arthroplasty, and massive proximal femoral bone loss can be salvaged with proximal femoral replacement using a megaprosthesis. The procedure is technically demanding and requires careful preoperative planning. Instability and aseptic loosening are the major complications, especially in younger and more active patients. The new generation of modular proximal femoral replacement megaprostheses and the increased experience obtained with these surgeries have reduced complication rates and improved outcomes. PMID- 25275971 TI - Osteochondral resurfacing with proximal row carpectomy: 8-year follow-up. AB - Degenerative arthrosis of the proximal row remains a challenging problem for both patients and surgeons. Proximal row carpectomy is a motion-preserving treatment option, with studies documenting acceptable long-term outcomes. Proximal row carpectomy is an attractive option because there is no need for fusion to occur between the carpal bones, as in 4-corner fusion. As a result, laborers and smokers may be able to return to work more quickly. However, capitate chondrosis traditionally has been considered a contraindication to proximal row carpectomy. The goal of this study was to review the long-term follow-up of patients who underwent osteochondral resurfacing of capitate chondrosis performed in the same setting as proximal row carpectomy. Final follow-up was obtained in 5 of 8 (63%) patients at an average of 101 months (range, 99-102) after surgery. Grip strength improved at each time point, but wrist flexion and extension decreased. The average Mayo Wrist Score was 74 (range, 65-85) and remained stable or improved in all patients between the 18-month visit and the final visit. The Disabilities of the Arm, Shoulder and Hand (DASH) score was unchanged at final follow-up compared with 18-month follow-up (P=.7). This study found that osteochondral resurfacing of the capitate in the setting of proximal row carpectomy for patients with capitate chondrosis offers good outcomes compared with standard proximal row carpectomy in patients without capitate chondrosis on patient-directed outcome tools (DASH, Mayo Wrist Score) at long-term follow-up of 101 months. PMID- 25275972 TI - Intra-articular injection of hyaluronate versus corticosteroid in adhesive capsulitis. AB - The goal of this study was to prospectively compare the early clinical results of intra-articular injection of hyaluronate or corticosteroid in patients with idiopathic adhesive capsulitis. The authors' hypothesis was that there would be no difference between groups. Sixty-eight patients with idiopathic adhesive capsulitis were equally randomized to receive either corticosteroid or hyaluronate injection. All patients underwent standard physical examination and magnetic resonance imaging. Intra-articular injection was performed through an anterior approach by the same orthopedic surgeon without image guidance. Patients were followed up 2 and 12 weeks after completion of the injection. The primary outcome was the Constant score at week 12. Secondary outcomes included the visual analog scale (VAS) pain score, the American Shoulder and Elbow Surgeons (ASES) score, and range of motion at each time point. No significant differences were noted in preoperative demographic features or baseline shoulder function between groups. After treatment, no significant differences were noted in early clinical outcomes (at weeks 2 and 12) with VAS, ASES, and Constant scores between groups (all P>.05). Evaluation of range of motion showed no difference in forward elevation or external rotation at each time point. Internal rotation was significantly lower at week 2 in the hyaluronate group compared with the corticosteroid group (P=.015). Internal rotation improved at week 12, with no significant difference between groups. Patients treated with intra-articular injection of hyaluronate and corticosteroid for idiopathic adhesive capsulitis showed significant improvement in early clinical scores and range of motion without significant differences between groups. PMID- 25275973 TI - Outcomes and cost of care for patients with distal radius fractures. AB - This study was designed to evaluate treatment patterns in open treatment and percutaneous fixation of distal radius fractures, compare morbidity rates for the 2 types of treatment, and compare costs associated with the procedure and treatment of complications up to 1 year after surgery. From a 5% sample of nationwide Medicare claims records (1997-2009), patients with distal radius fractures were identified with International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM), codes. Patients who underwent percutaneous fixation and open treatment were tracked with appropriate Current Procedural Terminology codes. Complications were identified at 3 and 12 months. Medicare charges and payments associated with the treatment groups were compiled from the claims data. The rate of surgical treatment increased from 44.7 to 82.0 surgeries per 100,000 persons (+83.0%) over the study period. A total of 9343 procedures met the inclusion criteria between 1998 and 2008. The proportion of open treatment procedures increased from 25.5% in 1998 to 73.4% in 2008. Percutaneous fixation was associated with lower adjusted risk of carpal tunnel syndrome and release and mononeuritis at 3 and 12 months. The percutaneous fixation group had lower adjusted risk of malunion/nonunion at 3 months and tendon rupture at 12 months. Average charges were lower in the percutaneous fixation group for the index operation as well as for treatment of morbidities at 3 and 12 months. The operative fixation rate for distal radius fractures in the Medicare population continues to rise, with a significant trend toward open fixation. Charges and payments associated with open treatment are significantly higher than those for percutaneous fixation. PMID- 25275974 TI - Primary tuberculosis of the clavicle. AB - Tuberculosis of the clavicle is a rare lesion, accounting for less than 1% of all osteoarticular tuberculosis. The lesion has been described in a few case reports. The lesion can have a varied presentation, ranging from dull, aching pain to bony swelling and a draining sinus. The rarity of the lesion, its nonspecific symptoms, and its striking resemblance to common cystic conditions such as bone tumors and metabolic conditions such as rickets make diagnosis difficult. The authors describe a series of 17 patients with primary tuberculosis of the clavicle. Radiographs and magnetic resonance images were obtained for all patients, and a preliminary diagnosis was made on the basis of clinical features and the results of erythrocyte sedimentation rate, C-reactive protein, and Mantoux tests. Erythrocyte sedimentation rate was uniformly elevated. Radiographs showed diffused thickening and honeycombing, eccentric expansile lytic lesions with surrounding osteopenia, or sequestration not unlike pyogenic infection. Magnetic resonance imaging is useful for determining the extent of the lesion and soft tissue involvement. The radiological and laboratory findings provided complementary information. The diagnosis was confirmed on biopsy material that was analyzed with histopathology, pus culture and sensitivities, gram stain, acid fast stain, and cultures on Lowenstein-Jensen medium. Patients were treated with multidrug antitubercular chemotherapy for 18 months and were assessed on pre- and posttreatment radiology, erythrocyte sedimentation rate, and University of California, Los Angeles (UCLA) shoulder rating scale. The results of conservative management of tubercular osteomyelitis were uniformly good, and all patients recovered well. PMID- 25275975 TI - Multiple radiographic projections in detecting intra-articular screw penetration during fixation of femoral neck fractures. AB - The authors performed a cadaveric study to evaluate the efficacy of multiple fluoroscopic projections in detecting intra-articular penetration of the screws during femoral neck fracture fixation and also to determine the most suitable radiographic projection. Models of intra-articular penetration in 8 normal proximal femur specimens were created by placing the pins in different quadrants of the femoral head and extending 1 mm beyond the femoral head surface. The tip to-surface distance was measured on anteroposterior (AP) and lateral views, with the femur positioned at varying degrees of rotation, flexion, adduction, and abduction. After correcting for differences in magnification, associations between the tip-to-surface distance and femur position were noted. In certain femur positions and K-wire placements, conventional AP and lateral views did not show that the wire extended beyond the surface of the femoral head. The tip-to surface distance on an AP radiograph with the femur in the neutral position was not comparable to that on the lateral view with the femur positioned at 20 degrees of adduction (P=.821). However, the tip-to-surface distance on an AP radiograph with the femur in the neutral position varied significantly (P<.001) from all other tip-to-surface distances on either the AP or lateral projection. A linear association was found between the tip-to-surface distance and femur rotation angles on AP views and between femur adduction and abduction angles on lateral views. In conclusion, fluoroscopy in varied projections at different angles can detect unrecognized intra-articular screw penetration during internal fixation of femoral neck fracture. Additional special projection methods are suggested to identify and prevent intra-articular screw penetration. PMID- 25275976 TI - Glenohumeral pressure with surface replacement arthroplasty versus hemiarthroplasty. AB - It is not known whether significant differences in the glenohumeral center of pressure and contact pressure exist between surface replacement arthroplasty and hemiarthroplasty compared with the native joint. Twelve fresh-frozen cadaveric shoulders were dissected free of soft tissue, and the joint capsule was removed. The scapula was potted with the glenoid parallel to the ground. A pressure sensitive sensor was placed in the glenohumeral joint, and each specimen was tested in sequence: intact, surface replacement, and hemiarthroplasty. Loading was done with a 440-N compression load at 0.5 Hz with the shoulder in 4 different positions. The center of pressure and contact pressure were measured at each position. The glenohumeral contact pressure with surface replacement was not different from intact pressure in 2 arm positions. Pressure with hemiarthroplasty was significantly different compared with the intact shoulder at all 4 arm positions and compared with the surface replacement group at 2 arm positions (P<=.05). Change in the anterior-posterior center of pressure from intact was significantly smaller with surface replacement compared with hemiarthroplasty with the humerus at 0 degrees flexion/0 degrees abduction and at 0 degrees flexion/90 degrees abduction (1.11+/-0.89 mm vs 2.38+/-1.62 mm, P=.02, and 0.68+/-0.50 mm vs 2.37+/-2.0 mm, P=.01, respectively). Change in the superior inferior center of pressure was significantly smaller with surface replacement vs hemiarthroplasty at 0 degrees flexion/0 degrees abduction and at 90 degrees flexion/90 degrees abduction (0.98+/-1.16 mm vs 2.33+/-1.38 mm, P=.02, and 1.50+/-1.28 mm vs 2.90+/-1.92 mm, P=.04, respectively). Compared with hemiarthroplasty, surface replacement arthroplasty more closely replicated the contact pressure and center of pressure in the intact glenohumeral joint. PMID- 25275977 TI - Association of Achilles tendinopathy and plantar spurs. AB - Plantar spurs and Achilles tendinopathy are common causes of heel pain. In the authors' practice, it was anecdotally noted that patients with Achilles tendinopathy often presented with plantar spurs. Nonetheless, there is a shortage of studies investigating whether Achilles tendinopathy and plantar spurs exist concomitantly. A better understanding of the association between the 2 pathologies might help physicians recognize and treat both conditions, educate patients about Achilles tendinopathy and plantar spurs, and ultimately investigate possible underlying causes of both pathologies that could be addressed together. The authors examined the prevalence of plantar spurs in patients diagnosed with Achilles tendinopathy as well as demographic differences within the unilateral and bilateral Achilles tendinopathy populations. A total of 785 patient records were retrospectively reviewed. Mean patient age was 56.2+/ 15.5 years (46.9% men and 53.1% women). Seventy-two (9.2%) patients were affected bilaterally by Achilles tendinopathy. Lateral radiographs were reviewed by an orthopedic surgeon to identify the presence of plantar spurs. A total of 329 (41.9%) patients with Achilles tendinopathy were found to have a concomitant plantar spur. Patients with unilateral Achilles tendinopathy and a plantar spur were more likely to be women (58.7% vs 49.8%, P=.020) and older (62.7 vs 51.7 years, P<.001). In the bilateral Achilles tendinopathy group, there were 46 (63.9%) patients with at least one foot presenting with a plantar spur. The study's findings suggest a significant association between Achilles tendinopathy and plantar spurs. Older women with Achilles tendinopathy are at greater risk of being affected by plantar spurs. PMID- 25275978 TI - Return to sport after hip arthroscopy: aggregate recommendations from high-volume hip arthroscopy centers. AB - Hip arthroscopy is a minimally invasive surgical technique often performed in athletes who want an expeditious return to sport. To the authors' knowledge, no studies in the literature provide a time frame or criteria for return to sport after hip arthroscopy. The purpose of this study was to develop an aggregate recommendation for return to sport after hip arthroscopy based on data assimilated from high-volume hip arthroscopy centers. Twenty-seven orthopedic surgeons from high-volume hip arthroscopy centers completed a survey regarding return to sport after hip arthroscopy. The questionnaire asked surgeons to give a time frame for return to sport and to choose meaningful criteria that an athlete must meet prior to return to sport. Surgeons were asked to categorize various common sports as high, medium, or low risk with regard to the hip. The aggregate results were used to create standardized recommendations for time, criteria, and risk for return to competitive sports. Regarding time frame for return to sport, 70% of surgeons recommended 12 to 20 weeks. In addressing criteria for return to sport, 85% of surgeons recommended that patients need to be able to reproduce all motions involved in their sport without pain. A majority of surgeons recommended criteria of pain-free running, jumping, lateral agility drills, and single-leg squats. Finally, surgeons categorized sports requiring the most movement and impact of the hip joint (football, basketball, wrestling, and martial arts) as high-risk sports. Sports with less impact on the hip, such as golf, were ranked as low risk. PMID- 25275979 TI - Effect of methotrexate on the mechanical properties and microstructure of calcium phosphate cement. AB - Calcium phosphate cement (CPC) is widely used as an antitumor bone-filling material. Methotrexate (MTX) is recognized as an effective chemotherapy medicine. The current study examined the effects of MTX on the mechanical properties and microstructure of CPC. Methotrexate-loaded CPC at mass ratios of 0%, 0.1%, 0.2%, and 0.5% were designated as groups A, B, C, and D, respectively, and were pressed into precast cylindrical molds. Solidification time, axial compressive strength, transverse compressive strength, and rotational tensile strength were measured, and scanning electron microscopy images were captured before and after MTX-CPC microstructure changes occurred. Average initial and final setting times increased gradually with increasing drug concentration, but this increase was not significant among the groups. Average axial transverse compressive strength and rotational tensile strength of groups B and C were not significantly different from those of group A (P>.05); however, there was a significant difference in these properties between groups A and D (P<.05). Scanning electron microscopy observations showed a porous crystalline structure. The addition of MTX to CPC does not significantly affect the basic crystal structure and setting time of CPC. Adding MTX at mass ratios of 0.1% and 0.2% to CPC does not lead to a significant difference in mechanical strength and can therefore be applied in clinical practice. This study may shed some light on the future application of MTX-loaded CPC in the treatment of bone defects after tumor excision. PMID- 25275980 TI - Medical treatment of osteonecrosis of the knee associated with thrombophilia hypofibrinolysis. AB - In 6 patients with stage II knee osteonecrosis, all 6 with thrombophilia and 4 with concurrent hypofibrinolysis, the authors prospectively determined whether anticoagulation with enoxaparin could prevent collapse and progression to osteoarthritis, ameliorate pain, and restore function. The 6 patients were treated with enoxaparin (40 to 60 mg/d for 3 or more months) as mandated by a US Food and Drug Administration-approved protocol. In post-enoxaparin prospective follow-up, patients were reassessed clinically every 4 to 6 months, and radiographs were obtained every year. The 6 patients followed up at 15.1, 7.5, 3.9, 2.25, 2, and 1 year, respectively. None progressed to joint collapse or severe osteoarthritis. Four became and remained asymptomatic at 2-, 3.9-, 7.5-, and 15.1-year follow-up, respectively. A fifth patient did not progress to collapse or severe osteoarthritis but had residual pain at 2.25-year follow-up. The sixth patient had no symptomatic benefit on enoxaparin but improved on rivaroxaban at 1-year follow-up. Two patients had recurrences of knee pain 1 and 4 years after their initial treatment with enoxaparin. One resolved after a second course of enoxaparin, and the other, with a second recurrence 1 year after the second course, resolved after a third course. Pretreatment, all 6 patients required canes, crutches, or wheelchairs, but after enoxaparin, no patient required them, and walking was unrestricted. Thrombophilia-hypofibrinolysis contributes to the pathogenesis of knee osteonecrosis. Thrombophilic hypofibrinolytic patients with stage II knee osteonecrosis treated with enoxaparin have had no collapse or progression to severe osteoarthritis, and most have had resolution of pain and restoration of full function. This represents a major improvement compared with the natural history of untreated spontaneous knee osteonecrosis. PMID- 25275981 TI - Decreasing incidence of femoral neck fractures in the Medicare population. AB - This study was designed to evaluate trends in incidence and treatment patterns for intracapsular hip fractures and to evaluate risk factors for complications and mortality. Patients with an intracapsular hip fracture who underwent internal fixation, hemiarthroplasty, or total hip arthroplasty (THA) were identified from a 5% nationwide sample of Medicare data (1998-2007). The authors identified 41,053 patients with intracapsular hip fractures between 1998 and 2007. The number of intracapsular hip fractures treated with internal fixation, hemiarthroplasty, or THA decreased by 21.8%, from 4602 in 1998 to 3601 in 2007. In 2007, 54.3% of patients with an intracapsular hip fracture were treated with hemiarthroplasty, compared with 41.2% who were treated with internal fixation and 4.5% who were treated with THA. Compared with internal fixation, hemiarthroplasty had higher adjusted risks of dislocation (+98%) and infection (+53%) at 90 days and higher rates of death (+8%) and reoperation (+33%) at 1 year. Patients who underwent THA had a higher risk of complications at 90 days compared with those who underwent hemiarthroplasty, with 114%, 39%, and 123% greater risk of dislocation, deep venous thrombosis, and mechanical complications, respectively. At 1 year, patients treated with THA had a 42% lower mortality risk and an 85% lower risk of reoperation compared with those who underwent internal fixation. Primary THA is performed more often in younger patients with fewer comorbidities. The incidence of intracapsular hip fracture decreased by 21.8% over the past decade. This decrease is likely the result of multiple factors, most significantly increased awareness and medical management of osteoporosis. PMID- 25275982 TI - Surgical treatment of extra-articular or simple intra-articular distal tibial fractures: MIPO versus supercutaneous plating. AB - Minimally invasive plate osteosynthesis (MIPO) has become a widely accepted technique to treat distal tibial fractures. Recently, the novel application of a locking plate used as an external fixator (supercutaneous plating) was introduced for the management of open fractures and infected nonunions and even as an adjunct in distraction osteogenesis, which is considered another less invasive method. The aim of this study was to compare the results of supercutaneous plating with closed reduction and minimally invasive plating in the treatment of distal tibial fractures. Forty-eight matched patients were divided according to age, sex, Injury Severity Score, and fracture pattern into the MIPO group and the supercutaneous plating group. Minimum follow-up was 12 months (mean, 18.5 months; range, 12-26 months). No patient had nonunion, hardware breakdown, or deep infection. Patients in the supercutaneous plating group had a significantly shorter mean operative time (65.6+/-13.2 vs 85.9+/-14.0 minutes; P=.000), hospital stay (7.5+/-2.0 vs 13.0+/-4.4 days; P=.000), and union time (15.2+/-2.4 vs 17.0+/-2.8 weeks; P=.000). In the MIPO group, 15 (62.5%) patients reported implant impingement or discomfort and there was 1 incidence of stripping of 15.6% at the time of locking screw removal, whereas in the supercutaneous plating group, no patient reported skin irritation, and removal of the supercutaneous plate was easily performed in clinic without anesthesia. Distal tibial fractures may be treated successfully with MIPO or supercutaneous plating. However, the supercutaneous plating technique may represent a superior surgical option because it offers advantages in terms of mean operative time, hospital stay, and union time; skin irritation; and implant removal. PMID- 25275983 TI - Intravascular migration of a broken cerclage wire into the left heart. AB - This article describes a patient in whom a broken cerclage wire migrated from the left hip into the left ventricle. A 71-year-old woman was admitted to the authors' hospital for preoperative examination before femoral hernia repair. Chest radiograph showed a metallic wire in the left ventricle. Twenty-four years earlier, she had a revision arthroplasty. During revision surgery, fragments of the osteotomy were fixed to the femur with multiple cerclage wires. During the past 5 years, radiographic follow-up showed progressive multiple ruptures of cerclage wires. The cerclage wiring was not removed because the patient had no related clinical symptoms. Radiograph of the left hip showed a well-fixed cemented acetabular ring and an uncemented femoral stem with a healed trochanteric osteotomy. All cerclage wires were broken into multiple parts, and it was very difficult to determine which part had migrated into the heart. Thoracic computed tomography scan showed wire that had migrated into the anterior left ventricular myocardial wall at the atrioventricular level. The patient had no clinical symptoms. Electrocardiogram showed a normal sinus rhythm and right bundle branch block. Because of the high risk of surgical left ventriculotomy associated with searching for wire that had migrated into the myocardial wall, patient monitoring was planned. Definitive management of this complication constitutes a dilemma. Although this complication is highly unusual, the possibility of intracardiac migration of broken wire should be considered when deciding on prophylactic surgical removal of hardware after fracture or osteotomy healing. PMID- 25275984 TI - Diabetic myonecrosis: likely an underrecognized entity. AB - Diabetic myonecrosis is a rare complication of long-standing diabetes mellitus that presents as acute onset of swelling and pain of the affected muscles. The differential diagnosis includes cellulitis/pyomyositis, necrotizing fasciitis, neoplasm, and deep venous thrombosis (DVT). Missed diagnoses can lead to unnecessary invasive diagnostic procedures and inappropriate treatment. The diagnosis is established by the clinical presentation and findings on magnetic resonance imaging (MRI) scan. A 30-year-old African-American man presented with a painful mass affecting the medial aspect of the right thigh for several months. Initial laboratory studies showed white blood cell count of 8800 cells/mm(3), D dimer value of 0.55 ug/mL, HgBA1c level of 15.1%, glucose level of 352 mg/dL, erythrocyte sedimentation rate of 22 mm/h, and C-reactive protein level of 222 mg/L. An MRI scan was obtained, and diabetic myonecrosis was diagnosed and treated. One year later, the patient had similar symptoms of pain in the contralateral thigh. Repeat workup and MRI scan were obtained. The MRI abnormalities originally seen in the right thigh 1 year earlier were present in the left thigh, with complete resolution of the abnormalities seen in the right thigh. Treatment with bed rest and analgesics resulted in symptom resolution. Patients with diabetic myonecrosis typically have no fever, normal white blood cell count, mildly increased erythrocyte sedimentation rate, and elevated C reactive protein level in 50% of cases. They lack the radiologic signs of fascial enhancement or well-defined, rim-enhancing collections that are seen in necrotizing fasciitis and pyomyositis/abscess. The onset of severe pain and the lack of mass effect on imaging differentiate diabetic myonecrosis from tumor-like conditions such as vascular malformations or soft tissue tumors. Normal D-dimer levels and ultrasound Doppler examination of the extremity help to rule out DVT. The typical MRI scan findings and clinical presentation can lead to the diagnosis of diabetic myonecrosis, allowing the physician to avoid invasive tests, such as muscle biopsy, and to reassure patients that this condition is self-limiting with appropriate treatment. PMID- 25275985 TI - Primary osseous inflammatory malignant fibrous histiocytoma masquerading as chronic osteomyelitis. AB - Inflammatory malignant fibrous histiocytoma, in addition to a mass lesion, may present with fever and other constitutional symptoms, mimicking an infectious process. This article presents an extremely rare and unique case of primary osseous inflammatory malignant fibrous histiocytoma, highlighting retrospectively the subtle clinical, radiologic, and pathologic features that can suggest this diagnosis. A 63-year-old woman with a history of nephrectomy for right kidney tuberculosis 20 years ago presented with slowly increasing left hip pain for 6 months. The relatively benign-appearing radiograph and biopsy report of chronic inflammation resulted in curettage and nailing of the lesion. The pathologic diagnosis was chronic osteomyelitis, but culture findings for bacteria and tuberculosis were negative. The patient remained well until 4 months later, when left thigh pain returned with fever and leukocytosis (white blood cell count as high as 20.7*10(9)/L, 80% neutrophils). No source of infection was localized. The patient showed no response to broad-spectrum antibiotics and antituberculous drugs. Radiographs showed substantial enlargement of the femoral lesion and extraosseous extension; biopsy results and review of previous histopathologic findings led to a diagnosis of inflammatory malignant fibrous histiocytoma. The fever gradually resolved and the white blood cell count returned to normal within a few days after segmental resection of the proximal femur tumor and its soft tissue extension. However, deep venous thrombosis developed, resulting in left foot ischemia and toe gangrene, necessitating left below-the-knee amputation. Disseminated metastasis occurred 3 months after tumor resection. The patient declined further aggressive treatment and died 13 months after initial presentation. PMID- 25275986 TI - Total knee arthroplasty in a patient with thrombocytopenia-absent radius syndrome. AB - Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic condition with a complex inheritance pattern. This syndrome is classically characterized by hypomegakaryocytic thrombocytopenia as well as bilateral absent radii, shortened ulna, and radially deviated 5-digit hands. During infancy, the predominant manifestations are hemorrhagic complications. Later in life, the bleeding disorder typically improves, but the musculoskeletal abnormalities become of greater concern because of the effects on quality of life. Although the classic musculoskeletal manifestations of TAR syndrome involve the upper extremity, multiple lower-extremity abnormalities have been described, especially dysplasia of the knee. Knee abnormalities include genu varum, varying degrees of laxity or stiffness, patellar abnormalities, concave distal femur, convex medial tibial plateau, and/or absence of the anterior cruciate ligament and posterior cruciate ligament. Several management strategies for lower-extremity abnormalities in TAR syndrome have been described, especially for pediatric patients. Management strategies have not halted the natural progression of knee disease in these patients, and the effect that these knee abnormalities have in adulthood is unclear. Management of knee abnormalities in adults with TAR syndrome is poorly described in the current literature. The authors report a 59-year-old patient with TAR syndrome and knee abnormalities who underwent successful total knee arthroplasty. The patient was followed to the 3-year postoperative visit. At various postoperative time points (7 weeks, 6 months, 1 year, and 3 years), Knee Society Scores and 12-Item Short Form Health Survey scores were recorded. Radiographs obtained at each clinical visit showed well-positioned, well-fixed components. The authors concluded that total knee arthroplasty may be a safe and effective surgical intervention for adults with TAR syndrome and associated knee osteoarthritis. PMID- 25275987 TI - Lyme arthritis of the pediatric ankle. AB - Lyme arthritis results from acute inflammation caused by the spirochete Borrelia burgdorferi. The number of cases per year has been rising since 2006, with a majority of patients being affected in the northeastern United States. Development of Lyme arthritis is of particular importance to the orthopedic surgeon because Lyme arthritis often presents as an acute episode of joint swelling and tenderness and may be confused with bacterial septic arthritis. Considering the vast difference in treatment management between these 2 pathologies, differentiating between them is of critical importance. Septic arthritis often needs to be addressed surgically, whereas Lyme arthritis can be treated with oral antibiotics alone. Laboratory testing for Lyme disease often results in a delay in diagnosis because many laboratories batch-test Lyme specimens only a few times per week because of increased expense. The authors present a case of Lyme arthritis in the pediatric ankle in an endemic region. No clear algorithm exists to delineate between septic arthritis and Lyme arthritis of the joint. Improved clinical guidelines for the identification and diagnosis of Lyme arthritis of the ankle are important so that appropriate antibiotics can be used and surgery can be avoided. PMID- 25275989 TI - Application of the Symphonological approach to faculty-to-faculty incivility in nursing education. AB - The nature of ethical interactions among nurse educators is crucial in modeling ethically based relationships for nursing students. This article focuses on the issue of uncivil faculty-to-faculty relationships in nursing education and is supported by a literature review of incivility in academic settings and the experiential reflections of seasoned nurse educators. The bioethical practice based theory of symphonology provides a new perspective for framing these reviews and reflections. This theory can facilitate decision making in difficult interactions and sustain a focus on the central agreements that are foundational to nursing education. Incivility exemplars are explored within the context of autonomy, freedom, objectivity, beneficence, and fidelity, and the integration of academia and ethics is discussed as essential to nursing education and human caring. PMID- 25275988 TI - Psychometric evaluation of a patient safety competency self-evaluation tool for nursing students. AB - This study aimed to evaluate the reliability and validity of a patient safety competency self-evaluation (PSCSE) tool. An exploratory factor analysis (EFA) was used to investigate the compositions of the PSCSE. The internal structure of the PSCSE was schematized using a confirmatory factor analysis (CFA). Three hundred fifty-four students attending six schools of nursing participated in the study. On the basis of the results of the CFA, the PSCSE consisted of 12 factors (four for attitude, six for skill, and two for knowledge) with a good model fit. It was confirmed that the structures of the PSCSE were identical between EFA and CFA. The PSCSE consisted of multidimensional structures of the 12 factors and hierarchical models of three categories. The PSCSE can be used to assess nursing students' perception of their own competency regarding patient safety and to develop educational strategies integrating patient safety competency into nursing curricula. PMID- 25275990 TI - Association of faculty perceptions of work-life with emotional exhaustion and intent to leave academic nursing: report on a national survey of nurse faculty. AB - The current and projected nurse faculty shortage threatens the capacity to educate sufficient numbers of nurses for meeting demand. As part of an initiative to foster strategies for expanding educational capacity, a survey of a nationally representative sample of 3,120 full-time nurse faculty members in 269 schools and programs that offered at least one prelicensure degree program was conducted. Nearly 4 of 10 participants reported high levels of emotional exhaustion, and one third expressed an intent to leave academic nursing within 5 years. Major contributors to burnout were dissatisfaction with workload and perceived inflexibility to balance work and family life. Intent to leave was explained not only by age but by several potentially modifiable aspects of work, including dissatisfaction with workload, salary, and availability of teaching support. Preparing sufficient numbers of nurses to meet future health needs will require addressing those aspects of work-life that undermine faculty teaching capacity. PMID- 25275991 TI - Mission possible: twenty-five years of university and college collaboration in baccalaureate nursing education. AB - In Canada, nurse educators from five postsecondary institutions in the province of British Columbia established a collaborative nursing education initiative in 1989, with a vision to transform RN college diploma programs to baccalaureate degree programs. The principles, processes, and structures that served to develop and sustain this nursing education initiative are briefly reviewed. Curriculum, scholarship, and education legislation serve as platforms to critically explore a 25-year history (1989-2014) of successes, challenges, and transitions within this unique nursing education collaboration. The importance of curriculum development as faculty development, program evaluation as an adjunct to pedagogical scholarship, diversity of cross-institutional mandates, political interplay in nursing education, collegiality, and courageous leadership are highlighted. Nurse educators seeking to create successful collaborations must draw upon well-defined principles and organizational structures and processes to guide pedagogical practices and inquiry while remaining mindful of and engaged in professional and societal developments. PMID- 25275992 TI - Evaluation of an integrated simulation courseware in a pediatric nursing practicum. AB - This study examined the effect of integrated pediatric nursing simulation courseware on students' critical thinking and clinical judgment. Ninety-five senior nursing students participated in this study. Every student followed the established courseware schedule, as well as the regular pediatric nursing practicum. The courseware schedule included two simple simulation scenarios and one comprehensive scenario on the first day of the first, second, and third weeks of the practicum. Students' critical thinking scores showed significant improvement after the use of simulation courseware using high-fidelity simulators and standardized patients. No significant predictors were found for improvement in critical thinking, but bivariate transformation of upper and lower groups in critical thinking achievement revealed a significant difference in the clinical judgment ability between the two groups. Simulation courseware supplementation is an innovative learning strategy for improving nursing students' critical thinking and clinical judgment during clinical practicum. Clinical judgment may play a role in facilitating nursing student improvement in critical thinking ability. PMID- 25275993 TI - Professional socialization of students enrolled in an online doctor of philosophy program in nursing. AB - A descriptive online survey design was used to describe professional socialization of students enrolled in an online Doctor of Philosophy (PhD) program in nursing. Twenty-six (48%) of 54 students participated by completing the Doctoral Student Socialization Questionnaire. Activities associated with four of the six dimensions of professional socialization, including student-peer interactions, supportive faculty environment, collegiality, and student scholarly encouragement, were prevalent in the analysis. Activities associated with student faculty interactions and preparation in scholarly activities were evident but were not prevalent. Students in an online PhD program in nursing can be socialized to the graduate school environment, as well as to their future role in an academic setting. Although challenging in the online environment, faculty need to promote activities related to student-faculty interactions and preparation in scholarly activities. PMID- 25275994 TI - Drug release from pH-sensitive polymeric micelles with different drug distributions: insight from coarse-grained simulations. AB - How to control the release of drugs from pH-sensitive polymeric micelles is an issue of common concern, which is important to the effectiveness of the micelles. The components and properties of polymers can notably influence the drug distributions inside micelles which is a key factor that affects the drug release from the micelles. In this work, the dissipative particle dynamics simulation method is first used to study the structural transformation of micelles during the protonation process and the drug release process from micelles with different drug distributions. And then the effects of polymer structures, including different lengths of hydrophilic blocks, pH-sensitive blocks and hydrophobic blocks, on drug release are also studied. In the end, several corresponding design principles of pH-sensitive polymers for drug delivery are proposed according to the simulation results. This work is in favor of establishing qualitative rules for the design and optimization of congener polymers for desired drug delivery, which is of great significance to provide a potential approach for the development of new multiblock pH-sensitive polymeric micelles. PMID- 25275999 TI - Nematicidal Effects of Silver Nanoparticles on Root-knot Nematode in Bermudagrass. AB - Certain nematodes are common soilborne organisms found in turfgrass in the United States that cause significant economic damage to golf course turf. One of the most prevalent plant-parasitic nematodes infesting turfgrass are root-knot nematodes (Meloidogyne spp.). Chemical treatment options for root-knot nematodes in turfgrass are limited, and there is a need for new nematicidal active ingredients to address this problem. In this study, we evaluated the use of silver nanoparticles (AgNP) as a potential nematicide in laboratory and field experiments. AgNP was synthesized by a redox reaction of silver nitrate with sodium borohydride using 0.2% starch as a stabilizer. When J2 of M. incognita were exposed to AgNP in water at 30 to 150 MUg/ml, >99% nematodes became inactive in 6 hr. When turfgrass and soil composite samples infested with M. graminis were treated with 150 MUg/ml AgNP, J2 were reduced in the soil samples by 92% and 82% after 4- and 2-d exposures, respectively, in the treated compared to the nontreated soil samples. Field trials evaluating AgNP were conducted on a bermudagrass (Cynodon dactylon * C. transvaalensis) putting green infested with M. graminis. Biweekly application of 90.4 mg/m(2) of AgNP improved turfgrass quality in one year and reduced gall formation in the roots in two years without phytotoxicity. The AgNP application did not significantly reduce the number of M. graminis J2 in plots during the growing season. The laboratory assays attested to the nematicidal effect of AgNP, and the field evaluation demonstrated its benefits for mitigating damage caused by root-knot nematode in bermudagrass. PMID- 25276000 TI - Efficacy of Organic Soil Amendments for Management of Heterodera glycines in Greenhouse Experiments. AB - In a repeated greenhouse experiment, organic soil amendments were screened for effects on population density of soybean cyst nematode (SCN), Heterodera glycines, and soybean growth. Ten amendments at various rates were tested: fresh plant material of field pennycress, marigold, spring camelina, and Cuphea; condensed distiller's solubles (CDS), ash of combusted CDS, ash of combusted turkey manure (TMA), marigold powder, canola meal, and pennycress seed powder. Soybeans were grown for 70 d in field soil with amendments and SCN eggs incorporated at planting. At 40 d after planting (DAP), many amendments reduced SCN egg population density, but some also reduced plant height. Cuphea plant at application rate of 2.9% (amendment:soil, w:w, same below), marigold plant at 2.9%, pennycress seed powder at 0.5%, canola meal at 1%, and CDS at 4.3% were effective against SCN with population reductions of 35.2%, 46.6%, 46.7%, 73.2%, and 73.3% compared with control, respectively. For Experiment 1 at 70 DAP, canola meal at 1% and pennycress seed powder at 0.5% reduced SCN population density 70% and 54%, respectively. CDS at 4.3%, ash of CDS at 0.2%, and TMA at 1% increased dry plant mass whereas CDS at 4.3% and pennycress seed powder at 0.1% reduced plant height. For Experiment 2 at 70 DAP, amendments did not affect SCN population nor plant growth. In summary, some amendments were effective for SCN management, but phytoxicity was a concern. PMID- 25276002 TI - Infectivity of Steinernema carpocapsae and S. feltiae to Larvae and Adults of the Hazelnut Weevil, Curculio nucum: Differential Virulence and Entry Routes. AB - We investigated the existing susceptibility differences of the hazelnut weevil, Curculio nucum L. (Coleoptera:, Curculionidae) to entomopathogenic nematodes by assessing the main route of entry of the nematodes, Steinernema carpocapsae strain B14 and S. feltiae strain D114, into larvae and adult insects, as well as host immune response. Our results suggested that S. carpocapsae B14 and S. feltiae D114 primarily entered adult insects and larvae through the anus. Larvae were more susceptible to S. feltiae D114 than S. carpocapsae B14 and adults were highly susceptible to S. carpocapsae B14 but displayed low susceptibility to S. feltiae D114. Penetration rate correlated with nematode virulence. We observed little evidence that hazelnut weevils mounted any cellular immune response toward S. carpocapsae B14 or S. feltiae D114. We conclude the differential susceptibility of hazelnut weevil larvae and adults to S. carpocapsae B14 and S. feltiae D114 primarily reflected differences in the ability of these two nematodes to penetrate the host. PMID- 25276001 TI - Identification of msp1 Gene Variants in Populations of Meloidogyne incognita Using PCR-DGGE. AB - Effectors of root-knot nematodes are essential for parasitism and prone to recognition by adapted variants of the host plants. This selective pressure initiates hypervariability of effector genes. Diversity of the gene variants within nematode populations might correlate with host preferences. In this study we developed a method to compare the distribution of variants of the effector gene msp1 among populations of Meloidogyne incognita. Primers were designed to amplify a 234-bp fragment of msp1. Sequencing of cloned PCR products revealed five msp1 variants from seven populations that were distinguishable in their reproduction on five host plants. A protocol for denaturing gradient gel electrophoresis (DGGE) was developed to separate these msp1 variants. DGGE for replicated pools of juveniles from the seven populations revealed ten variants of msp1. A correlation between the presence of a particular gene variant and the reproductive potential on particular hosts was not evident. Especially race 3 showed substantial variation within the population. DGGE fingerprints of msp1 tended to cluster the populations according to their reproduction rate on pepper. The developed method could be useful for analyzing population heterogeneity and epidemiology of M. incognita. PMID- 25276003 TI - Evaluation of 31 potential biofumigant brassicaceous plants as hosts for three meloiodogyne species. AB - Brassicaceous cover crops can be used for biofumigation after soil incorporation of the mowed crop. This strategy can be used to manage root-knot nematodes (Meloidogyne spp.), but the fact that many of these crops are host to root-knot nematodes can result in an undesired nematode population increase during the cultivation of the cover crop. To avoid this, cover crop cultivars that are poor or nonhosts should be selected. In this study, the host status of 31 plants in the family Brassicaceae for the three root-knot nematode species M. incognita, M. javanica, and M. hapla were evaluated, and compared with a susceptible tomato host in repeated greenhouse pot trials. The results showed that M. incognita and M. javanica responded in a similar fashion to the different cover cultivars. Indian mustard (Brassica juncea) and turnip (B. rapa) were generally good hosts, whereas most oil radish cultivars (Raphanus. sativus ssp. oleiferus) were poor hosts. However, some oil radish cultivars were among the best hosts for M. hapla. The arugula (Eruca sativa) cultivar Nemat was a poor host for all three nematode species tested. This study provides important information for chosing a cover crop with the purpose of managing root-knot nematodes. PMID- 25276005 TI - A trichodorus (triplonchida: trichodoridae) nematode from thrips (thysanoptera: panchaetothripinae). AB - A thrips insect Caliothrips sp. (Thysanoptera: Panchaetothripinae) from persimmon fruit (Ebenaceae: Diospyros sp.) from an unknown origin, possibly Asia, was intercepted in a passenger bag in November 2012 at the Peace Arch Border Crossing from Canada to Blaine, WA, by a USDA-APHIS-PPQ port inspector. Nematodes were attached to the abdomen of the female insect and sent to us in saline. Seven nematodes (five females, two males) were measured and these and others were processed for permanent slides. An adult female and a female juvenile were prepared for PCR. Morphologically these nematodes belonged to the Trichodorus sparsus group, and the 28S rDNA D2-D3 sequence showed greatest similarity to Trichodorus paragiennensis (94%) and T. giennensis (93%), with greatest morphological similarity to the latter species. Among other morphological differences, the innermost uterus width is wider than in related species. Trichodorus spp. are normally found in soil, so this is the first population seen in the atypical habitat of an insect. Morphological and molecular characteristics of Trichodorus sp. are presented, but a putative new species name is not currently advisable because of relatively poor condition of specimens. Ecological associations are also discussed. PMID- 25276004 TI - The Feeding Behavior of Adult Root-knot Nematodes (Meloidogyne incognita) in Rose Balsam and Tomato. AB - Meloidogyne incognita is a parasitic root-knot nematode that causes considerable yield loss in a wide range of plants. In this study we documented the movement of adult female nematodes for more than 2 hr in micro-slices of infected tomato (Solanum lycopersicum) and rose balsam (Impatiens balsamina) plants using light and video microscopy. Stylet thrusting was followed by short pumping actions of the esophagus, dorsal esophageal gland ampulla, and metacorpal bulb. Regular thrusting was normally accompanied by head turning and always preceded continuous stylet thrusting aimed at a single point (for 20 to 90 sec). Females often held the stylet in a protruded position, while pulsating the metacorpus bulb, for about 30 sec. Subsequently, the stylet was paused in a retracted position for 5 to 40 sec. This sequence of behavior took 290 to 380 sec to complete. The procedure developed in this study provides a useful cytological technique to investigate the interaction between root-knot nematodes and the giant cells formed by infected plants. Scanning electron microscopy revealed that the head of the adult nematode was located in the narrow intercellular spaces among several giant cells. The anterior part of the head of the adult was folded like a concertina, whereas that of the second-stage juvenile was not. The labial disc and medial lips of second-stage juveniles seemed expanded and sturdy, whereas those of the adult were star-shaped, appeared to be contracted, and softer. These morphological differences in the heads of adult and second-stage juveniles are discussed with respect to their movement. PMID- 25276006 TI - Electrodeposition of TiO2-RuO2-IrO2 coating on titanium substrate. AB - TiO2, RuO2, and IrO2 transition metal oxides have many applications in the field of applied electrochemistry. In this work, the mixed solid solutions of TiO2-RuO2 IrO2 coatings have been electrodeposited from aqueous-unaqueous baths. Moreover, the obtained coatings have been heated in the electric furnace at 450 degrees C. The microstructure of coating was characterized using scanning electron microscopy (SEM) and Atomic force microscopy (AFM). In order to investigate, the chemical composition and crystalline phases of coating, X-ray analysis, energy dispersive spectroscopy (EDS) were carried out. Furthermore, anodic polarization behavior of coating was investigated. Results show that heat treated coating at 450 degrees C with the chemical composition of TiO2/RuO2/IrO2 with molar ratio of 70/5/25 with six layer on substrate has the highest quality, stability, adhesion strength and minimum chlorine overvoltage. However, increasing the iridium content in electrolyte enhances the coating thickness and the quality of morphology. PMID- 25276007 TI - Comparison of Spatiotemporal Gait Parameters between Children with Normal Development and Children with Diplegic Cerebral Palsy. AB - [Purpose] The purpose of this study was to determine the differences in spatiotemporal gait parameters between children with spastic diplegic CP and children with normal development (ND). [Subjects and Methods] Sixteen children (eight children with spastic diplegic CP and eight ND children) were recruited for participation as volunteers in this study. The children with CP had a Gross Motor Function Classification (GMFC) System level of between I and II. [Results] Walking velocity, cadence, stride length, and step width of children with CP with a GMFC of between I and II were a level of 60%, 77%, 73%, and 160%, respectively, of those of ND children. The percentages of right and left double-limb support were 188% and 179% higher, respectively, and the proportion of single limb support was shorter by 83% and 82%. [Conclusion] Our results provide objective evidence of distinct differences in spatiotemporal gait parameters between children with spastic diplegic CP with a GMFC level I or II and ND children and would be helpful to persons involved in the care of these children. PMID- 25276008 TI - Change the myofascial pain and range of motion of the temporomandibular joint following kinesio taping of latent myofascial trigger points in the sternocleidomastoid muscle. AB - [Purpose] The purpose of this study was to identify the changes in the myofascial pain and range of the motion of temporomandibular joint when Kinesio taping is applied to patients with latent myofascial trigger points of the sternocleidomastoid muscle. [Subjects and Methods] The subjects were 42 males and females aged 20 to 30 years (male 17, female 25). They were randomly divided into the control group and the experimental group, which would receive Kinesio taping. Kinesio taping was applied to the sternocleidomastoid muscle three times per week for two weeks. The pain triggered when the taut band or nodule was palpated was measured. Pain intensity was measured using the visual analog scale (VAS) and pressure pain threshold (PPT). The range of motion of the temporomandibular joint was measured. In all subjects, VAS, PPT, and range of motion of the temporomandibular joint were measured before and after the intervention. [Results] In the experimental group, it was found that pain in the SCM was relived, as the VAS and PPT score decrease significantly and range of motion of temporomandibular joint increase significantly. In comparison between the groups, significant differences were shown in the VAS and PPT scores and in the range of motion of the temporomandibular joint. [Conclusion] Kinesio taping is thought to be an intervention method that can be applied to latent myofascial trigger points. PMID- 25276009 TI - Comparison between the Effects of Horseback Riding Exercise and Trunk Stability Exercise on the Balance of Normal Adults. AB - [Purpose] The aim of this study was to compare the effects of horseback riding exercise and trunk stability exercise on static and dynamic balance in normal adults. [Subjects and Methods] Twenty-two normal adults residing in communities were randomly divided into a horseback riding exercise group and a trunk stability exercise group, and they conducted exercise for eight weeks. [Results] Sway times of the COG (center of gravity) decreased significantly, and the A-P (anterior-posterior) and M-L (medial-lateral) velocities significantly decreased in both groups. A comparison of sway times of the COG after the intervention between the two groups revealed that the horseback riding exercise group showed larger decreases than the trunk stability exercise group. [Conclusion] In terms of the musculoskeletal factor, horseback riding may result in functional improvement and increased stability, and it may stimulate proprioceptive sense input in neurological terms. It is therefore considered a composite exercise method that may strengthen the two factors simultaneously. PMID- 25276011 TI - Effects of galvanic vestibular stimulation on visual memory recall and EEG. AB - [Purpose] This study aimed to examine the effects of galvanic vestibular stimulation (GVS) on visual memory recall and EEG. [Subjects and Methods] In the present study, 42 adults were selected and divided equally into two groups of 21 adults, the GVS group and the Sham group. The error rate was calculated as a percentage based on the total number of errors in the answers to 24 questions after stimulation, while the reaction time was measured in intervals between the time the questions were asked and the time it took the subjects to answer the questions. EEG data were obtained by attaching electrodes to the Fz, Cz, and Pz points during the question and answer phase. [Results] The error rate showed statistically significant differences in the interaction involving the time of response and group. The reaction time showed no statistically significant differences in the interaction involving the time of response and group. When relative band power parameters were analyzed, alpha waves showed no statistically significant differences in the interaction involving the time of response and group, but only the Fz area of beta waves showed statistically significant differences in the interaction involving the time of response and group. [Conclusion] GVS may improve visual memory recall in relation to a flower, a person, an animal, or a building. PMID- 25276010 TI - Influence of functional movement rehabilitation on quality of life in people with Parkinson's disease. AB - [Purpose] Parkinson's disease is one of the most frequent diseases of the central nervous system. Thorough knowledge of reasons for movement defects may contribute to the ability to quality of life at a good level as far as motor abilities are concerned. The aim of the study was to evaluate the influence of functional movement rehabilitation on the degree of intensity of movement symptoms in Parkinson's disease. [Subjects] The research was carried out in people diagnosed with stage III Parkinson's disease, according to the Hoehn and Yahr scale classification. [Methods] In order to establish the clinical state of patients, parts I, II, and III of the Unified Parkinson's Disease Rating Scale, the Schwab and England Activities of Daily Living scale, and the quality of life in Parkinson's disease questionnaire were applied. The intervention group took part in 60 minutes of functional movement rehabilitation twice a week for a period of 15 weeks. The main emphasis was placed on the ability to cope with everyday activities. [Results] A significant difference in scores for the given scales between before and after research the intervention period was observed in the intervention group. [Conclusion] The obtained results revealed positive that the influence of applied rehabilitation program had a positive influence on the degree of intensity of movement symptoms in people with Parkinson's disease. PMID- 25276012 TI - Factors Influencing the Dysmenorrhea among Korean Adolescents in Middle School. AB - [Purpose] This study aimed to examine the factors influencing dysmenorrhea among Korean middle school adolescents. [Subjects] The subjects included 572 female students in three different middle schools located in Seoul, South Korea. [Methods] A cross-sectional design was adopted. The measurement tools used included a demographic form and revised Menstrual distress Questionnaire (MDQ). [Results] The analyses showed that the prediction model was significant. The value of the adjusted R(2) was 0.282, which corresponds to an explanatory power of 28.2%. The factor found to have the most influence on dysmenorrhea among Korean middle school adolescents was stress, followed by health status, onset of dysmenorrhea, consecutive days of menstruation, and dietary habits. [Conclusion] Nursing intervention programs for alleviating dysmenorrhea in Korean middle school adolescents are essential in order to reduce their level of stress, improve their perceived health status, and help them to maintain regular dietary habits. Reflecting on the recent trend of female students menstruating at a younger age, public health education courses and counseling programs should offer customized methods for alleviating dysmenorrhea. PMID- 25276013 TI - Influences of Changes in the Level of Support and Walking Speed on the H Reflex of the Soleus Muscle and Circulatory Dynamics on Body Weight-supported Treadmill Training: Investigation in Healthy Adults. AB - [Purpose] To investigate the therapeutic usefulness of treadmill walking using a body weight support device (BWS), changes in circulatory dynamics and muscle activities with various levels of support were investigated. [Subjects and Methods] The subjects were divided into 3 groups: 20% BWS, 40% BWS, and full body weight (FBW). The subjects walked at maximum and normal speeds. Under each condition, H and M waves and skin temperature before and after walking and changes in the heart rate during walking were measured. [Results] The heart rate continued to increase after 3 minutes of FBW at the maximum walking speed, but a steady state was reached after 3 minutes under the other walking conditions. Regarding skin temperature, no significant difference from that at rest was noted 30 minutes after walking at the normal speed, but it was significantly higher than that at rest at 30 minutes after walking at the maximum speed. The H/M ratio was significantly higher after walking at the maximum walking speed in the FBW and 20% BWS groups compared with the 40% BWS groups. [Conclusion] Treatment with 40% BWS at the maximum walking speed was safe for the circulatory system and may be effective in elevating the skin temperature for a prolonged period compared with the effects of the other walking conditions at normal speed. PMID- 25276014 TI - Comparison of Lower Limb Muscle Activity during Eccentric and Concentric Exercises in Runners with Achilles Tendinopathy. AB - [Purpose] This study aimed to identify changes in muscle activation by comparing muscle activities of the affected side (AS) and non-affected side (NAS) during eccentric and concentric exercises in runners with unilateral Achilles tendinopathy. [Subjects] The study included 18 participants consisting of men and women with chronic Achilles tendinopathy in a single leg who had more than 1 year of running experience. [Methods] All subjects performed concentric and eccentric exercise with the Achilles tendon moving from full plantar flexion to full dorsiflexion for 8 seconds, and electromyography data was obtained. [Results] All muscles examined showed a significant increase in %maximal voluntary contraction (MVC) with concentric exercise compared with eccentric exercise. Compared with the NAS, the AS showed significant increases in %MVC of the rectus femoris, tibialis anterior, and lateral gastrocnemius. All interaction effects of exercise methods and injuries showed statistically significant changes. [Conclusion] Runners with Achilles tendinopathy show increases in medial gastrocnemius activity when performing eccentric exercise. PMID- 25276015 TI - Effects of pulsed electromagnetic field and swimming exercise on rats with experimental sciatic nerve injury. AB - [Purpose] The current study aimed to reveal the therapeutic effects of a pulsed electromagnetic field and swimming exercises on rats with experimental sciatic nerve injury, which was induced with crush-type neuropathy model damage, using electrophysiological methods. [Subjects] In the current study, the sample consisted of 28 adult male Wistar albino rats. [Methods] The rats were randomized into four groups (n=7). Swimming exercise and PEMF (2 Hz and 0.3 MT) were applied one hour a day, five days a week, for four weeks. Electroneuromyographic (ENMG) measurements were taken on day 7. [Results] When the data were evaluated, it was found that the 4 weeks of PEMF and swimming exercises led to an increase in motor conduction rates and a decrease in latency values, but the changes were not significant in comparison with the control and injury groups. The compound muscle action potential (CMAP) values of the left leg were lower in weeks 2, 3, and 4 in the swimming exercise group in comparison with the control group, although for the PEMF group, the CMAP values of the left leg reached the level observed in the control group beginning in week 3. [Conclusion] PEMF and swimming exercise made positive contributions to nerve regeneration after week 1, and regeneration was enhanced. PMID- 25276016 TI - Effects of open and closed kinetic chains of sling exercise therapy on the muscle activity of the vastus medialis oblique and vastus lateralis. AB - [Purpose] The muscle strength of the quadriceps muscle is critical in patellofemoral pain syndrome. The quadriceps muscle supplies the power for dynamic patellar movement, and the vastus medialis oblique (VMO) and vastus lateralis (VL) enable the patella to stabilize during tracking. We followed the theories about open and closed kinetic chain exercises to design two exercises, sling open chain knee extension (SOCKE) exercise and sling closed chain knee extension (SCCKE) exercise. The purpose of our study was to research the changes in quadriceps muscle activity during both exercises. [Methods] Electromyographic analysis was used to explore the different effects of the two exercises. The MVC% was calculated for the VMO and VL during exercise for analysis. [Results] We found that the mean MVC% values of the VMO and VL during the SOCKE exercise were higher than those during the SCCKE exercise. The ratio of the VMO to VL was 1.0 +/- 0.19 during the SOCKE exercise and 1.11 +/- 0.15 during the SCCKE exercise. [Conclusions] The SOCKE exercise is targeted at quadriceps muscle training and has a recruitment effect on the VMO. The beneficial effect of the SOCKE exercise is better than that of the SCCKE exercise. PMID- 25276017 TI - The Effects of Exercise Therapy on CVD Risk Factors in Women. AB - [Purpose] The purpose of this study was to search for the association of Type D personality and CVD risk factors through comparison of the association of exercise participation with CVD risk factors in women. [Subjects] The research subjects were randomly assigned to four groups: Type D+Exercise (n=12), Type D+non-exercise (n=12), non-Type D+Exercise (n=12), and non-Type D+non-exercise (n=10). The study consisted of 46 participants. [Methods] An aerobic exercise program and meditation were conducted in parallel for 10 months. Stretching was performed for 10 min as a warm-up, and then walking and running on a treadmill at 60 to 70% of HRmax were performed for 40 min three times a week. Blood samples were processed according to standard laboratory procedures. The concentrations of TG and HDL cholesterol were determined enzymatically using a clinical chemistry analyzer (Hitachi High-Technologies Corporation, Tokyo, Japan). [Results] The weight, percentage of body fat, waist circumference, triglyceride concentration, HDL cholesterol concentration, systolic blood pressure, and diastolic blood pressure showed a significant difference between measurement times in the exercise groups. [Conclusion] In conclusion, there were significant differences between groups in terms of cardiovascular disease risk factors. PMID- 25276018 TI - The effect of kinesio taping in forward bending of the lumbar spine. AB - [Purpose] The aim of this study was to evaluate the influence of a lumbar fascia Kinesio Taping((r)) technique forward bending range of motion. [Subjects and Methods] This was a longitudinal study with a randomized clinical trial composed of 39 subjects divided into three groups (control, Kinesio Without Tension-KWT, and Kinesio Fascia Correction-KFC). The subjects were assessed by Schober and fingertip-to-floor tests and left the tape in place for 48 hours before being reassessed 24 hours, 48 hours and 30 days after its removal. [Results] In all three experimental groups no significant differences were observed with the Schober test, but it was possible to observe an increase in lumbar flexion after 30 days. With the fingertip-to-floor distance assessment, the KFC and KWT groups showed significantly improved flexibility 24 hours and 48 hours after tape removal. [Conclusion] The Kinesio Taping((r)) influenced fascia mobility, allowing for slight improvement of lumbar flexibility. PMID- 25276019 TI - Physical Therapy Entry-level Education and Post-professional Training in Saudi Arabia: A Comparison of Perceptions of Physical Therapists from Five Regions. AB - [Purpose] The goal of this study was to examine potential differences in physical therapists' perceptions of content areas for the new entry-level Doctor of Physical Therapy (DPT) curricula and specialties for post-graduate residency and fellowship programs among five geographical regions in Saudi Arabia. [Subjects and Methods] All physical therapists in Saudi Arabia were invited to participate in this cross-sectional study, which was conducted via a web-based survey. The first domain queried the importance of introducing 10 content areas into future DPT curricula. The second domain concerned the importance of developing residency and fellowship programs in nine subspecialties. Descriptive statistics were generated, and an analysis of variance with a post hoc Tukey's HSD test was used to evaluate the significance of differences in the physical therapists' perceptions across the geographical regions. [Results] In total, 148 participants responded to the survey. Significant differences were found among respondents in different geographical regions for 4 of the 10 skills and 3 of the 9 subspecialties. [Conclusion] Understating the variations between the five regions would be helpful in developing a new model for future DPT and post-professional programs that addresses potentially unique needs perfectly. Future research is needed to confirm the findings in a wide range of stakeholders. PMID- 25276020 TI - The intervention effects of different treatments for chronic low back pain as assessed by the thickness of the musculus transversus abdominis. AB - [Purpose] The purpose of this study was to examine the immediate effects of an intervention comprising proprioceptive neuromuscular facilitation (PNF) or neuromuscular joint facilitation (NJF) on chronic low back pain as assessed by the thickness of musculus transversus abdominis [Subjects] The subjects were 12 young people (five males, seven females) who had chronic low back pain on one side for more than 6 months. [Methods] Subjects were asked to lie their sides with the painful side facing up. The subjects received PNF or NJF exercise treatments. The changes in the musculus transversus abdominis thickness were measured using ultrasonography. [Result] The thickness of the musculus transversus abdominis in the NJF group increased significantly and was higher than that in the PNF group and at rest. [Conclusion] The results showed that significantly better improvement can be obtained for chronic low back pain by applying NJF patterns to the musculus transversus abdominis. PMID- 25276021 TI - OSCE-based Clinical Skill Education for Physical and Occupational Therapists. AB - [Purpose] The aim of this study was to examine the applicability of the Objective Structured Clinical Examination (OSCE) to postgraduate education systems for novice and mid-career therapists in workplaces. [Subjects] Physical and occupational therapists with 1 to 5 years of clinical experience took the OSCE to assess their learning, with a physical or occupational therapy faculty member and a clinical supervisor as examiners. Another clinical supervisor acted as a simulated patient. [Methods] A Wilcoxon signed-rank test was performed to compare skills between before and after OSCE-based learning, and a Mann-Whitney U test was used to compare them between therapists with 1 to 2 years (novice) and 3 to 5 years (mid-career) of clinical experience. [Results] While no experience-related differences were observed in behavioral aspects, mid-career therapists exhibited markedly higher scores compared with novices in technical aspects, such as skills to guide patients for standing up, transfer, and dressing. [Conclusion] The OSCE may be sufficiently applicable to postgraduate education systems in workplaces. PMID- 25276022 TI - Ultrasound evaluation of muscle thickness changes in the external oblique, internal oblique, and transversus abdominis muscles considering the influence of posture and muscle contraction. AB - [Purpose] The aim of this study was to investigate muscle thickness changes in the external oblique (EO), internal oblique (IO), and transversus abdominis (TrA) muscles between the neutral position and trunk rotation, under a state of rest without voluntary contractions, and isometric contractions to both sides with resistance of 50% of the maximum trunk rotation strength. [Subjects] The subjects of this study were 21 healthy young men. [Methods] Muscle thickness changes in the EO, IO, and TrA in each position and state were evaluated by ultrasound. The range of motion at maximum trunk rotation and the maximum strength of trunk rotation were measured using a hand-held dynamometer. [Results] In the neutral position and at 50% trunk rotation to the right side, the thicknesses of the IO and TrA significantly increased with resistance. In both states, the thicknesses of the IO and TrA significantly increased at 50% trunk rotation to the right side. [Conclusion] The muscular contractions of the IO and TrA were stronger during ipsilateral rotation than in the neutral position and with resistance than at rest. Moreover, the muscular contraction was strongest in the resistive state during ipsilateral rotation. PMID- 25276023 TI - Comparison of Center of Force Trajectory during Sit-to-stand Movements Performed by Elderly and Old-old Elderly Subjects. AB - [Purpose] This study compared the center of force (COF) trajectory during sit-to stand (STS) movements performed by elderly and old-old elderly subjects. [Subjects] We recruited 9 elderly and 10 old-old elderly subjects with no knee joint pain or lower limb orthopedic problems. [Methods] The CONFORMat system was used to measure the length of the COF trajectory as the subjects performed the STS task. [Results] The total length of the COF trajectory during the STS movement was significantly greater for the old-old elderly group than for the elderly group. [Conclusion] Our results highlight the need for novel strategies or the development of assistive devices to reduce the COF trajectory during the STS movement for old-old elderly individuals. PMID- 25276024 TI - Evaluation of oxidative stress parameters and urinary deoxypyridinoline levels in geriatric patients with osteoporosis. AB - [Purpose] To evaluate the oxidative stress parameters and urinary deoxypyridinoline levels in geriatric patients with osteoporosis. [Subjects and Methods] Eighty geriatric patients aged over 65 years were recruited. Patients were divided into two groups: Group 1 (n=40) consisted of patients with osteoporosis, and Group 2 (n=40) consisted of patients without osteoporosis. Bone mineral density measurements were performed for all patients using DEXA. Oxidative stress parameters were analyzed in blood samples, and deoxypyridinoline levels were analyzed in 24-hour urinary samples. [Results] Compared to Group 2, the total antioxidant status and oxidative stress index levels of Group 1 were not significantly different; however, total oxidant status and 24-hour urinary deoxypyridinoline levels were significantly higher. Pearson correlation coefficients indicated that OSI and urinary deoxypyridinoline levels were not correlated with any biochemical parameters. ROC-curve analysis revealed that urinary deoxypyridinoline levels over 30.80 mg/ml predicted osteoporosis with 67% sensitivity and 68% specificity (area under the curve = 0.734; %95 CI: 0.624 0.844). [Conclusion] Our results indicate that oxidative stress would play a role in the pathogenesis of osteoporosis, and that urinary deoxypyridinoline levels may be a useful screening test for osteoporosis. PMID- 25276025 TI - Effect of training with whole body vibration on the sitting balance of stroke patients. AB - [Purpose] The purpose of this study was to determine the effects of task-oriented training with whole body vibration (WBV) on the sitting balance of stroke patients. [Subjects] The subjects were 30 stroke patients who were randomly divided into experimental (n1=15) and control (n2=15) groups. [Methods] Subjects in both groups received general training five times per week. Subjects in the experimental group practiced an additional task-oriented training program with WBV, which was performed for 15 minutes, five times per week, for four weeks. The center of pressure (COP) path length and average velocity were used to assess subjects static sitting balance, and the Modified Functional Reach Test (MFRT) was used to assess their dynamic sitting balance. The paired t-test was performed to test the significance of differences between before and after the intervention. The independent t-test was conducted to test the significance of differences between the groups. [Results] Following the intervention, the experimental group showed a significant change in MFRT. [Conclusion] The results of this study suggest that task-oriented training with WBV is feasible and efficacious for stroke patients. PMID- 25276026 TI - Treadmill sideways gait training with visual blocking for patients with brain lesions. AB - [Purpose] The aim of this study was to verify the effect of sideways treadmill training with and without visual blocking on the balance and gait function of patients with brain lesions. [Subjects] Twenty-four stroke and traumatic brain injury subjects participated in this study. They were divided into two groups: an experimental group (12 subjects) and a control group (12 subjects). [Methods] Each group executed a treadmill training session for 20 minutes, three times a week, for 6 weeks. The sideways gait training on the treadmill was performed with visual blocking by the experimental group and with normal vision by the control group. A Biodex Gait Trainer 2 was used to assess the gait function. It was used to measure walking speed, walking distance, step length, and stance time on each foot. The Five-Times-Sit-To-Stand test (FTSST) and Timed Up and Go test (TUG) were used as balance measures. [Results] The sideways gait training with visual blocking group showed significantly improved walking speed, walking distance, step length, and stance time on each foot after training; FTSST and TUG times also significantly improved after training in the experimental group. Compared to the control group, the experimental group showed significant increases in stance time on each foot. [Conclusion] Sideways gait training on a treadmill with visual blocking performed by patients with brain lesions significantly improved their balance and gait function. PMID- 25276027 TI - The affect on delayed onset muscle soreness recovery for ultrasound with bee venom. AB - [Purpose] The purpose of this study was to evaluate whether ultrasound alone or ultrasound with bee venom is effective in treating delayed onset muscle soreness of the biceps brachii muscle, using the visual analogue scale, range of motion test (flexion and extension), and serum creatine kinase level. [Subjects] Twenty women participated in this study. [Methods] Repeated eccentric contractions were used to induce delayed onset muscle soreness in the elbow flexor of the subjects. The subjects were randomized to be treated with ultrasound alone or ultrasound with bee venom. We evaluated the effects of treatments in the 2 groups. Individual subjects were assessed using the visual analogue scale, range of motion test, and serum creatine kinase level. The assessment parameters were evaluated 4 times: before exercise and 24, 48, and 72 hours after exercise. [Results] The visual analogue scale scores were significantly different before and after the experiment in both the group treated with ultrasound and the group treated with ultrasound and bee venom. The difference in elbow flexion and extension before and after the experiment was significantly different in both groups. No significant difference was found in the serum creatine kinase levels before and after the experiment. [Conclusion] Treatment with ultrasound and bee venom is effective for managing delayed onset muscle soreness. PMID- 25276028 TI - Analysis of Risk Factors for Work-related Musculoskeletal Disorders in Radiological Technologists. AB - [Purpose] The aim of this study was to analyze, through ergonomic analyses, those motions most used by radiological technologists that can cause musculoskeletal disorders. [Subjects and Methods] The subjects were 7 radiological technologists with work experience in hospitals for more than 5 years. For the analysis of working postures, we simulated the work posture of radiological technologists when moving patients, when pushing or pulling an apparatus, when conducting ultrasonography, and when handling a mouse for MRI were analyzed. [Results] In this study, the burdens on the radiological technologists' waists were shown to be high when they were moving patients for a CT scan. During mouse handling for an MRI scan, large burdens were imposed on the neck. In the case of ultrasonography working postures, larger burdens on the leg and neck were found when the patient's examination sites were located further away. The assessment of working postures when pushing a portable radiation apparatus showed that burdens on the musculoskeletal system increased as the weight of the apparatus increased. [Conclusion] The musculoskeletal disorders of radiological technologists occur in various regions of their bodies but occur most frequently in the shoulder and the lumbar region. Therefore, hospitals need to be educated regarding the concept of musculoskeletal disorders. PMID- 25276029 TI - Revision of the predictive method improves precision in the prediction of stroke outcomes for patients admitted to rehabilitation hospitals. AB - [Purpose] The purpose of this study was to confirm the accuracy of a revised method for predicting the Functional Independence Measure (FIM) at discharge when stroke patients are first admitted to a rehabilitation hospital. [Subjects and Methods] The predictive equation with logarithmic trend line was calculated based on the total score of the FIM at admission and discharge in 93 patients with cerebral infarction (CI) and 60 patients with intracerebral hemorrhage (ICH). In other patients with CI or ICH (validation group), the differences between the actual FIM and the predicted FIM at discharge calculated by the CI or ICH equation and the combined (CI + ICH) equation, as well as by the CI or ICH equation and combined equation used in a previous study, were calculated. [Results] The multiple correlation coefficients of the CI equation, ICH equation, and combined equation were 0.87, 0.71, and 0.8. The residual of the actual FIM and predicted FIM at discharge calculated by the CI equation was the smallest in the CI validation group. In the ICH validation group, the residual calculated for ICH patients alone was smaller than that calculated by the previous ICH equation. [Conclusion] This easy-to-use method using a new equation for prediction was more precise than the previous equation. Therefore, we should revise the equation for predicting stroke patient outcome strata according to data from within the governing medical administration system. PMID- 25276030 TI - Upper extremity problems in doner kebab masters. AB - [Purpose] Doner kebab is a food specific to Turkey; it is a cone-shaped meat placed vertically on a high stand. The doner kebab chefs stand against the meat and cut it by using both of their upper extremities. This work style may lead to recurrent trauma and correspondingly the upper extremity problems. The aim of this study was to investigate the upper extremity disorders of doner chefs. [Subjects and Methods] Doner kebab chefs were selected as the study group, and volunteers who were not doner kebab chefs and didn't exert intense effort with upper extremities their business lives were selected as the control group. A survey form was prepared to obtain data about the participants' ages, working experience (years), daily work hours, work at a second job, diseases, drug usage, and any musculoskeletal (lasting at least 1 week) complaint in last 6 months. [Results] A total of 164 individuals participated in the study, 82 doner chefs and 82 volunteers. In 20.6% of the study group and 15.6% of the control group, an upper extremity musculoskeletal system disorder was detected. Lateral epicondylitis was more frequently statistically significant in the work group. [Conclusion] Hand pain and lateral epicondylitis are more frequent in doner chefs than in other forms of business. PMID- 25276031 TI - A Three-dimensional Gait Analysis of People with Flat Arched Feet on an Ascending Slope. AB - [Purpose] The purpose of the study was to discover why people who have flat feet show a higher risk of damage to the musculoskeletal system than those who have normal feet. Furthermore, we examined the kinematic differences in the lower extremity between flat feet and normal feet in individuals on an ascending slope using three-dimensional gait analysis. [Subjects] This study was conducted on 30 adults having normal feet (N = 15) and flat feet (N = 15), all of whom were 21 to 30 years old. [Methods] A treadmill (AC5000M, SCIFIT, Berkshire, UK) was used to analyze the kinematic features during gait. These features were analyzed at slow, normal, and fast gait velocities on an ascending slope. Gait data were obtained using a 6-camera motion analysis system (Eagle system, Motion Analysis, Santa Rosa, CA, USA). [Results] Both groups showed significant differences in the sagittal, frontal, and transverse planes according to the speed changes. After comparing the lower extremity kinematics between those with flat feet and those with normal feet, significant differences were found with respect to hip adduction (frontal plane) in the stance phase and hip internal rotation (transverse plane) in the swing phase. [Conclusion] Due to hip adduction, the internal rotation angle of the lower extremity has a tendency to increase according to the increase in gait velocity on an ascending slope, and we can expect that the hip adductor muscles and internal rotator muscles in individuals with flat feet are used much more than would be the case for those with normal feet when they perform actions that require a lot of power, such as walking on an ascending slope and walking quickly. PMID- 25276032 TI - Effects of the Electrode Type on N100 and P300 in tDCS Applications. AB - [Purpose] This study investigated the effects of types of electrode on N100 and P300 in transcranial direct current stimulation (tDCS) applications. [Subjects and Methods] Thirty subjects were randomly assigned to two groups with 15 subjects in each group depending on the electrode types. A positive electrode on the primary motor area (C4) and a negative electrode on the left primary motor area (C3), and stimulation was applied for 20 minutes. Before and after tDCS, N100 and P300 were measured by attaching an electrode to Fp1 and Fp2. [Results] In tDCS applications, N100 and P300 showed no significant interaction effects between time and group for either latency or amplitude in the Fp1 and Fp 2 areas, but there was a statistically significant difference in the main effect duration. [Conclusion] The latencies of N100 and P300 were shortened and that their amplitudes increased in both the Fp1 and Fp2 areas, regardless of the type of electrode. PMID- 25276033 TI - Effects of the Indoor Horseback Riding Exercise on Electromyographic Activity and Balance in One-leg Standing. AB - [Purpose] This study investigated the influence of the indoor horseback riding exercise on the electromyographic activity of the lower extremity and balance during one-leg standing. [Subjects] Twenty normal adults were divided into an indoor horseback riding exercise group (IHREG, n=10), which performed the indoor horseback riding exercise using equipment 3 times a week for 3 weeks, and a control group (CG, n=10), which performed no exercise. [Methods] For comparitive analysis, an electromyographic test was performed to measure the electromyographic activities of the rectus femoris (RF), adductor longus (AL), and gluteus medius and the Biodex Balance System was used to measure the anteroposterior stability index (APSI), mediolateral stability index, and overall stability index (OSI). [Results] The electromyographic activities of RF and AL significantly increased and the balance abilities of APSI and OSI decreased significantly in the IHREG compared to the CG. [Conclusion] We consider indoor horseback riding exercise is an effective intervention for increasing electromyographic activities of the RF and AL, and the balance abilities of APSI and OSI of normal adults. PMID- 25276034 TI - Adapted low intensity ergometer aerobic training for early and severely impaired stroke survivors: a pilot randomized controlled trial to explore its feasibility and efficacy. AB - [Purpose] To evaluate the feasibility and efficacy of adapted low intensity ergometer aerobic training for early and severely impaired stroke survivors. [Subjects] The subjects were forty-eight early stroke survivors. [Methods] Eligible subjects were recruited and randomly assigned to an experimental group and a control group. Both groups participated in comprehensive rehabilitation training. Low intensity aerobic training was only performed by the experimental group. Outcome measures were the Fugl-Meyer motor score, Barthel index, exercise test time, peak heart rate, plasma glucose level and serum lipid profiles. [Results] Patients in the experimental group finished 88.6% of the total aerobic training sessions prescribed. In compliant participants (adherence>=80%), aerobic training significantly improved the Barthel index (from 40.1+/-21.1 to 79.2+/ 14.2), Fugl-Meyer motor score (from 26.4+/-19.4 to 45.4+/-12.7), exercise test time (from 12.2+/-3.62 min to 13.9+/-3.6 min), 2-hour glucose level (from 9.22+/ 1.16 mmol/L to 7.21+/-1.36 mmol/L) and homeostasis model of assessment for insulin resistence index (from 1.72+/-1.01 to 1.28+/-0.88). [Conclusion] Preliminary findings suggest that early and severely impaired stroke patients may benefit from low intensity ergometer aerobic training. PMID- 25276035 TI - Prevalence of Sport Injuries among Middle School Children and Suggestions for Their Prevention. AB - [Purpose] The purpose of this study was to determine the incidence of injuries of children participating in sports, and to present advice on injury prevention. [Subjects and Methods] The study subjects were 445 children involved in sports with a mean age of 12.74+/-1.03 years, a mean height of 156.56+/-10.82 cm, and a mean weight of 45.39+/-10.29 kg; 52.8% of the study subjects were male, and 47.2% were female. The subjects were surveyed using a questionnaire developed by the author. [Results] The highest incidence of sport injury was in the foot-ankle region, and the lowest incidence was in the hip-femur region. The incidences of injuries to the neck, shoulder, elbow, hand, wrist, superior dorsal region, waist, hip-femur region, knee, and foot-ankle regions weren't statistically significant. [Conclusion] This study established that children participating in competitive sports are at risk of injury. The causes of injuries were examined to propose preventive measures to minimize their occurrence and severity. It should not be overlooked that injuries can occur more easily among children because their musculoskeletal system is not fully developed, and coaches should be educated in the appropriate training intensities for children. PMID- 25276036 TI - Serum bone markers levels and bone mineral density in familial mediterranean Fever. AB - [Purpose] The aim of this study was to measure bone mineral density, serum and urinary bone turnover parameters, and to evaluate the influence of demographic and genetic factors on these parameters in FMF patients. [Subjects and Methods] Twenty-seven attack-free patients who were diagnosed with FMF (in accordance with Tel Hashomer criteria) were recruited at outpatient rheumatology clinics. We investigated whether there were any differences between the FMF patients and a control group in terms of lumbar and femur bone mineral density (BMD), standard deviation scores (Z scores and T scores) and bone markers. [Results] In terms of the median values of lumbar BMD (p = 0.21), lumbar T (p = 0.098) and Z (p = 0.109) scores, femoral neck BMD, femoral T and Z scores and total femur BMD, T (p = 0.788) and Z scores, there were no significant differences. [Conclusion] In our study, no statistically significant differences were found between FMF patients and a control group in terms of osteoporosis. The 25-OH vitamin D was found to be significantly lower in FMF patients than in the control group. PMID- 25276037 TI - Isokinetic training effect of ankle positions on knee extensor strength. AB - [Purpose] The purpose of this study was to determine which ankle position most influences knee extensor strength in training programs for strengthening the knee extensors using three different active ankle positions. [Subjects] Twenty-one healthy adults (6 males and 15 females) participated in this study. [Methods] Subjects were trained isokinetically in knee extension and flexion at 70 or 80% of 1RM under three actively and naturally fixed, contracted ankle conditions: dorsiflexion, plantarflexion, and resting position. After each group successfully executed the training four times a week for three weeks, mean peak torque (PT) and total work (TW) variables were measured and compared at 60 degrees /sec and 180 degrees /sec among the three groups. [Results] Significant differences were revealed in knee extensor TW at 60 degrees /sec, PT and TW at 180 degrees /sec, with the greatest PT and TW observed with the ankle in active dorsiflexion position. [Conclusion] These results suggest that active ankle dorsiflexion in a knee strength training program may be more effective at increasing knee extensor strength than a resting or plantarflexion position. PMID- 25276038 TI - Characteristics of upper quadrant posture of young women with temporomandibular disorders. AB - [Purpose] This study aimed to investigate the characteristics of upper quadrant posture of young women with temporomandibular disorders. [Subjects] The participants were 19 female patients with temporomandibular disorders (patient group: mean age, 30.1 years) and 14 controls (control group: mean age, 24.6 years). [Methods] Outcome measures were the neck inclination angle (formed by a line connecting C7 and the ear tragus with a horizontal line), the angle of the shoulder (formed by a line connecting C7 and the acromial angle with a horizontal line), the cranial rotation angle (formed by a line connecting the ear tragus and the corner of the eye with a horizontal line), and the neck-length/shoulder-width ratio [the ratio of the neck length (from C7 to the tragus) to the width of the shoulder between the acromial angle]. The maximum range of mouth opening was measured using a scale. [Results] The neck inclination angle and maximum range of mouth opening were significantly smaller in the patient group than in the control group. No significant differences were observed in the other outcome measures between the two groups. [Conclusion] Temporomandibular disorders with limited mouth opening in young females are associated with the head position relative to the trunk. PMID- 25276039 TI - The effect of trunk stabilization exercises with a swiss ball on core muscle activation in the elderly. AB - [Purpose] The purpose of this study was to investigate the effects of trunk stabilization exercise on the muscle EMG activations related to core stability. [Subjects and Methods] Fifteen elderly people in a geriatric hospital performed trunk stabilization exercises with a Swiss ball for 20 minutes five times per week for 8 weeks. Trunk muscle activations were measured using electromyography before and after the intervention. [Results] After the intervention, the muscle activations of the rectus abdominis, erector spinae, lateral low-back (quadratus lumborum and external oblique), and gluteus medius muscles increased significantly. [Conclusion] The trunk stabilization exercise with a Swiss ball significantly increased the muscle activities of the elderly. PMID- 25276040 TI - Comparison of children with joint angles in spastic diplegia with those of normal children. AB - [Purpose] The purpose of this study was to compare joint angles between normal children and those with spastic diplegia using three-dimensional gait analysis. [Subjects and Methods] The study subjects were eight patients with spastic diplegia and eight normal children. Three-dimensional gait analysis was used for the survey. The measured gait variables were the joints of the lower extremity in the sagittal plane, frontal plane, and transverse planes and the maximum and minimum angles of their stance phase and swing phases. [Results] In the sagittal plane, the maximum angles of both the right and left pelvis and hip joint in the stance phase and swing phases were significantly greater for children with spastic diplegia than for normal children. In the stance phase of the right side of the hip joint, the maximum angles of the hip in the swing phase and the knee joint's minimum angles in the stance phase differed significantly. In the transverse plane, there were a significant differences on the left side of the pelvis in the maximum angles in the swing and stance phases. There were also significant differences on the right side pelvis, in the maximum and minimum angles in the stance phase and minimum angles in the swing phase. [Conclusion] Children with spastic diplegia employ a different gait strategy and pattern from normal children. PMID- 25276041 TI - The effects of closed kinetic chain exercises and open kinetic chain exercises using elastic bands on electromyographic activity in degenerative gonarthritis. AB - [Purpose] The purpose of this study was to examine the effects of closed kinetic chain exercises (CKCEs) and open kinetic chain exercises (OKCEs) with elastic bands on the electromyographic activity of patients with degenerative gonarthritis. [Subjects] The study subjects were 30 degenerative gonarthritis patients who were divided into a CKCE group (CKCEG, n=10), an OKCE group (OKCEG, n=10), and a control group (CG, n=10). [Methods] The CKCEG and the OKCEG performed exercises with elastic bands, and the CG took part in a quadriceps strengthening exercise. All three groups performed the exercises three times per week for four weeks. The electromyographic activities of the subjects' vastus medialis (VM), rectus femoris (RF), vastus lateralis (VL), semitendinosus (ST), and biceps femoris (BF) muscles were measured and compared. [Results] Within group comparisons revealed that the electromyographic activities of the VM, RF, VL, ST, and BF muscles increased significantly in the CKCEG. The OKCEG displayed significant increases in the electromyographic activity of the VM, RF, ST, and BF muscles, and the CG showed significant increases in the electromyographic activities of the RF, VL, ST, and BF muscles. In between-group comparisons after the intervention, the electromyographic activities of the VM, RF, and VL muscles of the CKCEG were significantly higher than those of the CG. The electromyographic activities of the VM, RF, and ST muscles of the OKCEG were significantly higher than those of the CG. [Conclusion] We consider CKCEs with elastic bands are an effective intervention for increasing the electromyographic activities of the VM, RF, VL, ST, and BF muscles of degenerative gonarthritis patients, and OKCEs with elastic bands are an effective intervention for increasing the electromyographic activities of the VM, RF, ST, and BF muscles of degenerative gonarthritis patients. PMID- 25276042 TI - The effects of squat exercises in postures for toilet use on blood flow velocity of the leg vein. AB - [Purpose] The purpose of this study was to identify the effects of squat exercises performed in toilet-using postures on the blood flow velocity of the lower extremities for the prevention of deep vein thrombosis. [Subjects] The subjects were 28 students who were attending B University in Cheonan. They were divided into a group of 14 subjects of sitting toilet users and a group of 14 subjects of squat toilet users. [Methods] The subjects performed squat exercises in different toilet-using postures and we investigated the changes in blood flow velocity. [Results] The variations in blood flow velocities before and after the exercises showed significant differences in both groups but the differences between the two groups were not significant. [Conclusion] Based on the results of this study, we consider squat exercises are effective at improving the variation in lower-extremity blood flow velocity when using a toilet. PMID- 25276043 TI - Respiratory function of university students living at high altitude. AB - [Purpose] This study compared the respiratory function and oxygen saturation levels of university students living at high altitude, to present a new approach for improving respiratory function using high altitudes above sea level. [Subjects and Methods] The subjects were 100 female students attending a university located approximately 850 m above sea level and 104 female students attending a university located at low altitude. Oxygen saturation, heart rate (HR), and respiratory function levels were measured. [Results] For the students living at high altitude, HR, PEF, and FEV1/FVC levels were low. In contrast, their oxygen saturation, FEV1, and FVC levels were higher than the levels found in students living at low altitude. Differences in respiratory function were revealed in first- and second-year students living at high and low altitudes. On the other hand, no significant differences in respiratory function were found between third- and fourth-year students. [Conclusion] University students living at high altitude had a slower HR and higher oxygen saturation levels as well as higher lung and inspiratory capacity levels. Thus, physiological improvement in oxygen saturation levels and pulmonary function were seen in the individuals living at high altitude. PMID- 25276045 TI - Effects of individual strengthening exercises on subdivisions of the gluteus medius in a patient with sacroiliac joint pain. AB - [Purpose] We investigated the effects of individual strengthening exercises for subdivisions of the gluteus medius in a patient with sacroiliac joint pain. [Subject] A 32 year-old female who complained of pain in the posterior area of the left iliac crest and sacroiliac joints over a period of 6 months was the subject of this study. [Methods] She performed individual strengthening exercises for subdivisions of the gluteus medius over 3 weeks. Pain-provocation tests and VAS scores were evaluated before and after the intervention. [Results] After individual strengthening exercises for subdivisions of the gluteus medius, the subject showed no pain in the Gaenslen, Patrick, or REAB tests for the left sacroiliac joint. The VAS score was less the 3/10, compared with 7/10 initially. [Conclusion] Individual strengthening exercises for the subdivisions of the gluteus medius were effective at reducing SI joint pain for this patient. PMID- 25276044 TI - Physiotherapy for women with stress urinary incontinence: a review article. AB - [Purpose] This review article is designed to expose physiotherapists to a physiotherapy assessment of stress urinary incontinence (SUI) and the treatment and possibly preventive roles that they might play for women with SUI. Specifically, the goal of this article is to provide an understanding of pelvic floor muscle function and the implications that this function has for physiotherapy treatment by reviewing articles published in this area. [Methods] A range of databases was searched to identify articles that address physiotherapy for SUI, including the Cochrane Library, Medline, and CINAHL. [Results] According to the articles identified in our databases research, greater improvements in SUI occur when women receive a supervised exercise program of at least three months. The effectiveness of physiotherapy treatment is increased if the exercise program is based on some principles, such as intensity, duration, resembling functional task, and the position in which the exercise for pelvic floor muscles is performed. Biofeedback and electrical stimulation may also be clinically useful and acceptable modalities for some women with SUI. [Conclusion] We concluded that the plan for physiotherapy care should be individualized for each patient and include standard physiotherapy interventions. PMID- 25276046 TI - Supervised Phase II Cardiac Exercise Therapy Shortens the Recovery of Exercise Capacity in Patients with Acute Myocardial Infarction. AB - [Purpose] To investigate the effects of Phase II cardiac exercise therapy (CET) on exercise capacity and changes in coronary risk factors (CRFs) of patients with acute myocardial infarction (AMI). [Subjects] Thirty male subjects with AMI were divided into an experimental group (EG) and a control group (CG). Another 30 age matched subjects with patent coronary arteries served as a normal-control group (NCG). [Methods] Subjects in EG (n=20) trained using a stationary bicycle for 30 min at their target heart rate twice a week for 8 weeks. Exercise capacity was defined as the maximal metabolic equivalents (METs) that subjects reached during the symptom-limited maximal exercise test. HR, BP and RPP were recorded. Subjects in EG and CG received exercise tests and screening for CRFs at the beginning of, end of, and 3 months after Phase II CET, while subjects in NCG participated only in the 1st test. [Results] METs of CG did not improve until the 3rd test, while RPP at the 2nd test showed a significant increase. However, EG showed increased METs at the 2nd test without increase of RPP, and increased their high density lipoprotein cholesterol (HDL-C) during the follow-up period between the 2nd and 3rd tests. [Conclusion] Phase II CET shortens the recovery time of exercise capacity, helps to maintain the gained exercise capacity and increases HDL-C in phase III. PMID- 25276047 TI - Sniff nasal inspiratory pressure does not decrease in elderly subjects. AB - [Purpose] Measurements of inspiratory strength are critical for detecting inspiratory muscle weakness. Sniff nasal inspiratory pressure (SNIP) is a quick, noninvasive measurement of global inspiratory strength; however, it is not clear how many trials are needed for reliable measurements. [Subjects and Methods] One hundred and nineteen subjects (age 39.9+/-16.5, range 18-69 yrs) completed the study. They were divided into subgroups of different ages and gender. Subjects were asked to take 20 maximal sniffs after normal expiration, with 30 seconds rest in-between. The highest values among the first 10 and last 10 SNIP maneuvers were recorded as SNIP1-10, and SNIP11-20, respectively. The paired t-test was used to compare the differences. Two-way measures ANOVA was used to compare the effects of age and gender on SNIP. [Results] SNIP 11-20 was significantly greater than SNIP1-10, suggesting that 10 trials is not enough to eliminate learning effects. Age did not affect SNIP in either gender, suggesting SNIP is preserved. In stepwise multiple linear regression analysis, the SNIP values were positively related with body mass index in women and positively related with weight in men. [Conclusion] The results suggest that twenty trials are needed for reliable SNIP measurements. The mean value and lower limits of normal SNIP are provided for clinical comparison. PMID- 25276048 TI - Behavioral disorder amongst adolescents attending secondary school in southeast Nigeria. AB - BACKGROUND: Adolescents are prone to various forms of behavioral problems. These behavioral issues in adolescents can have serious consequences for the adolescents. OBJECTIVES: The objectives of the study are to determine the causative factors of adolescent problems and specific manifestations. METHODS: Behavioral problems were investigated using a random sampling of adolescents from secondary schools in southeast Nigeria from February to April, 2014. A self administered questionnaire was developed from Health Kids Colorado Questionnaire. RESULTS: A total of 763 subjects completed the questionnaire. Adolescents who reported to have used tobacco 3 to 5 and 6 to 9 times during the last 30 days are just 3.14% and 3.4%, respectively. Nineteen (2.49%) adolescents claimed that they have had sex before but not in the last 3 months. Adolescents who attempted suicide are from 15 years and peaked at 18. Eighty-three (11%) adolescents who are 15 years old attempted suicide in a year; this peaks at 17 years where 235 (30.8%) committed suicide. Majority of adolescents with behavioral disorder are from the upper class family. CONCLUSION: This study revealed that adolescents exhibit several forms of behavioral problems. PMID- 25276049 TI - Ecto-nucleotidases activities in the contents of ovarian endometriomas: potential biomarkers of endometriosis. AB - Endometriosis, defined as the growth of endometrial tissue outside the uterus, is a common gynecologic condition affecting millions of women worldwide. It is an inflammatory, estrogen-dependent complex disorder, with broad symptomatic variability, pelvic pain, and infertility being the main characteristics. Ovarian endometriomas are frequently developed in women with endometriosis. Late diagnosis is one of the main problems of endometriosis; thus, it is important to identify biomarkers for early diagnosis. The aim of the present work is to evaluate the ecto-nucleotidases activities in the contents of endometriomas. These enzymes, through the regulation of extracellular ATP and adenosine levels, are key enzymes in inflammatory processes, and their expression has been previously characterized in human endometrium. To achieve our objective, the echo guided aspirated fluids of endometriomas were analyzed by evaluating the ecto nucleotidases activities and compared with simple cysts. Our results show that enzyme activities are quantifiable in the ovarian cysts aspirates and that endometriomas show significantly higher ecto-nucleotidases activities than simple cysts (5.5-fold increase for ATPase and 20-fold for ADPase), thus being possible candidates for new endometriosis biomarkers. Moreover, we demonstrate the presence of ecto-nucleotidases bearing exosomes in these fluids. These results add up to the knowledge of the physiopathologic mechanisms underlying endometriosis and, open up a promising new field of study. PMID- 25276051 TI - Inflammation and growth in young children with obstructive sleep apnea syndrome before and after adenotonsillectomy. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with growth impairment that usually improves following effective treatment. In this study we investigated the mechanisms underlying the growth processes in young children diagnosed with OSA, before and after adenotonsillectomy (T&A). METHODS: Young children (6-36 months old) were enrolled and evaluated before and several months after T&A surgery for height, weight, circulating high sensitive C-reactive protein (CRP), and insulin-like growth factor 1 (IGF-1) levels. Caloric intake was assessed by a validated Short Food Frequency Questionnaire (SFFQ). RESULTS: Following T&A, children added 4.81 cm and 1.88 kg to their height and weight, respectively (P < 0.001 for both) and had a significant increase in BMI Z score (P = 0.002). Increased caloric intake of 377 kcal/day was noted (P < 0.001), with increased protein and decreased fat intake. The decrease in CRP levels correlated with the increase in body weight in boys (P < 0.05, adjusted for caloric intake). CONCLUSIONS: Adenotonsillectomy results in enhanced somatic growth in young children that correlates with a decrease in systemic inflammation and caloric intake increment. Our findings imply that systemic inflammation may have an important role in this OSA-related morbidity. PMID- 25276050 TI - Macrophage P2X7 receptor function is reduced during schistosomiasis: putative role of TGF- beta1. AB - Schistosomiasis is a chronic inflammatory disease whose macrophages are involved in immunopathology modulation. Although P2X7 receptor signaling plays an important role in inflammatory responses mediated by macrophages, no reports have examined the role of P2X7 receptors in macrophage function during schistosomiasis. Thus, we evaluated P2X7 receptor function in peritoneal macrophages during schistosomiasis using an ATP-induced permeabilization assay and measurements of the intracellular Ca(2+) concentration. ATP treatment induced significantly less permeabilization in macrophages from S. mansoni-infected mice than in control cells from uninfected animals. Furthermore, P2X7-mediated increases in intracellular Ca(2+) levels were also reduced in macrophages from infected mice. TGF-beta1 levels were increased in the peritoneal cavity of infected animals, and pretreatment of control macrophages with TGF-beta1 reduced ATP-induced permeabilization, mimicking the effect of S. mansoni infection. Western blot and qRT-PCR data showed no difference in P2X7 protein and mRNA between uninfected, infected, and TGF-beta1-treated groups. However, immunofluorescence analysis revealed reduced cell surface localization of P2X7 receptors in macrophages from infected and TGF-beta1-treated mice compared to controls. Therefore, our data suggest that schistosomiasis reduces peritoneal macrophage P2X7 receptor signaling. This effect is likely due to the fact that infected mice have increased levels of TGF-beta1, which reduces P2X7 receptor cell surface expression. PMID- 25276052 TI - The inhibitory effect of PIK-75 on inflammatory mediator response induced by hydrogen peroxide in feline esophageal epithelial cells. AB - Isoform-selective inhibitors of phosphoinositide 3-kinase (PI3K) activation have an anti-inflammatory effect by reducing proinflammatory cytokines. Cultured feline esophageal epithelial cells (EEC) of passages 3~4 were treated with hydrogen peroxide and PIK-75. The cell viability was measured by a MTT incorporation assay. The distribution of PI3K isoforms, p-Akt, IL-1beta, and IL-8 was inferred from Western blots. The release of IL-6 was determined by ELISA. The cell morphology was not considerably different from nontreated cells if the cells were pretreated with PIK-75 and treated with 300 MUM hydrogen peroxide. The density of p110alpha of PI3K was increased, but that of other types was not affected after the treatment with hydrogen peroxide. The density of p-Akt, when the cells were exposed to PIK-75 and hydrogen peroxide, was diminished dose dependently more than that of hydrogen peroxide treatment only. The decrease of p Akt showed an inhibition of PI3K by PIK-75. PIK-75 dose dependently reduced the expression of IL-1beta, IL-8, and the level of IL-6 compared with hydrogen peroxide treatment only. These results suggest evidence that p110alpha mediates esophageal inflammation and that PIK-75 has an anti-inflammatory effect by reducing proinflammatory cytokines on feline esophageal epithelial cultured cells. PMID- 25276053 TI - Nucleotides regulate secretion of the inflammatory chemokine CCL2 from human macrophages and monocytes. AB - CCL2 is an important inflammatory chemokine involved in monocyte recruitment to inflamed tissues. The extracellular nucleotide signalling molecules UTP and ATP acting via the P2Y2 receptor are known to induce CCL2 secretion in macrophages. We confirmed this in the human THP-1 monocytic cell line showing that UTP is as efficient as LPS at inducing CCL2 at early time points (2-6 hours). Expression and calcium mobilisation experiments confirmed the presence of functional P2Y2 receptors on THP-1 cells. UTP stimulation of human peripheral CD14+ monocytes showed low responses to LPS (4-hour stimulation) but a significant increase above background following 6 hours of treatment. The response to UTP in human monocytes was variable and required stimulation >6 hours. With such variability in response we looked for single nucleotide polymorphisms in P2RY2 that could affect the functional response. Sequencing of P2RY2 from THP-1 cells revealed the presence of a single nucleotide polymorphism altering amino acid 312 from arginine to serine (rs3741156). This polymorphism is relatively common at a frequency of 0.276 (n = 404 subjects). Finally, we investigated CCL2 secretion in response to LPS or UTP in human macrophages expressing 312Arg-P2Y2 or 312Ser-P2Y2 where only the latter exhibited significant UTP-induced CCL2 secretion (n = 5 donors per group). PMID- 25276054 TI - Tumor necrosis factor-alpha-induced colitis increases NADPH oxidase 1 expression, oxidative stress, and neutrophil recruitment in the colon: preventive effect of apocynin. AB - Reactive oxygen species- (ROS-) mediated injury has been implicated in several inflammatory disorders, including inflammatory bowel disease (IBD). NADPH oxidases (NOXs) are the major source of endogenous ROS. Here, we investigated the role of NOXs derived-ROS in a mouse model of colitis induced by the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal injection of TNFalpha (10 MUg . kg(-1)) induced an acute inflammation of the colon and a marked increase in expression of NADPH oxidase 1 (NOX1), a colon specific NADPH oxidase isoform. TNFalpha-induced colitis was also characterized by high production of keratinocyte-derived chemokine (KC) and mucosal infiltration of neutrophils, NOX2-expressing cells. Concomitantly, ROS production and lipid peroxidation were significantly enhanced while catalase activity and glutathione level were reduced indicating a redox imbalance in the colon. Furthermore, the redox-sensitive MAP kinases, ERK1/2 and p38 MAPK, were activated during TNFalpha-induced colitis. Pretreatment of mice with apocynin, an NADPH oxidase inhibitor with antioxidant properties, before TNFalpha challenge, prevented all these events. These data suggest that ROS derived from NADPH oxidases (mainly NOX1 and NOX2) and MAP kinase pathways could contribute to the induction and expansion of oxidative lesions characteristics of IBD and that apocynin could potentially be beneficial in IBD treatment. PMID- 25276055 TI - Pathogenic roles of the carotid body inflammation in sleep apnea. AB - Breathing difficulties in sleep are a hallmark of sleep-disordered breathing commonly observed in patients with sleep disorders. The pathophysiology of sleep apnea is in part due to an augmented activity of the carotid body chemoreflex. Arterial chemoreceptors in the carotid body are sensitive to inflammatory cytokines and immunogenic molecules in the circulation, because cytokine receptors are expressed in the carotid body in experimental animals and human. Intriguingly, proinflammatory cytokines are also locally produced and released in the carotid body. Also, there are significant increases in the expression of proinflammatory cytokines, cytokine receptors, and inflammatory mediators in the carotid body under hypoxic conditions, suggesting an inflammatory response of the carotid body. These upregulated cytokine signaling pathways could enhance the carotid chemoreceptor activity, leading to an overactivity of the chemoreflex adversely effecting breathing instability and autonomic imbalance. This review aims to summarize findings of the literature relevant to inflammation in the carotid body, with highlights on the pathophysiological impact in sleep apnea. It is concluded that local inflammation in the carotid body plays a pathogenic role in sleep apnea, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea. PMID- 25276056 TI - Inhibition of macrophage functions by the C-terminus of murine S100A9 is dependent on B-1 cells. AB - The protein S100A9 plays a key role in the control of inflammatory response. The C-terminus of the murine S100A9 protein (mS100A9p) downregulates the spreading and phagocytic activity of adherent peritoneal cells. Murine peritoneal cells are constituted by macrophages and B-1 cells, and the latter exert an inhibitory effect on macrophage functions by secreting interleukin- (IL-) 10. Here, we investigated the influence of B-1 cells on the inhibitory effect evoked by mS100A9p on macrophages. mS100A9p did not alter spreading and phagocytosis either by peritoneal macrophages obtained from mice deprived of B-1 cells or by bone marrow-derived macrophages (BMDMphi). Nevertheless, when BMDMphi were cocultivated by direct or indirect contact with B-1 cells treated with mS100A9p, the phagocytosis by BMDMphi was decreased, showing that the effect of mS100A9p on macrophages was modulated by B-1 cells and/or their secretory compounds. Furthermore, the inhibitory action of mS100A9p on phagocytosis by adherent peritoneal cells was abolished in cells obtained from IL-10 knockout mice. Taken together, the results show that mS100A9p has no direct inhibitory effect on macrophages; however, mS100A9p modulates B-1 cells, which in turn downregulates macrophages, at least in part, via IL-10. These data contribute to the characterization of S100A9 functions involving B-1 cells in the regulation of the inflammatory process. PMID- 25276057 TI - Predictive criteria to study the pathogenesis of malaria-associated ALI/ARDS in mice. AB - Malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS) often results in morbidity and mortality. Murine models to study malaria-associated ALI/ARDS have been described; we still lack a method of distinguishing which mice will develop ALI/ARDS before death. This work aimed to characterize malaria-associated ALI/ARDS in a murine model and to demonstrate the first method to predict whether mice are suffering from ALI/ARDS before death. DBA/2 mice infected with Plasmodium berghei ANKA developing ALI/ARDS or hyperparasitemia (HP) were compared using histopathology, PaO2 measurement, pulmonary X-ray, breathing capacity, lung permeability, and serum vascular endothelial growth factor (VEGF) levels according to either the day of death or the suggested predictive criteria. We proposed a model to predict malaria associated ALI/ARDS using breathing patterns (enhanced pause and frequency respiration) and parasitemia as predictive criteria from mice whose cause of death was known to retrospectively diagnose the sacrificed mice as likely to die of ALI/ARDS as early as 7 days after infection. Using this method, we showed increased VEGF levels and increased lung permeability in mice predicted to die of ALI/ARDS. This proposed method for accurately identifying mice suffering from ALI/ARDS before death will enable the use of this model to study the pathogenesis of this disease. PMID- 25276059 TI - Alleviation of antioxidant defense system by ozonized olive oil in DNBS-induced colitis in rats. AB - The aim of the study was to evaluate the potential protective effect of ozonized olive oil (OZO) in 2,4-dinitrobenzene sulphuric acid (DNBS) induced colitis in rats and to elucidate the role of some antioxidant defense system (superoxide dismutase "SOD," glutathione peroxidase "GSH-Px," and catalase "CAT") in these effects. The physicochemical parameters including viscosity, peroxide, and acid values of olive oil and OZO were evaluated. The animals were divided into several groups and the colitis was induced in the rats by intracolonic instillation of DNBS at dose of 15 mg/rat. Olive oil (OO) at dose of 6 mg/kg and OZO at doses of 3 and 6 mg/kg was administered orally for 7 days, starting the day before induction of colitis. Our results showed that macroscopic and microscopic damage scores were significantly reduced in a dose response manner in rats pretreated with OZO only. In contrast, CAT, GSH-Px, and SOD activities were significantly increased in the distal colon of inflamed animals pretreated with OZO with respect to control group dose dependently. Results demonstrate that OZO pretreatment exerts protective effects in DNBS induced colitis in rats and provide evidence that the protective effects of OZO are mediated by stimulation of some antioxidant enzymes. PMID- 25276058 TI - Trypanosoma cruzi infection and host lipid metabolism. AB - Trypanosoma cruzi is the causative agent of Chagas disease. Approximately 8 million people are thought to be affected worldwide. Several players in host lipid metabolism have been implicated in T. cruzi-host interactions in recent research, including macrophages, adipocytes, low density lipoprotein (LDL), low density lipoprotein receptor (LDLR), and high density lipoprotein (HDL). All of these factors are required to maintain host lipid homeostasis and are intricately connected via several metabolic pathways. We reviewed the interaction of T. cruzi with each of the relevant host components, in order to further understand the roles of host lipid metabolism in T. cruzi infection. This review sheds light on the potential impact of T. cruzi infection on the status of host lipid homeostasis. PMID- 25276061 TI - Antihyperlipidemic potential of Albizia amara (Roxb) Boiv. bark against Triton X 100 induced hyperlipidemic condition in rats. AB - BACKGROUND: The plant Albizia amara (Roxb.) Boiv. bark was used in traditional medical practices of India to treat cardiovascular diseases. Hyperlipidemia is the greatest risk factor of coronary heart disease. OBJECTIVE: The objective of this study was to screen the potential of A. amara against the condition of hyperlipidemia in rats. MATERIALS AND METHODS: The antihyperlipidemic activity of A. amara ethanolic extract (AAEE) was studied on Triton X-100 induced model of hyperlipidemia in rats. Hyperlipidemia in experimental rats was evidenced by an enhancement in the levels of serum cholesterol, triglycerides (TGs), low density lipoprotein (LDL), very LDL (VLDL) and decrease in high density lipoprotein (HDL). RESULTS: AAEE showed significant antihyperlipidemic effect by lowering the serum levels of biochemical parameters such as a significant reduction in the level of serum cholesterol, TG (104.1 +/- 3.39), LDL (48.2 +/- 2.19), VLDL (20.81 +/- 0.67) and increase in HDL (47.25 +/- 2.05) level with an increase in a dose of AAEE (41.39 +/- 1.24) < (47.25 +/- 2.05), which was similar to the standard drug atorvastatin. The results of serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase also revealed that the plant extract was found to be safe on liver. Histopathological evaluation also revealed the positive effect of the plant extract. Preliminary phytochemical analysis revealed the presence of phytoconstituents such as saponins, glycosides and tannins. The preliminary chemical constituents stood as a strong evidence for the study. CONCLUSION: Summing up the evidences of the pragmatic study, we can conclude that the extract of A. amara (Roxb.) Boiv. Bark aids in declining the condition of hyperlipidemia in rats. PMID- 25276062 TI - Antiallergic effect of an aqueous leaf extract of Pistia stratiotes in murine model of ovalbumin-induced allergic conjunctivitis. AB - AIM: The aim was to investigate the antiallergic effect of an aqueous leaf extract of Pistia stratiotes (ALPS) in a murine model of ovalbumin (OVA)-induced allergic conjunctivitis (AC). MATERIALS AND METHODS: Prior to topical challenge (instillation of 1.5 mg OVA in 10 MUL phosphate buffered saline into their conjunctival sacs) to induce AC, groups of sensitized Imprinting Control Region mice (injected IP, on day 1 and 7, with 0.2 ml solution of 100 MUg OVA and 0.01 mg aluminum hydroxide in phosphate buffered saline), were treated with 5 mg/kg cetirizine, 10, 50 or 100 mg/kg of ALPS, or 2 ml/kg normal saline per os. Conjunctival redness, lid edema, tearing and lid scratching (clinical symptoms of AC) were scored. Serum OVA specific immunoglobulins were determined using ELISA. Histopathological assessment of the conjunctival mucosal tissue was conducted. The extract was screened for secondary plant metabolites. RESULTS: Pretreatment with the extract significantly (P <= 0.05-0.01) and dose-dependently reduced the scores for clinical symptoms, which were marked in vehicle-pretreated mice. Pretreatment also lowered (P <= 0.01-0.001) serum OVA specific immunoglobulins. Mast cell infiltration and degranulation in conjunctival stroma (measured by an inflammatory score) in histopathological studies was also significantly low (P <= 0.05-0.01) on pretreatment. CONCLUSION: The ALPS exhibited interesting antiallergic activity and hence could be useful in managing AC. PMID- 25276060 TI - Jussara (Euterpe edulis Mart.) supplementation during pregnancy and lactation modulates the gene and protein expression of inflammation biomarkers induced by trans-fatty acids in the colon of offspring. AB - Maternal intake of trans-fatty acids (TFAs) in the perinatal period triggers a proinflammatory state in offspring. Anthocyanins contained in fruit are promising modulators of inflammation. This study investigated the effect of Jussara supplementation in the maternal diet on the proinflammatory state of the colon in offspring exposed to perinatal TFAs. On the first day of pregnancy rats were divided into four groups: control diet (C), control diet with 0.5% Jussara supplementation (CJ), diet enriched with hydrogenated vegetable fat, rich in TFAs (T), or T diet supplemented with 0.5% Jussara (TJ) during pregnancy and lactation. We showed that Jussara supplementation in maternal diet (CJ and TJ groups) reduced carcass lipid/protein ratios, serum lipids, glucose, IL-6, TNF alpha, gene expression of IL-6R, TNF-alphaR (P < 0.05), TLR-4 (P < 0.01), and increase Lactobacillus spp. (P < 0.05) in the colon of offspring compared to the T group. The IL-10 (P = 0.035) and IL-10/TNF-alpha ratio (P < 0.01) was higher in the CJ group than in the T group. The 0.5% Jussara supplementation reverses the adverse effects of perinatal TFAs, improving lipid profiles, glucose levels, body composition, and gut microbiota and reducing low-grade inflammation in the colon of 21-day-old offspring, and could contribute to reducing chronic disease development. PMID- 25276063 TI - Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei. AB - CONTEXT: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. AIMS: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. MATERIALS AND METHODS: Acute oral toxicity dose at 5000 mg/kg was conducted to evaluate the safety of this extract. Twenty mice were divided into control and experimental group. All the mice were observed for signs of toxicity, mortality, weight changes and histopathological changes. Antimalarial activity of different extract doses of 50, 200, 400 and 1000 mg/kg were tested in vivo against Plasmodium berghei infections in mice (five mice for each group) during early, established and residual infections. RESULTS: The acute oral toxicity test revealed that no mortality or evidence of adverse effects was seen in the treated mice. The extract significantly reduced the parasitemia by the 50 (P = 0.000), 200 (P = 0.000) and 400 mg/kg doses (P = 0.000) in the in vivo prophylactic assay. The percentage chemo-suppression was calculated as 83.33% for 50 mg/kg dose, 75.62% for 200 mg/kg dose and 90.74% for 400 mg/kg dose. Body weight of all treated groups; T1, T2, T3 and T4 also showed enhancement after 7 days posttreatment. Statistically no reduction of parasitemia calculated for curative and suppressive test. CONCLUSION: Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection. PMID- 25276064 TI - A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome. AB - BACKGROUND: Oxidative stress plays a major role in the pathogenesis of chronic fatigue syndrome (CFS). Keeping in view the proven antioxidant activity of Triticum aestivum L., this study has been undertaken to explore the potential therapeutic benefit of this plant in the treatment of CFS. OBJECTIVE: To study the protective effect of the ethanolic extract of the leaves of Triticum aestivum (EETA) in an experimental mice model of CFS. MATERIALS AND METHODS: Five groups of albino mice (20-25 g) were selected for the study, with five animals in each group. Group A served as the naive control and Group B served as the stressed control. Groups C and D received EETA (100 mg/kg and 200 mg/kg b.w.). Group E received imipramine (20 mg/kg b.w.). Except for Group A, mice in each group were forced to swim 6 min each for 7 days to induce a state of chronic fatigue. Duration of immobility was measured on every alternate day. After 7 days, various behavioral tests (mirror chamber and elevated plus maize test for anxiety, open field test for locomotor activity) and biochemical estimations (malondialdehyde [MDA] and catalase activity) in mice brain were performed. RESULTS: Forced swimming in the stressed group resulted in a significant increase in immobility period, decrease in locomotor activity and elevated anxiety level. The brain homogenate showed significantly increased MDA and decreased catalase levels. The extract-treated groups showed significantly (P < 0.05) improved locomotor activity, decreased anxiety level, elevated catalase levels and reduction of MDA. CONCLUSION: The study confirms the protective effects of EETA in CFS. PMID- 25276066 TI - Effects of L-citrulline diet on stress-induced cold hypersensitivity in mice. AB - BACKGROUND: L-citrulline is an amino acid discovered in watermelon (Citrullus lanatus, Cucurbitaceae) and is a known component of the nitric oxide (NO) cycle that plays an important role in adjusting blood circulation and supplying NO and a key component of the endothelium-derived relaxing factor. OBJECTIVE: The objective of this study is to evaluate the effect of L-citrulline on a newly established stress-induced cold hypersensitivity mouse model. MATERIALS AND METHODS: When normal mice were forced to swim in water at 25 degrees C for 15 min, their core body temperature dropped to 28.9 degrees C, and then quickly recovered to normal temperature after the mice were transferred to a dry cage at room temperature (25 degrees C). A 1-h immobilization before swimming caused the core body temperature to drop to ca. 24.1 degrees C (4.8 degrees C lower than normal mice), and the speed of core body temperature recovery dropped to 57% of the normal control. We considered this delay in recovery from hypothermia to be a sign of stress-induced cold hypersensitivity. Similar cold hypersensitivity was induced by administration of 50 mM L-NG-nitroarginine methyl ester, a NO synthesis inhibitor. RESULTS: In this study, we showed that recovery speed from the stress-induced hypothermia remarkably improved in mice fed a 1% L-citrulline containing diet for 20 days. Furthermore, the nonfasting blood level of L arginine and L-citrulline increased significantly in the L-citrulline diet group, and higher serum nitrogen oxide levels were observed during recovery from the cold. CONCLUSIONS: These results suggested that oral L-citrulline supplementation strengthens vascular endothelium function and attenuates stress-induced cold hypersensitivity by improving blood circulation. PMID- 25276065 TI - Amelioration of insulin resistance by Rk1 + Rg5 complex under endoplasmic reticulum stress conditions. AB - BACKGROUND: Diabetes mellitus is a metabolic syndrome exaggerated by stress conditions. Endoplasmic reticulum stress (ERS) impairs the insulin signaling pathway making the diabetic conditions worsen. Pharmacological agents are supplied externally to overcome this malfunction. Ginsenosides from Panax ginseng C.A Meyer possesses many pharmacological properties and are used for the treatment of diabetes. OBJECTIVE: To investigate the effects of the Rk1 +Rg5 complex on the amelioration of insulin resistance in 3T3-L1 cells under endoplasmic reticulum stress conditions. MATERIALS AND METHODS: Heat-processed ginseng extracts are found to contain many pharmacologically active ginsenosides. Among them Rk1 +Rg5 is found to be present in higher concentrations than the other minor ginsenosides. The Rk1 +Rg5 complex was tested for its effect in the 3T3-L1 insulin-resistant model and subjected to the MTT assay, glucose oxidase assay and gene expression studies using RT-PCR and real-time PCR under endoplasmic reticulum stress conditions. RESULTS: Rk1 +Rg5 treatment is found to increase the glucose uptake into the cells when compared to that of a positive control (tunicamycin treatment group, TM). Further we have analyzed the role at gene expression level. The Rk1 +Rg5 complex was found to show an effect on the IGF 2R receptor, CHOP-10, and C/EBP gene at a particular treated concentration (50 MUM). Moreover, stress condition (about 50% decreases) was overcome by the ginsenoside treatments at 50 MUM. CONCLUSION: The present results showed that under endoplasmic reticulum stress conditions Rk1 +Rg5 complex exhibits a potential protective role in insulin-resistant 3T3-L1 cells. PMID- 25276067 TI - Anticancer Active Homoisoflavone from the Underground Bulbs of Ledebouria hyderabadensis. AB - BACKGROUND: Ledebouria is a genus of deciduous or weakly evergreen bulbs in the Hyacinthaceae family. This is recognized as the first collection made of the new taxon Ledebouria hyderabadensis, exist in the Hyderabad city of Andhra Pradesh, India. OBJECTIVE: The goal of this work was to investigate the phytochemical constituents present in the new specifies and also to evaluate the cytotoxic properties of the extracts and pure compounds against human cancer cell lines. MATERIALS AND METHODS: The anticancer activity was evaluated in in vitro mode by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. RESULTS: Phytochemical investigation of underground bulbs of indigenous, rare, and recently identified herb L. hyderabadensis yielded a bioactive homoisoflavanone, Scillascillin 1. The structure of the compound was established on the basis of various nuclear magnetic resonance and mass spectral data. The compound Scillascillin was isolated for the first time from L. hyderabadensis. In vitro anticancer activity, performed using MTT assay, showed compound 1 as significantly active against human cancer cell lines MCF-7 (breast cancer) and DU 145 (prostate cancer) with inhibitory concentration (IC)50 values 9.59 and 11.32 MUg/ml respectively when compared with herb methanol extract (IC50 values 36.21 and 44.86 MUg/ml respectively). PMID- 25276068 TI - A comparative study of the effect of some nutritional medicinal plants effect on lead accumulation in the liver following different modes of administration. AB - CONTEXT AND OBJECTIVES: Lead (Pb) toxicity leads to cell damage in many organs of the body. Using different treatment interventions and modes of administration we comparatively examined the protective ability of some medicinal plants on liver Pb accumulation. MATERIALS AND METHODS: Rats were fed on either 7% w/w Zingiber officinale, 7% w/w Allium sativum, 10% w/w Lycopersicon esculentum, 5%, w/w Garcinia kola (all in rat chow), while Pb (100 ppm) was given in drinking water. The additives were administered together with (mode 1), a week after exposure to (mode 2) or a week before metal exposure to (mode 3) the metal for a period of 6 weeks. The metal accumulations in the liver were determined using atomic absorption spectrometry and compared using analysis of variance. RESULTS: Some additives significantly (P < 0.05) reduced, while others enhanced Pb accumulation. Mode 2 yielded the highest mean % protection and mode 3 the lowest, no significant interaction between modes of administration and time of measurement in their relationships to percentage protection, but there was statistically significant (P < 0.05) interaction between modes of administration and additive used in their relationships to percentage protection. CONCLUSION: Protective effects of medicinal plants are varied and depend on the nature of lead exposure. PMID- 25276069 TI - Antiproliferative effects of Plumbago rosea and its purified constituent plumbagin on SK-MEL 28 melanoma cell lines. AB - BACKGROUND: Plumbago rosea is used in traditional systems of medicine for the preparation of formulations used for treating inflammations, cough, bronchitis, and gastrointestinal disorders, and also in conjunction with cancer chemotherapy. In the present study, the cytotoxic and anti-proliferative effects of plumbagin, and the ethanolic root extract of P. rosea (ETPR) was evaluated on SK-MEL 28 melanoma cell lines and human lymphocytes. MATERIALS AND METHODS: MTT and apoptotic assays were used for the evaluation of cytotoxic and anti-proliferative effects, respectively. In addition, the effect of Plumbagin and ETPR in down regulation of BCL-2 expression is investigated using RT-PCR analysis. RESULTS: Both plumbagin and ETPR dose-dependently decreased the cell viability more potently in melanoma cell lines. P. rosea extract demonstrated significant synergy in inhibiting BCL-2 expression than plumbagin. Moreover plumbagin showed more toxicity in human lymphocytes. CONCLUSION: Plumbagin has anti-cancer potential, but the side effects limits its use; yet plumbagin, in combination with other ingredients in Plumbago rosea extract, displays significant synergy leading to a stronger anticancer effect with significantly less toxicity. PMID- 25276071 TI - Evaluation of the efficacy of 2% curcumin gel in the treatment of experimental periodontitis. AB - CONTEXT: Local drug delivery (LDD) systems have been proposed for the treatment of periodontitis. Curcumin could be a suitable agent as LDD for the treatment of periodontitis. AIM: To formulate, evaluate the anti-inflammatory activity and to assess the duration of the action and the efficacy of 2% curcumin gel in the treatment of experimental periodontitis in Wistar albino rat model. SETTINGS AND DESIGN: Twenty-one Wistar albino rats were randomly assigned to three groups. Periodontitis was induced using ligature model. Group 1: Control; group 2: Plain gel, and group 3: 2% curcumin gel. MATERIALS AND METHODS: About 2% curcumin gel was prepared. The anti-inflammatory activity and duration of action was assessed. Silk ligature 5-0 was used to induce periodontitis. Gingival index (GI) and probing pocket depth (PPD) were measured. Treatment was done. The rats were sacrificed. Morphometric analysis was performed using stereomicroscope and ImageJ software. STATISTICAL ANALYSIS USED: Analysis of variance followed by Bonferroni's test, Wilcoxon's test for inter-group comparison, Mann-Whitney test for P value computation was used. The observations are mean +/- standard deviation and standard error of the mean. P < 0.01 when compared to control was considered as statistically significant. RESULTS: About 2% curcumin gel showed 42.98% inhibition of edema and peak activity was noted at 24 h. There was statistically significant change in the GI and PPD. Morphometric analysis did not show any significant difference between groups. No toxic effects were seen on oral administration of 2000 mg/kg of curcumin. CONCLUSIONS: About 2% curcumin gel was effective in the treatment of experimental periodontitis. PMID- 25276072 TI - Novel strategies for optimized delivery of select components of Allium sativum. AB - BACKGROUND: Garlic (Allium sativum) has been known to exhibit a wide range of pharmacological activities which are attributed mainly to the organosulfur compounds present in it. Allicin and garlic oil, components obtained from garlic, have been explored and found to be biologically active on various fronts. Allicin is known to have major stability issues due to rapid degradation even at low temperatures, whereas garlic oil, being lipophilic, shows poor bioavailability after oral administration. OBJECTIVE: To develop novel strategies for optimum delivery of allicin and garlic oil so as to achieve effective availability in the physiological system. MATERIALS AND METHODS: Garlic cloves were lyophilized to obtain allicin-releasing garlic powder (ARGP). This powder was analyzed spectrophotometrically and was used to formulate buccal tablets. Garlic oil was obtained by hydrodistillation of garlic cloves and analyzed by gas chromatography. Self-nanoemulsifying systems (SNS) containing garlic oil were prepared using suitable surfactants and cosurfactants. The SNS were adsorbed on Aerosil 200 and filled in hard gelatin capsules. Both the formulations were suitably evaluated. RESULTS: Buccal tablets containing ARGP showed satisfactory physical parameters as well as in vitro drug release, mucoadhesive strength, moisture uptake capacity and drug content. Evaluation of capsules containing SNS of garlic oil also gave satisfactory results. The adsorbed SNS when dispersed in water formed nanoemulsions. CONCLUSION: Buccal tablets as well as capsules containing garlic oil SNS provide promising strategies to overcome the difficulties associated with formulation of allicin and garlic oil. PMID- 25276070 TI - Ameliorative effect of PhytoceeTM Cool against carbon tetrachloride-induced oxidative stress. AB - BACKGROUND: Antioxidants from natural sources have a major role in reversing the effects of oxidative stress and promoting health, growth and productivity in animals. OBJECTIVE: This study was undertaken to investigate the possible antioxidant activity and hepatoprotective effects of PhytoceeTM Cool on carbon tetrachloride (CCl4) induced oxidative stress and liver damage in rats. MATERIALS AND METHODS: Animals were pretreated with PhytoceeTM Cool for 10 days and were challenged with CCl4 (1:1 v/v) in olive oil on the 10(th) day. After 24 h of CCl4 administration blood was collected and markers of hepatocellular damage aspartate aminotransferase (AST), alanine aminotransferase (ALT) were evaluated. Rats were sacrificed and oxidative stress in liver was estimated using malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase. RESULTS: CCl4 caused a significant increase in serum AST, ALT, hepatic MDA and GSH levels, whereas the SOD and catalase activities were decreased. PhytoceeTM Cool pretreatment attenuated the MDA, AST ALT levels and increased the activities of SOD and catalase. CONCLUSION: PhytoceeTM Cool demonstrated antioxidant potential and hepatoprotective effects and plausibly be used in the amelioration of oxidative stress. PMID- 25276073 TI - Effect of licorice versus bismuth on eradication of Helicobacter pylori in patients with peptic ulcer disease. AB - BACKGROUND: Different therapeutic regimens were used for eradication of Helicobacter pylori, based on the cost, effectiveness and patient's compliance. The aim of this study was the evaluation of licorice compared with bismuth in quadruple regimen on eradication of H. pylori in patients with peptic ulcer disease (PUD). MATERIALS AND METHODS: In a double-blind clinical trial study, 60 patients with PUD and positive rapid urease test were enrolled. The patients were randomly allocated into two equal groups. In first group, licorice, amoxicillin, metronidazole and omeprazole and in the second (control) group, bismuth subsalicylate, amoxicillin, metronidazole and omeprazole were prescribed respectively, and 4 weeks after treatment, in order to evaluate H. pylori eradication, urea breath test was done in all patients. The outcome of the study was the preference usage of licorice as an effective medication for H. pylori eradication. RESULTS: Mean age of the patients in the control and case groups were 40.8 +/- 15.5 and 42.2 +/- 15.8 years, respectively (P = 0.726). Seventeen (56.7%) patients in control group and 16 (53.3%) in the case group were female (P = 0.795). Both groups were similar based on frequency of gastric or duodenal ulcer. Response to treatment were seen in 20 (67%) and 17 (57%) patients of case and control groups, respectively (P > 0.05). CONCLUSION: Our study showed that licorice is as effective as bismuth in H. pylori eradication; therefore, in patients whom bismuth is contraindicated, licorice can be used safely instead. PMID- 25276074 TI - Phytochemical screening and anti-inflammatory activity of Cnidoscolus quercifolius (Euphorbiaceae) in mice. AB - BACKGROUND: Cnidoscolus quercifolius is a species popularly known as favela and faveleira, and belonging to the Caatinga biome (semi-arid vegetation, Brazil), where is used in folk medicine as an anti-inflammatory. OBJECTIVE: The aim was to evaluate the anti-inflammatory effect of the ethanolic extract from barks (Cqb EtOH) and leaves (Cql-EtOH) of C. quercifolius in mice using experimental models of inflammation. MATERIALS AND METHODS: The preliminary phytochemical analysis of the ethanolic extract was performed. The activity was evaluated by paw edema induced by carrageenan and leukocytes migration to the peritoneal cavity induced by carrageenan methods. RESULTS: A preliminary analysis of Cqb-EtOH revealed that it contained coumarins, flavonoids, monoterpenes/diterpenes and naphthoquinones, while the Cql-EtOH showed positive reaction to coumarins, anthracene derivatives, flavonoids, lignans and triterpenes/steroids. Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan. In the peritonitis test, acute pretreatment with Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited the leukocyte migration. CONCLUSIONS: It can be concluded that extracts from the barks and leaves of C. quercifolius have anti-inflammatory activity, which supports the popular use of this plant to treat inflammation. Thus, extracts has significant anti-inflammatory properties, which are related probably to inhibition of release of mediators of the inflammatory process. PMID- 25276075 TI - Anticancer potential of Syzygium aromaticum L. in MCF-7 human breast cancer cell lines. AB - BACKGROUND: The common treatment for cancer is unfavorable because it causes many detrimental side effects, and lately, there has been a growing resistance toward anticancer drugs, which worsens the future of cancer treatment. Therefore, the focus has now shifted toward natural products, such as spices and plants, among many others, to save the future of cancer treatment. Cloves (Syzygium aromaticum L.) are spices with the highest antioxidant content among natural products. Besides acting as an antioxidant, cloves also possess many other functions, such as anti-inflammatory, antibacterial, and antiseptic, which makes them an ideal natural source to be developed as an anticancer agent. OBJECTIVE: This study aims to evaluate the cytotoxic activity of cloves toward MCF-7 human breast cancer cell lines. MATERIALS AND METHODS: Different concentrations of water extract, ethanol extract, and essential oil of cloves were investigated for their anticancer potential in vitro through a brine shrimp lethality test (BSLT) and an MTT assay. RESULTS: In both BSLT and MTT assays, the essential oil showed the highest cytotoxic effect, followed by ethanol and water extract. The LD50 concentration of essential oil in the 24 hours BSLT was 37 MUg/mL. Furthermore, the IC50 values in the 24 hours and 48 hours MTT assays of the essential oil were 36.43 MUg/mL and 17.6 MUg/mL, respectively. CONCLUSION: Cloves are natural products with excellent cytotoxicity toward MCF-7 cells; thus, they are promising sources for the development of anticancer agents. PMID- 25276076 TI - Laser-assisted in situ keratomileusis for correction of astigmatism and increasing contact lens tolerance after penetrating keratoplasty. AB - PURPOSE: To determine effectiveness of laser-assisted in situ keratomileusis (LASIK) in the treatment of astigmatism following penetrating keratoplasty (PK). METHODS: We performed a retrospective review of medical records of patients who underwent LASIK following PK and had over 1 year of follow-up data. RESULTS: Twenty-six patients (26 pairs of eyes) underwent LASIK following PK. Mean age of the patients at the time of LASIK was 40.7 years (range, 26 to 72 years). Following LASIK, the mean cylinder was reduced by 2.4 diopters and mean reduction of cylinder after LASIK was 65.4% from the preoperative values at the last follow up visit. Uncorrected visual acuity became 20 / 50 or better in 69.2% of the eyes after LASIK. Best-corrected visual acuity became 20 / 50 or better in 73.1% of the eyes after LASIK. All of them were intolerable to contact lenses before LASIK. After LASIK, 6 pairs (23.1%) did not need to use contact lenses and 18 pairs (69.2%) were tolerable to using contact lenses or spectacles. There were no significant endothelial cell density changes 12 months after LASIK (p = 0.239). CONCLUSIONS: LASIK is effective in the treatment of astigmatism following PK and increases contact lens and spectacle tolerance. PMID- 25276077 TI - Macular hole formation in rhegmatogenous retinal detachment after scleral buckling. AB - PURPOSE: To describe early macular hole (MH) development in rhegmatogenous retinal detachment (RRD) after scleral buckling (SB) based on optical coherence tomography (OCT) findings. METHODS: The medical records and spectral domain OCT images of patients in whom MH developed after RRD repair were evaluated retrospectively. RESULTS: A postoperative MH was detected in five eyes that underwent SB during a 6-year period. All had fovea-off RRD without MH at the time of surgery. OCT showed partial loss of the inner retina with a preserved photoreceptor layer in early postoperative days. On average, 7 days (range,5 to 8 days) after surgery, outer retinal tissues disappeared, resulting in the full thickness MH. CONCLUSIONS: Serial OCT findings revealed that partial-thickness lamellar holes progressed to full-thickness MHs, which were formed by the degeneration of the outer retina in eyes with preceding loss of the glial cone in the fovea. PMID- 25276079 TI - The short-term efficacy of subthreshold Micropulse yellow (577-nm) laser photocoagulation for diabetic macular edema. AB - PURPOSE: This pilot study aimed to evaluate the efficacy and safety of subthreshold micropulse yellow (577-nm) laser photocoagulation (SMYLP) in the treatment of diabetic macular edema (DME). METHODS: We reviewed 14 eyes of 12 patients with DME who underwent SMYLP with a 15% duty cycle at an energy level immediately below that of the test burn. The laser exposure time was 20 ms and the spot diameter was 100 um. Laser pulses were administered in a confluent, repetitive manner with a 3 * 3 pattern mode. RESULTS: The mean follow-up time was 7.9 +/- 1.6 months. The baseline-corrected visual acuity was 0.51 +/- 0.42 logarithm of the minimum angle of resolution (logMAR), which was improved to 0.40 +/- 0.35 logMAR (p = 0.025) at the final follow-up. The central macular thickness at baseline was 385.0 +/- 111.0 um; this value changed to 327.0 +/- 87.7 um (p = 0.055) at the final follow-up. CONCLUSIONS: SMYLP showed short-term efficacy in the treatment of DME and did not result in retinal damage. However, prospective, comparative studies are needed to better evaluate the efficacy and safety of this treatment. PMID- 25276078 TI - Diabetic retinopathy risk factors: plasma erythropoietin as a risk factor for proliferative diabetic retinopathy. AB - PURPOSE: The purpose of this study was to evaluate whether any stage of diabetic retinopathy (DR) is associated with levels of plasma erythropoietin and other plasma parameters. METHODS: It was examined a representative sample of 180 type 2 diabetes patients aged 40 to 79 years. Ophthalmic examination including a funduscopic examination, performed by an experienced ophthalmologist and the retinal finding were classified according to the grading system for diabetic retinopathy of ETDRS (Early Treatment Diabetic Retinopathy Study). It was measured the levels of plasma erythropoietin, cholesterol, triglyceride, apolipoproteins A and B, C-reactive protein, fasting blood glucose and hemoglobin A1C (HbA1C) in 88 DR patients and 92 controls without DR. Risk factors correlated with DR were compared between groups. RESULTS: The study group of 180 patients included 72 males and 108 females. The mean age of the patients with and without DR was 57.36 +/- 8.87 years and 55.33 +/- 8.28 years, respectively. Of the 88 patients with DR, only 9 (10%) had proliferative DR and the rest suffered from non-proliferative DR. The mean plasma levels of erythropoietin in proliferative DR group showed a significant difference in comparison to other groups. The mean plasma levels of cholesterol, triglyceride, apolipoproteins A and B, C-reactive protein, and fasting blood glucose were not significantly different in the three groups except for HbA1C. The absolute relative risk (ARR) also showed that erythropoietin was an increasing risk for proliferative DR (ARR, 1.17; 95% confidence interval, 1.060 to 1.420; odds ratio,1.060). CONCLUSIONS: Of the factors studied, erythropoietin level showed significant increase in proliferative DR group. The stepwise raised in mean plasma erythropoietin level which demonstrates significant correlation with proliferative DR versus remaining two groups, will be an indication of its role in proliferative DR. PMID- 25276080 TI - Predictive findings of visual outcome in spectral domain optical coherence tomography after ranibizumab treatment in age-related macular degeneration. AB - PURPOSE: To investigate which spectral domain optical coherence tomography (SD OCT) findings predict visual outcome after anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (NV-AMD). METHODS: We reviewed the medical records of patients with treatment-naive NV-AMD who underwent three or more consecutive anti-VEGF injections. The patients were divided into three groups according to their changes of visual acuity (VA); improved (group I), static (group S), or worsened (group W). We assessed the incidences and values of all available SD-OCT findings of these groups, compared these findings between the three groups and compared the initial values with the post-treatment values. RESULTS: Better initial VA and longer external limiting membrane (ELM) length were associated with less change in VA after anti-VEGF treatment. The initial VA was mildly correlated with initial photoreceptor inner and outer segment junction (IS/OS) length and initial ELM length. The final VA was also mildly correlated with the final IS/OS length and the final ELM length. VA was significantly changed after anti-VEGF treatment in groups W and I. With regard to incidence, disruption of the IS/OS (IS/OS-D), disruption of the ELM (ELM-D) and ELM length differed significantly between the three groups, particularly ELM-D. The incidences of IS/OS-D and ELM-D in group I were significantly lower than those in groups S and W, and those in group S were also lower than those in group W. The ELM length in group I was significantly longer than it was in groups S and W, and the ELM length in group S was longer than that for group W. However, these three findings did not change after the anti-VEGF treatment. CONCLUSIONS: Initial IS/OS-D, ELM length and particularly ELM-D can be useful predictors of the visual outcome after anti-VEGF treatment in NV-AMD patients. PMID- 25276081 TI - Augmentation of filtering blebs with viscoelastics in trabeculectomy. AB - PURPOSE: To evaluate the clinical outcome of viscoelastics (VE, sodium hyaluronate)-augmented trabeculectomy (VAT, 66 eyes) and conventional trabeculectomy (CT, 57 eyes) for glaucomatous eyes. METHODS: In the VAT group, half of the anterior chamber space was filled with VE via the paracentesis site at the end of CT and a balanced salt solution was injected into the anterior chamber. This procedure induced migration of VE from the anterior chamber into the bleb space; thus the bleb was elevated with underlying VE. Follow-up examinations were performed until 1 year after surgery. Success was defined as the attainment of an intraocular pressure (IOP) greater than 5 mmHg and less than 22 mmHg. If IOP was in the range of success without antiglaucoma medication, it was regarded as a complete success. RESULTS: The mean postoperative IOP was significantly lower in the VAT group at postoperative 1 day, 1 week, and 1 month. The complete success rate was significantly higher in the VAT group (89%) than in the CT group (75%), though the qualified success rate was not different between the two groups. The number of IOP-lowering medications at postoperative 1 year was significantly higher in the CT group (1.30 +/- 1.08 vs. 0.73 +/- 0.98, p = 0.003). Among postoperative procedures, laser suture lysis was required less frequently in the VAT group (p < 0.001). CONCLUSIONS: Placing VE within the bleb at the end of surgery may result in better IOP control and less need for IOP lowering medication without any additional materials, cost, or time. PMID- 25276082 TI - Comparing the efficacy of latanoprost (0.005%), bimatoprost (0.03%), travoprost (0.004%), and timolol (0.5%) in the treatment of primary open angle glaucoma. AB - PURPOSE: To compare the efficacy and safety of latanoprost, bimatoprost, travoprost and timolol in reducing intraocular pressure (IOP) in patients with primary open angle glaucoma. METHODS: This was a prospective study conducted at a tertiary-care centre. One hundred and forty patients with newly diagnosed primary open angle glaucoma were randomly assigned to treatment with latanoprost (0.005%), bimatoprost (0.03%), travoprost (0.004%) or timolol gel (0.5%); 35 patients were assigned to each group. All patients were followed for 2, 6, and 12 weeks. The main outcome measure studied was the change in IOP at week 12 from the baseline values. Safety measures included recording of adverse events. RESULTS: The mean IOP reduction from baseline at week 12 was significantly more with bimatoprost (8.8 mmHg, 35.9%) than with latanoprost (7.3 mmHg, 29.9%), travoprost (7.6 mmHg, 30.8%) or timolol (6.7 mmHg, 26.6%) (ANOVA and Student's t-tests, p < 0.001). Among the prostaglandins studied, bimatoprost produced a maximum reduction in IOP (-2.71; 95% confidence interval [CI], -2.25 to -3.18) followed by travoprost (-1.27; 95% CI, -0.81 to -1.27) and latanoprost (-1.25; 95% CI, 0.79 to -1.71); these values were significant when compared to timolol at week 12 (Bonferroni test, p < 0.001). Latanoprost and travoprost were comparable in their ability to reduce IOP at each patient visit. Ocular adverse-events were found in almost equal proportion in patients treated with bimatoprost (41.3%) and travoprost (41.9%), with a higher incidence of conjunctival hyperemia (24.1%) seen in the bimatoprost group. Timolol produced a significant drop in heart rate (p < 0.001) at week 12 when compared to the baseline measurements. CONCLUSIONS: Bimatoprost showed greater efficacy when compared to the other prostaglandins, and timolol was the most efficacious at lowering the IOP. Conjunctional hyperemia was mainly seen with bimatoprost. However, the drug was tolerated well and found to be safe. PMID- 25276083 TI - The effect of pattern scan laser photocoagulation on peripapillary retinal nerve fiber layer thickness and optic nerve morphology in diabetic retinopathy. AB - PURPOSE: To evaluate the effect of pattern scan laser (PASCAL) photocoagulation on peripapillary retinal nerve fiber layer (RNFL) thickness, central macular thickness (CMT), and optic nerve morphology in patients with diabetic retinopathy. METHODS: Subjects included 35 eyes for the PASCAL group and 49 eyes for a control group. Peripapillary RNFL thickness, cup-disc area ratio and CMT were measured before PASCAL photocoagulation and at 2 and 6 months after PASCAL photocoagulation in the PASCAL or control groups. RESULTS: The average RNFL thickness had increased by 0.84 um two months after and decreased by 0.4 um six months after PASCAL photocoagulation compared to baseline, but these changes were not significant (p = 0.83, 0.39). The cup-disc area ratio was unchanged after PASCAL photocoagulation. CMT increased by 18.11 um (p = 0.048) at two months compared to baseline thickness, and partially recovered to 11.82 um (p = 0.11) at six months in the PASCAL group. CONCLUSIONS: PASCAL photocoagulation may not cause significant change in the peripapillary RNFL thickness, CMT, and optic nerve morphology in patients with diabetic retinopathy. PMID- 25276084 TI - Accommodative esotropia who needs spectacles for good ocular alignment after refractive shift below +2.00 diopters. AB - PURPOSE: The aim of this study is to investigate the clinical characteristics of patients diagnosed with refractive accommodative esotropia (RAE) whose refractive errors were gradually reduced to below +2.00 diopters (D) during follow-up but use of spectacles was still required for maintenance of good ocular alignment. METHODS: We conducted a retrospective review of the medical records of patients diagnosed with RAE from 1995 to 2011. Patients were divided into 2 groups according to their ocular alignment at the last visit. Inclusion criteria were hyperopia >=+2.00 D detected with cycloplegic refraction at the initial visit, which then became mild hyperopia (<+2.00 D) or myopia during follow-up, with more than 5 years of follow-up. RESULTS: A total of 92 patients met the inclusion criteria. Twenty-six patients showed persistent esotropia (>=10 prism diopters [PD]) without spectacles (group A) and 66 patients showed good ocular alignment (<10 PD) without spectacles (group B) at the last visit. No statistically significant differences in the spherical equivalent of the refractive errors at the initial and last visit were observed between the two groups. A significantly lower number of positive responses on the Lang I stereotest was observed in group A (n = 1, 3.8%) compared to group B (n = 22, 33.3%) (p = 0.003). There were increasing trends toward group A with worsening stereoacuity measured by the Stereo Fly Stereotest between the two groups (p = 0.016, linear by linear association). The results of the Lang I test, Stereo Fly Stereotest, and duration between the onset of esotropia and prescribing spectacles showed a significant association with the discontinuation of spectacles in the univariate logistic analysis. CONCLUSIONS: Stereoacuity showed more significant associations than refractive errors in RAE with refractive error <+2.00 D but still required spectacles for maintenance of good ocular alignment. The prompt treatment of accommodative esotropia at the onset of esotropia is important for the discontinuation of spectacles. PMID- 25276085 TI - Long-standing asymptomatic intralenticular foreign body. PMID- 25276086 TI - Treatment of serous retinal detachment associated with choroidal ischemia with intravitreal bevacizumab following brain surgery. PMID- 25276087 TI - In situ peripheral iridoplasty in phakic eyes for the treatment of symptomatic peripheral iridotomy. PMID- 25276088 TI - Ethmoidal sinus mucocele as a cause of acquired brown syndrome. PMID- 25276089 TI - The changing pattern of upper gastrointestinal disorders by endoscopy: data of the last 40 years. AB - Objectives. We have investigated the changes in the incidence of various diagnoses that have been made in the endoscopy unit throughout the last 40 years. Methods. In this study, changes in the incidence of endoscopic diagnosis in upper gastrointestinal system between 1970 and 2010 were evaluated. Their diagnosis, age, and gender data were entered into the Excel software. Results. Of the 52816 cases who underwent esophagogastroduodenoscopy in the 40-year time period, the mean age was 48.17 +/- 16.27 (mean +/- SD). Although overall more than half of the patients were male (54.3%), in 1995 and after a marked increase was seen in the proportion of female gender (51-55%). The presence of hiatal hernia, reflux esophagitis, and the number of Barrett's esophaguses significantly increased. Erosive gastritis showed gradual increase, while the number of gastric ulcers decreased significantly. The presence of gastric and esophageal cancer significantly decreased. The number of duodenal ulcers significantly decreased. Conclusion. We detected that the incidences of esophagitis, Barrett's esophagus, and erosive gastritis significantly increased while the incidences of gastric/duodenal ulcer and gastric/esophageal cancer decreased throughout the last 40 years. PMID- 25276090 TI - Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling. AB - Heart failure is one of the leading causes of mortality in Western countries, and beta-blockers are a cornerstone of its treatment. However, the response to these drugs is variable among individuals, which might be explained, at least in part, by genetic differences. Pharmacogenomics is the study of genetic contributions to drug response variability in order to provide evidence for a tailored therapy in an individual patient. Several studies have investigated the pharmacogenomics of the adrenergic receptor system and its role in the context of the use of beta blockers in treating heart failure. In this review, we will focus on the most significant polymorphisms described in the literature involving adrenergic receptors and adrenergic receptor-related proteins, as well as genetic variations influencing beta-blocker metabolism. PMID- 25276091 TI - Developing genomic knowledge bases and databases to support clinical management: current perspectives. AB - Personalized medicine, the ability to tailor diagnostic and treatment decisions for individual patients, is seen as the evolution of modern medicine. We characterize here the informatics resources available today or envisioned in the near future that can support clinical interpretation of genomic test results. We assume a clinical sequencing scenario (germline whole-exome sequencing) in which a clinical specialist, such as an endocrinologist, needs to tailor patient management decisions within his or her specialty (targeted findings) but relies on a genetic counselor to interpret off-target incidental findings. We characterize the genomic input data and list various types of knowledge bases that provide genomic knowledge for generating clinical decision support. We highlight the need for patient-level databases with detailed lifelong phenotype content in addition to genotype data and provide a list of recommendations for personalized medicine knowledge bases and databases. We conclude that no single knowledge base can currently support all aspects of personalized recommendations and that consolidation of several current resources into larger, more dynamic and collaborative knowledge bases may offer a future path forward. PMID- 25276092 TI - Introducing an integrated intermediate care unit improves ICU utilization: a prospective intervention study. AB - BACKGROUND: Improvement of appropriate bed use and access to intensive care (ICU) beds is essential in optimizing utilization of ICU capacity. The introduction of an intermediate care unit (IMC) integrated in the ICU care may improve this utilization. METHOD: In a before-after prospective intervention study in a university hospital mixed ICU, the impact of introducing a six-bed mixed IMC unit supervised and staffed by ICU physicians was investigated. Changes in ICU utilization (length of stay, frequency of mechanical ventilation use), nursing workload assessed byTISS-28 score, as well as inappropriate bed use, accessibility of the ICU (number of referrals), and clinical outcome indicators (readmission and mortality rates) were measured. RESULTS: During 17 months, data of 1027 ICU patients were collected. ICU utilization improved significantly with an increased appropriate use of ICU beds. However, the number of referrals, readmissions to the ICU and mortality rates did not decrease after the IMC was opened. CONCLUSION: The IMC contributed to a more appropriate use of ICU facilities and did result in a significant increase in mean nursing workload at the ICU. PMID- 25276093 TI - Comparison of three point-of-care testing devices to detect hemostatic changes in adult elective cardiac surgery: a prospective observational study. AB - BACKGROUND: Bleeding complications in cardiac surgery may lead to increased morbidity and mortality. Traditional blood coagulation tests are not always suitable to detect rapid changes in the patient's coagulation status. Point-of care instruments such as the TEG (thromboelastograph) and RoTEM (thromboelastometer) have been shown to be useful as a guide for the clinician in the choice of blood products and they may lead to a reduction in the need for blood transfusion, contributing to better patient blood management. METHODS: The purpose of this study was to evaluate the ability of the TEG, RoTEM and Sonoclot instruments to detect changes in hemostasis in elective cardiac surgery with cardiopulmonary bypass and to investigate possible correlations between variables from these three instruments and routine hematological coagulation tests. Blood samples from thirty-five adult patients were drawn before and after surgery and analyzed in TEG, RoTEM, Sonoclot and routine coagulation tests. Data were compared using repeated measures analysis of variance and Pearson's test for linear correlation. RESULTS: We found significant changes for all TEG variables after surgery, for three of the RoTEM variables, and for one variable from the Sonoclot. There were significant correlations postoperatively between plasma fibrinogen levels and variables from the three instruments. CONCLUSIONS: TEG and RoTEM may be used to detect changes in hemostasis following cardiac surgery with CPB. Sonoclot seems to be less suitable to detect such changes. Variables from the three instruments correlated with plasma fibrinogen and could be used to monitor treatment with fibrinogen concentrate. PMID- 25276094 TI - Qualitative inquiry: a method for validating patient perceptions of palliative care while enrolled on a cancer clinical trial. AB - BACKGROUND: Palliative care is a vital component of patient-centered care. It has increasingly become central to the management and care of seriously ill patients by integrating physical, psychosocial, and spiritual supportive services. Through qualitative inquiry, this paper examines cancer patients' perceptions of the process and outcomes of the pain and palliative care consultative services they received while enrolled in a clinical trial. METHODS: A qualitative analysis of open-ended questions was conducted from a sub-sample of patients (n = 34) with advanced cancers enrolled in a randomized controlled trial exploring the efficacy of a palliative care consult service. Two open-ended questions focused on patient perceptions of continued participation on their primary cancer clinical trials and their perceptions of interdisciplinary communication. RESULTS: THREE OVERARCHING THEMES EMERGED WHEN ASKED WHETHER RECEIVING PAIN AND PALLIATIVE CARE SERVICES MADE THEM MORE LIKELY TO REMAIN ENROLLED IN THEIR PRIMARY CANCER CLINICAL TRIAL: patients' past experiences with care, self-identified personal characteristics and reasons for participation, and the quality of the partnership. Four themes emerged related to interdisciplinary communication including: the importance of developing relationships, facilitating open communication, having quality communication, and uncertainty about communication between the cancer clinical trial and palliative care teams. CONCLUSIONS: Our findings suggest the importance of qualitative inquiry methods to explore patient perceptions regarding the efficacy of palliative care services for cancer patients enrolled in a cancer clinical trial. Validation of patient perceptions through qualitative inquiry regarding their pain and palliative care needs can provide insight into areas for future implementation research. TRIAL REGISTRATION: NIH Office of Human Subjects Research Protection OHSRP5443 and University of Pennsylvania 813365. PMID- 25276095 TI - Characteristics of a palliative care consultation service with a focus on pain in a German university hospital. AB - BACKGROUND: A minority of patients with incurable and advanced disease receive specialised palliative care. Specialised palliative care services that complement the care of difficult and complex cases ought to be integrated with services that deliver general care for most patients. A typical setting in which this integrative concept takes place is the hospital setting, where patients suffering from incurable and advanced disease are treated in many different departments. The aim of the study is to investigate the profile and spectrum of a palliative care consultation service (PCCS) at a German university hospital with special reference to pain therapy. METHODS: We retrospectively analysed the PCCS documentation of three years. RESULTS: Most patients were referred from non surgical departments, 72% were inpatients, and 28% were outpatients. 98% of the patients suffered from cancer. Counselling in pain therapy was one of the key aspects of the consultation: For 76% of all consulted patients, modifications of the analgesic regimen were recommended, which involved opioids in 96%. Recommendations on breakthrough-pain medication were made for 70% of the patients; this was an opioid in most cases (68%). The most commonly used opioid was morphine. For 17% of the patients, additional diagnostic procedures were recommended. Besides pain management palliative care consultation implied a wide range of recommendations and services: In addition to organising home care infrastructure, palliative care services supported patients and their families in understanding the life-limiting diseases. They also coordinated physical therapy and social and legal advice. CONCLUSION: This survey clearly shows that for a consultation service to support patients with incurable or advanced disease, a multi-disciplinary approach is necessary to meet the complex requirements of a needs-adapted palliative care in inpatient or outpatient settings. Timely integration of palliative expertise may support symptom control and may give the required advice to patients, their carers, and their families. PMID- 25276096 TI - Two dimensional gel phosphoproteome of peripheral blood mononuclear cells: comparison between two enrichment methods. AB - BACKGROUND: Protein phosphorylation is considered a key event in signal transduction. Peripheral blood mononuclear cells (PBMCs) are a critical component of the immune system. The analysis of PBMCs phosphoproteome might help elucidate the signaling pathways essential to their biological role in health, immunological diseases and cancer. Enrichment of phosphoproteins becomes a prerequisite for phosphoproteome analysis and conventionally requires a multi step procedure and sophisticated equipments. In this study, we standardized 2D PAGE phosphoproteome analysis of PBMCs and compared two phosphoprotein enrichment methods, lanthanum chloride precipitation and affinity micro-column. Further, the different specificity for PBMCs phosphorylated proteins of each method was investigated. RESULTS: PBMCs were isolated from fresh whole blood of ten healthy donors. PBMCs phosphoproteins were enriched either by phosphoprotein precipitation using lanthanum chloride, with an overall yield of 8.9 +/- 4.7%, or by using an affinity micro-column, with a lower yield of 3.2 +/- 1.6% (p = 0.05). Image analysis of Sypro-stained analytical 2D-PAGE gels detected 554 +/- 68 protein spots for the lanthanum pattern [inter-assay coefficient of variation (CV) = 27.0%, intra-assay CV = 10.7%] and 575 +/- 35 protein spots for the micro column pattern (inter-assay CV = 26.8%; intra-assay CV = 11.0%) (p = 0.6), with 57% match of the spots detected by the 2 approaches. 1D gel electrophoresis and western blot analyses of the supernatants suggested a better lanthanum ions capability to deplete phosphoproteins in a PBMCs protein lysate compared to the affinity micro-column. On the other hand, 1D gel electrophoresis analysis of dephosphorylated PBMCs protein lysate revealed a relatively higher unspecificity for the lanthanum ions compared to affinity micro-column. Filamin-A, coronin 1A, pyruvate kinase isozymes M1/M2 and ficolin-1 were considerably more expressed in the lanthanum phosphoprotein pattern. Interestingly, ficolin-1 had not been reported in 2DE-PBMCs proteome profiles so far. CONCLUSION: Our results describe the differences and the validity of phosphoprotein enrichment methods and provide two successful and complementary approaches for the 2DE phosphoproteome analysis of PBMCs. PMID- 25276097 TI - Comparative proteomics and glycoproteomics of plasma proteins in Indian visceral leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis (VL) is a deadly parasitic diseases caused by Leishmania donovani; it is a major health problem in many countries. A lack of proper understanding of the disease biology, poor diagnostic methods and increasing drug resistance are the main reasons for the growing burden of VL infection. Comparative plasma proteomics are a relatively useful technique that can be used to investigate disease-associated alterations that can help in understanding host responses against pathogens, and might be useful in disease management and diagnosis. RESULT: In this study, a comparative proteomics and glycoproteomics approach using 2DE and 2D-DIGE was employed between early diagnosed VL patients of all age groups and healthy endemic and non-endemic controls in order to aid the recognition of disease-associated alterations in host plasma. Comparative proteomics was performed by the depletion of seven highly abundant plasma proteins. Comparative glycoproteomics was performed by the depletion of albumin and IgG, followed by purification of plasma glycoproteins using a multi lectin affinity column. From these two approaches, 39 differentially expressed protein spots were identified and sequenced using MALDI TOF/TOF mass spectrometry. This revealed ten distinct proteins that appeared in multiple spots, suggesting micro-heterogeneity. Among these proteins, alpha-1 antitrypsin, alpha-1-B glycoprotein and amyloid-A1 precursor were up-regulated, whereas vitamin-D binding protein, apolipoprotein-A-I and transthyretin were down regulated in VL. Alterations in the levels of these proteins in VL-infected plasma were further confirmed by western blot and ELISA. CONCLUSIONS: These proteins may be involved in the survival of parasites, resisting neutrophil elastase, and in their multiplication in macrophages, potentially maintaining endogenous anti-inflammatory and immunosuppressive conditions. Consequently, the results of this study may help in understanding the host response against L.donovani, which could help in the discovery of new drugs and disease management. Finally, these alterations on protein levels might be beneficial in improving early diagnosis considering those as biomarkers in Indian VL. PMID- 25276099 TI - Solution growth of NiO nanosheets supported on Ni foam as high-performance electrodes for supercapacitors. AB - Well-aligned nickel oxide (NiO) nanosheets with the thickness of a few nanometers supported on a flexible substrate (Ni foam) have been fabricated by a hydrothermal approach together with a post-annealing treatment. The three dimensional NiO nanosheets were further used as electrode materials to fabricate supercapacitors, with high specific capacitance of 943.5, 791.2, 613.5, 480, and 457.5 F g(-1) at current densities of 5, 10, 15, 20, and 25 A g(-1), respectively. The NiO nanosheets combined well with the substrate. When the electrode material was bended, it can still retain 91.1% of the initial capacitance after 1,200 charging/discharging cycles. Compared with Co3O4 and NiO nanostructures, the specific capacitance of NiO nanosheets is much better. These characteristics suggest that NiO nanosheet electrodes are promising for energy storage application with high power demands. PMID- 25276100 TI - The effect of two novel amino acid-coated magnetic nanoparticles on survival in vascular endothelial cells, bone marrow stromal cells, and macrophages. AB - Magnetic nanoparticles (MNPs) have been popularly used in many fields. Recently, many kinds of MNPs are modified as new absorbents, which have attracted considerable attention and are promising to be applied in waste water. In our previous study, we synthesized two novel MNPs surface-coated with glycine or lysine, which could efficiently remove many anionic and cationic dyes under severe conditions. It should be considered that MNP residues in water may exert some side effects on human health. In the present study, we evaluated the potential nanotoxicity of MNPs in human endothelial cells, macrophages, and rat bone marrow stromal cells. The results showed that the two kinds of nanoparticles were consistently absorbed into the cell cytoplasm. The concentration of MNPs@Gly that could distinctly decrease survival was 15 MUg/ml in human umbilical vascular endothelial cells (HUVECs) or bone marrow stromal cells (BMSCs) and 10 MUg/ml in macrophages. While the concentration of MNPs@Lys that obviously reduced viability was 15 MUg/ml in HUVECs or macrophages and 50 MUg/ml in BMSCs. Furthermore, cell nucleus staining and cell integrity assay indicated that the nanoparticles induced cell apoptosis, but not necrosis even at a high concentration. Altogether, these data suggest that the amino acid-coated magnetic nanoparticles exert relatively high cytotoxicity. By contrast, lysine-coated magnetic nanoparticles are more secure than glycine-coated magnetic nanoparticles. PMID- 25276102 TI - Nanostructured copper/porous silicon hybrid systems as efficient sound-emitting devices. AB - In the present work, the photo-acoustic emission from nanostructured copper/porous silicon hybrid systems was studied. Copper nanoparticles were grown by photo-assisted electroless deposition on crystalline silicon and nanostructured porous silicon (nanoPS). Both the optical and photo-acoustic responses from these systems were determined. The experimental results show a remarkable increase in the photo-acoustic intensity when copper nanoparticles are incorporated to the porous structure. The results thus suggest that the Cu/nanoPS hybrid systems are suitable candidates for several applications in the field of thermoplasmonics, including the development of sound-emitting devices of great efficiency. PMID- 25276101 TI - Improved conversion efficiency of amorphous Si solar cells using a mesoporous ZnO pattern. AB - To provide a front transparent electrode for use in highly efficient hydrogenated amorphous silicon (a-Si:H) thin-film solar cells, porous flat layer and micro patterns of zinc oxide (ZnO) nanoparticle (NP) layers were prepared through ultraviolet nanoimprint lithography (UV-NIL) and deposited on Al-doped ZnO (AZO) layers. Through this, it was found that a porous micro-pattern of ZnO NPs dispersed in resin can optimize the light-trapping pattern, with the efficiency of solar cells based on patterned or flat mesoporous ZnO layers increased by 27% and 12%, respectively. PMID- 25276103 TI - Fe effect on the optical properties of TiO2:Fe2O3 nanostructured composites supported on SiO2 microsphere assemblies. AB - The effect of Fe ion concentration on the morphological, structural, and optical properties of TiO2 films supported on silica (SiO2) opals has been studied. TiO2:Fe2O3 films were prepared by the sol-gel method in combination with a vertical dip coating procedure; precursor solutions of Ti and Fe were deposited on a monolayer of SiO2 opals previously deposited on a glass substrate by the same procedure. After the dip coating process has been carried out, the samples were thermally treated to obtain the TiO2:Fe2O3/SiO2 composites at the Fe ion concentrations of 1, 3, and 5 wt%. Scanning electron microscopy (SEM) micrographs show the formation of colloidal silica microspheres of about 50 nm diameter autoensembled in a hexagonal close-packed fashion. Although the X-ray diffractograms show no significant effect of Fe ion concentration on the crystal structure of TiO2, the MU-Raman and reflectance spectra do show that the intensity of a phonon vibration mode and the energy bandgap of TiO2 decrease as the Fe(+3) ion concentration increases. PMID- 25276098 TI - The functional role of long non-coding RNAs and epigenetics. AB - Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. The post-transcriptional regulation is influenced by these lncRNAs by interfering with the microRNA pathways, involving in diverse cellular processes. The regulation of gene expression by lncRNAs at the epigenetic level, transcriptional and post-transcriptional level have been well known and widely studied. Recent recognition that lncRNAs make effects in many biological and pathological processes such as stem cell pluripotency, neurogenesis, oncogenesis and etc. This review will focus on the functional roles of lncRNAs in epigenetics and related research progress will be summarized. PMID- 25276106 TI - Design parameters for enhanced photon absorption in vertically aligned silicon nanowire arrays. AB - Superior photon absorption in ordered nanowire arrays has been demonstrated recently. However, systematic studies are still missing to explore the limits of their implementation as functional photonic devices. With emphasis on silicon nanowires, we investigated the effects of nanowire diameter, length, morphology, and pitch on the photon absorption within the visible solar spectrum based on simulations. Our results reveal that these parameters are crucial but disclose a path to improve the absorbance drastically. PACS: 78.40.Fy; 78.67.Uh; 78.67.-n. PMID- 25276105 TI - Evaluation of optical and electronic properties of silicon nano-agglomerates embedded in SRO: applying density functional theory. AB - In systems in atomic scale and nanoscale such as clusters or agglomerates constituted by particles from a few to less than 100 atoms, quantum confinement effects are very important. Their optical and electronic properties are often dependent on the size of the systems and the way in which the atoms in these clusters are bonded. Generally, these nanostructures display optical and electronic properties significantly different to those found in corresponding bulk materials. Silicon agglomerates embedded in silicon rich oxide (SRO) films have optical properties, which have been reported to be directly dependent on silicon nanocrystal size. Furthermore, the room temperature photoluminescence (PL) of SRO has repeatedly generated a huge interest due to its possible applications in optoelectronic devices. However, a plausible emission mechanism has not been widely accepted in the scientific community. In this work, we present a short review about the experimental results on silicon nanoclusters in SRO considering different techniques of growth. We focus mainly on their size, Raman spectra, and photoluminescence spectra. With this as background, we employed the density functional theory with a functional B3LYP and a basis set 6 31G* to calculate the optical and electronic properties of clusters of silicon (constituted by 15 to 20 silicon atoms). With the theoretical calculation of the structural and optical properties of silicon clusters, it is possible to evaluate the contribution of silicon agglomerates in the luminescent emission mechanism, experimentally found in thin SRO films. PMID- 25276107 TI - Effect of atomic layer deposition temperature on the performance of top-down ZnO nanowire transistors. AB - This paper studies the effect of atomic layer deposition (ALD) temperature on the performance of top-down ZnO nanowire transistors. Electrical characteristics are presented for 10-MUm ZnO nanowire field-effect transistors (FETs) and for deposition temperatures in the range 120 degrees C to 210 degrees C. Well-behaved transistor output characteristics are obtained for all deposition temperatures. It is shown that the maximum field-effect mobility occurs for an ALD temperature of 190 degrees C. This maximum field-effect mobility corresponds with a maximum Hall effect bulk mobility and with a ZnO film that is stoichiometric. The optimized transistors have a field-effect mobility of 10 cm(2)/V.s, which is approximately ten times higher than can typically be achieved in thin-film amorphous silicon transistors. Furthermore, simulations indicate that the drain current and field-effect mobility extraction are limited by the contact resistance. When the effects of contact resistance are de-embedded, a field effect mobility of 129 cm(2)/V.s is obtained. This excellent result demonstrates the promise of top-down ZnO nanowire technology for a wide variety of applications such as high-performance thin-film electronics, flexible electronics, and biosensing. PMID- 25276108 TI - Uniaxial strain-induced mechanical and electronic property modulation of silicene. AB - We perform first-principles calculations of mechanical and electronic properties of silicene under uniaxial strains. Poisson's ratio and the rigidity of silicene show strong chirality dependence under large uniaxial strains. The ultimate strains of silicene with uniaxial strain are smaller than those with biaxial strain. We find that uniaxial strains induce Dirac point deviation from the high symmetry points in the Brillouin zone and semimetal-metal transitions. Therefore, no bandgap opens under the uniaxial strain. Due to its peculiar structure and variable sp (3)/sp (2) ratio of the chemical bond, the deviation directions of Dirac points from the high-symmetry points in the Brillouin zone and variation of Fermi velocities of silicene exhibit significant difference from those of graphene. Fermi velocities show strong anisotropy with respect to the wave vector directions and change slightly before the semimetal-metal transition. We also find that the work function of silicene increases monotonously with the increasing uniaxial strains. PACS NUMBERS: 61.46.-w; 62.20.D-; 73.22.Dj. PMID- 25276109 TI - Optimization of the dye-sensitized solar cell performance by mechanical compression. AB - In this study, the P25 titanium dioxide (TiO2) nanoparticle (NP) thin film was coated on the fluorine-doped tin oxide (FTO) glass substrate by a doctor blade method. The film then compressed mechanically to be the photoanode of dye sensitized solar cells (DSSCs). Various compression pressures on TiO2 NP film were tested to optimize the performance of DSSCs. The mechanical compression reduces TiO2 inter-particle distance improving the electron transport efficiency. The UV-vis spectrophotometer and electrochemical impedance spectroscopy (EIS) were employed to quantify the light-harvesting efficiency and the charge transport impedance at various interfaces in DSSC, respectively. The incident photon-to-current conversion efficiency was also monitored. The results show that when the DSSC fabricated by the TiO2 NP thin film compressed at pressure of 279 kg/cm(2), the minimum resistance of 9.38 Omega at dye/TiO2 NP/electrolyte interfaces, the maximum short-circuit photocurrent density of 15.11 mA/cm(2), and the photoelectric conversion efficiency of 5.94% were observed. Compared to the DSSC fabricated by the non-compression of TiO2 NP thin film, the overall conversion efficiency is improved over 19.5%. The study proves that under suitable compression pressure the performance of DSSC can be optimized. PMID- 25276110 TI - AHAPS-functionalized silica nanoparticles do not modulate allergic contact dermatitis in mice. AB - Allergic contact dermatitis (ACD) is a common skin disease in people and may become a potential site of exposure to nanoparticles (NP). Silica nanoparticles (SiO2-NP) possess a promising potential for various medical and non-medical applications, including normal and diseased skin as target organs. However, it has been shown that negatively charged SiO2-NP may act as proinflammatory adjuvant in allergic diseases. The effect of topical SiO2-NP exposure on preexisting ACD has not been studied to date although this reflects a common in vivo situation. Of particular interest are the potential effects of positively charged N-(6-aminohexyl)-aminopropyltrimethoxysilane (AHAPS)-functionalized SiO2 NP which are promising candidates for delivery systems, including gene delivery into the skin. Here, the effects of such AHAPS-functionalized SiO2-NP (55 +/- 6 nm in diameter) were studied in an oxazolone-induced ACD model in SKH1 mice and compared to ACD mice treated with vehicle only. The clinical course of the disease was assessed by monitoring of the transepidermal water loss (TEWL) and the erythema. In histologic and morphometric analyses, the distribution of particles, the degree of inflammation, epidermal thickness, and the inflammatory infiltrate were characterized and quantified by standard and special histological stains as well as immunohistochemistry for CD3+ lymphocytes. To assess possible systemic effects, serum immunoglobulin E (IgE) was determined by enzyme-linked immunosorbent assay. Following administration of AHAPS-SiO2-NP for five consecutive days, no effects were observed in all clinical, histologic, morphometric, and molecular parameters investigated. In conclusion, positively charged AHAPS-SiO2-NP seem not to affect the course of ACD during exposure for 5 days. PMID- 25276111 TI - Synthesis, Characterization, and Antifungal Studies of Cr(III) Complex of Norfloxacin and Bipiridyl Ligand. AB - A novel slightly distorted octahedral complex of Cr(III) of norfloxacin (Nor) with the formula [Cr(III)(Nor)(Bipy)Cl2]Cl.2CH3OH has been synthesized hydrothermally in the presence of a N-containing heterocyclic compound 2,2' bipyridyl (Bipy). The complex was characterized with FT-IR, elemental analysis, UV-visible spectroscopy, and X-ray crystallography. Spectral studies suggest that the Nor acts as a deprotonated bidentate ligand. Thermal studies were also carried out. The synthesised complex was screened against four fungi Pythium aphanidermatum (PA), Sclerotinia rolfsii (SR), Rhizoctonia solani (RS), and Rhizoctonia bataticola (RB). PMID- 25276112 TI - The Improvement of the Resistance to Candida albicans and Trichophyton interdigitale of Some Woven Fabrics Based on Cotton. AB - This paper presents the improvement of the antimicrobial character of woven fabrics based on cotton. The woven fabrics were cleaned in oxygen plasma and treated by padding with silver chloride and titanium dioxide particles. The existence of silver and titanium on woven fabrics was evidenced by electronic microscope images (SEM, EDAX) and by flame atomic absorption spectrophotometry. The antimicrobial tests were performed with two fungi: Candida albicans and Trichophyton interdigitale. The obtained antimicrobial effect was considerably higher compared to the raw fabrics. Treatment of dyed fabrics with a colloidal solution based on silver chloride and titanium dioxide particles does not considerably influence colour resistance of dyes. PMID- 25276113 TI - Synthesis, Structural Characterization, and Evaluation of the Biological Properties of Heteroleptic Palladium(II) Complexes. AB - Five heteroleptic palladium(II) complexes of the general formula Pd(PR3)(tu)Cl2, where PR3 = triphenylphosphine (1), diphenyl-o-tolylphosphine (2), diphenyl-p tolylphosphine (3), diphenyl-t-butylphosphine (4), and diphenyl-o methoxyphenylphosphine (5), and tu = 1,3-bis(2-methoxyphenyl) thiourea. They all have been synthesized and characterized by various spectroscopic techniques (elemental analysis, FTIR, and (1)H NMR and the ligand 1,3-bis(2-methoxyphenyl) thiourea was synthesized by single crystal X-ray diffraction technique). The synthesized compounds were screened for their antibacterial activity against four strains of bacteria (Escherichia coli, Shigella flexneri, Staphylococcus aureus, and Bacillus subtilis). The antitumor potential was evaluated in terms of activity against brine shrimp eggs and DNA interaction. The mixed ligand complexes have exhibited moderate antibacterial activity and promising antitumor potential. PMID- 25276114 TI - The simultaneous incidence of acute pancreatitis and autoimmune hemolytic anemia: a rare duo in a patient with SLE. AB - A young female presented with acute abdominal pain of two days duration consistent with acute pancreatitis. During her stay in the hospital she had a sudden drop in hemoglobin to 6 g/dl without any overt blood loss. On evaluation, it was evident that she had acute pancreatitis, in addition to displaying features of autoimmune hemolytic anemia. She had been a known case of systemic lupus erythematosus (SLE) and had discontinued her treatment. She was managed with methylprednisolone pulse therapy. Her clinical condition improved, and she has been regularly attending our clinic for the last 2 years. According to a literature search in Medline, it would appear that this is the first report of a case in which SLE with autoimmune hemolytic anemia has been associated with acute pancreatitis in a single case. PMID- 25276115 TI - Varus deformity of the left lower extremity causing degenerative lesion of the posterior horn of the left medial meniscus in a patient with Paget's disease of bone. AB - We report on a 42-year-old woman who presented with persistent pain in her left knee with no history of trauma. Sagittal T1-weighted MRI of the left knee showed discontinuity between the anterior and posterior horns of the left medial meniscus, causing effectively the development of degenerative lesion of the posterior horn. The latter was correlated to varus deformity of the left lower extremity associated with subsequent narrowing of the medial knee joint. The unusual craniofacial contour of the patient, the skeletal survey and the elevated serum alkaline phosphatase were compatible with the diagnosis of Paget's disease of the bone. To alleviate the adverse effect of the mal-alignment of the left femur onto the left knee, corrective osteotomy of the left femoral diaphysis by means of fixators was performed. To the best of our knowledge this is the first clinical report describing the management and the pathological correlation of a unilateral varus deformity of the femoral shaft and degenerative lesions of the left knee in a patient with Paget's disease of the bone. PMID- 25276116 TI - A pilot study of research methods for determining the impact of pictorial cigarette warning labels among smokers. AB - BACKGROUND: Science to determine the impact of pictorial cigarette warning labels can inform decisions about warning label implementation and adjustments to their contents to maximize impact. This pilot study builds from earlier research on plain cigarette packaging to examine the feasibility of a method for determining the impact of pictorial warnings among smokers. FINDINGS: The study was a prospective, within-subjects pilot trial where smokers ages 18-30 (n = 10) were exposed to pictorial warnings on their cigarette packs. On day one, participants completed a baseline interview with an expired carbon monoxide reading and affixed pictorial warning labels to their cigarette pack(s) they would use the next day. On day two, participants completed mobile phone text message assessments of smoking behaviors and protocol adherence. On day three, participants completed a follow-up interview similar to baseline. We achieved 100% sample retention and adherence with procedures. Compared with baseline assessments of perceptions and behaviors related to existing text-only warnings, at follow-up participants were more likely to report that pictorial warnings used during the study were noticeable (M 4.1, SD 1.3 vs. M 2.7, SD 1.2, p = .013), stopped them from smoking (M 1.6, SD 0.8 vs. M 1.1, SD 0.3, p = .052), and conveyed health risks of smoking (M 3.5 SD 1.3 vs. M 2.2, SD 1.1, p = .006). At follow-up, participants also reported the protocol was acceptable. CONCLUSIONS: These findings suggest this is a feasible method that with further validation could provide evidence that can inform decisions regarding implementation of pictorial cigarette warnings. PMID- 25276117 TI - Gastrointestinal bleeding in acute ischemic stroke: recent trends from the fukuoka stroke registry. AB - BACKGROUND: Gastrointestinal (GI) hemorrhage is a potentially serious complication of acute stroke, but its incidence appears to be decreasing. The aim of this study was to elucidate the etiology of GI bleeding and its impact on clinical outcomes in patients with acute ischemic stroke in recent years. METHODS: Using the database of the Fukuoka Stroke Registry, 6,529 patients with acute ischemic stroke registered between June 2007 and December 2012 were included in this study. We recorded clinical data including any previous history of peptic ulcer, prestroke drug history including the use of antiplatelets, anticoagulants, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs), and poststroke treatment with suppressing gastric acidity. GI bleeding was defined as any episode of hematemesis or melena on admission or during hospitalization. The cause and origin of bleeding were diagnosed endoscopically. Logistic regression analysis was used to identify risk factors for GI bleeding and its influence on deteriorating neurologic function, death, and poor outcome. RESULTS: GI bleeding occurred in 89 patients (1.4%) under the condition that 66% of the total patients received acid-suppressing agents after admission. Multivariate analysis revealed that GI bleeding was associated with the absence of dyslipidemia (p = 0.03), a previous history of peptic ulcer (p < 0.001), and the severity of baseline neurologic deficit (p = 0.002) but not with antiplatelet drugs, anticoagulants, and NSAIDs. The source was the upper GI tract in 51% of the cases; causes included peptic ulceration (28%) and malignancies (12%), and other or unidentified causes accounted for 60%. GI bleeding mostly occurred within 1 week after stroke onset. Hemoglobin concentration fell by a median value of 2.5 g/dl in patients with GI bleeding. Among them, 28 patients underwent blood transfusion (31.5%). After adjustment for confounding factors, GI bleeding was independently associated with neurologic deterioration (OR 3.9, 95% CI 2.3-6.6, p < 0.001), in hospital death (OR 6.1, 95% CI 3.1-12.1, p < 0.001), and poor outcome at 3 months (OR 6.8, 95% CI 3.7-12.7, p < 0.001). These associations were significant irrespective of whether patients underwent red blood cell transfusion. CONCLUSIONS: GI bleeding infrequently occurred in patients with acute ischemic stroke, which was mostly due to etiologies other than peptic ulcer. GI bleeding was associated with poor clinical outcomes including neurologic deterioration, in hospital mortality, and poor functional outcome. PMID- 25276118 TI - Is isolated aphasia associated with atrial fibrillation? A prospective study. AB - BACKGROUND: A cardioembolic source, usually atrial fibrillation (AF), is detected in 14-30% of strokes. If AF is found, anticoagulation therapy provides a substantial decrease of the risk of recurrent cerebrovascular ischemic events. AF is often paroxysmal, and extensive diagnostic procedures may be necessary to detect it in patients. Considering cost-effectiveness and patient burden, however, not every suspected patient can be thoroughly screened. Therefore, the identification of risk factors for AF may be helpful. Previous studies have identified isolated aphasia as a risk factor for AF as the cause of the stroke. These studies, however, were performed with small population samples, in a retrospective setting or focused on a specific subtype of aphasia. The aim of this observational study is to prospectively evaluate whether there is a relation between isolated aphasia and AF as the cause of cerebrovascular ischemia. METHODS: All patients admitted to the Atrium Medical Centre, Heerlen, the Netherlands, with cerebrovascular ischemia or transient ischemic attack in the period of August 2009 to March 2010 or October 2013 to January 2014 were included. The patients were evaluated by a neurologist and admitted to the Brain Care Unit for 24-48 h. Medical history, physical examination and diagnostic results were entered in a database. A diagnosis of isolated aphasia was assigned at admission using the National Institutes of Health Stroke Scale (NIHSS). Presence of AF was determined using a 12-lead electrocardiogram (ECG) on admission and continuous ECG monitoring for 1-2 days. During admission, aphasia tests were done, notably the ScreeLing Test and the Boston Naming Test. Data were analyzed using Pearson's chi(2) test, Fisher's exact test, the Mann-Whitney U test and univariate and multivariate logistic regression analyses. RESULTS: A total of 347 patients were included, of which 115 (33.1%) met the criteria for aphasia, with 26 (7.5%) meeting the criteria for isolated aphasia. Of all patients, 90 had a history of AF (66.7%) or AF was found during hospitalization (33.3%). Patients with AF, in contrast to those without, tended to present more often with any type of aphasia (41.1 vs. 30.4%) and isolated aphasia (10.0 vs. 6.6%), but these differences were not significant. A significant relation was found between global aphasia and AF (p = 0.011). Patients with AF scored significantly lower on the ScreeLing Test alone and on both aphasia tests together (p = 0.034). A history of transient ischemic attack significantly increased the risk for isolated aphasia (OR 2.66, 95% CI 1.09-6.47). CONCLUSIONS: A statistically significant relation between isolated aphasia and AF could not be established in this study. However, our results showed a tendency towards significance. Further studies, in which rhythm is observed for a longer period of time, may be required to confirm this hypothesis. PMID- 25276119 TI - Chronic kidney disease is an independent predictor of adverse clinical outcomes in patients with recent small subcortical infarcts. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with cerebral small vessel diseases (SVD) and predicts stroke, cardiovascular events and mortality. However, its association with recent small subcortical infarcts (RSSI), a novel subtype of cerebral SVD, has not yet been established in stroke patients. The aim of this longitudinal study was to clarify whether CKD can predict clinical outcome in patients with RSSI. METHODS: We enrolled patients with first-ever RSSI (formerly categorized as acute lacunar stroke). CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m(2) on admission. The patients were divided into two groups according to the presence or absence of CKD. The endpoints were recurrent stroke, cardiovascular events or all-cause mortality. The patients were followed up at 3, 6 and 12 months after stroke onset and yearly thereafter. Event free survival analysis was undertaken using Kaplan-Meier plots and the log-rank test. Cox's proportional-hazards analysis was conducted regarding age, sex and the presence of any cerebral SVD. RESULTS: A total of 152 patients (66% males; mean age: 67.6 years) were consecutively enrolled, and 44 (29%) had CKD. During the follow-up period (median: 3 years; interquartile range: 1-4), 27 patients (18%) reached endpoints. The numbers of patients per endpoint were as follows: all-cause mortality 14, ischemic stroke 9, hemorrhagic stroke 2 and aortic dissection 2. Patients with CKD were significantly older (77 vs. 64 years; p < 0.001), had higher serum creatinine (0.96 vs. 0.65 mg/dl; p < 0.001), higher brain natriuretic peptide (51.1 vs. 18.5 pg/ml; p < 0.001) and a higher National Institutes of Health Stroke Scale score on admission (3 vs. 2; p < 0.001), and were less likely to have modified Rankin Scale scores of 0-2 after stroke onset (52 vs. 77%; p = 0.003). Patients with white matter hyperintensity [odds ratio (OR) 3.0; 95% confidence interval (CI): 1.5-6.2; p = 0.003] and those with microbleeds (OR 2.5; 95% CI: 1.2-5.1; p = 0.015) had more pronounced CKD than the remaining patients. A Kaplan-Meier curve analysis showed that patients with CKD had a less favorable outcome than those without CKD (p < 0.001). The multivariate Cox proportional-hazards analysis revealed that CKD was associated with recurrent stroke, cardiovascular events or all-cause mortality (hazard ratio 2.22; 95% CI: 1.12-4.25; p = 0.02). CONCLUSIONS: CKD was found to be independently associated with recurrent stroke, cardiovascular events or all-cause mortality in patients with RSSI. PMID- 25276120 TI - Feature selection with neighborhood entropy-based cooperative game theory. AB - Feature selection plays an important role in machine learning and data mining. In recent years, various feature measurements have been proposed to select significant features from high-dimensional datasets. However, most traditional feature selection methods will ignore some features which have strong classification ability as a group but are weak as individuals. To deal with this problem, we redefine the redundancy, interdependence, and independence of features by using neighborhood entropy. Then the neighborhood entropy-based feature contribution is proposed under the framework of cooperative game. The evaluative criteria of features can be formalized as the product of contribution and other classical feature measures. Finally, the proposed method is tested on several UCI datasets. The results show that neighborhood entropy-based cooperative game theory model (NECGT) yield better performance than classical ones. PMID- 25276121 TI - Effect of Oral PUVAsol on the Quality of Life in Indian Patients Having Chronic Plaque Psoriasis. AB - Background. Psoriasis is associated with a high impact on health-related QoL (quality of life). PUVAsol has been successfully used for treating psoriasis instead of standard PUVA therapy in developing countries. However, data for PUVAsol therapy and its effect on QoL in psoriatic patients is meagre. Objective. To investigate the effect of PUVAsol on the quality of life in patients having chronic plaque psoriasis. Materials and Methods. An observational prospective study done in patients having chronic plaque psoriasis. PASI and DLQI were calculated before initiating treatment with oral PUVAsol. These were compared with the respective scores after 12 weeks of regular treatment with PUVAsol. Statistical analysis was done using SPSS version 20.0. Results. Both PASI and DLQI showed statistically significant reduction after 12 weeks of regular treatment. 90% of patients responded favourably to PUVAsol therapy in the study and all the domains of DLQI showed significant reduction except domain of "work and school." Conclusion. Our results show that regular PUVAsol treatment improves the physical appearance of disease as evident by decrease in PASI scores. It also improves the QoL of the patients. This study will add upon the growing evidence of efficacy of PUVAsol. PMID- 25276123 TI - Comparative Evaluation of Cytotoxic and Apoptogenic Effects of Several Coumarins on Human Cancer Cell Lines: Osthole Induces Apoptosis in p53-Deficient H1299 Cells. AB - Natural products are excellent resources for finding lead structures for the development of chemotherapeutic agents. Coumarins are a class of natural compounds found in a variety of plants. In this study, we evaluated the cytotoxic potential of coumarins isolated from Prangos ferulacea (L.) Lindl. in PC3, SKNMC, and H1299 (p53 null) human carcinoma cell lines. Osthole proved to be an outstanding potent cytotoxic agent especially against PC3 cells. Isoimperatorin exhibited moderate inhibitory effect against SKNMC and PC3 cell lines. Oxypeucedanin and braylin did not display any cytotoxic activity. In the next set of experiments, the apoptotic potentials of osthole and isoimperatorin were investigated. Induction of apoptosis by isoimperatorin was accompanied by an increase in activation of caspase-3, -8, and -9 in SKNMC cells and caspase-3 and 9 in PC3 cells. Moreover, isoimperatorin induced apoptosis by upregulating Bax and Smac/DIABLO genes in PC3 and SKNMC cells. Osthole induced apoptosis by downregulating antiapoptotic Bcl-2 in only PC3 cells and upregulating the proapoptotic genes Bax and Smac/DIABLO in PC3, SKNMC, and H1299 cells. The effects of osthole on H1299 cells are important because the loss of p53 has been associated with poor clinical prognosis in cancer treatment. PMID- 25276122 TI - Extent of Surgery and Implications of Transection Margin Status after Resection of IPMNs. AB - Appropriate surgical strategies for management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are a matter of debate. Preoperative and intraoperative evaluation of malignant potential of IPMN and of patient's comorbidities is of paramount importance to balance potential complications of surgery with tumors' risk of being or becoming malignant; the decision about the extent of pancreatic resection and the eventual total pancreatectomy needs to be determined on individual basis. The analysis of frozen-section margin of pancreas during operation is mandatory. The goal should be the complete resection of IPMN reaching negative margin, although there is still no agreed definition of "negative margin." Of note, the presence of deepithelization is often wrongly interpreted as absence of neoplasia. Management of resection margin status and stratification of surveillance of the remnant pancreas, based on characteristics of primary tumour, are of crucial importance in the management of IPMNs in order to decrease the risk of tumor recurrence after resection. Although risk of local and distant recurrence for invasive IPMNs is increased even in case of total pancreatectomy, also local recurrence after complete resection of noninvasive IPMNs is not negligible. Therefore, a long-term/life-time follow-up monitoring is of paramount importance to detect eventual recurrences. PMID- 25276124 TI - High Content Imaging and Analysis Enable Quantitative In Situ Assessment of CYP3A4 Using Cryopreserved Differentiated HepaRG Cells. AB - High-throughput imaging-based hepatotoxicity studies capable of analyzing individual cells in situ hold enormous promise for drug safety testing but are frequently limited by a lack of sufficient metabolically competent human cells. This study examined cryopreserved HepaRG cells, a human liver cell line which differentiates into both hepatocytes and biliary epithelial cells, to determine if these cells may represent a suitable metabolically competent cellular model for novel High Content Analysis (HCA) applications. Characterization studies showed that these cells retain many features characteristic of primary human hepatocytes and display significant CYP3A4 and CYP1A2 induction, unlike the HepG2 cell line commonly utilized for HCA studies. Furthermore, this study demonstrates that CYP3A4 induction can be quantified via a simple image analysis-based method, using HepaRG cells as a model system. Additionally, data demonstrate that the hepatocyte and biliary epithelial subpopulations characteristic of HepaRG cultures can be separated during analysis simply on the basis of nuclear size measurements. Proof of concept studies with fluorescent cell function reagents indicated that further multiparametric image-based assessment is achievable with HepaRG. In summary, image-based screening of metabolically competent human hepatocyte models cells such as HepaRG offers novel approaches for hepatotoxicity assessment and improved drug screening tools. PMID- 25276125 TI - Resveratrol sensitizes selectively thyroid cancer cell to 131-iodine toxicity. AB - Background. In this study, the radiosensitizing effect of resveratrol as a natural product was investigated on cell toxicity induced by (131)I in thyroid cancer cell. Methods. Human thyroid cancer cell and human nonmalignant fibroblast cell (HFFF2) were treated with (131)I and/or resveratrol at different concentrations for 48 h. The cell proliferation was measured by determination of the percent of the survival cells using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Results. Findings of this study show that resveratrol enhanced the cell death induced by (131)I on thyroid cancer cell. Also, resveratrol exhibited a protective effect on normal cells against (131)I toxicity. Conclusion. This result indicates a promising effect of resveratrol on improvement of cellular toxicity during iodine therapy. PMID- 25276126 TI - Study of microvessel density and the expression of vascular endothelial growth factors in adrenal gland pheochromocytomas. AB - Angiogenesis (neoangiogenesis), a process of neovascularization, is an essential step for local tumor growth and distant metastasis formation. We have analysed angiogenesis status: vascular architecture, microvessel density, and vascular endothelial growth factors expression in 62 adrenal pheochromocytomas: 57 benign and 5 malignant. Immunohistochemical evaluation revealed that vascular architecture and vessel density are different in the central and subcapsular areas of the tumor. Furthermore, we have observed a strong correlation between number of macrophages and microvessel density in the central and subcapsular areas of the tumor and between the expression of VEGF-A in tumor cells and microvessel density in central and subcapsular areas of the tumor. Secondary changes in these tumors influence the results and both vascular architecture and microvessel density are markedly disturbed by hemorrhagic and cystic changes in pheochromocytomas. These changes are partially caused by laparoscopic operation technique. However, no differences in vascular parameters were found between pheochromocytomas with benign and malignant clinical behavior. Our observation showed that analysis of angiogenesis, as a single feature, does not help in differentiating malignant and benign pheochromocytomas and has no independent prognostic significance. On the other hand, high microvessel density in pheochromocytoma is a promising factor for antiangiogenic therapy in malignant cases. PMID- 25276127 TI - The effects of soy bean flour enriched bread intake on anthropometric indices and blood pressure in type 2 diabetic women: a crossover randomized controlled clinical trial. AB - Previous studies showed that soy bean has the potential to improve many aspects of diabetes state and provide metabolic benefits that aid in weight management. We aimed to determine the effects of soy bean flour enriched bread on anthropometric indices and blood pressure among type 2 diabetic patients. This randomized, crossover, clinical trial was performed in 30 type 2 diabetic women. There were two trial periods for 6 weeks and a wash-out period for 4 weeks. In the soy bread diet period, 120 g of soy bean flour enriched bread was consumed each day instead of the same amount of their usual bread or other cereal products. After a 4-week wash-out period, participants were crossed over for another 6 weeks. Mean (+/-SD) age of study participants was 45.7 +/- 3.8 years. The results of our study showed no significant effects of soy bean flour enriched bread on anthropometric indices and blood pressure among diabetic patients. Despite the slight reduction in BMI, waist circumference, and percent of body fat, there were no significant differences in changes of these values between two groups. No significant changes in waist to hip ratio and blood pressure were seen. PMID- 25276128 TI - Circulating sclerostin and irisin are related and interact with gender to influence adiposity in adults with prediabetes. AB - Objectives. Sclerostin, an osteocyte-specific protein, has been found to be related to adiposity and glucose metabolism. Irisin, a myokine, can affect browning of white fat and influence glucose and energy homeostasis. Taken together, this suggests a probable network among fat, bone, and muscle that may influence health outcomes. The aims of this study were to investigate the relationship of circulating sclerostin and irisin and their association with adiposity (assessed by body mass index (BMI)). Materials/Methods. A cross sectional study included 98 adults with impaired fasting glucose and/or impaired glucose tolerance. 75 gm OGTT was performed in all subjects. Fasting plasma samples were obtained for glycated hemoglobin, calcium, creatinine, serum sclerostin and irisin. Results. Circulating irisin and sclerostin were highly correlated (r = -0.4; P < 0.001). After controlling for age, gender, and BMI, irisin was significantly related to sclerostin (P < 0.001). Multivariate linear regression analysis demonstrated that circulating sclerostin (beta = -0.45; P < 0.05) and irisin (beta = -0.46; P < 0.05) were negatively associated with BMI, independent of age in males. In females, no relationship of sclerostin or irisin to BMI was found. Conclusions. Circulating irisin and sclerostin are highly related. Interventions targeting irisin could affect sclerostin and vice versa. PMID- 25276130 TI - Sexual dysfunction in women with diabetic kidney. AB - Few studies address alteration of sexual function in women with diabetes and chronic kidney disease (CKD). Quality of life surveys suggest that discussion of sexual function and other reproductive issues are of psychosocial assessment and that education on sexual function in the setting of chronic diseases such as diabetes and CKD is widely needed. Pharmacologic therapy with estrogen/progesterone and androgens along with glycemic control, correction of anemia, ensuring adequate dialysis delivery, and treatment of underlying depression are important. Changes in lifestyle such as smoking cessation, strength training, and aerobic exercises may decrease depression, enhance body image, and have positive impacts on sexuality. Many hormonal abnormalities which occur in women with diabetes and CKD who suffer from chronic anovulation and lack of progesterone secretion may be treated with oral progesterone at the end of each menstrual cycle to restore menstrual cycles. Hypoactive sexual desire disorder (HSDD) is the most common sexual problem reported by women with diabetes and CKD. Sexual function can be assessed in women, using the 9-item Female Sexual Function Index, questionnaire, or 19 items. It is important for nephrologists and physicians to incorporate assessment of sexual function into the routine evaluation protocols. PMID- 25276129 TI - Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications. AB - Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal disorders and/or supraphysiological doses of corticosteroids. Physicians should be aware of potential neurological manifestations in children with adrenal dysfunction to achieve better prevention and timely diagnosis and treatment of these disorders. Further studies are needed to explore the potential neurological, cognitive, and psychiatric long-term consequences of high doses of prolonged corticosteroid administration in childhood. PMID- 25276131 TI - Gender differences in ghrelin association with cardiometabolic risk factors in arab population. AB - Ghrelin is a stomach produced hormone that has been shown to have protective role against development of CVD which is a leading cause of death in the Arab world. The objective of this study is to examine the gender difference in association between traditional CVD risk factors and plasma ghrelin among Arabs. 359 Arab residents in Kuwait participated in a cross-sectional survey (>=20 years old): 191 were females and 168 were males. Plasma level of ghrelin was assessed using Luminex-based assay. Ghrelin levels were significantly higher in females (935 +/- 78 pg/mL) than males (763 +/- 65 pg/mL) (P = 0.0007). Females showed inverse association with WC (r = -0.23, P = 0.001) and HbA1C (r = -0.19, P = 0.0102) as well as SBP (r = -0.15, P = 0.0383) and DBP (r = -0.16, P = 0.0230), respectively. Higher levels of ghrelin were shown to associate with increased insulin resistance, as measured by HOMAIR, in male Arab subjects (P-trend = 0.0202) but not in females. In this study we show that higher ghrelin level was negatively associated with measures of obesity, HbA1C, and blood pressure in females and positively associated with increased insulin resistance in Arab males. PMID- 25276132 TI - Endoscopic retroperitoneal adrenalectomy for adrenal metastases. AB - Objectives. To evaluate whether retroperitoneal approach for adrenalectomy is a safe and effective treatment for adrenal metastases (AM). Methods. From June 2004 to January 2014, nine consecutive patients with AM were treated with endoscopic retroperitoneal adrenalectomy (ERA). A retrospective study was conducted, and clinical data, tumor characteristics, and oncologic outcomes were acquired and analyzed. Results. Renal cancer was the primary site of malignancy in 44.4% of cases. The mean operative time was 132 +/- 10.4 min. There were 5 synchronous and 4 metachronous AM. One patient required conversion to transperitoneal laparoscopic procedure. No mortality or perioperative complications were observed. The median overall survival was 11 months (range: 2-42 months). Survival rates of 50% and 25% were identified at 1 and 3 years, respectively. At the end of the study, 4 patients were alive with a mean observed follow-up of 20 months. No patients presented with local tumor relapse or port-site metastases. Conclusions. This study shows that ERA is a safe and effective procedure for resection of AM and advances the surgical treatment of adrenal disease. The use of the retroperitoneal approach for adrenal tumors less than 6 cm can provide very favorable surgical outcomes. PMID- 25276133 TI - Male accessory gland infection: relevance of serum total testosterone levels. AB - Aim of the present study was to evaluate the different ultrasound characterization of fertile symptomatic patients with MAGI (male accessory gland infection) according to different serum concentrations of total T (TT). We analyzed the ultrasound and hormonal data of 200 patients aged between 24.0 and 67.0 years. Patients were divided into six groups according to the sextile distribution of TT. Patients with serum concentrations of TT < 3.6 ng mL(-1) had a higher mean duration of symptoms compared to the other examined groups. Patients with serum concentrations of TT > 6.6 ng mL(-1) showed a frequency of ultrasound criteria suggestive for bilateral form of prostatitis and prostate vesiculo-epididymitis and significantly lower compared to the other examined groups. At multivariate logistic regression analysis adjusted for age and BMI, TT was an independent predictive factor of prostatovesiculitis (OR = 0.818 [95% CI: 0.675-0.992]; P < 0.01) and prostate-vesiculo-epididymitis (OR = 0.714 [95% CI: 0.578-0.880]; P < 0.01), which represent the main forms of complicated MAGI. The results of this study suggest that male hypogonadism could be associated with a different ultrasound characterization of these patients. PMID- 25276134 TI - Genomically driven precision medicine to improve outcomes in anaplastic thyroid cancer. AB - Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes. PMID- 25276135 TI - Importance of "process evaluation" in audiological rehabilitation: examples from studies on hearing impairment. AB - The main focus of this paper is to discuss the importance of "evaluating the process of change" (i.e., process evaluation) in people with disability by studying their lived experiences. Detailed discussion is made about "why and how to investigate the process of change in people with disability?" and some specific examples are provided from studies on patient journey of persons with hearing impairment (PHI) and their communication partners (CPs). In addition, methodological aspects in process evaluation are discussed in relation to various metatheoretical perspectives. The discussion has been supplemented with relevant literature. The healthcare practice and disability research in general are dominated by the use of outcome measures. Even though the values of outcome measures are not questioned, there seems to be a little focus on understanding the process of change over time in relation to health and disability. We suggest that the process evaluation has an additional temporal dimension and has applications in both clinical practice and research in relation to health and disability. PMID- 25276137 TI - Hearing AIDS and the brain. PMID- 25276136 TI - Hearing preservation in cochlear implant surgery. AB - In the past, it was thought that hearing loss patients with residual low frequency hearing would not be good candidates for cochlear implantation since insertion was expected to induce inner ear trauma. Recent advances in electrode design and surgical techniques have made the preservation of residual low frequency hearing achievable and desirable. The importance of preserving residual low-frequency hearing cannot be underestimated in light of the added benefit of hearing in noisy atmospheres and in music quality. The concept of electrical and acoustic stimulation involves electrically stimulating the nonfunctional, high frequency region of the cochlea with a cochlear implant and applying a hearing aid in the low-frequency range. The principle of preserving low-frequency hearing by a "soft surgery" cochlear implantation could also be useful to the population of children who might profit from regenerative hair cell therapy in the future. Main aspects of low-frequency hearing preservation surgery are discussed in this review: its brief history, electrode design, principles and advantages of electric-acoustic stimulation, surgical technique, and further implications of this new treatment possibility for hearing impaired patients. PMID- 25276138 TI - Urate lowering therapy with febuxostat in daily practice-a multicentre, open label, prospective observational study. AB - Introduction. Febuxostat, a novel xanthine oxidase inhibitor for the treatment of symptomatic hyperuricemia, showed superiority over allopurinol in the reduction of serum uric acid levels in pivotal studies. Whether this holds true the FORTE (febuxostat in the oral urate lowering treatment: effectiveness and safety) study was conducted to evaluate treatment with febuxostat under daily practice conditions. Materials/Methods. The multicentre, open-label, and prospective observational study was conducted in 1,690 German medical practices from 9/2010 to 5/2011. Safety and efficacy data were assessed at baseline and week 4. Results. Data from 5,592 gout patients (72.6% male, mean age 63.7 years) were collected. Under urate lowering treatment with febuxostat mean serum uric acid levels decreased significantly from 8.9 +/- 1.9 mg/dL (534.0 +/- 114.6 MUmol/L) at baseline to 6.2 +/- 2.5 mg/dL (372.0 +/- 150.0 MUmol/L) at week 4. 67% which reached the mean uric acid target (6.1 +/- 1.0 mg/dL [366.0 +/- 59.4 MUmol/L]). Only 43.1% of patients received concomitant flare prophylaxis. A total of 178 adverse events (mostly gout flares) were reported in 152 patients (2.6%). Conclusion. Febuxostat lowers serum uric acid levels effectively in routine clinical practice. Overall, treatment with febuxostat in both available dosages (80 mg/120 mg) was safe and well tolerated. PMID- 25276139 TI - Pleural effusion: a rare side effect of nilotinib-a case report. AB - Pleural effusion, as a side effect of tyrosine kinases, may be seen as most commonly associated with dasatinib and very rarely seen with nilotinib. In this report we present a chronic phase of CML case that was treated with nilotinib due to imatinib (Gleevec) allergy and had pleural effusion with nilotinib at 5th year of treatment. If pleural effusion develops in patients taking nilotinib and if this effusion is exudative and lymphocyte predominant, after ruling out pulmonary and cardiac etiologies, it must be associated with nilotinib; according to stage of effusion drug should be discontinued and/or steroid should be started and/or surgery should be performed. PMID- 25276140 TI - Successful reversal of acute kidney failure by ultrasound-accelerated thrombolysis of an occluded renal artery. AB - Purpose. To describe the treatment of renal artery thrombosis with ultrasound accelerated thrombolysis and discuss the management of prolonged renal ischemia. Case. A 76-year-old patient with a single functional kidney, mild chronic renal impairment, and a recent history of endovascular repair of a thoracoabdominal aneurysm with an aortic branch graft presented with acute flank pain, anuria, and renal failure. The side branch from the aortic stent graft to his single, right, functional kidney appeared to be completely thrombosed. Symptoms had started after cessation of oral anticoagulants because of a planned mastectomy for breast cancer. After identification of the occlusion, ultrasound-accelerated thrombolysis was started 19 hours after the onset of anuria. Angiography, 4 hours after beginning of therapy, already showed partial dissolution of the thrombus and angiographic control after 18 hours showed complete patency of the renal artery side branch. Despite a long period of ischemia, renal function was completely recovered. Conclusion. In patients with acute renal ischemia due to thrombosis of the renal artery, complete recovery of function can be achieved with ultrasound-accelerated thrombolysis, even after prolonged periods of ischemia. PMID- 25276141 TI - Diagnosis and Monitoring of Choroidal Osteoma through Multimodal Imaging. AB - A 16-year-old Caucasian female with a 6-month history of decreased visual acuity and metamorphopsia in the left eye is reported. The fundus of the left eye revealed a well defined lesion in the macula region. Diagnosis of choroidal osteoma was established using spectral domain optical coherence tomography (OCT), fundus fluorescein angiography (FFA), indocyanine green angiography (ICG), and B scan ultrasonography. Subretinal fluid (SRF) and retinal pigment epithelium (RPE) detachment were noted in the absence of obvious classic choroidal neovascularisation (CNV). The patient was followed up for over 13 months without any treatment in the interim and the lesion was noted to have enlarged but visual acuity and SRF had remained stable. We report an interesting case where subretinal fluid was noted in the absence of evident choroidal neovascularisation and provide an example of the imaging modalities application in the era of "optical biopsy." PMID- 25276142 TI - An unusual presentation of primary lymphoma of the ilium. AB - Primary bone lymphoma involving the pelvic bone is a rare entity. It does not have distinct clinical features or radiological features that are diagnostic. Biopsy is the gold standard investigation. We present a case of primary pelvic lymphoma with initial histopathological features of chronic osteomyelitis. Upon further clinical follow-up, repeat biopsy of the lesion revealed features of B cell Non-Hodgkin's lymphoma, thus emphasizing the need for a high index of suspicion and close clinical follow-up. This case is presented for the diagnostic dilemma and the unique feature of lymphomatous lesion mimicking chronic osteomyelitis in its early stages. PMID- 25276143 TI - Fulminant Wilson's Disease Managed with Plasmapheresis as a Bridge to Liver Transplant. AB - New-onset jaundice can be a manifestation of multiple pathologic processes including hemolysis, parenchymal liver disease, and cholestasis; the differential diagnosis is broad and requires a systematic approach. We report a case of a patient who presented with jaundice after starting minocycline for the treatment of acne vulgaris and rapidly developed fulminant liver failure found to be due to Wilson's disease. She also manifested severe Coomb's negative hemolytic anemia and renal failure secondary to hepatorenal syndrome. As a bridge to liver transplant, she was successfully treated with plasmapheresis to decrease serum copper in addition to hemodialysis for acidosis and hyperkalemia. She was able to receive a liver and made a full recovery. The case highlights the use of plasmapheresis as an adjunctive treatment modality in cases of fulminant liver failure due to Wilson's disease. PMID- 25276144 TI - Aseptic splenic abscess as precursory extraintestinal manifestation of inflammatory bowel disease. AB - Splenic abscesses are most often secondary to aerobic bacterial infections due to Streptococcus, Staphylococcus, and Enterococcus species of organisms. Sterile splenic abscesses rarely occur and diagnosis and treatment of those are challenging. We report a case of a previously healthy young female presenting with aseptic splenic abscesses as the initial manifestation of Crohn's disease along with a review of the literature on aseptic splenic abscess as an extraintestinal manifestation of Crohn's disease. PMID- 25276145 TI - Effects of continuous positive airway pressure treatment on glycaemic control and insulin sensitivity in patients with obstructive sleep apnoea and type 2 diabetes: a meta-analysis. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is a prevalent disorder characterised by repetitive upper-airway obstruction during sleep, and it is associated with type 2 diabetes. Continuous positive airway pressure (CPAP) is the primary treatment for OSA. Prior studies investigating whether CPAP can improve insulin resistance or glucose control in OSA patients have resulted in conflicting findings. This meta-analysis investigated whether CPAP treatment could improve glucose metabolism and insulin resistance in patients with OSA and type 2 diabetes. MATERIAL AND METHODS: We performed a systematic literature search using Medline, Cochrane, EMBASE, and Google Scholar databases for randomised controlled prospective studies that investigated the effect of CPAP on glycaemic control or insulin sensitivity in subjects with type 2 diabetes. RESULTS: The combined standard (STD) paired difference in mean change in the levels of glycated haemoglobin (HbA1c) was -0.073% (standard error (SE): 0.126), indicating that CPAP treatment did not alter HbA1c levels. The combined STD paired difference in mean change of insulin sensitivity was observed as 0.552 umol/kg * min (SE = 0.196) and indicated insulin sensitivity significantly increased with CPAP treatment (p = 0.005). CONCLUSIONS: We found that the CPAP treatment did not alter HbA1c levels but did significantly improve insulin resistance, indicating treating OSA can positively impact the symptoms of type 2 diabetes. PMID- 25276146 TI - Clinical outcomes of second- versus first-generation drug-eluting stents in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: It remains unclear whether the clinical outcomes of patients with acute myocardial infarction (AMI) receiving second- and first-generation drug eluting stents (DES) are identical. The study aimed to investigate the differences in clinical utility between the two generations of DES in these specific subjects by a meta-analysis. MATERIAL AND METHODS: We systemically searched PubMed and EMBASE databases and the Cochrane Library up until January 2013. Randomized trials, which compared clinical outcomes of second-generation DES (everolimus- (EES) or zotarolimus-eluting stents (ZES)) with first-generation DES (sirolimus- or paclitaxel-eluting stents) in patients with AMI were included. RESULTS: Five trials with 1720 AMI subjects were included in the meta-analysis. Pooled analysis demonstrated a trend toward lower incidence of stent thrombosis with the second-generation DES relative to the first-generation one (risk ratio (RR), 0.53; 95% confidence intervals (CI): 0.25-1.13; p = 0.10). However, the second-generation DES did not offer a significant advantage over the first generation DES in reducing the incidence of target lesion revascularization (TLR) (RR = 1.73; 95% CI: 0.83-3.64; p = 0.15), major adverse cardiac events (MACEs) (RR = 0.97; p = 0.90), or all-cause death (RR = 1.00; p = 1.0). In addition, in elderly patients the second-generation DES seemed to reduce the occurrence of MACEs (RR = 0.65; p = 0.10) and stent thrombosis (RR = 0.40; p = 0.08), and the second-generation EES showed a potential benefit in lowering the MACE rate (RR = 0.55; p = 0.06). CONCLUSIONS: The second-generation DES appeared to lower the risk of stent thrombosis in AMI patients. There might be a lower incidence of MACEs associated with the second-generation EES. PMID- 25276147 TI - NQO1 C609T polymorphism and colorectal cancer susceptibility: a meta-analysis. AB - INTRODUCTION: A FEW STUDIES HAVE REPORTED AN ASSOCIATION BETWEEN NADP(H): quinine oxidoreductase 1 (NQO1) C609T polymorphism and susceptibility to colorectal cancer (CRC). However, the results were inconsistent rather than conclusive. We performed a meta-analysis to examine this association in various populations. MATERIAL AND METHODS: Eligible articles were identified by a search of several databases up until June 30, 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association. RESULTS: Overall, 14 case-control studies with 4,461 cases and 5,474 controls were included in this meta-analysis. The results indicated that the NQO1 C609T polymorphism was significantly associated with CRC susceptibility (summary ORs (95% CIs): 1.30 (1.07-1.59) for CT vs. CC, 1.64 (1.15-2.33) for TT vs. CC, 1.34 (1.10-1.64) for TT/CT vs. CC, and 1.43 (1.10-1.87) for TT vs. CT/CC). Subgroup analyses indicated that the T allele was significantly associated with CRC susceptibility in both Asians and Caucasians, and was also observed in high quality studies and hospital-based case-control studies. Specifically, we found a positive association between the NQO1 C609T polymorphism and CRC susceptibility in smokers, but not in non-smokers. CONCLUSIONS: The results of this meta analysis suggest that the NQO1 C609T polymorphism significantly contributes to increased susceptibility to CRC in both Asians and Caucasians. PMID- 25276148 TI - Prevalence of nontuberculous mycobacteria in patients with bronchiectasis: a meta analysis. AB - INTRODUCTION: Nontuberculous mycobacteria (NTM) have emerged as critical opportunistic pathogens of lung diseases recently. Patients with preexisting bronchiectasis are susceptible to NTM. Nevertheless, patients with preexisting bronchiectasis are susceptible to NTM but the prevalence of NTM pulmonary infection in different species and geographical areas is still not fully understood. MATERIAL AND METHODS: The relevant data of the prevalence of NTM in patients with bronchiectasis were retrieved by searching the main databases such as PubMed, MEDLINE, Cochrane Library, and EMBASE. This meta-analysis was performed using Rev. Man 5.1 and Stata 11.0 software. The collected information of NTM prevalence was chosen as the effect size. RESULTS: The results of the meta analysis showed that the overall prevalence of NTM was 9.3% in patients with bronchiectasis. The further stratification of subgroup analysis indicated that the combined prevalence of NTM was higher in studies whose "sample size" was more than or equal to 100 (p = 0.002), in studies in which "time of study" was after or equal to 2002 (p < 0.001), in studies in which "participants' geographic location" was Asian (p < 0.001) and in studies whose "method of study" was retrospective (p = 0.002) as well, compared with corresponding groups. CONCLUSIONS: Our findings suggested that the prevalence NTM infection is high in patients with bronchiectasis. A larger number of definitive randomized trials are still required to assess this research issue. PMID- 25276149 TI - The effect of melatonin on circadian blood pressure in patients with type 2 diabetes and essential hypertension. AB - INTRODUCTION: The aim of this study was to evaluate the effect of melatonin on blood pressure in patients with essential hypertension receiving medical treatment and with type 2 diabetes in good metabolic control. MATERIAL AND METHODS: The study lasted 8 weeks. Patients were equipped with a 24-hour ambulatory blood pressure monitor and took melatonin (3 mg a day in the evening) for 4 weeks. The patients were divided into four groups: group 1 (n = 32) including dippers, group 2 (n = 34) non-dippers treated with melatonin; and two control groups: group 3 (n = 28) including dippers and group 4 (n = 30) non dippers treated without melatonin. After 4 weeks patients took melatonin for the next 4 weeks (5 mg a day). In each visit were analyzed: systolic, diastolic and mean blood pressure in both day and night time. RESULTS: We observed that 29.5% non-dippers (n = 10) treated with melatonin in a dose of 3 mg/day achieved features of dippers compared to control group (p < 0.05). Five mg of melatonin per day restored normal diurnal blood pressure rhythm in 32.4% non-dippers (n = 11, p < 0.05). In non-dippers treated with melatonin significant decreases of diastolic, systolic and mean night blood pressure values (p < 0.05) were observed. CONCLUSIONS: More than 30% of non-dippers with type 2 diabetes treated with melatonin were restored to the normal circadian rhythm of blood pressure. The effect of melatonin in both doses (3 mg and 5 mg) was significant for non dippers only and included nocturnal systolic, diastolic and mean arterial pressure. PMID- 25276150 TI - Short-term ECG recordings for heart rate assessment in patients with chronic atrial fibrillation. AB - INTRODUCTION: There is no consensus on the length of ECG tracing that should be recorded to represent adequate rate control in patients with atrial fibrillation (AFib). The purpose of the study was to examine whether heart rate measurements based on short-term ECGs recorded at different periods of the day may correspond to the mean heart rate and rate irregularity analyzed from standard 24-hour Holter monitoring. MATERIAL AND METHODS: The study enrolled 50 consecutive patients with chronic AFib who underwent 24-hour Holter monitoring. Mean heart rate (mHR) and the coefficient of irregularity (CI) were assessed from 5- and 60 minute intervals of Holter recordings in different periods of the day. RESULTS: The highest correlation in mean heart rate interval within 24 h was found during a 6-hour sample and in the periods 11.00 AM-12.00 PM, 12 PM-1.00 PM, and 1.00 PM 2.00 PM. With respect to irregularity, only the CI measurements based on a 6-hour interval (7.00 AM-1.00 AM) show a correlation > 0.08 compared to data from the 24 hour recording. CONCLUSIONS: Only long-term (6-hour) recordings provide a high correlation within 24 h in mean heart rate interval and coefficient of irregularity. It seems that the mean heart rate interval in 1-hour periods between 11 AM and 2 PM might be predictive for 24-hour data. Short time recordings of the coefficient of irregularity of heart rate in AFib patients at this moment are not useful in clinical practice for long-term prognosis of ventricular irregularity. PMID- 25276151 TI - Contractile reserve assessed by dobutamine test identifies super-responders to cardiac resynchronization therapy. AB - INTRODUCTION: In this study, we sought to determine whether myocardial contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) can identify patients who experience nearly complete normalization of left ventricular (LV) function after the implantation of a cardiac resynchronization therapy (CRT) pacemaker. MATERIAL AND METHODS: The study group consisted of 55 consecutive patients with non-ischemic dilated cardiomyopathy, LV ejection fraction (LVEF) < 35%, and prolonged QRS complex duration, who were scheduled for CRT pacemaker implantation. The DSE (20 ug/kg/min) was performed in all patients. The CR assessment was based on a change in the wall motion score index (DeltaWMSI) and DeltaLVEF during DSE. Super-response was defined as an increase in LVEF to > 50% and reduction in left ventricular end-systolic dimension to < 40 mm 12 months following the CRT implantation. RESULTS: A total of 7 patients (12.7%) were identified as super-responders to CRT. When compared to non-super responders, these patients had significantly higher values of the dobutamine induced change in DeltaWMSI (1.031 +/-0.120 vs. 0.49 +/-0.371, p < 0.01), and DeltaEF (17.9 +/-2.2 vs. 8.8 +/-6.2, p < 0.01). Receiver operating characteristic analysis showed that dobutamine-induced changes in DeltaWMSI >= 0.7 and >= 14% for DeltaEF are the best discriminators for a super-response. Patients with DeltaWMSI >= 0.7 and DeltaEF >= 14% are significantly less often hospitalized (p < 0.01) for worsening of heart failure during 28.5 +/-3.0 months of the follow up. CONCLUSIONS: Contractile reserve assessed by DSE can identify patients with dilated cardiomyopathy who are likely to experience near normalization of LV function following CRT. PMID- 25276152 TI - Can echocardiographically estimated pulmonary arterial elastance be a non invasive predictor of pulmonary vascular resistance? AB - INTRODUCTION: Measurement of pulmonary vascular resistance (PVR) is essential in evaluating a patient with pulmonary hypertension. MATERIAL AND METHODS: Data from right heart catheterization (RHC) and echocardiograms performed within 90 days of each other on 45 non-consecutive adult patients were reviewed in this retrospective study. Patients were recruited using an assortment of strategies to ensure the presence of patients with a wide range of PVR. RESULTS: The linear regression equation between RHC-derived PVR and echocardiographic pulmonary arterial elastance (PAE) was: PVR = (562.6 * PAE) - 38.9 (R = 0.56, p < 0.0001). An adjustment for echocardiographic PAE was made by multiplying it by hemoglobin (in g/dl) and (right atrial area)(1.5) (in cm(3)). As RHC-derived PVR varies with blood hemoglobin, an adjustment for PVR was made for hemoglobin of 12 g/dl. Visualization of the XY scatter plot of adjusted PVR and adjusted PAE isolated a subset of patients with PVR higher than 8.8 Wood units, where a strong linear relationship existed (adjusted PVR = (0.89 * adjusted PAE) + 137.4, R = 0.89, p = 0.008). CONCLUSIONS: The correlation coefficient of the regression equation connecting echocardiographic PAE and RHC-derived PVR was moderate. In a subset of patients with very high PVR and after appropriate adjustment, a strong linear relationship existed with an excellent correlation coefficient. PMID- 25276153 TI - Relationship between exercise-induced heart rate increase and the formation of microbubbles and high-intensity transient signals in mechanical heart valve implanted patients. AB - INTRODUCTION: The formation and collapse of vapor-filled bubbles near a mechanical heart valve is called cavitation. Microbubbles can be detected in vivo by doppler ultrasonography (USG) as HITS (high intensity transient signals) in cranial circulation. We investigated the relationship between exercise induced heart rate increase and HITS formation in cranial circulation. MATERIAL AND METHODS: Thirty-nine mechanical heart valve implanted (8 aortic valve replacement (AVR) + mitral valve replacement (MVR), 9 AVR, 22 MVR) patients aged 18-80 years old were included in our study. Microbubbles were counted in the left ventricular cavity via transthoracic echocardiography at rest per cardiac cycle. Afterwards transcranial Doppler USG was performed and HITS were counted in each patient's middle cerebral artery at 5 min duration. Subsequently an exercise test according to the Bruce protocol was performed. After achieving maximal heart rate, microbubbles in the left ventricle and HITS were counted again. RESULTS: Microbubbles in the left ventricle and transcranial HITS increased after exercise significantly compared to resting values (15.79 +/-10.91 microbubbles/beat vs. 26.51 +/-18.00 microbubbles/beat, p < 0.001; 6.13 +/-8.07 HITS/5 min vs. 13.15 +/ 15.87 HITS/5 min, p = 0.001). There was a significant correlation between microbubbles and HITS counts after peak exercise (r = 0.55, p < 0.001). CONCLUSIONS: In our study, we found that the microbubbles were increasing as the heart rate increased and more HITS were propelled to the cerebral circulation. As previously shown, HITS can alter cognitive functions. Therefore heart rate control is essential in mechanical heart valve patients to protect neurocognitive functions. PMID- 25276154 TI - Intra- or extracardiac Fontan operation? A simple strategy when to do what. AB - INTRODUCTION: The complete Fontan circulation is the definite palliation for many complex congenital cardiac lesions. After bi-directional Glenn anastomosis (BDG), two well-established techniques - intracardiac tunneling and extracardiac prosthesis - are available for completion, although the choice of technique is still a matter of debate. MATERIAL AND METHODS: We retrospectively reviewed the surgical and clinical records of patients with single ventricle physiology, who underwent intracardiac (group I) or extracardiac (group II) Fontan palliation after BDG. RESULTS: Complete data were available in 72 patients. Thirty-eight patients received intracardiac (median weight: 12.6 kg) and 34 patients extracardiac repair (median weight: 15.6 kg). Patients with intracardiac tunneling had longer cardiopulmonary bypass (CBP) time (170 min vs. 104 min; p < 0.001), longer ventilatory (39 h vs. 21 h; p = 0.009) and longer inotropic support (48 h vs. 10 h; p < 0.001). Ventilatory and inotropic support were dependent on CPB (r = 0.69 and r = 0.637) and on aortic cross-clamping (r = 0.785 and r = 0.705 only group I), but not dependent on age, weight or pulmonary artery pressure (PAP). CONCLUSIONS: Both techniques are feasible without perioperative mortality. Normally developed children with good hemodynamics after BDG received an elective extracardiac procedure without fenestration later. Patients with developmental retardation, severe progressive cyanosis, myocardial dysfunction, or moderate to severe atrio-ventricular valve insufficiency are scheduled for an earlier intracardiac baffle repair with routine fenestration, as they are at higher risk. Prolonged CPB and aortic cross-clamping times adversely impact the early postoperative course. Further strategies must be developed to avoid these effects, particularly in the patient group at higher imminent risk. PMID- 25276155 TI - Long-term intense exposure to grass pollen can mask positive effects of allergenic immunotherapy on non-specific bronchial hyperresponsiveness. AB - INTRODUCTION: There are many potential factors that can modulate bronchial reactivity, including exposure to allergens, viral infections, and medications. The aim of this study was to analyze the effect of grass pollination intensity on the bronchial reactivity in seasonal allergic rhinitis (SAR) patients subjected to subcutaneous allergenic immunotherapy (SCIT). MATERIAL AND METHODS: This study, performed between 2005 and 2008, included 41 patients with confirmed sensitivity to grass pollens and predominating symptoms of SAR, randomly assigned to desensitization by pre-seasonal or maintenance SCIT. Bronchial provocation challenge with histamine was performed before the onset of immunotherapy, and repeated three times after each pollen season covered by this study. Bronchial reactivity was analyzed with regard to grass pollination intensity in 2005-2008 (air concentration of grass pollen grains, seasonal number of days when air concentration of grass pollen reached at least 20 or 50 grains per 1 m(3)). RESULTS: After 3 years of SCIT, a significant decrease in bronchial responsiveness was observed in the analyzed group as confirmed by an increase in PC20 FEV1 histamine values (p = 0.001). An inverse tendency was observed after 2 years of SCIT, however. This second year of SCIT corresponded to the 2007 season, when a significantly higher number of days with at least 50 grains of pollen per 1 m(3) of air was recorded. CONCLUSIONS: FLUCTUATIONS IN POLLINATION INTENSITY OBSERVED DURING CONSECUTIVE YEARS OF IMMUNOTHERAPY CAN INFLUENCE BRONCHIAL REACTIVITY IN PATIENTS SUBJECTED TO SCIT (ISRCTN REGISTER: ISRCTN 86562422). PMID- 25276156 TI - A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non small-cell lung cancers. AB - INTRODUCTION: The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first line treatment for patients with advanced non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m(2) or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m(2) (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. CONCLUSIONS: Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable. PMID- 25276157 TI - Associations of radiological features in Mycoplasma pneumoniae pneumonia. AB - INTRODUCTION: The associations of radiological features with clinical and laboratory findings in Mycoplasma pneumoniae infection are poorly understood. The purpose of this study was to assess the associations. MATERIAL AND METHODS: A retrospective cohort study of 1230 patients with community-acquired pneumonia was carried out between January 2005 and December 2009. The diagnosis of M. pneumoniae infection was made using the indirect microparticle agglutinin assay and enzyme-linked immunosorbent assay. RESULTS: Females were more susceptible to M. pneumoniae infection. Ground-glass opacification on radiographs was positively associated with M. pneumoniae-IgM titres (rank correlation coefficient (r s) = 0.141, p = 0.006). The left upper lobe was more susceptible to infection with M. pneumoniae compared with other pathogens. More increases in the risk of multilobar opacities were found among older or male patients with M. pneumoniae pneumonia (odds ratio, 1.065, 3.279; 95% confidence interval, 1.041-1.089, 1.812 5.934; p < 0.001, p < 0.001; respectively). Patients with M. pneumoniae pneumonia showing multilobar opacities or consolidation had a significantly longer hospital length of stay (r s = 0.111, r s = 0.275; p = 0.033, p < 0.001; respectively), incurring significantly higher costs (r s = 0.119, r s = 0.200; p = 0.022, p < 0.001; respectively). CONCLUSIONS: Our study highlighted female susceptibility to M. pneumoniae pneumonia and the association of ground-glass opacification with higher M. pneumoniae-IgM titres. The left upper lobe might be more susceptible to M. pneumoniae infection. Older or male patients with M. pneumoniae pneumonia were more likely to show multilobar opacities. Multilobar opacities and consolidation were positively associated with hospital length of stay and costs. PMID- 25276158 TI - The effects of brain stimulation of subthalamic nucleus surgery on gait and balance performance in Parkinson disease. A pilot study. AB - INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and bradykinesia. Gait and postural difficulties supersede tremor, rigidity and bradykinesia as drivers of disease burden in patients with advanced PD. The aim of this study was to describe the effects of deep brain stimulation of the subthalamic nucleus on gait ability and balance performance in patients with PD. MATERIAL AND METHODS: We studied 19 consecutive patients who underwent bilateral stimulation of the subthalamic nucleus. Patients were evaluated preoperatively and at the 5(th) day and 6(th) month after surgery. Timed Up and Go Test, 12 m Walking Test, Chair Stand Test and Berg Balance Scale (BBS) were used to assess mobility and balance performance. Unified Parkinson's Disease Rating Scale (UPDRS III) and Hoehn and Yahr Scale were also used. RESULTS: All the patients' mobility ability and balance performance improved after surgery (p < 0.05). At the 6th month after surgery, the Timed Up and Go Test scores were decreased from 56.05 +/-42.52 to 21.47 +/-20.36, the 12 m Walking Test scores were decreased from 100.44 +/-66.44 to 28.84 +/-19.79, the Chair Stand Test scores were increased from 4.00 +/-4.66 to 11.68 +/-4.43 and the BBS score was increased from 12.84 +/-6.89 to 38.89 +/ 8.79. UPDRS total scores were significantly improved 6 months after surgery (p < 0.001). UPDRS total scores were decreased from 98.26 +/-37.69 to 39.36 +/-18.85. The Hoehn and Yahr Scale score was significantly decreased after surgery (p < 0.05). CONCLUSIONS: Surgical therapy is an effective treatment to improve gait ability and balance performance in Parkinson's patients. PMID- 25276159 TI - Relation between abdominal subcutaneous fat tissue thickness and inflammatory markers during pregnancy. AB - INTRODUCTION: Subcutaneous abdominal fat thickness (SCFT) is important for predisposition to metabolic and cardiovascular diseases. Our aim was to evaluate maternal SCFT and metabolic changes (such as insulin resistance and high inflammatory markers) during pregnancy. MATERIAL AND METHODS: A total of 92 pregnant women between 24-28 weeks of gestation were enrolled in the study. The SCFT was measured by ultrasonography and patients were divided into 2 groups according to thickness of maternal SCFT and body mass index (BMI). Groups were compared with each other for oral glucose loading test (OGL) results, and for haematological, biochemical and fetal biometric parameters. RESULTS: After analysis of frequency for SCFT, the most appropriate cut-off value for grouping patients was found to be 15 mm for SCFT. In 48 cases SCFT was over 15 mm. High C reactive protein (CRP) was found in 47.9% (23) of cases with SCFT over 15 mm. Serum haemoglobin A1c (HbA1c) level was significantly correlated with SCFT thickness. The most important factors for determination of OGL level were found to be serum HbA1c level, BMI and SCFT. In obese subjects (BMI >= 25 kg/m(2)), levels of inflammatory markers and SCFT thickness were higher. The CRP and gamma glutamyltransferase (GGT) levels were significantly correlated with BMI and SCFT. CONCLUSIONS: High SCFT during pregnancy is associated with elevated inflammatory marker levels and HbA1c. Pregnant women with thicker SCFT may be susceptible to the development of metabolic complications of pregnancy, such as gestational diabetes mellitus (GDM) and hypertension, as well as risk of future metabolic and cardiovascular disease. PMID- 25276160 TI - First report on the association of drinking water hardness and endothelial function in children and adolescents. AB - INTRODUCTION: This study aims to investigate the relationship of water hardness and its calcium and magnesium content with endothelial function in a population based sample of healthy children and adolescents. MATERIAL AND METHODS: This case control study was conducted in 2012 among 90 individuals living in two areas with moderate and high water hardness in Isfahan County, Iran. The flow-mediated dilatation (FMD) of the brachial artery and the serum levels of soluble adhesion molecules (sICAM-1, sVCAM-1) were measured as surrogate markers of endothelial function, and high-sensitivity C-reactive protein (hs-CRP), as a marker of inflammation. RESULTS: Data of 89 participants (51% boys, mean age 14.75 (2.9) years) were complete. Those participants living in the area with high water hardness had higher FMD, hs-CRP, and soluble adhesion molecules (sICAM-1, sVCAM 1) than their counterparts living in the area with moderate water hardness. Multiple linear regression analysis showed that after adjustment for confounding factors of age, gender, body mass index, healthy eating index and physical activity level, total water hardness, as well as water content of calcium and magnesium, had a significant positive relationship with FMD. The corresponding associations were inverse and significant with soluble adhesion molecules (p < 0.05). CONCLUSIONS: This study, which to the best of our knowledge is the first of its kind in the pediatric age group, suggests that water hardness, as well as its calcium and magnesium content, may have a protective role against early stages of atherosclerosis in children and adolescents. PMID- 25276161 TI - Pressure-flow nomogram for women with lower urinary tract symptoms. AB - INTRODUCTION: Results of urodynamic studies performed in female patients are often difficult to interpret. The objective of the study was to develop a nomogram that would help in diagnosing functional bladder outlet obstruction (BOO) in neurologically intact women with any kind of lower urinary tract symptoms. MATERIAL AND METHODS: From the urodynamic database adult women were chosen with maximal flow rate (Q max ) <= 12 ml/s in a pressure-flow study. Four criteria were used to identify a group of patients suspected of BOO: thickened bladder wall, presence of bladder diverticula, subjective improvement on alpha blockers and improvement of voiding symptoms on any form of treatment. The line separating high and low pressure zones on the pressure-flow chart was established according to the position of patients who met at least one of them. RESULTS: Sixty-seven patientswere investigated. Twenty-one women met at least one of the specified criteria. They had significantly higher voiding pressures (p det(Qmax) 35 cm H2O vs. 16.5 cm H2O; p = 0.002). A new nomogram with one separating line (p det(Qmax) = 1.5 * Q max + 10) was proposed. The difference in the distribution of women fulfilling the criteria between high pressure zone and low pressure zone was highly significant (19/35 vs. 2/32; p < 0.0001). Sensitivity, specificity, positive and negative predictive values of our nomogram in identifying patients suspected of BOO was 90.5%, 65.2%, 54.3% and 94% respectively. CONCLUSIONS: The new nomogram can be considered a screening test which efficiently excludes obstruction among women with low Q max in a pressure-flow study. PMID- 25276162 TI - Incidental extraspinal findings on magnetic resonance imaging of intervertebral discs. AB - INTRODUCTION: We aimed to evaluate pathological extraspinal findings and congenital anomalies/anatomical variations that were incidentally detected on the magnetic resonance imaging (MRI) scans of intervertebral discs, to find the frequencies of these incidental findings, and to emphasise the clinical importance of them. MATERIAL AND METHODS: A retrospective study including 1031 consecutive patients (730 females and 301 males, with a median age of 46 years) was conducted by evaluating a total of 1106 MRI examinations of intervertebral discs. Examinations were performed with a 1.5 T MRI unit. Incidental findings were classified as pathological findings and congenital anomalies/anatomical variations. RESULTS: The percentages of incidental extraspinal pathological findings and congenital anomalies/anatomical variations were 16.6% (95% confidence interval (CI): 14.4-18.8) and 3.7% (95% CI: 2.6-4.3), respectively. The percentage of incidental extraspinal pathological findings on cervical spinal MRI was 25.7% (95% CI: 20.1-31.7), thyroid nodules being the most common incidental findings. On thoracic spinal MRI (n = 19), inferior pole thyroid nodules were demonstrated as incidental extraspinal pathological findings, with a percentage of 10.5% (95% CI: 9.6-11.5). On lumbar spinal MRI, incidental pathological findings were detected with a percentage of 14.2% (95% CI: 11.9 16.6), while the percentage of congenital anomalies/anatomical variations was 4.8% (95% CI: 3.4-6.3). Eventually, 6.5% (95% CI: 2.6-9.4) of all cases with incidental extraspinal pathological findings underwent surgery. CONCLUSIONS: On MRI examination of intervertebral discs, paying attention to incidentally detected pathological extraspinal findings and congenital anomalies/anatomical variations is very important due to the fact that they can alter the treatment of the patient or affect the patient's life. PMID- 25276163 TI - One-stage reconstruction with open bone grafting and vacuum-assisted closure for infected tibial non-union. AB - INTRODUCTION: Non-union of the tibia complicated by osteomyelitis is one of the most challenging problems in orthopaedic surgery. There remains a significant amount of debate and controversy regarding the optimal medical management of infected tibial non-union. There are few articles which have reported the outcomes of treatment for infected non-union of tibia from single-stage reconstruction with open bone grafting plus vacuum-assisted closure (VAC). MATERIAL AND METHODS: Our report covers experience between March 2007 and February 2010 of open bone grafting plus VAC in one stage for patients with infected tibial non-union. The time for bone union and wound healing to occur, the duration of hospitalisation, and the rate of resolution of infection were all analysed. The main outcome measures were based on a clinical scoring system that assessed functional ability, range of knee and ankle motion, shortening, infection and pain. Fifteen patients were involved in this study. RESULTS: All patients were followed up for an average of 22.6 months (range: 14-42 months). Bone union was achieved in 93.3% (14/15) of patients after a mean of 5.93 months (range: 3-10 months). All wounds healed within an average period of 5 weeks (range: 3-10 weeks), and the function and appearance of all limbs were satisfactory. CONCLUSIONS: Open bone grafting combined with VAC in a one-stage procedure can be a feasible alternative to the treatment of infected tibial non union, especially for those wounds which are not good candidates for microsurgery; however, further studies are required to confirm the likely benefits. PMID- 25276164 TI - Self-reported effects of attending the Health Foundation's Co-Creating Health self-management programme for patients with type 2 diabetes mellitus in London, England. AB - INTRODUCTION: The purpose of this study was to determine the impact of the Health Foundation's Co-Creating Health (CCH) group self-management programme (SMP) for adult patients with type 2 diabetes on patient activation and quality of life. MATERIAL AND METHODS: We conducted a multisite longitudinal study of 283 patients (mean age 62.3 years, SD 11.1; 43% ethnic minority; 51% female). Primary outcomes were patient activation, and diabetes and health related quality of life. Secondary outcomes included health status, psychological distress, and self management ability. Data were collected immediately before the first SMP session (baseline) and 6 months after completing the programme. Quantitative analyses were based on mixed models using intent-to-treat and per-protocol procedures. RESULTS: Sixty percent of patients who signed up for SMP completed the programme. Patient activation significantly improved 6 months after the SMP (p < 0.0001), and 60.2% of course completers showed meaningful improvement. Diabetes-related quality of life also improved significantly 6 months post course (p < 0.0001). About a quarter of SMP completers showed substantial improvement in self management skills. CONCLUSIONS: Attending the UK SMP for adults with type 2 diabetes leads to improvements in patient activation, diabetes-related quality of life, and improved confidence and ability to self-manage their condition. Improvement in patient activation is an important finding because activated patients participate in collaborative decision-making with their clinicians, report improved health-related behaviours and clinical outcomes, and better adhere to treatment. PMID- 25276165 TI - Cultural adaptation and psychometric evaluation of the Polish version of the Newcastle Satisfaction with Nursing Scale. AB - INTRODUCTION: The paper presents the methods of cultural adaptation of the Newcastle Satisfaction with Nursing Scale (NSNS) to the conditions in Polish hospitals. MATERIAL AND METHODS: The process of cultural adaptation of the research tool took into consideration an analysis of different equivalence levels, the translation procedure and the estimation of psychometric parameters. The Polish version of the NSNS questionnaire was correctly completed by 787 patients making up 59.36% of the total number of patients who received the scale. RESULTS: The Polish version of the NSNS questionnaire was correctly completed by 787 patients making up 59.36% of the total number of patients who received the scale. Cronbach's alpha coefficient was 0.921 for the "experience" scale and 0.981 for the "satisfaction" scale. The values of Spearman's rank correlation coefficient were from 0.224 to 0.797 for "experience" and 0.815-0.894 for "satisfaction". All questionnaire items of the Polish NSNS version exerted a statistically significant influence on the total results of the scale (p = 0.0001). CONCLUSIONS: The Polish NSNS version, similarly as the original version, can identify differences referring to "experience" and "satisfaction" with nursing care between the particular departments and between hospitals. The Polish NSNS version was conducted among patients during multicentre studies and it meets the criteria of functional, psychometric and facade equivalences. PMID- 25276166 TI - NLRP3 and downstream cytokine expression elevated in the monocytes of patients with coronary artery disease. AB - INTRODUCTION: Pattern recognition receptor (PRR)-mediated signaling pathways have recently been elucidated to bridge the innate immune system and atherosclerosis. NLRP3 is among the family members of NOD-like receptors (NLRs), a type of PRRs. At present, most studies about the NLRP3 inflammasome focus on animal models and immune cells. Limited information is available regarding the role of NLRP3 in patients with coronary artery disease (CAD). MATERIAL AND METHODS: In this study, we observed the expression of NLRP3 and downstream cytokines in patients with CAD by ELISA, real-time qPCR and Western blot. RESULTS: We found that NLRP3 and downstream cytokines were coupled with increasing severity of CAD and a dynamic variation exists in patients with acute myocardial infarction. We also found that NLRP3 was correlated with Gensini score, indicating that NLRP3 might be relevant not only for the severity of CAD but also for the severity of coronary atherosclerosis. CONCLUSIONS: This study provides a new theoretical basis for innate immune participation in atherosclerosis development and highlights the potential of the NLRP3 inflammasome as a target for prevention and treatment of CAD. PMID- 25276167 TI - Enzymatic activity of type 1 iodothyronine deiodinase in selected liver tumors. AB - INTRODUCTION: Type 1 iodothyronine deiodinase (D1) converts thyroxin (T4) into tri-iodothyronine (T3). Strong evidence indicates that thyroid hormone metabolism is disturbed in neoplasms such as thyroid and breast cancer. However, there is limited data concerning the function of the D1 enzyme in liver tumors. We aimed to estimate the enzymatic activity of D1 in two different common liver tumors. MATERIAL AND METHODS: We obtained 20 tumor samples from patients who had undergone a liver resection. Of the tissue samples, there were 13 benign lesions of focal nodular hyperplasia (FNH) and 7 malignant lesions of hepatocellular carcinomas (HCC). The D1 activity was assessed by measuring the amount of radioactive iodine released in reaction to D1-catalysed deiodination. Groups were compared by the Mann-Whitney non-parametrical test for independent trials, and the Kruskal Wallis test. RESULTS: The enzymatic activity of D1 was not significantly altered in the FNH group (median = 536 fmol/mg of protein/min; p = 0.972) and HCC group (367 fmol/mg; p = 0.128) when compared to matched normal liver parenchyma controls (546 fmol/mg and 556 fmol/mg, respectively). CONCLUSIONS: Liver parenchyma expresses high levels of D1. The results clearly revealed that D1 activity was not significantly different between benign and malignant tumors (FNH and HCC) compared to healthy liver parenchyma cells. PMID- 25276168 TI - Effects of ghrelin on protein expression of antioxidative enzymes and iNOS in the rat liver. AB - INTRODUCTION: We investigated the effects of ghrelin on protein expression of the liver antioxidant enzymes superoxide dismutases (SODs), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), nuclear factor kappaB (NFkappaB) and inducible nitric oxide synthase (iNOS). Furthermore, we aimed to investigate whether extracellular regulated protein kinase (ERK1/2) and protein kinase B (Akt) are involved in ghrelin-regulated liver antioxidant enzymes and iNOS protein expression. MATERIAL AND METHODS: Male Wistar rats were treated with ghrelin (0.3 nmol/5 ul) injected into the lateral cerebral ventricle every 24 h for 5 days, and 2 h after the last treatment the animals were sacrificed and the liver excised. The Western blot method was used to determine expression of antioxidant enzymes, iNOS, phosphorylation of Akt, ERK1/2 and nuclear factor kappaB (NFkappaB) subunits 50 and 65. RESULTS: There was significantly higher protein expression of CuZnSOD (p < 0.001), MnSOD (p < 0.001), CAT (p < 0.001), GPx, (p < 0.001), and GR (p < 0.01) in the liver isolated from ghrelin-treated animals compared with control animals. In contrast, ghrelin significantly (p < 0.01) reduced protein expression of iNOS. In addition, phosphorylation of NFkappaB subunits p65 and p50 was significantly (p < 0.001 for p65; p < 0.05 for p50) reduced by ghrelin when compared with controls. Phosphorylation of ERK1/2 and of Akt was significantly higher in ghrelin-treated than in control animals (p < 0.05 for ERK1/2; p < 0.01 for Akt). CONCLUSIONS: The results show that activation of Akt and ERK1/2 is involved in ghrelin-mediated regulation of protein expression of antioxidant enzymes and iNOS in the rat liver. PMID- 25276169 TI - Influence of ezetimibe on selected parameters of oxidative stress in rat liver subjected to ischemia/reperfusion. AB - INTRODUCTION: Ischemia/reperfusion (I/R) is considered to be one of the main causes of liver damage after transplantation. The authors evaluated the effect of ezetimibe on selected oxidative stress parameters in ischemic/reperfused (I/R) rat liver. MATERIAL AND METHODS: Rats were administered ezetimibe (5 mg/kg) (groups E and E-I/R) or saline solution (groups C and C-I/R) intragastrically for 21 days. Livers of animals in groups C-I/R and E-I/R were subjected to 60 min of partial ischemia (left lateral and median lobes) followed by 4 h of reperfusion. Alanine and asparagine aminotransferase (ALT, AST) activity was determined in blood before I/R and during reperfusion (at 15 and 240 min). After the reperfusion period, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GPx) were determined in liver homogenates using colorimetric methods. RESULTS: Ezetimibe caused a significant increase in GSH level in groups subjected to I/R (E-I/R (99.91 +/-9.01) vs. C-I/R (90.51 +/-8.87), p < 0.05). Additionally, under I/R the decrease of GPx activity in the drug-treated group was lower compared to the non-treated group (E-I/R (3.88 +/-1.11) vs. E (5.31 +/-1.83), p = 0.076). Neither ezetimibe nor I/R affected SOD or MDA levels. I/R produced a significant increase in aminotransferase levels (ALT240-0: C-I/R (42.23 +/-43.56) vs. C (9.75 +/-11.09), and E-I/R (39.85 +/-26.53) vs. E (4.38 +/-1.36), p < 0.05 in both cases; AST 240 0: E-I/R (53.87 +/-17.23) vs. E (24.10 +/-9.66), p < 0.05) but no effect of ezetimibe on those enzymes was found. CONCLUSIONS: Ezetimibe demonstrates antioxidant properties in rat livers subjected to I/R. However, neither a hepatoprotective nor a hepatotoxic effect of ezetimibe was demonstrated, regardless of I/R. PMID- 25276170 TI - Cystathionine-gamma-lyase inhibitor attenuates acute lung injury induced by acute pancreatitis in rats. AB - INTRODUCTION: Acute pancreatitis (AP) is known to induce injuries to extrapancreatic organs. Because respiratory dysfunction is the main cause of death in patients with severe AP, acute pancreatitis-associated lung injury (APALI) is a great challenge for clinicians. This study aimed to investigate the potential role of hydrogen sulfide (H2S) in the pathogenesis of APALI. MATERIAL AND METHODS: Fifty-four SD rats were randomly divided into three groups: the AP group of rats that received injection of sodium deoxycholate into the common bile duct, the control group that underwent a sham operation, and the treatment group made by intraperitoneal injection of propargylglycine (PAG), an inhibitor of cystathionine-gamma-lyase (CSE), into rats with AP. Histopathology of the lung was examined and the expression of CSE and TNF-alpha mRNA in lung tissue was detected by real-time polymerase chain reaction. The H2S level in the serum was detected spectrophotometrically. RESULTS: The serum concentration of H2S and CSE and TNF-alpha expression in the lung were increased in AP rats modeled after 3 h and 6 h than in control rats (p < 0.05). Intraperitoneal injection of PAG could reduce the serum concentration of H2S, reduce CSE and TNF-alpha expression, and alleviate the lung pathology (p < 0.05). CONCLUSIONS: Taken together, our findings suggest that the H2S/CSE system is crucially involved in the pathological process of APALI and represents a novel target for the therapy of APALI. PMID- 25276171 TI - Aliskiren - an alternative to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the therapy of arterial hypertension. AB - There has been enormous progress in antihypertensive therapy over the last few decades. However, the management of arterial hypertension is still insufficient and more efforts are needed to improve both non-pharmacological and pharmacological treatment of this widely prevalent disease. Renin-angiotensin aldosterone system (RAAS) inhibition is crucial both for blood pressure (BP) control and for prevention of organ damage or its development in patients with hypertension. Angiotensin-converting enzyme inhibitors and/or sartans block RAAS incompletely. Aliskiren is one of the novel drugs that has been introduced to antihypertensive therapy recently. Up to now no trial has confirmed that aliskiren is efficacious in reducing cardiovascular events. Double RAAS blockade with aliskiren was not always safe. This review article presents the current view on the place of aliskiren in the therapy of arterial hypertension. PMID- 25276173 TI - Amyloidosis of the head and neck: a clinicopathological study of cases with long term follow-up. PMID- 25276175 TI - Chain drugstores: Opportunities and Threats. PMID- 25276172 TI - Thyroid diseases in patients with acromegaly. AB - Acromegaly often involves the presence of different pathologies of the thyroid gland. Long-lasting stimulation of the follicular epithelium by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) can cause disorders in thyroid function, an increase in its mass and the development of goitre. Acromegalic patients present most frequently with non-toxic multinodular goitre. Nodules are more prevalent in patients with active acromegaly. It has been suggested that then thyroid size increases and it can be reduced through treatment with somatostatin analogues. The relationship between thyroid volume and the level of IGF-1 and the duration of the disease is unclear. Each acromegalic patient requires a hormonal and imaging evaluation of the thyroid when the diagnosis is made, and an accurate evaluation during further observation and treatment. Although the data concerning the co-occurrence of acromegaly and thyroid cancer still remain controversial, it is particularly important to diagnose the patient early and to rule out thyroid cancer. PMID- 25276174 TI - Use of an endoscopic bioptome for extraction of a retained pacemaker lead tip. PMID- 25276176 TI - Epidemiological review of scorpion envenomation in iran. AB - This epidemiological review was carried out to display the magnitude and the geographic distribution of scorpion envenomation in Iran with focus on the southwestern region of Iran, particularly. The Iranian recognized scorpions belonging to two families, including Buthidae and Scorpionidae. Buthidae family consists of 14 genuses, 26 species, and 18 sub-species, while Scorpionidae family has three genuses and four species. The lack of basic knowledge, including the geographical distribution, clinical manifestations, and specific treatments related to scorpiofauna justifies such multidisciplinary studies. The venom of two endemic Iranian scorpions, including Hemiscorpius lepturus (H. lepturus) and Odonthubuthus doriae (O.doriae) have considered as an effective source of new neurotoxin peptides for the further development of physio-pharmacological probes and designing the clinical trials. Such epidemiological information may improve the determinants of Iranian scorpion stings in order to plan and implement effective public health intervention. PMID- 25276177 TI - Effect of medicinal herbs on primary dysmenorrhoea- a systematic review. AB - Conventional treatment for primary dysmenorrhoea has a failure rate of 20% to 25% and may be contraindicated or not tolerated by some women. Herbal medicine may be a suitable alternative. To determine the efficacy and safety of Iranian herbal medicine for primary dysmenorrhea when compared with placebo, no treatment, and other treatment. Electronic searches of the Cochrane Menstrual Disorders and Dysmenorrhoea Group Register of controlled trials, Scopus, Google Scholar, Medline, Pubmed were performed to identify relevant randomized controlled trials (RCTs). The study abstraction and quality assessment of all studies were undertaken following the detailed descriptions of these categories as described in the JADAD Criteria for Systematic Reviews of Interventions. 25 RCTs involving a total of women were included in the review. The review found promising evidence in the form of RCTs for the use of herbal medicine in the treatment of primary dysmenorrhoea compared with pharmacological treatment. However, the results were limited by methodological flaws. Further rigorous no penetrating placebo controlled RCTs are warranted. The review found promising evidence supporting the use of herbal medicine for primary dysmenorrhoea; however, results are limited by the poor methodological quality of the included trials. PMID- 25276178 TI - Lyophilized Chitosan/xanthan Polyelectrolyte Complex Based Mucoadhesive Inserts for Nasal Delivery of Promethazine Hydrochloride. AB - The objective of this investigation was the development of chitosan/xanthan polyelectrolyte complex based mucoadhesive nasal insert of promethazine hydrochloride a drug used in the treatment of motion sickness. A 3(2) factorial design was applied for preparing chitosan/xanthan polyelectrolyte complex and to study the effect of independent variables i.e. concentration of xanthan [X1] and concentration of chitosan [X2] on various responses i.e. viscosity of polyelectrolyte complex solution, water uptake of nasal inserts (at pH 2, 5.5, 7.4), bioadhesion potential of nasal inserts and in-vitro drug release at Q6h through nasal inserts. FTIR and DSC analysis were carried out to confirm complex formation and on loaded and unloaded nasal insert to investigate any drug excipient interaction. The nasal inserts were also characterized by powder X-ray diffractometry (PXRD) and Scanning electron microscopy (SEM) and for ex-vivo permeation studies. The results show that higher amount of xanthan in polyelectrolyte complexes with respect to higher amount of chitosan retarded in vitro drug release. The water uptake behaviour of nasal insert was strongly influenced by pH of the medium and by polycation/ polyanion concentration. The investigation verifies the formation of polyelectrolyte complexes formation between chitosan and xanthan at pH values in the vicinity of pKa intervals of the two polymers and confirms their potential for the nasal delivery of promethazine hydrochloride. PMID- 25276179 TI - Evaluation of a Nanodispersion Formulation Prepared through Microfluidic Reactors for Pulmonary Delivery of Budesonide Using Nebulizers. AB - This study aimed to determine the aerosolization behavior of a nanodispersion of budesonide, prepared using microfluidic reactors. The size and morphology of budesonide nanoparticles were characterized by photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM). Processing/formulation parameters for formation of the nanoparticles were studied to determine their effects on the particle size. Results showed a narrow distribution for budesonide nanodispersion with spherical and smooth surfaced particles. To investigate the in-vitro aerosolization performance of the nanodispersion, the preparation was compared with a commercially available budesonide microsuspension using the Comite Europeen Normalization (CEN) methodology. Aerosolization results showed that the fine particle fraction (FPF) generated from the budesonide nanodispersion was significantly higher than that of the marketed budesonide (ie. mean (SD) 56.88 (3.37)% vs. 38.04 (7.82)%, respectively). Additionally, mass median aerodynamic diameter (MMAD) of nano-budesonide dispersion was significantly smaller than the microsuspension (ie. mean (SD) 3.91 (0.49) vs. 6.22 (1.09) MUm, respectively), with nebulization time of nano-budesonide dispersion significantly shorter than the marketed budesonide microsuspension (ie. 12.3 (0.37) vs. 14.85 (0.36) min, respectively). The produced nanodispersion was found to be stable over a period of 10 days if stored at 4 degrees C. PMID- 25276180 TI - A stability indicating capillary electrophoresis method for analysis of buserelin. AB - A simple and rapid stability indicating method based on capillary zone electrophoresis has been developed and validated for the analysis of buserelin (BUS). The best separations were achieved by using a bare fused silica capillary (75 MUm i.d.; 65.5 cm total, 57.0 cm effective length), phosphate buffer (pH = 3.00; 26.4 mM), at 35 degrees C. The sample was hydrodynamically injected at 50 mbar for 5 seconds; the applied voltage was 30 kV and detection was carried out by UV-absorbance at 200 nm. Method validation resulted in the following figures of merit : the method was linear in the concentration range between 0.781 and 500 MUg/mL (linear regression coefficient 0.9996), accuracy was between 99.3% and 100.9%, intra assay precision was between 0.3% and 1.0% and intermediate precision was between 1.0% and 2.1%. Evaluation of the specificity of the method showed no interference between excipients or products of force degradation and BUS. Under the selected conditions, separation of BUS and its degradation products was completed in less than 10 min, and BUS could be quantified after different stress conditions without any interference. The results enabled the conclusion that under thermal stress upon exposure to 90 degrees C BUS is degraded by first order kinetics. It was demonstrated that the method can be applied as a rapid and easy to use method for quantification and stability testing of BUS in biopharmaceutical formulations in quality control laboratories. PMID- 25276181 TI - Clarithromycin dissolution enhancement by preparation of aqueous nanosuspensions using sonoprecipitation technique. AB - Clarithromycin (CLM) is a member of macrolide family with broad spectrum antibiotic activity. It is practically insoluble in water and its poor solubility is pH dependent. In this study, series of nanosuspensions containing CLM and stabilizer such as HPMC, NaCMC, polysorbate 80, poloxamer 188 and polyvinyl alcohol in various ratios were prepared using sonoprecipitation method. Briefly, CLM was dissolved in acid solution and the pH of solution was raised under sonication and the effects of different stabilizers on particle size of nanoparticles were evaluated. Characterization of nanoparticles in terms of size, polydispersity index, zeta potential, differential scanning calorimetery and dissolution studies was performed. Antimicrobial activity of CLM nanosuspension was compared with coarse powder by using an agar well diffusion method. The results showed that HPMC was more efficient in size reduction of particles and presence of HPMC E5 with ratio of 3:5 to CLM in formulation led to develop the stable nanosuspension with particle size of 340 nm. The obtained nanosuspension successfully showed enhanced dissolution rate and antimicrobial activity. PMID- 25276182 TI - Docetaxel Loaded PEG-PLGA Nanoparticles: Optimized Drug Loading, In-vitro Cytotoxicity and In-vivo Antitumor Effect. AB - In this study a 3-factor, 3-level Box-Behnken design was used to prepare optimized docetaxel (DTX) loaded pegylated poly lactide-co-glycolide (PEG-PLGA) Nanoparticles (NPs) with polymer concentration (X1), drug concentration (X2) and ratio of the organic to aqueous solvent (X3) as the independent variables and particle size (Y1), poly dispersity index (PDI) (Y2) and drug loading (Y3) as the responses. The cytotoxicity of optimized DTX loaded PEG-PLGA NPs was studied in SKOV3 tumor cell lines by standard MTT assay. The in-vivo antitumor efficacy of DTX loaded PLGA-PEG NPs was assessed in tumor bearing female BALB/c mice. The optimum level of Y1, Y2 and Y3 predicted by the model were 188 nm, 0.16 and 9% respectively with perfect agreement with the experimental data. The in-vitro release profile of optimum formulation showed a burst release of approximately 20% (w/w) followed by a sustained release profile of the loaded drug over 288 h. The DTX loaded optimized nanoparticles showed a greater cytotoxicity against SKOV3 cancer cells than free DTX. Enhanced tumor-suppression effects were achieved with DTX-loaded PEG-PLGA NPs. These results demonstrated that optimized NPs could be a potentially useful delivery system for DTX as an anticancer agent. PMID- 25276183 TI - Biocompatibility Research of a Novel pH Sensitive Ion Exchange Resin Microsphere. AB - The main objective of this study was to investigate biocompatibility and provide in-vivo pharmacological and toxicological evidence for further investigation of the possibility of pH sensitive ion exchange resin microsphere for clinical utilizations. Acute toxicity study and general pharmacological studies were conducted on the pH sensitive ion exchange resin microsphere we prepared. The general pharmacological studies consist of the effects of the pH sensitive ion exchange resin microsphere on the nervous system of mice, the functional coordination of mice, the hypnosis of mice treated with nembutal at subliminal dose, the autonomic activities of tested mice, and the heart rate, blood pressure, ECG and breathing of the anesthetic cats. The LD50 of pH sensitive ion exchange resin microsphere after oral administration was more than 18.84 g.Kg( 1). Mice were orally administered with 16 mg.Kg(-1), 32 mg.Kg(-1) and 64 mg.Kg( 1) of pH sensitive ion exchange resin microsphere and there was no significant influence on mice nervous system, general behavior, function coordination, hypnotic effect treated with nembutal at subliminal dose and frequency of autonomic activities. Within the 90 min after 5 mg.Kg(-1), 10 mg.Kg(-1), 20 mg.Kg(-1) pH sensitive ion exchange resin microsphere was injected to cat duodenum, the heart rate, blood pressure, breathing and ECG of the cats didn't make significant changes in each experimental group compared with the control group. The desirable pharmacological and toxicological behaviors of the pH sensitive ion exchange resin microsphere exhibited that it has safe biocompatibility and is possible for clinical use. PMID- 25276184 TI - Microencapsulation of Probiotics by Calcium Alginate-gelatinized Starch with Chitosan Coating and Evaluation of Survival in Simulated Human Gastro-intestinal Condition. AB - Microencapsulation as one of the most modern methods has considerable effects on probiotic survival. In this study Lactobacillus casei (ATCC 39392) and Bifidobacterium bifidum (ATCC 29521) were encapsulated using calcium alginate gelatinized starch, chitosan coating and inulin via emulsion technique, and were incubated in simulated gastric juice (along with pepsin, pH=1.5) and simulated intestinal juice (along with pancreatin and bile salts, pH = 8) for 2 hours at 37 (o)C. The morphology and size of microcapsules were measured by scanning electron and optical microscopy. The results indicated that the survival of microencapsulated probiotic increased significantly in simulated gastro intestinal condition (P < 0.05). Chitosan coating played a significant role in the protection of probiotic bacteria in simulated gastro-intestinal condition and the diameter of the microcapsules increased with the addition of chitosan coating. In general, this study indicated that microencapsulation with alginate gelatinized starch coated with chitosan could successfully and significantly protect probiotic bacteria against adverse condition of simulated human gastro intestinal condition. PMID- 25276185 TI - A Rapid and Sensitive HPLC-Fluorescence Method for Determination of Mirtazapine and Its two Major Metabolites in Human Plasma. AB - A rapid and sensitive HPLC method has been developed for the quantification of mirtazapine (MRZ), a noradrenergic and specific serotonergic inhibitor antidepressant (NaSSA) and its two major metabolites N-desmethyl mirtazapine (NDM) and 8-hydroxymirtazapine (8-OHM) in human plasma. The separation was achieved using Chromolith C18 column and a mobile phase of acetonitrile: phosphate buffer (pH = 3, 20:80, v/v) in isocratic mode at a flow rate of 2 mL/min. A fluorescence detector was set at 290 and 350 nm for excitation and emission, respectively. Zolpidem was used as the internal standard. Liquid-liquid extraction was applied for sample clean up. All analytes were eluted in less than 5 minutes with LOQ of 1 ng/mL for MRZ and 2 ng/mL for both NDM and 8-OHM. The developed method was successfully applied to quantify MRZ and its metabolites in plasma of a healthy volunteer. PMID- 25276186 TI - Rapid Analysis of Glibenclamide Using an Environmentally Benign Stability Indicating RP-HPLC Method. AB - An environmentally benign RP-HPLC approach for rapid analysis of glibenclamide in pure form, developed nanoemulsion and commercial tablets was developed and validated in present investigation. The green chromatographic identification was performed on Lichrosphere 250 X 4.0 mm RP C8 column having a 5 MUm packing as a stationary phase using a combination of ethanol: methanol (50:50 % v/v) as a mobile phase, at a flow rate of 1.0 mL/min with UV detection at 245 nm. The proposed method was validated for linearity, selectivity, accuracy, precision, robustness, sensitivity and specificity as per international conference on harmonization (ICH) guidelines. The utility of proposed method was verified by assay of glibenclamide in developed nanoemulsion and commercial tablets. The proposed method was found to be satisfactory in terms of selectivity, precision, accuracy, robustness, sensitivity and specificity. The content of glibenclamide in developed nanoemulsion and commercial tablets was found to be 100.50 % and 99.15 % respectively. The proposed method successfully resoled glibenclamide peak in the presence of its all type of degradation products which indicated stability indicating property of the proposed method. These results indicated that the green chromatographic method could be successfully employed for routine analysis of glibenclamide in pure drug and various commercial formulations. PMID- 25276187 TI - Synthesis of some novel chromenopyrimidine derivatives and evaluation of their biological activities. AB - Pyrimidine nucleosides are constituents of fundamental structure of the cells. There has been considerable attentions in the chemistry of pyrimidine derivatives due to having a wide range of biological activities such as antiviral, anti malarial agents, cytostatic, antithelemintic, antibacterial, adenosine receptor ligands, anti-cancer agents, compounds targeting delayed-type hypersensivity and anti-convulsant agents. As a part of our research work in the synthesis of pyrimidines containing biological activities, a series of chromenopyrimidine derivatives were synthesized by reaction of an intermediate imine and ammonia derivatives in good to high yields. All synthesized compounds were characterized using IR and NMR ((1)H and (13)C) spectroscopy and elemental analysis data. The antibacterial activity of these compounds was investigated against Staphylococcus aureus (RTCC, 1885), and Escherichia Coli (ATCC, 35922). PMID- 25276188 TI - Synthesis and Biological Investigation of some Novel Sulfonamide and Amide Derivatives Containing Coumarin Moieties. AB - New sulfonamide and amide derivatives containing coumarin moieties; oxo-2H chromen-sulfamoylphenylacetamides and oxo-2H-chromen-arylacetamides were synthesized starting from diverse 2-chloroacetamide derivatives and a wide range of coumarins. The structures of compounds were elucidated by IR and NMR spectra and also analytical elemental analysis. In the next step, the above mentioned compounds were screened for their antimicrobial and antioxidant activities. Their antimicrobial activity was assigned using the conventional agar dilution method and the antioxidant activity was assessed using two methods, 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging method and ferric reducing antioxidant power (FRAP) assay. Although the compounds showed no remarkable antimicrobial activities, most of them exhibited good antioxidant activities. Compounds 5b showed the most potent DPPH activity, whereas 8c was the most efficient compound in FRAP assay. PMID- 25276189 TI - Biological Effect of Di (p-methylbenzoyl) Diselenide (In-vitro) and Its Acute Hepatotoxicity on Rats (In-vivo). AB - Selenium plays an important role in biological system due to its incorporation in glutathione peroxidases and thioredoxin reductase as prosthetic group, the pharmacological studies of synthetic organoseleno-compounds revealed these molecules to be used as antioxidants, enzyme inhibitors, neuroprotectors, antitumor, anti-infectious agents, cytokine inducers and immuno-modulators. The present study was undertaken to elucidate Synthesis and biological effect Di (p methylbenzoyl) diselenide (DMBDS) in-vitro. Di (p-methylbenzoyl) diselenide DMBDS was synthesized and its structure was confirmed by different spectroscopy techniques. In-vitro dose response of DMBDS on lipid peroxidation, nitrite content, GPx and arginase activities beside blood coagulation were measured. Acute toxicological effects were assessed by single orally injected Swiss albino mice with different DMBDS concentrations. In-vitro results revealed that DMBDS induces oxidative stress, elevation of arginase activity and acts as coagulant. PMID- 25276191 TI - Preparation, Physicochemical Characterization and Biological Evaluation of some Hesperidin Metal Complexes. AB - The ability of hesperidin (HP) to form complexes with five metals; cobalt, nickel, zinc, calcium and magnesium was investigated. The complexation was studied using U.V spectroscopic titration, in methanol as well as aqueous buffer solutions (physiological conditions). Potential complexes were studied by IR and NMR spectroscopy, melting point and their solubility were also evaluated. The interaction of HP and its metal complexes with DNA was investigated by U.V spectroscopy. HP and its potential complexes were also tested for their ability to inhibit alpha amylase and alpha glucosidase enzymes. The results indicated that HP can form 1:1 complexes with cobalt, nickel and zinc in methanolic solution but not in aqueous buffers. Both HP and its metal complexes were found to intercalate DNA, at physiological condition, with preference to GC rich sequences. HP-metal complexes appeared to have higher affinity towards poly A DNA than the free HP. Neither HP nor its complexes exhibited antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa or Candida albicans. Results showed that HP has little inhibitory action on glucosidase and amylase enzymes with no obvious effect of complexation on the behavior of free HP. In conclusion HP was shown to form 1:complexes with the studied metal in methanol but not in aqueous buffer solutions. In presence of DNA however, complex formation in aqueous solutions seem to be encouraged with differential effect between the complexes and free HP. PMID- 25276190 TI - Prediction of In-silico ADME Properties of 1,2-O-Isopropylidene Aldohexose Derivatives. AB - Retention behaviour of molecules mostly depends on their chemical structure. Retention data of biologically active molecules could be an indirect relationship between their structure and biological or pharmacological activity, since the molecular structure affects their behaviour in all pharmacokinetic stages. In the present paper, retention parameters (R M (0)) of biologically active 1,2-O isopropylidene aldohexose derivatives, obtained by normal-phase thin-layer chromatography (NP TLC), were correlated with selected physicochemical properties relevant to pharmacokinetics, i.e. absorption, distribution, metabolism, and elimination (ADME) properties. Conducted correlation analysis showed high dependence between R M (0) and blood brain barrier penetration, skin permeability, enzyme inhibition, binding affinity to nuclear receptor ligand and G protein-coupled receptors, as well as lipophilicity (expressed as Hansh-Leo's parameter Clog P). The statistical validity of the established polynomial dependence of the second degree between R M (0) and mentioned ADME properties was confirmed by standard statistical measures and leave-one-out cross-validation method. On the basis of in-silico calculated ADME properties and retention data, the similarity between studied molecules was examined using principal component analysis (PCA). The obtained results indicate the possibility of predicting ADME properties of studied compounds on the basis of their retention data (R M (0)). These preliminary results could be treated as guideline for selecting new 1,2-O isopropylidene aldohexose derivatives as drug candidates. PMID- 25276192 TI - Combination of Ethanolic Extract of Citrus aurantifolia Peels with Doxorubicin Modulate Cell Cycle and Increase Apoptosis Induction on MCF-7 Cells. AB - New approach of breast cancer therapy is developed toward combination therapy with agents that have a specific molecular target. Our previous study showed that Citrus aurantifolia lime peels ethanolic extract (CPE) increased the sensitivity of MCF-7 cells againts doxorubicin. This study aims to observe the mechanism of combination CPE and doxorubicin in cell cycle modulation and apoptosis on MCF-7 cells. The assays were performed in the study were cell cycle assay, apoptosis induction, and immunocytochemistry of MCF-7 cells.The effect on the modulation of cell cycle and apoptosis were observed by flowcytometry assay in both single dose of CPE and its combination with Doxorubicin. Cell cycle distribution were observed with flowcytometer FACS-Calibur and its data was analyzed by Cell Quest program. Apoptotic induction in MCF-7 cells was examined using acrydine orange ethidium bromide (AO-EtBr) double staining. Immunocytochemistry assay was done to observe the expression of apoptotic regulation protein p53 and Bcl-2. The result showed that CPE 6 MUg/mL induced apoptosis and cell accumulation at G1 phase, while CPE 15 MUg/mL induced apoptosis and cell accumulation at G2/M phase. The combination of doxorubicin 200 nM with CPE 6 MUg/mL increased apoptosis induction than their single treatment, and cell accumulation at G2/M phase. Evidence of apoptosis and protein expression of p53 and Bcl-2 indicated that both single applications and combinations of CPE and doxorubicin are able to increase apoptotic bodies of MCF-7 cells by increasing the proteins expression. This result suggested that CPE could perform as co-chemotherapeutic agent with doxorubicin on breast cancer cells. PMID- 25276193 TI - Method Development for Simultaneous Determination of 41 Pesticides in Rice Using LC-MS/MS Technique and Its Application for the Analysis of 60 Rice Samples Collected from Tehran Market. AB - A multi-residue method for simultaneous determination of 41 LC-amenable pesticides in rice, belonging to different chemical classes has been developed in Iran by LC-MS/MS. For the first time the pesticides were analyzed simultaneously in a single run using positive electrospray ionization with multiple reaction monitoring (MRM) after extraction with slightly modified QuEChERS method. The calibration curve for each analyte was linear over the concentration range of 0.02-1.0 MUg/g with a correlation coefficient range between 0.993 and 0.999. The LOQ and LOD were .025 MUg/g and 0.008 MUg/g respectively, for all 41 pesticides and the mean recoveries obtained for three fortification levels (0.025, 0.08 and 0.250 MUg/g) were 71-119% with satisfactory precision (RSD<20%). The developed method was used to investigate the occurrence of pesticides in 30 domestic and 30 imported rice samples collected from Tehran market. Five compounds were detected in 11 domestic and 9 imported positive samples in concentration range from 0.032 MUg/g to 0.081 MUg/g and 0.028 MUg/g to 0.074 MUg/g, respectively. With the exception of prohibited pesticides, phosphamidon and TCMTB, three permitted pesticides, cinosulfuron, triadimenol and tricyclazole, found in positive rice samples were below MRLs established by Institute of Standards and Industrial Research of Iran (ISIRI). PMID- 25276194 TI - Progesterone and cilostazol protect mice pancreatic islets from oxidative stress induced by hydrogen peroxide. AB - Reactive oxygen species and oxidative stress impair beta-cell function and reduce insulin secretion. It has been shown that progesterone and cilostazol possess antioxidant properties. The present study was aimed to investigate in-vitro pretreatment effect of progesterone and cilostazol on insulin secretion as well as their protective effects against hydrogen peroxide-induced oxidative stress in pancreatic isolated islets from mouse. Pancreatic islets were isolated from 84 male NMRI mice (25-30 g) by collagenase digestion method and pretreated for 48 h with cilostazol (10 MUM), progesterone (0.5 MUM) and glibenclamide (10 MUM) in culture medium. Then islets were exposed to hydrogen peroxide (H2O2. 500 MUM) for 2 h. Next, culture mediums containing glucose concentration of 2.8 mM or 16.7 mM were added to them and incubated in this status for 1 h. At the end, the rate of insulin output from islets, lipid peroxidation and antioxidant enzymes activities in islet tissues were assayed. Exposure of islets to H2O2, resulted in a significant decrease in insulin secretion, superoxide dismutase and catalase activities (P < 0.001). Also islets malondialdehyde levels were increased by H2O2, after addition of 2.8 mM (P < 0.05) and 16.7 mM (P < 0.001) glucose. 48 h pretreatment of islets with cilostazol and progesterone, significantly reverted back this changes (P < 0.05). Results of present study showed that cilostazol and progesterone protect mice pancreatic islets against H2O2-induced oxidative stress. At the end, our results suggested that protective effects of progesterone and cilostazol are mediated by augmentation the antioxidant defence system of islets. PMID- 25276195 TI - Evaluation of Protective Efficacy of Avicennia marina (Forssk.) Vierh Leaves against Complete Freund?s Adjuvant-induced Arthritis in Wistar. AB - Aviecennia marina (Avicenniaceae) is an endemic plant that widely distributed in the Southern parts of Iran. This plant has been used as treatment of rheumatism arthritis among the inhabitants of Southern parts of Iran. The Avicennia marina hydroalcoholic extract was prepared and its protective efficacy was investigated using measurement of ankle diameter, total WBC and RBC count, ESR, and Pro inflammatory cytokines levels in the complete Freund?s adjuvant (CFA)-induced arthritic rat. The increment in ESR and total WBC, reduction in RBC count and hemoglobin levels observed in the arthritic animals were also found to be significantly restored in HEA treated rats. A. marina at 400 mg/Kg significantly decreases the serum pro-inflammatory cytokines as well as normalizes ankle diameter of CFA rats. A. marina (400 mg/Kg) significantly normalizes changes observed in arthritic rats to near normal conditions, indicates that A. marina has promising protective efficacy against arthritic rats. PMID- 25276196 TI - Cytotoxicity of selected novel chalcone derivatives on human breast, lung and hepatic carcinoma cell lines. AB - Cancer is considered as a challenging deathly disease and discovering or synthesis of new cytotoxic agents is a worldwide attempt. In this study, a group of recently synthesized chalcones, with the structure of 1,3-diarylprop-2-en-1 one having different COX-1 and/or COX-2 selectivities have been examined on human hepatocarcinoma (HepG2), lung carcinoma (A549), and breast adenocarcinoma (MCF-7) cell line, using Sulforhodamine B (SRB) assay. Briefly, cells were treated with 1 100 MUM of each compound for 72, 96 and 168 hours. In each case, a control row was set with the exposure of cells to compounds-free solvents. Median lethal concentration (LC50) values (compared to controls) were calculated using regression fitness analysis on GraphPad Prism((r)) software. Our results show that the subgroup possessing p-azido COX-2 pharmacophore seems to be more cytotoxic, while the cells seem to show more acquired resistance to them and the subgroup possessing a p-MeSO2NH COX-2 pharmacophore is less cytotoxic, while the cells also acquire less resistance to them. In conclusion, considering the diversity in COX-1 or COX-2 inhibition among these compounds in each group, and also revealing no correlation between COX inhibition selectivity and cell death, it seems that selective inhibition of each isoenzyme doesn't cause substantial effect on toxicity potency. Further studies to determine the main mechanism(s) for these compounds induced cell death are encouraged. PMID- 25276197 TI - Intracellular Signaling Mechanisms Pharmacological Action of Jasminum amplexicaule Buch.-Ham. (Oleaceae) on Gastrointestinal Secretion. AB - Jasminum amplexicaule Buch-Ham. (Oleaceae) has been commonly used in the traditional medicine in dysentery, diarrhoea and bellyache in China. In the present work, the methanol extract of Jasminum amplexicaule (JME) was examined for pharmacology on human colonic epithelial cell line T84 by the short-circuit current technique. The results showed that pretreatment of T84 cells with JME produced a concentration-dependent (0-1000 MUg/mL. EC50 = 0.055 mg/ mL) inhibition effect on adrenalin (Adr.)-induced Cl- secretion. The maximal response was observed at 200 MUg/mL. It has been demonstrated that JME has a direct effect on the enterocyte. Our results also demonstrated that the JME exerted inhibitory effect on gastrointestinal Cl(-)secretion that effected by acting on basolateral beta-adrenoreceptors. These results suggested that the Chinese traditional medicine of JME can be used for the treatment of acute diarrhea and bellyache. PMID- 25276198 TI - Effect of Hydro-alcoholic Extract of Persian Oak (Quercus brantii) in Experimentally Gastric Ulcer. AB - Persian oak (Quercus brantii Lindl.) belongs the family Fagaceae, is a medicinal plant which seed flour is used to treat inflammatory and gastric ulcers by the tribes in south western Iran. The current study was done to evaluate the effect of hydro-alcoholic extract of Q. brantii seed flour for treatment of gastric ulcers induced by ethanol in Wistar rats. The hydro-alcoholic extract of Q. brantii was tested orally at doses of 250, 500, and 1000 mg/Kg, control group and standard drug (omperazole) on experimentally gastric ulceration. At the 3, 6, 9, and 14(th) days, ulcer index in mm(2) and histopathological findings were evaluated. Results indicated the size of ulcers significantly reduced at 9, and 14 days after of Q. brantii extract treatment. Curative effect in the hydro alcoholic induced gastric damage was 100% at 1000 mg/Kg and omeprazole, 99.8 % at 500 mg/Kg, and 95.4% at 250 mg/Kg after 14 days. Results of histopathological investigation showed the thickness of ulcerated mucosa was similar to the normal mucosa with 1000 mg/Kg of Q. brantii hydro-alcoholic extract after 14 days but in the groups treated by 250, and 500 mg/Kg, superficial erosions were visible in the central portion of the healed ulcers. In conclusion, the hydro-alcoholic extract of Q. brantii had active components (tannin = 8.2%) that accelerates ulcer healing and thus supported its traditional use. PMID- 25276199 TI - The comparison of the effects of acute and repeated morphine administration on fast synaptic transmission in magnocellular neurons of supraoptic nucleus, plasma vasopressin levels, and urine volume of male rats. AB - The activity of the magnocellular neurons (MCNs) of supraoptic nucleus (SON) is regulated by a variety of excitatory and inhibitory inputs. Opioids are one of the important compounds that affect these inputs at SON synapses. In this study, whole-cell patch clamp recording of SON neurons was used to investigate the effect of acute and repeated morphine administration on spontaneous inhibitory and excitatory post synaptic currents (sIPSCs and sEPSCs) in MCNs. While acute bath application of morphine to brain slice of intact rat produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency, repeated in-vivo administration of morphine produced opposite effect. Moreover, repetitive i.c.v. administration of morphine for three consecutive days caused significant increase in urine volume, but had no significant alteration in water consumption compared to control group. The increase in urine volume was consistent with a significant decrease in plasma arginine vasopressin (AVP) levels after repetitive i.p. morphine administration. The results suggest that acute administration of morphine stimulates whereas repeated administration of morphine inhibits the MCNs. Morphine-induced MCN inhibition could result in diminished plasma AVP levels and eventually an increase in urine volume of rats. PMID- 25276200 TI - A Possible Non-genomic Epileptogenic Properties of Estradiol Attenuated by MK801 and DNQX in Amygdala Kindled Rats. AB - Although the epileptogenic properties of estrogens have been widely demonstrated in several models and species, the mechanism(s) by which estrogens can acutely change seizure parameters including after discharge and seizure durationremains to be determined. In the present study, we examined the role of NMDA (N-methyl-D aspartate), non-NMDA andestrogen receptors in estradiol benzoate(EB) effects on kindled seizure parameters. Different groups of fully kindled male rats received either EB (30 MUg /Kg); EB plus MK801 (2 mg/Kg, as NMDA antagonist); DNQX (7.5 mg/Kg);tamoxifen (TAM, 0.1 mg/Kg, as non- NMDA antagonist) or intra-amygdala injection of anisomycine (30 mmol/mL, a protein synthesis inhibitor). Kindled seizure parameters including after discharge duration (ADD) and stage 5 duration(S5D) were determined at 0.25 and 3 h post sesame oil (EB solvent) or EB treatment. While pretreatment with either MK801 or DNQX could block the ADD prolongation induced by EB at 0.25 h, they had no effect on S5D prolongation at 3 h. Moreover, application of anisomycine or TAM had no effect on estradiol induced ADD and S5D prolongation. These results indicate that both NMDA and non-NMDA receptors could be involved in EB induced ADD prolongation. The observed short termnon-estrogenic receptor or protein synthesis dependent effects of EB may provide a non-genomic mechanism for the stimulatory effects of the steroid on seizure activity. PMID- 25276201 TI - Determination of antibiotics consumption in buali-sina pediatric hospital, sari 2010-2011. AB - The increasing prevalence of antibiotic-resistant bacteria is a major health-care problem worldwide. WHO recommends DID (daily defined dose per 100 Inhabitant per day) as a standard tool for measurement of antibiotic consumption. Since there was not any information regarding the antibiotics usage pattern in the north of Iran, the aim of this study was determine this in our centre. This cross sectional study was performed in Buali Sina hospital. Using the health information system (HIS) database, records of patients hospitalized during 22 Sep 2010 - 21 Sep 2011. Data of different wards including Neonatal, NICU, PICU, Pediatrics and Pediatric surgery were separately extracted and analyzed. Drug consumption data were expressed as DID. SPSS 16 software was used for statistical analysis. Independent samples t-test was used to compare the quantitative variables. A total of 4619 in-patients records during 1 year of study including 2494 patients in fall and winter and 2125 patients in spring and summer were evaluated. The most hospitalized patients were in Pediatric ward (43.9 %). The highest DID value were obtained for ceftriaxone (21.7), ampicillin (6.05) and vancomycin (4.7), while the lowest value was for gentamicin (0.01). In both cold and warm seasons, Ceftriaxone was the most frequent prescribed antibiotic. The rate of antibiotics consumption especially Ceftriaxone in our setting was significantly higher than the other centers. Strategies for more justified administration of antibiotics especially broad -spectrum ones are necessary. PMID- 25276202 TI - A Randomized Clinical Trial Study: Anti-Oxidant, Anti-hyperglycemic and Anti Hyperlipidemic Effects of Olibanum Gum in Type 2 Diabetic Patients. AB - Diabetes is a common metabolic disease in the world that has many adverse effects. Olibanum gum resin (from trees of the genus Boswellia) has traditionally been used in the treatment of various diseases such as diabetes. The aim of this study was the comparison of Olibanum gum resin effect with placebo on the treatment of type 2 diabetes. Inclusion criteria was diabetic patients with fasting blood sugar (FBS) =140-200 mg/dL. This study has been designed as double blined clinical trial on 71 patients with type 2 diabetes and the patients randomly were divided to interventional and placebo groups. The patients on standard anti-diabetic therapy (metformin) treated with Olibanum gum resin (400 mg caps) and placebo tow times per day for 12 weeks, respectively. At the end of the twelfth week, the FBS, HbA1c, Insulin, total Cholesterol (Chol), LDL, Triglyceride (TG), HDL and other parameters were measured. The Olibanum gum resin lowered the FBS, HbA1c, Insulin, Chol, LDL and TG levels significantly (p < 0.001, p < 0.001, p <0.001, p = 0.003, p < 0.001 and p < 0.001, respectively) without any significant effects on the other blood lipid levels and liver/kidney function tests (p > 0.05) compared with the placebo at the endpoint. Moreover, this plant showed anti-oxidant effect and also no adverse effects were reported. The results suggest that Olibanum gum resin could be used as a safe anti-oxidant, anti-hyperglycemic and anti-hyperlipidemic agent for type 2 diabetic patients. PMID- 25276203 TI - Effects of citrus aurantium (bitter orange) on the severity of first-stage labor pain. AB - Considering that vaginal delivery is a painful process, the present study investigated the effects of Citrus aurantium on the severity of first-stage labor pain in primiparous women. This study was a randomized clinical trial conducted with 126 eligible primiparous patients. The pain severity of patients was measured at the time of enrolling in the study. In the intervention group, (aromatherapy) gauze squares were soaked in 4 ml of C. aurantium distillated water, and in the control group, gauze squares were soaked in 4 ml of normal saline; each gauze square was attached to the respective patients' collar. The intervention was repeated every 30 min. Pain severity was measured after the intervention at 3-4, 5-7, and 8-10 cm cervix dilatations. The two groups were standardized with regard to age, profession, education, desire to conceive, and number and severity of uterine contractions. The Bishop's score was also calculated. Before intervention, pain severity was the same for both groups, but following intervention, pain severity reduced in the intervention group at 3-4 centimeter (P < 0.05), 7-5 centimeter (P < 0.05), and 8-10 centimeter (P < 0.05) dilatations compared with that in the control group. The findings of the study revealed that aromatherapy using C. aurantium distillated water alleviates labor pain. This method is recommended because of its ease of use and low cost and because it is a non-aggressive method to reduce labor pain. PMID- 25276204 TI - Comparative binding affinities of flavonoid phytochemicals with bovine serum albumin. AB - Dietary flavonoids show beneficial effects in the prevention of chronic diseases. However, flavonoid bioavailability is poor, probably due to their interaction with serum albumins. In the current work, the binding interactions of eight related flavonoids, sharing a similar core structure, with bovine serum albumin (BSA) were investigated by fluorescence spectroscopy. The binding affinities of the flavonoids with BSA were in the order hesperetin (KA=5.59 * 10(5))> quercetin (4.94 * 10(5)) > naringenin (3.04 * 10(5)) > isoquercitrin (4.66 * 10(4)) > icariin (3.60 * 10(4)) > rutin (1.65 * 10(4)) > hesperidin (2.50 * 10(3)) > naringin (8.70 * 10(2)). The associations of specific structural components of the flavonoids with their binding properties to BSA were also explored and hydrophobicity, functional group substituents, steric hindrance effects and the spatial arrangements of substituents seem to be the key factors for the affinities of flavonoids towards BSA. The results from the current work contribute to a better understanding of the transport of flavonoids in plasma and helping predict their physiological functions based on their intrinsic structures. PMID- 25276205 TI - Ethno-pharmaceutical Formulations in Kurdish Ethno-medicine. AB - Kermanshah is a city in west of Iran with a specific customs and cultures between the people who are living here. According to historical documents these cultures are very ancient and belong to more than one thousand years. The climate condition in this place forces people to find the solution of their problems using the plants and natural facilities. Therefore traditional healers were so active in Kermanshah. From 8000 of plant species in Iran more than 1200 species has grown in Kermanshah. The ancient customs, cultures, traditional medicine and formulations generally used by rural populations was transfer from ancient to modern people. Documentation of these traditional methods was studied in this research in order to compare and certified the traditional medicine with modern methods and find new dosage forms of drug with botanical source. It was established that about 50 plant species and 8 types of diseases were distinguished and cured by these people. It is also concluding that utilization of these plants approximately the same as application of plants in recent publications. PMID- 25276206 TI - Correlation between Sun Protection Factor and Antioxidant Activity, Phenol and Flavonoid Contents of some Medicinal Plants. AB - Long exposure of UV radiation increases risk of skin diseases such as cancer and photoallergic reactions. UV-B (280-320 nm) radiation is mainly responsible for inducing the skin problems. Skin protection is a suitable method against ultraviolet radiation-induced damage. Various synthetic agents have been used as photo protective but because of their potential toxicity in humans, they have limited usage. Natural substances have been recently considered as potential sunscreen resources due to their absorption in the UV region and their antioxidant activity. In the present study, the UV protective effects of 20 extracts from four common medicinal plants were evaluated. Their phenol and flavonoid contents and antioxidant activities were determined and correlation between SPF and these contents were evaluated. SPFs were between 0.102 and 24.470. The highest value was reached with ultrasonic extract of Crataegus pentagyna (SPF = 24.47) followed by methanolic extract of Feijoa sellowiana (SPF = 1.30). Good correlation was found between SPF and phenolic contents (Correlation Coefficient = 0.55 and p = 0.01) but no correlations were found between SPF and flavonoid contents or antioxidant activity. These extracts can be used alone or as additives in other sun screen formulations to enhance their SPF. PMID- 25276207 TI - Phytochemical Investigations on Chemical Constituents of Achillea tenuifolia Lam. AB - Achillea tenuifolia Lam. (Asteraceae) afforded a methanolic extract from which after fractionation in solvents with different polarities, two known flavones 3', 5- dihydroxy- 4', 6, 7- trimethoxy flavone (eupatorine, compound 3), 5- hydroxy- 3',4', 6, 7- tetramethoxyflavone (compound 4), besides stearic acid (compound 1), lupeol (compound 2), daucosterol (beta- sitosterol 3-O- beta- D- glucopyranoside, compound 5), 2, 4- dihydroxy methyl benzoate (compound 6) were isolated for the first time. The structure of isolated compounds was elucidated by means of different spectroscopic methods such as UV, IR, Mass and 1H- NMR (1D and 2D) and 13C-NMR. For further confirming the structures of isolated compounds, comparison of the spectral data of them with those reported in the litratures have been done. PMID- 25276208 TI - Identification of Chemical Constituents in the Extract and Rat Serum from Ziziphus Jujuba Mill by HPLC-PDA-ESI-MSn. AB - Chinese jujube (Ziziphus jujuba Mill.) has long been widely used for human consumption and medicinal purposes in China. It has been reported to possess several vital biological activities. However, the systematic study on the chemical constituents absorbed into plasma and their metabolites is still insufficient.A high-performance liquid chromatography-photodiode array detector electrospray ionization ion-mass spectrometry (HPLC-PDA-ESI-MS(n)) method was established to analyze the ethanol extract in Ziziphus jujuba Mill and the constituents absorbed into rat serum. In the present study, a dose of 10 mL/Kg of ethanol extract of jujube, which is equivalent to 12.5 g crude dried herb/Kg, was orally administrated to rats. The main components were analyzed in the ethanol extract of Ziziphus jujuba Mill and the parent constituents and metabolites were studied in rat plasma samples after oral administration of the ethanol extract of jujube.D101 macroporous polystyrene resin was a good pretreatment method to obtain better separation and impurity removal effect. Twenty-two compounds were identified in the ethanol extract of Ziziphus jujuba Mill. Four parent compounds and four metabolites were detected in rat serum. Among them, seventeen compounds were reported for the first time. PMID- 25276209 TI - Treatment of Paederus Dermatitis with Sambucus ebulus Lotion. AB - Paederus dermatitis is an irritant contact dermatitis due to accidental contact by a beetle belonging to the genus paederus. In this study, clinical efficacies of S. ebulus fruit extract solution in patients affected by paederus dermatitis were evaluated. A randomized double-blind, prospective, placebo-controlled clinical trial was performed in 62 patients with clinical symptoms and sings of dermatitis due to paederus beetles. The patients received either a topical solution of palemolin (a 5% S. ebulus fruit extract in ethanol 70%) or ethanol 70% topical solution thrice a day. Topical hydrocortisone ointment was prescribed for all patients. Palemolin was statistically more effective in controlling of burning, pain, inflammation, drying the wound, infections and acceleration of healing than control group (p <= 0.05). Specially in controlling of inflammation, palemolin had more significant efficacy (p < 0.001) than control group. About 63.6% of patients in palemolin group cured during first 24 h (versus 27.4% in control groups). The problems related to lesions in 93.9% of patients were eliminated completely during 48 hours after the beginning of the treatment by palemolin (versus 65.4% in control groups). Topical 5% solution of S. ebulus fruit extract is an effective pharmaceutical preparation in treatment of paederus dermatitis. PMID- 25276210 TI - Antimicrobial and Antioxidant Activities of Bauhinia racemosa Lam. and Chemical Content. AB - Methanol 70% extract of Bauhinia racemosa aerial parts was tested for antimicrobial activity against different bacterial and fungal strains and for antioxidant activity and also total content of polyphenols with phytochemical analysis of the extract was determined. The results have showed that the extract has a significant antimicrobial activity, it inhibited the growth of Bacillus subtilis and also it was highly active against Candida albicans suggesting that it can be used in the treatment of fungal infections. The extract has a good antioxidant activity, it has shown high values of the trolox equivalent antioxidant capacity and polyphenol content while it has shown a lower value of oxygen radical absorbance capacity. Phytochemical analysis has shown that it has interesting phytochemical bioconstituents, include flavonoids, tannins and others, and the deep phytochemical study results in the isolation of methyl gallate, gallic, kaempferol, quercetin, querection 3-O-alpha-rhamnoside, kaempferol 3-O-beta-glucoside, myricetin-3-O-beta- glucoside, querection-3-O rutinoside (Rutin). All compounds were identified by different spectroscopic analyses (UV, (1)H-NMR, (13)C-NMR) and Mass Spectrometry (MS). PMID- 25276211 TI - Assessment of some Herbal Drugs for Prophylaxis of Peptic Ulcer. AB - Aqueous (hydrophilic) and chloroform (Lipophilic) extracts of nine medicinal plants currently used in Egyptian traditional medicine to treat some gastrointestinal tract (GIT) disorders were tested for their gastro-protective effect against the incidence of peptic ulcer. Indomethacin-induced ulcer in a rat model was used for this testing. Mentha microphylla, Brassica oleracea Capitata (Cabbage), B. oleracea Botrytis (cauliflower) aqueous fraction, Portolaca oleracea polysaccharide fraction, Oreganum marjoranum, Matricaria recutita, Solanum nigrum hydrophilic and lipophilic fractions, in addition to the chloroform fraction of Portolaca oleracea and Cicorium intybus afforded high protection against the incidence of gastric ulcer (~95%). O. syriacum hydrophilic and lipophilic fractions and gum arabic afforded moderate prophylactic effect. L. sicerarea, C. intybus hydrophilic fractions and M. microphylla lipophilic fraction were inactive. Herbs represent excellent resources for cost-effective and readily available gastro-protective remedies without side effects. PMID- 25276212 TI - An Analysis of Job Satisfaction among Iranian Pharmacists through Various Job Characteristics. AB - INTRODUCTION: Pharmacists and pharmaceutical services are among the most important resources and programs in providing health for a society. Pharmacists as the key players in presenting health services, greatly impact on the health of a society and if they suffer low job satisfaction, their dissatisfaction may relatively threaten health in a society. This study was conducted to determine Iranian pharmacists' job satisfaction and additionally, some causes of dissatisfaction among pharmacists have been diagnosed. METHOD: A job satisfaction questionnaire was developed and reliability tests were done by some experts in field of pharmacy practice. A sample of 700 pharmacists was selected among ten leading provinces of the country and questionnaires were distributed at the continuing pharmacy education conferences. Three essential factors named "Endogenous Satisfaction", "Exogenous Satisfaction" and "Current Sense of Being Pharmacists" was considered as the main job satisfaction factors. RESULTS AND DISCUSSION: Generally low scores of exogenous and endogenous job satisfaction were concluded among pharmacists while most of them were highly satisfied with being pharmacist. Male pharmacists were more satisfied than their female colleagues and a positive relationship between age and work experience with exogenous job satisfaction was found. CONCLUSION: Low levels of job satisfaction which were found among Iranian pharmacists could be considered as a deficiency of health system in Iran. Fortunately, inherent interest in the pharmacy profession found among Iranian pharmacists is an optimistic point at which policy-makers could develop their modifying policies. Health policy-makers must endeavor to take other steps to issue solutions for this current problem. PMID- 25276213 TI - The Biological Activity and Composition of the Essential Oil of Sclerorhachis leptoclada (Asteraceae-Anthemideae) from Iran. AB - The biological activity and composition of the essential oil of Sclerorhachis leptoclada Rech. f. an endemic species from northeast of Iran was studied. The essential oil was isolated from the aerial flowering parts of the plant and analyzed by GC and GC-MS. Fifty-four compounds accounting for 95.9% of the total oil were characterized. The main constituents were (E)-nerolidol (14.5%), terpinen-4-ol (13.3%), camphor (6.1%), 1,8-cineole (4.8%) and p-cymene (4.5%). The antimicrobial activity of the essential oil of S. leptoclada was tested against eight microbial strains and a fungi. The results of the bioassays showed that the Gram-positive bacteria, Bacillus subtilis and Staphylococcus epidermidis, were the most sensitive to the oil than others with the MIC value of 1.8 mg/mL. The tested fungi, Saccharomyces cerevisiae was highly inhibited by the oil of S. leptoclada with MIC value of 10 mg/mL. In the case of cytotoxicity, IC50 values estimated to be 312, 1250, 625 and 1250 MUg oil/mL respectively, for the Vero, SW480, MCF7, and JET 3 cancer cell lines. PMID- 25276214 TI - "Budget impact analyses": a practical policy making tool for drug reimbursement decisions. AB - In the present article, Budget Impact Analysis as an effective, practical financial tool has been introduced to the policy makers for improving drug formulary and reimbursement decision making. In Iran, Ministry of Health (MOH), health insurance organizations, and health care providers such as hospitals could take the most advantage of the BIAs reports. PMID- 25276215 TI - Optimization of Cat's Whiskers Tea (Orthosiphon stamineus) Using Supercritical Carbon Dioxide and Selective Chemotherapeutic Potential against Prostate Cancer Cells. AB - Cat's whiskers (Orthosiphon stamineus) leaves extracts were prepared using supercritical CO2 (SC-CO2) with full factorial design to determine the optimum extraction parameters. Nine extracts were obtained by varying pressure, temperature, and time. The extracts were analysed using FTIR, UV-Vis, and GC-MS. Cytotoxicity of the extracts was evaluated on human (colorectal, breast, and prostate) cancer and normal fibroblast cells. Moderate pressure (31.1 MPa) and temperature (60 degrees C) were recorded as optimum extraction conditions with high yield (1.74%) of the extract (B2) at 60 min extraction time. The optimized extract (B2) displayed selective cytotoxicity against prostate cancer (PC3) cells (IC50 28 ug/mL) and significant antioxidant activity (IC50 42.8 ug/mL). Elevated levels of caspases 3/7 and 9 in B2-treated PC3 cells suggest the induction of apoptosis through nuclear and mitochondrial pathways. Hoechst and rhodamine assays confirmed the nuclear condensation and disruption of mitochondrial membrane potential in the cells. B2 also demonstrated inhibitory effects on motility and colonies of PC3 cells at its subcytotoxic concentrations. It is noteworthy that B2 displayed negligible toxicity against the normal cells. Chemometric analysis revealed high content of essential oils, hydrocarbon, fatty acids, esters, and aromatic sesquiterpenes in B2. This study highlights the therapeutic potentials of SC-CO2 extract of cat's whiskers in targeting prostate carcinoma. PMID- 25276216 TI - In Vivo Antiprotozoal Activity of the Chloroform Extract from Carica papaya Seeds against Amastigote Stage of Trypanosoma cruzi during Indeterminate and Chronic Phase of Infection. AB - In order to evaluate the antiprotozoal activity of the chloroform extract of Carica papaya seeds during the subacute and chronic phase of infection of Trypanosoma cruzi, doses of 50 and 75 mg/kg were evaluated during the subacute phase, including a mixture of their main components (oleic, palmitic, and stearic acids). Subsequently, doses of 50 and 75 mg/kg in mice during the chronic phase of infection (100 dpi) were also evaluated. It was found that chloroform extract was able to reduce the amastigote nests numbers during the subacute phase in 55.5 and 69.7% (P > 0.05) as well as in 56.45% in animals treated with the mixture of fatty acids. Moreover, the experimental groups treated with 50 and 75 mg/kg during the chronic phase of the infection showed a significant reduction of 46.8 and 53.13% respectively (P < 0.05). It is recommended to carry out more studies to determine if higher doses of chloroformic extract or its administration in combination with other antichagasic drugs allows a better response over the intracellular stage of T. cruzi in infected animal models and determine if the chloroform extract of C. papaya could be considered as an alternative for treatment during the indeterminate and chronic phase of the infection. PMID- 25276217 TI - Effects of an aqueous extract of dangguijagyagsan on serum lipid levels and blood flow improvement in ovariectomized rats. AB - Dangguijagyagsan (DJS), a traditional herbal prescription, has long been used to treat menopause-related symptoms. We identified the cardioprotective effects of an aqueous extract of DJS using an ovariectomized (OVX) and ferric chloride- (FeCl-) induced carotid thrombosis rat model. Female Sprague-Dawley (SD) rats were ovariectomized or Sham-operated (Sham-control). The ovariectomized rats were divided into three groups: OVX with saline (OVX-control), aspirin 30 mg/kg/day (OVX-ASA), and DJS 100 mg/kg/day (OVX-DJS). The treatments were administered for 5 weeks. Then, blood samples were collected to analyze the serum lipid levels and platelet aggregation. The topical application of 40% FeCl3 induced intravascular thrombosis, which was used to test thrombotic occlusion and for histological examination. Body weight and the levels of total cholesterol (TC), triglyceride (TG), and LDL-cholesterol (LDL-C) increased in the OVX rats. These effects were reduced by ASA and DJS treatment. In addition, ASA and DJS treatment significantly inhibited platelet aggregation. These treatments also increased time to occlusion and decreased both thrombus size and the presence of collagen fibers in surrounding vessel walls compared with the Sham-control and OVX-control groups. These results suggest that DJS has beneficial effects in terms of preventing cardiovascular disease in menopausal woman because it can reduce the serum lipid levels and improve blood flow by inhibiting platelet aggregation and thrombus formation. PMID- 25276218 TI - The Rhizome Mixture of Anemarrhena asphodeloides and Coptidis chinensis Ameliorates Acute and Chronic Colitis in Mice by Inhibiting the Binding of Lipopolysaccharide to TLR4 and IRAK1 Phosphorylation. AB - In the previous study, the mixture of the rhizome of Anemarrhena asphodeloides (AA, family Liliaceae) and the rhizome of Coptidis chinensis (CC, family Ranunculaceae) (AC-mix) improved TNBS- or oxazolone-induced colitis in mice. Therefore, to investigate its anticolitic mechanism, we measured its effect in acute and chronic DSS-induced colitic mice and investigated its anti-inflammatory mechanism in peritoneal macrophages. AC-mix potently suppressed DSS-induced body weight loss, colon shortening, myeloperoxidase activity, and TNF-alpha, IL-1beta, and IL-6 expressions in acute or chronic DSS-stimulated colitic mice. Among AC mix ingredients, AA, CC, and their main constituents mangiferin and berberine potently inhibited the expression of proinflammatory cytokines TNF-alpha and IL 1beta, as well as the activation of NF-kappaB in LPS-stimulated peritoneal macrophages. AA and mangiferin potently inhibited IRAK phosphorylation, but CC and berberine potently inhibited the binding of LPS to TLR4 on macrophages, as well as the phosphorylation of IRAK1. AC-mix potently inhibited IRAK phosphorylation and LPS binding to TLR4 on macrophages. Based on these findings, AC-mix may ameliorate colitis by the synergistic inhibition of IRAK phosphorylation and LPS binding to TLR4 on macrophages. PMID- 25276219 TI - A multiatlas segmentation using graph cuts with applications to liver segmentation in CT scans. AB - An atlas-based segmentation approach is presented that combines low-level operations, an affine probabilistic atlas, and a multiatlas-based segmentation. The proposed combination provides highly accurate segmentation due to registrations and atlas selections based on the regions of interest (ROIs) and coarse segmentations. Our approach shares the following common elements between the probabilistic atlas and multiatlas segmentation: (a) the spatial normalisation and (b) the segmentation method, which is based on minimising a discrete energy function using graph cuts. The method is evaluated for the segmentation of the liver in computed tomography (CT) images. Low-level operations define a ROI around the liver from an abdominal CT. We generate a probabilistic atlas using an affine registration based on geometry moments from manually labelled data. Next, a coarse segmentation of the liver is obtained from the probabilistic atlas with low computational effort. Then, a multiatlas segmentation approach improves the accuracy of the segmentation. Both the atlas selections and the nonrigid registrations of the multiatlas approach use a binary mask defined by coarse segmentation. We experimentally demonstrate that this approach performs better than atlas selections and nonrigid registrations in the entire ROI. The segmentation results are comparable to those obtained by human experts and to other recently published results. PMID- 25276220 TI - A wavelet transform based method to determine depth of anesthesia to prevent awareness during general anesthesia. AB - Awareness during general anesthesia for its serious psychological effects on patients and some juristically problems for anesthetists has been an important challenge during past decades. Monitoring depth of anesthesia is a fundamental solution to this problem. The induction of anesthesia alters frequency and mean of amplitudes of the electroencephalogram (EEG), and its phase couplings. We analyzed EEG changes for phase coupling between delta and alpha subbands using a new algorithm for depth of general anesthesia measurement based on complex wavelet transform (CWT) in patients anesthetized by Propofol. Entropy and histogram of modulated signals were calculated by taking bispectral index (BIS) values as reference. Entropies corresponding to different BIS intervals using Mann-Whitney U test showed that they had different continuous distributions. The results demonstrated that there is a phase coupling between 3 and 4 Hz in delta and 8-9 Hz in alpha subbands and these changes are shown better at the channel T 7 of EEG. Moreover, when BIS values increase, the entropy value of modulated signal also increases and vice versa. In addition, measuring phase coupling between delta and alpha subbands of EEG signals through continuous CWT analysis reveals the depth of anesthesia level. As a result, awareness during anesthesia can be prevented. PMID- 25276221 TI - Validation in principal components analysis applied to EEG data. AB - The well-known multivariate technique Principal Components Analysis (PCA) is usually applied to a sample, and so component scores are subjected to sampling variability. However, few studies address their stability, an important topic when the sample size is small. This work presents three validation procedures applied to PCA, based on confidence regions generated by a variant of a nonparametric bootstrap called the partial bootstrap: (i) the assessment of PC scores variability by the spread and overlapping of "confidence regions" plotted around these scores; (ii) the use of the confidence regions centroids as a validation set; and (iii) the definition of the number of nontrivial axes to be retained for analysis. The methods were applied to EEG data collected during a postural control protocol with twenty-four volunteers. Two axes were retained for analysis, with 91.6% of explained variance. Results showed that the area of the confidence regions provided useful insights on the variability of scores and suggested that some subjects were not distinguishable from others, which was not evident from the principal planes. In addition, potential outliers, initially suggested by an analysis of the first principal plane, could not be confirmed by the confidence regions. PMID- 25276222 TI - Influence of different geometric representations of the volume conductor on nerve activation during electrical stimulation. AB - Volume conductor models with different geometric representations, such as the parallel layer model (PM), the cylindrical layer model (CM), or the anatomically based model (AM), have been employed during the implementation of bioelectrical models for electrical stimulation (FES). Evaluating their strengths and limitations to predict nerve activation is fundamental to achieve a good trade off between accuracy and computation time. However, there are no studies aimed at clarifying the following questions. (1) Does the nerve activation differ between CM and PM? (2) How well do CM and PM approximate an AM? (3) What is the effect of the presence of blood vessels and nerve trunk on nerve activation prediction? Therefore, in this study, we addressed these questions by comparing nerve activation between CM, PM, and AM models by FES. The activation threshold was used to evaluate the models under different configurations of superficial electrodes (size and distance), nerve depths, and stimulation sites. Additionally, the influences of the sciatic nerve, femoral artery, and femoral vein were inspected for a human thigh. The results showed that the CM and PM had a high error rate, but the variation of the activation threshold followed the same tendency for electrode size and interelectrode distance variation as AM. PMID- 25276223 TI - Modeling the relationship between fluorodeoxyglucose uptake and tumor radioresistance as a function of the tumor microenvironment. AB - High fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in tumors has often been correlated with increasing local failure and shorter overall survival, but the radiobiological mechanisms of this uptake are unclear. We explore the relationship between FDG-PET uptake and tumor radioresistance using a mechanistic model that considers cellular status as a function of microenvironmental conditions, including proliferating cells with access to oxygen and glucose, metabolically active cells with access to glucose but not oxygen, and severely hypoxic cells that are starving. However, it is unclear what the precise uptake levels of glucose should be for cells that receive oxygen and glucose versus cells that only receive glucose. Different potential FDG uptake profiles, as a function of the microenvironment, were simulated. Predicted tumor doses for 50% control (TD50) in 2 Gy fractions were estimated for each assumed uptake profile and for various possible cell mixtures. The results support the hypothesis of an increased avidity of FDG for cells in the intermediate stress state (those receiving glucose but not oxygen) compared to well-oxygenated (and proliferating) cells. PMID- 25276224 TI - An ensemble-of-classifiers based approach for early diagnosis of Alzheimer's disease: classification using structural features of brain images. AB - Structural brain imaging is playing a vital role in identification of changes that occur in brain associated with Alzheimer's disease. This paper proposes an automated image processing based approach for the identification of AD from MRI of the brain. The proposed approach is novel in a sense that it has higher specificity/accuracy values despite the use of smaller feature set as compared to existing approaches. Moreover, the proposed approach is capable of identifying AD patients in early stages. The dataset selected consists of 85 age and gender matched individuals from OASIS database. The features selected are volume of GM, WM, and CSF and size of hippocampus. Three different classification models (SVM, MLP, and J48) are used for identification of patients and controls. In addition, an ensemble of classifiers, based on majority voting, is adopted to overcome the error caused by an independent base classifier. Ten-fold cross validation strategy is applied for the evaluation of our scheme. Moreover, to evaluate the performance of proposed approach, individual features and combination of features are fed to individual classifiers and ensemble based classifier. Using size of left hippocampus as feature, the accuracy achieved with ensemble of classifiers is 93.75%, with 100% specificity and 87.5% sensitivity. PMID- 25276225 TI - Catastrophic hemorrhage of adrenal pheochromocytoma following thrombolysis for acute myocardial infarction: case report and literature review. AB - We describe here the case of a 62-year-old man with acute abdominal syndrome and severe hemorrhagic shock following successful thrombolysis for acute cardiac infarction. Emergency surgical exploration revealed extensive intraperitoneal and retroperitoneal hemorrhage resulting from the rupture of a large adrenal tumor. The diagnosis of pheochromocytoma was confirmed by histological findings. The patient died a few hours after surgery from multiorgan failure despite resuscitation attempts. This report discusses the diagnosis difficulties, treatment approach, and relevant literature. PMID- 25276226 TI - Forkhead box O1 and muscle RING finger 1 protein expression in atrophic and hypertrophic denervated mouse skeletal muscle. AB - BACKGROUND: Forkhead box O (FoxO) transcription factors and E3 ubiquitin ligases such as Muscle RING finger 1 (MuRF1) are believed to participate in the regulation of skeletal muscle mass. The function of FoxO transcription factors is regulated by post-translational modifications such as phosphorylation and acetylation. In the present study FoxO1 protein expression, phosphorylation and acetylation as well as MuRF1 protein expression, were examined in atrophic and hypertrophic denervated skeletal muscle. METHODS: Protein expression, phosphorylation and acetylation were studied semi-quantitatively using Western blots. Muscles studied were 6-days denervated mouse hind-limb muscles (anterior tibial as well as pooled gastrocnemius and soleus muscles, all atrophic), 6-days denervated mouse hemidiaphragm muscles (hypertrophic) and innervated control muscles. Total muscle homogenates were used as well as separated nuclear and cytosolic fractions of innervated and 6-days denervated anterior tibial and hemidiaphragm muscles. RESULTS: Expression of FoxO1 and MuRF1 proteins increased 0.3-3.7-fold in all 6-days denervated muscles studied, atrophic as well as hypertrophic. Phosphorylation of FoxO1 at S256 increased about 0.8-1-fold after denervation in pooled gastrocnemius and soleus muscles and in hemidiaphragm but not in unfractionated anterior tibial muscle. A small (0.2-fold) but statistically significant increase in FoxO1 phosphorylation was, however, observed in cytosolic fractions of denervated anterior tibial muscle. A statistically significant increase in FoxO1 acetylation (0.8-fold) was observed only in denervated anterior tibial muscle. Increases in total FoxO1 and in phosphorylated FoxO1 were only seen in cytosolic fractions of denervated atrophic anterior tibial muscle whereas in denervated hypertrophic hemidiaphragm both total FoxO1 and phosphorylated FoxO1 increased in cytosolic as well as in nuclear fractions. MuRF1 protein expression increased in cytosolic as well as in nuclear fractions of both denervated atrophic anterior tibial muscle and denervated hypertrophic hemidiaphragm muscle. CONCLUSIONS: Increased expression of FoxO1 and MuRF1 in denervated muscles (atrophic as well as hypertrophic) suggests that these proteins participate in the tissue remodelling occurring after denervation. The effect of denervation on the level of phosphorylated and acetylated FoxO1 differed in the muscles studied and may be related to differences in fiber type composition of the muscles. PMID- 25276227 TI - Partial and complete trisomy 14 mosaicism: clinical follow-up, cytogenetic and molecular analysis. AB - BACKGROUND: Trisomy 14 mosaicism is a rare chromosomal abnormality. It is associated with multiple congenital anomalies. We report a 15 year-old female with an unusual karyotype with three cell lines: 47,XX,+mar/47,XX,+14/46,XX. At six months old she had short stature, cleft palate, hyperpigmented linear spots in arms and legs and developmental delay. At present, she has mild facial dysmorphism and moderate mental retardation. METHODS: Cytogenetic analysis was performed in peripheral blood lymphocytes and in the light and dark skin following standard methods. DNAarray - Oligo 180 k was carried out using Agilent Technologies and FISH analysis was accomplished using DNA BACs probes to confirm the result obtained by DNAarray. Methylation-Specific PCR (MS-PCR) of the MEG3 promoter and microsatellite analysis were performed. RESULTS: Microarray analysis confirmed partial trisomy 14 mosaicism; the marker chromosome was found to be from chromosome 14, the result was confirmed with FISH. Methylation (14q32.3) and microsatellite (14q11-14q32.33) analysis were carried out and UPD was discarded. The global result was: mos 47,XX,+del(14)(q11.2)[45]/47,XX,+14[10]/46,XX[45]. CONCLUSIONS: This is a unique case because of the coexistence of two abnormal cell lines, including one with +14 and another with +del(14)(q11.2). To our knowledge, only three patients have been reported with trisomy 14 and another abnormal cell line. The array analysis identified the marker chromosome and characterized the breakpoint. The del(14)(q11.2) does not seem to be related to any particular phenotypic characteristic of the patient; the clinical features of our patient observed until now, can be attributed to trisomy 14 mosaicism. Nevertheless, we cannot discard the manifestation of new symptoms related to her karyotype in the future. PMID- 25276228 TI - Use of intravesical valrubicin in clinical practice for treatment of nonmuscle invasive bladder cancer, including carcinoma in situ of the bladder. AB - OBJECTIVES: The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of valrubicin. METHODS: Patients >= 18 years with NMIBC who received had one or more instillations of valrubicin (October 2009- September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed. RESULTS: The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed valrubicin treatment. The median age was 75 years (range 42-95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9-61.3%), 30.4% (20.4-41.1%), and 16.4% (7.9-27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5-4.0) months after the first valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued valrubicin because of adverse events or LARs. CONCLUSIONS: Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate valrubicin safety and efficacy in the broader patient population with NMIBC. PMID- 25276229 TI - Experience in the use of collagenase clostridium histolyticum in the management of Peyronie's disease: current data and future prospects. AB - INTRODUCTION: Peyronie's disease (PD) is a chronic wound-healing disorder characterized by formation of fibrous inelastic scarring of the tunica albuginea resulting in a variety of penile deformities. In most cases, PD is accompanied by a physical and psychological impact. Xiaflex(r) is an injectable collagenase clostridium histolyticum (CCh) preparation consisting of a predetermined mixture of two distinct collagenases. Recently the US Food and Drug Administration (FDA) approved Xiaflex(r) for the nonsurgical treatment of men with PD with curvature of 30 degrees or more and tangible scar tissue plaque in their penis. METHOD: This article presents a comprehensive review of the updated information on the use of Xiaflex(r) for the nonsurgical treatment of PD. RESULTS: Mean improvements in penile curvature ranging from 29% to 34% and in bother domain scores have been reported. The majority of the reported adverse effects are mild or moderate and 79% resolve without intervention. CONCLUSION: The combined results of these trials have led to the FDA approval of CCh for the treatment of PD. However, the long-term effects and results need further investigation, with large follow-up series. Considering these results, future perspectives will probably result in the use of a combined or sequential therapy including CCh. PMID- 25276230 TI - Chronic lymphocytic leukemia of the bladder: an atypical etiology of gross hematuria. AB - Chronic lymphocytic leukemia (CLL) is a rare hematologic disorder with affected patients having complications of frequent infections and possible transformation to a more aggressive malignancy. The occurrence of CLL in the bladder is a rare event, with few reported cases. As a result, its aggressiveness and the optimal course for treatment are unknown. Despite this, its presence in the bladder warrants continued surveillance, as recurrence and progression to other bladder malignancies are possible. We present a 71-year-old woman initially diagnosed with CLL who was plagued by recurrent hematuria and dysuria for over a decade, which lead to multiple negative urologic workups. However, these continued workups eventually lead to her diagnosis of bladder CLL with a subsequent finding of carcinoma in situ that was prompted by a suspicious surveillance cystoscopy performed 4 months after her initial bladder diagnosis. Hence, infiltration of CLL in the urinary bladder merits close follow up, including additional urologic procedures. PMID- 25276231 TI - G9a co-suppresses LINE1 elements in spermatogonia. AB - BACKGROUND: Repression of retrotransposons is essential for genome integrity and the development of germ cells. Among retrotransposons, the establishment of CpG DNA methylation and epigenetic silencing of LINE1 (L1) elements and the intracisternal A particle (IAP) endogenous retrovirus (ERV) is dependent upon the piRNA pathway during embryonic germ cell reprogramming. Furthermore, the Piwi protein Mili, guided by piRNAs, cleaves expressed L1 transcripts to post transcriptionally enforce L1 silencing in meiotic cells. The loss of both DNA methylation and the Mili piRNA pathway does not affect L1 silencing in the mitotic spermatogonia where histone H3 lysine 9 dimethylation (H3K9me2) is postulated to co-repress these elements. RESULTS: Here we show that the histone H3 lysine 9 dimethyltransferase G9a co-suppresses L1 elements in spermatogonia. In the absence of both a functional piRNA pathway and L1 DNA methylation, G9a is both essential and sufficient to silence L1 elements. In contrast, H3K9me2 alone is insufficient to maintain IAP silencing in spermatogonia. The loss of all three repressive mechanisms has a major impact on spermatogonial populations inclusive of spermatogonial stem cells, with the loss of all germ cells observed in a high portion of seminiferous tubules. CONCLUSIONS: Our study identifies G9a-mediated H3K9me2 as a novel and important L1 repressive mechanism in the germ line. We also demonstrate fundamental differences in the requirements for the maintenance of L1 and IAP silencing during adult spermatogenesis, where H3K9me2 is sufficient to maintain L1 but not IAP silencing. Finally, we demonstrate that repression of retrotransposon activation in spermatogonia is important for the survival of this population and testicular homeostasis. PMID- 25276233 TI - When noise makes music: HIV reactivation with transcriptional noise enhancers. AB - Reactivating latent HIV is key to depleting the virus reservoir in AIDS patients. A recent paper has described the rationale for and discovery of a new class of drugs - transcriptional noise enhancers - that can synergize with conventional transcription activators to more effectively reactivate latently infected T cells. As well as describing a promising new strategy in the bid to find a cure for AIDS, this study more broadly highlights the utility of exploring drug combinations in treatment of human disease. PMID- 25276232 TI - Molecularly and clinically related drugs and diseases are enriched in phenotypically similar drug-disease pairs. AB - BACKGROUND: The incomplete understanding of disease causes and drug mechanisms of action often leads to ineffective drug therapies or side effects. Therefore, new approaches are needed to improve treatment decisions and to elucidate molecular mechanisms underlying pathologies and unwanted drug effects. METHODS: We present here the first analysis of phenotypically related drug-disease pairs. The phenotypic similarity between 4,869 human diseases and 1,667 drugs was evaluated using an ontology-based semantic similarity approach to compare disease symptoms with drug side effects. We assessed and visualized the enrichment over random of clinical and molecular relationships among drug-disease pairs that share phenotypes using lift plots. To determine the associations between drug and disease classes enriched among phenotypically related pairs we employed a network based approach combined with Fisher's exact test. RESULTS: We observed that molecularly and clinically related (for example, indication or contraindication) drugs and diseases are likely to share phenotypes. An analysis of the relations between drug mechanisms of action (MoAs) and disease classes among highly similar pairs revealed known and suspected MoA-disease relationships. Interestingly, we found that contraindications associated with high phenotypic similarity often involve diseases that have been reported as side effects of the drug, probably due to common mechanisms. Based on this, we propose a list of 752 precautions or potential contraindications for 486 drugs. CONCLUSIONS: Phenotypic similarity between drugs and diseases facilitates the proposal of contraindications and the mechanistic understanding of diseases and drug side effects. PMID- 25276235 TI - Thoracic ultrasound: Picture worth a thousand sounds. PMID- 25276234 TI - Association of adipokines, leptin/adiponectin ratio and C-reactive protein with obesity and type 2 diabetes mellitus. AB - OBJECTIVE: Alterations in plasma adipokines and/or inflammatory parameters in Type 2 DM remain vague as to whether they are due to obesity and/or directly associated with the diabetic state. Our objective was to compare plasma adiponectin, leptin, leptin/adiponectin ratio (LAR) and hs-CRP in obese non diabetic subjects and non-obese Type 2 DM patients, as well as determining the association of these adipokines with MetS and diabetes-related quantitative traits. METHODS: In this study, 92 Yemeni male volunteers aged 25-60 years old were enrolled, 31 of whom were healthy subjects with BMI < 25 kg/m(2) served as control; 30 non-diabetic obese subjects BMI >= 30 kg/m(2) and FBG < 6.1 mmol/l; and 31 non-obese Type 2 DM with FBG > 7 mmol/l and BMI < 25 kg/m(2). RESULTS: Adiponectin was lower in obese subjects, with no differences between non-obese Type 2 DM patients and controls. In contrast, leptin, LAR and hs-CRP were higher in both obese subjects and non-obese Type 2 DM patients. Linear regression analysis showed adiponectin to be associated negatively with BMI, waist circumference, insulin, HOMA-beta and HOMA-IR; whereas leptin, LAR and hs-CRP were associated positively with BMI, waist circumference, TG, FBG, insulin, HOMA beta and HOMA-IR. Moreover, adiponectin negatively correlated with leptin, LAR and hs-CRP; whereas leptin and LAR positively correlated with hs-CRP and with each other. CONCLUSION: Plasma adiponectin is not affected by diabetes per se, suggesting that its alterations in Type 2 DM may be due to obesity and may be an important link between adiposity, IR and Type 2 DM. PMID- 25276236 TI - Corticosteroids in the treatment of acute asthma. AB - Asthma is a prevalent chronic disease of the respiratory system and acute asthma exacerbations are among the most common causes of presentation to the emergency department (ED) and admission to hospital particularly in children. Bronchial airways inflammation is the most prominent pathological feature of asthma. Inhaled corticosteroids (ICS), through their anti-inflammatory effects have been the mainstay of treatment of asthma for many years. Systemic and ICS are also used in the treatment of acute asthma exacerbations. Several international asthma management guidelines recommend the use of systemic corticosteroids in the management of moderate to severe acute asthma early upon presentation to the ED. On the other hand, ICS use in the management acute asthma has been studied in different contexts with encouraging results in some and negative in others. This review sheds some light on the role of systemic and ICS in the management of acute asthma and discusses the current evidence behind their different ways of application particularly in relation to new developments in the field. PMID- 25276237 TI - Pictorial review of intrathoracic manifestations of progressive systemic sclerosis. AB - Intra-thoracic manifestations of progressive systemic sclerosis (PSS) are not well known particularly the imaging features, which forms the basis of accurate and timely diagnosis. The aim of this study is to familiarize the physicians and radiologists with these features. The diagnosis can remain elusive because of the non-specific nature of symptoms which mimic many common conditions. Thus, the diagnosis of PSS can be missed leading to continuous morbidity if the correct imaging is not pursued. The authors examined the records of rheumatology patient referrals of over a 5 year period. A hundred and seventy patients with systemic sclerosis and mixed connective tissue disorders were chosen for detailed study of the imaging available, which form the basis of this review. The images included conventional chest radiographs, digital radiographs computed radiography (CT) and high resolution computed tomography (HRCT). Where applicable computed pulmonary angiography (CTPA) and radionuclide scans were also interrogated. PMID- 25276238 TI - Pressure-controlled versus volume-controlled ventilation during one-lung ventilation in elderly patients with poor pulmonary function. AB - OBJECTIVE: THE AIM WAS TO INVESTIGATE THE EFFECTS OF TWO DIFFERENT VENTILATORY STRATEGIES: Pressure-controlled ventilation (PCV) versus volume-controlled ventilation (VCV) in elderly patients with poor pulmonary function during one lung ventilation (OLV). PATIENTS AND METHODS: The patients were enrolled into the study having poor pulmonary function (forced expiratory volume in 1 s <1.5 L) and undergoing radical resection of pulmonary carcinoma requiring at least 2 h of OLV. Patients were respectively allocated to VCV group and PCV group. The intraoperative data, arterial, and mixed venous blood gases were obtained at baseline, 20, 40, 60, 80, 100 and 120 min after OLV and end of surgery. The postoperative data had been recorded and arterial gas measurements were performed at 6, 12 and 24 h after surgery in Intensive Care Unit. RESULTS: Comparison of the VCV group and PCV group, PaO2 and P(A-a)O2 were higher and dead space to tidal volume was lower in the PCV group (P < 0.05) after the point of OLV +60, Ppeak was higher in the VCV group (P < 0.05). There were significant advantages in PCV groups with regard to the PaO2 of three points in postoperation, the duration of postoperative ventilation duration, intensive care duration of stay and the days stay in hospital after surgery. CONCLUSIONS: The use of PCV compared with VCV during OLV in elderly patients with poor pulmonary function has significant advantages of intraoperative and postoperative oxygenation and it might be a factor, which can beneficial to postoperative recovery. PMID- 25276239 TI - Pulmonary arterial hypertension in Saudi Arabia: Patients' clinical and physiological characteristics and hemodynamic parameters. A single center experience. AB - AIMS: The main objective of this study is to describe patients' clinical characteristics and physiological and hemodynamic parameters at the time of diagnosis in a pulmonary hypertension center in Saudi Arabia. MATERIALS AND METHODS: This study reports the results from a single pulmonary hypertension specialized center in Riyadh, Saudi Arabia, namely Prince Sultan Medical Military City/Cardiac Center (PSMMC & CC). Both newly diagnosed (incidence) and referred (prevalence) cases of pulmonary arterial hypertension are included. All characteristics, including clinical, physiological, and hemodynamic parameters at the time of diagnosis are described. RESULTS: A total of 107 patients were identified as having pulmonary arterial hypertension as diagnosed by right heart catheterization. The mean age at diagnosis was 36 (+/- 9) years, and there was a female preponderance of 62.6%. The mean duration between symptom onset and diagnosis was 27.8 (+/- 9.0) months. At the time of enrollment, 56.1% of patients were in functional class III and 16.8% were in functional class IV. Fifty five patients (51.4%) were diagnosed as idiopathic pulmonary arterial hypertension, 29 patients (27.1%) as congenital heart disease associated with pulmonary arterial hypertension, 16 patients (15.0%) as connective tissue diseases associated with pulmonary arterial hypertension, 4 patients (3.7%) as heritable pulmonary arterial hypertension, and 3 patients (2.8%) as portopulmonary hypertension. CONCLUSION: This data highlights the current situation of pulmonary arterial hypertension in Saudi Arabia. Our patients are much younger than patients described in other international registries but still detected as late in the course of the disease. A majority of patients displays severe functional and hemodynamic compromise. PMID- 25276240 TI - Allergic bronchopulmonary aspergillosis: A clinical review of 24 patients: Are we right in frequent serologic monitoring? AB - BACKGROUND: Allergic Broncho Pulmonary Aspergillosis (ABPA) is a rare disease characterized by an allergic inflammatory response to the colonization by aspergillus or other fungi in the airways. The aim was to study the clinical, radiological, and serological characteristics of patients of ABPA. MATERIALS AND METHODS: A prospective observational study of patients with breathlessness, chronic cough, blood eosinophilia, and infiltrates on chest X-ray were evaluated with serologic and allergic skin fungal tests using 15 common fungal antigens. Total of 24 patients were diagnosed as ABPA. RESULTS: Total 24 patients, 15 males (62%), 9 females (38%). Age range: 14-70 years, mean 49.13, standard deviation (SD) 14.12. Central bronchiectasis - sixteen patients, bronchocoele - one patient, consolidation - five patients, collapse with mucous plugging with areas of consolidation - three patients, one patient had bronchiectasis, consolidation with hemorrhagic pleural effusion. Fifty-eight percent of patients had received anti-tuberculosis medications prior to diagnosis. Serum total IgE varied from 340 to 18100 IU/mL. Two patients had IgE levels below 1,000 IU/mL. The mean decrease in Serum total IgE levels at the end of 1 month was 26.1% (range: 0.7-71.9%) and at the end of 2 months was 58.9% (range: 11.11-93.26%) (P value of 0.004). Two patients had skin sensitivity to fungal antigens other than aspergillus species. CONCLUSION: ABPA is a disease with varied clinical, radiological, and serological patterns. Serum IgE monitoring may be done at the end of 2 and 6 months. Further studies are required to simplify the diagnosis and treatment algorithms in resource-limited countries. PMID- 25276241 TI - Association of compliance of ventilator bundle with incidence of ventilator associated pneumonia and ventilator utilization among critical patients over 4 years. AB - BACKGROUND: Several studies showed that the implementation of the Institute for Healthcare Improvement (IHI) ventilator bundle alone or with other preventive measures are associated with reducing Ventilator-Associated Pneumonia (VAP) rates. However, the association with ventilator utilization was rarely examined and the findings were conflicting. The objectives were to validate the bundle association with VAP rate in a traditionally high VAP environment and to examine its association with ventilator utilization. MATERIALS AND METHODS: The study was conducted at the adult medical-surgical intensive care unit (ICU) at King Abdulaziz Medical City, Saudi Arabia, between 2010 and 2013. VAP data were collected by a prospective targeted surveillance as per Centers for Disease Control and Prevention (CDC)/National Healthcare Safety Network (NHSN) methodology while bundle data were collected by a cross-sectional design as per IHI methodology. RESULTS: Ventilator bundle compliance significantly increased from 90% in 2010 to 97% in 2013 (P for trend < 0.001). On the other hand, VAP rate decreased from 3.6 (per 1000 ventilator days) in 2010 to 1.0 in 2013 (P for trend = 0.054) and ventilator utilization ratio decreased from 0.73 in 2010 to 0.59 in 2013 (P for trend < 0.001). There were negative significant correlations between the trends of ventilator bundle compliance and VAP rate (cross correlation coefficients -0.63 to 0.07) and ventilator utilization (cross correlation coefficients -0.18 to -0.63). CONCLUSION: More than 70% improvement of VAP rates and approximately 20% improvement of ventilator utilization were observed during IHI ventilator bundle implementation among adult critical patients in a tertiary care center in Saudi Arabia. Replicating the current finding in multicenter randomized trials is required before establishing any causal link. PMID- 25276242 TI - 18F-FDG PET/CT rarely provides additional information other than primary tumor detection in patients with pulmonary carcinoid tumors. AB - AIM: The purpose of this study was to assess the contribution of (18)F fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT) in detection and staging of pulmonary carcinoid tumors. METHODS: A total of 22 patients with pulmonary carcinoid tumors (14 typical, 8 atypical) were reviewed in this retrospective study. PET/CT images of all patients were evaluated for primary tumor as well as metastatic regional lymph nodes, bone and other distant metastases. PET/CT positivity of primary tumors was determined by visual interpretation. Tumor size, SUVmax and Hounsfield Unit (HU) values of the tumors were used to test for differences between tumor groups (typical carcinoids and atypical carcinoids). RESULTS: SUVmax of carcinoids ranged from 1.24 to 11.1 (mean, 5.0; median, 2.67). The mean largest diameter of primary tumors was 2.7 +/ 1.3 cm, ranging from 1 to 5.5 cm. The overall sensitivity of FDG PET/CT for detection of pulmonary carcinoid tumors was 81.8%. Tumor size, SUVmax and Hounsfield Unit (HU) values of the atypical carcinoids were higher than those for typical carcinoids. However, the results were not statistically meaningful (P > 0.05). The sensitivity and specificity of FDG PET/CT in the detection of mediastinal and hilar lymph nodes metastases were 25% and 83% respectively. One patient had bone metastasis. CONCLUSION: Although FDG PET/CT can be a useful tool for the detection of pulmonary carcinoid tumors and distant metastasis, it cannot discriminate typical carcinoids from atypical ones and absence of an FDG avid lesion cannot exclude pulmonary carcinoid tumors. Moreover, PET/CT is not a reliable tool in the staging of mediastinal and hilar lymph nodes especially for those patients with typical carcinoids. PMID- 25276243 TI - Value of neutrophil/lymphocyte ratio in the differential diagnosis of sarcoidosis and tuberculosis. AB - INTRODUCTION: The differential diagnosis of sarcoidosis creates a challange due to tuberculosis also having lung and lymph node involvement. Because both diseases show granulomatous inflammation, it may not be possible to distinguish tuberculosis and sarcoidosis in pathological specimens. As a result of the complexity in the differential diagnosis of sarcoidosis and tuberculosis, new markers for differentiation are being investigated. OBJECTIVE: The aim of our study is to investigate the value of neutrophil/lymphocyte ratio (NLR) as a possible marker in differentiating sarcoidosis and tuberculosis. MATERIALS AND METHODS: In our study, 51 acid-fast bacilli (AFB) positive and/or culture positive patients with pulmonary tuberculosis, 40 patients with biopsy-proven sarcoidosis and a control group consisting of 43 patients were included. In our study, information was collected retrospectively based on hospital records. RESULTS: Leukocyte and neutrophil counts, NLR, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) were significantly higher, and albumin was significantly lower in the tuberculosis group compared with sarcoidosis (for all parameters P < 0.001). The most appropriate cut-off value of NLR to distinguish tuberculosis from sarcoidosis was determined as 2.55. For this cut-off value of NLR there was 79% sensitivity, 69% specificity, 73% positive predictive value (PPV), 75% negative predictive value (NPV), and area under the curve (AUC) was 0.788. For differentiation of sarcoidosis from tuberculosis, accuracy of the NLR test according to this cut-off value was found as 76%. CONCLUSION: NLR as a little known marker in respiratory medicine was found to be supportive in differentiation of tuberculosis and sarcoidosis. More studies on this issue is needed. PMID- 25276244 TI - Prevalence of sleep-related accidents among drivers in Saudi Arabia. AB - INTRODUCTION: The prevalence of sleepy driving and sleep-related accidents (SRA) varies widely, and no data exist regarding the prevalence of sleepy driving in Saudi Arabia. Therefore, this study was designed to determine the prevalence and predictors of sleepy driving, near-misses, and SRA among drivers in Saudi Arabia. MATERIALS AND METHODS: A questionnaire was developed to assess sleep and driving in detail based on previously published data regarding sleepy driving. The questionnaire included 50 questions addressing socio-demographics, the Epworth Sleepiness Scale (ESS), driving items, and the Berlin Questionnaire. In total, 1,219 male drivers in public places were interviewed face-to-face. RESULTS: The included drivers had a mean age of 32.4 +/- 11.7 years and displayed a mean ESS score of 7.2 +/- 3.8. Among these drivers, 33.1% reported at least one near-miss accident caused by sleepiness. Among those who had actual accidents, 11.6% were attributed to sleepiness. In the past six months, drivers reported the following: 25.2% reported falling asleep at least once during, driving and 20.8% had to stop driving at least once because of severe sleepiness. Young age, feeling very sleepy during driving, and having at least one near-miss accident caused by sleepiness in the past six months were the only predictors of accidents. CONCLUSION: Sleepy driving is prevalent among male drivers in Saudi Arabia. Near miss accidents caused by sleepiness are an important risk factor for car accidents and should be considered as a strong warning signal of future accidents. PMID- 25276245 TI - Hemoptysis due to pulmonary pseudosequestration secondary to gastro-pulmonary fistula after a revisional bariatric operation. AB - We report the case of a patient with a history of a complicated revisional bariatric operation who developed a lung pseudosequestration secondary to a gastro-pulmonary fistula. As the patient presented with recurrent hemoptysis, she was initially submitted to embolization of the aberrant vessels and later to a definite operation, which consisted on a diversion of the gastric fistula into a Roux-en-Y intestinal loop. It is an exceptional case about late complications of bariatric surgery, and it underlines the importance of discarding these complications even when the clinical manifestations affect another anatomic region different from the operated abdomen. PMID- 25276246 TI - Recurrent intrathoracic solitary fibrous tumor: Remarkable response to radiotherapy. AB - Solitary Fibrous Tumor of the Pleura (SFTP) is an uncommon neoplasm which grows slowly. For some cases, surgery is warranted. However, for unresectable ones, the standard strategy has not been established yet. We presented a rare case of recurrent malignant intrathoracic solitary fibrous tumor. It was impossible to resect the tumor. Radiotherapy alone achieved a significant improvement effect. PMID- 25276247 TI - High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq. AB - BACKGROUND: Extensive reprogramming and dysregulation of DNA methylation is an important characteristic of pancreatic cancer (PC). Our study aimed to characterize the genomic methylation patterns in various genomic contexts of PC. The methyl capture sequencing (methylCap-seq) method was used to map differently methylated regions (DMRs) in pooled samples from ten PC tissues and ten adjacent non-tumor (PN) tissues. A selection of DMRs was validated in an independent set of PC and PN samples using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), and methylation sensitive restriction enzyme-based qPCR (MSRE-qPCR). The mRNA and expressed sequence tag (EST) expression of the corresponding genes was investigated using RT-qPCR. RESULTS: A total of 1,131 PC-specific and 727 PN specific hypermethylated DMRs were identified in association with CpG islands (CGIs), including gene-associated CGIs and orphan CGIs; 2,955 PC-specific and 2,386 PN-specific hypermethylated DMRs were associated with gene promoters, including promoters containing or lacking CGIs. Moreover, 1,744 PC-specific and 1,488 PN-specific hypermethylated DMRs were found to be associated with CGIs or CGI shores. These results suggested that aberrant hypermethylation in PC typically occurs in regions surrounding the transcription start site (TSS). The BSP, MSP, MSRE-qPCR, and RT-qPCR data indicated that the aberrant DNA methylation in PC tissue and in PC cell lines was associated with gene (or corresponding EST) expression. CONCLUSIONS: Our study characterized the genome-wide DNA methylation patterns in PC and identified DMRs that were distributed among various genomic contexts that might influence the expression of corresponding genes or transcripts to promote PC. These DMRs might serve as diagnostic biomarkers or therapeutic targets for PC. PMID- 25276248 TI - Working Group Guidelines on the nursing roles in caring for patients with Crohn's disease and ulcerative colitis in Poland. AB - Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, present a major challenge for present-day gastroenterology due to their increasing incidence, chronic nature, risk of permanent worsening of quality of life of patients, and the costs of conservative and invasive treatment. Basic and advanced nursing care are important parts of the multidisciplinary care for patients. The developed guidelines on the nursing care, which are compliant with the European guidelines published by Nurses-European Crohn's & Colitis Organisation (N-ECCO), were adjusted to the current situation in Poland. Significant issues that are important for nursing teams have been identified, with particular emphasis on the specificity of working in centres specialising in the care of IBD patients. The Working Group paid attention to the conditions that should be satisfied in order to optimise the nursing care for IBD patients, and the necessity to develop professional and scientific cooperation with European centres within European Crohn's & Colitis Organisation (ECCO) and N-ECCO. PMID- 25276249 TI - Functional constipation in children - evaluation and management. AB - Almost 1/3 of gastrointestinal consultations are related to constipation, and over 90% of them are of functional origin. Proper diagnosis and adequate treatment (both nonpharmacological and pharmacological) may limit the number of specialist visits and can be beneficial for therapeutic effects. The treatment is long lasting and requires unique discipline of parents/guardians and coordination supervised by the referring doctor. This paper presents the most important aspects of diagnostic and therapeutic processes regarding functional constipation in neonates and toddlers. PMID- 25276250 TI - Mutations in the filaggrin gene and food allergy. AB - The results of long-term epidemiological studies show that the number of people suffering from allergic diseases, especially from food allergies and atopic dermatitis (AD), is still increasing. Although the research thus far has been conducted mainly in Europe, North America, and Asia, there are also data appearing from the first studies in that field among the African population. This may indicate the importance of the problem of allergic diseases. The discovery that loss-of-function mutations in the gene coding filaggrin (FLG) are the cause of ichthyosis vulgaris marked a significant breakthrough in understanding the pathogenesis of allergic diseases. The presence of mutations in the filaggrin gene is also an important factor that predisposes to such allergic diseases as: allergic rhinitis, atopic dermatitis, atopic asthma, and food allergy. So far, over 40 loss-of-function mutations and numerous silent mutations in filaggrin have been discovered. PMID- 25276252 TI - Effect of TRAIL in combination with DDP on the expression of MDR1 gene in gastric cancer cells. AB - INTRODUCTION: Gastric cancer is one of the most common malignant tumor, and gastric cancer is the second most common cause of cancer mortality worldwide. Although chemotherapy is one of the most important treatment options for gastric cancer, and could improve the overall survival rate and quality of live, one significant reason for its failure is multidrug resistance (MDR). AIM: To study the effect of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with chemotherapeutic drug cisplatin (DDP) on the expression of multidrug resistance gene 1 (MDR1) in the gastric cancer cell line SGC-7901/VCR. MATERIAL AND METHODS: SGC-7901/VCR cells were cultured with DDP and TRAIL in various concentrations. The apoptosis rate was separately measured by a flow cytometer in DDP (sub-toxic dose) alone, TRAIL (200 ug/l) alone and in a combination of the two. Expression levels of MDR1 mRNA and P-glycoprotein (P-gp) were detected by RT-PCR and ELISA analysis, respectively. RESULTS: The apoptosis rate in the combination group was significantly higher than that in the other groups (p < 0.05). According to the results of RT-PCR and ELISA, the expressions of MDR1 mRNA and P-gp in the combination group were statistically significant different compared with other groups (p < 0.05). CONCLUSIONS: The combination of TRAIL with DDP could reverse MDR phenotype in gastric cancer cell line SGC7901/VCR. The mechanism may be involved in the down-regulation of MDR1 mRNA and P-gp, which may play an essential role in overcoming the chemotherapeutic resistance of gastric cancer cells. This study indicates that a combination of chemotherapy and TRAIL may be an effective strategy to treat MDR gastric cancer. PMID- 25276251 TI - The role of hepcidin, ferroportin, HCP1, and DMT1 protein in iron absorption in the human digestive tract. AB - Iron is found in almost all foods, so dietary iron intake is related to energy intake. However, its availability for absorption is quite variable, and poor bioavailability is a major reason for the high prevalence of nutritional iron deficiency anaemia. Absorption occurs primarily in the proximal small intestine through mature enterocytes located at the tips of the duodenal villi. Two transporters: Hem Carrier Protein 1 (HCP1) and Divalent Metal Transporter 1 (DMT1) appear to mediate the entry of most if not all dietary iron into these mucosal cells. Absorption is regulated according to the body's needs. The results of studies suggest that iron absorption is regulated by the control of iron export from duodenal enterocytes to the circulating transferrin pool by ferroportin. Hepcidin, a 25-amino acid polypeptide, which is synthesised primarily in hepatocytes, reduces the iron absorption from the intestine by binding to the only known cellular iron exporter, ferroportin, causing it to be degraded. Therefore, hepcidin is now considered to be the most important factor controlling iron absorption. PMID- 25276253 TI - Quality of life in patients with ulcerative colitis treated surgically. AB - INTRODUCTION: Ulcerative colitis belongs to the group of inflammatory bowel diseases. The specific symptoms and chronic nature of the disease significantly affect the quality of patients' lives. Quality-of-life assessment helps to define its determining factors as well as the efficiency of surgical procedures. AIM: Quality-of-life evaluation of patients with ulcerative colitis treated surgically. MATERIAL AND METHODS: A retrospective review was carried out on 35 patients with ulcerative colitis, who were treated surgically in the Clinic of General and Colorectal Surgery, University of Medical Sciences in Poznan. The research tools used to assess the quality of life consisted of: the Inflammatory Bowel Disease Questionnaire, a Polish version of the Short Form Health Survey-36, and a questionnaire. RESULTS: The mean of the IBDQ scale was 152.51, and the median was 161. In this scale, a higher score indicates better quality of life. The situation in the subjective SF-36 scale is reversed: a lower score indicates better quality of life. The mean of the SF-36 was 115.94, and the median was 58. Many discrepancies in the field (e.g. the influence of determining factors) create a niche for further studies. CONCLUSIONS: Moreover, quality-of-life evaluation may lead to better patient care, understanding their problems or treatment modifications, and finally may become a kind of therapy efficiency parameter. PMID- 25276254 TI - Safety of endoscopic retrograde cholangiopancreatography in patients 80 years of age and older. AB - INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) is used in the diagnosis and therapy of biliary tract diseases. The ERCP is an invasive procedure that does not increase complications in the elderly. Few studies have assessed the safety of ERCP in the elderly. Life expectancy is rising, which causes an increasing demand for ERCP in the elderly. AIM: To show that therapeutic ERCP is safe and we compared the level of complications among the elderly (> 80 years of age) and the level among a younger group (< 65 years of age). MATERIAL AND METHODS: The study was designed retrospectively. The details of all patients 80 years of age and older undergoing ERCP were analysed. One hundred and fifty patients were included in each of the groups: > 80 years of age, older group A; and < 65 years of age, younger group B. RESULTS: In group A, 4 cases (2.7%) of bleeding (all mild) was observed, and perforation was not observed. The ERCP-related mild pancreatitis was observed in 7 patients (4.6%). There were no cases of mortality during procedures of ERCP in group A. In group B 6 bleeding cases (4%) (all mild) were observed. Perforation was not observed in group B. ERCP-related mild pancreatitis occurred in 11 patients (7.3%). There were no cases of mortality during procedures of ERCP in group B. Our study showed that ERCP is a safe and effective procedure in elderly patients. CONCLUSIONS: Outcomes of ERCP for diagnostic and therapeutic success, and complication rates, are similar to those in younger patients. The ERCP is effective and safe in the elderly. PMID- 25276255 TI - Serum anti-glycan antibodies in paediatric-onset Crohn's disease: association with disease phenotype and diagnostic accuracy. AB - INTRODUCTION: Antibodies reacting with various microbial epitopes have been described in inflammatory bowel disease (IBD) and are associated with a specific diagnosis and clinical presentation. AIM: To evaluate the profile of new anti glycan antibodies, their potential association with disease phenotype and diagnostic accuracy in paediatric Crohn's disease (CD). MATERIAL AND METHODS: Blood samples from 134 paediatric IBD patients (109 CD, 25 ulcerative colitis (UC)) and 67 controls were blindly analysed for anti-Saccharomyces cerevisiae (ASCA), anti-chitobioside carbohydrate (ACCA), anti-laminaribioside carbohydrate (ALCA), and anti-mannobioside carbohydrate (AMCA) antibodies using commercially available assays. The serological response to glycans was correlated with clinical disease characteristics. RESULTS: At least one of the tested anti-glycan antibodies was present in 75% of CD patients. Despite the high frequency of reactivity to glycan epitopes, a limited overlap of serological markers was observed. In total, 49% of ASCA-negative patients presented with one of the following: ACCA, ALCA, or AMCA. The occurrence of one antibody from the anti glycan panel was independently associated with complicated disease phenotype and ileocolonic disease location. A higher level of immune response as assessed by the quartile sum scores for ACCA, ALCA, and AMCA was linked with older age at diagnosis (10-17 years) and ileocolonic disease location. The ASCA had the greatest accuracy for diagnosis and differentiation of CD. CONCLUSIONS: Qualitative and quantitative serologicalal response to glycan epitopes was associated with distinct clinical presentation in paediatric CD patients. This raises the possibility for the use of these markers to differentiate subgroups of CD patients with more sever clinical presentation. The ASCA was the most accurate serological marker for CD; however, testing for the new anti-glycan antibodies may constitute an adjunctive tool in a specific group of patients to aid in the differentiation of CD with absent ASCA from ulcerative colitis. PMID- 25276256 TI - The impact of type D personality on health-related quality of life in patients with symptomatic haemorrhoids. AB - INTRODUCTION: Haemorrhoids are one of the most common reasons that patients seek consultation from a colon and rectal surgeon. Health-related quality of life (HrQoL) is a significant factor in describing the burden of illness and the impact of treatment in patients with gastrointestinal disease. Type D (distressed) personality is defined as the co-occurrence of negative affect and social inhibition. AIM: To assess the prevalence of type D personality in patients with haemorrhoids and to investigate whether the presence of a type D personality would affect HrQoL in patients with haemorrhoids. MATERIAL AND METHODS: One hundred and six outpatients with symptomatic haemorrhoids with no psychiatric comorbidity were consecutively enrolled, along with 96 healthy controls. The Type D Scale (DS14) and the General Health Survey Short Form-36 (SF 36) were used in the collection of data. RESULTS: Of 106 patients evaluated, 29.2% met criteria for type D personality. Patients with haemorrhoids scored lower on bodily pain and vitality dimensions of SF-36 than did healthy subjects (p < 0.001). Patients with a type D personality were found to score lower on bodily pain domain of HrQoL than patients without a type D personality. Linear regression analysis revealed a significant independent association of type D personality with bodily pain dimension of the SF-36 in patients with symptomatic haemorrhoids (r = -0.315, p < 0.01). CONCLUSIONS: Type D personality was associated with increased perceived bodily pain in patients with haemorrhoids. Consideration of type D personality construct personality traits could improve risk stratification in research and clinical practice in this patient group. PMID- 25276258 TI - Foreign body in a Zenker's diverticulum (looking for the lost dentures). AB - Zenker's diverticulum (ZD), an acquired false pharyngoesophageal diverticulum, is a rare pathology. The prevalence of ZD among the general population is believed to be between 0.01% and 0.11%. Most patients are elderly men with symptoms of dysphagia. The most common treatments are open surgical diverticulectomy with or without cricopharyngeal myotomy and endoscopic myotomy. The authors report the case of a dental prosthesis lodged within an asymptomatic ZD in a 73-year-old man. It was safely removed endoscopically. So far, there have only been single reports of entrapment of an enteroscopy capsule lodged in a ZD in medical literature. PMID- 25276257 TI - Effective treatment of solitary rectal ulcer syndrome using argon plasma coagulation. AB - Solitary rectal ulcer syndrome (SRUS) is a chronic, multiform, non-cancerous disorder of the rectum, the final diagnosis of which is based upon histopathological criteria. This disorder is often accompanied by latent proctoptosis. We present a patient who (in 1996) was the first case in which argon plasma coagulation (APC) was used for SRUS treatment. In the years 2004 2005 the same patient underwent 15 APC sessions (at monthly intervals) obtaining full recovery from SRUS, although she had been treated unsuccessfully for 17 years prior to that. Six-year observation did not show any relapse. Local therapy with APC seems to be an important alternative in SRUS treatment without prolapse of the rectum and could become a basic method for bleeding treatment in SRUS. PMID- 25276259 TI - Phosphorus Spectroscopy of Calf Muscles before and after Exercise. AB - BACKGROUND: The aim of this study was to determine (31)PMRS reference spectrum and intracellular pH of calf muscles in the dominant limb of healthy, young, male volunteers before and after intense physical effort. MATERIAL/METHODS: Examinations were performed with a 1.5 T MR system. FID CSI (Free Induction Decay Chemical Shift Imaging) sequence was used with the following parameters: TR=4000 ms, FA=90 degrees , NEX=2 and VOI (Volume Of Interest)=8*8*8 cm(3) (512 cm(3)) involving in calf muscles. Raw data was preprocessed using SAGE (GE) software. Authors analyzed relative concentrations ratios of selected metabolites: PCr/ATP and PCr/Pi. Intracellular pH and relative concentrations ratios of each metabolite (Pi, PCr, alpha-ATP, beta-ATP, gamma-ATP, ATP) were also calculated relative to the sum of concentrations of all metabolites. Results were compared with a t-test. RESULTS: Based on statistical analysis of results significant differences (p<0.05) were demonstrated for some of the studied metabolites and for intracellular pH. Increase in PCr concentration in relation to the sum of concentrations of all metabolites and to ATP concentration was noted. However, beta-ATP, alpha-ATP and ATP concentrations relative to the sum of concentrations of all metabolites become reduced. Decrease in pH after physical effort was demonstrated. There were no significant differences (p<0.05) in concentrations of remaining metabolites before and after exercise. Increase in PCr concentration relative to Pi concentration and decrease of Pi and gamma-ATP concentration relative to the sum of concentrations of all metabolites were demonstrated. CONCLUSIONS: The (31)PMRS method enables assessment of concentrations of phosphorus-containing metabolites as well as intercellular pH before and after exercise. This method is still under examination, but it has already shown promise as a diagnostic tool for the future. PMID- 25276260 TI - Quantitative perfusion- and diffusion-weighted magnetic resonance imaging of gastrointestinal cancers treated with multikinase inhibitors: a pilot study. AB - BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) are often used to detect the early response of solid tumors to an effective therapy. The early changes in intratumoral physiological parameters measured by DCE-MRI/DWI have been evaluated as surrogate biomarkers allowing a tailored treatment for the individual patient. METHODS: Patients with newly diagnosed, biopsy-proven, treatment-naive gastrointestinal stromal tumor (GIST) or hepatocellular carcinoma (HCC) were enrolled prospectively after institutional review board (IRB)-approved informed consent (5 patients per tumor type). Patients with GIST were treated with sunitinib over 6 weeks. DCE-MRI/DWI was applied before therapy (baseline imaging) and at 2 and 6 weeks after therapy initiation. Patients with HCC were treated with radiation during the first 2 weeks and then with sorafenib for the next 6 weeks. DCE MRI/DWI was applied in all patients with HCC before and after radiation therapy and at the end of sorafenib therapy. Tumor volume, perfusion parameters (K (trans), the forward volume-transfer constant, and k ep, the reverse reflux-rate constant) and the apparent diffusion coefficient (ADC) were measured. RESULTS: During 2 weeks of sunitinib therapy, GIST volume, K (trans), and k ep decreased 32 +/- 13, 45 +/- 24, and 42 +/- 15%, respectively, whereas ADC increased 76 +/- 24%. After 6 weeks of sunitinib therapy, GIST volume, K (trans), and k ep decreased 56 +/- 7, 70 +/- 7, and 50 +/- 12%, respectively, whereas ADC increased 85 +/- 33%. After completion of radiation therapy, HCC volume, K (trans), and k ep decreased 34 +/- 14, 35 +/- 12, and 4 +/- 21%, respectively, but ADC increased 21 +/- 9%. During the entire 10-week therapeutic period, HCC volume, K (trans), and k ep decreased 65 +/- 15, 40 +/- 9, and 26 +/- 2%, respectively, whereas ADC increased 28 +/- 10%. CONCLUSION: DCE-MRI/DWI can measure the perfusion and diffusion changes in GISTs or HCCs treated with multikinase inhibitors. PMID- 25276261 TI - Benefit of Adjuvant Chemoradiotherapy for Gastric Adenocarcinoma: A SEER Population Analysis. AB - BACKGROUND: Despite results of the Intergroup 0116 (INT-0116) study showing an overall survival benefit of adjuvant chemoradiotherapy in gastric adenocarcinoma, its use in the United States remains controversial. The Surveillance Epidemiology of End Results (SEER) database was used to compare cause-specific survival outcomes in resected gastric adenocarcinoma with various adjuvant therapies and patterns of care. METHODS: Individual data from 1988 to 2008 were selected for patients with resected, nonmetastatic gastric adenocarcinoma. These patients were stratified by stage (American Joint Committee on Cancer [AJCC], 6th edition), as well as treatment modalities (surgery alone, S; surgery followed by radiotherapy, SR; surgery with chemotherapy, SC; surgery followed by radiotherapy with chemotherapy, SRC; and radiotherapy followed by surgery with chemotherapy, RSC). Overall 21,472 patients (8335 stages IA and 1B; 5944 stage II, 4594 stage III, and 2599 stage IV) were included in this study. RESULTS: The median age of the cohort was 66 years, with 63.0% male and 66.4% white. The median number of lymph nodes examined was 17.6. Median survival by stage was 96 months for stage I, 30 months for stage II, 20 months for stage III, and 14 months for stage IV. Using the SRC group as the reference group, for stage I patients, S had the most favorable cause-specific survival (hazard ratio [HR], 0.67; confidence interval, [CI] 0.60-0.76). For patients with stage II, III, or IV, those treated with SRC had the best outcome compared with the other treatment modalities. After 1999, the number of patients treated with surgery alone decreased by at least 14%, whereas the number treated with SRC increased by approximately 12%. CONCLUSIONS: This large SEER database analysis showed that stage I patients benefited most from surgery alone, whereas those at more advanced stages benefited most from adjuvant radiotherapy with chemotherapy. This result is consistent with INT-0116 for gastric adenocarcinoma in support of trimodality therapy and is reflected by the increased fraction of patients receiving chemotherapy and adjuvant radiation. PMID- 25276262 TI - Maintenance therapy with capecitabine in patients with resected pancreatic adenocarcinoma after adjuvant therapy: a retrospective cohort study. AB - BACKGROUND: The 5-year survival of pancreatic adenocarcinoma with surgery and adjuvant chemotherapy is below 25%. The original Gastrointestinal Tumor Study Group (GITSG) adjuvant study demonstrated a survival benefit attributed to weekly intravenous boluses of 5-fluorouracil (5-FU) for 2 years in addition to chemoradiation compared to surgery alone. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest and kill them as they infrequently enter the G1/S phase. We retrospectively evaluated outcomes in patients who were treated with adjuvant chemotherapy and maintenance capecitabine compared with those who received only adjuvant chemotherapy. METHODS: Patients who had undergone surgical resection with curative intent and received adjuvant chemotherapy were analyzed. Those who subsequently received maintenance capecitabine therapy were compared to those who received adjuvant chemotherapy only. The primary end points were disease recurrence and all-cause mortality. RESULTS: The median overall survival (OS) of patients receiving maintenance capecitabine was greater than 48.4 months (the exact estimate was not available, since the survival probability curve does not cross 0.5). It was 22.0 months (95% confidence interval [CI], 16.6-29.2) in patients who received adjuvant chemotherapy only (P < .001 by log-rank test). The median recurrence-free survival (RFS) was also longer in the maintenance capecitabine group: 54.3 (95% CI, 22.2-Inf) compared to 14.1 (95% CI, 11.6-16.7) months (P < .001, by log-rank test). CONCLUSIONS: In this retrospective study, patients with resected pancreatic adenocarcinoma who received adjuvant chemotherapy had improved OS and RFS with additional maintenance therapy with capecitabine. These findings should be confirmed with a randomized, controlled trial. PMID- 25276263 TI - Challenges in combining antiangiogenic therapy with transarterial chemoembolization for hepatocellular carcinoma. AB - BACKGROUND: The combination of systemic antiangiogenic therapy and transarterial chemoembolization (TACE) for the treatment of unresectable hepatocellular carcinoma (HCC) is the subject of several ongoing clinical trials. We present a series of patients treated with sorafenib and TACE at our institution, highlighting the technical challenges of combining these two modalities of treatment. METHODS: We retrospectively identified patients with HCC treated with TACE and sorafenib at our institution. RESULTS: Five patients were treated with the combination of TACE and sorafenib given off-protocol based on preliminary reports in the literature. The first four patients started sorafenib 7 days prior to TACE resulting in intratumoral vascular pruning and poor visualization of lesions on angiography. This was managed by either superselective angiography or lobar TACE. The fifth patient stopped sorafenib 7 days prior to TACE with full visualization of multiple hypervascular lesions on angiography prior to embolization. CONCLUSIONS: Our observations suggest that the biologically preferable strategy of continuous antiangiogenic therapy should be weighed against the possibility of suboptimal TACE due to poor visualization of lesions on angiography and safety. PMID- 25276264 TI - From the liver to the foot: a case of systemic embolism and acrometastasis in hepatocellular carcinoma. PMID- 25276265 TI - Pseudomyxoma peritonei metastatic to the bone: case report and review of systemic management. PMID- 25276267 TI - Metastatic breast cancer masquerading as primary gastric cancer: case report and review of the literature. PMID- 25276266 TI - Hepatocellular Carcinoma With Intra-atrial Extension Responding to Transarterial Chemoembolization via the Right Hepatic and Right Inferior Phrenic Arteries. PMID- 25276268 TI - A case of primary colonic small-cell carcinoma arising in a patient with long standing ulcerative colitis. PMID- 25276269 TI - Benign schwannoma masquerading as a malignant metastatic lesion in a patient with renal cell carcinoma. PMID- 25276270 TI - Multiorgan Streptococcus milleri Abscesses During FOLFIRINOX Chemotherapy in a Patient With Metastatic Pancreatic Cancer. PMID- 25276271 TI - Trends in the Use of Neurotoxins and Dermal Fillers by US Physicians. AB - BACKGROUND: Demand for minimally invasive cosmetic procedures have led to an increased market of available products for facial rejuvenation. OBJECTIVE: To characterize trends in the usage of aesthetic products, specifically the use of botulinum toxins and dermal fillers, by United States physicians. METHODS: Data from the National Ambulatory Medical Care Survey was analyzed from 1993 to 2010 to evaluate the use of dermal fillers and neurotoxins in the United States outpatient setting. The types of physician specialties administering these products and their preferences in products were characterized. RESULTS: There were an estimated 100,000 annual cosmetic visits at which a dermal filler was administered from 1993 to 2010. From 2002 to 2010, there were 140,000 annual cosmetic visits for a dermal filler and 440,000 visits for a neurotoxin. While collagen was the most common filler used over the entire study period, its use declined eight percent annually. Hyaluronic acid fillers were preferred from 2002 to 2010, followed by calcium hydroxylapatite filler, representing 50 percent and 16.1 percent of visits, respectively. The leading neurotoxin was onabotulinumtoxin A, used at 87.1 percent of visits. Dermatologists were the leading specialty for the cosmetic use of both dermal fillers and neurotoxins. CONCLUSION: Providers' preference for cosmetic products appears to be influenced by their familiarity with them, with products that first came to market, such as the neurotoxin onabotulinumtoxin A and the hyaluronic acid fillers being used most frequently from 2002 to 2010. PMID- 25276272 TI - The effect of multiple sequential light sources to activate aminolevulinic Acid in the treatment of actinic keratoses: a retrospective study. AB - There is a lack of research regarding the sequential use of multiple light sources for topical 5-aminolevulinic acid activation in photodynamic therapy for actinic keratosis. This study evaluated 5-aminolevulinic acid-photodynamic therapy for actinic keratosis using blue light combined with red light, pulsed dye laser, and/or intense pulsed light in a retrospective fashion. Field-directed 5-aminolevulinic acid-photodynamic therapy was performed with blue light only, blue light + pulsed dye laser, blue light + intense pulsed light, blue light + pulsed dye laser + intense pulsed light, or blue light + red light + pulsed dye laser + intense pulsed light for nonhyperkeratotic actinic keratoses of face, scalp, or upper trunk. Blue light + intense pulsed light + pulsed dye laser produced greater patient-reported improvement in actinic keratoses than blue light or blue light + intense pulsed light and greater subject-reported improvement in overall skin quality than blue light + intense pulsed light. The addition of red light led to no further benefit in either outcome measure. Photodynamic therapy with multiple, sequential laser and light sources led to greater patient-graded improvement in actinic keratoses than that with a single light source (blue light), without significant differences in post-treatment adverse events. However, the small, widely disparate number of patients between groups and follow-up times between patients, as well as retrospective assessments based on subjective patient recall, severely limit the significance of these findings. Nevertheless, the results raise interesting questions regarding the use of multiple light and laser sources for photodynamic therapy of actinic keratoses and warrant further research with a prospective, randomized, controlled study. PMID- 25276273 TI - African american women, hair care, and health barriers. AB - OBJECTIVES: The objective of this study was to elucidate the prevalence of hair loss among African American women; explore the psychosocial impact of hair grooming difficulties; and examine both perceptions related to physician encounters in this group and the relationship between hair grooming, physical activity, and weight maintenance. DESIGN: An anonymous retrospective and qualitative survey, the Hair Care Assessment Survey, is an 18-question novel survey instrument designed at the Henry Ford Hospital Department of Dermatology Multicultural Dermatology Center. SETTING: The Hair Care Assessment Survey was distributed at church-related functions at predominantly African American metropolitan Detroit churches. PARTICIPANTS: Two hundred African American women from metropolitan Detroit, Michigan, aged 21 to 83. MEASUREMENTS: The Hair Care Assessment Survey collected data relating to hair loss and hair care, psychosocial experiences relating to hair loss, and hair care as it relates to exercise and body weight management. Data was collected on doctor-patient hair related medical visits and experiences with commercially available ethnic hair care products. RESULTS: More than 50 percent reported excessive hair loss. Twenty eight percent had visited a physician to discuss hair issues, but only 32 percent felt their physician understood African American hair. Forty-five percent reported avoiding exercise because of hair concerns, and 22 percent felt that their hair impeded maintaining healthy body weight. CONCLUSION: Hair loss affects a compelling number of African American women, and a significant number express dissatisfaction in hair-related physician encounters. Additionally, hair styling problems present a serious impediment to physical activity and weight management among this already high-risk population. PMID- 25276274 TI - Evaluation of safety and patient subjective efficacy of using radiofrequency and pulsed magnetic fields for the treatment of striae (stretch marks). AB - Stretch marks are common skin disorders that are dermal scars with associated epidermal atrophy. They are of significant concern or psychological concern to many. This manuscript describes the use of multipolar radiofrequency with pulsed magnetic fields that was successfully used to diminish these lesions in 16 subjects undergoing a series of treatments. The improvements noted were statistically significant and no serious adverse events were noted. PMID- 25276275 TI - Penetration of ((14)C)-Efinaconazole Topical Solution, 10%, Does Not Appear to be Influenced by Nail Polish. AB - Onychomycosis is a common nail disorder with significant medical impacts and aesthetic consequences. Patients seek treatment for several reasons, including the unsightliness of the nail(s). Even with successful management, it takes months for the diseased nail to appear cosmetically normal. Patients commonly apply nail polish to mask the appearance of the dystrophic nail, though it is contraindicated with the currently available topical lacquers for onychomycosis. The authors' nonclinical study using a cadaver nail model showed that penetration of efinaconazole topical solution, 10%, a new antifungal being developed for the treatment of mild-to-moderate toenail onychomycosis, was not influenced by application of nail polish. Polishes showed an increase in surface tackiness with repeated efinaconazole topical solution, 10% application. The medical and aesthetic significance of the authors' findings have yet to be assessed clinically. PMID- 25276276 TI - Vascular compromise from soft tissue augmentation: experience with 12 cases and recommendations for optimal outcomes. AB - The popularity of soft tissue fillers is, in part, due to their favorable side effect profile. However, serious complications can occur. The authors describe their extensive clinical experience with soft-tissue augmentation and the rare complication of vascular compromise, which can lead to necrosis and scarring. Over a 10-year period between January 2003 and January 2013, the authors observed a total of 12 cases of vascular compromise. Eight patients in their clinical practice showed evidence of vascular compromise out of a total of 14,355 filler injections (0.05%). In addition, four patients treated with an experimental particulate filler had vascular complications. All cases were examined for filler type, location of complication, risk factors, treatment, and outcomes. Although treatment plans differed for each patient in their series, all cases of vascular compromise resolved fully. The authors believe that an office-based protocol for both immediate and ongoing care-including a thorough individualized assessment and treatment plan for each patient-is critical to timely and effective resolution of side effects. They propose key recommendations for the prevention and management of vascular compromise to improve patient outcomes and reduce the risk of permanent complications. PMID- 25276277 TI - Bullous lesions in a patient with systemic lupus erythematosus. AB - Bullous eruptions in patients with lupus erythematosus can be difficult to diagnose as bullous lesions can develop in lupus-specific lesions, and primary blistering disorders can also occur. Additionally, these patients tend to have multiple co-morbidities making them more likely to be on many medications that can lead to bullous drug reactions. A thorough history, the clinical presentation, and histopathological findings along with direct immunofluorescence can be helpful in diagnosing most cases. The authors report the case of a woman with a long history of systemic lupus erythematosus who initially presented in their clinic for diagnosis and management of erythema dyschromicum perstans and one year later developed bullae in atypical targetoid lesions on the extremities and trunk. They discuss several blistering disorders that have been reported in patients with lupus erythematosus with a focus on features that help distinguish erythema multiforme, fixed drug eruption, and lupus erythematosus from Stevens Johnson syndrome/toxic epidermal necrolysis. In the patient described herein, the authors favor a diagnosis of Stevens-Johnson syndrome, but the classification between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis cannot be made in some cases. PMID- 25276278 TI - Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma. AB - With the increasing prevalence of living-donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC), some authors have reported a potential increase in the HCC recurrence rates among LDLT recipients compared to deceased-donor liver transplantation (DDLT) recipients. The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome, especially the recurrence of HCC, between LDLT and DDLT. While some studies report impaired recurrence - free survival and increased recurrence rates among LDLT recipients, others, including large database studies, report comparable recurrence - free survival and recurrence rates between LDLT and DDLT. Studies supporting the increased recurrence in LDLT have linked graft regeneration to tumor progression, but we found no association between graft regeneration/initial graft volume and tumor recurrence among our 125 consecutive LDLTs for HCC cases. In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients, there is no evidence to support the higher HCC recurrence after LDLT than DDLT, and LDLT remains a reasonable treatment option for HCC patients with cirrhosis. PMID- 25276279 TI - Liver involvement in systemic infection. AB - The liver is often involved in systemic infections, resulting in various types of abnormal liver function test results. In particular, hyperbilirubinemia in the range of 2-10 mg/dL is often seen in patients with sepsis, and several mechanisms for this phenomenon have been proposed. In this review, we summarize how the liver is involved in various systemic infections that are not considered to be primarily hepatotropic. In most patients with systemic infections, treatment for the invading microbes is enough to normalize the liver function tests. However, some patients may show severe liver injury or fulminant hepatic failure, requiring intensive treatment of the liver. PMID- 25276281 TI - Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection. AB - Significant advances have been made in nucleos(t)ide analogue (NA) therapy to treat chronic hepatitis B, and this therapy reduces the risk of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in some patients. However, whether NAs can also prevent recurrence after radical resection of HBV-related HCC remains controversial and is an important question, given that most patients will experience recurrence within a few years of curative surgery. Here we systematically reviewed the literature since 2004 on outcomes after administering NAs to patients with HBV-related HCC following radical resection. We focused on treatment indications, duration, effects on recurrence-free survival and overall survival, and the management of NA resistance. We find that patients with HCC should strongly consider NA therapy if they are positive for HBV-DNA, and that the available evidence suggests that postoperative NA therapy can increase both recurrence-free and overall survival. To minimize drug resistance, clinicians should opt for potent analogues with higher resistance barriers, and they should monitor the patient carefully for emergence of NA-resistant HBV. PMID- 25276280 TI - Vertical transmission of hepatitis C virus: Current knowledge and perspectives. AB - Hepatitis C virus (HCV) infection is a major global health issue. Infection by the HCV can cause acute and chronic liver diseases and may lead to cirrhosis, hepatocellular carcinoma or liver failure. The World Health Organization estimates that approximately 3% of the world population have been infected with HCV and the worldwide prevalence is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Following the introduction of blood product screening, vertical transmission becomes the leading cause of childhood HCV infection. The prevalence of pediatric HCV infection varies from 0.05% to 0.36% in developed countries and between 1.8% and 5% in the developing world. All children born to women with anti-HCV antibodies should be checked for HCV infection. Though universal screening is controversial, selective antenatal HCV screening on high-risk populations is highly recommended and should be tested probably. Multiple risk factors were shown to increase the possibility of HCV vertical transmission, including coinfections with human immunodeficiency virus, intravenous drug use and elevated maternal HCV viral load, while breastfeeding and HCV genotypes have been studied to have little impact. At present, no clinical intervention has been clearly studied and proved to reduce the HCV vertical transmission risk. Cesarean section should not be recommended as a procedure to prevent vertical transmission, however, breastfeeding is generally not forbidden. The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to reduce the burden of chronic liver disease. Future researches should focus on the interruption of vertical transmission, developments of HCV vaccine and direct-acting antivirals in infancy and early childhood. PMID- 25276282 TI - Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients. AB - AIM: To assess, in a routine practice setting, the sustained virologic response (SVR) to telaprevir (TPV) or boceprevir (BOC) in hepatitis C virus (HCV) null responders or relapsers with severe liver fibrosis. METHODS: One hundred twenty five patients were treated prospectively for 48 wk with TPV or BOC + pegylated interferon (peg-INF) alpha2a + ribavirin (PR) according to standard treatment schedules without randomization. These patients were treated in routine practice settings in 10 public or private health care centers, and the data were prospectively collected. Only patients with severe liver fibrosis (Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography), genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study. RESULTS: The Metavir fibrosis scores were F3 in 35 (28%) and F4 in 90 (72%) of the patients. In total, 62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy. The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%. The SVR was 65.9% in the TPV group and 44.1% in the BOC group. Independent predictive factors of an SVR included a response to previous treatment, relapsers vs null-responders [OR = 3.9; (1.4, 10.6), P = 0.0084], a rapid virological response (RVR) [OR 6.9 (2.6, 18.2), P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2 (2.3, 29.5), P = 0.001]. During treatment, 63 patients (50.8%) had at least one severe adverse event (SAE) of grade 3 or 4. A multivariate analysis identified two factors associated with SAEs: female gender [OR = 2.4 (1.1, 5.6), P = 0.037] and a platelet count below 150 * 10(3)/ mm(3) [OR = 5.3 (2.3, 12.4), P <= 0.001]. CONCLUSION: More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting. The SVR rate was influenced by the response to previous PR treatment, the RVR and liver stiffness. PMID- 25276283 TI - Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma. AB - AIM: To study the relationship between adverse events (AEs), efficacy, and nursing intervention for sorafenib therapy in patients with hepatocellular carcinoma (HCC). METHODS: We enrolled 37 consecutive patients with advanced HCC who received sorafenib therapy. Relationships among baseline characteristics as well as AE occurrence and tumor response, overall survival (OS), and treatment duration were analyzed. The nursing intervention program consisted of education regarding self-monitoring and AEs management, and telephone follow-up was provided once in 1-2 wk. RESULTS: A total of 37 patients were enrolled in the study, comprising 30 males (81%) with a median age of 71 years. The disease control rate at 3 mo was 41%, and the median OS and treatment duration were 259 and 108 d, respectively. Nursing intervention was given to 24 patients (65%). Every patient exhibited some kinds of AEs, but no patients experienced G4 AEs. Frequently observed AEs > G2 included anorexia (57%), skin toxicity (57%), and fatigue (54%). Factors significantly associated with longer OS in multivariate analysis demonstrated that age <= 70 years, presence of > G2 skin toxicity, and absence of > G2 hypoalbuminemia. The disease control rate in patients with > G2 skin toxicity was 13/20 (65%), which was significantly higher compared with that in patients with no or G1 skin toxicity. Multivariate analysis revealed that nursing intervention and > G2 skin toxicity were independent significant predictors for longer treatment duration. CONCLUSION: Skin toxicity was associated with favorable outcomes with sorafenib therapy for advanced HCC. Nursing intervention contributed to better adherence, which may improve the efficacy of sorafenib. PMID- 25276285 TI - Liver fibrosis in primary intestinal lymphangiectasia: An undervalued topic. AB - The relationship between primary intestinal lymphangiectasia (PIL) and liver fibrosis is an emerging topic with many obscure aspects due to the rarity of the disorder. A recent paper reported that a six-month low-fat diet improved liver fibrosis. We report the case of a 17-year-old girl affected by PIL whose hepatic fibrosis progressively worsened within one year, despite dietetic support. This and the previous case report describe extraordinary events, which do not allow clear-cut clinical aspects to be established. Nevertheless, both cases suggest that in patients with PIL, it is necessary to closely monitor liver morphology with in-depth investigations including not only ultrasonography, but also elastography. PMID- 25276284 TI - Insulin resistance and steatosis in HBV-HCV co-infected patients: Role of PNPLA3 polymorphisms and impact on liver fibrosis progression. AB - AIM: To evaluate steatosis, insulin resistance (IR) and patatin-like phospholipase domain-containing 3 (PNPLA3) and their relation to disease progression in hepatitis B and C viruses (HCV-HBV) co-infected patients. METHODS: Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled: 66 had HBV-HCV, 66 HBV and 198 HCV infection. Prevalence of steatosis, IR and PNPLA3 polymorphisms and their relation to anthropometric, biochemical, virological and histological parameters were evaluated. RESULTS: Prevalence of steatosis in group HBV-HCV was similar to that in HCV (47.0% vs 49.5%, respectively); group HBV showed the lowest steatosis (33.3%). Group HBV-HCV had a lesser degree of steatosis than HCV (P = 0.016), lower HCV RNA levels (P = 0.025) and lower prevalence and degree of IR (P = 0.01). PNPLA3 polymorphisms were associated with steatosis. Group HBV-HCV showed higher levels of liver fibrosis than group HCV (P = 0.001), but similar to that observed in HBV group. In HBV-HCV group, liver fibrosis was not associated with steatosis, IR or PNPLA3. HBV infection was the independent predictor of advanced liver fibrosis. CONCLUSION: HBV-HCV co-infected patients have lower degree of hepatic steatosis, IR and HCV RNA than HCV mono-infected; co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance. PMID- 25276286 TI - Increased postoperative complications after protective ileostomy closure delay: An institutional study. AB - AIM: To study the morbidity and complications associated to ileostomy reversal in colorectal surgery patients, and if these are related to the time of closure. METHODS: A retrospective analysis of 93 patients, who had undergone elective ileostomy closure between 2009 and 2013 was performed. Demographic, clinical and surgical variables were reviewed for analysis. All complications were recorded, and classified according to the Clavien-Dindo Classification. Statistical univariate and multivariate analysis was performed, setting a P value of 0.05 for significance. RESULTS: The patients had a mean age of 60.3 years, 58% male. The main procedure for ileostomy creation was rectal cancer (56%), and 37% had received preoperative chemo-radiotherapy. The average delay from creation to closure of the ileostomy was 10.3 mo. Postoperative complications occurred in 40% of the patients, with 1% mortality. The most frequent were ileus (13%) and wound infection (13%). Pseudomembranous colitis appeared in 4%. Increased postoperative complications were associated with delay in ileostomy closure (P = 0.041). Male patients had more complications (P = 0.042), mainly wound infections (P = 0.007). Pseudomembranous colitis was also associated with the delay in ileostomy closure (P = 0.003). End-to-end intestinal anastomosis without resection was significantly associated with postoperative ileus (P = 0.037). CONCLUSION: Although closure of a protective ileostomy is a fairly common surgical procedure, it has a high rate of complications, and this must be taken into account when the indication is made. The delay in stoma closure can increase the rate of complications in general, and specifically wound infections and colitis. PMID- 25276287 TI - Pancreatic extragastrointestinal stromal tumor: A case report and comprehensive literature review. AB - AIM: To provide an overview of the literature on pancreatic extragastrointestinal stromal tumors (EGISTs). METHODS: We report a case of pancreatic EGIST and review published studies on pancreatic EGIST accessed via the PubMed, MEDLINE, Google Scholar, and Google databases. The keywords used were "pancreas and GIST", "pancreas and extra GIST", "pancreas and gastrointestinal stromal tumor", and "pancreas and extragastrointestinal stromal tumor". Literature reviews and/or duplicate studies were excluded. The search included articles published in the English language between January 1, 2000 and May 15, 2014. RESULTS: From our literature survey, 30 manuscripts on pancreatic EGISTs were considered, of which 27 met the search criteria and three were excluded. The studies involved 30 patients (15 men, 15 women) with a mean age of 55.3 +/- 14.3 years (range 30-84 years). The mean age of the male patients was 50.8 +/- 13.7 years (range 30-84 years); that of the female patients was 59.9 +/- 13.3 years (range 38-81 years). Tumor dimensions were obtained for 28 cases (mean 114.4 +/- 78.6 mm; range 20-350 mm). Tumors were diagnosed incidentally in 23.3% of patients; abdominal discomfort and weight loss were the major complaints in symptomatic patients. Risk of aggressive behavior according to Fletcher criteria was determined in 25 of 30 patients (68%: high risk, 28%: intermediate risk, 4%: low risk). Histopathological examination revealed the presence of spindle cells in 96.1% of cases; CD117 and CD34 were present immunohistochemically in 96.6% and 84% of patients, respectively. The most common surgical procedures were distal pancreatectomy with splenectomy (n = 9) and pancreaticoduodenectomy (n = 7). The total follow-up period for the 28 patients ranged from 3-66 mo, during which locoregional or distant metastases were diagnosed in six patients and two patients died. CONCLUSION: Studies on EGISTs have only been published in the last decade. The lack of studies with large patient cohorts and long-term follow-up limits evidence-based commentary. In theory, each case should be assessed individually and further genetic and immunohistochemical studies are needed. PMID- 25276288 TI - Gastric necrosis: A late complication of nissen fundoplication. AB - Gastric necrosis is a rare condition because of the rich blood supply and the extensive submucosal vascular network of the stomach. "Gas-bloat" syndrome is a well known Nissen fundoplication postoperative complication. It may cause severe gastric dilatation, but very rarely an ischemic compromise of the organ. Other factors, such as gastric outlet obstruction, may concur to cause an intraluminal pressure enough to blockade venous return and ultimately arterial blood supply and oxygen deliver, leading to ischaemia. We report a case of a 63-year-old women, who presented a total gastric necrosis following laparoscopic Nissen fundoplication and a pyloric phytobezoar which was the trigger event. No preexisting gastric motility disorders were present by the time of surgery, as demonstrated in the preoperative barium swallow, thus a poor mastication (patient needed no dentures) of a high fiber meal (cabbage) may have been predisposing factors for the development of a bezoar in an otherwise healthy women at the onset of old age. A total gastrectomy with esophagojejunostomy was performed and patient was discharged home after a 7-d hospital stay with no immediate complications. We also discuss some technical aspects of the procedure that might be important to reduce the incidence of this complication. PMID- 25276289 TI - Retroanastomotic hernia after Moynihan's gastroenterostomy. AB - Retroanastomotic hernias after gastroenterostomies-either antecolic or retrocolic are extremely rare but are associated with high mortality rates due to delayed identification which precludes immediate surgical reduction. In this report, we present a 77-year-old man with retroanastomotic herniation of the efferent loop segments that occurred 14 years after a Moynihan's gastroenterostomy. PMID- 25276290 TI - African Americans, hypertension and the renin angiotensin system. AB - African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system (RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovascular and chronic kidney disease makes treatment with RAS inhibitors more compelling. Despite lower circulating renin levels and a less significant fall in blood pressure in response to RAS inhibitors in African Americans, numerous clinical trials support the efficacy of RAS inhibitors to improve clinical outcomes in this population, especially in those with hypertension and risk factors for cardiovascular and related diseases. Here, we discuss the rationale of RAS blockade as part of a comprehensive approach to attenuate the high rates of premature morbidity and mortality associated with hypertension among African Americans. PMID- 25276291 TI - Metabolic syndrome in hypertensive patients: An unholy alliance. AB - For many years, it has been recognized that hypertension tends to cluster with various anthropometric and metabolic abnormalities including abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, glucose intolerance, insulin resistance and hyperuricemia. This constellation of various conditions has been transformed from a pathophysiological concept to a clinical entity, which has been defined metabolic syndrome (MetS). The consequences of the MetS have been difficult to assess without commonly accepted criteria to diagnose it. For this reason, on 2009 the International Diabetes Federation, the American Heart Association and other scientific organizations proposed a unified MetS definition. The incidence of the MetS has been increasing worldwide in parallel with an increase in overweight and obesity. The epidemic proportion reached by the MetS represents a major public health challenge, because several lines of evidence showed that the MetS, even without type 2 diabetes, confers an increased risk of cardiovascular morbidity and mortality in different populations including also hypertensive patients. It is likely that the enhanced cardiovascular risk associated with MetS in patients with high blood pressure may be largely mediated through an increased prevalence of preclinical cardiovascular and renal changes, such as left ventricular hypertrophy, early carotid atherosclerosis, impaired aortic elasticity, hypertensive retinopathy and microalbuminuria. Indeed, many reports support this notion, showing that hypertensive patients with MetS exhibit, more often than those without it, these early signs of end organ damage, most of which are recognized as significant independent predictors of adverse cardiovascular outcomes. PMID- 25276293 TI - Multimodality imaging in apical hypertrophic cardiomyopathy. AB - Apical hypertrophic cardiomyopathy (AHCM) is a relatively rare morphologic variant of HCM in which the hypertrophy of myocardium is localized to the left ventricular apex. Symptoms of AHCM might vary from none to others mimic coronary artery disease including acute coronary syndrome, thus resulting in inappropriate hospitalization. Transthoracic echocardiography is the first-line imaging technique for the diagnosis of hypertrophic cardiomyopathies. However, when the hypertrophy of the myocardium is localized in the ventricular apex might results in missed diagnosis. Aim of this paper is to review the different imaging techniques used for the diagnosis of AHCM and their role in the detection and comprehension of this uncommon disease. PMID- 25276294 TI - Thrombus aspiration in acute myocardial infarction: Rationale and indication. AB - Reperfusion of myocardial tissue is the main goal of primary percutaneous coronary intervention (PPCI) with stent implantation in the treatment of acute ST segment elevation myocardial infarction (STEMI). Although PPCI has contributed to a dramatic reduction in cardiovascular mortality over three decades, normal myocardial perfusion is not restored in approximately one-third of these patients. Several mechanisms may contribute to myocardial reperfusion failure, in particular distal embolization of the thrombus and plaque fragments. In fact, this is a possible complication during PPCI, resulting in microvascular obstruction and no-reflow phenomenon. The presence of a visible thrombus at the time of PPCI in patients with STEMI is associated with poor procedural and clinical outcomes. Aspiration thrombectomy during PPCI has been proposed to prevent embolization in order to improve these outcomes. In fact, the most recent guidelines suggest the routine use of manual aspiration thrombectomy during PPCI (class IIa) to reduce the risk of distal embolization. Even though numerous international studies have been reported, there are conflicting results on the clinical impact of aspiration thrombectomy during PPCI. In particular, data on long-term clinical outcomes are still inconsistent. In this review, we have carefully analyzed literature data on thrombectomy during PPCI, taking into account the most recent studies and meta-analyses. PMID- 25276292 TI - Management of erectile dysfunction in hypertension: Tips and tricks. AB - Arterial hypertension is a major risk factor for cardiovascular disease and affects approximately one third of the adult population worldwide. The vascular origin of erectile dysfunction is now widely accepted in the vast majority of cases. Erectile dysfunction is frequently encountered in patients with arterial hypertension and greatly affects their quality of life of hypertensive patients and their sexual partners. Therefore, the management of erectile dysfunction in hypertensive patients is of paramount importance. Unfortunately, erectile dysfunction remains under-reported, under-recognized, and under-treated in hypertensive patients, mainly due to the lack of familiarity with this clinical entity by treating physicians. This review aims to discuss the more frequent problems in the management of hypertensive patients with erectile dysfunction and propose ways to overcome these problems in everyday clinical practice. PMID- 25276295 TI - Drug-eluting stents and acute myocardial infarction: A lethal combination or friends? AB - Primary percutaneous coronary intervention is the preferred reperfusion strategy for patients presenting with ST-segment elevation myocardial infarction (STEMI). First generation drug-eluting stents (DES), (sirolimus drug-eluting stents and paclitaxel drug-eluting stents), reduce the risk of restenosis and target vessel revascularization compared to bare metal stents. However, stent thrombosis emerged as a major safety concern with first generation DES. In response to these safety issues, second generation DES were developed with different drugs, improved stent platforms and more biocompatible durable or bioabsorbable polymeric coating. This article presents an overview of safety and efficacy of the first and second generation DES in STEMI. PMID- 25276297 TI - Ventricular tachycardia mapping and ablation in arrhythmogenic right ventricular cardiomyopathy/dysplasia: Lessons Learned. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is primarily believed to be an inherited cardiomyopathy that subsequently results in significant myocardial fibrosis. The arrhythmogenic consequences that result from the development of fibrosis are similar to other nonischemic cardiomyopathies, but the unique endocardial-epicardial disease process of ARVC/D requires a specialized approach for arrhythmia treatment in the electrophysiology laboratory. Although the association between ARVC/D and development of ventricular arrhythmias has become increasingly clear over the last 2 decades, our understanding of the arrhythmia mechanisms, underlying electrophysiologic substrate, and treatment strategies were significantly limited. Prospective studies performed in the electrophysiology laboratory allowed detailed characterization of the electrophysiologic and electroanatomic substrate underlying ventricular tachycardia in patients with ARVC/D. This has allowed clinician scientists to better characterize the arrhythmia mechanism and develop the necessary strategies to perform successful catheter ablation. Early in this experience, catheter ablation was considered a limited and largely unsuccessful treatment for patients experiencing painful and recurrent defibrillator therapy. Through our increased understanding of the disease process, catheter ablation has evolved to become an effective and preferred therapy for a majority of these patients. Our understanding of the disease and necessary approaches to provide successful treatment continues to evolve as the clinical experience grows. This article will review these important insights from the electrophysiology laboratory and how application of this knowledge has facilitated the development of a methodical approach to successfully perform ventricular tachycardia ablation in patients with ARVC/D. PMID- 25276296 TI - miRNome in myocardial infarction: Future directions and perspective. AB - MicroRNAs (miRNAs), which are small and non-coding RNAs, are genome encoded from viruses to humans. They contribute to various developmental, physiological and pathological processes in living organisms. A huge amount of research results revealed that miRNAs regulate these processes also in the heart. miRNAs may have cell-type-specific or tissue-specific expression patterns or may be expressed ubiquitously. Primary studies of miRNA involvement in hypertrophy, heart failure and myocardial infarction analyzed miRNAs that are enriched in or specific for cardiomyocytes; however, growing evidence suggest that other miRNAs, not cardiac or muscle-specific, play a significant role in cardiovascular disease. Abnormal miRNA regulation has been shown to be involved in cardiac diseases, suggesting that miRNAs might affect cardiac structure and function. In this review, we focus on miRNAs that have been found to contribute to the pathogenesis of myocardial infarction (MI) and the response post-MI and characterized as diagnostic, prognostic and therapeutic targets. The majority of these studies were performed using mouse and rat models of MI, with a focus on the identification of basic cellular and molecular pathways involved in MI and in the response post-MI. Much research has also been performed on animal and human plasma samples from MI individuals to identify miRNAs that are possible prognostic and/or diagnostic targets of MI and other MI-related diseases. A large proportion of research is focused on miRNAs as promising therapeutic targets and biomarkers of drug responses and/or stem cell treatment approaches. However, only a few studies have described miRNA expression in human heart tissue following MI. PMID- 25276299 TI - Is ABO blood group truly a risk factor for thrombosis and adverse outcomes? AB - ABO blood type is one of the most readily available laboratory tests, and serves as a vital determinant in blood transfusion and organ transplantation. The ABO antigens are expressed not only on red blood cell membranes, determining the compatibility of transfusion, but also on the surface of other human cells, including epithelium, platelet and vascular endothelium, therefore extending the research into other involvements of cardiovascular disease and postoperative outcomes. ABO blood group has been recognized as a risk factor of venous thrombosis embolism since the 1960's, effects now understood to be related to ABO dependent variations are procoagulant factor VIII (FVIII) and von Willebrand factor (vWF) levels. Levels of vWF, mostly genetically determined, are strongly associated with venous thromboembolism (VTE). It mediates platelet adhesion aggregation and stabilizes FVIII in plasma. Moreover, many studies have tried to identify the relationship between ABO blood types and ischemic heart disease. Unlike the clear and convincing associations between VTE and ABO blood type, the link between ABO blood type and ischemic heart disease is less consistent and may be confusing. Other than genetic factors, ischemic heart disease is strongly related to diet, race, lipid metabolism and economic status. In this review, we'll summarize the data relating race and genetics, including ABO blood type, to VTE, ischemic heart disease and postoperative bleeding after cardiac surgery. PMID- 25276300 TI - Cardiac manifestations in systemic sclerosis. AB - Primary cardiac involvement, which develops as a direct consequence of systemic sclerosis (SSc), may manifest as myocardial damage, fibrosis of the conduction system, pericardial and, less frequently, as valvular disease. In addition, cardiac complications in SSc may develop as a secondary phenomenon due to pulmonary arterial hypertension and kidney pathology. The prevalence of primary cardiac involvement in SSc is variable and difficult to determine because of the diversity of cardiac manifestations, the presence of subclinical periods, the type of diagnostic tools applied, and the diversity of patient populations. When clinically manifested, cardiac involvement is thought to be an important prognostic factor. Profound microvascular disease is a pathognomonic feature of SSc, as both vasospasm and structural alterations are present. Such alterations are thought to predict macrovascular atherosclerosis over time. There are contradictory reports regarding the prevalence of atherosclerosis in SSc. According to some authors, the prevalence of atherosclerosis of the large epicardial coronary arteries is similar to that of the general population, in contrast with other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the level of inflammation in SSc is inferior. Thus, the atherosclerotic process may not be as aggressive and not easily detectable in smaller studies. Echocardiography (especially tissue Doppler imaging), single photon emission computed tomography, magnetic resonance imaging and cardiac computed tomography are sensitive techniques for earlier detection of both structural and functional scleroderma-related cardiac pathologies. Screening for subclinical cardiac involvement via modern, sensitive tools provides an opportunity for early diagnosis and treatment, which is of crucial importance for a positive outcome. PMID- 25276302 TI - Newer methods of cardiac output monitoring. AB - Cardiac output (CO) is the volume of blood ejected by each ventricle per minute and is the product of stroke volume and heart rate. CO can thus be manipulated by alteration in heart rate or rhythm, preload, contractility and afterload. Moreover it gives important information about tissue perfusion and oxygen delivery. CO can be measured by various methods and thermodilution method using pulmonary artery catheter (PAC) is till date considered as gold standard method. Complications associated with PAC led to development of newer methods which are minimally or non-invasive. Newer methods fulfil other properties like continuous and reproducible reading, cost effective, reliable during various physiological states and have fast response time. These methods are validated against the gold standard with good level agreement. In this review we have discussed various newer methods of CO monitoring and their effectiveness in clinical use. PMID- 25276298 TI - Angiotensin II-related hypertension and eye diseases. AB - Systemic vascular disease, especially hypertension, has been suspected as a risk factor for some eye diseases including, diabetic retinopathy and age-related macular degeneration. Hypertension can contribute to chronic diseases by hemodynamic injury and/or cellular actions induced by hypertension-related hormones or growth factors. Among the most important is Angiotensin II (Ang II), which controls blood pressure and induces different cellular functions that may be dependent or independent of its effect on blood pressure. Importantly, as is true for heart, kidney and other organs, the renin-angiotensin system (RAS) is present in the eye. So, even in the absence of hypertension, local production of Ang II could be involved in eye diseases. The goal of this manuscript is to review the most relevant scientific evidence supporting the role of the RAS activation, in the development of age-related macular degeneration and diabetic retinopathy, and highlight the importance of Ang II in the etiology of these diseases. PMID- 25276303 TI - Does manual thrombus aspiration help optimize stent implantation in ST-segment elevation myocardial infarction? AB - AIM: To evaluate the impact of thrombus aspiration (TA) on procedural outcomes in a real-world ST-segment elevation myocardial infarction (STEMI) registry. METHODS: From May 2006 to August 2008, 542 consecutive STEMI patients referred for primary or rescue percutaneous coronary intervention were enrolled and the angiographic results and stent implantation characteristics were compared according to the performance of manual TA. RESULTS: A total of 456 patients were analyzable and categorized in TA group (156 patients; 34.2%) and non-TA (NTA) group (300 patients; 65.8%). Patients treated with TA had less prevalence of multivessel disease (39.7% vs 54.7%, P = 0.003) and higher prevalence of initial thrombolysis in myocardial infarction flow < 3 (P < 0.001) than NTA group. There was a higher rate of direct stenting (58.7% vs 45.5%, P = 0.009), with shorter (24.1 +/- 11.8 mm vs 26.9 +/- 15.7 mm, P = 0.038) and larger stents (3.17 +/- 0.43 mm vs 2.93 +/- 0.44 mm, P < 0.001) in the TA group as compared to NTA group. The number of implanted stents (1.3 +/- 0.67 vs 1.5 +/- 0.84, P = 0.009) was also lower in TA group. CONCLUSION: In an "all-comers" STEMI population, the use of TA resulted in more efficient procedure leading to the implantation of less number of stents per lesion of shorter lengths and larger sizes. PMID- 25276304 TI - Calcific left atrium: A rare consequence of endocarditis. AB - Usually, cardiac calcifications are observed in aortic and mitral valves, atrio ventricular plane, mitral annulus, coronary arteries, pericaridium (usually causing constrictive pericarditis) and cardiac masses. Calcifications of atrial walls are unusual findings that can be identified only using imaging with high spatial resolution, such as cardiac magnetic resonance and computed tomography. We report a case of a 43-year-old patient with no history of heart disease that underwent cardiac evaluation for mild dyspnoea. The echocardiogram showed a calcific aortic valve and a hyper-echogenic lesion located in atrio-ventricular plane. The patient was submitted to cardiac magnetic resonance and to computed tomography imaging to better characterize the localization of mass. The clinical features and location of calcified lesion suggest an infective aetiology causing an endocarditis involving the aortic valve, atrio-ventricular plane and left atrium. Although we haven't data to support a definite and clear diagnosis, the clinical features and location of the calcified lesion suggest an infective aetiology causing an endocarditis involving the aortic valve, atrio-ventricular plane and left atrium. The patient was followed for 12 mo both clinically and by electrocardiogram and echocardiography without worsening of clinical, electrocardiographic and echocardiographic data. Cardiac magnetic resonance imaging and computed tomography are ideal methods for identifying and following over time patients with calcific degeneration in the heart. PMID- 25276305 TI - Systemic venous atrium stimulation in transvenous pacing after mustard procedure. AB - We present the case of a young woman corrected with a Mustard procedure undergoing successful transvenous double chamber pacemaker implantation with the atrial lead placed in the systemic venous channel. The case presented demonstrates that, when the systemic venous atrium is separate from the left atrial appendage, the lead can be easily and safely placed in the systemic venous left atrium gaining satisfactory sensing and pacing thresholds despite consisting partially of pericardial tissue. PMID- 25276301 TI - Serum creatinine role in predicting outcome after cardiac surgery beyond acute kidney injury. AB - Serum creatinine is still the most important determinant in the assessment of perioperative renal function and in the prediction of adverse outcome in cardiac surgery. Many biomarkers have been studied to date; still, there is no surrogate for serum creatinine measurement in clinical practice because it is feasible and inexpensive. High levels of serum creatinine and its equivalents have been the most important preoperative risk factor for postoperative renal injury. Moreover, creatinine is the mainstay in predicting risk models and risk factor reduction has enhanced its importance in outcome prediction. The future perspective is the development of new definitions and novel tools for the early diagnosis of acute kidney injury largely based on serum creatinine and a panel of novel biomarkers. PMID- 25276306 TI - Acute myocarditis triggering coronary spasm and mimicking acute myocardial infarction. AB - A 24-year-old healthy man consulted to our center because of typical on-and-off chest-pain and an electrocardiogram showing ST-segment elevation in inferior leads. An urgent coronary angiography showed angiographically normal coronary arteries. Cardiovascular magnetic resonance imaging confirmed acute myocarditis. Although acute myocarditis triggering coronary spasm is an uncommon association, it is important to recognize it, particularly for the management for those patients presenting with ST-segment elevation and suspect myocardial infarction and angiographically normal coronary arteries. The present report highlights the role of cardiovascular magnetic resonance imaging to identify acute myocarditis as the underlying cause. PMID- 25276307 TI - Echography in brain imaging in intensive care unit: State of the art. AB - Transcranial sonography (TCS) is an ultrasound-based imaging technique, which allows the identification of several structures within the brain parenchyma. In the past it has been applied for bedside assessment of different intracranial pathologies in children. Presently, TCS is also used on adult patients to diagnose intracranial space occupying lesions of various origins, intracranial hemorrhage, hydrocephalus, midline shift and neurodegenerative movement disorders, in both acute and chronic clinical settings. In comparison with conventional neuroimaging methods (such as computed tomography or magnetic resonance), TCS has the advantages of low costs, short investigation times, repeatability, and bedside availability. These noninvasive characteristics, together with the possibility of offering a continuous patient neuro-monitoring system, determine its applicability in the monitoring of multiple emergency and non-emergency settings. Currently, TCS is a still underestimated imaging modality that requires a wider diffusion and a qualified training process. In this review we focused on the main indications of TCS for the assessment of acute neurologic disorders in intensive care unit. PMID- 25276309 TI - Imaging of Gaucher disease. AB - Gaucher disease is the prototypical lysosomal storage disease. It results from the accumulation of undegraded glucosylceramide in the reticuloendothelial system of the bone marrow, spleen and liver due to deficiency of the enzyme glucocerebrosidase. This leads to hematologic, visceral and skeletal maifestions. Build up of glucosylceramide in the liver and spleen results in hepatosplenomegaly. The normal bone marrow is replaced by the accumulating substrate leading to many of the hematologic signs including anemia. The visceral and skeletal manifestations can be visualized with various imaging modalities including radiography, computed tomography, magnetic resonance imaging (MRI) and radionuclide scanning. Prior to the development of enzyme replacement therapy, treatment was only supportive. However, once intravenous enzyme replacement therapy became available in the 1990s it quickly became the standard of care. Enzyme replacement therapy leads to improvement in all manifestations. The visceral and hematologic manifestations respond more quickly usually within a few months or years. The skeletal manifestations take much longer, usually several years, to show improvement. In recent years newer treatment strategies, such as substrate reduction therapy, have been under investigation. Imaging plays a key role in both initial diagnosis and routine monitoring of patient on treatment particularly volumetric MRI of the liver and spleen and MRI of the femora for evaluating bone marrow disease burden. PMID- 25276308 TI - From histology to micro-CT: Measuring and modeling resorption cavities and their relation to bone competence. AB - The process of bone remodelling plays an essential role in the emergence and maintenance of bone geometry and its internal structure. Osteoclasts are one of the three main bone cell types that play a crucial role in the bone remodelling cycle. At the microstructural level, osteoclasts create bone deficits by eroding resorption cavities. Understanding how these cavities impair the mechanical quality of the bone is not only relevant in quantifying the impact of resorption cavities in healthy bone and normal aging, but maybe even more so in quantifying their role in metabolic bone diseases. Metabolic bone diseases and their treatment are both known to affect the bone remodelling cycle; hence, the bone mechanical competence can and will be affected. However, the current knowledge of the precise dimensions of these cavities and their effect on bone competence is rather limited. This is not surprising considering the difficulties in deriving three-dimensional (3D) properties from two-dimensional (2D) histological sections. The measurement difficulties are reflected in the evaluation of how resorption cavities affect bone competence. Although detailed 3D models are generally being used to quantify the mechanical impact of the cavities, the representation of the cavities themselves has basically been limited to simplified shapes and averaged cavity properties. Qualitatively, these models indicate that cavity size and location are important, and that the effect of cavities is larger than can be expected from simple bone loss. In summary, the dimensions of osteoclast resorption cavities were until recently estimated from 2D measures; hence, a careful interpretation of resorption cavity dimensions is necessary. More effort needs to go into correctly quantifying resorption cavities using modern 3D imaging techniques like micro-computed tomography (micro-CT) and synchrotron radiation CT. Osteoclast resorption cavities affect bone competence. The structure-function relationships have been analysed using computational models that, on one hand, provide rather detailed information on trabecular bone structure, but on the other incorporate rather crude assumptions on cavity dimensions. The use of high-resolution representations and parametric descriptions could be potential routes to improve the quantitative fidelity of these models. PMID- 25276310 TI - Role of cardiac CTA in estimating left ventricular volumes and ejection fraction. AB - Left ventricular ejection fraction (LVEF) is an important predictor of cardiac outcome and helps in making important diagnostic and therapeutic decisions such as the treatment of different types of congestive heart failure or implantation of devices like cardiac resynchronization therapy-defibrillator. LVEF can be measured by various techniques such as transthoracic echocardiography, contrast ventriculography, radionuclide techniques, cardiac magnetic resonance imaging and cardiac computed tomographic angiography (CTA). The development of cardiac CTA using multi-detector row CT (MDCT) has seen a very rapid improvement in the technology for identifying coronary artery stenosis and coronary artery disease in the last decade. During the acquisition, processing and analysis of data to study coronary anatomy, MDCT provides a unique opportunity to measure left ventricular volumes and LVEF simultaneously with the same data set without the need for additional contrast or radiation exposure. The development of semi automated and automated software to measure LVEF has now added uniformity, efficiency and reproducibility of practical value in clinical practice rather than just being a research tool. This article will address the feasibility, the accuracy and the limitations of MDCT in measuring LVEF. PMID- 25276311 TI - Vascular anomalies: A pictorial review of nomenclature, diagnosis and treatment. AB - Vascular anomalies, including vascular malformations and tumors, are frequently straightforward to detect; however, accurate diagnosis and appropriate treatment are often challenging. Misdiagnosis of these lesions can lead clinicians in the wrong direction when treating these patients, which can have unfavorable results. This review presents an overview of the classification systems that have been developed for the diagnosis of vascular lesions with a focus on the imaging characteristics. Pictorial examples of each lesion on physical examination, as well as non-invasive and minimally invasive imaging are presented. An overview of the endovascular treatment of these lesions is also given. In some cases, vascular anomalies may be associated with an underlying syndrome and several of the most commonly encountered syndromes are discussed. Understanding of the classification systems, familiarity with the treatment options and knowledge of the associated syndromes are essential for all physicians working with this patient population. The approach to the described entities necessitates an organized multi-disciplinary team effort, with diagnostic imaging playing an increasingly important role in the proper diagnosis and a combined interventional radiologic and surgical treatment method showing promising results. PMID- 25276312 TI - Expectations from imaging for pre-transplant evaluation of living donor liver transplantation. AB - Living donor liver transplant (LDLT) is a major surgical undertaking. Detailed pre-operative assessment of the vascular and biliary anatomy is crucial for safe and successful harvesting of the graft and transplantation. Computed tomography (CT) and magnetic resonance imaging (MRI) are currently the imaging modalities of choice in pre-operative evaluation. These cross-sectional imaging techniques can reveal the vascular and biliary anatomy, assess the hepatic parenchyma and perform volumetric analysis. Knowledge of the broad indications and contraindications to qualify as a recipient for LDLT is essential for the radiologist reporting scans in a pre-transplant patient. Similarly, awareness of the various anatomical variations and pathological states in the donor is essential for the radiologist to generate a meaningful report of his/her observations. CT and MRI have largely replaced invasive techniques such as catheter angiography, percutaneous cholangiography and endoscopic retrograde cholangiopancreatography. In order to generate a meaningful report based on these pre-operative imaging scans, it is also mandatory for the radiologist to be aware of the surgeon's perspective. We intend to provide a brief overview of the common surgical concepts of LDLT and give a detailed description of the minimum that a radiologist is expected to seek and report in CT and MR scans performed for LDLT related evaluation. PMID- 25276313 TI - Radiation pneumonitis after stereotactic radiation therapy for lung cancer. AB - Stereotactic body radiation therapy (SBRT) has a local control rate of 95% at 2 years for non-small cell lung cancer (NSCLC) and should improve the prognosis of inoperable patients, elderly patients, and patients with significant comorbidities who have early-stage NSCLC. The safety of SBRT is being confirmed in international, multi-institutional Phase II trials for peripheral lung cancer in both inoperable and operable patients, but reports so far have found that SBRT is a safe and effective treatment for early-stage NSCLC and early metastatic lung cancer. Radiation pneumonitis (RP) is one of the most common toxicities of SBRT. Although most post-treatment RP is Grade 1 or 2 and either asymptomatic or manageable, a few cases are severe, symptomatic, and there is a risk for mortality. The reported rates of symptomatic RP after SBRT range from 9% to 28%. Being able to predict the risk of RP after SBRT is extremely useful in treatment planning. A dose-effect relationship has been demonstrated, but suggested dose volume factors like mean lung dose, lung V20, and/or lung V2.5 differed among the reports. We found that patients who present with an interstitial pneumonitis shadow on computed tomography scan and high levels of serum Krebs von den Lungen 6 and surfactant protein D have a high rate of severe radiation pneumonitis after SBRT. At our institution, lung cancer patients with these risk factors have not received SBRT since 2006, and our rate of severe RP after SBRT has decreased significantly since then. PMID- 25276314 TI - MRI in central nervous system infections: A simplified patterned approach. AB - Recognition and characterization of central nervous system infections poses a formidable challenge to the neuro-radiologist. Imaging plays a vital role, the lesions typically being relatively inaccessible to tisue sampling. The results of an accurate diagnosis are endlessly rewarding, given the availability of excellent pharmacological regimen. The availability of numerous magnetic resonance (MR) sequences which provide functional and molecular information is a powerful tool in the hands of the radiologist. However, the plethora of sequences and the possibilities on each sequence is also intimidating, and often confusing as well as time consuming. While a large number of reviews have already described in detail the possible imaging findings in each infection, we intend to classify infections based on their imaging characteristics. In this review we describe an algorithm for first classifying the imaging findings into patterns based on basic MR sequences (T1, T2 and enhancement pattern with Gadolinium), and then sub classify them based on more advanced molecular and functional sequences (Diffusion, Perfusion, Susceptibility imaging, MR Spectroscopy). This patterned approach is intended as a guide to radiologists in-training and in-practice for quickly narrowing their list of differentials when faced with a clinical challenge. The entire content of the article has also been summarised in the form of flow-charts for the purpose of quick reference. PMID- 25276315 TI - Low dose four-dimensional computerized tomography with volume rendering reconstruction for primary hyperparathyroidism: How I do it? AB - Modification of 4-dimensional computed tomography (4D-CT) technique with volume rendering reconstructions and significant dose reduction is a safe and accurate method of pre-operative localization for primary hyperparathyroidism. Modified low dose 4D-CT with volume rendering reconstructions provides precise preoperative localization and is associated with a significant reduction in radiation exposure compared to classic preoperative localizing techniques. It should be considered the preoperative localization study of choice for primary hyperparathyroidism. PMID- 25276316 TI - Malrotation: Current strategies navigating the radiologic diagnosis of a surgical emergency. AB - The most accurate and practical imaging algorithm for the diagnosis of intestinal malrotation can be a complex and sometimes controversial topic. Since 1900, significant advances have been made in the radiographic assessment of infants and children suspected to have anomalies of intestinal rotation. We describe the current methods of abdominal imaging of malrotation along with their pros and cons. When associated with volvulus, malrotation is a true surgical emergency requiring rapid diagnosis and treatment. We emphasize the importance of close cooperation and communication between radiology and surgery to perform an effective and efficient diagnostic evaluation allowing prompt surgical decision making. PMID- 25276317 TI - Magnetic resonance imaging correlates of bee sting induced multiple organ dysfunction syndrome: A case report. AB - Occasionally systemic complications with high risk of death, such as multiple organ dysfunction syndrome (MODS), can occur following multiple bee stings. This case study reports a patient who presented with MODS, i.e., acute kidney injury, hepatic and cardiac dysfunction, after multiple bee stings. The standard clinical findings were then correlated with magnetic resonance imaging (MRI) findings, which demonstrates that MRI may be utilized as a simpler tool to use than other multiple diagnostics. PMID- 25276318 TI - Squamoid cystosis of pancreatic ducts: a variant of a newly-described cystic lesion, with evidence for an obstructive etiology. AB - We describe a 40-year-old man who was found to have a cystic mass in the pancreatic tail during workup for weight loss and abdominal discomfort. Although computed tomography scan showed a single cyst associated with dilatation of the main pancreatic duct, gross and histologic examination of the distal pancreatectomy specimen actually revealed a central cyst that was surrounded by multiple smaller cystic spaces. This distinctive appearance was formed from extensive cystic dilatation and squamous metaplasia of the native pancreatic duct system. Further, a traumatic neuroma was discovered near the junction between normal and abnormal parenchyma. We believe that this case represents a variant of the newly-described squamoid cyst of pancreatic ducts which we term squamoid cystosis of pancreatic ducts. The presence of chronic pancreatitis and a traumatic neuroma supports the hypothesis that squamoid cysts are non-neoplastic lesions arising from prior duct obstruction. PMID- 25276319 TI - Dedifferentiated giant-cell tumor of bone with an undifferentiated round cell mesenchymal component. AB - The dedifferentiated giant-cell tumor of the bone is a very rare variant of the giant-cell tumor (GCT). We report the clinical, radiographic and histological findings of a dedifferentiated GCT in which the dedifferentiated component consisted of small round cells. We also comment on previously reported cases of dedifferentiated GCT, discuss the clinical implications of this dual histology, and analyze the information published about the coexistence of similar genetic abnormalities in GCT and small round cell tumors of the bone. PMID- 25276320 TI - Connection between Cell Phone use, p53 Gene Expression in Different Zones of Glioblastoma Multiforme and Survival Prognoses. AB - The aim of this paper is to investigate p53 gene expression in the central and peripheral zones of glioblastoma multiforme using a real-time reverse transcription polymerase chain reaction (RT-PCR) technique in patients who use cell phones >=3 hours a day and determine its relationship to clinicopathological findings and overall survival. Sixty-three patients (38 males and 25 females), diagnosed with glioblastoma multiforme (GBM), underwent tumor resection between 2008 and 2011. Patient ages ranged from 25 to 88 years, with a mean age of 55. The levels of expression of p53 in the central and peripheral zone of the GBM were quantified by RT-PCR. Data on p53 gene expression from the central and peripheral zone, the related malignancy and the clinicopatholagical findings (age, gender, tumor location and size), as well as overall survival, were analyzed. Forty-one out of 63 patients (65%) with the highest level of cell phone use (>=3 hours/day) had higher mutant type p53 expression in the peripheral zone of the glioblastoma; the difference was statistically significant (P=0.034). Results from the present study on the use of mobile phones for >=3 hours a day show a consistent pattern of increased risk for the mutant type of p53 gene expression in the peripheral zone of the glioblastoma, and that this increase was significantly correlated with shorter overall survival time. The risk was not higher for ipsilateral exposure. We found that the mutant type of p53 gene expression in the peripheral zone of the glioblastoma was increased in 65% of patients using cell phones >=3 hours a day. PMID- 25276321 TI - A case of cystic schwannoma in the neck masquerading as branchial cleft cyst. AB - One-third of schwannomas occur in head and neck region, mostly in the parapharyngeal region. Cystic change is seen in only 4% of schwannomas. The diagnosis of such tumors remains a challenge due to the rarity of these lesions and limited utility of fine needle aspiration cytology. When cystic, branchial cleft cyst is an important differential diagnosis more so due to radiological resemblance. We present a case of 42-year-old male with left sided neck mass masquerading as branchial cleft cyst clinically and radiologically. Multiple sections examined from the cystic areas of the mass revealed lymphoid aggregates beneath the cyst wall in addition to the schwannomatous areas. PMID- 25276322 TI - Diffuse intestinal submucosal lipomatosis with incidental epidermal inclusion cyst of caecum clinically masquerading as carcinoma caecum. AB - Symptomatic diffuse submucosal intestinal lipomatosis is a rare entity. Also few cases of epidermal inclusion cyst of caecum have been reported in literature. Here, we are presenting a rare case of intestinal submucosal lipomatosis with coincidence of epidermal inclusion cyst of caecum and presumptively diagnosed as carcinoma of ileocaecal region during surgery in a 55 years old male. Both are rare entity considering the location even they should be kept as a differential diagnosis in unusual cases of intestinal perforations with inconclusive radiological findings or clinical uncertainity. PMID- 25276323 TI - Aggressive Angiomyxoma of the Pelvis with a Cellular Nodule Composed of Tumor Cells showing Epithelioid Features. AB - A 49-year-old female presented with an aggressive pelvic angiomyxoma (AAM). The completely resected specimen revealed the usual myxedematous tumor with a nodule inside it. Histopathologically, the myxedematous area consisted of bland spindle shaped cells in the background of blood vessels of varying calibers, and the nodule was composed of tumor cells with epithelioid features. In the nodule, cellularity was increased and nuclear enlargement was observed, but nuclear atypia was not significant and mitotic figures were scarce. Immunohistochemically, both components were positive for desim, alphaSMA, estrogen receptors, and progesterone receptors. However, they were negative for AE1/3, EMA, S100, CD34, HMB45, and Melan A. The MIB-1 labeling index was 5.8% in the nodule and 1ess than 1% outside it. The nodule was therefore considered a benign component of AAM. To the best of our knowledge, the presence of such a nodule in AAM has not been reported previously. PMID- 25276324 TI - Rare primary central nervous system tumors. AB - There are close to 70,000 new cases of primary central nervous system tumors diagnosed annually in the United States. Meningiomas, gliomas, nerve sheath tumors and pituitary tumors account for 85% of them. There is abundant literature on these commonly occurring tumors but data from the literature on infrequently encountered tumors such as atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, ganglioglioma, hemangiopericytoma, and pleomorphic xanthoastrocytoma are limited. This review provides an overview of the clinicopathologic and therapeutic aspects of these rare primary central nervous system tumors. PMID- 25276325 TI - History of the rare cancer network and past research. AB - Approximately, twenty years ago, the Rare Cancer Network (RCN) was formed in Lausanne, Switzerland, to support the study of rare malignancies. The RCN has grown over the years and now includes 130 investigators from twenty-four nations on six continents. The network held its first international symposium in Nice, France, on March 21-22, 2014. The proceedings of that meeting are presented in two companion papers. This manuscript reviews the history of the growth of the RCN and contains the abstracts of fourteen oral presentations made at the meeting of prior RCN studies. From 1993 to 2014, 74 RCN studies have been initiated, of which 54 were completed, 10 are in progress or under analysis, and 9 were stopped due to poor accrual. Forty-four peer reviewed publications have been written on behalf of the RCN. PMID- 25276326 TI - The rare cancer network: ongoing studies and future strategy. AB - The Rare Cancer Network (RCN) was formed in the early 1990's to create a global network that could pool knowledge and resources in the studies of rare malignancies whose infrequency prevented both their study with prospective clinical trials. To date, the RCN has initiated 74 studies resulting in 46 peer reviewed publications. The First International Symposium of the Rare Cancer Network took place in Nice in March of 2014. Status updates and proposals for new studies were heard for fifteen topics. Ongoing studies continue for cardiac sarcomas, thyroid cancers, glomus tumors, and adult medulloblastomas. New proposals were presented at the symposium for primary hepatic lymphoma, solitary fibrous tumors, Rosai-Dorfman disease, tumors of the ampulla of Vater, salivary gland tumors, anorectal melanoma, midline nuclear protein in testes carcinoma, pulmonary lymphoepithelioma-like carcinoma, adenoid cystic carcinoma of the trachea, osteosarcomas of the mandible, and extra-cranial hemangiopericytoma. This manuscript presents the abstracts of those proposals and updates on ongoing studies, as well a brief summary of the vision and future of the RCN. PMID- 25276327 TI - Multicentric Castleman's Disease and Kaposi's Sarcoma in a HIV-Positive Patient on Highly Active Antiretroviral Therapy. AB - Castleman's disease is a group of rare lymphoproliferative disorders. The plasmablastic multicentric Castleman's disease is frequently discovered in HIV infected individuals in association with Kaposi sarcoma (HHV-8). Thirty-five year old male presented to our care with the main compliant of severe back pain for one week. His past medical problems include acquired immune deficiency syndrome diagnosed 12 years prior and Kaposi sarcoma, currently on highly active antiretroviral therapy (HAART). Radiographic imaging revealed hepatomegaly and diffuse lymphadenopathy. The HIV viral load was <20 polymerase chain reaction copies/mL, absolute CD4 count was 453 cells/mcL (490-1740 cells/mcL) and CD8 count was 4142 cells/mcL (180-1170 cells/ mcL). Excisional biopsy of the left supraclavicular lymph node was performed with pathological findings of HHV8+ Kaposi sarcoma in the background of multicentric Castleman's disease (plasmacytic variant). No evidence of transformation into large B-cell or plasmablastic lymphoma was noted. He was discharged on HAART and follow up to receive chemotherapy with cyclophosphamide, adriamycin, vincristine plus prednisone was started and rituximab plus prophylaxis for pneumocystis carinii. Multicentric Castleman's disease has become more relevant in recent years due to its association with HIV and HHV-8 (Kaposi sarcoma) and its potential to progress into plasmablastic B-cell lymphoma. The progression of MCD to B-cell lymphoma is a concern, especially in patients with HIV infection because it precludes the worst outcome and a high mortality, despite treatment. The most intriguing part of this case is that MCD occurred in a HIV-positive on HAART. This case signals a warning that a high suspicion for MCD can be justified even in those HIV-positive patients on HAART because the possibly of progression to plasmablastic B-cell lymphoma. PMID- 25276328 TI - Immature uterine teratoma associated with uterine inversion. AB - Teratomas are the most commonly diagnosed germ cell tumors and occur primarily in testes and ovaries. Platinum-based therapy followed by surgical resection of the residual lesion is generally the recommended treatment. In contrast, immature uterine teratomas are rare, with few cases reported in the literature. Moreover, there is no standard treatment for these tumors. Non-puerperal uterine inversion is also rare in women younger than 45 years of age, and neoplastic lesions are responsible for this condition. Here, we report a case of an immature uterine teratoma associated with uterine inversion. The patient underwent surgery followed by adjuvant chemotherapy and continues to be monitored. PMID- 25276330 TI - Lactobacillus endocarditis with prosthetic material: a case report on non surgical management with corresponding literature review. AB - Lactobacilli are rod shaped gram positive bacteria that naturally colonize the human gastrointestinal and genitourinary tracts and occasionally cause disease in humans. Lactobacillus infections are found in patients who are immunocompromized or have severe comorbidities. We report Lactobacillus endocarditis in a 17-year old adolescent girl with cardiac prosthetic material following surgical correction for complex cyanotic congenital heart disease. Accurate identification of the organism can be delayed. Despite in vivo susceptibility to vancomycin, our patient clinically failed vancomycin therapy but ultimately responded to a six week course of penicillin, in addition to a 4-week course of clindamycin and gentamicin. She recovered without the need for surgical intervention and has been symptom free for one year. Upon review of the literature, we found that Lactobacillus endocarditis has not been reported in a pediatric patient with complex cyanotic congenital heart disease. PMID- 25276329 TI - Intra-Pleural Colistin Methanesulfonate Therapy for Pleural Infection caused by Carbapenem-Resistant Acinetobacter Baumannii: A Successful Case Report. AB - Infections caused by carbapenem-resistant, Gram-negative bacteria are an increasing clinical challenge, since the antimicrobial treatment options are often limited to colistin methanesulfonate. No data are available regarding the pharmacokinetics of colistin in pleural fluid. We report the case of a 92-year old man with ventilator-associated pneumonia and pleurisy caused by Acinetobacter baumannii and Escherichia coli, which were both multidrug-resistant. After an unsuccessful treatment with intravenous colistin methanesulfonate and imipen-em cilastatin, the addition of intra-pleural colistin methanesulfonate to the intravenous treatment led to a prompt clinical, radiological and microbiological resolution. This is the first report of a successful use of intra-pleural colistin in the literature. The intra-pleural colistin therapy should be considered in selected cases of pleurisy caused by multi-resistant Gram-negative bacteria. PMID- 25276331 TI - Massive Alimentary Tract Bleeding due to Cytomegalovirus Infection in an Elderly Patient. AB - In recent years, cytomegalovirus (CMV) has been recognized as an important common pathogen in immunocompromized patients. This is due to the increasing number of immunosuppressive medications, intensive cancer chemotherapy use, recurrent transplantations, progressively aging population, and the higher number of human immunodeficiency virus infections. Cytomegalovirus infection especially interests the gastrointestinal tract, anywhere, from the mouth to the anus. Namely, the most commonly affected area is the colon, followed by duodenum, stomach, esophagus and small intestine. The most frequent manifestations of CMV colitis are: diarrhea, fever, gastrointestinal bleeding and abdominal pain. We report here the case of an 82-year-old woman, who was treated for non-Hodgkin lymphoma; she was admitted to the emergency department for abdominal pain and diffuse arthralgia, following massive upper- and lower- gastrointestinal bleeding, due to duodenal and colonic ulcers related to CMV infection. PMID- 25276332 TI - Disseminated cutaneous herpes zoster in an immunocompetent elderly patient. AB - Herpes zoster is a clinical syndrome which usually presents with a localized, vesicular rash in a dermatomal distribution. Cutaneous dissemination rarely occurs in immunocompetent patients, therefore little is known about the baseline demographic, clinical characteristics, management and outcome of these patients. Herein, we report a case of disseminated cutaneous herpes zoster in an immunocompetent patient along with a review and analysis of 28 cases previously reported in the literature. PMID- 25276333 TI - The influence of functional electrical stimulation on hand motor recovery in stroke patients: a review. AB - Neuromuscular stimulation has been used as one potential rehabilitative treatment option to restore motor function and improve recovery in patients with paresis. Especially stroke patients who often regain only limited hand function would greatly benefit from a therapy that enhances recovery and restores movement. Multiple studies investigated the effect of functional electrical stimulation on hand paresis, the results however are inconsistent. Here we review the current literature on functional electrical stimulation on hand motor recovery in stroke patients. We discuss the impact of different parameters such as stage after stoke, degree of impairment, spasticity and treatment protocols on the functional outcome. Importantly, we outline the results from recent studies investigating the cortical effects elicited by functional electrical stimulation giving insights into the underlying mechanisms responsible for long-term treatment effects. Bringing together the findings from present research it becomes clear that both, treatment outcomes as well as the neurophysiologic mechanisms causing functional recovery, vary depending on patient characteristics. In order to develop unified treatment guidelines it is essential to conduct homogenous studies assessing the impact of different parameters on rehabilitative success. PMID- 25276334 TI - The Porifera Ontology (PORO): enhancing sponge systematics with an anatomy ontology. AB - BACKGROUND: Porifera (sponges) are ancient basal metazoans that lack organs. They provide insight into key evolutionary transitions, such as the emergence of multicellularity and the nervous system. In addition, their ability to synthesize unusual compounds offers potential biotechnical applications. However, much of the knowledge of these organisms has not previously been codified in a machine readable way using modern web standards. RESULTS: The Porifera Ontology is intended as a standardized coding system for sponge anatomical features currently used in systematics. The ontology is available from http://purl.obolibrary.org/obo/poro.owl, or from the project homepage http://porifera-ontology.googlecode.com/. The version referred to in this manuscript is permanently available from http://purl.obolibrary.org/obo/poro/releases/2014-03-06/. CONCLUSIONS: By standardizing character representations, we hope to facilitate more rapid description and identification of sponge taxa, to allow integration with other evolutionary database systems, and to perform character mapping across the major clades of sponges to better understand the evolution of morphological features. Future applications of the ontology will focus on creating (1) ontology-based species descriptions; (2) taxonomic keys that use the nested terms of the ontology to more quickly facilitate species identifications; and (3) methods to map anatomical characters onto molecular phylogenies of sponges. In addition to modern taxa, the ontology is being extended to include features of fossil taxa. PMID- 25276336 TI - Conserved behavioral and genetic mechanisms in the pre-hatching molt of the nematode Pristionchus pacificus. AB - BACKGROUND: During development, juvenile nematodes undergo four molts. Although the number of molts appears to be constant within the Nematoda, the timing of the first molt can occur either before or after hatching. A previous study indicates that, as in some parasitic nematode lineages, a pre-hatching juvenile stage also exists in Diplogastrid nematodes. A detailed description of these sequence of events has yet to be shown for any single species. FINDINGS: To delineate the timing of the pre-hatching molt in the beetle-associated Pristionchus pacificus, we tracked individual mid-J1 stage worms inside the eggshell through the J1-J2 transition and hatching. We found that active movement ended 21 hours after egg laying, followed by lethargus and hatching. We inferred that lethargus behavior represents the onset of the first molt, which precedes each post-hatching molt in C. elegans and P. pacificus. The onset of the J1-J2 molt was also marked by the upregulation of the P. pacificus molting marker Ppa-pnhr-1. We further corroborated the pre-hatching molt with the isolation of two genetic mutants that exhibited aberrant molting both inside the egg and after hatching, as characterized by protracted and often-aborted shedding of the old cuticle. CONCLUSION: Our results describe in detail the pre-hatching juvenile molt in P. pacificus, provide strong visual evidence of a pre-hatching molt, and show support for common genetic mechanisms regulating molting in the pre-hatching and post-hatching developmental stages. Our findings support the hypothesis that the evolution of pre-hatching development in Diplogastrid nematodes is likely due to a heterochronic shift between the timing of the first molt and hatching. PMID- 25276335 TI - Structuring research methods and data with the research object model: genomics workflows as a case study. AB - BACKGROUND: One of the main challenges for biomedical research lies in the computer-assisted integrative study of large and increasingly complex combinations of data in order to understand molecular mechanisms. The preservation of the materials and methods of such computational experiments with clear annotations is essential for understanding an experiment, and this is increasingly recognized in the bioinformatics community. Our assumption is that offering means of digital, structured aggregation and annotation of the objects of an experiment will provide necessary meta-data for a scientist to understand and recreate the results of an experiment. To support this we explored a model for the semantic description of a workflow-centric Research Object (RO), where an RO is defined as a resource that aggregates other resources, e.g., datasets, software, spreadsheets, text, etc. We applied this model to a case study where we analysed human metabolite variation by workflows. RESULTS: We present the application of the workflow-centric RO model for our bioinformatics case study. Three workflows were produced following recently defined Best Practices for workflow design. By modelling the experiment as an RO, we were able to automatically query the experiment and answer questions such as "which particular data was input to a particular workflow to test a particular hypothesis?", and "which particular conclusions were drawn from a particular workflow?". CONCLUSIONS: Applying a workflow-centric RO model to aggregate and annotate the resources used in a bioinformatics experiment, allowed us to retrieve the conclusions of the experiment in the context of the driving hypothesis, the executed workflows and their input data. The RO model is an extendable reference model that can be used by other systems as well. AVAILABILITY: The Research Object is available at http://www.myexperiment.org/packs/428 The Wf4Ever Research Object Model is available at http://wf4ever.github.io/ro. PMID- 25276337 TI - Transition to annual life history coincides with reduction in cell cycle speed during early cleavage in three independent clades of annual killifish. AB - BACKGROUND: Annual killifishes inhabit temporary ponds and their embryos survive the dry season encased in the mud by entering diapause, a process that arrests embryonic development during hostile conditions. Annual killifishes are present within three clades distributed in Africa (one East and one West of the Dahomey gap) and South America. Within each of these phylogenetic clades, a non-annual clade is sister taxon to a annual clade and therefore represent an example of convergent evolution. Early cleavage of teleost embryos is characterized by a very fast cell cycle (15-30 minutes) and lack of G1 and G2 phases. Here, we decided to investigate rates of early cleavage in annual killifishes. In addition, we specifically tested whether also annual killifish embryos lack G1 and G2 phases. RESULTS: We used time lapse brightfield microscopy to investigate cell division kinetics during the first developmental stages of annual- and non annual species belonging to the three different phylogenetic clades. Annual killifishes of all three clades showed cleavage times significantly longer when compared to their non-annual sister taxa (average 35 min vs. average 75 min). Using FUCCI fluorescent imaging of the cell cycle after microinjection in the annual species Nothobranchius furzeri, we demonstrate that the first 5 division are synchronous and do not show a G1 phase. Cell cycle synchronization is lost after the 5th cleavage division. CONCLUSIONS: Our results show, for the first time, that cell cycle rate during cleavage, a trait thought to be rather evolutionary conserved can undergo convergent evolutionary change in response to variations in life-history. PMID- 25276338 TI - Extraction of echocardiographic data from the electronic medical record is a rapid and efficient method for study of cardiac structure and function. AB - BACKGROUND: Measures of cardiac structure and function are important human phenotypes that are associated with a range of clinical outcomes. Studying these traits in large populations can be time consuming and costly. Utilizing data from large electronic medical records (EMRs) is one possible solution to this problem. We describe the extraction and filtering of quantitative transthoracic echocardiographic data from the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study, a large, racially diverse, EMR-based cohort (n = 15,863). RESULTS: There were 6,076 echocardiography reports for 2,834 unique adult subjects. Missing data were uncommon with over 90% of data points present. Data irregularities are primarily related to inconsistent use of measurement units and transcriptional errors. The reported filtering method requires manual review of very few data points (<1%), and filtered echocardiographic parameters are similar to published data from epidemiologic populations of similar ethnicity. Moreover, the cohort is comparable in size, and in some cases larger than community-based cohorts of similar race/ethnicity. CONCLUSIONS: These results demonstrate that echocardiographic data can be efficiently extracted from EMRs, and suggest that EMR-based cohorts have the potential to make major contributions toward the study of epidemiologic and genotype-phenotype associations for cardiac structure and function in diverse populations. PMID- 25276339 TI - Neoadjuvant treatment of Dermatofibrosarcoma Protuberans of pancreas with Imatinib: case report and systematic review of literature. AB - Dermatofibrosarcoma Protuberans (DFSP) is a rare skin tumor, characterized by frequent local recurrence but is seldom metastatic. It is histologically characterized by storiform arrangement of spindle cells. Cytogenetically, most tumors are characterized by translocation 17:22 leading to overexpression of tyrosine kinase PDGFB which can be targeted with tyrosine kinase inhibitor, Imatinib. We describe the first case of unresectable pancreatic metastases from DFSP treated with neoadjuvant Imatinib and subsequently R0 metastectomy. Additionally, a comprehensive systematic review of DFSP pancreatic metastases and the current published data on the use of Imatinib in DFSP is summarized. PMID- 25276340 TI - Successful use of pazopanib for treatment of refractory metastatic hemangiopericytoma. AB - Hemangiopericytoma is a rare disease entity of soft-tissue sarcoma (STS) that can be cured with surgical resection. In cases of inoperable recurrence or metastasis, palliative chemotherapy is indicated, though there is currently no approved chemotherapy regimen. Therefore new treatment regimens are needed. We describe three cases of metastatic hemangiopericytoma. In the first case, five lines of chemotherapeutic agents were used unsuccessfully in a patient with a 12 year history of metastatic hemangiopericytoma. After one cycle of pazopanib therapy, however, chest radiography showed a decrease in tumor volume of more than 30%. A marked decrease in FDG uptake on PET CT was also noted, and the patient is now on her 5(th) month of pazopanib therapy. The second case is a patient with a brain hemangiopericytoma with multiple liver, lung, and bone metastases. Pazopanib induced radiologic stabilization of metastatic disease over the course of 8 months. The third case is a patient with a retroperitoneal hemangiopericytoma with pleural and peri-renal metastases. For more than 8 months, he has exhibited stable disease with pazopanib treatment. Pazopanib may be useful for treatment of metastatic hemangiopericytoma, though further studies are needed to confirm the efficacy of this medication and to investigate its molecular mechanism of action. PMID- 25276341 TI - Two classes of nucleic acid translocation motors: rotation and revolution without rotation. AB - Biomotors are extensively involved in biological processes including cell mitosis, bacterial binary fission, DNA replication, DNA repair, homologous recombination, Holliday junction resolution, RNA transcription, and viral genome packaging. Traditionally, they were classified into two categories including linear and rotation motors. In 2013, a third class of motor by revolution mechanism without rotation was discovered. In this issue of "Structure and mechanisms of nanomotors in the cells", four comprehensive reviews are published to address the latest advancements of the structure and motion mechanism of a variety of biomotors in archaea, animal viruses, bacteria, and bacteriophages. PMID- 25276342 TI - Peanut immunotherapy. AB - Peanut allergy is common and can be a cause of severe, life-threatening reactions. It is rarely outgrown like other food allergies, such as egg and milk. Peanut allergy has a significant effect on the quality of life of sufferers and their families, due to dietary and social restrictions, but mainly stemming from fear of accidental peanut ingestion. The current management consists of strict avoidance, education and provision of emergency medication, but a disease- modifying therapy is needed for peanut allergy. Recent developments involve the use of immunotherapy, which has shown promise as an active form of treatment. Various routes of administration are being investigated, including subcutaneous, oral, sublingual and epicutaneous routes. Other forms of treatment, such as the use of vaccines and anti-IgE molecules, are also under investigation. So far, results from immunotherapy studies have shown good efficacy in achieving desensitisation to peanut with a good safety profile. However, the issue of long term tolerance has not been fully addressed yet and larger, phase III studies are required to further investigate safety and efficacy. An assessment of cost/benefit ratio is also required prior to implementing this form of treatment. The use of immunotherapy for peanut allergy is not currently recommended for routine clinical use and should not be attempted outside specialist allergy units. PMID- 25276344 TI - Progress in the study of biological effects of hydrogen on higher plants and its promising application in agriculture. AB - While the medical effects of hydrogen have been broadly analyzed, research into the effects of hydrogen on higher plants has often been of lesser concern. Recent studies on the botanical effects of hydrogen have shown that it is involved in signal transduction pathways of plant hormones and can improve the resistance of plants to stressors, such as drought, salinity, cold and heavy metals. In addition, hydrogen could delay postharvest ripening and senescence of fruits. Observational evidence has also shown that hydrogen can regulate the flowering time of plants. These results indicate that hydrogen may have great potential applications within agricultural production, indicating that there may be a new 'hydrogen agricultural era' to come. PMID- 25276343 TI - Extravasation into brain and subsequent spread beyond the ischemic core of a magnetic resonance contrast agent following a step-down infusion protocol in acute cerebral ischemia. AB - BACKGROUND: Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia reperfusion for bolus injection and step-down infusion (SDI) protocols. METHODS: Male Wistar rats underwent middle cerebral artery (MCA) occlusion for 3 h followed by reperfusion. Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow (CBF) deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient (ADC) of water with diffusion-weighted imaging. Vascular injury was assessed via MRCA, gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) penetration, by Look-Locker T1 weighted MR imaging after either a bolus injection (n = 8) or SDI (n = 6). Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2.5 min intervals. RESULTS: The mean ADC lesion was 20 +/- 7% of the hemispheric area whereas the CBF deficit area was 60 +/- 16%, with the difference between the areas suggesting the possible presence of a penumbra. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued. The integrated area from SDI extravasation was significantly larger than that for the bolus (p = 0.03). The total number of pixels covered by the SDI at its maximum was significantly larger than the pixels covered by bolus maximum (p = 0.05). CONCLUSIONS: These results demonstrate that the SDI protocol resulted in a spread of the MRCA beyond the ischemic core. Whether plasma-borne acute stroke therapeutics can be delivered to the ischemic penumbra in a similar way needs to be investigated. PMID- 25276345 TI - Changing incidence of bovine babesiosis in Ireland. AB - BACKGROUND: In Ireland bovine babesiosis is caused by the tick-borne blood parasite, Babesia divergens. A survey of veterinary practitioners and farmers in the 1980's revealed an annual incidence of 1.7% associated with considerable economic losses. However, two subsequent surveys in the 1990's indicated a decline in clinical babesiosis. Recent evidence from continental Europe suggests that, probably due to climate change, the distribution of the tick vector of B. divergens, Ixodes ricinus is extending to more northerly regions and higher altitudes. In addition, milder winters are thought to widen the window of tick activity. In order to determine whether any such changes have affected the incidence of bovine babesiosis in Ireland, a questionnaire survey of farmers and veterinarians was carried out and compared with data from previous surveys. RESULTS: Our survey indicates that while the incidence of clinical disease has continued to decline, cases can occur at any time of year. In contrast to previous surveys, affected farms were the same size as unaffected ones. There was no correlation between disease risk and the presence of deer on the land. Disease severity and mortality rates were increased because many infections were advanced by the time they were detected and treated. CONCLUSION: While the precise reasons for the decline in the incidence of redwater are unknown, changes in agricultural practice are likely to be of importance. A reversal of the trend could be devastating, as vigilance among farmers and veterinarians is flagging and the national herd is losing its protective immunity to disease. PMID- 25276346 TI - Fluid therapy in critical illness. AB - Major surgery and critical illnesses such as sepsis and trauma all disturb normal physiological fluid handling. Intravenous fluid therapy for resuscitation and fluid maintenance is a central part of medical care during these conditions, yet the evidence base supporting practice in this area lacks answers to a number of important questions. Recent research developments include a refinement of our knowledge of the endothelial barrier structure and function and a focus on the potential harm that may be associated with intravenous fluid therapy. Here, we briefly describe the contemporary view of fluid physiology and how this may be disrupted by pathological processes. The important themes in critical illness fluid research are discussed, with a particular focus on two emerging ideas: firstly, that individualising fluid treatment to the patient, their underlying disease state and the phase of that illness may be key to improving clinical outcomes using fluid interventions and, secondly, that fluids should be considered to be drugs, with specific indications and contraindications, dose ranges and potential toxicities. PMID- 25276347 TI - Factors influencing survival after kidney transplant failure. AB - BACKGROUND: The failure of a kidney transplant is now a common reason for initiation of dialysis therapy. Kidney transplant recipients commencing dialysis have greater morbidity and mortality than transplant-naive, incident dialysis patients. This study aimed to identify variables associated with survival after graft failure. METHODS: All recipients of first, deceased donor kidney transplants performed in Northern Ireland between 1986 and 2005 who had a functioning graft at 12 months were included (n = 585). Clinical and blood derived variables (age, gender, primary renal disease, diabetic status, smoking status, human leukocyte antigen (HLA) mismatch, acute rejection episodes, immunosuppression, cardiovascular disease, graft survival, haemoglobin, albumin, phosphate, C reactive protein, estimated glomerular filtration rate (eGFR), rate of eGFR decline, dialysis modality, and access) were collected prospectively and investigated for association with re-transplantation and survival. The association between re-transplantation and survival was explored by modelling re transplantation as a time-dependent covariate. RESULTS: Median follow-up time was 12.1 years. Recipients with a failing graft (158/585) demonstrated rapid loss of eGFR prior to graft failure, reducing the time available to plan for alternative renal replacement therapy. Median survival after graft failure was 3.0 years. In multivariate analysis, age and re-transplantation were associated with survival after graft failure. Re-transplantation was associated with an 88% reduction in mortality. CONCLUSIONS: Optimal management of kidney transplant recipients with failing grafts requires early recognition of declining function and proactive preparation for re-transplantation given the substantial survival benefit this confers. The survival benefit associated with re-transplantation persists after prolonged exposure to immunosuppressive therapy. PMID- 25276348 TI - Crowdfunding the Azolla fern genome project: a grassroots approach. AB - Much of science progresses within the tight boundaries of what is often seen as a "black box". Though familiar to funding agencies, researchers and the academic journals they publish in, it is an entity that outsiders rarely get to peek into. Crowdfunding is a novel means that allows the public to participate in, as well as to support and witness advancements in science. Here we describe our recent crowdfunding efforts to sequence the Azolla genome, a little fern with massive green potential. Crowdfunding is a worthy platform not only for obtaining seed money for exploratory research, but also for engaging directly with the general public as a rewarding form of outreach. PMID- 25276349 TI - Chaperone-mediated autophagy: roles in neurodegeneration. AB - Chaperone-mediated autophagy (CMA) selectively delivers cytosolic proteins with an exposed CMA-targeting motif to lysosomes for degradation and plays an important role in protein quality control and cellular homeostasis. A growing body of evidence supports the hypothesis that CMA dysfunction may be involved in the pathogenic process of neurodegenerative diseases. Both down-regulation and compensatory up-regulation in CMA activities have been observed in association with neurodegenerative conditions. Recent studies have revealed several new mechanisms by which CMA function may be involved in the regulation of factors critical for neuronal viability and homeostasis. Here, we summarize these recent advances in the understanding of the relationship between CMA dysfunction and neurodegeneration and discuss the therapeutic potential of targeting CMA in the treatment of neurodegenerative diseases. PMID- 25276350 TI - Quantitative analysis of ruminal methanogenic microbial populations in beef cattle divergent in phenotypic residual feed intake (RFI) offered contrasting diets. AB - BACKGROUND: Methane (CH4) emissions in cattle are an undesirable end product of rumen methanogenic fermentative activity as they are associated not only with negative environmental impacts but also with reduced host feed efficiency. The aim of this study was to quantify total and specific rumen microbial methanogenic populations in beef cattle divergently selected for residual feed intake (RFI) while offered (i) a low energy high forage (HF) diet followed by (ii) a high energy low forage (LF) diet. Ruminal fluid was collected from 14 high (H) and 14 low (L) RFI animals across both dietary periods. Quantitative real time PCR (qRT PCR) analysis was conducted to quantify the abundance of total and specific rumen methanogenic microbes. Spearman correlation analysis was used to investigate the association between the relative abundance of methanogens and animal performance, rumen fermentation variables and diet digestibility. RESULTS: Abundance of methanogens, did not differ between RFI phenotypes. However, relative abundance of total and specific methanogen species was affected (P < 0.05) by diet type, with greater abundance observed while animals were offered the LF compared to the HF diet. CONCLUSIONS: These findings suggest that differences in abundance of specific rumen methanogen species may not contribute to variation in CH4 emissions between efficient and inefficient animals, however dietary manipulation can influence the abundance of total and specific methanogen species. PMID- 25276352 TI - Early assessment of high-intensity focused ultrasound treatment of benign thyroid nodules by scintigraphic means. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) allows to inflict intracorporal thermal lesions without penetrating the skin or damaging the surrounding tissue. This analysis intends to assess the magnitude of HIFU-induced ablations within benign thyroid nodules using scintigraphic imaging with (99m)Tc. METHODS: Ten cold, hot, or indifferent nodules were treated using multiple pulses of HIFU to induce temperatures of around 85 degrees C within the ablation zone. Pre- and posttreatment, uptake values of (99m)Tc-pertechnetate or (99m)Tc-MIBI were recorded. The pre-post reduction of nodular uptake was evaluated to assess ablation magnitude. RESULTS: Relative nodular uptake in relation to total thyroidal uptake decreased after one session of HIFU in all cases. Median (99m)Tc MIBI uptake reduction was 35.5% (ranging from 11% to 57%; p < 0.1), while (99m)Tc pertechnetate scintigraphy showed a median uptake reduction of 27% (range 10% to 44%; p < 0.1). No major complications were observed. CONCLUSIONS: HIFU appears to be safe and is an easy to perform means of thermal ablation. This study shows that HIFU treatment in thyroidal nodules can be evaluated by scintigraphic means shortly after the intervention. Due to small sample size, the exact magnitude of HIFU ablation efficiency in thyroidal nodules remains a value to be assessed in a larger study. PMID- 25276353 TI - Bilateral adrenal gland haemorrhage: an unusual cause. AB - Our patient had drainage of a large amoebic liver abscess. This got complicated by a severe degree of hypotension, which required aggressive fluid resuscitation and hydrocortisone support. Computerised tomography (CT) of the abdomen revealed bilateral adrenal gland haemorrhage (BAH) resulting in primary adrenal gland failure, which was the cause for hypotension. Patient was on long-term warfarin for provoked deep vein thrombosis of lower limb, which was discontinued before the procedure. Thrombophilia profile indicated the presence of lupus anticoagulant factor with prolonged activated partial thromboplastin time (aPTT). Patient was discharged on lifelong warfarin. This case emphasises the need for strong clinical suspicion for diagnosing BAH, rare but life-threatening condition, and its association with amoebic liver abscess and anti-phospholipid antibody syndrome (APLS). LEARNING POINTS: Recognition of BAH as a rare complication of sepsis.APLS can rarely cause BAH. PMID- 25276354 TI - Thoracoscopic sleeve resection-the better approach? PMID- 25276355 TI - Breast cancer control in China: challenges and opportunities of the use of population-based routine data studies. PMID- 25276356 TI - Moving beyond the boundary: the emerging role of video-assisted thoracic surgery for bronchoplastic resections. AB - Sleeve resections with parenchymal sparing should be attempted whenever possible when operating a central lung cancer rather than performing a pneumonectomy. Long term results conclusively favored sleeve procedures in improved survival, quality of life, reduced loss in lung function, and improved operative mortality. Therefore, all surgeons should own this technique in their surgical armamentarium. In the last two decades, the minimally invasive surgical approach has slowly gained positions in Thoracic Surgery and now more and more patients ask for a minimally invasive procedure when surgery is required. This technical revolution in thoracic surgery advocates that almost every open procedure could be done in video-assisted thoracic surgery (VATS). Nevertheless, like all other minimally invasive procedures, VATS sleeve lobectomy has a long learning curve. With the skills and the experience derived from major VATS procedures, these demanding surgical operations may also be performed with a minimally invasive approach. PMID- 25276357 TI - Wedge resection for localized infectious lesions: high margin/lesion ratio guaranteed operational safety. AB - OBJECTIVE: This study aims to elucidate the risk factors of pulmonary complications for localized infectious lesions with limited resection. METHODS: We retrospectively investigated 139 cases for which wedge resection had been performed for localized pulmonary infectious lesions. Patients included 85 males and 54 females with a median age of 53 years (range: 21-74 years old). Forty-six patients had focal organizing pneumonia (OP), sixty patients had lung abscess, twenty-three patients had aspergilloma, five patients had lung abscess combining aspergillus fumigatus, and five patients had lung abscess combined with tuberculosis granuloma. Information regarding perioperative manipulations, surgical complications, and follow-ups were collected for further analysis. RESULTS: Prominent pneumonia developed in eight cases post-operation. In follow up, one patient had a recurrence of lung abscess five months post-operation and underwent a left upper lobectomy and one patient died two months after discharge because of respiratory failure that resulted from pneumonia. Univariate and multivariate analysis showed a significant difference in the margin/lesion ratio (distance between staple margins to lesion/the maximum tumor diameter) between patients with pulmonary complications and those without complications (P=0.01). The best cut-off value of margin/lesion ratio to complication was 0.985, and a margin/lesion ratio less than 0.985 was associated with high post-operative complications. CONCLUSIONS: The present case series shows that partial resection for localized pulmonary infection is an acceptable surgical manipulation. A high margin/lesion ratio achievement may guarantee operational safety. PMID- 25276358 TI - Effectiveness and safety of a protocolized mechanical ventilation and weaning strategy of COPD patients by respiratory therapists. AB - INTRODUCTION: Prior researches have showed that weaning protocols may decrease the duration of mechanical ventilation. The effect of these protocols on chronic obstructive pulmonary disease (COPD) patients is unknown. The purpose of this study was to evaluate the impact of an extensive mechanical ventilation protocol including weaning applied by a respiratory therapist (RT) on the duration of mechanical ventilation and intensive care unit (ICU) stay in COPD patients. MATERIALS AND METHODS: A novel mechanical ventilation protocol including weaning was developed and initiated for all intubated COPD patients by a respiratory therapist. Outcomes of patients treated using this protocol during a 6-month period were compared to those of patients treated by physicians without a protocol during the preceding 6 months. RESULTS: A total of 170 patients were enrolled. Extubation success was significantly higher (98% vs. 78%, P=0.014) and median durations of weaning, mechanical ventilation and ICU stay compared with time to event analysis were significantly shorter in the protocol based group (2 vs. 26 hours, log rank P<0.001, 3.1 vs. 5 days, log rank P<0.001 and 6 vs. 12 days, log rank P<0.001, respectively). Patients who were successfully extubated and patients in the protocol based group were more likely to have shorter ventilation duration [HR: 1.87, 95% confidence intervals (CI): 1.13-3.08, P=0.015 and HR: 2.08, 95% CI: 1.40-3.10, P<0.001 respectively]. CONCLUSIONS: In our center, a protocolized mechanical ventilation and weaning strategy improved weaning success and shortened the total duration of mechanical ventilation and ICU stay in COPD patients requiring mechanical ventilation. PMID- 25276359 TI - An analysis of and new risk factors for reexpansion pulmonary edema following spontaneous pneumothorax. AB - BACKGROUND: The major risk factor for reexpansion pulmonary edema (RPE) following the treatment of spontaneous pneumothorax is thought to be chronic lung collapse. However, a long-term collapsed lung does not always cause RPE. The purpose of this study was to define other risk factors for RPE among patients undergoing drainage for the treatment of spontaneous pneumothorax. METHODS: We retrospectively reviewed all the patients with spontaneous pneumothorax who had been treated at our hospital during a 5-year period. The duration of symptoms, location and size of the pneumothorax, size of the chest tube, and pleural effusion, which can occur coincidentally with pneumothorax, were compared in patients who did and did not experience RPE. RESULTS: Forty patients were underwent drainage for the treatment of a spontaneous pneumothorax between January 2007 and December 2012. RPE developed in 13 of the 40 (32.5%) patients. In the multivariate analysis, the presence of pleural effusion coincident with pneumothorax contributed to the risk for RPE [odds ratios (OR), 1.557; 95% confidence intervals (CI), 1.290-1.880]. The duration of symptoms, location and size of the pneumothorax and size of the chest tube were similar between the groups. Symptomatic RPE was associated with a larger pneumothorax size. CONCLUSIONS: The rate of RPE following spontaneous pneumothorax is higher than was previously reported. Our findings suggest the presence of pleural effusion coincidentally with pneumothorax may therefore be a new risk factor for RPE. PMID- 25276360 TI - Rapid detection of Streptococcus pneumoniae by real-time fluorescence loop mediated isothermal amplification. AB - BACKGROUND AND AIM OF STUDY: A significant human pathogenic bacterium, Streptococcus pneumoniae was recognized as a major cause of pneumonia, and is the subject of many humoral immunity studies. Diagnosis is generally made based on clinical suspicion along with a positive culture from a sample from virtually any place in the body. But the testing time is too long. This study is to establish a rapid diagnostic method to identification of Streptococcus pneumoniae. METHODS: Our laboratory has recently developed a new platform called real-amp, which combines loop-mediated isothermal amplification (LAMP) with a portable tube scanner real-time isothermal instrument for the rapid detection of Streptococcus pneumonia. Two pairs of amplification primers required for this method were derived from a conserved DNA sequence unique to the Streptococcus pneumoniae. The amplification was carried out at 63 degree Celsius using SYBR Green for 60 minutes with the tube scanner set to collect fluorescence signals. Clinical samples of Streptococcus pneumoniae and other bacteria were used to determine the sensitivity and specificity of the primers by comparing with traditional culture method. RESULTS: The new set of primers consistently detected in laboratory maintained isolates of Streptococcus pneumoniae from our hospital. The new primers also proved to be more sensitive than the published species-specific primers specifically developed for the LAMP method in detecting Streptococcus pneumoniae. CONCLUSIONS: This study demonstrates that the Streptococcus pneumoniae LAMP primers developed here have the ability to accurately detect Streptococcus pneumoniae infections by real-time fluorescence LAMP. PMID- 25276361 TI - Airway bacterial colonization in patients with non-small cell lung cancer and the alterations during the perioperative period. AB - BACKGROUND: To observe the alterations in airway bacterial colonization during the perioperative period in patients with non-small cell lung cancer (NSCLC) and evaluate their clinical implications. METHODS: Patients with resectable primary NSCLC were enrolled from October 2011 to April 2012. Airway secretions were harvested for microbiological study after admission, immediately after surgery, and before endotracheal extubation. Spontaneous sputum was collected when patients presented with signs of postoperative pneumonia (POP). Detailed data on the isolated pathogens were carefully recorded. Risk factors for airway colonization and POP were analyzed. RESULTS: A total of 78 consecutive patients were enrolled. Fourteen patients (17.9%) had airway colonization at admission, including four cases of fungi and ten cases of Gram-negative bacilli (GNB). Five patients (6.4%) had colonized pathogens at the end of surgery, including three cases of GNB and two cases of Gram-positive cocci. Nine (11.5%) patients had positive culture of airway secretions collected before extubation, including seven cases of GNB and two cases of fungi. Eighteen patients (23.1%) had POP, of whom one suffered from bronchopleural fistula and one died of POP. Pathogens of POP were confirmed in 11 patients, including nine cases of GNB and two cases of fungi. Three patients had the same pathogens as preoperative colonization. The proportion of more antibiotic-resistant strains increased gradually. Advanced age [odds ratio (OR), 2.263; 95% confidence interval (95% CI), 1.030-4.970] and smoking (OR, 2.163; 95% CI, 1.059-4.429) were risk factors for airway colonization. Decreased diffusion capacity of the lung for carbon monoxide (OR, 5.838; 95% CI, 1.318-25.854), prolonged operation time (OR, 6.366; 95% CI, 1.349 30.033), and preoperative airway colonization (OR, 9.448; 95% CI, 2.206-40.465) were risk factors of POP. CONCLUSIONS: Airway colonized pathogens altered and more antibiotic-resistant GNB emerged during the perioperative period. These pathogens played an important role in the presence of POP. PMID- 25276362 TI - Corticosteroid therapy against treatment-related pulmonary toxicities in patients with lung cancer. AB - BACKGROUND: With the recent increased use of new anti-neoplastic agents, molecular-targeted drugs and radiation in patients with lung cancer, there has been an increase in the occurrence drug-induced or radiation-induced pulmonary toxicities. We conducted this study to evaluate the clinical characteristics of patients with lung cancer who presented with treatment-related pulmonary toxicities and to analyze the dosage pattern of corticosteroid therapy against them. METHODS: To collect the baseline data from the patients with lung cancer who developed treatment-related pulmonary toxicities, we initially selected those who were prescribed corticosteroids between January 1, 2008 and December 31, 2012. Depending on clinical and radiological diagnoses, we classified pulmonary toxicities into drug-induced interstitial lung disease (DILD), radiation pneumonitis, acute exacerbation of chronic obstructive pulmonary disease (AE COPD) and others. RESULTS: We divided total patients (n=398) into four groups, and these include 88 cases (22%) of DILD, 189 cases (47%) of radiation pneumonitis, 47 cases (12%) of AE COPD and 74 cases (19%) of others. The prescribed rate of pulse or high-dose steroid was measured as 73%, 20%, 40% and 38%, respectively (P<0.001). In DILD radiologic findings, the 2-month mortality was significantly higher in the patients with the diffuse alveolar damage (DAD) pattern (100%) as compared with those with the non-specific interstitial pneumonia (NSIP) or bronchiolitis obliterans with organizing pneumonia (BOOP) one (62% or 42%, respectively) (P=0.032). CONCLUSIONS: This study showed that the natural course of DILD had more unfavorable outcome requiring higher dose steroid therapy as compared with those with radiation pneumonitis or AE COPD. According to a subgroup analysis of the patients with DILD, BOOP and NSIP radiographic patterns showed more favorable outcomes. PMID- 25276363 TI - Comparison of outcomes of open and minimally invasive esophagectomy in 183 patients with cancer. AB - BACKGROUND AND OBJECTIVES: Only few randomized trials or comparative studies with large number of patients have been reported on the outcomes of thoracoscopic and laparoscopic esophagectomy (TLE) with cervical anastomosis and open 3-field esophagectomy (OE) for patients with esophageal cancer. The objective of this study is to compare the safety, feasibility, and short-term outcomes between TLE and OE (via right throax, abdomen, and left neck) for esophageal cancer. METHODS: Clinical and surgical data of patients with esophageal cancer who underwent either TLE or OE between February 2011 and December 2013 were retrospectively analyzed. Demographic characteristics, pathological data, operative procedures, and intraoperative and postoperative outcomes and survival in patients were compared between both groups. RESULTS: Of the 183 patients included in this retrospective analysis, 94 underwent TLE and 89 underwent OE. Demographics, pathologic data, inpatient mortality, and overall surgical morbidity in both cohorts were almost identical. A significant difference was observed in blood loss (182.6+/-78.3 vs. 261.4+/-87.2 mL, P<0.001), hospital stay (13.9+/-7.5 vs. 17.1+/-10.2 days, P=0.017), overall surgical morbidity (25.5% vs. 46.1%, P=0.004), and rate of pulmonary and cardiac complication (9.6% vs. 27.0%, P=0.002; 4.1% vs. 12.4%, P=0.046) between TLE and OE groups; however, no difference in survival period was observed between the groups. CONCLUSIONS: The procedure of TLE for esophageal cancer possesses advantages in intraoperative and postoperative outcomes compared with OE. The TLE procedure results in similar or potentially better outcomes. PMID- 25276364 TI - Is video-assisted thoracic surgery lobectomy in benign disease practical and effective? AB - BACKGROUND: The aim of this study was to analyze the surgical outcomes of video assisted thoracic surgery (VATS) lobectomy for benign pulmonary disease and to propose surgical guidelines based on the retrospective cohort study. METHODS: From January 2004 to December 2009, all lobectomies performed in a university based tertiary care hospital were analyzed. The inclusion criteria were as follows: (I) VATS lobectomy for benign disease; (II) thoracotomy conversion cases initially approached by VATS lobectomy. All malignant cases were excluded. Electronic medical records were retrospectively analyzed and patients were divided into two groups: with infection and without infection. The primary outcomes were the thoracotomy conversion rate, length of hospital stay, period of thoracic drainage and complications. RESULTS: VATS was performed in 163 (42%) of 385 patients who underwent lobectomy for benign disease. There were 68 in the infection group and 95 in the group without infection. VATS lobectomy was successful in 157 (96%) patients while 6 were converted into thoracotomy. The mean operation time and blood loss were 160 minutes and 326 mL. Comparing two groups, operation time and blood loss were not statistically different (P value =0.92, 0.63). Moreover conversion rate, length of hospital stay, period of thoracic drainage and complications (P value =0.67, 0.18, 0.25, and 0.50) were not different. CONCLUSIONS: VATS lobectomy for benign disease is practical and effective in selected cases regardless of the presence of infection. However, because various technical obstacles may be encountered during the procedure, therefore, careful patient selection is needed. PMID- 25276365 TI - Risk factors for postoperative complications after lung resection for non-small cell lung cancer in elderly patients at a single institution in China. AB - OBJECTIVE: The purpose of this study was to assess the postoperative complications after lung resection for non-small cell lung cancer (NSCLC) in elderly patients and to identify possible associated risk factors. METHODS: All patients aged 70 years or older who underwent pulmonary resection for NSCLC by either an open approach or by a thoracoscopic approach between January 2003 and December 2013 at our institution were reviewed. Postoperative events were divided into minor and major complications. Risk factors for complications were assessed by univariate and multivariate logistic regression analysis. A matched case control study was performed to determine if the utilization of video-assisted thoracic surgery (VATS) for lung resection for NSCLC in elderly patients' results in decreased complications compared with thoracotomy. RESULTS: During the study period, 476 consecutive patients (410 thoracotomy, 66 thoracoscopy) older than 70 years underwent resection for NSCLC. Postoperative complications occurred in 169 patients (35.5%) and the overall operative mortality was 2.3% (11 patients). Univariate predictors of complications included history of smoking (P=0.032), CCI scores >=3 (P<0.001), pneumonectomy (P=0.016), as well as the duration of surgery (P=0.003). After multiple logistic regression analysis, CCI scores >=3 [odds ratio (OR) =29.95, P<0.001], pneumonectomy (OR =2.26, P=0.029) and prolonged surgery (>=180 min) (OR =1.93, P=0.003) remained the only independent risk factors. After matching based on age, gender, the Charlson Comorbidity Index (CCI), pathologic stage, and the type of resection, there were 60 patients in each group. Patients had similar preoperative characteristics. A VATS approach resulted in a significantly lower rate of complications (25.0% vs. 43.3%, P=0.034) and a shorter median length of stay (19 days, range, 12 to 35 vs. 21 days, range, 13 to 38, P=0.013) compared with thoracotomy. CONCLUSIONS: Pulmonary resection for NSCLC in patients older than 70 years shows acceptable morbidity and mortality. Postoperative complications are more likely to develop in patients with CCI scores >=3, those who undergo pneumonectomy, and those with a prolonged surgery. Thoracoscopic minimally invasive surgery for NSCLC in elderly patients is associated with fewer complications as well as a shorter hospital stay compared with thoracotomy. PMID- 25276366 TI - Impact of EGFR mutation status on tumor response and progression free survival after first-line chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis. AB - OBJECTIVES: Non-small-cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations derive greater benefits from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than those with wild type tumors. However, whether EGFR mutation status is associated with the efficacy of cytotoxic chemotherapy or prognosis in advanced NSCLC patients remained controversial. Thus, we sought to conduct a meta-analysis to answer this question. METHODS: Electronic databases were searched for eligible literatures. The primary outcomes were objective response rate (ORR) and 6-month progression free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random effects model. Subgroup analyses stratified by study types, EGFR mutation detection methods, chemotherapy regimens, and patient origins were proposed. RESULTS: A total of 14 studies involving 1,772 advanced NSCLC patients with known EGFR mutation status who had received first-line chemotherapy were included. Patients with positive EGFR mutation had numerically higher ORR than wild type patients (36.2% vs. 30.1%) without significant differences (OR 1.24, 95% CI, 0.90 to 1.70; P=0.19). However, patients with EGFR mutants had significantly superior 6-month PFS rate than wild-type patients (58.6% vs. 47.2%; OR 1.88, 95% CI, 1.33 to 2.65; P=0.0003). Results of the subgroup analyses were concordant with the overall ones. CONCLUSIONS: This comprehensive analysis revealed that advanced NSCLC patients with sensitivity EGFR mutation had higher 6-month PFS rate and potentially greater ORR compared with wild-type patients after first-line chemotherapy. It suggested that EGFR mutation status should be considered a significant factor for patient stratification in evaluating the efficacy of antitumor agents in addition to EGFR-TKIs. PMID- 25276367 TI - Lesion with morphologic feature of organizing pneumonia (OP) in CT-guided lung biopsy samples for diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP): a retrospective study of 134 cases in a single center. AB - BACKGROUND: Small biopsy samples are generally considered inconclusive for bronchiolitis obliterans organizing pneumonia (BOOP) diagnosis despite their potential to reveal organizing pneumonia (OP) pathologically, necessitating risky invasive tissue biopsy during surgery for reliable confirmation. OBJECTIVE: OP by CT-guided lung biopsy was to evaluate the role in the diagnosis of BOOP. METHODS: A retrospective review of 134 cases with the OP feature in the CT-guided lung biopsy samples between 2004 and 2011 at a single center was conducted. Diagnostic accuracy of OP by CT-guided lung biopsy and clinical-radiographic data alone were compared. RESULTS: After exclusion of 11 cases due to pathology with others besides OP and 15 cases for loss to follow-up, 108 were included. Of these, 95 cases and 13 cases were classified as BOOP and non-BOOP group, respectively. Among BOOP group, only 30 were initially diagnosed as BOOP according to the typical clinical and radiographic features. The other 65 cases with atypical features were diagnosed as BOOP mainly based on OP by CT-guided lung biopsy. Among non-BOOP group, one was misdiagnosed as BOOP, and others were not BOOP according to clinical and radiographic findings. Thus, OP by CT-guided lung biopsy produced a diagnostic accuracy of 87.96% (95/108), much higher than 31.25% (30/96) observed using clinical and radiographic data alone. Combined, these techniques produced diagnostic accuracy of 98.96% (95/96). CONCLUSIONS: OP by CT guided lung biopsy can be effectively used as the pathological evidence for BOOP diagnosis and reducing unnecessary surgery. PMID- 25276368 TI - Elevated pretreatment serum globulin albumin ratio predicts poor prognosis for advanced non-small cell lung cancer patients. AB - BACKGROUND: The aim of the present study was to explore the association between the pretreatment globulin albumin ratio (GAR) and the survival of advanced non small cell lung cancer (NSCLC) patients. METHODS: Patients hospitalized between January 2007 and December 2010 were enrolled and eliminated according to the inclusion and exclusion criteria. GAR was defined as the absolute globulin value divided by the absolute albumin value. Chi-squared test was performed to compare clinical characteristics in different groups. Kaplan-Meier and Cox regression model were used to determine independent prognostic factors. A P value of <=0.05 was considered to be statistically significant. RESULTS: Total 316 patients were finally enrolled. The median progression free survival (PFS) and overall survival (OS) were 210.0 and 430.0 days, respectively. The statistical analyses indicated that pretreatment GAR >0.58 [hazard ratio (HR) =1.52, 95% confidence interval (95% CI): 1.12-2.08, P=0.008 for PFS, HR =1.65, 95% CI: 1.20-2.26, P=0.002 for OS], and pretreatment albumin <=35 g/L (HR =2.09, 95% CI: 1.20-3.65, P=0.003 for PFS, HR =1.92, 95% CI: 1.10-3.36, P=0.022 for OS) were independent prognostic factors for both PFS and OS. CONCLUSIONS: Our study first established a connection between pretreatment GAR and advanced NSCLC patients, suggesting that GAR was an independent prognostic factor and could be the biomarker for prognosis. PMID- 25276369 TI - Effects of different LAD-blocked sites on the development of acute myocardial infarction and malignant arrhythmia in a swine model. AB - OBJECTIVE: To explore the effects of various left anterior descending (LAD) artery-blocked sites on the development of acute myocardial infarction (AMI) and malignant arrhythmia in a swine model. METHODS: Twenty-two pigs underwent occlusion of the coronary artery with balloon angioplasty were randomly divided into three groups according to the blocked site of the balloon: middle-site blocked LAD group, bottom-third-blocked LAD group and control group. Then, the development of AMI and malignant arrhythmia, including ventricular tachycardia and ventricular fibrillation during the process of model creation, were recorded. Changes of the hemodynamics, blood gas analysis, electrocardiography, and myocardial enzymes were analyzed in each group before and after occlusion. RESULTS: Middle-site-LAD blockage resulted in a larger infarction size and the corresponding incidence of ventricular fibrillation was significantly higher than that of the bottom-third-blocked group (P<0.05). After the occlusion, the QTc interval of the Middle-site-blocked LAD group was significantly longer than that in the other groups (P<0.01). Moreover, mean arterial blood pressure (MAP), left ventricular ejection fraction (LVEF), and partial pressure of oxygen (PaO2) were significantly lower, but partial pressure of carbon dioxide (PaCO2) increased, in the Middle-site-blocked-LAD group compared with that in the bottom-third-blocked group (P<0.01). Compared with the control group, the two LAD-blocked groups showed significantly higher levels of Mb, CK-MB, LDH, AST and cTnT (P<0.01) four hours after the artery occlusion. However, these indexes were not significantly different between the two LAD-blocked groups (P>0.05). CONCLUSIONS: Location of LAD blockages in swine models may affect the development of AMI and malignant arrhythmia. PMID- 25276370 TI - Adiponectin protects rat heart from left ventricular remodeling induced by chronic intermittent hypoxia via inhibition of TGF-beta/smad2/3 pathway. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders. Chronic intermittent hypoxia (CIH) is the primary player in OSAS of the many associated factors. This study was in order to investigate the effects of the Adiponectin (Ad) on left ventricular remodeling induced by CIH. METHODS: Forty-five rats were randomly divided into three groups: normal control (NC) group, CIH group and CIH plus Ad supplemented (CIH + Ad) group. After 35 days' CIH exposure, masson analysis was used to detect the left ventricular fibrosis and western blot was used to measure the protein expression of collagen I, collagen III and TGF-beta/smad2/3 pathway. Gene analysis by RT-PCR was used to study the MMP2 and TIMP2. RESULTS: After CIH exposure, the fibrosis of left ventricular in CIH group was significantly remarkable than that in both NC and CIH + Ad groups (P<0.05), although statistical difference existed between NC and CIH + Ad groups (P<0.05). In addition, the protein expression of collagen I as well as collagen III and the ratio of mRNA levels of MMP2/TIMP2 were the highest in CIH group but the lowest in NC group, with CIH + Ad group in between. There was a significant difference among three groups (all P<0.05). The TGF beta/smad2/3 pathway was activated obviously in CIH group, but less noticeably in CIH + Ad group (P<0.05) with a significant difference in the two groups. CONCLUSIONS: The present study showed that Ad could ameliorate the left ventricular remodeling induced by CIH via inhibition of the expression of TGF beta/smad2/3 pathway. PMID- 25276371 TI - FDG PET-CT combined with TBNA for the diagnosis of atypical relapsing polychondritis: report of 2 cases and a literature review. AB - OBJECTIVE: To explore the value of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) combined with transbronchial needle aspiration (TBNA) in diagnosing atypical relapsing polychondritis (RP). METHODS: Data from two patients with atypical RP, which had been diagnosed in our hospital using FDG PET-CT combined with TBNA, were retrospectively analyzed. A review of the relevant literature was also performed. RESULTS: Consistent with the previously reported 20 cases of RP that had been diagnosed using FDG PET-CT, the two patients in the present study showed the involvement of multiple organs, including the nose, throat, trachea, bronchi, costicartilage and joint cartilages, and increased FDG uptake was found in these areas. The mean value of SUVmax was 5.14. PET-CT revealed that 86.4% of the patients with RP had airway involvement. TBNA technique was used for biopsy of the hypermetabolic lesions, and pathologic examinations confirmed the diagnosis of RP. The time to diagnosis in these two patients and the 20 cases reported previously was about 6.9 months, significantly shorter than the average diagnosis time (20 months). CONCLUSIONS: FDG PET-CT has several advantages for diagnosing RP, especially atypical RP. TBNA is a minimally invasive and safe technique for obtaining airway cartilage. Combining PET-CT with TBNA may play an important role in shortening the time to diagnosis in patients with RP involvement of airway. PMID- 25276372 TI - Construction and management of ARDS/sepsis registry with REDCap. AB - OBJECTIVE: The study aimed to construct and manage an acute respiratory distress syndrome (ARDS)/sepsis registry that can be used for data warehousing and clinical research. METHODS: The workflow methodology and software solution of research electronic data capture (REDCap) was used to construct the ARDS/sepsis registry. Clinical data from ARDS and sepsis patients registered to the intensive care unit (ICU) of our hospital formed the registry. These data were converted to the electronic case report form (eCRF) format used in REDCap by trained medical staff. Data validation, quality control, and database management were conducted to ensure data integrity. RESULTS: The clinical data of 67 patients registered to the ICU between June 2013 and December 2013 were analyzed. Of the 67 patients, 45 (67.2%) were classified as sepsis, 14 (20.9%) as ARDS, and eight (11.9%) as sepsis-associated ARDS. The patients' information, comprising demographic characteristics, medical history, clinical interventions, daily assessment, clinical outcome, and follow-up data, was properly managed and safely stored in the ARDS/sepsis registry. Data efficiency was guaranteed by performing data collection and data entry twice weekly and every two weeks, respectively. CONCLUSIONS: The ARDS/sepsis database that we constructed and manage with REDCap in the ICU can provide a solid foundation for translational research on the clinical data of interest, and a model for development of other medical registries in the future. PMID- 25276373 TI - Application of piezoelectric nanogenerator in medicine: bio-experiment and theoretical exploration. AB - BACKGROUND: A large number of wearable and implantable electronic medical devices are widely used in clinic and playing an increasingly important role in diagnosis and treatment, but the limited battery capacity restricts their service life and function expansion. Piezoelectric nanogenerators can convert mechanical energy into electrical energy. Our experiment tries to find out if the piezoelectric nanogenerator fixed to the surface of the heart can convert the natural contractions and relaxations of the heart into stable electric energy for electronic medical devices such as pacemakers. METHODS: We used Chinese miniature pig and prepared with standard open chest procedure. Then we fixed two opposite edges of the rectangular nanogenerator at the following three positions of the heart respectively to detect the electric voltage output: Position A, right ventricular surface, near the atrioventricular groove, parallel to the long axis of the heart; Position B, right ventricular surface, parallel to the atrioventricular groove; and Position C, left ventricular surface, near cardiac apex, parallel to the left anterior descending branch. Then we selected the place which has the highest voltage output to fix both ends of the nanogenerator and closed the chest of pig. We recorded the voltage output of nanogenerator under closed chest condition (natural condition) and compared the result with open chest condition. Finally we used Dopamine (positive inotropic agents) and Esmolol (negative inotropic agents) respectively to detect the relation between voltage output of nanogenerator and myocardial contractility. RESULTS: With its both ends fixed on the surface of the heart, the piezoelectric nanogenerator produced stable voltage output from the mechanical contractions of the heart. Piezoelectric nanogenerator which was fixed at Position A produced the highest voltage output (3.1 V), compared with those fixed at Position B or Position C. The voltage is enough for the pacemaker's operation. The voltage output of piezoelectric nanogenerator at the natural condition (closed chest) was the same as the open chest condition and made a light emitting diode (LED) light continue to shine, which further confirmed its clinical application value. The voltage output of piezoelectric nanogenerator is positively correlated with the myocardial contractile force. The voltage output increased after we used positive inotropic agents and decreased after we used negative inotropic agents. CONCLUSIONS: Piezoelectric nanogenerators can convert the kinetic energy of the heart during the contractions and relaxations of the muscles to electric energy. The output voltage was stable in three positions on the surface of the heart. The highest voltage appeared on the surface of right ventricle, near atrioventricular groove, parallel to the long axis direction of the heart, which can be the potential new energy source for pacemakers. Piezoelectric nanogenerator can be used as cardiac function monitor in the future for its voltage output is positively correlated with myocardial contractile force. PMID- 25276374 TI - Malignant giant cell tumor of the rib with lung metastasis in a man. AB - Malignant giant cell tumor of bone (MGCTB) accounts for 0.07% of all cases of primary bone tumor. The rarity and complexity of this tumor give rise to some arguments about its histological differentiation, diagnosis, treatment and prognosis. In this paper, we present a 57-year-old man who has a large MGCTB in his rib with lung-targeted metastasis at the time of initial diagnosis. He underwent an operation followed by radiotherapy. The man has been free of recurrence or metastasis for 18 months. PMID- 25276375 TI - Calcified amorphous tumor in left atrium presenting with cerebral infarction. AB - Calcified amorphous tumor (CAT) of the heart is an extremely rare cardiac mass. We describe a case of cardiac CAT in a 70-year-old Korean female who presented with acute onset dysarthria and right side weakness. Echocardiography and chest computed tomography revealed a left atrial mass that originated from the interatrial septum. The patient underwent surgical resection and pathologic examination demonstrated CAT. Postoperative course was uneventful and she was followed without recurrence. PMID- 25276376 TI - Single-staged uniportal VATS major pulmonary resection for bilateral synchronous multiple primary lung cancers. AB - It is difficult to make diagnosis and treatment decision for patient with bilateral multiple pulmonary foci. Surgical resection can offer sufficient specimens for diagnostic differentiation and the greatest chance for long-term survival in patient with presumptive synchronous multiple primary lung cancers (SMPLC). Since uniportal video-assisted thoracoscopic surgery (VATS) is a less invasive technique and has been attempted in lung cancer surgery, we transferred it into the management of SMPLC. In this paper, we report two cases of bilateral SMPLC managed through single-staged uniportal VATS with major pulmonary resection. This successful attempt provides an optimized idea to accomplish simplified mini-invasive diagnosis and synchronous treatment using the less invasive uniportal VATS technique for the management of SMPLC, especially for those with multiple bilateral lesions. PMID- 25276377 TI - Cardiovascular, diabetes, and cancer strips: evidences, mechanisms, and classifications. AB - OBJECTIVES: To report and name firstly that there are cardiovascular disease (CVD), diabetes mellitus (DM) and cancers (CDC) strips; and disclose their mechanisms, classifications, and clinical significances. STUDY DESIGN: Narrative and systematic review study and interpretive analysis. METHODS: DATA SOURCES AND STUDY SELECTION: to collect and present related evidences on CDC strips from evidence-based, open-access, both Chinese- and English-language literatures in recent 10 years on clinical trials from PubMed according to keywords "CVD, DM and cancers" as well as authors' extensive clinical experience with the treatment of more than fifty thousands of patients with CVD, diabetes and cancers over the past decades, and analyze their related mechanisms and categories which based on authors' previous works. DATA EXTRACTION: data were mainly extracted from 48 articles which are listed in the reference section of this review. Qualitative, quantitative and mixed data were included, narratively and systematically reviewed. RESULTS: With several conceptual and technical breakthrough, authors present related evidences on CDC strips, these are, CVD and DM, DM and cancers, cancers and CVD linked, respectively; And "Bad SEED" +/- "bad soil" theory or doctrine may explain this phenomenon due to "internal environmental injure, abnormal or unbalance" in human body resulting from the role of risk factors (RFs) related multi-pathways and multi-targets, which including organ & tissue (e.g., vascular-specific), cell and gene-based mechanisms. Their classifications include main strips/type B, and Branches/type A as showed by tables and figures in this article. CONCLUSIONS: There are CDC strips and related mechanisms and classifications. CDC strips may help us to understand, prevent, and control related common non-communicable diseases (NCDs) as well as these high risk strips. PMID- 25276379 TI - The challenging management of hepatopulmonary fistulas. AB - Hepatopulmonary fistula although benign in nature carries an unacceptable mortality risk up to 10.3% in some case series mainly due to surgical complications. From the first description by Ferguson and Burford in 1967 till present different approaches have been applied and with the introduction of less invasive techniques the results have significantly improved. Interestingly the prevalence of the different etiological factors has changed over the years especially with the advance of liver ablating techniques and surgery. A step by step approach to this entity, from diagnosis to treatment has to be reestablished in order to identify the role of interventional modalities and to develop a management algorithm. PMID- 25276378 TI - The latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers. AB - Triple negative breast cancer (TNBC) is one type of breast cancer (BC), which is defined as negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (Her2). Its origins and development seem to be elusive. And for now, drugs like tamoxifen or trastuzumab which specifically apply to ER, PR or Her2 positive BC seem unforeseeable in TNBC clinical treatment. Due to its extreme malignancy, high recurrence rate and poor prognosis, a lot of work on the research of TNBC is needed. This review aims to summarize the latest findings in TNBC in risk factors, possible therapeutic targets and possible prognostic makers. PMID- 25276381 TI - The chicken-and-egg debate about statistics and research. PMID- 25276380 TI - Magnetic resonance imaging for lung cancer screen. AB - Lung cancer is the leading cause of cancer related death throughout the world. Lung cancer is an example of a disease for which a large percentage of the high risk population can be easily identified via a smoking history. This has led to the investigation of lung cancer screening with low-dose helical/multi-detector CT. Evidences suggest that early detection of lung cancer allow more timely therapeutic intervention and thus a more favorable prognosis for the patient. The positive relationship of lesion size to likelihood of malignancy has been demonstrated previously, at least 99% of all nodules 4 mm or smaller are benign, while noncalcified nodules larger than 8 mm diameter bear a substantial risk of malignancy. In the recent years, the availability of high-performance gradient systems, in conjunction with phased-array receiver coils and optimized imaging sequences, has made MR imaging of the lung feasible. It can now be assumed a threshold size of 3-4 mm for detection of lung nodules with MRI under the optimal conditions of successful breath-holds with reliable gating or triggering. In these conditions, 90% of all 3-mm nodules can be correctly diagnosed and that nodules 5 mm and larger are detected with 100% sensitivity. Parallel imaging can significantly shorten the imaging acquisition time by utilizing the diversity of sensitivity profile of individual coil elements in multi-channel radiofrequency receive coil arrays or transmit/receive coil arrays to reduce the number of phase encoding steps required in imaging procedure. Compressed sensing technique accelerates imaging acquisition from dramatically undersampled data set by exploiting the sparsity of the images in an appropriate transform domain. With the combined imaging algorithm of parallel imaging and compressed sensing and advanced 32-channel or 64-channel RF hardware, overall imaging acceleration of 20 folds or higher can then be expected, ultimately achieve free-breathing and no ECG gating acquisitions in lung cancer MRI screening. Further development of protocols, more clinical trials and the use of advanced analysis tools will further evaluate the real significance of lung MRI. PMID- 25276382 TI - Video-assisted thoracoscopic sleeve lobectomy. AB - Although minimally invasive video-assisted thoracic surgery (VATS) lobectomy has proved to be equal and in some aspects superior to open lobectomy in T1 and T2 lung cancers, video-assisted thoracic sleeve lobectomy is not widely practiced. Reconstruction is one of the most problematic techniques in thoracic surgery. We present a case of a patient who underwent VATS right-sided sleeve lobectomy due to right lung cancer. Based on the preoperative examinations, our VATS technique consisted of four incisions: three ports and a 3-4 cm long utility incision without any kind of rib spreading. Total surgery time was 180 min and blood loss was 100 mL. The chest tube was removed on the 5th post-operative day and the patient was discharged home on the 10th postoperative day. The final histopathological examination confirmed squamous cell lung cancer (T2aN0M0 stage IB). In the authors' opinion VATS right-sided sleeve lobectomy should be performed by a surgeon with adequate experience with this approach. Despite limited indications for VATS right-sided sleeve lobectomy, if the patients fulfill the sleeve lobectomy inclusion criteria in general, they may gain from all the advantages of minimally invasive techniques. PMID- 25276383 TI - Laparoscopic and thoracoscopic esophagectomy with intrathoracic anastomosis for middle or lower esophageal carcinoma. AB - Thoracoscopic mobilization of esophagus and laparoscopic mobilization of stomach with cervical anastomosis is employed widely in minimally invasive esophagectomy (MIE) for esophageal carcinoma. However, it is associated with high incidence of complications, including recurrent laryngeal nerve injury and anastomotic leak. This paper summarizes the key techniques in total laparoscopic and thoracoscopic esophagectomy with intrathoracic anastomosis for MIE in 62 patients of middle or lower esophageal cancer between March 2012 and August 2013. Total laparoscopic and thoracoscopic esophagectomy with intrathoracic anastomosis was performed to treat the middle or lower esophageal cancer. Laparoscopic and thoracoscopic Ivor Lewis esophagectomy was performed using a circular stapler (Johnson and Johnson) intrathoracically to staple esophagogastric anastomosis and reconstruct the digestive tract. In addition, we performed tension-relieving anastomotic suture and embedded with pedicled omental flap. Compared with the trans-orally inserted anvil (OrVil) approach, the technique reported here is safe, feasible and user friendly. Total thoracoscopic intrathoracic anastomosis can be performed with a circular stapler (Johnson and Johnson). PMID- 25276385 TI - Prof. De-Min Li: what we expect from da Vinci robotic surgery. PMID- 25276384 TI - Unidirectionally thoracoscopic resection of lingual segment of the left upper pulmonary lobe. AB - A patient with adenocarcinoma in situ was reported to undergo unidirectionally thoracoscopic resection of lingual segment of the left upper pulmonary lobe and lymphadenectomy in the order of the lingual segmental vein, the lingual segmental bronchus, the lingual segmental artery, and the pulmonary tissues of the lingual segment in turn. As the concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are defined in the latest international classification of lung adenocarcinoma, pulmonary segmentectomy has been initially used in some multi-center clinical studies to treat these early lung cancer lesions. Pulmonary segmentectomy is currently one of the most minimally invasive lung surgeries, with its unique technical essentials different from those of pulmonary lobectomy. Some studies have shown that pulmonary segmentectomy for early lung cancer, especially for tumors with a diameter of less than 2 cm can achieve a similar long-term survival rate as pulmonary lobectomy, yet its effectiveness and safety should be confirmed in further large-scale prospective studies. PMID- 25276386 TI - Prof. Shijiang Zhang: the development of hybrid surgery in China. PMID- 25276387 TI - Mei-Shin Shih: a surgeon, master, and mentor. PMID- 25276388 TI - Gastrointestinal bleeding in lung leiomyosarcoma history: report of a case. AB - The paper presents an unusual case of single small bowel metastasis from primary lung leiomyosarcoma (PLL) presenting with abdominal pain and gastrointestinal (GI) bleeding successfully treated by surgery with radical aim. PMID- 25276389 TI - Primary pleural liposarcoma, pleomorphic variant. AB - Primary pleural liposarcoma (PPL) is a rare tumor derived from primitive mesenchymal tissue. We report a case of a 49-year-old female patient complaining of thoracic pain and dyspnea for 3 months. The chest X-ray showed a left basal opacity of lobulated contours and the thoracic computer tomography (CT) scan revealed a left pleural collection/mass, of 18 HU density and passive pulmonary atelectasis. The patient was taken to surgery and the cytologic examination of the gelatinous mass found in the procedure confirmed the diagnosis of a pleomorphic variant of pleural liposarcoma. We emphasise in the importance of careful inspection of the origin of the tumor in the diagnostic images to allow accurate diagnosis. PMID- 25276390 TI - Pulmonary arteriovenous malformations presenting as refractory heart failure. AB - A 22-year-old young man with a history of idiopathic dilated cardiomyopathy (IDC) was admitted to our hospital due to difficult-to-control heart failure. A thoracic X-ray showed multiple nodules at the both pulmonary hilus and upper lobe of the right lung. Computed tomography (CT) angiography of the thorax confirmed arteriovenous malformation (AVM). However, effective treatment was impossible due to the poor physical condition; he died a few days later. Here we reported on the case of pulmonary arteriovenous malformations (PAVMs) being misdiagnosed as refractory heart failure. PMID- 25276391 TI - Mediastino-hepato-renal cystic lymphangiomas-diagnostic and surgical considerations. AB - Cystic lymphangiomas or hygromas are rare benign vascular tumours, caused by congenital malformation of the lymphatic vessels. It appears as a progressive swelling in the head or neck of children during 2-5 years of life, yet rarely seen in the mediastinum or abdomen. Symptomatic mediastinal cystic lymphangiomas provide symptoms such as chest pain, breathlessness, cough, and dysphagia, making it difficult to differentiate from other mediastinal tumours. The tumour can become larger due to infections, inflammations, obstructions and bleedings. Chest X-ray, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) provide helpful information but the diagnosis appears merely after surgical resection and histological examination. Only a few cases have been reported. Hence, we report the first case of a mediastinal and asymptomatic renal and multiple hepatic cystic lymphangiomas in a 71-year-old male with respiratory symptoms and sever reduction in lung capacity. The symptoms regressed fully after surgical excision and lung diffusions capacity increased significantly. PMID- 25276392 TI - A case of heart failure due to alcoholic cardiomyopathy combined with acute pulmonary embolism. AB - It has not been reported that cases of alcoholic cardiomyopathy (ACM) combined with acute pulmonary embolism (PE). We hereby present a case of a 48-year-old male with ACM with significant enlargement of the heart and heart failure is described. Then, the patient was seized with acute PE which was confirmed by specific examination and his symptoms. PMID- 25276393 TI - Primary myelolipoma in posterior mediastinum. AB - Myelolipoma in posterior mediastinum is indeed rare. As a benign tumor, it consists of mature fat with scattered foci of haematopoietic elements resembling bone marrow. The computed tomography (CT) and magnetic resonance imaging (MRI) are effective methods to detect them, while the definite diagnosis still depends on pathological diagnosis. Up to now, there is no standard treatment for this disease. Surgery is thought to be the best choice in some literatures reports. In this paper, two patients with primary posterior mediastinal tumor are reported, both of whom were underwent Video-assisted thoracoscopic surgery (VATS). Postoperative pathological diagnosis was myelolipoma. PMID- 25276394 TI - Undifferentiated pleiomorphic sarcoma simultaneously occuring with thymoma. AB - We report here a case of thymoma simultaneously associated with neuroendocrine tumor. A 65-year-old male, presented with cough. Radiographic studies showed a mediastinal mass. On fine needle aspiration cytology and histopathological examination, a diagnosis of thymoma with coexisting undifferentiated pleomorphic sarcoma was made. Although thymoma is associated with many extrathymic malignancies, its association with neuroendocrine tumor is rare. This case is being reported on to reinforce that clinicians should bear in mind the possibility of extrathymic malignancies in patients with thymoma. PMID- 25276395 TI - The burden of Lophomonas blattarum under the light microscope. PMID- 25276396 TI - The importance of definition of active pulmonary tuberculosis and non-tuberculous pulmonary diseases in studies of diagnostic accuracy in high incidence areas. PMID- 25276397 TI - Red cell distribution width: a novel predictor of mortality in critically ill patients. PMID- 25276398 TI - Too much covariates in a multivariable model may cause the problem of overfitting. PMID- 25276399 TI - Pulse rate trends in obstructive sleep apnea: a reliable tool to predict long term response to CPAP? PMID- 25276400 TI - Response from the authors to the letter "Pulse rate trends in obstructive sleep apnoea: a reliable tool to predict long term response to CPAP?". PMID- 25276401 TI - ICC policy statement concerning ICC sponsorship funds. PMID- 25276402 TI - Cost-effective medicine vs. the medical-industrial complex. PMID- 25276404 TI - Rectal cancer: a truly multidisciplinary challenge. PMID- 25276405 TI - The evolution of colorectal cancer genetics-Part 1: from discovery to practice. AB - Colorectal cancer (CRC) is an increasing burden on our society. Identifying those who are at the greatest risk and improving triage for treatment will have the greatest impact on healthcare. CRC is a prime paradigm for cancer genetics: the majority of disease results from stages of progression lending itself to prevention by early detection of the pre-disease (neoplastic) state. Approximately 10% represent well defined hereditary cancer syndromes. Hereditary CRC has the added benefit that many are slow growing and family members are armed with the knowledge of potential risk of associated carcinomas and empowerment to reduce the disease burden. This knowledge provides the indication for early endoscopic and/or surgical intervention for prevention or treatment of an entire family cohort. The molecular basis of CRC allows enhanced characterization of carcinomas, leading to targeted therapies. PMID- 25276407 TI - A critical review of the role of local excision in the treatment of early (T1 and T2) rectal tumors. AB - The optimal treatment of early (T1 and T2) rectal adenocarcinomas remains controversial. Local excision and radical resection with total mesorectal excision are the two surgical techniques for excising early rectal cancer. Each has their respective benefits, with local excision allowing for decreased operative morbidity and mortality while radical resection provides an oncologically complete treatment through lymphadenectomy. Local excision can be accomplished via transanal endoscopic microsurgery or transanal excision. There is no significant difference in the recurrence rates (21% vs. 33%) or overall survival (80% vs. 66%) between the two local excision modalities; however, transanal endoscopic microsurgery does allow for a higher rate of R0 resection. Current selection criteria for local excision include well to moderately differentiated tumors without high-risk features such as lymphovascular invasion, perineural invasion, or mucinous components. In addition, tumors should ideally be <3 cm in size, excised with a clear margin, occupy less than 1/3 of the circumference of the bowel and be mobile/nonfixed. Despite these stringent inclusion criteria, local excision continues to be plagued with a high recurrence rate in both T1 and T2 tumors due to a significant rate of occult locoregional metastases (20% to 33%). For both tumor groups, the recurrence rate in the local excision group is more than double compared to radical resection. However, the overall survival is not significantly different between those with and without metastases. With intense postoperative surveillance, these recurrences can be identified early while they are confined to the pelvis allowing for salvage surgical options. Recently, neoadjuvant therapy followed by local excision has shown favorable short and long-term oncological outcomes to radical resection in the treatment of T2 rectal cancer. Ultimately, the management of early rectal cancer must be individualized to each patient's expectations of quality and quantity of life. With informed consent, patients may be willing to accept a higher failure rate and an increased post-operative surveillance regimen to preserve a perceived increased quality of life. PMID- 25276406 TI - The evolution of colorectal cancer genetics-Part 2: clinical implications and applications. AB - The genetic understanding of colorectal cancer (CRC) continues to grow, and it is now estimated that 10% of the population has a known hereditary CRC syndrome. This article will examine the evolving surgical and medical management of hereditary CRC syndromes, and the impact of tumor genetics on therapy. This review will focus on the most common hereditary CRC-prone diseases seen in clinical practice, which include Lynch syndrome (LS), familial adenomatous polyposis (FAP) & attenuated FAP (AFAP), MutYH-associated polyposis (MAP), and serrated polyposis syndrome (SPS). Each section will review the current recommendations in the evaluation and treatment of these syndromes, as well as review surgical management and operative planning. A highly detailed multigeneration cancer family history with verified genealogy and pathology documentation whenever possible, coupled with germline mutation testing when indicated, is critically important to management decisions. Although caring for patients with these syndromes remains complex, the application of this knowledge facilitates better treatment of both individuals and their affected family members for generations to come. PMID- 25276408 TI - Therapeutic approaches in the management of locally advanced rectal cancer. AB - Combined-modality therapy, using radiotherapy and chemotherapy with surgery, has been the traditional therapeutic algorithm for locally advanced rectal cancer. Standard of care in the United States has evolved to include neoadjuvant concurrent chemotherapy and radiotherapy followed by surgical excision and adjuvant chemotherapy. This approach has led to a significant improvement in local recurrences (LR), to the point where distant sites are the more common site of failure. Further improvements in local control have failed to improve overall survival. This article reviews historical trials that shifted the treatment paradigm to the current standard of care, as well as recent research trials, which have sought to incorporate new treatment methodologies, and treatment agents to improve outcomes. Finally this article describes ongoing studies and their potential impact on the future of therapeutic management of locally advanced rectal cancer. PMID- 25276409 TI - The emerging role of neoadjuvant chemotherapy for rectal cancer. AB - Locally advanced rectal cancer remains a substantial public health problem. Historically, the disease has been plagued by high rates of both distant and local recurrences. The standardization of pre-operative chemoradiation and transmesorectal excision (TME) have greatly lowered the rates of local recurrence. Efforts to improve treatment through use of more effective radiosensitizing therapies have proven unsuccessful in rectal cancer. Presently, due to improved local therapies, distal recurrences represent the dominant problem in this disease. Adjuvant chemotherapy is currently of established benefit in colorectal cancer. As such, adjuvant chemotherapy, consisting of fluoropyrimidine and oxaliplatin, represent the standard of care for many patients. However, after pre-operative chemoradiotherapy and rectal surgery, the administration of highly effective chemotherapy regimens has proven difficult. For this reason, novel neoadjuvant approaches represent appealing avenues for investigation. Strategies of neoadjuvant chemotherapy alone, neoadjuvant chemotherapy followed by chemoradiation and neoadjuvant chemoradiation followed by chemotherapy are under investigation. Initial encouraging results have been noted, though definitive phase III data is lacking. PMID- 25276411 TI - Addressing sexual dysfunction in colorectal cancer survivorship care. AB - Despite the high prevalence of sexual dysfunction in survivors of colorectal cancer, studies have shown that patients and providers rarely discuss how these symptoms may be influencing overall quality of life. The type and severity of symptoms of sexual dysfunction can vary greatly depending on the type of colorectal cancer and treatment, and assessment of sexual dysfunction is key to understanding how patients may be affected by these symptoms. Although patients would like to discuss these issues with their provider, they are often reluctant to ask questions about sexual functioning during appointments. Likewise, health care providers may hesitate to address sexual dysfunction due to time limitations or lack of knowledge regarding treatment of sexual problems. Health care providers can facilitate discussion of sexual dysfunction by (I) assessing sexual functioning throughout treatment; (II) initiating discussions about symptoms of sexual dysfunction at each appointment; and (III) maintaining adequate referral resources for treatment of sexual dysfunction. PMID- 25276412 TI - Psychosocial issues in colorectal cancer survivorship: the top ten questions patients may not be asking. AB - Advances in colorectal cancer screening and treatment have increased survivorship significantly in recent years. This has led to an increased emphasis on the need for continuing patient care long after cancer treatment is completed. Colorectal cancer survivors may face a number of psychosocial issues following treatment, including cancer-related distress, adjustment to physical changes following treatment, and challenges related to returning to work. Although there are many resources available to assist with these challenges, many patients may not seek this information from their providers during follow-up care visits. This article highlights some of the most common patient concerns related to survivorship in colorectal cancer and serves as a reminder to ask about these concerns throughout the course of treatment and follow-up care. PMID- 25276413 TI - Subthreshold Micropulse Photocoagulation for Persistent Macular Edema Secondary to Branch Retinal Vein Occlusion including Best-Corrected Visual Acuity Greater Than 20/40. AB - To assess the efficacy of subthreshold micropulse diode laser photocoagulation (SMDLP) for persistent macular edema secondary to branch retinal vein occlusion (BRVO), including best-corrected visual acuity (BCVA) > 20/40, thirty-two patients (32 eyes) with macular edema secondary to BRVO were treated by SMDLP. After disease onset, all patients had been followed for at least 6 months prior to treatment. Baseline Snellen visual acuity was used to categorize the eyes as BCVA <= 20/40 (Group I) or BCVA > 20/40 (Group II). Main outcome measures were reduction in central macular thickness (CMT) in optical coherence tomography (OCT) and BCVA at 6 months. In the total subject-pool at 6 months, BCVA had not changed significantly but CMT was significantly reduced. Group I exhibited no significant change in CMT at 3 months but exhibited significant reductions at 6 and 12 months. Group II exhibited a marginally significant reduction in CMT at 3 months and a significant reduction at 6 months. In patients with persistent macular edema secondary to BRVO, SMDLP appears to control macular edema with minimal retinal damage. Our findings suggest that SMDLP is an effective treatment method for macular edema in BRVO patients with BCVA > 20/40. PMID- 25276414 TI - High-Resolution Imaging of Patients with Bietti Crystalline Dystrophy with CYP4V2 Mutation. AB - The purpose of this study was to determine the retinal morphology of eyes with Bietti crystalline dystrophy (BCD) associated with a CYP4V2 mutation using high resolution imaging techniques. Three subjects with BCD underwent detailed ophthalmic examinations. High-resolution fundus images were obtained with an adaptive optics (AO) fundus camera. A common homozygous mutation was detected in the three patients. Funduscopic examination of the three patients revealed the presence of crystalline deposits in the retina, and all of the crystalline deposits were also detected in the infrared (IR) images. The crystals observed in the IR images were seen as bright reflective plaques located on the RPE layer in the SD-OCT images. The clusters of hyperreflective signals in the AO images corresponded to the crystals in the IR images. High-magnification AO images revealed that the clusters of hyperreflective signals consisted of circular spots that are similar to the signals of cone photoreceptors. Most of these circular spots were detected in healthy areas in the FAF images. There is a possibility that circular spots observed by AO are residual cone photoreceptors located over the crystals. PMID- 25276415 TI - Effects of preoperative intravenous clonidine in patients undergoing cataract surgery: a double-blind, randomized trial. AB - Objectives. The aim of this study was to assess the effects of clonidine on intraoperative analgesia, sedation, intraocular and blood pressure, arrhythmia, and ischemia. Methods. Forty patients undergoing cataract surgery were allocated into two groups. They were monitored with Holter machine, the pupil was dilated, and 30 minutes later, 20 patients received clonidine (4 ug/kg), while the other 20 patients were given a 0.9% saline intravenously. Twenty minutes later, 2% lidocaine gel was applied. There were assessed intraoperative analgesia, intraocular pressure, blood pressure, heart rate, and the occurrence of arrhythmias and myocardial ischemia. Results. Pain intensity was lower in G1 during the phacoemulsification, irrigation, aspiration, and intraocular lens implantation. The HR and BP were lower with clonidine. The IOP was lower with clonidine after 15 minutes and at the end of the surgery. Sedation was higher with clonidine. The incidence of arrhythmia was lower at the end of surgery with clonidine. The incidence of myocardial ischemia did not differ between the groups. Conclusions. Clonidine (4 ug/kg) before a phacoemulsification reduced the intensity of pain during cataract surgery. It also induced sedation, reduction of BP, HR, and incidence of arrhythmia at the end of the surgery, and did not alter myocardial ischemia. This trial is registered with Clinicaltrials.gov NCT01677351. PMID- 25276416 TI - Orbital epidermoid cysts: a diagnosis to consider. AB - Background. Orbital epidermoids form a rare pathological entity that is separate from dermoid cysts. They have variable clinical and radiological presentations and they should be considered in the differential diagnosis of orbital cystic lesions. This work describes the various clinical and radiological presentations of 17 cases of epidermoid cysts and the surgical outcome. Method. A prospective interventional study was conducted on 17 patients diagnosed with epidermoid cysts. Patients' symptoms and signs were recorded; CT scan was done for all patients. All lesions were removed through anterior orbitotomy and histopathological diagnosis confirmed. Results. Mean age of patients was 16.3 years +/- 10.54. Main complaints were lid swelling, masses, ocular dissimilarity, chronic pain, and ocular protrusion. Clinical signs varied from lid swelling and masses in all cases to proptosis, globe displacement, limitation of ocular motility, and scars. Radiological findings ranged from homogenous hypodense masses (58.8%) to homogenous radiolucent (17.6%) and heterogenous masses (23.5%). No recurrences following surgeries were reported throughout the follow-up (mean 18.8 months +/- 0.72). Conclusion. Deep orbital epidemoid cysts are a separate entity that can behave like deep orbital epidermoid; however, they usually present at a relatively older age. They can be associated with increased orbital volume but not necessarily related to bony sutures. PMID- 25276410 TI - Liver-directed therapies in metastatic colorectal cancer. AB - Colorectal cancer (CRC) is a major health concern in the United States (US) with over 140,000 new cases diagnosed in 2012. The most common site for CRC metastases is the liver. Hepatic resection is the treatment of choice for colorectal liver metastases (CLM), with a 5-year survival rate ranging from 35% to 58%. Unfortunately, only about 20% of patients are eligible for resection. There are a number of options for extending resection to more advanced patients including systemic chemotherapy, portal vein embolization (PVE), two stage hepatectomy, ablation and hepatic artery infusion (HAI). There are few phase III trials comparing these treatment modalities, and choosing the right treatment is patient dependent. Treating hepatic metastases requires a multidisciplinary approach and knowledge of all treatment options as there continues to be advances in management of CLM. If a patient can undergo a treatment modality in order to increase their potential for future resection this should be the primary goal. If the patient is still deemed unresectable then treatments that lengthen disease free and overall-survival should be pursued. These include chemotherapy, ablation, HAI, chemoembolization, radioembolization (RE) and stereotactic radiotherapy. PMID- 25276417 TI - Clinical outcomes after complete intracorneal ring implantation and corneal collagen cross-linking in an intrastromal pocket in one session for keratoconus. AB - Purpose. The aim of this work was to evaluate the results after combined surgery implantation of full rings and CXL in one session in a group of patients with keratoconus during a 12-month follow-up. Material and Methods. The study included 22 eyes of 20 keratoconic patients, mean age of 28.41 (from 18 to 50) years. A full ring was inserted and afterwards 0.1% riboflavin solution was injected into the corneal pocket through the incision tunnel. The cornea was irradiated with UV A light for 30 minutes. Postoperative visits were scheduled for the first week and months 1, 3, 6, 12, and 24 after surgery. Minimal follow-up time was 12 months. Results. The mean UDVA improved by 6 lines from before the operation to 1 year after the operation, the mean CDVA improved by approximately 2.5 lines, and the mean K improved by 3.94 D. Statistically significant reductions of sphere (P < 0.001), cylinder (P = 0.004), and spherical (P < 0.001) equivalents were found 1 month after surgery. Conclusion. The combined surgery MyoRing implantation and CXL seems to be a safe method in the treatment of keratoconus. We noticed an improvement of the refractive error in all of our patients. PMID- 25276418 TI - A Comparative Study between Olanzapine and Risperidone Regarding Drug-Induced Electrocardiographic Changes. AB - Introduction. Among atypical antipsychotics, none has been linked to torsade de pointes. In the present study, the electrocardiographic changes induced by olanzapine have been compared with risperidone. Method and Materials. 268 patients were entered into an open study for random assignment to olanzapine or risperidone. ECG was taken at baseline and at the end of the treatment. The parameters that had been assessed included Q-T interval (corrected = Q-Tc) and other related parameters. Correction of the observed Q-T interval was done according to Frederica's formula (QTcF). Results. While 14.86% and 25% of the cases in the olanzapine group showed prolongation and shortening of QTcF, respectively, comparable changes in the risperidone group were restricted to its prolongation (32.5%). Comparison of means between baseline QTcF of risperidone group versus its posttreatment measurement showed a significant increment (P = 0.02). Also, the quantity of cases with shortening of QTcF in the olanzapine group was significantly more than its opposite (P = 0.02). Conclusion. Comparable propensity of olanzapine and risperidone for induction of electrocardiographic changes demands adequate cautiousness by clinicians, particularly with respect to shortening of Q-T interval, which was mainly noticeable in the olanzapine group. PMID- 25276419 TI - Analysis of Nucleotide Sequences of the 16S rRNA Gene of Novel Escherichia coli Strains Isolated from Feces of Human and Bali Cattle. AB - Livestock especially cattle are known as a main reservoir of Escherichia coli O157:H7. This bacterium is considered as a pathogenic agent characterized by producing toxins, which are familiarly known as Shiga-like toxin-1 (Stx1) and Stx2. The aim of this work was to analyse the novel sequence of the 16S rRNA gene of strains isolated in this study in order to know the phylogenetic relationships between these sequences and those between the sequences of bacteria available in databanks. The results of this analysis showed that the strains KL-48(2) and SM25(1) that originated from human and cattle feces, respectively, are closely related among them and with respect to E. coli EDL 933, E. coli Sakai, E. coli ATCC 43894, E. coli O111:H-, E. coli O121:H19, E. coli O104:H4, and Shigella sonnei with more than 99% similarity values. PMID- 25276420 TI - Effect of Temperature on Xylanase II from Trichoderma reesei QM 9414: A Calorimetric, Catalytic, and Conformational Study. AB - The secondary structure of xylanase II from Trichoderma reesei is lost in an apparent irreversible cooperative process as temperature is increased with a midpoint transition of 58.8 +/- 0.1 degrees C. The shift of the spectral centre of mass above 50 degrees C is also apparently cooperative with midpoint transition of 56.3 +/- 0.2 degrees C, but the existence of two isofluorescent points in the fluorescence emission spectra suggests a non-two-state process. Further corroboration comes from differential scanning calorimetry experiments. At protein concentrations <=0.56 mg.mL(-1) the calorimetric transition is reversible and the data were fitted to a non-two-state model and deconvoluted into six transitions, whereas at concentrations greater than 0.56 mg.mL(-1) the calorimetric transition is irreversible with an exothermic contribution to the thermogram. The apparent T m increased linearly with the scan rate according to first order inactivation kinetics. The effect of additives on the calorimetric transition of xylanase is dependent on their nature. The addition of sorbitol transforms reversible transitions into irreversible transitions while stabilizing the protein as the apparent T m increases linearly with sorbitol concentration. d Glucono-1,5-lactone, a noncompetitive inhibitor in xylanase kinetics, and soluble xylan change irreversible processes into reversible processes at high protein concentration. PMID- 25276421 TI - Trigonella foenum-graecum seeds lowers postprandial blood glucose in overweight and obese individuals. AB - This study determined the effects of fenugreek on postprandial plasma glucose (PPG) and satiety among overweight and obese individuals. Fourteen subjects were studied in the morning after overnight fasts on four separate occasions. Glycaemic responses elicited by 50 g carbohydrate portions of white bread and jam with or without 5.5 g of fenugreek and fried rice with or without 5.5 g fenugreek were determined over 2 h. The primary endpoint was the incremental area under the plasma glucose response curve (IAUC). Adding fenugreek to both foods significantly reduced the IAUC compared to the food alone: white bread and jam, 180 +/- 22 versus 271 +/- 23 mmol * min/L (P = 0.001); fried rice, 176 +/- 20 versus 249 +/- 25 mmol * min/L (P = 0.001). Fenugreek also significantly reduced the area under the satiety curve for white bread with jam (134 +/- 27 versus 232 +/- 33 mm * hr, P = 0.01) and fried rice (280 +/- 37 versus 379 +/- 36 mm * hr, P = 0.01). It is concluded that fenugreek significantly decreased the PPG response and increased satiety among overweight and obese individuals. PMID- 25276422 TI - The Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis. AB - Administering drugs as fixed-dose combinations (FDCs) versus the same active drugs administered as separate pills is assumed to enhance treatment adherence. We synthesized evidence from randomized controlled trials (RCTs) about the effect of FDCs versus separate pills on adherence. We searched PubMed for RCTs comparing a FDC with the same active drugs administered as separate pills, including a quantitative estimate of treatment adherence, without restriction to medical condition. The odds ratio (OR) of optimal adherence with FDCs versus separate pills was used as common effect size and aggregated into a pooled effect estimate using a random effect model with inverse variance weights. Out of 1258 articles screened, only six studies fulfilled inclusion criteria. Across medical conditions, administering drugs as FDC significantly increased the likelihood of optimal adherence (OR 1.33 (95% CI, 1.03-1.71)). Within subgroups of specific medical conditions, the favourable effect of FDCs on adherence was of borderline statistical significance for HIV infection only (OR 1.46 (95% CI, 1.00-2.13)). We observed a remarkable paucity of RCTs comparing the effect on adherence of administering drugs as FDC versus as separate pills. Administering drugs as FDC improved medication adherence. However, this conclusion is based on a limited number of RCTs only. PMID- 25276423 TI - Endovascular recanalization for chronic symptomatic intracranial vertebral artery total occlusion. AB - Purpose. The outcome of recanalization in patients with chronic symptomatic intracranial vertebral artery (ICVA) total occlusion is poor. This paper reports the technical feasibility and long-term outcome of ICVA stenting in patients with chronic symptomatic total occlusion. Methods. Retrospective review of our prospectively maintained intracranial intervention database to identify patients with symptomatic total occlusion of ICVA with revascularization attempted >1 month after index ischemic event. Results. Eight patients (mean age 58 years) were identified. One had stroke and 7 had recurrent transient ischemic attacks. Four had bilateral ICVA total occlusion and 4 had unilateral ICVA total occlusion with severe stenosis contralaterally. Seven of 8 patients underwent endovascular recanalization, which was achieved in 6. Periprocedural complications included cerebellum hemorrhage, arterial dissection, perforation, and subacute in-stent thrombosis which occurred in 3 patients. One patient died of cerebellum hemorrhage. The other patients improved clinically after endovascular therapy. Conclusions. Stent-supported recanalization of ICVA total occlusion is technically feasible, and may become a viable treatment option in selected patients. PMID- 25276424 TI - The quality of tuberculosis services in health care centres in a rural district in Uganda: the providers' and clients' perspective. AB - Quality of care plays an important role in the status of tuberculosis (TB) control, by influencing timely diagnosis, treatment adherence, and treatment completion. In this study, we aimed at establishing the quality of TB service care in Kamuli district health care centres using Donabedian structure, process, and outcomes model of health care. A cross-sectional study was conducted in 8 health care facilities, among 20 health care workers and 392 patients. Data was obtained using face-to-face interviews, an observation guide, a check list, and record review of the TB unit and laboratory registers. Data entry and analysis were done using EPI INFO 2008 and STATA 10 versions, respectively. A high number 150 (87.21%) of TB patients were not aware of all the signs to stop TB medication, and 100 (25.51%) patients received laboratory results after a period of 3-5 working days. The major challenges faced by health workers were poor attitude of fellow health workers, patients defaulting treatment, and fear of being infected with TB. One of the worst performance indicators was low percentage of cure. Comprehensive strengthening of the health system focusing on quality of support supervisions, patient follow up, promoting infection control measures, and increasing health staffing levels at health facilities is crucial. PMID- 25276425 TI - Mental health services for individuals with high functioning autism spectrum disorder. AB - Adolescents and adults with an autism spectrum disorder (ASD) who do not have an intellectual impairment or disability (ID), described here as individuals with high-functioning autism spectrum disorder (HFASD), represent a complex and underserved psychiatric population. While there is an emerging literature on the mental health needs of children with ASD with normal intelligence, we know less about these issues in adults. Of the few studies of adolescents and adults with HFASD completed to date, findings suggest that they face a multitude of cooccurring psychiatric (e.g., anxiety, depression), psychosocial, and functional issues, all of which occur in addition to their ASD symptomatology. Despite this, traditional mental health services and supports are falling short of meeting the needs of these adults. This review highlights the service needs and the corresponding gaps in care for this population. It also provides an overview of the literature on psychiatric risk factors, identifies areas requiring further study, and makes recommendations for how existing mental health services could include adults with HFASD. PMID- 25276426 TI - Dose-dense epirubicin and cyclophosphamide followed by weekly Paclitaxel in node positive breast cancer. AB - Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement in node-positive breast cancer patients but the optimal dose schedule has still remained undetermined. Objectives. The feasibility of dose-dense epirubicin in combination with cyclophosphamide (EC) followed by weekly paclitaxel as adjuvant chemotherapy in node-positive breast cancer patients was investigated. Methods. All patients were treated with epirubicin (100 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every two weeks for four cycles with daily Pegfilgrastim (G-CSF) that was administered 3-10 days after each cycle of epirubicin and cyclophosphamide infusion which followed by (80 mg/m(2)) paclitaxel for twelve consecutive weeks. Results. Sixty consecutive patients were analyzed, of whom 57 patients (95%) completed the regimen and no case of toxicity related death was observed. Grade 3/4 hematologic toxicity was uncommon and the most common grade 3/4 nonhematological adverse event was neuropathy disorders. Conclusions. Dose-dense epirubicin and cyclophosphamide followed by weekly paclitaxel with G-CSF support is a well-tolerated and feasible regimen in node positive breast cancer patients without serious complications. PMID- 25276427 TI - Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. AB - Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15-30% of breast cancers and 10-30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2. PMID- 25276429 TI - Serum prolidase activity and oxidative stress in diabetic nephropathy and end stage renal disease: a correlative study with glucose and creatinine. AB - Association of oxidative stress and serum prolidase activity (SPA) has been reported in many chronic diseases. The study was aimed at evaluating the correlation of glucose and creatinine to SPA and oxidative stress in patients with diabetic nephropathy (DN) and end stage renal disease (ESRD) concerned with T2DM. 50 healthy volunteers, 50 patients with T2DM, 86 patients with DN, and 43 patients with ESRD were considered as control-1, control-2, case-1, and case-2, respectively. Blood glucose, creatinine, SPA, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were measured by colorimetric tests. SPA, TOS, and OSI were significantly increased in case-1 and case-2 than control-1 and control-2, while TAS was significantly decreased (P < 0.001). Blood glucose was linearly correlated to SPA, TOS, TAS, and OSI in control-2, case-1 and case-2 (P < 0.001). Serum creatinine was linearly correlated with SPA, TOS, TAS and OSI in control-2 and case-1 (P < 0.001). In case-2, serum creatinine was significantly correlated with SPA only (P < 0.001). Thus, the study concluded that SPA and oxidative stress significantly correlated with blood glucose and creatinine. SPA, TOS, TAS, and OSI can be used as biomarkers for diagnosis of kidney damage. PMID- 25276428 TI - Regulatory Variants and Disease: The E-Cadherin -160C/A SNP as an Example. AB - Single nucleotide polymorphisms (SNPs) occurring in noncoding sequences have largely been ignored in genome-wide association studies (GWAS). Yet, amounting evidence suggests that many noncoding SNPs especially those that are in the vicinity of protein coding genes play important roles in shaping chromatin structure and regulate gene expression and, as such, are implicated in a wide variety of diseases. One of such regulatory SNPs (rSNPs) is the E-cadherin (CDH1) promoter -160C/A SNP (rs16260) which is known to affect E-cadherin promoter transcription by displacing transcription factor binding and has been extensively scrutinized for its association with several diseases especially malignancies. Findings from studying this SNP highlight important clinical relevance of rSNPs and justify their inclusion in future GWAS to identify novel disease causing SNPs. PMID- 25276430 TI - A Comparative Study of Palatal Rugae Patterns among Igbo and Ikwerre Ethnic Groups of Nigeria: A University of Port Harcourt Study. AB - Background. Palatal rugae pattern of an individual is species specific and is said to be as unique as finger print. Aims and Objectives. The aim of this study was to identify and compare the rugae pattern of Igbo and Ikwerre populations in Nigeria for human identification purposes. Materials and Methods. The present study was conducted from random sampling of University of Port Harcourt students. A total number of 140 subjects (70 Igbos and 70 Ikwerres) of age bracket of 18-30 were used. Results. The different shapes of rugae were obviously observed with varying degrees of predominance among the two tribes. The most predominant patterns are wavy and curvy followed by straight. The Igbos were predominantly wavy while the Ikwerres were predominantly of curve and straight patterns. The Igbo males and females had more wavy pattern with percentage values of 51.6% and 59.9% which is significantly higher in proportion (P < 0.05) as compared to the Ikwerre males and females with percentage values of 35.6% and 40.6%. On the other hand, Ikwerre males and females proved to be curve dominant with percentage values of 45.2% and 34.4% and this showed significant difference in proportion (P < 0.05) as compared to the Igbo males and females with percentage curve values of 27.9% and 26.1%. Conclusion. The result obtained from this study is clear evidence of ethnic differences in relation to sex; hence the incidence of predominance is population dependent. PMID- 25276431 TI - Microanatomical Study of Embryonic Gonadal Development in Japanese Quail (Coturnix japonica). AB - Gonadal development of quail embryos was examined histologically using histological and histochemical methods. In the present study, quail embryos were studied at various stages of incubation period based on phases of gonadogenesis. Germ cell migration was observed on day 3-4 but gonadal differentiation and gonadal function were observed on day 6-8 and day 11-14, respectively. During germ cell migration, quail primordial germ cells (qPGCs) were successfully detected in both left and right genital ridges as well as the dorsal mesentery by lectin histochemistry. Unexpectedly, qPGCs-like cells were found next to the neural tube by Mallory-AZAN stain. During gonadal differentiation, embryonic sex can be distinguished histologically since day 8 of incubation. Embryonic testis exhibited a thin cortex, whereas embryonic ovary exhibited a thick cortex. Testicular cord formation was found in the medulla of embryonic testes while the lacunae and fat-laden cells were found in the medulla of embryonic ovary during gonadal function. This is the first report on a comparison of phases of gonadogenesis and histochemical study of quail embryonic gonads in both sexes. PMID- 25276432 TI - Clinical understanding of spasticity: implications for practice. AB - Spasticity is a poorly understood phenomenon. The aim of this paper is to understand the effect of spasticity on daily life and identify bedside strategies that enhance patient's function and improve comfort. Spasticity and clonus result from an upper motor neuron lesion that disinhibits the tendon stretch reflex; however, they are differentiated in the fact that spasticity results in a velocity dependent tightness of muscle whereas clonus results in uncontrollable jerks of the muscle. Clinical strategies that address function and comfort are paramount. This is a secondary content analysis using a qualitative research design. Adults experiencing spasticity associated with neuromuscular disorder were asked to participate during inpatient acute rehabilitation. They were asked to complete a semistructured interview to explain and describe the nature of their experienced spasticity on daily basis. Spasticity affects activities of daily living, function, and mobility. Undertreated spasticity can lead to pain, immobility, and risk of falls. There were missed opportunities to adequately care for patients with spasticity. Bedside care strategies identified by patients with spasticity are outlined. Uses of alternative therapies in conjunction with medications are needed to better manage spasticity. Patient reports on spasticity are important and should be part of clinical evaluation and practice. PMID- 25276433 TI - The effects of two different ankle-foot orthoses on gait of patients with acute hemiparetic cerebrovascular accident. AB - Objective. To compare the effects of two types of ankle-foot orthoses on gait of patients with cerebrovascular accident (CVA) and to evaluate their preference in using each AFO type. Design. Thirty individuals with acute hemiparetic CVA were tested without an AFO, with an off-the-shelf carbon AFO (C-AFO), and with a custom plastic AFO (P-AFO) in random order at the time of initial orthotic fitting. Gait velocity, cadence, stride length, and step length were collected using an electronic walkway and the subjects were surveyed about their perceptions of each device. Results. Subjects walked significantly faster, with a higher cadence, longer stride, and step lengths, when using either the P-AFO or the C-AFO as compared to no AFO (P < 0.05). No significant difference was observed between gait parameters of the two AFOs. However, the subjects demonstrated a statistically significant preference of using P-AFO in relation to their balance, confidence, and sense of safety during ambulation (P < 0.05). Moreover, if they had a choice, 50.87 +/- 14.7% of the participants preferred the P-AFO and 23.56 +/- 9.70% preferred the C-AFO. Conclusions. AFO use significantly improved gait in patients with acute CVA. The majority of users preferred the P AFO over the Cf-AFO especially when asked about balance and sense of safety. PMID- 25276434 TI - Whole body vibration exercises and the improvement of the flexibility in patient with metabolic syndrome. AB - Vibrations produced in oscillating/vibratory platform generate whole body vibration (WBV) exercises, which are important in sports, as well as in treating diseases, promoting rehabilitation, and improving the quality of life. WBV exercises relevantly increase the muscle strength, muscle power, and the bone mineral density, as well as improving the postural control, the balance, and the gait. An important number of publications are found in the PubMed database with the keyword "flexibility" and eight of the analyzed papers involving WBV and flexibility reached a level of evidence II. The biggest distance between the third finger of the hand to the floor (DBTFF) of a patient with metabolic syndrome (MS) was found before the first session and was considered to be 100%. The percentages to the other measurements in the different sessions were determined to be related to the 100%. It is possible to see an immediate improvement after each session with a decrease of the %DBTFF. As the presence of MS is associated with poorer physical performance, a simple and safe protocol using WBV exercises promoted an improvement of the flexibility in a patient with MS. PMID- 25276435 TI - TET2 Inhibits Differentiation of Embryonic Stem Cells but Does Not Overcome Methylation-Induced Gene Silencing. AB - TET2 is a methylcytosine dioxygenase that is frequently mutated in myeloid malignancies, notably myelodysplasia and acute myeloid leukemia. TET2 catalyses the conversion of 5'-methylcytosine to 5'-hydroxymethylcytosine within DNA and has been implicated in the process of genomic demethylation. However, the mechanism by which TET2 loss of function results in hematopoietic dysplasia and leukemogenesis is poorly understood. Here, we show that TET2 is expressed in undifferentiated embryonic stem cells and that its knockdown results in reduction of 5'-hydroxymethylcytosine in genomic DNA. We also present DNA methylation data from bone marrow samples obtained from patients with TET2-mutated myelodysplasia. Based on these findings, we sought to identify the role of TET2 in regulating pluripotency and differentiation. We show that overexpression of TET2 in a stably integrated transgene leads to increased alkaline phosphatase expression in differentiating ES cells and impaired differentiation in methylcellulose culture. We speculate that this effect is due to TET2-mediated expression of stem cell genes in ES cells via hydroxylation of 5'-methylcytosines at key promoter sequences within genomic DNA. This leads to relative hypomethylation of gene promoters as 5'-hydroxymethylcytosine is not a substrate for DNMT1-mediated maintenance methylation. We sought to test this hypothesis by cotransfecting the TET2 gene with methylated reporter genes. The results of these experiments are presented. PMID- 25276436 TI - Blockade of lysosomal acid ceramidase induces GluN2B-dependent Tau phosphorylation in rat hippocampal slices. AB - The lysosomal acid ceramidase, an enzyme known to limit intracellular ceramide accumulation, has been reported to be defective in neurodegenerative disorders. We show here that rat hippocampal slices, preincubated with the acid ceramidase inhibitor (ACI) d-NMAPPD, exhibit increased N-methyl-D-aspartate (NMDA) receptor mediated field excitatory postsynaptic potentials (fEPSPs) in CA1 synapses. The ACI by itself did not interfere with either paired pulse facilitation or alpha amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated fEPSPs, indicating that its influence on synaptic transmission is postsynaptic in origin and specific to the NMDA subtype of glutamate receptors. From a biochemical perspective, we observed that Tau phosphorylation at the Ser262 epitope was highly increased in hippocampal slices preincubated with the ACI, an effect totally prevented by the global NMDA receptor antagonist D/L(-)-2-amino-5 phosphonovaleric acid (AP-5), the calcium chelator 1,2-bis(o-aminophenoxy)ethane N,N,N',N'-tetraacetic acid (BAPTA), and the GluN2B (but not the GluN2A) receptor antagonist RO25-6981. On the other hand, preincubation of hippocampal slices with the compound KN-62, an inhibitor known to interfere with calcium/calmodulin dependent protein kinase II (CaMKII), totally abolished the effect of ACI on Tau phosphorylation at Ser262 epitopes. Collectively, these results provide experimental evidence that ceramides play an important role in regulating Tau phosphorylation in the hippocampus via a mechanism dependent on GluN2B receptor subunits and CaMKII activation. PMID- 25276437 TI - Disentangling tinnitus distress and tinnitus presence by means of EEG power analysis. AB - The present study investigated 24 individuals suffering from chronic tinnitus (TI) and 24 nonaffected controls (CO). We recorded resting-state EEG and collected psychometric data to obtain information about how chronic tinnitus experience affects the cognitive and emotional state of TI. The study was meant to disentangle TI with high distress from those who suffer less from persistent tinnitus based on both neurophysiological and behavioral data. A principal component analysis of psychometric data uncovers two distinct independent dimensions characterizing the individual tinnitus experience. These independent states are distress and presence, the latter is described as the perceived intensity of sound experience that increases with tinnitus duration devoid of any considerable emotional burden. Neuroplastic changes correlate with the two independent components. TI with high distress display increased EEG activity in the oscillatory range around 25 Hz (upper beta-band) that agglomerates over frontal recording sites. TI with high presence show enhanced EEG signal strength in the delta-, alpha-, and lower gamma-bands (30-40 Hz) over bilateral temporal and left perisylvian electrodes. Based on these differential patterns we suggest that the two dimensions, namely, distress and presence, should be considered as independent dimensions of chronic subjective tinnitus. PMID- 25276439 TI - Oral mucosal ulceration caused by the topical application of a concentrated propolis extract. AB - Propolis is a resinous mixture that is collected by honey bees from tree buds, sap flow, and other botanical sources. Propolis has been extensively used in medicine, dentistry, and cosmetics; however, unwanted effects have been reported. This paper reports a case of oral mucosal burn in a 50-year-old patient, who used an overnight application of concentrated propolis to overcome a throbbing pain in the right upper posterior mucosa. The patient was otherwise healthy and was not receiving any medication. She presented with painful shallow multiple irregular ulcers measuring 0.3-1 cm in diameter that were located on the right buccal mucosa and hard palate mucosa, in addition to the gingival mucosa surrounding tooth 17. Propolis-induced oral mucosal burn was diagnosed. The ulcer cleared after the prescription of tetracycline mouthwash, accompanied with Doloneurobion. The patient was further treated with carbamazepine to address the persistent throbbing pain in the affected area, which was suspected to be trigeminal neuralgia. This report provides another alert to clinicians about the potential adverse effects of propolis use for the treatment of oral diseases, despite its natural origin. PMID- 25276438 TI - Abeta(1-42) enhances neuronal excitability in the CA1 via NR2B subunit-containing NMDA receptors. AB - Neuronal hyperexcitability is a phenomenon associated with early Alzheimer's disease. The underlying mechanism is considered to involve excessive activation of glutamate receptors; however, the exact molecular pathway remains to be determined. Extracellular recording from the CA1 of hippocampal slices is a long standing standard for a range of studies both in basic research and in neuropharmacology. Evoked field potentials (fEPSPs) are regarded as the input, while spiking rate is regarded as the output of the neuronal network; however, the relationship between these two phenomena is not fully clear. We investigated the relationship between spontaneous spiking and evoked fEPSPs using mouse hippocampal slices. Blocking AMPA receptors (AMPARs) with CNQX abolished fEPSPs, but left firing rate unchanged. NMDA receptor (NMDAR) blockade with MK801 decreased neuronal spiking dose dependently without altering fEPSPs. Activating NMDARs by small concentration of NMDA induced a trend of increased firing. These results suggest that fEPSPs are mediated by synaptic activation of AMPARs, while spontaneous firing is regulated by the activation of extrasynaptic NMDARs. Synaptotoxic Abeta(1-42) increased firing activity without modifying evoked fEPSPs. This hyperexcitation was prevented by ifenprodil, an antagonist of the NR2B NMDARs. Overall, these results suggest that Abeta(1-42) induced neuronal overactivity is not dependent on AMPARs but requires NR2B. PMID- 25276440 TI - Creeping attachment involving dental implants: two case reports with a two-year follow-up from an ongoing clinical study. AB - Introduction. This paper describes case reports where coronal growth of soft tissue on implant threads was observed after surgery for soft tissue graft. This phenomenon is known as "creeping attachment." Methods. Two patients were submitted to gingival graft procedure including subepithelial connective tissue graft and masticatory mucosal graft. A two-year follow-up appointment was performed. Results. After a two-year follow-up gingival growth over titanium surfaces characterizing the "creeping attachment" phenomenon was observed. This gingival growth happened over abutment and threads surfaces. Conclusion. The creeping attachment phenomenon is possible over titanium surfaces and has not yet been reported in the relevant literature over this kind of structure. PMID- 25276441 TI - Ulcerated radiodermatitis induced after fluoroscopically guided stent implantation angioplasty. AB - Cases of radiation-induced skin injury after fluoroscopically guided procedures have been reported since 1996, though the majority of them have been published in Radiology and Cardiology literature, less frequently in Dermatology journals. Chronic radiation dermatitis induced by fluoroscopy can be difficult to diagnose; a high grade of suspicion is required. We report a case of an obese 46-year-old man with hypertension, dyslipidemia, and severe coronary artery disease. He developed a pruritic and painful atrophic ulcerated skin plaque over his left scapula, six months after fluoroscopically guided stent implantation angioplasty. The diagnosis of radiodermatitis was confirmed histologically. We report this case to emphasize the importance of recognizing fluoroscopy as a cause of radiation dermatitis. A good clinical follow-up at regular intervals is important after long and complicated procedures, since the most prevalent factor for injury is long exposure time. PMID- 25276442 TI - Acute methotrexate toxicity: a fatal condition in two cases of psoriasis. AB - We describe two fatal cases of low dose methotrexate (MTX) toxicity in patients with psoriasis, emphasizing the factors that exacerbate MTX toxicity. The first patient was a 50-year-old male of psoriasis on intermittent treatment with MTX. After a treatment-free period of six months, he had self-medication of MTX along with analgesic for joint pain for one week which followed ulceration of the lesions, bone marrow suppression, and eventually death. The second patient was a 37-year-old male of psoriasis, who has taken MTX one week earlier without prior investigations. He had painful ulcerated skin lesions and bone marrow suppression. On investigations, he showed high creatinine level and atrophied, nonfunctioning right kidney on ultrasonography. In spite of dialysis, he succumbed to death. MTX is safe and effective if monitored properly, but inadvertent use may lead to even death also. Prior workup and proper counseling regarding the drug interactions as well as self-medication should be enforced. PMID- 25276444 TI - Sphenoid brown tumor associated with a parathyroid carcinoma. AB - Brown tumors are osteolytic bone lesions that occur as a result of persistent hyperparathyroidism. They usually appear late in the natural history of the disease and are currently very rare due to an earlier diagnosis of primary hyperparathyroidism. We present the case of a 53-year-old female with a 2-month history of bitemporal hemianopsia and diplopia. A computed tomography showed an osteolytic bone lesion that involved the sphenoid corpus and clivus. A biopsy was made and the histopathology result was consistent with a brown tumor. The aforementioned location is very infrequent to such tumors, and therefore represented a diagnostic challenge. However, in this case, its association to primary hyperparathyroidism was the clue for the diagnosis. The association of a brown tumor secondary to a parathyroid carcinoma has been seldom reported. This case represents, to our knowledge, one of the few brown tumors described in such location and the first secondary to a parathyroid carcinoma. PMID- 25276443 TI - A case of adenomatous goiter involving diffuse, acute, and painful thyroid enlargement after fine-needle aspiration cytology. AB - The patient was a 44-year-old woman who exhibited a diffuse goiter during health screening. Her medical history did not include any significant medication-based treatment. An echographic examination detected a solid cystic tumor, which measured 21 * 14 * 10 mm, in her right thyroid lobe; however, she displayed normal thyroid function. After fine-needle aspiration cytology had been performed with a 22 G injection needle, the patient immediately complained of compression and pain extending from the front of her neck to her lower chin, which was not accompanied by dyspnea. A second echographic examination revealed diffuse and edematous enlargement and increased internal blood flow in the bilateral thyroid lobes as well as a thyroid nodule. We immediately iced the patient's neck and administered 125 mg methylprednisolone via an intravenous infusion. Within one hour, her symptoms had markedly improved, but acute pain remained. Thus, we continued the steroid (prednisone) treatment, but the dose was gradually reduced from 10 mg/day to 5 mg/day at 1 week after the patient's symptoms disappeared. The mechanism responsible for the patient's condition remains unclear. PMID- 25276445 TI - Myeloid sarcoma presenting with leukemoid reaction in a child treated for acute lymphoblastic leukemia. AB - Background. Myeloid sarcoma is an extramedullary neoplasm of immature myeloid cells. Our study reports a presentation of myeloid sarcoma which presented with severe leukemoid reaction as a secondary malignancy in a patient who was treated for acute lymphoblastic leukemia previously. The case emphasizes the difficulties in diagnosis of patients who do not have concomitant leukemia. Case Presentation. A 6-year-old girl who was treated for acute lymphoblastic leukemia previously presented with fatigue, paleness, and hepatosplenomegaly. Peripheral blood smear and bone marrow aspirate examination did not demonstrate any blasts in spite of severe leukemoid reaction with a white cell count 158000/mm(3). FDG/PET CT revealed slight uptake in cervical and supraclavicular lymph nodes. Excisional lymph node biopsy was performed from these lymph nodes and it showed myeloid sarcoma. Conclusion. Myeloid sarcoma can develop as a secondary malignancy in children who are treated for acute lymphoblastic leukemia. It can be associated with severe leukemoid reaction and diagnosis may be difficult if there is not concomitant leukemia. PET/CT is helpful in such cases. PMID- 25276446 TI - A case of recurrent cryptococcal meningoencephalitis in an immunocompetent female. AB - Cryptococcus neoformans is commonly associated with meningoencephalitis in immunocompromised patients and occasionally in apparently healthy individuals. Duration and regimen of antifungal treatment vary depending on the nature of the host and extent of disease and CNS shunts are placed in persistently elevated intracranial pressures. Recurrence of infection after initial treatment is not uncommon in HIV positive patients, Kaya et al. (2012) and Illnait-zaragozi et al. (2010). We describe a 39-year-old immunocompetent female that presented with neurologic deficits and increased intracranial pressure (ICP) due to cryptococcal meningoencephalitis that had a complicated course with drug induced hepatitis and persistently increased ICP that ultimately required shunt placement and presented again with relapse of cryptococcal meningoencephalitis after completion of antifungal treatment. Our case shows that recurrent cryptococcal meningitis can be seen in immunocompetent patients due to prolonged placement of CNS shunt and suggests that shunts should be removed after resolution of meningitis. PMID- 25276447 TI - Video self-modeling is an effective intervention for an adult with autism. AB - With the increases in size and strength that come with adulthood, challenging behaviours among those with autism spectrum disorders (ASD) can become critical. Few studies have explored behavioural interventions in adults with ASD, though recent studies have shown video self-modeling (VSM) to be effective in children with ASD. VSM involves an individual watching videos of himself demonstrating prosocial behaviours, while those behaviours are pointed out and encouraged. In the current study, VSM was used to encourage prosocial behaviours and to reduce problematic behaviour displayed by an adult with ASD. Results reveal a decrease in the tendency to invade others' personal space and make inappropriate loud noises. VSM may be an effective intervention and improve the lives of adults with ASD. PMID- 25276448 TI - Unusually High Levels of CA19-9 Associated with Mature Cystic Teratoma of the Ovary. AB - Introduction. Mature cystic teratoma is the benign tumor of the ovary. CA19-9 levels, although a marker of pancreatic malignancy, have been found to be raised in large ovarian mature cystic teratomas. Case Report. We report a case of a young female who had unusually high levels of CA19-9 in the blood associated with large ovarian mature cystic teratoma. The levels returned to normal 12 weeks after cystectomy was performed. Conclusion. This case highlights the fact that although raised tumor marker may be associated with a benign pathology thorough evaluation to rule out malignancy still must be done. PMID- 25276449 TI - Intraperitoneal solitary fibrous tumor. AB - Solitary fibrous tumors of the pelvis are rare. We report the case of a 32-years old patient who presented with abdominopelvic mass. The imaging studies showed a right adnexal mass of more than 10 cm. Exploratory laparotomy revealed a 20 cm mass at the Douglas pouch which was adhered to the posterior wall of the uterus. Complete resection of the mass was performed. Histological analysis showed a spindle cell undifferentiated tumor whose morphological and immunohistochemical profile are consistent with solitary fibrous tumor. It is important to know that although these tumors are rare, their evolution can be pejorative. Therefore, long-term followup should be recommended. PMID- 25276451 TI - Transient anisocoria after corneal collagen cross-linking. AB - Purpose. To report a case with transient anisocoria after corneal collagen cross linking (CXL). Methods. Case report. Results. A 24-year-old male underwent corneal collagen cross-linking (CXL) in his right eye for keratoconus. At the end of the procedure, the pupil of the treated eye was irregular and dilated, while the pupil of the fellow eye was round, regular, and reactive (anisocoria). The following day, pupils were round, regular, and reactive in both eyes. Conclusion. Anisocoria may be a transient and innocuous complication after CXL. A possible cause for this complication might be the anesthetic drops used before and during the surgical procedure or/and the ultraviolet A irradiation during the treatment. PMID- 25276450 TI - High dose radiotherapy to automated implantable cardioverter-defibrillator: a case report and review of the literature. AB - We report a case of successful full-dose chemoradiotherapy to stage IIIB nonsmall cell lung cancer (NSCLC) in a 59-year-old man with extensive cardiac history and an automated implantable cardioverter-defibrillator (AICD) located within the radiotherapeutic field. In this case, the AICD was a St. Jude Medical Fortify Assura VR 1257-40Q ICD, and it was implanted prophylactically during bypass grafting. Although we do not recommend routine radiotherapy dose to exceed recommended current guidelines due to the potential risks to the patient, this is a situation where relocation of the device was not possible. Fortunately, our patient was not AICD-dependent; so following much discussion and deliberation, the decision was made to treat the patient with AICD in place. The patient completed definitive chemoradiotherapy with concurrent cisplatin and etoposide and thoracic irradiation to 69.6 Gy. The minimum, maximum, and mean doses to the AICD directly were 13.5 Gy, 52.4 Gy, and 29.3 Gy, respectively. The device withstood full thoracic radiation dose, and the patient denied cardiac symptoms during the time before, during, and after completion of therapy. We sought to offer this case for both teaching and guidance in practice and to contribute to the published literature currently available in this area. PMID- 25276452 TI - Acute central retinal vein occlusion secondary to reactive thrombocytosis after splenectomy. AB - The diagnosis and treatment of central retinal vein occlusion was reported in a young patient. Central retinal vein occlusion was probably related to secondary to reactive thrombocytosis after splenectomy. The patient was treated with steroids for papilledema and administered coumadin and aspirin. The symptoms resolved, and the findings returned to normal within three weeks. Current paper emphasizes that, besides other well-known thrombotic events, reactive thrombocytosis after splenectomy may cause central retinal vein occlusion, which may be the principal symptom of this risky complication. Thus, it can be concluded that followup for thrombocytosis and antithrombotic treatment, when necessary, are essential for these cases. PMID- 25276453 TI - Adjacent lumbar disc herniation after lumbar short spinal fusion. AB - A 70-year-old outpatient presented with a chief complaint of sudden left leg motor weakness and sensory disturbance. He had undergone L4/5 posterior interbody fusion with L3-5 posterior fusions for spondylolisthesis 3 years prior, and the screws were removed 1 year later. He has been followed up for 3 years, and there had been no adjacent segment problems before this presentation. Lumbar magnetic resonance imaging (MRI) showed a large L2/3 disc hernia descending to the L3/4 level. Compared to the initial MRI, this hernia occurred in an "intact" disc among multilevel severely degenerated discs. Right leg paresis and bladder dysfunction appeared a few days after admission. Microscopic lumbar disc herniotomy was performed. The right leg motor weakness improved just after the operation, but the moderate left leg motor weakness and difficulty in urination persisted. PMID- 25276454 TI - One-stage femoral osteotomy and computer-assisted navigation total knee arthroplasty for osteoarthritis in a patient with femoral subtrochanteric fracture malunion. AB - Extra-articular femoral deformity in total knee arthroplasty (TKA) is realigned by either intra-articular correction or extra-articular osteotomy. The more distant the deformity is away from knee joint, the more likely it is corrected by the former method. No report described the use of antegrade cephalomedullary femoral nail to fix the osteotomy followed by computer-assisted navigation TKA. This report described the unusual use of this method to manage a 64-year-old man with femoral subtrochanteric fracture malunion and osteoarthritis of knee. He demonstrated a satisfactory functional outcome and good lower limb alignment. PMID- 25276455 TI - Traumatic distal ulnar artery thrombosis. AB - This paper is about a posttraumatic distal ulnar artery thrombosis case that has occurred after a single blunt trauma. The ulnar artery thrombosis because of chronic trauma is a frequent condition (hypothenar hammer syndrome) but an ulnar artery thrombosis because of a single direct blunt trauma is rare. Our patient who has been affected by a single blunt trauma to his hand and developed ulnar artery thrombosis has been treated by resection of the thrombosed ulnar artery segment. This report shows that a single blunt trauma can cause distal ulnar artery thrombosis in the hand and it can be treated merely by thrombosed segment resection in suitable cases. PMID- 25276456 TI - A solitary malignant schwannoma in the choana and nasal septum. AB - Malignant schwannoma is an extremely rare tumor and the risk of malignant schwannoma increases in patients with von Recklinghausen's disease. Recently, we encountered a case of solitary malignant schwannoma in the choana and posterior nasal septum. Malignant schwannoma has not been previously reported in these locations. A 53-year-old man, who was immunologically healthy and showed no abnormal dermatological lesions, presented with a polypoid mass in the right nasal cavity and underwent endoscopic mass excision. The mass originated from the choana and the posterior portion of the right nasal septum. This mass was confirmed as a malignant schwannoma on histological examination and immunohistochemical staining. After endoscopic excision, postoperative adjuvant radiotherapy was administered, and there was no recurrence at 1 year after treatment. This case suggests that a solitary malignant schwannoma should be considered in the differential diagnosis of a mass in the posterior nasal cavity. PMID- 25276457 TI - A pediatric case of ramsay hunt syndrome. AB - Ramsay Hunt syndrome (RHS) is characterized by facial paralysis, inner ear dysfunction, periauricular pain, and herpetiform vesicles. The reported incidence in children is 2.7/100,000. The pathogenesis involves the reactivation of latent varicella zoster virus (VZV) in the geniculate ganglion of the facial nerve. The recovery rate is better in children than in adults. This paper discusses a 12 year-old girl with a rare case of peripheral facial paralysis caused by RHS and reviews the literature. PMID- 25276458 TI - Unusual postrhinoplasty complication: nasal dorsum cyst. AB - AMONG ALL THE POSSIBLE COMPLICATIONS OF AESTHETIC RHINOPLASTY, A RARE ONE IS THE DEVELOPMENT OF CYSTIC MASSES ON THE NASAL DORSUM: several theories suggest that cysts develop commonly by entrapment of nasal mucosa in the subcutaneous space, but they can also originate from foreign body reactions. This report deals with two cases of nasal dorsum cysts with different pathogenesis: both patients had undergone aesthetic rhinoplasty in the past (26 years ago and 14 years ago, resp.). Both cystic masses were removed via a direct open approach and nasal reconstruction was performed successfully with autologous vomer bone. The pathologic investigations showed a foreign body inclusion cyst associated with latex rubber in the first case and a sequestration of a mucosal-lined nasal bone was not removed at the time of primary rhinoplasty in the second case. A brief review of the literature focuses on the pathophysiology and treatment options for nasal dorsal cysts following aesthetic rhinoplasty. PMID- 25276459 TI - Case study of a parotid gland adenocarcinoma dedifferentiated from epithelial myoepithelial carcinoma. AB - Dedifferentiation is defined as high-grade malignant tumor development out of a low-grade malignant tumor. We present an adenocarcinoma tumor of the parotid gland that was dedifferentiated from a low-grade epithelial-myoepithelial carcinoma and was followed up for 3 years. Our patient, a 46-year-old female, presented with a left parotid mass of 20-year duration. Histopathologic results showed that there was only one area of typical epithelial-myoepithelial carcinoma, with foci of poorly differentiated adenocarcinoma (not otherwise specified; NOS) and clear cytoplasm in the parotid gland. Immunohistochemical staining results showed SMA (+), P63 (+), CK8 (+), and S100 (+) on epithelial cells. A review of the literature revealed 22 previously reported cases of dedifferentiated epithelial-myoepithelial carcinoma. In these cases, the malignant tumors that dedifferentiated from epithelial-myoepithelial carcinoma were adenoid cystic carcinoma, actinic cell carcinoma, polymorphous low-grade adenocarcinoma, mucoepidermoid carcinoma, and intraductal carcinoma. In our case, the malignant tumor that dedifferentiated from the epithelial-myoepithelial carcinoma was a poorly differentiated adenocarcinoma. Histopathological results showed that metastases were not seen in the neck-dissection material. As a result, our case will make a contribution to the literature in terms of prognosis, because there are very few reported cases of dedifferentiated adenocarcinoma development arising from epithelial-myoepithelial carcinoma. PMID- 25276460 TI - A Rare Case of Neonatal Complicated Appendicitis in a Child with Patau's Syndrome. AB - Neonatal appendicitis is a rare condition with high mortality rate. Signs and symptoms are often nonspecific, imaging modalities are not always diagnostic, and preoperative diagnosis is difficult with subsequent delay and complications. Its pathophysiology may be different from appendicitis in older children and comorbidities can be found. We report a case of a female neonate with Patau's syndrome, intestinal malrotation, and Fallot tetralogy in whom perforated appendix, probably occurring during fetal period due to vascular insufficiency, was found at laparotomy. PMID- 25276461 TI - Tracheal penetration and tracheoesophageal fistula caused by an esophageal self expanding metallic stent. AB - Tracheal penetration of esophageal self-expanding metallic stents (SEMS) with/without tracheoesophageal fistula (TEF) formation is a rare occurrence. We report the case of a 66-year-old female patient with advanced esophageal squamous cell carcinoma who had undergone palliative esophageal stenting on three occasions for recurrent esophageal stent obstruction. On evaluation of symptoms of breathing difficulty and aspiration following third esophageal stent placement, tracheal erosion and TEF formation due to the tracheal penetration by esophageal stent were diagnosed. The patient was successfully managed by covered tracheal SEMS placement under flexible bronchoscopy. PMID- 25276462 TI - Tracheomalacia treatment using a large-diameter, custom-made airway stent in a case with mounier-kuhn syndrome. AB - Mounier-Kuhn Syndrome (MKS) is a rare congenital disease that presents with abnormal enlargement in the central airways. In MKS, tracheomegaly is accompanied by difficulty in expelling recurrent lung infections and bronchiectasia. We presented a patient with MKS where commercially made stents were inadequate for stabilization and a custom-made, self-expandable metallic stent with a diameter of 28 mm and length of 100 mm was used. Chest pain that was thought to develop due to the stent and that disappeared after stent removal may be considered the main complication leading to stent removal. Continuous positive airway pressure therapy (CPAP) therapy was planned for the control of symptoms, which re-emerged after stent removal. This case is presented as an example that complications developing due to the stent as well as patient noncompliance may lead to stent removal, even when useful results are obtained from treatment of MKS. PMID- 25276463 TI - Relapsing polychondritis in a patient with ankylosing spondylitis using etanercept. AB - Relapsing polychondritis (RP) is an autoimmune disease characterized by recurrent episodes of inflammation and progressive destruction of cartilaginous tissues, especially of the ears, nose, joints, and tracheobronchial tree. Its etiology is not well understood, but some studies have linked its pathophysiology with autoimmune disease and autoantibody production. We described a case of a 46-year old male patient with ankylosing spondylitis who developed RP after the use of etanercept. Few similar cases have been described in the literature. However, they show a possible association between the use of biological inhibitors of tumor necrosis factor (anti-TNFalpha), which potentially produces autoantibodies, and the development of RP. The treatment was based on data in the literature and included the cessation of biological therapy and the addition of corticosteroids with substantial improvement. PMID- 25276465 TI - Angiomyolipoma of the thoracic wall: an extremely rare diagnostic challenge. AB - Extrarenal angiomyolipoma (AML) is an extremely uncommon lesion, accounting for less than 9% of all angiomyolipomas. We present a previously unreported case of a rarely located gigantic extrarenal angiomyolipoma at the posterolateral chest wall of a 35-year-old woman. Clinically, the lesion had all the characteristics of a benign tumor, being soft in palpation, painless, and growing in size in a slow rate. Histologically, the lesion consisted of convoluted thick-walled blood vessels without an elastic layer, interlacing fascicles of smooth muscle, and mature adipose tissue, features consistent with an angiomyolipoma. The mass was surgically removed, without any postoperative complications, and the patient has an uneventful postoperative course. Signs of local recurrence have not been observed. The purpose of this brief report is to point out the necessity of including angiomyolipoma in the differential diagnosis of adipose layer lesions. PMID- 25276464 TI - A Fatal Case of Wernicke's Encephalopathy after Sleeve Gastrectomy for Morbid Obesity. AB - For legal reasons, the publisher has withdrawn this article from public view. For additional information, please contact the publisher. PMID- 25276466 TI - Nonocclusive mesenteric ischemia associated with ogilvie syndrome. AB - Nonocclusive mesenteric ischemia (NOMI) is one type of acute mesenteric ischemia. Colonic pseudoobstruction, known as Ogilvie syndrome, is a disorder defined by colonic distension in the absence of mechanical obstruction. A relationship between these diseases has not yet been reported, based on a review of the literature. We report a patient with NOMI secondary to Ogilvie syndrome. An 82 year-old woman reported three days of intermittent abdominal pain. Plain computed tomography scan showed colonic obstruction at the rectosigmoid colon. Colonoscopy was performed that showed a large amount of stool and no evidence of tumor or other physical causes of obstruction. We diagnosed the patient with Ogilvie syndrome and continued nonoperative management. On the third hospital day, she complained of abdominal distension. A repeat CT scan showed pneumatosis intestinalis in the small bowel and ascending colon, with portal venous gas. Emergency laparotomy was performed with diagnosis of mesenteric ischemia. Intraoperatively, there were multiple skip ischemic lesions in the small intestine and cecum. We resected the ischemic bowel and performed a distal jejunostomy. Her residual small bowel measured just 20 cm in length. Postoperatively, her general status gradually improved. She was discharged with total parenteral nutrition and a small amount of enteral nutrition. PMID- 25276468 TI - Penile gangrene with abscess formation after modified Al-ghorab shunt for idiopathic ischemic priapism. AB - Penile gangrene is a rare but unfortunate complication of surgical intervention and priapism shunts. The literature regarding penile gangrene following surgical correction of priapism is sparse, the majority of which dates back to thirty to forty years. Here, we present the case of a 60-year-old man who presented with priapism that required operative management with a modified Al-Ghorab shunt and eventually suffered from complete necrosis of the penis with abscess formation in both corpora cavernosa. PMID- 25276467 TI - Diffuse hepatic epithelioid hemangioendothelioma developed in a patient with hepatitis C cirrhosis. AB - Hepatic epithelioid hemangioendothelioma (HEHE) is an infrequent vascular tumor of endothelial origin that primarily occurs in women in the mid-fifth decade of life without underlying chronic liver disease or cirrhosis. Liver transplant should be the first-line of therapy in patients with large or diffuse unresectable tumors even in the presence of metastatic disease due to the favorable long-term outcome. We report the case of a 48-year-old female who complained of abdominal pain and weight loss. She has a history of cirrhosis secondary to chronic hepatitis C (HCV) and was treated with interferon and ribavirin with sustained virological response. Her work-up revealed multiple confluent infiltrating bilobar liver masses diagnosed as HEHE. She underwent a successful liver transplant without evidence of recurrent HCV infection. She developed cervical spine (C4-C6) HEHE metastases 4 years after transplant. She underwent surgical resection and local radiotherapy after resection with good clinical response. To the best of our knowledge, this is the first report of HEHE that developed in a patient with HCV cirrhosis successfully treated with antiviral therapy before transplant and liver transplant with good allograft function without evidence of recurrent liver tumor or HCV infection but developed metastases to the cervical spine 4 years after transplant. PMID- 25276469 TI - Successful treatment of iatrogenic vertebral pseudoaneurysm using pipeline embolization device. AB - Traumatic pseudoaneurysms are uncommon and one of the most difficult lesions to treat. Traditional treatment methods have focused on parent vessel sacrifice with or without revascularization. We report the case of a patient who underwent successful treatment of an iatrogenic extracranial vertebral artery pseudoaneurysm using the Pipeline Embolization Device. A 47-year-old man sustained an inadvertent injury to the left vertebral artery during C1-C2 fixation. Subsequent imaging revealed an iatrogenic vertebral artery pseudoaneurysm. Immediate angiogram was normal. A repeat angiogram done after 3 days of the surgery revealed a vertebral artery pseudoaneurysm. He underwent aneurysm exclusion and vascular reconstruction using the Pipeline Embolization Device. Although flow-diverting stents are currently not being used for treating traumatic pseudoaneurysms, their use may be considered in such cases if active bleeding has ceased. In our case, the patient did well and the aneurysm was excluded from circulation while reconstructing the vessel wall. PMID- 25276470 TI - Live Combined Bacillus subtilis and Enterococcus faecium Ameliorate Murine Experimental Colitis by Immunosuppression. AB - Live combined Bacillus subtilis and Enterococcus faecium ameliorate murine experimental colitis by immunosuppression manifested by downregulation of TLRs, macrophages, Th1, and Th2 but upregulation of Tregs. PMID- 25276471 TI - Concern and risk perception: effects on osteoprotective behaviour. AB - This study aimed to determine the effect that level of concern for osteoporosis, as well as self-perceived risk of osteoporosis and fracture, has on supplementation use, seeking medical advice, bone mineral density (BMD) testing, and antiosteoporosis medication (AOM) use. Study subjects were 1,095 female Australian participants of the Global Longitudinal study of Osteoporosis in Women (GLOW) untreated for osteoporosis at baseline. Study outcomes from self administered questionnaires included calcium and vitamin D supplementation, self reported seeking of medical advice regarding osteoporosis, BMD testing, and AOM use in the last 12 months at the late assessment. Logistic regression was used in the analysis. Concern significantly increased the likelihood of seeking medical advice and, however, had no significant impact on screening or treatment. Heightened self-perceived risks of osteoporosis and fracture both significantly increased the likelihood of seeking medical advice and BMD testing while elevated self-perceived risk of fracture increased AOM use. Supplementation use was not significantly associated with concern levels and risk perception. Concern and risk perceptions to osteoporosis and fracture were significantly associated with certain bone-protective behaviours. However, the disconnect between perceived osteoporosis risk and AOM use illustrates the need to emphasize the connection between osteoporosis and fracture in future education programs. PMID- 25276472 TI - Challenges and economic implications in the control of foot and mouth disease in sub-saharan Africa: lessons from the zambian experience. AB - Foot and mouth disease is one of the world's most important livestock diseases for trade. FMD infections are complex in nature and there are many epidemiological factors needing clarification. Key questions relate to the control challenges and economic impact of the disease for resource-poor FMD endemic countries like Zambia. A review of the control challenges and economic impact of FMD outbreaks in Zambia was made. Information was collected from peer reviewed journals articles, conference proceedings, unpublished scientific reports, and personal communication with scientists and personal field experiences. The challenges of controlling FMD using mainly vaccination and movement control are discussed. Impacts include losses in income of over US$ 1.6 billion from exports of beef and sable antelopes and an annual cost of over US$ 2.7 million on preventive measures. Further impacts included unquantified losses in production and low investment in agriculture resulting in slow economic growth. FMD persistence may be a result of inadequate epidemiological understanding of the disease and ineffectiveness of the control measures that are being applied. The identified gaps may be considered in the annual appraisal of the FMD national control strategy in order to advance on the progressive control pathway. PMID- 25276474 TI - Distribution and length of osteophytes in the lumbar vertebrae and risk of rupture of abdominal aortic aneurysms: a study of dry bones from Chiang Mai, Thailand. AB - Vertebral osteophytes are a characteristic feature of intervertebral disc degeneration. In the lumbar spinal region, the two major structures in close proximity anterior to the spine are the inferior vena cava and the abdominal aorta, both of which have been reported to be affected by osteophytes. The purpose of this study was to determine the distribution, classification and lengths of osteophytes in the lumbar vertebrae. One hundred and eighty lumbar columns of 90 males and 90 females from Chiang Mai, Thailand, in the age range 15 to 96 years (mean age, 63 years) were collected. The measuring length of osteophytes was assessed on vertebral body and articular facet. Statistical analysis was performed by descriptive analysis, chi-square and Pearson Correlation. Lumbar osteophytes were presented in 175 specimens (97.2%), 88 males and 87 females. The highest frequency was at L4, most were on the superior, inferior surface of body and articular facet (39.7%, 38.4%, and 22%), respectively. The greatest mean length was 3.47+/-2.21 mm at L5, and the longest length of anterior superior surface of body was 28.56 mm. The osteophyte length was significantly correlated directly with age (P<0.01), and males were significantly greater than females (P<0.05). The highest prevalence of osteophytes was on the anterior side of superior surface of body (30.4%), and the classification was traction. It can be proposed that the abdominal aorta could be damaged, especially a risk of rupture of abdominal aortic aneurysm. PMID- 25276473 TI - Neuroprotection of antioxidant enzymes against transient global cerebral ischemia in gerbils. AB - Experimentally transient global cerebral ischemia using animal models have been thoroughly studied and numerous reports suggest the involvement of oxidative stress in the pathogenesis of neuronal death in ischemic lesions. In animal models, during the reperfusion period after ischemia, increased oxygen supply results in the overproduction of reactive oxygen species (ROS), which are involved in the process of cell death. ROS, such as superoxide anions, hydroxyl free radicals, hydrogen peroxide and nitric oxide are produced as a consequence of metabolic reactions and central nervous system activity. These reactive species are directly involved in the oxidative damage of cellular macromolecules such as nucleic acids, lipids and proteins in ischemic tissues, which can lead to cell death. Antioxidant enzymes are believed to be among the major mechanisms by which cells counteract the deleterious effect of ROS after cerebral ischemia. Consequently, antioxidant strategies have been long suggested as a therapy for experimental ischemic stroke; however, clinical trials have not yet been able to promote the translation of this concept into patient treatment regimens. This article focuses on the contribution of oxidative stress or antioxidants to the post-ischemic neuronal death following transient global cerebral ischemia by using a gerbil model. PMID- 25276475 TI - Effect of nicotine on the structure of cochlea of guinea pigs. AB - Smoking has been positively associated with hearing loss in human. However, its effect on the cochlea has not been previously evaluated. Aim of work is to investigate the effect of nicotine, which is the primary pharmacological component of tobacco, on the structure of the cochlea of adult male guinea pigs. Fifteen male guinea pigs were classified into two groups: group I (control) and group II (nicotine treated group). Group II was further subdivided into two subgroups; IIA and IIB according to the dose of nicotine (3 mg/kg and 6 mg/kg, respectively). The cochlea was harvested and processed for light microscopy, transmission electron microscopy and scanning electron microscopy. Nicotine administration induced damage of outer hair cells which were distorted in shape with vacuolated cytoplasm and heterochromatic nuclei. Topography revealed damage of the stereocilia which included disorganization, bent and limp or complete loss and expansion of the surrounding supporting cells. These changes were more pronounced in the basal turn of the cochlea and mainly involved the outer hair cells. High dose induced more damage and resulted in protrusion of the apical poles of hair cells (blebing), particularly the outer two rows. Nicotine is proved to be harmful to the cells of the cochlea, particularly the outer hair cells of the basal turn. High doses induce blebing of hair cells. PMID- 25276476 TI - Effect of saffron (Crocus sativus L.) on sodium valporate induced cytogenetic and testicular alterations in albino rats. AB - The present study investigated the cytogenetic and testicular damage induced by the antiepileptic drug, sodium valporate (SVP) in albino rats and the effect of saffron aqueous extracts. Treating rats with SVP caused a significant increase in the chromosomal aberrations either structural or numerical and decreased the mitotic index. Besides, animals administered SVP showed DNA damage appeared in the single strand breaks (comet assay). Testis of SVP-treated rats showed many histopathological changes. A significant decrease in seminiferous tubules and their epithelial heights diameters and inhibition of spermatogenesis was recorded. In addition, the number of sperm head abnormalities was increased. Biochemical results revealed an increase in malondialdhyde (MDA) which is lipid peroxidation marker and a significant decrease in the level of serum antioxidant enzyme, catalase (CAT) and reducing antioxidant power (RAP). Animals given SVP and saffron showed an improvement in chromosomal aberrations, mitotic index, DNA damage and testicular alterations caused by SVP. Moreover, MDA decreased and CAT and RAP increased. It is concluded from the present results that the ameliorative effects of saffron extract against SVP-induced cytogenetic and testicular damage in albino rats may be due to the presence of one or more antioxidant components of saffron. PMID- 25276477 TI - Localization of S-100 proteins in the testis and epididymis of poultry and rabbits. AB - The present investigation was conducted to demonstrate S-100 protein in the testis and epididymis of adult chickens, Sudani ducks, pigeons, and rabbits. This study may represent the first indication for the presence of S-100 in the male reproductive organs of these species and might therefore serve as a milestone for further reports. In the testis of chickens, pigeons and rabbits, intense S-100 was seen in Sertoli cells. S-100 was also seen in the endothelial lining of blood vessels in rabbit testis. On the contrary, no S-100 reaction was detected in the Sertoli cells of Sudani ducks. In epididymis, the localization of S-100 had varied according to species studied; it was seen in the basal cells (BC) of epididymal duct in duck, non-ciliated cells of the distal efferent ductules in pigeons and ciliated cells of the efferent ductules and BC of rabbit epididymis. Conversely, S-100 specific staining was not detected in the epithelial lining of the rooster and pigeon epididymal duct as well as the principal cells of the rabbit epididymis. In conclusion, the distribution of the S-100 proteins in the testis and epididymis might point out to its roles in the male reproduction. PMID- 25276478 TI - Variations in the origin of middle hepatic artery: a cadaveric study and implications for living donor liver transplantation. AB - Living donor liver transplantation has been associated with severe vascular complications like hepatic artery thrombosis, which commonly involves the hepatic segment 4. Most authors have defined the artery to this segment as the middle hepatic artery. The present study was undertaken to characterize the origin of middle hepatic artery and classify the variations observed in cadaveric livers, and also to analyze the significance (if any) of the findings in relation to living donor liver transplantation. The study was conducted on 125 adult livers, without macroscopic abnormalities, retrieved from human cadavers (age, 55-78 years; male, 77; female, 48) obtained from clinical wards. The hepatic arterial system was exposed, the origin of the middle hepatic artery was identified in each liver specimen and the variations observed in its origin were noted across all the specimen. Six types of hepatic arterial configurations were observed based on variations in the origin of middle hepatic artery, taking into consideration the presence of accessory hepatic arteries. It was noted in 19 (15.2%) livers that in the presence of an accessory left hepatic artery, the middle hepatic artery arose as a sub-branch of the right hepatic artery. Presence of the above hepatic arterial configuration in the donor could possibly be associated with an increased risk of intra-operative injury to the middle hepatic artery during right/left lobe living donor liver transplantation and this may subsequently lead to serious post-operative vascular complications like hepatic artery thrombosis. PMID- 25276479 TI - Sex determination using upper limb bones in Korean populations. AB - The purpose of this research is to establish metric standards for the determination of sex from the upper limb bones of Korean. We took a set of eleven measurements on each of 175 right sides of adult skeletons chosen at Korean sample. Classification accuracy dropped only one or two individuals when only vertical head diameter of humerus is used. Variables in relation with maximal length were less accurate than head diameter of humerus. Two variables were selected by the stepwise procedure: maximal length of humerus, vertical head diameter of humerus. The combined accuracy was 87%. This study of modern Korean skeletons underscores the need for population-specific techniques, not only for medicolegal investigations, but also for the study of population affinities and factors affecting bone configurations. PMID- 25276480 TI - Mastoid emissary foramina: an anatomical morphological study with discussion on their evolutionary and clinical implications. AB - The identification of mastoidal emissary veins is of importance in the neurosurgical practice to diagnose abnormal and normal structures. In the present study, the objectives were to estimate the prevalence rate of mastoidal emissary foramina in the temporal bones of the adult skull and to study their number and morphology. The present study included 48 adult human skulls which were obtained from the gross anatomy laboratory of our institution. The mastoid parts of 96 temporal bones were macroscopically observed for the prevalence, number and morphology of the emissary foramina. It is observed that, the mastoidal emissary foramen was present in 88 temporal bones (91.7%) of our specimens. The foramen was observed single in 60 temporal bones (62.5%), double in 22 bones (22.9%), and triple in 6 temporal bones (6.2%). The mastoidal emissary foramen was absent in 8 (8.3%) temporal bones. The foramen was bilaterally absent in 3 (3.1%) skulls. It was unilaterally absent in 2 (2.1%) skulls and both were on the left side. The mastoidal emissary vein is prevalent in a large number (91.7%) of cases. It was observed that the accessory mastoidal emissary foramina were present in 29.1% of cases. Recognition of the mastoid emissary veins and accessory mastoid emissary veins during the otologic surgery is critical to avoid the significant bleeding. In the neurosurgical practice, the knowledge is important due to variability in the number of mastoidal emissary veins and their connection to the venous sinuses. PMID- 25276481 TI - Semimembranosus ganglion cyst. AB - Ganglion cysts are tumor-like lesions in the soft tissues, generated by mucoid degeneration of the joint capsule, tendon or tendon sheaths on the dorsum of hand, wrist and foot. However, an intratendinous origin for a ganglion cyst is extremely rare. During dissection of the popliteal fossa, a cyst of 2.5 cm*2 cm*0.5 cm was observed in the tendon of right semimembranosus, 3.5 cm above the insertion of the muscle. Contrast X-ray revealed the cyst as not communicating with the knee joint or any adjacent bursae. Histopathological examination confirmed the diagnosis of ganglion cyst. PMID- 25276482 TI - Absent portal vein bifurcation: a rare variant and its clinical significance. AB - Portal vein branching anomaly occurs due to aberration of normal anastomotic patterns and involution of vitelline veins during development of portal vein. Anatomical knowledge of portal vein and its branching pattern is important for hepatobiliary surgeon and gastrointestinal intervention radiologist. We are reporting a case of absence of portal vein bifurcation showing single main intrahepatic portal vein with gradual decreasing caliber distally, in a young female patient on contrast-enhanced computed tomography study of abdomen. Few cases of absence of portal bifurcation have been reported in literature so far. PMID- 25276483 TI - Eight prehilar branches of the right renal artery. AB - Imaging technology with its advancement in the field of urology is the boon for the patients who require minimally invasive approaches for various kidney disorders. These approaches require a precise knowledge of the normal and variant anatomy of vessels at the hilum of the kidney. During routine dissections, a variation in the branching pattern of the right renal artery was noted in an adult male cadaver. The right renal artery divided into upper and lower divisions 6cm away from the hilum of the kidney. The upper division gave 4 branches, and the lower division gave two branches. These two branches further bifurcated and gave 2 branches each. Thus, there were 8 prehilar branches of renal artery. The multiple prehilar branches led to a congested atmosphere at the hilum of the kidney. This arterial congestion might result in hindering the blood flow at the renal hilum. Apart from this, it might cause difficulties in diagnostic and therapeutic invasive procedures. Knowledge of this variation is of importance to radiologists and urologists in particular. PMID- 25276484 TI - What the Genetic Background of Individuals with Asthma and Obesity Can Reveal: Is beta2-Adrenergic Receptor Gene Polymorphism Important? AB - The goal of this review was to evaluate the association of beta2-adrenergic receptor (ADRB2) gene polymorphisms with asthma and obesity. Asthma is the most common pediatric inflammatory disorder. The prevalence, severity, and hospitalization index for asthma have increased markedly in the last several decades. Interestingly, asthma is often diagnosed along with obesity. Genetic factors are essential for both conditions, and some of the candidate pleiotropic genes thought to be involved in the development of these diseases are ADRB2, vitamin D receptor (VDR), leptin (LEP), protein kinase C alpha (PRKCA), and tumor necrosis factor alpha (TNFalpha). The ADRB2 has been studied in multiple populations and more than 80 polymorphisms, mainly single-nucleotide polymorphisms, have been identified. For nonsynonymous Arg16Gly, Gln27Glu, and Thr164Ile, functional effects have been shown. In vivo, these polymorphisms have been evaluated to determine their association with both obesity and asthma, but the results are inconsistent and depend on the population studied or how the disease was defined. Currently, there are only few reports describing the genetic background for the comorbidity of asthma and obesity. PMID- 25276486 TI - Relationship Between Adiposity and Pulmonary Function in School-Aged Canadian Children. AB - Reduced lung function has been observed in adults with excess adiposity; however, in children, the relationship between adiposity and lung function is not clearly understood. A sample of 1,583 children, less than 18 years of age, from the Canadian Health Measures Survey (CHMS) was used to examine the associations of various anthropometric and skinfold measures with lung function parameters. The mean age of the sample was 12.15 (0.096). In normal weight boys, body mass index (BMI) was positively associated with forced vital capacity (FVC), FEV0.75 and FEV1; while in overweight or obese boys, waist circumference (WC) and waist-to hip ratio showed inverse correlations with pulmonary function measures. Similarly, in normal weight girls, BMI and WC had positive associations with lung function measures but no inverse effect of adiposity was observed in overweight or obese girls. Skinfold analysis showed that only triceps skinfold had a significant inverse association with FVC and borderline significant associations with FEV0.75 and FEV1 in normal weight boys; while in overweight or obese boys, all the skinfold indicators displayed inverse correlations with lung function. The best predictor of lung function was triceps skinfold with betastd=-0.3869 for FVC, -0.3496 for FEV0.75 and -0.3668 for FEV1. No inverse correlations between skinfolds and lung function were observed in girls. Adiposity had differing effects on respiratory function that were dependent on sex and BMI group with the most significant effect on the overweight or obese boys. The most important indicator of adiposity in boys with BMI <30 kg/m2 was triceps skinfold. In girls, adiposity was not associated with poor lung function. PMID- 25276485 TI - Pediatric Pulmonologists' Perceptions of Family Socioeconomic Status in Asthma Care. AB - Background: Physicians' assumptions about patients' socioeconomic status (SES) have been shown to influence clinical decision making in adult patients. The goal of this study is to assess the factors associated with pediatric pulmonologists' (PPs') subjective ratings of their patients' SES, and whether these factors differ by patient race/ethnicity. Methods: Parents of children with asthma (n=171) presenting for pulmonary care reported their SES using the MacArthur Subjective SES 10-rung ladder. The PPs (n=7) also estimated each family's SES. Two-level linear regression models with random intercepts (level 1: PP's SES ratings; level 2: PPs) were used to assess the predictors of PP-estimated family SES. The analyses were then stratified by race/ethnicity. Results: Parental educational, insurance type, age, and race/ethnic background were associated with PPs' SES ratings. Black/African American families were rated lower than white families, accounting for other demographic factors (b=-0.60, p<0.01), but families of other races/ethnicities were not (b=-0.10, p=0.29). Even when comparing families with the same level of parental education, black/African American families, but not families of other backgrounds, were judged to have lower SES than white families (from 0.77 rungs lower among parents with some college, to 1.2 rungs lower among parents with high school or less; both p<0.05). Conclusions: Racial differences in PPs' ability to estimate families' subjective SES in asthma care may be a function of unconscious societal biases about race and class. Collecting subjective SES from families and PPs during the office visit could facilitate discussions about material and psychosocial needs and resources that influence treatment effectiveness. PMID- 25276487 TI - Sensitivity to Five Types of House Dust Mite in a Group of Allergic Egyptian Children. AB - Background: The published data on house dust mite (HDM) sensitization from Egypt are scanty. We sought to investigate the sensitization to five different types of HDM among a group of allergic children in a trial to outline the most frequent sensitizing strains in the Cairo Province. Methods: We consecutively enrolled 100 asthmatic patients, aged 1-7 years, of whom 22 had concomitant skin allergy. Skin prick testing was performed using allergen extracts of Dermatophagoides pteronyssinus, Dermatophagoides farinae, Lepidoglyphus destructor, Tyrophagus putrescentiae, and Acarus siro. Results: Twenty-four patients (24%) were sensitized to one or more strains of HDM. Sensitization to one strain was revealed in 12% of the studied sample, while sensitization to two or three strains was detected in 8% and 4% respectively. Twelve percent of the enrolled children were sensitive to D. pteronyssinus, 11% to D. farinae, 7% to L. destructor, 6% to T. putrescentiae, and 4% to A. siro. Eight out of the 12 (66%) children sensitive to one strain had mild intermittent asthma, while five out of eight (62.5%) sensitive to two strains had moderate persistent asthma. All children sensitized to three strains of HDM had persistent rather than intermittent asthma. HDM sensitization did not correlate significantly to the history of sun exposure, bed mattresses and pillows, living in farms, or exposure to stored grains. The co-existence of atopic dermatitis tended to have a higher rate of HDM sensitization. Conclusion:D. pteronyssinus and D. farinae represent the most common sensitizing strains in the studied sample. Wider-scale population based studies are needed to assess the prevalence of HDM allergy and its clinical correlates in our country. PMID- 25276488 TI - Ischemic stroke: a consequence of a diseased immune system? PMID- 25276489 TI - Cytokines: their role in stroke and potential use as biomarkers and therapeutic targets. AB - Inflammatory mechanisms both in the periphery and in the CNS are important in the pathophysiologic processes occurring after the onset of ischemic stroke (IS). Cytokines are key players in the inflammatory mechanism and contribute to the progression of ischemic damage. This literature review focuses on the effects of inflammation on ischemic stroke, and the role pro-inflammatory and anti inflammatory cytokines play on deleterious or beneficial stroke outcome. The discovery of biomarkers and novel therapeutics for stroke has been the focus of extensive research recently; thus, understanding the roles of pro-inflammatory and anti-inflammatory cytokines that are up-regulated during stroke will help us further understand how inflammation contributes to the progression of ischemic damage and provide potential targets for novel therapeutics and biomarkers for diagnosis and prognosis of stroke. PMID- 25276491 TI - Catecholamines, steroids and immune alterations in ischemic stroke and other acute diseases. AB - The outcome of stroke patients is not only determined by the extent and localization of the ischemic lesion, but also by stroke-associated infections. Stroke-induced immune alterations, which are related to stroke-associated infections, have been described over the last decade. Here we review the evidence that catecholamines and steroids induced by stroke result in stroke-induced immune alterations. In addition, we compare the immune alterations observed in other acute diseases such as myocardial infarction, brain trauma, and surgical trauma with the changes seen in stroke-induced immune alterations. PMID- 25276494 TI - Barriers to the Use of Psychosocial Support Services Among Adolescent and Young Adult Survivors of Pediatric Cancer. AB - Purpose: Adolescent and young adult (AYA) survivors of pediatric cancer commonly report both functional and emotional difficulties, yet many of their mental health needs are not met. Given the unique needs of these survivors, this study examined barriers to psychosocial support service utilization in this population, including accessibility, personal preferences, and practical barriers such as insurance and transportation. Methods: Thirty-six adolescent and young adult survivors of pediatric cancer (aged 15-29) with mental health difficulties (i.e., anxiety or depression) completed surveys assessing access and utilization of services and barriers to utilization. Services assessed included the use of mental health professionals, a pastor or someone in a place of worship, and support groups. Results: Half of the participants utilized a mental health professional, but other forms of support were used less frequently. Utilization of services was related to insurance status and use of prescription medication. Greater time since completion of treatment was a barrier to utilizing psychosocial support services. Conclusion: Use of psychosocial support services is linked closely with use of other healthcare services, including taking prescription medication for mood difficulties. Results have implications for how primary care and oncology providers address barriers to these services among AYA survivors of pediatric cancer. PMID- 25276492 TI - 17beta-estradiol and inflammation: implications for ischemic stroke. AB - Although typically associated with maintenance of female reproductive function, estrogens mediate physiological processes in nearly every body tissue, including the central nervous system. Numerous pre-clinical studies have shown that estrogen, specifically 17-beta-estradiol (17beta-E2), protects the brain from ischemic injury following stroke. There are multiple mechanisms of 17beta-E2's neuroprotection, including activation of several neuroprotective pathways in the brain, but 17beta-E2 also mediates the local and systemic immune response to ischemic stroke. This review summarizes the immune response to stroke, sex differences in stroke pathophysiology, and the role of estrogen as an immunomodulator. This review will focus almost entirely on the role of 17beta-E2; however, there will be a brief review and comparison to other forms of estrogen. Understanding the immunomodulatory action of estrogens may provide an opportunity for the use of estrogens in treatment of stroke and other inflammatory disease. PMID- 25276495 TI - Electronic Personal Health Records for Childhood Cancer Survivors: An Exploratory Study. AB - Purpose: Childhood cancer survivors have complex healthcare needs that may be effectively communicated using electronic personal health records. This study explores the knowledge, interest, and attitudes of a sample of survivors and some of their caregivers towards electronic personal health records (ePHRs). Methods: This descriptive study was conducted in a pediatric hematology-oncology clinic and associated survivorship clinic with a convenience sample of caregivers of survivors who were <14 years old and survivors >=14 years old along with their caregivers when present. A semi-structured interview was conducted with survivors and some caregivers to understand their knowledge, interest, and attitudes towards adoption of ePHRs. Results: Interviews were completed with 11 caregivers of young survivors, four survivors alone, and five survivor-caregiver dyads. Survivors ranged in age at diagnosis from 1 to 17 years old. Among the ethnically diverse sample, approximately half of the nine survivors and 25% of 16 caregivers reported having some knowledge of ePHRs. Eighty-nine percent (8/9) of the survivors and 81% (13/16) of the caregivers reported that they were somewhat or very comfortable using the internet. All nine survivors and 75% of caregivers were interested in the adoption of ePHRs. Data security and privacy were the primary concerns expressed. Conclusions: Interest in adoption of ePHRs to manage cancer survivorship-related health information was high. Most felt that the privacy and security concerns would not prevent adoption. Additional research is needed on larger and more representative samples of survivors to understand what types of support and education are needed to effectively implement ePHRs. PMID- 25276490 TI - The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review. AB - It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response. Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke. A better understanding of the intricate and complex events that take place following immune response activation, to acute cerebral ischemia, is imperative for the development of effective novel immunomodulatory therapies for the treatment of acute stroke. PMID- 25276496 TI - Cancer-Related Disclosure Among Adolescent and Young Adult Cancer Survivors: A Qualitative Study. AB - Purpose: Adolescents and young adults (AYAs) employ self-disclosure in normative social interactions and in promoting identity development. Disclosure is associated with numerous psychological and physical benefits. Little research has examined how AYA cancer survivors diagnosed during adolescence disclose their cancer history. Methods: Using a qualitative design, this study explored cancer related disclosures among survivors (N=26) 16-24 years old at study (M=19.6 years), 14-18 years old at diagnosis (M=15.6 years), and currently at least 6 months post-treatment (M=3.2 years). Semi-structured interview guides were developed and used. Disclosure-related topics included survivorship communications and others' responses to AYAs' disclosure of their cancer experiences. Results: Grounded theory and thematic content analysis guided analyses, with an inductive data-driven approach. Three themes and eight subthemes emerged: "it depends" decision-making processes (don't ask/don't tell, shared experience, relationship potential), perceptions of others' responses (perceived apprehension, positive responses), and methods of disclosure (verbal, written, behavioral). No thematic differences were found by gender or age, although females reported greater frequency of disclosures. Conclusion: Disclosure emerged as a nuanced and complex process. "It depends" decision-making processes were most frequently endorsed, consistent with developmental complexities of this age group. This reflects social and psychological changes and highlights unique challenges for AYA survivors. This also reflects the importance of peers and social interactions as variables that influence disclosure. In the context of AYA cancer survivorship, understanding ways in which disclosure may bolster or hinder social support can assist survivors, clinicians, and families navigate survivorship. Implications for future research are discussed. PMID- 25276493 TI - Epigenetics and social context: implications for disparity in cardiovascular disease. AB - BACKGROUND: Although it is well established that African Americans (AA) experience greater social stressors than non-Hispanic Whites (NHW), the extent to which early life adversity and cumulative social stressors such as perceived discrimination, neighborhood violence, subjective social status, and socioeconomic status contribute to disparity in coronary heart disease (CHD) and stroke between AA and NHW are not well understood. PURPOSE: The purpose of this paper is to propose a conceptual model based upon McEwen's Allostatic Load Model suggesting how the relationships among social context, early life adversity, psychological stress, inflammation, adaptation, and epigenetic signature may contribute to the development of CHD and ischemic stroke. We hypothesize that social context and prior life adversity are associated with genome-wide as well as gene-specific epigenetic modifications that confer a proinflammatory epigenetic signature that mediates an enhanced proinflammatory state. Exposure to early life adversity, coupled with an increased allostatic load places individuals at greater risk for inflammatory based diseases, such as CHD and ischemic stroke. RESULTS: Based on a review of the literature, we propose a novel model in which social context and psychological stress, particularly during early life, engenders a proinflammatory epigenetic signature, which drives a heightened inflammatory state that increases risk for CHD and stroke. In the proposed model, a proinflammatory epigenetic signature and adaptation serve as mediator variables. CONCLUSIONS: Understanding the extent to which epigenetic signature bridges the psycho-social environment with inflammation and risk for CHD may yield novel biomarkers that can be used to assess risk, development, and progression of CHD/stroke. Epigenetic biomarkers may be used to inform preventive and treatment strategies that can be targeted to those most vulnerable, or to those with early signs of CHD, such as endothelial dysfunction. Furthermore, epigenetic approaches, including lifestyle modification and stress reduction programs, such as mindfulness-based stress reduction, offer promise to reduce health inequity linked to social disadvantage, as emerging evidence demonstrates that adverse epigenetic marks can be reversed. PMID- 25276498 TI - Structured Open Urban Data: Understanding the Landscape. AB - A growing number of cities are now making urban data freely available to the public. Besides promoting transparency, these data can have a transformative effect in social science research as well as in how citizens participate in governance. These initiatives, however, are fairly recent and the landscape of open urban data is not well known. In this study, we try to shed some light on this through a detailed study of over 9,000 open data sets from 20 cities in North America. We start by presenting general statistics about the content, size, nature, and popularity of the different data sets, and then examine in more detail structured data sets that contain tabular data. Since a key benefit of having a large number of data sets available is the ability to fuse information, we investigate opportunities for data integration. We also study data quality issues and time-related aspects, namely, recency and change frequency. Our findings are encouraging in that most of the data are structured and published in standard formats that are easy to parse; there is ample opportunity to integrate different data sets; and the volume of data is increasing steadily. But they also uncovered a number of challenges that need to be addressed to enable these data to be fully leveraged. We discuss both our findings and issues involved in using open urban data. PMID- 25276497 TI - Effects of Short-Term Training of Community-Dwelling Elderly with Modular Interactive Tiles. AB - Objective: The objective of this study is to test for the increased mobility, agility, balancing, and general fitness of community-dwelling elderly individuals as a result of short-term training involving playing with modular interactive tiles (Entertainment Robotics, Odense, Denmark) at two community activity centers for the elderly. Three different tests from the Senior Fitness Test were used in order to test a variety of health parameters of the community-dwelling elderly, including those parameters related to fall prevention. Materials and Methods: Eighteen community-dwelling elderly individuals (63-95 years of age; mean, 83.2 years of age) were assessed in one intervention group without the use of a control group. The intervention group performed nine group sessions (1-1.5 hours each) of playful training with the modular interactive tiles over a 12-week period in two community activity centers for the elderly. Data were collected using pre-tests and post-tests of the 6-Minute Walk Test (6MWT), the 8-foot Timed Up & Go Test (TUG), and the Chair-Stand Test (CS). Data were analyzed for statistically significant differences and increases of means. Results: The 6MWT, TUG, and CS measurements showed statistically significant differences and increases of means between the pre-tests and post-tests with the 6MWT (P<0.001) (means difference, 22.4 percent), TUG (P<0.001) (means difference, 15 percent), and CS (P<0.002) (means difference, 14 percent). Fifty-six percent of the elderly progressed from one health risk level to a better level, according to the three tests. Conclusions: Statistically significant increases in scores were found across all tests, suggesting an improvement of many different health parameters for the elderly. Well-established research has shown the relationship between such test scores and fall incidents, balancing, mobility, agility, etc. This significant improvement in the health status of the elderly is obtained in as few as nine training sessions over a 12-week period of "playing" exergames with the modular interactive tiles. PMID- 25276499 TI - A Big Data Guide to Understanding Climate Change: The Case for Theory-Guided Data Science. AB - Global climate change and its impact on human life has become one of our era's greatest challenges. Despite the urgency, data science has had little impact on furthering our understanding of our planet in spite of the abundance of climate data. This is a stark contrast from other fields such as advertising or electronic commerce where big data has been a great success story. This discrepancy stems from the complex nature of climate data as well as the scientific questions climate science brings forth. This article introduces a data science audience to the challenges and opportunities to mine large climate datasets, with an emphasis on the nuanced difference between mining climate data and traditional big data approaches. We focus on data, methods, and application challenges that must be addressed in order for big data to fulfill their promise with regard to climate science applications. More importantly, we highlight research showing that solely relying on traditional big data techniques results in dubious findings, and we instead propose a theory-guided data science paradigm that uses scientific theory to constrain both the big data techniques as well as the results-interpretation process to extract accurate insight from large climate data. PMID- 25276500 TI - Hard Data Analytics Problems Make for Better Data Analysis Algorithms: Bioinformatics as an Example. AB - Data mining and knowledge discovery techniques have greatly progressed in the last decade. They are now able to handle larger and larger datasets, process heterogeneous information, integrate complex metadata, and extract and visualize new knowledge. Often these advances were driven by new challenges arising from real-world domains, with biology and biotechnology a prime source of diverse and hard (e.g., high volume, high throughput, high variety, and high noise) data analytics problems. The aim of this article is to show the broad spectrum of data mining tasks and challenges present in biological data, and how these challenges have driven us over the years to design new data mining and knowledge discovery procedures for biodata. This is illustrated with the help of two kinds of case studies. The first kind is focused on the field of protein structure prediction, where we have contributed in several areas: by designing, through regression, functions that can distinguish between good and bad models of a protein's predicted structure; by creating new measures to characterize aspects of a protein's structure associated with individual positions in a protein's sequence, measures containing information that might be useful for protein structure prediction; and by creating accurate estimators of these structural aspects. The second kind of case study is focused on omics data analytics, a class of biological data characterized for having extremely high dimensionalities. Our methods were able not only to generate very accurate classification models, but also to discover new biological knowledge that was later ratified by experimentalists. Finally, we describe several strategies to tightly integrate knowledge extraction and data mining in order to create a new class of biodata mining algorithms that can natively embrace the complexity of biological data, efficiently generate accurate information in the form of classification/regression models, and extract valuable new knowledge. Thus, a complete data-to-information-to-knowledge pipeline is presented. PMID- 25276501 TI - Translation, adaptation, validation and performance of the American Weight Efficacy Lifestyle Questionnaire Short Form (WEL-SF) to a Norwegian version: a cross-sectional study. AB - Background. Researchers have emphasized a need to identify predictors that can explain the variability in weight management after bariatric surgery. Eating self efficacy has demonstrated predictive impact on patients' adherence to recommended eating habits following multidisciplinary treatment programs, but has to a limited extent been subject for research after bariatric surgery. Recently an American short form version (WEL-SF) of the commonly used Weight Efficacy Lifestyle Questionnaire (WEL) was available for research and clinical purposes. Objectives. We intended to translate and culturally adapt the WEL-SF to Norwegian conditions, and to evaluate the new versions' psychometrical properties in a Norwegian population of morbidly obese patients eligible for bariatric surgery. Design. Cross-sectional Methods. A total of 225 outpatients selected for Laparoscopic sleeve gastrectomy (LSG) were recruited; 114 non-operated and 111 operated patients, respectively. The questionnaire was translated through forward and backward procedures. Structural properties were assessed performing principal component analysis (PCA), correlation and regression analysis were conducted to evaluate convergent validity and sensitivity, respectively. Data was assessed by mean, median, item response, missing values, floor- and ceiling effect, Cronbach's alpha and alpha if item deleted. Results. The PCA resulted in one factor with eigenvalue > 1, explaining 63.0% of the variability. The WEL-SF sum scores were positively correlated with the Self-efficacy and quality of life instruments (p < 0.001). The WEL-SF was associated with body mass index (BMI) (p < 0.001) and changes in BMI (p = 0.026). A very high item response was obtained with only one missing value (0.4%). The ceiling effect was in average 0.9 and 17.1% in the non-operated and operated sample, respectively. Strong internal consistency (r = 0.92) was obtained, and Cronbach's alpha remained high (0.86 0.92) if single items were deleted. Conclusion. The Norwegian version of WEL-SF appears to be a valid questionnaire on eating self-efficacy, with acceptable psychometrical properties in a population of morbidly obese patients. PMID- 25276502 TI - Livestock as a potential biological control agent for an invasive wetland plant. AB - Invasive species threaten biodiversity and incur costs exceeding billions of US$. Eradication efforts, however, are nearly always unsuccessful. Throughout much of North America, land managers have used expensive, and ultimately ineffective, techniques to combat invasive Phragmites australis in marshes. Here, we reveal that Phragmites may potentially be controlled by employing an affordable measure from its native European range: livestock grazing. Experimental field tests demonstrate that rotational goat grazing (where goats have no choice but to graze Phragmites) can reduce Phragmites cover from 100 to 20% and that cows and horses also readily consume this plant. These results, combined with the fact that Europeans have suppressed Phragmites through seasonal livestock grazing for 6,000 years, suggest Phragmites management can shift to include more economical and effective top-down control strategies. More generally, these findings support an emerging paradigm shift in conservation from high-cost eradication to economically sustainable control of dominant invasive species. PMID- 25276503 TI - Role of enzymatic activity in muscle damage and cytotoxicity induced by Bothrops asper Asp49 phospholipase A2 myotoxins: are there additional effector mechanisms involved? AB - Viperid venoms often contain mixtures of Asp49 and Lys49 PLA2 myotoxin isoforms, relevant to development of myonecrosis. Given their difference in catalytic activity, mechanistic studies on each type require highly purified samples. Studies on Asp49 PLA2s have shown that enzyme inactivation using p-bromophenacyl bromide (p-BPB) drastically affects toxicity. However, based on the variable levels of residual toxicity observed in some studies, it has been suggested that effector mechanisms independent of catalysis may additionally be involved in the toxicity of these enzymes, possibly resembling those of the enzymatically inactive Lys49 myotoxins. A possibility that Lys49 isoforms could be present in Asp49 PLA2 preparations exists and, if undetected in previous studies, could explain the variable residual toxicity. This question is here addressed by using an enzyme preparation ascertained to be free of Lys49 myotoxins. In agreement with previous reports, inactivation of the catalytic activity of an Asp49 myotoxin preparation led to major inhibition of toxic effects in vitro and in vivo. The very low residual levels of myotoxicity (7%) and cytotoxicity (4%) observed can be attributed to the low, although detectable, enzyme remaining active after p-BPB treatment (2.7%), and would be difficult to reconcile with the proposed existence of additional catalytic-independent toxic mechanisms. These findings favor the concept that the effector mechanism of toxicity of Asp49 PLA2 myotoxins from viperids fundamentally relies on their ability to hydrolyze phospholipids, arguing against the proposal that membrane disruption may also be caused by additional mechanisms that are independent of catalysis. PMID- 25276504 TI - Turf algae-mediated coral damage in coastal reefs of Belize, Central America. AB - Many coral reefs in the Caribbean experienced substantial changes in their benthic community composition during the last decades. This often resulted in phase shifts from scleractinian coral dominance to that by other benthic invertebrate or algae. However, knowledge about how the related role of coral algae contacts may negatively affect corals is scarce. Therefore, benthic community composition, abundance of algae grazers, and the abundance and character of coral-algae contacts were assessed in situ at 13 Belizean reef sites distributed along a distance gradient to the Belizean mainland (12-70 km): Mesoamerican Barrier Reef (inshore), Turneffe Atoll (inner and outer midshore), and Lighthouse Reef (offshore). In situ surveys revealed significantly higher benthic cover by scleractinian corals at the remote Lighthouse Reef (26-29%) when compared to the other sites (4-19%). The abundance of herbivorous fish and the sea urchin Diadema antillarum significantly increased towards the offshore reef sites, while the occurrence of direct coral-algae contacts consequently increased significantly with decreasing distance to shore. About 60% of these algae contacts were harmful (exhibiting coral tissue damage, pigmentation change, or overgrowth) for corals (mainly genera Orbicella and Agaricia), particularly when filamentous turf algae were involved. These findings provide support to the hypothesis that (turf) algae-mediated coral damage occurs in Belizean coastal, near-shore coral reefs. PMID- 25276505 TI - Habitat creation and biodiversity maintenance in mangrove forests: teredinid bivalves as ecosystem engineers. AB - Substantial amounts of dead wood in the intertidal zone of mature mangrove forests are tunnelled by teredinid bivalves. When the tunnels are exposed, animals are able to use tunnels as refuges. In this study, the effect of teredinid tunnelling upon mangrove forest faunal diversity was investigated. Mangrove forests exposed to long emersion times had fewer teredinid tunnels in wood and wood not containing teredinid tunnels had very few species and abundance of animals. However, with a greater cross-sectional percentage surface area of teredinid tunnels, the numbers of species and abundance of animals was significantly higher. Temperatures within teredinid-attacked wood were significantly cooler compared with air temperatures, and animal abundance was greater in wood with cooler temperatures. Animals inside the tunnels within the wood may avoid desiccation by escaping the higher temperatures. Animals co existing in teredinid tunnelled wood ranged from animals found in terrestrial ecosystems including centipedes, crickets and spiders, and animals found in subtidal marine ecosystems such as fish, octopods and polychaetes. There was also evidence of breeding within teredinid-attacked wood, as many juvenile individuals were found, and they may also benefit from the cooler wood temperatures. Teredinid tunnelled wood is a key low-tide refuge for cryptic animals, which would otherwise be exposed to fishes and birds, and higher external temperatures. This study provides evidence that teredinids are ecosystem engineers and also provides an example of a mechanism whereby mangrove forests support intertidal biodiversity and nurseries through the wood-boring activity of teredinids. PMID- 25276506 TI - Swarm: robust and fast clustering method for amplicon-based studies. AB - Popular de novo amplicon clustering methods suffer from two fundamental flaws: arbitrary global clustering thresholds, and input-order dependency induced by centroid selection. Swarm was developed to address these issues by first clustering nearly identical amplicons iteratively using a local threshold, and then by using clusters' internal structure and amplicon abundances to refine its results. This fast, scalable, and input-order independent approach reduces the influence of clustering parameters and produces robust operational taxonomic units. PMID- 25276507 TI - Chronic playback of boat noise does not impact hatching success or post-hatching larval growth and survival in a cichlid fish. AB - Anthropogenic (man-made) noise has been shown to have a negative impact on the behaviour and physiology of a range of terrestrial and aquatic animals. However, direct assessments of fitness consequences are rare. Here we examine the effect of additional noise on early life stages in the model cichlid fish, Neolamprologus pulcher. Many fishes use and produce sounds, they are crucial elements of aquatic ecosystems, and there is mounting evidence that they are vulnerable to anthropogenic noise; adult N. pulcher have recently been shown to change key behaviours during playback of motor boat noise. Using a split-brood design to eliminate potential genetic effects, we exposed half of the eggs and fry from each clutch to four weeks of playbacks of noise originally recorded from small motor boats with the other half acting as a control (receiving no noise playback). There was no significant effect of additional noise on hatching success or fry survival, length or weight at the end of the exposure period. Although care should be taken not to generalize these findings on a single species from a laboratory study, our data suggest that moderate noise increases do not necessarily have direct negative impacts on early-life survival and growth. Further studies on a range of species in natural conditions are urgently needed to inform conservation efforts and policy decisions about the consequences of anthropogenic noise. PMID- 25276508 TI - The self prefers itself? Self-referential versus parental standards in face attractiveness. AB - Preference for phenotypic similarity in assortative mating may be influenced by either a preference for self-similarity or parent-similarity. The aim of the current study was to assess whether people's preference in face attractiveness is influenced by resemblance to the opposite sex parent's face (parental phenotype) or their own face (self-based phenotype or "self-imprinting"). We used computerized image manipulations of facial photographs of participants, their mothers and fathers. The original photographs were combined with 78% of the participants' opposite sex prototype face (i.e., male and female prototypes made from equal contributions of a hundred faces), creating morphs where the contribution from the familiar faces went unnoticed. Female and male participants ranked these images together with the opposite-sex prototype different familiar morphs. Each participant did the same for the morphs generated with other same sex participants' faces and of their parents. We found that the female participants preferred the self-based morphs to the prototype faces. Male participants showed a general tendency towards self-referential standard. Parental face morphs were ranked low in attractiveness, which may be accounted for by the age difference of the faces blended into the self-based versus parental face morphs, since we used present-time photographs of both the participants and their parents. PMID- 25276509 TI - Open-source collaboration for Global Health: Science and Practice. AB - USAID and the Schools of Public Health at JHU and GWU welcome you to the inaugural issue of GHSP-an open-access, peer-reviewed journal for the global health community, particularly program implementers, to contribute to and benefit from a dialogue based on science and practical programmatic experience. PMID- 25276510 TI - A journal for global health programming. AB - GHSP aims to improve how programs function at scale, targeting implementers who actually support and carry out programs across all of global health. Thus, we emphasize specific implementation details, using a crisp, accessible, interactive style. PMID- 25276511 TI - Chlorhexidine for umbilical cord care: game-changer for newborn survival? AB - A simple technology with potential to prevent 500,000 global neonatal deaths annually. PMID- 25276512 TI - Contraceptive implants: providing better choice to meet growing family planning demand. AB - Contraceptive implants are extremely effective, long acting, and suitable for nearly all women-to delay, space, or limit pregnancies-and they are increasingly popular. Now, markedly reduced prices and innovative service delivery models using dedicated non-physician service providers offer a historic opportunity to help satisfy women's growing need for family planning. PMID- 25276513 TI - GeneXpert for TB diagnosis: planned and purposeful implementation. AB - Xpert MTB/RIF is a major advance for TB diagnostics, especially for multidrug resistant (MDR) TB and HIV-associated TB. But implementation concerns including cost, technical support requirements, and challenging demands of providing second line TB drugs for diagnosed MDR-TB cases call for gradual, careful introduction based on country circumstances. PMID- 25276514 TI - Global health diplomacy: advancing foreign policy and global health interests. AB - Attention to global health diplomacy has been rising but the future holds challenges, including a difficult budgetary environment. Going forward, both global health and foreign policy practitioners would benefit from working more closely together to achieve greater mutual understanding and to advance respective mutual goals. PMID- 25276515 TI - Can we stop AIDS with antiretroviral-based treatment as prevention? AB - Challenges to scaling up treatment as prevention (TasP) of HIV transmission are considerable in the developing-world context and include accessing at-risk populations, human resource shortages, adherence and retention in care, access to newer treatments, measurement of treatment effects, and long-term sustainable funding. Optimism about ending AIDS needs to be tempered by the realities of the logistic challenges of strengthening health systems in countries most affected and by balancing TasP with overall combination prevention approaches. PMID- 25276517 TI - Effectiveness of a community-based positive prevention intervention for people living with HIV who are not receiving antiretroviral treatment: a prospective cohort study. AB - BACKGROUND: We report effectiveness of an HIV-prevention intervention delivered by community health workers (CHWs) in Mombasa, Kenya, to PLHIV who have not initiated or who have discontinued ART-an often difficult-to-reach population because they fall outside the ambit of health care and prevention services. METHODS: A 2-arm cohort study assessed a structured risk-reduction intervention involving at least 4 one-to-one counseling sessions and personalized support. The control group received standard prevention services. CHWs recruited treatment naive people living with HIV (PLHIV) or those who had previously taken antiretroviral drugs. Data were analyzed using a Propensity Score Matched (PSM) sample to control for baseline differences between the groups. RESULTS: 634 PLHIV were recruited and followed for 6 months. Median age was 35 years, and 74.3% were female. Participants in the intervention group reported reduced risky sexual behaviors both at endline compared with baseline and compared with the control group. At endline, in the PSM analysis, participants in the intervention arm were less likely than participants in the control group to report unprotected sex with a spouse (Odds Ratio [OR] = 0.08, 95% confidence interval [CI] = 0.03-0.24), and they reported fewer unprotected sex acts (12.3% versus 46.0%, respectively; OR = 0.16, 95% CI = 0.09-0.29; P<0.001). Further, 92.4% of participants in the intervention group reported zero unsafe sex acts (with partners of negative or unknown HIV status) compared with 70.8% in the control group (P<0.001), and more participants in the intervention arm were receiving ART (34.3% versus 12.7%, respectively; P<0.001). CONCLUSION: CHWs effectively reached PLHIV who had never received or who had discontinued ART, and they delivered a risk-reduction intervention that led to declines in reported sexual risk behaviors, as well as to increases in ART uptake. A scaled-up intervention warrants consideration. PMID- 25276516 TI - Reducing child global undernutrition at scale in Sofala Province, Mozambique, using Care Group Volunteers to communicate health messages to mothers. AB - BACKGROUND: Undernutrition contributes to one-third of under-5 child mortality globally. Progress in achieving the Millennium Development Goal of reducing under 5 mortality is lagging in many countries, particularly in Africa. This paper shares evidence and insights from a low-cost behavior-change innovation in a rural area of Mozambique. INTERVENTION: About 50,000 households with pregnant women or children under 2 years old were organized into blocks of 12 households. One volunteer peer educator (Care Group Volunteer, or CGV) was selected for each block. Approximately 12 CGVs met together as a group every 2 weeks with a paid project promoter to learn a new child-survival health or nutrition message or skill. Then the CGVs shared the new message with mothers in their assigned blocks. METHODS OF EVALUATION: Household surveys were conducted at baseline and endline to measure nutrition-related behaviors and childhood nutritional status. FINDINGS: More than 90% of beneficiary mothers reported that they had been contacted by CGVs during the previous 2 weeks. In the early implementation project area, the percentage of children 0-23 months old with global undernutrition (weight-for-age with z-score of less than 2 standard deviations below the international standard mean) declined by 8.1 percentage points (P<0.001), from 25.9% (95% confidence interval [CI] = 22.2%-29.6%) at baseline to 17.8% at endline (95% CI = 14.6%-20.9%). In the delayed implementation area, global undernutrition declined by 11.5 percentage points (P<0.001), from 27.1% (95% CI = 23.6%-30.6%) to 15.6% (95% CI = 12.6%-18.6%). Total project costs were US$3.0 million, representing an average cost of US$0.55 per capita per year (among the entire population of 1.1 million people) and US$2.78 per beneficiary (mothers with young children) per year. CONCLUSION: Using the Care Group model can improve the level of global undernutrition in children at scale and at low cost. This model shows sufficient promise to merit further rigorous testing and broader application. PMID- 25276518 TI - Successful polio eradication in Uttar Pradesh, India: the pivotal contribution of the Social Mobilization Network, an NGO/UNICEF collaboration. AB - In Uttar Pradesh, India, in response to low routine immunization coverage and ongoing poliovirus circulation, a network of U.S.-based CORE Group member and local nongovernmental organizations partnered with UNICEF, creating the Social Mobilization Network (SMNet). The SMNet's goal was to improve access and reduce family and community resistance to vaccination. The partners trained thousands of mobilizers from high-risk communities to visit households, promote government-run child immunization services, track children's immunization history and encourage vaccination of children missing scheduled vaccinations, and mobilize local opinion leaders. Creative behavior change activities and materials promoted vaccination awareness and safety, household hygiene, sanitation, home diarrheal disease control, and breastfeeding. Program decision-makers at all levels used household-level data that were aggregated at community and district levels, and senior staff provided rapid feedback and regular capacity-building supervision to field staff. Use of routine project data and targeted research findings offered insights into and informed innovative approaches to overcoming community concerns impacting immunization coverage. While the SMNet worked in the highest-risk, poorly served communities, data suggest that the immunization coverage in SMNet communities was often higher than overall coverage in the district. The partners' organizational and resource differences and complementary technical strengths posed both opportunities and challenges; overcoming them enhanced the partnership's success and contributions. PMID- 25276519 TI - Meeting the community halfway to reduce maternal deaths? Evidence from a community-based maternal death review in Uttar Pradesh, India. AB - BACKGROUND: Uttar Pradesh (UP) is the most populous state in India with the second highest reported maternal mortality ratio in the country. In an effort to analyze the reasons for maternal deaths and implement appropriate interventions, the Government of India introduced Maternal Death Review guidelines in 2010. METHODS: We assessed causes of and factors leading to maternal deaths in Unnao District, UP, through 2 methods. First, we conducted a facility gap assessment in 15 of the 16 block-level and district health facilities to collect information on the performance of the facilities in terms of treating obstetric complications. Second, teams of trained physicians conducted community-based maternal death reviews (verbal autopsies) in a sample of maternal deaths occurring between June 1, 2009, and May 31, 2010. RESULTS: Of the 248 maternal deaths that would be expected in this district in a year, we identified 153 (62%) through community workers and conducted verbal autopsies with families of 57 of them. Verbal autopsies indicated that 23% and 30% of these maternal deaths occurred at home and on the way to a health facility, respectively. Most of the women who died had been taken to at least 2 health facilities. The facility assessment revealed that only the district hospital met the recommended criteria for either basic or comprehensive emergency obstetric and neonatal care. CONCLUSIONS: Life-saving treatment of obstetric complications was not offered at the appropriate level of government facilities in a representative district in UP, and an inadequate referral system provided fatal delays. Expensive transportation costs to get pregnant women to a functioning medical facility also contributed to maternal death. The maternal death review, coupled with the facility gap assessment, is a useful tool to address the adequacy of emergency obstetric and neonatal care services to prevent further maternal deaths. PMID- 25276520 TI - Women's growing desire to limit births in sub-Saharan Africa: meeting the challenge. AB - Demographic and Health Survey data from 18 countries were analyzed to better understand the characteristics of women wishing to limit childbearing. Demand for limiting (14% of all women) is less than that that for spacing (25%) but is still substantial. The mean "demand crossover age" (the average age at which demand to limit births begins to exceed demand to space) is generally around age 33, but in some countries it is as low as 23 or 24. Young women often intend to limit their births, contrary to the assumption that only older women do. Large numbers of women have exceeded their desired fertility but do not use family planning, citing fear of side effects and health concerns as barriers. When analysis is restricted to married women, demand for limiting nearly equals that for spacing. Many women who want no more children and who use contraception, especially poor women and those with less education, use less effective temporary contraceptive methods. A sizable number of women in sub-Saharan Africa-nearly 8 million-have demand for limiting future births. Limiting births has a greater impact on fertility rates than spacing births and is a major factor driving the fertility transition. Family planning programs must prepare to meet this demand by addressing supply- and demand-side barriers to use. Meeting the growing needs of sub-Saharan African women who want to limit births is essential, as they are a unique audience that has long been overlooked and underserved. PMID- 25276521 TI - "Man, what took you so long?" Social and individual factors affecting adult attendance at voluntary medical male circumcision services in Tanzania. AB - BACKGROUND: In 2009, the Government of Tanzania embarked on scaling up voluntary medical male circumcision (VMMC) services for HIV prevention in 8 priority regions, with the aim of serving 2.8 million boys and men ages 10-34 years by 2013. By mid-2012, more than 110,000 boys and men in Iringa and Njombe regions had received VMMC. The majority (85%) of these VMMC clients were under 19 years old (average age, 16 years). This study aimed to identify potential barriers and facilitators to VMMC among older men. METHODS: We conducted 16 focus group discussions, stratified by sex and age, with 142 purposefully selected participants in 3 districts of Iringa and Njombe regions. RESULTS: Both men and women generally had positive attitudes toward VMMC. Social and personal barriers to obtaining VMMC among adult men included shame associated with seeking services co-located with younger boys and perceived inappropriateness of VMMC after puberty, particularly after marriage and after having children. Additional barriers included concerns about partner infidelity during the post-surgical abstinence period, loss of income, and fear of pain associated with post-surgical erections. Facilitators included awareness of the HIV-prevention benefit and perceptions of cleanliness and enhanced attractiveness to women. CONCLUSIONS: While men and women in Iringa and Njombe regions in Tanzania generally view VMMC as a desirable procedure, program implementers need to address barriers to VMMC services among adult men. Selected service delivery sites in the Iringa and Njombe regions will be segregated by age to provide services that are "friendly" to adult men. Services will be complemented with behavior change communication initiatives to address concerns of older men, encourage women's support for circumcision and adherence to the post-surgical abstinence period, and change social norms that inhibit older men from seeking circumcision. PMID- 25276522 TI - Lessons learned from scaling up a community-based health program in the Upper East Region of northern Ghana. AB - Ghana's Community-Based Health Planning and Service (CHPS) initiative is envisioned to be a national program to relocate primary health care services from subdistrict health centers to convenient community locations. The initiative was launched in 4 phases. First, it was piloted in 3 villages to develop appropriate strategies. Second, the approach was tested in a factorial trial, which showed that community-based care could reduce childhood mortality by half in only 3 years. Then, a replication experiment was launched to clarify appropriate activities for implementing the fourth and final phase-national scale up. This paper discusses CHPS progress in the Upper East Region (UER) of Ghana, where the pace of scale up has been much more rapid than in the other 9 regions of the country despite exceedingly challenging economic, ecological, and social circumstances. The UER employed 5 strategies that facilitated scale up: (1) nurse recruitment from their home districts to improve worker morale and cultural grounding, balanced with some social distance from the village community to ensure client confidentiality, particularly regarding family planning use; (2) prioritization of CHPS planning and continuous review in management meetings to make necessary modifications to the initiative's approach; (3) community engagement and advocacy to local politicians to mobilize resources for financing start-up costs; (4) a shared and consistent vision about CHPS among health administration leaders to ensure appropriate resources and commitment to the initiative; and (5) knowledge exchange visits between new and advanced CHPS implementers to facilitate learning and scale up within and between districts. PMID- 25276523 TI - From housewife to health worker: touching other lives and changing my own. PMID- 25276524 TI - The 6 domains of behavior change: the missing health system building block. AB - Behavior is crucial throughout global health interventions. The discipline of behavior change offers distinct expertise needed across 6 different domains of behavior. Such expertise is in short supply, however. We will not have effective and sustainable health systems, nor achieve our ambitious global health goals, without seriously addressing behavior change. PMID- 25276525 TI - Making the most of food aid to help prevent child and maternal deaths. AB - Advances in child nutrition over the last several decades are creating momentum for a programmatic push to reduce undernutrition worldwide. The contribution of food aid may be small, but, nonetheless, U.S. food aid policy should be revamped to benefit more effectively and more efficiently the children and mothers in need. PMID- 25276526 TI - Focusing on implementation: the power of executing many small advances well. AB - Success often comes through many small, incremental, well-executed improvements. PMID- 25276527 TI - Achieving better maternal and newborn outcomes: coherent strategy and pragmatic, tailored implementation. AB - Maternal and newborn health program effort needs to: shift from mere contact to the actual content or substance of care; respond better to local context; ensure delivery of all key interventions needed during pregnancy, labor and delivery, and postnatally; and actively monitor performance to manage and improve programs. PMID- 25276528 TI - Multiplicity in public health supply systems: a learning agenda. AB - Supply chain integration-merging products for health programs into a single supply chain-tends to be the dominant model in health sector reform. However, multiplicity in a supply system may be justified as a risk management strategy that can better ensure product availability, advance specific health program objectives, and increase efficiency. PMID- 25276529 TI - mHealth innovations as health system strengthening tools: 12 common applications and a visual framework. AB - This new framework lays out 12 common mHealth applications used as health systems strengthening innovations across the reproductive health continuum. PMID- 25276530 TI - High and equitable mass vitamin A supplementation coverage in Sierra Leone: a post-event coverage survey. AB - BACKGROUND: In Sierra Leone, children ages 6-59 months receive twice-yearly vitamin A supplementation (VAS) through Maternal and Child Health Week (MCHW) events. VAS coverage in 2011 was calculated using government tally sheets of vitamin A capsule distribution and outdated population projections from the 2004 census. We conducted a national post-event coverage (PEC) survey to validate coverage and inform strategies to reach universal coverage of VAS in Sierra Leone. METHODOLOGY: Immediately following the November 2011 MCHW event, we conducted a national PEC survey by interviewing caregivers with children ages 6 59 months using a randomized 30X30 cluster design (N = 900). We also interviewed one health worker and one community health worker in each cluster to determine their knowledge about VAS (N = 60). RESULTS: VAS coverage was 91.8% among children ages 6-59 months, which was lower than the 105.1% reported through tally sheets. Coverage was high and equitable among all districts and between age groups (98.5% for infants ages 6-11 months and 90.5% for children ages 12-59 months). Major reasons for not receiving VAS were that the child was out of the area (42.4%), the household was not visited by community health workers (28.0%), and the caretaker was not aware of the event (11.9%). CONCLUSION: Twice-yearly delivery of VAS through MCHW events achieved consistently high and equitable coverage in Sierra Leone. Universal coverage may be achieved through continued focus on communication and targeted outreach to hard-to-reach areas during the MCHWs. PMID- 25276531 TI - Client-centered counseling improves client satisfaction with family planning visits: evidence from Irbid, Jordan. AB - BACKGROUND: High levels of unmet need for family planning and high contraceptive discontinuation rates persist in Jordan, prompting the Jordan Health Communication Partnership (JHCP) to initiate a client-centered family planning service program called "Consult and Choose" (CC), together with community-based activities to encourage women with unmet need to visit health centers. METHODS: We held exit interviews with 461 family planning clients between November December 2011 to assess, from the clients' perspective, whether trained providers followed the CC protocol and used the CC tools, as well as to measure client satisfaction. We also tracked referral card information from community-based activities to health centers and examined service statistics to explore trends in family planning use. RESULTS: On average, clients reported that providers performed 5.6 of the 7 steps outlined in the CC protocol. Nearly 83% of respondents were very satisfied with their clinic visits. Logistic regression analysis found that the odds of being "very satisfied" increases by 20% with each additional counseling protocol step performed and by 70% with each increase in the number of CC materials used. Between June 2011 and August 2012, 14,490 referral cards from community-based activities were collected in health centers, 59% of which were for family planning services. Service statistic trends indicate an increase in the number of new family planning users and in couple-years of protection after starting the CC program. CONCLUSIONS: Implementation of the CC program at health centers nationally, in tandem with community-based interventions, could play a key role in attaining Jordan's goal of reducing its total fertility rate to 2.1 by 2030. Although this initiative would likely be replicated most readily in other middle-income countries, lower-resource countries could also adapt the tested CC approach. PMID- 25276532 TI - Food commodity pipeline management in transitional settings: challenges and lessons learned from the first USAID food development program in South Sudan. AB - Despite decades of support for international food assistance programs by the U.S. Agency for International Development (USAID) Office of Food for Peace, relatively little is known about the commodity pipeline and management issues these programs face in post-conflict and politically volatile settings. Based on an audit of the program's commodity tracking system and interviews with 13 key program staff, this case study documents the experiences of organizations implementing the first USAID-funded non-emergency (development) food assistance program approved for Sudan and South Sudan. Key challenges and lessons learned in this experience about food commodity procurement, transport, and management may help improve the design and implementation of future development food assistance programs in a variety of complex, food-insecure settings around the world. Specifically, expanding shipping routes in complex political situations may facilitate reliable and timely commodity delivery. In addition, greater flexibility to procure commodities locally, rather than shipping U.S.-procured commodities, may avoid unnecessary shipping delays and reduce costs. PMID- 25276533 TI - Use of modern contraception increases when more methods become available: analysis of evidence from 1982-2009. AB - OBJECTIVE: To examine how much contraceptive use increases as additional methods are made available to populations. METHODS: We used data estimating contraceptive use from representative national surveys and data estimating method availability from special surveys to make comparisons for 6 modern contraceptive methods, in each of 6 years: 1982, 1989, 1994, 1999, 2004, and 2009. To estimate method availability, we used various method accessibility rules governing different proportions of the total population (ranging from 20% to 80%) that must have access to a method in order for it to qualify as "available." RESULTS: Contraceptive use is greater when more methods are available to a large portion of the population, both cross-sectionally and over time. The addition of 1 method available to at least half the population correlates with an increase of 4-8 percentage points in total use of the 6 modern methods, for example, from 40% to 44% or 48%. A consistent pattern emerges for the relationship of contraceptive use and choice among multiple methods. CONCLUSIONS: Use of contraception may be increased by extending the availability of current methods, by improving features of current methods, or by introducing new methods. A wider choice of methods also improves the ability to meet the individual needs of women and couples. Although the method mix has been improving over time, current availability is far from ideal; in 2009, only about 3.5 methods, on average, were available to at least half of the population in the 113 countries included in our analysis. PMID- 25276534 TI - Improving performance of Zambia Defence Force antiretroviral therapy providers: evaluation of a standards-based approach. AB - BACKGROUND: The Zambia Defence Force (ZDF) has applied the Standards-Based Management and Recognition (SBM-R(r)) approach, which uses detailed performance standards, at some health facilities to improve HIV-related services offered to military personnel and surrounding civilian communities. This study examines the effectiveness of the SBM-R approach in improving facility readiness and provider performance at ZDF facilities. METHODS: We collected data on facility readiness and provider performance before and after the 2010-2012 intervention at 4 intervention sites selected for their relatively poor performance and 4 comparison sites. Assessors observed whether each facility met 16 readiness standards and whether providers met 9 performance standards during consultations with 354 returning antiretroviral therapy (ART) clients. We then calculated the percentages of criteria achieved for each readiness and performance standard and conducted bivariate and multivariate analyses of provider performance data. RESULTS: Facilities' ART readiness scores exceeded 80% before the intervention at both intervention and comparison sites. At endline, scores improved on 4 facility readiness standards in the intervention group but on only 1 standard in the comparison group. Multivariate analysis found that the overall provider performance score increased significantly in the intervention group (from 58% to 84%; P<.01) but not in the comparison group (from 62% to 70%). The before-and after improvement in scores was significantly greater among intervention sites than among comparison sites for 2 standards-initial assessment of the client's condition and nutrition counseling. CONCLUSION: The standards-based approach, which involved intensive and mutually reinforcing intervention activities, showed modest improvements in some aspects of providers' performance during ART consultations. Further research is needed to determine whether improvements in provider performance affect client outcomes such as adherence to ART. PMID- 25276535 TI - Islam and family planning: changing perceptions of health care providers and medical faculty in Pakistan. AB - A USAID-sponsored family planning project called "FALAH" (Family Advancement for Life and Health), implemented in 20 districts of Pakistan, aimed to lower unmet need for family planning by improving access to services. To enhance the quality of care offered by the public health system, the FALAH project trained 10,534 facility-based health care providers, managers, and medical college faculty members to offer client-centered family planning services, which included a module to explain the Islamic viewpoint on family planning developed through an iterative process involving religious scholars and public health experts. At the end of the FALAH project, we conducted a situation analysis of health facilities including interviews with providers to measure family planning knowledge of trained and untrained providers; interviewed faculty to obtain their feedback about the training module; and measured changes in women's contraceptive use through baseline and endline surveys. Trained providers had a better understanding of family planning concepts than untrained providers. In addition, discussions with trained providers indicated that the training module on Islam and family planning helped them to become advocates for family planning. Faculty indicated that the module enhanced their confidence about the topic of family planning and Islam, making it easier to introduce and discuss the issue with their students. Over the 3.5-year project period, which included several components in addition to the training activity, we found an overall increase of 9 percentage points in contraceptive prevalence in the project implementation districts-from 29% to 38%. The Islam and family planning module has now been included in the teaching program of major public-sector medical universities and the Regional Training Institutes of the Population Welfare Department. Other countries with sizeable Muslim populations and low contraceptive prevalence could benefit from this module. PMID- 25276536 TI - Forest cover associated with improved child health and nutrition: evidence from the Malawi Demographic and Health Survey and satellite data. AB - Healthy forests provide human communities with a host of important ecosystem services, including the provision of food, clean water, fuel, and natural medicines. Yet globally, about 13 million hectares of forests are lost every year, with the biggest losses in Africa and South America. As biodiversity loss and ecosystem degradation due to deforestation continue at unprecedented rates, with concomitant loss of ecosystem services, impacts on human health remain poorly understood. Here, we use data from the 2010 Malawi Demographic and Health Survey, linked with satellite remote sensing data on forest cover, to explore and better understand this relationship. Our analysis finds that forest cover is associated with improved health and nutrition outcomes among children in Malawi. Children living in areas with net forest cover loss between 2000 and 2010 were 19% less likely to have a diverse diet and 29% less likely to consume vitamin A rich foods than children living in areas with no net change in forest cover. Conversely, children living in communities with higher percentages of forest cover were more likely to consume vitamin A-rich foods and less likely to experience diarrhea. Net gain in forest cover over the 10-year period was associated with a 34% decrease in the odds of children experiencing diarrhea (P = .002). Given that our analysis relied on observational data and that there were potential unknown factors for which we could not account, these preliminary findings demonstrate only associations, not causal relationships, between forest cover and child health and nutrition outcomes. However, the findings raise concerns about the potential short- and long-term impacts of ongoing deforestation and ecosystem degradation on community health in Malawi, and they suggest that preventing forest loss and maintaining the ecosystem services of forests are important factors in improving human health and nutrition outcomes. PMID- 25276537 TI - Limited electricity access in health facilities of sub-Saharan Africa: a systematic review of data on electricity access, sources, and reliability. AB - BACKGROUND: Access to electricity is critical to health care delivery and to the overarching goal of universal health coverage. Data on electricity access in health care facilities are rarely collected and have never been reported systematically in a multi-country study. We conducted a systematic review of available national data on electricity access in health care facilities in sub Saharan Africa. METHODS: We identified publicly-available data from nationally representative facility surveys through a systematic review of articles in PubMed, as well as through websites of development agencies, ministries of health, and national statistics bureaus. To be included in our analysis, data sets had to be collected in or after 2000, be nationally representative of a sub Saharan African country, cover both public and private health facilities, and include a clear definition of electricity access. RESULTS: We identified 13 health facility surveys from 11 sub-Saharan African countries that met our inclusion criteria. On average, 26% of health facilities in the surveyed countries reported no access to electricity. Only 28% of health care facilities, on average, had reliable electricity among the 8 countries reporting data. Among 9 countries, an average of 7% of facilities relied solely on a generator. Electricity access in health care facilities increased by 1.5% annually in Kenya between 2004 and 2010, and by 4% annually in Rwanda between 2001 and 2007. CONCLUSIONS: Energy access for health care facilities in sub-Saharan African countries varies considerably. An urgent need exists to improve the geographic coverage, quality, and frequency of data collection on energy access in health care facilities. Standardized tools should be used to collect data on all sources of power and supply reliability. The United Nations Secretary-General's "Sustainable Energy for All" initiative provides an opportunity to comprehensively monitor energy access in health care facilities. Such evidence about electricity needs and gaps would optimize use of limited resources, which can help to strengthen health systems. PMID- 25276539 TI - Successful use of tablet personal computers and wireless technologies for the 2011 Nepal Demographic and Health Survey. AB - Computer-Assisted Personal Interviewing (CAPI), coupled with the use of mobile and wireless technology, is growing as a data collection methodology. Nepal, a geographically diverse and resource-scarce country, implemented the 2011 Nepal Demographic and Health Survey, a nationwide survey of major health indicators, using tablet personal computers (tablet PCs) and wireless technology for the first time in the country. This paper synthesizes responses on the benefits and challenges of using new technology in such a challenging environment from the 89 interviewers who administered the survey. Overall, feedback from the interviewers indicate that the use of tablet PCs and wireless technology to administer the survey demonstrated potential to improve data quality and reduce data collection time-benefits that outweigh manageable challenges, such as storage and transport of the tablet PCs during fieldwork, limited options for confidential interview space due to screen readability issues under direct sunlight, and inconsistent electricity supply at times. The introduction of this technology holds great promise for improving data availability and quality, even in a context with limited infrastructure and extremely difficult terrain. PMID- 25276541 TI - Injectable contraception provided by community-based health workers: one important step toward meeting unmet need. AB - Community-based provision of injectable contraception continues to advance and is gaining wider acceptance-a major step toward meeting unmet need. However, fully addressing family planning need will require access to a much wider range of methods, including long-acting reversible contraception and permanent methods. PMID- 25276542 TI - Fulfilling the PEPFAR mandate: a more equitable use of PEPFAR resources across global health. AB - As PEPFAR moves beyond its "emergency stage," it should now help support a more sustainable development mode, including an equitable platform for meeting a broad range of priority health needs, while continuing to pursue the goal of an AIDS free generation. PMID- 25276538 TI - Operations research to add postpartum family planning to maternal and neonatal health to improve birth spacing in Sylhet District, Bangladesh. AB - BACKGROUND: Short birth intervals are associated with increased risk of adverse maternal and neonatal health (MNH) outcomes. Improving postpartum contraceptive use is an important programmatic strategy to improve the health and well-being of women, newborns, and children. This article documents the intervention package and evaluation design of a study conducted in a rural district of Bangladesh to evaluate the effects of an integrated, community-based MNH and postpartum family planning program on contraceptive use and birth-interval lengths. INTERVENTION: The study integrated family planning counseling within 5 community health worker (CHW)-household visits to pregnant and postpartum women, while a community mobilizer (CM) led community meetings on the importance of postpartum family planning and pregnancy spacing for maternal and child health. The CM and the CHWs emphasized 3 messages: (1) Use of the Lactational Amenorrhea Method (LAM) during the first 6 months postpartum and transition to another modern contraceptive method; (2) Exclusive, rather than fully or nearly fully, breastfeeding to support LAM effectiveness and good infant breastfeeding practices; (3) Use of a modern contraceptive method after a live birth for at least 24 months before attempting another pregnancy (a birth-to-birth interval of about 3 years) to support improved infant health and nutrition. CHWs provided only family planning counseling in the original study design, but we later added community-based distribution of methods, and referrals for clinical methods, to meet women's demand. METHODS: Using a quasi-experimental design, and relying primarily on pre/post-household surveys, we selected pregnant women from 4 unions to receive the intervention (n = 2,280) and pregnant women from 4 other unions (n = 2,290) to serve as the comparison group. Enrollment occurred between 2007 and 2009, and data collection ended in January 2013. PRELIMINARY RESULTS: Formative research showed that women and their family members generally did not perceive birth spacing as a priority, and most recently delivered women were not using contraception. At baseline, women in the intervention and comparison groups were similar in terms of age, husband's education, religion, and parity. CHWs visited over 90% of women in both intervention and comparison groups during pregnancy and the first 3 months postpartum. DISCUSSION: This article provides helpful intervention-design details for program managers intending to add postpartum family planning services to community-based MNH programs. Outcomes of the intervention will be reported in a future paper. Preliminary findings indicate that the package of 5 CHW visits was feasible and did not compromise worker performance. Adding doorstep delivery of contraceptives to the intervention package may enhance impact. PMID- 25276543 TI - Provider-generated barriers to health services access and quality still persist. AB - Barriers to access and quality, such as long waits, disrespectful provider behavior, and medical barriers, continue to constrain health programs. Reducing them further requires a multipronged management approach that includes understanding and addressing provider behavior and the real problems providers face. PMID- 25276544 TI - Routine immunization: an essential but wobbly platform. AB - Despite their vital role, routine immunization programs are taken for granted. Coverage levels are poor in some countries and have stagnated in others, while addition of new vaccines is an additional stressor. We need to strengthen: (1) policy processes, (2) monitoring and evaluation, (3) human resources, (4) regular delivery and supply systems, (5) local political commitment and ownership, (6) involvement of civil society and communities, and (7) sustainable financing. Rebalancing immunization direction and investment is needed. PMID- 25276545 TI - Providing technical assistance to ministries of health: lessons learned over 30 years. AB - Pursuing true country ownership for effective programs requires a long-term approach involving persistence, patience, keen understanding of counterparts' perspective, deference, building trust, focus on priorities, technical competence, and sustained optimism. PMID- 25276546 TI - "A cup of tea with our CBD agent ... ": community provision of injectable contraceptives in Kenya is safe and feasible. AB - BACKGROUND: In rural areas of Kenya, where the majority of Kenya's population lives, contraceptive use remains low compared with that in urban areas (37% vs. 47%). Inadequate access to family planning services in rural areas is partly due to fewer health facilities and the shortage of health care workers. Community based access to injectable contraceptives can improve access for rural populations and expand the range of contraceptive methods available. Our pilot project sought to generate local evidence on safety, feasibility, and acceptability of the provision of injectable depot medroxyprogesterone acetate (DMPA) by community health workers (CHWs). DESIGN: We trained 31 CHWs in Tharaka District to provide injectable DMPA in addition to pills and condoms. Data were collected on family planning clients served by CHWs in Tharaka District as well as those who received services from health facilities from August 2009 to September 2010. Service statistics were collected from 3 pilot health facilities in the CHW service catchment area. RESULTS: In the 12-month study period, CHWs reached 1,210 women with family planning services including referrals for long acting and permanent methods. Family planning use in the pilot sites for all methods increased an estimated fivefold, from 9% in facilities to 46% when facilities and CHWs were combined (32% for CHWs and 14% for facilities). The majority (69%) of clients served by CHWs chose DMPA. No client reported any signs of infection at the injection site nor did any CHW report needlestick injuries or other adverse events. The re-injection rate was 68% at the third visit, which compares favorably with other DMPA continuation studies. Two main reasons given for discontinuing were change of residence and temporary separation from spouse. CONCLUSION: Community-based provision of DMPA along with other contraceptive methods increased the use of family planning and improved method choice during the study period. Injectable contraception provided by trained CHWs is a safe, acceptable, and feasible service delivery option in Kenya. PMID- 25276547 TI - Building on safety, feasibility, and acceptability: the impact and cost of community health worker provision of injectable contraception. AB - BACKGROUND: A critical shortage of doctors, nurses, and midwives in many sub Saharan African countries inhibits efforts to expand access to family planning services, especially in rural areas. One way to fill this gap is for community health workers (CHWs) to provide injectable contraceptives, an intervention for which there is growing evidence and international support. In 2009, with approval from the Government of Zambia (GoZ), FHI 360 collaborated with ChildFund Zambia to design and implement such an intervention as part of its existing CHW family planning program. METHODS: The safety of CHW provision of injectable DMPA (depot medroxyprogesterone acetate) was measured by client reports and by a 21-item structured observation checklist. Feasibility and acceptability were measured by interviews with CHWs and a subset of DMPA clients. The impact of adding DMPA to pill and condom provision was assessed by family planning uptake among the clients of trained CHWs from February 2010 to February 2011. Costs were documented using spreadsheets over the period November 2009 to February 2011. RESULTS: Scores were high on all measures of safety, feasibility, and acceptability. Couple-years of protection (CYP, protection from pregnancy for 1 year) was provided to 51 condom clients, 391 pill clients, and 2,206 DMPA clients. Of the 1,739 clients new to family planning, 85% chose injectable DMPA, while 13% chose pills and 2% chose condoms. Continuation rates were also high, at 63% after 1 year as compared with 47% for pill users. Incremental costs per couple-year were US$21.24 if 50% of users continue with CHW-provided DMPA. CONCLUSION: The study affirms that the provision of injectable contraceptives by CHWs is safe, acceptable, and feasible in the Zambian context, with very high rates of uptake in hard-to-reach areas. High continuation rates among clients mean that costs of the intervention can be low when added to an existing community-based distribution program-a finding that is relevant to program replication (now underway in Zambia). PMID- 25276548 TI - Understanding where parents take their sick children and why it matters: a multi country analysis. AB - BACKGROUND: Developing effective context-specific strategies to ensure that a high proportion of children receive timely and appropriate care requires knowing the source from which care is sought. Although Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) collect such data in disaggregated form, they are not made available in the standard DHS and MICS reports. METHODS: Secondary data analysis was done on 42 DHS and MICS surveys conducted since 2005 for care seeking for acute respiratory illness (DHS and MICS), diarrhea (DHS only), and fever (DHS only), disaggregating by urban-rural settings. Eight categories were used for source of care. Stata, version 12, was used for the analysis. RESULTS: Patterns varied considerably, with care seeking in most of sub-Saharan Africa predominantly from public-sector providers, in South Asia predominantly from the private sector, and in Southeast Asia from a mix of public and private sources. Community health workers were not an important source of care. CONCLUSIONS: Variation in care-seeking patterns has implications for effective strategy, as described in more detail in 5 country examples from Asia and Africa. The analysis also suggests that it may be inappropriate to focus program efforts on community health workers to the exclusion of more widely used sources of care. The authors argue that, in order to ensure sounder program approaches, disaggregated care-seeking data should be routinely included in DHS and MICS reports. Finally, the authors call for more data on actual care provided in order to improve quality of care. PMID- 25276549 TI - Obesity as a public health problem among adult women in rural Tanzania. AB - BACKGROUND: For many developing countries, obesity and its sequelae have become a challenge of a magnitude similar to hunger and undernutrition. The main objective of this study was, therefore, to investigate the weight status of women in rural Tanzania with reference to season as well as the link between women's weight, food consumption, and attitudes toward obesity. METHODS: Three cross-sectional surveys in 3 different seasons within 1 year interviewed the same 210 women, ages 17-45 years, from 3 rural districts of northeastern and central Tanzania. These surveys assessed body mass index (BMI), food intake, and dietary diversity through 24-hour recalls, women's attitudes toward obesity, vegetable production, and socioeconomic status. RESULTS: Although 71% of the women had a normal BMI, 7% were underweight, 16% overweight, and 6% obese. The BMI was correlated with the Dietary Diversity Score (DDS), the Food Variety Score (FVS), with the consumption of foods from the food groups "bread/cakes," "sugar," and "tea," and with the production of exotic vegetables. In a multiple regression model, FVS was directly associated with BMI. When asked to describe the typical characteristics of an obese person, women mentioned more negative than positive characteristics. CONCLUSION: The prevalence of overweight and obesity was 3 times higher than that of underweight. Apparently, even in rural areas of Tanzania, a nutrition transition is underway. No direct association was identified between vegetable consumption and BMI. Although this study did not assess behavioral factors, such behavioral factors as activity levels as well as attitudes need to be considered, even in rural settings, to address all facets of malnutrition. PMID- 25276551 TI - Does free pregnancy testing reduce service denial in family planning clinics? A cluster-randomized experiment in Zambia and Ghana. AB - BACKGROUND: In many countries, pregnancy tests are not freely available in family planning clinics. As a result, providers sometimes deny services to non menstruating clients due to uncertainty about pregnancy. Few clients are actually pregnant, yet denied clients run the risk of becoming pregnant, and those sent to pharmacies pay inflated prices for inexpensive tests. To assess the programmatic effect of free pregnancy testing, we conducted cluster-randomized trials in Ghana and Zambia, assessing clients' uptake of contraception in family planning clinics. METHODS: In each country, 5 clinics were randomized to intervention status and 5 to control. Service data from 2,028 new, non-menstruating clients in Zambia and 1,556 in Ghana were collected. Intervention clinics received supplies of pregnancy tests, and staff were instructed to use tests as needed to help exclude pregnancy. Control clinics received no intervention. The primary outcome was the proportion of non-menstruating clients denied an effective contraceptive method. Cost-effectiveness was also evaluated. RESULTS: In Zambia, clients in intervention and control clinics faced a similar risk of service denial at baseline, 15% and 17%, respectively. At follow-up, denial remained unchanged at 17% in control clinics, but decreased significantly to 4% in intervention sites. Clients in Zambia were 4.4 (95% confidence interval [CI] = 1.3-14.4) times more likely to be denied a method in control sites versus intervention sites (P<.01). Results from Ghana were inconclusive. Cost of a "denial averted" in Zambia was estimated to be US$0.59. INTERPRETATION: Zambia results suggest that availability of free pregnancy testing significantly reduced contraceptive service denial, although results from Ghana preclude an unqualified recommendation. Authors conclude that free pregnancy testing in family planning clinics may make strong public health sense in those developing countries where denial to non menstruating clients remains a problem. Although pregnancy can usually be excluded with a client history, pregnancy tests are often necessary. PMID- 25276550 TI - Early pregnancy detection by female community health volunteers in Nepal facilitated referral for appropriate reproductive health services. AB - BACKGROUND: Female community health volunteers (FCHVs) are a possible entry point for Nepali women to access timely reproductive health services at the village level. This evaluation assessed the success of a pilot program that trained FCHVs in early pregnancy detection using urine pregnancy tests (UPTs), counseling, and referral to appropriate antenatal, safe abortion, or family planning services. METHODS: Between July 2008 and June 2009, the program trained 1,683 FCHVs from 6 districts on how to provide UPTs and appropriate counseling and referral; 1,492 FCHVs (89%) provided follow-up data on the number of clients served and the type of services provided. In addition, the program conducted in-depth interviews with selected FCHVs and other reproductive health service providers on their perceptions of the program. RESULTS: Of the FCHVs with follow-up data, 80% reported providing UPTs to women in the 8-month follow-up period. In total, they conducted 4,598 UPTs, with a mean number of 3.1 tests per FCHV. Among the women with a negative pregnancy test (47%), FCHVs provided 24% of them with oral contraceptive pills and 20% with condoms; referred 10% for other contraceptive services; and provided contraceptive counseling only to 46%. Among the women with positive pregnancy tests (53%), FCHVs referred 68% for antenatal care and 32% for safe abortion services. CONCLUSIONS: Providing FCHVs with the skills and supplies required for early pregnancy detection allowed them to make referrals for appropriate reproductive health services. Results of this evaluation suggest that community health workers such as FCHVs are a promising channel for early pregnancy detection and referral. As the intervention is scaled up, the focus should be on ensuring service availability and awareness of available services, UPT supply, and creating viable options for record keeping. PMID- 25276552 TI - Child malnutrition in Haiti: progress despite disasters. AB - Undernutrition, a chief child killer in developing countries, has been a major public health problem in Haiti. Following the 2010 disasters (earthquake and cholera) and the intensive relief efforts to address them, we sought to determine the trends of child undernutrition in Haiti using data from the 2005-06 Haiti Demographic and Health Survey (HDHS) and from a Standardized Monitoring and Assessment of Relief and Transitions (SMART) survey in 2012. Growth data analyses included 2,463 (HDHS) and 4,727 (SMART) children ages 0-59 months. We calculated the prevalence of stunting, wasting, and underweight for each survey using World Health Organization 2006 growth standards. To account for sampling design, probability weights were applied to all analyses. Statistical significance was determined by non-overlapping confidence intervals around estimates. Stunting prevalence declined from 28.5% (95% confidence interval [CI] = 25.9, 31.3) in 2005-06 to 22.2% (95% CI = 20.2, 24.3) in 2012; wasting, from 10.1% (95% CI = 8.2, 12.7) to 4.3% (95% CI = 3.6, 5.2); and underweight, from 17.7 % (95% CI = 15.6, 20.1) to 10.5% (95% CI = 9.3, 11.9). Additionally, stunting declined more in rural areas, from 33.6% (95% CI = 30.1, 37.2) in 2005-06 to 25% (95% CI = 23.4, 26.7) in 2012, than in urban areas, from 18.6% (95% CI = 15.3, 22.5) in 2005-06 to 18.4% (95% CI = 16.7, 20.1) in 2012, for reasons that remain unknown. Results of the 2012 HDHS confirmed the observed trends. Thus, undernutrition among Haitian children under 5 declined significantly between 2005-06 and 2012. Our results should be interpreted in view of investments and changes that occurred in different sectors (within and outside health and nutrition) before and after the earthquake. PMID- 25276553 TI - As good as physicians: patient perceptions of physicians and non-physician clinicians in rural primary health centers in India. AB - BACKGROUND: Attracting physicians to rural areas has been a long-standing challenge in India. Government efforts to address the shortage of rural physicians include posting non-physician clinicians (NPCs) at primary health centers (PHCs) in select areas. Performance assessments of NPCs have typically focused on the technical quality of their care with little attention to the perspectives of patients. This study investigates patient views of physicians (Medical Officers) and NPCs in terms of patient satisfaction, perceived quality, and provider trust. NPCs include: Indian system of medicine physicians (AYUSH Medical Officers) and clinicians with 3 years of training, such as Rural Medical Assistants (RMAs). At PHCs without clinicians, paramedics provide clinical care, although they are not trained for this. METHODS: PHCS IN THE STATE OF CHHATTISGARH WERE STRATIFIED BY PROVIDER TYPE: Medical Officer, AYUSH Medical Officer, RMA, or paramedic. PHCs were randomly sampled in each group. A total of 1,082 exiting patients were sampled from138 PHCs. Factor analysis was used to identify perceived quality domains. Multiple regression analysis was used to test for group differences. RESULTS: Patients of Medical Officers and NPCs reported similar levels of satisfaction, trust, and perceived quality, with scores of 84% for Medical Officers, 80% for AYUSH Medical Officers, and 85% for RMAs. While there were no significant differences in these outcomes between these groups, scores for paramedical staff were significantly lower, at 73%. CONCLUSIONS: Physicians and NPCs performed similarly in terms of patient satisfaction, trust, and perceived quality. From a patient's perspective, this supports the use and scale up of NPCs in primary care settings in India. Leaving clinician posts vacant undermines public trust and quality perceptions of government health services. PMID- 25276554 TI - Factors limiting immunization coverage in urban Dili, Timor-Leste. AB - BACKGROUND: Timor-Leste's immunization coverage is among the poorest in Asia. The 2009/2010 Demographic and Health Survey found that complete vaccination coverage in urban areas, at 47.7%, was lower than in rural areas, at 54.1%. The city of Dili, the capital of Timor-Leste, had even lower coverage (43.4%) than the national urban average. OBJECTIVE: To better understand the service- and user related factors that account for low vaccination coverage in urban Dili, despite high literacy rates and relatively good access to immunization services and communication media. METHODS: A mixed-methods (mainly qualitative) study, conducted in 5 urban sub-districts of Dili, involved in-depth interviews with18 Ministry of Health staff and 6 community leaders, 83 observations of immunization encounters, 37 exit interviews with infants' caregivers at 11 vaccination sites, and 11 focus group discussions with 70 caregivers of vaccination-eligible children ages 6 to 23 months. RESULTS: The main reasons for low vaccination rates in urban Dili included caregivers' knowledge, attitudes, and perceptions as well as barriers at immunization service sites. Other important factors were access to services and information, particularly in the city periphery, health workers' attitudes and practices, caregivers' fears of side effects, conflicting priorities, large family size, lack of support from husbands and paternal grandmothers, and seasonal migration. CONCLUSION: Good access to health facilities or health services does not necessarily translate into uptake of immunization services. The reasons are complex and multifaceted but in general relate to the health services' insufficient understanding of and attention to their clients' needs. Almost all families in Dili would be motivated to have their children immunized if services were convenient, reliable, friendly, and informative. PMID- 25276555 TI - Dedicated inserter facilitates immediate postpartum IUD insertion. AB - A specially designed inserter aims at facilitating IUD insertion within 10 minutes to 48 hours after delivery during the postpartum period when demand for, and health benefits of, contraception are high. PMID- 25276556 TI - Cell phones and CHWs: a transformational marriage? AB - Mobile phones can be transformative for community health workers (CHWs) in enhancing their influence and status and helping to solve practical problems. While formal intervention research can help advance mHealth application, most progress will come through a "diffusion of innovation" process. PMID- 25276557 TI - A bright future for IUD use in Africa? AB - High uptake of IUDs under the mobile outreach service delivery model in Kenya bodes well for IUDs in sub-Saharan Africa, if delivered with good access and quality. PMID- 25276558 TI - It's about time: WHO and partners release programming strategies for postpartum family planning. AB - The postpartum period is a critical time to address high unmet family planning need and to reduce the risks of closely spaced pregnancies. Practical tools are included in the new resource for integrating postpartum family planning at points when women have frequent health system contact, including during antenatal care, labor and delivery, postnatal care, immunization, and child health care. PMID- 25276559 TI - The imperative for health promotion in universal health coverage. AB - Health promotion and disease prevention have huge impact on health, yet given low priority, risk being overlooked in universal health coverage efforts. To effectively prioritize promotion and prevention, strong cadres of personnel are needed with expertise in legislation and health policy, social and behavior change communication, prevention and community health, health journalism, environmental health, and multisectoral health promotion. PMID- 25276560 TI - Taking knowledge for health the extra mile: participatory evaluation of a mobile phone intervention for community health workers in Malawi. AB - In Malawi, where the majority of the population resides in rural areas, community health workers (CHWs) are the first, and often only, providers of health services. An assessment of health information needs, however, found that these frontline workers often lacked essential health information. A pilot project, implemented in 2 rural districts of Malawi between 2010 and 2011, introduced a mobile phone system to strengthen knowledge exchange within networks of CHWs and district staff. To evaluate the mobile phone intervention, a participatory evaluation method called Net-Map was used, an approach built on traditional social network analysis. Together, CHWs and district personnel discussed information needs and gaps and the roles of different actors in their information networks. They then used drawings and 3-dimensional objects to create baseline and endline maps showing the linkages and levels of influence among members of the information network. Net-Map provided them with powerful evidence of differences before and after the mobile phone initiative. At baseline, CHWs were not mentioned as actors in the information network, while at endline they were seen to have significant connections with colleagues, beneficiaries, supervisors, and district health facilities, as both recipients and providers of information. Focus groups with CHWs complemented the Net-Map findings with reports of increased self-confidence and greater trust by their communities. These qualitative results were bolstered by surveys that showed decreases in stockouts of essential medicines, lower communication costs, wider service coverage, and more efficient referrals. As an innovative, participatory form of social network analysis, Net-Map yielded important visual, quantitative, and qualitative information at reasonable cost. PMID- 25276561 TI - SMS versus voice messaging to deliver MNCH communication in rural Malawi: assessment of delivery success and user experience. AB - OBJECTIVE: To determine the difference in delivery success of health messages delivered through pushed SMS, pushed voice messages sent to personal phones, and voice messages retrieved from a community phone ("retrieved voice messaging"), as well as the difference in quality of the user experience. METHODS: We analyzed the project's electronic monitoring data between September 2011 and June 2013, including demographics, enrollment data, and messages sent and successfully delivered. We also collected and analyzed information from quarterly phone-based surveys with users to assess quality of the user experience, including acceptability, comprehension, new information learned, and reported behavior change. RESULTS: More than half of subscribers enrolled in the retrieved voice messaging service while nearly one-third enrolled in the pushed SMS service and less than 10% in pushed voice messaging. Message delivery success was highest among pushed SMS subscribers and lowest among retrieved voice subscribers. Overall, 99% of survey respondents reported trusting messages they received, and about 75% of respondents recalled the last message they received and learned something new. Almost 75% of respondents reported that they had already changed or intended to change their behavior based on received messages. Intended or actual behavior change was significantly higher among pushed SMS enrollees than among pushed or retrieved voice messaging enrollees (P = .01). CONCLUSION: All message modalities led to high levels of satisfaction, comprehension, and new information learned. Due to lower cost, higher delivery success, and higher levels of intended or actual behavior change, SMS is the preferred delivery modality. However, the majority of users included in this study did not have access to a personal phone, and retrieved voice messages provided an opportunity to access a population that otherwise could not be served. Providing multiple methods by which users could access the service was crucial in extending reach beyond literate personal phone owners. PMID- 25276562 TI - Introduction of the levonorgestrel intrauterine system in Kenya through mobile outreach: review of service statistics and provider perspectives. AB - BACKGROUND: The levonorgestrel intrauterine system (LNG IUS) was developed over 30 years ago, but the product is currently too expensive for widespread use in many developing countries. In Kenya, one organization has received donated commodities for 5 years, providing an opportunity to assess impact and potential future role of the product. METHODS: We reviewed service statistics on insertions of the LNG IUS, copper intrauterine device (IUD), and subdermal implant from 15 mobile outreach teams during the 2011 calendar year. To determine the impact of the LNG IUS introduction, we analyzed changes in uptake and distribution of the copper IUD and subdermal implant by comparing periods of time when the LNG IUS was available with periods when it was not available. In addition, we interviewed 27 clinicians to assess their views of the product and of its future role. RESULTS: When the LNG IUS was not available, intrauterine contraception accounted for 39% of long-acting method provision. The addition of the LNG IUS created a slight rise in intrauterine contraception uptake (to 44%) at the expense of the subdermal implant, but the change was only marginally significant (P = .08) and was largely attributable to the copper IUD. All interviewed providers felt that the LNG IUS would increase uptake of long-acting methods, and 70% felt that the noncontraceptive benefits of the product are important to clients. CONCLUSIONS: The LNG IUS was well-received among providers and family planning clients in this population in Kenya. Although important changes in service statistics were not apparent from this analysis (perhaps due to the small quantity of LNG IUS that was available), provider enthusiasm for the product was high. This finding, above all, suggests that a larger-scale introduction effort would have strong support from providers and thus increase the chances of success. Adding another proven and highly acceptable long-acting contraceptive technology to the method mix could have important reproductive health impact. PMID- 25276563 TI - Moving malaria in pregnancy programs from neglect to priority: experience from Malawi, Senegal, and Zambia. AB - BACKGROUND: Pregnant women and infants are particularly vulnerable to malaria. National malaria in pregnancy (MIP) programs in Malawi, Senegal, and Zambia were reviewed to identify promising strategies that have helped these countries achieve relatively high coverage of MIP interventions as well as ongoing challenges that have inhibited further progress. METHODS: We used a systematic case study methodology to assess health system strengths and challenges in the 3 countries, including desk reviews of available reports and literature and key informant interviews with national stakeholders. Data were collected between 2009 and 2011 and analyzed across 8 MIP health systems components: (1) integration of programs and services, (2) policy, (3) commodities, (4) quality assurance, (5) capacity building, (6) community involvement, (7) monitoring and evaluation, and (8) financing. Within each program area, we ranked degree of scale up across 4 stages and synthesized the findings in a MIP table of analysis to reveal common themes related to better practices, remaining bottlenecks, and opportunities to accelerate MIP coverage, strengthen MIP programs, and improve results. FINDINGS: Each of the 3 countries has malaria policies in place that reflect current MIP guidance from the World Health Organization. The 3 countries successfully integrated MIP interventions into a platform of antenatal care services, but coordination at the national level was disjointed. All 3 countries recognized the importance of having a MIP focal person to ensure collaboration and planning at the national level, but only Malawi had appointed one. Commodity stockouts were frequent due to problems at all levels of the logistics system, from quantification to distribution. Lack of support for quality assurance and weak monitoring and evaluation mechanisms across all 3 countries affected optimal coverage. CONCLUSIONS: MIP programs should address all 8 interconnected MIP health systems areas holistically, in the context of a health systems approach to building successful programs. The MIP table of analysis can be a useful tool for other malaria-endemic countries to review their programs and improve MIP outcomes. PMID- 25276564 TI - Scaling up delivery of contraceptive implants in sub-Saharan Africa: operational experiences of Marie Stopes International. AB - Contraceptive implants offer promising opportunities for addressing the high and growing unmet need for modern contraceptives in sub-Saharan Africa. Marie Stopes International (MSI) offers implants as one of many family planning options. Between 2008 and 2012, MSI scaled up voluntary access to implants in 15 sub Saharan African countries, from 80,041 implants in 2008 to 754,329 implants in 2012. This 9-fold increase amounted to more than 1.7 million implants delivered cumulatively over the 5-year period. High levels of client satisfaction were attained alongside service provision scale up by using existing MSI service delivery channels-mobile outreach, social franchising, and clinics-to implement strategies that broadened access for underserved clients and maintained service quality. Use of adaptive and context-specific service delivery models and attention to key operational components, including sufficient numbers of trained providers, strong supply chains, diverse financing mechanisms, and implant removal services, underpinned our service delivery efforts. Accounting for 70% of the implants delivered by MSI in 2012, mobile outreach services through dedicated MSI provider teams played a central role in scale-up efforts, fueled in part by the provision of free or heavily subsidized services. Social franchising also demonstrated promise for future program growth, along with MSI clinics. Continued high growth in implant provision between 2011 and 2012 in all sub-Saharan African countries indicates the region's capacity for further service delivery expansion. Meeting the expected rising demand for implants and ensuring long-term sustainable access to the method, as part of a comprehensive method mix, will require continued use of appropriate service delivery models, effective operations, and ongoing collaboration between the private, public, and nongovernmental sectors. MSI's experience can be instructive for future efforts to ensure contraceptive access and choice in sub-Saharan Africa, especially as the global health community works to achieve its Family Planning 2020 (FP2020) commitments to expand family planning access to 120 million new users. PMID- 25276565 TI - Safety of adult medical male circumcision performed by non-physician clinicians in Kenya: a prospective cohort study. AB - BACKGROUND: Male circumcision reduces the risk of heterosexually acquired HIV infection in men by approximately 60%. The Government of Kenya is rolling out voluntary medical male circumcision (VMMC) services, but struggles with health worker shortages, particularly with physician shortages. OBJECTIVE: To evaluate the safety of male circumcision performed by non-physician clinicians in Kenya. METHODS: Between December 2009 and December 2010, we conducted a prospective study of VMMC procedures performed by 15 nurses and 11 clinical officers, all trained to competence, in 11 public health facilities in Nyanza Province, Kenya. Providers reported surgical complications and adverse events (AEs), based on standardized definitions, immediately after the procedure and at 7 days and 60 days post-circumcision. We also assessed clients' satisfaction with the circumcision at 60 days. RESULTS: We recruited 2,244 men and boys, ages 13-54. The retention rate was high, with 2,192 participants (98%) returning for the 7 day follow-up visit and 1,845 (82%) for the 60-day visit. There was no difference in rates of moderate and severe AEs between participants whose circumcision was performed by a nurse (2.1%) or a clinical officer (1.9%) at 7 days post circumcision. The most common AE was excess swelling (1.1%). Risk factors associated with an AE at 7 days post-circumcision included being employed and participant age >= 18 years. Participants circumcised by a provider with >= 6 years of professional experience were less likely to have an AE. Nearly all participants reported being satisfied with their circumcision at the 60-day follow-up visit. CONCLUSIONS: Trained nurses and clinical officers provided safe VMMC in Nyanza Province, Kenya. AE rates in this study were similar to those reported in typical service-delivery settings. These results add to the current body of evidence suggesting that trained non-physicians can provide safe medical male circumcision, thereby facilitating increased availability and access to circumcision services. PMID- 25276566 TI - Keeping community health workers in Uganda motivated: key challenges, facilitators, and preferred program inputs. AB - INTRODUCTION: In the face of global health worker shortages, community health workers (CHWs) are an important health care delivery strategy for underserved populations. In Uganda, community-based programs often use volunteer CHWs to extend services, including family planning, in rural areas. This study examined factors related to CHW motivation and level of activity in 3 family planning programs in Uganda. METHODS: Data were collected between July and August 2011, and sources comprised 183 surveys with active CHWs, in-depth interviews (IDIs) with 43 active CHWs and 5 former CHWs, and service statistics records. Surveys included a discrete choice experiment (DCE) to elicit CHW preferences for selected program inputs. RESULTS: Service statistics indicated an average of 56 visits with family planning clients per surveyed CHW over the 3-month period prior to data collection. In the survey, new skills and knowledge, perceived impact on the community, and enhanced status were the main positive aspects of the job reported by CHWs; the main challenges related to transportation. Multivariate analyses identified 2 correlates of CHWs being highly vs. less active (in terms of number of client visits): experiencing problems with supplies and not collaborating with peers. DCE results showed that provision of a package including a T-shirt, badge, and bicycle was the program input CHWs preferred, followed by a mobile phone (without airtime). IDI data reinforced and supplemented these quantitative findings. Social prestige, social responsibility, and aspirations for other opportunities were important motivators, while main challenges related to transportation and commodity stockouts. CHWs had complex motivations for wanting better compensation, including offsetting time and transportation costs, providing for their families, and feeling appreciated for their efforts. CONCLUSION: Volunteer CHW programs in Uganda and elsewhere need to carefully consider appropriate combinations of financial and nonfinancial inputs for optimal results. PMID- 25276567 TI - Meningococcal vaccine introduction in Mali through mass campaigns and its impact on the health system. AB - OBJECTIVE: To evaluate the impact of the meningococcal A (MenA) vaccine introduction in Mali through mass campaigns on the routine immunization program and the wider health system. METHODS: We used a mixed-methods case-study design, combining semi-structured interviews with 31 key informants, a survey among 18 health facilities, and analysis of routine health facility data on number of routine vaccinations and antenatal consultations before, during, and after the MenA vaccine campaign in December 2010. Survey and interview data were collected at the national level and in 2 regions in July and August 2011, with additional interviews in January 2012. FINDINGS: Many health system functions were not affected-either positively or negatively-by the MenA vaccine introduction. The majority of effects were felt on the immunization program. Benefits included strengthened communication and social mobilization, surveillance, and provider skills. Drawbacks included the interruption of routine vaccination services in the majority of health facilities surveyed (67%). The average daily number of children receiving routine vaccinations was 79% to 87% lower during the 10-day campaign period than during other periods of the month. Antenatal care consultations were also reduced during the campaign period by 10% to 15%. Key informants argued that, with an average of 14 campaigns per year, mass campaigns would have a substantial cumulative negative effect on routine health services. Many also argued that the MenA campaign missed potential opportunities for health systems strengthening because integration with other health services was lacking. CONCLUSION: The MenA vaccine introduction interrupted routine vaccination and other health services. When introducing a new vaccine through a campaign, coverage of routine health services should be monitored alongside campaign vaccine coverage to highlight where and how long services are disrupted and to mitigate risks to routine services. PMID- 25276568 TI - mHealth resources to strengthen health programs. AB - A suite of resources provides implementation guidance for mHealth initiatives, particularly in less developed countries. The suite includes an eLearning course, online guide, evidence database, and a High-Impact Practices brief, along with the mHealth Working Group and website. PMID- 25276569 TI - The centrality of behavior change in health systems development. PMID- 25276570 TI - The centrality of behavior change in health systems development - Author's response. PMID- 25276571 TI - Taking Exception. Reduced mortality leads to population growth: an inconvenient truth. AB - Reduced mortality has been the predominant cause of the marked global population growth over the last 3/4 of a century. While improved child survival increases motivation to reduce fertility, it comes too little and too late to forestall substantial population growth. And, beyond motivation, couples need effective means to control their fertility. It is an inconvenient truth that reducing child mortality contributes considerably to the population growth destined to compromise the quality of life of many, particularly in sub-Saharan Africa. Vigorous child survival programming is of course imperative. Wide access to voluntary family planning can help mitigate that growth and provide many other benefits. PMID- 25276572 TI - Urban health: it's time to get moving! AB - The global health community should mainstream urban health and implement urban health programs to address the triple health burden of communicable diseases, noncommunicable diseases, and injuries in low- and middle-income countries. PMID- 25276573 TI - Getting family planning and population back on track. AB - After a generation of partial neglect, renewed attention is being paid to population and voluntary family planning. Realistic access to family planning is a prerequisite for women's autonomy. For the individual, family, society, and our fragile planet, family planning has great power. PMID- 25276574 TI - Are pregnant women prioritized for bed nets? An assessment using survey data from 10 African countries. AB - BACKGROUND: Malaria in pregnancy is a major public health concern, contributing to roughly 11% of neonatal deaths and to 25% of all maternal deaths in some parts of the world. The World Health Organization has recommended priority interventions for malaria during pregnancy, including use of insecticide-treated nets (ITNs), but net distribution has shifted recently to a universal coverage paradigm rather than one targeting vulnerable populations. METHODS: To determine whether and to what extent pregnant women are prioritized within the household for ITN use, we assessed national survey data from 2009-2013 in 10 African countries. Proportion of pregnant women who slept under an ITN the previous night and 95% confidence intervals were calculated and compared between countries. Within-country logistic regression examined whether pregnancy was significantly associated with ITN use the previous night compared with other risk groups, and the predicted probability of net use for each risk group was calculated holding other covariates constant. RESULTS: A median 58% of households reported owning at least 1 ITN. On average, across all 10 countries, 35% of pregnant women in households with at least 1 ITN used a net. Households with universal coverage (at least 1 ITN per 2 people) had higher levels of net use among all family members; for example, 79% of pregnant women, on average, used a net in such households. In all countries, the predicted probability of ITN use by pregnant women was significantly higher than the probability of net use by most other household members except non-pregnant women of reproductive age. CONCLUSION: These findings suggest that both pregnant women and non-pregnant women of reproductive age are being prioritized within the household for net use. However, behavior change communication strategies are needed to achieve ITN use goals for pregnant women. PMID- 25276575 TI - The quality-coverage gap in antenatal care: toward better measurement of effective coverage. AB - BACKGROUND: The proportion of pregnant women receiving 4 or more antenatal care visits (ANC 4+) is used prominently as a global benchmark indicator to track maternal health program performance. This has contributed to an inappropriate focus on the number of contacts rather than on the content and process of care. This paper presents analysis of specific elements of care received among women reporting 4 or more ANC visits. METHODS: We conducted secondary analysis using Demographic and Health Survey data from 41 countries to determine coverage for specific elements of antenatal care. The analysis was conducted for: (1) women who delivered during the 2 years preceding the survey and who reported receiving 4 or more ANC visits, and (2) all women who delivered during the preceding 2 years. The specific ANC services that we assessed were: blood pressure measurement, tetanus toxoid vaccination, first ANC visit at less than 4 months gestation, urine testing, counseling about danger signs, HIV counseling and testing, iron-folate supplementation (>= 90 days), and at least 2 doses of sulfadoxine/pyramethamine for malaria prevention. The difference between expected (100%) and actual coverage (the quality-coverage gap) was calculated for each service across the 41 surveys. RESULTS: Coverage for specific elements of care among women reporting 4 or more ANC visits was generally low for most of the specific elements assessed. Blood pressure and tetanus toxoid performed best, with median quality-coverage gaps of 5% and 18%, respectively. The greatest gaps were for iron-folate supplementation (72%) and malaria prevention (86%). Coverage for specific interventions was generally much lower among all pregnant women (reflecting population effective coverage) than among only those who had received ANC 4+ visits. Although ANC 4+ and average coverage across the elements of care correlated relatively well (Pearson r(2) = 0.56), most countries had lower average coverage for the content of care than for ANC 4+ (among all pregnant women). CONCLUSION: We argue for the adoption of a summary indicator that better reflects the content of antenatal care than does the current ANC 4+ indicator. We propose, as an alternative, the simple average of a set of ANC content indicators available through surveys and routine health information systems. PMID- 25276576 TI - Preferences for a potential longer-acting injectable contraceptive: perspectives from women, providers, and policy makers in Kenya and Rwanda. AB - BACKGROUND: Between 1995 and 2005, injectable use doubled worldwide. However, discontinuation rates remain high, partly because of side effects but also because of missed appointments for reinjection. A longer-acting injectable (LAI) may improve compliance by reducing the required number of reinjection visits, thereby reducing unintentional discontinuation. This study examined acceptability of LAI characteristics comprising the target product profile (TPP). METHODS: In 2012, we conducted qualitative case studies in Kenya and Rwanda, consisting of 19 focus group discussions (FGDs) with 177 current, previous, or never users of injectables and 46 in-depth interviews (IDIs) with providers, program implementers, and policy makers. FGDs and IDIs assessed current injectable experiences; attitudes toward potential LAI products; and perceptions of TPP attributes, including ranking preferences for the most and least important characteristics. In addition, we obtained completed electronic surveys from 28 international family planning opinion leaders about the perceived need for an LAI, important product characteristics, and challenges to LAI development or introduction. RESULTS: Many FGD participants and interviewees spontaneously expressed strong interest in an LAI, but there was some variation in TPP preferences. The majority of participants ranked effectiveness as the most important TPP attribute. Providers were generally more concerned about side effects than potential users; some potential users suggested that side effects were related less to the product than to their own body chemistry and that side effects were acceptable as long as they did not last a long time or disrupt daily activities. Women and providers, especially in Kenya, preferred a method with a predictable return to fertility. Some participants associated amenorrhea with delayed or reduced fertility. Most women and providers preferred delivery of the LAI in a single, prepackaged, disposable injection system to facilitate injections by providers and to reduce the risk of pain or discomfort for women. While providers and policy makers ranked cost as one of the most important issues, it was among the least important issues for most potential users. Many Kenyan, but few Rwandan, participants appeared willing to pay for an LAI, with some presuming cost savings from reduced menstruation and fewer clinic visits. CONCLUSIONS: Some TPP preferences for an LAI have implications for product development decisions about formulation, delivery mechanism, or presentation, while others point to the need for tailored communication and counseling approaches to ensure acceptability and adherence within clinical trials and beyond. PMID- 25276577 TI - Rising cesarean deliveries among apparently low-risk mothers at university teaching hospitals in Jordan: analysis of population survey data, 2002-2012. AB - BACKGROUND: Cesarean delivery conducted without medical indication places mothers and infants at risk for adverse outcomes. This study assessed changes in trends of, and factors associated with, cesarean deliveries in Jordan, from 2002 to 2012. METHODS: Data for ever-married women ages 15-49 years from the 2002, 2007, and 2012 Jordan Population and Family Health Surveys were used. Analyses were restricted to mothers who responded to a question regarding the hospital-based mode of delivery for their last birth occurring within the 5 years preceding each survey (2002, N = 3,450; 2007, N = 6,307; 2012, N = 6,365). Normal birth weight infants and singleton births were used as markers for births that were potentially low risk for cesarean delivery, because low/high birth weight and multiple births are among the main obstetric variables that have been documented to increase risk of cesareans. Weighted descriptive and multivariate analyses were conducted using 4 logistic regression models: (1) among all mothers; and among mothers stratified (2) by place of delivery; (3) by birth weight of infants; and (4) by singleton vs. multiple births. RESULTS: The cesarean delivery rate increased significantly over time, from 18.2% in 2002, to 20.1% in 2007, to 30.3% in 2012. Place of delivery, birth weight, and birth multiplicity were significantly associated with cesarean delivery after adjusting for confounding factors. Between 2002 and 2012, the rate increased by 99% in public hospitals vs. 70% in private hospitals; by 93% among normal birth weight infants vs. 73% among low/high birth weight infants; and by 92% among singleton births vs. 29% among multiple births. The changes were significant across all categories except among multiple births. Further stratification revealed that the cesarean delivery rate was 2.29 times higher in university teaching hospitals (UTHs) than in private hospitals (P< .001), and 2.31 times higher than in government hospitals (P< .001). Moreover, in UTHs, the rate was higher among normal birth weight infants (adjusted OR = 2.15) and singleton births (adjusted OR = 2.39). CONCLUSION: The rising cesarean delivery rate among births that may have been at low risk for cesarean delivery, particularly in UTHs, indicates that many cesarean deliveries may increasingly be performed without any medical indication. More vigilant monitoring of data from routine health information systems is needed to reduce unnecessary cesarean deliveries in apparently low-risk groups. PMID- 25276578 TI - Medical barriers to emergency contraception: a cross-sectional survey of doctors in North India. AB - BACKGROUND: Some medical doctors in India have publicly expressed opposition to making emergency contraceptive pills (ECPs) easily accessible, even though ECPs are included in the method mix of the Ministry of Health and Family Welfare program and as an over-the-counter (OTC) product. Such opposition affects access to ECPs by influencing policy, procurement, and distribution, besides stigmatizing the ECP user. This study was conducted to assess ECP knowledge, attitudes, and practices of doctors in North India. METHODS: A cross-sectional survey of 83 doctors who provide ECPs, randomly selected from 3 cities in the state of Uttar Pradesh, was conducted in 2011. The quantitative data were complemented by 19 in-depth interviews with purposively selected senior gynecologists and other opinion leaders. RESULTS: All surveyed physicians cited the correct dose and regimen for ECPs. However, the large majority of those surveyed believed that ECPs work by preventing implantation. (The best evidence currently indicates that ECPs do not work by preventing implantation.) Most doctors also believed incorrectly that ECPs have several contraindications and side effects. They also had strong reservations against OTC provision of ECPs by pharmacists and community health workers (CHWs) and negative attitudes toward ECP users, which serve as serious medical barriers to mainstreaming use of ECPs. CONCLUSION: Physicians and their professional associations exert a strong influence on the operationalization of national contraceptive policies. Evidence based advocacy and educational campaigns targeting doctors are needed to address and resolve their reservations about ECPs, particularly about its provision as an OTC product and its distribution by CHWs. Partnerships with medical associations can help reduce doctors' negative attitudes and create a conducive environment for influencing clinical practices. Such changes are needed to increase the availability and use of ECPs as part of a package of a full range of contraceptive method options to prevent unwanted pregnancy among the most vulnerable populations. PMID- 25276579 TI - Evaluation of community-based interventions to improve TB case detection in a rural district of Tanzania. AB - In Tanzania, people with tuberculosis (TB) commonly self-medicate or visit traditional healers before seeking formal medical care. Between 2009 and 2011, we piloted a community-based project in Kisarawe District to improve TB case notification. The project trained 15 traditional healers and 15 pharmacists to identify and refer individuals with TB symptoms to diagnostic facilities. In addition, the project trained 2 community members to collect and fix sputum from symptomatic individuals onto slides, which they then delivered by bicycle to the nearest diagnostic facility. To determine effectiveness, we analyzed routine case detection data and referrals from traditional healers and pharmacists and conducted a cross-sectional survey of recently diagnosed smear-positive TB patients (N = 150) to understand their treatment-seeking behavior. From 2009 to 2011, smear-positive TB case notification increased by 68% in Kisarawe District, from 28/100,000 to 47/100,000, even while TB case notification nationally stayed the same (at approximately 14/100,000). The traditional healers and pharmacists referred 434 people with presumptive TB to diagnostic facilities, 419 of whom (97%) went to the facilities; of those who went to facilities for testing, 104 people (25%) were diagnosed with TB. The percentage of new TB case notifications that were referred through the network ranged from 38% to 70% per reporting quarter. Sputum fixers collected and delivered specimens from 178 individuals, 17 of whom (10%) were diagnosed with TB. Almost 60% of surveyed smear-positive TB patients first visited a pharmacist or traditional healer before seeking care at a diagnostic facility. These results prompted scale up of community interventions to 9 more districts in 2011 and to another 26 districts in 2013. Establishing referral networks that bring TB information and services closer to community members can contribute to improved TB case notification. PMID- 25276580 TI - Integrating family planning into postpartum care through modern quality improvement: experience from Afghanistan. AB - To address low contraceptive use in Afghanistan, we supported 2 large public maternity hospitals and 3 private hospitals in Kabul to use modern quality improvement (QI) methods to integrate family planning into postpartum care. In 2012, QI teams comprising hospital staff applied root cause analysis to identify barriers to integrated postpartum family planning (PPFP) services and to develop solutions for how to integrate services. Changes made to service provision to address identified barriers included creating a private counseling space near the postpartum ward, providing PPFP counseling training and job aids to staff, and involving husbands and mothers-in-law in counseling in person or via mobile phones. After 10 months, the proportion of postpartum women who received family planning counseling before discharge in the 5 hospitals increased from 36% to 55%, and the proportion of women who received family planning counseling with their husbands rose from 18% to 90%. In addition, the proportion of postpartum women who agreed to use family planning and left the hospital with their preferred method increased from 12% to 95%. Follow-up telephone surveys with a random sample of women who had received PPFP services in the 2 public hospitals and a control group of postpartum women who had received routine hospital services found significant differences in the proportion of women with self reported pregnancies: 3% vs. 15%, respectively, 6 months after discharge; 6% vs. 22% at 12 months; and 14% vs. 35% at 18 months (P < .001). Applying QI methods helped providers recognize and overcome barriers to integration of family planning and postpartum services by testing changes they deemed feasible. PMID- 25276581 TI - Systems approach to monitoring and evaluation guides scale up of the Standard Days Method of family planning in Rwanda. AB - There is no guarantee that a successful pilot program introducing a reproductive health innovation can also be expanded successfully to the national or regional level, because the scaling-up process is complex and multilayered. This article describes how a successful pilot program to integrate the Standard Days Method (SDM) of family planning into existing Ministry of Health services was scaled up nationally in Rwanda. Much of the success of the scale-up effort was due to systematic use of monitoring and evaluation (M&E) data from several sources to make midcourse corrections. Four lessons learned illustrate this crucially important approach. First, ongoing M&E data showed that provider training protocols and client materials that worked in the pilot phase did not work at scale; therefore, we simplified these materials to support integration into the national program. Second, triangulation of ongoing monitoring data with national health facility and population-based surveys revealed serious problems in supply chain mechanisms that affected SDM (and the accompanying CycleBeads client tool) availability and use; new procedures for ordering supplies and monitoring stockouts were instituted at the facility level. Third, supervision reports and special studies revealed that providers were imposing unnecessary medical barriers to SDM use; refresher training and revised supervision protocols improved provider practices. Finally, informal environmental scans, stakeholder interviews, and key events timelines identified shifting political and health policy environments that influenced scale-up outcomes; ongoing advocacy efforts are addressing these issues. The SDM scale-up experience in Rwanda confirms the importance of monitoring and evaluating programmatic efforts continuously, using a variety of data sources, to improve program outcomes. PMID- 25276582 TI - Informed push distribution of contraceptives in Senegal reduces stockouts and improves quality of family planning services. AB - Contraceptive use in Senegal is among the lowest in the world and has barely increased over the past 5 years, from 10% of married women in 2005 to 12% in 2011. Contraceptive stockouts in public facilities, where 85% of women access family planning services, are common. In 2011, we conducted a supply chain study of 33 public-sector facilities in Pikine and Guediawaye districts of the Dakar region to understand the magnitude and root causes of stockouts. The study included stock audits, surveys with 156 consumers, and interviews with facility staff, managers, and other stakeholders. At the facility level, stockouts of injectables and implants occurred, on average, 43% and 83% of the year, respectively. At least 60% of stockouts occurred despite stock availability at the national level. Data from interviews revealed that the current "pull-based" distribution system was complex and inefficient. In order to reduce stockout rates to the commercial-sector standard of 2% or less, the Government of Senegal and the Senegal Urban Reproductive Health Initiative developed the informed push distribution model (IPM) and pilot-tested it in Pikine district between February 2012 and July 2012. IPM brings the source of supply (a delivery truck loaded with supplies) closer to the source of demand (clients in health facilities) and streamlines the steps in between. With a professional logistician managing stock and deliveries, the health facilities no longer need to place and pick up orders. Stockouts of contraceptive pills, injectables, implants, and intrauterine devices (IUDs) were completely eliminated at the 14 public health facilities in Pikine over the 6-month pilot phase. The government expanded IPM to all 140 public facilities in the Dakar region, and 6 months later stockout rates throughout the region dropped to less than 2%. National coverage of the IPM is expected by July 2015. PMID- 25276583 TI - Evidence-based public health: not only whether it works, but how it can be made to work practicably at scale. AB - Because public health must operate at scale in widely diverse, complex situations, randomized controlled trials (RCTs) have limited utility for public health. Other methodologies are needed. A key conceptual backbone is a detailed "theory of change" to apply appropriate evidence for each operational component. Synthesizing patterns of findings across multiple methodologies provides key insights. Programs operating successfully across a variety of settings can provide some of the best evidence. Challenges include judging the quality of such evidence and assisting programs to apply it. WHO and others should shift emphasis from RCTs to more relevant evidence when assessing public health issues. PMID- 25276584 TI - Oxytocin: taking the heat. AB - Oxytocin-in-Uniject satisfied the standards of its temperature-time indicator (TTI) in severe home storage conditions, although that required resupply every 30 days-a logistically onerous programmatic standard. Possible advances include: (1) incorporating TTIs with packaged batches of less expensive and more widely used conventional vials of oxytocin; (2) using TTIs calibrated more closely to the actual temperature sensitivity of oxytocin; and (3) researching whether a lower dose of oxytocin would be equally efficacious in preventing postpartum hemorrhage. PMID- 25276585 TI - Combating trafficking in persons: a call to action for global health professionals. AB - Health care professionals can help identify victims of human trafficking, who commonly come into contact with providers during captivity. Providers can also help restore the physical and mental health of trafficking survivors. Training should focus on recognizing trafficking signs, interviewing techniques, and recommended responses when a victim is identified. PMID- 25276586 TI - Maximizing the benefits of improved cookstoves: moving from acquisition to correct and consistent use. AB - The adoption of clean cooking technologies goes beyond mere product acquisition and requires attention to issues of cooking traditions, user engagement, gender dynamics, culture, and religion to effect correct and consistent use. PMID- 25276587 TI - Are national policies and programs for prevention and management of postpartum hemorrhage and preeclampsia adequate? A key informant survey in 37 countries. AB - INTRODUCTION: Although maternal mortality has declined substantially in recent years, efforts to address postpartum hemorrhage (PPH) and preeclampsia/eclampsia (PE/E) must be systematically scaled up in order for further reduction to take place. In 2012, a key informant survey was conducted to identify both national and global gaps in PPH and PE/E program priorities and to highlight focus areas for future national and global programming. METHODS: Between January and March 2012, national program teams in 37 countries completed a 44-item survey, consisting mostly of dichotomous yes/no responses and addressing 6 core programmatic areas: policy, training, medication distribution and logistics, national reporting of key indicators, programming, and challenges to and opportunities for scale up. An in-country focal person led the process to gather the necessary information from key local stakeholders. Some countries also provided national essential medicines lists and service delivery guidelines for comparison and further analysis. RESULTS: Most surveyed countries have many elements in place to address PPH and PE/E, but notable gaps remain in both policy and practice. Oxytocin and magnesium sulfate were reported to be regularly available in facilities in 89% and 76% of countries, respectively. Only 27% of countries, however, noted regular availability of misoprostol in health facilities. Midwife scope of practice regarding PPH and PE/E is inconsistent with global norms in a number of countries: 22% of countries do not allow midwives to administer magnesium sulfate and 30% do not allow them to perform manual removal of the placenta. CONCLUSIONS: Most countries surveyed have many of the essential policies and program elements to prevent/manage PPH and PE/E, but absence of commodities (especially misoprostol), limitations in scope of practice for midwives, and gaps in inclusion of maternal health indicators in the national data systems have impeded efforts to scale up programs nationally. PMID- 25276588 TI - Cumulative effects of heat exposure and storage conditions of Oxytocin-in-Uniject in rural Ghana: implications for scale up. AB - OBJECTIVE: Postpartum hemorrhage can be reduced substantially in home deliveries attended by community-based workers by using Oxytocin-in-Uniject (OIU) devices affixed with temperature-time indicators. We characterized the distribution of time to discard of these devices when stored under normal field conditions in Ghana. METHODS: Two drug storage simulation studies were conducted in rural Ghana in 2011 and 2012. Devices were transported under refrigeration from manufacture (Argentina) to storage at the study site. Twenty-three field workers each stored at home (unrefrigerated) 25 OIU devices and monitored them daily to record: (1) time to transition from usable to unusable, and (2) continuous digital ambient temperature to determine heat exposure over the simulation period. Time to discard was estimated and compared with mean kinetic temperature exposure of the devices during the shipment and storage phases and with characteristics of the storage locations using Weibull regression models. We used the time to discard distributions in a Monte Carlo simulation to estimate wastage rates in a hypothetical program setting. RESULTS: Time for shipment and transfer to long term refrigerated storage and mean kinetic temperature during the shipment phase was 8.6 days/10.3 degrees C and 13.4 days/12.1 degrees C, for the first and second simulation studies, respectively. Median (range) time to discard when stored under field conditions (unrefrigerated) was 43 (6 to 59) days and 33 (14 to 50) days, respectively. Mean time to discard was 10.0 days shorter in the second simulation, during which mean kinetic temperature exposure was 3.9 degrees C higher. Simulating a monthly distribution system and assuming typical usage, predicted wastage of product was less than 10%. CONCLUSION: The time to discard of devices was highly sensitive to small changes in temperature exposure. Under field conditions typical in rural Ghana, OIU packages will have a half-life of approximately 30 to 40 days based on the temperature monitor used during the study. Program managers will need to carefully consider variations in both ambient temperature and rate of use to allocate the appropriate supply level that will maximize coverage and minimize stock loss. PMID- 25276589 TI - Strategic contracting practices to improve procurement of health commodities. AB - Public-sector entities responsible for procurement of essential medicines and health commodities in developing countries often lack the technical capacity to efficiently ensure supply security. Under strict public scrutiny and pressures to be transparent, many agencies continue to use archaic procurement methods and to depend on inflexible forecasts and cumbersome tendering processes. On the basis of semi-structured literature reviews and interviews, we identified framework agreements as a strategic procurement practice used by the U.S. federal government that may also be suitable for global health supply chains. Framework agreements are long-term contracts that provide the terms and conditions under which smaller repeat purchasing orders may be issued for a defined period of time. Such agreements are common in U.S. and United Nations procurement systems and in other developed countries and multilateral organizations. In contrast, framework agreements appear to be seldom used in procurement of health commodities in countries of sub-Saharan Africa. The current practice of floating tenders multiple times a year contributes to long lead times and stock-outs, and it hampers the manufacturer's or supplier's ability to plan and respond to the government's needs. To date, government's use of strategic contracting practices in public procurement of health commodities has not received much attention in most developing countries. It may present an opportunity for substantial improvements in procurement efficiency and commodity availability. Enabling legislation and strengthened technical capacity to develop and manage long-term contracts could facilitate the use of framework contracts in sub-Saharan Africa, with improved supply security and cost savings likely to result. PMID- 25276590 TI - Major challenges to scale up of visual inspection-based cervical cancer prevention programs: the experience of Guatemalan NGOs. AB - BACKGROUND: Like many other low- and middle-income countries, Guatemala has adopted visual inspection with acetic acid (VIA) as a low-resource alternative to the Pap smear for cervical cancer screening. Nongovernmental organizations (NGOs) introduced VIA to Guatemala in 2004, and a growing number of NGOs, working both independently and in collaboration with the Guatemalan Ministry of Health, employ VIA in cervical cancer prevention programs today. While much research describes VIA efficacy and feasibility in Latin America, little is known about NGO involvement with VIA programming or experiences with VIA outside the context of clinical trials and pilot projects in the region. METHODS: To explore challenges faced by NGOs implementing VIA programs in Guatemala, we conducted semi structured interviews with 36 NGO staff members involved with 20 VIA programs as direct service providers, program administrators, and training course instructors. Additionally, we collected data through observation at 30 NGO sponsored cervical cancer screening campaigns, 8 cervical cancer prevention conferences, and 1 week-long NGO-sponsored VIA training course. RESULTS: Frequently highlighted challenges included staff turnover, concerns over training quality, a need for opportunities for continued supervision, and problems with cryotherapy referrals when immediate treatment for VIA-positive women was unavailable. CONCLUSIONS: Reducing staff turnover, budgeting to train replacement providers, standardizing training curricula, and offering continued supervision are key strategies to improve VIA service quality and program sustainability. Alternative training methods, such as on-the-job mentoring and course prerequisites of online learning, could help increase training time available for clinical supervision. Efforts should be made to ensure that VIA testing is coupled with immediate cryotherapy, that providers trained in VIA are also trained in cryotherapy, and that cryotherapy supplies and equipment are maintained. Where this is not possible and only VIA screening is available, referral systems must be strengthened. PMID- 25276591 TI - Can traditional birth attendants be trained to accurately identify septic infants, initiate antibiotics, and refer in a rural African setting? AB - BACKGROUND: Neonatal sepsis is a major cause of neonatal mortality. In populations with limited access to health care, early identification of bacterial infections and initiation of antibiotics by community health workers (CHWs) could be lifesaving. It is unknown whether this strategy would be feasible using traditional birth attendants (TBAs), a cadre of CHWs who typically have limited training and educational backgrounds. METHODS: We analyzed data from the intervention arm of a cluster-randomized trial involving TBAs in Lufwanyama District, Zambia, from June 2006 to November 2008. TBAs followed neonates for signs of potential infection through 28 days of life. If any of 16 criteria were met, TBAs administered oral amoxicillin and facilitated referral to a rural health center. RESULTS: Our analysis included 1,889 neonates with final vital status by day 28. TBAs conducted a median of 2 (interquartile range 2-6) home visits (51.4% in week 1 and 48.2% in weeks 2-4) and referred 208 neonates (11%) for suspected sepsis. Of referred neonates, 176/208 (84.6%) completed their referral. Among neonates given amoxicillin, 171/183 (93.4%) were referred; among referred neonates, 171/208 (82.2%) received amoxicillin. Referral and/or initiation of antibiotics were strongly associated with neonatal death (for referral, relative risk [RR] = 7.93, 95% confidence interval [CI] = 4.4-14.3; for amoxicillin administration, RR = 4.7, 95% CI = 2.4-8.7). Neonates clinically judged to be "extremely sick" by the referring TBA were at greatest risk of death (RR = 8.61, 95% CI = 4.0-18.5). CONCLUSION: The strategy of administering a first dose of antibiotics and referring based solely on the clinical evaluation of a TBA is feasible and could be effective in reducing neonatal mortality in remote rural settings. PMID- 25276592 TI - Nationwide implementation of integrated community case management of childhood illness in Rwanda. AB - BACKGROUND: Between 2008 and 2011, Rwanda introduced integrated community case management (iCCM) of childhood illness nationwide. Community health workers in each of Rwanda's nearly 15,000 villages were trained in iCCM and equipped for empirical diagnosis and treatment of pneumonia, diarrhea, and malaria; for malnutrition surveillance; and for comprehensive reporting and referral services. METHODS: We used data from the Rwanda health management information system (HMIS) to calculate monthly all-cause under-5 mortality rates, health facility use rates, and community-based treatment rates for childhood illness in each district. We then compared a 3-month baseline period prior to iCCM implementation with a seasonally matched comparison period 1 year after iCCM implementation. Finally, we compared the actual changes in all-cause child mortality and health facility use over this time period with the changes that would have been expected based on baseline trends in Rwanda. RESULTS: The number of children receiving community-based treatment for diarrhea and pneumonia increased significantly in the 1-year period after iCCM implementation, from 0.83 cases/1,000 child-months to 3.80 cases/1,000 child-months (P = .01) and 0.25 cases/1,000 child-months to 5.28 cases/1,000 child-months (P<.001), respectively. On average, total under-5 mortality rates declined significantly by 38% (P<.001), and health facility use declined significantly by 15% (P = .006). These decreases were significantly greater than would have been expected based on baseline trends. CONCLUSIONS: This is the first study to demonstrate decreases in both child mortality and health facility use after implementing iCCM of childhood illness at a national level. While our study design does not allow for direct attribution of these changes to implementation of iCCM, these results are in line with those of prior studies conducted at the sub-national level in other low-income countries. PMID- 25276593 TI - Plausible role for CHW peer support groups in increasing care-seeking in an integrated community case management project in Rwanda: a mixed methods evaluation. AB - BACKGROUND: The Kabeho Mwana project (2006-2011) supported the Rwanda Ministry of Health (MOH) in scaling up integrated community case management (iCCM) of childhood illness in 6 of Rwanda's 30 districts. The project trained and equipped community health workers (CHWs) according to national guidelines. In project districts, Kabeho Mwana staff also trained CHWs to conduct household-level health promotion and established supervision and reporting mechanisms through CHW peer support groups (PSGs) and quality improvement systems. METHODS: The 2005 and 2010 Demographic and Health Surveys were re-analyzed to evaluate how project and non project districts differed in terms of care-seeking for fever, diarrhea, and acute respiratory infection symptoms and related indicators. We developed a logit regression model, controlling for the timing of the first CHW training, with the district included as a fixed categorical effect. We also analyzed qualitative data from the final evaluation to examine factors that may have contributed to improved outcomes. RESULTS: While there was notable improvement in care-seeking across all districts, care-seeking from any provider for each of the 3 conditions, and for all 3 combined, increased significantly more in the project districts. CHWs contributed a larger percentage of consultations in project districts (27%) than in non-project districts (12%). Qualitative data suggested that the PSG model was a valuable sub-level of CHW organization associated with improved CHW performance, supervision, and social capital. CONCLUSIONS: The iCCM model implemented by Kabeho Mwana resulted in greater improvements in care seeking than those seen in the rest of the country. Intensive monitoring, collaborative supervision, community mobilization, and CHW PSGs contributed to this success. The PSGs were a unique contribution of the project, playing a critical role in improving care-seeking in project districts. Effective implementation of iCCM should therefore include CHW management and social support mechanisms. Finally, re-analysis of national survey data improved evaluation findings by providing impact estimates. PMID- 25276594 TI - Exclusive breastfeeding: aligning the indicator with the goal. AB - While the global objective is exclusive breastfeeding (EBF) for a full 6 months duration, the standard indicator is a "prevalence" indicator, that is, the percentage of all children under age 6 months who are exclusively breastfed at a point in time. That yields a higher percentage than a more direct indicator of duration and can be easily misunderstood, exaggerating the amount of EBF. A measurement of actual percentage of children exclusively breastfeeding for a full 6 months can be easily calculated from standard DHS and MICS data. PMID- 25276596 TI - Reaching out to a community to improve maternal health in Ghana: the story of one midwife. AB - The story below of a Ghanaian midwife from the Ashanti region illustrates how one person was able to mobilize local community members in rural Piase in the Bosomtwi district to create demand for, and improve access to and use of, emergency and routine maternal health services. Her story demonstrates how involving communities in maternal health issues can improve both access to services and maternal health outcomes. PMID- 25276595 TI - Development and use of a master health facility list: Haiti's experience during the 2010 earthquake response. AB - Master health facility lists (MHFLs) are gaining attention as a standards-based means to uniquely identify health facilities and to link facility-level data. The ability to reliably communicate information about specific health facilities can support an array of health system functions, such as routine reporting and emergency response operations. MHFLs support the alignment of donor-supported health information systems with county-owned systems. Recent World Health Organization draft guidance promotes the utility of MHFLs and outlines a process for list development and governance. Although the potential benefits of MHFLs are numerous and may seem obvious, there are few documented cases of MHFL construction and use. The international response to the 2010 Haiti earthquake provides an example of how governments, nongovernmental organizations, and others can collaborate within a framework of standards to build a more complete and accurate list of health facilities. Prior to the earthquake, the Haitian Ministry of Health (Ministere de la Sante Publique et de la Population [MSPP]) maintained a list of public-sector health facilities but lacked information on privately managed facilities. Following the earthquake, the MSPP worked with a multinational group to expand the completeness and accuracy of the list of health facilities, including information on post-quake operational status. This list later proved useful in the response to the cholera epidemic and is now incorporated into the MSPP's routine health information system. Haiti's experience demonstrates the utility of MHFL formation and use in crisis as well as in the routine function of the health information system. PMID- 25276597 TI - Intracranial injectable tumor model: technical advancements. AB - Background and Objectives Few simulation models are available that provide neurosurgical trainees with the challenge of distorted skull base anatomy despite increasing importance in the acquisition of safe microsurgical and endoscopic techniques. We have previously reported a unique training model for skull base neurosurgery where a polymer is injected into a cadaveric head where it solidifies to mimic a skull base tumor for resection. This model, however, required injection of the polymer under direct surgical vision via a complicated alternative approach to that being studied, prohibiting its uptake in many neurosurgical laboratories. Conclusion We report our updated skull base tumor model that is contrast-enhanced and may be easily and reliably injected under fluoroscopic guidance. We have identified a map of burr holes and injection corridors available to place tumor at various intracranial sites. Additionally, the updated tumor model allows for the creation of mass effect, and we detail the variation of polymer preparation to mimic different tumor properties. These advancements will increase the practicality of the tumor model and ideally influence neurosurgical standards of training. PMID- 25276598 TI - Balance, falls risk, and related disability in untreated vestibular schwannoma patients. AB - Background Many vestibular schwannoma (VS) patients complain of balance dysfunction; however, validated standardized assessments are lacking. The relative contribution of imbalance and factors like anxiety to disability is unknown. Because imbalance significantly affects quality of life in this group and vestibular rehabilitation may improve outcomes, determining the severity of balance dysfunction is important to understand long-term rehabilitation needs. Aim To assess functional balance (Vertigo Symptom Scale-Vertigo [VSS-VER] and Functional Gait Assessment [FGA]) and the relative contribution of symptom severity (VSS-VER), ambulant posture (FGA), and anxiety symptoms (Vertigo Symptom Scale-Anxiety [VSS-SA]) to disability in untreated patients. Methods Patients not exposed to surgery completed the VSS, Vertigo Handicap Questionnaire (VHQ), and FGA. VSS scores were compared with migrainous vertigo (MV) patients, a mixed neuro-otological group, and healthy controls. Results A correlation was found between decreased FGA and increasing age (r = - 0.35; p < 0.01), female sex (r = 0.42; p = 0.001), increasing handicap (r = - 0.55; p < 0.001), and symptom severity (r = - 0.52; p < 0.001). In 12 of 21 patients (57%) > 60 years of age the FGA score was <= 22 suggesting increased falls risk. VSS-VER scores were higher than in healthy controls (p < 0.001) but lower than MV (p < 0.001) and mixed neuro-otology controls (p < 0.001). VSS-SA scores in VS patients with balance symptoms were higher than normal controls (p < 0.05) and correlated with handicap (r = 0.59; p < 0.001) and symptom severity (r = 0.74; p < 0.001). After controlling for age and sex, the VSS-VER, VSS-SA, and FGA explained 47% of the variation in VHQ scores. Conclusion Older VS patients are at significant risk of falls. Balance symptoms are more severe than in healthy controls but less than other neuro-otological patients. Balance symptom severity, anxiety symptoms, and ambulant posture were significant contributors to disability and should be the focus of vestibular rehabilitation strategies. PMID- 25276599 TI - The pursuit of a cholesteatoma by harvey cushing: staged approach to a complex skull base tumor. AB - Objective The evolution of neurosurgical techniques during Harvey Cushing's practice was immense. The authors illustrate this evolution using archived historical records from Harvey Cushing. Setting Historical patient records retained by the Cushing Center at Yale University Department of Neurosurgery. Design The authors present the case of one of Cushing's patients with a cholesteatoma. Results Cushing's surgical treatment of a cholesteatoma extending into the skull base is an example of his meticulous documentation and accelerated surgical techniques. Conclusions This case demonstrates how neurosurgical techniques advanced in the management of complex skull base tumors via a staged approach through the middle and posterior fossae at a time long before the development of modern skull base surgery. PMID- 25276600 TI - Comparison of surgical freedom and area of exposure in three endoscopic transmaxillary approaches to the anterolateral cranial base. AB - Objective Endoscopic ipsilateral endonasal transmaxillary, contralateral endonasal transseptal transmaxillary, and Caldwell-Luc approaches can access lesions within the retromaxillary space and pterygopalatine fossa. We compared the exposure and surgical freedom of these transmaxillary approaches to assist with surgical decision making. Design Four cadaveric heads were dissected bilaterally using the three approaches just described. Prior to dissection, stereotactic computed tomography (CT) scans were obtained on each head to obtain anatomical measurements. Surgical freedom and area of exposure were determined by stereotaxis. Main Outcome Measures Area of exposure was calculated as the extent of the orbital floor, maxillary sinus floor, nasal floor, and mandibular ramus exposed through each approach. Surgical freedom was the area through which the proximal end of the endoscope could be freely moved while moving the tip of the endoscope to the edges of the exposed area. Results The mean exposed area was similar: 9.9 +/- 2.5 cm(2) (Caldwell-Luc), 10.4 +/- 2.6 cm(2) (ipsilateral endonasal), and 10.1 +/- 2.1 cm(2) (contralateral transseptal) (p > 0.05). The surgical freedom of the Caldwell-Luc approach (113 +/- 7 cm(2)) was greater than for either endonasal approach, 76 cm(2 )+/- 15 (p = 0.001) (ipsilateral endonasal) and 83 cm(2) +/- 15 (p = 0.003) contralateral transseptal. Conclusions Our work demonstrates that the Caldwell-Luc endonasal approach offers greater surgical freedom than either approach for anterolateral skull base targets, although these approaches offer similar exposure. PMID- 25276601 TI - Impact of Chemoradiotherapy on CSF Leak Repair after Skull Base Surgery. AB - Background Transnasal endoscopic resection (TER) has become the treatment of choice for many skull base tumors. A major limitation of TER is the management of large dural defects and the need for repair of cerebrospinal fluid (CSF) leaks, particularly among patients who are treated with chemotherapy (CTX) or radiotherapy (RT). The objective of this study is to determine the impact of CTX and RT on the success of CSF leak repair after TER. Methods We performed a retrospective chart review of a single-institution experience of TER from 1992 to 2011. Results We identified 28 patients who had endoscopic CSF leak repair after resection of malignant skull base tumors. Preoperative RT was utilized in 18 patients, and 9 had undergone CTX. All patients required CSF leak repair with rotational flaps after cribriform and/or dural resection. CSF leak repair failed in three patients (11%). A history of RT or CTX was not associated with failed CSF leak repair. Conclusion Adjuvant or neoadjuvant CTX or RT is not associated with failed CSF leak repair. Successful CSF leak repair can be performed in patients with malignant skull base tumors with an acceptable risk profile. PMID- 25276603 TI - Five-strand hamstring autograft for anterior cruciate ligament reconstruction. AB - Four-strand hamstring autograft is a common choice for anterior cruciate ligament reconstruction. A potential disadvantage of hamstring autograft for anterior cruciate ligament reconstruction is the inherent variability in graft diameter. Multiple studies have shown increased revision rates when using an undersized hamstring graft. Using an EndoButton (Smith & Nephew, Andover, MA) for femoral tunnel fixation, we convert a standard quadrupled hamstring graft into a 5-strand graft by creating 3 equal strands of the typically larger semitendinosus combined with a double-stranded gracilis. This technique may help alleviate some surgeon reluctance to use a hamstring graft by providing an intraoperative "bailout" option for an unexpectedly small tendon. On the basis of current data, increasing the diameter of the graft in these situations may decrease revision rates. PMID- 25276602 TI - Management of petroclival meningiomas: a review of the development of current therapy. AB - The surgical management of petroclival meningioma remains challenging, due to the difficulty of accessing the region and the vital structures adjacent to the origin of these tumors. Petroclival meningiomas were originally considered largely unresectable. Until the 1970s, resection carried a 50% mortality rate, with very high rates of operative morbidity if attempted. However, in the past 40 years, advances in neuroimaging and approaches to the region were refined, and results from resection of petroclival meningiomas have become more acceptable. Today, the developments of a multitude of surgical approaches as well as innovations in neuroimaging and stereotactic radiotherapy have proved powerful options for multimodality management of these challenging tumors. PMID- 25276604 TI - Arthroscopic Acetabular Microfracture With the Use of Flexible Drills: A Technique Guide. AB - Chondral injuries of the hip joint are often symptomatic and affect patient activity level. Several procedures are available for addressing chondral injuries, including microfracture. Microfracture is a marrow-stimulating procedure, which creates subchondral perforation in the bone, allowing pluripotent mesenchymal stem cells to migrate from the marrow into the chondral defect and form fibrocartilaginous tissue. In the knee, microfracture has been shown to relieve pain symptoms. In the hip, microfracture has been studied to a lesser extent, but published studies have shown promising clinical outcomes. The depth, joint congruity, and geometry of the hip joint make microfracture technically challenging. The most common technique uses hip-specific microfracture awls, but the trajectory of impaction is not perpendicular to the subchondral plate. Consequently, the parallel direction of impaction creates poorly defined channels. We describe an arthroscopic microfracture technique for the hip using a flexible microfracture drill. The drill and angled guides simplify access to the chondral defect. The microfracture drill creates clear osseous channels, avoiding compaction of the surrounding bone and obstruction of the channels. Furthermore, this technique allows for better control of the angle and depth of the drill holes, which enhances reproducibility and may yield improved clinical outcomes. PMID- 25276605 TI - The chula knot: a new sliding locking knot with a special property. AB - There are many types of sliding locking knots used in arthroscopic surgery. Each type has its advantages and disadvantages. This technical note describes a new sliding locking knot, the Chula knot. This knot has been used for arthroscopic shoulder surgery in more than 500 cases at our hospital. The Chula knot has a special property in that it can be unfastened and retightened in case of premature locking and unintended loop loosening. This retensioning ability cannot be found in other configurations of arthroscopic knots. The Chula knot also has other benefits: It has high ultimate tensile strength and is easy to tie. PMID- 25276606 TI - The modified mid-anterior portal for hip arthroscopy. AB - The modified mid-anterior portal is a utilitarian hip arthroscopy working portal that permits dual-portal comprehensive surgery for femoroacetabular impingement and related chondrolabral procedures without the need for interportal exchange. Its distal location facilitates labral reparative and reconstructive procedures while minimizing iatrogenic acetabular chondral damage. The relatively lateral location permits instrument navigation not only along the anterosuperior acetabular rim and anterolateral proximal femur typically required for acetabuloplasty and femoroplasty but even to the posterior regions of the hip in cases of global pincer femoroacetabular impingement and posterior extensions of cam morphology and the anteromedial proximal femur while avoiding direct injury to the lateral femoral cutaneous nerve. PMID- 25276607 TI - Arthroscopic repair of rotator cuff tears using extracellular matrix graft. AB - Despite advances in surgical technology, as well as generally good outcomes, repairs of full-thickness rotator cuff tears show a retear rate of 25% to 57% and may fail to provide full return of function. The repairs tend to fail at the suture-tendon junction, which is due to several factors, including tension at the repair site, quality of the tendon, and defective tissue repair. One strategy to augment repair of large to massive rotator cuff tears is the development of biological scaffold materials, composed of extracellular matrix (ECM). The goal is to strengthen and evenly distribute the mechanical load across the repair site, thus minimizing the rupture risk of the native tendon while providing the biological elements needed for healing. The promising results of ECM-derived materials and their commercial availability have increased their popularity among shoulder surgeons. In contrast to a traditional open or arthroscopically assisted mini-open approach, this completely arthroscopic technique offers the full advantages warranted by the use of a minimally invasive approach. This technical guide describes arthroscopic rotator cuff repair using an ECM graft technique. PMID- 25276608 TI - Long head of the biceps tendon allis clamp evaluation technique. AB - Disorders of the long head of the biceps brachii are a common finding in conjunction with other causes of shoulder pathology. Nonoperative means as first line treatment are often successful; however, surgery can be indicated for refractory tendinopathy. There is debate as to the best surgical treatment of the long head of the biceps tendon (LHBT) with different types of arthroscopic and open techniques. The decision on what treatment option to perform is often made at the time of surgery after arthroscopic evaluation of the LHBT. Certain examples of tendon disease are easily visible intra-articularly; however, a large portion of the tendon is not intra-articular and not readily viewed during routine arthroscopy. This study describes a simple arthroscopic technique for evaluation of an increased portion of the LHBT using an Allis clamp. The clamp is inserted through the anterior portal, placed around the LHBT, and rotated such that the tendon is wrapped around itself, bringing the distal tendon into the joint for arthroscopic viewing. This procedure is a routine part of our assessment of the LHBT during arthroscopy. PMID- 25276609 TI - Tibia rotational technique to drill femoral bone tunnel in anatomic double-bundle anterior cruciate ligament reconstruction. AB - In anatomic anterior cruciate ligament (ACL) reconstruction, several pitfalls in creating the femoral bone tunnels at the correct position are of great concern. Our new method, the tibia rotational (TR) technique, may contribute to resolving these. The purpose of this study is to describe further details about the TR technique in anatomic double-bundle ACL reconstruction. Both anteromedial and posterolateral femoral bone tunnels were drilled through a posterolateral tibial bone tunnel using tibial rotation without deep knee flexion. When it is difficult to reach the mark with the rigid guide pin, the narrow curved TR technique guide and the flexible drill system allow drilling femoral bone tunnels in the correct position. The TR technique offers the technical ease required for widespread acceptance while prioritizing the fundamental goals of an anatomic double-bundle ACL reconstruction. PMID- 25276610 TI - Knee medial collateral ligament and posteromedial corner anatomic repair with internal bracing. AB - An internal brace is a ligament repair bridging concept using braided ultrahigh molecular-weight polyethylene/polyester suture tape and knotless bone anchors to reinforce ligament strength as a secondary stabilizer after repair and return to sports, which may help resist injury recurrence. An internal brace may provide augmentation during knee medial and posteromedial corner anatomic repair. In patients with combined, chronic, symptomatic anterior cruciate ligament (ACL) posteromedial corner laxity, combined ACL reconstruction with posteromedial corner reconstruction is indicated. Our ACL technique was previously published with video illustration in Arthroscopy and Arthroscopy Techniques. The purpose of this article is to describe, with video illustration, knee posteromedial corner reconstruction using anatomic repair with internal brace augmentation. PMID- 25276611 TI - Hip Arthroscopic Synovectomy and Labral Repair in a Patient With Rheumatoid Arthritis With a 2-Year Follow-up. AB - The arthroscopic surgical procedures reported previously for a rheumatic hip joint have been primarily performed as diagnostic procedures. Only a few studies have reported the success of arthroscopic surgery in hip joint preservation. We encountered a special case in which joint remodeling was seen in a patient with rheumatoid arthritis treated with biological drugs after hip arthroscopic synovectomy and labral repair. We report the case of a 39-year-old woman with rheumatism, which was controlled with tocilizumab, prednisolone, and tacrolimus. The hip joint showed Larsen grade 3 destruction, and the Harris Hip Score was 55 points. Because of the patient's strong desire to undergo a hip preservation operation, we performed hip arthroscopic synovectomy and repair of a longitudinal labral tear. After 2.5 years, the joint space had undergone rebuilding with improvement to Larsen grade 2, and the Harris Hip Score had improved to 78 points; the patient was able to return to work with the use of 1 crutch. It is possible to perform hip arthroscopic surgery for rheumatoid arthritis with a hip preservation operation with biological drugs. PMID- 25276612 TI - Intraprocedural guidance: which imaging technique ranks highest and which one is complementary for closing paravalvular leaks? AB - Echocardiographic guidance is critical for procedural success of paravalvular leak closure. Transesophageal echocardiography (TEE) and particularly three dimensional echocardiography represent the gold standards. Fusion imaging provides real-time integration of three-dimensional echocardiography and X-ray fluoroscopy and can further facilitate spatial orientation, wire placement and device deployment. Intracardiac echocardiography (ICE) is a secondary approach possibly beneficial in selected cases. PMID- 25276613 TI - Fragmented QRS on surface electrocardiogram is not a reliable predictor of myocardial scar, angiographic coronary disease or long term adverse outcomes. AB - PURPOSE: Conflicting evidence remains regarding the value of fragmented QRS (fQRS) on surface electrocardiogram (EKG). We present the 5-year outcome of patients with fQRS on EKG and its correlation to SPECT and coronary angiography (CA). METHODS: We retrospectively studied EKG's in 248 consecutive patients undergoing SPECT and CA with known or suspected coronary artery disease (CAD). The presence of fQRS or Q waves in two contiguous EKG leads was correlated with major coronary artery distributions on SPECT and cath. Patients with bundle branch block, paced-rhythm or absence of EKG within one month of SPECT were excluded. The final EKG data for 238 patients were analyzed and compared with myocardial scar on SPECT and the presence of significant (>50%) coronary stenosis on CA. Predictors of MACE (death, MI, heart failure) were evaluated. Freedom from all-cause mortality was assessed by Kaplan-Meier analysis. RESULTS: Of 238 patients, no significant difference was noted in the presence of scar on SPECT in fQRS (3/77; 3.8%) versus no fQRS (11/161; 6.8%) (P=0.56); or CA based CAD (55/77; 71% fQRS) and no fQRS (99/161, 61.4%) (P=0.20). EKG Q wave presence was similar in both groups: (12/77; 15.5% fQRS), (17/161; 10.5% no fQRS) (P=0.3). Patients with CA based significant LAD disease were 3.680 times more likely to have fQRS (P=0.04), however, fQRS was not significantly associated with MACE (P=0.92) or all-cause mortality (P=0.93). CONCLUSIONS: This study does not support routine assessment of fQRS on surface EKG as a reliable predictor of SPECT myocardial scar, MACE or all-cause mortality over a long period of follow-up. PMID- 25276614 TI - Site-specific intravascular ultrasound analysis of remodelling index and calcified necrosis patterns reveals novel blueprints for coronary plaque instability. AB - AIMS: Post-mortem pathological studies have shown that a "vulnerable" plaque is the dominant patho-physiological mechanism responsible for acute coronary syndromes (ACS). One way to improve our understanding of these plaques in vivo is by using histological "surrogates" created by intravascular ultrasound derived virtual histology (IVUS-VH). Our aim in this analysis was to determine the relationship between site-specific differences in individual plaque areas between ACS plaques and stable plaques (SP), with a focus on remodelling index and the pattern of calcifying necrosis. METHODS AND RESULTS: IVUS-VH was performed before percutaneous intervention in both ACS culprit plaques (CP) n=70 and stable disease (SP) n=35. A total of 210 plaque sites were examined in 105 lesions at the minimum lumen area (MLA) and the maximum necrotic core site (MAX NC). Each plaque site had multiple measurements made including some novel calculations to ascertain the plaque calcification equipoise (PCE) and the calcified interface area (CIA). CP has greater amounts of positive remodelling at the MLA (RI@MLA): 1.1 (+/-0.17) vs. 0.95 (+/-0.14) (P<0.001); lower values for PCE 30% vs. 54% (P<0.001) but a higher CIA 5.38 (+/-2.72) vs. 3.58 (+/-2.26) (P=0.001). These features can provide discriminatory ability between plaque types with area under the curve (AUC) measurements between 0.65-0.86. The cut-off values with greatest sensitivity and specificity to discriminate CP morphologies were: RI @ MLA >1.12; RI @ MAX NC >1.22; PCE @ MLA <47.1%; PCE @MAX NC <47.3%; CIA @ MLA >2.6; CIA @ MAX NC >3.1. CONCLUSIONS: Determining the stage of calcifying necrosis, along with the remodelling index can discriminate between stable and ACS related plaques. These findings could be applied in the future to help detect plaques that have a vulnerable phenotype. PMID- 25276615 TI - Superior CT coronary angiography image quality at lower radiation exposure with second generation 320-detector row CT in patients with elevated heart rate: a comparison with first generation 320-detector row CT. AB - BACKGROUND: This study aims to compare the image quality of second generation versus first generation 320-computed tomography coronary angiography (CTCA) in patients with heart rate >=65 bpm as it has not been specifically reported. METHODS: Consecutive patients who underwent CTCA using second-generation-320 detector-row-CT were prospectively enrolled. A total of 50 patients with elevated (>=65 bpm) heart rate and 50 patients with controlled (<65 bpm) heart rate were included. Age and gender matched patients who were scanned with the first generation-320-detector-row-CT were retrospectively identified. Image quality in each coronary artery segment was assessed by two blinded CT angiographers using the five-point Likert scale. RESULTS: In the elevated heart rate cohorts, while there was no significant difference in heart rate during scan-acquisition (66 vs. 69 bpm, P=0.308), or body mass index (28.5 vs. 29.6, P=0.464), the second generation scanner was associated with better image quality (3.94+/-0.6 vs. 3.45+/-0.8, P=0.001), and with lower radiation (2.8 vs. 4.3 mSv, P=0.009). There was no difference in scan image quality for the controlled heart rate cohorts. CONCLUSIONS: The second generation CT scanner provides better image quality at lower radiation dose in patients with elevated heart rate (>=65 bpm) compared to first generation CT scanner. PMID- 25276616 TI - Cardiac imaging in prosthetic paravalvular leaks. AB - Prosthetic paravalvular leaks (PVL) is an uncommon but serious complication after surgical valve replacement. Although surgery has been the traditional treatment of choice in hemodynamically significant PVL, percutaneous transcatheter closure is emerging as a novel and less invasive option for patients with high operative risk. Cardiac imaging, especially two- and three-dimensional transoesophageal echocardiography, plays an essential role in the diagnosis, guidance of intervention and subsequently in the evaluation of the outcomes of the procedure. The aim of this manuscript is to review the role of cardiac imaging techniques in the interventional management of patients with symptomatic PVL. PMID- 25276617 TI - Use of novel oral anticoagulant agents in atrial fibrillation: current evidence and future perspective. AB - The increasing availability of novel oral anticoagulants (NOAC) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) offers alternatives for patients currently prescribed warfarin. This article provides a brief overview on the mechanism and clinical use of these drugs as well as a review of the pivotal clinical trials providing the basis for each agent's safety and efficacy. While these agents are currently Food and Drug Administration (FDA) approved for anticoagulation of patients with nonvalvular AF, additional studies continually emerge offering further insight into the application of these agents in other areas. PMID- 25276620 TI - Small worlds. PMID- 25276618 TI - Molecular mechanisms of vascular dysfunction and cardiovascular biomarkers in type 2 diabetes. AB - Prevalence of obesity and type 2 diabetes (T2DM) is alarmingly increasing worldwide. Albeit advances in therapy have reduced morbidity and mortality in T2DM, cardiovascular risk is far to be eradicated and mechanism-based therapeutic approaches are in high demand. In this perspective, deciphering novel molecular networks of vascular disease will be instrumental to develop novel diagnostic and therapeutic strategies in people affected by diabetes. There is therefore a need to address current knowledge gaps in disease aetiology in order to support innovation in diagnosis and treatment. Unfortunately, we are still lacking cost effective markers able to identify atherosclerotic vascular disease at an early stage. The issue of risk stratification deserves attention because not every T2DM patient carries the same degree of inflammation and oxidative stress. The diversity of metabolic phenotypes with different outcomes underscores the need for cardiovascular risk stratification within such heterogeneous population. Early predictors of vascular damage are mandatory to implement intensive treatment strategies and, hence, reduce cardiovascular disease burden in this setting. In this review we critically discuss novel molecular mechanisms of diabetic vascular disease and their possible translation to the clinical setting. PMID- 25276621 TI - Comparisons are odious. PMID- 25276619 TI - Coronary steal due to ruptured right coronary aneurysm causing myocardial infarction in a patient with systemic lupus erythematosus. AB - A 34-year-old female with a history of systemic lupus erythematosus (SLE) developed an acute inferior myocardial infarction while hospitalized for methicillin-resistant Staphylococcus Aureus sepsis. An emergent coronary angiography revealed an ectatic proximal left coronary artery and a huge aneurysm (37 mm * 32 mm) in the mid-portion of the right coronary artery, which had ruptured into the right atrium. A "steal phenomenon" due to significant left to right shunt resulting from the ruptured aneurysm was the cause of the myocardial infarction. Infection of the wall of the aneurysm might have contributed to the growth and the rupture in the presence of a pre-existing coronary aneurysm. PMID- 25276622 TI - Insurance in clinical research. AB - AIMS AND OBJECTIVES: Sponsors need to pay for management of all serious adverse events suffered by subjects in a clinical trial and to compensate for injuries or deaths related to the trial. This study examines if insurance policies of trials, cover all contingencies that require reimbursement or compensation. MATERIALS AND METHODS: Insurance policies of trials submitted to Sahyadri Hospitals between January 2013 and December 2013 were studied, with respect to the policy period, the limit of liability, deductibles, and preconditions if any. RESULTS: All the policies studied had some deficiencies, in one respect or the other and none had a provision to pay full compensation if required. Some insurers have put in preconditions that could jeopardize the payment of compensation to subjects. CONCLUSIONS: Insurances are complicated documents, and need to be critically examined by the ethics committee before approval of the study documents. PMID- 25276624 TI - Multiple treatment and indirect treatment comparisons: An overview of network meta-analysis. AB - Randomized control trials and its meta-analysis has occupied the pinnacle in levels of evidence available for research. However, there were several limitations of these trials. Network meta-analysis (NMA) is a recent tool for evidence-based medicine that draws strength from direct and indirect evidence generated from randomized control trials. It facilitates comparisons across multiple treatment options, direct comparisons of which have not been attempted till date due to multitude of reasons. These indirect treatment comparisons of randomized controlled trials are based on similarity and consistency assumptions that follow Bayesian or frequentist statistics. Most NMAuntil date use Microsoft Windows WinBUGs Software for analysis which relies on Bayesian statistics. Methodology of NMA is expected to undergo further refinements and become robust with usage. Power and precision of indirect comparisons in NMA is a concern as it is dependent on effective number of trials, sample size and complete statistical information. However, NMA can synthesize results of considerable relevance to experts and policy makers. PMID- 25276625 TI - Basics of case report form designing in clinical research. AB - Case report form (CRF) is a specialized document in clinical research. It should be study protocol driven, robust in content and have material to collect the study specific data. Though paper CRFs are still used largely, use of electronic CRFs (eCRFS) are gaining popularity due to the advantages they offer such as improved data quality, online discrepancy management and faster database lock etc. Main objectives behind CRF development are preserving and maintaining quality and integrity of data. CRF design should be standardized to address the needs of all users such as investigator, site coordinator, study monitor, data entry personnel, medical coder and statistician. Data should be organized in a format that facilitates and simplifies data analysis. Collection of large amount of data will result in wasted resources in collecting and processing it and in many circumstances, will not be utilized for analysis. Apart from that, standard guidelines should be followed while designing the CRF. CRF completion manual should be provided to the site personnel to promote accurate data entry by them. These measures will result in reduced query generations and improved data integrity. It is recommended to establish and maintain a library of templates of standard CRF modules as they are time saving and cost-effective. This article is an attempt to describe the methods of CRF designing in clinical research and discusses the challenges encountered in this process. PMID- 25276626 TI - Effect of vitamin D3 on mild to moderate persistent asthmatic patients: A randomized controlled pilot study. AB - BACKGROUND: Asthma is a common chronic inflammatory disease of the bronchial airways. Well defined treatment options for asthma are very few. The role of vitamin D3 on asthma is still baffling. AIM: We have examined the effect of vitamin D3 supplementation in mild to moderate persistent asthma patients. MATERIALS AND METHODS: We conducted an open labeled, randomized comparative trial in 48 asthma patients. The study duration was about 90 days. The study had a run in-period of 2 weeks. At the end of run-in-period, patients were divided into two groups: Usual care group (n = 31) patients received budesonide and formoterol and intervention care group (n = 32) patients received vitamin D3 supplementation along with their regular medicine. RESULTS: The primary outcome of the study was to measure the improvement in forced expiratory volume in 1 second (FEV1). Patients in both groups had a significant improvement in FEV1 at the end of the study. The mean difference in percentage predicted FEV1 in usual care and intervention care group was 4.95 and 7.07 respectively. CONCLUSION: The study concluded that adjunctive therapy of vitamin D3 is effective in asthma patients. The present study will be an evidence based report; however, future studies are warranted in longer duration of time to substantiate the present findings. PMID- 25276623 TI - Contradicting/negative results in clinical research: Why (do we get these)? Why not (get these published)? Where (to publish)? AB - Obtaining negative or contradicting results, whereas conducting a study has always been overlooked as inadequacies on the part of the researcher. Many-a times, negative results are arrived at even after conducting the study with great care and effort. This cannot be considered, a flaw, always. Contradicting results may be arrived at because of various reasons and should be considered and published in order to arrive at a definitive result. Various journals are available which publish these contradicting results exclusively. It is the duty of the researcher to know in detail the cause and effect of these, considering the pros and cons. This article gives a bird's eye view of when, where and how to manage negative or contradicting results of a study. PMID- 25276627 TI - Intravenous paracetamol infusion: Superior pain management and earlier discharge from hospital in patients undergoing palliative head-neck cancer surgery. AB - BACKGROUND: Paracetamol; a cyclooxygenase inhibitor; acts through the central nervous system as well as serotoninergic system as a nonopioid analgesic. A prospective, double-blinded, and randomized-controlled study was carried out to compare the efficacy of preoperative 1g intravenous (iv) paracetamol with placebo in providing postoperative analgesia in head-neck cancer surgery. MATERIALS AND METHODS: From 2008 February to 2009 December, 80 patients for palliative head neck cancer surgery were randomly divided into (F) and (P) Group receiving ivplacebo and iv paracetamol, respectively, 5 min before induction. Everybody received fentanyl before induction and IM diclofenac for pain relief at8 hourly for 24 h after surgery. Visual analogue scale (VAS) and amount of fentanyl were measured for postoperative pain assessment (24 h). RESULTS AND STATISTICAL ANALYSIS: The mean VAS score in 1(st), 2(nd) postoperative hour, and fentanyl requirement was less and the need for rescue analgesic was delayed in ivparacetamol group which were all statistically significant. Paracetamol group had a shorter surgical intensive care unit (SICU) and hospital stay which was also statistically significant. CONCLUSION: The study demonstrates the effectiveness of ivparacetamol as preemptive analgesic in the postoperative pain control after head-neck cancer surgery and earlier discharge from hospital. PMID- 25276628 TI - Drug utilization pattern in South Indian pediatric population: A prospective study. AB - BACKGROUND: Studies on the process of drug utilization focus on factors related to prescribing, dispensing, administering and taking of medication and its associated events. AIMS: The aim of this study is to assess the prescribing patterns of medicines, apply the World Health Organization (WHO) core indicators and to assess the appropriateness of prescribed medicines in a pediatric unit. MATERIALS AND METHODS: A prospective observational drug utilization study was carried out in a pediatric unit of a super specialty hospital in South India for a period of 9 months. Patients who attended the pediatric unit with the age newborn to 18 years were included in the study and patients who were not willing to participate in the study were excluded and the data collected from the pediatric unit were analyzed. RESULTS: Out of 209 patients, the average number of drugs per patient was 4.56. The percentage of drugs prescribed with the generic name was found to be 19.16%. Among 209 prescriptions 49.78% of the drugs were essential drugs. Among the antibiotics 33.33% prescribed, cephalosporin group were the most commonly prescribed followed by amino glycoside and penicillin. Nearly, 21.80% of the medicines were given as intravenous and the prescriptions without drugs were 1.43%. Only 75.6% of patients have knowledge about their dosage schedule and almost all the prescriptions were appropriate. CONCLUSION: The assessment of WHO core indicators helped to improvise the prescribing pattern, identify significant problems involved in the knowledge gap of patients or caretakers understanding of instructions provided by consultants and even to minimize the cost burden on patient. PMID- 25276629 TI - Utilization of potentially inappropriate medications in elderly patients in a tertiary care teaching hospital in India. AB - AIM: To evaluate the use of potentially inappropriate medicines in elderly inpatients in a tertiary care teaching hospital. MATERIALS AND METHODS: Retrospective analysis was performed for cases of elderly patients admitted between January 2010 and December 2010. Data on age, gender, diagnosis, duration of hospital stay, treatment, and outcome were collected. Prescriptions were assessed for the use of potentially inappropriate medications in geriatric patients by using American Geriatric Society Beer's criteria (2012) and PRISCUS list (2010). RESULTS: A total of 676 geriatric patients (52.12% females) were admitted in the medicine ward. The average age of geriatric patients was 72.69 years. According to Beer's criteria, at least one inappropriate medicine was prescribed in 590 (87.3%) patients. Metoclopramide (54.3%), alprazolam (9%), diazepam (8%), digoxin > 0.125 mg/day (5%), and diclofenac (3.7%) were the commonly used inappropriate medications. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in heart and renal failure patients was the commonly identified drug-disease interaction. According to PRISCUS list, at least one inappropriate medication was prescribed in 210 (31.06%) patients. CONCLUSION: Use of inappropriate medicines is highly prevalent in elderly patients. PMID- 25276630 TI - Comparative evaluation of aliskiren, ramipril, and losartan on psychomotor performance in healthy volunteers: A preliminary report. AB - AIM: To compare the effects of aliskiren, ramipril, and losartan on the psychomotor performance in healthy volunteers. MATERIALS AND METHODS: In this preliminary, single-dose, open-label, cross-over study conducted in 12 healthy volunteers, psychomotor assessment was carried out by four tests: Simple reaction time (SRT), multiple choice reaction time test (MCRT), critical flicker fusion frequency threshold test (CFFT), and tracking performance test (TPT). Each volunteer received a single dose of each of the three test drugs with a washout period of 10 days between different test sessions and then evaluated for post drug scores at 2-h intervals up to 12 h and then at 24 h. The changes from the baseline scores by the test drug were statistically analyzed. RESULTS: All the three antihypertensive drugs caused significant improvement in a similar fashion on SRT, MCRT calculated as error index, CFFT, and TPT. Aliskiren caused numerically more improvement than the other two test drugs, suggesting better cognitive profile. However, inter-drug comparisons were nonsignificant. CONCLUSION: The results of the study highlight improvement of the cognitive functions equally by ramipril, losartan, and aliskiren. The results of the study could be of immense clinical utility in ambulatory hypertensive patients especially engaged in sensory-motor coordination tasks like driving and operating on mechanical tools. PMID- 25276631 TI - Indian regulatory update: june-august 2014. PMID- 25276632 TI - The (mis)use of statistics: Which test where? PMID- 25276633 TI - Analysis of CrossCheck Data on Two Years' Worth of Papers Submitted to Archives of Plastic Surgery. PMID- 25276635 TI - Transaxillary endoscopic breast augmentation. AB - The axillary technique is the most popular approach to breast augmentation among Korean women. Transaxillary breast augmentation is now conducted with sharp electrocautery dissection under direct endoscopic vision throughout the entire process. The aims of this method are clear: both a bloodless pocket and a sharp non-traumatic dissection. Round textured or anatomical cohesive gel implants have been used to make predictable well-defined inframammary creases because textured surface implants demonstrated a better stability attributable to tissue adherence compared with smooth surface implants. The axillary endoscopic technique has greatly evolved, and now the surgical results are comparable to those with the inframammary approach. The author feels that this technique is an excellent choice for young patients with an indistinct or absent inframammary fold, who do not want a scar in the aesthetic unit of their chest. PMID- 25276634 TI - Proliferation of keratinocytes induced by adipose-derived stem cells on a chitosan scaffold and its role in wound healing, a review. AB - In the field of tissue engineering and reconstruction, the development of efficient biomaterial is in high demand to achieve uncomplicated wound healing. Chronic wounds and excessive scarring are the major complications of tissue repair and, as this inadequate healing continues to increase, novel therapies and treatments for dysfunctional skin repair and reconstruction are important. This paper reviews the various aspects of the complications related to wound healing and focuses on chitosan because of its unique function in accelerating wound healing. The proliferation of keratinocytes is essential for wound closure, and adipose-derived stem cells play a significant role in wound healing. Thus, chitosan in combination with keratinocytes and adipose-derived stem cells may act as a vehicle for delivering cells, which would increase the proliferation of keratinocytes and help complete recovery from injuries. PMID- 25276637 TI - Self-reported speech problems in adolescents and young adults with 22q11.2 deletion syndrome: a cross-sectional cohort study. AB - BACKGROUND: Speech problems are a common clinical feature of the 22q11.2 deletion syndrome. The objectives of this study were to inventory the speech history and current self-reported speech rating of adolescents and young adults, and examine the possible variables influencing the current speech ratings, including cleft palate, surgery, speech and language therapy, intelligence quotient, and age at assessment. METHODS: In this cross-sectional cohort study, 50 adolescents and young adults with the 22q11.2 deletion syndrome (ages, 12-26 years, 67% female) filled out questionnaires. A neuropsychologist administered an age-appropriate intelligence quotient test. The demographics, histories, and intelligence of patients with normal speech (speech rating=1) were compared to those of patients with different speech (speech rating>1). RESULTS: Of the 50 patients, a minority (26%) had a cleft palate, nearly half (46%) underwent a pharyngoplasty, and all (100%) had speech and language therapy. Poorer speech ratings were correlated with more years of speech and language therapy (Spearman's correlation= 0.418, P=0.004; 95% confidence interval, 0.145-0.632). Only 34% had normal speech ratings. The groups with normal and different speech were not significantly different with respect to the demographic variables; a history of cleft palate, surgery, or speech and language therapy; and the intelligence quotient. CONCLUSIONS: All adolescents and young adults with the 22q11.2 deletion syndrome had undergone speech and language therapy, and nearly half of them underwent pharyngoplasty. Only 34% attained normal speech ratings. Those with poorer speech ratings had speech and language therapy for more years. PMID- 25276638 TI - Three-dimensional pre-bent titanium implant for concomitant orbital floor and medial wall fractures in an East asian population. AB - BACKGROUND: The objective of this article is to evaluate clinical outcomes of combined orbital floor and medial wall fracture repair using a three-dimensional pre-bent titanium implant in an East Asian population. METHODS: Clinical and radiologic data were analyzed for 11 patients with concomitant orbital floor and medial wall fractures. A combined transcaruncular and inferior fornix approach with lateral canthotomy was used for the exposure of fractures. An appropriate three-dimensional preformed titanium implant was selected and inserted according to the characteristics of a given defect. RESULTS: Follow-up time ranged from 2 to 6 months (median, 4.07 months). All patients had a successful treatment outcome without any complications. Clinically significant enophthalmos was not observed after treatment. CONCLUSIONS: Three-dimensional pre-bent titanium implants are appropriate for use in the East Asian population, with a high success rate of anatomic restoration of the orbital volume and prevention of enophthalmos in combined orbital floor and medial wall fracture cases. PMID- 25276639 TI - Correlation between the Time to Surgery and That to Recovery from Postoperative Diplopia Based on a Single-Center, Retrospective Experience: A Case Series of 11 Patients. AB - BACKGROUND: We conducted this study to identify the correlation between the time to surgery and that to recovery from postoperative diplopia. METHODS: In the current single-center, retrospective study, we enrolled a total of 11 patients (n=11) who were diagnosed with white-eyed blowout fracture and underwent surgical operation at our institution between January 2009 and January 2013. To identify the correlation between the time to surgery and that to recovery from postoperative diplopia, we divided our patients into the three groups: the group A (time to surgery, <2 days) (n=4), the group B (time to surgery, 3-7 days) (n=4) and the group C (n=3) (time to surgery, 8-60 days). Then, we compared such variables as sex, age, signs of soft tissue injury, preoperative nausea/vomiting, the degree of preoperative diplopia and the side of the fracture on computed tomography scans between the three groups. RESULTS: In our series, mean age at the onset of trauma was nine years (range, 5-16 years); the mean time to surgery was 30 days (range, 2-60 days); and the mean follow-up period was one year (range, 6 months-2 years). Our results showed that the time to recovery was shorter in the patients with a shorter time to surgery. CONCLUSIONS: We found that the degree of recovery from impaired ocular motility and diplopia was the highest in the patients undergoing surgical operations within 48 hours of the onset of trauma with the reconstruction of the fracture sites using implant materials. PMID- 25276640 TI - An anthropometric and three-dimensional computed tomographic evaluation of two point fixation of zygomatic complex fractures. AB - BACKGROUND: Maintaining stability and restoring the aesthetic appearance are the fundamental goals when managing zygomatic fractures. We aimed to evaluate the stability and anthropometric outcomes of zygomatic fracture patients who underwent two-point fixation involving the infraorbital rim and zygomaticomaxillary buttress via the transconjunctival and gingivobuccal approaches without any skin incisions. METHODS: We examined 15 zygomatic fracture patients who underwent two-point fixation during a 3-year period. Stability was evaluated using three-dimensional facial bone computed tomography. Superoinferior and anteroposterior displacement of the zygoma was quantified. The aesthetic appearance of the periorbital region was evaluated using indirect anthropometry with standardized clinical photographs. The ratios between the eye fissure height and width, and lower iris coverage ratio were used to evaluate aesthetical changes. The bony displacement and aesthetic ratios were analyzed using Wilcoxon or Friedman tests. The correlation between the preoperative zygoma position and anthropometric values was analyzed. RESULTS: The positions of the zygoma were similar to those on the contralateral side at the long-term follow-up. The preoperative anthropometric measurements on the fractured side differed from those on the contralateral side, although these values were close to the normal values at the long-term follow-up. Furthermore, we noted that the anteroposterior displacement strongly positively correlated with the lower iris coverage rate (Spearman's coefficient= 0.678, P=0.005). CONCLUSIONS: Two-point fixation of zygomatic fractures achieved stable outcomes on long-term follow-up, and also appeared to be reliable in restoring the aesthetic appearance of the periorbital region. PMID- 25276636 TI - Effect of recombinant human epidermal growth factor impregnated chitosan film on hemostasis and healing of blood vessels. AB - BACKGROUND: Bleeding can be a problem in wound debridement. In search for an effective hemostatic agent, we experimented with a chitosan film combined with the recombinant human epidermal growth factor (rh-EGF), hypothesizing that it would achieve effective hemostasis and simultaneously enhance arterial healing. METHODS: Forty-eight Sprague-Dawley rats were used, and 96 puncture wounds were made. The wounds were divided into the following four groups: treated with sterile gauze, treated with gelatin sponge, treated with chitosan, and treated with chitosan combined with rh-EGF. Immediate hemostasis was evaluated, and arterial healing was observed histologically. RESULTS: Groups B, C, and D showed a significant rate of immediate hemostasis as compared to group A (P<0.05), but there were no significant differences among groups B, C, and D. Histologically, only group D showed good continuity of the vessel wall after 1 week. It was the only group to show smooth muscle cell nuclei of the vessel wall. CONCLUSIONS: We observed that chitosan has an effective hemostatic potential and the mix of rh EGF and chitosan does not interfere with chitosan's hemostatic capabilities. We also identified enhanced healing of vessel walls when rh-EGF was added to chitosan. Further research based on these positive findings is needed to evaluate the potential use of this combination on difficult wounds like chronic diabetic ulcerations. PMID- 25276641 TI - When are circular lesions square? A national clinical education skin lesion audit and study. AB - BACKGROUND: Skin cancer is the most prevalent cancer by organ type and referral accuracy is vital for diagnosis and management. The British Association of Dermatologists (BAD) and literature highlight the importance of accurate skin lesion examination, diagnosis and educationally-relevant studies. METHODS: We undertook a review of the relevant literature, a national audit of skin lesion description standards and a study of speciality training influences on these descriptions. Questionnaires (n=200), with pictures of a circular and an oval lesion, were distributed to UK dermatology/plastic surgery consultants and speciality trainees (ST), general practitioners (GP), and medical students (MS). The following variables were analysed against a pre-defined 95% inclusion accuracy standard: site, shape, size, skin/colour, and presence of associated scars. RESULTS: There were 250 lesion descriptions provided by 125 consultants, STs, GPs, and MSs. Inclusion accuracy was greatest for consultants over STs (80% vs. 68%; P<0.001), GPs (57%) and MSs (46%) (P<0.0001), for STs over GPs (P<0.010) and MSs (P<0.0001) and for GPs over MSs (P<0.010), all falling below audit standard. Size description accuracy sub-analysis according to circular/oval dimensions was as follows: consultants (94%), GPs (80%), STs (73%), MSs (37%), with the most common error implying a quadrilateral shape (66%). Addressing BAD guidelines and published requirements for more empirical performance data to improve teaching methods, we performed a national audit and studied skin lesion descriptions. To improve diagnostic and referral accuracy for patients, healthcare professionals must strive towards accuracy (a circle is not a square). CONCLUSIONS: We provide supportive evidence that increased speciality training improves this process and propose that greater focus is placed on such training early on during medical training, and maintained throughout clinical practice. PMID- 25276642 TI - Risk acceptance and expectations of laryngeal allotransplantation. AB - BACKGROUND: Laryngeal allotransplantation (LA) is a technique involving transplantation of a deceased donor's larynx into a recipient, and it may be substituted for conventional laryngeal reconstruction. There are widely different views on LA, as the recipient is administered continuous, potentially life threatening, immunosuppressive therapy for a functional or aesthetic result, which is not directly related to life extension. The purpose of this study was to analyze the difference in risk acceptance and expectations of LA between four population groups. METHODS: A survey was performed to examine patients' risk acceptance and expectations of LA. The survey included 287 subjects in total (general public, n=100; kidney transplant recipients, n=53; post-laryngectomy patients, n=34; doctors, n=100), using a Korean translated version of the louisville instrument for transplantation (LIFT) questionnaire. RESULTS: All four groups responded differently at various levels of their perception in risk acceptance and expectations. The kidney transplant recipients reported the highest risk acceptance and expectations, and the doctor group the lowest. CONCLUSIONS: This study examined the disparate perception between specific population groups of the risks and benefits of using LA for the promotion of the quality of life. By addressing the information gaps about LA in the different populations that have been highlighted from this survey, we suggest that LA can become a more viable alternative to classical surgery with resultant improved quality of life for patients. PMID- 25276643 TI - Immediate partial breast reconstruction with endoscopic latissimus dorsi muscle flap harvest. AB - BACKGROUND: Currently, breast conservation therapy is commonly performed for the treatment of early breast cancer. Depending on the volume excised, patients may require volume replacement, even in cases of partial mastectomy. The use of the latissimus dorsi muscle is the standard method, but this procedure leaves an unfavorable scar on the donor site. We used an endoscope for latissimus dorsi harvesting to minimize the incision, thus reducing postoperative scars. METHODS: Ten patients who underwent partial mastectomy and immediate partial breast reconstruction with endoscopic latissimus dorsi muscle flap harvest were reviewed retrospectively. The total operation time, hospital stay, and complications were reviewed. Postoperative scarring, overall shape of the reconstructed breast, and donor site deformity were assessed using a 10-point scale. RESULTS: In the mean follow-up of 11 weeks, no tumor recurrence was reported. The mean operation time was 294.5 (+/-38.2) minutes. The postoperative hospital stay was 11.4 days. Donor site seroma was reported in four cases and managed by office aspiration and compressive dressing. Postoperative scarring, donor site deformity, and the overall shape of the neobreast were acceptable, scoring above 7. CONCLUSIONS: Replacement of 20% to 40% of breast volume in the upper and the lower outer quadrants with a latissimus dorsi muscle flap by using endoscopic harvesting is a good alternative reconstruction technique after partial mastectomy. Short incision benefits from a very acceptable postoperative scar, less pain, and early upper extremity movement. PMID- 25276644 TI - Partial breast reconstruction using various oncoplastic techniques for centrally located breast cancer. AB - BACKGROUND: As the breast cancer incidence has increased, breast-conserving surgery has replaced total mastectomy as the predominant procedure. However, centrally located breast cancers pose significant challenges to successful breast conserving surgeries. Therefore, we performed partial mastectomy and oncoplastic procedures on centrally located breast cancer as a means of partial breast reconstruction. The authors examined and evaluated the functional and aesthetic usefulness of this reconstruction method. METHODS: From January 2007 to June 2011, 35 patients with centrally located breast cancers who underwent various oncoplastic procedures based on the breast size and resection volume. The oncoplastic procedures performed included volume displacement surgical techniques such as purse-string suture, linear suture, and reduction mammaplasty. Other oncoplastic procedures included volume replacement procedures with an adipofascial, thoracoepigastric, intercostal artery perforator, thoracodorsal artery perforator, or latissimus dorsi flap. RESULTS: Mean patient age was 49 years, and mean follow-up period was 11 months. In cases of small to moderate sized breasts and resection volumes <50 g, volume displacement procedures were performed. In cases of resection volumes >50 g, volume replacement procedures were performed. In cases of larger breasts and smaller resection volumes, glandular reshaping was performed. Finally, in cases of larger breasts and larger resection volumes, reduction mammaplasty was performed. This reconstruction method also elicits a high patient satisfaction rate with no significant complications. CONCLUSIONS: In centrally located breast cancer, oncoplastic surgery considering breast size and resection volume is safe and provides appropriate aesthetic outcomes. Therefore, our method is advisable for breast cancer patients who elect to conserve their breasts and retain a natural breast shape. PMID- 25276645 TI - Immediate direct-to-implant breast reconstruction using anatomical implants. AB - BACKGROUND: In 2012, a new anatomic breast implant of form-stable silicone gel was introduced onto the Korean market. The intended use of this implant is in the area of aesthetic breast surgery, and many reports are promising. Thus far, however, there have been no reports on the use of this implant for breast reconstruction in Korea. We used this breast implant in breast reconstruction surgery and report our early experience. METHODS: From November 2012 to April 2013, the Natrelle Style 410 form-stable anatomically shaped cohesive silicone gel-filled breast implant was used in 31 breasts of 30 patients for implant breast reconstruction with an acellular dermal matrix. Patients were treated with skin-sparing mastectomies followed by immediate breast reconstruction. RESULTS: The mean breast resection volume was 240 mL (range, 83-540 mL). The mean size of the breast implants was 217 mL (range, 125-395 mL). Breast shape outcomes were considered acceptable. Infection and skin thinning occurred in one patient each, and hematoma and seroma did not occur. Three cases of wound dehiscence occurred, one requiring surgical intervention, while the others healed with conservative treatment in one month. Rippling did not occur. So far, complications such as capsular contracture and malrotation of breast implant have not yet arisen. CONCLUSIONS: By using anatomic breast implants in breast reconstruction, we achieved satisfactory results with aesthetics better than those obtained with round breast implants. Therefore, we concluded that the anatomical implant is suitable for breast reconstruction. PMID- 25276646 TI - The efficacy of simultaneous breast reconstruction and contralateral balancing procedures in reducing the need for second stage operations. AB - BACKGROUND: Patients having unilateral breast reconstruction often require a second stage procedure on the contralateral breast to improve symmetry. In order to provide immediate symmetry and minimize the frequency and extent of secondary procedures, we began performing simultaneous contralateral balancing operations at the time of initial reconstruction. This study examines the indications, safety, and efficacy of this approach. METHODS: One-hundred and two consecutive breast reconstructions with simultaneous contralateral balancing procedures were identified. Data included patient age, body mass index (BMI), type of reconstruction and balancing procedure, specimen weight, transfusion requirement, complications and additional surgery under anesthesia. Unpaired t-tests were used to compare BMI, specimen weight and need for non-autologous transfusion. RESULTS: Average patient age was 48 years. The majority had autologous tissue-only reconstructions (94%) and the rest prosthesis-based reconstructions (6%). Balancing procedures included reduction mammoplasty (50%), mastopexy (49%), and augmentation mammoplasty (1%). Average BMI was 27 and average reduction specimen was 340 grams. Non-autologous blood transfusion rate was 9%. There was no relationship between BMI or reduction specimen weight and need for transfusion. We performed secondary surgery in 24% of the autologous group and 100% of the prosthesis group. Revision rate for symmetry was 13% in the autologous group and 17% in the prosthesis group. CONCLUSIONS: Performing balancing at the time of breast reconstruction is safe and most effective in autologous reconstructions, where 87% did not require a second operation for symmetry. PMID- 25276647 TI - The influence of pfannenstiel incision scarring on deep inferior epigastric perforator. AB - BACKGROUND: Abdominal wall free flaps are used most frequently in autologous breast reconstruction, and these flaps require intact and robust deep inferior epigastric perforator (DIEP) vessels. Pfannenstiel incisions are often present during preoperative visits for breast reconstruction and could potentially signal compromised blood supply to the lower abdominal wall. In this study, we compared the number of DIEP vessels between patients with and without Pfannenstiel incisions undergoing autologous breast reconstruction. METHODS: A retrospective review of medical records was performed for patients with (study) and without (control) Pfannelstiel incisions (n=34 for each group) between June 2010 and July 2013. In addition to patient demographics, number of caesarian sections, and outcomes of free flap reconstruction, abdominal wall vasculature was compared using the preoperative computed tomography angiographic data between the groups. For each patient, vessels measuring greater than 1 mm were counted and divided into four sections of the lower abdominal wall. RESULTS: The mean number of perforator vessels was 10.6 in the study group and 11.4 in the control group, which was not statistically different (P=0.575). Pfannenstiel incisions with history of repeat caesarian sections were not associated with decreased number of perforator vessels. CONCLUSIONS: Pfannenstiel scars are associated with neither a change in the number of DIEP vessels nor decreased viability of a free transverse rectus abdominis myocutaneous and DIEP flap. Lower abdominal free flaps based on DIEP vessels appear safe even in patients who have had multiple caesarian sections through Pfannenstiel incisions. PMID- 25276648 TI - Our Experiences in Nipple Reconstruction Using the Hammond flap. AB - BACKGROUND: Nipple reconstruction following breast mound reconstruction is the final step in breast reconstruction. Although nipple reconstruction is a simple surgery, the psychological aspects of nipple reconstruction are thought to be important. Nipple projection is a key factor in determining patient satisfaction with the surgery. In the present study, the Hammond flap technique was introduced for nipple reconstruction. METHODS: Twenty-six patients who had undergone breast reconstruction from February 2008 to March 2012 were enrolled in this prospective study. All patients were evaluated based on preoperative photos, and their nipple diameters and heights were measured. Postoperative evaluation was conducted 3, 6, 9, and 12 months following nipple reconstruction. A questionnaire on patient satisfaction with the nipple reconstruction was administered 12 months after nipple reconstruction. Moreover, the same plastic surgeon scored nipple projection and overall cosmetic result of the new nipple. RESULTS: The mean projection was 4.4 mm (range, 3-6 mm), and it well matched the contralateral nipple. Twelve months following nipple reconstruction, the mean reduction rate in the nipple projection was 43.6%. Patients were satisfied or very satisfied with the nipple projection and the overall cosmetic result in 80.7% cases. CONCLUSIONS: In the present study, compared with other techniques, the use of the Hammond flap technique in nipple reconstruction showed competitive results with regard to nipple projection and patient satisfaction. PMID- 25276649 TI - Use of the anterolateral thigh and vertical rectus abdominis musculocutaneous flaps as utility flaps in reconstructing large groin defects. AB - BACKGROUND: Groin dissections result in large wounds with exposed femoral vessels requiring soft tissue coverage, and the reconstructive options are diverse. In this study we reviewed our experience with the use of the pedicled anterolateral thigh and vertical rectus abdominis musculocutaneous flaps in the reconstruction of large groin wounds. METHODS: Groin reconstructions performed over a period of 10 years were evaluated, with a mean follow up of two years. We included all cases with large or complex (involving perineum) defects, which were reconstructed with the pedicled anterolateral thigh musculocutaneous or the vertical rectus abdominis musculocutaneous (VRAM) flaps. Smaller wounds which were covered with skin grafts, locally based flaps and pedicled muscle flaps were excluded. RESULTS: Twenty-three reconstructions were performed for large or complex groin defects, utilising the anterolateral thigh (n=10) and the vertical rectus abdominis (n=13) pedicled musculocutaneous flaps. Femoral vein reconstruction with a prosthetic graft was required in one patient, and a combination flap (VRAM and gracilis muscle flap) was performed in another. Satisfactory coverage was achieved in all cases without major complications. No free flaps were used in our series. CONCLUSIONS: The anterolateral thigh and vertical rectus abdominis pedicled musculocutaneous flaps yielded consistent results with little morbidity in the reconstruction of large and complex groin defects. A combination of flaps can be used in cases requiring extensive cover. PMID- 25276650 TI - Through knee amputation: technique modifications and surgical outcomes. AB - BACKGROUND: Knee disarticulations (KD) are most commonly employed following trauma or tumor resection but represent less than 2% of all lower extremity amputations performed in the United States annually. KDs provide enhanced proprioception, a long lever arm, preservation of adductor muscle insertion, decreased metabolic cost of ambulation, and an end weight-bearing stump. The role for KDs in the setting of arterial insufficiency or overwhelming infection is less clear. The purpose of this study is to describe technique modifications and report surgical outcomes following KDs at a high-volume Limb Salvage Center. METHODS: A retrospective study of medical records for all patients who underwent a through-knee amputation performed by the senior author (C.E.A.) between 2004 and 2012 was completed. Medical records were reviewed to collect demographic, operative, and postoperative information for each of the patients identified. RESULTS: Between 2004 and 2012, 46 through-knee amputations for 41 patients were performed. The mean patient age was 68 and indications for surgery included infection (56%), arterial thrombosis (35%), and trauma (9%). Postoperative complications included superficial cellulitis (13%), soft tissue infection (4%), and flap ischemia (4%) necessitating one case of surgical debridement (4%) and four trans-femoral amputations (9%). 9 (22%) patients went on to ambulate. Postoperative ambulation was greatest in the traumatic cohort and for patients less than 50 years of age, P<0.05. Alternatively, diabetes mellitus and infection reduced the likelihood of postoperative ambulation, P<0.01. CONCLUSIONS: Knee disarticulations are a safe and effective alternative to other lower extremity amputations when clinically feasible. For patient unlikely to ambulate, a through knee amputation maximizes ease of transfers, promotes mobility by providing a counterbalance, and eliminates the potential for knee flexion contracture with subsequent skin breakdown. PMID- 25276652 TI - Muscle-sparing blepharoplasty: a prospective left-right comparative study. AB - BACKGROUND: Standard upper blepharoplasty involves removal of both the skin and a portion of the underlying orbicularis oculi muscle. The senior author had observed sluggishness of eyelid closure, lagophthalmos as well as varying degrees of eye irritation in certain patients during the early postoperative period. He postulated that these findings could be due to orbicularis muscle excision. He therefore undertook a prospective study 27 years ago comparing standard blepharoplasty on one eyelid to skin-only excision on the fellow eyelid. METHODS: A randomized, prospective, single-blinded study was designed using the fellow eye as an internal control. 22 patients undergoing upper blepharoplasty procedure requiring greater than 5 mm of skin resection and with no history of ophthalmologic disease, dry eye, or previous eyelid surgery were selected. Upper blepharoplasty was performed with skin-only removal on one side, and combined skin-muscle removal on the other side. Patients were evaluated until six months after surgery except for two patients who were lost to follow-up after three months. Sluggish eyelid closure, lagophthalmos, dry eye and aesthetic result were outcome measures scored by patient survey, the operating surgeon, and a blinded expert panel. RESULTS: There were comparable aesthetic outcomes in both eyelids. The incidence of sluggish eyelid closure, lagophthalmos and dry eye syndrome were significantly higher in eyelids where wide segments of muscle had been resected. CONCLUSIONS: Muscle-sparing upper blepharoplasty produces similar aesthetic outcomes as conventional blepharoplasty, while significantly reducing the complications of sluggish eyelid closure, lagophthalmos and dry eye disease. The authors therefore recommend muscle-sparing upper blepharoplasty. PMID- 25276651 TI - Disulfiram Implantation for the Treatment of Alcoholism: Clinical Experiences from the Plastic Surgeon's Point of View. AB - BACKGROUND: Disulfiram implantation is a widely used treatment alternative for alcohol abuse, yet reports on the surgical aspect of disulfiram implantation with respect to patient and drug-related treatment efficacy and wound complications are very limited. We present our clinical experiences with disulfiram implantation and discuss the surgical outcomes obtained with different anatomical planes for implantation. METHODS: Medical records of all patients referred to our clinic from the psychiatry department between 2007 and 2013 for disulfiram implantation were retrospectively analyzed. Implantation was carried out using 10 sterile Disulfiram tablets (WZF Polfa S.A.), each tablet containing 100 mg of disulfiram. The procedure was carried out by implanting the tablets randomly in either a subcutaneous or an intramuscular plane. The location and the plane of implantation and the complications were recorded for each patient and compared to determine the differences in the outcomes. RESULTS: A total of 32 implantation procedures were evaluated for this study. Twenty-five implants were placed in the intramuscular plane (78.2%), while seven implants were placed subcutaneously (21.8%). Exposure was encountered in three of the seven subcutaneous implants (42.9%), while no exposure was seen with the intramuscular implants. Incomplete absorption of the tablets was encountered in one patient with a previous subcutaneous implant who presented 1 year later for re-implantation as part of the continuation of therapy. CONCLUSIONS: To overcome the issue of treatment continuation in the case of disulfiram therapy, which may be ceased due to frequently encountered wound complications, we believe that implantation in the subscapular intramuscular plane allows both uneventful healing and an out-of reach implant location. PMID- 25276653 TI - Computer simulation surgery for mandibular reconstruction using a fibular osteotomy guide. AB - In the present study, a fibular osteotomy guide based on a computer simulation was applied to a patient who had undergone mandibular segmental ostectomy due to oncological complications. This patient was a 68-year-old woman who presented to our department with a biopsy-proven squamous cell carcinoma on her left gingival area. This lesion had destroyed the cortical bony structure, and the patient showed attenuation of her soft tissue along the inferior alveolar nerve, indicating perineural spread of the tumor. Prior to surgery, a three-dimensional computed tomography scan of the facial and fibular bones was performed. We then created a virtual computer simulation of the mandibular segmental defect through which we segmented the fibular to reconstruct the proper angulation in the original mandible. Approximately 2-cm segments were created on the basis of this simulation and applied to the virtually simulated mandibular segmental defect. Thus, we obtained a virtual model of the ideal mandibular reconstruction for this patient with a fibular free flap. We could then use this computer simulation for the subsequent surgery and minimize the bony gaps between the multiple fibular bony segments. PMID- 25276654 TI - Lymphedema fat graft: an ideal filler for facial rejuvenation. AB - Lymphedema is a chronic disorder characterized by lymph stasis in the subcutaneous tissue. Lymphatic fluid contains several components including hyaluronic acid and has many important properties. Over the past few years, significant research has been performed to identify an ideal tissue to implant as a filler. Because of its unique composition, fat harvested from the lymphedema tissue is an interesting topic for investigation and has significant potential for application as a filler, particularly in facial rejuvenation. Over a 36-month period, we treated and assessed 8 patients with lymphedematous limbs who concurrently underwent facial rejuvenation with lymphedema fat (LF). We conducted a pre- and post-operative satisfaction questionnaire survey and a histological assessment of the harvested LF fat. The overall mean general appearance score at an average of 6 months after the procedure was 7.2+/-0.5, demonstrating great improvement. Patients reported significant improvement in their skin texture with a reading of 8.5+/-0.7 and an improvement in their self-esteem. This study demonstrates that LF as an ideal autologous injectable filler is clinically applicable and easily available in patients with lymphedema. We recommend the further study and clinical use of this tissue as it exhibits important properties and qualities for future applications and research. PMID- 25276655 TI - Gluteal reshaping in the massive weight loss patient. PMID- 25276656 TI - Prosopoplasty: a new term? PMID- 25276657 TI - Reconstruction of a Posterior Trunk Defect using a Pedicled Dorsolateral Posterior Intercostal Artery Perforator Flap. PMID- 25276659 TI - Localized hypertrichosis after index finger revascularization and complex regional pain syndrome. PMID- 25276658 TI - Liposarcoma in the axilla developed from a longstanding lipoma. PMID- 25276660 TI - A rare giant cell tumor of the tendon sheath of the dorsal hand in a child. PMID- 25276661 TI - Dermoid Cyst Excision under Muller Muscle in a Patient with Blepharoptosis. PMID- 25276662 TI - Reconstruction of ear deformity from post-piercing perichondritis. PMID- 25276663 TI - Axillary Fistula and Scar Contracture due to Uncontrolled Chronic Infection after Trans-Axillary Augmentation Mammaplasty. PMID- 25276664 TI - Ebola virus disease - a global threat. PMID- 25276666 TI - Daptomycin resistance in methicillin-resistant Staphylococcus aureus: a report from Southern India. PMID- 25276665 TI - Efficacy and safety of darunavir (Prezista((r))) with low-dose ritonavir and other antiretroviral medications in subtype F HIV-1 infected, treatment experienced subjects in Romania: a post-authorization, open-label, one-cohort, non-interventional, prospective study. AB - INTRODUCTION: The aim of the study was to assess the safety and efficacy of darunavir (Prezista((r))) used in subtype F human immunodeficiency virus - type 1 (HIV-1) infected, antiretroviral therapy (ART)-experienced patients in Romania in routine clinical practice. METHODS: This was a post-authorization, open-label, one-cohort, non-interventional, prospective study conducted at multiple sites in Romania to assess efficacy (CD4 cell count, viral load, and treatment compliance) and safety ([serious] adverse events, clinical laboratory evaluation, and vital signs) of darunavir in combination with low-dose ritonavir (DRV/r) and other antiretroviral (ARV) medications in subtype F HIV-1 infected subjects in naturalistic settings. Seventy-eight subjects were recruited by 9 investigational sites and received 600/100 mg DRV/r twice daily. RESULTS: Treatment with DRV/r administered with other ARV medications resulted in the expected, statistically relevant improvement of CD4 cell count and viral load in subjects eligible for such treatment. In addition, adherence to treatment was high and the treatment emergent safety profile observed during this study was consistent with the established safety profile of darunavir. CONCLUSION: DRV/r administered in combination with other ARV medications in subtype F HIV-1 infected subjects in naturalistic settings proved to be an effective and safe treatment in Romania. TRIAL REGISTRATION: NCT01253967. PMID- 25276667 TI - Bacterial prints in human infectious diseases. PMID- 25276668 TI - Is there any relationship between medication compliance and affective temperaments in patients with type 2 diabetes? AB - BACKGROUND: Type 2 diabetes mellitus (DM) is the most common type of diabetes.The number of patients with this disease is expected torise in future. Given the increasing prevalence of diabetes, there is an urgent need for the treatment of diabetes and the associated complications. Glycemic control largely depends on compliance with medication therapies. In fact, the most common problem in patients with diabetes is lack of medication compliance. This study aimed to determine the relationship between affectivetemperaments and medication compliance in patients with type 2 diabetes. METHODS: In this cross-sectional research, the study population consisted of all patients referring to the endocrinology clinic of Ayatollah Taleghani Hospital of Tehran in 2010 and 2011. Two hundreds and seven patients were selected, using available sampling method. In this study, we used Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto questionnaire (TEMPS-A), a single-item scale of medication compliance, Beck Depression Inventory-II (BDI-II), and a researcher-made questionnaire to assess the patients' demographic information. All participants completed the questionnaires related to affective temperaments, medication compliance, depression and demographic information. The obtained data were recorded on the prepared sheets. RESULTS: Of 207 patients, 79 (38.2%) and 128 (61.8%) subjects were male and female, respectively. The mean and standard deviation of demographic data were calculated. In total, 13.5%, 19.3%, and 8.2%of the participants had mild, moderate, and severe depression, respectively. In this study, as the single-item rating scale indicated, medication compliance and non compliance were reported in 75.4% and 24.6% of the patients, respectively. Among the demographic characteristics and clinical variables, frequency of patient referral and glycated hemoglobin level were predictors of medication compliance. Also, among affective temperaments, irritable temperament was a predictor of medication compliance. CONCLUSIONS: The obtained findings emphasize the importance of psychological factors such as personality characteristics in medication compliance of patients with diabetes. In case a patient obtains high scores in irritable temperament (which indicate poor medication compliance), he/she should follow special training programs to improve his/her medication compliance. PMID- 25276669 TI - Communicating contraceptive effectiveness: a randomized controlled trial. AB - INTRODUCTION: Increasing the knowledge of women on effectiveness of contraceptive methods can lead to the use of more effective methods and reduce unwanted pregnancies and adverse outcomes. We aimed to compare three different approaches for increasing women's understanding of effectiveness of contraceptive methods. METHODS: We ran-domly assigned 630 eligible women of reproductive age to one of the three groups. Each woman received one of three charts presenting pregnancy risk with each contraceptive method. Participants before and while reviewing the chart, answered to three key ques-tions about the effectiveness of the methods. The data were analyzed using chi-square, ANOVA and McNemar's tests in SPSS version 13. RESULTS: The most important reasons for choosing contraceptive methods were their effectiveness (45%), ease of use (18%) and few side effects (14%). At baseline, the participants' knowledge about the effective-ness of the methods was poor. Correct answers were 44% about comparing the effec-tiveness of the combined pills vs. that of condoms, 50% about intrauterine devices vs. injectables, and 52% about condoms vs. withdrawal. While reviewing the charts, the percentages significantly (p < 0.001) increased to 80%, 84% and 85%, respectively. All the three charts almost equally increased the correct responds to the questions. CONCLUSION: The three approaches had considerable and nearly identical effects on the promotion of women's knowledge about effectiveness of the contraceptive methods. Therefore, appropriate use of the charts is required during counseling sessions for contraceptive choice because it is impossible to have informed choice of the method without understanding their effectiveness. PMID- 25276670 TI - The View of Nurses toward Prioritizing the Caring Behaviors in Cancer Patients. AB - INTRODUCTION: There are many opportunities for nurses to assist improving patient's ex-perience of cancer. In fact, in every stage of cancer process, nurses can provide the re-quired and necessary cares and supports by representing substantial caring behaviors. Thus, by identifying and understanding the importance of caring behaviors which led to nurse-patient effective interactions, nurses would be able to care better for patients and so to enhance patients' satisfaction toward nursing services. However, a few studies have ever been done about perception of oncology nurses about prioritization of caring behaviors. METHODS: This was a descriptive study done among all the nurses of oncology wards (n = 40) in Shahid-Ghazi-Tabatabaei Hospital of Tabriz in 2009. Data collection performed using Larson's CARE-Q tool that assessed the importance of caring beha viors in six subscales as the following: "Monitors and follows through", "Explains and facilitates", "Physical and emotional comforts", "Trusting relationship", "Anticipates" and "Being accessible". RESULTS: In this study, the importance of caring behaviors was evaluated in moderate to high level and the priorities of care dimensions were deter-mined. "Monitors and follows through" and "Being accessible" received a high priority and "Anticipates", "Explains and facilitates", "Physical and emotional comforts" and "Trusting relationship" were given the low priority by nurses. CONCLUSION: The difference of caring prioritization by the nurses of this study compared to other studies can be attributed to the influence of cultural background on caring. Considering the high prioritizing of "Monitors and follows through" and "Being accessible", nursing service officials and planners are recommended to attempt providing prerequisites of these two caring aspects. PMID- 25276671 TI - Comparing the effects of two teaching methods on healing of diabetic foot ulcer. AB - INTRODUCTION: Some studies have reported that diabetic patients do not adhere well to the foot care recommendations. Reasons for non-adherence are less evident and the methods used in education programs may have an effect. Therefore, the aim of the present study was to compare the effects of lecture method and combined method of education on foot care of patients and healing rates of diabetic foot ulcers. METHODS: A matched controlled trial study was conducted on a sample of 45 diabetic patients with foot ulcers. The two intervention groups were taught with similar content but different methods. Patients' foot care and healing rates of diabetic foot ulcers were assessed at the beginning of study and after 3 months in the two training groups as well as the control group. RESULTS: Ulcer surface was decreased by 46%, 61% and 81.6% in the control, lecture group and com-bined group, respectively. The ulcer depth was also decreased by 66.7%, 97.5% and 69.1% in the three groups respectively. A significant relationship was observed between the group adherence of the self-care program and the amount of decrease in the ulcer surface area (r = 0.36, p = 0.04). CONCLUSION: The foot care education could significantly affect the healing of diabetic foot ulcer, especially in terms of the ulcers' surface area. Therefore, a self-care education program should be integrated in the health system to empower those living with diabetes to manage their own foot appropriately. PMID- 25276672 TI - Investigation of Stress Symptoms among Primary School Children. AB - INTRODUCTION: Experience of chronic stress in children plays an important role in enhancing future physical, mental and social problems. It is very essential and vital that families, teachers and professional groups possess necessary abilities to diagnose stress symptoms in children. According to the statistics of Education Ministry, there were almost 5.5 million primary school students in Iran in 2008 2009. However, there are very limited studies about stress in 7 to 12-year-old children. The present study aimed to review stress symptoms in school-aged children. METHODS: In a descriptive study, 839 third to fifth grade students were selected from five randomly chosen districts of Tabriz using random sampling method in the schools. The data were collected by means of children’s stress symptom scale (CSSS) through interviewing by children. Accuracy of translation was checked and content validity and reliability were confirmed using test retest method. RESULTS: The entire twenty-six items of the questionnaire were reported as stress symptoms. More than half of the study subjects reported worry, fast heart beating, being afraid, chills and feeling sad as their signs of stress. Headache (46.6%) and tiredness (41.8%) were also reported. In examining every stress symptoms, there was a statistically significant correlation between some symptoms with age, grade and type of school. CONCLUSION: Children showed a wide range of symptoms in facing with stressful events. Accurate identification of symptoms can inform parents, teachers and professional health staff about physical and mental status of school-aged children and result in interventions to reduce their stress. PMID- 25276673 TI - Self-care ability in hemodialysis patients. AB - INTRODUCTION: Considering the numerous physical and psychological problems in hemo-dialysis patients, they are dependent on others in some daily activities and in fact, they do not have full self-care ability. A few studies have ever been done, particularly in Iran, on self-care ability of hemodialysis patients. The present study aimed to determine self-care ability of these patients in addition to evaluate its association with some demo-graphic characteristics. METHODS: This was a descriptive study in 2009 done in Marag-heh, Bonab and Miandoab Hospitals. The study population included 115 hemodialysis patients who were eligible. Data were collected using a combined and modified ques-tionnaire including demographic characteristics and self-care ability items. RESULTS: Self-care ability was desirable in 78.3 percent of the patients. The highest desirable self-care ability in the study participants was related to vascular access (73%) and the highest undesirable self-care ability was related to follow the diet. There was a significant asso-ciation between self-care ability and some demographic characteristics including age, gender, marital status and employment status. CONCLUSION: Hemodialysis patients did not have full self-care ability. It is necessary to enhance their knowledge about diet, complications of hemodialysis and preventive methods through accurate and permanent education so that they can increase their self-care ability. PMID- 25276674 TI - Clinical breast exam, and mammography in women referred to health centers in Tabriz, Iran. AB - INTRODUCTION: Breast cancer is the most common cancer and the second principal cause of cancer death in women as well as the most common cause of death in Iranian women aged 35-55 years. Detection of breast cancer in its early stages is amenable to almost complete cure. Breast cancer screening comprises breast self examination (BSE), clinical breast examination (CBE) and mammography. The study aimed to examine the performance of CBE and mammography among women referring to health centers of Tabriz, Iran. METHODS: This was a descriptive-analytical research carried out on 400 women aged 20-50 years. The samples were chosen through random multistage sampling among health centers of Tabriz then active records of women. A questionnaire and observational checklist was used to elicit socio-demographic information and performance of women towards breast cancer screening methods. Descriptive and inferential statistics (chi-square and Fisher’s exact test) were used to analyze the data through SPSS 13. RESULTS: Only 19.1% of women had clinical breast examination and 3.3% had mammogram. The main reasons why women had not performed breast cancer screening were as follows: being unaware of breast screening methods, not having a breast problem and not feeling the necessity... There was a significant correlation between performing CBE and history of breast tumor and also, between performing the mammography and family history of breast cancer and history of breast tumor (P < 0.05). CONCLUSION: The findings showed that the performance of breast cancer screening methods was not satisfactory. In addition, their performance in high risk women was very desirable than others. The presentation of imperative education about breast cancer screening methods through health staff especially in pregnancy, post-partum and even in premarriage councelling periods seems necessary. PMID- 25276675 TI - Effect of continuous midwifery care on length of labor. AB - INTRODUCTION: The process of pregnancy and labor has a dramatic impact on society's health. Considering the importance of obstetrical cares and the role and presence of midwife at parturient bedside, this study aimed to evaluate the impact of care and conti-nuous presence of midwifery on labor duration. METHODS: This was a semi-experimental study. The study population included parturient women referred to 29 Bahman Hospital in Tabriz who had normal vaginal delivery indication. 100 women were randomly se-lected and divided into experimental and control groups (50 in each group). In the expe-rimental group, obstetrical cares were provided by one midwife since the beginning of active phase of labor with her continuous presence at the bedside of parturient (continu-ing care) whereas in the control group, cares were provided by several midwives and without their continuous presence. Labor consequences (including labor duration) rec-orded for both groups. The data were analyzed through SPSS13 and inferential statistics including independent sample t-test. RESULTS: In the experimental group, the lengths of the first and second stages were shorter (per minute) than those of control group (p = 0.001). However, the length of the third stage of labor had no significant difference between the two groups (p = 0.083). Totally, the lengths of delivery including the first, second and third stages were shorter in the experimental group than in control group (p = 0.001). CONCLUSION: The results showed that low number of midwives and their continuous presence on bedside of parturient had a positive effect on reducing the deli-very duration. Therefore, being with "parturient" not only does promote the quality of obstetric care, also can promote the health of society. PMID- 25276676 TI - Emergency contraception: providers' knowledge and attitudes and their relationship with users' knowledge and attitudes at public health centers/posts of tabriz. AB - INTRODUCTION: Emergency contraceptives are accessible and acceptable methods for most women, which their proper use could prevent about three quarters of unwanted pregnancies. In this study, we aimed to determine the providers' knowledge, attitudes and their relation with the pills and condoms users' knowledge of and attitudes towards emergency contraception at public health centers/posts in Tabriz, Iran. METHODS: In this cross-sectional study, subjects were 140 health providers working in randomly selected 19 health centers and 33 health posts and 280 married women aged 15 to 49 years who were using contraceptive pills or condoms (two clients of each selected provider). A self-administered questionnaire was used to collect data from the providers, while the questionnaire for the clients was filled up by face-to-face interview. The relationships were determined by Pearson's correlation test. RESULTS: Mean score of the providers' knowledge and attitude was 69.4 +/- 11.8 and 70.1 +/- 12.8, respectively (possible score range was 0-100). The providers' knowledge score was good only in 35% (score > 75.0). High majority (95.7%) had positive attitudes (score > 50.0). Overall, there were no sig-nificant relationships, neither between the provider's and users' knowledge nor between their attitudes (p > 0.05). CONCLUSION: The providers' knowledge was insufficient, and there was no significant association between the providers' and users' knowledge and attitudes. Thus, in addition to the need for promoting providers' knowledge, the other barriers should also be recognized and removed in order to promote using this method. PMID- 25276677 TI - The effect of phenytoin cream in comparison with betadine solution on episiotomy pain of primiparous women. AB - INTRODUCTION: Episiotomy is a medical intervention in delivery which is still one of the most common surgical procedures. Topical phenytoin cream possesses analgesic, anti-bacterial and anti-inflammation effects as well as accelerating tissue healing. Hence, the present study aimed to compare the effect of topical phenytoin cream with betadine solu-tion on pain reduction of episiotomy incision. METHODS: In this double-blind clinical trial, 120 primiparous women with episiotomy that were referred to Al-Zahra Medical Center of Tabriz in 2010 were randomly allocated to phenytoin or betadine groups (60 in each group). Pain assessment was determine and compared using visual analog scale (VAS) in the first 24-hours and then in the 10(th) day after delivery. Data analysis per formed using chi-square, independent t-student and repeated measurements ANOVA tests. RESULTS: The mean pain intensity in the first 24-hours postpartum was 4.39 +/- 1.11 in phenytoin group and in betadine group it was 7.11 +/- 1.48 (p < 0.001). In the tenth day after delivery, mean pain intensity in phenytoin and betadine groups was 0.72 +/- 1.04 and 3.45 +/- 2.00 respectively (p < 0.001). CONCLUSION: The results showed that local phenytoin is effective on reducing the pain of episiotomy wound and can be replaced with betadine. PMID- 25276678 TI - The Relation between Awareness of Cancer Diagnosis and Spiritual Health among Cancer Patients. AB - INTRODUCTION: Disclosure of cancer diagnosis is one the main challenges in caring of patients with cancer since it may have negative effects on the spiritual health of patients. No study has ever been performed in Iran to investigate the relationship between awareness of cancer diagnosis and spiritual health in cancer patients. Therefore, the present study aimed to review the effects of awareness of cancer on spiritual health in patients with cancer. METHODS: This was a descriptive-comparative study conducted in Shahid Ghazi Tabatabaei University Hospital in 2009. The subjects included 150 patients aware of their cancer diagnosis and 150 unaware patients. The patients were selected through convenient sampling method. Using a questionnaire, the patient's spiritual health was assessed. Data analysis was conducted in SPSS17 using descriptive and inferential statistics. RESULTS: RESULTS showed the mean (SD) of spiritual health among aware and unaware patients to be 75.1 (3.8) and 75.4 (3.9), respectively. Statistically, there was no significant difference between the spiritual health of the two groups (p = 0.96). CONCLUSION: These findings showed that awareness of cancer diagnosis had no effects on spiritual health of patients. It is not surprising considering Iranian culture. However, confirmation of this finding requires further studies. PMID- 25276679 TI - The efficacy of massage therapy and breathing techniques on pain intensity and physiological responses to labor pain. AB - INTRODUCTION: There are many non-pharmacological methods for relieving labor pain. The preferable method is certainly the one that is effective and harmless. Therefore, we decided to compare the efficacy of massage therapy and breathing techniques on pain intensity, physiological responses to labor pain, labor type and the outcomes. METHODS: A quasi-experimental study was conducted in Alzahra Hospital in Tabriz. At first, 4o primigravidas, satisfying the inclusion criteria, were selected and randomly divided into two groups of massage 1 (M1) and breathing 1 (B1). Then, another 42 mothers were selected based on the same criteria and randomly divided into two groups of massage 2 (M2) and breathing 2 (B2). An educated researcher assistant (ERA) provided practical training to (B1 and B2 groups) by holding one educational session. As the labor process started, the ERA, who was present at the labor room, repeated the breathing technique for B1 and B2 groups. The breathing groups employed the techniques during the first or second stage of labor at 4, 6, 8 and 10 centimeter of dilatation for 30 minutes. The intensity of pain was measured by a numerical rating scale (NRS) 30 minutes after determining dilatation. The physiological responses were evaluated at the same time intervals. The ERA performed massaging at the same dilatations for M1 and M2 groups. The data was collected similarly. Labor progression was evaluated by the partograph. RESULTS: Massage at 4 and 6 cm dilatations and breathing at most dilatations decreased pain scores significantly. The mean difference of pain intensity and physiological responses to pain was not significant between the massaging and breathing groups at most dilatations. CONCLUSION: Based on the findings of this research, providing the possibility of choosing one or both methods for labor pain relief and decreasing cesarean section rate is suggested. PMID- 25276680 TI - Quality of nursing care in psychiatric wards of university hospitals in northwest of iran from the perceptions of nurses. AB - INTRODUCTION: Nursing care is considered as an essential component of health services. Patients' health improvement depends upon the quality of nursing care. As an important principle, perceptions of nurses as well as their active participation in decision-makings has an important role in the quality of services. This study aimed to determine the percep-tion of nurses toward the quality of nursing care in psychiatric wards. METHODS: In this descriptive study, we used census sampling. Seventy-six nurses employed at psychiatric wards of university hospitals in Northwest of Iran participated in this study. Quality Patient Care Scale (QUALPAC) was used to collect data. The score of each aspect and total scores were categorized as desirable, partly desirable and undesirable. The collected data were analyzed using descriptive statistics. RESULTS: Findings showed that 60.5% of nurses perceived the quality of nursing care as desirable, while 65.8% and 53.9% reported the quality of physical and communicational aspects of care as desirable. Moreover, 51.3% of nurses considered the quality of care in psychosocial aspect as partly desirable. CONCLUSION: Although research findings indicated the desirability of care quality from the perceptions of most nurses, designing and applying educational programs and continuous evaluation are necessary to improve nursing care quality especially in psychosocial aspects in these centers. PMID- 25276681 TI - Factors affecting the neonatal intensive care unit stay duration in very low birth weight premature infants. AB - INTRODUCTION: Improved survival of very low birth weight (VLBW) premature infants requires urgent intensive care, professional nursing and medical care. On the other hand, long hospital stay period imposes emotional and economic burdens on the family and society. Therefore, it is necessary to clarify the most important factors affecting their hospitalization duration to lessen unwanted outcomes of premature birth and to eliminate or relieve the problems. METHODS: In a descriptive-analytical study, 170 low birth weight premature infants were assessed in a regular daily follow-up in Alzahra Hospital, Tabriz, Iran. Probable factors affecting NICU (neonatal intensive care unit) stay, such as birth age and weight, time of trophic feeding initiation, time of regain birth weight, and duration of parenteral nutrition, were evaluated. Data was analyzed using descriptive statistics and linier regression model in SPSS14. Statistical significance was considered at 0.05. RESULTS: Mean birth weight and age of infants were 1310.26 +/- 804.26 g and 30.51 +/- 0.34 weeks, respectively. Duration of NICU stay was 14.51 +/- 10.12 days. Intrauterine growth retardation, positive C-reactive protein (CRP) and blood culture during hospitalization stay, bloody or bile stained gastric remnants, days to regain birth weight, and total enteral nutrition intolerance were the most important factors affecting NICU stay among the studied infants. CONCLUSION: It seems that eliminating risk factors of intrauterine growth retardation during pregnancy, preventing perinatal and nosocomial infections and taking suitable and tolerable feeding strategies will be effective on NICU stay duration in low birth weight premature infants. Therefore, required policies, especially early trophic feeding, are suggested to eliminate the existing difficulties. PMID- 25276682 TI - Individual Potentials Related to Evidence-Based Nursing among Nurses in Teaching Hospitals Affiliated to Tabriz University of Medical Sciences, Tabriz, Iran. AB - INTRODUCTION: Knowledge, attitude, and skills of nurses regarding evidence-based medicine are some of the important individual potentials in the implementation of these cares. There is no evidence indicating Iranian nurses to have these individual potentials. Therefore, the aim of this study was to determination the perceptions of nurses about individual potentials in evidence-based nursing and its related factors. METHODS: In this descriptive correlational study, all nurses (n = 600) working in teaching hospitals affiliated to Tabriz University of Medical Sciences, Tabriz, Iran were included. Valid and reliable translated questionnaires were used to collect data. Descriptive and inferential statistics were employed in SPSS to analyze the data. RESULTS: Based on our findings, moderate levels of knowledge, attitude, and skills were possessed by 274 (45.7%), 394 (65.7%), and 411 (68.5%) nurses, respectively. In addition, male nurses (p = 0.002) and those with a master's degree (p = 0.001) were more knowledgeable. Likewise, more positive attitudes were demonstrated by females (p = 0.004) and nurses with a master's degree (p = 0.04). A statistically significant difference was found between skills and employment status of nurses (p = 0.002). CONCLUSION: The moderate level of attitude among nurses can provide a good potential in promoting evidence-based nursing in teaching hospitals affiliated to Tabriz University of Medical Sciences. Therefore, more attention should be paid to enhance the awareness and skills of nurses toward evidence-based care. PMID- 25276683 TI - Lifestyle of hemodialysis patients in comparison with outpatients. AB - INTRODUCTION: Nowadays, the chronic diseases are known to be associated with lifestyle risk factors. Hemodialysis patients encounter considerable amount of physical, mental and social pressure. Lifestyle is important because it affects quality of life and has important role in prevention. This study aimed to compare the lifestyle of hemodialysis patients and outpatients in health clinics of Tabriz. METHODS: This was a case-control study on 155 hemodialysis patients and 155 outpatients referring to five dialysis centers and clinics, who met the inclusion criteria. Demographic data and some questions about lifestyle in nutrition, stress, physical activity and smoking were asked. RESULTS: The history of hypertension among hemodialysis patients was 34.6% greater than outpatients. High daily salt consumption (more than two tablespoons a day) was 40.5% higher among hemodialysis patients than outpatients. In terms of saturated oil intake, it was 30.8%higher among hemodialysis patients. Problem in communicating with family members was 69.8% higher in hemodialysis patients. In terms of physical activity, 46.4% of outpatients had higher physical activity like walking. CONCLUSION: Lifestyle in different dimensions was associated with chronic kidney disease (CKD); therefore, the officials of health system are recommended to develop a program to combat chronic diseases and integrate it with providing the first-level health services. It seems that public education can have a major role in life-style modification and in chronic kidney diseases prevention. PMID- 25276684 TI - Quality of life in cancer patients and its related factors. AB - INTRODUCTION: Despite the importance of quality of life (QOL) in outcomes of cancer pa-tients, there have been a few Iranian studies investigating the Iranian patients' quality of life. The present study aimed to assess the cancer patients' QOL and its related factors. METHODS: This cross-sectional study conducted in Shahid Ghazi Tabatabaei Hospital affiliated to Tabriz University of Medical Sciences in 2009. The samples included 150 cancer patients aged more than 18 years who were aware of their own diagnosis. They were selected through convenient sampling method and European Organization for Research and Treatment of Cancer-Quality of life questionnaire (EORTC-QOL 30) were completed. RESULTS: Our findings showed that 44.1% of the patients had moderate QOL. QOL had a significant correlation with the level of family support (p = 0.002). CONCLUSION: Many of cancer patients have a moderate QOL. However, confirmation of such finding requires further investigations. PMID- 25276685 TI - The experiences of mothers with asthmatic children: a content analysis. AB - INTRODUCTION: Having children with chronic diseases such as asthma creates conditions that cause emotional and behavioral problems in parents. In most families, the mother tends to have the first role in caring for her child and therefore mothers endure greater psychological pressure than other family members. These mothers' experiences and problems are different due to cultural and economic differences and the health services they receive. This study aimed to explore the experiences of mothers of an asthmatic child. METHODS: In this qualitative study data was collected through unstructured, in-depth interviews with 10 mothers who had an asthmatic child. The Graneheim and Lundman's qualitative content analysis method was used for analyzing the data. RESULTS: The analysis of data showed five main themes including constant concern, feeling of having an unusual life, the need for help from others, feeling of guilt, and the desire to constantly monitor the child. CONCLUSION: The mothers of asthmatic children expressed feelings and experiences that demonstrated their need for support and empathy. Therefore, in addition to the necessity of developing strategies to support these mothers, future studies aiming to reveal methods to provide them with support are also required. PMID- 25276686 TI - The effects of intravenous hydration on amniotic fluid volume and pregnancy outcomes in women with term pregnancy and oligohydramnios: a randomized clinical trial. AB - INTRODUCTION: Amniotic fluid is an important factor in the prediction of fetal survival. The aim of this research was to evaluate the effects of intravenous hydration of mothers on amniotic fluid volume and in turn on pregnancy outcomes. METHODS: The current single blind controlled clinical trial was conducted on 20 pregnant mothers with amniotic fluid index of lower or equal to 5 cm and gestational age of 37-41 weeks. The subjects were divided into two groups of case and control through simple random sampling. Amniotic fluid index was measured in all participants. The case group received one liter of isotonic saline during 30 minutes by the bolus method. Reevaluations of amniotic fluid index in both groups were made 90 minutes after baseline measurement. Independent t-test and paired t test were used to compare the two groups and mean amniotic fluid index before and after treatment, respectively. RESULTS: Hydration of mothers significantly increased the amniotic fluid index in the case group (mean change: 1.5 cm; 95%CI: 0.46 - 2.64; P = 0.01). The mean change of amniotic fluid index in the control group did not significantly increase (P = 0.06). The elevation of amniotic fluid index in the hydration group (32%) was significantly higher than the control group (1%) (P = 0.03). CONCLUSION: In this study intravenous hydration increased amniotic fluid index of mothers with term pregnancy and oligohydramnios. Since it caused no complications for the mother and the fetus, it can be used as an effective method in management of oligohydramnios. PMID- 25276687 TI - Effects of hand massage on anxiety in patients undergoing ophthalmology surgery using local anesthesia. AB - INTRODUCTION: Anxiety is a common disorder in patients before surgery. Inappropriately managed anxiety can cause psychological and physiological reactions and will affect the process of surgery and recovery. Therefore, this study examined the effects of hand massage on anxiety in patients undergoing ophthalmology surgery using local anesthesia. METHODS: In this interventional study, 52 patients who were supposed to undergo ophthalmology surgery using local anesthesia were studied. Patients were randomly assigned to two groups of intervention, who received hand massage before surgery (n = 27) and control (n = 25). Massaging lasted for 5 minutes (2.5 minutes on each hand) before surgery. Stroking and scrubbing methods were performed by 2 trained researchers. Anxiety level, blood pressure, heart rate, and respiratory rate were measured before and after the intervention in both groups. Anxiety was evaluated using Spielberger State-Trait Anxiety Inventory. Data was analyzed by chi-square, independent samples t-test, and paired t-test. RESULTS: There were no significant differences in mean anxiety, systolic blood pressure, diastolic blood pressure, heart rate, and respiratory rate between the two groups before the intervention (p > 0.05). However, there was a significant differenc in the mean stress level between the two groups after the intervention (p < 0.05). The two groups did not differ significantly in terms of physiological variables (p > 0.05). CONCLUSION: Our findings suggested that 5 minutes of hand massage before ophthalmology surgery (under local anesthesia) could reduce anxiety. Therefore, this method can be used to increase patient comfort and reduce anxiety before surgical interventions. PMID- 25276688 TI - Effect of eye mask on sleep quality in patients with acute coronary syndrome. AB - INTRODUCTION: Sleep is one of the basic human needs and sleep deprivation causes nu-merous adverse effects on the human body and mind. Due to reduced sleep quality in patients with acute coronary syndrome, this study was carried out to determine the effect of eye mask on sleep quality in patients with acute coronary syndrome. METHODS: In this two-group controlled clinical trial, sixty patients with acute coronary syndrome in the coronary care units of Baqiyatallah Hospital in Tehran in 2010 were selected by purposeful sampling method and randomly allocated to two groups of case and control. In the case group, in the second night stay, the intervention of eye mask was done per night and by using the Petersburg's sleep quality index; sleep quality was evaluated during and at the end of hospitalization. Then data were analyzed by paired t-test, independent t test, Spearman and Pearson's correlation coefficient and SPSS software version 19. RESULTS: Total sleep quality score of the case group was significantly decreased after intervention (4.86 +/- 1.88) from before intervention (10.46 +/- 4.09) (p < 0.000). In addi-tion, total score of sleep quality after intervention in the case group (4.86 +/- 1.88) was significant different from the control group (8.43 +/- 1.97) (p < 0.005). CONCLUSION: Using eye mask, as an economical and uncomplicated method, can improve sleep quality in patients with acute coronary syndrome in the coronary care units and can be used as an alternative method of treatment instead of drug therapy. PMID- 25276689 TI - Down syndrome screening methods in Iranian pregnant women. AB - INTRODUCTION: Down syndrome is one of the most prevalent genetic diseases. Screening methods for this syndrome are easy and safe and are recommended to all pregnant women particularly mothers over 35 years of age. This study aimed to review the status of Down syndrome screening and related factors in Iranian pregnant women. METHODS: This descriptive analytical study was carried out in 2011. It included 400 women who were randomly selected from those referring to Alzahra Hospital (Tabriz, Iran) during their third trimester of pregnancy. Data was collected through a question-naire whose reliability and validity have been approved. The data was analyzed by chi-square test in SPSS13. RESULTS: The results showed that while 28 and 26 women imple-mented screening tests during the first and second trimesters, respectively, only 5 sub-jects benefited from both (integrated test). Chi-square test showed significant correla-tions between the implementation of screening methods and age, education level, in-come, and the location of prenatal care (p < 0.05). CONCLUSION: The findings of the present study showed women to poorly implement Down syndrome screening methods. Therefore, the necessity of providing appropriate educational programs for health staff and mothers seems undeniable. Moreover, paying attention to the related factors such as income, educational level, and adequate training of mothers during pregnancy is essential. PMID- 25276690 TI - The Relation between Early Pregnancy Anthropometric Indices among Primiparous Women and Macrosomia. AB - INTRODUCTION: The prevalence of obesity is increasing in both developed and developing nations. Body mass index (BMI) is the most common index for obesity assessment and its relation with most complications among non-pregnant and pregnant women is known. However, no study has evaluated the relation between abdominal obesity and macrosomia among pregnant women. METHODS: In this prospective study, anthropometric indices including weight, height, and waist circumference (WC) of 1140 nulliparous pregnant women during their first trimester of pregnancy (6(th)-10(th) weeks) were measured by the researcher. According to the classification of the World Health Organization, women with BMI > 25 kg/m(2) were considered as overweight or obese. Abdominal obesity was defined as WC >= 88 cm. Finally, mothers were followed up and fetal macrosomia was recorded in a checklist. Data was analyzed in SPSS15. RESULTS: The results showed that 77.5% of women aged 20-35 years and 92.7% were housewives. The mean (SD) values of BMI and WC were 24.32 (4.08) kg/m(2) and 81.84 (9.25) cm, respectively. The prevalence of overweight (BMI = 25-29.9 kg/m(2)) and obesity (BMI > 29.9 kg/m) was 27.6% and 8.8%, respectively. Abdominal obesity based on WC was found in 34.8% of the subjects. CONCLUSION: Findings of this study revealed obesity in over one third of nulliparous pregnant women during their first trimester. Moreover, the high prevalence of macrosomia, in these women confirmed the importance of maternal education about obesity-related complications in order to change their lifestyle and prevent obesity. PMID- 25276692 TI - The effects of continuous and interrupted episiotomy repair on pain severity and rate of perineal repair: a controlled randomized clinical trial. AB - INTRODUCTION: Perineal pain is the most common complaint after episiotomy. It imposes extra pressure on mothers who attempt to adapt to their new conditions. Therefore, the present study was performed to compare pain severity and perineal repair in two episiotomy repair methods. METHODS: In this clinical trial, 100 primiparous women who referred to hospitals of Tabriz (Iran) for delivery were randomly allocated into two groups of 50 to undergo either continuous or interrupted episiotomy repair. A visual analogue scale (VAS) was used to evaluate pain severity 12-18 hours after episiotomy repair and also 10 days after delivery. Perineal repair rate was also assessed using the REEDA (redness, edema, ecchymosis, discharge, and approximation) scoring scale. The obtained data was analyzed in SPSS15. RESULTS: Statistical tests did not show significant differences between the 2 groups in pain severity variations or REEDA scores at 12-18 hours and the 10th day after delivery. However, the mean required time for repair and the number of used threads were significantly lower in the continuous repair group (p < 0.001). CONCLUSION: The results of this study showed that pain severity and episiotomy repair rate were similar in the two methods. Nevertheless, shorter time of repair and fewer threads were required using the continuous repair method. Therefore, this method would provide better services for mothers and reduce the required time, energy, and costs. PMID- 25276693 TI - The effect of sex education on the sexual function of women in the first half of pregnancy: a randomized controlled trial. AB - INTRODUCTION: There is lack of information on couple's sexual relation during pregnancy and also the lack of a national written training protocol in this regard in Iran. State authorities want to develop and implement such a protocol. Therefore, this study aimed to determine the effectiveness of a sex education package on the sexual function of pregnant women. METHODS: 88 women in their 8 to 14 weeks of pregnancy were randomly allocated into two groups of intervention and control. In the intervention group a midwife carried out sex education in two 60 minutes lecture sessions and group discussions for the participants. Moreover, educational booklets were distributed at the end of the first session and couple's questions were answered by telephone. In the control group women were taught nutritional education with the same procedure. Sexual function was evaluated using the female sexual function index (FSFI) before and four weeks after the education. Paired t-test, student's t-test and chi square were used to analyze the data. RESULTS: There were no significant differences among the groups in terms of their baseline characteristics, including mean sexual function scores before the education. After the education the mean of the total score of sexual function was significantly higher in the intervention group compared with the control group [mean difference 7.0 (95% CI 4.1, 9.9)]. Such a significant difference also existed in all the six domains of sexual function, i.e. desire, arousal, lubrication, orgasm, satisfaction and pain (p < 0.001). CONCLUSION: Providing such sexual education during routine prenatal care may improve couples' sexual health during pregnancy. PMID- 25276694 TI - Effects of magnesium and vitamin b6 on the severity of premenstrual syndrome symptoms. AB - INTRODUCTION: The importance of resolving the problem of premenstrual syndrome for patients has been emphasized due to its direct and indirect economical effects on the society. The aim of the current study was to evaluate the effects of magnesium and vitamin B6 on the severity of premenstrual syndrome in patients referring to health centers affiliated to Isfahan University of Medical Sciences, Iran, during 2009-10. METHODS: This two-stage double-blind clinical trial was conducted on 126 women who were randomly allocated into 3 groups to receive magnesium, vitamin B6, or placebo. The study was performed in 10 selected health centers in Isfahan and lasted for 4 months. To confirm premenstrual syndrome, the participants were asked to complete a menstrual diary for 2 months at home. Drug interventions were continued for two cycles and the results of before and after the intervention were compared. RESULTS: The findings of this study showed that the mean scores of premenstrual syndrome significantly decreased after the intervention in all groups (p < 0.05). CONCLUSION: According to our findings, vitamin B6 and placebo had the most and least efficiency in improving the mean premenstrual syndrome score. PMID- 25276695 TI - The effects of massage with coconut and sunflower oils on oxygen saturation of premature infants with respiratory distress syndrome treated with nasal continuous positive airway pressure. AB - INTRODUCTION: Nowadays particular emphasis is placed on the developmental aspects of premature infants care. Massage therapy is one of the best-known methods of caring. Due to the minimal touch policy in neonatal intensive care units (NICUs), massaging is not usually performed on premature infants. However, there is not sufficient evidence to support the claim that newborn infants with complex medical conditions should not be massaged. This study aimed to determine the effects of massage with coconut and sunflower oils on oxygen saturation of infants with respiratory distress syndrome (RDS) treated with nasal continuous positive airway pressure (NCPAP). METHODS: This was a randomized controlled trial on 90 newborns who were admitted to Alzahra Hospital (Tabriz, Iran). The infants were divided into control and massage therapy groups (massage with coconut and sunflower oils). Data was collected using a hospital documentation form. A 15 minute daily massage was performed for 3 days. Respiratory rate (RR), fraction of inspired oxygen (FiO2) and oxygen saturation were measured 5 minutes before the massage, 3 times during the massage, and 5 minutes after the massage. The collected data was analyzed using a mixed model. RESULTS: In comparison to coconut oil and control groups, mean oxygen saturation of sunflower oil group was improved. In addition, the coconut massage group showed lower oxygen saturation than the control group but was all values were within the normal range. Although massage decreased oxygen saturation, there was no need to increase FiO2. CONCLUSION: Massage therapy can provide developmental care for infants treated with NCPAP. PMID- 25276691 TI - Health-Related Quality of Life and its Predictive Factors among Infertile Women. AB - INTRODUCTION: The present study aimed to determine health-related quality of life (HRQOL) and its predictive factors among infertile women. METHODS: This cross sectional study was conducted on infertile women referring to Majidi Infertility Center (Tabriz, Iran). The data was collected through self-administered questionnaires including clinical and demographic characteristics and the Persian version of 36-item short form health survey (SF-36). One-sample t-test, independent t-test, one-way analysis of variance (ANOVA), and logistic regression were used for data analysis. RESULTS: Overall, 1012 infertile women were studied. The quality of life scores of infertile women in all eight subscales were significantly lower than normative data for Iranian women. Low physical component summary was more frequent in younger [adjusted odds ratio (AOR):1.45; 95% CI: 1.07-1.96], less educated (AOR: 1.75; 95% CI: 1.27-2.41), and low income (AOR: 1.52; 95% CI: 1.06-2.16) participants. It was less frequent in individuals whose infertility duration was 3-9 years (AOR: 0.65; 95% CI: 0.48-0.86), had male (AOR: 0.58; 95% CI: 0.43-0.78) or female and male factors infertility (AOR: 0.48; 95% CI: 0.30-0.78), or had a history of 1-2 in vitro fertilization (IVF), intrauterine insemination (IUI), or intracytoplasmic sperm injection (ICSI). Low mental component summary was associated with low income (AOR: 1.56; 95% CI: 1.11 2.18) and unexplained cause of infertility (AOR: 0.52; 95% CI: 0.32-0.56). CONCLUSION: The findings of this study indicated low quality of life among infertile women. The findings suggested the need for providing this group, especially those at higher risk such as low educated or low income females, with necessary support. PMID- 25276696 TI - Predictors of health-related quality of life in postmenopausal women: a population-based study. AB - INTRODUCTION: There have been limited studies on quality of life and its predictors among postmenopausal women. Due to the importance of this subject in health promotion, this study was performed to assess quality of life and its predictive factors in postmenopausal women living in Ilam, Iran. METHODS: In this descriptive correlational study, 400 postmenopausal married women who aged 50-59 years old and lived in Ilam were recruited from 80 randomly selected clusters. The participants were interviewed by a female interviewer using the standard questionnaire of quality of life (SF-36). Data was analyzed by analysis of variance (ANOVA), student's t-test, and linear regression analysis in SPSS. RESULTS: Mean scores (standard deviation) of quality of life in 4 dimensions of physical functioning, general health, mental health, and vitality were 76.8 (19.2), 71.1 (29.2), 74.3 (18.8), and 73.1 (19.6), respectively (with possible range of 0-100). According to linear regression analysis, women with chronic diseases, vasomotor symptoms, or insufficient family income and divorced and widowed subjects had significantly lower scores in all the 4 dimensions of quality of life. Aging was associated with reduced quality of life only in physical functioning dimension (p < 0.001). Although in univariate analysis, quality of life was significantly lower among illiterate participants and those with more children and longer duration of menopause at least in one dimension, the differences were not found to be significant in linear regression analysis. CONCLUSION: Chronic diseases, vasomotor symptoms and insufficient income were strong predictors of all the 4 dimensions of quality of life of postmenopausal women. Therefore, interventions are necessary to improve quality of life and health among this group of individuals. PMID- 25276697 TI - Self-Care Behaviors among Patients with Heart Failure in Iran. AB - INTRODUCTION: Recovery from heart failure and dealing with its effects is significantly influenced by patient's self-care. In order to maximize the effects of behavioral interventions and for educational planning, it is essential to know how much experience and information do patients with heart failure have about their disease and self-care behaviors. The present study aimed to identify self care behaviors in patients with heart failure. METHODS: Eighty heart failure patients hospitalized in Shahid Madani Training Center in Tabriz, Iran, participated in this study. Data collection was done through Self-Care of Heart Failure Index (SCHFI) that contained 22 questions in three sections including self-care behaviors, self-care management and confidence in performing self-care behaviors. RESULTS: The patient's self-care behaviors in three behavioral sub categories of maintaining, managing and confidence were low. The most repeated self-care behavior in the participating patients was taking medication and visiting the doctor. CONCLUSION: The results of the study showed low levels of self-care behaviors in patients with heart failure, which notes the need for patient empowerment. It is necessary to develop appropriate strategies in this regard by the authorities. PMID- 25276698 TI - Studying the Relationship between Individual and Organizational Factors and Nurses' Perception of Patient Safety Culture. AB - INTRODUCTION: Safety culture is considered as an important factor in improving patient safety. Therefore, identifying individual and organizational factors affecting safety culture is crucial. This study was carried out to determine individual and organizational factors associated with nurses' perception of patient safety culture. METHODS: The present descriptive study included 940 nurses working in four training hospitals affiliated with Urmia University of Medical Sciences (Iran). Data was collected through the self-report questionnaire of patient safety culture. Descriptive (number, percent, mean, and standard deviation) and inferential (t-test and analysis of variance) statistics were used to analyze the data in SPSS. RESULTS: Nurses' perception of patient safety culture was significantly correlated with marital status, workplace, and overtime hours. CONCLUSION: The results of this study revealed that some individual and organizational factors can impact on nurses' perception of patient safety culture. Nursing authorities should thus pay more attention to factors which promote patient safety culture and ultimately the safety of provided services. PMID- 25276699 TI - Impact of patient-controlled analgesia on pain relief after coronary artery bypass graft surgery: a randomized clinical trial. AB - INTRODUCTION: Pain has been pointed out as one of the concerns of cardiac surgery patients. Acute pain management has been a challenge for health professionals and several regiments have been described. We designed this study to evaluate the effectiveness of pain control with patient-controlled analgesia (PCA) versus conventional nurse-controlled analgesia (NCA) during the postoperative period in the intensive care unit (ICU) after coronary artery bypass graft (CABG) surgery. METHODS: In this randomized clinical trial, 80 elective CABG candidates were selected by convenience sampling. They were randomly allocated to two groups to receive either PCA or NCA. PCA plus continuous infusion of morphine started immediately after transferring the patients to the ICU. NCA was based on intravenous injections of morphine on demand. Pain was assessed using a verbal rating scale (VRS). Sedation level and morphine consumption were also evaluated from extubation until 48 hours after surgery. Data was analyzed using SPSS13. RESULTS: VRS scores were higher in the NCA group compared to the PCA group [3.27 (1.17) vs. 0.75 (0.66); p < 0.001]. Morphine consumption was significantly higher in the PCA group compared to the NCA group [28.43 (7.15) mg vs. 8.37 (5.36) mg; p < 0.001]. PCA was safe and respiratory depression was not observed in any of the subjects. Mean sedation scores did not differ between the two groups. CONCLUSION: PCA with background infusion of morphine increases morphine consumption and improves pain relief. It appears to be superior to NCA and can be recommended for patients after CABG surgery. PMID- 25276700 TI - Medication Error Reporting Rate and its Barriers and Facilitators among Nurses. AB - INTRODUCTION: Medication errors are among the most prevalent medical errors leading to morbidity and mortality. Effective prevention of this type of errors depends on the presence of a well-organized reporting system. The purpose of this study was to explore medication error reporting rate and its barriers and facilitators among nurses in teaching hospitals of Urmia University of Medical Sciences(Iran). METHODS: In a descriptive study in 2011, 733 nurses working in Urmia teaching hospitals were included. Data was collected using a questionnaire based on Haddon matrix. The questionnaire consisted of three items about medication error reporting rate, eight items on barriers of reporting, and seven items on facilitators of reporting. The collected data was analyzed by descriptive statistics in SPSS14 . RESULTS: The rate of reporting medication errors among nurses was far less than medication errors they had made. Nurses perceived that the most important barriers of reporting medication errors were blaming individuals instead of the system, consequences of reporting errors, and fear of reprimand and punishment. Some facilitating factors were also determined. CONCLUSION: Overall, the rate of medication errors was found to be much more than what had been reported by nurses. Therefore, it is suggested to train nurses and hospital administrators on facilitators and barriers of error reporting in order to enhance patient safety. PMID- 25276701 TI - Nurse's Perception of Stressors Associated with Coronary Artery Bypass Surgery. AB - INTRODUCTION: Cardiac surgery has many physiological, psychological, emotional, growth and spiritual potential consequences due to stress. Identifying and understanding the nature of stress can help nurses in controlling and reducing it. However, few studies have been conducted to identify the stressors. Therefore, the objective of this study was to determine nurses' perceptions of patients' stressors associated with coronary artery bypass surgery. METHODS: During a two month investigation, qualified nurses (n = 68) of patients undergoing coronary artery bypass were selected on the third to fifth day after surgery. With the use of Revised Cardiac Surgery Stressors Scale (RCSSS), interpersonal, intrapersonal and extrapersonal stressors were determined. RESULTS: The findings showed that the most interpersonal, intrapersonal and extrapersonal stressors were; "the need to have cardiac surgery", "death due to illness or surgery", "needing assistance with various activities", "doctors and nurses discussing about other patients", "having chest tube" and "Payment of hospital and medical bills". CONCLUSION: Identification of stressors in patients with coronary artery bypass graft helps nurses in taking better care of them. It would make a better ground for the officials and practitioners towards managing the stressors, especially interpersonal and extrapersonal stressors. Thereby patients are helped to cope with stressors. PMID- 25276702 TI - Sources of stress for nurses in neonatal intensive care units of East azerbaijan province, iran. AB - INTRODUCTION: Stress is one of the main factors affecting one's efficiency as well as staff health and quality of nursing services. Neonatal intensive care units (NICUs) can be stressful environments for nurses, infants and families as well. Since there is no evidence in this regard in Iran, the present study aimed to determine stress levels related to care delivering in NICU from the viewpoint of nurses in NICUs of East Azerbaijan Province, Iran during 2011. METHODS: This was a descriptive study including a purposive sample of 110 nurses working in NICUs of hospitals in East Azerbaijan Province. The data collection tool was a self-report questionnaire. The validity and reliability of the questionnaire were assessed by content validity and Cronbach's alpha coefficient (alpha = 0.84). RESULTS: According to factor analysis, the stressors included environmental and nurse and human factors. Stress sources in total and separately in each category were reported as moderate. The mean and 95% confidence interval of the factors in the categories were 2.75 (0.84); 2.59-2.91 and 3.21 (0.72); 3.07-3.35, respectively. Therefore, human factors caused significantly higher levels of stress compared to environmental factors (p < 0.05). CONCLUSION: Stressors involved in NICU nursing include environmental and human factors. Planning to remove or reduce their impact can improve the quality of nursing services in intensive care units and, thus, decrease the adverse effects of stress on workers. PMID- 25276703 TI - Inhaled lavender effect on anxiety and pain caused from intrauterine device insertion. AB - INTRODUCTION: Intrauterine device (IUD) is the most common reliable, effective and reversible contraceptive method used worldwide and in areas with high growth rate is of particular importance. IUD insertion is associated with high anxiety in most people that causes pain and discomfort. The aim of this study was to determine the effects of aromatherapy on anxiety and pain caused by IUD insertion. METHODS: This study was conducted on 106 women in a health care center located in Ardebil, Iran. Participants were divided into two groups by randomized blocks of 4 and 6. In the experimental group lavender scent was inhaled and in the control group the placebo was inhaled 30 minutes before IUD insertion. The anxiety of the participants was measured by Spielberger questionnaire, and the pain of IUD insertion was measured immediately after the insertion using visual analog scale (range 0-10). RESULTS: The mean score (standard deviation) of anxiety before intervention was 43.2 (9.2) in the experimental group that decreased after intervention to 39.0 (10.5) (p < 0.001), while this score was 42.2 (9.0) and 41.5 (8.4) before and after the intervention in the control group (p = 0.21). Mean differences of anxiety in both groups was statistically significant (p < 0.001). The pain score after intervention did not show significant difference between two groups (p = 0.51). CONCLUSION: Aromatherapy with lavender inhalation was effective in decreasing anxiety in IUD procedure, and this method can be used in health care centers as complementary treatments. PMID- 25276704 TI - The effect of training problem-solving skills on coping skills of depressed nursing and midwifery students. AB - INTRODUCTION: Nurses have a considerable role in caring and health promotion. Depressed nurses are deficient in their coping skills that are important in mental health. This study evaluated the effectiveness of training problem-solving skills on coping skills of depressed nursing and midwifery students. METHODS: The Beck Depression Scale and coping skills questionnaire were administered in Tabriz and Urmia nursing and midwifery schools. 92 students, who had achieved a score above 10 on the Beck Depression Scale, were selected. 46 students as study group and 46 students as control group were selected randomly. The intervention group received six sessions of problem-solving training within three weeks. Finally, after the end of sessions, coping skills and depression scales were administered and analyzed for both groups. RESULTS: Comparing the mean coping skills showed that before the intervention there were no significant differences between the control and study groups. However, after the intervention, a significant difference was observed between the control group and the study group. By comparing the mean coping skills before and after the intervention, a significant difference was observed in the study group. CONCLUSION: Training problem-solving skills increased the coping skills of depressed students. According to the role of coping skills in people's mental health, increasing coping skills can promote mental health, provide the basis for caring skills, and improve the quality of nurses' caring skills. PMID- 25276705 TI - Effect of educational program on quality of life of patients with heart failure: a randomized clinical trial. AB - INTRODUCTION: Heart failure is one of the most common cardiovascular diseases which decrease the quality of life. Most of the factors influencing the quality of life can be modified with educational interventions. Therefore, this study examined the impact of a continuous training program on quality of life of patients with heart failure. METHODS: This randomized clinical trial study was conducted during May to August 2011. Forty four participants with heart failure referred to Shahid Madani's polyclinics of Tabriz were selected through convenient sampling method and were randomly allocated to two groups. The intervention group (n = 22) received ongoing training including one-to-one teaching, counseling sessions and phone calls over 3 months. The control group (n = 22) received routine care program. Data on quality of life was collected using the Minnesota Living with Heart Failure Questionnaire at baseline as well as three months later. RESULTS: The statistical tests showed significant differences in the physical, emotional dimensions and total quality of life in intervention group. But in control group, no significant differences were obtained. There was not any significant association in demographic characteristics and quality of life. CONCLUSION: Ongoing training programs can be effective in improving quality of life of patients with heart failure. Hence applying ongoing educational program as a non-pharmacological intervention can help to improve the quality of life of these patients. PMID- 25276706 TI - Assessment of sound levels in a neonatal intensive care unit in tabriz, iran. AB - INTRODUCTION: High levels of sound have several negative effects, such as noise induced hearing loss and delayed growth and development, on premature infants in neonatal intensive care units (NICUs). In order to reduce sound levels, they should first be measured. This study was performed to assess sound levels and determine sources of noise in the NICU of Alzahra Teaching Hospital (Tabriz, Iran). METHODS: In a descriptive study, 24 hours in 4 workdays were randomly selected. Equivalent continuous sound level (Leq), sound level that is exceeded only 10% of the time (L10), maximum sound level (Lmax), and peak instantaneous sound pressure level (Lzpeak) were measured by CEL-440 sound level meter (SLM) at 6 fixed locations in the NICU. Data was collected using a questionnaire. SPSS13 was then used for data analysis. RESULTS: Mean values of Leq, L10, and Lmax were determined as 63.46 dBA, 65.81 dBA, and 71.30 dBA, respectively. They were all higher than standard levels (Leq < 45 dB, L10 <=50 dB, and Lmax <=65 dB). The highest Leq was measured at the time of nurse rounds. Leq was directly correlated with the number of staff members present in the ward. Finally, sources of noise were ordered based on their intensity. CONCLUSION: Considering that sound levels were higher than standard levels in our studied NICU, it is necessary to adopt policies to reduce sound. PMID- 25276707 TI - The effect of communication skills training on quality of care, self-efficacy, job satisfaction and communication skills rate of nurses in hospitals of tabriz, iran. AB - INTRODUCTION: Having an effective relationship with the patient in the process of treatment is essential. Nurses must have communication skills in order to establish effective relationships with the patients. This study evaluated the impact of communication skills training on quality of care, self-efficacy, job satisfaction and communication skills of nurses. METHODS: This is an experimental study with a control group that has been done in 2012. The study sample consisted of 73 nurses who work in hospitals of Tabriz; they were selected by proportional randomizing method. The intervention was only conducted on the experimental group. In order to measure the quality of care 160 patients, who had received care by nurses, participated in this study. The Data were analyzed by SPSS (ver.13). RESULTS: Comparing the mean scores of communication skills showed a statistically significant difference between control and experimental groups after intervention. The paired t-test showed a statistically significant difference in the experimental group before and after the intervention. Independent t-test showed a statistically significant difference between the rate of quality of care in patients of control and experimental groups after the intervention. CONCLUSION: The results showed that the training of communication skills can increase the nurse's rate of communication skills and cause elevation in quality of nursing care. Therefore, in order to improve the quality of nursing care it is recommended that communication skills be established and taught as a separate course in nursing education. PMID- 25276708 TI - Professional's Efforts to Simultaneously Discharge Infants and Mother from Neonatal Intensive Care Unit in Iran: A Qualitative Study. AB - INTRODUCTION: Discharge rate of surviving infants from neonatal intensive care unit (NICU) has recently increased dramatically. It is deemed to have a discharge plan with the aim of decreasing rehospitalization, morbidity, and mortality. The aim of this study was to explore and describe the professionals' efforts toward discharging the infants and their mothers from NICU. METHODS: This qualitative study used a content analysis approach to define and describe the efforts implemented for discharging the infants and their mothers. Data collection was done through the interviews with twenty nurses, physicians, and mothers in the NICUs of some Iranian University Hospitals. RESULTS: In the present study, two categories and five subcategories were identified namely the process of teaching/training the mothers of high risk infants (mothers' intrinsic motivation, considering mothers' learning needs, and enabling trainings) and providing infant discharge criteria (maintaining infant's health and believed abilities). CONCLUSION: The results of the study revealed that mothers' intrinsic motivation and considering their learning needs are essential points in the learning process. Some of the efforts such as enabling trainings are insufficient and must be improved to yield desirable discharge plan. PMID- 25276709 TI - The Effects of Intravenous Hydration on Amniotic Fluid Index in Pregnant Women with Preterm premature Rupture of Membranes: A Randomized Clinical Trial. AB - INTRODUCTION: Preterm premature rupture of membranes (PPROM) can result in fetal complications such as oligohydramnios. This study aimed to determine the effects of intravenous (IV) fluid bolus on amniotic fluid index (AFI) in pregnant women with PPROM. METHODS: 24 women with PPROM during singleton live pregnancy of 28 to 34 weeks whose baseline AFI was <= 5cm were randomized into two groups. The study group received one liter intravenous fluid bolus of isotonic Ringer serum during 30-minute period. Reevaluations of amniotic fluid index in both groups were made 90 minutes and 48 hours after baseline measurement. Independent t-test and paired t-test were used to compare the two groups and mean amniotic fluid index before and after treatment, respectively. RESULTS: The results of this study demonstrate that AFI decreased statistically significant in both the control and study groups. AFI decreased in both groups at 48 hours later. This decrease was not statistically significant in any group. The mean change in AFI (90 minutes and baseline) and (48 hours and baseline) between the two groups were not significant. The time between mean baseline measurements and delivery were 196.41 and 140.58 hours in the study and control groups, respectively. This difference was not statistically significant. CONCLUSION: This study did not find significant impact of hydration On AFI as a prophylactic method on oligohydramnios in pregnant women with PPROM. PMID- 25276710 TI - Quality of life of the elderly after hip fracture surgery: a case-control study. AB - INTRODUCTION: Hip fracture is common in the elderly. However, the quality of life of the elderly after hip fracture surgery has been largely ignored. Therefore, this study was conducted to compare the quality of life of the elderly with and without history of hip fracture surgery. METHODS: In a case-control study, 70 individuals with a history of hip fracture surgery at least three months before the study (case group) were compared with 70 elderly with the same specifications except the history of hip fracture (control group). The five-dimensional instrument of Euro Qol (EQ5D) was used to collect data. Chi-square test, t-test, analysis of variance (ANOVA) and calculating the odds ratio were used for data analysis. RESULTS: Compared to the control group, mobility, pain/discomfort, anxiety/depression, health status, self-care, and level of activity were lower in patients with the history of hip fracture. The mean scores of quality of life were also significantly lower in the case group regardless of all demographic variables such as age, sex, living arrangements, income, marriage, level of education, and job. CONCLUSION: The chance of undesirable quality of life in patients with a history of hip fracture surgery was 9.17 times greater than the elderly without a similar history. Therefore, developing supportive systems and rehabilitation facilities may improve patients' quality of life. PMID- 25276711 TI - The congruence of nurses' performance with developmental care standards in neonatal intensive care units. AB - INTRODUCTION: Many studies support the positive short and long-term developmental care for premature infants. This study aimed to determine the congruence of nurses' activity in four areas of developmental care in order to obtain basic information for authorities to provide a program to achieve related standards in the future. METHODS: The study was performed on 70 nurses working in neonatal intensive care units in Tabriz, Iran. Nurses answered to a questionnaire retrieved from Robison's developmental program. Content validity and reliability (Cronbach's alpha) of translated version were evaluated. Data were analysed using SPSS. RESULTS: The mean (standard deviation) of total score was 3.06 (0.44). It was 3.02 (0.50) for individualized care, 3.01 (0.63) for appropriate development environment for the child and family, 3 (0.46) in supporting family relationship and approving the relationship between infant and family and 3.22 (0.56) for collaboration among all care factors. Score 4 was considered as completely meet standards. Therefore, a mean of 3.20 and above was considered as observance higher than 80% and was favorable. The Friedman test showed statistically significant difference among the activities related to the four areas (p = 0.001). The collaboration field had the highest mean score and providing services in this field had more congruence with the related standard of developmental care. CONCLUSION: The study showed that the congruence of nurses' performance with standards of developmental care still requires more efforts. Therefore, it is necessary to train the staff in this regard and prepare them for structural and functional facilities. PMID- 25276712 TI - The Effect of Educational and Modifying Intervention on Asthma Control among Adolescents: a Randomized Clinical Trial. AB - INTRODUCTION: Controlling over allergens and environmental irritants is one of the essential elements of controlling asthma. Asthma control in adolescents is a challenge. The current study was performed with the goal of investigating the effect of an educational and modifying intervention about asthma triggers on asthma control among adolescents. METHODS: The current study was a randomized clinical trial. 60 adolescents of 12-18 years of age participated in this study. The participants were randomly divided into the two control and experimental groups. The Juniper's Asthma Control Questionnaire was completed by the adolescents before and 5 weeks after the intervention. Training sessions, planning for modification of asthma triggers and telephone follow-up were performed in the experimental group. RESULTS: There was a significant difference between the asthma control score before and after the intervention in the control and experimental groups. The asthma control status improved in the experimental group. In other words, the educational interventions to modify asthma triggers were effective in improving asthma control. CONCLUSION: Since this intervention method can improve the asthma control in adolescents, it is recommended that adolescents directly participate in such programs about asthma triggers and the education become less parent-centred. Moreover, the necessity of such an intervention in clinics and outpatient clinics is emphasized. PMID- 25276713 TI - Anticipatory grief reactions in fathers of preterm infants hospitalized in neonatal intensive care unit. AB - INTRODUCTION: Entering the state of fatherhood combined with the birth of a preterm neonate puts fathers' mental health at risk. Paying attention to fathers as a major supporter for mothers is essential. Therefore, the present study was conducted to evaluate anticipatory grief reactions among fathers with premature infants hospitalized in neonatal intensive care unit. METHODS: The current descriptive, cross-sectional study was conducted on 120 fathers with premature infants hospitalized in neonatal intensive care unit in hospitals of Tabriz (Iran) during 2011. Fathers were selected using convenience sampling method. Data was collected using a valid and reliable anticipatory grief scale which rated items as 0-3. RESULTS: All fathers reported anticipatory grief reactions. The mean score of items was 1.47. The most common reactions were unremitting mental engagement with the infant and feeling of sadness. Irritability and feeling of anger were reported to be less severe. The least important reactions were related physical reactions such as disorders of sleep and appetite and feeling of guilt. CONCLUSION: Fathers experience anticipatory grief after the birth of premature infants and their hospitalization in neonatal intensive care unit. Therefore, it is essential for the health care providers to pay more attention to cognitive and emotional reactions of fathers. PMID- 25276715 TI - The effects of an educational and supportive relactation program on weight gain of preterm infants. AB - INTRODUCTION: Re-establishing breastfeeding (relactation) is necessary in preterm infants who are deprived of breastfeeding due to hospitalized in the neonatal intensive care unit (NICU). Although NICU nurses train mothers about breastfeeding and relactation to some degree, there exists a lack of support or evaluation for restarting breastfeeding. The present study tried to determine the effects of an educational and supportive relactation program on weight gain of preterm infants. METHODS: This clinical trial study was performed on 60 preterm infants with mean gestational age of 29 weeks hospitalized in NICU of Alzahra Hospital (Tabriz, Iran). The infants were evaluated in two groups of 30. The mothers of infants in the control group received routine training and support about relactation while the intervention group received routine training as well as the designed educational and supportive relactation program including breast pumping, increasing milk agents and kangaroo mother care. Daily follow-up was conducted by the researcher. All the infants were weighed by a co-researcher. RESULTS: On the 14(th) day of the study, the mean (SD) weight of infants in the control and intervention groups was 1666.67 (136.08) and 1765.86 (156.96) g, respectively. CONCLUSION: Providing mothers with support from the medical team and training on relactation and kangaroo mother care can lead to better weight gain of the low birth weight premature infants. PMID- 25276714 TI - Diagnostic value of fetal movement counting by mother and the optimal recording duration. AB - INTRODUCTION: Fetal movement counting is a method used by mother to quantify her baby's movements. However, the optimal number of movements and the ideal duration of counting them have not been recognized. The aim of this study was to determine the diagnostic value of the two common fetal movements counting methods by mother including "ten fetal movements counting in two hours" and "three fetal movements counting in one hour" and to compare the required mean time for counting fetal movements in the two methods. METHODS: 300 subjects were selected by random sampling among clients with complains of decreased fetal movements referring to AL-Zahra teaching hospital in Tabriz, Iran. Full training about how to perform the two methods of fetal movements counting and how to record in related tables was instructed by researcher. Immediately after counting movements, biophysical profile test was performed. RESULTS: Among 291 mothers in the two groups, 99.7% had active fetuses based on both methods of fetal movement counting. 96.9% of these active fetuses obtained score of 10 in biophysical profile. There was a statistically significant relation between the results of both two methods of fetal movement counting and the biophysical profile as the gold standard. Sensitivity, specificity, positive and negative predictive values of both methods were equally 100%, 96%, 10% and 100%, respectively.Mean time (SD) for ten movement counting was 22.1(4.6) and for three movementcounting was 8.0(2.8) minutes CONCLUSION: The findings of this study showed that fetal movement counting test can be used as an initial screening method in predicting fetal health. PMID- 25276716 TI - Effect of black cohosh (cimicifuga racemosa) on vasomotor symptoms in postmenopausal women: a randomized clinical trial. AB - INTRODUCTION: Hot flash is considered to be an early and common symptom of menopause. The present study aimed to determine the impact of black cohosh (Cimicifuga racemosa) on vasomotor symptoms in postmenopausal women. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial. This study was performed on 84 postmenopausal women. The participants were randomly divided into control and intervention groups. The participants of the intervention group received one black cohosh tablet per day and the control group received one placebo tablet per day for eight weeks. The severity of vasomotor symptoms and number of hot flashes were recorded during the pre-intervention phase, and 4 and 8 weeks after the intervention. The data were analyzed using repeated measures ANOVA and ANCOVA tests. The level of significance was considered lower than 0.05. RESULTS: There was a significant difference between the two groups in terms of severity and number of hot flashes in weeks 4 and 8 by controlling the intensity of vasomotor symptoms and number of hot flashes before the intervention. Moreover, using repeated measures ANOVA, the intergroup comparison indicated a significant difference in bothgroups (the test and control groups) in terms of severity of vasomotor symptoms and number of hot flashes. CONCLUSION: According to the findings of the study, it seems that black cohosh can be used as an effective alternative medicine in relieving menopausal vasomotor symptoms. PMID- 25276717 TI - Pressure to the p6 acupoint and post-appendectomy pain, nausea, and vomiting: a randomized clinical trial. AB - INTRODUCTION: The use of acupressure is growing. Several studies have applied pressure to the P6 to reduce postoperative nausea, vomiting, and pain but have reported conflicting results. This study aimed to investigate the effects of pressure to the P6 point on pain, nausea and vomiting after appendectomy. METHODS: A single-blind, randomized controlled clinical trial was conducted on 88 patients after appendectomy. The subjects were randomly assigned to two groups. After the patients in the intervention group had regained their consciousness, pressure was applied to the P6 acupoint using special Acubands. In the control group, the Acubands were fastened loosely on the patients' wrists. The bracelets were kept for seven hours and pain, nausea, and vomiting were measured hourly. Student's t-test and chi-square test were used to analyze data. All analyses were performed in SPSS11.5. RESULTS: The two groups were not significantly different in terms of age, body mass index, duration of anesthesia, and length of incision. The mean pain intensity in the two groups was not significantly different at different times. Overall, 45.4% of the P6 group and 47.7% of the control group experienced postoperative nausea. The two groups were not significantly different in the mean intensity of nausea at different postoperative hours. In total, 12 patients in the P6 group and 18 in the control group had vomiting CONCLUSION: Pressure to the P6 did not significantly reduce pain and nausea after appendectomy. However, the incidence of vomiting was less in the P6 group. This method can be used to reduce vomiting after appendectomy. Similar studies are suggested to apply pressure with the onset of pain or nausea and vomiting. PMID- 25276718 TI - The effect of acupressure on sanyinjiao and hugo points on labor pain in nulliparous women: a randomized clinical trial. AB - INTRODUCTION: Most women have experienced child birth and its pain, which is inevitable. If this pain is not controlled it leads to prolonged labor and injury to the mother and fetus. This study was conducted to identify the effect of acupressure on sanyinjiao and hugo points on delivery pain in nulliparous women. METHODS: This was a randomized controlled clinical trial on 84 nulliparous women in hospitals of Ardebil, Iran. The participants were divided by randomized blocks of 4 and 6 into two groups. The intervention was in the form of applying pressure at sanyinjiao and hugo points based on different dilatations. The intensity of the pain before and after the intervention was recorded by visual scale of pain assessment. To determine the effect of pressure on the intensity of labor pain, analytical descriptive test was conducted in SPSS (version 13). RESULTS: There was a significant decrease in mean intensity of pain after each intervention in the experimental group with different dilatations (4, 6, 8, and 10 cm). Moreover, the Student's independent t-test results indicated that the mean intensity of pain in the experimental group after the intervention in all four dilatations was significantly lower than the control group. Repeated measures ANOVA test indicated that in both experimental and control groups in four time periods, there was a statistically significant difference. CONCLUSION: Acupressure on sanyinjiao and hugo points decreases the labor pain. Therefore, this method can be used effectively in the labor process. PMID- 25276720 TI - Sexual function in breastfeeding women in family health centers of tabriz, iran, 2012. AB - INTRODUCTION: There are conflicting evidences about the effects of breastfeeding on postpartum maternal sexual functioning. With regard to the methodological weaknesses of previous studies and cultural differences affecting their issue, the present study aims to evaluate sexual functions of lactating women and its components. METHODS: This is a descriptive study in which 200 eligible postpartum women were selected from eight health centers of Tabriz (25 from each center). The eligible women were called and invited to attend the health center. The evaluation was performed using the Persian version of normalized questionnaire of the Female Sexual Function Index (FSFI). The participants' sexual function scores above 28 were considered desirable (regarding the cut-off point mentioned in the Persian version of the questionnaire). RESULTS: Almost all of the lactating women suffered from sexual dysfunctions. Regarding the sexual performance's components the lowest scores were for libido and sexual arousal. CONCLUSION: According to the findings of the studies, in order to prevent the effects of sexual dysfunction on lactating women and their family members it is necessary to develop sexual health programs in health centers. PMID- 25276719 TI - The effect of folic Acid on menopausal hot flashes: a randomized clinical trial. AB - INTRODUCTION: The use of alternative therapies for the treatment of menopausal hot flashes has increased due to the serious risk of hormone therapy. Most alternative therapies have not been accepted by women. Therefore, conducting a study to find effective treatment, which has a low rate of complications and is more acceptable, is necessary. The aim of this study was to assess the effects of folic acid on menopausal hot flashes. METHODS: In the present study 70 menopausal women were placed into two groups of 35 with random allocation, and were treated with folic acid 1 mg tablets and placebo tablets once a day during four weeks. Information was gathered by questionnaire, interviews, and hot flash diary during five stages. Comparisons of within-group RESULTS were performed by ANOVA and between-group results were performed using ANCOVA. Data were analyzed by SPSS for Windows. RESULTS: There was a significant difference between mean severity, duration, and frequency of hot flashes before and after treatment within both groups. In comparing the results between the groups, mean hot flash severity in second, third, and fourth weeks were significantly different. The mean hot flash frequency was significantly different in third and fourth weeks, and the mean hot flash duration was significantly different in the fourth week. CONCLUSION: The results of the present study indicated that folic acid was effective in reducing the severity, duration, and frequency of hot flashes during menopause. Therefore, it can be recommended as an affordable and accessible method for treating menopausal hot flash for women. PMID- 25276721 TI - The effect of telephone support on postpartum depression: a randomized controlled trial. AB - INTRODUCTION: Postpartum depression is a common disorder. Systematic reviews emphasized the need to conduct more trials about interventions to prevent postpartum depression. The aim of this study was to determine the effect of postpartum telephone support on maternal depression. METHODS: 366 postpartum women with no history of known depression were randomly assigned into control (244 subjects) and intervention (122 subjects) groups. The control group received only routine postpartum care. In the intervention group, telephone support was provided twice in the first week and once a week during the second to sixth week of postpartum by a trained midwife in addition to the routine care. In order to meet their unpredicted needs, the mothers could contact the consultant 24 hours a day. Postpartum depression was assessed using the self-administered Edinburgh Depression Scale at 60 to 65 days of postpartum. Mothers with scores of 13 and above were considered to have depression. Logistic regression and Student's t test were used for the data analysis. RESULTS: There was no significant difference regarding frequency of depression between the intervention and control groups (29.9% vs. 31.6%; Odds ratio 0.91, 95% CI 0.56 to 1.49). Mean of depression score was not significantly different between the groups [9.2 (6.1) vs. 10.4 (5.8); mean difference -1.19, 95%CI -2.5 to 0.13]. CONCLUSION: This study did not provide evidence to show that telephone support of a midwife during postpartum period have a preventive effect on postpartum depression. PMID- 25276723 TI - The Scope of Pre-Pregnancy Care Conducted at Health Centers of Tabriz, Iran: Women's Viewpoints. AB - Pre-pregnancy care is considered as preventive medicine related to pregnancy and delivery. This Questionnaire based study upon 384 women in the first half of the pregnancy showedthe scope of pre-pregnancy care in the area of physical health was either weak (75%) or average (25%). All women declared that they had not received mental health-related care during the pre-pregnancy care. The scope of pre-pregnancy care in the area of life-style was categorized as weak, average, and good by 69.79%, 29.69%, and 0.52% of the studied women, respectively. PMID- 25276722 TI - The Effect of Simulation Teaching on Baccalaureate Nursing Students' Self confidence Related to Peripheral Venous Catheterization in Children: A Randomized Trial. AB - INTRODUCTION: In recent decades, nursing instructors have tended to use simulation rather than traditional methods due to benefits such as increased self confidence. However, little academic literature is available to verify this claim. The procedure of establishing peripheral venous catheterization in pediatric patients is of great importance. Therefore, the researchers attempted to review the effect of the simulation teaching method on nursing students' self confidence related to peripheral venous catheterization in pediatric patients. METHODS: In this trial, 45 students in the 5(th) and 6(th) semester of nursing school in the first half of school year 2012 from the Faculty of Nursing and Midwifery, Tabriz University of Medical Sciences, Iran, were randomly assigned to three groups (a control group, and two intervention groups). They were trained in establishing peripheral venous catheterization in pediatric patients through simulation teaching method and practical training. The students' self-confidence was assessed by C-Scale before and after the intervention. RESULTS: The students' self-confidence score showed a significant increase in the simulation group after the intervention in comparison to other groups (p = 0.03). CONCLUSION: RESULTS revealed a significant increase in self-confidence of nursing students related to peripheral venous catheterization in pediatric patients by simulation. This substantiates the assertion that simulation can improve self-confidence. Due to the low sample size, further studies with larger population are suggested. PMID- 25276724 TI - Novice nurses' perception of working night shifts: a qualitative study. AB - INTRODUCTION: Nursing is always accompanied by shift working and nurses in Iran have to work night shifts in some stages of their professional life. Therefore, the present study aimed to describe the novice nurses' perception of working night shifts. METHODS: The present qualitative study was conducted on 20 novice nurses working in two university hospitals of Jahrom, Iran. The study data were collected through focus group interviews. All the interviews were recorded, transcribed, and analyzed using constant comparative analysis and qualitative content analysis. RESULTS: The study findings revealed five major themes of value system, physical and psychological problems, social relationships, organizational problems, and appropriate opportunity. CONCLUSION: The study presented a deep understanding of the novice nurses' perception of working night shifts, which can be used by the managers as a basis for organizing health and treatment systems. PMID- 25276725 TI - A standardized shift handover protocol: improving nurses' safe practice in intensive care units. AB - INTRODUCTION: For maintaining the continuity of care and improving the quality of care, effective inter-shift information communication is necessary. Any handover error can endanger patient safety. Despite the importance of shift handover, there is no standard handover protocol in our healthcare settings. METHODS: In this one-group pretest-posttest quasi-experimental study conducted in spring and summer of 2011, we recruited a convenience sample of 56 ICU nurses. The Nurses' Safe Practice Evaluation Checklist was used for data collection. The Content Validity Index and the inter-rater correlation coefficient of the checklist was 0.92 and 89, respectively. We employed the SPSS 11.5 software and the Mc Nemar and paired-samples t test for data analysis. RESULTS: Study findings revealed that nurses' mean score on the Safe Practice Evaluation Checklist increased significantly from 11.6 (2.7) to 17.0 (1.8) (P < 0.001). CONCLUSION: using a standard handover protocol for communicating patient's needs and information improves nurses' safe practice in the area of basic nursing care. PMID- 25276726 TI - Living with and caring for patients with Alzheimer's disease in nursing homes. AB - INTRODUCTION: Many of the patients with Alzheimer disease are taken care of in nursing homes. However the literature on the experiences of Iranian formal caregivers of older adults with Alzheimer disease is scarce. This qualitative study explored the caring experiences of formal caregivers in nursing homes that can improve the quality of care and patient's quality of life. METHODS: This qualitative study used the principles of descriptive content analysis to analyze these data. Our participants included 11 female and 3 male caregivers aged 25 to 38 years who were selected for interviewing based on a purposive sampling method. The data were analyzed with a content analysis method. RESULTS: Nearly 900 initial codes were extracted and categorized into 6 main themes including "managing difficult behaviors", "dependence on familial care", "continuum of different feelings", "care for a child", "living with the patients" and "not understanding the patients", which was further analyzed in the two subcategories "caring without enough information" and " a dead man moving". conclusion: The care provided by our informants was mainly influenced by attitudes, culture and religious beliefs of caregivers about family attachment and ample driven reward of helping and caring frail or old people in Islam. These cultural and religious beliefs could facilitate provision of care and confrontation with patients' child like behaviors. It is suggested that employment of trained staff and plans for their continued education can improve the quality of care and the quality of the patient's life. PMID- 25276727 TI - Nurses empathy and family needs in the intensive care units. AB - INTRODUCTION: The patients' families in intensive care units (ICUs) experience excessive stress which may disrupt their performance in daily life. Empathy is basic to the nursing role and has been found to be associated with improved patient outcomes and greater satisfaction with care in patient and his/her family. However, few studies have investigated the nursing empathy with ICU patients. This study aimed to assess nursing empathy and its relationship with the needs, from the perspective of families of patients in ICU. METHODS: In this cross-sectional study, 418 subjects were selected among families of patients admitted to ICUs in Tabriz, Iran, by convenience sampling, from May to August 2012. Data were collected through Barrett-Lennard Relationship inventory (BLRI) empathy scale and Critical Care Family Needs Intervention (CCFNI) inventories and were analyzed using descriptive and inferential statistical tests. RESULTS: Findings showed that most of the nurses had high level of empathy to the patients (38.8%). There was also statistically significant relationship between nurses' empathy and needs of patients' families (p < 0.001). CONCLUSION: In this study we found that by increasing the nurse's empathy skills, we would be able to improve providing family needs. Through empathic communication, nurses can encourage family members to participate in planning for the care of their patients. However, further studies are necessary to confirm the results. PMID- 25276728 TI - Patients' Point of View about Nurses' Support of Individualized Nursing Care in Training Hospitals Affiliated with Tabriz University of Medical Sciences. AB - INTRODUCTION: Individualized nursing care is the key element in quality of nursing care. In fact, it changes all standardized nursing procedures and activities. In addition, it tailored nursing activities with unique peculiarity of each patient. Focusing on patient during care process is one main reason for supporting individualized care. Individual differences among patients in terms of their health, illness and needs which emphasize on providing individualized care. This research aimed to demonstrate patients' point of view about nurses' support of individualized care. METHODS: A descriptive study conducted with participation of 400 being discharged patients from internal and surgical units in teaching hospitals of Tabriz University of Medical Sciences. Proportional stratified random sampling method was used. Data was collected by interviewing with patients using Suhonen Individualized Care Scale, after assessing its content validity and reliability with Chronbach's alpha method. Data analysis were done by using SPSS ver. 13. RESULTS: The mean of patients' point of view about nurses' support of individualized care was 2.60 (1.14). The results showed the mean of support for clinical situation 2.61 (1.27), support for personal life situation 2.36 (1.28), and support for decisional control over care 2.77 (1.17). Comparing aspects of support showed that support for decisional control over care was the highest and the lowest was support for personal life situation. CONCLUSION: According to results of the study and comparison with other researches in other countries, it is recommended that nursing care planners pay more attention to the aspects of nursing support based on individuals. PMID- 25276729 TI - The effect of different local anesthesia methods on pain relief in outpatient endometrial biopsy: randomized clinical trial. AB - INTRODUCTION: Endometrial biopsy is necessary for diagnosing the reason of abnormal uterine bleeding in perimenopausal women. Currently outpatient endometrial biopsy is used for evaluation of abnormal uterine bleeding which is associated with moderate to severe pain. Using lidocaine is one of the procedures which is used for pain relief while biopsy. This study is aimed at comparing the effect of different local anesthesia procedures on pain relief during endometrial biopsy. METHODS: In this randomized clinical trial, 160 multiparous 40-55 years old women with AUB, candidates for endometrial biopsy, were randomly assigned into four equal groups, to receive: 1-intrauterine lidocaine; 2-cervical spray lidocaine; 3- intrauterine lidocaine plus cervical spray lidocaine; or 4 intrauterine distilled water. Pain relief was measured at 3 different times: during endometrial biopsy, just after and 15 minutes after biopsy. RESULTS: Pain intensity was reduced significantly at different times in intrauterine lidocaine and intrauterine lidocaine with cervical spray lidocaine receivers in compare with the groups which received cervical spray lidocaine and distilled water. The mean of difference pain relief during biopsy and 15 minutes after that was reduced significantly in the group which received intrauterine lidocaine and intrauterine lidocaine with cervical spray lidocaine in comparison with the other two groups. CONCLUSION: Intrauterine lidocaine was effective during endometrial biopsy, and using it with cervical spray lidocaine had no more beneficial effect. PMID- 25276730 TI - Knowledge and Performance about Nursing Ethic Codes from Nurses' and Patients' Perspective in Tabriz Teaching Hospitals, Iran. AB - INTRODUCTION: Nursing profession requires knowledge of ethics to guide performance. The nature of this profession necessitates ethical care more than routine care. Today, worldwide definition of professional ethic code has been done based on human and ethical issues in the communication between nurse and patient. To improve all dimensions of nursing, we need to respect ethic codes. The aim of this study is to assess knowledge and performance about nursing ethic codes from nurses' and patients' perspective. METHODS: A descriptive study Conducted upon 345 nurses and 500 inpatients in six teaching hospitals of Tabriz, 2012. To investigate nurses' knowledge and performance, data were collected by using structured questionnaires. Statistical analysis was done using descriptive and analytic statistics, independent t-test and ANOVA and Pearson correlation coefficient, in SPSS13. RESULTS: Most of the nurses were female, married, educated at BS degree and 86.4% of them were aware of Ethic codes also 91.9% of nurses and 41.8% of patients represented nurses respect ethic codes. Nurses' and patients' perspective about ethic codes differed significantly. Significant relationship was found between nurses' knowledge of ethic codes and job satisfaction and complaint of ethical performance. CONCLUSION: According to the results, consideration to teaching ethic codes in nursing curriculum for student and continuous education for staff is proposed, on the other hand recognizing failures of the health system, optimizing nursing care, attempt to inform patients about Nursing ethic codes, promote patient rights and achieve patient satisfaction can minimize the differences between the two perspectives. PMID- 25276731 TI - Barriers of referral system to health care provision in rural societies in iran. AB - INTRODUCTION: Health care delivery systems in rural areas face numerous challenges in meeting the community's needs. This study aimed to describe barriers of health care process in rural societies in Iran. METHODS: In this qualitative study, 26 participants (21 rural health care providers and five rural patients) were selected through purposive sampling. The data was collected via semi-structured individual interviews and small focus group discussions. Data was analyzed with qualitative content analysis. RESULTS: One category, "ineffective referral system", and five subcategories, i.e. being far from the ideal referral system, lack of adequate governmental referral system, lack of connection between different levels of the referral system, self-referential and bypassing the referral system, and insufficient knowledge about the referral system, were found. CONCLUSION: Considering the obstacles to the referral system, improvements in its structure are necessary to promote the quality of health care in rural areas. Such changes require coordination between the three levels of the referral system, strengthening the public sector of the system, increasing public awareness about the referral system, and prevention of self-referential. PMID- 25276732 TI - The effect of peers support on postpartum depression: a single-blind randomized clinical trial. AB - INTRODUCTION: Postpartum depression and its consequences not only involve mothers and their children but it will also affect their families. Therefore, this study aimed to investigate the effect of mothers receiving peer support on postpartum depression. METHODS: 100 eligible primiparous women participated in a randomized clinical trial. The intervention group received phone calls by their peers from the last three months of pregnancy until two months after delivery. The control group only had access to routine care. Both groups in the second month after delivery were checked regarding depression using Edinburgh Postnatal Depression Scale. Data analysis was performed using independent t-test, chi-square test and covariance analysis. RESULTS: Mean depression score before intervention was 13.92 (3.23) in the control group and 14.06 (3.12) in the intervention group. In week 8 after delivery, mean score of depression in control group was 13.29 (4.08) but in the intervention group it was reduced to 10.25 (4.18). Difference in the reduction of mean postpartum depression score between the two groups showed statistically significant difference (p < 0.001). CONCLUSION: This study showed that peer support was effective in the prevention of postpartum depression, therefore, it is recommended to be used in the reduction of postpartum depression. PMID- 25276733 TI - Comparing the effect of mefenamic Acid and vitex agnus on intrauterine device induced bleeding. AB - INTRODUCTION: Increased bleeding is the most common cause of intrauterine device (IUD) removal. The use of alternative therapies to treat bleeding has increased due to the complications of medications. But most alternative therapies are not accepted by women. Therefore, conducting studies to find the right treatment with fewer complications and being acceptable is necessary. This study aimed to compare the effect of mefenamic acid and vitex agnus castus on IUD induced bleeding. METHODS: This was a double blinded randomized controlled clinical trial. It was conducted on 84 women with random allocation in to two groups of 42 treated with mefenamic acid and vitex agnus capsules taking three times a day during menstruation for four months. Data were collected by demographic questionnaire and Higham 5 stage chart (1 month before the treatment and 4 months during the treatment)., Paired t-test, independent t-test, chi-square test, analysis of variance (ANOVA) with repeated measurements, and SPSS software were used to determine the results. RESULTS: Mefenamic acid and vitex agnus significantly decreased bleeding. This decrease in month 4 was 52% in the mefenamic acid group and 47.6% in the vitex agnus group. The mean bleeding score changes was statistically significant between the two groups in the first three months and before the intervention. In the mefenamic acid group, the decreased bleeding was significantly more than the vitex agnus group. However, during the 4(th) month, the mean change was not statistically significant. CONCLUSION: Mefenamic acid and vitex agnus were both effective on IUD induced bleeding; however, mefenamic acid was more effective. PMID- 25276734 TI - The role of continuous care in reducing readmission for patients with heart failure. AB - INTRODUCTION: About 20-50% of patients with heart failure are readmitted to hospitals in 14 day to 6 months of hospital discharge. Several supportive programs are developed to reduce post discharge hospital readmissions. The present study was performed to review the clinical trials conducted to determine the effect of post-discharge follow-up on readmission of patients with heart failure (HF). METHODS: Internet search was conducted to identify clinical trial studies that have been conducted on post-discharge follow-up care for patients with HF. Databases of Science direct, Pubmed, Iranmedex, SID and also the Google's search engine were searched for studies that have been published between the years 1995 and 2013. Keywords used in searching Persian databases were included readmission, heart failure, continuous care, and follow-up. Keywords used in searching English databases were included of heart failure, readmission, follow-up and home monitoring. RESULTS: 21 clinical trials were reviewed. 16 studies have shown that continuous care through patient education before discharge, home visits, and telephone follow up could significantly reduce the rate of post discharge readmissions of patients with HF. However, five studies did not show significant reductions in post-discharge readmissions. CONCLUSION: Patient education and continuous post-discharge follow up interventions conducted by nurses could significantly reduce the rates of readmissions to the hospital or to the physicians' office. Considering limited health care resources, using one or a combination of follow-up methods, can reduce the number of readmissions of patients with HF. PMID- 25276735 TI - Determinants of Nurses' Caring Behaviors (DNCB): Preliminary Validation of a Scale. AB - INTRODUCTION: Nurses' Caring behaviors might be affected by many variables. The aim of this study was to develop and test a valid and reliable questionnaire to specify these determinants. METHODS: Both qualitative and quantitative methods were applied to develop the questionnaire. The development process of the instrument was conducted in three phases. The first phase consisted of four steps: in-depth interviews, development of the preliminary version of the 38-item DNCB, expert panel review, and language revision. The second phase involved examining 143 qualified nurses for psychometric properties of the DNCB. The participants were selected, based on quota sampling approach, from four educational hospitals affiliated to Urmia University of Medical Sciences, Iran. The final phase involved testing of the revised instrument using exploratory factor analysis. RESULTS: The results showed good CVI (0.89), test-retest correlation coefficient (0.91), internal consistency reliability (0.93), and acceptable face and construct validity. RESULTS of the factor analysis revealed a 6-factor solution, determined by Eigen values greater than 1, accounted for 77.736 of the total variance. CONCLUSION: This instrument is a simple scale with a good reliability and validity that can provide comprehensive information about the determinants of caring behaviors in a short time. PMID- 25276736 TI - The Impact of Aloe vera and Calendula on Perineal Healing after Episiotomy in Primiparous Women: A Randomized Clinical Trial. AB - INTRODUCTION: Episiotomy is used for enlarging the perineum. Aloe vera and Calendula have been used for treating different diseases from ancient times, limited researches have been done regarding the healing of these plants. Since the effect of their ointment on episiotomy healing has not been studied, this study is being done for determining the impact of Aloe vera and Calendula on episiotomy healing in primiparous women. METHODS: This clinical trial involves 111 qualified primiparous women admitted in Lolagar hospital. They were randomly categorized into three groups of control (n=1) and experimental (n=2) groups. The women in experimental group used Aloe vera and Calendula Ointment every 8 hours and the control group used hospital routine on episiotomy for 5 days. The data were collected by demographic questionnaire and redness, edema, ecchymosis, discharge and approximation scale (REEDA) which investigated the episiotomy healing before and five days after intervention in two groups. ANOVA, Tukey test, Kruskal-wallis, Chi-square were used for data analysis. RESULTS: The three groups do not have statistically significant different regarding demographic and other intervening variables. Comparing the mean of REEDA in five days after delivery showed statistically significant difference between control and experimental groups. CONCLUSION: According to the results, using Aloe vera and Calendula ointment considerably increases the speed of episiotomy wound healing so it can be used for quickening the episiotomy healing. PMID- 25276737 TI - Serum Levels of Melatonin and Oxidative Stress Markers and Correlation between Them in Infertile Men. AB - INTRODUCTION: Infertility is the problem of 15% of young couples in different societies. One of the factors that could affect fertility is oxidative stress. Therefore, the aim of the present study is to investigate the level of Melatonin, a free radical scavenger, and its correlation with oxidative biomarkers in infertile men. METHODS: For this purpose, fertile and infertile men in 2 groups, 30 people in each group, were studied. The fertile men were selected from husbands of patients admitted to Alzahra obstetric and gynecology hospital, according to WHO standards. The infertile men were selected from patients referred to infertility ward. Blood sampling from the participants carried out at a specific time, sera collected and the levels of malondialdehyde, total antioxidant capacity and Melatonin were detected in the sera. The data were analyzed using t-test and Sperman's correlation method. RESULTS: Melatonin level in the sera from fertile men were 522 (39.32) ng/L and in infertile men were 511.78 (34.6) ng/L. MDA level in fertile and infertile men were 2.26 (0.34) vs 2.99 (0.44) nmol/ml which was significantly different. The level of TAC in the sera from fertile men were significantly higher than in infertile men. The result obtained for correlation coefficient Spearman's test revealed a significant, strong and direct correlation between Melatonin and TAC and a significant and reverse correlation between melatonin and MDA. CONCLUSION: It is concluded that melatonin could be involved in infertility. In other word, melatonin treatment and antioxidant-rich nutrition could help fertility by combating oxidative stress. PMID- 25276738 TI - Quality of sleep and its relationship to quality of life in hemodialysis patients. AB - INTRODUCTION: Despite many advances in the treatment of chronic renal failure, the quality of sleep in patients who suffer from this disease is at the risk. The high prevalence of sleep disorders in hemodialysis patients, which is concomitant with physical, behavioral, and psychological problems, has always affected these patients' quality of life (QOL). This study aimed to determine the relationship between quality of sleep and quality of life in hemodialysis patients. METHODS: By using a descriptive and correlational design, this study was conducted on 245 hemodialysis patients in 2012. Patients were selected by convenience sampling from the hemodialysis ward of four training hospitals of Tabriz and Maragheh. Quality of sleep was measured by the Pittsburgh Sleep Quality Index (PSQI), and the quality of life for patients was measured by the Kidney Disease Quality Of Life questionnaire (KDQOL-SF). RESULTS: 83.3% of hemodialysis patients had poor quality of sleep. Poor quality of life was significantly associated with poor quality of sleep. There was a significant negative correlation between global PSQI and important aspects of quality of life including physical health, symptoms and problems, the impact of kidney disease on daily life, burden of kidney disease, mental health, social support, and sexual function. CONCLUSION: The low quality of sleep in hemodialysis patients has an effect on the deterioration of their quality of life. Therefore, training, counseling, and advocacy programs should be developed to improve the patients' quality of sleep and quality of life, especially those with lower education level and income, and older people. PMID- 25276739 TI - The effect of footbath on sleep quality of the elderly: a blinded randomized clinical trial. AB - INTRODUCTION: The progressive increase in the elderly population of developing countries has drawn attention to their health. Sleep Pattern and quality can affect life quality in old people. We need more documents about footbath (a non invasive method). The purpose of this research was to examine footbath on sleep quality of the elderly. METHODS: This study is a blinded, randomized, clinical trial on 46 old men that had health documents in health center, 2013. Participants in the research were divided into two groups. One group had footbath (experimental group) and another group did not have footbath (control group). The experimental group participants were asked to put their feet in warm water (41-42 oC) for 20 minutes before sleeping for 6 weeks. The co-researcher completed the Pittsburgh Sleep Quality Index (PSQI) before and after the intervention by individual interview. Data were analyzed by SPSS software. RESULTS: The comparison of changes in sleep quality score the old men showed the sleep duration and total sleep quality has significantly improved in the experimental group. CONCLUSION: According to the study results, the maximum effect of footbath was on sleep latency and sleep duration disturbances. In this study, the researchers had limited access to the elderly in Tabriz; therefore, it is recommended that future research be conducted in a higher number of health centers. PMID- 25276740 TI - Association of coping style and psychological well-being in hospital nurses. AB - INTRODUCTION: Nursing jobs are among the occupations experiencing high levels of stress. Level of psychological well-being and coping style with stressful situations among nurses has large impact on their job performance. Limited information exists about the relationship between coping styles and psychological well-being among nurses, so the present study examined the way of coping and the level of psychological well-being as well as their relationships among nurses. METHODS: In this correlational study, 100 nurses from Shahid Sadoughi University of Medical Sciences were selected by multi-stage random sampling in 2012. Lazarus and Folkman's coping styles and Ryff's psychological well-being Questionnaires were completed by self-report method. Collected data were entered software SPSS ver. 13 and then analyzed using Pearson correlation test. RESULTS: The results showed EFCSwere more used but PFCSstyle was less used with a little difference by mean (SD) of 87.91 (10.76) vs. 73.12 (12.15). Between EFCSand some psychological well-being dimensions such as purpose in life (P=0.01, r= -0.28) and personal development (P=0.03, r=-0.024), a significant negative association and between PFCSstyle and purpose in life, a significant positive relationship was found (P=0.006, r=0.31). CONCLUSION: Considering that PFCSstyle is more effective in solving problems and job stress, as well as, the increased use of EFCSis associated with adverse health consequences, improvement of nurses' coping strategies to cope better with stressful events by skill training and promotion of nurses' psychological well-being level is recommended. PMID- 25276742 TI - Moving the self-esteem of people with epilepsy by supportive group: a clinical trial. AB - INTRODUCTION: People with epilepsy (PWE) face physical and mental illness, and social stigma, which affect their self-esteem and quality of life. The purpose of this study was to examine the effects of a support group on the self-esteem of PWE. METHODS: A Quasi-experimental study was performed on 120 PWE in the Epilepsy Clinic at Srinagarind Hospital. The experimental group (N=60) attended the support group before receiving regular health care services. The control group (N=60) received only regular healthcare services. Data was collected by using the Rosenberg self-esteem scale scoring before and after the experiment. The score was analyzed by using a paired t-test and an independent t-test. RESULTS: The study showed that before the experiment, the self-esteem score of the control group was significantly higher than the experimental group. After the experiment, the scores of the control group and the experimental group showed a significant statistical difference. The score in the control group was significantly lower than the experimental group, while the score in the experimental group was significantly higher than before the experiment. CONCLUSION: The support group improves the self-esteem of PWE. Medical personnel should set up a support group for PWE to enhance their self-esteem. PMID- 25276741 TI - What are important for patient centered care? A quantitative study based on perception of patients' with cancer. AB - INTRODUCTION: Today in all aspects of health care, there is a considerable emphasis on the provision of patient centered care. Various researches in cancer wards have demonstrated that from view of patients, there were some similarities and differences in importance of care in different cultural area. This study aimed to assess what are important for patient centered care in cancer wards. METHODS: This is a descriptive study conducted with participation of 200 patients with cancer from a cancer center in Tabriz. Convenience sampling was used. The data were collected using Care-Questionnaire, developed by Larson. The Caring behaviors were ordered in 6 dimensions: "Being accessible", "Explains and facilitates", "Comforts", "Anticipates", "Trusting relationship", "Monitors and follows through" and ordered on a 5-point Likert-type scale. The data were analyzed using SPSS ver. 13.0. RESULTS: The results showed that patients with cancer evaluated most of nurses caring behaviors with higher scores (moderate to high) and assigned the "Monitors and follows through" and "Being accessible" as patients' higher priorities vs the "Comforts" 4.06 (0.50) and "Trusting Relationships" as lower priorities. CONCLUSION: The findings of the present study, indicate that the "Monitors and follows through" and "Being accessible" caring behaviors have more importance by patients with cancer, so these conduces nurses to notice and perform these behaviors in their nursing care. By so doing, moving to the main goal of patient centered care can be provided. PMID- 25276743 TI - Comparison of clustered care with three and four procedures on physiological responses of preterm infants: randomized crossover clinical trial. AB - INTRODUCTION: Preterm infants are under different procedures as a part of their care in the Neonatal Intensive Care Unit (NICU). Reduction of their stress and to provide rest opportunity for them is very important. In this regard, clustering of routine care is recommended. The aim of this study was to compare of physiological responses in preterm infants to clustered care with three and four noninvasive procedures (Respectively 7 & 10 point stressor). METHODS: A randomized crossover clinical trial performed in NICU of Al-Zahra teaching hospital, Tabriz, Iran in 2013. Thirty one preterm infants were studied at 32 weeks gestational age. The tool for data collection was a researcher-made data gathering sheet that personal information and measurement of primary outcomes (heart rate, respiratory rate and blood oxygen saturation) were recorded. The analysis of data was done with use of mixed model method at 0.05 significant level. RESULTS: Mean of oxygen saturation in before, during and after of clustered care with three procedures were respectively 97.52, 97.32, 97.84 and four procedures 97.29, 97.16, 97.35, heart rate of three procedures 146.26, 149.90, 149.97 and four procedures 146.45, 150.39, 151.13, respiratory rate of three procedures 51.68, 48.87, 47.71 and four procedures 51.71, 50.26, 52.35 that all of them were at normal range. Significant differences were not found between mean of physiological responses in two interventions. CONCLUSION: There was no significant difference between clustered care with four and three procedures. Both of them could be recommended for preterm infants in 32 weeks. PMID- 25276744 TI - The Relationship Between Social Support and Adherence of Dietary and Fluids Restrictions among Hemodialysis Patients in Iran. AB - INTRODUCTION: Patient's noncompliance dietary and fluids intake can lead to a build-up of toxic fluids and metabolic end-products in the blood stream which may result in an increased morbidity and premature death. The aim of the study is investigate relationship between the social support and adherence to dietary and fluid restrictions in hemodialysis patients. METHODS: In this correlational study upon 237 hemodialysis patients, the data was collected with the dialysis diet and fluids non-adherences hemodialysis questionnaire (DDFQ), and the multidimensional scale of perceived Social Support (MSP). Interdialytic weight gain, predialytic serum potassium levels, and predialytic serum phosphate levels was considered as biochemical indicators of dietary and fluid adherence. Data were analyzed by SPSS Ver.11.5. RESULTS: About 41.1% of patients reported non-adherence to diet and 45.2% of them reported non-adherence to fluid. Frequency of non-adherence to fluid was more common in patients. The highest level of perceived support was the family support 11.19 (1.34). There was a significant relationship between social support and adherence to dietary and fluid restrictions. Noncompliances to dietary and fluid restrictions were related to laboratory results. CONCLUSION: This way those patients who more supported had more adherences of diet and fluid restrictions and had lower level of phosphorus and potassium in laboratory results. Nurses have the main role to identify different methods providing social support for patients, also to encourage the families to support their hemodialysis patients. PMID- 25276746 TI - Empathy from the nurses' viewpoint in teaching hospitals of tabriz university of medical sciences, iran. AB - INTRODUCTION: Empathy is the ability to put one in the place of others and to better understand their feelings and experiences. According to researchers, there is a type of challenge in using this concept in nursing field. In most cases, the term empathy substitutes other concepts. Regarding this point, it seems quite necessary to research and discuss different dimensions of this concept in different studies. This study aimed to determine empathy regarding the nurses' point of view. METHODS: In this descriptive study sample size was selected according to study population or in the other hand all the nurses in 3 general hospital was selected because they are the most important teaching hospital in Tabriz. LEP (La Monica Empathy Profile) was used as empathy tool. Data were analyzed by SPSS Ver. 13.0. RESULTS: In nonverbal behavior dimension, touching the patient was considered as the most effective methods. On the other hand, nurses could not always be able to control stress and they could not always being with patients to show their empathy. Many people believe that nurses showed very little feelings while raggedly the reflective enclosure and they occasionally had to change their schedules to talk to patients. CONCLUSION: In most cases the nurses support nonverbal behavior, such as reflective, close and touching encountering in establishing relationship with the patient. However, to improve this situation, planning for nurses to become familiar with the ways through which they can express their interest to show empathy would be effective. PMID- 25276745 TI - Effect of Toys and Preoperative Visit on Reducing Children's Anxiety and their Parents before Surgery and Satisfaction with the Treatment Process. AB - INTRODUCTION: Hospital anxiety and surgery has an unpleasant and disturbing feeling for a child and his/her family. This study aimed to determine the effect of toys and visit in reducing children's anxiety before the surgery and their mothers and satisfaction with the treatment process. METHODS: This was a quasi experimental study in posttest design with a control group. 60 children aged 3 to 8 years, who were undergoing ear, nose and throat surgery in Tabriz Amiralmomenin hospital, were chosen, and regarding their age and gender, were recruited into the control or experiment group. For the experiment group, the interventions before surgery were applied. The level of anxiety in children and parents was evaluated by Observation Scale of Behavioral Distress (OSBD-R) and Spielberger State Anxiety Inventory (STAI). The level of parental satisfaction with the treatment process before being discharged from the hospital was evaluated by the process of treatment satisfaction questionnaire (PSQ-18). Data were analyzed by SPSS ver.13. RESULTS: Mean anxiety scores of the children and mothers in the experimental group were lower than the control group. Mean maternal satisfaction score of the treatment process in the experimental group was higher than the mean scores of the control group. However, in the subscales of general satisfaction, interpersonal behavior, and financial aspects of satisfaction with treatment, no statistical significant difference was found between the experimental and control groups. CONCLUSION: Based on the findings, providing toys for children and informing the parents about medical information has a major effect in reducing children's and other's anxiety and increasing maternal satisfaction with the treatment process. PMID- 25276747 TI - Mental health and its personal and social predictors in infertile women. AB - INTRODUCTION: Infertility is considered a traumatic stressor for infertile couples, and it becomes a psychosocial crisis for that person. Considering the importance of fertility and based on the cultural and social aspects of it in Iran, the present study aimed to determine mental health and its individual and social predictors in infertile women referring to the infertility center of Al Zahra hospital in Tabriz, Iran, during 2012-2013. METHODS: This was a descriptive correlational study on 345 infertile women referring to Al-Zahra hospital in Tabriz, Iran, via convenient sampling. Data was gathered by the perceived social support questionnaire and mental health questionnaire. To determine the relationship between social support and personal and social characteristics, and mental health, multivariate linear regression was used. Data were analyzed using SPSS software. RESULTS: The mean (SD) total score of mental health of women was 29.70 (11.50), the score ranged from 0 to 84. The best condition was below the depression scale, and the worst condition was below the social dysfunction scale. Social support from the family was also a predictor of the mental health of infertile women. CONCLUSION: The findings of this study showed that infertile women, in terms of mental health and its subscales, have unfavorable conditions. Moreover, social support from the family is an important factor influencing mental health. Therefore, strengthening the social support of the family to improve the mental health of infertile women seems necessary. PMID- 25276748 TI - Association between Perception of Prognosis and Spiritual Well-being among Cancer Patients. AB - INTRODUCTION: Disclosure of cancer prognosis is one of the most difficult challenges in caring of cancer patients. An exact effect of prognosis disclosure on spiritual well-being of cancer patient was not completely investigated. Therefore, the present study aimed to investigate the relationship between perception of prognosis and spiritual well-being among cancer patients. METHODS: In this descriptive-correlational study, which conducted in 2013, two hundred cancer patients referred to Shahid Ghazi Hospital and private offices of two oncologists in Tabriz participated with convenience sampling method. Perception of prognosis was investigated by Perception of Prognosis Inventory and spiritual well-being of cancer patients was investigated by Paloutzian and Ellison Inventory. Data were analyzed using descriptive statistics and Pearson correlation test. RESULTS: Participants reported positive perception about the prognosis of their disease (score 11 from 15) and rated their spiritual well being as high (score 99 from 120). There was a positive correlation between the perception of prognosis and spiritual health among cancer patients. CONCLUSION: Disclosure of cancer prognosis has negative effects on cancer patients. This result highlights the importance of considering cultural factors in disclosure of cancer prognosis. According to limitations of the present study approving these results need more studies. PMID- 25276749 TI - Relationship between Fathers' Depression and Perceived Social Support and Stress in Postpartum Period. AB - INTRODUCTION: The evidence suggests that some men experience depression after the childbirth of their wife, and this real and unknown phenomenon will adversely affect them as well as their families. Regarding the lack of understanding about the paternal depression and its complex and multifaceted etiology, the present study was done to assess the paternal postpartum depression and its relationship with perceived stress and social support components. METHODS: In this descriptive study, 205 new fathers were assessed from 6th to 12th week postpartum in seven health centers, affiliated to Shahid Beheshti University. Collected data with the Edinburgh Postnatal Depression Scale, Perceived Stress Scale, and the Perceived Social Support Scale were analyzed by descriptive statistics, correlation tests and linear regression analysis. RESULTS: 11.7% of the fathers scored 12 or above in the Edinburgh scale, which indicated depression symptom. The postnatal depression scores had a significant positive correlation with the perceived stress scores and a significant negative correlation with the perceived social support components scores. Perceived stress was key predictor of paternal postpartum depression. Perceived social support components cannot significantly predict the paternal postpartum depression. CONCLUSION: Assessment of paternal postpartum depression and its risk factors is recommended. Healthcare providers should pay more attention to the increasing public awareness, stress management and communication skills training, and support of fathers during the postnatal period. PMID- 25276750 TI - Factors affecting the nurse-patients' family communication in intensive care unit of kerman: a qualitative study. AB - INTRODUCTION: The communication between nurses and patients' families impacts patient well-being as well as the quality and outcome of nursing care, this study aimed to demonstrated the facilitators and barriers which influence the role of communication among Iranian nurses and families member in ICU. METHODS: This study is a qualitative study with content analysis. Participants were eight registered nurses and ten of patients' families. Patients were admitted to the ICU of two large university hospitals in Kerman, Iran. We used non-structured interviews for data collection. All interviews were transcribed verbatim with a simultaneous, constant comparative analysis of the audio tapes. RESULTS: According to data analysis, facilitative factors between nurses and families' communication consisted of spiritual care, emotional support, Participation, notification and consultation and barriers that were misunderstandings regarding treatment, job and patient difficulties. CONCLUSION: The findings led into the recognition of the important barriers and facilitators in communication between ICU team and the family of the patients. By identification of the barriers and facilitators of communication, establishing new rules and using creative methods in education and establishing the communication of ICU team especially using patient-based approach we can have effective communication. PMID- 25276751 TI - Comparing the effects of swaddled and conventional bathing methods on body temperature and crying duration in premature infants: a randomized clinical trial. AB - INTRODUCTION: Maintaining body temperature and reducing stress are important challenges in bathing preterm infants. Swaddle bathing, which includes in itself the principles of developmental care, can be used as a low-stress and appropriate bathing method for premature infants. Given the limitations of the researches carried out on this bathing method, the present study was conducted with the aim of comparing the effects of swaddled and conventional bathing methods on body temperature and crying duration in premature infants. METHODS: In this randomized clinical trial study, 50 premature infants hospitalized in Neonatal Intensive Care Unit (NICU) who were eligible for the study were divided by random allocation into two experimental and control groups. The infants in the experimental group were bathed using the swaddle bathing method and the infants in the control group were bathed using the conventional bathing method. Body temperature was measured 10 minutes before and 10 minutes after the bath. To record the crying, the infants' faces were filmed during the bath. The data were analyzed using chi-squared test, independent t-test, paired t-test and Mann Whitney U test. RESULTS: The mean temperature loss was significantly less in the swaddle-bathed newborns compared to the conventionally-bathed newborns. Furthermore, crying time was significantly less in the experimental group than in the control group. CONCLUSION: Given the positive effect of swaddled bathing in maintaining body temperature and reducing stress, it can be used as an appropriate bathing method in NICU. PMID- 25276752 TI - First and Fourth-Year Student's Perceptions about Importance of Nursing Care Behaviors: Socialization toward Caring. AB - INTRODUCTION: The essence of professional nursing is caring and so, nursing education must make caring as a significant part of their curricula. In this regard, little research exists about how nursing students perceive caring. The aim of this study is to investigate the nursing students' perception toward caring and thus, the impact of socialization process on their perception of caring will be determined. METHODS: A cross-sectional study was done among all first and fourth-year nursing students (n=230) in Tabriz and Urmia faculties of nursing, 2012. Data were collected using Larson's Caring Questionnaire that assessed the importance of nursing care behaviors (n=50) in six dimensions: "being accessible", "explains and facilitates", "comforts", "anticipates", "trusting relationship" and "monitors and follows through". RESULTS: The importance of caring behaviors was evaluated by the first and fourth-year nursing students in moderate to high level and also, the both groups considered higher ranks for "monitors and follows through" and "being accessible" and lower ranks for "anticipates" and "trusting relationships". The fourth-year students only ranked "explains and facilitates" higher than the first-year students, but the "comforts" dimension is not differed significantly between groups. CONCLUSION: The findings demonstrated that nursing education in this study has not likely succeeded in producing intended changes in the nursing students' perceptions. It is recommended to exactly find the perceptual changes or in principle the professional socialization process of nursing students, more research using longitudinal designs be conducted to examine the differences in students' perceptions of caring upon entering and completing the nursing program. PMID- 25276753 TI - The effect of stationary walking on the quality of life of the elderly women: a randomized controlled trial. AB - INTRODUCTION: Aging has a profound effect on all the body organs and quality of life. One of the appropriate interventions is exercises such as walking. Nevertheless, the risk of falling and its complications are lower in stationary walking than walking on ground. Due to the higher life expectancy in women than men, the increasing number of elderly, and the low quality of life of women compared to men, this study aimed to assess the impact of stationary walking on the quality of life of the elderly women. METHODS: In this clinical trial, 66 household elderly women covered by health centers of Maragheh were randomly selected and divided into experimental and control groups. Six weeks exercise intervention was conducted. The participants completed the quality of life questionnaire of the elderly, before and after the intervention. SPSS software was used to analyze the data. RESULTS: Mean scores of quality of life, in various aspects of the experimental group, before and after intervention, showed significant difference; there was no statistically significant difference in the control group. In addition, there was a significant difference in the mean and standard deviation of different aspects of quality of life in pre- and post-test of experiment and control groups. CONCLUSION: Using regular and constant exercise program such as stationary walking can increase the quality of life of the elderly women. It can improve healthy aging and having a healthy life at this age, too. Therefore, it is recommended to have stationary walking program in daily lives of the elderly. PMID- 25276754 TI - Access family functioning and related factors from the viewpoints of male cancer patients. AB - INTRODUCTION: Assessment of family functioning is essential prior to planning any family-based intervention for cancer patients. In an extensive literature review, any relevant studies related to the functions of Iranian families with cancer patient was not found. Therefore, the aims of present study were to investigate the function of Iranian families with a male cancer patient and its related factors from patients' perspectives. METHODS: This was a descriptive- corelational study in which 101 men with cancer admitted to Tabriz Shahid Ghazi hospital were participated by convenience sampling method. Family assessment device was used for data collection that investigates family functioning in problem solving, communication, roles, affective involvement, affective responsiveness, behavior control, and general functioning domains. Also, demographic characteristics were collected. The higher score indicates better family functioning. Data analyzed by SPSS software version13 using descriptive and inferential statistics is including independent samples t-test, one-way ANOVA and Pearson correlation tests. RESULTS: Male participants in this study reported inappropriate family functioning in all domains. The lower score was on communication and the higher score was on behavior control domain. There was significant statistical correlation between patients' perception of family functioning with the participants' education level and job, while, there was no significant correlation between patients' score of family functioning with age, life situation, number of children, age of senior child, marriage duration and time passed since diagnosis. CONCLUSION: Inappropriate family functioning reported by the male cancer patients indicates importance of providing consultation services for cancer patients and their family. PMID- 25276756 TI - The effect of spiritual and religious group psychotherapy on suicidal ideation in depressed patients: a randomized clinical trial. AB - INTRODUCTION: Suicide is a great economical, social and public health problem. It is prevalent worldwide and has a lot of negative effects on individuals, families and society. Depression is often prelude to Suicide. An important part of the treatment of the mentally ill patients is spiritual-religious psychotherapy which should be done after physical treatment. The aim of this study was to determine the effect of spiritual and religious group psychotherapy on suicidal ideation in depressed patients. METHODS: 51 depressed patients with suicidal ideation from Razi hospital (Tabriz, Iran) participated in this clinical trial. To collect Data questionnaire was used which included demographic and Beck Suicide Scale Ideation. Experimental group participated in 10 sessions of group psychotherapy. Each section lasted 1 hour. Two weeks after the last section post test was done. Statistical software SPSS ver 13 was used for data analysis. RESULTS: RESULTS of independent t-test revealed no difference between two groups in terms of suicidal ideation before intervention but after study there is a statistical difference. Also the results of ANCOVA test showed a significant relationship between spiritual group therapy and decrease in suicidal ideation, so that this intervention can make 57% of variance in suicidal ideation of experimental group. CONCLUSION: Regarding positive effect of spiritual and religious group psychotherapy on decreasing suicidal ideation of depressed patients, we suggest this intervention to be held in Psychiatric Wards and also more study on depression and other psychiatric patients with greater sample size would be helpful. PMID- 25276755 TI - The effects of triggers' modifying on adolescent self-efficacy with asthma: a randomized controlled clinical trial. AB - INTRODUCTION: The management of asthma during adolescence has specific challenges and is likely influenced, to some extent, by the patient's belief in their ability to affect change, their self-efficacy. Bolstering self-efficacy could potentially improve an adolescent's ability to self-manage their asthma. The aim of this study was to examine the effects of a triggers' educational-modifying intervention on self-efficacy among adolescents diagnosed with asthma living in Iran. METHODS: Sixty adolescents, aged 12 to 18 years, diagnosed with asthma participated in this randomized clinical trial. Participants randomly assigned to the control group received standard care while those assigned to the experimental group participated in a 5 week, nurse led, triggers modifying educational intervention in specialized clinics of lung in Tabriz, Iran. The self-efficacy scale developed by Bursh et al., was used for data collection. RESULTS: The level of self- efficacy in two groups before intervention was not statistically significant, while the post intervention measures were statistically significant. Intervention was effective in improving adolescents' self-efficacy. CONCLUSION: Since this type of intervention has the potential to improve Self- efficacy in adolescents with asthma, it is suggested that adolescence directly education about asthma triggers along with modulating triggers will be of value and parent centered could be diminished. The need for such interventions emphasizes in clinic and outpatient clinics. PMID- 25276757 TI - Comparison the Effect of Teaching of SBAR Technique with Role Play and Lecturing on Communication Skill of Nurses. AB - INTRODUCTION: Ineffective communication is a main factor in engender of unwanted hospital errors and impede suitable patient care. SBAR technique (Situation Background- Assessment- Recommendation) is a standard tool for building communication among healthcare professionals. While educating the SBAR technique requires appropriate educational methods, but this issue has been less investigated. So, the aim of present study was to compare the effect of educating the SBAR technique with role play and lecturing on communication skills of nurses in transferring patients to next shift. METHODS: This quasi-experimental study conducted by participating 78 nurses who assigned to role play and lecturing groups randomly. SBAR technique was educated to each group separately. At the end of the learning session in each group, the skills of the participants in performing SBAR technique were investigated by the standard SBAR scale. Data analysis was performed by using SPSS statistical software version 11.5. RESULTS: Comparison the total score of performing SBAR technique using independent samples t-test showed statistical differences between mean score of role play and lecturing groups. Similarly, comparison the scores of skill in performing each four parts of SBAR technique showed statistical differences between two groups. CONCLUSION: Role play is an effective educational method in teaching SBAR technique for nurses and it can be used as a tool for build effective communication between healthcare professionals. PMID- 25276758 TI - Effect of supportive nursing care on self esteem of patients receiving electroconvulsive therapy: a randomized controlled clinical trial. AB - INTRODUCTION: Self-esteem is an important potential indicator in etiology, diagnosis and treatment of patients with severe mental illness. ECT is a popular treatment for these patients that can effect on their self-esteem and reinforce their problems. The purpose of this study is to determine the effect of supportive nursing care in increasing self esteem of patients receiving ECT. METHODS: This clinical trial was conducted in the Baharan psychiatric hospital of Zahedan. A total of 70 cases of patients who received ECT were randomly allocated to control (n=35) and intervention (n=35) groups. The data were collected by demographic characteristics questionnaire and Rosenberg Self Esteem Scale (RSES). Intervention group received the supportive nursing care. The control group received only routine treatment. Self esteem level was measured and compared before and after intervention for two groups. The data was analyzed by SPSS using the chi(2), t-test and ANCOVA. RESULTS: RESULTS showed that both groups were homogeneous on the socio- demographic characteristics. The mean self esteem in the intervention group compared with the control group was significantly increased. While controlling the effects of individual and social variables, the result shows significant differences between two groups in the mean scores of self esteem after the intervention. CONCLUSION: The results suggest that supportive nursing care can have positive effect on self esteem of patients receiving ECT. It is recommended to use this method for increasing self esteem of these patients. PMID- 25276759 TI - Comparison the effects of shallow and deep endotracheal tube suctioning on respiratory rate, arterial blood oxygen saturation and number of suctioning in patients hospitalized in the intensive care unit: a randomized controlled trial. AB - INTRODUCTION: Endotracheal tube suctioning is essential for improve oxygenation in the patients undergoing mechanical ventilation. There are two types of shallow and deep endotracheal tube suctioning. This study aimed to evaluate the effect of shallow and deep suctioning methods on respiratory rate (RR), arterial blood oxygen saturation (SpO2) and number of suctioning in patients hospitalized in the intensive care units of Al-Zahra Hospital, Isfahan, Iran. METHODS: In this randomized controlled trial, 74 patients who hospitalized in the intensive care units of Isfahan Al-Zahra Hospital were randomly allocated to the shallow and deep suctioning groups. RR and SpO2 were measured immediately before, immediately after, 1 and 3 minute after each suctioning. Number of suctioning was also noted in each groups. Data were analyzed using repeated measures analysis of variance (RMANOVA), chi-square and independent t-tests. RESULTS: RR was significantly increased and SpO2 was significantly decreased after each suctioning in the both groups. However, these changes were not significant between the two groups. The numbers of suctioning was significantly higher in the shallow suctioning group than in the deep suctioning group. Conclusion : Shallow and deep suctioning had a similar effect on RR and SpO2. However, shallow suctioning caused further manipulation of patient's trachea than deep suctioning method. Therefore, it seems that deep endotracheal tube suctioning method can be used to clean the airway with lesser manipulation of the trachea. PMID- 25276760 TI - Effect of vimala massage on physiological jaundice in infants: a randomized controlled trial. AB - INTRODUCTION: Considering the prevalence of Jaundice in newborn infants and the risk of developing acute Bilirubin encephalopathy, in early weeks after birth. the importance of Infancy, as well as positive effects of giving massage on physical and behavioral growth and evolution of infants, the current study has been aimed to investigate the effects of Vimala massage on neonatal physiological Jaundice. METHODS: This is a single blind clinical trial study, 43 healthy term infants, with 1(st) day Bilirubin levels of less than 5mg/dl, carried out in Tabriz Al-Zahra hospital. Newborns were selected through convenience sampling and then randomly assigned to intervention and control groups. Control group received routine care, while newborns of intervention group received four days of Vimala massage starting from the first day of their birth. Main variables of study include transcutaneous Bilirubin and frequency of defecation. Collected data were analyzed by SPSS Ver.13 through Chi-square and Mann-Whitney tests. RESULTS: There were no statistical significant differences between two groups for skin bilirubin, however the number of defecations in the intervention group exceeded than of control group, and was statistically significant. CONCLUSION: The RESULTS show that Vimala massage within four days has no effect on increasing process of bilirubin, yet can affect the incidence rate of physiological Jaundice and care of infants by increasing defecation frequency. PMID- 25276761 TI - Health-promoting Lifestyle and its Demographic Predictors in Infertile Couples Referred to Infertility Clinic of Tabriz Al-Zahra Hospital, 2013. AB - INTRODUCTION: Improving the lifestyle of infertile couples led to the preservation of their performance, increase their quality of life, and reduce health cost. So, the aims of this study were to determine the health-promoting lifestyle and its predictors among infertile couples. METHODS: In a cross sectional, analytical study 322 infertile couples referred to an infertility clinic in Tabriz was participated with convenience sampling method. The demographic and the standard Health Promoting Lifestyle-II (HPLP II) questionnaires were completed by all couples individually. For determining the demographic predictors of health-promoting lifestyle, the multivariate linear regression was used. RESULTS: The mean (standard deviation) score of health promoting lifestyle in couples was 2.4 (0.4) of the achievable score ranged from 1 to 4. The highest mean score was for nutrition subscale 2.6 (0.5) in both men and women and the lowest mean score was for physical activity subscale in women 2.1(0.5) and men 2.3(0.5) and health responsibility subscale (2.3(0.5) in both men and women. Educational level, cause of infertility, adequacy of income for living expense, and living situation were predictors of health-promoting lifestyle. CONCLUSION: The results showed that participants do not carry out all health-promoting behaviors, especially physical activity and health responsibility, in an acceptable level. These behaviors have an important role in improving the quality of life, health maintenance, and fertility. Thus, the provision of strategies, including those in accordance with predictors of health promoting behaviors, is important for improving the health status of infertile couples. PMID- 25276762 TI - The Impact of Multimedia Education on Knowledge and Self-efficacy among Parents of Children with Asthma: A Randomized Clinical Trial. AB - INTRODUCTION: Asthma is one of the most common chronic disease among children, and is considered as a global health problem. According to the guidelines of childhood Asthma, parental education in order to improve their knowledge and self efficacy should be considered in clinical care. Therefore, this study was performed with the purpose of investigating the influence of multimedia education on knowledge and self-efficacy of the parents of children with Asthma. METHODS: This study is a clinical trial which was carried out on 50 parents of children with Asthma. Data collection instrument included the demographic questionnaires, assessing knowledge and self-efficacy of the parents of children with Asthma. Reliability and validity of the instruments were assessed and the multimedia education was carried out for the experimental group. Data analysis was done using SPSS 13 and descriptive inferential statistical tests (independent t-test and Mann-Whitney). RESULTS: History of Asthma was present in majority 52% of the families of the children and 54% reported smoking in their home. The average scores of knowledge and self-efficacy of the study samples in the experimental group showed an increase after multimedia education methods, so that there was a statistically significant difference between the experimental and control groups. CONCLUSION: The results obtained in this study also demonstrate that educating parents through multimedia technology increase their knowledge and self-efficacy in their care of children. PMID- 25276763 TI - Comparing Hemorrhages and Dysmenorrhea with Copper T380A and Multiload 375 Intrauterine Devices: A Randomized Clinical Trial. AB - INTRODUCTION: One of the most common complications of IUD users is bleeding and dysmenorrhea. These complications vary in the different types of IUDs. The aim of this study was to compare the bleeding and dysmenorrhea in ML CU 375 IUD and Copper T 380A IUD. METHODS: This randomized double-blind controlled clinical trial was performed on 48 women in a health care centres from January to October 2012, in Tabriz, Iran. Participants allocated into two equal groups of receiving IUD ML CU 375 or receiving IUD Copper T 380A in randomized blocking method. Data were collected by demographic questionnaire and Higham chart and Visual Analog Scale 1 month before IUD insertion and 4 months after IUD insertion. Analysis of covariance, ANOVA with repeated measures, Friedman, Ordinal regression and SPSS Ver. 13 were used to analysis the data. RESULTS: The results showed that the mean score of bleeding in the first four months after IUD insertion in IUD ML CU 375 users was significantly lower than IUD Copper T 380A group. In the third and fourth months in both groups showed severity of dysmenorrhea in group IUD ML CU 375 was lower than IUD Copper T 380A. The results showed that the duration of dysmenorrhea in the first four months after IUD insertion in IUD ML CU 375 group was significantly lower than IUD Copper T 380A group. CONCLUSION: Counseling and educating women by family planning service providers about both Copper T 380A and ML CU 375 IUDs before taking IUD is recommended. PMID- 25276764 TI - Seroprevalence of Toxoplasma Gondii Infection among High School Girls in Ajabshir from East Azarbaijan Province, Iran. AB - INTRODUCTION: Toxoplasmosis is a disease parasite which can infect human and animals. The infection may be serious if is transmitted to the fetus during pregnancy. The aim of this study was to determine the prevalence of specific antibodies and the associated risk factors for toxoplasmosis in students attending high-school in Ajabshir. METHODS: In this descriptive study, 549 blood samples were collected from high school girls. The samples divided into two groups (147 and 402 samples from rural and urban schools respectively). IgG and IgM specific antibodies to Toxoplasma gondii were detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: The results of study showed that from 402 urban samples, 50 (12.4) and 34(8.5) cases and from 147 rural samples, 38 (25.9) and 32 (21.8) cases were seropositive for anti-Toxoplasma IgG and IgM antibodies respectively. Of the risk factors studied, the significant association was found between T. gondii-specific antibodies with residency and age. CONCLUSION: Based on data found in our study, 87.6% of young girls from urban areas in Ajabshir did not have antibodies to Toxoplasma and this is a very important issue, because these young women were in fertile age. Therefore required Preventive and control programs especially in these cases in order to reduce the rate of disease. PMID- 25276765 TI - The incidence of hypertension and the follow-up rate in a sample of population over 30 years old in kashan 2013. AB - INTRODUCTION: Studies indicate that hypertension is prevalent in Iran, however, the reports are heterogeneous. The aim of this study was to estimate the incidence of hypertension and the rate of follow-up in a sample of population over 30 years old in Kashan city. METHODS: A descriptive study was conducted on people screened for hypertension in the project of "monitoring the health of Iranian population" in Kashan city at April 2013. Among all completed screening forms, 5000 forms were selected randomly. Required data were extracted from these forms and were recorded on a checklist that was consisted of 9 questions on demographics characteristics and 10 questions about follow-up. Descriptive statistics, independent sample t-test, paired t-test and pearson correlation coefficient was used to analyze the data. RESULTS: Totally, 5% of the enrolled people had a systolic blood pressure over 140 mmHg and a diastolic pressure over 90 mmHg. Only 92 subjects with high blood pressure were available via telephone. Also, 42.42% of cases refused to answer. From all subjects who were available and answered the study questions, 50% had been referred to a physician after 5.17 (6.05) days. Of these, 52.2% were diagnosed as being hypertensive. Lacking time was the main reason for non-referral. CONCLUSION: The incidence of hypertension was less than other studies but the rate of follow-up was low. Nurses and Iranian nursing organization are suggested to conduct a nationwide screening and follow up project to improve the rate of early diagnosis and help people in better management of hypertension. PMID- 25276766 TI - Thromboembolism and Thrombosis during Pregnancy and After Delivery between 2009 and 2012 in Al-Zahra Educational Center. AB - Venous thromboembolism (VTE) is considered as one of the leading causes of maternal mortality during pregnancy and postpartum period. In this retrospective study the medical records of 81 women diagnosed with Pulmonary thromboembolism (PTE) and Deep venous thrombosis (DVT) between 2009 and 2012 in Tabriz Al-Zahra hospital was participated. These cases were evaluated regarding frequency, maternal and fetus risk factors associated with VTE. During 3 years 33 patients were diagnosed as PTE; 7 women were diagnosed as DVT and PTE; and 41 women were diagnosed as DVT. Most frequent underlying disease was hypertension (13.5%) and most frequent symptoms of PTE and DVT were dyspnea (100%) and swelling of lower limb (100%) respectively. 93% of PTE and 79% of DVT incidences occurred during and after the third trimester of pregnancy. Additionally, 38% of PTE occurred during or after childbirth (33% following cesarean and 5% following vaginal delivery). Therefore, it seems that vaginal delivery is safer than cesarean surgery. In addition, the importance of third trimester of pregnancy and postpartum period is obvious. PMID- 25276767 TI - Superoxide dismutase 1 loss disturbs intracellular redox signaling, resulting in global age-related pathological changes. AB - Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body. In vivo studies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1(-/-)) mice show various aging like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation in Sod1(-/-) mice. This review will focus on various age-related pathologies caused by the loss of Sod1 and will discuss the molecular mechanisms underlying the pathogenesis in Sod1(-/ ) mice. PMID- 25276768 TI - Development of a wheelchair skills home program for older adults using a participatory action design approach. AB - Restricted mobility is the most common impairment among older adults and a manual wheelchair is often prescribed to address these limitations. However, limited access to rehabilitation services results in older adults typically receiving little or no mobility training when they receive a wheelchair. As an alternative and novel approach, we developed a therapist-monitored wheelchair skills home training program delivered via a computer tablet. To optimize efficacy and adherence, principles of self-efficacy and adult learning theory were foundational in the program design. A participatory action design approach was used to engage older adult wheelchair users, care providers, and prescribing clinicians in an iterative design and development process. A series of prototypes were fabricated and revised, based on feedback from eight stakeholder focus groups, until a final version was ready for evaluation in a clinical trial. Stakeholder contributions affirmed and enhanced the foundational theoretical principles and provided validation of the final product for the target population. PMID- 25276769 TI - Potential cardiovascular risk protection of bilirubin in end-stage renal disease patients under hemodialysis. AB - We evaluated the potential cardiovascular risk protection of bilirubin in hemodialysis (HD) patients. An enlarged set of studies were evaluated in 191 HD patients, including hematological study, lipid profile, iron metabolism, nutritional, inflammatory markers, and dialysis adequacy. The TA duplication screening in the UDP-glucuronosyltransferase 1 A1 (UGT1A1) promoter region was also performed. The UGT1A1 genotype frequencies in HD patients were 49.2%, 42.4%, and 8.4% for 6/6, 6/7, and 7/7 genotypes, respectively. Although no difference was found in UGT1A1 genotype distribution between the three tertiles of bilirubin, significant differences were found with increasing bilirubin levels, namely, a decrease in platelet, leukocyte, and lymphocyte counts, transferrin, oxidized low-density lipoprotein (ox-LDL), ox-LDL/low-density lipoprotein cholesterol ratio, apolipoprotein (Apo) A, Apo B, and interleukin-6 serum levels and a significant increased concentration of hemoglobin, hematocrit, erythrocyte count, iron, transferrin saturation, Apo A/Apo B ratio, adiponectin, and paraoxonase 1 serum levels. After adjustment for age these results remained significant. Our data suggest that higher bilirubin levels are associated with beneficial effects in HD patients, by improving lipid profile and reducing the inflammatory grade, which might contribute to increase in iron availability. These results suggest a potential cardiovascular risk protection of bilirubin in HD patients. PMID- 25276770 TI - Effects of the combined PDL/Nd:YAG laser on surgical scars: vascularity and collagen changes evaluated by in vivo confocal microscopy. AB - The aim of this study was to investigate the efficacy of the sequential combined 585 nm PDL and the 1064 nm neodymium:yttrium-aluminium-garnet laser (PDL/Nd:YAG) in the treatment of surgical scars and to evaluate the short-term effects by in vivo confocal microscopy (RCM) and the long-term effects by clinical assessment of the scars. Twenty-five patients were enrolled with 39 postoperative linear scars; each scar was divided into two fields. One half was treated with the combined PDL/Nd:YAG laser, whereas the other half remained untreated. Each scar was treated three times at monthly intervals. Scars were evaluated by an independent examiner, using the Vancouver Scar Scale. The combined PDL/Nd:YAG laser significantly improved the appearance of the scars. In order to study the short-term effects of combined laser treatment, six additional patients were enrolled with 7 postoperative linear scars. One half of scars was treated once with the combined PDL/Nd:YAG laser. One week after this laser treatment, both the treated and the nontreated parts of the scars were examined by dermoscopy and RCM. The dermoscopic pictures revealed improvements even in treated areas. In conclusion, the combined PDL/Nd:YAG laser was found to be effective in improving the quality and appearance of the surgical scars. PMID- 25276771 TI - A network meta-analysis on randomized trials focusing on the preventive effect of statins on contrast-induced nephropathy. AB - Contrast-induced nephropathy is a common complication of iodinated contrast administration. Statins may reduce the risk of contrast-induced nephropathy, but data remain inconclusive. We summarized the evidence based on statins for the prevention of contrast-induced nephropathy with a network meta-analysis. Randomized trials focusing on statins were searched and pooled with random-effect odds ratios. A total of 14 trials (6,160 patients) were included, focusing on atorvastatin (high/low dose), rosuvastatin (high dose), simvastatin (high/low dose), and placebo or no statin therapy before contrast administration. The risk of contrast-induced nephropathy was reduced by atorvastatin high dose and rosuvastatin high dose, with no difference between these two agents. Results for atorvastatin low dose and simvastatin (high/low dose) in comparison to placebo were inconclusive. Atorvastatin and rosuvastatin administered at high doses and before iodinated contrast administration have a consistent and beneficial preventive effect on contrast-induced nephropathy and may actually halve its incidence. PMID- 25276772 TI - Highlighting the structure-function relationship of the brain with the Ising model and graph theory. AB - With the advent of neuroimaging techniques, it becomes feasible to explore the structure-function relationships in the brain. When the brain is not involved in any cognitive task or stimulated by any external output, it preserves important activities which follow well-defined spatial distribution patterns. Understanding the self-organization of the brain from its anatomical structure, it has been recently suggested to model the observed functional pattern from the structure of white matter fiber bundles. Different models which study synchronization (e.g., the Kuramoto model) or global dynamics (e.g., the Ising model) have shown success in capturing fundamental properties of the brain. In particular, these models can explain the competition between modularity and specialization and the need for integration in the brain. Graphing the functional and structural brain organization supports the model and can also highlight the strategy used to process and organize large amount of information traveling between the different modules. How the flow of information can be prevented or partially destroyed in pathological states, like in severe brain injured patients with disorders of consciousness or by pharmacological induction like in anaesthesia, will also help us to better understand how global or integrated behavior can emerge from local and modular interactions. PMID- 25276774 TI - Reliability and validity of the Nigerian (Hausa) version of the Stroke Impact Scale (SIS) 3.0 index. AB - This study aims to test the translated Hausa version of the stroke impact scale SIS (3.0) and further evaluate its psychometric properties. The SIS 3.0 was translated from English into Hausa and was tested for its reliability and validity on a stratified random sample adult stroke survivors attending rehabilitation services at stroke referral hospitals in Kano, Nigeria. Psychometric analysis of the Hausa-SIS 3.0 involved face, content, criterion, and construct validity tests as well as internal and test-retest reliability. In reliability analyses, the Cronbach's alpha values for the items in Strength, Hand function, Mobility, ADL/IADL, Memory and thinking, Communication, Emotion, and Social participation domains were 0.80, 0.92, 0.90, 0.78, 0.84, 0.89, 0.58, and 0.74, respectively. There are 8 domains in stroke impact scale 3.0 in confirmatory factory analysis; some of the items in the Hausa-SIS questionnaire have to be dropped due to lack of discriminate validity. In the final analysis, a parsimonious model was obtained with two items per construct for the 8 constructs (Chi-square/df < 3, TLI and CFI > 0.9, and RMSEA < 0.08). Cross validation with 1000 bootstrap samples gave a satisfactory result (P = 0.011). In conclusion, the shorter 16-item Hausa-SIS seems to measure adequately the QOL outcomes in the 8 domains. PMID- 25276773 TI - Decreased fast ripples in the hippocampus of rats with spontaneous recurrent seizures treated with carbenoxolone and quinine. AB - BACKGROUND: In models of temporal lobe epilepsy and in patients with this pathology, high frequency oscillations called fast ripples (FRs, 250-600 Hz) can be observed. FRs are considered potential biomarkers for epilepsy and, in the light of many in vitro and in silico studies, we thought that electrical synapses mediated by gap junctions might possibly modulate FRs in vivo. METHODS: Animals with spontaneous recurrent seizures induced by pilocarpine administration were implanted with movable microelectrodes in the right anterior and posterior hippocampus to evaluate the effects of gap junction blockers administered in the entorhinal cortex. The effects of carbenoxolone (50 nmoles) and quinine (35 pmoles) on the mean number of spontaneous FR events (occurrence of FRs), as well as on the mean number of oscillation cycles per FR event and their frequency, were assessed using a specific algorithm to analyze FRs in intracranial EEG recordings. RESULTS: We found that these gap junction blockers decreased the mean number of FRs and the mean number of oscillation cycles per FR event in the hippocampus, both during and at different times after carbenoxolone and quinine administration. CONCLUSION: These data suggest that FRs may be modulated by gap junctions, although additional experiments in vivo will be necessary to determine the precise role of gap junctions in this pathological activity associated with epileptogenesis. PMID- 25276775 TI - Four-dimensional computed tomography based respiratory-gated radiotherapy with respiratory guidance system: analysis of respiratory signals and dosimetric comparison. AB - PURPOSE: To investigate the effectiveness of respiratory guidance system in 4 dimensional computed tomography (4 DCT) based respiratory-gated radiation therapy (RGRT) by comparing respiratory signals and dosimetric analysis of treatment plans. METHODS: The respiratory amplitude and period of the free, the audio device-guided, and the complex system-guided breathing were evaluated in eleven patients with lung or liver cancers. The dosimetric parameters were assessed by comparing free breathing CT plan and 4 DCT-based 30-70% maximal intensity projection (MIP) plan. RESULTS: The use of complex system-guided breathing showed significantly less variation in respiratory amplitude and period compared to the free or audio-guided breathing regarding the root mean square errors (RMSE) of full inspiration (P = 0.031), full expiration (P = 0.007), and period (P = 0.007). The dosimetric parameters including V(5 Gy), V(10 Gy), V(20 Gy), V(30 Gy), V(40 Gy), and V(50 Gy) of normal liver or lung in 4 DCT MIP plan were superior over free breathing CT plan. CONCLUSIONS: The reproducibility and regularity of respiratory amplitude and period were significantly improved with the complex system-guided breathing compared to the free or the audio-guided breathing. In addition, the treatment plan based on the 4D CT-based MIP images acquired with the complex system guided breathing showed better normal tissue sparing than that on the free breathing CT. PMID- 25276776 TI - Neuroprotective effects of lipoxin A4 in central nervous system pathologies. AB - Many diseases of the central nervous system are characterized and sometimes worsened by an intense inflammatory response in the affected tissue. It is now accepted that resolution of inflammation is an active process mediated by a group of mediators that can act in synchrony to switch the phenotype of cells, from a proinflammatory one to another that favors the return to homeostasis. This new genus of proresolving mediators includes resolvins, protectins, maresins, and lipoxins, the first to be discovered. In this short review we provide an overview of current knowledge into the cellular and molecular interactions of lipoxins in diseases of the central nervous system in which they appear to facilitate the resolution of inflammation, thus exerting a neuroprotective action. PMID- 25276777 TI - Economic impact of NMMO pretreatment on ethanol and biogas production from pinewood. AB - Processes for ethanol and biogas (scenario 1) and biomethane (scenario 2) production from pinewood improved by N-methylmorpholine-N-oxide (NMMO) pretreatment were developed and simulated by Aspen plus. These processes were compared with two processes using steam explosion instead of NMMO pretreatment ethanol (scenario 3) and biomethane (scenario 4) production, and the economies of all processes were evaluated by Aspen Process Economic Analyzer. Gasoline equivalent prices of the products including 25% value added tax (VAT) and selling and distribution expenses for scenarios 1 to 4 were, respectively, 1.40, 1.20, 1.24, and 1.04 ?/l, which are lower than gasoline price. The profitability indexes for scenarios 1 to 4 were 1.14, 0.93, 1.16, and 0.96, respectively. Despite the lower manufacturing costs of biomethane, the profitability indexes of these processes were lower than those of the bioethanol processes, because of higher capital requirements. The results showed that taxing rule is an effective parameter on the economy of the biofuels. The gasoline equivalent prices of the biofuels were 15-37% lower than gasoline; however, 37% of the gasoline price contributes to energy and carbon dioxide tax which are not included in the prices of biofuels based on the Swedish taxation rules. PMID- 25276778 TI - Cardioprotection: a review of current practice in global ischemia and future translational perspective. AB - The idea of protecting the heart from ischemic insult during heart surgery to allow elective cardiac arrest is as old as the idea of cardiac surgery itself. The current gold standard in clinical routine is a high potassium regimen added either to crystalloid or blood cardioplegic solutions inducing depolarized arrest. Ongoing patient demographic changes with increasingly older, comorbidly ill patients and increasing case complexity with increasingly structurally abnormal hearts as morphological correlate paired with evolutions in pediatric cardiac surgery allowing more complex procedures than ever before redefine requirements for cardioprotection. Many, in part adversarial, regimens to protect the myocardium from ischemic insults have entered clinical routine; however, functional recovery of the heart is still often impaired due to perfusion injury. Myocardial reperfusion damage is a key determinant of postoperative organ functional recovery, morbidity, and mortality in adult and pediatric patients. There is a discrepancy between what current protective strategies are capable of and what they are expected to do in a rapidly changing cardiac surgery community. An increased understanding of the molecular players of ischemia reperfusion injury offers potential seeds for new cardioprotective regimens and may further displace boundaries of what is technically feasible. PMID- 25276780 TI - Improved efficacy of transcatheter arterial chemoembolization using warmed miriplatin for hepatocellular carcinoma. AB - The aim of this study was to evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) using warmed and nonwarmed miriplatin for hepatocellular carcinoma. Eighty patients (117 nodules), treated between January 2010 and June 2013, were evaluated. Thirty-two and 85 nodules were treated with nonwarmed and warmed miriplatin, respectively. The efficacy of TACE was evaluated on a per nodule basis according to treatment effect (TE). Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. TE grades were significantly improved in the warmed group compared to the nonwarmed group (nonwarmed: TE 4, 12.5%; TE 3, 0%; TE 2, 15.6%; TE 1, 71.9%; warmed: TE 4, 34.1%; TE 3, 5.9%; TE 2, 9.4%; TE 1, 50.6%; P = 0.017) . Multivariate analysis revealed significant impact of warming miriplatin on objective response rate (odds ratio, 12.35; 95% confidence interval, 2.90-90.0; P = 0.0028). CTCAE grades of elevated aspartate and alanine transaminase after TACE were significantly higher in the warmed group (P = 0.0083 and 0.0068, resp.); however, all adverse events were only transient. The use of warmed miriplatin in TACE significantly improved TE without causing serious complications. PMID- 25276781 TI - Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. AB - INTRODUCTION: We investigated the use of autologous bone marrow concentrate (BMC) with and without an adipose graft, for treatment of knee osteoarthritis (OA). METHODS: Treatment registry data for patients who underwent BMC procedures with and without an adipose graft were analyzed. Pre- and posttreatment outcomes of interest included the lower extremity functional scale (LEFS), the numerical pain scale (NPS), and a subjective percentage improvement rating. Multivariate analyses were performed to examine the effects of treatment type adjusting for potential confounding factors. The frequency and type of adverse events (AE) were also examined. RESULTS: 840 procedures were performed, 616 without and 224 with adipose graft. The mean LEFS score increased by 7.9 and 9.8 in the two groups (out of 80), respectively, and the mean NPS score decreased from 4 to 2.6 and from 4.3 to 3 in the two groups, respectively. AE rates were 6% and 8.9% in the two groups, respectively. Although pre- and posttreatment improvements were statistically significant, the differences between the groups were not. CONCLUSION: BMC injections for knee OA showed encouraging outcomes and a low rate of AEs. Addition of an adipose graft to the BMC did not provide a detectible benefit over BMC alone. PMID- 25276783 TI - Translational research in peripheral nerve repair and regeneration. PMID- 25276779 TI - Electroacoustic stimulation: now and into the future. AB - Cochlear implants have provided hearing to hundreds of thousands of profoundly deaf people around the world. Recently, the eligibility criteria for cochlear implantation have been relaxed to include individuals who have some useful residual hearing. These recipients receive inputs from both electric and acoustic stimulation (EAS). Implant recipients who can combine these hearing modalities demonstrate pronounced benefit in speech perception, listening in background noise, and music appreciation over implant recipients that rely on electrical stimulation alone. The mechanisms bestowing this benefit are unknown, but it is likely that interaction of the electric and acoustic signals in the auditory pathway plays a role. Protection of residual hearing both during and following cochlear implantation is critical for EAS. A number of surgical refinements have been implemented to protect residual hearing, and the development of hearing protective drug and gene therapies is promising for EAS recipients. This review outlines the current field of EAS, with a focus on interactions that are observed between these modalities in animal models. It also outlines current trends in EAS surgery and gives an overview of the drug and gene therapies that are clinically translatable and may one day provide protection of residual hearing for cochlear implant recipients. PMID- 25276785 TI - Combined home exercise is more effective than range-of-motion home exercise in patients with ankylosing spondylitis: a randomized controlled trial. AB - Home exercise is often recommended for management of patients with ankylosing spondylitis (AS); however, what kind of home exercise is more beneficial for patients with AS has not been determined yet. We aimed to compare the effectiveness of combined home exercise (COMB) and range-of-motion home exercise (ROM) in patients with AS. Nineteen subjects with AS completed either COMB (n = 9) or ROM (n = 10) program. The COMB program included range-of-motion, strengthening, and aerobic exercise while the ROM program consisted of daily range-of-motion exercise only. After exercise instruction, subjects in each group performed home exercise for 3 months. Assessment included cardiopulmonary exercise test, pulmonary function test, spinal mobility measurement, chest expansion, Bath Ankylosing Spondylitis Functional Index (BASFI), and other functional ability and laboratory tests. After exercise, the COMB group showed significant improvement in peak oxygen uptake (12.3%, P = 0.008) and BASFI (P = 0.028), and the changed score between pre- and postexercise data was significantly greater in the COMB group regarding peak oxygen uptake and BASFI. Significant improvement in finger-to-floor distance after 3-month exercise was found only in the COMB group (P = 0.033). This study demonstrates that a combined home exercise is more effective than range-of-motion home exercise alone in aerobic capacity and functional ability. PMID- 25276782 TI - Role of miRNA let-7 and its major targets in prostate cancer. AB - Prostate cancer is worldwide the sixth leading cause of cancer related death in men thus early detection and successful treatment are still of major interest. The commonly performed screening of the prostate-specific antigen (PSA) is controversially discussed, as in many patients the prostate-specific antigen levels are chronically elevated in the absence of cancer. Due to the unsatisfying efficiency of available prostate cancer screening markers and the current treatment outcome of the aggressive hormone refractory prostate cancer, the evaluation of novel molecular markers and targets is considered an issue of high importance. MicroRNAs are relatively stable in body fluids orchestrating simultaneously the expression of many genes. These molecules are currently discussed to bear a greater diagnostic potential than protein-coding genes, being additionally promising therapeutic drugs and/or targets. Herein we review the potential impact of the microRNA let-7 family on prostate cancer and show how deregulation of several of its target genes could influence the cellular equilibrium in the prostate gland, promoting cancer development as they do in a variety of other human malignant neoplasias. PMID- 25276786 TI - Imaging mass spectrometry by matrix-assisted laser desorption/ionization and stress-strain measurements in iontophoresis transepithelial corneal collagen cross-linking. AB - PURPOSE: To compare biomechanical effect, riboflavin penetration and distribution in transepithelial corneal collagen cross-linking with iontophoresis (I-CXL), with standard cross linking (S-CXL) and current transepithelial protocol (TE CXL). MATERIALS AND METHODS: The study was divided into two different sections, considering, respectively, rabbit and human cadaver corneas. In both sections corneas were divided according to imbibition protocols and irradiation power. Imaging mass spectrometry by matrix-assisted laser desorption/ionization (MALDI IMS) and stress-strain measurements were used. Forty-eight rabbit and twelve human cadaver corneas were evaluated. RESULTS: MALDI-IMS showed a deep riboflavin penetration throughout the corneal layers with I-CXL, with a roughly lower concentration in the deepest layers when compared to S-CXL, whereas with TE-CXL penetration was considerably less. In rabbits, there was a significant increase (by 71.9% and P = 0.05) in corneal rigidity after I-CXL, when compared to controls. In humans, corneal rigidity increase was not significantly different among the subgroups. CONCLUSIONS: In rabbits, I-CXL induced a significant increase in corneal stiffness as well as better riboflavin penetration when compared to controls and TE-CXL but not to S-CXL. Stress-strain in human corneas did not show significant differences among techniques, possibly because of the small sample size of groups. In conclusion, I-CXL could be a valid alternative to S-CXL for riboflavin delivery in CXL, preserving the epithelium. PMID- 25276787 TI - Dynamics of alloplastic bone grafts on an early stage of corticotomy-facilitated orthodontic tooth movement in beagle dogs. AB - Alveolar augmented corticotomy is effective in accelerating orthodontic tooth movement, but the effect only lasts for a relatively short time. Therefore, the purpose of this study was to investigate the underlying biology of the immediate periodontal response to orthodontic tooth movement after a corticotomy with alloplastic bone grafts. The results demonstrated that measurable tooth movement began as early as 3 days after the intervention in beagle dogs. Based on the results and histological findings, augmented corticotomy-facilitated orthodontic tooth movement might enhance the condition of the periodontal tissue and the stability of the outcomes of orthodontic treatment. PMID- 25276784 TI - Management of non-vitamin K antagonist oral anticoagulants in the perioperative setting. AB - The field of oral anticoagulation has evolved with the arrival of non-vitamin K antagonist oral anticoagulants (NOACs) including an anti-IIa agent (dabigatran etexilate) and anti-Xa agents (rivaroxaban and apixaban). The main specificities of these drugs are predictable pharmacokinetics and pharmacodynamics but special attention should be paid in the elderly, in case of renal dysfunction and in case of emergency. In addition, their perioperative management is challenging, especially with the absence of specific antidotes. Effectively, periods of interruption before surgery or invasive procedures depend on half-life and keeping a permanent balance between bleeding and thromboembolic risks. In addition, few data regarding the link between plasma concentrations and their effects are provided. Routine laboratory tests are altered by NOACs and quantitative measurements are not widely performed. This paper provides a review on the management of NOACs in the perioperative setting, including the estimation of the bleeding and thrombotic risk, the periods of interruption, the indication of heparin bridging, the usefulness of laboratory tests before surgery or invasive procedure, and the time of resuming. Most data are based on expert's opinions. PMID- 25276789 TI - The effect of multiwalled carbon nanotubes on hepatotoxicity of Cd2+ in accumulated cadmium-metallothione in mice. AB - The effects of oxidized multiwalled carbon nanotubes (oMWCNTs) on the behavior and hepatotoxicity of Cd(2+) in accumulated cadmium-metallothionein mice were investigated. The results indicated that, after exposure of oMWCNTs to normal mice, oMWCNTs could not induce the liver to produce metallothionein (MT). When exposing Cd-MT mouse to different doses of oMWCNTs oMWCNTs could cause Cd(2+) release from the accumulated Cd-MT; subsequently, one part of the free Cd(2+) was eliminated with blood circulation; the other part adsorbed by oMWCNTs would remain in the tissues together with oMWCNTs. The results of the activities changes of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), and blood urea nitrogen (BUN) in plasma showed that the hepatotoxicity of coexposure was lower than that of single exposure, and the hepatotoxicity and accumulation of oMWCNTs in livers depended strongly on the exposure dosage of oMWCNTs. The histology of liver and kidney tissue also confirmed the previous results. Therefore, the author inferred that MT could be connected with oMWCNTs to reduce their hepatotoxicity, but the detailed mechanism needs to be further studied. PMID- 25276791 TI - Modelling the formation of liver zones within the scope of fractional order derivative. AB - We develop and extend earlier results related to mathematical modelling of the liver formation zone by the adoption of noninteger order derivative. The hidden uncertainties in the model are captured and controlled thanks to the Caputo derivative. The stationary states are investigated and the time-dependent solution is approximated using two recent iteration methods. In particular, we discuss the convergence of these methods by constructing a suitable Hilbert space. PMID- 25276790 TI - Lung cancer stem cell lose their stemness default state after exposure to microgravity. AB - Microgravity influences cell differentiation by modifying the morphogenetic field in which stem cells are embedded. Preliminary data showed indeed that stem cells are committed to selective differentiation when exposed to real or simulated microgravity. Our study provides evidence that a similar event occurs when cancer stem cells (CSCs) are cultured in microgravity. In the same time, a significant increase in apoptosis was recorded: those data point out that microgravity rescues CSCs from their relative quiescent state, inducing CSCs to lose their stemness features, as documented by the decrease in ALDH and the downregulation of both Nanog and Oct-4 genes. Those traits were stably acquired and preserved by CSCs when cells were placed again on a 1 g field. Studies conducted in microgravity on CSCs may improve our understanding of the fundamental role exerted by biophysical forces in cancer cell growth and function. PMID- 25276788 TI - Applications of flow cytometry to characterize bacterial physiological responses. AB - Although reports of flow cytometry (FCM) applied to bacterial analysis are increasing, studies of FCM related to human cells still vastly outnumber other reports. However, current advances in FCM combined with a new generation of cellular reporter probes have made this technique suitable for analyzing physiological responses in bacteria. We review how FCM has been applied to characterize distinct physiological conditions in bacteria including responses to antibiotics and other cytotoxic chemicals and physical factors, pathogen-host interactions, cell differentiation during biofilm formation, and the mechanisms governing development pathways such as sporulation. Since FCM is suitable for performing studies at the single-cell level, we describe how this powerful technique has yielded invaluable information about the heterogeneous distribution of differently and even specialized responding cells and how it may help to provide insights about how cell interaction takes place in complex structures, such as those that prevail in bacterial biofilms. PMID- 25276792 TI - Cytotoxicity of probiotics from Philippine commercial dairy products on cancer cells and the effect on expression of cfos and cjun early apoptotic-promoting genes and Interleukin-1 beta and Tumor Necrosis Factor-alpha proinflammatory cytokine genes. AB - This study determined cytotoxicity of probiotic Lactobacillus spp. from Philippine dairy products on cancer cells and normal fibroblasts and their effects on expression of early apoptotic-promoting cfos, cjun and proinflammatory cytokine IL-1beta, TNF-alpha genes. Cultures were from Yakult, Bear Brand Probiotic Drink, Nido3+ Powdered Milk. Filter-sterilized supernatants from cultures of Lactobacillus spp. were evaluated for cytotoxicity to colon cancer cells (HT-29 and HCT116), leukemia cells (THP-1), and normal human dermal fibroblasts (HDFn) using PrestoBlue. Bleomycin was the positive control. Absolute quantification of transcript levels was conducted using qRT-PCR. Cytotoxicity index profiles on HDFn, THP-1 of all probiotic supernatants and negative controls suggest nontoxicity to the cells when compared to bleomycin, whereas all probiotic supernatants were found to be cytotoxic to HT-29 and HCT-116 colon cancer cell lines. Expression of cfos, cjun transcripts was significantly upregulated in HT-29 and HCT116 cells treated with probiotic supernatants compared to untreated baseline levels (P < 0.05). Expression of IL-1beta and TNF alpha by lipopolysaccharide-treated macrophages was significantly downregulated in cells with probiotic supernatants compared to those exposed to MRS medium (P < 0.05). Results provide strong support for the role of Lactobacillus spp. studied in anticancer therapy and in prevention of inflammation that may act as precursor to carcinogenesis. PMID- 25276793 TI - Clinical evaluation of the regenerative potential of EMD and NanoHA in periodontal infrabony defects: a 2-year follow-up. AB - INTRODUCTION: The aim of this retrospective study was to compare the clinical efficacy of four different surgical techniques in promoting periodontal regeneration in patients with infrabony defects: open flap debridement, application of enamel matrix derivatives (EMD), nanohydroxyapatite (nanoHA) application, and combined nanoHA and EMD application. Probing attachment level (PAL), pocket depth (PD), and position of gingival margin at completion of therapy (REC) were measured. MATERIALS AND METHODS: Data were collected from 64 healthy patients (34 women and 30 men, mean age 37,7 years). Clinical indices were measured by a calibrated examiner at baseline and at 12, 18, and 24 months. The values obtained for each treatment were compared using nonparametric tests. RESULTS: All treatments resulted in a tendency toward PD reduction over time, with improvements in REC and PAL. The differences in PD, REC, and PAL values at baseline compared with values after 12, 18, and 24 months were statistically significant for all treatments. Statistically significant differences in PAL and PD were detected between nanoHA and nanoHA + EMD at 12, 18, and 24 months. CONCLUSION: In this study, EMD and nanoHA used together in patients with infrabony periodontal lesions had better clinical efficacy than nanoHA alone, EMD alone, or open flap debridement. PMID- 25276797 TI - Security mechanism based on Hospital Authentication Server for secure application of implantable medical devices. AB - After two recent security attacks against implantable medical devices (IMDs) have been reported, the privacy and security risks of IMDs have been widely recognized in the medical device market and research community, since the malfunctioning of IMDs might endanger the patient's life. During the last few years, a lot of researches have been carried out to address the security-related issues of IMDs, including privacy, safety, and accessibility issues. A physician accesses IMD through an external device called a programmer, for diagnosis and treatment. Hence, cryptographic key management between IMD and programmer is important to enforce a strict access control. In this paper, a new security architecture for the security of IMDs is proposed, based on a 3-Tier security model, where the programmer interacts with a Hospital Authentication Server, to get permissions to access IMDs. The proposed security architecture greatly simplifies the key management between IMDs and programmers. Also proposed is a security mechanism to guarantee the authenticity of the patient data collected from IMD and the nonrepudiation of the physician's treatment based on it. The proposed architecture and mechanism are analyzed and compared with several previous works, in terms of security and performance. PMID- 25276794 TI - The purinergic system and glial cells: emerging costars in nociception. AB - It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel "druggable" glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states. PMID- 25276796 TI - A participatory approach to develop the Power Mobility Screening Tool and the Power Mobility Clinical Driving Assessment tool. AB - The electric powered wheelchair (EPW) is an indispensable assistive device that increases participation among individuals with disabilities. However, due to lack of standardized assessment tools, developing evidence based training protocols for EPW users to improve driving skills has been a challenge. In this study, we adopt the principles of participatory research and employ qualitative methods to develop the Power Mobility Screening Tool (PMST) and Power Mobility Clinical Driving Assessment (PMCDA). Qualitative data from professional experts and expert EPW users who participated in a focus group and a discussion forum were used to establish content validity of the PMCDA and the PMST. These tools collectively could assess a user's current level of bodily function and their current EPW driving capacity. Further multicenter studies are necessary to evaluate the psychometric properties of these tests and develop EPW driving training protocols based on these assessment tools. PMID- 25276795 TI - Patched targeting peptides for imaging and treatment of hedgehog positive breast tumors. AB - High tumor hedgehog expression is correlated with poor prognosis in invasive ductal carcinoma. Peptides which bind the patched receptor have recently been reported to have a growth inhibitory effect in tumors with activated hedgehog signaling. We sought to examine growth inhibition with these peptides in breast cancer cells and use these peptides as molecular imaging probes to follow changes in hedgehog expression after chemotherapy. Significant growth inhibition was observed in breast cancer cell lines treated with PTCH-blocking peptides. Significant in vitro uptake was observed with both FITC- and (99m)Tc-EC-peptide conjugates. In vivo imaging studies displayed greater accumulation of (99m)Tc labeled peptides within tumors as compared to adjacent muscle tissue. Patched receptor expression increased after treatment and this correlated with an increase in tumor radiotracer uptake. These studies suggest that peptides which bind the sonic hedgehog docking site in patched receptor correlate with patched expression and can be used to image patched in vivo. Further, our data suggest that radiolabeled peptides may enable us to examine the activity of the hedgehog signaling pathway and to evaluate response to anti-cancer therapies. PMID- 25276798 TI - Acute toxicity study of zerumbone-loaded nanostructured lipid carrier on BALB/c mice model. AB - Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration. PMID- 25276799 TI - Timing of peripheral blood stem cell yield: comparison of alternative methods with the classic method for CD34+ cell determination. AB - Hematopoietic stem cells (HSCs), still represent a certain mystery in biology, have a unique property of dividing into equal cells and repopulating the hematopoietic tissue. This potential enables their use in transplantation treatments. The quality of the HSC grafts for transplantation is evaluated by flow cytometric determination of the CD34(+) cells, which enables optimal timing of the first apheresis and the acquisition of maximal yield of the peripheral blood stem cells (PBSCs). To identify a more efficient method for evaluating CD34(+) cells, we compared the following alternative methods with the reference method: hematopoietic progenitor cells (HPC) enumeration (using the Sysmex XE 2100 analyser), detection of CD133(+) cells, and quantification of aldehyde dehydrogenase activity in the PBSCs. 266 aphereses (84 patients) were evaluated. In the preapheretic blood, the new methods produced data that were in agreement with the reference method. The ROC curves have shown that for the first-day apheresis target, the optimal predictive cut-off value was 0.032 cells/mL for the HPC method (sensitivity 73.4%, specificity 69.3%). HPC method exhibited a definite practical superiority as compared to other methods tested. HPC enumeration could serve as a supplementary method for the optimal timing of the first apheresis; it is simple, rapid, and cheap. PMID- 25276801 TI - Determining the best treatment for coronal angular deformity of the knee joint in growing children: a decision analysis. AB - This study aimed to determine the best treatment modality for coronal angular deformity of the knee joint in growing children using decision analysis. A decision tree was created to evaluate 3 treatment modalities for coronal angular deformity in growing children: temporary hemiepiphysiodesis using staples, percutaneous screws, or a tension band plate. A decision analysis model was constructed containing the final outcome score, probability of metal failure, and incomplete correction of deformity. The final outcome was defined as health related quality of life and was used as a utility in the decision tree. The probabilities associated with each case were obtained by literature review, and health-related quality of life was evaluated by a questionnaire completed by 25 pediatric orthopedic experts. Our decision analysis model favored temporary hemiepiphysiodesis using a tension band plate over temporary hemiepiphysiodesis using percutaneous screws or stapling, with utilities of 0.969, 0.957, and 0.962, respectively. One-way sensitivity analysis showed that hemiepiphysiodesis using a tension band plate was better than temporary hemiepiphysiodesis using percutaneous screws, when the overall complication rate of hemiepiphysiodesis using a tension band plate was lower than 15.7%. Two-way sensitivity analysis showed that hemiepiphysiodesis using a tension band plate was more beneficial than temporary hemiepiphysiodesis using percutaneous screws. PMID- 25276800 TI - Structural comparison, substrate specificity, and inhibitor binding of AGPase small subunit from monocot and dicot: present insight and future potential. AB - ADP-glucose pyrophosphorylase (AGPase) is the first rate limiting enzyme of starch biosynthesis pathway and has been exploited as the target for greater starch yield in several plants. The structure-function analysis and substrate binding specificity of AGPase have provided enormous potential for understanding the role of specific amino acid or motifs responsible for allosteric regulation and catalytic mechanisms, which facilitate the engineering of AGPases. We report the three-dimensional structure, substrate, and inhibitor binding specificity of AGPase small subunit from different monocot and dicot crop plants. Both monocot and dicot subunits were found to exploit similar interactions with the substrate and inhibitor molecule as in the case of their closest homologue potato tuber AGPase small subunit. Comparative sequence and structural analysis followed by molecular docking and electrostatic surface potential analysis reveal that rearrangements of secondary structure elements, substrate, and inhibitor binding residues are strongly conserved and follow common folding pattern and orientation within monocot and dicot displaying a similar mode of allosteric regulation and catalytic mechanism. The results from this study along with site-directed mutagenesis complemented by molecular dynamics simulation will shed more light on increasing the starch content of crop plants to ensure the food security worldwide. PMID- 25276802 TI - Effect of wheelchair frame material on users' mechanical work and transmitted vibration. AB - Wheelchair propulsion exposes the user to a high risk of shoulder injury and to whole-body vibration that exceeds recommendations of ISO 2631-1:1997. Reducing the mechanical work required to travel a given distance (WN-WPM, weight normalized work-per-meter) can help reduce the risk of shoulder injury, while reducing the vibration transmissibility (VT) of the wheelchair frame can reduce whole-body vibration. New materials such as titanium and carbon are used in today's wheelchairs and are advertised to improve both parameters, but current knowledge on this matter is limited. In this study, WN-WPM and VT were measured simultaneously and compared between six folding wheelchairs (1 titanium, 1 carbon, and 4 aluminium). Ten able-bodied users propelled the six wheelchairs on three ground surfaces. Although no significant difference of WN-WPM was found between wheelchairs (P < 0.1), significant differences of VT were found (P < 0.05). The carbon wheelchair had the lowest VT. Contrarily to current belief, the titanium wheelchair VT was similar to aluminium wheelchairs. A negative correlation between VT and WN-WPM was found, which means that reducing VT may be at the expense of increasing WN-WPM. Based on our results, use of carbon in wheelchair construction seems promising to reduce VT without increasing WN-WPM. PMID- 25276803 TI - Unconventional use of intense pulsed light. AB - According to the literature, intense pulsed light (IPL) represents a versatile tool in the treatment of some dermatological conditions (i.e., pigmentation disorders, hair removal, and acne), due to its wide range of wavelengths. The authors herein report on 58 unconventional but effective uses of IPL in several cutaneous diseases, such as rosacea (10 cases), port-wine stain (PWS) (10 cases), disseminated porokeratosis (10 cases), pilonidal cyst (3 cases), seborrheic keratosis (10 cases), hypertrophic scar (5 cases) and keloid scar (5 cases), Becker's nevus (2 cases), hidradenitis suppurativa (2 cases), and sarcoidosis (1 case). Our results should suggest that IPL could represent a valid therapeutic support and option by providing excellent outcomes and low side effects, even though it should be underlined that the use and the effectiveness of IPL are strongly related to the operator's experience (acquired by attempting at least one specific course on the use of IPL and one-year experience in a specialized centre). Moreover, the daily use of these devices will surely increase clinical experience and provide new information, thus enhancing long-term results and improving IPL effectiveness. PMID- 25276804 TI - Craniofacial and cervical morphology related to sagittal spinal posture in children and adolescents. AB - Studies on the relationship between body posture and craniofacial parameters often focus on the cervical spine. Thus, less attention has been paid to the morphology of the vertebra C2 that serves as both a structural and functional link between the craniofacial area and the other part of the spine. The objective of this study was to assess the relation of craniofacial features to certain morphological and positional characteristics of the cervical vertebrae and the spine during growth. We determined body posture indices for 69 children and adolescents by means of a radiation-free method (rasterstereography). The morphological and positional analysis of the craniofacial area and the cervical vertebrae was based on standardized lateral X-ray cephalograms. Medium to strong correlations were found between body posture, C2 morphology, and craniofacial parameters. We found significant correlations between the C2 dens axis height and maxillary indices as well as between the C2 dens axis inclination and cephalometrical values of the mandibular area. Similarly the correlation between the C2 dens axis inclination and the postural index fleche cervicale was highly significant (P < 0.05, r = 0.333). These results suggest that morphological features of the odontoid process may serve as valuable predictive markers in interdisciplinary orthopedic-orthodontic diagnostics. PMID- 25276805 TI - Saccharin sulfonamides as inhibitors of carbonic anhydrases I, II, VII, XII, and XIII. AB - A series of modified saccharin sulfonamides have been designed as carbonic anhydrase (CA) inhibitors and synthesized. Their binding to CA isoforms I, II, VII, XII, and XIII was measured by the fluorescent thermal shift assay (FTSA) and isothermal titration calorimetry (ITC). Saccharin bound the CAs weakly, exhibiting the affinities of 1-10 mM for four CAs except CA I where binding could not be detected. Several sulfonamide-bearing saccharines exhibited strong affinities of 1-10 nM towards particular CA isoforms. The functional group binding Gibbs free energy additivity maps are presented which may provide insights into the design of compounds with increased affinity towards selected CAs. PMID- 25276807 TI - Cerebral vasospasm after aneurysmal subarachnoid hemorrhage: mechanism and therapies. PMID- 25276806 TI - The characteristics of ubiquitous and unique Leptospira strains from the collection of Russian centre for leptospirosis. AB - BACKGROUND AND AIM: Leptospira, the causal agent of leptospirosis, has been isolated from the environment, patients, and wide spectrum of animals in Russia. However, the genetic diversity of Leptospira in natural and anthropurgic foci was not clearly defined. METHODS: The recent MLST scheme was used for the analysis of seven pathogenic species. 454 pyrosequencing technology was the base of the whole genome sequencing (WGS). RESULTS: The most wide spread and prevalent Leptospira species in Russia were L. interrogans, L. kirschneri, and L. borgpetersenii. Five STs, common for Russian strains: 37, 17, 199, 110, and 146, were identified as having a longtime and ubiquitous distribution in various geographic areas. Unexpected properties were revealed for the environmental Leptospira strain Bairam-Ali. WGS of this strain genome suggested that it combined the features of the pathogenic and nonpathogenic strains and may be a reservoir of the natural resistance genes. Results of the comparative analysis of rrs and rpoB genes and MLST loci for different Leptospira species strains and phenotypic and serological properties of the strain Bairam-Ali suggested that it represented separate Leptospira species. CONCLUSIONS: Thus, the natural and anthropurgic foci supported ubiquitous Leptospira species and the pool of genes important for bacterial adaptivity to various conditions. PMID- 25276808 TI - Dynamic contact angle analysis of protein adsorption on polysaccharide multilayer's films for biomaterial reendothelialization. AB - Atherosclerosis is a major cardiovascular disease. One of the side effects is restenosis. The aim of this work was to study the coating of stents by dextran derivates based polyelectrolyte's multilayer (PEM) films in order to increase endothelialization of injured arterial wall after stent implantation. Films were composed with diethylaminoethyl dextran (DEAE) as polycation and dextran sulphate (DS) as polyanion. One film was composed with 4 bilayers of (DEAE-DS)4 and was labeled D-. The other film was the same as D- but with an added terminal layer of DEAE polycation: (DEAE-DS)4-DEAE (labeled D+). The dynamic adsorption/desorption of proteins on the films were characterized by dynamic contact angle (DCA) and atomic force microscopy (AFM). Human endothelial cell (HUVEC) adhesion and proliferation were quantified and correlated to protein adsorption analyzed by DCA for fibronectin, vitronectin, and bovine serum albumin (BSA). Our results showed that the endothelial cell response was optimal for films composed of DS as external layer. Fibronectin was found to be the only protein to exhibit a reversible change in conformation after desorption test. This behavior was only observed for (DEAE-DS)4 films. (DEAE-DS)4 films could enhance HUVEC proliferation in agreement with fibronectin ability to easily change from conformation. PMID- 25276809 TI - Combating kidney fibrosis. PMID- 25276810 TI - Design of CGMP production of 18F- and 68Ga-radiopharmaceuticals. AB - OBJECTIVE: Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals. METHODS: The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for (68)Ga-DOTATATE and (18)F FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of (68)Ga-DOTATATE and (18)F-FDG were established. RESULTS: CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of (68)Ga-DOTATATE and (18)F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free. CONCLUSION: CGMP compliance of radiopharmaceuticals has been reviewed. (68)Ga-DOTATATE and (18)F-FDG were synthesized with high radiochemical yield under CGMP process. PMID- 25276813 TI - Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. AB - Unlike other tissues in the body, peripheral nerve regeneration is slow and usually incomplete. Less than half of patients who undergo nerve repair after injury regain good to excellent motor or sensory function and current surgical techniques are similar to those described by Sunderland more than 60 years ago. Our increasing knowledge about nerve physiology and regeneration far outweighs our surgical abilities to reconstruct damaged nerves and successfully regenerate motor and sensory function. It is technically possible to reconstruct nerves at the fascicular level but not at the level of individual axons. Recent surgical options including nerve transfers demonstrate promise in improving outcomes for proximal nerve injuries and experimental molecular and bioengineering strategies are being developed to overcome biological roadblocks limiting patient recovery. PMID- 25276812 TI - Alterations in the anandamide metabolism in the development of neuropathic pain. AB - Endocannabinoids (EC), particularly anandamide (AEA), released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs) and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI). All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development. PMID- 25276814 TI - Hyaluronan-phosphatidylethanolamine polymers form pericellular coats on keratinocytes and promote basal keratinocyte proliferation. AB - Aged keratinocytes have diminished proliferative capacity and hyaluronan (HA) cell coats, which are losses that contribute to atrophic skin characterized by reduced barrier and repair functions. We formulated HA-phospholipid (phosphatidylethanolamine, HA-PE) polymers that form pericellular coats around cultured dermal fibroblasts independently of CD44 or RHAMM display. We investigated the ability of these HA-PE polymers to penetrate into aged mouse skin and restore epidermal function in vivo. Topically applied Alexa(647)-HA-PE penetrated into the epidermis and dermis, where it associated with both keratinocytes and fibroblasts. In contrast, Alexa(647)-HA was largely retained in the outer cornified layer of the epidermis and quantification of fluorescence confirmed that significantly more Alexa(647)-HA-PE penetrated into and was retained within the epidermis than Alexa(647)-HA. Multiple topical applications of HA-PE to shaved mouse skin significantly stimulated basal keratinocyte proliferation and epidermal thickness compared to HA or vehicle cream alone. HA PE had no detectable effect on keratinocyte differentiation and did not promote local or systemic inflammation. These effects of HA-PE polymers are similar to those reported for endogenous epidermal HA in youthful skin and show that topical application of HA-PE polymers can restore some of the impaired functions of aged epidermis. PMID- 25276816 TI - Hyperautofluorescence in outer retinal layers thinning. AB - PURPOSE: To evaluate if paracentral hyperautofluorescence (HAF) retinal regions, which can be occasionally found and analyzed by optical coherence tomography (OCT), were related to retinal layer changes and to detect which layer was involved. METHODS: This is a cross-sectional and retrospective study. 648 OCT files were revised. OCTs that showed a paracentral HAF area by using the fundus autofluorescence imaging in Heidelberg Spectralis (Heidelberg Engineering, Germany) were selected. Then retinal layer morphology was analyzed observing OCT scans and a retinal thickness was measured. RESULTS: 31 patients were selected: 20 patients had chronic serous epitheliopathy (CSE), 8 patients had resolved central serous chorioretinopathy (CSC), and 3 patients wet age related macular degeneration (ARMD). The HAF zones corresponded to areas of thickness reduction of the external hyporeflective band. In all these areas the retinal pigment epithelium was not atrophic and the neuroepithelium was more or less dystrophic. In particular the retinal thickness was 264 um, 232 um, and 243 um in wet ARMD, CSE, and CSC, respectively; the reduction was significant (P < 0.01) compared to the same area of the other eye. DISCUSSION: The presence of HAF imaging might be mostly due to a "window effect" rather than an accumulation of lipofuscin. PMID- 25276815 TI - Silencing of plasma membrane Ca2+-ATPase isoforms 2 and 3 impairs energy metabolism in differentiating PC12 cells. AB - A close link between Ca(2+), ATP level, and neurogenesis is apparent; however, the molecular mechanisms of this relationship have not been completely elucidated. Transient elevations of cytosolic Ca(2+) may boost ATP synthesis, but ATP is also consumed by ion pumps to maintain a low Ca(2+) in cytosol. In differentiation process plasma membrane Ca(2+) ATPase (PMCA) is considered as one of the major players for Ca(2+) homeostasis. From four PMCA isoforms, the fastest PMCA2 and PMCA3 are expressed predominantly in excitable cells. In the present study we assessed whether PMCA isoform composition may affect energy balance in differentiating PC12 cells. We found that PMCA2-downregulated cells showed higher basal O2 consumption, lower NAD(P)H level, and increased activity of ETC. These changes associated with higher [Ca(2+)]c resulted in elevated ATP level. Since PMCA2-reduced cells demonstrated greatest sensitivity to ETC inhibition, we suppose that the main source of energy for PMCA isoforms 1, 3, and 4 was oxidative phosphorylation. Contrary, cells with unchanged PMCA2 expression exhibited prevalence of glycolysis in ATP generation. Our results with PMCA2- or PMCA3-downregulated lines provide an evidence of a novel role of PMCA isoforms in regulation of bioenergetic pathways, and mitochondrial activity and maintenance of ATP level during PC12 cells differentiation. PMID- 25276817 TI - Minocycline enhances the effectiveness of nociceptin/orphanin FQ during neuropathic pain. AB - Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5 5 MUg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [(35)S]GTPgammaS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain. PMID- 25276818 TI - Pollution status of Pakistan: a retrospective review on heavy metal contamination of water, soil, and vegetables. AB - Trace heavy metals, such as arsenic, cadmium, lead, chromium, nickel, and mercury, are important environmental pollutants, particularly in areas with high anthropogenic pressure. In addition to these metals, copper, manganese, iron, and zinc are also important trace micronutrients. The presence of trace heavy metals in the atmosphere, soil, and water can cause serious problems to all organisms, and the ubiquitous bioavailability of these heavy metal can result in bioaccumulation in the food chain which especially can be highly dangerous to human health. This study reviews the heavy metal contamination in several areas of Pakistan over the past few years, particularly to assess the heavy metal contamination in water (ground water, surface water, and waste water), soil, sediments, particulate matter, and vegetables. The listed contaminations affect the drinking water quality, ecological environment, and food chain. Moreover, the toxicity induced by contaminated water, soil, and vegetables poses serious threat to human health. PMID- 25276819 TI - Serum metal ion concentrations in paediatric patients following total knee arthroplasty using megaprostheses. AB - The purpose of this study was to determine the concentrations of cobalt, chromium, and molybdenum in the serum of paediatric tumour patients after fixed hinge total knee arthroplasty. Further, these metal ion levels were compared with serum metal ion levels of patients with other orthopaedic devices such as hip and knee prostheses with metal-on-metal or metal-on-polyethylene articulation to find differences between anatomical locations, abrasion characteristics, and bearing surfaces. After an average follow-up of 108 months (range: 67 to 163) of 11 paediatric patients with fixed hinge total knee arthroplasty, the mean concentrations for Co and Cr were significantly increased while Mo was within the limits compared to the upper values from the reference laboratory. Furthermore, these serum concentrations were significantly higher compared to patients with a standard rotating hinge device (P = 0.002 and P < 0.001) and preoperative controls (P < 0.001). On the other hand, the serum levels of patients following MoM THA or rotating hinge arthroplasty using megaprostheses were higher. Therefore, periodic long-term follow-ups are recommended due to the rising concerns about systemic metal ion exposure in the literature. Upon the occurrence of adverse reactions to metal debris the revision of the fixed hinge implant should be considered. PMID- 25276820 TI - Wear behavior of an unstable knee: stabilization via implant design? AB - BACKGROUND: Wear-related failures and instabilities are frequent failure mechanisms of total knee replacements. High-conforming designs may provide additional stability for the joint. This study analyzes the effects of a ligamentous insufficiency on the stability and the wear behavior of a high conforming knee design. METHODS: Two simulator wear tests were performed on a high-conforming total knee replacement design. In the first, a ligamentous-stable knee replacement with a sacrificed anterior cruciate ligament was simulated. In the second, a ligamentous-unstable knee with additionally insufficient posterior cruciate ligament and medial collateral ligament was simulated. Wear was determined gravimetrically and wear particles were analyzed. Implant kinematics was recorded during simulation. RESULTS: Significantly higher wear rates (P <= 0.001) were observed for the unstable knee (14.58 +/- 0.56 mg/10(6) cycles) compared to the stable knee (7.97 +/- 0.87 mg/10(6) cycles). A higher number of wear particles with only small differences in wear particle characteristics were observed. Under unstable knee conditions, kinematics increased significantly for translations and rotations (P <= 0.01). This increase was mainly attributed to higher tibial posterior translation and internal rotations. CONCLUSION: Higher kinematics under unstable test conditions is a result of insufficient stabilization via implant design. Due to the higher kinematics, increased wear was observed in this study. PMID- 25276821 TI - Acknowledged signatures of matrix metalloproteinases in Takayasu's arteritis. AB - Takayasu's arteritis (TA) was reported as an eye disease in the year 1905 and later was confirmed as a vasculitis. Since then, the etiology of the disease remains unknown; however, characteristic clinical features suggest multiple causative factors. Recent progress in vascular biology and other disciplines enlightens the pathophysiology of TA and demonstrated induction of various nonspecific inflammatory symptoms and destruction of the arterial wall, which leads to aneurysms and rupture of the affected arteries. Matrix metalloproteinases (MMPs) as an enzyme family have well-established roles in several vascular pathologies including intima formation, atherosclerosiss and aneurysms. MMPs have been proposed to be one of the molecules with a potential of having dual role in the course of TA, first as an active participant in pathophysiology and secondly as a diagnostic biomarker for TA disease. The desire to improve our understanding of the importance of MMPs and their endogenous inhibitors (TIMPs) in TA disease and for the development of therapeutic agents has inspired basic and clinical scientists for over a decade. In the present paper, we summarized the scientific rationale which highlights the signatures of matrix metalloproteinases and their endogenous inhibitors in pathophysiology as well as their being a potential candidate as biomarker for Takayasu's arteritis. PMID- 25276822 TI - Increased sialylation of anti-Thomsen-Friedenreich antigen (CD176) antibodies in patients with gastric cancer: a diagnostic and prognostic potential. AB - AIM: To study whether alterations in the sialylation of antibodies (Ab) specific to the Thomsen-Friedenreich (TF) glycotope have a diagnostic and prognostic potential in gastric cancer. METHODS: Serum samples were taken from patients with gastric carcinoma (n = 142) and controls (n = 61). The level of TF-specific antibodies and their sialylation was detected using ELISA with synthetic TF polyacrylamide conjugate as antigen and sialic acid-specific Sambucus nigra agglutinin (SNA). RESULTS: The level of TF-specific IgM was significantly decreased in cancer compared with controls (P <= 0.001). Cancer patients showed a higher level of SNA binding to anti-TF IgM and IgA (P <= 0.001) irrespective of disease stage, tumor morphology, and gender. Changes in the SNA/Ab index demonstrated moderate sensitivity (66-71%) and specificity (60-73%) for stomach cancer. The best diagnostic accuracy (100%) was achieved in 29% patients with high SNA binding and low anti-TF IgM level. This subset of patients demonstrated the poorest survival. CONCLUSION: Our findings are the first evidence that the increased sialylation of TF-specific Abs combined with a low level of anti-TF IgM is strongly linked to gastric cancer and patients survival, which can be used as a novel biomarker for cancer detection and prognosis. PMID- 25276823 TI - Gene expression profiling of biological pathway alterations by radiation exposure. AB - Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders. PMID- 25276826 TI - Emerging biomarkers in renal damage. PMID- 25276824 TI - Periodontal responses to augmented corticotomy with collagen membrane application during orthodontic buccal tipping in dogs. AB - This prospective randomized split-mouth study was performed to examine the effects of absorbable collagen membrane (ACM) application in augmented corticotomy using deproteinized bovine bone mineral (DBBM), during orthodontic buccal tipping movement in the dog. After buccal circumscribing corticotomy and DBBM grafting into the decorticated area, flaps were repositioned and sutured on control sides. ACM was overlaid and secured with membrane tacks, on test sides only, and the flaps were repositioned and sutured. Closed coil springs were used to apply 200 g orthodontic force in the buccolingual direction on the second and third premolars, immediately after primary flap closure. The buccal tipping angles were 31.19 +/- 14.60 degrees and 28.12 +/- 11.48 degrees on the control and test sides, respectively. A mean of 79.5 +/- 16.0% of the buccal bone wall was replaced by new bone on the control side, and on the test side 78.9 +/- 19.5% was replaced. ACM application promoted an even bone surface. In conclusion, ACM application in augmented corticotomy using DBBM might stimulate periodontal tissue reestablishment, which is useful for rapid orthodontic treatment or guided bone regeneration. In particular, ACM could control the formation of mesenchymal matrix, facilitating an even bone surface. PMID- 25276825 TI - Characterization of individuals with sacroiliac joint bridging in a skeletal population: analysis of degenerative changes in spinal vertebrae. AB - The aim of this study was to characterize the individuals with sacroiliac joint bridging (SIB) by analyzing the degenerative changes in their whole vertebral column and comparing them with the controls. A total of 291 modern Japanese male skeletons, with an average age at death of 60.8 years, were examined macroscopically. They were divided into two groups: individuals with SIB and those without bridging (Non-SIB). The degenerative changes in their whole vertebral column were evaluated, and marginal osteophyte scores (MOS) of the vertebral bodies and degenerative joint scores in zygapophyseal joints were calculated. SIB was recognized in 30 individuals from a total of 291 males (10.3%). The average of age at death in SIB group was significantly higher than that in Non-SIB group. The values of MOS in the thoracic spines, particularly in the anterior part of the vertebral bodies, were consecutively higher in SIB group than in Non-SIB group. Incidence of fused vertebral bodies intervertebral levels was obviously higher in SIB group than in Non-SIB group. SIB and marginal osteophyte formation in vertebral bodies could coexist in a skeletal population of men. Some systemic factors might act on these degenerative changes simultaneously both in sacroiliac joint and in vertebral column. PMID- 25276827 TI - Systematic expression profiling analysis identifies specific microRNA-gene interactions that may differentiate between active and latent tuberculosis infection. AB - Tuberculosis (TB) is the second most common cause of death from infectious diseases. About 90% of those infected are asymptomatic--the so-called latent TB infections (LTBI), with a 10% lifetime chance of progressing to active TB. To further understand the molecular pathogenesis of TB, several molecular studies have attempted to compare the expression profiles between healthy controls and active TB or LTBI patients. However, the results vary due to diverse genetic backgrounds and study designs and the inherent complexity of the disease process. Thus, developing a sensitive and efficient method for the detection of LTBI is both crucial and challenging. For the present study, we performed a systematic analysis of the gene and microRNA profiles of healthy individuals versus those affected with TB or LTBI. Combined with a series of in silico analysis utilizing publicly available microRNA knowledge bases and published literature data, we have uncovered several microRNA-gene interactions that specifically target both the blood and lungs. Some of these molecular interactions are novel and may serve as potential biomarkers of TB and LTBI, facilitating the development for a more sensitive, efficient, and cost-effective diagnostic assay for TB and LTBI for the Taiwanese population. PMID- 25276828 TI - Successive nonstatistical and statistical approaches for the improved antibiotic activity of rare actinomycete Nonomuraea sp. JAJ18. AB - The selection and optimization of nutritional constituents as well as their levels for the improved production of antibiotic by Nonomuraea sp. JAJ18 were carried out using combination of both nonstatistical one-factor-at-a-time (OFAT) method and statistical response surface methodology (RSM). Using OFAT method, starch and (NH4)2SO4 were identified as suitable carbon and nitrogen sources, respectively. Subsequently, starch, NaCl, and MgSO4 . 7H2O were recognized as the most significant media components with confidence level of above 95% using the Plackett-Burman design. The levels of the three media components were further optimized using RSM employed with Box-Behnken design. Accordingly, a second-order polynomial regression model was fitted into the experimental data. By analyzing the response surface plots as well as using numerical optimization method, the optimal levels for starch, NaCl, and MgSO4 . 7H2O were determined as 15.6 g/L, 0.8 g/L, and 1.98 g/L, respectively. With the optimized medium, 15.5% increase was observed in antibiotic activity of JAJ18. Results further support the use of RSM for media optimization. To the best of our knowledge, this is the first report of statistical media optimization for antibiotic production in rare actinomycete Nonomuraea species, which will be useful for the development of Nonomuraea cultivation process for efficient antibiotic production on a large scale. PMID- 25276829 TI - Human umbilical cord mesenchymal stem cells infected with adenovirus expressing HGF promote regeneration of damaged neuron cells in a Parkinson's disease model. AB - Parkinson's disease (PD) is a neurodegenerative movement disorder that is characterized by the progressive degeneration of the dopaminergic (DA) pathway. Mesenchymal stem cells derived from human umbilical cord (hUC-MSCs) have great potential for developing a therapeutic agent as such. HGF is a multifunctional mediator originally identified in hepatocytes and has recently been reported to possess various neuroprotective properties. This study was designed to investigate the protective effect of hUC-MSCs infected by an adenovirus carrying the HGF gene on the PD cell model induced by MPP+ on human bone marrow neuroblastoma cells. Our results provide evidence that the cultural supernatant from hUC-MSCs expressing HGF could promote regeneration of damaged PD cells at higher efficacy than the supernatant from hUC-MSCs alone. And intracellular free Ca(2+) obviously decreased after treatment with cultural supernatant from hUC MSCs expressing HGF, while the expression of CaBP-D28k, an intracellular calcium binding protein, increased. Therefore our study clearly demonstrated that cultural supernatant of MSC overexpressing HGF was capable of eliciting regeneration of damaged PD model cells. This effect was probably achieved through the regulation of intracellular Ca(2+) levels by modulating of CaBP-D28k expression. PMID- 25276831 TI - Glatiramer acetate and nanny proteins restrict access of the multiple sclerosis autoantigen myelin basic protein to the 26S proteasome. AB - We recently showed that myelin basic protein (MBP) is hydrolyzed by 26S proteasome without ubiquitination. The previously suggested concept of charge mediated interaction between MBP and the proteasome led us to attempt to compensate or mimic its positive charge to inhibit proteasomal degradation. We demonstrated that negatively charged actin and calmodulin (CaM), as well as basic histone H1.3, inhibit MBP hydrolysis by competing with the proteasome and MBP, respectively, for binding their counterpart. Interestingly, glatiramer acetate (GA), which is used to treat multiple sclerosis (MS) and is structurally similar to MBP, inhibits intracellular and in vitro proteasome-mediated MBP degradation. Therefore, the data reported in this study may be important for myelin biogenesis in both the normal state and pathophysiological conditions. PMID- 25276832 TI - Hyperuricemic PRP in tendon cells. AB - Platelet-rich plasma (PRP) is injected within tendons to stimulate healing. Metabolic alterations such as the metabolic syndrome, diabetes, or hyperuricemia could hinder the therapeutic effect of PRP. We hypothesise that tendon cells sense high levels of uric acid and this could modify their response to PRP. Tendon cells were treated with allogeneic PRPs for 96 hours. Hyperuricemic PRP did not hinder the proliferative actions of PRP. The gene expression pattern of inflammatory molecules in response to PRP showed absence of IL-1b and COX1 and modest expression of IL6, IL8, COX2, and TGF-b1. IL8 and IL6 proteins were secreted by tendon cells treated with PRP. The synthesis of IL6 and IL8 proteins induced by PRP is decreased significantly in the presence of hyperuricemia (P = 0.017 and P = 0.012, resp.). Concerning extracellular matrix, PRP-treated tendon cells displayed high type-1 collagen, moderate type-3 collagen, decorin, and hyaluronan synthase-2 expression and modest expression of scleraxis. Hyperuricemia modified the expression pattern of extracellular matrix proteins, upregulating COL1 (P = 0.036) and COMP (P = 0.012) and downregulating HAS2 (P = 0.012). Positive correlations between TGF-b1 and type-1 collagen (R = 0.905, P = 0.002) and aggrecan (R = 0.833, P = 0.010) and negative correlations between TGF b1 and IL6 synthesis (R = -0.857, P = 0.007) and COX2 (R = -0.810, P = 0.015) were found. PMID- 25276830 TI - Helminth parasites alter protection against Plasmodium infection. AB - More than one-third of the world's population is infected with one or more helminthic parasites. Helminth infections are prevalent throughout tropical and subtropical regions where malaria pathogens are transmitted. Malaria is the most widespread and deadliest parasitic disease. The severity of the disease is strongly related to parasite density and the host's immune responses. Furthermore, coinfections between both parasites occur frequently. However, little is known regarding how concomitant infection with helminths and Plasmodium affects the host's immune response. Helminthic infections are frequently massive, chronic, and strong inductors of a Th2-type response. This implies that infection by such parasites could alter the host's susceptibility to subsequent infections by Plasmodium. There are a number of reports on the interactions between helminths and Plasmodium; in some, the burden of Plasmodium parasites increased, but others reported a reduction in the parasite. This review focuses on explaining many of these discrepancies regarding helminth-Plasmodium coinfections in terms of the effects that helminths have on the immune system. In particular, it focuses on helminth-induced immunosuppression and the effects of cytokines controlling polarization toward the Th1 or Th2 arms of the immune response. PMID- 25276833 TI - Spine curvature analysis between participants with obesity and normal weight participants: a biplanar electromagnetic device measurement. AB - To analyse and compare standing thoracolumbar curves in normal weight participants and participants with obesity, using an electromagnetic device, and to analyse the measurement reliability. MATERIAL AND METHODS: Cross-sectional study was carried out. 36 individuals were divided into two groups (normal-weight and participants with obesity) according to their waist circumference. The reference points (T1-T8-L1-L5 and both posterior superior iliac spines) were used to perform a description of thoracolumbar curvature in the sagittal and coronal planes. A transformation from the global coordinate system was performed and thoracolumbar curves were adjusted by fifth-order polynomial equations. The tangents of the first and fifth lumbar vertebrae and the first thoracic vertebra were determined from their derivatives. The reliability of the measurement was assessed according to the internal consistency of the measure and the thoracolumbar curvature angles were compared between groups. RESULTS: Cronbach's alpha values ranged between 0.824 (95% CI: 0.776-0.847) and 0.918 (95% CI: 0.903 0.949). In the coronal plane, no significant differences were found between groups; however, in sagittal plane, significant differences were observed for thoracic kyphosis. CONCLUSION: There were significant differences in thoracic kyphosis in the sagittal plane between two groups of young adults grouped according to their waist circumference. PMID- 25276834 TI - In vitro bioactivity and antimicrobial tuning of bioactive glass nanoparticles added with neem (Azadirachta indica) leaf powder. AB - Silica and phosphate based bioactive glass nanoparticles (58SiO2-33CaO-9P2O5) with doping of neem (Azadirachta indica) leaf powder and silver nanoparticles were prepared and characterised. Bioactive glass nanoparticles were produced using sol-gel technique. In vitro bioactivity of the prepared samples was investigated using simulated body fluid. X-ray diffraction (XRD) pattern of prepared glass particles reveals amorphous phase and spherical morphology with a particle size of less than 50 nm. When compared to neem doped glass, better bioactivity was attained in silver doped glass through formation of hydroxyapatite layer on the surface, which was confirmed through XRD, Fourier transform infrared (FTIR), and scanning electron microscopy (SEM) analysis. However, neem leaf powder doped bioactive glass nanoparticles show good antimicrobial activity against Staphylococcus aureus and Escherichia coli and less bioactivity compared with silver doped glass particles. In addition, the biocompatibility of the prepared nanocomposites reveals better results for neem doped and silver doped glasses at lower concentration. Therefore, neem doped bioactive glass may act as a potent antimicrobial agent for preventing microbial infection in tissue engineering applications. PMID- 25276836 TI - Female aging alters expression of human cumulus cells genes that are essential for oocyte quality. AB - Impact of female aging is an important issue in human reproduction. There was a need for an extensive analysis of age impact on transcriptome profile of cumulus cells (CCs) to link oocyte quality and developmental potential with patient's age. CCs from patients of three age groups were analyzed individually using microarrays. RT-qPCR validation was performed on independent CC cohorts. We focused here on pathways affected by aging in CCs that may explain the decline of oocyte quality with age. In CCs collected from patients >37 years, angiogenic genes including ANGPTL4, LEPR, TGFBR3, and FGF2 were significantly overexpressed compared to patients of the two younger groups. In contrast genes implicated in TGF-beta signaling pathway such as AMH, TGFB1, inhibin, and activin receptor were underexpressed. CCs from patients whose ages are between 31 and 36 years showed an overexpression of genes related to insulin signaling pathway such as IGFBP3, PIK3R1, and IGFBP5. A bioinformatic analysis was performed to identify the microRNAs that are potential regulators of the differentially expressed genes of the study. It revealed that the pathways impacted by age were potential targets of specific miRNAs previously identified in our CCs small RNAs sequencing. PMID- 25276835 TI - Saliva-based biosensors: noninvasive monitoring tool for clinical diagnostics. AB - Saliva is increasingly recognised as an attractive diagnostic fluid. The presence of various disease signalling salivary biomarkers that accurately reflect normal and disease states in humans and the sampling benefits compared to blood sampling are some of the reasons for this recognition. This explains the burgeoning research field in assay developments and technological advancements for the detection of various salivary biomarkers to improve clinical diagnosis, management, and treatment. This paper reviews the significance of salivary biomarkers for clinical diagnosis and therapeutic applications, with focus on the technologies and biosensing platforms that have been reported for screening these biomarkers. PMID- 25276837 TI - Computational biophysical, biochemical, and evolutionary signature of human R spondin family proteins, the member of canonical Wnt/beta-catenin signaling pathway. AB - In human, Wnt/beta-catenin signaling pathway plays a significant role in cell growth, cell development, and disease pathogenesis. Four human (Rspo)s are known to activate canonical Wnt/beta-catenin signaling pathway. Presently, (Rspo)s serve as therapeutic target for several human diseases. Henceforth, basic understanding about the molecular properties of (Rspo)s is essential. We approached this issue by interpreting the biochemical and biophysical properties along with molecular evolution of (Rspo)s thorough computational algorithm methods. Our analysis shows that signal peptide length is roughly similar in (Rspo)s family along with similarity in aa distribution pattern. In Rspo3, four N glycosylation sites were noted. All members are hydrophilic in nature and showed alike GRAVY values, approximately. Conversely, Rspo3 contains the maximum positively charged residues while Rspo4 includes the lowest. Four highly aligned blocks were recorded through Gblocks. Phylogenetic analysis shows Rspo4 is being rooted with Rspo2 and similarly Rspo3 and Rspo1 have the common point of origin. Through phylogenomics study, we developed a phylogenetic tree of sixty proteins (n = 60) with the orthologs and paralogs seed sequences. Protein-protein network was also illustrated. Results demonstrated in our study may help the future researchers to unfold significant physiological and therapeutic properties of (Rspo)s in various disease models. PMID- 25276839 TI - Remote dose-dependent effects of dry needling at distant myofascial trigger spots of rabbit skeletal muscles on reduction of substance P levels of proximal muscle and spinal cords. AB - BACKGROUND: Dry needling at distant myofascial trigger points is an effective pain management in patients with myofascial pain. However, the biochemical effects of remote dry needling are not well understood. This study evaluates the remote effects of dry needling with different dosages on the expressions of substance P (SP) in the proximal muscle, spinal dorsal horns of rabbits. METHODS: Male New Zealand rabbits (2.5-3.0 kg) received dry needling at myofascial trigger spots of a gastrocnemius (distant muscle) in one (1D) or five sessions (5D). Bilateral biceps femoris (proximal muscles) and superficial laminaes of L5-S2, T2 T5, and C2-C5 were sampled immediately and 5 days after dry needling to determine the levels of SP using immunohistochemistry and western blot. RESULTS: Immediately after dry needling for 1D and 5D, the expressions of SP were significantly decreased in ipsilateral biceps femoris and bilateral spinal superficial laminaes (P < .05). Five days after dry needling, these reduced immunoactivities of SP were found only in animals receiving 5D dry needling (P < .05). CONCLUSIONS: This remote effect of dry needling involves the reduction of SP levels in proximal muscle and spinal superficial laminaes, which may be closely associated with the control of myofascial pain. PMID- 25276838 TI - From bench to bedside: immunotherapy for prostate cancer. AB - The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided. PMID- 25276840 TI - A simple method for establishing adherent ex vivo explant cultures from human eye pathologies for use in subsequent calcium imaging and inflammatory studies. AB - A novel, simple, and reproducible method for cultivating pathological tissues obtained from human eyes during surgery was developed using viscoelastic material as a tissue adherent to facilitate cell attachment and expansion and calcium imaging of cultured cells challenged by mechanical and acetylcholine (ACh) stimulation as well as inflammatory studies. Anterior lens capsule-lens epithelial cells (aLC-LECs) from cataract surgery and proliferative diabetic retinopathy (PDR) fibrovascular epiretinal membranes (fvERMs) from human eyes were used in the study. We hereby show calcium signaling in aLC-LECs by mechanical and acetylcholine (ACh) stimulation and indicate presence of ACh receptors in these cells. Furthermore, an ex vivo study model was established for measuring the inflammatory response in fvERMs and aLC-LECs upon TNFalpha treatment. PMID- 25276843 TI - On a new three-step class of methods and its acceleration for nonlinear equations. AB - A class of derivative-free methods without memory for approximating a simple zero of a nonlinear equation is presented. The proposed class uses four function evaluations per iteration with convergence order eight. Therefore, it is an optimal three-step scheme without memory based on Kung-Traub conjecture. Moreover, the proposed class has an accelerator parameter with the property that it can increase the convergence rate from eight to twelve without any new functional evaluations. Thus, we construct a with memory method that increases considerably efficiency index from 8(1/4) ~ 1.681 to 12(1/4) ~ 1.861. Illustrations are also included to support the underlying theory. PMID- 25276844 TI - A Novel Latin hypercube algorithm via translational propagation. AB - Metamodels have been widely used in engineering design to facilitate analysis and optimization of complex systems that involve computationally expensive simulation programs. The accuracy of metamodels is directly related to the experimental designs used. Optimal Latin hypercube designs are frequently used and have been shown to have good space-filling and projective properties. However, the high cost in constructing them limits their use. In this paper, a methodology for creating novel Latin hypercube designs via translational propagation and successive local enumeration algorithm (TPSLE) is developed without using formal optimization. TPSLE algorithm is based on the inspiration that a near optimal Latin Hypercube design can be constructed by a simple initial block with a few points generated by algorithm SLE as a building block. In fact, TPSLE algorithm offers a balanced trade-off between the efficiency and sampling performance. The proposed algorithm is compared to two existing algorithms and is found to be much more efficient in terms of the computation time and has acceptable space-filling and projective properties. PMID- 25276841 TI - Complement system in pathogenesis of AMD: dual player in degeneration and protection of retinal tissue. AB - Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease. PMID- 25276842 TI - Immunological aspects of acute and recurrent herpes simplex keratitis. AB - Herpes simplex keratitis (HSK) belongs to the major causes of visual morbidity worldwide and available methods of treatment remain unsatisfactory. Primary infection occurs usually early in life and is often asymptomatic. Chronic visual impairment and visual loss are caused by corneal scaring, thinning, and vascularization connected with recurrent HSV infections. The pathogenesis of herpetic keratitis is complex and is still not fully understood. According to the current knowledge, corneal scarring and vascularization are the result of chronic inflammatory reaction against HSV antigens. In this review we discuss the role of innate and adaptive immunities in acute and recurrent HSV ocular infection and present the potential future targets for novel therapeutical options based on immune interventions. PMID- 25276845 TI - The trigonometric polynomial like Bernstein polynomial. AB - A symmetric basis of trigonometric polynomial space is presented. Based on the basis, symmetric trigonometric polynomial approximants like Bernstein polynomials are constructed. Two kinds of nodes are given to show that the trigonometric polynomial sequence is uniformly convergent. The convergence of the derivative of the trigonometric polynomials is shown. Trigonometric quasi-interpolants of reproducing one degree of trigonometric polynomials are constructed. Some interesting properties of the trigonometric polynomials are given. PMID- 25276846 TI - Insights into the prevalence of software project defects. AB - This paper analyses the effect of the effort distribution along the software development lifecycle on the prevalence of software defects. This analysis is based on data that was collected by the International Software Benchmarking Standards Group (ISBSG) on the development of 4,106 software projects. Data mining techniques have been applied to gain a better understanding of the behaviour of the project activities and to identify a link between the effort distribution and the prevalence of software defects. This analysis has been complemented with the use of a hierarchical clustering algorithm with a dissimilarity based on the likelihood ratio statistic, for exploratory purposes. As a result, different behaviours have been identified for this collection of software development projects, allowing for the definition of risk control strategies to diminish the number and impact of the software defects. It is expected that the use of similar estimations might greatly improve the awareness of project managers on the risks at hand. PMID- 25276847 TI - Security enhanced anonymous multiserver authenticated key agreement scheme using smart cards and biometrics. AB - An anonymous user authentication scheme allows a user, who wants to access a remote application server, to achieve mutual authentication and session key establishment with the server in an anonymous manner. To enhance the security of such authentication schemes, recent researches combined user's biometrics with a password. However, these authentication schemes are designed for single server environment. So when a user wants to access different application servers, the user has to register many times. To solve this problem, Chuang and Chen proposed an anonymous multiserver authenticated key agreement scheme using smart cards together with passwords and biometrics. Chuang and Chen claimed that their scheme not only supports multiple servers but also achieves various security requirements. However, we show that this scheme is vulnerable to a masquerade attack, a smart card attack, a user impersonation attack, and a DoS attack and does not achieve perfect forward secrecy. We also propose a security enhanced anonymous multiserver authenticated key agreement scheme which addresses all the weaknesses identified in Chuang and Chen's scheme. PMID- 25276848 TI - Shape optimization of rubber bushing using differential evolution algorithm. AB - The objective of this study is to design rubber bushing at desired level of stiffness characteristics in order to achieve the ride quality of the vehicle. A differential evolution algorithm based approach is developed to optimize the rubber bushing through integrating a finite element code running in batch mode to compute the objective function values for each generation. Two case studies were given to illustrate the application of proposed approach. Optimum shape parameters of 2D bushing model were determined by shape optimization using differential evolution algorithm. PMID- 25276849 TI - Coordinated control of slip ratio for wheeled mobile robots climbing loose sloped terrain. AB - A challenging problem faced by wheeled mobile robots (WMRs) such as planetary rovers traversing loose sloped terrain is the inevitable longitudinal slip suffered by the wheels, which often leads to their deviation from the predetermined trajectory, reduced drive efficiency, and possible failures. This study investigates this problem using terramechanics analysis of the wheel-soil interaction. First, a slope-based wheel-soil interaction terramechanics model is built, and an online slip coordinated algorithm is designed based on the goal of optimal drive efficiency. An equation of state is established using the coordinated slip as the desired input and the actual slip as a state variable. To improve the robustness and adaptability of the control system, an adaptive neural network is designed. Analytical results and those of a simulation using Vortex demonstrate the significantly improved mobile performance of the WMR using the proposed control system. PMID- 25276850 TI - Remarks on residual stress measurement by hole-drilling and electronic speckle pattern interferometry. AB - Hole drilling is the most widespread method for measuring residual stress. It is based on the principle that drilling a hole in the material causes a local stress relaxation; the initial residual stress can be calculated by measuring strain in correspondence with each drill depth. Recently optical techniques were introduced to measure strain; in this case, the accuracy of the final results depends, among other factors, on the proper choice of the area of analysis. Deformations are in fact analyzed within an annulus determined by two parameters: the internal and the external radius. In this paper, the influence of the choice of the area of analysis was analysed. A known stress field was introduced on a Ti grade 5 sample and then the stress was measured in correspondence with different values of the internal and the external radius of analysis; results were finally compared with the expected theoretical value. PMID- 25276851 TI - An order insertion scheduling model of logistics service supply chain considering capacity and time factors. AB - Order insertion often occurs in the scheduling process of logistics service supply chain (LSSC), which disturbs normal time scheduling especially in the environment of mass customization logistics service. This study analyses order similarity coefficient and order insertion operation process and then establishes an order insertion scheduling model of LSSC with service capacity and time factors considered. This model aims to minimize the average unit volume operation cost of logistics service integrator and maximize the average satisfaction degree of functional logistics service providers. In order to verify the viability and effectiveness of our model, a specific example is numerically analyzed. Some interesting conclusions are obtained. First, along with the increase of completion time delay coefficient permitted by customers, the possible inserting order volume first increases and then trends to be stable. Second, supply chain performance reaches the best when the volume of inserting order is equal to the surplus volume of the normal operation capacity in mass service process. Third, the larger the normal operation capacity in mass service process is, the bigger the possible inserting order's volume will be. Moreover, compared to increasing the completion time delay coefficient, improving the normal operation capacity of mass service process is more useful. PMID- 25276852 TI - Rough set approach to incomplete multiscale information system. AB - Multiscale information system is a new knowledge representation system for expressing the knowledge with different levels of granulations. In this paper, by considering the unknown values, which can be seen everywhere in real world applications, the incomplete multiscale information system is firstly investigated. The descriptor technique is employed to construct rough sets at different scales for analyzing the hierarchically structured data. The problem of unravelling decision rules at different scales is also addressed. Finally, the reduct descriptors are formulated to simplify decision rules, which can be derived from different scales. Some numerical examples are employed to substantiate the conceptual arguments. PMID- 25276853 TI - Experimental and numerical studies on wave breaking characteristics over a fringing reef under monochromatic wave conditions. AB - Fringing reefs play an important role in protecting the coastal area by inducing wave breaking and wave energy dissipation. However, modeling of wave transformation and energy dissipation on this topography is still difficult due to the unique structure. In the present study, two-dimensional laboratory experiments were conducted to investigate the cross-shore variations of wave transformation, setup, and breaking phenomena over an idealized fringing reef with the 1/40 reef slope and to verify the Boussinesq model under monochromatic wave conditions. One-layer and two-layer model configurations of the Boussinesq model were used to figure out the model capability. Both models predicted well (r (2) > 0.8) the cross-shore variation of the wave heights, crests, troughs, and setups when the nonlinearity is not too high (A 0/h 0 < 0.07 in this study). However, as the wave nonlinearity and steepness increase, the one-layer model showed problems in prediction and stability due to the error on the vertical profile of fluid velocity. The results in this study revealed that one-layer model is not suitable in the highly nonlinear wave condition over a fringing reef bathymetry. This data set can contribute to the numerical model verification. PMID- 25276854 TI - Measurements of the stiffness and thickness of the pavement asphalt layer using the enhanced resonance search method. AB - Enhanced resonance search (ERS) is a nondestructive testing method that has been created to evaluate the quality of a pavement by means of a special instrument called the pavement integrity scanner (PiScanner). This technique can be used to assess the thickness of the road pavement structure and the profile of shear wave velocity by using the principle of surface wave and body wave propagation. In this study, the ERS technique was used to determine the actual thickness of the asphaltic pavement surface layer, while the shear wave velocities obtained were used to determine its dynamic elastic modulus. A total of fifteen locations were identified and the results were then compared with the specifications of the Malaysian PWD, MDD UKM, and IKRAM. It was found that the value of the elastic modulus of materials is between 3929 MPa and 17726 MPa. A comparison of the average thickness of the samples with the design thickness of MDD UKM showed a difference of 20 to 60%. Thickness of the asphalt surface layer followed the specifications of Malaysian PWD and MDD UKM, while some of the values of stiffness obtained are higher than the standard. PMID- 25276855 TI - A novel vehicle stationary detection utilizing map matching and IMU sensors. AB - Precise navigation is a vital need for many modern vehicular applications. The global positioning system (GPS) cannot provide continuous navigation information in urban areas. The widely used inertial navigation system (INS) can provide full vehicle state at high rates. However, the accuracy diverges quickly in low cost microelectromechanical systems (MEMS) based INS due to bias, drift, noise, and other errors. These errors can be corrected in a stationary state. But detecting stationary state is a challenging task. A novel stationary state detection technique from the variation of acceleration, heading, and pitch and roll of an attitude heading reference system (AHRS) built from the inertial measurement unit (IMU) sensors is proposed. Besides, the map matching (MM) algorithm detects the intersections where the vehicle is likely to stop. Combining these two results, the stationary state is detected with a smaller timing window of 3 s. A longer timing window of 5 s is used when the stationary state is detected only from the AHRS. The experimental results show that the stationary state is correctly identified and the position error is reduced to 90% and outperforms previously reported work. The proposed algorithm would help to reduce INS errors and enhance the performance of the navigation system. PMID- 25276856 TI - Predicting welding distortion in a panel structure with longitudinal stiffeners using inherent deformations obtained by inverse analysis method. AB - Welding-induced deformation not only negatively affects dimension accuracy but also degrades the performance of product. If welding deformation can be accurately predicted beforehand, the predictions will be helpful for finding effective methods to improve manufacturing accuracy. Till now, there are two kinds of finite element method (FEM) which can be used to simulate welding deformation. One is the thermal elastic plastic FEM and the other is elastic FEM based on inherent strain theory. The former only can be used to calculate welding deformation for small or medium scale welded structures due to the limitation of computing speed. On the other hand, the latter is an effective method to estimate the total welding distortion for large and complex welded structures even though it neglects the detailed welding process. When the elastic FEM is used to calculate the welding-induced deformation for a large structure, the inherent deformations in each typical joint should be obtained beforehand. In this paper, a new method based on inverse analysis was proposed to obtain the inherent deformations for weld joints. Through introducing the inherent deformations obtained by the proposed method into the elastic FEM based on inherent strain theory, we predicted the welding deformation of a panel structure with two longitudinal stiffeners. In addition, experiments were carried out to verify the simulation results. PMID- 25276857 TI - Design and development of turbodrill blade used in crystallized section. AB - Turbodrill is a type of hydraulic axial turbomachinery which has a multistage blade consisting of stators and rotors. In this paper, a turbodrill blade that can be applied in crystallized section under high temperature and pressure conditions is developed. On the basis of Euler equations, the law of energy transfer is analyzed and the output characteristics of turbodrill blade are proposed. Moreover, considering the properties of the layer and the bole-hole conditions, the radical size, the geometrical dimension, and the blade profile are optimized. A computational model of a single-stage blade is built on the ANSYS CFD into which the three-dimensional model of turbodrill is input. In light of the distribution law of the pressure and flow field, the functions of the turbodrill blade are improved and optimized. The turbodrill blade optimization model was verified based on laboratory experiments. The results show that the design meets the deep hard rock mineral exploration application and provides good references for further study. PMID- 25276858 TI - Land use/cover change detection and urban sprawl analysis in Bandar Abbas city, Iran. AB - The process of land use change and urban sprawl has been considered as a prominent characteristic of urban development. This study aims to investigate urban growth process in Bandar Abbas city, Iran, focusing on urban sprawl and land use change during 1956-2012. To calculate urban sprawl and land use changes, aerial photos and satellite images are utilized in different time spans. The results demonstrate that urban region area has changed from 403.77 to 4959.59 hectares between 1956 and 2012. Moreover, the population has increased more than 30 times in last six decades. The major part of population growth is related to migration from other parts the country to Bandar Abbas city. Considering the speed of urban sprawl growth rate, the scale and the role of the city have changed from medium and regional to large scale and transregional. Due to natural and structural limitations, more than 80% of barren lands, stone cliffs, beach zone, and agricultural lands are occupied by built-up areas. Our results revealed that the irregular expansion of Bandar Abbas city must be controlled so that sustainable development could be achieved. PMID- 25276859 TI - Global practical tracking by output feedback for nonlinear systems with unknown growth rate and time delay. AB - This paper is the further investigation of work of Yan and Liu, 2011, and considers the global practical tracking problem by output feedback for a class of uncertain nonlinear systems with not only unmeasured states dependent growth but also time-varying time delay. Compared with the closely related works, the remarkableness of the paper is that the time-varying time delay and unmeasurable states are permitted in the system nonlinear growth. Motivated by the related tracking results and flexibly using the ideas and techniques of universal control and dead zone, an adaptive output-feedback tracking controller is explicitly designed with the help of a new Lyapunov-Krasovskii functional, to make the tracking error prescribed arbitrarily small after a finite time while keeping all the closed-loop signals bounded. A numerical example demonstrates the effectiveness of the results. PMID- 25276860 TI - Comparative study on interaction of form and motion processing streams by applying two different classifiers in mechanism for recognition of biological movement. AB - Research on psychophysics, neurophysiology, and functional imaging shows particular representation of biological movements which contains two pathways. The visual perception of biological movements formed through the visual system called dorsal and ventral processing streams. Ventral processing stream is associated with the form information extraction; on the other hand, dorsal processing stream provides motion information. Active basic model (ABM) as hierarchical representation of the human object had revealed novelty in form pathway due to applying Gabor based supervised object recognition method. It creates more biological plausibility along with similarity with original model. Fuzzy inference system is used for motion pattern information in motion pathway creating more robustness in recognition process. Besides, interaction of these paths is intriguing and many studies in various fields considered it. Here, the interaction of the pathways to get more appropriated results has been investigated. Extreme learning machine (ELM) has been implied for classification unit of this model, due to having the main properties of artificial neural networks, but crosses from the difficulty of training time substantially diminished in it. Here, there will be a comparison between two different configurations, interactions using synergetic neural network and ELM, in terms of accuracy and compatibility. PMID- 25276861 TI - Developing a web-based advisory expert system for implementing traffic calming strategies. AB - Lack of traffic safety has become a serious issue in residential areas. In this paper, a web-based advisory expert system for the purpose of applying traffic calming strategies on residential streets is described because there currently lacks a structured framework for the implementation of such strategies. Developing an expert system can assist and advise engineers for dealing with traffic safety problems. This expert system is developed to fill the gap between the traffic safety experts and people who seek to employ traffic calming strategies including decision makers, engineers, and students. In order to build the expert system, examining sources related to traffic calming studies as well as interviewing with domain experts have been carried out. The system includes above 150 rules and 200 images for different types of measures. The system has three main functions including classifying traffic calming measures, prioritizing traffic calming strategies, and presenting solutions for different traffic safety problems. Verifying, validating processes, and comparing the system with similar works have shown that the system is consistent and acceptable for practical uses. Finally, some recommendations for improving the system are presented. PMID- 25276862 TI - Integer-linear-programing optimization in scalable video multicast with adaptive modulation and coding in wireless networks. AB - The advancement in wideband wireless network supports real time services such as IPTV and live video streaming. However, because of the sharing nature of the wireless medium, efficient resource allocation has been studied to achieve a high level of acceptability and proliferation of wireless multimedia. Scalable video coding (SVC) with adaptive modulation and coding (AMC) provides an excellent solution for wireless video streaming. By assigning different modulation and coding schemes (MCSs) to video layers, SVC can provide good video quality to users in good channel conditions and also basic video quality to users in bad channel conditions. For optimal resource allocation, a key issue in applying SVC in the wireless multicast service is how to assign MCSs and the time resources to each SVC layer in the heterogeneous channel condition. We formulate this problem with integer linear programming (ILP) and provide numerical results to show the performance under 802.16 m environment. The result shows that our methodology enhances the overall system throughput compared to an existing algorithm. PMID- 25276863 TI - Provably-secure (Chinese government) SM2 and simplified SM2 key exchange protocols. AB - We revisit the SM2 protocol, which is widely used in Chinese commercial applications and by Chinese government agencies. Although it is by now standard practice for protocol designers to provide security proofs in widely accepted security models in order to assure protocol implementers of their security properties, the SM2 protocol does not have a proof of security. In this paper, we prove the security of the SM2 protocol in the widely accepted indistinguishability-based Bellare-Rogaway model under the elliptic curve discrete logarithm problem (ECDLP) assumption. We also present a simplified and more efficient version of the SM2 protocol with an accompanying security proof. PMID- 25276864 TI - Determine the compressive strength of calcium silicate bricks by combined nondestructive method. AB - The paper deals with the application of combined nondestructive method for assessment of compressive strength of calcium silicate bricks. In this case, it is a combination of the rebound hammer method and ultrasonic pulse method. Calibration relationships for determining compressive strength of calcium silicate bricks obtained from nondestructive parameter testing for the combined method as well as for the L-type Schmidt rebound hammer and ultrasonic pulse method are quoted here. Calibration relationships are known for their close correlation and are applicable in practice. The highest correlation between parameters from nondestructive measurement and predicted compressive strength is obtained using the SonReb combined nondestructive method. Combined nondestructive SonReb method was proved applicable for determination of compressive strength of calcium silicate bricks at checking tests in a production plant and for evaluation of bricks built in existing masonry structures. PMID- 25276865 TI - Modified fractional variational iteration method for solving the generalized time space fractional Schrodinger equation. AB - Based on He's variational iteration method idea, we modified the fractional variational iteration method and applied it to construct some approximate solutions of the generalized time-space fractional Schrodinger equation (GFNLS). The fractional derivatives are described in the sense of Caputo. With the help of symbolic computation, some approximate solutions and their iterative structure of the GFNLS are investigated. Furthermore, the approximate iterative series and numerical results show that the modified fractional variational iteration method is powerful, reliable, and effective when compared with some classic traditional methods such as homotopy analysis method, homotopy perturbation method, adomian decomposition method, and variational iteration method in searching for approximate solutions of the Schrodinger equations. PMID- 25276866 TI - Rituximab-Au nanoprobes for simultaneous dark-field imaging and DAB staining of CD20 over-expressed on Raji cells. AB - A novel dual-modal cell immunodetection method based on both dark-field imaging and catalysis functions of gold nanoparticles has been established, where the Rituximab-Au conjugates were used as nanoprobes to label and image specifically the CD20 overexpressed on the surface of malignant lymphoma cells of Raji with high affinity. PMID- 25276867 TI - Chinese-restaurant syndrome. PMID- 25276868 TI - Risk and liabilities of prescribing compounded medications. AB - Complications resulting from the use of compounded medications have become a troubling trend nationwide. There is a significant potential for patients to suffer serious harm from the use of substandard medications prepared by compounding pharmacies, and the reality of this problem has been demonstrated in several well-publicized incidences of serious medical complications, including patient deaths, that directly resulted from the use of medications prepared at compounding pharmacies. Unlike US Food and Drug Administration (FDA)-approved drugs, compounded products are not required to meet evidentiary standards for establishing safety and efficacy. Moreover, these products are not held to Good Manufacturing Practices, which require regular inspections, quality control testing, and rejection of material not meeting specifications. Physicians, as well as other prescribers, need to be aware that when a patient suffers harm from using a compounded medication, those injured patients may bring negligence and malpractice claims, not only against the pharmacy and the pharmacist responsible for preparing the medication, but also against the prescribing physician and the physician's practice. Consequently, the best way for physicians to manage professional risk and avoid both litigation and potential negative patient outcomes related to compounded pharmaceuticals is to not use these products if there is an FDA-approved product available. However, if the use of a compounded medication is medically necessary, then physicians should adhere to the FDA guidance concerning traditional compounding. Moreover, it would be prudent for any physician who intends to either resell or participate in the distribution of compounded products beyond the direct treatment of their patients to consider obtaining the appropriate insurance coverage for this activity. PMID- 25276869 TI - [Subjective tympanophonia. The current concepts of therapy]. AB - The authors overview the current concepts of the management of the patients complaining of subjective tympanophonia with special reference to the medicamental and medicamental treatment of this condition and rehabilitation. Bearing in mind a great variety of approaches to addressing this problem, only the most important, widely applied, and clinically verified methods for this purpose are considered. PMID- 25276870 TI - [The rheologic characteristics of nasal secretion]. AB - The objective of the present study was to analyse the available data on the qualitative and quantitative composition of nasal secretion (NS) obtained from the healthy subjects and the patients presenting with various diseases of the nose and paranasal sinuses (PHS). The author maintains that investigations for the identification of organic and inorganic components contained in the nasal secretion and for the measurement of their contents as well as the studies of its properties with the use of the biochemical and physical methods are of primary diagnostic and prognostic importance. It is supposed that the physical properties of NS can be described in terms of the notions and principles of rheology. i.e. the science of the flow of matter. For this reason, airway secretion plays an important role in the functioning of the respiratory organs and the maintenance of homeostasis of the internal environment of the body. The composition of secretion from the nasal cavity and paranasal sinuses is considered to be a factor of of pathogenesis and indicator of the pathological processes in the respiratory tract. It is recommended that the adequate mucolytic medicines should be included into the treatment protocol of PNS diseases to liquefy the thick pus and viscous secretion in order to improve the mucociliary clearance and facilitate the release of secretion from the sinuses. PMID- 25276871 TI - Catching up: Latino health coverage gains and challenges under the Affordable Care Act: results from the Commonwealth Fund Affordable Care Act Tracking Survey. AB - For decades, Latinos have had the highest uninsured rates of any racial or ethnic group in the United States. Less than one year after the Affordable Care Act's health insurance marketplaces opened for enrollment, the overall Latino uninsured rate dropped from 36 percent to 23 percent, according to the Commonwealth Fund Affordable Care Act Tracking Survey, conducted April 9 to June 2, 2014. However, the high uninsured rate among Latinos in states that had not expanded their Medicaid program at the time of the survey--33 percent--remained statistically unchanged. These states are home to about 20 million Latinos, the majority of whom live in Texas and Florida. PMID- 25276872 TI - Mine, thine, and ours: collaboration and co-authorship in the material culture of the mid-twentieth century chemical laboratory. AB - Patterns of collaboration and co-authorship in chemical science from the 1920s to the 1960s are examined with an eye to frequency of co-authorship and differences in allocation of credit during a period of increasing team research and specialization within chemical research groups. Three research leaders in the cross-disciplinary and cutting edge field of X-ray crystallography and molecular structure are the focus of this historical study within a framework of sociological literature on different collaborative patterns followed by eminent scientists. The examples of Michael Polanyi in Berlin and Manchester, Linus Pauling in Pasadena, and Dorothy Crowfoot Hodgkin in Oxford demonstrate the need to de-centre historical narrative from the heroic 'he' or 'she' to the collaborative 'they.' These cases demonstrate, too, the roles of disciplinary apprenticeships, local conditions, and individual personalities for historical explanation that transcends universal generalizations about scientific practice, material culture, and sociological trends. PMID- 25276873 TI - Distilling reliable remedies: Hieronymus Brunschwig's Liber de arte distillandi (1500) between alchemical learning and craft practice. AB - Hieronymus Brunschwig's Liber de arte distillandi, written in German and first published in Strasbourg in 1500, was the first printed manual on the distillation of medicinal waters. Although influential among early modern audiences and well known to modern scholars, its intriguing blend of intellectual and practical traditions has thus far received little attention. This paper identifies these strands in Brunschwig's technical instructions and shows how they intertwine in the production of reliable remedies. Exploring the intellectual dimension of Brunschwig's work, I argue that his concept of distillation is shaped by an alchemical understanding of matter, especially by the writings on 'quintessence' of the fourteenth-century alchemist John of Rupescissa. To realise this concept in the workshop, Brunschwig emphasises the central importance of the body and its senses to ensure true craftsmanship. Brunschwig's printed manual was as much a product of skilled artisanal practices as the distilled waters it describes, and I argue that it was shaped by the same concerns about technical precision and reliability. PMID- 25276874 TI - Pedagogical progeniture or tactical translation? George Fordyce's additions and modifications to William Cullen's philosophical chemistry--Part II. AB - This paper compares the affinity theories and the associated affinity diagrams of William Cullen (1710-1790) and George Fordyce (1736-1802), exploring in particular one episode that took place during the brief hiatus between Fordyce's student years at Edinburgh University and the start of his own pedagogical career in London. This investigation complements that contained in Part I of this paper, which compared the chemistry courses given by Cullen and Fordyce, demonstrating that the knowledge originally imparted to Fordyce by Cullen in his Edinburgh lectures was augmented and translated by Fordyce for his own pedagogical purposes. Part II offers greater insight into the flow of knowledge between Fordyce and Cullen. Their correspondence suggests that the relationship between master and student transmuted into something more complicated after Fordyce left Edinburgh, while the model of knowledge transmission between the two can be seen to be more collaborative than might be expected. PMID- 25276875 TI - A conflict of analysis: analytical chemistry and milk adulteration in Victorian Britain. AB - This article centres on a particularly intense debate within British analytical chemistry in the late nineteenth century, between local public analysts and the government chemists of the Inland Revenue Service. The two groups differed in both practical methodologies and in the interpretation of analytical findings. The most striking debates in this period were related to milk analysis, highlighted especially in Victorian courtrooms. It was in protracted court cases, such as the well known Manchester Milk Case in 1883, that analytical chemistry was performed between local public analysts and the government chemists, who were often both used as expert witnesses. Victorian courtrooms were thus important sites in the context of the uneven professionalisation of chemistry. I use this tension to highlight what Christopher Hamlin has called the defining feature of Victorian public health, namely conflicts of professional jurisdiction, which adds nuance to histories of the struggle of professionalisation and public credibility in analytical chemistry. PMID- 25276877 TI - "Success is not final, failure is not fatal"! PMID- 25276876 TI - The little known Mineral and Chemical History of Iron and A History of Brass by an eighteenth-century technologist, William Lewis (1708-1781). AB - Sometime during the 1920s, Cardiff Public Libraries (later to become Cardiff Central Library) acquired a six-volume handwritten manuscript collection entitled Mineral & Chemical History of Iron. The author of the manuscripts is named as William Lewis. Now uniformly bound in half-leather and cloth boards, this impressive holding provides, in more than a thousand handwritten pages, an early attempt to produce a full-scale treatise in English on the history of iron.' This note traces the route by which the collection reached Cardiff, and also presents evidence for the existence of a hitherto unknown work on the history of brass by the same author. PMID- 25276879 TI - Genomics. PMID- 25276878 TI - Importance of clinical excellence. PMID- 25276880 TI - Is your workplace toxic? PMID- 25276881 TI - Community health workers. PMID- 25276883 TI - [Possibilities of computed tomography in the diagnosis of primary pulmonary vasculitis]. AB - OBJECTIVE: To study the main computed tomography (CT) signs of primary pulmonary vasculitis at different stages of disease development. MATERIAL AND METHODS: Eighty-nine patients, including those with Wegener's granulomatosis (WG) (n = 60), Churg-Strauss syndrome (CSS) (n = 24), or microscopic polyangiitis (MPA) (n = 5), were examined. Vasculitis was diagnosed on the basis of comprehensive clinical, X-ray, and morphological examination. CT study was performed in 40 (85.1%) patients over time. Radiography encompassed chest X-ray and computed tomography. RESULTS: The CT signs of WG were as follows: parenchymal infiltrates in 41 (68.3%) patients, vast zones of ground glass and consolidation in 16 (21.6%), and bronchial wall thickening in 27 (46.7%). The infiltrates showed aseptic decay cavities in 26 (63.4%) cases. In CSS, the CT changes included ground glass symptom (100%), consolidation symptom (54.2%), bronchial wall thickening concurrent with bronchial dilatation (87.5%), and increased peripheral pulmonary vessel diameter (45.8%). CSS was typified by migratory infiltrates. The pulmonary manifestations of MPA were characterized by the regions of alveolar infiltration of varying intensity and extent. CONCLUSION: The use of CT in pulmonary vasculitis makes it possible to reliably detect and differentiate pathological changes in the lung, to estimate their extent and monitor the efficiency of treatment. PMID- 25276882 TI - [Characteristics of lung foci revealed by computed tomography in high-risk children and adolescents for tuberculosis]. AB - OBJECTIVE: To give an X-ray pattern of single lung foci revealed by computed tomography (CT) in children and adolescents examined for tuberculosis. MATERIAL AND METHODS: The results of CT in 52 children and adolescents infected by Mycobacterium tuberculosis were analyzed. All the followed up children and adolescents underwent X-ray study using a two-slice spiral Somatom Emotion Duo (Siemens). The study used first the conventional chest spiral CT scanning procedure for children according to the Thorax Routine program and then reconstruction. Target spiral scanning of the area of interest was, if needed, carried out by employing high resolution CT with 2-mm thick images taken at 1.5 mm spacing. A maximal intensity project program was used to separate vessels and foci. RESULTS: The single foci were encountered frequently in the lung of the examinees and characterized by a perilymphatic site; in 88.0% they were connected with the interlobular interstitium, interlobar fissure, and paracostal pleura; in 92.2% the foci were detectable in the subpleural and cortical parts of the lung, had a moderate intensity, well-defined outlines, and were 2-6 mm in size. At the same time, there were no pathological changes in the lymph nodes of the lung roots and mediastinum. The long-term (2-month-to-5-year) followup in this group of children indicated that there were no X-ray changes in the lung foci revealed by CT. CONCLUSION: The single foci in the lung of Mycobacterium tuberculosis infected children without X-ray changes in the lymph nodes of the lung roots and mediastinum may be manifestations of the normal lung structure--these may be intrapulmonary lymph nodes. Further follow-up in this group of these children must be in agreement with the management tactics of those infected with Mycobacterium tuberculosis. PMID- 25276884 TI - [Visualization of sinus node arteries by multislice spiral computed tomography coronary angiography]. AB - OBJECTIVE: To assess the capabilities of multislice spiral computed tomography coronary angiography (MSCT-CA) to visualize the anatomy of the sinus node artery (SNA). MATERIAL AND METHODS: The retrospective analysis of coronary artery examinations covered 46 patients with the referral diagnosis of coronary heart disease. MSCT-CA showed no evidence of coronary artery stenosis. This sample included 23 (50%) men and 23 (50%) women; the mean age of the patients was 52.4 +/- 9.1 years; the mean height was 170 +/- 6.67 cm; the mean weight was 80.7 +/- 12.1 kg. X-ray computed tomography was carried out using a SOMATOM Definition AS+ 128-slice computed tomography scanner with retrospective ECG synchronization, reconstructed slice thicknesses of 1 and 3-mm. The Spearman correlation test was used for statistical data analysis. RESULTS: The SNA was visualized in 83% of the patients. It originated from the right coronary artery (RCA) and the circumflex branch of the left coronary artery in 84 and 16% of cases, respectively. No significant association was found between the type of heart blood supply and that of sinus node one (r = 0.06). In 18% of cases, the SNA was visualized only at the level of the ostium, allowing the assessment of the origin of the artery, and at the level of its mid-third in 32%; the distal SNA bed was visualized up to its division; in 10% of them the artery could be visualized all the way, including the division (the dissipation site). Unclear visualization of the proximal SNA was observed among 17% of the patients in whom the SNA could not be visualized with a heart rate (HR) of more than 80 beats/min in 62.5% of the patients, less than 41 beats/min in 12.5%, and 60-61 beats/min in 25%. HR was not found to be associated with the quality of SNA visualization (r = 0.09). CONCLUSION: MSCT can assess the anatomy of SNA up to the distal bed and dissipation site. In the overwhelming majority of the patients, the SNA originated from the RCA (84%) regardless of the type of heart blood supply. The best SNA visualization was noted with a HR of 50 to 80 beats per minute. There was no statistical relationship of the quality of visualization to HR. PMID- 25276885 TI - [Experience with virtual sonography of the breast]. AB - OBJECTIVE: To assess the capabilities of and the first experience with an ACUSON S2000 automated breast volume scanner (ABVS) (Siemens, Germany) to detect abnormal breast lumps. MATERIAL AND METHODS: Examinations were made in 97 patients who underwent radiological studies encompassing digital mammography, B mode ultrasonography of the breast, and its pathomorphological examination. All the cases were classified according to the BI-RADS system. Abnormal breast lumps (BI-RADS 1) were not found in 27 cases; clearly defined benign masses (BI-RADS 2) were detected in 18, and pathomorphologically verified breast cancer (BC) (BI RADS 5) in 29 cases. All the patients also underwent breast ultrasonography using an ACUSON S2000 system (Siemens, Germany). The results of ABVS examination were compared with those of standard comprehensive breast radiologic examination. Having no preliminary additional information on each patient, an independent expert--a radiologic diagnostician appraised all ultrasound scanning data at a special review station. RESULTS: The sensitivity of the automated scanning assay in detecting breast abnormalities was 100%; its specificity and diagnostic accuracy were 40 and 88%, respectively. The independent expert established the diagnosis of BC in 26 (90%) of the 29 cases. According to the results of automated breast scanning, pre-examination using a set of radiation methods was recommended in 66 (66%) cases. The hyperdiagnosis was 24%. CONCLUSION: Taking into consideration the fact that none of the BC case was overlooked, the first experience with ABVS showed encouraging results and the need for further clinical tests of the automated breast scanning system. PMID- 25276886 TI - [Computed tomography in the diagnosis of congenital cystic adenomatoid malformation of the lung in children]. AB - Cystic adenomatoid malformations of the lung belong to a group of abnormalities, the only treatment is surgery. This raises the question as to the earliest detection of this lung abnormality in children. Up to the present, there have been cases of late diagnosis of this abnormality masked by an inflammatory process in the lung, its abscess, and even tuberculosis lesion of lung tissue. We describe a case of cystic adenomatoid malformation of the lung in a child, by discussing the capabilities of chest computed tomography in the diagnosis of lung malformations in children. When inflammatory lung changes are found in children, it is necessary to keep in mind that these alterations may develop in the presence of the malformation. To clarify the pattern of the disease, by applying current radiodiagnostic techniques, allows the choice of optimal treatment policy and the time and volume of surgical intervention. PMID- 25276887 TI - [Clinical use of proton magnetic resonance spectroscopy in brain tumors and adjacent tissues]. AB - Magnetic resonance spectroscopy (MRS) is a noninvasive technique to measure the concentration of chemical substances, which estimates biochemical changes in health and different diseases in vivo. The technique opens up a wide range of possibilities for both primary diagnosis and evaluation of the efficiency of further treatment--medical or surgical one. This review of literature is dedicated to proton MRS used in different tumors of the brain, its tunics, and adjacent nerves. It contains and systematizes data related to the problems of primary diagnosis, differential diagnosis, and evaluation of the efficiency of treatment for tumors and gives references to both basic researches in this area and recent investigations. PMID- 25276888 TI - [No-reflow phenomenon in the practice of an endovascular surgeon]. AB - No-reflow phenomenon is a complication of percutaneous coronary intervention and is the absence of distal coronary bed filling. The main cause of this phenomenon is distal embolism of the coronary artery by atheromatous and thrombotic masses. The paper gives different classifications for evaluation of myocardial and coronary reperfusion. The use of aspiration catheters, glycoprotein IIb/IIIa receptor inhibitors and other drugs that affect prognosis in patients with this phenomenon is also touched upon. PMID- 25276889 TI - [Transradial approach during percutaneous coronary interventions. Part 1. Evidence base for applying a transradial approach]. AB - The use of the radial artery as an approach to percutaneous coronary interventions is becoming increasing popular now. The success of this approach depends on both the accumulated experience of an operator and a health care facility. The paper analyzes an investigation of the comparative characteristics of both a transradial approach and a transfemoral one and the impact of the former on the success of the procedure. It considers the role of the transradial approach in the present-day practice of X-ray endovascular diagnosis and treatment specialists and discusses the problems of education and choice of optimal clinical indications. PMID- 25276890 TI - [Errors when performing computed tomographic colonography (virtual colonoscopy) and assessing its results]. AB - Computed tomographic colonography (CTC) is a noninvasive diagnostic method for significantly identifying clinically relevant colonic and rectal tumors. Good colonic preparation that includes laxatives or residue-free diet, as well as labelling the intestinal contents is needed to adequately interpret CTC data. However, errors in interpreting the results of CTC can be associated with not only the imperfections of large bowel preparation for examination, but also due to those of the latter and because of the anatomic features of the colon. The paper describes difficulties and the most common errors in CTC, including own experience. PMID- 25276892 TI - Germs of service. A sick cancer survivor has concerns about contamination. PMID- 25276891 TI - [In memory of Professor Boris Ionovich ISHCHENKO]. PMID- 25276893 TI - Organizational leadership. Good leaders enable caregivers to operate successfully on their own. PMID- 25276894 TI - Creating a culture of safety: Colorado's story. EMS safety is a problem that demands to be solved. PMID- 25276896 TI - A loyal subject. Who deserves your loyalty, and how do you show it? PMID- 25276895 TI - Aortic dissections and aneurysms. Prehospital care of these rare but life threatening emergencies. AB - Aortic dissections and aneurysms are seen with low frequency and have high risk for deterioration during prehospital care. It is essential to include both dissections and aneurysms in your differential diagnoses whenever evaluating patients with chest or abdominal complaints. Often a good history is the best indication of one of these grave vascular emergencies. Consider thoracic aortic dissection in your differential diagnosis for any patient who complains of chest pain and aortic aneurysm in patients who have any sort of abdominal discomfort or syncope with an unknown etiology. When either is suspected transport rapidly to a facility with cardiothoracic and vascular surgery capability, and provide care that prepares you to manage the patient quickly should a rupture occur. PMID- 25276897 TI - Agribusiness, the family farm, and the politics of technological determinism in the post-World War II United States. PMID- 25276898 TI - Mobilizing the fetus. Julie Roberts, the Visualised Foetus Malcolm Nicolson and John E. E. Fleming, Imaging and Imagining the Fetus. PMID- 25276899 TI - Colorectal cancer screening: current status. PMID- 25276901 TI - Serum cholinesterase is an excellent biomarker of liver cirrhosis. AB - BACKGROUND: Serum cholinesterase (ChE) is an enzyme synthesised by hepatocytes and its serum levels reflect the synthetic function of liver. METHODS: In patients with cirrhosis, liver function tests, PT INR and serum ChE levels were done within a week of enrolment. We studied 178 cirrhosis patients and 154 healthy controls prospectively. Receiver operator characteristics (ROC) curve analysis was employed to compute an optimal cut-off level to distinguish these groups. Correlation between ChE activity and serum bilirubin, albumin, PT INR and MELD score (Model for End-Stage Liver Disease) was analysed. RESULTS: Median serum ChE in cirrhotics was 1590 IU/L (110-8143) compared to controls 7886 IU/L (2022- 21673), p < 0.001. Serum ChE levels below 3506 had a 98.7% sensitivity and 80.3% specificity in predicting cirrhosis. Median serum ChE was higher (p < 0.001) in CC (n = 51) 4246 IU/L (680-8143) compared to DC (n = 127) 1324 IU/L (110-4550). ChE level less than 2385 IU/L had 80.1% sensitivity and 88.2% specificity in predicting DC. Follow-up levels in 25 patients showed good correlation with clinical course. The correlation coefficient between ChE and albumin was -0.67, 0.53 with PT INR and 0.59 with MELD score, (p < 0.001). CONCLUSIONS: Serum ChE is an excellent biomarker of cirrhosis with good sensitivity and specificity. It shows good correlation with serum albumin, PT INR and MELD score. Since it distinguishes DC from CC well, low levels in cirrhosis may serve as a useful prognostic marker of advanced liver disease. Long-term follow-up studies are warranted to define its exact role in clinical practice. PMID- 25276900 TI - Radiological interventions in portal hypertension. AB - The role of radiologists in the management of portal hypertension (PHT) had been confined to its diagnosis and treatment planning. However, with the advancements in the field of interventional radiology various minimally invasive techniques have been evolved for the management of portal hypertension and its complications such as recanalisation techniques, shunt creation and variceal bleeding control. Thus, with these technical advances, there is shift in the role of radiologist from diagnosis to management of portal hypertension. In this review, we discuss the nuances of various radiological interventions available for the treatment of portal hypertension. PMID- 25276904 TI - Prospective study of short-term complications following pancreatoduodenectomy based on international definitions. AB - BACKGROUND AND AIM: Though, the morbidity following pancreatoduodenectomy remains high the mortality rate has reduced to < 5% in many high volume centres. The aim of this prospective study was to quantify the complications following pylorus preserving pancreatoduodenectomy using international definitions and to prove that pylorus preservation and retrocolic duodenojejunostomy are not associated with increased incidence of delayed gastric emptying. METHODS: This was a prospective observational study at a single GI surgery referral unit, conducted from January 2010 to December 2012. Patients who underwent pylorus preserving pancreatoduodenectomy for various indications were included; barring those who underwent major surgical procedures along with pancreatoduodenectomy. RESULTS: 76 patients (M:F = 37:39) underwent pylorus preserving pancreatoduodenectomy during the study period; with median age 52 yrs (range: 29-83) and hospital stay 11 days (range: 8-50). Overall mortality and significant morbidity were 7.89% and 12.5%, respectively. Four patients each (5.26%) developed significant delayed gastric emptying (DGE) and pancreatic fistula. Presence of comorbidity (p = 0.019; odds ratio: 3.16) and periampullary tumours (p = 0.011; odds ratio: 7.91) were identified as risk factors for the development of complications. Pancreatic juice amylase levels in chronic pancreatitis were very low (p < 0.005). CONCLUSION: Pylorus preserving pancreatoduodenectomy can be performed with very low mortality and morbidity at high volume centres. DGE is not significantly increased with pylorus preservation and retrocolic duodenojejunostomy, and is often secondary to post-op complications. The International Study Group of Pancreatic Fistula (ISGPF) definition may miss pancreatic fistula in chronic pancreatitis. PMID- 25276903 TI - Clinicopathological profile and management of severe autoimmune hepatitis. AB - BACKGROUND: Severe autoimmune hepatitis is an entity which has been rarely reported in the Indian literature. We describe here the clinicopathological profile and treatment of severe autoimmune hepatitis (SAH) which is to the best of our knowledge the first report from India addressing this illness. METHODS AND RESULTS: Between September 2010 and March 2013, 13 patients seeking treatment at our centre were diagnosed as SAH and treated with steroids. Jaundice along with coagulopathy was the presenting symptom in all these patients. Ascites was present in ten and encephalopathy in 6 patients. The median serum IgG was 2135 mg/dl (range: 1122-5490).Significant titers of autoantibodies were present in all patients except one. Transjugular liver biopsy in 9 patients showed characteristic features of SAH such as extensive bridging necrosis and moderate to dense portal inflammation. With corticosteroid therapy, 10 patients survived while three died. In those who survived, biochemical improvement was seen as early as seven days with excellent long-term remission. CONCLUSIONS: Clinical suspicion supported by liver biopsy and autoimmune serology led to the diagnosis of SAH in a cohort of patients with unexplained liver failure. Corticosteroids were beneficial in majority of patients affording excellent results and this could be predicted by early reduction in serum bilirubin within 7-15 days. PMID- 25276905 TI - Management of incidentally detected gallbladder carcinomas in a high prevalence area of gallbladder cancer. AB - BACKGROUND: There is an increasing incidence of advanced unresectable gallbladder cancer even in patients who undergo re-exploration and these cases are marked by poor survival even after undergoing curative resection and adjuvant chemotherapy. Lack of suspicion during primary surgery, unavailability of frozen section facilities and delayed referrals are believed to contribute to this high incidence. AIM: Our aim was to evaluate the results of re-surgery in incidental gallbladder cancers detected after open or laparoscopic cholecystectomy and to assess the outcome in patients who underwent complete radical cholecystectomy and adjuvant therapy. METHOD: We retrospectively analyzed the data from a prospectively maintained computerized database of all patients with incidentally detected gallbladder cancers operated in the Department of Surgical Oncology, from June 2006 to January 2013. RESULTS: Forty-two patients with incidental gallbladder cancer were re-explored. The median time of re-exploration after initial surgery was 65 days. Eighteen (43%) patients were found inoperable due to locally advanced unresectable or metastatic disease. Among the 24 (57%) patients who underwent completion radical cholecystectomy, 11 developed recurrence over a median time of 11 months. CONCLUSION: Despite the dismal prognosis, more than half of the incidentally detected gallbladder carcinoma patients could receive curative treatment. Identification of patients with incidentally discovered gallbladder cancer and early referral to an oncology center may ensure these patients receive curative resection thereby increasing their chances for long term disease free survival. PMID- 25276909 TI - Successful liver transplantation for a hepatitis B flare following cessation of prolonged chemotherapy prophylaxis. PMID- 25276907 TI - A rare case of atypical hemangioma showing centrifugal enhancement. PMID- 25276908 TI - Steatohepatitic variant hepatocellular carcinoma: a case report of new histological variant. PMID- 25276910 TI - Unsuspected hepatic schistosomiasis in a liver explant. PMID- 25276906 TI - Corrosive esophageal injury due to elemental sodium ingestion. PMID- 25276902 TI - Emerging role for colorectal cancer screening in Asian countries. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) is one of the leading causes of cancer related mortality globally. Though Asia has traditionally been considered a relatively low incidence area for colorectal cancer, the incidence is reportedly increasing. The Asia Pacific Working Group for Colorectal Cancer has recommended screening of individuals at average risk starting from 50 years of age. Based on these recommendations we conducted a pilot study to assess the need and feasibility of a colorectal cancer screening program in the state of Qatar. METHODS AND RESULTS: We screened 1385 individuals by fecal immunochemical testing for occult blood, at the primary health center level and positive cases were referred for colonoscopy. Among those who tested positive for fecal occult blood, we picked up five patients with cancers and seven with neoplastic polyps. CONCLUSION: Our results compare with the yield of screening programs in western countries thus suggesting an emerging role for colorectal cancer screening in Asian countries. PMID- 25276911 TI - Celiac disease complicated by lymphoma. PMID- 25276913 TI - A case of postcholecystectomy benign biliary stricture with atrophy-hypertrophy complex, mimicking a type IV bismuth stricture. PMID- 25276912 TI - Biliary atresia with cytomegalovirus infection and its response to ganciclovir. PMID- 25276914 TI - New technique of railroading procedure for transnasal placement of devices following transoral endoscopy. PMID- 25276915 TI - An unusual case of epidermoid-splenic cyst. PMID- 25276916 TI - Reply: A reply to Tarone et al., Campobasso and Introna, and Michaud et al. PMID- 25276917 TI - Intrapuparial development of Chrysomya putoria (Diptera: Calliphoridae). AB - The intrapuparial development of 150 pupae of Chrysomya putoria (Wiedemann, 1830) was analyzed. The material was kept in a climate chamber at 27 degrees C (day) and 25 degrees C (night), 60 +/- 10% relative humidity (RH), and a photoperiod of 14:10 (L:D) h, which started at 06:00 a.m. Daily, 30 pupae were frozen at - 15 degrees C, for the sacrifice of the insects, and the immatures obtained were photomicrographed until the emergence of the adults. The following stages were observed: pupariation process: during this process, reduction of the larvae's first three body segments and the darkening of the cuticle occur; cryptocephalic phase after 18 h; phanerocephalic phase after 24 h; body division after 48 h. Between the third and the fourth days of the development, the stage ofpharate adult was reached, characterized by the following changes in the color of the compounds eyes: 1) orange eyes, after 66 h; 2) red eyes, after 72 h; 3) dark red eyes, after 90 h; 4) brown eyes, after 96 h. The time of intrapuparial development of C. putoria at 2 degrees C (day) and 25 degrees C (night), 60 +/- 10% RH, and a photoperiod of 14:10 (L:D) h was 5 d. PMID- 25276918 TI - Effectiveness of mosquito magnet in preserved area on the coastal Atlantic rainforest: implication for entomological surveillance. AB - A variety of traps are used for sampling, surveillance, and monitoring of mosquito vector species associated with parasite and pathogen transmission. Here, we assessed the performance of the Mosquito Magnet Independence trap with Lurex3 (MMI), by comparing its effectiveness with those of a Centers forDisease Control and Prevention light trap (CDC-LT) and CDC with CO2 and Lurex3 (CDC-A) in a dense tropical rainforest. Multivariate generalized linear models revealed significant differences among the traps regarding mosquito composition and abundance (deviance = 768; P = 0.016). Variance analyses indicated that the MMI captured significantly more mosquitoes compared with CDC-LT (P < 0.01) and CDC-A (P < 0.03). The abundance values did not significantly differ between the CDC-LT and CDC-A traps (P = 0.7). Mosquito species richness was higher from the MMI than from the CDC-LT and CDC-A traps. Furthermore, medically important mosquito species captured by the three traps showed high association with MMI. These results suggest the potential to use the MMI in studies aiming to obtain entomological surveillance information about medically important mosquitoes that occur in tropical rainforest areas. The MMI could also be used in faunal studies focusing on increasing knowledge about mosquito diversity. Considering the present positive results, the effectiveness of the MMI should additionally be evaluated in other Brazilian natural ecosystems. Further studies are also needed to address demographic data from the mosquito population sampled by the MMI. PMID- 25276919 TI - Survival and fecundity of two strains of Cimex lectularius (Hemiptera: Heteroptera). AB - Knowledge of development of the bed bug Cimex lectularius L. (Hemiptera: Heteroptera) under specific environmental conditions could lead to improved management techniques. Developmental rates, age-, and stage-specific life tables were compared for a laboratory strain and a field strain of bed bugs reared on human blood. Both strains were then crossed reciprocally to produce four F1 generations and subsequent age- and stage-specific life tables were constructed. No significant differences were found in the overall survival of the parental strains, but significant differences were found in development rate within various instars based on strain. Parallel results were derived from the F1 generation hybrids. Stable age distribution calculations predict that 80% of bedbugs within exponentially growing populations will be immature. PMID- 25276920 TI - Influence of temperature on oviposition by Dermacentor andersoni (Acari: Ixodidae). AB - The effects of temperature on oviposition by Dermacentor andersoni (Stiles) was examined using replete females ranging in weight from 30 to 1,198 mg. Survivorship was >96% during the preoviposition periods and declined during oviposition period. Egg production peaked earlier and at greater levels as temperature increased. Longevity, preoviposition period, and oviposition period declined as temperature increased. Replete weight had minor effects on measures of time, but smaller females tended to have greater longevity and preoviposition periods, and shorter oviposition periods. Temperature and replete weight both had large effects on measures of oviposition success such as the amount of eggs laid, the conversion efficiency index, and daily egg production. Lower temperatures and replete weight resulted in greater oviposition failure, and reduced egg production and conversion efficiency. Oviposition was greatly inhibited at 10 degrees C, suggesting this is near the lower temperature limit for development. However, egg production was reduced at temperatures < 20 degrees C, suggesting that the northern edge of the distribution may be influenced by the effects of temperature on oviposition. PMID- 25276921 TI - Community of chewing lice (Phthiraptera: Amblycera and Ischnocera) parasites of resident birds at the Archipelago of Sao Pedro and Sao Paulo in northeast Brazil. AB - The current study describes the chewing lice community associated with seabird populations resident at the Sao Pedro and Sao Paulo Archipelago in the Atlantic Ocean in Pernambuco State, Brazil. Adults of three species of seabirds were captured using hand-nets for the collection of biometric data and specimens of ectoparasites. In total, 320 birds were examined (120 Sula leucogaster (Boddaert), Brown Booby; 120 Anous stolidus (L.), --Brown Noddy; and 80 Anous minutus Boie, Black Noddy) of which 95% were infested with 8,625 chewing lice, representing eight species of the genera Actornithophilus, Austromenopon, Eidmanniella, Pectinopygus, Quadraceps, and Saemundssonia. On S. leucogaster, Pectinopygus garbei (Pessoa & Guimaraes) was more prevalent and had a mean and median intensity of infestation significantly greater than those recorded for Eidmanniella albescens (Piaget). On the two Noddies, the species of Actornithophilus and Quadraceps were significantly more prevalent and abundant than Austromenopon atrofulvum (Piaget) and Saemundssonia remota Timmermann Most of the louse species had a highly aggregated distribution, with k exponent of the negative binomial distribution ranging from 0.04 to 3.06. A weak but significant correlation was found between the abundance of chewing lice and morphometric variables (body weight, wing, beak, tail, and tarsus lengths). It is possible that high rates of infestation have a negative effect on the morphological characteristics of the hosts, including the health of the plumage. All the lice species collected--except for P. garbei (ex S. leucogaster)--were reported for the first time from Brazilian populations of these seabird species. PMID- 25276922 TI - Ability for Aedes albopictus (Diptera: Culicidae) to survive at the climatic limits of its potential range in eastern Australia. AB - Aedes albopictus (Skuse) is one of the most invasive mosquito species in the world and has infested islands in the Torres Strait, off the northern coast of Australia since at least 2004. This has led to fears that it may establish on the Australian mainland, including highly populated cities in southern temperate regions. To supplement theoretical projections addressing the range expansion of Ae. albopictus into Australia, laboratory-based trials were conducted to assess the performance of a Torres Strait Ae. albopictus population under a range of Australian conditions. First-instar larvae were placed in individual microcosms and maintained on a natural food resource, under average climatic conditions representing different regions of Australia's east coast. Larvae could not survive winter conditions in southern Australia. As the population performance index was >1.0 for tropical winter and summer conditions, and temperate summer conditions, populations would likely increase during these times. To test whether Ae. albopictus could overwinter during adverse conditions as eggs, we exposed cohorts to four different temperature (7, 17, 27, and 33 degrees C) and relative humidity (35, 55, and 80%) combinations for up to 3 mo. High temperatures and low humidity were most detrimental to egg survival. However, those eggs maintained under cooler climates remained viable after 3 mo, including 17% of eggs kept at 7 degrees C. Overall, this study suggests that a Torres Strait Ae. albopictus strain could proliferate all year round under northern tropical conditions and could overwinter in the egg stage before proliferating in the summer in southern temperate regions. PMID- 25276923 TI - Identification and analysis of NADPH-cytochrome P450 reductase in Aedes sollicitans (Diptera: Culicidae). AB - An NADPH-cytochrome P450 reductase (CPR) gene was identified in Aedes sollicitans Walker (Diptera: Culicidae). The open reading frame is 2,040 bp long, encoding a 679-residue polypeptide. Amino acid sequence analysis indicates that the Ae. sollicitans CPR carries conserved ligand-binding domains and belongs to the same phylogenetic group as CPRs in other mosquitoes. The cDNA of the CPR gene was cloned, and the recombinant protein was expressed in Escherichia coli. Cytochrome c reductase activity was detected in the bacterial cytosolic and membrane fractions and in larval microsomes from two New Jersey Ae. sollicitans populations, indicating that the Ae. sollicitans CPR is enzymatically functional and closely related to that in other dipterans. PMID- 25276924 TI - Simultaneous detection of pyrethroid, organophosphate, and cyclodiene target site resistance in Haematobia irritans (Diptera: Muscidae) by multiplex polymerase chain reaction. AB - The horn fly, Haematobia irritans irritans (L., 1758) (Diptera: Muscidae), is an important pest that causes significant economic losses to the livestock industry, but insecticide resistance in horn fly populations has made horn fly control increasingly difficult to achieve. In this study, we developed a multiplex polymerase chain reaction (PCR) assay to simultaneously detect target site resistance to pyrethroids (kdr mutation), organophosphates (G262A acetylcholinesterase mutation), and cyclodienes (Rdl mutation) and used the new procedure to follow the progression of these three mutations after exposure to different insecticide pressure. We assayed flies collected at the Macon Ridge research station, Winnsboro, LA, from 2008 to 2012. The multiplex PCR showed robust results in all our assays. The kdr mutation remained at high frequencies during all years, even after 4 yr with no use of pyrethroids. The G262A acetylcholinesterase mutation fluctuated from 7.5 to 23.8% during the studied years, while the Rdl mutation was rare in 2008, 2009, and June 2010, and then significantly increased after the first use of endosulfan. The possibility of screening for all the known target site resistance mutations in a single PCR reaction makes the multiplex PCR a useful and affordable tool that can be used to help diagnose insecticide resistance. PMID- 25276925 TI - Acaricidal properties of the essential oil from Zanthoxylum caribaeum against Rhipicephalus microplus. AB - Zanthoxylum caribaeum Lamarck (Rutaceae) is plant species with a variety of medical applications, including insecticidal activity. This study determined the bioacaricidal activity of the essential oil from Z. caribaeum leaves against engorged Rhipicephalus (Boophilus) microplus (Canestrini, 1887) females using the adult immersion test. For this purpose, three serial concentrations (5.0, 2.5, and 1.25%, vol:vol, in 1% dimetilsulfoxide) of the essential oil were used. Essential oil 5% caused 65% mortality on the first day after treatment, 85% on the second day, and 100% mortality by the fifth day. To our knowledge, this is the first demonstration of the acaricidal activity of the essential oil from Z. caribaeum leaves against cattle ticks. PMID- 25276926 TI - Molecular detection of knockdown resistance (kdr) in Blattella germanica (Blattodea: Blattellidae) from northwestern Iran. AB - Pyrethroid insecticides are highly insecticidal compounds that are widely used against the German cockroach, a significant household insect pest. In several insect species, there is a point mutation in the para-type sodium channel gene associated with knockdown resistance (kdr). In the current study, genomic DNA was analyzed in the region where the kdr and super-kdr (an enhanced form of pyrethroid resistance) mutations reside in Blatella germanica (L., 1767) (Blattodea: Blattellidae) collected from Iran. Studies on the extracted DNA from hand-captured German cockroach specimens were conducted by polymerase chain reaction and sequencing to detect related mutations. The kdr mutation, substitution of G for C (L1014F), which results in amino acid replacement (leucine with phenylalanine), was detected in all 18 sequenced specimens from three different locations. However, the super-kdr mutation (M918T), which is detected in super-kdr house flies, was not found in the sequences of the current study. The high ratio of the kdr mutation in a field population of B. germanica in Urmia confirms that the individuals are homozygous. These data should be helpful in designing and implementing a control program and resistance management. PMID- 25276928 TI - Insecticidal activity of Torricellia tiliifolia extracts against Musca domestica and Aedes albopictus. AB - Insecticidal toxicity of extracts from leaves, stems, and bark of Torricellia tiliifolia de Candolle against adult Musca domestica L. and larval Aedes albopictus (Skuse) was evaluated in this study. Bark extract proved to be the most toxic to these two species with the chloroform fraction the most active with LC50 values of 306.15 microg/g and 23.05 microg/ml for the house fly and mosquito, respectively. At the same time, water fractions against M. domestica and petroleum ether against Ae. albopictus were comparatively less toxic. Two compounds from T. tiliifolia extracts, torrilliolide and torricelline, were highly toxic to both species. The LC50 values of torrilliolide and torricelline in adult M. domestica 48 h after topical application were 0.40 and 0.33 microg per adult, respectively, and equal to the commercially available, plant-derived insecticide, rotenone. These results showed that T. tiliifolia possess compounds with considerable bioactivity and worthy of further research. PMID- 25276927 TI - Field evaluations of topical arthropod repellents in North, Central, and South America. AB - Recently, vector-borne diseases have been resurging in endemic areas and expanding their geographic range into nonendemic areas. Such changes have refocused attention to the potential for major public health events, as naive populations are exposed to these pathogens. Personal topical repellents, recommended by the United States Centers for Disease Control and Prevention and World Health Organization, remain a first line of protection against infection. The current study evaluated the repellent efficacy of four new U.S. Environmental Protection Agency-registered topical repellent products, two with picaridin as the active ingredient and two with IR3535, against a standard DEET (N,N-diethyl-3 methylbenzamide)-based product. All products were evaluated against a wide range of vector species under field conditions across the Americas. Human volunteers were used to evaluate product efficacy as compared with a well-known DEET-based formulation and determine suitability for use by the U.S. military. Findings demonstrated the new formulations performed as well as the standard U.S. military repellent and could be recommended for use. PMID- 25276929 TI - Survival and fate of Salmonella enterica serovar Montevideo in adult horn flies (Diptera: Muscidae). AB - Contamination of cattle peripheral lymph nodes with Salmonella enterica is proposed to occur via a transdermal route of entry. If so, bacteria may be introduced to cattle by biting arthropods. Biting flies, such as horn flies (Haematobia irritans irritans (L.)) (Diptera: Muscidae), are intriguing candidates for transmitting Salmonella to cattle because they provide a route of entry when they breach the skin barrier during blood feeding. Using a green fluorescent protein-expressing strain of Salmonella Montevideo (S. Montevideo GFP), the current study demonstrated that horn fly grooming subsequent to tactile exposure to the bacteria resulted in acquisition of the bacteria on mouthparts as well as microbial ingestion. Consumption of a bloodmeal containing approximately 10(2), approximately 10(4), or 10(6) S. Montevideo-GFP resulted in horn fly colonization for up to 72 h postingestion (PI). Epifluorescent microscopy indicated that the bacteria were not localized to the crop but were observed within the endoperitrophic space, suggesting that regurgitation is not a primary route of transmission. S. Montevideo-GFP were cultured from excreta of 100% of flies beginning 6-7 h PI of a medium or high dose meal and > 12 h PI in excreta from 60% of flies fed the low-dose meal. Animal hides and manure pats are sources for horn flies to acquire the Salmonella and mechanically transmit them to an animal while feeding. Mean quantities of 5.65-67.5 x 10(2) CFU per fly were cultured from fly excreta passed within 1 d after feeding, suggesting the excreta can provide an additional microbial source on the animal's hide. PMID- 25276930 TI - Preliminary biological studies on larvae and adult Anopheles mosquitoes (Diptera: Culicidae) in Miraflores, a malaria endemic locality in Guaviare department, Amazonian Colombia. AB - In the malaria endemic municipality of Miraflores in southeastern Amazonian Colombia, several aspects of the biology of local Anopheles species were investigated to supplement the limited entomological surveillance information available and to provide baseline data for malaria prevention and vector control. Anopheles darlingi Root, 1926 was the most abundant species (95.6%), followed by Anopheles braziliensis (Chagas) (3.6%) and Anopheles oswaldoi s.l. (Peryassu) (0.7%). During the dry season, exophagic activity was prevalent only between 1800 2100 hours; after this (2100-0600 hours) only endophagy was encountered. In contrast, during the rainy season, both endophagy and exophagy occurred throughout the collection period. The human biting rate for An. darlingi was 8.6. This species was positive for Plasmodium vivax VK210 with a sporozoite rate = 0.13 (1/788). Breeding sites corresponded to stream (n = 7), flooded excavations (n = 4), flooded forest (n = 1), wetlands (n = 2), and an abandoned water reservoir (n = 1). An. darlingi predominated in these sites in both seasons. Based on these data, An. darlingi is the main local malaria vector, and we recommend that local prevention and control efforts focus on strengthening entomological surveillance to determine potential changes of species biting behavior and time to reduce human-vector interactions. PMID- 25276931 TI - Flight behavior and performance of Rhodnius pallescens (Hemiptera: Reduviidae) on a tethered flight mill. AB - ABSTRACT Flight dispersal of the triatomine bug species Rhodnius pallescens Barber, the principal vector of Chagas disease in Panama, is an important mechanism for spreading Trypanosoma cruzi, causative agent of Chagas disease. This study measures R. pallescens flight performance using a tethered flight mill both when uninfected, and when infected with T. cruzi or Trypanosoma rangeli. Forty-four out of the 48 (91.7%) insects initiated flight across all treatments, and trypanosome infection did not significantly impact flight initiation. Insects from all treatments flew a cumulative distance ranging from 0.5 to 5 km before fatiguing. The median cumulative distance flown before insect fatigue was higher in T. cruzi- and T. rangeli-infected insects than in control insects; however, this difference was not statistically significant. There was a positive relationship between parasite load ingested and time until flight initiation in T. rangeli-infected bugs, and T. rangeli- and T. cruzi-infected females flew significantly faster than males at different time points. These novel findings allow for a better understanding of R. pallescens dispersal ability and peridomestic management strategies for the prevention of Chagas disease in Panama. PMID- 25276932 TI - Dengue vectors, human activity, and dengue virus transmission potential in the lower Rio Grande Valley, Texas, United States. AB - Dengue virus is an emerging disease of concern in the Americas. Recent outbreaks in Florida highlight the potential for the virus to return to the United States. The Lower Rio Grande Valley region of Texas directly borders Mexico, and has experienced dengue transmission in the past concurrent with outbreaks in Mexico along the border region. We examined the potential for dengue virus transmission by examining the vectors in the region, as well as assessing human behavior. We further hypothesized that dengue vector abundance would influence human behavior. Two dengue vectors, Aedes aegypti (L.) and Aedes albopictus (Skuse), were found in the region in high abundance. More mosquitoes were collected in rural sites and sites with high vegetation. Of the two species, only Ae. albopictus showed any significant habitat preferences, being more common in rural site. While there was no correlation between human behavior and mosquito abundance, the results support a significant correlation between knowledge of mosquitoes and dengue virus and behavioral practices that might reduce risk of disease transmission. Dengue risk may be higher in certain regions of the Lower Rio Grande Valley based on socioeconomic conditions, specifically in economically poor regions such as the undeveloped colonias found in the region. Because of the proximity of this region to an area with endemic dengue, continued surveillance and risk assessment is suggested. PMID- 25276933 TI - Relapsing fever group Borrelia in Southern California rodents. AB - Wild rodent reservoir host species were surveyed prospectively for infection with Borrelia hermsii, the causative agent of tick-borne relapsing fever in the western United States. Trapping occurred during the summer of 2009-2012 at field sites surrounding Big Bear Lake, CA, a region where human infection has been reported for many years. Using quantitative polymerase chain reaction (qPCR), we tested 207 rodents from 11 species and found chipmunks (Tamias spp.) and a woodrat (Neotoma macrotis) infected. Chipmunks represented the majority of captures at these sites. Sixteen of the 207 (7.7%; CI = 4.6-12.4) animals were qPCR-positive for Borrelia spp. associated with relapsing fever, and of those, we obtained bacterial DNA sequences from eight. The phylogram made from these sequences depict a clear association with B. hermsii genomic group I. In addition, we identified an infection with Borrelia coriaceae in a Tamias merriami, a potentially nonpathogenic member of the tick-borne relapsing fever group. Our findings support the hypothesis that chipmunk species play an important role in the maintenance of Borrelia species that cause tick-borne relapsing fever in the western United States, and therefore the risk of infection to people. PMID- 25276934 TI - Community-based sampling methods for surveillance of the Chagas disease vector, Triatoma dimidiata (Hemiptera: Reduviidae: Triatominae). AB - In Guatemala, the most widespread vector of Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae), the causative agent of Chagas disease, is Triatoma dimidiata (Latreille) (Hemiptera: Reduviidae: Triatominae). T. dimidiata is native to Guatemala and is present in both domestic and sylvatic habitats. Consequently, control of T. dimidiata is difficult because after successful elimination from homes, individual insects can recolonize homes from the surrounding environment. Therefore, intensive long-term surveillance of this species is essential to ensure adequate control is achieved. Manual inspection for signs of infestation, the current method used to monitor Triatominae throughout Central and South America, is labor and time-consuming, so cost-effective alternatives are needed. The current study compared the effectiveness of the current method of surveillance of T. dimidiata with community-based techniques of G6mez-Nunez sensor boxes, collection and observation of bugs by householders, and presence of triatomine-like feces on walls. Although manual inspection was the most sensitive method when used alone, collection by householders also was sensitive and specific and involved less effort. Sensor boxes were not sensitive indicators of T. dimidiata infestation when used alone. Two recorded variables, visual inspection for feces and the sighting of bugs by householders, were sensitive and specific indicators of infestation, and in combination with collection by householders and sensor boxes these methods were significantly more likely to detect infestations than manual inspection alone. A surveillance program that combines multiple community-based techniques should have low cost and involve minimal effort from the government and at the same time promote sustainable community involvement in disease prevention. PMID- 25276936 TI - Description of third instars of Cochliomyia minima (Diptera: Calliphoridae) from West Indies, and updated identification key. AB - The blow fly Cochliomyia minima Shannon is endemic to the Caribbean, and it has great potential for forensic applications because of its abundance and broad distribution in the region. However, its larval stages are unknown. Here, I update previously published identification keys by describing for the first time the morphology of C. minima larvae. The larvae of C. minima are found to be very similar to those of Cochliomyia macellaria F., but the former can be easily identified by the oral sclerite completely pigmented, visible as a spike between mouth hooks. The description of C. minima larvae in this study will be useful to forensic scientists in the Caribbean region. PMID- 25276935 TI - Factors associated with peridomestic Triatoma sanguisuga (Hemiptera: Reduviidae) presence in southeastern Louisiana. AB - Although rare, there have been isolated reports of autochthonous transmission of Trypanosoma cruzi Chagas in the United States. In June 2006, a human case of domestically transmitted T. cruzi was identified in southern Louisiana. To examine the localized risk of human T. cruzi infection in the area surrounding the initial human case, environmental surveys of households in the area and a serological survey of the residents were performed between September 2008 and November 2009. Human T. cruzi infection was determined using a rapid antigen field test, followed by confirmatory enzyme-linked immunosorbent assay testing in the laboratory. A perimeter search of each participating residence for Triatoma sanguisuga (LeConte), the predominant local triatomine species, was also performed. No participating individuals were positive for antibodies against T. cruzi; however, high levels of T. cruzi infection (62.4%) were detected in collected T. sanguisuga. Households with T. sanguisuga presence were less likely to use air conditioning, and more likely to have either chickens or cats on the property. While the human risk for T cruzi infection in southeastern Louisiana is low, a high prevalence of infected T. sanguisuga does indicate a substantial latent risk for T. cruzi peridomestic transmission. Further examination of the behavior and ecology of T. sanguisuga in the region will assist in refining local T. cruzi risk associations. PMID- 25276937 TI - Coleoptera associated with buried carrion: potential forensic importance and seasonal composition. AB - Burial has a unique effect on carrion fauna and this may affect the decomposition rate, consequently interfering with postmortem estimates. We surveyed the Coleoptera on buried rabbit carcasses between April 2008 and March 2009. The insects of forensic importance totaled 1,502 individuals, constituting 87.12% of the Coleoptera collected. The composition of the beetle community varied seasonally. Exposed carcasses lost weight much faster than buried ones. The weight lost by exposed cadavers in a week was greater than those carcasses buried for 10 wk. The temperature variations of the buried carcasses and the soil were around three times less variable than the environmental temperature. The proximity between the temperature variations of the soil and buried carcasses was because of the absence of larval masses. The results show differences in decomposition and faunal composition, demonstrating their relevance in the interpretation of cases with bodies in a similar situation. PMID- 25276938 TI - Comparing growth of pork- and venison-reared Phormia regina (Diptera: Calliphoridae) for the application of forensic entomology to wildlife poaching. AB - Laboratory rearing of Phormia regina Meigen larvae on pork and venison was conducted as part of a study to determine whether forensic entomology approaches can be used in wildlife poaching investigations. Larvae were reared at 30 degrees C, 75% relative humidity, and a photoperiod of 14:10 (L:D) h on pork or venison diets, and samples were collected every 8 h until >90% of the maggots reached the third-instar wandering or prepupal stage. Significant differences were found in the distribution of lengths of the third instar and combined instars for maggots reared on the two different meat sources. Maggots reared on venison reached the prepupal wandering stage significantly faster (approximately 6 h) compared with maggots on the pork diet. Mean adult weight and wing length of venison-reared flies were significantly greater than for flies reared on pork. The lower crude fat content of venison appears to make this meat source a more suitable medium than pork for larvae of P. regina. The difference in growth rate could introduce error into PMImin estimations from third-instar maggots in deer poaching cases if estimates are based on data from studies in which maggots were reared on pork. PMID- 25276939 TI - Bed bugs are back and also arriving is the southernmost record of Cimex lectularius (Heteroptera: Cimicidae) in South America. AB - The arrival and establishment of the bed bug Cimex lectularius L., 1755 in Magallanes Region (Chile) is reported. The present record is the southernmost for this species in America. The circumstances that provided for the species reaching this southern locality are discussed. PMID- 25276940 TI - Envenomation by Trachelas tranquillus (Araneae: Corrinidae) in Connecticut. AB - We report a case of envenomation by Trachelas tranquillus (Hentz) in Connecticut in late September 2013. The bitten subject, a 50 yr-old-female Caucasian, reported a painful wasp-like sting and brushed the spider from her leg. An erythematous macule formed at the site of the bite. The macule was gone by the next day and there was no associated necrosis. The spider was collected and brought to our laboratory for identification. This is the second confirmed case of envenomation by T. tranquillus and the only case reported from Connecticut. PMID- 25276942 TI - Survey of ticks (Acari: Ixodidae) and tick-borne pathogens in North Dakota. AB - Ticks were sampled at nine locations throughout North Dakota during early summer of 2010, using flagging techniques and small mammals trapping. In total, 1,762 ticks were collected from eight of the nine locations. The dominant species were Dermacentor variabilis (Say) (82%), found throughout the state, and Ixodes scapularis Say (17%), found in northeastern counties. A few nymphal and adult I. scapularis tested positive for Borrelia burgdorferi (3%) and Anaplasma phagocytophilum (8%). This is the first report of I. scapularis and associated pathogens occurring in North Dakota and provides evidence for continued westward expansion of this important vector tick species in the United States. PMID- 25276941 TI - Evaluation of the effect of host immune status on short-term Yersinia pestis infection in fleas with implications for the enzootic host model for maintenance of Y. pestis during interepizootic periods. AB - Plague, a primarily flea-borne disease caused by Yersinia pestis, is characterized by rapidly spreading epizootics separated by periods of quiescence. Little is known about how and where Y. pestis persists between epizootics. It is commonly proposed, however, that Y pestis is maintained during interepizootic periods in enzootic cycles involving flea vectors and relatively resistant host populations. According to this model, while susceptible individuals serve as infectious sources for feeding fleas and subsequently die of infection, resistant hosts survive infection, develop antibodies to the plague bacterium, and continue to provide bloodmeals to infected fleas. For Y. pestis to persist under this scenario, fleas must remain infected after feeding on hosts carrying antibodies to Y. pestis. Studies of other vector-borne pathogens suggest that host immunity may negatively impact pathogen survival in the vector. Here, we report infection rates and bacterial loads for fleas (both Xenopsylla cheopis (Rothschild) and Oropsylla montana (Baker)) that consumed an infectious bloodmeal and subsequently fed on an immunized or age-matched naive mouse. We demonstrate that neither the proportion of infected fleas nor the bacterial loads in infected fleas were significantly lower within 3 d of feeding on immunized versus naive mice. Our findings thus provide support for one assumption underlying the enzootic host model of interepizootic maintenance of Y. pestis. PMID- 25276943 TI - Natural vertical transmission of ndumu virus in Culex pipiens (Diptera: Culicidae) mosquitoes collected as larvae. AB - Ndumu virus (NDUV) is a member of the family Togaviridae and genus Alphavirus. In Kenya, the virus has been isolated from a range of mosquito species but has not been associated with human or animal morbidity. Little is know about the transmission dynamics or vertebrate reservoirs of this virus. NDUV was isolated from two pools of female Culex pipiens mosquitoes, IJR37 (n = 18) and IJR73 (n = 3), which were collected as larvae on 15 April 2013 from two dambos near the village of Marey, Ijara District, Garissa County, Kenya, and reared to adults and identified to species. These results represent the first field evidence of vertical transmission of NDUV among mosquitoes. PMID- 25276944 TI - [Systematic view on medicinal property theory based on self-similarity principle]. AB - Studies on the prescription combination regularity based on medicinal tastes focus on the internal relations between the structure and hierarchy of the prescription combination system. In this paper, with the systematic and scientific self-similarity theory as the core ideology, authors systematically interpreted the self-similarity theory of medicinal properties, defined the self similarity of prescriptions with identical or similar medicinal properties, and built the systematic view of medicinal property theory based on the prescription combination based on the entity grammar system. As a result, the system was conducive to integrating traditional Chinese medicinal knowledge of syndromes, therapeutic principles, efficacies, medicinal properties and tastes and achieving the automatic design and optimization process from symptoms to prescriptions, and providing scientific and feasible methods and technical systems for the application of the medicinal property theory, with a guiding significance to the technology, methodology and theory of decoction pieces compatibility, component compatibility and compound medicine design. PMID- 25276945 TI - [Study on self-similarity relationship between decoction pieces property and component property]. AB - OBJECTIVE: To predict part of medicinal properties of traditional Chinese medicine components and traditional Chinese medicine decoction pieces by using the traditional Chinese medicinal property data prediction platform, in order to establish the relationship between properties of traditional Chinese medicine components and traditional Chinese medicine decoction pieces. METHOD: The properties of traditional Chinese medicine components were predicted by using the medicinal property data prediction platform based on the pharmacological effects of the components. RESULT: The total sum of identical or similar results of the prediction for the properties of traditional Chinese medicine components and traditional Chinese medicine decoction pieces accounted for over 75%. CONCLUSION: The self-similarity exists between properties of traditional Chinese medicine components and traditional Chinese medicine decoction pieces, which reflects the inheritance, additivity and emergence among different properties of traditional Chinese medicines. PMID- 25276946 TI - [Study on self-similarity of property combination mode of traditional Chinese medicines]. AB - The combination of medicinal properties refers to expression forms of elements with active properties combined according to a specific sequence. The mode of medicinal property combination refers to the compatible relationship multiple medicinal property combinations. In this paper, based on the mode, safflower, Taohong Siwu decoction, Xuefu Zhuyu decoction and Buyang Huanwu decoction were taken for example to study the characteristics of the compatibility among single herb, herbal pairs and prescriptions. The authors discovered the similarities and differences among them, interpreted the self-similarity in medicinal property combinations of traditional Chinese medicines, and analyzed the compatible relationship among multiple medicinal property combinations, so as to bring forth new ideas in discovering the correlation between the compatibility study mode of traditional Chinese medicines based medicinal property combinations and the efficient compatibility of medicinal property combination. PMID- 25276947 TI - [Predictive study on properties of traditional Chinese medicine components based on pharmacological effects]. AB - OBJECTIVE: To study the relationship between pharmacological effects and properties of traditional Chinese medicine by the decision tree algorithm. METHOD: Based on of pharmacological effects of traditional Chinese medicine, the decision tree algorithm was applied in the study on the relationship between pharmacological effects and properties of traditional Chinese medicines. A model was established with the decision tree algorithm for the purpose of predicting the properties of traditional Chinese medicine components. RESULT: The established model was reliable and stable, and could be used to predict the properties of traditional Chinese medicine components. CONCLUSION: The prediction for the properties of traditional Chinese medicine components with a decision tree model could reflect the theoretical connotation of the properties of traditional Chinese medicine components to some extent and provide a new method for studying the properties of traditional Chinese medicine components. PMID- 25276948 TI - [Study on prescription combination and design method based on dichotomy and greedy algorithm]. AB - The prescription combinations of traditional Chinese medicine (TCM) focuses on the taste and channel tropism, the Qi movement, as well as the compatibility according to multiple combination principles and medicinal property and flavor combination of several traditional Chinese medicines. With the in-depth study on the prescription compatibility, researchers have realized that the medicinal property theory is the core of TCM combinations. However, there is no definite method for combinations based on medicinal properties. In this paper, the authors put forward an method for designing prescription combinations based on bipartite graph and the greedy algorithm. With the medicinal property combinations of Siweilurong Pills for example, the authors proved this method could provide ideas for quickly choosing herbal medicines for prescription combinations, and discussed the prospect of this method in substituting previous and endangered herbal medicines and banned medicinal materials. PMID- 25276949 TI - [Design of traditional Chinese medicines with antihypertensive components based on medicinal property combination modes]. AB - Multi-component traditional Chinese medicines are an innovative research mode for traditional Chinese medicines. Currently, there are many design methods for developing multi-component traditional Chinese medicines, but their common feature is the lack of effective connection of the traditional Chinese medicine theory. In this paper, the authors discussed the multi-component traditional Chinese medicine design methods based on medicinal property combination modes, provided the combination methods with the characteristics of traditional Chinese medicine for the prescription combinations, and proved its feasibly with hypertension cases. PMID- 25276950 TI - [Formula method of medicated diet based on medicinal property combination patterns]. AB - To propose a formula method of medicated diet based on medicinal property combination patterns in this paper under the context of lack of innovation in medicated diets. By analyzing the property combination patterns of traditional Chinese medicine and commonly used foods recorded in the pharmacopoeia, medicated diet formulae were optimized by using the greedy algorithm, with the property combination patterns of classical formulae based on the syndrome differentiation and treatment. In this paper, the Baihu Rensheng decoction, which is a classical formula for treating lung and stomach heat-derived diabetes, was taken for example in the formula design. As a result, totally 18 medicated diet formulae were developed and proved to be rational in the analysis on traditional Chinese medicines and nutriology. This method expands the way of thinking for personalized diet therapies and provides theoretical basis the industrial development and clinical application of medicated diets. PMID- 25276951 TI - [Discovery of topiramate's new functions based on medicinal property combinations and study on its mechanism]. AB - OBJECTIVE: To study topiramate's new functions according to the medicinal property combinations, in order to apply the traditional Chinese medicinal theory in discovering new purposes of old drugs. METHOD: According to New Traditional Chinese Medicinal Families--Chemical Traditional Chinese Medicines, the authors found out topiramate's property. Then based on the therapeutic principle of diabetes, hypertension, epilepsy and lung cancer, as well as the relations of efficacies and medicinal property combinations, they summarized the corresponding medicinal property combination modes, compared topiramate's medicinal property combination mode with corresponding medicinal property combination modes of these diseases, and predict topiramate's new functions. RESULT: According to the comparison, the corresponding medicinal property combinations were consistent with topiramate's medicinal property combinations as evidenced by corresponding literatures, whereas other medicinal property combinations were not. CONCLUSION: Based on medicinal property combination modes, the authors screened topiramate's new functions according to e of TCM clinical experience, discovered topiramate's therapeutic effects on diabetes, hypertension and lung cancer in addition to epilepsy, and explore new drug function according to medicinal property combination modes, which could help greatly shorten the new drug R&D period. PMID- 25276952 TI - [Study on characteristics of pharmacological effects of traditional Chinese medicines distributing along lung meridian based on medicinal property combination]. AB - OBJECTIVE: Medicinal properties are the basic attribute of traditional Chinese medicines (TCM), while the medicinal property theory is the core theoretical foundation of TCM formula combination. In this particle, authors studied the characteristics of pharmacological effects of property combination of traditional Chinese medicines distributing along meridians, with the aim to introduce the medicinal property combination regularity into the design and optimization process of compound TCMs, and bring the medicinal property theory into full play in guiding the formula combination. METHOD: In this paper, TCMs distributing along "the lung meridian" was taken for example. The medicinal property combinations of TCMs distributing along "the lung meridian" recorded in Pharmacopeia (2010) was collected and processed. Besides, Chinese journal full text database (CNKI) was used to collect all of pharmacological study literatures concerning the above TCMs that have been published since 1980. The pharmacological information was also supplemented by reference to Science of Chinese Materia Medica and Clinical Science of Chinese Materia Medica. RESULT: TCMs distributing along the lung meridian with different properties and tastes showed significant differences in pharmacological effects. For example, mild sweet-lung medicines could lower blood sugar levels, decrease anoxia and enhance immunity; Mild-bitter-lung medicines showed anti-bacterial, anti-hypertension, anti-oxidation effects; Hot-sweet-lung medicines showed antibechic and anti bacterial effects. And Hot-bitter-lung medicines showed phlegm eliminating and anti-inflammatory effects. Meanwhile, TCMs distributing along the lung meridian had similar pharmacological characteristics, such as anti-bacterial and anti inflammatory effects, which is consistent with lung's feature in susceptibility to exogenous pathogenic factors. CONCLUSION: In this study, authors discovered pharmacological characteristics of different TCMs distributing along the lung meridian, which links TCM theory with modern study achievements and lays a foundation for establishing a TCM property formula combination system. PMID- 25276953 TI - [Study on characteristics of pharmacological effects of traditional Chinese medicines distributing along stomach meridian based on medicinal property combination]. AB - At present, studies on traditional Chinese medicine (TCM) properties are mostly restricted to a single or two kinds of medicinal properties, but deviated from the holism of the theoretical system of TCMs. In this paper, the characteristics of pharmacological effects of different property combinations of TCMs distributing in the stomach meridian were take as the study objective. The data of properties of TCMs distributing in the stomach meridian was collected from the Pharmacopoeia of the People's Republic of China (2005). The data of pharmacological effects of TCMs distributing in the stomach meridian was collected from all of literatures recorded in Chinese Journal Full-text Database (CNKI) since 1980, Science of Chinese Materia Medica (Yan Zhenghua, People's Medical Publishing House, 2006) and Clinical Science of Chinese Materia Medica (Gao Xuemin, Zhong Gansheng, Hebei Science and Technology Publishing House, 2005). The corresponding pharmacological effects of property combinations of TCMs distributing in the stomach meridian was mined by the method of association rules. The results of the association rules were consistent with the empirical knowledge, and showed that different medicinal property combinations had respective pharmacological characteristics, including differences and similarities in pharmacological effects of different medicinal property combinations. Medicinal property combinations with identical four properties or five tastes showed similar pharmacological effects; whereas medicinal property combinations with different four properties or five tastes showed differentiated pharmacological effects. However, medicinal property combinations with different four properties or five tastes could also show similar pharmacological effects. In this study, the medicinal property theory and the pharmacological effects of TCMs were combined to reveal the main characteristics and regularity of pharmacological effects of TCMs distributing in the stomach meridian and provide a new way of thinking and method for revealing the mechanism action of TCMs distributing in the stomach meridian and discovering the pharmacological effects of TCMs distributing in the stomach meridian. PMID- 25276954 TI - [Study on pharmacologic action characteristics of traditional Chinese medicines distributed along liver meridian based on medicinal properties combinations]. AB - OBJECTIVE: To establish a characterization system of traditional Chinese medicinal properties in line with modern scientific cognition regularity, in order to reveal properties of traditional Chinese medicines distributed along liver meridian and relations of effects of medicinal properties. METHOD: By collecting data about traditional Chinese medicinal properties recorded in the Pharmacopoeia of the People's Republic of China (2005 Edition), literature and data about pharmacological effects of traditional Chinese medicines recorded in the Chinese Materia Medica, by using the method of association rules, the authors dug pharmacological effect rules corresponds to relevant medicinal property combinations, with the medicinal property combination of traditional Chinese medicines distributed along liver meridian as the target. RESULT: It was found that either obvious different pharmacological effects or identical pharmacological characteristics existed in traditional Chinese medicines distributed along liver meridian. CONCLUSION: With the aim to explore the correlations between traditional Chinese medicine medicinal properties and pharmacological effects, the authors linked the traditional Chinese medicine theory with modern research achievements, in order to provide the ideas and methods for interpreting mechanisms of medicinal properties. PMID- 25276955 TI - [Study on characteristics of pharmacological effects of traditional Chinese medicines distributing along kidney meridian based on medicinal property combination]. AB - To study the characteristics of pharmacological effects of property combinations of traditional Chinese medicines (TCMs) distributing in the stomach meridian based on medicinal property combination, in order to further define the association relationship between properties of TCMs and their pharmacological effects, and build a bridge for the interpenetration and combination between the medicinal property theory of TCMs and their pharmacological effects. On the basis of the studies on the medicinal property theory of TCMs distributing along the kidney meridian and their pharmacological effects, efforts were made to collect relevant data for medicinal properties and pharmacological effects and mine the characteristics of pharmacological effects that were corresponding to relevant medicinal property combination by processing materials related to medicinal properties and pharmacological effects with the association rules method. According to the analysis, TCMs distributing along the kidney meridian with different medicinal property combinations were significantly differentiated in the pharmacological effects, but shared identical pharmacological effects, such as immunological enhancement. In this study, TCMs distributing along the kidney meridian with different medicinal property combinations were taken as the carriers to closely integrate the traditional Chinese medicine theory with the modem study achievements, lay a solid foundation for further developing and enriching the traditional Chinese medical property theory, while providing a new perspective on the development of modem medicine. PMID- 25276956 TI - [Analysis on anti-hepatoma effect of medicine invigorating blood circulation and eliminating blood stasis based on warm-pungent-liver efficiency network]. AB - OBJECTIVE: The efficiency network is a complicated network for revealing the efficient mechanism of traditional Chinese medicines (TCMs) and relations among efficiencies. The efficiency-property relations were used to establish a warm pungent-liver efficiency network to explain the principle of treating hepatoma with medicines invigorating blood circulation and eliminating blood stasis. Safflower, a warm-pungent medicine distributing along the live meridian, was taken for example to discuss the efficiency network' s application in the identification of active ingredients of TCMs and the combination. METHOD: In the early stage of this study, combined warm-pungent-liver medicines distributed along the liver meridian and invigorating blood circulation and eliminating blood stasis were taken as the study objects to collect the pharmacological effect data of warm-pungent-liver medicines and obtain the pharmacological effect combinations with the highest blood circulation-invigorating association by the association rules and the chi-square test. The pharmacological target data recorded in the DrugBank database is used to establish the warm-pungent-liver efficiency network according to the principle line of "efficiency-property pharmacology-target-protein interaction" under the background of the protein interaction network. RESULT: The blood circulation-invigorating medicines could directly treat hepatoma by impacting protooncogene, cancer suppressor gene, cell apoptosis and anti-inflammation, and indirectly treat hepatoma by resisting coagulation and adhesion, regulating local blood circulation, preventing cancer cell metastasis and enhancing the tissues' sensitivity to the anticancer drugs. Among the active ingredients of safflower screened based on the blood circulation invigorating network targets, carthamin yellow, quercetin and luteolin have been proved to have the anti-hepatoma effect in literatures, which indicated the reliability of this study's results and the purpose of the efficiency network. CONCLUSION: The efficiency network is an effective method for revealing the TCM's mechanism, and lays a foundation for discovering key active ingredients of TCMs for treating specific diseases. PMID- 25276958 TI - [To accelerate pace of studying standard pieces of Chinese medicine as standard material]. AB - OBJECTIVE: To elucidate the necessary and research of accelerating basic research of Chinese standard pieces as standard materials. METHOD: According to over 10 years accumulated experience and be keenly aware of the author, the evaluation method of standardized processing technology and Chinese pieces quality, aimed at consummated the standard material of the quality evaluation of Chinese herbal pieces at the current situation, and inaccordance with the need of improving quality standard system of Chinese herbal pieces, illustrate the necessity of accelerating basic research of Chinese standard pieces as standard materials; from the technical specification for collecting and processing of raw materials, and the technical specification, homogenized sample, packaging, storage and etc., for processing of candidate standard pieces, determine the methods and steps of technical specifications for standard pieces as the standard substance, determine the methods and steps of technical specifications for standard pieces as the standard substance. RESULT AND CONCLUSION: To speed up the basic research of standard of Chinese medicine pieces as of standard material is very necessary. The research objective is to specificate the processing technical for a number of standard pieces, to identify technical specifications and to ascertain the guiding principle and technical specification of decoction pieces as standard substance. This research will provide basic scientific data relevant national departments to apply for the accreditation of the standard substance. PMID- 25276957 TI - [Study on relations between transient receptor potential vanilloid 1 and pungent property of traditional Chinese medicines]. AB - The five-flavor theory of traditional Chinese medicines (TCM) and the flavor efficacy generation mechanism has long been focuses and difficulties in studies on traditional Chinese medicinal properties. In this paper, by using the pharmacophore-based virtual screening technique, the authors discussed the relations between the pungent property and transient receptor potential vanilloid 1 (TRPV1) by studying the TCM components' role in regulating TRPV1 ion channel. The results showed that the matching relationship between TRPV1 agonist pharmacophore model and TCM chemical components could identify the active ingredients from pungent herbs. Therefore, the authors proposed that TRPV1 is one of the potential targets for efficient pungent herbs. The pungent property of TCMs is decided by its chemical components, and consistent with the inherited and additive characteristics. PMID- 25276959 TI - [Advances in studies on growth metabolism and response mechanisms of medicinal plants under drought stress]. AB - Drought stress exerts a considerable effect on growth, physiology and secondary metabolisms of the medicinal plants. It could inhabit the growth of the medicinal plants but promote secretion of secondary metabolites. Other researches indicated that the medicinal plants could depend on the ABA signaling pathway and secreting osmotic substances to resist the drought stress and reduce the damage by it. The article concludes the changes in growth, physiology, secondary metabolisms and response mechanisms of medicinal plants to drought stress that provides a theoretical basis for exploring the relationship between medicinal plants and drought stress. PMID- 25276960 TI - [Advances of chemical constituents and pharmacological activities of Myristica genus]. AB - The genus Myristica (Myristicaceae) consists of 120 species, which were distributed in South Asia, from west Polynesia, Oceania, eastern India to the Philippines. Phytochemical studies showed that 164 compounds including a majority of lignans, along with phenglpropanoids, flavonoids and phenolics, have been isolated from this genus, which exhibited anti-microbial, anti-inflammatory, anticancer, hyperglycemic and hepatic protective activities. This article summarizes research progress of the chemical compositions and their pharmacological activities from this genus, which could provide reference for the in-depth development and utilization of the Myristica plants. PMID- 25276961 TI - [Varieties textual research and usage investigation of white flos gentianae, a Tibetan medicine]. AB - OBJECTIVE: To clarity the original plants and the main application varieties of White Flos Gentianae. METHOD: Herbal textual research, wild specimen collection, investigation and collection of the samples from Tibetan hospital, Tibetan pharmaceutical factory and medical material market were carried out simultaneously to identify the original plants of White Flos Gentianae. RESULT: The results of varieties textual research and specimen identification showed that Gentiana szechenyii, G. purdomii and G. algida were in accord with the record of Tibetan herbal textual The three species above were the original plants of White Flos Gentianae. The identification of 20 batches samples showed that G. szechenyii was the main application variety. The other varieties were only used in Tibetan hospitals. All the samples above were flowering branches. CONCLUSION: It was necessary to strengthen the research on variety systematization of White Flos Gentianae make a further discussion on the taxonomy position of G. purdomii, G. algida and the white flos population. Its was also nessary to establish and improve the quality standard of different variety based on the principle of "one species, one name". The quality specification of White Flos Gentianae should be established and improved to standard clinical utilization and produce feeding. More study of resources investigation and cultivation of G. szechenyii should be carried on to meet the demand of produce and clinic. PMID- 25276962 TI - [Multiple analysis of relationship between morphologic traits and yield formation of Anoectochilus roxburghii]. AB - Nine morphologic traits, plant height, ground diameter, leaf length, leaf width, leaf area of plant, leaf fresh weight, blades, length/width ratio, plant fresh weight of Anoectochilus roxburghii from 13 different areas were determined for correlation analysis, path analysis and principal components analysis. Different source of morphological trait variation coefficient of A. roxburghii was 2.96% 12.59%, plant fresh weight was significant positively correlated with ground diameter, plant height and leaf number, and positively correlated with leaf fresh weight. Path analysis showed that plant height had the largest positive direct effect on plant fresh weight, the leaf fresh weight and blades number had indirect effects on the plant fresh weight. Through principal component analysis, morphological traits of A. roxburghii can be divided into "Determinants of high yielding morphology" and "Determinants of leaf production". In the actual process of production and breeding of A. roxburghii, we should pay attention to plant height, leaf fresh weight, blades numbers and other traits. PMID- 25276963 TI - [Effects of plant-derived smoke water on accumulation of biomass and active substance of Salvia miltiorrhiza f. alba]. AB - To study the effect of plant-derived smoke water on the accumulation of biomass and active substance of Salvia miltiorrhiza f. alba, seedlings of S. miltiorrhiza were treated with different concentrations of smoke water (1:500, 1: 1 000, 1: 2 000). The fresh weight and dry weight of underground part, the number of split root, maximum root diameter, average root diameter, average root length, the content of lipophilic components and water-soluble components were measured. Results showed that fresh weight and dry weight of underground part were respectively improved by 98.01%, 44.32% and 85.71%, 28.57% with significant difference by smoke water treatment with concentration of 1: 500 and 1: 1 000. Maximum root diameter and dry weight of underground part were respectively enhanced by 58.44% and 85.71% by smoke water with concentration of 1:500. The content of tanshinone I and tanshinone II(A) were improved by smoke water treatment, however there were no significantly difference on the content of cryptotanshinone and dihydrotan shinone. This study indicates that smoke water treatment could be used to improve the accumulation of biomass and active substance content of S. miltiorrhiza f. alba, which could provide new ideas for its green cultivating. PMID- 25276964 TI - [Determination of myclobutanil 25% WG degradation dynamics in ginseng root, stem, leaf and soil by HPLC-MS/MS]. AB - A high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) method was developed for determining degradation dynamics and final residues of myclobutanil 25% WG in ginseng root, stem, leaf and soil. The samples were extracted with acetonitrile, cleaned-up with primary secondary amine (PSA) solid phase extraction cartridge, separated by Kromasil Eternity-5-C18 (2.1 mm x 150 mm, 5 microm) column with a gradient of acetonitrile and 0.1% formate in water as mobile phases, and analyzed with the multiple reaction monitoring (MRM) in positive ion mode by employing the external standard method. The average recoveries and the relative standard derivations (RSDs) of myclobutanil at the spiked level of 0.01-0.20 mg x kg(-1) were 80.9%-90.7% and 5.54%-9.29%, respectively, and the limit of quantification (LOQ) was 0.005 mg x kg(-1). The method with good reproducible, high precision and low detection limit could meet the requirements of residual analysis on ginseng production. The half-lives of myclobutanil were from 6.25 days to 9.94 days in ginseng root, stem, leaf and soil at spraying dosage of 1 152 g x hm(-2) The final residues were below 0.060 1 mg x kg(-1) in root, below 0.081 7 mg x kg(-1) in stem, 0.006 0-0.102 2 mg x kg( 1) in leaf and below 0.037 6 mg x kg(-1) in soil at spraying dosage range from 576 to 1 152 g x hm(-2). It is recommended that the MRLs of myclobutanil in dried ginseng may be suggested to be 0.10 mg x kg(-1) temporarily, and the preharvest interval was set at 35 days. PMID- 25276965 TI - [Analysis of critical genes expression of chlorogenic acid and luteolin biosyntheses in Lonicera confusa]. AB - This study analysed the tissue specific expression of critical genes involved in chlorogenic acid and luteolin biosynthesis, for exploiting the molecular mechanism of components biosynthesis in Lonicera confusa. Expression of PAL, 4CL, C4H, CHS, CHI, FNS and HQT gene families of chlorogenic acid and luteolin biosynthesis-related genes in buds and leaves of L. confusa were analyed by Real time PCR. Expressions of PAL1, C4H1, 4CL1, CHS1, CHI3 and HQT2 in buds were lower than that in leaves, and expressions of PAL3, 4CL2, CHI2 and FNS2 in buds were higher than that in leaves. The results indicated that that PAL3 and 4CL2 may be associated with accumulation of chlorogenic acid, and the expression patterns of PAL1, CHS1, CHI3 and HQT2 in buds and leaves of L. confusa were different with L. japonica. This study provided some theoretical basis for the further research on genetic mechanism of active components differences in L. confusa and L. japonica. PMID- 25276966 TI - [Studies on main interspecific association of rare and endangered medicinal plant Sinopodophyllum hexandrum community in Kangding Zheduo mountain of Sichuan province]. AB - Based on the 2 x 2 contingency table, by using multi-species relevance (variance ratio, VR), chi2-test, Ochiai index, Dice index, Jaccard index, t-test of v/x and F-test of Morisita, s index, the interspecific relationships and the spatial distribution pattern between 20 dominants in Kangding Zheduo Mountain of Sichuan province were studied. The results indicated that the interspecific association between dominants of Sinopodophyllum hexandrum community in this area did not show significant association, which suggested that the S. hexandrum community was in mature stage, and showed stronger independency, among total 190 pairs in 20 dominant species, 2 species pairs exhibited extremely significantly positive association, 12 species pairs showed significantly positive association, 6 species pairs exhibited significantly negative association and there were no pairs showed extremely significantly negative association. S. hexandrum in community did not show significant association, which indicates they are independent in community, the spatial distribution pattern of S. hexandrum is characterized by random distribution. PMID- 25276967 TI - [Wild resources survey of Marsdenia tenacissima in Honghe, Yunnan]. AB - To ascertain current situation of wild Marsdenia tenacissima resources in Honghe, Yunnan province, the distribution, habitat characteristic and resources reserves of M. tenacissima were surveyed based on interviews and investigation. The results showed that M. tenacissima was found in 7 counties such as Jinping, Mengzi etc, and distributed mainly on the mountainsides from 800 m to 1 200 m. And distribution was affected by many factors, such as light, heat, topography, soil, and vegetation. M. tenacissima grew well in distribution areas. M. tenacissima had averagely a weight of 2.8 kg per plant. Resources reserve of M. tenacissima in Honghe was estimated to 1 300 tons by now but it reduced rapidly in resent years, the wild resources reserve may not meet demand of market. Resources protection and wildlife tending would be conducted to deal with increasing medication requirements. PMID- 25276968 TI - [Compared with colloidal silica and porous silica as baicalin solid dispersion carrier]. AB - OBJECTIVE: To compare the dissolution characteristics of colloidal silica and porous silica as the solid dispersion carrier, with baicalin as the model drug. METHOD: The baicalin solid dispersion was prepared by the solvent method, with colloidal silica and porous silica as the carriers. In the in vitro dissolution experiment, the solid dispersion was identified by scanning electron microscopy, differential scanning and X-ray diffraction. RESULT: The solid dispersion carriers prepared with both colloidal silica and porous silica could achieve the purpose of rapid release. Along with the increase in the proportion of the carriers, the dissolution rate is accelerated to more than 80% within 60 min. Baicalin existed in the solid dispersion carriers in the non-crystalline form. CONCLUSION: The release behaviors of the baicalin solid dispersion prepared with two types of carrier were different. Among the two solid dispersion carriers, porous silica dissolved slowly than colloidal silica within 60 min, and they showed similar dissolutions after 60 min. PMID- 25276969 TI - [Preparation and pharmacokinetic evaluation of long-acting injectable oily suspensions for ophiopogonis radix polysaccharide MDG-1]. AB - OBJECTIVE: To evaluate in vivo pharmacokinetics of Ophiopogonis Radix polysaccharide MDG-1 oily suspension injection prepared with different prescriptions in rats, and explore the feasibility of the long-acting drug delivery of MDG-1 Injection by using the oily suspension drug release system. METHOD: MDG-1 microparticles were prepared by the anti-solvent precipitation method. Their size and size distribution were characterized. Castor oil with a high viscosity or aluminum stearate were added into soybean oil with a low viscosity, in order to prepare oily media with different viscosities, detect their rheological properties and screen out superior prescriptions for in vivo evaluation. RESULT: The average size of microparticles was 21.81 microm, and the span between them was 2.63. The in vivo evaluation was conducted for prescriptions of mixed oil (soybean oil/castor oil, 2: 3) and soybean oils gelled by 2% and 4% aluminium stearate. Among them, the prescription of soybean gelled by 4% aluminium stearate could significantly reduce C(max) and prolong the apparent t1/2, with the MDG-1 release time of several days. CONCLUSION: It is feasible to achieve the long-acting MDG-1 drug delivery by using oily media with a high viscosity. PMID- 25276970 TI - [Multi-objective optimization of extraction process for red ginseng based upon extraction efficiency and cost control]. AB - It is the objective of this study to optimize the extraction process of red ginseng to minimize the unit cost of extracting effective ingredients. The relation between the target variables of total quantity of ginsenosides and first extraction time, first extraction solution amount, second extraction time, second extract solution amount were studied with Box-Behnken experimental design method. At the same we also considered the cost of extraction solution and energy usage. The objective function was set as unit cost of target (total quantity of ginsenosides or its purity) for the multi-objective optimization of extraction process. As a result, the optimal process parameters were found as first extraction time (108.7 min), first extraction solution amount folds (12), second extraction time (30 min), second extraction solution amount folds (8) to minimize the unit cost. It indicated that this approach could potentially be used to optimize industrial extraction process for manufacturing Chinese medicine. PMID- 25276971 TI - [Optmization for cutting procedure of astragali radix with Box-Behnken design and response surface method]. AB - Astragali Radix was firstly recorded in the "Shen Nong's Herbal Classic" as a top grade and commonly used traditional Chinese medicine. Its frequently used slices include raw Astragali Radix and honey-processed products. In current studies, many reports were made on honey-processed Astragali Radix, whereas fewer study reports were made on the cutting process of Astragali Radix. Currently, because Astragali Radix is primarily cut by drug workers according to their operating experience, but with out specific cutting parameters, it is easy to cause the loss or mildew of active ingredients. As a result, the quality of Astragali Radix circulated in the market is not guaranteed, and the quality of their slices and preparations are hard to be controlled, which seriously impact the clinical efficacy. In response, this experiment was performed, in which the optimum cutting process of Astragali Radix was taken as the study objective, the Box Benhnken central composite design in the response surface analysis was adopted, and the content and appearance character of astragaloside and calycosin-7 glucoside were regarded as the study indicators. Three factors, namely the softening time, the drying temperature and the drying time, were selected to optimize the cutting process of Astragali Radix and obtain the optimum cutting process parameters as follows: the softening time was 3 hours, the drying temperature was 50 degrees C, and the drying time was 4 hours. According to the verification test, the Astragali Radix cutting process is steady and feasible, which has certain significance for normalizing the cutting process of Astragali Radix. PMID- 25276972 TI - [Study on method of paeonia radix alba producing and concocting integration processing]. AB - OBJECTIVE: To study the origin pre-treating and processing integration techniques of Paeonia Radix Alba. METHOD: Different processing integration techniques were adopted and compared with traditional processing techniques to determine drying rate, aqueous extracts and peoniflori content. RESULT: Half-dry slices baked at 100 degrees C for 20 min and steamed at 100 degrees C for 10 min had the highest peoniflori contents. Half-dry slices baked at 100 degrees C for 20 min had the highest content of aqueous extracts. Products processed with conventional method and sulfur-fumigation had the lowest content of aqueous extracts. CONCLUSION: The origin processing integration techniques of Paeonia Radix Alba lose less active ingredients than conventional processing methods. PMID- 25276973 TI - [Purification technology of procymidone residues in ginseng extracts by macroporous resins]. AB - The macroporous resin separation technology has been mainly applied in the enrichment of saponins, flavonoids, alkaloids and other ingredients, and used in the removal of heavy metal impurities and pesticide residues in recent years. This paper focuses on the synthesis of the new-type macroporous adsorption resin LKS-11 according to the molecular structure characteristics of procymidone. Specifically, the selective absorptive property and other advantages of macroporous resin were utilized to analyze the procymidone removal efficiency in ginseng extracts from different sources. The type of macroporous resins, absorptive property and desorption conditions were observed respectively by static and dynamic adsorption methods to determined the optimum process conditions. According to the results, LKS-11 showed a good absorptive property to procymidone in ginseng extracts and provided a theoretical basis for studies on the removal of procymidone residues from ginseng extracts by using macroporous adsorption resin. Because of no secondary pollution on samples, low production and operation costs, high procymidone removal efficiency and high product recovery rate, this method is suitable to be applied in production. PMID- 25276974 TI - [Identification of phenylpropanoids in ciwujia injection by HPLC-MS]. AB - There are reports about the chemical compounds of Ciwujia herbs, but with no study report about the chemical material basis of Ciwujia injection (CWJI). In this study, LC-MS(n) and LC-Q-TOF-MS techniques were adopted for a qualitative analysis on phenylpropanoids in CWJI. The Ultmate XB-C18 column (4.6 mm x 250 mm, 5 microm) was adopted and eluted with the mobile phase of 0.5% formic acid-water and acetonitrile, with the flow rate at 0.8 mL x min(-1) and the column temperature at 20 degrees C. Based on the data of high-resolution and multi-stage MS, control products and literatures, altogether 54 phenylpropanoids were identified in Ciwujia Injection, including 34 phenylpropanoids, 16 ligans and 4 coumarins. Among them, 28 were reported for the first time in Ciwujia, and 14 compound structures were identified in comparison with the control products. The method established in this study could be used to simply and rapidly identify phenylpropanoids in CWJI. The findings provide scientific data for defining the chemical material basis of CWJI. PMID- 25276975 TI - [Chemical constituents from seeds of Brassica campestris]. AB - Fourteen compounds were isolated by column chromatography from the ethyl acetate extract of the seeds of Brassica campestris. Their structures were elucidated by physicochemical properties and spectroscopic data analysis. The isolated compounds were respectively identified as (5Z,7E)-4, 4-dimethyl-5-acetyl-5, 7 nonadienoic acid (1), indole-3-carboxaldehyde (2), blumenol A (3), vinylsyringol (4), sinapinic acid (5), sinapic acid ethyl ester (6), protocatechuic acid (7), crinosterol (8), campesterol (9), 7-oxo-stigmasterol (10), kaempferol (11), 2,5 dihydroxybenzoic acid (12), syringic acid (13) and daucosterol (14). Compound 1 was a new compound and the other compounds were isolated from this plant for the first time except for compounds 4, 5 and 13. PMID- 25276976 TI - [Chemical constituents of Illicium burmanicum]. AB - Chemical constituents of ethyl acetate extract of Illicium burmanicum were isolated and purified by various chromatographic methods,including Silica gel, Sephadex LH-20, C18 reverse-phased silica gel, Preparative TLC and Preparative HPLC. Their structures were identified by spectral analysis including NMR and MS data. Fourteen compounds were separated from I. burmanicum and their structures were identified as 7S,8R-erythro-4,7,9,9'-tetrahydroxy-3,3'-dimethoxy-8-O-4' neolignan (1), 7R,8R-threo-4,7, 9,9'-tetrahydroxy-3,3 '-dimethoxy-8-O-4' neolignan(2) ,polystachyol(3), (-) -massoniresinol(4), angustanoic acid F (5), trans-sobrerol(6), (3S,6R) -6,7-dihydroxy-6,7-dihydrolinalool (7), (3S, 6S) -6,7 dihydroxy-6,7-dihydrolinalool (8), 2,6-dimethoxy-4-allyl-phenol (9), 3,5 dihydroxy4-hydroxy benzaldehyde (10), 3-hydroxy4-methoxybenzaldehyde (11), methyl vanillate (12), shikimic acid ethylester (13) and beta-sitosrerol (14). Except compound 14, the rest thirteen compounds were separated from this plant for the first time. PMID- 25276977 TI - [Chemical constituents of Artemisia lactiflora(II)]. AB - To study the chemical constituents of Artemisia lactiflora. The compounds were isolated by column chromatography with silica gel, C18 reverse-phase silica gel, semi-preparative HPLC, and their structures were elucidated on the basis of spectral analysis. Twelve compounds were isolated from alcohol extracts of A. lactiflora and identified as 7-hydroxycoumarin (1), 7-methoxycoumarin (2), balanophonin (3), aurantiamide (4), aurantiamide acetate (5), isovitexin (6), kaempferol-3-O-beta-D-rutinoside (7), rutin (8), caffeic acid ethyl ester (9), quercetin (10), methyl 3, 5-di-O-caffeoyl quinate (11) and methyl 3, 4-di-O caffeoyl quinate (12), respectively. Compounds 3-12 were obtained from this plant for the first time. PMID- 25276978 TI - [Comprehensive chemical pattern recognition of atractylodis rhizoma]. AB - A method of comprehensive chemical pattern recognition of Atractylodis Rhizoma was established by GC-MS fingerprint, principal component analysis, cluster analysis and discriminant analysis. A DB-wax column (0.25 mm x 60 m, 0.25 microm) with El ion source and 70 V electron multiplier were used for GC-MS analysis. Using principal component analysis, cluster analysis, and discriminant analysis, 15 common peaks of sample fingerprints for chemical pattern recognition research were analysed. The same results were obtained from the fingerprint, principal component analysis and cluster analysis, which could use to distinguish genuine Atractylodes lancea, ungenuine A. lancea and A. chinensis. Thus, this method could be used for the quality control and comprehensive evaluation of Atractylodis Rhizoma. PMID- 25276979 TI - [HPLC fingerprints of tibetan medicinal herb "songdi" (Saxifraga umbellulata var. pectinata)]. AB - The research was carried out to establish HPLC fingerprints of Tibetan medicinal herb "Songdi" (Saxifraga umbellulata var. pectinata), and to provide reference for identification an quality control of it. It was performed on an Amethyst-C18 P (4.6 mm x 250 mm, 5 microm) column with the mobile phase of methanol-0.4% formic acid in a linear gradient mode at a flow rate of 1.0 mL x min(-1). The column temperature was 30 degrees C, and the detection wavelength was set at 254 nm. The software for chromatographic fingerprint was applied to analyse the pattern analysis, the common peaks and similarity. Cluster analysis was done based on the common peaks data of 33 samples from different plant species and sources by SPSS software. Ten common chromatographic peaks were identified by fingerprint, showing a low similarity in constituent and variety. Flavonoids and saponins were the principal components. The number and area of peaks were affected by the collection sources and method. The high similarity are showed by the samples derived from the same area with high accuracy and high purity. The method is so simple, exclusive, stable and high repeatable that it can provide reference for identification and quality assessment of "Songdi" (S. umbellulata var. pectinata). PMID- 25276980 TI - [Study on preventive and therapeutic effects of combined application of yindanxinnaotong soft capsule and exercise on atherosclerotic rats]. AB - To explore the prevention effect of the joint combination of Yindanxinnaotong soft capsule (YDXNT) and exercise (swimming) on atherosclerotic rats. The method of 3 x 3 factorial design, including two factors (YDXNT and swimming) and three levels (0, 1, 2 g x kg(-1) YDXNT; 0, 0.5, 1 h swimming), was mainly adopted. The atherosclerotic rat model was established by ligating their left common carotid arteries and feeding high-fat diet. After 8 weeks, blood samples were collected from their thoracic aorta to determine blood viscosity, plasma viscosity, fibrinogen (FIB), nitric oxide (NO), 6-keto-PGF(1alpha) endothelin (ET) and thromboxane B2 (TXB2). The tissues of left common carotid arteries of the rats were collected to detect the positive expression of SM22alpha and determine the semi-quantitation through the immunohistochemical staining. The result showed that the combination of YDXNT and swimming can significantly decrease the plasma viscosity (F = 3.241, P = 0.017), the high and low shear blood viscosity (F = 6.444, P = 0.001; F = 3.002, P = 0.024) and FIB (F = 4.046, P = 0.005). The increased NO and 6-keto-PGF(1alpha) and the decreased ET and TXB2 indicated a significant interaction (P < 0.05). The swimming showed an obvious main effect in the expression of up-regulated protein SM22alpha (F = 8.088, P = 0.001). The study suggested that the combined administration of YDXNT and swimming could improve the hemorheological parameters of atherosclerotic rats, protect the vascular endothelium, inhibit the vascular remodeling in atherosclerosis and positively prevent the atherosclerosis. PMID- 25276981 TI - [Effect of different compatibility of zhizi dahuang decoction on pharmacokinetics of naringenin and hesperetin]. AB - An HPLC-UV method was developed for the determination of total naringenin and total hesperetin in rat plasma after oral administration of Citrus aurantium Immaturus extracts and Zhizi Dahuang decoction. Plasma samples were pretreated with liquid-liquid extraction procedure and acid hydrolysis method was used for converting conjugated naringenin and hesperetin to their respective free forms. Plasma samples were separated on a C18 column (4.6 mm x 150 mm, 5 microm), using 0.1% phosphoric acid and methanol as mobile phase at a flow rate of 1.0 mL x min( 1) with gradient elution. DAS 2.0 software was applied to calculate the pharmacokinetic parameters while the SPSS 16.0 software was used for statistical analysis. Significant differences were observed, the C(max) AUC(0-t) of total naringenin in ZS group was 73.5% and 65.9% higher than those in ZZDHD group, respectively; the C(max), AUC(0-t) of total hesperetin in ZS group was 63.5% and 119.1% higher than those in ZZDHD group, respectively. There is a obvious decrease in C(max) and AUC(0-t) of total naringenin and total hesperetin after compatibility and their pharmacokinetic characteristics changed greatly due to the combination of other herbs. The established method was rapid, sensitive, selective and accurate, and it could be applied in the determination of total naringenin and total hesperetin in rat plasma. PMID- 25276982 TI - [Pharmacokinetic study on peoniflorin, astilbin, rosmarinic acid, isofraxidin and liquiritin in rat blood after oral administration of shaolin xiaoyin tablets]. AB - To establish a method for the determination of astilbin, peoniflorin, rasmarinci acid, isofraxidin and liquiritin contained in Shaolin Xiaoyin tablets, in order to lay a foundation for designing late-stage dosage forms and clinical medication schemes. In this paper, efforts were made to establish a method for the determination of the blood concentration of the five components and study the in vivo pharmacokinetics in rats. The blood concentration was determined by HPLC. Phenomenex C18 column (4.6 mm x 250 mm, 5 microm) was adopted and eluted with methanol-acetonitrile-0.05% formic acid, the flow rate was 0.8 mL x min(-1), and the wavelength was 275 nm. The samples were processed by the solid phase extraction method. After oral administration of Shaoling Xiaoyin tablets, the rat bloods were collected at different time points to determine the blood concentrations. The experimental results showed that the baseline separation could be adopted for the five components, and astilbin, peoniflorin, rasmarinci acid, isofraxidin and liquiritin showed good linear relations within ranges of 2.48-248, 0.213 6-21.36, 0.531-53.1, 0.704-70.4, 0.253-25.3 mg x L(-1). All the five components could be absorbed in blood and excreted quickly. The method established in this paper is rapid and accurate, and could be used for in vivo analysis on preparations containing similar components. The main components in Shaoling Xiaoyin tablets could be absorbed and excreted quickly, and thus suitable to be made into sustained release tablets. Common preparations are required to be taken for 4-6 times a day. PMID- 25276983 TI - [Effect of xingnaojing injection combined with minimally invasive percutaneous drainage in treating brain edema and content of serum AQP4 in patients with moderate hypertensive basal ganglia hemorrhage]. AB - OBJECTIVE: To observe the effect of Xingnaojing Injection combined with minimally invasive percutaneous drainage on brain edema and content of serum aquaporin-4 (AQP4) in patients with moderate hypertensive basal ganglia hemorrhage, and discuss the treatment mechanism of Xingnaojing injection combined with minimally invasive percutaneous drainage for cerebral hemorrhage. METHOD: Forty-two patients with moderate (25-50 mL) hypertensive basal ganglia hemorrhage (< 24 h) were selected and randomly divided into two groups: the observation group (n = 22) and the control group (n = 20). The neurological severity score were evaluated by the NIHSS (national institutes of health stroke scale), the volume of brain edemas were measured by head CT, the serum levels of AQP4 were determined by ELISA method on admission and 1 and 2 weeks after treatment. RESULT: On admission, there was no significant difference in the scores of NIHSS, the volume of brain edemas and the level of serum AQP4 between the observation group and the control group. At the end of the first week after the treatment, the score of NIHSS of the observation group were lower than that of the control group, with significant different (P < 0.05); the observation group showed reduced volume of brain edemas than that on admission (P < 0.05), whereas the control group the control group showed increased volume of brain edemas than that on admission; the control group displayed increased level of serum AQP4 than that on admission, but without significant difference; the observation group displayed decreased level of serum AQP4 than that on admission (P < 0.05). At the end of the second week after the treatment, the control group showed decreased score of NIHSS than that on admission and at the end of the first week after treatment (P < 0.05). Compared with the control group, the observation group showed a much lower score of NIHSS (P < 0.01), the control group displayed reduced volume of brain edemas than that on admission and at the end of the first week after treatment, but the observation group was even lower than the control group. Both of observation and control groups displayed significantly reduced level of AQP4 (P < 0.05), but the observation group showed a lower AQP4 level than that of the control group (P < 0.05). CONCLUSION: The therapy of Xingnaojing injection combined with minimally invasive percutaneous drainage could remarkably reduce brain edema, and promote neural functional recovery, thus could be selected as a therapeutic regimen for patients with moderate hypertensive basal ganglia hemorrhage. PMID- 25276984 TI - [Essence of professor SHI Xin-de's experience in application of persicae ramulus associated prescriptions]. AB - Persicae Ramulus decoction, as the first prescription in Treatise on febrile Diseases, has been recommended by physicians of successive generations. It is also the general prescription for harmonizing yingfen and weifen, yin and yang, qi and blood. Although it only consists of five herbal medicines, it has a wider range of application and more categorized formulas than other prescriptions. Though Persicae Ramulus decoction was originally formulated to treat taiyang apoplexy, it has functions beyond the treatment of exopathic diseases. This formula is also effective in treating internal diseases, surgical diseases, gynecologic diseases, paediatric diseases, etc. KE Yun-bo praised it as the No. 1 formula among ZHANG Zhong-jin's formulas as well as the general prescription for harmonizing Yin and Yang, yingfen and weifen, resolving fleshy exterior and inducing perspiration. Professor SHI Xin-de has been expert at treating intractable diseases by using Persicae Ramulus-associated prescriptions, such as Xiaojianzhong decoction and Baohe pill for children's chronic eczema, Persicae Ramulus and Puerariae Lobatae Radix decoction and Yupingfeng powder for chronic nephritis, and Persicae Ramulus and Longgu Muli decoction for insomnia. Instead of being restricted to Chinese or Western disease names, he prescribed appropriate formulas according to syndromes, thereby achieving a good efficacy. PMID- 25276985 TI - [Study on safety of Tibetan medicine zuotai and preliminary study on clinical safety of its compound dangzuo]. AB - Zuotai (gTso thal) is a typical representative of Tibetan medicines containing heavy metals, but there is still lack of modem safety evaluation data so far. In this study, acute toxicity test, sub-acute toxicity test, one-time administration mercury distribution experiment, long-term mercury accumulative toxicity experiment and preliminary study on clinical safety of Compound Dangzuo were conducted in the hope of obtain the medicinal safety data of Zuotai. In the acute toxicity test, half of KM mice given the lethal dose of Zuotai were not died or poisoned, and LD50 was not found. The maximum tolerated dose of Zuotai was 80 g x kg(-1). In the subacute toxicity test, Zuotai could reduce ALT, AST, Crea levels in serums under low dose (13.34 mg x kg(-1) x d(-1)) and medium dose (53.36 mg x kg(-1) x d(-1)), with significant difference under low dose, and increase the levels of ALT, AST, MDA, Crea in serums under high dose (2 000 mg x kg(-1) x d( 1)); besides, the levels of BUN and GSH in serums reduced with the increase in dose of Zuotai, indicating a significant dose-effect relationship. In the one time administration distribution experiment, the content of mercury in rat kidney, liver and lung increased after the one-time administration with Zuotai, with a significant dose-dependent relationship in kidney. In the long-term mercury accumulative toxicity experiment, KM mice were administered with equivalent doses of Zuotai for 4.5 months and then stopped drug administration for 1.5 months. Since the 2.5th month, they showed significant mercury accumulation in kidney, which gradually reduced after drug withdrawal, without significant change in mercury content in liver, spleen and brain and ALT, AST, TBIL, BUN and Crea in serum. At the 4.5th month after drug administration, KM mice showed slight structural changes in kidney, liver and spleen tissues, and gradually recovered to normal after drug withdrawal. Besides, no significant difference in weight gain was found between the Zuotai group and the control group. According to the findings of the clinical safety study of Dangzuo, after subjects administered Dangzuo under clinical dose for one month, their serum biochemical indicators, blood routine indicators and urine routine indicators showed no significant adverse change. This study proved that traditional Tibetan medicine Zuotai was slightly toxic, with a better safety in clinical combined administration and no adverse effects on bodies under the clinical dose and clinical medication cycle. However, long-term high-dose administration of Zuotai may have a certain effect on kidney. PMID- 25276986 TI - [Combination analysis of new drug discovery with "Xiaohe Silian" method and traditional Chinese medicine clinical pharmacy]. AB - With the kernel of efficacy, "Xiaohe Silian" was a pattern and method for new drug discovery which was constituted with "metabolism-efficacy, toxicity efficacy, quality-efficacy and structure-efficacy". Its connotation was in keeping with traditional Chinese medicine (TCM) clinical pharmacy. This paper systematically summarized the research method of new drug discovery practice process for TCM. To avoid western drug like in TCM new drug discovery, we carried out combination analysis with TCM clinical pharmacy. The correlation analysis between basic elements of "Xiaohe Silian(n) and TCM clinical pharmacy was studied to guarantee this method could integrate closely with TCM clinic from all angles. Hence, this method aimed to provide a new method for TCM new drug discovery on the basis of TCM clinical pharmacy with insisting on holistic view of multicomponent study, kinetic view of metabolic process when the curative effect occurred and molecular material view of quality control and structure-activity exposition. PMID- 25276987 TI - Revitalization. PMID- 25276988 TI - Plant a seed, watch it grow. PMID- 25276989 TI - Responsiveness of the patient's perception of hemodialysis scale. AB - OBJECTIVES: To assess hemodialysis (HD) patients' physical health, social supports, psychosocial well-being and the interrelationship among patients' experiences, demographics, illness characteristics, and biochemical indicators of health. To determine responsiveness of the Patient's Perception of Hemodialysis Scale (PPHS) to change in health status and critical events. METHODS: Using a longitudinal design HD patients (n = 85) were assessed at two time periods. Data analysis included measures of central tendency and tests of difference to assess interrelationships and responsiveness of the PPHS. RESULTS: There were no significant changes in PPHS's subscales scores between measurement times or groups based on demographic variables. Significant differences were found in the number of co-morbid illnesses, illness severity, albumin, and urea reduction. The Psychosocial Distress subscale varied significantly in relation to time on HD, reason for admission to hospital, and number of admissions. Physical Health scores were significantly different for subgroups divided by illness, illness severity, number of illnesses, age, albumin and reason for admission. PPHS subscale mean scores were responsive to positive events in the predicted direction most of the time and appeared to have had more of an effect on the PPHS scores than negative critical events. CONCLUSION: The PPHS is responsive to a change in physical health and positive critical events, but results were unsubstantiated for patient's reaction to negative critical events. The PPHS is reliable, valid, and responsive to physical changes and positive critical events. This instrument offers health care professionals a viable method for assessing important factors capable of predicting quality outcomes. PMID- 25276990 TI - Should statins be used to prevent cardiovascular disease in patients on hemodialysis? AB - There now exists current evidence that the initiation of statin therapy in patients on hemodialysis does not provide the same cardiovascular benefit as in non-hemodialysis patients. The KDIGO guidelines suggest not to initiate statin therapy in hemodialysis-dependent CKD patients, but to continue therapy in patients who are already on a statin at the time of hemodialysis initiation. A closer monitoring of myopathy is warranted for hemodialysis patients on a statin therapy. PMID- 25276991 TI - The absentee hemodialysis patient. PMID- 25276992 TI - [Approximation to the medieval arabian lexicon of epidemics and plague]. PMID- 25276993 TI - [Biochemistry and embryos. The embryologic work of Jose Maria Genis Galvez (1924 2003) during Franco dictatorship]. PMID- 25276994 TI - [Coffee and the pancreas: a half life of medical truth]. PMID- 25276995 TI - [Pancreatic cancer in 2014: screening and epidemiology]. AB - Pancreatic cancer remains today the cancer with the worst prognosis with 330300 deaths per year worldwide with a cancer prevalence of 211500 cases in 2012. Despite progress made in the understanding of the pathophysiology of this neoplasia, morbidity and mortality have not been modified. Tobacco remains the only modifiable risk factor with an impact on the incidence of pancreatic cancer. Screening programs involving medical imaging and serum markers have so far failed to alter the incidence and prognosis of the disease, even in selected populations with high risk. However, screening programs allowed some high-risk patients to be diagnosed early and therefore have been received care at an asymptomatic stage. The impact on the prognosis has nevertheless not been demonstrated yet. PMID- 25276997 TI - [Extra-hepatic morbidity and mortality related to hepatitis C virus infection]. AB - In addition to liver-related complications, HCV infection is associated with extra-hepatic manifestations. Patients have an increased risk of developing insulin resistance or type II diabetes. HCV infection is also associated with cryoglobulinemia which manifests itself with skin lesions, renal failure, or peripheral nervous system involvement. The risk of developing non-Hodgkin lymphoma, typically derived from B cells, is also increased. Patients may present with symptoms of CNS involvement. The association with cardiovascular events is likely but not proven with certainty. In some cases, the management of extra hepatic manifestations of HCV will require antiviral therapy. PMID- 25276996 TI - [Microscopic colitis: update 2014]. AB - Microscopic colitis, which includes lymphocytic colitis and collagenous colitis, represents a frequent cause of chronic watery diarrhea especially in the elderly population. Several medications, such as nonsteroidal antiinflammatory drugs, proton pump inhibitors or antidepressants, as well as cigarette smoking have been recognized as risk factors for microscopic colitis. The diagnosis of microscopic colitis is based on a macroscopically normal ileo-colonoscopy and several biopsies from the entire colon, which demonstrate the pathognomonic histopathologic findings. Therapy is mainly based on the use of budesonide. Other medications, such as mesalazine, cholestyramine and bismuth, have been evaluated as well but the evidence is less solid. PMID- 25276998 TI - [New hepatitis C treatments: pharmacological considerations and potential for drug interactions]. AB - Progress in the understanding of the hepatitis C virus life cycle allowed the development of new, very promising antiviral therapies. Although these new drugs have a favourable profile in terms of efficacy, tolerance and interaction potential, their prescription in the setting of comedication and impaired renal or hepatic function remains a challenge. Here, we provide a summary of pharmacological considerations, focusing on sofosbuvir, simeprevir and daclatasvir. A better understanding of their metabolic pathways and transporters may help the prescriber to identify and manage drug interactions especially in patients under immunosuppressive or anti-HIV therapy. Recommendations for the prescription of these drugs in specific situations are also discussed. PMID- 25276999 TI - [Management of refractory ascites by the automated low flow pump system (Alfapump)]. AB - Refractory ascites affects 10% of patients with advanced cirrhosis. Recurrent ascites is commonly managed by repeat large volume paracentesis with volume expansion, and in selected patients, by the implantation of a transjugular intrahepatic portosystemic shunt (TIPS). Both approaches are associated with potential complications, including vascular traumatic injuries in the setting of paracentesis. A new automatic pump has been developed to mechanically remove ascites from the peritoneal cavity to the bladder. The benefit of this pump in terms of reduced frequency of paracentesis should be balanced by the risk of adverse events that include infection, catheter dysfunction, and renal insufficiency. The place of this new device in the management of ascites due either to portal hypertension or to cancer remains to be determined. PMID- 25277000 TI - [Hepatic encephalopathy: recent developments]. AB - Hepatic encephalopathy is a neurological syndrome occurring in patients with liver failure or in those with a large porto-systemic shunt. In cirrhotic patients, the current classification comprises covert and overt encephalopathy. Diagnosis of covert encephalopathy requires sensitive tests. Lactulose and rifaximin are the two leading therapeutic options. Rifaximin is efficacious for maintaining remission from hepatic encephalopathy. Liver transplantation should be discussed in cirrhotic patients with encephalopathy. PMID- 25277001 TI - ["I am a little out of breath". When a commonplace symptom hides a rare disease: cardiac amyloidosis]. AB - Based on a case report, this article reviews the different forms of cardiac involvement in amyloidosis. This affection refers to the extracellular tissue deposition of protein fibrils (the amyloid substance), which gradually invades a variety of organs, disrupting their function. The clinical presentation depends on the type of the amyloidogenic protein and on its main distribution. The most severe cardiac impairment and with the worse prognosis is seen in its primary form (or AL), while it is less frequent, with a slower course and a better prognosis in its other forms: secondary (AA), familial (ATTR) or senile (SSA). PMID- 25277002 TI - [Introduction. Future physicians survey the community]. PMID- 25277003 TI - [Organ shortage: more selective waiting list requirements or an improvement in kidney donation?]. PMID- 25277004 TI - [Sex workers: difficult access to care]. PMID- 25277005 TI - [Melanoma: a cancer that tans]. PMID- 25277006 TI - [The health of the food industry. Health and nutrition assertions]. PMID- 25277007 TI - [Cyberchondria]. PMID- 25277008 TI - [Is the World Health Organization guilty of delaying the fight against Ebola?]. PMID- 25277009 TI - [Legal and criminal superego]. PMID- 25277010 TI - [The fight against the hepatitis C epidemic: lessons from Egypt]. PMID- 25277011 TI - [In children, obesity and lack of sleep are linked]. PMID- 25277012 TI - [Revolutionary messages from Dr. Cabanis (1757-1808)]. PMID- 25277014 TI - Effects of intelligent advanced warnings on drivers negotiating the dilemma zone. AB - OBJECTIVE: We investigated whether intelligent advanced warnings of the end of green traffic signals help drivers negotiate the dilemma zone (DZ) at signalized intersections and sought to identify behavioral mechanisms for any warning related benefits. BACKGROUND: Prior research suggested that warnings of end of green can increase slowing and stopping frequency given the DZ, but drivers may sometimes respond to warnings by speeding up. METHOD: In two simulator studies, we compared six types of roadway or in-vehicle warnings with a no-warning control condition. Using multilevel modeling, we tested mediation models of the behavioral mechanisms underlying the effects of warnings. RESULTS: In both studies, warnings led to more stopping at DZ intersections and milder decelerations when stopping compared with no warning. Drivers' predominant response to warnings was anticipatory slowing on approaching the intersection, not speeding up. The increased stopping with warning was mediated by increased slowing. In Study I, anticipatory slowing given warnings generalized to green light intersections where no warning was given. In Study 2, we found that lane specific warnings (e.g., LED lights embedded in each lane) sometimes led to fewer unsafe emergency stops than did non-lane-specific roadside warnings. CONCLUSION: End-of-green warnings led to safer behavior in the DZ and on the early approach to intersections. The main mechanism for the benefits of warnings was drivers' increased anticipatory slowing on approaching an intersection. Lane-specific warnings may have some benefits over roadside warnings. APPLICATION: Applications include performance models of how drivers use end-of-green warnings, control algorithms and warning displays for intelligent intersections, and statistical methodology in human factors research. PMID- 25277015 TI - Displaying contextual information reduces the costs of imperfect decision automation in rapid retasking of ISR assets. AB - OBJECTIVE: The impact of a decision support tool designed to embed contextual mission factors was investigated. Contextual information may enable operators to infer the appropriateness of data underlying the automation's algorithm. BACKGROUND: Research has shown the costs of imperfect automation are more detrimental than perfectly reliable automation when operators are provided with decision support tools. Operators may trust and rely on the automation more appropriately if they understand the automation's algorithm. The need to develop decision support tools that are understandable to the operator provides the rationale for the current experiment. METHOD: A total of 17 participants performed a simulated rapid retasking of intelligence, surveillance, and reconnaissance (ISR) assets task with manual, decision automation, or contextual decision automation differing in two levels of task demand: low or high. Automation reliability was set at 80%, resulting in participants experiencing a mixture of reliable and automation failure trials. Dependent variables included ISR coverage and response time of replanning routes. RESULTS: Reliable automation significantly improved ISR coverage when compared with manual performance. Although performance suffered under imperfect automation, contextual decision automation helped to reduce some of the decrements in performance. CONCLUSION: Contextual information helps overcome the costs of imperfect decision automation. APPLICATION: Designers may mitigate some of the performance decrements experienced with imperfect automation by providing operators with interfaces that display contextual information, that is, the state of factors that affect the reliability of the automation's recommendation. PMID- 25277016 TI - Stages and levels of automation in support of space teleoperations. AB - OBJECTIVE: This study examined the impact of stage of automation on the performance and perceived workload during simulated robotic arm control tasks in routine and off-nominal scenarios. BACKGROUND: Automation varies with respect to the stage of information processing it supports and its assigned level of automation. Making appropriate choices in terms of stages and levels of automation is critical to ensure robust joint system performance. To date, this issue has been empirically studied in domains such as aviation and medicine but not extensively in the context of space operations. METHOD: A total of 36 participants played the role of a payload specialist and controlled a simulated robotic arm. Participants performed fly-to tasks with two types of automation (camera recommendation and trajectory control automation) of varying stage. Tasks were performed during routine scenarios and in scenarios in which either the trajectory control automation or a hazard avoidance automation failed. RESULTS: Increasing the stage of automation progressively improved performance and lowered workload when the automation was reliable, but incurred severe performance costs when the system failed. CONCLUSION: The results from this study support concerns about automation-induced complacency and automation bias when later stages of automation are introduced. The benefits of such automation are offset by the risk of catastrophic outcomes when system failures go unnoticed or become difficult to recover from. APPLICATION: A medium stage of automation seems preferable as it provides sufficient support during routine operations and helps avoid potentially catastrophic outcomes in circumstances when the automation fails. PMID- 25277017 TI - Effect of feedback mode and task difficulty on quality of timing decisions in a zero-sum game. AB - OBJECTIVE: The objective was to investigate the interaction between the mode of performance outcome feedback and task difficulty on timing decisions (i.e., when to act). BACKGROUND: Feedback is widely acknowledged to affect task performance. However, the extent to which feedback display mode and its impact on timing decisions is moderated by task difficulty remains largely unknown. METHOD: Participants repeatedly engaged a zero-sum game involving silent duels with a computerized opponent and were given visual performance feedback after each engagement. They were sequentially tested on three different levels of task difficulty (low, intermediate, and high) in counterbalanced order. Half received relatively simple "inside view" binary outcome feedback, and the other half received complex "outside view" hit rate probability feedback. The key dependent variables were response time (i.e., time taken to make a decision) and survival outcome. RESULTS: When task difficulty was low to moderate, participants were more likely to learn and perform better from hit rate probability feedback than binary outcome feedback. However, better performance with hit rate feedback exacted a higher cognitive cost manifested by higher decision response time. CONCLUSION: The beneficial effect of hit rate probability feedback on timing decisions is partially moderated by task difficulty. APPLICATION: Performance feedback mode should be judiciously chosen in relation to task difficulty for optimal performance in tasks involving timing decisions. PMID- 25277018 TI - Effects of conversation on situation awareness and working memory in simulated driving. AB - OBJECTIVE: In the present research, we investigated the hypothesis that working memory mediates conversation-induced impairment of situation awareness (SA) while driving. BACKGROUND: Although there is empirical evidence that conversation impairs driving performance, the cognitive mechanisms that mediate this relationship remain underspecified. Researchers have reported that a phonological working memory task decreased drivers' SA for vehicles located behind them whereas a visuospatial working memory task impaired SA for vehicles ahead. Conversation, therefore, might impair SA for vehicles behind the driver by preferentially taxing the phonological loop. METHOD: A 20-questions task was used as a proxy for natural conversation. In Experiment I, driving performance was measured across three within-subjects conversation conditions (i.e., no conversation, driver asks questions, driver answers questions) with the use of a driving simulator. In Experiment 2, participants drove in the same simulator while either conversing (20-questions task) or not Participants estimated the positions of other vehicles after the screens were blanked at the end of each trial. RESULTS: Speed monitoring and responses to visual probes were impaired by the 20-questions conversation task (Experiment 1). As predicted, conversation impaired SA for the location of other vehicles more for vehicles located behind the driver than for those in front (Experiment 2). CONCLUSION: Conversation impairs drivers' SA of vehicles behind them by taxing working memory's phonological loop and impairs SA generally by taxing working memory's central executive. APPLICATION: Provides a theoretical framework that links driver SA to working memory and a mechanism for understanding why conversation impairs driving performance. PMID- 25277019 TI - On-the-fly scheduling as a manifestation of partial-order planning and dynamic task values. AB - OBJECTIVE: The aim of this study was to develop a computational account of the spontaneous task ordering that occurs within jobs as work unfolds ("on-the-fly task scheduling"). BACKGROUND: Air traffic control is an example of work in which operators have to schedule their tasks as a partially predictable work flow emerges. To date, little attention has been paid to such on-the-fly scheduling situations. METHOD: We present a series of discrete-event models fit to conflict resolution decision data collected from experienced controllers operating in a high-fidelity simulation. RESULTS: Our simulations reveal air traffic controllers' scheduling decisions as examples of the partial-order planning approach of Hayes-Roth and Hayes-Roth. The most successful model uses opportunistic first-come-first-served scheduling to select tasks from a queue. Tasks with short deadlines are executed immediately. Tasks with long deadlines are evaluated to assess whether they need to be executed immediately or deferred. CONCLUSION: On-the-fly task scheduling is computationally tractable despite its surface complexity and understandable as an example of both the partial-order planning strategy and the dynamic-value approach to prioritization. PMID- 25277020 TI - Positive effects of basic training on cognitive performance and mood of adult females. AB - OBJECTIVE: This study investigated whether a stressful military training program, the 9- to 10-week U.S. Army basic combat training (BCT) course, alters the cognitive performance and mood of healthy young adult females. BACKGROUND: Structured training programs including adolescent boot camps, sports training camps, learning enrichment programs, and military basic training are accepted methods for improving academic and social functioning. However, limited research is available on the behavioral effects of structured training programs in regard to cognitive performance and mood. METHOD: Two separate, within-subject studies were conducted with different BCT classes; in total 212 female volunteers were assessed before and after BCT. In Study 1, Four-Choice Reaction Time, Match-to Sample, and Grammatical Reasoning tests were administered. The Psychomotor Vigilance Test (PVT) was administered in Study 2. The Profile of Mood States (POMS) was administered in both studies. RESULTS: In Study 1, reaction time to correct responses on all three of the performance tests improved from pre- to post-BCT. In Study 2, PVT reaction time significantly improved. All POMS subscales improved over time in the second study, whereas POMS subscales in the first study failed to meet criteria for statistically significant differences over time. CONCLUSION: Cognition and mood substantially improved over military basic training. These changes may be a result of structured physical and mental training experienced during basic training or other factors not as yet identified. APPLICATION: Properly structured training may have extensive, beneficial effects on cognitive performance and mood; however, additional research is needed to determine what factors are responsible for such changes. PMID- 25277021 TI - The effect of mild motion sickness and sopite syndrome on multitasking cognitive performance. AB - OBJECTIVE: In this study, we investigated the effects of mild motion sickness and sopite syndrome on multitasking cognitive performance. BACKGROUND: Despite knowledge on general motion sickness, little is known about the effect of motion sickness and sopite syndrome on multitasking cognitive performance. Specifically, there is a gap in existing knowledge in the gray area of mild motion sickness. METHOD: Fifty-one healthy individuals performed a multitasking battery. Three independent groups of participants were exposed to two experimental sessions. Two groups received motion only in the first or the second session, whereas the control group did not receive motion. Measurements of motion sickness, sopite syndrome, alertness, and performance were collected during the experiment RESULTS: Only during the second session, motion sickness and sopite syndrome had a significant negative association with cognitive performance. Significant performance differences between symptomatic and asymptomatic participants in the second session were identified in composite (9.43%), memory (31.7%), and arithmetic (14.7%) task scores. The results suggest that performance retention between sessions was not affected by mild motion sickness. CONCLUSION: Multitasking cognitive performance declined even when motion sickness and soporific symptoms were mild. The results also show an order effect. We postulate that the differential effect of session on the association between symptomatology and multitasking performance may be related to the attentional resources allocated to performing the multiple tasks. Results suggest an inverse relationship between motion sickness effects on performance and the cognitive effort focused on performing a task. APPLICATION: Even mild motion sickness has potential implications for multitasking operational performance. PMID- 25277022 TI - Use of EEG workload indices for diagnostic monitoring of vigilance decrement. AB - OBJECTIVE: A study was run to test which of five electroencephalographic (EEG) indices was most diagnostic of loss of vigilance at two levels of workload. BACKGROUND: EEG indices of alertness include conventional spectral power measures as well as indices combining measures from multiple frequency bands, such as the Task Load Index (TLI) and the Engagement Index (El). However, it is unclear which indices are optimal for early detection of loss of vigilance. METHOD: Ninety-two participants were assigned to one of two experimental conditions, cued (lower workload) and uncued (higher workload), and then performed a 40-min visual vigilance task. Performance on this task is believed to be limited by attentional resource availability. EEG was recorded continuously. Performance, subjective state, and workload were also assessed. RESULTS: The task showed a vigilance decrement in performance; cuing improved performance and reduced subjective workload. Lower-frequency alpha (8 to 10.9 Hz) and TLI were most sensitive to the task parameters. The magnitude of temporal change was larger for lower-frequency alpha. Surprisingly, higher TLI was associated with superior performance. Frontal theta and El were influenced by task workload only in the final period of work. Correlational data also suggested that the indices are distinct from one another. CONCLUSIONS: Lower-frequency alpha appears to be the optimal index for monitoring vigilance on the task used here, but further work is needed to test how diagnosticity of EEG indices varies with task demands. APPLICATION: Lower frequency alpha may be used to diagnose loss of operator alertness on tasks requiring vigilance. PMID- 25277023 TI - Using scanpaths as a learning method for a conflict detection task of multiple target tracking. AB - OBJECTIVE: The objective was to determine whether the scanpaths of air traffic controllers (ATCs) could be used to improve the performance of novices in a conflict detection task. BACKGROUND: Studies in other domains show that novice performance can be improved by exposure to experts' scanpaths. Whether this effect can be found for an aircraft conflict detection task is unknown. METHOD: Scanpaths of 25 professional ATCs ("experts") were recorded using a medium fidelity air traffic control simulation with realistic scripted traffic that included aircraft pairs that would lose separation. A total of 20 novices were exposed to experts' scanpaths ("treatment"), and their performance (for both loss of separation detection rates and false alarm rates) was compared to that of 20 novices given no treatment or instructions ("control") and 20 novices who were verbally instructed to attend to altitude ("instruction-only"). Interviews were held about the helpfulness of the exposure. The scanpaths were analyzed to find pattern differences among the three groups. RESULTS: Chi-square tests showed significant differences for false alarm rates across the three groups (p = .001). Pairwise Mann-Whitney tests showed that the number of false alarms for the treatment group was significantly lower than that for the control group (p = .005), and trended lower than the instruction-only group (p = .08). Treatment group participants responded that experts' scanpaths helped. Analysis of scanpaths showed an increased tendency of the scanpath treatment group to follow the experts' scanpath. CONCLUSION: The scanpath training intervention improved novice performance by reducing false alarms. APPLICATION: Implementing experts' scanpaths into novices' active learning process shows promise in enhancing training effectiveness and reducing training time. PMID- 25277025 TI - Control order and visuomotor strategy development for joystick-steered underground shuttle cars. AB - OBJECTIVE: In this simulator-based study, we aimed to quantify performance differences between joystick steering systems using first-order and second-order control, which are used in underground coal mining shuttle cars. In addition, we conducted an exploratory analysis of how users of the more difficult, second order system changed their behavior over time. BACKGROUND: Evidence from the visuomotor control literature suggests that higher-order control devices are not intuitive, which could pose a significant risk to underground mine personnel, equipment, and infrastructure. METHOD: Thirty-six naive participants were randomly assigned to first- and second-order conditions and completed three experimental trials comprising sequences of 90 degrees turns in a virtual underground mine environment, with velocity held constant at 9 km/h(-1). Performance measures were lateral deviation, steering angle variability, high frequency steering content, joystick activity, and cumulative time in collision with the virtual mine wall. RESULTS: The second-order control group exhibited significantly poorer performance for all outcome measures. In addition, a series of correlation analyses revealed that changes in strategy were evident in the second-order group but not the first-order group. CONCLUSION: Results were consistent with previous literature indicating poorer performance with higher order control devices and caution against the adoption of the second-order joystick system for underground shuttle cars. APPLICATION: Low-cost, portable simulation platforms may provide an effective basis for operator training and recruitment. PMID- 25277024 TI - Manually locating physical and virtual reality objects. AB - OBJECTIVE: In this study, we compared how users locate physical and equivalent three-dimensional images of virtual objects in a cave automatic virtual environment (CAVE) using the hand to examine how human performance (accuracy, time, and approach) is affected by object size, location, and distance. BACKGROUND: Virtual reality (VR) offers the promise to flexibly simulate arbitrary environments for studying human performance. Previously, VR researchers primarily considered differences between virtual and physical distance estimation rather than reaching for close-up objects. METHOD: Fourteen participants completed manual targeting tasks that involved reaching for corners on equivalent physical and virtual boxes of three different sizes. Predicted errors were calculated from a geometric model based on user interpupillary distance, eye location, distance from the eyes to the projector screen, and object. RESULTS: Users were 1.64 times less accurate (p < .001) and spent 1.49 times more time (p = .01) targeting virtual versus physical box corners using the hands. Predicted virtual targeting errors were on average 1.53 times (p < .05) greater than the observed errors for farther virtual targets but not significantly different for close-up virtual targets. CONCLUSION: Target size, location, and distance, in addition to binocular disparity, affected virtual object targeting inaccuracy. Observed virtual box inaccuracy was less than predicted for farther locations, suggesting possible influence of cues other than binocular vision. APPLICATION: Human physical interaction with objects in VR for simulation, training, and prototyping involving reaching and manually handling virtual objects in a CAVE are more accurate than predicted when locating farther objects. PMID- 25277026 TI - Text mining to decipher free-response consumer complaints: insights from the NHTSA vehicle owner's complaint database. AB - OBJECTIVE: This study applies text mining to extract clusters of vehicle problems and associated trends from free-response data in the National Highway Traffic Safety Administration's vehicle owner's complaint database. BACKGROUND: As the automotive industry adopts new technologies, it is important to systematically assess the effect of these changes on traffic safety. Driving simulators, naturalistic driving data, and crash databases all contribute to a better understanding of how drivers respond to changing vehicle technology, but other approaches, such as automated analysis of incident reports, are needed. METHOD: Free-response data from incidents representing two severity levels (fatal incidents and incidents involving injury) were analyzed using a text mining approach: latent semantic analysis (LSA). LSA and hierarchical clustering identified clusters of complaints for each severity level, which were compared and analyzed across time. RESULTS: Cluster analysis identified eight clusters of fatal incidents and six clusters of incidents involving injury. Comparisons showed that although the airbag clusters across the two severity levels have the same most frequent terms, the circumstances around the incidents differ. The time trends show clear increases in complaints surrounding the Ford/Firestone tire recall and the Toyota unintended acceleration recall. Increases in complaints may be partially driven by these recall announcements and the associated media attention. CONCLUSION: Text mining can reveal useful information from free response databases that would otherwise be prohibitively time-consuming and difficult to summarize manually. APPLICATION: Text mining can extend human analysis capabilities for large free-response databases to support earlier detection of problems and more timely safety interventions. PMID- 25277028 TI - Influence of CAD/CAM on the fit accuracy of implant-supported zirconia and cobalt chromium fixed dental prostheses. AB - STATEMENT OF PROBLEM: Relatively little information is available on the accuracy of the abutment-implant interface in computer-aided design and computer-aided manufacturing (CAD/CAM)-fabricated zirconia and cobalt-chromium frameworks. PURPOSE: The purpose of this study was to compare the fit accuracy of CAD/CAM fabricated zirconia and cobalt-chromium frameworks and conventionally fabricated cobalt-chromium frameworks. MATERIAL AND METHODS: Four groups of 3-unit, implant supported, screw-retained frameworks were fabricated to fit an in vitro model with 3 implants. Eight frameworks were fabricated with the CAD/CAM system: 4 in zirconia and 4 in cobalt-chromium. Another 8 were cast in cobalt-chromium with conventional casting, including 4 with premachined abutments and 4 with castable abutments. The vertical misfit at the implant-framework interface was measured with scanning electron microscopy when only 1 screw was tightened and when all screws were tightened. Data were analyzed with the Kruskal-Wallis and Mann Whitney tests (alpha=.05). RESULTS: The mean vertical misfit values when all screws were tightened was 5.9 +/-3.6 MUm for CAD/CAM-fabricated zirconia, 1.2 +/ 2.2 MUm for CAD/CAM-fabricated cobalt-chromium frameworks, 11.8 +/-9.8 MUm for conventionally fabricated cobalt-chromium frameworks with premachined abutments, and 12.9 +/-11.0 MUm for the conventionally fabricated frameworks with castable abutments; the Mann-Whitney test found significant differences (P<.05) among all frameworks, except between the conventionally fabricated frameworks (P=.619). No significant differences were found among the groups for passive fit gap measurements (P>.05). CONCLUSIONS: When all of the screws were tightened, the CAD/CAM frameworks exhibited better fit accuracy compared with the conventionally fabricated frameworks. High levels of passive fit were achieved for the evaluated techniques. PMID- 25277029 TI - Finite element analysis of stability and functional stress with implant-supported maxillary obturator prostheses. AB - STATEMENT OF PROBLEM: Maxillary resections jeopardize the stability and functional stress generated by implanted-supported prostheses. PURPOSE: The purpose of this study was to evaluate the stability and functional stress caused by implanted-supported obturator prostheses in simulated maxillary resections of an edentulous maxilla corresponding to Okay Classes Ib, II, and III, with no surgical reconstruction. MATERIAL AND METHODS: Implants were positioned in the residual maxilla, and bar-clip retention systems were designed for each experimental model. The 3-dimensional models of the maxillary resection and corresponding implanted-supported obturator prosthesis, constructed from a computed tomography scan, were used to develop a finite element mesh. Loads were simultaneously applied to the occlusal (80 N) and anterior (35 N) platforms corresponding to the prosthetic teeth. Qualitative analysis was based on the scale of maximum principal stress; values obtained by means of quantitative analysis were expressed in MPa. RESULTS: The implant-supported obturator prostheses tended to rotate toward the surgical resection, the region with no osseous support. Tensile and compressive stresses in the gingival mucosa and in the cortical bone increased as the osseous support and the numbers of implants and clips diminished. CONCLUSIONS: All evaluated bar-clip retention systems displayed a tendency toward dislodgment of the obturator prosthesis, increasing as the osseous resection area amplified. The osseous tensile and compressive stresses resulting from the bar-clip retention system for Okay Classes Ib, II, and III maxillectomy may not be favorable to the survival rate of implants. PMID- 25277027 TI - Iron upregulates melanogenesis in cultured retinal pigment epithelial cells. AB - The purpose of our studies was to examine the relationship between iron and melanogenesis in retinal pigment epithelial cells, as prior observations had suggested that iron may promote melanogenesis. This relationship has potential clinical importance, as both iron overload and hyperpigmentation are associated with age-related macular degeneration (AMD). Human fetal retinal pigment epithelial cells and ARPE-19 cells were treated with iron in the form of ferric ammonium citrate, after which quantitative RT-PCR and electron microscopy were performed. Melanogenesis genes tyrosinase, tyrosinase-related protein 1, Hermansky-Pudlak Syndrome 3, premelanosome protein and dopachrome tautomerase were upregulated, as was the melanogenesis-controlling transcription factor, microphthalmia-associated transcription factor (MITF). Iron-treated cells had increased pigmentation and melanosome number. Multiple transcription factors upstream of MITF were upregulated by iron. PMID- 25277031 TI - Complete oral rehabilitation of a patient with hereditary gingival fibromatosis: a clinical report. AB - Hereditary gingival fibromatosis is a rare disease that has several debilitating oral and psychological manifestations, especially with young children and adolescents. The complexity of the treatment as well as the timing relative to the growth and maturation of the patient present a challenge. Few treatment options have been reported in the literature. This clinical report presents a multidisciplinary approach to treating a young patient with hereditary gingival fibromatosis by using implant-supported prostheses. The treatment steps and its outcome are discussed. PMID- 25277030 TI - Influence of maxillary obturator prostheses on facial morphology in patients with unilateral maxillary defects. AB - STATEMENT OF PROBLEM: Facial asymmetry is prominent with individuals with unilateral bone resorption and can lead to decreased quality of life. PURPOSE: The purpose of this study was to investigate the influence of maxillary obturator prostheses on facial morphology of individuals with unilateral maxillary defects by using 3-dimensional digital stereophotogrammetry. MATERIAL AND METHODS: The facial data of 8 participants with unilateral maxillary defects were acquired with a noncontact 3-dimensional digitizer, both with and without maxillary prostheses. The mid-facial plane was established by overlapping an original facial image with its mirror image. Displacement at 18 measurement points, including 7 bilateral pairs, was compared between the 2 sides, with and without the prostheses. Asymmetry indices of these 7 pairs also were calculated. Multivariate repeated-measures ANOVA was used to determine differences. RESULTS: Displacements of the lateral and inferior points at the ala of the nose were significantly greater on the defect side than on the normal side. The distances between the ideal and defect side points at the superior ala, the upper lip, and the angle of the mouth decreased significantly with the prosthesis. No significant differences were found in asymmetry indices, but the angle of the upper lip line to the mid-sagittal plane increased significantly with the prosthesis. CONCLUSIONS: The 3-dimensional analyzing method developed in this study can be useful in evaluating facial reconstruction with maxillary obturator prostheses with individuals with unilateral maxillary defects. The prostheses affect the region of the nasal ala, the upper lip, and the angles of the mouth. PMID- 25277032 TI - A modified technique for fabricating a mirror image wax pattern for an auricular prosthesis. AB - This article describes a technique for fabricating a wax pattern for an auricular prosthesis by tracing the shape of a sliced cast of the contralateral ear at an interval of 1-mm and transferring the shape of each 1-mm slice to a similar dimension modeling wax sheet. In this way, slices of modeling wax are obtained, which can be reversed and placed over the previous slice to produce a mirror image wax pattern of the contralateral ear. PMID- 25277034 TI - Incidence of attachment loss of canines in an overdenture population. AB - STATEMENT OF PROBLEM: Caries and periodontal disease are the most common cause of tooth loss in overdenture populations. Longitudinal data on attachment loss in this population have not been well reported. PURPOSE: The purpose of this longitudinal study was to measure periodontal attachment loss in overdenture abutments. MATERIAL AND METHODS: In this longitudinal overdenture study, 272 persons fulfilled all of the inclusion criteria. These persons had 662 teeth, 465 (70.2%) of which were canines. This report focused only on participants with canines who returned for 3 consecutive recalls in the 42 months of the study and included 53 persons with 116 canines. During this 42-month period, 6 teeth were extracted. Attachment loss was measured at baseline and at 6 to 18 months, 19 to 30 months, and 31 to 42 months at the mesial, distal, mid-buccal, and mid-lingual surface of each tooth, and was calculated as the combination of pocket probing depth plus height above the gingiva. Attachment loss was compared at each recall. A single examiner made all the measurements. RESULTS: At baseline, the greatest amount of loss was at the mid-buccal surface (5.43 mm), followed by the mid lingual (4.95 mm), distal (4.41 mm), and mesial (4.35 mm) surfaces. This pattern of attachment loss did not change over the 3 time periods, except that, at the 6 to 18-month recall, the distal measurement was less than at baseline. This decrease could be due to the wear of the abutment or loss of a restoration due to caries. Attachment loss was greater on the mandibular abutments than on the maxillary abutments and could be due to the greater amount of movement of the mandibular overdenture, especially in a buccolingual direction. CONCLUSION: Attachment loss varied by arch and by site in patients who wore overdentures. PMID- 25277033 TI - A direct bonded fixed partial dental prosthesis: a clinical report. AB - A direct bonded fixed partial dental prosthesis, with a composite resin denture tooth as a pontic, a tri-n-butylborane initiated adhesive resin, and screw posts for reinforcement, was still functioning after an observation period of 20 years. The prosthesis was found to be reliable for long-term clinical use when chemically and mechanically reinforced. PMID- 25277036 TI - Translucency of ceramic material in different core-veneer combinations. AB - STATEMENT OF PROBLEM: Understanding the translucency of ceramic materials is important to achieve good esthetics. Ceramic thickness is related to translucency; however, less information about core-veneer thickness in combination is available. PURPOSE: The purpose of this study was to investigate the translucency parameters of core-veneer thicknesses in 2 different ceramic materials. MATERIAL AND METHODS: A total of 56 ceramic disks of different thickness were fabricated as cores according to the manufacturer's recommendations and divided into groups (n=7). Each was veneered with its compatible veneer ceramic with a different thickness (0.2, 0.5, 0.7 mm). One group of each ceramic type was left without veneer. The groups were named according to core names (group IPS e.max Press [EP], group IPS Empress Esthetic [EE]), and numbers were given according to thickness combination: 1=(1.00+0.5); 2=(0.8+0.7); 3=(1.00); 4=(0.8+0.2). All surfaces were measured by profilometry to ensure consistency within the groups. A glass disk (1.5 mm) positive control (group P) and a metal core (1.5 mm) negative control (group N) were prepared. The translucency parameter values were calculated by using spectrophotometry to calculate the color differences of the specimens over black and white backgrounds. RESULTS: A 1-way ANOVA found significant differences among the translucency parameter values of the ceramic groups (P<.01). A 1-sample t test determined thickness consistency, and 1-way analysis was performed to ensure surface roughness consistency within the groups (P>.05). CONCLUSIONS: Total ceramic thickness affected the translucency; higher combined ceramic thickness resulted in lower translucency parameter values. When total thickness decreases, the translucency of core material has more effect than that of veneer material on translucency parameter values. PMID- 25277035 TI - Mechanical properties of components of the bonding interface in different regions of radicular dentin surfaces. AB - STATEMENT OF PROBLEM: The mechanical properties of the adhesive materials used in intraradicular treatments could vary according to the interaction between the restorative material and dentin substrate. An evaluation of these properties is essential to determine the success of the luting procedures performed on glass fiber posts. PURPOSE: The purpose of this study was to evaluate the mechanical properties of dentin adhesives, resin cements, and the dentin that underlies the bonding interface in different thirds of intraradicular dentin. MATERIAL AND METHODS: Forty extracted, single-rooted human teeth were used in this study. After the endodontic treatment of the post spaces, the teeth were divided into 5 groups (n=8): Adper Single Bond 2 + RelyX ARC, Excite DSC + RelyX ARC, Adper SE Plus + RelyX ARC, RelyX Unicem, and Set. The hardness and elastic modulus values were measured at the adhesive interface in different thirds of the radicular dentin by using an ultramicrohardness tester. The data were subjected to 2-way ANOVA and the Fisher protected least significant difference test (alpha=.05). RESULTS: In the underlying dentin, the highest Martens hardness values were found in the apical region for all groups; the exceptions were the groups with the self etching adhesive. In the adhesive layer, the highest Martens hardness values were obtained for the Adper SE Plus + RelyX ARC group; further, no statistical differences were found among the different regions for this group. RelyX ARC had the lowest Martens hardness and elastic modulus values in the apical regions when used with Adper Single Bond 2 and Adper SE Plus. No differences were found in the Martens hardness and elastic modulus values for the self-adhesive resin cement in the regions investigated. CONCLUSION: The mechanical properties of adhesive materials and the underlying dentin are influenced by the interaction between the two as well as by the depth of the analyzed intraradicular area. PMID- 25277037 TI - Effect of hydrothermal degradation on three types of zirconias for dental application. AB - STATEMENT OF PROBLEM: Concern has been expressed with regard to hydrothermal aging of yttria-stabilized tetragonal zirconia polycrystalline. PURPOSE: The purpose of this study was to assess the accelerated aging characteristics of a new yttria-stabilized tetragonal zirconia polycrystalline material and 2 commercially available yttria-stabilized tetragonal zirconia polycrystalline materials by exposing specimens to hydrothermal treatments in steam at 134 degrees C, 0.2 MPa, and at 180 degrees C, 1.0 MPa. MATERIAL AND METHODS: Thin bars of zirconia: Prettau, Zirprime, and a new zirconia, ZirTough, n = 55 for each brand (22 * 3 * 0.2 mm) were cut and ground from blocks sintered according to the manufacturer's specifications. The control specimens for each group were evaluated in the nonaged condition, and their chemical composition was measured with energy dispersive spectroscopy. The experimental specimens were artificially aged under standard autoclave sterilization conditions, 134 degrees C at 0.2 MPa (n = 5 per group at 5, 50, 100, 150, and 200 hours), and under standard industrial ceramic aging conditions, 180 degrees C at 1.0 MPa (n = 5 per group at 8, 16, 24, and 48 hours). The tetragonal to monoclinic transformation was measured by using x-ray diffraction for all groups. Flexural strength was measured with a 4-point bend test (ASTM 1161-B) for all the groups, and the fracture surfaces were examined with scanning electron microscopy. The data were analyzed as a function of aging time. To test for an aging effect on the flexural strength and the monoclinic-tetragonal ratio, a 1-way ANOVA (with heteroscedasticity-consistent standard errors) was used to test for a general time effect. For the analyses of the monoclinic-tetragonal ratio, the same specimens were used at 0 hours and after aging, and the data were analyzed with an ANOVA for an incomplete block design. The relationship between flexural strength and monoclinic-tetragonal ratio was assessed with the Spearman rank correlation coefficient based on the average value at each aging. RESULTS: After 200 hours at 134 degrees C and 0.2 MPa, the flexural strength decreased from a mean (standard deviation) of 1328 +/- 89.9 MPa to all fractured during aging for Prettau (P < .001); 1041 +/- 130 to 779 +/- 137 MPa for Zirprime (P = .<.001) and 1436 +/- 136 to 1243 +/- 101 MPa for ZirTough (P = .017). After 200 hours at 134 degrees C and 0.2 MPa, a portion of the tetragonal crystals transformed to the monoclinic phase in all specimens. The mean (standard deviation) monoclinic phase fraction increased from 3.08% +/- 0.28% to 78.8% +/- 2.0% for Prettau, 1.95% +/- 0.48% to 74.8% +/- 0.52% for Zirprime, and 12.4% +/- 0.60% to 31.4% +/- 4.4% for ZirTough (all P < .001). After 16 hours at 180 degrees C and 1.0 MPa, all Prettau specimens had spontaneously fractured during aging. The Zirprime and ZirTough specimens were intact after 48 hours at 180 degrees C and 1.0 MPa, and the mean (standard deviation) flexural strength had decreased from 1041 +/- 130 MPa to 595 +/- 88.4 MPa for Zirprime and 1436 +/- 136 MPa to 1068 +/- 76.8 MPa for ZirTough (all P < .001). The mean (standard deviation) monoclinic phase fraction increased from 3.08% +/- 0.28% to 79.0% +/- 0.13% for Prettau, from 1.95% +/- 0.48% to 68.1% +/- 4.4%, for Zirprime, and from 12.4% +/- 0.60% to 39.5% +/- 5.56% for ZirTough (all P<.001). The flexural strength decreased with an increase in the monoclinic phase for all the groups (Spearman rank correlation coefficients, 0.71 to -1.0). Scanning electron microscope micrographs revealed a transformed layer on the fracture surfaces. The decrease in flexural strength was related to the increase in monoclinic phase from long-term degradation. CONCLUSION: Hydrothermal aging of zirconia caused a statistically significant decrease in flexural strength of thin bars of zirconia, which was the result of the transformation from tetragonal to monoclinic crystal structure. ZirTough exhibited the least decrease in strength and smallest amount of monoclinic phase after aging. PMID- 25277038 TI - In vitro assessment of 3 dentifrices containing fluoride in preventing demineralization of overdenture abutments and root surfaces. AB - STATEMENT OF PROBLEM: Caries development under overdentures has been a continuing problem and requires the daily use of fluoride to prevent demineralization. PURPOSE: The purpose of this in vitro study was to compare the effectiveness of dentifrices containing tricalcium phosphate or calcium phosphosilicate in combination with fluoride to prevent the demineralization of overdenture abutments and root surfaces. MATERIAL AND METHODS: A total of 56 caries-free extracted teeth were prepared as overdenture abutments. The teeth were painted with acid-resistant varnish, leaving one 1*4-mm window on occlusal and root surfaces. The teeth were randomly divided into 4 groups: a control group treated with distilled/deionized water only, a group treated with ClinPro 5000, a group treated with ReNew, and a group treated with Prevident 5000 gel. Each tooth was subjected to a demineralizing/remineralizing cycling protocol for 12 days with the appropriate treatment products. The teeth were sectioned longitudinally through both windows. Photomicrographs were made of 3 representative sections from each tooth. A representative section was defined as one that included both windows and was cut from the part of the tooth that had the flattest surface to reduce the edge effect. The depths of the lesions were measured on representative sections from each group. A 1-way MANOVA and a 1-way ANOVA with the post hoc Tukey-Kramer test were used to evaluate the treatment effects on the criterion variables (alpha=.05). RESULTS: The total lesion depths of the control teeth on the occlusal surface were not statistically significantly deeper than for the 3 dentifrices (P=.7705). However, all 3 dentifrices had narrower cavitation depths than the control (mean cavitation band depth, 43.59 [ReNew] versus 37.99 [Prevident 5000 gel] versus 36.70 [ClinPro 5000] versus 246.86 [control]) (P<.001). The mean remineralization band depth for ClinPro 5000 was significantly greater than for the other 2 treatment groups (118.03 [ClinPro 5000] versus 107.80 [ReNew] versus 102.28 [Prevident 5000 gel]) (P<.001). On root surfaces, the total lesion depth for the control group was statistically significantly deeper than for the 3 dentifrices (mean total lesion depth, 150.31 [control] versus 82.05 [ReNew] versus 68.10 [ClinPro 5000] versus 56.97 [Prevident 5000 gel]) (P<.001). The data indicated that teeth treated with Prevident 5000 gel had the shallowest total lesion depth and were statistically significantly different from those treated with ReNew and ClinPro 5000. Moreover, teeth treated with ReNew were found to have the largest remineralization band depth, which was statistically significantly different compared with ClinPro 5000 and Prevident 5000 gel (mean remineralization band depth, 49.66 [ReNew] versus 36.14 [ClinPro 5000] versus 23.27 [Prevident 5000 gel]) (P<.001), but no difference was found in cavitation depth of the root lesions between the 3 dentifrices. CONCLUSIONS: The addition of tricalcium phosphate or calcium phosphosilicate to fluoride containing dentifrices (5000 ppm) does not significantly improve their ability to prevent demineralization of the cut dentin surface of overdenture abutments. However, on root surfaces, ReNew, which contains calcium phosphosilicate, was found to improve remineralization of the lesions compared with Prevident 5000 gel or ClinPro 5000. PMID- 25277039 TI - Fabrication of a provisional nasal prosthesis. AB - A technique for making a provisional nasal prosthesis for interim use after the ablation of a midface tumor is described. The technique is especially useful for the re-creation of a nasal form in an expedient and cost-effective manner. A preoperative definitive cast, or moulage, of the patient that includes a nasal form is used to fabricate a vacuum form of the midface. The vacuum form is evaluated on the patient, the extension is adjusted, and an external adhesive knit liner is applied to give the appearance of a contoured nasal bandage. The provisional nasal prosthesis is attached with medical adhesive tape and removed daily by the patient. The prosthesis is easily replaced during the course of treatment and has been found to be functional and esthetically acceptable to those patients receiving care from the Dental Service at Memorial Sloan Kettering Cancer Center. PMID- 25277040 TI - Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. AB - In Alzheimer's disease, the contribution of inflammation is still controversially discussed. The aim of this study was to identify a particular immune profile in the peripheral blood (PB) and cerebrospinal fluid (CSF) in patients with mild Alzheimer's disease (mAD) and mild cognitive impairment (MCI) and its potential functional relevance and association with neurodegeneration. A total of 88 patients with cognitive decline (54 mAD, 19 MCI, and 15 other dementias) were included in this study and compared with a group of younger (mean age, 31.3 years) and older (mean age, 68.9 years) healthy volunteers. Patients underwent detailed neurologic and neuropsychological examination, magnetic resonance imaging including voxel-based morphometry of gray matter, voxel-based diffusion tensor imaging, and white matter lesion volumetry, and PB and CSF analysis including multiparameter flow cytometry. Multiparameter flow cytometry revealed that proportions of activated HLA-DR positive CD4(+) and CD8(+) T-cells were slightly and significantly increased in the PB of MCI and mAD patients, respectively, when compared with healthy elderly controls but not in patients with other dementias. Although only a slight enhancement of the proportion of activated CD4(+) T-cells was observed in the CSF of both MCI and mAD patients, the proportion of activated CD8(+) T-cells was significantly increased in the CSF of mAD patients when compared with healthy elderly individuals. A slight increase in the proportion of activated CD8(+) T-cells was also observed in the intrathecal compartment of MCI patients. Activation of cytotoxic CD8(+) T-cells was considerably related to AD-typical neuropsychological deficits. Voxel-based regression analysis revealed a significant correlation between CD8(+) T-cell activation and microstructural tissue damage within parahippocampal areas as assessed by diffusion tensor imaging. Taken together, peripheral and intrathecal CD8(+) T-cell activation in mAD was significantly different from other dementias, suggesting a specific adaptive immune response. Lymphocyte activation seems to have a clinical impact because levels of activated CD8(+) T-cells were correlated with clinical and structural markers of AD pathology. PMID- 25277042 TI - Designation of obesity as a disease: lessons learned from alcohol and tobacco. AB - Obesity is a leading cause of preventable death in the USA. The American Medical Association recently recognized obesity as meeting the definition of a chronic disease. This declaration had the intention of improving screening and long-term treatment and is historically similar to the designation of tobacco and alcohol dependence as a chronic disease. Nevertheless, it has ignited a nationwide debate in both academia and public opinion. The current article reviews the implications of treating obesity as a chronic disease, comparing the similarities in pathophysiology of obesity and other addictions, and discusses the pros and cons of this designation as it pertains to health care workers and patients. PMID- 25277041 TI - Reduction in the retinotopic early visual cortex with normal aging and magnitude of perceptual learning. AB - Although normal aging is known to reduce cortical structures globally, the effects of aging on local structures and functions of early visual cortex are less understood. Here, using standard retinotopic mapping and magnetic resonance imaging morphologic analyses, we investigated whether aging affects areal size of the early visual cortex, which were retinotopically localized, and whether those morphologic measures were associated with individual performance on visual perceptual learning. First, significant age-associated reduction was found in the areal size of V1, V2, and V3. Second, individual ability of visual perceptual learning was significantly correlated with areal size of V3 in older adults. These results demonstrate that aging changes local structures of the early visual cortex, and the degree of change may be associated with individual visual plasticity. PMID- 25277043 TI - Differential diagnosis of Crohn's disease versus ileal tuberculosis. AB - Both intestinal tuberculosis and Crohn's disease are chronic granulomatous inflammatory diseases of the bowel having overlap of clinical, endoscopic, radiological, and histological features. Differentiating between the two disorders is relevant not only in Asian countries but also in the West. In spite of diagnostic criteria for both diseases being available, still the dilemma of segregating the two diseases remains. Nearly one third of the patients with Crohn's disease may receive anti-tuberculosis treatment also. Diagnosis should be based on the combination of all disease-specific and corroborative evidences. PMID- 25277044 TI - The effects of anterior vacuum disc on surgical outcomes of degenerative versus spondylolytic spondylolisthesis: at a minimum two-year follow-up. AB - BACKGROUND: The vacuum phenomenon within the intervertebral disc usually represents disc degeneration. There are no reports in the English literature that focus on the effect of an anterior vacuum disc on surgical outcome of same segment spondylolisthesis. METHODS: Patients with degenerative spondylolisthesis (DS) or isthmic spondylolisthesis (IS) who underwent a spinal surgery between January 2005 and December 2006 were reviewed. Patients who met certain criteria, including (1) only mono-segment spondylolisthesis, (2) gas air within the disc space of the spondylolisthesis segment on preoperative radiographs, (3) having received posterior decompression, posterior pedicle screw fixation, and posterolateral fusion, and (4) at least 12 months of follow-up radiographs available to define the posterolateral fusion rate, were enrolled into the study. Four radiographic parameters (disc height, translation, intradiscal angle, segmental angle) were assessed. Two-year postoperative radiographs were used to determine whether the posterolateral segment was fused or not. Clinical outcome and complications during the follow-up period were documented. RESULTS: Incidence of the disc vacuum phenomenon was significantly higher in the IS group than in the DS group (p < 0.001). The IS group had more listhesis and a narrower disc height on preoperative static radiographs; however, the DS group had a more prominent angle and listhesis change in preoperative dynamic variables. The posterolateral fusion rate was significantly higher in the IS group (p = 0.019). The preoperative Oswestry Disability Index (ODI) score, the final ODI, and the ODI difference were similar between groups. More excellent and good results were seen in the IS group. Besides, better final ODI and results were seen in the bilateral fusion group than in the nonfusion group. CONCLUSION: The disc vacuum phenomenon is not equal to anterior instability absolutely. Determination of stability or instability in a vacuum disc should be considered by a combination of dynamic radiographs. In the present study, vacuum discs in the DS group showed more instability and a higher posterolateral pseudoarthrosis rate. PMID- 25277045 TI - Identification of membrane proteins associated with phenylpropanoid tolerance and transport in Escherichia coli BL21. AB - Phenylpropanoids are phytochemicals produced by some plants and possess a wide variety of biological activities. These compounds exist in plants in low amounts. Production of them in genetically engineered microorganisms has many advantages. A majority of functional phenylpropanoids are toxic to microbial hosts. Export of these compounds may relieve the cellular toxicity and increase the yield. However, proteins and mechanisms involved in phenylpropanoids transport and tolerance remain poorly understood. In this study, 16 membrane proteins that were differentially expressed in Escherichia coli in response to three typical phenylpropanoids (resveratrol, naringenin and rutin) were identified using a membrane proteomics approach. These proteins included outer membrane proteins OmpA, OmpF, OmpW, FadL, TolC, LamB, and YaeT, peripheral membrane proteins AtpD, AtpH, YgaU, OppA, MalK, and MalE, and cytoplasmic membrane proteins OppD, PotG, and ManX. Functions of these proteins were determined by using gene overexpression and silencing. The results suggest that OmpA and FadL may play important roles in the transmembrane export of phenylpropanoids in E. coli. LamB, MalE, MalK and ManX may participate in phenylpropanoid uptake. The role of YgaU in enhancing the tolerance to phenylpropanoids remains to be determined. These results may assist the engineering of microorganisms with enhanced phenylpropanoid producing capabilities. BIOLOGICAL SIGNIFICANCE: Phenylpropanoids are phytochemicals produced by some plants and possess a wide variety of biological activities. Both the tolerance and the transport of phenylpropanoids play important roles in systematic metabolic engineering of microorganisms to produce these phytochemicals. Both specific and non-specific transporters are essential for these functions but remain poorly understood. This research utilized membrane proteomics to identify E. coli BL21 (DE3) membrane proteins that may be involved in phenylpropanoid transport and tolerance. These results may facilitate the construction of more efficient microbial phenylpropanoid producers through genetic engineering of membrane transporter proteins. PMID- 25277047 TI - Basic data underlying decision making in nonatherosclerotic causes of intermittent claudication. AB - Although most cases of vasculogenic intermittent claudication are caused by atherosclerosis, there is an important minority of cases that are due to nonatherosclerotic causes. Because of their rarity and younger population affected, often without traditional atherosclerotic risk factors, there is frequently a significant delay in diagnosis of nonatherosclerotic peripheral arterial diseases by several months to years in some cases. Here, we review the literature on nonatherosclerotic causes of lower extremity claudication, symptoms, management including surgical and endovascular interventions, and outcomes. Conditions included are popliteal artery entrapment syndrome, cystic adventitial disease, pseudoxanthoma elasticum, persistent sciatic artery, fibromuscular disease, giant cell arteritis, iliac endofibrosis, neurogenic claudication, and chronic exertional compartment syndrome. PMID- 25277046 TI - Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation. AB - Biomarker analysis of blood samples by liquid chromatography (LC) mass spectrometry (MS) is extremely challenging due to the high protein concentration range, characterised by abundant proteins that suppress and mask other proteins of lower abundance. This situation is further aggravated when using fast high throughput methods, which are necessary for analysis of hundreds and thousands of samples in clinical laboratories. The blood proteins IGF1, IGF2, IBP2, IBP3 and A2GL have been proposed as indirect biomarkers for detection of GH administration and as putative biomarkers for breast cancer diagnosis. We describe a sensitive and scalable method to quantify these 5 proteins of medium and low abundance by selected reaction monitoring (SRM) LC-MS/MS analysis in blood samples. Our method requires 7MUL of plasma and reaches a throughput of up to ca. 80 analyses per day. It includes an initial protein precipitation protocol optimised for extraction of low mass proteins from blood samples for reduced signal suppression and increased sensitivity in LC-MS/MS. We benchmarked this method for the analysis of 40 individual blood samples including 20 patients diagnosed with breast cancer. BIOLOGICAL SIGNIFICANCE: The interest for MS-based biomarker analysis in body fluids is steadily increasing as proteomics methodology translates into clinical laboratories. We describe a method for detection of 5 distinct proteins of low mass and medium to low abundance, which are of interest in anti-doping and clinical analysis. The analytical setup is simple and robust and is suitable for high-throughput instrument configurations. PMID- 25277048 TI - Re: "abdominal aortic rupture and spondylodiscitis: emergent EVAR and staged spinal fixation". PMID- 25277049 TI - Comment on treatment results for spontaneous isolated superior mesenteric artery dissection according to our previous guidelines and collective literature review. PMID- 25277050 TI - Popliteal endarterectomy for localized popliteal artery disease. AB - BACKGROUND: The incidence of localized popliteal disease is rare. Currently, patients presenting with symptomatic popliteal disease are offered femoropopliteal or tibial bypass if the disease is not amenable to radiologic intervention. We feel that popliteal endarterectomy by means of a posterior approach with patch angioplasty as a primary procedure is a viable surgical option. Our aim was to assess the durability of popliteal endarterectomy in patients with localized popliteal disease, in which radiologic intervention is not feasible. METHODS: This is a retrospective review of all patients who underwent popliteal endarterectomy for localized popliteal disease in our institution over the past 3 years. All patients underwent a preoperative assessment with computed tomography angiography. Angioplasty was attempted in all patients before surgical intervention. Patency was assessed radiologically 6 weeks after operation. Patients had follow-up appointments at intervals of 6 weeks, 3 months, 6 months, and a year after surgery. RESULTS: A total of 7 patients (5 men and 2 women) underwent popliteal endarterectomy. The mean age was 64.3 years, with a mean follow-up period of 9.9 months (range, 2-26 months). Four patients were treated for activity-limiting claudication (<100 yards), whereas 3 patients were treated for ischemic rest pain. The procedural success rate was 100% without mortalities or in-hospital morbidities. Symptomatic resolution was achieved in 6 patients. One patient occluded 1 month after endarterectomy because of a critical stenosis at the tibial bifurcation. CONCLUSIONS: Popliteal endarterectomy through posterior approach is advantageous in managing popliteal artery pathology restricted to the popliteal fossa. It is safe with good short term results. PMID- 25277051 TI - Complications of cannulation in extracorporeal membrane oxygenation. PMID- 25277053 TI - Re: comparative study of venous arterialization and pedal bypass in a patient cohort with critical limb ischemia. PMID- 25277052 TI - Re: "chronic rupture of abdominal aortic aneurysm with vertebral erosion. An uncommon but important cause of back pain". PMID- 25277054 TI - The evidence for nonoperative management of visceral artery dissections: a single center experience. AB - BACKGROUND: Spontaneous isolated visceral artery dissection is an uncommon condition encountered by clinicians. Presentation may vary from asymptomatic to acute intestinal ischemia, although a clear natural history has yet to be elucidated. No consensus exists on how best to manage these patients in the absence of true intestinal ischemia; however, much of the literature suggests that intervention is required. We present our institution's experience with 10 patients, both symptomatic and asymptomatic, all but 1 of whom was managed medically. METHODS: From September 2009 to August 2013, 10 patients presented to our institution with celiac or mesenteric artery dissection. We retrospectively reviewed these patients' clinical presentation, treatment, and follow-up. RESULTS: The mean age of the patients was 61.5 +/- 10.3 (standard deviation [SD]) years (range, 41-77 years), and the mean follow-up period was 14.7 +/- 11.6 (SD) months (range, 1-31 months). Four (40%) patients had abdominal pain and no ischemic changes of the bowel. There were 1 type I, 6 type II, 2 type III, and 1 type IV dissections according to Sakamoto classification. Treatments included observation without anticoagulation treatment in 8 patients (80%), anticoagulation treatment in 1 patient (10%), and endovascular stenting in 1 patient (10%) with unremitting abdominal pain. Anticoagulation was used in the 1 symptomatic patient with radiographic evidence of associated thrombus. The disease stabilized in all patients during follow-up. CONCLUSIONS: Most authors tend to advocate an endovascular or even operative repair for these processes. In our experience, most of these patients have a self-limited course of symptoms or their dissections are found incidentally. We believe that the results of conservative management in our cohort of patients support the conservative approach over the once recommended operative repair. PMID- 25277055 TI - Little thunder may be the first sign of a perfect storm: a case of postmortem diagnosed AEF and slitted esophagus. PMID- 25277056 TI - Sodium iodate influences the apoptosis, proliferation and differentiation potential of radial glial cells in vitro. AB - BACKGROUND/AIMS: Sodium iodate (NaIO3)-induced acute retinal injury is typically used as an animal model for degenerative retinal disease; however, how NaIO3 influences the apoptosis, proliferation and differentiation of endogenous retinal stem cells is unknown. METHODS: We exposed a radial glial cells (RGCs) line (L2.3) to different NaIO3 concentrations and determined the influence of NaIO3 on apoptosis, proliferation, and differentiation using flow cytometry and immunofluorescence assays. We used a real-time polymerase chain reaction assay to analyze the levels of mRNAs encoding GSK-3beta, AXIN2, beta-catenin, TGF-beta1, SMAD2, SMAD3, NOG (Noggin), and BMP4. RESULTS: Cell density decreased dramatically as a function of the NaIO3 dose. NaIO3 increased apoptosis, inhibited mitosis, proliferation, and the Wnt/beta-catenin pathway. CHIR99021 (Wnt agonist) treatment efficiently reversed the effects of NaIO3 on the apoptosis and proliferation of RGCs. The number of neuronal class III beta tubulin-positive cells decreased markedly, whereas that of glial fibrillary acidic protein-positive cells increased significantly when RGCs were exposed to NaIO3. During differentiation, the Nog mRNA level decreased and transforming growth factor-beta1 (Tgf-beta1) and Smad2/3 mRNA levels increased significantly when RGCs were exposed to NaIO3. CONCLUSION: NaIO3 increased apoptosis, influenced the proliferation of RGCs and drove them toward astrocytic differentiation, likely through inhibition of the Wnt/beta-catenin and noggin pathways and activation of the TGF-beta1/SMAD2/3 pathway. PMID- 25277057 TI - Surgical management of chronic salivary aspiration. AB - AIM OF THE STUDY: Sialorrhoea and chronic salivary aspiration are a major problem in many neurologically impaired children causing embarrassment, skin issues and recurrent lower respiratory tract infections (LRTI). The aim of this study was to assess the efficacy of salivary gland surgery in the treatment of chronic salivary aspiration in such children. OBJECTIVES: To compare admission rates for LRTI per annum before and after surgical intervention. METHODS: Retrospective review of all patients who underwent salivary management surgery for chronic aspiration under Princess Margaret Hospital's (PMH) Otolaryngology department from 2006 until 2013. RESULTS: Twelve patients were included in this review. Their ages ranged from 3 to 21 years (mean=11.4). Their genders were equally distributed. Two patients had underlying congenital disorders; one had an acquired brain injury, while the majority (n=9, 75%) had cerebral palsy secondary to a sustained perinatal injury. Most patients (n=11, 91.7%) had bilateral submandibular gland excision and parotid duct ligation as a primary procedure. One patient had a laryngotracheal separation. Two patients went on to have a second procedure. The mean follow up time was five years. Using Wilcoxon Signed Rank test we showed that the median rate of admission per annum for LRTI pre operatively was 1.0. This was reduced to 0.5 post-operatively, which was statistically significant (p<=0.05). CONCLUSIONS: We hypothesize that the combination of bilateral submandibular gland excision and bilateral parotid duct ligation is effective in reducing admissions with aspiration pneumonia in neurologically impaired children, and therefore improves the quality of life in these patients. PMID- 25277058 TI - Antiadhesive effect of bioresorbable polylactide film in abraded middle ear mucosa. AB - BACKGROUND AND OBJECTIVE: Polylactide film (PLF) is used to prevent postoperative peridural adhesion in spinal surgery. Up until now, the antiadhesive effect of bioresorbable PLF in ear middle surgery has not been reported. The purpose of this study is to evaluate the antiadhesive effect of PLF in guinea pigs serving as a model for middle ear mucosal trauma. MATERIALS AND METHODS: The animals were divided into two groups: the PLF group and the silastic sheeting group. There were seven guinea pigs (fourteen ears) in both groups. Under aseptic conditions, the middle ear mucosa was abraded using a pick inserted transbullaly. A PLF or silicone sheet was then placed into the guinea pigs' middle ear cavities. The auditory brainstem responses (ABRs) were assessed preoperatively and at three weeks postoperatively while the animals were under general anesthesia. A histopathological study was performed 3 weeks after the operation. RESULTS: The difference between the ABR results before the operation and three weeks postoperatively were not statistically significant. The adhesion formation did not appeared in either group. Prominent fibrous capsule formation and inflammation were observed in the silastic sheeting group, but not in the PLF group. Mild fibrous thickening of regenerated mucosa was observed in the PLF group. CONCLUSION: From our results, bioresorbable PLF is nonototoxic and biocompatible with the guinea pig's middle ear cavity by short-term evaluation. Further long-term evaluation study is necessary before clinical application. PMID- 25277060 TI - Diversity in human behavioral ecology. AB - As befitting an evolutionary approach to the study of human behavior, the papers in this special issue of Human Nature cover a diversity of topics in modern and traditional societies. They include the goals of hunting in foraging societies, social bias, cooperative breeding, the impact of war on women, leadership, and social mobility. In combination these contributions demonstrate the utility of selectionist's thinking on a wide variety of topics. While many of the contributions employ standard evolutionary biological approaches such as kin selection, cooperative breeding and the Trivers-Willard model, others examine important human issues such as the problems of trust, the cost of war to women, the characteristics of leaders, and what might be called honest or rule-bound fights. One striking feature of many of the contributions is a novel reexamination of traditional research questions from an evolutionary perspective. PMID- 25277059 TI - Neuropeptides encoded by the genomes of the Akoya pearl oyster Pinctata fucata and Pacific oyster Crassostrea gigas: a bioinformatic and peptidomic survey. AB - BACKGROUND: Oysters impart significant socio-ecological benefits from primary production of food supply, to estuarine ecosystems via reduction of water column nutrients, plankton and seston biomass. Little though is known at the molecular level of what genes are responsible for how oysters reproduce, filter nutrients, survive stressful physiological events and form reef communities. Neuropeptides represent a diverse class of chemical messengers, instrumental in orchestrating these complex physiological events in other species. RESULTS: By a combination of in silico data mining and peptide analysis of ganglia, 74 putative neuropeptide genes were identified from genome and transcriptome databases of the Akoya pearl oyster, Pinctata fucata and the Pacific oyster, Crassostrea gigas, encoding precursors for over 300 predicted bioactive peptide products, including three newly identified neuropeptide precursors PFGx8amide, RxIamide and Wx3Yamide. Our findings also include a gene for the gonadotropin-releasing hormone (GnRH) and two egg-laying hormones (ELH) which were identified from both oysters. Multiple sequence alignments and phylogenetic analysis supports similar global organization of these mature peptides. Computer-based peptide modeling of the molecular tertiary structures of ELH highlights the structural homologies within ELH family, which may facilitate ELH activity leading to the release of gametes. CONCLUSION: Our analysis demonstrates that oysters possess conserved molluscan neuropeptide domains and overall precursor organization whilst highlighting many previously unrecognized bivalve idiosyncrasies. This genomic analysis provides a solid foundation from which further studies aimed at the functional characterization of these molluscan neuropeptides can be conducted to further stimulate advances in understanding the ecology and cultivation of oysters. PMID- 25277062 TI - Melatonin prevents dexamethasone-induced testicular oxidative stress and germ cell apoptosis in golden hamster, Mesocricetus auratus. AB - This study investigated the protective effect of melatonin on dexamethasone (Dex), an extensively used anti-inflammatory and immunosuppressive synthetic glucocorticoid, induced testicular oxidative stress and germ cell apoptosis in golden hamster. Hamsters were randomly divided into four groups (n = 7): group I control; group II - melatonin treated (10 mg kg(-1) day(-1) ); group III - Dex treated (7 mg kg(-1) day(-1) ) and group IV - combination of Dex and melatonin. All the injections were administered intraperitoneally for seven consecutive days. The histopathological changes, specific biochemical markers, including antioxidative enzymes, plasma melatonin level and the markers for germ cell apoptosis were evaluated. Dex administration decreased antioxidant enzyme activities (SOD, CAT, GSH-PX ), plasma melatonin level and melatonin receptor (MT1) expression with a concomitant increase in lipid peroxidation (TBARS) and altered testicular histopathology which might culminate into increased germ cell apoptosis as evident from increased Bax/Bcl-2 ratio and caspase-3 expression. However, melatonin pre-treatment enhanced enzyme activities for SOD, CAT, GSH-PX with a simultaneous decrease in Bax/Bcl-2 ratio and caspase-3 expression. Our findings clearly suggest that melatonin improved defence against Dex-induced testicular oxidative stress and prevented germ cell apoptosis, suggesting a novel combination therapeutic approach for management of male reproductive health. PMID- 25277061 TI - Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm. AB - Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola(r) taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration. PMID- 25277064 TI - A new naloxone auto-injection device to treat opioid overdose. PMID- 25277063 TI - Novel alpha-spectrin mutation in trans with alpha-spectrin causing severe neonatal jaundice from hereditary spherocytosis. AB - We evaluated a neonate with severe jaundice but a negative family history. Spherocytes were present and suspected hereditary spherocytosis was confirmed by osmotic fragility and eosin-5-maleimide erythrocyte staining. We found he was a compound heterozygote for two pathogenic mutations in the gene encoding alpha spectrin: a previously reported alpha(LEPRA) inherited from his asymptomatic mother, and a novel alpha-spectrin mutation in intron 45 +1 disrupting the consensus splice site, from his asymptomatic father. PMID- 25277065 TI - Does resident or family preference always control? Resident-centered care versus regulatory compliance. PMID- 25277066 TI - Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line. AB - Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane undergoes a complex metabolization, giving rise to some already identified metabolites, the 17beta-hydroxy-6-methylenandrosta-1,4 dien-3-one (17-betaHE) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione (6-HME). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6beta-spirooxiranandrosta-1,4-diene-3,17-dione (2), 1alpha,2alpha-epoxy-6-methylenandrost-4-ene-3,17-dione (3) and 17-betaHE (4)) while one was acquired, the 6-HME (6). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure-activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-betaHE (4) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC50 0.25 MUM vs 0.90 MUM, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells. PMID- 25277069 TI - Glyconanoparticles for colorimetric bioassays. AB - Carbohydrate molecules are involved in many of the cellular processes that are important for life. By combining the specific analyte targeting of carbohydrates with the multivalent structure and change of solution colour as a consequence of plasmonic interactions with the aggregation of metal nanoparticles, glyconanoparticles have been used extensively for the development of bioanalytical assays. The noble metals used to create the nanocore, the methodologies used to assemble the carbohydrates on the nanoparticle surface, the carbohydrate chosen for each specific target, the length of the tether that separates the carbohydrate from the nanocore and the density of carbohydrates on the surface all impact on the structural formation of metal based glyconanoparticles. This tutorial review highlights these key components, which directly impact on the selectivity and sensitivity of the developed bioassay, for the colorimetric detection of lectins, toxins and viruses. PMID- 25277067 TI - Discovery of diamine-linked 17-aroylamido-17-demethoxygeldanamycins as potent Hsp90 inhibitors. AB - Heat shock protein 90 (Hsp90) is an attractive target for the development of antitumor agents. Geldanamycin (GA), the first Hsp90 inhibitor, has potent antitumor activity, but showed significant hepatotoxicity. To get rid of the hepatotoxicity of GA, in this study we incorporated aroyl groups via three types of linkers (4-aminomethylpiperidine, 1,4-butanediamine, and 1,6-hexanediamine) to the 17-position of GA and synthesized fifty-three 17-diamine-linked 17-aroylamido 17-demethoxygeldanamycins. All the derivatives were evaluated by MTT assay for their inhibitory activities against human breast cancer cell line MDA-MB-231. Among these compounds, 17-(6-(3,4,5-trimethoxycinnamamido)hexylamino)-17 demethoxygeldanamycin (7h29) showed the most potent cytotoxicity against MDA-MB 231 (IC50 = 0.19 +/- 0.02 MUM) with the lowest hepatotoxicity (AST = 181.0 +/- 23.6 U/L, ALT = 40.4 +/- 11.8 U/L). Compared to tanespimycin (17-AAG), 7h29 exhibited lower hepatotoxicity in mice, higher Hsp90 inhibitory activity in vitro and antitumor activity in human breast carcinoma (MDA-MB-231) xenograft nude mice. PMID- 25277068 TI - Physicians' knowledge, beliefs, and use of race and human genetic variation: new measures and insights. AB - BACKGROUND: Understanding physician perspectives on the intersection of race and genomics in clinical decision making is critical as personalized medicine and genomics become more integrated in health care services. There is a paucity of literature in the United States of America (USA) and globally regarding how health care providers understand and use information about race, ethnicity and genetic variation in their clinical decision making. This paper describes the development of three scales related to addressing this gap in the literature: the Bonham and Sellers Genetic Variation Knowledge Assessment Index--GKAI, Health Professionals Beliefs about Race-HPBR, and Racial Attributes in Clinical Evaluation-RACE scales. METHODS: A cross-sectional, web survey of a national random sample of general internists in the USA (N = 787) was conducted. Confirmatory factor analysis was used to assess the construct validity of the scales. Scale items were developed through focus groups, cognitive interviews, expert advisory panels, and exploratory factor analysis of pilot data. RESULTS: GKAI was measured as a count of correct answers (Mean = 3.28 SD = 1.17). HPBR yielded two domains: beliefs about race as a biological phenomenon (HPBR-BD, alpha = .69, 4 items) and beliefs about the clinical value of race and genetic variation for understanding risk for disease (HPBR-CD alpha = .61, 3 items). RACE yielded one factor (alpha = .86, 7 items). CONCLUSIONS: GKAI is a timely knowledge scale that can be used to assess health professional knowledge of race and human genetic variation. HPBR is a promising new tool for assessing health professionals' beliefs about the role of race and its relationship with human genetic variation in clinical practice. RACE offers a valid and reliable tool for assessing explicit use of racial attributes in clinical decision making. PMID- 25277070 TI - Anatomical characteristics of the accessory antero-lateral talar facet. AB - BACKGROUND: We examined the anatomical features of the accessory antero-lateral talar facet (AALTF) in adults. METHODS: The sample comprised 44 feet (male: 10 cadavers and 20 feet; female: 12 cadavers and 24 feet) obtained from 22 cadavers used for systemic autopsy. The mean age was 86.5 years. The talus and calcaneus were obtained from the autopsy cadavers, and the soft tissue was surgically removed from the bone. The talus and calcaneus were then separated and their anatomical features were observed. RESULTS: The AALTF was identified in 11 of 44 (25 %) feet. The presence or absence of the AALTF and calcaneal facet opposing the AALTF were classified into four groups: (1) joint type with articular cartilage on both the talus and calcaneus; (2) talar type with articular cartilage on the talus only; (3) calcaneal type with articular cartilage on the calcaneus only; and (4) non-joint type with no articular cartilage on either the talus or calcaneus. CONCLUSIONS: When the AALTF is present, the talus comes into contact with the calcaneus, and thus even slight changes around the talus and calcaneus can easily cause impingement. PMID- 25277071 TI - Realisation and characterization of conductive hollow fibers for neuronal tissue engineering. AB - In this article, conductive hollow fibers have been fabricated using melt spinning technique. Multiwalled carbon nanotubes (MWNTs) and poly(3 hexylthiophene-2,5-diyl) (P3HT) have been used to fabricate conductive poly caprolactone (PCL) composites. The hollow fibers have inner and outer diameter in the range of 300 um and 500 um, respectively. Critical parameters to tune the dimension of hollow fibers have been defined following two-dimensions mathematical model. Evaluation of the mechanical properties showed that the incorporation of 1-3 wt % MWNTs and 5-8 wt % P3HT increased Young Modulus of 10% and 20% respectively, compared with pure PCL. The electrical property assessment demonstrated that a minimum incorporation of 3 wt % MWNT and 8 wt % P3HT in PCL matrix transformed composite materials into conductive materials. In addition, SH SY5Y human neuroblastoma cells were seeded on the fabricated samples an their adhesion, proliferation and neurite length growth were analysed. In particular we observed that these materials promoted cell activities and in particular on MWNT/PCL composites there was a significant increase of neurite growth. PMID- 25277072 TI - Trans-flap anchoring suture technique for tension-free skin flap interposition. PMID- 25277073 TI - Composition and physicochemical properties of fasted-state human duodenal and jejunal fluid: a critical evaluation of the available data. AB - Various methods of sampling and analyzing intestinal fluids have been applied over the years. In this report, data that have been published to date about the composition of fasted-state human intestinal fluid (HIF) and its physicochemical properties are summarized and the influence of the methods used to generate the data is discussed. Key physiological parameters summarized include pH, buffer capacity, osmolarity, and ionic strength in both the fasted duodenum and jejunum. Furthermore, the bile salts and phospholipids in the fasted small intestine are addressed in terms of both qualitative and quantitative composition with respect to the different types and degrees of hydroxylation of bile salts. Taurocholate, glycocholate, and glycochenodeoxycholate were identified as the main bile salts. Lysolecithin was identified as the predominant phospholipid species in fasted HIF because of the enzymatic degradation of lecithin. Together with other intestinal surfactants, such as cholesterol and free fatty acids, the influence of bile acids and phospholipids on the surface tension of fasted HIF was evaluated. A good working knowledge of all the above-mentioned parameters is important to optimize the composition of biorelevant media, with a view to improving the prediction of in vivo dissolution and release performance of drugs and dosage forms. PMID- 25277074 TI - Regional, annual, and individual variations in the dihydroxyacetone content of the nectar of manuka (Leptospermum scoparium) in New Zealand. AB - A method was designed and validated for the analysis of dihydroxyacetone in the floral nectar of manuka (Leptospermum scoparium). The method was applied to samples collected from different regions of the North Island and the Nelson region of the upper South Island of New Zealand during the period 2009-2012 as well as to nectar samples from some Australian Leptospermum species. The ratio of dihydroxyacetone to total sugar (DHA/Tsugar) was classified as low (<0.001 mg/mg), moderate (0.001-0.002 mg/mg), or high (>0.002 mg/mg). Inter- and intraregional variation were observed as well as interannual variation with variation from low to high classification occurring within one region and from low to moderate between years. Australian species also demonstrated elevated levels of dihydroxyacetone in the nectar. Some garden cultivars were shown to produce very high nectar DHA/Tsugar, and a survey of cultivars was undertaken; cultivars with single-flowered red or pink flowers were the most common producers of very high nectar DHA/Tsugar. PMID- 25277075 TI - NMDA receptor dysregulation in chronic state: a possible mechanism underlying depression with BDNF downregulation. AB - Several lines of evidence indicate that chronic stress and downregulation of brain-derived neurotrophic factor (BNDF) are the key components of depression pathology. Evidence from animal models of depression demonstrates that chronic stress impairs hippocampal BDNF expression and that antidepressant drug effects correlate with increased BDNF synthesis and activity in the hippocampus. Studies with human carriers of BDNF Met-allele polymorphism link stress vulnerability and risk for depression. The mechanism by which chronic stress downregulates BDNF and promotes depressive-like responses is not established yet. It has been reported that chronic stress mediates alterations in several calcium-related components involved in BDNF synthesis, including CAMKII, CAMKIV and cAMP-response element binding protein (CREB), and glutamatergic neurotransmission through N-Methyl-D Aspartate receptors (NMDAR). Treatments with NMDAR antagonists like ketamine modulate glutamate signals, upregulate CREB and BDNF expression, and correct stress-induced cognitive and behavioral alterations. With the increasing interest to develop NMDAR modulators, it is crucial to understand the conditions that lead to depression pathology in order to develop rational therapies aimed at reestablishing proper neuronal function. We present here the current knowledge regarding the relation between chronic stress, BDNF and NMDARs and its implications in depression. We discuss a plausible mechanism where chronic stress induced NMDAR stimulation could lead to dysregulated calcium signaling and decreased BDNF activity. In these circumstances, neurons become vulnerable to the effects of stress, leading to dysfunctional neurotransmission and behavioral alterations. We propose that treatment with NMDAR antagonists may help to return the balance of calcium signaling, promote proper BDNF signaling and correct depressive symptoms. PMID- 25277076 TI - Differential response of miRNA-21 and its targets after traumatic brain injury in aging mice. AB - The present study investigated the possible role of miR-21, a miRNA that has known prosurvival function, in poor outcomes in the elderly following traumatic brain injury compared to adults. Controlled cortical impact injury was induced in adult (5-6 months) and aged (22-24 months) C57/BL6 mice. miR-21 and four of its targets (PDCD4, TIMP3, RECK, PTEN) were analyzed at 1, 3, 7 days post injury in samples of injured cortex using real-time PCR analysis. Basal miR-21 expression was higher in the aged brain than in the adult brain. In the adult brain, miR-21 expression increased in response to injury, with the maximum increase 24 hours after injury followed by a gradual decrease, returning to baseline 7 days post injury. In contrast, in aged mice, miR21 showed no injury response, and expression of miR-21 target genes (PTEN, PDCD4, RECK, TIMP3) was up-regulated at all post injury time points, with a maximal increase at 24 hours post injury. Based on these results, we conclude that the diminished miR21 injury response in the aged brain leads to up-regulation of its targets, with the potential to contribute to the poor prognosis following TBI in aging brain. Therefore, strategies aimed at up-regulation of miR-21 and/or down regulation of its targets might be useful in improving outcomes in the elderly following TBI. PMID- 25277077 TI - In aging, the vulnerability of rat brain mitochondria is enhanced due to reduced level of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP) and subsequently increased permeability transition in brain mitochondria in old animals. AB - Aging is accompanied by progressive dysfunction of mitochondria associated with a continuous decrease of their capacity to produce ATP. Mitochondria isolated from brain of aged animals show an increased mitochondrial permeability transition pore (mPTP) opening. We recently detected new regulators of mPTP function in brain mitochondria, the enzyme 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and its substrates 2', 3'-cAMP and 2', 3'-cNADP, and the neuronal protein p42(IP4). Here, we compared parameters of mPTP opening in non-synaptic brain mitochondria isolated from young and old rats. In mitochondria from old rats (>18 months), mPTP opening occurred at a lower threshold of Ca(2+) concentration than in mitochondria from young rats (<3 months). mPTP opening in mitochondria from old rats was accelerated by 2', 3'-cAMP, which further lowered the threshold Ca(2+) concentration. In non-synaptic mitochondria from old rats, the CNP level was decreased by 34%. Lowering of the CNP level in non-synaptic mitochondria with aging was accompanied by decreased levels of voltage-dependent anion channel (VDAC; by 69%) and of p42(IP4) (by 59%). Thus, reduced levels of CNP in mitochondria could lead to a rise in the concentration of the mPTP promoter 2', 3'-cAMP. The level of CNP and p42(IP4) and, probably VDAC, might be essential for myelination and electrical activity of axons. We propose that in aging the reduction in the level of these proteins leads to mitochondrial dysfunction, in particular, to a decreased threshold Ca(2+) concentration to induce mPTP opening. This might represent initial steps of age-related mitochondrial dysfunction, resulting in myelin and axonal pathology. PMID- 25277078 TI - A holistic approach to the critically ill and Maslow's hierarchy. PMID- 25277079 TI - Structural limitations for optimizing garnet-type solid electrolytes: a perspective. AB - Lithium ion batteries exhibit the highest energy densities of all battery types and are therefore an important technology for energy storage in every day life. Today's commercially available batteries employ organic polymer lithium conducting electrolytes, leading to multiple challenges and safety issues such as poor chemical stability, leakage and flammability. The next generation lithium ion batteries, namely all solid-state batteries, can overcome these limitations through employing a ceramic Li(+) conducting electrolyte. In the past decade, there has been a major focus on the structural and ionic transport properties of lithium-conducting garnets, and the extensive research efforts have led to a thorough understanding of the structure-property relationships in this class of materials. However, further improvement seems difficult due to structural limitations. The purpose of this Perspective article is to provide a brief structural overview of Li conducting garnets and the structural influence on the optimization of Li-ionic conductivities. PMID- 25277080 TI - Interpersonal variability in timing strategy and temporal accuracy in rapid interception task with variable time-to-contact. AB - In rapid interceptive actions such as hitting a baseball, cricket ball or tennis ball, ball speed varies between trials, and players have to compensate the time lag by controlling the moment of movement onset and movement duration. Previous studies have found that these two variables can flexibly co-vary and are robustly influenced by target speed (i.e. velocity-coupling effect: faster movement for faster target). However, some studies reported an interpersonal variability in the timing control strategy and the relationship between the strategy and temporal accuracy in rapid interception is unclear. We used a baseball-simulated rapid interceptive task to assess this issue. Under relatively easy time constraints, there was a large interpersonal variability, and participants were distinctively divided into two groups: those who mainly modulated their movement duration and those who mainly controlled their movement onset. When the time constraint became severe, the second strategy shifted to the first strategy in most of the second group participants. In the both cases, being able to mainly control movement onset resulted in higher temporal accuracy. These results suggest that minimising the velocity-coupling effect is an important factor to achieve high temporal accuracy in rapid interception. PMID- 25277081 TI - Could the devastation from Ebola occur in Asia? PMID- 25277082 TI - Copper-mediated oxidative trifluoromethylthiolation of unactivated terminal alkenes. AB - A general method to form a C(SP(3))-SCF3 bond via copper-mediated oxidative trifluoromethylthiolation of unactivated alkenes with stable nucleophilic AgSCF3 was developed. This protocol provides a direct and efficient access to a series of trifluoromethylthiolated allylic compounds with broad functional group tolerance. PMID- 25277083 TI - Hearing preservation outcomes with different cochlear implant electrodes: Nucleus(r) HybridTM-L24 and Nucleus FreedomTM CI422. AB - OBJECTIVES: In recent years, it has been possible to preserve hearing after cochlear implantation in patients with significant amounts of low-frequency residual hearing. Due to the dimensions and characteristics of the cochlear implants (CIs) Nucleus(r) HybridTM-L24 and Nucleus FreedomTM CI422, both can be used to preserve residual hearing. The aim was to investigate the degree and progression of hearing preservation over a longitudinal postoperative period in a large consecutive cohort of implanted patients with preoperative residual hearing who received either the Nucleus Hybrid-L24 or the Nucleus Freedom CI422 implant. The intention was to examine potential characteristics and triggers of resulting postoperative hearing loss which may support a differentiation of CI candidacy criteria for a certain implant type. METHODS: A retrospective data analysis of patient files on consecutively implanted subjects presenting with a severe-to profound sensorineural hearing loss at frequencies>1,500 Hz and substantial residual hearing at frequencies<=1,500 Hz, implanted with a Nucleus Hybrid-L24 (n=97) or a CI422 implant (n=100), was undertaken. A single-subject repeated measure design comparing the mean threshold shift for pure-tone thresholds under headphones up to 24 months after implantation was used. RESULTS: Hearing preservation is observed in the majority of subjects with either implant (250 1,500 Hz frequency range). Hybrid-L24 patients exhibited a median hearing loss of 10 dB at initial fitting (n=97) and of 15 dB after 24 months (n=51). A 14.4-dB decrease in median hearing loss at initial fitting (n=100) and a 30-dB decrease after 24 months (n=28) was observed with the CI422 electrode. At initial fitting, 54.6% of the Hybrid-L24 (n=97) and 49.0% of the CI422 (n=100) subjects showed a mean threshold shift<15 dB. After 24 months, 58.8% (Hybrid-L24, n=51) and 28.6% (CI422, n=28) of the patients showed a mean threshold shift<15 dB. CONCLUSIONS: The results indicate that residual hearing was preserved for the majority of implanted patients with the Hybrid-L24 and the CI422 implant. Patients implanted with the Hybrid-L24 implant demonstrate greater stability and less median hearing loss over time than those with the CI422 implant. Assessments of onset and stability of hearing loss prior to implantation are important factors to consider during candidacy evaluation for electrode selection to potentially maximize the performance outcome for each patient. PMID- 25277084 TI - Application of the British Food Standards Agency nutrient profiling system in a French food composition database. AB - Nutrient profiling systems are powerful tools for public health initiatives, as they aim at categorising foods according to their nutritional quality. The British Food Standards Agency (FSA) nutrient profiling system (FSA score) has been validated in a British food database, but the application of the model in other contexts has not yet been evaluated. The objective of the present study was to assess the application of the British FSA score in a French food composition database. Foods from the French NutriNet-Sante study food composition table were categorised according to their FSA score using the Office of Communication (OfCom) cut-off value ('healthier' <= 4 for foods and <= 1 for beverages; 'less healthy' >4 for foods and >1 for beverages) and distribution cut-offs (quintiles for foods, quartiles for beverages). Foods were also categorised according to the food groups used for the French Programme National Nutrition Sante (PNNS) recommendations. Foods were weighted according to their relative consumption in a sample drawn from the NutriNet-Sante study (n 4225), representative of the French population. Classification of foods according to the OfCom cut-offs was consistent with food groups described in the PNNS: 97.8 % of fruit and vegetables, 90.4 % of cereals and potatoes and only 3.8 % of sugary snacks were considered as 'healthier'. Moreover, variability in the FSA score allowed for a discrimination between subcategories in the same food group, confirming the possibility of using the FSA score as a multiple category system, for example as a basis for front-of-pack nutrition labelling. Application of the FSA score in the French context would adequately complement current public health recommendations. PMID- 25277085 TI - Association of filaggrin variants with asthma and rhinitis: is eczema or allergic sensitization status an effect modifier? AB - BACKGROUND: Associations of variants of the filaggrin gene, i.e. FLG with asthma and rhinitis have been shown to be modulated by eczema status. However, it is unknown whether allergic sensitization status modifies this association. The aim of this study was to determine whether FLG variants need eczema and/or allergic sensitization as a necessary component to execute adverse effects on coexisting and subsequent asthma and rhinitis. METHODS: In the Isle of Wight birth cohort, repeated measurements of asthma, rhinitis, eczema and allergic sensitization (documented by skin-prick tests) were taken in 1,456 children at the ages of 1, 2, 4, 10 and 18 years. Filaggrin haploinsufficiency was defined as having at least the minor allele of R501X, 2282del4 or S3247X variants. log-binomial regression models were used to test associations and statistical interactions. RESULTS: FLG variants increased the risk of asthma [risk ratio (RR) 1.39, 95% confidence interval (CI) 1.06-1.80] and rhinitis (RR 1.37, 95% CI 1.16-1.63). In the delayed-effects models, 'FLG variants plus allergic sensitization' and 'FLG variants plus eczema' increased the risk of subsequent asthma by 4.93-fold (95% CI 3.61-6.71) and 3.33-fold (95% CI 2.45-4.51), respectively, during the first 18 years of life. In contrast, neither eczema nor allergic sensitization in combination with FLG variants increased the risk of later rhinitis. CONCLUSIONS: Allergic sensitization and eczema modulated the association between FLG variants and asthma but not rhinitis. Our results imply that the mechanisms and pathways through which FLG variants predispose to an increased risk of asthma and rhinitis may be different. PMID- 25277086 TI - Is liquid-based cytology the magic bullet for performing molecular techniques? AB - OBJECTIVE: The role of pathology has evolved from the first microscopic definitions of diseases by Virchow to the new concept of molecular cytopathology. The management of diseases is now a multidisciplinary approach with the translation of morphological, imagery and molecular findings to therapeutic protocols. Obtaining the most reliable diagnostic material is the essential part of the medical management of patients. STUDY DESIGN: Here, we try to gain a concise insight into the available data regarding the role of cytology in the application of molecular techniques, focusing on cancer cytopathology. RESULTS: Obtaining cytological material is now feasible by different methods, and in some cases it is the only possible approach to a lesion which is not easily accessible for tissue sampling. The methods of obtaining cytological material have evolved in recent years in parallel with rapid advances in high-throughput molecular techniques, opening new windows for the diagnosis and management of diseases. CONCLUSIONS: Different kinds of cytological material are reliable for the application of molecular techniques. Cytological material obtained in a liquid base has advantages such as the better preservation of cytomorphological features and the use of the remaining liquid for nucleic acid extraction even after long storage and the application of molecular methods. PMID- 25277087 TI - Specificity, polyspecificity, and heterospecificity of antibody-antigen recognition. AB - The concept of antibody specificity is analyzed and shown to reside in the ability of an antibody to discriminate between two antigens. Initially, antibody specificity was attributed to sequence differences in complementarity determining regions (CDRs), but as increasing numbers of crystallographic antibody-antigen complexes were elucidated, specificity was analyzed in terms of six antigen binding regions (ABRs) that only roughly correspond to CDRs. It was found that each ABR differs significantly in its amino acid composition and tends to bind different types of amino acids at the surface of proteins. In spite of these differences, the combined preference of the six ABRs does not allow epitopes to be distinguished from the rest of the protein surface. These findings explain the poor success of past and newly proposed methods for predicting protein epitopes. Antibody polyspecificity refers to the ability of one antibody to bind a large variety of epitopes in different antigens, and this property explains how the immune system develops an antibody repertoire that is able to recognize every antigen the system is likely to encounter. Antibody heterospecificity arises when an antibody reacts better with another antigen than with the one used to raise the antibody. As a result, an antibody may sometimes appear to have been elicited by an antigen with which it is unable to react. The implications of antibody polyspecificity and heterospecificity in vaccine development are pointed out. PMID- 25277088 TI - Tuning the binding of coumarin 6 with DNA by molecular encapsulators: effect of beta-cyclodextrin and C-hexylpyrogallol[4]arene. AB - We report in this paper that the binding of coumarin 6 (C6) to DNA can be tuned by complexing it with host structures, viz. beta-cyclodextrin (beta-CD) and C hexylpyrogallol-4-arene (C-HPA). Because host molecules are used as carriers of small molecules onto target sites, the exposed part of the guest molecule needs to be found out, and the relationship between the host : guest ratio and the mode of binding with the target macromolecule, that is, the DNA needs to be analyzed, in order to comprehend the preferred binding moiety and tune the binding. In this paper, the formation of the inclusion complex of C6 with beta-CD and with C-HPA is studied by UV-visible, fluorescence, 2D rotating-frame nuclear Overhauser effect correlation spectroscopy and diffusion-ordered spectroscopy nuclear magnetic resonance spectra and molecular modeling. C6 forms a 1:1 complex with beta-CD and a 1:2 complex with C-HPA. The studies on the protonation of C6 in the presence and the absence of the host molecules suggest that the chromone part of C6 is outside the beta-CD molecule, whereas it is fully covered by C-HPA. The binding of C6 with calf thymus DNA (ctDNA) occurs through intercalation and hydrogen bonding, and the host-guest structures remain intact on binding with ctDNA. The oxygens of the C6 molecules are exposed when inside the host molecules and aid in the hydrogen bonding with DNA. PMID- 25277089 TI - Molecular recognition of HER-1 in whole-blood samples. AB - Multimode sensing was proposed for molecular screening and recognition of HER-1 in whole blood. The tools used for molecular recognition were platforms based on nanostructured materials such as the complex of Mn(III) with meso-tetra (4 carboxyphenyl) porphyrin, and maltodextrin (dextrose equivalence between 4 and 7), immobilized in diamond paste, graphite paste or C60 fullerene paste. The identification of HER-1 in whole-blood samples, at molecular level, is performed using stochastic mode and is followed by the quantification of it using stochastic and differential pulse voltammetry modes. HER-1 can be identified in the concentration range between 280 fg/ml and 4.86 ng/ml using stochastic mode, this making possible the early detection of cancers such as gastrointestinal, pancreatic and lung cancers. The recovery tests performed using whole-blood samples proved that the platforms can be used for identification and quantification of HER-1 with high sensitivity and reliability in such samples, these making them good molecular screening tools. PMID- 25277091 TI - Atomic force microscopy on plasma membranes from Xenopus laevis oocytes containing human aquaporin 4. AB - Atomic force microscopy (AFM) is a unique tool for imaging membrane proteins in near-native environment (embedded in a membrane and in buffer solution) at ~1 nm spatial resolution. It has been most successful on membrane proteins reconstituted in 2D crystals and on some specialized and densely packed native membranes. Here, we report on AFM imaging of purified plasma membranes from Xenopus laevis oocytes, a commonly used system for the heterologous expression of membrane proteins. Isoform M23 of human aquaporin 4 (AQP4-M23) was expressed in the X. laevis oocytes following their injection with AQP4-M23 cRNA. AQP4-M23 expression and incorporation in the plasma membrane were confirmed by the changes in oocyte volume in response to applied osmotic gradients. Oocyte plasma membranes were then purified by ultracentrifugation on a discontinuous sucrose gradient, and the presence of AQP4-M23 proteins in the purified membranes was established by Western blotting analysis. Compared with membranes without over expressed AQP4-M23, the membranes from AQP4-M23 cRNA injected oocytes showed clusters of structures with lateral size of about 10 nm in the AFM topography images, with a tendency to a fourfold symmetry as may be expected for higher order arrays of AQP4-M23. In addition, but only infrequently, AQP4-M23 tetramers could be resolved in 2D arrays on top of the plasma membrane, in good quantitative agreement with transmission electron microscopy analysis and the current model of AQP4. Our results show the potential and the difficulties of AFM studies on cloned membrane proteins in native eukaryotic membranes. PMID- 25277090 TI - Immobilized palladium(II) ion affinity chromatography for recovery of recombinant proteins with peptide tags containing histidine and cysteine. AB - Fusion of peptide-based tags to recombinant proteins is currently one of the most used tools for protein production. Also, immobilized metal ion affinity chromatography (IMAC) has a huge application in protein purification, especially in research labs. The combination of expression systems of recombinant tagged proteins with this robust chromatographic system has become an efficient and rapid tool to produce milligram-range amounts of proteins. IMAC-Ni(II) columns have become the natural partners of 6xHis-tagged proteins. The Ni(II) ion is considered as the best compromise of selectivity and affinity for purification of a recombinant His-tagged protein. The palladium(II) ion is also able to bind to side chains of amino acids and form ternary complexes with iminodiacetic acid and free amino acids and other sulfur-containing molecules. In this work, we evaluated two different cysteine- and histidine-containing six amino acid tags linked to the N-terminal group of green fluorescent protein (GFP) and studied the adsorption and elution conditions using novel eluents. Both cysteine-containing tagged GFPs were able to bind to IMAC-Pd(II) matrices and eluted successfully using a low concentration of thiourea solution. The IMAC-Ni(II) system reaches less than 20% recovery of the cysteine-containing tagged GFP from a crude homogenate of recombinant Escherichia coli, meanwhile the IMAC-Pd(II) yields a recovery of 45% with a purification factor of 13. PMID- 25277092 TI - Probing interactions between human lung adenocarcinoma A549 cell and its aptamers at single-molecule resolution. AB - Because cell-specific aptamers have high potential for biomedical applications, investigation of the interaction between cell and its aptamers may be of key importance for an improved understanding of biochemical processes. Herein, the interaction between human lung adenocarcinoma A549 cell and its four aptamers was explored using single-molecule force spectroscopy (SMFS). The values of the unbinding force varied from 117.1 to 171.0 pN at the loading rate of 1.8 * 10(5) pN/s. Based on the dependence of singe molecule force on the atomic force microscopy loading rate, the corresponding kinetic parameters were obtained. The results revealed two activation barriers and two transient states in the unbinding process of aptamer/cell interaction. More importantly, the binding sites on A549 cells with its four aptamers were defined to be different using SMFS and flow cytometry. This work demonstrated that SMFS can be used as a powerful tool for exploring the aptamer/cell binding behavior at the single molecule level, and may provide valuable information for the design and application of aptamer probes. PMID- 25277093 TI - Ratiometric fluorescent scaffold giving discrete response towards iodide ion: a combined experimental and DFT study. AB - A novel ratiometric fluorescent receptor (Z)-2-(4-[diethylamino]-2 hydroxybenzylideneamino) pyridine-3-carbaldehyde (3) bearing one phenolic OH and one aldehyde group as recognition sites was synthesized and characterized. The anion recognition behaviour of receptor 3 was evaluated by various spectroscopic (UV-visible, fluorescence and (1) H nuclear magnetic resonance) methods and was validated by computational studies. The receptor showed fast response time, excellent selectivity and reproducibility towards iodide ion detection among the other surveyed anions, with a binding constant of 6.12 * 10(4) M(-1) and a detection limit of 0.24 MUM, thus confirming its potential applicability as a fluorescent sensor for iodide. PMID- 25277096 TI - "Is it going to hurt?": the impact of the diagnostic odyssey on children and their families. AB - The pediatric diagnostic odyssey is a period of uncertainty and emotional turmoil for families, often characterized by multiple minor medical procedures (such as venipuncture) that children may find distressing. Interventions to reduce distress are rarely offered, despite evidence that this is crucial both for avoiding anticipatory anxiety before future procedures and for improving healthcare compliance in adulthood. We interviewed ten mothers of children with neuromuscular disorders, asking about their perceptions of their child's experiences with different medical procedures, the emotional impact of the diagnostic odyssey, implications of obtaining a diagnosis, and interactions with healthcare providers. We coded interviews in ATLAS.ti (version 7.0) based on a priori and emergent themes, and analyzed them based on the principles of interpretive description. We found that predicting and assessing children's reactions to procedures is challenging; parents reported non-invasive procedures such as x-rays were distressing for some children, and that providers did not detect subtle indicators of distress. Parents valued obtaining a diagnosis because it validated their concerns, enabled planning for the child's future healthcare needs, and allowed access to established support networks. This study suggests that healthcare providers can improve the experience of the diagnostic odyssey by validating family concerns and connecting them to support services that are available without a diagnosis. PMID- 25277095 TI - Adding insult to injury: childhood and adolescent risk factors for psychosis predict lower fractional anisotropy in the superior longitudinal fasciculus in healthy adults. AB - Although epidemiological studies provide strong support for demographic and environmental risk factors in psychotic disorders, few data examine how these risk factors relate to the putative aberrant neurodevelopment associated with illness. The present study examined how the accumulation of risk factors including low IQ, low parental socioeconomic status (SES), history of adolescent cannabis use and childhood trauma, and high levels of subclinical psychotic-like experiences (PLEs) contributed to aberrant neurodevelopmental outcomes in 112 otherwise healthy adults recruited from the community. Participants were studied with diffusion tensor imaging (DTI), and voxel-wise statistical analysis of fractional anisotropy (FA) using tract-based spatial statistics (TBSS) was used to examine the relation between cumulative risk (CR) for psychosis and white matter (WM) integrity across the whole brain. Analyses revealed that higher CR was significantly associated with lower FA in a cluster in the left superior longitudinal fasciculus (SLF). These results suggest that risk factors previously associated with psychotic disorders are associated with WM integrity even in otherwise healthy adults and may provide insight into how previously identified risk factors contribute to the structural brain abnormalities associated with psychotic illness. Prospective longitudinal studies examining the effect of risk factors on the developmental trajectory of brain WM are warranted. PMID- 25277098 TI - Facile semi-automated forensic body fluid identification by multiplex solution hybridization of NanoString(r) barcode probes to specific mRNA targets. AB - A DNA profile from the perpetrator does not reveal, per se, the circumstances by which it was transferred. Body fluid identification by mRNA profiling may allow extraction of contextual 'activity level' information from forensic samples. Here we describe the development of a prototype multiplex digital gene expression (DGE) method for forensic body fluid/tissue identification based upon solution hybridization of color-coded NanoString((r)) probes to 23 mRNA targets. The method identifies peripheral blood, semen, saliva, vaginal secretions, menstrual blood and skin. We showed that a simple 5 min room temperature cellular lysis protocol gave equivalent results to standard RNA isolation from the same source material, greatly enhancing the ease-of-use of this method in forensic sample processing. We first describe a model for gene expression in a sample from a single body fluid and then extend that model to mixtures of body fluids. We then describe calculation of maximum likelihood estimates (MLEs) of body fluid quantities in a sample, and we describe the use of likelihood ratios to test for the presence of each body fluid in a sample. Known single source samples of blood, semen, vaginal secretions, menstrual blood and skin all demonstrated the expected tissue-specific gene expression for at least two of the chosen biomarkers. Saliva samples were more problematic, with their previously identified characteristic genes exhibiting poor specificity. Nonetheless the most specific saliva biomarker, HTN3, was expressed at a higher level in saliva than in any of the other tissues. Crucially, our algorithm produced zero false positives across this study's 89 unique samples. As a preliminary indication of the ability of the method to discern admixtures of body fluids, five mixtures were prepared. The identities of the component fluids were evident from the gene expression profiles of four of the five mixtures. Further optimization of the biomarker 'CodeSet' will be required before it can be used in casework, particularly with respect to increasing the signal-to-noise ratio of the saliva biomarkers. With suitable modifications, this simplified protocol with minimal hands on requirement should facilitate routine use of mRNA profiling in casework laboratories. PMID- 25277097 TI - Role of soluble epoxide hydrolase in age-related vascular cognitive decline. AB - P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15 dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI. PMID- 25277099 TI - MicroRNA expression as risk biomarker of breast cancer metastasis: a pilot retrospective case-cohort study. AB - BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in post-transcriptional gene regulation and have recently been shown to play a role in cancer metastasis. In solid tumors, especially breast cancer, alterations in miRNA expression contribute to cancer pathogenesis, including metastasis. Considering the emerging role of miRNAs in metastasis, the identification of predictive markers is necessary to further the understanding of stage-specific breast cancer development. This is a retrospective analysis that aimed to identify molecular biomarkers related to distant breast cancer metastasis development. METHODS: A retrospective case cohort study was performed in 64 breast cancer patients treated during the period from 1998-2001. The case group (n = 29) consisted of patients with a poor prognosis who presented with breast cancer recurrence or metastasis during follow up. The control group (n = 35) consisted of patients with a good prognosis who did not develop breast cancer recurrence or metastasis. These patient groups were stratified according to TNM clinical stage (CS) I, II and III, and the main clinical features of the patients were homogeneous. MicroRNA profiling was performed and biomarkers related to metastatic were identified independent of clinical stage. Finally, a hazard risk analysis of these biomarkers was performed to evaluate their relation to metastatic potential. RESULTS: MiRNA expression profiling identified several miRNAs that were both specific and shared across all clinical stages (p <= 0.05). Among these, we identified miRNAs previously associated with cell motility (let-7 family) and distant metastasis (hsa-miR-21). In addition, hsa-miR-494 and hsa-miR 21 were deregulated in metastatic cases of CSI and CSII. Furthermore, metastatic miRNAs shared across all clinical stages did not present high sensitivity and specificity when compared to specific-CS miRNAs. Between them, hsa-miR-183 was the most significative of CSII, which miRNAs combination for CSII (hsa-miR-494, hsa-miR-183 and hsa-miR-21) was significant and were a more effective risk marker compared to the single miRNAs. CONCLUSIONS: Women with metastatic breast cancer, especially CSII, presented up-regulated levels of miR-183, miR-494 and miR-21, which were associated with a poor prognosis. These miRNAs therefore represent new risk biomarkers of breast cancer metastasis and may be useful for future targeted therapies. PMID- 25277100 TI - A comparison of thought and perception disorders in borderline personality disorder and schizophrenia: psychotic experiences as a reaction to impaired social functioning. AB - BACKGROUND: Although previous studies suggest a high frequency of psychotic symptoms in DSM-IV Borderline Personality Disorder (BPD) there is currently no consensus on their prevalence and characteristics (type, frequency, duration, location etc.). Similarly, there are few papers addressing psychotic reactivity, the crucial aspect of BPD included in the ninth criterion for DSM-IV BPD, which remained unchanged in DSM-IV-TR and DSM-5. The purposes of the present study were to compare thought and perception disorders in patients with DSM-IV BPD and schizophrenia (SC), investigating their relationship with social functioning. METHODS: Thought and perception disorders and social functioning over the previous two years were assessed by the Diagnostic Interview for Borderline Revised (DIB-R) and Personal and Social Performance scale (PSP) respectively in outpatients with DSM-IV BPD (n = 28) or DSM-IV SC (n = 28). RESULTS: Quasi psychotic thought (i.e. transient, circumscribed and atypical psychotic experiences) was more frequent in BPD (BPD = 82.1%, SC = 50%, p = 0.024); whereas true psychotic thought (i.e. Schneiderian first-rank, prolonged, widespread and bizarre psychotic symptoms) was more frequent in SC (SC = 100%, BPD = 46.4%, p < 0.001). However both types of psychotic features were prevalent in both groups. Non-delusional paranoia (e.g. undue suspiciousness and ideas of references) was ubiquitous but was more severe in BPD than SC patients (U(54) = 203.5, p = 0.001). In the BPD group there was a strong negative correlation between personal and social functioning and non-delusional paranoia (tau(28) = 0.544, p = 0.002) and level of personal and social functioning was a significant predictor of the severity of non-delusional paranoia only in the BPD group (beta = -0.16, t(23) = 2.90, p = 0.008). CONCLUSIONS: BPD patients reported less severe psychotic experiences with more frequent quasi-psychotic thought, less frequent true psychotic thought and more severe non-delusional paranoia than SC patients. Interpersonal functioning seems to predict non-delusional paranoia in BPD, which would validate the "stress-related paranoid ideation", included in the ninth diagnostic criterion for DSM-IV and DSM-5 BPD. PBD patients had higher scores on the psychotic experiences subscale that support the use of a dimensional assessment of the severity of thought and perception disorders, for example the Clinician-Rated Dimensions of Psychosis Symptom Severity introduced in DSM-5, Section III. PMID- 25277101 TI - Facile preparation of organic-inorganic hybrid polymeric ionic liquid monolithic column with a one-pot process for protein separation in capillary electrochromatography. AB - An organic-inorganic hybrid monolithic column based on 1-vinyl-3 dodecylimidazolium bromide (VC12Im(+)Br(-)) has been prepared in a single step by combining radical copolymerization with a non-hydrolytic sol-gel (NHSG) process. The NHSG process was significantly shortened to 6 h by using formic acid as catalyst. For comparison, we also prepared polymeric ionic liquid (PIL) monolithic columns by hydrolytic sol-gel and organic polymeric process, respectively. The resulting monolithic columns were characterized by Fourier transform infrared spectra, scanning electron microscopy, and Brunauer-Emmett Teller. Under the capillary electrochromatography mode, these columns were applied to separate alkylbenzenes, anilines, and proteins, respectively. The results indicated that the NHSG-based hybrid PIL monolithic column exhibited the highest column efficiency among the three types of columns; organic solvent, commonly required by the traditional columns to achieve satisfactory separation efficiency for proteins, was absent in the NHSG-based hybrid PIL monolithic column because of the biocompatibility of the VC12Im(+)Br(-), which was beneficial to analysis of protein containing samples. In order to demonstrate its application potential, the developed NHSG-based hybrid PIL monolithic column was also employed to separate egg white sample. PMID- 25277102 TI - Direct detection of chloramphenicol in honey by neutral desorption-extractive electrospray ionization mass spectrometry. AB - Herein, we constructed a platform of neutral desorption-extractive electrospray ionization mass spectrometry (ND-EESI-MS) for direct and rapid detection of chloramphenicol (CAP) in honey samples diluted with methanol. Under the optimized working conditions, the quantitative information of CAP residues was acquired effectively by EESI-Ion Trap MS (n) . Using heated methanol-N2 as spray reagent, we reduced the limit of determination (LOD) from 73.3 ng/mL to 0.3 ng/mL, and the CAP detection is linear in the range of 1-5000 ng/mL (R = 0.9947). For the honey samples with CAP of 10, 100, and 1000 ng/mL, the recoveries were 133.0, 80.6, and 101.1%, and the relative standard deviations were 5.96, 8.82, and 8.71%, respectively. The reproducibility assays showed the stability of this method. Therefore, this ND-EESI-MS method is powerful for direct, rapid, and quantitative CAP analysis in honey samples with high sensitivity, precision, and specificity. PMID- 25277103 TI - Liquid chromatography tandem mass spectrometry method using solid-phase extraction and bead-beating-assisted matrix solid-phase dispersion to quantify the fungicide tebuconazole in controlled frog exposure study: analysis of water and animal tissue. AB - This paper presents the development, optimization, and validation of a LC-MS/MS methodology to determine the concentration of the antifungal drug and fungicide tebuconazole in a controlled exposure study of African clawed frogs (Xenopus laevis). The method is validated on animal tank water and on tissue from exposed and non-exposed adult X. laevis. Using solid-phase extraction (SPE), the analytical method allows for quantification of tebuconazole at concentrations as low as 3.89 pg mL(-1) in 10 mL water samples. Using bead-beating-assisted matrix solid-phase dispersion (MSPD), it was possible to quantify tebuconazole down to 0.63 pg mg(-1) wet weight liver using 150 mg tissue. The deuterated analogue of tebuconazole was used as internal standard, and ensured method accuracy in the range 80.6-99.7% for water and 68.1-109% for tissue samples. The developed method was successfully applied in a 4-week X. laevis repeated-exposure study, revealing high levels of tebuconazole residues in adipose and liver tissue, and with experimental bioconcentration factors up to 18,244 L kg(-1). PMID- 25277104 TI - Micro-solid-phase extraction coupled to desorption electrospray ionization-high resolution mass spectrometry for the analysis of explosives in soil. AB - Home-made micro-solid-phase extraction (SPE) cartridges using different adsorbent materials were tested for the desorption electrospray ionization-high-resolution mass spectrometry (DESI-HRMS) determination of explosives like 2,4,6 trinitrotoluene, cyclotrimethylene-trinitramine, cyclotetramethylene tetranitramine, pentaerythritol tetranitrate, and trinitrophenylmethylnitramine in soil samples. Quantitation limits in the low nanogram per kilogram range proved the reliability of the method for the detection of explosives at ultra trace levels. The reduced sample preparation allowed for low costs and high throughput analyses. Finally, the superior extraction capability of the method was proved by obtaining DESI-HRMS responses at least five times higher than those achieved by performing DESI-HRMS analyses of solid-liquid extracts spotted onto commercial polytetrafluoroethylene slides. PMID- 25277105 TI - Epigenetic information from ancient DNA provides new insights into human evolution. Commentary on Gokhman D et al. (2014): Reconstructing the DNA methylation maps of the Neanderthal and the Denisovan. Science 344:523-527. PMID- 25277106 TI - Overexpressed NLRC3 acts as an anti-inflammatory cytosolic protein. AB - The novel nucleotide oligomerization domain (NOD)-like receptor (NLR) with a caspase activation and recruitment domain (CARD) 3 (NLRC3) protein belongs to the NLR family of cytosolic pathogen recognition receptors. NLRC3 has the characteristic NOD and leucine-rich repeat configuration with a less well defined CARD. T lymphocytes are known to have high NLRC3 expression, which may be involved in suppression of T cell activation. Here, we report that NLRC3 is a cytoplasmic protein that negatively regulates pro-IL-1beta maturation. Among well known inflammasome components, NLRC3 can interact with apoptosis-associated speck like protein containing a CARD (ASC) and caspases 1 and 5. Transient transfection of NLRC3 into stable EGFP-ASC-expressing HEK293FT cells reduces NLR family, pyrin domain-containing 3 (NLRP3)/cryopyrin-induced formation of ASC specks in a dose- and time-dependent manner. This suggests that NLRC3 can regulate ASC speck formation, caspase-1 activation and IL-1beta maturation. We show for the first time that inflammasome-like complexes assemble when caspase-1 and ASC are cotransfected together with NLRC3 in HEK293FT cells. However, overexpression of NLRC3 with NLRP3/cryopyrin inflammasome components suppresses pro-caspase-1 cleavage and IL-1beta processing. Our study suggests that NLRC3 negatively regulates inflammatory responses. PMID- 25277107 TI - Dry-air-stable lithium silicide-lithium oxide core-shell nanoparticles as high capacity prelithiation reagents. AB - Rapid progress has been made in realizing battery electrode materials with high capacity and long-term cyclability in the past decade. However, low first-cycle Coulombic efficiency as a result of the formation of a solid electrolyte interphase and Li trapping at the anodes, remains unresolved. Here we report LixSi-Li2O core-shell nanoparticles as an excellent prelithiation reagent with high specific capacity to compensate the first-cycle capacity loss. These nanoparticles are produced via a one-step thermal alloying process. LixSi-Li2O core-shell nanoparticles are processible in a slurry and exhibit high capacity under dry-air conditions with the protection of a Li2O passivation shell, indicating that these nanoparticles are potentially compatible with industrial battery fabrication processes. Both Si and graphite anodes are successfully prelithiated with these nanoparticles to achieve high first-cycle Coulombic efficiencies of 94% to >100%. The LixSi-Li2O core-shell nanoparticles enable the practical implementation of high-performance electrode materials in lithium-ion batteries. PMID- 25277108 TI - Natural history of angiomyolipoma in lymphangioleiomyomatosis: implications for screening and surveillance. AB - BACKGROUND: LAM is a rare disease of women categorised by lung cysts and lymphatic abnormalities. The disease occurs sporadically or associated with Tuberous Sclerosis Complex (TSC-LAM). Angiomyolipoma, a benign tumour, prone to haemorrhage, occurs mostly in the kidneys in many of these patients. Treatment guidelines exist for angiomyolipoma in patients with TSC but the natural history of angiomyolipoma in sporadic LAM has not been studied. AIMS: To document the natural history of angiomyolipoma in a national cohort of patients with sporadic LAM to inform tumour screening and surveillance protocols. METHODS: Demographic data, clinical features, lung function and tumour size were obtained from clinical records of patients attending the National Centre for LAM in Nottingham, UK. RESULTS: 122 patients with definite or probable LAM by European Respiratory Society criteria were identified. One hundred and seven had sporadic LAM, of which 53 (50%) had at least one angiomyolipoma. In patients with sporadic LAM presentation of angiomyolipoma preceded or followed onset of lung symptoms by up to 11 and 38 years respectively. Mean tumour size was 28 mm (range 5-140 mm) at presentation and growth was 1.8 mm/yr (95% C.I. 0.42-3.82) thereafter. Eleven patients with sporadic LAM had had a nephrectomy due to angiomyolipoma bleeding. The need for intervention did not differ between those with TSC-LAM and sporadic LAM. CONCLUSIONS: Patients with LAM have a high prevalence of symptomatic angiomyolipoma which can present at any time. Angiomyolipoma in sporadic-LAM have a similar risk of bleeding to those with TSC. All patients should be screened for angiomyolipoma at diagnosis of lung disease by MRI scanning and the tumours require continuous monitoring. PMID- 25277109 TI - [Sleep and sleep disorders in the elderly. Part 2: therapy]. AB - Sleep disorders need to be treated if they affect the quality of life, lead to functional problems in daily life or unfavorably affect self-sufficiency. The large number of sleep disorders is reflected in the number of different and varied available therapeutic procedures. The basic therapeutic procedure for any sleep disorder is the use of sleep hygiene. Sleeplessness (insomnia) is most effectively treated through behavioral therapy, with stimulus control and sleep restriction as the most effective measures, whereas pharmacotherapy is considerably less effective and has side effects. Sleep-disordered breathing is also the most common cause of hypersomnia in the elderly and is most effectively treated by nocturnal positive pressure breathing. PMID- 25277110 TI - The associations between polymorphisms in the CD36 gene, fat oxidation and cardiovascular disease risk factors in a young adult Australian population: a pilot study. AB - Our pilot study in a young adult Australian cohort aimed to investigate potential associations between CD36 polymorphisms (rs1527479 and rs1984112), fat oxidation and cardiovascular disease risk. CD36 genotype was associated with fat oxidation during sub-maximal exercise, resting heart rate and blood pressure, indicating increased chronic disease risk in this otherwise healthy cohort. PMID- 25277111 TI - Normal-pressure microwave rapid synthesis of hierarchical SnO2@rGO nanostructures with superhigh surface areas as high-quality gas-sensing and electrochemical active materials. AB - Hierarchical SnO2@rGO nanostructures with superhigh surface areas are synthesized via a simple redox reaction between Sn(2+) ions and graphene oxide (GO) nanosheets under microwave irradiation. XRD, SEM, TEM, XPS, TG-DTA and N2 adsorption-desorption are used to characterize the compositions and microstructures of the SnO2@rGO samples obtained. The SnO2@rGO nanostructures are used as gas-sensing and electroactive materials to evaluate their property microstructure relationship. The results show that SnO2 nanoparticles (NPs) with particle sizes of 3-5 nm are uniformly anchored on the surfaces of reduced graphene oxide (rGO) nanosheets through a heteronucleation and growth process. The as-obtained SnO2@rGO sample with a hierarchically sesame cake-like microstructure and a superhigh specific surface area of 2110.9 m(2) g(-1) consists of 92 mass% SnO2 NPs and ~8 mass% rGO nanosheets. The sensitivity of the SnO2@rGO sensor upon exposure to 10 ppm H2S is up to 78 at the optimal operating temperature of 100 degrees C, and its response time is as short as 7 s. Compared with SnO2 nanocrystals (5-10 nm), the hierarchical SnO2@rGO nanostructures have enhanced gas-sensing behaviors (i.e., high sensitivity, rapid response and good selectivity). The SnO2@rGO nanostructures also show excellent electroactivity in detecting sunset yellow (SY) in 0.1 M phosphate buffer solution (pH = 2.0). The enhancement in gas-sensing and electroactive performance is mainly attributed to the unique hierarchical microstructure, high surface areas and the synergistic effect of SnO2 NPs and rGO nanosheets. PMID- 25277113 TI - Sphere-forming capacity as an enrichment strategy for epithelial-like stem cells from equine skin. AB - BACKGROUND: Mammal skin plays a pivotal role in several life preserving processes and extensive damage may therefore be life threatening. Physiological skin regeneration is achieved through ongoing somatic stem cell differentiation within the epidermis and the hair follicle. However, in severe pathological cases, such as burn wounds, chronic wounds, and ulcers, the endogenous repair mechanisms might be insufficient. For this reason, exogenous purification and multiplication of epithelial-like stem/progenitor cells (EpSCs) might be useful in the treatment of these skin diseases. However, only few reports are available on the isolation, purification and characterization of EpSCs using suspension cultures. METHODS: In the present study, skin was harvested from 6 mares and EpSCs were isolated and purified. In addition to their characterization based on phenotypic and functional properties, sphere formation was assessed upon isolation, i.e. at passage 0 (P0), and at early (P4) and late (P10) passages using different culture conditions. RESULTS: On average 0.53 +/- 0.28% of these primary skin-derived cells showed the capacity to form spheres and hence possessed stem cell properties. Moreover, significantly more spheres were observed in EpSC medium versus differentiation medium, corroborating the EpSCs' privileged ability to survive in suspension. Furthermore, the number of cells per sphere significantly increased over time as well as with subsequent passaging. Upon immunophenotyping, the presumed EpSCs were found to co-express cytokeratin (CK) 14, Casein kinase 2 beta and Major Histocompatibility Complex (MHC) I and expressed no pan CK and wide CK. Only a few cells expressed MHC II. Their differentiation towards keratinocytes (at P4 and P10) was confirmed based on co-expression of CK 14, Casein kinase 2 beta, pan CK and wide CK. In one of six isolates, a non-EpSC cell type was noticed in adherent culture. Although morphological features and immunohistochemistry (IHC) confirmed a keratinocyte phenotype, this culture could be purified by seeding the cells in suspension at ultralow clonal densities (1 and 10 cells/cm(2)), yet with a significantly lower sphere forming efficiency in comparison to pure EpSCs (P = 0.0012). CONCLUSION: The present study demonstrated sphere formation as a valuable tool to purify EpSCs upon their isolation and assessed its effectiveness at different clonal seeding densities for eliminating a cellular contamination. PMID- 25277114 TI - Dynamics of propionic acid degradation in a two-phase anaerobic system. AB - This paper reports on propionic acid (HPr) degradation in a laboratory scale two phase anaerobic system, where HPr was accumulated in the acidogenic reactor and degraded in the methanogenic reactor. Batch tests using biomass from the two phase anaerobic system showed HPr degradation was rarely detectable in the acidogenic reactor when HPr concentration ranged from 639 to 4531mgHPrL(-1) and at pH 4.50 to 6.50. Biomass from the methanogenic reactor could, however, successfully degrade HPr at its initial concentration of up to 4585mgHPrL(-1) at pH 6.40-7.30. ATP results showed that differences in the degradation ability of HPr by the acidogenic and methanogenic biomass may be related with their respective different biomass activities. Results from pyrosequencing showed that the predominant propionic acid oxidizing bacteria (POB) in the methanogenic reactor were Smithella (2.68%) and Syntrophobacter (0.35%); while poor degradation of HPr in the acidogenic reactor may be associated with the low abundance of POB (0.02% Desulfacinum and 0.08% Desulfobulbus). This might have been induced by the long-term unfavorable environment for POB growth in the acidogenic reactor. PMID- 25277116 TI - Predictors of severity for postnatal cytomegalovirus infection in preterm infants and implications for treatment. AB - Postnatal cytomegalovirus (CMV) infection is common in neonates and is mostly acquired through infected breast milk from seropositive mothers. In this review, risk factors of postnatal CMV transmission and predictors of severity, preventive measures and treatment of symptomatic postnatal CMV infection in preterm infants are discussed. Several viral, transmission route and host factors have been associated with a higher risk of postnatal CMV transmission from mother to child. Severity predictors of symptomatic postnatal CMV infection may include extreme prematurity (gestational age <26 weeks), timing of postnatal infection as well as comorbidities. Further research in postnatally infected preterm infants at risk for severe symptoms is essential with respect to preventive measures involving the infected breast milk and antiviral treatment. PMID- 25277115 TI - Structure and function of the nucleosome-binding PWWP domain. AB - PWWP domain-containing proteins are often involved in chromatin-associated biological processes, such as transcriptional regulation and DNA repair, and recent studies have shown that the PWWP domain specifies chromatin localization. Mutations in the PWWP domain, a 100-150 amino acid motif, have been linked to various human diseases, emphasizing its importance. Structural studies reveal that PWWP domains possess a conserved aromatic cage for histone methyl-lysine recognition, and synergistically bind both histone and DNA, which contributes to their nucleosome-binding ability and chromatin localization. Furthermore, the PWWP domain often cooperates with other histone and DNA 'reader' or 'modifier' domains to evoke crosstalk between various epigenetic marks. Here, we discuss these recent advances in understanding the structure and function of the PWWP domain. PMID- 25277118 TI - Photocatalytic aptitude of titanium dioxide impregnated chitosan beads for the reduction of Cr(VI). AB - This article describes the photo-reduction of heavy metal Cr(VI) in aqueous solution using titanium dioxide impregnated chitosan beads (TCB) in the presence of UV irradiation. The synergistic role of TCB results in excellent photocatalytic behavior. The reduction of Cr(VI) by the TCB is mainly due to adsorption coupled photocatalytic reduction mechanism. The characterization of TCB was made by Fourier transform Infrared (FTIR) Spectral studies, Scanning Electron Microscope (SEM), Energy Dispersive Analysis of X-ray (EDAX) and Electron Paramagnetic Resonance (EPR) studies. The kinetics of photo-reduction of Cr(VI) is explained on the basis of Langmuir-Hinshelwood mechanism. A comparative study on the percentage removal of chromium using chitosan (CS), titanium dioxide (TiO2) and titanium dioxide impregnated chitosan beads (TCB) in the presence of UV irradiation at 60 min of contact time have been found to be 19.4%, 54.8% and 91.4% respectively. Effects of experimental parameters such as irradiation time, dose, pH, initial concentration, and co-ions were optimized for Cr(VI) removal. Suitability of TCB at field condition was tested with a sample taken from a nearby industrial area. PMID- 25277119 TI - Production of copolymer, poly (hydroxybutyrate-co-hydroxyvalerate) by Halomonas campisalis MCM B-1027 using agro-wastes. AB - For cost effective production of PHA, agro-wastes like fruit peels, bagasse and deoiled cakes were screened as a sole source of carbon. Halomonas campisalis MCM B-1027, which was isolated from one of the extreme environment, i.e. Lonar Lake, India, was explored for the production of PHA using fruit peels and bagasse having fermentable sugars. Among the agro-wastes tested, 1% (v/v) aqueous extract of bagasse was found to be the optimum carbon source with 47% PHA production on dry cell weight basis. Significant amount of total sugars are utilized and converted into cell mass and PHA, e.g. 62% sugar utilized from bagasse extract, 84% from orange peel extract and 71% from banana peel extract as compared to 51% in case of maltose. Hence the cost of production would be positively reduced. The detailed characterization of PHA formed by H. campisalis using bagasse extract as sole carbon source revealed that the organism produces a copolymer of PHB-co-PHV (94.4:5.6) having molecular weight M(w) 1.394 * 10(6) and melting temperature 168.9 degrees C. Production of PHA by H. campisalis using aqueous extract of fruit peels and a copolymer PHB-co-PHV using aqueous extract of bagasse is presumably the first report. PMID- 25277120 TI - Tunable electrofluorochromic device from electrochemically controlled complementary fluorescent conjugated polymer films. AB - The fluorescent behavior of the electrofluorochromic devices (Type I) of greenish yellow emitting P1 and blue emitting P2 can be reversibly switched between the nonfluorescent (oxidized) state and the fluorescent (neutral) state with a superb on/off ratio of 23.8 and 21.9, respectively. Moreover, a tunable electrofluorochromic device (Type II) based on two P1 and P2 polymeric layers that are coated individually on two independent ITO electrodes shows switchable blue-white-(greenish-yellow) multifluorescence states. PMID- 25277121 TI - Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men. AB - OBJECTIVE: Study associations between three measures of alcohol consumption (recent, typical/habitual, binging), semen quality and serum reproductive hormones. DESIGN: Cross-sectional population based study. SETTING AND PARTICIPANTS: 1221 young Danish men, aged 18-28 years were recruited when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. Total alcohol consumption: (1) in the week preceding (habitual/typical) the visit (recent alcohol intake), (2) in a typical week and (3) frequency of 'binge drinking' (consuming more than 5 units/day)) in the past 30 days was estimated. MAIN OUTCOME MEASURES: Semen quality (volume, sperm concentration, total sperm count, and percentages of motile and morphologically normal spermatozoa) and serum concentration of reproductive hormones (follicle stimulating hormone, luteinising hormone, testosterone, sex hormone binding globulin, oestradiol, free testosterone and inhibin B). RESULTS: Sperm concentration, total sperm count and percentage of spermatozoa with normal morphology were negatively associated with increasing habitual alcohol intake. This association was observed in men reporting at least 5 units in a typical week but was most pronounced for men with a typical intake of more than 25 units/week. Men with a typical weekly intake above 40 units had a 33% (95% CI 11% to 59%) reduction in sperm concentration compared to men with an intake of 1-5 units/week. A significant increase in serum free testosterone with increasing alcohol consumption the week preceding the visit was found. Binging was not independently associated with semen quality. CONCLUSIONS: Our study suggests that even modest habitual alcohol consumption of more than 5 units per week had adverse effects on semen quality although most pronounced associations were seen in men who consumed more than 25 units per week. Alcohol consumption was also linked to changes in testosterone and SHBG levels. Young men should be advised to avoid habitual alcohol intake. PMID- 25277123 TI - EMAS position statement: individualized breast cancer screening versus population based mammography screening programmes. AB - INTRODUCTION: Breast cancer is the most prevalent cancer in women, with slightly more than ten percent developing the disease in Western countries. Mammography screening is a well established method to detect breast cancer. AIMS: The aim of the position statement is to review critically the advantages and shortcomings of population based mammography screening. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSION: Mammography screening programmes vary worldwide. Thus there are differences in the age at which screening is started and stopped and in the screening interval. Furthermore differences in screening quality (such as equipment, technique, resolution, single or double reading, recall rates) result in a sensitivity varying from 70% to 94% between studies. Reporting results of screening is subject to different types of bias such as overdiagnosis. Thus because of the limitations of population-based mammography screening programmes an algorithm for individualized screening is proposed. PMID- 25277122 TI - Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. AB - Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in alpha granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin alphavbeta3-Delta744 or treatment with the anti-human alphavbeta3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin alphavbeta3 in this process. The present results establish a new mechanism for platelet contribution to LPA dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis. PMID- 25277124 TI - Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). OBJECTIVE: To better characterize PG features and management among an IBD cohort. METHODS: Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. RESULTS: Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. CONCLUSIONS: We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients. PMID- 25277126 TI - Faculty analysis of distributed medical education in Northern Canadian Aboriginal communities. AB - CONTEXT: In 2005 the Northern Ontario School of Medicine (NOSM) in Canada implemented the world's first and (still) only mandatory Aboriginal community placement for all its medical students. ISSUES: The Aboriginal placement was created in part to address social accountability, defined as the obligation of medical schools to direct education, research and service activities towards addressing the priority health concerns of the community they serve. Concurrently, Aboriginal health policies have increasingly emphasized the need to involve Aboriginal people in healthcare planning and design health care that involves Aboriginal concepts of health and culturally safe care. Aboriginal delegates provided recommendations for the development of an Aboriginal health curriculum, which included the need for the medical school to acknowledge and respect Aboriginal history, health priorities and develop an Aboriginal community placement for all medical students. LESSONS LEARNED: To anticipate the challenges (e.g., distance, communication, technologies, student and cultural safety, pedagogical effectiveness/appropriateness) presented by a mandatory placement for first-year students in Aboriginal communities a pilot placement project was designed. The locations of the communities were carefully selected in order to assess a variety of challenges that might be encountered with rural and remote Aboriginal community placements. Pilot lessons included managing student expectations, which leaned towards a clinical rather than a community-based cultural placement focus. Areas for increased coordination and administrative support were identified, as well as the need for more extensive community level support. The students had an overall positive experience and learned about the realities of health care in the communities. Aboriginal community staff commented that the experience with the students was fulfilling and beneficial. It was also recognized that curriculum delivery methods required major adjustments and that the students required significant Aboriginal health curriculum in preparation to move forward from the pilot placement to a sustainable Aboriginal community curriculum. Two medical anthropologists, assisted and supported by an historian of medicine, identified and developed the core areas of academic knowledge required for students to begin their journey towards becoming culturally safe medical practitioners. Another important aspect of preparing students was a series of mandatory sessions led by the Aboriginal Affairs Office designed to complement academic sessions with practical information such as how to conduct oneself in the community, and current politics and treaties. A self-study project was developed to guide students through a process of increasing self-awareness of their own attitudes and perceptions about Aboriginal people and communities, and develop their competence to provide culturally safe medical care. New learning from several iterations of the placement was employed to fine-tune the curriculum, information technologies and supporting policies as the placement evolved into a cornerstone of the curriculum. CONCLUSIONS: Cultural immersion in Aboriginal communities is a way for medical students to gain an understanding of the needs and strengths of Aboriginal communities and learn what physicians might do to contribute effectively to Aboriginal health and wellbeing. Research is required to improve understanding about the aspects of this education experience that are most effective. PMID- 25277125 TI - Walking Reduces Postprandial Insulin Secretion in Obese Adolescents Consuming a High-Fructose or High-Glucose Diet. AB - BACKGROUND: This study assessed if walking at a self-selected pace could improve postprandial glucose and insulin concentrations in obese adolescents consuming high-fructose (HF) or high-glucose (HG) diets. METHODS: Seven obese male and female adolescents (18 +/- 1 yr) performed 4, 15-day trials in a random order, including 1) HF-diet (50 g fructose/d added to normal diet) while being sedentary, 2) HG-diet (50 g glucose/d) while sedentary, 3) HF-diet with additional walking, and 4) HG-diet with additional walking. On the 15th day of each trial, the participants performed mixed meal testing in the laboratory in which they consumed three liquid shakes (either HF or HG) and during the HF and HG sedentary trials, the participants took < 4000 steps while in the laboratory but during the walking trials took >= 13,000 steps during testing. RESULTS: Walking did not alter postprandial glucose concentrations. Although walking reduced insulin secretion by 34% and 25% during the HF- and HG-diet, respectively (P < .05), total insulin concentrations were only significantly reduced (P > .05) with walking during the HF trial, possibly because walking enhanced insulin clearance to a greater extent during the HF-diet. CONCLUSIONS: Walking reduces postprandial insulin secretion in obese adolescents consuming a high-fructose or high-glucose diet. PMID- 25277127 TI - Bio-alteration of metallurgical wastes by Pseudomonas aeruginosa in a semi flow through reactor. AB - Metallurgical activities can generate a huge amount of partially vitrified waste products which are either landfilled or recycled. Lead Blast Furnace (LBF) slags are often disposed of in the vicinity of metallurgical plants, and are prone to weathering, releasing potentially toxic chemical components into the local environment. To simulate natural weathering in a slag heap, bioweathering of these LBF slags was studied in the presence of a pure heterotrophic bacterial strain (Pseudomonas aeruginosa) and in a semi-flow through reactor with intermittent leachate renewal. The evolution of water chemistry, slag composition and texture were monitored during the experiments. The cumulative bulk release of dissolved Fe, Si, Ca and Mg doubled in the presence of bacteria, probably due to the release of soluble complexing organic molecules (e.g. siderophores). In addition, bacterial biomass served as the bioadsorbent for Pb, Fe and Zn as 70 80% of Pb and Fe, 40-60% of Zn released are attached to and immobilized by the bacterial biomass. PMID- 25277128 TI - Predictors of clinical trial data sharing: exploratory analysis of a cross sectional survey. AB - BACKGROUND: A number of research funders, biomedical journals, pharmaceutical companies, and regulatory agencies have adopted policies advocating or mandating that clinical trialists share data with external investigators. We therefore sought to determine whether certain characteristics of trialists or their trials are associated with more unfavorable perceptions of data sharing. To date, no prior research has addressed this issue. METHODS: We conducted an exploratory analysis of responses to a cross-sectional, web-based survey. The survey sample consisted of trialists who were corresponding authors of clinical trials published in 2010 or 2011 in one of six general medical journals with the highest impact factors in 2011. The following key characteristics were examined: trialists' academic productivity and geographic location, trial funding source and size, and the journal in which it was published. Main outcome measures included: support for data sharing in principle, concerns with data sharing through repositories, and reasons for granting or denying requests. Chi-squared tests and Fisher's exact tests were used to assess statistical significance. RESULTS: Of 683 potential respondents, 317 completed the survey (response rate 46%). Both support for data sharing and reporting of specific concerns with sharing data through repositories exceeded 75%, but neither differed by trialist or trial characteristics. However, there were some significant differences in explicit reasons to share or withhold data. Respondents located in Western Europe more frequently indicated they have or would share data in order to receive academic benefits or recognition when compared with respondents located in the United States or Canada (58 versus 31%). In addition, respondents who were the most academically productive less frequently indicated they have or would withhold data in order to protect research subjects when compared with less academically productive respondents (24 versus 40%), as did respondents who received industry funding when compared with those who had not (24 versus 43%). CONCLUSIONS: Respondents indicated strong support for data sharing overall. There were few notable differences in how trialists viewed the benefits and risks of data sharing when categorized by trialists' academic productivity and geographic location, trial funding source and size, and the journal in which it was published. PMID- 25277129 TI - Synthesis of structural and optical characterization of surfactant capped ZnO nanocrystalline. AB - The presence of surfactant (CTAB) at three different concentrations viz., (0.5, 1 and 1.5 M) on zinc oxide (ZnO) nanocrystalline at 550 degrees C was synthesized. The optical properties of each surfactant capped zinc oxide nanocrystalline were investigated using UV-Visible absorption. The characterization of these nanocrystalline was performed by X-ray diffractometer Spectrum (XRD), Scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS), and Atomic force microscopy (AFM) and Fourier transformer infrared (FTIR) spectroscopy. The effect of CTAB on the morphology of the ZnO was studied by SEM/EDS which revealed that the diameter of the product is in the range of 42-70 nm. Out of the three surfactant concentrations CTAB (0.5 M) capped zinc oxide nanoparticle has smallest crystalline size of 19.4 nm. Thus, the presence of surfactant on the surface of zinc oxide plays a significant role in reducing defect. The excitonic UV emission has been observed at 275 nm. PMID- 25277131 TI - Upregulation of miR-184 enhances the malignant biological behavior of human glioma cell line A172 by targeting FIH-1. AB - BACKGROUND: In recent years, miRNAs have been suggested to play key roles in the formation and development of human glioma. The aim of this study is to investigate the effect and mechanism of miR-184 expression on the malignant behavior of human glioma cells. METHODS: The relative quantity of miR-184 was determined in human glioma cell lines, and the expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) was explored using western blotting. The effects of miR-184 inhibition on cell viability and apoptosis were explored, and the miR-184 target gene was determined using a luciferase assay and western blotting. Flow cytometry and Hoechst staining were used to evaluate cell growth and apoptosis. Matrigel invasion and scratch assays were performed to measure the ability of cell invasion and migration. RESULTS: miR-184 and HIF-1alpha protein levels were significantly upregulated in human glioma cells. Downregulation of miR-184 inhibited cell viability and increased the HEB cell apoptotic rate. Luciferase and western blot assays verified that FIH-1 was the target gene of miR-184 and negatively controlled the protein level of HIF-1alpha. Inhibition of HIF-1alpha by siRNA facilitated the apoptosis of HEB cells and suppressed A172 cell invasion and migration. CONCLUSION: miR-184 upregulation enhanced the malignant phenotype of human glioma cancer cells by reducing FIH-1 protein expression. PMID- 25277130 TI - A systematic analysis of protein palmitoylation in Caenorhabditis elegans. AB - BACKGROUND: Palmitoylation is a reversible post-translational protein modification which involves the addition of palmitate to cysteine residues. Palmitoylation is catalysed by the DHHC family of palmitoyl-acyl transferases (PATs) and reversibility is conferred by palmitoyl-protein thioesterases (PPTs). Mutations in genes encoding both classes of enzymes are associated with human diseases, notably neurological disorders, underlining their importance. Despite the pivotal role of yeast studies in discovering PATs, palmitoylation has not been studied in the key animal model Caenorhabditis elegans. RESULTS: Analysis of the C. elegans genome identified fifteen PATs, using the DHHC cysteine-rich domain, and two PPTs, by homology. The twelve uncategorised PATs were officially named using a dhhc-x system. Genomic data on these palmitoylation enzymes and those in yeast, Drosophila and humans was collated and analysed to predict properties and relationships in C. elegans. All available C. elegans strains containing a mutation in a palmitoylation enzyme were analysed and a complete library of RNA interference (RNAi) feeding plasmids against PAT or PPT genes was generated. To test for possible redundancy, double RNAi was performed against selected closely related PATs and both PPTs. Animals were screened for phenotypes including size, longevity and sensory and motor neuronal functions. Although some significant differences were observed with individual mutants or RNAi treatment, in general there was little impact on these phenotypes, suggesting that genetic buffering exists within the palmitoylation network in worms. CONCLUSIONS: This study reports the first characterisation of palmitoylation in C. elegans using both in silico and in vivo approaches, and opens up this key model organism for further detailed study of palmitoylation in future. PMID- 25277132 TI - Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases. AB - Our phase I Hepatic Immunotherapy for Metastases (HITM) trial tested the safety of chimeric antigen receptor-modified T-cell (CAR-T) hepatic artery infusions (HAI) for unresectable carcinoembryonic antigen (CEA)+ liver metastases (LM). High neutrophil:lymphocyte ratios (NLR) predict poor outcome in cancer patients and we hypothesized that NLR changes would correlate with early responses to CAR T HAI. Six patients completed the protocol. Three patients received CAR-T HAI in dose escalation (1 * 10(8), 1 * 10(9) and 1 * 10(10) cells) and the remainder received three doses (1 * 10(10) cells) with interleukin (IL)2 support. Serum cytokines and NLR were measured at multiple time points. The mean NLR for all patients was 13.9 (range 4.8-38.1). NLR increased in four patients following treatment with a mean fold change of 1.9. Serum IL6 levels and NLR fold changes demonstrated a trend towards a positive correlation (r=0.77, P=0.10). Patients with poor CEA responses were significantly more likely to have higher NLR level increases (P=0.048). Increased NLR levels were associated with poor responses following CAR-T HAI. NLR variations and associated cytokine changes may be useful surrogates of response to CAR-T HAI. PMID- 25277134 TI - Living vs. deceased donor liver transplantation provides comparable recovery of renal function in patients with hepatorenal syndrome: a matched case-control study. AB - Outcomes of living versus deceased donor liver transplantation in patients with chronic liver disease and hepatorenal syndrome (HRS) was compared using a matched pair study design. Thirty patients with HRS receiving a live donor liver transplantation (LDLT) and 90 HRS patients receiving a full graft deceased donor liver transplantation (DDLT) were compared. LDLT versus DDLT of patients with HRS was associated with decreased peak aspartate aminotransferase levels (339 +/- 214 vs. 935 +/- 1253 U/L; p = 0.0001), and similar 7-day bilirubin (8.42 +/- 7.89 vs. 6.95 +/- 7.13 mg/dL; p = 0.35), and international normalized ratio levels (1.93 +/- 0.62 vs. 1.78 +/- 0.78; p = 0.314). LDLT vs. DDLT had a decreased intensive care unit (2 [1-39] vs. 4 [0-93] days; p = 0.004), and hospital stay (17 [4-313] vs. 26 [0-126] days; p = 0.016) and a similar incidence of overall postoperative complications (20% vs. 27%; p = 0.62). No difference was detected between LDLT and DDLT patients regarding graft survival at 1 (80% vs. 82%), at 3 (69% vs. 76%) and 5 years (65% vs. 76%) (p = 0.63), as well as patient survival at 1 (83% vs. 82%), 3 (72% vs. 77%) and 5 years (72% vs. 77%) (p = 0.93). The incidence of chronic kidney disease post-LT (10% vs. 6%; p = 0.4) was similar between both groups. LDLT results in identical long-term outcome when compared with DDLT in patients with HRS. PMID- 25277133 TI - Local control of giant cell tumors of the long bone after aggressive curettage with and without bone cement. AB - BACKGROUND: Aggressive curettage has been well established for the treatment of giant cell tumors (GCTs) of the bone. The purpose of this study was to review our experience and evaluate the role of different implant materials in patients with GCTs of the extremities after aggressive curettage. METHODS: A total of 119 patients with GCTs of the long bone were treated at the First Affiliated Hospital of Sun Yat-Sen University between 2004 and 2009. We excluded patients presenting metastases, recurrent tumors, and soft tissue involvement and those with Jaffe pathological grade III. The remaining 65 patients were treated with aggressive curettage using a bone graft or bone cement to fill the cavity. The recurrence rates and functional scores associated with the different fillings were analyzed. RESULTS: Aggressive curettage and bone grafting was performed in 34 cases (52.3%), and aggressive curettage with bone cement was performed in 31 cases (47.7%). The overall recurrence rate after the aggressive intralesional procedures was 35.3% with bone grafting and 12.9% when bone cement was used as an adjuvant filling. The recurrence rate following aggressive curettage and bone grafting was higher than that following aggressive curettage with cement (p = 0.038). The Musculoskeletal Tumor Society (MSTS) score for bone graft patients was 91.1%, which was significantly lower than that for patients treated with bone cement (94.7%). CONCLUSIONS: The use of bone cement was associated with a significantly lower recurrence rate than bone grafting following aggressive intralesional curettage to treat benign giant cell tumors of the long bone. Better MSTS functional results were also observed in the bone cement group compared to the bone graft group. PMID- 25277135 TI - Resting-state functional MRI in pediatric epilepsy surgery. AB - Resting-state functional MRI (rs-fMRI) identifies resting-state networks (RSN) in the human brain by analyzing the connectivity of anatomically remote neuronal populations with synchronous low-frequency fluctuation in blood oxygen level dependent (BOLD) signal. Network analysis has informed the understanding of functional brain organization and is beginning to reveal the impact that neurological disorders such as epilepsy may have on the developing cerebral cortex. Among children undergoing epilepsy surgery, mapping the brain networks supporting language, sensorimotor and visual function is a critical part of the preoperative evaluation. However, task-based functional mapping techniques are particularly difficult in immature patients and those with severe impairment. Functional mapping of RSN is a promising tool that may help circumvent the challenges of adequate cooperation and limited abilities of developmentally disabled children to perform age-appropriate functions. We discuss the current methodology of rs-fMRI in the pediatric population, review the literature of rs fMRI in pediatric epilepsy and present our experience of using rs-fMRI for functional network mapping in children undergoing epilepsy surgery. PMID- 25277136 TI - Exploring the impact of common assessment instrumentation on communication and collaboration in inpatient and community-based mental health settings: a focus group study. AB - BACKGROUND: Recognition that integrated services can lead to more efficient and effective care has made the principle of integration a priority for health systems worldwide for the last decade. However, actually bringing fully integrated services to life has eluded most health care organizations. Mental health has followed the rule, rather than the exception, when it comes integrating services. The lack of effective mechanisms to evaluate the needs of persons across mental health care services has been an important barrier to communication between professionals involved in care. This study sought to understand communication among inpatient and community-based mental health staff during transfers of care, before and after implementation of compatible assessment instrumentation. METHODS: Two focus groups were held with staff from inpatient (n = 10) and community (n = 10) settings in an urban, specialized psychiatric hospital in Ontario (Canada) - prior to and one year after implementation of compatible instrumentation in the community program. Transcripts were coded and aggregated into themes. RESULTS: Very different views of current communication patterns during transfers of care emerged. Inpatient mental health staff described a predictable, well-known process, whereas community-based staff emphasized unpredictability. Staff also discussed issues related to trust and the circle of care. All agreed that compatible assessments in inpatient and community mental health settings would facilitate communication through use of a common assessment language. However, no change in communication patterns was reported one year post implementation of compatible instrumentation. CONCLUSIONS: Though all participants agreed on the potential for compatible instrumentation to improve communication during transfers of care, this cannot happen overnight. A number of issues related to trust, evidence-based practice, and organizational factors act as barriers to communication. In particular, staff noted the need for the results of comprehensive mental health assessments to be transformed into meaningful, user-friendly clinical summaries to facilitate uptake of assessment information, and consequently use of a common assessment language across mental health settings. PMID- 25277137 TI - Chiari III malformation with a giant encephalocele Sac: case report and a review of the literature. PMID- 25277138 TI - Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer. AB - The role of intestinal human pregnane X receptor (PXR) in colon cancer was determined through investigation of the chemopreventive role of rifaximin, a specific agonist of intestinal human PXR, toward azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer. Rifaximin treatment significantly decreased the number of colon tumors induced by AOM/DSS treatment in PXR humanized mice, but not wild-type or Pxr-null mice. Additionally, rifaximin treatment markedly increased the survival rate of PXR-humanized mice, but not wild-type or Pxr-null mice. These data indicated a human PXR-dependent therapeutic chemoprevention of rifaximin toward AOM/DSS-induced colon cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells-mediated inflammatory signaling was upregulated in AOM/DSS-treated mice, and inhibited by rifaximin in PXR-humanized mice. Cell proliferation and apoptosis were also modulated by rifaximin treatment in the AOM/DSS model. In vitro cell-based assays further revealed that rifaximin regulated cell apoptosis and cell cycle in a human PXR-dependent manner. These results suggested that specific activation of intestinal human PXR exhibited a chemopreventive role toward AOM/DSS-induced colon cancer by mediating anti-inflammation, antiproliferation, and proapoptotic events. PMID- 25277140 TI - The antimalarial drug proguanil is an antagonist at 5-HT3 receptors. AB - Proguanil is an antimalarial prodrug that is metabolized to 4-chlorophenyl-1 biguanide (CPB) and the active metabolite cycloguanil (CG). These compounds are structurally related to meta-chlorophenyl biguanide (mCPBG), a 5 hydroxytryptamine 3 (5-HT3) receptor agonist. Here we examine the effects of proguanil and its metabolites on the electrophysiology and ligand-binding properties of human 5-HT3A receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. 5-HT3 receptor responses were reversibly inhibited by proguanil, with an IC50 of 1.81 MUM. Competitive antagonism was shown by a lack of voltage-dependence, Schild plot (Kb = 1.70 MUM), and radioligand competition (Ki = 2.61 MUM) with the 5-HT3 receptor antagonist [(3)H]granisetron. Kinetic measurements (kon = 4.0 * 10(4) M(-1) s(-1) ; koff = 0.23 s(-1)) were consistent with a simple bimolecular reaction scheme with a Kb of 4.35 MUM. The metabolites CG and CPB similarly inhibited 5-HT3 receptors as assessed by IC50 (1.48 and 4.36 MUM, respectively), Schild plot (Kb = 2.97 and 11.4 MUM), and radioligand competition (Ki = 4.89 and 0.41 MUM). At higher concentrations, CPB was a partial agonist (EC50 = 14.1 MUM; I/Imax = 0.013). These results demonstrate that proguanil competitively inhibits 5-HT3 receptors, with an IC50 that exceeds whole-blood concentrations following its oral administration. They may therefore be responsible for the occasional gastrointestinal side effects, nausea, and vomiting reported following its use. Clinical development of related compounds should therefore consider effects at 5 HT3 receptors as an early indication of possible unwanted gastrointestinal side effects. PMID- 25277139 TI - Endocannabinoids anandamide and 2-arachidonoylglycerol are substrates for human CYP2J2 epoxygenase. AB - The endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are arachidonic acid (AA) derivatives that are known to regulate human cardiovascular functions. CYP2J2 is the primary cytochrome P450 in the human heart and is most well known for the metabolism of AA to the biologically active epoxyeicosatrienoic acids. In this study, we demonstrate that both 2-AG and AEA are substrates for metabolism by CYP2J2 epoxygenase in the model membrane bilayers of nanodiscs. Reactions of CYP2J2 with AEA formed four AEA epoxyeicosatrienoic acids, whereas incubations with 2-AG yielded detectable levels of only two 2-AG epoxides. Notably, 2-AG was shown to undergo enzymatic oxidative cleavage to form AA through a NADPH-dependent reaction with CYP2J2 and cytochrome P450 reductase. The formation of the predominant AEA and 2-AG epoxides was confirmed using microsomes prepared from the left myocardium of porcine and bovine heart tissues. The nuances of the ligand-protein interactions were further characterized using spectral titrations, stopped-flow small-molecule ligand egress, and molecular modeling. The experimental and theoretical data were in agreement, which showed that substitution of the AA carboxylic acid with the 2-AG ester-glycerol changes the binding interaction of these lipids within the CYP2J2 active site, leading to different product distributions. In summary, we present data for the functional metabolomics of AEA and 2-AG by a membrane-bound cardiovascular epoxygenase. PMID- 25277141 TI - Neurophysiologic and antipsychotic profiles of TASP0433864, a novel positive allosteric modulator of metabotropic glutamate 2 receptor. AB - Excess glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, and the activation of metabotropic glutamate 2 (mGlu2) receptor may exert antipsychotic effects by normalizing glutamate transmission. In the present study, we investigated the neurophysiologic and antipsychotic profiles of TASP0433864 [(2S)-2-[(4-tert-butylphenoxy)methyl]-5-methyl-2,3-dihydroimidazo[2,1 b][1,3]oxazole-6-carboxamide], a newly synthesized positive allosteric modulator (PAM) of mGlu2 receptor. TASP0433864 exhibited PAM activity at human and rat mGlu2 receptors with EC50 values of 199 and 206 nM, respectively, without exerting agonist activity at rat mGlu2 receptor. TASP0433864 produced a leftward and upward shift in the concentration-response curve of glutamate-increased guanosine 5'-O-(3-[(35)S]thio)triphosphate binding to mGlu2 receptor. In contrast, TASP0433864 had negligible activities for other mGlu receptors, including mGlu3 receptor, and did not have any affinity for other receptors or transporters. In hippocampal slices, TASP0433864 potentiated an inhibitory effect of DCG-IV [(2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine], a mGlu2/3 receptor agonist, on the field excitatory postsynaptic potentials in the dentate gyrus, indicating that TASP0433864 potentiates the mGlu2 receptor-mediated presynaptic inhibition of glutamate release. Moreover, TASP0433864 inhibited both MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate]- and ketamine-increased cortical gamma band oscillation in the rat cortical electroencephalogram, which have been considered to reflect the excess activation of cortical pyramidal neurons. The inhibitory effect of TASP0433864 on cortical activation was also observed in the mouse 2-deoxy-glucose uptake study. In a behavioral study, TASP0433864 significantly inhibited both ketamine- and methamphetamine-increased locomotor activities in mice and rats, respectively. Collectively, these findings indicate that TASP0433864 is a selective mGlu2 receptor PAM with antipsychotic activity, and the attenuation of excess glutamatergic neurotransmission may be involved in the action of TASP0433864. PMID- 25277142 TI - Clinical effects of vitamin D in children with asthma. AB - OBJECTIVE: Both asthma and vitamin D deficiency are common among children. The results from studies examining the relationship between them are contradictory. The aim of this study is to determine the relationship between the clinical parameters of asthma and vitamin D status in children. METHODS: One hundred and twenty children diagnosed with asthma and followed-up in our hospital were included in the study. The control group included 74 children with no evidence of allergic disease. The eosinophil counts, IgE levels and serum 25 OH cholecalciferol [25(OH)D] levels were measured. RESULTS: The patient group consisted of 73 (60.8%) males and 47 (39.2%) females with a mean age of 4.4 +/- 1.2 years. There was no significant difference between the patient and control groups with respect to gender and age. The mean 25(OH)D level was 21.49 +/- 7.74 ng/ml in the study group and 23.94 +/- 8.97 ng/ml in the control group, and this difference was not significant (p = 0.094). The patients with asthma were grouped according to their vitamin D status as 'deficient' (group 1), 'insufficient' (group 2) and 'normal' (group 3). The sociodemographic features, duration of illness, number of hospitalizations, number of sensitivities to allergens, eosinophil count and serum IgE levels were not found to be different between the groups. However, the total number of exacerbations, asthma severity and systemic glucocorticoid need in the previous year were significantly higher in the deficiency group (p < 0.05). CONCLUSION: Vitamin D levels were not significantly different in patients with asthma. Vitamin D deficiency was common in the study group as well as in the control group. The clinical severity of disease, the number of exacerbations and the systemic glucocorticoid need were related to vitamin D level. PMID- 25277143 TI - Interferon-gamma inhibits nonopsonized phagocytosis of macrophages via an mTORC1 c/EBPbeta pathway. AB - Bacterial infection often follows virus infection due to pulmonary interferon gamma (IFN-gamma) production during virus infection, which down-regulates macrophage phagocytosis. The molecular mechanisms for this process are still poorly understood. In the present study, IFN-gamma treatment significantly inhibited the ability of mouse macrophages to phagocytize nonopsonized chicken red blood cells (cRBCs), bacteria and beads in vitro, while it enhanced IgG- and complement-opsonized phagocytosis. IFN-gamma treatment decreased the expression of MARCO (macrophage receptor with collagenous structure) in macrophages. Macrophages showed lower binding to and phagocytic ability of cRBCs when MARCO was blocked with antibody. In addition, IFN-gamma induced high activity of mTOR (mammalian target of rapamycin) and decreased the expression of c/EBPbeta (CCAAT enhancer-binding protein beta) in macrophages. Rapamycin, a specific mTOR inhibitor, significantly reversed the inhibitory effect of IFN-gamma on nonopsonized phagocytosis of macrophages and restored c/EBPbeta and MARCO expression. Biochemical assays showed that c/EBPbeta directly bound to the MARCO gene promoter. Rapamycin significantly hampered the viral-bacterial synergy and protected influenza-infected mice from subsequent bacterial infection. Thus, IFN gamma inhibited the nonopsonized phagocytosis of macrophages through the mTOR c/EBPbeta-MARCO pathway. The present study offered evidence indicating that mTOR may be one of the key target molecules for the prevention of secondary bacterial infection caused by primary virus infection. PMID- 25277144 TI - Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. AB - OBJECTIVE: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. METHODS: This was a double-blind, placebo controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 ug; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 ug between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. RESULTS: Dose levels of selexipag up to 1,600 MUg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT 333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. CONCLUSIONS: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials. PMID- 25277145 TI - Parental care influences leukocyte telomere length with gender specificity in parents and offsprings. AB - BACKGROUND: There have been several reports suggesting that adverse childhood experiences such as physical maltreatment and long institutionalization influence telomere length. However, there has been no study examining the relationship of telomere length with variations in parental rearing. In the present study, we examined the relationship of leukocyte telomere length with parental rearing in healthy subjects. METHODS: The subjects were 581 unrelated healthy Japanese subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument consisting of the care and protection factors. Leukocyte relative telomere length was determined by a quantitative real-time PCR method for a ratio of telomere/single copy gene. RESULTS: In the multiple regression analyses, shorter telomere length in males was related to lower scores of paternal care (beta = 0.139, p < 0.05), while that in females was related to lower scores of maternal care (beta = 0.195, p < 0.01). CONCLUSION: The present study suggests that there is linear relationship between parental care and telomere length which covers both lower and higher ends of parental care, and that the effects of parental care on telomere length are gender-specific in parents and offsprings. PMID- 25277146 TI - Differential sensitivity of osteoblasts and bacterial pathogens to 405-nm light highlighting potential for decontamination applications in orthopedic surgery. AB - Healthcare associated infections pose a major threat to patients admitted to hospitals and infection rates following orthopedic arthroplasty surgery are as high as 4%. A 405-nm high-intensity narrow spectrum light has been proven to reduce environmental contamination in hospital isolation rooms, and there is potential to develop this technology for application in arthroplasty surgery. Cultured rat osteoblasts were exposed to varying light intensities and it was found that exposures of up to a dose of 36 J/cm2 had no significant effect on cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], function (alkaline phosphatase activity), and proliferation rate (BrdU cell proliferation assay). High irradiance exposures (54 J/cm2) significantly affected the cell viability indicating that the effects of 405-nm light on osteoblasts are dose dependent. Additionally, exposure of a variety of clinically related bacteria to a dose of 36 J/cm2 resulted in up to 100% kill. These results demonstrating the differential sensitivity of osteoblasts and bacteria to 405-nm light are an essential step toward developing the technique for decontamination in orthopedic surgery. PMID- 25277147 TI - Spectral-spatial classification for noninvasive cancer detection using hyperspectral imaging. AB - Early detection of malignant lesions could improve both survival and quality of life of cancer patients. Hyperspectral imaging (HSI) has emerged as a powerful tool for noninvasive cancer detection and diagnosis, with the advantage of avoiding tissue biopsy and providing diagnostic signatures without the need of a contrast agent in real time. We developed a spectral-spatial classification method to distinguish cancer from normal tissue on hyperspectral images. We acquire hyperspectral reflectance images from 450 to 900 nm with a 2-nm increment from tumor-bearing mice. In our animal experiments, the HSI and classification method achieved a sensitivity of 93.7% and a specificity of 91.3%. The preliminary study demonstrated that HSI has the potential to be applied in vivo for noninvasive detection of tumors. PMID- 25277148 TI - Automated computational framework of blood vessel quantification in chick chorioallantoic membrane angiogenesis. AB - Chick chorioallantoic membrane (CAM) angiogenesis assay has been widely used for finding drugs targeting new blood vessel development in cancer research. In addition to the setup materials and protocols, laboratory findings depend on the quantification and analysis of microscopic blood vessel images. However, it is still a challenging problem because of the high complexity of blood vessel branching structures. We applied preprocessing on CAM microscopic images by keeping the integrity of minor branches in the vessel structure. We then proposed an efficient way to automatically extract blood vessel centerlines based on vector tracing starting from detected seed points. Finally, all branches were coded to construct an abstract model of the branching structure, which enabled more accurate modeling for in-depth analysis. The framework was applied in quantifying Icaritin (ICT) inhibition effects on angiogenesis in a CAM model. Experimental results showed the high accuracy in blood vessel quantification and modeling compared with semimanual measurements. Meanwhile, a set of blood vessel growth indicators were extracted to provide fully automated analysis for angiogenesis assays. Further analysis proved that ICT took effect in a dose dependent manner which could be applied in suppressing tumor blood vessel growth. PMID- 25277149 TI - Volumetric fat ratio and not body mass index is predictive of ileocolectomy outcomes in Crohn's disease patients. AB - BACKGROUND: Crohn's disease (CD) patients are typically underweight; however, a growing cohort of overweight CD patients is emerging. The current study investigates whether body mass index (BMI) or volumetric fat parameters can be used to predict morbidity after ileocolectomy for CD. METHODS: One hundred and forty-three CD patients who underwent elective ileocolectomy were identified from our Inflammatory Bowel Disease (IBD) Registry. Patient demographics and operative outcomes were recorded. Visceral (VA) and subcutaneous (SA) adiposity and abdominal circumference (AC) were analyzed on preoperative CT scans using Aquarius iNtuition software. A visceral/subcutaneous ratio (VSR) was calculated. RESULTS: BMI correlated with SA (p = 0.0001), VA (p = 0.0001) and AC (p = 0.0001) but not VSR (p > 0.05). BMI, VA and AC did not predict surgical morbidity (p > 0.05). In multivariate regression analysis, family history of IBD (p = 0.009), high American Society of Anesthesiologists score (p = 0.02) and increased VSR (p = 0.03) were independent predictors of postoperative morbidity. CONCLUSIONS: The visceral/subcutaneous fat ratio is a more reliable predictor of postoperative outcomes in CD patients undergoing ileocolectomy than conventional adiposity markers such as BMI. Preoperative calculation of the visceral/subcutaneous fat ratio offers the opportunity to optimize high-risk surgical patients, thus improving outcomes. PMID- 25277152 TI - Determining volcanic eruption styles on Earth and Mars from crystallinity measurements. AB - Both Earth and Mars possess different styles of explosive basaltic volcanism. Distinguishing phreatomagmatic eruptions, driven by magma-water interaction, from 'magmatic' explosive eruptions (that is, strombolian and plinian eruptions) is important for determining the presence of near-surface water or ice at the time of volcanism. Here we show that eruption styles can be broadly identified by relative variations in groundmass or bulk crystallinity determined by X-ray diffraction. Terrestrial analogue results indicate that rapidly quenched phreatomagmatic ejecta display lower groundmass crystallinity (<35%) than slower cooling ejecta from strombolian or plinian eruptions (>40%). Numerical modelling suggests Martian plinian eruptive plumes moderate cooling, allowing 20-30% syn eruptive crystallization, and thus reduce the distinction between eruption styles on Mars. Analysis of Mars Curiosity rover CheMin X-ray diffraction results from Gale crater indicate that the crystallinity of Martian sediment (52-54%) is similar to pyroclastic rocks from Gusev crater, Mars, and consistent with widespread distribution of basaltic strombolian or plinian volcanic ejecta. PMID- 25277150 TI - A prospective observational study of Gallium-68 ventilation and perfusion PET/CT during and after radiotherapy in patients with non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is the leading cause of cancer deaths. Radiation therapy (RT), alone or in combination with chemotherapy, is the standard of care for curative intent treatment of patients with locally advanced or inoperable NSCLC. The ability to intensify treatment to achieve a better chance for cure is limited by the risk of injury to the surrounding lung. METHODS/DESIGN: This is a prospective observational study of 60 patients with NSCLC receiving curative intent RT. Independent human ethics board approval was received from the Peter MacCallum Cancer Centre ethics committee. In this research, Galligas and Gallium-68 macroaggregated albumin (MAA) positron emission tomography (PET) imaging will be used to measure ventilation (V) and perfusion (Q) in the lungs. This is combined with computed tomography (CT) and both performed with a four dimensional (4D) technique that tracks respiratory motion. This state-of-the-art scan has superior resolution, accuracy and quantitative ability than previous techniques. The primary objective of this research is to observe changes in ventilation and perfusion secondary to RT as measured by 4D V/Q PET/CT. Additionally, we plan to model personalised RT plans based on an individual's lung capacity. Increasing radiation delivery through areas of poorly functioning lung may enable delivery of larger, more effective doses to tumours without increasing toxicity. By performing a second 4D V/Q PET/CT scan during treatment, we plan to simulate biologically adapted RT depending on the individual's accumulated radiation injury. Tertiary aims of the study are assess the prognostic significance of a novel combination of clinical, imaging and serum biomarkers in predicting for the risk of lung toxicity. These biomarkers include spirometry, (18)F Fluorodeoxyglucose PET/CT, gamma-H2AX signals in hair and lymphocytes, as well as assessment of blood cytokines. DISCUSSION: By correlating these biomarkers to toxicity outcomes, we aim to identify those patients early who will not tolerate RT intensification during treatment. This research is an essential step leading towards the design of future biologically adapted radiotherapy strategies to mitigate the risk of lung injury during dose escalation for patients with locally advanced lung cancer. TRIALS REGISTRATION: Universal Trial Number (UTN) U1111 1138-4421. PMID- 25277154 TI - Enhanced DNA toehold exchange reaction on a chip surface to discriminate single base changes. AB - In this study, a single-base change discrimination strategy was developed through enhanced DNA toehold exchange reaction on a chip surface. A DNA strand with single-base change (SNPs, insertion or deletion) at an arbitrary position was clearly discriminated with nucleic acid concentrations from 0.8 nM to 1 MUM through this method. PMID- 25277153 TI - Enantioselective hydroacylation of olefins with rhodium catalysts. AB - Over thirty years ago, James and Young reported the first enantioselective olefin hydroacylation by using rhodium catalysts. This viewpoint highlights the advances in this area, including 4-pentenal cyclisations, medium-ring syntheses, and intermolecular variants. PMID- 25277155 TI - Tailoring viscoelastic response of carbon nanotubes cellular structure using electric field. AB - Cellular structures of carbon nanotubes (CNT) are novel engineering materials, which are finding applications due to their remarkable structural and functional properties. Here, we report the effects of electric field, one of the most frequently used stimulants for harnessing the functional properties of CNT, on the viscoelastic response, an important design consideration for the structural applications of a cellular CNT sample. The application of an electric field results in electrostriction induced large actuation in freestanding CNT samples; however, if the CNT are prohibited to expand, an electric field dependent force is exerted by the sample on the constraining platens. In addition, the above force monotonically decreases with the pre-compressive strain imposed onto the sample. The viscoelastic recovery reveals a decrease in the stress relaxation with an increase in the pre-compressive strain in both the presence and absence of the electric field; however, the stress relaxation was significantly higher in the presence of the electric field. A model, based on a simple linear viscoelastic solid incorporating electric field, is developed to understand the experimental observations. PMID- 25277151 TI - A novel controllable hydrogen sulfide-releasing molecule protects human skin keratinocytes against methylglyoxal-induced injury and dysfunction. AB - BACKGROUND/AIM: Delayed wound healing is a common skin complication of diabetes, which is associated with keratinocyte injury and dysfunction. Levels of methylglyoxal (MGO), an alpha-dicarbonyl compound, are elevated in diabetic skin tissue and plasma, while levels of hydrogen sulfide (H2S), a critical gaseous signaling molecule, are reduced. Interestingly, the gas has shown dermal protection in our previous study. To date, there is no evidence demonstrating whether MGO affects keratinocyte viability and function or H2S donation abolishes these effects and improves MGO-related impairment of wound healing. The current study was conducted to examine the effects of MGO on the injury and function in human skin keratinocytes and then to evaluate the protective action of a novel H2S-releasing molecule. METHODS: An N-mercapto-based H2S donor (NSHD)-1 was synthesized and its ability to release H2S was observed in cell medium and cells, respectively. HaCaT cells, a cell line of human skin keratinocyte, were exposed to MGO to establish an in vitro diabetic wound healing model. NSHD-1 was added to the cells before MGO exposure and the improvement of cell function was observed in respect of cellular viability, apoptosis, oxidative stress, mitochondrial membrane potential (MMP) and behavioral function. RESULTS: Treatment with MGO decreased cell viability, induced cellular apoptosis, increased intracellular reactive oxygen species (ROS) content and depressed MMP in HaCaT cells. The treatment also damaged cell behavioral function, characterized by decreased cellular adhesion and migration. The synthesized H2S-releasing molecule, NSHD-1, was able to increase H2S levels in both cell medium and cells. Importantly, pretreatment with NSHD-1 inhibited MGO-induced decreases in cell viability and MMP, increases in apoptosis and ROS accumulation in HaCaT cells. The pretreatment was also able to improve adhesion and migration function. CONCLUSION: These results demonstrate that the novel synthesized H2S donor is able to protect human skin keratinocytes against MGO-induced injury and behavior dysfunction. We believe that more reasonable H2S-releasing molecules will bring relief to patients suffering from delayed wound healing in diabetes mellitus in the future. PMID- 25277156 TI - Sodium thiosulfate-assisted synthesis of NiS2 nanostructure by using nickel(II) Salen precursor: optical and magnetic properties. AB - A NiS2 nanostructure with a protective layer of Ni(2+) and SO4(2-) ions around it has been successfully synthesized using the Ni(II)-Salen (Salen = N,N' bis(salicylidene)ethylenediamine) complex via a simple solvothermal approach in the presence of anhydrous sodium thiosulfate (Na2S2O3) as sulfur source and stabilizer. Unexpectedly, no one kind of pure nickel sulfide nanostructure was prepared using the Ni(II)-Salophen complex or some of the simple mono and bidentate Ni(II) complexes as starting materials and the obtained products were a mixture of nickel sulfides. In the photoluminescence spectrum of the prepared NiS2, two peaks were evident at 400 and 420 nm with emission maxima, and one broad peak with emission minima was located at 800 nm. The as-synthesized NiS2 nanostructure displays a weak ferromagnetic behaviour at room temperature, which has small remanent magnetization and saturation magnetization compared to bulk NiS2. These changes might be attributed to the existence of a protective layer of nickel and sulfate ions around the NiS2 nanostructures that was confirmed by Energy-dispersive X-ray spectroscopy (EDS), Fourier transform infrared (FTIR) and Raman spectroscopy. The prepared nanostructure has been characterized structurally, electrochemically, optically and magnetically by available methods like X-ray powder diffraction (XRD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Energy-dispersive X-ray spectroscopy, Fourier transform infrared and Raman spectroscopy, Cyclic voltammetry (CV), Photoluminescence (PL) spectroscopy and vibrating sample magnetometer (VSM). PMID- 25277157 TI - Molecular recognisation of 3a, 4-dihydro-3-H-indeno [1, 2-C] pyrazole-2- carboxamide/carbothioamide anticonvulsant analogues towards GABA-aminotransferase an in silico approach. AB - Convulsion generally occurs as a result of the diminishing concentration of GABA below a threshold level in the brain. This degradation pathway of GABA is catalyzed by the gamma-aminobutyric acid amino transferase. The objective of the current study is to propose the binding interaction of 3a, 4-Dihydro-3-H-indeno [1, 2-C] pyrazole-2-Carboxamide/ Carbothioamides anticonvulsant analogs with a three-dimensional structural model of the gamma -aminobutyric acid amino transferase. For a flexible type of molecular docking, we proposed that these molecules could successfully bind to the active pocket of the enzyme with good predicted affinities in comparison to standard vigabatrin. In this series, 4b, 4c, 4i, 4f and 4a showed significant binding free energy of -9.64, -9.31, -9.01, 8.99 and -8.29 with predicted inhibitory constant values of 0.086, 0.149, 0.237, 0.257 and 0.831 uM, respectively. PMID- 25277159 TI - Bilateral carpal tunnel syndrome in two children: common manifestation of an uncommon disease. AB - Carpal tunnel syndrome (CTS) is a rare entity in children and usually has a different clinical presentation than in adults. The majority of these cases are related to a genetic condition. The most common aetiology is a lysosomal storage disease such as mucopolysaccharidoses or mucolipidoses (ML). Two siblings with bilateral median nerve neuropathy, wrist contractures and skeletal deformity on a background of mild facial coarsening and normal cognition are presented. There was a family history of similar complaints in first cousins. Nerve conduction studies were suggestive of bilateral median neuropathy with conduction block at the wrists. Biochemical investigation showed high levels of plasma lysosomal enzymes. Both patients underwent bilateral flexor retinaculum release. The findings at surgery were severe compression of the median nerve by the thickened flexor retinaculum. The histopathology of the thickened tissue showed a fibrosed and vascularised flexor retinaculum. On electron microscopy, macrophages with membrano-vacuolated inclusion zebra bodies were seen. Both patients had an uneventful recovery with symptomatic improvement. CTS is rarely seen in children except in association with genetic disorders. There is usually a delay in the diagnosis as attention is paid to the contractures rather than to the median nerve compression. The presence of CTS is typically seen in ML types II and III. Surgical intervention helps in improving the quality of life and hand function of these patients. PMID- 25277158 TI - Early intervention to protect the mother-infant relationship following postnatal depression: study protocol for a randomised controlled trial. AB - BACKGROUND: At least 13% of mothers experience depression in the first postnatal year, with accompanying feelings of despair and a range of debilitating symptoms. Serious sequelae include disturbances in the mother-infant relationship and poor long-term cognitive and behavioural outcomes for the child. Surprisingly, treatment of maternal symptoms of postnatal depression does not improve the mother-infant relationship for a majority of women. Targeted interventions to improve the mother-infant relationship following postnatal depression are scarce and, of those that exist, the majority are not evaluated in randomised controlled trials. This study aims to evaluate a brief targeted mother-infant intervention, to follow cognitive behavioural therapy treatment of postnatal depression, which has the potential to improve developmental outcomes of children of depressed mothers. METHODS/DESIGN: The proposed study is a two-arm randomised controlled trial with follow-up to 6 months. One hundred participants will be recruited via referrals from health professionals including maternal and child health nurses and general practitioners, as well as self-referrals from women who have seen promotional materials for the study. Women who meet inclusion criteria (infant aged <12 months, women 18+ years of age) will complete the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV-TR Axis I Disorders. Those with a clinical diagnosis of current major or minor depressive disorder and who do not meet exclusion criteria (that is, currently receiving treatment for depression, significant difficulty with English, medium to high suicide risk, current self-harm, current substance abuse, current post traumatic stress disorder, current manic/hypomanic episode or psychotic symptoms) will be randomised to receive either a 4-session mother-infant intervention (HUGS: Happiness Understanding Giving and Sharing) or a 4-session attention placebo playgroup (Playtime) following a 12-session postnatal depression group treatment programme. Primary outcome measures are the Parenting Stress Index (self-report measure) and the Parent-child Early Relational Assessment (observational measure coded by a blinded observer). Measurements are taken at baseline, after the postnatal depression programme, post-HUGS/Playtime, and at 6 months post-HUGS/Playtime. DISCUSSION: This research addresses the need for specific treatment for mother-infant interactional difficulties following postnatal depression. There is a need to investigate interventions in randomised trials to prevent detrimental effects on child development and make available evidence-based treatments. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register: ACTRN12612001110875. Date Registered: 17 October 2012. PMID- 25277160 TI - Identification of genes related to the early stage of Angiotensin II-induced acute renal injury by microarray and integrated gene network analysis. AB - BACKGROUND/AIMS: Angiotensin II (Ang II) mediated signaling plays a key role in the development of chronic kidney damage that contributes to renal fibrosis. However, the gene expression changes regulated by Ang II in the early stage of acute renal injury remain unclear. METHODS: C57BL/6 wild-type (WT) mice were injected with Ang II (1500 ng/kg/min) for 1, 3 and 7 days. A time series analysis of microarrays was performed to evaluate Ang II-induced differentially gene expression in the kidneys. The data of gene expression in the kidney was further dissected by ANOVA analysis, gene expression profiles, gene network construction and quantitative real-time RT-PCR. Ang II-induced renal inflammation and fibrosis in mice were confirmed by pathological examination. RESULTS: Our microarray data showed that a total of 1,511 differentially expressed genes were identified in the kidneys at 1, 3 and 7 days after Ang II infusion. These genes function in multiple biological processes, including response to stimuli, immune response, cell adhesion, metabolic process, kidney development, regulation of blood pressure, and ion transport, which may play critical roles in the pathobiology of Ang II-induced acute renal injury at the early stage. Furthermore, among these genes, 20 genes were further selected for final investigation. The dynamic gene network analysis demonstrated that fatty acid binding protein 1 (Fabp1) localized in the core of the network. CONCLUSIONS: Our data suggests that genes involved in lipid metabolic process, especially Fabp1, may play a central role in the development of Ang II-induced acute renal injury at the early stage. PMID- 25277161 TI - Adjustment of endogenous concentrations in pharmacokinetic modeling. AB - PURPOSE: Estimating pharmacokinetic parameters in the presence of an endogenous concentration is not straightforward as cross-reactivity in the analytical methodology prevents differentiation between endogenous and dose-related exogenous concentrations. This article proposes a novel intuitive modeling approach which adequately adjusts for the endogenous concentration. METHODS: Monte Carlo simulations were carried out based on a two-compartment population pharmacokinetic (PK) model fitted to real data following intravenous administration. A constant and a proportional error model were assumed. The performance of the novel model and the method of straightforward subtraction of the observed baseline concentration from post-dose concentrations were compared in terms of terminal half-life, area under the curve from 0 to infinity, and mean residence time. RESULTS: Mean bias in PK parameters was up to 4.5 times better with the novel model assuming a constant error model and up to 6.5 times better assuming a proportional error model. CONCLUSIONS: The simulation study indicates that this novel modeling approach results in less biased and more accurate PK estimates than straightforward subtraction of the observed baseline concentration and overcomes the limitations of previously published approaches. PMID- 25277162 TI - Knowledge, attitudes and beliefs of patients and carers regarding medication adherence: a review of qualitative literature. AB - PURPOSE: The aim of this review is to cohere evidence on the knowledge, attitudes and beliefs of patients and carers regarding medication adherence. Medication adherence refers to "the extent to which the patient's action matches the agreed recommendations". Medication adherence is vital in preventing, managing and curing illnesses and, hence, is linked with positive health outcomes. METHODS: A search was conducted using the following databases: CINAHL, Embase, PubMed and Web of Knowledge from inception to November 2013. Titles and abstracts were screened for inclusion in the review according to pre-defined inclusion and exclusion criteria. Studies were assessed for quality, and data were extracted into a data extraction form. Results were analysed thematically. RESULTS: The final results included 34 articles. Eight analytical themes were identified: (i) beliefs and experiences of medicines, (ii) family support and culture, (iii) role of and relationship with health-care practitioners, (iv) factors related to the disease, (v) self-regulation, (vi) communication, (vii) cost and (viii) access. The theme, "beliefs and experiences of medicines", was present in 33 studies, with many discussing the influence that side effects have on medication adherence. CONCLUSIONS: There are a number of variables that impact upon the knowledge, attitudes and beliefs of patients and carers regarding medication adherence. This review presents an overview of the analytical themes which offers the opportunity to examine interventions and their relative efficacies to increase medication adherence. PMID- 25277164 TI - Tinea cruris and tinea corporis masquerading as tinea indecisiva: case report and review of the literature. AB - BACKGROUND: Tinea indecisiva is characterized by concentric scaly rings simulating tinea imbricata but caused by dermatophytes other than Trichophyton concentricum. OBJECTIVE: Tinea indecisiva has been rarely reported. We report a unique case and review of the previously reported cases, pathogenesis, and management. METHODS: An adult Indian man developed extensive tinea cruris and tinea corporis with concentric rings of scaly lesions over the groin, buttocks, and thighs following the use of oral corticosteroids and antifungal-steroid cream for 3 months. Mycologic and immunologic studies were performed for diagnosis. RESULTS: Diagnosis of tinea indecisiva was confirmed on the appearance of "ring within-a-ring" lesions clinically and isolation of Trichophyton mentagrophytes var. interdigitale as the etiologic agent on mycologic testing. Intradermal testing with Trichophyton extract showed fluctuating hypersensitivity responses. Four-week treatment with daily oral terbinafine resulted in complete resolution. CONCLUSION: Tinea indecisiva should be considered in a patient with tinea imbricata-like lesions with local immunosuppression caused by a non-concentricum dermatophyte. PMID- 25277165 TI - Systematic verification of bioanalytical similarity between a biosimilar and a reference biotherapeutic: committee recommendations for the development and validation of a single ligand-binding assay to support pharmacokinetic assessments. AB - For biosimilar drug development, it is critical to demonstrate similar physiochemical characteristics, efficacy, and safety of the biosimilar product compared to the reference product. Therefore, pharmacokinetic (PK) and immunogenicity (antidrug antibody, ADA) assays that allow for the demonstration of biosimilarity are critical. Under the auspices of the American Association of Pharmaceutical Scientists (AAPS) Ligand-Binding Assay Bioanalytical Focus Group (LBABFG), a Biosimilars Action Program Committee (APC) was formed in 2011. The goals of this Biosimilars APC were to provide a forum for in-depth discussions on issues surrounding the development and validation of PK and immunogenicity assays in support of biosimilar drug development and to make recommendations thereof. The Biosimilars APC's recommendations for the development and validation of ligand-binding assays (LBAs) to support the PK assessments for biosimilar drug development are presented here. Analytical recommendations for the development and validation of LBAs to support immunogenicity assessments will be the subject of a separate white paper. PMID- 25277166 TI - Simultaneous enrichment and separation of flavonoids from Herba Epimedii by macroporous resins coupled with preparative chromatographic method. AB - An efficient, feasible enrichment and separation method of epimedins A, B, C and icariin from Herba Epimedii was developed by the combination of microwave assisted extraction, macroporous resins and preparative HPLC. WDX-5 macroporous resin shows better recoveries at 96.2%, 97.0%, 98.2% and 97.1% for epimedins A, B, C and icariin than other macroporous resins used in the experiments. As a result, epimedins A (5.1 mg), B (15.3 mg), C (7.6 mg) and icariin (14.3 mg) were obtained from 6.0 g crude Herba Epimedii with the recoveries at 70.8%, 68.9%, 66.7% and 95.3%, respectively. The method developed in this study may provide scientific references for the enrichment and separation of flavonoids from Herba Epimedii. PMID- 25277163 TI - Global identification of Smad2 and Eomesodermin targets in zebrafish identifies a conserved transcriptional network in mesendoderm and a novel role for Eomesodermin in repression of ectodermal gene expression. AB - BACKGROUND: Nodal signalling is an absolute requirement for normal mesoderm and endoderm formation in vertebrate embryos, yet the transcriptional networks acting directly downstream of Nodal and the extent to which they are conserved is largely unexplored, particularly in vivo. Eomesodermin also plays a role in patterning mesoderm and endoderm in vertebrates, but its mechanisms of action, and how it interacts with the Nodal signalling pathway are still unclear. RESULTS: Using a combination of ChIP-seq and expression analysis we identify direct targets of Smad2, the effector of Nodal signalling in blastula stage zebrafish embryos, including many novel target genes. Through comparison of these data with published ChIP-seq data in human, mouse and Xenopus we show that the transcriptional network driven by Smad2 in mesoderm and endoderm is conserved in these vertebrate species. We also show that Smad2 and zebrafish Eomesodermin a (Eomesa) bind common genomic regions proximal to genes involved in mesoderm and endoderm formation, suggesting Eomesa forms a general component of the Smad2 signalling complex in zebrafish. Combinatorial perturbation of Eomesa and Smad2 interacting factor Foxh1 results in loss of both mesoderm and endoderm markers, confirming the role of Eomesa in endoderm formation and its functional interaction with Foxh1 for correct Nodal signalling. Finally, we uncover a novel, role for Eomesa in repressing ectodermal genes in the early blastula. CONCLUSION: Our data demonstrate that evolutionarily conserved developmental functions of Nodal signalling occur through maintenance of the transcriptional network directed by Smad2. This network is modulated by Eomesa in zebrafish which acts to promote mesoderm and endoderm formation in combination with Nodal signalling, whilst Eomesa also opposes ectoderm gene expression. Eomesa therefore regulates the formation of all three germ layers in the early zebrafish embryo. PMID- 25277167 TI - Achievement of NKF/K-DOQI recommended target values for bone and mineral metabolism in incident hemodialysis patients: results of the FARO-2 cohort. AB - BACKGROUND: Mineral Bone Disorders (MBD) is prevalent in hemodialysis (HD) patients and associated with increased cardiovascular mortality. The FARO-2 study evaluated the achievement of the NKF/K-DOQI guidelines on recommended target values for serum calcium (Ca), phosphorous (P) and intact parathyroid hormone (PTH) levels on survival in incident HD patients. METHODS: Data were collected by questionnaire from 568 incident HD patients followed prospectively over a 3-year period from 26 Italian dialysis units. The cumulative probability of time-to death for CKD-MBD treatment characteristics was determined by the Kaplan-Meier curves. RESULTS: Serum PTH levels (median values at 6 months vs. 36 months; 225 vs. 254 pg/ml), Ca (8.8 vs. 8.9 g/dl) and P (5.1 vs. 4.8 mg/dl) were not significantly different at 6 months versus follow-up. The majority of incident HD patients (60-70%) who were followed up for 36 months did not achieve the NKF/K DOQI recommended target values. Survival rates were higher in patients on target for three parameters versus patients off target (survival at 24 months: at target 95.7% (95% CI: 84.0-98.9) versus not on target 71.1% (95% CI: 66.3-75.4, p < 0.01)). The 30.1% of patients on target for three MBD parameters at least once during the follow-up period had better survival rates compared to those not reaching these targets (survival at 24 months: at least once 88.0% (95% CI: 81.9 92.1); 67.7% (95% CI: 61.9-72.8, p < 0.01)). CONCLUSION: Our findings indicate that incident HD patients who achieved target levels (for three MBD parameters) for at least one visit have a lower risk of mortality. PMID- 25277168 TI - Effect of temperature and glia in brain size enlargement and origin of allometric body-brain size scaling in vertebrates. AB - BACKGROUND: Brain signaling requires energy. The cost of maintaining and supporting energetically demanding neurons is the key constraint on brain size. The dramatic increase in brain size among mammals and birds cannot be understood without solving this conundrum: larger brains, with more neurons, consume more energy. RESULTS: Here we examined the intrinsic relationships between metabolism, body-brain size ratios and neuronal densities of both endothermic and ectothermic animals. We formulated a general model to elucidate the key factors that correlate with brain enlargement, and the origin of allometric body-brain size scaling. This framework identified temperature as a critical factor in brain enlargement via temperature-regulated changes in metabolism. Our framework predicts that ectothermic animals living in tropical climates should have brain sizes that are several times larger than those of ectothermic animals living in cold climates. This prediction was confirmed by data from experiments in fish brains. Our framework also suggests that a rapid increase in the number of less energy-demanding glial cells may be another important factor contributing to the ten-fold increase in the brain sizes of endotherms compared with ectotherms. CONCLUSIONS: This study thus provides a quantitative theory that predicts the brain sizes of all the major types of animals and quantifies the contributions of temperature-dependent metabolism, body size and neuronal density. PMID- 25277169 TI - Intensity-dependent reductions in resting blood pressure following short-term isometric exercise training. AB - To reduce resting blood pressure, a minimum isometric exercise training (IET) intensity has been suggested, but this is not known for short-term IET programmes. We therefore compared the effects of moderate- and low-intensity IET programmes on resting blood pressure. Forty normotensive participants (22.3 +/- 3.4 years; 69.5 +/- 15.5 kg; 170.2 +/- 8.7 cm) were randomly assigned to groups of differing training intensities [20%EMGpeak (~23%MVC, maximum voluntary contraction, or 30%EMGpeak (~34%MVC)] or control group; 3 weeks of IET at 30%EMGpeak resulted in significant reductions in resting mean arterial pressure (e.g. -3.9 +/- 1.0 mmHg, P < 0.001), whereas 20%EMGpeak did not (-2.3 +/- 2.9 mmHg; P > 0.05). Moreover, after pooling all female versus male participants, IET induced a 6.9-mmHg reduction in systolic blood pressure in female participants, but only a 1.5-mmHg reduction in systolic blood pressure in male participants, although the difference was not significant. An IET intensity between 20%EMGpeak and 30%EMGpeak is sufficient to elicit significant resting blood pressure reductions in a short-term training period (3 weeks). In addition, sexual dimorphism may exist in the magnitude of reductions, but further work is required to confirm this possibility, which could be important in understanding the mechanisms responsible. PMID- 25277171 TI - Anticoagulant therapy is not a risk factor for choroidal haemorrhage. PMID- 25277170 TI - The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). AB - BACKGROUND: There is no consensus regarding resection of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastatic colorectal cancer (CRC). A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour in later stages of the disease. We here propose a randomized trial in order to demonstrate that resection of the primary tumour improves overall survival. METHODS/DESIGN: The CAIRO4 study is a multicentre, randomized, phase III study of the Dutch Colorectal Cancer Group (DCCG). Patients with synchronous unresectable metastases of CRC and few or absent symptoms of the primary tumour are randomized 1:1 between systemic therapy only, and resection of the primary tumour followed by systemic therapy. Systemic therapy will consist of fluoropyrimidine-based chemotherapy in combination with bevacizumab. The primary objective of this study is to determine the clinical benefit in terms of overall survival of initial resection of the primary tumour. Secondary endpoints include progression free survival, surgical morbidity, quality of life and the number of patients requiring resection of the primary tumour in the control arm. DISCUSSION: The CAIRO4 study is a multicentre, randomized, phase III study that will assess the benefit of resection of the primary tumour in patients with synchronous metastatic CRC. TRIAL REGISTRATION: The CAIRO4 study is registered at clinicaltrials.gov (NCT01606098). PMID- 25277172 TI - Comparing new and conventional methods to estimate benthic algal biomass and composition in freshwaters. AB - We compared conventional microscope-based methods for quantifying biomass and community composition of stream benthic algae with output obtained for these parameters from a new instrument (the BenthoTorch), which measures fluorescence of algal pigments in situ. Benthic algae were studied in 24 subarctic oligotrophic (1.7-26.9, median 7.2 MUg total phosphorus L(-1)) streams in Northern Sweden. Readings for biomass of the total algal mat, quantified as chlorophyll a, did not differ significantly between the BenthoTorch (median 0.52 MUg chlorophyll a cm(-2)) and the conventional method (median 0.53 MUg chlorophyll a cm(-2)). However, quantification of community composition of the benthic algal mat obtained using the BenthoTorch did not match those obtained from conventional methods. The BenthoTorch indicated a dominance of diatoms, whereas microscope observations showed a fairly even distribution between diatoms, blue-green algae (mostly nitrogen-fixing) and green algae (mostly large filamentous), and also detected substantial biovolumes of red algae in some streams. These results most likely reflect differences in the exact parameters quantified by the two methods, as the BenthoTorch does not account for variability in cell size and the presence of non-chlorophyll bearing biomass in estimating the proportion of different algal groups, and does not distinguish red algal chlorophyll from that of other algal groups. Our findings suggest that the BenthoTorch has utility in quantifying biomass expressed as MUg chlorophyll a cm( 2), but its output for the relative contribution of different algal groups to benthic algal biomass should be used with caution. PMID- 25277173 TI - Contact inhibition against senescence. PMID- 25277174 TI - Targeting STAT6 in PMBL. PMID- 25277177 TI - Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas. AB - The intrinsic signaling cascades and cell states associated with the Glioma CpG Island Methylator Phenotype (G-CIMP) remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that G-CIMP+ tumors harbor decreased EGFR signaling using three independent datasets, including the Chinese Glioma Genome Atlas(CGGA; n=155), the REMBRANDT dataset (n=288), and The Cancer Genome Atlas (TCGA; n=406). Additionally, an independent collection of 25 fresh-frozen glioblastomas confirmed lowered pERK levels in G CIMP+ specimens (p<0.001), indicating suppressed EGFR signaling. Analysis of TCGA glioblastomas revealed that G-CIMP+ glioblastomas harbored lowered mRNA levels for EGFR and H-Ras. Induction of G-CIMP+ state by exogenous expression of a mutated isocitrate dehydrogenase 1, IDH1-R132H, suppressed EGFR and H-Ras protein expression as well as pERK accumulation in independent glioblastoma models. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. The IDH1 R132H expression-induced pERK suppression can be reversed by exogenous expression of H-RasG12V. Finally, the G-CIMP+ Ink4a-Arf-/- EGFRvIII glioblastoma line was more resistant to the EGFR inhibitor, Gefitinib, relative to its isogenic G-CIMP- counterpart. These results suggest that G-CIMP epigenetically regulates EGFR signaling and serves as a predictive biomarker for EGFR inhibitors in glioblastoma patients. PMID- 25277178 TI - Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness. AB - Novel biomarkers predicting prostate cancer (PCa) aggressiveness and docetaxel therapy response of PCa patients are needed. In this study the correlation between nuclear Eg5-expression, PCa docetaxel response and PCa aggressiveness was assessed. Immunohistochemical staining for nuclear Eg5 was performed on 117 archival specimens from 110 PCa patients treated with docetaxel between 2004 and 2012. Samples were histologically categorized as positive/negative. Median follow up time from diagnosis was 11.6 years. Nuclear Eg5-expression was significantly related to docetaxel response (p=0.036) in tissues acquired within three years before docetaxel initiation. Nuclear Eg5-expression was not related to Gleason score (p=0.994). Survival of patients after docetaxel initiation did not differ based on nuclear Eg5-expression (p=0.540). Analyzing samples taken before hormonal therapy, overall survival and time to docetaxel use were significantly decreased in patients with nuclear Eg5-expressing tumors (p<0.01). Eg5-positive nuclei were found more frequently in T4-staged tumors (p=0.04), Gleason 8-10 tumors (p=0.08), and in metastasized tumors (p<0.01). Multivariate analyses indicated that nuclear Eg5-expression may be an independent parameter for tumor aggressiveness. Limitations of a retrospective analysis apply. In conclusion, nuclear Eg5-expression may be a predictive biomarker for docetaxel response in metastatic castrate-resistant PCa patients and a prognostic biomarker for hormone naive PCa patients. Prospective validation studies are needed. PMID- 25277176 TI - The structural basis for cancer treatment decisions. AB - Cancer treatment decisions rely on genetics, large data screens and clinical pharmacology. Here we point out that genetic analysis and treatment decisions may overlook critical elements in cancer development, progression and drug resistance. Two critical structural elements are missing in genetics-based decision-making: the mechanisms of oncogenic mutations and the cellular network which is rewired in cancer. These lay the foundation for the structural basis for cancer treatment decisions, which is rooted in the physical principles of the molecular conformational behavior of single molecules and their interactions. Improved tumor mutational analysis platforms and knowledge of the redundant pathways which can take over in cancer, may not only supplement known actionable findings, but forecast possible cancer progression and resistance. Such forward looking can be powerful, endowing the oncologist with mechanistic insight and cancer prognosis, and consequently more informed treatment options. Examples include redundant pathways taking over after inhibition of EGFR constitutive activation, mutations in PIK3CA p110alpha and p85, and the non-hotspot AKT1 mutants conferring constitutive membrane localization. PMID- 25277179 TI - 18 FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation. AB - The aim of this study was to investigate the prognostic value of 18F-fluoro deoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30% of patients. Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management. PMID- 25277180 TI - NM23-H1 expression of head and neck squamous cell carcinoma in association with the response to cisplatin treatment. AB - We recently reported that low NM23-H1 expression of head and neck squamous cell carcinoma (HNSCC) correlated with poor patients' prognosis. Growing evidence has indicated that high tumor NM23-H1 expression contributes to a good response to chemotherapy. Therefore, we investigated the role of NM23-H1 in susceptibility of HNSCC cells to cisplatin and its clinical significance, as well as the in vitro study for validation was performed. Using immunohistochemistry, we analyzed NM23 H1 expression in surgical specimens from 46 HNSCC patients with cervical metastases receiving surgery and adjuvant chemoradiotherapy. Low tumor NM23-H1 expression correlated with locoregional recurrence of HNSCC following postoperative cisplatin-based therapy (p = 0.056) and poor patient prognosis (p = 0.001). To validate the clinical observation and the effect of NM23-H1 on cisplatin cytotoxicity, we established several stable clones derived from a human HNSCC cell line (SAS) by knockdown and overexpression. Knockdown of NM23-H1 attenuated the chemosensitivity of SAS cells to cisplatin, which was associated with reduced cisplatin-induced S-phase accumulation and downregulation of cyclin E1 and A. Overexpression of NM23-H1 reversed these results, indicating the essential role of NM23-H1 in treatment response to cisplatin. NM23-H1 may participate in HNSCC cell responses to cisplatin and be considered a potential therapeutic target. PMID- 25277175 TI - Molecular pathways and targets in prostate cancer. AB - Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge. PMID- 25277181 TI - Common reduction of the Raf kinase inhibitory protein in clear cell renal cell carcinoma. AB - Despite the recent progress in our understanding of clear cell renal cell carcinomas (ccRCCs), the etiology of ccRCC remains unclear. We reported here a prevailing reduction of the raf kinase inhibitory protein (RKIP) in ccRCC. In our examination of more than 600 ccRCC patients by western blot and immunohistochemistry, RKIP was significantly reduced in 80% of tumors. Inhibition of RKIP transcription in ccRCC occurs to greater levels than VHL transcription based on the quantification analysis of their transcripts in six large datasets of DNA microarray available in OncomineTM with the median rank of suppression being 582 and 2343 for RKIP and VHL, respectively. Collectively, the magnitude of RKIP reduction and the levels of its downregulation match those of VHL. Furthermore, RKIP displays tumor suppressing activity in ccRCC. While modulation of RKIP expression did not affect the proliferation of A498 and 786-0 ccRCC cells and neither their ability to form xenograft tumors in NOD/SCID mice, ectopic expression or knockdown of RKIP inhibited or enhanced A498 and 786-0 ccRCC cell invasion, respectively. This was associated with robust changes in vimentin expression, a marker of EMT. Taken together, we demonstrate here that downregulation of RKIP occurs frequently at a rate that reaches that of VHL, suggesting RKIP being a critical tumor suppressor for ccRCC. This is consistent with RKIP being a tumor suppressor for other cancers. PMID- 25277182 TI - Applicability of the methylated CpG sites of paired box 5 (PAX5) promoter for prediction the prognosis of gastric cancer. AB - Paired box gene 5 (PAX5), a member of the paired box gene family, is involved in control of organ development and tissue differentiation. In previous study, PAX5 promoter methylation was found in gastric cancer (GC) cells and tissues. At present study, we found that the inconsistently methylated levels of PAX5 promoter were identified in the different GC tissues. The methylated CpG site count and the methylated statuses of four CpG sites (-236, -183, -162, and -152) were significantly associated with the survival of 460 GC patients, respectively. Ultimately, the methylated CpG -236 was the optimal prognostic predictor of patients identified by using the Cox regression with AIC value calculation. These findings indicated that the methylated CpG -236 of PAX5 promoter has the potential applicability for clinical evaluation the prognosis of GC. PMID- 25277183 TI - Selenocysteine derivative overcomes TRAIL resistance in melanoma cells: evidence for ROS-dependent synergism and signaling crosstalk. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as one of the most promising targeted drug for new cancer therapeutics, is limited in clinical application by the evolution of resistance in many cancer cell lines, especially in malignant melanoma. Thus, it is urgently needed to identify chemosensitizers to enhance the apoptotic inducing efficacy of TRAIL and overcome resistance of malignant melanoma cells. Herein, we reported that 3,3'-diselenodipropionic acid (DSeA), a Selenocysteine derivative, could synergistically enhance the growth inhibitory effect of TRAIL on A375 melanoma cells though induction of ROS dependent apoptosis with involvement of PTEN-mediated Akt inactivation and DNA damage-mediated p53 phosphorylation, which subsequently activated mitochondrial and death receptor apoptotic pathways. Moreover, silencing of p53 down-regulated the expression levels of p53-inducible genes, and effectively blocked the cell apoptosis. Suppression of PI3K significantly increased the apoptotic cell death. In contrast, antioxidants effectively reversed the cell apoptosis through regulation of Akt and p53 signaling pathways. Taken together, the combination of DSeA and TRAIL could be a novel strategy to overcome TRAIL resistance in malignant melanoma, and DSeA may be candidates for further evaluation as a chemosensitizer in clinical trails. PMID- 25277184 TI - TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma. AB - In some tumours, despite a wild-type p53 gene, the p53 pathway is inactivated by alterations in its regulators or by unknown mechanisms, leading to resistance to cytotoxic therapies. Understanding the mechanisms of functional inactivation of wild-type p53 in these tumours may help to define prospective targets for treating cancer by restoring p53 activity. Recently, we identified TRIM8 as a new p53 modulator, which stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. In this paper we demonstrated that TRIM8 deficit dramatically impairs p53-mediated cellular responses to chemotherapeutic drugs and that TRIM8 is down regulated in patients affected by clear cell Renal Cell Carcinoma (ccRCC), an aggressive drug-resistant cancer showing wild-type p53. These results suggest that down regulation of TRIM8 might be an alternative way to suppress p53 activity in RCC. Interestingly, we show that TRIM8 expression recovery in RCC cell lines renders these cells sensitive to chemotherapeutic treatments following p53 pathway re-activation. These findings provide the first mechanistic link between TRIM8 and the drug resistance of ccRCC and suggest more generally that TRIM8 could be used as enhancer of the chemotherapy efficacy in cancers where p53 is wild-type and its pathway is defective. PMID- 25277186 TI - Liposome encapsulated Disulfiram inhibits NFkappaB pathway and targets breast cancer stem cells in vitro and in vivo. AB - Breast cancer stem cells (BCSCs) are pan-resistant to different anticancer agents and responsible for cancer relapse. Disulfiram (DS), an antialcoholism drug, targets CSCs and reverses pan-chemoresistance. The anticancer application of DS is limited by its very short half-life in the bloodstream. This prompted us to develop a liposome-encapsulated DS (Lipo-DS) and examine its anticancer effect and mechanisms in vitro and in vivo. The relationship between hypoxia and CSCs was examined by in vitro comparison of BC cells cultured in spheroid and hypoxic conditions. To determine the importance of NFkappaB activation in bridging hypoxia and CSC-related pan-resistance, the CSC characters and drug sensitivity in BC cell lines were observed in NFkappaB p65 transfected cell lines. The effect of Lipo-DS on the NFkappaB pathway, CSCs and chemosensitivity was investigated in vitro and in vivo. The spheroid cultured BC cells manifested CSC characteristics and pan-resistance to anticancer drugs. This was related to the hypoxic condition in the spheres. Hypoxia induced activation of NFkappaB and chemoresistance. Transfection of BC cells with NFkappaB p65 also induced CSC characters and pan resistance. Lipo-DS blocked NFkappaB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted the CSC population in vivo and showed very strong anticancer efficacy. Mice tolerated the treatment very well and no significant in vivo nonspecific toxicity was observed. Hypoxia induced NFkappaB activation is responsible for stemness and chemoresistance in BCSCs. Lipo-DS targets NFkappaB pathway and CSCs. Further study may translate DS into cancer therapeutics. PMID- 25277185 TI - High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression. AB - The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell beta-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy. PMID- 25277188 TI - Array-based genome-wide RNAi screening to identify shRNAs that enhance p53 related apoptosis in human cancer cells. AB - p53 transduction is a potentially effective cancer therapy but does not result in a good therapeutic response in all human cancers due to resistance to apoptosis. To discover factors that overcome resistance to p53-induced apoptosis, we attempted to identify RNAi sequences that enhance p53-induced apoptosis. We screened a genome-wide lentiviral shRNA library in liver cancer Huh-7 and pancreatic cancer Panc-1 cells, both of which resist p53-induced apoptosis. After the infection of adenovirus expressing p53 or LacZ as a control, shRNA-treated populations were analyzed by microarray. We identified shRNAs that were significantly decreased in p53-infected cells compared with control cells. Among these shRNAs, shRNA-58335 was markedly decreased in both cancer cell lines tested. shRNA-58335 enhanced p53-related apoptosis in vitro and augmented the inhibitory effect of adenoviral p53 transduction on tumor growth in vivo. Furthermore, the enhanced apoptotic response by shRNA-58335 was also confirmed by treatment with PRIMA-1, which reactivates mutant p53, instead of adenoviral p53 transduction. We found that shRNA-58335 evokes the apoptotic response following p53 transduction or functional restoration of p53 with a small molecule drug in cancer cells resistant to p53-induced apoptosis. The combination of p53 restoration and RNAi-based drugs is expected to be a promising novel cancer therapy. PMID- 25277187 TI - EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer. AB - Circulating tumor cells (CTCs) are frequently associated with epithelial mesenchymal transition (EMT).The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer. PMID- 25277189 TI - Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-kappaB signaling. AB - Transforming growth factor (TGF)-beta-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-kappaB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-kappaB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo. Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression. PMID- 25277190 TI - Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells. AB - The tumor microenvironment plays an important role in cancer progression. Here, we focused on the role of reactive mesenchymal stem cells (MSC) in osteosarcoma (OS), and used human adipose MSC and a panel of OS cell lines (Saos-2, HOS, and 143B) to investigate the mutual effect of normal-cancer cell metabolic programming. Our results showed that MSC are driven by oxidative stress induced by OS cells to undergo Warburg metabolism, with increased lactate production. Therefore, we analyzed the expression of lactate monocarboxylate transporters. By real time PCR and immunofluorescence, in MSC we detected the expression of MCT-4, the transporter for lactate efflux, whereas MCT-1, responsible for lactate uptake, was expressed in OS cells. In agreement, silencing of MCT-1 by siRNA significantly affected the ATP production in OS cancer cells. Thus, cancer cells directly increase their mitochondrial biogenesis using this energy-rich metabolite that is abundantly provided by MSC as an effect of the altered microenvironmental conditions induced by OS cells. We also showed that lactate produced by MSC promotes the migratory ability of OS cells. These data provide novel information to be exploited for cancer therapies targeting the mutual metabolic reprogramming of cancer cells and their stroma. PMID- 25277191 TI - Osteoblast-derived WNT-induced secreted protein 1 increases VCAM-1 expression and enhances prostate cancer metastasis by down-regulating miR-126. AB - Bone metastases of prostate cancer (PCa) may cause intractable pain. Wnt-1 induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in bone formation. We found that osteoblast-conditioned medium (OBCM) stimulates migration and vascular adhesion molecule-1 (VCAM)-1 expression in human PCa (PC3 and DU145) cells. Osteoblast transfection with WISP 1 shRNA reduced OBCM-mediated PCa migration and VCAM-1 expression. Stimulation of PCa with OBCM or WISP-1 elevated focal adhesion kinase (FAK) and p38 phosphorylation. Either FAK and p38 inhibitors or siRNA abolished osteoblast derived WISP-1-induced migration and VCAM-1 expression. Osteoblast-derived WISP-1 inhibited miR-126 expression. Moreover, miR-216 mimic reversed the WISP-1 enhanced migration and VCAM-1 expression. This study suggests that osteoblast derived WISP-1 promotes migration and VCAM-1 expression in human PCa cells by down-regulating miR-126 expression via alphavbeta1 integrin, FAK, and p38 signaling pathways. Thus, WISP-1 may be a new molecular therapeutic target in PCa bone metastasis. PMID- 25277192 TI - MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer. AB - Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR 145 targets 3' untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR 145 as a novel regulator of MUC13 in pancreatic cancer. PMID- 25277193 TI - Silencing of miRNA-148a by hypermethylation activates the integrin-mediated signaling pathway in nasopharyngeal carcinoma. AB - MicroRNAs (miRNAs) play a pivotal role in carcinogenesis by suppressing oncogenes or tumor suppressor genes. Various studies have identified numerous miRNAs and their diverse targets; however, the consequences of dysregulated miRNAs in nasopharyngeal carcinoma (NPC) remain unclear. For this study, we found that miR 148a is downregulated through hypermethylation in NPC biopsies and NPC cell lines compared with adjacent normal and NP cells respectively. Promoter assays demonstrated that upstream stimulatory factor 1 (USF1) is a crucial transcription factor that activates miR-148a promoter activity. EMSA assays confirmed that purified USF1 binds better toward the unmethylated than the methylated CG containing USF1 consensus probe. The ectopic expression of miR-148a inhibits cell migration in NPC cells through the suppression of integrin-mediated signaling by targeting VAV2, WASL and ROCK1. Biochemical and functional assays provided supporting evidence that these 3 genes are the downstream targets of miR-148a in NPC cells. Furthermore, immunohistochemical staining and Western blotting analysis revealed that the 3 oncogenic targets of miR-148a were overexpressed in NPC biopsies, suggesting that the inactivation of miR-148a caused by DNA methylation promotes NPC progression. Overall, our findings revealed that miR 148a can act as tumor suppressor miRNA and serve as a biomarker as well as a therapeutic target for NPC. PMID- 25277194 TI - N-Myc-induced up-regulation of TRPM6/TRPM7 channels promotes neuroblastoma cell proliferation. AB - Intracellular levels of the divalent cations Ca2+ and Mg2+ are important regulators of cell cycle and proliferation. However, the precise mechanisms by which they are regulated in cancer remain incompletely understood. The channel kinases TRPM6 and TRPM7 are gatekeepers of human Ca2+/Mg2+ metabolism. Here, we investigated the human neuroblastoma cell line SHEP-21N in which the MYCN oncogene (encoding N-Myc) can be reversibly expressed under control of an inducible repressor. We report that N-Myc expression increases cell growth and up regulates both TRPM6 and TRPM7 expression. Membrane current analyses reveal that endogenous TRPM6/TRPM7 currents exhibit reduced Mg.ATP suppression, increased Mg2+ sensitivity, and diminished sensitivity to 2-APB inhibition. These properties are consistent with N-Myc-induced increase of heteromeric TRPM7/TRPM6 channels promoting Ca2+ and Mg2+ uptake. Genetic suppression of TRPM6/TRPM7 through siRNA inhibits cell proliferation, suggesting that N-Myc can promote neuroblastoma cell proliferation through up-regulation of divalent cation transporting channels. PMID- 25277195 TI - MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape. AB - Malignant gliomas are intrinsic brain tumors with a dismal prognosis. They are well-adapted to hypoxic conditions and poorly immunogenic. NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DL). Here we evaluated the impact of miRNA on the expression of NKG2DL in glioma cells including stem-like glioma cells. Three of the candidate miRNA predicted to target NKG2DL were expressed in various glioma cell lines as well as in glioblastomas in vivo: miR-20a, miR-93 and miR-106b. LNA inhibitor mediated miRNA silencing up-regulated cell surface NKG2DL expression, which translated into increased susceptibility to NK cell-mediated lysis. This effect was reversed by neutralizing NKG2D antibodies, confirming that enhanced lysis upon miRNA silencing was mediated through the NKG2D system. Hypoxia, a hallmark of glioblastomas in vivo, down-regulated the expression of NKG2DL on glioma cells, associated with reduced susceptibility to NK cell-mediated lysis. This process, however, was not mediated through any of the examined miRNA. Accordingly, both hypoxia and the expression of miRNA targeting NKG2DL may contribute to the immune evasion of glioma cells at the level of the NKG2D recognition pathway. Targeting miRNA may therefore represent a novel approach to increase the immunogenicity of glioblastoma. PMID- 25277196 TI - CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies but the molecular genetic basis of this disease remains unclear. By using genome-wide methylation profiling analysis, we identified CLDN3 as an epigenetically regulated gene in cancer. Here, we investigated its function and clinical relevance in human HCC. CLDN3 downregulation occurred in 87/114 (76.3%) of primary HCCs, where it was correlated significantly with shorter survival of HCC patients (P=0.021). Moreover, multivariate cyclooxygenase regression analysis showed that CLDN3 was an independent prognostic factor for overall survival (P=0.014). Absent expression of CLDN3 was also detected in 67% of HCC cell lines, which was significantly associated with its promoter hypermethylation. Ectopic expression of CLDN3 in HCC cells could inhibit cell motility, cell invasiveness, and tumor formation in nude mice. Mechanistic investigations suggested through downregulation of GSK3B, CTNNB1, SNAI2, and CDH2, CLDN3 could significantly suppress metastasis by inactivating the Wnt/beta-catenin-epithelial mesenchymal transition (EMT) axis in HCC cells. Collectively, our findings demonstrated that CLDN3 is an epigenetically silenced metastasis suppressor gene in HCC. A better understanding of the molecular mechanism of CLDN3 in inhibiting liver cancer cell metastasis may lead to a more effective management of HCC patients with the inactivation of CLDN3. PMID- 25277197 TI - A central role for TRPS1 in the control of cell cycle and cancer development. AB - The eukaryotic cell cycle is controlled by a complex regulatory network, which is still poorly understood. Here we demonstrate that TRPS1, an atypical GATA factor, modulates cell proliferation and controls cell cycle progression. Silencing TRPS1 had a differential effect on the expression of nine key cell cycle-related genes. Eight of these genes are known to be involved in the regulation of the G2 phase and the G2/M transition of the cell cycle. Using cell synchronization studies, we confirmed that TRPS1 plays an important role in the control of cells in these phases of the cell cycle. We also show that silencing TRPS1 controls the expression of 53BP1, but not TP53. TRPS1 silencing also decreases the expression of two histone deacetylases, HDAC2 and HDAC4, as well as the overall HDAC activity in the cells, and leads to the subsequent increase in the acetylation of histone4 K16 but not of histone3 K9 or K18. Finally, we demonstrate that TRPS1 expression is elevated in luminal breast cancer cells and luminal breast cancer tissues as compared with other breast cancer subtypes. Overall, our study proposes that TRPS1 acts as a central hub in the control of cell cycle and proliferation during cancer development. PMID- 25277199 TI - Expression and functions of galectin-7 in ovarian cancer. AB - There is a critical need to develop effective new strategies for diagnosis and treatment of ovarian cancer. In the present work, we investigated the expression of galectin-7 (gal-7) in epithelial ovarian cancer (EOC) cells and studied its functional relevance. Immunohistochemical analysis of gal-7 expression in tissue microarrays showed that while gal-7 was not detected in normal ovarian tissues, positive cytoplasmic staining of gal-7 was detected in epithelial cells in all EOC histological subtypes but was more frequent in high grade tumors and metastatic samples. Gal-7 expression correlated with a significant difference in the overall survival of patients with ovarian serous cystadenocarcinoma. Furthermore, using human EOC cell lines, we found that gal-7 expression was induced by mutant p53. Mechanistically, Matrigel invasion assays and live cell imaging showed that gal-7 increased the invasive behavior of ovarian cancer cells by inducing MMP-9 and increasing cell motility. EOC cells can also secrete gal-7. Recombinant human gal-7 kills Jurkat T cells and human peripheral T cells, suggesting that gal-7 also has immunosuppressive properties. Taken together, our study validates the clinical significance of gal-7 overexpression in ovarian cancer and provides a rationale for targeting gal-7 to improve the outcome of patients with this disease. PMID- 25277198 TI - Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. AB - Dysregulation of cellular transcription and translation is a fundamental hallmark of cancer. As CDK9 and Mnks play pivotal roles in the regulation of RNA transcription and protein synthesis, respectively, they are important targets for drug development. We herein report the cellular mechanism of a novel CDK9 inhibitor CDKI-73 in an ovarian cancer cell line (A2780). We also used shRNA mediated CDK9 knockdown to investigate the importance of CDK9 in the maintenance of A2780 cells. This study revealed that CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. This subsequently caused a decrease in the eIF4E phosphorylation by blocking Mnk1 kinase activity. Consistently, CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis. The study confirmed that CDK9 is required for cell survival and that ovarian cancer may be susceptible to CDK9 inhibition strategy. The data also implied a role of CDK9 in eIF4E-mediated translational control, suggesting that CDK9 may have important implication in the Mnk-eIF4E axis, the key determinants of PI3K/Akt/mTOR- and Ras/Raf/MAPK-mediated tumorigenic activity. As such, CDK9 inhibitor drug candidate CDKI-73 should have a major impact on these pathways in human cancers. PMID- 25277200 TI - Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner. AB - Platinum resistance has long been a major issue in the treatment of various cancers. We previously reported that enhanced annexin A4 (ANXA4) expression, a Ca2+-regulated phospholipid-binding protein, induces chemoresistance to platinum based drugs. In this study, we investigated the role of annexin repeats, a conserved structure of all the annexin family, responsible for platinum resistance as well as the effect of knockdown of ANXA4. ANXA4 knockdown increased sensitivity to platinum-based drugs both in vitro and in vivo. To identify the domain responsible for chemoresistance, ANXA4 deletion mutants were constructed by deleting annexin repeats one by one from the C terminus. Platinum resistance was induced both in vitro and in vivo in cells expressing either full-length ANXA4 or the deletion mutants, containing at least one intact annexin repeat. However, cells expressing the mutant without any calcium-binding sites in the annexin repeated sequence, which is essential for ANXA4 translocation from the cytosol to plasma membrane, failed to acquire platinum resistance. After cisplatin treatment, the intracellular chloride ion concentration, whose channel is partly regulated by ANXA4, significantly increased in the platinum-resistant cells. These findings indicate that the calcium-binding site in the annexin repeat induces chemoresistance to the platinum-based drug by elevating the intracellular chloride concentration. PMID- 25277201 TI - Co-ordination of cell cycle, migration and stem cell-like activity in breast cancer. AB - Migration, proliferation and stem cell-like activity are all key cellular characteristics which aid the formation and progression of breast cancer, in addition to involvement in treatment resistance. Many current therapies aim to target tumour proliferation, and although successful, mortality rates in breast cancer remain significant. Our main objectives were to investigate the relationship between proliferation, migration and stem cell-like activity in breast cancer. We used a panel of cell lines and primary human breast cancer samples to assess the relationship between migration, proliferation and stem cells. We performed live cell sorting according to cell cycle (Hoechst-33324) and in combination with stem-cell markers (CD44/CD24/ESA) followed by assessment of migration and stem cell activity (mammosphere formation). We identified an inverse relationship between proliferation and migration/stem cell-like activity. G0/1 cells showed increased migration and mammosphere formation. Furthermore we identified a subpopulation of low proliferative stem-like cells (CD44+/24lo/ESA+) with increased migration and mammosphere formation that are specifically inhibited by Dickkopf 1 (DKK1) and Dibenzazepine (DBZ) known stem-cell inhibitors. These data show the co-ordination of migration, proliferation and stem cell activity in breast cancer, and has identified a sub-population of stem like cells, greatly adding to our understanding of the complex nature of stem cell biology. PMID- 25277202 TI - Integrated analysis of epigenomic and genomic changes by DNA methylation dependent mechanisms provides potential novel biomarkers for prostate cancer. AB - Epigenetic silencing mediated by CpG methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with tumor progression may identify potential prognostic markers for prostate cancer (PCa). We treated two PCa cell lines, 22Rv1 and DU-145 with the demethylating agent 5 Aza 2'-deoxycitidine (DAC) and global methylation status was analyzed by performing methylation-sensitive restriction enzyme based differential methylation hybridization strategy followed by genome-wide CpG methylation array profiling. In addition, we examined gene expression changes using a custom microarray. Gene Set Enrichment Analysis (GSEA) identified the most significantly dysregulated pathways. In addition, we assessed methylation status of candidate genes that showed reduced CpG methylation and increased gene expression after DAC treatment, in Gleason score (GS) 8 vs. GS6 patients using three independent cohorts of patients; the publically available The Cancer Genome Atlas (TCGA) dataset, and two separate patient cohorts. Our analysis, by integrating methylation and gene expression in PCa cell lines, combined with patient tumor data, identified novel potential biomarkers for PCa patients. These markers may help elucidate the pathogenesis of PCa and represent potential prognostic markers for PCa patients. PMID- 25277203 TI - miR-200c overexpression is associated with better efficacy of EGFR-TKIs in non small cell lung cancer patients with EGFR wild-type. AB - Several randomized trials have demonstrated non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations can achieve favorable clinical outcomes on treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation is considered as a predictive marker for efficacy of EGFR-TKIs in NSCLC. Here we show miR-200c overexpression was correlated with the epithelial phenotype and sensitivity to gefitinib in EGFR wild-type NSCLC cell lines. Up-regulated miR-200c could regain the sensitivity to gefitinib in the EGFR wild-type cell lines and miR-200c could regulate epithelial to mesenchymal transition through PI3K/AKT and MEK/ERK pathways. NSCLC patients at advanced stage (N=150) who received EGFR-TKIs (gefitinib or erlotinib) as second- or third-line therapy from September 2008 to December 2012 were included in the study. In 66 NSCLC patients with wild-type EGFR, high levels of miR-200c expression was associated with higher disease control rate (DCR), longer progression-free survival (PFS) and longer overall survival (OS) compared with low miR-200c expression subgroup. In the subgroup with EGFR mutation, the trend remained the same but not statistically significant. Overall, these findings indicated that miR-200c might be a predictive biomarker for sensitivity to EGFR TKIs in advanced NSCLC patients with wild-type EGFR. PMID- 25277204 TI - Estrogen receptor alpha prevents bladder cancer via INPP4B inhibited akt pathway in vitro and in vivo. AB - Clinical reports show males have a higher bladder cancer (BCa) incidence than females. The sexual difference of BCa occurrence suggests that estrogen and its receptors may affect BCa development. Estrogen receptor alpha (ERalpha) is the classic receptor to convey estrogen signaling, however, the function of ERalpha in BCa development remains largely unknown. To understand the in vivo role of ERalpha in BCa development, we generated total and urothelial specific ERalpha knockout mice (ERalphaKO) and used the pre- carcinogen BBN to induce BCa. Earlier reports showed that ERalpha promotes breast and ovarian cancers in females. Surprisingly and of clinical importance, our results showed that ERalpha inhibits BCa development and loss of the ERalpha gene results in an earlier onset and higher incidence of BBN-induced in vivo mouse BCa. Supportively, carcinogen induced malignant transformation ability was reduced in ERalpha expressing urothelial cells as compared to ERalpha negative cells. Mechanism studies suggest that ERalpha could control the expression of INPP4B to reduce AKT activity and consequently reduce BCa cell growth. In addition, IHC staining of clinical sample analyses show that INPP4B expression, in correlation with reduced ERalpha, is significantly reduced in human BCa specimens. Together, this is the first report using the in vivo cre-loxP gene knockout mouse model to characterize ERalpha roles in BCa development. Our studies provide multiple in vitro cell studies and in vivo animal model data as well as human BCa tissue analyses to prove ERalpha plays a protective role in BCa initiation and growth at least partly via modulating the INPP4B/Akt pathway. PMID- 25277206 TI - FAK inhibition with small molecule inhibitor Y15 decreases viability, clonogenicity, and cell attachment in thyroid cancer cell lines and synergizes with targeted therapeutics. AB - Focal adhesion kinase (FAK) is up-regulated in thyroid cancer and small molecule FAK scaffolding inhibitor, Y15, was shown to decrease cancer growth in vitro and in vivo. We sought to test the effectiveness of Y15 in thyroid cancer cell lines, profile gene expression with Y15 compared with clinical trial FAK inhibitor PF 04554878, and use Y15 in novel drug combinations. Cell viability was decreased in a dose dependent manner in four thyroid cancer cell lines with Y15 and with higher doses in PF-04554878. Y397 FAK and total FAK were decreased with Y15 and decreased less with PF-04554878. Detachment and necrosis were increased in a dose dependent manner in all cell lines with Y15. Clonogenicity was decreased in a dose-dependent manner for both Y15 and PF-04554878. We compared gene profiles between papillary thyroid cell lines, TPC1, BCPAP and K1, and 380, 109, and 74 genes were significantly >2-fold changed with Y15 treatment, respectively. Common up-regulated genes were involved in apoptosis, cell cycle, transcription and heat shock; down-regulated genes were involved in cell cycle, cell-to-cell interactions, and cancer stem cell markers. We also compared gene profiles of TT cells treated with Y15 versus PF-04554878. Y15 caused 144 genes to change over 4 fold and PF-04554878 caused 208 gene changes >4-fold (p<0.05). Among genes changed 4 fold, 11 were shared between the treatments, including those involved in metabolism, cell cycle, migration and transcription. Y15 demonstrated synergy with PF-04554878 in TT cells and also synergy with Cabozantinib, Sorafenib, Pazopanib, and strong synergy with Sunitinib in resistant K1 cells. This report revealed the biological effect of Y15 inhibitor, detected the unique and common gene signature profiles in response to Y15 in 4 different thyroid cancer cell lines, demonstrated differential response changes with Y15 and PF-04554878 treatment, and showed the synergy of Y15 with PF-04554878, Cabozantinib, Sorafenib, Pazopanib, and Sunitinib. PMID- 25277205 TI - Mutant NRASQ61 shares signaling similarities across various cancer types- potential implications for future therapies. AB - Oncogenic mutations in the Neuroblastoma Rat Sarcoma oncogene (NRAS) are frequent in melanoma, but are also found in several other cancer types, such as lung cancer, neuroblastoma and colon cancer. We designed our study to analyze changes in NRAS mutant tumor cells derived from malignancies other than melanoma. A variety of small molecule inhibitors as well as their combinations was tested in order to find beneficial inhibitory modalities in NRASQ61mutant lung cancer and neuroblastoma cell lines. Signaling changes after incubation with inhibitors were studied and compared to those found in NRAS mutant melanoma. All cell lines were most sensitive to inhibition in the MAPK pathway with the MEK inhibitor trametinib. MEK/AKT and MEK/CDK4,6 inhibitor combinations did not show any beneficial effects in vitro. However, we observed strong synergism combining MEK and PI3K/mTOR inhibitors in all cell lines. Our study provides evidence that NRAS mutant cancers share signaling similarities across different malignancies. We demonstrate that dual pathway inhibition of the MAPK and PI3K/AKT/mTOR pathway synergistically reduces cell viability in NRAS mutant cancers regardless of their tissue origin. Our results suggest that such inhibitor combinations may be a potential treatment option for non-melanoma tumors harboring activating NRAS mutations. PMID- 25277208 TI - A qualitative study of integrated care from the perspectives of patients with chronic obstructive pulmonary disease and their relatives. AB - BACKGROUND: Disease management programmes have been developed for chronic obstructive pulmonary disease (COPD) to facilitate the integration of care across healthcare settings. The purpose of the present study was to examine the experiences of COPD patients and their relatives of integrated care after implementation of a COPD disease management programme. METHODS: Seven focus groups and five individual interviews were held with 34 patients with severe or very severe COPD and two focus groups were held with eight of their relatives. Data were analysed using inductive content analysis. RESULTS: Four main categories of experiences of integrated care emerged: 1) a flexible system that provides access to appropriate healthcare and social services and furthers patient involvement; 2) the responsibility of health professionals to both take the initiative and follow up; 3) communication and providing information to patients and relatives; 4) coordination and professional cooperation. Most patients were satisfied with their care and raised few criticisms. However, patients with more unstable and severe disease tended to experience more problems. CONCLUSIONS: Participant suggestions for optimizing the integration of healthcare included assigning patients a care coordinator, telehealth solutions for housebound patients and better information technology to support interprofessional cooperation. Further studies are needed to explore these and other possible solutions to problems with integrated care among COPD patients. A future effort in this field should be informed by detailed knowledge of the extent and relative importance of the identified problems. It should also be designed to address variable levels of severity of COPD and relevant comorbidities and to deliver care in ways appropriate to the respective healthcare setting. Future studies should also take health professionals' views into account so that interventions may be planned in the light of the experiences of all those involved in the treatment of COPD patients. PMID- 25277209 TI - Conserved MHC gene orthologs genetically map to the turkey MHC- B. AB - The avian MHC-associated gene set includes orthologs to genes found throughout the human major histocompatibility complex (MHC), including some loci of the evolutionarily conserved class III region. In the turkey and other Galliformes, genes linked to the MHC have been identified because they are closely associated with class I or class II genes. This study was designed to evaluate additional class III genes for linkage to the avian MHC to further determine conservation of these loci in birds. BLAST searches were used to locate sequences in the turkey genome with similarity to genes shared between the MHC of Xenopus and humans. Primers were designed to target 25 genes, and putative orthologs were amplified by PCR and sequenced. Sequence polymorphisms were identified for 15 genes in turkey reference mapping families, and 8 genes showed significant genetic linkage to the turkey MHC-B locus. These new genetic markers and linkage relationships broaden our understanding of the composition of the avian MHC and expand the gene content for the turkey MHC-B. PMID- 25277207 TI - Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. AB - The majority of oligodendrogliomas (ODGs) exhibit combined losses of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH1-R132H or IDH2-R172K). Approximately 70% of ODGs with 1p19q co-deletions harbor somatic mutations in the Capicua Transcriptional Repressor (CIC) gene on chromosome 19q13.2. Here we show that endogenous long (CIC-L) and short (CIC-S) CIC proteins are predominantly localized to the nucleus or cytoplasm, respectively. Cytoplasmic CIC-S is found in close proximity to the mitochondria. To study wild type and mutant CIC function and motivated by the paucity of 1p19q co-deleted ODG lines, we created HEK293 and HOG stable cell lines ectopically co-expressing CIC and IDH1. Non mutant lines displayed increased clonogenicity, but cells co-expressing the mutant IDH1-R132H with either CIC-S-R201W or -R1515H showed reduced clonogenicity in an additive manner, demonstrating cooperative effects in our assays. Expression of mutant CIC-R1515H increased cellular 2-Hydroxyglutarate (2HG) levels compared to wild type CIC in IDH1-R132H background. Levels of phosphorylated ATP-citrate Lyase (ACLY) were lower in cell lines expressing mutant CIC-S proteins compared to cells expressing wild type CIC-S, supporting a cytosolic citrate metabolism-related mechanism bof reduced clonogenicity in our in vitro model systems. ACLY or phospho-ACLY were similarly reduced in CIC-mutant 1p19q co-deleted oligodendroglioma patient samples. PMID- 25277210 TI - In silico analysis of the core signaling proteome from the barley powdery mildew pathogen (Blumeria graminis f.sp. hordei). AB - BACKGROUND: Compared to other ascomycetes, the barley powdery mildew pathogen Blumeria graminis f.sp. hordei (Bgh) has a large genome (ca. 120 Mbp) that harbors a relatively small number of protein-coding genes (ca. 6500). This genomic assemblage is thought to be the result of numerous gene losses, which likely represent an evolutionary adaptation to a parasitic lifestyle in close association with its host plant, barley (Hordeum vulgare). Approximately 8% of the Bgh genes are predicted to encode virulence effectors that are secreted into host tissue and/or cells to promote pathogenesis; the remaining proteome is largely uncharacterized at present. RESULTS: We provide a comparative analysis of the conceptual Bgh proteome, with an emphasis on proteins with known roles in fungal development and pathogenicity, for example heterotrimeric G proteins and G protein coupled receptors; components of calcium and cAMP signaling; small monomeric GTPases; mitogen-activated protein cascades and transcription factors. The predicted Bgh proteome lacks a number of proteins that are otherwise conserved in filamentous fungi, including two proteins that are required for the formation of anastomoses (somatic hyphal connections). By contrast, apart from minor modifications, all major canonical signaling pathways are retained in Bgh. A family of kinases that preferentially occur in pathogenic species of the fungal clade Leotiomyceta is unusually expanded in Bgh and its close relative, Blumeria graminis f.sp. tritici. CONCLUSIONS: Our analysis reveals characteristic features of the proteome of a fungal phytopathogen that occupies an extreme habitat: the living plant cell. PMID- 25277211 TI - miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6. AB - Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-kappaB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR 98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop. PMID- 25277213 TI - Suggested statistical reappraisal of data from comparative study of febuxostat and allopurinol in chronic kidney disease. PMID- 25277212 TI - Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential. AB - Ovarian cancer is the most lethal gynaecologic malignancy in the United States, and advanced serous ovarian adenocarcinoma is responsible for most ovarian cancer deaths. However, the stroma-derived molecular determinants that modulate patient survival are yet to be characterized. Here we identify a stromal gene signature for advanced high-grade serous ovarian cancer using microdissected stromal ovarian tumour samples and find that stromal microfibrillar-associated protein 5 (MFAP5) is a prognostic marker for poor survival. Further functional studies reveal that FAK/CREB/TNNC1 signalling pathways mediate the effect of MFAP5 on ovarian cancer cell motility and invasion potential. Targeting stromal MFAP5 using MFAP5-specific siRNA encapsulated in chitosan nanoparticles significantly decreases ovarian tumour growth and metastasis in vivo, suggesting that it may be a new modality of ovarian cancer treatment. PMID- 25277214 TI - Invasive slug populations (Arion vulgaris) as potential vectors for Clostridium botulinum. AB - BACKGROUND: Norwegian meadows, including those for silage production, are recently found heavily invaded by the slug Arion vulgaris in exposed areas. As a consequence, large numbers of slugs might contaminate grass silage and cause a possible threat to animal feed quality and safety. It is well known that silage contaminated by mammalian or avian carcasses can lead to severe outbreaks of botulism among livestock. Invertebrates, especially fly-larvae (Diptera), are considered important in the transfer of Clostridium botulinum type C and its toxins among birds in wetlands. C. botulinum form highly resistant spores that could easily be consumed by the slugs during feeding. This study aimed to determine whether Arion vulgaris could hold viable C. botulinum and enrich them, which is essential knowledge for assessing the risk of botulism from slug contaminated silage. Slug carcasses, slug feces and live slugs were tested by a quantitative real-time PCR (qPCR) method after being fed ? 5.8 * 104 CFU C. botulinum type C spores/slug. RESULTS: Low amounts of C. botulinum were detected by qPCR in six of 21 slug carcasses with an even spread throughout the 17 day long experiment. Declining amounts of C. botulinum were excreted in slug feces up to day four after the inoculated feed was given. C. botulinum was only quantified the first two days in the sampling of live slugs. The viability of C. botulinum was confirmed for all three sample types (slug carcasses, slug feces and live slugs) by visible growth in enrichment media combined with obtaining a higher quantification cycle (Cq) value than from the non-enriched samples. CONCLUSIONS: Neither dead nor live invasive Arion vulgaris slugs were shown to enrich Clostridium botulinum containing the neurotoxin type C gene in this study. Slugs excreted viable C. botulinum in their feces up to day four, but in rapidly decreasing numbers. Arion vulgaris appear not to support enrichment of C. botulinum type C. PMID- 25277215 TI - Relax, it's just laparoscopy! A prospective randomized trial on heart rate variability of the surgeon in robot-assisted versus conventional laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic surgery might be beneficial for the patient, but it imposes increased physical and mental strain on the surgeon. Robot-assisted laparoscopic surgery addresses some of the laparoscopic drawbacks and may potentially reduce mental strain. This could reduce the risk of surgeon's fatigue, mishaps and strain-induced illnesses, which may eventually improve the safety of laparoscopic surgical procedures. METHODS: To test this hypothesis, a randomized study was performed, comparing both heart rate and heart rate variability (HRV) of the surgeon as a measure of total and mental strain, respectively, during conventional and robot-assisted laparoscopic cholecystectomy. RESULTS: Both heart rate and HRV (the low-frequency band/high frequency band ratio) were significantly decreased when using robotic assistance. CONCLUSIONS: These data suggest the use of the daVinci(r) Surgical System leads to less physical and mental strain of the surgeon during surgery. However, assessing mental strain by means of HRV is cumbersome since there is no clear cutoff point or scale for maximum tolerated strain levels and its related effects on surgeon's health. PMID- 25277216 TI - Synaptic development and neuronal myelination are altered with growth restriction in fetal guinea pigs. AB - This study examines aberrant synaptogenesis and myelination of neuronal connections as possible links to neurological sequelae in growth-restricted fetuses. Pregnant guinea pig sows were subjected to uterine blood flow restriction or sham surgeries at midgestation. The animals underwent necropsy at term with fetuses grouped according to body weight and brain-to-liver weight ratios as follows: appropriate for gestational age (n = 12); asymmetrically fetal growth restricted (aFGR; n = 8); symmetrically fetal growth restricted (sFGR; n = 8), and large for gestational age (n = 8). Fetal brains were perfusion fixed and paraffin embedded to determine immunoreactivity for synaptophysin and synaptopodin as markers of synaptic development and maturation, respectively, and for myelin basic protein as a marker for myelination, which was further assessed using Luxol fast blue staining. The most pertinent findings were that growth restricted guinea pig fetuses exhibited reduced synaptogenesis and synaptic maturation as well as reduced myelination, which were primarily seen in subareas of the hippocampus and associated efferent tracts. These neurodevelopmental changes were more pronounced in the sFGR compared to the aFGR animals. Accordingly, altered hippocampal development involving synaptogenesis and myelination may represent a mechanism by which cognitive deficits manifest in human growth-restricted offspring in later life. PMID- 25277217 TI - Excimer formation in organic emitter films associated with a molecular orientation promoted by steric hindrance. AB - White emission with two sharp strong peaks - a molecular emission peak at 455 nm and an excimer emission peak at 591 nm - was obtained by introducing a terphenyl group into a highly twisted core chromophore, which promoted a molecular orientation in the film state suitable for excimer formation. PMID- 25277220 TI - Effect of water on the thermo-physical properties of Reline: An experimental and molecular simulation based approach. AB - Increasing applications of ionic liquids and their analogues, namely Deep Eutectic Solvents (DESs), requires further investigation into the effect of moisture content on the physico-chemical characteristics of these fluids. Although it is common practice to synthesize these fluids in a moisture controlled environment, as moisture is generally considered to have an impact on their properties, there are no systematic studies on this. We herein examine the effects of water on Reline, a Type-III DES composed of urea and choline chloride. Experiments were performed to obtain the physical properties of aqueous Reline solution. We observed moderate changes in density, speed of sound, refractive index, and pH with increasing water fraction; however, the change in viscosity and conductivity was strong and exponential. In addition, molecular dynamics simulations were performed to analyze the intermolecular interactions of Reline and aqueous Reline solutions. The simulations primarily present the significance of urea-anion interaction to explain the low melting point of the DES. In the presence of water, the anion is preferentially hydrated as compared to urea or the cation. More interestingly, simulations help to classify the effects of water into different regimes. At low water fractions (<5%) the urea-urea interactions are enhanced, as is revealed through the hydrogen bond analysis. Beyond 25% water fractions, the components of Reline are individually hydrated and have high diffusivity, which is further reflected in the change in transport properties. The results presented herein provide valuable information on aqueous Reline solutions both in terms of experimental data and molecular insights, which in turn, we believe, might assist in developing further applications of Reline and other related DESs. PMID- 25277219 TI - What we mean when we talk about MRD in myeloma. A review of current methods. Part 1 of a two-part series. AB - Assessment of minimal residual disease (MRD) is becoming standard of care for potentially curable cancers, like some leukemias. For diseases not currently curable, like multiple myeloma (MM), the optimal methodology to assess MRD is much less clear, let alone the clinical significance. In this two-part series, we review each of these aspects of MRD in MM. In part 1, we review different methodologies available for MRD assessment, with an emphasis on multiparameter flow cytometry (MFC) and duplex immunohistochemistry. There is currently a strong push in the MM community for the use of MFC, based on studies demonstrating MRD negativity by MFC being associated with delayed time to relapse. After participating in a recent international meeting of leaders in the field, convened to discuss this topic, we review and assess the voiced opinions and published data. While great strides have been made toward the standardization of MFC for MRD, we review not only intrinsic biologic differences between MM and leukemia but also the technical challenges that follow from these differences, including the need for live cells, a difficult to characterize immunophenotype, and significant interlaboratory variability in MFC testing and interpretation. PMID- 25277218 TI - Comparison of transverse and modified subtrochanteric femoral shortening osteotomy in total hip arthroplasty for developmental dysplasia of hip: a meta analysis. AB - BACKGROUND: Subtrochanteric femoral shortening osteotomy is a crucial procedure to prevent nerve injury in total hip arthroplasty for severe developmental dysplasia of the hip. Transverse osteotomy was first applied, and other modified methods have also been reported. Each has its own advantages and limitations, but no definitive conclusions regarding differences in outcomes have been reached to date. METHODS: We therefore performed a comprehensive meta-analysis to compare the outcomes of different approaches. 37 studies (795 hips) were included in the final analysis. Meta-analysis, subgroup analysis and meta-regression were performed. RESULTS: Meta-analysis and subgroup analysis showed no significant difference between transverse and modified method. This is further confirmed by meta-regression. Method of osteotomy was found to be not associated with nonunion rate (P = 0.472), as well as other post-operative outcomes including nerve palsy (P = 0.240), dislocation (P = 0.735), revision (P = 0.653) and Harris hip score improvement (P = 0.562). In addition, western countries (P = 0.010) and duration of follow-up more than 5 years (P = 0.014) were associated with higher revision rate. CONCLUSIONS: Transverse osteotomy and modified osteotomy appear to be equivalent in terms of nonunion, safety and efficacy. Transverse osteotomy may be recommended, due to its simplicity and convenience in adjusting the anteversion angle. Well-designed and large-sample-size randomized controlled trials are expected to confirm and update the findings of this analysis. PMID- 25277221 TI - Outcome of cryoballoon ablation for atrial fibrillation. Medium-term follow-up from a single center. AB - OBJECTIVE: We analyzed the medium-term follow-up of cryoballoon ablation (CBA) for atrial fibrillation (AF) and the clinical risk factors predicting outcome. METHODS: AF patients treated for the first time with CBA in a 4.5-year period were studied retrospectively. Pulmonary vein isolation (PVI) was achieved via a single cryoballoon with diameter of 28 mm. Left atrial diameter (LAD) was measured by transthoracic echocardiography. Failure of cryoablation treatment was defined as detection of an episode of AF, atrial flutter, or atrial tachycardia lasting more than 30 s during the 3-month follow-up. RESULTS: A total of 212 patients were enrolled and in 87.7 % patients PVI was achieved by CBA. The complication rate was 2.83 %. The mean follow-up was 28 +/- 15 months; in 166 patients follow-up was complete. The rate of successful treatment for primary CBA was 45.8 %. The percentage of patients who experienced atrial arrhythmia recurrence in the first 12 months was 84.44 %. Patients in whom treatment failed had a larger LAD (47 +/- 6 mm vs. 43 +/- 5 mm, p < 0.0001). The Kaplan-Meier curve showed that the patients with LAD < 45 mm had a higher success rate than patients with LAD >= 45 mm [57.9 % (44/76) vs. 35.6 % (32/90), log rank = 5.492, p = 0.019]. The LAD [odds ratio, OR = - 0.1053(0.303, 12.2040), p = 0.0005] was shown in logistic regression analysis to be independently predictive of CBA treatment failure. CONCLUSION: The CBA procedure for AF patients is safe and effective. Most atrial arrhythmia recurrences occurred during the first 12 months after CBA. The LAD can independently predict failure of CBA treatment. PMID- 25277222 TI - ECG-gated coronary angiography enables submillisievert imaging in invasive cardiology. AB - BACKGROUND: The median dose area products (DAP) and effective doses (ED) of patients arising from coronary angiography (CA) are considerable: According the 2013 National German Registry, they amount to 19.8 Gy * cm(2) and 4.0 mSv, respectively. METHODS: We investigated the feasibility of prospective electrocardiogram (ECG)-gated coronary angiography (CA)-a novel technique in invasive cardiology-with respect to possible reduction in irradiation effects. Instead of universally fix-rated radiographic acquisition within 7.5-15 frames/s, one single frame/heartbeat was triggered toward the diastolic moment immediately before atrial contraction (77 % of ECG-RR interval) most likely to provide motion free and hence optimized resolution of the coronary tree. For 200 patients (body mass index 27.8 kg/m(2), age 67.5 years, male 55 %, 68 bpm) undergoing ECG-gated CA, we measured various median (interquartile range) parameters for radiation exposure. RESULTS: The total DAP was 0.64 (0.46-1.00), radiographic fraction was 0.30 (0.19-0.43), and fluoroscopic fraction was 0.35 (0.21-0.57) Gy * cm(2). Radiographic imaging occurred within 21.7 s (17.1-26.3), with 25 frames (20-30) over the course of 7 runs (6-8). Fluoroscopy time was 119 s (94-141). Radiographic DAP was 12.6 mGy * cm(2)/frame and 13.8 mGy * cm(2)/s. Fluoroscopic DAP was 0.8 mGy * cm(2)/pulse and 3.1 mGy * cm(2)/s. Patient reference point air kerma was 17.0 mGy (11.1-28.1) and contrast volume was 70 ml (60-85). CONCLUSION: In conclusion, invasive ECG-gated coronary imaging is feasible in clinical routine and enables patient EDs of approx. 3 % of typical values in invasive cardiology: 0.13 mSv (0.09-0.20). PMID- 25277223 TI - Hereditary angioedema in Greece: the first results of the greek hereditary angioedema registry. AB - BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients recorded by the Greek Hereditary Angioedema Registry over the last 3 years (July 2010 to June 2013). METHODS: A systematic recording of HAE cases was undertaken following a physician awareness campaign and confirmation of diagnosis. A questionnaire was also used for the assessment of key parameters of the patients' disease-specific quality of life. RESULTS: One hundred and sixteen patients from 41 non-related families were recorded. There were 33 (80.5%) families with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1 inhibitor (C1-INH), non FXII HAE. Two further non-C1-INH, non-FXII HAE sporadic cases were recorded. An investigation of non-symptomatic family members revealed another 6 asymptomatic individuals with C1-INH deficiency. The average delay in diagnosis was 16.5 years and the incidence of death in the families of patients was 1 for every 2 families. The use of newer therapeutic agents seems to fall significantly short of the existing needs. HAE was found to affect the quality of life slightly in 14%, greatly in 63% and significantly in 23% of the patients. CONCLUSION: Until recently, there has been a significant degree of underdiagnosis of HAE in Greece. Very low compliance with the provisions of the applicable international guidelines and consensus positions, with adverse consequences on the patients' quality of life, was also observed. The centralized model we used to uncover the patients could be effective in other countries presenting with comparable disease characteristics. PMID- 25277224 TI - Cross-sectional online survey of research productivity in young Japanese nursing faculty. AB - AIM: To investigate the factors affecting the research productivity of young nursing faculty in Japan. METHODS: An online survey targeting young nursing scholars (aged <= 39 years) who were members of the Japan Academy of Nursing Science was conducted from October to November 2012. Of 1634 potential respondents, 648 completed the survey (39.7%), and 400 full-time faculty of a baccalaureate degree program were selected for the analysis. The numbers of English-language and Japanese publications in the past 3 years were regressed onto personal characteristics, such as academic degree and type of university. RESULTS: The mean numbers of publications in English and Japanese in the past 3 years were 0.41 and 1.63, respectively. Holding a doctoral degree was significantly related to a higher number of publications in English and Japanese (e(beta) = 5.78 and e(beta) = 1.89, respectively). Working at a national university (e(beta) = 2.15), having a research assistant (e(beta) = 2.05), and the ability to read research articles in English (e(beta) = 2.27) were significantly related to more English-language publications. Having the confidence to conduct quantitative research (e(beta) = 1.67) was related to a larger number of Japanese publications. The lack of mentoring (e(beta) = 0.97) and university workload (e(beta) = 0.96) were associated with a lesser number of Japanese publications. CONCLUSION: The research productivity of young nursing faculty appeared to be quite low. Strategies to enhance research productivity in young nursing faculty, such as encouraging the achievement of a doctoral degree or enrichment of research resources, should be undertaken. PMID- 25277225 TI - Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review. AB - Populations living at high altitudes (HA), particularly in the Peruvian Central Andes, are characterised by presenting subjects with erythrocytosis and others with excessive erythrocytosis (EE)(Hb>21 g dl(-1) ). EE is associated with chronic mountain sickness (CMS), or lack of adaptation to HA. Testosterone is an erythropoietic hormone and it may play a role on EE at HA. The objective of the present review was to summarise findings on role of serum T levels on adaptation at HA and genes acting on this process. Men at HA without EE have higher androstenedione levels and low ratio androstenedione/testosterone than men with EE, suggesting low activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and this could be a mechanism of adaptation to HA. Higher conversion of dehydroepiandrosterone to testosterone in men with EE suggests nigher 17beta-HSD activity. Men with CMS at Peruvian Central Andes have two genes SENP1, and ANP32D with higher transcriptional response to hypoxia relative to those without. SUMO specific protease 1 (SENP1) is an erythropoiesis regulator, which is essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1alpha) under hypoxia. SENP1 reverses the hormone-augmented SUMOylation of androgen receptor (AR) increasing the transcription activity of AR.In conclusion, increased androgen activity is related with CMS. PMID- 25277226 TI - N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors. AB - The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol. Four, six, nine and twelve carbon atom alkyl chains have been introduced. The study of two distinct D-gluco and L-ido stereochemistries for the tetrol pattern as well as R and S configurations for the C-2 carbon bearing the C-alkyl chain is reported. We observed that C alkylation of the L-ido tetrahydroxylated azepane converts it from an alpha-L fucosidase to a beta-glucosidase and beta-galactosidase inhibitor while N alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent beta-glucosidase, beta-galactosidase, alpha-L rhamnosidase and beta-glucuronidase inhibitors whatever the stereochemistry of the alkyl chain. Interestingly, the N-alkyl chain length usually parallels the azepane inhibitor potency as exemplified by the identification of a potent glucocerebrosidase inhibitor (Ki 1 MUM) bearing a twelve carbon atom chain. Additionally, several C-alkyl azepanes demonstrated promising F508del-CFTR correction unlike the parent tetrahydroxyazepanes. None of the C-alkyl and N alkyl azepanes did inhibit ER alpha-glucosidases I or II. PMID- 25277227 TI - The river and the sea: fieldwork in human ecology and ethnobiology. AB - This article is a commentary on the experiences that motivated my decision to become a human ecologist and ethnobiologist. These experiences include the pleasure of studying and of having the sense of being within nature, as well as the curiosity towards understanding the world and minds of local people. In particular, such understanding could be driven by addressing the challenging questions that originate in the interactions of such individuals with their natural surroundings. I have been particularly interested in the sea and the riverine forests that are inhabited by coastal or riverine small-scale fishers. Sharing the distinctive world of these fishers enjoyably incited my curiosity and challenged me to understand why fishers and their families 'do as they do' for their livelihoods including their beliefs. This challenge involved understanding the rationality (or the arguments or views) that underlies the decisions these individuals make in their interaction with nature. This curiosity was fundamental to my career choice, as were a number of reading interests. These reading interests included political economy and philosophy; evolution and sociobiology; evolutionary, human, and cultural ecology; cultural transmission; fisheries; local knowledge; ecological economics; and, naturally, ethnobiology. PMID- 25277228 TI - Biocompatibility and functionality of a tissue-engineered living corneal stroma transplanted in the feline eye. AB - PURPOSE: Corneal tissue shortage has become a major concern worldwide, which has motivated the search for alternative solutions to eye bank human eyes for corneal transplantation. Minimally invasive lamellar transplantation and tissue engineering may offer new opportunities for the rehabilitation of diseased corneas. The aim of this study was to evaluate the biocompatibility and functionality of stromal lamellar grafts tissue-engineered (TE) in vitro and transplanted in vivo in the cornea of a feline model. METHODS: The corneal stromas were engineered in culture from corneal stromal cells using the self assembly approach, without the addition of exogenous material or scaffold. Eight healthy animals underwent two intrastromal grafts in one eye and the contralateral eye was used as a control. Animals were followed with slit-lamp ophthalmic examination, corneal esthesiometry and optical coherent tomography. Confocal microscopy, immunofluorescence, histology, and transmission electron microscopy (TEM) were performed at 4 months. RESULTS: Four months after transplantation, the TE-stromal grafts were transparent, functional, and well tolerated by the eye. All grafts remained avascular, with no signs of immune rejection, despite a short course of low-dose topical steroids. Corneal sensitivity returned to preoperative level and reinnervation of the grafts was confirmed by confocal microscopy and immunofluorescence. Histology and TEM of the TE-grafts showed a lamellar stromal structure with regular collagen fibril arrangement. CONCLUSIONS: These results open the way to an entirely new therapeutic modality. Intracorneal filling using a biocompatible, transparent, and malleable TE-stroma could be the basis for multiple types of novel therapeutic options in corneal interventional surgery. PMID- 25277229 TI - Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health. AB - PURPOSE: Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM). METHODS: Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of 11 subjects with ACHM and 7 age-matched controls. Images were obtained, processed, and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure. RESULTS: All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/CNGB3 associated ACHM. CONCLUSIONS: We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerosity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not be expected to add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change. PMID- 25277230 TI - The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. AB - PURPOSE: To investigate the effect of K-115, a novel Rho kinase (ROCK) inhibitor, on retinal ganglion cell (RGC) survival in an optic nerve crush (NC) model. Additionally, to determine the details of the mechanism of K-115's neuroprotective effect in vivo and in vitro. METHODS: ROCK inhibitors, including K-115 and fasudil (1 mg/kg/d), or vehicle were administered orally to C57BL/6 mice. Retinal ganglion cell death was then induced with NC. Retinal ganglion cell survival was evaluated by counting surviving retrogradely labeled cells and measuring RGC marker expression with quantitative real-time polymerase chain reaction (qRT-PCR). Total oxidized lipid levels were assessed with a thiobarbituric acid-reactive substances (TBARS) assay. Reactive oxygen species (ROS) levels were assessed by co-labeling with CellROX and Fluorogold. Expression of the NADPH oxidase (Nox) family of genes was evaluated with qRT-PCR. RESULTS: The survival of RGCs after NC was increased 34 +/- 3% with K-115, a significantly protective effect. Moreover, a similar effect was revealed by the qRT-PCR analysis of Thy-1.2 and Brn3a, RGC markers. Levels of oxidized lipids and ROS also increased with time after NC. NC-induced oxidative stress, including oxidation of lipids and production of ROS, was significantly attenuated by K-115. Furthermore, expression of the Nox gene family, especially Nox1, which is involved in the NC-induced ROS production pathway, was dramatically reduced by K 115. CONCLUSIONS: The results indicated that oral K-115 administration delayed RGC death. Although K-115 may be mediated through Nox1 downregulation, we found that it did not suppress ROS production directly. Our findings show that K-115 has a potential use in neuroprotective treatment for glaucoma and other neurodegenerative diseases. PMID- 25277232 TI - R-spondin1 regulates cell proliferation of corneal endothelial cells via the Wnt3a/beta-catenin pathway. AB - PURPOSE: To evaluate the effect of Roof plate-specific spondin 1 (R-spondin1) on the proliferation of corneal endothelial cells (CECs) and to determine whether the Wnt/beta-catenin pathway is involved in the activities of R-spondin1. METHODS: The proliferation of rabbit CECs (RCECs) and human CECs (HCECs) was measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation into DNA. The effect of R-spondin1 on CEC density was evaluated in ex vivo organ-cultured rabbit and human corneal tissues. The cell density of HCECs cultured with R-spondin1 was also evaluated in vitro. The subcellular localization of function-associated markers of CECs (zona occludens 1 [ZO-1] and Na+/K+-ATPase) was determined by immunohistocytochemistry. The expression of cell cycle proteins and localization of beta-catenin were determined by immunoblotting. RESULTS: The in vitro proliferation of RCECs and HCECs increased by 1.2- to 1.3-fold in response to R spondin1. The CEC densities of rabbit and human corneal tissues were increased significantly by R-spondin1 treatment. Na+/K+-ATPase and ZO-1 were well preserved on the plasma membranes. When HCECs were maintained in the presence of R-spondin1 for up to 90 days, the maximum cell density was observed at approximately 50 days, and the cell density was maintained for up to 90 days. R-spondin1 facilitated the nuclear import of beta-catenin in RCECs within 30 minutes, which subsequently upregulated cyclin D and downregulated p27, leading to G1/S progression by hyperphosphorylation of the retinoblastoma protein. CONCLUSIONS: The unique effects of R-spondin1 on the proliferation of CECs, regardless of species, indicate that R-spondin1 may play a key role in maintaining corneal endothelium homeostasis through the Wnt/beta-catenin pathway. PMID- 25277231 TI - Exposure of a corneal epithelial cell line (hTCEpi) to Demodex-associated Bacillus proteins results in an inflammatory response. AB - PURPOSE: A role for a bacterium, Bacillus oleronius, originally isolated from a Demodex mite, in the induction of ocular rosacea has been proposed. The aim of this work was to characterize the response of a corneal epithelial cell line to Bacillus proteins, as this might give an insight into how such proteins contribute to the symptoms of ocular rosacea in vivo. METHODS: The effect of exposing Bacillus protein preparation on human telomerase-immortalized corneal epithelial cells (hTCEpi) was measured by monitoring changes in cell proliferation and the expression of a number of genes associated with inflammation. The production of inflammatory cytokines was measured and the expression and activity of MMP-9 was quantified. RESULTS: Exposure of hTCEpi cells to 2 or 6 MUg/mL Bacillus protein resulted in a dose-dependent reduction in cell proliferation. Exposure of cells to 6 MUg/mL Bacillus protein did not induce apoptosis, but there was an increase in the expression of genes coding for IL-6 (13.8-fold), IL-1beta (4.0-fold), IL-8 (11.1-fold), and TNF-alpha (4.1-fold). Increased expression of genes coding for the defensins, CCL20 (4.5-fold) and S100A7 (6.8-fold) also was observed. Elevated production of IL-6 and IL-8 was evident from cells exposed to 2 and 6 MUg/mL Bacillus protein. The hTCEpi cells demonstrated increased MMP-9 expression (3.2-fold, P = 0.003) and activity (2.2 fold, P = 0.0186) after 48 hours of exposure to 6 MUg/mL Bacillus protein preparation. CONCLUSIONS: The results suggest that interaction of Demodex associated Bacillus proteins with the corneal surface could lead to tissue degradation and inflammation, possibly leading to corneal scarring. PMID- 25277233 TI - Cerebral microinfarcts in primary open-angle glaucoma correlated with DTI-derived integrity of optic radiation. AB - PURPOSE: To evaluate the correlation between the extent of cerebral white matter lesions (WMLs) and the integrity of the visual pathway represented by fractional anisotropy (FA) in patients with primary open-angle glaucoma (POAG). METHODS: This case-control study included a total of 61 German patients (39 POAG patients, 22 controls) matched for age and sex. Fractional anisotropy of the optic radiation was determined by 3-Tesla diffusion tensor imaging. White matter lesions and brain volumes were manually measured by using a T2-weighted, 3-D fluid-attenuated inversion recovery sequence. RESULTS: In POAG patients WML volumes were significantly (P = 0.04) increased in the subcortical area. This applied for both absolute and relative units to the specific patient's brain volume, compared to controls. The WML volumes were significantly (P = 0.003) greater in middle-aged (40-59 years) POAG patients than control patients. In controls there was a significant age correlation of WML volumes in the total brain, subcortical, and optic radiation regions of interest. There was a significant correlation between FA and WML in POAG regarding the total brain, the periventricular region, and the optic radiation in both hemispheres. In POAG, FA left and right optic radiation correlated significantly with age (P = 0.002). CONCLUSIONS: We were able to demonstrate that (1) POAG patients aged 40 to 60 years had higher volumes of cerebral microinfarcts and (2) POAG patients showed a significant correlation between cerebral microinfarcts and degeneration of the optic radiation. This indicates that cerebral microinfarcts might be an intracerebral risk factor for glaucomatous optic nerve atrophy. PMID- 25277235 TI - The effect of spectral property and intensity of light on natural refractive development and compensation to negative lenses in guinea pigs. AB - PURPOSE: To investigate the effect of spectral composition and light intensity on refractive development in guinea pigs. METHODS: One-week-old guinea pigs were randomly assigned to groups exposed to broad-spectrum Solux halogen light (BS) or spiked-spectrum fluorescent light (FL) at both high (Hi, 10,000 lux) and low (Lo, 500 lux) intensities under a 12:12 light/dark cycle. Half of the animals in each group were used as controls (n = 24, 20, 22, and 20, respectively), and half were fitted with binocular -4-diopter (D) lenses (L, lenses; n = 22, 20, 24, and 22, respectively). Refractive error, corneal curvature, and axial dimensions were determined by cycloplegic retinoscopy, photokeratometry, and A-scan ultrasonography, respectively. RESULTS: Guinea pigs exposed to FL and BS showed similar changes in refraction under both high (HiFL: 2.26 +/- 0.55 D versus HiBS: 2.17 +/- 0.65 D, P > 0.05)- and low-intensity lighting (LoFL: 1.39 +/- 0.88 D versus LoBS: 1.40 +/- 0.93 D, P > 0.05). This was also true for the groups wearing lenses (HiFL-L: -1.81 +/- 0.73 D versus HiBS-L: -1.45 +/- 0.99 D, P > 0.05; LoFL-L: -2.58 +/- 0.65 D versus LoBS-L: -2.29 +/- 0.50 D, P > 0.05). Nevertheless, animals under high-intensity lighting exhibited a significantly larger hyperopic shift compared with those under low-intensity lighting (HiFL versus LoFL: P < 0.01; HiBS versus LoBS: P < 0.05). Similarly, a significantly smaller myopic shift was observed with brighter light in the lens condition (HiFL L versus LoFL-L: P < 0.05; HiBS-L versus LoBS-L: P < 0.05). CONCLUSIONS: In guinea pigs, spectrally spiked light and broad-spectrum light have similar effects on natural refractive development and negative lens compensation. As found in other species, effects of light intensity on refractive development were also observed in guinea pigs in both illuminants. PMID- 25277234 TI - Human limbal mesenchymal cells support the growth of human corneal epithelial stem/progenitor cells. AB - PURPOSE: We tested the viability of human limbal mesenchymal cells (LMCs) to support the expansion of human corneal epithelial stem/progenitor cells (LSCs). METHODS: Human LMCs were isolated from sclerocorneal tissue using collagenase A. Primary limbal epithelial cells (LECs) in the form of single cell suspension or cell clusters were cocultured on a monolayer of either 3T3 cells (control) or LMCs (SC-LMC culture). The LEC clusters also were grown directly on LMCs (CC-LMC culture) and in an optimized 3-dimensional culture method (3D CC-LMC culture). Colony-forming efficiency (CFE) and LEC proliferation were analyzed. The phenotype of the cultured LECs was assessed by their expression level of putative stem cell markers and a differentiation marker by qRT-PCR and immunocytochemistry. RESULTS: The LECs in the SC-LMC culture had a very limited growth and the stem/progenitor phenotype was lost compared to the control. Growth and cell morphology improved using the CC-LMC culture. The 3D CC-LMC culture method was the best to support the growth of the LSC population. Expression of ATP-binding cassette family G2 and DeltaNp63 at the mRNA level was maintained or increased in CC-LMCs and 3D CC-LMC cultures compared to the control. The percentage of the K14(+) and K12(+) cells was comparable in these three cultures. There was no significant difference in the percentage of p63alpha high expressing cells in the control (21%) and 3D CC-LMC culture (17%, P > 0.05). CONCLUSIONS: Human LMCs can substitute 3T3 cells in the expansion of LSCs using the 3 dimensional culture system. PMID- 25277236 TI - Abnormal brain responses to social fairness in depression: an fMRI study using the Ultimatum Game. AB - BACKGROUND: Depression is a prevalent disorder that significantly affects the social functioning and interpersonal relationships of individuals. This highlights the need for investigation of the neural mechanisms underlying these social difficulties. Investigation of social exchanges has traditionally been challenging as such interactions are difficult to quantify. Recently, however, neuroeconomic approaches that combine multiplayer behavioural economic paradigms and neuroimaging have provided a framework to operationalize and quantify the study of social interactions and the associated neural substrates. METHOD: We investigated brain activation using functional magnetic resonance imaging (fMRI) in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic paradigm, the Ultimatum Game (UG). In this task, participants accept or reject monetary offers from other players. RESULTS: In comparison to controls, depressed participants reported decreased levels of happiness in response to 'fair' offers. With increasing fairness of offers, controls activated the nucleus accumbens and the dorsal caudate, regions that have been reported to process social information and responses to rewards. By contrast, participants with depression failed to activate these regions with increasing fairness, with the lack of nucleus accumbens activation correlating with increased anhedonia symptoms. Depressed participants also showed a diminished response to increasing unfairness of offers in the medial occipital lobe. CONCLUSIONS: Our findings suggest that depressed individuals differ from healthy controls in the neural substrates involved with processing social information. In depression, the nucleus accumbens and dorsal caudate may underlie abnormalities in processing information linked to the fairness and rewarding aspects of other people's decisions. PMID- 25277237 TI - Transient thrombosis of mechanical bileaflet aortic valve prosthesis. PMID- 25277239 TI - Not enough cash goes to brain tumour research, doctors say. PMID- 25277238 TI - Pulmonary sarcoid-like granulomatosis after multiple vaccinations of a long-term surviving patient with metastatic melanoma. AB - Autoimmune side effects are frequent in patients with cancer treated with immune checkpoint-targeting antibodies, but are rare with cancer vaccines. Here, we present a case report on a patient with metastatic melanoma who developed pulmonary sarcoid-like granulomatosis following repetitive vaccinations with peptides and CpG. Despite multiple metastases, including one lesion in the brain, the patient is alive and well more than 13 years after the diagnosis of metastatic disease. The strongly activated tumor-specific CD8(+) T cells showed robust long-term memory and effector functions. It is possible that long-term survival and adverse autoimmune events may become more common for vaccines inducing robust anticancer immune responses as were present in this patient. PMID- 25277240 TI - Development and characterization of sorbitan monostearate and sesame oil-based organogels for topical delivery of antimicrobials. AB - The current study explains the development of sorbitan monostearate and sesame oil-based organogels for topical drug delivery. The organogels were prepared by dissolving sorbitan monostearate in sesame oil (70 degrees C). Metronidazole was used as a model antimicrobial. The formulations were characterized using phase contrast microscopy, infrared spectroscopy, viscosity, mechanical test, and differential scanning calorimetry. Phase contrast microscopy showed the presence of needle-shaped crystals in the organogel matrix. The length of the crystals increased with the increase in the sorbitan monostearate concentration. XRD studies confirmed the amorphous nature of the organogels. Viscosity study demonstrated shear thinning behavior of the organogels. The viscosity and the mechanical properties of the organogels increased linearly with the increase in the sorbitan monostearate concentration. Stress relaxation study confirmed the viscoelastic nature of the organogels. The organogels were biocompatible. Metronidazole-loaded organogels were examined for their controlled release applications. The release of the drug followed zero-order release kinetics. The drug-loaded organogels showed almost similar antimicrobial activity against Escherichia coli when compared to the commercially available Metrogyl(r) gel. In gist, it can be proposed that the developed organogels had sufficient properties to be used for controlled delivery of drugs. PMID- 25277241 TI - Overexpression of reactive oxygen species scavenger enzymes is associated with a good prognosis in triple-negative breast cancer. AB - OBJECTIVE: The aim of this study was to investigate the expression of redox proteins in triple-negative breast cancer (TNBC), a breast cancer type which harbors an aggressive phenotype, and to demonstrate the relationships between the expression of reactive oxygen species (ROS) markers and clinical outcome. METHODS: From 2000 to 2005, we analyzed tissue samples from 135 cases of TNBC obtained from curative surgeries at the Severance Hospital, Seoul, South Korea. Immunochemical staining for redox proteins was performed. RESULTS: The median patient age was 48 (range 27-76) years. TNM staging was as follows: T1 (n = 52, 38.5%), T2 (n = 81, 60%), T3 (n = 2, 1.5%), N0 (n = 88, 65.2%), N1 (n = 35, 25.9%), N2 (n = 8, 5.9%) and N3 (n = 4, 3.0%). Median follow-up was 59 (range 12 99) months. The high-expression catalase group tended to have a lower N stage (p = 0.016), lower tumor recurrence (p = 0.02) as well as longer overall survival rates (p = 0.05). After adjusting for patient age as well as tumor and nodal stage, we found that primary breast cancers with high catalase expression levels did not have an improved clinical outcome. A high MTC4 expression in the stroma was strongly associated with increased manganese superoxide dismutase expression (p = 0.015) and a significantly longer overall survival (p = 0.032). CONCLUSION: Considering the lack of targeted molecules as well as molecular heterogeneity of TNBC, ROS markers may provide clues to clinical outcome in TNBC. PMID- 25277242 TI - Expression of the RIP-1 gene and its role in growth and invasion of human gallbladder carcinoma. AB - BACKGROUND AND AIM: Receptor interacting protein(RIP)-1 is thought to have a significant role in inflammation signaling pathways; however, the role of RIP-1 in malignant tumors is largely unknown. METHODS: The present study examined the functions and underlying mechanisms of RIP-1 in gallbladder cancer in vitro and in vivo. In this study we determined the expression and role of RIP-1 in 60 clinical specimens from patients with gallbladder cancer and 3 gallbladder cancer cell lines. Using siRNA targeting RIP-1, plasmid vectors (phU6-EGFP-puro/siRIP-1) were constructed and transfected into the gallbladder cells to characterize the biological effect of RIP-1. Results : In vitro experiments indicated that silencing of RIP-1 in NOZ cells significantly suppressed growth and invasion. Furthermore, silencing of RIP-1 affected the RIP1-NF-kappaB/c-jun(AP-1)-VEGF-C pathways in NOZ cells. Silencing of RIP-1 in vivo inhibited tumor growth in a NOZ cell subcutaneous xenograft model. Immunohistochemstry analysis of the tumor in thesubcutaneous xenograft model also suggested that RIP-1 mediates the expression of VEGF-C. CONCLUSION: We have elucidated therelationship between RIP-1 overexpression and the growth and invasion of gallbladder cancer from clinical specimens using a xenograft model. We provide evidence that a reduction in the expression of RIP-1 in gallbladder cancer cells can exert inhibitory effects on the ability of cells to grow and invade in vitro. Thus, targeting RIP-1may be useful in the treatment of gallbladder cancer. PMID- 25277243 TI - Analysis of differential expression patterns of mRNA and protein during cold acclimation and de-acclimation in Arabidopsis. AB - Overwintering plants are capable of exhibiting high levels of cold tolerance, which is acquired through the process of cold acclimation (CA). In contrast to CA, the acquired freezing tolerance is rapidly reduced during cold de-acclimation (DA) and plants resume growth after sensing warm temperatures. In order to better understand plant growth and development, and to aid in the breeding of cold tolerant plants, it is important to decipher the functional mechanisms of the DA process. In this study, we performed comparative transcriptomic and proteomic analyses during CA and DA. As revealed by shotgun proteomics, we identified 3987 peptides originating from 1569 unique proteins and the corresponding mRNAs were analyzed. Among the 1569 genes, 658 genes were specifically induced at the transcriptional level during the process of cold acclimation. In order to investigate the relationship between mRNA and the corresponding protein expression pattern, a Pearson correlation was analyzed. Interestingly, 199 genes showed a positive correlation of mRNA and protein expression pattern, indicating that both their transcription and translation occurred during CA. However, 226 genes showed a negative correlation of mRNA and protein expression pattern, indicating that their mRNAs were transcribed during CA and were stored for the subsequent DA step. Under this scenario, those proteins were specifically increased during DA without additional transcription of mRNA. In order to confirm the negative correlation of mRNA and protein expression patterns, qRT-PCR and western blot analyses were performed. Mitochondrial malate dehydrogenase 1 (mMDH1) exhibited a negative correlation of mRNA and protein levels, which was characterized by CA-specific mRNA induction and protein accumulation specifically during DA. These data indicate that the expression of specific mRNAs and subsequent accumulation of corresponding proteins are not always in accordance under low temperature stress conditions in plants. PMID- 25277245 TI - Clinical characteristics and preferential location of intracranial mirror aneurysms: a comparison with non-mirror multiple and single aneurysms. AB - INTRODUCTION: The purpose of our study was to compare the clinical characteristics and preferential localization of aneurysms in three patient groups: single aneurysm, non-mirror multiple aneurysms, and mirror aneurysms. METHODS: We retrospectively reviewed the clinical and radiological data of 2223 consecutive patients harboring 3068 aneurysms registered at the Toronto Western Hospital between May 1994 and November 2010. The patients were divided into single, non-mirror multiple, or mirror aneurysm groups. Expected incidences of mirror aneurysms at each location were calculated on the basis of the single aneurysm incidences at each location. RESULTS: Patients with mirror aneurysms (n = 197) did not differ from patients with non-mirror multiple aneurysms (n = 392) in having female predominance (81.7 vs. 76.3 %) or a family history of intracranial aneurysm (20.5 vs. 17.6 %). When compared with expected incidences at each location, mirror aneurysms were more frequently found at the cavernous internal carotid artery (30 vs. 11.5 %) (p < 0.0001). Mirror aneurysms involving the posterior circulation were less frequent (6.7 %) than aneurysms in the single (19.6 %) or non-mirror multiple aneurysm groups (18.9 %) (p < 0.05). CONCLUSION: Patients with mirror aneurysms had similar clinical characteristics to non-mirror multiple aneurysm patients. Mirror aneurysms showed a predilection for the cavernous carotid artery, whereas they were comparatively rare in the posterior circulation. PMID- 25277246 TI - Suspected cerebral foreign body granuloma following endovascular treatment of intracranial aneurysm: imaging features. PMID- 25277244 TI - The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets. AB - Previously, we identified the stress-induced chaperone, Hsp27, as highly overexpressed in castration-resistant prostate cancer and developed an Hsp27 inhibitor (OGX-427) currently tested in phase I/II clinical trials as a chemosensitizing agent in different cancers. To better understand the Hsp27 poorly-defined cytoprotective functions in cancers and increase the OGX-427 pharmacological safety, we established the Hsp27-protein interaction network using a yeast two-hybrid approach and identified 226 interaction partners. As an example, we showed that targeting Hsp27 interaction with TCTP, a partner protein identified in our screen increases therapy sensitivity, opening a new promising field of research for therapeutic approaches that could decrease or abolish toxicity for normal cells. Results of an in-depth bioinformatics network analysis allying the Hsp27 interaction map into the human interactome underlined the multifunctional character of this protein. We identified interactions of Hsp27 with proteins involved in eight well known functions previously related to Hsp27 and uncovered 17 potential new ones, such as DNA repair and RNA splicing. Validation of Hsp27 involvement in both processes in human prostate cancer cells supports our system biology-predicted functions and provides new insights into Hsp27 roles in cancer cells. PMID- 25277247 TI - Surgical revision of hepaticojejunostomy strictures after pancreatectomy. AB - BACKGROUND: After pancreatic surgery hepaticojejunostomy (HJ) stricture is a rare condition. Usually, management is conservative, while operative revision ("redo") is only rarely performed. METHODS: This was an observational cohort design that analyzed the outcome of patients who had a surgical revision of HJ strictures after pancreatic surgery at a specialized pancreatic center. RESULTS: During a period of 7 years from January 2004 until December 2010, 887 patients underwent pancreaticoduodenectomy (PD) or HJ. Among this patient population, 3 % (23/887) underwent a redo of the HJ secondary to stricture formation. Major symptoms of HJ strictures were recurrent cholangitis in 91 % (21/23) and jaundice in 39 % (9/23). The median time from the index operation until redo of the HJ was 16 +/- 27 months. The median survival of patients with malignancy after redo of the HJ was 45 +/- 67 months. Major surgical morbidity was 9 % (2/23), and mortality was 0 % (0/23). In 78 % (18/23), there were no further episodes of cholangitis after a median follow of 49 +/- 73 months, while none of the patients with redo of the HJ developed a restenosis of the HJ. CONCLUSION: Surgical revision (redo) of HJ strictures can be safely performed by an experienced pancreatic surgeon with a low morbidity without mortality with good long-term results. PMID- 25277248 TI - Cancer patients under maintenance hemodialysis: relationship between quality of life, depression, sleep quality and malnutrition-inflammation score. AB - BACKGROUND: The kidney is one major organ affected by cancer and its associated therapies. The aim of this study was to compare the levels of depression, quality of life and sleep quality in hemodialysis patients with or without cancer, and to analyze the associations with the malnutrition-inflammation score (MIS). PATIENTS AND METHODS: In this cross-sectional study, 40 cancer patients under hemodialysis and 44 patients under hemodialysis without cancer who served as the control group were included. Participants underwent structured interviews to investigate depression, quality of life, sleep quality and restless legs syndrome. RESULTS: Hemodialysis patients with cancer had a greater depression score (16.5 +/- 4.8 vs. 10.8 +/- 5.2, p < 0.001). Patients had similar physical and mental composite quality of life scores. Patients under hemodialysis with cancer had poor quality of sleep (mean score 8.8 +/- 3.5 vs. 6.4 +/- 4.1, p = 0.011) and a higher prevalence of restless leg syndrome (55.9 vs. 25.7%, p = 0.011). These features were associated with MIS in patients without cancer but not in patients with cancer. CONCLUSION: Cancer patients undergoing hemodialysis present a higher prevalence of depression, poor quality of life, sleep disorders; however, associations of these features with MIS are different in hemodialysis patients with or without cancer. These findings can change the clinical approach to these patients. PMID- 25277249 TI - The effects of transcranial LED therapy (TCLT) on cerebral blood flow in the elderly women. AB - During aging processes, there is a range of functional changes, where we can highlight the disease related to the central nervous system, such as Alzheimer disease and others forms of dementia. This study investigated the effects of transcranial light emitting diode (LED) on cerebral blood flow in healthy elderly women analyzed by transcranial Doppler ultrasound (TCD) of the right and left middle cerebral artery and basilar artery. Twenty-five noninstitutionalized elderly women (mean age 72 years old), with a cognitive status >24, were assessed using transcranial Doppler ultrasound on two separate occasions: pre-irradiation and post-transcranial LED therapy (TCLT). Prior to this, they answered two questionnaires: the perceived stress scale and the general health questionnaire. TCLT (627 nm, 70 mW/cm(2), 10 J/cm(2)) was performed at four points of the frontal and parietal region for 30 s each, totaling 120 s two times per week for 4 weeks. Paired t-test results showed that there was a significant improvement after TCLT with increase in the systolic and diastolic velocity of the left middle cerebral artery (25 and 30%, respectively) and basilar artery (up to 17 and 25%), as well as a decrease in the pulsatility index and resistance index values of the three cerebral arteries analyzed (p < 0.05). TCD parameters showed improvement in the blood flow on the arteries analyzed. TCLT promoted a blood and vasomotor behavior of the basilar and middle cerebral arteries in healthy elderly women. PMID- 25277250 TI - Effect of C7-substitution of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines on the selectivity towards a subclass of histone deacetylases. AB - This study focused on the substitution effect at position C7 of 1-arylsulfonyl-5 (N-hydroxyacrylamide)indolines. Compound 9, (E)-3-(7-amino-1-(4 methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide, displayed 4- to 14-fold more potent antiproliferative activity than vorinostat (SAHA, 1). Notably, 9 possessed specific histone deacetylase (HDAC) inhibitory activity toward HDAC1 and HDAC2, but had no effect on HDAC6, indicating that 9 has the potential to be developed as a class I HDAC inhibitor. In a xenograft tumor model, 9 suppressed the growth of HCT116 cells at 100 mg kg(-1), which led to a TGI (tumor growth inhibition) of 40.3%. Taken together, the C7 substitutions have a crucial effect on class I HDACs, which is beneficial for synthesizing efficient anticancer agents. PMID- 25277251 TI - GC-MS characterisation and biological activity of essential oils from different vegetative organs of Plectranthus barbatus and Plectranthus caninus cultivated in north Italy. AB - Essential oils (EOs) from the roots, stems and leaves of Plectranthus barbatus (A) and Plectranthus caninus (B), cultivated in north Italy, were obtained by steam distillation and chemically characterised by gas chromatography-mass spectrometry. The highest yields were obtained from roots (268.15 and 673.60 mg/kg from A and B), followed by leaves (64.34 and 26.65 mg/kg) and stems (19.76 and 18.63 mg/kg). A total of 128 structures were identified in A and 121 in B. Fe(++) chelating and antiradical activities (DPPH and ABTS) were evaluated: root and stem EOs showed the strongest activities, while EOs from leaves did not show relevant activities. All EOs were tested for their in vitro antimicrobial activity, showing optimal growth-inhibition in antibiogram (?>35 mm) and MIC tests (32-64 MUg/mL) against Candida albicans, while EOs from leaves of both species showed a good activity (25 < ? < 34 mm, MIC 64-128 MUg/mL) against Escherichia coli. PMID- 25277254 TI - Neuroscience and psychopathology. PMID- 25277253 TI - Smoking behaviour and compensation: a review of the literature with meta analysis. AB - The extent of compensation when switching to lower yield cigarettes is important for assessing risk of reduced yield products. Both completeness of and reasons for compensation are judged differently in the scientific and health community. We quantified compensation in a meta-analysis of suitable cross-sectional and brand-switching studies. For each dataset, we derived a compensation index (CI), 1 indicating complete and 0 no compensation. Meta-analyses provided overall estimates. We also reviewed evidence on compensation for nicotine and other factors. The unweighted mean CI (95% confidence interval) was 0.628 (0.513 to 0.742) from 38 estimates from 26 cross-sectional studies, and 0.723 (0.651 to 0.796) from 23 estimates from 19 brand-switching studies. Inverse-variance weighted estimates were 0.781 (0.720 to 0.842) and 0.744 (0.682 to 0.806). Brand switching data indicate smokers compensate more completely over a narrower yield range. Smokers predominantly compensate by changing puffing volume, and little by changing cigarette consumption. The findings support compensation for nicotine, but other factors may also be relevant. Further investigation is needed using larger studies and different approaches to elucidate their role. We conclude that smokers switching to lower-yield cigarettes only partially compensate. Pharmacological nicotine effects are important, but other factors, including cigarette draw resistance, sensory effects of nicotine and conditioned stimuli may also contribute. PMID- 25277252 TI - Alcohol use disorders negatively influence antiretroviral medication adherence among men who have sex with men in Peru. AB - As international guidelines increase access to antiretroviral therapy (ART) globally, ART adherence becomes increasingly important to achieve HIV treatment as prevention (TasP) goals. In the concentrated HIV epidemic among men who have sex with men (MSM) and transgendered women (TGW) in Lima, Peru, the independent correlates of ART nonadherence were examined to inform treatment intervention priorities. Cross sectional survey of HIV-infected MSM and TGW who are engaged in clinical care in Lima, Peru. From June to August 2012, 302 HIV-infected Peruvian MSM/TGW from three clinical care sites were recruited using convenience sampling to participate in a cross-sectional computer-assisted adherence survey. Several standardized screening measures associated with ART nonadherence were examined in order to determine the independent correlates of optimal (>=90%) and perfect (100%) adherence, which were assessed using logistic regression. Of the 302 participants recruited, 263 (87.1%) were prescribed ART. Among those prescribed ART, 229 (87.1%) reported optimal and 146 (55.5%) reported perfect adherence. The prevalence of alcohol use disorders (AUD; 43.2%), alcohol dependence (5.3%), recent drug use (6.0%), and depression (44.5%) was high, and most participants had some evidence of neurocognitive impairment. Meeting criteria for having an AUD and depression were collinear (p < 0.001). On multivariate analysis, having an AUD was inversely related and the only independent correlate of optimal (AOR = 0.427; 95% CI = 0.187-0.976) and perfect (AOR = 0.552; 95% CI = 0.327-0.930) ART adherence. AUDs are highly prevalent among Peruvian HIV-infected MSM and contribute significantly to ART nonadherence. These findings support the need for screening and treating underlying AUDs. In order to meet HIV TasP goals, evidence based strategies targeting AUDs are likely to directly improve ART adherence and indirectly improve overall individual health, HIV treatment engagement, and reduce transmission to sexual partners among this vulnerable and disproportionally affected population. PMID- 25277255 TI - Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer. AB - BACKGROUND: Castration resistant prostate cancer (CRPC) is a leading cause of cancer-related deaths in men. The primary cause of mortality and morbidity in patients is bone metastases and remodeling resulting in osteoblastic and osteolytic lesions. Recently, cabozantinib, a multi-kinase inhibitor (VEGFR2 and c-MET inhibitor), was shown to have efficacy on bone lesions in patients. In this study we tested multi-kinase inhibitors: axitinib (VEGFR inhibitor) and crizotinib (c-MET inhibitor) in a combination trial in mice models. METHODS: VCaP Luc cells were grown as subcutaneous implants in intact and castrated NOD-SCID gamma (NSG) mice to confirm the androgen dependency. For bone metastasis model two cohorts of NSG mice (castrated and intact) received orthotopic injection of VCaP-Luc cells into the bone marrow cavity of left tibia. Mice were monitored weekly for tumor growth using bioluminescence imaging. Animals were randomized into 4 groups based on the tumor bioluminescence signal: vehicle, crizotinib alone, axitinib alone, crizotinib and axitinib in combination. Animals were imaged weekly by in vivo 2-D X-ray imaging to monitor bone remodeling. At the end of the study animals were euthanized and both tibias were extracted for ex vivo high-resolution 3-D micro-computed tomography (MUCT) imaging. RESULTS: Subcutaneous model showed that androgen stimulation may be helpful but not essential for the growth of VCaP-Luc cells. VCaP-Luc cells grown intra-tibially in intact animals caused extensive remodeling of bone with mixed osteoblastic (bone formation) and osteolytic (bone matrix dissolution) lesions. The osteoblastic lesions were predominant and at times extended beyond the tibial shaft into the surrounding tissue. In contrast, only osteolytic lesions were prominent throughout the study in castrated animals. Treatment with crizotinib alone reduced the osteolytic lesions in castrated animals. Axitinib alone reduced the osteoblastic lesions in the intact animals. Combination therapy with axitinib and crizotinib remarkably inhibited the tibial remodeling by VCaP-Luc cells which resulted in a significant reduction of both osteoblastic and osteolytic lesions. CONCLUSION: Our data show that combined inhibition of c-MET and VEGFR can be beneficial for treatment of metastatic bone disease in CRPC and that the drugs act on two different stages of the disease. PMID- 25277257 TI - The impact of biochar on the bioaccessibility of (14)C-phenanthrene in aged soil. AB - Biochar is a carbon rich product from the incomplete combustion of biomass and it has been shown to reduce bioavailability of organic contaminants through adsorption. This study investigated the influence of 0%, 1%, 5% and 10% of two different particle sized wood biochars (<=2 mm and 3-7 mm) on the bioaccessibility of (14)C-phenanthrene (10 mg kg(-1)) in aged soil. The extent of (14)C-phenanthrene mineralisation by phenanthrene-degrading Pseudomonas sp. inoculum was monitored over a 14 day period in respirometric assays and compared to hydroxypropyl-beta-cyclodextrin (HPCD) aqueous extraction. Notably, biochar amendments showed significant reduction in extents of mineralisation and HPCD extraction. Linear correlations between HPCD extractability and the total amount mineralised revealed good correlations, with 2 mm biochar showing a best fit (r(2) = 0.97, slope = 1.11, intercept = 1.72). Biochar reduced HPCD extractability and bioaccessibility of (14)C-phenanthrene to microorganisms in a similar manner. Biochar can aid risk reduction to phenanthrene exposure to biota in soil and HPCD can serve as a useful tool to assess the extent of exposure in biochar-amended soils. PMID- 25277256 TI - A transcriptomic analysis of Chrysanthemum nankingense provides insights into the basis of low temperature tolerance. AB - BACKGROUND: A major constraint affecting the quality and productivity of chrysanthemum is the unusual period of low temperature occurring during early spring, late autumn, and winter. Yet, there has been no systematic investigation on the genes underlying the response to low temperature in chrysanthemum. Herein, we used RNA-Seq platform to characterize the transcriptomic response to low temperature by comparing different transcriptome of Chrysanthemum nankingense plants and subjecting them to a period of sub-zero temperature, with or without a prior low temperature acclimation. RESULTS: Six separate RNA-Seq libraries were generated from the RNA samples of leaves and stems from six different temperature treatments, including one cold acclimation (CA), two freezing treatments without prior CA, two freezing treatments with prior CA and the control. At least seven million clean reads were obtained from each library. Over 77% of the reads could be mapped to sets of C. nankingense unigenes established previously. The differentially transcribed genes (DTGs) were identified as low temperature sensing and signalling genes, transcription factors, functional proteins associated with the abiotic response, and low temperature-responsive genes involved in post-transcriptional regulation. The differential transcription of 15 DTGs was validated using quantitative RT-PCR. CONCLUSIONS: The large number of DTGs identified in this study, confirmed the complexity of the regulatory machinery involved in the processes of low temperature acclimation and low temperature/freezing tolerance. PMID- 25277258 TI - "Oops! I forgot HIV": resident physician self-audits and universal HIV screening. AB - BACKGROUND: Innovations are needed to increase universal HIV screening by primary care providers. One potential intervention is self-audit feedback, which describes the process of a clinician reviewing their own patient charts and reflecting on their performance. METHODS: The effectiveness of self-audit feedback was investigated using a mixed methods approach. A total of 2111 patient charts were analyzed in a quantitative pre-post intervention study design, where the intervention was providing self-audit feedback to all internal medicine residents at one institution through an annual chart review. Qualitative data generated from the subsequent resident focus group discussions explored the motivation and mechanism for change using a knowledge-attitude-behavior framework. RESULTS: The proportion of primary care patients screened for HIV increased from 17.9% (190/1060) to 40.3% (423/1051). The adjusted odds ratio of a patient being screened following resident self-audited feedback was 3.17 (95% CI 2.11, 4.76, p<0.001). Focus group participants attributed the improved performance to the self-audit feedback. CONCLUSIONS: Self-audit feedback is a potentially effective intervention for increasing universal HIV screening in primary care. This strategy may be most useful in settings where (1) baseline performance is low, (2) behavioral change is provider-driven, and (3) resident trainees are targeted. PMID- 25277259 TI - Relationship between thermal behaviour of lignocellulosic components and properties of biomass. AB - Five different biomass samples were selected for this study, including miscanthus, distillers dried grain (DDG), wheat shorts, wheat straw and UK wood. These samples were thermochemically treated to alter the lignin, cellulose and hemicellulose composition. Thermogravimetric tests were carried out on these samples to determine thermal behaviours of biomass and its individual lignocellulosic components. The relationship between thermal behaviour of biomass and its corresponding lignocellulosic composition was revealed. The reliability of this relationship was proved by thermogravimetric analysis of samples of artificial biomass prepared by mixing commercially obtained lignin, cellulose and hemicellulose at various blending ratios. It is shown that actual biomass profiles can be predicted with some degree of accuracy based on the lignocellulosic composition. PMID- 25277260 TI - Membrane fouling control using a rotary disk in a submerged anaerobic membrane sponge bioreactor. AB - Despite significant research efforts over the last few decades, membrane fouling in anaerobic membrane bioreactors (AnMBRs) remains an unsolved problem that increases the overall operational costs and obstructs the industrial applications. Herein, we developed a method for effectively controlling the membrane fouling in a sponge-submerged AnMBRs using an anaerobic rotary disk MBR (ARMBR). The disk rotation led the effective collision between the sponge and membrane surface; thus successfully enhanced the membrane permeability in the ARMBR. The effect of the disk rotational speed and sponge volume fraction on the membrane permeability and the relationship between the water flow direction and membrane permeability were investigated. The long-term feasibility was tested over 100days of synthetic wastewater treatment. As a result, stable and economical performance was observed without membrane replacement and washing. The proposed integrated rotary disk-supporting media appears to be a feasible and even beneficial option in the AnMBR technology. PMID- 25277261 TI - Biochar enables anaerobic digestion of aqueous phase from intermediate pyrolysis of biomass. AB - Intermediate pyrolysis produces a two-phase liquid whose aqueous phase is characterized by low heating value and high water content (aqueous pyrolysis liquid, APL). Anaerobic digestion can be the straightest way to produce a fuel (methane) from this material. Batch tests showed poor performance in anaerobic digestion of APL, which underlined the inhibition of biological process. Nutrient supplementation was ineffective, whereas biochar addition increased yield of methane (60+/-15% of theoretical) with respect to pure APL (34+/-6% of theoretical) and improved the reaction rate. On the basis of batch results, a semi-continuous biomethanation test was set up, by adding an increasingly amount of APL in a 30ml reactor preloaded with biochar (0.8gml(-1)). With a daily input of 5gd(-1)l(-1) of APL (corresponding to overall amount of 0.1kgl(-1) added before the end of the study) the yield of methane was 65+/-5% of the theoretical. PMID- 25277262 TI - Discovery of a reductase-producing strain recombinant E. coli CCZU-A13 using colorimetric screening and its whole cell-catalyzed biosynthesis of ethyl (R)-4 chloro-3-hydroxybutanoate. AB - An NADH-dependent reductase (SsCR) was discovered by genome data mining. After SsCR was overexpressed in E. coli BL21, recombinant E. coli CCZU-A13 with high reductase activity and excellent stereoselectivity for the reduction of ethyl 4 chloro-3-oxobutanoate (COBE) into ethyl (R)-4-chloro-3-hydroxybutanoate ((R) CHBE) was screened using one high-throughput colorimetric screening strategy. After the reaction optimization, a highly stereoselective bioreduction of COBE into (R)-CHBE (>99% ee) with the resting cells of E. coli CCZU-A13 was successfully demonstrated in n-butyl acetate-water (10:90, v/v) biphasic system. Biotransformation of 600mM COBE for 8h in the biphasic system, (R)-CHBE (>99% ee) could be obtained in the high yield of 100%. Moreover, the broad substrate specificity in the reduction of aliphatic and aromatic carbonyl compounds was also found. Significantly, E. coli CCZU-A13 shows high potential in the industrial production of (R)-CHBE (>99% ee) and its derivatives. PMID- 25277264 TI - Five-minute resolved spatial distribution of radiocesium in sea sediment derived from the Fukushima Dai-ichi Nuclear Power Plant. AB - The spatial distributions of radiocesium concentration in sea sediment to a core depth of 14 cm were investigated in the offshore region from the Fukushima Prefecture to the northern part of the Ibaraki Prefecture in February and July 2012, at a spatial resolution of 5 min of latitude and longitude. The concentrations in the area south of the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) were generally higher than those in the area north of it. In the southern area, a band of especially high concentration with a width about 20 km was present in the region shallower than 100 m, and a narrow minimal concentration band was found along the 200-m isobaths. In more than half of all cases, the vertical core profiles of radiocesium concentration generally showed an exponential decreasing trend with depth. However, in the area north of the FDNPP, where the radiocesium concentrations tended to be very low, radiocesium concentrations that had similar or larger magnitude compared with those of the most-surface layer were often found in deeper layers. Relatively good correlations were found between radiocesium concentrations and grain sizes of the most-surface sediment. The vertical profile of radiocesium concentration also had a relationship with grain size. In other case, the radiocesium concentration in the sediment seems to have had a dependence on the radiocesium concentration in bottom seawater, suggesting that the quantity of radiocesium supplied and the grain size were major factors determining the spatial distribution pattern of the radiocesium concentration after the FDNPP accident. PMID- 25277263 TI - Visualizing the replication of respiratory syncytial virus in cells and in living mice. AB - Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease in calves and young children, yet no human vaccine nor efficient curative treatments are available. Here we describe a recombinant human RSV reverse genetics system in which the red fluorescent protein (mCherry) or the firefly luciferase (Luc) genes are inserted into the RSV genome. Expression of mCherry and Luc are correlated with infection rate, allowing the monitoring of RSV multiplication in cell culture. Replication of the Luc-encoding virus in living mice can be visualized by bioluminescent imaging, bioluminescence being detected in the snout and lungs of infected mice after nasal inoculation. We propose that these recombinant viruses are convenient and valuable tools for screening of compounds active against RSV, and can be used as an extremely sensitive readout for studying effects of antiviral therapeutics in living mice. PMID- 25277265 TI - A retrospective analysis of pregnancy outcomes after kidney transplantation in a single center. AB - BACKGROUND: We reported pregnancy outcomes after kidney transplantation in a single transplant center. METHODS: We reviewed the perinatal outcomes of female kidney transplant patients of reproductive age (18-40 years) from 1987 to 2011. RESULTS: A total of 246 patients were reviewed. Of these, 43 women registered a pregnancy following kidney transplantation. The mean patient age was 31.3 +/- 4.2 years (range 24-40). The mean transplant-conception interval was 35.9 +/- 12.6 months (range 24-120); 9 patients had a cadaveric allograft. The human leukocyte antigen match was >=3/6 for 34 patients. The rate of live births was 29/43 (67.4%), miscarriage 10/43 (23.2%), preterm delivery 7/29 (24.1%), preeclampsia 5/29 (17.2%), and intrauterine growth retardation 2/29 (6.9%). Overall, 3/29 patients (10.3%) received a blood transfusion during pregnancy due to persistent symptomatic anemia, despite iron replacement and erythropoietin therapy; 24 patients (82%) had a cesarean section delivery; 3 patients had kidney rejection during pregnancy, with 2 occurring during the 6th postpartum month. CONCLUSION: Pregnancy should be considered a high risk in renal transplant recipients, necessitating close follow-up. PMID- 25277266 TI - Lactic acid bacteria in dairy food: surface characterization and interactions with food matrix components. AB - This review gives an overview of the importance of interactions occurring in dairy matrices between Lactic Acid Bacteria and milk components. Dairy products are important sources of biological active compounds of particular relevance to human health. These compounds include immunoglobulins, whey proteins and peptides, polar lipids, and lactic acid bacteria including probiotics. A better understanding of interactions between bioactive components and their delivery matrix may successfully improve their transport to their target site of action. Pioneering research on probiotic lactic acid bacteria has mainly focused on their host effects. However, very little is known about their interaction with dairy ingredients. Such knowledge could contribute to designing new and more efficient dairy food, and to better understand relationships between milk constituents. The purpose of this review is first to provide an overview of the current knowledge about the biomolecules produced on bacterial surface and the composition of the dairy matter. In order to understand how bacteria interact with dairy molecules, adhesion mechanisms are subsequently reviewed with a special focus on the environmental conditions affecting bacterial adhesion. Methods dedicated to investigate the bacterial surface and to decipher interactions between bacteria and abiotic dairy components are also detailed. Finally, relevant industrial implications of these interactions are presented and discussed. PMID- 25277267 TI - Low-dose photon irradiation alters cell differentiation via activation of hIK channels. AB - To understand the impact of ionizing irradiation from diagnostics and radiotherapy on cells, we examined K(+) channel activity before and immediately after exposing cells to X-rays. Already, low dose in the cGy range caused in adenocarcinoma A549 cells within minutes a hyperpolarization following activation of the human intermediate-conductance Ca(2+)-activated K(+) channel (hIK). The response was specific for cells, which functionally expressed hIK channels and in which hIK activity was low before irradiation. HEK293 cells, which do not respond to X-ray irradiation, accordingly develop a sensitivity to this stress after heterologous expression of hIK channels. The data suggest that hIK activation involves a Ca(2+)-mediated signaling cascade because channel activation is suppressed by a strong cytosolic Ca(2+) buffer. The finding that an elevation of H2O2 causes an increase in the concentration of cytosolic Ca(2+) suggests that radicals, which emerge early in response to irradiation, trigger this Ca(2+) signaling cascade. Inhibition of hIK channels by specific blockers clotrimazole and TRAM-34 slowed cell proliferation and migration in "wound" scratch assays; ionizing irradiation, in turn, stimulated the latter process presumably via its activation of the hIK channels. These data stress an indirect radiosensitivity of hIK channels with an impact on cell differentiation. PMID- 25277268 TI - The cystic fibrosis transmembrane conductance regulator is an extracellular chloride sensor. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl(-) channel that governs the quantity and composition of epithelial secretions. CFTR function is normally tightly controlled as dysregulation can lead to life-threatening diseases such as secretory diarrhoea and cystic fibrosis. CFTR activity is regulated by phosphorylation of its cytosolic regulatory (R) domain, and ATP binding and hydrolysis at two nucleotide-binding domains (NBDs). Here, we report that CFTR activity is also controlled by extracellular Cl(-) concentration ([Cl( )]o). Patch clamp current recordings show that a rise in [Cl(-)]o stimulates CFTR channel activity, an effect conferred by a single arginine residue, R899, in extracellular loop 4 of the protein. Using NBD mutants and ATP dose response studies in WT channels, we determined that [Cl(-)]o sensing was linked to changes in ATP binding energy at NBD1, which likely impacts NBD dimer stability. Biochemical measurements showed that increasing [Cl(-)]o decreased the intrinsic ATPase activity of CFTR mainly through a reduction in maximal ATP turnover. Our studies indicate that sensing [Cl(-)]o is a novel mechanism for regulating CFTR activity and suggest that the luminal ionic environment is an important physiological arbiter of CFTR function, which has significant implications for salt and fluid homeostasis in epithelial tissues. PMID- 25277269 TI - Growth and by-product profiles of Kluyveromyces marxianus cells immobilized in foamed alginate. AB - The aim of this research was to study how the yeast cell immobilization technique influences the growth and fermentation profiles of Kluyveromyces marxianus cultivated on apple/chokeberry and apple/cranberry pomaces. Encapsulation of the cells was performed by droplet formation from a foamed alginate solution. The growth and metabolic profiles were evaluated for both free and immobilized cells. Culture media with fruit waste produced good growth of free as well as immobilized yeast cells. The fermentation profiles of K. marxianus were different with each waste material. The most varied aroma profiles were noted for immobilized yeast cultivated on apple/chokeberry pomace. PMID- 25277270 TI - Should nocturia not be called a lower urinary tract symptom? PMID- 25277273 TI - Solid-state supramolecular synthesis based on the N-H...O heterosynthon: an approach to solve the polymorphism problem in famotidine. AB - Famotidine (FMT), a histamine H2 -receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single crystal X-ray diffraction reveals that (FMT)(+) in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)(+) side chain. Nonconventional pi stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT. PMID- 25277274 TI - Resting-state functional connectivity in women with Major Depressive Disorder. AB - OBJECTIVE: Limited research has focused on whole-brain functional connectivity in a well-characterized sample of subjects with current Major Depressive Disorder (MDD). We aimed to investigate resting-state functional connectivity and the extent to which this is correlated with depression severity in unmedicated depressed subjects without comorbidities. METHODS: We utilized Independent Component Analysis (ICA) to investigate whole-brain functional connectivity in a sample of healthy controls (n = 26) and unmedicated subjects diagnosed only with current MDD (n = 20). Correlations were calculated between network connectivity strength and depression severity. RESULTS: Depressed subjects demonstrated significantly decreased connectivity in the right frontoparietal (p = 0.03), left frontoparietal (p = 0.01), and language (p = 0.02) networks compared to healthy control subjects. CONCLUSION: We found abnormal resting-state functional connectivity not previously reported in MDD. Decreased connectivity in the frontoparietal and language networks may represent depression-related difficulties in attention, cognitive control, goal-directed cognition, and language. Findings from this study may further elucidate functional connectivity as a diagnostic marker of depression severity. PMID- 25277272 TI - Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation of the Glass Model and Development of a Novel Simplified Prognostic Model. AB - BACKGROUND: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis. OBJECTIVE: To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model. DESIGN, SETTING, AND PARTICIPANTS: NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS). RESULTS AND LIMITATIONS: For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index. CONCLUSION: A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP. PATIENT SUMMARY: We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival. PMID- 25277271 TI - A genome-wide pleiotropy scan for prostate cancer risk. AB - BACKGROUND: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). OBJECTIVE: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: SNPs implicated in any phenotype other than prostate cancer (p<=10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. RESULTS AND LIMITATIONS: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6*10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22*10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86 0.94; p=2.5*10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67*10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. CONCLUSIONS: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology. PATIENT SUMMARY: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified. PMID- 25277276 TI - Relationship between Achilles tendon properties and foot strike patterns in long distance runners. AB - The purpose of this study was to investigate the relationship between Achilles tendon properties and foot strike patterns in long-distance runners. Forty-one highly trained male long-distance runners participated in this study. Elongation of the Achilles tendon and aponeurosis of the medial gastrocnemius muscle were measured using ultrasonography, while the participants performed ramp isometric plantar flexion up to the voluntary maximum. The relationship between the estimated muscle force and tendon elongation during the ascending phase was fit to a linear regression, the slope of which was defined as stiffness. In addition, the cross-sectional area of the Achilles tendon was measured using ultrasonography. Foot strike patterns (forefoot, midfoot and rearfoot) during running were determined at submaximal velocity (18 km . h(-1)) on a treadmill. The number of each foot strike runner was 12 for the forefoot (29.3%), 12 for the midfoot (29.3%) and 17 for the rearfoot (41.5%). No significant differences were observed in the variables measured for the Achilles tendon among the three groups. These results suggested that the foot strike pattern during running did not affect the morphological or mechanical properties of the Achilles tendon in long-distance runners. PMID- 25277275 TI - Variation in 12 porcine genes involved in the carbohydrate moiety assembly of glycosphingolipids does not account for differential binding of F4 Escherichia coli and their fimbriae. AB - BACKGROUND: Glycosphingolipids (GSLs) are important membrane components composed of a carbohydrate structure attached to a hydrophobic ceramide. They can serve as specific membrane receptors for microbes and microbial products, such as F4 Escherichia coli (F4 ETEC) and isolated F4 fimbriae. The aim of this study was to investigate the hypothesis that variation in genes involved in the assembly of the F4 binding carbohydrate moiety of GSLs (i.e. ARSA, B4GALT6, GAL3ST1, GALC, GBA, GLA, GLB1, GLB1L, NEU1, NEU2, UGCG, UGT8) could account for differential binding of F4 ETEC and their fimbriae. RESULTS: RT-PCR could not reveal any differential expression of the 12 genes in the jejunum of F4 receptor-positive (F4R(+)) and F4 receptor-negative (F4R(-)) pigs. Sequencing the complete open reading frame of the 11 expressed genes (NEU2 was not expressed) identified 72 mutations. Although some of them might have a structural effect, none of them could be associated with a F4R phenotype. CONCLUSION: We conclude that no regulatory or structural variation in any of the investigated genes is responsible for the genetic susceptibility of pigs towards F4 ETEC. PMID- 25277277 TI - The immunomodulatory role of bile acids. AB - Enzymatic oxidation of cholesterol generates numerous distinct bile acids which function both as detergents that facilitate the digestion and absorption of dietary lipids and as hormones that activate five distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility, bacterial growth, inflammation, and in the liver-gut axis. This review focuses on the present knowledge regarding the physiologic and pathologic role of bile acids and their immunomodulatory role, with particular attention to bacterial lipopolysaccharides (endotoxins) and bile acid and immunological disorders. The specific role that bile acids play in the regulation of innate immunity, various systemic inflammations, inflammatory bowel diseases, allergy, psoriasis, cholestasis, obesity, metabolic syndrome, alcoholic liver disease, and colon cancer will be reviewed. PMID- 25277278 TI - Prevalence and spectrum of illness among hospitalized adults with malaria in Blantyre, Malawi. AB - BACKGROUND: As control interventions are rolled out, the burden of malaria may shift from young children to older children and adults as acquisition of immunity is slowed and persistence of immunity is short-lived. Data for malaria disease in adults are difficult to obtain because of co-morbid conditions and because parasitaemia may be asymptomatic. Regular surveys of adult admissions to a hospital in Malawi were conducted to characterize the clinical spectrum of malaria and to establish a baseline to monitor changes that occur in future. METHODS: In 2011-2012, at Queen Elizabeth Hospital, Blantyre, four separated one week surveys in the peak malaria transmission period (wet season) and three one week surveys in the low transmission period (dry season) were conducted using rapid diagnostic tests (RDT) with confirmation of parasitaemia by microscopy. All adults (aged >=15) being admitted to the adult medical wards regardless of the suspected diagnosis, were enrolled. Participants with a positive malaria test underwent a standardized physical examination and laboratory tests. Malaria syndromes were characterized by reviewing charts and laboratory results on discharge. RESULTS: 765 adult admissions were screened. 63 (8.2%) were RDT positive with 61 (8.0%) positive by microscopy. Over the course of the seven study weeks, two patients were judged to have incidental parasitaemia, 31 (4.1%) had uncomplicated malaria and 28 (3.7%) had severe malaria. Both uncomplicated and severe malaria cases were more common in the rainy season than the dry season. Prostration (22/28 cases) and hyperparasitaemia (>250,000 parasites/MUl) (9/28) were the most common features of severe malaria. Jaundice (4/28), severe anaemia (2/28), hyperlactataemia (2/28), shock (1/28) and haemoglobinuria (1/28) were less commonly seen, and no patient had severe metabolic derangement or organ failure. There were no deaths attributable to malaria. CONCLUSION: In this study of adults admitted to hospital in southern Malawi, an area with year-round transmission of Plasmodium falciparum, classical metabolic and organ complications of malaria were not encountered. Prostration and hyperparasitaemia were more common indicators of severity in patients admitted with malaria, none of whom died. These data will provide a baseline for monitoring trends in the frequency and clinical patterns of severe malaria in adults. PMID- 25277279 TI - Safety risk categorization of organic extractables associated with polymers used in packaging, delivery and manufacturing systems for parenteral drug products. AB - PURPOSE: To develop and justify a Risk Evaluation Matrix for estimating the safety risk associated with extractables from plastic materials used in pharmaceutical applications and to apply that matrix to approximately 510 extractables to assess the risk that they would accumulate in drug products at levels sufficiently high to affect patient safety. METHOD: The Risk Evaluation Matrix considers toxicological, availability and solubility characteristics of extractables. Safety Risk categories were established based on certain scaled values for these characteristics, Total Risk Scores were calculated for each extractable and the extractables were categorized with respect to their safety risk based on these calculations. RESULTS: The Total Risk Scores were normally distributed around a value of 20 to 23, corresponding to safety risk categories of moderate and intermediate risk. The range in Risk Scores defined by the mean +/- one standard deviation encompassed the entire region of moderate and intermediate risk. Approximately 15% of the extractables were categorized as lowest risk while 3% of the extractables were categorized as highest risk. CONCLUSIONS: Categorization of extractables could facilitate the selection of materials for use in pharmaceutical systems, the analytical testing of extracts and the selection of target extractables. PMID- 25277280 TI - Care transitions: a leverage point for safe and effective medication use in older adults--a mini-review. AB - Older adults often face challenges as they transition out of the acute care hospital, especially with regard to adhering to their medications. In this narrative review, we discuss medication adherence in older adults across the continuum of care, describing reasons for nonadherence, methods to assess adherence and tools to improve adherence, with particular focus on emerging techniques and technologies. Taking steps at care transitions to assess medications and foster adherence to the medication regimen can increase the safety of older adults following hospitalization. PMID- 25277281 TI - Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome. AB - Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30 MUg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1-7 (IC50 = 12.8 +/- 1.5 to 65.2 +/- 4.5 MUM) showed stronger NA inhibitory activity than the tertiary alkaloids 8-10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor-ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth. PMID- 25277282 TI - Experimental public speaking: contributions to the understanding of the serotonergic modulation of fear. AB - Public speaking is widely used as a model of experimental fear and anxiety. This review aimed to evaluate the effects of pharmacological challenges on public speaking responses and their implications for the understanding of the neurobiology of normal and pathological anxiety, specifically panic disorder. We also describe methodological features of experimental paradigms using public speaking as an inducer of fear and stress. Public speaking is a potent stressor that can provoke significant subjective and physiological responses. However, variations in the manners in which public speaking is modelled can lead to different responses that need to be considered when interpreting the results. Results from pharmacological studies with healthy volunteers submitted to simulated public speaking tests have similarities with the pharmacological responses of panic patients observed in clinical practice and panic patients differ from controls in the response to the public speaking test. These data are compatible with the Deakin and Graeff hypothesis that serotonin inhibits fear, as accessed by public speaking tasks, and that this inhibition is likely related to the actions of serotonin in the dorsal periaqueductal grey matter. PMID- 25277284 TI - [Intravesical instillations of colistin in urine infections with multiresistant pathogens]. PMID- 25277286 TI - Layered gadolinium-based nanoparticle as a novel delivery platform for microRNA therapeutics. AB - Specific expression patterns of microRNA (miRNA) molecules have been linked to cancer initiation, progression, and metastasis. The accumulating evidence for the role of oncogenic or tumor-suppressing miRNAs identified the need for nano-scaled platform that can help deliver nucleotides to modulate miRNAs. Here we report the synthesis of novel layered gadolinium hydroxychloride (LGdH) nanoparticles, a member of the layered double hydroxide (LDH) family, with physiochemical properties suitable for cell uptake and tracing via magnetic resonance (MR) imaging. As a proof of concept, we demonstrate the inhibition of mature miRNA-10b in metastatic breast cancer cell line using LGdH nanoparticle as a delivery platform. Through characterization analysis, we show that nanoparticles are easily and stably loaded with anti-miRNA oligonucleotides (AMO) and efficiently penetrate cell membranes. We demonstrate that AMOs delivered by LGdH nanoparticles remain functional by inducing changes in the expression of its downstream effector and by curbing the invasive properties. Furthermore, we demonstrate the traceability of LGdH nanoparticles via T1 weighted MR imaging. LGdH nanoparticles, which are biocompatible with cells in vitro, provide a promising multifunctional platform for microRNA therapeutics through their diagnostic, imaging, and therapeutic potentials. PMID- 25277285 TI - [Unexpected hemorrhage complications in association with celecoxib. Spontaneously reported case series after perioperative pain treatment in gynecological operations]. AB - A series of cases of postoperative bleeding were reported to the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Arzteschaft, AkdA) within the spontaneous reporting system after the regimen for postoperative pain treatment was changed from diclofenac (150 mg per day) to celecoxib (400 mg per day). All patients underwent elective gynecological surgery and 7 out of 11 patients with postoperative bleeding required revision surgery. Although alternative causes for the hemorrhage incidents could not be excluded, the documented circumstances could have been indicative of a possible causal association. Studies on perioperative pain treatment with celecoxib had previously shown no increased risk of hemorrhage. The tendency to hemorrhage observed in the registered cases could not be pharmacologically explained; however, due to the high dosages of celecoxib and the extensive co-medications used, a relative overdosing due to drug interactions or differences in the metabolism of the affected patients was conceivable. Celecoxib is not approved for the treatment of acute postoperative pain although a number of studies were carried out on the effectiveness and safety in patients undergoing surgery. PMID- 25277287 TI - Self-assembly and antimicrobial activity of long-chain amide-functionalized ionic liquids in aqueous solution. AB - Surface active amide-functionalized ionic liquids (ILs) consisting of a long alkyl chain (C6C14) connected to a polar head group (methylimidazolium or pyridinium cation) via an amide functional group were synthesized and their thermal stability, micellar properties and antimicrobial activity in aqueous solution investigated. The incorporation of an amide group increased the thermal stability of the functionalized ionic liquids compared to simple alkyl chain substituted ionic liquids. The surface activity and aggregation behaviour in aqueous solution of amide-functionalized ionic liquids were examined by tensiometry, conductivity and spectrofluorimetry. Amide-functionalized ILs displayed surface activity and their critical micelle concentration (cmc) in aqueous media decreased with the elongation of the alkyl side chain as occurs for typical surfactants. Compared to non-functionalized ILs bearing the same alkyl chain, ionic liquids with an amide moiety possess higher surface activity (pC20) and lower cmc values. The introduction of an amide group in the hydrophobic chain close to the polar head enhances adsorption at the air/water interface and micellization which could be attributed to the H-bonding in the headgroup region. The antimicrobial activity was evaluated against a panel of representative Gram negative and Gram-positive bacteria and fungi. Amide-functionalized ILs with more than eight carbon atoms in the side chain showed broad antimicrobial activity. Antibacterial activities were found to increase with the alkyl chain length being the C12 homologous the most effective antimicrobial agents. The introduction of an amide group enhanced significantly the antifungal activity as compared to non functionalized ILs. PMID- 25277288 TI - Osteoblast activity of MG-63 cells is enhanced by growth on a lactoferrin immobilized titanium substrate. AB - The aim of this study was to develop a lactoferrin (LF)-immobilized titanium (Ti) substrate to enhance the osteoblast activity of MG-63 cells. Ti substrates were first modified through heparin-dopamine (Hep-DOPA) anchorage. Then, LF was immobilized on the Hep-Ti substrates via electrostatic interactions. Hep-Ti substrates, with or without LF, were evaluated by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and contact angle measurements. Sustained release of LF on the Ti substrates was observed over a 28-day period. In vitro studies of osteoblast activity showed increased alkaline phosphatase activity and calcium deposition by MG-63 cells cultured on LF-immobilized Ti substrates as compared to those cultured on pristine Ti substrates, indicating that LF-immobilized Ti substrates were effective at enhancing osteoblast activity. PMID- 25277289 TI - Redox and pH-responsive poly (amidoamine) dendrimer-poly (ethylene glycol) conjugates with disulfide linkages for efficient intracellular drug release. AB - Nanocarriers with low toxicity, high stability, long circulation in blood and triggered drug release at target sites are extremely needed for cancer therapy. In this study, different molar ratios of poly (ethylene glycol) (PEG) were conjugated to poly (amidoamine) dendrimer (PAMAM) by cleavable disulfide bonds, yielding redox and pH dual-responsive nanocarriers (PSSP). The redox sensitivity of the PSSP conjugates was confirmed by measuring the change in particle size and zeta potential under reductive environment by dynamic light scattering (DLS). Meanwhile, all conjugates showed slight hemolytic ratio and high stability in 10% FBS for 24h. Phagocytosis experiments indicated that the PSSP conjugates could effectively escape the engulfment of macrophage. Doxorubicin (DOX) was loaded into the hydrophobic core of the conjugates with loading content of 10%. In vitro release studies suggested that release rate as well as cumulative release amount of DOX from the PSSP conjugates were pronouncedly enhanced in reductive environment as compared with the non-cleavable counterparts. Besides, all conjugates exhibited excellent acid-triggered release performance. Significantly, PEGylation degree of the conjugates had critical impact on drug release. Cytotoxicity tests displayed that DOX-loaded PSSP conjugates were more potent in killing B16 and A549 tumor cells than the non-cleavable counterparts. Curiously, PSSP conjugate with the highest PEGylation degree showed the best antitumor effect despite the somewhat less cell uptake. Therefore, the dual-responsive PSSP conjugates seem promising candidates for efficient intracellular release of antitumor drugs. PMID- 25277290 TI - UV-vis spectra as an alternative to the Lowry method for quantify hair damage induced by surfactants. AB - It is well known that long term use of shampoo causes damage to human hair. Although the Lowry method has been widely used to quantify hair damage, it is unsuitable to determine this in the presence of some surfactants and there is no other method proposed in literature. In this work, a different method is used to investigate and compare the hair damage induced by four types of surfactants (including three commercial-grade surfactants) and water. Hair samples were immersed in aqueous solution of surfactants under conditions that resemble a shower (38 degrees C, constant shaking). These solutions become colored with time of contact with hair and its UV-vis spectra were recorded. For comparison, the amount of extracted proteins from hair by sodium dodecyl sulfate (SDS) and by water were estimated by the Lowry method. Additionally, non-pigmented vs. pigmented hair and also sepia melanin were used to understand the washing solution color and their spectra. The results presented herein show that hair degradation is mostly caused by the extraction of proteins, cuticle fragments and melanin granules from hair fiber. It was found that the intensity of solution color varies with the charge density of the surfactants. Furthermore, the intensity of solution color can be correlated to the amount of proteins quantified by the Lowry method as well as to the degree of hair damage. UV-vis spectrum of hair washing solutions is a simple and straightforward method to quantify and compare hair damages induced by different commercial surfactants. PMID- 25277291 TI - Green synthesis of bacterial gold nanoparticles conjugated to resveratrol as delivery vehicles. AB - Bio-directed synthesis of metal nanoparticles is gaining importance in view of their biocompatibility, low toxicity and eco-friendly characteristics. The present study describes the application of resveratrol conjugated gold nanoparticles as effective delivery vehicles. The green chemistry approach was used for the synthesis of gold nanoparticles by using the culture supernatant of Delftia sp. strain KCM-006. The synthesized gold nanoparticles were mono dispersed, spherical in shape with an average size of 11.3 nm. They were found to be photoluminescent and crystalline in nature with a zeta potential of -25 mV, indicating their high stability. Resveratrol, an anticancer drug, was conjugated to these gold nanoparticles (RSV-AuNP). The cell viability and immunocytochemistry analysis with human lung cancer cell line (A549) demonstrated that RSV-AuNPs were 65% more effective as drug when compared to resveratrol alone. In vitro observations on the drug release from these nanoparticles exhibited pH dependency; the release was significant (95%) under acidic conditions (pH 5.2) when compared to physiological conditions (pH 7.4). PMID- 25277292 TI - Peripheral venoarterial extracorporeal membrane oxygenation in combination with intra-aortic balloon counterpulsation in patients with cardiovascular compromise. AB - OBJECTIVES: Patients with profound cardiovascular compromise have poor prognosis despite inotropic and intra-aortic balloon pump (IABP) support. Peripheral venoarterial extracorporeal membrane oxygenation (V-A ECMO) offers these patients temporary support as a bridge to various options including the 'bridge to recovery'. METHODS: We studied the outcomes of 135 patients who underwent peripheral V-A ECMO and concomitant IABP implantation in our hospital from 2007 to 2012 for various clinical indications. The ECMO circuit consisted of a centrifugal pump and an oxygenator. RESULTS: V-A ECMO was implanted in the cardiac catheterization laboratory in 51 patients (37.8%), at the bedside in 5 (3.7%) and in the operating room in 79 (58.5%). Mean duration of support was 8.5 +/- 7.1 days. Median length of stay was 28 days (interquartile range 14-62). Complications included bleeding at the access site in 14.1%, stroke in 11.1% and vascular complications requiring intervention in 16.3%. Overall inhospital survival was 57.8% with outcomes including heart transplantation (3%), implantable left ventricular assist device (8.1% as bridge to transplantation and 6.7% as destination therapy), surgery (7.4%) and myocardial recovery (40.7%). Prior IABP use and axillary cannulation were independent predictors of reduced inhospital mortality, stroke or vascular injury. CONCLUSIONS: Peripheral V-A ECMO with IABP is an effective therapy for patients with severely compromised cardiovascular function. It offers reasonable survival and a spectrum of definitive options from 'bridge to recovery' to heart transplantation for the management of this critically ill population. PMID- 25277294 TI - Increasing phenotypic and genetic variations in hyperactivity/inattention problems from age 3 to 13 years: a cross-sectional twin study. AB - A twin design was used to examine the developmental nature of genetic, environmental, and phenotypic variations in hyperactivity and inattention problems (HIP). Mothers of 662 complete pairs of twins (273 monozygotic [MZ] pairs and 389 dizygotic [DZ] pairs) aged from 3 to 13 years (mean [SD] age = 8.3 [2.9] years) responded to the items of the HIP scale of the Strengths and Difficulties questionnaire via a telephone interview. Maximum likelihood MZ and DZ twin correlations in the total sample were 0.47 (95% CI: 0.37-0.55) and -0.01 (95% CI: -0.11-0.09). A standard univariate model incorporating age as a modifier was applied to the raw data. Results of model-fitting analyses showed that the phenotypic variation of HIP monotonically increased from age 3 to age 12 and that this increase was completely due to an increase in genetic variance, suggesting that it is genes that expand individual difference in ADHD symptoms with age during childhood. Child-specific environmental variance was constant during this age period. In terms of relative influences, total genetic factors increased from 33% (95% CI: 27-44%) at age 3 to 51% (95% CI: 28-71%) at age 13 and this increase was accompanied by a decrease in relative influences of child-specific environmental factors from 67% (95% CI: 56-73%) at age 3 to 49% (95% CI: 29-72%) at age 13. These estimates of genetic influences were somewhat lower than those found in most twin studies of ADHD symptoms. However, the increasing trend of genetic influences with age during childhood was consistent with the results of a recent meta-analysis of ADHD symptoms. PMID- 25277283 TI - Autism, oxytocin and interoception. AB - Autism is a pervasive developmental disorder characterized by profound social and verbal communication deficits, stereotypical motor behaviors, restricted interests, and cognitive abnormalities. Autism affects approximately 1% of children in developing countries. Given this prevalence, identifying risk factors and therapeutic interventions are pressing objectives-objectives that rest on neurobiologically grounded and psychologically informed theories about the underlying pathophysiology. In this article, we review the evidence that autism could result from a dysfunctional oxytocin system early in life. As a mediator of successful procreation, not only in the reproductive system, but also in the brain, oxytocin plays a crucial role in sculpting socio-sexual behavior. Formulated within a (Bayesian) predictive coding framework, we propose that oxytocin encodes the saliency or precision of interoceptive signals and enables the neuronal plasticity necessary for acquiring a generative model of the emotional and social 'self.' An aberrant oxytocin system in infancy could therefore help explain the marked deficits in language and social communication as well as the sensory, autonomic, motor, behavioral, and cognitive abnormalities seen in autism. PMID- 25277293 TI - High-performance two-ply yarn supercapacitors based on carbon nanotube yarns dotted with Co3 O4 and NiO nanoparticles. AB - Yarn supercapacitors are promising power sources for flexible electronic applications that require conventional fabric-like durability and wearer comfort. Carbon nanotube (CNT) yarn is an attractive choice for constructing yarn supercapacitors used in wearable textiles because of its high strength and flexibility. However, low capacitance and energy density limits the use of pure CNT yarn in wearable high-energy density devices. Here, transitional metal oxide pseudocapacitive materials NiO and Co3 O4 are deposited on as-spun CNT yarn surface using a simple electrodeposition process. The Co3 O4 deposited on the CNT yarn surface forms a uniform hybridized CNT@Co3 O4 layer. The two-ply supercapacitors formed from the CNT@Co3 O4 composite yarns display excellent electrochemical properties with very high capacitance of 52.6 mF cm(-2) and energy density of 1.10 MUWh cm(-2) . The high performance two-ply CNT@Co3 O4 yarn supercapacitors are mechanically and electrochemically robust to meet the high performance requirements of power sources for wearable electronics. PMID- 25277295 TI - The divided communities of shared concerns: mapping the intellectual structure of e-Health research in social science journals. AB - PURPOSE: Social scientific approach has become an important approach in e-Health studies over the past decade. However, there has been little systematical examination of what aspects of e-Health social scientists have studied and how relevant and informative knowledge has been produced and diffused by this line of inquiry. This study performed a systematic review of the body of e-Health literature in mainstream social science journals over the past decade by testing the applicability of a 5A categorization (i.e., access, availability, appropriateness, acceptability, and applicability), proposed by the U.S. Department of Health and Human Services, as a framework for understanding social scientific research in e-Health. METHODS: This study used a quantitative, bottom up approach to review the e-Health literature in social sciences published from 2000 to 2009. A total of 3005 e-Health studies identified from two social sciences databases (i.e., Social Sciences Citation Index and Arts & Humanities Citation Index) were analyzed with text topic modeling and structural analysis of co-word network, co-citation network, and scientific food web. RESULTS: There have been dramatic increases in the scale of e-Health studies in social sciences over the past decade in terms of the numbers of publications, journal outlets and participating disciplines. The results empirically confirm the presence of the 5A clusters in e-Health research, with the cluster of applicability as the dominant research area and the cluster of availability as the major knowledge producer for other clusters. The network analysis also reveals that the five distinctive clusters share much more in common in research concerns than what e-Health scholars appear to recognize. CONCLUSIONS: It is time to explicate and, more importantly, tap into the shared concerns cutting across the seemingly divided scholarly communities. In particular, more synergy exercises are needed to promote adherence of the field. PMID- 25277297 TI - MRS features during encephalopathic crisis period in 11 years old case with GA-1. AB - Glutaric aciduria type-1 (GA-1) is a disorder of amino acid metabolism. The usual clinical-onset is an acute encephalopathic crisis in early childhood. There are only a few cases diagnosed in older age groups. MRI features of the disease are well defined. However, there are limited number of studies concerning advanced neuroimaging findings. We present DWI and MRS findings of an 11 year-old GA-1 patient admitted with an encephalopathic crisis. Diffusion restrictions in bilateral basal ganglia, corpus callosum and periventricular deep white matter were observed. In left occipital periventricular white matter and left basal ganglia, mild increased Cho/Cr and MI/Cr ratios and decreased NAA/Cr ratio were detected. Also inverted double lactate peak (TE: 135 ms) was present at 1.33 ppm in the left basal ganglia. In addition to these findings, a peak at 1.56 ppm above the baseline was seen on both short and long echo-time MRS in left occipital lobe deep white matter which may show accumulation of degradation products of amino acids in the GCDH enzyme deficiency. PMID- 25277296 TI - Differential diagnosis of delirious behavior in children with influenza. AB - Delirious behavior (DB) in children infected with influenza virus is an important symptom associated with encephalopathy. As children with influenza-associated DB with encephalopathy may require therapy whereas children with influenza associated DB without encephalopathy do not, distinguishing between these conditions is essential. To clarify these differences and identify the most common features of acute encephalopathy, we retrospectively reviewed the clinical course, laboratory data, magnetic resonance imaging (MRI) and electroencephalography (EEG) findings, therapy, and prognosis of 48 children with influenza exhibiting DB. Of the 48 children, 37 and 11 were diagnosed with influenza A and B, respectively. Moreover, 40 were diagnosed with DB without encephalopathy (DBNE group) and 8, with DB with encephalopathy (DBE group). Reversible splenial lesion (RESLE) was detected in 7 patients in the DBNE group, mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in 2 patients, and a mild form of acute encephalopathy with biphasic seizures and late reduced diffusion in 1 patient in the DBE group. Serum sodium levels <136mEq/L were observed in 28 cases. Disturbance of consciousness was observed in 25 cases, seizure in 20, and slow waves on EEG in 22. Methylprednisolone pulse therapy was administered in 8 cases. No cases of neurological sequelae were observed. Although most of the clinico-radiological features of the DBNE and DBE groups did not differ substantially, marked differences were observed in the age at onset, initial neurological symptoms, duration of DB, rate of seizure, and slowing of background activity on EEG. These differences should be considered when distinguishing between DBNE and DBE in children. PMID- 25277299 TI - Identification of a pentatricopeptide repeat RNA editing factor in Physcomitrella patens chloroplasts. AB - The moss Physcomitrella patens has two RNA editing sites in the chloroplasts. Here we identified a novel DYW-subclass pentatricopeptide repeat (PPR) protein, PpPPR_45, as a chloroplast RNA editing factor in P. patens. Knockdown of the PpPPR_45 gene reduced the extent of RNA editing at the chloroplast rps14-C2 site, whereas over-expression of PpPPR_45 increased the levels of RNA editing at both the rps14-C2 site and its neighboring C site. This indicates that the expression level of PpPPR_45 affects the extent of RNA editing at the two neighboring sites. PMID- 25277298 TI - The role of intrinsic apoptotic signaling in hemorrhagic shock-induced microvascular endothelial cell barrier dysfunction. AB - Hemorrhagic shock leads to endothelial cell barrier dysfunction resulting in microvascular hyperpermeability. Hemorrhagic shock-induced microvascular hyperpermeability is associated with worse clinical outcomes in patients with traumatic injuries. The results from our laboratory have illustrated a possible pathophysiological mechanism showing involvement of mitochondria-mediated "intrinsic" apoptotic signaling in regulating hemorrhagic shock-induced microvascular hyperpermeability. Hemorrhagic shock results in overexpression of Bcl-2 family of pro-apoptotic protein, BAK, in the microvascular endothelial cells. The increase in BAK initiates "intrinsic" apoptotic signaling cascade with the release of mitochondrial cytochrome c in the cytoplasm and activation of downstream effector caspase-3, leading to loss of endothelial cell barrier integrity. Thus, this review article offers a brief overview of important findings from our past and present research work along with new leads for future research. The summary of our research work will provide information leading to different avenues in developing novel strategies against microvascular hyperpermeability following hemorrhagic shock. PMID- 25277301 TI - Reply to: 'Glaucoma prescribing trends in England 2000 to 2012'. PMID- 25277302 TI - The incidence of serious complications associated with intravitreal therapy in a quaternary ARMD service (2008-2014). PMID- 25277300 TI - Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus. AB - This review aims to assess the efficacy and safety of epithelial removal (ER) and transepithelial (TE) corneal collagen crosslinking (CXL) for the treatment of keratoconus. We used MEDLINE to identify all ER and TE CXL studies on keratoconic eyes (n>=20, follow-up >=12 months). Ex vivo and studies for non-keratoconus indications or in conjunction with other procedures were excluded. Data on uncorrected (UDVA) and corrected (CDVA) distance visual acuity, refractive cylinder, maximum keratometry (Kmax), and adverse events were collected at the latest follow-up and 1 year. Only one randomised controlled trial (RCT) qualified inclusion. Forty-four ER and five TE studies were included. For logMAR UDVA, CDVA, mean spherical equivalent, refractive cylinder and Kmax, at latest follow up 81, 85, 93, 62, and 93% ER studies vs 66.7, 80, 75, 33, and 40% TE studies reported improvement, respectively. Whereas at 1 year, 90, 59, and 91% ER studies vs 80, 50, and 25% TE studies reported improvement, respectively. The majority of studies showed reduced pachymetry in both groups. Treatment failure, retreatment rates, and conversion to transplantation were reported to be up to 33, 8.6, and 6.25%, respectively, in ER studies only. Stromal oedema, haze, keratitis, and scarring were only reported in ER studies, whereas endothelial cell counts remained variable in both groups. Both ER and TE studies showed improvement in visual acuity, refractive cylinder but Kmax worsened in most TE studies. Adverse events were reported more with ER studies. This review calls for more high quality ER and TE studies with comparable parameters for further assessment of safety and efficacy. PMID- 25277304 TI - Association of choroidal thickness with eye growth: a cross-sectional study of individuals between 4 and 23 years. AB - BACKGROUND AND AIMS: We aimed to evaluate the association of subfoveal choroidal thickness (SFCT) with age and to determine its relationship with axial length (AL) and ocular biometric parameters, in children and young adults during growth period. METHODS: One hundred and sixty patients (80 male, 80 female) aged between 4 and 23 years were included. Patients were classified into five groups according to their ages as group 1 (4-7 years of age), group 2 (8-11 years), group 3 (12-15 years), group 4 (16-19 years), and group 5 (20-23 years). SFCT was assessed using spectral-domain optical coherence tomography (3D OCT-2000). The measurements were taken at the same daytime (1000-1200 hours) to avoid diurnal fluctuation. Ocular AL and anterior segment parameters were measured using optical biometry (Lenstar LS900)). RESULTS: The average SFCT was 308.1+/-47.6 MUm, ranging from 206 to 410 MUm. The mean SFCT values in group 1 to 5 were measured as 306.8+/-42.0, 297.8+/ 48.1, 283.2+/-38.9, 326.9+/-57.4, and 325.8+/-35.9 MUm, respectively. The mean CT of group 3 was significantly thinner than group 4 and 5 (P<0.05 for two groups), however, there was no statistical significance compared with group 1 (P=0.227) and group 2 (P=0.693). On stepwise regression analysis, age exhibited a positive association with SFCT (B=2.8, P<0.001) and AL exhibited a negative association with choroidal thickness (B=-16.7, P<0.001). CONCLUSIONS: We found that SFCT shows no age-related difference until age of 15, whereas 16-23-year old participants had thicker SFCT compared with the younger ones. In that aspect, a thicker choroid associated with age in certain age groups suggests an age period of SFCT increase to a plateau in young adulthood. Larger studies are warranted to elucidate the age-related changes in SFCT in childhood, as improved evaluation of normal choroidal thicknesses during eye growth should assist in the diagnosis of choroidal abnormalities associated with eye disease. PMID- 25277303 TI - Choroidal thickness in regressed retinopathy of prematurity. AB - PURPOSE: To compare choroidal thickness in patients with regressed retinopathy of prematurity (ROP) with healthy controls using enhanced depth imaging optical coherence tomography (EDI OCT) METHODS: Twenty-four children and young adults (41 eyes) with regressed ROP>=stage 3 had undergone EDI OCT with Spectralis FD-OCT as part of their clinical record. Their refraction, best-corrected visual acuity, and ophthalmoscopic findings were recorded. Corresponding data was collected prospectively from 33 healthy controls (58 eyes) who had been born at term. Choroidal thickness was measured independently by two observers subfoveally and at 1500 MUm nasal and temporal to the fovea using EDI OCT. RESULTS: Mean subfoveal choroidal thickness, adjusted for refraction, was 271.1 MUm (95% CI, 247.8-294.5) in the ex-ROP group, which was significantly thinner than 327.4 MUm (95% CI, 293.8-360.9) in controls (P=0.008). Similarly, mean adjusted temporal choroidal thickness was 257.2 MUm (95% CI, 240.2-274.2) in ex-ROP's vs 320.5 MUm (95% CI, 288.6-352.3) in controls (P=0.001). There was no statistically significant difference in the nasal measurement. In the ex-ROP group, there was no significant correlation between subfoveal choroidal thickness and gestational age (r(s)=0.16, P=0.46) or birthweight (r(s)=0.03, P=0.90). In eyes without copathology in addition to regressed ROP (29 eyes, 19 patients), there was no significant correlation between subfoveal choroidal thickness and visual acuity. CONCLUSIONS: Our findings of thinner subfoveal and temporal macular choroidal thickness in regressed ROP support the case for choroidal involvement in the pathogenesis of this condition. PMID- 25277307 TI - Comment on 'The effect of erythropoietin on the severity of retinopathy of prematurity'. PMID- 25277306 TI - Peripheral hypertrophic subepithelial corneal degeneration presenting with bilateral nasal and temporal corneal changes. AB - PURPOSE: To characterise the history, clinical and histopathological features of patients with bilateral nasal and temporal peripheral hypertrophic subepithelial corneal degeneration in a German population. METHODS: A detailed ophthalmological and dermatological history and clinical findings were recorded of nine patients with bilateral simultaneous nasal and temporal peripheral corneal degeneration from two centers in Germany. Excised tissues were studied by histopathology, immunohistochemistry, and transmission electron microscopy. RESULTS: Foreign body sensation and need of artificial tear substitutes were the only symptoms reported regularly. Schirmer's and Jones-test were normal in all, but fluorescein break-up time of >10 s was found in five eyes of four patients. Best corrected visual acuity was reduced only under glare conditions. Corneal topography revealed irregular astigmatism in 13 of 14 eyes. Follow-up median time was 35 months. Most cases were stable within the follow-up period. Light and electron microscopy revealed the findings of superficial vascularised corneal hypertrophic scars, oxytatlan fibers, and discontinued Bowmans layer. CONCLUSION: In this series of German patients with peripheral hypertrophic subepithelial corneal degeneration, the changes were predominantly located in the palpebral aperture and often present in both eyes. No associated surface disease could be established in this study. Light and transmission electron microscopy showed histological features that are similar to Salzmann's corneal changes without any inflammation. We hypothesise that light exposure and a localised limbal insufficiency could be involved in the pathogenesis. PMID- 25277305 TI - Earlier therapeutic effects associated with high dose (2.0 mg) Ranibizumab for treatment of vascularized pigment epithelial detachments in age-related macular degeneration. AB - SUMMARY STATEMENT: Intravitreal high dose (2 mg) ranibizumab may lead to quicker resolution of choroidal neovascularization (CNV) and associated retinal pigment epithelial detachment in eyes with exudative age-related macular degeneration, although it may possibly correlate with RPE tears in certain cases. PURPOSE: This prospective study compared the outcomes of 0.5 vs 2.0 mg intravitreal ranibizumab injections (RI) for treating vascularized pigment epithelial detachment (vPED) due to age-related macular degeneration. METHODS: Patients with vPED were randomized to receive 2.0 vs 0.5 mg RI monthly for 12 months or for 4 months and then repeated on a pro-re nata basis. Optical coherence tomography, fundus photography, and fluorescein and indocyanine-green angiography were obtained at baseline and subsequent specific intervals. Outcome measures were best-corrected standardized visual acuities, central 1-mm thickness, surface area (SA), greatest linear diameter (GLD), heights (PED and CNV), and amount of subretinal fluid (SRF) and cystoid macular edema (CME). RESULTS: Both groups yielded reductions of the central 1-mm thickness, PED and CNV SA and PED height and GLD, SRF, and CME. Vision improvement and reduction in SRF and PED height occurred earlier for eyes receiving the 2.0 mg dose. Cataract progression was similar but RPE tears developed more often with the 2.0 mg dose. CONCLUSIONS: There were similar visual and anatomical outcomes at the end of the study; however, the higher dose yielded more rapid reductions and more complete resolution of the PED, although there was possible increased tendency for an RPE tear with the higher dose. PMID- 25277308 TI - FPR1 interacts with CFH, HTRA1 and smoking in exudative age-related macular degeneration and polypoidal choroidal vasculopathy. AB - PURPOSE: To determine the genetic association of an inflammation-related gene, formyl peptide receptor 1 (FPR1), in exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: The coding region of FPR1 gene was sequenced in 554 unrelated Chinese individuals: 155 exudative AMD patients, 179 PCV patients, and 220 controls. Interactions and combined effects of FPR1 with complement factor H (CFH), high temperature requirement factor A1 (HTRA1), and smoking were also investigated. RESULTS: A total of 28 polymorphisms in FPR1 were identified. Single nucleotide polymorphisms (SNP) rs78488639 increased the risk to exudative AMD (P=0.043) and PCV (P=0.016), whereas SNP rs867229 decreased the risk to exudative AMD (P=0.0026), but not PCV. Homozygous G allele of rs1042229 was associated with exudative AMD (P=0.0394, odds ratio (OR)=2.27, 95% confident interval: 1.08-4.74), but not with PCV. Exudative AMD, but not PCV, was associated with the heterozygous genotypes of rs2070746 (P=0.019, OR=0.57) and rs867229 (P=0.0082, OR=0.54). Significantly, interactions were identified among FPR1 rs78488639, CFH rs800292, and HTRA1 rs11200638 in both exudative AMD and PCV. Combined heterozygous risk alleles of CFH rs800292 GA and FPR1 rs78488639 CA were posed to PCV (P=2.22 * 10(-4), OR=10.47), but not exudative AMD. Furthermore, FPR1 rs78488639 CA combining with HTRA1 rs11200638 and smoking was also predisposed risks to exudative AMD and PCV. CONCLUSION: FPR1 is associated with exudative AMD and PCV in a Hong Kong Chinese cohort. FPR1 rs78488639 interacted with CFH rs800292, HTRA1 rs11200638, and smoking, enhancing risk to exudative AMD and PCV. PMID- 25277309 TI - Variations in the cone packing density with eccentricity in emmetropes. AB - AIM: To describe the parafoveal cone arrangement in emmetropic subjects and its variations with eccentricity, meridians and change in axial length in Indian eyes. METHODS: We imaged 25 subjects using compact adaptive optics (AO) retinal camera prototype, the rtx1. Imaging was done at 1, 2, and 3 degrees eccentricity from the fovea in four meridians: nasal, temporal, superior, and inferior. RESULTS: A statistically significant drop in the cone packing density was observed from 2 to 3 degrees (2 degrees eccentricity=25 350/mm(2) (5300/mm(2), 8400-34 800/mm(2)) 3 degrees eccentricity=20 750/mm(2) (6000 mm(2), 9000-33 670/mm(2))) P<0.05. The spacing correspondingly increased with increase in distance from the fovea (2 degrees eccentricity=6.9 MUm (0.70 MUm, 5.95-11.6 MUm)) and 3 degrees eccentricity=7.80 MUm (1.00 MUm, 6.5-13.5 MUm) P<0.05. As the axial length increases, the cone density significantly decreases. Interocular variations were noted. CONCLUSION: With the advent of AO, visualization at the cellular level is now possible. Understanding the photoreceptor mosaic in the parafoveal space in terms of its density, spacing, and arrangement is crucial so as to detect early pathology and intervene appropriately. Newer therapeutic modalitites that are targeted at the cellular level like yellow micropulse laser, stem cells, gene therapy and so on may be better monitored in terms of safety and efficacy. PMID- 25277310 TI - The use of early postoperative prostate-specific antigen to stratify risk in patients with positive surgical margins after radical prostatectomy. AB - BACKGROUND: It is well recognized that the presence of positive surgical margins (PSM) after radical prostatectomy (RP) adversely affects cancer specific outcomes and recent evidence from randomized trials supports the use of adjuvant radiotherapy in these cases. However, not all of the patients with PSM develop disease recurrence and the policy of adjuvant radiation could result in considerable over-treatment. We investigated the ability of early postoperative prostate specific antigen (PSA) and PSA decline rates to stratify the risk of disease progression during the first weeks after the surgery thereby allowing adequate time for planning eventual adjuvant therapy. METHODS: We studied 116 consecutive patients with the finding of PSM after RP for localized prostate cancer between 2001 and 2012. No patients were treated with radiation or hormonal therapy. An intensive postoperative PSA monitoring using ultrasensitive assay started first at day 14 after the surgery, then at day 30, 60, 90 and 180, and subsequently in 3 monthly intervals. Biochemical recurrence (BCR) presented the failure of surgical treatment and it was defined as PSA >=0.2 ng/ml. The ability of PSA decline parameters to predict BCR was assessed using Cox regression model and area under the curve (AUC) calculation. RESULTS: Overall 55 (47%) patients experienced BCR during median follow-up of 31.4 months (range 6-69). Preoperative PSA, pathologic Gleason sum and pathologic grade failed to reveal any association with observation of BCR. Postoperative PSA levels achieved significant predictive accuracy already on day 30 (AUC 0.74). PSA >0.073 ng/ml at day 30 increased significantly the risk of BCR (HR 4.35, p < 0.001). Predictive accuracy was significantly exceeded on day 60 (AUC 0.84; p < 0.001), while further enhancements on day 90 (AUC 0.84) and 180 (AUC 0.91) were not significant. CONCLUSIONS: The level of ultrasensitive PSA yields valuable information about the prostatectomy outcome already at the first month after the surgery and should aid risk stratification in patients with PSM. Patients not likely to experience subsequent disease progression may be spared the toxicity of immediate adjuvant radiotherapy. PMID- 25277311 TI - HLA dosage effect in narcolepsy with cataplexy. AB - Narcolepsy with cataplexy is a sleep disorder caused by the loss of hypocretin producing neurons in the hypothalamus. It is tightly associated with a specific human leukocyte antigen (HLA)-allele: HLA-DQB1*06:02. Based on this, an autoimmune process has been hypothesized. A functional HLA-DQ molecule consists of a DQalpha and a DQbeta chain. HLA-DQB1*06:02 (DQbeta) has a strong preference for binding to HLA-DQA1*01:02 (DQalpha), and together they form the functional DQ0602 dimer. A dosage effect would be expected if the HLA-DQ0602 dimer itself is directly involved in the aetiology. An increased expression of the HLA-DQ0602 dimer is expected in individuals homozygous for HLA-DQB1*06:02-DQA1*01:02, but is also hypothesized in individuals heterozygous for HLA-DQB1*06:02 and homozygous for HLA-DQA1*01:02. To study the impact of the expression of the HLA-DQ0602 dimer on narcolepsy susceptibility, 248 Dutch narcolepsy patients and 1272 Dutch control subjects, all of them positive for DQB1*06:02 (heterozygous and homozygous), were HLA-genotyped with attention not only to DQB1 but also to DQA1*01:02. DQB1*06:02-DQA1*01:02 homozygosity was significantly more often seen in patients compared to controls (O.R. 2.29) confirming previous observations. More importantly, a significantly higher prevalence of homozygosity for DQA1*01:02 was found in HLA-DQB1*06:02 heterozygous patients compared to controls (O.R. 2.37, p < 0.001). The latter finding clearly supports a direct role of the HLA-DQ molecule in the development of disease. PMID- 25277312 TI - California Breast Cancer Prevention Initiatives: Setting a research agenda for prevention. AB - The environment is an underutilized pathway to breast cancer prevention. Current research approaches and funding streams related to breast cancer and the environment are unequal to the task at hand. We undertook the California Breast Cancer Prevention Initiatives, a four-year comprehensive effort to set a research agenda related to breast cancer, the environment, disparities and prevention. We identified 20 topics for Concept Proposals reflecting a life-course approach and the complex etiology of breast cancer; considering the environment as chemical, physical and socially constructed exposures that are experienced concurrently: at home, in the community and at work; and addressing how we should be modifying the world around us to promote a less carcinogenic environment. Redirecting breast cancer research toward prevention-oriented discovery could significantly reduce the incidence and associated disparities of the disease among future generations. PMID- 25277314 TI - Congenital fulminant Kaposiform hemangioendothelioma of the leg. AB - Kaposiform hemangioendothelioma is a rare locally aggressive vascular tumor associated with Kasabach Merritt syndrome. We present a case of congenital Kaposiform hemangioendothelioma of the leg in a female infant who was born to a mother treated with various medications including etanercept, a TNF antagonist, due to rheumatoid arthritis. The neonate suffered from a fulminant form of Kasabach Merritt syndrome with disseminated intravascular coagulation (DIC) resulting in multi-organ failure which led to her demise. PMID- 25277315 TI - Surface charge and dosage dependent potential developmental toxicity and biodistribution of iron oxide nanoparticles in pregnant CD-1 mice. AB - Iron oxide nanoparticles have attracted much attention because of their potential applications, such as drug delivery, biomedical imaging, and photocatalysis. Due to their small size and the potential to cross the placental barrier, the risk to pregnant women and the developing fetus from exposure to nanoparticles is of great concern. The developmental toxicity and biodistribution of a single dose versus multiple doses of iron oxide nanoparticles with positive or negative surface charges were investigated in vivo. Multiple doses of positively-charged nanoparticles given over several days resulted in significantly increased fetal deaths and accumulation of iron in the fetal liver and placenta. These results indicate both positively and negatively charged iron oxide nanoparticles have the ability to cross the placenta and accumulate in the fetus, though greater bioaccumulation and toxicity was observed with a positively-charged surface coating. PMID- 25277313 TI - Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer. AB - Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as well as breast cancer later in life. Gestational exposure of rodents to a related compound, the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary cancer during adulthood, long after cessation of exposure. Exposure to BPA during gestation induces morphological alterations in both the stroma and the epithelium of the fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. BPA would then alter the reciprocal stroma-epithelial interactions that mediate mammogenesis. In addition to this direct effect on the mammary gland, BPA is postulated to affect the hypothalamus and thus in turn affect the regulation of mammotropic hormones at puberty and beyond. PMID- 25277316 TI - Establishment of trigger levels to steer the follow-up of radiation effects in patients undergoing fluoroscopically-guided interventional procedures in Belgium. AB - The accumulated dose to the skin of the patient during fluoroscopically-guided procedures can exceed the thresholds for tissue reactions. In practice, interventionalists have no direct information about the local procedure-related skin doses in their patient, causing suboptimal or delayed treatment. In current study, the accumulated Kerma-Area-Product (KAP) values were registered, as well as the reference air kerma (Ka,r) values, if available, for almost 200 cases undergoing seven different procedures. A sheet filled with 50 thermoluminescent dosemeters was wrapped around each patient to measure the peak skin dose. In a significant part of the Transjugular Intrahepatic Portosystemic Shunt (TIPSS) procedures, chemo-embolizations of the liver and cerebral embolizations, the threshold values for deterministic skin damage (2 Gy) were attained. Trigger values in terms of KAP, corresponding to a peak skin dose of 2 Gy, were determined. In general, our results comply reasonably well with the values proposed in the NCRP 168 report, with a KAP value of 425 Gy cm2 and a Ka,r value of 3 Gy, corresponding to a peak skin dose of 3 Gy. Only for the TIPSS procedure a considerably lower value of 2 Gy was obtained at the published Ka,r and for the RF ablations we obtained a considerably lower value of 250 Gy cm2 in terms of KAP. PMID- 25277317 TI - Short- and long-term outcomes of pancreatectomy with or without biliary tract and duodenum preservation for benign and borderline neoplasms. AB - OBJECTIVES: The aim of this study was to compare short- and long-term outcomes of biliary tract and duodenum-preserving pancreatectomy (BT-DPP) versus non conservative pancreatectomy (NCP). PATIENTS AND METHODS: From 2008 to 2012, 39 of 259 patients underwent pancreatectomy for benign or borderline neoplasms. Patients were classified as BT-DPP (n = 15) or NCP (n = 24). Data were prospectively collected and retrospectively analyzed on an intention-to-treat basis. RESULTS: Both groups were comparable regarding demography, intra- and postoperative data (operative time, blood loss) and length of hospital stay. Overall complications occurred in 10 and 19 (p = 0.31), postpancreatectomy fistula in 2 and 4 (p = 0.6), biliary fistula in 3 and 1 (p = 0.15), and postpancreatectomy hemorrhage in 3 and 7 (p = 0.4) patients in the BT-DPP and NCP groups, respectively. One patient in the NCP group died. The median follow-up was 27 (4.4-56.5) and 23.4 (0.3-53) months in the BT-DPP and NCP groups, respectively. One BT-DPP patient had biliary stenosis treated endoscopically and 1 patient in the NCP group required surgery. The incidence of diabetes was equal. CONCLUSION: Our study shows that BT-DPP is feasible without an increase in morbidity compared with NCP. In the long term, BT-DPP was not associated with higher morbidity. PMID- 25277318 TI - Differences in cardiac autonomic function contributes to heart rate abnormalities in POTS and IST. AB - Our objective was to examine the differences in cardiac autonomic function in Postural Tachycardia Syndrome (POTS) versus inappropriate sinus tachycardia (IST). Subjects (IST, n = 8; POTS, n = 12) were studied using standard measurements of the autonomic reflex screen, baroreflex function and spectral analysis. Data was compared to age/gender-matched controls (n = 20). The components of the autonomic reflex screen did not differ between groups. The exception was the significant but expected difference in postural heart rate increment on head-up tilt in POTS (47.9 +/- 13.8; n = 12) compared to IST (30.9 +/- 9.7; n = 8; p = 0.008). Accordingly the Orthostatic Intolerance Scale showed significantly greater orthostatic symptoms in POTS (2.6 +/- 0.5; n = 12) versus IST patients (0.4 +/- 0.5; n = 8; p < 0.001). Conversely, IST patients had a significantly higher resting heart rate (96 +/- 12; n = 8) when compared to POTS patients (73 +/- 12; n = 12; p = 0.001). There was a significant difference in vagal baroreflex sensitivity (BRSv) in POTS (8.21 +/- 2.3, n = 12) compared to IST patients (5.30 +/- 2.94, n = 8, p = 0.036) during the Valsalva maneuver. Only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) with tilt (FFT, 8.29 +/- 6.38; AR, 7.84 +/- 5.24) compared to the supine position (FFT, 2.25 +/- 1.75; AR, 1.99 +/- 1.38; p < 0.05) for both frequency domains. Differences in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings shed further light on the autonomic dysfunction underlying POTS and IST. PMID- 25277319 TI - Therapeutic applications of the cell-penetrating HIV-1 Tat peptide. AB - Over the past decades, many new therapeutic approaches have been developed for several conditions, including neurodegenerative diseases. However, efficient biodistribution and delivery at biological target sites are hampered by the presence of cell and tissue barriers, and a clinical therapy is prevented by the requirement of invasive administration routes. Candidate drug conjugation to cell penetrating peptides, which are able to cross cellular membranes and reach biological targets even when administered systemically, represents a promising tool to overcome this issue. Here, we review the biology, classification and mechanisms of internalization of cell-penetrating peptides. We focus our attention on the cell-penetrating peptide: HIV-derived Tat peptide, and discuss its efficient but controversial use in basic, preclinical and clinical research from its discovery to the present day. PMID- 25277320 TI - Hybrid poly(lactic-co-glycolic acid) nanoparticles: design and delivery prospectives. AB - Poly(lactic-co-glycolic acid) (PLGA), a US Food and Drug Administration (FDA) approved copolymer, has been exploited widely in the design of nanoparticles because it is biodegradable, biocompatible, protects the drug molecules from degradation, and aids in producing sustained and targeted delivery. However, certain constraints associated with PLGA nanoparticles, such as poor drug encapsulation, polymer degradation, and scale-up issues, have led to the development of emerging hybrid PLGA delivery systems. These hybrid nanoparticles are core-shell nanostructures comprising either a PLGA core or a PLGA shell combining multiple functionalities within one system and, thus, exhibiting the complementary characteristics of two different platforms used for the delivery of a wide range of therapeutics and imaging. PMID- 25277321 TI - Variant of prostatic adenocarcinoma with Paneth cell-like neuroendocrine differentiation readily misdiagnosed as Gleason pattern 5. AB - This study focused on 11 cases of prostatic adenocarcinoma with Paneth cell-like change, which had sparse to no Paneth cell-like granules; grading the tumor conventionally would have resulted in assigning a Gleason pattern 5 for the primary or secondary pattern. Ten cases were entirely composed of the Paneth cell like component. Architectural patterns included the following: nest and cord-like architecture (n = 4; 36.4%), nests only (n = 6; 54.5%), and cords only (n = 1; 9.1%). All 11 cases had amphophilic cytoplasm. Among the 11 cases, 7 had rare granules, 1 had 10% of the cells with granules, and 3 had no granules. Within the Paneth cell-like feature component, rare nucleolar prominence was seen in only 4 (36.4%) of 11 cases. Eight cases were diffusely positive for chromogranin and synaptophysin, 2 for chromogranin only, and 1 for synaptophysin only. In the 3 cases where performed, Ki-67 showed a very low rate of less than 5%. The keys to recognizing these cases are as follows: (1) nests and cords in a small focus, (2) deeply amphophilic cytoplasm with careful search in most cases revealing rare Paneth cell-like eosinophilic granules, (3) indistinct nucleoli, and (4) immunohistochemical staining for neuroendocrine markers. Based on follow-up from prior studies and the current work, these tumors appear to have a favorable prognosis. The importance of recognizing this variant of adenocarcinoma with Paneth cell-like differentiation is that if these tumors were graded conventionally, 9 of the 11 cases would have been assigned a misleading Gleason score of 5 + 5 = 10 or 5 + 4 = 9. PMID- 25277322 TI - Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. AB - Curcumin possesses many properties which may prevent or ameliorate pathological processes underlying age-related cognitive decline, dementia or mood disorders. These benefits in preclinical studies have not been established in humans. This randomized, double-blind, placebo-controlled trial examined the acute (1 and 3 h after a single dose), chronic (4 weeks) and acute-on-chronic (1 and 3 h after single dose following chronic treatment) effects of solid lipid curcumin formulation (400 mg as Longvida(r)) on cognitive function, mood and blood biomarkers in 60 healthy adults aged 60-85. One hour after administration curcumin significantly improved performance on sustained attention and working memory tasks, compared with placebo. Working memory and mood (general fatigue and change in state calmness, contentedness and fatigue induced by psychological stress) were significantly better following chronic treatment. A significant acute-on-chronic treatment effect on alertness and contentedness was also observed. Curcumin was associated with significantly reduced total and LDL cholesterol and had no effect on hematological safety measures. To our knowledge this is the first study to examine the effects of curcumin on cognition and mood in a healthy older population or to examine any acute behavioral effects in humans. Results highlight the need for further investigation of the potential psychological and cognitive benefits of curcumin in an older population. PMID- 25277323 TI - Evidence of a suffocation alarm system sensitive to clinically-effective treatments with the panicolytics clonazepam and fluoxetine. AB - Dyspnea, 'hunger for air', and the urge to flee are the cardinal symptoms of respiratory-type panic attacks. Patients also show baseline respiratory abnormalities and a higher rate of comorbid and antecedent respiratory diseases. Panic attacks are also precipitated by both the infusion of 0.5 M sodium lactate and the inhalation of 5-7% carbon dioxide (CO2) in predisposed patients, but not in healthy volunteers nor patients without panic disorder. Further studies show that patients with panic are also hyper-responsive to hypoxia. These and other observations led Klein (1993) to suggest that clinical panic is the misfiring of a suffocation alarm system. In rats, cytotoxic hypoxia of chemoreceptor cells by intravenous injection of potassium cyanide (KCN) produces short-lasting flight behaviors reminiscent of panic attacks. KCN-induced flight behaviors are blocked both by denervation of chemoreceptor cells and lesion of dorsal periaqueductal gray matter, a likely substrate of panic. Herein, we show that KCN-evoked flight behaviors are also attenuated by both acute and chronic treatment with clonazepam (0.01-0.3 mg/kg, intraperitoneally (i.p.)) and fluoxetine (1-4 mg/kg/day, i.p. for 21 days), respectively. Attenuation of KCN-evoked panic-like behaviors by clinically-effective treatment with panicolytics adds fresh evidence to the false suffocation alarm theory of panic disorder. PMID- 25277324 TI - Cancer-related therapies at the end of life in hospitalized cancer patients from four Swiss cantons: SAKK 89/09. AB - The use of cancer-related therapies in cancer patients hospitalized at the end of life has increased in many countries over time. Given the scarcity of published Swiss data, the objective of this study was to evaluate the influence of hospital type and other factors on the delivery of health care during the last month before death. Claims data were used to assess health care utilization of cancer patients (identified by cancer registry data of four participating Swiss cantons) who deceased between 2006 and 2008. Primary endpoints were delivery of cancer related therapies during the last 30 days before death. Multivariate logistic regression assessed the explanatory value of hospital type, patient and geographic characteristics. Of 3,809 identified cancer patients in the claims database, 2,086 patients dying from cancer were hospitalized during the last 30 days before death, generating 2,262 inpatient episodes. Anticancer drug therapy was given in 22.2% and radiotherapy in 11.7% of episodes. Besides age and cancer type, the canton of residence and hospital type showed independent, statistically significant associations with intensity of care, which was highest in university hospitals. These results should initiate a discussion among oncologists in Switzerland and may question the compliance with standard of care guidelines for terminal cancer patients. PMID- 25277325 TI - Cameron promises to ringfence NHS budget in next parliament. PMID- 25277327 TI - Liver fat contents, abdominal adiposity and insulin resistance in non-diabetic prevalent hemodialysis patients. AB - BACKGROUND: The liver fat contents and abdominal adiposity correlate well with insulin resistance (IR) in the general population. However, the relationship between liver fat content, abdominal adiposity and IR in non-diabetic hemodialysis (HD) patients remains unclear. This study aimed to clarify the associations among these factors. METHODS: This is a cross-sectional, observational study. All patients received abdominal ultrasound for liver fat content. Abdominal adiposity was quantified with the conicity index (Ci) and waist circumference (WC). We checked the homeostasis model assessment for insulin resistance index (HOMA-IR) for IR. RESULTS: A total of 112 patients (60 women) were analyzed. Subjects with higher liver fat contents and WC had higher IR indices. But Ci did not correlate with IR indices. In both the multi-variable linear regression model and the logistic regression model, only higher liver fat content predicted a severe IR status. CONCLUSIONS: Liver fat contents have a remarkable correlation with IR; however, abdominal adiposity, measured either by Ci or WC, dose not independently correlate with IR in non-diabetic prevalent HD patients. PMID- 25277326 TI - Down-regulation of miR-4500 promoted non-small cell lung cancer growth. AB - BACKGROUND: Lung cancer is the lead cause of cancer-related mortality around the world. Non-small cell lung cancer (NSCLC) accounts for nearly 85% of all case of lung cancer. Accumulating evidence revealed the importance of miRNAs in the pathogenesis of NSCLC. Whether miR-4500 promotes NSCLC or not is still unknown. The potential targeted genes needed to be investigated. METHODS: The level of miR 4500 was measured by qRT-PCR. The role of miR-4500 in patient survival was revealed by the Kaplan-Meier plot of overall survival of NSCLC patients. miR-4500 was up or down regulated by miRNAs mimics or ASO transfection. Cell proliferation and apoptosis were assayed by the MTT assay and FACS analysis separately. Targeted genes were predicted by a bioinformatic algorithm and confirmed by the Dual Luciferase reporter assay system. RESULTS: NSCLC cell lines and tissues showed lower level of miR-4500. High miR-4500 expression was correlated with high patient survival rate. MiR-4500 overexpression inhibited NSCLC proliferation and induced apoptosis and vice versa. LIN28B and NRAS were targeted by miR-4500. CONCLUSIONS: Low expression of miR-4500 in NSCLC promoted tumor growth by targeting LIN28B and NRAS. MiR-4500 may be a prognosis predictor and potential target for NSCLC therapy. PMID- 25277328 TI - Prevalence, incidence, mortality and co-morbidities amongst human immunodeficiency virus (HIV) patients in Stockholm County, Sweden - the Greater Stockholm HIV Cohort Study. AB - Our aim was to study the prevalence and incidence of patients with human immunodeficiency virus (HIV) in the general population in Stockholm, Sweden. We also aimed to study mortality among individuals with HIV and to explore co morbidities. The study population included all living persons who resided in Stockholm County, Sweden, as of 31 December 2012 (N = 2,212,435). Information on all consultations between 2007 and 2012 was obtained from primary health care, specialist outpatient care and inpatient care. Analyses were done by age and gender. All patients with a recorded diagnosis of HIV were included. The prevalence of HIV was calculated using 2012 data. The prevalence of HIV in Stockholm area as per end of December 2012 was as low as 0.1% in females and 0.2% in males, and the annual incidence of HIV continued to decline over the years. In recent years, cancers, diabetes and hypertension were about as common in individuals with HIV as in the general population. Males with HIV had 3- to 4 fold higher age-adjusted odds of being diagnosed with depression and 3-fold higher odds of anxiety disorders and women had 1.6 to 2-fold higher age-adjusted odds of depression and anxiety disorders, than males and females in the general population, respectively. The relatively good somatic health observed in this study could be attributed to nearly optimal HIV therapy in Sweden. The mental health of HIV patients was significantly worse than that in the general population and needs further attention. PMID- 25277329 TI - Erratum to: Radiology medical malpractice suits in gastrointestinal radiology: prevalence, causes, and outcomes. PMID- 25277330 TI - Emerging antidepressants to treat major depressive disorder. AB - Depression is a common disorder with an annual risk of a depressive episode in the United States of 6.6%. Only 30-40% of patients remit with antidepressant monotherapy, leaving 60-70% of patients who do not optimally respond to therapy. Unremitted depressive patients are at increased risk for suicide. Considering the prevalence of treatment resistant depression and its consequences, treatment optimization is imperative. This review summarizes the latest treatment modalities for major depressive disorder including pharmacotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation and psychotherapy. Through advancements in research to better understand the pathophysiology of depression, advances in treatment will be realized. PMID- 25277331 TI - Defective inflammatory monocyte development in IRF8-deficient mice abrogates migration to the West Nile virus-infected brain. AB - IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow. These cells traffic via the blood to the infected brain, where they give rise to proinflammatory macrophages. Here, we show that WNV-infected IRF8-deficient (IRF8-/-) mice had significantly reduced numbers of Ly6C+ monocytes in the periphery, with few of these cells found in the blood. Furthermore, low numbers of inflammatory monocyte-derived macrophages were observed in the brains of IRF8-/- mice throughout infection. Adoptive transfer of IRF8-/- Ly6C+ monocytes demonstrated that these cells were intrinsically unable to traffic to the inflamed brain. Low expression of the chemokine receptor CCR2 and integrin VLA-4 by IRF8-/- monocytes likely contributed to this defect, as the interactions between these proteins and their ligands are critical for monocyte egress and migration to inflammatory foci. These data highlight a critical role for IRF8 in inflammatory monocyte differentiation and migration during WNV infection. PMID- 25277333 TI - Primary versus secondary role of left anterior descending coronary artery "wraparound" in takotsubo syndrome. PMID- 25277332 TI - Development and validation of a clinical prediction rule to identify suspected breast cancer: a prospective cohort study. AB - BACKGROUND: The number of primary care referrals of women with breast symptoms to symptomatic breast units (SBUs) has increased exponentially in the past decade in Ireland. The aim of this study is to develop and validate a clinical prediction rule (CPR) to identify women with breast cancer so that a more evidence based approach to referral from primary care to these SBUs can be developed. METHODS: We analysed routine data from a prospective cohort of consecutive women reviewed at a SBU with breast symptoms. The dataset was split into a derivation and validation cohort. Regression analysis was used to derive a CPR from the patient's history and clinical findings. Validation of the CPR consisted of estimating the number of breast cancers predicted to occur compared with the actual number of observed breast cancers across deciles of risk. RESULTS: A total of 6,590 patients were included in the derivation study and 4.9% were diagnosed with breast cancer. Independent clinical predictors for breast cancer were: increasing age by year (adjusted odds ratio 1.08, 95% CI 1.07-1.09); presence of a lump (5.63, 95% CI 4.2-7.56); nipple change (2.77, 95% CI 1.68-4.58) and nipple discharge (2.09, 95% CI 1.1-3.97). Validation of the rule (n = 911) demonstrated that the probability of breast cancer was higher with an increasing number of these independent variables. The Hosmer-Lemeshow goodness of fit showed no overall significant difference between the expected and the observed numbers of breast cancer (chi(2)HL: 6.74, p-value: 0.56). CONCLUSIONS: This study derived and validated a CPR for breast cancer in women attending an Irish national SBU. We found that increasing age, presence of a lump, nipple discharge and nipple change are all associated with increased risk of breast cancer. Further validation of the rule is necessary as well as an assessment of its impact on referral practice. PMID- 25277334 TI - Analysis of early out-of hospital mortality after transcatheter aortic valve implantation among patients with aortic stenosis successfully discharged from the hospital and alive at 30 days (from the placement of aortic transcatheter valves trial). AB - In high-risk or inoperable patients with severe symptomatic aortic stenosis, transcatheter aortic valve implantation (TAVI) is a proven alternative to standard (i.e., medical) therapy or surgical aortic valve replacement. Concerns have been raised, however, about patients who survive the procedure but have short subsequent survival. The aim of this study was therefore to identify correlates of early out-of-hospital mortality (EOHM) in patients who underwent successful TAVI, rendering TAVI potentially "futile." Patients who were discharged from the hospital and survived >30 days but <12 months after TAVI were identified (the EOHM group). Independent predictors of EOHM were explored, including patient-level factors and procedural nonfatal major complications (NFMCs). A sensitivity analysis was also performed, excluding patients with NFMCs. Among 485 patients who were discharged from the hospital and survived 30 days after TAVI, 101 (21%) were dead within 1 year. Independent predictors of EOHM included serum creatinine, liver disease, coagulopathy, mental status, body mass index, male gender, and Society of Thoracic Surgeons score. Although NFMCs were strongly associated with EOHM, patient-level risk factors for EOHM were similar between patients who did and those who did not experience NFMCs. Compared with standard therapy, TAVI patients with EOHM had similar 6-month 6-minute walk distances and functional classes, with higher rates of repeat hospitalization. In conclusion, in high-risk or inoperable patients who underwent TAVI and were discharged and alive at 30 days, EOHM was not infrequent and was determined largely by presenting characteristics and the occurrence of periprocedural NFMCs. Careful screening and minimization of NFMCs may maximize the benefit of TAVI. PMID- 25277335 TI - Efficacy of an Embolic Protection Stent as a Function of Delay to Reperfusion in ST-Segment Elevation Myocardial Infarction (from the MASTER Trial). AB - The ability of stent implantation to improve indexes of reperfusion may depend on the time to reperfusion in acute ST-segment elevation myocardial infarction (STEMI) and may also vary with stent type. The purpose of this prespecified analysis from the randomized MGUARD for Acute ST Elevation Reperfusion trial was to evaluate the impact of delay to reperfusion on outcomes in patients with STEMI undergoing primary percutaneous coronary intervention with the MGuard embolic protection stent or standard metallic stents. A total of 431 patients were divided according to symptom-onset-to-balloon time (SBT) into 2 groups: SBT <=3 hours (167 patients; 39%) and SBT >3 hours (264 patients; 61%). Complete ST segment resolution (STR) after percutaneous coronary intervention was more often achieved in patients with shorter SBT (58.6% vs 47%, p = 0.02). At 1 year, the all-cause mortality rate was lower in patients with shorter SBT (0% vs 3.5%, p = 0.02). STR was achieved in 58% of MGuard patients and in 45% of the control stent patients (p = 0.008). STR was 57% in the MGuard group versus 38% in the control group (p = 0.002 for SBT >3 hours) and 60% versus 57% (p = 0.72), respectively, for SBT <=3 hours (p for interaction = 0.11). In conclusion, longer delay to mechanical reperfusion remains an important factor negatively influencing outcomes in patients with STEMI. Use of the MGuard embolic protection stent compared with conventional metallic stents resulted in superior rates of complete STR, even in patients with longer delays to reperfusion. PMID- 25277337 TI - A convenient base-mediated synthesis of 3-aryol-4-methyl (or benzyl)-2-methylthio furans from alpha-oxo ketene dithioacetals and propargyl alcohols via domino coupling/annulations. AB - A convenient base-mediated strategy to synthesize 3-aryol-4-methyl (or benzyl)-2 methylthio furans 2 (trisubstituted furans) has been developed through the domino coupling/annulations between available alpha-oxo ketene dithioacetals 1 and propargyl alcohols. In this strategy, these types of bases play an important role in driving the domino coupling reaction of propargyl alcohols and further intramolecular annulations to realize the target compounds. The possible mechanism for the formation of the various products is believed to involve the generation of allenes 7, followed by intramolecular annulations. PMID- 25277336 TI - Identification and functional analysis of long non-coding RNAs in mouse cleavage stage embryonic development based on single cell transcriptome data. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) regulate embryonic development and cell fate decision in various ways, such as modulation of chromatin modification and post-transcription regulation of gene expression. However, the profiles and roles of lncRNAs in early mammalian development have not yet been demonstrated. Here, we reported a comprehensive analysis of mouse cleavage stage embryonic lncRNA profiles based on public single-cell RNA-seq data. RESULTS: We reconstructed 50,006 high-confidence transcripts in 22,827 loci, and identified 5563 novel lncRNAs from 3492 loci expressed in mouse cleavage stage embryos. These lncRNAs share similar characteristics with previously reported vertebrate lncRNAs, such as relatively short length, low exon number, low expression level and low sequence conservation. Expression profile analysis revealed that the profiles of lncRNA vary considerably at different stages of cleavage stage embryos, suggesting that many lncRNAs in cleavage stage embryos are stage specifically expressed. Co-expression network analysis suggested many lncRNAs in cleavage stage embryos are associated with cell cycle regulation, transcription, translation and oxidative phosphorylation to regulate the process of cleavage stage embryonic development. CONCLUSIONS: This study provides the first catalog of lncRNAs expressed in mouse cleavage stage embryos and gives a revealing insight into the molecular mechanism responsible for early embryonic development. PMID- 25277338 TI - Editorial: international reviews of immunology. PMID- 25277339 TI - Feasibility analysis of p62 (SQSTM1)-encoding DNA vaccine as a novel cancer immunotherapy. AB - Cancer immunotherapy is a thriving field, but its clinical achievements are modest so far. One of its major hurdles seems to be finding a feasible cancer antigen as a target for immune response. After many years of research, three major criteria for choice of tumor antigens emerged. An antigen should be: (i) immunogenic; (ii) essential for cancers cells (to avoid its loss through immunoediting), but dispensable for normal tissues to reduce the risk of toxicity, and (iii) overexpressed in tumors as compared to the normal tissues. Here we argue that p62 (SQSTM1), a protein involved in autophagy and signal transduction, fits all the above criteria and can be chosen as a novel cancer antigen. Accordingly, we carried out an extensive study and found antitumor and antimetastatic activity of p62-encoding DNA vaccine in five types of commonly used transplantable tumor models of mice and rats, and spontaneous tumors in several dogs. Given that toxicity of p62 vaccine was minimal, if any, we believe that p62-encoding vaccine merits further clinical development. PMID- 25277341 TI - Communication during resuscitation: time for a change? PMID- 25277340 TI - Age as a determinant of phosphate flame retardant exposure of the Australian population and identification of novel urinary PFR metabolites. AB - The demand for alternative flame retardant materials such as phosphate flame retardants and plasticizers (PFRs) is increasing, although little is known of their possible effects on human health and development. To date, no information on the exposure of children or general Australian population to PFRs is available. The objectives of this study were to characterize the average levels and age-related patterns of PFR metabolites in urine in the general Australian population and to identify novel hydroxylated PFR metabolites in urine. Surplus pathology urine samples from Queensland, Australia were stratified and pooled by age and sex (3224 individuals aged 0 to 75years into 95 pools) according to two different pooling strategies at two different time periods. Samples were analyzed by solid phase extraction and liquid chromatography-tandem mass spectrometry following enzymatic treatment. Nine PFR metabolites were measured in the Australian population, including the first report of a hydroxylated metabolite of TCIPP (BCIPHIPP). Diphenyl phosphate (DPHP), BCIPHIPP and bis(1,3-dichloro-2 propyl) phosphate (BDCIPP) were detected in >95% of samples. DPHP, a metabolite of aryl-PFRs, was found in several samples at levels which were one order of magnitude higher than previously reported (up to 730ng/mL). Weighted linear regression revealed a significant negative association between log-normalized BDCIPP and DPHP levels and age (p<0.001). Significantly greater levels of BDCIPP and DPHP were found in children's urine compared with adults, suggesting higher exposure to PFRs in young children. BCIPHIPP was identified for inclusion in future PFR biomonitoring studies. PMID- 25277342 TI - Introduction of performance coaching during cardiopulmonary resuscitation improves compression depth and time to defibrillation in out-of-hospital cardiac arrest. AB - INTRODUCTION: Quality cardiopulmonary resuscitation (CPR) and timely defibrillation are associated with increasing survival to hospital discharge from out-of-hospital cardiac arrest (OHCA). The objective of this study was to demonstrate that performance coaching during an OHCA would improve compression depth and time to defibrillation (TTD). METHODS: This study was conducted in a single emergency medical services (EMS) agency and utilized data collected from 815 patients treated between 1/1/2012 and 12/31/2013. The intervention used multiple Plan-Do-Study-Act (PDSA) cycles to train fire captains to translate performance data into active direction. Testing began in simulation with small scale expansions prior to system-wide implementation. Performance metrics included average (reported as a percentage) and actual compression depth (reported in millimeters), and TTD (an average in seconds). Analysis was conducted using Xbar and S control charts with standard assessment of special cause for performance data. A statistical shift was seen in means and standard deviations for both depth metrics. RESULTS: Average depth of compressions improved from 69.8% (SD=28.0%) to 80.4 (SD=21.8%). Depth of compressions delivered increased from 43.6mm (SD=8.2mm) to 47.2mm (SD=8.1mm). Analysis of the S charts indicates a statistical shift in process variation for TTD. CONCLUSION: Early results indicate that utilization of a CPR coach during OHCA improves compression depth and TTD. Further data are needed to assess sustainability. PMID- 25277343 TI - CPR-related injuries after manual or mechanical chest compressions with the LUCASTM device: a multicentre study of victims after unsuccessful resuscitation. AB - AIM: The reported incidence of injuries due to cardiopulmonary resuscitation using manual chest compressions (manual CPR) varies greatly. Our aim was to elucidate the incidence of CPR-related injuries by manual chest compressions compared to mechanical chest compressions with the LUCAS device (mechanical CPR) in non-survivors after out-of-hospital cardiac arrest. METHODS: In this prospective multicentre trial, including 222 patients (83 manual CPR/139 mechanical CPR), autopsies were conducted after unsuccessful CPR and the results were evaluated according to a specified protocol. RESULTS: Among the patients included, 75.9% in the manual CPR group and 91.4% in the mechanical CPR group (p=0.002) displayed CPR-related injuries. Sternal fractures were present in 54.2% of the patients in the manual CPR group and in 58.3% in the mechanical CPR group (p=0.56). Of the patients in the manual CPR group, there were 64.6% with at least one rib fracture versus 78.8% in the mechanical CPR group (p=0.02). The median number of rib fractures among patients with rib fractures was 7 in the manual CPR group and 6 in the mechanical CPR group. No CPR-related injury was considered to be the cause of death. CONCLUSION: In patients with unsuccessful CPR after out-of hospital cardiac arrest, rib fractures were more frequent after mechanical CPR but there was no difference in the incidence of sternal fractures. No injury was deemed fatal by the pathologist. PMID- 25277345 TI - Evaluation of CellSolutions BestPrep(r) automated thin-layer liquid-based cytology Papanicolaou slide preparation and BestCyte(r) cell sorter imaging system. AB - OBJECTIVE: A double-blind study was conducted to compare the performance of the new BestPrep(r) (CellSolutions) liquid-based thin-layer Papanicolaou (Pap) test with ThinPrep(r) (Hologic). STUDY DESIGN: Samples from the study patients (n = 105) were collected twice in the same encounter with the ThinPrep sample always taken first and the BestPrep sample collected second. Slides were prepared according to both manufacturers' protocols and evaluated using manual microscopic review and the BestCyte(r) cell sorter imaging system (CellSolutions). Diagnostic truth for each case was determined by independent manual review of both slides by multiple pathologists and histology when available. The presence of atypical squamous cells of undetermined significance was the threshold for positive for sensitivity and specificity calculations. RESULTS: BestPrep and ThinPrep, by manual review, had sensitivities for high-grade squamous intraepithelial lesion (HSIL) cases of 100 and 95.6%, respectively. Using the BestCyte cell sorter, both had 100% sensitivity. For the same HSIL cases, the digene HC2 high-risk human papillomavirus DNA test had sensitivities of 100% (BestPrep) and 95.6% (ThinPrep). Specificities were 71.4% (BestPrep) and 54.8% (ThinPrep). CONCLUSIONS: BestPrep was equivalent to ThinPrep for manual review even though BestPrep was always the second sample collected. The BestCyte cell sorter provides a practical alternative to manual review for both BestPrep and ThinPrep slides. PMID- 25277344 TI - Aptamer-conjugated theranostic hybrid graphene oxide with highly selective biosensing and combined therapy capability. AB - Cancer is a life-threatening disease, which is rapidly becoming a global pandemic. Driven by this need, here we report for the first time an aptamer conjugated theranostic magnetic hybrid graphene oxide-based assay for highly sensitive tumor cell detection from blood samples with combined therapy capability. AGE-aptamer-conjugated theranostic magnetic nanoparticle-attached hybrid graphene oxide was developed for highly selective detection of tumor cells from infected blood samples. Experimental data indicate that hybrid graphene can be used as a multicolor luminescence platform for selective imaging of G361 human malignant melanoma cancer cells. The reported results have also shown that indocyanine green (ICG)-bound AGE-aptamer-attached hybrid graphene oxide is capable of combined synergistic photothermal and photodynamic treatment of cancer. Targeted combined therapeutic treatment using 785 nm near-infrared (NIR) light indicates that the multimodal therapeutic treatment is highly effective for malignant melanoma cancer therapy. The reported data show that this aptamer conjugated theranostic graphene oxide-based assay has exciting potential for improving cancer diagnosis and treatment. PMID- 25277346 TI - Absorption, distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats. AB - The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of (14)C-ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography nuclear magnetic resonance spectroscopy data revealed that O-glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When (14)C-ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of (14)C-ASP3258 to bile-cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258-derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species. PMID- 25277347 TI - Neutrophil-to-Lymphocyte Ratio Positively Correlates to Age in Healthy Population. AB - BACKGROUND: Neutrophil to lymphocyte ratio (NLR) was reported to be an independent easy-to-measure marker for many diseases, while the distribution of NLR in healthy population was not formally studied. So we investigated NLR in healthy people in this study. METHODS: Data include NLR, systolic pressure, diastolic pressure, and body mass index (BMI), which were collected from 3,262 healthy population. Correlations of NLR with variables were analyzed with SPSS16.0. RESULTS: Results demonstrated that NLR was positively associated with age (P < 0.001). The eldest age group possessed the highest NLR and the youngest age group had the lowest NLR. NLR was also slightly positively associated with systolic pressure, diastolic pressure, and BMI (P < 0.001). CONCLUSION: Older people possessed relatively high NLR in healthy population. PMID- 25277348 TI - Co-pyrolysis of Chinese lignite and biomass in a vacuum reactor. AB - A vacuum fixed bed reactor was applied to pyrolyze lignite, biomass (rice husk) and their blend with high temperature (900 degrees C) and low heating rate (10 degrees C/min). Pyrolytic products were kept in the vacuum reactor during the whole pyrolysis process, guaranteeing a long contact time (more than 2 h) for their interactions. Remarkable synergetic effects were observed. Addition of biomass obviously influenced the tar and char yields, gas volume yield, gas composition, char structure and tar composition during co-pyrolysis. It was highly possible that char gasification, gaseous phase interactions, and secondary tar cracking were facilitated when lignite and biomass were co-pyrolyzed. PMID- 25277349 TI - The risk of malignancy anywhere in the body after linear accelerator (LINAC) stereotactic radiosurgery. AB - BACKGROUND: Despite the conformity of stereotactic radiosurgery (SRS) treatment, there are concerns about the risk of malignancy. OBJECTIVE: We compared the number of cancer cases observed after treatment in a group of SRS patients to the number of cancer cases that would be expected in an age- and gender-matched group. METHODS: We collected data from the University of Florida SRS database for patients treated for meningiomas, intracranial schwannomas, arteriovenous malformations (AVMs), trigeminal neuralgia, pituitary adenomas, cavernous angiomas, and metastases. We used the Florida Cancer Data System (FCDS) to determine the actual cancer rates for SRS-treated patients, and we compared these to the cancer rates in similar groups of non-SRS-treated patients based on rates available from the SEER (surveillance epidemiology and end results) database. RESULTS: A total of 2,369 patients were analyzed. Of these, 862 were patients with metastases who were analyzed only to ensure the sensitivity of using the FCDS to determine malignancy rates. The results for patients with more than 5 years of follow-up are reported. Without the metastases patients, a total of 627 patients had more than 5 years of follow-up data. Follow-up in patient-years was 1,711 for the meningioma patients, 1,851 for the schwannoma patients, 1,407 for the AVM patients and 338 for patients with a diagnosis of 'other'. The observed cancer rate in the meningioma patients was 3.96% compared to the expected rate of 10% (binomial 95% confidence interval, CI = 1.85-7.94). The observed cancer rate in the schwannoma patients was 4.93% compared to the expected rate of 12.5% (95% CI = 2.61-8.89). The observed cancer rate in the AVM patients was 3.64% compared to the expected rate of 4.43% (95% CI = 1.49-8.10). The observed cancer rate in patients treated for other diagnoses (e.g. pituitary adenoma or trigeminal neuralgia) was 0% compared to the expected rate of 6.36% (95% CI = 0-11.7). CONCLUSIONS: In a large population of SRS-treated patients, there was no increased risk of malignancy compared to the general population. PMID- 25277350 TI - Screening breast magnetic resonance imaging in women with atypia or lobular carcinoma in situ. AB - BACKGROUND: Atypical lesions and lobular carcinoma in situ (LCIS) are associated with an increased risk of breast malignancy. The utility of breast magnetic resonance imaging (MRI) screening in this cohort of women after excision of a high-risk lesion has not been previously established. The objective of this study was to investigate outcomes of breast MRI surveillance in this subgroup of high risk patients. MATERIALS AND METHODS: We performed a retrospective review of women who required excision of an atypical lesion or LCIS who underwent at least one screening breast MRI from April 2005-December 2011. We collected information on demographics, number of second-look imaging studies recommended, number of biopsies performed and pathologic outcomes. RESULTS: A total of 179 patients met the inclusion criteria, including 131 (73%) with atypical lesions and 48 (27%) with LCIS. Second-look imaging was recommended for 31 of 131 (23.7%) patients with atypical lesions and 8 of 48 (16.7%) with LCIS. Ten biopsies were performed in the atypical cohort (7.6%) with two revealing a malignancy (Positive Predictive Value [PPV] of 20%). In the LCIS cohort, five biopsies were performed (10.4%) with one revealing a malignancy (PPV of 20%). CONCLUSIONS: The benefit of breast MRI surveillance in patients after excision of atypical lesions or LCIS has not been clearly delineated previously. Our data demonstrate that the use of screening breast MRI in this cohort results in additional work-up in one-fifth of patients, but a PPV of only 20%. Large, prospective studies would be needed to determine whether breast cancer outcomes differ between patients undergoing conventional breast screening and those undergoing conventional breast screening plus breast MRI surveillance. PMID- 25277351 TI - Defect closure with "8-shaped crisscross tensile suture" technique. AB - BACKGROUND: Sutures and suturing techniques compose the basis of the surgery. Although many surgical methods such as the skin grafts or flaps has been described for the closure of large defects, proper primary suturing may sometimes yield very successful results and decrease the need of complicated procedures. In this article, a new combined skin-subcutaneous tissue suturing technique called as "8-shaped crisscross tensile suture (8CTS)" designed for the closure of large skin defects is presented. PATIENTS AND METHODS: One hundred forty-nine patients with an age distribution between 14 and 65 y were operated for large skin defects by using the 8CTS technique. The most common etiology of the defects was free flap donor sites, and the most common defect localization was the anterolateral thigh region. The average defect width on the axis of primary closure was calculated as 14.6 cm. The 8CTS technique is a combination of both skin and subcutaneous layers suturation and may even involve deeper layers suturation according to the depth of the defect. RESULTS: Eight complications including wound dehiscence, early recurrence of pilonidal sinus disease, seroma formation, skin-edge necrosis, and incisional hernia were observed. The wounds of 141 patients were treated successfully. CONCLUSIONS: The 8CTS technique is a useful method for the closure of large defects eliminating the need of more complex procedures and providing acceptable cosmetic results while supporting both skin and subcutaneous tissue in one suture. PMID- 25277352 TI - Letter to the editor regarding primary closure after laparoscopic common bile duct exploration versus T-tube. PMID- 25277353 TI - Cellular changes of the colon after mechanical bowel preparation. AB - BACKGROUND: The purpose of this study was to evaluate the effect of mechanical bowel preparation (MBP) on the intracellular environment, specifically evaluating butyrate transport, within the colon of the Sprague-Dawley rat. METHODS: Sixty eight Sprague-Dawley rats were randomized to either an MBP group (n = 34) or a control group (n = 34). Twenty-four hours after the completion of the MBP, both groups were euthanized, and the colons were harvested. The level of cellular apoptosis was investigated after DNA fragmentation, poly(ADP-ribose) polymerase cleavage, and caspase assays. Western blot analysis was performed to measure the expression of the butyrate transporter protein, monocarboxylate transporters 1, and proliferating cell nuclear antigen (a marker for tissue proliferation). Immunohistochemical staining was performed to further investigate cellular proliferation. Statistical significance (P < 0.05) was determined using two tailed t-test. RESULTS: Apoptosis was detected without significant differences in both groups. Western Blot analysis demonstrated that the expression of the monocarboxylate transporters 1 protein is downregulated in the MBP group (10.18 +/- 3.09) compared with the control group (16.73 +/- 7.39, P = 0.001), and proliferating cell nuclear antigen levels showed a decrease in cellular proliferation in the MBP group (13.35 +/- 5.88) compared with the control (20.07 +/- 7.55, P = 0.018). Immunohistochemistry confirmed a decrease in cellular proliferation after MBP with 23.4 +/- 7.8% of the cells staining positive for Ki 67 in the MBP group versus 28.6 +/- 7.9% in the control group (P = 0.006). CONCLUSIONS: MBP has a negative impact on cellular proliferation and intracellular transport of butyrate within the rat colon, not related to apoptosis. This is the first study to demonstrate the intracellular effects that MBP has on the rat colon. PMID- 25277354 TI - Measuring the real value of surgical effort (Commentary to: RVUs poorly correlate with measures of surgical effort and complexity). PMID- 25277355 TI - Prioritizing injury care: a review of trauma capacity in low and middle-income countries. AB - BACKGROUND: Trauma is a large contributor to the global burden of disease, particularly in low and middle-income countries (LMICs). This study aimed to summarize the literature assessing surgical capacity in LMICs to provide a current assessment of trauma capacity, which will help guide future efforts. MATERIALS AND METHODS: The MEDLINE database was queried via PubMed to identify studies assessing baseline surgical capacity in individual LMICs. Data were collected from each study by extracting the relevant information from the full published text or tables. Trauma capacity was evaluated using 12 surrogate criteria of trauma care, including laparotomy, cricothyroidotomy and chest tube insertion capabilities, and accessibility to a blood bank. RESULTS: Seventeen studies were reviewed, documenting data from 531 hospitals in seventeen countries. None of the countries had access to all twelve trauma criteria in all their hospitals. Endotracheal intubation and cricothyrotomy or tracheostomy were available at 48% (107/222) and 41% (163/418) of facilities, respectively. Bag mask valves were available at 61% (234/383) of the institutions. Although 87% (193/221) of facilities responded that they were able to provide initial resuscitation, only 48% (169/349) of them had access to a blood bank and 70% (191/271) had access to intravenous fluids. A third or less of district hospitals had access to basic resuscitation (33%; 8/24), endotracheal tubes (32%; 31/97), blood banks (31%; 32/102), and cricothyrotomies and/or tracheostomies (32%; 30/95). CONCLUSIONS: Deficiencies in trauma capacity in LMICs remain widespread. This study provides specific avenues for improved evaluations of trauma capacity and for strengthening trauma systems in LMICs. PMID- 25277356 TI - Obtaining secure stapling of a double stapling anastomosis. AB - BACKGROUND: Anastomotic leakage is a serious complication after rectal surgery. The aim of this study was to assess the effect of waiting time during firing of stapling devices on optimal staple formation. METHODS: An endoscopic linear stapler (Echelon Flex 60 Endopath) with either a 60 mm blue or gold cartridge was applied to the cardiac and pyloric portions of 27 fresh porcine stomachs. Three different waiting times were used for the precompression and interstroke periods (0/0, 2/0, and 2/2 min). The staple line was divided into four portions (oral, anal and top, base), and the shape of each staple was evaluated. Optimal staple formation was also assessed using the circular stapler (CDH 29). RESULTS: Mean thickness of the cardiac and pyloric portions was 2.4 +/- 0.35 mm and 4.0 +/- 0.4 mm, respectively. The waiting time improved optimal staple formation for the blue cartridge, especially when it was used for the pyloric portion. Staple malformation was observed more commonly in the top portion than in the base portion; however, the former was improved by an interstroke waiting time. Staple formation using the circular stapler was satisfactory and not influenced by the prefiring waiting time or tissue thickness. CONCLUSIONS: Employment of a waiting time improves optimal staple formation when the endoscopic linear stapler is used for challenging tissue. PMID- 25277358 TI - Anesthesia type and perioperative outcome: open colectomies in the United States. AB - BACKGROUND: Adding neuraxial to general anesthesia (GA) has been associated with improved perioperative outcome after orthopedic surgery. Presuming a similar effect in major abdominal surgery we studied its effect on perioperative outcome in open colectomy patients. MATERIALS AND METHODS: Retrospective study using the Premier Perspective database (n = 98,290 elective open colectomies, 2006-2012). Multilevel multivariable logistic regression models measured the association between anesthesia type (GA or general and neuraxial anesthesia combined [GNA]) and perioperative outcome with odds ratios (OR) and 95% confidence intervals (CI). Outcomes were thromboembolism, acute myocardial infarction, postoperative infection, postoperative ileus, cerebrovascular events, blood transfusion, admission to an intensive care unit, and mechanical ventilation. RESULTS: GA was used in 93.9%, GNA in 6.1%, with a similar Charlson comorbidity index between the groups (2.66 versus 2.72, respectively; P = 0.121). The multivariable analyses showed GNA (versus GA) to be associated with a significantly decreased risk for thromboembolism (OR 0.74; CI 0.58-0.93) and cerebrovascular events (OR 0.67; CI 0.51-0.88), whereas the association was nonsignificant for wound infections, pneumonia, and mechanical ventilation. However, GNA use was significantly associated with increased risk for acute myocardial infarction (OR 2.74; CI 2.19 3.43), urinary tract infection (OR 1.35; CI 1.21-1.50), postoperative ileus (OR 1.17; CI 1.09-1.26), blood transfusion (OR 1.12; CI 1.01-1.24), and admission to intensive care unit (OR 1.32; CI 1.22-1.43). CONCLUSIONS: We found no clear pattern of consistent favorable results for patients undergoing their open colectomy under GNA. Further prospective research is needed to help identify those who are more likely to benefit from GNA use and its mechanism of actions. PMID- 25277357 TI - Ulinastatin prevents acute lung injury led by liver transplantation. AB - BACKGROUND: Little is known regarding the effect of ulinastatin (UTI) on acute lung injury (ALI) induced by orthotopic liver transplantation. This study aims to investigate the protective effect of UTI on ALI induced by orthotopic autologous liver transplantation (OALT) in a rat model and to explore the potential underlying mechanism. MATERIALS AND METHODS: Rats were randomly allocated into the following four groups (n = 8 each): (i) sham control group (group sham); (ii) model group (underwent OALT) (group model); (iii) low-dose UTI-treated group (group u1), with UTI (50 U/g) administered intravenously both before the portal vein was occluded and after liver reperfusion started; and (iv) high-dose UTI treated group (group uh), with UTI (100 U/g) given in the same way as group ul. The lung pathologic parameters, lung water content, and levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD) activity, RanBP-type and C3HC4-type zinc finger containing protein 1 (RBCK1), and peroxiredoxin-2 (Prx-2) were assessed 8 h after OALT was performed. RESULTS: According to histology, there was severe damage in the lung of group model accompanied by increases in the TNF-alpha, IL-1beta, IL 6, and MDA levels and decreases in SOD activity and the expression of RBCK1 and Prx-2. UTI treatment significantly reduced the pathologic scores, lung water content, and TNF-alpha, IL-1beta, IL-6, and MDA levels while restoring the SOD activity and expression of RBCK1 and Prx-2. Furthermore, compared with group u1, treatment with a high dose of UTI resulted in a better protective effect on the lung when assessed by the TNF-alpha, IL-1beta, IL-6, and MDA levels and SOD activity. CONCLUSIONS: UTI dose-dependently attenuates ALI that is induced by OALT in this rat model, which is mainly due to the suppression of the inflammatory response and oxidant stress, which may, in turn, be mediated by the upregulation of RBCK1 and Prx-2 expression. PMID- 25277359 TI - Cytokine and radical inhibition in septic intestinal barrier failure. AB - BACKGROUND: Breakdown of the intestinal barrier is a driving force of sepsis and multiple organ failure. Radical scavengers or cytokine inhibitors may have a therapeutic impact on intestinal failure. Therapeutic effects on different sites of small intestine and colon have not been compared. Therefore, we investigated time-dependent intestinal permeability changes and their therapeutic inhibition in colon and small intestine with an ex vivo model. METHODS: Male Sprague-Dawley rats were either pretreated for 24 h with lipopolysaccharide (LPS) intraperitoneally alone or in combination with a radical scavenger (pyruvate or Tempol) or a cytokine inhibitor (parecoxib or vasoactive intestinal peptide). The gastrointestinal permeability was measured by time-dependent fluorescein isothiocyanate inulin diffusion using washed and everted tube-like gut segments. Blood and tissue samples were taken to investigate the development of inflammatory cytokine level (interleukin 6) in the context of cytokine inhibition and reactive oxygen species level via nicotinamide adenine dinucleotide phosphate oxidase activity in radical scavenger groups. RESULTS: After LPS treatment, mucosal permeability was enhanced up to 170% in small intestine and colon. In the small intestine the most significant reduction in permeability was found for pyruvate and parecoxib. Treatment with vasoactive intestinal peptide and parecoxib resulted in the most pronounced reduction of permeability in the colon. CONCLUSIONS: Our data suggest that cytokine inhibitors and radical scavengers have pronounced effects in LPS-induced disrupted intestinal barrier of the colon and small intestine. Our novel model comparing different anatomic sites and different points in time after the onset of sepsis may contribute to gain new insight into mechanisms and treatment options of sepsis-related gut mucosal breakdown. PMID- 25277360 TI - Effectiveness of sildenafil and U-74389G in a rat model of colitis. AB - BACKGROUND: Crohn disease is still incurable. Compounds with anti-inflammatory and/or antioxidative effects are tested in various preclinical models of the disease. Our aim was to investigate the effects of sildenafil and lazaroid U 74389G in an experimental rat model of trinitrobenzenesulfonic acid-induced colitis. MATERIALS AND METHODS: Trinitrobenzenesulfonic acid was instilled into the colon of all male Wistar rats except for the rats belonging to the first group. For 6 days, the animals in group 3 were administered daily sildenafil orally, the rats in group 4 were administered daily U-74389G intravenously, and the rats in group 5 were coadministered daily sildenafil orally and intravenous U 74389G. The rats in groups 1 and 2 were not administered any treatment. During the study, the weights were recorded as a marker of clinical condition. The colon damage was evaluated using macroscopic colon mucosal damage index (CMDI), microscopic (Geboes score), and biochemical methods (tissue tumor necrosis factor [TNF]-alpha and malondialdehyde [MDA]). RESULTS: Sildenafil reduced TNF-alpha tissue levels and increased body weight. U-74389G reduced TNF-alpha, the macroscopic index of mucosal damage score (CMDI) and increased body weight. The combined treatment with sildenafil and U-74389G reduced tissue levels of both TNF alpha and MDA, lowered CMDI and microscopic Geboes score, and increased body weight. CONCLUSIONS: U-74389G demonstrated a significant anti-inflammatory activity related to its ability to reduce colonic TNF-alpha, CMDI score, and improve weight change. We confirmed that sildenafil has anti-inflammatory capacity by reducing colonic TNF-alpha and by improving body weight. Finally, the combined treatment showed superior effects by reducing colonic TNF-alpha, colonic MDA, CMDI score, Geboes score, and by improving weight. PMID- 25277362 TI - Kyphoscoliotic type of Ehlers-Danlos Syndrome (EDS VIA) in six Egyptian patients presenting with a homogeneous clinical phenotype. AB - The kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA) is a rare recessively inherited connective tissue disorder characterized by bruisable, hyperextensible skin, generalized joint laxity, severe muscular hypotonia at birth and progressive congenital scoliosis or kyphosis. Deficiency of the enzyme lysyl hydroxylase 1 (LH1) due to mutations in PLOD1 results in underhydroxylation of collagen lysyl residues and, hence, in the abnormal formation of collagen cross-links. Here, we report on the clinical, biochemical, and molecular findings in six Egyptian patients from four unrelated families severely affected with EDS VIA. In addition to the frequently reported p.Glu326_Lys585dup, we identified two novel sequence variants p.Gln208* and p.Tyr675*, which lead either to loss of function of LH1 or to its deficiency. All affected children presented with similar clinical features of the disorder, and in addition, several dysmorphic craniofacial features, not yet described in EDS VIA. These were specific for the affected individuals of each family, but absent in their parents and their unaffected siblings. CONCLUSION: Our description of six patients presenting with a homogeneous clinical phenotype and dysmorphic craniofacial features will help pediatricians in the diagnosis of this rare disorder. PMID- 25277363 TI - The key role of polymer grafted nanoparticles in the phase miscibility of an LCST mixture. AB - Blends of bromo-terminated polystyrene (PS-Br) and poly(vinyl methylether) (PVME) exhibit lower critical solution temperatures. In this study, PS-Br was designed by atom transfer radical polymerization and was converted to thiol-capped polystyrene (PS-SH) by reacting with thiourea. The silver nanoparticles (nAg) were then decorated with covalently bound PS-SH macromolecules to improve the phase miscibility in the PS-Br-PVME blends. Thermally induced demixing in this model blend was followed in the presence of polystyrene immobilized silver nanoparticles (PS-g-nAg). The graft density of the PS macromolecules was estimated to be ca. 0.78 chains per nm(2). Although the matrix and the grafted molecular weights were similar, PS-g-nAg particles were expelled from the PS phase and were localized in the PVME phase of the blends. This was addressed with respect to intermediate graft density and favourable PS-PVME contacts from microscopic interactions point of view. Interestingly, blends with 0.5 wt% PS-g nAg delayed the spinodal decomposition temperature in the blends by ca. 18 degrees C with respect to the control blends. The scale of cooperativity, as determined by differential scanning calorimetry, increased only marginally in the case of PS-g-nAg; however, it increased significantly in the presence of bare nAg particles. PMID- 25277364 TI - Allergenic profile to Phleum pratense and immunological changes induced after grass allergen-specific immunotherapy. AB - BACKGROUND: The introduction of molecular diagnoses has provided evidence of the existence of several different allergenic profiles in grass-sensitised individuals, reflecting the large number of allergens involved. This methodology has become a potent tool for a correct diagnosis and for the selection of the most appropriate immunotherapy. Based on these concepts, the objectives of this study were to determine the sensitisation profile of a grass-allergic population, and to treat them with specific immunotherapy. METHODS: Patients suffering from rhinitis and/or asthma associated with grass pollen were recruited. The active group was treated with depigmented-polymerised allergenic extract of mixed grass pollen. sIgE and sIgG4 to Phleum pratense, and to its individual components (Phl p 1, 2, 4, 5b, 6, 7, 11 and 12) were determined at the beginning and end of the study. RESULTS: The inclusion criteria were fulfilled by 139 individuals (36 in the control group and 103 in the active group). Phl p 1 (96.4%) and Phl p 4 (91.2%) were the most recognised allergens, and 15.3% of individuals had positive IgE to cross-reactive carbohydrate determinants. Levels of antigen-specific IgG4 increased significantly after treatment, and the IgE/IgG4 ratio decreased significantly in all allergens after receiving allergen-specific immunotherapy. Non-significant differences were observed in the control group. CONCLUSIONS: A high percentage of sensitisation to Phl p 4 was observed. Immunological efficacy was studied by measuring sIgG4 levels and the IgE/IgG4 ratio before and after treatment. Sensitisation profiles should be taken into consideration to prepare the most appropriate immunotherapy containing all the relevant and needed allergens. PMID- 25277361 TI - Applying fault tree analysis to the prevention of wrong-site surgery. AB - Wrong-site surgery (WSS) is a rare event that occurs to hundreds of patients each year. Despite national implementation of the Universal Protocol over the past decade, development of effective interventions remains a challenge. We performed a systematic review of the literature reporting root causes of WSS and used the results to perform a fault tree analysis to assess the reliability of the system in preventing WSS and identifying high-priority targets for interventions aimed at reducing WSS. Process components where a single error could result in WSS were labeled with OR gates; process aspects reinforced by verification were labeled with AND gates. The overall redundancy of the system was evaluated based on prevalence of AND gates and OR gates. In total, 37 studies described risk factors for WSS. The fault tree contains 35 faults, most of which fall into five main categories. Despite the Universal Protocol mandating patient verification, surgical site signing, and a brief time-out, a large proportion of the process relies on human transcription and verification. Fault tree analysis provides a standardized perspective of errors or faults within the system of surgical scheduling and site confirmation. It can be adapted by institutions or specialties to lead to more targeted interventions to increase redundancy and reliability within the preoperative process. PMID- 25277366 TI - Disentangling the impact of resistance and ambivalence on therapy outcomes in cognitive behavioural therapy for generalized anxiety disorder. AB - Resistance and ambivalence about change are increasingly recognized as important determinants of treatment outcomes. Moreover, resistance and ambivalence are thought to be theoretically related in that clients who are more ambivalent about change are more likely to demonstrate resistance to the process and tasks of treatment. In the context of cognitive behavioural therapy (CBT) for generalized anxiety disorder, the present study simultaneously examined early resistance and ambivalence using two observer-based coding systems in order to determine their inter-relationship and, importantly, to investigate their relative contributions to outcome. Resistance was also coded during mid-treatment in order to investigate possible mediation pathways. Early ambivalence (clients' arguments against change or counter-change talk) was found to be no longer related to outcomes when early resistance was taken into account, suggesting that disharmony in the therapeutic relationship is more important to outcomes than ambivalence per se. Moreover, mid-treatment resistance partially mediated the relationship between early resistance and post-treatment worry severity. That is, higher early opposition to therapist direction is related to poorer outcomes, in part because it is associated with greater resistance during the working phase of CBT. The findings underscore the critical need for therapists to be sensitive to identifying resistance early and throughout treatment. PMID- 25277365 TI - Performance of statistical methods on CHARGE targeted sequencing data. AB - BACKGROUND: The CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Sequencing Project is a national, collaborative effort from 3 studies: Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), and Atherosclerosis Risk in Communities (ARIC). It uses a case-cohort design, whereby a random sample of study participants is enriched with participants in extremes of traits. Although statistical methods are available to investigate the role of rare variants, few have evaluated their performance in a case-cohort design. RESULTS: We evaluate several methods, including the sequence kernel association test (SKAT), Score-Seq, and weighted (Madsen and Browning) and unweighted burden tests. Using genotypes from the CHARGE targeted-sequencing project for FHS (n = 1096), we simulate phenotypes in a large population for 11 correlated traits and then sample individuals to mimic the CHARGE Sequencing study design. We evaluate type I error and power for 77 targeted regions. CONCLUSIONS: We provide some guidelines on the performance of these aggregate-based tests to detect associations with rare variants when applied to case-cohort study designs, using CHARGE targeted sequencing data. Type I error is conservative when we consider variants with minor allele frequency (MAF) < 1%. Power is generally low, although it is relatively larger for Score-Seq. Greater numbers of causal variants and a greater proportion of variance improve the power, but it tends to be lower in the presence of bi-directionality of effects of causal genotypes, especially for Score-Seq. PMID- 25277368 TI - Integrating a redox-coupled dye-sensitized photoelectrode into a lithium-oxygen battery for photoassisted charging. AB - With a high theoretical specific energy, the non-aqueous rechargeable lithium oxygen battery is a promising next-generation energy storage technique. However, the large charging overpotential remains a challenge due to the difficulty in electrochemically oxidizing the insulating lithium peroxide. Recently, a redox shuttle has been introduced into the electrolyte to chemically oxidize lithium peroxide. Here, we report the use of a triiodide/iodide redox shuttle to couple a built-in dye-sensitized titanium dioxide photoelectrode with the oxygen electrode for the photoassisted charging of a lithium-oxygen battery. On charging under illumination, triiodide ions are generated on the photoelectrode, and subsequently oxidize lithium peroxide. Due to the contribution of the photovoltage, the charging overpotential is greatly reduced. The use of a redox shuttle to couple a photoelectrode and an oxygen electrode offers a unique strategy to address the overpotential issue of non-aqueous lithium-oxygen batteries and also a distinct approach for integrating solar cells and batteries. PMID- 25277367 TI - Global and local genetic diversity at two microsatellite loci in Plasmodium vivax parasites from Asia, Africa and South America. AB - BACKGROUND: Even though Plasmodium vivax has the widest worldwide distribution of the human malaria species and imposes a serious impact on global public health, the investigation of genetic diversity in this species has been limited in comparison to Plasmodium falciparum. Markers of genetic diversity are vital to the evaluation of drug and vaccine efficacy, tracking of P. vivax outbreaks, and assessing geographical differentiation between parasite populations. METHODS: The genetic diversity of eight P. vivax populations (n=543) was investigated by using two microsatellites (MS), m1501 and m3502, chosen because of their seven and eight base-pair (bp) repeat lengths, respectively. These were compared with published data of the same loci from six other P. vivax populations. RESULTS: In total, 1,440 P. vivax samples from 14 countries on three continents were compared. There was highest heterozygosity within Asian populations, where expected heterozygosity (He) was 0.92-0.98, and alleles with a high repeat number were more common. Pairwise FST revealed significant differentiation between most P. vivax populations, with the highest divergence found between Asian and South American populations, yet the majority of the diversity (~89%) was found to exist within rather than between populations. CONCLUSIONS: The MS markers used were informative in both global and local P. vivax population comparisons and their seven and eight bp repeat length facilitated population comparison using data from independent studies. A complex spatial pattern of MS polymorphisms among global P. vivax populations was observed which has potential utility in future epidemiological studies of the P. vivax parasite. PMID- 25277369 TI - Ripening stage and extraction method effects on physical properties, polyphenol composition and antioxidant activities of cumin (Cuminum cyminum L.) seeds. AB - The effects of two extraction methods, used at three ripening stages on the total polyphenol contents and the antioxidant activities of Cumin (Cuminum cyminum L.) seed extracts were studied. The ripening stage effect on some physical properties of cumin seed was significant. The increase of dry matter (from 10.3 to 87.5%) during ripeness was correlated negatively with that of moisture content (from 89.7 to 12.5%). Besides results showed that the full ripe seeds were richer on polyphenols and condensed tannin than unripe ones, and consequently exhibited higher antioxidant activities. However, the unripe seeds had a higher total flavonoid content compared to those of half ripe and full ripe ones. The comparison of two extraction methods showed that soxhlet extracts contained the greatest amount of polyphenols and flavonoids, while maceration samples exhibited higher antiradical and bleaching power assay. Total phenolic contents and IC50 (concentration required to cause a 50% DPPH inhibition) values in cumin seed during their maturation allowed to conclude that antioxidant activity does not depend only on the high content of total phenolics but also on the phenolic composition. A total of 19 phenolic compounds were successfully identified by HPLC analysis during the ripening of cumin seeds. Rosmarinic acid was the major phenolic acid for the unripe seeds. Furthermore, half ripe and full ripe seeds were dominated by p-coumaric acid. These compounds might be considered as interesting bioactive natural substances that may be used in several fields, such as nutraceuticals, cosmetics and agro-food industry. PMID- 25277371 TI - Surgical removal of retroperitoneal tumors after chemotherapy treated testicular tumors. AB - In the era of chemotherapy, patients with advanced testicular tumor often presents with residual mass after completion of chemotherapy. Post chemotherapy RPLND is an important part of the multimodality treatment in these patients. According to current guidelines and recommendations, post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is recommended in NSGCT patients with all residual lesions and normalized tumor markers. In seminomas, surgery is considered in patients with residual tumor > 3 cm and a positive positron emission tomography (PET) scan. A conventional bilateral template should be performed for patients undergoing PC-RPLND. However, a modified template can be performed in select patients with low volume disease to reduce the long-term morbidities and peri-operative complications. Laparoscopic PC-RPLND is safe and feasible. The oncological outcome of PC-RPLND is excellent if all tumors are resected. PC-RPLND is a complex surgery and should be done in high volume tertiary centers. PMID- 25277372 TI - The role of sleep and circadian rhythms in health: a snapshot of key research interrogations. PMID- 25277374 TI - Computational investigation of the initial two-electron, two-proton steps in the reaction mechanism of hydroxylamine oxidoreductase. AB - Reported here is a computational study based on density functional theory that presents the first attempt to investigate the 2-electron 2-proton reaction of Fe(III)-H2NOH to Fe(III)-HNO in the catalytic cycle of hydroxylamine oxidoreductase-a multiheme-containing enzyme that catalyzes the conversion of hydroxylamine (HA) to nitrite in nitrifying bacteria. Two subsequent protonation events are proposed to initiate the process, of which the second is suggested to be concerted with a one-electron oxidation. The final one-electron oxidation is further proposed to be accompanied by a third deprotonation process, suggesting that Fe(III)-HNO may not be an isolable intermediate in the HAO catalytic cycle. Further explorations are suggested to be focused on the following steps in the catalytic cycle, the influence of the lateral substituents of the heme (and especially of the Cys and Tyr cross-links), the comparative study of hydrazine oxidation, the proton delivery network in the distal site and, possibly, on linkage isomerism. PMID- 25277373 TI - How big is this neoplasia? live colonoscopic size measurement using the Infocus Breakpoint. AB - Colonoscopy is the reference medical examination for early diagnosis and treatment of colonic diseases. This minimally invasive technique allows endoscopists to explore the colon cavity and remove neoplasias - abnormal growths of tissue - which may develop into malignant tumors. The size, shape and appearance of a neoplasia are essential cues for diagnostic. However, the size is difficult to estimate because the absolute scale of the observed tissue is not directly conveyed in the 2D colonoscopic images. An erroneous size estimate may lead to inappropriate treatment. There currently exist no solutions to reproducible neoplasia size measurement adapted to colonoscopy. We propose a colonoscopic size measurement system for neoplasias. By using a simple planar geometry, the key technical problem is reduced to resolving scale. Our core contribution is introducing the Infocus-Breakpoint (IB) that allows us to resolve scale from a regular colonoscopic video. We define the IB as the lower limit of the colonoscope's depth of field. The IB corresponds to a precise colonoscope to tissue distance, called the reference depth, which we calibrate preoperatively. We detect the IB intraoperatively thanks to two novel modules: deformable Blur Estimating Tracking (BET) and Blur-Model Fitting (BMF). With our system, the endoscopist may interactively measure the length and area of a neoplasia in a 2D colonoscopic image directly. Our system needs no hardware modification to standard monocular colonoscopes, yet reaching a size measurement accuracy of the order of a millimeter, as shown on several phantom and patient datasets. PMID- 25277375 TI - Localization of folate metabolic enzymes, methionine synthase and 5,10 methylenetetrahydrofolate reductase in human placenta. AB - BACKGROUND: Normal fetal development requires adequate folate levels during pregnancy. Although folate metabolic enzymes have important roles in the maintenance of normal fetal development, the location of folate metabolic enzymes, methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR), has not been previously examined. METHODS: We investigated the expression of MTR and MTHFR in human term placenta obtained from normal and pregnancy-induced hypertension (PIH) patients. RESULTS: MTR is expressed in the villous syncytiotrophoblast and MTHFR is expressed in the extravillous trophoblast. There was no difference in the quantity and location of these enzymes between control and PIH patients. CONCLUSION: These results suggest that MTR in the villous trophoblast participates in the metabolism of homocysteine by using folate, and MTHFR in the extravillous trophoblast is associated with extratrophoblast invasion. PMID- 25277370 TI - Electrophysiological correlates of the BOLD signal for EEG-informed fMRI. AB - Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are important tools in cognitive and clinical neuroscience. Combined EEG-fMRI has been shown to help to characterise brain networks involved in epileptic activity, as well as in different sensory, motor and cognitive functions. A good understanding of the electrophysiological correlates of the blood oxygen level dependent (BOLD) signal is necessary to interpret fMRI maps, particularly when obtained in combination with EEG. We review the current understanding of electrophysiological-haemodynamic correlates, during different types of brain activity. We start by describing the basic mechanisms underlying EEG and BOLD signals and proceed by reviewing EEG-informed fMRI studies using fMRI to map specific EEG phenomena over the entire brain (EEG-fMRI mapping), or exploring a range of EEG-derived quantities to determine which best explain colocalised BOLD fluctuations (local EEG-fMRI coupling). While reviewing studies of different forms of brain activity (epileptic and nonepileptic spontaneous activity; cognitive, sensory and motor functions), a significant attention is given to epilepsy because the investigation of its haemodynamic correlates is the most common application of EEG-informed fMRI. Our review is focused on EEG-informed fMRI, an asymmetric approach of data integration. We give special attention to the invasiveness of electrophysiological measurements and the simultaneity of multimodal acquisitions because these methodological aspects determine the nature of the conclusions that can be drawn from EEG-informed fMRI studies. We emphasise the advantages of, and need for, simultaneous intracranial EEG-fMRI studies in humans, which recently became available and hold great potential to improve our understanding of the electrophysiological correlates of BOLD fluctuations. PMID- 25277377 TI - Highly efficient molecular nickel catalysts for electrochemical hydrogen production from neutral water. AB - A series of nickel complexes containing N5-pentadentate ligands with different amine-to-pyridine ratios were studied for electrochemical H2 production in neutral water and the one with a diamine-tripyridine ligand displays a TON of up to 308,000 over 60 h electrolysis at -1.25 V vs. SHE, with a Faradaic efficiency of ~91%. PMID- 25277376 TI - Sensitization of neurons in the central nucleus of the amygdala via the decreased GABAergic inhibition contributes to the development of neuropathic pain-related anxiety-like behaviors in rats. AB - BACKGROUND: Despite high prevalence of anxiety accompanying with chronic pain, the mechanisms underlying pain-related anxiety are largely unknown. With its well documented role in pain and emotion processing, the amygdala may act as a key player in pathogenesis of neuropathic pain-related anxiety. Pain-related plasticity and sensitization of CeA (central nucleus of the amygdala) neurons have been shown in several models of chronic pain. In addition, firing pattern of neurons with spike output can powerfully affect functional output of the brain nucleus, and GABAergic neurons are crucial in the modulation of neuronal excitability. In this study, we first investigated whether pain-related plasticity (e.g. alteration of neuronal firing patterns) and sensitization of CeA neurons contribute to nerve injury-evoked anxiety in neuropathic rats. Furthermore, we explored whether GABAergic disinhibition is responsible for regulating firing patterns and intrinsic excitabilities of CeA neurons as well as for pain-related anxiety in neuropathic rats. RESULTS: We discovered that spinal nerve ligation (SNL) produced neuropathic pain-related anxiety-like behaviors in rats, which could be specifically inhibited by intra-CeA administration of anti anxiety drug diazepam. Moreover, we found potentiated plasticity and sensitization of CeA neurons in SNL-induced anxiety rats, of which including: 1) increased burst firing pattern and early-adapting firing pattern; 2) increased spike frequency and intrinsic excitability; 3) increased amplitude of both after depolarized-potential (ADP) and sub-threshold membrane potential oscillation. In addition, we observed a remarkable reduction of GABAergic inhibition in CeA neurons in SNL-induced anxiety rats, which was proved to be important for altered firing patterns and hyperexcitability of CeA neurons, thereby greatly contributing to the development of neuropathic pain-related anxiety. Accordantly, activation of GABAergic inhibition by intra-CeA administration of muscimol, a selective GABAA receptors agonist, could inhibit SNL-induced anxiety-like behaviors in neuropathic rats. By contrast, suppression of GABAergic inhibition by intra-CeA administration of bicuculline, a selective GABAA receptors antagonist, produced anxiety-like behavior in normal rats. CONCLUSIONS: This study suggests that reduction of GABAergic inhibition may be responsible for potentiated plasticity and sensitization of CeA neurons, which likely underlie the enhanced output of amygdala and neuropathic pain-related anxiety in SNL rats. PMID- 25277378 TI - Integrity of (111)In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse. AB - INTRODUCTION: Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo. METHODS: We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with (59)Fe, (14)C-oleic acid, and (111)In. RESULTS: Mouse biodistributions showed (111)In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of (59)Fe than (111)In in liver and spleen, but lower levels of (14)C. CONCLUSIONS: While there is some degree of dissociation between the (111)In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component. PMID- 25277380 TI - How can screening for malnutrition among hospitalized patients be improved? An automatic e-mail alert system when admitting previously malnourished patients. AB - BACKGROUND & AIMS: Screening for malnutrition is not often done in the management of hospitalized patients. An original computer tool was developed at the Dunkerque hospital to detect readmissions of patients with malnutrition during a previous stay and generate e-mail alerts to the nutrition department. The aim of the study was to describe and evaluate this tool and the activity of the nutrition department in connection with the alerts sent. METHODS: The number of alerts sent, dietary consultations conducted, assessments of the nutritional status and the number of malnourished patients diagnosed were collected from September 1st to November 30th 2012. The positive predictive value (PPV) of the malnutrition screening tool was estimated. The evolution of the nutritional status between the last and the current hospitalization was also evaluated. RESULTS: A total of 531 e-mail alerts were sent (mean of 8.2 per working day), leading to 205 dietary consultations but only 144 recorded assessments of the nutritional status (lack of information in medical records). Of the latter, 128 diagnoses of malnutrition were made, i.e. a PPV of 88.9%, 95% Confidence Interval = [83.8%, 94%]. Overall, only one quarter of readmitted patients had improved nutritional status. CONCLUSIONS: The automatic e-mail alert system is operational and useful to effectively detect patients at risk of malnutrition and make follow up possible. In addition, an unfavorable evolution of the nutritional status of malnourished patients was observed. PMID- 25277379 TI - Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR. AB - Cisplatin is an effective and widely used first-line chemotherapeutic drug for treating cancers. However, many patients sustain cisplatin-induced peripheral neuropathy (CIPN), often leading to a reduction in drug dosages or complete cessation of treatment altogether. Therefore, it is important to understand cisplatin mechanisms in peripheral nerve tissue mediating its toxicity and identify signaling pathways for potential intervention. Rho GTPase activation is increased following trauma in several models of neuronal injury. Thus, we investigated whether components of the Rho signaling pathway represent important neuroprotective targets with the potential to ameliorate CIPN and thereby optimize current chemotherapy treatment regimens. We have developed a novel CIPN model in the mouse. Using this model and primary neuronal culture, we determined whether LM11A-31, a small-molecule, orally bioavailable ligand of the p75 neurotrophin receptor (p75(NTR)), can modulate Rho GTPase signaling and reduce CIPN. Von Frey filament analysis of sural nerve function showed that LM11A-31 treatment prevented decreases in peripheral nerve sensation seen with cisplatin treatment. Morphometric analysis of harvested sural nerves revealed that cisplatin-induced abnormal nerve fiber morphology and the decreases in fiber area were alleviated with concurrent LM11A-31 treatment. Cisplatin treatment increased RhoA activity accompanied by the reduced tyrosine phosphorylation of SHP2, which was reversed by LM11A-31. LM11A-31 also countered the effects of calpeptin, which activated RhoA by inhibiting SHP2 tyrosine phosphatase. Therefore, suppression of RhoA signaling by LM11A-31 that modulates p75(NTR) or activates SHP2 tyrosine phosphatase downstream of the NGF receptor enhances neuroprotection in experimental CIPN in mouse model. PMID- 25277381 TI - Postprandial hypotension in older adults: Can it be prevented by drinking water before the meal? AB - BACKGROUND & AIMS: An important consequence of ageing is a tendency for postprandial blood pressure to decline, which can lead to fainting. As a possible countermeasure, we investigated in healthy older adults the impact of drinking water before a breakfast meal on postprandial cardiovascular and autonomic functions. METHODS: After a stable cardiovascular baseline recording for at least 20 min, twelve older adult (67 +/- 1 y) test subjects ingested, in a crossover study design, either 100 mL or 500 mL of tap water over 4 min, which was followed by the consumption of the test breakfast meal (1708 kJ) over a period of 15 min. Then, cardiovascular recordings were resumed for 90 min after the meal. Eleven young (25 +/- 1 y) and healthy subjects served as a control group. Measurements included beat-to-beat blood pressure, heart rate, impedance cardiography and autonomic variables. RESULTS: In older adults, systolic and diastolic blood pressure started to decline around 30 min after the meal, with the lowest values around 60 min; these effects were not observed in the young control group. Postprandial systolic blood pressure decreased between 30 and 90 min to a greater extent in response to 100 mL than to 500 mL (-6.4 vs. -3.3 mmHg, P < 0.05). Drinking 500 mL of water tended to increase stroke volume, cardiac output and vagal markers to a greater extent than 100 mL. CONCLUSIONS: Our data suggest that drinking a large volume (500 mL) of water before a meal may attenuate postprandial hypotension in older adults. PMID- 25277382 TI - [Venoarterial extracorporeal membrane oxygenation: be-all and end-all of cardiopulmonary support]. PMID- 25277383 TI - Doxycycline as an inhibitor of the epithelial-to-mesenchymal transition and vasculogenic mimicry in hepatocellular carcinoma. AB - This study was conducted to examine the effects of doxycycline on the survival time and proliferation of hepatocellular carcinoma (HCC) in vivo and on the biologic functions of HCC in vitro. This study was also designed to evaluate the effects of doxycycline on epithelial-to-mesenchymal transition (EMT)- and vasculogenic mimicry (VM)-related protein expression and on matrix metalloproteinase (MMP) and DNA methyltransferase (DNMT) activity in vitro. Human MHCC97H cells were injected into BALB/c mice, which were divided into treatment and control groups. Doxycycline treatment prolonged the mouse survival time and partly suppressed the growth of engrafted HCC tumor cells, with an inhibition rate of 43.39%. Higher amounts of VM and endothelium-dependent vessels were found in the control group than the treatment group. IHC indicated that epithelial (E) cadherin expression was increased in the doxycycline-treated mice compared with the control group. In in vitro experiments, doxycycline promoted HCC cell adhesion but inhibited HCC cell viability, proliferation, migration, and invasion. Western blot analysis, semiquantitative RT-PCR, qRT-PCR, and immunofluorescence demonstrated that doxycycline inhibited the degradation of the epithelial marker E-cadherin and downregulated the expression levels of EMT promoters, the mesenchymal marker vimentin, and the VM-associated marker vascular endothelial (VE)-cadherin. Furthermore, the activities of MMPs and DNMTs were examined in different groups via gelatin zymography and a DNMT activity assay kit. A methylation-specific PCR was performed to assess the promoter methylation of CDH1 (the gene encoding E-cadherin). Doxycycline prolonged the mouse survival time by inhibiting EMT progression and VM formation. PMID- 25277385 TI - PET imaging of beta-glucuronidase activity by an activity-based 124I-trapping probe for the personalized glucuronide prodrug targeted therapy. AB - Beta-glucuronidase (betaG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image betaG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of betaG activity for medical usage is not yet available. Here, we developed a radioactive betaG activity-based trapping probe for positron emission tomography (PET). We generated a (124)I-tyramine-conjugated difluoromethylphenol beta glucuronide probe (TrapG) to form (124)I-TrapG that could be selectively activated by betaG for subsequent attachment of (124)I-tyramine to nucleophilic moieties near betaG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half life of (124)I-TrapG. betaG targeting of (124)I-TrapG in vivo was examined by micro-PET. The biodistribution of (131)I-TrapG was investigated in different organs. Finally, we imaged the endogenous betaG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at betaG-expressing CT26 (CT26/mbetaG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. (124)I-TrapG preferentially accumulated in CT26/mbetaG but not CT26 cells. Meanwhile, micro-PET and whole-body autoradiography results demonstrated that (124)I-TrapG signals in CT26/mbetaG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous betaG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. (124)I TrapG exhibited low cytotoxicity allowing long-term monitoring of betaG activity in vivo to aid in the optimization of prodrug targeted therapy. PMID- 25277384 TI - Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress. AB - Activation of the p53 pathway has been considered a therapeutic strategy to target cancers. We have previously identified several p53-activating small molecules in a cell-based screen. Two of the compounds activated p53 by causing DNA damage, but this modality was absent in the other four. We recently showed that one of these, BMH-21, inhibits RNA polymerase I (Pol I) transcription, causes the degradation of Pol I catalytic subunit RPA194, and has potent anticancer activity. We show here that three remaining compounds in this screen, BMH-9, BMH-22, and BMH-23, cause reorganization of nucleolar marker proteins consistent with segregation of the nucleolus, a hallmark of Pol I transcription stress. Further, the compounds destabilize RPA194 in a proteasome-dependent manner and inhibit nascent rRNA synthesis and expression of the 45S rRNA precursor. BMH-9- and BMH-22-mediated nucleolar stress was detected in ex vivo cultured human prostate tissues indicating good tissue bioactivity. Testing of closely related analogues showed that their activities were chemically constrained. Viability screen for BMH-9, BMH-22, and BMH-23 in the NCI60 cancer cell lines showed potent anticancer activity across many tumor types. Finally, we show that the Pol I transcription stress by BMH-9, BMH-22, and BMH-23 is independent of p53 function. These results highlight the dominant impact of Pol I transcription stress on p53 pathway activation and bring forward chemically novel lead molecules for Pol I inhibition, and, potentially, cancer targeting. PMID- 25277386 TI - False positive or negative results of shear-wave elastography in differentiating benign from malignant breast masses: analysis of clinical and ultrasonographic characteristics. AB - BACKGROUND: Shear-wave elastography (SWE) has the potential to improve diagnostic performance of conventional ultrasound (US) in differentiating benign from malignant breast masses. PURPOSE: To investigate false positive or negative results of SWE in differentiating benign from malignant breast masses and to analyze clinical and imaging characteristics of the masses with false SWE findings. MATERIAL AND METHODS: From May to October 2013, 166 breast lesions of 164 consecutive women (mean age, 45.3 +/- 10.1 years) who had been scheduled for biopsy were included. Conventional US and SWE were performed in all women before biopsy. Clinical, ultrasonographic morphologic features and SWE parameters (pattern classification and standard deviation [SD]) were recorded and compared with the histopathology results. Patient and lesion factors in the "true" and "false" groups were compared. RESULTS: Of the 166 masses, 118 (71.1%) were benign and 48 (28.9%) were malignant. False SWE features were more frequently observed in benign masses. False positive rates of benign masses and false negative rates of malignancy were 53% and 8.2%, respectively, using SWE pattern analysis and were 22.4% and 10.3%, respectively, using SD values. A lesion boundary of the masses on US (P = 0.039) and younger patient age (P = 0.047) were significantly associated with false SWE findings. CONCLUSION: These clinical and ultrasonographic features need to be carefully evaluated in performance and interpretation of SWE examinations. PMID- 25277387 TI - The imaging spectrum of pulmonary tuberculosis: a critical appraisal. PMID- 25277388 TI - Pneumomediastinum and pneumoperitoneum on computed tomography after peroral endoscopic myotomy (POEM): postoperative changes or complications? AB - BACKGROUND: Many of the acute alterations after peroral endoscopic myotomy (POEM) may be of little clinical significance, while others may herald major clinical problems. The question whether pneumomediastinum/pneumoperitoneum is a normal postoperative finding after POEM, or should be regarded as a sign of a complication needs to be evaluated. Familiarity with these findings in computed tomography (CT) is essential for radiologists. PURPOSE: To evaluate whether or not pneumomediastinum/pneumoperitoneum detected by chest CT is a sign of a complication after POEM using CO2 insufflation for esophageal achalasia. MATERIAL AND METHODS: One hundred and eight patients with esophageal achalasia who underwent chest CT within 30 hours after POEM were included. CT findings were retrospectively reviewed by two radiologists in consensus. The correlation between pneumomediastinum and/or pneumoperitoneum shown on CT and the development of complications was analyzed. RESULTS: Abnormal findings were identified on post treatment CT, including pneumomediastinum and/or pneumoperitoneum (53.7%, 58/108), pneumothorax (0.9%, 1/108), subcutaneous emphysema (29.6%, 32/108), pleural effusion (69.4%, 75/108), segmental atelectasis of lung tissue (29.6%, 32/108), minor inflammation of lungs (69.4%, 75/108), and ascites (0.9%, 1/108). Pneumomediastinum and pneumoperitoneum were observed simultaneously in 29 cases. The incidence rate of mild complications was high (79.6%, 86/108), while the rate of severe complications was low (2.8%, 3/108). There was no significant correlation between the occurrence of pneumomediastinum and/or pneumoperitoneum on CT and the development of complications (P = 0.542), or the development of severe complications including delayed hemorrhage, esophageal perforation, and retroperitoneal abscess. CONCLUSION: Pneumomediastinum and pneumoperitoneum detected by CT occur frequently after POEM and may be regarded as normal postoperative changes. PMID- 25277389 TI - Factors affecting the decline in incidence of diabetes in the Diabetes Prevention Program Outcomes Study (DPPOS). AB - During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (-42%) and metformin (-25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: "effective intervention" (changes in weight and other factors due to intensive lifestyle intervention) and "exhaustion of susceptible" (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates of progression in the intensive lifestyle intervention group. Different patterns in the average genetic risk score over time were consistent with exhaustion of susceptibles. Results were consistent with exhaustion of susceptibles for the change in incidence rates, but not the availability of intensive lifestyle intervention to all persons before the beginning of the DPPOS. Thus, effective intervention did not explain the lower diabetes rates in the DPPOS among subjects in the placebo and metformin groups compared with those in the DPP. PMID- 25277390 TI - Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia. AB - Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 international units [IU] (10 and 20 IU every 15 min) of the insulin analog aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via intravenous infusion of ins-asp at a dose of 0.12 IU/kg/24 h (n = 10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia. PMID- 25277391 TI - Insulin receptor substrate-2 (Irs2) in endothelial cells plays a crucial role in insulin secretion. AB - Endothelial cells are considered to be essential for normal pancreatic beta-cell function. The current study attempted to demonstrate the role of insulin receptor substrate-2 (Irs2) in endothelial cells with regard to insulin secretion. Endothelial cell-specific Irs2 knockout (ETIrs2KO) mice exhibited impaired glucose-induced, arginine-induced, and glucagon-induced insulin secretion and showed glucose intolerance. In batch incubation and perifusion experiments using isolated islets, glucose-induced insulin secretion was not significantly different between the control and the ETIrs2KO mice. In contrast, in perfusion experiments, glucose-induced insulin secretion was significantly impaired in the ETIrs2KO mice. The islet blood flow was significantly impaired in the ETIrs2KO mice. After the treatment of these knockout mice with enalapril maleate, which improved the islet blood flow, glucose-stimulated insulin secretion was almost completely restored to levels equal to those in the control mice. These data suggest that Irs2 deletion in endothelial cells leads to a decreased islet blood flow, which may cause impaired glucose-induced insulin secretion. Thus, Irs2 in endothelial cells may serve as a novel therapeutic target for preventing and ameliorating type 2 diabetes and metabolic syndrome. PMID- 25277392 TI - Niche-dependent regulations of metabolic balance in high-fat diet-induced diabetic mice by mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) have great potential to maintain glucose homeostasis and metabolic balance. Here, we demonstrate that in mice continuously fed with high-fat diet (HFD) that developed non-insulin-dependent diabetes, two episodes of systemic MSC transplantations effectively improve glucose tolerance and blood glucose homeostasis and reduce body weight through targeting pancreas and insulin-sensitive tissues and organs via site-specific mechanisms. MSCs support pancreatic islet growth by direct differentiation into insulin-producing cells and by mitigating the cytotoxicity of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the pancreas. Localization of MSCs in the liver and skeletal muscles in diabetic animals is also enhanced and therefore improves glucose tolerance, although long-term engraftment is not observed. MSCs prevent HFD-induced fatty liver development and restore glycogen storage in hepatocytes. Increased expression of IL-1 receptor antagonist and Glut4 in skeletal muscles after MSC transplantation results in better blood glucose homeostasis. Intriguingly, systemic MSC transplantation does not alter adipocyte number, but it decreases HFD-induced cell infiltration in adipose tissues and reduces serum levels of adipokines, including leptin and TNF-alpha. Taken together, systemic MSC transplantation ameliorates HFD-induced obesity and restores metabolic balance through multisystemic regulations that are niche dependent. Such findings have supported systemic transplantation of MSCs to correct metabolic imbalance. PMID- 25277393 TI - Cadherin engagement improves insulin secretion of single human beta-cells. AB - The aim of this study was to assess whether cadherin-mediated adhesion of human islet cells was affected by insulin secretagogues and explore the role of cadherins in the secretory activity of beta-cells. Experiments were carried out with single islet cells adherent to chimeric proteins made of functional E-, N-, or P-cadherin ectodomains fused to the Fc fragment of immunoglobulin (E-cad/Fc, N cad/Fc, and P-cad/Fc) and immobilized on an inert substrate. We observed that cadherin expression in islet cells was not affected by insulin secretagogues. Adhesion tests showed that islet cells attached to N-cad/Fc and E-cad/Fc acquired, in a time- and secretagogue-dependent manner, a spreading form that was inhibited by blocking cadherin antibodies. By reverse hemolytic plaque assay, we showed that glucose-stimulated insulin secretion of single beta-cells was increased by N-cad/Fc and E-cad/Fc adhesion compared with control. In the presence of E-cad/Fc and after glucose stimulation, we showed that total insulin secretion was six times higher in spreading beta-cells compared with round beta cells. Furthermore, cadherin-mediated adhesion induced an asymmetric distribution of cortical actin in beta-cells. Our results demonstrate that adhesion of beta cells to E- and N-cadherins is regulated by insulin secretagogues and that E- and N-cadherin engagement promotes stimulated insulin secretion. PMID- 25277394 TI - Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis. AB - Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP 1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or beta-cell mass. GLP 1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3alpha and Reg3beta gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice. PMID- 25277395 TI - Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats. AB - 1-Deoxysphingolipids (1-deoxySLs) are atypical neurotoxic sphingolipids that are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1 deoxySL concentrations cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), an axonal neuropathy associated with several missense mutations in SPT. Oral L-serine supplementation suppressed the formation of 1-deoxySLs in patients with HSAN1 and preserved nerve function in an HSAN1 mouse model. Because 1 deoxySLs also are elevated in patients with type 2 diabetes mellitus, L-serine supplementation could also be a therapeutic option for diabetic neuropathy (DN). This was tested in diabetic STZ rats in a preventive and therapeutic treatment scheme. Diabetic rats showed significantly increased plasma 1-deoxySL concentrations, and L-serine supplementation lowered 1-deoxySL concentrations in both treatment schemes (P < 0.0001). L-serine had no significant effect on hyperglycemia, body weight, or food intake. Mechanical sensitivity was significantly improved in the preventive (P < 0.01) and therapeutic schemes (P < 0.001). Nerve conduction velocity (NCV) significantly improved in only the preventive group (P < 0.05). Overall NCV showed a highly significant (P = 5.2E 12) inverse correlation with plasma 1-deoxySL concentrations. In summary, our data support the hypothesis that 1-deoxySLs are involved in the pathology of DN and that an oral L-serine supplementation could be a novel therapeutic option for treating DN. PMID- 25277396 TI - Postnatal beta-cell proliferation and mass expansion is dependent on the transcription factor Nkx6.1. AB - All forms of diabetes are characterized by a loss of functional beta-cell mass, and strategies for expanding beta-cell mass could have significant therapeutic benefit. We have recently identified the transcription factor Nkx6.1 as an essential maintenance factor of the functional beta-cell state. In addition, Nkx6.1 has been proposed to control beta-cell proliferation, but a role for Nkx6.1 in regulating beta-cell mass has not been demonstrated. Here, we show that Nkx6.1 is required for postnatal beta-cell mass expansion. Genetic inactivation of Nkx6.1 in newly formed beta-cells caused a drastic decrease in early postnatal beta-cell proliferation, leading to reduced beta-cell mass and glucose intolerance. Interestingly, Nkx6.1 was dispensable for prenatal beta-cell proliferation. We found that Nkx6.1 regulates the expression of several beta-cell maturation markers as well as expression of the nutrient sensors Glut2 and Glp1r. Manifestation of the beta-cell mass defect at the transition to postnatal feeding suggests that Nkx6.1 could regulate beta-cell growth by enabling beta-cells to respond to nutrient-dependent proliferation signals, such as glucose and Glp1. Identification of beta-cell-intrinsic regulators that connect nutrient-sensing and proliferation suggests new therapeutic targets for expanding functional beta cell mass. PMID- 25277397 TI - Inactivation of corticotropin-releasing hormone-induced insulinotropic role by high-altitude hypoxia. AB - We have shown that hypoxia reduces plasma insulin, which correlates with corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) in rats, but the mechanism remains unclear. Here, we report that hypobaric hypoxia at an altitude of 5,000 m for 8 h enhances rat plasma CRH, corticosterone, and glucose levels, whereas the plasma insulin and pancreatic ATP/ADP ratio is reduced. In islets cultured under normoxia, CRH stimulated insulin release in a glucose- and CRH level-dependent manner by activating CRHR1 and thus the cAMP-dependent protein kinase pathway and calcium influx through L-type channels. In islets cultured under hypoxia, however, the insulinotropic effect of CRH was inactivated due to reduced ATP and cAMP and coincident loss of intracellular calcium oscillations. Serum and glucocorticoid-inducible kinase 1 (SGK1) also played an inhibitory role. In human volunteers rapidly ascended to 3,860 m, plasma CRH and glucose levels increased without a detectable change in plasma insulin. By contrast, volunteers with acute mountain sickness (AMS) exhibited a marked decrease in HOMA insulin sensitivity (HOMA-IS) and enhanced plasma CRH. In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP/ADP ratio, cAMP and calcium influx, and upregulated SGK1. Hypoxia may not affect HOMA-IS in healthy volunteers but reduces it in AMS volunteers. PMID- 25277398 TI - Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model. AB - We generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG(OE)), which results in an increase in liver glycogen. When fed a high fat diet (HFD), these animals reduced their food intake. The resulting effect was a lower body weight, decreased fat mass, and reduced leptin levels. Furthermore, PTG overexpression reversed the glucose intolerance and hyperinsulinemia caused by the HFD and protected against HFD-induced hepatic steatosis. Of note, when fed an HFD, PTG(OE) mice did not show the decrease in hepatic ATP content observed in control animals and had lower expression of neuropeptide Y and higher expression of proopiomelanocortin in the hypothalamus. Additionally, after an overnight fast, PTG(OE) animals presented high liver glycogen content, lower liver triacylglycerol content, and lower serum concentrations of fatty acids and beta hydroxybutyrate than control mice, regardless of whether they were fed an HFD or a standard diet. In conclusion, liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of an HFD, and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity. PMID- 25277399 TI - Ozone exposure triggers insulin resistance through muscle c-Jun N-terminal kinase activation. AB - A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels, but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 parts per million), we demonstrated that exposure of rats to ozone induced whole-body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, c-Jun N terminal kinase (JNK) activation, and disruption of insulin signaling in skeletal muscle. Bronchoalveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pretreatment with the chemical chaperone 4-phenylbutyric acid, the JNK inhibitor SP600125, or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress, and JNK activation to impair insulin signaling in muscle. This study is the first to report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases. PMID- 25277400 TI - Left atrial passive emptying function is preserved in patients with permanent atrial fibrillation--a 320-slice multidetector computed tomography study. AB - OBJECTIVE: Left atrial (LA) mechanical function is thought to be virtually inexistent in patients with permanent atrial fibrillation (AF). Due to recent advances in multidetector computed tomography (MDCT) technology, it is now possible to acquire images of the entire heart in a single heartbeat. The objective of this study was to compare individual components of LA function assessed by MDCT in patients with permanent AF and patients in sinus rhythm (SR). METHODS: 320-slice MDCT was performed in 30 patients with permanent AF. Measurements of LA volumes during the cardiac cycle were compared to 30 patients in SR, who were matched with respect to age, sex, left ventricular ejection fraction and body surface area. RESULTS: LA volumes were significantly larger in patients with AF than SR patients at all times during the cardiac cycle (LA maximal volume; 82 vs. 55 ml/m(2), p < 0.0001, LA minimal volume; 71 vs. 30 ml/m(2), p < 0.0001). However, except for the absence of active LA emptying, the overall trend of the LA time-volume curve was similar in patients with AF and SR. CONCLUSION: Compared to SR patients, patients with permanent AF have significantly increased LA volumes throughout the cardiac cycle. Yet, a residual hemodynamic role of LA function may be maintained during permanent AF. PMID- 25277401 TI - Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer. AB - Enhancing therapeutic efficacy is essential for successful treatment of chemoresistant cancers such as metastatic hormone-refractory prostate cancer (HRPC). To improve the efficacy of doxorubicin (DOX) for treating chemoresistant disease, the feasibility of using nanodiamond (ND) particles was investigated. Utilizing the pH responsive properties of ND, a novel protocol for complexing NDs and DOX was developed using a pH 8.5 coupling buffer. The DOX loading efficiency, loading on the NDs, and pH responsive release characteristics were determined utilizing UV-Visible spectroscopy. The effects of the ND-DOX on HRPC cell line PC3 were evaluated with MTS and live/dead cell viability assays. ND-DOX displayed exceptional loading efficiency (95.7%) and drug loading on NDs (23.9 wt%) with optimal release at pH 4 (80%). In comparison to treatment with DOX alone, cell death significantly increased when cells were treated with ND-DOX complexes demonstrating a 50% improvement in DOX efficacy. Of the tested treatments, ND-DOX with 2.4 MUg mL(-1) DOX exhibited superior efficacy (60% cell death). ND-DOX with 1.2 MUg mL(-1) DOX achieved 42% cell death, which was comparable to cell death in response to 2.4 MUg mL(-1) of free DOX, suggesting that NDs aid in decreasing the DOX dose necessary to achieve a chemotherapeutic efficacy. Due to its enhanced efficacy, ND-DOX can be used to successfully treat HRPC and potentially decrease the clinical side effects of DOX. PMID- 25277402 TI - Fluorescent nanosensor for probing histone acetyltransferase activity based on acetylation protection and magnetic graphitic nanocapsules. AB - Protein acetylation catalyzed by histone acetyltransferases (HATs) is significant in biochemistry and pharmacology because of its crucial role in epigenetic gene regulations. Herein, an antibody-free fluorescent nanosensor is developed for the facile detection of HAT activity based on acetylation protection against exopeptidase cleavage and super-quenching ability of nanomaterials. It is shown for the first time that HAT-catalyzed acetylation could protect the peptide against exopeptidase digestion. FITC-tagged acetylated peptide causes the formation of a nano-quenchers/peptide nano-complex resulting in fluorescence quenching, while the unacetylated peptide is fully degraded by exopeptidase to release the fluorophore and restore fluorescence. Four kinds of nano-quenchers, including core-shell magnetic graphitic nanocapsules (MGN), graphene oxide (GO), single-walled carbon nanotubes (SWCNTs), and gold nanoparticles (AuNPs), are comprehensively compared. MGN shows the best selectivity to recognize the acetylated peptide and the lowest detection limit because of its excellent quenching efficiency and magnetic enrichment property. With this MGN-based nanosensor, HAT p300 is detected down to 0.1 nM with wide linear range from 0.5 to 100 nM. This sensor is feasible to assess HAT inhibition and detect p300 activity in cell lysate. The proposed nanosensor is simple, sensitive, and cost effective for HAT assay, presenting a promising toolkit for epigenetic research and HAT-targeted drug discovery. PMID- 25277403 TI - What existential palliative care can learn from Carl Sagan. PMID- 25277404 TI - Abnormal local field potentials precede clinical complications after DBS surgery for Parkinson's disease: a case report. PMID- 25277405 TI - [Spondylodiscitis due to Mycobacterium tuberculosis and Streptococcus agalactiae]. PMID- 25277406 TI - Function of VP2 protein in the stability of the secondary structure of virus-like particles of genogroup II norovirus at different pH levels: function of VP2 protein in the stability of NoV VLPs. AB - VP2 is the minor structural protein of noroviruses (NoV) and may function in NoV particle stability. To determine the function of VP2 in the stability of the NoV particle, we constructed and purified two kinds of virus-like particles (VLPs), namely, VLPs (VP1) and VLPs (VP1+VP2), from Sf9 cells infected with recombinant baculoviruses by using a Bac-to-Bac(r) baculovirus expression system. The two kinds of VLPs were treated with different phosphate buffers (pH 2 to pH 8); the secondary structure was then analyzed by far UV circular dichroism (CD) spectroscopy. Results showed that significant disruptions of the secondary structure of proteins were not observed at pH 2 to pH 7. At pH 8, the percentages of a-helix, beta-sheet, and beta-turn in VLPs (VP1) were decreased from 11% to 8%, from 37% to 32%, and from 20% to 16%, respectively. The percentage of coil was increased from 32% to 44%. By contrast, the percentages of alpha-helix, beta sheet, and beta-turn in VLPs (VP1+VP2) were decreased from 11% to 10%, from 37% to 35%, and from 20% to 19%, respectively. The percentage of coil was increased from 32% to 36%. VLPs (VP1+VP2) was likely more stable than VLPs (VP1), as indicated by the percentage of the secondary structures analyzed by CD. These results suggested that VP2 could stabilize the secondary structure of VLPs under alkaline pH conditions. This study provided novel insights into the molecular mechanism of the function of VP2 in the stability of NoV particles. PMID- 25277407 TI - Use of selected lactic acid bacteria in the eradication of Helicobacter pylori infection. AB - Helicobacter pylori is among the major pathogenic bacteria that cause chronic gastritis and peptic ulcer disease and is related to the development of gastric cancer. Several chemicals, including antibiotics, have been used to eradicate H. pylori; however, they do not always curb the infection. Ten representative type strains of lactic acid bacteria (LAB) were screened for antagonism toward H. pylori via inhibition of urease activity. Strains inhibiting the binding of H. pylori to human gastric cell line cells and suppressing H. pylori-induced interleukin-8 (IL-8) production were also screened. Of these, Pediococcus pentosaseus (SL4), which inhibited the adhesion of H. pylori to MKN-45 gastric cancer cells, Bifidobacterium longum (BG7), with urease inhibiting activity, and Lactococcus lactis (SL3), and Enterococcus faecalis (SL5), which suppressed H. pylori-induced IL-8 production within MKN-45 and AGS cells, were selected. In mouse model, these LAB stains in combination significantly suppressed IL-8 levels in serum. Gastric pH also recovered to normal values after the administration of these LAB. These stains effectively suppressed H. pylori viability, although not to the extent of antibiotic treatment. When used as probiotics, LAB may help decrease the occurrence of gastritis and reduce the risk of H. pylori infection without, inducing side effects. PMID- 25277408 TI - FgFlbD regulates hyphal differentiation required for sexual and asexual reproduction in the ascomycete fungus Fusarium graminearum. AB - Fusarium graminearum is a filamentous fungal plant pathogen that infects major cereal crops. The fungus produces both sexual and asexual spores in order to endure unfavorable environmental conditions and increase their numbers and distribution across plants. In a model filamentous fungus, Aspergillus nidulans, early induction of conidiogenesis is orchestrated by the fluffy genes. The objectives of this study were to characterize fluffy gene homologs involved in conidiogenesis and their mechanism of action in F. graminearum. We characterized five fluffy gene homologs in F. graminearum and found that FlbD is the only conserved regulator for conidiogenesis in A. nidulans and F. graminearum. Deletion of fgflbD prevented hyphal differentiation and the formation of perithecia. Successful interspecies complementation using A. nidulans flbD demonstrated that the molecular mechanisms responsible for FlbD functions are conserved in F. graminearum. Moreover, abaA-wetA pathway is positively regulated by FgFlbD during conidiogenesis in F. graminearum. Deleting fgflbD abolished morphological effects of abaA overexpression, which suggests that additional factors for FgFlbD or an AbaA-independent pathway for conidiogenesis are required for F. graminearum conidiation. Importantly, this study led to the construction of a genetic pathway of F. graminearum conidiogenesis and provides new insights into the genetics of conidiogenesis in fungi. PMID- 25277409 TI - Salinity as a regulator of DMSP degradation in Ruegeria pomeroyi DSS-3. AB - Dimethylsulfoniopropionate (DMSP) is an important carbon and sulfur source to marine bacterial communities and the main precursor of dimethylsulfide (DMS), a gas that influences atmospheric chemistry and potentially the global climate. In nature, bacterial DMSP catabolism can yield different proportions of DMS and methanethiol (MeSH), but relatively little is known about the factors controlling the pathways of bacterial degradation that select between their formation (cleavage vs. demethiolation). In this study, we carried out experiments to evaluate the influence of salinity on the routes of DMSP catabolism in Ruegeria pomeroyi DSS-3. We monitored DMS and MeSH accumulation in cell suspensions grown in a range of salinities (10, 20, 30 ppt) and with different DMSP amendments (0, 50, 500 uM). Significantly higher concentrations of DMS accumulated in low salinity treatments (10 ppt; P < 0.001), in both Marine Basal Medium (MBM) and half-strength Yeast Tryptone Sea Salts (1/2 YTSS) media. Results showed a 47.1% and 87.5% decrease of DMS accumulation, from salinity 10 to 20 ppt, in MBM and 1/2 YTSS media, respectively. On the other hand, MeSH showed enhanced accumulations at higher salinities (20, 30 ppt), with a 90.6% increase of MeSH accumulation from the 20 ppt to the 30 ppt salinity treatments. Our results with R. pomeroyi DSS-3 in culture are in agreement with previous results from estuarine sediments and demonstrate that salinity can modulate selection of the DMSP enzymatic degradation routes, with a consequent potential impact on DMS and MeSH liberation into the atmosphere. PMID- 25277411 TI - Hydroxypropyl-beta-cyclodextrin-mediated alterations in cell permeability, lipid and protein profiles of steroid-transforming Arthrobacter simplex. AB - Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) enhances steroid 1-dehydrogenation biotransformation by Arthrobacter simplex. In this work, HP-beta-CD-induced improvement of A. simplex CPCC 140451 cell envelope permeability which had positive effects on the steroid bioconversion was confirmed by a comparative investigation which showed a lower dehydrogenase activity and higher cell permeability of the cells after being incubated with HP-beta-CD. Atomic force microscopy and transmission electron microscopy micrographs showed that HP-beta CD altered the size, sharpness, and surface structure of the cell envelope. The analysis of lipid composition revealed that the proportion of extractable lipids decreased and the fatty acids profile was considerably altered. The contents of unsaturated fatty acids and long-chain fatty acids were reduced by 11.77 and 14.98%, respectively. The total leakage of protein level increased to 8%. Proteins belonging to the ATP-binding cassette superfamily and major facilitator superfamily were observed outside the cell. These alterations can explain the change of permeability on the molecular level under HP-beta-CD treatment. Results showed the material basis and mechanisms underlying the cellular changes, thus most likely contributing to the conversion rate in addition to cyclodextrins known effects on substrate solubility. PMID- 25277412 TI - Metabolic engineering of itaconate production in Escherichia coli. AB - Interest in sustainable development has led to efforts to replace petrochemical based monomers with biomass-based ones. Itaconic acid, a C5-dicarboxylic acid, is a potential monomer for the chemical industry with many prospective applications. cis-aconitate decarboxylase (CadA) is the key enzyme of itaconate production, converting the citric acid cycle intermediate cis-aconitate into itaconate. Heterologous expression of cadA from Aspergillus terreus in Escherichia coli resulted in low CadA activities and production of trace amounts of itaconate on Luria-Bertani (LB) medium (<10 mg/L). CadA was primarily present as inclusion bodies, explaining the low activity. The activity was significantly improved by using lower cultivation temperatures and mineral medium, and this resulted in enhanced itaconate titres (240 mg/L). The itaconate titre was further increased by introducing citrate synthase and aconitase from Corynebacterium glutamicum and by deleting the genes encoding phosphate acetyltransferase and lactate dehydrogenase. These deletions in E. coli's central metabolism resulted in the accumulation of pyruvate, which is a precursor for itaconate biosynthesis. As a result, itaconate production in aerobic bioreactor cultures was increased up to 690 mg/L. The maximum yield obtained was 0.09 mol itaconate/mol glucose. Strategies for a further improvement of itaconate production are discussed. PMID- 25277410 TI - MicroRNA 29 targets nuclear factor-kappaB-repressing factor and Claudin 1 to increase intestinal permeability. AB - BACKGROUND & AIMS: Some patients with irritable bowel syndrome with diarrhea (IBS D) have intestinal hyperpermeability, which contributes to their diarrhea and abdominal pain. MicroRNA 29 (MIR29) regulates intestinal permeability in patients with IBS-D. We investigated and searched for targets of MIR29 and investigated the effects of disrupting Mir29 in mice. METHODS: We investigated expression MIR29A and B in intestinal biopsies collected during endoscopy from patients with IBS (n = 183) and without IBS (controls) (n = 36). Levels were correlated with disease phenotype. We also generated and studied Mir29(-/-) mice, in which expression of Mir29a and b, but not c, is lost. Colitis was induced by administration of 2,4,6-trinitrobenzenesulfonic acid; intestinal tissues were collected and permeability was assessed. Microarray analysis was performed using tissues from Mir29(-/-) mice. Changes in levels of target genes were measured in human colonic epithelial cells and small intestinal epithelial cells after knockdown of MIR29 with anti-MIRs. RESULTS: Intestinal tissues from patients with IBS-D (but not IBS with constipation or controls) had increased levels of MIR29A and B, but reduced levels of Claudin-1 (CLDN1) and nuclear factor-kappaB repressing factor (NKRF). Induction of colitis and water avoidance stress increased levels of Mir29a and Mir29b and intestinal permeability in wild-type mice; these increased intestinal permeability in colons of far fewer Mir29(-/-) mice. In microarray and knockdown experiments, MIR29A and B were found to reduce levels of NKRF and CLDN1 messenger RNA, and alter levels of other messenger RNAs that regulate intestinal permeability. CONCLUSIONS: Based on experiments in knockout mice and analyses of intestinal tissue samples from patients with IBS-D, MIR29 targets and reduces expression of CLDN1 and NKRF to increase intestinal permeability. Strategies to block MIR29 might be developed to restore intestinal permeability in patients with IBS-D. PMID- 25277413 TI - Effect of hydraulic retention time (HRT) on the biodegradation of trichloroethylene wastewater and anaerobic bacterial community in the UASB reactor. AB - This study utilizes the unique merits of an 8-L laboratory upflow anaerobic sludge blanket (UASB) reactor for treating synthetic wastewater containing trichloroethylene (TCE). The reactor was operated at different hydraulic retention times (HRT) of 25, 20, 15, 10, and 5 h. TCE removal efficiency decreased from 99 to 85 % when the HRT was lowered down from 25 to 5 h, as well as chemical oxygen demand (COD) removal efficiency (from 95 to 84.15 %). Using Illumina 16S rRNA gene MiSeq sequencing, we investigated the evolution of bacterial communities in the anaerobic sludge under five different conditions of HRT. In total, 106,387 effective sequences of the 16S rRNA gene were generated from 5 samples that widely represented the diversity of microbial community. Sequence analysis consisting of several novel taxonomic levels ranging from phyla to genera revealed the percentages of these bacterial groups in each sample under different HRTs. The differences found among the five samples indicated that HRT had effects on the structures of bacterial communities and the changes of bacterial communities associated with the effect of HRT on the performance of the reactor. Sequence analyses showed that Bacteroidetes and Firmicutes were the dominant phyla. It is notable that the class Dehalococcoidia was found in the samples at HRT of 5, 10, 20, and 25 h, respectively, in which there were some dechlorination strains. Moreover, a tremendous rise of TCE removal efficiency from HRT of 5 h to HRT of 10 h was found. PMID- 25277414 TI - Efficient pullulan production by bioconversion using Aureobasidium pullulans as the whole-cell catalyst. AB - In this study, pullulan production was achieved by whole-cell bioconversion with Aureobasidium pullulans CCTCC M 2012259. Response surface methodology was applied to optimize the seed medium for incubating cells with high capability of pullulan bioconversion. Three medium components, namely, yeast extract, MgSO4.7H2O, and glucose were identified by Plackett-Berman design as significant factors affecting the cells' pullulan bioconversion capability. A three-level Box-Behnken design was then employed to determine the optimal levels of the three components. A mathematical model was developed to show the influence of each medium component and its effects on the cells' pullulan bioconversion capability. The model predicted a maximum pullulan bioconversion capability of 32.28 mg/g/h at the optimal yeast extract, MgSO4.7H2O, and glucose concentrations of 3.57, 0.18, and 63.97 g/l, respectively. The validation experiments showed that the cells' pullulan bioconversion capability was improved by 23.1% when the optimal medium was used, as compared with that obtained with the basic medium. Subsequently, the gene expression and activities of the key enzymes involved in pullulan biosynthesis were evaluated. When the optimal medium was employed, the transcriptional levels of pgm1 and fks were up-regulated by 2.5- and 1.2-fold, respectively, and the alpha-phosphoglucose mutase and glucosyltransferase activities were increased by 17 and 19%, respectively, when compared with those achieved using the basic medium. These results indicated that pullulan bioconversion using A. pullulans CCTCC M 2012259 as the whole-cell catalyst is an attractive approach for efficient pullulan production and can be applied for the production of other polysaccharides. PMID- 25277417 TI - Enhanced hydrogen peroxide generation accompanies the beneficial bioenergetic effects of methylene blue in isolated brain mitochondria. AB - The redox dye methylene blue (MB) is proven to have beneficial effects in various models of neurodegenerative diseases. Here we investigated the effects of MB (100 nM, 300 nM, and 1 MUM) on key bioenergetic parameters and on H2O2 production/elimination in isolated guinea pig brain mitochondria under normal as well as respiration-impaired conditions. As measured by high-resolution Oxygraph the rate of resting oxygen consumption was increased, but the ADP-stimulated respiration was unaffected by MB with any of the substrates (glutamate malate, succinate, or alpha-glycerophosphate) used for supporting mitochondrial respiration. In mitochondria treated with inhibitors of complex I or complex III MB moderately but significantly increased the rate of ATP production, restored DeltaPsim, and increased the rate of Ca(2+) uptake. The effects of MB are consistent with transferring electrons from upstream components of the electron transport chain to cytochrome c, which is energetically favorable when the flow of electrons in the respiratory chain is compromised. On the other hand, MB significantly increased the production of H2O2 measured by Amplex UltraRed fluorimetry under all conditions, in resting, ATP-synthesizing, and respiration impaired mitochondria, with each substrate combination supporting respiration. Furthermore, it also decreased the elimination of H2O2. Generation of H2O2 without superoxide formation, observed in the presence of MB, is interpreted as a result of reduction of molecular oxygen to H2O2 by the reduced MB. The elevated generation and impaired elimination of H2O2 should be considered for the overall oxidative state of mitochondria treated with MB. PMID- 25277416 TI - Testing the effectiveness of a self-efficacy based exercise intervention for adults with venous leg ulcers: protocol of a randomised controlled trial. AB - BACKGROUND: Exercise and adequate self-management capacity may be important strategies in the management of venous leg ulcers. However, it remains unclear if exercise improves the healing rates of venous leg ulcers and if a self-management exercise program based on self-efficacy theory is well adhered to. METHOD/DESIGN: This is a randomised controlled in adults with venous leg ulcers to determine the effectiveness of a self-efficacy based exercise intervention. Participants with venous leg ulcers are recruited from 3 clinical sites in Australia. After collection of baseline data, participants are randomised to either an intervention group or control group. The control group receive usual care, as recommended by evidence based guidelines. The intervention group receive an individualised program of calf muscle exercises and walking. The twelve week exercise program integrates multiple elements, including up to six telephone delivered behavioural coaching and goal setting sessions, supported by written materials, a pedometer and two follow-up booster calls if required. Participants are encouraged to seek social support among their friends, self-monitor their weekly steps and lower limb exercises. The control group are supported by a generic information sheet that the intervention group also receive encouraging lower limb exercises, a pedometer for self-management and phone calls at the same time points as the intervention group. The primary outcome is the healing rates of venous leg ulcers which are assessed at fortnightly clinic appointments. Secondary outcomes, assessed at baseline and 12 weeks: functional ability (range of ankle motion and Tinetti gait and balance score), quality of life and self management scores. DISCUSSION: This study seeks to address a significant gap in current wound management practice by providing evidence for the effectiveness of a home-based exercise program for adults with venous leg ulcers. Theory-driven, evidence-based strategies that can improve an individual's exercise self-efficacy and self-management capacity could have a significant impact in improving the management of people with venous leg ulcers. Information gained from this study will provide much needed information on management of this chronic disease to promote health and independence in this population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000475842. PMID- 25277418 TI - Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue. AB - Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10-100 MUM) to pharmacological levels (>1 mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100 MUM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue. PMID- 25277419 TI - Are free radicals involved in thiol-based redox signaling? AB - Cells respond to many stimuli by transmitting signals through redox-regulated pathways. It is generally accepted that in many instances signal transduction is via reversible oxidation of thiol proteins, although there is uncertainty about the specific redox transformations involved. The prevailing view is that thiol oxidation occurs by a two electron mechanism, most commonly involving hydrogen peroxide. Free radicals, on the other hand, are considered as damaging species and not generally regarded as important in cell signaling. This paper examines whether it is justified to dismiss radicals or whether they could have a signaling role. Although there is no direct evidence that radicals are involved in transmitting thiol-based redox signals, evidence is presented that they are generated in cells when these signaling pathways are activated. Radicals produce the same thiol oxidation products as two electron oxidants, although by a different mechanism, and at this point radical-mediated pathways should not be dismissed. There are unresolved issues about how radical mechanisms could achieve sufficient selectivity, but this could be possible through colocalization of radical-generating and signal-transducing proteins. Colocalization is also likely to be important for nonradical signaling mechanisms and identification of such associations should be a priority for advancing the field. PMID- 25277421 TI - [The prevention of transfusion-associated circulatory overload]. AB - Hydrostatic pulmonary edema is a frequent and severe complication of blood transfusion. Recent epidemiological studies open the way for a better prevention of Transfusion-Associated Circulatory Overload. Preventive measures rely solely on the medical and nursing staff. Mitigation strategies include a careful identification of patients and conditions at-risk, a single-unit transfusion policy in patients with chronic anemia, the use of slow infusion rates, the careful monitoring of patient vital signs (particularly systemic arterial blood pressure). Peritransfusion IV diuretics use is likely to be helpful, although optimal prescribing patterns have not been defined. PMID- 25277422 TI - [Evaluation of transfusion hemochromatosis prevalence, SFVTT-01 study: preliminary results of the SFVTT working group]. AB - RATIONAL: Although notification of post-transfusion hemosiderosis is mandatory since 1994 among the French hemovigilance network, it is so far largely under reported. PATIENTS AND METHODS: We screened 42,443 patients hospitalized for blood diseases in France in 2009 and 2010 and determined which patients had received more than 20 PRC. Among them, we selected those having at least one measure of serum ferritin, and subsequently those which ferritin was greater than or equal to 1000 ng/mL. RESULTS: Three thousand eight hundred and twelve patients (9%) received more than 20 PRC, 1935 (4.5%) had a ferritin assay, which was increased in 1216 patients (2.9%). Eight hundred and eighty-one patients underwent an hemovigilance report form. Forty-nine percent had low-risk myelodysplasia or acute leukemia, 7% hemoglobinopathies. Hemosiderosis was asymptomatic for 680 patients (77%), serious 188 (88%) and life-threatening for 11 (1%). Two patients died of terminal heart failure. The most severe hemosiderosis (>= grade 2) were low-risk myelodysplasia and idiopathic aplastic anemia. Ninety-two percent of thalassemia patients and 46% of sickle cell anemia patients received an iron chelator. For low-risk myelodysplastic syndromes and idiopathic aplastic anemia, 228 of the 317 patients whose treatment is known and who could benefit from iron chelation (72%) have not received it. CONCLUSION: These results encourage seeking optimal transmission of information (over 20 CGR) to the clinician, and prolonging hemovigilance action towards a more comprehensive statement of post-transfusion hemochromatosis. PMID- 25277423 TI - [Platelet allo-antibodies identification strategies for preventing and managing platelet refractoriness]. AB - Platelet refractoriness is a serious complication for patients receiving recurrent platelet transfusions, which can be explained by non-immune and immune causes. Human Leukocyte Antigens (HLA) allo-immunization, especially against HLA class I, is the major cause for immune platelet refractoriness. To a lesser extent, allo-antibodies against specific Human Platelet Antigen (HPA) are also involved. Pregnancy, transplantation and previous transfusions can lead to allo immune reaction against platelet antigens. After transfusion, platelet count is decreased by accelerated platelet destruction related to antibodies fixation on incompatible platelet antigens. New laboratory tests for allo-antibodies identification were developed to improve sensibility and specificity, especially with the LUMINEX((r)) technology. The good use and interpretation of these antibodies assays can improve strategies for platelet refractoriness prevention and management with a patient adapted response. Compatible platelets units can be selected according to their identity with recipient typing or immune compatibility regarding HLA or HPA antibodies or HLA epitope compatibility. Prospective studies are needed to further confirm the clinical benefit of new allo-antibodies identification methods and consensus strategies for immune platelet refractoriness management. PMID- 25277420 TI - The Warburg effect: evolving interpretations of an established concept. AB - Metabolic reprogramming and altered bioenergetics have emerged as hallmarks of cancer and an area of active basic and translational cancer research. Drastically upregulated glucose transport and metabolism in most cancers regardless of the oxygen supply, a phenomenon called the Warburg effect, is a major focuses of the research. Warburg speculated that cancer cells, due to defective mitochondrial oxidative phosphorylation (OXPHOS), switch to glycolysis for ATP synthesis, even in the presence of oxygen. Studies in the recent decade indicated that while glycolysis is indeed drastically upregulated in almost all cancer cells, mitochondrial respiration continues to operate normally at rates proportional to oxygen supply. There is no OXPHOS-to-glycolysis switch but rather upregulation of glycolysis. Furthermore, upregulated glycolysis appears to be for synthesis of biomass and reducing equivalents in addition to ATP production. The new finding that a significant amount of glycolytic intermediates is diverted to the pentose phosphate pathway (PPP) for production of NADPH has profound implications in how cancer cells use the Warburg effect to cope with reactive oxygen species (ROS) generation and oxidative stress, opening the door for anticancer interventions taking advantage of this. Recent findings in the Warburg effect and its relationship with ROS and oxidative stress controls will be reviewed. Cancer treatment strategies based on these new findings will be presented and discussed. PMID- 25277424 TI - A retrospective analysis of psychosocial risk factors modulating adolescent alcohol binge drinking. AB - BACKGROUND/AIMS: Adolescent alcohol binge-induced hospital admissions (BIHAs) are an increasing problem in Europe. We investigated whether psychosocial factors (e.g., drinking situations, drinking occasions and neighborhood unemployment) are associated with particularly risky patterns of alcohol or substance use. METHOD: We performed a systematic retrospective chart review of all the respective cases in 2003-2008 (n = 586; age range: 12-17 years) from both pediatric hospitals in the city of Dresden, Germany. RESULTS: The vast majority of adolescent BIHAs were associated with drinking together with peers at weekend parties. Compared to this 'typical' drinking pattern, adolescents drinking 'atypically' (i.e., drinking either alone, to cope or despite the fact that the next day was a school/work day) more often had already used alcohol and illegal substances before and were more often diagnosed with substance use disorders and other mental disorders prior to BIHA. The unemployment rate in the patients' neighborhood was positively related to the incidence proportion of adolescent BIHAs in the respective subdistricts (r(s) = 0.61). CONCLUSION: Adolescent atypical drinking may indicate an increased risk for the development of alcohol and substance use disorders. This information is quickly accessible and can alert clinicians to initiate psychosocial aftercare; their infrastructure should address the strong relation between BIHA probability and neighborhood unemployment rates. PMID- 25277427 TI - Stem cells and regenerative medicine in domestic and companion animals: a multispecies perspective. AB - Since their original isolation, the majority of the work on embryonic stem cells (ESC) has been carried out in mice. While the mouse is an outstanding model for basic research, it also has considerable limitations for translational work, especially in the area of regenerative medicine. This is due to a combination of factors that include physiological and size differences when compared to humans. In contrast, domestic animal species, such as swine, and companion animal species, such as dogs, provide unique opportunities to develop regenerative medicine protocols that can then be utilized in humans. Unfortunately, at present, the state of knowledge related to, and availability of, ESC from domestic animals vary among species such as pig, horse, dog and cat, and without exception lags significantly behind the mouse and human. It is clear that much still needs to be discovered. The 'stem cell-like' cell lines being reported are still not satisfactorily used in regenerative medicine, due to reasons such as heterogeneity and chromosomal instability. As a result, investigators have searched for alternate source of cells that can be used for regenerative medicine. This approach has uncovered a range of adult stem cells and adult progenitor cells that have utility in both human and veterinary medicine. Here, we review a range of stem cells, from ESC to induced pluripotent stem cells, and discuss their potential application in the field of regenerative medicine. PMID- 25277425 TI - Development and validation of the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ). AB - Physical function and functional recovery are important aspects of the acute pain experience in children and adolescents in hospitalized settings. Measures of function related to pediatric acute pain do not exist currently, limiting understanding of recovery in youth undergoing acute and procedural pain. To address this gap, we developed and assessed the clinical utility and preliminary validity of the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ). We evaluated psychometric properties of this measure in 159 patients with sickle cell disease, ages 7 to 21 years, who were hospitalized for vaso-occlusive episodes at 4 urban children's hospitals. The YAPFAQ demonstrated strong internal reliability and test-retest reliability. An exploratory factor analysis was conducted to examine the preliminary factor structure and to help reduce the number of items for the final scale. Evidence for moderate construct validity was demonstrated among validated measures of pain burden, motor function, functional ability, and quality of life. The YAPFAQ is a new measure of youth functional ability in the acute pain setting. Further evaluation of this measure in additional pediatric populations is needed to understand applicability across a spectrum of youth experiencing acute pain related to illness, trauma, and medical/surgical procedures. PERSPECTIVE: Measures of function in response to acute pain are needed in order to more comprehensively evaluate acute pain interventions in pediatrics; however, no specific measures are available. Our preliminary psychometric evaluation of an acute pain functional ability measure for youth indicates that it may be a promising tool for further refinement in additional pediatric acute pain populations. PMID- 25277428 TI - Melatonin in sperm biology: breaking paradigms. AB - Melatonin is a ubiquitous molecule, present in a wide range of organisms, and involved in multiple functions. Melatonin relays the information about the photoperiod to the tissues that express melatonin-binding sites in both central and peripheral nervous systems. This hormone has a complex mechanism of action. It can cross the cell plasma membrane and exert its actions in all cells of the body. Certain melatonin actions are mediated by receptors that belong to the superfamily of G-protein-coupled receptors (GPCRs), the MT1 and MT2 membrane. Melatonin can also bind to calmodulin as well as to nuclear receptors of the retinoic acid receptor family, RORalpha1, RORalpha2 and RZRbeta. The purpose of this review is to report on recent developments in the physiological role of melatonin and its receptors. Specific issues concerning the biological function of melatonin in mammalian seasonal reproduction and spermatozoa are considered. The significance of the continuous presence of melatonin in seminal plasma with a fairly constant concentration is also discussed. PMID- 25277429 TI - Hormone-free protocols for the control of reproduction and artificial insemination in goats. AB - The dairy goat industry is of great economic importance to certain rural areas of the European Union (EU), especially the Mediterranean region. Its sustainability, however, is severely affected by the seasonality of goat reproduction, which leads to fluctuations in the availability of final products. Classical hormone treatments based on progestagens and eCG are the main tools employed in the effort to achieve fertility outside of the normal breeding season. They are also used to induce and synchronize oestrus and ovulation in artificial insemination programs. The food safety policy of the EU is becoming ever stricter with regard to the use of hormonal treatments for reproductive purposes, pushing livestock raising towards ever cleaner and greener production systems. Recent advances in the use of natural methods able to generate endocrine signals that induce the ovulatory process have improved our capacity to foster reproduction in the non breeding season. When used in a fashion appropriate for the latitude at which animals live, their breed, and the management system under which they are raised, environmental (photoperiod), nutritional and sociosexual (the male effect) signals offer alternatives to classic hormonal techniques. This affords the fragile and heterogeneous goat production sector with new opportunities. This article describes the most representative advances made in the use of the male effect as a natural method of inducing ovulation during seasonal anoestrus. Its association with other methods for optimizing responses and synchronizing induced ovulation is also discussed; such associations allow it to be used as an alternative to hormonal treatment in artificial insemination programs. PMID- 25277430 TI - Understanding sperm heterogeneity: biological and practical implications. AB - Sperm are the most diverse cell type known. This diversity is thought to reflect adaptation to conditions under which sperm function as a way to ensure the survival of sperm in fertilization environments and to maximize fertilizing capacity thereof. The existence of morphological diversity among species is widely assumed, although this diversity seems less clear as we go deeper (between males, between ejaculates from the same male and even within the same ejaculate), with different theories addressing this heterogeneity. Moreover, the development of assisted reproductive techniques (ART) has led to changes in the physiological conditions in which sperm fertilize, which could lead, ultimately, to a selection towards more favourable sperm design. Regardless of the origin of this diversity, when studying the relationship between shape and function of sperm, it is advisable to assess the degree of heterogeneity of sperm and takes into account to be more likely to identify those morphological characteristics determining the fertile ability of sperm. Otherwise, these relationships could be hidden as a result of considering an average shape not representative of morphological characteristics of sperm. In addition, the knowledge of this morphological diversity in terms of changes arising from modifications in the sperm environment and mechanisms that generate these changes could be useful for understanding the reproductive capacity of males but also in enhancing their fertile ability. PMID- 25277431 TI - Current status of in vitro embryo production in sheep and goats. AB - Sheep and goat production is an important economic activity in Spain with an increasing interest in milk production. Multiovulation and Embryo Transfer (MOET) and In vitro Embryo Production (IVEP) are assisted reproductive technologies aimed at increasing the genetic diffusion of females. In vitro embryo production is a multi-step methodology comprising the following procedures: (i) In vitro Maturation (IVM) of oocytes recovered directly from the follicles, (ii) In vitro Fertilization (IVF) or co-incubation of capacitated spermatozoa with in vitro matured oocytes and (iii) In vitro culture (IVC) of zygotes up to the blastocyst stage. In vitro embryo production from oocytes recovered from prepubertal females is called JIVET (Juvenile in vitro Embryo Transfer) and allows shortened generation intervals and increased genetic gain. Embryo production together with embryo cryoconservation would allow large-scale embryo marketing, a pathogen-free genetic movement and easier and cheaper germplasm commercial transactions. Commercial Embryo activity in small ruminants is low compared to cows in the European Union (data from the European Embryo Transfer Association) and in the world (data from the International Embryo Transfer Association). There is less IVEP research in small ruminants compared to other livestock species. The aim of this review was to provide an overview of the current status of IVEP of small ruminant with an emphasis on (i) description of the main methodologies currently used for IVM, IVF and IVC of embryos (ii) comparing procedures and outputs from JIVET and IVEP of adult females and (iii) the future research perspectives of this technology. PMID- 25277432 TI - Reproductive and nutritional management on ovarian response and embryo quality on rabbit does. AB - Rabbit does in modern rabbitries are under intensive reproductive rhythms. Females are high milk producers with high energetic expenses due to the extensive overlap between lactation and gestation. This situation leads to a negative energy balance with a mobilization of body fat especially in primiparous rabbit does. Poor body condition and poor health status severely affect the reproductive features (fertility rate and lifespan of the doe as well as ovarian physiology). This paper reviews some reproductive and nutritional approaches used in the last years to improve the reproductive performance of rabbit females, mainly focusing on the influence on ovarian response and embryo quality and with emphasis on epigenetic modifications in pre-implantation embryos and offspring consequences. PMID- 25277433 TI - Transcervical artificial insemination in dogs and cats: review of the technique and practical aspects. AB - The technique of transcervical catheterization for artificial insemination has gained practical importance over the last 3 and 1 decades in bitches and queens, respectively. The vagina of both species has a thickening of the dorsal aspect called dorsal medial fold, which restricts the lumen of the paracervix, making catheterization of the cervix difficult both with manual and endoscopic techniques. Manual catheters have been used initially in the bitch and are now gradually being replaced by rigid endoscopy through the adaptation of human cystoscopes and ureteroscopes. Cystoscopes provide excellent imaging of the vagina, but cervical catheterization is more difficult due to the oblique 30 degrees viewing angle of its telescope and may not be long enough to catheterize large size bitches. Ureteroscopes allow an acceptable view of the vaginal mucosa and offer advantages such as the possibility to catheterize the cervix of bitches of all body sizes, manipulate the cervical tubercle when the external cervical os is not visible, offer a better visualization of the cervix using the shunt (a large Foley catheter which allows insufflation and distention of the vagina). Feline cervical catheterization has been achieved with three different types of catheters; the last one, developed following careful anatomical studies of how the feline vaginal lumen changes during estrus, allows cervical catheterization thanks to digital manipulation of the cervix through the rectum. PMID- 25277434 TI - Clinical use of deslorelin (GnRH agonist) in companion animals: a review. AB - Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin(r), Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets. PMID- 25277435 TI - Current status of freeze-drying technology to preserve domestic animals sperm. AB - In recent years, there has been an increased interest in new preservation techniques that facilitate sperm storage and distribution, with freeze-drying (FD) having been proposed as an alternative method for sperm preservation and maintenance of genetic resources in different animal species. FD is a method in which frozen material is dried by sublimation of ice, thereby involving a direct transition from a solid (ice) to a vapour (gas) phase. One of the main advantages of FD is that nitrogen and dry ice are no longer required for the storage and shipment of frozen sperm, which can be stored at room temperature or 4 degrees C, thereby resulting in enormous reductions in storage and shipping costs. Unlike sperm cryopreserved after gradual freezing, the sperm membrane may be further damaged by both snap-freezing and drying stresses during the FD procedure. As mammalian spermatozoa lose their motility, viability and, at least partially, their DNA integrity when freeze-dried, they must be microinjected into an oocyte by intracytoplasmic sperm injection (ICSI). Although the efficiency of ICSI is limited when freeze-dried spermatozoa are used, embryos and live offspring can be produced. DNA fragmentation in freeze-dried spermatozoa is one of the main causes of failure of embryonic development and successful pregnancy. In this regard, it has been suggested that endonucleases are among the leading causes of DNA fragmentation in spermatozoa along with oxidative stress caused by the release of reactive oxygen species (ROS). Many factors influence the FD process, and it is not clear how FD affects specific components of sperm from different animal species. As such, a sound understanding of the FD process would result in increased production of embryos and/or live offspring. The aim of this review was to study the various stages and techniques used in the FD process and to further evaluate the results obtained. PMID- 25277436 TI - Physiopathologic mechanisms involved in mare endometrosis. AB - Endometrosis is a degenerative chronic process, characterized by paramount fibrosis development in mare endometrium. This condition is one of the major causes of subfertility/infertility in mares. As in other organs, fibrosis might be a pathologic sequel of many chronic inflammatory diseases. However, aetiology and physiopathologic mechanisms involved in endometrial fibrosis are still controversial. This review presents new hypotheses based on our newest data. As the first line of innate immune defence, systemic neutrophils arrive in the uterus at mating or in the presence of pathogens. A novel paradigm is that neutrophils cast out their DNA in response to infectious stimuli and form neutrophil extracellular traps (NETs). We have shown that bacterial strains of Streptococcus zooepidemicus, Escherichia coli or Staphylococcus capitis, known to cause endometritis in mares were able to induce NETs release in vitro by equine PMN to different extents. An intriguing dilemma is the dual action of NETs. While NETs play a desirable role fighting micro-organisms in mare uterus, they may also contribute to endometrial fibrosis. A long-term in vitro exposure of mare endometrium explants to NETs components (myeloperoxidase, elastase and cathepsin G) up-regulated fibrosis markers TGFbeta and Tissue inhibitor of metalloproteinase (TIMP-1). Also, pro-fibrotic cytokines regulated collagen deposition and fibrosis. Changes in expression of connective tissue growth factor (CTGF), interleukins (IL)1-alpha, IL-1beta, IL-6 and receptors in endometrium with different degrees of fibrosis and/or inflammation were observed. A putative role of CTGF, IL and NETs components in endometrosis development should be considered. Additionally, we speculate that in sustained endometritis in mares, prostaglandins may not only cause early luteolysis or early pregnancy loss, but may also be related to endometrial fibrosis pathogenesis by stimulating collagen deposition. PMID- 25277437 TI - Use of colour and spectral Doppler ultrasonography in stallion andrology. AB - Doppler ultrasonography is an important tool in the andrological evaluation in humans; however, this method is not so extensively used by equine andrologists. Spectral or pulse Doppler is a useful non-invasive method for the early diagnosis of subfertility problems in the male, especially those triggered by vascular disturbance. The identification of any disturbance in the blood flow of the testis is crucial for a correct diagnosis of various testicular and scrotal disorders but also to monitor the therapeutic outcome following treatment. The aim of this review is to provide an update on the current use of colour and spectral Doppler ultrasound in stallion andrology, and to promote the use of this technique during the soundness reproductive examination of the stallion, as this particular branch of reproductive medicine is receiving increasing interest. PMID- 25277440 TI - Analysis of the forearm rotational efficiency in extant hominoids: new insights into the functional implications of upper limb skeletal structure. AB - The greatly diversified locomotor behaviors in the Hominoidea impose different mechanical requirements in the upper limb of each species. As forearm rotation has a major role in locomotion, the skeletal structures involved in this movement may display differences among taxa that reflect functional adaptations. To test this, we use a biomechanical model that quantifies the rotatory capacity of pronator teres (rotational efficiency) from skeletal measurements. Using a large sample of hominoids, we aim to identify the morphological adaptations that confer differences in the mechanics of forearm motion and to assess the functional advantage of these adaptations. Forearm positions along the pronation-supination range where rotational efficiency is maximal depend on the orientation of the humeral medial epicondyle and differ among taxa. Our results indicate that these are related to locomotor mode. Knuckle-walkers exhibit a medial epicondyle more posteriorly directed, which, in elbow angles close to extension, causes rotational efficiency to be maximal in pronated positions of the forearm. Species with a significant amount of arboreal locomotion, such as vertical climbing, i.e., Pongo spp., Pan troglodytes and Gorilla gorilla, display more proximally oriented epicondyles, which, in elbow flexion, leads to maximum rotational efficiencies in supinated positions of the forearm. Hylobatidae, with the less posteriorly and proximally oriented epicondyle, show their maximum rotational efficiencies closer to the forearm neutral position throughout most of the flexion-extension range, which may be linked to brachiation in this taxon. In humans, the epicondylar orientation and thus the positions of the maximum rotational efficiencies fall between arboreal and terrestrial hominoids. This may be related to the enhanced manipulative skills of the upper limb. In conclusion, the current analysis indicates that the orientation of the humeral medial epicondyle is linked to the locomotor habits of extant hominoids and therefore can be used for locomotor inferences in fossil taxa. PMID- 25277441 TI - N3-substituted temozolomide analogs overcome methylguanine-DNA methyltransferase and mismatch repair precipitating apoptotic and autophagic cancer cell death. AB - Glioblastoma multiforme (GBM) treatment includes temozolomide (TMZ) chemotherapy. O6-Methylguanine lesions are repaired by methylguanine-DNA methyltransferase (MGMT). Response to TMZ requires low MGMT and functional mismatch repair (MMR); resistance, conferred by MGMT or MMR deficiency, represents a barrier to successful treatment. TMZ analogs were synthesized, substituting N3-methyl with propargyl (1) or sulfoxide (2). MTT assays were conducted in SNB19 and U373 isogenic glioma cell lines (V = vector control; M = MGMT-transfected). TMZ potency was reduced >5-fold in SNB19M and U373M cells; in contrast, MGMT expressing cells were equisensitive as vector controls to analogs 1 and 2 . GI50 values <50 MUM of analogs 1 or 2 were detected in V cells possessing acquired TMZ resistance: SNB19VR (hMSH6 loss) and U373VR (MGMT upregulation). Analogs 1 and 2 inhibited MMR-deficient colorectal carcinoma cell growth (irrespective of p53); G2/M cell cycle arrest preceded apoptosis. gammaH2AX foci inferred the generation of DNA double-strand breaks by analogs 1 and 2 . Acridine orange-stained vesicles, intracellular punctate GFP-LC3 protein and double-membraned autophagosomes indicate that TMZ, 1 and 2 induce autophagy in apoptotis-resistant GBM cells. Analogs 1 and 2 elicit in vitro antitumor activity irrespective of MGMT, MMR and p53. Such imidazotetrazines may treat MGMT+ GBM and possess broader spectrum activity causing apoptosis and autophagy in malignancies which evade apoptosis. PMID- 25277442 TI - The responses of autophagy and apoptosis to oxidative stress in nucleus pulposus cells: implications for disc degeneration. AB - BACKGROUND/AIMS: Apoptosis and autophagy are two patterns of programmed cell death which play important roles in the intervertebral disc degeneration. Oxidative stress is an important factor for the induction of programmed cell death. However, the cellular reactions linking autophagy to apoptosis of disc cells under oxidative stress have never been described. This study investigated the responses of autophagy and apoptosis and their interactions in the nucleus pulposus cells (NP cells) under oxidative stress, with the aim to better understand the mechanism of disc degeneration. METHODS: NP cells isolated from rat lumbar discs were subjected to different concentrations of H2O2 for various time periods. Cell viability was determined by CCK-8 assay, and their apoptosis and autophagy responses were evaluated by fluorescent analysis, flow cytometry and western blotting, et al. The interactions of autophagy and apoptosis and the possible signaling pathways were also investigated by using autophagy modulators. RESULTS: H2O2 increased the lysosomal membrane permeability in the NP cells and induced apoptosis through the mitochondrial pathway subsequently. Meanwhile, H2O2 stimulated an early autophagy response through the ERK/m-TOR signaling pathway. Autophagy inhibition significantly decreased the apoptosis incidence in the cells insulted by H2O2. CONCLUSION: These results suggested that controlling the autophagy response in the NP cells under oxidative stress should be beneficial for the survival of the cells and probably delay the process of disc degeneration. PMID- 25277443 TI - Adjusting hemodialysis dose for protein catabolic rate. AB - BACKGROUND: Patients dialyzed with equal eKt/V may have huge variations in their urea concentrations. METHODS: Urea generation rate, distribution volume and renal clearance were determined in 205 hemodialysis sessions of 33 patients with double pool urea kinetic modeling using dialyzer clearance from online monitoring. From these data, optimized prescriptions were computed. RESULTS: In simulated dialysis sessions, the HEMO standard-dose equivalent clearance was not sufficient to keep time-averaged concentration (TAC) and average predialysis concentration (PAC) of urea below the defined upper limits (20 and 30 mmol/l), if normalized protein catabolic rate (nPCR) was greater than 1.3 g/kg/day. Protein catabolic rate was taken into account in the optimized prescription by cutting high urea concentrations. CONCLUSIONS: If patients having high urea concentrations with conventional clearance will benefit from higher dialysis dose - an unconfirmed hypothesis - this approach helps in identifying those who need more than three sessions per week. PMID- 25277444 TI - Retropubic, laparoscopic, and robot-assisted radical prostatectomy: surgical, oncological, and functional outcomes: a systematic review. AB - OBJECTIVES: Despite the wide diffusion of minimally invasive approaches, such as laparoscopic (LRP) and robot-assisted radical prostatectomy (RALP), few studies compare the results of these techniques with the retropubic radical prostatectomy (RRP) approach. The aim of this study is to compare the surgical, functional, and oncological outcomes and cost-effectiveness of RRP, LRP, and RALP. METHODS: A systematic review of the literature was performed in the PubMed and Embase databases in December 2013. A 'free-text' protocol using the term 'radical prostatectomy' was applied. A total of 16,085 records were found. The authors reviewed the records to identify comparative studies to include in the review. RESULTS: 44 comparative studies were identified. With regard to the perioperative outcome, LRP and RALP were more time-consuming than RRP, but blood loss, transfusion rates, catheterisation time, hospitalisation duration, and complication rates were the most optimal in the laparoscopic approaches. With regard to the functional and oncological results, RALP was found to have the best outcomes. CONCLUSION: Our study confirmed the well-known perioperative advantage of minimally invasive techniques; however, available data were not sufficient to prove the superiority of any surgical approach in terms of functional and oncologic outcomes. On the contrary, cost comparison clearly supports RRP. PMID- 25277445 TI - Activation of salicylic acid metabolism and signal transduction can enhance resistance to Fusarium wilt in banana (Musa acuminata L. AAA group, cv. Cavendish). AB - Fusarium wilt caused by the fungus Fusarium oxysporum f. sp. cubens (Foc) is the most serious disease that attacks banana plants. Salicylic acid (SA) can play a key role in plant-microbe interactions. Our study is the first to examine the role of SA in conferring resistance to Foc TR4 in banana (Musa acuminata L. AAA group, cv. Cavendish), which is the greatest commercial importance cultivar in Musa. We used quantitative real-time reverse polymerase chain reaction (qRT-PCR) to analyze the expression profiles of 45 genes related to SA biosynthesis and downstream signaling pathways in a susceptible banana cultivar (cv. Cavendish) and a resistant banana cultivar (cv. Nongke No. 1) inoculated with Foc TR4. The expression of genes involved in SA biosynthesis and downstream signaling pathways was suppressed in a susceptible cultivar and activated in a resistant cultivar. The SA levels in each treatment arm were measured using high-performance liquid chromatography. SA levels were decreased in the susceptible cultivar and increased in the resistant cultivar. Finally, we examined the contribution of exogenous SA to Foc TR4 resistance in susceptible banana plants. The expression of genes involved in SA biosynthesis and signal transduction pathways as well as SA levels were significantly increased. The results suggest that one reason for banana susceptibility to Foc TR4 is that expression of genes involved in SA biosynthesis and SA levels are suppressed and that the induced resistance observed in banana against Foc TR4 might be a case of salicylic acid-dependent systemic acquired resistance. PMID- 25277446 TI - Trajectory of physical health, cognitive status, and psychological well-being among Chinese elderly. AB - This study investigates the trajectory of various dimensions of health status among the Chinese elderly in their late years. We used growth-curve analyses on a subsample (n~2000) of the elderly from the Chinese Longitudinal Health Longevity Survey (CLHLS) who had longitudinal information from 1998 to 2005. Analyses controlled for a large set of individual and family characteristics. Our findings indicate that elderly who had relatively advantaged childhood socioeconomic status (SES) and who regularly engaged in physical and/or leisure activities had significantly healthier well-being than their respective counterparts on all dimensions considered. In addition, regularly participating in physical and/or leisure activities was associated with slow deterioration of health well-being among the Chinese elderly. The results indicate the potential benefits of engaging in physical and/or leisure activities, and consequently, the importance of implementing programs that promote such activities among elders in China. PMID- 25277447 TI - AMPA receptor complex dynamics in time and space. AB - Using a comprehensive proteomic approach, Schwenk et al. (2014), in this issue of Neuron, resolve the differential composition of AMPA receptor complexes in brain regions and through development. This work reveals a specificity in AMPA receptor complex assembly that is dynamic in both space and time. PMID- 25277448 TI - Going for broke: dopamine influences risky choice. AB - Dopamine neurons track reward by increasing or decreasing their firing rate when a reward is present or absent. In this issue of Neuron, Stopper et al. (2014) demonstrate that artificially eliminating these dopamine bursts or dips can alter risky decision-making. PMID- 25277449 TI - A cortical rein on the tectum's gain. AB - The superior colliculus, or tectum, is a key sensorimotor structure that long predates the cortex. In this issue of Neuron, Zhao et al. (2014) show that the visual cortex controls the tectum's gain precisely and retinotopically, without otherwise altering its operations. PMID- 25277450 TI - When brains flip coins. AB - In a recent study in the journal Cell, Tervo et al. (2014) show that animals can implement stochastic choice policies in environments unfavorable to predictive strategies. The shift toward stochastic behavior was driven by noradrenergic signaling in the anterior cingulate cortex. PMID- 25277451 TI - Neurobiology and the humanities. PMID- 25277452 TI - Toward a science of computational ethology. AB - The new field of "Computational Ethology" is made possible by advances in technology, mathematics, and engineering that allow scientists to automate the measurement and the analysis of animal behavior. We explore the opportunities and long-term directions of research in this area. PMID- 25277453 TI - Isolating pathogenic mechanisms embedded within the hippocampal circuit through regional vulnerability. AB - Some of the most common and devastating disorders of the brain target the hippocampal formation. The hippocampal formation is a complex circuit of interconnected regions, and it is assumed that clues into the causes of these disorders are embedded within the circuit. Neuroimaging tools have been optimized to interrogate the malfunctioning hippocampal circuit, and by applying these tools to patients in the earliest stages of disease and to animal models, patterns of regional vulnerability have been established for Alzheimer's disease, schizophrenia, and cognitive aging. More recently, studies have begun deciphering the cellular and molecular reasons underlying regional dysfunction. Collectively, this information clarifies the pathophysiology of these disorders and informs on therapeutic strategies. PMID- 25277455 TI - Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. AB - CREB is a pivotal mediator of activity-regulated gene transcription that underlies memory formation and allocation. The contribution of a key CREB cofactor, CREB-regulated transcription coactivator 1 (CRTC1), has, however, remained elusive. Here we show that several constitutive kinase pathways and an activity-regulated phosphatase, calcineurin, converge to determine the nucleocytoplasmic shuttling of CRTC1. This, in turn, triggered an activity dependent association of CRTC1 with CREB-dependent regulatory elements found on IEG promoters. Forced expression of nuclear CRTC1 in hippocampal neurons activated CREB-dependent transcription, and was sufficient to enhance contextual fear memory. Surprisingly, during contextual fear conditioning, we found evidence of nuclear recruitment of endogenous CRTC1 only in the basolateral amygdala, and not in the hippocampus. Consistently, CRTC1 knockdown in the amygdala, but not in the hippocampus, significantly attenuated fear memory. Thus, CRTC1 has a wide impact on CREB-dependent memory processes, but fine-tunes CREB output in a region specific manner. PMID- 25277454 TI - MEK-ERK1/2-dependent FLNA overexpression promotes abnormal dendritic patterning in tuberous sclerosis independent of mTOR. AB - Abnormal dendritic complexity is a shared feature of many neurodevelopmental disorders associated with neurological defects. Here, we found that the actin crosslinking protein filamin A (FLNA) is overexpressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic complexity. Both under- and overexpression of FLNA in wild-type neurons led to more complex dendritic arbors in vivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1(null) neurons, knocking down FLNA in vivo prevented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1(null) neurons was dependent on MEK1/2 but not mTOR activity, despite both pathways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1(null) neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner. PMID- 25277456 TI - Experience-dependent remodeling of basket cell networks in the dentate gyrus. AB - The structural organization of neural circuits is strongly influenced by experience, but the underlying mechanisms are incompletely understood. We found that, in the developing dentate gyrus (DG), excitatory drive promotes the somatic innervation of principal granule cells (GCs) by parvalbumin (PV)-positive basket cells. In contrast, presynaptic differentiation of GCs and interneuron subtypes that inhibit GC dendrites is largely resistant to loss of glutamatergic neurotransmission. The networks of PV basket cells in the DG are regulated by vesicular release from projection entorhinal cortical neurons and, at least in part, by NMDA receptors in interneurons. Finally, we present evidence that glutamatergic inputs and NMDA receptors regulate these networks through a presynaptic mechanism that appears to control the branching of interneuron axons. Our results provide insights into how cortical activity tunes the inhibition in a subcortical circuit and reveal new principles of interneuron plasticity. PMID- 25277457 TI - Diagnosing serious infections in acutely ill children in ambulatory care (ERNIE 2 study protocol, part A): diagnostic accuracy of a clinical decision tree and added value of a point-of-care C-reactive protein test and oxygen saturation. AB - BACKGROUND: Acute illness is the most common presentation of children to ambulatory care. In contrast, serious infections are rare and often present at an early stage. To avoid complications or death, early recognition and adequate referral are essential. In a recent large study children were included prospectively to construct a symptom-based decision tree with a sensitivity and negative predictive value of nearly 100%. To reduce the number of false positives, point-of-care tests might be useful, providing an immediate result at bedside. The most probable candidate is C-reactive protein, as well as a pulse oximetry. METHODS: This is a diagnostic accuracy study of signs, symptoms and point-of-care tests for serious infections. Acutely ill children presenting to a family physician or paediatrician will be included consecutively in Flanders, Belgium. Children testing positive on the decision tree will get a point-of-care C-reactive protein test. Children testing negative will randomly either receive a point-of-care C-reactive protein test or usual care. The outcome of interest is hospital admission more than 24 hours with a serious infection within 10 days. Aiming to include over 6500 children, we will report the diagnostic accuracy of the decision tree (+/- the point-of-care C-reactive protein test or pulse oximetry) in sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values. New diagnostic algorithms will be constructed through classification and regression tree and multiple logistic regression analysis. DISCUSSION: We aim to improve detection of serious infections, and present a practical tool for diagnostic triage of acutely ill children in primary care. We also aim to reduce the number of investigations and admissions in children with non-serious infections. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02024282. PMID- 25277458 TI - Transcriptome reconstruction and annotation of cynomolgus and African green monkey. AB - BACKGROUND: Non-human primates (NHPs) and humans share major biological mechanisms, functions, and responses due to their close evolutionary relationship and, as such, provide ideal animal models to study human diseases. RNA expression in NHPs provides specific signatures that are informative of disease mechanisms and therapeutic modes of action. Unlike the human transcriptome, the transcriptomes of major NHP animal models are yet to be comprehensively annotated. RESULTS: In this manuscript, employing deep RNA sequencing of seven tissue samples, we characterize the transcriptomes of two commonly used NHP animal models: Cynomolgus macaque (Macaca fascicularis) and African green monkey (Chlorocebus aethiops). We present the Multi-Species Annotation (MSA) pipeline that leverages well-annotated primate species and annotates 99.8% of reconstructed transcripts. We elucidate tissue-specific expression profiles and report 13 experimentally validated novel transcripts in these NHP animal models. CONCLUSION: We report comprehensively annotated transcriptomes of two non-human primates, which we have made publically available on a customized UCSC Genome Browser interface. The MSA pipeline is also freely available. PMID- 25277459 TI - Effects of an ascorbic acid-derivative dentifrice in patients with gingivitis: a double-masked, randomized, controlled clinical trial. AB - BACKGROUND: Reactive oxygen species might be associated with the onset and progression of gingival inflammation. The aim of this study is to investigate the effect of a dentifrice containing L-ascorbic acid 2-phosphate magnesium salt (APM), a long-acting ascorbic acid derivative with antioxidant properties, on gingival inflammation. METHODS: The clinical effects of APM were investigated in a multicenter, randomized, parallel-group, controlled clinical trial comprising 300 individuals with gingivitis. Half of the participants were given an APM containing dentifrice and half were given a control dentifrice. The primary outcome was the gingival index (GI) at 3 months. Secondary outcomes included gingival redness as an indicator of the degree of local gingival inflammation, gingival bleeding as a measure of the gingivitis severity index, and total antioxidant activity of the saliva. RESULTS: Under the intent-to-treat analysis, GI did not significantly differ between the groups (P = 0.12). However, under the per-protocol analysis, GI was significantly lower in the APM group (P = 0.01) than in the control group. In the APM group, gingival redness was significantly lower, and the difference from the baseline gingivitis severity index was significantly greater (P = 0.04 and P = 0.02, respectively). The total antioxidant activity of the saliva was significantly higher in the APM group (P = 0.03). The incidence of adverse events did not significantly differ between the groups (P > 0.15). CONCLUSION: These findings indicate that the regular application of an APM-containing dentifrice could reduce gingival inflammation. PMID- 25277460 TI - Syntheses, crystal structures and antioxidant study of Zn(II) complexes with morin-5'-sulfonic acid (MSA). AB - The study of modified synthetic procedure of water soluble morin-5'-sulfonic acid sodium salt (NaMSA) involving less aggressive chemicals and carried out at mild conditions was described. The NaMSA salt is a convenient source of anionic morin 5'-sulfonic ligand (MSA) in ion exchange reactions. The coordination ability of MSA ligand towards the zinc cations was investigated in aqueous solution and in solid state. Novel zinc complexes of morin-5'-sulfonate were obtained by a reaction of Zn(NO3)2 with morin-5'-sulfonate in water. Resulting compounds were characterized by single-crystal X-ray diffraction analysis, as well as spectral and thermal methods. The coordination interaction, hydrogen bond and pi-pi stacking lead to the formation of a 1D chain or 3D coordination polymers. The antioxidant activity of the Zn(II)-MSA complexes was evaluated by means of 1,1 diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. In this work, we have shown that the studied compounds are more effective free radical scavengers than the natural flavonoids like plain morin. PMID- 25277461 TI - Cytotoxic malonate platinum(II) complexes with 1,2,4-triazolo[1,5-a]pyrimidine derivatives: structural characterization and mechanism of the suppression of tumor cell growth. AB - A series of malonate (mal) platinum(II) complexes of the general formula [Pt(mal)(L)2], where L=5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) (1), 7 isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) (2) or 5,7-ditertbutyl 1,2,4-triazolo[1,5-a]pyrimidine (dbtp) (3), has been prepared and characterized using multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR, IR and electrospray ionization mass spectrometry (ESIMS). Furthermore, the crystal structures of [Pt(mal)(dmtp)2]?4H2O (1a) and [Pt(mal)(dbtp)2]?CHCl3 (3a) have been determined using single-crystal X-ray diffraction. The spectroscopic characterization unambiguously confirmed the square-planar geometry of Pt(II) with two monodentate N3-bonded 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines and one O-chelating malonate. The antiproliferative activities of the compounds against the human cell lines T47D (cisplatin-resistant human ductal breast epithelial tumor cell line) and A549 (lung adenocarcinoma epithelial cell line) and the mouse cell line 4T1 (mouse breast tumor model) were assessed using an in vitro screening assay. Compounds (2) and (3) exhibited substantial antigrowth properties against T47D cells, whereas only (3) exhibited an IC50 value that was lower than cisplatin and carboplatin against the 4T1 cell line. Additionally, compounds (2, 3) are capable of arresting the cell cycle of A549 cells at the G0/G1 phase, whereas cisplatin and carboplatin arrested the cells at the G2/M phase, indicating differences in the mechanism of the suppression of tumor cell growth. Finally, in the quest for low toxicity platinum drugs, the in vitro antiproliferative activity against normal mouse fibroblast cells (BALB/3T3) was evaluated. The inhibition of BALB/3T3 cell proliferation by the evaluated Pt(II) complexes increased in the order (1)<(2)<100mg MED) therapy. At 1 year after initiation, 7.5% (n=41,197) of the LTOT sample had discontinued opioids. Among those who discontinued (20%, n=108,601), the median time to discontinuation was 317 days. Factors significantly associated with discontinuation included both younger and older age, lower average dosage, and having received less than 90 days of opioids in the previous year. Although tobacco use disorders decreased the likelihood of discontinuation, co-morbid mental illness and substance use disorders increased the likelihood of discontinuation. LTOT is common in the VHA system and is marked by extended duration of use at relatively low daily doses with few discontinuation events. Opioid discontinuation is more likely in veterans with mental health and substance use disorders. Further research is needed to delineate causes and consequences of opioid discontinuation. PMID- 25277464 TI - Targeting inhaled therapy beyond the lungs. AB - Pulmonary disease has been the primary target of inhaled therapeutics for over 50 years. During that period, increasing interest has arisen in the use of this route of administration to gain access to the systemic circulation for the treatment of a number of diseases beyond the airways. In order to effectively employ this route, the barriers to transport from the lungs following deposition of aerosols must be considered, including the nature of the disease (whether proximal, as in pulmonary hypertension, or distal, as in diabetes). Delivery to the systemic circulation begins with the efficiency of aerosol generation and subsequent deposition in the airways and proceeds to the influence of mechanisms of clearance, including absorption, metabolism, and mucociliary and cell-mediated transport, on the residence time of the drugs in the lungs. The nature of the drug (small or large molecules/low or high molecular weight), susceptibility to degradation and general physicochemical properties play a role in the chemistry of its formulation, physics of aerosol delivery and biology of disposition. PMID- 25277467 TI - Coextraction and PCR Based Analysis of Nucleic Acids From Formalin-Fixed Paraffin Embedded Specimens. AB - BACKGROUND: Retrospective studies of archived human specimens, with known clinical follow-up, are used to identify predictive and prognostic molecular markers of disease. Due to biochemical differences, however, formalin-fixed paraffin embedded (FFPE) DNA and RNA have generally been extracted separately from either different tissue sections or from the same section by dividing the digested tissue. Our optimized co-extraction approach provides the option of collecting DNA, which would otherwise be discarded or degraded, for additional or subsequent studies because of the high importance and less availability of clinical FFPE specimen. METHODS: Coextraction of DNA and RNA from a single gastric cancer FFPE specimen was optimized by using TRIzol and purifying DNA from the lower aqueous and RNA from the upper organic phases. The protocol involves modification of incubation period for 30 min with proteinase K in glycin-tris ethylenediamine tetra acetic acid buffer before adding TRIzol. RESULTS: All samples tested successfully performed semiquantitative gene expression by reverse transcriptase PCR. The quantity and quality of DNA from FFPE samples was high which resulted in successful PCR amplification. The isolated DNA also aided in detection of Helicobacter pylori by amplifying the ribosomal 16S gene in a multiplex PCR reaction along with cagA. CONCLUSION: These results show that the RNA/DNA isolated by this method can be used for easy clinical diagnosis of disease-related gene expression as well as mutation and pathogen detection from a homogenous population of tumor cells. PMID- 25277468 TI - Betulinic acid attenuates lung injury by modulation of inflammatory cytokine response in experimentally-induced polymicrobial sepsis in mice. AB - Sepsis commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity and mortality. Septic ALI is characterized by excessive production of proinflammatory mediators. It remained refractory to present therapies and new therapies need to be developed to improve further clinical outcomes. Betulinic acid (BA), a pentacyclic lupane group triterpenoid has been shown to have anti-inflammatory activities in many studies. However, its therapeutic efficacy in polymicrobial septic ALI is yet unknown. Therefore, we investigated the effects of BA on septic ALI using cecal ligation and puncture (CLP) model in mice. Vehicle or BA (3, 10, and 30mg/kg) was administered intraperitoneally, 3 times (0, 24 and 48h) before CLP and CLP was done on 49(th)h of the study. Survival rate was observed till 120h post CLP. Lung tissues were collected for analysis by sacrificing mice 18h post CLP. BA at 10 and 30mg/kg dose significantly reduced sepsis-induced mortality and lung injury as implied by attenuated lung histopathological changes, decreased protein and neutrophils infiltration. BA also decreased lung NF-kappaB expression, cytokine, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and matrix metalloproteinase-9 levels. These evidences suggest that, the protective effects of BA on lungs are associated with defending action against inflammatory response and BA could be a potential modulatory agent of inflammation in sepsis-induced ALI. PMID- 25277469 TI - Electrocautery-induced localized colonic injury elicits increased levels of pro inflammatory cytokines in small bowel and decreases jejunal alanine absorption. AB - BACKGROUND: Colitis is associated with functional abnormalities in proximal non inflamed gut areas, but animal models to study small bowel dysfunction in colitis have limitations. This study aims to determine small intestinal alanine absorption and cytokine expression in a novel model of colonic ulceration induced by electro-cautery. METHODS: A descending colon ulcer was induced in rats by a bipolar electro-cautery probe. Ulcer score was determined using Satoh's criteria. Jejunal alanine absorption was measured immediately and at different time intervals post ulcer induction. Levels of interleukin-1 (IL-1), interleukin-6 (IL 6), and tumor necrosis factor-alpha (TNF-alpha) protein and m-RNA were determined in mucosal scrapings obtained from the colon, duodenum, jejunum and ileum at various time intervals after colonic ulcer induction. RESULTS: The mean ulcer score was 3 up to 48h, followed by healing by 96h post ulcer induction. Small bowel histology was normal throughout. Jejunal alanine absorption was reduced by 12-34% immediately and up to 72h after cautery and returned to normal at 96h. IL 1 and TNF-alpha mRNA increased significantly in the colon, duodenum, jejunum and ileum 3h post electro-cautery and returned to normal at 48h, while that of IL-6 increased significantly at 48h post ulcer induction. Similarly, IL-1, IL-6 and TNF-alpha protein levels increased in the duodenum, jejunum, ileum and colon up to 48h post ulcer induction. CONCLUSIONS: Electrically induced localized colonic injury increased production of pro-inflammatory cytokines in non-inflamed segments of the small intestine and was associated with derangements of jejunal absorptive function. PMID- 25277470 TI - Cutaneous drug delivery of capsaicin after in vitro administration of the 8% capsaicin dermal patch system. AB - OBJECTIVE: Epicutaneous application of capsaicin causes a long-lasting analgesic effect by binding to the membrane transient receptor potential vanilloid 1 (TRPV1) on mechanoheat-sensitive C and Adelta fibres, changing axonal integrity and inhibiting neurogenic inflammatory processes. To date, no information is available regarding the cutaneous drug delivery of capsaicin following patch application. METHODS: Using a Franz diffusion cell, the cutaneous concentration time profiles 30, 60 and 90 min after application of a patch containing 8% capsaicin (640 ug/cm(2)) on ex vivo thin (mamma) and thick (plantar) human skin were investigated at 32 degrees C, and additionally at 42 degrees C for thin skin and 10 degrees C for thick skin. An HPLC-MS method was used for the analytic detection of capsaicin. RESULTS: The results show that already after a 30-min application of the 8% capsaicin patch, an equilibrium reservoir can be found in the stratum corneum in both thick and thin skin. Under physiological temperature conditions, a sufficient bioavailability of capsaicin in the cutaneous target compartments can be found. Raising the temperature to 42 degrees C has no relevant impact on the concentration-time profile, while reducing the temperature to 10 degrees C leads to a significantly lower bioavailability. CONCLUSION: After 30 min of application, a sufficient cutaneous bioavailability of capsaicin is reached in thick as well as thin skin. Whether shorter application times may suffice to achieve therapeutic effectiveness requires further investigation. PMID- 25277471 TI - The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm. AB - OBJECTIVE: Dating back to the first published report of the Fontan circulation in 1971, multiple studies have examined the long-term results of this standard procedure for palliation of single-ventricle heart disease in children. Although the technique has evolved over the last 4 decades to include a polytetrafluorethylene (PTFE) conduit for a large percentage of patients, the long-term outcome has not yet been established. The aim of the current study was to investigate the possibility of a late increasing risk for death after 15 years among patients with a modern Fontan operation and to evaluate late morbidity. METHODS: Between January 1, 1988, and December 31, 2011, 207 patients underwent the Fontan procedure using an internal or external PTFE conduit plus a bidirectional cavopulmonary connection. Survival and late adverse events were analyzed. Risk factors for early and late mortality were examined using hazard function methodology. RESULTS: At 1, 10, and 20 years, survival for the entire cohort was 95%, 88%, and 76%, respectively, with no deaths in the last 6 years of the study. Hazard modeling showed a 1.3% risk of death per year 24 years after the Fontan procedure, with no late increasing hazard phase. Freedom from reoperations was greater than 90% at 20 years and freedom from thrombotic complications was 98% at 20 years (with greater than 80% of patients on aspirin alone). Survival curves were superimposable for 16- to 20-mm conduits, and the freedom from any reoperation including transplantation was greater than 90% after 20 years. Multivariable risk factor analysis identified only earlier date of operation as a predictor of early and late mortality. By era of surgery, the 10 year predicated survival is 89% for patients undergoing surgery in 2000 and 94% for patients in 2010. CONCLUSIONS: Early and late survival after a Fontan operation with a PTFE conduit is excellent, with no late phase of increasing death risk after 20 years. Late functional status is good, the need for late reoperation is rare, and thrombotic complications are uncommon on a standard medical regimen including aspirin as the only anticoagulation medication. PMID- 25277472 TI - Discussion. PMID- 25277473 TI - Single-port laparoscopic colorectal surgery shows equivalent or better outcomes to standard laparoscopic surgery: results of a 190-patient, 7-criterion case match study. AB - INTRODUCTION: Single-port (SP) surgery has been characterized as having limited applicability regarding procedure, disease, and patient characteristics. There is a question if SP procedures offer disadvantages or advantages to multiport (MP) colorectal surgery. We hypothesize that SP is equivalent to MP and is a safe alternative in the full spectrum of colorectal disease and procedures. METHODS: A case-matched analysis of a prospectively maintained database to compare perioperative outcomes in SP versus MP was performed. Criteria included age, gender, BMI, previous abdominal surgery, previous XRT, disease process, and procedure. 95 exact matches for all 7 criteria were found between 159 SP and 1,617 MP cases. Perioperative outcomes, surgical technique, morbidity, mortality, local recurrence, and 5-year survival were analyzed. RESULTS: There was lower mean EBL in SP but no difference in transfusion requirement. OR time for SP left colectomy was shorter, with a trend to shorter OR times found in all procedures. 99 % SP and 98 % MP had no intra-operative complications. Conversion to open was equivalent (0/1). Mean largest incision was smaller for SP. There were no differences in return of bowel function or length of hospital stay. There were no mortalities. There were no differences in perioperative morbidity, local recurrence, distant metastasis, or overall 5-year survival. CONCLUSIONS: SP is a safe alternative to MP colorectal surgery across the full array of procedures in equivalent patients. This study demonstrates SP has less blood loss, smaller incisions, is quicker in left colectomy, and tends to be quicker across all procedures. Conversion and morbidity rates are equivalent to MP, without compromise in quality of surgical technique. While proper training is essential, concerns regarding the inability to use SP laparoscopic colorectal surgery safely are unfounded in nearly exactly matched patients. These issues will require further study as SP laparoscopic colorectal surgery is practiced more widely. PMID- 25277474 TI - Circumferential submucosal incision prior to endoscopic mucosal resection provides comparable clinical outcomes to submucosal dissection for well differentiated neuroendocrine tumors of the rectum. AB - BACKGROUND: Small rectal neuroendocrine tumors (NETs) can be treated with endoscopic resection. Endoscopic submucosal dissection (ESD) has been accepted as a reliable technique, but it is difficult. We evaluated the feasibility and efficacy of precut and endoscopic mucosal resection (CSI-EMR) for rectal NETs compared to ESD. METHODS: Patients with rectal NETs were enrolled consecutively. ESD or CSI-EMR was performed at operator's discretion. Histological and clinical outcomes were measured and compared between the two treatment modalities. RESULTS: Thirty-three patients were enrolled in the study. Seventeen NETs were treated by the ESD method and 16 were treated by CSI-EMR. Both groups had similar mean tumor diameters (ESD 7.53 +/- 1.94 vs. CSI-EMR 6.63 +/- 1.99 mm; p = 0.197). En bloc resection was achieved in 100 % of ESD group and 87.5 % of CSI-EMR group. Lateral margin involvement occurred in one patient in ESD group and two in CSI EMR group. The histologically complete resection rate was 88.2 % (15 of 17) in the ESD group and 81.2 % (13 of 16) in CSI-EMR group (p = 0.592). One case of perforation occurred in both groups. Delayed bleeding did not occur. None of the measured outcomes were different between the two groups. Operating time was significant shorter in CSI-EMR group than in ESD group (9.69 vs. 20.12 min, respectively; p value = 0.004). CONCLUSIONS: CSI-EMR results in reliable clinical outcomes for small rectal NETs comparable to those of ESD. CSI-EMR is technically feasible and more time saving. PMID- 25277475 TI - Laparoscopic surgery after endoscopic resection for rectal cancer and neuroendocrine tumors. AB - BACKGROUND: Endoscopic resection (ER) of tumors causes inflammation, edema, fibrosis, and adhesions in the surrounding tissue. However, little is known about the effect of ER on subsequent laparoscopic surgery for rectal tumors. The objective of this retrospective study was to analyze the effect of ER on subsequent laparoscopic surgery for rectal tumors. METHODS: Twenty-eight patients underwent laparoscopic surgery for rectal adenocarcinoma with submucosal invasion or a rectal neuroendocrine tumor at our hospital between January 2005 and December 2012. A group of 14 patients who underwent laparoscopic surgery with previous ER was compared to a group of 14 patients who underwent laparoscopic surgery without previous ER. RESULTS: Though most fibrosis involved the submucosa after polypectomy and endoscopic mucosal resection, fibrosis after endoscopic submucosal dissection involved the muscularis propria in two patients, and the subserosa in one patient. There were no statistically significant differences in clinical outcomes between the groups. CONCLUSION: Laparoscopic surgery after ER for rectal tumors is safe and feasible. Laparoscopic surgery is the reasonable first-choice for radical treatment of rectal tumors after ER. PMID- 25277476 TI - Routine use of fluorescent incisionless cholangiography as a new imaging modality during laparoscopic cholecystectomy. AB - BACKGROUND: Intraoperative incisionless fluorescent cholangiography (IOIFC) has been described to identify extrahepatic biliary anatomy. Potential advantages of the routine use of intraoperative incisionless fluorescent cholangiography were evaluated in a consecutive series of cases. METHODS: A total of 45 patients undergoing laparoscopic cholecystectomy between January and July 2013 were consented and included in this study. We analyzed a prospectively collected database for feasibility, cost, time, usefulness, teaching tool, safety, learning curve, X-ray exposure, complexity, and real-time surgery of IOIFC. A single dose of 0.05 mg/kg of Indocyanine green was administered prior to surgery. During the procedure, a laparoscopic fluorescence system was used. RESULTS: IOIFC could be performed in all 45 patients, whereas intraoperative cholangiography could be performed in 42 (93 %). Individual median cost of performing IOFC was cheaper than IOC (13.97 +/- 4.3 vs 778.43 +/- 0.4 USD) per patient, p = 0.0001). IOFC was faster than IOC (0.71 +/- 0.26 vs 7.15 +/- 3.76 minutes, p < 0.0001). The cystic duct was identified by IOFC in 44 out of 45 patients (97.77 %). CONCLUSION: IOIFC appears to be a feasible, low-cost, expeditious, useful, and effective imaging modality when performing LC. It is safe, easy to perform and interpret, and does not require a learning curve or X-ray. It can be used for real time surgery to delineate the extrahepatic biliary structures. PMID- 25277477 TI - Learning curve for robotic-assisted surgery for rectal cancer: use of the cumulative sum method. AB - BACKGROUND: Few data are available to assess the learning curve for robotic assisted surgery for rectal cancer. The aim of the present study was to evaluate the learning curve for robotic-assisted surgery for rectal cancer by a surgeon at a single institute. METHODS: From December 2011 to August 2013, a total of 80 consecutive patients who underwent robotic-assisted surgery for rectal cancer performed by the same surgeon were included in this study. The learning curve was analyzed using the cumulative sum method. This method was used for all 80 cases, taking into account operative time. RESULTS: Operative procedures included anterior resections in 6 patients, low anterior resections in 46 patients, intersphincteric resections in 22 patients, and abdominoperineal resections in 6 patients. Lateral lymph node dissection was performed in 28 patients. Median operative time was 280 min (range 135-683 min), and median blood loss was 17 mL (range 0-690 mL). No postoperative complications of Clavien-Dindo classification Grade III or IV were encountered. We arranged operative times and calculated cumulative sum values, allowing differentiation of three phases: phase I, Cases 1 25; phase II, Cases 26-50; and phase III, Cases 51-80. CONCLUSIONS: Our data suggested three phases of the learning curve in robotic-assisted surgery for rectal cancer. The first 25 cases formed the learning phase. PMID- 25277478 TI - Short- and long-term outcomes of laparoscopic gastrectomy in elderly patients with gastric cancer. AB - BACKGROUND: Elderly patients are regarded as being at increased risk during major abdominal surgery because of a lack of functional reserve and an increased number of comorbidities. The aim of this study was to compare short- and long-term outcomes of laparoscopic gastrectomy between elderly and young gastric cancer patients. METHODS: Two-hundred ten patients who underwent laparoscopic gastrectomy for gastric cancer at our institution between January 2001 and December 2011 were included in this retrospective study. Patients were divided into two age groups (younger than 70 years and older than 70 years) and were evaluated with respect to postoperative morbidity, quality of life (QOL), and survival. RESULTS: Postoperative morbidity was similar in elderly and young groups (18.3 vs. 21.6 %; P = 0.718). Overall survival of the elderly group was significantly worse than that of the young group (P < 0.001). However, disease specific survival was not significantly different between the two groups. Longitudinal postoperative change in QOL in the elderly group showed a recovery similar to that in the young group. CONCLUSIONS: Laparoscopic gastrectomy can be performed as safely in elderly patients as in young patients, with comparable postoperative results and long-term outcomes, including QOL, although the life expectancy of elderly patients is shorter. PMID- 25277479 TI - A noble method for intraoperative fine localization during laparoscopic gastric local resection: endoscopic submucosal cutting and light transmission. AB - BACKGROUND: The main requirements when performing laparoscopic local resection for early mucosal tumors of the stomach are a clearly defined cancer-free margin and precise tumor localization. In this study, a novel method for precise intraoperative tumor localization and appropriate resection in a porcine model is introduced: endoscopic submucosal cutting and light transmission (ESCLT). METHODS: A total of 15 cases of laparoscopic local resection were performed in 6 pigs. The size of the target lesions was approximately 20 mm. The imaginary lesions were located in the high body anterior wall, posterior wall, lower body posterior wall, angle, and antrum anterior wall of the stomach. Mucosal marking around the lesions, mucosal precutting surrounding the marking, and submucosal cutting along the precutting line using white light endoscopy were sequentially performed. Next, an endoscopic light source was placed directly in front of the lesion. Exact oval-shaped submucosal cutting margins were identified via laparoscopy. Laparoscopic local resection was performed after the minimal distance from the stapler line to the submucosal cutting line was confirmed. The sizes of the mucosal marking, submucosal cutting line, and the entire resected mucosa and serosa were measured. RESULTS: The procedure was completed successfully in all pigs. Local resection was completed on all of the lesions. The mean endoscopic and laparoscopic procedure times were 26.1 and 12.7 min, respectively. The mean size of the resected specimens was: (i) marking lesion, 22 * 19.5 mm; (ii) submucosal cutting line, 26.7 * 23.2 mm; (iii) entire resected mucosa, 37 * 31 mm; and (iv) entire resected serosa, 41.7 * 33.1 mm. There was no intraoperative morbidity. CONCLUSION: ESCLT provides a precise and useful method of intraoperative tumor localization during laparoscopic local resection of the stomach in terms of minimizing the resection of normal stomach tissue and guaranteeing adequate mucosal safety margins. PMID- 25277480 TI - Immediate technical and delayed clinical outcome of fistula closure using an over the-scope clip device. AB - BACKGROUND AND STUDY AIMS: An over-the-scope clip (OTSC) device was designed for closure of acute perforations, fistulas, leaks, and non-variceal gastrointestinal bleeding. Previous data show a high rate of early fistula closure using the OTSC; however, data on long-term fistula closure are scant. We report our experience using an OTSC for closure of chronic gastrointestinal fistulas. PATIENTS AND METHODS: Retrospective review of all patients, who underwent OTSC placement at Mayo Clinic Rochester and Virginia Mason Medical Center for closure of chronic fistulas from October 2011 to September 2012, was performed. Initial technical success was defined by lack of contrast extravasation immediately after OTSC placement. Delayed success was defined by resolution of the fistula without the need for additional therapies. Recurrent fistula was defined by the recurrence of symptoms and/or re-demonstration of fistula after initial success. RESULTS: Forty seven unique patients (24 men; mean age 57 +/- 14 years) underwent 60 procedures using the OTSC for closure of gastrointestinal fistulas. Fistula locations were: small bowel (n = 18), stomach (n = 16), colo-rectum (n = 10), and esophagus (n = 3). Fistulas related to previous percutaneous endoscopic gastrostomy/jejunostomy (n = 10) or prior bariatric procedure (n = 10) were the most common etiologies. Initial technical success occurred in 42/47 (89%) index cases; however, 19/41 (46%) patients developed fistula recurrence at a median of 39 days (IQR 26-86 days). The retained OTSC was present adjacent to the fistula in 16/19 (84%) at repeat intervention. Patients were followed for a median length of 178 days (IQR 63-326 days), and only 25/47 (53%) patients demonstrated delayed clinical success using OTSC. CONCLUSIONS: Initial technical fistula closure can be achieved using OTSCs. Recurrent fistulas at the same location occur in approximately 50% of cases despite frequent OTSC clip retention. PMID- 25277481 TI - Early gastric cancer with mixed histology predominantly of differentiated type is a distinct subtype with different therapeutic outcomes of endoscopic resection. AB - BACKGROUND: Safety of endoscopic resection (ER) for early gastric cancers (EGC) with mixed histology predominantly of differentiated type has not been securely established, since those lesions tend to exhibit lymph node metastasis, compared to pure differentiated type. The purpose of this study was to evaluate clinicopathologic characteristics, therapeutic outcomes, and risk for lymph node metastasis in predominantly differentiated mixed EGC treated by ER. METHODS: A total of 1,016 patients with 1,039 EGCs underwent ER between January 2007 and June 2013. Enrolled lesions were divided into groups of either pure differentiated (n = 1,011) or predominantly differentiated mixed (n = 28), according to the presence of mixed histology predominantly of differentiated type in ER specimen. RESULTS: Mixed histology predominantly of differentiated type was diagnosed in 2.7% of lesions. Larger size, mid-third location, and moderately differentiated histology on forceps biopsy were independent risk factors for the predominantly differentiated mixed histologic type of EGC in multivariate analysis. En bloc resection rate tended to be lower, and complete and curative resection rates were significantly lower in the predominantly differentiated mixed group. The rate of lymph node metastasis in the lesions with additional operation tended to be higher, in this mixed histology group. CONCLUSIONS: Larger size, mid-third location, and moderately differentiated histology on forceps biopsy carry the significant risk for mixed histology predominantly of differentiated type. EGC with predominantly differentiated mixed histologic type affects therapeutic outcomes and consequent clinical course accompanied by possibly higher risk for lymph node metastasis. The safety of ER for predominantly differentiated mixed EGC should be validated by further prospective investigation. PMID- 25277482 TI - Quality of life after single-port laparoscopic surgery versus conventional laparoscopic surgery for benign gynecologic disease. AB - BACKGROUND: The aim of current study was to determine whether single-port laparoscopic surgery (SP-LS) improves the health-related quality of life (QoL) compared with conventional laparoscopic surgery (conventional LS) in women with benign gynecologic disease. METHODS: We performed a prospective case-control study from October 2010 to December 2012. A total of 273 women with benign gynecologic disease participated in this study, and 135 of them were in the SP-LS group and 138 in the conventional LS. We evaluated QoL after SP-LS or conventional LS. All patients were asked to complete short-form 36 (SF-36) QoL health surveys preoperatively and at 1, 3, and 6 months postoperatively. RESULTS: Clinical characteristics and operative outcomes showed no significant differences between both groups. SP-LS had no benefits in QoL compared with conventional LS in the main categories, even though SP-LS showed statistically significant higher scores than conventional LS for the role of physical domain at 1 month postoperatively and for social function at 3 months postoperatively. In contrast to this, conventional LS had statistically significant higher scores than SP-LS for role function, bodily pain, general health, vitality, and emotional well being at 6 months postoperatively. CONCLUSIONS: With a 6-month follow-up, SP-LS does not offer a QoL benefit over conventional LS in women with benign gynecologic disease. However, a larger prospective randomized study would be required to confirm this. PMID- 25277485 TI - O2 adsorption dependent photoluminescence emission from metal oxide nanoparticles. AB - Optical properties of metal oxide nanoparticles are subject to synthesis related defects and impurities. Using photoluminescence spectroscopy and UV diffuse reflectance in conjunction with Auger electron spectroscopic surface analysis we investigated the effect of surface composition and oxygen adsorption on the photoluminescence properties of vapor phase grown ZnO and MgO nanoparticles. On hydroxylated MgO nanoparticles as a reference system, intense photoluminescence features exclusively originate from surface excitons, the radiative deactivation of which results in collisional quenching in an O2 atmosphere. Conversely, on as prepared ZnO nanoparticles a broad yellow emission feature centered at hnuEm = 2.1 eV exhibits an O2 induced intensity increase. Attributed to oxygen interstitials as recombination centers this enhancement effect originates from adsorbate-induced band bending, which is pertinent to the photoluminescence active region of the nanoparticles. Annealing induced trends in the optical properties of the two prototypical metal oxide nanoparticle systems, ZnO and MgO, are explained by changes in the surface composition and underline that particle surface and interface changes that result from handling and processing of nanoparticles critically affect luminescence. PMID- 25277484 TI - Risk of recurrent or refractory strictures and outcome of endoscopic dilation for radiation-induced esophageal strictures. AB - BACKGROUND: Radiation therapy for head, neck, and esophageal cancer can result in esophageal strictures that may be difficult to manage. Radiation-induced esophageal strictures often require repeat dilation to obtain relief of dysphagia. This study aimed to determine the long-term clinical success and rates of recurrent and refractory stenosis in patients with radiation-induced strictures undergoing dilation. METHODS: Retrospective cohort study of patients with radiation-induced strictures who underwent endoscopic dilation by a single provider from October 2007-October 2012. Outcomes measured included long-term clinical efficacy, interval between sessions, number of dilations, and proportion of radiation strictures that were recurrent or refractory. Risk factors for refractory strictures were assessed. RESULTS: 63 patients underwent 303 dilations. All presented with a stricture >30 days after last radiation session. Clinical success to target diameter was achieved in 52 patients (83%). A mean of 3.3 (+/-2.6) dilations over a median period of 4 weeks was needed to achieve initial patency. Recurrence occurred in 17 (33%) at a median of 22 weeks. Twenty seven strictures (43%) were refractory to dilation therapy. Fluoroscopy during dilation (OR 22.88; 95% CI 3.19-164.07), severe esophageal stenosis (lumen <9 mm) (OR 10.51; 95% CI 1.94-56.88), and proximal location with prior malignancy extrinsic to the lumen (OR 6.96; 95% CI 1.33-36.29) were independent predictors of refractory strictures in multivariate analysis. CONCLUSIONS: (1) Radiation induced strictures have a delayed onset (>30 days) from time of radiation injury. (2) Endoscopic dilation can achieve medium-term luminal remediation but the strictures have a high long-term recurrence rate of up to 33%. (3) Remediation of radiation strictures following laryngectomy can be achieved but require frequent dilations. (4) Clinical and procedural predictors may identify patients at high risk of refractory strictures. (5) The optimal strategy in highly selected refractory patients is not clear. PMID- 25277483 TI - Bismuth classification is associated with the requirement for multiple biliary drainage in preoperative patients with malignant perihilar biliary stricture. AB - BACKGROUND: Single preoperative biliary drainage for malignant perihilar biliary stricture occasionally fails to control jaundice and cholangitis. Multiple biliary drainage is required in such cases, but their clinical background is unclear. We determined the clinical characteristics associated with the requirement for multiple biliary drainage. METHODS: The consecutive 122 patients with malignant perihilar biliary stricture were enrolled in a single-center retrospective study. Preoperative biliary drainage was initially performed on the future remnant hepatic lobe. Additional drainage was performed if jaundice failed to improve or cholangitis developed in undrained hepatic lobes. Detailed clinical characteristics and the number of preoperative biliary drainage procedures required before operation were analyzed. RESULTS: Thirty-one patients (25.4%) initially underwent multiple biliary drainage. However, 69 (56.7%) required multiple biliary drainage by the time of the operation. In the univariate analysis, the initial serum bilirubin level, cholangitis, percutaneous portal vein embolization, history of inserted endoscopic biliary stenting, length of preoperative period, operative procedure, and Bismuth classification were significant factors. In the multivariate analysis using these factors, Bismuth classification was independently associated with the requirement for multiple biliary drainage. The number of patients who required multiple biliary drainage was higher in those with Bismuth-II (91.9%), Bismuth-IIIa (65.7%), and Bismuth-IV (92.9%) than in those with Bismuth-I (22.2%) and Bismuth-IIIb (18.2%). CONCLUSIONS: Patients with Bismuth-II, Bismuth-IIIa, and Bismuth-IV are at higher risk for multiple biliary drainage. A strategy based on the Bismuth classification for performing preoperative biliary drainage is important for patients with malignant perihilar biliary stricture. PMID- 25277486 TI - Consequences of splitting whole-genome sequencing effort over multiple breeds on imputation accuracy. AB - BACKGROUND: The aim of this study was to determine the consequences of splitting sequencing effort over multiple breeds for imputation accuracy from a high density SNP chip towards whole-genome sequence. Such information would assist for instance numerical smaller cattle breeds, but also pig and chicken breeders, who have to choose wisely how to spend their sequencing efforts over all the breeds or lines they evaluate. Sequence data from cattle breeds was used, because there are currently relatively many individuals from several breeds sequenced within the 1,000 Bull Genomes project. The advantage of whole-genome sequence data is that it carries the causal mutations, but the question is whether it is possible to impute the causal variants accurately. This study therefore focussed on imputation accuracy of variants with low minor allele frequency and breed specific variants. RESULTS: Imputation accuracy was assessed for chromosome 1 and 29 as the correlation between observed and imputed genotypes. For chromosome 1, the average imputation accuracy was 0.70 with a reference population of 20 Holstein, and increased to 0.83 when the reference population was increased by including 3 other dairy breeds with 20 animals each. When the same amount of animals from the Holstein breed were added the accuracy improved to 0.88, while adding the 3 other breeds to the reference population of 80 Holstein improved the average imputation accuracy marginally to 0.89. For chromosome 29, the average imputation accuracy was lower. Some variants benefitted from the inclusion of other breeds in the reference population, initially determined by the MAF of the variant in each breed, but even Holstein specific variants did gain imputation accuracy from the multi-breed reference population. CONCLUSIONS: This study shows that splitting sequencing effort over multiple breeds and combining the reference populations is a good strategy for imputation from high-density SNP panels towards whole-genome sequence when reference populations are small and sequencing effort is limiting. When sequencing effort is limiting and interest lays in multiple breeds or lines this provides imputation of each breed. PMID- 25277487 TI - Immunomodulation in patients with chronic hand eczema treated with oral alitretinoin. AB - BACKGROUND: Oral alitretinoin (9-cis-retinoic acid; 9-cis-RA) has shown clinical efficacy in patients with chronic hand eczema (CHE). Herein, we investigated the impact of oral 9-cis-RA on the local and systemic immune response in patients with CHE. METHODS: Twenty patients with CHE were treated with oral alitretinoin (10 or 30 mg/day) for at least 24 weeks. Blood samples were taken for flow cytometry, and serum samples were assessed by ELISA to determine immunoglobulin (Ig) levels. Skin biopsies from lesional skin were evaluated immunohistochemically. RESULTS: Upon 9-cis-RA treatment, improvement of the CHE was observed in all patients. A significant decrease in plasmablasts in the peripheral blood and a significant reduction of serum IgE levels were determined. Furthermore, we detected a significant reduction of CD4+ cells and regulatory T cells in the peripheral blood upon treatment. By contrast, these cell subsets were significantly increased in the affected skin. Cytokine analysis of activated CD154-positive T cells showed a reduction of interleukin (IL)-17 but not of IL-4 or IFN-gamma production. CONCLUSIONS: Overall, our data indicate a disease modifying effect of 9-cis-RA, including a systemic decrease in IL-17-positive cells, but decreased serum IgE and CD23 expression. The increased frequency of FoxP3-positive cells in the skin upon treatment may suggest a mechanism by which hand eczema is therapeutically targeted by 9-cis-RA, but this will need to be proven in the future studies. PMID- 25277488 TI - Cognitive constructs and social anxiety disorder: beyond fearing negative evaluation. AB - Pioneering models of social anxiety disorder (SAD) underscored fear of negative evaluation (FNE) as central in the disorder's development. Additional cognitive predictors have since been identified, including fear of positive evaluation (FPE), anxiety sensitivity, and intolerance of uncertainty (IU), but rarely have these constructs been examined together. The present study concurrently examined the variance accounted for in SAD symptoms by these constructs. Participants meeting criteria for SAD (n = 197; 65% women) completed self-report measures online. FNE, FPE, anxiety sensitivity, and IU all accounted for unique variance in SAD symptoms. FPE accounted for variance comparable to FNE, and the cognitive dimension of anxiety sensitivity and the prospective dimension of IU accounted for comparable variance, though slightly less than that accounted for by FNE and FPE. The results support the theorized roles that these constructs play in the etiology of SAD and highlight both FNE and FPE as central foci in SAD treatment. PMID- 25277489 TI - The development and evaluation of a computerized diagnosis scheme for pneumoconiosis on digital chest radiographs. AB - PURPOSE: To diagnose pneumoconiosis using a computer-aided diagnosis system based on digital chest radiographs. METHODS: Lung fields were first extracted by combining the traditional Otsu-threshold method with a morphological reconstruction on digital radiographs (DRs), and then subdivided into six non overlapping regions (region (a-f)). Twenty-two wavelet-based energy texture features were calculated exclusively from each region and selected using a decision tree algorithm. A support vector machine (SVM) with a linear kernel was trained using samples with texture features to classify an individual region of a healthy subject or a pneumoconiosis patient. The final classification results were obtained by integrating these individual classifiers with the weighted voting method. All models were developed on a dataset of 85 healthy controls and 40 stage I or II pneumoconiosis patients and validated by using the bootstrap resampling with replacement method. RESULTS: The areas under receiver operating characteristic curves (AUCs) of regions (c) and (f) were 0.688 and 0.563, which were worse than those of the other four regions. Region (c) and (f) were both excluded from the individual classifiers that were going to be assembled further. When built on the selected texture features, each individual SVM showed a higher diagnostic performance for the training set and the test set. The classification performance after an ensemble was 0.997 and 0.961 of the AUC value for the training and test sets, respectively. The final results were 0.974 +/- 0.018 for AUC value and 0.929 +/- 0.018 for accuracy. CONCLUSION: The integrated SVM model built on the selected feature set showed the highest diagnostic performance among all individual SVM models. The model has good potential in diagnosing pneumoconiosis based on digital chest radiographs. PMID- 25277490 TI - Biocompatibility of quantum dots (CdSe/ZnS ) in human amniotic membrane-derived mesenchymal stem cells in vitro. AB - BACKGROUND AND AIM: Amniotic membrane-derived mesenchymal stem cells (hAM-dMSCs) are a potential source of mesenchymal stem cells which could be used to repair skin damage. The use of mesenchymal stem cells to repair skin damage requires safe, effective and biocompatible agents to evaluate the effectiveness of the result. Quantum dots (QDs) composed of CdSe/ZnS are semiconductor nanocrystals with broad excitation and narrow emission spectra, which have been considered as a new chemical and fluorescent substance for non-invasively labeling different cells in vitro and in vivo. This study investigated the cytotoxic effects of QDs on hAM-dMSCs at different times following labeling. METHODS: Using 0.75, 1.5 and 3.0 MUL between quantum dots, labeled human amniotic mesenchymal stem cells were collected on days 1, 2 and 4 and observed morphological changes, performed an MTT cell growth assay and flow cytometry for mesenchymal stem cells molecular markers. RESULTS: Quantum dot concentration 0.75 MUg/mL labeled under a fluorescence microscope, cell morphology was observed, The MTT assay showed cells in the proliferative phase. Flow cytometry expression CD29, CD31, CD34, CD44, CD90, CD105 and CD106. CONCLUSIONS: Within a certain range of concentrations between quantum dots labeled human amniotic mesenchymal stem cells has good biocompatibility. PMID- 25277491 TI - Prostate specific antigen. Current clinical application and future prospects. AB - BACKGROUND: Prostate-specific antigen (PSA) is a glycoprotein produced by the prostate gland and its production can be enhanced in benign and malignant diseases. The introduction of PSA testing has greatly increased the detection of prostate cancer. However there is continuing controversy and confusion over the most appropriate application of the PSA test. METHODS: PubMed and Web of Science databases were used to search original and review articles on the historical aspects, clinical utilization and possible future directions in PSA. CONCLUSIONS: After its discovery, PSA was quickly established as an exquisitely sensitive tumor marker for prostate cancer detection, assessment of treatment responses and follow-up among patients with prostate cancer. Nevertheless, controversy exists about the proper threshold for recommending prostate biopsy. If this limit is lowered to improve the sensitivity even more, patients with low-risk prostate cancer would be subsequently detected. Post-treatment PSA levels can certainly provide valuable information about the effectiveness of the therapy given. Recently introduced ultrasensitive PSA detection techniques are offering new insight into the changes in serum PSA at very low concentrations. This has resulted in identification of valuable postoperative prognostic variables together with the possibility of earlier cancer relapse detection. The development of assays that may show superior sensitivity and specificity in prostate cancer diagnosis is focused on proteins possibly complexed with PSA and other potential markers detectable both in serum and urine. The goal of newly discovered prostate cancer biomarkers is greater cancer specificity in order to reduce the overdiagnosis, overtreatment and financial cost. PMID- 25277492 TI - Genetic analysis of post-weaning growth traits of Thalli sheep under tropical conditions. AB - Present investigation was carried out to study the influence of genetic and non genetic factors affecting post-weaning performance traits in Thalli sheep. Data on post-weaning growth of Thalli sheep maintained at Livestock Experiment Station, Rakh Ghulaman, District Bhakkar-Punjab, Pakistan during 1977-2003 were subjected to genetic analysis. The average values for weight at 180 and 270 days of age, yearling weight and post-weaning average daily gain were 22.37 +/- 4.21, 25.96 +/- 4.90 and 28.93 +/- 5.20 kg and 28 +/- 0.01 g/day, respectively. Weight at 180, 270 and 365 days of age and post-weaning average daily gain were significantly affected by year of birth, sex, type of birth and weaning weight (covariable) whereas season of birth was a significant source of variation for 180 and 270 days of age. The heritability estimates for 180 and 270 days, yearling weight and post-weaning average daily gain were 0.07 +/- 0.02, 0.08 +/- 0.02, 0.07 +/- 0.02 and 0.07 +/- 0.02, respectively. PMID- 25277493 TI - Effects of steam-treated rice straw feeding on growth, digestibility, and plasma volatile fatty acids of goats under different housing systems. AB - In order to use rice straw as forage in livestock feeding, the effects of steam treated rice straw (at 15.5 kgf/cm(2) for 120 s) feeding on growth performance, plasma volatile fatty acid profile, and nutrient digestibility of goats were determined. Twenty male goats (18.69 +/- 0.34 kg) were used in an 84-day trial. The goats were divided into four groups of five goats each to receive steam treated (STRS) or untreated (UTRS) rice straw diet under closed house (CH) and open house (OH) systems. The results revealed that the goats fed with STRS had significantly higher dry matter (DM), organic matter (OM), crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) digestibility; similarly, the average daily weight gain and feed conversion ratio were higher for STRS groups under both CH and OH systems than those for UTRS. The plasma protein and insulin in STRS and cholesterol in UTRS groups was higher (P < 0.05) at 60 days but found not different (P > 0.05) at 30 days. The plasma amylase, lipase, T3, T4 and glucagon at 30 and 60 days were not different (P > 0.05) among the groups. The plasma acetate, propionate, butyrate, and total volatile fatty acid were higher (P < 0.05) in STRS groups at 30 and 60 days. The housing conditions had no effects (P > 0.05) on these parameters. It could be concluded that steam treatment of rice straw at 15.5 kgf/cm(2) for 120 s increased apparent nutrient digestibility, hence increased the growth and feed efficiency of growing goats. PMID- 25277494 TI - Molecular pathotyping and phylogenesis of the first Newcastle disease virus strain isolated from backyard chickens in Qatar. AB - The first Newcastle disease virus (NDV) field strain (NDV-QC08), previously isolated and identified in Qatar, was further subjected to molecular characterization and phylogenic analysis at passage levels two. Initial amplification and detection of the complementary DNA (cDNA) fragment of the NDV RNA amnioallantoic fluid (AAF) extract demonstrated the positive virus identity using real-time reverse transcriptase chain reaction (RRT-PCR). Partial sequence of the totally amplified 216 bp of the functional cleavage region encoding the F gene retrieved (112)R-R-Q-K-R-F(117) amino acid motif indicating the velogenic nature of the strain, and confirming the previously investigated in-vivo pathotyping. Phylogenic analysis and genotypic clustering studies classified the strain under NDV subgenotype VIId. PMID- 25277495 TI - Manipulating item proportion and deception reveals crucial dissociation between behavioral, autonomic, and neural indices of concealed information. AB - Developed as an alternative to traditional deception detection methods, the concealed information test (CIT) assesses recognition of critical (e.g., crime relevant) "probes." Most often, recognition has been measured as enhanced skin conductance responses (SCRs) to probes compared to irrelevant foils (CIT effect). More recently, also differentially enlarged reaction times (RTs) and increased neural activity in the bilateral inferior frontal gyrus, the right middle frontal gyrus, and the right temporo-parietal junction have been observed. The aims of the current functional magnetic resonance imaging (fMRI) study were to (1) investigate the boundary conditions of the CIT effects in all three measures and thereby (2) gain more insight into the relative contribution of two mechanisms underlying enhanced responding to concealed information (i.e., orienting versus response inhibition). Therefore, we manipulated the proportion of probe versus irrelevant items, and whether suspects were instructed to actively deny recognition of probe knowledge (i.e., deceive) during the test. Results revealed that whereas overt deception was not necessary for the SCR CIT effect, it was crucial for the RT and the fMRI-based CIT effects. The proportion manipulation enhanced the CIT effect in all three measures. The results indicate that different mental processes might underlie the response pattern in the CIT. While skin conductance responding to concealed information may best be explained by orienting theory, it seems that response inhibition drives RT and blood oxygen level dependent responding to concealed information. PMID- 25277496 TI - The effectiveness of an attention bias modification program as an adjunctive treatment for Post-Traumatic Stress Disorder. AB - Attention bias modification (ABM) may be an effective treatment for anxiety disorders (Beard, Sawyer, & Hofmann, 2012). As individuals with PTSD possess an attentional bias towards threat-relevant information ABM may prove effective in reducing PTSD symptoms. We examined the efficacy of ABM as an adjunct treatment for PTSD in a real-world setting. We administered ABM in conjunction with prolonged exposure or cognitive-processing therapy and medication in a community inpatient treatment facility for military personnel diagnosed with PTSD. Participants were randomized to either ABM or an attention control condition (ACC). While all participants experienced reductions in PTSD symptoms, participants in the ABM group experienced significantly fewer PTSD and depressive symptoms at post-treatment when compared to the ACC group. Moreover, change in plasticity of attentional bias mediated this change in symptoms and initial attentional bias moderated the effects of the treatment. These results suggest that ABM may be an effective adjunct treatment for PTSD. PMID- 25277497 TI - Comparing chronic interpersonal and noninterpersonal stress domains as predictors of depression recurrence in emerging adults. AB - Understanding how persistent interpersonal difficulties distinctly affect the course of major depressive disorder (MDD) during emerging adulthood is critical, given that early experiences impact future coping resources and functioning. Research on stress and MDD has mostly concentrated on stressful life events, while chronic stress largely has not been explored. The present study examined interpersonal (intimate relationship, close friendships, social life, family relationships) and noninterpersonal (academic, work, financial, personal health, and family members' health) domains of chronic stress as time-varying predictors of depressive recurrence in emerging adults. Baseline assessments identified previously depressed emerging adults (N = 119), who subsequently completed 6 month, 12-month and 18-month follow-up interviews to determine chronic stress experiences and onset of new major depressive episodes. Survival analyses indicated that time-varying total chronic stress and chronic interpersonal stress predicted higher risk for depression recurrence; however, chronic noninterpersonal stress was not associated with recurrence. Intimate relationship stress, close friendship stress, family relationship stress, personal health, and family members' health independently predicted MDD recurrence, over and above well-established depression risk factors of dysfunctional cognitions and personality disorder symptoms. Evidence that interpersonal stress could have substantial impact on course of depression is consistent with theories of emerging adulthood, a time when young people are individuating from the family and experiencing significant social transition. PMID- 25277498 TI - A study of the anthropometric correlations between upper limb measurements for personal identification in Sudanese population. AB - The presence of multiple isolated commingled fleshed limbs or limb parts generates a significant challenge for forensic investigators in wars, mass disasters, and criminal assaults in the process of identification. Although upper limb measurements have been used to establish individual identity in terms of sex and stature with high success, there is a scarcity of data concerning the correlations within upper limb parts. Hence, this study aims to assess the relationships within upper limb parts and develop regression formulae to reconstruct the parts from one another. The study participants were 376 Sudanese adults (187 males and 189 females). The results of this study indicated significant sexual dimorphism for all variables. The results indicated a significant correlation within the upper limb parts. Linear and multiple regression equations were developed to reconstruct the upper limb parts in the presence of a single or multiple dimension(s) from the identical limb. Multiple regression equations generated better reconstructions than simple equations. These results are significant in forensics and orthopedic reconstructive surgery. PMID- 25277500 TI - Asymmetric catalysis with short-chain peptides. AB - Within this review article we describe recent developments in asymmetric catalysis with peptides. Numerous peptides have been established in the past two decades that catalyze a wide variety of transformations with high stereoselectivities and yields, as well as broad substrate scope. We highlight here catalytically active peptides, which have addressed challenges that had thus far remained elusive in asymmetric catalysis: enantioselective synthesis of atropoisomers and quaternary stereogenic centers, regioselective transformations of polyfunctional substrates, chemoselective transformations, catalysis in-flow and reactions in aqueous environments. PMID- 25277501 TI - Biorepository regulatory frameworks: building parallel resources that both promote scientific investigation and protect human subjects. AB - Clinical samples contained in biorepositories represent an important resource for investigating the many factors that drive human biology. The biological and chemical markers contained in clinical samples provide important measures of health and disease that when combined with such medical evaluation data can aid in decision making by physicians. Nearly all disciplines in medicine and every "omic" depend upon the readouts obtained from such samples, whether the measured analyte is a gene, a protein, a lipid, or a metabolite. There are many steps in sample processing, storage, and management that need to understood by the researchers who utilize biorepositories in their own work. These include not only the preservation of the desired analytes in the sample but also good understanding of the moral and legal framework required for subject protection irrespective of where the samples have been collected. Today there is a great deal of effort in the community to align and standardize both the methodology of sample collection and storage performed in different locations and the necessary frameworks of subject protection including informed consent and institutional review of the studies being performed. There is a growing trend in developing biorepositories around the focus of large population-based studies that address both active and silent nonsymptomatic disease. Logistically these studies generate large numbers of clinical samples and practically place increasing demand upon health care systems to provide uniform sample handling, processing, storage, and documentation of both the sample and the subject as well to ensure that safeguards exist to protect the rights of the study subjects for deciding upon the fates of their samples. Currently the authority to regulate the entire scope of biorepository usage exists as national practice in law in only a few countries. Such legal protection is a necessary component within the framework of biorepositories, both now and in the future. In this brief overview, we provide practical information to the potential users of biorepositories about some of the current developments in both the methodology of sample acquisition and in the regulatory environment governing their use. PMID- 25277502 TI - Knowledge and attitude towards menopause and hormone replacement therapy in Chinese women. AB - OBJECTIVE: To explore the knowledge and prevalence of menopausal symptoms as well as the use and attitude toward hormone replacement therapy (HRT) in Chinese women. METHODS: A cross-sectional study was conducted between May 2011 and April 2012 in Shanghai, China. The structured questionnaire addressing sociodemographic characteristics, knowledge and prevalence of menopausal symptoms, and knowledge and attitude towards HRT and its use were investigated. RESULTS: 3,619 women aged 40-65 years were included in the analysis. The majority of the women had knowledge of menopause. Symptoms were prevalent in 16.1% of premenopausal women and in 49.3% of peri-, post- and surgical-menopausal women. Back and joint pain, sleeplessness, fatigue and sweating/hot flushes were frequently reported. HRT awareness among women was 3.5% and was related to menopausal, working and marital status; 75 (2.1%) women had used or were using HRT, of which 57.3% used HRT with a doctor's prescription and 29.3% experienced side effects from the use of HRT. CONCLUSION: Most Chinese women had knowledge of menopause and thought menopausal symptoms should not be treated. The awareness of HRT was poor and influenced by menopausal, working and marital status. Chinese health care providers have to assume responsibility for educating women about menopause and HRT use. PMID- 25277504 TI - Risk of contralateral breast cancer after tamoxifen use among Danish women. AB - PURPOSE: Tamoxifen reduces the risk of contralateral breast cancer (CBC), but little is known about the long-term risk. METHODS: From the database under the Danish Breast Cancer Cooperative Group (DBCG), we identified 15,863 users and 21,670 nonusers of tamoxifen among women diagnosed with breast cancer during 1977 to 2007. Information on CBC was obtained from the Danish Cancer Registry and the Danish Breast Cancer Cooperative Group database. Cox regression analyses were carried out with estimation of hazard ratios (HRs) of CBC. We also estimated the HRs of current and past use of tamoxifen. RESULTS: Current use of tamoxifen was associated with reduced HRs of CBC independently of menopausal status and calendar-period. The HRs associated with past use of tamoxifen, however, varied among postmenopausal users from 1.50 (95% confidence interval [CI], 1.20-1.87) among users in 1977 to 1989 to 0.87 (95% CI, 0.70-1.06) and 1.05 (95% CI, 0.68 1.63) among users in 1990 to 1998 and 1999 to 2007, respectively. No excesses or deficits of CBC were found 10 or more years since the last use in postmenopausal women in any calendar-period. CONCLUSIONS: Our study confirms that tamoxifen protects against CBC while being treated. The effect of tamoxifen after cessation of treatment was not clear because of the inconsistency in results by calendar period. PMID- 25277499 TI - Phosphatidylserine receptors: enhancers of enveloped virus entry and infection. AB - A variety of both RNA and DNA viruses envelop their capsids in a lipid bilayer. One of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (PtdSer). Surface exposure of PtdSer disguises viruses as apoptotic bodies; tricking cells into engulfing virions. This mechanism is termed apoptotic mimicry. Several PtdSer receptors have been identified to enhance virus entry and we have termed this group of proteins PtdSer-mediated virus entry enhancing receptors or PVEERs. These receptors enhance entry of a range of enveloped viruses. Internalization of virions by PVEERs provides a broad mechanism of entry with little investment by the virus itself. PVEERs may allow some viruses to attach to cells, thereby making viral glycoprotein/cellular receptor interactions more probable. Alternatively, other viruses may rely entirely on PVEERs for internalization into endosomes. This review provides an overview of PtdSer receptors that serve as PVEERs and the biology behind virion/PVEER interaction. PMID- 25277505 TI - Assessing differences in groups randomized by recruitment chain in a respondent driven sample of Seattle-area injection drug users. AB - PURPOSE: Respondent-driven sampling (RDS) is a form of peer-based study recruitment and analysis that incorporates features designed to limit and adjust for biases in traditional snowball sampling. It is being widely used in studies of hidden populations. We report an empirical evaluation of RDS's consistency and variability, comparing groups recruited contemporaneously, by identical methods and using identical survey instruments. METHODS: We randomized recruitment chains from the RDS-based 2012 National HIV Behavioral Surveillance survey of injection drug users in the Seattle area into two groups and compared them in terms of sociodemographic characteristics, drug-associated risk behaviors, sexual risk behaviors, human immunodeficiency virus (HIV) status and HIV testing frequency. RESULTS: The two groups differed in five of the 18 variables examined (P <= .001): race (e.g., 60% white vs. 47%), gender (52% male vs. 67%), area of residence (32% downtown Seattle vs. 44%), an HIV test in the previous 12 months (51% vs. 38%). The difference in serologic HIV status was particularly pronounced (4% positive vs. 18%). In four further randomizations, differences in one to five variables attained this level of significance, although the specific variables involved differed. CONCLUSIONS: We found some material differences between the randomized groups. Although the variability of the present study was less than has been reported in serial RDS surveys, these findings indicate caution in the interpretation of RDS results. PMID- 25277503 TI - Strategies for modern biomarker and drug development in oncology. AB - Technological advancements in the molecular characterization of cancers have enabled researchers to identify an increasing number of key molecular drivers of cancer progression. These discoveries have led to multiple novel anticancer therapeutics, and clinical benefit in selected patient populations. Despite this, the identification of clinically relevant predictive biomarkers of response continues to lag behind. In this review, we discuss strategies for the molecular characterization of cancers and the importance of biomarkers for the development of novel antitumor therapeutics. We also review critical successes and failures in oncology, and detail the lessons learnt, which may aid in the acceleration of anticancer drug development and biomarker discovery. PMID- 25277506 TI - Elevated hepatic enzymes and incidence of venous thromboembolism: a prospective study. AB - PURPOSE: Approximately 10% of the general population has elevated blood concentrations of hepatic enzymes, which are linked to increased coagulation markers. We tested whether elevated hepatic enzymes are associated with increased risk of venous thromboembolism (VTE). METHODS: We followed 12,604 adults with measurements of alanine transaminase, aspartate aminotransferase (AST), and gamma glutamyl transpeptidase (GGT) prospectively for VTE occurrence. RESULTS: AST and GGT above the laboratory normal values were associated over two decades of follow up with increased risk of total (n = 532) and provoked VTE (n = 332), but with not unprovoked VTE (n = 200). In a model adjusted for age, race, sex, hormone replacement, alcohol intake, diabetes, body mass index, estimated glomerular filtration rate, and C-reactive protein, the hazard ratios (HR) (95% confidence interval) for high versus normal AST were 1.46 (1.00-2.11) for total VTE and 1.83 (1.21-2.79) for provoked VTE. For high GGT, the HR were 1.34 (1.06-1.69) for total VTE and 1.43 (1.07-1.91) for provoked VTE. When follow-up was limited to the first 10 years, associations were even stronger (HR ~ 1.7 for total VTE). CONCLUSIONS: Elevated concentrations of two hepatic enzymes (AST and GGT) in this general middle-aged population are associated with a modestly increased risk of VTE. PMID- 25277508 TI - Further evidence for discrete-state mediation in recognition memory. AB - The two high threshold model (2HTM) of recognition memory makes strong predictions regarding differences between receiver operating characteristics (ROC) functions across strength manipulations. Province and Rouder (2012) tested these predictions and showed that the 2HTM provided a better account of the data than a continuous signal detection model using an extended two-alternative forced choice task. The present study replicates and extends Province and Rouder's findings at the level of confidence-rating responses as well as their associated response times. Model-mimicry simulations are also reported, ascertaining that the models can be well discriminated in this experimental design. PMID- 25277509 TI - A man with acute epigastric pain. PMID- 25277507 TI - Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. AB - Laboratory animal models play an important role in the study of human diseases. Using appropriate animals is critical not only for basic research but also for the development of therapeutics and diagnostic tools. Rabbits are widely used for the study of human atherosclerosis. Because rabbits have a unique feature of lipoprotein metabolism (like humans but unlike rodents) and are sensitive to a cholesterol diet, rabbit models have not only provided many insights into the pathogenesis and development of human atherosclerosis but also made a great contribution to translational research. In fact, rabbit was the first animal model used for studying human atherosclerosis, more than a century ago. Currently, three types of rabbit model are commonly used for the study of human atherosclerosis and lipid metabolism: (1) cholesterol-fed rabbits, (2) Watanabe heritable hyperlipidemic rabbits, analogous to human familial hypercholesterolemia due to genetic deficiency of LDL receptors, and (3) genetically modified (transgenic and knock-out) rabbits. Despite their importance, compared with the mouse, the most widely used laboratory animal model nowadays, the use of rabbit models is still limited. In this review, we focus on the features of rabbit lipoprotein metabolism and pathology of atherosclerotic lesions that make it the optimal model for human atherosclerotic disease, especially for the translational medicine. For the sake of clarity, the review is not an attempt to be completely inclusive, but instead attempts to summarize substantial information concisely and provide a guideline for experiments using rabbits. PMID- 25277510 TI - Impact of admission medication reconciliation performed by clinical pharmacists on medication safety. AB - BACKGROUND: Many activities contribute to reduce drug-related problems. Among them, the medication reconciliation (MR) is used to compare the best possible medication history (BPMH) and the current admission medication order (AMO) to identify and solve unintended medication discrepancies (UMD). This study aims to assess the impact of the implementation of admission MR by clinical pharmacists on UMD. METHOD: This prospective study was carried out in two units of general medicine and infectious and tropical diseases in a 1844-bed French hospital. A retroactive MR performed in an observational period was compared to a proactive MR realized in an interventional period. We used a logistic regression to identify risk factors of UMD. RESULTS: During both periods, 394 patients were enrolled and 2,725 medications were analyzed in the BPMH. Proactive MR reduced the percentage of patients with at least one UMD compared with retroactive process (respectively 2.1% vs. 45.8%, p<0.001). Patients with at least one UMD during both periods were older compared to patients without UMD (79 vs. 72, p<0.005) and had more medications at admission (7 vs. 6, p<0.0001). UMD occur 38 times more often when there is no clinical pharmacist intervention. Among the 226 UMD detected in both periods, 42% would have required monitoring or intervention to preclude harm, and 10% had potential harm to the patient and 2% were life threatening. CONCLUSION: Proactive MR performed by clinical pharmacists is an acute process of detection and correction of UMD, but it requires a lot of human resources. PMID- 25277511 TI - Superconducting nanowire quantum interference device based on Nb ultrathin films deposited on self-assembled porous Si templates. AB - Magnetoresistance oscillations were observed on networks of superconducting ultrathin Nb nanowires presenting evidence of either thermal or quantum activated phase slips. The magnetic transport data, discussed in the framework of different scenarios, reveal that the system behaves coherently in the temperature range where the contribution of the fluctuations is important. PMID- 25277512 TI - An adenosine A1 agonist 2-chloro-N6 cyclopentyladenosine inhibits the angiotensin II-induced cardiomyocyte hypertrophy through the calcineurin pathway. AB - OBJECTIVES: The aim of this investigation was to study the underlying mechanism of an adenosine A1 receptor agonist 2-chloro-N6 cyclopentyladenosine (CCPA) inhibiting cardiomyocyte hypertrophy induced by angiotensin II (AngII). METHODS: Neonatal rat cardiomyocytes were treated with AngII to generate a cardiomyocyte hypertrophy model. Cardiomyocyte cultures were randomized into 5 groups: control; AngII; AngII + cyclosporin A (CsA); AngII + CCPA, and AngII + CCPA + DPCPX. Cardiomyocyte viability was measured by MTT assay. Protein synthesis was assessed by the application of (3)H leucine ((3)H-Leu) incorporation into protein. The mRNA expressions of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (beta-MHC) and calcineurin Abeta (CnAbeta) were measured by real-time quantitative PCR. The protein level of CnAbeta was dissected by Western blotting. RESULTS: AngII administration at lower concentrations increased the cardiomyocytes viabilities gradually. Surface area, mRNA expressions of ANP, BNP and beta-MHC, and (3)H-Leu incorporation of AngII induced cardiomyocytes were increased in a dose-dependent manner. As a calcineurin-specific inhibitor, CsA inhibited (3)H-Leu incorporation, surface area, mRNA expressions of ANP, BNP, beta-MHC, CnAbeta and protein expression of CnAbeta of AngII-induced cardiomyocytes. CCPA also suppressed the mRNA and protein expressions of CnAbeta and exerted antihypertrophic effects to a greater degree than CsA. The inhibition of CCPA on cardiomyocyte hypertrophy was counteracted by the A1 receptor antagonist DPCPX. CONCLUSION: The A1 receptor agonist CCPA could significantly inhibit AngII-induced cardiomyocyte hypertrophy via the calcineurin signaling pathway. PMID- 25277514 TI - The facial artery musculomucosal flap revisited: surgical technique and critical functional appraisal: our experience in nine patients. PMID- 25277513 TI - Finding a cure for human immunodeficiency virus-1 infection. AB - Remarkable advances have been made in the treatment of human immunodeficiency virus (HIV)-1 infection, but in the entire history of the epidemic, only 1 patient has been cured. Herein we review the fundamental mechanisms that render HIV-1 infection difficult to cure and then discuss recent clinical and experimental situations in which some form of cure has been achieved. Finally, we consider approaches that are currently being taken to develop a general cure for HIV-1 infection. PMID- 25277515 TI - Effects of the environmental estrogenic contaminants bisphenol A and 17alpha ethinyl estradiol on sexual development and adult behaviors in aquatic wildlife species. AB - Endocrine disrupting chemicals (EDCs), including the mass-produced component of plastics, bisphenol A (BPA) are widely prevalent in aquatic and terrestrial habitats. Many aquatic species, such as fish, amphibians, aquatic reptiles and mammals, are exposed daily to high concentrations of BPA and ethinyl estradiol (EE2), estrogen in birth control pills. In this review, we will predominantly focus on BPA and EE2, well-described estrogenic EDCs. First, the evidence that BPA and EE2 are detectable in almost all bodies of water will be discussed. We will consider how BPA affects sexual and neural development in these species, as these effects have been the best characterized across taxa. For instance, such chemicals have been in many cases reported to cause sex-reversal of males to females. Even if these chemicals do not overtly alter the gonadal sex, there are indications that several EDCs might demasculinize male-specific behaviors that are essential for attracting a mate. In so doing, these chemicals may reduce the likelihood that these males reproduce. If exposed males do reproduce, the concern is that they will then be passing on compromised genetic fitness to their offspring and transmitting potential transgenerational effects through their sperm epigenome. We will thus consider how diverse epigenetic changes might be a unifying mechanism of how BPA and EE2 disrupt several processes across species. Such changes might also serve as universal species diagnostic biomarkers of BPA and other EDCs exposure. Lastly, the evidence that estrogenic EDCs-induced effects in aquatic species might translate to humans will be considered. PMID- 25277518 TI - Hydrocortisone and triiodothyronine regulate hyaluronate synthesis in a tissue engineered human dermal equivalent through independent pathways. AB - Hydrocortisone (HC) and triiodothyronine (T3) have both been shown to be capable of independently inhibiting hyaluronate (HA, hyaluronic acid) synthesis in a self assembled human dermal equivalent (human dermal matrix). We sought to investigate the action of these two hormones in concert on extracellular matrix formation and HA inhibition in the tissue engineered human dermal matrix. To this end, neonatal human dermal fibroblasts were cultured in defined serum-free medium for 21 days in the presence of each hormone alone, or in combination, in varying concentrations. Through a process of self-assembly, a substantial dermal extracellular matrix formed that was characterized. The results of these studies demonstrate that combinations of the hormones T3 and hydrocortisone showed significantly higher levels of hyaluronate inhibition as compared to each hormone alone in the human dermal matrix. In order to gain preliminary insight into the genes regulating HA synthesis in this system, a differential gene array analysis was conducted in which the construct prepared in the presence of 200 MUg/mL HC and 0.2 nM T3 was compared to the normal construct (0.4 MUg/mL HC and 20 pM T3). Using a GLYCOv4 gene chip containing approximately 1260 human genes, we observed differential expression of 131 genes. These data suggest that when these two hormones are used in concert a different mechanism of inhibition prevails and a combination of degradation and inhibition of HA synthesis may be responsible for HA regulation in the human dermal matrix. PMID- 25277516 TI - Tumour Microenvironment: Overview with an Emphasis on the Colorectal Liver Metastasis Pathway. AB - The tumour microenvironment (TME) represents a dynamic network that plays an important role in tumour initiation, proliferation, growth, and metastasis. Cell behaviour may be regulated by interplay of molecular interactions involving positive and negative reinforcement as well as a high level of cross-talk, which determines this system. Additionally, cancer involves cell proliferation, its malignancy defined by the tumour's ability to break down normal tissue architecture and by a dynamic process of invasion and metastasis. The metastatic cascade is regulated by a chain of molecular steps which triggers the progression of the developing cancer cell in the primary tumour into a number of transformations, leading to invasion and proceeding to metastases. Tumour associated macrophages (TAMs) play a key-role in the progression from inflammatory conditions to cancer; TAMs are also capable of infiltrating the tumour microenvironment. Furthermore, myeloid-derived suppressor cells (MDSCs), a population of inhibitory immune cells, have been reported to increase in various cancer types, although characterising human MDSCs remains difficult, as their phenotype is quite variable. The future of cancer treatment is likely to involve creating more drugs that target these elements as well as others. An overview of the tumour's microenvironment is, therefore, presented in this paper, focusing on the metastatic pathways of primary colorectal cancer to the liver. PMID- 25277519 TI - Involvement of the yciW gene in l-cysteine and l-methionine metabolism in Escherichia coli. AB - We here analyzed a sulfur index of Escherichia coli using LC-MS/MS combined with thiol-specific derivatization by monobromobimane. The obtained sulfur index was then applied to evaluate the L-cysteine producer. E. coli cells overexpressing the yciW gene, a novel Cys regulon, accumulated l-homocysteine, suggesting that YciW is involved in L-methionine biosynthesis. PMID- 25277520 TI - The effect of mark enhancement techniques on the subsequent detection of semen/spermatozoa. AB - Fingermarks, footwear marks, blood and semen are amongst the most commonly encountered types of evidence at crime scenes. Previous work has extensively investigated fingermark and blood enhancement techniques and a sequence developed to maximise evidence recovery; however, there is limited research as to the effect of these techniques on the subsequent detection of body fluids such as semen. In this study, seven fingermark and blood enhancement techniques (e.g. powder suspension, cyanoacrylate fuming and acid violet 17) were employed followed by the subsequent detection of semen/spermatozoa. Other variables included in the study were the use of two substrates (white ceramic tiles and grey laminate flooring), a depletion series and ageing periods of 1, 7, 14 and 28 days. The effect these techniques had on the subsequent detection of semen was assessed by visual and fluorescence examination followed by presumptive and confirmatory testing for semen and spermatozoa. The results found that protein stains (acid violet 17 and acid yellow 7) caused a loss in presumptive test reactivity; however, sperm heads were still observed using microscopic examination after extraction and staining. The use of black magnetic powder, Bluestar((r)) Forensic Magnum luminol, LumicyanoTM 4% and cyanoacrylate fuming followed by basic yellow 40 staining did not hinder subsequent presumptive and confirmatory tests for semen and sperm heads. Powder suspension caused a loss in both presumptive test reactivity and sperm heads from the substrate. In general, the enhancement techniques resulted in the improved visualisation of the semen stains under white and violet/blue light. The results from this study aim to provide a strategy to maximise evidence recovery and improve efficiency in an integrated forensic approach. PMID- 25277521 TI - Intravoxel incoherent motion diffusion imaging of the liver: optimal b-value subsampling and impact on parameter precision and reproducibility. AB - PURPOSE: To increase diffusion sampling efficiency in intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) of the liver by reducing the number of diffusion weightings (b-values). MATERIALS AND METHODS: In this IRB approved HIPAA compliant prospective study, 53 subjects (M/F 38/15, mean age 52 +/- 13 y) underwent IVIM DWI at 1.5T using 16 b-values (0-800s/mm(2)), with 14 subjects having repeat exams to assess IVIM parameter reproducibility. A biexponential diffusion model was used to quantify IVIM hepatic parameters (PF: perfusion fraction, D: true diffusion and D*: pseudo diffusion). All possible subsets of the 16 b-values were probed, with number of b values ranging from 4 to 15, and corresponding parameters were quantified for each subset. For each b value subset, global parameter estimation error was computed against the parameters obtained with all 16 b-values and the subsets providing the lowest error were selected. Interscan estimation error was also evaluated between repeat exams to assess reproducibility of the IVIM technique in the liver. The optimal b values distribution was selected such that the number of b-values was minimal while keeping parameter estimation error below interscan reproducibility error. RESULTS: As the number of b-values decreased, the estimation error increased for all parameters, reflecting decreased precision of IVIM metrics. Using an optimal set of 4 b-values (0, 15, 150 and 800s/mm(2)), the errors were 6.5, 22.8 and 66.1% for D, PF and D* respectively. These values lie within the range of test retest reproducibility for the corresponding parameters, with errors of 12.0, 32.3 and 193.8% for D, PF and D* respectively. CONCLUSION: A set of 4 optimized b values can be used to estimate IVIM parameters in the liver with significantly shorter acquisition time (up to 75%), without substantial degradation of IVIM parameter precision and reproducibility compared to the 16 b-value acquisition used as the reference. PMID- 25277522 TI - An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability. AB - Neuropilins (NRPs) are trans-membrane receptors involved in axon guidance and vascular development. Many growth factors and other signalling molecules bind to NRPs through a carboxy (C)-terminal, basic sequence motif (C-end Rule or CendR motif). Peptides with this motif (CendR peptides) are taken up into cells by endocytosis. Tumour-homing CendR peptides penetrate through tumour tissue and have shown utility in enhancing drug delivery into tumours. Here we show, using RNAi screening and subsequent validation studies, that NRP1-mediated endocytosis of CendR peptides is distinct from known endocytic pathways. Ultrastructurally, CendR endocytosis resembles macropinocytosis, but is mechanistically different. We also show that nutrient-sensing networks such as mTOR signalling regulate CendR endocytosis and subsequent intercellular transport of CendR cargo, both of which are stimulated by nutrient depletion. As CendR is a bulk transport pathway, our results suggest a role for it in nutrient transport; CendR-enhanced drug delivery then makes use of this natural pathway. PMID- 25277523 TI - The polyamine catabolic enzyme SAT1 modulates tumorigenesis and radiation response in GBM. AB - Glioblastoma multiforme (GBM) is the most common and severe form of brain cancer. The median survival time of patients is approximately 12 months due to poor responses to surgery and chemoradiation. To understand the mechanisms involved in radioresistance, we conducted a genetic screen using an shRNA library to identify genes in which inhibition would sensitize cells to radiation. The results were cross-referenced with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors and associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors, and correlates with poor outcomes. Knockdown of SAT1 using shRNA and siRNA approaches in multiple cell and neurosphere lines resulted in sensitization of GBM cells to radiation in colony formation assays and tumors, and decreased tumorigenesis in vivo. Radiosensitization occurred specifically in G2-M and S phases, suggesting a role for SAT1 in homologous recombination (HR) that was confirmed in a DR-GFP reporter system. Mechanistically, we found that SAT1 promotes acetylation of histone H3, suggesting a new role of SAT1 in chromatin remodeling and regulation of gene expression. In particular, SAT1 depletion led to a dramatic reduction in BRCA1 expression, explaining decreased HR capacity. Our findings suggest that the biologic significance of elevated SAT1 expression in GBM lies in its contribution to cell radioresistance and that SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies. PMID- 25277524 TI - Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. AB - It is increasingly evident that long noncoding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Taken together, our results identify a noncoding regulatory pathway for the CD44 oncogene, shedding new light on the basis for gastric cancer cell invasiveness. PMID- 25277526 TI - Physical activity at home, at leisure, during transportation and at work in French adults with type 2 diabetes: the ENTRED physical activity study. AB - AIM: Our study assessed the distribution of physical activity during various typical tasks of daily life in adults with type 2 diabetes (T2D), a population typified by low physical activity. METHODS: We investigated the duration and intensity of physical activity in four domains (work, leisure, transportation and domestic), and how individual determinants might influence the repartition. The long-form International Physical Activity Questionnaire (IPAQ) was administered to participants from the echantillon national temoin representatif des personnes diabetiques (ENTRED), a study of French adults with T2D (n=724, 65% men, age 62+/ 10y, BMI 29+/-5kg.m(-2), HbA1c 7.1+/-1.1%), and the associations between sociodemographic/clinical characteristics and categories of physical activity intensity (low, moderate or high) were examined by logistic regression. RESULTS: The median total physical activity was 2079 [Q1=893, Q3=3915]MET-min.week(-1). The main contributors to total physical activity were domestic chores, followed by leisure-time activities and transportation (median: 630, 347 and 198MET min.week(-1), respectively). Absence of cardiovascular complications (OR=1.87, 95% CI=1.01-3.47), age<65y (OR=2.28, 95% CI=1.30-4.01) and better self-perceived health (OR=2.12, 95% CI=1.18-3.83) were associated with more physical activity. In all patient subgroups (defined by category of physical activity intensity or stratified by determinants of physical activity level), domestic chores were always the main contributor to total physical activity (P<0.0001). CONCLUSION: Domestic chores are the predominant routine whereby adults with T2D engage in physical activity. This emphasizes the vast potential for promoting voluntary leisure-time physical activity in this population. PMID- 25277527 TI - Labral and cartilage abnormalities in young patients with hip pain: accuracy of 3 Tesla indirect MR arthrography. AB - OBJECTIVE: Assess the diagnostic accuracy of 3-T indirect magnetic resonance arthrography (iMRA) for hip cartilage and labral pathology detection using arthroscopy as the reference standard and compare it to the published performance of direct magnetic resonance arthrography (dMRA). MATERIALS AND METHODS: Between 2009 and 2011, 290 patients suspected of having femoroacetabular impingement underwent iMRA. Our study group consisted of 41 of these patients (17 males, mean age 35 years; 24 females, mean age 33 years) who did not have a prior history of hip surgery and who subsequently underwent arthroscopy. Two experienced musculoskeletal radiologists separately evaluated the randomized and anonymized studies for the presence and quadrant location of labral and cartilage pathology. These recorded data were compared to arthroscopic reports. RESULTS: Forty-one patients had labral pathology, 34 patients had acetabular and 5 patients had femoral cartilage pathology at arthroscopy. Sensitivity, specificity, accuracy, negative- and positive-predictive values for labral lesion detection were respectively 98, 99, 99, 99 and 98 %; for acetabular cartilage lesion detection they were 69, 98, 89, 87 and 95 %; for femoral cartilage lesion detection they were 69, 95, 93 and 39 %. Sensitivities of iMRA by quadrant (anteroinferior, anterosuperior, posteroinferior, posterosuperior) for the labrum were 100.0, 95.0, NA and 85.7 %, for acetabular cartilage were NA, 58.8, NA and 39.5 % and for femoral cartilage were 50.0, 33.3, 75.0 and 75.0 %). NA indicates results not available because of the absence of findings in those quadrants. Specificities of iMRA by quadrant (anteroinferior, anterosuperior, posteroinferior, posterosuperior) for the labrum (95.0, 100.0, 95.1, 67.5 %), acetabular (100.0, 85.7, 92.6, 79.5 %) and femoral cartilage (100.0, 94.7, 96.2, 85.9 %). CONCLUSION: iMRA at 3 T is accurate in detecting labral pathology suggesting that it is a viable alternative to dMRA. PMID- 25277528 TI - Reproductive development of male goat kids reared with or without permanent contact with adult females until 10 months of age. AB - Adult male ruminants that were reared in contact with females display greater sexual behavior than those reared in single male groups. The aim of the experiment was to compare the reproductive development of prepubertal male kids reared with or without direct permanent contact with adult females until they were 10 months old. Seventeen Saanen male kids were maintained in two groups until 44 weeks of age: kids reared in permanent direct contact with four adult goats (group FEM, N = 8) and kids that remained isolated from females (group ISO, N = 9). All goats in the FEM group became pregnant approximately when bucks attained 28 weeks of age. Scrotal circumference and testosterone concentration were measured, and semen was obtained by electroejaculation to avoid female contact in the ISO group. Scrotal circumference was greater in FEM kids at 12 and 14 weeks of age (P < 0.0001) and testosterone when they were 20 and 22 weeks old (P < 0.0001). Testosterone concentration was greater in ISO kids from 28 to 44 weeks of age. All semen characteristics increased with age (P < 0.0001). Individual motility was greater in FEM kids than that in ISO kids at 15 and 17 weeks (P < 0.005); mass motility was greater in ISO than that in FEM kids at 32 weeks (P < 0.05); total number of spermatozoa/ejaculate was greater in ISO kids at 30, 32, and 40 weeks and in FEM kids at 43 weeks (P < 0.005); total number of motile spermatozoa was greater in ISO kids at 32 and 40 weeks, whereas at 43 weeks, it was greater in FEM kids (P < 0.005). It was concluded that permanent contact with adult goats had transient and short-time positive effects in male kids' reproductive traits during prepubertal development. However, positive effects stopped after goats used as stimulus became pregnant. PMID- 25277525 TI - BET protein inhibitor JQ1 attenuates Myc-amplified MCC tumor growth in vivo. AB - Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin currently with no cure. In this study, we have first demonstrated that c-Myc overexpression is common in MCC. By targeting c-Myc, bromodomain inhibitors have demonstrated antitumor efficacy in several preclinical human cancer models. Thus, we interrogated the role of c-Myc inhibition in MCC with c-Myc amplification by using the BET inhibitor JQ1. We have uncovered that c-Myc can be regulated by JQ1 in MCC cells with pathologic c-Myc activation. Moreover, JQ1 potently abrogates c Myc expression in MCC cells and causes marked G1 cell-cycle arrest. Mechanistically, JQ1-induced cell-cycle arrest coincides with downregulation of cyclin D1 and upregulation of p21, p27, and p57, whereas JQ1 exerts no effect on apoptosis in MCC cells. Further knockdown of p21, p27, or p57 by shRNA partially protects cells from JQ1-induced cell-cycle arrest. In addition, c-Myc knockdown by shRNA generates significant cell-cycle arrest, suggesting that c-Myc overexpression plays a role in MCC pathogenesis. Most importantly, JQ1 significantly attenuates tumor growth in xenograft MCC mouse models. Our results provide initial evidence, indicating the potential clinical utility of BET protein inhibitors in the treatment of MCC with pathologic activation of c-Myc. PMID- 25277529 TI - Effects of AY9944 A-7 on gonadotropin-induced meiotic resumption of oocytes and development of parthenogenetic embryos in sheep. AB - Follicular fluid meiosis-activating sterol (FF-MAS), an intermediate in the cholesterol biosynthetic pathway, has been identified as a compound that induces the resumption of meiosis in mammalian oocyte. Follicular fluid meiosis activating sterol is converted to testis meiosis-activating sterol by a sterol Delta14-reductase. An inhibitor of Delta14-reductase and Delta7-reductase, AY9944 A-7, causes accumulation of FF-MAS by inhibiting its metabolism. The objective of this research was to investigate the specific contribution of AY9944 A-7 on gonadotropin-induced meiotic resumption and its interactive effects with FSH or LH on meiotic maturation of oocytes and preimplantation development of parthenogenetic embryo in sheep by addition of AY9944 A-7 during IVM to cause accumulation of FF-MAS. First, ovine cumulus-oocyte complexes (COCs) were cultured in the presence of FSH (10 MUg/mL), LH (10 MUg/mL), AY9944 A-7 (20 MUmol/L), FSH (10 MUg/mL)+AY9944 A-7 (20 MUmol/L), or LH (10 MUg/ml) + AY9944 A-7 (20 MUmol/L) with an inhibitor hypoxanthine (Hx) to prevent spontaneous meiosis of oocytes. The resumption of meiosis was assessed by the frequency of germinal vesicle breakdown and the first polar body (PBI) extrusion. The kinetics of gonadotropin and AY9944 A-7-induced meiotic resumption in vitro was also evaluated in the study. The numbers of oocytes resuming meiosis and undergoing germinal vesicle breakdown were counted after the COCs were cultured for 2, 4, 8, 12, 16, 20, and 24 hours. Matured oocytes extruding PBI were selected for parthenogenetic activation, and the percentages developing to the two-cell stage and blastocyst stage were recorded as indicators of parthenogenetic embryo developmental competence. It was observed that FSH could induce the resumption of meiosis of ovine COCs cultured in the presence of Hx, but LH could not. AY9944 A 7 had a synergistic effect with FSH on nuclear maturation and developmental competence of embryos produced by parthenogenetic activation, whereas it had no added advantage on LH action. However, the kinetics of meiotic resumption after AY9944 A-7 stimulation was remarkably delayed when compared with FSH-induced maturation. In conclusion, the current study suggested that AY9944 A-7 supplementation in IVM medium optimized the beneficial effects of FSH on meiotic maturation of ovine oocytes and subsequent developmental competence of embryos produced by parthenogenetic activation. This work had important potential for developing a novel technique in IVM of ovine oocytes. PMID- 25277530 TI - Sperm membrane proteome in wild Japanese macaque (Macaca fuscata) and Sika deer (Cervus nippon). AB - Whereas recent advances in proteome-related techniques have accumulated a lot of information about sperm proteins in model animals, the information in non-model wildlife species is absolutely deficient, although this knowledge would be valuable to regulate wildlife overabundance. To characterize the repertoires of sperm membrane proteins in Japanese overpopulated wildlife, our study focuses on the following two species: Macaca fuscata and Cervus nippon. We enriched sperm membrane proteins by the phase partitioning with Triton X-114, and then separated them by two-dimensional electrophoresis, and, finally, they were comprehensively identified by peptide mass fingerprinting. Sperm membrane proteins were successfully enriched. They included some proteins with unknown function and fertility-related proteins that work in sperm development, motility, capacitation, transport, protection, acrosome reaction, and fertilization. Additionally, beta-defensin 126 and epithelial chloride channel were strongly detected in M. fuscata but not in C. nippon, whereas lactadherin and NADH cytochrome b5 reductase 1 were strongly detected in C. nippon alone. This study is an initiative case showing that the sperm of wildlife conserve major fertility related proteins, but express some proteins in a species-specific manner. In the development of a practical method for fertility control, this aspect may be taken into consideration. PMID- 25277531 TI - Polymorphism -433 C>T of the Osteopontin gene is associated with the susceptibility to develop gliomas and their prognosis in a Chinese cohort. AB - AIM: To investigate role of the Osteopontin (OPN) genetic polymorphisms in the susceptibility to gliomas and their prognosis. METHODS: A total of 248 Chinese glioma patients and 281 age and sex matched healthy controls were recruited. The genetic polymorphisms at three loci, namely, -156 GG>G, -443 C>T and -66T>G, were determined. The log-rank test and Kaplan- Meier analysis were introduced to assess the effect of OPN gene polymorphisms on patient survival. RESULTS: We found that the genotype frequencies of OPN -443 C>T polymorphism were significantly different between glioma patients and controls. Multivariable analyses showed a higher risk for gliomas in -443 CC genotype carriers compared to -443TT carriers (P<0.001). In addition, we also found the OPN -443 C>T polymorphism was closely related to the gliomas' tumor grade. The -443 C>T polymorphism also affected the tumor OPN expression level, but not the serum OPN level. More importantly, the -443 C>T polymorphism was significantly associated with the prognosis of these patients regardless of their treatment status. The patients with -443CC genotype had a poorer prognosis than those with -443TT and 443CT genotypes. In contrast, the -156 G>GG and -66T>G polymorphisms were not associated with risk, clinical characteristics, or prognosis of gliomas. CONCLUSION: This study suggests that the -443C>T gene polymorphisms may be used as a molecular marker for glioma occurrence and clinical outcome in glioma patients. PMID- 25277532 TI - Phase II study of preoperative concurrent chemoradiotherapy with S-1 plus bevacizumab for locally advanced resectable rectal adenocarcinoma. AB - OBJECTIVE: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of preoperative chemoradiotherapy (CRT) with concurrent S-1, bevacizumab, and radiation in patients with locally advanced rectal cancer (LARC). METHODS: Fifty-two patients with LARC were enrolled. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, S-1 was administered orally twice a day on days 1-14 and 22-35, and bevacizumab was administered on days 1, 15, and 29. Surgical resection was scheduled 8 weeks (6-10 weeks) after completing the CRT. RESULTS: All 52 patients underwent R0 radical surgery. Sphincter preservation was possible in 38 (73.1%) patients. A pathologic complete response was obtained in 10 (19.2%) patients, a pathologic downstaging was achieved in 37 (71.2%) patients, and the tumor shrinkage rate was 77.1%. The only grade 3 adverse events were leukopenia and rash in 1 (1.9%) patient. The rate of postoperative complications was 28.8%. Anastomotic leakage occurred in 9 (23.7%) of the 38 patients who underwent sphincter-preserving surgery. Perineal wound dehiscence developed in 2 (14.3%) of the 14 patients who received an abdominoperineal resection. CONCLUSIONS: Adding bevacizumab to S-1 clearly increased the incidence of wound-related complications, with no distinct enhancement of tumor response. PMID- 25277533 TI - Prevalence of degenerative changes of the atlanto-axial joints. AB - BACKGROUND CONTEXT: Degeneration of the atlantodens and atlanto-axial joints is associated with cervical spine pain and may also be associated with an increased risk of dens fracture. However, there is paucity of literature describing the prevalence of specific degenerative changes in the atlantodens and atlanto-axial facet joints. PURPOSE: To document age-related degenerative changes of the cervical spine in a large cohort of patients. STUDY DESIGN/SETTING: This is a retrospective cohort study. PATIENT SAMPLE: Adult trauma patients were admitted to our Level 1 trauma center. OUTCOME MEASURES: Osteoarthritis of the atlantodens and atlanto-axial facet joints of the cervical spine and the presence of intraosseous cyst and calcific synovitis, as determined by computed tomography (CT) scans. METHODS: We conducted a retrospective study of 1,543 adult trauma patients who received a cervical spine CT scan. The anterior atlantodens joint interval was measured. The presence or absence of intraosseous cysts and calcific synovitis was recorded. Degeneration of the atlantodens and atlanto-axial facet joints at age intervals was quantified. RESULTS: The atlantodens interval narrowed linearly with age (R(2)=0.992, p<.001). The prevalence of intraosseous cysts increased exponentially with age from 4.2% to 37.4%, and calcific synovitis increased from 0% to 11.1%. Intraosseous cyst formation generally began in the second and third decades of life and synovitis in the fifth and sixth decades of life. Facet joints also demonstrated age-related changes; however, the rate of degenerative changes was lower than in the atlantodens joint. CONCLUSIONS: To our knowledge, this is the first study that documents specific changes of both atlantodens and atlanto-axial facet joints as a function of age in a large cohort of 1,543 patients. These changes increased exponentially with age and may contribute to pain and limitation in motion. In light of our findings and recent studies demonstrating the association between degeneration and dens fracture in elderly, cervical spine radiographs of elderly patients should be carefully assessed for these changes. PMID- 25277534 TI - Association between physical activity and menopausal symptoms in perimenopausal women. AB - BACKGROUND: Physical activity may be an effective way of preventing or attenuating menopause-related symptoms, and it has been shown to improve quality of life in menopausal women. However, there have been some inconsistencies regarding between exercise and menopausal symptoms, and study investigating this association has been scarce in Korea. In this study, the association between physical activity and menopausal symptoms in perimenopausal women in Korea was assessed. METHODS: This cross-sectional observational study was conducted between November 2012 and March 2013. In total, 2,204 healthy women aged 44-56 years were recruited from a healthcare center at the Kangbuk Samsung hospitals for investigating women's attitudes towards menopause. To investigate the influence of physical activity on perimenopause-associated symptoms, 631 perimenopausal women were selected for this study. Their physical activity levels were assessed using the International Physical Activity Questionnaire (IPAQ) short form. The Menopause-specific Quality of Life (MENQOL) questionnaire was used to assess menopause-related symptoms. RESULTS: The study participants were, on average, 48.5 +/- 2.7 years old and had a mean body mass index of 22.8 +/- 3.1 kg/m2. The total MENQOL score and the psychosocial and physical subscores exhibited U-shaped trends in relation to the level of physical activity. Multiple linear regression analysis adjusted for confounding variables showed that perimenopausal women who performed moderate physical activity reported significantly lower psychosocial (beta = -0.413, P = 0.012) and physical symptoms (beta = -0.445, P = 0.002) than women who performed low physical activity. By contrast, a high level of physical activity did not influence the MENQOL total score and subscores relative to the low activity group. In addition, no associations were observed between physical activity and the vasomotor and sexual symptoms in any group. CONCLUSIONS: Moderate level of physical activity was associated with reduced psychosocial and physical menopause symptoms in perimenopausal Korean women. Although these findings must be confirmed by prospective longitudinal studies, they suggest that physical activity may improve the symptoms of menopause, thereby increasing quality of life. PMID- 25277535 TI - Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis. AB - Methylosome protein 50 (MEP50) is a component of methylosome where MEP50 binds protein substrates and activates the oncogenic protein arginine methyl transferase 5 (PRMT5). MEP50 is also a coactivator for androgen receptor (AR) and estrogen receptor (ER), and transforms cells in the presence of androgen or estrogen. To extend the understanding of how MEP50 transforms cells, we investigated whether MEP50 could transform cells independent of AR and ER, and clarified whether PRMT5 could contribute to the MEP50-caused tumor formation. Microarray and Western blot analyses revealed the association of MEP50 with many human cancers including lung cancer. Knockdown of MEP50 retarded cell growth and migration in selected lung cancer cell lines, which expressed very low level of AR and ER and were insensitive to inhibitors of AR and ER. Moreover, overexpression of Myc-MEP50 enhanced cell transforming activities of 293T cells which are known lack of expression of AR and ER. Mechanistic analyses showed that MEP50 controlled G2 progression, upregulated cyclin-dependent kinase 1(CDK1)/cyclin B1, and activated the survival cascade Phosphoinositide 3-kinase (PI3K)/AKT. MEP50 promoted cell migration, and activated the cell migration pathways such as Ras-related C3 botulinum toxin substrate 1 (Rac1)/vasodilator stimulated phosphoprotein (VASP), and forkhead box protein A2 (FOXA2)/slug/cadherin cascades. Further analyses revealed that MEP50 activated the survival factor PI3K through PRMT5-catalyzed dimethylation of PI3K. Collectively, it is concluded that MEP50 can transform cells independent of AR and ER, and PRMT5 has partial contribution to that process. PMID- 25277537 TI - Hyperhomocysteinemia and risk of cognitive decline: a meta-analysis of prospective cohort studies. AB - OBJECTIVE: To evaluate the association between hyperhomocysteinemia (HHcy) and risk of cognitive decline. METHODS: Electronic databases such as PubMed and EMBASE were searched for prospective cohort studies that involved the relationship between HHcy and risk of cognitive decline. Adjusted risk ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were calculated by Review Manager 5.2.7. Subgroup analyses were conducted on stratification of some important variables. RESULTS: Fourteen publications were included in the analysis. The pooled RR was 1.53 (95% CI, 1.23-1.91; p = 0.0002) for patients with HHcy compared to subjects without HHcy. Subgroup analyses indicated that the pooled RRs were 1.51 (95% CI, 1.10-2.05; p = 0.01) for more than five-year follow up studies and 1. 56 (95% CI, 1.13-2.14; p = 0.007) for less than five-year follow-up studies. The pooled RRs were 1.66 (95% CI, 1.21-2.26; p = 0.001) for studies excluding the confounder of B vitamins and 1.34 (95% CI, 1.08-1.66; p = 0.008) for non-excluded studies. In terms of region, the pooled RR was 1.60 (95% CI, 1.21-2.13; p = 0.001) for European and American countries, while the pooled RR was 1.27 (95% CI, 1.02-1.59; p = 0.03) for other regions. CONCLUSION: As one of the independent risk factors, HHcy was associated with an increased risk of cognitive decline. PMID- 25277538 TI - Occurrence of Rabl-like telomere clustering in the holocentric chromosomes of the peach potato aphid Myzus persicae (Hemiptera; Aphididae). AB - Several studies demonstrated that chromosome anchoring to nuclear structures is involved in the organization of the interphase nucleus. The Rabl configuration, a well-studied chromosome organization in the interphase nucleus, has been deeply studied in organisms with monocentric chromosomes but just slightly touched in species with holocentric chromosomes. In the present paper, by means of the isolation and chromosomal mapping of the C0t DNA fraction and chromatin immunoprecipitation with anti-LEM-2 antibodies, we evidenced the presence of few foci where telomeres and subtelomeric regions cluster in the aphid interphase nuclei, suggesting the occurrence of a Rabl-like chromosome configuration. The same experimental approaches also evidenced that most of the repetitive DNA of the 2 X chromosomes is located at the periphery of the nucleus, whereas the ribosomal genes, located at 1 telomere of each X chromosome, are present towards the inner portion of the nucleus, favoring their transcriptional activity. PMID- 25277539 TI - Automatic Detection of Masses in Mammograms Using Quality Threshold Clustering, Correlogram Function, and SVM. AB - Breast cancer is the second most common type of cancer in the world. Several computer-aided detection and diagnosis systems have been used to assist health experts and to indicate suspect areas that would be difficult to perceive by the human eye; this approach has aided in the detection and diagnosis of cancer. The present work proposes a method for the automatic detection of masses in digital mammograms by using quality threshold (QT), a correlogram function, and the support vector machine (SVM). This methodology comprises the following steps: The first step is to perform preprocessing with a low-pass filter, which increases the scale of the contrast, and the next step is to use an enhancement to the wavelet transform with a linear function. After the preprocessing is segmentation using QT; then, we perform post-processing, which involves the selection of the best mass candidates. This step is performed by analyzing the shape descriptors through the SVM. For the stage that involves the extraction of texture features, we used Haralick descriptors and a correlogram function. In the classification stage, the SVM was again used for training, validation, and final test. The results were as follows: sensitivity 92.31 %, specificity 82.2 %, accuracy 83.53 %, mean rate of false positives per image 1.12, and area under the receiver operating characteristic (ROC) curve 0.8033. Breast cancer is notable for presenting the highest mortality rate in addition to one of the smallest survival rates after diagnosis. An early diagnosis means a considerable increase in the survival chance of the patients. The methodology proposed herein contributes to the early diagnosis and survival rate and, thus, proves to be a useful tool for specialists who attempt to anticipate the detection of masses. PMID- 25277540 TI - Communication disorders and executive function impairment after severe traumatic brain injury: an exploratory study using the GALI (a grid for linguistic analysis of free conversational interchange). AB - Following severe traumatic brain injury (TBI), failure to adjust language to communication abilities has been described and attributed by many authors to executive function impairment. Interactional dysfunctions may damage family based, social and vocational equilibrium, and they are of key importance in prognosis of rehabilitation outcome. In conversation, frequently occurring inappropriate formulations connote difficulties in discursive organization and are likely to include numerous digressions, if not confabulations. OBJECTIVE: The main objective of this study was to improve assessment of the non-verbal as well as the verbal aspects of the communication disorders observed in TBI subjects. We have developed and are proposing the grid for linguistic analysis (GALI) of free conversational interchange that constitutes an original French-language tool. We wish to demonstrate its validity as a means of measuring interactive skills in a given population. METHOD: We assessed 17 severely brain injured patients presenting executive dysfunction, who were compared with 34 matched and healthy individuals. Fifty-one 10-minute sequences of free conversation between study participants and therapists were filmed and analyzed by applying the GALI. Three independent raters coded the conversations. Inter-rater reproducibility was considered statistically satisfactory. RESULTS: The results successfully distinguished TBI patients from healthy subjects and thereby underscored the discriminatory value of the tool. A significant correlation was found between the patients' performances in executive tests and in the GALI. CONCLUSIONS: In severe TBI a social handicap results from several associated cognitive disorders. Interactive discourse analysis combining non-verbal with verbal aspects confirms the existence of difficulties in communication that are usually underestimated in classic formal language testing methods. The GALI is likely to meet speech therapists' need for reliable assessment of their patients' interactional difficulties and their consequences in social life. PMID- 25277536 TI - Stromal-dependent tumor promotion by MIF family members. AB - Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT. PMID- 25277541 TI - Childhood adversity in bipolar disorder. PMID- 25277542 TI - Follow-up interventions in persons with schizophrenia and metabolic syndrome. PMID- 25277544 TI - Infection susceptibility of crosslinked and non-crosslinked biological meshes in an experimental contaminated environment. AB - BACKGROUND: This experimental study investigates infectious complications and functional outcome of biological meshes in a contaminated environment. METHODS: In 90 rats peritonitis was induced, and after 24 hours, a biological mesh was implanted intraperitoneally including 2 non-crosslinked mesh groups (Strattice and Surgisis) and 2 crosslinked mesh groups (CollaMendFM and Permacol). Sacrifice was after 90 and 180 days. RESULTS: More mesh infections occurred in crosslinked meshes compared with non-crosslinked meshes (70% vs 4%; P < .001). Mesh infection was the highest in crosslinked CollaMendFM (81.2%) and lowest in non-crosslinked Strattice groups (0%). Incorporation into the abdominal wall was poor in all meshes (0% to 39%). After 180 days no residue of non-crosslinked Surgisis mesh was found. After 180 days, shrinkage was .8% in crosslinked Permacol and 20% in Strattice groups. Strattice showed the least adhesion formation (median 5%). CONCLUSIONS: Infection rate of biological meshes in a contaminated field was the highest in crosslinked meshes. All biological meshes showed poor incorporation, which makes long-term abdominal wall repair questionable. PMID- 25277543 TI - Optimizing antibiotic prescribing for acutely ill children in primary care (ERNIE2 study protocol, part B): a cluster randomized, factorial controlled trial evaluating the effect of a point-of-care C-reactive protein test and a brief intervention combined with written safety net advice. AB - BACKGROUND: Despite huge public campaigns, there is still overconsumption of antibiotics in children with self-limiting diseases. Possible explanations may be the physicians' and parents' uncertainty about the gravity of the disease and inadequate communication between physicians and parents leading to lack of reassurance for the parents. In this paper we describe the design and methods of a trial aiming to rationalize antibiotic prescribing by decreasing this uncertainty and parental anxiety. METHODS/DESIGN: Acutely ill children without suspected serious disease consulting their family physician will be consecutively included in a four-armed cluster randomized factorial controlled trial. The intervention will consist a Point-of-Care C-reactive protein test and/or a brief intervention with safety net advice. The control group will receive usual care. We intend to include 2560 patients in 88 family practices. Patients will be followed up until cure. The primary outcome measure is the immediate antibiotic prescribing rate. Secondary outcomes are: comparison between groups of speed of clinical recovery, parental concern, parental perception of the quality of the communication, parental satisfaction, use of medication, use of diagnostic tests and medical services during the illness episode, and cost-effectiveness of the interventions. Besides this, we will observationally analyse data of the children included in the large ERNIE2-trial, but excluded in the cluster randomized trial, namely children suspected of serious disease presenting in primary care and children who initially present at the out-patient paediatric clinic or emergency department. We will search for predictors of antibiotic prescribing, speed of clinical recovery, parental concern, parental perception of communication, parental satisfaction, use of medication, diagnostic tests and medical services. DISCUSSION: This is a unique multifaceted intervention, in that it targets both physicians and parents by aiming specifically at their uncertainty and concerns during the consultation. Both interventions are easy to implement without special training. When proven effective, they could offer a feasible way to decrease inappropriate antibiotic prescribing for children in family practice and thus avoid emergence of bacterial resistance, side effects and unnecessary healthcare costs. Moreover, the observational part of the study will increase our insight in the course, management and parent's concern of acute illness in children. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02024282. PMID- 25277545 TI - In vitro interactions between the defense systems of resistant and susceptible Biomphalaria alexandrina and sporocysts of Schistosoma mansoni. AB - Biomphalaria species that act as an intermediate host for Schistosoma mansoni have different degrees of susceptibility and different internal defense system responses against parasites. Of these species, Biomphalaria alexandrina represents the only intermediate host in Egypt. Given the limited data on the efficacy of the B. alexandrina internal defense system in comparison to that of other species, we sought to better understand its defense against S. mansoni. We performed in vitro hemocyte adherence assay using whole hemolymph and in vitro reaction using the hemocyte-free hemolymph of susceptible and resistant snails against transformed mother sporocysts. The results demonstrated that the interacting factors between the parasite and the hemolymph of the resistant and susceptible snails do not act in a similar manner. Destruction of the parasite was a restricted function of the hemocytes among resistant snails only. This study demonstrates the key role played by snail hemocytes as a first line of defense against the parasite. The incubation of the hemocyte-free hemolymph of both susceptible and resistant snails with the sporocysts did not lead to any changes in the sporocysts shape or integrity. This immunological variance demonstrated between susceptible and resistant snails could be useful to differentiate between susceptible and resistant snails in future field studies. In addition, the results may help further studies to explain the process of attraction, encapsulation and subsequent killing of S. mansoni in its intermediate host. PMID- 25277546 TI - SNP array profiling of mouse cell lines identifies their strains of origin and reveals cross-contamination and widespread aneuploidy. AB - BACKGROUND: The crisis of Misidentified and contaminated cell lines have plagued the biological research community for decades. Some repositories and journals have heeded calls for mandatory authentication of human cell lines, yet misidentification of mouse cell lines has received little publicity despite their importance in sponsored research. Short tandem repeat (STR) profiling is the standard authentication method, but it may fail to distinguish cell lines derived from the same inbred strain of mice. Additionally, STR profiling does not reveal karyotypic changes that occur in some high-passage lines and may have functional consequences. Single nucleotide polymorphism (SNP) profiling has been suggested as a more accurate and versatile alternative to STR profiling; however, a high throughput method for SNP-based authentication of mouse cell lines has not been described. RESULTS: We have developed computational methods (Cell Line Authentication by SNP Profiling, CLASP) for cell line authentication and copy number analysis based on a cost-efficient SNP array, and we provide a reference database of commonly used mouse strains and cell lines. We show that CLASP readily discriminates among cell lines of diverse taxonomic origins, including multiple cell lines derived from a single inbred strain, intercross or wild caught mouse. CLASP is also capable of detecting contaminants present at concentrations as low as 5%. Of the 99 cell lines we tested, 15 exhibited substantial divergence from the reported genetic background. In all cases, we were able to distinguish whether the authentication failure was due to misidentification (one cell line, Ba/F3), the presence of multiple strain backgrounds (five cell lines), contamination by other cells and/or the presence of aneuploid chromosomes (nine cell lines). CONCLUSIONS: Misidentification and contamination of mouse cell lines is potentially as widespread as it is in human cell culture. This may have substantial implications for studies that are dependent on the expected background of their cell cultures. Laboratories can mitigate these risks by regular authentication of their cell cultures. Our results demonstrate that SNP array profiling is an effective method to combat cell line misidentification. PMID- 25277547 TI - Approaches to design non-covalent inhibitors for human granzyme B (hGrB). AB - A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand "hot spots". In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (>=25 MUM IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses. PMID- 25277550 TI - Design of donor-acceptor star-shaped oligomers for efficient solution-processible organic photovoltaics. AB - This contribution describes recent progress in the design, synthesis and properties of solution-processible star-shaped oligomers and their application in organic photovoltaics. Even though alternative chemistry has been used to design such oligomers, the most successful approach is based on a triphenylamine donor branching center, (oligo)thiophene conjugated spacers and dicyanovinyl acceptor groups. These are mainly amorphous low band-gap organic semiconductors, though crystalline or liquid crystalline ordering can sometimes be realized. It was shown that the solubility, thermal behavior and structure of such molecules in the bulk strongly depend on the presence and position of alkyl groups, as well as on their length. The photovoltaic properties of solution-processed molecules of this type are now approaching 5% which exceeds those of vacuum-sublimed devices. The design rules and future perspectives of this class of organic photovoltaic molecules are discussed. PMID- 25277549 TI - Cost-effectiveness of endobronchial valve therapy for severe emphysema: a model based projection based on the VENT study. AB - BACKGROUND: Endobronchial valve (EBV) therapy is an innovative treatment that has been shown to be safe and effective in selected subgroups of patients with severe emphysema. OBJECTIVES: The objective of our study was to assess the cost effectiveness of EBV therapy compared to the medical management of patients with high heterogeneity, complete fissures and lobar exclusion in the context of the German health-care system. METHODS: Clinical data from a subset of VENT (Endobronchial Valve for Emphysema Palliation Trial) provided information about clinical events, health-related quality of life, and disease staging for 12 months. This information was subsequently used to project long-term disease progression, mortality, and health resource utilization. We computed the 5- and 10-year incremental cost-effectiveness ratio (ICER) in euros per quality-adjusted life year (QALY). Costs and effects were discounted at 3% per year. RESULTS: EBV therapy led to clinically meaningful disease restaging at 12 months (37.8% of the cohort improved staging, compared to 0% in the controls). Over 5 years, EBV therapy was projected to increase survival from 66.4 to 70.7%, and to add 0.22 QALYs. Costs were estimated to increase by EUR 10,299, resulting in an ICER of EUR 46,322 per QALY. Over 10 years, 0.41 QALYs were gained at an additional cost of EUR 10,425, yielding an ICER of EUR 25,142 per QALY. CONCLUSIONS: Our model based analysis suggests that EBV therapy leads to clinically meaningful changes in disease staging and progression when compared to medical management, with resulting gains in unadjusted and quality-adjusted life expectancy. Our results indicate that EBV therapy is cost-effective in the German health-care system. PMID- 25277548 TI - Allosteric regulation of the partitioning of glucose-1-phosphate between glycogen and trehalose biosynthesis in Mycobacterium tuberculosis. AB - BACKGROUND: Mycobacterium tuberculosis is a pathogenic prokaryote adapted to survive in hostile environments. In this organism and other Gram-positive actinobacteria, the metabolic pathways of glycogen and trehalose are interconnected. RESULTS: In this work we show the production, purification and characterization of recombinant enzymes involved in the partitioning of glucose-1 phosphate between glycogen and trehalose in M. tuberculosis H37Rv, namely: ADP glucose pyrophosphorylase, glycogen synthase, UDP-glucose pyrophosphorylase and trehalose-6-phosphate synthase. The substrate specificity, kinetic parameters and allosteric regulation of each enzyme were determined. ADP-glucose pyrophosphorylase was highly specific for ADP-glucose while trehalose-6-phosphate synthase used not only ADP-glucose but also UDP-glucose, albeit to a lesser extent. ADP-glucose pyrophosphorylase was allosterically activated primarily by phosphoenolpyruvate and glucose-6-phosphate, while the activity of trehalose-6 phosphate synthase was increased up to 2-fold by fructose-6-phosphate. None of the other two enzymes tested exhibited allosteric regulation. CONCLUSIONS: Results give information about how the glucose-1-phosphate/ADP-glucose node is controlled after kinetic and regulatory properties of key enzymes for mycobacteria metabolism. GENERAL SIGNIFICANCE: This work increases our understanding of oligo and polysaccharides metabolism in M. tuberculosis and reinforces the importance of the interconnection between glycogen and trehalose biosynthesis in this human pathogen. PMID- 25277551 TI - Establishment and Evaluation of a One-Step Microplate Chemiluminescence Immunoassay to Detect IgG Antibody Against Treponema Pallidum. AB - BACKGROUND: The serological detection of specific antibodies against Treponema pallidum is of particular importance in the diagnosis of syphilis. The chemiluminescence immunoassay (CLIA) has been widely used for clinical diagnosis because they remit no radical waste products, cause no enzyme precipitation, and exhibit an excellent sensitivity. METHODS: A one-step CLIA was established to detect T. pallidum IgG antibody based on microplate coated with a mixture of recombinant T. pallidum antigens TpN15, TpN17, and TpN47. The Chinese national reference substances standard panel for T. pallidum diagnosis was applied to test the accuracy, stability, interference, and cross-reactivity of the established CLIA. The validation of efficacy for clinical application was performed by comparing the established method with the marketed T. pallidum particle agglutination (TPPA) kit and the Abbott ARCHITEC Auto System. RESULTS: The established method met the requirement of the Chinese national reference substances standard for T. pallidum diagnosis. When compared with TPPA (n = 1,052), the specificity, sensitivity, and overall concordance were 99.7%, 99.0%, and 98.8% respectively, showing a great agreement with a kappa value of 0.81. When compared with the Abbott ARCHITEC Auto System (n = 352), the results showed that the specificity, sensitivity, and overall concordance were 98.6.0%, 96.6% and 98.6% respectively, and a high-degree agreement was observed (kappa value = 0.95). CONCLUSION: The established rapid, specific, sensitive, and stable microplate CLIA method to detect IgG antibody against T pallidum will provide an efficient alternative to the treponemal tests and wide application in clinical laboratory. PMID- 25277552 TI - Biodegradation of aliphatic hydrocarbons in the presence of hydroxy cucurbit[6]uril. AB - Aliphatic hydrocarbons are one of the major environmental pollutants with reduced bioavailability. The present study focuses on the effect of hydroxy cucurbit[6]uril on the bioavailability of hydrocarbons. A bacterial consortium was used for biodegradation studies under saline and non-saline conditions. Based on denaturing gradient gel electrophoresis results it was found that the consortium under saline conditions had two different strains. The experiment was conducted in microcosms with tetradecane, hexadecane, octadecane and mixture of the mentioned hydrocarbons as the sole carbon source. The residual hydrocarbon was quantified using gas chromatography every 24h. It was found that biodegradation of tetradecane and hexadecane, as individual carbon source increased in the presence of hydroxy CB[6], probably due to the increase in their bioavailability. In case of octadecane this did not happen. Bioavailability of all three aliphatic hydrocarbons was increased when provided as a mixture to the consortium under saline conditions. PMID- 25277553 TI - Elmidae Curtis, 1830 (Coleoptera, Polyphaga, Byrrhoidea) of the Neotropical region. AB - A bibliography of significant taxonomic papers on Elmidae (Coleoptera, Polyphaga, Byrrhoidea), and a checklist of valid species and subspecies and their geographic distributions are provided. Forty-seven genera and 430 valid species are included. Maps show the geographic distribution of the genera by country. PMID- 25277554 TI - On the genus Scalopidia Stimpson, 1858 (Crustacea: Brachyura: Goneplacoidea: Scalopidiidae), with the description of one new genus and three new species. AB - A revision of Scalopidia Stimpson, 1858 (Brachyura: Goneplacoidea: Scalopidiidae) has resulted in the description of two new species of Scalopidia from the Indian Ocean and Papua New Guinea, as well as a new genus and new species from Madagascar. The type species of Scalopidia, S. spinosipes Stimpson, 1858, is redescribed and Hypophthalmus leuchochirus Richters, in Lenz & Richters, 1881, is synonymised with S. spinosipes. PMID- 25277555 TI - On the family- and genus-series nomina in Gyrinidae Latreille, 1810 (Coleoptera, Adephaga). AB - All available genus- and family- group nomina for the Gyrinidae (Coleoptera: Adephaga) are listed along with original citation, original and current status, type nominal taxon with method of designation, and known synonymies and incorrect subsequent spellings. The nomina included follow the most current classification. Discussion is provided clarifying numerous nomenclatural problems with original spellings, correct authorship and type designation. Dineutini Ochs, 1926 syn. nov. is found to be a junior homonym of Dineutini Desmarest, 1851, and Enhydrini Regimbart, 1882 syn. nov. and its justified emendation Enhydrusini (Anonymous 2012) are here synonymized with Dineutini Desmarest, 1851. PMID- 25277556 TI - Trevathana noae, a new species of coral inhabiting barnacle (Cirripedia: Thoracica: Pyrgomatidae). AB - We describe a new species from the genus Trevathana Anderson, 1992, collected from the Cocos/Keeling Islands in the Indian Ocean. Trevathana noae sp. nov. is similar to other species of Trevathana by its external shell and opercular valve morphology. It is distinct from congeners in that the tergum has a distinct spur which lacks an internal tooth in adult specimens. A key to the known species of Trevathana is given. PMID- 25277557 TI - A checklist of the cicadas (Hemiptera: Cicadidae) of Hainan Island, China, with description of a new species. AB - A total of 54 cacada species, belonging to 28 genera, nine tribes and three subfamilies of the family Cicadidae, are identified to comprise the cicada fauna of Hainan Island, based on the examination of material collected between 2007 and 2011. One species, Semia hainanensis sp. n., is described as new to science. Nine species are recorded as new to Hainan Island, of which two species, Pomponia subtilita Lee, 2009 and Becquartina bleuzeni Boulard, 2005, are reported for the first time from China. In addition, six species formerly recorded from Hainan are removed from the list of Hainan cicadas. Taxonomic remarks and information on geographic distributions are also provided. PMID- 25277558 TI - New species of the spider genera Aysenia and Aysenoides from Chile and Argentina: description and phylogenetic relationships (Araneae: Anyphaenidae, Amaurobioidinae). AB - New spider species of the genera Aysenia Tullgren and Aysenoides Ramirez are described and their phylogenetic relationships discussed. The new species Aysenia paposo, from the coastal desert in northern Chile is sister to Aysenia araucana Ramirez. The diagnosis of Aysenia araucana is updated and new somatic variability is reported for the species. We present new records for other species of Aysenia and Aysenoides. The new species Aysenoides simoi, from temperate forests in Chile and adjacent Argentina is sister to Aysenoides nahuel. The phylogenetic analysis confirmed the monophyly of both genera. The support values of the genera are relatively high, but some internal branches show low support values. The genus Aysenia is supported by three synapomorphies, two of these from leg spination and one from the male genitalia. Aysenoides is supported by three synapomorphies from male and female genitalia. PMID- 25277559 TI - Odontobuthus tirgari sp. nov. (Scorpiones, Buthidae) from the eastern region of the Iranian Plateau . AB - A new species of scorpions in the genus Odontobuthus (Scorpiones, Buthidae) is described from Khorasan Province, Iran. Currently, Odontobuthus includes two species in Iran, Odontobuthus doriae Thorell, 1876, which is restricted to high elevations of the central Iranian Plateau and Odontobuthus bidentatus Lourenco & Pezier, 2002 from the Zagros Mountains. The results of morphological comparisons, univariate and multivariate statistical analyses and phylogenetic analysis of COI sequence data clearly confirm a deep split between populations from the eastern Iranian Plateau and O. bidentatus Lourenco & Pezier, 2002 and O. doriae Thorell, 1876. Therefore, according to comparative morphological and molecular analyses, a new species, Odontobuthus tigari sp. nov. (??) was described from eastern Iran. This addition represents the third species of this genus from Iran. PMID- 25277560 TI - Molecular evidence for taxonomic status of the gudgeon genus Huigobio Fang, 1938 (Teleostei: Cypriniformes), with a description of a new species from Guangdong Province, South China. AB - The gudgeon cyprinid genus Huigobio Fang, 1938 is re-diagnosed. It can be distinguished from all other genera of Armatogobionina Kryzhanovsky, 1947 and the Gobioninae by its uniquely modified lower lip. The lower lip has a small, heart shaped, longitudinally non-bisected central pad and two lateral lobes expanded as a wing-shaped flap completely covered with papillae. The lobes contact each other posteromedially, but are not completely confluent. Huigobio exilicauda, new species, is described from the Zhu-Jiang drainage of Guangdong Province, South China. It differs from H. chenhsienensis in caudal-peduncle thickness and interorbital width. PMID- 25277561 TI - Hypocaccus (Baeckmanniolus) laevis Therond, 1963 is not synonymous with H. (B.) virescens Therond, 1963 (Coleoptera: Histeridae: Saprininae). AB - The synonymy of Hypocaccus (Baeckmanniolus) virescens Therond, 1963 and Hypocaccus (Baeckmanniolus) laevis Therond, 1963 is rejected following the examination of the type specimens of both species. Hypocaccus (Baeckmanniolus) laevis stat. restit. is reinstated as valid. The two species differ mainly in the dorsal sculpture, pronotal shape, shape of protibia as well as in other minor characters. Hypocaccus (B.) laevis is newly recorded from Kenya. PMID- 25277562 TI - A new parthenogenetic bagworm Reisseronia imielinella sp. nov. from Poland (Lepidoptera, Psychidae). AB - Reisseronia imielinella sp. nov. is described from the province of Upper Silesia (Slaskie voivodship) in southern Poland and compared with its closest parthenogenetic relative Reisseronia gertrudae Sieder, 1962. The new species is well characterized by the structures of the female antennae and legs. The breeding of an F1 generation was successful and is described, as is the species' habitat and life history. PMID- 25277563 TI - A new species of Pristimantis (Amphibia: Anura: Strabomantidae) from the Rio Abiseo National Park, Peru. AB - We describe a new species of Pristimantis from the Rio Abiseo National Park in the Andes of northern Peru. Specimens were collected from 2650 to 3000 m elevation. The new species has a snout-vent length of 24.9-34.2 mm (n = 7) in adult females, and 15.3-23.5 mm (n = 29) in adult males. It differs from other species of Pristimantis in having the snout with a broad, slightly upwards curved, fleshy process. The most similar species, P. phoxocephalus has the snout with a vertical fleshy keel, but differs from the new species by being larger (female SVL up to 38.4 mm vs. 34.2 mm), by having prominent dentigerous processes of vomers (minute in the new species), by lacking an inner tarsal fold (present), by lacking heel tubercles (present), and by having the dorsum in life grey, red or brown and the groin with black and orange or yellow mottling, whereas in the new species the dorsum is rusty reddish-brown with lighter blotches or tannish brown chevrons, and the groin tan with pale brown flecks. PMID- 25277564 TI - The genus Loxosceles Heineken & Lowe (Araneae: Sicariidae) in Cuba and Hispaniola, West Indies. AB - The three known species of the genus Loxosceles Heineken & Lowe from Cuba and Hispaniola are revised and two new species, Loxosceles maisi sp. nov. and Loxosceles mogote sp. nov., are described from the eastern region of Cuba. These new species are included in the reclusa group, and are considered close to Loxosceles taino Gertsch & Ennik as they have a greatly thickened male palpal tibia, a projecting cymbium, and large receptacles in the female genitalia. The distribution ranges of the known Cuban and Hispaniolan species are extended. PMID- 25277565 TI - A new species of Ultratenuipalpus (Acari: Tenuipalpidae) from Cook Islands, with a key to the known species. AB - The genus Ultratenuipalpus (Acariformes: Tenuipalpidae) was represented by 24 species prior to this study. In this paper, we describe and illustrate Ultratenuipalpus avarua sp. nov, from Cocos sp. (Arecaceae) in Avarua, Rarotonga, the Cook Islands. A key to the world species of Ultratenuipalpus is provided. PMID- 25277566 TI - First zoeal stage of ?Cataleptodius parvulus (Fabricius, 1793) and Xanthodius denticulatus (White, 1848) (Decapoda: Brachyura): larval evidences and systematic position. AB - The first zoeal stages of ?Cataleptodius parvulus and Xanthodius denticulatus are described and compared with zoeae of other members of the subfamily Xanthinae. The larvae of ?C. parvulus and X. denticulatus differ mainly in: 1) spinulation of rostral and dorsal spines; 2) type of antenna; 3) setation of the basis of first maxilliped; and 4) type of telson. Features common to both species include a carapace provided with well-developed spines on the dorsal (1), rostral (1), and lateral (2) portions; and the antennal protopod and rostrum similar in length. The morphological differences between the zoea I of X. denticulatus and ?C. parvulus are nevertheless consistent enough to suggest that these species do not belong to the same genus Xanthodius Stimpson, 1859 as previously supposed. Also we presume that ?C. parvulus does not belong to the genus Cataleptodius. PMID- 25277567 TI - Taxonomic notes and redescriptions of some Japanese erythroneurine leafhoppers (Hemiptera, Cicadellidae, Typhlocybinae). AB - In the Japanese typhlocybine fauna, three already known and three newly recorded species of the genera Anufrievia, Empoascanara, and Anzygina are redescribed and reported with brief notes on their taxonomy and biology: A. akazu (Matsumura), A. ciconia Dworakowska, E. bisignatella (Matsumura) comb. nov., new record, E. kotoshonis (Matsumura) new record, E. sonani (Matsumura) and A. honiloa (Kirkaldy) new record. Male specimens of A. akazu and E. bisignatella are described for the first time. PMID- 25277568 TI - A new species of Brycon (Characiformes: Characidae) from Nicaragua and Costa Rica, with a key to the lower Mesoamerican species of the genus. AB - A new species of Brycon is described from the Atlantic slope of Nicaragua and Costa Rica. Brycon costaricensis n. sp. differs from all other Central American Brycon species by the following combination of characters: 49 to 54 scales in the lateral line; 5 or 6 rows of scales between lateral line and pectoral fin base; 9 to 11 rows of scales between lateral line and dorsal fin base; 5 to 7 rows of scales between lateral line and anal fin base; anal fin notably longer than head, with 33 to 37 total rays; and a elongated and shallow caudal peduncle, whose length is 1.78 to 2.35 times its depth. A key to lower Mesoamerican species of the genus is also presented. PMID- 25277569 TI - A taxonomic review of the genus Antodynerus de Saussure, 1855 (Hymenoptera: Vespidae: Eumeninae) from the Indian subcontinent. AB - The genus Antodynerus de Saussure, 1855 is reviewed from the Indian subcontinent. Three species with one additional subspecies are present, namely Antodynerus flavescens flavescens (Fabricius, 1775), A. f. karachiensis Giordani Soika, 1970, A. limbatus (de Saussure, 1852), and A. punctatipennis (de Saussure, 1853). The parasitic association of strepsipteran insects and the symbiotic association of mites are reported for the first time in the genus Antodynerus. The distribution of A. f. flavescens (Fabricius) and A. limbatus (de Saussure) in the Indian states is augmented. The latter species is newly recorded from China (Tibet). A key to species of the Indian subcontinent is provided. PMID- 25277570 TI - Geophagus crocatus, a new species of geophagine cichlid from the Berbice River, Guyana, South America (Teleostei: Cichlidae). AB - We describe a new Geophagus from the Berbice River of Guyana, bringing the total number of described species in the genus to 19, and of Guianese species to six.. Geophagus crocatus, new species, is distinguished from all species of Geophagus outside of the G. surinamensis group by the presence of an incomplete suborbital stripe (vs. complete), and the presence of six lateral bars, with bars 2 and 3 slightly sloping toward each other and fusing dorsally at the base of the dorsal fin. Geophagus crocatus is the only Geophagus species known from the Berbice River, and it is present above and below the Itabru Falls. PMID- 25277571 TI - Channa andrao, a new species of dwarf snakehead from West Bengal, India (Teleostei: Channidae). AB - Channa andrao, new species, from Lefraguri swamp, West Bengal, India, differs from all its congeners except, C. asiatica, C. bleheri and C. burmanica and the recently described C. hoaluensis and C. ninhbinhensis by the absence of pelvic fins. It can be distinguished from all other pelvic fin-less species of snakeheads by its colour pattern, and differs further in its number of vertebrae, dorsal- and anal-fin rays, and lateral-line scales from individual snakehead species in this complex. Channa andrao raises the number of snakehead species endemic to the Eastern Himalaya biodiversity hotspot to ten, representing almost one third of the known species in the genus. PMID- 25277572 TI - A new Lobosceliana Dirsh species (Orthoptera: Pamphagidae: Porthetinae) from coastal Tanzania, East Africa. AB - A new flightless species of Lobosceliana is described from coastal Tanzania, East Africa. This is the first species within this genus with shortened wings in the male sex. The antennal formula is special in this species as well since it differs from that of other Lobosceliana species, questioning the systematic value of the number of antennal segments in Porthetinae as a useful generic character. PMID- 25277573 TI - Amphipoda (crustacea) from Palau, Micronesia: families Dexaminidae, Eusiridae, Hyalidae, Ischyroceridae, Leucothoidae and Lysianassidae. AB - Thirteen species of amphipod in the families Dexaminidae (1), Eusiridae (1), Hyalidae (1), Ischyroceridae (1), Leucothoidae (8) and Lysianassidae (1) are recorded from Palau in Micronesia. Of these, Ventojassa palauensis sp. nov., Leucothoe beobeldabensis sp.nov., L. pseudepidemos sp. nov., L. serratissima sp. nov., L. tumida sp. nov., L. whiteae sp. nov and Paranamixis dentidactylus sp. nov. are new to science and are described and figured. PMID- 25277574 TI - Shenahweum minutum (Hemiptera, Aphidoidea: Drepanosiphinae)-taxonomic position and description of sexuales. AB - The oviparous female and winged male of Shenahweum minutum (Davis) are described and illustrated in detail for the first time. Notes on distribution and host plants are presented as well as additional taxonomic data on the genus. PMID- 25277575 TI - Dario kajal, a new species of badid fish from Meghalaya, India (Teleostei: Badidae). AB - Dario kajal, new species, is described from Seinphoh stream in the Jaintia Hills of Meghalaya, India. It can be distinguished from all other congeners by the presence of a postorbital stripe that continues behind the eye in line with the preorbital stripe and by the presence in males of a series of double bars restricted to the upper half of the body. The discovery of D. kajal in the Meghna River drainage raises the number of Dario species to five and raises interesting questions about the biogeography of the genus. PMID- 25277576 TI - First record of the genus Ctenipocoris (Heteroptera: Naucoridae) in Central America, with a preliminary key to the American species and description of a new species. AB - A new naucorid species, Ctenipocoris oscari Herrera NEW SPECIES, is herein described for Costa Rica. It is the first species to be described in Central America and the sixth American species. Comparative notes are provided to differentiate this species from the others. Type material is deposited at the Zoological Museum of the University of Costa Rica (MZUCR), San Jose, Costa Rica. A preliminary key to the American species of the genus is provided. PMID- 25277577 TI - Rediscovery of the earless microteiid lizard Anotosaura collaris Amaral, 1933 (Squamata: Gymnophthalmidae): a redescription complemented by osteological, hemipenial, molecular, karyological, physiological and ecological data. AB - More than a century after its discovery by Ernest Garbe, and almost 80 years after its original description, we obtained a series of specimens of the earless gymnophthalmid Anotosaura collaris, the type species of the genus, up to now known only by a single specimen. On the basis of the material obtained at and close to the type locality we redescribe the species, adding information about the external and hemipenial morphology, osteology and karytoype. Molecular data confirm its sister relationship with Anotosaura vanzolinia as well as the close relationship of Anotosaura with the Ecpleopodini Colobosauroides and Dryadosaura. We supplement this information with thermophysiological, ecogeographical, karyotypic and ecological data. PMID- 25277578 TI - New microbombyliids (Diptera: Mythicomyiidae) from Eocene Baltic and Rovno ambers, with notes on previously described amber species. AB - New mythicomyiids from Baltic and Rovno amber are described and illustrated herein including one new genus: Riga, n. gen.; and five new species: Glabellula aggregata Evenhuis, n. sp., Glabellula perkovskyi Evenhuis, n. sp., Riga toni Evenhuis, n. sp., Carmenelectra shehuggme Evenhuis, n. sp. and Carmenelectra pernigra Evenhuis, n. sp. The genus Riga is very closely related to the extant genus Reissa, which is known from a single species in the Canary Islands. A key to the seven Tertiary species of Glabellula is given. Notes are given clarifying the synonymy of Glabellula; and acting as First Reviser, Mythicomyia dominicana Evenhuis is selected as a correct original spelling. With the description of the new species in this study, the Tertiary fauna of Mythicomyiidae is now 17 species in 8 genera known from Baltic, Saxon, Bitterfeld, French, Rovno (all Eocene), and Dominican (Miocene) ambers. PMID- 25277579 TI - First records of the antlion genus Solter Navas from southern Africa, with description of a new species (Neuroptera: Myrmeleontidae: Myrmecaelurini). AB - A new species of Solter Navas is described from South Africa, representing the first record of this genus from Africa south of the equator. This is a significant extension to the known distribution range of this predominantly Palaearctic genus. The species described here is characteristically reddish brown with a banded abdomen, and was recorded at three localities in arid rocky areas in the Northern Cape Province of South Africa. PMID- 25277580 TI - A new species of the Stenus cephalotes group (Coleoptera, Staphylinidae) from Guangxi, South China. AB - A new species of the Stenus cephalotes group, S. mawenliae sp. n. from Guangxi, South China, is described and illustrated. The latest key to Chinese species of the group is modified to include the new species. PMID- 25277581 TI - Epeorus petersi, a new species of Heptageniidae (Ephemeroptera) from the Western Ghats of southern India. PMID- 25277583 TI - Validation of certain family, generic and species names in Krapp-Schickel & Muller, 2011 and Lowry & Myers, 2013. PMID- 25277582 TI - Happy birthday Willi Hennig!-Hyptia hennigi sp. nov. (Hymenoptera: Evaniidae), a fossil ensign wasp from Eocene Baltic amber. AB - The ensign wasp genus Hyptia Illiger was previously known from 52 extant New World species and one fossil species from Lower Miocene to Upper Oligocene Mexican amber. Hyptia hennigi sp. nov., from Eocene Baltic amber, is the oldest known species and the first member of the genus from the Old World. PMID- 25277584 TI - The tiger beetles (Coleoptera: Carabidae, Cicindelinae) of Angola: a descriptive catalogue and designation of neotypes. AB - An annotated catalogue of the species and subspecies of tiger beetles (Coleoptera: Carabidae, Cicindelinae) hitherto known from Angola is given. A total of 89 forms (74 species and 15 subspecies) is recorded from this southwestern country of Africa. Within this assemblage there are 31 endemic forms (33.3%). Some species are represented by only the holotype specimen (some without locality) or the type series. Others were recorded based on a single specimen. Records for six species previously unknow from Angola are given: Foveodromica sp. n. 1, Foveodromica sp. n. 2, Ophryodera rufomarginata bradshawi Peringuey, 1888, Elliptica muata parallelestriata (W. Horn, 1923), Lophyra differens (W. Horn, 1892) and Myriochila jucunda (Peringuey, 1892). A historical review, as well as some considerations on the distribution and conservation status of these beetles in Angola are also presented. PMID- 25277585 TI - Morphology and identification of the pupae of several species of soil-dwelling broad-nosed weevils from Central Europe (Coleoptera, Curculionidae, Entiminae). AB - The pupae of Otiorhynchus (Arammichnus) dieckmanni Magnano, 1979, O. (s.str.) tenebricosus (Herbst, 1784) form lugdunensis Boheman, 1843, Peritelus sphaeroides Germar, 1824, Strophosoma (Neliocarus) c.f. sus Stephens, 1831 and Tanymecus (s. str.) palliatus (Fabricius, 1787) are described and illustrated for the first time. The pupae of Barypeithes (Exomias) pellucidus (Boheman, 1834), Brachyderes (s. str.) incanus (Linnaeus, 1758), Liophloeus (s. str.) tessulatus (Muller, 1776), Phyllobius intrusus Kono, 1948 (= Parascythopus exsulans Heijerman & Magnano, 2000) and Phyllobius (s. str.) pyri (Linnaeus, 1758) are redescribed and illustrated. Characteristic features including chaetotaxy, habitus and measurements are given. Pupae of the genera Peritelus, Strophosoma, and Tanymecus are described for the first time. Keys to the pupae of 14 genera of broad-nosed weevils, and to several species of Phyllobius and Otiorhynchus are also presented. PMID- 25277586 TI - Phylogeography of the reed frog Hyperolius castaneus (Anura: Hyperoliidae) from the Albertine Rift of Central Africa: implications for taxonomy, biogeography and conservation. AB - We examine the systematics of multiple populations of the Albertine Rift endemic amphibian Hyperolius castaneus, which currently incorporates four subspecies. Standard morphometric data were analyzed with principal components analyses and analyses of covariance. Phylogenetic analyses of two mitochondrial (16S, cyt b) and one nuclear (RAG1) genes were analyzed from 41 samples representing three subspecies. Results indicated some significant morphometric differences between the nominate subspecies H. c. castaneus and the Itombwe Plateau subspecies H. c. constellatus, and phylogenetic analyses of molecular data recovered these taxa as reciprocally monophyletic groups. We recognize these two allopatric populations as recently diverged, but distinct species, H. castaneus and H. constellatus. The subspecies H. c. submarginatus from the Kabobo Plateau is transferred to the synonymy of H. constellatus, but the status of the unsampled subspecies H. c. rhodogaster, described from mid-elevations of the western Itombwe Plateau, remains problematic. The phylogeographic pattern of our study resembles some, but not all, Albertine Rift vertebrates that have been examined with molecular data. Hyperolius constellatus is restricted to the Itombwe and Kabobo plateaus, which are of special conservation concern because of high levels of amphibian diversity and endemism, and multiple threats from deforestation, mining activities and road construction. PMID- 25277587 TI - Taxonomy of the Oriental genus Bolbochromus: a generic overview and descriptions of four new species (Coleoptera: Geotrupidae: Bolboceratinae). AB - A taxonomic overview of the essentially Oriental genus Bolbochromus Boucomont, 1909 is given. Two new southeast Asian subgenera are proposed: Metabolbochromus (type species Scarabaeus sulcicollis Wiedemann, 1819), characterised by unique male genitalia (lacking separated parameres), and Bolbochromops (type species Bolboceras ludekingi Lansberge, 1886), with a distinctly two-horned head (but with separated parameres). The remaining known Bolbochromus, apparently all with a distinct pair of parameres and a distinct frontovertexal protrusion only, are left in the nominotypical subgenus, awaiting a reappraisal of the poorly sampled continental fauna. Four new species are described and compared with close relatives, all in the nominotypical subgenus: Bolbochromus (Bolbochromus) dumogensis (Sulawesi), B. (Bolbochromus) mindanaicus (Philippines), B. (Bolbochromus) pumilus (south India), and B. (Bolbochromus) sinensis (south China). Identity of type species of Bolbochromus to be established (type of Bolboceras laetus Westwood, 1852 not found, and type locality Ceylon doubtful). All named Bolbochromus taxa are listed and characterised (some of them tentatively) in a synoptic table. The southeast Asian island taxa are all keyed and diagnosed, along with notes on variation, range extensions, taxon ranking, and illustrations. PMID- 25277588 TI - Revision of Taxigramma pseudaperta Seguy, 1941 and comparisons with sympatric T. multipunctata (Rondani, 1859) (Diptera: Sarcophagidae). AB - The identity of the nominal taxon Taxigramma pseudaperta Seguy, 1941 [type locality: France, Corse] is revised and an improved circumscription based partly on reared material of both sexes is presented through comparison with the very similar and sympatric species T. multipunctata (Rondani, 1859). A table is provided to separate first instars, puparia, males and females of these two taxa. PMID- 25277589 TI - Bioacoustics reveals two new syntopic species of Adenomera Steindachner (Anura: Leptodactylidae: Leptodactylinae) in the Cerrado of central Brazil. AB - In this paper, we describe two syntopic species of Adenomera from the Chapada dos Veadeiros microregion, northern State of Goias, central Brazil, recognized based on morphology, color patterns, and bioacoustics. Specimens and calls were obtained in the Municipality of Teresina de Goias, central Brazil. Adenomera cotuba sp. nov. is diagnosed from the other 16 congeneric species by its 1) small size (adult male SVL 18.6-20.5 mm) and very robust body; 2) dorsum glandular/granular with no distinctive dorsal granular rows or dorsolateral folds; 3) black or very dark dorsal coloration with no distinctive color patterns (e.g., dorsolateral or vertebral stripes); 4) toe tips not developed into flattened disks; 5) presence of antebrachial tubercle; and 6) advertisement call consisting of a well-defined series of pulsed calls (7-32 calls/series) with progressive increment in amplitude in the first third of each call series when it reaches a sustained plateau. Adenomera juikitam sp. nov. is diagnosed from the other 16 congeneric species by its 1) dorsum profusely glandular/granular with no distinctive dorsal granular rows or dorsolateral folds; 2) dorsum with a marble like and red coloration with no distinctive color patterns (e.g., dorsolateral or vertebral stripes); 3) toe tips not developed into flattened disks; 4) small size (adult male SVL 19.1-19.5 mm) and very robust body; and 5) long (148-202 ms) advertisement call composed of 16-21pulses. Both new taxa occur in syntopy, and our data allow us to differentiate them both in temporal (pulses/call) and spectral (frequency peaks) traits of their advertisement calls. Besides, dorsal coloration is distinctive, Adenomera cotuba sp. nov. has a black or very dark colored dorsum, whereas Adenomera juikitam sp. nov. has a marble-like and red colored dorsum, in addition to the presence (A. cotuba sp. nov.) or absence (A. juikitam sp. nov.) of antebrachial tubercle. PMID- 25277590 TI - A new species of Crossodactylodes (Anura: Leptodactylidae) from Minas Gerais, Brazil: first record of genus within the Espinhaco Mountain Range. AB - The genus Crossodactylodes comprises three species of Atlantic Rainforest endemic frogs strictly dependent on bromeliads where they spend their entire life cycle. The current geographic distribution of the genus covers highland areas of Atlantic Rainforest in the States of Rio de Janeiro and Espirito Santo, Southeastern Brazil. We describe a new species of the genus from Parque Estadual do Pico do Itambe, at Santo Antonio do Itambe municipality, State of Minas Gerais, Southeastern Brazil. Crossodactylodes itambe sp. nov. is characterized by the following combination of traits: male SVL 16.2 +/- 1.3 (14.0-17.6 mm, n = 10), female SVL 16.2 +/- 1.0 (13.5-18.0 mm, n = 15); snout short, rounded in dorsal view, sloping in lateral view; absence of vocal sac and vocal slits in males; absence of vomerine teeth; males with upper arms and forearms hypertrophied; cloacal flap prominent, simple; dorsal skin coarsely granular. The new species inhabits rupicolous bromeliads in open areas of rocky fields, and is recorded in altitudes between 1836 and 2062 m above sea level. This record extends the genus distribution for about 325 km northwest from where it was known. Crossodactylodes sp. nov. is the only species of the genus that occurs in open field habitats (campos rupestres), in very high altitudes of a non-costal mountain range (the Espinhaco Range). PMID- 25277591 TI - Two new species of stone loaches of the genus Schistura from the Koladyne basin, Mizoram, India (Teleostei: Cobitoidei: Nemacheilidae). AB - Two new species of Schistura are described from the Koladyne basin of Mizoram, India. Schistura nebeshwari is distinguished from its congeners by the combination of the following characters: a prominent dorsal adipose crest on the caudal peduncle, 11-14 dark olivaceous bars on the body, the entire ventral surface of head with numerous small melanophores, an incomplete lateral line, three black spots at the dorsal-fin base, a complete prominent black basicaudal bar, lower jaw with a shallow median notch, and no suborbital flaps in males. Schistura scyphovecteta differs from its congeners by the combination of the following characters: six dark brown saddles, each one continuing to the flank, forming globular-shaped bars overlaying a background brown stripe along the lateral line, a complete lateral line, two black spots at the dorsal-fin base, an incomplete black basicaudal bar, no median notch on the lower jaw, and a suborbital flap present in males. PMID- 25277592 TI - New and little known ptyctimous mites (Acari, Oribatida) from India. AB - In 2012, we registered a total of 22 species, 12 genera and five families of ptyctimous mites in India. Three new species, Apoplophora paraspinosa Niedbala sp. nov., Oribotritia duotrisetosa Niedbala sp. nov. and Plonaphacarus kaluzi Niedbala sp. nov., are described. Some remarks on descriptions of Indian Sumatrotritia inusitata Mahunka, 1989, Euphthiracarus meghalayensis Sanyal, 1988, Phthiracarus obscurus Niedbala, 1986 and Hoplophthiracarus concinuus (Niedbala, 1982) are presented. Hoplophthiracarus tropicus Mondal & Kundu, 1988 is recognized as a junior synonym of the species Hoplophthiracarus concinuus. PMID- 25277593 TI - Is Leopoldamys neilli (Rodentia, Muridae) a synonym of Leopoldamys herberti? A reply to Balakirev et al. (2013). AB - Recently, Balakirev et al. (2013) presented a taxonomic revision of the genus Leopoldamys based on phylogenetic analyses. They identified five main Leopoldamys genetic lineages and suggested to rename several of them. According to these authors, the genetic lineage previously thought to belong to L. edwardsi (lineage L1) should be assigned to L. revertens while L. neilli (lineage L2) should be considered as a junior synonym of L. herberti. Using molecular and morphological data from a large sampling of Leopoldamys specimens, the aim of the present study was to investigate the taxonomic status of L. herberti and L. neilli. This study reveals that, contrary to Balakirev et al.'s statement, both genetic lineages L1 and L2 occur in Nakhon Ratchasima Province, close to the type locality of L. herberti. We also show that the external measurements and color pattern of L. herberti are highly similar to those of L1 specimens but are not consistent with the morphology of L2 specimens. Therefore these results strongly suggest that L. herberti should be assigned to the genetic lineage L1. Consequently L. neilli should not be considered as a junior synonym of L. herberti and this study confirms that the appropriate name of the genetic lineage L2 is L. neilli. Moreover, as our results show that L. herberti should be assigned to the lineage L1, this name has nomenclatural priority over L. revertens, the species name suggested by Balakirev et al. (2013) for this lineage. PMID- 25277595 TI - Swiss voters reject plan to switch from private to public health system. PMID- 25277594 TI - A new record of Megatoma (Pseudohadrotoma) graeseri (Coleoptera: Dermestidae: Megatominae) from Manitoba, Canada. AB - Megatoma (Pseudohadrotoma) graeseri (Reitter, 1887), an eastern Palaearctic species, is newly recorded in North America, with specimens reported from Manitoba, Canada. PMID- 25277596 TI - Understanding the adsorption mechanism of noble gases Kr and Xe in CPO-27-Ni, CPO 27-Mg, and ZIF-8. AB - An experimental study of Xe and Kr adsorption in metal-organic frameworks CPO-27 Ni, CPO-27-Mg, and ZIF-8 was carried out. In situ synchrotron X-ray powder diffraction experiments allowed precise determination of the adsorption sites and sequence of their filling with increasing of gas pressure at different temperatures. Structural investigations were used for interpretation of gas adsorption measurements. PMID- 25277598 TI - Assessment of genetic diversity in the endangered populations of Breonadia salicina (Rubiaceae) growing in the kingdom of Saudi Arabia using inter-simple sequence repeat markers. AB - BACKGROUND: Breonadia salicina (Rubiaceae) is a critically endangered plant at the local scale native to southwestern Saudi Arabia. To understand the levels and partitioning of genetic variation across populations and geographical regions of this species, we assessed its genetic diversity using inter-simple sequence repeat (ISSR) markers. RESULTS: Fourteen ISSR primers selected from 43 primers gave rise to 211 amplified loci, of which 68 were polymorphic. The percentage of polymorphic loci (PPL) at the population level ranged from 17.1 to 23.7%, with an average of 21.3%. Nei's gene diversity (h) and Shannon's information index (I) were 0.086 and 0.125, respectively. At the species level, PPL was 32.2%, while h and I were 0.116 and 0.172, respectively. A hierarchical analysis of molecular variance revealed a high level of genetic differentiation among populations (17% of total variance, P = 0.001), consistent with the gene differentiation coefficient (G ST = 0.256). Nevertheless, the evaluated genetic diversity was very low within populations; while relatively high among populations, levels were insufficient for long-term survival. Saudi Arabian accessions were also compared to accessions of a population from Yemen, where the species is more widespread. The Yemeni population also showed low genetic diversity but clustered separately. CONCLUSIONS: Breonadia salicina in Saudi Arabia is characterized by low within population genetic diversity and high among-population genetic differentiation. Based on our findings, this locally endangered species is on the verge of local extinction. The species' survival depends on successful implementation of suggested strategies for its long-term conservation. PMID- 25277599 TI - Rational design of K173A substitution enhances thermostability coupled with catalytic activity of Enterobacter sp. Bn12 lipase. AB - ELBn12 is a lipase isolated from Enterobacter sp. Bn12 with potential application in biotechnology. Homology modeling and rational design were applied to improve thermal stability of the lipase. K173A substitution introduced an AXXXA motif on the lipase model and it may have role in dimerization and thermostability of the protein. Site-directed mutagenesis was performed to construct the lipase variant. The mutated lipase was expressed in Escherichia coli pLysS and partially purified. Thermostability of the mutated lipase after 1 h of incubation at 70 degrees C was twice that of wild-type lipase under the same conditions. Catalytic activity of the variant was about 1.5-fold towards tricaprylin at 60 degrees C and pH 8.0; moreover, the lipase variant preserved its stability within the pH range of 7.0-11.0. Substitution of superficial hydrophilic Lys with hydrophobic Ala residue increased stability of the mutated lipase in the presence of nonionic surfactants, but this substitution caused lower stability towards polar solvents. Analysis of circular dichroism spectroscopy showed that the K173A mutation altered the secondary structure of the lipase into a more helical one. In conclusion, results of this study demonstrate the positive role of generation of a stabilizing protein motif through rational protein engineering that improves the enzyme characteristics. PMID- 25277597 TI - Morbidity in children with frequently relapsing nephrosis: 10-year follow-up of a randomized controlled trial. AB - BACKGROUND: To investigate the long-term outcome in children with frequently relapsing nephrotic syndrome (FRNS) we conducted a follow-up of a previous randomized controlled trial (RCT) 10 years after the initiation of the treatment protocol. METHODS: We previously conducted an RCT on the efficacy of cyclosporine for treating children with FRNS. After 2 years of treatment, a recommended a management protocol of steroids, and immunosuppressants was provided. RESULTS: Valid information was available for 46 of the 56 patients (82.1 %) enrolled in the original RCT. The median follow-up period was 10.3 years from the start of protocol treatment with cyclosporine. At last follow-up (mean age 18.7 years), only ten patients (21.7 %) showed disease-free remission (no relapse for at least 2 years). In contrast, 23 (50.0 %) continued to relapse frequently or were on immunosuppressants, eight patients (17.4 %) had infrequent relapses without immunosuppressants. Adverse effects attributable to treatment included short stature (6 patients), osteoporosis (six patients), obesity (4 patients), cataracts (3 patients) and hypertension (3 patients). No lethal event or renal dysfunction occurred during follow-up. CONCLUSIONS: This 10-year follow-up study shows that most children with FRNS experience relapses after 2 years of cyclosporine treatment, in adolescence and into adulthood. Outcomes in terms of life expectancy and renal function are favorable. PMID- 25277600 TI - Host specificity and clade dependent distribution of putative virulence genes in Moritella viscosa. AB - Moritella viscosa is the aetiological agent of winter-ulcer disease in farmed salmonids in the North Atlantic. Previously, two major (typical and variant) genetic clades have been demonstrated within this bacterial species, one of which is almost solely related to disease in Atlantic salmon (Salmo salar). In the present study infection trials demonstrated that 'typical' M. viscosa isolated from Norwegian Atlantic salmon was highly virulent in this fish species but resulted in lower levels of mortality in rainbow trout. 'Variant' M. viscosa isolated from rainbow trout resulted in modest mortality levels in both Atlantic salmon and rainbow trout. To investigate the possible genetic background for inter-strain virulence differences, 38 M. viscosa isolates of diverse geographical origin and host species and a number of other Moritella spp. were investigated for the presence/absence of putative virulence related homologs. All isolates were positive for DNA sequences coding for; the Type VI secretion ATPase (clpV), hemolysin co-regulated protein (hcp), bacterioferritins (bfrA and bfrB), lectin (hemG), phospholipase D (pld), multifunctional autoprocessing repeats-in toxin (martxA), aerolysin (aer), invasin (inv), and cytotoxic necrotizing factor (cnf), with the exception of one isolate in which cnf could not be confirmed. The product of an ABC transporter metal-binding lipoprotein (mat) was consistently detected although 11 isolates, all phylogenetically related, appear to produce a truncated version. A putative insecticidal toxin complex (mitABC) was detected almost exclusively in 'typical' Atlantic salmon isolates, and our data indicate that this complex of genes is expressed and co-transcribed. Transmission electron microscopy investigation revealed pili and flagella surface structures on nine M. viscosa representing both typical and variant isolates. Our results provide strong support for the existence of host specificity/high virulence in 'typical' M. viscosa related to Atlantic salmon. The gene distribution also provides further support for the genetic division within M. viscosa, and constitutes a basis for further study of the importance of the mitABC complex in winter-ulcer pathogenesis. PMID- 25277601 TI - Comparing male escorts' sexual behaviour with their last male client versus non commercial male partner. AB - Apart from research suggesting that male escorts are less likely to have condomless anal sex (CAS) with their male clients compared with male non-clients, little is known about how male escorts' behaviour differs between their clients and non-clients. In spring 2013, 387 Internet-based male escorts completed an online survey that included identical questions about their sexual behaviour with their last male client and male non-client. Encounters with non-commercial partners were significantly more likely to involve a greater range of sexual behaviours, including giving oral sex to partner, kissing, anal receptive sex and sex without condoms. These findings suggest that escorts may display a greater sexual repertoire with non-commercial partners compared to their clients. Encounters with non-commercial partners were also rated as more satisfying than with clients. Condomless anal sex was less common with clients, suggesting that escorts and clients may take active roles in mitigating risks for HIV and STI transmission with each other. Although the modal response for CAS was to abstain, more than half of participants reported CAS during at least one of the two encounters assessed. Behavioural and/or biomedical HIV-prevention strategies would be appropriate for some male escorts to reduce HIV transmission risk. PMID- 25277602 TI - Investigation of magnetically controlled water intake behavior of Iron Oxide Impregnated Superparamagnetic Casein Nanoparticles (IOICNPs). AB - Iron oxide impregnated casein nanoparticles (IOICNPs) were prepared by in-situ precipitation of iron oxide within the casein matrix. The resulting iron oxide impregnated casein nanoparticles (IOICNPs) were characterized by Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR), Vibrating sample magnetometer (VSM) and Raman spectroscopy. The FTIR analysis confirmed the impregnation of iron oxide into the casein matrix whereas XPS analysis indicated for complete oxidation of iron (II) to iron(III) as evident from the presence of the observed representative peaks of iron oxide. The nanoparticles were allowed to swell in phosphate buffer saline (PBS) and the influence of factors such as chemical composition of nanoparticles, pH and temperature of the swelling bath, and applied magnetic field was investigated on the water intake capacity of the nanoparticles. The prepared nanoparticles showed potential to function as a nanocarrier for possible applications in magnetically targeted delivery of anticancer drugs. PMID- 25277603 TI - Agonist activation of estrogen receptor beta (ERbeta) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity. AB - BACKGROUND: Estrogen receptor (ER) beta acts as a tumor suppressor in malignant mesotheliomas. METHODS: Here we explored the anti-proliferative and anti tumorigenic efficacy of the selective ERbeta agonist, KB9520, in human mesothelioma cell lines in vitro and in a mesothelioma mouse model in vivo. RESULTS: KB9520 showed significant anti-proliferative effect in ERbeta positive human malignant pleural mesothelioma cells in vitro. Selective activation of ERbeta with KB9520 sensitized the cells to treatment with cisplatin, resulting in enhanced growth inhibition and increased apoptosis. Furthermore, in CD1 nude mice mesothelioma tumor growth was significantly inhibited when KB9520 was added on top of the standard of care chemo combination cisplatin/pemetrexed, as compared to the cisplatin/pemetrexed alone group. Importantly, KB9520 exerted a protective effect to cisplatin toxicity in the non-malignant mesothelium derived MET5A cells. CONCLUSIONS: Together, the data presented suggest that selective targeting of ERbeta may be an efficacious stand-alone treatment option and/or become an important add-on to existing malignant mesothelioma therapy. PMID- 25277604 TI - Synthesis of [18F]-labelled maltose derivatives as PET tracers for imaging bacterial infection. AB - PURPOSE: To develop novel positron emission tomography (PET) agents for visualization and therapy monitoring of bacterial infections. PROCEDURES: It is known that maltose and maltodextrins are energy sources for bacteria. Hence, (18)F-labelled maltose derivatives could be a valuable tool for imaging bacterial infections. We have developed methods to synthesize 4-O-(alpha-D-glucopyranosyl) 6-deoxy-6-[(18)F]fluoro-D-glucopyranoside (6-[(18)F]fluoromaltose) and 4-O-(alpha D-glucopyranosyl)-1-deoxy-1-[(18)F]fluoro-D-glucopyranoside (1 [(18)F]fluoromaltose) as bacterial infection PET imaging agents. 6 [(18)F]fluoromaltose was prepared from precursor 1,2,3-tri-O-acetyl-4-O-(2',3', di-O-acetyl-4',6'-benzylidene-alpha-D-glucopyranosyl)-6-deoxy-6-nosyl-D glucopranoside (5). The synthesis involved the radio-fluorination of 5 followed by acidic and basic hydrolysis to give 6-[(18)F]fluoromaltose. In an analogous procedure, 1-[(18)F]fluoromaltose was synthesized from 2,3, 6-tri-O-acetyl-4-O (2',3',4',6-tetra-O-acetyl-alpha-D-glucopyranosyl)-1-deoxy-1-O-triflyl-D glucopranoside (9). Stability of 6-[(18)F]fluoromaltose in phosphate-buffered saline (PBS) and human and mouse serum at 37 degrees C was determined. Escherichia coli uptake of 6-[(18)F]fluoromaltose was examined. RESULTS: A reliable synthesis of 1- and 6-[(18)F]fluoromaltose has been accomplished with 4 6 and 5-8% radiochemical yields, respectively (decay-corrected with 95 % radiochemical purity). 6-[(18)F]fluoromaltose was sufficiently stable over the time span needed for PET studies (~96% intact compound after 1-h and ~65% after 2 h incubation in serum). Bacterial uptake experiments indicated that E. coli transports 6-[(18)F]fluoromaltose. Competition assays showed that the uptake of 6 [(18)F]fluoromaltose was completely blocked by co-incubation with 1 mM of the natural substrate maltose. CONCLUSION: We have successfully synthesized 1- and 6 [(18)F]fluoromaltose via direct fluorination of appropriate protected maltose precursors. Bacterial uptake experiments in E. coli and stability studies suggest a possible application of 6-[(18)F]fluoromaltose as a new PET imaging agent for visualization and monitoring of bacterial infections. PMID- 25277606 TI - Ebselen protects against behavioral and biochemical toxicities induced by 3 nitropropionic acid in rats: correlations between motor coordination, reactive species levels, and succinate dehydrogenase activity. AB - The protective effect of ebselen was investigated against 3-nitropropionic acid (3-NP)-induced behavioral and biochemical toxicities in rats. Ebselen (10 or 25 mg/kg, intragastrically) was administered to rats 30 min before 3-NP (20 mg/kg, intraperitoneally) once a day for a period of 4 days. Locomotor activity, motor coordination, and body weight gain were determined. The striatal content of reactive oxygen species (ROS), reduced glutathione (GSH), ascorbic acid (AA), and protein carbonyl as well as catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) activities was determined 24 h after the last dose of 3-NP. Na(+)/ K(+)-ATPase, succinate dehydrogenase (SDH), and delta-aminolevulinic dehydratase (delta-ALA-D) activities were also determined. The results demonstrated that ebselen at a dose of 25 mg/kg, but not at 10 mg/kg, protected against (1) a decrease in locomotor activity, motor coordination impairment, and body weight loss; (2) striatal oxidative damage, which was characterized by an increase in ROS levels, protein carbonyl content, and GR activity, an inhibition of CAT and GPx activities, and a decrease in GSH levels; and (3) an inhibition of SDH and Na(+)/K(+)-ATPase activities, induced by 3-NP. GST activity and AA levels were not modified by ebselen or 3-NP. Ebselen was not effective against the inhibition of delta-ALA-D activity induced by 3-NP. The results revealed a significant correlation between SDH activity and ROS levels, and SDH activity and latency to fall (rotarod test). The present study highlighted the protective effect of ebselen against 3-NP induced toxicity in rats. PMID- 25277605 TI - Manifold regularized multitask feature learning for multimodality disease classification. AB - Multimodality based methods have shown great advantages in classification of Alzheimer's disease (AD) and its prodromal stage, that is, mild cognitive impairment (MCI). Recently, multitask feature selection methods are typically used for joint selection of common features across multiple modalities. However, one disadvantage of existing multimodality based methods is that they ignore the useful data distribution information in each modality, which is essential for subsequent classification. Accordingly, in this paper we propose a manifold regularized multitask feature learning method to preserve both the intrinsic relatedness among multiple modalities of data and the data distribution information in each modality. Specifically, we denote the feature learning on each modality as a single task, and use group-sparsity regularizer to capture the intrinsic relatedness among multiple tasks (i.e., modalities) and jointly select the common features from multiple tasks. Furthermore, we introduce a new manifold based Laplacian regularizer to preserve the data distribution information from each task. Finally, we use the multikernel support vector machine method to fuse multimodality data for eventual classification. Conversely, we also extend our method to the semisupervised setting, where only partial data are labeled. We evaluate our method using the baseline magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) data of subjects from AD neuroimaging initiative database. The experimental results demonstrate that our proposed method can not only achieve improved classification performance, but also help to discover the disease related brain regions useful for disease diagnosis. PMID- 25277607 TI - Immunohistochemical identification of osteoclasts and multinucleated macrophages. AB - Osteoclasts are bone-resorbing multinuclear cells derived from hematopoietic stem cells which are specialised to carry out lacunar bone resorption. The immunophenotype of giant cell-containing bone lesions in a wide range of osteoclast-like giant cells was similarly assessed. Both multinucleated macrophages and osteoclasts were found to express CD68. Multinucleated macrophages, but not osteoclasts, expressed GrB and Ki67. CD13+/CD14+/CD68+/GrB /Ki67-/CD56- all giant-cell lesions noted in giant cells of bone. Giant cells have an osteoclast phenotype in most giant cell-rich lesions of bone, which do not express the macrophage-associated antigens GrB and Ki67. Our results indicate that they are formed from osteoclast precursors of mononuclear phagocyte. PMID- 25277608 TI - National trends in the utilization of short-term mechanical circulatory support: incidence, outcomes, and cost analysis. AB - BACKGROUND: The number of alternatives to intra-aortic balloon counterpulsation in the treatment of anticipated and established acute circulatory failure is growing. Despite the clinical importance and significant cost of short-term mechanical circulatory support (MCS) devices, the state of their present use has not been analyzed on a national scale. OBJECTIVES: The purpose of this study was to characterize the demographics, treatment practices, survival rates, and cost of short-term MCS. METHODS: In this serial cross-sectional study, we analyzed all adult patients receiving short-term MCS in the United States from 2004 to 2011 by using the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project. RESULTS: From 2007 to 2011, use of percutaneous devices for short-term MCS increased by 1,511% compared with a 101% increase in nonpercutaneous devices. Mortality rates declined over this period (p for trend = 0.027) from 41.1% in 2004 to 2007 to 33.4% in 2008 to 2011. A similar trend was observed for the subset of patients with cardiogenic shock, decreasing from 51.6% to 43.1% (p for trend = 0.012). Hospital costs also declined over this period (p for trend = 0.011). Multivariable analysis revealed balloon pumps (odds ratio [OR]: 2.00; 95% confidence interval [CI]: 1.58 to 2.52), coagulopathy (OR: 2.35; 95% CI: 1.88 to 2.94), and cardiopulmonary resuscitation (OR: 3.50; 95% CI: 2.20 to 5.57) before short-term MCS were among the most significant predictors of mortality. CONCLUSIONS: Use of short-term MCS in the United States has increased rapidly, whereas rates of in-hospital mortality have decreased. These changes have taken place in the context of declining hospital costs associated with short-term MCS. PMID- 25277609 TI - The changing landscape of advanced heart failure therapeutics. PMID- 25277610 TI - Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. AB - BACKGROUND: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. OBJECTIVES: This study used (18)F fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. METHODS: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. RESULTS: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 +/- 0.27 vs. 1.92 +/ 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (beta = 0.001; p = 0.02) and atherosclerosis risk factors (beta = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 +/- 118 mg/dl vs. 127 +/- 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 +/- 0.31 vs. 1.91 +/- 0.33; p < 0.02). CONCLUSIONS: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins. PMID- 25277611 TI - Lipoprotein apheresis and acute reduction of arterial inflammation: FDG-PET as an imaging biomarker of nonpharmacological effects on the vessel wall. PMID- 25277612 TI - Incidence, source, determinants, and prognostic impact of major bleeding in outpatients with stable coronary artery disease. AB - BACKGROUND: Although there is evidence that patients who experience major bleeding after an acute coronary event are at higher risk of death in the months after the event, the incidence and impact on outcome of bleeding beyond 1 year of follow-up in patients with stable coronary artery disease (CAD) are largely unknown. OBJECTIVES: The goal of this study was to assess the incidence, source, determinants, and prognostic impact of major bleeding in stable CAD. METHODS: We prospectively included 4,184 consecutive CAD outpatients who were free from any myocardial infarction (MI) or coronary revascularization for >1 year at inclusion. Follow-up was performed at 2 years, with major bleeding defined as a type >=3 bleed using the Bleeding Academic Research Consortium (BARC) definition. RESULTS: There were 51 major bleeding events during follow-up (0.6%/year). Most events were BARC type 3a bleeds with 12 fatal bleeds (type 5). In most cases (54.9%), the site of bleeding was gastrointestinal. Major bleeding was significantly associated with mortality (adjusted hazard ratio: 2.89; 95% confidence intervals: 1.73 to 4.83; p < 0.0001). The increased risk of bleeding associated with vitamin K antagonist (VKA) treatment was particularly evident when VKA was combined with an antiplatelet therapy (APT). In contrast, the risk of cardiovascular death, MI, or nonhemorrhagic stroke did not differ in patients who received VKA + APT versus patients on VKA alone. CONCLUSIONS: In patients with stable CAD (i.e., >1 year, with no acute events), major bleeding events are rare, but such events are an independent predictor of death. When oral anticoagulation is required, concomitant APT should not be prescribed in the absence of a recent cardiovascular event. PMID- 25277613 TI - Reconsidering the necessity of aspirin in stable coronary artery disease. PMID- 25277615 TI - n-3 polyunsaturated fatty acids for atrial fibrillation recurrence: is the horse already out of the barn? PMID- 25277614 TI - Fish oil for the reduction of atrial fibrillation recurrence, inflammation, and oxidative stress. AB - BACKGROUND: Recent trials of fish oil for the prevention of atrial fibrillation (AF) recurrence have provided mixed results. Notable uncertainties in the existing evidence base include the roles of high-dose fish oil, inflammation, and oxidative stress in patients with paroxysmal or persistent AF not receiving conventional antiarrhythmic (AA) therapy. OBJECTIVES: The aim of this study was to evaluate the influence of high-dose fish oil on AF recurrence, inflammation, and oxidative stress parameters. METHODS: We performed a double-blind, randomized, placebo-controlled, parallel-arm study in 337 patients with symptomatic paroxysmal or persistent AF within 6 months of enrollment. Patients were randomized to fish oil (4 g/day) or placebo and followed, on average, for 271 +/- 129 days. RESULTS: The primary endpoint was time to first symptomatic or asymptomatic AF recurrence lasting >30 s. Secondary endpoints were high sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO). The primary endpoint occurred in 64.1% of patients in the fish oil arm and 63.2% of patients in the placebo arm (hazard ratio: 1.10; 95% confidence interval: 0.84 to 1.45; p = 0.48). hs-CRP and MPO were within normal limits at baseline and decreased to a similar degree at 6 months (Deltahs-CRP, 11% vs. -11%; DeltaMPO, -5% vs. -9% for fish oil vs. placebo, respectively; p value for interaction = NS). CONCLUSIONS: High-dose fish oil does not reduce AF recurrence in patients with a history of AF not receiving conventional AA therapy. Furthermore, fish oil does not reduce inflammation or oxidative stress markers in this population, which may explain its lack of efficacy. (Multi-center Study to Evaluate the Effect of N-3 Fatty Acids [OMEGA-3] on Arrhythmia Recurrence in Atrial Fibrillation [AFFORD]; NCT01235130). PMID- 25277617 TI - Keeping the genie in the bottle: growth hormone and cardiovascular disease. PMID- 25277616 TI - Fasting levels of high-sensitivity growth hormone predict cardiovascular morbidity and mortality: the Malmo Diet and Cancer study. AB - BACKGROUND: Both pathological excess and deficiency of growth hormone (GH) are associated with cardiovascular mortality. OBJECTIVES: The goal of this study was to test whether fasting levels of growth hormone measured with a high-sensitivity assay (hs-GH) predict cardiovascular morbidity and mortality at the population level. METHODS: We studied 4,323 participants (age 46 to 68 years; mean age 58 years; 59% women) of the Swedish, population-based Malmo Diet and Cancer study examined in 1991 to 1994. Using multivariate-adjusted Cox proportional hazards models, we related baseline levels of fasting hs-GH to incidence of coronary artery disease, stroke, congestive heart failure, all-cause mortality, and cardiovascular mortality. RESULTS: During a median follow-up of 16.2 years, hs-GH (hazard ratio [HR]/SD increment of natural logarithm of fasting hs-GH) was independently associated with increased risk of coronary artery disease (397 events; HR: 1.11; 95% confidence interval [CI]: 1.01 to 1.23; p = 0.04), stroke (251 events; HR: 1.18; 95% CI: 1.04 to 1.34; p = 0.01), congestive heart failure (107 events; HR: 1.25; 95% CI: 1.03 to 1.52; p = 0.02), all-cause mortality (645 events; HR: 1.17; 95% CI: 1.08 to 1.26; p < 0.001) and cardiovascular mortality (186 events; HR: 1.43; 95% CI: 1.24 to 1.66; p < 0.001). The addition of hs-GH to a model with conventional cardiovascular risk factors significantly reclassified risk, with a category-free net reclassification improvement (>0) of 0.542 (95% CI: 0.205 to 0.840) in cardiovascular mortality. CONCLUSIONS: Higher values of hs GH were associated with an increased risk of cardiovascular morbidity and mortality. PMID- 25277618 TI - Quantitative assessment of myocardial perfusion in the detection of significant coronary artery disease: cutoff values and diagnostic accuracy of quantitative [(15)O]H2O PET imaging. AB - BACKGROUND: Recent studies have demonstrated improved diagnostic accuracy for detecting coronary artery disease (CAD) when myocardial blood flow (MBF) is quantified in absolute terms, but there are no uniformly accepted cutoff values for hemodynamically significant CAD. OBJECTIVES: The goal of this study was to determine cutoff values for absolute MBF and to evaluate the diagnostic accuracy of quantitative [(15)O]H2O positron emission tomography (PET). METHODS: A total of 330 patients underwent both quantitative [(15)O]H2O PET imaging and invasive coronary angiography in conjunction with fractional flow reserve measurements. A stenosis >90% and/or fractional flow reserve <=0.80 was considered obstructive; a stenosis <30% and/or fractional flow reserve >0.80 was nonobstructive. RESULTS: Hemodynamically significant CAD was diagnosed in 116 (41%) of 281 patients who fulfilled study criteria for CAD. Resting perfusion was 1.00 +/- 0.25 and 0.92 +/ 0.23 ml/min/g in regions supplied by nonstenotic and significantly stenosed vessels, respectively (p < 0.001). During stress, perfusion increased to 3.26 +/- 1.04 ml/min/g and 1.73 +/- 0.67 ml/min/g, respectively (p < 0.001). The optimal cutoff values were 2.3 and 2.5 for hyperemic MBF and myocardial flow reserve, respectively. For MBF, these cutoff values showed a sensitivity, specificity, and accuracy for detecting significant CAD of 89%, 84%, and 86%, respectively, at a per-patient level and 87%, 85%, and 85% at a per-vessel level. The corresponding myocardial flow reserve values were 86%, 72%, and 78% (per patient) and 80%, 82%, and 81% (per vessel). Age and sex significantly affected diagnostic accuracy of quantitative PET. CONCLUSIONS: Quantitative MBF measurements with the use of [(15)O]H2O PET provided high diagnostic performance, but both sex and age should be taken into account. PMID- 25277619 TI - PET-determined hyperemic myocardial blood flow: further progress to clinical application. PMID- 25277620 TI - An innovator ahead of her time. PMID- 25277621 TI - What we teach: a fellow's perspective on house staff education. PMID- 25277622 TI - Triggering of symptomatic atrial fibrillation by negative emotion. PMID- 25277623 TI - Does speckle tracking really improve diagnosis and risk stratification in patients with HF with normal EF? PMID- 25277624 TI - Reply: does speckle tracking really improve diagnosis and risk stratification in patients with HF with normal EF? PMID- 25277625 TI - Integrated solid-phase extraction-capillary liquid chromatography (speLC) interfaced to ESI-MS/MS for fast characterization and quantification of protein and proteomes. AB - The high peptide sequencing speed provided by modern hybrid tandem mass spectrometers enables the utilization of fast liquid chromatographic (LC) separation techniques. We present a robust solid-phase extraction/capillary LC system (speLC) for 5-10 min separation of semicomplex peptide mixtures prior to ESI-MS/MS for peptide sequencing. This speLC-MS/MS system eliminates sample-to sample carry-over by using disposable micropipette solid-phase extraction tips (StageTips) for peptide sample loading, concentration, and desalting. Automated analysis of 192 replicates of E. coli peptide mixtures in 30 h demonstrated the throughput, stability, and reproducibility of the system. The speLC-MS/MS system detected low-femtomole amounts of peptides and allowed sequencing of 1 MUg of HeLa cells protein extracts at a rate of ~ 90 peptides/min, identifying more than 1500 peptides (>500 proteins) in a 10 min speLC-MS/MS experiment. Analysis by selected reaction monitoring by speLC-SRM-MS/MS of distinct peptides derived from the blood proteins IGF1, IGF2, IBP2, and IBP3 demonstrated protein quantification with CV values below 10% across 96 replicates. The speLC-MS/MS system is ideally suited for fast screening and characterization of large numbers of peptide containing samples in biological, biomedical, and clinical laboratories. PMID- 25277626 TI - Finite time control for MIMO nonlinear system based on higher-order sliding mode. AB - Considering a class of MIMO uncertain nonlinear system, a novel finite time stable control algorithm is proposed based on higher-order sliding mode concept. The higher-order sliding mode control problem of MIMO nonlinear system is firstly transformed into finite time stability problem of multivariable system. Then continuous control law, which can guarantee finite time stabilization of nominal integral chain system, is employed. The second-order sliding mode is used to overcome the system uncertainties. High frequency chattering phenomenon of sliding mode is greatly weakened, and the arbitrarily fast convergence is reached. The finite time stability is proved based on the quadratic form Lyapunov function. Examples concerning the triple integral chain system with uncertainty and the hovercraft trajectory tracking are simulated respectively to verify the effectiveness and the robustness of the proposed algorithm. PMID- 25277627 TI - Investigation of structure, vibrational, electronic, NBO and NMR analyses of 2 chloro-4-nitropyridine (CNP), 2-chloro-4-methyl-5-nitropyridine (CMNP) and 3 amino-2-chloro-4-methylpyridine (ACMP) by experimental and theoretical approach. AB - This study reports about the optimized molecular structures, vibrational wavenumbers, atomic charges, molecular electrostatic potentials, NBO, electronic properties, (1)H NMR and (13)C NMR chemical shifts for the molecules 2-chloro-4 nitropyridine (CNP), 2-chloro-4-methyl-5-nitropyridine (CMNP) and 3-amino-2 chloro-4-methylpyridine (ACMP). Theoretical calculations were performed by density functional theory (DFT)/B3LYP method using 6-311++G (d,p) basis set. The stability and charge delocalization of the title molecules were studied by natural bond orbital (NBO) analysis. Molecular electrostatic potential maps (MEP) were calculated to predict the reactive sites. The reactivity of the title compounds were investigated by HOMO-LUMO energies and global descriptors. The electronic properties of the compounds were also discussed and the transitions were found to be pi->pi(*). In addition, the thermodynamic properties were studied for the title compounds and corresponding relations between the properties and temperature were also discussed. The hyperpolarizability values (betatot) were calculated for the title compounds. Hyperpolarizability value (betatot) of CMNP was found to be high and nineteen times greater than that of urea. PMID- 25277628 TI - Supramolecular interaction of Moxifloxacin and beta-cyclodextrin spectroscopic characterization and analytical application. AB - The supramolecular interaction of Moxifloxacin (Moxi) and beta-cyclodextrin (beta CD) has been examined by UV-VIS, FTIR, H(1)NMR, SEM and fluorescence spectroscopy. The formation of inclusion complex has been confirmed on the base of changes of spectroscopy properties. The results showed that beta-CD reacted with Moxi to form an inclusion complex. The Moxi and beta-CD complex formed a host-guest complex in 1:1 stoichiometry and inclusion constant (K=3.95*10(2) L mol(-1)) was ascertained by the typical double reciprocal plots. Furthermore, the thermodynamic parameters (DeltaH degrees , DeltaS degrees and DeltaG degrees ) associated with the inclusion process were also determined. Based on the significant enhancement of the fluorescence intensity of Moxi produced through complex formation, a simple, accurate, rapid and highly sensitive spectrofluorometric method for the determination of Moxi in pharmaceutical formulation was developed. The measurement of relative fluorescence intensity was carried out at 464 nm with excitation at 289 nm. The factors affecting the inclusion complex formation were studied and optimized. Under the optimum reaction conditions, linear relationships with good correlation coefficients (0.99973) were in the concentration range of 10-60 ng/mL for spectrofluorimetry. The limit of detection (LOD) was found to be 1.6 ng/mL. The proposed method was successfully applied to the analysis of Moxi in pharmaceutical preparation. PMID- 25277629 TI - Optical properties and device characteristics of 2-(antipyrin-4-ylhydrazono)-2-(4 nitrophenyl)acetonitrile thin films for photodiode applications. AB - 2-(Antipyrin-4-ylhydrazono)-2-(4-nitrophenyl)acetonitrile (AHNA) films were deposited via thermal evaporation technique. The optical properties of AHNA films and electrical characteristics of Au/AHNA/n-Si/Au heterojunction diode have been reported. The optical properties of AHNA films were investigated using the spectrophotometric measurements of optical transmittance and reflectance over spectral range 190-2500 nm. The films have indirect allowed optical band gap of 3.6 eV. The refractive index of the films was calculated and the dispersion parameters of the films were determined on the light of the single oscillator model. The electrical properties of Au/AHNA/n-Si/Au heterojunction diode were studied in terms of current-voltage characteristics. The device showed rectification behaviour with a rectification ratio of 100 at +/-1 V. The conduction mechanisms and diode parameters such as ideality factor, barrier height and series resistance of the device were determined. The device under illumination showed photovoltaic properties. The short circuit current and open circuit voltage were found to be function of illumination intensity. The device satisfies the conditions to be used as photodiode. PMID- 25277630 TI - Micas from mariupolite of the Oktiabrski massif (SE Ukraine): an insight into the host rock evolution--geochemical data supported by Raman microspectroscopy. AB - Muscovite and two dark mica varieties (the coarse-crystalline, pegmatitic, and fine-crystalline with signs of early weathering) representing members of the biotite series, originating from mariupolite of the Oktiabrski massif, (Ukraine), were investigated along with their solid inclusions using electron microprobe and Raman micro-spectroscopy to discuss their genesis and relationship to the parental magma. The coarse-crystalline, pegmatitic biotite, (K1.90Rb0.02Na0.01)(Fe3.56(2+)Mg1.34Ti0.36Fe0.34(3+)Mn0.03)[(Si5.73Al2.10Fe0.17(3 ))O20](OH3.24 F0.76) represents the primary, magmatic annite that crystallized from an alkaline, Fe-rich and Mg-depleted host magma, whereas the fine crystalline biotite, partly altered to vermiculite, (K1.75Rb0.03Na0.03)(Fe3.23(3+)Fe1.16(2+)Mg0.26Mn0.04Ti0.10)[(Si5.16 Al2.84)O20](OH)4.00, devoid of F, represents a re-equilibrated or secondary, post magmatic Fe(3+)-bearing mica crystallized from alkaline to the subalkaline host magma. Muscovite, (K1.96Na0.06)(Al3.97Fe0.06(2+))[(Si5.99Al2.01)O20](OH)4, with low Na/(Na+K) ratio, low Fe and devoid of Ti and also F, forms only tiny, subhedral flakes formed in the post-magmatic, hydrothermal stage. The primary, unaltered biotite contains numerous solid inclusions of primary origin (albite, aegirine, zircon, K-feldspar, nepheline, pyrochlore, magnetite) and secondary origin (natrolite, hematite, Ti-Mn oxides/hydroxides); most of them are accompanied by a carbonaceous substance, all confirmed by scanning electron microscopy and Raman microspectroscopy. PMID- 25277631 TI - Micrometer size rod formed by secondary self assembly of omeprazole with alpha- and beta-cyclodextrins. AB - Self assembly of alpha-cyclodextrin (alpha-CD) and beta-cyclodextrin (beta-CD) micro rods induced by omeprazole (OMP) were observed by SEM and TEM. OMP/CD inclusion complexes have formed the secondary self assembly micro meter size rod like structure. This structure was driven by the intermolecular hydrogen bonding as well as van der Waals forces. Both forces induced the ordered assembly and arrangement of OMP/CD inclusion complexes, whereas CD molecules acted as molecular bricks. The OMP/CD inclusion complexes primary assembled form individual nanorods and then secondary self aggregate nanorods were form a micro meter rod structure. The results indicate that inter-nanotubular hydrogen bonding plays a crucial role in the formation of the self assembled micro rods. The inclusion complexes were also characterized using FT-IR, DSC, powder XRD, (1)H NMR, absorption, fluorescence, life time measurements and molecular modeling methods. PMID- 25277632 TI - QM/MM methodology, docking and spectroscopic (FT-IR/FT-Raman, NMR, UV) and Fukui function analysis on adrenergic agonist. AB - The Fourier transform infrared, FT-Raman, UV and NMR spectra of Ternelin have been recorded and analyzed. Harmonic vibrational frequencies have been investigated with the help of HF with 6-31G (d,p) and B3LYP with 6-31G (d,p) and LANL2DZ basis sets. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by GIAO method. The polarizability (alpha) and the first hyperpolarizability (beta) values of the investigated molecule have been computed using DFT quantum mechanical calculations. Stability of the molecule arising from hyper conjugative interactions, and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The electron density based local reactivity descriptors such as Fukui functions were calculated to explain the chemical selectivity or reactivity site in Ternelin. Finally the calculated results were compared to simulated infrared and Raman spectra of the title compound which show good agreement with observed spectra. Molecular docking studies have been carried out in the active site of Ternelin and reactivity with ONIOM was also investigated. PMID- 25277633 TI - Large-scale neural circuit mapping data analysis accelerated with the graphical processing unit (GPU). AB - BACKGROUND: Modern neuroscience research demands computing power. Neural circuit mapping studies such as those using laser scanning photostimulation (LSPS) produce large amounts of data and require intensive computation for post hoc processing and analysis. NEW METHOD: Here we report on the design and implementation of a cost-effective desktop computer system for accelerated experimental data processing with recent GPU computing technology. A new version of Matlab software with GPU enabled functions is used to develop programs that run on Nvidia GPUs to harness their parallel computing power. RESULTS: We evaluated both the central processing unit (CPU) and GPU-enabled computational performance of our system in benchmark testing and practical applications. The experimental results show that the GPU-CPU co-processing of simulated data and actual LSPS experimental data clearly outperformed the multi-core CPU with up to a 22* speedup, depending on computational tasks. Further, we present a comparison of numerical accuracy between GPU and CPU computation to verify the precision of GPU computation. In addition, we show how GPUs can be effectively adapted to improve the performance of commercial image processing software such as Adobe Photoshop. COMPARISON WITH EXISTING METHOD(S): To our best knowledge, this is the first demonstration of GPU application in neural circuit mapping and electrophysiology-based data processing. CONCLUSIONS: Together, GPU enabled computation enhances our ability to process large-scale data sets derived from neural circuit mapping studies, allowing for increased processing speeds while retaining data precision. PMID- 25277634 TI - The interaction between rejection sensitivity and emotional maltreatment in borderline personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is a prevalent psychiatric disorder associated with significant distress, dysfunction, and treatment utilization. Though, theoretically, BPD is posited to arise from a combination of trait and environmental risk factors, few studies have tested trait-by environment interactions in BPD. We investigated the roles of rejection sensitivity (RS) and childhood emotional neglect and abuse (ENA) as well as their interaction in BPD. SAMPLING AND METHODS: Eighty-five adults with a lifetime mood disorder who were recruited for outpatient studies in a psychiatric clinic were assessed for ENA using the Childhood Trauma Questionnaire and for RS with the Adult Rejection Sensitivity Questionnaire. BPD diagnoses were made by consensus using data collected on the Structured Clinical Interview for DSM-IV. Hierarchical logistic regression was used to test associations between RS, ENA, their interaction and BPD. RESULTS: RS and ENA interacted to predict co-occurring BPD in our sample of mood-disordered patients, with the strength of the relationship between RS and BPD depending on the severity of ENA. In the context of little or no ENA, RS and BPD were more strongly related than when ENA was more severe. CONCLUSIONS: Our results extend previous findings suggesting RS and ENA are risk factors for BPD. They also provide preliminary support for contemporary theories of BPD positing trait-by-environment interactions in the development of BPD. Prospective studies are needed to confirm these findings. PMID- 25277635 TI - Early versus delayed administration of norepinephrine in patients with septic shock. AB - INTRODUCTION: This study investigated the incidence of delayed norepinephrine administration following the onset of septic shock and its effect on hospital mortality. METHODS: We conducted a retrospective cohort study using data from 213 adult septic shock patients treated at two general surgical intensive care units of a tertiary care hospital over a two year period. The primary outcome was 28 day mortality. RESULTS: The 28-day mortality was 37.6% overall. Among the 213 patients, a strong relationship between delayed initial norepinephrine administration and 28-day mortality was noted. The average time to initial norepinephrine administration was 3.1 +/- 2.5 hours. Every 1-hour delay in norepinephrine initiation during the first 6 hours after septic shock onset was associated with a 5.3% increase in mortality. Twenty-eight day mortality rates were significantly higher when norepinephrine administration was started more than or equal to 2 hours after septic shock onset (Late-NE) compared to less than 2 hours (Early-NE). Mean arterial pressures at 1, 2, 4, and 6 hours after septic shock onset were significantly higher and serum lactate levels at 2, 4, 6, and 8 hours were significantly lower in the Early-NE than the Late-NE group. The duration of hypotension and norepinephrine administration was significantly shorter and the quantity of norepinephrine administered in a 24-hour period was significantly less for the Early-NE group compared to the Late-NE group. The time to initial antimicrobial treatment was not significantly different between the Early-NE and Late-NE groups. CONCLUSION: Our results show that early administration of norepinephrine in septic shock patients is associated with an increased survival rate. PMID- 25277636 TI - Con: The challenges of utilizing expanded-criteria donors for orthotopic heart transplantation. PMID- 25277637 TI - Complications of catheter-based electrophysiology procedures in adults with congenital heart disease: a national analysis. AB - OBJECTIVE: To determine whether adult congenital heart disease patients (ACHD) undergoing catheter-based electrophysiology (EP) procedures have an increased risk for complications compared with adults without congenital heart disease. DESIGN: Retrospective cohort study of a national administrative database. SETTING: Nationwide Inpatient Sample, 1998 through 2011. PARTICIPANTS: All admission records of patients who underwent a catheter-based electrophysiology procedure, categorized based on the presence or absence of ACHD. INTERVENTIONS: ACHD and non-ACHD cohorts were compared with respect to baseline, procedural, and outcome characteristics. MEASUREMENTS AND MAIN RESULTS: ACHD patients accounted for n=15,133 (1.7%) of n=873,437 EP procedure admissions and comprised a significantly increasing proportion over the study period (from 0.8% in 1998 to 2.4% in 2011, p<0.0001). ACHD patients were younger than non-ACHD patients (52.5+/-0.3 years v 61.9+/-0.04 years; p<0.0001), had a longer length of stay (4.6+/-0.1 days v 4.4+/-0.01 days, p=0.013), higher total hospital charges ($89,485+/-$1,543 v $70,456+/-$175, p<0.0001), and a higher rate of procedure related complications (odds ratio 1.66, 95% confidence interval 1.49-1.85, p<0.0001). On multivariate analysis, ACHD patients continued to demonstrate an increased risk of procedural complications (odds ratio 1.95, 95% confidence interval 1.75-2.19, p<0.0001). CONCLUSIONS: ACHD patients experienced greater morbidity after catheter-based EP procedures. This finding will be of increasing significance as ACHD patients occupy a growing segment of the population undergoing these procedures. Further investigations are warranted to determine whether this increased risk is modifiable, with the aim of improving patient safety. PMID- 25277638 TI - Coadministration of intravenous remifentanil and morphine for post-thoracotomy pain: comparison with intravenous morphine alone. AB - OBJECTIVES: In this double-blind, randomized study, the authors compared the effects of a patient-controlled remifentanil and morphine combination with morphine alone on post-thoracotomy pain, analgesic consumption, and side effects. DESIGN: A prospective, randomized, double-blind clinical study. SETTING: University hospital. PARTICIPANTS: Volunteer patients at a university hospital undergoing elective thoracotomy surgery. INTERVENTIONS: Patients were allocated randomly into 2 groups to receive patient-controlled analgesia: the morphine (M) group or the morphine plus remifentanil (MR) group. Pain, discomfort, sedation scores, cumulative patient-controlled morphine consumption, rescue analgesic (meperidine) requirement and side effects were recorded for 24 hours. MEASUREMENTS AND MAIN RESULTS: Sixty patients were allocated randomly to receive intravenous patient-controlled analgesia with morphine alone (M) or morphine plus remifentanil (MR) in a double-blind manner. Patients were allowed to use bolus doses of morphine (0.02 mg/kg) or the same dose of a morphine plus remifentanil (0.2 ug/kg) mixture every 10 minutes without a background infusion. VAS scores were lower in the MR group than in the M group at 30 minutes (p = 0.04), 1 hour (p = 0.03), and 2 hours (p = 0.04). Mean cumulative doses of morphine were not significantly different at 27.8+/-15 mg for the M group and 21.9+/-10.5 mg for the MR group. Significantly more patients needed meperidine in the M group (p = 0.039); these also experienced more nausea (p = 0.01). CONCLUSIONS: Coadministration of PCA remifentanil with morphine for the treatment of post thoracotomy pain did not reduce morphine consumption but provided superior analgesia, less use of rescue analgesics, and fewer side effects compared to morphine alone. PMID- 25277639 TI - Revisiting the question of the appropriate left double-lumen endobronchial tube size for an individual patient. PMID- 25277640 TI - In response: Thromboelastograph with platelet mapping and prediction of postoperative chest tube amount in patients undergoing coronary artery bypass surgery. PMID- 25277641 TI - Thromboelastograph with platelet mapping and prediction of postoperative chest tube amount in patients undergoing coronary artery surgery. PMID- 25277642 TI - Checklist usage decreases critical task omissions when training residents to separate from simulated cardiopulmonary bypass. AB - OBJECTIVE: Separation from cardiopulmonary bypass (CPB) requires multiple preparatory steps, during which mistakes, omissions, and human errors may occur. Checklists have been used extensively in aviation to improve performance of complex, multistep tasks. The aim of this study was to (1) develop a checklist using a modified Delphi process to identify essential steps necessary to prepare for separation from CPB, and (2) compare the frequency of completed items with and without the use of a checklist in simulation. It was hypothesized that the use of a checklist would reduce the number of omissions. DESIGN: High-fidelity simulation study. SETTING: University-affiliated tertiary care facility. PARTICIPANTS: Seven cardiac anesthesiologists created a checklist using a modified Delphi process. Ten residents participated in 4 scenarios separating from CPB in simulation. INTERVENTIONS: Each scenario was performed first without a checklist and then again with a checklist. An observer graded participants' performance. MEASUREMENTS AND MAIN RESULTS: A pre-separation checklist containing 9 tasks was created using the Delphi process. Without using this checklist, 4 tasks were completed in at least 75% of scenarios, and 8 tasks were completed at least 75% of the time when using the checklist. There was a significant improvement in completion of 5 of the 9 items (p< 0.01). CONCLUSIONS: A modified Delphi process can be used to create a checklist of steps in preparing to separate from CPB. Using this checklist during simulation resulted in increased frequency of completing designated tasks in comparison to relying on memory alone. Checklists may reduce omission errors during complex periods of anesthesiologists' perioperative workflow. PMID- 25277643 TI - Bestowing structure upon the pores of a supramolecular network. AB - Trigonal molecules compartmentalise the pores of a honeycomb network of 3,4:9,10 tetracarboxylic diimide (PTCDI) and 1,3,5-triazine-2,4,6-triamine (melamine). Extending the 1,3,5-tri(phenylene-ethynylene)benzene core by a phenyl group allows for a well-defined accommodation of the molecule into two symmetry equivalent positions in the pore. The corresponding styryl or phenylene ethynylene derivatives exceed the pore size and, thus, impede pore modification. PMID- 25277644 TI - Empty fenestration of the internal jugular vein: a rare phenomenon. AB - Though there are common variations of the internal jugular vein (IJV), fenestrations are extremely rare. The lateral branch of the accessory nerve classically goes through the fenestration. We report a case of an empty fenestration of the IJV that was discovered during clearance of cervical lymph nodes. Original operative and radiographic images are shown. PMID- 25277645 TI - Use of metronidazole as part of an empirical antibiotic regimen after incision and drainage of infections of the odontogenic spaces. AB - The combination of amoxicillin/clavulanate and metronidazole is a widely-accepted empirical regimen for infections of the odontogenic spaces. Once adequate drainage has been established micro-organisms are less likely to grow and multiply, particularly anaerobes. This may obviate the need for anaerobic coverage after drainage in healthy hosts. We studied 60 patients in this randomised prospective study, the objective of which was to evaluate metronidazole as part of an empirical antibiotic regimen after drainage of infections of the odontogenic spaces. Samples of pus were sent for culture and testing for sensitivity. Amoxicillin/clavulanate and metronidazole were given to all patients. After incision and drainage the patients were randomly allocated to two groups. In the first group both antibiotics were continued, and in the second metronidazole was withdrawn. The groups were compared both clinically and microbiologically. There were no significant differences between the groups in the resolution of infection. Thirteen patients (n=6 in the 2-antimicrobial group, and n=7 in the amoxicillin/clavulanate group) showed no improvement during the 48 h postoperatively. Overall there was need to substitute another antibiotic for amoxicillin/clavulanate in only 6 cases. Six patients in the amoxicillin/clavulanate group required the addition of metronidazole after drainage. We conclude that in healthy subjects metronidazole is not necessary in the period after drainage, but its prescription should be based on assessment of clinical and laboratory markers of infection. PMID- 25277646 TI - Unusual case of cervical syphilis with Piringer-Kuchinka-like lymphadenitis. AB - Syphilis rarely presents with cervical lymphadenopathy. We describe a patient with a cervical mass associated with weight loss, asthenia, and night sweats. The mass was excised and histological examination suggested Piringer-Kuchinka lymphadenitis, which is usually present in cervical toxoplasmosis. To the best of our knowledge, Piringer-Kuchinka lymphadenitis has not previously been reported in cervical syphilis. PMID- 25277648 TI - Spatially digitized tactile pressure sensors with tunable sensitivity and sensing range. AB - When developing an electronic skin with touch sensation, an array of tactile pressure sensors with various ranges of pressure detection need to be integrated. This requires low noise, highly reliable sensors with tunable sensing characteristics. We demonstrate the operation of tactile pressure sensors that utilize the spatial distribution of contact electrodes to detect various ranges of tactile pressures. The device consists of a suspended elastomer diaphragm, with a carbon nanotube thin-film on the bottom, which makes contact with the electrodes on the substrate with applied pressure. The electrodes separated by set distances become connected in sequence with tactile pressure, enabling consecutive electrodes to produce a signal. Thus, the pressure is detected not by how much of a signal is produced but by which of the electrodes is registering an output. By modulating the diaphragm diameter, and suspension height, it was possible to tune the pressure sensitivity and sensing range. Also, adding a fingerprint ridge structure enabled the sensor to detect the periodicity of sub millimeter grating patterns on a silicon wafer. PMID- 25277647 TI - Omega-3 fatty acids, EPA and DHA induce apoptosis and enhance drug sensitivity in multiple myeloma cells but not in normal peripheral mononuclear cells. AB - The n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to enhance the effect of chemotherapeutic drugs in clinical studies in cancer patients and to induce apoptotic tumor cell death in vitro. Until now, EPA and DHA have never been investigated in multiple myeloma (MM). Human myeloma cells (L363, OPM-1, OPM-2 and U266) and normal peripheral blood mononuclear cells were exposed to EPA and DHA, and effects on mitochondrial function and apoptosis, caspase-3 activation, gene expression and drug toxicity were measured. Exposure to EPA and DHA induced apoptosis and increased sensitivity to bortezomib in MM cells. Importantly, they did not affect viability of normal human peripheral mononuclear cells. Messenger RNA expression arrays showed that EPA and DHA modulated genes involved in multiple signaling pathways including nuclear factor (NF) kappaB, Notch, Hedgehog, oxidative stress and Wnt. EPA and DHA inhibited NFkappaB activity and induced apoptosis through mitochondrial perturbation and caspase-3 activation. Our study suggests that EPA and DHA induce selective cytotoxic effects in MM and increase sensitivity to bortezomib and calls for further exploration into a potential application of these n-3 polyunsaturated fatty acids in the therapy of MM. PMID- 25277650 TI - Constructive effects of long alkyl chains on the electroluminescent properties of cationic iridium complex-based light-emitting electrochemical cells. AB - A series of cationic iridium complexes (1-6) were synthesized using alkylated imidazole-based ancillary ligands, and the photophysical and electrochemical properties of these complexes were subsequently evaluated. Light-emitting electrochemical cells (LECs) were fabricated from these complexes, and the effects of the alkyl chain length on the electroluminescent properties of the devices were investigated. The LECs based on these complexes resulted in yellow emission (complexes 1, 3, and 5) and green emission (complexes 2, 4, and 6) with Commission Internationale de L'Eclairage (CIE) coordinates of (0.49, 0.50) and (0.33, 0.59), respectively. Our results indicate that the luminance and efficiency of the LECs can consistently be enhanced by increasing the alkyl chain length of the iridium complexes as a result of suppressed intermolecular interaction and self-quenching. Subsequently, a high luminance of 7309 cd m(-2) and current efficiency of 3.85 cd A(-1) were achieved for the LECs based on complex 5. PMID- 25277651 TI - Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo. AB - CD31, a trans-homophilic inhibitory receptor expressed on both T- and B lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction. Here, we show that intact CD31 molecules, which are able to drive an inhibitory signal, are concentrated at the periphery of the IS but are excluded from the center of the IS. At this site, were the cells establish the closest contact, the CD31 molecules are cleaved, and most of the extracellular portion of the protein, including the trans-homophilic binding sites, is shed from the cell surface. T cells lacking CD31 trans homophilic binding sites easily establish stable interactions with B cells; at the opposite, CD31 signaling agonists inhibit T/B IS formation as well as the ensuing helper T cell activation and function. Confocal microscopy and flow cytometry analysis of experimental T/B IS shows that the T cell inhibitory effects of CD31 agonists depend on SHP-2 signaling, which reduces the phosphorylation of ZAP70. The analysis of synovial tissue biopsies from patients affected by rheumatoid arthritis showed that T cell CD31 molecules are excluded from the center of the T/B cell synapses in vivo. Interestingly, the administration of CD31 agonists in vivo significantly attenuated the development of the clinical signs of collagen-induced arthritis in DBA1/J mice. Altogether, our data indicate that the T cell co-inhibitory receptor CD31 prevents the formation of functional T/B immunological synapses and that therapeutic strategies aimed at sustaining CD31 signaling will attenuate the development of autoimmune responses in vivo. PMID- 25277652 TI - Variation in protection of four divergent avian influenza virus vaccine seed strains against eight clade 2.2.1 and 2.2.1.1. Egyptian H5N1 high pathogenicity variants in poultry. AB - BACKGROUND: Highly pathogenic (HP) H5N1 avian influenza virus (AIV) was introduced to Egyptian poultry in 2006 and has since become enzootic. Vaccination has been utilized as a control tool combined with other control methods, but for a variety of reasons, the disease has not been eradicated. In 2007, an antigenically divergent hemagglutinin subclade, 2.2.1.1, emerged from the original clade 2.2.1 viruses. OBJECTIVES: The objective was to evaluate four diverse AIV isolates for use as vaccines in chickens, including two commercial vaccines and two additional contemporary isolates, against challenge with numerous clade 2.2.1 and clade 2.2.1.1 H5N1 HPAIV Egyptian isolates to assess the variation in protection among different vaccine and challenge virus combinations. METHODS: Vaccination-challenge studies with four vaccines and up to eight challenge strains with each vaccine for a total of 25 vaccination-challenge groups were conducted with chickens. An additional eight groups served as sham vaccinated controls. Mortality, mean death time, morbidity, virus, and pre challenge antibodies were evaluated as metrics of protection. Hemagglutination inhibition data were used to visualize the antigenic relatedness of the isolates. RESULTS AND CONCLUSIONS: Although all but one vaccine-challenge virus combination significantly reduced shed and mortality as compared to sham vaccinates, there were differences in protection among the vaccines relative to one another based on challenge virus. This emphasizes the difficulty in vaccinating against diverse, evolving virus populations, and the importance of selecting optimal vaccine seed strains for successful HPAIV control. PMID- 25277653 TI - Nationwide rate of attention-deficit hyperactivity disorder diagnosis and pharmacotherapy in Korea in 2008-2011. AB - INTRODUCTION: Using the National Health Insurance database in Korea, we examined the diagnostic and treatment incidence and comorbidity of attention-deficit hyperactivity disorder (ADHD). METHODS: During 2007-2011, we chose subjects aged 6-18 years, who had at least one medical claim containing an International Classification of Diseases, 10th Revision code for diagnosis of ADHD (F90.0) with no medication use in the previous 360 days. Then, we analyzed the data for 2008 2011 to determine the mean annual incidence and prevalence of newly diagnosed and medicated patients, as well as comorbidity. RESULTS: The average annual diagnostic incidence of ADHD was 0.357% (29,310.5/8,218,252), and the incidence of medication use for ADHD was 0.248% (20,340.3/8,218,252) during 2008-2011 with no significant annual difference. The transition rate from diagnosis to medication among newly diagnosed ADHD patients was 69%. The overall prevalence rate of ADHD diagnosis and medication during 2008-2011 was 0.799% (65,702/8,218,252) and 0.610% (50,127/8,218,252), respectively. Among newly diagnosed patients with ADHD, osmotic-controlled release oral delivery system methylphenidate was the most commonly used first medication, and depression was the most common comorbid psychiatric diagnosis. DISCUSSION: This is the first report of the nationwide data on the current diagnosis and pharmacotherapy of ADHD in the whole population aged 6-18 years. We need further investigation to find the factors of low diagnostic and treatment incidence compared with high prevalence of ADHD. PMID- 25277654 TI - First experimental evidence for the presence of a CRISPR toxin in sulfolobus. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR associated (cas) genes constitute the adaptive immune system in bacteria and archaea. Although the CRISPR-Cas systems have been hypothesized to encode potential toxins, no experimental data supporting the hypothesis are available in the literature. In this work, we provide the first experimental evidence for the presence of a toxin gene in the type I-A CRISPR system of hyperthermophilic archaeon Sulfolobus. csa5, under the control of its native promoter in a shuttle vector, could not be transformed into CRISPR-deficient mutant Sulfolobus solfataricus Sens1, demonstrating a strong toxicity in the cells. A single-amino acid mutation destroying the intersubunit bridge of Csa5 attenuated the toxicity, indicative of the importance of Csa5 oligomerization for its toxicity. In line with the absence of Csa5 toxicity in S. solfataricus InF1 containing functional CRISPR systems, the expression of csa5 is repressed in InF1 cells. Induced from the arabinose promoter in Sens1 cells, Csa5 oligomers resistant to 1% SDS co occur with chromosome degradation and cell death, reinforcing the connection between Csa5 oligomerization and its toxicity. Importantly, a rudivirus was shown to induce Csa5 expression and the formation of SDS-resistant Csa5 oligomers in Sulfolobus cells. This demonstrates that the derepression of csa5 and the subsequent Csa5 oligomerization take place in native virus-host systems. Thus, csa5 is likely to act as a suicide gene under certain circumstances to inhibit virus spreading. PMID- 25277657 TI - Rrp1B gene polymorphism (1307T>C) in metastatic progression of breast cancer. AB - Rrp1B (ribosomal RNA processing1 homolog B) is a novel candidate metastasis modifier gene in breast cancer. Functional gene assays demonstrated that a physical and functional interaction existing between Rrp1b and metastasis modifier gene SIPA1 causes reduction in the tumor growth and metastatic potential. Ectopic expression of Rrp1B modulates various metastasis predictive extra cellular matrix (ECM) genes associated with tumor suppression. The aim of this study is to determine the functional significance of single nucleotide polymorphism (SNP) in human Rrp1B gene (1307 T>C; rs9306160) with breast cancer development and progression. The study consists of 493 breast cancer cases recruited from Nizam's Institute of Medical Sciences, Hyderabad, and 558 age matched healthy female controls from rural and urban areas. Genomic DNA was isolated by non-enzymatic method. Genotyping was done by amplification refractory mutation system (ARMS-PCR) method. Genotypes were reconfirmed by sequencing and results were analyzed statistically. We have performed Insilco analysis to know the RNA secondary structure by using online tool m fold. The TT genotype and T allele frequencies of Rrp1B1307 T>C polymorphism were significantly elevated in breast cancer (chi (2); p = <0.008) cases compared to controls under different genetic models. The presence of T allele had conferred 1.75-fold risk for breast cancer development (OR = 1.75; 95% CI = 1.15-2.67). The frequency of TT genotype of Rrp1b 1307T>C polymorphism was significantly elevated in obese patients (chi (2); p = 0.008) and patients with advanced disease (chi (2); p = 0.01) and with increased tumor size (chi (2); p = 0.01). Moreover, elevated frequency of T allele was also associated with positive lymph node status (chi (2); p = 0.04) and Her2 negative receptor status (chi (2); p = 0.006). Presence of Rrp1b1307TT genotype and T allele confer strong risk for breast cancer development and progression. PMID- 25277656 TI - A highly conserved region essential for NMD in the Upf2 N-terminal domain. AB - Upf1, Upf2, and Upf3 are the principal regulators of nonsense-mediated mRNA decay (NMD), a cytoplasmic surveillance pathway that accelerates the degradation of mRNAs undergoing premature translation termination. These three proteins interact with each other, the ribosome, the translation termination machinery, and multiple mRNA decay factors, but the precise mechanism allowing the selective detection and degradation of nonsense-containing transcripts remains elusive. Here, we have determined the crystal structure of the N-terminal mIF4G domain from Saccharomyces cerevisiae Upf2 and identified a highly conserved region in this domain that is essential for NMD and independent of Upf2's binding sites for Upf1 and Upf3. Mutations within this conserved region not only inactivate NMD but also disrupt Upf2 binding to specific proteins, including Dbp6, a DEAD-box helicase. Although current models indicate that Upf2 functions principally as an activator of Upf1 and a bridge between Upf1 and Upf3, our data suggest that it may also serve as a platform for the association of additional factors that play roles in premature translation termination and NMD. PMID- 25277655 TI - Mechanisms of integral membrane protein insertion and folding. AB - The biogenesis, folding, and structure of alpha-helical membrane proteins (MPs) are important to understand because they underlie virtually all physiological processes in cells including key metabolic pathways, such as the respiratory chain and the photosystems, as well as the transport of solutes and signals across membranes. Nearly all MPs require translocons--often referred to as protein-conducting channels--for proper insertion into their target membrane. Remarkable progress toward understanding the structure and functioning of translocons has been made during the past decade. Here, we review and assess this progress critically. All available evidence indicates that MPs are equilibrium structures that achieve their final structural states by folding along thermodynamically controlled pathways. The main challenge for cells is the targeting and membrane insertion of highly hydrophobic amino acid sequences. Targeting and insertion are managed in cells principally by interactions between ribosomes and membrane-embedded translocons. Our review examines the biophysical and biological boundaries of MP insertion and the folding of polytopic MPs in vivo. A theme of the review is the under-appreciated role of basic thermodynamic principles in MP folding and assembly. Thermodynamics not only dictates the final folded structure but also is the driving force for the evolution of the ribosome translocon system of assembly. We conclude the review with a perspective suggesting a new view of translocon-guided MP insertion. PMID- 25277658 TI - GRP78 mediates the therapeutic efficacy of curcumin on colon cancer. AB - Glucose-regulated protein 78 (GRP78) is the key regulator of endoplasmic reticular (ER) function. Expression of GRP78 was correlated with malignancy in different cancers. However, the role of GRP78 in the cytotoxic effect of curcumin on colon cancer cells is still unclear. A silencing RNA (siRNA) technique was used to knock down GRP78 expression. The anticancer effects of curcumin were assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometric cell cycle analysis, and a terminal dexynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. HT-29 cells expressed lower GRP78 compared with DLD-1 cells. The MTT assay revealed that HT-29 cells were more resistant to curcumin treatment than DLD-1 cells. GRP78KD cells showed more resistance to curcumin treatment compared with scrambled control cells. Overexpressed GRP78 in HT-29 cells increased the sensitivity to curcumin treatment. According to the cell cycle analysis and TUNEL assay, we found that apoptosis dramatically increased in scrambled control cells compared to GRP78KD DLD-1 cells after curcumin treatment. Finally, we evaluated levels of Bcl-2, BAX, and Bad and found that an increase of Bcl-2 level was observed in GRP78KD cells treated with curcumin. Those results were consistent with the increasing of resistance to curcumin after silencing of GRP78. The levels of GRP78 expression might determine the therapeutic efficacy of curcumin against colon cancer cells. PMID- 25277660 TI - SKULL-STRIPPING WITH DEFORMABLE ORGANISMS. AB - Segmenting brain from non-brain tissue within magnetic resonance (MR) images of the human head, also known as skull-stripping, is a critical processing step in the analysis of neuroimaging data. Though many algorithms have been developed to address this problem, challenges remain. In this paper, we apply the "deformable organism" framework to the skull-stripping problem. Within this framework, deformable models are equipped with higher-level control mechanisms based on the principles of artificial life, including sensing, reactive behavior, knowledge representation, and proactive planning. Our new deformable organisms are governed by a high-level plan aimed at the fully-automated segmentation of various parts of the head in MR imagery, and they are able to cooperate in computing a robust and accurate segmentation. We applied our segmentation approach to a test set of human MRI data using manual delineations of the data as a reference "gold standard." We compare these results with results from three widely used methods using set-similarity metrics. PMID- 25277659 TI - AZD1152-HQPA induces growth arrest and apoptosis in androgen-dependent prostate cancer cell line (LNCaP) via producing aneugenic micronuclei and polyploidy. AB - Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR) positive prostate cancer cells. LNCaP was used as androgen-dependent prostate cancer cell line. We explored the effects of AZD1152-HQPA on cell viability, DNA content, micronuclei formation, and expression of genes involved in apoptosis and cell cycle. Moreover, the expression of Aurora B and AR were investigated in 23 benign prostatic hyperplasia and 38 prostate cancer specimens. AZD1152-HQPA treatment induced defective cell survival, polyploidy, and cell death in LNCaP cell line. Centromeric labeling with fluorescence in situ hybridization (FISH) showed that the loss of whole chromosomes is the origin of micronuclei, indicating on aneugenic action of AZD1152-HQPA. Treatment of AZD1152-HQPA decreased expression of AR. Moreover, we found weak positive correlations between the expression of Aurora B and AR in both benign prostatic hyperplasia and prostate cancer specimens (r = 0.25, r = 0.41). This is the first time to show that AZD1152-HQPA can be a useful therapeutic strategy for the treatment of androgen-dependent prostate cancer cell line. AZD1152-HQPA induces aneugenic mechanism of micronuclei production. Taken together, this study provides new insight into the direction to overcome the therapeutic impediments against prostate cancer. PMID- 25277661 TI - Intermittent hypoxia upregulates serum VEGF. PMID- 25277662 TI - Time for screening? PMID- 25277663 TI - Sleep duration in Chinese adolescents: biological, environmental, and behavioral predictors. AB - OBJECTIVE: To examine sleep duration-related risk factors from multidimensional domains among Chinese adolescents. METHODS: A random sample of 4801 adolescents aged 11-20 years participated in a cross-sectional survey. A self-reported questionnaire was used to collect information about the adolescents' sleep behaviors and possible related factors from eight domains. RESULTS: In all, 51.0% and 9.8% of adolescents did not achieve optimal sleep duration (defined as <8.0 h per day) on weekdays and on weekends, respectively. According to multivariate logistic regression models, after adjusting for all possible confounders, 17 factors were associated with sleep duration <8 h. Specifically, 13 factors from five domains were linked to physical and psychosocial condition, environment, and behaviors. These factors were overweight/obesity, chronic pain, bedtime anxiety/excitement/depression, bed/room sharing, school starting time earlier than 07:00, cram school learning, more time spent on homework on weekdays, television viewing >= 2 h/day, physical activity <1 h/day, irregular bedtime, and shorter sleep duration of father. CONCLUSION: Biological and psychosocial conditions, sleep environments, school schedules, daily activity and behaviors, and parents' sleep habits significantly may affect adolescents' sleep duration, indicating that the existing chronic sleep loss in adolescents could be, at least partly, intervened by improving adolescents' physical and psychosocial conditions, controlling visual screen exposure, regulating school schedules, improving sleep hygiene and daytime behaviors, and changing parents' sleep habits. PMID- 25277664 TI - Insomnia in shift work. AB - BACKGROUND: Shift work disorder involves insomnia and/or excessive sleepiness associated with the work schedule. The present study examined the impact of insomnia on the perceived physical and psychological health of adults working on night and rotating shift schedules compared to day workers. METHODS: A total of 418 adults (51% women, mean age 41.4 years), including 51 night workers, 158 rotating shift workers, and 209 day workers were selected from an epidemiological study. An algorithm was used to classify each participant of the two groups (working night or rotating shifts) according to the presence or absence of insomnia symptoms. Each of these individuals was paired with a day worker according to gender, age, and income. Participants completed several questionnaires measuring sleep, health, and psychological variables. RESULTS: Night and rotating shift workers with insomnia presented a sleep profile similar to that of day workers with insomnia. Sleep time was more strongly related to insomnia than to shift work per se. Participants with insomnia in the three groups complained of anxiety, depression, and fatigue, and reported consuming equal amounts of sleep-aid medication. Insomnia also contributed to chronic pain and otorhinolaryngology problems, especially among rotating shift workers. Work productivity and absenteeism were more strongly related to insomnia. CONCLUSION: The present study highlights insomnia as an important component of the sleep difficulties experienced by shift workers. Insomnia may exacerbate certain physical and mental health problems of shift workers, and impair their quality of life. PMID- 25277665 TI - Pineal gland calcification is not associated with sleep-related symptoms. A population-based study in community-dwelling elders living in Atahualpa (rural coastal Ecuador). PMID- 25277666 TI - Development and validation of a novel SPR-based assay principle for bispecific molecules. AB - Surface plasmon resonance (SPR) is increasingly applied in drug discovery, early development and production. However, there are remarkably few reports describing the application of SPR in a regulated environment. Here, we describe a novel SPR based assay, which enables us to assess the binding activity of a bivalent bispecific anti-Ang-2/anti-VEGF antibody to both targets in a single setup. Validation of the assay revealed a high level of precision, accuracy, linearity and specificity. Upon analysis of temperature stressed samples it could be shown that firstly, the assay is able to indicate function-loss and secondly, it allows the parallel analysis of an additional interaction. Therefore, the described assay is highly suitable for quality assessment of the Ang-2/VEGF CrossMab. Additionally, the use of SPR in the context of assay development and routine use in a GMP environment is discussed. PMID- 25277667 TI - Determination of hydroxytyrosol and tyrosol by liquid chromatography for the quality control of cosmetic products based on olive extracts. AB - An analytical method for the simultaneous determination of hydroxytyrosol and tyrosol in different types of olive extract raw materials and cosmetic cream samples has been developed. The determination was performed by liquid chromatography with UV spectrophotometric detection. Different chromatographic parameters, such as mobile phase pH and composition, oven temperature and different sample preparation variables were studied. The best chromatographic separation was obtained under the following conditions: C18 column set at 35 degrees C and isocratic elution of a mixture ethanol: 1% acetic acid solution at pH 5 (5:95, v/v) as mobile phase pumped at 1 mL min(-1). The detection wavelength was set at 280 nm and the total run time required for the chromatographic analysis was 10 min, except for cosmetic cream samples where 20 min runtime was required (including a cleaning step). The method was satisfactorily applied to 23 samples including solid, water-soluble and fat-soluble olive extracts and cosmetic cream samples containing hydroxytyrosol and tyrosol. Good recoveries (95 107%) and repeatability (1.1-3.6%) were obtained, besides of limits of detection values below the MUg mL(-1) level. These good analytical features, as well as its environmentally-friendly characteristics, make the presented method suitable to carry out both the control of the whole manufacture process of raw materials containing the target analytes and the quality control of the finished cosmetic products. PMID- 25277668 TI - Functional ultrasound imaging of intrinsic connectivity in the living rat brain with high spatiotemporal resolution. AB - Long-range coherences in spontaneous brain activity reflect functional connectivity. Here we propose a novel, highly resolved connectivity mapping approach, using ultrafast functional ultrasound (fUS), which enables imaging of cerebral microvascular haemodynamics deep in the anaesthetized rodent brain, through a large thinned-skull cranial window, with pixel dimensions of 100 MUm * 100 MUm in-plane. The millisecond-range temporal resolution allows unambiguous cancellation of low-frequency cardio-respiratory noise. Both seed-based and singular value decomposition analysis of spatial coherences in the low-frequency (<0.1 Hz) spontaneous fUS signal fluctuations reproducibly report, at different coronal planes, overlapping high-contrast, intrinsic functional connectivity patterns. These patterns are similar to major functional networks described in humans by resting-state fMRI, such as the lateral task-dependent network putatively anticorrelated with the midline default-mode network. These results introduce fUS as a powerful novel neuroimaging method, which could be extended to portable systems for three-dimensional functional connectivity imaging in awake and freely moving rodents. PMID- 25277669 TI - Association of 10-year and lifetime predicted cardiovascular disease risk with subclinical atherosclerosis in South Asians: findings from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. AB - BACKGROUND: Ten-year and lifetime cardiovascular risk assessment algorithms have been adopted into atherosclerotic cardiovascular disease (ASCVD) prevention guidelines, but these prediction models are not based on South Asian populations and may underestimate the risk in Indians, Pakistanis, Bangladeshis, Nepali, and Sri Lankans in the United States. Little is known about ASCVD risk prediction and intermediate endpoints such as subclinical atherosclerosis in US individuals of South Asian ancestry. METHODS AND RESULTS: South Asians (n=893) from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study who were 40 to 79 years and free of ASCVD were included. Ten-year ASCVD predicted risk was calculated using the 2013 Pooled Cohort Equations. Lifetime predicted risk was based on risk factor burden. Baseline levels of subclinical atherosclerosis (coronary artery calcium [CAC] and carotid intima media thickness [CIMT]) were compared across 10-year and lifetime risk strata: (1) high (>=7.5%) 10-year and low (<7.5%) 10-year risk; (2) high (>=39%) lifetime and low (<39%) lifetime risk. South Asian men and women with high 10-year predicted risk had a significantly greater CAC burden than those with low 10-year risk. South Asians with high lifetime predicted risk had a significantly increased odds for CAC higher than 0 (odds ratio: men 1.97; 95% CI, 1.2 to 3.2; women 3.14; 95% CI, 1.5, 6.6). Associations between risk strata and CIMT were also present. CONCLUSION: This study is the first to provide evidence that contemporary ASCVD risk assessment algorithms derived from non-Hispanic white and African-American samples can successfully identify substantial differences in atherosclerotic burden in US South Asians. PMID- 25277670 TI - In vitro neuraminidase inhibitory activity of four neuraminidase inhibitors against clinical isolates of influenza virus in the Japanese 2012-2013 season. AB - The neuraminidase inhibitors (NAIs) oseltamivir phosphate (Tamiflu((r))), zanamivir (Relenza((r))), laninamivir octanoate (Inavir((r))), and peramivir (Rapiacta((r))) have been available for the treatment of influenza in Japan since 2010. The emergence of resistant virus to any of the NAIs is a great concern for influenza treatment. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of each NAI for influenza virus isolates in the 2012-2013 influenza season and compared the results to those of the 2010-2011 and 2011-2012 influenza seasons. Viral isolation of specimens obtained prior to treatment was done using Madine-Darby canine kidney cells, and the type and subtype of influenza, A(H1N1)pdm09, A(H3N2), or influenza B, was determined by RT PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 329 influenza viruses were isolated:5 influenza A(H1N1)pdm09 (1.5%), 316 influenza A(H3N2) (96.1%), and 8 influenza B (2.4%). No isolate showed an IC50 value exceeding 50 nM for any of the neuraminidase inhibitors. The IC50 values for A(H3N2) and B were similar to those of the 2010-2011 and 2011-2012 seasons. No isolate showed an increased IC50 value for A(H1N1)pdm09. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC50 values to increase at present. PMID- 25277671 TI - Therapy of endocrine disease. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis. AB - OBJECTIVE: Diabetes mellitus (DM) is associated with endothelial dysfunction, reducing nitric oxide-dependent vasodilation, and increasing production of pro inflammatory factors, leading to an increased risk of long-term cardiovascular disease. As the effects of phosphodiesterase 5 inhibitors (PDE5i) on endothelial function have not been systematically investigated, we conducted a meta-analysis of available randomized clinical trials (RCTs). DESIGN: A thorough search of the literature was carried out. Relevant studies were considered according to RCT study design, enrollment of men with type 2 DM, chronic administration of PDE5i, and evaluation of endothelial function through both hemodynamic and endothelial inflammation-related parameters. RESULTS: Fifteen studies fulfilled the eligibility criteria but only six RCTs met the inclusion criteria and were analyzed for 476 diabetic men, 239 randomized to Sildenafil, and 237 to placebo respectively. Four RCTs evaluated flow-mediated dilation (FMD), demonstrating a weighted mean increase of 2.19% (95% CI 0.48 to 3.90). This result showed a high heterogeneity (I(2): 98%). Thus, a further sub-group meta-analysis was performed and this analysis confirmed a significant, Sildenafil-related FMD improvement. Sildenafil improved endothelin 1 and high sensitivity C-reactive protein by ~ 0.94 pg/ml and -0.36 mg/l, respectively, not reaching statistical significance (P=0.69 and P=0.22 respectively). Finally, Sildenafil administration significantly reduced serum levels of interleukin 6 (IL6, -0.82 pg/ml; 95% CI 1.58 to -0.07). CONCLUSION: This meta-analysis suggests a beneficial effect of chronic PDE5i administration on endothelial function. Chronic Sildenafil administration seems to improve hemodynamic (FMD) and serum pro-inflammatory makers (IL6) in diabetic men. Larger studies are needed to confirm the effects of chronic PDE5i on endothelial function. PMID- 25277672 TI - The Impact of Uncertainty in Barrett's Esophagus Progression Rates on Hypothetical Screening and Treatment Decisions. AB - BACKGROUND: Estimates for the annual progression rate from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) vary widely. In this explorative study, we quantified how this uncertainty affects the estimates of effectiveness and efficiency of screening and treatment for EAC. DESIGN: We developed 3 versions of the University of Washington / Microsimulation Screening Analysis-EAC model. The models differed with respect to the annual progression rate from BE to EAC (0.12% or 0.42%) and the possibility of spontaneous regression of dysplasia (yes or no). All versions of the model were calibrated to the observed Surveillance, Epidemiology, and End Results esophageal cancer incidence rates from 1998 to 2009. To identify the impact of natural history, we estimated the incidence and deaths prevented as well as numbers needed to screen (NNS) and treat (NNT) of a one-time perfect screening at age 65 years that detected all prevalent BE cases, followed by a perfect treatment intervention. RESULTS: Assuming a perfect screening and treatment intervention for all patients with BE, the maximum EAC mortality reduction (64%-66%) and the NNS per death prevented (470-510) were similar across the 3 model versions. However, 3 times more people needed to be treated to prevent 1 death (24 v. 8) in the 0.12% regression model compared with the 0.42% progression model. Restricting treatment to those with dysplasia or only high-grade dysplasia resulted in smaller differences in NNT (2-3 to prevent one EAC case) but wider variation in effectiveness (mortality reduction of 15% 24%). CONCLUSION: The uncertainty in the natural history of the BE to EAC sequence influenced the estimates of effectiveness and efficiency of BE screening and treatment considerably. This uncertainty could seriously hamper decision making about implementing BE screening and treatment interventions. PMID- 25277674 TI - Single-lesion measurement per organ for assessing tumor response in advanced gastric cancer. AB - OBJECTIVE: The criterion of two target lesions per organ in the revised Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) is an arbitrary decision. We assumed that measuring the single largest lesion per organ (modified RECIST 1.1, hereafter referred to as mRECIST 1.1) instead of two (RECIST 1.1) might be enough to assess tumor responses. METHODS: We compared tumor response using computed tomography according to the RECIST 1.1 and mRECIST 1.1 in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. RESULTS: A total of 51 patients who had at least two target lesions in any organ according to the RECIST 1.1 were included in the study. The level of concordance in the tumor response between the RECIST 1.1 and mRECIST 1.1 was excellent (k = 0.904). Only 3 patients (5.9%) showed a disagreement of tumor responses between the two criteria. The overall response rate was not significantly different between the two criteria (45.1% by RECIST 1.1 vs. 49.0% by mRECIST 1.1, p = 0.692). CONCLUSION: The mRECIST 1.1 showed a high concordance with the original RECIST 1.1 in the assessment of tumor response for patients with AGC. Our result suggests that it may be possible to measure the single largest target lesion per organ for assessing tumor response in clinical practice. PMID- 25277673 TI - The impact of numeracy on verbatim knowledge of the longitudinal risk for prostate cancer recurrence following radiation therapy. AB - OBJECTIVE: . Given the long natural history of prostate cancer, we assessed differing graphical formats for imparting knowledge about the longitudinal risks of prostate cancer recurrence with or without 'hormone' or 'androgen deprivation' therapy. METHODS: . Male volunteers without a history of prostate cancer were randomized to 1 of 8 risk communication instruments that depicted the likelihood of prostate cancer returning or spreading over 1, 2, and 3 years. The tools differed in format (line, pie, bar, or pictograph) and whether the graph also included no numbers, 1 number (indicating the number of affected individuals), or 2 numbers (indicting both the number affected and the number unaffected). The main outcome variables evaluated were graphical preference and knowledge. RESULTS: . A total of 420 men were recruited; respondents were least familiar and experienced with pictographs (P < 0.0001), and only 10% preferred this particular format. Overall accuracy ranged from 79% to 92%, and when assessed across all graphical subtypes, the addition of numerical information did not improve verbatim knowledge (P = 0.1). Self-reported numeracy was a strong predictor of accuracy of responses (odds ratio [OR] = 2.6, P = 0.008), and the impact of high numeracy varied across graphical type, having a greater impact on line (OR = 5.1; 95% confidence interval [CI] = 1.6-16; P = 0.04) and pie charts (OR = 7.1; 95% CI = 2.6-19; P =0.01), without an impact on pictographs (OR = 0.4; 95% CI = 0.1-1.7; P = 0.17) or bar charts (OR = 0.5; 95% CI = 0.1-1.8; P = 0.24). CONCLUSION: . For longitudinal presentation of risk, baseline numeracy was strongly prognostic for outcome. However, the addition of numbers to risk graphs improved only the delivery of verbatim knowledge for subjects with lower numeracy. Although subjects reported the least familiarity with pictographs, they were one of the most effective means of transferring information regardless of numeracy. PMID- 25277675 TI - Progesterone and norgestrel alter transcriptional expression of genes along the hypothalamic-pituitary-thyroid axis in zebrafish embryos-larvae. AB - The aim of this study was to investigate the effects of progestins on the hypothalamic-pituitary-thyroid (HPT) axis in the early stage of zebrafish. Zebrafish embryos were exposed to progesterone (P4) or norgestrel (NGT) at 5, 50 and 100 ng L(-1) for 144 h post fertilization (hpf), and the transcriptional levels of target genes along the hypothalamic-pituitary-thyroid axis were determined daily. The results showed that P4 had only minor effects on the mRNA expression of thyroglobulin (Tg), iodothyronine deiodinase type Iota (Dio1) and thyroid hormone receptor beta (Thrb) genes. Similarly, the effects of NGT on transcripts of thyrotropin-releasing hormone (Trh), Dio1, iodothyronine deiodinase type II (Dio2) and thyroid hormone receptor alpha (Thra) genes were generally low. In addition, NGT resulted in some alterations of Tg and Thrb transcripts at different time points. However, a strong induction of Nis mRNA by P4 and NGT was observed in zebrafish embryos-larvae. The overall results showed that besides Nis no effects on the hypothalamic-pituitary-thyroid (HPT) axis are observed following exposure to P4 and NGT, which imply that both P4 and NGT have potential effects on the thyroid endocrine system by inducing transcript of Nis gene during the early stage of zebrafish. PMID- 25277676 TI - Variability in antioxidant/detoxification enzymes of Labeo rohita exposed to an azo dye, acid black (AB). AB - The aim of the present study was to evaluate effect of a highly toxic azo dye, acid black (AB) (CI: 20470, 96 h LC50=10 mg/L) on the biochemical responses of Labeo rohita. Antioxidant/detoxification enzymes such as glutathione-S transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), acetylcholinesterase (AChE), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), acid phosphatase (AcP), alkaline phosphatase (AKP), alanine transaminase (ALT) and aspartate transaminase (AST) were determined in liver, kidney, gill, muscle and brain of L. rohita after 96 h exposure to 6 mg/L (LC10), 8 mg/L (LC30) and 10 mg/L (LC50) of dye with an aim to find out the target tissue and biomarker enzyme for AB. The fish were then kept for a recovery period of 90 days, and activity of the selected enzymes was determined at the end of this period. Present dye altered the activities of all these enzymes in the selected tissues of the experimental fish in a dose dependent manner. SOD was the maximally affected enzyme, and liver was the most affected tissue. The results indicate that AB is very toxic to L. rohita as there was a significant effect of even 6 mg/L dose of the dye and the toxicity prolonged for a long time because the fish was not able to recover from the stress even 90 days after the exposure. The study suggests that SOD can be used as a biomarker enzyme and liver is the target tissue for AB. PMID- 25277677 TI - Functional expression and regulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in mouse iPS cell-derived cardiomyocytes after UTF1 -neo selection. AB - BACKGROUND/AIMS: In vitro reprogramming of somatic cells holds great potential to serve as an autologous source of cells for tissue repair. However, major difficulties in achieving this potential include obtaining homogeneous and stable cells for transplantation. High electrical activity of cells such as cardiomyocytes (CMs) is crucial for both, safety and efficiency of cell replacement therapy. Moreover, the function of the cardiac pacemaker is controlled by the activities of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Here we have examined changes in HCN gene expression and function during cardiomyogenesis. METHODS: We differentiated murine iPS cells selected by an undifferentiated transcription factor 1 (UTF1) -promoter-driven G418 resistance to CMs in vitro and characterized them by RT-PCR, immunocytochemistry, and electrophysiology. RESULTS: As key cardiac markers alpha actinin and cardiac troponin T could be identified in derived CMs. Immunocytochemical staining of CMs showed the presence of all HCN subunits (HCN1 4). Electrophysiology experiments revealed developmental changes of action potentials and If currents as well as functional hormonal regulation and sensitivity to If channel blockers. CONCLUSION: We conclude that iPS cells derived from UTF-selection give rise to functional CMs in vitro, with established hormonal regulation pathways and functionally expressed If current in a development-dependent manner; and have all phenotypes with the pacemaker as predominant subtype. This might be of great importance for transplantation purposes. PMID- 25277678 TI - Ebola: a call for blood transfusion strategy in sub-Saharan Africa. PMID- 25277679 TI - Antimicrobial steroidal saponin and oleanane-type triterpenoid saponins from Paullinia pinnata. AB - BACKGROUND: Paullinia pinnata L. (Sapindaceae) is an African woody vine, which is widely used in traditional medicine for the treatment of human malaria, erectile dysfunction and bacterial infections. A phytochemical investigation of its methanol leaf and stem extracts led to the isolation of seven compounds which were evaluated for their antimicrobial properties. METHODS: The extracts were fractionated and compounds were isolated by chromatographic methods. Their structures were elucidated from their spectroscopic data in conjunction with those reported in literature. The antimicrobial activities of the crude extracts, fractions and compounds were evaluated against bacteria, yeasts and dermatophytes using the broth micro-dilution technique. RESULTS: Seven compounds: 2-O-methyl-L chiro-inositol (1), beta-sitosterol (2), friedelin (3), 3beta-(beta-D Glucopyranosyloxy) stigmast-5-ene (4), (3beta)-3-O-(2'-Acetamido-2'-deoxy-beta-D glucopyranosyl) oleanolic acid (5), (3beta,16alpha-hydroxy)-3-O-(2'-Acetamido-2' deoxy-beta-D-glucopyranosyl) echinocystic acid (6) and (3beta)-3-O-[beta-D glucopyranosyl-(1"-3')-2'-acetamido-2'-deoxy-beta-D-galactopyranosyl]oleanolic acid (7) were isolated. Compounds 5 and 7 showed the best antibacterial and anti yeast activities respectively (MIC value range of 0.78-6.25 and 1.56-6.25 MUg/ml), while 6 exhibited the best anti-dermatophytic activity (MIC value range of 6.25-25 MUg/ml). CONCLUSION: The results of the present findings could be considered interesting, taking into account the global disease burden of these susceptible microorganisms, in conjunction with the search for alternative and complementary medicines. PMID- 25277680 TI - Spray-by-spray in situ cross-linking alginate hydrogels delivering a tea tree oil microemulsion. AB - In this paper we propose an in situ forming ionically cross-linked alginate (Alg) hydrogel delivering a Tea Tree Oil microemulsion (MeTTO) and potentially useful as an advanced dressing for infected wounds. Alg hydrogels were prepared by a spray-by-spray deposition method with the aim to minimize the discomforts during application. From pseudoternary phase diagrams, it was found that proper combination of TTO, water, polysorbate 80 and ethanol gave stable spherical MeTTO with good antimicrobial activity. On this basis, MeTTO at 20% TTO was selected for further inclusion in an Alg hydrogel prepared by alternating sprays of Alg/MeTTO and calcium chloride solutions. Homogeneous dispersion of MeTTO inside cross-linked Alg was assessed by different macroscopic and microscopic methods demonstrating the superior propensity of MeTTO to be integrated in the water based hydrogel as compared to TTO. Antimicrobial effect of Alg/MeTTO hydrogels on Escherichia Coli strains was remarkable, highlighting the potential of the system as bioactive wound dressing. PMID- 25277681 TI - Lenalidomide in heavily pretreated refractory diffuse large B-cell lymphoma: a case report. AB - INTRODUCTION: In diffuse large B-cell lymphoma, first-line treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; salvage with cisplatin-based regimens for relapsing patients; and autologous stem cell therapy are standards of care. Treatment approaches are less clear for patients who are refractory or who are not candidates for autologous stem cell therapy. Options may include palliative regimens or clinical trial enrollment. One therapy under investigation in diffuse large B-cell lymphoma is lenalidomide, an immunomodulatory agent with antiangiogenic activity. CASE PRESENTATION: We present the case of a 55-year-old Caucasian male patient diagnosed with diffuse large B-cell lymphoma who had an early relapse after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. He then had a subsequent early relapse after cisplatin-based salvage consolidated with autologous stem cell therapy. The efficacy of gemcitabine-cisplatin-rituximab was limited to five months, followed by systemic and central nervous system progression. Fourth-line treatment with lenalidomide plus rituximab and involved field radiotherapy followed by lenalidomide monotherapy greatly improved this patient's quality of life and performance status, allowing over two years of progression-free survival to date (excluding a brief relapse due to treatment interruption). CONCLUSION: A lenalidomide-based regimen was highly effective in this patient with diffuse large B-cell lymphoma. PMID- 25277682 TI - Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune demyelination disorder of the central nervous system (CNS) and its etiology remains unknown. The inflammatory environment in demyelinating lesions leads to the generation of oxygen- and nitrogen-free radicals as well as proinflammatory cytokines, which contribute to the development and progression of multiple sclerosis. Inflammation can lead to oxidative stress and vice versa. Thus, oxidative stress is involved in the inflammation leading demyelination and neurodegeneration in the pathogenesis of multiple sclerosis. SUMMARY: The present study aims to determine two biochemical markers of oxidative stress: TAC and MDA and to show their correlations whether oxidative stress reaction occurs in the demyelination through analyzing samples including peripheral blood and cerebrospinal fluid (CSF) from patients with relapsing-remitting MS (RR-MS). Totally, there were 20 patients in the control groups made from individuals with normal pressure hydrocephalus. Thirty MS patients diagnosed with McDonald diagnostic criteria (2010) treated with methylprednisolone were included in this study. Data were stratified by the degree of severity in order to clarify the role of oxidative stress in the mechanisms of MS and to assess its potential as a biomarker. Thirty clinically definite RRMS patients were enrolled in this study. Levels of MDA, GSH, total antioxidant capacity TAC, GSH-Px and ROS, were determined in serum of the control group and RRMS patients in 7 days before MP (methylprednisolone) treatment and one month after MP treatment. Statistical analysis was performed with one-way analysis of variance (ANOVA), followed by LSD's post hoc tests. KEY MESSAGES: Oxidative stress precedes the inflammatory response in the multiple sclerosis patients. And methylprednisolone treatment can decrease brain antioxidant enzymes to reduce the neuroinflammatory attack. PMID- 25277683 TI - Reduced contralateral cerebrovascular reserve in patients with unilateral steno occlusive disease. AB - The purpose of this study was to evaluate cerebrovascular reactivity (CVR) of major arterial vascular territories, particularly in the contralateral hemodynamically unaffected hemisphere, in patients with unilateral internal carotid artery (ICA) steno-occlusive disease compared to control subjects with risk factors for cerebrovascular disease. METHODS: In this retrospective observational study, twenty-seven patients with right-sided unilateral ICA steno occlusive disease (age range, 25 to 91 years; 17 males) and twenty-one patients with left-sided unilateral ICA steno-occlusive disease (age range, 24 to 83 years; 14 males) and 41 control subjects were studied. CVR was quantitated as the change in blood oxygen level dependent (BOLD) MRI signal (as a surrogate of cerebral blood flow), in response to a consistently applied step change in the arterial partial pressure of carbon dioxide (PaCO2). The CVR of each major arterial vascular territory was assessed in the ipsilateral hemodynamically affected hemisphere and compared to the corresponding territory in the contralateral hemisphere. RESULTS: In patients, a significant reduction in CVR was observed in the ipsilateral anterior circulation compared to that of the corresponding territory on the contralateral side (0.027 +/- 0.083 vs. 0.109 +/- 0.066% BOLD change/mm Hg, p < 0.0001) and to controls (0.195 +/- 0.054% BOLD change/mm Hg, p < 0.0001). The CVR of the contralateral anterior circulation was reduced on average by 50% compared to controls (p < 0.0001). CONCLUSIONS: The implication of these findings is that unilateral carotid stenosis affects the vascular reserve of both sides of the brain compared to control subjects. This indicates that the collateral blood flow support from the contralateral to the ipsilateral hemisphere comes at a cost of reduced reserve capacity in the contralateral hemisphere. The findings suggest that there may be a reduction in functional hyperemia associated with neuronal activation, not only affecting the hemisphere ipsilateral to an occlusion, but also the hemisphere contralateral to an occlusion. It remains to be determined if 'stealing' from the 'rich' to support the 'poor' has clinical consequences over the long term. PMID- 25277685 TI - Occurrence of Mycobacterium avium subspecies paratuberculosis and Neospora caninum in Alberta cow-calf operations. AB - Mycobacterium avium subsp. paratuberculosis (MAP) and Neospora caninum (NC) are two pathogens causing important production limiting diseases in the cattle industry. Significant impacts of MAP and NC have been reported on dairy cattle herds, but little is known about the importance, risk factors and transmission patterns in western Canadian cow-calf herds. In this cross-sectional study, the prevalence of MAP and NC infection in southwest Alberta cow-calf herds was estimated, risk factors for NC were identified, and the reproductive impacts of the two pathogens were assessed. Blood and fecal samples were collected from 840 cows on 28 cow-calf operations. Individual cow and herd management information was collected by self-administered questionnaires and one-on-one interviews. Bayesian estimates of the true prevalence of MAP and NC were computed, and bivariable and multivariable statistical analysis were done to assess the association between the NC serological status and ranch management risk factors, and the clinical effects of the two pathogens. Bayesian estimates of true prevalence indicated that 20% (95% probability interval: 8-38%) of herds had at least one MAP-positive cow, with a within-herd prevalence in positive herds of 22% (8-45%). From the Bayesian posterior distributions of NC prevalence, the median herd-level prevalence was 66% (33-95%) with 10% (4-21%) cow-level prevalence in positive herds. Multivariable analysis indicated that introducing purchased animals in the herd might increase the risk of NC. The negative association of NC with proper carcass disposal and presence of horses on ranch (possibly in relation to herd monitoring and guarding activities), may suggest the importance of wild carnivores in the dynamics of this pathogen in the study area. We also observed an association between MAP and NC serological status and the number of abortions. Additional studies should be done to further examine specific risk factors for MAP and NC, assess the consequences on the reproductive performances in cow-calf herds, and evaluate the overall impact of these pathogens on cow-calf operations. PMID- 25277687 TI - Abstracts of the 9th international congress on spondyloarthritis, 23-25 October, 2014, Gent, Belgium. PMID- 25277684 TI - The function of nicotinamide phosphoribosyltransferase in the heart. AB - In addition to its roles as a coenzyme and an electron transfer molecule, nicotinamide adenine dinucleotide (NAD+) has emerged as a substrate of sirtuins, a family of enzymes that control aging and metabolism. Nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in the NAD+ salvage pathway, plays an important role in controlling the level of NAD+ and the activity of Sirt1 in the heart and the cardiomyocytes therein. Nampt protects the heart from ischemia and reperfusion injury by stimulating Sirt1. In this review, we summarize what is currently known regarding the function of Nampt in the heart. PMID- 25277688 TI - High-volume postdilution hemodiafiltration is a feasible option in routine clinical practice. AB - Hemodiafiltration (HDF) with 20-22 L of substitution fluid is increasingly recognized as associated with significant benefits regarding patient outcome. However, some doubt exists as to whether these high volumes can be achieved in routine clinical practice. A total of 4176 sessions with 366 patients on postdilution HDF were analyzed in this 1-month observational cohort study with prospective data collection. All dialysis machines were equipped with AutoSub plus signal analysis software that automatically and continuously adapts the substitution fluid flow according to the blood flow, blood viscosity, and dialyzer characteristics. Percentages of sessions with different types of vascular access were compared regarding achievement of >=21 L substitution fluid. Logistic regression analysis was conducted to study the independent relationship of selected variables with achievement of >=21 L substitution volume. Patient- and dialysis-related variables that showed an association with the convection volume were entered in a multivariable model that included hematocrit up front. Respectively, 87%, 84%, and 33% of routine sessions conducted with fistulas, grafts, and catheters qualified as high-volume HDF. Serum albumin levels >=4.2 g/dL were positively associated with the achievement of at least 21 L substitution volume. Positive associations were also observed for blood flows in the ranges 350-399 and >=400 mL/min compared with the reference range (300-350 mL/min), for longer treatment time, for fistula versus catheter, for higher filtration fraction, and for dialysis conducted at the end of the week versus Monday. It can be concluded that implementation and sustainability of high-volume HDF is possible in routine clinical practice for almost all patients treated with fistulas and grafts. PMID- 25277689 TI - Effect of reduced dietary protein and supplementation with a docosahexaenoic acid product on broiler performance and meat quality. AB - 1. Chicken breast meat is a lean meat due to its low content of intramuscular fat (IMF) resulting in an overall lower acceptability by consumers due to a decrease in juiciness, flavour and increased chewiness. Recently, studies performed in pigs suggested the possibility of increasing IMF by decreasing dietary crude protein (CP) content, an effect possibly mediated through an increased lipogenesis. 2. Dietary supplementation with lipids rich in omega 3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) may modulate an increase in the content of these fatty acids in meat from monogastric animals and, thus, promote the daily intake of n-3 LC-PUFA by humans. 3. LC-PUFA are very susceptible to oxidation, resulting in off-flavours that affect meat quality and consumers' acceptability. 4. This trial was conducted to assess the effect of reducing dietary CP, from 21% to 17%, on chicken's meat IMF content and, simultaneously, to evaluate if a complementary supplementation with a proprietary n-3 LC-PUFA source (DHA GoldTM) could improve meat quality. These effects were assessed by measuring productive performance and meat quality, oxidative stability, sensory traits and fatty acid profile. 5. A reduction in CP content of broiler diets, from 21% to 17%, balanced for lysine, improved performance while it was not sufficient to increase IMF content in chicken meat. In contrast, DHA GoldTM supplementation had a positive impact both in broiler productive parameters and in meat fatty acid profile. 6. In addition, incorporation of 7.4% of DHA GoldTM in the diet promoted carcass yield but negatively affected chicken meat acceptability by consumers, due to a decrease of meat oxidative stability. 7. Overall the data suggest that neither a dietary supplementation with DHA GoldTM nor a reduction in CP have a direct positive effect in the levels of IMF present in broiler meat. PMID- 25277690 TI - Binding action and emotion in first-episode schizophrenia. AB - BACKGROUND/AIMS: Several components of social cognition are compromised in schizophrenia (SCZ) from the early stage of the illness. In this study we first investigated whether mirror neuron-driven embodied simulation (mnES) is altered in first-episode SCZ. Second, we tested whether emotional cues impact on the mnES in SCZ patients. METHODS: Twenty-two SCZ patients and 22 healthy controls (HCs) observed goal-related actions in either a neutral or emotional context during functional magnetic resonance imaging scanning. RESULTS: Observation of neutral action elicited a lower activity in the frontoparietal network in SCZ patients, as compared to HCs. Particularly, activation in the left inferior parietal lobule in response to the same condition negatively correlated with patients' self experience disturbances. Moreover, observation of an action performed by an angry agent produced poorer neural activity in the right anterior insula in SCZ patients as compared to HCs. This difference was mostly due to the negative beta values shown by SCZ patients, which positively correlated with their empathy scores. No differences were found contingent upon the observation of an action performed by a happy agent. CONCLUSION: Our results show that emotional cues allow SCZ patients to partially recover mnES. However, their understanding of the emotional components of the actions of others will likely remain deficient. PMID- 25277691 TI - Do American States with more religious or conservative populations search more for sexual content on google? AB - In America, religiosity and conservatism are generally associated with opposition to non-traditional sexual behavior, but prominent political scandals and recent research suggest a paradoxical private attraction to sexual content on the political and religious right. We examined associations between state-level religiosity/conservatism and anonymized interest in searching for sexual content online using Google Trends (which calculates within-state search volumes for search terms). Across two separate years, and controlling for demographic variables, we observed moderate-to-large positive associations between: (1) greater proportions of state-level religiosity and general web searching for sexual content and (2) greater proportions of state-level conservatism and image specific searching for sex. These findings were interpreted in terms of the paradoxical hypothesis that a greater preponderance of right-leaning ideologies is associated with greater preoccupation with sexual content in private internet activity. Alternative explanations (e.g., that opposition to non-traditional sex in right-leaning states leads liberals to rely on private internet sexual activity) are discussed, as are limitations to inference posed by aggregate data more generally. PMID- 25277692 TI - The effects of alcohol, relationship power, and partner type on perceived difficulty implementing condom use among African American adults: an experimental study. AB - African American adults are disproportionately affected by HIV in the United States, underscoring the need for additional research on barriers to condom use. Guided by the theory of gender and power, this experimental study used a series of vignettes to test causal hypotheses regarding the influence of event-level alcohol use (present and absent), partner type (serious and casual), and relationship power (low and equal) on perceived difficulty implementing condom use. A total of 299 (151 women and 148 men) heterosexual African American adults indicated how "difficult" it would be to use a condom after reading 8 hypothetical sexual encounters, presented in a random order. A 2 * 2 * 2 * 2 repeated measures analysis of covariance with one between subjects factor (gender) and one covariate (condom use self-efficacy) was used to estimate the effects of these variables on an index of perceived difficulty. The women in the study reported significantly higher ratings of difficulty implementing condom use in vignettes characterized by low relationship power (p < .001) and presence of alcohol use (p < .001); the manipulated independent variables did not produce any main effects for men. Both men and women's ratings of perceived difficulty decreased as condom use self-efficacy increased (p < .001). This is the first study to use an experimental methodology to test hypotheses about barriers to condom use among a community-based sample of African American adults. These data can be used to enhance existing HIV prevention interventions. PMID- 25277693 TI - The Psychometric Structure of Items Assessing Autogynephilia. AB - Autogynephilia, or paraphilic sexual arousal in a man to the thought or image of himself as a woman, manifests in a variety of different behaviors and fantasies. We examined the psychometric structure of 22 items assessing five known types of autogynephilia by subjecting them to exploratory factor analysis in a sample of 149 autogynephilic men. Results of oblique factor analyses supported the ability to distinguish five group factors with suitable items. Results of hierarchical factor analyses suggest that the five group factors were strongly underlain by a general factor of autogynephilia. Because the general factor accounted for a much greater amount of the total variance of the 22 items than did the group factors, the types of autogynephilia that a man has seem less important than the degree to which he has autogynephilia. However, the five types of autogynephilia remain conceptually useful because meaningful distinctions were found among them, including differential rates of endorsement and differential ability to predict other relevant variables like gender dysphoria. Factor-derived scales and subscales demonstrated good internal consistency reliabilities, and validity, with large differences found between autogynephilic men and heterosexual male controls. Future research should attempt to replicate our findings, which were mostly exploratory. PMID- 25277694 TI - Perceptions of consent, permission structures and approaches to the community: a rapid ethical assessment performed in North West Cameroon. AB - BACKGROUND: Understanding local contextual factors is important when conducting international collaborative studies in low-income country settings. Rapid ethical assessment (a brief qualitative intervention designed to map the ethical terrain of a research setting prior to recruitment of participants), has been used in a range of research-naive settings. We used rapid ethical assessment to explore ethical issues and challenges associated with approaching communities and gaining informed consent in North West Cameroon. METHODS: This qualitative study was carried out in two health districts in the North West Region of Cameroon between February and April 2012. Eleven focus group discussions (with a total of 107 participants) were carried out among adult community members, while 72 in-depth interviews included health workers, non-government organisation staff and local community leaders. Data were collected in English and pidgin, translated where necessary into English, transcribed and coded following themes. RESULTS: Many community members had some understanding of informed consent, probably through exposure to agricultural research in the past. Participants described a centralised permission-giving structure in their communities, though there was evidence of some subversion of these structures by the educated young and by women. Several acceptable routes for approaching the communities were outlined, all including the health centre and the Fon (traditional leader). The importance of time spent in sensitizing the community and explaining information was stressed. CONCLUSIONS: Respondents held relatively sophisticated understanding of consent and were able to outline the structures of permission-giving in the community. Although the structures are unique to these communities, the role of certain trusted groups is common to several other communities in Kenya and Ethiopia explored using similar techniques. The information gained through Rapid Ethical Assessment will form an important guide for future studies in North West Cameroon. PMID- 25277695 TI - Sexual partners, sexually transmitted infections, and prostate cancer risk. AB - BACKGROUND: The etiology of prostate cancer (PCa) is poorly understood. Sexual activity and sexually transmitted infections (STIs) are among factors under scrutiny, with controversial findings to date. METHODS: We examined the association between the number and gender of sexual partners, STIs and PCa risk in the context of PROtEuS, a population-based case-control study set amongst the mainly French-speaking population in Montreal, Canada. The study included 1590 histologically-confirmed PCa cases diagnosed in a Montreal French hospital between 2005 and 2009, and 1618 population controls ascertained from the French electoral list, Montreal residents, frequency-matched to cases by age. In-person interviews elicited information on sociodemographic, lifestyle and environmental factors. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between sexually related factors and PCa risk, adjusting for age, ancestry, family history of PCa, and PCa screening history. RESULTS: Subjects with more than 20 sexual partners in their lifetime had a decreased risk of PCa (OR 0.78, 95% CI 0.61-1.00) as did subjects who specifically had more than 20 female sexual partners (OR 0.72, 95% CI 0.56-0.94). By contrast, having had several male sexual partners appeared to confer some excess in risk of PCa. No association emerged for history of STIs and PCa but STIs prevalence was low. CONCLUSION: Our findings are in support of a role for the number of sexual partners in PCa development. The gender of sexual partners should be taken into account in future studies investigating this association. PMID- 25277696 TI - Coffee: A Selected Overview of Beneficial or Harmful Effects on the Cardiovascular System? AB - With a history that began in 800 A.D., coffee is the most popular drink known and as a result, the issues regarding its physiologic effects deserve attention. Maintaining alertness is a wellknown benefit and in addition, the cardiovascular (CV) effects of the active compounds, which include polyphenols and caffeine, must be considered. Genetics are relevant and where slow caffeine metabolism is inherent, the risk of nonfatal myocardial (MI) has been shown to be increased. Overall risk for coronary heart disease (CHD) is not supported and unless there is excessive intake, congestive heart failure (CHF) is not adversely affected; in moderation, there may be some benefit for CHF. There is no apparent increased risk of sudden cardiac death (SCD). Overall, there also appears to be a beneficial inverse association with all-cause mortality, although this is not absolute for extra heavy intake. Benefit in reducing stroke also has supportive evidence. Hypertension is not increased by coffee. Boiled and unfiltered coffee appears to increase plasma cholesterol and triglycerides but for the overall metabolic syndrome, there appears to be benefit. There is also some evidence that paper-filtered coffee results in an increase in some markers of inflammation. Association of coffee with arrhythmias has been a major concern though in moderation it is not a significant overall problem. Therefore, only if a patient were to associate major arrhythmic symptoms with coffee would cessation have to be advised. Where coffee clearly shines from a CV standpoint is in the established decrease in onset of type 2 diabetes mellitus (DM). Any benefit or harm has always been attributed to caffeine as the apparent major component. However, coffee contains a myriad of compounds, including polyphenols. These other substances may be most relevant for potential benefit or harm and some of these may be partially removed or altered by coffee preparation methods such as paper filtration. Multiple studies support this by what appears to be no CV advantage or disadvantage for decaffeinated coffee. The bottom line on coffee, for those who enjoy the brew, is that it is a wonderful beverage with rare associated CV disadvantage and with much to recommend it from an overall CV standpoint. PMID- 25277697 TI - Not Simply a Matter of Fish Intake. AB - BACKGROUND AND AIMS: Recent findings have highlighted enhanced fish consumption as a potential measure to increase intake of healthy fatty acids, particularly omega-3. The generalizability of this recommendation, however, may fall short of differences in fish species and cooking techniques. Hence, we investigated how these 2 variables affect the lipid content in fish flesh. METHODS AND RESULTS: Nine species of freshwater, deep sea or shore fish were grilled, steamed or fried with or without the addition of soybean oil, olive oil or butter. The lipid composition was analysed and a significant difference was observed in cholesterol, saturated fatty acids, polyunsaturated fatty acids, omega-3 fatty acids and omega-6 fatty acids contents between species (p<0.05). The use of soybean or olive oil was associated with a significant change in flesh concentration of polyunsaturated, omega-3 and omega-6 fatty acids (p<0.05). CONCLUSION: This study calls attention to the specific lipid content that must be expected from different fish species and cooking techniques. PMID- 25277698 TI - Acute pain management in burn patients: appraisal and thematic analysis of four clinical guidelines. AB - OBJECTIVE: Burn patients suffer excruciating pain due to their injuries and procedures related to surgery, wound care, and mobilization. Acute Stress Disorder, Post-Traumatic Stress Disorder, chronic pain and depression are highly prevalent among survivors of severe burns. Evidence-based pain management addresses and alleviates these complications. The aim of our study was to compare clinical guidelines for pain management in burn patients in selected European and non-European countries. We included pediatric guidelines due to the high rate of children in burn units. METHOD: The study had a comparative retrospective design using combined methodology of instrument appraisal and thematic analysis. Three investigators appraised guidelines from burn units in Denmark (DK), Sweden (SE), New Zealand (NZ), and USA using the AGREE Instrument (Appraisal of Guidelines for Research & Evaluation), version II, and identified core themes in the guidelines. RESULTS: The overall scores expressing quality in six domains of the AGREE instrument were variable at 22% (DK), 44% (SE), 100% (NZ), and 78% (USA). The guidelines from NZ and USA were highly recommended, the Swedish was recommended, whereas the Danish was not recommended. The identified core themes were: continuous pain, procedural pain, postoperative pain, pain assessment, anxiety, and non-pharmacological interventions. CONCLUSION: The study demonstrated variability in quality, transparency, and core content in clinical guidelines on pain management in burn patients. The most highly recommended guidelines provided clear and accurate recommendations for the nursing and medical staff on pain management in burn patients. We recommend the use of a validated appraisal tool such as the AGREE instrument to provide more consistent and evidence-based care to burn patients in the clinic, to unify guideline construction, and to enable interdepartmental comparison of treatment and outcomes. PMID- 25277699 TI - Reply: home hydrotherapy in the postoperative rehabilitation phase of the burn injury patients. PMID- 25277700 TI - Recent progress in ferrofluids research: novel applications of magnetically controllable and tunable fluids. AB - Ferrofluids are suspensions of magnetic nanoparticles that have the attractive feature of being controlled by applied magnetic fields. Ferrofluids have been studied for decades in an ever growing number of applications that take advantage of their response to applied magnetic fields. Here, we provide a summary of recent advances in established and emerging applications of ferrofluids, including applications in optics, sensors, actuators, seals, lubrication, and static/dynamic magnetically driven assembly of structures. PMID- 25277701 TI - Rapid development of a simple ranula in a child. AB - OBJECTIVE: A simple ranula is a gradually progressive, benign condition of the salivary gland. The report here describes a very rare case of a simple ranula enlarging in an acute fashion, resulting in airway obstruction. CASE REPORT: A 7 year-old girl presented with swelling in the floor of the mouth, pushing the tongue upward and backward, requiring immediate nasotracheal intubation. Magnetic resonance imaging suggested a simple ranula requiring urgent surgery. The patient was followed up 4 weeks after discharge, at which time she was doing well. CONCLUSION: To the best of the authors' knowledge, this is the first case reported of a simple ranula presenting in an acute fashion, leading to airway compromise in a pediatric patient. The literature is reviewed and features of diagnosis and treatment are presented. PMID- 25277702 TI - Temporary inactivation of NCM, an auditory region, increases social interaction and decreases song perception in female zebra finches. AB - The caudomedial nidopallium (NCM) is an important site for the storage of auditory memories, particularly song, in passerines. In zebra finches, males sing and females do not, but females use song to choose mates. The extent to which the NCM is necessary for female mate choice is not well understood. To investigate the role of NCM in partner preferences, adult female zebra finches were bilaterally implanted with chronic cannulae directed at the NCM. Lidocaine, a sodium channel blocker, or saline (control) was infused into the NCM of females using a repeated measures design. Females were then tested in 3 separate paradigms: song preference, sexual partner preference, and pairing behavior/partner preference. We hypothesized that lidocaine would increase interactions with males by decreasing song discrimination and that this would be further evident in the song discrimination task. Indeed, females, when treated with lidocaine, had no preference for males singing unaltered song over males singing distorted song. These same females, when treated with saline, demonstrated a significant preference for males singing normal song. Furthermore, females affiliated with males more after receiving lidocaine than after receiving saline in the pairing paradigm, although neither treatment led to the formation of a partner preference. Our results support the hypothesis that NCM plays an important role not only in song discrimination, but also affiliation with a male. PMID- 25277703 TI - Dose-dependent response of tissue-engineered intervertebral discs to dynamic unconfined compressive loading. AB - Because of the limitations of current surgical methods in the treatment of degenerative disc disease, tissue-engineered intervertebral discs (TE-IVDs) have become an important target. This study investigated the biochemical and mechanical responses of composite TE-IVDs to dynamic unconfined compression. TE IVDs were manufactured by floating an injection molded alginate nucleus pulposus (NP) in a type I collagen annulus fibrosus (AF) that was allowed to contract for 2 weeks before loading. The discs were mechanically stimulated at a range of strain amplitude (1-10%) for 2 weeks with a duty cycle of 1 h on-1 h off-1 h on before being evaluated for their biochemical and mechanical properties. Mechanical loading increased all properties in a dose-dependent manner. Glycosaminoglycans (GAGs) increased between 2.8 and 2.2 fold in the AF and NP regions, respectively, whereas the hydroxyproline content increased between 1.2 and 1.8 fold. The discs also experienced a 2-fold increase in the equilibrium modulus and a 4.3-fold increase in the instantaneous modulus. Full effects for all properties were seen by 5% strain amplitude. These data suggest that dynamic loading increases the functionality of our TE-IVDs with region-dependent responses using a method that may be scaled up to larger disc models to expedite maturation for implantation. PMID- 25277704 TI - Detection of Hepatitis B Virus Large Surface Protein Using a Time-Resolved Immunofluorometric Assay. AB - BACKGROUND: To establish a novel method based on time-resolved immunofluorometric assay (TR-IFMA) with higher sensitivity and a broader detection range for detecting serum hepatitis B virus large surface protein (L protein). METHODS: The precision, sensitivity, specificity, coefficient of recovery, and stability of the assay were evaluated and comparison with the classical enzyme-linked immunosorbent assay (ELISA) was also executed. RESULTS: The precision, specificity, and sensitivity of the TR-IFMA were clearly better than ELISA. Particularly, the sensitivity was 0.1 ng/ml; moreover, the specificity was 100%, 96%, 92.5%, 96.9%, 97.8%, and 100% in the sera of healthy blood donors, systemic lupus erythematosus (SLE) patients, rheumatoid arthritis (RA) patients, hepatitis C virus (HCV) patients, cytomegalovirus (CMV) infection patients, and pregnant patients, respectively. Meanwhile, we observed that the established TR-IFMA kit has a wider acceptable linear range of 0.63-10,367 ng/ml rather than the regular commercial ELISA kit having range of only 10.12-1095.9 ng/ml. Subsequently, correlation coefficient between the TR-IFMA and ELISA was 0.8009. The intra- and interassay precision rates were less than 5% for three different concentrations. The average recovery rate for L protein was 101.17%. In sum, the established assay kit performed better in terms of stability than the commercial ELISA kit. CONCLUSION: The TR-IFMA that we developed for L protein presented a higher sensitivity and wider detecting range than regular commercial ELISA. Therefore, this TR-IFMA has promising value both in the screening of HBV and monitoring of antiviral therapy. PMID- 25277707 TI - NICE will develop 70 more quality standards on public health. PMID- 25277706 TI - Hypotension does not always make computed tomography scans unfeasible in the management of blunt abdominal trauma patients. AB - INTRODUCTION: Computed tomography (CT) scans have been used worldwide to evaluate patients with blunt abdominal trauma (BAT). However, CT scans have traditionally been considered to be a part of a secondary survey that can only be performed after the patient's haemodynamics have stabilised. In this study, we attempted to evaluate the role of the CT scan in managing BAT patients with hypotension. MATERIAL AND METHODS: Patients who fulfilled the criteria for a major torso injury in our institution were treated according to the Advanced Trauma Life Support guidelines. The selection of diagnostic modalities for patients with stable and unstable haemodynamics was discussed. Furthermore, patients with hypotension after resuscitation who were administered haemostasis procedures were the focus of our analysis. We also delineated the influence of CT scans on the time interval between arrival and definitive treatment for these patients. RESULTS: During the study period, 909 patients were enrolled in this study. Ninety-one patients (10.0%, 91/909) had a systolic blood pressure (SBP) <90mmHg after resuscitation. Fifty-eight of the patients (63.7%) received CT scans before they received definitive treatment. There was no significant difference in the CT scan application rate between the patients with and without hypotension after resuscitation (63.7% vs. 68.8%, p=0.382). Among the 79 patients with hypotension after resuscitation who underwent a haemostasis procedure (surgery or angioembolisation), there was no significant difference in the time between arrival and definitive haemostasis between the patients who received CT scans and those who did not (surgery: 57.8 (standard deviation (SD) 6.4) vs. 61.6 (SD 14.5)min, p=0.218; angioembolisation: [147.0 (SD 33.4) vs. 139.3 (SD 16.7)min, p=0.093). CONCLUSION: The traditional priority of diagnostic modalities used to manage BAT patients should be reconsidered because of advancements in facilities and understanding of BAT. With shorter scanning times and transportation distances, hypotension does not always make performing a CT scan unfeasible. PMID- 25277705 TI - Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection. AB - BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-beta (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-beta). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1beta, IL-4, IL-5, IL-6, IL-12(p40), IFN-gamma, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1beta, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-gamma. Silencing of retinoic acid-inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection. PMID- 25277708 TI - Characterization of fluorescent-dissolved organic matter and identification of specific fluorophores in textile effluents. AB - This study focused on the characterization of fluorescent-dissolved organic matter and identification of specific fluorophores in textile effluents. Samples from different textile wastewater treatment plants were characterized by high performance liquid chromatography and size exclusion chromatography as well as fluorescence excitation-emission matrix spectra. Despite the highly heterogeneous textile effluents, the fluorescent components and their physicochemical properties were found relatively invariable, which is beneficial for the combination of biological and physicochemical treatment processes. The humic-like substance with triple-excitation peaks (excitation (Ex) 250, 310, 365/emission (Em) 460 nm) presented as the specific fluorescence indicator in textile effluents. It was also the major contributor to UV absorbance at 254 nm and resulted in the brown color of biologically treated textile effluents. By spectral comparison, the specific fluorophore in textile effluents could be attributed to the intermediate structure of azo dyes 1-amino-2-naphthol, which was transferred into the special humic-like substances during biological treatment. PMID- 25277709 TI - Do coal consumption and industrial development increase environmental degradation in China and India? AB - The present study is aimed to explore the relationship between coal consumption, industrial production, and CO2 emissions in China and India for the period of 1971-2011. The structural break unit root test and cointegrating approach have been applied. The direction of causal relationship between the variables is investigated by applying the VECM Granger causality test. Our results validate the presence of cointegration among the series in both countries. Our results also validate the existence of inverted U-shaped curve between industrial production and CO2 emissions for India, but for China, it is a U-shaped relationship. Coal consumption adds in CO2 emissions. The causality analysis reveals that industrial production and coal consumption Granger cause CO2 emissions in India. In the case of China, the feedback effect exists between coal consumption and CO2 emissions. Due to the importance of coal in China and India, any reduction in coal consumption will negatively affect their industrial value added as well as economic growth. PMID- 25277710 TI - Partitioning of the pesticide trifluralin between dissolved organic matter and water using automated SPME-GC/MS. AB - Solid-phase microextraction (SPME) was used to determine the equilibrium association constant for a pesticide, trifluralin (TFR), with dissolved organic matter (DOM). After optimization of the SPME method for the analysis of TFR, partition coefficients (K DOM) with three different sources of DOM were determined in buffered solutions at pH 7. Commercial humic acids and DOM fractions isolated from two surface waters were used. The values of log K DOM varied from 4.3 to 5.8, depending on the nature of the organic material. A good correlation was established between log K DOM and DOM properties (as measured with the H/O atomic ratio and UV absorbance), in agreement with literature data. This is consistent with the effect of polarity and aromaticity for governing DOM pollutant associations, regardless of the origin of DOM. This association phenomenon is relevant to better understand the behavior of pesticides in the environment since it controls part of pesticide leaching and fate in aquatic systems. PMID- 25277711 TI - Variation of nonylphenol-degrading gene abundance and bacterial community structure in bioaugmented sediment microcosm. AB - Nonylphenol (NP) can accumulate in river sediment. Bioaugmentation is an attractive option to dissipate heavy NP pollution in river sediment. In this study, two NP degraders were isolated from crude oil-polluted soil and river sediment. Microcosms were constructed to test their ability to degrade NP in river sediment. The shift in the proportion of NP-degrading genes and bacterial community structure in sediment microcosms were characterized using quantitative PCR assay and terminal restriction fragment length polymorphism analysis, respectively. Phylogenetic analysis indicated that the soil isolate belonged to genus Stenotrophomonas, while the sediment isolate was a Sphingobium species. Both of them could almost completely clean up a high level of NP in river sediment (150 mg/kg NP) in 10 or 14 days after inoculation. An increase in the proportion of alkB and sMO genes was observed in sediment microcosms inoculated with Stenotrophomonas strain Y1 and Sphingobium strain Y2, respectively. Moreover, bioaugmentation using Sphingobium strain Y2 could have a strong impact on sediment bacterial community structure, while inoculation of Stenotrophomonas strain Y1 illustrated a weak impact. This study can provide some new insights towards NP biodegradation and bioremediation. PMID- 25277714 TI - Central American ants of the genus Megalomyrmex Forel (Hymenoptera: Formicidae): six new species and keys to workers and males. AB - Megalomyrmex Forel is a distinctive lineage of Neotropical ants, some of which are specialized parasites or predators of the fungus-growing ants Attini. Here we review and key the Central American fauna. Six new species are described from both female castes: M. brandaoi sp. n., M. fungiraptor sp. n., M. longinoi sp. n., M. milenae sp. n., M. megadrifti sp. n. and M. osadrifti sp. n. A worker based key to all Central American species is presented, and all species are illustrated. Megalomyrmex drifti Kempf is redescribed and the first descriptions of queens for M. miri Brandao and M. foreli Emery are provided. New biological information, several new geographic records, and a discussion of the species group schema of Brandao (1990) are presented. The male sex of Megalomyrmex is diagnosed at the genus-level and keyed to species for the Central American fauna, where known. The male of each species treated in the key is diagnosed, described, or redescribed. Males are known for fourteen out of twenty total Central American Megalomyrmex species. A distinct but unassociated male is described and keyed (M. male 01). The males of M. miri Brandao and M. wettereri Brandao are described for the first time, and the distinctness of these two species is confirmed. One potential synapomorphy of Megalomyrmex present in males and workers is the presence of a carina which posteriorly delimits the basalmost region of the petiolar dorsum. PMID- 25277713 TI - Polycyclic aromatic hydrocarbons in Chinese surface soil: occurrence and distribution. AB - In this study, 16 polycyclic aromatic hydrocarbons (PAHs) were analyzed in 157 concurrently collected soil samples in 2005 over China. Higher concentration of ?16PAHs was found in urban soil, followed by rural and background soil. The results indicated that PAHs in Chinese surface soil showed a primary distribution pattern, which was confirmed by the positive correlation with emission inventory. Based on the results of literature over the past 10 years (2004-2013) in China, the spatial distribution of PAHs in urban and rural soil was established. An obvious geographical distribution with PAH concentration was found, as higher in Eastern China and lower in Middle and Western China. Furthermore, PAH pollution in Chinese riverbank soil was summarized and showed higher levels, indicating their potential sources from polluted rivers. According to our knowledge, this is the first time to comprehensively study the PAH pollution status in Chinese surface soil on the national scale based on monitoring results. PMID- 25277712 TI - Phytoremediation: role of terrestrial plants and aquatic macrophytes in the remediation of radionuclides and heavy metal contaminated soil and water. AB - Nuclear power reactors are operating in 31 countries around the world. Along with reactor operations, activities like mining, fuel fabrication, fuel reprocessing and military operations are the major contributors to the nuclear waste. The presence of a large number of fission products along with multiple oxidation state long-lived radionuclides such as neptunium ((237)Np), plutonium ((239)Pu), americium ((241/243)Am) and curium ((245)Cm) make the waste streams a potential radiological threat to the environment. Commonly high concentrations of cesium ((137)Cs) and strontium ((90)Sr) are found in a nuclear waste. These radionuclides are capable enough to produce potential health threat due to their long half-lives and effortless translocation into the human body. Besides the radionuclides, heavy metal contamination is also a serious issue. Heavy metals occur naturally in the earth crust and in low concentration, are also essential for the metabolism of living beings. Bioaccumulation of these heavy metals causes hazardous effects. These pollutants enter the human body directly via contaminated drinking water or through the food chain. This issue has drawn the attention of scientists throughout the world to device eco-friendly treatments to remediate the soil and water resources. Various physical and chemical treatments are being applied to clean the waste, but these techniques are quite expensive, complicated and comprise various side effects. One of the promising techniques, which has been pursued vigorously to overcome these demerits, is phytoremediation. The process is very effective, eco-friendly, easy and affordable. This technique utilizes the plants and its associated microbes to decontaminate the low and moderately contaminated sites efficiently. Many plant species are successfully used for remediation of contaminated soil and water systems. Remediation of these systems turns into a serious problem due to various anthropogenic activities that have significantly raised the amount of heavy metals and radionuclides in it. Also, these activities are continuously increasing the area of the contaminated sites. In this context, an attempt has been made to review different modes of the phytoremediation and various terrestrial and aquatic plants which are being used to remediate the heavy metals and radionuclide-contaminated soil and aquatic systems. Natural and synthetic enhancers, those hasten the process of metal adsorption/absorption by plants, are also discussed. The article includes 216 references. PMID- 25277716 TI - Executive functioning in children with developmental dyslexia. AB - The term "executive function" has been used to describe several higher-order cognitive processes. This study examined the processing speed, shifting, planning, and verbal fluency of a sample of 50 Portuguese children with developmental dyslexia (DD) and 50 typically developing children (TDC; chronological-age-matched controls) between 8 and 12 years of age to evaluate the children's executive functioning. Compared to TDC, children with DD revealed significant processing speed, shifting, and verbal fluency deficits. After controlling for differences in the general intellectual ability, significant group differences remained for shifting, verbal fluency and marginally for processing speed. No significant differences in planning ability were observed between the groups. No significant interaction of group, gender, and age was found for any of the executive functions measures studied. Word productivity in both semantic and phonemic verbal fluency tasks decreased significantly over the 60 seconds for both groups. Shifting was the only significant predictor of DD in the binary logistic regression analysis and yielded the highest area under the curve value (receiver operating characteristics curve analysis). Therefore, although these findings highlight the presence of specific executive functions deficits in children with DD, they should not be interpreted as indicative of the presence or absence of this learning disorder. PMID- 25277715 TI - Molecular characterization of clinical isolates of Moraxella catarrhalis by randomly amplified polymorphic DNA fingerprinting. AB - Moraxella catarrhalis, a less virulent microorganism that colonizes the upper respiratory tract, has recently been associated with lower respiratory disease, especially in HIV-positive immunocompromised individuals and children. Here, we correlated the DNA clustering pattern of 24 clinical isolates of M. catarrhalis for beta-lactamase production and drug resistance, from different disease groups using three different arbitrarily selected primers, P1 (5'-TCACGATGCA-3'), P14 (5'-GATCAAGTCC-3') and P17 (5'-GATCTGACAC-3'). M. catarrhalis revealed three distinct banding patterns with primer P1, four with P14 and P17. 71% (n = 17) of the isolates revealed pattern 2 with primer P1, which discriminated majority (12/21) of the isolates grouped under the major branch of the dendrogram. The minor branch had only three isolates. Separation of M. catarrhalis into two subpopulations (major and minor clusters) with primer P1 is suggestive of diverse genetic lineage. A high level of concordance between RAPD and antibiotic profile was observed. Clustering of M. catarrhalis recovered from different disease groups reflect the identical clinical background or the common geographical/temporal factors. The presence or absence of beta-lactamase in a cluster confirmed their single source of origin. PMID- 25277717 TI - Psychometric evaluation, using Rasch analysis, of the WHOQOL-BREF in heroin dependent people undergoing methadone maintenance treatment: further item validation. AB - BACKGROUND: The brief version of World Health Organization Quality of Life assessment (WHOQOL-BREF), a useful outcome measure for clinical decision making, has been evaluated using classical test theory (CTT) for psychometric properties on heroin-dependent patients. However, CTT has a major disadvantage of invalid summated score, and using Rasch models can overcome the shortcoming. The purpose of this study was using Rasch models to evaluate the psychometric properties of the WHOQOL-BREF for heroin-dependent patients, and the hypothesis was that each WHOQOL-BREF domain is unidimensional. METHODS: Two hundred thirty six participants (24 females, mean [SD] age = 38.07 [7.44] years, first used heroin age = 26.13 [6.32] years), with a diagnosis of opioid dependence, were recruited from a methadone maintenance treatment program. Each participant filled out the WHOQOL-BREF. Parallel analysis (PA) and Rasch rating scale models were used for statistical analyses. RESULTS: Based on the PA analyses, four domains of the WHOQOL-BREF were unidimensional. The Rasch analyses showed three negatively worded items (2 in Physical and 1 in Psychological) reported as misfits that may not contribute to the Physical and Psychological domains; one positively worded item in the Physical domain may be redundant. All values for the separation indices were above 2 except for the person separation index in the Physical domain (1.93). Category functioning and item independency of four WHOQOL-BREF domains were supported by the Rasch analyses, and there were 5 items showing the differential item function (DIF) for positive versus negative HIV (human immunodeficiency virus) infection. CONCLUSIONS: The WHOQOL-BREF is a valid outcome measure for assessing general quality of life for substance abusers in terms of physical, psychological, social, and environmental factors. It can also be used as a treatment outcome measure to evaluate the effect of treatments for substance abusers. However, the three misfit negatively worded items should be used with caution because the substance abuser may not fully understand their meaning. Future research may apply cognitive interviews to determine the cognitive functioning of substance abusers and their interpretation of negatively worded items. PMID- 25277719 TI - A two-layer classification framework for protein fold recognition. AB - Protein fold recognition is one of the interesting studies in bioinformatic to predicting the tertiary structure of proteins. In this paper, an individual method and a fusion method are proposed for protein fold recognition. A Two Layer Classification Framework (TLCF) is proposed as individual method. This framework comprises of two layers: in the first layer, the structural class of protein is predicted. The classifier in this layer classifies the instances into four structural classes: all alpha, all beta, alpha/beta, and alpha+beta. Then, the classification results will be added as a new feature to further training and testing datasets. Using the results of the first layer, we employ another classifier for predicting 27 folding classes in the second layer. The results indicate that the proposed approach is very effective to improve the prediction accuracy where the measured values of MCC, specificity, and sensitivity are promising. TLCF(*) is proposed as a fusion method that exploits TLCF as a base model. The experimental results indicate that the proposed methods improve prediction accuracy by 2-10% on a benchmark dataset. PMID- 25277718 TI - Transient silencing of CHALCONE SYNTHASE during fruit ripening modifies tomato epidermal cells and cuticle properties. AB - Tomato (Solanum lycopersicum) fruit ripening is accompanied by an increase in CHALCONE SYNTHASE (CHS) activity and flavonoid biosynthesis. Flavonoids accumulate in the cuticle, giving its characteristic orange color that contributes to the eventual red color of the ripe fruit. Using virus-induced gene silencing in fruits, we have down-regulated the expression of SlCHS during ripening and compared the cuticles derived from silenced and nonsilenced regions. Silenced regions showed a pink color due to the lack of flavonoids incorporated to the cuticle. This change in color was accompanied by several other changes in the cuticle and epidermis. The epidermal cells displayed a decreased tangential cell width; a decrease in the amount of cuticle and its main components, cutin and polysaccharides, was also observed. Flavonoids dramatically altered the cuticle biomechanical properties by stiffening the elastic and viscoelastic phase and by reducing the ability of the cuticle to deform. There seemed to be a negative relation between SlCHS expression and wax accumulation during ripening that could be related to the decreased cuticle permeability to water observed in the regions silencing SlCHS. A reduction in the overall number of ester linkages present in the cutin matrix was also dependent on the presence of flavonoids. PMID- 25277720 TI - Cognitive remediation in anorexia nervosa and related conditions: a systematic review. AB - Research evidence for cognitive remediation therapy's (CRT) effectiveness for anorexia nervosa (AN) has been gathering. This approach is also increasingly being implemented in other disorders including major depressive disorder, obsessive-compulsive disorder and autistic spectrum disorder that share commonalities with AN in neuropsychological profiles and clinical presentations. This systematic literature review identified and appraised the current evidence base to see whether evidence from related conditions could be integrated into the theoretical understanding of CRT for AN as well as future AN treatment developments and research. Overall, CRT studies in AN report promising findings, and CRT appears to be associated with improvements in set-shifting and in central coherence. Cognitive remediation approaches in other conditions also show promising evidence in associated improvements in areas of executive functioning and information processing; links are made between AN treatment and what future treatment developments could consider. PMID- 25277722 TI - Personalized symptoms forecasting for pollen-induced allergic rhinitis sufferers. AB - Hay fever is a pollen-induced allergic reaction that strongly affects the overall quality of life of many individuals. The disorder may vary in severity and symptoms depending on patient-specific factors such as genetic disposition, individual threshold of pollen concentration levels, medication, former immunotherapy, and others. Thus, information services that improve the quality of life of hay fever sufferers must address the needs of each individual separately. In this paper, we demonstrate the development of information services that offer personalized pollen-induced symptoms forecasts. The backbone of these services consists of data of allergic symptoms reported by the users of the Personal Hay Fever Diary system and pollen concentration levels (European Aeroallergen Network) in several sampling sites. Data were analyzed using computational intelligence methods, resulting in highly customizable forecasting models that offer personalized warnings to users of the Patient Hay Fever Diary system. The overall system performance for the pilot area (Vienna and Lower Austria) reached a correlation coefficient of r = 0.71 +/- 0.17 (average +/- standard deviation) in a sample of 219 users with major contribution to the Pollen Hay Fever Diary system and an overall performance of r = 0.66 +/- 0.18 in a second sample of 393 users, with minor contribution to the system. These findings provide an example of combining data from different sources using advanced data engineering in order to develop innovative e-health services with the capacity to provide more direct and personalized information to allergic rhinitis sufferers. PMID- 25277721 TI - Retrotransposon-based profiling of mammalian epigenomes: DNA methylation of IAP LTRs in embryonic stem, somatic and cancer cells. AB - In the current study, we have used HT-TREBS to individually analyze the DNA methylation pattern of 4799 IAP LTR retrotransposons in embryonic stem, somatic and Neuro2A cells. According to the results, half of the loci within this family show constant methylation patterns between the three cell types whereas the remaining half display variable levels of methylation. About half of the variably methylated IAP LTRs tend to be hypomethylated in ES cells, and nearly all in this group are hypomethylated in Neuro2A cells. The observed hypomethylation in both cell types occur in a non-uniform, locus-specific manner and to various degrees of severity, with some of them being easily detectible by COBRA. Overall, this study demonstrates the feasibility of HT-TREBS to study DNA methylation changes at retrotransposons in a locus-specific manner in multiple cell types and further suggests the potential utility of this technique in developing epigenetic biomarkers for tracking disease progression. PMID- 25277723 TI - Noble-metal-free BODIPY-cobaloxime photocatalysts for visible-light-driven hydrogen production. AB - In this study a series of supramolecular BODIPY-cobaloxime systems Co-Bn (n = 1 4): [{Co(dmgH)2Cl}{4,4-difluoro-8-(4-pyridyl)-1,3,5,7-tetramethyl-4-bora-3a,4a diaza-s-indacene}] (Co-B1), [{Co(dmgH)2Cl}{4,4-difluoro-8-(4-pyridyl)-1,3,5,7 tetramethyl-2,6-diiodo-4-bora-3a,4a-diaza-s-indacene}] (Co-B2), [{Co(dmgH)2Cl}{4,4-difluoro-8-(3-pyridyl)-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza s-indacene}] (Co-B3), and [{Co(dmgH)2Cl}{4,4-difluoro-8-(3-pyridyl)-1,3,5,7 tetramethyl-2,6-diiodo-4-bora-3a,4a-diaza-s-indacene}] (Co-B4) (BODIPY = boron dipyrromethene, dmgH = dimethylglyoxime) have been synthesized by replacing one axial chlorine of cobaloxime moieties with the pyridine residues of BODIPYs, and structurally characterized. Absorption spectra show that the optical properties of the BODIPY-cobaloximes are essentially the sum of their constituent components, indicating weak interactions between the cobaloxime units and BODIPY chromophores in the ground state. If any, electronic communications may take place through the intramolecular electron transfer across their orthogonal structures. The possibility of intramolecular electron transfer is further supported by the results of the density functional theory (DFT) calculations at UB3LYP/LANL2DZ levels on Co-B2(-) and Co-B4(-), which show that the highest occupied molecular orbitals (HOMOs) possess predominantly BODIPY character, while the lowest unoccupied molecular orbitals (LUMOs) are located on the cobalt centers. The HOMO -> LUMO transition is an electron-transfer process (BODIPY(-) radical anions -> cobaloxime fragments). In view of the possible occurrence of electron transfer, these noble-metal-free BODIPY-cobaloximes are studied as single-component homogeneous photocatalysts for H2 generation in aqueous media. Under optimized conditions, the 2,6-diiodo BODIPY-sensitized cobaloxime Co-B4 that contains a meta-pyridyl at the 8-position of BODIPY presents excellent H2 photoproduction catalytic activity with a turnover number (TON) of 85, which is comparable to that of its analogue Co-B2 that has a para-pyridyl attached onto 2,6-diiodo BODIPY (TON = 82); however, both of the noniodinated BODIPY-sensitizer cobaloximes (Co-B1, Co-B3) exhibit a complete lack of activity under the same experimental conditions. These results show that the presence of heavy atoms in the core of BODIPY is essential for the catalytic process and reductive quenching pathways (namely, the intramolecular electron transfers from BODIPY(-) species to the cobalt centers) for these photocatalytically active systems of Co-Bn (n = 2 and 4) are thermodynamically feasible for the hydrogen-evolving reaction. PMID- 25277724 TI - Targeting specific nutrient deficiencies in protein-restricted diets: some practical facts in PKU dietary management. AB - Among aminoacidopathies, phenylketonuria (PKU) is the most prevalent one. Early diagnosis in the neonatal period with a prompt nutritional therapy (low natural protein and phenylalanine diet, supplemented with phenylalanine-free amino acid mixtures and special low-protein foods) remains the mainstay of the treatment. Data considering nutrient contents of cooked dishes is lacking. In this study, fourteen dishes specifically prepared for PKU individuals were analysed, regarding the lipid profile and iron and zinc contents. These dishes are poor sources of essential nutrients like Fe, Zn or n-3 fatty acids, reinforcing the need for adequate supplementation to cover individual patients' needs. This study can contribute to a more accurate adjustment of PKU diets and supplementation in order to prevent eventual nutritional deficiencies. This study contributes to a better understanding of nutrient intake from PKU patients' meals, showing the need for dietary supplementation. PMID- 25277725 TI - Postoperative intubation time is associated with acute kidney injury in cardiac surgical patients. AB - INTRODUCTION: Acute kidney injury (AKI) is a frequent complication after cardiac surgery and is associated with a poor prognosis. Mechanical ventilation is an important risk factor for developing AKI in critically ill patients. Ventilation with high tidal volumes has been associated with postoperative organ dysfunction in cardiac surgical patients. No data are available about the effects of the duration of postoperative respiratory support in the immediate postoperative period on the incidence of AKI in patients after cardiac surgery. METHOD: We performed a secondary analysis of 584 elective cardiac surgical patients enrolled in an observational trial on the association between preoperative cerebral oxygen saturation and postoperative organ dysfunction and analyzed the incidence of AKI in patients with different times to extubation. The latter variable was graded in 4 h intervals (if below 16 h) or equal to or greater than 16 h. AKI was staged according to the AKI Network criteria. RESULTS: Overall, 165 (28.3%) patients developed AKI (any stage), 43 (7.4%) patients needed renal replacement therapy. Patients developing AKI had a significantly (P <0.001) lower renal perfusion pressure (RPP) in the first 8 hours after surgery (57.4 mmHg (95% CI: 56.0 to 59.0 mmHg)) than patients with a postoperatively preserved renal function (60.5 mmHg ((95% CI: 59.9 to 61.4 mmHg). The rate of AKI increased from 17.0% in patients extubated within 4 h postoperatively to 62.3% in patients ventilated for more than 16 h (P <0.001). Multivariate logistic regression analysis of variables significantly associated with AKI in the univariate analysis revealed that the time to the first extubation (OR: 1.024/hour, 95% CI: 1.011 to 1.044/hour; P <0.001) and RPP (OR: 0.963/mmHg; 95% CI: 0.934 to 0.992; P <0.001) were independently associated with AKI. CONCLUSION: Without taking into account potentially unmeasured confounders, these findings are suggestive that the duration of postoperative positive pressure ventilation is an important and previously unrecognized risk factor for AKI in cardiac surgical patients, independent from low RPP as an established AKI trigger, and that even a moderate delay of extubation increases AKI risk. If replicated independently, these findings may have relevant implications for clinical care and for further studies aiming at the prevention of cardiac surgery associated AKI. PMID- 25277726 TI - Women, drugs and HIV. AB - BACKGROUND: Women who use drugs, irrespective of whether these are injected or not, are faced with multiple issues which enhance their vulnerability to HIV. METHODS: In this commentary, we explore the HIV risks and vulnerabilities of women who use drugs as well as the interventions that have been shown to reduce their susceptibility to HIV infection. RESULTS: Women who inject drugs are among the most vulnerable to HIV through both unsafe injections and unprotected sex. They are also among the most hidden affected populations, as they are more stigmatized than their male counterparts. Many sell sex to finance their own and their partner's drug habit and often their partner exerts a significant amount of control over their sex work, condom use and injection practices. Women who use drugs all over the world face many different barriers to HIV service access including police harassment, judgmental health personnel and a fear of losing their children. CONCLUSION: In order to enable these women to access life-saving services including needle-syringe and condom programs, opioid substitution therapy and HIV testing and treatment, it is essential to create a conducive environment and provide tailor-made services that are adapted to their specific needs. PMID- 25277728 TI - [New horizons for minimally invasive treatment of acromioklavikular joint injuries]. AB - BACKGROUND: A novel radiation-free electromagnetic navigation system (ENS) method was developed and the feasibility and accuracy for transklavikular-transkorakoid drilling procedures were evaluated in an experimental setting. METHODS: In this study ten arthroscopically assisted, electromagnetically navigated transkorakoid transklavikular drilling procedures with subsequent implantation of two TightRope(r) (Arthrex, Naples, FL.) devices (anatomical reconstruction) were performed on five human cadavers. Postoperative computed tomography (CT) scan analysis was carried out to determine tunnel placement accuracy. All procedures were performed without fluoroscopy. RESULTS: The mean overall operation time was 28.5 +/- 6.6 min. Successful anatomical tunnel placement was achieved in 98.8 %. During the navigated drilling procedure no misguidance of the drill requiring directional readjustments or restarts occurred. No cortical breaches, fractures or complications occurred. CONCLUSION: The electromagnetically navigated transkorakoid-transklavikular drilling procedure used in this study demonstrated high targeting accuracy, required no intraoperative x-ray radiation and was associated with no complications. PMID- 25277727 TI - [More patients in a shorter inpatient stay with better outcome in treatment of femoral neck fracture: external quality assurance in Westfalia-Lippe on 50,354 patients]. AB - BACKGROUND: We show a comparison between two patient groups of the inpatient population suffering from femoral neck fractures registered in the external quality assurance between 1993 and 1997 and between 2005 and 2009. RESULTS: The comparison between two patient groups showed the following developments: an increase in patient numbers per year from 4,229 to 5,842 where the average age remained constant but the proportion of elderly patients over 70 years old increased; the period of hospitalization was clearly shorter (from 27 days to 18 days); an increase in comorbidities (according to the ASA classification) with simultaneous decrease of the complication rate (from 11.1% to 7.6%). The inhospital mortality remained constant at 5.3%. At the same time the number of hospitals which treat patients with femoral neck fractures decreased from 166 to 150. Concurrently the number of patients per hospital and year increased from 23.6 to 41.3 cases. CONCLUSION: The technique of operative treatment changed and while during the 1990s many patients with femoral neck fractures were treated by implanting a total endoprosthesis, in the 2000s treatment was dominated by the hemi prosthesis. During the two periods of study use of the osteosynthesis technique decreased. In conclusion, the study showed an obvious compression of performance in trauma surgery but despite everything there was a clear improvement of treatment quality with respect to complication rates. PMID- 25277729 TI - [Compartment syndrome caused by rhabdomyolysis in the context of pychogenic polydipsia]. AB - Psychogenic polydipsia leading to severe hyponatremia is well documented in the literature. This electrolyte disorder can result in encephalopathy, cerebral edema and epileptic seizures. Another rare effect is rhabdomyolysis with all its well known complications (e.g. renal failure, hyperkalemia and cardiac arrhythmia) and even resulting in compartment syndrome due to severe muscle edema. We present the case of a patient with severe hyponatremia caused by psychogenic polydipsia leading to rhabdomyolysis and compartment syndrome. PMID- 25277730 TI - [Shortening deformities of the clavicle after diaphyseal clavicular fractures : Influence on patient-oriented assessment of shoulder function]. AB - OBJECTIVE: The aim of this study was the evaluation of patient-oriented outcome scores for shoulder function and residual complaints after diaphyseal clavicular fractures with respect to shortening deformities. MATERIAL AND METHODS: The analysis was based on data of 172 adult patients (mean age 39 +/- 14 years) with healed clavicular fractures treated operatively (n = 104) or conservatively (n = 67). The control population consisted of 35 healthy adults without shoulder problems and 25 patients with nonunion after conservative treatment. The subjective estimation of the level of pain was collated on a visual analog scale (VAS 1-100 points), together with the relative Constant and Murley score, the Cologne clavicle score, the disabilities of the arm, shoulder and hand (DASH) score and a bilateral comparison of the length difference of the clavicles. RESULTS: Patients with a clavicular length difference of > 2 cm had significantly (p < 0.001) more pain, a greater loss of mobility and significantly lower values in the scoring system of Constant and Murley, the DASH and Cologne clavicle scores compared to patients with clavicular length differences < 0.5 cm and healthy controls (p < 0.001). CONCLUSION: The results of this study showed that shortening deformities after clavicular fractures in adults have a large impact on the functional result and patient-oriented outcome scores. The aim of the therapy of diaphyseal clavicular fractures should therefore concentrate on reconstruction of the anatomical length of the clavicle. PMID- 25277731 TI - [Sternal fracture in growing children : A rare and often overlooked fracture? Documentation of four cases]. AB - BACKGROUND: Sternal fractures in childhood are rare. The aim of the study was to investigate the accident mechanism, the detection of radiological and sonographical criteria and consideration of associated injuries. METHOD: In the period from January 2010 to December 2012 all inpatients and outpatients with sternal fractures were recorded according to the documentation. RESULTS: A total of 4 children aged 5-14 years with a sternal fracture were treated in 2 years, 2 children were hospitalized for pain management and 2 remained in outpatient care. CONCLUSION: Isolated sternal fractures in childhood are often due to typical age related traumatic incidents. Ultrasonography is a useful diagnostic tool for fracture detection and radiography is the method of choice for visualization of the extent of the dislocation. PMID- 25277732 TI - [Conservative treatment of distal radius fracture. Consequences of an uncritical follow-up]. AB - A 74-year-old woman sustained a fracture of the distal radius with an additional fracture of the styloid process of the ulna due to a fall. After reduction under local anesthesia immobilization treatment in a forearm cast was initiated. Despite increasing secondary dislocation during radiological x-ray follow-up control, the bone was described as correctly aligned by the treating physician and non-operative treatment was continued. After a total treatment period of 9 months including 7 months of physiotherapy the patient still presented a limited range of motion and local soft tissue swelling of the right wrist. The patient filed a complaint for wrong treatment of the distal radius fracture resulting in severe pain and considerable deformity of the right wrist leading to a significant handicap during activities of daily living. The expert opinion of the arbitration board ascertained a case of medical malpractice in terms of the indications. Due to the initial presence of criteria of radiological instability, an operative treatment had already been indicated at the first presentation. In addition, secondary dislocation during radiological follow-up examination should have led to conversion of treatment in favor of surgery. The arbitration board furthermore concluded that iatrogenic malpractice led to a severe deformity of the right wrist which would result in a loss of grip strength and future arthritic deformation of the wrist. Legal aspects of the case are discussed. PMID- 25277733 TI - Endogenous endophthalmitis complicated by pyogenic liver abscess: a review of 17 years' experience at a single center. AB - BACKGROUND: Endogenous endophthalmitis is a rare complication of pyogenic liver abscess. It is a devastating intraocular infection which constitutes a vision threatening emergency. Recently, a significant increase in the incidence of endogenous endophthalmitis associated with pyogenic liver abscess has been reported in East Asia. In this study, the authors investigated the incidence, risk factors, clinical features, and treatment outcomes of endogenous endophthalmitis arising as a complication of pyogenic liver abscess. METHODS: The medical records of 8 cases of endogenous endophthalmitis associated with a pyogenic liver abscess treated from 1997 to 2013 at a single tertiary hospital in Korea were retrospectively reviewed. RESULTS: Median patient age was 71.1 +/- 9.8 years. The most common underlying disease was diabetes mellitus (4 patients, 50%). Klebsiella pneumoniae was isolated from all patients, and all were treated with intravenous antibiotics including ceftriaxone. Seven patients received an intravitreal injection. Four patients needed additional surgical interventions. Outcomes were generally poor; only 1 patient achieved a slight improvement in visual outcome. CONCLUSION: Old age, diabetes mellitus, and K. pneumoniae infection could predispose the development of endogenous endophthalmitis in patients with a pyogenic liver abscess. Physicians should pay attention to ocular symptoms as early diagnosis and intensive treatment are required to achieve improvements in visual outcome. PMID- 25277735 TI - Using the Five Senses of Success framework to understand the experiences of midwifery students enroled in an undergraduate degree program. AB - BACKGROUND: developing a student's sense of capability, purpose, resourcefulness, identity and connectedness (five-senses of success) are key factors that may be important in predicting student satisfaction and progression within their university program. AIM: the study aimed to examine the expectations and experiences of second and third year midwifery students enroled in a Bachelor of Midwifery program and identify barriers and enablers to success. METHOD: a descriptive exploratory qualitative design was used. Fifty-six students enroled in either year 2 or 3 of the Bachelor of Midwifery program in SE Queensland participated in an anonymous survey using open-ended questions. In addition, 16 students participated in two year-level focus groups. Template analysis, using the Five Senses Framework, was used to analyse the data set. FINDINGS: early exposure to 'hands on' clinical midwifery practice as well as continuity of care experiences provided students with an opportunity to link theory to practice and increased their perception of capability as they transitioned through the program. Students' sense of identity, purpose, resourcefulness, and capability was strongly influenced by the programs embedded meta-values, including a 'woman centred' approach. In addition, a student's ability to form strong positive relationships with women, peers, lecturers and supportive clinicians was central to developing connections and ultimately a sense of success. A sense of connection not only fostered an ongoing belief that challenges could be overcome but that students themselves could initiate or influence change. CONCLUSIONS: the five senses framework provided a useful lens through which to analyse the student experience. Key factors to student satisfaction and retention within a Bachelor of Midwifery program include: a clearly articulated midwifery philosophy, strategies to promote student connectedness including the use of social media, and further development of clinicians' skills in preceptorship, clinical teaching and facilitation. Program delivery methods and student support systems should be designed to enable maximum flexibility to promote capability and resourcefulness and embed sense of purpose and identity early in the program. PMID- 25277734 TI - Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization. AB - BACKGROUND: The lastly identified claudin-low (CL) subtype of breast cancer (BC) remains poorly described as compared to the other molecular subtypes. We provide a comprehensive characterization of the largest series of CL samples reported so far. METHODS: From a data set of 5447 invasive BC profiled using DNA microarrays, we identified 673 CL samples (12,4%) that we describe comparatively to the other molecular subtypes at several levels: clinicopathological, genomic, transcriptional, survival, and response to chemotherapy. RESULTS: CL samples display profiles different from other subtypes. For example, they differ from basal tumors regarding the hormone receptor status, with a lower frequency of triple negative (TN) tumors (52% vs 76% for basal cases). Like basal tumors, they show high genomic instability with many gains and losses. At the transcriptional level, CL tumors are the most undifferentiated tumors along the mammary epithelial hierarchy. Compared to basal tumors, they show enrichment for epithelial-to-mesenchymal transition markers, immune response genes, and cancer stem cell-like features, and higher activity of estrogen receptor (ER), progesterone receptor (PR), EGFR, SRC and TGFbeta pathways, but lower activity of MYC and PI3K pathways. The 5-year disease-free survival of CL cases (67%) and the rate of pathological complete response (pCR) to primary chemotherapy (32%) are close to those of poor-prognosis and good responder subtypes (basal and ERBB2 enriched). However, the prognostic features of CL tumors are closer to those observed in the whole BC series and in the luminal A subtype, including proliferation-related gene expression signatures (GES). Immunity-related GES valuable in basal breast cancers are not significant in CL tumors. By contrast, the GES predictive for pCR in CL tumors resemble more to those of basal and HER2 enriched tumors than to those of luminal A tumors. CONCLUSIONS: Many differences exist between CL and the other subtypes, notably basal. An unexpected finding concerns the relatively high numbers of ER-positive and non-TN tumors within CL subtype, suggesting a larger heterogeneity than in basal and luminal A subtypes. PMID- 25277736 TI - Effect of high-fat and high-carbohydrate diets on pulmonary O2 uptake kinetics during the transition to moderate-intensity exercise. AB - Mitochondrial pyruvate dehydrogenase (PDH) regulates the delivery of carbohydrate derived substrate to the mitochondrial tricarboxylic acid cycle and electron transport chain. PDH activity at rest and its activation during exercise is attenuated following high-fat (HFAT) compared with high-carbohydrate (HCHO) diets. Given the reliance on carbohydrate-derived substrate early in transitions to exercise, this study examined the effects of HFAT and HCHO on phase II pulmonary O2 uptake (Vo2 p) kinetics during transitions into the moderate intensity (MOD) exercise domain. Eight active adult men underwent dietary manipulations consisting of 6 days of HFAT (73% fat, 22% protein, 5% carbohydrate) followed immediately by 6 days of HCHO (10% fat, 10% protein, 80% carbohydrate); each dietary phase was preceded by a glycogen depletion protocol. Participants performed three MOD transitions from a 20 W cycling baseline to work rate equivalent to 80% of estimated lactate threshold on days 5 and 6 of each diet. Steady-state Vo2 p was greater (P < 0.05), and respiratory exchange ratio and carbohydrate oxidation rates were lower (P < 0.05) during HFAT. The phase II Vo2 p time constant (tauVo2 p) [HFAT 40 +/- 16, HCHO 32 +/- 19 s (mean +/- SD)] and Vo2 p gain (HFAT 10.3 +/- 0.8, HCHO 9.4 +/- 0.7 ml.min(-1.)W(-1)) were greater (P < 0.05) in HFAT. The overall adjustment (effective time constant) of muscle deoxygenation (Delta[HHb]) was not different between diets (HFAT 24 +/- 4 s, HCHO 23 +/- 4 s), which coupled with a slower tauVo2 p, indicates a slowed microvascular blood flow response. These results suggest that the slower Vo2 p kinetics associated with HFAT are consistent with inhibition and slower activation of PDH, a lower rate of pyruvate production, and/or attenuated microvascular blood flow and O2 delivery. PMID- 25277738 TI - The use of doubly labeled milk protein to measure postprandial muscle protein synthesis rates in vivo in humans. AB - We aimed to determine the impact of precursor pool dilution on the assessment of postprandial myofibrillar protein synthesis rates (MPS). A Holstein dairy cow was infused with large amounts of L-[1-(13)C]phenylalanine and L-[1-(13)C]leucine, and the milk was collected and fractionated. The enrichment levels in the casein were 38.7 and 9.3 mole percent excess, respectively. In a subsequent human experiment, 11 older men (age: 71 +/- 1 y, body mass index: 26 +/- 0.1 kg.m(-2)) received a primed constant infusion of L-[ring-(2)H5]phenylalanine and L-[1 (13)C]leucine. Blood and muscle samples were collected before and after the ingestion of 20-g doubly labeled casein to assess postprandial MPS based on the 1) constant tracer infusion of L-[ring-(2)H5]phenylalanine, 2) ingestion of intrinsically L-[1-(13)C]phenylalanine-labeled casein, and 3) constant infusion of L-[1-(13)C]leucine in combination with the ingestion of intrinsically L-[1 (13)C]leucine-labeled casein. Postprandial MPS was increased (P < 0.05) after protein ingestion (~70% above postabsorptive values) based on the L-[1 (13)C]leucine tracer. There was no significant stimulation of postprandial MPS (~27% above postabsorptive values) when the calculated fractional synthesis rate was based on the L-[ring-(2)H5]phenylalanine (P = 0.2). Comparisons of postprandial MPS based on the primed continuous infusion of L-[1-(13)C]leucine or the ingestion of intrinsically L-[1-(13)C]phenylalanine-labeled casein protein demonstrated differences compared with the primed continuous infusion of L-[ring (2)H5]phenylalanine (P > 0.05). Our findings confirm that the postprandial MPS assessed using the primed continuous tracer infusion approach may differ if tracer steady-state conditions in the precursor pools are perturbed. The use of intrinsically doubly labeled protein provides a method to study the metabolic fate of the ingested protein and the subsequent postprandial MPS response. PMID- 25277739 TI - Exercise physiology: from performance studies to muscle physiology and cardiovascular adaptations. PMID- 25277737 TI - The extraction of neural strategies from the surface EMG: an update. AB - A surface EMG signal represents the linear transformation of motor neuron discharge times by the compound action potentials of the innervated muscle fibers and is often used as a source of information about neural activation of muscle. However, retrieving the embedded neural code from a surface EMG signal is extremely challenging. Most studies use indirect approaches in which selected features of the signal are interpreted as indicating certain characteristics of the neural code. These indirect associations are constrained by limitations that have been detailed previously (Farina D, Merletti R, Enoka RM. J Appl Physiol 96: 1486-1495, 2004) and are generally difficult to overcome. In an update on these issues, the current review extends the discussion to EMG-based coherence methods for assessing neural connectivity. We focus first on EMG amplitude cancellation, which intrinsically limits the association between EMG amplitude and the intensity of the neural activation and then discuss the limitations of coherence methods (EEG-EMG, EMG-EMG) as a way to assess the strength of the transmission of synaptic inputs into trains of motor unit action potentials. The debated influence of rectification on EMG spectral analysis and coherence measures is also discussed. Alternatively, there have been a number of attempts to identify the neural information directly by decomposing surface EMG signals into the discharge times of motor unit action potentials. The application of this approach is extremely powerful, but validation remains a central issue. PMID- 25277741 TI - A virtual rat for simulating environmental and exertional heat stress. AB - Severe cases of environmental or exertional heat stress can lead to varying degrees of organ dysfunction. To understand heat-injury progression and develop efficient management and mitigation strategies, it is critical to determine the thermal response in susceptible organs under different heat-stress conditions. To this end, we used our previously published virtual rat, which is capable of computing the spatiotemporal temperature distribution in the animal, and extended it to simulate various heat-stress scenarios, including 1) different environmental conditions, 2) exertional heat stress, 3) circadian rhythm effect on the thermal response, and 4) whole body cooling. Our predictions were consistent with published in vivo temperature measurements for all cases, validating our simulations. We observed a differential thermal response in the organs, with the liver experiencing the highest temperatures for all environmental and exertional heat-stress cases. For every 3 degrees C rise in the external temperature from 40 to 46 degrees C, core and organ temperatures increased by ~0.8 degrees C. Core temperatures increased by 2.6 and 4.1 degrees C for increases in exercise intensity from rest to 75 and 100% of maximal O2 consumption, respectively. We also found differences as large as 0.8 degrees C in organ temperatures for the same heat stress induced at different times during the day. Even after whole body cooling at a relatively low external temperature (1 degrees C for 20 min), average organ temperatures were still elevated by 2.3 to 2.5 degrees C compared with normothermia. These results can be used to optimize experimental protocol designs, reduce the amount of animal experimentation, and design and test improved heat-stress prevention and management strategies. PMID- 25277740 TI - Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n back performance in chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) with orthostatic intolerance is characterized by neurocognitive deficits and impaired working memory, concentration, and information processing. In CFS, upright tilting [head-up tilt (HUT)] caused decreased cerebral blood flow velocity (CBFv) related to hyperventilation/hypocapnia and impaired cerebral autoregulation; increasing orthostatic stress resulted in decreased neurocognition. We loaded the baroreflex with phenylephrine to prevent hyperventilation and performed n-back neurocognition testing in 11 control subjects and 15 CFS patients. HUT caused a significant increase in heart rate (109.4 +/- 3.9 vs. 77.2 +/- 1.6 beats/min, P < 0.05) and respiratory rate (20.9 +/- 1.7 vs. 14.2 +/- 1.2 breaths/min, P < 0.05) and decrease in end-tidal CO2 (ETCO2; 42.8 +/- 1.2 vs. 33.9 +/- 1.1 Torr, P < 0.05) in CFS vs. control. HUT caused CBFv to decrease 8.7% in control subjects but fell 22.5% in CFS. In CFS, phenylephrine prevented the HUT-induced hyperventilation/hypocapnia and the significant drop in CBFv with HUT (-8.1% vs. 22.5% untreated). There was no difference in control subject n-back normalized response time (nRT) comparing supine to HUT (106.1 +/- 6.9 vs. 97.6 +/- 7.1 ms at n = 4), and no difference comparing control to CFS while supine (97.1 +/- 7.1 vs 96.5 +/- 3.9 ms at n = 4). However, HUT of CFS subjects caused a significant increase in nRT (148.0 +/- 9.3 vs. 96.4 +/- 6.0 ms at n = 4) compared with supine. Phenylephrine significantly reduced the HUT-induced increase in nRT in CFS to levels similar to supine (114.6 +/- 7.1 vs. 114.6 +/- 9.3 ms at n = 4). Compared with control subjects, CFS subjects are more sensitive both to orthostatic challenge and to baroreflex/chemoreflex-mediated interventions. Increasing blood pressure with phenylephrine can alter CBFv. In CFS subjects, mitigation of the HUT-induced CBFv decrease with phenylephrine has a beneficial effect on n-back outcome. PMID- 25277742 TI - Synergist ablation induces rapid tendon growth through the synthesis of a neotendon matrix. AB - Mechanical loading can increase tendon cross-sectional area (CSA), but the mechanisms by which this occurs are largely unknown. To gain a greater understanding of the cellular mechanisms of adult tendon growth in response to mechanical loading, we used a synergist ablation model whereby a tenectomy of the Achilles tendon was performed to induce growth of the synergist plantaris tendon. We hypothesized that after synergist ablation progenitor cells in the epitenon would proliferate and increase the size of the existing tendon matrix. Adult male mice were subjected to a bilateral Achilles tenectomy, and plantaris tendons were isolated from mice at 0, 2, 7, 14, and 28 days after surgery. Tendons were sectioned stained with either fast green and hematoxylin, prepared for fluorescent microscopy, or prepared for gene expression of scleraxis and type I collagen. After overload, there was a dramatic increase in total CSA of tendons, whereas the size of the original tendon matrix was not changed. Growth primarily occurred through the formation of a neotendon matrix between the original tendon and the epitenon, and contained cells that were proliferative and scleraxis positive. Additionally, an initial expansion of fibroblast cells occurred before the synthesis of new extracellular matrix. Fibroblasts in the original tendon did not re-enter the cell cycle. The results from this study provide new insight into the mechanisms of tendon growth, indicate tendon consists mostly of postmitotic cells, and that growth of tendon primarily occurs from the most superficial layers outward. PMID- 25277743 TI - Development of modified cable models to simulate accurate neuronal active behaviors. AB - In large network and single three-dimensional (3-D) neuron simulations, high computing speed dictates using reduced cable models to simulate neuronal firing behaviors. However, these models are unwarranted under active conditions and lack accurate representation of dendritic active conductances that greatly shape neuronal firing. Here, realistic 3-D (R3D) models (which contain full anatomical details of dendrites) of spinal motoneurons were systematically compared with their reduced single unbranched cable (SUC, which reduces the dendrites to a single electrically equivalent cable) counterpart under passive and active conditions. The SUC models matched the R3D model's passive properties but failed to match key active properties, especially active behaviors originating from dendrites. For instance, persistent inward currents (PIC) hysteresis, frequency current (FI) relationship secondary range slope, firing hysteresis, plateau potential partial deactivation, staircase currents, synaptic current transfer ratio, and regional FI relationships were not accurately reproduced by the SUC models. The dendritic morphology oversimplification and lack of dendritic active conductances spatial segregation in the SUC models caused significant underestimation of those behaviors. Next, SUC models were modified by adding key branching features in an attempt to restore their active behaviors. The addition of primary dendritic branching only partially restored some active behaviors, whereas the addition of secondary dendritic branching restored most behaviors. Importantly, the proposed modified models successfully replicated the active properties without sacrificing model simplicity, making them attractive candidates for running R3D single neuron and network simulations with accurate firing behaviors. The present results indicate that using reduced models to examine PIC behaviors in spinal motoneurons is unwarranted. PMID- 25277744 TI - On the role of gallbladder emptying and incretin hormones for nutrient-mediated TSH suppression in patients with type 2 diabetes. AB - Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T4) to the biologically active triiodothyronine (T3). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T3 and free T4) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T3 and T4 concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a 'gut-thyroid pituitary' axis seems questionable. PMID- 25277745 TI - Comparison of Etests and Vitek 2 (r) to broth microdilution for the susceptibility testing of Cryptococcus neoformans. AB - We determined the susceptibility of 102 clinical isolates Cryptococcus neoformans from Durban, South Africa, to amphotericin B, fluconazole, flucytosine, and voriconazole using broth microdilution (BMD) according to the Clinical and Laboratory Standards Institute M27-A3 document and compared these results with Etest and Vitek 2((r)). Essential agreement (EA) of Etest and Vitek 2((r)) compared to BMD was determined. Low MICs that were below the epidemiological cutoff values of the 4 antifungal agents tested were demonstrated by all isolates. The EA of Etests for fluconazole, amphotericin, and voriconazole was 95.1%, 83.3%, and 91.2%, respectively, and for Vitek 2((r)) EA for fluconazole, amphotericin, and flucytosine was 97.1%, 95.1%, and 97.1%, respectively. The Vitek 2((r)) showed good agreement with BMD and is a suitable alternative. Etests demonstrated good EA for azoles only. Clinical cryptococcal isolates from Durban remain susceptible to current recommended antifungal therapy. PMID- 25277746 TI - A multiplexed droplet digital PCR assay performs better than qPCR on inhibition prone samples. AB - We demonstrate the development of a multiplex droplet digital PCR assay for human cytomegalovirus (CMV), human adenovirus species F, and an internal plasmid control that may be useful for PCR inhibition-prone clinical samples. This assay performs better on inhibition-prone stool samples than a quantitative PCR assay for CMV and is the first published clinical virology droplet digital PCR assay to incorporate an internal control. PMID- 25277747 TI - Selling dreams: an overview of slimming products' advertisements in Switzerland. AB - OBJECTIVE: The aim of this work was to assess weight loss claims of slimming products available in Switzerland. METHOD: Between May 2008 and February 2013, 31 advertisements for 13 slimming products were analyzed. RESULTS: Total daily weight loss claims ranged between 300 g and 1 kg. 84% of the advertisements included the photograph of a woman, 61% showed a picture of a person before and after using the product, and 51% claimed that the product had improved marital relationships. The terms 'natural', 'miracle/extraordinary' and 'scientific' were present in 92%, 77% and 31% of the advertisements, respectively. Cost for one package of the product ranged between CHF 49.00 and 59.00 (USD 52.00 and 63.00), and no correlation was found between cost and weight loss claims. No differences were found for weight loss claims according to presence or absence of a picture or of the terms 'natural', 'miracle/extraordinary', and 'scientific'. Assuming that 5.3% of readers bought the product, yearly revenues would range between CHF 12.5 and 33.8 million (USD 13.4 and 36.2 million). CONCLUSIONS: In Switzerland, advertisements for slimming products use positive and reassuring terms to attract consumers, which are lured by unreachable, false promises of rapid and easy weight loss. PMID- 25277748 TI - Psychometric properties for the Children's Power of Food Scale in a diverse sample of pre-adolescent youth. AB - PURPOSE: The Children's Power of Food Scale measures appetitive responsiveness across three domains, food available, food present, and food tasted but not eaten, and a total aggregate score. Although validated in adult populations it has not been tested in youth. The purpose was to establish psychometric properties for the Children's Power of Food Scale (C-PFS) for use in youth. METHODS: Six content experts were recruited to establish content validity (CVI). Reliability was established using 2-week test-retest procedures following lunch period in 47 ethnically diverse 10-14 year olds. RESULTS: CVI for the aggregate score was 0.87. Factor and aggregate score Cronbach's alphas were 0.61-0.89. Intra-class correlation factors scores were 0.28-0.68. Kappa (kappa) ranged from 0.19 to 0.69 for individual questions. CONCLUSIONS: The C-PFS may serve as a useful instrument to identify youth more vulnerable to food preoccupation and overconsumption given the obesogenic food environment. Factor 2, food present not tasted, should be interpreted with caution in English language learners. PMID- 25277749 TI - Nucleic acid aptamer-mediated drug delivery for targeted cancer therapy. AB - Aptamers are emerging as promising therapeutic agents and recognition elements. In particular, cell-SELEX (systematic evolution of ligands by exponential enrichment) allows in vitro selection of aptamers selective to whole cells without prior knowledge of the molecular signatures on the cell surface. The advantage of aptamers is their high affinitiy and binding specificity towards the target. This Minireview focuses on single-stranded (ss) oligonucleotide (DNA or RNA)-based aptamers as cancer therapeutics/theranostics. Specifically, aptamer nanomaterial conjugates, aptamer-drug conjugates, targeted phototherapy and targeted biotherapy are covered in detail. In reviewing the literature, the potential of aptamers as delivery systems for therapeutic and imaging applications in cancer is clear, however, major challenges remain to be resolved, such as the poorly understood pharmacokinetics, toxicity and off-target effects, before they can be fully exploited in a clinical setting. PMID- 25277750 TI - Trends in mortality decrease and economic growth. AB - The vast literature on extrapolative stochastic mortality models focuses mainly on the extrapolation of past mortality trends and summarizes the trends by one or more latent factors. However, the interpretation of these trends is typically not very clear. On the other hand, explanation methods are trying to link mortality dynamics with observable factors. This serves as an intermediate step between the two methods. We perform a comprehensive analysis on the relationship between the latent trend in mortality dynamics and the trend in economic growth represented by gross domestic product (GDP). Subsequently, the Lee-Carter framework is extended through the introduction of GDP as an additional factor next to the latent factor, which provides a better fit and better interpretable forecasts. PMID- 25277751 TI - Downregulation of Th17 cells and the related cytokines with treatment in Kawasaki disease. AB - Given the inflammatory nature of Kawasaki disease (KD) and the pro-inflammatory properties of Th17, this study aimed to determine the frequency of Th17 cells and the levels of corresponding cytokines in acute phase of KD and to evaluate their alterations one and eight weeks after treatment. Th17 and the related cytokine levels were measured in 21 KD patients and 42 positive and negative controls, using flow cytometry and ELISA, respectively. Th17, IL-17, IL-22 and IL-23 were significantly higher (P<0.05) in patients compared with negative controls, but no significant differences (P>0.05) with the positive controls. Furthermore, Th17, IL-17, IL-22 and IL-23 were significantly higher in patients before treatment than those one and eight weeks after. Considering the downregulation of Th17 and its related cytokines with aspirin and intravenous immunoglobulin therapy implies the probable role of Th17 in KD pathogenesis. PMID- 25277752 TI - Biogas upgrading by chemical absorption using ammonia rich absorbents derived from wastewater. AB - The use of ammonia (NH3) rich wastewaters as an ecological chemical absorption solvent for the selective extraction of carbon dioxide (CO2) during biogas upgrading to 'biomethane' has been studied. Aqueous ammonia absorbents of up to 10,000 gNH3 m(-3) demonstrated CO2 absorption rates higher than recorded in the literature for packed columns using 20,000-80,000 g NH3 m(-3) which can be ascribed to the process intensification provided by the hollow fibre membrane contactor used in this study to support absorption. Centrifuge return liquors (2325 g m(-3) ionised ammonium, NH4(+)) and a regenerant (477 gNH4(+) m(-3)) produced from a cationic ion exchanger used to harvest NH4(+) from crude wastewater were also tested. Carbon dioxide fluxes measured for both wastewaters compared reasonably with analogue ammonia absorption solvents of equivalent NH3 concentration. Importantly, this demonstrates that ammonia rich wastewaters can facilitate chemically enhanced CO2 separation which eliminates the need for costly exogenic chemicals or complex chemical handling which are critical barriers to implementation of chemical absorption. When testing NH3 analogues, the potential to recover the reaction product ammonium bicarbonate (NH4HCO3) in crystalline form was also illustrated. This is significant as it suggests a new pathway for ammonia separation which avoids biological nitrification and produces ammonia stabilised into a commercially viable fertiliser (NH4HCO3). However, in real ammonia rich wastewaters, sodium bicarbonate and calcium carbonate were preferentially formed over NH4HCO3 although it is proposed that NH4HCO3 can be preferentially formed by manipulating both ion exchange and absorbent chemistry. PMID- 25277754 TI - Anomalous glass transition behavior of SBR-Al2O3 nanocomposites at small filler concentrations. AB - Elastomers filled with hard nanoparticles are of great technical importance for the rubber industry. In general, fillers improve mechanical properties of polymer materials, e.g. elastic moduli, tensile strength etc. The smaller the size of the particles, the larger is the interface where interactions between polymer molecules and fillers can generate new properties. Using temperature-modulated differential scanning calorimetry and dynamic mechanical analysis, we investigated the properties of pure styrene-butadiene rubber (SBR) and SBR/alumina nanoparticles. Beside a reinforcement effect seen in the complex elastic moduli, small amounts of nanoparticles of about 2 wt% interestingly lead to an acceleration of the relaxation modes responsible for the thermal glass transition. This leads to a minimum in the glass transition temperature as a function of nanoparticle content in the vicinity of this critical concentration. The frequency dependent elastic moduli are used to discuss the possible reduction of the entanglement of rubber molecules as one cause for this unexpected behavior. PMID- 25277753 TI - Src family kinases and Syk are required for neutrophil extracellular trap formation in response to beta-glucan particles. AB - We report that particles of beta-glucan, one of the surface components of yeasts, are powerful inducers of neutrophil extracellular trap (NET) formation in human neutrophils. beta-Glucan triggered a prolonged phosphorylation of Src family kinases and Syk that were suppressed by the Src family inhibitor 4-amino-5-(4 chlorophenyl)-7-(t-butyl)pyrazolo[3, 4-d] pyrimidine (PP2) and a novel Syk inhibitor, PRT-060318, respectively. PP2 and PRT-060318 also inhibited beta glucan-induced NET formation and reactive oxygen species (ROS) generation, suggesting that both responses are triggered by a Src/Syk-regulated signaling pathway. Given that the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) markedly inhibited NET formation, our findings suggest that ROS are required for the full-blown formation of NETs in response to beta-glucan particles. Contrary to beta-glucan, ROS generation triggered by phorbol myristate acetate (PMA) was unaffected by PP2 and PRT-060318, but these compounds, as well as DPI, suppressed Src/Syk phosphorylation triggered by PMA. Whereas PP2 had no effect on PMA-induced NET formation, PRT-060318 had a significant, albeit partial, inhibitory effect, thus suggesting that ROS induce NET formation in part via activation of Syk. These findings were substantiated by the evidence that neutrophils from mice with the conditional deletion of Syk were defective in formation of NETs in response to beta-glucan. PMID- 25277756 TI - Ultrasound-assisted synthesis of nano-structured 3D zinc(II) metal-organic polymer: precursor for the fabrication of ZnO nano-structure. AB - Nanorods of a three-dimensional Zn(II) metal-organic framework, [Zn2(btec)(DMF)2]n (1) (btec=1,2,4,5-benzenetetracarboxylate, DMF=N,N dimethylformamide), have been synthesized by a sonochemical process and characterized by field emission scanning electron microscopy (FE-SEM), powder XRD and FT-IR spectroscopy. Structural determination of compound 1 was determined by single crystal X-ray diffraction. The thermal stability of compound 1 has been studied by thermal gravimetric analysis (TGA), too. The role of initial reagent concentrations and power ultrasound irradiation and also time, on size and morphology of nano-structured compound 1 have been studied. ZnO nano-structures also were simply synthesized by direct calcination of the single crystals and nano-sized compound 1 at 600 degrees C. The size and morphology of the ZnO nano structures are dependent upon the particles size of compound 1. A decrease in the particles size of compound 1 leads to a decrease in the particles size of the ZnO. PMID- 25277755 TI - Calreticulin levels determine onset of early muscle denervation by fast motoneurons of ALS model mice. AB - Although the precise signaling mechanisms underlying the vulnerability of some sub-populations of motoneurons in ALS remain unclear, critical factors such as metallo-proteinase 9 expression, neuronal activity and endoplasmic reticulum stress have been shown to be involved. In the context of SOD1(G93A) ALS mouse model, we previously showed that a two-fold decrease in calreticulin (CRT) is occurring in the vulnerable fast motoneurons. Here, we asked to which extent the decrease in CRT levels was causative to muscle denervation and/or motoneuron degeneration. Toward this goal, a hemizygous deletion of the crt gene in SOD1(G93A) mice was generated since the complete ablation of crt is embryonic lethal. We observed that SOD1(G93A);crt(+/-) mice display increased and earlier muscle weakness and muscle denervation compared to SOD1(G93A) mice. While CRT reduction in motoneurons leads to a strong upregulation of two factors important in motoneuron dysfunction, ER stress and mTOR activation, it does not aggravate motoneuron death. Our results underline a prevalent role for CRT levels in the early phase of muscle denervation and support CRT regulation as a potential therapeutic approach. PMID- 25277757 TI - Examination of the Positive and Negative Syndrome Scale factor structure and longitudinal relationships with functioning in early psychosis. AB - AIM: We examined the factor structure of the Positive and Negative Syndrome Scale (PANSS) in early-episode psychosis and its relationships with functioning at baseline and follow-up. METHODS: A total of 240 consecutive admissions to an early intervention in psychosis clinic were assessed at intake to the program with the PANSS, Global Assessment of Functioning (GAF) and Social and Occupational Functioning Assessment Scale (SOFAS). Seventy individuals were reassessed at follow-up. A maximum likelihood factor analysis was conducted on baseline PANSS scores and the ability of each factor to predict baseline and follow-up GAF and SOFAS was examined. RESULTS: A five-factor model with varimax rotation was the best fit to our data and was largely congruent with factors found previously. The negative symptom factor was the best predictor of GAF and SOFAS at baseline and follow-up. CONCLUSION: Negative symptoms are the best symptomatic predictor of functioning in individuals with early psychosis and are an important treatment target to improve recovery. PMID- 25277759 TI - The MBD4 gene plays an important role in porcine adipocyte differentiation. AB - BACKGROUND: MBD4 (methyl-CpG binding domain protein 4) is an important G: T glycosylase that can identify T-G mismatches. It plays a role in active demethylation through base excision repair. Overexpression of MBD4 gene can cause the demethylation of numerous genes, and the remethylation of MBD4-associated genes can occur when the MBD4 gene is knocked out. To date, the functions and regulatory mechanisms of the MBD4 gene in the differentiation of porcine preadipocytes have not been clearly established. METHODS: Subcutaneous fat cells from 1- to 7-day-old Junmu-1 piglets were cultured in vitro, induced to differentiate, and then identified. A real-time fluorescence-based quantitative polymerase chain reaction (PCR) analysis was conducted to detect MBD4 messenger RNA (mRNA) expression. Cells were treated with MBD4-siRNA (small interfering RNA) and induced to differentiate. Changes in the lipid droplets were observed by oil red O staining. Changes in the mRNA and protein expression levels of MBD4 and the adipose differentiation-associated genes C/EBPalpha (CCAAT-enhancer-binding protein alpha), PPARgamma (peroxisome proliferator-activated receptor gamma), and aP2 (adipocyte protein 2) were detected. In addition, the bisulfite sequencing method was used to detect changes in methylation in the promoters of certain genes associated with adipose differentiation. RESULTS: Levels of MBD4 mRNA and protein expression varied with time over the course of the porcine adipocyte differentiation, with the highest levels of this expression observed on day two of the differentiation process. After silencing MBD4 and inducing differentiation, the production of lipid droplets decreased, the mRNA expression levels of C/EBPalpha, PPARgamma, and aP2 were significantly reduced, and DNA methylation modification levels were significantly elevated in the examined promoter regions. CONCLUSION: The silencing of the MBD4 gene can influence the DNA methylation levels of preadipocyte differentiation-related genes and subsequently inhibit the differentiation of porcine preadipocytes. PMID- 25277758 TI - Comparative analysis of a novel disease phenotype network based on clinical manifestations. AB - Systems approaches to analyzing disease phenotype networks in combination with protein functional interaction networks have great potential in illuminating disease pathophysiological mechanisms. While many genetic networks are readily available, disease phenotype networks remain largely incomplete. In this study, we built a large-scale Disease Manifestation Network (DMN) from 50,543 highly accurate disease-manifestation semantic relationships in the United Medical Language System (UMLS). Our new phenotype network contains 2305 nodes and 373,527 weighted edges to represent the disease phenotypic similarities. We first compared DMN with the networks representing genetic relationships among diseases, and demonstrated that the phenotype clustering in DMN reflects common disease genetics. Then we compared DMN with a widely-used disease phenotype network in previous gene discovery studies, called mimMiner, which was extracted from the textual descriptions in Online Mendelian Inheritance in Man (OMIM). We demonstrated that DMN contains different knowledge from the existing phenotype data source. Finally, a case study on Marfan syndrome further proved that DMN contains useful information and can provide leads to discover unknown disease causes. Integrating DMN in systems approaches with mimMiner and other data offers the opportunities to predict novel disease genetics. We made DMN publicly available at nlp/case.edu/public/data/DMN. PMID- 25277760 TI - Neuroprotective effects of Psoralea corylifolia Linn seed extracts on mitochondrial dysfunction induced by 3-nitropropionic acid. AB - BACKGROUND: Mitochondrial dysfunction has been implicated in neuronal apoptosis associated with neurodegenerative diseases such as Huntington's disease (HD). Animals that are administered 3-nitropropionic acid (3-NP), a mitochondrial toxin that specifically inhibits complex II of the mitochondrial electron transport chain, manifest HD-like symptoms. METHODS: Psoralea corylifolia Linn seed extracts against 3-NP induced mitochondrial dysfunction in cultured rat pheochromocytoma (PC12) cells, which are used for neurobiological studies. RESULTS: In this study showed that 3-NP-treated PC12 cells had decreased ATP levels, lower cellular oxygen consumption, and reduced mitochondrial membrane potential than those of untreated PC12 cells. Psoralea corylifolia Linn seed extracts stimulated mitochondrial respiration with uncoupling and induced an increased bioenergetic reserve capacity. Furthermore, PC12 cells pretreated with P. corylifolia Linn seed extracts significantly attenuated 3-NP-induced cell death, reduced ATP levels, and lowered the mitochondrial membrane potential. CONCLUSIONS: These results demonstrate that P. corylifolia Linn seed extracts have a significant protective effect against 3-NP induced cytotoxicity. Thus, our results indicate that P. corylifolia Linn seed extracts may have potential applications as therapeutic agents for treating neurodegenerative disease. PMID- 25277761 TI - A case-crossover analysis of the impact of PM(2.5) on cardiovascular disease hospitalizations for selected CDC tracking states. AB - BACKGROUND: Information is currently being collected by the CDC Environmental Public Health Tracking (EPHT) network on hospitalizations due to Acute Myocardial Infarction (AMI) and there is interest by CDC in exploring the relationship between fine particulate matter (PM2.5) and other cardiovascular (CVD) outcomes in the context of the EPHT program. The goal of this study was to assess the short term effects of daily PM(2.5) air pollution levels on hospitalizations for CVD for seven states within the CDC EPHT network (Florida, Massachusetts, New Hampshire, New Jersey, New Mexico, New York, and Washington). METHODS: Hospitalization data was obtained for 2001-2008 admissions for circulatory disease (primary discharge diagnosis of ICD-9 codes 390-459) from data stewards in those states and included admission date, age, gender, and zip code of residence. We used CMAQ-derived predicted daily PM2.5 data as estimated by EPA at the centroid of each Census Bureau Zip Code Tabulation Area (ZCTA) and linked to zip code of patient residence. A time-stratified case-crossover study design with conditional logistic regression was used to evaluate the short-term association of PM2.5 on risk of non-elective hospitalizations for CVD. Specifically, we considered all circulatory disease, ischemic heart disease, acute myocardial infarction, heart failure, cardiac arrhythmia, cerebrovascular disease and peripheral vascular disease endpoints. RESULTS: Data were obtained on over 7,500,000 hospitalizations for this time period. Mean annual PM2.5 exposure levels were lowest for New Mexico and Washington (6.5 MUg/m3 PM2.5 and 8.4 MUg/m3 PM2.5). New Jersey, New York and Massachusetts exhibited the highest annual averages for PM2.5, (12.8 MUg/m3, 11.1 MUg/m3 and 10.8 MUg/m3), respectively. The Northeast states (Massachusetts, New Jersey, New Hampshire and New York) exhibited significant effects of PM2.5 during the cooler months across most disease categories after adjustment for ozone and maximum apparent temperature. Ischemic heart disease risk per 10 MUg/m3 increase in PM2.5 varied from 1.02 to 1.05 for the cooler months. The largest lag effect was noted on lag days 0 and 1. New Mexico and Washington exhibited no cool or warm month significant effects. Although Florida showed no cooler month effects, significant increases were noted in odds ratios for the warm weather months for all outcomes except peripheral vascular disease. This study is one of the first large scale applications of linkage of hospitalization data by state with national US EPA statistically modeled air pollution data. The results demonstrate that state-wide, there are multiple cardiovascular outcomes in addition to AMI which may be impacted by particulate air pollution. PMID- 25277762 TI - Acetabular defect reconstruction in revision hip arthroplasty with a modular revision system and biological defect augmentation. AB - PURPOSE: Revision of failed total hip arthroplasty with severe acetabular bone loss represents a rare but challenging problem. Anatomic reconstruction with biological defect augmentation as solid bone transplants or cancellous bone restores bone stock while providing good component stability. The objective of this study was to present short- to mid-term results of revision total hip arthroplasty with a modular ring system in a consecutive series of patients with severe acetabular bone loss. METHODS: We retrospectively reviewed 39 consecutive patients (39 hips) with severe acetabular bone loss (Paprosky type 3 A and 3 B) reconstructed with revision total hip arthroplasty using the cementless modular ring system MRS-Titan(r). The MRS-Titan(r) consists of independent ring systems that are adapted modularly to the defect situation. Combined with acetabular defect reconstruction by using cancellous bone in impaction grafting technique, the MRS-Titan(r) system offers a cement-free revision system that enables defect adapted customization to individual anatomic matters, bridging of the acetabular bone defect and reconstruction of the centre of rotation. Initial stability of the implant was obtained by screw fixation. Harris hip score and sequential radiographs were used to evaluate clinical and radiographic results. RESULTS: At an average follow up of 31 months (range 12-69 months) 33 of 39 (84.6 %) of the implants were considered radiographically stable without signs of acetabular migration of more than 2 mm in the horizontal or vertical direction, implant rotation or screw breakage. Complications included six implant failures (15 %). We recorded one aseptic loosening of the MRS prosthesis after 20 months. Five patients (12.8 %) had to undergo revision surgery because of periprosthetic joint infection. Two patients had a dislocation postoperatively. The mean Harris hip score improved from 27 +/- 14 points preoperatively to 76 +/- 15 points at the time of last follow up. CONCLUSION: By achieving stable implant fixation and providing potential for biological fixation, treatment of severe acetabular bone loss in revision total hip arthroplasty with the modular ring system MRS-Titan provides a durable solution with good clinical and radiographic results and allows us to accomplish major goals of reconstruction. PMID- 25277763 TI - Investigation of neutrophilic peptides in periprosthetic tissue by matrix assisted laser desorption ionisation time-of-flight imaging mass spectrometry. AB - PURPOSE: The accurate diagnosis of periprosthetic joint infection (PJI) relies on clinical investigation, laboratory parameters, radiological methods, sterile joint aspiration for synovial fluid leucocyte count and microbiological analysis and tissue sampling for histopathology. Due to the limits in specificity and sensitivity of these methods, molecular techniques and new biomarkers were introduced into the diagnostic procedure. Histological examination is related to the amount of neutrophils in the periprosthetic tissue in frozen sections and formalin-fixed paraffin embedded material (FFPE). However, the threshold of neutrophils per defined area of tissue among various studies is very inconsistent. METHODS: We have applied matrix-assisted laser desorption ionisation time-of-flight imaging mass spectrometry (MALDI IMS) to a total of 32 periprosthetic tissue samples of patients with PJI to detect peptides associated with areas of neutrophil infiltration. RESULTS: Specific peaks associated with a high amount of neutrophils were detected. Of these m/z peaks, four could be assigned to predictive neutrophil molecules. These peptides include annexin A1, calgizzarin (S100A11), calgranulin C (S100A12) and histone H2A. By MALDI IMS, these peptides could be shown to be co-localised with the infiltration of neutrophils in the immediate vicinity of the periprosthetic interface, whereas more distant areas did not show neutrophil invasion or infection-related peptides. CONCLUSIONS: MALDI IMS is a new method allowing identification of neutrophil peptides in periprosthetic tissues and may be a surrogate for counting neutrophils as an objective parameter for PJI. PMID- 25277765 TI - Post-stroke fatigue: epidemiology, clinical characteristics and treatment. AB - Fatigue is a disabling and persistent symptom affecting many stroke survivors and is a predictor for death after stroke onset. Post-stroke fatigue is a multidimensional motor-perceptive, emotional and cognitive experience that has become of interest for stroke researchers only in the recent past. More studies are still needed to understand the pathophysiology, clinical characteristics, associated factors and best treatment strategy. The aim of this narrative review was to provide a comprehensive knowledge, from current literature, regarding the epidemiology, clinical characteristics and treatment of fatigue in order to provide physicians with better tools for treating this debilitating symptom that worsens outcome. PMID- 25277764 TI - Ratio of cord to maternal serum PCB concentrations in relation to their congener specific physicochemical properties. AB - The aim was to characterize placental transfer of some congeners of polychlorinated biphenyls (PCBs) and to relate human in utero exposure to these pollutants to their physicochemical properties. We included into the study 1134 births during the period 2002-2003 from two highly PCB contaminated districts in eastern Slovakia. Concentrations of 15 PCB congeners (IUPAC No. 28, 52, 101, 123(+149), 118, 114, 153, 105, 138(+163), 167, 156(+171), 157, 180, 170, and 189) in umbilical cord (C) and maternal serum (M) were determined. The C/M ratios were significantly related, either positively or inversely depending on parameter, to the logarithm of partition coefficient octanol-water (KOW), to fusion enthalpy at the melting point, molecular weight, water solubility, total surface area of the molecule, solvent accessible surface area, melting point, molar volume, and molecular electronegativity distance vector. We found an inverse association between logKOW and lipid adjusted logC/M (const=1.078, b1=-0.179, p<0.001, R(2)=0.039). Parameters evaluated were interrelated except fusion enthalpy at the melting point and electron affinity vs. solubility. We discuss the possible role of cholesterol as a transplacental transporter of PCBs. PMID- 25277766 TI - Temporal expression of calcium channel subunits in satellite cells and bone marrow mesenchymal cells. AB - Bone marrow-derived mesenchymal stem cells (MSC) can be differentiated into myocytes, as well as adipocytes, chondrocytes, and osteocytes in culture. Calcium channels mediate excitation-contraction coupling and are essential for the function of muscle. However, little is known about the expression of calcium channel subunits and calcium handling in stem cells. We examined whether the expression of calcium channel subunits in MSC is similar to that of skeletal muscle satellite cells and if their levels of expression are modified after treatment with bone morphogenetic protein-4 (BMP4). We found that during myogenic differentiation, MSC first express the alpha2delta1 subunit and the cardiac channel subunit Cav1.2. In contrast to the alpha2delta1 subunit levels, the Cav1.2 subunit decreases rapidly with time. The skeletal channel subunit Cav1.1 is detected at day 3 but its expression increases considerably, resembling more closely the expression of the subunits in satellite cells. Treatment of MSC with BMP4 caused a significant increase in expression of Cav1.2, a delay in expression of Cav1.1, and a reduction in the duration of calcium transients when extracellular calcium was removed. Calcium currents and transients followed a pattern related to the expression of the cardiac (Cav1.2) or skeletal (Cav1.1) alpha1subunits. These results indicate that differentiation of untreated MSC resembles differentiation of skeletal muscle and that BMP4 reduces skeletal muscle calcium channel expression and promotes the expression of cardiac calcium channels during myogenic differentiation. PMID- 25277767 TI - Estimating exotic gene flow into native pine stands: zygotic vs. gametic components. AB - Monitoring contemporary gene flow from widespread exotic plantations is becoming an important problem in forest conservation genetics. In plants, where both seed and pollen disperse, three components of exotic gene flow with potentially unequal consequences should be, but have not been, explicitly distinguished: zygotic, male gametic and female gametic. Building on a previous model for estimating contemporary rates of zygotic and male gametic gene flow among plant populations, we present here an approach that additionally estimates the third (female gametic) gene flow component, based on a combination of uni- and biparentally inherited markers. Using this method and a combined set of chloroplast and nuclear microsatellites, we estimate gene flow rates from exotic plantations into two Iberian relict stands of maritime pine (Pinus pinaster) and Scots pine (Pinus sylvestris). Results show neither zygotic nor female gametic gene flow but moderate (6-8%) male gametic introgression for both species, implying significant dispersal of pollen, but not of seeds, from exotic plantations into native stands shortly after introduced trees reached reproductive maturity. Numerical simulation results suggest that the model yields reasonably accurate estimates for our empirical data sets, especially for larger samples. We discuss conservation management implications of observed levels of exposure to nonlocal genes and identify research needs to determine potentially associated hazards. Our approach should be useful for plant ecologists and ecosystem managers interested in the vectors of contemporary genetic connectivity among discrete plant populations. PMID- 25277768 TI - Optical readout of the intracellular environment using nanoparticle transducers. AB - There is rapid growth in the use of multi-functional nanoparticles as transducers to probe the intracellular environment. New designs of nanoparticles can provide quantitative information at sub-cellular resolution on parameters such as pH, temperature and concentration of nicotinamide adenine dinucleotide (NADH) or selected metal ions. This new work builds on the existing practice of using nanoparticles and fluorescent dyes to provide enhanced microscopic images of cells, but goes beyond it by adding new functionalities and analytical capabilities. In this review, we discuss the recent literature on the development of such nanoparticles for simultaneous biosensing and imaging. We explore and examine the different measurements that will be possible, and analyze the likely accuracy and resolution that could be achieved. PMID- 25277769 TI - Mechanical exfoliation of track-etched two-dimensional layered materials for the fabrication of ultrathin nanopores. AB - Mechanical exfoliation of ion-track-etched two-dimensional layered materials yields nanometer-thin nanoporous sheets that can be suspended atop a silicon window to controllably fabricate single- or multi-pore nanofluidic devices. PMID- 25277770 TI - Serum vaspin levels and vaspin mRNA expression in subcutaneous adipose tissue in women with gestational diabetes mellitus. AB - OBJECTIVE: To compare serum vaspin level and mRNA and protein levels of vaspin in adipose tissue in women with gestational diabetes mellitus (GDM) and normal glucose tolerance (NGR), along with the correlation between serum vaspin level with fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and birth-weight. STUDY DESIGN: Thirty-seven women with GDM and 36 with NGR were enrolled. Total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), FINS and vaspin levels were measured. The mRNA and protein levels were detected using RT-PCR and Western blot. Pearson correlation analysis (PCA) was performed to reveal the correlation between serum vaspin level and FINS, HOMA-IR. Spearman correlation analysis (SCA) was conducted to examine the association between serum vaspin level and birth-weight. RESULTS: HDL-C level in GDM was lower than NGR group (P<0.05), and there were no statistical differences in TC, TG, LDL-C, FPG, FINS and HOMA-IR between the two groups. Serum vaspin level, mRNA and protein expression levels of vaspin in GDM were higher than NGR group (P<0.05). Serum vaspin level was not significantly correlated with FINS and HOMA-IR, but had a positive correlation with birth-weight (P=0.023). CONCLUSION: Serum vaspin level cannot serve as an independent predictor of IR. The increased serum vaspin level and increased vaspin mRNA and protein expression in adipose tissues in GDM women indicate that vaspin may be involved in the pathogenesis of GDM, but its exact mechanism needs further study. PMID- 25277772 TI - Adhesive retention tape supporting atrophic skin on a tripolar advancement flap: a novel wound closure option for atrophic skin in an aging population. PMID- 25277771 TI - Conservative management of uterine artery pseudoaneurysm after laparoscopic assisted myomectomy and subsequent pregnancy outcome: case series and review of the literature. AB - OBJECTIVE: Uterine artery pseudoaneurysm is a rare potentially life-threatening complication after myomectomy. Its clinical characteristics and management, and the outcomes of subsequent pregnancy, are not well understood. The purpose of this study was to clarify these important issues. STUDY DESIGN: Retrospective analysis of a case series of uterine artery pseudoaneurysm detected after laparoscopic-assisted myomectomy (LAM) in a single center over a 13-year period. During the early postoperative course, gray scale ultrasonographic evaluation was carried out routinely by searching for an anechoic or hypoechoic well-defined cystic structure in the post-myomectomy scar. In suspicious cases, further evaluation was performed by color Doppler flow analysis and three-dimensional computerized tomographic angiography. After finally confirming the diagnosis by digital subtraction angiography, uterine artery pseudoaneurysm was conservatively managed by angiographic intervention. In cases achieving successful conception, cesarean delivery was chosen and the uterine scar was evaluated. RESULTS: Uterine artery pseudoaneurysm was diagnosed in 9 out of 854 cases of LAM. One case was undiagnosed until massive uterine hemorrhage occurred in the late postoperative period, while the other eight cases were diagnosed in the early postoperative course without hemorrhagic complication. Eight cases were managed by uterine artery embolization, but spontaneous resolution of pseudoaneurysm was observed in one case during a difficult prolonged attempt to superselect the offending branch of the uterine artery. Postembolization course was uneventful, except in a 41 year-old woman who developed oligomenorrhea. Among five women desiring preserved fertility, three women including one after spontaneous miscarriage achieved live birth by cesarean section. One woman experienced spontaneous miscarriage and one did not become pregnant by fertility treatment. In a case with elective cesarean delivery, severe early postpartum hemorrhage occurred from the placental bed and was conservatively managed by emergency uterine artery embolization. CONCLUSION: The development of uterine artery pseudoaneurysm after myomectomy may be more common than previously considered, and should be carefully monitored to avoid potentially life-threatening hemorrhage and loss of fertility. Although spontaneous resolution may occur, conservative management by angiographic intervention could be a feasible management option for future fertility preservation, once a diagnosis has been made. PMID- 25277773 TI - Tenofovir disoproxil fumarate in Asian or Pacific Islander chronic hepatitis B patients with high viral load (>= 9 log10 copies/ml). AB - BACKGROUND & AIMS: We evaluated the antiviral response of Asian or Pacific Islander (API) patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as pre-treatment hepatitis B virus (HBV) DNA >=9 log10 copies/ml, following up to 288 weeks of tenofovir disoproxil fumarate (TDF) treatment. METHODS: A total of 205 HBeAg-negative and HBeAg-positive self described API patients received 48 weeks of TDF 300 mg (HVL n = 18) or adefovir dipivoxil 10 mg (HVL n = 15) in a blinded fashion, followed by open-label TDF for an additional 240 weeks. The proportions of HVL vs. non-HVL patients with HBV DNA <400 copies/ml were compared. Mean declines in HBV DNA were evaluated in API vs. non-API patients. RESULTS: Throughout the first 72 weeks of treatment, a smaller proportion of HVL API patients reached HBV DNA <400 copies/ml than non-HVL API patients. However, after this timepoint similar proportions of HVL and non-HVL API patients achieved HBV DNA <400 copies/ml (100% vs. 97%, respectively), which was maintained through week 288, where 92% of HVL patients and 99% of non-HVL API patients on treatment had HBV DNA <400 copies/ml. During the 288 weeks of treatment, API patients had similar mean HBV DNA declines as non-API patients, regardless of whether patients were HVL or non-HVL. No API HVL patient had persistent viremia at week 288. No resistance was detected among HVL or non-HVL patients. CONCLUSIONS: API patients with HVL CHB achieve HBV DNA <400 copies/ml with long-term TDF treatment; however, achieving viral suppression may take longer for HVL patients relative to non-HVL API patients. PMID- 25277774 TI - Highly effective inhibition of lung cancer growth and metastasis by systemic delivery of siRNA via multimodal mesoporous silica-based nanocarrier. AB - Lung cancer has been the leading type of cancers with regard to mortality and mobility. New versions of RNAi-based therapy are greatly required to tackle the challenges of lung cancer. In this study, we developed a novel siRNA delivery vector based on our magnetic mesoporous silica nanoparticles (M-MSNs) platform. This nanocarrier was constructed by loading siRNAs into the mesopores of M-MSNs, followed by polyethylenimine (PEI) capping, PEGylation and fusogenic peptide KALA modification. The resultant delivery system exhibited prolonged half-life in bloodstream, enhanced cell membrane translocation and endosomal escapablity, and favorable tissue biocompatibility and biosafety. Systemic application of vascular endothelial growth factor (VEGF) siRNA via this nanocarrier resulted in remarkable tumor suppression, both in subdermal and orthotopic lung cancer models, while tumor metastasis was also significantly reduced, overall leading to improved survival. In addition, the magnetic core of the particles and the functionalized fluorescence markers conveniently enabled in vivo imaging of target tissues. Taken together, this M-MSNs-based siRNA delivery vehicle has shown very favorable applicability for cancer therapy. PMID- 25277776 TI - Facial angioedema and stroke. AB - BACKGROUND: Angioedema (AE) in stroke has been reported exclusively after thrombolysis with recombinant tissue-type plasminogen activator (rtPA). Previous studies proposed the insular cortex to play a specific role in the development of AE after stroke. We evaluated the incidence of AE in acute stroke and tried to identify the predominantly involved brain structures. METHODS: We performed a retrospective search of our stroke database for patients with an AE. MRI data were analyzed by adapting the images to a standard size and superimposing the infarctions. The areas of overlap were assumed to represent the areas of interest. RESULTS: 865 of 4,789 (18.1%) consecutive patients with acute stroke received IV rtPA, 20 of them (2.3%) developed AE. One patient developed AE without prior thrombolysis. The odds ratio for AE after rtPA was 93 (95% CI: 12 693). Of the 21 AE patients, 15 (71.4%) had ACE-inhibitor treatment (ACEi) and 7 (33.3%) had diabetes. In all but one patient, AE was clearly lateralized; then the AE was contralateral to the side of the ischemia in 18 of 20 patients (90.0%). An insular/peri-insular involvement was detected in 17/21 (81.0%). About 80.0% of the patients had a suspected MCA branch occlusion. CONCLUSIONS: In contrast to AE in other conditions, AE in stroke seems to feature a unique cerebral pathology because it is mostly lateralized (contralateral to an infarction), is associated with a distinct brain area, may even occur without rtPA, and is far more frequent than after thrombolysis for other indications. rtPA is the major risk factor. Similar to prior studies, we identified ACEi to be another risk factor, and a diabetic autonomic instability might further increase the risk. Central pathways involving the insular and peri-insular cortex seem to play a major role in the pathophysiology of AE in stroke. PMID- 25277777 TI - In vivo analysis of cervical range of motion after revised C1-C2 pedicle screw technique for pediatric atlantoaxial instability. AB - OBJECTIVE: The purpose of this study was to analyze the cervical range of motion (ROM) after revised C1-C2 pedicle screw fixation for pediatric patients with atlantoaxial instability. METHODS: 17 pediatric patients (age range 5-14 years; mean 8.3 years) underwent the revised C1-C2 pedicle screw technique. Pre- and postoperative cervical ROM during flexion/extension, rotation and lateral bending were measured using a head-mounted motion goniometer. Plain radiographs, CT scans and MRI were performed to assess spinal cord compression, the accuracy of screw placement, and bone fusion. The American Spinal Injury Association classification was used to evaluate neurological function. RESULTS: Revised atlantoaxial pedicle screw fixation was successfully performed in all 17 pediatric patients. There were no perioperative complications. All cases showed evidence of bone fusion 6 months after surgery by CT scan. During the follow-up period (24-92 months), of 6 patients with preoperative myelopathy, 3 improved from grade D to grade E and 3 from grade C to grade D. The final follow-up cervical ROM was significantly greater than the preoperative and 6-month postoperative ROM. There was a statistically significant difference between preoperative and 6-month postoperative ROM for flexion, extension, and left and right axial rotation movements. CONCLUSION: As a short-segmental fixation technique, revised C1-C2 pedicle screw fixation can provide effective biomechanical stability. Final follow-up cervical ROM is significantly increased through alleviating cervical pain and symptoms of myelopathy after surgery and possible subaxial compensation. PMID- 25277775 TI - SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer. AB - EPHB3 is a critical cellular guidance factor in the intestinal epithelium and an important tumor suppressor in colorectal cancer (CRC) whose expression is frequently lost at the adenoma-carcinoma transition when tumor cells become invasive. The molecular mechanisms underlying EPHB3 silencing are incompletely understood. Here we show that EPHB3 expression is anti-correlated with inducers of epithelial-mesenchymal transition (EMT) in primary tumors and CRC cells. In vitro, SNAIL1 and SNAIL2, but not ZEB1, repress EPHB3 reporter constructs and compete with the stem cell factor ASCL2 for binding to an E-box motif. At the endogenous EPHB3 locus, SNAIL1 triggers the displacement of ASCL2, p300 and the Wnt pathway effector TCF7L2 and engages corepressor complexes containing HDACs and the histone demethylase LSD1 to collapse active chromatin structure, resulting in rapid downregulation of EPHB3. Beyond its impact on EPHB3, SNAIL1 deregulates markers of intestinal identity and stemness and in vitro forces CRC cells to undergo EMT with altered morphology, increased motility and invasiveness. In xenotransplants, SNAIL1 expression abrogated tumor cell palisading and led to focal loss of tumor encapsulation and the appearance of areas with tumor cells displaying a migratory phenotype. These changes were accompanied by loss of EPHB3 and CDH1 expression. Intriguingly, SNAIL1-induced phenotypic changes of CRC cells are significantly impaired by sustained EPHB3 expression both in vitro and in vivo. Altogether, our results identify EPHB3 as a novel target of SNAIL1 and suggest that disabling EPHB3 signaling is an important aspect to eliminate a roadblock at the onset of EMT processes. PMID- 25277778 TI - Unusual, photo-induced self-assembly of azobenzene-containing amphiphiles. AB - Stimuli-responsive self-assembly is playing an increasingly important role in emerging applications, ranging from smart materials to biosensors. However, obtaining essential information for further development, such as molecular arrangement and interaction, is still experimentally challenging. A molecular level understanding of the stimuli-responsive self-assembly is needed. Azobenzene containing (azo-containing) amphiphiles organize into photo-responsive assemblies because of the cis-trans isomerization triggered by the irradiation of ultraviolet (UV) and visible light. In this study, we applied a coarse grained (CG) molecular dynamics (MD) simulation, with the necessary potential parameters fitted from theoretical calculation data, to study the photo-induced self assembly of 4,4'-bis(hydroxymethyl)-azobenzene (AzoCO), a simple azo-containing amphiphile. An unusual "chaotic micelle" and "monolayer phase" were obtained with cis- and trans-AzoCO molecules, respectively. The structural information and formation mechanism were studied. The "chaotic micelle" possesses a chaotic but not a pure hydrophobic interior as commonly understood. Through comparative simulations, we found that the azo (-N[double bond, length as m-dash]N-) group of azobenzene plays a crucial role in the formation of the "chaotic micelle". The "monolayer phase" is arranged by abreast rod-like trans-AzoCO molecules; the axial symmetry of the trans-AzoCO molecule drives the formation of this structure. The novel "chaotic micelle" and "monolayer phase" have potential applications in nanotechnology and bioengineering. This work is expected to trigger further studies on stimuli-responsive phenomena and materials. PMID- 25277779 TI - Congenital factor V deficiency: comparison of the severity of clinical presentations among patients with rare bleeding disorders. AB - BACKGROUND: Factor V deficiency (FVD) is a rare bleeding disorder (RBD) mostly present in regions with a high rate of consanguinity. FVD after FXIII deficiency is the next more prevalent RBD in Sistan and Baluchistan (S&B) in southeastern Iran. The aim of this study was to evaluate the clinical manifestations and severity of bleeding diathesis in patients with FVD. METHODS: This descriptive study was conducted on 23 patients with FVD in S&B province. FVD was diagnosed by clinical findings and routine laboratory tests. Bleeding diatheses were classified into three grades (I-III) depending on the severity of symptoms. The severity of bleeding episodes in our patients was compared with other RBDs. RESULT: Based on residual plasma FV activity, 6 (26%), 16 (69.5%) and 1 (4.5%) patients had mild, moderate and severe factor deficiency, respectively. 24% of the patients had grade III life-threatening bleeding episodes which in comparison with FVII deficiency (17.4%) and FI deficiency (21%) had a higher incidence, and in comparison with FX deficiency (41.7%) and FXIII deficiency (63.1) had a lower incidence. Grade II and grade I bleeding diathesis were observed in 56.2 and 16.7% of the patients, respectively. CONCLUSION: FVD is the second most common type of RBD in S&B province and grade II bleeding episodes were the major bleeding presentation and observed in more than half of the patients. PMID- 25277780 TI - Community-level correlates of physical violence against unmarried female adolescents in Bangladesh. AB - BACKGROUND: While the majority of research in Bangladesh has focused on intimate partner violence (IPV) against women, less is known about the correlates of physical violence against unmarried female adolescents, particularly community level characteristics that may increase their risk of experiencing violence. METHODS: We used multilevel logistic regression analysis to assess the variability in physical violence against unmarried female adolescents at the community level and to explore the role of community-level characteristics in explaining this variability. The data for this analysis were taken from a 2005 nationally representative survey of 20,000 adolescents aged 10 to 24 living in Bangladesh. Data from 4,370 unmarried female adolescents were included in the final model. RESULTS: Communities in Bangladesh have, on average, high levels of physical violence against unmarried female adolescents, and these levels vary widely across communities. Community-level acceptance of physical punishment against adolescents was related to unmarried female adolescents' risk of experiencing physical violence. CONCLUSIONS: It is important to find and target communities in which unmarried adolescent girls are at higher risk of experiencing physical violence. Programs and policies must focus specifically on changing attitudes regarding treatment of women and girls. As these attitudes accepting of physical violence are found in adolescents aged 10 to 19, school and community-based programs should particularly target this age group. PMID- 25277781 TI - The trouble with halos: invited commentary on Kim, S., & Harris, P. L. (2014). Children prefer to learn from mind-readers. British Journal of Developmental Psychology. AB - This commentary on Kim and Harris (2014) addresses the authors' interpretation of the halo effect, in which 5- to 6-year-old children preferentially agreed with an informant who could read other people's minds, regardless of domain of knowledge. PMID- 25277782 TI - Selecting among extraordinary informants. AB - In our reply to the commentaries by Jacqui Woolley and Rebekah Richert, we discuss the following: (1) possible effects that religious educations have on individual differences and (2) how older children may construe mind-readers. PMID- 25277784 TI - Fetal programming--expands the obstetrician's field of work. PMID- 25277783 TI - Patient information leaflets: informing or frightening? A focus group study exploring patients' emotional reactions and subsequent behavior towards package leaflets of commonly prescribed medications in family practices. AB - BACKGROUND: The purpose of patient information leaflets (PILs) is to inform patients about the administration, precautions and potential side effects of their prescribed medication. Despite European Commission guidelines aiming at increasing readability and comprehension of PILs little is known about the potential risk information has on patients. This article explores patients' reactions and subsequent behavior towards risk information conveyed in PILs of commonly prescribed drugs by general practitioners (GPs) for the treatment of Type 2 diabetes, hypertension or hypercholesterolemia; the most frequent cause for consultations in family practices in Germany. METHODS: We conducted six focus groups comprising 35 patients which were recruited in GP practices. Transcripts were read and coded for themes; categories were created by abstracting data and further refined into a coding framework. RESULTS: Three interrelated categories are presented: (i) The vast amount of side effects and drug interactions commonly described in PILs provoke various emotional reactions in patients which (ii) lead to specific patient behavior of which (iii) consulting the GP for assistance is among the most common. Findings show that current description of potential risk information caused feelings of fear and anxiety in the reader resulting in undesirable behavioral reactions. CONCLUSIONS: Future PILs need to convey potential risk information in a language that is less frightening while retaining the information content required to make informed decisions about the prescribed medication. Thus, during the production process greater emphasis needs to be placed on testing the degree of emotional arousal provoked in patients when reading risk information to allow them to undertake a benefit-risk-assessment of their medication that is based on rational rather than emotional (fearful) reactions. PMID- 25277785 TI - Effect of the frizzle gene (F) on egg production and egg quality of laying hens kept in tropical villages. AB - 1. Two experiments were conducted to determine the influence of the frizzle gene (F) on the production and quality of chicken eggs kept on village farms in Ghana. 2. In the first experiment, 144 pullets, 72 each of Ff and ff pullets from F1 birds, were compared in a randomised complete block design (RCBD), with three villages and 4 batches of hatch as blocks and the two feather genotypes (Ff and ff) as the treatments. 3. The Ff pullets were superior (P < 0.05) to their ff counterparts in terms of the number of eggs per clutch, egg mass and hen-housed and hen-d rates of lay, whereas age at first egg was lower (P < 0.05) in ff layers compared to Ff ones. 4. The eggs of the F1 heterozygous frizzle (Ff) layers had higher values for albumen height, Haugh unit and yolk height compared with eggs from their normal feathered counterparts. 5. In the second experiment, 144 pullets, 48 each of FF, Ff and ff pullets, were compared in a RCBD, with three villages and 4 batches of hatch as blocks and the two feather genotypes (Ff and ff) as the treatments. 6. The F2 birds with genotypes Ff and FF were better than their ff counterparts in terms of the number of eggs per clutch, egg mass, and hen-housed and hen-d rates of lay. Age at first egg was significantly lower in ff layers compared to FF and Ff ones. 7. The Haugh unit value was higher in the homozygous and heterozygous frizzles compared to the normal feathered ones. 8. The presence of the frizzle gene (F) in egg type chickens led to an improvement in egg production and egg quality traits in village chickens, and the cross-breeding scheme evaluated in this project could contribute to improved productivity. PMID- 25277786 TI - Technical aspects of right subcostal incisional hernia repair. PMID- 25277787 TI - Antigen Expression Patterns of Plasma Cell Myeloma: An Association of Cytogenetic Abnormality and International Staging System (ISS) for Myeloma. AB - BACKGROUND: Immunophenotyping of plasma cell has become an important diagnostic tool for plasma cell myeloma. There have been a few studies for association of antigen expression and cytogenetic abnormality of plasma cell myeloma. METHODS: A total of 68 symptomatic/smoldering plasma cell myeloma case were analyzed by multicolor flow cytometry using CD38 and CD138 for primary gating of plasma cells. A conventional cytogenetics and fluorescence in situ hybridization (FISH) studies for detection of del(13q) or aneuploidy, del(17p), and IGH/FGFR translocation were done. We statistically analyzed the association of antigen expression and cytogenetic abnormality/myeloma stage (international staging system for multiple myeloma). RESULTS: Positive expression of CD19, CD28, CD45, CD56, CD117, and CD274 was detected in 8.8%, 50.0%, 50.0%, 75.0%, 39.7%, and 2.9% of cases, respectively. CD117-negative cases were associated with hypodiploidy (P = 0.017). CD45-negative cases were associated with deletion 13 or aneuploidy (P < 0.001) and del(17p)(P = 0.011) by FISH. CD45-negativity or CD117-negativity was associated with advanced stage (P = 0.012 and P = 0.016, respectively). CONCLUSION: The antigen expression patterns of myeloma plasma cell were associated with cytogenetic abnormality and stage. PMID- 25277789 TI - Sublingual misoprostol as an adjunct to oxytocin during cesarean delivery in women at risk of postpartum hemorrhage. AB - OBJECTIVE: To evaluate whether a combination of misoprostol and oxytocin more effectively reduces blood loss during and after cesarean delivery than does oxytocin alone among women with known risk factors for postpartum hemorrhage (PPH). METHODS: A prospective, randomized, double-blind, placebo-controlled trial was performed at a tertiary care center in Kolkata, India, between October 2012 and December 2013. Women were eligible if they were undergoing emergency cesarean under spinal anesthesia and were at high risk for PPH. Participants were randomly assigned (1:1) to receive 400 MUg misoprostol or matched placebo sublingually after delivery of the newborn using a computer-generated random number sequence (block size eight). Participants and providers were masked to assignment. All participants received 20 IU oxytocin. The primary outcomes were intraoperative and postoperative blood loss. RESULTS: Both groups contained 198 women. Mean intraoperative blood loss was significantly lower in the misoprostol group (505.4+/-215.5 mL) than in the placebo group (587.3+/-201.5 mL; P<0.001). Mean postoperative blood loss was slightly lower in the misoprostol group (96.9+/-57.3 mL) than in the placebo group (103.4+/-58.4 mL; P=0.07). Shivering and pyrexia were more frequently associated with misoprostol (P<0.05 for both). CONCLUSION: Misoprostol as an adjunct to oxytocin seemed to more effectively reduce blood loss than did oxytocin alone. Clinical Trial Registry India:CTRI/2013/05/003645. PMID- 25277790 TI - Appropriate second-line therapies for management of severe postpartum hemorrhage. AB - OBJECTIVE: To explore appropriate second-line therapies for management of severe postpartum hemorrhage at cesarean delivery. METHODS: A retrospective study was done of 87 women who underwent cesarean delivery and received uterotonics after placental separation at the Beijing Haidian Maternal and Child Health Hospital, China, between 2009 and 2013. Group 1 (n=52) included patients with 500-700 mL of blood loss before application of intrauterine gauze tamponade or B-Lynch suture as second-line therapy, while group 2 (n=35) included patients with blood loss of more than 700 mL before application of either gauze tamponade or B-Lynch suture. RESULTS: Management was successful in all patients in group 1. In group 2, additional management was needed in three of four patients who underwent a B lynch suture. Factors significantly associated with total blood loss were blood loss before application of second-line therapy (P<0.001), fibrinogen levels (P<0.001), and time from placental separation to second-line therapy (P=0.015). CONCLUSION: When blood loss is 500-700 mL, compression sutures or intrauterine gauze tamponade can be used as second-line treatment of postpartum hemorrhage. When blood loss is more than 700 mL, intrauterine gauze tamponade should be used. PMID- 25277788 TI - Mesenchymal stromal cells reset the scatter factor system and cytokine network in experimental kidney transplantation. AB - BACKGROUND: In former studies we showed in a rat model of renal transplantation that Mesenchymal Stromal Cells (MSC) prevent acute rejection in an independent way of their endowing in the graft. In this study we investigated whether MSC operate by resetting cytokine network and Scatter Factor systems, i.e. Hepatocyte Growth Factor (HGF), Macrophage Stimulating Protein (MSP) and their receptors Met and RON, respectively. METHODS: MSC were injected into the renal artery soon after reperfusion. Controls were grafted untreated and normal rats. Rats were sacrificed 7 days after grafting. Serum and renal tissue levels of IFN-gamma, IL 1, IL-2, IL-4, IL-6, IL-10, MSP/RON, HGF/Met systems, Treg lymphocytes were investigated. RESULTS: In grafted untreated rats IFN-gamma increased in serum and renal tissue and IL-6 rose in serum. MSC prevented both the phenomena, increased IL-10 serum levels and Treg number in the graft. Furthermore MSC increased serum and tissue HGF levels, Met tubular expression and prevented the suppression of tubular MSP/RON expression. CONCLUSIONS: Our results demonstrate that MSC modify cytokine network to a tolerogenic setting, they suppress Th1 cells, inactivate monocytes/macrophage, recruit Tregs. In addition, MSC sustain the expression of the Scatter Factor systems expression, i.e. systems that are committed to defend survival and stimulate regeneration of tubular cells. PMID- 25277791 TI - Reproducibility of coronary artery calcium measurements using 0.8-mm-thickness 256-slice coronary CT. AB - PURPOSE: Coronary artery calcium (CAC) measurement has been utilized as an important indicator of coronary artery disease and predictor of cardiovascular risk. The reproducibility of CAC measurements makes it clinically useful for the assessment of progression and regression of coronary atherosclerosis. This study assessed the reproducibility of the Agatston CAC score among patients undergoing 256-slice multidetector computed tomography (MDCT) scans using 0.8-mm slice thickness. MATERIALS AND METHODS: One hundred four patients (aged 62.8 +/- 9.0 years, 56.7 % males) with CAC scores >0 on 256-slice MDCT underwent additional MDCT imaging at 2-week intervals. The CAC score was quantified using the Agatston score, which was measured independently by two radiologists. RESULTS: The variability between observers and MDCT scan measurements was determined by the mean value of absolute and percentage differences: inter-scan/inter-observer (14.45 +/- 21.84, 12.51 +/- 21.84 %), intra-scan/intra-observer (1.75 +/- 5.85, 1.26 +/- 3.69 %), intra-scan/inter-observer (3.3 +/- 9.1, 4.8 +/- 21.3 %), and inter-scan/intra-observer (13.45 +/- 20.7, 10.04 +/- 10.46 %). CONCLUSION: Reproducibility in CAC measurements using the 0.8-mm-thickness 256-slice MDCT showed low inter-scan/inter-observer variability. Therefore, this CT imaging has potential to be used in prospective, longitudinal CAC assessments. PMID- 25277792 TI - Current controversies in the initial post-surgical radioactive iodine therapy for thyroid cancer: a narrative review. AB - Differentiated thyroid cancer (DTC) is the most common endocrine malignancy and the fifth most common cancer in women. DTC therapy requires a multimodal approach, including surgery, which is beyond the scope of this paper. However, for over 50 years, the post-operative management of the DTC post-thyroidectomy patient has included radioactive iodine (RAI) ablation and/or therapy. Before 2000, a typical RAI post-operative dose recommendation was 100 mCi for remnant ablation, 150 mCi for locoregional nodal disease, and 175-200 mCi for distant metastases. Recent recommendations have been made to decrease the dose in order to limit the perceived adverse effects of RAI including salivary gland dysfunction and inducing secondary primary malignancies. A significant controversy has thus arisen regarding the use of RAI, particularly in the management of the low-risk DTC patient. This debate includes the definition of the low-risk patient, RAI dose selection, and whether or not RAI is needed in all patients. To allow the reader to form an opinion regarding post-operative RAI therapy in DTC, a literature review of the risks and benefits is presented. PMID- 25277793 TI - Evaluation of human papillomavirus type replacement postvaccination must account for diagnostic artifacts: masking of HPV52 by HPV16 in anogenital specimens. AB - It has been hypothesized that, following a reduction in human papillomavirus (HPV) vaccine-targeted genotypes, an increase in prevalence of other HPV types may occur due to reduced competition during natural infection. Any apparent postvaccination increase must be distinguished from diagnostic artifacts consequent to consensus PCR assays failing to detect HPV types present in low copy numbers in coinfected specimens (under the assumption that with a drop in vaccine-preventable types there may be increased detection of previously "masked" types). We reanalyzed anogenital specimens to evaluate unmasking of HPV52 that may be caused by elimination of HPV16. Using highly sensitive type-specific real time HPV52 PCR, we retested 1,200 anogenital specimens (all HPV52 negative according to consensus PCR assays) from six epidemiologic studies (200 specimens/study; 100 HPV16(+)/study). Multivariate logistic regression, with adjustment for age and number of sexual partners, was used to evaluate the association between HPV16 positivity and detection of HPV52. In our pooled analysis (n = 1,196), the presence of HPV16 was positively associated with HPV52 detection [adjusted OR, 1.47; 95% confidence interval (CI), 0.76-2.82]. In our separate (study specific) analyses, a statistically significant association was observed in one study that included HIV-infected males (HIPVIRG study; adjusted OR, 3.82; 95% CI, 1.19-12.26). We observed a positive association between HPV16 viral load (tertiles) and detection of HPV52 (P for trend = 0.003). These results indicate that diagnostic artifacts, resulting from unmasking of HPV52, may occur in some settings in the evaluation of HPV type replacement. Additional studies exploring the extent and severity of unmasking are needed. PMID- 25277795 TI - Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. AB - To date, all population-based epidemiologic data on gastrointestinal stromal tumor (GIST) in the United States predate the 2001 implementation of GIST specific histology coding. As such, results from previous studies were limited because of inclusion of non-GIST abdominal or gastrointestinal sarcomas. We used a national cancer registry with modern day histologic codes to gain greater insight into the true epidemiology of GIST in the United States. We identified 6,142 patients diagnosed with GIST between 2001 and 2011 in the Surveillance, Epidemiology, and End Results database. Incidence, survival, demographic risk factors, and prognostic factors were analyzed. Annual age-adjusted incidence rose from 0.55/100,000 in 2001 to 0.78/100,000 in 2011 and increased with age, peaking among 70- to 79-year-olds (3.06/100,000). GIST was also more common in males than females [rate ratio (RR), 1.35], non-Hispanics than Hispanics (RR, 1.23), and blacks (RR, 2.07) or Asians/Pacific Islanders (RR, 1.50) than whites. The study period had 5-year overall and GIST-specific survival rates of 65% and 79%, respectively. The 5-year overall survival rates for those with localized, regional, and metastatic disease at diagnosis were 77%, 64%, and 41%, respectively. Multivariate analyses demonstrated that older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors for worse overall survival. Multivariate analysis also showed the four aforementioned characteristics, along with earlier year of diagnosis, to be independent risk factors for worse GIST-specific survival. As the first population-based, epidemiologic study of histologically confirmed disease, our findings provide a robust representation of GIST in the era of immunohistochemical diagnoses. PMID- 25277794 TI - UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in european and african american smokers. AB - BACKGROUND: Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo. METHODS: Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles. RESULTS: Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P <= 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008-0.04) and cotinine (P = <0.001-0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02-0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007 0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02-0.03) variants in African Americans were nominally associated with NNAL glucuronidation. CONCLUSIONS: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation. IMPACT: Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94-104. (c)2014 AACR. PMID- 25277796 TI - Challenges and opportunities in international molecular cancer prevention research: An ASPO Molecular Epidemiology and the Environment and International Cancer Prevention Interest Groups Report. AB - The International Agency for Research on Cancer estimates that over half of the new cancer cases and almost two-thirds of the cancer deaths in 2012 occurred in low and middle income countries. To discuss the challenges and opportunities to reducing the burden of cancer worldwide, the Molecular Epidemiology and the Environment and the International Issues in Cancer Special Interest Groups joined forces to hold a session during the 38th Annual Meeting of the American Society of Preventive Oncology (March 2014, Arlington, Virginia). The session highlighted three topics of particular interest to molecular cancer prevention researchers working internationally, specifically: 1) biomarkers in cancer research; 2) environmental exposures and cancer; and 3) molecular pathological epidemiology. A major factor for successful collaboration illuminated during the discussion was the need for strong, committed, and reliable international partners. A key element of establishing such relationships is to thoroughly involve individual international collaborators in the development of the research question; engaged international collaborators are particularly motivated to champion and shepherd the project through all necessary steps, including issues relating to institutional review boards, political sensitivity, laboratory-based assays, and tumor subtyping. Also essential is allotting time for the building, maintaining, and investing in such relationships so that successful international collaborations may take root and bloom. While there are many challenges inherent to international molecular cancer research, the opportunities for furthering the science and prevention of cancer worldwide are great, particularly at this time of increasing cancer incidence and prevalence in low and middle income countries. PMID- 25277797 TI - Does urea alter the collective hydrogen-bond dynamics in water? A dielectric relaxation study in the terahertz-frequency region. AB - We report the ultrafast collective hydrogen-bond dynamics of water in the extended hydration layer of urea by using terahertz time-domain spectroscopy in the frequency region of 0.3-2.0 THz. The complex dielectric function has been fitted using a Debye relaxation model, and the timescales obtained are in the order of approximately 9 ps and 200 fs for bulk water; this exhibits a considerable acceleration beyond the 4 M urea concentration and indicates a possible disruption in the collective hydrogen-bonded water-network structure, which, in turn, provides an indirect support for the water "structure-breaking" ability of urea. With 5 M urea in the presence of different concentrations of trimethylamine-N-oxide (TMAO), it was found that these parameters essentially follow the trend observed for TMAO itself, which signifies that any possible disruption of the water structure by urea is outdone by the strong hydrogen bonding ability of TMAO, which explains its ability to revive urea-denatured proteins to their respective native states. PMID- 25277798 TI - SIM2 maintains innate host defense of the small intestine. AB - The single-minded 2 (SIM2) protein is a basic helix-loop-helix transcription factor regulating central nervous system (CNS) development in Drosophila. In humans, SIM2 is located within the Down syndrome critical region on chromosome 21 and may be involved in the development of mental retardation phenotype in Down syndrome. In this study, knockout of SIM2 expression in mice resulted in a gas distention phenotype in the gastrointestinal tract. We found that SIM2 is required for the expression of all cryptdins and numerous other antimicrobial peptides (AMPs) expressed in the small intestine. The mechanism underlying how SIM2 controls AMP expression involves both direct and indirect regulations. For the cryptdin genes, SIM2 regulates their expression by modulating transcription factor 7-like 2, a crucial regulator in the Wnt/beta-catenin signaling pathway, while for other AMP genes, such as RegIIIgamma, SIM2 directly activates their promoter activity. Our results establish that SIM2 is a crucial regulator in controlling expression of intestinal AMPs to maintain intestinal innate immunity against microbes. PMID- 25277801 TI - Cuts in aid are linked to Ebola crisis, say MPs. PMID- 25277799 TI - Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis. AB - Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of alpha1 and alpha2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6 OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-beta-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis. PMID- 25277802 TI - Pregnancy rate in endometriosis patients according to the severity of the disease after using a combined approach of laparoscopy, GnRH agonist treatment and in vitro fertilization. AB - AIM: To evaluate the effects of combined treatment approaches on endometriosis associated infertility in different stages of endometriosis using laparoscopy, gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and in vitro fertilization (IVF). METHODS: This retrospective study was carried out on 179 women with surgically confirmed endometriosis. Patients were divided into subgroups: group 1 (stage I-II, n = 121) and group 2 (stage III-IV, n = 58). Patients eligible for IVF, who were found to have adenomyosis or moderate to severe endometriosis, were also given postoperative GnRHa. Pregnancy and delivery rates were cumulatively calculated during 5 years according to the severity of the disease. RESULTS: The overall pregnancy, delivery and miscarriage rates were 66.5, 56.4 and 15.1%, respectively, for all patients following spontaneous and assisted conception. There were no significant differences in reproductive outcomes between the study groups. The pregnancy and delivery rates were also comparable within group 1 between the patients with and without GnRHa treatment. CONCLUSION: Pregnancy and delivery rates at different stages of endometriosis were not affected by the different approaches used for infertility treatment, with >60 and >50% of patients having conceived and delivered a baby, respectively, in both groups. The usefulness of GnRHa treatment for endometriosis patients with minimal to mild forms is questionable and deserves further studies. PMID- 25277800 TI - Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion. AB - On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL) derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen 3beta-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID- 25277803 TI - Multiple hydroxyphenethyl glucosinolate isomers and their tandem mass spectrometric distinction in a geographically structured polymorphism in the crucifer Barbarea vulgaris. AB - Two distinct glucosinolate (GSL) chemotypes (P and G-types) of Barbarea vulgaris (Brassicaceae) were known from southern Scandinavia, but whether the types were consistent in a wider geographic area was not known. Populations (26) from Eastern and Central Europe were analyzed for GSLs in order to investigate whether the two types were consistent in this area. Most (21) could be attributed to one of the previously described GSL profile types, the P-type (13 populations) and the G-type (8 populations), based on differences in the stereochemistry of 2 hydroxylation, presence or absence of phenolic glucobarbarin derivatives, and qualitative differences in indole GSL decoration (tested for a subset of 8+6 populations only). The distinction agreed with previous molecular genetic analysis of the same individuals. Geographically, the P-type typically occurred in Eastern Europe while the G-type mainly occurred in Central Europe. Of the remaining five populations, minor deviations were observed in some individuals from two populations genetically assigned to the G-type, and a hybrid population from Finland contained an additional dihydroxyphenethyl GSL isomer attributed to a combinatorial effect of P-type and G-type genes. Major exceptions to the typical GSL profiles were observed in two populations: (1) A G-type population from Slovenia deviated by a high frequency of a known variant in glucobarbarin biosynthesis ('NAS form') co-occurring with usual G-type individuals. (2) A population from Caucasus exhibited a highly deviating GSL profile dominated by p hydroxyphenethyl GSL that was insignificant in other accessions, as well as two GSLs investigated by NMR, m-hydroxyphenethylGSL and a partially identified m,p disubstituted hydroxy-methoxy derivative of phenethylGSL. Tandem HPLC-MS of seven NMR-identified desulfoGSLs was carried out and interpreted for increased certainty in peak identification and as a tool for partial structure elucidation. The distinct, geographically separated chemotypes and rare variants are discussed in relation to future taxonomic revision and the genetics and ecology of GSLs in B. vulgaris. PMID- 25277804 TI - Involvement of CSE/ H2S in high glucose induced aberrant secretion of adipokines in 3T3-L1 adipocytes. AB - BACKGROUND: Deregulated secretion of adipokines contributes to subclinical systemic inflammation associated with type 2 diabetes mellitus (T2DM). However, the mechanisms underlying are not fully understood. Hydrogen sulfide (H2S), as an endogenous gasotransmitter, possesses an anti-inflammation activity. The aim of this study was to examine the possible involvement of H2S in high glucose induced adipokine secretion in 3T3-L1 adipocytes. METHODS: The expression of cystathionine-gamma-lyase (CSE), the H2S-forming enzyme, was evaluated by Western blotting and real-time PCR. The secretion of TNF-alpha, MCP-1 and adiponectin was determined by radioimmunoassay and enzyme-linked immunosorbent assay (ELISA), respectively. Lentiviral empty vector and vector expressing mouse CSE were used for in vitro transduction. RESULTS: High glucose (HG) significantly decreased CSE expression at both protein and mRNA levels in mature 3T3-L1 adipocytes. In parallel, HG significantly increased secretion of MCP-1 while decreasing secretion of adiponectin, but had no effect on secretion of TNF-alpha. HG induced changes in MCP-1 and adiponectin secretion were partly attenuated by forced expression of CSE or sodium hydrosulfide (NaHS), a source of exogenous H2S. CONCLUSION: High glucose induces aberrant secretion of adipokines in mature 3T3 L1 adipocytes, favoring inflammation. The mechanism is partly related to inhibition of CSE/ H2S system. PMID- 25277805 TI - Osteochondroma of the glenoid fossa--report of two cases with sudden onset of symptoms. AB - Osteochondroma of the temporomandibular joint is a rare condition that most frequently affects the mandibular condyle. Fixed osteochondroma originating from the glenoid fossa is extremely rare and a literature search identified only two reported cases. The cases of two additional patients in whom osteochondroma developed in the posterior part of the glenoid fossa leading to the sudden onset of chin deviation and malocclusion are reported herein. We conclude that osteochondroma of the glenoid fossa is a slow growing benign tumour with typical clinical and radiological features. It requires surgical treatment, comprising resection of the tumour. Recurrence appears unlikely. PMID- 25277806 TI - Practitioner experience with sonic osteotomy compared to bur and ultrasonic saw: a pilot in vitro study. AB - The aim of the present study was to compare subjective experiences using bur, ultrasonic, and sonic osteotomy systems. Ten novice (N) and 10 expert (E) practitioners performed osteotomies on bovine ribs with each system. They scored ease of handling and sense of accuracy on visual analogue scales. The duration of the osteotomy procedure and the amount of noise were recorded objectively. Learning experience was evaluated in a second run. The Mann-Whitney U-test, Wilcoxon signed rank tests, and Spearman's rank correlation coefficient were used for the statistical analyses. The sonic system was significantly slower, with the worst noise impact (92.9dB; standard deviation (SD) 7.1). However, both user groups improved significantly in the second run (N 7.9, E 7.6). There were no significant differences in handling. The sense of accuracy was evaluated to be significantly best for the sonic system (N 8.4, E 8.4), compared to the ultrasonic system (N 7.1, E 7.1; both P=0.043) and bur system (N 5.5, P=0.002; E 6.0, P=0.006). The practitioners had a promising experience with the application of the ultrasonic system and particularly with the sonic system. PMID- 25277807 TI - Thermographic monitoring of wound healing and oral health-related quality of life in patients treated with laser (aPDT) after impacted mandibular third molar removal. AB - The objective of this study was to assess the impact of low-level laser therapy on wound swelling, wound temperature changes, and oral health-related quality of life (OHRQoL) after surgical removal of impacted lower third molars. Forty patients with impacted lower third molars requiring surgical removal participated in this study; all were Pell-Gregory class IIB or IIC. The patients were divided randomly into two groups for post-extraction therapy. One group received antimicrobial photodynamic therapy (aPDT) and the other received no additional therapy (placebo group). Temperature measurements were done using an infrared thermographic camera on days 3 and 7 postoperative. OHRQoL was assessed in both groups on day 7 using the Oral Health Impact Profile questionnaire translated into Croatian (OHIP-14-CRO). Prior to surgical treatment, there was no difference in patient characteristics between the two groups. A significantly lower temperature and less wound swelling were recorded on day 3 postoperative in the aPDT group compared to the control group (P<0.001). Participants in the aPDT group also had significantly lower OHIP-14-CRO summary scores (P<0.01). The present study showed beneficial effects of the aPDT modality of low-level laser therapy: postoperative wound swelling was reduced and wound temperature decreased, and OHRQoL was better through the 7-day postoperative period in comparison to the placebo group. PMID- 25277809 TI - Neotropical Ablabesmyia Johannsen (Diptera: Chironomidae, Tanypodinae)-part I. AB - This is a series of three manuscripts about the genus Ablabesmyia. In the first new species are described, three species are re-examined and keys to males, pupae and larvae of known neotropical species are provided and an emended generic diagnosis of Ablabesmyia is given. The second manuscript will analyze the molecular data of Neotropical species and the third one will check, through a phylogenetic analysis, the truth of subgenera. In this study, twenty-four new species of Ablabesmyia Johannsen are described and figured: A. arquata, A. cauame, A. commata, A. communiba, A. cordeiroi, A, depaulai, A. diversa, A. ducke, A. fazzari, A. fusariae, A. gessnerae, A. gigas, A. jaquirana, A. laurindoi, A. manauara, A. martha, A. novema, A. parannulata, A. parareissi, A. pinhoi, A. rafaeli, A. separata, A. strixinoae and A. suiamissu. We re-examined A. cinctipes (Johannsen), A. infumata (Edwards) and A. metica Roback. The species were collected in Brazil, in lentic systems. Keys to males, pupae and larvae of known neotropical species of the genus Ablabesmyia are provided and an emended generic diagnosis of Ablabesmyia is given. PMID- 25277810 TI - Semiconducting single-walled carbon nanotubes sorting with a removable solubilizer based on dynamic supramolecular coordination chemistry. AB - Highly pure semiconducting single-walled carbon nanotubes (SWNTs) are essential for the next generation of electronic devices, such as field-effect transistors and photovoltaic applications; however, contamination by metallic SWNTs reduces the efficiency of their associated devices. Here we report a simple and efficient method for the separation of semiconducting- and metallic SWNTs based on supramolecular complex chemistry. We here describe the synthesis of metal coordination polymers (CP-Ms) composed of a fluorene-bridged bis-phenanthroline ligand and metal ions. On the basis of a difference in the 'solubility product' of CP-M-solubilized semiconducting SWNTs and metallic SWNTs, we readily separated semiconducting SWNTs. Furthermore, the CP-M polymers on the SWNTs were simply removed by adding a protic acid and inducing depolymerization to the monomer components. We also describe molecular mechanics calculations to reveal the difference of binding and wrapping mode between CP-M/semiconducting SWNTs and CP M/metallic SWNTs. This study opens a new stage for the use of such highly pure semiconducting SWNTs in many possible applications. PMID- 25277808 TI - Prevalence of vitamin D inadequacy in athletes: a systematic-review and meta analysis. AB - BACKGROUND: Vitamin D is essential for maintaining optimal bone health. The prevalence of vitamin D inadequacy in athletes is currently unclear. OBJECTIVE: The objective of this study is to determine the prevalence of vitamin D inadequacy in athletes. METHODS: We conducted a systematic review and meta analysis. Multiple databases were searched and studies assessing serum 25 hydroxyvitamin D [25(OH)D] status in athletes were identified. Serum 25(OH)D is measured to clinically determine vitamin D status. Reviewers independently selected the eligible articles, assessed the methodological quality, and extracted data. Disagreements were resolved by consensus. Weighted proportions of vitamin D inadequacy [serum 25(OH)D <32 ng/mL] were calculated (DerSimonian-Laird random-effects model) and compared using Chi-squared (chi (2)) test. Subgroup analyses were conducted and risk ratios (RRs) with 95 % confidence intervals (CIs) were reported. RESULTS: Twenty-three studies with 2,313 athletes [mean (standard deviation) age 22.5 (5.0) years, 76 % male] were included. Of 2,313 athletes, 56 % (44-67 %) had vitamin D inadequacy that significantly varied by geographical location (p < 0.001). It was significantly higher in the UK and in the Middle East. The risk significantly increased for winter and spring seasons (RR 1.85; 95 % CI 1.27-2.70), indoor sport activities (RR 1.19; 95 % CI 1.09 1.30), and mixed sport activities (RR 2.54; 95 % CI 1.03-6.26). The risk was slightly higher for >40 degrees N latitude [RR 1.14 (95 % CI 0.91-1.44)] but it increased significantly [RR 1.85 (1.35-2.53)] after excluding the Middle East as an outlier. Seven studies with 359 athletes reported injuries. The prevalence of injuries in athletes was 43 % (95 % CI 20-68) [bone related = 19 % (95 % CI 7 36); muscle and soft-tissue = 37.5 % (95 % CI 11.5-68.5)]. CONCLUSION: Despite the limitations of the current evidence, the prevalence of vitamin D inadequacy in athletes is prominent. The risk significantly increases in higher latitudes, in winter and early spring seasons, and for indoor sport activities. Regular investigation of vitamin D status using reliable assays and supplementation is essential to ensure healthy athletes. The prevalence of injuries in athletes is notable but its association with vitamin D status is unclear. A well-designed longitudinal study is needed to answer this possible association. PMID- 25277811 TI - Pathogenesis of non-antibody mediated transfusion-related acute lung injury from bench to bedside. AB - Transfusion-related acute lung injury (TRALI) is a major cause of transfusion related mortality. Causative factors are divided in antibody mediated TRALI and non-antibody mediated TRALI. Antibody mediated TRALI is caused by passive transfusion of cognate antibodies and non-antibody mediated TRALI is caused by transfusion of aged cellular blood products. This review focuses on mechanisms in non-antibody mediated TRALI which includes soluble mediators accumulating during storage of red blood cells (RBCs) and platelets (PLTs), as well as changes in morphology and function of aged PLTs and RBCs. These mediators cause TRALI in two hit animal models and have been implicated in TRALI onset in clinical studies. Pre-clinical studies show a clear relation between TRALI and increased storage time of cellular blood products. Observational clinical studies however report conflicting data. Knowledge of pathophysiological mechanisms of TRALI is necessary to improve storage conditions of blood products, develop prevention strategies and develop a therapy for TRALI. PMID- 25277812 TI - Detection of Bacillus thuringiensis Cry1Ab protein based on surface plasmon resonance immunosensor. AB - Two novel surface plasmon resonance immunosensors were fabricated for detection of the Bacillus thuringiensis Cry1Ab protein and to demonstrate their performance in analyzing Cry1Ab protein in crop samples. Sensor 2 was modified by 1,6 hexanedithiol, Au/Ag alloy nanoparticles, 3-mercaptopropionic acid, and protein A (or not [sensor 1]), with Cry1Ab monoclonal antibody. As a result, both of the immunosensors exhibited satisfactory linear responses in the Cry1Ab protein concentration ranges of 10 to 500ngml(-1) and 8 to 1000ngml(-1), and the detection limits were 5.0 and 4.8ngml(-1), respectively. The immunosensors possessed good specificity and acceptable reproducibility. In addition, crop samples could be analyzed after a simple treatment. The transgenic crops could be easily identified from the conventional ones by the two immunosensors. PMID- 25277813 TI - Improved reproducibility in genome-wide DNA methylation analysis for PAXgene fixed samples compared with restored formalin-fixed and paraffin-embedded DNA. AB - Formalin fixation has been the standard method for conservation of clinical specimens for decades. However, a major drawback is the high degradation of nucleic acids, which complicates its use in genome-wide analyses. Unbiased identification of biomarkers, however, requires genome-wide studies, precluding the use of the valuable archives of specimens with long-term follow-up data. Therefore, restoration protocols for DNA from formalin-fixed and paraffin embedded (FFPE) samples have been developed, although they are cost-intensive and time-consuming. An alternative to FFPE and snap-freezing is the PAXgene Tissue System, developed for simultaneous preservation of morphology, proteins, and nucleic acids. In the current study, we compared the performance of DNA from either PAXgene or formalin-fixed tissues to snap-frozen material for genome-wide DNA methylation analysis using the Illumina 450K BeadChip. Quantitative DNA methylation analysis demonstrated that the methylation profile in PAXgene-fixed tissues showed, in comparison with restored FFPE samples, a higher concordance with the profile detected in frozen samples. We demonstrate, for the first time, that DNA from PAXgene conserved tissue performs better compared with restored FFPE DNA in genome-wide DNA methylation analysis. In addition, DNA from PAXgene tissue can be directly used on the array without prior restoration, rendering the analytical process significantly more time- and cost-effective. PMID- 25277814 TI - Highly reproducible quantification of apoptotic cells using micropatterned culture of neurons. AB - The quantification of apoptotic cells is an integral component of many cell-based assays in biological studies. However, current methods for quantifying apoptotic cells using conventional random cultures have shown great limitations, especially for the quantification of primary neurons. Randomly distributed neurons under primary culture conditions can lead to biased estimates, and vastly different estimates of cell numbers can be produced within the same experiment. In this study, we developed a simple, accurate, and reliable technique for quantifying apoptotic neurons by means of micropatterned cell cultures. A polydimethylsiloxane (PDMS) microstencil was used as a physical mask for micropatterning cell cultures, and primary granular neurons (GNs) were successfully cultured within the micropattern-confined regions and homogeneously distributed over the entire field of each pattern. As compared with the conventional method based on random cultures, the micropatterned culture method allowed for highly reproducible quantification of apoptotic cells. These results were also confirmed by using GNs derived from mice with neurodegeneration. We hope that this micropatterning method based on the use of a PDMS microstencil can overcome the technical obstacles existing in current biological studies and will serve as a powerful tool for facilitating the study of apoptosis-involved diseases. PMID- 25277815 TI - A new peptide substrate for enhanced botulinum neurotoxin type B detection by endopeptidase-liquid chromatography-tandem mass spectrometry/multiple reaction monitoring assay. AB - Botulinum neurotoxins (BoNTs) are the most toxic proteins in nature. Rapid and sensitive detection of BoNTs is achieved by the endopeptidase-mass spectrometry (Endopep-MS) assay. In this assay, BoNT cleaves a specific peptide substrate and the cleaved products are analyzed by MS. Here we describe the design of a new peptide substrate for improved detection of BoNT type B (BoNT/B) in the Endopep MS assay. Our strategy was based on reported BoNT/B-substrate interactions integrated with analysis method efficiency considerations. Incorporation of the new peptide led to a 5-fold increased sensitivity of the assay both in buffer and in a clinically relevant human spiked serum. PMID- 25277816 TI - Immunofluorescent detection of the activation of the small GTPase Rac1 in mouse skeletal muscle fibers. AB - The small GTPase Rac1 acts as a molecular switch of intracellular signaling in mammals. For understanding the regulatory mechanism, it is important to identify subcellular locations in which Rac1 is activated following multiple extracellular stimuli. However, it is difficult to detect Rac1 activation in situ in animal tissues, and thus a novel method is highly desirable. Here, we report a simple method to visualize the activation of endogenous Rac1 in mouse skeletal muscle fibers. In this assay, specific interaction between activated Rac1 and a binding polypeptide is detected by immunofluorescent microscopy. This approach is readily applicable to other small GTPases. PMID- 25277818 TI - Pelvic arterial occlusive disease affects the RhoA/Rho-kinase pathway in bladder smooth muscle. AB - PURPOSE: We investigated the effect of pelvic arterial occlusive disease on the RhoA/Rho-kinase pathway in a rat model of chronic bladder ischemia. MATERIALS AND METHODS: Male adult Sprague Dawley(r) rats at age 16 weeks were divided into arterial endothelial injury and control groups. The injury group underwent balloon endothelial injury of the bilateral iliac arteries and received a 2% cholesterol diet to induce pelvic arterial occlusive disease. The control group received a regular diet. At 8 weeks cystometrograms were performed. Bladder tissue was harvested for pharmacological studies and Western blot. RESULTS: Cystometrograms showed significantly lower bladder capacity in the arterial endothelial injury group than in controls. Organ bath studies revealed significantly decreased phasic contractions induced by carbachol in bladder strips from the injury group than from controls. In controls bladder strip tonic contractions induced by carbachol were significantly decreased compared with phasic contractions. However, no significant difference was observed between phasic and tonic contractions in the injury group. The Rho-kinase inhibitor Y 27632 produced a concentration dependent decrease in tonic contractions, which was more pronounced in the injury group. Western blot showed significantly increased RhoA and Rho-kinase beta expression in the injury group. CONCLUSIONS: Our results suggest that pelvic arterial occlusive disease can affect the RhoA/Rho-kinase pathway in the bladder. This pathway might possibly be involved in the maintenance of tonic contraction and contribute to the bladder hyperactivity caused by pelvic arterial occlusive disease. PMID- 25277817 TI - Gene Therapy for Autoimmune Disease. AB - Advances in understanding the immunological and molecular basis of autoimmune diseases have made gene therapy a promising approach to treat the affected patients. Gene therapy for autoimmune diseases aims to regulate the levels of proinflammatory cytokines or molecules and the infiltration of lymphocytes to the effected sites through successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain the immune tolerance to the relevant autoantigens and improve clinical outcomes for patients. Here, we summarize the recent progress in identifying genes responsible for autoimmune diseases and present examples where gene therapy has been applied as treatments or prevention in autoimmune diseases both in animal models and the clinical trials. Discussion on the advantages and pitfalls of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of autoimmune diseases. PMID- 25277819 TI - Risk of contralateral second primary breast cancer according to hormone receptor status in Germany. AB - INTRODUCTION: Hormone receptor (HR) status has become an established target in treatment strategies of breast cancer. Population-based estimates of contralateral breast cancer (CBC) incidence by HR subtype in particular are limited. The aim of this study was to provide detailed data on CBC incidence for Germany. METHODS: Invasive breast cancer data were extracted on 49,804 women yielding 594 second primaries from the cancer registries of the Federal States of Brandenburg and Saarland and the area of Munich for the period from 1998 to 2007. Multiple imputation was used on missing values for HR status. We estimated standardized incidence ratios (SIRs) with 95% confidence intervals (95%CIs). RESULTS: SIR estimates of CBC among women diagnosed with an invasive first primary breast cancer (FBC) of any HR subtype ranged from 1.0 to 1.5 in the three registries. Pooling three registries' data, the SIR of HR-positive CBC was 0.7 (95%CI: 0.6 to 0.8) among women with HR-positive FBC. For those women with HR negative FBC, the SIR of HR-negative CBC was 8.9 (95%CI: 7.1 to 11.1). Among women with FBC diagnosed before the age of 50 years, incidence of CBC was increased, especially for HR-negative FBC (SIR: 9.2; 95%CI: 7.1 to 11.9). CONCLUSIONS: HR status of the first primary and age at first diagnosis is relevant for predicting risk of CBC. Particularly, patients with HR-negative FBC had elevated risks. PMID- 25277821 TI - Single-molecule surface-enhanced Raman spectroscopy with nanowatt excitation. AB - We demonstrate the possibility of single molecule (SM) detection via surface enhanced Raman spectroscopy (SERS) in two seemingly challenging and unexpected cases: first with ultra-low excitation powers of the order of nanowatts and second in as-synthesized and not deliberately-aggregated silver colloid solution. The experiments are carried out using the bi-analyte method on a methylated form of Rhodamine 6G and one of its isotopologues excited at 514 nm close to the electronic resonance. This study spectacularly highlights the fact that SM-SERS detection is much more common and easier to achieve than typically thought, in particular in the case of resonance Raman excitation. As a result, SM-SERS detection in such cases should not be viewed as an indication of good SERS substrate performance as sometimes implicitly assumed. PMID- 25277820 TI - Predicting post-vaccination autoimmunity: who might be at risk? AB - Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded in improving public health. However, adverse effects, including autoimmune conditions may occur following vaccinations (autoimmune/inflammatory syndrome induced by adjuvants--ASIA syndrome). It has been postulated that autoimmunity could be triggered or enhanced by the vaccine immunogen contents, as well as by adjuvants, which are used to increase the immune reaction to the immunogen. Fortunately, vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the number of individuals developing post-vaccination ASIA. In this perspective we defined four groups of individuals who might be susceptible to develop vaccination-induced ASIA: patients with prior post-vaccination autoimmune phenomena, patients with a medical history of autoimmunity, patients with a history of allergic reactions, and individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases; asymptomatic carriers of autoantibodies; carrying certain genetic profiles, etc.). PMID- 25277822 TI - Molecular mapping of adult plant resistance to Parastagonospora nodorum leaf blotch in bread wheat lines 'Shanghai-3/Catbird' and 'Naxos'. AB - KEY MESSAGE: The field resistance to Parastagonospora nodorum leaf blotch in SHA3/CBRD is based on many genes with minor effects. Parastagonospora nodorum leaf blotch is a severe wheat disease in Norway and other regions with humid and rainy climate. It causes grain shriveling and reduced yield in years of epidemics. Shanghai-3/Catbird (SHA3/CBRD), a CIMMYT breeding line, was observed to be resistant to P. nodorum leaf blotch in the field. The objective of the current study was to map the genetic factors related to its resistance. A recombinant inbred line population from a cross between SHA3/CBRD and the susceptible German spring cv. Naxos was tested in field trials over 4 years (2010, 2011, 2012 and 2013) with natural infection supplied with mist irrigation. Leaf blotch severity was scored together with plant height, heading date and maturity date in these trials. A testing data set was also available from other field trials with the same population. Totally, two major and six minor QTL were detected for leaf blotch resistance. The major QTL on chromosome 3BL with resistance contributed by Naxos was consistent across all environments and explained up to 12 % of the phenotypic variation. Another major QTL on 3B with resistance from SHA3/CBRD was significant in 2010, 2013 and the testing data set and explained up to 12 % of the phenotypic variation. Minor QTL were detected on 1B, 3AS, 5BS, 5BL, 7A and 7B. The 5BS QTL was likely caused by Snn3-B1, with sensitivity contributed by Naxos. The 5BL QTL mapped to the Tsn1 region, but was likely caused by other mechanisms since both parents were insensitive to ToxA. PMID- 25277823 TI - Use of residual banana for polyhydroxybutyrate (PHB) production: case of study in an integrated biorefinery. AB - Polyhydroxybutyrate is a type of biopolymer that can be produced from hydrolyzed polysaccharide materials and could eventually replace polypropylene and polyethylene, being biodegradable, biocompatible and produced from renewable carbon sources. However, polyhydroxybutyrate is not still competitive compared to petrochemical polymers due to their high production costs. The improvement of the production processes requires a search for new alternative raw materials, design of the pretreatment technique and improvement in the fermentation and separation steps. In addition, if the polyhydroxybutyrate production is coupled into a multiproduct biorefinery it could increase the economic and environmental availability of the process through energy and mass integration strategies. In this work alternatives of energy and mass integrations for the production of polyhydroxybutyrate into a biorefinery from residual banana (an agro-industrial waste) were analyzed. The results show that the energetic integration can reduce up to 30.6% the global energy requirements of the process and the mass integration allows a 35% in water savings. Thus, this work demonstrates that energy and mass integration in a biorefinery is a very important way for the optimal use of energy and water resources hence decreasing the production cost and the negative environmental impacts. PMID- 25277824 TI - Comparison of the food waste degradation rate and microbial community in the matrix between two biodegradation agents in a food waste disposer. AB - To reduce the proportion of food waste in municipal solid waste, a food waste biodegradation experiment with two biodegradation agents was conducted for seven weeks with 500 g of food waste added every day into each disposer. The agent containing four biodegradation bacterial strains showed higher degradation rates and matrix temperatures than that containing two. Furthermore, significant differences in the microbiological community structures of the matrixes were found not only between the two biodegradation systems but also among different stages in the same degradation system based on DGGE profiles. The F2 strain exhibited the highest DGGE optical density (OD) value among biodegradation systems and at all experimental stages, suggesting it was a dominant strain during food waste degradation. PMID- 25277825 TI - Stabilization of heavy metals in MSWI fly ash using silica fume. AB - The objective of this work was to investigate the feasibility and effectiveness of silica fume on stabilizing heavy metals in municipal solid waste incineration (MSWI) fly ash. In addition to compressive strength measurements, hydrated pastes were characterized by X-ray diffraction (XRD), thermal-analyses (DTA/TG), and MAS NMR ((27)Al and (29)Si) techniques. It was found that silica fume additions could effectively reduce the leaching of toxic heavy metals. At the addition of 20% silica fume, leaching concentrations for Cu, Pb and Zn of the hydrated paste cured for 7 days decreased from 0.32 mg/L to 0.05 mg/L, 40.99 mg/L to 4.40 mg/L, and 6.96 mg/L to 0.21 mg/L compared with the MSWI fly ash. After curing for 135 days, Cd and Pb in the leachates were not detected, while Cu and Zn concentrations decreased to 0.02 mg/L and 0.03 mg/L. The speciation of Pb and Cd by the modified version of the European Community Bureau of Reference (BCR) extractions showed that these metals converted into more stable state in hydrated pastes of MSWI fly ash in the presence of silica fume. Although exchangeable and weak-acid soluble fractions of Cu and Zn increased with hydration time, silica fume addition of 10% can satisfy the requirement of detoxification for heavy metals investigated in terms of the identification standard of hazardous waste of China. PMID- 25277826 TI - Making in-roads across the youth mental health landscape in Singapore: the Community Health Assessment Team (CHAT). AB - AIM: Adolescence and early adulthood is marked by physical, emotional and psychological changes, and is the peak onset of mental disorders. Internationally, one-fifth of children and adolescents have serious mental health problems, yet services catering to them are scarce. Locally, traditional mental health services are associated with much stigma. In 2009, the Community Health Assessment Team (CHAT), a youth-focused outreach and assessment service, was set up to address service gaps and care barriers. METHODS: CHAT's key offering is a free and confidential mental health assessment service to facilitate help-seeking individuals between the ages of 16 and 30 gain access to early treatment. Young persons' profile and assessment outcomes were collected and entered into a database. RESULTS: Between May 2009 and March 2013, CHAT received 601 referrals: 40.1% (241/601) from young persons themselves and 40.9% (246/601) from school or community counsellors. 79.2% (313/395) of those assessed had mental health issues. 61.5% (243/395) were referred to specialist clinics and 28.6% (113/395) to school or community counsellors. CONCLUSION: There is a steady increase in our referrals; majority are self-referred or referred from school and community counsellors. This attests to the success of our general outreach and targeted capacity-building efforts. Cognizant of young persons' distress, CHAT continues to work with downstream services for continuity of care, which also presents opportunities to consolidate and expand our network of specialist and community partners. Future directions seek to address current challenges: having a mobile platform to complement our face-to-face assessments, and building collaborations to provide holistic services for young persons. PMID- 25277827 TI - A new tool to evaluate postgraduate training posts: the Job Evaluation Survey Tool (JEST). AB - BACKGROUND: Three reports in 2013 about healthcare and patient safety in the UK, namely Berwick, Francis and Keogh have highlighted the need for junior doctors' views about their training experience to be heard. In the UK, the General Medical Council (GMC) quality assures medical training programmes and requires postgraduate deaneries to undertake quality management and monitoring of all training posts in their area. The aim of this study was to develop a simple trainee questionnaire for evaluation of postgraduate training posts based on the GMC, UK standards and to look at the reliability and validity including comparison with a well-established and internationally validated tool, the Postgraduate Hospital Educational Environment Measure (PHEEM). METHODS: The Job Evaluation Survey Tool (JEST), a fifteen item job evaluation questionnaire was drawn up in 2006, piloted with Foundation doctors (2007), field tested with specialist paediatric registrars (2008) and used over a three year period (2008 11) by Foundation Doctors. Statistical analyses including descriptives, reliability, correlation and factor analysis were undertaken and JEST compared with PHEEM. RESULTS: The JEST had a reliability of 0.91 in the pilot study of 76 Foundation doctors, 0.88 in field testing of 173 Paediatric specialist registrars and 0.91 in three years of general use in foundation training with 3367 doctors completing JEST. Correlation of JEST with PHEEM was 0.80 (p < 0.001). Factor analysis showed two factors, a teaching factor and a social and lifestyle one. CONCLUSION: The JEST has proved to be a simple, valid and reliable evaluation tool in the monitoring and evaluation of postgraduate hospital training posts. PMID- 25277828 TI - [Consensus statement: Stroke prevention in nonvalvular atrial fibrillation in special consideration of the new direct oral anticoagulants]. AB - The introduction of new direct oral anticoagulants has changed the treatment of nonvalvular atrial fibrillation. However, these changes are not yet fully reflected in current guidelines.This consensus statement, endorsed by six Austrian medical societies, provides guidance to current prophylactic approaches of thromboembolic events in nonvalvular atrial fibrillation on the basis of current evidence and published guidelines. Furthermore, some special subjects are treated, like changes in laboratory parameters and their interpretation under treatment with direct oral anticoagulants, treatment of bleedings, approach to operations, cardioversion and ablation, and specific neurological aspects. For a CHA2DS2-VASc-Score of >= 2, anticoagulation is recommended with a high level of evidence (1A). At the end of the consensus statement, recommendations for a number of specific patient subgroups can be found, in order to help treating physicians to arrive at appropriate therapeutic decisions. PMID- 25277830 TI - Linear and nonlinear analyses of multi-channel mechanomyographic recordings reveal heterogeneous activation of wrist extensors in presence of delayed onset muscle soreness. AB - In this study, we applied multi-channel mechanomyographic (MMG) recordings in combination with linear and nonlinear analyses to investigate muscular and musculotendinous effects of high intensity eccentric exercise. Twelve accelerometers arranged in a 3 * 4 matrix over the dominant elbow muscles were used to detect MMG activity in 12 healthy participants. Delayed onset muscle soreness was induced by repetitive high intensity eccentric contractions of the wrist extensor muscles. Average rectified values (ARV) as well as percentage of recurrence (%REC) and percentage of determinism (%DET) extracted from recurrence quantification analysis were computed from data obtained during static-dynamic contractions performed before exercise, immediately after exercise, and in presence of muscle soreness. A linear mixed model was used for the statistical analysis. The ARV, %REC, and %DET maps revealed heterogeneous MMG activity over the wrist extensor muscles before, immediately after, and in presence of muscle soreness (P<0.01). The ARVs were higher while the %REC and %DET were lower in presence of muscle soreness compared with before exercise (P<0.05). The study provides new key information on linear and nonlinear analyses of multi-channel MMG recordings of the wrist extensor muscles following eccentric exercise that results in muscle soreness. Recurrence quantification analysis can be suggested as a tool for detection of MMG changes in presence of muscle soreness. PMID- 25277829 TI - Postoperative immunosuppression markers and the occurrence of sepsis in patients with benign and malignant disease. AB - AIM: To investigate associations between the postoperative immune response and the levels of extracellular circulating DNA (cDNA), C-reactive protein (CRP), neutrophil/lymphocyte (N/L) ratio, and regulatory T (Treg) cells in the peripheral blood and their role as potential predictors of postoperative septic complications. METHODS: This was a prospective observational study involving 115 adult patients who underwent elective surgery. Patients were divided into three groups: with benign disease, with malignant disease, and with malignant disease and administration of dexamethasone. Serum CRP levels, N/L ratio, monocyte human leukocyte antigen-DR (HLA-DR) expression, proportion of Treg cells, and cDNA levels were measured at different time points before and after surgery. RESULTS: All patients had increased CRP levels after surgery. Septic patients had higher serum CRP levels at baseline. Compared with the other groups, the dexamethasone group had significantly higher CRP levels before and after surgery, a significantly higher N/L ratio before surgery, a significantly lower rise in the N/L ratio after surgery, and a significantly lower HLA-DR expression at baseline, which remained stable after surgery. In the malignant-disease group, we observed a significant postoperative decrease in the HLA-DR expression. CONCLUSIONS: Our results suggest that the immunosuppressive effect of surgery and the presence of a malignant disease may contribute to a higher risk of postoperative sepsis. Preoperative CRP levels may be a reliable predictor of sepsis in oncological patients. PMID- 25277831 TI - A method for carpal motion hysteresis quantification in 4-dimensional imaging of the wrist. AB - INTRODUCTION: Carpal bones motions exhibit hysteresis that is dependent on the direction of wrist motion, which can be seen during 4-dimensional (3D plus time) imaging of the wrist. In vitro studies have demonstrated the phenomenon of carpal hysteresis and have reported that hysteresis area increases with carpal instabilities. However, their techniques required implantation of bone markers and thus cannot be used clinically. The objective of this study is to use noninvasive 4-dimensional computed tomography (4 DCT) technique to quantify carpal hysteresis, and to determine the reliability of this method. METHOD: A cadaveric wrist mounted on a custom motion simulator was imaged using a dual source CT scanner while undergoing periodic radioulnar deviation. Ten image phases of this motion was reconstructed through retrospective cardiac gating. The rotational angles of scaphoid, lunate and triquetrum in each phase were derived through manual registration using Matlab after segmenting the bones in Analyze 8.1. These angles were then plotted against global wrist positional angles to produce the hysteresis curves and the area was calculated. The image segmentation and measurements were repeated by 2 raters to derive intra- and inter-rater reliability assessments. RESULTS: The hysteresis area was found to be larger in the lunate (96.5 deg(2)) followed by triquetrum (92.3 deg(2)) and scaphoid (67.5 deg(2)). The measurement of the total hysteresis area of the scaphoid had the highest reliability with intra- and inter-rater reliability of 95.5% and 95.4% respectively. DISCUSSION: We have demonstrated that our approach of using 4 DCT imaging can be used to assess and quantify the hysteresis of the carpal motion with good reliability. PMID- 25277832 TI - Molecularly imprinted silica-silver nanowires for tryptophan recognition. AB - We report on silver nanowires (AgNWs) coated with molecularly imprinted silica (MIP SiO2) for recognition of tryptophan (Trp). The use of AgNWs as a template confers an imprinted material with adequate mechanical strength and with a capability of recognizing Trp due to its nanomorphology when compared to spherical microparticles with a similar surface-to-volume ratio. Studies on adsorption isotherms showed the MIP-SiO2-AgNWs to exhibit homogeneous affinity sites with narrow affinity distribution. This suggests that the synthesized material behaves as a 1D nanomaterial with a large area and small thickness with very similar affinity sites. Trp release from MIP-SiO2-AgNWs was demonstrated to be dominated by the diffusion rate of Trp as controlled by the specific interactions with the imprinted silica shell. Considering these results and the lack of toxicity of silica sol-gel materials, the material offers potential in the field of drug or pharmaceutical controlled delivery, but also in optoelectronic devices, electrodes and sensors. PMID- 25277833 TI - Barriers and facilitators for medication adherence in stroke patients: a qualitative study conducted in French neurological rehabilitation units. AB - OBJECTIVE: To describe the perceptions of French patients, caregivers and healthcare professionals on stroke and secondary preventive medications. METHOD: A qualitative study was conducted, based on four predetermined topics: stroke, secondary prevention medications, patient's experience, relationship between patient/caregiver and healthcare team. RESULTS: Twenty-six interviews were conducted. Difficulties in taking medications, lack of knowledge on stroke and medication benefits, fear of over medication were identified as barriers for adherence in patients. Doubts about generic drugs were expressed by caregivers. Healthcare professionals reported lack of knowledge and absence of clinical symptoms as barriers. On the other hand, support from caregivers and healthcare professional support is essential for compliance in all participants. Patients and caregivers expressed that fear of recurrence was a facilitator for treatment compliance. CONCLUSION: This study highlights the barriers and facilitators for stroke treatment adherence and underlines the similarities and differences between the perceptions of patients, caregivers and healthcare professionals. These results must be integrated into the future French educational programs to improve medication adherence. PMID- 25277834 TI - Chemical synthesis of a synthetic analogue of the sialic acid-binding lectin siglec-7. AB - As a basis for the development of an artificial carbohydrate-binding lectin, we chemically synthesized a domain of siglec-7, a well-characterized sialic-acid binding lectin. The full polypeptide (127 amino acids) was constructed by sequential native chemical ligation (NCL) of five peptide segments. Because of poor cysteine availability for NCL, cysteine residues were introduced at suitable ligation sites; these cysteine residues were alkylated in order to mimic native glutamine or asparagine residues, or converted to an alanine residue by desulfurization after NCL. After folding the full-length polypeptide, the sialic acid-binding activity of the synthetic siglec-7 was clearly demonstrated by STD NMR and ELISA experiments. We succeeded in the synthesis of siglec-7 by installing three extra cysteine residues with side-chain modifications and found that these modifications did not affect the binding activity. PMID- 25277835 TI - Synthesis and biological evaluation of novel pyridine derivatives as potential anticancer agents and phosphodiesterase-3 inhibitors. AB - Phosphodiesterases (PDEs) have been studied in a variety of tumours; data have suggested that the levels of PDE activities are elevated and, therefore, the ratios of cGMP to cAMP are affected. In addition, PDE inhibitors are potential targets for tumour cell growth inhibition and induction of apoptosis. Nonselective PDE inhibitors, such as theophylline or aminophylline, are known regulators of growth in a variety of carcinoma cell lines, suggesting a potential role for PDE inhibitors as anticancer drugs. In the current study, we reported the synthesis of novel derivatives of 6-aryl-4-imidazolyl-2-imino-1,2 dihydropyridine-3-carbonitriles (Ia,b,c) and their 2-oxo isosteres (IIa,b,c,d). All the compounds were evaluated for their PDE3A inhibitory effects, as well as their cytotoxic effects on MCF-7 and HeLa cell lines. Moreover, structure activity relationships were studied. 4-(1-benzyl-2-ethylthio-5-imidazolyl)-6-(4 bromophenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ib) exhibited the strongest PDE3A inhibitory effects with an IC50 of 3.76+/-1.03nM. Compound Ib also showed the strongest cytotoxic effects on both the HeLa and MCF-7 cells with an IC50 of 34.3+/-2.6MUM and 50.18+/-1.11MUM, respectively. There was a direct correlation between PDE3 inhibition and anticancer activity for the synthesised compounds. The data reported here support our view that PDEs represent promising cellular targets for antitumor treatment. PMID- 25277836 TI - Breastfeeding shows a protective trend toward adolescents with higher abdominal adiposity. AB - OBJECTIVE: The question of whether breastfeeding has a protective effect against the development of overweight or obesity later in life remains controversial, especially during adolescence. The objective was to assess the relationship between breastfeeding and adolescents' body composition. METHODS: The HELENA study is a cross-sectional study involving 3,528 adolescents from 10 European cities. The outcome measures were body weight and height, subscapular skinfolds as well as waist circumferences. Breastfeeding, smoking status, and parental socioeconomic status were assessed by self-administered questionnaires. Dietary intake was recorded using two 24-hour recall surveys. Two adjustment approaches were used: i) covariance analysis adjusted for confounding factors (propensity score adjustment) and ii) multivariate quantile regression. RESULTS: After adjustment, no significant associations were observed between breastfeeding and body composition parameters (BMI Z-score; sum of skinfolds; waist-to-height ratio). An adjusted quantile regression analysis showed a non-significant trend for a protective effect of breastfeeding toward the highest percentiles of adiposity in boys but not in girls. This is of particular interest with respect to the superiority of the waist-to-height ratio over waist circumference and BMI for detecting cardiometabolic risk factors. CONCLUSION: This first European study, including a large set of factors influencing adolescents' body composition, showed a non-significant trend toward a protective effect of breastfeeding on highest percentiles of adolescent's abdominal adiposity. PMID- 25277837 TI - Occurrence of a myxozoan parasite Myxidium streisingeri n. sp. in laboratory zebrafish Danio rerio. AB - Over several years of screening diagnostic cases, the Zebrafish International Resource Center Health Services has encountered a myxozoan parasite of the ducts associated with the kidney in zebrafish, Danio rerio , from an average of 21% of facilities submitting specimens over 5 yr. The parasite is coelozoic and is associated with no appreciable histological changes. Plasmodia bear ovoid spores with 3 sutural ridges. Spores are consistent with the genus Myxidium, but they are distinct from any known species and are thus described as Myxidium streisingeri n. sp. Phylogenetically, this parasite is a member of the polyphyletic urinary bladder clade, which is consistent with the site of infection. The common occurrence of a myxozoan in this closed husbandry system is unexpected because these parasites are known to have complex life cycles, alternating between a vertebrate and invertebrate host. It may be that biofilters provide habitat for suitable invertebrate hosts or perhaps M. streisingeri n. sp. can be transmitted directly. Future control of this parasite in zebrafish research laboratories depends on a better understanding of this life cycle. PMID- 25277838 TI - Dissemination of ESBL-producing Escherichia coli of chicken origin to the nearby river water. AB - The dissemination of drug-resistant bacteria from animal farms to aquatic environments can pose a potential threat to public health. In this study, antimicrobial resistance, resistance genes, and genetic similarity of extended spectrum beta-lactamase (ESBL)-producing Escherichia coli of different origins (chicken feces and upstream and downstream river waters) were analyzed to track the spread of drug-resistant bacteria of animals. The results showed that a total of 29 ESBL-producing E. coli were obtained from 258 samples, and isolation rates of the ESBL-producing E. coli from chicken feces and upstream and downstream waters were 10.7% (16/150), 3.7% (1/27), and 14.8% (12/81), respectively. The ESBL-producing E. coli from upstream water was resistant to 7 antibiotics, but isolates from feces and downstream water had a higher resistance rate. In 29 ESBL producing E. coli, the most common gene was CTX-M and the SHV gene was not detected. Five ESBL-producing isolates from downstream water showed >90% similarity with the fecal isolates, while the only one isolate from upstream water had <70% similarity with fecal isolates. The results suggest that animal farms' effluent, especially the untreated wastewater, could contribute to the spread of resistance genes. PMID- 25277839 TI - Discovery and development of new antibacterial agents targeting Gram-negative bacteria in the era of pandrug resistance: is the future promising? AB - Multidrug-resistant Gram-negative bacteria continue to pose a threat, with many infections caused by these pathogens being virtually untreatable. A number of new antibacterial agents are in late stage clinical development to treat these infections. Drugs in known classes such as new quinolones, aminoglycosides, tetracyclines, and beta-lactams have been designed to evade many of the known resistance mechanisms, whereas newer drug classes include novel beta-lactamase inhibitors in combination with new or approved beta-lactams, and a peptidomimetic that have entered full clinical development. The establishment of public-private partnerships and an increase in pharmaceutical interest in antibacterial R&D are encouraging signs for the future. PMID- 25277840 TI - Expression of inflammatory markers in a genetic rodent model of depression. AB - The complex bidirectional communication between the central nervous system and the peripheral immune system is of possible relevance for both normal brain functions and the development of psychiatric disorders. The aim of this investigation was to study central expression of inflammatory markers in a genetic rat model of depression (the Flinders sensitive line (FSL) and its control, the Flinders resistant line (FRL)). A peripheral immune activation was induced by lipopolysaccharide (LPS) in order to investigate possible differences in immune reactions between the two rat lines. To confirm behavioural differences between the rat lines the forced swim test was performed, a test to assess depressive-like behaviour. Expression of candidate inflammatory genes was measured in amygdala, hippocampus, hypothalamus, prefrontal cortex and striatum using quantitative real time PCR. Our results show, for the first time, significantly lower central expression of the glial-specific protein S100B and complement factor C3 in several brain regions of the FSL rats compared to controls, both at baseline and after peripheral immune stimulation. No significant differences in immune responses to LPS were observed between the rats lines. Both S100B and C3 have been suggested to be of relevance for brain development and plasticity as well as brain disorders. These proteins may be of importance for the behavioural differences between the FSL and FRL rats, and this model may be useful in studies exploring the influence of the immune system on brain functions. PMID- 25277842 TI - Challenges in computational modelling of food breakdown and flavour release. AB - A dynamic, three dimensional (3D) computational model that predicts the breakdown of food and the release of tastants and aromas could enhance the understanding of how food is perceived during consumption. This model could also shorten the development process of new foods because many virtual foods could be assessed, and discarded if unsuitable, before any physical prototyping is required. The construction and testing of a complete 3D model of mastication presents many challenges including an accurate representation of: the anatomical movements of the oral cavity (including the teeth, tongue, cheeks and palates), the breakdown behaviour of the food, the interactions between comminuted food and saliva as the bolus is formed, the release and transport of taste and aromas and how these physical and chemical processes are perceived by a person. These challenges are discussed in reference to previous experimental and simulation work and using results of new applications of a coupled biomechanical-smoothed particle hydrodynamics (B-SPH) model. The B-SPH model is demonstrated to simulate several complicated aspects of mastication including: (1) the sensitivity of particle size to changes in the movements of the jaw and tongue; (2) large strain behaviour of food due to softening by heating; (3) interactions between solid and liquid food components; (3) the release of tastants into the saliva; and (4) the transport of tastants to the taste buds. These applications show the possibilities of a model to viably simulate mastication, but highlight the many modelling and experimental challenges that remain. PMID- 25277841 TI - Comfort for uncertainty in pathological gamblers: a fMRI study. AB - This study examined neural anticipation of monetary reward in pathological gamblers (PG) by varying the type of uncertainty associated with the reward. Ten PG and ten controls were scanned while deciding whether to accept ("bet" option, featuring high-uncertain monetary rewards) or reject ("safe" option, featuring low-certain rewards) a bet, within situations of decision-making under risk (probability of the "bet" reward is known) or ambiguity (probability of the "bet" reward is unknown). During decision under risk (as compared to ambiguity), controls exhibited activation in brain areas involved in reward processing (putamen), interoception (insula) and cognitive control (dorsolateral prefrontal cortex; middle frontal gyrus). By contrast, PG exhibited no differential brain activation as a function of the type of uncertainty associated with the "bet" option. Moreover, prior choosing of the "safe" option (as compared to "bet" choices), controls exhibited activation in the posterior insula, dorsolateral prefrontal cortex and middle frontal gyrus. By contrast, PG exhibited higher neural activation during the elaboration of "bet" choices, and in motivational arousal areas (caudate; putamen; posterior insula). Between-groups contrasts revealed that, as compared to controls, PG showed (i) decreased neural activity in the globus pallidus for decision-making under risk, as opposed to decision under ambiguity, and (ii) increased neural activity within the putamen prior to bet choices, as opposed to safe choices. These findings suggest that (i) unlike control participants, a variation in the level of uncertainty associated with monetary rewards seems to have no significant impact on PGs' decision to gamble and (ii) PG exhibit stronger brain activation while anticipating high-uncertain monetary rewards, as compared with lower-certain rewards. PMID- 25277843 TI - Role of continuous high thoracic epidural anesthesia in hippocampal apoptosis after global cerebral ischemia in rats. AB - BACKGROUND: Cervical sympathetic blockade has been found to reduce cerebral vascular resistance and improve focal cerebral ischemia/reperfusion injury. In this study, we tested the hypothesis that the sympathetic blockade of high thoracic epidural anesthesia (HTEA) would reduce hippocampal apoptosis after global cerebral ischemia (GCI) injury. METHODS: Fifteen-minute global ischemia was established by 4-vessel occlusion in adult male Wistar rats. And 0.5% bupivacaine or 0.9% saline (20 MUl//h) was infused continuously to the thoracic epidural space through the T4-5 intervertebral space from 15 minutes before ischemia to 24 hours or 72 hours after ischemia. Cerebral blood flow (CBF), Mortality, neurodeficit scores (NDS), Nissl and TUNEL staining, hippocampal superoxide dismutase (SOD) activity, malondialdehyde (MDA) concentrations, western blot of poly (ADP-ribose) polymerase (PARP) and immunohistochemical staining (PARP, Bax and Bcl-2) were determined. RESULTS: Both the hyperpefusion and hypoperfusion after reperfusion were improved by HTEA. HTEA decreased the number of apoptotic neurons in cornu ammonis area 1 (CA1), reduced PARP and Bax expressions with a decrease of Bax/Bcl-2 ratio induced by ischemic injury. The upregulation of SOD activity and the downregulation of MDA were obvious in the HTEA group compared with the GCI group. HTEA also improved NDS but not the mortality rate. CONCLUSION: Our study demonstrated that continuous HTEA attenuates hippocampal apoptosis and a behavioral deficit after global cerebral ischemia, and that these protective effects are associated with the improved microcirculation, reduced oxidative stress and the less activation of PARP. PMID- 25277844 TI - Recognition of facial emotions and identity in patients with mesial temporal lobe and idiopathic generalized epilepsy: an eye-tracking study. AB - PURPOSE: To describe visual scanning pattern for facial identity recognition (FIR) and emotion recognition (FER) in patients with idiopathic generalized (IGE) and mesial temporal lobe epilepsy (MTLE). Secondary endpoint was to correlate the results with cognitive function. METHODS: Benton Facial Recognition Test (BFRT) and Ekman&Friesen series were performed for FIR and FER respectively in 23 controls, 20 IGE and 19 MTLE patients. Eye movements were recorded by a Hi-Speed eye-tracker system. Neuropsychological tools explored cognitive function. RESULTS: Correct FIR rate was 78% in controls, 70.7% in IGE and 67.4% (p=0.009) in MTLE patients. FER hits reached 82.7% in controls, 74.3% in IGE (p=0.006) and 73.4% in MTLE (p=0.002) groups. IGE patients failed in disgust (p=0.005) and MTLE ones in fear (p=0.009) and disgust (p=0.03). FER correlated with neuropsychological scores, particularly verbal fluency (r=0.542, p<0.001). Eye tracking revealed that controls scanned faces more diffusely than IGE and MTLE patients for FIR, who tended to top facial areas. A longer scanning of the top facial area was found in the three groups for FER. Gap between top and bottom facial region fixation time decreased in MTLE patients, with more but shorter fixations in bottom facial region. However, none of these findings were statistically significant. CONCLUSION: FIR was impaired in MTLE patients, and FER in both IGE and MTLE, particularly for fear and disgust. Although not statistically significant, those with impaired FER tended to perform more diffuse eye-tracking over the faces and have cognitive dysfunction. PMID- 25277845 TI - Pre-deployment differences in glucocorticoid sensitivity of leukocytes in soldiers developing symptoms of PTSD, depression or fatigue persist after return from military deployment. AB - Deployed soldiers are at risk of developing stress-related conditions, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and severe fatigue. We previously observed condition- and cell-specific differences in sensitivity of immune cells for regulation by glucocorticoids (GCs) pre deployment between male soldiers with and without subsequent development of high levels of these stress-related symptoms. Here we investigated whether these pre deployment dysregulations in GC-sensitivity of immune cells persisted after return from military deployment. In a prospective, longitudinal study including 721 male and female soldiers, the in vitro GC-sensitivity of monocytes and T cells was assessed prior to deployment and one and six months post-deployment. Differences in the longitudinal course of sensitivity for regulation by dexamethasone (DEX) of LPS-stimulated TNF-alpha production and PHA-stimulated T cell proliferation between soldiers with and without subsequent symptom development were investigated using linear mixed models. Within the whole group, DEX-sensitivity of monocytes was significantly decreased at six months post deployment compared to the assessments pre-deployment and one month post deployment. The DEX-sensitivity of T-cells did not significantly change over time. Participants developing high levels of PTSD symptoms showed high DEX sensitivity of T-cells, while participants developing high levels of depressive symptoms showed low DEX-sensitivity of T-cells before deployment that persisted at the two time points after return. In addition, participants developing severe fatigue had low DEX-sensitivity of monocytes at all assessments. Our finding that the previously observed pre-deployment group differences in peripheral GC sensitivity persisted until at least six months after return indicates that in vitro GC-sensitivity of T-cells and monocytes may represent a persistent biological vulnerability factor for development of stress-related conditions PTSD, depression and fatigue. PMID- 25277847 TI - Fluorescence lifetime-based sensing of sodium by an optode. AB - We report a 1,2,3-triazol fluoroionophore for detecting Na(+) that shows in vitro enhancement in the Na(+)-induced fluorescence intensity and decay time. The Na(+) selective molecule 1 was incorporated into a hydrogel as a part of a fiber optical sensor. This sensor allows the direct determination of Na(+) in the range of 1-10 mM by measuring reversible fluorescence decay time changes. PMID- 25277846 TI - Malignant infiltration of the liver presenting as acute liver failure. AB - There have been few reports of acute liver failure (ALF), with encephalopathy and coagulopathy, caused by infiltration of the liver by malignant cells. We describe a case series of 27 patients with ALF caused by malignancy. We examined a large, multicenter ALF registry (1910 patients; mean age, 47.1 +/- 13.9 y) and found only 27 cases (1.4%) of ALF attributed to malignancy. Twenty cases (74%) presented with abdominal pain and 11 presented with ascites. The most common malignancies included lymphoma or leukemia (33%), breast cancer, (30%), and colon cancer (7%); 90% of the patients with lymphoma or leukemia had no history of cancer, compared with 25% of patients with breast cancer. Overall, 44% of the patients had evidence of liver masses on imaging. Diagnosis was confirmed by biopsy in 15 cases (55%) and by autopsy for 6 cases. Twenty-four patients (89%) died within 3 weeks of ALF. PMID- 25277848 TI - ACC/AAP/AHA/ASE/HRS/SCAI/SCCT/SCMR/SOPE 2014 appropriate use criteria for initial transthoracic echocardiography in outpatient pediatric cardiology: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Academy of Pediatrics, American Heart Association, American Society of Echocardiography, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography. PMID- 25277849 TI - A 6 year longitudinal study of accelerometer-measured physical activity and sedentary time in Swedish adults. AB - OBJECTIVES: The aim of this study was to investigate changes over six years in physical activity and sedentary behavior assessed with accelerometry in a representative sample of Swedish adults. DESIGN: A longitudinal study over six years. METHODS: The cohort consisted of 1172 participants (46% males) in 2002 and 511 participants (46% males) in 2008, of which 478 (45% males) had valid data on both occasions. Mean (SD) age at baseline was 45 (15) years. To analyze changes over time, a mixed linear model for average intensity physical activity (counts/min) and time in sedentary behavior and light- and moderate- or higher intensity physical activity was conducted, stratified for sex and age, and adjusted for BMI, education, self-rated health and Delta wear time. RESULTS: Over a six year period no significant changes were seen in the total cohort for average intensity and time in moderate- or higher intensity physical activity. A significant decrease in average intensity physical activity was found for men (p=0.006) and those aged 60+ years at baseline (p<0.001). A significant increase (26 min/day) for sedentary time in the total cohort (p<0.001) and for time in moderate or higher intensity physical activity among women (p<0.001) and those aged 40-59 years at baseline (p=0.014) was found over the follow-up period. CONCLUSIONS: The overall increase in sedentary time and decrease in average physical activity among men and the elderly are of concern, since they might result in an elevated risk of developing chronic diseases. PMID- 25277850 TI - Retrospective Review of Folliculitis Decalvans in 23 Patients with Course and Treatment Analysis of Long-standing Cases. AB - BACKGROUND: To date, there is no standard treatment of folliculitis decalvans (FD), a rare type of cicatricial alopecia. OBJECTIVE AND METHODS: The records of 23 patients with FD (1998-2012) were retrospectively analyzed, with added data review on the course and treatment of long-standing cases. RESULTS: Initial management consisted mostly of intralesional triamcinolone acetonide, clobetasol lotion, and either cephalexin, minocycline, doxycycline, or tetracycline. Alternatives consisted of rifampicin, clindamycin, ciprofloxacin, and isotretinoin. Remission was achieved in weeks to months in more than half of the cases, with low occurrence of relapse. The poor responders had a protracted course of temporary improvement and multiple relapses. CONCLUSION: The majority of patients showed improvement and subsequent remission with oral antibiotics. In some patients, it took years of slow taper before the antibiotic could be discontinued. Only a few patients had recalcitrant disease, with minimal response to their initial and alternative medications. PMID- 25277851 TI - Extraintestinal manifestations of inflammatory bowel disease and the influence of smoking. AB - AIMS: To define the number/frequency of organ systems affected by extraintestinal manifestations (EIMs), to identify factors affecting the clinical course of inflammatory bowel disease (IBD) and EIM development, and to determine the impact of smoking, disease duration and location on the diagnosis of EIMs in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: IBD patients were derived from a single university colorectal surgery practice. Smoking data were obtained through a modified Behavioral Risk Factor Surveillance System survey. The frequencies of arthritis/arthralgia, primary sclerosing cholangitis (PSC), ocular and cutaneous EIMs were determined. RESULTS: Of the 757 patients evaluated (CD 488, UC 269), 50% had >=1 EIM. Arthritis/arthralgia, cutaneous and ocular EIMs were significantly higher in frequency in CD compared to UC patients. Prolonged disease duration was associated with increased prevalence of arthritis/arthralgia in IBD (p <= 0.001) as well as PSC (p = 0.049), ocular (p = 0.030) and cutaneous (p = 0.009) EIMs in CD. Disease location affected the occurrence of EIMs in CD. Smoking appeared to increase the prevalence of ocular EIMs in UC (p = 0.026). CONCLUSION: Arthritis/arthralgia, cutaneous and ocular EIMs occurred in a significantly higher proportion of CD patients. CD patients with longer disease duration had a significantly higher prevalence of PSC, ocular and cutaneous EIMs. Smoking was found to increase ocular EIMs in UC. PMID- 25277852 TI - Listening to the body's response--a dedication to the teachings of Dr. Steve C. Haskins. PMID- 25277860 TI - Measuring farm sustainability using data envelope analysis with principal components: the case of Wisconsin cranberry. AB - Measuring farm sustainability performance is a crucial component for improving agricultural sustainability. While extensive assessments and indicators exist that reflect the different facets of agricultural sustainability, because of the relatively large number of measures and interactions among them, a composite indicator that integrates and aggregates over all variables is particularly useful. This paper describes and empirically evaluates a method for constructing a composite sustainability indicator that individually scores and ranks farm sustainability performance. The method first uses non-negative polychoric principal component analysis to reduce the number of variables, to remove correlation among variables and to transform categorical variables to continuous variables. Next the method applies common-weight data envelope analysis to these principal components to individually score each farm. The method solves weights endogenously and allows identifying important practices in sustainability evaluation. An empirical application to Wisconsin cranberry farms finds heterogeneity in sustainability practice adoption, implying that some farms could adopt relevant practices to improve the overall sustainability performance of the industry. PMID- 25277861 TI - Comparison of soil solution sampling techniques to assess metal fluxes from contaminated soil to groundwater. AB - The unsaturated zone plays a major role in elemental fluxes in terrestrial ecosystems. A representative chemical analysis of soil pore water is required for the interpretation of soil chemical phenomena and particularly to assess Trace Elements (TEs) mobility. This requires an optimal sampling system to avoid modification of the extracted soil water chemistry and allow for an accurate estimation of solute fluxes. In this paper, the chemical composition of soil solutions sampled by Rhizon(r) samplers connected to a standard syringe was compared to two other types of suction probes (Rhizon(r) + vacuum tube and Rhizon(r) + diverted flow system). We investigated the effects of different vacuum application procedures on concentrations of spiked elements (Cr, As, Zn) mixed as powder into the first 20 cm of 100-cm columns and non-spiked elements (Ca, Na, Mg) concentrations in two types of columns (SiO2 sand and a mixture of kaolinite + SiO2 sand substrates). Rhizon(r) was installed at different depths. The metals concentrations showed that (i) in sand, peak concentrations cannot be correctly sampled, thus the flux cannot be estimated, and the errors can easily reach a factor 2; (ii) in sand + clay columns, peak concentrations were larger, indicating that they could be sampled but, due to sorption on clay, it was not possible to compare fluxes at different depths. The different samplers tested were not able to reflect the elemental flux to groundwater and, although the Rhizon(r) + syringe device was more accurate, the best solution remains to be the use of a lysimeter, whose bottom is kept continuously at a suction close to the one existing in the soil. PMID- 25277862 TI - Calcium signalling in the ciliated protozoan model, Paramecium: strict signal localisation by epigenetically controlled positioning of different Ca2+-channels. AB - The Paramecium tetraurelia cell is highly organised, with regularly spaced elements pertinent to Ca(2+) signalling under epigenetic control. Vesicles serving as stationary Ca(2+) stores or undergoing trafficking contain Ca(2+) release channels (PtCRCs) which, according to sequence and domain comparison, are related either to inositol 1,4,5-trisphosphate (InsP3) receptors (IP3R) or to ryanodine receptor-like proteins (RyR-LP) or to both, with intermediate characteristics or deviation from conventional domain structure. Six groups of such PtCRCs have been found. The ryanodine-InsP3-receptor homology (RIH) domain is not always recognisable, in contrast to the channel domain with six trans membrane domains and the pore between transmembrane domain 5 and 6. Two CRC subtypes tested more closely, PtCRC-II and PtCRC-IV, with and without an InsP3 binding domain, reacted to InsP3 and to caffeine, respectively, and hence represent IP3Rs and RyR-LPs. IP3Rs occur in the contractile vacuole complex where they allow for stochastic constitutive Ca(2+) reflux into the cytosol. RyR-LPs are localised to cortical Ca(2+) stores; they are engaged in dense core-secretory vesicle exocytosis by Ca(2+) release, superimposed by Ca(2+)-influx via non ciliary Ca(2+)-channels. One or two different types of PtCRCs also occur in other vesicles undergoing trafficking. Since the PtCRCs described combine different features they are considered derivatives of primitive precursors. The highly regular, epigenetically controlled design of a Paramecium cell allows it to make Ca(2+) available very locally, in a most efficient way, along predetermined trafficking pathways, including regulation of exocytosis, endocytosis, phagocytosis and recycling phenomena. The activity of cilia is also regulated by Ca(2+), yet independently from any CRCs, by de- and hyperpolarisation of the cell membrane potential. PMID- 25277864 TI - Recruited metastasis suppressor NM23-H2 attenuates expression and activity of peroxisome proliferator-activated receptor delta (PPARdelta) in human cholangiocarcinoma. AB - BACKGROUND: Peroxisome proliferator-activated receptor delta (PPARdelta) is a versatile regulator of distinct biological processes and overexpression of PPARdelta in cancer may be partially related to its suppression of its own co regulators. AIMS: To determine whether recruited suppressor proteins bind to and regulate PPARdelta expression, activity and PPARdelta-dependent cholangiocarcinoma proliferation. METHODS: Yeast two-hybrid assays were done using murine PPARdelta as bait. PPARdelta mRNA expression was determined by qPCR. Protein expression was measured by western blot. Immunohistochemistry and fluorescence microscopy were used to determine PPARdelta expression and co localization with NDP Kinase alpha (NM23-H2). Cell proliferation assays were performed to determine cell numbers. RESULTS: Yeast two-hybrid screening identified NM23-H2 as a PPARdelta binding protein and their interaction was confirmed. Overexpressed PPARdelta or treatment with the agonist GW501516 resulted in increased cell proliferation. NM23-H2 siRNA activated PPARdelta luciferase promoter activity, upregulated PPARdelta RNA and protein expression and increased GW501516-stimulated CCA growth. Overexpression of NM23-H2 inhibited PPARdelta luciferase promoter activity, downregulated PPARdelta expression and AKT phosphorylation and reduced GW501516-stimulated CCA growth. CONCLUSIONS: We report the novel association of NM23-H2 with PPARdelta and the negative regulation of PPARdelta expression by NM23-H2 binding to the C-terminal region of PPARdelta. These findings provide evidence that the metastasis suppressor NM23-H2 is involved in the regulation of PPARdelta-mediated proliferation. PMID- 25277865 TI - The possible association between exposure to air pollution and the risk for congenital malformations. AB - BACKGROUND: Over the last decade, there is growing evidence that exposure to air pollution may be associated with increased risk for congenital malformations. OBJECTIVES: To evaluate the possible association between exposures to air pollution during pregnancy and congenital malformations among infants born following spontaneously conceived (SC) pregnancies and assisted reproductive technology (ART) pregnancies. METHODS: This is an historical cohort study comprising 216,730 infants: 207,825 SC infants and 8905 ART conceived infants, during the periods 1997-2004. Air pollution data including sulfur dioxide (SO2), particulate matter <10 um (PM10), nitrogen oxides (NOx) and ozone (O3) were obtained from air monitoring stations database for the study period. Using a geographic information system (GIS) and the Kriging procedure, exposure to air pollution during the first trimester and the entire pregnancy was assessed for each woman according to her residential location. Logistic regression models with generalized estimating equation (GEE) approach were used to evaluate the adjusted risk for congenital malformations. RESULTS: In the study cohort increased concentrations of PM10 and NOx pollutants in the entire pregnancy were associated with slightly increased risk for congenital malformations: OR 1.06(95% CI, 1.01 1.11) for 10 ug/m(3) increase in PM10 and OR 1.03(95% CI, 1.01-1.04) for 10 ppb increase in NOx. Specific malformations were evident in the circulatory system (for PM10 and NOx exposure) and genital organs (for NOx exposure). SO2 and O3 pollutants were not significantly associated with increased risk for congenital malformations. In the ART group higher concentrations of SO2 and O3 in entire pregnancy were associated (although not significantly) with an increased risk for congenital malformations: OR 1.06(95% CI, 0.96-1.17) for 1 ppb increase in SO2 and OR 1.15(95% CI, 0.69-1.91) for 10 ppb increase in O3. CONCLUSIONS: Exposure to higher levels of PM10 and NOx during pregnancy was associated with an increased risk for congenital malformations. Specific malformations were evident in the circulatory system and genital organs. Among ART pregnancies possible adverse association of SO2 and O3 exposure was also observed. Further studies are warranted, including more accurate exposure assessment and a larger sample size for ART pregnancies, in order to confirm these findings. PMID- 25277863 TI - Environmental drivers of ectomycorrhizal communities in Europe's temperate oak forests. AB - Ectomycorrhizal fungi are major ecological players in temperate forests, but they are rarely used in measures of forest condition because large-scale, high resolution, standardized and replicated belowground data are scarce. We carried out an analysis of ectomycorrhizas at 22 intensively monitored long-term oak plots, across nine European countries, covering complex natural and anthropogenic environmental gradients. We found that at large scales, mycorrhizal richness and evenness declined with decreasing soil pH and root density, and with increasing atmospheric nitrogen deposition. Shifts in mycorrhizas with different functional traits were detected; mycorrhizas with structures specialized for long-distance transport related differently to most environmental variables than those without. The dominant oak-specialist Lactarius quietus, with limited soil exploration abilities, responds positively to increasing nitrogen inputs and decreasing pH. In contrast, Tricholoma, Cortinarius and Piloderma species, with medium-distance soil exploration abilities, show a consistently negative response. We also determined nitrogen critical loads for moderate (9.5-13.5 kg N/ha/year) and drastic (17 kg N/ha/year) changes in belowground mycorrhizal root communities in temperate oak forests. Overall, we generated the first baseline data for ectomycorrhizal fungi in the oak forests sampled, identified nitrogen pollution as one of their major drivers at large scales and revealed fungi that individually and/or in combination with others can be used as belowground indicators of environmental characteristics. PMID- 25277866 TI - Risk of intracerebral hemorrhage after thrombolysis in patients with asymptomatic hemorrhage on T2*. AB - BACKGROUND: Intravenous thrombolysis using the tissue-type plasminogen activator (t-PA) is contraindicated for patients with a history of intracerebral hemorrhage (ICH). T2*-weighted magnetic resonance imaging (MRI) is able to detect asymptomatic ICH. If there is an association between asymptomatic ICH on T2* before t-PA therapy and ICH after t-PA therapy, we may be able to take preventive measures before starting t-PA therapy in patients with MRI-proven hemorrhage. The aim of the present study was to investigate whether asymptomatic ICH seen on T2* increases the risk of new ICH after t-PA therapy. METHODS: Patients who had consecutive stroke treated with t-PA between October 2005 and November 2013 were enrolled. A hypointense T2* signal with a diameter >5 mm was defined as asymptomatic ICH before t-PA therapy. The presence of new ICH at 24 h after t-PA therapy was assessed using T2*. Symptomatic ICH (sICH) was defined as new ICH combined with an increase in the National Institutes of Health Stroke Scale score >=4. At 3 months after onset, good and poor outcomes were defined as modified Rankin Scale (mRS) scores of 0-1 and 4-6, respectively. RESULTS: Of 300 patients (age 77 [68-83] years; 173 [58%] males), 25 (8%) had an asymptomatic ICH on T2* before t-PA therapy. Eleven (45%) patients showed an isolated asymptomatic ICH. Three (12%) patients had a round hypointense lesion similar to microbleeds. Nine (36%) patients had a hemorrhagic transformation within a prior infarcted area. Multiple asymptomatic ICHs were seen in 2 (8%) patients. The rates of good and poor outcomes at 3 months were 24 and 59% of patients with asymptomatic ICH and 38 and 41% of patients without asymptomatic ICH (p = 0.300 and 0.202, respectively). At 24 h after t-PA therapy, 11 (44%) of the 25 patients with asymptomatic ICH before t-PA therapy and 87 (32%) of 275 without asymptomatic ICH had new ICH (p = 0.265). Only 1 (4%) of 25 patients with asymptomatic ICH before t-PA therapy and 6 (2%) of 275 without asymptomatic ICH had sICH within 24 h (p = 0.460). On multivariate logistic regression analysis, neither new ICH (odds, 1.19; 95% CI, 0.40-3.54, p = 0.753) nor sICH (odds, 0.95; 95% CI, 0.08-11.90, p = 0.970) was related to asymptomatic ICH on T2* before t-PA therapy. CONCLUSION: The presence of T2* hypointensity as a marker of asymptomatic ICH may not be associated with new ICH and sICH after t-PA therapy. PMID- 25277867 TI - Can multiparametric MRI and FDG-PET predict outcome in diffuse brainstem glioma? A report from a prospective phase-II study. AB - PURPOSE: To study the impact of multiparametric MRI and (18)F-FDG-PET on the outcome of children with diffuse intrinsic pontine gliomas (DIPG). MATERIALS AND METHODS: Imaging data from a phase-II prospective therapeutic study in children with newly diagnosed DIPG were considered for evaluation. They included baseline MRI with contrast enhancement before treatment. Functional imaging included MR spectroscopy, MR perfusion and FDG-PET studies. All patients (n = 20) had baseline MRI and 11 patients had FDG-PET. Response was assessed by MRI and PET 4 weeks after therapy. Baseline imaging findings were correlated with survival. Presence or absence of adverse parameters on MRI (heterogeneous contrast enhancement, hyperperfusion or increased choline:NAA ratio) was used to develop a cumulative radiological prognostic index (RPI). Sensitivity and specificity of each imaging modality in tumour grading was estimated. RESULTS: The cumulative RPI was able to classify the patients into different grades and was predictive of overall survival (p = 0.02). MR perfusion also predicted survival (p = 0.039). Sensitivity and specificity of MRI and FDG-PET to detect low-grade gliomas were low to moderate (33-66%), but moderate to high in detecting high-grade gliomas (50-100%). Baseline FDG uptake on PET scan did not correlate with survival (p = 0.7). CONCLUSIONS: Cumulative RPI was able to classify tumours into different grades and predicted clinical outcome. At baseline, MR hyperperfusion indicated a shorter survival for DIPG patients. Sensitivity and specificity of imaging modalities to detect low-grade gliomas were poor. PMID- 25277868 TI - Drawing trauma: the therapeutic potential of witnessing the child's visual testimony of war. AB - Countertransference plays an often neglected role in witnessing children's testimony of war and trauma. A dual notion of countertransference, based on the work of Winnicott and Klein, is offered that involves both internal conflict related to early life experience and socially mediated notions of childhood, war, and trauma circulating in a given time and place. A drawing by a thirteen-year old boy living in the refugee camps in Darfur is used to show how countertransference affects our interpretation of the image, even while its symbolization in language establishes the conditions for a potentially therapeutic response. It is argued that a psychoanalytic reading can supplement the "legal-conscious terminology" in which the Darfur archive has been predominantly framed (Felman 2002, p. 5). This expanded view of witnessing involves reading the child's testimony both for the history of violence it conveys and for the social and emotional histories it calls up in the witness as the ground and possibility of justice. PMID- 25277869 TI - Mourning the body as bedrock: developmental considerations in treating transsexual patients analytically. AB - This paper introduces the concept of massive gender trauma, a clinical syndrome arising at the onerous intersection of the misgendering of transgender patients and the subjective, anguished experience of the natal body. Analysts have become increasingly aware in recent years of the complex interactions between psyche, soma, and culture. Consequently, the field is increasingly hospitable to considering the psychic risks inherent in misgendering. However, patients' body dysphoria is often left unaddressed even by analysts who seek to work within their analysands' gendered experience. Through a detailed, in-depth account of work with a five-year-old trans girl (female-identified, male-bodied), the developmental implications of the natal body's not becoming sufficiently mentalized in the course of treatment are tracked and explored. Attention to unconscious fantasy and its transformations shows the importance of helping transgender patients whose bodies are a source of suffering to be able to psychically represent their pain as a critical step in the process of a psychologically healthy transition. PMID- 25277870 TI - After the storm: living and dying in psychoanalysis. PMID- 25277871 TI - Correlates of hepcidin and NTBI according to HFE status in patients referred to a liver centre. AB - BACKGROUND/AIMS: Innately low hepcidin levels lead to iron overload in HFE associated hereditary haemochromatosis. METHODS: This study compared hepcidin and non-transferrin bound iron (NTBI) levels in untreated iron-loaded and non-iron loaded C282Y homozygotes to levels in C282Y/H63D compound heterozygotes and individuals with other HFE genotypes associated with less risk of iron overload. RESULTS: As the genotypic risk for iron overload increased, transferrin saturation and serum NTBI levels increased while serum hepcidin levels decreased. Overweight and obese male C282Y homozygotes had significantly higher hepcidin levels than male C282Y homozygotes with a normal BMI. Pearson product-moment analysis showed that serum hepcidin levels significantly correlated with HFE status, serum ferritin, age, NTBI, transferrin saturation, gender and BMI. Subsequent multiple regression analysis showed that HFE status and serum ferritin were significant independent correlates of serum hepcidin levels. CONCLUSIONS: In summary, this study has shown that while serum ferritin and HFE status are the most important determinants of hepcidin levels, factors such age, gender, BMI, transferrin saturation and NTBI all interact closely in the matrix of homeostatic iron balance. PMID- 25277872 TI - Portrayal of electronic cigarettes on YouTube. AB - BACKGROUND: As the most popular video sharing website in the world, YouTube has the potential to reach and influence a huge audience. This study aims to gain a systematic understanding of what e-cigarette messages people are being exposed to on YouTube by assessing the quantity, portrayal and reach of e-cigarette videos. METHODS: Researchers identified the top 20 search results on YouTube by relevance and view count for the following search terms: "electronic cigarettes", "e cigarettes", "ecigarettes", "ecigs", "smoking electronic cigarettes", "smoking e cigarettes", "smoking ecigarettes", "smoking ecigs". A sample of 196 unique videos was coded for overall portrayal and genre. Main topics covered in e cigarette videos were recorded and video statistics and viewer demographic information were documented. RESULTS: Among the 196 unique videos, 94% (n = 185) were "pro" to e-cigarettes and 4% (n = 8) were neutral, while there were only 2% (n = 3) that were "anti" to e-cigarettes. The top 3 most prevalent genres of videos were advertisement, user sharing and product review. 84.3% of "pro" videos contained Web links for e-cigarette purchase. 71.4% of "pro" videos claimed that e-cigarettes were healthier than conventional cigarettes. Audience was primarily from the United States, the United Kingdom and Canada and "pro" e-cigarette videos were watched more frequently and rated much more favorably than "anti" ones. CONCLUSIONS: The vast majority of information on YouTube about e-cigarettes promoted their use and depicted the use of e-cigarettes as socially acceptable. It is critical to develop appropriate health campaigns to inform e-cigarette consumers of potential harms associated with e-cigarette use. PMID- 25277873 TI - Prior response to infliximab and early serum drug concentrations predict effects of adalimumab in ulcerative colitis. AB - BACKGROUND: Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce. AIMS: To study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations. METHODS: In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response. RESULTS: Overall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1 year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58 MUg/mL for week 12 and 7.0 MUg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8-33.3; P = 0.006] and an adalimumab concentration >=4.58 MUg/mL at week 4 (OR 4.85; 95% CI 1.3-18.6; P = 0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14-23.8; P = 0.034) and adalimumab concentration at week 4 of >=7 MUg/mL (OR 3.56; 95% CI 1.17-10.79; P = 0.025). CONCLUSION: Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis. PMID- 25277874 TI - Screening for frailty among older patients with cancer that qualify for abdominal surgery. AB - OBJECTIVE: The Geriatric Assessment (GA) is an established method for evaluating and optimizing diagnostic and treatment plans. However, it requires experience and is time-consuming. Therefore, a variety of screening methods have been developed. The aim of this study was to compare their accuracy for predicting frailty among older patients with cancer qualified for abdominal surgery based on comparison to the GA. MATERIAL AND METHODS: One hundred and thirty five consecutive patients >=65years of age were prospectively enrolled. The diagnostic performance of eight screening tests was evaluated: The Vulnerable Elderly Survey (VES-13), Triage Risk Screening Tool (TRST), Geriatric 8 (G8), Groningen Frailty Index (GFI), abbreviated Comprehensive Geriatric Assessment (aCGA), Rockwood, Balducci and Fried score. RESULTS: The prevalence of frailty as diagnosed by the GA was 73%. Screening methods identified frail patients in 40-75.5% of cases. The sensitivity and specificity of these tests in predicting frailty were 52%-97% (Fried score-G8) and 44-100% (G8-Rockwood score), respectively. The positive and negative predictive values were 82-100% (Balducci-Rockwood) and 43-84% (TRST-G8), respectively. Age significantly influenced the predictive value of the screening tests whereas gender and type of cancer did not. CONCLUSION: At present, there is no universal screening test that adequately identifies frailty in at risk older patients. The results of this study showed that the aCGA and G8 were the best screens for older patients with cancer that qualified for elective abdominal surgery; the G8 had the highest sensitivity and negative predictive value and the aCGA was a good overall assessment tool. PMID- 25277875 TI - Knockout of MIMP protein in lactobacillus plantarum lost its regulation of intestinal permeability on NCM460 epithelial cells through the zonulin pathway. AB - BACKGROUND: Previous studies indicated that the micro integral membrane protein located within the media place of the integral membrane protein of Lactobacillus plantarum CGMCC 1258 had protective effects against the intestinal epithelial injury. In our study, we mean to establish micro integral membrane protein knockout Lactobacillus plantarum (LPKM) to investigate the change of its protective effects and verify the role of micro integral membrane protein on protection of normal intestinal barrier function. METHODS: Binding assay and intestinal permeability were performed to verify the protective effects of micro integral membrane protein on intestinal permeability in vitro and in vivo. Molecular mechanism was also determined as the zonulin pathway. Clinical data were also collected for further verification of relationship between zonulin level and postoperative septicemia. RESULTS: LPKM got decreased inhibition of EPEC adhesion to NCM460 cells. LPKM had lower ability to alleviate the decrease of intestinal permeability induced by enteropathogenic-e.coli, and prevent enteropathogenic-e.coli -induced increase of zonulin expression. Overexpression of zonulin lowered the intestinal permeability regulated by Lactobacillus plantarum. There was a positive correlation between zonulin level and postoperative septicemia. Therefore, micro integral membrane protein could be necessary for the protective effects of Lactobacillus plantarum on intestinal barrier. CONCLUSION: MIMP might be a positive factor for Lactobacillus plantarum to protect the intestinal epithelial cells from injury, which could be related to the zonulin pathway. PMID- 25277876 TI - Relationship of the Serum CRP Level With the Efficacy of Metformin in the Treatment of Type 2 Diabetes Mellitus: A Meta-Analysis. AB - BACKGROUND: Metformin, an anti-diabetes drug, is always used as a first-line agent for the management of T2DM. This meta-analysis was conducted to investigate whether CRP was sensitive in predicting the efficacy of metformin in the treatment of T2DM. METHODS: Potential relevant studies were identified covering the following databases: MEDLINE, Science Citation Index database, the Cochrane Library Database, PubMed, EMBASE, CINAHL, Current Contents Index, the Chinese Biomedical Database, the Chinese Journal Full-Text Database, and the Weipu Journal Database. Data from eligible studies were extracted and included into the meta-analysis using a random effects model. Statistical analyses were calculated using the version 12.0 STATA software. RESULTS: A total of 33 articles including 1,433 subjects were collected for analysis. Pooled SMD of those studies revealed that serum levels of CRP and hs-CRP significantly decreased in patients with T2DM after receiving the metformin treatment. Subgroup analysis by country yielded significant different estimates in the serum levels of CRP between the baseline and after metformin treatment in the China, Israel and India subgroups; but only detected only in the China subgroup considering serum levels of hs-CRP. Follow-up time-stratified analyses indicated that serum levels of CRP were markedly reduced in the metformin-treated group in all subgroups. While differences in serum hs CRP levels were not observed in two subgroups. CONCLUSION: Decreased serum levels of CRP and hs-CRP may contribute to a more sensitive prediction in providing a more accurate efficacy reference in the metformin drug in T2DM patients. PMID- 25277877 TI - Factors influencing persistence of Legionella pneumophila serogroup 1 in laboratory cocultures. AB - BACKGROUND: Risk for infections from Legionella pneumophila for immunocompromised individuals increases greatly when this species is present within the biofilm of the water distribution systems of hospitals or other health facilities. Multiplication and persistence of Legionella may dependent also upon planktonic growth in alternative to sessile growth. Here we compared the persistence of L. pneumophila serogroup 1 in experimental planktonic co-cultures subsided with iron, Pseudomonas aeruginosa and other non Legionella bacteria (quantified as Heterotrophic Plate Count, HPC at 37 degrees C), isolated from drinking water sources of a large hospital. RESULTS: Concentrations of L. pneumophila showed a decreasing pattern with incubation time in all co-cultures, the degree of reduction depending on the experimental treatment. In co-cultures with added P. aeruginosa, no L. pneumophila was detectable already after 4 days of incubation. In contrast in co-cultures without P. aeruginosa, HPC but not iron were significant factors in explaining the pattern of L. pneumophila, although the HPC effect was different according to the incubation time (HPC x time interaction, p < 0.01). CONCLUSIONS: Our results highlight the need of controlling for both HPC and metal constituents of the water systems of buildings used by individuals at particular risk to the effects of Legionella exposure. PMID- 25277878 TI - Translation and usability of autism screening and diagnostic tools for autism spectrum conditions in India. AB - There is a critical need for screening and diagnostic tools (SDT) for autism spectrum conditions (ASC) in regional languages in South Asia. To address this, we translated four widely used SDT (Social Communication Disorder Checklist, Autism Spectrum Quotient, Social Communication Questionnaire, and Autism Diagnostic Observation Schedule) into Bengali and Hindi, two main regional languages (~ 360 million speakers), and tested their usability in children with and without ASC. We found a significant difference in scores between children with ASC (n = 45 in Bengali, n = 40 in Hindi) and typically developing children (n = 43 in Bengali, n = 42 in Hindi) on all SDTs. These results demonstrate that these SDTs are usable in South Asia, and constitute an important resource for epidemiology research and clinical diagnosis in the region. PMID- 25277879 TI - Capsule commentary on Paul et al., Size misperception among overweight and obese families. PMID- 25277880 TI - Community nurses' judgement for the management of venous leg ulceration: a judgement analysis. AB - BACKGROUND: Nurses caring for the large numbers of people with leg ulceration play a key role in promoting quality in health via their diagnostic and treatment clinical judgements. In the UK, audit evidence suggests that the quality of these judgements is often sub optimal. Misdiagnosis and incorrect treatment choices are likely to affect healing rates, patients' quality of life, patient safety and healthcare costs. OBJECTIVES: To explore the diagnostic judgements and treatment choices of UK community nurses managing venous leg ulceration. DESIGN: A judgement analysis based on Brunswik's psychological Lens Model theory. SETTING: UK community and primary care nursing services. PARTICIPANTS: 18 community generalist nurses working in district (home) nursing teams and general practitioner services and 18 community tissue viability specialist nurses. METHODS: During 2011 and 2012, 36 nurses made diagnostic judgements and treatment choices in response to 110 clinical scenarios. Scenarios were generated from real patient cases and presented online using text and wound photographs. The consensus judgements of a panel of nurses with advanced knowledge of leg ulceration judged the same scenarios and provided a standard against which to compare the participants. Correlations and logistic regression models were constructed to generate various indices of judgement and decision "performance": accuracy (R(a)), consistency (R(s)) and information use (G) and uncertainty (R(e)). RESULTS: Taking uncertainty into account, nurses could theoretically have achieved a diagnostic level of accuracy of 0.63 but the nurses only achieved an accuracy of 0.48. For the treatment judgement (whether applying high compression was warranted) nurses could have achieved an accuracy of 0.88 but achieved only an accuracy of 0.49. This may have been due to the nurses giving insufficient weight to the diagnostic cues of medical history and appearance of the leg and ulcer and insufficient weight to the treatment cues of type of leg ulcer and pain. CONCLUSION: Clinical judgements and decisions made by nurses managing leg ulceration are complex and uncertain and some of the variability in judgements and choices can be explained by the ways in which nurses process the information and handle the uncertainties, present in clinical encounters. PMID- 25277881 TI - Somatic mutations are not observed by exome sequencing of lymphocyte DNA from monozygotic twins discordant for congenital hypothyroidism due to thyroid dysgenesis. AB - BACKGROUND/AIMS: Congenital primary hypothyroidism (CH) is a rare pediatric disorder estimated to occur in about 1:2,500 live births. Approximately half of these cases entail ectopic thyroid tissue, which is believed to result from a migration defect during embryogenesis. Approximately 3% of CH cases are explained by mutation(s) in known genes, most of which are transcription factors implicated in the embryology of the thyroid gland. Surprisingly, monozygotic (MZ) twins are usually discordant for CH due to thyroid dysgenesis, suggesting that most cases are not caused by transmitted genetic variation. One possible explanation is somatic mutation in genes involved in thyroid migration occurring after zygotic twinning. Such mutations should be observed only in the affected twin. METHODS: To test the hypothesis of somatic mutation, we performed whole exome sequencing of DNA from three pairs of MZ twins discordant for CH with ectopic glands. RESULTS: We found no somatic mutations exclusive to any of the three affected twins or in any of the unaffected twins. CONCLUSION: Either somatic mutations are not significant for the etiology of CH or else such mutations lie outside regions of the genome accessible by exome sequencing technology. PMID- 25277883 TI - Analysis of generalized interictal discharges using quantitative EEG. AB - Experimental evidence from animal models of the absence seizures suggests a focal source for the initiation of generalized spike-and-wave (GSW) discharges. Furthermore, clinical studies indicate that patients diagnosed with idiopathic generalized epilepsy (IGE) exhibit focal electroencephalographic abnormalities, which involve the thalamo-cortical circuitry. This circuitry is a key network that has been implicated in the initiation of generalized discharges, and may contribute to the pathophysiology of GSW discharges. Quantitative electroencephalogram (qEEG) analysis may be able to detect abnormalities associated with the initiation of GSW discharges. The objective of this study was to determine whether interictal GSW discharges exhibit focal characteristics using qEEG analysis. In this study, 75 EEG recordings from 64 patients were analyzed. All EEG recordings analyzed contained at least one GSW discharge. EEG recordings were obtained by a 22-channel recorder with electrodes positioned according to the international 10-20 system of electrode placement. EEG activity was recorded for 20 min including photic stimulation and hyperventilation. The EEG recordings were visually inspected, and the first unequivocally confirmed generalized spike was marked for each discharge. Three methods of source imaging analysis were applied: dipole source imaging (DSI), classical LORETA analysis recursively applied (CLARA), and equivalent dipole of independent components with cluster analysis. A total of 753 GSW discharges were identified and spatiotemporally analyzed. Source evaluation analysis using all three techniques revealed that the frontal lobe was the principal source of GSW discharges (70%), followed by the parietal and occipital lobes (14%), and the basal ganglia (12%). The main anatomical sources of GSW discharges were the anterior cingulate cortex (36%) and the medial frontal gyrus (23%). Source analysis did not reveal a common focal source of GSW discharges. However, there was a predominance of GSW discharges originating from the cingulate gyrus and the frontal lobe. PMID- 25277884 TI - Object and proper name retrieval in temporal lobe epilepsy: a study of difficulties and latencies. AB - PURPOSE: Retrieving a specific name is sometimes difficult and can be even harder when pathology affects the temporal lobes. Word finding difficulties have been well documented in temporal lobe epilepsy (TLE) but analyses have mostly concentrated on the study of accuracy. Our aim here was to go beyond simple accuracy and to provide both a quantitative and a qualitative assessment of naming difficulties and latencies in patients with TLE. METHODS: Thirty-two patients with temporal lobe epilepsy (16 with epilepsy affecting the cerebral hemisphere dominant for language (D-TLE) and 16 with epilepsy affecting the cerebral hemisphere non-dominant for language (ND-TLE)) and 34 healthy matched control subjects were included in the study. The experiment involved naming 70 photographs of objects and 70 photographs of celebrities as fast as possible. Accuracy and naming reaction times were recorded. Following each trial, a questionnaire was used to determine the specific nature of each subject's difficulty in retrieving the name (e.g., no difficulty, paraphasia, tip of the tongue, feeling of knowing the name, etc). Reaction times were analysed both across subjects and across trials. KEY FINDINGS: D-TLE patients showed consistent and quasi-systematic impairment compared to matched control subjects on both object and famous people naming. This impairment was characterized not only by lower accuracy but also by more qualitative errors and tip of the tongue phenomena. Furthermore, minimum reaction times were slowed down by about 70 ms for objects and 150 ms for famous people naming. In contrast, patients with ND TLE were less impaired, and their impairment was limited to object naming. SIGNIFICANCE: These results suggest that patients with TLE, in particular D-TLE, show a general impairment of lexical access. Furthermore, there was evidence of subtle difficulties (increased reaction times) in patients with TLE. PMID- 25277882 TI - Diastolic wall strain: a simple marker of abnormal cardiac mechanics. AB - BACKGROUND: Diastolic wall strain (DWS), defined using posterior wall thickness (PWT) measurements from standard echocardiographic images (DWS = [PWT(systole) PWT(diastole)]/PWT(systole)), has been proposed as a marker of left ventricular (LV) diastolic stiffness. However, the equation for DWS is closely related to systolic radial strain, and whether DWS is associated with abnormal cardiac mechanics (reduced systolic strains and diastolic tissue velocities) is unknown. We sought to determine the relationship between DWS and systolic and diastolic cardiac mechanics. METHODS: We calculated DWS and performed speckle-tracking analysis in a large population- and family-based study (Hypertension Genetic Epidemiology Network [HyperGEN]; N=1907 after excluding patients with ejection fraction [EF] <50% or posterior wall motion abnormalities). We measured global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively) and early diastolic (e') tissue velocities, and we determined the independent association of DWS with cardiac mechanics using linear mixed effects models to account for relatedness among study participants. We also prospectively performed receiver-operating characteristic (ROC) analysis of DWS for the detection of abnormal cardiac mechanics in a separate, prospective validation study (N=35). RESULTS: In HyperGEN (age 51 +/- 14 years, 59% female, 45% African American, 57% hypertensive), mean DWS was 0.38 +/- 0.05. DWS decreased with increasing comorbidity burden (beta-coefficient -0.013 [95% CI -0.015, -0.011]; P<0.0001). DWS was independently associated with GLS, GCS, GRS, and e' velocity (adjusted P<0.05) but not LV chamber compliance (EDV20, P=0.97). On prospective speckle-tracking analysis, DWS correlated well with GLS, GCS, and GRS (R=0.61, 0.57, and 0.73, respectively; P<0.001 for all comparisons). C-statistics for DWS as a diagnostic test for abnormal GLS, GCS, and GRS were: 0.78, 0.79, and 0.84, respectively. CONCLUSIONS: DWS, a simple parameter than can be calculated from routine 2D echocardiography, is closely associated with systolic strain parameters and early diastolic (e') tissue velocities but not LV chamber compliance. PMID- 25277885 TI - Increased cerebral oxygenation precedes generalized tonic clonic seizures. AB - Based on previous fMRI and SPECT studies, it has been suggested seizures may be preceded by increased cerebral blood flow. Recently, we demonstrated transcutaneous regional cerebral oxygen saturation (rSO2) sensors are feasible for use in patients undergoing video EEG monitoring. We reanalyzed our data to determine if seizures were consistently marked by increased cerebral oxygenation. Patients with histories of generalized tonic clonic seizures (GTCS) were recruited into our study. All subjects were evaluated with continuous 30-channel scalp EEG and 2 rSO2 sensors placed on each side of the forehead. We calculated the mean rSO2 value for the 1h epochs in the non-ictal (2h prior to seizure onset) and pre-ictal (1h prior to onset) periods. Seven primary/secondarily GTCS from 5 patients were captured. The mean rSO2 value in the non-ictal period was 75.6 +/- 5.7%. This increased to 76.0 +/- 6% in the pre-ictal period (p=0.032). Four of the 7GTCS (57.1%) were marked by >= 3 sequential rSO2 values in the pre ictal period that were >= 3 SDs greater than the mean non-ictal rSO2 value. Three GTCS (42.9%) were marked by sustained cerebral hyperemia for >= 15 consecutive readings. Our results suggest increased cerebral blood flow could be non invasively used to predict seizure occurrence. PMID- 25277886 TI - Whey protein preloads are more beneficial than soy protein preloads in regulating appetite, calorie intake, anthropometry, and body composition of overweight and obese men. AB - High-protein diets exert beneficial effects on appetite, anthropometry, and body composition; however, the effects of protein preloads depend on the amount, type, and time of consumption. Therefore, we hypothesized that long-term supplemental preloads of whey protein concentrate (WPC) and soy protein isolate (SPI) consumed 30 minutes before the largest meal would decrease appetite, calorie intake (CI), and anthropometry and improve body composition in overweight and obese men in free-living conditions. The subjects included 45 men with a body mass index between 25 and 40 kg/m(2) and who were randomly allocated to either the WPC (n = 26) or SPI (n = 19) groups. For 12 weeks, the subjects consumed 65 g WPC or 60 g SPI that was dissolved in 500 mL water 30 minutes before their ad libitum lunch. Appetite, CI, anthropometry, and body composition were assessed before and after the study and biweekly throughout. After 12 weeks, mean changes between the groups were significant for appetite (P = .032), CI (P = .045), anthropometry (body weight [P = .008], body mass index [P = .006], and waist circumference), and body composition (body fat mass and lean muscle [P < .001]). Relative to baseline, within-group mean changes from WPC were significant for appetite, CI, anthropometry, and body composition (P < .001). In the SPI group, mean changes were significant, relative to baseline, for all variables except lean muscle (P = .37). According to this 12-week study, WPC preloads conducted 30 minutes prior to the ad libitum main meal exerted stronger beneficial effects than did SPI preloads on appetite, CI, anthropometry, and body composition of free-living overweight and obese men. PMID- 25277887 TI - Serum DJ-1 level is positively associated with improvements in some aspects of metabolic syndrome in Japanese women through lifestyle intervention. AB - DJ-1 is a protein that is associated with Parkinson disease and cancer, and the reduction of DJ-1 function and expression is also thought to be a cause of diabetes and hypertension. However, little is known about the association between the plasma concentration of DJ-1 and risk of metabolic syndrome. We hypothesized that a lifestyle intervention would increase serum DJ-1 and that up-regulated DJ 1 functions will result in the prevention of metabolic syndrome. The objective of our study is to examine whether the level of serum DJ-1 is associated with the risk of metabolic syndrome. Therefore, to reveal the association between DJ-1 and metabolic syndrome, this study investigated lifestyle intervention in a control group (n = 37) and intervention group (n = 45). The results showed that body mass index, body fat ratio, waist-hip ratio, waist circumference, blood pressure, and plasma glucose level were improved in the intervention group, as compared with those in the control group. Furthermore, serum levels of DJ-1 were increased in the intervention group, when compared with those in the control group. These results suggest that serum DJ-1 is increased by lifestyle intervention and that increased serum DJ-1 prevents metabolic syndrome. Thus, the level of serum DJ-1 will become one of the indexes for the risk of metabolic syndrome. PMID- 25277888 TI - Continuous EEG monitoring in aneurysmal subarachnoid hemorrhage: a systematic review. AB - BACKGROUND: Continuous EEG (cEEG) may allow monitoring of patients with aneurysmal subarachnoid hemorrhage (SAH) for delayed cerebral ischemia (DCI) and seizures, including non-convulsive seizures (NCSz), and non-convulsive status epilepticus (NCSE). We aimed to evaluate: (a) the diagnostic accuracy of cEEG as a confirmatory test, (b) the prognostic value of EEG patterns suggestive of seizures and DCI, and (c) the effectiveness of intensified neuromonitoring using cEEG in terms of improved clinical outcome following SAH. METHODS: A systematic review was performed with eligible studies selected from multiple indexing databases through June 2014. The methodological quality of these studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. RESULTS: Eighteen studies were identified, including cEEG data from 481 patients with aneurysmal SAH. NCSz were diagnosed in 7-18 % of patients; NCSE in 3-13 %. NCSE was associated with increased age (mean age 68 years) and mortality (82-100 %) compared to the entire patient population (53.9 years; mortality 13 %; p values <0.05). DCI was diagnosed in 20-46 % of patients. Quantitative EEG patterns suggestive of DCI included decreased alpha/delta ratio, relative alpha variability, and total power. All studies were subject to a high risk of bias concerning patient selection and cEEG methodology. CONCLUSIONS: cEEG monitoring following SAH detects an increased number of subclinical seizures and may predict DCI many hours in advance. NCSE is associated with high mortality and morbidity, whereas for DCI identified by cEEG this association is less clear. Prospective randomized controlled multicenter trials are needed to evaluate the benefits (or risks) of intensified treatment of seizures and DCI following SAH. PMID- 25277889 TI - CD160 expression defines a uniquely exhausted subset of T lymphocytes in HTLV-1 infection. AB - HTLV-1 infection is a life-long retroviral infection. Chronic viral antigenic stimulation induces persistent infection which results in a clinically asymptomatic carrier state. Only a minor proportion of infected individuals develop adult T cell leukemia/lymphoma (ATLL) or HTLV-1-associated myelopathy/tropical spastic myelopathy (HAM/TSP). This is dependent on a balance of host and genetic factors. CD8+ cytotoxic T lymphocyte function is important in the immune response against viral infection; however, the contribution of CD160 receptor associated with CD8+ T lymphocytes is unclear. Thus, we sought to decipher its role on CTL function in HTLV-1 infection. Here, we report high frequencies of CD160 on CD8+ T cells, with significantly higher levels on HTLV-1 specific CD8+ T cells. Intercepting the CD160 pathway via blockade of the receptor or its ligand, herpes virus entry mediator (HVEM) resulted in improved perforin production and CD107a degranulation of HTLV-1 specific CD8+ T cells. Analysis of the CD160-expressing CD8+ cells demonstrated a unique subset associated with a highly differentiated effector memory based on CD45RA and CCR7 co-expression, increased expression of inhibitory molecules, 2B4 and PD1. Altogether, these results suggest a role for CD160/HVEM pathway in regulating immune response against HTLV-1 infection which may prove promising in the development of immune therapies for the treatment of HTLV-1 infection and other associated disorders. PMID- 25277890 TI - The American genus Dactuliothrips (Thysanoptera: Aeolothripidae) with three new species. AB - Three new species of Dactuliothrips Moulton are described, two from Mendoza, Argentina and one from Southern California, USA: D. prosopis sp.n. from Prosopis alpataco (Fabaceae), D. monttea sp.n. from Monttea aphylla (Scrophulariaceae), and D. ephedra sp.n. from Ephedra sp. (Ephedraceae). A revised diagnosis and an illustrated identification key to the nine recognized species of Dactuliothrips are also provided. Pictures and notes about the host plants for the species from Argentina are included, together with new records for D. kaszabi from Argentina. PMID- 25277891 TI - Contribution to the knowledge of the genus Dicronychus (Coleoptera: Elateridae) from the Kingdom of Saudi Arabia. AB - Examination of specimens of Dicronychus Brulle in the King Saud University Museum of Arthropods, Riyadh, Saudi Arabia revealed the presence of two new species, D. latifae n. sp. and D. bushrae n. sp. In addition, the descriptions of D. talhouki Platia and Schimmel and D. brancuccii Platia and Schimmel are augmented after examination of both type material and recently collected specimens from the Kingdom of Saudi Arabia. PMID- 25277892 TI - New species and new records of deepwater munidid squat lobsters from north western Australia: Onconida, Bathymunida, Crosnierita, Plesionida and Torbenella. AB - Seven species of Munididae are reported from the continental margin of north western Australia. Three species are new to science: Crosnierita adela sp. nov., Onconida ariel sp. nov. and Plesionida aurelia sp. nov., each presently known only from Western Australia. Four species are reported for the first time from Australian waters, Bathymunida balssi Van Dam, 1838, Bathymunida dissimilis Baba & de Saint Laurent, 1996, Crosnierita yante (Macpherson, 1994) and Torbenella orbis (Baba, 2005). Keys to the world species of the genera represented are provided. PMID- 25277893 TI - A new species of Scutopalus (Acari: Cunaxidae: Cunaxoidinae) from Rio Grande do Sul State, Brazil with a key to world species. AB - Scutopalus tomentosus sp. nov. is described and illustrated from Plantago tomentosa Lam. (Plantaginaceae) in a vineyard agroecosystem at Dois Lajeados county, State of Rio Grande do Sul, Brazil. This is the first species of this genus described from the Americas. A key to world species is included. PMID- 25277894 TI - A new record of the giant freshwater prawn, Macrobrachium spinipes (Schenkel, 1902) (Crustacea: Decapoda: Palaemonidae) from Taiwan, with notes on its taxonomy. AB - The giant freshwater prawn Macrobrachium spinipes (Schenkel, 1902) is recorded from Taiwan for the first time and extends the distribution of the species to north of the Tropic of Cancer. The Taiwanese specimens differ slightly from material from Indonesian Papua in the density of the spination of the adult second pereipods, the relative length of the ridge of the posterior submedian plate of thoracite sternite 4, and the color of the carapace, abdomen and pleural condyles. PMID- 25277895 TI - A new species of Sphenomorphus Fitzinger, 1843 (Squamata: Sauria: Scincidae) from Vietnam . AB - A new forest skink species of the genus Sphenomorphus is described from Kon Tum Plateau, southern Central Vietnam. Sphenomorphus sheai sp. nov. is similar to the other montane skink species from the Indochina region, Lygosoma veunsaiensis, Scincella apraefrontalis, Sphenomorphus tetradactylus, and Sphenomorphus tridigitus, in having a small size and the absence of external ear openings. However, the new species is differentiated from aforementioned species and other members of Sphenomorphus from China and mainland Southeast Asia by a unique suite of morphological characters. The discovery of S. sheai brings the total species number of Sphenomorphus known from Vietnam to twelve. PMID- 25277896 TI - Two new species of Metrocoris Mayr (Hemiptera: Heteroptera: Gerridae) from India. AB - Metrocoris morsei sp. nov., and Metrocoris shillongensis sp. nov., are described from India and compared with known congeners. Metrocoris morsei sp. nov. from Great Nicobar Biosphere Reserve (GNBR), Nicobar Islands, cannot be assigned to any of the known species groups of Metrocoris, so it forms the Metrocoris morsei group. M. shillongensis sp. nov. from Shillong, Meghalaya, belongs to the M. obscurus-species group and is the second species in this group. The distribution maps of these two new species are given. PMID- 25277897 TI - A new species of Robertsella Guinot, 1969 (Crustacea: Brachyura: Panopeidae) from the southwestern Atlantic. AB - A new species of deep-water brachyuran crab, Robertsella meridionalis, from Brazil is described and illustrated. The new species can be easily separated from its northwestern Atlantic counterpart, R. mystica Guinot, 1969, by a suite of carapace and appendage characters. Robertsella mystica is redescribed and illustrated. Putative sound-producing structures in the genus Robertsella are first described. PMID- 25277898 TI - A new species of Sicoderus Vanin from Bolivia (Coleoptera: Curculionidae: Curculioninae: Otidocephalini). AB - Sicoderus robini sp. nov. (type locality: Bolivia, Santa Cruz de la Sierra, Buena Vista, El Cairo) is described and illustrated. The new species is assigned to the Sicoderus appendiculatus species group, compared with similar species of the group and with the two other species of Sicoderus that occur in Bolivia. The previously published key for species identification of the S. appendiculatus group is updated to include the new species. PMID- 25277899 TI - On the Nazeris fauna of Guangxi, China. II. The species of Daming Shan (Coleoptera, Staphylinidae, Paederinae). AB - Two new species of Nazeris Fauvel collected from Daming Shan, Guangxi Province, are described and illustrated: N. damingshanus Hu & Li, sp. n., N. longilobus Hu & Li, sp. n. An identification key to the Nazeris species from Guangxi is provided. PMID- 25277900 TI - A new species of Laccobius Erichson, 1837 from China (Coleoptera: Hydrophilidae). AB - A new species of the water scavenger beetle, Laccobius (Cyclolaccobius) martini sp. nov., is described from Shiwandashan, southern Guangxi Automomous Region, China. Digital photographs of several useful taxonomic features are provided. Additionally, the identification key to Laccobius (Cyclolaccobius) of China and neighbouring countries is updated to include this new species. PMID- 25277901 TI - Two new Xestia Hubner, 1818 species from China (Lepidoptera, Noctuidae) . AB - Beginning with the fundamental works of Boursin (1954, 1963, 1964), Old World exploration of the genus Xestia (s. l.) Hubner, 1818 traditionally focused on reddish-brown species from the generally monsoon, high mountains Himalayan region (Hacker (1990), Yoshimoto (1995), Hreblay & Ronkay (1997, 1998, 1999), Hreblay et al., (1998) and Kononenko et al., (2012)). More recent investigation of the southeast and eastern Tibetan plateau in the drier high altitude of Sichuan and Yunnan provinces resulted in the discovery of seven new species of Xestia (s. l.) described by Gyulai at al.(2011). Two additional new species from this region collected by Irene and Alessandro Floriani and the third author are described herein. PMID- 25277902 TI - Description of three new species of the genus Herichthys (Perciformes: Cichlidae) from eastern Mexico, with redescription of H. labridens, H. steindachneri, and H. pantostictus. AB - Three new species of the genus Herichthys are described on the basis of chromatic, morphometric, and meristic characters. Herichthys pratinus sp. nov. from the Rio Salto in San Luis Potosi is characterized by a steep and shallow predorsal profile, a concavity before the eye, and adult males with a prominent forehead forming a nuchal hump, DXV-XVI, 10-11; and AV, 8-9. Herichthys pame sp. nov. from the Rio Tamasopo in San Luis Potosi is characterized by a gradual and acute predorsal contour, lack of concavity before the eye, and mouth angled slightly downward. Herichthys. molango sp. nov. from Laguna Azteca, Hidalgo is distinguished by small eyes and a slender (slightly broader than long), well spaced, and indented lower pharyngeal plate with 2 rows of 8-9 medium-sized, lightly pigmented molars flanking the midline. We also provide redescriptions for three species of Herichthys, H. pantostictus, H. labridens, and H. steindachneri and a review of H. bartoni. PMID- 25277903 TI - Two new species of Centruroides Marx 1890 (Scorpiones: Buthidae) from Oaxaca, Mexico. AB - Centruroides franckei, n. sp. and Centruroides rodolfoi, n. sp. are described from Oaxaca, Mexico. These species belong to the "striped" group within the genus. Thirteen species of the genus are reported for the state, six of them belonging to the "striped" group (infamatus-nigrovariatus subgroup). Both new species are compared to their most morphological similar species. A map with the six "striped" (infamatus-nigrovariatus subgroup) species in the state is also provided. PMID- 25277904 TI - Two new species of Armascirus (Acari: Prostigmata: Cunaxidae) from Slovakia. AB - Two new mite species from Central Europe, viz. Armascirus fendai sp. nov. and Armascirus masani sp. nov. (Acari: Prostigmata, Cunaxidae) are described and figured. The keys to the known species (females and males) of the genus Armascirus are given. PMID- 25277905 TI - A new species and new record of the commensal genus Alcyonosyllis Glasby & Watson, 2001 and a new species of Parahaplosyllis Hartmann-Schroder, 1990, (Annelida: Syllidae: Syllinae) from Philippines Islands. AB - A new species of Alcyonosyllis (Annelida: Syllidae), A. aidae n.sp. is described from Luzon island, Philippines, associated with the alcyonacean Dendronephthya sp. (Nephthydae). This is the sixth known species of this genus living in the Indo-Pacific region. The new species differs from other Alcyonosyllis in having long and slender cirri with the first pair of dorsal cirri slightly thicker than remaining, bidentate chaetae with distal tooth larger than proximal one, and a distinct colour pattern, with a median longitudinal, slender reddish line, and two wider lateral bands, giving a tri-lineate appearance. A new report of the recently described species, A. hinterkircheri, previously known only from an area close to Bohol, in Philippines, is also included, being the first report of this species in Luzon Island. A new species of the genus Parahaplosyllis Hartmann Schroder, 1990, is also described. Up to now, only the type species of the genus was known, from New South Wales, Australia; this is the second known species of this genus. It differs from P. brevicirra Hartmann-Schroder, 1990 by having unidentate dorsal simple chaetae (instead of bidentate ones as in P. brevicirra), ventral simple chaeta with shorter and less curved basal spur, more distinctly articulated dorsal cirri, with a long distal article, and a shorter proventricle. Finally, new different types of stolons are described for both genera. PMID- 25277906 TI - Scolopendromorph centipedes (Chilopoda: colopendromorpha) in the Natural History Museum (London): a review of the hitherto unidentified species collected in Africa, with remarks on taxonomy and distribution, and a new species of Otostigmus (Parotostigmus). AB - The collection of centipedes in the Natural History Museum (NHM) in London is one of the most taxonomically and geographically complete in the world. Type material includes many species described by William Leach, George Newport, and especially Reginald I. Pocock. The present paper provides a survey of previously unidentified centipedes in the collections in the NHM, and is focused on scolopendromorph specimens collected during expeditions to Africa between 1892 and 1967. It deals with material gathered in numerous regions, provinces and islands across the African continent, mainly by British naturalists. Species of the genera Alipes Imhoff, 1854, Asanada Meinert, 1886, Cormocephalus Newport, 1844, Cryptops Leach, 1815, Ethmostigmus Pocock, 1898, Otostigmus Porat, 1876, Rhysida Wood, 1862, Scolopendra Linnaeus, 1758 and Scolopocryptops Newport, 1844, were examined. A total of 32 species and subspecies are identified, one of which, is described as new: Otostigmus (Parotostigmus) coltellus n. sp., from Sao Tome, while many of them are new to the fauna of certain African regions/countries. The syntypes of Otostigmus (Parotostigmus) productus Karsch, 1888, include two species, one of which is O. (P.) coltellus; a lectotype is selected to stabilize the name. Cormocephalus westwoodi anceps and Rhysida lithobioides paucidens have been returned to specific rank. PMID- 25277907 TI - A new genus of huntsman spiders (Araneae, Sparassidae, Sparianthinae) from the Neotropical region. AB - Uaiuara gen. nov. is described to include Sparianthis amazonica Simon from Brazil, Sparianthis barroana Chamberlin from Panama, and five new species, namely: Uaiuara quyguaba sp. nov. from the states of Amazonas, Para and Amapa; Uaiuara ope sp. nov. from Acre and Uaiuara jirau sp. nov. from Rondonia, all in northern Brazil, Uaiuara palenque sp. nov. from Ecuador and Uaiuara dianae sp. nov. from Peru. The genus is easily distinguished from the remaining Neotropical Sparianthinae by the very recurved anterior eye row, the large number of ventral spines on tibiae of legs I-II, the retrolateral grove on the male palpal cymbium and the convoluted duct system of the female vulva. In addition, the female of S. barroana and the male of S. amazonica are described for the first time. The latter species is newly recorded from Colombia, Suriname, Ecuador and Bolivia. PMID- 25277908 TI - Identification of sand frogs (Anura: Pyxicephalidae: Tomopterna) from Kenya with the description of two new species. AB - African sand frogs in the genus Tomopterna presently include 13 species. These are known to be highly cryptic and morphologically similar. Despite increased effort in the recent past, the taxonomy of the group is still unresolved and some populations e.g. in Kenya have remained largely unstudied. This paper starts to address this gap using molecular, advertisement call and morphological comparisons. We test the boundaries of the Kenyan species based on mitochondrial 16S rRNA sequence data. Two new species are recognised and described: Tomopterna wambensis sp. nov. and Tomopterna gallmanni sp. nov. Further molecular and advertisement call studies of Tomopterna populations in Kenya are recommended, especially for those populations previously identified as T. cryptotis and T. tandyi. PMID- 25277909 TI - Nomenclatural issues in ornithology: the incredible controversy on the identity of a long overlooked Brazilian bird. AB - The identity of Scytalopus speluncae (Menetries, 1835) (Aves: Passeriformes: Rhinocryptidae), a tapaculo from southeastern Brazil, has been the matter of debate during the last eight years. A group of ornithologists considers that the nomen Scytalopus speluncae should be attributed to a species endemic to coastal mountains of southeastern Brazil, whereas another group considers it a species from the drier environments of another mountain belt in Minas Gerais, southeastern Brazil. Both research groups disagree on the identity of the still extant but damaged alleged holotype, deposited at the Zoological Institute of the Russian Academy of Sciences, St. Petersburg, on the identity of the holotype specimen illustration from a plate accompanying the species description, and even on the type locality. To further complicate this matter of identity, members of each research group, based on their own interpretations of the identity of Scytalopus speluncae, described and named again the two species with different nomina, erecting at least one unnecessary nomen. After almost ten years of a debate, there is still no consensus on the identity of the species, and there are now at least three available nomina for apparently only two distinct biological species. As taxonomists belonging to fields of zoology other than ornithology, and realizing the above situation is mainly a nomenclatural one, we herein present a summary of the contentious issue, try to distinguish what seems to be facts and speculation and based on these we consider the rules of the International Code of Zoological Nomenclature (the Code) whenever appropriate, in the hope of bringing some objectivity to the debate. We conclude that no unequivocal evidence was presented to decide to which species the type specimen belongs solely based on its morphological characters, since the holotype presents considerable damage. On the other hand, the original designation of the type locality by Menetries (1835) as Sao Joao del Rei, in southeastern Brazil, is unquestionable. Thus, the posterior re-designation of the type locality by a group of ornithologists was not done according to the Code. Contrary to the proposition made by a group of ornithologists that the nomen Scytalopus speluncae should be maintained to the species so called up to 2006 until further evidence confirms the identity of the holotype, we here argue that for now the nomen should be applied to the only species known to occur in the vicinities of the type locality, as established by the author of the species. Nevertheless, we also agree that obtaining molecular data from the holotype should be attempted to definitely solve the query. PMID- 25277910 TI - Morphology and life history of Brachypeplus glaber LeConte(Coleoptera: Nitidulidae), with a discussion of multiple life stage data for phylogenetic analyses. AB - A detailed description of the sap beetle Brachypeplus glaber LeConte (Nitidulidae) is provided, including egg, larval, pupal and adult stages. Rearing and DNA barcoding were used to confirm life stage identifications. This is the first New World Brachypeplus species for which larval and pupal descriptions are available. Characters and character states for larvae, pupae, and adults are discussed at the species and generic levels within the context of phylogenetic revisions at different hierarchical levels. PMID- 25277911 TI - New or interesting Peritelini of the West-Mediterranean fauna. XXIV. Two new Simmeiropsis Pierotti & Bello, 2013 from Portugal (Coleoptera, Curculionidae, Entiminae). AB - Simmeiropsis algharbensis sp. n. and S. lusitana sp. n. are described and illustrated. The new species were discovered in the Algarve region in the south of Portugal. The records of these new species confirm the presence of the tribe Peritelini in Portugal and suggest that additional research is needed to explore the diversity and distribution of this group in the central and western parts of the Iberian Peninsula. PMID- 25277912 TI - Four new cavernicolous species of the millipede genus Eutrichodesmus Silvestri, 1910 from southern China (Diplopoda: Polydesmida: Haplodesmidae). AB - Four new species of the large oriental genus Eutrichodesmus Silvestri, 1910 are described from caves in southern China: E. digitatus sp. n. (Guangdong), E. simplex sp. n. (Jiangxi), E. spinatus sp. n. (Hunan) and E. planatus sp. n. (Guangxi). PMID- 25277913 TI - Two new species of Halichondrida (Demospongiae) and the first record of Phycopsis and Ciocalapata for Brazil. AB - Two new species of the genera Phycopsis and Ciocalapata are described from the shallow waters off the Brazilian coast. This is the first record of Phycopsis in South Atlantic, with Phycopsis styloxeata sp. nov. being the only species of the genus that presents three categories of spicules: two of styles and one of oxeas. Ciocalapata, here represented by Ciocalapata minuspiculifera sp. nov., displays smaller oxeas and styles when compared to its congeneric C. amorphosa (Ridley & Dendy, 1886). The definition of this genus was modified and its geographical and bathymetric distributions now extend from the coast of Argentina to the northeastern coast of Brazil (state of Bahia) and from deep (1.097 m) to shallow (14-20 m) waters, respectively. PMID- 25277914 TI - The spider genus Kukulcania in South America (Araneae: Filistatidae): a redescription of K. brevipes (Keyserling) and new records of K. hibernalis (Hentz). AB - Two species of the spider genus Kukulcania are known from South America. Kukulcania brevipes (Keyserling), originally described from Peru, is here diagnosed, illustrated and redescribed, with several new records provided for eastern Peru and northern Chile. The synanthropic Kukulcania hibernalis (Hentz) is illustrated and diagnosed, with several new records extending the distribution of this species from northern Venezuela to southern Brazil. PMID- 25277915 TI - A new gall-inducing genus and species of Eriococcidae (Hemiptera: Sternorrhyncha: Coccoidea) on Sapindaceae from Brazil. AB - A new gall-inducing genus and species of felt scales (Hemiptera: Coccoidea: Eriococcidae) found on the leaves and twigs of Matayba guianensis (Sapindaceae) in Brazil is described: Bystracoccus Hodgson gen n. and B. mataybae Hodgson, Isaias & Oliveira sp. n. This is the first record of an eriococcid inducing leaf and stem galls on Sapindaceae and is only the second example of a member of the Eriococcidae to induce stem galls in which the insects diapause during the dry (winter) season. Only the adult female, second-instar female and crawler are known. The species overwinters as the first-instar nymph in pit galls on the twigs but spends the rest of the year associated with two-chambered galls on the leaves. It has recently become clear that South America has a rich felt-scale insect fauna many of which induce galls. It has proved very difficult to place this new genus in a family as it appears to fall between the Eriococcidae and Beesoniidae but is here placed in the eriococcids based on the similarity of the first-instar nymphs and the abundance of this family in the Neotropics. However, the dorsum of the abdomen of the mature adult female becomes heavily sclerotised, forming a round plug-like structure that completely fills the gall orifice. This structure shows remarkable morphological similarities to that of the beesoniid Danumococcus parashoreae Takagi & Hodgson found on Parashorea tomentella (Dipterocarpaceae) in Sabah, Malaysia, with which it is compared along with other eriococcid genera known from South America. PMID- 25277916 TI - A re-appraisal of the systematic status of selected genera in Palaemoninae (Crustacea: Decapoda: Palaemonidae). AB - Recent phylogenetic work (Ashelby et al., 2012) has demonstrated the need for a fresh appraisal of the systematic status of some Palaemoninae genera. In the present contribution the accumulated morphological as well as molecular evidence is reviewed. The genera Palaemonetes, Exopalaemon and Coutierella are demonstrated to be junior synonyms of Palaemon, which now contains 83 species. As a result of this systematic re-arrangement, two replacement names are needed. Palaemon kwantung nom. nov. now replaces Exopalaemon guangdongensis Guo, Wang & Zhang, 2005, nec Palaemon guangdongensis Liu, Liang & Yan, 1990. Palaemon mundusnovus nom. nov. is the replacement name for Palaemonetes intermedius Holthuis, 1949, nec Palaemon intermedius (Stimpson, 1860). PMID- 25277917 TI - New Noctuidae (s.l.) species from the Korean fauna with description of a new species of Bryophila Treitschke, 1825 (Lepidoptera: Erebidae and Noctuidae). AB - Eight Erebidae and Noctuidae species are reported for the first time from Korea. The taxonomic positions of another two formerly misidentified species, Abrostola korbi and Diachrysia witti, are discussed. The Korean species of the Bryoleuca granitalis species-group are characterised and a new species of the group, Bryoleuca volodia sp. n. from Vietnam, is described and illustrated. PMID- 25277918 TI - Larvae of Cueta sauteri (Esben-Petersen) and Myrmeleon bore (Tjeder) (Neuroptera, Myrmeleontidae): description and behavioral notes. AB - Antlion larvae of Cueta sauteri (Esben-Petersen) and Myrmeleon bore (Tjeder) from mainland China were collected in the field and reared to adults in the laboratory. Larval morphology of each species was described and complemented with behavioral observations. Their most important diagnostic characteristics are head capsule markings, mandibular length, mandibular teeth length, distance between mandibular teeth, bristle number between the distal mandibular tooth and apex of the mandible, morphology of labial palpi and antennae, peduncle of mesothoracic spiracle and the arrangement of digging bristles. Larvae of these two species construct similar conical pits and wait for prey at the bottom of the traps. PMID- 25277919 TI - Rediscovery of the rare ant genus Bannapone (Hymenoptera: Formicidae: Amblyoponinae) and description of the worker caste. AB - The genus Bannapone was described in 2000 on the basis of a single dealate queen specimen. Since its original collection in Yunnan, China, no other specimen has been reported, making it one of the rarest ant genera in the world. Here we report the collection of two workers of Bannapone also from Yunnan province. The description of the worker caste is presented. Furthermore, we found significant differences with the described B. mulanae Xu, 2000 which leads us to describe the workers as a new species, B. scrobiceps n. sp.. Finally, we briefly discuss the importance of leaf-litter collection methods to collect taxa considered as "rare". PMID- 25277920 TI - A new species of deep-sea squat lobster of the genus Munida Leach, 1820 (Crustacea: Decapoda: Anomura: Munididae) from a hydrothermal field in the southwestern Indian Ocean. AB - A new species of the genus Munida Leach, 1820, is described and illustrated based on a single specimen from the deep-sea hydrothermal area in the southwestern Indian Ocean. Munida manqingae sp. nov. closely resembles M. tiresias Macpherson 1994, but differs in the morphology of the carapace, basal segment of the antennular peduncles, first segment of the antennal peduncle. PMID- 25277921 TI - A new species of Siamites Franz (Coleoptera, Staphylinidae, Scydmaeninae) from Thailand. AB - A new species of so far monospecific genus Siamites, S. complicatus sp. n., is described. The type specimens were collected in the Krabi Province of Thailand. Morphology of the new species is described and illustrated in details, including male genitalia, and the distribution of Siamites is summarized. PMID- 25277922 TI - Abcharis nom. nov., a new substitute name for Notiocharis Eaton, 1913 (Diptera: Psychodidae: Psychodinae) with world check-list of species. AB - Abcharis nom. nov. is established as a new substitute name for Notiocharis Eaton, 1913 (Diptera: Psychodidae: Psychodinae), which is a junior homonym of Notiocharis Gistel, 1856 (Coleoptera: Carabidae). The following new combinations are proposed: Abcharis assimilis (Quate & Quate, 1967) comb. nov.; A. dimorpha (Satchell, 1953) comb. nov.; A. femoralis (Quate, 1965) comb. nov.; A. filipinae (Quate, 1965) comb. nov.; A. fragilis (Quate & Quate, 1967) comb. nov.; A. insignis (Eaton, 1913) comb. nov.; A. kalabakensis (Quate, 1962) comb. nov.; A. lanceolata (Quate & Quate, 1967) comb. nov.; A. maai (Quate & Quate, 1967) comb. nov.; A. mangrophila (Jezek, 2000) comb. nov.; A. miranda (Quate & Quate, 1967) comb. nov.; A. pallida (Satchell, 1953) comb. nov.; A. papuensis (Quate & Quate, 1967) comb. nov.; A. paxillosa (Quate & Quate, 1967) comb. nov.; A. phlyctis (Quate & Quate, 1967) comb. nov.; A. sarawakensis (Quate, 1962) comb. nov.; A. stellae (Quate, 1962) comb. nov.; and A. wilsoni (Duckhouse, 1966) comb. nov. A world checklist of the included species with information about type material and distribution is provided. PMID- 25277923 TI - Synonymy of the North African spider genus Castanilla Caporiacco, 1936 with Micaria Westring, 1851 (Araneae: Gnaphosidae). AB - The spider genus Castanilla Caporiacco, 1936 is presently represented by two species, C. quinquemaculata Caporiacco, 1936 (type species) and C. marchesii Caporiacco, 1936, both described from Libya. The genus has never been revised and neither of the two species have ever been redescribed (Platnick 2013). The placement of the genus has up to now also been rather uncertain. Caporiacco (1936a,b) described and placed its two species in the Clubionidae, Reiskind (1969) placed it in Clubionidae: Castianeirinae, and it is currently included in the Corinnidae (Platnick 2013). PMID- 25277925 TI - Tanaidaceans from Brunei, IV. The Families Kalliapseudidae, Pagurapseudopsidae, Parapseudidae and Apseudidae (Crustacea: Peracarida: Tanaidacea: Apseudomorpha), with descriptions of a new genus and six new species. AB - Apseudomorph tanaidaceans from recent samples of the South China Sea benthos off Brunei have been examined. The habitats were sandy substrata from between 5 and 90 m depth. Fourteen species of the four families considered here were discovered. A new species of Tanapseudes is described. The distribution of Phoxokalliapseudes gobinae is analyzed. Biropalostoma goofi is recorded for the first time in Brunei waters. One new species of the Apseudidae (in the genus Bunakenia) and four new species of the Parapseudidae (one each in the genera Platylicoa and Pakistanapeudes, and two in a new genus Actenos, of the subfamily Pakistanapseudinae) are described. The genus Platylicoa is moved to the Pakistanapseudinae, and the genus Hainanius is returned to the Parapseudidae (Parapseudinae). Apseudes tenuicorporeus is moved from Biropalostoma to the new pakistanapseudin genus described herein. PMID- 25277924 TI - New replacement name for the planthopper genus Potiguara Hoch et Ferreira, 2013 (Hemiptera: Fulgoromorpha: Kinnaridae). AB - The Kinnaridae genus Potiguara was established by Hoch & Ferreira (2013) with the type species Potiguara troglobia Hoch et Ferreira, 2013 from Brazil. So far, this genus includes only the type species. Nevertheless, the name Potiguara is preoccupied and it was initially introduced by Machado et Brito, 2006 for an extinct genus of the fish family Pycnodontidae (with the type species Coelodus rosadoi Silva Santos, 1963 from Brazil). Thus, the genus Potiguara Hoch et Ferreira, 2013 is a junior homonym of the genus Potiguara Machado et Brito, 2006. According to Article 60 of the International Code of Zoological Nomenclature, we propose the new replacement name Kinnapotiguara nom. nov. for Potiguara Hoch et Ferreira, 2013. Accordingly, a new combination is herein proposed for the kinnarid planthopper species currently included in this genus: Kinnapotiguara troglobia (Hoch et Ferreira, 2013) comb. nov. PMID- 25277926 TI - Three new species of Kerria (Hemiptera: Coccoidea: Tachardiidae) from India. AB - Three new species of Kerria Targioni-Tozzetti from India, namely Kerria pennyae Ahmad & Ramamurthy sp. nov. on Schleichera oleosa from Orissa, Kerria dubeyi Ahmad & Ramamurthy sp. nov. on Ficus bengalensis from Bangalore and Kerria varshneyi Ahmad & Ramamurthy sp. nov. on Ziziphus mauritiana from Punjab are described and illustrated, and a key is provided to species of Kerria known from India. PMID- 25277928 TI - A new, prairie-restricted species of Filatima Busck (Lepidoptera: Gelechiidae) from Illinois. AB - Filatima revisensis (Gelechiidae) is described from individuals collected as larvae feeding inside shelters constructed of silked-together leaflets of leadplant, Amorpha canescens (Fabaceae). Filatima revisensis is bivoltine; overwintering occurs in the larval stage. Because this insect is restricted to tallgrass prairie, it is likely to be of concern to conservation biologists. In the interest of naming this moth and clarifying its identity, a description is provided, and diagnoses are given to differentiate it from F. ornatifimbriella, F. xanthuris, F. adamsi, and F. occidua, all of which are externally similar to F. revisensis. PMID- 25277927 TI - Synonymy, new species and new combinations in the leafhopper genus Matsumurina Dworakowska (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini) . AB - The leafhopper genus Takama Dworakowska & Viraktamath, 1975 is considered a junior synonym of Matsumurina Dworakowska, 1972, with seven known species all transferred to the latter. Another new combination is proposed: Matsumurina macra (Kuoh, 1982) n. comb. Seven additional species: Matsumurina abbreviata, M. angusta, M. furcata, M. longa, M. longissima, M. qini and M. serriformis spp. nov. are newly described and illustrated. A key for identification of adult males of Matsumurina is provided. PMID- 25277929 TI - On the taxonomic status of Phlebotomus breviductus Barretto, 1950 (Diptera: Psychodidae: Phlebotominae). AB - The taxonomic status of Phlebotomus breviductus Barretto, 1950 was evaluated based on the morphological and morphometric analysis of the male holotype described from Fazenda Jerusalem, located in the municipality of Alegre, Espirito Santo state, Brazil. After measuring, drawing and photographing the holotype, we concluded that the head and wing of this specimen belong to Trichopygomyia sp., but that the thorax and abdomen belong to a different species, Nyssomyia umbratilis, with an anomalous gonostylus having five spines. The holotype slide consists of parts of specimens representing two different species, thus P. breviductus is not a valid species. PMID- 25277930 TI - On a collection of calappid crabs (Crustacea: Decapoda: Brachyura) from Fiji, with a description of a new species of Mursia. AB - Seven species of calappid crabs were identified from material collected during four IRD-MNHN expeditions conducted in 1998 and 1999 in shallow and deep waters off Fiji. Six species are reported for the first time from the islands. One new species, Mursia murimura n. sp., is described and illustrated. The new species differs from the closely related M. diwata Galil & Takeda, 2004, with which it shares a stout, distally auriculated first male pleopod, by possessing much longer lateral carapacial and cheliped spines. PMID- 25277931 TI - A new species of the genus Interphasma Chen & He, 2008 (Phasmida: Clitumninae: Medaurini) from Sichuan, China. AB - Chen and He erected the genus Interphasma in 2008 (Chen & He, 2008). Thirteen species are recognized in this Chinese endemic genus which is distributed in eastern to south-western China (Chen & He, 2008; Chen & Zhang, 2008; Xu et al., 2010). In this paper, a new species, I. lizipingense sp. nov., is described and illustrated from Sichuan, China. A key to the species of the genus is given. The types are deposited in the Museum of Hebei University (HBU) and Hong Kong Entomological Society (HKEM). Full measurements are given to all the types in millimeter (mm.). PMID- 25277932 TI - Alairhynchus, a new name for the genus Gigantorhynchus Sapelnikov & Malygina 1977 (Brachiopoda: Camarotoechioidea) preoccupied by Gigantorhynchus Hamann 1892 (Vermes: Acanthocephala). PMID- 25277933 TI - Baltidrilus nom. nov., a substitute name for the genus Heterochaeta Claparede, 1863 (Annelida, Clitellata, Tubificidae) non Heterochaeta Westwood, 1843 (Insecta, Mantodea, Mantidae). PMID- 25277934 TI - Redescription of the subgenus Parancistrum Verhoeff, 1943, an eastern Mediterranean lineage of the millipede genus Megaphyllum Verhoeff, 1894 (Diplopoda: Julida: Julidae: Brachyiulini). AB - The subgenus Parancistrum Verhoeff, 1943 is redefined on the basis of the examination of type and non-type material. The subgenus is currently settled to comprise 6 species, of which Megaphyllum arcuatum sp. n. is described as new, while M. adanense (Verhoeff, 1943) syn. n. and M. palaestinum (Jawlowski, 1931) syn. n. are established as junior subjective synonyms of M. curvifolii (Verhoeff, 1898) and M. genezarethanum (Verhoeff, 1923) comb. nov., respectively. A neotype is designed for Chromatoiulus tenenbaumi Jawlowski, 1931 under ICZN Article 75.1. The distribution pattern of the studied group is discussed, and some preliminary phylogenetic ideas about Megaphyllum and the tribe Brachyiulini are presented. PMID- 25277935 TI - Mites of the superfamily Rhodacaroidea (Acari: Mesostigmata) from Colombia, with a key for the world species of Desectophis Karg (Ologamasidae). AB - Three species of Rhodacaroidea are reported from soil in Colombia. Desectophis anthuriumsetis n. sp. (Ologamasidae) and Multidentorhodacarus colombianus n. sp. (Rhodacaridae) are described from newly-collected material. Multidentorhodacarus triramulus (Karg, 1998) is redescribed from the holotype and adult females collected in this study. A key for the separation of females of the five recognisable world species of Desectophis Karg is provided. PMID- 25277936 TI - The taxonomic position of Tonkinomys daovantieni (Rodentia: Muridae) based on karyological and molecular data. AB - Tonkinomys daovantieni was recently described from Northern Vietnam, but very sparse information exists for the taxon. We report for the first time the karyotype of this species and investigate its phylogenetic position in the Dacnomys division using both mitochondrial and nuclear genetic data. The diploid chromosome number of the species is 2n=44. This chromosomal set consists of one submetacentric pair, one metacentric pair, and nineteen pairs of subtelocentric/acrocentric autosomes progressively decreasing in size. The X chromosome is submetacentric and approximately equal in size to the largest subtelocentric autosome. The Y chromosome is metacentric and equal in size to the smallest pair of autosomes. The phylogenetic reconstruction based on the Cyt b COI and GHR genes reveals that Saxotilomys paulinae, a species distributed in the karst formations of the Lao PDR, is the closest relative to T. daovantieni. These two taxa are similar not only in a number of morphological characters, but also in their major ecological preferences (both are petrophylic species associated with limestone karst formations). Based on our data, we can conclude that the similarities among the ecological adaptations, natural conditions and habitat preferences of these species are a reflection of their phylogenetic relationship. PMID- 25277937 TI - Description of Paravulvus moroccanus sp. n. (Nematoda, Dorylaimida, Nygolaimidae) from the High Atlas Mountains, Morocco, with notes on the taxonomy of the genus. AB - Paravulvus moroccanus sp. n., collected in the Moroccan eastern High Atlas, is described and illustrated. The new species is characterized by its 1.06-1.36 mm long body, lip region offset by marked depression and 11-13 um broad, mural tooth solididentoid and 5.5-6.5 um long, neck 229-270 um long, pharyngeal expansion 108 126 um long or occupying less than one-half (42-48%) of total neck length, uterus 27-47 MUm long or 0.7-1.1 times the corresponding body diameter, V = 46-56, paravulvae absent, female tail rounded conoid (21-27 um, c = 42-64, c' = 1.1 1.5), and male unknown. The taxonomy of Paravulvus is updated, with comments on its definition, a discussion of its relationships, and the provision of a list of species along with a key to their identification and a compendium of their morphometrics. PMID- 25277938 TI - Erpetogomphus molossus, a new species from Sonora, Mexico (Odonata: Anisoptera: Gomphidae). AB - Erpetogomphus molossus is described from 3 male and 3 female specimens (holotype and allotype in collection of Instituto Biologico de la Universidad Nacional Autonoma de Mexico) from the intermittent pine-oak woodland of the Yecora municipio in east-central Sonora, Mexico. Diagnostic features of the new species include the seemingly bulbous tip (in lateral view) and prominent baso-ventral process of the male cerci and the notched and denticled posteromesal corners of the female subgenital plate. PMID- 25277939 TI - Taxonomic status of Pseudopaludicola riopiedadensis Mercadal de Barrio and Barrio, 1994 (Anura, Leptodactylidae, Leiuperinae). AB - Pseudopaludicola riopiedadensis was described by Mercadal de Barrio and Barrio (1994) based on two adult females collected by Luiz Dino Vizotto in 1963 from Rio Piedade, Sao Jose do Rio Preto, Sao Paulo, Brazil. This taxon was differentiated from P. ternetzi based on a series of qualitative and morphometric characters. Nevertheless, the original description and the type material of P. ternetzi were not considered by Mercadal de Barrio and Barrio, and the morphological variation of P. ternetzi was not documented. This work reviews the sample collected by Vizotto in P. riopiedadensis type locality, evaluates the advertisement calls obtained from such population, the two vouchers assigned to P. riopiedadensis, and a large data set, including type specimens of P. ternetzi to document the morphological variation along its known distribution. Results indicate that P. riopiedadensis was described on the basis of highly variable characters applied to a small sample and share the unique P. ternetzi autapomorphy, a robust body structure with immaculate belly. The lack of differentiation in both advertisement call and morphology rejects the status of P. riopiedadensis as distinct species, and we therefore suggest to formally consider P. riopiedadensis as junior synonym of P. ternetzi. PMID- 25277940 TI - Leafhopper genus Pediopsoides Matsumura (Hemiptera: Cicadellidae: Macropsinae), with descriptions of two new species from China. AB - Two new macropsine species, Pediopsoides (Celopsis) montaninversa and P. (Pediopsoides) anchorides spp. nov. are described and illustrated from China. A key to distinguish males of Chinese species in this genus is provided, along with a checklist of the known species worldwide. PMID- 25277941 TI - First recorded cave-dwelling terrestrial isopods (Isopoda: Oniscidea) in Iran with a description of a new species . AB - Cave-dwelling terrestrial isopods from the province of Kohgiluyeh and Boyerahmad, southwestern Iran, are reported here. These include three accidental and one troglobitic species namely Protracheoniscus gakalicus n. sp., which is also the first recorded troglobitic species from the genus Protracheoniscus. The new species is readily distinguished by the lack of eyes and pigmentation. PMID- 25277942 TI - A new species of Miroculis Edmunds, 1963 (Ephemeroptera, Leptophlebiidae) from northern Brazil. PMID- 25277943 TI - Structural alterations in Pseudomonas aeruginosa by zingerone contribute to enhanced susceptibility to antibiotics, serum and phagocytes. AB - AIMS: Excessive use of antibiotics has led to evolutionary adaptation resulting in emergence of multidrug resistance in P. aeruginosa. The aim of the present study was oriented towards exploiting zingerone (active component of ginger) in making P. aeruginosa more susceptible to killing with antibiotics, humoral/cellular defences and studying its underlying mechanism. MAIN METHOD: Effect of zingerone treatment on antibiotic susceptibility, serum, and phagocytic killing of P. aeruginosa was studied. The underlying mechanism was evaluated in terms of cell surface hydrophobicity, alginate and LPS production. TNF-alpha and MIP-2 cytokine production by mouse macrophages was also checked. Structural analysis was carried out using scanning electron microscopy (SEM) and liquid chromatography-mass spectrometry (LC-MS) analysis. KEY FINDINGS: Zingerone treated cells showed increased susceptibility to variety of antibiotics, serum as well as macrophages (p<0.05). Zingerone treatment significantly reduced cell surface hydrophobicity, alginate and LPS production (p<0.05). Zingerone treated cells showed significant decrease in TNF-alpha and MIP-2 cytokine production as compared to non-treated cells. Coupled with this, reduction in the production of extracellular protective matrix and modulation of chemical structure of LPS was also observed by scanning electron microscopy and liquid chromatography-mass spectrometric (LC-MS) respectively. Zingerone significantly influence surface structure of P. aeruginosa which contributes towards enhanced susceptibility to antibiotics and innate immune system. SIGNIFICANCE: Use of phytochemicals may prove to be a novel therapeutic approach by enhancing susceptibility of pathogenic microorganisms to antibiotics and immune system. Zingerone has proved to be one such agent which can be employed as a potential anti-virulent drug candidate against P. aeruginosa infections. PMID- 25277945 TI - Microalgae for the prevention of cardiovascular disease and stroke. AB - This review focuses on and discusses the primary phytochemicals present in microalgal biomass - carotenoids, phenolic compounds, antioxidant vitamins, sterols, and polyunsaturated fatty acids - and also on the exopolysaccharides, which are produced by some types of microalgae and may play a significant role in the prevention of cardiovascular diseases (CVD) and strokes. We have listed several preclinical trials and clinical studies supporting the health benefits that most of these compounds may provide. Microalgae are very easy to grow and are not vulnerable to contaminants when grown under controlled conditions. Proper handling and growth conditions may improve the production of phytochemicals. Therefore, they may represent an excellent source of nutraceuticals and food supplements once their safety as a food supplement has been confirmed. PMID- 25277944 TI - Myocardial interstitial serotonin and its major metabolite, 5-hydroxyindole acetic acid levels determined by microdialysis technique in rat heart. AB - AIMS: The aim of this study was to elucidate myocardial interstitial serotonin (5 HT) kinetics in the heart, including 5-HT reuptake and enzymatic degradation to 5 hydroxyindole acetic acid (5-HIAA) via monoamine oxidase (MAO). MAIN METHODS: Using microdialysis technique in anesthetized rats, we simultaneously monitored myocardial interstitial levels of 5-HT and its major metabolite, 5-HIAA, in the left ventricle and examined the effects of local administration of a MAO inhibitor, pargyline, or a 5-HT uptake inhibitor, fluoxetine. KEY FINDINGS: Pargyline increased dialysate 5-HT concentration from 1.8+/-0.3 at baseline to 3.9+/-0.5nM but decreased dialysate 5-HIAA concentration from 20.7+/-1.0 at baseline to 15.8+/-1.4nM at 60-80min of administration. Fluoxetine increased dialysate 5-HT concentration from 1.9+/-0.4 at baseline to 6.5+/-0.9nM at 60 80min of administration, but did not change dialysate 5-HIAA concentration. Local administration of ADP (100mM) increased dialysate 5-HT and 5-HIAA concentrations. Pargyline did not affect ADP-induced increase in dialysate 5-HT concentration but suppressed ADP-induced increase in dialysate 5-HIAA concentration during 60min of ADP administration. Fluoxetine increased dialysate 5-HT concentration at 40-60min of ADP administration, but did not affect ADP-induced increase in dialysate 5 HIAA concentration. SIGNIFICANCE: Simultaneous monitoring of myocardial interstitial 5-HT and 5-HIAA levels provides valuable information on 5-HT kinetics including reuptake and enzymatic degradation by MAO, which play a role in the regulation of myocardial interstitial 5-HT levels at baseline and when 5 HT levels are elevated. PMID- 25277946 TI - The intriguing dual-directing effect of 2-cyanobenzyl ether for a highly stereospecific glycosylation reaction. AB - The diverse presence as well as their very specific bio-responses of glycoconjugates found in all living species requires scientists to synthesize the precise structure of these complex oligosaccharides for various studies on glycoscience. Very few approaches were able to offer the sole alpha- or beta glycosylated products, even at the cost of complicating the preparative route or usage of exotic chiral auxiliaries to drive the stereoselectivity. In this report, the unification of solvent assistance and neighbouring group participation concepts have led us to the use of 2-cyanobenzyl ether as the dual directing auxiliary for stereospecific construction of alpha- and beta-glycosidic bonds from a single starting material, and both isomers can be obtained in exclusive stereoselectivity. This work demonstrates the difference in reactivities of glycosyl acceptors can be employed to completely drive the stereoselectivity, drawing the parallel comparison with the arming/disarming concept, which has been exclusively confined to glycosyl donors. PMID- 25277947 TI - Personal prayer counteracts self-control depletion. AB - Praying over longer time spans can foster self-control. Less is known about the immediate, short-term consequences of praying. Here we investigated the possibility that praying may counteract self-control depletion. Participants suppressed or did not suppress thoughts about a white bear before engaging in a brief period of either personal prayer or free thought. Then, all participants completed a Stroop task. As expected, thought suppression led to poorer Stroop performance in the free thought, but not in the prayer condition. This effect emerged on a dependent variable devoid of any religious or moral associations (Stroop task). Possible mediating mechanisms and directions for future research are discussed. PMID- 25277948 TI - Tools for in silico target fishing. AB - Computational target fishing methods are designed to identify the most probable target of a query molecule. This process may allow the prediction of the bioactivity of a compound, the identification of the mode of action of known drugs, the detection of drug polypharmacology, drug repositioning or the prediction of the adverse effects of a compound. The large amount of information regarding the bioactivity of thousands of small molecules now allows the development of these types of methods. In recent years, we have witnessed the emergence of many methods for in silico target fishing. Most of these methods are based on the similarity principle, i.e., that similar molecules might bind to the same targets and have similar bioactivities. However, the difficult validation of target fishing methods hinders comparisons of the performance of each method. In this review, we describe the different methods developed for target prediction, the bioactivity databases most frequently used by these methods, and the publicly available programs and servers that enable non-specialist users to obtain these types of predictions. It is expected that target prediction will have a large impact on drug development and on the functional food industry. PMID- 25277949 TI - An advanced Ag-based photocatalyst Ag2Ta4O11 with outstanding activity, durability and universality for removing organic dyes. AB - Constructing Ag-based photocatalysts by the incorporation of Ag(+) ions into metal/nonmetal oxides for removing organic pollutants is a recently developed strategy, but overcoming their own photocorrosion is still a tremendous challenge. In this work, an advanced Ag-based photocatalyst Ag2Ta4O11 is obtained by this strategy, which exhibits improved photocatalytic activity compared with Ta2O5 and the universality for degrading several organic dyes. Importantly, the Ag2Ta4O11 photocatalyst has outstanding durability and reusability, which indicates that it has potential application prospects for organic wastewater treatment in the printing and dyeing industry. PMID- 25277950 TI - Primary non Hodgkin's lymphoma of talus in a child-a rare presentation. AB - We report a rare case of primary non-Hodgkin's lymphoma of bone which presented with an osteolytic lesion of the head of the right talus which to the best of our knowledge is the first case to be reported in the paediatric age group. Early and accurate identification is necessary as it has a good prognosis. PMID- 25277951 TI - Eighteen year weight trajectories and metabolic markers of diabetes in modernising China: which timescale is most relevant? PMID- 25277952 TI - Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells. AB - Insulin secretory vesicles contain high concentrations of adenine nucleotides, which are co-released with insulin during exocytosis. There is strong evidence that ATP and ADP serve as autocrine messengers in pancreatic beta cells, but the functional effects and detailed mechanisms of action are under debate. In this issue of Diabetologia, Khan and colleagues (DOI: 10.1007/s00125-014-3368-8 ) present the results of their study of autocrine purinergic signalling in isolated human beta cells. Using a combination of electrophysiological techniques, Ca(2+) imaging and measurements of insulin secretion, it is demonstrated that voltage dependent Ca(2+) influx triggers release of ATP/ADP, which activates purinergic receptors of the Gq/11-coupled P2Y1 isoform. Activation of these receptors leads to membrane depolarisation and phospholipase C-mediated mobilisation of Ca(2+) from endoplasmic reticulum stores, which amplifies the exocytosis-triggering Ca(2+) signal. In contrast, there is little evidence for involvement of ionotropic P2X receptors in the autocrine stimulation of human beta cells. This commentary discusses these findings as well as various functional and therapeutic implications of the complex purinergic signalling network in the pancreatic islet. PMID- 25277953 TI - Inhibition of NADPH oxidase-1 preserves beta cell function. AB - AIMS/HYPOTHESIS: Upregulation of the reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX)-1 in islets and beta cells follows acute exposure to inflammatory cytokines and is concomitant with beta cell dysfunction. NOX-1 is a candidate mediator of inflammation-induced beta cell dysfunction. This study aimed to determine whether selective inhibition of NADPH oxidase-1 presents a new strategy to preserve beta cell function. METHODS: Induced beta cell dysfunction was studied in primary human donor islets, isolated mouse islets and murine beta cell lines. Islets and beta cells were stimulated with inflammatory cytokines (TNF-alpha, IL-1beta, IFN-gamma). NOX-1 activity was blocked by the selective inhibitor ML171. RESULTS: Cytokine induction of intracellular ROS was reduced 80% with 1 MUmol/l ML171 in murine beta cell lines (p < 0.01). Cytokine-induced apoptosis, measured by caspase-3 activation or quantified fluorescence microscopy, was prevented in islets and beta cell lines up to 100% with ML171 in a concentration-dependent manner (p < 0.05). Functionally, glucose-stimulated insulin secretion was abolished by cytokine exposure but preserved by ML171 in isolated mouse islets and murine beta cell lines. A feed-forward regulation of NOX-1 in islets and beta cell lines was disrupted by ML171. CONCLUSIONS/INTERPRETATION: Stimulation of NOX-1 activity is a major component of inflammatory cytokine-induced beta cell dysfunction. Significant protection of beta cells is conferred with selective inhibition of NOX-1. Suppression of NOX-1 activity may present a new therapeutic strategy to preserve and protect beta cell function in diabetes. PMID- 25277954 TI - Cognitive processing of cluster headache patients: evidence from event-related potentials. AB - BACKGROUND: The peripheral and central origins of pain in cluster headache (CH) have been a matter of much debate. The development and application of functional imaging techniques have provided more evidence supporting the hypothesis that CH is not a disorder exclusively peripheral in origin, and in fact central regions might be more important. Event-related potentials confer advantages in the functional evaluation of the cortex, but few studies thus far have employed this method in cluster headache. METHODS: Seventeen cluster patients (15 males; mean age = 35.4 years) and 15 age-matched healthy participants (13 males; mean age = 34.6 years) were recruited. A visual oddball paradigm was employed to analyze target processing using event-related potentials. We investigated the P3/P3d components in the experiment. RESULTS: P3/P3d amplitudes were decreased in CH patients (P3, 3.82 MUV; P3d, 5.8 MUV) compared with controls (P3, 7.28 MUV; P3d, 8.95 MUV), F(1,30) = 4.919, p < 0.05, eta2 = 0.141 for P3 and F(1,30) = 8.514, p < 0.05, eta2 = 0.221 for P3d, respectively). Moreover, the amplitudes of P3/P3d were no significantl difference in the side of pain as compared to contralateral one (p > 0.05). CONCLUSIONS: These results provide evidence of dysfunction in the cognitive processing of CH patients, which may also contribute to the pathophysiology of CH. PMID- 25277956 TI - Accessibility, availability and utilisation of malaria interventions among women of reproductive age in Kilosa district in central Tanzania. AB - BACKGROUND: Universal access to and utilization of malaria prevention measures is defined as every person at malaria risk sleeping under a quality insecticide treated mosquito net (ITN) and every pregnant woman at risk receiving at least two doses of sulfadoxine-pyrimethamine (SP). This study aimed to determine factors affecting accessibility, availability and utilisation of malaria interventions among women of reproductive age in Kilosa district in central Tanzania. METHODS: Women of reproductive age with children <5 years old or those who had been pregnant during the past 5 years were included in the study. A structured questionnaire was used to seek information on malaria knowledge, accessibility and utilization of malaria interventions during pregnancy. RESULTS: A total of 297 women (mean age=29+/-6.8 years) were involved. Seventy percent of the women had attained primary school education. About a quarter of women had two children of <5 years while over 58% had >=3 children. Most (71.4%) women had medium general knowledge on malaria while only eight percent of them had good knowledge on malaria in pregnancy. A significant proportion of women were not aware of the reasons for taking SP during pregnancy (35%), timing for SP (18%), and the effect of malaria on pregnancy (45.8%). Timing for first dose of SP for intermittent preventive treatment in pregnancy (IPTp) was 1-3 months (28.4%) and 4-6 months (36.8%). Some 78.1% were provided with SP under supervision of the health provider. Knowledge on malaria in pregnancy had a significant association with levels of education (p=0.024). Ninety-eight percent had an ITN, mostly (87.1%) received free from the government. All women attended the ANC during their last pregnancy. The coverage of IPT1 was 53.5% and IPTp2 was 41.1%. The proportion of women making more ANC visits decreased with increasing parity. CONCLUSION: This study showed that the knowledge of the pregnant women on malaria in pregnancy and IPTp was average and is likely to have an impact on the low IPTp coverage. Campaigns that provide educational massages on the risk of malaria during pregnancy and the usefulness of IPTp need to be emphasised. PMID- 25277955 TI - Independent impact of gout on the risk of diabetes mellitus among women and men: a population-based, BMI-matched cohort study. AB - OBJECTIVE: Evidence on the potential independent impact of gout on the risk of diabetes is limited to a single study of men with a high cardiovascular risk profile. Our objective was to examine this relation in the general population, particularly among women. METHODS: We conducted a sex-stratified matched cohort study using data from The Health Improvement Network (THIN), an electronic medical records database representative of the UK general population. Up to five non-gout individuals were matched to each case of incident gout by year of birth, year of enrolment and body mass index (BMI). Multivariate HRs for incident diabetes were calculated after additionally adjusting for smoking, alcohol consumption, physician visits, comorbidities and medication use. RESULTS: Among 35 339 gout patients (72.4% men, mean age of 62.7 years), the incidence rates of diabetes in women and men were 10.1 and 9.5 cases per 1000 person-years, respectively, whereas the corresponding rates were 5.6 and 7.2 cases per 1000 person-years among 137 056 non-gout subjects. The BMI-matched univariate and multivariate HRs of diabetes were higher among women compared with those among men (1.71; 95% CI 1.51 to 1.93 vs 1.22; 95% CI 1.13 to 1.31) and (1.48; 95% CI 1.29 to 1.68 vs 1.15; 95% CI 1.06 to 1.24), respectively (p values for interaction <0.001). This sex difference persisted across age-specific subgroups. CONCLUSIONS: This general population-based study suggests that gout may be independently associated with an increased risk of diabetes and that the magnitude of association is significantly larger in women than in men. PMID- 25277957 TI - Recent developments in dye-sensitized solar cells. AB - The knowledge of dye-sensitized solar cells (DSCs) has expanded considerably in recent years. They are multiparameter and complex systems that work only if various parameters are tuned simultaneously. This makes it difficult to target to a single parameter to improve the efficiency. There is a wealth of knowledge concerning different DSC structures and characteristics. In this review, the present knowledge and recent achievements are surveyed with emphasis on the more promising cell materials and designs. PMID- 25277958 TI - ZnO nanowires with Au contacts characterised in the as-grown real device configuration using a local multi-probe method. AB - We demonstrate here a method using a multi-probe UHV instrument to isolate and measure individual metal contacts controllably fabricated on the tips of free standing ZnO nanowires (NWs). The measurements show Au can form reliable Ohmic and rectifying contacts by exercising control over the surface properties. In the as-grown state the Au contacts display low-resistance characteristics which are determined by the adsorbed species and defects on the NW surface. Subjecting the NWs to an oxidising agent (H2O2) increases the surface potential barrier creating more rectifying contacts. These developments are crucial for controllable NW array devices. PMID- 25277959 TI - Worried together: a qualitative study of shared anxiety in patients with metastatic non-small cell lung cancer and their family caregivers. AB - PURPOSE: Anxiety is prevalent, distressing, and understudied among patients with advanced lung cancer and their family caregivers. Preliminary evidence suggests that anxiety is not only present in both patients and caregivers but shared by the dyad. Few studies have examined the nature of shared anxiety and its impact on patient-caregiver dyads. METHODS: This study was developed to identify shared causes and manifestations of anxiety experienced by patients with stage IV non small cell lung cancer (NSCLC) and their primary caregivers. Data were collected through in-depth semi-structured interviews with ten matched patient-caregiver dyads and one unmatched patient (N = 21) recruited from two comprehensive cancer care centers. RESULTS: Using grounded theory, eight themes emerged characterizing shared causes and manifestations of anxiety: (1) uncertainty, (2) loss and impending loss, (3) changing roles, (4) conflict outside the dyad, (5) finances, (6) physical symptoms, (7) fears of decline and dying, and (8) life after the patient's passing. All themes were shared by patients and caregivers. CONCLUSIONS: Implications for future research include the development and evaluation of interventions to reduce anxiety in cancer patient-caregiver dyads. PMID- 25277960 TI - An explorative study of the views and experiences of food and weight loss in patients with operable pancreatic cancer perioperatively and following surgical intervention. AB - PURPOSE: Malnutrition and weight loss are highly prevalent in patients with pancreatic cancer. However, little is known about how patients experience such changes after completion of a surgery. The aim of this study was to explore the views and experiences about weight loss and food in patients with operable pancreatic cancer perioperatively and following surgical treatment. METHODS: An exploratory study underpinned by hermeneutic phenomenological philosophy was conducted. Thirteen post-surgery patients with pancreatic cancer were recruited from a National Health Service (NHS) Trust in the north of England. Sampling was purposive and data were collected using semi-structured in-depth interviews. Each interview was digitally recorded, transcribed verbatim and analysed using NVivo 8. RESULTS: Six themes emerged from the data that represented the patients' views and experience of foods and weight loss after surgery: "struggling with weight loss", "being pressured to eat", "experiences with nutrition support therapy", "perception of the role of the dietitians", "lacking appropriate dietary instructions" and "road to recovery". CONCLUSIONS: The study has found that sufficient dietary advice, appropriate nutrition support and patient self management are significant factors that affect how people recover from surgery for pancreatic cancer. Further work is required to understand the nature and effect of weight loss in surgical patients with pancreatic cancer and the role of food in their weight management. PMID- 25277961 TI - Effects of unidentified renal insufficiency on the safety and efficacy of chemotherapy for metastatic colorectal cancer patients: a prospective, observational study. AB - BACKGROUND: This is a single-center, prospective, observational study aiming to determine the effects of unidentified renal insufficiency (URI) on the safety and efficacy of chemotherapy for metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: mCRC patients with normal serum creatinine and who were treated with CapeOx as the first-line therapy were included. Creatinine clearance (CrCL) was estimated using the Cockcroft-Gault formula. URI was characterized by a CrCL of less than 60 ml/min. Logistic regression was used to assess the effects of URI on toxicities and response rates. Kaplan-Meier curve was used to evaluate the effect of URI on survival. RESULTS: A total of 143 patients were enrolled, of whom 34.9 % had URI. Compared with the control group, the URI group had longer toxicity durations and developed significantly more grade 1 to 2 toxicities after adjusting for age, gender, and body mass index. The toxicities include cytopenia (76 vs. 61 %, OR = 1.86, 95 % CI = 0.39-2.53, P < 0.001), diarrhea (34 vs. 29 %, OR = 3.76, 95 % CI = 0.95-6.53, P = 0.007), stomatitis (10 vs. 6 %, OR = 2.81, 95 % CI = 1.10-4.28, P = 0.002), and hand-foot syndrome (18 vs. 11 %, OR = 2.56, 95 % CI = 0.86-5.41, P = 0.045). The response rate and time to progression were significantly lower in the URI group than in the control group (4.5 vs. 5.5 months, HR = 1.57, 95 % CI = 1.09-2.25, P = 0.015), whereas the overall survival rates of the two groups were similar. CONCLUSION: In conclusion, URI can increase the toxicity and decrease the TTP of CapeOx-treated mCRC patients. Renal function screening via CrCL estimation is required for all mCRC patients before initial chemotherapy. PMID- 25277962 TI - Aquaporin-1 antibody in neuromyelitis optical patients. AB - BACKGROUND/METHODS: To find out the prevalence of aquaporin-antibody (Aqp-Ab) and characterize Aqp-Ab associated clinical features in NMO, Aqp-1 and Aqp-4-Abs were examined using radioimmunoprecipitation and cell-based assays, respectively. RESULTS: Aqp-4 and Aqp-1-Abs were detected in 20/30 and 8/30 NMO patients, respectively. One patient was Aqp-1-Ab single-positive, 13 patients were Aqp-4-Ab single-positive, 7 patients were Aqp-4/Aqp-1-Ab double-positive and 9 patients were seronegative. All double-positive patients had optic neuritis during the first attack. Only 2/29 MS patients and none of the control idiopathic intracranial hypertension patients were Aqp-1-Ab positive. CONCLUSION: Aqp-1-Ab is usually detected in Aqp-4-Ab positive NMO patients and might be involved in optic neuritis pathogenesis. PMID- 25277963 TI - Concomitant development of hypersexuality and delusional jealousy in patients with Parkinson's disease: a case series. AB - BACKGROUND: Both impulse-control disorders and delusional jealousy (DJ) may be considered non-motor side-effects of dopamine agonist therapy in Parkinson's disease (PD). We aimed to investigate the possible concomitant development of these features in PD and their clinical correlates. METHODS: We performed a cross sectional investigation in 1063 consecutive PD patients with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's disease and the Parkinson's Psychosis Questionnaire. RESULTS: 81 patients presented ICDs (prevalence 7.61%) and 23 patients presented DJ (17 males, 6 females; prevalence 2.16%). 9 male PD patients presented both DJ and ICDs (39.13% of patients with DJ, 11.11% of patients with ICDs; prevalence of 0.84% in the whole PD sample), with a concomitant onset of delusional jealousy and hypersexuality in 8 cases and a concomitant onset of delusional jealousy and pathological gambling in 2 cases. DISCUSSION: Hypersexuality and delusional jealousy may occur independently in PD patients "on" dopamine agonist therapy, but may develop together probably reflecting a common alteration of sexuality (sexual arousal and jealousy) The presence of both of these clinical features and sexuality more in general should be investigated when features of either one of them appear. Further confirmation is needed in larger samples of patients. PMID- 25277964 TI - Empathy as a neuropsychological heuristic in social decision-making. AB - Decision-making in social dilemmas is suggested to rely on three factors: the valuation of a choice option, the relative judgment of two or more choice alternatives, and individual factors affecting the ease at which judgments and decisions are made. Here, we test whether empathy-an individual's relative ability to understand others' thoughts, emotions, and intentions-acts as an individual factor that alleviates conflict resolution in social decision-making. We test this by using a framed, iterated prisoners' dilemma (PD) game in two settings. In a behavioral experiment, we find that individual differences in empathic ability (the Empathy Quotient, EQ) were related to lower response times in the PD game, suggesting that empathy is related to faster social choices, independent of whether they choose to cooperate or defect. In a subsequent neuroimaging experiment, using functional magnetic resonance imaging, we find that EQ is positively related to individual differences in the engagement of brain structures implemented in mentalizing, including the precuneus, superior temporal sulcus, and dorsolateral prefrontal cortex. These results suggest that empathy is related to the individual difference in the engagement of mentalizing in social dilemmas and that this is related to the efficiency of decision-making in social dilemmas. PMID- 25277965 TI - Assessment of EDTA heap leaching of an agricultural soil highly contaminated with heavy metals. AB - The efficiency of heavy metal removal from soil by EDTA leaching was assessed in a column leaching experiment at the laboratory scale and field heap leaching at the pilot scale using a sandy loam sierozem agricultural soil contaminated with Cd, Cu, Pb, and Zn. Soil amendment and aging were conducted to recover leaching soils. The percentages of Cd, Cu, Pb, and Zn removed by column leaching were 90%, 88%, 90%, and 67%, respectively, when 3.9 bed volumes of 50mM EDTA were used. At the pilot scale, on-site metal removal efficiencies using the selected leaching procedure were 80%, 69%, 73% and 62% for Cd, Cu, Pb and Zn, respectively. EDTA leaching decreased soil CEC, total P, total K and available K concentrations but increased organic matter and total Kjeldahl N concentrations. The subsequent amendment and soil aging further reduced the DTPA-extractable heavy metals in the leached soils. Growth of the first crop of pak choi in the leached soil was inhibited but the second crop grew well after the soil was aged for one year and the concentrations of Cd and Pb in the edible parts were below the Chinese statutory limits. The results demonstrate the potential feasibility of the field leaching technique using EDTA combined with subsequent amendment and soil aging for the remediation of heavy metal-contaminated agricultural soils. PMID- 25277966 TI - Culturable endophytic bacteria enhance Ni translocation in the hyperaccumulator Noccaea caerulescens. AB - In this work, both culture-dependent and independent approaches were used to identify and isolate endophytic bacteria from roots of the Ni hyperaccumulator Noccaea caerulescens. A total of 17 isolates were cultured from root samples, selected for tolerance to 6mM Ni and grouped by restriction analysis of 16S rDNA. Bacterial species cultivated from roots belonged to seven genera, Microbacterium, Arthrobacter, Agreia, Bacillus, Sthenotrophomonas, Kocuria and Variovorax. The culture-independent approach confirmed the presence of Microbacterium and Arthrobacter while only other five clones corresponding to different amplified ribosomal DNA restriction patterns were detected. Five selected highly Ni resistant bacteria showing also plant growth promoting activities, were inoculated into seeds of N. caerulescens, and in vivo microscopic analysis showed rapid root colonisation. Inoculated plants showed increased shoot biomass, root length and root-to-shoot Ni translocation. Root colonisation was also evident, but not effective, in the non-hyperaccumulating Thlaspi perfoliatum. Seed inoculation with selected Ni-resistant endophytic bacteria may represent a powerful tool in phytotechnologies, although transferring it to biomass species still requires further studies and screening. PMID- 25277967 TI - Characterization and biotoxicity assessment of dissolved organic matter in RO concentrate from a municipal wastewater reclamation reverse osmosis system. AB - Reverse osmosis (RO) concentrate from municipal wastewater reclamation reverse osmosis (mWRRO) system containing organic compounds may associate with toxic risk, and its discharge might pose an environmental risk. To identify a basis for the selection of feasible technology in treating RO concentrates, the characteristics and biotoxicity of different fractions of dissolved organic matter (DOM) in RO concentrates from an mWRRO system were investigated. The results indicated that the hydrophilic neutrals (HIN), hydrophobic acids (HOA) and hydrophobic bases (HOB) accounted for 96% of the dissolved organic carbon (DOC) of the total DOM in the RO concentrate. According to the SEC chromatograph detected at 254 nm wavelength of UV, the DOM with molecular weight (MW) 1-3 kDa accounted for the majority of the basic and neutral fractions. The fluorescence spectra of the excitation emission matrix (EEM) indicated that most aromatic proteins, humic/fulvic acid-like and soluble microbial by-product-like substances existed in the fractions HOA and hydrophobic neutrals (HON). The genotoxicity and anti-estrogenic activity of the RO concentrate were 1795.6 +/- 57.2 MUg 4-NQOL( 1) and 2.19 +/- 0.05 mg TAM L(-1), respectively. The HIN, HOA, and HOB contributed to the genotoxicity of the RO concentrate, and the HIN was with the highest genotoxic level of 1007.9 +/- 94.8 MUg 4-NQOL(-1). The HOA, HON, and HIN lead to the total anti-estrogenic activity of the RO concentrate, and HOA occupied approximately 60% of the total, which was 1.3 +/- 0.17 mg TAM L(-1). PMID- 25277968 TI - Enhancement of sludge reduction and methane production by removing extracellular polymeric substances from waste activated sludge. AB - The management of waste activated sludge (WAS) recycling is a concern that affects the development of the future low-carbon society, particularly sludge reduction and biomass utilization. In this study, we investigated the effect of removing extracellular polymeric substances (EPS), which play important roles in the adhesion and flocculation of WAS, on increased sludge disintegration, thereby enhancing sludge reduction and methane production by anaerobic digestion. EPS removal from WAS by ethylenediaminetetraacetic acid (EDTA) significantly enhanced sludge reduction, i.e., 49 +/- 5% compared with 27 +/- 1% of the control at the end the digestion process. Methane production was also improved in WAS without EPS by 8881 +/- 109 CH4 MUmol g(-1) dry-weight of sludge. Microbial activity was determined by denaturing gradient gel electrophoresis and real-time polymerase chain reaction, which showed that the hydrolysis and acetogenesis stages were enhanced by pretreatment with 2% EDTA, with a larger methanogenic community and better methane production. PMID- 25277969 TI - Rats fed diets with different energy contribution from fat do not differ in adiposity. AB - OBJECTIVE: To determine whether rats reaching the same body mass, having been fed either a low-fat (LFD) or a high-fat diet (HFD), differ in white adipose tissue (WAT) deposition. METHODS: In experiment 1, 22 Sprague-Dawley rats of the same age were divided into 11 rats with body mass below the batch median and fed a HFD, and 11 above the median and fed a LFD. In experiment 2, 20 Sprague-Dawley rats of the same age and starting body mass were randomised to either a HFD or LFD. When all groups reached similar final body mass, WAT was quantified using magnetic resonance imaging (MRI), dissection, and plasma leptin. RESULTS: In experiment 1, both groups reached similar final body mass at the same age; in experiment 2 the HFD group reached similar final body mass earlier than the LFD group. There were no significant differences in WAT as assessed by MRI or leptin between the HFD and LFD groups in both experiments. Dissection revealed a trend for higher retroperitoneal and epididymal adiposity in the HFD groups in both experiments. CONCLUSIONS: We conclude that at similar body mass, adiposity is independent of the macronutrient composition of the feeding regimen used to achieve it. PMID- 25277970 TI - Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration. AB - Regulation of adult stem cells (SCs) is fundamental for organ maintenance and tissue regeneration. On the body surface, different ectodermal organs exhibit distinctive modes of regeneration and the dynamics of their SC homeostasis remain to be unraveled. A slow cycling characteristic has been used to identify SCs in hair follicles and sweat glands; however, whether a quiescent population exists in continuously growing nails remains unknown. Using an in vivo label retaining cells (LRCs) system, we detected an unreported population of quiescent cells within the basal layer of the nail proximal fold, organized in a ring-like configuration around the nail root. These nail LRCs express the hair stem cell marker, keratin 15 (K15), and lineage tracing show that these K15-derived cells can contribute to both the nail structure and peri-nail epidermis, and more toward the latter. Thus, this stem cell population is bifunctional. Upon nail plucking injury, the homeostasis is tilted with these SCs dominantly delivering progeny to the nail matrix and differentiated nail plate, demonstrating their plasticity to adapt to wounding stimuli. Moreover, in vivo engraftment experiments established that transplanted nail LRCs can actively participate in functional nail regeneration. Transcriptional profiling of isolated nail LRCs revealed bone morphogenetic protein signaling favors nail differentiation over epidermal fate. Taken together, we have found a previously unidentified ring configured population of bifunctional SCs, located at the interface between the nail appendage organ and adjacent epidermis, which physiologically display coordinated homeostatic dynamics but are capable of rediverting stem cell flow in response to injury. PMID- 25277971 TI - Reply to Cheung et al.: The cognitive map hypothesis remains the best interpretation of the data in honeybee navigation. PMID- 25277972 TI - Still no convincing evidence for cognitive map use by honeybees. PMID- 25277973 TI - Tug-of-war between driver and passenger mutations in cancer and other adaptive processes. AB - Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations--a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies. PMID- 25277974 TI - Heme oxygenase-1 promoter polymorphisms and neonatal jaundice. AB - BACKGROUND: Heme oxygenase (HO) is the initial, rate-limiting enzyme in the conversion of heme to bilirubin. Dinucleotide (GT)n repeat length in the promoter region of the encoding gene modulates transcription: shorter alleles, in contrast with longer allele counterparts, are associated with greater gene expression and should result in increased heme catabolism. OBJECTIVE: We compared the rates of heme catabolism and plasma total bilirubin (TB) between HO-1 promoter genotypes of varying (GT)n repeat lengths in glucose-6-phosphate dehydrogenase (G6PD) normal and -deficient neonates. METHODS: HO-1 promoter length was determined from genomic DNA from previous studies by size discrimination of fluorescently-labeled PCR products with capillary electrophoresis. Sizing was confirmed by sequencing homozygote samples. Alleles were categorized as: short (<=24 GT repeats), medium (25-33 GT repeats), and long (>=34 GT repeats). Previously determined values for blood carboxyhemoglobin, corrected for inspired carbon monoxide (COHbc), and TB were used to determine the rate of heme catabolism and 3rd day TB values for each HO-1 promoter length genotype, respectively. G6PD Mediterranean was determined by PCR analysis. RESULTS: Neither COHbc nor TB values were significantly different between various HO-1 promoter genotypes for either G6PD-normal or -deficient neonates. CONCLUSIONS: In the steady state, HO-1 promoter genotypes, based on the length of (GT)n repeats, do not modulate heme catabolism or 3rd day TB values in either G6PD-normal or -deficient neonates. PMID- 25277975 TI - Pelvic girdle pain affects the whole life--a qualitative interview study in Norway on women's experiences with pelvic girdle pain after delivery. AB - BACKGROUND: The aim of this study was to explore how pelvic girdle pain after delivery influences women's daily life in Norway. Knowledge about living with post-partum pelvic girdle pain is lacking. METHOD: A phenomenological hermeneutical design with qualitative semi-structured interviews was used. A strategic selection procedure was chosen to recruit participants from physiotherapy clinics and a regional hospital in Norway. Five women with clinically verified pelvic girdle pain after delivery were included. Data were imported into NVivo9 and analysed in three steps: naive reading, structural analysis and comprehensive understanding of the text. RESULTS: Three themes influencing the women's daily life were identified: 1) activity and pain, 2) lack of acknowledgment of pain and disability, and 3) changed roles. A daily life with pain and limited physical activity was difficult to accept and made some of the women feel discouraged, isolated and lonely. Despite this, the women had a positive attitude to their problems, which may have positively increased their ability to cope. The findings also revealed the importance of a reciprocal influence between the woman and her environment, and that social support was crucial. CONCLUSIONS: Pelvic girdle pain may influence women's lives for months and years after delivery. Health care professionals should appreciate and focus on the patient's knowledge and skills. Understanding the daily experiences of women with pelvic girdle pain might help improve rehabilitation strategies for these patients. PMID- 25277976 TI - A resting-state functional connectivity study in patients at high risk for sudden unexpected death in epilepsy. AB - OBJECTIVE: Seizure-related respiratory and cardiac dysfunctions were once thought to be the direct cause of sudden unexpected death in epilepsy (SUDEP), but both may be secondary to postictal cerebral inhibition. An important issue that has not been explored to date is the neural network basis of cerebral inhibition. Our aim was to investigate the features of neural networks in patients at high risk for SUDEP using a blood oxygen level-dependent (BOLD) resting-state functional connectivity (FC) approach. SUBJECTS AND METHODS: Resting-state functional magnetic resonance imaging (Rs-fMRI) data were recorded from 13 patients at high risk for SUDEP and 12 patients at low risk for SUDEP. Thirteen cerebral regions that are closely related to cardiorespiratory activity were selected as regions of interest (ROIs). The ROI-wise resting-state FC analysis was compared between the two groups. RESULTS: Compared with patients at low risk for SUDEP, patients at high risk exhibited significant reductions in the resting-state FC between the pons and the right thalamus, the midbrain and the right thalamus, the bilateral anterior cingulate cortex (ACC) and the right thalamus, and the left thalamus and the right thalamus. CONCLUSIONS: This investigation is the first to use neuroimaging methods in research on the mechanism of SUDEP and demonstrates the abnormally decreased resting-state FC in the ACC-thalamus-brainstem circuit in patients at high risk for SUDEP. These findings highlight the need to understand the fundamental neural network dysfunction in SUDEP, which may fill the missing link between seizure-related cardiorespiratory dysfunction and SUDEP, and provide a promising neuroimaging biomarker for risk prediction of SUDEP. PMID- 25277977 TI - What Epilepsy & Behavior has taught us about the comorbidities of epilepsy. PMID- 25277978 TI - Absence of hyperplasia in Gasp-1 overexpressing mice is dependent on myostatin up regulation. AB - BACKGROUND/AIMS: Overexpression of Gasp-1, an inhibitor of myostatin, leads to a hypermuscular phenotype due to hypertrophy rather than hyperplasia in mice. However to date, the cellular and molecular mechanisms underlying this phenotype are not investigated. METHODS: Skeletal muscles of overexpressing Gasp-1 mice, called Tg(Gasp-1) mice, were analyzed by histological methods. Satellite cell derived myoblasts from these mice were used to investigate the molecular mechanisms. RESULTS: We demonstrated that hypertrophy in Tg(Gasp-1) mice was related to a myonuclear accretion during the first 3 postnatal weeks and an activation of the pro-hypertrophic Akt/mTORC/p70S6K signaling. In accordance with these results, we showed that overexpressing Gasp-1 primary myoblasts proliferated faster and myonuclei average per myotube was increased during differentiation. Molecular analysis revealed that Gasp-1 overexpression resulted in increased myostatin expression related to its auto-regulation. Despite its inhibition, myostatin led to Pax7 deregulation through its non-canonical Erk1/2 signaling pathway. Consistent with this, inhibition of Erk1/2 signaling pathway as well as neutralization of secreted myostatin rescue the Pax7 expression in overexpressing Gasp-1 myoblasts. CONCLUSION: Our study shows that myostatin is able to act independently of its canonical pathway to regulate the Pax7 expression. Altogether, our results indicate that myostatin could regulate muscle development despite its protein inhibition. PMID- 25277979 TI - Systematic mediastinal lymphadenectomy or mediastinal lymph node sampling in patients with pathological stage I NSCLC: a meta-analysis. AB - BACKGROUND: To evaluate the evidence comparing systematic mediastinal lymphadenectomy (SML) and mediastinal lymph node sampling (MLS) in the treatment of pathological stage I NSCLC using meta-analytical techniques. METHODS: A literature search was undertaken until January 2014 to identify the comparative studies evaluating 1-, 3-, and 5-year survival rates. The pooled odds ratios (OR) and the 95 % confidence intervals (95 % CI) were calculated with either the fixed or random effect models. RESULTS: One RCT study and four retrospective studies were included in our meta-analysis. These studies included a total of 711 patients: 317 treated with SML, and 394 treated with MLS. The SML and the MLS did not demonstrate a significant difference in the 1-year survival rate. There were significant statistical differences between the 3-year (P = 0.03) and 5-year survival rates (P = 0.004), which favored SML. CONCLUSIONS: This meta-analysis suggests that in pathological stage I NSCLC, the MLS can get the similar outcome to the SML in terms of 1-year survival rate. However, the SML is superior to MLS in terms of 3- and 5-year survival rates. PMID- 25277980 TI - Assessment of the availability of technology for trauma care in India. AB - BACKGROUND: We sought to assess the status of availability of technology for trauma care in a state in India and to identify factors contributing to both adequate levels of availability and to deficiencies. We also sought to identify potential solutions to deficiencies in terms of health system management and product development. METHODS: Thirty-two technology-related items were selected from the World Health Organization's Guidelines for Essential Trauma Care. The status of these items was assessed at 43 small and large hospitals in Gujarat State. Site visits utilized direct inspection and interviews with administrative, clinical, and bioengineering staff. RESULTS: Many specific individual items could be better supplied, including many that were very low cost (e.g., chest tubes). Many deficiencies arose because of mismatch of resources, such as availability of equipment in the absence of personnel trained to use it. Several locally manufactured items were fairly well supplied: pulse oximetry, image intensification, and X-ray machines. Ventilators were often deficient because of inadequate numbers of units and frequent breakdowns. CONCLUSIONS: Availability of a range of lower-cost items could be improved by better organization and planning, such as: better procurement and stock management; eliminating mismatch of resources, including optimizing training for use of existing resources; and by strengthening service contracts and in-house repair capabilities. From a product development viewpoint, there is a need for lower cost, more durable, and easier to repair ventilators. Promoting increased capacity for local manufacturing should also be considered as a potential method to decrease cost and increase availability of a range of equipment. PMID- 25277981 TI - Delayed laparotomy after selective non-operative management of penetrating abdominal injuries. AB - BACKGROUND: Main concern during the practice of selective non-operative management (SNOM) for abdominal stab wounds (SW) and gunshot wounds (GSW) is the potential for harm in patients who fail SNOM and receive a delayed laparotomy (DL). The aim of this study is to determine whether such patients suffer adverse sequelae because of delays in diagnosis and treatment when managed under a structured SNOM protocol. METHODS: 190 patients underwent laparotomy after an abdominal GSW or SW (5/04-10/12). Patients taken to operation within 120 min of admission were included in the early laparotomy (EL) group (n =153, 80.5 %) and the remaining in the DL group (n =37, 19.5 %). Outcomes included mortality, hospital stay, and postoperative complications. RESULTS: The median time from hospital arrival to operation was 43 min (range: 17-119) for EL patients and 249 min (range: 122-1,545) for DL patients. The average number and type of injuries were similar among the groups. Mortality and negative laparotomy were observed only in the EL group. There was no significant difference in the hospital stay between the groups. The overall complications were higher in the EL group (44.4 vs. 24.3 %, p =0.026). DL was independently associated with a lower likelihood for complications (OR 0.39, 95 % CI 0.16-0.98, p =0.045). Individual review of all DL patients did not reveal an incident in which complications could be directly attributed to the delay. CONCLUSIONS: In a structured protocol, patients who fail SNOM and require an operation are recognized and treated promptly. The delay in operation does not cause unnecessary morbidity or mortality. PMID- 25277982 TI - Can red cell distribution width predict acute mesenteric ischemia? PMID- 25277983 TI - Moderate intra-abdominal free fluid on computed tomogram in patients with blunt trauma abdomen: time to shun non-operative approach: reply. PMID- 25277984 TI - Antireflux surgery for dysplastic Barrett's esophagus. PMID- 25277985 TI - Avoiding overfeeding in high cell density fed-batch cultures of E. coli during the production of heterologous proteins. AB - Heterologous protein production often causes a significant metabolic burden in Escherichia coli cells which manifests itself in a substantial decrease in their physiological characteristics such as the maximal specific growth rate on a given substrate, the maximal substrate uptake rate as well as the maximal specific oxygen uptake rate. In high-cell-density cultures, the substrate feed rate must be adapted to this changing capabilities of the cells in order to avoid overfeeding and thus the formation of by-products that inhibit the cell performance further. This requires the precise knowledge about the changes in these specific rates, particularly during the product formation phase. In order to precisely investigate the time profile of the critical specific substrate uptake rate sigmacrit of microorganisms, i.e. the maximal rate at which the cells can fully oxidize their substrate, a new online tracking technique is presented. The feed rate F is modulated in such a way that the specific substrate uptake rate sigma is linearly raised towards its critical value sigmacrit. When this is reached the feed rate is automatically reduced and the procedure is repeated. In this way the method automatically follows the changing time profile of sigmacrit during the entire cultivation and avoids significant acetate formation rates. This procedure considerably increases the identifiability of sigmacrit. The high precision of the technique also results from replacing the pO2 measurements that seem to suggest themselves for monitoring maximal oxygen uptake rate, by measuring the total oxygen consumption rate tOUR, which is available at a much higher signal-to-noise ratio and is not as prone to distortions. An important advantage of measuring tOUR is that it allows keeping pO2 controlled at its optimal value. The applicability of the new tracking technology is demonstrated at E. coli cultures. The resulting sigmacrit(t) profile allows determining the substrate feed rate profile and other key variables that can be used for advanced feedback control in protein production processes. The technique can be considered a PAT tool and is well suited to industrial fermentations. PMID- 25277986 TI - High salt buffer improves integrity of RNA after fluorescence-activated cell sorting of intracellular labeled cells. AB - Over the past years, massive progress has been made in the ability to collect large-scale gene expression data from a limited sample size. Combined with improvements in multiplex flow cytometry-based techniques, this has made it possible to isolate and characterize specific cellular subtypes within heterogeneous populations, with a great impact on our understanding of different biological processes. However, sorting based on intracellular markers requires fixation and permeabilization of samples, and very often the integrity of RNA molecules is compromised during this process. Many attempts have been made to improve the quality of nucleic acids from such samples, but RNA degradation still remains a limiting factor for downstream analyses. Here we present a method to isolate high quality RNA from cells that have been fixed, permeabilized, intracellularly labeled and sorted. By performing all incubation steps in the presence of a high salt buffer, RNA degradation was avoided and samples with remarkable integrity were obtained. This procedure offers a straightforward and very affordable technique to retrieve high quality RNA from isolated cell populations, which increases the possibilities to characterize gene expression profiles of subpopulations from mixed samples, a technique with implications in a broad range of research fields. PMID- 25277987 TI - Recurrent spontaneous clinical perimitral atrial tachycardia in the context of atrial fibrillation ablation. AB - BACKGROUND: Recurrent perimitral atrial tachycardia (AT) is a challenging arrhythmia and is frequently encountered in the context of atrial fibrillation (AF) ablation. OBJECTIVE: The purpose of this study was to investigate the clinical characteristics and the procedural and clinical outcomes in patients with recurrent perimitral atrial tachycardia (PMAT) after AF ablation. METHODS: Among 520 consecutive ablation procedures for recurrent AT/AF after AF ablation, 40 procedures (patients) were performed for clinically recurrent PMAT 12.1 +/- 13.6 months after the last procedure (total 2.2 +/- 1.3 procedures). Previously, mitral isthmus (MI) linear ablation was performed in 26 of 40 procedures, including 13 procedures with complete block and 13 with 159.0 +/- 23.0 ms of conduction delay without block. As a reference group, conduction delay was evaluated in 55 patients with incomplete MI block and absence of spontaneous PMAT during the follow-up period. RESULTS: Recurrent PMATs were terminated by MI linear ablation in 26 of 40 patients. Bidirectional block across the MI and anterior line joining the mitral annulus and left atrial roof was achieved in 33 (82.5%) and 2 (5%) patients, respectively. At mean follow-up of 26.7 +/- 14.5 months, 2 patients (5%) underwent reablation for spontaneously recurrent PMAT. At 12 months after the ablation procedure for PMAT, 73.5% of the patients were free from AT/AF. Conduction delay >149 ms predicted the occurrence of spontaneous PMAT with 80.0% sensitivity and 87.3% specificity. CONCLUSION: PMAT can recur even after successful bidirectional MI linear block. Substantial conduction delay without block across the MI from a previous procedure(s) could predispose to recurrent PMAT. Although most clinical PMATs can be successfully treated by catheter ablation, very late recurrence is possible. PMID- 25277988 TI - Ventricular lead redundancy to prevent cardiovascular events and sudden death from lead fracture in pacemaker-dependent children. AB - BACKGROUND: Children requiring a permanent epicardial pacemaker (PM) traditionally have a single lead placed on the right ventricle. Lead failure in pacemaker-dependent (PMD) children, however, can result in cardiovascular events (CVEs) and death. OBJECTIVE: The purpose of this study was to determine if redundant ventricular lead systems (RVLS) can safeguard against CVE and death in PMD children. METHODS: This was a single-center study of PMD patients undergoing placement of RVLS from 2002-2013. Patients <=21 years of age who were PMD were included. Patients with a biventricular (BiV) system placed for standard resynchronization indications were excluded. RVLS patients were compared to PMD patients with only a single pacing lead on the ventricle (SiV). RESULTS: Seven hundred sixty-nine patients underwent PM/implantable cardioverter-defibrillator placement with 76 BiV implants; 49 patients (6%) were PMD. Thirteen patients underwent implantation of an RVLS. There was no difference between the RVLS group (n = 13) and SiV PMD control group (n = 24) with regard to age (RVLS 9.5 +/- 5.8 years vs SiV 9.4 +/- 6.7 years, P = .52), weight (RVLS 38.2 +/- 32.6 kg vs SiV 35.2 +/- 29.3 kg, P = .62), indication for pacing, procedural complications, or time to follow-up. There were 2 lead fractures (17%) in the RVLS group (mean follow-up 3.8 +/- 2.9 years), with no deaths or presentations with CVE. The SiV control group had 3 lead fractures (13%) (mean follow-up 2.8 +/- 2.9 years), with no deaths, but all 3 patients presented with CVE and required emergent PM placement. CONCLUSION: RVLS systems should be considered in children who are PMD and require permanent epicardial pacing. BiV pacing and RVLS may decrease the risk of CVE in the event of lead failure in PMD patients. PMID- 25277990 TI - The talin-integrin interface under mechanical stress. AB - The major mechanical function of talin is to couple the beta-integrin cytoplasmic tails to actin filaments. A variety of beta-integrin tails contain conserved binding motifs for talin, and recent research shows that beta-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links beta3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the beta-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the beta-integrin still remains bound to talin. The epithelial integrin beta6 reportedly activates latent TGFbeta1, and we propose that its function may involve direct interaction with talin. PMID- 25277989 TI - Declining incidence of sudden cardiac death from 1990-2010 in a general middle aged and elderly population: The Rotterdam Study. AB - BACKGROUND: Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking. OBJECTIVE: The purpose of this study was to investigate the current incidence of SCD and its trend over the past 2 decades in a general middle-aged and elderly population. METHODS: This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001 2010. RESULTS: From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence [CI] 1.56-2.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09 1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence. CONCLUSION: We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990 2010, a period during which the diagnosis and treatment of heart disease greatly improved. PMID- 25277991 TI - The perils of rational design--unexpected irreversible elimination of fluoride from 3-fluoro-2-methylacyl-CoA esters catalysed by alpha-methylacyl-CoA racemase (AMACR; P504S). AB - alpha-Methylacyl-CoA racemase (AMACR; P504S) catalyses 'racemization' of 2 methylacyl-CoAs, the activation of R-ibuprofen and is a promising cancer drug target. Human recombinant AMACR 1A catalyses elimination of 3-fluoro-2 methyldecanoyl-CoAs to give E-2-methyldec-2-enoyl-CoA and fluoride anion, a previously unknown reaction. 'Racemization' of 2-methyldec-3-enoyl-CoAs was also catalysed, without double bond migration. PMID- 25277992 TI - Time to change course: comment on the section regarding automated external defibrillator use in the 2013 American Heart Association consensus statement on in-hospital resuscitation. PMID- 25277993 TI - Ageing as developmental decay: insights from p16(INK4a.). AB - The p16(INK4a) cell cycle regulator is one of the best ageing biomarkers because it is suppressed in early embryogenesis and progressively induced during ageing. p16(INK4a) plays a crucial role in key cell fate decisions which contribute to ageing, such as cellular senescence and stem cell dynamics. Detailed examination of the pathways regulating p16(INK4a) expression has revealed an overlap with those regulating early development. We present the hypothesis that ageing might be primarily driven by gradual functional decay of developmental pathways. To support this, we summarise the role of p16(INK4a) in ageing and our current knowledge on p16(INK4a) regulation. The developmental decay hypothesis implies that the much-evidenced damage associated with all aspects of ageing might be secondary to such decay. PMID- 25277995 TI - Minimally invasive thoracic surgery for early stage non-small cell lung cancer. PMID- 25277994 TI - Long term survival with thoracoscopic versus open lobectomy: propensity matched comparative analysis using SEER-Medicare database. AB - OBJECTIVE: To compare long term survival after minimally invasive lobectomy and thoracotomy lobectomy. DESIGN: Propensity matched analysis. SETTING: Surveillance, Epidemiology and End Results (SEER)-Medicare database. PARTICIPANTS: All patients with lung cancer from 2007 to 2009 undergoing lobectomy. MAIN OUTCOME MEASURE: Influence of less invasive thoracoscopic surgery on overall survival, disease-free survival, and cancer specific survival. RESULTS: From 2007 to 2009, 6008 patients undergoing lobectomy were identified (n=4715 (78%) thoracotomy). The median age of the entire cohort was 74 (interquartile range 70-78) years. The median length of follow-up for entire group was 40 months. In a matched analysis of 1195 patients in each treatment category, no statistical differences in three year overall survival, disease-free survival, or cancer specific survival were found between the groups (overall survival: 70.6% v 68.1%, P=0.55; disease-free survival: 86.2% v 85.4%, P=0.46; cancer specific survival: 92% v 89.5%, P=0.05). CONCLUSION: This propensity matched analysis showed that patients undergoing thoracoscopic lobectomy had similar overall, cancer specific, and disease-free survival compared with patients undergoing thoracotomy lobectomy. Thoracoscopic techniques do not seem to compromise these measures of outcome after lobectomy. PMID- 25277996 TI - Antibiotic treatment failure in primary care. PMID- 25277998 TI - beta-blocker therapy is not associated with adverse outcomes in patients with pulmonary arterial hypertension: a propensity score analysis. AB - BACKGROUND: The safety of beta-blockers in patients with isolated right ventricular failure because of pulmonary arterial hypertension (PAH) is unclear. METHODS AND RESULTS: We studied 564 PAH patients (total cohort) referred to our center from 1982 to 2013. Propensity score-matching was used to match pairs of PAH patients with and without beta-blocker use (matched cohort). We compared all cause mortality between the groups in the total cohort and the matched cohort using bootstrap validation, Kaplan-Meier, and Cox proportional hazard analyses. Seventy-one of the 564 patients in the total cohort were on beta-blockers. They were older, had higher prevalence of comorbidities, and were more often on diuretics, digoxin, and angiotensin converting enzyme inhibitors. The severity of PAH and right ventricular failure was similar between those with and without beta blocker use. After propensity matching, 63 patients with beta-blocker use were compared with 51 patients without beta-blocker use. During a median follow-up time of 4.8 years, there were 339 (60%) deaths in the total cohort and 70 deaths (61%) in the matched cohort. There was no difference in absolute mortality between those with and without beta-blockers (P=0.71). beta-Blocker use was not associated with increased all-cause mortality in the total cohort after adjusting for propensity score (adjusted hazard ratio, 1.0; 95% confidence interval, 0.7 1.5) and in the matched cohort (hazard ratio, 1.2; 95% confidence interval, 0.8 2.0). CONCLUSIONS: There was no statistically significant difference in long-term mortality between propensity score-matched pairs of PAH patients with and without beta-blocker use. These findings need further validation in prospective clinical trials. PMID- 25277997 TI - Elevation in high-sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696. AB - BACKGROUND: Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction. METHODS AND RESULTS: We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 MUg/L) was found in 55% of patients and was associated with older age, history of diabetes mellitus, higher N-terminal pro-brain natriuretic peptide, lower estimated glomerular filtration rate, and larger left atrial size, left ventricular volume, and mass. LCZ696 treatment reduced hs-TnT to a greater extent at 12 weeks (12% reduction; P=0.05) and at 36 weeks (14% reduction; P=0.03) compared with valsartan. CONCLUSIONS: Troponin T was elevated in a substantial number of patients enrolled in a heart failure with preserved ejection fraction clinical trial and was associated with abnormalities of cardiac structure, function, and elevated baseline N-terminal pro-brain natriuretic peptide. Decreases in hs-TnT with LCZ696 in parallel with improvement in N terminal pro-brain natriuretic peptide and left atrial size suggest that the angiotensin receptor neprilysin inhibitor LCZ696 may reduce this measure of myocardial injury in heart failure with preserved ejection fraction. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588. PMID- 25277999 TI - Activation of liver-X-receptor alpha but not liver-X-receptor beta protects against myocardial ischemia/reperfusion injury. AB - BACKGROUND: Liver-X-receptors, LXRalpha (NR1H3) and LXRbeta (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXRalpha and LXRbeta subtypes have discrete roles in the regulation of cardiac physiology/pathology is unknown. We determine the role of each LXR subtype in myocardial ischemia/reperfusion (MI/R) injury. METHODS AND RESULTS: Mice (wild type; those genetically depleted of LXRalpha, LXRbeta, or both; and those overexpressing LXRalpha or LXRbeta by in vivo intramyocardial adenoviral vector) were subjected to MI/R injury. Both LXRalpha and LXRbeta were detected in wild-type mouse heart. LXRalpha, but not LXRbeta, was significantly upregulated after MI/R. Dual activation of LXRalpha and LXRbeta by natural and synthetic agonists reduced myocardial infarction and improved contractile function after MI/R. Mechanistically, LXR activation inhibited MI/R-induced oxidative stress and nitrative stress, attenuated endoplasmic reticulum stress and mitochondrial dysfunction, and reduced cardiomyocyte apoptosis in ischemic/reperfused myocardium. The aforementioned cardioprotective effects of LXR agonists were impaired in the setting of cardiac specific gene silencing of LXRalpha, but not LXRbeta subtype. Moreover, LXRalpha/beta double-knockout and LXRalpha-knockout mice, but not LXRbeta knockout mice, increased MI/R injury, exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic reticulum stress and mitochondrial dysfunction. Furthermore, cardiac LXRalpha, not LXRbeta, overexpression via adenoviral transfection suppressed MI/R injury. CONCLUSIONS: Our study provides the first direct evidence that the LXRalpha, but not LXRbeta, subtype is a novel endogenous cardiac protective receptor against MI/R injury. Drug development strategies specifically targeting LXRalpha may be beneficial in treating ischemic heart disease. PMID- 25278000 TI - Age-related differences in phosphodiesterase activity and effects of chronic phosphodiesterase inhibition in idiopathic dilated cardiomyopathy. AB - BACKGROUND: Despite the application of proven adult heart failure therapies to children with idiopathic dilated cardiomyopathy (IDC), prognosis remains poor. Clinical experience with phosphodiesterase 3 inhibitors (PDE3i) in pediatric patients with IDC, however, demonstrates improved heart failure symptoms without the increased incidence of sudden death seen in adults treated with PDE3i. We sought to determine age-related differences in PDE activity and associated intracellular signaling responsible for the efficacy and relative safety of chronic PDE3i in pediatric heart failure. METHODS AND RESULTS: cAMP levels, PDE activity, and phospholamban phosphorylation (pPLB) were determined in explanted human left ventricular myocardium (pediatric n=41; adult n=88). Adults and children with IDC (not treated with PDE3i) had lower cAMP and pPLB compared with nonfailing controls. In contrast to their adult counterparts, pediatric IDC patients chronically treated with PDE3i had elevated cAMP (P=0.0403) and pPLB (P=0.0119). In addition, total PDE- and PDE3-specific activities were not altered in pediatric IDC patients on PDE3i, whereas adult IDC patients on PDE3i demonstrated higher total PDE-specific (74.6+/-13.8 pmol/mg per minute) and PDE3 specific (48.2+/-15.9 pmol/mg per minute) activities in comparison with those of nonfailing controls (59.5+/-14.4 and 35.5+/-12.8 pmol/mg per minute, respectively). CONCLUSIONS: Elevated cAMP and higher pPLB may contribute to sustained hemodynamic benefits in pediatric IDC patients treated with PDE3i. In contrast, higher total PDE and PDE3 activities in adult IDC patients treated with PDE3i may perpetuate lower myocardial cAMP and pPLB levels, limiting the potential benefits of PDE3i therapy. PMID- 25278001 TI - Cardiac rehabilitation referral, attendance and mortality in women. AB - BACKGROUND: Cardiac rehabilitation (CR) reduces mortality in women and men with coronary artery disease (CAD). The objective of this study was to examine sex differences in long-term mortality, based on CR referral rates and attendance patterns in a large CAD population. DESIGN: This is a retrospective cohort study. METHODS: The Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) and Cardiac Wellness Institute of Calgary (CWIC) databases were used to obtain information on all patients. Rates of referral to and attendance at CR were compared by sex. Logistic regression models were constructed to assess whether sex predicted CR referral or completion. The association between referral, completion, and survival was assessed by sex using Cox proportional hazard models. RESULTS: 25,958 subjects (6374-24.6%-were women) with at least one vessel CAD were included. Females experienced reduced rates of CR referral (31.1% vs 42.2%, p < 0.0001) and completion (50.1 vs 60.4%, p < 0.0001). Adjusting for demographic and clinical characteristics, relative to men, CR referral was significantly lower in women (adjusted odds ratio (OR) 0.74, 95% CI 0.69, 0.79) as was CR completion (adjusted OR 0.73, 95% CI 0.66, 0.81). Women completing CR experienced the greatest reduction in mortality (HR 0.36, 95% CI 0.28, 0.45) with a relative benefit greater than men (HR 0.51, 95% CI 0.46, 0.56). CONCLUSION: This is the first large cohort study to demonstrate that referral to and attendance at CR is associated with a significant mortality reduction in women, comparatively better than that in men. PMID- 25278002 TI - Risk of gastrointestinal bleeding with dabigatran: a head-to-head comparative study with rivaroxaban. AB - INTRODUCTION: The risk of gastrointestinal (GI) bleeding of dabigatran and rivaroxaban is relatively unexplored. The aim of our study was to compare this risk in both drugs. METHODS: We examined the medical records of patients on either dabigatran or rivaroxaban from October 2010 to April 2013 in two hospitals. RESULTS: A total of 374 patients (147 rivaroxaban vs. 227 dabigatran) were identified. GI bleeding occurred in 5.3% in the dabigatran when compared to 4.8% in the rivaroxaban group (p = 0.8215). Multivariate analysis showed that the odds of GI bleeding while on dabigatran for <=40 days when compared to >=40 days was 8.3 (p < 0.0001). In the rivaroxaban group, patients who were on the drug for <=40 days had a higher incidence of bleeding when compared to those >40 days (OR = 2.8, p = 0.023). Concomitant use of antiplatelets (single or dual) or non steroidal anti-inflammatory drugs was not associated with increased bleeding in the dabigatran group; however, the use of dual antiplatelet agents with rivaroxaban was associated with an increased risk of GI bleeding (OR = 7.4, p = 0.0378). Prior GI bleeding had a higher risk of bleeding in the rivaroxaban group (OR = 15.5, p = 0.0002). CONCLUSION: Dabigatran was not associated with a higher incidence of GI bleeding. Both drugs had a higher bleeding risk in the first 40 days. PMID- 25278003 TI - Evidence of effective delivery of the human papillomavirus (HPV) vaccine through a publicly funded, school-based program: the Ontario Grade 8 HPV Vaccine Cohort Study. AB - BACKGROUND: Proper administration of the human papillomavirus (HPV) vaccine (three doses at 0, 2, and 6 months) will likely influence the vaccine's effectiveness and the impact of vaccination programs on health outcomes. Therefore, we assessed HPV vaccine series completion and on-time dosing in Canada's largest publicly funded, school-based HPV vaccination program. METHODS: Using administrative health and immunization databases, we identified a population-based cohort of girls eligible for Ontario's Grade 8 HPV vaccination program in the 2007/08-2009/10 program years who received at least one dose of the vaccine. We determined the number of doses received and calculated the percentage of girls that completed the three-dose series in Grade 8 and Grades 8 9. To assess on-time dosing, the number of days between doses 1-2, 2-3, and 1-3 was calculated and categorized (e.g., too short, on schedule, too long) based on the manufacturer's recommendations. Analyses were also stratified by program year. RESULTS: We identified a cohort of 55,798 girls who initiated the vaccination series. Series completion was high in the Grade 8 window (81.8%) and increased by approximately 6% in Grade 9. Series completion was similar across the three program years. 70.8%, 98.5%, and 86.1% of girls were classified as 'on schedule' for dosing intervals 1-2, 2-3, and 1-3, respectively; 70.0% of girls received all three doses in perfect accordance with dosing recommendations. Stratification revealed that on-time dosing was highest in the first two years of the program (85.6% and 80.6%), but dropped to 42.1% in the 2009/10 year when H1N1 vaccination programs were prioritized. CONCLUSIONS: Our study demonstrates that delivery of the HPV vaccine through a free, school-based program is an effective method of ensuring high completion and on-time dosing, but may not be sufficient to guarantee high coverage. PMID- 25278004 TI - Cambridge and Peterborough CCG selects NHS consortium for L800m flagship contract. PMID- 25278005 TI - Manual therapies for primary chronic headaches: a systematic review of randomized controlled trials. AB - This is to our knowledge the first systematic review regarding the efficacy of manual therapy randomized clinical trials (RCT) for primary chronic headaches. A comprehensive English literature search on CINHAL, Cochrane, Medline, Ovid and PubMed identified 6 RCTs all investigating chronic tension-type headache (CTTH). One study applied massage therapy and five studies applied physiotherapy. Four studies were considered to be of good methodological quality by the PEDro scale. All studies were pragmatic or used no treatment as a control group, and only two studies avoided co-intervention, which may lead to possible bias and makes interpretation of the results more difficult. The RCTs suggest that massage and physiotherapy are effective treatment options in the management of CTTH. One of the RCTs showed that physiotherapy reduced headache frequency and intensity statistical significant better than usual care by the general practitioner. The efficacy of physiotherapy at post-treatment and at 6 months follow-up equals the efficacy of tricyclic antidepressants. Effect size of physiotherapy was up to 0.62. Future manual therapy RCTs are requested addressing the efficacy in chronic migraine with and without medication overuse. Future RCTs on headache should adhere to the International Headache Society's guidelines for clinical trials, i.e., frequency as primary end-point, while duration and intensity should be secondary end-point, avoid co-intervention, includes sufficient sample size and follow-up period for at least 6 months. PMID- 25278006 TI - Genetic variation in human leukocyte antigen and susceptibility to acute myeloid leukemia. PMID- 25278007 TI - [A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopenia]. AB - INTRODUCTION: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappa-deleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopenia. OBJECTIVES: To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopenia. MATERIAL AND METHODS: Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<15 copies/MUl, KRECS<10 copies/MUl, ACTB (beta-actin)>1000 copies/MUl. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included. RESULTS: A total of 1068 out of 1088 neonates (mean GA 39 weeks (38-40) and BW 3238g (2930-3520) were enrolled in the study. Mean (median, min/max) copies/MUl, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<8 and KRECS<4 copies/MUl), all the samples tested were normal and the internal and external controls were correctly identified. CONCLUSION: This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved. PMID- 25278010 TI - Treatment of vitiligo patients by excimer laser improves patients' quality of life. AB - BACKGROUND: Vitiligo can negatively affect patients' quality of life (QoL). Assessment of QoL provides relevant information about treatment benefits. OBJECTIVES: To examine the effects of excimer laser treatment on vitiligo patients' QoL and to identify overall patient satisfaction. The literature review failed to show any study concerning the same field. METHODS: A total of 134 vitiligo patients (with 386 lesions) were studied. The Dermatology Life Quality Index (DLQI) was used to assess the effect of excimer laser treatment on patients' QoL. A visual analogue scale (VAS) was used to rate patients' overall life satisfaction and disturbance. RESULTS: Excimer laser treatment significantly improved QoL in vitiligo patients, with improvement observed in five of six DLQI domains. Treatment-induced changes in the VAS score showed a significant decline in life disturbance and improvement in life satisfaction. Multivariate analysis revealed that sex and treatment duration were independent factors influencing treatment outcomes. CONCLUSIONS: Treatment of vitiligo with excimer laser can positively influence patients' QoL. Patients with multiple focal lesions should be treated by excimer laser even if some lesions may not show significant clinical improvement. PMID- 25278009 TI - Impact of feedback on physical activity levels of individuals with chronic obstructive pulmonary disease during pulmonary rehabilitation: A feasibility study. AB - This study aimed at investigating whether providing feedback on physical activity (PA) levels to patients with chronic obstructive pulmonary disease (COPD) is feasible and enhances daily PA during pulmonary rehabilitation (PR). Patients with COPD participated in a 12-week PR program. Daily PA was measured using activity monitors on weeks 1, 7, and 12, and feedback was given in the following weeks on the number of steps, time spent in sedentary, light, and moderate-to vigorous intensity activities, and time spent standing, sitting, and lying. Compliance with PA monitoring was collected. Two focus groups were conducted to obtain patients' perspectives on the use of activity monitors and on the feedback given. Differences in PA data were also assessed. Sixteen patients (65.63 +/- 10.57 years; forced expiratory volume in one second (FEV1) 70.31 +/- 22.74% predicted) completed the study. From those, only eleven participants used the activity monitors during all monitoring days. Participants identified several problems regarding the use of activity monitors and monitoring duration. Daily steps (p = 0.026) and standing time (p = 0.030) were improved from week 1 to week 7; however, the former declined from week 7 to week 12. Findings suggest that using feedback to improve PA during PR is feasible and results in improved daily steps and standing time on week 7. The subsequent decline suggests that additional strategies may be needed to stimulate/maintain PA improvements. Further research with more robust designs is needed to investigate the impact of feedback on patients' daily PA. PMID- 25278011 TI - PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche. AB - INTRODUCTION: Prostate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide. METHODS: PCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2(-/-); gamma c(-/-) mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR. RESULTS: PCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < = 0.008) and increased AR (p < = 0.032) relative to control. CONCLUSIONS: PCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche. PMID- 25278012 TI - A Community Health Worker "logic model": towards a theory of enhanced performance in low- and middle-income countries. AB - BACKGROUND: There has been a resurgence of interest in national Community Health Worker (CHW) programs in low- and middle-income countries (LMICs). A lack of strong research evidence persists, however, about the most efficient and effective strategies to ensure optimal, sustained performance of CHWs at scale. To facilitate learning and research to address this knowledge gap, the authors developed a generic CHW logic model that proposes a theoretical causal pathway to improved performance. The logic model draws upon available research and expert knowledge on CHWs in LMICs. METHODS: Construction of the model entailed a multi stage, inductive, two-year process. It began with the planning and implementation of a structured review of the existing research on community and health system support for enhanced CHW performance. It continued with a facilitated discussion of review findings with experts during a two-day consultation. The process culminated with the authors' review of consultation-generated documentation, additional analysis, and production of multiple iterations of the model. RESULTS: The generic CHW logic model posits that optimal CHW performance is a function of high quality CHW programming, which is reinforced, sustained, and brought to scale by robust, high-performing health and community systems, both of which mobilize inputs and put in place processes needed to fully achieve performance objectives. Multiple contextual factors can influence CHW programming, system functioning, and CHW performance. CONCLUSIONS: The model is a novel contribution to current thinking about CHWs. It places CHW performance at the center of the discussion about CHW programming, recognizes the strengths and limitations of discrete, targeted programs, and is comprehensive, reflecting the current state of both scientific and tacit knowledge about support for improving CHW performance. The model is also a practical tool that offers guidance for continuous learning about what works. Despite the model's limitations and several challenges in translating the potential for learning into tangible learning, the CHW generic logic model provides a solid basis for exploring and testing a causal pathway to improved performance. PMID- 25278008 TI - Genome-wide association discoveries of alcohol dependence. AB - OBJECTIVE: To report the genome-wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions. METHODS: We searched in PubMed for all genome-wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: genome-wide significant associations in an individual sample, the combined samples, or the meta-analysis (p < 5 * 10(-8) ); top-ranked associations in an individual sample (p < 10(-5) ) that were nominally replicated in other samples (p < .05); and nominally replicable associations across at least three independent GWAS samples (p < .05). These results were meta-analyzed. cis-eQTLs in human, RNA expression in rat and mouse brains and bioinformatics properties of all of these risk variants were analyzed. RESULTS: The variants located within the alcohol dehydrogenase (ADH) cluster were significantly associated with alcohol dependence at the genome-wide level (p < 5 * 10(-8) ) in at least one sample. Some associations with the ADH cluster were replicable across six independent GWAS samples. The variants located within or near SERINC2, KIAA0040, MREG-PECR or PKNOX2 were significantly associated with alcohol dependence at the genome-wide level (p < 5 * 10(-8) ) in meta-analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within NRD1, GPD1L-CMTM8 or MAP3K9-PCNX were suggestive (5 * 10(-8) < p < 10(-5) ) in some samples, and nominally replicable in other samples. The associations with the variants at HTR7 and OPA3 were nominally replicable across at least three independent GWAS samples (10(-5) < p < .05). Some risk variants at the ADH cluster, SERINC2, KIAA0040, NRD1, and HTR7 had potential biological functions. CONCLUSION: The most robust risk locus was the ADH cluster. SERINC2, KIAA0040, NRD1, and HTR7 were also likely to play important roles in alcohol dependence. PKNOX2, MREG, PECR, GPD1L, CMTM8, MAP3K9, PCNX, and OPA3 might play less important roles in risk for alcohol dependence based on the function analysis. This conclusion will significantly contribute to the post-GWAS follow up studies on alcohol dependence. PMID- 25278013 TI - Circulating muramyl dipeptide is negatively associated with interleukin-10 in the frail elderly. AB - Elevated levels of serum cytokines, a marker of immune activation and chronic inflammation, are commonly associated with age and are a significant risk factor for all-cause mortality in the elderly. This phenomenon is very similar to that exhibited by individuals with diseases of inflammatory etiology and chronic viral infections such as human immunodeficiency virus (HIV). Although the origin of chronically elevated cytokines with age is unknown, for chronic diseases and viral infections, a role for circulating bacterial products and other pattern recognition receptor (PRR) ligands has been suggested. Given this, we sought to examine whether the levels of circulating cytokines (tumour necrosis factor (TNF), interferon-gamma (IFN-gamma), interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12) in the advanced-age, frail elderly (n = 135) correlated with plasma levels of lipopolysaccharide (LPS), muramyl dipeptide (MDP), 16S ribosomal DNA, total cell-free DNA and host-derived mitochondrial DNA. After adjusting for multiple testing, no associations between circulating products and donor age, sex or comorbidities were observed. However, a significant negative correlation between MDP and IL-10 was identified. Given the anti-inflammatory nature of IL-10, a negative relationship with a potent inflammatory agonist such as MDP is not surprising and suggests a potential role for circulating MDP in the propagation of age-related immune activation. PMID- 25278014 TI - [Contraindications and adverse reactions to intravenous contrast media]. PMID- 25278015 TI - Bioprocess and downstream optimization of recombinant bovine chymosin B in Pichia (Komagataella) pastoris under methanol-inducible AOXI promoter. AB - A clone of the methylotrophic yeast Pichia pastoris strain GS115 transformed with the bovine prochymosin B gene was used to optimize the production and downstream of recombinant bovine chymosin expressed under the methanol-inducible AOXI promoter. Cell growth and recombinant chymosin production were analyzed in flask cultures containing basal salts medium with biodiesel-byproduct glycerol as the carbon source, obtaining values of biomass level and milk-clotting activity similar to those achieved with analytical glycerol. The effect of biomass level at the beginning of methanol-induction phase on cell growth and chymosin expression was evaluated, determining that a high concentration of cells at the start of such period generated an increase in the production of chymosin. The impact of the specific growth rate on chymosin expression was studied throughout the induction stage by methanol exponential feeding fermentations in a lab-scale stirred bioreactor, achieving the highest production of heterologous chymosin with a constant specific growth rate of 0.01h(-1). By gel filtration chromatography performed at a semi-preparative scale, recombinant chymosin was purified from exponential fed-batch fermentation cultures, obtaining a specific milk-clotting activity of 6400IMCU/mg of chymosin and a purity level of 95%. The effect of temperature and pH on milk-clotting activity was analyzed, establishing that the optimal temperature and pH values for the purified recombinant chymosin are 37 degrees C and 5.5, respectively. This study reported the features of a sustainable bioprocess for the production of recombinant bovine chymosin in P. pastoris by fermentation in stirred-tank bioreactors using biodiesel-derived glycerol as a low-cost carbon source. PMID- 25278016 TI - Age increases the risk of immediate postoperative dysphagia and pneumonia after odontoid screw fixation. AB - INTRODUCTION: Type II odontoid fractures are the most common spinal fracture in the elderly population and may be managed with halo immobilization, posterior fusion, and anterior odontoid screw fixation. Anterior odontoid screw fixation has several advantages over posterior fusion, including: reduced surgical time, decreased post-operative pain, preserved range of motion, earlier mobilization, and decreased postoperative narcotic requirement. We review our experience using anterior odontoid screw fixation in type II odontoid fractures in the elderly and non-elderly populations. METHODS: Demographic and outcome data were retrospectively collected in 30 consecutive patients with type II odontoid fractures treated with anterior odontoid screw fixation. RESULTS: Mean patient age was 70.7 (range 20-92); 18 of the patients were male and 12 were female. All patients had successful placement of a single anterior odontoid screw without intra-operative complication. Complications included pneumonia in nine patients (30%), gastrostomy tube placement due to patient failing swallow evaluation in 13 patients (43%), and vocal cord paralysis in one patient (3.3%). Patients over the age of 75 accounted for 12 of the 13 (92%) gastrostomy tube placements and eight of the nine (88.9%) pneumonias, respectively. The difference in rates of gastrostomy tube placement and pneumonia for the older patients were both found to be statistically significant with P<.0001 for gastrostomy tubes and P<.02 for pneumonias. CONCLUSIONS: Anterior odontoid screw fixation is an effective treatment option for patients with Type II odontoid fractures. In the elderly population, however, the benefits of the procedure must be weighed against the risks of postoperative dysphagia requiring gastrostomy and pneumonia. PMID- 25278017 TI - Endocrinological outcomes following endoscopic and microscopic transsphenoidal surgery in 113 patients with acromegaly. AB - BACKGROUND: To describe outcomes and complications in patients undergoing transsphenoidal surgery for acromegaly using the 2010 consensus criteria for biochemical remission. METHODS: Retrospective review of 113 treatment naive patients who underwent transsphenoidal surgery with the endoscopic (n=66) and the endonasal microscopic technique (n=47). Cure was defined if the age and sex adjusted IGF-1 level was normal and either the basal GH was <1 ng/ml or the nadir GH was <0.4 ng/ml following oral glucose suppression at last follow-up. RESULTS: The mean age at presentation was 38.1 +/- 7.1 years and 86% of tumors were macroadenomas. Adenoma sizes averaged 21.1 +/- 9.7 mm, but 56% of all tumors were >= 2 cm in size and 43.4% were invasive. Remission rates between endoscopic and microscopic transsphenoidal surgery did not differ significantly overall (28.8% versus 36.2%). On univariate analysis, a preoperative GH level <40 ng/ml, adenoma size <20mm and non-invasiveness were predictors of remission at follow-up. Although there were no statistically significant differences in remission rates between the endoscopic and microsurgical groups, surgically induced hypopituitarism was less frequent with the former. CONCLUSIONS: We report our surgical experience with predominantly large, invasive GH adenomas using the 2010 criteria for cure. Patients with smaller, non-invasive tumors with lower preoperative GH levels are most likely to achieve remission. Outcomes with either the microscopic or endoscopic approach do not differ significantly, although the rate of surgically induced hypopituitarism may be higher with the former. Transsphenoidal surgery remains the first line of treatment for patients with acromegaly, but invasive adenomas will frequently require adjuvant therapy. PMID- 25278018 TI - A novel approach to decrease sialic acid expression in cells by a C-3-modified N acetylmannosamine. AB - Due to its position at the outermost of glycans, sialic acid is involved in a myriad of physiological and pathophysiological cell functions such as host pathogen interactions, immune regulation, and tumor evasion. Inhibitors of cell surface sialylation could be a useful tool in cancer, immune, antibiotic, or antiviral therapy. In this work, four different C-3 modified N-acetylmannosamine analogs were tested as potential inhibitors of cell surface sialylation. Peracetylated 2-acetylamino-2-deoxy-3-O-methyl-D-mannose decreases cell surface sialylation in Jurkat cells in a dose-dependent manner up to 80%, quantified by flow cytometry and enzyme-linked lectin assays. High-performance liquid chromatography experiments revealed that not only the concentration of membrane bound but also of cytosolic sialic acid is reduced in treated cells. We have strong evidence that the observed reduction of sialic acid expression in cells is caused by the inhibition of the bifunctional enzyme UDP-GlcNAc-2-epimerase/ManNAc kinase. 2-Acetylamino-2-deoxy-3-O-methyl-D-mannose inhibits the human ManNAc kinase domain of the UDP-GlcNAc-2-epimerase/ManNAc kinase. Binding kinetics of the inhibitor and human N-acetylmannosamine kinase were evaluated using surface plasmon resonance. Specificity studies with human N-acetylglucosamine kinase and hexokinase IV indicated a high specificity of 2-acetylamino-2-deoxy-3-O-methyl-D mannose for MNK. This substance represents a novel class of inhibitors of sialic acid expression in cells, targeting the key enzyme of sialic acid de novo biosynthesis. PMID- 25278019 TI - Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway. AB - The lack of the neuropeptide orexin, also known as hypocretin, results in narcolepsy, a chronic sleep disorder characterized by frequent sleep/cataplexy attacks and rapid eye movement sleep abnormalities. However, the downstream pathways of orexin signaling are not clearly understood. Here, we show that orexin activates the mTOR pathway, a central regulator of cell growth and metabolism, in the mouse brain and multiple recombinant cell lines that express the G protein-coupled receptors (GPCRs), orexin 1 receptor (OX1R) or orexin 2 receptor (OX2R). This orexin/GPCR-stimulated mTOR activation is sensitive to rapamycin, an inhibitor of mTOR complex 1 (mTORC1) but is independent of two well known mTORC1 activators, Erk and Akt. Rather, our studies indicate that orexin activates mTORC1 via extracellular calcium influx and the lysosome pathway involving v-ATPase and Rag GTPases. Moreover, a cytoplasmic calcium transient is sufficient to mimic orexin/GPCR signaling to mTORC1 activation in a v-ATPase dependent manner. Together, our studies suggest that the mTORC1 pathway functions downstream of orexin/GPCR signaling, which plays a crucial role in many physiological and metabolic processes. PMID- 25278020 TI - FliT selectively enhances proteolysis of FlhC subunit in FlhD4C2 complex by an ATP-dependent protease, ClpXP. AB - We previously reported that the ClpXP ATP-dependent protease specifically recognizes and degrades the flagellar master transcriptional activator complex, FlhD4C2, to negatively control flagellar biogenesis. The flagellum-related protein, FliT, is also a negative regulator of flagellar regulon by inhibiting the binding of FlhD4C2 to the promoter DNA. We have found a novel pathway of FliT inhibition of FlhD4C2 activity connected to ClpXP proteolysis. An in vitro degradation assay using purified proteins shows that FliT selectively increases ClpXP proteolysis of the FlhC subunit in the FlhD4C2 complex. FliT behaves specifically to ClpXP-dependent proteolysis of FlhC. An in vitro interaction assay detects the ternary complex of FliT-FlhD4C2-ClpX. FliT promotes the affinity of ClpX against FlhD4C2 complex, whereas FliT does not directly interact with ClpX. Thus, FliT interacts with the FlhC in FlhD4C2 complex and increases the presentation of the FlhC recognition region to ClpX. The DNA-bound form of FlhD4C2 complex is resistant to ClpXP proteolysis. We suggest that the role of FliT in negatively controlling the flagellar gene expression involves increasing free molecules of FlhD4C2 sensitive to ClpXP proteolysis by inhibiting the binding to the promoter DNA as well as enhancing the selective proteolysis of FlhC subunit by ClpXP. PMID- 25278021 TI - UL52 primase interactions in the herpes simplex virus 1 helicase-primase are affected by antiviral compounds and mutations causing drug resistance. AB - Herpes simplex virus 1 (HSV-1) UL5/8/52 helicase-primase complex is required for DNA unwinding at the replication fork and synthesis of primers during virus replication, and it has become a promising novel target for antiviral therapy. Using molecular cloning, we have identified three separate domains of UL52. Co immunoprecipitation experiments in extracts from cells transiently expressing HA tagged UL5, FLAG-UL8, and enhanced GFP-tagged UL52 domains revealed that the N terminal domain of UL52 primase binds UL5 helicase and the middle domain interacts with the UL8 accessory protein. In addition, an interaction between the single strand DNA-binding protein ICP8 and the UL52 middle domain was observed. The complex between UL5 and UL52 was stabilized by the antiviral compound BAY 54 6322, and mutations providing resistance to the drug obliterate this effect. Our results also suggest a mechanism for accommodating conformational strain resulting from movement of UL5 and UL52 in opposite directions on the lagging strand template, and they identify molecular complexes that can be further examined by structural biology techniques to resolve the mechanism of primer synthesis during herpesvirus replication. Finally, they help to explain the mechanism of action of a novel class of antiviral compounds currently being evaluated in clinical trials. PMID- 25278022 TI - The E3 ubiquitin ligase MID1 catalyzes ubiquitination and cleavage of Fu. AB - SHH (Sonic Hedgehog)-GLI signaling plays an important role during embryogenesis and in tumorigenesis. The survival and growth of several types of cancer depend on autonomously activated SHH-GLI signaling. A protein complex containing the ubiquitin ligase MID1 and protein phosphatase 2A regulates the nuclear localization and transcriptional activity of GLI3, a transcriptional effector molecule of SHH, in cancer cell lines with autonomously activated SHH signaling. However, the exact molecular mechanisms that mediate the interaction between MID1 and GLI3 remained unknown. Here, we show that MID1 catalyzes the ubiquitination and proteasomal cleavage of the GLI3 regulator Fu. Our data suggest that Fu ubiquitination and cleavage is one of the key elements connecting the MID1-PP2A protein complex with GLI3 activity control. PMID- 25278023 TI - Specific phosphorylations transmit signals from leukocyte beta2 to beta1 integrins and regulate adhesion. AB - The regulation of integrins expressed on leukocytes must be controlled precisely, and members of different integrin subfamilies have to act in concert to ensure the proper traffic of immune cells to sites of inflammation. The activation of beta2 family integrins through the T cell receptor or by chemokines leads to the inactivation of very late antigen 4. The mechanism(s) of this cross-talk has not been known. We have now elucidated in detail how the signals are transmitted from leukocyte function-associated antigen 1 and show that, after its activation, the signaling involves specific phosphorylations of beta2 integrin followed by interactions with cytoplasmic signaling proteins. This results in loss of beta1 phosphorylation and a decrease in very late antigen 4 binding to its ligand vascular cell adhesion molecule 1. Our results show how a member of one integrin family regulates the activity of another integrin. This is important for the understanding of integrin-mediated processes. PMID- 25278025 TI - Identification and characterization of receptors for ion transport peptide (ITP) and ITP-like (ITPL) in the silkworm Bombyx mori. AB - Ion transport peptide (ITP) and its alternatively spliced variant, ITP-like (ITPL), are insect peptides that belong to the crustacean hyperglycemic hormone family. These peptides modulate the homeostatic mechanisms for regulating energy metabolism, molting, and reproduction and are specifically conserved in ecdysozoans. Many of the details of the molecular mechanisms by which crustacean hyperglycemic hormone family peptides exert pleiotropy remain to be elucidated, including characterization of their receptors. Here we identified three Bombyx mori orphan neuropeptide G protein-coupled receptors (BNGRs), BNGR-A2, -A24, and A34, as receptors for ITP and ITPL (collectively referred to as ITPs). BNGR-A2 and -A34 and BNGR-A24 respond to recombinant ITPs, respectively, with EC50 values of 1.1-2.6 * 10(-8) M, when expressed in a heterologous expression system. These three candidate BNGRs are expressed at larval B. mori tissues targeted by ITPs, with cGMP elevation observed after exposure to recombinant ITPs. ITPs also increased the cGMP level in B. mori ovary-derived BmN cells via membrane-bound and soluble guanylyl cyclases. The simultaneous knockdown of bngr-A2 and -A34 significantly decreased the response of BmN cells to ITP, whereas knockdown of bngr-A24 led to decreased responses to ITPL. Conversely, transient expression of bngr-A24 potentiated the response of BmN cells to ITPL. An in vitro binding assay showed direct interaction between ITPs and heterologously expressed BNGRs in a ligand-receptor-specific manner. Taken together, these data demonstrate that BNGR A2 and -A34 are ITP receptors and that BNGR-A24 is an ITPL receptor in B. mori. PMID- 25278027 TI - HuD promotes progression of oral squamous cell carcinoma. AB - Head and neck cancer, including oral squamous cell carcinoma (OSCC), ranks as the sixth most common malignancy worldwide. Overall 5-year survival rates of OSCC have not significantly improved during the past 3 decades and the 5-year survival rate is less than 50%. Several invasion grading systems have been employed in OSCC, however, their utility is still controversial. HuD belongs to the Hu protein family and acts as an RNA-binding protein involved in mRNA stability and translational regulation. Although HuD has a pivotal role for neuronal differentiation, the functional role of HuD in OSCCs is still unclear. In this study, we examined HuD expression in 82 OSCC cases. Expression of HuD was observed in 36.6% of OSCCs and significantly associated with histological differentiation, nodal metastasis and mode of invasion. HuD expression in high metastatic HSC3 cells was higher than in low-metastatic HSC4 cells, and inhibition of invasion ability and activation of caspase-3 were shown by HuD siRNA-treated HSC3 cells. Furthermore, we clarified that HuD regulates expression of vascular endothelial growth factor (VEGF)-A, VEGF-D, matrix metallopeptidase (MMP)-2 and MMP-9. These results suggest that HuD is a useful diagnostic and therapeutic target in OSCCs. PMID- 25278026 TI - The 3'-5' DNA exonuclease TREX1 directly interacts with poly(ADP-ribose) polymerase-1 (PARP1) during the DNA damage response. AB - The main function of the 3'-5' DNA exonuclease TREX1 is to digest cytosolic single-stranded DNA to prevent activation of cell-intrinsic responses to immunostimulatory DNA. TREX1 translocates to the nucleus following DNA damage with its nuclear activities being less well defined. Although mutations in human TREX1 have been linked to autoimmune/inflammatory diseases, the mechanisms contributing to the pathogenesis of these diseases remain incompletely understood. Here, using mass spectrometry and co-immunoprecipitation assays and in vivo overexpression models, we show that TREX1 interacts with poly(ADP-ribose) polymerase-1 (PARP1), a nuclear enzyme involved in the DNA damage response. Two zinc finger domains at the amino terminus of PARP1 were required for the interaction with TREX1 that occurs after nuclear translocation of TREX1 in response to DNA damage. Functional studies suggested that TREX1 may contribute to stabilization of PARP1 levels in the DNA damage response and its activity. These results provide new insights into the mechanisms of single-stranded DNA repair following DNA damage and alterations induced by gene mutations. PMID- 25278028 TI - Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells. AB - Genome-wide association studies implicate dysregulation of immune mechanisms in the pathogenesis of multiple sclerosis (MS). Particularly, polymorphisms in genes involved in T helper (TH) cell differentiation are associated with risk of developing MS. However, the underlying mechanism by which these risk alleles influence MS susceptibility has remained elusive. Initiation of neuroinflammation in animal models of MS has been shown to be dependent on TH cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). We here report association of GM-CSF expression by human TH cells with MS disease severity. GM CSF is strongly induced by interleukin 2 (IL-2). We show that an MS-associated polymorphism in the IL-2 receptor alpha (IL2RA) gene specifically increases the frequency of GM-CSF-producing TH cells. The IL2RA polymorphism regulates IL-2 responsiveness of naive TH cells and their propensity to develop into GM-CSF producing memory TH cells. These findings mechanistically link an immunologically relevant genetic risk factor with a functional feature of TH cells in MS. PMID- 25278024 TI - Structural re-arrangement and peroxidase activation of cytochrome c by anionic analogues of vitamin E, tocopherol succinate and tocopherol phosphate. AB - Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, alpha-tocopherol succinate (alpha-TOS) and alpha-tocopherol phosphate (alpha TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that alpha-TOS and alpha-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with alpha-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by alpha-TOS may contribute to its known anti-cancer pharmacological activity. PMID- 25278029 TI - In situ adenocarcinoma of the ileum in Crohn's disease: a possible link with latent CMV infection? PMID- 25278031 TI - Non-invasive cardiac output monitoring in preterm infants undergoing patent ductus arteriosus ligation: a comparison with echocardiography. AB - BACKGROUND: Non-invasive cardiac output monitoring (NICOM; NICOMTM) may be useful in the management of extremely premature preterm infants. OBJECTIVES: To evaluate a new bioreactance-based method of continuous NICOM in preterm infants following patent ductus arteriosus (PDA) ligation. METHODS: Infants underwent three paired NICOM and echocardiography assessments of stroke volume (SV) and left ventricular output (LVO) in the postoperative period: at 1, 6-8, and 16-18 h postoperatively. NICOM- and echocardiography-measured SV and LVO during those periods were compared using Bland-Altman analysis and the intraclass correlation coefficient (ICC). RESULTS: Twenty-five infants with a median (interquartile range) gestational age and birth weight of 25.0 weeks (24.5-25.9) and 700 g (615-775), respectively, were included. The overall systematic bias (limits of agreement) across all time points between the NICOM and echocardiography SV readings was 39% (8-69) with NICOM consistently underestimating echocardiography values. There was moderate consistency between NICOM and echocardiography SV values (ICC 0.78, p < 0.001). Compared with the 1-hour scans, the 6- to 8- and 16- to 18-hour scans had increased biases of 7.9% (95% CI 2.5-13.2) and 9.7% (95% CI 3.6-15.8), respectively. CONCLUSION: Continuous LVO measurement using NICOM was feasible and demonstrated a consistent systematic bias compared with echocardiography in unstable extremely preterm infants without a PDA ligation. NICOM may be used as a trending tool for continuous monitoring in this population, but wide limits of agreement and increasing bias over time suggest it is not interchangeable with echocardiography. (c) 2014 S. Karger AG, Basel. PMID- 25278030 TI - Variations of chromosomes 2 and 3 gene expression profiles among pulmonary telocytes, pneumocytes, airway cells, mesenchymal stem cells and lymphocytes. AB - Telocytes (TCs) were identified as a distinct cellular type of the interstitial tissue and defined as cells with extremely long telopodes (Tps). Our previous data demonstrated patterns of mouse TC-specific gene profiles on chromosome 1. The present study focuses on the identification of characters and patterns of TC specific or TC-dominated gene expression profiles in chromosome 2 and 3, the network of principle genes and potential functional association. We compared gene expression profiles of pulmonary TCs, mesenchymal stem cells, fibroblasts, alveolar type II cells, airway basal cells, proximal airway cells, CD8(+) T cells from bronchial lymph nodes (T-BL), and CD8(+) T cells from lungs (T-LL). We identified that 26 or 80 genes of TCs in chromosome 2 and 13 or 59 genes of TCs up- or down-regulated in chromosome 3, as compared with other cells respectively. Obvious overexpression of Myl9 in chromosome 2 of TCs different from other cells, indicates that biological functions of TCs are mainly associated with tissue/organ injury and ageing, while down-expression of Pltp implies that TCs may be associated with inhibition or reduction of inflammation in the lung. Dominant overexpression of Sh3glb1, Tm4sf1 or Csf1 in chromosome 3 of TCs is mainly associated with tumour promotion in lung cancer, while most down expression of Pde5 may be involved in the development of pulmonary fibrosis and other acute and chronic interstitial lung disease. PMID- 25278032 TI - Hierarchical organization in liquid crystal-in-liquid crystal emulsions. AB - We report the formation and characterization of hierarchical ordering in systems comprised of micrometer-sized droplets of thermotropic nematic liquid crystals (LCs) dispersed in continuous nematic phases of a lyotropic chromonic LC (disodium cromoglycate (DSCG)). Significantly, we find the orientations of the two LC phases to be coupled, with nematic droplets of 4'-pentyl-4-cyanobiphenyl (5CB) exhibiting a bipolar configuration with an axis of symmetry aligned orthogonal to the far-field director of the DSCG phase. We determine that this coupling of orientations does not result from either anisometric LC droplet shape or interfacial ionic phenomena but rather is consistent with the influence of van der Waals interactions that arise from the anisotropic polarizabilities of nematic 5CB (Deltan = +0.18) and DSCG (Deltan = -0.02) phases. We also find that it is possible to rotate and uniformly align the nematic droplets by using a weak magnetic field (B ~ 0.3 T). An analysis of the dynamics of relaxation of the orientations of the 5CB droplets following removal of the magnetic field reveals the DSCG and 5CB droplets to be coupled by energies of ~10(4) kT, consistent with a simple theoretical estimate of the influence of anisotropic van der Waals interactions. We also observed the nematic 5CB droplets to form dimers and larger assemblies mediated by the elasticity of the nematic DSCG. Overall, these results reveal that LC-in-LC emulsions define a new class of hierarchically ordered soft matter in which both thermotropic and lyotropic LCs are coupled in their ordering. PMID- 25278034 TI - CNS stimulants. PMID- 25278033 TI - Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors. AB - GABAA receptors are important for inhibition in the CNS where neurosteroids and protein kinases are potent endogenous modulators. Acting individually, these can either enhance or depress receptor function, dependent upon the type of neurosteroid or kinase and the receptor subunit combination. However, in vivo, these modulators probably act in concert to fine-tune GABAA receptor activity and thus inhibition, although how this is achieved remains unclear. Therefore, we investigated the relationship between these modulators at synaptic-type alpha1beta3gamma2L and extrasynaptic-type alpha4beta3delta GABAA receptors using electrophysiology. For alpha1beta3gamma2L, potentiation of GABA responses by tetrahydro-deoxycorticosterone was reduced after inhibiting protein kinase C, and enhanced following its activation, suggesting this kinase regulates neurosteroid modulation. In comparison, neurosteroid potentiation was reduced at alpha1beta3(S408A,S409A)gamma2L receptors, and unaltered by PKC inhibitors or activators, indicating that phosphorylation of beta3 subunits is important for regulating neurosteroid activity. To determine whether extrasynaptic-type GABAA receptors were similarly modulated, alpha4beta3delta and alpha4beta3(S408A,S409A)delta receptors were investigated. Neurosteroid potentiation was reduced at both receptors by the kinase inhibitor staurosporine. By contrast, neurosteroid-mediated potentiation at alpha4(S443A)beta3(S408A,S409A)delta receptors was unaffected by protein kinase inhibition, strongly suggesting that phosphorylation of alpha4 and beta3 subunits is required for regulating neurosteroid activity at extrasynaptic receptors. Western blot analyses revealed that neurosteroids increased phosphorylation of beta3(S408,S409) implying that a reciprocal pathway exists for neurosteroids to modulate phosphorylation of GABAA receptors. Overall, these findings provide important insight into the regulation of GABAA receptors in vivo, and into the mechanisms by which GABAergic inhibitory transmission may be simultaneously tuned by two endogenous neuromodulators. PMID- 25278035 TI - Gender- and site-specific differences of colorectal neoplasia relate to vitamin D. AB - BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 +/- 9.7 years; 719 females, 59.7 +/- 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation. PMID- 25278036 TI - Perigastric appendagitis: CT and clinical features in eight patients. AB - AIM: To describe perigastric appendagitis (PA) on CT as a new and distinct clinical entity to enable recognition and prevent additional unnecessary investigation or intervention. MATERIALS AND METHODS: Institutional review board approval was obtained and informed consent was waived. Retrospective review of the clinical data and CT findings in eight patients with PA encountered over 10 years at one institution was performed. The English literature was reviewed and summarized. Two experienced abdominal radiologists reviewed the CT images by consensus. RESULTS: Seven of eight patients had moderate to severe epigastric pain for 1-7 days. All eight patients (four men, four women; mean age 44 years, range 33-81 years) had no fever or leukocytosis. All underwent abdominal CT which showed ovoid fat inflammation along the course of the perigastric ligaments (gastrohepatic, gastrosplenic, and falciform). Two had gastric wall thickening. Although the inflammation was correctly described, the specific diagnosis was not made on initial interpretation in five patients. Subsequently, they underwent further diagnostic testing [an upper gastrointestinal examination and hepatobiliary iminodiacetic acid (HIDA) cholescintigraphy, an upper endoscopy and MRI examination, HIDA cholescintigraphy, another CT, and an MRI examination, respectively]. The HIDA cholescintigraphy, upper GI examination, and upper endoscopy examinations were normal. No repeated examination was performed on the other three patients. Pain resolved spontaneously in all within two days. CONCLUSION: Perigastric appendagitis can present with an acute abdomen, which is safely managed conservatively if diagnosed correctly. Radiologists should be aware of the entity to avoid unnecessary intervention, and recognize the CT findings of ovoid fat inflammation in the distribution of the perigastric ligaments. PMID- 25278037 TI - Diabetes self-management arrangements in Europe: a realist review to facilitate a project implemented in six countries. AB - BACKGROUND: Self-management of long term conditions can promote quality of life whilst delivering benefits to the financing of health care systems. However, rarely are the meso-level influences, likely to be of direct relevance to these desired outcomes, systematically explored. No specific international guidelines exist suggesting the features of the most appropriate structure and organisation of health care systems within which to situate self-management approaches and practices. This review aimed to identify the quantitative literature with regard to diabetes self-management arrangements currently in place within the health care systems of six countries (The United Kingdom, The Netherlands, Norway, Spain, Bulgaria, and Greece) and explore how these are integrated into the broader health care and welfare systems in each country. METHODS: The methodology for a realist review was followed. Publications of interest dating from 2000 to 2013 were identified through appropriate MeSH terms by a systematic search in six bibliographic databases. A search diary was maintained and the studies were assessed for their quality and risk of bias. RESULTS: Following the multi-step search strategy, 56 studies were included in the final review (the majority from the UK) reporting design methods and findings on 21 interventions and programmes for diabetes and chronic disease self-management. Most (11/21, 52%) of the interventions were designed to fit within the context of primary care. The majority (11/21, 52%) highlighted behavioural change as an important goal. Finally, some (5/21, 24%) referred explicitly to Internet-based tools. CONCLUSIONS: This review is based on results which are derived from a total of at least 5,500 individuals residing in the six participating countries. It indicates a policy shift towards patient-centred self-management of diabetes in a primary care context. The professional role of diabetes specialist nurses, the need for multidisciplinary approaches and a focus on patient education emerge as fundamental principles in the design of relevant programmes. Socio-economic circumstances are relevant to the capacity to self-manage and suggest that any gains and progress will be hard to maintain during economic austerity. This realist review should be interpreted within the wider context of a whole systems approach regarding self-care support and chronic illness management. PMID- 25278038 TI - Estimation of expectedness: predictive accuracy of standard therapy outcomes in randomized phase 3 studies in epithelial ovarian cancer. AB - BACKGROUND: The anticipated clinical outcome of the standard/control arm is an important parameter in the design of randomized phase 3 (RP3) trials to properly calculate sample size, power, and study duration. Changing patterns of care or variation in the study population enrolled may lead to a deviation from the initially anticipated outcome. The authors hypothesized that recent changes in patterns of care in epithelial ovarian cancer (EOC) have led to challenges in correctly estimating the outcome of control groups. METHODS: A systematic review of the literature was conducted for RP3 trials of EOC published between January 2000 and December 2010. The expected outcome of the control arm as well as the actual outcome achieved by this cohort was collected and a ratio (actual-over expected ratio) was calculated. The estimation of outcome was deemed accurate if the outcome of the control arm was between 0.75 to 1.25 times the anticipated outcome. RESULTS: A total of 35 trials were eligible for analysis. Fifteen trials had survival as the primary endpoint whereas 20 had a progression-based primary endpoint. In total, 12 of 15 trials with a survival-based endpoint significantly underestimated the outcome of the control arm, whereas only 4 of 20 trials with a progression-based endpoint did. Studies with a survival endpoint underestimated outcome more frequently than those with a progression endpoint (P<.001). CONCLUSIONS: Survival of the control arm has frequently been underestimated in recent EOC RP3 trials. This underestimation means that the initial statistical assumptions of these trials may have been inaccurate. Underestimating the outcome of the control arm may result in trials being underpowered to demonstrate the absolute benefit they were designed to show. PMID- 25278039 TI - beta-Cyclodextrin/thermosensitive containing polymer brushes grafted onto magnetite nano-particles for extraction and determination of venlafaxine in biological and pharmaceutical samples. AB - In this paper, a novel nano-sorbent is fabricated by the surface grafting of poly[beta-CD/allylamine-co-N-isopropylacrylamide] onto modified magnetite nano particles by 3-mercaptopropyltrimethoxysilane. The polymer grafted magnetite nano particles was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, elemental analysis, scanning electron microscopy, and transmission electron microscopy. The feasibility of employing this nano-sorbent for extraction of trace venlafaxine in pharmaceutical samples and human biological fluids are investigated. The effect of various parameters such as pH, reaction temperature, and contact time was evaluated. The result revealed that the best sorption of venlafaxine by the magnetite nano-sorbent occurred at 35 degrees C at an optimum pH of 5. The kinetics of the venlafaxine shows accessibility of active sites in the grafted polymer onto the drug. The equilibrium data of venlafaxine by grafted magnetite nano-sorbent are well represented by the Langmuir and Freundlich isotherm models. The adsorption capacity of venlafaxine is found 142.8 mg g(-1) and indicated the homogeneous sites onto polymer grafted magnetite nano-sorbent surface. Nearly 80% of venlafaxine was released in simulated intestinal fluid, pH 7.4, in 30 h and 90% in simulated gastric fluid, pH 1.2, in 1 h. The venlafaxine loaded-polymer grafted magnetite nano-particles were successfully applied for the extraction in urine and pharmaceutical samples. PMID- 25278040 TI - Engineering of nano-crystalline drug suspensions: employing a physico-chemistry based stabilizer selection methodology or approach. AB - This paper describes a systematic approach to select optimum stabilizer for the preparation of nano-crystalline suspensions of an active pharmaceutical ingredient (API). The stabilizer can be either a dispersant or a combination of dispersant and wetting agent. The proposed screening method is a quick and efficient way to investigate a large number of stabilizers based on the principles of physical-chemistry and employs a stepwise approach. The methodology has been divided in two main parts; the first part being focused on the qualitative screening with the objective of selecting the best candidate(s) for further investigation, the second part has been focused on quantitative screening with the objective to optimize the ratio and amount of wetting and dispersing agents, based on wettability, surface charges measurement, adsorption evaluation, process-ability evaluation and storage stability. The results showed clearly that SDS/PVP 40/60% (w/w) (sodium dodecyl sulfate/poly(vinyl pyrrolidone)) at a total concentration of 1.2% was the optimum stabilizer composition, at which the resulting nanosuspensions were stable for more than 50 days at room temperature. PMID- 25278041 TI - Are two-station biased random walkers always potential molecular motors? AB - The short answer to the title question is no. Despite their tremendous complexity, many nanomachines are simply one-dimensional systems undergoing a biased, that is, unidirectional, walk on a two-minima potential energy curve. The initially prepared state, or station, is higher in energy than the final equilibrium state that is reached after overcoming an energy barrier. All chemical reactions comply with this scheme, which does not necessarily imply that a generic chemical reaction is a potential molecular motor. If the barrier is low, the system may walk back and the motion will have a large purely Brownian component. Alternatively, a large distance from the barrier of either of the two stations may introduce a Brownian component. Starting from a general inequality that leverages on the idea that the amount of heat dissipated along the potential energy curve is a good indication of the effectiveness of the biased walk, we provide guidelines for the selection of the features of artificial molecular motors. PMID- 25278042 TI - Nomenclatural and taxonomic problems related to the electronic publication of new nomina and nomenclatural acts in zoology, with brief comments on optical discs and on the situation in botany. AB - In zoological nomenclature, to be potentially valid, nomenclatural novelties (i.e., new nomina and nomenclatural acts) need first to be made available, that is, published in works qualifying as publications as defined by the International Code of zoological Nomenclature ("the Code"). In September 2012, the Code was amended in order to allow the recognition of works electronically published online after 2011 as publications available for the purpose of zoological nomenclature, provided they meet several conditions, notably a preregistration of the work in ZooBank. Despite these new Rules, several of the long-discussed problems concerning the electronic publication of new nomina and nomenclatural acts have not been resolved. The publication of this amendment provides an opportunity to discuss some of these in detail. It is important to note that: (1) all works published only online before 2012 are nomenclaturally unavailable; (2) printed copies of the PDFs of works which do not have their own ISSN or ISBN, and which are not obtainable free of charge or by purchase, do not qualify as publications but must be seen as facsimiles of unavailable works and are unable to provide nomenclatural availability to any nomenclatural novelties they may contain; (3) prepublications online of later released online publications are unavailable, i.e., they do not advance the date of publication; (4) the publication dates of works for which online prepublications had been released are not those of these prepublications and it is critical that the real release date of such works appear on the actual final electronic publication, but this is not currently the case in electronic periodicals that distribute such online prepublications and which still indicate on their websites and PDFs the date of release of prepublication as that of publication of the work; (5) supplementary online materials and subsequent formal corrections of either paper or electronic publications distributed only online are nomenclaturally unavailable; (6) nomenclatural information provided on online websites that do not have a fixed content and format, with ISSN or ISBN, is unavailable. We give precise examples of many of these nomenclatural problems. Several of them, when they arise, are due to the fact that the availability of nomenclatural novelties now depends on information that will have to be sought not from the work itself but from extrinsic evidence. As shown by several examples discussed here, an electronic document can be modified while keeping the same DOI and publication date, which is not compatible with the requirements of zoological nomenclature. Therefore, another system of registration of electronic documents as permanent and inalterable will have to be devised. ZooBank also clearly needs to be improved in several respects. Mention in a work of its registration number (LSID) in ZooBank would seem to be possible only if this registration has occurred previously, but some works that have purportedly been registered in ZooBank are in fact missing on this web application. In conclusion, we offer recommendations to authors, referees, editors, publishers, libraries and the International Commission on Zoological Nomenclature, in the hope that such problems can be limited along with the potential chaos in zoological nomenclature that could result, if careful attention is not paid to the problems we highlight here, from a somewhat misplaced, and perhaps now widespread, understanding that electronic publication of nomenclatural novelties is now allowed and straightforward. We suggest that, as long as the problematic points linked to the new amendment and to electronic publication as a whole are not resolved, nomenclatural novelties continue to be published in paper-printed journals that have so far shown editorial competence regarding taxonomy and nomenclature, which is not the case of several recent electronic-only published journals. PMID- 25278043 TI - The potential use of diisononyl phthalate metabolites hair as biomarkers to assess long-term exposure demonstrated by a rat model. AB - Diisononyl phthalate (DINP) is a widely used industrial plasticizer. People come into contact with this chemical by using plastic products made with it. Human health can be adversely affected by long-term DINP exposure. However, because the body rapidly excretes DINP metabolites, the use of single-point urine analysis to assess long-term exposure may produce inconsistent results in epidemiologic studies. Hair analysis has a useful place in biomonitoring, particularly in estimating long-term or historical exposure for some chemicals. Several studies have reported using hair analysis to assess the concentrations of heavy metals, drugs and organic pollutants in humans. As a biomarker, DINP metabolites were measured in rat hair in animal experiments to evaluated long-term exposure to DINP. In addition, we evaluated the correlation between the levels of DINP metabolites in hair and in urine. The levels of DINP metabolites in rat hair were significantly higher in the exposure group, relative to the control group (p<0.05). DINP metabolites had a positive correlation with increasing administered dose. Significant positive correlations for MINP, MOINP and MHINP were found between hair and urine (r=0.86, r=0.79 and r=0.74, respectively, p<0.05). Several metabolites in urine showed earlier saturation than in hair. In this report, we detected eight metabolites in hair and demonstrate that hair analysis has potential applications in the assessment of long-term exposure to DINP. PMID- 25278045 TI - Stress-shielding induced bone remodeling in cementless shoulder resurfacing arthroplasty: a finite element analysis and in vivo results. AB - Cementless surface replacement arthroplasty (CSRA) of the shoulder was designed to preserve the individual anatomy and humeral bone stock. A matter of concern in resurfacing implants remains the stress shielding and bone remodeling processes. The bone remodeling processes of two different CSRA fixation designs, conical crown (Epoca RH) and central-stem (Copeland), were studied by three-dimensional (3-D) finite element analysis (FEA) as well as evaluation of contact radiographs from human CSRA retrievals. FEA included one native humerus model with a normal and one with a reduced bone stock quality. Compressive strains were evaluated before and after virtual CSRA implantation and the results were then compared to the bone remodeling and stress-shielding pattern of eight human CSRA retrievals (Epoca RH n=4 and Copeland n=4). FEA revealed for both bone stock models increased compressive strains at the stem and outer implant rim for both CSRA designs indicating an increased bone formation at those locations. Unloading of the bone was seen for both designs under the central implant shell (conical-crown 50-85%, central-stem 31-93%) indicating high bone resorption. Those effects appeared more pronounced for the reduced than for the normal bone stock model. The assumptions of the FEA were confirmed in the CSRA retrieval analysis which showed bone apposition at the outer implant rim and stems with highly reduced bone stock below the central implant shell. Overall, clear signs of stress shielding were observed for both CSRAs designs in the in vitro FEA and human retrieval analysis. Especially in the central part of both implant designs the bone stock was highly resorbed. The impact of these bone remodeling processes on the clinical outcome as well as long-term stability requires further evaluation. PMID- 25278044 TI - The PI3K/Akt and ERK pathways elevate thyroid hormone receptor beta1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p,p'-DDE. AB - PCBs and DDT cause the disturbance of thyroid hormone (TH) homeostasis in humans and animals. To test the hypothesis that the PI3K/Akt and MAPK pathways would play significant roles in TH imbalance caused by PCBs and DDT, Sprague-Dawley rats were dosed with PCB153 and p,p'-DDE intraperitoneally for 5 consecutive days, and human thyroid follicular epithelial (Nthy-ori 3-1 cell line) were treated with PCB153 and p,p'-DDE for different time. Results showed that serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were decreased, whereas serum free triiodothyronine (FT3) and thyrotropin releasing hormone (TRH) were not changed. The PI3K/Akt and ERK pathways were activated in vivo and in vitro after the treatment with PCB153 and p,p'-DDE. Moreover, TH receptor beta1 (TRbeta1) was elevated after the activation of the PI3K/Akt pathway and was depressed after the inhibition of the PI3K/Akt pathway; TRH receptor (TRHr) was increased after the activation of the ERK pathway and was decreased after the inhibition of the ERK pathway. Though TH receptor alpha1 (TRalpha1) level was increased in the hypothalamus, TRalpha1 and TSHr were not influenced by the status of signaling pathways in in vitro study. Taken together, after exposure to PCB153 and p,p' DDE, activated PI3K/Akt and ERK pathways disrupt the hypothalamic-pituitary thyroid (HPT) axis via TRbeta1 and TRHr and then decrease TH levels, and that would be a potential mechanism by which PCBs and DDT disturb TH homeostasis. PMID- 25278046 TI - Cyclic cryopreservation affects the nanoscale material properties of trabecular bone. AB - Tissues such as bone are often stored via freezing, or cryopreservation. During an experimental protocol, bone may be frozen and thawed a number of times. For whole bone, the mechanical properties (strength and modulus) do not significantly change throughout five freeze-thaw cycles. Material properties at the trabecular and lamellar scales are distinct from whole bone properties, thus the impact of freeze-thaw cycling at this scale is unknown. To address this, the effect of repeated freezing on viscoelastic material properties of trabecular bone was quantified via dynamic nanoindentation. Vertebrae from five cervine spines (1.5 year-old, male) were semi-randomly assigned, three-to-a-cycle, to 0-10 freeze thaw cycles. After freeze-thaw cycling, the vertebrae were dissected, prepared and tested. ANOVA (factors cycle, frequency, and donor) on storage modulus, loss modulus, and loss tangent, were conducted. Results revealed significant changes between cycles for all material properties for most cycles, no significant difference across most of the dynamic range, and significant differences between some donors. Regression analysis showed a moderate positive correlation between cycles and material property for loss modulus and loss tangent, and weak negative correlation for storage modulus, all correlations were significant. These results indicate that not only is elasticity unpredictably altered, but also that damping and viscoelasticity tend to increase with additional freeze-thaw cycling. PMID- 25278047 TI - Avian picornaviruses: molecular evolution, genome diversity and unusual genome features of a rapidly expanding group of viruses in birds. AB - Picornaviridae is one of the most diverse families of viruses infecting vertebrate species. In contrast to the relative small number of mammal species compared to other vertebrates, the abundance of mammal-infecting picornaviruses was significantly overrepresented among the presently known picornaviruses. Therefore most of the current knowledge about the genome diversity/organization patterns and common genome features were based on the analysis of mammal infecting picornaviruses. Beside the well known reservoir role of birds in case of several emerging viral pathogens, little is known about the diversity of picornaviruses circulating among birds, although in the last decade the number of known avian picornavirus species with complete genome was increased from one to at least 15. However, little is known about the geographic distribution, host spectrum or pathogenic potential of the recently described picornaviruses of birds. Despite the low number of known avian picornaviruses, the phylogenetic and genome organization diversity of these viruses were remarkable. Beside the common L-4-3-4 and 4-3-4 genome layouts unusual genome patterns (3-4-4; 3-5-4, 3-6-4; 3 8-4) with variable, multicistronic 2A genome regions were found among avian picornaviruses. The phylogenetic and genomic analysis revealed the presence of several conserved structures at the untranslated regions among phylogenetically distant avian and non-avian picornaviruses as well as at least five different avian picornavirus phylogenetic clusters located in every main picornavirus lineage with characteristic genome layouts which suggests the complex evolution history of these viruses. Based on the remarkable genetic diversity of the few known avian picornaviruses, the emergence of further divergent picornaviruses causing challenges in the current taxonomy and also in the understanding of the evolution and genome organization of picornaviruses will be strongly expected. In this review we would like to summarize the current knowledge about the taxonomy, pathogenic potential, phylogenetic/genomic diversity and evolutional relationship of avian picornaviruses. PMID- 25278048 TI - A special osteoarthritis and cartilage issue on imaging in osteoarthritis. PMID- 25278050 TI - 2D and 3D MOCART scoring systems assessed by 9.4 T high-field MRI correlate with elementary and complex histological scoring systems in a translational model of osteochondral repair. AB - OBJECTIVE: To compare the 2D and 3D MOCART system obtained with 9.4 T high-field magnetic resonance imaging (MRI) for the ex vivo analysis of osteochondral repair in a translational model and to correlate the data with semiquantitative histological analysis. METHODS: Osteochondral samples representing all levels of repair (sheep medial femoral condyles; n = 38) were scanned in a 9.4 T high-field MRI. The 2D and adapted 3D MOCART systems were used for grading after point allocation to each category. Each score was correlated with corresponding reconstructions between both MOCART systems. Data were next correlated with corresponding categories of an elementary (Wakitani) and a complex (Sellers) histological scoring system as gold standards. RESULTS: Correlations between most 2D and 3D MOCART score categories were high, while mean total point values of 3D MOCART scores tended to be 15.8-16.1 points higher compared to the 2D MOCART scores based on a Bland-Altman analysis. "Defect fill" and "total points" of both MOCART scores correlated with corresponding categories of Wakitani and Sellers scores (all P <= 0.05). "Subchondral bone plate" also correlated between 3D MOCART and Sellers scores (P < 0.001). CONCLUSIONS: Most categories of the 2D and 3D MOCART systems correlate, while total scores were generally higher using the 3D MOCART system. Structural categories "total points" and "defect fill" can reliably be assessed by 9.4 T MRI evaluation using either system, "subchondral bone plate" using the 3D MOCART score. High-field MRI is valuable to objectively evaluate osteochondral repair in translational settings. PMID- 25278051 TI - Three-dimensional reconstruction of rat knee joint using episcopic fluorescence image capture. AB - OBJECTIVE: Development of the knee joint was morphologically investigated, and the process of cavitation was analyzed by using episcopic fluorescence image capture (EFIC) to create spatial and temporal three-dimensional (3D) reconstructions. METHODS: Knee joints of Wister rat embryos between embryonic day (E)14 and E20 were investigated. Samples were sectioned and visualized using an EFIC. Then, two-dimensional image stacks were reconstructed using OsiriX software, and 3D reconstructions were generated using Amira software. RESULTS: Cavitations of the knee joint were constructed from five divided portions. Cavity formation initiated at multiple sites at E17; among them, the femoropatellar cavity (FPC) was the first. Cavitations of the medial side preceded those of the lateral side. Each cavity connected at E20 when cavitations around the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) were completed. CONCLUSION: Cavity formation initiated from six portions. In each portion, development proceeded asymmetrically. These results concerning anatomical development of the knee joint using EFIC contribute to a better understanding of the structural feature of the knee joint. PMID- 25278049 TI - Functional imaging in OA: role of imaging in the evaluation of tissue biomechanics. AB - Functional imaging refers broadly to the visualization of organ or tissue physiology using medical image modalities. In load-bearing tissues of the body, including articular cartilage lining the bony ends of joints, changes in strain, stress, and material properties occur in osteoarthritis (OA), providing an opportunity to probe tissue function through the progression of the disease. Here, biomechanical measures in cartilage and related joint tissues are discussed as key imaging biomarkers in the evaluation of OA. Emphasis will be placed on the (1) potential of radiography, ultrasound, and magnetic resonance imaging to assess early tissue pathomechanics in OA, (2) relative utility of kinematic, structural, morphological, and biomechanical measures as functional imaging biomarkers, and (3) improved diagnostic specificity through the combination of multiple imaging biomarkers with unique contrasts, including elastography and quantitative assessments of tissue biochemistry. In comparison to other modalities, magnetic resonance imaging provides an extensive range of functional measures at the tissue level, with conventional and emerging techniques available to potentially to assess the spectrum of preclinical to advance OA. PMID- 25278052 TI - In vitro glycation of articular cartilage alters the biomechanical response of chondrocytes in a depth-dependent manner. AB - OBJECTIVE: To determine if increasing cartilage cross-links through in vitro glycation of cartilage explants can alter the biomechanical response of chondrocytes to compressive deformation. METHOD: Bovine osteochondral explants were either incubated with cell culture solution supplemented with (n = 7) or without (n = 7) ribose for 42 h in order to induce glycation. Deformation-induced changes in cell volume, dimensions and local tissue strains were determined through confocal laser scanning microscopy (CLSM) and the use of a custom built micro-compression device. Osteochondral explants were also utilized to demonstrate changes in depth-wise tissue properties, biomechanical tissue properties and cross-links such as pentosidine (Pent), hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP). RESULTS: The ribose treated osteochondral samples experienced reduced cell volume deformation in the upper tissue zone by ~ 8% (P = 0.005), as compared the control samples, through restricting cell expansion. In the deeper tissue zone, cell volume deformation was increased by ~ 12% (P < 0.001) via the transmission of mechanical signals further into the tissue depth. Biomechanical testing of the ribose treated osteochondral samples demonstrated an increase in the equilibrium and dynamic strain dependent moduli (P < 0.001 and P = 0.008, respectively). The biochemical analysis revealed an increase in Pent cross-links (P < 0.001). Depth-wise tissue property analyses revealed increased levels of carbohydrate content, greater levels of fixed charge density and an increased carbohydrate to protein ratio from 6 to 16%, 55-100% and 72-79% of the normalized tissue thickness (from the surface), respectively, in the ribose-treated group (P < 0.05). CONCLUSION: In vitro glycation alters the biomechanical response of chondrocytes in cartilage differently in upper and deeper zones, offering possible insights into how aging could alter cell deformation behavior in cartilage. PMID- 25278054 TI - Imaging following acute knee trauma. AB - Joint injury has been recognized as a potent risk factor for the onset of osteoarthritis. The vast majority of studies using imaging technology for longitudinal assessment of patients following joint injury have focused on the injured knee joint, specifically in patients with anterior cruciate ligament injury and meniscus tears where a high risk for rapid onset of post-traumatic osteoarthritis is well known. Although there are many imaging modalities under constant development, magnetic resonance (MR) imaging is the most important instrument for longitudinal monitoring after joint injury. MR imaging is sensitive for detecting early cartilage degeneration and can evaluate other joint structures including the menisci, bone marrow, tendons, and ligaments which can be sources of pain following acute injury. In this review, focusing on imaging following acute knee trauma, several studies were identified with promising short term results of osseous and soft tissue changes after joint injury. However, studies connecting these promising short-term results to the development of osteoarthritis were limited which is likely due to the long follow-up periods needed to document the radiographic and clinical onset of the disease. Thus, it is recommended that additional high quality longitudinal studies with extended follow-up periods be performed to further investigate the long-term consequences of the early osseous and soft tissue changes identified on MR imaging after acute knee trauma. PMID- 25278053 TI - Rapid, automated imaging of mouse articular cartilage by microCT for early detection of osteoarthritis and finite element modelling of joint mechanics. AB - OBJECTIVE: Mouse articular cartilage (AC) is mostly assessed by histopathology and its mechanics is poorly characterised. In this study: (1) we developed non destructive imaging for quantitative assessment of AC morphology and (2) evaluated the mechanical implications of AC structural changes. METHODS: Knee joints obtained from naive mice and from mice with osteoarthritis (OA) induced by destabilization of medial meniscus (DMM) for 4 and 12 weeks, were imaged by phosphotungstic acid (PTA) contrast enhanced micro-computed tomography (PTA-CT) and scored by conventional histopathology. Our software (Matlab) automatically segmented tibial AC, drew two regions centred on each tibial condyle and evaluated the volumes included. A finite element (FE) model of the whole mouse joint was implemented to evaluate AC mechanics. RESULTS: Our method achieved rapid, automated analysis of mouse AC (structural parameters in <10 h from knee dissection) and was able to localise AC loss in the central region of the medial tibial condyle. AC thickness decreased by 15% at 4 weeks and 25% at 12 weeks post DMM surgery, whereas histopathology scores were significantly increased only at 12 weeks. FE simulations estimated that AC thinning at early-stages in the DMM model (4 weeks) increases contact pressures (+39%) and Tresca stresses (+43%) in AC. CONCLUSION: PTA-CT imaging is a fast and simple method to assess OA in murine models. Once applied more extensively to confirm its robustness, our approach will be useful for rapidly phenotyping genetically modified mice used for OA research and to improve the current understanding of mouse cartilage mechanics. PMID- 25278055 TI - Adiabatic rotating frame relaxation of MRI reveals early cartilage degeneration in a rabbit model of anterior cruciate ligament transection. AB - OBJECTIVE: To investigate the sensitivity of seven quantitative magnetic resonance imaging (MRI) parameters (adiabatic T1rho, adiabatic T2rho, continuous wave (CW) T1rho, relaxation along a fictitious field (RAFF), T2 measured with adiabatic double echo (DE) and Carr-Purcell-Meiboom-Gill (CPMG) sequence, and T1 during off-resonance saturation [magnetization transfer (MT)]) to detect early osteoarthritic changes in a rabbit model of anterior cruciate ligament transection (ACLT). METHODS: ACLT was unilaterally induced in the knees of New Zealand White rabbits (n = 8) while contralateral joints served as controls. Femoral condyles of the joints were harvested 4 weeks post-ACLT. MRI was performed at 9.4 T. For reference, quantitative histology, Mankin grading and biomechanical measurements were conducted. RESULTS: Reference methods demonstrated early, superficial cartilage degeneration in the ACLT group, including significant loss of proteoglycans in both medial and lateral compartments, increased collagen fibril anisotropy in the lateral condyle and decreased biomechanical properties at both medial and lateral compartments. CW T1rho was prolonged in the lateral compartment of ACLT joints while adiabatic T1rho and T2rho detected degenerative changes in tissue in both lateral and medial condyles (P < 0.05). DE-T2 was significantly (P < 0.05) elevated only in the lateral compartment while CPMG-T2, MT or RAFF did not show a statistically significant difference between the groups. CONCLUSIONS: Adiabatic T1rho and T2rho relaxation times detected most sensitively early degenerative changes in cartilage 4 weeks post-ACLT in a rabbit model. PMID- 25278056 TI - Changes to the articular cartilage thickness profile of the tibia following anterior cruciate ligament injury. AB - OBJECTIVES: We sought to determine if anterior cruciate ligament (ACL)-injured subjects demonstrated side-to-side differences in tibial cartilage thickness soon after injury, and if uninjured-control subjects displayed side-to-side symmetry in cartilage thickness. Second, we aimed to investigate associations between body mass index (BMI), cross-sectional area (CSA) of the proximal tibia, and articular cartilage thickness differences. METHODS: Bilateral Magnetic Resonance Images (MRIs) were obtained on 88 ACL-injured subjects (27 male; 61 female) a mean 27 days post-injury, and 88 matched uninjured control subjects. Within ACL-injured and uninjured control subjects, side-to-side differences in medial and lateral tibial articular cartilage thickness were analyzed with adjustment for tibial position relative to the femur during MRI acquisition. Associations between tibial CSA and cartilage thickness differences were tested within high and low BMI groups. RESULTS: Within the medial tibial compartment, ACL-injured females displayed significant increases: mean (confidence interval (CI)) = +0.18 mm (0.17, 0.19) and decreases: mean (CI) = -0.14 mm (-0.13, -0.15) in tibial cartilage thickness within the central and posterior cartilage regions respectively. Adjustment for tibial position revealed a decreased area of significant cartilage thickness differences, though 46% of points maintained significance. In the lateral compartment anterior region, there was a significantly different relationship between cartilage thickness differences and CSA, within high and low BMI groups (BMI group*CSA interaction, P = 0.007). Within the low BMI group, a significant negative correlation between cartilage thickness and CSA was identified (P = 0.03). CONCLUSIONS: ACL-injured females displayed cartilage thickness differences in the central, and posterior medial tibial cartilage regions. Tibial position effected thickness differences, but did not account for all significant differences. PMID- 25278058 TI - The role of imaging in early hip OA. AB - Hip osteoarthritis (OA) is characterized by cartilage degradation, subchondral bone sclerosis and osteophyte formation. Nowadays, OA is thought to develop via different etiologies that all lead to a similar form of end stage joint degradation. One of these subtypes is related to an abnormal shaped hip joint, like acetabular dysplasia and a cam deformity. These bony abnormalities are highly predictive for development of hip OA, but they are likely to already be present from childhood. This suggests that these deformations induce OA changes in the hip, well before extensive hip degradation becomes present three to four decades later. Accurate detection and successful characterization of these early OA events might lead to better treatment options for hip OA besides nowadays available invasive joint replacement surgery. However, current diagnostic imaging techniques like radiographs or plain magnetic resonance imaging (MRI), are not sensitive enough to detect these subtle early OA changes. Nor are they able to disentangle intertwined and overlapping cascades from different OA subtypes, and neither can they predict OA progression. New and more sensitive imaging techniques might enable us to detect first OA changes on a cellular level, providing us with new opportunities for early intervention. In this respect, shape analysis using radiography, MRI, computed tomography (CT), single photon emission computed tomography (SPECT)/CT, and positron emission tomography (PET) might prove promising techniques and be more suited to detect early pathological changes in the hip joint. A broad application of these techniques might give us more understanding what can be considered physiological adaptation of the hip, or when early OA really starts. With a more clear definition of early OA, more homogenous patient populations can be selected and help with the development of new disease modifying OA interventions. PMID- 25278057 TI - In vivo fluorescence reflectance imaging of protease activity in a mouse model of post-traumatic osteoarthritis. AB - OBJECTIVE: Joint injuries initiate a surge of inflammatory cytokines and proteases that contribute to cartilage and subchondral bone degeneration. Detecting these early processes in animal models of post-traumatic osteoarthritis (PTOA) typically involves ex vivo analysis of blood serum or synovial fluid biomarkers, or histological analysis of the joint. In this study, we used in vivo fluorescence reflectance imaging (FRI) to quantify protease, matrix metalloproteinase (MMP), and Cathepsin K activity in mice following anterior cruciate ligament (ACL) rupture. We hypothesized that these processes would be elevated at early time points following joint injury, but would return to control levels at later time points. DESIGN: Mice were injured via tibial compression overload, and FRI was performed at time points from 1 to 56 days after injury using commercially available activatable fluorescent tracers to quantify protease, MMP, and cathepsin K activity in injured vs uninjured knees. PTOA was assessed at 56 days post-injury using micro-computed tomography and whole-joint histology. RESULTS: Protease activity, MMP activity, and cathepsin K activity were all significantly increased in injured knees relative to uninjured knees at all time points, peaking at 1-7 days post-injury, then decreasing at later time points while still remaining elevated relative to controls. CONCLUSIONS: This study establishes FRI as a reliable method for in vivo quantification of early biological processes in a translatable mouse model of PTOA, and provides crucial information about the time course of inflammation and biological activity following joint injury. These data may inform future studies aimed at targeting these early processes to inhibit PTOA development. PMID- 25278059 TI - Location-specific hip joint space width for progression of hip osteoarthritis- data from the osteoarthritis initiative. AB - OBJECTIVE: To establish the performance of a location-specific computer-assisted quantitative measure of hip joint space width (JSW), by measuring responsiveness in those with hip osteoarthritis (OA) and pain and those without. Secondary purposes included investigating the most responsive location and comparison to minimum joint space width (mJSW). METHODS: DESIGN: nested case-control. DATA: from the Osteoarthritis Initiative (OAI), a longitudinal cohort study of knee OA. All participants had standardized standing anterior-posterior (AP) pelvis radiographs at baseline and 48 months. Case definition (1): subjects with a total hip replacement (THR) after the 48 month visit (n = 27) were selected and matched (1:1) on sex and age to subjects without a THR. Case definition (2): subjects with a THR at any point after baseline (n = 79) were selected and the contralateral (CL) hip was designated the case hip, and subjects were matched (1:1) as above. Pain: the CL hip group were examined for the presence/absence of pain. Measurements of superior hip JSW were made at three fixed locations relative to a landmark-based line, facilitated by software. The standardized response mean (SRM) was used to examine sensitivity to change from baseline to 48 months. Paired t-tests were used to compare cases and controls. RESULTS: Significant differences were observed between cases and controls and those with and without pain. The location-specific measure outperformed mJSW in all analyses, with SRM ranging from 0.53 (contralateral hip) to 1.06 (THR hip). The superior-medial location was most responsive. CONCLUSION: A new computer-assisted location-specific measure of hip JSW may provide a superior method to mJSW for radiographic OA progression. The superior-medial location was the most responsive. PMID- 25278060 TI - Three-dimensional hip cartilage quality assessment of morphology and dGEMRIC by planar maps and automated segmentation. AB - OBJECTIVE: The quantitative interpretation of hip cartilage magnetic resonance imaging (MRI) has been limited by the difficulty of identifying and delineating the cartilage in a three-dimensional (3D) dataset, thereby reducing its routine usage. In this paper a solution is suggested by unfolding the cartilage to planar two-dimensional (2D) maps on which both morphology and biochemical degeneration patterns can be investigated across the entire hip joint. DESIGN: Morphological TrueFISP and biochemical delayed gadolinium enhanced MRI of cartilage (dGEMRIC) hip images were acquired isotropically for 15 symptomatic subjects with mild or no radiographic osteoarthritis (OA). A multi-template based label fusion technique was used to automatically segment the cartilage tissue, followed by a geometric projection algorithm to generate the planar maps. The segmentation performance was investigated through a leave-one-out study, for two different fusion methods and as a function of the number of utilized templates. RESULTS: For each of the generated planar maps, various patterns could be seen, indicating areas of healthy and degenerated cartilage. Dice coefficients for cartilage segmentation varied from 0.76 with four templates to 0.82 with 14 templates. Regional analysis suggests even higher segmentation performance in the superior half of the cartilage. CONCLUSIONS: The proposed technique is the first of its kind to provide planar maps that enable straightforward quantitative assessment of hip cartilage morphology and dGEMRIC values. This technique may have important clinical applications for patient selection for hip preservation surgery, as well as for epidemiological studies of cartilage degeneration patterns. It is also shown that 10-15 templates are sufficient for accurate segmentation in this application. PMID- 25278062 TI - How to define subregional osteoarthritis progression using semi-quantitative MRI osteoarthritis knee score (MOAKS). AB - OBJECTIVE: Recently, the MRI Osteoarthritis Knee Score (MOAKS), a new semi quantitative magnetic resonance imaging (MRI) scoring tool, was introduced by a panel of experienced researchers in osteoarthritis (OA). The MOAKS is primarily applicable to quantify OA status, since the interpretation of change in the MOAKS features was not described. In order to enable longitudinal evaluation, we propose definitions for progression and improvement of the main MOAKS features. METHOD: Clear definitions for progression and improvement of the main MOAKS features are given in this brief report. 687 baseline and 30 months follow-up MRIs of the knees of 348 overweight and obese middle-aged women, free of OA at baseline, were scored using the MOAKS. Baseline prevalence and the change of MOAKS features after 30 months follow-up, based on our definitions for progression and improvement, are presented. RESULTS: The proposed definitions showed 3% to 23% progression and 0% to 11% improvement in the MOAKS features during the 30 months follow-up. Overall, progression rates were higher in the medial than in the lateral tibiofemoral (TF) joint. Progression of bone marrow lesions (BMLs) and cartilage defects was highest in the patellofemoral (PF) joint. Inter-rater reliability of the MOAKS scores was moderate to nearly perfect (PABAK 0.77-0.88), with high percentage of agreement overall (89-94%). CONCLUSION: This brief report presents definitions for progression and improvement of the main MOAKS features for the longitudinal evaluation of knee OA features on MRI. We advocate uniform usage of the proposed definitions across studies, but welcome suggestions for optimization. PMID- 25278063 TI - Rates and sensitivity of knee cartilage thickness loss in specific central reading radiographic strata from the osteoarthritis initiative. AB - OBJECTIVE: To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. METHODS: One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). RESULTS: The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 +/- 152 vs 134 +/- 100 MUm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 +/- 159 vs -31 +/- 126 MUm; P = 0.02). For comparison, the loss in grade3 knees was -72 +/- 122 MUm. CONCLUSIONS: In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs). PMID- 25278064 TI - Longitudinal analysis of MR spin-spin relaxation times (T2) in medial femorotibial cartilage of adolescent vs mature athletes: dependence of deep and superficial zone properties on sex and age. AB - OBJECTIVE: Cartilage spin-spin magnetic resonance imaging (MRI) relaxation time (T2) represents a promising imaging biomarker of "early" osteoarthritis (OA) known to be associated with cartilage composition (collagen integrity, orientation, and hydration). However, no longitudinal imaging studies have been conducted to examine cartilage maturation in healthy subjects thus far. Therefore, we explore T2 change in the deep and superficial cartilage layers at the end of adolescence. METHODS: Twenty adolescent and 20 mature volleyball athletes were studied (each 10 men and 10 women). Multi-echo spin-echo (MESE) images were acquired at baseline and 2-year follow-up. After segmentation, cartilage T2 was calculated in the deep and superficial cartilage layers of the medial tibial (MT) and the central, weight-bearing part of the medial femoral condyle (cMF), using five echoes (TE 19.4-58.2 ms). RESULTS: 16 adolescent (6 men, 10 women, baseline age 15.8 +/- 0.5 years) and 17 mature (nine men, eight women, age 46.5 +/- 5.2 years) athletes had complete baseline and follow-up images of sufficient quality to compute T2. In adolescents, a longitudinal decrease in T2 was observed in the deep layers of MT (-2.0 ms; 95% confidence interval (CI): [-3.4, -0.6] ms; P < 0.01) and cMF (-1.3 ms; [-2.4, -0.3] ms; P < 0.05), without obvious differences between males and females. No significant change was observed in the superficial layers, or in the deep or superficial layers of the mature athletes. CONCLUSION: In this first pilot study on quantitative imaging of cartilage maturation in healthy, athletic subjects, we find evidence of cartilage compositional change in deep cartilage layers of the medial femorotibial compartment in adolescents, most likely related to organizational changes in the collagen matrix. PMID- 25278061 TI - Imaging of cartilage and bone: promises and pitfalls in clinical trials of osteoarthritis. AB - Imaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes. PMID- 25278065 TI - Variability of CubeQuant T1rho, quantitative DESS T2, and cones sodium MRI in knee cartilage. AB - OBJECTIVE: To measure the variability of T1rho relaxation times using CubeQuant, T2 relaxation times using quantitative double echo in steady state (DESS), and normalized sodium signals using 3D cones sodium magnetic resonance imaging (MRI) of knee cartilage in vivo at 3 T. DESIGN: Eight healthy subjects were scanned at 3 T at baseline, 1 day, 5 months, and 1 year. Ten regions of interest (ROIs) of knee cartilage were segmented in the medial and lateral compartments of each subject's knee. T1rho and T2 relaxation times and normalized sodium signals were measured and the root-mean-square coefficient of variation (CVRMS) was calculated. Intra-subject variability was measured over short, moderate and long term, as well as intra-observer and inter-observer variability. RESULTS: The average intra-subject CVRMS measurements over short, moderate, and long-term time periods were 4.6%, 6.1%, and 6.0% for the T1rho measurements, 6.4%, 9.3%, and 10.7% for the T2 measurements and 11.3%, 11.6%, and 12.9% for the sodium measurements, respectively. The average CVRMS measurements for intra-observer and inter-observer segmentation were 3.8% and 5.7% for the T1rho measurements, 4.7% and 6.7% for the T2 measurements, and 8.1% and 11.4% for the sodium measurements, respectively. CONCLUSIONS: These CVRMS measurements are substantially lower than previously measured changes expected in patients with advanced osteoarthritis compared to healthy volunteers, suggesting that CubeQuant T1rho, quantitative DESS T2 and 3D cones sodium measurements are sufficiently sensitive for in vivo cartilage studies. PMID- 25278067 TI - Articular cartilage degeneration classification by means of high-frequency ultrasound. AB - CONTEXT: To date only single ultrasound parameters were regarded in statistical analyses to characterize osteoarthritic changes in articular cartilage and the potential benefit of using parameter combinations for characterization remains unclear. OBJECTIVE: Therefore, the aim of this work was to utilize feature selection and classification of a Mankin subset score (i.e., cartilage surface and cell sub-scores) using ultrasound-based parameter pairs and investigate both classification accuracy and the sensitivity towards different degeneration stages. DESIGN: 40 punch biopsies of human cartilage were previously scanned ex vivo with a 40-MHz transducer. Ultrasound-based surface parameters, as well as backscatter and envelope statistics parameters were available. Logistic regression was performed with each unique US parameter pair as predictor and different degeneration stages as response variables. The best ultrasound-based parameter pair for each Mankin subset score value was assessed by highest classification accuracy and utilized in receiver operating characteristics (ROC) analysis. RESULTS: The classifications discriminating between early degenerations yielded area under the ROC curve (AUC) values of 0.94-0.99 (mean +/- SD: 0.97 +/- 0.03). In contrast, classifications among higher Mankin subset scores resulted in lower AUC values: 0.75-0.91 (mean +/- SD: 0.84 +/- 0.08). Variable sensitivities of the different ultrasound features were observed with respect to different degeneration stages. CONCLUSIONS: Our results strongly suggest that combinations of high-frequency ultrasound-based parameters exhibit potential to characterize different, particularly very early, degeneration stages of hyaline cartilage. Variable sensitivities towards different degeneration stages suggest that a concurrent estimation of multiple ultrasound-based parameters is diagnostically valuable. In-vivo application of the present findings is conceivable in both minimally invasive arthroscopic ultrasound and high-frequency transcutaneous ultrasound. PMID- 25278066 TI - Cross-relaxation imaging of human patellar cartilage in vivo at 3.0T. AB - OBJECTIVE: To compare quantitative magnetization transfer (qMT) parameters of patellar cartilage measured using cross-relaxation imaging (CRI) in asymptomatic volunteers and patients with osteoarthritis. DESIGN: The study was performed with Institutional Review Board approval and with all subjects signing informed consent. CRI of the knee joint was performed at 3.0T on 20 asymptomatic volunteers and 11 patients with osteoarthritis. The fraction of macromolecular bound protons (f), the exchange rate constant between macromolecular bound protons and free water protons (k), and the T2 relaxation time of macromolecular bound protons (T2(B)) of patellar cartilage were measured. Mann-Whitney-Wilcoxon rank-sum tests were used to compare qMT parameters between asymptomatic volunteers and patients with osteoarthritis. RESULTS: Average f, k, and T2(B) of patellar cartilage was 12.46%, 7.22 s(-1), and 6.49 MUs respectively for asymptomatic volunteers and 12.80%, 6.13 s(-1), and 6.80 MUs respectively for patients with osteoarthritis. There were statistically significant differences between groups of subjects for k (P < 0.01) and T2(B) (P < 0.0001) but not f (P = 0.38) of patellar cartilage. CONCLUSION: Patients with osteoarthritis had significantly lower k and significantly higher T2(B) of patellar cartilage than asymptomatic volunteers which suggests that qMT parameters can detect changes in the macromolecular matrix of degenerative cartilage. PMID- 25278068 TI - The degeneration and destruction of femoral articular cartilage shows a greater degree of deterioration than that of the tibial and patellar articular cartilage in early stage knee osteoarthritis: a cross-sectional study. AB - OBJECTIVE: The aim of the present study was to examine whether the degenerative and morphological changes of articular cartilage in early stage knee osteoarthritis (OA) occurred equally for both femoral- and tibial- or patellar- articular cartilage using magnetic resonance imaging (MRI)-based analyses. DESIGN: This cross-sectional study was approved by the ethics committee of our university. Fifty patients with early stage painful knee OA were enrolled. The patients underwent 3.0 T MRI on the affected knee joint. Healthy volunteers who did not show MRI-based OA changes were also recruited as controls (n = 19). The degenerative changes of the articular cartilage were quantified by a T2 mapping analysis, and any structural changes were conducted using Whole Organ Magnetic Resonance Imaging Score (WORMS) technique. RESULTS: All patients showed MRI detected OA morphological changes. The T2 values of femoral condyle (FC) (P < 0.0001) and groove (P = 0.0001) in patients with early stage knee OA were significantly increased in comparison to those in the control, while no significant differences in the T2 values of patellar and tibial plateau (TP) were observed between the patients and the control. The WORMS cartilage and osteophyte scores of the femoral articular cartilage were significantly higher than those in the patellar- (P = 0.001 and P = 0.007, respectively) and tibial- (P = 0.0001 and P < 0.0001, respectively) articular cartilage in the patients with early stage knee OA. CONCLUSIONS: The degradation and destruction of the femoral articular cartilage demonstrated a greater degree of deterioration than those of the tibial and patellar- articular cartilage in patients with early stage knee OA. PMID- 25278069 TI - Imaging of non-osteochondral tissues in osteoarthritis. AB - OBJECTIVE: The aim of this review is to describe imaging techniques for evaluation of non-osteochondral structures such as the synovium, menisci in the knee, labrum in the hip, ligaments and muscles and to review the literature from recent clinical and epidemiological studies of OA. METHODS: This is a non systematic narrative review of published literature on imaging of non osteochondral tissues in OA. PubMed and MEDLINE search for articles published up to 2014, using the keywords osteoarthritis, synovitis, meniscus, labrum, ligaments, plica, muscles, magnetic resonance imaging (MRI), ultrasound, computed tomography (CT), scintigraphy, and positron emission tomography (PET). RESULTS: Published literature showed imaging of non-osteochondral tissues in OA relies primarily on MRI and ultrasound. The use of semiquantitative and quantitative imaging biomarkers of non-osteochondral tissues in clinical and epidemiological OA studies is reported. We highlight studies that have compared both imaging methodologies directly, and those that have established a relationship between imaging biomarkers and clinical outcomes. We provide recommendations as to which imaging protocols should be used to assess disease-specific changes regarding synovium, meniscus in the knee, labrum in the hip, and ligaments, and highlight potential pitfalls in their usage. CONCLUSION: MRI and ultrasound are currently the most useful imaging modalities for evaluation of non-osteochondral tissues in OA. MRI evaluation of any tissue needs to be performed using appropriate MR pulse sequences. Ultrasound may be particularly useful for evaluation of small joints of the hand. Nuclear medicine and CT play a limited role in imaging of non osteochondral tissues in OA. PMID- 25278070 TI - The responsiveness of novel, dynamic, contrast-enhanced magnetic resonance measures of total knee synovitis after intra-articular corticosteroid for painful osteoarthritis. AB - OBJECTIVE: Sensitive biomarkers are needed to understand synovial response to therapy in osteoarthritis (OA). Dynamic, contrast-enhanced magnetic resonance imaging (DCE MRI) provides quantitative, novel measures of synovial inflammation. This exploratory study examined DCE-assessed synovial response to intra-articular corticosteroid (IACS). METHODS: People with ACR clinical criteria OA knee underwent 3 T MRI pre- and 2 weeks post-IACS. Five MRI variables were assessed blindly: total synovial volume (semi-automated computer program), early enhancement rate (EER) and late enhancement ratio of the entire knee, synovial volume * late enhancement and a semi-quantitative (SQ) score (six sites scored 0 3). Clinical symptoms were assessed using pain visual analogue score (VAS) and WOMAC. RESULTS: 13 participants (5 male, mean age 63, mean pain VAS 66 mm mean body mass index (BMI) 31.3 kg/m(2)) were included. The majority of MRIs demonstrated no change in SQ score although the DCE variables changed to some extent in all. There was generally a reduction in synovial volume ((Wilcoxon test) median (interquartile range (IQR)) reduction 14 cm(3) (-1, 29)), EER (0.2% (-0.3, 0.6)) and late enhancement ratio (8% (-0.5, 41)). Synovial volume * late enhancement ratio demonstrated a substantive reduction (2250 (-930, 5630)) as well as the largest effect size, r = 0.45. There was a median 26% reduction in EER in participants with good symptomatic response to IACS, contrasting with a 23% increase in those who responded poorly. CONCLUSIONS: DCE MRI may be more sensitive than a SQ score at detecting post-therapy synovial changes. The association between EER and symptomatic response to IACS may reflect a closer relation of this biomarker to synovial inflammation than with volumetric assessment. PMID- 25278071 TI - Synovial pathology detected on ultrasound correlates with the severity of radiographic knee osteoarthritis more than with symptoms. AB - OBJECTIVE: To [1] compare the frequency and severity of ultrasound (US) features in people with normal knees (controls), knee pain (KP), asymptomatic radiographic OA (ROA), and symptomatic OA (SROA), [2] examine relationships between US features, pain and radiographic severity, [3] explore the relationship between change in pain and US features over a 3-month period. METHOD: Community participants were recruited into a multiple group case-control study. All underwent assessment for pain, knee radiographs and US examination for effusion, synovial hypertrophy, popliteal cysts and power Doppler (PD) signal within the synovium. A 3-month follow-up was undertaken in over half of control and SROA participants. RESULTS: 243 participants were recruited (90 controls; 59 KP; 32 ROA; 62 SROA). Effusion and synovial hypertrophy were more common in ROA and SROA participants. Severity of effusion and synovial hypertrophy were greater in SROA compared to ROA (P < 0.05). Severity of US effusion and synovial hypertrophy were correlated with radiographic severity (r = 0.6 and r = 0.7, P < 0.01) but the relationship between pain severity and US features was weak (r = 0.3, P < 0.01). In SROA participants, pain severity did not change in tandem with a change in synovial hypertrophy over time. CONCLUSION: US abnormalities are common in OA. Effusion and synovial hypertrophy were moderately correlated with radiographic severity but the relationship with pain is less strong. The degree to which these features reflect "active inflammation" is questionable and they may be better considered as part of the total organ pathology in OA. Further studies are warranted to confirm these findings. PMID- 25278072 TI - Thigh muscle cross-sectional areas and strength in knees with early vs knees without radiographic knee osteoarthritis: a between-knee, within-person comparison. AB - OBJECTIVE: To compare cross-sectional and longitudinal side-differences in thigh muscle anatomical cross-sectional areas (ACSAs), muscle strength, and specific strength (strength/ACSA), between knees with early radiographic change vs knees without radiographic knee osteoarthritis (RKOA), in the same person. DESIGN: 55 (of 4796) Osteoarthritis Initiative (OAI) participants fulfilled the inclusion criteria of early RKOA in one limb (definite tibiofemoral osteophytes; no radiographic joint space narrowing [JSN]) vs no RKOA (no osteophyte; no JSN) in the contralateral limb. ACSAs of the thigh muscles and quadriceps heads were determined using axial MRIs at 33%/30% femoral length (distal to proximal). Isometric extensor and flexor muscle strength were measured (Good Strength Chair). Baseline quadriceps ACSA and extensor (specific) strength represented the primary analytic focus, and 2-year changes of quadriceps ACSAs the secondary focus. RESULTS: No statistically significant side-differences in quadriceps (or other thigh muscle) ACSAs, muscle strength, or specific strength were observed between early RKOA vs contralateral limbs without RKOA (P >= 0.44), neither in men nor in women. The 2-year reduction in quadriceps ACSA in limbs with early RKOA was -0.9 +/- 6% (mean +/- standard deviation) vs -0.5 +/- 6% in limbs without RKOA (statistical difference P = 0.85). CONCLUSION: Our results do not provide evidence that early unilateral radiographic changes, i.e., presence of osteophytes, are associated with cross-sectional or longitudinal differences in quadriceps muscle status compared with contralateral knees without RKOA. At the stage of early unilateral RKOA there thus appears to be no clinical need for countervailing a potential dys-balance in quadriceps ACSAs and strength between both knees. PMID- 25278073 TI - Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties. AB - OBJECTIVE: We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. METHODS: Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). RESULTS: Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. CONCLUSION: We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. PMID- 25278074 TI - The course of ultrasonographic abnormalities in knee osteoarthritis: 1 year follow up. AB - OBJECTIVE: Imaging of (peri)articular structures and inflammation with Ultrasonography (US) during the course of osteoarthritis (OA) might contribute to knowledge about early diagnosis of OA, prognosis and possibly the effect of disease modifying drugs. Our goal was to identify the prevalence of distinct patterns (stable vs fluctuating) in a set of US features in a cohort of patients receiving standard multimodal treatment for knee OA at T = 0, T = 3 months and T = 12 months. DESIGN: This was a prospective, explorative study including 55 patients fulfilling the American College of Rheumatology clinical criteria for knee OA. Six US features were investigated including: effusion, synovial proliferation, infrapatellar bursitis, meniscal protrusion, Baker's cyst and cartilage thickness at three time points during 1 year. A composite inflammatory score was composed. Overall prevalence was assessed as well as individual patterns which were appointed as stable or unstable. RESULTS: Inflammation like effusion and synovial hypertrophy does occur in over 40% of patients at some time in the year of follow up and shows a fluctuating pattern. Meniscal protrusion and Baker's cyst however are more stable features. CONCLUSIONS: Our study gives insight in the prevalence and course of US abnormalities in patients with knee OA and contributes to the knowledge on the possible role of this imaging modality in research. PMID- 25278076 TI - A new method to measure anatomic knee alignment for large studies of OA: data from the osteoarthritis initiative. AB - OBJECTIVE: To develop and validate a new and improved software method to rapidly determine femur-tibia angle (FTA). METHODS: Three readers, two skilled and one unskilled, without any formal medical training, measured FTA in 142 subjects from the Osteoarthritis Initiative (OAI). The reader reliability was assessed using the intra-class correlation coefficient (ICC), root mean square standard deviation (RMSSD), and Bland-Altman plots, comparing the existing and new FTA methods. Gender-specific linear regression assessed the relationship of FTA with the hip-knee-ankle angle (HKA). RESULTS: The ICC (RMSSD) for intra- and inter reader reproducibility of the existing FTA method was 0.96 (0.77 degrees ) and 0.92 (1.38 degrees ), respectively, and for the new technique was 0.98 (0.25 degrees ) and 0.98 (0.37 degrees ), with similar results for all three readers. Bland-Altman 95% limits of agreement were greater than +/-2 degrees for the existing, and +/-1 degrees for the new method. The r-value for the relation of FTA to HKA was 0.68 and 0.72 for the existing and new methods, respectively. Varus (HKA <= -2 degrees )/neutral (-2 degrees < HKA < 2 degrees )/valgus (HKA >= 2 degrees ) alignment based on predicted HKA agreed moderately with measured HKA (weighted kappa = 0.53), and had moderate sensitivity (73%) and specificity (84%) for varus malalignment. The new FTA was related to HKA using a linear equation with a slope of 0.98 and an offset of 4.0 degrees . CONCLUSIONS: Since it is largely automated and uses unambiguous anatomical landmarks, the new method is highly reproducible and can be made on a standard posteroanterior (PA) knee radiograph by a relatively unskilled reader. PMID- 25278075 TI - 3D osteoarthritic changes in TMJ condylar morphology correlates with specific systemic and local biomarkers of disease. AB - OBJECTIVE: To assess 3D morphological variations and local and systemic biomarker profiles in subjects with a diagnosis of temporomandibular joint osteoarthritis (TMJ OA). DESIGN: Twenty-eight patients with long-term TMJ OA (39.9 +/- 16 years), 12 patients at initial diagnosis of OA (47.4 +/- 16.1 years), and 12 healthy controls (41.8 +/- 12.2 years) were recruited. All patients were female and had cone beam CT scans taken. TMJ arthrocentesis and venipuncture were performed on 12 OA and 12 age-matched healthy controls. Serum and synovial fluid levels of 50 biomarkers of arthritic inflammation were quantified by protein microarrays. Shape Analysis MANCOVA tested statistical correlations between biomarker levels and variations in condylar morphology. RESULTS: Compared with healthy controls, the OA average condyle was significantly smaller in all dimensions except its anterior surface, with areas indicative of bone resorption along the articular surface, particularly in the lateral pole. Synovial fluid levels of ANG, GDF15, TIMP-1, CXCL16, MMP-3 and MMP-7 were significantly correlated with bone apposition of the condylar anterior surface. Serum levels of ENA-78, MMP-3, PAI-1, VE-Cadherin, VEGF, GM-CSF, TGFbetab1, IFNgammag, TNFalphaa, IL-1alphaa, and IL-6 were significantly correlated with flattening of the lateral pole. Expression levels of ANG were significantly correlated with the articular morphology in healthy controls. CONCLUSIONS: Bone resorption at the articular surface, particularly at the lateral pole was statistically significant at initial diagnosis of TMJ OA. Synovial fluid levels of ANG, GDF15, TIMP-1, CXCL16, MMP-3 and MMP-7 were correlated with bone apposition. Serum levels of ENA-78, MMP 3, PAI-1, VE-Cadherin, VEGF, GM-CSF, TGFbeta1, IFNgamma, TNFalpha, IL-1alpha, and IL-6 were correlated with bone resorption. PMID- 25278078 TI - The role of imaging modalities in the diagnosis, differential diagnosis and clinical assessment of peripheral joint osteoarthritis. AB - Peripheral joint osteoarthritis (OA) is predominantly a clinical diagnosis, though imaging may provide confirmation and aid with differential diagnosis where there is clinical doubt. Whilst radiographs (X-rays (XR)) are usually the first line imaging modality selected, magnetic resonance imaging (MRI), ultrasound and computed tomography (CT) may all have a valuable role in assessing a person with OA, although each has its particular advantages and disadvantages. MRI is of particular use for diagnosing bone conditions that may cause a rapid increase in symptoms, such as avascular necrosis (AVN) or a subchondral insufficiency fracture (SIF), while providing concomitant soft tissue assessment. Ultrasound offers rapid assessment of peripheral joints and can easily assess for features of inflammatory arthritis. CT is faster to perform than MRI and can also image the subchondral bone, but does involve ionising radiation. Selecting the correct imaging modality, in the context of its advantages when visualising a specific joint (e.g., hand vs knee) and with clinical context in mind, will enhance the added value of imaging in clinical practice. PMID- 25278077 TI - An ultrasound score for knee osteoarthritis: a cross-sectional validation study. AB - OBJECTIVE: To develop standardized musculoskeletal ultrasound (MUS) procedures and scoring for detecting knee osteoarthritis (OA) and test the MUS score's ability to discern various degrees of knee OA, in comparison with plain radiography and the 'Knee injury and Osteoarthritis Outcome Score' (KOOS) domains as comparators. METHOD: A cross-sectional study of MUS examinations in 45 patients with knee OA. Validity, reliability, and reproducibility were evaluated. RESULTS: MUS examination for knee OA consists of five separate domains assessing (1) predominantly morphological changes in the medial compartment, (2) predominantly inflammation in the medial compartment, (3) predominantly morphological changes in the lateral compartment, (4) predominantly inflammation in the lateral compartment, and (5) effusion. MUS scores displayed substantial reliability and reproducibility, with interclass correlations coefficients ranging from 0.75 to 0.97 for the five domains. Construct validity was confirmed with statistically significant correlation coefficients (0.47-0.81, P < 0.01). CONCLUSION: The MUS score suggested in this study was reliable and valid in detecting knee OA. In comparison with standing radiographs of the knees, the score detected all aspects of knee OA with relevant precision. PMID- 25278079 TI - The relationship between clinical characteristics, radiographic osteoarthritis and 3D bone area: data from the osteoarthritis initiative. AB - BACKGROUND: Radiographic measures of osteoarthritis (OA) are based upon two dimensional projection images. Active appearance modelling (AAM) of knee magnetic resonance imaging (MRI) enables accurate, 3D quantification of joint structures in large cohorts. This cross-sectional study explored the relationship between clinical characteristics, radiographic measures of OA and 3D bone area (tAB). METHODS: Clinical data and baseline paired radiographic and MRI data, from the medial compartment of one knee of 2588 participants were obtained from the NIH Osteoarthritis Initiative (OAI). The medial femur (MF) and tibia (MT) tAB were calculated using AAM. 'OA-attributable' tAB (OA-tAB) was calculated using data from regression models of tAB of knees without OA. Associations between OA-tAB and radiographic measures of OA were investigated using linear regression. RESULTS: In univariable analyses, height, weight, and age in female knees without OA explained 43.1%, 32.1% and 0.1% of the MF tAB variance individually and 54.4% when included simultaneously in a multivariable model. Joint space width (JSW), osteophytes and sclerosis explained just 5.3%, 14.9% and 10.1% of the variance of MF OA-tAB individually and 17.4% when combined. Kellgren Lawrence (KL) grade explained approximately 20% of MF OA-tAB individually. Similar results were seen for MT OA-tAB. CONCLUSION: Height explained the majority of variance in tAB, confirming an allometric relationship between body and joint size. Radiographic measures of OA, derived from a single radiographic projection, accounted for only a small amount of variation in 3D knee OA-tAB. The additional structural information provided by 3D bone area may explain the lack of a substantive relationship with these radiographic OA measures. PMID- 25278080 TI - Radiographic scoring methods in hand osteoarthritis--a systematic literature search and descriptive review. AB - OBJECTIVE: This systematic literature review aimed to evaluate the use of conventional radiography (CR) in hand osteoarthritis (OA) and to assess the metric properties of the different radiographic scoring methods. DESIGN: Medical literature databases up to November 2013 were systematically reviewed for studies reporting on radiographic scoring of structural damage in hand OA. The use and metric properties of the scoring methods, including discrimination (reliability, sensitivity to change), feasibility and validity, were evaluated. RESULTS: Of the 48 included studies, 10 provided data on reliability, 11 on sensitivity to change, four on feasibility and 36 on validity of radiographic scoring methods. Thirteen different scoring methods have been used in studies evaluating radiographic hand OA. The number of examined joints differed extensively and the obtained scores were analyzed in various ways. The reliability of the assessed radiographic scoring methods was good for all evaluated scoring methods, for both cross-sectional and longitudinal radiographic scoring. The responsiveness to change was similar for all evaluated scoring methods. There were no major differences in feasibility between the evaluated scoring methods, although the evidence was limited. There was limited knowledge about the validity of radiographic OA findings compared with clinical nodules and deformities, whereas there was better evidence for an association between radiographic findings and symptoms and hand function. CONCLUSIONS: Several radiographic scoring methods are used in hand OA literature. To enhance comparability across studies in hand OA, consensus has to be reached on a preferred scoring method, the examined joints and the used presentation of data. PMID- 25278081 TI - Quantification of differences in bone texture from plain radiographs in knees with and without osteoarthritis. AB - OBJECTIVE: To quantify differences in bone texture between subjects with different stages of knee osteoarthritis (OA) and age- and gender-matched controls from plain radiographs using advanced image analysis methods. DESIGN: Altogether 203 knees were imaged using constant X-ray parameters and graded according to Kellgren-Lawrence (KL) grading scale (KL0: n = 110, KL1: n = 28, KL2: n = 27, KL3: n = 31, KL4: n = 7). Bone density-related and structure-related parameters were calculated from medial and lateral tibial subchondral bone plate and trabecular bone and from femur. Density-related parameters were derived from grayscale values and structure-related parameters from Laplacian- and local binary patterns (LBP)-based images. RESULTS: Reproducibilities of structure related parameters were better than bone density-related parameters. Bone density related parameters were significantly (P < 0.05) higher in KL2-4 groups than in control group (KL0) in medial tibial subchondral bone plate and trabecular bone. LBP-based structure parameters differed significantly between KL0 and KL2-4 groups in medial subchondral bone plate, between KL0 and KL1-4 groups in medial and lateral trabecular bone, and between KL0 and KL1-4/KL2-4 in medial and lateral femur. Laplacian-based parameters differed significantly between KL0 and KL2-4 groups in medial side regions-of-interest (ROIs). CONCLUSIONS: Our results indicate that the changes in bone texture in knee OA can be quantitatively evaluated from plain radiographs using advanced image analysis. Based on the results, increased bone density can be directly estimated if the X-ray imaging conditions are constant between patients. However, structural analysis of bone was more reproducible than direct evaluation of grayscale values, and is therefore better suited for quantitative analysis when imaging conditions are variable. PMID- 25278082 TI - Comparison of biochemical cartilage imaging techniques at 3 T MRI. AB - OBJECTIVE: To prospectively compare chemical-exchange saturation-transfer (CEST) with delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping to assess the biochemical cartilage properties of the knee. METHOD: Sixty-nine subjects were prospectively included (median age, 42 years; male/female = 32/37) in three cohorts: 10 healthy volunteers, 40 patients with clinically suspected cartilage lesions, and 19 patients about 1 year after microfracture therapy. T2 mapping, dGEMRIC, and CEST were performed at a 3 T MRI unit using a 15-channel knee coil. Parameter maps were evaluated using region-of-interest analysis of healthy cartilage, areas of chondromalacia and repair tissue. Differentiation of damaged from healthy cartilage was assessed using receiver-operating characteristic (ROC) analysis. RESULTS: Chondromalacia grade 2-3 had significantly higher CEST values (P = 0.001), lower dGEMRIC (T1-) values (P < 0.001) and higher T2 values (P < 0.001) when compared to the normal appearing cartilage. dGEMRIC and T2 mapping correlated moderately negative (Spearman coefficient r = -0.56, P = 0.0018) and T2 mapping and CEST moderately positive (r = 0.5, P = 0.007), while dGEMRIC and CEST did not significantly correlate (r = 0.311, P = 0.07). The repair tissue revealed lower dGEMRIC values (P < 0.001) and higher CEST values (P < 0.001) with a significant negative correlation (r = 0.589, P = 0.01), whereas T2 values were not different (P = 0.54). In healthy volunteers' cartilage, CEST and dGEMRIC showed moderate positive correlation (r = 0.56), however not reaching significance (P = 0.09). ROC-analysis demonstrated non-significant differences of T2 mapping vs CEST (P = 0.14), CEST vs dGEMRIC (P = 0.89), and T2 mapping vs dGEMRIC (P = 0.12). CONCLUSION: CEST is able to detect normal and damaged cartilage and is non-inferior in distinguishing both when compared to dGEMRIC and T2 mapping. PMID- 25278084 TI - Personal genomics in Greece: an overview of available direct-to-consumer genomic services and the relevant legal framework. AB - BACKGROUND: This article provides an overview of direct-to-consumer (DTC) genomic services that are currently available in Greece and the legal framework within which they operate. METHODS: Here, we describe the landscape of the DTC genomic testing companies and laboratories by conducting a systematic Iotanternet search for relevant websites. We examine the existing legal framework regarding genetic testing in Greece by a review of present regulation. Although Greece does not have explicit legal provisions for DTC genomics, several other laws, including soft law mechanisms, create the broader legal framework within which DTC genomic services may exist. RESULTS/CONCLUSIONS: While the current legal framework creates a flexible environment that is conducive to DTC genomic operations, it is also ambiguous about the legality of some specific services. Given the growing DTC activity in Greece, we argue that it is important to both enforce compliance with existing law and clarify legal ambiguities that may risk limiting the power of legal protections that ought to be afforded to consumers. PMID- 25278083 TI - Progression of cartilage damage and meniscal pathology over 30 months is associated with an increase in radiographic tibiofemoral joint space narrowing in persons with knee OA--the MOST study. AB - PURPOSE: To determine the association of MRI-assessed worsening of tibiofemoral cartilage damage, meniscal damage, meniscal extrusion, separately and together, with progression of radiographic joint space narrowing (JSN). METHOD AND MATERIALS: The Multicenter Osteoarthitis Study (MOST) Study is a cohort study of subjects with or at risk for knee osteoarthritis (OA). Knees with radiographic OA Kellgren-Lawrence grade 2 at baseline and with baseline and 30-month 1.0 T MRIs were selected for reading using the WORMS system for cartilage damage, meniscal damage, and meniscal extrusion. The association of worsening of cartilage damage, meniscal damage, and/or meniscal extrusion with increases in the JSN was performed using logistic regression. RESULTS: A total of 276 knees (one per subject) were included (women 68.5%, mean age 62.9 +/- 7.8, mean body mass index (BMI) 30.2 +/- 5.0). Worsening of each MRI feature was associated with any increase in JSN (P < 0.01). Worsening of cartilage damage was more frequently observed than worsening of meniscal damage and extrusion, and was significantly associated with both slow and fast progression of JSN. An increasing risk of JSN worsening was associated with increasing number of worsening MRI features (P for trend < 0.0001). CONCLUSION: Worsening of tibiofemoral cartilage damage, meniscal damage, and meniscal extrusion are independent predictors of JSN progression in the same compartment. Worsening of cartilage damage is more frequently observed in JSN when compared to meniscal worsening. A strong cumulative effect on JSN progression is observed for worsening of more than one MRI feature. PMID- 25278085 TI - Graphene-mediated surface enhanced Raman scattering in silica mesoporous nanocomposite films. AB - Silica mesoporous nanocomposite films containing graphene nanosheets and gold nanoparticles have been prepared via a one-pot synthesis using silicon tetrachloride, gold(III) chloride tetrahydrate, a 1-N-vinyl-2-pyrrolidone dispersion of exfoliated graphene and Pluronic F127 as a structuring agent. The composite films have shown graphene-mediated surface-enhanced Raman scattering (G SERS). Graphene has been introduced as dispersed bilayer sheets while gold has been thermally reduced in situ to form nanoparticles of around 6 nm which preferentially nucleate on the surface of the graphene nanosheets. The presence of graphene and gold nanoparticles does not interfere with the self-assembly process and the formation of silica mesoporous films ordered as 2D hexagonal structures. The material has shown a remarkable analytical enhancement factor ranging from 80 up to 136 using rhodamine 6G as a Raman probe. The films have been characterised by grazing incidence X-ray diffraction, FTIR and UV-vis spectroscopy studies; transmission electron microscopy and spectroscopic ellipsometry have been used to study the morphology, thickness and porosities of the samples. Raman spectroscopy has been employed to characterise the graphene nanosheets embedded into the mesoporous films and the enhanced Raman scattering. PMID- 25278087 TI - Intervention with substance-abusing mothers: Are there rural-urban differences? AB - OBJECTIVE: The purpose of this study was to examine rural-urban differences among substance-abusing mothers enrolled in the Parent-Child Assistance Program (PCAP) from 1998 to 2008 in Washington State. METHODS: This was a longitudinal study utilizing PCAP data reports of 773 women enrolled from 1998 to 2008. Differences across urban-rural PCAP participants were examined. RESULTS: Rural participants were more likely to report alcohol use and binge drinking at program intake and at the 3-year program exit. In addition, throughout the program, rural women were less likely to complete outpatient substance abuse treatment compared to urban participants. Rural women also used less services during the last year including alcohol/drug support and mental health provider services. Findings are troubling when we consider that at program exit, rural participants also reported higher use of alcohol and more suicidal thoughts than those residing in urban areas. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Data presented indicate there are important differences between urban and rural residing participants. Findings highlight the importance of considering the barriers that rural or remote locations might create. Identifying community-specific needs of substance abusing pregnant or parenting women in both rural and urban settings is crucial for the successful development and improvement of treatment and intervention programs for this vulnerable population of women. (Am J Addict 2014;XX:1-9). PMID- 25278088 TI - A new continuous cell line from Blaps rhynchoptera Fairmaire (Coleoptera: Tenebrionidae). AB - The first continuous cell line from the neonate larval tissues of Blaps rhynchoptera, which has been used as a folk medicine in Yunnan Province, China, was established and designated RIRI-BR1. This cell line was serially subcultured in Schneider's medium supplemented with 15% fetal bovine serum (FBS). The cells grew adherent to culture flasks and exhibited spindle-like and polygonal shapes. The growth rate was determined at the 50th passage, and the population doubling time was calculated to be 79.5 h. The post-thaw viability of the cell line at different passages showed that the cells from higher passages could be recovered easier after cryopreservation than the cells from lower passages. The average chromosome numbers from cells of the RIRI-BR1 cell line at passages 5 to 50 ranged from 12 to 130. The rDNA internal transcribed spacer (ITS) sequence analysis indicated that the RIRI-BR1 cell line was derived from B. rhynchoptera. PMID- 25278086 TI - A randomised trial to evaluate the immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with routine childhood vaccines in Singapore and Malaysia. AB - BACKGROUND: The immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with routine childhood vaccines were evaluated among infants from Singapore and Malaysia, where PHiD-CV has been licensed. METHODS: In the primary vaccination phase, 298 infants from Singapore and 168 infants from Malaysia were randomised to receive the Phase III Clinical (Clin) or the Commercial (Com) lot of PHiD-CV at 2, 3, and 5 months of age. In the booster vaccination phase, 238 toddlers from Singapore received one dose of the PHiD-CV Commercial lot at 18-21 months of age. Immune responses to pneumococcal polysaccharides were measured using 22F-inhibition enzyme-linked immunosorbent assay (ELISA) and functional opsonophagocytic activity (OPA) assay and to protein D, using ELISA. RESULTS: Immune responses induced by primary vaccination with the PHiD-CV Commercial lot were non-inferior to the Phase III Clinical lot in terms of adjusted antibody geometric mean concentration (GMC) ratios for each vaccine pneumococcal serotype and protein D. For each vaccine pneumococcal serotype, >=93.6% and >=88.5% of infants from Malaysia and Singapore had post-primary vaccination antibody concentrations >=0.2 MUg/mL and OPA titres >=8, in the Clin and Com groups, respectively. For each vaccine pneumococcal serotype, >=60.8% and >=98.2% of toddlers from Singapore had pre- and post-booster antibody concentrations >=0.2 MUg/mL, in the Clin and Com groups, respectively. All children, except one, had measurable anti-protein D antibodies and the primary and booster doses of the co-administered vaccines were immunogenic. The incidence of each grade 3 solicited symptom was <=11.1% in both study phases. No serious adverse events considered causally related to vaccination were reported throughout the study. CONCLUSIONS: PHiD-CV given as three-dose primary vaccination to infants in Singapore and Malaysia and booster vaccination to toddlers in Singapore was shown to be immunogenic with a clinically acceptable safety profile.This study has been registered at http://www.clinicaltrials.govNCT00808444 and NCT01119625. PMID- 25278089 TI - Prognostic significance of pretreatment plasma fibrinogen and platelet levels in patients with early-stage cervical cancer. AB - BACKGROUND: Hyperfibrinogenaemia and thrombocytosis, which usually occur in cancer patients, have been shown to contribute to cancer cell growth, progression, and metastasis. The aims of the present study were to assess the prognostic significance of pretreatment plasma fibrinogen and platelet levels in early-stage cervical cancer patients. METHODS: The present study was a retrospective analysis of 220 cervical cancer patients with stage I-IIA disease. The pretreatment plasma fibrinogen and platelet levels were investigated along with clinicopathological findings and survival data. RESULTS: The incidences of hyperfibrinogenaemia and thrombocytosis were 11.8 and 25.5%, respectively. Elevated fibrinogen levels were associated with advanced tumour stage, older age, large tumour size, deep stromal invasion, and tumour recurrence, whereas higher platelet levels correlated significantly with advanced tumour stage, large tumour size, and tumour recurrence. Kaplan-Meier analysis showed that hyperfibrinogenaemia and thrombocytosis were significantly associated with shorter disease-free and overall survival. Furthermore, patients with hyperfibrinogenaemia and thrombocytosis may suffer from a higher risk of recurrence. Multivariate survival analyses showed that fibrinogen levels, but not platelet levels, were an independent prognostic factor for poor survival in early stage patients. CONCLUSION: Hyperfibrinogenaemia and thrombocytosis may be valuable biomarkers for predicting recurrence in patients with early-stage cervical cancer. PMID- 25278090 TI - Expression of PTHrP and PTH/PTHrP receptor 1 in the superior cervical ganglia of rats. AB - PTHrP and its receptor PTHR1 are found in the CNS and peripheral nervous system. The presence of PTHrP mRNA has been detected in the superior cervical ganglion (SCG), but there are no data on the cellular distribution of PTHrP and PTHR1 in the SCG. Although it is known that ovarian activity and reproductive status influence sympathetic activity, and the PTHrP/PTHR1 system is influenced by estrogens in different tissues, it is not known whether these factors have a similar effect on expression of PTHrP and PTHR1 in the nervous system. Hence, we investigated the presence and distribution of PTHrP and PTHR1 in neurons and glia of the SCG of rats, as well as the influence of ovariectomy on their expression, by using immunohistochemistry. PTHrP and PTHR1 immunoreactivity was observed in cytoplasm as well as in nuclei of almost all neurons in the SCG. In male rats, intensity of PTHrP fluorescence was significantly higher in cytoplasm of NPY-, in comparison to NPY+ neurons (p < 0.05). In female rats, 2 months post-ovariectomy, significantly lower intensity of PTHrP fluorescence in cytoplasm of the SCG neurons was observed in comparison to sham operated animals (p < 0.05). In addition to neurons, PTHrP and PTHR1 immunoreactivity was observed in most of the glia and was not influenced by ovariectomy. Results show the expression of PTHrP and its receptor, PTHR1, in the majority of neurons and glial cells in the SCG of rats. Expression of PTHrP, but not PTHR1 in the cytoplasm of SCG neurons is influenced by ovarian activity. PMID- 25278092 TI - B7-1 immunostaining in proteinuric kidney disease. PMID- 25278091 TI - Alcohol and tobacco consumption affects bacterial richness in oral cavity mucosa biofilms. AB - BACKGROUND: Today there are more than 2 billion alcohol users and about 1.3 billion tobacco users worldwide. The chronic and heavy use of these two substances is at the heart of numerous diseases and may wreak havoc on the human oral microbiome. This study delves into the changes that alcohol and tobacco may cause on biofilms of the human oral microbiome. To do so, we used swabs to sample the oral biofilm of 22 subjects; including 9 control-individuals with no or very low consumption of alcohol and no consumption of tobacco, 7 who were chronic and heavy users of both substances and 6 active smokers that reported no significant alcohol consumption. DNA was extracted from swabs and the V1 region of the 16S rRNA gene was PCR amplified and sequenced using the Ion Torrent PGM platform, generating 3.7 million high quality reads. DNA sequences were clustered and OTUs were assigned using the ARB SILVA database and Qiime. RESULTS: We found no differences in species diversity and evenness among the groups. However, we found a significant decrease in species richness in only smokers and in smokers/drinkers when compared to controls. We found that Neisseria abundance was significantly decreased in both groups when compared to controls. Smokers had significant increases in Prevotella and Capnocytophaga and reductions in Granulicatella, Staphylococcus, Peptostreptococcus and Gemella when compared to the two other groups. Controls showed higher abundance of Aggregibacter, whilst smokers/drinkers had lower abundances of Fusobacteria. Samples from only smokers clustered closer together than to controls and smokers/drinkers, and also had a significant reduction in inter-group dissimilarity distances, indicating a more homogenous group than controls. CONCLUSIONS: Our results indicate that the continued use of tobacco or alcohol plus tobacco significantly reduces bacterial richness, which apparently leads to a reduction in inter-group variability, turning the respective biofilms into a more homogenous microenvironment in terms of bacterial community composition, with possible consequences for human oral diseases. PMID- 25278093 TI - Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade. AB - BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. STUDY DESIGN: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin converting enzyme inhibition. SETTING & PARTICIPANTS: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50+/-13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). PREDICTOR: Plasma carboxy-terminal FGF-23 levels. OUTCOMES: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. RESULTS: Higher baseline FGF 23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized beta=-0.46; P=0.001; model R(2)=0.71). For every 100 RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized beta=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. LIMITATIONS: Observational study, limited sample size. CONCLUSIONS: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction. PMID- 25278094 TI - Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor. AB - Liver resection has become a common treatment for liver tumors and hepatocellular carcinoma over the past decades. However, after surgery, the remnant livers in some patients fail to regenerate. Therefore, there is an urgent medical need to develop drugs that can promote liver regeneration. The purpose of the current study is to investigate the promotive effect of alisol B 23-acetate (AB23A) on liver regeneration in mice following partial hepatectomy (PH), and further elucidate the involvement of farnesoid X receptor (FXR) in the liver regeneration promotive effect using in vivo and in vitro experiments. The results showed that AB23A dose-dependently promoted hepatocyte proliferation via upregulating hepatocyte proliferation-related protein forkhead box M1b (FoxM1b), Cyclin D1 and Cyclin B1 expression, and attenuated liver injury via an inhibition in Cyp7a1 and an induction in efflux transporters Bsep expression resulting in reduced hepatic bile acid levels. These changes in the genes, as well as accelerated liver regeneration in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly showed the regulation of these genes by AB23A was abrogated when FXR was silenced. Luciferase reporter assay in HepG2 cells and molecular docking further demonstrated the effect of AB23A on FXR activation in vitro. In conclusions, AB23A produces promotive effect on liver regeneration, due to FXR-mediated regulation of genes involved in hepatocyte proliferation and hepato-protection. AB23A has the potential to be a novel therapeutic option for facilitating efficient liver regeneration in patients subjected to liver resection. PMID- 25278096 TI - Preparation of water-free PEDOT dispersions in the presence of reactive polyisoprene stabilizers. AB - Poly(3,4-ethylenedioxythiophene) nanoparticles with narrow size distribution were prepared in organic dispersant media in the presence of both iron(III) dodecylbenzenesulfonate {Fe(DBS)3}-acting as both an oxidant and a stabilizer-and omega-functionalized polyisoprenes (omega-R-PI) as costabilizers. The effects of the solvent nature and concentration of Fe(DBS)3 on the size and morphology of the PEDOT particles were first studied in the absence of costabilizer. Second, the effects of the molar mass, concentration, and nature of the functional end group of the polyisoprene costabilizer were investigated. PEDOT nano-objects were characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and conductivity measurements. PMID- 25278095 TI - Clinical outcomes of prenatally diagnosed cases of isolated and nonisolated pericardial effusion. AB - OBJECTIVE: The purpose of this study was to investigate the clinical outcome of fetal pericardial effusion (PE). METHODS: This study involved a retrospective review of prenatally diagnosed PE cases. The criterion for inclusion was pericardial fluid in an area greater than 2 mm in diameter. RESULTS: A total of 276 cases of PE and 252 cases diagnosed with other anomalies were initially reviewed. PE is associated with cardiac malformation, hydrops fetalis, extracardiac abnormalities, infections, anemias, intrauterine growth restriction, and aneuploidy markers in fetuses. Of these reviewed cases, 24 cases of isolated fetal PE were studied. In all cases, pericardial fluid filled an area ranging from 2 to 17 mm in diameter. Four cases of isolated PE had an abnormal postnatal condition, and 3 cases were excluded due to lack of follow-up. The size of the PE was not related to the regression of pericardial fluid, adverse outcomes or mortality rate associated with the isolated PE. All newborns were healthy, and there were no chromosomal abnormalities in the study population. CONCLUSIONS: There were no adverse clinical outcomes or chromosomal abnormalities in the fetuses diagnosed with isolated PE. Most cases of isolated PE resolved spontaneously and were associated with a good prognosis. PMID- 25278097 TI - Effect of imposing changes in kick frequency on kinematics during undulatory underwater swimming at maximal effort in male swimmers. AB - Undulatory underwater swimming (UUS) is an important swimming technique after a start and after turns. It was considered that a higher swimming velocity (U) resulted from a higher kick frequency (f), and greater propelling efficiency, i.e., Strouhal number (St) and Froude efficiency (etaF), resulted from a lower f. The aim of this study was to investigate whether changing f affected U and St, etaF plus other kinematics of UUS. Ten national-level male swimmers participated in the study. First, the swimmers performed maximal UUS (Pre; this f was defined as 100% F). Second, the swimmers synchronized their f with the sound of a metronome and with six frequencies (85% F, 90% F, 95% F, 105% F, 110% F, and 115% F) randomly presented. During the higher f sessions, kick amplitude (A) significantly decreased from Pre (115% F: -10.8%, p<.05); however, U was unchanged. In contrast, in lower f sessions, St and etaF were unchanged, but the wavelength per body length (lambdaBL), which indicates UUS mode, significantly decreased (90% F: -1.3%, p<.05). In conclusion, these results suggest that increasing f for UUS would not affect U, but a decrease in f may be suitable for human undulation training. PMID- 25278098 TI - Deception effects on standing center of pressure. AB - Accurate deception detection is a desirable goal with many applications including credibility assessment, security screening, counter-terrorism, and homeland security. However, many deception detection methodologies involve intrusive sensors or other limitations that preclude their use in a covert manner. Posturography may overcome these limitations by using minimally invasive force platform technology. In this study, we tested the hypothesis that posturography would reveal deception-related increases in postural rigidity similar to those observed with previous methodologies. Participants were randomly assigned to a control (CG) or experimental group (EG), and interviewed about the contents of a backpack in their possession while standing on a force platform. EG participants were asked to conceal the presence of several "prohibited" items in the backpack from the interviewer. Center of pressure (COP) measures from the force platform were used to characterize postural sway during participants' verbal responses. We observed a significant deception-related increase in sway frequency, an effect primarily occurring during longer responses that is likely related to increased cognitive load. These findings suggest deception-related increases in postural rigidity as reported in previous work, and demonstrate the feasibility of using posturography as a deception detection tool. PMID- 25278100 TI - High prevalence but uncertain clinical significance of orthostatic hypotension without symptoms. PMID- 25278099 TI - Transforming growth factor beta-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling. AB - BACKGROUND: Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown. METHODS AND RESULTS: Here, we identified an obligate function for TAK1 (transforming growth factor beta-activated kinase 1, gene name Map3k7) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. Cardiac specific ablation of Map3k7 in mice induced spontaneous apoptosis and necroptosis that led to adverse remodeling and heart failure, and these effects were abolished by ablation of tumor necrosis factor receptor-1. Mechanistically, TAK1 functions as a molecular switch in tumor necrosis factor receptor-1 signaling by regulating the formation of 2 cell death complexes, RIP 1 (receptor-interacting protein 1)-FADD (Fas-associated protein with death domain)-caspase 8 and RIP1 RIP3, a process that is dependent on FADD and caspase 8 as scaffolding molecules. Importantly, inhibition of RIP1 or RIP3 largely blocked necroptotic cell death, adverse remodeling, and heart failure in TAK1-deficient mice. CONCLUSIONS: These results indicate that TAK1 functions as a key survival factor in the heart by directly antagonizing necroptosis, which is critical for the maintenance of myocardial homeostasis and the prevention of adverse myocardial remodeling. PMID- 25278101 TI - Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA). AB - BACKGROUND: In this report, we provide the first normative reference data and prevalence estimates of impaired orthostatic blood pressure (BP) stabilization, initial orthostatic hypotension, and orthostatic hypotension based on beat-to beat blood pressure methods in a population-representative sample. METHODS AND RESULTS: Participants were recruited from a nationally representative cohort study (>=50 years). Beat-to-beat systolic BP, diastolic BP, and heart rate records were analyzed among those who underwent an active stand test (n=4475). Normograms were estimated by use of generalized additive models for location, shape, and scale with Box-Cox power exponential distribution. Prevalence estimates of impaired BP stabilization, initial orthostatic hypotension, and orthostatic hypotension are reported. Orthostatic BP responses in adults aged 50 to 59 years stabilized within 30 seconds of standing, with older groups taking 30 seconds or longer. The total prevalence of impaired BP stabilization was 15.6% (95% confidence interval [CI], 14.1%-17.1%), increasing with age to 41.2% (95% CI, 30.0%-52.4%) in people >=80 years old. Initial orthostatic hypotension occurred in 32.9% (95% CI, 31.2%-34.6%) of the population aged >=50 years, with no age gradient evident. The prevalence of orthostatic hypotension was 6.9% (95% CI, 5.9%-7.8%) in the total population, increasing to 18.5% (95% CI, 9.0%-28.0%) in those aged >=80 years old. CONCLUSIONS: Significant age-related differences exist in the time course of postural BP responses, with abnormal responses taking longer than 30 seconds to stabilize. Impaired BP stabilization is more common as we age, affecting more than two-fifths of the population aged >=80 years, and may play a future role in the management of falls and syncope. PMID- 25278102 TI - Identification of loci that cause phenotypic variation in diverse species with the reciprocal hemizygosity test. AB - The reciprocal hemizygosity test is a straightforward genetic test that can positively identify genes that have evolved to contribute to a phenotypic difference between strains or between species. The test involves a comparison between hybrids that are genetically identical throughout the genome except at the test locus, which is rendered hemizygous for alternative alleles from the two parental strains. If the two reciprocal hemizygotes display different phenotypes, then the two parental alleles must have evolved. New methods for targeted mutagenesis will allow application of the reciprocal hemizygosity test in many organisms. This review discusses the principles, advantages, and limitations of the test. PMID- 25278103 TI - Use of very-high-dose olanzapine in treatment-resistant schizophrenia. AB - Schizophrenia is a chronic illness with a progressive course that can be marked by resistance to antipsychotic treatment. This can make therapeutic support challenging for the practitioner, with results that are partial and unsatisfactory. In the literature, treatment with high-dose olanzapine (>20mg/day) appears to be a good alternative to clozapine, the gold standard for treatment-resistant schizophrenia. In the present observational prospective study, we studied the clinical and biological profiles of patients treated with olanzapine doses up to 100mg/day. In total, 50 patients were clinically and biologically assessed. We found a linear relationship between oral dose and serum concentration (Pearson's r=0.83, p<0.001) with effects of tobacco (p<0.05) and of coffee and tea consumption (p<0.01). Tolerance seemed to be good regardless of dose. No link was found between concentration and efficiency. Despite a nonexhaustive assessment of pharmacokinetic parameters, not least pharmacogenetic data (e.g., genotyping of cytochrome P450-1A2 or glycoprotein P Abcb1a), pharmacokinetic aspects alone cannot account for why the disease may sometimes be resistant to 20mg of olanzapine but respond to higher doses. A nuclear imaging study exploring brain occupancy by high-dose olanzapine, coupled with the abovementioned pharmacokinetic assessment, may prove a relevant experimental paradigm for studying the pathophysiological mechanisms of resistant schizophrenia. PMID- 25278104 TI - Facial emotion recognition in paranoid schizophrenia and autism spectrum disorder. AB - Schizophrenia (SZ) and autism spectrum disorder (ASD) share deficits in emotion processing. In order to identify convergent and divergent mechanisms, we investigated facial emotion recognition in SZ, high-functioning ASD (HFASD), and typically developed controls (TD). Different degrees of task difficulty and emotion complexity (face, eyes; basic emotions, complex emotions) were used. Two Benton tests were implemented in order to elicit potentially confounding visuo perceptual functioning and facial processing. Nineteen participants with paranoid SZ, 22 with HFASD and 20 TD were included, aged between 14 and 33 years. Individuals with SZ were comparable to TD in all obtained emotion recognition measures, but showed reduced basic visuo-perceptual abilities. The HFASD group was impaired in the recognition of basic and complex emotions compared to both, SZ and TD. When facial identity recognition was adjusted for, group differences remained for the recognition of complex emotions only. Our results suggest that there is a SZ subgroup with predominantly paranoid symptoms that does not show problems in face processing and emotion recognition, but visuo-perceptual impairments. They also confirm the notion of a general facial and emotion recognition deficit in HFASD. No shared emotion recognition deficit was found for paranoid SZ and HFASD, emphasizing the differential cognitive underpinnings of both disorders. PMID- 25278105 TI - Does employment alter the course and outcome of schizophrenia and other severe mental illnesses? A systematic review of longitudinal research. AB - INTRODUCTION: This review synthesized prospective evidence to assess whether achieving employment alters the course of schizophrenia-spectrum disorder. METHOD: Researchers identified relevant analyses for review via PubMed, expert referral, and reference review and systematically applied two levels of screening to 1484 citations using seven a priori criteria. RESULTS: A total of 12 analyses representing eight cohorts, or 6844 participants, compared illness course over time by employment status in majority schizophrenia-spectrum samples. Employment was consistently associated with reductions in outpatient psychiatric treatment (2 of 2 studies) as well as improved self-esteem (2 of 2 studies). Employment was inconsistently associated with positive outcomes in several other areas, including symptom severity, psychiatric hospitalization, life satisfaction, and global wellbeing. Employment was consistently unrelated to worsening outcomes. DISCUSSION: Achieving employment does not cause harm among people with schizophrenia-spectrum disorder and other severe mental illnesses. Further detailed mechanistic analyses of adequately powered long-term follow-up studies using granular descriptions of employment are needed to clarify the nature of associations between employment and hypothesized benefit. PMID- 25278107 TI - Balancing competing motives: adaptive trade-offs are necessary to satisfy disease avoidance and interpersonal affiliation goals. AB - The current research provides novel evidence for motivational trade-offs between the two fundamental human goals of pursuing social affiliation and avoiding disease. In Study 1, participants completed a writing prime that manipulated inclusionary status and found that socially excluded participants indicated lower feelings of current disease susceptibility compared with control and socially included participants. In Study 2, participants were included or excluded via Cyberball and then indicated their preferences for symmetrical versus asymmetrical faces. Socially excluded participants displayed lower preferences for symmetrical faces--a cue associated with greater disease resistance. Finally, in Study 3, participants were primed with either disease threat or a general negative affective state and then indicated their current affiliation interest. Activated disease concerns uniquely led participants to display less interest in social affiliation. Taken together, affiliation needs result in disease avoidance down-regulation to aid reaffiliation, whereas disease concerns result in affiliation down-regulation to facilitate pathogen avoidance. PMID- 25278108 TI - The face-time continuum: lifespan changes in facial width-to-height ratio impact aging-associated perceptions. AB - Aging influences how a person is perceived on multiple dimensions (e.g., physical power). Here we examined how facial structure informs these evolving social perceptions. Recent work examining young adults' faces has revealed the impact of the facial width-to-height ratio (fWHR) on perceived traits, such that individuals with taller, thinner faces are perceived to be less aggressive, less physically powerful, and friendlier. These perceptions are similar to those stereotypically associated with older adults. Examining whether fWHR might contribute to these changing perceptions over the life span, we found that age provides a shifting context through which fWHR differentially impacts aging related social perceptions (Study 1). In addition, archival analyses (Study 2) established that fWHR decreases across age, and a subsequent study found that fWHR mediated the relationship between target age and multiple aging-related perceptions (Study 3). The findings provide evidence that fWHR decreases across age and influences stereotypical perceptions that change with age. PMID- 25278106 TI - Does diffusion MRI tell us anything about the white matter? An overview of methods and pitfalls. AB - One key pitfall in diffusion magnetic resonance imaging (dMRI) clinical neuroimaging research is the challenge of understanding and interpreting the results of a complex analysis pipeline. The sophisticated algorithms employed by the analysis software, combined with the relatively non-specific nature of many diffusion measurements, lead to challenges in interpretation of the results. This paper is aimed at an intended audience of clinical researchers who are learning about dMRI or trying to interpret dMRI results, and who may be wondering "Does dMRI tell us anything about the white matter?" We present a critical review of dMRI methods and measures used in clinical neuroimaging research, focusing on the most commonly used analysis methods and the most commonly reported measures. We describe important pitfalls in every section, and provide extensive references for the reader interested in more detail. PMID- 25278109 TI - Health literacy among refugees in Sweden - a cross-sectional study. AB - BACKGROUND: Refugees have poorer health compared to indigenous populations, which may be explained by lower health literacy, i.e. not being able to access, understand, appraise or apply health information. This study aims to determine levels of functional and comprehensive health literacy, and factors associated with inadequate health literacy, in refugees coming to Sweden. METHOD: A cross sectional study was performed among 455 adult refugees speaking Arabic, Dari, Somali or English. Participants in 16 strategically selected language schools for immigrants responded to a questionnaire. Health literacy was measured using the Swedish Functional Health Literacy Scale and the HLS-EU-Q16 questionnaire. Uni- and multivariate statistical methods were used to investigate group differences. RESULTS: The majority of the participating refugees had inadequate or limited functional health literacy and comprehensive health literacy. About 60% of them had inadequate functional health literacy and 27% had inadequate comprehensive health literacy. Low education and/or being born in Somalia were factors associated with an increased risk of having inadequate functional health literacy. Having inadequate functional health literacy was associated with an increased risk of having inadequate comprehensive health literacy. CONCLUSIONS: The majority of refugees in the language schools had limited or poor health literacy. Health literacy should be taken into consideration in contexts and in activities addressing migrants. More research is needed to better understand health literacy among refugees and to develop strategies and methods to increase health literacy and make life easier for those with low health literacy. PMID- 25278110 TI - Floating arterial thrombus related stroke treated by intravenous thrombolysis. AB - BACKGROUND: The effects of intravenous thrombolysis on floating thrombi in cervical and intracranial arteries of acute ischemic stroke patients are unknown. Similarly, the best prevention methods of early recurrences remain controversial. This study aimed to describe the clinical and radiological outcome of thrombolyzed strokes with floating thrombi. METHODS: We retrospectively analyzed all thrombolyzed stroke patients in our institution between 2003 and 2010 with floating thrombi on acute CT-angiography before the intravenous thrombolysis. The floating thrombus was diagnosed if an elongated thrombus of at least 5 mm length, completely surrounded by contrast on supra-aortic neck or intracerebral arteries, was present on CT-angiography. Demographics, vascular risk factors, and comorbidities were recorded and stroke etiology was determined after a standardized workup. Repeat arterial imaging was performed by CTA at 24 h or before if clinical worsening was noted and then by Doppler and MRA during the first week and at four months. RESULTS: Of 409 thrombolyzed stroke patients undergoing acute CT Angiography, seven (1.7%) had a floating thrombus; of these seven, six had it in the anterior circulation. Demographics, risk factors and stroke severity of these patients were comparable to the other thrombolyzed patients. After intravenous thrombolysis, the floating thrombi resolved completely at 24 h in four of the patients, whereas one had an early recurrent stroke and one developed progressive worsening. One patient developed early occlusion of the carotid artery with floating thrombus and subsequently a TIA. The two patients with a stable floating thrombus had no clinical recurrences. In the literature, only one of four reported cases were found to have a thrombolysis related early recurrence. CONCLUSIONS: Long-term outcome seemed similar in thrombolyzed patients with floating thrombus, despite a possible increase of very early recurrence. It remains to be established whether acute mechanical thrombectomy could be a safer and more effective treatment to prevent early recurrence. However, intravenous thrombolysis should not be withheld in eligible stroke patients. PMID- 25278111 TI - Anaerobic co-digestion of forage radish and dairy manure in complete mix digesters. AB - Pilot-scale digesters (850 L) were used to quantify CH4 and H2S production when using forage radish cover crops as a co-digestion feedstock in dairy manure-based digesters. During two trials, triplicate mixed digesters were operated in batch mode with manure-only or radish+manure (27% and 13% radish by wet weight in Trial 1 and 2, respectively). Co-digestion increased CH4 production by 11% and 39% in Trial 1 and 2, respectively. As H2S production rapidly declined in the radish+manure digesters, CH4 production increased reaching high levels of CH4 (?67%) in the biogas. Over time, radish co-digestion lowered the H2S concentration in the biogas (0.20%) beyond that of manure-only digestion (0.34 0.40%), although cumulative H2S production in the radish+manure digesters was higher than manure-only. Extrapolated to a farm-scale (200 cows) continuous mixed digester, co-digesting with radish could generate 3150 m(3) CH4/month, providing a farmer additional revenue up to $3125/month in electricity sales. PMID- 25278113 TI - Relay cooperation of K2S2O8 and O2 in oxytrifluoromethylation of alkenes using CF3SO2Na. AB - A new radical oxytrifluoromethylation of alkenes via an aerobic Cvinyl-heteroatom bond oxygenation process is reported, in which O2 and a catalytic amount of K2S2O8 work in concert to activate CF3SO2Na. Mechanistic investigation disclosed that CF3SO2 could react with O2 to reinitiate radical chain process. PMID- 25278112 TI - Utilization of palm oil sludge through pyrolysis for bio-oil and bio-char production. AB - In this study, pyrolysis technique was utilized for converting palm oil sludge to value added materials: bio-oil (liquid fuel) and bio-char (soil amendment). The bio-oil yield obtained was 27.4+/-1.7 wt.% having a heating value of 22.2+/-3.7 MJ/kg and a negligible ash content of 0.23+/-0.01 wt.%. The pH of bio-oil was in alkaline region. The bio-char yielded 49.9+/-0.3 wt.%, which was further investigated for sorption efficiency by adsorbing metal (Cd(2+) ions) from water. The removal efficiency of Cd(2+) was 89.4+/-2%, which was almost similar to the removal efficiency of a commercial activated carbon. The adsorption isotherm was well described by Langmuir model. Therefore, pyrolysis is proved as an efficient tool for palm oil sludge management, where the waste was converted into valuable products. PMID- 25278114 TI - Data logger device applicability for wheelchair tennis court movement. AB - Assessment of movement logging devices is required to ensure suitability for the determination of court-movement variables during competitive sports performance and allow for practical recommendations to be made. Hence, the purpose was to examine wheelchair tennis speed profiles to assess data logger device applicability for court-movement quantification, with match play stratified by rank (HIGH, LOW), sex (male, female) and format (singles, doubles). Thirty-one wheelchair tennis players were monitored during competitive match play. Mixed sampling was employed (male = 23, female = 8). Friedman's test with Wilcoxon signed-rank post hoc testing revealed a higher percentage of time below 2.5 m . s(-1) [<2.5 vs. >=2.5 m . s(-1): 89.4 (5.0) vs. 1.2 (3.5)%, Z = -4.860, P < 0.0005, r = 0.87] with the remaining time [9.0 (4.9%)] spent stationary. LOW ranked players were stationary for longer than HIGH-ranked counterparts [12.6 (8.7) vs. 8.2 (5.1)%, U = 30.000, P = 0.011, r = 0.46] with more time at low propulsion speeds (<1.0 m . s(-1)). HIGH-ranked and doubles players spent more time in higher speed zones than respective counterparts. Females spent more time in the 1.0-1.49 m . s(-1) zone (U = 48.000, P = 0.047, r = 0.36). Regardless of rank, sex or format, propulsion speeds during wheelchair tennis match play are consistent with data logger accuracy. Hence, data logging is appropriate for court-movement quantification. PMID- 25278115 TI - New multiple sclerosis phenotypic classification. AB - BACKGROUND: In 1996, the clinical course of multiple sclerosis (MS) was characterized as relapsing-remitting, primary progressive, secondary progressive or progressive relapsing. Since then, an increased understanding of MS and its pathology prompted a re-examination of these clinical phenotypes. Main recommendations of the 2013 revisions are provided herein. SUMMARY: Clinically isolated syndrome has been added, and progressive relapsing MS has been eliminated, from the clinical course descriptions. All forms of MS should be further subcategorized as either active or non-active. Active MS is defined as the occurrence of clinical relapse or the presence of new T2 or gadolinium enhancing lesions over a specified period of time, preferably at least one year. An additional subcategory for patients with progressive MS differentiates between those who have shown signs of disability progression over a given time period and those who have remained stable. The term 'worsening' is recommended to describe patients whose disease is advancing for any reason, whereas 'disease progression' should be reserved for those with progressive disease who are truly progressing (as opposed to worsening from a relapse). The term 'benign' should be used with caution as the course of MS can worsen at any time, even after many years of apparent stability. Key Messages: Newer characterizations of MS phenotypes include a consideration of disease activity (based on the clinical relapse rate and imaging findings) and disease progression. Accurate clinical course descriptions are useful for communication, prognostication, clinical trial design and to guide everyday clinical decision-making. PMID- 25278116 TI - Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways. AB - BACKGROUND: Spasticity arises from hyperexcitability of the neural stretch reflex arc secondary to injury of the corticospinal tract. In response to injury, the density of glutamatergic inputs from afferent 1A fibers to motor neurons increases dramatically and adaptive changes occur in the morphology of microglia cells in the spinal cord. SUMMARY: Involvement of the endocannabinoid system in pathophysiological mechanisms responsible for spasticity has been demonstrated in animal models of MS. Stimulation of cannabinoid (CB)1 receptors reduces the hyperglutamatergic drive from sensory afferents to spinal cord motor neurons and blocks the synaptic effects of activated microglia and pro-inflammatory mediators (e.g. TNF-alpha) on glutamatergic transmission. Enhancing corticospinal tract excitability through intermittent theta burst stimulation inhibits the stretch reflex and spasticity by promoting long-term potentiation, a form of synaptic plasticity that requires stimulation of CB1 receptors. Evidence indicates that the antispasticity effects of THC:CBD oromucosal spray (Sativex(r)) are associated with enhanced cortical long-term potentiation. Key Messages: Glutamatergic and GABAergic pathways are involved in the regulation of muscle tone. CB1 receptors, which are associated with movement, postural control, and pain and sensory perception, influence glutamatergic pathways. THC:CBD oromucosal spray was shown to reverse motor cortex plasticity from long-term depression through long-term potentiation of synaptic transmission, thereby restoring, at least in part, effective corticospinal inputs to spinal circuits. PMID- 25278117 TI - Advances in the management of multiple sclerosis spasticity: recent clinical trials. AB - BACKGROUND: Most patients with multiple sclerosis (MS) experience spasticity as the clinical course evolves. Associated symptoms include (often painful) spasms, urinary dysfunction and sleep disturbances. THC:CBD oromucosal spray (Sativex(r)) is approved for symptom improvement in adult patients with moderate to severe MS related spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. SUMMARY: In pivotal clinical trials of THC:CBD oromucosal spray, a meaningful proportion of patients with treatment-resistant MS spasticity achieved clinically relevant improvement with active treatment versus placebo. The utility of a 4-week trial of therapy to identify patients who respond to treatment was demonstrated in an enriched-design study. THC:CBD oromucosal spray was well tolerated in these studies, with no evidence of effects typically associated with recreational cannabis use. In a subsequent post approval clinical trial, THC:CBD oromucosal spray had no statistically significant effect on cognition and mood compared with placebo. Moreover, after 50 weeks' treatment, approximately two-thirds of patients, physicians and caregivers reported improvement from baseline in spasticity based on global impressions of change. Key Messages: In phase III clinical trials, approximately one-third of MS patients with treatment-resistant spasticity had a clinically relevant and statistically significant response to THC:CBD oromucosal spray. In addition to a reduction in spasticity, responders experienced meaningful relief from associated symptoms. THC:CBD oromucosal spray was generally well tolerated and efficacy was maintained over the longer term. A post approval clinical trial indicated no effect of THC:CBD oromucosal spray on cognition or mood after 50 weeks of use. PMID- 25278118 TI - Advances in the management of MS spasticity: recent observational studies. AB - BACKGROUND: Clinical trials demonstrate the efficacy and tolerability of an intervention under experimental conditions, but information on use under daily practice conditions is required to confirm the effectiveness and safety of new management options. SUMMARY: Clinical outcomes for THC:CBD oromucosal spray (Sativex(r)) in patients with treatment-resistant MS spasticity have been collected in post-marketing safety registries from the UK and Germany, a safety study from Spain and two observational studies from Germany, including one investigating its effects on driving ability. Collectively, findings from daily practice support the long-term effectiveness and safety of THC:CBD oromucosal spray. The proportion of patients with a clinically relevant response (>=30% improvement from baseline on the spasticity 0-10 Numerical Rating Scale) at 3 months was similar to that reported in a large enriched-design pivotal clinical trial (41 vs. 36%). There was no evidence of abuse/misuse or other adverse events of special interest with a cannabis-based medicine and no impairment of driving ability. In actual clinical practice, average daily doses were ~25% lower than those used in clinical trials. Key Messages: Observational data and real world experience reinforce the efficacy and safety of THC:CBD oromucosal spray as reported in phase III clinical trials. (c) 2014 S. Karger AG, Basel. PMID- 25278119 TI - Clinical case reviews and poster sessions in multiple sclerosis spasticity: main outcomes and highlights. AB - BACKGROUND: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary : Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex(r)) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic 'priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity. PMID- 25278120 TI - Multidisciplinary management of multiple sclerosis symptoms. AB - BACKGROUND: Effective management of multisymptomatic chronic diseases such as multiple sclerosis (MS) requires a multimodal, interdisciplinary approach. At MS clinics, numerous healthcare specialties are coordinated to provide patients with quality clinical care for all aspects of their disease. Settings and resource availability may vary between countries. Four specific specialty services from different EU countries are examined in more detail. SUMMARY: The multidisciplinary neurorehabilitation team in Rennes, France, provides specialized consultations (e.g. spasticity, urodynamic unit, devices), inpatient and outpatient intensive rehabilitation programs and therapeutic education. Management approaches are based on a patient's level of impairment as assessed by the Expanded Disability Status Scale. In Girona, Spain, neuropsychologists perform assessments as part of the neurological protocol for all patients with MS. Depending on the level of impairment and patients' characteristics (e.g. working or not working), cognitive deficits may be treated at home or at a neurorehabilitation center. In Barcelona, Spain, neuro-ophthalmologists are involved in the differential diagnosis and follow-up care of MS patients with visual disturbances; particular attention is given to patients' vision-related quality of life. Pain specialists at the Marianne Straubeta Klinik in Berg, Germany, have developed a system for classifying MS pain syndromes and differentiating MS-related pain from non MS-related pain. Chronic pain management involves numerous disciplines and requires active engagement by patients in developing treatment plans. Key Messages: MS affects several body systems and patients invariably require specialized interdisciplinary support. Insight into services provided by various specialties and their fit within multidisciplinary care models at MS centers may facilitate the design or refinement of care models in other locations. PMID- 25278121 TI - Pediatric multiple sclerosis: update in diagnosis and management. PMID- 25278122 TI - Multiple sclerosis databases: present and future. PMID- 25278123 TI - Intrathecal baclofen in multiple sclerosis. PMID- 25278124 TI - Treatment of relapsing-remitting multiple sclerosis: current and future algorithms. PMID- 25278125 TI - Pregnancy in multiple sclerosis. AB - BACKGROUND: The incidence of multiple sclerosis (MS) is increasing, particularly in young women (20-40 years). In line, experience in the management of pregnancies and use of disease-modifying therapy (DMT) in women with MS is accumulating. SUMMARY: Fertility is generally not affected in MS. If assisted reproduction techniques (ART) are required, unsuccessful procedures are associated with an increased relapse risk, particularly in the first few months post-ART. During pregnancy, the risk of relapse declines continuously, especially in the third trimester, then increases early postpartum (3 months) and returns to pre-pregnancy levels at 4-6 months. The progression of MS disability is probably not influenced by pregnancy. Obstetrical outcomes show no increased risk for miscarriage/malformations, and the course of pregnancy is similar to that of women without MS, but with a tendency towards assisted delivery/cesarean section and reduced birth weights. Safety data regarding DMT in pregnancy and breastfeeding are limited. Exclusive breastfeeding may be beneficial and, hence, should not be discouraged in favour of resuming DMT except in cases of highly active disease. Key Messages: The course of pregnancy in women with MS is broadly similar to that in women without MS; risk-to-benefit assessments are warranted when considering halting DMT before pregnancy and resuming DMT postpartum. PMID- 25278126 TI - Activities of the European multiple sclerosis platform. AB - BACKGROUND: The European Multiple Sclerosis Platform (EMSP) is an umbrella organization for national multiple sclerosis (MS) patients' associations in 34 European countries. Its focus is to improve the quality of life (QoL) of individuals with MS and inform society about the challenges of living with this chronic and debilitating disease. SUMMARY: The EMSP, which is comprised of 39 MS societies across Europe, represents the interests of more than 600,000 individuals with MS and another 1.5 million persons affected by the disease, including family and caregivers. The organization works to achieve high quality, equitable treatment and support for persons with MS throughout Europe, as reflected in its main activities and projects. These include: the European Code of Good Practice in MS; a European MS register (EUReMS); a MS Barometer to assess QoL; the MS Nurse PROfessional curriculum to provide standards for MS nurse training; a photographic exhibition entitled Under Pressure; the Believe and Achieve project which focuses on employment for young people with MS; and collaboration in World MS Day, an international MS awareness day. Key Messages: The activities and projects of the EMSP are geared towards making a difference in the lives of individuals with MS in Europe and their wider support networks, including physicians, neurologists, nurses and carers. PMID- 25278127 TI - Acute myeloid leukemia is a disease associated with HLA-C3. AB - BACKGROUND: We aimed to observe human leukocyte antigen (HLA) associations with human acute myeloid leukemia (AML) in a large population, in order to investigate the roles of HLA in leukemogenesis. Furthermore, we examined the HLA association according to morphological, cytogenetic, immunological, and clinical classifications. MATERIALS AND METHODS: We performed HLA genotyping, bone marrow studies, cytogenetic analyses, and fluorescence-activated cell sorting analyses. A clinical outcome database was constructed, and the HLA frequency, gene frequency, relative risk (RR), linkage disequilibrium, and the 2-locus and 3 locus haplotype frequency using the Mattiuz formula were calculated. For the healthy controls, Korean HLA data published by Park and co-workers were used. RESULTS: AML was found to be associated with HLA-C3 (RR = 1.46; p < 0.001). In the French-American-British (FAB) classification, acute myelomonocytic leukemia (AML-M4) was associated with HLA-C3 (47.2 vs. 74.1%; RR = 3.13; p = 0.005), in cytogenetic classification, del(9), which is frequently observed in AML-M4, was also associated with HLA-C3 (47.2 vs. 100%; RR = 13.43; p = 0.024), and in clinical classification, incomplete remission was associated with HLA-C3 as well (47.2 vs. 63.2%; RR = 1.92; p = 0.002). No correlations between AML and immunological classifications were observed. Moreover, and in terms of 2-locus haplotypes, AML was found to be associated with HLA-C3/B62 (HLA-C3 gene frequency 0.3415; HLA-B62 gene frequency 0.1361; linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 6.0%; p < 0.05). In clinical classification, incomplete remission (linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 13.6%; p = 0.013) and relapse (linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 71.0%; p = 0.044) were associated with HLA-C3/B62, whereas no association was observed for FAB, cytogenetic and immunological classifications. No association was observed for the 3-locus haplotype. CONCLUSION: The HLA-C3 antigen and the 2 locus haplotype are associated with AML. PMID- 25278128 TI - Inactivation of AMPK mediates high phosphate-induced extracellular matrix accumulation via NOX4/TGFbeta-1 signaling in human mesangial cells. AB - BACKGROUND/AIMS: High phosphate (Pi) levels and extracellular matrix (ECM) accumulation are associated with chronic kidney disease progression. However, how high Pi levels contribute to ECM accumulation in mesangial cells is unknown. The present study investigated the role and mechanism of high Pi levels in ECM accumulation in immortalized human mesangial cells (iHMCs). METHODS: iHMCs were exposed to normal (0.9 mM) or increasing Pi concentrations (2.5 and 5 mM) with or without diferent blockers or activators. NOX4, phosphorylated AMPK (p-AMPK), phosphorylated SMAD3 (p-SMAD3), fibronectin (F/N), collagen IV (C-IV) and alpha smooth muscle actin (alpha-SMA) expression was assessed via western blot and immunofluorescence. Lucigenin-enhanced chemiluminescence, and dihydroethidium (DHE) assessed NADPH oxidase activity and superoxide (SO), respectively. RESULTS: In iHMCs, a Pi transporter blocker (PFA) abrogated high Pi-induced AMPK inactivation, increase in NADPH oxidase-induced reactive oxygen species (ROS) levels, NOX4, p-SMAD3, alpha-SMA and C-IV expression. AMPK activation by AICAR, NOX4 silencing or NADPH oxidase blocker prevented high Pi-induced DHE levels, p SMAD3, F/N, C-IV and alpha-SMA expression. CONCLUSION: AMPK inactivation with NOX4-induced ROS formation and transforming growth factor beta-1 (TGFbeta-1) signaling activation mediates high Pi-induced ECM accumulation in iHMCs. Maneuvers increasing AMPK or reducing NOX4 activity may contribute to renal protection under hyperphosphatemia. PMID- 25278129 TI - Designability landscape reveals sequence features that define axial helix rotation in four-helical homo-oligomeric antiparallel coiled-coil structures. AB - Coiled coils are widespread protein domains comprising alpha-helices wound around each other in a regular fashion. Owing to their regularity, coiled-coil structures can be fully described by parametric equations. This in turn makes them an excellent model for studying sequence-structure relationships in proteins. Here, we used computational design to identify sequence features that determine the degree of helix axial rotation in four-helical homo-oligomeric antiparallel coiled coils. We designed 135,000 artificial sequences for a repertoire of backbone models representing all theoretically possible axial rotation states. Analysis of the designed sequences revealed features that precisely define the rotation of the helices. Based on these features we implemented a bioinformatic tool, which given a coiled-coil sequence, predicts the rotation of the helices in its structure. Moreover, we showed that another structural parameter, helix axial shift, is coupled to helix axial rotation and that dependence between these two parameters narrows the number of possible axial rotation states. PMID- 25278130 TI - Near-atomic resolution reconstructions using a mid-range electron microscope operated at 200 kV. AB - A new era has begun for single particle cryo-electron microscopy (cryoEM) which can now compete with X-ray crystallography for determination of protein structures. The development of direct detectors constitutes a revolution that has led to a wave of near-atomic resolution cryoEM reconstructions. However, regardless of the sample studied, virtually all high-resolution reconstructions reported to date have been achieved using high-end microscopes. We demonstrate that the new generation of direct detectors coupled to a widely used mid-range electron microscope also enables obtaining cryoEM maps of sufficient quality for de novo modeling of protein structures of different sizes and symmetries. We provide an outline of the strategy used to achieve a 3.7 A resolution reconstruction of Nudaurelia capensis omega virus and a 4.2 A resolution reconstruction of the Thermoplasma acidophilum T20S proteasome. PMID- 25278131 TI - One hand or the other? Effector selection biases in right and left handers. AB - Much debate in the handedness literature has centred on the relative merits of questionnaire-based measures assessing hand preference versus simple movement tasks such as peg moving or finger tapping, assessing hand performance. A third paradigm has grown in popularity, which assesses choices by participants when either hand could be used to execute movements. These newer measures may be useful in predicting possible "reversed" asymmetries in proportions of non-right handed ("adextral") people. In the current studies we examine hand choice in large samples of dextral (right handed) and adextral participants. Unlike in some previous experiments on choice, we found that left handers were as biased towards their dominant hand as were right handers, for grasping during a puzzle-making task (study 1). In a second study, participants had to point to either of two suddenly appearing targets with one hand or the other. In study 2, left handers were not significantly less one handed than their right-handed counterparts as in study 1. In a final study, we used random effects meta analysis to summarise the possible differences in hand choice between left handers and right handers across all hand choice studies published to date. The meta analysis suggests that right handers use their dominant hand 12.5% more than left handers favour their dominant hand (with 95% confidence that the real difference lies between 7% and 18%). These last results suggest that our two experiments reported here may represent statistical Type 2 errors. This mean difference may be related to greater left hemispheric language and praxic laterality in right handers. Nevertheless, more data are needed regarding the precise proportions of left and right handers who favour their preferred hands for different tasks. PMID- 25278133 TI - The cerebellum is not necessary for visually driven recalibration of hand proprioception. AB - Decades of research have implicated both cortical and subcortical areas, such as the cerebellum, as playing an important role in motor learning, and even more recently, in predicting the sensory consequences of movement. Still, it is unknown whether the cerebellum also plays a role in recalibrating sensory estimates of hand position following motor learning. To test this, we measured proprioceptive estimates of static hand position in 19 cerebellar patients with local ischemic lesions and 19 healthy controls, both before and after reach training with altered visual feedback of the hand. This altered visual feedback, (30 degrees cursor-rotation) was gradually introduced in order to facilitate reach adaptation in the patient group. We included two different types of training (in separate experiments): the typical visuomotor rotation training where participants had full volition of their hand movements when reaching with the cursor, and sensory exposure training where the direction of participants' hand movements were constrained and gradually deviated from the cursor motion (Cressman, E. K., Henriques, D. Y., 2010. Reach adaptation and proprioceptive recalibration following exposure to misaligned sensory input. J. Neurophysiol., vol. 103, pp. 1888-1895). We found that both healthy individuals and patients showed equivalent shifts in their felt hand position following both types of training. Likewise, as expected given that the cursor-rotation was introduced gradually, patients showed comparable reach aftereffects to those of controls in both types of training. The robust change in felt hand position across controls and cerebellar patients suggests that the cerebellum is not involved in proprioceptive recalibration of the hand. PMID- 25278132 TI - Counting or chunking? Mathematical and heuristic abilities in patients with corticobasal syndrome and posterior cortical atrophy. AB - A growing amount of empirical data is showing that the ability to manipulate quantities in a precise and efficient fashion is rooted in cognitive mechanisms devoted to specific aspects of numbers processing. The analog number system (ANS) has a reasonable representation of quantities up to about 4, and represents larger quantities on the basis of a numerical ratio between quantities. In order to represent the precise cardinality of a number, the ANS may be supported by external algorithms such as language, leading to a "precise number system". In the setting of limited language, other number-related systems can appear. For example the parallel individuation system (PIS) supports a "chunking mechanism" that clusters units of larger numerosities into smaller subsets. In the present study we investigated number processing in non-aphasic patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA), two neurodegenerative conditions that are associated with progressive parietal atrophy. The present study investigated these number systems in CBS and PCA by assessing the property of the ANS associated with smaller and larger numerosities, and the chunking property of the PIS. The results revealed that CBS/PCA patients are impaired in simple calculations (e.g., addition and subtraction) and that their performance strongly correlates with the size of the numbers involved in these calculations, revealing a clear magnitude effect. This magnitude effect was correlated with gray matter atrophy in parietal regions. Moreover, a numeral-dots transcoding task showed that CBS/PCA patients were able to take advantage of clustering in the spatial distribution of the dots of the array. The relative advantage associated with chunking compared to a random spatial distribution correlated with both parietal and prefrontal regions. These results shed light on the properties of systems for representing number knowledge in non-aphasic patients with CBS and PCA. PMID- 25278135 TI - Idiopathic infant pyocele: a case report and review of the literature. AB - BACKGROUND: Pyocele is a rare emergent urologic condition that requires rapid recognition and treatment to prevent testicular loss. Cases of pediatric pyocele have not been previously reported in the emergency medicine literature. CASE REPORT: We describe a case of a 6-week-old male who presented to the emergency department for a sepsis evaluation. The patient displayed subtle scrotal findings but had an otherwise benign physical examination. Subsequent sonographic imaging suggested a possible scrotal abscess and surgical exploration revealed a pyocele. A literature review of previously reported cases of patients with pyocele is also presented. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A pyocele is a rare cause of both an acute scrotum and neonatal fever. It is important for emergency physicians to consider this entity when evaluating pediatric patients with fever, particularly those with symptoms related to the scrotum. PMID- 25278134 TI - Hemispheric differences in orthographic and semantic processing as revealed by event-related potentials. AB - Differences in how the right and left hemispheres (RH, LH) apprehend visual words were examined using event-related potentials (ERPs) in a repetition paradigm with visual half-field (VF) presentation. In both hemispheres (RH/LVF, LH/RVF), initial presentation of items elicited similar and typical effects of orthographic neighborhood size, with larger N400s for orthographically regular items (words and pseudowords) than for irregular items (acronyms and meaningless illegal strings). However, hemispheric differences emerged on repetition effects. When items were repeated in the LH/RVF, orthographically regular items, relative to irregular items, elicited larger repetition effects on both the N250, a component reflecting processing at the level of visual form (orthography), and on the N400, which has been linked to semantic access. In contrast, in the RH/LVF, repetition effects were biased toward irregular items on the N250 and were similar in size across item types for the N400. The results suggest that processing in the LH is more strongly affected by wordform regularity than in the RH, either due to enhanced processing of familiar orthographic patterns or due to the fact that regular forms can be more readily mapped onto phonology. PMID- 25278136 TI - A comparison of accidental and nonaccidental trauma: it is worse than you think. AB - BACKGROUND: Child abuse, or nonaccidental trauma (NAT), is a major cause of pediatric morbidity and mortality, and is often unrecognized. Our hypothesis was that injuries due to accidental trauma (AT) and NAT are significantly different in incidence, injury, severity, and outcome, and are often unrecognized. OBJECTIVE: Our aim was to carry out an examination of the differences between pediatric injuries due to AT and NAT regarding incidence, demographics, injury severity, and outcomes. METHODS: A 4-year retrospective review of the Trauma Registry at Children's Medical Center Dallas, a large Level I pediatric trauma center, comparing incidence, age, race, trauma activation, intensive care unit (ICU) need, Injury Severity Score (ISS), and mortality between AT and NAT patients was carried out. RESULTS: There were 5948 admissions, 92.5% were AT and 7.5% were NAT victims. The NAT patients were younger (1.8 +/- 3.3 years vs. 6.8 +/- 4.2 years for AT patients; p < 0.01), more often required an ICU stay (NAT 36.5% vs. 13.8% for AT patients; p < 0.0001), and had a higher ISS 14.0 +/- 9.7 vs. 7.5 +/- 7.2; p < 0.0001). The mortality rate in NAT was 8.9% vs. 1.4% for AT (p < 0.001). Of the 40 NAT patients who ultimately died, 17.5% were not initially diagnosed as NAT. CONCLUSIONS: NAT victims differ significantly from the AT patients, with a greater severity of injury and a 6-fold higher mortality rate. Delayed recognition of NAT occurred in almost 20% of the cases. It is generally accepted that NAT is underestimated. Its increased mortality rate and severity of injury are also not well recognized compared to the typical pediatric trauma child. PMID- 25278137 TI - The "syringe" technique: a hands-free approach for the reduction of acute nontraumatic temporomandibular dislocations in the emergency department. AB - BACKGROUND: The traditional intraoral manual reduction of temporomandibular joint (TMJ) dislocations is time consuming, difficult, and at times ineffective, and commonly requires conscious sedation. OBJECTIVES: We describe a novel technique for the reduction of acute nontraumatic TMJ dislocations in the emergency department (ED). METHODS: This study was a prospective convenience sample population during a 3-year period at two university teaching-hospital EDs where acute nontraumatic TMJ dislocations were reduced utilizing our syringe technique. Demographics, mechanism, duration of dislocation, and reduction time were collected. Briefly, the "syringe" technique is a hands-free technique that requires a syringe to be placed between the posterior molars as they slide over the syringe to glide the anteriorly displaced condyle back into its normal anatomical position. Procedural sedation or intravenous analgesia is not required. RESULTS: Of the 31 patients, the mean age was 38 years. Thirty patients had a successful reduction (97%). The majority of dislocations were reduced in <1 min (77%). The two most common mechanisms for acute TMJ dislocations were due to chewing (n = 19; 61%) and yawning (n = 8; 29%). There were no recurrent dislocations at 3-day follow-up. CONCLUSION: We describe a novel technique for the reduction of the acutely nontraumatic TMJ dislocation in the ED. It is simple, fast, safe, and effective. PMID- 25278138 TI - Clinical features, risk factors, and treatment experience: a review of 74 patients with ST-segment elevation myocardial infarction complicated by ventricular fibrillation. AB - BACKGROUND: Ventricular fibrillation (VF) is one of the most serious complications of acute myocardial infarction, with a high mortality rate. There is a lack of value of rescue thrombolysis in ST-segment elevation myocardial infarction (STEMI) complicated by VF. OBJECTIVE: To examine the relationship between risk factors and mortality, and assess the value of rescue thrombolysis in STEMI complicated by VF. METHODS: A total 74 cases of STEMI complicated by VF were enrolled. The experimental group consisted of 26 patients who underwent rescue thrombolysis, and the control group included 48 cases without rescue thrombolysis. The two groups were compared in terms of demographic and clinical features including gender, age, onset time, blood pressure, patient's history, creatine kinase-MB, infarct area, complications, therapy, and outcomes, including mortality. RESULTS: The mortality rate of the experimental group was 15.38%, lower than 37.50% of the control group (p < 0.05). The bleeding rate was 34.62% (n = 9) in the experimental group. The risk factors of smoking, shock, and rescue thrombolysis were correlated with mortality of STEMI complicated by VF (p < 0.05 for all): Smoking and shock both were positively correlated with mortality, their regression coefficients/odds ratios (OR) were, respectively, 4606/100,041 and 5552/247,711; the rescue thrombolysis was negatively correlated with mortality, its regression coefficient/OR was -1942/0.143. CONCLUSIONS: Rescue thrombolysis combined with cardiopulmonary resuscitation and defibrillation is beneficial to patients with STEMI complicated by VF. Smoking, shock upon admission, and lack of rescue thrombolysis were risk factors for mortality in STEMI complicated by VF. PMID- 25278140 TI - Bovine tuberculosis: historical perspective. PMID- 25278139 TI - Comparison of therapeutic effects of magnesium sulfate vs. dexamethasone/metoclopramide on alleviating acute migraine headache. AB - BACKGROUND: There is controversy about the efficacy of currently used treatment modalities to alleviate migraine headaches. OBJECTIVE: We aimed to evaluate and compare the effects of magnesium sulfate and combined use of dexamethasone/metoclopramide on relieving acute migraine headache. METHODS: We randomly divided 70 patients who had been referred to an emergency department, into two equal treatment groups with the two treatment plans, and analyzed pain severity at baseline using a numeric rating scale (NRS). We gave dexamethasone/metoclopramide to one group and magnesium sulfate to the other group, and evaluated pain severity at 20 min and at 1- and 2-h intervals after infusion. Finally, we used repeated-measure and two-way analysis of variance for intra- and inter-group evaluations of pain severity and complications, respectively. RESULTS: We found no significant differences in demographic data and pain severity at baseline (8.2 vs. 8.0) between the two groups (p < 0.05). In the dexamethasone/metoclopramide group, pain severity (mean +/- standard deviation) was 7.4 +/- 1.4 (p = 0.36), 6.0 +/- 2.4, and 2.5 +/- 2.9 (p < 0.0001) at 20-min, 1-h, and 2-h intervals after treatment, respectively, with statistically significant differences between the baseline values and 1-h and 2-h interval values. Administration of magnesium sulfate was associated with decreased pain severity at the three intervals (5.2 +/- 1.7, 2.3 +/- 1.9, and 1.3 +/- 0.66, respectively), exhibiting significant differences compared to baseline values and the corresponding time intervals in the dexamethasone/metoclopramide group (p < 0.0001). CONCLUSIONS: According to the results, magnesium sulfate was a more effective and fast-acting medication compared to a combination of dexamethasone/metoclopramide for the treatment of acute migraine headaches. PMID- 25278141 TI - Hepatocyte growth factor-induced up-regulation of Twist drives epithelial mesenchymal transition in a canine mammary tumour cell line. AB - Epithelial-mesenchymal transition (EMT) is a crucial step in tumour progression. However, the molecular mechanisms underlying EMT in canine tumours remain to be elucidated. In this study, the similarity or difference in the molecular mechanism of EMT in canine cells was evaluated and compared with that reported in human and mouse cells. We used eight cell lines derived from canine mammary cancers. Stimulation with hepatocyte growth factor (HGF) increased cell motility and changed EMT-related markers towards mesenchyme in CHMm cell line. These changes were accompanied by an increase in Twist expression and did not occur in CHMm transfected with Twist siRNA, indicating that Twist plays a key role in this phenomenon in CHMm. However, the down-regulation of E-cadherin was not observed by HGF stimulation. Further studies are required to elucidate the difference between human and canine Twist. PMID- 25278142 TI - Anthelmintic efficacy of ivermectin and abamectin, administered orally for seven consecutive days (100 ug/kg/day), against nematodes in naturally infected pigs. AB - The present study aimed to evaluate ivermectin and abamectin, both administered orally in naturally infected domestic swine, as well as analysing if the EPG (eggs per gram of faeces) values were equivalent with the ivermectin and abamectin efficacy obtained by parasitological necropsies. The animals were randomly selected based on the average of three consecutive EPG counts of Strongylida, Ascaris suum and Trichuris for experiment I, and of Strongylida and Trichuris for experiment II. After the random draw, eight animals were treated, orally, during seven consecutive days with 100 ug/kg/day ivermectin (Ivermectina(r) premix, Ouro Fino Agronegocios), eight other animals were treated, orally, during seven consecutive days with 100 ug/kg/day abamectin (Virbamax(r) premix - Virbac do Brasil Industria e Comercio Ltda.), and eight pigs were kept as controls. EPG counts were performed for each individual animal at 14th day post-treatment (DPT). All animals (control and treatment) were necropsied at the 14th DPT. The results from both experiments demonstrate that both ivermectin and abamectin, administered orally for a continuous period of seven days, at a daily dosage of 100 ug/kg, were highly effective (>95%) against Hyostrongylus rubidus, Strongyloides ransomi, Ascaris suum and Metastrongylus salmi. Against Oesophagostomum dentatum, abamectin presented over 95% efficacy against both evaluated strains, while ivermectin reached other strain as resistant. Regarding T. suis, both ivermectin and abamectin were effective (efficacies >90%) against one of the tested strains, while the other one was classified as resistant. Furthermore, the EPG values were equivalent with the ivermectin and abamectin efficacy obtained by parasitological necropsies. PMID- 25278143 TI - Membrane proteins of arterivirus particles: structure, topology, processing and function. AB - Arteriviruses, such as equine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV), are important pathogens in veterinary medicine. Despite their limited genome size, arterivirus particles contain a multitude of membrane proteins, the Gp5/M and the Gp2/3/4 complex, the small and hydrophobic E protein and the ORF5a protein. Their function during virus entry and budding is understood only incompletely. We summarize current knowledge of their primary structure, membrane topology, (co-translational) processing and intracellular targeting to membranes of the exocytic pathway, which are the budding site. We profoundly describe experimental data that led to widely believed conceptions about the function of these proteins and also report new results about processing steps for each glycoprotein. Further, we depict the location and characteristics of epitopes in the membrane proteins since the late appearance of neutralizing antibodies may lead to persistence, a characteristic hallmark of arterivirus infection. Some molecular features of the arteriviral proteins are rare or even unique from a cell biological point of view, particularly the prevention of signal peptide cleavage by co-translational glycosylation, discovered in EAV-Gp3, and the efficient use of overlapping sequons for glycosylation. This article reviews the molecular mechanisms of these cellular processes. Based on this, we present hypotheses on the structure and variability of arteriviral membrane proteins and their role during virus entry and budding. PMID- 25278145 TI - Gallbladder dysfunction: how much longer will it be controversial? AB - BACKGROUND: Motility disorders of the biliary tree [biliary dyskinesia, including both gallbladder dysfunction (GBD), and sphincter of Oddi dysfunction] are difficult to diagnose and to treat. SUMMARY: There is controversy in the literature in particular regarding the criteria that should be used to select patients for cholecystectomy (CCY) in cases of suspected GBD. The current review covers the history, diagnosis, and treatment of GBD. Key Messages: Only >85% of patients with suspected GBD have relief following CCY, a much lower rate than the nearly 100% success rate following CCY for gallstone disease. Unfortunately, the literature is lacking, and there are no universally agreed-upon criteria for selecting which patients to refer for operation, although cholecystokinin (CCK) enhanced hepatobiliary iminodiacetic acid scan is often used, with emphasis on an abnormally low gallbladder ejection fraction or pain reproduction at CCK administration. There is a clear need for large, well-designed, more definitive, prospective studies to better identify the indications for and efficacy of CCY in cases of GBD. PMID- 25278144 TI - Coronavirus non-structural protein 16: evasion, attenuation, and possible treatments. AB - The recent emergence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), nearly a decade after the Severe Acute Respiratory Syndrome (SARS) CoV, highlights the importance of understanding and developing therapeutic treatment for current and emergent CoVs. This manuscript explores the role of NSP16, a 2'O methyl-transferase (2'O-MTase), in CoV infection and the host immune response. The review highlights conserved motifs, required interaction partners, as well as the attenuation of NSP16 mutants, and restoration of these mutants in specific immune knockouts. Importantly, the work also identifies a number of approaches to exploit this understanding for therapeutic treatment and the data clearly illustrate the importance of NSP16 2'O-MTase activity for CoV infection and pathogenesis. PMID- 25278146 TI - Patterns and correlates of non-fatal heroin overdose at 11-year follow-up: findings from the Australian Treatment Outcome Study. AB - BACKGROUND: Overdose is a major cause of morbidity and mortality amongst opioid users. This paper reported recent non-fatal overdose amongst the Australian Treatment Outcome Study (ATOS) cohort at 11-year follow-up, and characteristics that predict recent overdose. METHODS: Longitudinal cohort, with 431 (70.1%) of the original 615 participants interviewed. Participants were administered the ATOS structured interview, addressing demographics, treatment history, drug use, heroin overdose, criminality, health and psychopathology. FINDINGS: Mean time since heroin initiation was 20.4 years. By 11-year follow-up, the proportion who had overdosed was 67.5%, and 24.4% had experienced five or more overdoses. In the 12 months preceding 11-year follow-up, 4.9% had overdosed (11.8% of those who had used heroin in that period). Of the 21 participants who had recently overdosed, 20 (95.2%) had overdosed previously, and 19 (90.5%) were not enrolled in a treatment programme at the time. Those who had recently overdosed reported higher levels of use of opiates other than heroin (57.1% vs 24.9%), benzodiazepines (61.9% vs 30.5%,), methamphetamine (38.1% vs 16.8%) and cocaine (19.0% vs 3.7%). They also had exhibited higher levels of heroin use and other drug use at baseline, 12 and 24 month follow-ups. CONCLUSIONS: While the prevalence had declined, overdoses still occurred. A history of overdose and polydrug use patterns continued to provide strong markers for those at continued risk. PMID- 25278147 TI - Relationship between trait impulsivity and cortical volume, thickness and surface area in male cocaine users and non-drug using controls. AB - BACKGROUND: Trait impulsivity is commonly associated with cocaine dependence. The few studies that have investigated the relation between trait impulsivity and cortical morphometry, have shown a distinct relation between impulsivity and cortical volume (CV) of temporal, frontal and insula cortex. As CV is the function of cortical surface area (SA) and cortical thickness (CT) impulsivity may be differently associated to SA than to CT. METHOD: Fifty-three cocaine users (CU) and thirty-five controls (HC) (males aged 18-55 years) completed the Barrat impulsiveness scale and a structural scan was made on a 3T MRI scanner. CV, SA and CT were measured using Freesurfer. Multivariate analysis was used to test for group differences and group by impulsivity interaction effects in CV, SA and ST across nine regions of interest in the temporal, frontal and insular cortices. Possible confounding effects of drug- and alcohol exposure were explored. RESULTS: Compared to HC, CU had a smaller SA of the superior temporal cortex but a larger SA of the insula. There were divergent relations between trait impulsivity and SA of the superior temporal cortex and insula (positive in HC, negative in CU) and CT of the anterior cingulate cortex (negative in HC, positive in CU). Within CU, there was a negative association between monthly cocaine use and CT of the insula and superior temporal cortex. DISCUSSION: The distinct relation between trait impulsivity and cortical morphometry in CU and HC might underlie inefficient control over behavior resulting in maladaptive impulsive behaviour such as cocaine abuse. PMID- 25278149 TI - Delay in Diagnosis of Congenital Linear Scleroderma until Adulthood. AB - BACKGROUND: Scleroderma encompasses a spectrum of disorders characterized by thickening of the skin and subcutaneous tissue with increased collagen deposition. Linear scleroderma is subdivided into progressive hemifacial atrophy and en coup de sabre subtype. OBJECTIVE: We report a case of congenital linear scleroderma identified in an adult, misdiagnosed since birth as birth trauma. METHODS: We completed a review of the literature for similar cases using PubMed and Medline. RESULTS: This is the first report of congenital linear scleroderma en coup de sabre diagnosed in an adult following an initial misdiagnosis of birth trauma. The sequelae of linear scleroderma can be significant as it can result in growth retardation, muscle atrophy, contractures, limb length discrepancy, and disfigurement. CONCLUSIONS: This report emphasizes the importance of educating practitioners about linear scleroderma. Early recognition is key as a delay in diagnosis can result in potentially preventable, irreversible growth defects and disfigurements. PMID- 25278148 TI - Fluorescent hydrogels with tunable nanostructure and viscoelasticity for formaldehyde removal. AB - Hydrogels with ultrahigh water content, ~99 wt %, and highly excellent mechanical strength were prepared by 4'-para-phenylcarboxyl-2,2':6',2"-terpyridine (PPCT) in KOH aqueous solution. The self-assembled structure, rheological properties, and the gel-sol transformation temperature (Tgel-sol) of PPCT/KOH hydrogels that depend on PPCT and KOH concentrations were studied, indicating easily controllable conditions for producing hydrogels in PPCT and KOH mixtures. An important finding was that the hydration radius (Rh) of cations (M(+) = Li(+), Na(+), K(+), Cs(+), NH4(+), (CH3)4N(+), (CH3CH2)4N(+), (CH3CH2CH2)4N(+), (CH3CH2CH2CH2)4N(+)) plays a vital role in gelation of PPCT/MOH systems. To produce hydrogels in PPCT/MOH systems, the Rh of M(+) must be in a suitable region of 3.29 to 3.58 A, e.g., K(+), Na(+), Cs(+), and the capability of M(+) for inducing PPCT to form hydrogels is K(+) > Na(+) > Li(+), which is followed by the Hofmeister series. The hydrogels of PPCT and KOH mixtures are responsive to external stimuli including temperature and shearing force, and present gelation induced enhanced fluorescence emission property. The states of being sensitive to the stimuli can readily recover to the original hydrogels, which are envisaged to be an attracting candidate to produce self-healing materials. A typical function of the hydrogels of PPCT and KOH mixtures is that formaldehyde (HCHO) can speedily be adsorbed via electrostatic interaction and converted into nontoxic salts (HCOOK and CH3OK), making it a promising candidate material for HCHO removal in home furnishings to reduce indoor environmental pollutants. PMID- 25278150 TI - Hyalinizing trabecular tumor of thyroid: does frozen section prevent unnecessarily aggressive operation? Six new cases and a literature review. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) is very accurate in detecting papillary thyroid carcinomas (PTCs). According to the Bethesda system for reporting thyroid cytopathology, the risk for malignancy is 97-99% when FNAC is used to diagnose PTC; the malignancy risk is 60-75% when FNAC results in suspected PTCs. The presence of hyalinizing trabecular tumor (HTT) of the thyroid can cause misdiagnosis because its cytological features mimic PTCs. However, the use of frozen section analysis can assist in the recognition of unique architecture features of HTT, and thus may help prevent the undertaking of an unnecessarily aggressive operation. METHODS: We retrospectively reviewed all patients diagnosed with HTT by permanent histopathology from February 2009 to October 2013. After acquired agreement of the patients, we analyzed all data and reviewed another nine cases of HTT reported in the English-language medical literature to examine the efficacy of frozen section. RESULTS: There were six patients included in our research (5 women and 1 man), with an average age of 48.8 years. Using frozen section, four patients were diagnosed with HTT and two patients were misinterpreted as PTC. Consequently, four patients had lobectomy and two patients had total thyroidectomy, with no surgical complications. Of the nine cases of HTT reviewed from the English literature, the use of frozen section showed three HTT cases, three PTC cases, two medullary thyroid carcinoma cases, and one deferral case. Overall, the use of frozen section as a diagnostic method prevented additional surgical resection in eight patients (53%). CONCLUSION: Frozen section can sometimes but not always be used to diagnose HTT. When HTT is diagnosed by its trabecular pattern through the use of frozen section, it may prevent total thyroidectomy. PMID- 25278151 TI - The role of headache chronicity among predictors contributing to quality of life in patients with migraine: a hospital-based study. AB - BACKGROUND: Headache chronicity has been known to elicit deleterious effects on quality of life (QOL). We evaluated the contribution of headache chronicity to QOL in relation to clinical, psychiatric, and psychosocial variables in patients with migraine. METHODS: Subjects were recruited from a headache clinic and completed self-report questionnaires including the Migraine Disability Assessment (MIDAS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Migraine-Specific Quality of Life (MSQoL). We obtained predictors of MSQoL by multiple regression analyses. A path analysis model was constructed to analyze interrelationships between the variables. RESULTS: Among 251 eligible patients, 183 (72.9%) had episodic migraine (EM) and 68 (27.1%) had chronic migraine (CM). Patients with CM had more serious clinical, psychiatric, and poor QOL than did patients with EM. The strongest predictor of the MSQoL score in all patients with migraine was the BDI score (beta = -0.373, p < 0.001), followed by the MIDAS score (beta = -0.223, p < 0.001), female gender (beta = -0.192, p < 0.001), attack duration (beta = -0.159, p = 0.001), and headache chronicity (beta = 0.130, p = 0.012). Headache chronicity had a direct effect on the MSQoL score and exerted an indirect effect on the MSQoL score through the MIDAS and the BDI scores. CONCLUSIONS: Chronic migraine appears to impair QOL directly as well as indirectly by provoking disability and depression. PMID- 25278153 TI - Sexual dimorphism in immunity: improving our understanding of vaccine immune responses in men. AB - Weaker immune responses are often observed in males compared to females. Since female hormones have proinflammatory properties and androgens have potent immunomodulatory effects, this sexual dimorphism in the immune response seems to be hormone dependent. Despite our current knowledge about the effect of sex hormones on immune cells, definition of the factors driving the sex differences in immunoclinical outcomes, such as the diminished response to infection and vaccination observed in men or the higher rates of autoimmunity observed in females, remains elusive. Recently, systems approaches to immune function have started to suggest a way toward establishing this connection. Such studies promise to improve our understanding of the mechanisms underlying the sexual dimorphism observed in the human immune system. PMID- 25278154 TI - Impact of ionic liquid-type imidazolium surfactant addition on dynamic properties of BSA adsorption layers at different pH. AB - The dynamic interfacial properties of mixed solutions of bovine serum albumin (BSA) and the ionic liquid-type imidazolium surfactant ([C16mim]Br) were measured as a function of the interface age, surfactant concentration and solution pH. Three BSA conformers were investigated: the normal N form as well as the fast F and aged A forms, corresponding to the different solution pH, respectively. The interfacial tension and the interfacial dilational elasticity isotherms for the mixed adsorption layers indicate that the addition of [C16mim]Br to the different structures of BSA isomers influences the properties of the adsorption layer at the decane/water interface. The addition of [C16mim]Br does not influence the structure of the protein at pH below the isoelectric point of BSA, but at higher solution pH, the addition of surfactants significantly influences the dynamic interfacial properties of BSA solutions due to the electrostatic interaction between the components. PMID- 25278152 TI - Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. AB - Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy. PMID- 25278155 TI - Dosage-based parameters for characterization of puff dispersion results. AB - A set of parameters is introduced to characterize the dispersion of puff releases based on the measured dosage. These parameters are the dosage, peak concentration, arrival time, peak time, leaving time, ascent time, descent time and duration. Dimensionless numbers for the scaling of the parameters are derived from dimensional analysis. The dimensionless numbers are tested and confirmed based on a statistically representative wind tunnel dataset. The measurements were carried out in a 1:300 scale model of the Central Business District in Oklahoma City. Additionally, the effect of the release duration on the puff parameters is investigated. PMID- 25278156 TI - Selection and application of agricultural wastes as solid carbon sources and biofilm carriers in MBR. AB - This paper examined the feasibility of agricultural wastes used as solid carbon sources and the effect of determined agricultural wastes on improving denitrification. Eight agricultural wastes were evaluated in MBR tests to find out their carbon release capacity, denitrification potential, leaching elements and surface properties. The results showed that retinervus luffae fructus, wheat straw, corncob and rice straw had higher carbon release capacity with COD of 13.17-21.07 mg g(-1)day(-1), BOD5 of 3.33-7.33 mg g(-1)day(-1) and respirable carbon of 8.64-10.71 mg g(-1)day(-1). Correspondingly, they displayed a good denitrification potential of 105.3-140.1mg NO3(-)-Ng(-1). Rice straw, retinervus luffae fructus and corncob were then applied in MBRs. These three agricultural wastes were found to be effective in enhancing the denitrification process, where the TN removal increased from 43.44% (control MBR) to 82.34, 68.92 and 62.97%, respectively. PMID- 25278157 TI - Preparation of carbon microspheres decorated with silver nanoparticles and their ability to remove dyes from aqueous solution. AB - Solid, but not hollow or porous, carbon microspheres decorated with silver nanoparticles (AgNP-CMSs) were prepared from silver nitrate and CMSs by a redox reaction at room temperature. The CMSs and AgNP-CMSs were characterized using X ray diffraction, scanning electron microscopy, field emission scanning electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and UV-vis spectrophotometry. Though with non-high specific surface area, the AgNP-CMSs exhibited a high adsorption capacity toward methylene blue (MB) in an aqueous solution. The AgNP-CMSs were able to remove all the MB from a solution of 30 mg/L MB in water within 1 min when the adsorbent concentration was 0.12 g/L. The AgNP-CMSs also exhibited good adsorption and photocatalytic activity in the decomposition of aqueous Rhodamine B as well as MB under visible light. FTIR was used to examine the interaction between AgNP-CMSs and MB, and the spectrum and more extra experiments suggest ionic interactions between cationic dyes and the negatively charged groups can be formed but not the presence of abundant pi-pi conjugations between dye molecules and the aromatic rings. The origin of the photocatalytic activity of AgNP-CMSs was attributed to a surface plasmon resonance (SPR) effect of the silver nanoparticles on the CMSs. PMID- 25278158 TI - Coupling of OECD standardized test and immunomarkers to select the most environmentally benign ionic liquids option--towards an innovative "safety by design" approach. AB - This paper proposed a potential industrial accompaniment to reduce ionic liquid harmfulness by a novel combination of OECD Daphnia magna standardized test and fish immunomarkers. The combination of these two tests allowed multicriteria examination of ILs impacts in different organisms and trophic levels. The work provided new data for legislation and opened a door towards an integrative environmental evaluation due to direct implications of immune system in fish and ecosystem health. Whatever the species, each IL tested induced deleterious effects suggesting that toxic impact was especially due to IL lipophilicity properties. Nevertheless, cation moieties of ILs seemed to draw overall toxicity of ILs to significant extent as supported by lower cell mortality shown with imidazolium-based ILs compared to phosphonium-based ILs. However, the anions moieties have some additional effect, as revealed by quite dissimilar toxicity within same IL family. Concerning the more integrative biomarkers, the cationic based ILs tested possessed also dissimilar effect on immune system of fish, especially on leucocyte distribution, lysosomal membrane integrity and phagocytosis activity. These results confirm that ILs toxicity could be influenced by design and that chemical engineering processes can integrate ecological footprint reduction strategies for successful IL utilization in the future. PMID- 25278161 TI - Mass-transfer properties of insulin on core-shell and fully porous stationary phases. AB - The mass-transfer properties of three superficially-porous packing materials, with 2.6 and 3.6MUm particle and 1.9, 2.6, and 3.2MUm inner core diameter, respectively, were investigated and compared with those of fully porous packings with similar particle properties. Several sources of band spreading in the chromatographic bed have been identified and studied according to the general rate model of chromatography. Besides the axial dispersion in the stream of the mobile phase, and the external mass transfer resistance, the intraparticle diffusion was studied in depth. The first absolute and the second central moments of the peaks of human insulin, over a wide range of mobile phase velocities were measured and used for the calculation of the mass-transfer coefficients. The experimental data were also analyzed using the stochastic or molecular dynamic model of Giddings and Eyring. The dissimilarities of the mass-transfer observed in the different columns were identified and evaluated. PMID- 25278160 TI - Fat-mass and obesity-associated gene polymorphisms and weight gain after risperidone treatment in first episode schizophrenia. AB - BACKGROUND: Obesity induced by antipsychotics severely increases the risk of many diseases and significantly reduces quality of life. Genome Wide Association Studies has identified fat-mass and obesity-associated (FTO) gene associated with obesity. The relationship between the FTO gene and drug-induced obesity is unclear. METHOD: Two hundred and fifty drug naive, Chinese Han patients with first-episode schizophrenia were enrolled in the study, and genotyped for four single nucleotide polymorphisms (SNPs rs9939609, rs8050136, rs1421085 and rs9930506) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Body weight and body mass index (BMI) were measured at baseline and six months after risperidone treatment. RESULTS: At baseline, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609; body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p's < 0.05). After 6 months of risperidone treatment, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609 (p's <0.01); body weight and BMI of CC homozygotes were lower than those of A allele carriers in rs8050136 (p's < 0.05); body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p's < 0.05). After controlling for age, gender, age of illness onset, disease duration, weight at baseline and education, weight gain of TT homozygotes at 6 months remained to be lower than those of A allele carriers in rs9939609 (p < 0.01); weight gain of CC homozygotes at 6 months was lower than those of A allele carriers in rs8050136 (p = 0.01). Stepwise multiple regression analysis suggested that, among 4 SNPs, rs9939609 was the strongest predictor of weight gain after 6 months of risperidone treatment (p = 0.001). CONCLUSIONS: The FTO gene polymorphisms, especially rs9939609, seem to be related to weight gain after risperidone treatment in Chinese Han patients with first episode schizophrenia. PMID- 25278162 TI - Microextraction by packed sorbent and high performance liquid chromatography determination of seven non-steroidal anti-inflammatory drugs in human plasma and urine. AB - This paper reports a new MEPS-HPLC-PDA method for the simultaneous analysis of seven non-steroidal anti-inflammatory drugs (Furprofen, Indoprofen, Ketoprofen, Fenbufen, Flurbiprofen, Indomethacin, and Ibuprofen) in human plasma and urine. NSAIDs were resolved on a Gemini C18 column (4.6 mm * 250 mm; 5 MUm particle size) using a gradient elution mode with a run time of 25 min, comprising re equilibration, without further purification. The method was validated over the concentration range from 0.1 to 10 MUg/mL for all the analytes both in human plasma and urine, using Benzyl 4-hydroxybenzoate as the internal standards. This method was successfully tested to NSAIDs analyses in real matrices, in order to check the method potentiality and the correct response. The results from assay validations show that the method is selective, sensitive and robust. The limit of quantification of the method was 0.1 MUg/mL for all analytes, and weighted-matrix matched standard curves showed a good linearity up to 10 MUg/mL. In order to check the correct response for over-range samples, parallelism tests were also assessed. In the entire analytical range the intra and inter-day precision (RSD%) values were <= 7.31% and <= 13.5%, respectively. For all the analytes the intra and inter-day trueness (Bias%) values ranged from -11.3% to 10.2%. To our knowledge, this is the first MEPS-HPLC-PDA based method that uses MEPS procedure for simultaneous determination of these seven NSAIDs in plasma and urine samples. PMID- 25278163 TI - Assessment of Becton Dickinson Plain and Serum Separator Tubes in Measurement of 25-Hydroxyvitamin D3 (25OHD3) by HPLC and Immunoassay Methods. AB - BACKGROUND: The accuracy of 25-hydroxyvitamin D3 (25OHD3) measurement on specimens collected into serum separator tubes (SSTs) has been questioned because of possible interference by the gel. Possible interference was investigated in SSTs from Becton Dickinson (BD). DESIGN AND METHODS: Blood specimens were collected simultaneously from 50 normal subjects into plain tubes and SSTs. 25OHD3 was assayed on serum using high performance liquid chromatography (Chromsystems), and Architect (Abbott) and Liaison (Diasorin) immunoassays. RESULTS: There were no significant differences between 25OHD3 results (means +/- SE, nmol/l) obtained from specimens collected into plain tubes and SSTs assayed by HPLC (39.0 +/- 2.7 vs. 39.3 +/- 2.7), Liaison (32.9 +/- 2.2 vs. 32.8 +/- 2.3), or Architect (43.1 +/- 2.8 vs. 43.2 +/- 2.8). In specimens collected into plain tubes and SSTs, 25OHD3 measurements by HPLC correlated significantly (P < 0.0001) with those from the Architect (r = 0.895, r = 0.908) and Liaison (r = 0.907, r = 0.913), respectively. CONCLUSIONS: The gel in SSTs (BD) does not interfere with the measurement of 25OHD3 by HPLC or common immunoassays. This important finding may enable clinical laboratories to make cost savings by using SSTs without concerns about inaccuracy. PMID- 25278159 TI - Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999 2010. AB - The Collaborative Islet Transplant Registry (CITR) collects data on clinical islet isolations and transplants. This retrospective report analyzed 1017 islet isolation procedures performed for 537 recipients of allogeneic clinical islet transplantation in 1999-2010. This study describes changes in donor and islet isolation variables by era and factors associated with quantity and quality of final islet products. Donor body weight and BMI increased significantly over the period (p<0.001). Islet yield measures have improved with time including islet equivalent (IEQ)/particle ratio and IEQs infused. The average dose of islets infused significantly increased in the era of 2007-2010 when compared to 1999 2002 (445.4+/-156.8 vs. 421.3+/-155.4*0(3) IEQ; p<0.05). Islet purity and total number of beta cells significantly improved over the study period (p<0.01 and <0.05, respectively). Otherwise, the quality of clinical islets has remained consistently very high through this period, and differs substantially from nonclinical islets. In multivariate analysis of all recipient, donor and islet factors, and medical management factors, the only islet product characteristic that correlated with clinical outcomes was total IEQs infused. This analysis shows improvements in both quantity and some quality criteria of clinical islets produced over 1999-2010, and these parallel improvements in clinical outcomes over the same period. PMID- 25278164 TI - Controlling molecular conductance: switching off pi sites through protonation. AB - Conductance switching through chemical modification of a molecular bridge is a major goal in molecular electronics, with the potential to lead to molecule-based functional devices. In terms of switching speed, mechanisms that rely on only minor rearrangements of molecular structures are particularly promising. We demonstrate, based on density functional theory calculations combined with a coherent tunneling approach, how protonation and deprotonation of amine substituted or amine-bridged model molecular wires can switch off and on pi-sites and thus: a) remove or introduce interference features in the electron transmission, and b) decrease or increase coupling along a chain. This mechanism may also be relevant for interactions between molecular bridges and metal cations, for example, in sensor applications. PMID- 25278165 TI - Vitiligo Area Scoring Index and Vitiligo European Task Force assessment: reliable and responsive instruments to measure the degree of depigmentation in vitiligo. AB - BACKGROUND: Vitiligo is a common skin disorder causing depigmented macules that can impair a patient's quality of life. Currently, there are no standardized outcome measures to assess the degree of depigmentation. Moreover, there is limited knowledge on the measurement properties of outcome measures in vitiligo. OBJECTIVES: To assess the reliability and responsiveness of the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force assessment (VETFa), two well-described clinician-reported outcomes. METHODS: We included three vitiligo patient groups. In one group of 31 patients, the interobserver reliability was assessed by three observers. In 27 patients the intraobserver reliability was assessed by two repeated measures by one of the observers. To assess the responsiveness the repigmentation was calculated after 6 months of phototherapy in 33 patients and tested against hypotheses. RESULTS: The interobserver reliability was high for VASI [intraclass correlation coefficient (ICC) 0.93] and VETFa depigmentation (ICC 0.88). The intraobserver reliability was high for VASI (ICC 0.93) and VETFa depigmentation (ICC 0.97). The smallest detectable changes (SDCs) were 7.1% and 10.4% for interobserver reliability and 4.7% and 2.9% for intraobserver reliability in VASI and VETFa depigmentation, respectively. All four responsiveness hypotheses formulated a priori were confirmed. CONCLUSIONS: VASI and VETFa are reliable and responsive instruments to assess the degree of depigmentation in vitiligo. VASI and VETFa for depigmentation are potential instruments for vitiligo research in the future. However, for use in individual patient care, caution is needed when interpreting score changes in individual patients because of the relatively large SDC. PMID- 25278167 TI - The fifth dimension of innate immunity. AB - Innate immunity has evolved as a first line defense against invading pathogens. Cellular and humoral elements of the innate immune system detect infectious parasites, initiate inflammatory resistance reactions and finally contribute to the elimination of the invaders. Repeated attacks by pathogenic agents induce adaptive responses of the innate immune system. Typically, reapplication of pathogens provokes tolerance of the affected organism. However, also stimulatory effects of primary infections on subsequent innate immune responses have been observed. The present overview touches an undervalued aspect in the innate immune response: Its pronounced dependency on pathogen load. In addition to localization and timing of innate immune responses the pathogen dose dependency might be considered as a "fifth dimension of innate immunity". Experimental results and literature data are presented proposing a hormetic reaction pattern of innate immune cells depending on the dose of pathogens. PMID- 25278168 TI - The legacy of the Cartwright report: "lest it happen again". AB - The 1987 Cartwright Report into events at New Zealand's National Women's Hospital catalysed sweeping changes to promote and protect patients' rights. A generation on, it is comfortable to believe that such sustained and deliberate violations of patient rights "couldn't happen here" and "couldn't happen now." And yet, contemporary examples beg a different truth. Three of Cartwright's messages hold an enduring relevance for health practitioners and patients: the need for patients to be respected as people; to be supported to make informed choices; and to have their voices heard, even when they whisper. These challenges cannot be met in isolation from broader determinants of patients' rights and will require social, technological, and cultural change in order to prevent another "unfortunate experiment." PMID- 25278169 TI - In reply to Krabbe et al. PMID- 25278170 TI - HBsAg plasma level kinetics: a new role for an old marker as a therapy response predictor in vertically infected children on combination therapy. AB - We aimed to investigate the ability of HBsAg plasma level kinetics to predict therapy response by studying 23 children with infancy-acquired chronic hepatitis B (CHB) during combination sequential therapy with lead-in lamivudine (LAM) and add-on interferon-alpha (IFN-alpha) [5 responders (R = anti-HBs seroconversion) and 18 nonresponders (NR)] and to assess their relationship with pretreatment intrahepatic HBV-DNA and cccDNA and HBsAg and HBcAg liver expression. Plasma HBsAg levels were measured in samples before (treatment week 0 = TW0), during (TW9, TW28, TW52) and after (follow-up week = FUW24) therapy by Abbott ARCHITECT((r)) assay [log10 IU/mL]. Baseline liver HBV-DNA and cccDNA were quantified by real-time TaqMan PCR [log10 copies/ng genomic DNA]. HBsAg and HBcAg liver expression was evaluated by immunostaining of formalin-fixed, paraffin embedded specimens [number of positive cells/1000 hepatocytes]. All results are presented as medians. Plasma: at baseline, on-treatment and during follow-up, HBsAg levels were lower in R than NR (TW0: 4.36 vs 4.75;TW28: 2.44 vs 4.35;TW52: 0 vs 4.08 and FUW24: 0.17 vs 4.35, all P < 0.05). Liver: baseline HBV-DNA (3.82 vs 4.71, P = 0.16) and cccDNA (1.98 vs 2.26, P = 0.18) tended to be lower in R than NR, HBsAg expression was lower in R than NR (0.5 vs 4.7, P = 0.03), and HBcAg expression was similar between R and NR. There were positive correlations between plasma HBsAg levels and liver HBV-DNA (r = 0.44, P = 0.04), cccDNA (r = 0.41, P = 0.04) and HBsAg liver expression (r = 0.38, P = 0.05). Lower baseline HBsAg plasma levels, lower HBsAg expression in liver and on-treatment decline of plasma HBsAg levels heralds HBsAg clearance and response to treatment in tolerant children with CHB. PMID- 25278166 TI - BioAge: toward a multi-determined, mechanistic account of cognitive aging. AB - The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline. PMID- 25278171 TI - Five-year follow-up of a patient with bilateral carotid body tumors after unilateral surgical resection. AB - BACKGROUND: Carotid body tumors are rare, highly vascularized neoplasms that arise from the paraganglia located at the carotid bifurcation. Surgery is the only curative treatment. However, treatment of bilateral carotid body tumors represents a special challenge due to potential neurovascular complications. CASE REPORT: We present the therapeutic management of a 34-year-old woman with bilateral carotid body tumors. The patient underwent surgical resection of the largest tumor. It was not possible to resect the tumor without sacrificing the ipsilateral vagal nerve. Due to unilateral vagal palsy, we decide to withhold all invasive therapy and to observe contralateral tumor growth with serial imaging studies. The patient is free of disease progression 5 years later. CONCLUSIONS: Treatment of bilateral CBTs should focus on preservation of the quality of life rather than on cure of the disease. In patients with previous contralateral vagal palsies, the choice between surgery and watchful waiting is a balance between the natural potential morbidity and the predictable surgical morbidity. Therefore, to avoid bilateral cranial nerve deficits, these patients may be observed until tumor growth is determined, and, if needed, treated by radiation therapy. PMID- 25278172 TI - Economic evaluation of pharmacogenomics: a value-based approach to pragmatic decision making in the face of complexity. AB - Evidence of the value of pharmacogenomic testing is needed to inform policymakers and clinicians for decision making related to adoption and coverage, and to facilitate prioritization for research and development. Pharmacogenomics has an important role in creating a more efficient healthcare system, and this article addresses how economic evaluation can strategically target evidence gaps for public health priorities with examples from pharmacogenomic medicine. This article begins with a review of the need for and use of economic evaluations in value-based decision making for pharmacogenomic testing. Three important gaps are described with examples demonstrating how they can be addressed: (1) projected impact of hypothetical new technology, (2) pre-implementation assessment of a specific technology, and (3) post-implementation assessment from relevant analytical stakeholder perspectives. Additional needs, challenges and approaches specific to pharmacogenomic economic evaluation in the developing world are also identified. These pragmatic approaches can provide much needed evidence to support real-world value-based decision making for pharmacogenomic-based screening and treatment strategies. PMID- 25278173 TI - Single-source-precursor synthesis of dense SiC/HfC(x)N(1-x)-based ultrahigh temperature ceramic nanocomposites. AB - A novel single-source precursor was synthesized by the reaction of an allyl hydrido polycarbosilane (SMP10) and tetrakis(dimethylamido)hafnium(iv) (TDMAH) for the purpose of preparing dense monolithic SiC/HfC(x)N(1-x)-based ultrahigh temperature ceramic nanocomposites. The materials obtained at different stages of the synthesis process were characterized via Fourier transform infrared (FT-IR) as well as nuclear magnetic resonance (NMR) spectroscopy. The polymer-to-ceramic transformation was investigated by means of MAS NMR and FT-IR spectroscopy as well as thermogravimetric analysis (TGA) coupled with in situ mass spectrometry. Moreover, the microstructural evolution of the synthesized SiHfCN-based ceramics annealed at different temperatures ranging from 1300 degrees C to 1800 degrees C was characterized by elemental analysis, X-ray diffraction, Raman spectroscopy and transmission electron microscopy (TEM). Based on its high temperature behavior, the amorphous SiHfCN-based ceramic powder was used to prepare monolithic SiC/HfC(x)N(1-x)-based nanocomposites using the spark plasma sintering (SPS) technique. The results showed that dense monolithic SiC/HfC(x)N(1-x)-based nanocomposites with low open porosity (0.74 vol%) can be prepared successfully from single-source precursors. The average grain size of both HfC0.83N0.17 and SiC phases was found to be less than 100 nm after SPS processing owing to a unique microstructure: HfC0.83N0.17 grains were embedded homogeneously in a beta SiC matrix and encapsulated by in situ formed carbon layers which acted as a diffusion barrier to suppress grain growth. The segregated Hf-carbonitride grains significantly influenced the electrical conductivity of the SPS processed monolithic samples. While Hf-free polymer-derived SiC showed an electrical conductivity of ca. 1.8 S cm(-1), the electrical conductivity of the Hf containing material was analyzed to be ca. 136.2 S cm(-1). PMID- 25278174 TI - Administration of DHEA augments progesterone production in a woman with low ovarian reserve being transplanted with cryopreserved ovarian tissue. PMID- 25278175 TI - Targeted survival improvements in clinical trials: are you an absolutist or relativist? PMID- 25278176 TI - Azithromycin and other macrolides for prevention of bronchopulmonary dysplasia: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Ureaplasma spp. infection has been associated with bronchopulmonary dysplasia (BPD) in preterm infants. Macrolides have been used for the treatment of Ureaplasma spp. infection, with an intention to prevent BPD. The objective of this meta-analysis is to evaluate the use of macrolides in the prevention of BPD in preterm infants. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials, abstracts of the major pediatric society meetings and bibliographies of retrieved articles. We included randomized controlled trials assessing the effects of macrolides therapy on BPD in preterm infants. A random/fixed-effect model was used to synthesize predefined outcomes. RESULTS: Six studies involving 469 preterm infants were eligible for the analysis. Macrolides when used prophylactically (4 studies) did not show significant reduction in BPD (risk ratio, RR, 0.88, 95% confidence interval, CI, 0.75-1.03), death (RR 0.89, 95% CI 0.79-1.01) or in the composite outcome of BPD/death. Similarly, there was no significant reduction in BPD (RR 0.64, 95% CI 0.31-1.31) or the composite outcome of BPD/death (RR 0.41, 95% CI 0.05-3.13), when macrolides were used in Ureaplasma-positive infants. However, prophylactic azithromycin therapy (3 studies) was associated with significant reduction in BPD (RR 0.83, 95% CI 0.71-0.97; number needed to treat, NNT, 10) and composite outcome of BPD/death (RR 0.86, 95% CI 0.77-0.97; NNT 10). CONCLUSION: This meta analysis demonstrates prophylactic azithromycin therapy was associated with statistically significant reduction in BPD and the composite outcome of BPD/death in preterm infants. However, given the limited information on pharmacokinetics and potential harmful effects, further studies should be done before routine use of azithromycin in the neonatal population. PMID- 25278177 TI - Evaluation of toxic endpoints for a set of cosmetic ingredients with CAESAR models. AB - The randomly selected set of 558 chemicals from Cosmetic inventory was studied with internet accessible program package CAESAR. Four toxic endpoints were considered: mutagenicity, carcinogenicity, developmental toxicity and skin sensitization. The CAESAR program provides beside the predictions comprehensive information on applicability domain and the similarity between the considered compound and the compounds from model's training set. This information was used to implement for clustering and classification of chemicals. As the technique the Self Organizing Maps was applied. This technique also enables us to define to each cluster the cluster indicator, i.e., the characteristic compound, which is considered as a representative for a cluster. PMID- 25278178 TI - Investigation of fine chalk dust particles' chemical compositions and toxicities on alveolar macrophages in vitro. AB - The aim of the study is to investigate chemical compositions of fine chalk dust particles (chalk PM2.5) and examine their adverse effects on alveolar macrophages (AMs) in vitro. Morphologies and element concentrations of individual chalk particles were analyzed by using the quantitative energy-dispersive electron probe X-ray microanalysis (ED-EPMA). The oxidative response of AMs and the potential to generate nitric oxide (NO) by luminol-dependent chemiluminescence (CL) and nitrate reductase method were assessed 4h following the treatment of AMs with differing dosages of fine chalk particles, respectively. Oxidative stress and cytotoxicity elicited by chalk PM2.5 were also examined. The results showed that fine chalk particles were mainly composed of gypsum, calcite, dolomite and a little amount of organic adhesives. Exposure to chalk PM2.5 at 100 MUg mL(-1) or 300 MUg mL(-1) significantly increased intracellular catalase, malondialdehyde, and NO levels and decreased superoxide dismutase level in AMs, leading to leakage of lactate dehydrogenase (LDH) and reduction of the cell viability. Furthermore, luminol-dependent CL from respiratory burst in AMs was enhanced. It was suggested that chalk PM2.5 could make oxidative damages on AMs and result in cytotoxicity, being likely attributed to excessive reactive oxygen species or reactive nitrogen species induced by mixture of fine gypsum and calcite/dolomite particles. PMID- 25278179 TI - Energy-based modelling to assess effects of chemicals on Caenorhabditis elegans: a case study on uranium. AB - The ubiquitous free-living nematode Caenorhabditis elegans is a powerful animal model for measuring the evolutionary effects of pollutants which is increasingly used in (eco) toxicological studies. Indeed, toxicity tests with this nematode can provide in a few days data on the whole life cycle. These data can be analysed with mathematical tools such as toxicokinetic-toxicodynamic modelling approaches. In this study, we assessed how a chronic exposure to a radioactive heavy metal (uranium) affects the life-cycle of C. elegans using a mechanistic model. In order to achieve this, we exposed individuals to a range of seven concentrations of uranium. Growth and reproduction were followed daily. These data were analysed with a model for nematodes based on the Dynamic Energy Budget theory, able to handle a wide range of plausible biological parameters values. Parameter estimations were performed using a Bayesian framework. Our results showed that uranium affects the assimilation of energy from food with a no-effect concentration (NEC) of 0.42 mM U which would be the threshold for effects on both growth and reproduction. The sensitivity analysis showed that the main contributors to the model output were parameters linked to the feeding processes and the actual exposure concentration. This confirms that the real exposure concentration should be measured accurately and that the feeding parameters should not be fixed, but need to be reestimated during the parameter estimation process. PMID- 25278180 TI - Sinonasal squamous cell carcinoma and the prognostic implications of its histologic variants: a population-based study. AB - BACKGROUND: Variants of squamous cell carcinoma (SCC) make up 15% of all cases of SCC of the upper aerodigestive tract. There are 5 main histologic variants of SCC in the head and neck region: verrucous (VSCC), papillary (PSCC), spindle cell (sarcomatoid) (SCSC), basaloid (BSCC), and adenosquamous (ASC). Conventional sinonasal SCC has been studied extensively, but far less is known about its major variants. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to extract frequency and survival data from 1973 to 2009. A total of 4382 cases of conventional sinonasal SCC and 328 cases of its major variants were found. Statistical comparisons of data for sinonasal SCC and its variants were carried out with respect to varying demographic and disease specific parameters, such as gender, race, age at diagnosis, and specific anatomic site affected. RESULTS: Sinonasal BSCC was diagnosed at a significantly lower mean age than sinonasal SCC. Sinonasal SCSC significantly affected the maxillary sinus more commonly than SCC. In the setting of advanced stage disease, sinonasal VSCC, PSCC, and BSCC appear to be associated with a better prognosis than conventional sinonasal SCC, whereas the impact of histologic subtype on prognosis in early stage disease appears to be more limited. Survival for SCSC and ASC, both regarded as more lethal variants, was statistically similar to conventional SCC. CONCLUSION: Our study supports the practice of distinguishing between conventional sinonasal SCC and its major histologic variants, because histologic subtype appears to carry important prognostic implications. PMID- 25278181 TI - Comparisons of the chemical profiles, cytotoxicities and anti-inflammatory effects of raw and rice wine-processed Herba Siegesbeckiae. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Although slightly toxic, the Chinese medicinal herb Herba Siegesbeckiae (HS) has long been used as a remedy for traditional Chinese medicine symptoms that resemble inflammatory joint disorders, because it can eliminate the wind-dampness and soothe painful joints. Proper processing can reduce the toxicity and/or enhance the efficacy of raw herbs. In this study, we aim to examine if processing with rice wine reduces the cytotoxicities and/or enhances the anti-inflammatory effects of HS, and to explore the chemical basis behind the potential changes of medicinal properties caused by the processing. MATERIALS AND METHODS: We used cell models to examine the cytotoxicities and anti inflammatory effects of HS and rice wine-processed HS (WHS). The chemical profiles of HS and WHS were compared using the ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) analysis. RESULTS: We found that WHS was less toxic than HS in cultured cells as shown in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Both HS and WHS had anti-inflammatory effects as demonstrated by their abilities to reduce nitric oxide (NO) production as well as protein and mRNA expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effects of WHS were more potent than that of HS at the concentration of 100 MUg/mL. By comparing the chemical profiles, we found that 19 peaks were lower, while 2 other peaks were higher in WHS than in HS. Four compounds including neo-darutoside, darutoside, stigmasterol and 16-O acetyldarutoside corresponding to 4 individual changed peaks were tentatively identified by matching with empirical molecular formulae and mass fragments. CONCLUSION: Our study showed that processing with rice wine significantly reduced the cytotoxicities and enhanced the anti-inflammatory effects of HS as demonstrated in cell models. We also developed a UPLC/Q-TOF-MS method to clearly differentiate HS from WHS by their different chemical profiles. Further study is warranted to establish the relationship between the alteration of chemical profiles and the changes of medicinal properties caused by processing with rice wine. PMID- 25278182 TI - The Roman and Islamic spice trade: New archaeological evidence. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tropical spices have long been utilized in traditional medicine and cuisine. New archaeological evidence highlights temporal changes in the nature and scale of the ancient spice trade and in the ancient usage of these plants. Furthermore, a study of their 'materiality' highlights that the impact of spices extends beyond their material properties. Here the botanical remains of spices recovered from archaeological excavations at a port active in the Roman and medieval Islamic spice trade are evaluated. MATERIALS AND METHODS: Recent excavations at Quseir al-Qadim, an ancient port located on the Red Sea coast of Egypt, have provided new evidence for the spice trade. Due to the arid conditions ancient botanical remains were preserved in abundance and these included spices, as well as a wide range of other food plants. Quseir al Qadim was active as a transport hub during both the Roman and Islamic periods (ca. AD 1-250, known as Myos Hormos, and again during ca. AD 1050-1500, known as Kusayr), and the remains thus facilitate a study of temporal change in the trade and usage of these spices. Standard archaeobotanical methods were used to recover, identify and analyze these remains. RESULTS: At least seven tropical spices were recovered from the excavations, as well as several other tropical imports, including black pepper (Piper nigrum), ginger (Zingiber officinale), cardamom (Elettaria cardamomum), turmeric (Curcuma sp.), fagara (cf. Tetradium ruticarpum), myrobalan (Terminalia bellirica and Terminalia chebula) and betelnut (Areca catechu). A marked contrast between the two chronological periods in the range of spices recovered points to changes in the nature and scale of the trade between the Roman and medieval Islamic periods, while differences in the contexts from which they were recovered help to identify temporal changes in the way in which the spices were utilized during those periods. CONCLUSION: Archaeological and textual evidence suggest that in antiquity spices were used in ritual (funeral rites, offerings), in perfumery, and in medicinal remedies, with black pepper the only tropical spice regularly employed in cuisine. By the medieval period the culinary role of spices had grown significantly, both in the Middle East and in Europe, while retaining their importance in medicinal applications. In both time periods they were luxuries available only to the upper strata of society, but the material properties of spices and their elite status made them desirable to a wider section of society. In their pursuit of spices people became entangled in a meshwork of relationships, altered social realities and political power struggles. Globalization is one such entanglement, highlighting that the potency of spices goes far beyond their ability to stimulate our taste buds, delight our sense of smell and cure our ailments. PMID- 25278183 TI - Effects of combinations of Xiexin decoction constituents on diabetic nephropathy in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xiexin decoction (XXD) has been used as a treatment for diabetes mellitus for more than 1300 years. XXD constituents with protective effects against diabetic nephropathy (DN) include Rhizoma Coptidis alkaloids (RA), Radix et Rhizoma Rhei polysaccharides (RP), and Radix Scutellaria flavones (RF). The aim of the study is to investigate the effects of combinations of RA, RP, and RF on DN and their mechanisms of action. MATERIALS AND METHODS: In vitro, high glucose-induced rat mesangial cells were treated with RA, RP, RF, and combinations thereof. Cell proliferation and levels of inflammatory factors were measured. In vivo, high-fat diet and streptozotocin-induced diabetic rats were treated with different combinations of RA, RP, and RF once per day for 12 weeks. Blood and urine biochemical parameters, renal tissue morphology, and inflammation were investigated. RESULTS: In vitro, the combination of the three groups of components inhibited mesangial cell proliferation and reduced the levels of monocyte chemotactic protein-1 (MCP-1) and collagen IV. The effects of the three constituent groups in combination were stronger than those of each group alone or combinations of two groups. In diabetic rats, combinations of the three groups of herb components ameliorated blood glucose, urinary albumin excretion and decreased renal mesangial matrix expansion and basement membrane thickening. In addition, the combinations reduced renal tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) protein levels, down-regulated the expression of nuclear factor kappaB (NF-kappaB) and transforming growth factor beta 1 (TGF-beta1), and up-regulated the expression of inhibitor of nuclear factor kappaB (IkappaB) protein. Among the three groups of herb components, RA produced the strongest effects, followed by RP, and then by RF. CONCLUSIONS: The combination of the three groups of herb components produced anti-DN effects through inhibition of inflammation mediated by NF-kappaB. Among the three groups of herb components, RA produced the strongest effect while RP and RF produced weaker effects. PMID- 25278184 TI - Neolignans from Aristolochia elegans as antagonists of the neurotropic effect of scorpion venom. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The high frequency of poisoning by sting or bite from venomous animals has begun to be a serious public health problem in Mexico where scorpion sting is the most common. Because of this, there is the need to seek active substances in plant species with an antagonistic effect against neurotropic activity of scorpion venom. The aim of this work was to demonstrate which of the compounds contained in the n-hexane extract from Aristolochia elegans roots display activity against scorpion venom. MATERIAL AND METHODS: Antagonist activity displayed by extract, fractions and isolated compounds obtained from Aristolochia elegans was guided by the inhibition of smooth muscle contraction induced by scorpion venom (Centruroides limpidus limpidus) in a model of isolated guinea pig ileum. The neolignans obtained from this extract were isolated and analyzed by chromatographic methods including HPLC. The chemical characterization of these compounds was performed by the analysis of (1)H and (13)C NMR spectra. RESULTS: The bio-guided chromatographic fractionation allowed us to isolate 4 known neolignans: Eupomatenoid-7 (1), licarin A (2), licarin B (3), eupomatenoid-1 (4) and other new neolignan which was characterized as 2-(3' hydroxy-4'-methoxyphenyl)-3-methyl-5-[(E)-alpha-propen-gamma-al]-7-methoxy-benzo [b] furan (5). This compound was named as eleganal. Compounds 1 and 2 were purified from the most active fraction AeF3 (EC50 of 149.9MUg/mL, Emax of 65.66%). A doses-response analysis of eupomatenoid-7(1) and licarin A(2) allowed us to establish EC50 values (65.96MUg/mL and 51.96MUg/mL) respectively. CONCLUSIONS: The antagonistic effect against Centuroides limpidus limpidus scorpion venom displayed by the n-hexane extract from Aristolochia elegans roots is due to the presence of neolignans 1-2 contained in the fraction AeF3. Chemical analysis of fraction AeF2 allowed the isolation of a new compound which was identified as 2-(3'-hydroxy-4'-methoxyphenyl)-3-methyl-5-[(E)-alpha-propen-gamma al]-7-methoxy-benzo[b]furan (5), denominated as eleganal. PMID- 25278185 TI - Renal "hyperfiltrators" are at elevated risk of death and chronic diseases. AB - BACKGROUND: The definition of glomerular hyperfiltration has not been agreed upon and the pathophysiological mechanisms have not been well explored. Low serum creatinine concentrations may be associated with increased risk of coronary heart disease (CHD) or cardiopulmonary events the impact of which needs further study. METHODS: Consecutive applicants to a cardiovascular hospital free of moderate/severe chronic kidney disease (age 55.6 +/- 8.2 years) were grouped into those without ("healthy", n = 469) and with CHD (320 stable and acute coronary syndrome cases) at baseline and into sex-specific quartiles of CKD-EPI equation estimated glomerular filtration rate (eGFR). New or recurrent cardiovascular (myocardial infarction, stroke, heart failure [HF]) events, obstructive pulmonary disease (COPD) and death were determined during 3-years' follow-up. RESULTS: Among 25 deaths and 75 cardiopulmonary events, HF was the leading nonfatal event. Age, serum uric acid and left ventricular ejection fraction proved the best independent inverse covariates of eGFR in the "healthy" sample. The highest eGFR quartile ("hyperfiltrators"), exhibiting significantly lower serum LDL cholesterol levels, significantly predicted the combined outcome (at a RR of 6) in "healthy" subjects, after adjustment for sex, age, body mass index, smoking status and presence of hypertension. This finding was paralleled by the highest eGFR quartile calculated also by the MDRD equation, replicating this also in the CHD group. CONCLUSION: Renal "hyperfiltrators" represent individuals with autoimmune activation (involving serum creatinine, partly escaping assay), are misclassified into optimal renal function and actually are at significantly higher risk of death, HF or cardiopulmonary events. Low serum creatinine levels may represent a clue to the existence of autoimmune activation. PMID- 25278186 TI - You'll know when you're ready: a qualitative study exploring how patients decide when the time is right for joint replacement surgery. AB - BACKGROUND: While some studies have identified patient readiness as a key component in their decision whether to have total joint replacement surgery (TJR), none have examined how patients determine their readiness for surgery. The study purpose was to explore the concept of patient readiness and describe the factors patients consider when assessing their readiness for TJR. METHODS: Nine focus groups (4 pre-surgery, 5 post-surgery) were held in four Canadian cities. Participants had been either referred to or seen by an orthopaedic surgeon for TJR or had undergone TJR. The method of analysis was qualitative thematic analysis. RESULTS: There were 65 participants, 66% female and 34% male, 80% urban, with an average age of 65 years (SD 10). Readiness reflected both the surgeon's advice that the patient was clinically ready for surgery and the patient's feeling that they were both mentally and physically ready for surgery. Mental readiness was described as an internal state or feeling of being ready or prepared while physical readiness was described as being physically fit and in good shape for surgery. Factors associated with readiness included: 1) pain: its severity, the ability to cope with it, and how it affected their quality of life; 2) mental preparation; 3) physical preparation; 4) the optimal timing of surgery, including age, anticipated rate of deterioration, prosthesis lifespan and the length of the waiting list. CONCLUSIONS: Patient readiness should be assessed prior to TJR. By assessing patient readiness, health professionals can elucidate and deal with concerns and fears, understand and calibrate expectations, assess coping strategies, and use this information to help determine optimal timing, both before and after the surgical consultation. PMID- 25278187 TI - MicroSPECT/CT imaging of primary human AML engrafted into the bone marrow and spleen of NOD/SCID mice using 111In-DTPA-NLS-CSL360 radioimmunoconjugates recognizing the CD123+ / CD131- epitope expressed by leukemia stem cells. AB - Engraftment of primary human acute myeloid leukemia (AML) specimens into the bone marrow (BM) of NOD/SCID mice has been used to study leukemia biology and new treatments for the disease. CSL360 is a chimeric IgG1 monoclonal antibody that recognizes CD123 (IL-3 receptor alpha-subchain) expressed in the absence of CD131 (beta-subchain), an epitope that is displayed by leukemia stem cells (LSCs). We are studying CSL360 modified with diethylenetriaminepentaacetic acid (DTPA) for complexing 111In and 13-mer nuclear translocation sequence (NLS) peptides to enable nuclear importation in LSCs for Auger electron radioimmunotherapy (RIT) of AML. We demonstrate that microSPECT/CT imaging using 111In-DTPA-NLS-CSL360 revealed engraftment of primary human AML specimens into the BM and spleen of NOD/SCID mice. Our results suggest that microSPECT/CT imaging is a powerful tool which enables non-invasive assessment of the engraftment of AML into NOD/SCID mice and in the current study specifically probes an epitope displayed by the LSC subpopulation. The targeting of 111In-DTPA-NLS-CSL360 to sites of AML engraftment in the NOD/SCID mouse model is encouraging for future RIT studies. Ultimately, SPECT imaging could be applied in AML patients to assess the delivery of 111In DTPA-NLS-CSL360 to sites of leukemia and be combined with Auger electron RIT using the same agent targeting the LSC population as a "theranostic" pair. PMID- 25278188 TI - The crystal structure of paramagnetic copper(II) oxalate (CuC2O4): formation and thermal decomposition of randomly stacked anisotropic nano-sized crystallites. AB - Synthetic copper(II) oxalate, CuC2O4, was obtained in a precipitation reaction between a copper(II) solution and an aqueous solution of oxalic acid. The product was identified from its conventional X-ray powder patterns which match that of the copper mineral Moolooite reported to have the composition CuC2O4.0.44H2O. Time resolved in situ investigations of the thermal decomposition of copper(II) oxalate using synchrotron X-ray powder diffraction showed that in air the compound converts to Cu2O at 215 degrees C and oxidizes to CuO at 345 degrees C. Thermo gravimetric analysis performed in an inert Ar-gas reveals that the material contains no crystal water and reduces to pure Cu at 295 degrees C. Magnetic susceptibility measurements in the temperature range from 2 K to 300 K show intriguing paramagnetic behaviour with no sign of magnetic order down to 2 K. A crystal structure investigation is made based on powder diffraction data using one neutron diffraction pattern obtained at 5 K (lambda = 1.5949(1) A) combined with one conventional and two synchrotron X-ray diffraction patterns obtained at ambient temperature using lambda = 1.54056, 1.0981 and lambda = 0.50483(1) A, respectively. Based on the X-ray synchrotron data the resulting crystal structure is described in the monoclinic space group P21/c (#14) in the P121/n1 setting with unit cell parameters a = 5.9598(1) A, b = 5.6089(1) A, c = 5.1138 (1) A, beta = 115.320(1) degrees . The composition is CuC2O4 with atomic coordinates determined by FullProf refinement of the neutron diffraction data. The crystal structure consists of a random stacking of CuC2O4 micro-crystallites where half the Cu-atoms are placed at (2a) and the other half at (2b) positions with the corresponding oxalate molecules centred around the corresponding (2b) and (2a) site positions, respectively. The diffraction patterns obtained for both kinds of radiation show considerable broadening of several Bragg peaks caused by highly anisotropic microstructural size and strain effects. In contrast to the water reported to be present in Moolooite, neither thermogravimetric nor the in situ thermal decomposition investigations and crystal structure analysis of the neutron diffraction data revealed any trace of water. An appendix contains details about the profile parameters for the diffractometers used at the European Synchrotron Radiation Facility and the Institute Max von Laue-Paul Langevin. PMID- 25278189 TI - Determining auditory-evoked activities from multiple cells in layer 1 of the dorsal cortex of the inferior colliculus of mice by in vivo calcium imaging. AB - Layer 1 of the dorsal cortex of the inferior colliculus (DCIC) is distinguished from other layers by its cytoarchitecture and fiber connections. However, the information of the sound types represented in layer 1 of the DCIC remains unclear because placing electrodes on such thin structures is challenging. In this study, we utilized in vivo calcium imaging to assess auditory-evoked activities in multiple cells in layer 1 of DCIC and to characterize sound stimuli producing strong activity. Most cells examined showed strong responses to broad-band noise and low-frequency tone bursts of high sound intensity. In some cases, we successfully obtained frequency response areas, which are receptive fields to tone frequencies and intensities, and ~30% of these showed V-shape tunings. This is the first systematic study to record auditory responses of cells in layer 1 of DCIC. These results indicate that cells in this area are selective to tones with low frequency, implying the importance of such auditory information in the neural circuitry of layer 1 of DCIC. PMID- 25278191 TI - Influences of frailty syndrome on open-loop and closed-loop postural control strategy. AB - BACKGROUND: As the population of older adults quickly increases, the incidence of frailty syndrome, a reduction in physiological reserve across multiple physiological systems, likewise increases. To date, impaired balance has been associated with frailty; however, the underlying frailty-related postural balance mechanisms remain unclear. OBJECTIVE: The aim of the current study was to use open-loop (OL; postural muscles) and closed-loop (CL; postural muscles plus sensory feedback) mechanisms to explore differences in postural balance mechanisms between nonfrail (n = 44), prefrail (n = 59) and frail individuals (n = 19). METHODS: One hundred and twenty-two older adults (age >=65 years) without major mobility disorders were recruited, and frailty was measured using Fried's criteria. Each participant performed two 15-second trials of Romberg balance assessment, once with their eyes open and once with their eyes closed. Body-worn sensors were used to estimate center of gravity (COG) plots. Body-sway (traditional stabilogram analysis) and OLCL (stabilogram diffusion analysis) parameters were derived using COG plots and compared between groups using ANOVA. Frailty and prefrailty were estimated using a multiple variable logistic regression while controlling for age, body mass index, body-sway and OLCL parameters. RESULTS: Between-group differences in the parameters of interest were more pronounced during the eyes-closed condition, for which OL duration was approximately 33 and 22% shorter, respectively, in the frail and prefrail groups when compared to nonfrail controls (mean = 1.9 +/- 1.1 s, p = 0.01). The average rate of sway during the OL was 164 and 66% higher, respectively, in frail and prefrail when compared to nonfrail subjects (0.03 +/- 0.02 cm(2)/s, p < 0.001). RESULTS also suggest that OLCL parameters can predict frail and prefrail categories when compared to nonfrail controls. Using this method, frailty was identified with a sensitivity and specificity of 97 and 88% (as compared to nonfrail), and prefrailty with 82 and 92%, respectively. CONCLUSIONS: This study suggested an innovative method to differentiate between frailty status using sensory dependency characteristics of postural control. RESULTS suggest that postural muscle deconditioning may compromise balance in frail elders, leading to dependency on somatosensory feedback to compensate for errors and stabilize the system. PMID- 25278192 TI - Forensics as a proactive science. PMID- 25278190 TI - Mu-opioid receptor (MOR) expression in the human spiral ganglia. AB - Opioid peptides and their receptors have been localized to the inner ear of the rat and guinea pig mammalian models. The expression of mu opioid receptor (MOR) in the human and mouse cochlea is not yet known. We present MOR protein localization by immunohistochemistry and mRNA expression by in situ hybridization in the human and mouse spiral ganglia (SG) and organ of Corti. In the human most of the (SG) neurons were immunoreactive; a subset was non-immunoreactive. In situ hybridization revealed a similar labeling pattern across the neurons of the SG. A similar distribution MOR pattern was demonstrated in the mouse SG. In the mouse organ of Corti MOR was expressed in inner and outer hair cells. Fibers underneath the inner hair cells were also MOR immunoreactive. These results are consistent with a role of MOR in neuromodulation of the auditory periphery. The present results show that the expression of MORs is well-conserved across multiple mammalian species, indicative of an important role in auditory processing. PMID- 25278193 TI - The role of isotope ratio mass spectrometry as a tool for the comparison of physical evidence. AB - This paper considers how likelihood ratios can be derived for a combination of physical, chemical and isotopic measurements. Likelihood ratios were formulated based on the characteristics of a small convenience sample of 20 duct tapes. The propositions considered were: The physical and isotopic characteristics of ten rolls of duct tape were shown to be consistent throughout each roll. The width and thickness of the tapes and the density of the scrim fibres provided equivalent information and the combined physical characteristics provided a basis upon which to discriminate between many of the samples. Scatter-plots and confidence ellipses provided a convenient method to group the isotopic composition of the tape backing material and provided a basis to discriminate between samples which were physically indistinguishable. Considering both the physical and isotopic characteristics it was possible, at best, to ascertain that the evidence provided moderately strong support for the proposition that two samples of tape were derived from the same batch (LR=400). Kernel density estimates were used to model the distribution of isotopic compositions of the backing material. Using this technique it was possible to estimate objectively the probability that a sample with given characteristics could be drawn, at random, from the background population and to calculate a likelihood ratio based on the propositions above. The strength of evidence which could be presented by either model was ultimately limited by the size of the background sample. PMID- 25278194 TI - Geographical variation of shoeprint comparison class correspondences. AB - The underlying principles involved in the interpretation of shoeprint comparisons have become a topical subject due to criticisms in the 2009 National Academy of Science (NAS) report on forensic sciences[1]. Difficulties in the application and understanding of these principles were also highlighted in a recent court ruling [2-5] and subsequent discussion of the ruling. We report here a survey that may inform some aspects of this interpretation and discuss the implications of findings from this survey in the light of that court ruling and more importantly the NAS report. 1,511 shoeprints were taken from student volunteers in Auckland, Wellington and Dunedin, New Zealand. 500 shoeprints were sampled from student volunteers at Australian universities. 100 from each of the University of Technology in Sydney, University of Queensland in Brisbane, University of Newcastle, Charles Sturt University in Bathurst and University of Canberra, Australia. These cities are distributed along the east coast of Australia. The shoeprints, taken from each country, were compared against each other for the presence of any pattern correspondences However shoeprints have not been compared between countries. In all locations the pattern of some common and many rare outsole patterns was repeated, with Converse Chuck Taylor All Stars and Vans Canvas Era common in all locations. PMID- 25278195 TI - Monitoring substance use in prisons: Assessing the potential value of wastewater analysis. AB - Prison substance use is a major concern for prison authorities and the wider community. Australia has responded to this problem by implementing the National Corrections Drug Strategy. Across Australia, the true extent of prison substance use cannot be determined. As a result, the effectiveness of the interventions employed as part of this strategy cannot be properly assessed. This has important implications for the allocation of corrective services resources and future policy development. This article explores the benefits and limitations, as well as the ethical and practical issues in using wastewater analysis (WWA) to measure levels of substance use in prisons. It reports results from the first application of WWA to an Australian prison, which supports the use of WWA in this context. Given the increasing concern for prescription misuse in prisons, we also highlight the novel use of WWA to measure the extent of prescription misuse by prisoners. The article concludes that as a result of its objectivity, sensitivity and cost-effectiveness, the use of WWA in prisons warrants further consideration in Australia. PMID- 25278197 TI - Parallel artificial membrane permeability assay for blood-brain permeability determination of illicit drugs and synthetic analogues. AB - With the number of designer drugs on the streets rampantly on the rise, it's becoming more and more important to be able to rapidly characterize them in a biologically relevant way. Using a parallel artificial membrane permeability assay (PAMPA) to assess the blood brain barrier permeability has shown to be a high throughput way to compare new drugs with currently controlled substances via their effective permeability values. This combined with direct infusion electrospray ionization-mass spectrometry creates a rapid technique for characterization of new designer drugs. PAMPA has successfully determined the effective permeabilities of cocaine, methamphetamine, heroin, MDMA, and several tryptamine derivatives. PMID- 25278196 TI - A model study into the effects of light and temperature on the degradation of fingerprint constituents. AB - Determining the order of events in a criminal investigation can be crucial in many ways. Although the use of fingermarks is one of the most important forensic tools as a modality of individualisation, placing them in time is a long lasting difficulty. In the study presented in this paper we describe the effects of light and the temperature on depositions of standard solutions containing squalene and cholesterol on paper. The results obtained give a clear view on what type of processes take place during a temperature and a light influenced degradation of the two materials in this study. Using well known methods for the determination of reaction constants it was determined that the degradation mechanism of cholesterol is following a radical route, where the decay of squalene is more affected by temperature. PMID- 25278198 TI - Immunolabeling and the compatibility with a variety of fingermark development techniques. AB - Much information can be obtained from the chemical composition of a fingermark, which can be helpful in crime scene investigation. Immunolabeling can be used to extract information about the donor of the fingermark and it can also act as a fingermark development tool in sequence with the standard fingermark development techniques. However, before immunolabeling can be used in forensic practice more information on the possibilities and limitations of this technique is required. In this study, our aim was to investigate if immunolabeling is compatible with standard development protocols (indanedione-zinc, indanedione-zinc followed by ninhydrin spraying, physical developer, cyanoacrylate fuming, cyanoacrylate followed by basic yellow staining, lumicyanoacrylate fuming and polycyanoacrylate fuming). Immunolabeling was carried out successfully on all developed fingermarks, whereby dermcidin was selected as antigen of interest. We can conclude that immunolabeling is compatible with a wide variety of different fingermark developers. This finding in combination with previous findings, makes immunolabeling an interesting technique, which can be of great value in the forensic field. PMID- 25278199 TI - Selecting relevant Fourier transform infrared spectroscopy wavenumbers for clustering authentic and counterfeit drug samples. AB - This paper proposes a novel method for selecting subsets of wavenumbers provided by attenuated total reflectance by Fourier transform infrared (ATR-FTIR) spectroscopy able to improve the clustering of medicine samples into two groups; i.e., authentic or fraudulent. For that matter, we apply principal components analysis (PCA) to ATR-FTIR data, and derive two variable importance indices from the PCA parameters. Next, an iterative variable (i.e. wavenumbers) elimination procedure and sample clustering through k-means and Fuzzy C-means techniques are carried out; clustering performance is assessed by the Silhouette Index (SI). The performance of the proposed method is compared with a greedy variable selection method, the "leave one variable out at a time" approach, in terms of clustering quality, percent of retained variables, and computational time. When applied to Viagra ATR-FTIR data, our propositions increased the average SI from 0.5307 to 0.8603 using 0.61% of the original 661 wavenumbers; as for Cialis ATR-FTIR data, clustering quality increased from 0.7548 to 0.8681 when 1.21% of the original wavenumbers were retained in the procedure. The retained wavenumbers, located in the 1091-1046cm(-1) region, comprise the lactose typically hailed as key substance to discriminate between authentic and counterfeit samples. PMID- 25278200 TI - Retrospective study of the impact of miniSTRs on forensic DNA profiling of touch DNA samples. AB - The theoretical advantages of miniSTRs are undeniable. Several studies show that miniSTRs are more sensitive and robust in the analysis of low template and degraded DNA. In this study we want to show the overall benefit of using miniSTRs in real forensic casework samples and show the percentage of samples that benefit from analysis with additional miniSTR loci in terms of resulting in a useful profile. The considered samples were 3064 touch DNA samples, analyzed in our accredited routine forensic DNA profiling laboratory between mid 2009 and mid 2013. Of these 3064 samples, 618 samples were analyzed using 13 loci, 532 samples using 15 loci and 1914 samples using 20 loci of which 5 were the mini- and midi STR loci that were added to the extended European Standard Set (ESS). The retrospective results show a small increased success rate after implementation of extra loci and an even smaller increase after the implementation of the mini- and midi-STR analysis. The percentage of touch DNA samples that benefit from the analysis of additional mini- and midi-STR loci is limited. PMID- 25278201 TI - Is it to the advantage of a defendant to infer a greater number of contributors to a questioned sample than is necessary to explain the observed DNA profile? AB - When a forensic scientist presents the results of a comparison between a DNA profile from a questioned sample with that of a defendant the interpretation will be based on the premise of a given number of contributors. It is quite common practice for defence counsel to ask how consideration of a greater number of putative contributors to the profile would affect the interpretation. This note discusses the response to such a request. PMID- 25278202 TI - Experimental results of fingerprint comparison validity and reliability: A review and critical analysis. AB - Our purpose in this article is to determine whether the results of the published experiments on the accuracy and reliability of fingerprint comparison can be generalized to fingerprint laboratory casework, and/or to document the error rate of the Analysis-Comparison-Evaluation (ACE) method. We review the existing 13 published experiments on fingerprint comparison accuracy and reliability. These studies comprise the entire corpus of experimental research published on the accuracy of fingerprint comparisons since criminal courts first admitted forensic fingerprint evidence about 120years ago. We start with the two studies by Ulery, Hicklin, Buscaglia and Roberts (2011, 2012), because they are recent, large, designed specifically to provide estimates of the accuracy and reliability of fingerprint comparisons, and to respond to the criticisms cited in the National Academy of Sciences Report (2009). Following the two Ulery et al. studies, we review and evaluate the other eleven experiments, considering problems that are unique to each. We then evaluate the 13 experiments for the problems common to all or most of them, especially with respect to the generalizability of their results to laboratory casework. Overall, we conclude that the experimental designs employed deviated from casework procedures in critical ways that preclude generalization of the results to casework. The experiments asked examiner subjects to carry out their comparisons using different responses from those employed in casework; the experiments presented the comparisons in formats that differed from casework; the experiments enlisted highly trained examiners as experimental subjects rather than subjects drawn randomly from among all fingerprint examiners; the experiments did not use fingerprint test items known to be comparable in type and especially in difficulty to those encountered in casework; and the experiments did not require examiners to use the ACE method, nor was that method defined, controlled, or tested in these experiments. Until there is significant progress in defining and measuring the difficulty of fingerprint test materials, and until the steps to be followed in the ACE method are defined and measurable, we conclude that new experiments patterned on these existing experiments cannot inform the fingerprint profession or the courts about casework accuracy and errors. PMID- 25278203 TI - In response to Haber and Haber, "Experimental results of fingerprint comparison validity and reliability: A review and critical analysis". PMID- 25278204 TI - Generalization in fingerprint matching experiments. PMID- 25278205 TI - A comment on experimental results of fingerprint comparison validity and reliability: A review and critical analysis. AB - We respond to the article "Experimental results of fingerprint comparison validity and reliability: A review and critical analysis" by Ralph and Lyn Haber which offers (a) a one-sided criticism of the state of affairs in latent print examination, (b) lack of original data supporting that their suggested approach, and (c) a host of incorrect statements, inaccuracies, or obscure interpretations of the existing data. PMID- 25278206 TI - Can fingerprint casework accuracy be evaluated by experiments? PMID- 25278207 TI - The interaction of stress and urgency urinary incontinence and its effect on quality of life. AB - INTRODUCTION AND HYPOTHESIS: The objective was to estimate the impact of stress and urgency urinary incontinence (UI) on the quality of life (QOL), and to determine whether the impact varies according to UI severity. METHODS: We used data from the General Longitudinal Overactive Bladder Evaluation-UI study in women. Stress and urgency UI symptom severity scores ranged from 0 to 8. We used logistic regression to test the relation among different severity levels of stress and urgency UI, and their interaction with the Incontinence Impact Questionnaire (IIQ-7). This was categorized according to percentage ranges as 0 40% (reference), 41-80%, and 81-100%. RESULTS: Both stress and urgency UI were significantly associated with IIQ-7. Higher scores had higher odds ratios (ORs). The OR for urgency vs stress UI was greater at the same severity level. For instance, comparing IIQ-7 quintiles (0-40% vs 41-80%), the OR for an association with an urgency UI score of 5-6 was 5.27 (95% CI = 3.78-7.33) vs 2.76 (95% CI = 2.07-3.68) for a stress UI score of 5-6. Both UI subtypes were more strongly related to the upper (81-100%) than the to the lower (41-80%) quintiles. There was a strong positive urgency UI and stress UI interaction with the upper (i.e., 81-100%) but not the two next lower (41-80%) quintiles. CONCLUSION: The impact of UI subtypes on QOL varies according to the score of IIQ-7, stress and urgency UI, and their interaction. Urgency vs stress UI has a stronger impact. The effect is greatest for high IIQ-7 scores with a significant share mediated by the interaction of the two UI subtypes. PMID- 25278208 TI - Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12): psychometric validation of the Iranian version. AB - INTRODUCTION AND HYPOTHESIS: Sexual health is an important aspect of women's health. Women with urinary incontinence (UI) and pelvic organ prolapse (POP) have more complaints about sexual dysfunctions than do women without. In Iran, there is no questionnaire to assess sexual function in women who with UI; thus, this study aimed to translate the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) and provide evidence for psychometric properties. METHODS: This cross-sectional study was conducted from April 2012 to October 2012 in a sample of women who attended an urogynecology clinic. Participants were divided into two groups (incontinent with or without POP and normal). All types of UI were assessed. The PISQ-12 was translated into Iranian based on international standards, and its reliability was assessed using test/retest reliability and internal consistency. In addition, its validity was evaluated using face and content validity, comparison with known groups, and convergent validity. Both exploratory and confirmatory factor analyses were conducted. RESULTS: Mean participant age was 47.52 years. Cronbach's alpha coefficient was 0.84 for PISQ-12 and 0.70-0.79 for all domains. Pearson's correlation coefficient between PISQ-12 and the Female Sexual Function Index (FSFI) was 0.73. Exploratory factor analysis loaded three factors; confirmatory factor analysis confirmed factor structures. DISCUSSION: This study showed that the Iranian version of PISQ 12 was a short, useful, valid, reliable, and condition-specific instrument to assess sexual function in women with UI/POP. PMID- 25278209 TI - Deep sequencing of HetR-bound DNA reveals novel HetR targets in Anabaena sp. strain PCC7120. AB - BACKGROUND: Anabaena (also Nostoc) sp. strain PCC7120, hereafter Anabaena, is a cyanobacterium that fixes atmospheric N2 in specialized cells called heterocysts. Heterocyst differentiation is regulated by a homodimeric transcription factor, HetR. HetR is expressed at a basal level in all cells but its expression increases in differentiating cells early after nitrogen deprivation. HetR is required for heterocyst development, and therefore nitrogen fixation and diazotrophic growth. Overexpression of HetR leads to multiple contiguous heterocysts (Mch phenotype). HetR binds in vitro to DNA fragments upstream of several genes upregulated in heterocysts, including hetZ, hetP, hepA, patS, pknE, and hetR itself. HetR binds an inverted repeat sequence upstream of a few of these genes; however, HetR binds to promoters that do not contain this sequence, such as the promoter regions for patS and pknE. RESULTS: We employed chromatin pull-down and deep sequencing (ChIP-seq) to globally identify HetR DNA targets in vivo at six hours after fixed-nitrogen deprivation. We identified novel DNA binding targets of tagged HetR-6xHis and defined a consensus HetR binding site from these HetR target sequences. Promoter-gfp reporter fusions were used to determine the spatiotemporal expression of four potential HetR-target genes. The promoter region for asr1469 was expressed transiently in differentiating heterocysts, alr3758 was upregulated in heterocysts, asl2028 was expressed in vegetative cells, and alr2242 was derepressed in vegetative cells of a hetR mutant strain. CONCLUSIONS: In addition to identifying known HetR target genes hetR and hetP, the ChIP-seq data were used to identify new potential HetR targets and to define a consensus HetR-binding site. The in vivo ChIP-seq analysis of HetR's regulon suggests a possible role for HetR in vegetative cells in addition to its role in heterocyst development. The potential HetR target genes identified in this study provide new subjects for future work on the role of HetR in gene regulation. PMID- 25278210 TI - rs11613352 polymorphism (TT genotype) associates with a decrease of triglycerides and an increase of HDL in familial hypercholesterolemia patients. AB - INTRODUCTION AND OBJECTIVES: Recent genome-wide association studies have identified a locus on chromosome 12q13.3 associated with plasma levels of triglyceride and high-density lipoprotein cholesterol, with rs11613352 being the lead single nucleotide polymorphism in this genome-wide association study locus. The aim of the study is to investigate the involvement of rs11613352 in a population with high cardiovascular risk due to familial hypercholesterolemia. METHODS: The single nucleotide polymorphism was genotyped by Taqman((r)) assay in a cohort of 601 unrelated familial hypercholesterolemia patients and its association with plasma triglyceride and high-density lipoprotein cholesterol levels was analyzed by multivariate methods based on linear regression. RESULTS: Minimal allele frequency was 0.17 and genotype frequencies were 0.69, 0.27, and 0.04 for CC, CT, and TT genotypes, respectively. The polymorphism is associated in a recessive manner (TT genotype) with a decrease in triglyceride levels (P=.002) and with an increase in high-density lipoprotein cholesterol levels (P=.021) after adjusting by age and sex. CONCLUSIONS: The polymorphism rs11613352 may contribute to modulate the cardiovascular risk by modifying plasma lipid levels in familial hypercholesterolemia patients. PMID- 25278212 TI - Impact of the new American and British guidelines on the management and treatment of dyslipidemia in a Spanish working population. AB - INTRODUCTION AND OBJECTIVES: The guidelines of the American College of Cardiology/American Heart Association and the British National Institute for Health and Clinical Excellence on the management and treatment of dyslipidemia recommend significant changes, such as the abolition of therapeutic targets and the use of new risk tables. This study aimed to evaluate the impact of the use of these new guidelines compared with the application of European guidelines. METHODS: Observational study conducted among Spanish workers. We included all workers registered with the Sociedad de Prevencion de Ibermutuamur in 2011 whose cardiovascular risk could be evaluated. Cardiovascular risk was calculated for each worker using the Systematic Coronary Risk Evaluation cardiovascular risk tables for low-risk countries, as well as the tables recommended by the American and British guidelines. RESULTS: A total of 258,676 workers were included (68.2% men; mean age, 39.3 years). High risk was found in 3.74% of the population according to the Systematic Coronary Risk Evaluation tables and in 6.85% and 20.83% according to the British and American tables, respectively. Treatment would be needed in 20 558 workers according to the American guidelines and in 13,222 according to the British guidelines, but in only 2612 according to the European guidelines. By following the American guidelines, the cost of statins would increase by a factor of 8. CONCLUSIONS: The new recommendations would result in identifying more high-risk patients and in treating a larger fraction of the population with lipid-lowering drugs than with the European recommendations, which would result in increased costs. PMID- 25278213 TI - Metastatic pulmonary chondrosarcoma: clinical description and literature review. PMID- 25278211 TI - Spanish Catheter Ablation Registry. 13th Official Report of the Spanish Society of Cardiology Working Group on Electrophysiology and Arrhythmias (2013). AB - INTRODUCTION AND OBJECTIVES: This report presents the results of the 2013 Spanish Catheter Ablation Registry. METHODS: Data were collected using 2 systems: retrospectively by completing a dedicated form and prospectively by reporting to a central database. Each participating center chose 1 of the 2 data collection methods. RESULTS: Eighty centers voluntarily contributed data to the registry. A total of 11 987 ablation procedures were performed, with a mean (standard deviation) of 149 (105) procedures per center. The 3 main arrhythmic substrates treated were atrioventricular nodal reentrant tachycardia (n=2959; 24.6%), cavotricuspid isthmus ablation (n=2700; 22.5%), and atrial fibrillation (n=2201; 18.4%). The number of ventricular ablation procedures was similar to the 2012 activity, but there was a slight increase in procedures for scar-related postmyocardial infarction ventricular tachycardia. The success rate was 94.4%, major complications occurred in 1.8%, and the mortality rate was 0.03%. CONCLUSIONS: In line with previous reports, the data from the 2013 registry show a continuing increase in the number of ablations performed. Overall, there was a high success rate and few complications. Ablation of complex substrates has continued to increase. PMID- 25278214 TI - Migratory pulmonary nodules in a patient with ulcerative colitis. PMID- 25278215 TI - Task Force for the Review, Modification and Development of Quality Indicators for Respiratory Intensive Care Units in Mexico. PMID- 25278216 TI - Uncommon ectopic parathyroid adenoma. PMID- 25278217 TI - Person-by-person prediction of intuitive economic choice. AB - Decision making is an interdisciplinary field, which is explored with methods spanning from economic experiments to brain scanning. Its dominant paradigms such as utility theory, prospect theory, and the modern dual-process theories all resort to formal algebraic models or non-mathematical postulates, and remain purely phenomenological. An approach introduced by Grossberg deployed differential equations describing neural networks and bridged the gap between decision science and the psychology of cognitive-emotional interactions. However, the limits within which neural models can explain data from real people's actions are virtually untested and remain unknown. Here we show that a model built around a recurrent gated dipole can successfully forecast individual economic choices in a complex laboratory experiment. Unlike classical statistical and econometric techniques or machine learning algorithms, our method calibrates the equations for each individual separately, and carries out prediction person-by-person. It predicted very well the behaviour of 15%-20% of the participants in the experiment-half of them extremely well-and was overall useful for two thirds of all 211 subjects. The model succeeded with people who were guided by gut feelings and failed with those who had sophisticated strategies. One hypothesis is that this neural network is the biological substrate of the cognitive system for primitive-intuitive thinking, and so we believe that we have a model of how people choose economic options by a simple form of intuition. We anticipate our study to be useful for further studies of human intuitive thinking as well as for analyses of economic systems populated by heterogeneous agents. PMID- 25278218 TI - Insights into the organization of plumatellid larvae (lophotrochozoa, Bryozoa) by means of 3D-imaging and confocal microscopy. AB - Within the Lophotrochozoa, the Bryozoa or Ectoprocta remain one of the phyla whose phylogenetic relation to other lophotrochozoans is still controversely discussed. To complement existing data and to gain more insight into bryozoan character evolution, we analyzed the morphology of the larva of the phylactolaemate Plumatella sp. The larva of Plumatella spp. consists of an outer ciliated mantle that covers two differentiated polypides. The muscular and serotonergic nervous system of the polypides correspond to previous studies. The two polypides and their corresponding buds differ in size, which, together with a comparison among bryozoans, indicates that a single polypide is the basal condition. The whole larval mantle and mantle fold are supplied with circular and longitudinal muscles, the former being more pronounced in the mantle fold. The apical plate on the anterior side contains a diffuse mesh of crossing fibers and thus differs from previous descriptions, which recognized a regular muscular grid. The serotonergic nervous system in the mantle and mantle fold consists of a diffuse basiepidermal nerve net with its highest concentration at the apical plate. Serotonin immunoreactivity so far has not been detected in the mantle fold. However, the presence of other neurotransmitters in the mantle fold shown by previous studies indicates that this nerve net is a common feature of phylactolaemate larvae. The main difference between currently analyzed phylactolaemate larvae seems to be the complexity of the larval mantle musculature, which most likely plays an important role during metamorphosis. This study confirms previous interpretations that the apical plate pole does not correspond to the apical pole of gymnolaemate larvae but to their oral side. Accelerated asexual development on the aboral pole leads to the suggestion that an apical organ is never formed and the apical plate compensates for its absence in the free-swimming period. PMID- 25278219 TI - Treating MERS-CoV during an outbreak. PMID- 25278221 TI - Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. AB - BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with high mortality and has no approved antiviral therapy. We aimed to compare ribavirin and interferon alfa-2a treatment for patients with severe MERS CoV infection with a supportive therapy only. METHODS: In this retrospective cohort study, we included adults (aged >=16 years) with laboratory-confirmed MERS CoV infection and pneumonia needing ventilation support, diagnosed between Oct 23, 2012, and May 1, 2014, at the Prince Sultan Military Medical City (Riyadh, Saudi Arabia). All patients received appropriate supportive care and regular clinical and laboratory monitoring, but patients diagnosed after Sept 16, 2013, were also given oral ribavirin (dose based on calculated creatinine clearance, for 8-10 days) and subcutaneous pegylated interferon alfa-2a (180 MUg per week for 2 weeks). The primary endpoint was 14-day and 28-day survival from the date of MERS-CoV infection diagnosis. We used chi(2) and Fischer's exact test to analyse categorical variables and the t test to analyse continuous variables. FINDINGS: We analysed 20 patients who received ribavirin and interferon (treatment group; initiated a median of 3 days [range 0-8] after diagnosis) and 24 who did not (comparator group). Baseline clinical and laboratory characteristics were similar between groups, apart from baseline absolute neutrophil count, which was significantly lower in the comparator group (5.88 * 10(9)/L [SD 3.95] vs 9.88 * 10(9)/L [6.63]; p=0.023). 14 (70%) of 20 patients in the treatment group had survived after 14 days, compared with seven (29%) of 24 in the comparator group (p=0.004). After 28 days, six (30%) of 20 and four (17%) of 24, respectively, had survived (p=0.54). Adverse effects were similar between groups, apart from reduction in haemoglobin, which was significantly greater in the treatment group than in the comparator group (4.32 g/L [SD 2.47] vs 2.14 g/L [1.90]; p=0.002). INTERPRETATION: In patients with severe MERS-CoV infection, ribavirin and interferon alfa-2a therapy is associated with significantly improved survival at 14 days, but not at 28 days. Further assessment in appropriately designed randomised trials is recommended. FUNDING: None. PMID- 25278222 TI - Pollution and skin: from epidemiological and mechanistic studies to clinical implications. AB - In recent years, the health effects associated with air pollution have been intensively studied. Most studies focus on air pollution effects on the lung and the cardiovascular system. More recently, however, epidemiological and mechanistic studies suggest that air pollution is also affecting skin integrity. This state-of-the-art review focuses on this latter aspect; it was developed with the collaboration of European and Chinese board of experts with specific interests in environmental health, clinical and basic research in dermatology and cosmetic dermatology. A literature review limited to pollution and health effects and (sensitive) skin was performed using PubMed. Review and original articles were chosen. We summarize the existing scientific evidence that air pollution exerts detrimental effects on human skin, discuss potential clinical implications and suggest specific and unspecific cosmetic protective measures. PMID- 25278223 TI - Role of the epidermal growth factor receptor in ultraviolet radiation induction of Snail family transcription factors. PMID- 25278224 TI - Recurrence predictive models for patients with hepatocellular carcinoma after radiofrequency ablation using support vector machines with feature selection methods. AB - BACKGROUND AND OBJECTIVE: Recurrence of hepatocellular carcinoma (HCC) is an important issue despite effective treatments with tumor eradication. Identification of patients who are at high risk for recurrence may provide more efficacious screening and detection of tumor recurrence. The aim of this study was to develop recurrence predictive models for HCC patients who received radiofrequency ablation (RFA) treatment. METHODS: From January 2007 to December 2009, 83 newly diagnosed HCC patients receiving RFA as their first treatment were enrolled. Five feature selection methods including genetic algorithm (GA), simulated annealing (SA) algorithm, random forests (RF) and hybrid methods (GA+RF and SA+RF) were utilized for selecting an important subset of features from a total of 16 clinical features. These feature selection methods were combined with support vector machine (SVM) for developing predictive models with better performance. Five-fold cross-validation was used to train and test SVM models. RESULTS: The developed SVM-based predictive models with hybrid feature selection methods and 5-fold cross-validation had averages of the sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the ROC curve as 67%, 86%, 82%, 69%, 90%, and 0.69, respectively. CONCLUSIONS: The SVM derived predictive model can provide suggestive high-risk recurrent patients, who should be closely followed up after complete RFA treatment. PMID- 25278220 TI - A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium. AB - Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances. PMID- 25278225 TI - Etiologic classification of TIA and minor stroke by A-S-C-O and causative classification system as compared to TOAST reduces the proportion of patients categorized as cause undetermined. AB - BACKGROUND: The assortment of patients based on the underlying pathophysiology is central to preventing recurrent stroke after a transient ischemic attack and minor stroke (TIA-MS). The causative classification of stroke (CCS) and the A-S-C O (A for atherosclerosis, S for small vessel disease, C for Cardiac source, O for other cause) classification schemes have recently been developed. These systems have not been specifically applied to the TIA-MS population. We hypothesized that both CCS and A-S-C-O would increase the proportion of patients with a definitive etiologic mechanism for TIA-MS as compared with TOAST. METHODS: Patients were analyzed from the CATCH study. A single-stroke physician assigned all patients to an etiologic subtype using published algorithms for TOAST, CCS and ASCO. We compared the proportions in the various categories for each classification scheme and then the association with stroke progression or recurrence was assessed. RESULTS: TOAST, CCS and A-S-C-O classification schemes were applied in 469 TIA-MS patients. When compared to TOAST both CCS (58.0 vs. 65.3%; p < 0.0001) and ASCO grade 1 or 2 (37.5 vs. 65.3%; p < 0.0001) assigned fewer patients as cause undetermined. CCS had increased assignment of cardioembolism (+3.8%, p = 0.0001) as compared with TOAST. ASCO grade 1 or 2 had increased assignment of cardioembolism (+8.5%, p < 0.0001), large artery atherosclerosis (+14.9%, p < 0.0001) and small artery occlusion (+4.3%, p < 0.0001) as compared with TOAST. Compared with CCS, using ASCO resulted in a 20.5% absolute reduction in patients assigned to the 'cause undetermined' category (p < 0.0001). Patients who had multiple high-risk etiologies either by CCS or ASCO classification or an ASCO undetermined classification had a higher chance of having a recurrent event. CONCLUSION: Both CCS and ASCO schemes reduce the proportion of TIA and minor stroke patients classified as 'cause undetermined.' ASCO resulted in the fewest patients classified as cause undetermined. Stroke recurrence after TIA-MS is highest in patients with multiple high-risk etiologies or cryptogenic stroke classified by ASCO. PMID- 25278226 TI - Intravenous insulin therapy during lung resection does not affect lung function or surfactant proteins. AB - BACKGROUND: The surgical resection of lung disrupts glucose homeostasis and causes hyperglycemia, as in any other major surgery or critical illness. We performed a prospective study where we carefully lowered hyperglycemia by insulin administration during the surgery, and for the first time we monitored immediate insulin effects on lung physiology and gene transcription. METHODS: The levels of blood gases (pH, pCO2, pO2, HCO3-, HCO3- std, base excess, FiO2, and pO2/FiO2) were measured at the beginning of surgery, at the end of surgery, and two hours after. Samples of healthy lung tissue surrounding the tumour were obtained during the surgery, anonymized and sent for subsequent blinded qPCR analysis (mRNA levels of surfactant proteins A1, A2, B, C and D were measured). This study was done on a cohort of 64 patients who underwent lung resection. Patients were randomly divided, and half of them received insulin treatment during the surgery. RESULTS: We demonstrated for the first time that insulin administered intravenously during lung resection does not affect levels of blood gases. Furthermore, it does not induce immediate changes in the expression of surfactant proteins. CONCLUSION: According to our observations, short insulin treatment applied intravenously during resection does not affect the quality of breathing. PMID- 25278227 TI - A seamless phase IIB/III adaptive outcome trial: design rationale and implementation challenges. AB - BACKGROUND: The licensed four-valent prophylactic human papillomavirus vaccine is highly efficacious in preventing cervical, vulvar, vaginal, and anal cancers and related precancers caused by human papillomavirus types 6, 11, 16, and 18. These four types account for approximately 70% of cervical cancers. A nine-valent human papillomavirus vaccine, including the four original types (6, 11, 16, and 18) plus the next five most prevalent types in cervical cancer (31, 33, 45, 52, and 58) could provide approximately 90% overall cervical cancer coverage. To expedite the nine-valent human papillomavirus vaccine clinical development, an adaptive, seamless Phase IIB/III outcome trial with ~ 15,000 subjects was conducted to facilitate dose formulation selection and provide pivotal evidence of safety and efficacy for regulatory registrations. PURPOSE: We discuss the design rationale and implementation challenges of the outcome trial, focusing on the adaptive feature of the seamless Phase IIB/III design. METHODS: Subjects were enrolled in two parts (Part A and Part B). Approximately 1240 women, 16-26 years of age, were enrolled in Part A for Phase IIB evaluation and equally randomized to one of three dose formulations of the nine-valent human papillomavirus vaccine or the four-valent human papillomavirus vaccine (active control). Based on an interim analysis of immunogenicity and safety, one dose formulation of the nine-valent human papillomavirus vaccine was selected for evaluation in the Phase III part of the study. Subjects enrolled in Part A who received the selected dose formulation of the nine-valent human papillomavirus vaccine or four-valent human papillomavirus vaccine continued to be followed up and contributed to the final efficacy and safety analyses. In addition, ~ 13,400 women 16-26 years of age were enrolled in Part B, randomized to nine-valent human papillomavirus vaccine at the selected dose formulation or four-valent human papillomavirus vaccine, and followed for immunogenicity, efficacy, and safety. RESULTS: A seamless Phase IIB/III design was justified by the extensive pre-existing knowledge of the licensed four-valent human papillomavirus vaccine and the development objectives for the nine-valent human papillomavirus vaccine. Subjects enrolled in Part A who received either the selected nine-valent human papillomavirus formulation or four valent human papillomavirus vaccine contributed ~ 10% of person-years of follow up due to its earlier start-thereby maximizing the overall efficiency of the trial. Some of the challenges encountered in the implementation of the adaptive design included practical considerations during Phase IIB formulation selection by internal and external committees, End-of-Phase II discussion with health authorities and managing changes in the assay for immunological endpoints. LIMITATIONS: Application of the experience and lesson learned from this seamless adaptive design to other clinical programs may depend on case-by-case consideration. CONCLUSION: A seamless Phase IIB/III adaptive design was successfully implemented in this large outcome study. The development time of the second-generation nine-valent human papillomavirus vaccine was shortened due to improved statistical efficiency. PMID- 25278229 TI - Clinician-trialist rounds: 25. Designing an evidence-based introductory graduate course in clinical trials. Part 2: Applying the evidence to your RCT course design. PMID- 25278228 TI - Clinical trials in crisis: Four simple methodologic fixes. AB - There is growing consensus that the US clinical trials system is broken, with trial costs and complexity increasing exponentially, and many trials failing to accrue. Yet, concerns about the expense and failure rate of randomized trials are only the tip of the iceberg; perhaps what should worry us most is the number of trials that are not even considered because of projected costs and poor accrual. Several initiatives, including the Clinical Trials Transformation Initiative and the "Sensible Guidelines Group" seek to push back against current trends in clinical trials, arguing that all aspects of trials-including design, approval, conduct, monitoring, analysis, and dissemination-should be based on evidence rather than contemporary norms. Proposed here are four methodologic fixes for current clinical trials. The first two aim to simplify trials, reducing costs, and increasing patient acceptability by dramatically reducing eligibility criteria-often to the single criterion that the consenting physician is uncertain which of the two randomized arms is optimal-and by clinical integration, investment in data infrastructure to bring routinely collected data up to research grade to be used as endpoints in trials. The second two methodologic fixes aim to shed barriers to accrual, either by cluster randomization of clinicians (in the case of modifications to existing treatment) or by early consent, where patients are offered the chance of being randomly selected to be offered a novel intervention if disease progresses at a subsequent point. Such solutions may be partial, or result in a new set of problems of their own. Yet, the current crisis in clinical trials mandates innovative approaches: randomized trials have resulted in enormous benefits for patients, and we need to ensure that they continue to do so. PMID- 25278230 TI - Design, synthesis and exploring the quantitative structure-activity relationship of some antioxidant flavonoid analogues. AB - A series of flavonoid analogues were synthesized and screened for the in vitro antioxidant activity through their ability to quench 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical. The activity of these compounds, measured in comparison to the well-known standard antioxidants (29-32), their precursors (38-42) and other bioactive moieties (38-42) resembling partially the flavone skeleton was analyzed further to develop Quantitative Structure-Activity Relationship (QSAR) models using the Genetic Function Approximation (GFA) technique. Based on the essential structural requirements predicted by the QSAR models, some analogues were designed, synthesized and tested for activity. The predicted and experimental activities of these compounds were well correlated. Flavone analogue 20 was found to be the most potent antioxidant. PMID- 25278231 TI - In vitro apoptotic effect of cassaine-type diterpene amides from Erythrophleum fordii on PC-3 prostate cancer cells. AB - Cytotoxic activity-guided fractionation of Erythrophleum fordii led to the isolation of two new cassaine diterpenoid-diterpenoid amide dimers, erythrophlesins H-I (1, 2). Spectral data indicated that they consist of asymmetrical dimeric structure via an ester bond between two cassaine diterpenoids. MTT assay confirmed that compound 1, erythrophlesin H, had the strongest cytotoxic effect toward the human prostate cancer cell line, PC-3. The molecular mechanism by which this compound induced apoptosis cell in prostate cancer remains unknown. Erythrophlesin H induced apoptosis in a dose-dependent manner. Acridine orange and annexin V-FITC/PI double staining confirmed that erythrophlesin H effectively induces apoptosis in PC-3 cells. PMID- 25278232 TI - The discovery of isoxazoline oxime ethers as a new class of ectoparasiticides for the control of Haematobia irritans (horn fly) in cattle. AB - Haematobia irritans (horn fly) infestation in cattle is responsible for over a billion dollars a year in global economic loss due to decreased milk production and lower feed conversion. There is significant need for new insecticidal agents since current treatments such as organophosphates and pyrethroids suffer from field resistance. Isoxazoline oxime ethers represent a new class of gamma aminobutyric acid (GABA) receptor channel blockers which show good activity (LD(90) = 1.0 MUg/mL) against horn flies in an in vitro feed assay and have demonstrated efficacy (>90% reduction at 1.0mg/kg) as a topical treatment in a field study. PMID- 25278233 TI - Synthesis and structure-activity relationship of 4-azaheterocycle benzenesulfonamide derivatives as new microtubule-targeting agents. AB - A series of 1-sulfonyl indolines was synthesized and evaluated for antiproliferative activity. The most potent compounds 9 a and 9 e showed significant cytotoxicity (IC50 in the range of 0.055-0.105 and 0.039-0.112 MUM, respectively) against four human cancer cell lines HCT116, PC3, HepG2 and SK-OV 3. The structure-activity relationship of this series of sulfonamides, including the influence of azaheterocycle rings, substituent at the different positions of indoline, and the cyclopropane moiety, was described. PMID- 25278234 TI - Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists. AB - Bivalent heterodimeric IAP antagonists that incorporate (R) tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line. PMID- 25278235 TI - Oxo- and thiooxo-imidazo[1,5-c]pyrimidine molecule library: beyond their interest in inhibition of Brucella suis histidinol dehydrogenase, a powerful protection tool in the synthesis of histidine analogues. AB - Histidinol dehydrogenase (HDH) has been established as a virulence factor for the human pathogen bacterium Brucella suis. Targeting such a virulence factor is a relevant anti-infectious approach as it could decrease the frequency of antibiotic resistance appearance. In this paper, we describe the synthesis of a family of oxo- and thioxo-imidazo[1,5-c]pyrimidines, potential enzyme inhibitors. Beyond their anti-HDH activity, the synthesis approach of these molecules, never described before, is highly original and these oxo- and thioxo- derivatives can improve dramatically the efficiency of the histidine protection pathway for the synthesis of histidine analogues. PMID- 25278236 TI - Synthesis and anti-tumor activity of glycosyl oxadiazoles derivatives. AB - A new series of glycosyl oxadiazoles compounds were synthesized and characterized through (1)H NMR, (13)C NMR, IR and HRMS. The anti-tumor activities for MDA-MB 231 of all these new compounds were screened in vitro by MTT assay. Due to the modification of gastrodin analogues, the anti-tumor activities of these 1,3,4 oxadiazoles derivatives were greatly improved. Six compounds (6 c, 6 d, 6 i, 6 j, 6 k and 6 l) displayed relatively higher MDA-MB-231 potency with IC50 values (0.89, 0.26, 1.35, 3.60, 0.95 and 1.08 MUM) compared with the reference medicine Rosiglitazone (5.23 MUM). PMID- 25278237 TI - Halenaquinone inhibits RANKL-induced osteoclastogenesis. AB - Halenaquinone was isolated from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells. It inhibited the RANKL (receptor activator of nuclear factor-kappaB ligand)-induced upregulation of TRAP (tartrate-resistant acid phosphatase) activity as well as the formation of multinuclear osteoclasts. In addition, halenaquinone substantially suppressed RANKL-induced IkappaB degradation and Akt phosphorylation. Thus, these results suggest that halenaquinone inhibits RANKL induced osteoclastogenesis at least by suppressing the NF-kappaB and Akt signaling pathways. PMID- 25278238 TI - Two new spirooxindole alkaloids from rhizosphere strain Streptomyces sp. xzqh-9. AB - Two new spirooxindole alkaloids spindomycins A (1) and B (2) were isolated from rhizosphere strain Streptomyces sp. xzqh-9. Their structures were elucidated by comprehensive spectroscopic analyses of NMR and MS data. The absolute configurations of 1 and 2 were determined by experimental and theoretical calculation of electronic circular dichroism (ECD). Antitumor, lactate dehydrogenase, and tyrosine kinase inhibitory activities of two compounds were evaluated, while only spindomycin B (2) exhibited weak inhibitory activity against tyrosine kinase Bcr-Abl. PMID- 25278239 TI - Visible-light-induced chemoselective reductive decarboxylative alkynylation under biomolecule-compatible conditions. AB - We report a visible-light-induced reductive decarboxylative C(sp(3))-C(sp) bond coupling reaction to construct aryl, alkyl and silyl substituted alkynes at room temperature in organic solvents or neutral aqueous solutions. This chemoselective alkynylation was compatible with various functional groups and biomolecules, and did not affect the protein enzyme activity. PMID- 25278240 TI - Assessment of total body water and its compartments in elite judo athletes: comparison of bioelectrical impedance spectroscopy with dilution techniques. AB - Bioelectrical impedance spectroscopy (BIS) is an inexpensive and non-invasive technique to measure total body water (TBW), extracellular water (ECW), and intracellular water (ICW). The purpose of this study was to validate TBW, ECW and ICW assessed by BIS, using dilution techniques as the reference method (REF) in elite judo athletes. Thirty-two Portuguese elite male judo athletes were evaluated during a period of weight stability. TBW, ECW and ICW were assessed by BIS (Xitron 4000). Deuterium and bromide dilution techniques were used as the criterion method for measuring TBW and ECW, while ICW was calculated as the difference between the two. BIS explained 96%, 77% and 94% of the total variability from REFs for TBW, ECW and ICW, respectively. BIS also demonstrated high precision (rho >= 0.88) and accuracy (Cb = 0.98), with a minimum concordance coefficient correlation of 0.87 for ECW. The mean bias demonstrated that BIS slightly overestimated the REF in 1.1 kg (2.3%), 0.3 kg (1.6%) and 0.8 kg (2.7%) for TBW, ECW and ICW, respectively. The 95% limits of agreement ranged from -1.2 to 3.3 kg in TBW, from -1.8 to 2.4 kg in ECW and from -1.0 to 2.6 kg in ICW. A non-significant trend was found between the difference and the mean of reference and alternative methods. These findings highlight the efficacy of BIS as a valid non-biased tool for the assessment of TBW and its compartments in elite male judo athletes, during a period of weight stability. PMID- 25278241 TI - Intractable occipital lobe epilepsy: clinical characteristics, surgical treatment, and a systematic review of the literature. AB - PURPOSE: We reported our experience in the surgical treatment of a relatively large cohort of patients with occipital lobe epilepsy (OLE). We also carried out a systematic review of the literature on OLE. METHODS: Thirty-five consecutive patients who underwent occipital resection for epilepsy were included. Diagnoses were made following presurgical evaluations, including magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), scalp video electroencephalogram (EEG) monitoring, and intracranial EEG monitoring. At last follow-up, seizure outcome was classified using the Engel classification scheme. RESULTS: Twenty-five of 35 patients experienced/had experienced >=1 type of aura before the seizure. Invasive recordings were used to define the epileptogenic area in 30 of 35 patients (85.7 %). All patients underwent occipital lesionectomies or topectomies. Histopathology revealed: cortical dysplasias, gliosis, dysembryoplastic neuroepithelial tumor, ganglioglioma, and tuberous sclerosis. After a mean follow-up of 44 months, 25 patients (71.4 %) were seizure free (Engel class I), 3 (8.6 %) rarely had seizures (Engel class II), 5 (14.3 %) improved more than 75 % (Engel class III), and 2 (5.7 %) had no significant improvement (Engel class IV). Preoperatively, 12 of 33 patients (36.4 %) had visual field deficits. Postoperatively, 25 patients (75.8 %) had new or aggravated visual field deficits. CONCLUSIONS: The management of OLE has been aided greatly by the availability of high-resolution diagnosis. Postoperative visual field deficits occur in a significant proportion of patients. Comprehensive intracranial EEG coverage of all occipital surfaces helps to define the epileptogenic area and preserve visual function, especially in cases of focal cortical dysplasia undetectable by MRI. PMID- 25278242 TI - Electropermeabilization of adherent cells with cochlear implant electrical stimulation in vitro. AB - Cochlear implant stimulation creates a reduction in electrode impedance that returns to pre-stimulation levels following cessation of stimulation and is presumed to be associated with the fibrous tissue covering over the electrode array. This study assessed the possibility that transitory impedance reduction originates from a change in the membrane permeability of cells on the electrode (electropermeabilization). These changes can be recorded using the dye propidium iodide, which fluoresces upon entry into the leaky cell. The in vitro model used showed impedance reduction and dye uptake into adherent cells overlying planar gold electrodes stimulated with as little as 5 min of clinically relevant cochlear implant stimulation. The delayed additions of propidium iodide showed a similar dye uptake to those groups with concurrent dye addition, suggesting the electropermeabilization was not reversible. Further understanding of the mechanisms behind these impedance and cell permeability changes with cochlear implant electrical stimulation may provide opportunities for creating long lasting reductions in electrode impedance. PMID- 25278243 TI - MicroRNA-409-3p functions as a tumor suppressor in human lung adenocarcinoma by targeting c-Met. AB - BACKGROUND/AIMS: Dysregulation of microRNAs is correlated with tumor development. The aim of this study is to investigate the clinicopathologic and prognostic significance of microRNA (miR)-409-3p and its tumor suppressor roles in lung adenocarcinoma (LAD). METHODS: Quantitative real-time PCR (qRT-PCR) was performed to detect miR-409-3p expression in LAD tissues and corresponding noncancerous tissues. Additionally, the correlations of miR-409-3p expression with clinicopathologic factors and prognosis of patients were statistically analyzed. Next, we investigated whether miR-409-3p could function as a tumor suppressor in LAD cells via regulation of Akt signaling by targeting receptor tyrosine kinase (c-Met). RESULTS: MiR-409-3p was significantly downregulated in LAD tissues compared with corresponding noncancerous tissues. Low miR-409-3p expression was observed to be significantly correlated with poorer tumor differentiation, advanced pTNM stage and higher incidence of lymph node metastasis. Multivariate Cox regression analyses showed that miR-409-3p expression was an independent prognostic factor for LAD patients. Functional analyses indicated that miR-409-3p could inhibit growth, induce apoptosis, reduce migration and invasion in LAD cells via inactivation of Akt signaling by targeting c-Met. CONCLUSIONS: MiR-409 3p was an independent prognostic factor and functioned as a tumor suppressor in LAD via regulation of Akt signaling by targeting c-Met. PMID- 25278244 TI - Computed tomography findings of acute gastric volvulus. AB - PURPOSE: To assess the diagnostic performance of CT signs of gastric volvulus in both confirmed cases and control subjects. MATERIALS AND METHODS: We retrospectively reviewed CT findings in 10 patients with surgically confirmed acute gastric volvulus and 20 control subjects with gastric distension. Two radiologists independently evaluated CT images for risk factors of gastric volvulus, direct findings of gastric volvulus by assessing gastric dilatation, the presence of an antropyloric transition point, the respective position of the different stomach segments and of the greater and lesser curvatures, stenosis of the gastric segments through the oesophageal hiatus and for findings of gastric ischemia. The sensitivity and specificity of each finding were calculated. RESULTS: The most sensitive direct signs of gastric volvulus were an antropyloric transition point without any abnormality at the transition zone and the antrum at the same level or higher than the fundus. The presence of both these two findings as diagnostic criteria of gastric volvulus had 100% sensitivity and specificity for the diagnosis of gastric volvulus. There was no association between CT signs of ischemia and final bowel ischemia at pathology. CONCLUSION: CT is both highly sensitive and specific for diagnosing acute gastric volvulus. KEY POINTS: CT is highly reliable for diagnosing acute gastric volvulus with two findings. The two signs are gastropyloric transition zone and abnormal location of the antrum. This allows fast surgical management of this emergency. PMID- 25278246 TI - Primary hepatic angiosarcoma: multi-institutional comprehensive cancer centre review of multiphasic CT and MR imaging in 35 patients. AB - OBJECTIVE: To assess the imaging features of primary hepatic angiosarcoma on multiphasic CT and MR. METHODS: Multi-institutional review identified 35 adults (mean age, 57.1 years; 22M/13F) with pathologically proven hepatic angiosarcoma and pretreatment multiphasic CT (n = 33) and/or MR (n = 7). RESULTS: Multifocal hepatic involvement was seen in all 35 cases, with at least 10 lesions in 74.3% (26/35). Mean size of the dominant mass was 8.9 +/- 4.7 cm (range, 2.6-20 cm). Individual nodules were typically circumscribed. Arterial-phase foci of hypervascular enhancement without washout were seen in 89.7% (26/29). Heterogeneously expanding foci of enhancement generally followed blood pool in 88.6% (31/35). Progressive centripetal (n = 16) or diffuse "flash-fill" (n = 4) enhancement pattern resembling cavernous haemangiomas predominated in 20 cases, whereas a "reverse haemangioma" centrifugal pattern predominated in 11 cases. Rapid interval growth was seen in 24 (96.0%) of 25 cases with serial imaging. Vascular invasion was not seen in any case. Underlying cirrhotic morphology was seen in 42.3% (15/35). CONCLUSION: Primary hepatic angiosarcomas typically manifest as aggressive multifocal tumors containing small heterogeneous hypervascular foci that progressively expand and follow blood pool. The appearance can mimic cavernous haemangiomas, but distinction is generally possible. In the setting of cirrhosis, lack of tumour washout and vascular invasion argue against multifocal hepatocellular carcinoma. KEY POINTS: * Hepatic angiosarcoma manifests on CT and MR as rapidly progressive multifocal tumours * Multiphasic imaging demonstrates hypervascular foci that progressively expand and follow blood pool * Enhancement pattern can resemble cavernous haemangiomas or show a "reverse" centrifugal pattern * Lack of tumour washout of hypervascular lesions argues against multifocal hepatocellular carcinoma * Careful assessment of the cross-sectional imaging findings may suggest the diagnosis. PMID- 25278247 TI - Interdependencies of acquisition, detection, and reconstruction techniques on the accuracy of iodine quantification in varying patient sizes employing dual-energy CT. AB - PURPOSE: To assess the impact of patient habitus, acquisition parameters, detector efficiencies, and reconstruction techniques on the accuracy of iodine quantification using dual-source dual-energy CT (DECT). MATERIALS AND METHODS: Two phantoms simulating small and large patients contained 20 iodine solutions mimicking vascular and parenchymal enhancement from saline isodensity to 400 HU and 30 iodine solutions simulating enhancement of the urinary collecting system from 400 to 2,000 HU. DECT acquisition (80/140 kVp and 100/140 kVp) was performed using two DECT systems equipped with standard and integrated electronics detector technologies. DECT raw datasets were reconstructed using filtered backprojection (FBP), and iterative reconstruction (SAFIRE I/V). RESULTS: Accuracy for iodine quantification was significantly higher for the small compared to the large phantoms (9.2 % +/- 7.5 vs. 24.3 % +/- 26.1, P = 0.0001), the integrated compared to the conventional detectors (14.8 % +/- 20.6 vs. 18.8 % +/- 20.4, respectively; P = 0.006), and SAFIRE V compared to SAFIRE I and FBP reconstructions (15.2 % +/- 18.1 vs. 16.1 % +/- 17.6 and 18.9 % +/- 20.4, respectively; P <= 0.003). A significant synergism was observed when the most effective detector and reconstruction techniques were combined with habitus-adapted dual-energy pairs. CONCLUSION: In a second-generation dual-source DECT system, the accuracy of iodine quantification can be substantially improved by an optimal choice and combination of acquisition parameters, detector, and reconstruction techniques. PMID- 25278248 TI - Time of flight MR angiography assessment casts doubt on the association between transient global amnesia and intracranial jugular venous reflux. AB - PURPOSE: Evidence of intracranial venous reflux flow due to jugular venous reflux (JVR) on time of flight (TOF) MR angiography (MRA) is thought to be highly associated with transient global amnesia (TGA)-evidence that supports the venous congestion theory of TGA pathophysiology. However, recent studies indicate that intracranial JVR on TOF MRA is occasionally observed in normal elderly. Therefore, the purpose of this study was to compare the prevalence of intracranial JVR on TOF MRA in patients with TGA and two control groups. METHODS: Three age- and sex-matched groups of subjects that received MRI and MRA were enrolled. The groups comprised 167 patients with TGA, 167 visitors to the emergency room (ER) and 167 visitors to a health promotion centre (HPC). Intracranial JVR was defined as abnormal venous signals in the inferior petrosal, sigmoid and/or transverse sinuses on TOF MRA. The prevalence of intracranial JVR was assessed across the three groups. RESULTS: Intracranial JVR was seen in seven (4.2 %) TGA patients, eight (4.8 %) ER visitors and three (1.8 %) HPC visitors, respectively. No statistically significant differences were observed among the three groups. CONCLUSION: TGA patients showed a low prevalence of intracranial JVR on TOF MRA, and no statistical differences were found in comparison with control groups. PMID- 25278245 TI - Clinical indications for computed tomographic colonography: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline. PMID- 25278249 TI - Outcomes after fluoroscopy-guided iliopsoas bursa injection for suspected iliopsoas tendinopathy. AB - OBJECTIVES: To report patient outcomes up to 1 month after fluoroscopy-guided iliopsoas bursa injection for suspected iliopsoas tendinopathy. METHODS: Thirty nine consecutive patients (mean age 45 years; range 15-77) who underwent fluoroscopy-guided therapeutic iliopsoas bursa injection using an anterolateral approach and who returned an outcomes questionnaire were prospectively included. The Patients' Global Impression of Change (PGIC) scale was recorded 1 day, 1 week, and 1 month after the injection (primary outcome measure). Patients' subjective pain level data were collected prior to the injection (baseline) using a numeric rating scale (NRS; 0 = no pain; 10 = maximum pain). NRS scores were completed 15 min, 1 day, 1 week, and 1 month post-injection and compared to baseline. RESULTS: Forty-nine per cent of patients reported clinically relevant 'improvement' (PGIC) 1 month post-injection. Mean NRS score prior to injection was 5.9 +/- 2.1. Mean NRS scores after 15 min (3.6 +/- 2.7), 1 day (4.4 +/- 2.7), 1 week (3.4 +/- 1.9), and 1 month (3.5 +/- 2.5) were statistically significantly lower (p <= 0.001) compared to baseline. Reduction of NRS >=50 % after 15 min was achieved in 49 % (56 % of those unimproved at 1 month). CONCLUSIONS: Fluoroscopy guided iliopsoas bursa injection leads to a relevant 'improvement' at 1 month or significant pain reduction after 15 min in most patients. PMID- 25278251 TI - Electrophysiological evidence for a specific neural correlate of musical violation expectation in primary-school children. AB - The majority of studies on music processing in children used simple musical stimuli. Here, primary schoolchildren judged the appropriateness of musical closure in expressive polyphone music, while high-density electroencephalography was recorded. Stimuli ended either regularly or contained refined in-key harmonic transgressions at closure. The children discriminated the transgressions well above chance. Regular and transgressed endings evoked opposite scalp voltage configurations peaking around 400ms after stimulus onset with bilateral frontal negativity for regular and centro-posterior negativity (CPN) for transgressed endings. A positive correlation could be established between strength of the CPN response and rater sensitivity (d-prime). We also investigated whether the capacity to discriminate the transgressions was supported by auditory domain specific or general cognitive mechanisms, and found that working memory capacity predicted transgression discrimination. Latency and distribution of the CPN are reminiscent of the N400, typically observed in response to semantic incongruities in language. Therefore our observation is intriguing, as the CPN occurred here within an intra-musical context, without any symbols referring to the external world. Moreover, the harmonic in-key transgressions that we implemented may be considered syntactical as they transgress structural rules. Such structural incongruities in music are typically followed by an early right anterior negativity (ERAN) and an N5, but not so here. Putative contributive sources of the CPN were localized in left pre-motor, mid-posterior cingulate and superior parietal regions of the brain that can be linked to integration processing. These results suggest that, at least in children, processing of syntax and meaning may coincide in complex intra-musical contexts. PMID- 25278250 TI - Lost for emotion words: what motor and limbic brain activity reveals about autism and semantic theory. AB - Autism spectrum conditions (ASC) are characterised by deficits in understanding and expressing emotions and are frequently accompanied by alexithymia, a difficulty in understanding and expressing emotion words. Words are differentially represented in the brain according to their semantic category and these difficulties in ASC predict reduced activation to emotion-related words in limbic structures crucial for affective processing. Semantic theories view 'emotion actions' as critical for learning the semantic relationship between a word and the emotion it describes, such that emotion words typically activate the cortical motor systems involved in expressing emotion actions such as facial expressions. As ASC are also characterised by motor deficits and atypical brain structure and function in these regions, motor structures would also be expected to show reduced activation during emotion-semantic processing. Here we used event related fMRI to compare passive processing of emotion words in comparison to abstract verbs and animal names in typically-developing controls and individuals with ASC. Relatively reduced brain activation in ASC for emotion words, but not matched control words, was found in motor areas and cingulate cortex specifically. The degree of activation evoked by emotion words in the motor system was also associated with the extent of autistic traits as revealed by the Autism Spectrum Quotient. We suggest that hypoactivation of motor and limbic regions for emotion word processing may underlie difficulties in processing emotional language in ASC. The role that sensorimotor systems and their connections might play in the affective and social-communication difficulties in ASC is discussed. PMID- 25278252 TI - Incident urothelial cancer in the Malmo Diet and Cancer Study: cohort characteristics and further validation of ezrin as a prognostic biomarker. AB - BACKGROUND: Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with poor prognosis in urothelial bladder cancer in several independent studies. The present study provides a first description of clinicopathological characteristics of incident urothelial cancers, not only located to the bladder, in the prospective, population-based cohort study Malmo Diet and Cancer. In addition, the prognostic value of ezrin expression is validated in primary tumours, and the longitudinal expression of ezrin examined in a subset of primary and recurrent tumours (n=28). METHODS: Among a total number of 355 incident tumours registered up until Dec 31 2010, 335 were located to the bladder. Immunohistochemical expression of cytoplasmic and membranous ezrin was evaluated in tissue microarrays with primary tumours from 272 cases and recurrent tumours from 28 cases. A combined score of the minimum, mean and maximum fraction and percentage of staining was calculated. Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test, univariable and multivariable Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin expression on 5-year overall survival (OS). RESULTS: Ezrin expression could be evaluated in 263/272 primary and all 28 recurrent tumours. Membranous but not cytoplasmic ezrin was significantly reduced in recurrent compared to primary tumours (p < 0.001). Low cytoplasmic and membranous ezrin expression were associated with more advanced T-stage (p = 0.004, p < 0.001) and high-grade tumours (p = 0.025, p < 0.001), but not with age, sex, tumour location or smoking status. Both low cytoplasmic and membranous ezrin staining were associated with a significantly reduced 5-year OS (HR = 1.65; 95% CI 1.06-2.57 and HR = 2.51, 95% CI 1.52-4.17), but only low membranous ezrin remained prognostic after adjustment for age, sex, stage, grade and smoking status (HR = 1.69, 95% CI 1.00-2.85). CONCLUSIONS: This study provides a first description of the clinicopathological characteristics of 355 incident urothelial cancers in the Malmo Diet and Cancer Study up until 2010. In addition, the value of ezrin expression as a prognostic biomarker is further consolidated in this type of cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_189. PMID- 25278253 TI - Diallyl sulfide inhibits diethylstilbestrol induced DNA damage in human breast epithelial cells (MCF-10A). AB - Breast cancer is the second leading cause of cancer deaths in women in the United States. Diethylstilbestrol (DES) is a synthetic estrogen that has been shown to cause cancer in animals and humans, altering cell viability as well as inducing DNA damage. Diallyl sulfide (DAS) is a garlic organosulfide that has been shown to inhibit both the initiation and promotion phases of cancer in vivo and in vitro, as well as reduce the risk of cancer in epidemiological studies. MCF-10A cells, regarded as a normal breast epithelial cell line, were treated with varying concentrations of DES, DAS or various dose combinations of DES and DAS concomitantly, and assessed for cell viability, DNA strand breaks, and lipid peroxidation. DES (10MUM) in combination with 1, 10, or 100MUM DAS resulted in a 31%, 34%, or 36% respective increase in cell viability compared to the DES treatment alone, after 24h. At the same time point, 1, 10, and 100MUM DAS were all effective in significantly reducing DES (100MUM)-induced strand breaks to near that of the vehicle control. Additionally, 1MUM DAS was effective in significantly reducing DES (100MUM)-induced lipid peroxidation after 3h. The results of this research suggest that DAS is effective in recovering cell viability, attenuating DNA strand breaks, and decreasing lipid peroxidation in MCF-10A cells. PMID- 25278254 TI - Steroidal pyrazolines and pyrazoles as potential 5alpha-reductase inhibitors: synthesis and biological evaluation. AB - Taking pregnenolone as the starting material, two series of pyrazolinyl and pyrazolyl pregnenolones were synthesized through different routes. The synthesis of the analogs of both series is multistep and proceeds in good overall yields. While the key step in the synthesis of pyrazolinyl pregnenolones is the heterocyclization of benzylidine derivatives (3) in presence of hydrazine hydrate, it is the condensation of 3beta-hydroxy-21-hydroxymethylidenepregn-5-en 3beta-ol-20-one (5) with phenylhydrazine in the synthesis of pyrazolyl derivatives. Compounds of both the series were tested for their 5alpha-reductase inhibitory activities. Amongst all the compounds screened for their 5alpha reductase inhibitory activities, compound 4b, 4c and 6b were found to be the most active. PMID- 25278255 TI - Chronic prenatal ethanol exposure alters expression of central and peripheral insulin signaling molecules in adult guinea pig offspring. AB - Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150-200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 +/- 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF 1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity. PMID- 25278256 TI - ROS-triggered and regenerating anticancer nanosystem: an effective strategy to subdue tumor's multidrug resistance. AB - Drug delivery strategies utilizing tumor microenvironment are recognized as a critical doorway to overcome multidrug resistance (MDR). However, the variability of tumor microenvironment at different disease stages would definitely minimize stimuli generation and eventually the therapeutic effects of these stimuli sensitive systems. Herein, we report a unique reactive oxygen species (ROS) triggered nanosystem that can replenish the ROS upon disassembly to maintain its high level. This was accomplished by a new amphiphilic polymer (TBH) composed of D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), hyaluronic acid (HA) and arylboronic ester. As a linker of TPGS to HA, arylboronic ester could efficiently degrade in response to ROS resulting in dismantling of nanosystem followed by rapid release of TPGS. Owing to ROS inducing activity of TPGS with mitochondrial respiratory complex II, ROS regeneration was observed for TBH nanosystem both in MCF-7/ADR cells and tumor tissues xenografted with MCF-7/ADR cells. Furthermore, doxorubicin-loaded TBH nanosystem (DOX-TBH) revealed higher drug cytotoxicity due to enhanced retention effect on account of ROS triggered DOX release and P-gp inhibitory mechanism of TPGS. Moreover, HA significantly improved tumor targeting capability of DOX-TBH, while ROS based triggering and regenerating mechanism lead to marked inhibition of the tumor growth in the xenograft MCF-7/ADR tumor-bearing nude mice. PMID- 25278257 TI - Dual pH-sensitive oxidative stress generating micellar nanoparticles as a novel anticancer therapeutic agent. AB - Cancer cells are under oxidative stress due to a large production of reactive oxygen species (ROS), which involve in cell proliferation and cancer promotion and progression. On the other hand, ROS promotes cell death, depending on the rate of ROS production and the activity of antioxidant systems. Recently, "oxidation therapy" has arisen as a promising anticancer strategy, which can be achieved by inducing the generation of cytotoxic level of ROS or inhibiting the antioxidant systems in tumor cells. Here, we report oxidative stress amplifying nanoplatforms as novel anticancer therapeutics, which are able not only to suppress antioxidant but also to generate ROS simultaneously in acidic tumor microenvironments. The oxidative stress amplifying nanoplatforms are composed of dual pH-sensitive PBCAE copolymer, polymeric prodrug of BCA (benzoyloxycinnamaldehyde) and heme oxygenase-1 (HO-1) inhibiting zinc protoporphyrin (ZnPP). PBCAE was designed to incorporate ROS-generating BCA in its backbone via acid-cleavable acetal linkages and self-assemble to form micelles that encapsulate ZnPP. In vitro proof-of-concept studies revealed that ZnPP encapsulated in PBCAE micelles suppressed HO-1 to make cancer cells more vulnerable to BCA-induced ROS, leading to enhanced apoptotic cell death. In addition, ZnPP-loaded PBCAE micelles significantly suppressed the tumor growth in human cancer xenograft mouse models. We believe that oxidative stress amplifying micellar nanoparticles have a great potential as novel redox anticancer therapeutics. PMID- 25278258 TI - Targeted cutaneous delivery of ciclosporin A using micellar nanocarriers and the possible role of inter-cluster regions as molecular transport pathways. AB - Oral administration of ciclosporin A (CsA) is indicated in the treatment of severe recalcitrant plaque psoriasis. However, CsA is both nephro- and hepatotoxic and its systemic administration also exposes the patient to other severe side effects. Although topical delivery of CsA, targeted directly to psoriatic skin, would offer significant advantages, there are no topical formulations approved for dermatological use. The aim of this work was to formulate CsA loaded polymeric micelles using the biodegradable and biocompatible MPEG-dihexPLA diblock copolymer and to evaluate their potential for delivering the drug selectively into the skin without concomitant transdermal permeation. Micelle formulations were characterised with respect to drug content, size and morphology. Micelle and drug penetration pathways were subsequently visualised with confocal laser scanning microscopy (CLSM) using fluorescein labelled CsA (Fluo-CsA) and Nile-Red (NR) labelled copolymer. Visualisation studies typically use fluorescent dyes as "model drugs"; however, these may have different physicochemical properties to the drug molecule under investigation. Therefore, in this study it was decided to chemically modify CsA and to use this structurally similar fluorescent analogue to visualise molecular distribution and transport pathways. Molecular modelling techniques and experimental determination of log D served as molecular scale and macroscopic methods to compare the lipophilicity of CsA and Fluo-CsA. The spherical, homogeneous and nanometre-scale micelles (with Zav from 25 to 52 nm) increased the aqueous solubility of CsA by 518-fold. Supra-therapeutic amounts of CsA were delivered to human skin (1.4+/ 0.6 MUg/cm2, cf. a statistically equivalent 1.1+/-0.5 MUg/cm2 for porcine skin) after application of the formulation with the lowest CsA and copolymer content (1.67+/-0.03 mg/ml of CsA and 5mg/ml of copolymer) for only 1h without concomitant transdermal permeation. Fluo-CsA was successfully synthesised, characterised and incorporated into fluorescent NR-MPEG-dihexPLA micelles; its conformation was not modified by the addition of fluorescein and its log D, measured from pH4 to 8, was equivalent to that of CsA. Fluo-CsA and NR-MPEG dihexPLA copolymer were subsequently visualised in skin by CLSM. The images indicated that micelles were preferentially deposited between corneocytes and in the inter-cluster regions (i.e. between the clusters of corneocytes). Fluo-CsA skin penetration was deeper in these structures, suggesting that inter-cluster penetration is probably the preferred transport pathway responsible for the increased cutaneous delivery of CsA. PMID- 25278259 TI - Classification of intestinal lymphangiectasia with protein-losing enteropathy: white villi type and non-white villi type. AB - BACKGROUND/AIMS: We classified intestinal lymphangiectasia (IL) into two categories, the white and non-white villi types, and evaluated their clinical characteristics and therapeutic responses. METHODS: Of the 988 patients who underwent double-balloon enteroscopy, 14 consecutive patients (7 men and 7 women, median age at onset 34 years) were enrolled with immunohistochemically confirmed IL with protein-losing enteropathy. RESULTS: Enteroscopically the white villi type (n = 8) showed white plaques and white-tipped villi were scattered in the small bowel, while non-white villi type (n = 6) showed that apparently normal but under more detailed observation, low and round villi with a normal color were diffused. The serum albumin levels and fecal alpha1-antitrypsin clearance before treatment were significantly worse in the non-white villi type (p = 0.017 and 0.039, respectively), whereas the serum immunoglobulin A and M levels were significantly lower in the white villi type (p = 0.010 and 0.046, respectively). At gastroscopy, a non-cirrhotic snakeskin appearance was significantly observed in the non-white villi type (p = 0.015). The corticosteroid response was better in the non-white villi type (p = 0.015). CONCLUSION: Two distinct subgroups were found in IL. This classification was useful in pathophysiological clustering and in predicting the therapeutic response. PMID- 25278260 TI - Cationic conjugated polymer/fluoresceinamine-hyaluronan complex for sensitive fluorescence detection of CD44 and tumor-targeted cell imaging. AB - Simple, rapid, and sensitive detection of CD44 is of paramount importance since it plays pivotal roles in tumor initiation, growth and metastasis. Herein, we describe a novel method for sensitive, visual and facile fluorescence detection of CD44 and CD44-mediated cancer cell imaging, using a probe based on cationic conjugated polymer (CCP)-PFEP and fluoresceinamine-hyaluronan (FA-HA). HA is an anionic natural glycosaminoglycan that can specifically bind to the overexpressed CD44 on various kinds of cancer cells. PFEP and FA-HA formed a complex through electronic interactions, resulting in a highly efficient fluorescence resonance energy transfer (FRET) from PFEP to FA-HA; moreover, the efficiencies of FRET correlated with the concentrations of CD44 because the specific binding of HA CD44 would separate FA-HA away from PFEP. This method did not require laborious and expensive dual-labeling or protein-labeling needed in previously reported detection methods of CD44. Just mix the sample and test solution containing the PFEP/FA-HA complex, and the results allowed naked-eye detection by observing fluorescent color of solutions with the assistance of a UV lamp. Most importantly, the use of a conjugated polymer with excellent amplification property as well as the specific binding of HA-CD44 endowed this method with high sensitivity and specificity, making it applicable for reliable quantitative detection of CD44. Furthermore, the PFEP/FA-HA complex formed nanoparticles in aqueous solution, and the nanoparticles can be selectively taken up by MCF-7 cells (cancer cell) through the HA-CD44 interaction, thereby giving rise to a dual-color tumor-targeted imaging probe with good photostability. The development of this fluorescent probe showed promising potential to make a reliable and routine method available for early diagnosis of cancer. PMID- 25278261 TI - Remission of refractory benign familial chronic pemphigus (hailey-hailey disease) with the addition of systemic cyclosporine. AB - BACKGROUND: Benign chronic familial pemphigus (BFCP) is an autosomal dominant dermatosis characterized by flares of painful and often debilitating blistering lesions in high friction areas of the body such as the groin, axillae, lateral neck, and intergluteal cleft. Limited knowledge of its pathophysiology has made treatment of BFCP a considerable challenge and efficacy with current first line therapies, topical corticosteroids and antibiotics, is variable. CASE REPORT: We present a case of this disease in a 52 year old woman that has responded dramatically to the addition of oral cyclosporine to her existing regimen of oral acitretin, with significant improvement of skin lesions, mobility, and quality of life. Cyclosporine's mechanism of action in BFCP is poorly understood, although it possibly acts through inhibition of proinflammatory cytokines in keratinocytes or modulation of intracellular calcium. BFCP, the use of cyclosporine for its treatment, and possible mechanisms of action of cyclosporine are reviewed. PMID- 25278262 TI - Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production. AB - Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC SIGN drives follicular T helper cell (TFH) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKepsilon, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3. Notably, ISGF3 induces expression of IL-27 subunit p28, and subsequent IL-27 secreted by DC-SIGN-primed DCs is pivotal for the induction of Bcl-6(+)CXCR5(+)PD-1(hi)Foxp1(lo) TFH cells, IL-21 secretion by TFH cells and T-cell-dependent IgG production by B cells. Thus, we have identified an essential role for DC-SIGN-induced ISGF3 by fucose-based PAMPs in driving IL-27 and subsequent TFH polarization, which might be harnessed for vaccination design. PMID- 25278263 TI - Experimental study of the magnetic field enhanced Payne effect in magnetorheological elastomers. AB - The dynamic modulus and the loss factor of magnetorheological elastomers (MREs) of various compositions and anisotropies are studied by dynamic torsion oscillations performed in the absence and in the presence of an external magnetic field. The emphasis is on the Payne effect, i.e. the dependence of the elastomer magnetorheological characteristics on the strain amplitude and their evolution with cyclically increasing and decreasing strain amplitudes. MREs are based on two silicone matrices differing in storage modulus (soft, G' ~ 10(3) Pa, and hard, G' ~ 10(4) Pa, matrices). For each matrix, the concentration of carbonyl iron particles with diameters of 3-5 MUm was equal to 70 and 82 mass% (22 and 35 vol%, respectively) in the composite material. Samples for each filler content, isotropic and aligned-particles, are investigated. It is found that the Payne effect significantly increases in the presence of an external magnetic field and varies with the cyclical loading which reaches saturation after several cycles. The results are interpreted as the processes of formation-destruction-reformation of the internal filler structure under the simultaneously applied mechanical force and magnetic field. Impacts of matrix elasticity and magnetic interactions on the filler alignment are elucidated. PMID- 25278265 TI - Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency. AB - BACKGROUND: Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures. METHODS: We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the proposed design and its context in the drug development program, as well as the responses of the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAWP), were extracted and categorized. For 41 more recent procedures (1 January 2009 to 8 May 2012), additional details of the trial design and the CHMP/SAWP responses were assessed. In addition, case studies are presented as examples. RESULTS: Over a range of 51/2 years, 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials. Almost all were proposed as confirmatory phase III or phase II/III studies. The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment. While 12 (20%) of the 59 proposals for an adaptive clinical trial were not accepted, the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%). In the more recent 41 procedures, the most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias. CONCLUSIONS: For the majority of proposed adaptive clinical trials, an overall positive opinion was given albeit with critical comments. Type I error rate control, bias and the justification of the design are common issues raised by the CHMP/SAWP. PMID- 25278266 TI - Trade-off between growth and immunity: role of brassinosteroids. AB - A balance between growth and immunity exists in plants. Recently, the growth promoting hormones brassinosteroids (BR) have emerged as crucial regulators of the growth-immunity trade-off, although the molecular mechanisms underlying this role remained unclear. New evidence obtained from the model plant Arabidopsis thaliana points at an indirect crosstalk between BR signaling and immunity, mediated by the transcription factors BZR1 and HBI1, which suppress immunity upon BR perception. The core transcriptional cascade formed by BZR1 and HBI1 seems to act as a regulatory hub on which multiple signaling inputs impinge, ensuring effective fine-tuning of the trade-off between growth and immunity in a timely and cost-efficient manner. PMID- 25278264 TI - Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. AB - Mixed chimerism approaches for induction of tolerance of solid organ transplants have been applied successfully in animal models and in the clinic. However, in xenogeneic models (pig-to-primate), host macrophages participate in the rapid clearance of porcine hematopoietic progenitor cells, hindering the ability to achieve mixed chimerism. CD47 is a cell-surface molecule that interacts in a species-specific manner with SIRPalpha receptors on macrophages to inhibit phagocytosis and expression of human CD47 (hCD47) on porcine cells has been shown to inhibit phagocytosis by primate macrophages. We report here the generation of hCD47 transgenic GalT-KO miniature swine that express hCD47 in all blood cell lineages. The effect of hCD47 expression on xenogeneic hematopoietic engraftment was tested in an in vivo mouse model of human hematopoietic cell engraftment. High-level porcine chimerism was observed in the bone marrow of hCD47 progenitor cell recipients and smaller but readily measurable chimerism levels were observed in the peripheral blood of these recipients. In contrast, transplantation of WT progenitor cells resulted in little or no bone marrow engraftment and no detectable peripheral chimerism. These results demonstrate a substantial protective effect of hCD47 expression on engraftment and persistence of porcine cells in this model, presumably by modulation of macrophage phagocytosis. PMID- 25278267 TI - Do chlorophyllous orchids heterotrophically use mycorrhizal fungal carbon? AB - The roots of orchids associate with mycorrhizal fungi, the rhizoctonias, which are considered to exchange mineral nutrients against plant carbon. The recent discovery that rhizoctonias grow endophytically in non-orchid plants raises the possibility that they provide carbon to orchids, explaining why some orchids differ in isotopic abundances from autotrophic plants. PMID- 25278268 TI - Change your TPLATE, change your fate: plant CME and beyond. AB - Clathrin-mediated endocytosis (CME) is the predominant and evolutionarily conserved pathway by which eukaryotes internalize cargoes (i.e., plasma membrane proteins, lipids, and extracellular material) that are engaged in a variety of processes. Initiation of CME relies on adaptor proteins, which precisely select the cargoes for internalization, recruit the clathrin cage, and start membrane curvature. The recently identified CME early adaptor complex, the TPLATE complex (TPC), is essential for CME in plants. Phylogenetic analyses suggest that the TPC evolved from an ancient protein complex involved in vesicle trafficking in early eukaryotes, which raises questions about CME evolution and adaptation within the eukaryotic Kingdoms. In this review, we focus on the early events of plant CME and explore evolutionary aspects related to CME in other eukaryotes. PMID- 25278269 TI - Reversion-Inducing-Cysteine-Rich Protein With Kazal Motifs (RECK) Gene Single Nucleotide Polymorphism With Hepatocellular Carcinoma: A Case-Control Study. AB - BACKGROUND: The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) gene is a transformation suppressor gene that can negatively regulate matrix metalloproteinases (MMPs) and inhibit tumor invasion, angiogenesis, and metastasis. So, the aim of this study was to analyze the effect of RECK gene rs 11788747 single nucleotide polymorphism (SNP) on hepatocellular carcinoma (HCC) susceptibility and its relation to various clinical and laboratory data of the patients. METHODS: This is a case-control study including 200 HCC patients and 200 healthy controls. RECK rs 11788747 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: RECK rs 11788747 A/G and G/G genotypes frequencies were significantly higher in HCC patients compared to the healthy controls. The HCC patients possessing at least one polymorphic G allele were significantly at a higher risk of developing lymph nodes involvement and distant metastasis. CONCLUSION: This study revealed the role of RECK rs 11788747 SNP in HCC in Egyptian patients, which consequently might be used as a prognostic tool and could be added to its therapeutic strategies. PMID- 25278270 TI - High accuracy NMR chemical shift corrected for bulk magnetization as a tool for structural elucidation of microemulsions. Part 2 - Anionic and nonionic dilutable microemulsions. AB - In our previous report we suggested a new analytical tool, high accuracy NMR chemical shift corrected for bulk magnetization as a supplementary tool to study structural transitions and droplet size and shape of dilutable microemulsions. The aim of this study was to show the generality of this technique and to demonstrate that in almost any type of microemulsion this technique provides additional valuable structural information. The analysis made by the technique adds to the elucidation of some structural aspects that could not be clearly determined by other classical techniques. Therefore, in this part we are extending the study to three additional systems differing in the type of oil phase (toluene and cyclohexane), the nature of the surfactants (anionic and nonionic), and other microemulsion characteristics. We studied sodium dodecyl sulfate (SDS)-based anionic microemulsions with different oils and a nonionic microemulsion based on Tween 20 as the surfactant and toluene as the oil phase. All the microemulsions were fully dilutable with water. We found that the change in the slope of chemical shift against dilution reflects phase transition points of the microemulsion (O/W, bicontinuous, W/O). Chemical shift changes were clearly observed with the transition between spherical and non-spherical (wormlike, etc.) droplet shapes. We compared the interaction of cyclohexane and toluene and used the anisotropic effect of toluene's ring current to determine its preferred orientation relative to SDS. Chemical shifts of the microemulsion components are therefore a useful addition to the arsenal of techniques for characterizing microemulsions. PMID- 25278271 TI - Enhanced charge efficiency and reduced energy use in capacitive deionization by increasing the discharge voltage. AB - Capacitive deionization (CDI) is an electrochemical method for water desalination using porous carbon electrodes. A key parameter in CDI is the charge efficiency, Lambda, which is the ratio of salt adsorption over charge in a CDI-cycle. Values for Lambda in CDI are typically around 0.5-0.8, significantly less than the theoretical maximum of unity, due to the fact that not only counterions are adsorbed into the pores of the carbon electrodes, but at the same time coions are released. To enhance Lambda, ion-exchange membranes (IEMs) can be implemented. With membranes, Lambda can be close to unity because the membranes only allow passage for the counterions. Enhancing the value of Lambda is advantageous as this implies a lower electrical current and (at a fixed charging voltage) a reduced energy use. We demonstrate how, without the need to include IEMs, the charge efficiency can be increased to values close to the theoretical maximum of unity, by increasing the cell voltage during discharge, with only a small loss of salt adsorption capacity per cycle. In separate constant-current CDI experiments, where after some time the effluent salt concentration reaches a stable value, this value is reached earlier with increased discharge voltage. We compare the experimental results with predictions of porous electrode theory which includes an equilibrium Donnan electrical double layer model for salt adsorption in carbon micropores. Our results highlight the potential of modified operational schemes in CDI to increase charge efficiency and reduce energy use of water desalination. PMID- 25278272 TI - Photoresponsive stripe pattern in achiral azobenzene liquid crystals. AB - A periodic stripe pattern is found in the nematic phase close to the smectic phase of photoresponsive achiral liquid-crystalline compounds. The origin of the stripe patterns can be ascribed to an extremely large bent elastic constant K33 . In addition, we succeeded in controlling the pattern by the following two methods: 1) the stripe disappears by a trans-cis photoisomerization upon UV light irradiation and reappears upon light termination, and 2) the stripe pattern is stabilized over the whole nematic phase, at approximately 10 degrees C, by polymerization of the compounds. PMID- 25278273 TI - Comparative sequence analysis and mutagenesis of ethylene forming enzyme (EFE) 2 oxoglutarate/Fe(II)-dependent dioxygenase homologs. AB - BACKGROUND: Ethylene is one of the most used chemical monomers derived from non renewable sources and we are investigating the possibility of producing it in yeast via the ethylene forming enzyme (EFE) from Pseudomonas syringae. To enable engineering strategies to improve the enzyme, it is necessary to identify the regions and amino acid residues involved in ethylene formation. RESULTS: We identified the open reading frame for the EFE homolog in Penicillium digitatum and also showed its capability of mediating ethylene production in yeast. The sequence of the EFE homologs from P.digitatum and P. syringae was compared to that of the non-functional EFE-homolog from Penicillium chrysogenum and ten amino acids were found to correlate with ethylene production. Several of these amino acid residues were found to be important for ethylene production via point mutations in P. syringae EFE. The EFE homolog from P. chrysogenum was engineered at 10 amino acid residues to mimic the P. syringae EFE, but this did not confer ethylene producing capability.Furthermore, we predicted the structure of EFE by homology to known structures of 2-oxoglutarate/Fe(II) dependent dioxygenases. Three of the amino acids correlating with ethylene production are located in the predicted 2-oxoglutarate binding domain. A protein domain specific for the EFE class was shown to be essential for activity. Based on the structure and alanine substitutions, it is likely that amino acids (H189, D191 and H268) are responsible for binding the Fe(II) ligand. CONCLUSION: We provide further insight into the structure and function of the ethylene forming (EFE) - subclass of 2 oxoglutarate/Fe(II) dependent dioxygenases. We conclude that residues in addition to the 10 identified positions implicated in ethylene production by sequence comparison, are important for determining ethylene formation. We also demonstrate the use of an alternative EFE gene. The data from this study will provide the basis for directed protein engineering to enhance the ethylene production capability and properties of EFE. PMID- 25278274 TI - Country of birth, parental background and self-rated health among adolescents: a population-based study. AB - AIMS: The aim of this study was to investigate differences according to country of birth and parental country of birth, in relation to poor self-rated health (SRH), in Swedish adolescents. METHODS: The Scania public health survey among children and adolescents, conducted in 2012, is a cross-sectional study including most pupils in grade 9 (15 years old), including in 32 of 33 municipalities. The participation rate was 83% (9,791 of 11,735). We performed logistic regressions to investigate the association between the students' country of birth, parental country of birth and poor SRH. RESULTS: Boys born outside Europe had an odds ratio (OR) 2.1 (1.6-2.8) of poor SRH in the unadjusted model, which was reduced to 0.7 (0.4-1.3) in the multiple model, as compared to boys born in Sweden with both or one parent born in Sweden. Boys born in Europe had an OR 0.4 (0.2-0.9) of poor SRH, after multiple adjustments. Girls born in Sweden with both parents born abroad, and girls born outside of Europe had significantly lower ORs of poor SRH in the multiple model. In particular, adjustment for socio-demographic and psychosocial factors reduced the ORs of poor SRH among boys, but did so to a lesser extent among girls. CONCLUSIONS: Differences in socio-demographic and psychosocial factors explained the higher odds of poor SRH among boys born outside of Europe. Girls born in Sweden with both parents born abroad, and girls born outside Europe, had significantly lower ORs of poor SRH. Our results indicate that there are gender differences in the factors behind poor self-rated health, according to the country-related background of adolescents in Sweden. PMID- 25278275 TI - Cohort profile: Norwegian Epidemiologic Osteoporosis Studies (NOREPOS). AB - AIMS: This paper describes the history, purpose, data collection and contributions in the research collaboration Norwegian Osteoporosis Epidemiologic Studies (NOREPOS). METHODS: NOREPOS encompasses almost 85,000 bone mineral density measurements within Cohort of Norway and data on almost 140,000 hip fractures in Norway 1994-2008. Included are anthropometric measurements, blood pressure, lipids and glucose, and 50 standard questions on sociodemographic factors, diseases and risk factors. Blood samples/DNA are stored. The main research question posed in NOREPOS is why hip fracture rates in Norway are the highest in the world. Data on hip fractures 2009-2013 will be added in 2014. RESULTS: Main findings include: Every hour a Norwegian suffers a hip fracture; hip fracture incidence rates declined after 1999; only 16% of patients used anti osteoporosis drugs 1 year after hip fracture; 25% of patients died within 1 year after the fracture; 12% suffered a new hip fracture within 10 years; rural dwellers had lower hip and forearm fracture incidence than city dwellers; magnesium in tap water may be protective whereas bacterial contamination, cadmium and lead may be harmful to bone health; low serum vitamin D and E levels were associated with higher hip fracture risk; vitamin A was not associated with fracture risk; and abdominal obesity increased the risk of hip fracture when BMI was accounted for. CONCLUSIONS: NOREPOS encompasses a unique source of information for aetiological research, genetic studies as well as for biomarkers of osteoporosis and fractures. Because of the increasing number of elderly people in Europe, hip fractures will continue to pose an international public health and health care challenge. PMID- 25278276 TI - Perceived shared understanding in teams: The motivational effect of being 'on the same page'. AB - This study examines the role of perceived shared understanding with regard to team performance, taking into account the motivational mechanisms (i.e., group potency and team effort) involved in this relationship and the moderating role of task routineness. Using a multisource approach and a team-level design, we collected data from 101 teams (i.e., 381 members and their 101 immediate superiors) working in a Canadian public safety organization. The results support the mediating role of group potency and team effort in the relationship between perceived shared understanding and team performance. Moreover, the results show that the relationship between team effort and team performance is moderated by task routineness, such that this relationship is stronger when task routineness is high. On the whole, the findings of this study help to better understand why and under what circumstances perceived shared understanding may enhance team performance. PMID- 25278277 TI - Respiratory tract infections in the military environment. AB - Military personnel fighting in contemporary battlefields as well as those participating in combat training are at risk of contracting respiratory infections. Epidemiological studies have demonstrated that soldiers deployed to the harsh environment have higher rates of newly reported respiratory symptoms than non-deployers. Acute respiratory diseases are the principle reason for outpatient treatment and hospitalization among military personnel, with an incidence exceeding that of the adult civilian population by up to three-fold. Adenoviruses, influenza A and B viruses, Streptococcus pneumoniae, Streptococcus pyogenes, coronaviruses and rhinoviruses have been identified as the main causes of acute respiratory infections among the military population. Although infective pathogens have been extensively studied, a significant proportion of illnesses (over 40%) have been due to unknown causative agents. Other health hazards, which can lead to respiratory illnesses among troops, are extreme air temperatures, desert dust, emissions from burn pits, industrial pollutants, and airborne contaminants originating from degraded soil. Limited diagnostic capabilities, especially inside the area of operations, make it difficult to accurately estimate the exact number of respiratory diseases in the military environment. The aim of the study was to discuss the occurrence of respiratory tract infections in army personnel, existing risk factors and preventive measures. PMID- 25278278 TI - Thrombotic thrombocytopenic purpura. PMID- 25278279 TI - Neonatal nursing: an unmet challenge in India. AB - Nurses comprise a key component to maternal and newborn health care delivery, including the care of 'at-risk' or sick newborns. However, the efficiency and effectiveness of services rely heavily on adequate numbers of highly skilled neonatal nurses. Currently, in India, a significant shortage of trained nurses in the field of newborn care is contributing to poor neonatal outcomes. Specifically, nurses caring for newborns lack the competency and experience needed to ensure optimal care. This deficiency has been linked to a lack of expert faculty, standardized training and minimal or no exposures to newborn clinical care areas during pre service education. Moreover, in addition to a lack of operational research in the area, nurses who provide care for newborns are often faced with numerous system related issues that impede their ability to provide optimal care. Most notably, frequent changes of work place, poor wages, and lack of continuing education, skill maintenance, recognition, and collaborative team culture further compromise the nursing care. All these lead to poor motivation and competency. To meet this challenge, it is essential that emphasis be placed on the identification and support of nursing faculty with expertise in newborn and neonatal care who are able to ensure that nurses receive standardized education for pre-service, in-service and ongoing care. In addition, importance should be placed on encouraging newborn nursing research as well as on governmental increases in salary compensation. Lastly, given the shortage of physicians to take care of sick neonates in remote areas, the creation of a cadre of Neonatal nurse practitioner/ advanced practice nurses would be an invaluable solution in developing countries. Furthermore, centralized oversight of newborn education and training would be best served, if responsibility was placed with Reproductive maternal newborn child health (RMNCH) workers and district level officers. PMID- 25278280 TI - Inflammatory mediators as predictors of outcome in perinatal asphyxia. AB - OBJECTIVES: To identify biomarkers for neuronal injury and outcome in perinatal asphyxia. METHODS: This prospective cohort study was done in authors' level III NICU involving 80 neonates - 40 babies with perinatal asphyxia and 40 weight and gender matched normal neonates. Levels of cytokines IL-6, IL -1beta, IL-2 and TNF -alpha in cord blood of these neonates were estimated and correlated with the severity of asphyxia and developmental outcome at 6 mo using Baroda Developmental Score. RESULTS: The baseline parameters revealed that there was no statistically significant difference between the two groups in terms of maternal age, parity, gestational age, gender and birth weight. The levels of cytokines IL-6 (p < 0.001) and IL-1beta (p < 0.03) were significantly higher in babies with perinatal asphyxia and correlated with the severity of asphyxia. The levels of IL-6 and IL 1beta had significant negative correlation with developmental score at 6 mo. A cut off level of 14.18 pg/ml for IL-6 had 92.3 % sensitivity and 57.7 % specificity [Area under the curve = 0.80 (0.62-0.84)] for adverse neuro developmental outcome while it was 11.17 pg/ml for IL-1beta with a sensitivity of 69.2 % and specificity of 71.2 % [Area under the curve = 0.67 (0.57-0.80)]. CONCLUSIONS: IL-6 and IL-1 beta are good predictive markers of severity of asphyxia and adverse neurological outcome. PMID- 25278282 TI - A comparative study of the beneficial effects of ipratropium and beclomethasone against insulin-induced tracheal tissue contraction in a guinea pig model. AB - OBJECTIVE: To evaluate the acute effects of insulin on airway reactivity and the protective effects of beclomethasone and ipratropium against insulin-induced airway hyperresponsiveness on isolated tracheal smooth muscle in a guinea pig model. MATERIALS AND METHODS: The trachea of each guinea pig was excised; one end of the tracheal strip was attached to the hook of the oxygen tube of a tissue bath and the other end was connected to a research-grade isometric force displacement transducer. The effects of varying concentrations of insulin (10(-7) to 10(-3)M) and insulin pretreated with a fixed concentration of beclomethasone (10(-6)M) and ipratropium (10(-6)M) on the isolated tracheal tissue were studied by constructing cumulative concentration-response curves. Changes in tracheal smooth muscle contractions were recorded on a 4-channel oscillograph. RESULTS: The means +/- standard error of the mean of the maximum amplitude of contraction with increasing concentrations of insulin and of insulin pretreated with fixed concentrations of beclomethasone and ipratropium were 35 +/- 1.13, 22 +/- 1.15 and 27.8 +/- 1.27 mm, respectively. CONCLUSION: The data showed that beclomethasone inhibited the contractile response of insulin to a greater extent than ipratropium. Thus we suggest that inhalational insulin pretreated with beclomethasone may be more efficacious than with ipratropium for the amelioration of potential respiratory adverse effects such as bronchoconstriction. PMID- 25278281 TI - Disease severity and staging of obesity: a rational approach to patient selection. AB - The increasing prevalence of obesity places ever-increasing cost demands on healthcare systems. One million individuals are eligible for bariatric surgery in the UK, and yet less than 6000 bariatric procedures are performed annually. Bariatric surgery reverses or improves almost all the medical and psychosocial co morbidities associated with obesity. Although the BMI is a simple method to estimate adiposity at a population level, it is relatively inaccurate within an individual and provides little-to-no indication of overall health status or disease severity. Staging systems overcome the inherent limitations of BMI and allow highly informed decision-making for an individual. At a societal level, this helps to identify those most likely to gain and maximise economic benefit. This review summarises the co-morbidities associated with obesity and the evidence for their improvement following surgery. The rationale for new staging criteria and appropriate patient selection are discussed. PMID- 25278284 TI - Estimating characteristic phase and delay from broadband interaural time difference tuning curves. AB - Characteristic delay and characteristic phase are shape parameters of interaural time difference tuning curves. The standard procedure for the estimation of these parameters is based on the measurement of delay curves measured for tonal stimuli with varying frequencies. Common to all procedures is the detection of a linear behavior of the phase spectrum. Hence a reliable estimate can only be expected if sufficiently many relevant frequencies are tested. Thus, the estimation precision depends on the given bandwidth. Based on a linear model, we develop and implement methods for the estimation of characteristic phase and delay from a single broadband tuning curve. We present two different estimation algorithms, one based on a Fourier-analytic interpretation of characteristic delay and phase, and the other based on mean square error minimization. Estimation precision and robustness of the algorithms are tested on artificially generated data with predetermined characteristic delay and phase values, and on sample data from electrophysiological measurements in birds and in mammals. Increasing the signal to-noise ratio or the bandwidth increases the estimation accuracy of the algorithms. Frequency band location and strong rectification also affect the estimation accuracy. For realistic bandwidths and signal-to-noise ratios, the minimization algorithm reliably and robustly estimates characteristic delay and phase and is superior to the Fourier-analytic method. Bandwidth-dependent significance thresholds allow to assess whether the estimated characteristic delay and phase values are meaningful shape parameters of a measured tuning curve. These thresholds also indicate the sampling rates needed to obtain reliable estimates from interaural time difference tuning curves. PMID- 25278283 TI - pH-responsive biocompatible fluorescent polymer nanoparticles based on phenylboronic acid for intracellular imaging and drug delivery. AB - To address current medical challenges, there is an urgent need to develop drug delivery systems with multiple functions, such as simultaneous stimuli-responsive drug release and real-time imaging. Biocompatible polymers have great potential for constructing smart multifunctional drug-delivery systems through grafting with other functional ligands. More importantly, novel biocompatible polymers with intrinsic fluorescence emission can work as theranostic nanomedicines for real-time imaging and drug delivery. Herein, we developed a highly fluorescent nanoparticle based on a phenylboronic acid-modified poly(lactic acid) poly(ethyleneimine)(PLA-PEI) copolymer loaded with doxorubicin (Dox) for intracellular imaging and pH-responsive drug delivery. The nanoparticles exhibited superior fluorescence properties, such as fluorescence stability, no blinking and excitation-dependent fluorescence behavior. The Dox-loaded fluorescent nanoparticles showed pH-responsive drug release and were more effective in suppressing the proliferation of MCF-7 cells. In addition, the biocompatible fluorescent nanoparticles could be used as a tool for intracellular imaging and drug delivery, and the process of endosomal escape was traced by real time imaging. These pH-responsive and biocompatible fluorescent polymer nanoparticles, based on phenylboronic acid, are promising tools for intracellular imaging and drug delivery. PMID- 25278285 TI - Serial diffusion tensor images during infancy and their relationship to neuromotor outcomes in preterm infants. AB - BACKGROUND: Even preterm infants with normal magnetic resonance imaging (MRI) results are at greater risk for neuromotor dysfunction. OBJECTIVES: Our aim was to compare serial diffusion tensor imaging (DTI) data from preterm infants without apparent brain abnormalities on magnetic resonance imaging with those from term controls and to investigate the white matter (WM) region associated with neuromotor outcomes. METHODS: We obtained serial DTIs from 21 preterm infants at term-equivalent age (TEA) and 1 year of corrected age. As controls, 15 term neonates and 20 newly recruited term infants aged 1 year underwent DTI. Preterm and term infants at 1 year of age were assessed with the Bayley Scales of Infant Development, second edition. Tract-based spatial statistics and regions of interest were used for analysis. RESULTS: At TEA, the entire WM development was delayed in the preterm infants compared with the term controls, but at 1 year of age, the WM development, except for that of the corpus callosum (CC), had reached the development level of the term controls. The psychomotor developmental index was positively correlated with the fractional anisotropy (FA) in the CC (particularly in the body and splenium) at 1 year of age after correcting for gestational age, chronic lung disease, and postnatal infection. CONCLUSIONS: The CC of the preterm infants was consistently underdeveloped compared with that of the term controls. The FA in the CC, particularly in the body and splenium at 1 year of age, well reflected the degree of motor function in infants without apparent brain abnormalities. PMID- 25278286 TI - The significance of response shift in sinus surgery outcomes. AB - BACKGROUND: Functional endoscopic sinus surgery (FESS) aims to improve quality-of life (QOL). Perception of QOL can change according to one's current medical or emotional state. This is known as response shift. It can be measured by the "then test," which asks patients to report pretreatment symptoms after receiving treatment. Patients often do not understand their disease burden until their symptoms are improved. This study aims to assess the significance of response shift in FESS outcomes. METHODS: This was a prospective cohort study that included chronic rhinosinusitis patients from 2010 to 2012 who completed a preoperative 20-item Sino-Nasal Outcome Test (SNOT-20). Two SNOT-20 forms were mailed approximately 6 months after surgery. Patients completed 1 SNOT-20 according to their preoperative symptoms in light of their current state of health ("then-test") and the other based on postoperative symptoms. The preoperative and postoperative SNOT-20 difference represented the treatment effect and the preoperative SNOT-20 and then-test difference represented the response shift. RESULTS: Thirty-two completed responses were obtained. Using a 0 to 5 scale, mean treatment effect was -0.96 (p < 0.01), which signifies a QOL improvement. Mean response shift was +0.42 (p = 0.01). This positive value signifies that patients felt they were worse off preoperatively, likely due to a positive change in health status. The actual treatment effect is the sum of the measured treatment effect and response shift, which was -1.38. CONCLUSION: Response shift exists and can be quantified. The actual treatment effect was more profound when response shift was included. Therefore, future studies should account for this often unmeasured, potential change in QOL. PMID- 25278287 TI - Canonical and noncanonical vascular endothelial growth factor pathways: new developments in biology and signal transduction. AB - The past 5 years have witnessed a significant expansion in our understanding of vascular endothelial growth factor (VEGF) signaling. In particular, the process of canonical activation of VEGF receptor tyrosine kinases by homodimeric VEGF molecules has now been broadened by the realization that heterodimeric ligands and receptors are also active participants in the signaling process. Although heterodimer receptors were described 2 decades ago, their impact, along with the effect of additional cell surface partners and novel autocrine VEGF signaling pathways, are only now starting to be clarified. Furthermore, ligand-independent signaling (noncanonical) has been identified through galectin and gremlin binding and upon rise of intracellular levels of reactive oxygen species. Activation of the VEGF receptors in the absence of ligand holds immediate implications for therapeutic approaches that exclusively target VEGF. The present review provides a concise summary of the recent developments in both canonical and noncanonical VEGF signaling and places these findings in perspective to their potential clinical and biological ramifications. PMID- 25278288 TI - Redundancy and interaction of thrombin- and collagen-mediated platelet activation in tail bleeding and carotid thrombosis in mice. AB - OBJECTIVE: Current antiplatelet strategies to prevent myocardial infarction and stroke are limited by bleeding risk. A better understanding of the roles of distinct platelet-activating pathways is needed. We determined whether platelet activation by 2 key primary activators, thrombin and collagen, plays distinct, redundant, or interacting roles in tail bleeding and carotid thrombosis in mice. APPROACH AND RESULTS: Platelets from mice deficient for the thrombin receptor protease-activated receptor-4 (Par4) and the collagen receptor glycoprotein VI protein (GPVI) lack responses to thrombin and collagen, respectively. We examined tail bleeding and FeCl3-induced carotid artery occlusion in mice lacking Par4, GPVI, or both. We also examined a series of Par mutants with increasing impairment of thrombin signaling in platelets. Ablation of thrombin signaling alone by Par4 deficiency increased blood loss in the tail bleeding assay and impaired occlusive thrombus formation in the carotid occlusion assay. GPVI deficiency alone had no effect. Superimposing GPVI deficiency on Par4 deficiency markedly increased effect size in both assays. In contrast to complete ablation of thrombin signaling, 9- and 19-fold increases in EC50 for thrombin-induced platelet activation had only modest effects. CONCLUSIONS: The observation that loss of Par4 uncovered large effects of GPVI deficiency implies that Par4 and GPVI made independent, partially redundant contributions to occlusive thrombus formation in the carotid and to hemostatic clot formation in the tail under the experimental conditions examined. At face value, these results suggest that thrombin- and collagen-induced platelet activation can play partially redundant roles, despite important differences in how these agonists are made available to platelets. PMID- 25278289 TI - Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis. AB - OBJECTIVE: Black individuals are at an increased risk of myocardial infarction and stroke, 2 vascular diseases with strong thrombotic components. Platelet activation is a key step in platelet clot formation leading to myocardial infarction and stroke, and recent work supports a racial difference in platelet aggregation through the thrombin protease-activated receptors (PARs). The underlying mechanism for this racial difference, however, has not been established. Determining where in the signaling cascade these racial differences emerge will aid in understanding why individuals of differing racial ancestry may possess an inherent difference in their responsiveness to antiplatelet therapies. APPROACH AND RESULTS: Washed human platelets from black volunteers were hyperaggregable in response to PAR4-mediated platelet stimulation compared with whites. Interestingly, the racial difference in PAR4-mediated platelet aggregation persisted in platelets treated ex vivo with aspirin and 2MeSAMP (2 methylthioadenosine 5'-monophosphate triethylammonium salt hydrate), suggesting that the racial difference is independent of secondary feedback. Furthermore, stimulation of platelets from black donors with PAR4-activating peptide showed a potentiated level of activation through the Gq pathway compared with platelets from white donors. Differences in signaling included increased Ca(2+) mobilization, Rap1 (Ras-related protein 1) activation, and integrin alphaIIbbeta3 activation with no observed difference in platelet protein expression between the groups tested. CONCLUSIONS: Our study is the first to demonstrate that the Gq pathway is differentially regulated by race after PAR4 stimulation in human platelets. Furthermore, the racial difference in PAR4-mediated platelet aggregation persisted in the presence of cyclooxygenase and P2Y12 receptor dual inhibition, suggesting that current antiplatelet therapy may provide less protection to blacks than whites. PMID- 25278291 TI - PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort study. AB - OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipoprotein receptor. The aims of this cross sectional cohort-study were to examine whether the PCSK9 R46L loss of function variant found in a cohort of familial hypercholesterolemia (FH) patients was associated with lower low density lipoprotein cholesterol, lower frequency of xanthomata, and cardiovascular risk. APPROACH AND RESULTS: We studied FH patients attending the IRCM (Institut de Recherches Cliniques de Montreal) Lipid Clinic and whose DNA genotyping was positive for a low density lipoprotein receptor mutation. The presence of the PCSK9 loss of function R46L missense variant was determined among a cohort of 582 FH patients by genotyping. Frequency of the R46L variant was 3%. Carriers had significantly lower low density lipoprotein cholesterol (11%, P=0.002), total cholesterol (9%, P=0.007), apolipoprotein B (10%, P=0.037), and non-high density lipoprotein (12%, P<0.001) concentrations compared with noncarriers. Furthermore, R46L carriers showed a decreased average number of xanthoma per individual compared with noncarriers (0.33 and 0.76, respectively; P<0.001). Importantly, the R46L genetic variant was associated with a significant 86% lower odd of presenting a cardiovascular event (odds ratio, 0.14; 95% confidence interval, 0.032-0.63; P=0.001). CONCLUSIONS: Even though the R46L variant was present in 3% of our FH population, carriers of this polymorphism showed attenuated effect of the low density lipoprotein receptor mutation on parameters, such as low density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non-high density lipoprotein. More importantly, this mutation is associated with a significant lower risk of cardiovascular disease compared with noncarriers. It is therefore likely that targeting PCSK9 in FH patients with novel anti-PCSK9 therapies will be useful in reducing cardiovascular risk in affected subjects. PMID- 25278293 TI - Individualized diffeomorphic mapping of brains with large cortical infarcts. AB - Whole brain mapping of stroke patients with large cortical infarcts is not trivial due to the complexity of infarcts' anatomical location and appearance in magnetic resonance image. In this study, we proposed an individualized diffeomorphic mapping framework for solving this problem. This framework is based on our recent work of large deformation diffeomorphic metric mapping (LDDMM) in Du et al. (2011) and incorporates anatomical features, such as sulcal/gyral curves, cortical surfaces, brain intensity image, and masks of infarcted regions, in order to align a normal brain to the brain of stroke patients. We applied this framework to synthetic data and data of stroke patients and validated the mapping accuracy in terms of the alignment of gyral/sulcal curves, sulcal regions, and brain segmentation. Our results revealed that this framework provided comparable mapping results for stroke patients and healthy controls, suggesting the importance of incorporating individualized anatomical features in whole brain mapping of brains with large cortical infarcts. PMID- 25278290 TI - Identification of small proline-rich repeat protein 3 as a novel atheroprotective factor that promotes adaptive Akt signaling in vascular smooth muscle cells. AB - OBJECTIVE: Atherosclerosis is the primary driver of cardiovascular disease, the leading cause of death worldwide. Identification of naturally occurring atheroprotective genes has become a major goal for the development of interventions that will limit atheroma progression and associated adverse events. To this end, we have identified small proline-rich repeat protein (SPRR3) as selectively upregulated in vascular smooth muscle cells (VSMCs) of atheroma bearing arterial tissue versus healthy arterial tissue. In this study, we sought to determine the role of SPRR3 in atheroma pathophysiology. APPROACH AND RESULTS: We found that atheroprone apolipoprotein E-null mice lacking SPRR3 developed significantly greater atheroma burden. To determine the cellular driver(s) of this increase, we evaluated SPRR3-dependent changes in bone marrow-derived cells, endothelial cells, and VSMCs. Bone marrow transplant of SPRR3-expressing cells into SPRR3(-/-)apolipoprotein E-deficient recipients failed to rescue atheroma burden. Similarly, endothelial cells did not exhibit a response to SPRR3 loss. However, atheromas from SPRR3-deficient mice exhibited increased TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive VSMCs compared with control. Cell death in SPRR3-deficient VSMCs was significantly increased in vitro. Conversely, SPRR3-overexpressing VSMCs exhibited reduced apoptosis compared with control. We also observed a PI3K (phosphatidylinositol 3 kinase)/Akt-dependent positive association between SPRR3 expression and levels of active Akt in VSMCs. The survival advantage seen in SPRR3-overexpressing VSMCs was abrogated after the addition of a PI3K/Akt pathway inhibitor. CONCLUSIONS: These results indicate that SPRR3 protects the lesion from VSMC loss by promoting survival signaling in plaque VSMCs, thereby significantly decreasing atherosclerosis progression. As the first identified atheroma-specific VSMC prosurvival factor, SPRR3 represents a potential target for lesion-specific modulation of VSMC survival. PMID- 25278294 TI - Reliability analysis of nutrient removal from stormwater runoff with green sorption media under varying influent conditions. AB - To support nutrient removal, various stormwater treatment technologies have been developed via the use of green materials, such as sawdust, tire crumbs, sand, clay, sulfur, and limestone, as typical constituents of filter media mixes. These materials aid in the physiochemical sorption and precipitation of orthophosphates as well as in the biological transformation of ammonia, nitrates and nitrites. However, these processes are dependent upon influent conditions such as hydraulic residence time, influent orthophosphate concentrations, and other chemical species present in the inflow. This study aims to compare the physiochemical removal of orthophosphate by isotherm and column tests under differing influent conditions to realize the reliability of orthophosphate removal process with the aid of green sorption media. The green sorption media of interest in this study is composed of a 5:2:2:1 (by volume) mixture of cement sand, tire crumb, fine expanded clay, and limestone. Scenarios of manipulating the hydraulic residence time of the water from 18 min and 60 min, the influent dissolved phosphorus concentrations of 1.0 mg.L(-1) and 0.5 mg.L(-1), and influent water types of distilled and pond water, were all investigated in the column tests. Experimental data were compared with the outputs from the Thomas Model based on orthophosphate removal to shed light on the equilibrium condition versus kinetic situation. With ANOVA tests, significant differences were confirmed between the experimental data sets of the breakthrough curves in the column tests. SEM imaging analysis helps to deepen the understanding of pore structures and pore networks of meta materials being used in the green sorption media. Life expectancy curves derived from the output of Thomas Model may be applicable for future system design of engineering processes. PMID- 25278292 TI - Hemoglobin alpha/eNOS coupling at myoendothelial junctions is required for nitric oxide scavenging during vasoconstriction. AB - OBJECTIVE: Hemoglobin alpha (Hb alpha) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling of eNOS and Hb alpha regulates nitric oxide signaling, vascular reactivity, and blood pressure using a mimetic peptide of Hb alpha to disrupt this interaction. APPROACH AND RESULTS: In silico modeling of Hb alpha and eNOS identified a conserved sequence of interaction. By mutating portions of Hb alpha, we identified a specific sequence that binds eNOS. A mimetic peptide of the Hb alpha sequence (Hb alpha X) was generated to disrupt this complex. Using in vitro binding assays with purified Hb alpha and eNOS and ex vivo proximity ligation assays on resistance arteries, we have demonstrated that Hb alpha X significantly decreased interaction between eNOS and Hb alpha. Fluorescein isothiocyanate labeling of Hb alpha X revealed localization to holes in the internal elastic lamina (ie, myoendothelial junctions). To test the functional effects of Hb alpha X, we measured cyclic guanosine monophosphate and vascular reactivity. Our results reveal augmented cyclic guanosine monophosphate production and altered vasoconstriction with Hb alpha X. To test the in vivo effects of these peptides on blood pressure, normotensive and hypertensive mice were injected with Hb alpha X, which caused a significant decrease in blood pressure; injection of Hb alpha X into eNOS(-/-) mice had no effect. CONCLUSIONS: These results identify a novel sequence on Hb alpha that is important for Hb alpha/eNOS complex formation and is critical for nitric oxide signaling at myoendothelial junctions. PMID- 25278296 TI - The mechanism of transition-metal (Cu or Pd)-catalyzed synthesis of benzimidazoles from amidines: theoretical investigation. AB - In this study, the Cu(OAc)2- and [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines were theoretically investigated using density functional theory calculations. For the Cu-catalyzed system, our calculations supported a four-step-pathway involving C-H activation of an arene with Cu(II) via concerted metalation-deprotonation (CMD), followed by oxidation of the Cu(II) intermediate and deprotonation of the imino group by Cu(III), and finally reductive elimination from Cu(III). In our calculations, the barriers for the CMD step and the oxidation step are the same. The results are different from the ones reported by Fu et al. in which the whole reaction mechanism includes three steps and the CMD step is rate determining. On the basis of the calculation results for the [PdCl2(PhCN)2]-catalyzed system, C-H bond breaking by CMD occurs first, followed by the rate-determining C-N bond formation and N-H deprotonation. Pd(III) species is not involved in the [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines. PMID- 25278295 TI - Cross-sectional research into counselling for non-physician assisted suicide: who asks for it and what happens? AB - BACKGROUND: In the Netherlands, people with a wish to die can request physician assistance in dying. However, almost two thirds of the explicit requests do not result in physician assistance in dying. Some people with a wish to end life seek counselling outside the medical context to end their own life. The aim of this cross-sectional research was to obtain information about clients receiving counselling for non-physician assisted suicide, and the characteristics and outcome of the counselling itself. METHODS: All counsellors working with foundation De Einder (an organisation that offers professional counselling for people with a wish to end life) (N=12) filled in registration forms about all clients they counselled in 2011 and/or 2012. Only client registration data forms with at least one face-to-face contact with the counsellor were selected for analysis (n=595). RESULTS: More than half of the clients were over 65 years old. More than one third of the clients had no wish to end life and 16% had an urgent wish to end life. Almost two thirds of the clients had not requested physician assistance in dying. Half of the clients had others involved in the counselling. More than half of the clients received explicit practical information concerning non-physician assisted suicide, while 13% of all clients actually ended their own life through non-physician assisted suicide. Clients without a (severe) disease were older than clients with a severe disease. They also had more problems of old age and existential suffering and more often wanted to be prepared for self determination. The clients without a (severe) disease more often had no wish to end life and requested physician assistance in dying less often than clients with a severe disease. CONCLUSION: While some of the clients receiving counselling for non-physician assisted suicide seem to be looking for a peaceful death to escape from current suffering, others have no wish to end life and seem to be looking for reassurance in anticipation of prospective suffering. If non-physician assisted suicide is be distinguished from 'mutilating' suicide, this asks for a different approach than suicide crisis intervention, for example suicide-attempt prevention. PMID- 25278297 TI - Predictors of 25(OH)D half-life and plasma 25(OH)D concentration in The Gambia and the UK. AB - Predictors of 25(OH)D3 half-life were factors associated with vitamin D metabolism, but were different between people in The Gambia and the UK. Country was the strongest predictor of plasma 25(OH)D concentration, probably as a marker of UVB exposure. 25(OH)D3 half-life may be applied as a tool to investigate vitamin D expenditure. INTRODUCTION: The aim of this study was to investigate predictors of 25(OH)D3 half-life and plasma 25(OH)D concentration. METHODS: Plasma half-life of an oral tracer dose of deuterated-25(OH)D3 was measured in healthy men aged 24-39 years, resident in The Gambia, West Africa (n = 18) and in the UK during the winter (n = 18), countries that differ in calcium intake and vitamin D status. Plasma and urinary markers of vitamin D, calcium, phosphate and bone metabolism, nutrient intakes and anthropometry were measured. RESULTS: Normally distributed data are presented as mean (SD) and non-normal data as geometric mean (95% CI). Gambian compared to UK men had higher plasma concentrations of 25(OH)D (69 (13) vs. 29 (11) nmol/L; P < 0.0001); 1,25(OH)2D (181 (165, 197) vs. 120 (109, 132) pmol/L; P < 0.01); and parathyroid hormone (PTH) (50 (42, 60) vs. 33 (27, 39); P < 0.0001). There was no difference in 25(OH)D3 half-life (14.7 (3.5) days vs. 15.6 (2.5) days) between countries (P = 0.2). In multivariate analyses, 25(OH)D, 1,25(OH)2D, vitamin D binding protein and albumin-adjusted calcium (Caalb) explained 79% of variance in 25(OH)D3 half life in Gambians, but no significant predictors were found in UK participants. For the countries combined, Caalb, PTH and plasma phosphate explained 39 % of half-life variability. 1,25(OH)2D, weight, PTH and country explained 81% of variability in 25(OH)D concentration; however, country alone explained 74%. CONCLUSION: Factors known to affect 25(OH)D metabolism predict 25(OH)D3 half life, but these differed between countries. Country predicted 25(OH)D, probably as a proxy measure for UVB exposure and vitamin D supply. This study supports the use of 25(OH)D half-life to investigate vitamin D metabolism. PMID- 25278298 TI - Kefir improves bone mass and microarchitecture in an ovariectomized rat model of postmenopausal osteoporosis. AB - SUMMARY: Kefir treatment in ovariectomized (OVX) rats could significantly decrease the levels of bone turnover markers and prevent OVX-induced bone loss, deterioration of trabecular microarchitecture, and biomechanical dysfunction that may be due to increase intracellular calcium uptake through the TRPV6 calcium channel. INTRODUCTION: Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to an increased fracture risk. The incidence of osteoporosis increases with age and occurs most frequently in postmenopausal women due to estrogen deficiency, as the balance between bone resorption and bone formation shifts towards increased levels of bone resorption. Among various methods of prevention and treatment for osteoporosis, an increase in calcium intake is the most commonly recommended preventive measure. Kefir is a fermented milk product made with kefir grains that degrade milk proteins into various peptides with health-promoting effects, including immunomodulating-, antithrombotic-, antimicrobial-, and calcium-absorption-enhancing bioactivities. METHODS: The aim of this study is to investigate the effect of kefir on osteoporosis prophylaxis in an ovariectomized rat model. A total of 56 16-week old female Sprague-Dawley (SD) rats were divided into 7 experimental groups: sham (normal), OVX/Mock, OVX/1X kefir (164 mg/kg BW/day), OVX/2X kefir (328 mg/kg BW/day), OVX/4X kefir (656 mg/kg BW/day), OVX/ALN (2.5 mg/kg BW/day), and OVX/REBONE (800 mg/kg BW/day). After 12-week treatment with kefir, the bone physiology in the OVX rat model was investigated. Accordingly, the aim of this study was to investigate the possible transport mechanism involved in calcium absorption using the Caco-2 human cell line. RESULTS: A 12-week treatment with kefir on the OVX-induced osteoporosis model reduced the levels of C-terminal telopeptides of type I collagen (CTx), bone turnover markers, and trabecular separation (Tb. Sp.). Additionally, treatment with kefir increased trabecular bone mineral density (BMD), bone volume (BV/TV), trabecular thickness (Tb. Th), trabecular number (Tb. N), and the biomechanical properties (hardness and modulus) of the distal femur with a dose-dependent efficacy. In addition, in in vitro assay, we found that kefir increased intracellular calcium uptake in Caco-2 cell through TRPV6 calcium channels and not through L-type voltage-operated calcium channels. CONCLUSION: The protective effect of kefir in the OVX rat model may occur through increasing intracellular calcium uptake through the TRPV6 calcium channel. PMID- 25278299 TI - Sex- and age-specific associations between income and incident major osteoporotic fractures in Canadian men and women: a population-based analysis. AB - We investigated sex- and age-specific associations between income and fractures at the hip, humerus, spine, and forearm in adults aged >=50 years. Compared to men with the highest income, men with the lowest income had an increased fracture risk at all skeletal sites. These associations were attenuated in women. INTRODUCTION: Associations between income and hip fractures are contested, even less is known about other fracture sites. We investigated sex- and age-specific associations between income and major osteoporotic fractures (MOF) at the hip, humerus, spine, and forearm. METHODS: Incident fractures were identified from administrative health data for adults aged >=50 years in Manitoba, Canada, 2000 2007. Mean neighborhood (postal code area) annual household incomes were extracted from 2006 census files and categorized into quintiles. We calculated age-adjusted and age-specific sex-stratified fracture incidence across income quintiles. We estimated relative risks (RR) and 95% CI for income quintile 1 (Q1, lowest income) vs. income quintile 5 (Q5) and tested the linear trend across quintiles. RESULTS: We identified 15,094 incident fractures (4736 hip, 3012 humerus, 1979 spine, and 5367 forearm) in 2718 men and 6786 women. For males, the RR of fracture for the lowest vs. highest income quintile was 1.63 (95% CI 1.42 1.87) and the negative trend was statistically significant (p < 0.0001); individual skeletal sites showed similar associations. For females, the RR of fracture for the lowest vs. highest income quintile was 1.14 (95% CI 1.01-1.28), with a statistically significant negative trend (p = 0.0291); however, the only skeletal site associated with income in women was the forearm (Q1 vs. Q5 RR 1.09, 95% CI 1.01-1.28). CONCLUSIONS: Compared to men with the highest income, men with the lowest income had an increased fracture risk at all skeletal sites. These associations were attenuated in women. For men, these effect sizes seem large enough to warrant public health concern. PMID- 25278300 TI - Merkel cell carcinoma: differences between sun-exposed and non-sun-exposed variants--a clinical analysis of 36 cases. AB - BACKGROUND: There are few studies focusing on the clinical characteristics of Merkel cell carcinoma (MCC). OBJECTIVE: To retrospectively analyze the clinical features of our patients and their relationship with sun exposure. METHODS: Thirty-six patients diagnosed with MCC (20 men and 16 women, mean age 72.08 years) were included in the study. RESULTS: 21 patients developed MCC in sun exposed skin and 15 patients in non-sun-exposed areas. MCC was >2 cm in 19 cases. Six of the 7 patients who died as a result of MCC had non-sun-exposed tumors. Only tumor size >2 cm significantly influenced survival (p = 0.033). CONCLUSION: Sun-exposed lesions tended to be <2 cm in diameter and were more common in men, while non-sun-exposed tumors were larger, usually occurring in women and carrying a greater likelihood of death by MCC. Non-sun-exposed tumors usually present as fast-growing, multilobar nodular lesions with a smooth shiny surface. PMID- 25278301 TI - Snapshots April-August 2014. PMID- 25278302 TI - A prospective study of the Bedside Index for Severity in Acute Pancreatitis (BISAP) score in acute pancreatitis: an Indian perspective. AB - INTRODUCTION: A simple and easily applicable system for stratifying patients with acute pancreatitis is lacking. The aim of our study was to evaluate the ability of BISAP score to predict mortality in acute pancreatitis patients from our institution and to predict which patients are at risk for development of organ failure, persistent organ failure and pancreatic necrosis. METHODS: All patients with acute pancreatitis were included in the study. BISAP score was calculated within 24 h of admission. A Contrast CT was used to differentiate interstitial from necrotizing pancreatitis within seven days of hospitalization whereas Marshall Scoring System was used to characterize organ failure. RESULTS: Among 246 patients M:F = 153:93, most common aetiology among men was alcoholism and among women was gallstone disease. 207 patients had no organ failure and remaining 39 developed organ failure. 17 patients had persistent organ failure, 16 of those with BISAP score >=3. 13 patients in our study died, out of which 12 patients had BISAP score >=3. We also found that a BISAP score of >=3 had a sensitivity of 92%, specificity of 76%, a positive predictive value of 17%, and a negative predictive value of 99% for mortality. DISCUSSION: The BISAP score is a simple and accurate method for the early identification of patients at increased risk for in hospital mortality and morbidity. PMID- 25278303 TI - The loss of alphaSNAP downregulates the expression of occludin in the intestinal epithelial cell of acute pancreatitis model. AB - BACKGROUND AND OBJECTIVE: Intestinal barrier damage is an important event during the occurrence and progression of severe acute pancreatitis. The expression of occludin, one of the main components of the intestinal barrier proteins, is regulated by various factors related to intestinal barrier formation and the remodeling process. The alphaSNAP, as a novel membrane protein, is ubiquitously expressed in intestinal epithelial cells. This study aimed to investigate the role of alphaSNAP in acute pancreatitis and the relationship between occludin and alphaSNAP. METHODS: Mild and severe acute pancreatitis models were established by retrograde injections of 0.5% and 3.8% sodium taurocholate solutions, respectively, into rat pancreaticobiliary ducts. The animals were killed at 1, 2, and 3 days after the injection, and the pathological changes of the pancreas and intestinal mucosa, the changes in intestinal permeability, and the protein expression of occludin and alphaSNAP were assessed. Cultured epithelial IEC-6 cells were further infected with lentiviral alphaSNAP shRNA, cell apoptosis was determined with flow cytometry (FCM), and any changes in occludin expression were detected by Western blotting and immunofluorescent staining. RESULTS: This pathologic study of a rat acute pancreatitis model indicated pancreatic tissue necrosis and inflammatory cell infiltration; the intestinal villi in the severe acute pancreatitis (SAP) group demonstrated edema, lodging, atrophy, and intestinal epithelial cell necrosis, and shedding. The intestinal permeability in rats with pancreatitis increased significantly. The SAP group showed significantly increased levels of serum TNF-alpha and endotoxins. The results of immunofluorescent staining and Western blotting revealed that compared with the SO (sham operation) and MAP (mild acute pancreatitis) groups, the SAP group displayed significantly downregulated protein expressions of alphaSNAP and occludin in the intestinal epithelial cells. After the lentiviral transduction of alphaSNAP shRNA, apoptosis in IEC-6 cells was drastically increased, whereas the expression of occludin was decreased significantly. CONCLUSION: The downregulated expression of alphaSNAP in intestinal epithelial cells leads to reduced occludin expression and enhanced apoptosis of intestinal epithelial cells. Hence, the permeability of the intestinal barrier may be increased in a severe acute pancreatitis model. PMID- 25278304 TI - Prevalence of exocrine pancreatic insufficiency in type 2 diabetes mellitus with poor glycemic control. AB - OBJECTIVES: To evaluate the relationship between exocrine pancreatic insufficiency and the level of glycemic control in diabetes (DM). METHODS: Patients with type 2 DM treated in our clinic were prospectively recruited into the study. Pancreatic diabetes was excluded. Cases with HbA1c >=7% formed Group A (n = 59), and with HbA1c <7% Group B (n = 42). The fecal level of pancreatic elastase (PE-1) was measured and morphological examinations of the pancreas were performed. RESULTS: The PE-1 level was significantly lower in Group A than in Group B (385.9 +/- 171.1 MUg/g, vs. 454.6 +/- 147.3 MUg/g, p = 0.038). The PE-1 level was not correlated with HbA1c (r = -0.132, p = 0.187), the duration of DM (r = -0.046, p = 0.65), age (r = 0.010, p = 0.921), BMI (r = 0.203, p = 0.059), or pancreatic steatosis (r = 0.117, p = 0.244). The size of the pancreas did not differ significantly between Groups A and B. CONCLUSIONS: An exocrine pancreatic insufficiency demonstrated by fecal PE-1 determination is more frequent in type 2 DM patients with poor glycemic control. The impaired exocrine pancreatic function cannot be explained by an alteration in the size of the pancreas or by pancreatic steatosis. PMID- 25278305 TI - The relationship between pancreatic atrophy after steroid therapy and diabetes mellitus in patients with autoimmune pancreatitis. AB - BACKGROUND/OBJECTIVES: Many patients with autoimmune pancreatitis (AIP) have an association with diabetes mellitus. It has not been clarified whether steroid therapy for AIP improves or worsens the condition of diabetes mellitus. The aim of this study was thus to investigate the relationship between pancreatic atrophy after steroid therapy and the clinical course of diabetes. METHODS: Thirty-one AIP patients, who were treated by steroid therapy, were included in this study during December 2005 to March 2013. Pancreatic atrophy 6 months after the beginning of steroid therapy was defined to be present when the width of the pancreatic body was less than 10 mm. The relationships between pancreatic atrophy and patient characteristics as well as the course of diabetes were examined. RESULTS: Steroid therapy was effective in all treated patients. Pancreatic atrophy was observed in 12 patients and not in 19 patients after the steroid therapy. AIP patients with pancreatic atrophy showed higher incidences of diabetes mellitus (p = 0.001, 9/12 vs. 2/19), diabetes control worsening (p = 0.007, 7/12 vs. 2/17), and new onset of diabetes (p = 0.02, 5/7 vs. 1/18) than those without atrophy. It was not associated with gender, other organ involvement, pattern of pancreas swelling (diffuse/focal), serum IgG4 level, alcohol intake, and pancreatic calcification on CT. Patients with new onset of diabetes needed insulin therapy, even in the maintenance therapy of AIP. CONCLUSIONS: AIP patients with pancreatic atrophy after steroid therapy have a high incidence of diabetes mellitus. New onset of diabetes is closely associated with pancreatic atrophy after steroid therapy. PMID- 25278306 TI - Increase diagnostic accuracy in differentiating focal type autoimmune pancreatitis from pancreatic cancer with combined serum IgG4 and CA19-9 levels. AB - BACKGROUND/OBJECTIVES: To distinguish autoimmune pancreatitis (AIP), especially focal type, from pancreatic cancer, is a greatest challenge for clinician. The aim of the study is to compare the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of combined serum IgG4 and CA19-9 levels to differentiate AIP from pancreatic cancer by HISORt, Asian and international consensus diagnostic criteria. METHODS: We measured serum IgG4, CEA, and CA19-9 levels in 188 AIP patients, 86 non-AIP chronic pancreatitis patients, and 130 pancreatic cancer patients. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were compared with different diagnostic criteria. We also compared the diagnostic performance in patients with or without jaundice. RESULTS: The serum level of IgG4 was significantly higher in AIP than those in non-AIP chronic pancreatitis and pancreatic cancer. The optimal cutoffs of IgG4 and CA19-9 to differentiate AIP from pancreatic cancer were 175 mg/dL and 85.0 U/ml based on ROC analysis. Combining IgG4 level over 280 mg/dL and CA19-9 below 85.0 U/ml could yield a best diagnostic accuracy (85.6%) to distinguishing AIP from pancreatic cancer in all of the HISORt, Asian and international consensus diagnostic criteria. With the combination of serological test, focal type AIP could be diagnosed with comparable accuracy as diffuse type AIP. CONCLUSIONS: Our study demonstrated that combined use of serum IgG4 (over 280 mg/dL) and CA19-9 9 (below 85.0 U/ml) together increases the diagnostic accuracy to distinguish AIP from pancreatic cancer non-invasively, especially in focal type autoimmune pancreatitis. PMID- 25278307 TI - Relationship between autoimmune pancreatitis and pancreatic cancer: a single center experience. AB - OBJECTIVES: Ordinary chronic pancreatitis (CP), such as alcoholic CP, is well established to have the increased risk for pancreatic cancer (PaC), nevertheless an association between autoimmune pancreatitis (AIP) and PaC is still unknown. The aims of this study are to examine the frequency of patients who developed PaC during follow-up after being diagnosed with type 1 AIP and to compare the incidence rate of PaC between patients with type 1 AIP and CP. METHODS: Sixty three patients with type 1 AIP and 41 patients with CP were enrolled. We examined development of PaC during follow-up from their clinical records. RESULTS: The mean follow-up period was 62.4 months in AIP group and 49.2 months in CP group. The occurrence of PaC was observed in 3 patients with AIP during the mean follow up period of 94.7 months (range, 31-186), whereas a single CP patient developed PaC 38 months after CP diagnosis. The incident rate of PaC during follow-up was comparable between the 2 groups [4.8% (3/63) in type 1 AIP group vs. 2.4% (1/41) in CP group]. In all of 3 AIP patients who developed accompanying PaC, the clinical remission of AIP was achieved with maintenance steroid therapy, when tumors were discovered. In the histological examination of one surgical patient with PaC, lymphoplasmacytic infiltration in storiform fibrosis with abundant IgG4 positive cell infiltration was observed around the PaC area. CONCLUSIONS: Similar to patients with ordinary CP, surveillance for development of PaC is needed at regular interval during follow-up in AIP patients. PMID- 25278308 TI - Diagnostic yield of EUS-FNA-based cytology distinguishing malignant and benign IPMNs: a systematic review and meta-analysis. AB - OBJECTIVES: Differential diagnosis of malignant and benign intraductal papillary mucinous neoplasms (IPMNs) is essential to determine the optimal treatment. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is currently used to diagnose pancreatic cystic lesions worldwide, but few studies have focused on the diagnostic yield to distinguish malignant and benign IPMNs. Therefore, we aim to systematically review the diagnostic yield of EUS-FNA-based cytology to distinguish malignant and benign IPMNs. METHODS: Relevant studies with a reference standard of definitive surgical histology which published between 2002 and 2012 were identified via MEDLINE and SCOPUS. Malignant IPMNs included invasive adenocarcinoma, carcinoma in situ, and high-grade dysplasia. RESULTS: Four studies with 96 patients were included in this meta-analysis. For diagnostic yield of EUS-FNA-based cytology distinguishing malignant and benign IPMNs, the pooled sensitivity and specificity were 64.8% (95% CI, 0.44-0.82) and 90.6% (95% CI, 0.81-0.96), respectively. Similarly, the positive likelihood ratio and negative likelihood ratio were 6.35 (95% CI, 2.95-13.68) and 0.43 (95% CI, 0.14 1.34), respectively. Malignant IPMNs were observed in 20.8% (20/96) of patients in EUS-FNA studies. CONCLUSIONS: EUS-FNA-based cytology has good specificity but poor sensitivity in differentiating benign from malignant IPMNs. Newer techniques or markers are needed to improve diagnostic yield. PMID- 25278309 TI - Hypoxia-inducible factor 1alpha expression and its clinical significance in pancreatic cancer: a meta-analysis. AB - BACKGROUND AND AIMS: Pancreatic cancer is characterized by inadequate vascularization and considerable tumor hypoxia is prevalent. However, whether hypoxia-inducible factor 1alpha (HIF-1alpha) is significantly correlated with clinical prognosis in pancreatic cancer remains unclear. We aimed to determine the value of HIF-1alpha as a predictor of survival in pancreatic cancer through a meta-analysis of available cohort studies. METHODS: We performed a literature search of the MEDLINE, Embase, and Cochrane Library databases to identify cohort studies on the prognostic value of HIF-1alpha in pancreatic cancer. We conducted a meta-analysis to examine the clinical status and overall survival of patients with high HIF-1alpha expression compared to those with low expression. RESULTS: We analyzed eight studies involving 557 patients. HIF-1alpha was associated with higher rate of lymph node metastasis (odd ratio [OR] = 3.16; 95% confidence interval [CI] = 1.95-5.11; p < 0.05) and advanced tumor stage (OR = 3.66; 95% CI = 2.01-6.69; p < 0.05), while no significant difference was detected for tumor diameter (OR = 1.58; 95% CI = 0.46-5.47; p > 0.05). Notably, HIF-1alpha overexpression was significantly correlated with poor overall survival (hazard ratio [HR] = 1.88; 95% CI = 1.39-2.56; p < 0.05). CONCLUSIONS: We believe that HIF-1alpha overexpression is significantly associated with poor prognosis in pancreatic cancer, and may serve as an important parameter for evaluating the biological behavior and prognosis of pancreatic cancer. PMID- 25278310 TI - A phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression. AB - BACKGROUND: Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5'-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. METHODS: Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). RESULTS: Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. CONCLUSION: This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma. PMID- 25278312 TI - Complete pathological response after FOLFIRINOX for locally advanced pancreatic cancer. The beginning of a new era? Case report and review of the literature. AB - Neoadjuvant treatments (chemo or chemoradiation therapy) are used for patients with locally advanced Pancreatic Ductal Adeno-Carcinoma (PDAC). FOLFIRINOX is now considered an effective treatment modality for patients with metastatic pancreatic cancer and a promising option for patients with locally advanced PDAC. Complete pathologic response after neoadjuvant therapies is anecdotic and its prognostic impact is completely unclear. We report the case of a complete pathological response after treatment with FOLFIRINOX in a patient affected by a locally advanced PDAC with a review of the literature regarding the use of FOLFIRINOX for locally advanced PDAC. PMID- 25278313 TI - Third trimester-equivalent ethanol exposure is characterized by an acute cellular stress response and an ontogenetic disruption of genes critical for synaptic establishment and function in mice. AB - The developing brain is remarkably sensitive to alcohol exposure, resulting in the wide range of cognitive and neurobehavioral characteristics categorized under the term fetal alcohol spectrum disorders (FASD). The brain is particularly susceptible to alcohol during synaptogenesis, a process that occurs heavily during the third trimester and is characterized by the establishment and pruning of neural circuitry; however, the molecular response of the brain to ethanol during synaptogenesis has not been documented. To model a binge-like exposure during the third-trimester neurodevelopmental equivalent, neonate mice were given a high (5 g/kg over 2 h) dose of ethanol at postnatal day 7. Acute transcript changes within the brain were assessed using expression arrays and analyzed for associations with gene ontology functional categories, canonical pathways, and gene network interactions. The short-term effect of ethanol was characterized by an acute stress response and a downregulation of energetically costly cellular processes. Further, alterations to a number of genes with roles in synaptic transmission and hormonal signaling, particularly those associated with the neuroendocrine development and function, were evident. Ethanol exposure during synaptogenesis was also associated with altered histone deacetylase and microRNA transcript levels, suggesting that abnormal epigenetic patterning may maintain some of the persistent molecular consequences of developmental ethanol exposure. The results shed insight into the sensitivity of the brain to ethanol during the third-trimester equivalent and outline how ethanol-induced alterations to genes associated with neural connectivity may contribute to FASD phenotypes. PMID- 25278311 TI - Role of pancreatic fat in the outcomes of pancreatitis. AB - The role of obesity in relation to various disease processes is being increasingly studied, with reports over the last several years increasingly mentioning its association with worse outcomes in acute disease. Obesity has also gained recognition as a risk factor for severe acute pancreatitis (SAP).The mortality in SAP may be as high as 30% and is usually attributable to multi system organ failure (MSOF) earlier in the disease, and complications of necrotizing pancreatitis later [9-11]. To date there is no specific treatment for acute pancreatitis (AP) and the management is largely expectant and supportive. Obesity in general has also been associated with poor outcomes in sepsis and other pathological states including trauma and burns. With the role of unsaturated fatty acids (UFA) as propagators in SAP having recently come to light and with the recognition of acute lipotoxicity, there is now an opportunity to explore different strategies to reduce the mortality and morbidity in SAP and potentially other disease states associated with such a pathophysiology. In this review we will discuss the role of fat and implications of the consequent acute lipotoxicity on the outcomes of acute pancreatitis in lean and obese states and during acute on chronic pancreatitis. PMID- 25278314 TI - Processes controlling the fate of chloroethenes emanating from DNAPL aged sources in river-aquifer contexts. AB - This work dealt with the physical and biogeochemical processes that favored the natural attenuation of chloroethene plumes of aged sources located close to influent rivers in the presence of co-contaminants, such as nitrate and sulfate. Two working hypotheses were proposed: i) Reductive dechlorination is increased in areas where the river-aquifer relationship results in the groundwater dilution of electron acceptors, the reduction potential of which exceeds that of specific chloroethenes; ii) zones where silts predominate or where textural changes occur are zones in which biodegradation preferentially takes place. A field site on a Quaternary alluvial aquifer at Torello, Catalonia (Spain) was selected to validate these hypotheses. This aquifer is adjacent to an influent river, and its redox conditions favor reductive dechlorination. The main findings showed that the low concentrations of nitrate and sulfate due to dilution caused by the input of surface water diminish the competition for electrons between microorganisms that reduce co-contaminants and chloroethenes. Under these conditions, the most bioavailable electron acceptors were PCE and metabolites, which meant that their biodegradation was favored. This led to the possibility of devising remediation strategies based on bioenhancing natural attenuation. The artificial recharge with water that is low in nitrates and sulfates may favor dechlorinating microorganisms if the redox conditions in the mixing water are sufficiently maintained as reducing and if there are nutrients, electron donors and carbon sources necessary for these microorganisms. PMID- 25278316 TI - Version 3 of the historical-clinical-risk management-20 (HCR-20V3): relevance to violence risk assessment and management in forensic conditional release contexts. AB - The conditional release of insanity acquittees requires decisions both about community risk level and the contextual factors that may mitigate or aggravate risk. This article discusses the potential role of the newly revised Historical Clinical-Risk Management-20 (HCR-20, Version 3) within the conditional release context. A brief review of the structured professional judgment (SPJ) approach to violence risk assessment and management is provided. Version 2 of the HCR-20, which has been broadly adopted and evaluated, is briefly described. New features of Version 3 of the HCR-20 with particular relevance to conditional release decision-making are reviewed, including: item indicators; ratings of the relevance of risk factors to an individual's violence; risk formulation; scenario planning; and risk management planning. Version 3 of the HCR-20 includes a number of features that should assist evaluators and decision-makers to determine risk level, as well as to anticipate and specify community conditions and contexts that may mitigate or aggravate risk. Research on the HCR-20 Version 3 using approximately 800 participants across three settings (forensic psychiatric, civil psychiatric, correctional) and eight countries is reviewed. PMID- 25278315 TI - Item response theory-based measure of global disability in multiple sclerosis derived from the Performance Scales and related items. AB - BACKGROUND: The eight Performance Scales and three assimilated scales (PS) used in North American Research Committee on Multiple Sclerosis (NARCOMS) registry surveys cover a broad range of neurologic domains commonly affected by multiple sclerosis (mobility, hand function, vision, fatigue, cognition, bladder/bowel, sensory, spasticity, pain, depression, and tremor/coordination). Each scale consists of a single 6-to-7-point Likert item with response categories ranging from "normal" to "total disability". Relatively little is known about the performances of the summary index of disability derived from these scales (the Performance Scales Sum or PSS). In this study, we demonstrate the value of a combination of classical and modern methods recently proposed by the Patient Reported Outcome Measurement Information System (PROMIS) network to evaluate the psychometric properties of the PSS and derive an improved measure of global disability from the PS. METHODS: The study sample included 7,851adults with MS who completed a NARCOMS intake questionnaire between 2003 and 2011. Factor analysis, bifactor modeling, and item response theory (IRT) analysis were used to evaluate the dimension(s) of disability underlying the PS; calibrate the 11 scales; and generate three alternative summary scores of global disability corresponding to different model assumptions and practical priorities. The construct validity of the three scores was compared by examining the magnitude of their associations with participant's background characteristics, including unemployment. RESULTS: We derived structurally valid measures of global disability from the PS through the proposed methodology that were superior to the PSS. The measure most applicable to clinical practice gives similar weight to physical and mental disability. Overall reliability of the new measure is acceptable for individual comparisons (0.87). Higher scores of global disability were significantly associated with older age at assessment, longer disease duration, male gender, Native-American ethnicity, not receiving disease modifying therapy, unemployment, and higher scores on the Patient Determined Disease Steps (PDDS). CONCLUSION: Promising, interpretable and easily-obtainable IRT scores of global disability were generated from the PS by using a sequence of traditional and modern psychometric methods based on PROMIS recommendations. Our analyses shed new light on the construct of global disability in MS. PMID- 25278317 TI - Compassion, commitment, and dedication: Epilepsy & behavior on its 15th anniversary. PMID- 25278318 TI - Epilepsy, behavior, and neuropsychiatry. PMID- 25278320 TI - Prescriptions by mail improve access and affordability to medications for Medicare Part D beneficiaries. PMID- 25278321 TI - Medical cost offsets from prescription drug utilization among Medicare beneficiaries. AB - This brief commentary extends earlier work on the value of adherence to derive medical cost offset estimates from prescription drug utilization. Among seniors with chronic vascular disease, 1% increases in condition-specific medication use were associated with significant (P less than 0.001) reductions in gross nonpharmacy medical costs in the amounts of 0.63% for dyslipidemia, 0.77% for congestive heart failure, 0.83% for diabetes, and 1.17% for hypertension. PMID- 25278322 TI - An early examination of access to select orphan drugs treating rare diseases in health insurance exchange plans. AB - BACKGROUND: Patients with rare diseases often face significant health care access challenges, particularly since the number of available treatment options for rare diseases is limited. The implementation of health insurance exchanges promises improved access to health care. However, when purchasing a plan, patients with rare diseases need to consider multiple factors, such as insurance premium, access to providers, coverage of a specific medication or treatment, tier placement of drug, and out-of-pocket costs. OBJECTIVE: To provide an early snapshot of the exchange plan landscape from the perspective of patients with select rare diseases by evaluating the degree of access to medications in a subset of exchange plans based on coverage, tier placement, associated cost sharing, and utilization management (UM) applied. METHODS: The selection of drugs for this analysis began by identifying rare diseases with FDA-approved treatment options using the National Institutes of Health Office of Rare Diseases' webpage and further identification of a subset of drugs based on select criteria to ensure a varied sample, including the characteristics and prevalence of the condition. The medications were categorized based on whether alternative therapies have FDA approval for the same indication and whether there are comparators based on class or therapeutic area. The list was narrowed to 11 medications across 7 diseases, and the analysis was based on how these drugs are listed in exchange plan outpatient pharmacy benefit formularies. This analysis focused on 84 plans in 15 states with the highest expected exchange enrollment and included a variety of plan types to ensure that variability in the marketplace was represented. To best approximate plans that will have the greatest enrollment, the analysis focused on silver and bronze plan formularies because consumers in this market are expected to be sensitive to premiums. Data on drug coverage, tier placement, cost, and UM were collected from these plans beginning October 1, 2013, with the launch of the open enrollment period. RESULTS: Coverage and use of UM for selected medications vary within and across states. This study found that bronze plans were far less likely than silver plans to cover the 11 products included in this analysis. Results also showed that select drugs identified as the only FDA-approved product indicated for a certain rare disease experienced relatively robust coverage (at least 65% of plans) but often included some form of UM. However, coverage of selected rare disease therapies also is complicated by the fact that plans cover certain products under the medical benefit versus the pharmacy benefit. At the time of this analysis, transparency of medical benefit coverage for these products in exchange plans was limited.Selected medications are most likely to appear on the highest tiers of 4 tier formularies or are not covered at all. Although there are no requirements to designate certain tiers as "specialty tiers," more than 70% of plans in this study use coinsurance for the highest tiers of their formularies. Rates of coinsurance for medications on highest tiers range from 10% to 50% in silver plans and 15% to 50% in bronze plans. Among those plans utilizing copayments rather than coinsurance, ranges of copayments for these select products vary between $20 and $250 per prescription across both silver plans and bronze plans. CONCLUSIONS: This preliminary analysis of access to treatments for patients with select rare diseases revealed the complexities involved for patients with specific needs when selecting a plan with appropriate coverage. For patients with rare diseases, the process of identifying and selecting a plan centers on understanding if and how the plan covers a specific treatment or set of treatments. Access factors will likely vary substantially across plans, as demonstrated by the findings from this analysis. With limited treatment options and the potential for cost sharing and UM barriers, increased data transparency to assist patients in navigating formularies will be a critical step for patients to fully understand their access to needed therapies in each plan. PMID- 25278323 TI - Adherence and persistence among chronic myeloid leukemia patients during second line tyrosine kinase inhibitor treatment. AB - BACKGROUND: Chronic myeloid leukemia (CML) treatment is lifelong, and while it is important for patients to remain adherent to treatment, there are conflicting findings with respect to differences in adherence and persistence with dasatinib or nilotinib during second-line treatment. OBJECTIVE: To compare the rates of adherence, persistence, and discontinuation of 2 oral second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, in CML patients during their first 12 months of second-line treatment. METHODS: Adult CML patients (ICD-9-CM: 205.1x) with 2 consecutive dasatinib or nilotinib prescription claims within 12 months were identified from the Truven Health MarketScan Databases (January 1, 2006-September 30, 2011). Patients were excluded if they had FDA-approved non-CML indications for imatinib, had less than 6 months continuous enrollment, or had a stem cell/bone marrow transplant in the 6 months pre-index. Patients were followed until the first occurrence of index TKI discontinuation/switch; enrollment end; December 31, 2011; or 12 months follow-up post-index. Index treatment (dasatinib <= 100 mg or nilotinib) was categorized as second-line if there was evidence of only 1 alternative TKI exposure (e.g., imatinib, dasatinib, or nilotinib) anytime during the patient's available claims history. When comparing adherence, persistence, and discontinuation, inverse probability treatment weighting (IPTW) was used. Adherence and persistence measures were calculated as specified by the International Society for Pharmacoeconomics and Outcomes Research Medication Compliance and Persistence Special Interest Group. Treatment adherence was calculated using medication possession ratio (MPR) and was reported as both continuous and binary measures (i.e., high adherence = MPR >= 85%). Persistence was reported as the proportion of days covered (PDC) and estimated level of persistence (ELPT). Finally, discontinuation was defined as a treatment gap of greater than 90 days and absence of index TKI during the remainder of the follow-up period. Time to discontinuation and high adherence of index TKI were compared using weighted Cox proportional hazards and logistic regression models, respectively. RESULTS: After propensity weighting, the 219 second-line dasatinib patients and the 158 second-line nilotinib patients were similar in mean age, gender, cancer complexity, and comorbidity burden at baseline. Age as a categorical measure, population density, and index year remained imbalanced and were, therefore, included as covariates in the multivariate analysis of adherence. In the bivariate analyses, mean MPR (88.2% vs. 84.4%, P = 0.036); proportion of patients with high adherence (72.7% vs. 63.3%, P = 0.006); and ELPT (70.4% vs. 62.7%, P = 0.026) were significantly higher among dasatinib patients than nilotinib patients. Mean PDC was not significantly different between dasatinib and nilotinib patients (0.79 vs. 0.77, P = 0.328) after propensity weighting. In addition, a significantly lower proportion of second-line dasatinib patients discontinued their index therapy compared with second-line nilotinib patients (4.4% vs. 8.6%, P = 0.020). With a hazard ratio (HR) of 0.50 (95% CI = 0.27-0.93, P = 0.029), dasatinib patients had half the possibility of discontinuing treatment compared with nilotinib patients at any point in time. After accounting for the baseline factors remaining imbalanced and controlling for cancer complexity and number of concomitant medications at baseline, second-line dasatinib patients were 1.7 times (95% CI = 1.2-2.4) more likely to be highly adherent than second-line nilotinib patients (P = 0.0016). CONCLUSIONS: Among second-line TKI-treated CML patients, dasatinib patients had significantly higher adherence and lower discontinuation rates compared with patients receiving second-line nilotinib. PMID- 25278324 TI - Medication adherence to specific drug classes in chronic heart failure. AB - BACKGROUND: Adherence to medication is crucial to improve clinical outcomes in patients with heart failure (HF). However, at least 1 out of 4 patients is nonadherent to his or her medication. Several studies have quantified medication adherence in HF patients, monitoring only 1 drug with the Medication Event Monitoring System (MEMS). Some authors have argued that monitoring 1 drug reflects the whole adherence behavior, although there is some evidence of important differences in adherence to distinct drug classes. Furthermore, medication characteristics could be a relevant predictor of adherence, and different drugs could pose different barriers to patients. OBJECTIVES: To (a) quantify medication adherence to angiotensin-converting enzyme inhibitors (ACEI), beta blockers, and loop diuretics and (b) compare the agreement in adherence among drug classes in chronic HF. METHODS: Medication adherence to 3 different drugs was monitored using MEMS in 63 patients (81% male, mean age 63.5 years). Medication adherence was measured as the percentage of prescribed doses effectively taken. Patients were considered to be adherent when at least 88% of prescribed doses were taken. Adherence agreement between drug classes was analyzed with Bland-Altman plots and Kappa coefficients. RESULTS: The mean adherence was 97.3% for ACEI, 97.2% for beta blockers, and 96.0% for loop diuretics. Individual patients did not adhere equally to all drug classes, with differences within the same patient ranging from -35% to 33%. The proportion of patients classified as adherent was 77.8% to ACEI, 69.8% to beta blockers, and 69.8% to loop diuretics. The agreement between each of 2 drugs regarding adherence was substantial (beta blocker vs. ACEI: K = 0.72; beta blocker vs. diuretic: K = 0.62; ACEI vs. diuretic: K = 0.72). If patients were classified as adherent and nonadherent based only on 1 drug, 20% of patients would be misclassified regarding the other drugs. CONCLUSIONS: Patients can adhere differently to medication used in HF treatment, with lowest adherence to loop diuretic and beta blockers and highest adherence to ACEI. Studies measuring medication adherence should always specify the drug class being analyzed and should not mix different drug classes to generalize about adherence behavior. PMID- 25278325 TI - A retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center. AB - BACKGROUND: Clinical trials evaluating the efficacy of dabigatran followed a very strict protocol, which included close monitoring and follow-up. Patients followed in this controlled environment had an average medication possession ratio (MPR) greater than 0.95. However, very few studies have evaluated patient adherence to dabigatran in a real-world setting. Other studies of chronic medications indicate patients are not reliably adherent to twice daily regimens. Adherence to therapy is particularly important for direct thrombin inhibitors because there may be a risk of increased thromboembolic events associated with poor adherence to these agents. OBJECTIVE: To identify the MPR for patients prescribed dabigatran at a large academic medical center and affiliated clinics. METHODS: This retrospective descriptive study evaluated the MPR for patients prescribed dabigatran between January 1, 2012, and December 31, 2012. Patients included in this study had to receive dabigatran for a minimum of 3 months, have a primary care physician or cardiologist at the medical center or affiliated clinics, and must not use a mail order pharmacy. Patient MPR was calculated based on prescriptions picked up from the patient. RESULTS: After screening 400 patients, 159 patients met eligibility criteria. The mean MPR for the patients in this study was 0.63. Overall, 43% of the patients had an MPR of less than 0.80, and the mean MPR for this subgroup was 0.39 +/- 0.27; 57% of the study population had an MPR of 0.80 or higher, with a mean MPR of 0.94 +/- 0.08. There was a significantly higher proportion of men (67.7%, P = 0.0112) and a larger number of "as needed medications" prescribed (1.73 vs. 0.86, P = 0.0039) in patients with an MPR less than 0.80. There were 5 patients hospitalized during the study period (3 for bleeding, 1 for confusion, and 1 death not related to dabigatran therapy). CONCLUSIONS: The relatively low mean MPR seen in this study may indicate that there is a need for improved anticoagulation services and follow-up for patients taking dabigatran. PMID- 25278326 TI - Evaluation of an outpatient pharmacy clinical services program on adherence and clinical outcomes among patients with diabetes and/or coronary artery disease. AB - BACKGROUND: Poor medication adherence among patients with chronic diseases can result in complications and increased health care expenditures. An outpatient pharmacy clinical service (OPCS) program targeted nonadherent diabetes mellitus (DM) and/or coronary artery disease (CAD) patients with hemoglobin A1c (HbA1c) and/or low-density lipoprotein cholesterol (LDL-C) outside clinical goals. Pharmacists engaged identified patients with a face-to-face B-SMART consult, a consultation methodology to identify Barriers to medication adherence, work on Solutions to identified barriers, Motivate patients, recommend Adherence tools, reinforce the pharmacist-patient Relationship, and Triage if needed, to other services such as health education to improve outcomes. OBJECTIVES: To (a) assess rates of medication adherence and clinical outcomes in the OPCS program compared with usual care in an integrated health care system and (b) estimate return-on investment (ROI) from this intervention. METHODS: This retrospective cohort study used data from the Kaiser Permanente Southern California region to identify patients who received OPCS consultations and usual care patients from March 2009 through December 2010, with 1 year of follow-up from the initial consult (index date). Four patients from usual care were matched to each patient in the OPCS program and were assigned the same index date as the matching OPCS patient. Additional selection criteria were applied after matching. All patients were required to have a medication possession ratio (MPR) of less than 0.80 for their diabetes or dyslipidemia oral medications 1 year prior to the index date, indicating lower adherence to the prescribed therapy. Diabetic patients or dyslipidemic patients had to have a HbA1c or LDL-C lab result outside of clinical goals prior to the index date to be included in the study, respectively. Adherence outcomes as well as clinical outcomes were measured 12 months after the index date using chi-square tests for differences in percentages and t-tests for differences in means. The ROI was based on a cost-avoidance model that compared the cost of the OPCS program with the cost savings gained through reduced hospitalizations and emergency department (ED) visits. The diabetes and dyslipidemia cohorts were combined for the ROI analysis. RESULTS: Demographic and clinical characteristics at baseline were similar between the OPCS group (n = 1,480) and usual care group (n = 1,477). Among patients with diabetes, a higher percentage in the OPCS group than in the usual care group were adherent with their diabetes medications (53.5% vs. 37.4%, P = 0.001). There was no significant difference in average MPR between groups. However, patients in the OPCS group had a greater increase in mean MPR (0.19 vs. 0.15, P = 0.024); were less likely to discontinue taking their diabetes medications (11.7% vs. 35.5%, P = 0.001); and were more likely to have a timely first fill after the index date (34.8% vs. 12.9%, P = 0.001). The average number of days to the first fill after the index date was significantly shorter for the OPCS group (79.3 vs. 156.3, P = 0.001). Regarding clinical outcomes, patients with diabetes in the OPCS group had a lower mean HbA1c (8.48 vs. 8.80, P = 0.024) and a greater reduction in HbA1c (-1.25 vs. -0.75, P = 0.001) than in the usual care group. They were also less likely to have an ED visit (1.67% vs. 4.21%, P = 0.040), but there was no significant difference in the percentage of patients with a hospital admission. Among patients with dyslipidemia, the mean MPR was significantly lower for the OPCS group than the usual care group (0.70 vs. 0.74, P = 0.003). There were no significant differences in the percentage of adherent patients or the change in mean MPR from baseline. However, the OPCS group was significantly less likely to discontinue dyslipidemia medications (21.1% vs. 35.4%, P less than 0.001) and more likely to have a timely fill (28.3% vs. 15.1%, P less than 0.001). The average days to first fill after the index date was 106.9 for the OPCS group, compared with 162.6 for the usual care group (P less than 0.001). The OPCS group had a lower mean LDL-C (105.1 vs. 110.4, P = 0.001) and a greater reduction in LDL-C (-30.5 vs. -22.4, P = 0.001) than the usual care group. There were no significant differences in the percentage of patients with an ED visit or a hospital admission. In terms of ROI, assuming that 58% of hospitalizations and 8.5% of ED visits incurred in the usual care group were avoidable, approximately $5.79 could be saved for every dollar spent on the OPCS program. CONCLUSION: By engaging nonadherent patients to restart their DM or lipid medications during a face-to-face consult, the OPCS pharmacist was able to influence and improve medication adherence and clinical outcomes, particularly among patients with diabetes. A positive ROI was demonstrated. PMID- 25278328 TI - Measuring pharmacy performance in the area of medication adherence: addressing the issue of risk adjustment. AB - BACKGROUND: Pharmacies and pharmacists play an important role in the health care system, improving health outcomes and enhancing quality through better pharmaceutical care. Yet, little information is available to accurately evaluate pharmacy store quality and thereby encourage quality improvement at the pharmacy store level. OBJECTIVES: To (a) assess pharmacy performance in the area of medication adherence and (b) examine the impact of risk adjustment of performance scores on pharmacy rankings. METHODS: We used proportion of days covered (PDC) to compute pharmacy performance scores using the 2007 Mississippi Medicare administrative claims dataset. We calculated unadjusted and adjusted quality scores for 685 pharmacies serving 137,497 eligible Medicare beneficiaries. Risk adjusted quality scores were computed using a hierarchical logistic regression model (Method 1) and the shrinkage estimators of the model (Method 2). Patient demographics, income subsidy status, and comorbidity burden were used as variables for risk adjustment. RESULTS: Unadjusted scores showed low levels of agreement (Cohen's kappa less than 0.45) with risk-adjusted scores in identifying statistical outliers based on 95% CIs. Unadjusted scores also failed to identify 39%-43% of the top 20% and bottom 20% of pharmacies and displayed moderate agreement (0.4 less than kappa less than 0.5) with risk-adjusted scores. Pharmacy classifications based on risk-adjusted scores obtained from different statistical methods showed high levels of agreement (0.79 less than kappa less than 0.98). CONCLUSIONS: In the risk-adjustment methods presented here, we account for many patient characteristics previously reported to be associated with medication adherence and available in our dataset. Risk-adjusted scores produced more robust indicators of pharmacy quality than unadjusted scores. Depending on the availability of important variables in the source data, the use of risk-adjusted quality indicators may lead to better evaluation of pharmacy quality and should be considered when providing public reports on pharmacy quality. PMID- 25278327 TI - Persistence and adherence with urinary antispasmodic medications among employees and the impact of adherence on costs and absenteeism. AB - BACKGROUND: Overactive bladder (OAB) and related conditions, such as urge urinary incontinence (UI), can interfere with work, leisure activities, and healthy sleep patterns. OBJECTIVES: To report (a) employee urinary antispasmodic (UA) medication persistence and adherence; (b) the impact of salary and copay on adherence; and (c) the impact of UA adherence on medical, pharmacy, sick leave (SL), short- and long-term disability (STD, LTD), workers' compensation costs, work absence days, and turnover. METHODS: This retrospective study used a 2001 2011 database of claims, payroll, and demographic data from 27 large U.S. employers. Employees aged 18-64 years taking UA medications with health plan enrollment from 6 months before the index UA medication prescription to 12 months after were included. Persistence (days until first >= 30-day gap in UA medication supply) and adherence (percentage of the annual post-index period with available medication) were assessed using survival analysis and generalized linear regression models that controlled for demographics, job-related factors, copay, and pre-index employee benefit utilization. RESULTS: 2,960 employees met study criteria. Median days of persistence by OAB subtype were 76, 82, 43, 66, and 60 for urge UI, mixed UI, nocturnal UI, other OAB, and no diagnosis, respectively (P less than 0.05 for urge and mixed vs. no diagnosis). Increased copay and copay as a percentage of salary were associated with lower adherence. Employees with >= 80% adherence had lower medical, SL, and STD and higher overall drug costs than employees with less than 80% adherence. CONCLUSIONS: This study suggests potential economic benefits to employers from increased UA adherence. Additionally, economic factors such as ability to pay influence adherence to UA medications. PMID- 25278329 TI - Unifying external and internal immune defences. AB - External immune defence, such as antimicrobial secretions, is not generally viewed as part of the immune system. Nevertheless, it constitutes a first barrier to pathogens and manipulates the microbial environment. Hygienic measures from the protection of oneself or conspecifics, of the nesting site, or of stored food might be more efficient with secreted antimicrobials. Here, we argue that antimicrobial secretions represent an extended arm of the immune system, forming an underappreciated selective force in the evolution of immune systems. Integrating external immunity into the immune system and general host physiology provides an amenable concept for the understanding of immune system variation and life-history trade-offs. Future research should evaluate complementary or additive roles of antimicrobial secretions in relation to internal immunity. PMID- 25278331 TI - Fluorogenic supramolecular complexes formed between pyrenyl-beta-cyclodextrin and glyco-rhodamine for the selective detection of lectins. AB - Fluorogenic supramolecular complexes formed between tubular-shaped pyrenyl-beta cyclodextrins and glyco-rhodamine are determined to respond to a selective lectin with 'turn-on' fluorescence with excellent selectivity over a range of competing species. PMID- 25278330 TI - Supporting the ceftaroline fosamil/avibactam Enterobacteriaceae breakpoint determination using humanised in vivo exposures in a thigh model. AB - Previous in vivo studies using a human-simulated regimen of ceftaroline/avibactam 600/600mg every 8h (q8h) showed activity against extended-spectrum beta-lactamase , AmpC- and KPC-producing Enterobacteriaceae with minimum inhibitory concentrations (MICs) <= 1 MUg/mL. Here we sought to determine the efficacy of this human-simulated regimen against organisms with MICs >= 1 MUg/mL to help determine a breakpoint value that would reliability predict efficacy in humans. In total, 31 isolates (1 Escherichia coli, 9 Klebsiella pneumoniae, 9 Enterobacter cloacae, 1 Citrobacter koseri, 2 Serratia marcescens, 1 Klebsiella oxytoca and 8 Pseudomonas aeruginosa) with ceftaroline/avibactam MICs of 1 to 16 MUg/mL were tested in a murine immunocompromised thigh infection model; 15 isolates were also tested in an immunocompetent model. Doses were given to simulate human free drug exposures of ceftaroline fosamil/avibactam 600/600 mg q8h over 24h as a 1-h infusion by targeting the fT>MIC profile. Efficacy was evaluated as the change in log10 CFU compared with 0-h controls after 24h. Reductions in bacterial CFU in the neutropenic model were seen against a majority of isolates tested with MICs <= 4 MUg/mL, where fT>MIC was >55%. More variable efficacy was seen in isolates with MICs >= 8 MUg/mL, where fT>MIC drops below 40%. Overall activity was enhanced in the immunocompetent model. The humanised regimen of ceftaroline fosamil/avibactam 600/600 mg q8h as a 1-h infusion showed predictable efficacy against isolates with various genotypic and phenotypic profiles and MICs <= 4 MUg/mL. These data provide valuable information to help determine a ceftaroline/avibactam breakpoint for Enterobacteriaceae. PMID- 25278332 TI - XXIV Annual Meeting of the Sociedad Latino-Americana de Endocrinologia Pediatrica (SLEP). Playa del Carmen, Riviera Maya, Mexico, August 27-30, 2014: Abstracts. PMID- 25278334 TI - Patient-reported outcomes associated with use of physical therapist services by older adults with a new visit for back pain. AB - BACKGROUND: Among older adults, it is not clear how different types or amounts of physical therapy may be associated with improvements in back pain and function. OBJECTIVE: The study objective was to investigate the association between types or amounts of physical therapist services and 1-year outcomes among older adults with back pain. DESIGN: This was a prospective cohort study. METHODS: A total of 3,771 older adults who were enrolled in a cohort study and who had a new primary care visit for back pain participated. Physical therapy use was ascertained from electronic health records. The following patient-reported outcomes were collected over 12 months: back-related disability (Roland-Morris Disability Questionnaire) and back and leg pain intensity (11-point numerical rating scale). Marginal structural models were used to estimate average effects of different amounts of physical therapy use on disability and pain for all types of physical therapy and for active, passive, and manual physical therapy. RESULTS: A total of 1,285 participants (34.1%) received some physical therapy. There was no statistically significant gradient in relationships between physical therapy use and back related disability score. The use of passive or manual therapy was not consistently associated with pain outcomes. Higher amounts of active physical therapy were associated with decreased back and leg pain and increased odds of clinically meaningful improvements in back and leg pain relative to results obtained with no active physical therapy. LIMITATIONS: The fact that few participants had high amounts of physical therapy use limited precision and the ability to test for nonlinear relationships for the amount of use. CONCLUSIONS: Higher amounts of active physical therapy were most consistently related to the greatest improvements in pain intensity; however, as with all observational studies, the results must be interpreted with caution. PMID- 25278336 TI - Efficacy of the McKenzie method in patients with chronic nonspecific low back pain: a protocol of randomized placebo-controlled trial. AB - BACKGROUND: The McKenzie method is widely used as an active intervention in the treatment of patients with nonspecific low back pain. Although the McKenzie method has been compared with several other interventions, it is not yet known whether this method is superior to placebo in patients with chronic low back pain. OBJECTIVE: The purpose of this trial is to assess the efficacy of the McKenzie method in patients with chronic nonspecific low back pain. DESIGN: An assessor-blinded, 2-arm, randomized placebo-controlled trial will be conducted. SETTING: This study will be conducted in physical therapy clinics in Sao Paulo, Brazil. PARTICIPANTS: The participants will be 148 patients seeking care for chronic nonspecific low back pain. INTERVENTION: Participants will be randomly allocated to 1 of 2 treatment groups: (1) McKenzie method or (2) placebo therapy (detuned ultrasound and shortwave therapy). Each group will receive 10 sessions of 30 minutes each (2 sessions per week over 5 weeks). MEASUREMENTS: The clinical outcomes will be obtained at the completion of treatment (5 weeks) and at 3, 6, and 12 months after randomization. The primary outcomes will be pain intensity (measured with the Pain Numerical Rating Scale) and disability (measured with the Roland-Morris Disability Questionnaire) at the completion of treatment. The secondary outcomes will be pain intensity; disability and function; kinesiophobia and global perceived effect at 3, 6, and 12 months after randomization; and kinesiophobia and global perceived effect at completion of treatment. The data will be collected by a blinded assessor. LIMITATIONS: Therapists will not be blinded. CONCLUSIONS: This will be the first trial to compare the McKenzie method with placebo therapy in patients with chronic nonspecific low back pain. The results of this study will contribute to better management of this population. PMID- 25278335 TI - Safety of aerobic exercise in people with diabetic peripheral neuropathy: single group clinical trial. AB - BACKGROUND: Exercise is recommended for people with diabetes, but little is known about exercise in people with diabetic peripheral neuropathy (DPN). OBJECTIVE: The primary purpose of this preliminary study was to examine adverse events (AEs) during moderate-intensity, supervised aerobic exercise in people with DPN. The secondary purpose was to examine changes in fatigue, aerobic fitness, and other outcomes after intervention. DESIGN: This was a single-group preliminary study. SETTING: The setting was an academic medical center. PARTICIPANTS: Participants were 18 people who were sedentary and had type 2 diabetes and peripheral neuropathy (mean age=58.1 years, SD=5). INTERVENTION: The intervention was a supervised 16-week aerobic exercise program (3 times per week at 50% to >70% oxygen uptake reserve). MEASUREMENTS: Adverse events were categorized as related or unrelated to the study, anticipated or unanticipated, and serious or not serious. Outcomes included fatigue (Multidimensional Fatigue Inventory), cardiovascular fitness (peak oxygen uptake), body composition (dual-energy x-ray absorptiometry), sleep quality, plasma metabolic markers, and peripheral vascular function. RESULTS: During the study, 57 nonserious AEs occurred. Improvements were found in general fatigue (mean change=-3.5; 95% confidence interval [95% CI]=-1.3, -5.3), physical fatigue (mean change=-3.1; 95% CI=-1.2, -5.0), peak oxygen uptake (mean change=1.1 mL.kg(-1).min(-1); 95% CI=0.2, 1.9), total body fat (mean change=-1%; 95% CI=-0.3, -1.7), fat mass (mean change=-1,780 g; 95% CI= 616.2, -2,938.7), and peripheral blood flow (mean change=2.27%; 95% CI=0.6, 4.0). LIMITATIONS: This was a small-scale, uncontrolled study. A future randomized controlled trial is needed to fully assess the effects of exercise on the outcomes. CONCLUSIONS: This study provides new support for supervised aerobic exercise in people with DPN. However, it is important for physical therapists to carefully prescribe initial exercise intensity and provide close monitoring and education to address the anticipated AEs as people who are sedentary and have DPN begin an exercise program. PMID- 25278337 TI - Does cardiac rehabilitation after an acute cardiac syndrome lead to changes in physical activity habits? Systematic review. AB - BACKGROUND: Optimal physical activity levels have health benefits for patients with acute coronary syndrome (ACS) and are an important goal of cardiac rehabilitation (CR). PURPOSE: The purpose of this study was to systematically review literature regarding short-term effects (<6 months after completion of CR) and long-term effects (>=6 months after completion) of standard CR on physical activity levels in patients with ACS. DATA SOURCES: PubMed, EMBASE, CINAHL, and PEDro were systematically searched for relevant randomized clinical trials (RCTs) published from 1990 until 2012. STUDY SELECTION: Randomized clinical trials investigating CR for patients with ACS reporting physical activity level were reviewed. DATA EXTRACTION: Two reviewers independently selected articles, extracted data, and assessed methodological quality. Results were summarized with a best evidence synthesis. Results were categorized as: (1) center-based/home based CR versus no intervention, (2) comparison of different durations of CR, and (3) comparison of 2 types of CR. DATA SYNTHESIS: A total of 26 RCTs were included. Compared with no intervention, there was, at most, conflicting evidence for center-based CR and moderate evidence for home-based CR for short-term effectiveness. Limited evidence and no evidence were found for long-term maintenance for center-based and home-based CR, respectively. When directly compared with center-based CR, moderate evidence showed that home-based CR has better long-term effects. There was no clear evidence that increasing training volume, extending duration of CR, or adding an extra intervention to CR is more effective. LIMITATIONS: Because of the variety of CR interventions in the included RCTs and the variety of outcome measures in the included RCTs, pooling of data was not possible. Therefore, a best evidence synthesis was used. CONCLUSIONS: It would appear that center-based CR is not sufficient to improve and maintain physical activity habits. Home-based programs might be more successful, but the literature on these programs is limited. More research on finding successful interventions to improve activity habits is needed. PMID- 25278333 TI - Cellular and metabolic functions for autophagy in cancer cells. AB - Autophagy is a lysosomal degradation pathway that acts as a dynamic regulator of tumorigenesis. Specifically, autophagy has been shown to impede early cancer development while facilitating advanced tumor progression. Recent studies have uncovered several tumor-promoting functions for autophagy; these include the maintenance of multiple metabolic pathways critical for aggressive tumor growth and the promotion of tumor cell survival downstream of the unfolded protein response. Furthermore, autophagy supports anoikis resistance and cancer cell invasion. At the same time, because autophagy cargo receptors, which are essential for selective autophagy, lie upstream of diverse cancer-promoting signaling pathways, they may profoundly influence how alterations in autophagy affect tumor development. This review focuses on how these tumor cell autonomous functions of autophagy broadly impact tumorigenesis. PMID- 25278338 TI - Habitual physical activity of independently ambulant children and adolescents with cerebral palsy: are they doing enough? AB - BACKGROUND: Despite the health benefits of regular physical activity, children with cerebral palsy (CP) are thought to participate in reduced levels of physical activity. OBJECTIVE: The study objective was to assess physical activity and determine the proportion adhering to the recommended 60 minutes of moderate-to vigorous physical activity (MVPA) daily in independently ambulant children and adolescents with unilateral CP. DESIGN: This was a cross-sectional study. METHOD: Children (N=102; 52 boys, 50 girls; mean age=11 years 3 months, SD=2 years 4 months) with spastic hemiplegia classified at Gross Motor Function Classification System (GMFCS) levels I (n=44) and II (n=58) recorded physical activity over 4 days using an accelerometer. Activity counts were converted to daily and hourly time spent inactive and in light physical activity or MVPA using uniaxial cutpoints (inactive: <=100 vertical counts.min(-1), light: 101 to 2,295 vertical counts.min(-1), MVPA: >=2,296 vertical counts.min(-1)) and recorded step counts. Differences between groups were examined using t tests. RESULTS: Of a potential 396 days, 341 days (86%) were recorded. The average wear time was 11:44 (SD=1:56) hours. On a typical day, participants recorded 438 (SD=234) counts.min(-1), took 7,541 (SD=3,894) steps, spent 8:36 (SD=1:09) hours inactive, spent 2:38 (SD=0:51) hours in light activity, and spent 0:44 (SD=0:26) hours in MVPA. Only 25% of participants met the recommended level of MVPA on at least one day. Physical activity was highest in boys (versus girls), in children (versus adolescents), and on weekdays (versus weekends). LIMITATIONS: Participants were limited to children with unilateral spasticity who were classified at GMFCS levels I and II. CONCLUSIONS: The majority of independently ambulant children with unilateral CP did not perform sufficient physical activity to meet public health recommendations. PMID- 25278339 TI - Physical therapist practice in the emergency department observation unit: descriptive study. AB - BACKGROUND: An upward trend in the number of hospital emergency department (ED) visits frequently results in ED overcrowding. The concept of the emergency department observation unit (EDOU) was introduced to allow patients to transfer out of the ED and remain under observation for up to 24 hours before making a decision regarding the appropriate disposition. No study has yet been completed to describe physical therapist practice in the EDOU. OBJECTIVE: The objectives of this study were: (1) to describe patient demographics, physical therapist management and utilization, and discharge dispositions of patients receiving physical therapy in the EDOU and (2) to describe these variables according to the most frequently occurring diagnostic groups. DESIGN: This was a descriptive study of patients who received physical therapist services in the EDOU of Massachusetts General Hospital during the months of March, May, and August 2010. METHODS: Data from 151 medical records of patients who received physical therapist services in the EDOU were extracted. Variables consisted of patient characteristics, medical and physical therapist diagnoses, and physical therapist management and utilization derived from billing data. Descriptive statistics were used to analyze data. RESULTS: The leading EDOU medical diagnoses of individuals receiving physical therapist services included people with falls without fracture (n=30), back pain (n=27), falls with fracture (n=22), and dizziness (n=22). There were significant differences in discharge disposition, age, and total physical therapy time among groups. LIMITATIONS: This was a retrospective study, so there was no ability to control how data were recorded. CONCLUSIONS: This study provides information on common patient groups seen in the EDOU, physical therapist service utilization, and discharge disposition that may guide facilities in anticipated staffing needs associated with providing physical therapist services in the EDOU. PMID- 25278340 TI - Ankle fracture spur sign is pathognomonic for a variant ankle fracture. AB - BACKGROUND: The hyperplantarflexion variant ankle fracture is composed of a posterior tibial lip fracture with posterolateral and posteromedial fracture fragments separated by a vertical fracture line. This infrequently reported injury pattern often includes an associated "spur sign" or double cortical density at the inferomedial tibial metaphysis. The objective of this study was to quantitatively establish the association of the ankle fracture spur sign with the hyperplantarflexion variant ankle fracture. METHODS: Our clinical database of operative ankle fractures was retrospectively reviewed for the incidence of hyperplantarflexion variant and nonvariant ankle fractures as determined by assessment of injury radiographs, preoperative advanced imaging, and intraoperative observation. Injury radiographs were then evaluated for the presence of the spur sign, and association between the spur sign and variant fractures was analyzed. RESULTS: The incidence of the hyperplantarflexion variant fracture among all ankle fractures was 6.7% (43/640). The spur sign was present in 79% (34/43) of variant fractures and absent in all nonvariant fractures, conferring a specificity of 100% in identifying variant fractures. Positive predictive value and negative predictive value were 100% and 99%, respectively. CONCLUSION: The ankle fracture spur sign was pathognomonic for the hyperplantarflexion variant ankle fracture. It is important to identify variant fractures preoperatively as patient positioning, operative approach, and fixation construct of variant fractures often differ from those employed for osteosynthesis of nonvariant fractures. Identification of the spur sign should prompt acquisition of advanced imaging to formulate an appropriate operative plan to address the variant fracture pattern. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25278342 TI - Self-control training leads to enhanced cardiovascular exercise performance. AB - The purpose of the study was to investigate the effects of two weeks of self control strength training on maximum cardiovascular exercise performance. Forty one participants completed a cognitive self-control depletion task (Stroop task) followed by a maximal graded cycling test and were randomized to training (maximal endurance contractions of spring handgrip trainers, twice daily) or no treatment control groups. At follow-up (2 weeks), half of each group completed either a time-matched or trial-matched Stroop task followed by another maximal graded cycling test. Results showed a significant 2-way (training X time) interaction (P < 0.001), and a trend for the 3-way (training X time X cognitive task) interaction (P = 0.07). Decomposition of the interactions revealed that across sessions cycling performance increased in both training groups, did not change in the trial-matched cognitive task control group, and declined in the time-matched control group. We conclude that isometric handgrip training leads to self-control strength adaptations that enhance maximal cardiovascular exercise performance or tolerance of exercise at maximal levels of effort. PMID- 25278341 TI - Psychophysiology and posttraumatic stress disorder symptom profile in pregnant African-American women with trauma exposure. AB - While female sex is a robust risk factor for posttraumatic stress disorder (PTSD), pregnant women are an understudied population in regards to PTSD symptom expression profiles. Because circulating hormones during pregnancy affect emotionality, we assessed whether pregnant women would have increased expression of the intermediate phenotypes of hyperarousal and fear-potentiated startle (FPS) compared to non-pregnant women. We examined PTSD symptom profiles in pregnant (n = 207) and non-pregnant women (n = 370). In a second study, FPS responses were assessed in 15 pregnant and 24 non-pregnant women. All participants were recruited from the obstetrics and gynecology clinic at a public hospital serving a primarily African-American, low socioeconomic status, inner-city population. Our results indicate that overall PTSD symptoms were not different between the groups of women. However, pregnant women reported being more hypervigilant (p = 0.036) than non-pregnant women. In addition, pregnant women showed increased FPS to a safety signal compared to non-pregnant women (p = 0.024). FPS to a safety signal in pregnant women was significantly correlated with PTSD hyperarousal symptoms (r = 0.731, p < 0.001). Furthermore, discrimination between danger and safety signals was present in non-pregnant women (p = 0.008), but not in pregnant women (p = 0.895). Together, these data suggest that pregnant women show clinical and psychophysiological hyperarousal compared to non-pregnant women, and support screening for PTSD and assessment of PTSD risk in pregnant women. PMID- 25278343 TI - Involvement of L-arginine/NO/cGMP/K(ATP) channel pathway in the peripheral antinociceptive actions of ellagic acid in the rat formalin test. AB - The present study was conducted to evaluate the local antinociceptive actions of EA and the possible involvement of l-arginine/NO/cGMP/KATP channel pathway in this effect using formalin test in rats. To evaluate the involvement of l arginine/NO/cGMP/KATP channel pathway in the antinociceptive action of EA, rats were pre-treated intraplantarlly with l-NAME (NOS inhibitor, 25-100MUg/paw), methylene blue (guanylyl cyclase inhibitor, 100-400MUg/paw), glibenclamide (ATP sensitive K(+) channel blocker, 25-100MUg/paw), l-arginine (a nitric oxide precursor, 25-100MUg/paw) and sodium nitroprusside (125-500MUg/paw). The local peripheral ipsilateral, but not contralateral, administration of EA into the right paw (30-300MUg/paw) produced a dose-related antinociception during both early and late phases of formalin test which is comparable with morphine (25MUg/paw). Moreover, local pre-treatment with l-NAME, methylene blue and glibenclamide dose-dependently prevented EA (100MUg/paw)-induced antinociception in late phase. Additionally, administration of l-arginine and sodium nitroprusside significantly potentiated the antinociception induced by EA in the late phase. However, these treatments had no significant effect on antinociceptive response of EA in the early phase of the formalin test. The results of the present study showed that EA-induced local peripheral antinociception during the both phases of formalin test. Also, our data suggested the activation of the l-arginine/NO/cGMP/KATP channels pathway in EA-induced antinociception in late phase of formalin test. Topical application of EA by ointment or jelly might be a useful method to relieving the inflammatory pain states. PMID- 25278344 TI - [Possibilities for use of Scheimpflug technology in cataract surgery]. AB - BACKGROUND: Since its first use in geography 100 years ago Scheimpflug photography has undergone much refinement making it a standard technique in anterior segment diagnostics and even surgical therapy. This review presents the perioperative applications of Scheimpflug photography in cataract and refractive lens surgery. OBJECTIVES: Possible perioperative applications of Scheimpflug photography in cataract surgery and refractive lens surgery. METHODS: Selective review of the literature and personal experiences. RESULTS: In recent years there have been numerous new applications for Scheimpflug photography, with its main use in preoperative diagnostics and surgical planning. There are also useful applications for intraoperative visualization and postoperative counseling. CONCLUSION: Multifunctional devices which enable a variety of further examinations besides Scheimpflug technology alone make the use of this technology possible and reasonable even in hospitals and practices without a focus on refractive surgery. PMID- 25278345 TI - [Corneal topography and keratoconus diagnostics with Scheimpflug photography]. AB - BACKGROUND: Corneal Scheimpflug tomography is a commonly used non-invasive imaging technique. OBJECTIVES: This review article summarizes the principles of the technique and recent results from the literature with a focus on keratoconus diagnostics. MATERIAL AND METHODS: Review of the literature, own data and expert opinions. RESULTS: Corneal Scheimpflug tomography allows topography of the anterior and posterior surfaces as well as spatially resolved pachymetry and densitometry. Measurements obtained with currently available systems are highly reproducible but not interchangeable. Combining topographic and pachymetric data allows a highly sensitive and specific diagnostic modality for the early diagnosis of keratoconus. CONCLUSIONS: Due to the versatility, precision and easy handling, corneal Scheimpflug tomography is the most important imaging technique for the anterior segment of the eye. PMID- 25278346 TI - [Schleimpflug photography detects alterations in corneal density and thickness in patients with dry eye disease]. AB - BACKGROUND: Dry eye disease is a common ocular surface disease that significantly affects the quality of life. Little is known about a potential impact of the disease on corneal morphology. This study was carried out to investigate for the first time if dry eye disease induces changes in corneal density and thickness. METHODS: In total 97 patients suffering from dry eye disease and 33 healthy age matched individuals were included in this prospective, randomized study. Corneal morphology was documented with Scheimpflug photography and analyzed for central corneal thickness and corneal density in five anatomical layers (i.e. epithelium, Bowman membrane, corneal stroma, Descemet membrane and endothelium). RESULTS: Corneal density was significantly reduced in the epithelium (p = 0.0053), Bowman membrane (p = 0.0049) and Descemet's membrane (p = 0.0385) in patients with dry eye syndrome compared to healthy controls. This decrease was age-dependant. Furthermore, central corneal thickness was significantly reduced in patients with dry eye syndrome compared to the control group (p = 0.0495). The change was again dependent on age with lower values at higher age. Central corneal thickness increased with age in the control group. CONCLUSION: The results of this study indicate that corneal morphology is subject to significant alterations in patients with dry eye disease. Scheimpflug photography provides not only unique information in lens trials but is also able to detect changes of corneal anatomy. However, further investigations with other anterior segment imaging techniques, such spectral domain optical coherence tomography (SD OCT/Pentacam(r)) are necessary to further evaluate the clinical consequences of these findings. PMID- 25278347 TI - [Treatment of serous macular retinal detachment with antihistamines]. AB - The etiology of retinal detachment in central serous retinopathy (CSR) is unknown; however, three facts are generally accepted: (1) the serous exudate which raises the layers of the receptors/pigment epithelium is formed due to hyperpermeability in the choriocapillaries, (2) patients frequently suffer from headaches and (3) stress promotes the incidence of CSR. A high blood plasma histamine concentration can cause the abovementioned symptoms which suggests that histamine might provoke CSR. Within 1 week after administration of the antihistamine loratadin a considerable reduction in the retinal exudate and restoration of vision were observed. This supports the hypothesis that histamine could be involved in the process of retinal detachment. Further investigations and large scale clinical trials should clarify if this hypothesis can be proved or disproved and whether antihistamines can be used for age-related macular degeneration (AMD). PMID- 25278348 TI - [Retinoblastoma in Malawi: why are admissions too late?]. AB - BACKGROUND: A total of 82 % of stationary admissions with the diagnosis of retinoblastoma (2009-2011) to the tertiary ophthalmology unit in Blantyre, Malawi (n = 58) presented with advanced stage disease. PATIENTS AND METHODS: In another study in 2012 we sought to identify why children mostly presented in advanced stages of disease and whether the delay was unique to children with cancer. In depth interviews (IDI) were conducted at the hospital with 40 parents or guardians of children with retinoblastoma, congenital cataract, congenital glaucoma and corneal perforation (10 each). RESULTS: Most delays and delayed admissions occurred at the family (27.5 %, 11 out of 40) and primary health centre levels (30.0 %, 12 out of 40). Lack of money for transport caused delays (15.0 %, 6 out of 40) at all care levels. In contrast, children with painful conditions presented to a health facility within 24 h of onset without any complaints about lack of money for transport. CONCLUSION: Education about retinoblastoma and other non-painful eye diseases could be improved by a poster campaign to both parents and professionals at all medical healthcare levels. Transport for such cases between the various healthcare centers should be provided free of charge. There is room for improvement in initial diagnosis, referral and management within the healthcare service in the tertiary sector. PMID- 25278349 TI - Simple and robust ICP-MS method for simultaneous determination of serum Co and Cr in routine clinical practice. AB - BACKGROUND: Chromium (Cr) and cobalt (Co) metal ions released from orthopedic prostheses, such as metal-on-metal (MoM) bearings, may be related to wear of the bearing surface. These ions may serve as indicators of the in vivo performance of MoM bearing surfaces. We developed a simple and sensitive assay suitable for the simultaneous measurement of serum Cr and Co using inductively coupled plasma-mass spectrometry (ICP-MS) in clinical routine laboratory practice to evaluate analytical performance and clinical utility. METHODS: We evaluated the linearity, precision, and lower limit of quantification (LOQ) of an ICP-MS method to determine serum Cr and Co concentration in accordance with U.S. Food and Drug Administration guidance for bioanalytical method validation. This method was used to determine the serum Cr and Co levels of 236 clinical samples from 74 patients with MoM hip prosthesis and 51 healthy controls. RESULTS: The assay showed good linearity (0-20 MUg/l, r(2)>0.999) and satisfactory accuracy for all tested concentrations of Cr and Co (%bias, -1.5% to 2.5%, -3.3% to 1.6%, respectively). The CVs for both metal ions were <10% for LOQ (0.02 MUg/l Cr, 0.01 MUg/l Co) and within 5% for other concentrations (intra- and inter-assay CV, 1.2-2.6 and 1.9 4.4% of Cr; 1.4-2.7 and 1.9-4.7% of Co). The serum Cr and Co concentrations (mean +/- SD) were 0.60 +/- 0.12 MUg/l and 0.29 +/- 0.15 MUg/l in 51 healthy subjects. In 74 patients (185 serum samples) after HRA (median duration implanted, 48 months; range, 1-138 months), the concentrations of Cr and Co were 2.75 MUg/l (range, 0.61-116.80 MUg/l) and 1.49 MUg/l (range, 0.12-127.80 MUg/l), respectively. CONCLUSIONS: ICP-MS can simultaneously quantify serum Cr and Co levels with suitable analytical performance including a wide analytical range and very low LOQ. This assay will be very useful for evaluating the nutritional status of Cr and Co in healthy humans as well as monitoring the performance of orthopedic prostheses after hip resurfacing arthroplasty. PMID- 25278350 TI - HDL functionality and crystal-based sterile inflammation in atherosclerosis. AB - Change is inevitable. In early evolution, due to the limited availability of resources, the sole purpose of living organisms was to survive long enough to transmit their genes to the next generation. During their short lifetime, organisms used pathogen-associated and damage-associated molecular pattern pathways as an inflammatory response against pathogens (exogenous factors) and tissue damage (endogenous factors), respectively. Despite advances in human lifespan, it appears that an increasing number of diseases such as atherosclerosis are associated with inflammation. Excessive glucose, lipid and protein intake leads to the formation of endogenous crystals, i.e., cholesterol, which can induce a sterile inflammatory immune response that manifests as a vicious cycle. In this review, we evaluate the possible relationship between crystal-based sterile inflammatory response and HDL functionality. PMID- 25278352 TI - Platelet-rich plasma in arthroscopic rotator cuff repair: a meta-analysis of randomized controlled trials. AB - PURPOSE: The purpose of this study was to appraise the retear rate and clinical outcomes of platelet-rich plasma use in patients undergoing arthroscopic full thickness rotator cuff repair. METHODS: We searched the Cochrane Library, PubMed, and EMBASE databases for randomized controlled trials comparing the outcomes of arthroscopic rotator cuff surgery with or without the use of platelet-rich plasma. Methodological quality was assessed by the Detsky quality scale. When there was no high heterogeneity, we used a fixed-effects model. Dichotomous variables were presented as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous data were measured as mean differences with 95% CIs. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assess the quality of evidence for each individual outcome. RESULTS: Eight randomized controlled trials were included, with the sample size ranging from 28 to 88. Overall methodological quality was high. Fixed-effects analysis showed that differences were not significant between the 2 groups in retear rate (RR, 0.94; 95% CI, 0.70 to 1.25; P = .66), Constant score (mean difference, 1.12; 95% CI, -1.38 to 3.61; P = .38), and University of California at Los Angeles (UCLA) score (mean difference, -0.68; 95% CI, -2.00 to 0.65; P = .32). The strength of GRADE evidence was categorized respectively as low for retear, moderate for Constant score, and low for UCLA shoulder score. CONCLUSIONS: Our meta-analysis does not support the use of platelet-rich plasma in the arthroscopic repair of full-thickness rotator cuff tears over repairs without platelet-rich plasma because of similar retear rates and clinical outcomes. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II randomized controlled trials. PMID- 25278353 TI - Diagnosis and 2-year outcomes of endoscopic treatment for ischiofemoral impingement. AB - PURPOSE: The purposes of this study were to investigate the clinical and radiographic presentation of patients with ischiofemoral impingement (IFI) and to assess the outcomes of endoscopic treatment with partial resection of the lesser trochanter. METHODS: Five patients with IFI who underwent endoscopic treatment with partial resection of the lesser trochanter were retrospectively reviewed. The outcomes were assessed at a mean follow-up of 2.3 years (range, 2 to 2.5 years) through the modified Harris Hip Score and a visual analog scale score for pain. Physical examination tests provoking the impingement between the lesser trochanter and ischium were used for the diagnosis of IFI, including the IFI test and reproducible pain lateral to the ischium with the long-stride walking test. The presence of quadratus femoris muscle edema and a decreased ischiofemoral space on magnetic resonance imaging was also necessary for the diagnosis. RESULTS: The mean modified Harris Hip Score increased from 51.3 points (range, 34.1 to 73.7 points) preoperatively to 94.2 points (range, 78.1 to 100 points) at the final follow-up (P = .003). The mean visual analog scale score for pain decreased from 6.6 (range, 6 to 7.3) before surgery to 1 (range, 0 to 4) at the final follow-up (P = .001). The mean duration to return to sport after surgery was 4.4 months (range, 1 to 7 months) for the 5 patients in this study. No complication was observed. CONCLUSIONS: The endoscopic treatment of IFI was effective at 2 years in 5 patients with consistent clinical and imaging diagnostic findings. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25278351 TI - Discontinuation of cART postpartum in a high prevalence district of South Africa in 2014. AB - BACKGROUND: Combination antiretroviral therapy (cART) is the current strategy to prevent mother-to-child transmission (PMTCT) of HIV. Women initiated on cART should continue taking treatment life-long or stop after cessation of breastfeeding depending on their CD4 cell count or on their World Health Organization (WHO) staging. Keeping people living with HIV on treatment is essential for the success of any antiretroviral therapy (ART) programme. There has been a rapid scale-up of cART in the PMTCT programme in South Africa. cART is supposed to be taken life-long or until cessation of breastfeeding, but premature or unmanaged discontinuation of cART postpartum is not unusual in South Africa and is confirmed by studies from around the world. Discontinuation of cART can lead to mother-to-child transmission (MTCT), drug resistance and poor maternal outcomes. The extent of this problem in the South African context however is unclear. This study aims to determine the prevalence of and identify risk factors associated with discontinuation of cART postpartum amongst women who were initiated on antiretroviral treatment during their index pregnancy. METHODS: An observational analytic cross-sectional study design will be conducted in six health facilities in a high prevalence district in KwaZulu-Natal, South Africa over a period of 3 months in 2014. An interviewer-administered questionnaire will be used to collect data from mothers who initiated cART during their index pregnancy. The prevalence of discontinuation of cART postpartum will be measured, and the association between those who discontinue cART postpartum and independent variables will be estimated using multivariable-adjusted prevalence odds ratios for discontinuation. PMID- 25278354 TI - Role of calorie restriction in alleviation of age-related morphological and biochemical changes in sciatic nerve. AB - BACKGROUND: Aging is associated with structural, functional and biochemical alterations in the nervous system. Calorie restriction (CR) was found to retard most physiological indices of aging. OBJECTIVES: This work aimed to investigate the effect of CR on age-related changes in sciatic nerves. MATERIALS AND METHODS: Thirty male albino rats aged 1 month were equally divided into three groups; Group I [control adult-ad libitum AL]: fed a regular diet and sacrificed at the age of 6 months, group II (aged-AL group): fed a regular diet AL and sacrificed at the age of 18 months, and group III (aged CR) fed a 40% calorie restricted diet and sacrificed at the age of 18 months. Rats were anesthetized and sciatic nerves were processed for light, electron microscope and morphometric studies. Oxidative stress in sciatic nerves was investigated by estimation of lipid perioxidation by product malondialdehyde (MDA) tissue level and antioxidant enzyme; superoxide dismutase activity (SOD). RESULTS: The aged (AL) sciatic nerves appeared disorganized, with thick perineurium and increased collagen fibers associated with decreased g-ratio. Abnormal myelin forms were seen as outfolded myelin loops, thin denuded myelin, splitting of myelin into myelin figures and interlamellar vacuoles. Schwann cells revealed vacuolated cytoplasm. There was also significant increase in MDA level and a significant decrease in SOD activity in comparison to control adult (AL). Apparent structural and histomorphological improvement were noticed after CR in aged rats. CONCLUSION: Aging caused structural and biochemical alterations in sciatic nerves with alleviating effect of calorie restriction on such effects. PMID- 25278355 TI - Reply to: "Chronic kidney disease after liver transplantation". PMID- 25278357 TI - Biopsy sampling and histopathological markers for diagnosis of prostate cancer. AB - Prostate cancer is one of the most common malignant tumors and a leading cause of cancer-related morbidity and mortality. Irrespective of the method that allows for risk stratification of prostate cancer suspects, diagnosis relies on tissue sampling through prostate biopsy and subsequent histopathological evaluation. This provides critical information about disease aggressiveness, which is required for adequate patient management. Prostate biopsy methods have significantly evolved over the years, including the definition of indications, sampling schemes and use of imaging techniques (ultrasound and MRI) that allow for more accurate tissue sampling. In response to the challenges emerging from more precise collection of minute prostate tissue samples for analysis, histopathological assessment should include not only the observation of routinely stained sections, but also, and increasingly so, a series of ancillary techniques, especially immunohistochemistry, which increment the accuracy of prostate cancer diagnosis and may provide relevant information to guide patient management. PMID- 25278358 TI - Electro-osmosis of non-Newtonian fluids in porous media using lattice Poisson Boltzmann method. AB - Electro-osmosis in porous media has many important applications in various areas such as oil and gas exploitation and biomedical detection. Very often, fluids relevant to these applications are non-Newtonian because of the shear-rate dependent viscosity. The purpose of this study was to investigate the behaviors and physical mechanism of electro-osmosis of non-Newtonian fluids in porous media. Model porous microstructures (granular, fibrous, and network) were created by a random generation-growth method. The nonlinear governing equations of electro-kinetic transport for a power-law fluid were solved by the lattice Poisson-Boltzmann method (LPBM). The model results indicate that: (i) the electro osmosis of non-Newtonian fluids exhibits distinct nonlinear behaviors compared to that of Newtonian fluids; (ii) when the bulk ion concentration or zeta potential is high enough, shear-thinning fluids exhibit higher electro-osmotic permeability, while shear-thickening fluids lead to the higher electro-osmotic permeability for very low bulk ion concentration or zeta potential; (iii) the effect of the porous medium structure depends significantly on the constitutive parameters: for fluids with large constitutive coefficients strongly dependent on the power-law index, the network structure shows the highest electro-osmotic permeability while the granular structure exhibits the lowest permeability on the entire range of power law indices considered; when the dependence of the constitutive coefficient on the power law index is weaker, different behaviors can be observed especially in case of strong shear thinning. PMID- 25278359 TI - Preparation of asymmetrically distributed bimetal ceria (CeO2) and copper (Cu) nanoparticles in nitrogen-doped activated carbon micro/nanofibers for the removal of nitric oxide (NO) by reduction. AB - A novel multi-scale web of carbon micro/nanofibers (ACF/CNF) was prepared by the catalytic chemical vapor deposition (CCVD), in which CeO2 and Cu nanoparticles (NPs) were in-situ incorporated during a synthesis step. The CVD temperature was adjusted such that the prepared material had asymmetric distribution of the bimetals, with the Cu NPs located at the tips of the CNFs and the CeO2 particles adhered to the surface of the ACF substrate. The prepared bimetals-dispersed web of ACF/CNF was treated with pyridine and the surface functionalized material was applied for the removal of NO by reduction. The complete reduction of NO was achieved at 500 degrees C and for 400ppm NO concentration. Whereas the Cu NPs acted as the catalyst for the reduction, CeO2 facilitated the incorporation of nitrogen from the pyridine source into the ACF/CNF surface. The produced nitrogen containing surface functional groups enhanced the reactivity of the material toward the NO. The bimetals CeO2 and Cu nanoparticles (NPs)-dispersed ACF/CNF produced in this study is a potential candidate for effectively removing NO by reduction, without requiring urea or ammonia used in conventional abatement methods. PMID- 25278356 TI - The financial impact of increasing home-based high dose haemodialysis and peritoneal dialysis. AB - BACKGROUND: Evidence suggests that high dose haemodialysis (HD) may be associated with better health outcomes and even cost savings (if conducted at home) versus conventional in-centre HD (ICHD). Home-based regimens such as peritoneal dialysis (PD) are also associated with significant cost reductions and are more convenient for patients. However, the financial impact of increasing the use of high dose HD at home with an increased tariff is uncertain. A budget impact analysis was performed to investigate the financial impact of increasing the proportion of patients receiving home-based dialysis modalities from the perspective of the England National Health Service (NHS) payer. METHODS: A Markov model was constructed to investigate the 5 year budget impact of increasing the proportion of dialysis patients receiving home-based dialysis, including both high dose HD at home and PD, under the current reimbursement tariff and a hypothetically increased tariff for home HD (L575/week). Five scenarios were compared with the current England dialysis modality distribution (prevalent patients, 14.1% PD, 82.0% ICHD, 3.9% conventional home HD; incident patients, 22.9% PD, 77.1% ICHD) with all increases coming from the ICHD population. RESULTS: Under the current tariff of L456/week, increasing the proportion of dialysis patients receiving high dose HD at home resulted in a saving of L19.6 million. Conducting high dose HD at home under a hypothetical tariff of L575/week was associated with a budget increase (L19.9 million). The costs of high dose HD at home were totally offset by increasing the usage of PD to 20-25%, generating savings of L40.0 million - L94.5 million over 5 years under the increased tariff. Conversely, having all patients treated in-centre resulted in a L172.6 million increase in dialysis costs over 5 years. CONCLUSION: This analysis shows that performing high dose HD at home could allow the UK healthcare system to capture the clinical and humanistic benefits associated with this therapy while limiting the impact on the dialysis budget. Increasing the usage of PD to 20-25%, the levels observed in 2005-2008, will totally offset the additional costs and generate further savings. PMID- 25278360 TI - Fluorescent carbonaceous nanospheres as biological probe for noninvasive brain imaging. AB - Fluorescent carbonaceous nanospheres (CDs) have generated much excitement in bioimaging because of their impressive fluorescent properties and good biocompatibility. In this study, we evaluated the potential application of CDs in noninvasive brain imaging. A new kind of CDs was prepared by a heat treating method using glutamic acid and glucose as the precursors. The hydrated diameter and zeta potential of CDs were 101.1 nm (PDI=0.110) and -22.4 mV respectively. Palpable emission spectrum could be observed from 400 nm to 600 nm when excited at corresponding wavelength, suggesting CDs could be used as a noninvasive bio probe for in vivo imaging. Additionally, several experiments indicated that CDs possess good serum stability and hemocompatibility with low cytotoxicity. In vitro, the CDs could be efficiently taken up by bEnd.3 cells in a concentration- and time-dependent manner. In vivo, CDs could be used for noninvasive brain imaging due to its high accumulation in brain region, which was demonstrated by in vivo imaging and ex vivo tissue imaging. Moreover, the fluorescent distribution in tissue slice showed CDs accumulated in brain with high intensity. In conclusion, CDs were prepared using a simple one-step method with unique optical and good biological properties and could be used for noninvasive brain imaging. PMID- 25278361 TI - Quercetin conjugated superparamagnetic magnetite nanoparticles for in-vitro analysis of breast cancer cell lines for chemotherapy applications. AB - The magnetic nanoparticles attract increasing interest due to their opportunities in cancer therapy and used as drug carriers for several other diseases. The present study investigates the quercetin conjugated superparamagnetic Fe3O4 nanoparticles for in-vitro analysis of breast cancer cell lines for chemotherapy. A simple precipitation method was used to prepare the dextran coated Fe3O4 nanoparticles and the anticancer flavonoid quercetin was conjugated on the surface via carboxylic/amine group using nanoprecipitation method. The structural, morphological and the magnetic properties of the prepared materials were studied by using X-ray diffractometer (XRD), Fourier transformed infer-red spectrometer (FTIR), transmission electron microscope (TEM) and vibrating sample magnetometer (VSM). The MTT (3-(4,5-dimethylthiahiazol-2-yl)-2,5-diphenyl tetrazolium) assay of dextran coated Fe3O4 nanoparticles did not exhibit notable toxicity against MCF7 cells, whereas the cytotoxicity of quercetin conjugated Fe3O4 nanoparticles increased significantly in comparison with pure quercetin. The incubation of MCF-7 cells with quercetin conjugated Fe3O4 nanoparticles (QCMNPs) shows significant changes in cellular morphology observed through fluorescent microscopy. The results validate the prepared quercetin conjugated Fe3O4 nanoparticles are promising anticancer agents for targeted drug delivery. PMID- 25278362 TI - On the supramacromolecular structure of core-shell amphiphilic macromolecules derived from hyperbranched polyethyleneimine. AB - The supramacromolecular structure of core-shell amphiphilic macromolecules (CAMs) with hyperbranched polyethyleneimine (HPEI) cores and fatty acid chain shells (HPEI-Cn) for different chain lengths was investigated both, in colloidal suspension, solid phase and at the air-water interface using Small Angle X-ray Scattering (SAXS), Wide Angle X-ray Scattering (WAXS), X-ray Reflectometry (XRR) and Langmuir isotherms. At low temperatures colloidal toluene suspensions of the HPEI-Cn polymers form, as evidenced by peaks arising in the structure factor of the system showing mean particle-to-particle distances correlated with the length of the aliphatic chains forming the shells of HPEI-Cn unimicelles. The CAM sizes as found from the SAXS experiments also display a clear dependence on shell thickness suggesting that the aliphatic chains adopt a brush-like configuration. After solvent extraction, HPEI-Cn adopts ordered structures with hexagonal packing of the aliphatic chains. Submitted to lateral pressure Pi at the air water interface, HPEI-Cn undergoes a disorder-order transition with increasing transition pressure for increasing chain lengths. The CAMs show different behaviors in-plane and out-of-plane. While out-of-plane the aliphatic chains behave as a brush remaining almost fully unfolded, whereas parallel to the air water interface the chains fold down in a mushroom way with increasing lateral pressure Pi. PMID- 25278363 TI - Zinc oxide/silver nanoarrays as reusable SERS substrates with controllable 'hot spots' for highly reproducible molecular sensing. AB - HYPOTHESIS: The reproducible surface enhanced Raman scattering (SERS)-based sensing of an analyte relies on high quality SERS substrates that offer uniformity over large areas. Uniform ZnO nanoarrays are expected to offer an appropriate platform for SERS sensing. Moreover, since ZnO has good photocatalytic properties, controllable decoration of silver nanoparticles on ZnO nanoarrays may offer an additional opportunity to clean up SERS substrates after each sensing event. EXPERIMENTS: This study employs a facile soft chemical synthesis strategy to fabricate Raman-active and recyclable ZnO/Ag nanorod arrays as reproducible SERS substrates. Arrays of ZnO nanorods were synthesized using hydrothermal method, which was followed by controllable decoration of ZnO with silver nanoparticles (AgNPs) using an electroless plating technique. FINDINGS: The uniform density of SERS-active 'hot-spots' on ZnO nanoarrays could be controlled on a large 1*1 cm(2) substrate. These ZnO/Ag nanoarrays showed high reproducibility (0.132 RSD) towards acquiring SERS spectra of rhodamine B (RB) at 30 random locations on a single substrate. The photocatalytic nature of ZnO/Ag semiconductor/metal hybrid endowed these substrates with reusability characteristics. By controlling metal loading on a semiconductor surface, photocatalytic activity and high SERS performance can be integrated within a single package to obtain high quality, reproducible, stable and recyclable SERS substrates. PMID- 25278364 TI - Unusual case of finger lipoma: a case report and literature review. PMID- 25278365 TI - E-NTPDase and E-ADA activities in rats experimental infected by Cryptococcus neoformans. AB - Cryptococcus neoformans, the etiological agent of cryptococcosis, is an opportunistic fungal pathogen of immunocompromised individuals. The aim of this study was to evaluate the activities of E-NTPDase and E-ADA in rats experimentally infected by C. neoformans var. grubii. Adult rats (35) were divided in two groups: 18 for the control group (uninfected) (A), and 17 for the infected group (B). Each group was separated into three sub-groups (A1, A2, A3 B1, B2, B3), and samples were collected on 10, 20, and 30 days post-infection (PI). Leukocyte counts, IFN-gamma, TNF-alpha, IgM, IgG levels, and E-NTPDase and E-ADA activities were analyzed. It was possible to observe that IgG and IgM seric levels of infected rats were significantly elevated (P<0.01) on days 10, 20 and 30 PI, as well as the levels of TNF-alpha and INF-gamma when compared to uninfected rodents. Regarding E-NTPDase activity in lymphocytes, it was possible to observe that the ATP hydrolysis was significantly decreased on days 20 (P<0.01) and 30 PI (P<0.05), while ADP hydrolysis was significantly reduced only on day 20 PI (P<0.01) when compared with uninfected group. Seric E-ADA activity had a significant reduction (P<0.01) during all three evaluated periods when compared to the control group, while E-ADA activity in lymphocytes increased significantly (P<0.01) when compared to the group A on day 10 PI; however on days 20 and 30 PI, its activity was considerable reduced in lymphocytes of infected animals (P<0.01). Therefore, it is possible to conclude that the infection caused by C. neoformans in immunocompetent rats leads to changes in the purinergic signaling (NTPDase and E-ADA), concomitantly with an inflammatory response (increased levels of cytokines and immunoglobulins) associated with inflammatory infiltrates and histological lesions in the lung. PMID- 25278366 TI - Pathogenesis of porcine epidemic diarrhea virus isolate (US/Iowa/18984/2013) in 3 week-old weaned pigs. AB - Porcine epidemic diarrhea virus (PEDV) is associated with clinical diarrhea in naive swine of all ages. This report describes timing of antibody generation and disease progression following infection with a US PEDV isolate by assessing fecal viral shedding, morphometric analysis of intestinal lesions, and magnitude of immunohistochemical staining. Sixty-three, 3-week-old pigs were randomly allocated into control (n=27) and challenged (n=36) groups. Challenged pigs were administered 1 mL of 1 * 10(3) PFU/mL of US/Iowa/18984/2013 PEDV isolate by oro gastric gavage. Three control and four challenged pigs were necropsied on days post-inoculation (dpi) 1, 2, 3, 4, 7, and weekly thereafter, until study termination on dpi 35. Clinical disease, fecal shedding, body weight, and temperature were monitored during the study period. Diarrhea was observed in challenged pigs beginning for some on dpi 2, affecting a majority of pigs by dpi 6 and subsiding by dpi 10. Average daily gain was significantly lower (P<0.001) for one week post-infection in challenged pigs. PEDV was detected in feces by PCR on dpi 1 and continued in a subset of pigs until dpi 24. PEDV-specific antigen was detected in villous enterocytes of challenged pigs by immunohistochemistry (IHC) on dpi 1, 2, 3, 4, 7, and 14. Microscopic lesions included severe diffuse atrophic enteritis with significantly reduced (P<0.001) villous length observed on dpi 3, 4, and 7. Under the conditions of this study, fecal shedding of PEDV and IHC staining can precede and continue beyond the observation of clinical signs, thus increasing the risk of viral transmission. PMID- 25278367 TI - The medial prefrontal cortex in constructing personality models. AB - A recent study by Hassabis et al. suggests that the brain constructs 'personality models' of other people. When imagining another individual, multi-voxel patterns of fMRI activation in the medial prefrontal cortex (mPFC) contained information about the individual's unique combination of personality traits. The authors propose that, in concert with other regions, the mPFC assembles a model of another's personality that is ultimately used to predict behavior. PMID- 25278369 TI - Response to Block et al.: first-person perspectives are both necessary and troublesome for consciousness science. PMID- 25278370 TI - Sequential growth of zinc oxide nanorod arrays at room temperature via a corrosion process: application in visible light photocatalysis. AB - Many photocatalyst systems catalyze chemical reactions under ultraviolet (UV) illumination, because of its high photon energies. Activating inexpensive, widely available materials as photocatalyst using the intense visible part of the solar spectrum is more challenging. Here, nanorod arrays of the wide-band-gap semiconductor zinc oxide have been shown to act as photocatalysts for the aerobic photo-oxidation of organic dye Methyl Orange under illumination with red light, which is normally accessible only to narrow-band semiconductors. The homogeneous, 800-1000-nm-thick ZnO nanorod arrays show substantial light absorption (absorbances >1) throughout the visible spectral range. This absorption is caused by defect levels inside the band gap. Multiple scattering processes by the rods make the nanorods appear black. The dominantly crystalline ZnO nanorod structures grow in the (0001) direction, i.e., with the c-axis perpendicular to the surface of polycrystalline zinc. The room-temperature preparation route relies on controlled cathodic delamination of a weakly bound polymer coating from metallic zinc, an industrially produced and cheaply available substrate. Cathodic delamination is a sequential synthesis process, because it involves the propagation of a delamination front over the base material. Consequently, arbitrarily large sample surfaces can be nanostructured using this approach. PMID- 25278368 TI - Impaired self-awareness in human addiction: deficient attribution of personal relevance. AB - Compromised self-awareness of illness-related deficits and behaviors in psychopathology (e.g., schizophrenia) has been associated with deficient functioning of cortical midline regions including the ventromedial prefrontal cortex (vmPFC), implicated in personal relevance. Here, we review and critically analyze recent evidence to suggest that vmPFC abnormalities could similarly underlie deficient tagging of personal relevance in drug addiction, evidenced by a constellation of behaviors encompassing drug-biased attention, negative outcome insensitivity, self-report/behavior dissociation, and social inappropriateness. This novel framework might clarify, for example, why drug-addicted individuals often ruin long-standing relationships or forego important job opportunities while continuing to engage in uncontrolled drug-taking. Therapeutic interventions targeting personal relevance and associated vmPFC functioning could enhance self awareness and facilitate more adaptive behavior in this chronically relapsing psychopathology. PMID- 25278371 TI - tigaR: integrative significance analysis of temporal differential gene expression induced by genomic abnormalities. AB - BACKGROUND: To determine which changes in the host cell genome are crucial for cervical carcinogenesis, a longitudinal in vitro model system of HPV-transformed keratinocytes was profiled in a genome-wide manner. Four cell lines affected with either HPV16 or HPV18 were assayed at 8 sequential time points for gene expression (mRNA) and gene copy number (DNA) using high-resolution microarrays. Available methods for temporal differential expression analysis are not designed for integrative genomic studies. RESULTS: Here, we present a method that allows for the identification of differential gene expression associated with DNA copy number changes over time. The temporal variation in gene expression is described by a generalized linear mixed model employing low-rank thin-plate splines. Model parameters are estimated with an empirical Bayes procedure, which exploits integrated nested Laplace approximation for fast computation. Iteratively, posteriors of hyperparameters and model parameters are estimated. The empirical Bayes procedure shrinks multiple dispersion-related parameters. Shrinkage leads to more stable estimates of the model parameters, better control of false positives and improvement of reproducibility. In addition, to make estimates of the DNA copy number more stable, model parameters are also estimated in a multivariate way using triplets of features, imposing a spatial prior for the copy number effect. CONCLUSION: With the proposed method for analysis of time course multilevel molecular data, more profound insight may be gained through the identification of temporal differential expression induced by DNA copy number abnormalities. In particular, in the analysis of an integrative oncogenomics study with a time-course set-up our method finds genes previously reported to be involved in cervical carcinogenesis. Furthermore, the proposed method yields improvements in sensitivity, specificity and reproducibility compared to existing methods. Finally, the proposed method is able to handle count (RNAseq) data from time course experiments as is shown on a real data set. PMID- 25278372 TI - Pentacyclic triterpenoids from spikes of Prunella vulgaris L. inhibit glycogen phosphorylase and improve insulin sensitivity in 3T3-L1 adipocytes. AB - Phytochemical investigation of methanol extract from the spikes of Prunella vulgaris L. led to the isolation of two new pentacyclic triterpenoid glycosides Vulgasides I (1) and II (2) along with 13 known compounds (3-15). Their structures were established on the basis of nuclear magnetic resonance (1D and 2D) and mass spectroscopic data analysis. All the isolated compounds were screened for glycogen phosphorylase inhibitory activity and also evaluated for their effect on insulin sensitivity in 3T3-L1 adipocytes. Two new compounds (1, 2) did not demonstrate the glycogen phosphorylase inhibitory activity, but other compounds (3-11) exhibited varying degrees of glycogen phosphorylase inhibitory activity with IC50 values in the range from 30.69 to 68.85 MUM. Compounds 3, 6, 7, 11, and 13 demonstrated markedly increased insulin-mediated glucose consumption in 3T3-L1 adipocytes. PMID- 25278373 TI - Efficient selective and atom economic catalytic conversion of glycerol to lactic acid. AB - The availability of glycerol is rapidly increasing due to the expanding biodiesel industry, which produces this polyol as the main waste material. Several value added chemicals have been synthesized using glycerol as a feedstock; however, the conversion of glycerol to lactic acid has been investigated to a lesser extent despite the numerous and novel uses of lactic acid. We report a family of iridium complexes as the first homogeneous catalysts for the conversion of glycerol to lactic acid. These have higher activity and selectivity than the previously reported heterogeneous systems. In addition, hydrogen gas is generated as a useful byproduct. Unlike prior systems, the reactions can be performed in air, under mild conditions and without solvent. Our method has even been applied to samples of crude glycerol waste derived from the biodiesel industry without prior purification, albeit with somewhat lower activity while maintaining the same high selectivity. PMID- 25278374 TI - Diseases of abnormal sensitivity to cold in children on psychostimulant drugs. AB - BACKGROUND: Oral psychostimulant (PS) drugs, the pharmacologic treatment of choice for attention-deficit/hyperactivity disorder (ADHD), have been associated with diseases of abnormal sensitivity to cold (DASC) such as Raynaud phenomenon and acrocyanosis. OBJECTIVES: In a cohort of pediatric patients with DASC, we sought to identify prevalence and clinical features of patients on PS drugs. METHODS: A 6-year retrospective chart review (2005-2011) of Ste-Justine University Hospital Center DASC patients with and without exposure to PS drugs was performed. Clinical data were analyzed with descriptive statistical methods. RESULTS: Of 43 patients with DASC, 11 (25%) were exposed to PS drugs. In this group males were overrepresented, there was no evidence of collagen vascular diseases, serologic findings were not significant and the mean duration of PS intake was of 2.5 years. DASC age of onset was similar in both exposed and nonexposed patients. The incidence of more than one DASC type was greater in teenager patients with a positive family history of autoimmune and/or collagen vascular diseases. LIMITATIONS: This study is limited by its small population size, short follow-up period and its retrospective nature. CONCLUSION: Physicians should be aware of PS drugs as possible triggers for DASC. PMID- 25278375 TI - Iterative type I polyketide synthases involved in enediyne natural product biosynthesis. AB - Enediyne natural products are potent antibiotics structurally characterized by an enediyne core containing two acetylenic groups conjugated to a double bond in a 9 or 10-membered carbocycle. The biosynthetic gene clusters for enediynes encode a novel iterative type I polyketide synthase (PKSE), which is generally believed to initiate the biosynthetic process of enediyne cores. This review article will cover research efforts made since its discovery to elucidate the role of the PKSE in enediyne core biosynthesis. Topics covered include the unique domain architecture, identification, and characterization of turnover products, and interaction with partner thioesterase protein. PMID- 25278377 TI - A structure-based proposal for a comprehensive myotoxic mechanism of phospholipase A2-like proteins from viperid snake venoms. AB - Envenomation via snakebites is an important public health problem in many tropical and subtropical countries that, in addition to mortality, can result in permanent sequelae as a consequence of local tissue damage, which represents a major challenge to antivenom therapy. Venom phospholipases A2 (PLA2s) and PLA2 like proteins play a leading role in the complex pathogenesis of skeletal muscle necrosis, nevertheless their precise mechanism of action is only partially understood. Recently, detailed structural information has been obtained for more than twenty different members of the PLA2-like myotoxin subfamily. In this review, we integrate the available structural, biochemical and functional data on these toxins and present a comprehensive hypothesis for their myotoxic mechanism. This process involves an allosteric transition and the participation of two independent interaction sites for docking and disruption of the target membrane, respectively, leading to a five-step mechanism of action. Furthermore, recent functional and structural studies of these toxins complexed with ligands reveal diverse neutralization mechanisms that can be classified into at least three different groups. Therefore, the data summarized here for the PLA2-like myotoxins could provide a useful molecular basis for the search for novel neutralizing strategies to improve the treatment of envenomation by viperid snakes. PMID- 25278378 TI - Quantitative analysis of a phosphoproteome readily altered by the protein kinase CK2 inhibitor quinalizarin in HEK-293T cells. AB - CK2 is an extremely pleiotropic Ser/Thr protein kinase, responsible for the generation of a large proportion of the human phosphoproteome and implicated in a wide variety of biological functions. CK2 plays a global role as an anti apoptotic agent, a property which is believed to partially account for the addiction of many cancer cells to high CK2 levels. To gain information about the CK2 targets whose phosphorylation is primarily implicated in its pro-survival signaling advantage has been taken of quinalizarin (QZ) a cell permeable fairly specific CK2 inhibitor, previously shown to be able to block endogenous CK2 triggering an apoptotic response. HEK-293T cells either treated or not for 3h with 50MUM QZ were exploited to perform a quantitative SILAC phosphoproteomic analysis of phosphosites readily responsive to QZ treatment. Our analysis led to the identification of 4883 phosphosites, belonging to 1693 phosphoproteins. 71 phosphosites (belonging to 47 proteins) underwent a 50% or more decreased occupancy upon QZ treatment. Almost 50% of these fulfilled the typical consensus sequence recognized by CK2 (S/T-x-x-E/D/pS) and in several cases were validated as bona fide substrates of CK2 either based on data in the literature or by performing in vitro phosphorylation experiments with purified proteins. The majority of the remaining phosphosites drastically decreased upon QZ treatment display the pS/T-P motif typical of proline directed protein kinases and a web logo extracted from them differentiates from the web logo extracted from all the proline directed phosphosites quantified during our analysis (1151 altogether). A paradoxical outcome of our study was the detection of 116 phosphosites (belonging to 92 proteins altogether) whose occupancy is substantially increased (50% or more), rather than decreased by QZ treatment: 40% of these display the typical motif recognized by proline directed kinases, while about 25% fulfill the CK2 consensus. Collectively taken our data on one side have led to the disclosure of a subset of CK2 targets which are likely to be implicated in the early steps of CK2 signaling counteracting apoptosis, on the other they provide evidence for the existence of side and off-target effects of the CK2 inhibitor quinalizarin, paving the road toward the detection of other kinases susceptible to this compound. This article is part of a Special Issue entitled: Medical Proteomics. PMID- 25278379 TI - Perioperative continuous cerebrospinal fluid pressure monitoring in patients with spontaneous cerebrospinal fluid leaks. AB - BACKGROUND: Elevated intracranial pressure (ICP) is an inciting factor for cerebrospinal fluid (CSF) leaks and can be measured by CSF pressure (CSFP) monitoring. Current CSFP literature is limited to the assessments of opening pressure. This study reinvestigates a previously discussed monitoring approach that evaluates continuous CSFP parameters, physiologic measurements, and treatment outcomes in patients undergoing endoscopic repair of spontaneous CSF leaks. METHODS: Retrospective review of patients undergoing endoscopic endonasal repair of spontaneous CSF leaks. All participants had a lumbar catheter placed for 24-hour continuous preoperative pressure monitoring, and 24 hours of continuous monitoring starting 48 hours after repair. In addition to patient characteristics, mean and peak CSFP, pulse waveform amplitudes (PWAs), and related parameters were calculated. RESULTS: Twenty-five patients underwent monitoring between 2004 and 2013, with a mean follow-up of 526 days. The mean age was 49.2 years, the mean body mass index (BMI) 38.5, and 8 of 25 (32%) had obstructive sleep apnea. Although mean CSFP and PWA decreased after the repair, mean peak CSFP increased by 1.56 cmH2O (1.15 mmHg). Six patients (24%) had elevation in their CSFP >25 cmH2O (18.4 mmHg) for a minimum of 4% of the recording time. Based on their continuous pressure monitoring data, 9 patients (36%) underwent treatment for high ICP, either with acetazolamide or a ventricular shunt. There were no CSF leak recurrences. CONCLUSION: Continuous perioperative CSFP monitoring provides valuable insight into multiple physiologic parameters. Systematic continuous CSFP monitoring can identify individuals in need of ICP-lowering therapy, possibly improving the outcomes in CSF leak repair surgeries. PMID- 25278376 TI - Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. AB - This Phase III randomized trial examined efficacy and safety of a novel once daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation. PMID- 25278380 TI - Study on bioactivity of cell-free filtrates from dairy propionibacteria. AB - In this paper, the bioactivity of cell-free extracts obtained by dairy propionibacteria strains was investigated. Probiotic bifidobacteria and lactobacilli were used as microbial targets. The extracellular filtrates were added as ingredient (1% v/v) into the growth medium; the effect of cell-free filtrates was evaluated through viable count of microbial targets on appropriate media, monitoring the response of target microorganisms both in growth and death phase. The Gompertz equation was used to model the experimental data. Kinetics and time parameters were estimated in order to quantify the effectiveness of cell free filtrates effect. To emphasize the results about the bioactivity of cell free extract, supporting a complete picture of response, a new approach was developed: Probiotic Stability Time was calculated. This temporal parameter, defined as the time over that the cell load preserve a living value upper than 10(7) cfu ml(-1), was very useful to evaluate the probiotic capability and effectiveness. A stimulant effect was registered on growth and a positive one was recordered on survival of both bifidobacteria and lactobacilli strains, and the results obtained suggest that a prebiotic activity by dairy propionibacteria cell free filtrates could be supposed. The cell-free filtrate obtained from Propionibacterium freudenreichii subsp. shermanii was the most effective, in our experimental conditions. Although bifidobacteria were the most sensitive to the effect of cell-free filtrates, lactobacilli have been showed a similar probiotic stability time, showing a high sensitivity to the filtrates. This paper is the first report of a positive bioactivity by propionibacteria cell-free filtrates on lactobacilli. PMID- 25278381 TI - Genotype-phenotype correlations in severe acne in a han Chinese population. AB - BACKGROUND: Two novel susceptibility gene loci (1q24.2 and 11p11.2) for severe acne have been identified in a genome-wide association study of a Han Chinese population. OBJECTIVE: The current study investigated the relationships of these gene loci with clinical phenotypes, including onset age, atrophic scarring, hypertrophic scarring and family history. Furthermore, we investigated the correlations between these four clinical phenotypes. METHODS: We used the chi2 test to compare the allele frequency among the different clinical phenotypes. We calculated Spearman's correlation coefficient to measure the relationship between the different clinical phenotypes. RESULTS: We identified significant associations between the 11p11.2 locus and disease family history (p < 0.05). We also determined that hypertrophic scarring was moderately correlated with atrophic scarring (rs = 0.315). CONCLUSIONS: This study suggests that the susceptibility gene locus 11p11.2 may contribute to the complex phenotypes of severe acne, particularly in cases of hereditary severe acne, whereas there are also correlations between the different phenotypes. PMID- 25278382 TI - Use of a live attenuated Salmonella enterica serovar Typhimurium vaccine on farrow-to-finish pig farms. AB - Salmonella enterica infection in pigs is economically important and poses a zoonotic risk. In this study, the efficacy of an attenuated S. enterica serovar Typhimurium strain was evaluated in three farrow-to-finish pig herds. In each herd, 120 piglets were vaccinated orally at 3 and 24 days of age, while 120 piglets served as unvaccinated controls. Faeces, ileocaecal lymph nodes and caecal contents were examined for S. Typhimurium by isolation and serum was analysed for antibodies against S. Typhimurium by ELISA. All pigs were weighed at pre-weaning and slaughter to determine daily weight gain. In vaccinated pigs prior to slaughter, significantly fewer animals excreted S. enterica, there was a significantly lower S. enterica-specific mean antibody titre and there was a significantly higher mean daily weight gain compared to unvaccinated controls. In two herds, there were significantly lower proportions of S. enterica positive ileocaecal lymph nodes and caecal contents at slaughter between the vaccinated and control groups, but this difference was not significant across all three herds. S. enterica with the same auxotrophic characteristics and genotype as the vaccine strain was isolated from several samples of faeces, ileocaecal lymph nodes and caecal contents from vaccinated pigs. These findings indicate that vaccination with an attenuated S. Typhimurium strain reduces S. enterica shedding, but the reduction is not consistent and the vaccine strain may persist in tissues. PMID- 25278383 TI - Degenerative lumbosacral stenosis in dogs: will we see progress in the next 30 years? PMID- 25278385 TI - Academy of managed care pharmacy 2014 nexus meeting abstracts. AB - Abstracts provide a forum during which authors can share their insights and outcomes to advance managed care practice through publication in AMCP's Journal of Managed Care Specialty Pharmacy (JMCP). Of the abstracts accepted for publication, most are presented as posters, so interested AMCP meeting attendees can review the findings and query authors. PMID- 25278384 TI - Risk of false positive genetic associations in complex traits with underlying population structure: a case study. AB - Genome-wide association (GWA) studies are widely used to investigate the genetic etiology of diseases in domestic animals. In the horse, GWA studies using 40 50,000 single nucleotide polymorphisms (SNPs) in sample sizes of 30-40 individuals, consisting of only 6-14 affected horses, have led to the discovery of genetic mutations for simple monogenic traits. Equine neuroaxonal dystrophy is a common inherited neurological disorder characterized by symmetric ataxia. A case-control GWA study was performed using genotypes from 42,819 SNP marker loci distributed across the genome in 99 clinically phenotyped Quarter horses (37 affected, 62 unaffected). A significant GWA was not achieved although a suggestive association was uncovered when only the most stringently phenotyped NAD-affected horses (n = 10) were included (chromosome 8:62130605 and 62134644 [log(1/P) = 5.56]). Candidate genes (PIK3C3, RIT2, and SYT4) within the associated region were excluded through sequencing, association testing of uncovered variants and quantitative RT-PCR. It was concluded that variants in PIK3C3, RIT2, and SYT4 are not responsible for equine neuroaxonal dystrophy. This study demonstrates the risk of false positive associations when performing GWA studies on complex traits and underlying population structure when using 40 50,000 SNP markers and small sample size. PMID- 25278386 TI - American Journal of Infection Control objectives in support of APIC's Strategic Plan. PMID- 25278387 TI - Infection prevention and you. PMID- 25278388 TI - The rise in Clostridium difficile infection incidence among hospitalized adults in the United States: 2001-2010. AB - BACKGROUND: Clostridium difficile infection (CDI) incidence is a growing concern. This study provides national estimates of CDI over 10 years and identifies trends in mortality and hospital length of stay (LOS) among hospitalized adults with CDI. METHODS: We conducted a retrospective analysis of the US National Hospital Discharge Surveys from 2001-2010. Eligible cases included adults aged >= 18 years discharged from a hospital with an ICD-9-CM diagnosis code for CDI (008.45). Data weights were used to derive national estimates. CDI incidence rates were depicted as CDI discharges per 1,000 total adult discharges. RESULTS: These data represent 2.2 million adult hospital discharges for CDI over the study period. CDI incidence increased from 4.5 CDI discharges per 1,000 total adult discharges in 2001 to 8.2 CDI discharges per 1,000 total adult discharges in 2010. The overall in-hospital mortality rate was 7.1% for the study period. Mortality increased slightly over the study period, from 6.6% in 2001 to 7.2% in 2010. Median hospital LOS was 8 days (interquartile range, 4-14 days), and remained stable over the study period. CONCLUSIONS: The incidence of CDI among hospitalized adults in the United States nearly doubled from 2001-2010. Furthermore, there is little evidence of improvement in patient mortality or hospital LOS. PMID- 25278389 TI - Evolution of the resistance to antibiotics of bacteria involved in urinary tract infections: a 7-year surveillance study. AB - BACKGROUND: We conducted a retrospective analysis on the identification and antibiogram of all bacteria isolated from urine samples with microbiological confirmation of urinary tract infection (UTI) in a Spanish reference hospital over a 7-year period. METHODS: A retrospective analysis was performed of the identification and antibiogram data. RESULTS: A total of 31,758 uropathogens were isolated. Escherichia coli accounted for the majority (55.2%) of these, followed by Enterococcus faecalis (18.0%) and Klebsiella spp (10.3%). The highest E coli susceptibility rates were to imipenem (93.0%-99.8%), amikacin (97.3%-99.5%), nitrofurantoin (96.7%-98.9%), and fosfomycin (95.3%-100%), and the lowest were to cefuroxime (67.8%-86.4%), ciprofloxacin (61.2%-69.8%), and co-trimoxazole (55.0% 65.5%). We highlight the overall high activity of imipenem, piperacillin tazobactam, nitrofurantoin, and fosfomycin on isolates versus the low activity of fluoroquinolones, co-trimoxazole, or cephalosporins. The activity of amoxicillin clavulanic acid and fosfomycin decreased significantly over the 7-year study period. CONCLUSIONS: Imipenem and piperacillin-tazobactam appear to be good options for the empiric treatment of UTI acquired in hospital or requiring hospitalization, whereas nitrofurantoin and fosfomycin can be first-choice antibiotics for the treatment of uncomplicated community-acquired cystitis. However, surveillance studies are required to detect resistance to these antibiotics, given that an increase in uropathogen resistance rates may contraindicate its future use in empiric UTI therapy. PMID- 25278390 TI - Clinical, patient experience and cost impacts of performing active surveillance on known methicillin-resistant Staphylococcus aureus positive patients admitted to medical-surgical units. AB - BACKGROUND: There is a large and growing body of evidence that methicillin resistant Staphylococcus aureus (MRSA) screening programs are cost effective, but such screening represents a significant cost burden for hospitals. This study investigates the clinical, patient experience and cost impacts of performing active surveillance on known methicillin-resistant S aureus positive (MRSA+) patients admitted to 7 medical-surgical units of a large regional hospital, specifically to allow discontinuation of contact isolation. METHODS: We conducted mixed-methods retrospective evaluation of a process improvement project that screened admitted patients with known MRSA+ status for continued MRSA colonization. RESULTS: Of those eligible patients on our institution's MRSA+ list who did complete testing, 80.2% (130/162) were found to be no longer colonized, and only 19.8% (32/162) were still colonized. Forty-one percent (13/32) of interviewed patients in contact isolation for MRSA reported that isolation had affected their hospital stay, and 28% (9/32) of patients reported emotional distress resulting from their isolation. Total cost savings of the program are estimated at $101,230 per year across the 7 study units. CONCLUSION: Our findings provide supporting evidence that a screening program targeting patients with a history of MRSA who would otherwise be placed in isolation has the potential to improve outcomes and patient experience and reduce costs. PMID- 25278391 TI - National HIV/AIDS mortality, prevalence, and incidence rates are associated with the Human Development Index. AB - BACKGROUND: HIV/AIDS is a worldwide threat to human health with mortality, prevalence, and incidence rates varying widely. We evaluated the association between the global HIV/AIDS epidemic and national socioeconomic development. METHODS: We obtained global age-standardized HIV/AIDS mortality, prevalence, and incidence rates from World Health Statistics Report of the World Health Organization. The human development indexes (HDIs) of 141 countries were obtained from a Human Development Report. Countries were divided into 4 groups according to the HDI distribution. We explored the association between HIV/AIDS epidemic and HDI information using Spearman correlation analysis, regression analysis, and the Kruskal-Wallis test. RESULTS: HIV/AIDS mortality, prevalence, and incidence rates were inversely correlated with national HDI (r = -0.675, -0.519, and 0.398, respectively; P < .001), as well as the 4 indicators of HDI (ie, life expectancy at birth, mean years of schooling, expected years of schooling, and gross national income per capita). Low HDI countries had higher HIV/AIDS mortality, prevalence, and incidence rates than that of medium, high, and very high HDI countries. Quantile regression results indicated that HDI had a greater negative effect on the HIV/AIDS epidemic in countries with more severe HIV/AIDS epidemic. CONCLUSIONS: Less-developed countries are likely to have more severe HIV/AIDS epidemic. There is a need to pay more attention to HIV/AIDS control in less-developed countries, where lower socioeconomic status might have accelerated the HIV/AIDS epidemic more rapidly. PMID- 25278392 TI - Microbiological analysis of environmental samples collected from child care facilities in North and South Carolina. AB - BACKGROUND: Children cared for outside the home are at an increased risk of enteric disease. Microbiological analyses were performed on environmental samples collected from child care facilities in North and South Carolina. METHODS: There were 326 samples collected from 40 facilities corresponding to common surfaces (77% of samples) and the hands of care providers (23% of samples). Samples were analyzed for total aerobic plate counts (APCs), total coliforms, biotype I Escherichia coli, and pathogens Shigella spp, Salmonella enterica, E coli O157, Campylobacter jejuni, and human norovirus. RESULTS: Median APCs and coliform counts for hands were 4.6 and 1.0 log10 colony-forming units (CFU) per hand, respectively. Median APCs for surfaces were 2.0 and 2.6 log10 CFU for flat and irregular surfaces, respectively. Coliforms were detected in 16% of samples, with counts ranging from 1.0 log10 to > 4.3 log10 CFU, with higher counts most often observed for hand rinse samples. Biotype I E coli counts were below assay detection limits (< 1 log10 CFU) for all but 1 sample. No samples were positive for any of the 4 bacterial pathogens, whereas 4 samples showed evidence of human norovirus RNA. CONCLUSION: The relative absence of pathogens and biotype I E coli in environmental samples suggests the child care facilities sampled in this study managed fecal contamination well. PMID- 25278393 TI - Evaluation of the effectiveness of an infection control program in adult intensive care units: a report from a middle-income country. AB - BACKGROUND: The rates of hand hygiene improvement and health care-associated infections (HAIs) were evaluated after the introduction in 2004 of an infection surveillance and prevention program at a university teaching hospital in a low- to middle-income country. METHODS: Data on hand hygiene compliance, HAI rate, multiresistant organisms, and antibiotic consumption in 4 adult intensive care units (ICUs; medical, general surgery, anesthesiology and reanimation, and neurosurgery) were collected retrospectively for each year from 2004 to 2012. Negative binomial regression modeling with a log link was used to adjust for overdispersion in observations, and the first year of observations served as the baseline for comparing changes in incidence rate ratio (IRR) over the subsequent years. RESULTS: Total hand hygiene compliance improved from 30.5% in 2004 to 43.5% by 2010 (IRR, 1.3; P <.0001) and reached 63.8% by 2012 (IRR, 1.9; P < .0001). The HAI rate was 42.6/1,000 patient-days at baseline and increased significantly thereafter until 2012, when it decreased by 20% to 33.6/1,000 patient-days (IRR, 0.8; P = .001). The rate of central line-associated bloodstream infection was 7.85 (95% confidence interval [CI], 5.89-10.26)/1,000 catheter-days in 2004 and increased to 12.4 (95% CI, 9.98-14.39)/1,000 catheter days in 2012 (IRR, 1.5; P = .024). The rate of ventilator-associated pneumonia remained stable from the 2004 baseline rate of 31.66/1,000 ventilator-days to the 2012 rate of 24.04/ 1,000 ventilator-days (IRR, 0.88; P = .574). The rate of catheter-associated urinary tract infection remained relatively stable between 2004 and 2012 (from 7.92/1,000 catheter-days to 4.97/1,000 catheter-days; P = .101). The rate of methicillin-resistant Staphylococcus aureus infection was 6.24/1,000 patient-days at baseline and decreased significantly to 0.73/1,000 patient-days by 2007 (IRR, 0.13; P <.001) and continued to remain below 2/1,000 patient-days for the next 5 years. The rate of Pseudomonas aeruginosa infection decreased significantly from 8.66/1,000 patient-days in 2004 to 6.09/1,000 patient-days in 2010 (IRR, 0.72; P = .026) and to 5.44/1,000 patient-days by 2012 (IRR, 0.63; P = .002). The rate of Acinetobacter baumannii infection was 14.3/1,000 patient-days at baseline, decreased significantly by 2005 (IRR, 0.73; P = .012), fluctuated between 2006 and 2010, and then decreased significantly to 10.44/1,000 patient-days in 2011 (IRR, 0.74; P = .007) and then to 7.6/1,000 patient-days in 2012 (IRR, 0.53; P < .001). Antibiotic consumption did not decrease noticeably over the 9-year study period. CONCLUSIONS: Hand hygiene improved in all of the ICUs evaluated. Measuring changes in HAI rates in a single health care setting can be statistically challenging, and a bias in the detection rates is not uncommon in the early years of a new infection prevention program. Here, for the first time, implementation of an infection surveillance and prevention program was associated with a reduction in HAI rate. PMID- 25278394 TI - Vancomycin-resistant Enterococcus colonization in the intensive care unit: clinical outcomes and attributable costs of hospitalization. AB - BACKGROUND: The clinical and economic impact of vancomycin-resistant Enterococcus (VRE) colonization remains unclear. Little data are available on factors affecting hospitalization length of stay (LOS) and costs. This study aimed to estimate mortality, LOS, and hospitalization costs for VRE colonized patients compared with a matched hospital population. METHODS: We performed a retrospective propensity score matched cohort study comparing the outcomes of patients with VRE colonization with those of uncolonized subjects matched at the time they were admitted to the intensive care unit (ICU). Between January 2008 and December 2010, we obtained rectal swab cultures within 24 hours of ICU admission to detect VRE colonization. RESULTS: During the study period, 567 (7.2%) of the 7,703 patients were colonized with VRE. There were 199 VRE colonized patients compared with 199 uncolonized patients using the propensity score. VRE colonized patients when compared with uncolonized patients were likely to have a higher case fatality rate (24.6% vs 17.1%; OR, 2.35). Longer total admission days were observed in the VRE colonized patients (28.7 vs 21.4 days; multiplicative effect, 1.25; P = .004). VRE colonization is found to be a significant factor associated with increased ICU cost in the multivariable regression model ($6,065 vs $5,298; multiplicative effect, 1.22; P = .029). Multivariable analysis identified the factors affecting ICU cost as follows: VRE colonization (odds ratio [OR], 1.20; P = .038), ICU length of stay (OR, 1.93; P < .001), ICU type (OR, 1.51; P = .001), valvular heart disease (OR, 2.38; P = .27), hospitalization within 12 months (OR, 1.21; P = .037), and use of invasive devices (OR, 1.28; P = .017). CONCLUSION: Compared with a matched hospital population, VRE colonization was associated with increased mortality, LOS, and costs. Strict infection control programs, including preemptive isolation for a high-risk group, should be helpful. PMID- 25278395 TI - Observer accuracy and behavior analysis: Data collection procedures on hand hygiene compliance in a neurovascular unit. AB - BACKGROUND: Although observational studies are popular, little has been done to study the integrity of human observers and the data collection process. Issues of data collection integrity threaten functional findings, leading to problematic interpretation and decreased replication. In our study the response effort associated with hand hygiene data collection in a hospital setting was manipulated using an altered data collection tool. METHODS: A counterbalanced ABAB design was implemented across 2 semesters of a hand hygiene data collection practicum course. RESULTS: When response effort increased, compliant audits decreased and when response effort decreased, compliant audits increased. These results were statistically significant, with an overall level change z that had a P value of .001 (first semester) and .007 (second semester). CONCLUSION: These findings may warrant an increased awareness of data collection procedures where recording options include a less effortful response. The results of our study support basic research on response effort and choice behavior in an applied setting, bringing into question the integrity of data collection procedures and the integrity of the data collected. These results also suggest the need for standardizing reporting systems to ensure hand hygiene collection and reporting procedures are comparable across settings. PMID- 25278396 TI - Hospital hand hygiene compliance improves with increased monitoring and immediate feedback. AB - BACKGROUND: Health care-associated infections are serious complications impacting 2 million patients and accounting for approximately 100,000 deaths per year. In the present study, we evaluated the effectiveness of a new hand hygiene monitoring program (HHMP) and measured the sustainability of this effectiveness over a 1-year period. METHODS: The HHMP consisted of 4 key components: extensive education, conspicuous and visible monitors, immediate feedback concerning compliance to health care workers, and real-time data dissemination to leadership. The HHMP was implemented in 2 hospital care units. Two different, but similar, departments served as controls, and hand hygiene compliance was monitored via the "secret shopper" technique. All 4 departments were followed for 12 months. RESULTS: Both experimental departments showed statistically significant increases in hand hygiene compliance. Experimental department 1 increased compliance from 49% to an average of 90%, and experimental department 2 increased compliance from 60% to an average of 96%. Both experimental departments were able to sustain these results for at least 6 months. Compliance rates were significantly higher in the experimental departments compared with the control departments. No significant changes were seen in the control departments. CONCLUSIONS: These finding suggest that continuous monitoring by salient observers and immediate feedback are critical to the success of hand hygiene programs. PMID- 25278397 TI - Application of a modified microbiologic criterion for identifying pediatric ventilator-associated pneumonia. AB - BACKGROUND: Prevention of ventilator-associated pneumonia (VAP) is a major patient safety goal, but accurate identification of VAP in pediatric patients remains challenging. METHODS: We performed a retrospective cohort study to demonstrate feasibility of endotracheal culture and Gram's stain to support VAP diagnosis. Pediatric intensive care unit and cardiac intensive care unit patients with >= 1 endotracheal specimen having growth of >= 1 organism in conjunction with moderate/many polymorphonuclear leukocytes (ie, the modified microbiologic criterion) were included. Medical records were reviewed for presence/absence of clinical and radiographic Centers for Disease Control and Prevention (CDC) criteria for VAP. Antimicrobial use data were collected before and after culture results were known. RESULTS: Of 102 patients meeting inclusion criteria, 28% (n = 28) also met both clinical and radiographic CDC criteria for VAP (ie, diagnosis of PNU2). An additional 63% (n = 64) met clinical (36%; n = 37) or radiographic (27%; n = 27) criteria, but not both. Ten patients (9%) had neither clinical nor radiographic criteria for VAP. The majority (63%; n = 64) were receiving antibiotics at time of endotracheal specimen collection. Culture identification resulted in altered antimicrobial therapy in 66% of patients (n = 67). CONCLUSIONS: Our study demonstrates the feasibility of endotracheal Gram's stain and culture for diagnosis of pediatric VAP that could potentially standardize accurate surveillance and management of pediatric VAP. PMID- 25278398 TI - Utility of routine surveillance blood cultures in asymptomatic allogeneic hematopoietic stem cell transplant recipients with indwelling central venous catheters at a comprehensive cancer center. AB - BACKGROUND: Many transplant centers obtain surveillance blood cultures (SBCs) from asymptomatic allogeneic hematopoietic stem cell transplant (allo-HCT) recipients with central venous catheters for early detection of potential blood stream infections. The aim of this study was to determine the utility of this practice. METHODS: We conducted a retrospective study of all patients who underwent allo-HCT to determine the frequency, clinical significance, and costs associated with SBCs. RESULTS: From 776 patients, 6,801 SBCs were obtained (median, 9 per patient). Most (96.89%) were negative. Of the 211 positive SBCs, 171 (81%) had minimal clinical significance. The remaining 40 positive cultures (19%) were considered potentially significant. The frequency of potentially significant SBCs was 5.1% for the entire cohort and 0.59% of all SBCs drawn. CONCLUSION: All potentially significant cultures and some that were deemed to have minimal significance led to medical intervention, some of which were probably unnecessary. No adverse outcomes occurred in patients with positive SBCs for the first 30 days following the positive result, regardless of the pathogen isolated or the quantitative colony count. The frequency of clinically significant positive SBCs in asymptomatic adult allo-HCT recipients is very low. Routine use of this practice leads to some unnecessary medical interventions and added costs. PMID- 25278400 TI - Evaluation of surgical glove integrity during surgery in a Brazilian teaching hospital. AB - BACKGROUND: A cross-sectional study was conducted in a large university hospital in Belo Horizonte, Minas Gerais, Brazil to evaluate surgical glove integrity after use during surgery. METHODS: This 6-month study was conducted by a gastroenterological, cardiovascular, and pediatric surgical team consisting of surgeons (main surgeon and first and second assistants), medical students, and scrub nurses. The gloves used during surgery were examined postsurgery for microperforations using the watertight test as described in European Norm EN 455 1. RESULTS: A total of 116 medical professionals conducted the 100 surgeries monitored. Of the 1090 gloves analyzed, 131 (12%) had a perforation detected postsurgery, 39 of which (37.5%) were recognized by users at the time of occurrence. The highest incidence of perforations occurred among surgeons (P = .033) in the index finger, followed by the thumb of the nondominant hand; in outer gloves (76.9%) when double-gloving was used (P = .014); in open surgery (P = .019); and in surgeries lasting >= 150 minutes (P < .05). CONCLUSION: These findings reaffirm the importance of double-gloving, using a perforation indicator system, and changing gloves in surgeries of >= 150 minutes duration, especially in procedures involving open incisions. PMID- 25278399 TI - Surgical site infection rates in 4 cities in Colombia: findings of the International Nosocomial Infection Control Consortium (INICC). AB - BACKGROUND: Surgical site infections (SSIs) are a threat to patient safety. However, there are no available data on SSI rates stratified by surgical procedure (SP) in Colombia. METHODS: From January 2008-December 2010, a prospective surveillance study on SSIs was conducted by the International Nosocomial Infection Control Consortium (INICC) in 4 hospitals in 4 cities within Colombia using the definitions of the Centers for Disease Control and Prevention National Healthcare Safety Network (CDC-NHSN). SPs were classified into 10 types, according to ICD-9 criteria. RESULTS: We recorded 193 SSIs associated with 5,063 SPs. SSI rates per type of SP were the following, compared with INICC and CDC NHSN rates, respectively: 9.1% for laminectomy (vs 1.7% and 1.0%), 8.3% for cardiac surgery (vs 5.6% and 1.3%), 3.9% for appendix surgery (vs 2.9% and 1.4%), 5.5% for abdominal hysterectomy (vs 2.7% and 1.6%), 4.4% for prostate surgery (vs 2.1% and 1.2%), 4.5% for spleen surgery (vs 5.6% and 2.3%), 4.3% for vaginal hysterectomy (vs 2.0% and 0.9%), and 3.0% for gallbladder surgery (vs 2.5% and 0.6%). CONCLUSIONS: Compared with CDC-NHSN rates, SSIs rates in our study hospitals were higher in most types of SPs, whereas compared with INICC, they were similar in 5 of the analyzed types, and higher in 4 types. This study represents an important advance toward knowledge of epidemiology in Colombia that will allow us to introduce targeted interventions. PMID- 25278401 TI - N95 respirator use during advanced pregnancy. AB - BACKGROUND: To determine the physiological and subjective effects of wearing an N95 filtering facepiece respirator (N95 FFR) in advanced stages of pregnancy. METHODS: Healthy pregnant women (n = 22) and nonpregnant women (n = 22) had physiological and subjective measurements taken with and without wearing an N95 FFR during exercise and postural sedentary activities over a 1-hour period. RESULTS: There were no differences between the pregnant and nonpregnant women with respect to heart rate, respiratory rate, oxygen saturation, transcutaneous carbon dioxide level, chest wall temperature, aural temperature, and subjective perceptions of exertion and thermal comfort. No significant effect on fetal heart rate was noted. CONCLUSIONS: Healthy pregnant women wearing an N95 FFR for 1 hour during exercise and sedentary activities did not exhibit any significant differences in measured physiological and subjective responses compared with nonpregnant women. PMID- 25278402 TI - Subglottic secretion drainage and continuous control of cuff pressure used together save health care costs. AB - BACKGROUND: Preventive strategies to reduce ventilator-associated respiratory infection (VARI) include the use of an endotracheal tube incorporating a lumen for subglottic secretion drainage (SSD) and a system for continuous control of endotracheal tube cuff pressure (CCCP). The health care costs associated with the combined use of these 2 measures aimed at preventing VARI are not known, however. The objective of this study was to determine whether the simultaneous use of these 2 preventive measures for VARI could save health care costs. METHODS: We performed a prospective observational study of patients who needed mechanical ventilation in an intensive care unit. The health care costs considered here included only the costs of the endotracheal tube, cuff control, and antimicrobials used to treat VARI. RESULTS: The study cohort comprised 656 patients, including 241 with intermittent control of cuff pressure and without SSD (standard group), 260 with CCCP and without SSD (CCCP group), 84 with intermittent control of cuff pressure and with SSD (SSD group), and 71 with CCCP and SSD (CCCP + SSD group). The incidence of VARI and health care costs were lower in the CCCP + SSD group compared with the standard, CCCP, and SSD groups. CONCLUSIONS: The combined use of SSD and CCCP reduced the incidence of VARI and saved health care costs. PMID- 25278404 TI - Hospital roommates and development of health care-onset Clostridium difficile infection. AB - There is potential for person-to-person transmission in Clostridium difficile outbreak settings. A limited number of studies have examined the role of hospital roommates in the development of nosocomial infections. This retrospective cohort study evaluated room cooccupancy and duration of exposure to roommates as predictors of health care-onset C difficile infection (CDI). Among roommates of patients with CDI, duration of room cooccupancy was significantly longer in those developing CDI. PMID- 25278403 TI - Patient empowerment begins with knowledge: consumer perceptions and knowledge sources for hand hygiene compliance rates. AB - A survey of 1,000 US consumers quantified their knowledge of health care worker hand hygiene compliance, their information sources on hand hygiene rates, and their past behavior of asking health care workers to perform hand hygiene. Sixty nine percent of respondents believed compliance is above 50%; 17% of respondents had asked a health care worker to perform hand hygiene. Our findings suggest that an organized plan of disclosure about hand hygiene rates may be a way to empower through knowledge. PMID- 25278405 TI - The 24-hour report as an effective monitoring and communication tool in infection prevention and control in nursing homes. AB - Twenty-four-hour reports are filled out by nurses daily to monitor nursing home residents and document any changes in resident status. Semistructured interviews conducted with ICPs from 12 southeast Michigan nursing homes showed that although 24-hour reports were used, they were not standardized for infection prevention activities. Our results indicate 24-hour reports can be an effective communication tool and potentially aid in early recognition of infections and outbreaks. PMID- 25278406 TI - Factors influencing intensive care nurses' knowledge and attitudes regarding ventilator-associated pneumonia and oral care practice in intubated patients in Croatia. AB - Adequate oral care in intubated patients may reduce occurrence of ventilator associated pneumonia. The purpose of this study was to explore knowledge, attitudes, and oral care practice in Croatian intensive care units and influencing factors. Nurses' knowledge is insufficient; however, most of them reported positive attitude toward the importance of oral care. Performed oral hygiene measures are mostly inappropriate. There is a need to improve the knowledge of ventilator-associated pneumonia and oral care. PMID- 25278407 TI - Endemic methicillin-resistant Staphylococcus aureus: Nurses' risk perceptions and attitudes. AB - Dissemination of methicillin-resistant Staphylococcus aureus (MRSA) remains one of the most difficult challenges for prevention, control, and treatment of health care-associated infections. A survey and interviews were conducted on nurses from a hospital center. We found that most nurses' perceived risk of acquiring MRSA related to themselves (72%), other nurses (88.5%), and patients (97.8%). This perception influences attitudes, leading to compliance with the existing recommendations. PMID- 25278408 TI - Are the risk factors associated with Staphylococcus aureus nasal carriage in patients the same than in healthy volunteers? Data from a cohort of patients scheduled for orthopedic material implantation. AB - The risk factors for Staphylococcus aureus nasal carriage have been mainly defined in healthy volunteers. Using data from a large multicenter prospective clinical cohort of orthopedic surgical patients we showed that obesity (BMI > 30) and younger age were independent risk factors for persistent carriage. In the absence of recommendations for S aureus decolonization in orthopedic surgery, this study suggests that at least obese patients should be targeted to prevent surgical site infections. PMID- 25278409 TI - Multidrug-resistant organisms contaminating supply carts of contact isolation patients. AB - Contamination of supply carts stored within rooms of patients on contact isolation for multidrug-resistant organisms was assessed. Despite the presence of environmentally persistent organisms, very little contamination occurred to these carts or the supplies stored within them. A single isolate containing a multidrug resistant Acinetobacter baumannii was isolated, representing 1.3% of the 80 swabs collected. PMID- 25278410 TI - Identification and characterization of catheter-related bloodstream infections due to viridans group streptococci in patients with cancer. AB - Viridans group streptococci (VGS), a leading cause of bloodstream infection (BSI) in cancer patients, are thought to arise from the gastrointestinal tract. We sought to determine whether central venous catheters may serve as the source of VGS BSI, and to compare the ability of the newly proposed mucosal barrier injury laboratory-confirmed BSI definition to assign a VGS BSI source compared with the catheter-related BSI definition. PMID- 25278411 TI - Cost/benefit analysis of chlorhexidine-silver sulfadiazine-impregnated venous catheters for femoral access. AB - Sixty-four patients with chlorhexidine-silver sulfadiazine-impregnated catheters had a lower rate of catheter-related bloodstream infection and lower central venous catheter-related costs per catheter day than 190 patients with a standard catheter. PMID- 25278412 TI - Infection control for extrapulmonary tuberculosis at a tertiary care cancer center. AB - Extrapulmonary tuberculosis (TB) can be infectious when diagnostic or therapeutic procedures are performed on infected lesions. We retrospectively describe infection control and evaluate isolation failure rates during the manipulation of active extrapulmonary TB lesions at a comprehensive cancer center over a 5-year period. Among patients with a high suspicion of cancer, extrapulmonary TB was not suspected, and airborne precautions often were not used when manipulating infected lesions. PMID- 25278413 TI - Lessons from audit and feedback of hospitalized patients with bacteriuria. AB - We sought to prevent the initiation of antimicrobial therapy for asymptomatic bacteriuria (ASB) by providing audit and feedback of newly reported positive urine cultures to test whether this could empower providers to leave ASB untreated. Despite success in providing feedback before antibiotics could be initiated in most cases, these recommendations only reduced treatment duration, without affecting antibiotic initiation. This study highlights the limitations of educational initiatives in overcoming engrained beliefs about bacteriuria even when advice is provided in real time. PMID- 25278414 TI - Reply to "Use of adenosine triphosphate bioluminescence assays to measure cleaning: The role of spores and Clostridium difficile infection rates". PMID- 25278415 TI - Clinical implications of dual-positive rapid influenza diagnostic tests during influenza season: Co-colonization, coinfection, or false positive test? PMID- 25278416 TI - Practice of cupping (Hijama) and the risk of bloodborne infections. PMID- 25278417 TI - Establishment of supermicrosurgical lymphaticovenular anastomosis model in rat. AB - BACKGROUND: Lymphaticovenular anastomosis (LVA) is becoming a choice of treatment for compression-refractory lymphedema. However, LVA requires highly sophisticated microsurgical technique called supermicrosurgery, and no training model for LVA has been developed. This study aimed to develop and evaluate feasibility of a new LVA model using rat thigh lymphatic vessels. METHODS: Ten Sprague-Dawley rats were used for the study. After preoperative indocyanine green (ICG) lymphography, lymphatic vessels in posteromedial aspect of the thigh were dissected. In right limbs, the largest lymphatic vessel was anastomosed to the short saphenous vein or its branch, and the remaining lymphatic vessels were ligated (LVA group). In left limbs, all lymphatic vessels were ligated (control group). Anastomosis patency was evaluated intraoperatively and at postoperative 7 days. RESULTS: Courses of lymphatic vessels in the thigh were constant; lymphatic vessels run along the short saphenous vein. The mean diameter of lymphatic vessel used for LVA was 0.240 +/- 0.057 mm, and the mean diameter of vein was 0.370 +/- 0.146 mm. All lymphatic vessels were translucent and very thin like human intact lymphatic vessels. In LVA group, intra- and post-operative anastomosis patency rates were 100% (10/10) based on ICG lymphography. In control group, intra- and post operative patency rates were 0% (0/10). CONCLUSIONS: Rat lymphatic vessels are thin, translucent, and fragile similar to intact human lymphatic vessels. The LVA model uses easily accessible lymphatic vessels in the thigh, and is useful for training of supermicrosurgical LVA. (c) 2014 Wiley Periodicals, Inc. Microsurgery 37:57-60, 2017. PMID- 25278418 TI - Speed discrimination predicts word but not pseudo-word reading rate in adults and children. AB - Visual processing in the magnocellular pathway is a reputed influence on word recognition and reading performance. However, the mechanisms behind this relationship are still unclear. To explore this concept, we measured reading rate, speed-discrimination, and contrast detection thresholds in adults and children with a wide range of reading abilities. We found that speed discrimination thresholds are higher in children than in adults and are correlated with age. Speed discrimination thresholds are also correlated with reading rates but only for real words, not pseudo-words. Conversely, we found no correlations between contrast detection thresholds and the reading rates. We also found no correlations between speed discrimination or contrast detection and WASI subtest scores. These findings indicate that familiarity is a factor in magnocellular operations that may influence reading rate. We suggest this effect supports the idea that the magnocellular pathway contributes to word reading through an analysis of letter position. PMID- 25278419 TI - Developmental differences in the influence of phonological similarity on spoken word processing in Mandarin Chinese. AB - The developmental trajectory of spoken word recognition has been well established in Indo-European languages, but to date remains poorly characterized in Mandarin Chinese. In this study, typically developing children (N=17; mean age 10; 5) and adults (N=17; mean age 24) performed a picture-word matching task in Mandarin while we recorded ERPs. Mismatches diverged from expectations in different components of the Mandarin syllable; namely, word-initial phonemes, word-final phonemes, and tone. By comparing responses to different mismatch types, we uncovered evidence suggesting that both children and adults process words incrementally. However, we also observed key developmental differences in how subjects treated onset and rime mismatches. This was taken as evidence for a stronger influence of top-down processing on spoken word recognition in adults compared to children. This work therefore offers an important developmental component to theories of Mandarin spoken word recognition. PMID- 25278420 TI - Disease knowledge, perceived risk, and health behavior engagement among adolescents and adults with congenital heart disease. AB - OBJECTIVE: Survivors of congenital heart disease (CHD) are at risk for life threatening complications as they age. This study aimed to examine the association of knowledge of future health risks, perceived risk, and health behaviors among adolescents and adults with CHD. METHODS: CHD survivors (N = 200, ages 15-39; 23% simple, 44% moderate, 33% complex lesions) completed measures of risk knowledge accuracy and perceived risk for developing complications, and reported physical activity and saturated fat intake. RESULTS: CHD survivors reported poor risk knowledge and consuming high-fat diets. Adolescents reported more physical activity than young adults. Greater risk knowledge was associated with lower fat intake, and participants who exercised more expected fewer future complications, and this difference remained statistically significant when accounting for education and age. CONCLUSIONS: CHD survivors, regardless of age, have poor risk knowledge and diets. Survivors may benefit from emphasis on future health risks and health behaviors from both pediatric and adult providers. PMID- 25278421 TI - LPS-conditioned dendritic cells confer endotoxin tolerance contingent on tryptophan catabolism. AB - Dendritic cells (DCs) are specialized antigen-presenting cells with a bipolar nature. Depending on environmental factors, DCs will promote either inflammatory or anti-inflammatory effects. Lipopolysaccharide (LPS), a ligand of Toll-like receptor (TLR)4 and a most potent proinflammatory stimulus, is responsible for complex signaling events in different cell types, including DCs. LPS effects range from protective inflammation-capable of counteracting growth and dissemination of gram-negative bacteria - to hyperacute detrimental responses, as it occurs in endotoxic shock. Consistent with the plasticity of TLR4 signaling, a low dosage of LPS will induce a regulatory response capable of protecting mice against a subsequent, otherwise lethal challenge ('endotoxin tolerance'). By examining CD11c(+) DCs ('conventional' DCs, or cDCs), we investigated whether DC flexibility in promoting either inflammation or tolerance can be differentially affected by single vs. repeated exposure to LPS in vitro. cDCs stimulated twice with LPS expressed high levels of indoleamine 2,3-dioxygenase 1 (IDO1) - one of the most effective mediator of anti-inflammatory activity by DCs - and of TGF beta, an immunoregulatory cytokine capable of upregulating IDO1 expression and function. In contrast, a single exposure to LPS failed to upregulate IDO1, and it was instead associated with high-level production of IL-6, a cytokine that promotes inflammation and proteolysis of IDO1. When adoptively transferred in vivo, only cDCs on double endotoxin exposure greatly improved the outcome of an otherwise lethal LPS challenge. The protective effect required that the transferred cDCs be fully competent for IDO1 and the host for TGF-beta production. Thus cDCs, conditioned by LPS in vitro to mimic an endotoxin-tolerant state, can protect recipients from endotoxic shock, pointing to adoptive transfer of tolerance as a new option for controlling potentially harmful responses to TLR4 signaling. PMID- 25278422 TI - Continuity across inpatient and outpatient mental health care or specialisation of teams? A systematic review. AB - BACKGROUND: A central question for the organisation of mental health care is whether the same clinicians should be responsible for a patient's care across inpatient and outpatient settings (continuity of care) or if there should be separate teams (specialisation). Current reforms in Europe are inconsistent on which to favour, and are based on little research evidence. This review is the first systematic appraisal of the existing evidence comparing continuity of care and specialisation across inpatient and outpatient mental health care. METHOD: A systematic search for studies of any design comparing mental health care systems based on continuity or specialisation of care was performed. Differences in clinical, social and cost-effective outcomes, and the views and experiences of patients and staff were assessed using narrative synthesis. RESULTS: Seventeen studies met the inclusion criteria. All studies had methodological shortcomings, but findings point towards reduced length and number of hospitalisations, and faster or more flexible transitions between services in continuity systems. Survey and qualitative findings suggest advantages of both systems, whilst patients and staff appear to prefer a continuity system. CONCLUSION: The evidence base suggests better outcomes and stakeholder preferences for continuity of care systems, but the quality of existing studies is insufficient to draw definitive conclusions. Higher quality comparative studies across various settings and population groups are urgently needed. PMID- 25278423 TI - A lophotrochozoan-specific nuclear hormone receptor is required for reproductive system development in the planarian. AB - Germ cells of sexually reproducing organisms receive an array of cues from somatic tissues that instruct developmental processes. Although the nature of these signals differs amongst organisms, the importance of germline-soma interactions is a common theme. Recently, peptide hormones from the nervous system have been shown to regulate germ cell development in the planarian Schmidtea mediterranea; thus, we sought to investigate a second class of hormones with a conserved role in reproduction, the lipophilic hormones. In order to study these signals, we identified a set of putative lipophilic hormone receptors, known as nuclear hormone receptors, and analyzed their functions in reproductive development. We found one gene, nhr-1, belonging to a small class of functionally uncharacterized lophotrochozoan-specific receptors, to be essential for the development of differentiated germ cells. Upon nhr-1 knockdown, germ cells in the testes and ovaries fail to mature, and remain as undifferentiated germline stem cells. Further analysis revealed that nhr-1 mRNA is expressed in the accessory reproductive organs and is required for their development, suggesting that this transcription factor functions cell non-autonomously in regulating germ cell development. Our studies identify a role for nuclear hormone receptors in planarian reproductive maturation and reinforce the significance of germline-soma interactions in sexual reproduction across metazoans. PMID- 25278424 TI - Predictors of cessation treatment outcome and treatment moderators among smoking parents receiving quitline counselling or self-help material. AB - OBJECTIVE: Several cessation treatments effectively enhance cessation, but it is not always clear which treatment may be most suitable for a particular client. We examined predictors of treatment outcome and treatment moderators among smoking parents in the Netherlands. METHOD: We conducted secondary analyses of a randomized controlled trial in which smoking parents received either quitline counselling (n=256) or a self-help brochure (n=256). Data collection was completed in October 2012. Endpoints were 7-day point prevalence abstinence and 6 month prolonged abstinence at 12-month follow-up. Potential predictors and moderators included socio-demographic characteristics, smoking-related variables, and child-related variables. RESULTS: Male gender, higher employment status, lower daily cigarette consumption, higher levels of confidence in quitting, presence of a child with a chronic respiratory illness, and wanting to quit for the health of one's child predicted abstinence at 12months. Significant treatment moderators were intention to quit and educational level. Quitline counselling was effective regardless of intention to quit and educational level, but self-help material was less effective among less motivated and lower educated parents. CONCLUSION: Certain subgroups of smokers, such as parents who are concerned about the health of their child, are particularly receptive to cessation support. Individual characteristics should be considered in treatment selections. PMID- 25278425 TI - IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. AB - IL-33 is a nuclear cytokine from the IL-1 family constitutively expressed in epithelial barrier tissues and lymphoid organs, which plays important roles in type-2 innate immunity and human asthma. Recent studies indicate that IL-33 induces production of large amounts of IL-5 and IL-13 by group 2 innate lymphoid cells (ILC2s), for initiation of allergic inflammation shortly after exposure to allergens or infection with parasites or viruses. IL-33 appears to function as an alarmin (alarm signal) rapidly released from producing cells upon cellular damage or cellular stress. In this review, we discuss the cellular sources, mode of action and regulation of IL-33, and we highlight its crucial roles in vivo with particular emphasis on results obtained using IL33-deficient mice. PMID- 25278426 TI - Diurnal modulation and sources of variation affecting ventricular repolarization in Warmblood horses. AB - OBJECTIVES: Irregularities in cardiac repolarization are known to predispose for arrhythmias and sudden cardiac death in humans. The QT interval is a quantitative measurement of repolarization, and clinically, the QTc (QT interval corrected for heart rate) and Tpeak to Tend intervals (TpTe) are used as repolarization markers. To support the use of these markers in horses, we sought to describe the possible influence of the environment, time of day, day-to-day effects, T wave conformation, age, body weight (BW), and horse-to-horse variation on repolarization measurements. ANIMALS: 12 Warmblood geldings, age 10.8 +/- 4.8 years. METHODS: Holter ECGs were performed on days 0, 7 and 14. Measures of RR, QT, QTp, QTc and TpTe intervals and T wave conformation were obtained each hour during the recordings. An ANCOVA analysis was performed to estimate diurnal variation and the sources of variation affecting these intervals. RESULTS: Differences between individual horses were the largest source of repolarization variability although the environment had a significant effect on repolarization as well. Diurnal variation affected both the RR interval and the repolarization markers. The QT, QTc and TpTe intervals were prolonged on day 0. Biphasic T waves shortened the TpTe interval approximately 10 ms. Age and BW did not appear to affect repolarization. CONCLUSIONS: Equine repolarization markers exhibit significant variation. Factors affecting repolarization measurements include horse-to-horse variation, diurnal variation, the environment, and T wave conformation. These factors must be considered if markers of equine repolarization are used diagnostically. PMID- 25278427 TI - 14.8% perovskite solar cells employing carbazole derivatives as hole transporting materials. AB - Three novel carbazole-based molecules have been synthesized and successfully applied as hole-transporting materials (HTMs) of CH3NH3PbI3-based perovskite solar cells. In particular, the perovskite cell with SGT-405, having a three-arm type structure, exhibited a remarkable photovoltaic conversion efficiency (PCE) of 14.79%. PMID- 25278428 TI - Sequential roles of primary somatosensory cortex and posterior parietal cortex in tactile-visual cross-modal working memory: a single-pulse transcranial magnetic stimulation (spTMS) study. AB - BACKGROUND: Both monkey neurophysiological and human EEG studies have shown that association cortices, as well as primary sensory cortical areas, play an essential role in sequential neural processes underlying cross-modal working memory. OBJECTIVE: The present study aims to further examine causal and sequential roles of the primary sensory cortex and association cortex in cross modal working memory. METHODS: Individual MRI-based single-pulse transcranial magnetic stimulation (spTMS) was applied to bilateral primary somatosensory cortices (SI) and the contralateral posterior parietal cortex (PPC), while participants were performing a tactile-visual cross-modal delayed matching-to sample task. Time points of spTMS were 300 ms, 600 ms, 900 ms after the onset of the tactile sample stimulus in the task. RESULTS: The accuracy of task performance and reaction time were significantly impaired when spTMS was applied to the contralateral SI at 300 ms. Significant impairment on performance accuracy was also observed when the contralateral PPC was stimulated at 600 ms. CONCLUSION: SI and PPC play sequential and distinct roles in neural processes of cross-modal associations and working memory. PMID- 25278429 TI - Complementary treatment of contact lens-induced corneal ulcer using honey: a case report. AB - The aim of this study was to report the complementary use of honey for treatment of a contact lens-induced corneal ulcer. A 23-year-old contact lens user presented with a corneal ulcer in her left eye. She had visual acuity reduced to hand movement. There was a history of wearing contact lenses while swimming in a lake seven days before presentation. The cultures from corneal scrapings and contact lenses were positive for Klebsiella oxytoca, Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Pseudomonas spp. The treatment with topical levofloxacin and 25% (w/v) gamma-irradiated honeydew honey solution was effective and the patient achieved final best corrected visual acuity of affected eye. In addition to positive clinical outcome, honeydew honey was shown to be highly effective in vitro against ocular isolates, in particular S. maltophilia. The minimal inhibitory concentrations for honeydew honey ranged from 5% to 10%. These results demonstrate that honey is a promising antibacterial agent in management of corneal ulcers. Moreover, honey exhibits anti-biofilm and anti-inflammatory properties, and thus becomes an interesting ophthalmologic agent. PMID- 25278430 TI - Cardiorespiratory performance and physical activity in normal weight and overweight Finnish adolescents from 2003 to 2010. AB - We investigated changes in cardiorespiratory performance, BMI and leisure-time physical activity among Finnish adolescents from 2003 to 2010. In addition, we compared cardiorespiratory performance levels between normal weight and overweight adolescents, grouped according to their physical activity. Participants were a national representative samples of 15-16-year-old adolescents in their final (ninth) year of comprehensive school in 2003 (n = 2258) and in 2010 (n = 1301). They performed an endurance shuttle run test and reported their height and weight and leisure time physical activity on a questionnaire. Results showed no significant secular changes in cardiorespiratory performance from 2003 to 2010. The mean BMI increased in boys. Leisure-time physical activity increased among normal weight girls. Adolescents of normal weight had better cardiorespiratory performance than those classified as overweight at both assessment points. BMI-adjusted physical activity was a significant determinant for cardiorespiratory performance among overweight adolescents, and very active overweight adolescents had similar cardiorespiratory performance levels as moderately active adolescents of normal weight. The results of the present study support the idea that the physical activity has the great importance for the cardiorespiratory performance in adolescents. Overweight adolescents, in particular, benefit from higher levels of physical activity. PMID- 25278431 TI - How food cues can enhance and inhibit motivation to obtain and consume food. AB - Learning may play an important role in over-eating. One example is Pavlovian-to instrumental transfer (PIT), whereby reward cues facilitate responding to obtain that reward. Whilst there is increasing research indicating PIT for food in humans, these studies have exclusively tested PIT under instrumental extinction (i.e. when the food is no longer available), which may reduce their ecological validity. To address this, we conducted two experiments exploring PIT for food in humans when tested under instrumental reinforcement. Participants first underwent Pavlovian discrimination training with an auditory cue paired with a chocolate reward (CS+) and another auditory cue unpaired (CS-). In instrumental training participants learnt to press a button to receive the chocolate reward on a VR10 schedule. In the test phase, each CS was presented whilst participants maintained the opportunity to press the button to receive chocolate. In Experiment 1, the PIT test was implemented after up to 20 min of instrumental training (satiation) whereas in Experiment 2 it was implemented after only 4 min of instrumental training. In both experiments there was evidence for differential PIT, but the pattern differed according to the rate of responding at the time of the PIT test. In low baseline responders the CS+ facilitated both button press responding and consumption, whereas in high baseline responders the CS- suppressed responding. These findings suggest that both excitatory and inhibitory associations may be learnt during PIT training and that the expression of these associations depends on motivation levels at the time the cues are encountered. Particularly concerning is that a food-paired cue can elicit increased motivation to obtain and consume food even when the participant is highly satiated and no longer actively seeking food, as this may be one mechanism by which over-consumption is maintained. PMID- 25278432 TI - Habitual intake of fruit juice predicts central blood pressure. AB - Despite a common perception that fruit juice is healthy, fruit juice contains high amounts of naturally occurring sugar without the fibre content of the whole fruit. Frequent fruit juice consumption may therefore contribute to excessive sugar consumption typical of the Western society. Although excess sugar intake is associated with high blood pressure (BP), the association between habitual fruit juice consumption and BP is unclear. The present study investigated the association of fruit juice consumption with brachial and central (aortic) BP in 160 community dwelling adults. Habitual fruit juice consumption was measured using a 12 month dietary recall questionnaire. On the same day, brachial BP was measured and central (aortic) BP was estimated through radial artery applanation. Frequency of fruit juice consumption was classified as rare, occasional or daily. Those who consumed fruit juice daily, versus rarely or occasionally, had significantly higher central systolic BP (F (2, 134) = 6.09, p <0.01), central pulse pressure (F (2, 134) = 4.16, p <0.05), central augmentation pressure (F (2, 134) = 5.98, p <0.01) and central augmentation index (F (2, 134) = 3.29, p <0.05) as well as lower pulse pressure amplification (F (2, 134) = 4.36, p <0.05). There were no differences in brachial BP. Central systolic BP was 3-4 mmHg higher for those who consumed fruit juice daily rather than rarely or occasionally. In conclusion, more frequent fruit juice consumption was associated with higher central BPs. PMID- 25278433 TI - Front-of-pack symbols are not a reliable indicator of products with healthier nutrient profiles. AB - BACKGROUND: Front-of-pack (FOP) nutrition rating systems and symbols are a form of nutrition marketing used on food labels worldwide. In the absence of standardized criteria for their use, it is unclear if FOP symbols are being used to promote products more nutritious than products without symbols. OBJECTIVES: To compare the amount of calories, saturated fat, sodium, and sugar in products with FOP symbols, and different FOP symbol types, to products without symbols. METHODS: The median calorie, saturated fat, sodium, and sugar content per reference amount of products with FOP symbols were compared to products without FOP symbols using data from the Food Label Information Program, a database of 10,487 Canadian packaged food labels. Ten food categories and 60 subcategories were analyzed. Nutrient content differences were compared using Wilcoxon rank-sum test; differences greater than 25% were deemed nutritionally relevant. RESULTS: Products with FOP symbols were not uniformly lower in calories, saturated fat, sodium, and sugar per reference amount than products without these symbols in any food category and the majority of subcategories (59/60). None of the different FOP types examined were used to market products with overall better nutritional profiles than products without this type of marketing. CONCLUSION: FOP symbols are being used to market foods that are no more nutritious than foods without this type of marketing. Because FOP symbols may influence consumer perceptions of products and their purchases, it may be a useful public health strategy to set minimum nutritional standards for products using FOP symbol marketing. PMID- 25278434 TI - Aortic valve surgery in octogenarians: Risk factors and long-term impact. AB - BACKGROUND AND OBJECTIVES: To understand the risk factors and long-term impact and results of aortic valve surgery in patients over age 80. PATIENTS AND METHODS: We consecutively evaluated 255 octogenarians who were operated on between 2000 and 2013 and referred for aortic valve disease (isolated or combined with coronary artery disease), which, even when associated with other diseases, was the primary cause of the patient's functional limitation. RESULTS: The mortality rate decreased from 14.08% (2000-2004) to 7.7% (isolated valve surgery, 4.4%; with coronary bypass, 3.3%) (2010-2013). The independent risk factors associated with mortality were urgent surgery, combined procedures, peripheral vascular disease, a postsurgery hematocrit level <24% and the need for transfusion. More than 50% of the patients experienced a postoperative complication. Blood product transfusions were associated with renal and respiratory failure, and preoperative anemia was associated with an increased rate of myocardial infarction and stroke. Survival at 1, 3, 5 and 10 years was 79.5, 74.3, 63.6 and 30.5%, respectively, with 91.5% of patients in NYHA functional class I-II. Long-term survival was lower for cases of preoperative left ventricular dysfunction. The EuroSCORE I logistics score was not useful for our population as a predictor of mortality or of medium to long-term survival. CONCLUSIONS: The morbidity and mortality of aortic valve surgery for patients over age 80 has decreased in recent years, although it remains higher when valve surgery is combined with coronary surgery. The presence of preoperative left ventricular dysfunction decreases long-term survival. PMID- 25278435 TI - Multiple hospitalizations at the Department of Internal Medicine of a tertiary hospital. AB - BACKGROUND AND OBJECTIVES: Patient who require multiple hospitalizations result in a considerable consumption of healthcare resources. In this study, we analyzed the factors associated with the multiple hospitalizations of a cohort of patients treated at a department of internal medicine. PATIENTS AND METHODS: A total of 613 consecutive hospitalizations were analyzed. A multiple-hospitalization patient was defined as one who at the time of admission had been hospitalized 3 or more times in the past year. We analyzed the relationship between demographic, clinical and societal factors on one hand and having been hospitalized on multiple occasions on the other. We also analyzed readmissions in the 6 months after discharge, as well as mortality during the hospitalization and in the 6 and 12 months after discharge. RESULTS: When compared with patients who have not been hospitalized on multiple occasions, multiple-hospitalization patients are more likely to be male, younger and to have greater comorbidity, greater consumption of medicines and higher Katz Index scores. The main cause for admission for multiple-hospitalizations patients was chronic disease decompensation (87.3%). The diseases that were most obviously associated with multiple hospitalizations were heart failure, diabetes mellitus and chronic obstructive pulmonary disease. In the first 6 months after discharge, multiple-hospitalization patients had a greater number of readmissions. During the study period, 40.4% of the multiple hospitalization patients died, and 28.8% of the nonmultiple-hospitalization patients died. CONCLUSIONS: Multiple-hospitalization patients have a greater clinical complexity than nonmultiple-hospitalization patients, and multiple hospitalizations are associated with chronic diseases, polypharmacy, functional impairment and high mortality rates. PMID- 25278436 TI - An intriguing low prevalence of atrial fibrillation in Spain. PMID- 25278437 TI - Salvaging urospermic ejaculates from brown bear (Ursus arctos). AB - The objective of this study was to reverse the osmotic stress of sperm in urine contaminated bear ejaculates that were obtained by electroejaculation using pre freezing washing or density gradient centrifugation isolation. In Experiment 1, ejaculates were divided into six aliquots, five were diluted in each washing extender: 200, 300, 400, 500 and 700 mOsm/kg (prepared from a Tes-Tris-Fructose base, adding water or fructose as corresponds), at a 1:2 ratio (raw semen: washing solution, v/v); and the other aliquot was handled without washing (Control group). Samples were centrifuged at 600 * g for 6 min prior to freezing. In Experiment 2, ejaculates were divided into two aliquots: one was diluted 1:1 with TCG (Tris-Citric acid-Glucose) and centrifuged at 600 * g for 6 min (Centrifugation Control; C-Control); the other was treated with PureSperm density gradient column. After treatments, samples were cryopreserved. Sperm motility, viability (SYBR-14/propidium iodide (PI)) and acrosomal status (peanut agglutinin fluorescein isothiocyanate (PNA-FITC)/PI) were analyzed before and after freezing. Ejaculates with an initial osmolality of less than 120 mOsm/kg treated with pre-freezing washing, and the Control sample had greater pre-freezing sperm motility than the raw ejaculate, but sperm viability was not different among these groups. The samples washed with 700 mOsm/kg solutions had the least pre freezing viability. In the post-thawing evaluation, pre-freezing washing treatments did not provide any improvement in comparison with the Control sample, and treatment with 700 mOsm/kg extender had deleterious effects in all urospermic samples. PureSperm density gradient centrifugation applied to urospermic raw semen was suitable for improving sperm motility and viability of pre-freezing samples and the selected spermatozoa had greater freezing capacity. PMID- 25278439 TI - Ligand-controlled syntheses of copper(I) complexes with metal-metal interactions: crystal structure and relativistic density functional theory investigation. AB - A family of di-, tri-, and tetranuclear copper(I) complexes supported by length controlled silaamidinate ligands have been synthesized to show short Cu(I)-Cu(I) distances (2.43-2.62 A) and feature a linear or bent metal-metal arrangement, which is elucidated by a relativistic density functional theory calculation. PMID- 25278438 TI - Cryopreservation of bull sperm: effects of extender supplemented with different cryoprotectants and antioxidants on sperm motility, antioxidant capacity and fertility results. AB - The objectives of this study were to compare glycerol (G) and ethylene glycol (EG) at different concentrations and trehalose (T) or cysteine (C; with/without) in Tris extender for cryopreservation of bull semen. Twenty-four ejaculates obtained from three bulls were included in the study. Each ejaculate was divided into four equal aliquots and diluted using both of the Tris extenders with G (5% or 7%) or EG (3% or 5%). After that, each extenders were divided into three equal aliquots and diluted using both of the 5 mM C or 25 mM T, and control (without additives) was cooled to 4 degrees C and frozen in 0.25 ml French straws. The addition of 3% and 5% EG without antioxidants resulted in the least Computer Assisted Sperm motility Analysis (CASA) motility as compared with the other groups. Treatment with 25 mM T in 3% EG beneficially effected acrosome morphology as compared with the other groups. Also, treatment with 3% EG with 25 mM T and 5% EG resulted in a greater rate of total abnormalities. Treatment with 3% G yielded a slightly greater percentage of membrane integrity by Hypo-Osmotic Swelling Test (HOST) assessment than that of the other groups. Treatment with 3% EG with 5 mM C resulted in the greatest concentration of malondialdehyde (MDA). The glutathione peroxidase (GPx) antioxidant activity was increased in the C-treatment groups when compared to the other groups. Treatment with 5% EG and 5 mM C resulted in less chromatin damage and detrimental impacts on tail moment. Treatment with 5% EG led to greater non-return rates of inseminated cows. However, this result was not considered to be statistically important. PMID- 25278440 TI - Modulation of Cox-1, 5-, 12- and 15-Lox by popular herbal remedies used in southern Italy against psoriasis and other skin diseases. AB - Acanthus mollis (Acanthaceae), Achillea ligustica, Artemisia arborescens and Inula viscosa (Asteraceae) are used in Southern Italy against psoriasis and other skin diseases that occur with an imbalanced production of eicosanoids. We here assessed their in vitro effects upon 5-, 12-, 15-LOX and COX-1 enzymes as well as NFkappaB activation in intact cells as their possible therapeutic targets. All methanol crude extracts inhibited both 5-LOX and COX-1 activities under 200 ug/mL, without significant effects on the 12-LOX pathway or any relevant in vitro free radical scavenging activity. NFkappaB activation was prevented by all extracts but A. mollis. Interestingly, A. ligustica, A. arborescens and A. mollis increased the biosynthesis of 15(S)-HETE, an anti-inflammatory eicosanoid. A. ligustica (IC50 =49.5 ug/mL) was superior to Silybum marianum (IC50 =147.8 ug/mL), which we used as antipsoriatic herbal medicine of reference. Its n hexane, dichloromethane and ethyl acetate fractions had also inhibitory effects on the LTB4 biosynthesis (IC50 s=9.6, 20.3 and 68 ug/mL, respectively) evidencing that the apolar extracts of A. ligustica are promising active herbal ingredients for future phytotherapeutical products targeting psoriasis. PMID- 25278441 TI - Detection of Abeta-interacting proteins via a novel Abeta-adsorbents that use immobilized regular comb polymer. AB - A detailed study of individual Abeta-interacting proteins has always been a difficult task because Abeta has a wide range of molecular weights and can easily form aggregates. In this study, we established a novel method for isolating Abeta interacting proteins by utilizing regular comb polymer immobilized on Sepharose CL-4B. To achieve site-directed ligation of Abeta, a cysteine residue was added at the N-terminus of Abeta. Asp and Asp12, which have 2 and 13 carboxyl groups, respectively, were selected as the carriers for the regular comb polymer. Firstly, the N-termini of Asp and Asp12 were immobilized on Sepharose CL-4B. Next, modified Abeta molecules were coupled to the carboxyl groups of Asp and Asp12 using bromoethylamine as a spacer. To obtain homogeneous comb polymer, the efficiency of the reaction was controlled during the synthesis process. Thioflavin T staining indicated that homogeneous Abeta was achieved. The prepared Abeta-adsorbents were used to isolate Abeta-interacting proteins from mice brain extracts. The results showed that the adsorption capacity of the Abeta-adsorbents for proteins in mice brain extracts increased with the ages of the animals. SDS PAGE analysis of the Abeta-interacting proteins showed that many kinds of brain proteins were selectively adsorbed by the Abeta adsorbents, and the levels of some of these proteins varied with the ages of the animals. The results indicated that Abeta-interacting proteins could be successfully obtained through the use of immobilized comb polymer. Similar method could also be used to isolate other amyloid-interacting proteins. PMID- 25278442 TI - Effect of the addition of low rare earth elements (lanthanum, neodymium, cerium) on the biodegradation and biocompatibility of magnesium. AB - Rare earth elements are promising alloying element candidates for magnesium alloys used as biodegradable devices in biomedical applications. Rare earth elements have significant effects on the high temperature strength as well as the creep resistance of alloys and they improve magnesium corrosion resistance. We focused on lanthanum, neodymium and cerium to produce magnesium alloys with commonly used rare earth element concentrations. We showed that low concentrations of rare earth elements do not promote bone growth inside a 750 MUm broad area around the implant. However, increased bone growth was observed at a greater distance from the degrading alloys. Clinically and histologically, the alloys and their corrosion products caused no systematic or local cytotoxicological effects. Using microtomography and in vitro experiments, we could show that the magnesium-rare earth element alloys showed low corrosion rates, both in in vitro and in vivo. The lanthanum- and cerium-containing alloys degraded at comparable rates, whereas the neodymium-containing alloy showed the lowest corrosion rates. PMID- 25278443 TI - Protection of yttria-stabilized zirconia for dental applications by oxidic PVD coating. AB - In this study, the application of transparent physical vapor deposition (PVD) coatings on zirconia ceramics was examined as an approach to retard the low temperature degradation of zirconia for dental applications. Transparent monolayers of titanium oxide (TixOy) and multilayers consisting of titanium oxide alumina-titanium oxide (TixOy-AlxOy-TixOy) were deposited onto standardized discs of 3Y-TZP using magnetron sputtering. Using X-ray photospectroscopy and time-of flight secondary-ion mass spectrometry, the compositions of the coatings were verified, and an approximate thickness of 50 nm for each type of coating was ascertained. After aging the coated and uncoated samples in water vapor at 134 degrees C and 3 bar for 4, 8, 16, 32, 64 and 128 h, the monoclinic phase content was determined using X-ray diffraction, and its impact on mechanical properties was assessed in biaxial flexural strength tests. In addition, the depth of the transformation zone was measured from scanning electron microscopy images of the fracture surfaces of hydrothermally aged samples. The results revealed that the tetragonal-to-monoclinic phase transformation of the zirconia ceramic was retarded by the application of PVD coatings. During the first stages of aging, the coated samples exhibited a significantly lower monoclinic phase content than the uncoated samples and, after 128 h of aging, showed a transformation zone which was only ~12-15 MUm thick compared to ~30 MUm in the control group. Biaxial flexural strength decreased by ~10% during aging and was not influenced by the application of a PVD coating. PMID- 25278444 TI - Creating capillary networks within human engineered tissues: impact of adipocytes and their secretory products. AB - The development of tissue-engineered substitutes of substantial volume is closely associated with the need to ensure rapid vascularization upon grafting. Strategies promoting angiogenesis include the in vitro formation of capillary like networks within engineered substitutes. We generated both connective and adipose tissues based on a cell sheet technology using human adipose-derived stromal cells. This study evaluates the morphology and extent of the capillary networks that developed upon seeding of human microvascular endothelial cells during tissue production. We posited that adipocyte presence/secretory products could modulate the resulting capillary network when compared to connective substitutes. Analyses including confocal imaging of CD31-labeled capillary-like networks indicated slight differences in their morphological appearance. However, the total volume occupied by the networks as well as the frequency distribution of the structure's volumes were similar between connective and adipose tissues. The average diameter of the capillary structures tended to be 20% higher in reconstructed adipose tissues. Quantification of pro-angiogenic molecules in conditioned media showed greater amounts of leptin (15*), angiopoietin-1 (3.4*) and HGF (1.7*) secreted from adipose than connective tissues at the time of endothelial cell seeding. However, this difference was attenuated during the following coculture period in endothelial cell-containing media, correlating with the minor differences noted between the networks. Taken together, we developed a protocol allowing reconstruction of both connective and adipose tissues featuring well-developed capillary networks in vitro. We performed a detailed characterization of the network architecture within engineered tissues that is relevant for graft assessment before implantation as well as for in vitro screening of angiogenic modulators using three-dimensional models. PMID- 25278445 TI - Chirality-mediated polypeptide micelles for regulated drug delivery. AB - Two kinds of triblock poly(ethylene glycol)-polyleucine (PEG-PLeu) copolymers were synthesized through the ring-opening polymerization of L-Leu N carboxyanhydride (NCA), or equivalent D-Leu NCA and L-Leu NCA with amino terminated PEG as a macroinitiator. The amphiphilic copolymers spontaneously self assembled into spherical micellar aggregations in an aqueous environment. The micelle with a racemic polypeptide core exhibited smaller critical micelle concentration and diameter compared to those with a levorotatory polypeptide core. A model anthracycline antineoplastic agent, i.e., doxorubicin (DOX), was loaded into micelles through nanoprecipitation, and the PEG-P(D,L-Leu) micelle exhibited higher drug-loading efficacy than that with a P(L-Leu) core-this difference was attributed to the flexible and compact P(L-Leu) core. Sustained in vitro DOX release from micelles with both levorotatory and racemic polypeptide cores was observed, and the DOX-loaded PEG-P(D,L-Leu) micelle exhibited a slower release rate. More interestingly, DOX-loaded micelles exhibited chirality mediated antitumor efficacy in vitro and in vivo, which are all better than that of free DOX. Furthermore, both enhanced tumor inhibition and excellent security in vivo were confirmed by histopathological or in situ cell apoptosis analyses. Therefore, DOX-loaded PEG-PLeu micelles appear to be an interesting nanoscale polymeric formulation for promising malignancy chemotherapy. PMID- 25278446 TI - Effect of dialysis initiation for preemptively listed candidates in the revised kidney allocation policy. AB - The new allocation policy for deceased donor kidneys in the United States is expected to begin in late 2014. As part of this policy, prioritization to the highest quality deceased donor kidneys is dependent on candidate's estimated posttransplant survival (EPTS) score. In particular, candidates with low (<=20%) EPTS (indicating better estimated survival) will have greater access to donor offers. We evaluated the effect of dialysis initiation on preemptively listed candidates' EPTS score. Using current estimates, approximately 10% (n = 19,406) of candidates placed on the waiting list between 2008 and 2013 were listed preemptively and would have qualified for top 20% status. These patients were more likely younger, female, Caucasian and nondiabetic compared to other candidates. Among nondiabetic preemptively listed candidates, dialysis initiation decreases EPTS score (indicating better estimated survival and higher allocation priority) for approximately 5 months. In contrast, diabetic patients' EPTS score significantly increases (approximately 6%) immediately upon dialysis initiation. Our results reveal a counterintuitive aberration in the EPTS formula, which is important for decision making regarding organ selection and timing of dialysis initiation in the new allocation system. Revision of the EPTS formula should be considered to address these findings and further understanding of the impact of the new allocation system on candidates' prognosis is important. PMID- 25278447 TI - Terpene chemistry of eastern hemlocks resistant to hemlock woolly adelgid. AB - Recent studies have identified a small number of individual eastern hemlock trees that demonstrate relative resistance to the introduced sap-feeding insect, the hemlock woolly adelgid. Using gas chromatography, we compared concentrations of twenty-two terpenoids in susceptible and relatively resistant trees, both in the forest and in propagated cuttings in a common-garden setting. Terpenoid concentrations were higher in twig tissue of resistant versus susceptible trees, across six sampling dates and at both sites. These changes may be particularly important because the hemlock woolly adelgid feeds on twig tissue. Because the common-garden cuttings were free of herbivores, the higher terpenoid concentrations are interpreted as a constitutive defense. Increased levels of monoterpenes and sesquiterpenes imply an overall increase in the input of carbon precursors to both terpenoid synthesis pathways. PMID- 25278448 TI - Sinus culture poorly predicts resident microbiota. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disorder of the paranasal sinuses in which bacteria are implicated. Culture-based assays are commonly used in clinical and research practice; however, culture conditions may not accurately detect the full range of microorganisms present in a sample. The objective of this study was to determine the accuracy of clinical culture of CRS specimens compared with DNA-based molecular techniques. METHODS: Ethmoid samples from 54 CRS patients collected during endoscopic sinus surgery were analyzed by both clinical culture and 16S ribosomal RNA (rRNA) gene sequencing. The association between 16S relative abundance and detection by culture was determined using logistic regression. RESULTS: Each subject had an average of 3 isolates identified by bacterial culture and 21.5 +/- 12.5 species identified by 16S sequencing. On average, 1.6 dominant taxa (>10% abundance) per subject were identified using molecular techniques, but only 47.7% of these taxa were identified by culture. Low abundance taxa (abundance <1%) were detected in only 4.5% of cultures. The odds that any organism would be detected by culture were 2.3 times higher with each 10% increase in relative abundance (p < 0.01). Conversely, only 29.5% of isolates identified by culture represented the dominant species, whereas 40% accounted for species with 1% to 10% abundance. Interestingly, 12% of isolates detected by culture were not identified by 16S pyrosequencing. CONCLUSION: Standard clinical culture is a poor representation of resident microbiota. The incorporation of modern culture-independent techniques into clinical and research practices provides additional information that may be relevant for CRS. PMID- 25278449 TI - Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer. AB - PURPOSE: AEZS-108, formerly AN-152, is a cytotoxic hybrid molecule consisting of a luteinizing hormone-releasing hormone (LHRH) agonist moiety covalently coupled to doxorubicin, allowing it to deliver doxorubicin selectively to cells expressing LHRH receptors. LHRH receptors are expressed on the cell membrane of many tumors, including prostate cancer. This phase I study determined the maximum tolerated dose (MTD) of AEZS-108 in men with taxane- and castration-resistant prostate cancer (CRPC) while providing additional information on the safety profile and efficacy of this agent. EXPERIMENTAL DESIGN: AEZS-108 was administered as an intravenous infusion every 21 days until progression or unacceptable toxicity in cohorts of 3 or 6 patients until the MTD was reached. Blood was collected for capture of circulating tumor cells (CTC) to visualize internalization of AEZS-108, an autofluorescent molecule. RESULTS: The MTD of AEZS-108 in this cohort was 210 mg/m(2), which was lower than that seen in a phase I study conducted in women with endometrial or ovarian cancers. The dose limiting toxicity was persistent neutropenia. Three patients had a PSA response with an additional 10 patients maintaining PSA stable disease. Of the 10 patients evaluable by RECIST criteria, 9 achieved stable disease. AEZS-108 internalization in CTCs was routinely visualized using its autofluorescence. CONCLUSION: These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with prostate cancer, and that internalization of AEZS-108 in prostate cancer CTCs may be a viable pharmacodynamic marker. A phase II study in men with prostate cancer is ongoing. PMID- 25278450 TI - Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome. AB - PURPOSE: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear. EXPERIMENTAL DESIGN: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole exome sequencing data, and gene expression profiles. RESULTS: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome. CONCLUSIONS: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy. PMID- 25278451 TI - A phase I, dose-escalation study of the multitargeted receptor tyrosine kinase inhibitor, golvatinib, in patients with advanced solid tumors. AB - PURPOSE: Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron. EXPERIMENTAL DESIGN: Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a "3+3" design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose (MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort. RESULTS: Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased gamma-glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence >10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85-237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD. CONCLUSIONS: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation. PMID- 25278452 TI - Promising cell-based immunotherapy using gamma delta T cells: together is better. AB - Gamma delta T-cell response to cellular stress signals expressed by tumor cells makes them promising candidates for cancer immunotherapy. The proof of concept for clinical scale propagation of polyclonal gammadelta T-cell lines with efficient in vitro and in vivo response against cancer is an important step in this direction. PMID- 25278453 TI - iNOS expression in CD4+ T cells limits Treg induction by repressing TGFbeta1: combined iNOS inhibition and Treg depletion unmask endogenous antitumor immunity. AB - PURPOSE: Expression of inducible nitric oxide synthase (iNOS) in different cellular compartments may have divergent effects on immune function. We used a syngeneic tumor model to functionally characterize the role of iNOS in regulation of CD4(+)FOXP3(+) regulatory T cells (Treg), and optimize the beneficial effects of iNOS inhibition on antitumor immunity. EXPERIMENTAL DESIGN: Wild-type (WT) or iNOS knockout mice bearing established MT-RET-1 melanoma were treated with the small-molecule iNOS inhibitor L-NIL and/or cyclophosphamide alone or in combination. The effect of iNOS inhibition or knockout on induction of Treg from mouse and human CD4(+) T cells in ex vivo culture was determined in parallel in the presence or absence of TGFbeta1-depleting antibodies, and TGFbeta1 levels were assessed by ELISA. RESULTS: Whereas intratumoral myeloid-derived suppressor cells (MDSC) were suppressed by iNOS inhibition or knockout, systemic and intratumoral FOXP3(+) Treg levels increased in tumor-bearing mice. iNOS inhibition or knockout similarly enhanced induction of Treg from activated cultured mouse splenocytes or purified human or mouse CD4(+) T cells in a TGFbeta1-dependent manner. Although either iNOS inhibition or Treg depletion with low-dose cyclophosphamide alone had little effect on growth of established MT RET1 melanoma, combination treatment potently inhibited MDSC and Treg, boosted tumor-infiltrating CD8(+) T-cell levels, and arrested tumor growth in an immune dependent fashion. CONCLUSIONS: iNOS expression in CD4(+) T cells suppresses Treg induction by inhibiting TGFbeta1 production. Our data suggest that iNOS expression has divergent effects on induction of myeloid and lymphoid-derived regulatory populations, and strongly support development of combinatorial treatment approaches that target these populations simultaneously. PMID- 25278454 TI - Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. AB - PURPOSE: The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma and is upregulated in pancreatic adenocarcinoma cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of the HH pathway. This study assessed the effect of GDC-0449-mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity. RESULTS: On pretreatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On posttreatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22, and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and postbiopsy. The median progression-free and overall survival for all treated patients were 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki 67, GLI1, PTCH1 (baseline values or relative change on posttreatment biopsy), and survival. Grade >= 3 adverse events were noted in 56% of patients. CONCLUSION: We show that GDC-0449 for 3 weeks leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer. PMID- 25278455 TI - Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission. AB - Whether the number of chemotherapy cycles required to obtain a first morphological remission affects prognosis of patients with acute myeloid leukemia (AML) remains controversial. To clarify how achievement of early remission might influence outcome of allogeneic hematopoietic cell transplantation (HCT), we studied 220 consecutive adults with AML in first morphological remission who underwent transplantation after myeloablative or nonmyeloablative conditioning to investigate how the number of standard- or high-dose induction courses required to achieve remission impacted post-HCT outcome. Three-year estimates of overall survival were 65% (95% confidence interval [CI] 56% to 73%), 56% (95% CI, 43% to 67%), and 23% (95% CI, 6% to 46%) for patients requiring 1 course, 2 courses, or >2 courses of induction therapy; corresponding relapse estimates were 24% (95% CI, 17% to 31%), 43% (95% CI, 31% to 55%), and 58% (95% CI, 30% to 78%), respectively. After covariate adjustment (minimal residual disease status, conditioning, age, cytogenetic disease risk, type of consolidation chemotherapy, pre-HCT karyotype, and pre-HCT peripheral blood count recovery), the hazard ratios for 2 or >2 induction courses versus 1 induction were 1.16 (95% CI, .73 to 1.85, P = .53) and 2.63 (95% CI, 1.24 to 5.57, P = .011) for overall mortality, and 2.10 (95% CI, 1.27 to 3.48, P = .004) and 3.32 (95% CI, 1.42 to 7.78, P = .006), respectively, for relapse. These findings indicate that the number of induction courses required to achieve morphological remission in AML adds prognostic information for post-HCT outcome that is independent of other prognostic factors. PMID- 25278456 TI - Efficacy of vinorelbine plus granulocyte colony-stimulation factor for CD34+ hematopoietic progenitor cell mobilization in patients with multiple myeloma. AB - We aimed to assess the efficacy of vinorelbine plus granulocyte colony stimulating factor (G-CSF) for chemo-mobilization of CD34(+) hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 MUg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 * 10(6) CD34(+) cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34(+) cells collected was 6.56 * 10(6) (range, .18 to 25.9 * 10(6)) per kg BW at the first day of leukapheresis and 7.65 * 10(6) (range, .18 to 25.9 * 10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients. PMID- 25278457 TI - Recommendations for donor human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). AB - The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts large, multi-institutional clinical trials with the goal of improving the outcomes of hematopoietic cell transplantation (HCT) for patients with life-threatening disorders. Well-designed HCT trials benefit from standardized criteria for defining diagnoses, treatment plans, and graft source selection. In this perspective, we summarize evidence supporting criteria for the selection of related and unrelated adult volunteer progenitor cell donors or umbilical cord blood units. These standardized criteria for graft source selection have been adopted by the BMT CTN to enhance the interpretation of clinical findings within and among future clinical protocols. PMID- 25278459 TI - Progesterone and mental imagery interactively predict emotional memories. AB - Different lines of research suggest that the consolidation of emotional memories is influenced by (a) endogenous levels of sex hormones, and (b) individual differences in the capacity to use vivid mental imagery. No studies to date have investigated how these factors may interact to influence declarative emotional memories. This study examined the interacting influence of progesterone and mental imagery strength on emotional memory consolidation. Twenty-four men, 20 women from the low progesterone (follicular) menstrual phase, and 20 women from the high progesterone (mid-luteal) phase of the cycle were assessed using an objective performance-based measure of mental imagery strength, and then shown a series of aversive and neutral images. Half of the images were accompanied by instructions to process sensory features, and the remaining half to process the conceptual characteristics of the images. Two days later, all participants returned for a surprise free recall memory test. The interaction of progesterone and mental imagery strength significantly predicted recall of visually processed, but not verbally processed, negative images. These data suggest that mental imagery strength may be one mechanism underlying the documented association between endogenous progesterone and enhanced emotional memory performance in the literature. PMID- 25278460 TI - Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats. AB - Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention. PMID- 25278458 TI - Impact of donor age on outcome after allogeneic hematopoietic cell transplantation. AB - As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-versus-host disease (GVHD), and nonrelapse mortality (NRM) among 1174 consecutive patients undergoing myeloablative and 367 patients undergoing nonmyeloablative HCT from HLA-matched related or unrelated donors with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and nonmyeloablative conditioning, respectively, for grafts from donors < 60 years old (younger; n = 1416) and 98% and 100%, respectively, for those from donors >= 60 years old (older; n = 125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = .04). CD34(+) cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and nonmyeloablative recipients with older sibling donors had significantly less grade II to IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III and IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors >= 60 years old do not adversely affect outcomes of allogeneic HCT compared with grafts from younger donors. PMID- 25278461 TI - G1-4A, a polysaccharide from Tinospora cordifolia induces peroxynitrite dependent killer dendritic cell (KDC) activity against tumor cells. AB - Dendritic cells (DC) play a central role in the development of an adaptive immune response against tumor. In addition to its role in antigen presentation, DC also possesses cytotoxic activity against tumor cells. We have earlier shown phenotypic and functional maturation of bone marrow derived dendritic cells (BMDC) by G1-4A, an arabinogalactan derived from Tinospora cordifolia. In this study, we have investigated the killer phenotype of BMDC matured in the presence of G1-4A, [mBMDC (G1-4A)] on tumor cells. We have observed several fold increase in killing of tumor cells by mBMDC (G1-4A). The tumoricidal activity was not specific to syngeneic tumors cells but could kill xenogenic tumors also. Nitric oxide released by mBMDC (G1-4A) generates peroxynitrite in tumor cells and is responsible for killing of target cells. This killing was completely abrogated by inducible nitric oxide synthase (iNOS) inhibitor 1400W and NADPH oxidase inhibitor apocyanin. The killed target cells are phagocytosed by BMDC which further activate syngeneic cytotoxic T cells. These results thus show that G1-4A treated mBMDC acquire killer phenotype along with maturation which plays an important role in activation of cytotoxic T cells. PMID- 25278462 TI - A novel KCNQ3 gene mutation in a child with infantile convulsions and partial epilepsy with centrotemporal spikes. PMID- 25278463 TI - Gait shows a sex-specific pattern of associations with daily functioning in a community-dwelling population of older people. AB - BACKGROUND: Gait is increasingly considered an important indicator of health. Yet, little is known on the relation of gait with established health indicators, e.g. daily functioning. Although gait differs by sex, it is unknown whether different gait domains provide different health indicators in men or women. We investigated how gait associates with basic and instrumental activities of daily living (BADL and IADL) in community-dwelling persons. METHODS: In 2500 participants of the population-based Rotterdam Study (aged >= 50 yrs), gait was assessed by electronic walkway and summarized into seven independent gait domains: Pace, Rhythm, Phases, Tandem, Turning, Variability, Base of Support, which were averaged into Global Gait. We assessed BADL with the disability index of the Stanford Health Assessment Questionnaire and IADL with the Instrumental Activities of Daily Living scale. BADL and IADL were analyzed as continuous scores, and dichotomised: with impairment defined as moderate to very severe disability. RESULTS: In men, Global Gait, Pace, and Rhythm associated with BADL in linear analyses. In contrast, all domains except Base of Support associated with BADL or IADL in women. Associations of Global Gait and Phases with BADL were significantly stronger in women (p-interaction < 0.05). Similarly, associations of Global Gait, Rhythm, and Phases with IADL were stronger in women (p interaction < 0.05). For dichotomised analyses, higher Global Gait, Pace, and Rhythm associated with less BADL-impairment in men, while Global Gait associated with less BADL and IADL-impairment in women. CONCLUSIONS: In men, Pace and Rhythm may suffice as health indicators, while women may require comprehensive gait assessment to better estimate their health status. PMID- 25278464 TI - How fear of falling can increase fall-risk in older adults: applying psychological theory to practical observations. AB - It is widely reported that fear of falling (FOF) has a profound and largely detrimental effect on balance performance in older adults. However, the mechanisms by which FOF influence postural stability are poorly understood. In the current article, we use psychological theory to explain FOF-related changes to postural control. First, we review literature describing associations between FOF and the 'stiffening' strategies observed during control of posture, including observations of eye and head movements. Second, we present a framework illustrating the interactions between increased age, FOF, and altered attentional processes, which in turn influence balance performance and fall-risk. Psychological theory predicts that anxiety can cause attentional bias for threatening and task-irrelevant stimuli and compromise the efficiency of working memory resources. We argue that while the adoption of stiffening strategies is likely to be beneficial in avoiding a loss of balance during simple postural tasks, it will ultimately compromise performance in dynamic and highly demanding functional tasks. The adoption of stiffening strategies leads to inadequate acquisition of the sensory information necessary to plan and execute dynamic and interactive movements. We conclude with some suggestions for future research. PMID- 25278465 TI - Brief report: The interaction of impulsivity with risk-taking is associated with early alcohol use initiation. AB - Early alcohol use initiation is a well-established risk factor for the subsequent development of alcohol abuse and dependence. Separate lines of research indicate that impulsivity and risk-taking each are associated with early alcohol use. In this research, the association of the interaction of risk-taking and impulsivity with early alcohol initiation was examined. Results suggest the interaction between impulsivity and risk-taking was related to early alcohol initiation. Among children with lower levels of risk-taking, level of impulsivity was associated with beginning to drink. By contrast, among children with higher levels of risk-taking, level of impulsivity was not associated with the likelihood of initiating alcohol use. These findings suggest that early adolescence is a critical developmental period in which implementing an intervention to reduce impulsivity and risk-taking may be particularly effective to prevent the early initiation of alcohol use. PMID- 25278467 TI - Encoding wide-field motion and direction in the central complex of the cockroach Blaberus discoidalis. AB - In the arthropod brain, the central complex (CX) receives various forms of sensory signals and is associated with motor functions, but its precise role in behavior is controversial. The optomotor response is a highly conserved turning behavior directed by visual motion. In tethered cockroaches, 20% procaine injected into the CX reversibly blocked this behavior. We then used multichannel extracellular recording to sample unit activity in the CX in response to wide field visual motion stimuli, moving either horizontally or vertically at various temporal frequencies. For the 401 units we sampled, we identified five stereotyped response patterns: tonically inhibited or excited responses during motion, phasically inhibited or excited responses at the initiation of motion, and phasically excited responses at the termination of motion. Sixty-seven percent of the units responded to horizontal motion, while only 19% responded to vertical motion. Thirty-eight percent of responding units were directionally selective to horizontal motion. Response type and directional selectivity were sometimes conditional with other stimulus parameters, such as temporal frequency. For instance, 16% of the units that responded tonically to low temporal frequencies responded phasically to high temporal frequencies. In addition, we found that 26% of wide-field motion responding units showed a periodic response that was entrained to the temporal frequency of the stimulus. Our results show a diverse population of neurons within the CX that are variably tuned to wide-field motion parameters. Our behavioral data further suggest that such CX activity is required for effective optomotor responses. PMID- 25278466 TI - An integrated transcriptomic and comparative genomic analysis of differential gene expression in Arctic charr (Salvelinus alpinus) following seawater exposure. AB - High-throughput RNA sequencing was used to compare expression profiles in two Arctic charr (Salvelinus alpinus) families post-seawater exposure to identify genes and biological processes involved in hypo-osmoregulation and regulation of salinity tolerance. To further understand the genetic architecture of hypo osmoregulation, the genomic organization of differentially expressed (DE) genes was also analysed. Using a de novo gill transcriptome assembly we found over 2300 contigs to be DE. Major transporters from the seawater mitochondrion-rich cell (MRC) complex were up-regulated in seawater. Expression ratios for 257 differentially expressed contigs were highly correlated between families, suggesting they are strictly regulated. Based on expression profiles and known molecular pathways we inferred that seawater exposure induced changes in methylation states and elevated peroxynitrite formation in gill. We hypothesized that concomitance between DE immune genes and the transition to a hypo osmoregulatory state could be related to Cl(-) sequestration by antimicrobial defence mechanisms. Gene ontology analysis revealed that cell division genes were up-regulated, which could reflect the proliferation of ATP1alpha1b-type seawater MRCs. Comparative genomics analyses suggest that hypo-osmoregulation is influenced by the relative proximities among a contingent of genes on Arctic charr linkage groups AC-4 and AC-12 that exhibit homologous affinities with a region on stickleback chromosome Ga-I. This supports the hypothesis that relative gene location along a chromosome is a property of the genetic architecture of hypo-osmoregulation. Evidence of non-random structure between hypo-osmoregulation candidate genes was found on AC-1/11 and AC-28, suggesting that interchromosomal rearrangements played a role in the evolution of hypo-osmoregulation in Arctic charr. PMID- 25278468 TI - Shaving increases daily energy expenditure in free-living root voles. AB - Experimental manipulation of energy expenditure has long been recognized as an effective means for identifying causative effects and avoiding confounded interpretations arising from spurious correlations. This approach has been successfully applied mainly to studies on birds, particularly on reproducing adults, whereas manipulations in mammals have proved more problematic. Here, we tested the hypothesis that shaving off 50% of the dorsal pelage should effectively increase energy expenditure in wild root voles (Microtus oeconomus) in their natural environment. We measured daily energy expenditure (DEE), using doubly labelled water in shaved and unshaved voles at the beginning of winter. The difference in DEE (corrected for body mass and year effects) between experimental and control group fluctuated from 11.5% to 17.3%. Probability of recapture over the 3 day DEE assay was strongly dependent on body mass, but did not differ between shaved and unshaved animals; however, a prevalence of larger (heavier) shaved individuals was observed. Shaved animals lost more weight between the first and second trapping. Shaving therefore appears to be an effective method of increasing the cost of total DEE in wild endotherms in their natural environment. PMID- 25278470 TI - Conditioned discrimination of magnetic inclination in a spatial-orientation arena task by homing pigeons (Columba livia). AB - It has been well established that homing pigeons are able to use the Earth's magnetic field to obtain directional information when returning to their loft and that their magnetic compass is based, at least in part, on the perception of magnetic inclination. Magnetic inclination has also been hypothesized in pigeons and other long-distance navigators, such as sea turtles, to play a role providing positional information as part of a map. Here we developed a behavioral paradigm which allows us to condition homing pigeons to discriminate magnetic inclination cues in a spatial-orientation arena task. Six homing pigeons were required to discriminate in a circular arena between feeders located either in a zone with a close to 0 deg inclination cue or in a zone with a rapidly changing inclination cue (-3 deg to +85 deg when approaching the feeder and +85 deg to -3 deg when moving away from the feeder) to obtain a food reward. The pigeons consistently performed this task above chance level. Control experiments, during which the coils were turned off or the current was running anti-parallel through the double wound coil system, confirmed that no alternative cues were used by the birds in the discrimination task. The results show that homing pigeons can be conditioned to discriminate differences in magnetic field inclination, enabling investigation into the peripheral and central neural processing of geomagnetic inclination under controlled laboratory conditions. PMID- 25278469 TI - Musculoskeletal modelling deconstructs the paradoxical effects of elastic ankle exoskeletons on plantar-flexor mechanics and energetics during hopping. AB - Experiments have shown that elastic ankle exoskeletons can be used to reduce ankle joint and plantar-flexor muscle loading when hopping in place and, in turn, reduce metabolic energy consumption. However, recent experimental work has shown that such exoskeletons cause less favourable soleus (SO) muscle-tendon mechanics than is observed during normal hopping, which might limit the capacity of the exoskeleton to reduce energy consumption. To directly link plantar-flexor mechanics and energy consumption when hopping in exoskeletons, we used a musculoskeletal model of the human leg and a model of muscle energetics in simulations of muscle-tendon dynamics during hopping with and without elastic ankle exoskeletons. Simulations were driven by experimental electromyograms, joint kinematics and exoskeleton torque taken from previously published data. The data were from seven males who hopped at 2.5 Hz with and without elastic ankle exoskeletons. The energetics model showed that the total rate of metabolic energy consumption by ankle muscles was not significantly reduced by an ankle exoskeleton. This was despite large reductions in plantar-flexor force production (40-50%). The lack of larger metabolic reductions with exoskeletons was attributed to increases in plantar-flexor muscle fibre velocities and a shift to less favourable muscle fibre lengths during active force production. This limited the capacity for plantar-flexors to reduce activation and energy consumption when hopping with exoskeleton assistance. PMID- 25278471 TI - Cold acclimation increases cardiac myofilament function and ventricular pressure generation in trout. AB - Reducing temperature below the optimum of most vertebrate hearts impairs contractility and reduces organ function. However, a number of fish species, including the rainbow trout, can seasonally acclimate to low temperature. Such ability requires modification of physiological systems to compensate for the thermodynamic effects of temperature on biological processes. The current study tested the hypothesis that rainbow trout compensate for the direct effect of cold temperature by increasing cardiac contractility during cold acclimation. We examined cardiac contractility, following thermal acclimation (4, 11 and 17 degrees C), by measuring the Ca(2+) sensitivity of force generation by chemically skinned cardiac trabeculae as well as ventricular pressure generation using a modified Langendorff preparation. We demonstrate, for the first time, that the Ca(2+) sensitivity of force generation was significantly higher in cardiac trabeculae from 4 degrees C-acclimated trout compared with those acclimated to 11 or 17 degrees C, and that this functional change occurred in parallel with a decrease in the level of cardiac troponin T phosphorylation. In addition, we show that the magnitude and rate of ventricular pressure generation was greater in hearts from trout acclimated to 4 degrees C compared with those from animals acclimated to 11 or 17 degrees C. Taken together, these results suggest that enhanced myofilament function, caused by modification of existing contractile proteins, is at least partially responsible for the observed increase in pressure generation after acclimation to 4 degrees C. In addition, by examining the phenotypic plasticity of a comparative model we have identified a strategy, used in vivo, by which the force-generating capacity of cardiac muscle can be increased. PMID- 25278472 TI - Influence of reproductive mode on metabolic costs of reproduction: insight from the bimodal lizard Zootoca vivipara. AB - Examination of the selective forces behind the transition from oviparity to viviparity in vertebrates must include an understanding of the relative energy costs of the two reproductive modes. However, interspecific comparisons of reproductive mode are confounded by numerous other inherent differences among the species. Therefore, we compared oxygen consumption, as a reflection of energy costs, during reproduction in oviparous and viviparous females of the reproductively bimodal lizard Zootoca vivipara (Jaquin 1787). Female oxygen consumption progressively increased over the course of reproduction, peaking just prior to parition when it was 46% (oviparous form) and 82% (viviparous form) higher than it was at the pre-reproductive stage. Total increase in oxygen consumption (TIOC) during the pre-ovulation period was not different between the reproductive modes. Conversely, post-ovulation TIOC was more than three times higher in viviparous females, reflecting a dramatic increase in embryonic metabolism as well as maternal metabolic costs of pregnancy (MCP). MCP accounted for 22% of total metabolism in viviparous females, whereas it was negligible in oviparous females. Our results demonstrate that egg retention through the first third of development, as is typical of most oviparous squamates, entails minimal maternal energy demand, while extending retention imposes much greater metabolic constraints. Selection for transition from oviparity to viviparity must therefore provide benefits that outweigh not only the added burden associated with prolonged embryonic retention, but also the substantial additional energy costs that are incurred. PMID- 25278474 TI - Nitrogen fixation in the mucus of Red Sea corals. AB - Scleractinian corals are essential constituents of tropical reef ecological diversity. They live in close association with diazotrophs [dinitrogen (N2) fixing microbes], which can fix high rates of N2. Whether corals benefit from this extrinsic nitrogen source is still under debate. Until now, N2 fixation rates have been indirectly estimated using the acetylene reduction assay, which does not permit assessment of the amount of nitrogen incorporated into the different compartments of the coral holobiont. In the present study, the (15)N2 technique was applied for the first time on three Red Sea coral species. Significant (15)N enrichment was measured in particles released by corals to the surrounding seawater. N2 fixation rates were species specific and as high as 1.6 2 ng N day(-1) l(-1). However, no significant enrichment was measured in the symbiotic dinoflagellates or the coral host tissues, suggesting that corals do not benefit from diazotrophic N2 fixation. PMID- 25278473 TI - Targeted inactivation of the rickets receptor in muscle compromises Drosophila viability. AB - Bursicon is a hormone that modulates wing expansion, cuticle hardening and melanization in Drosophila melanogaster. Bursicon activity is mediated through its cognate G protein-coupled receptor (GPCR), rickets. We have developed a membrane-tethered bursicon construct that enables spatial modulation of rickets mediated physiology in transgenic flies. Ubiquitous expression of tethered bursicon throughout development results in arrest at the pupal stage. The few organisms that eclose fail to undergo wing expansion. These phenotypes suggest that expression of tethered bursicon inhibits rickets-mediated function. Consistent with this hypothesis, we show in vitro that sustained stimulation of rickets by tethered bursicon leads to receptor desensitization. Furthermore, tissue-specific expression of the tethered bursicon inhibitor unraveled a critical role for rickets in a subset of adult muscles. Taken together, our findings highlight the utility of membrane-tethered inhibitors as important genetic/pharmacological tools to dissect the tissue-specific roles of GPCRs in vivo. PMID- 25278475 TI - Localization of K+, H+, Na+ and Ca2+ fluxes to the excretory pore in Caenorhabditis elegans: application of scanning ion-selective microelectrodes. AB - Although Caenorhabditis elegans is commonly used as a model organism for studies of cell biology, development and physiology, the small size of the worm has impeded measurements of ion transport by the excretory cell and hypodermis. Here, we use the scanning ion-selective microelectrode technique to measure efflux and influx of K(+), H(+), Na(+) and Ca(2+) in intact worms. Transport of ions into, or out of, immobilized worms produces small gradients in ion concentration in the unstirred layer near the surface of the worm. These gradients are readily detectable with ion-selective microelectrodes and the corresponding ion fluxes can be estimated using the Fick equation. Our data show that effluxes of K(+), H(+), Na(+) and Ca(2+) are localized to the region of the excretory pore, consistent with release of these ions from the excretory cell, and that effluxes increase after experimental preloading with Na(+), K(+) or Ca(2+). In addition, the hypodermis is a site of Na(+) influx. PMID- 25278476 TI - Expression of cytoskeletal and molt-related genes is temporally scheduled in the hypodermis of the crayfish Procambarus clarkii during premolt. AB - The rigid crustacean exoskeleton, the cuticle, is composed of the polysaccharide chitin, structural proteins and mineral deposits. It is periodically replaced to enable growth and its construction is an energy-demanding process. Ecdysis, the shedding event of the old cuticle, is preceded by a preparatory phase, termed premolt, in which the present cuticle is partially degraded and a new one is formed underneath it. Procambarus clarkii (Girard 1852), an astacid crustacean, was used here to comprehensively examine the changing patterns of gene expression in the hypodermis underlying the cuticle of the carapace at seven time points along ~14 premolt days. Next generation sequencing was used to construct a multi tissue P. clarkii transcript sequence assembly for general use in a variety of transcriptomic studies. A reference transcriptome was created here in order to perform digital transcript expression analysis, determining the gene expression profiles in each of the examined premolt stages. The analysis revealed a cascade of sequential expression events of molt-related genes involved in chitin degradation, synthesis and modification, as well as synthesis of collagen and four groups of cuticular structural genes. The new description of major transcriptional events during premolt and the determination of their timing provide temporal markers for future studies of molt progress and regulation. The peaks of the expression of the molt-related genes were preceded by expression peaks of cytoskeletal genes that are hypothesized to be essential for premolt progress through regulating protein synthesis and/or transport, probably by remodeling the cytoskeletal structure. PMID- 25278478 TI - Protective effect of beta-carotene against titanium dioxide nanoparticles induced apoptosis in mouse testicular tissue. AB - In this study, the effects of beta-carotene (BC) on testicular germ cell apoptosis arising from titanium dioxide nanoparticles (NTiO2 ) have been evaluated. In NTiO2 -treated mice, expression of apoptotic related genes including Bid, FasL, caspase-3 and p38MAPK was significantly increased. Measurement apoptosis using TUNEL method showed significant increase in apoptotic index of germ cells in NTiO2 -treated mice (P < 0.05). TUNEL assessments showed that the increase of apoptotic index of testicular germ cells in NTiO2 -treated mice was reversed by BC. Beta-carotene pre-treatment could also effectively attenuate the expression of apoptotic related genes. The application of BC may serve as a beneficial medication to protect germ cells against apoptosis induced by nanoparticles and be helpful for male fertility. PMID- 25278477 TI - Symptom assessment in early psychosis: the use of well-established rating scales in clinical high-risk and recent-onset populations. AB - Symptom assessment in early psychosis research typically relies on scales validated in chronic schizophrenia samples. Our goal was to inform investigators who are selecting symptom scales for early psychosis research. We described measure characteristics, baseline scores, and scale inter-relationships in clinical-high-risk (CHR) and recent-onset psychotic disorder (RO) samples using the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms; for the CHR group only, we included the Scale of Prodromal Symptoms. For investigators selecting symptom measures in intervention or longitudinal studies, we also examined the relationship of symptom scales with psychosocial functioning. In both samples, symptom subscales in the same domain, across measures, were moderately to highly intercorrelated. Within all measures, positive symptoms were not correlated with negative symptoms, but disorganized symptoms overlapped with both positive and negative symptoms. Functioning was significantly related to negative and disorganized, but not positive, symptoms in both samples on most measures. Findings suggest strong overlap in symptom severity ratings among the most common scales. In recent-onset samples, each has strengths and weaknesses. In CHR samples, they appear to add little information above and beyond the SOPS. PMID- 25278479 TI - Osteogenic differentiation regulated by Rho-kinase in periodontal ligament cells. AB - The periodontal ligament is a multifunctional soft connective tissue, which functions not only as a cushion supporting the teeth against occlusal force, but is also a source of osteogenic cells that can regenerate neighboring hard tissues. Periodontal ligament cells (PDL cells) contain heterogeneous cell populations, including osteogenic cell progenitors. However, the precise mechanism underlying the differentiation process remains elusive. Cell differentiation is regulated by the local biochemical and mechanical microenvironment that can modulate gene expression and cell morphology by altering actin cytoskeletal organization mediated by Rho-associated, coiled-coil containing protein kinase (ROCK). To determine its role in PDL cell differentiation, we examined the effects of ROCK on cytoskeletal changes and kinetics of gene expression during osteogenic differentiation. PDL cells were isolated from human periodontal ligament on extracted teeth and cultured in osteogenic medium for 14 days. Y-27632 was used for ROCK inhibition assay. Osteogenic phenotype was determined by monitoring alkaline phosphatase (ALP) activity and calcium deposition by Alizarin Red staining. ROCK-induced cytoskeletal changes were examined by immunofluorescence analysis of F-actin and myosin light chain 2 (MLC2) expression. Real-time PCR was performed to examine the kinetics of osteogenic gene expression. F-actin and phospho-MLC2 were markedly induced during osteogenic differentiation, which coincided with upregulation of ALP activity and mineralization. Subsequent inhibition assay indicated that Y-27632 significantly inhibited F-actin and phospho-MLC2 expression in a dose-dependent manner with concomitant partial reversal of the PDL cell osteogenic phenotype. PCR array analysis of osteogenic gene expression indicated that extracellular matrix genes, such as fibronectin 1, collagen type I and III, and biglycan, were significantly downregulated by Y27632. These findings indicated crucial effects of ROCK in cytoskeletal reorganization and differentiation of PDL cells toward osteogenic cells. ROCK contributes to induction of osteogenic differentiation by synergistic increases in extracellular matrix gene expression in PDL cells. PMID- 25278480 TI - Aptamers as a replacement for antibodies in enzyme-linked immunosorbent assay. AB - The application of antibodies in enzyme-linked immunosorbent assay (ELISA) is the basis of this diagnostic technique which is designed to detect a potpourri of complex target molecules such as cell surface antigens, allergens, and food contaminants. However, development of the systematic evolution of Ligands by Exponential Enrichment (SELEX) method, which can generate a nucleic acid-based probe (aptamer) that possess numerous advantages compared to antibodies, offers the possibility of using aptamers as an alternative molecular recognition element in ELISA. Compared to antibodies, aptamers are smaller in size, can be easily modified, are cheaper to produce, and can be generated against a wide array of target molecules. The application of aptamers in ELISA gives rise to an ELISA derived assay called enzyme-linked apta-sorbent assay (ELASA). As with the ELISA method, ELASA can be used in several different configurations, including direct, indirect, and sandwich assays. This review provides an overview of the strategies involved in aptamer-based ELASA. PMID- 25278481 TI - Dopamine fluorescent sensors based on polypyrrole/graphene quantum dots core/shell hybrids. AB - A facilely prepared fluorescent sensor was developed for dopamine (DA) detection with high sensitivity and selectivity based on polypyrrole/graphene quantum dots (PPy/GQDs) core/shell hybrids. The composites exhibit strong fluorescence emission, which is dramatically enhanced as high as three times than pristine GQDs. The prepared sensor allows a highly sensitive determination of DA by fluorescent intensity decreasing with the addition of DA and presents a good linearity in range of 5-8000 nM with the detection limit of 10 pM (S/N = 3). Furthermore, the application of the proposed approach have been demonstrated in real samples and showed promise in diagnostic purposes. PMID- 25278482 TI - Upper extremity ischemia is superior to lower extremity ischemia for remote ischemic conditioning of antero-lateral thigh cutaneous blood flow. AB - Remote ischemic conditioning (RIC) is known to improve microcirculation in various settings, but little is known about the impact of the amount of ischemic tissue mass or the limb itself. Since ischemia and subsequent necrosis of flaps is one of the most dreaded complications in reconstructive surgery, adjuvant methods to improve microcirculation are desirable. We therefore performed a randomized trial to compare the effect of arm versus leg ischemia for RIC of the cutaneous microcirculation of the antero-lateral thigh. Forty healthy volunteers were randomized to undergo 5 min of ischemia of either the upper or lower extremity, followed by 10 min of reperfusion.Ischemia was induced by a surgical tourniquet applied to the proximal limb, which was inflated to 250 mmHg for the upper and 300 mgHg for the lower extremity. This cycle was repeated a total of three times. Cutaneous microcirculation was assessed by combined laser doppler spectrophotometry on the antero-lateral aspect of the thigh to measure cutaneous blood flow (BF), relative hemoglobin content (rHb), and oxygen saturation (StO2). Baseline measurements were performed for 10 min, after which the ischemia/reperfusion cycles were begun. Measurements were performed continuously and were afterwards pooled to obtain a mean value per minute. Both groups showed significant increases in all three measured parameters of cutaneous microcirculation after three cycles of ischemia/reperfusion when compared to baseline (BF: 95.1% (P < 0.001) and 27.9% (P = 0.002); rHb: 9.4% (P < 0.001) and 5.9% (P < 0.001), StO2: 8.4% (P = 0.045) and 9.4% (P < 0.001). When comparing both groups, BF was significantly higher in the arm group (P = 0.019 after 11 min., P = 0.009 after 45 min). In conclusions, both ischemic conditioning of the upper and lower extremity is able to improve cutaneous BF on the ALT donor site. However, RIC of the upper extremity seems to be a superior trigger for improvement of cutaneous BF. PMID- 25278483 TI - Choroidal neovascularization associated with extensive macular atrophy with pseudodrusen-like appearance. AB - PURPOSE: Extensive macular atrophy with pseudodrusen-like appearance (EMAP) is a recently described entity. We describe the first observations of choroidal neovascularization (CNV) associated with EMAP in 3 patients. METHODS: Nineteen consecutive patients with EMAP were retrospectively investigated for the presence of CNV and treatment outcomes. Each patient underwent a complete ophthalmologic examination including color fundus photograpy, fluorescein angiography (FA), indocyanine green angiography (ICG) and spectral-domain optical coherence tomography (SD-OCT). RESULTS: Retrospective analysis revealed choroidal neovascularization in 3 patients (4 eyes) out of 19 patients with EMAP. In these patients, laser photocoagulation or intravitreal injections of ranibizumab led to resolution of retinal exudation with limited functional improvement. CONCLUSION: CNV is a possible complication of EMAP, a recently reported form of macular atrophy resembling geographic atrophy. Laser photocoagulation and anti-VEGF treatment appear to be two valuable therapeutic options. PMID- 25278484 TI - Roles of chromatin remodellers in DNA double strand break repair. AB - Now that we have a good understanding of the DNA double strand break (DSB) repair mechanisms and DSB-induced damage signalling, attention is focusing on the changes to the chromatin environment needed for efficient DSB repair. Mutations in chromatin remodelling complexes have been identified in cancers, making it important to evaluate how they impact upon genomic stability. Our current understanding of the DSB repair pathways suggests that each one has distinct requirements for chromatin remodelling. Moreover, restricting the extent of chromatin modifications could be a significant factor regulating the decision of pathway usage. In this review, we evaluate the distinct DSB repair pathways for their potential need for chromatin remodelling and review the roles of ATP-driven chromatin remodellers in the pathways. PMID- 25278485 TI - Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S-Nampt. AB - Recently, we reported that cancer cells that recover from a potentially lethal damage gain new phenotypic features comprised of mitochondrial structural remodeling associated with increased glycolytic dependency and drug resistance. Here, we demonstrate that a subset of cancer cells, upon recovery from a potentially lethal damage, undergo dedifferentiation and express genes, which are characteristic of undifferentiated stem cells. While these cells are competent in maintaining differentiated progeny of tumor, they also exhibit transdifferentiation potential. Dedifferentiation is characterized by accumulation of hydrogen sulfide (H2S), which triggers up-regulation of nicotinamide phosphoribosyltransferase (Nampt) accompanied by changes in the redox state. The molecular events triggered by Nampt include elevated production of NAD(+) and up-regulation of H2S producing enzymes, cystathionine beta synthase (CBS) and cystathionase (CTH) with 3-mercaptopyruvate sulfurtransferase (MST) being detectable only in 3D spheroids. Suppression of Nampt, or inactivation of H2S producing enzymes, all reduce H2S production and reverse the ability of cells to dedifferentiate. Moreover, H2S induced stem cell markers in parental cancer cells in a manner similar to that observed in damage recovered cells. These data suggest of existence of a positive feedback loop between H2S and Nampt that controls dedifferentiation in cancer cells that recover from a potentially lethal damage. PMID- 25278487 TI - Intersections between disability, type of impairment, gender and socio-economic disadvantage in a nationally representative sample of 33,101 working-aged Australians. AB - BACKGROUND: People with disabilities are socio-economically disadvantaged and have poorer health than people without disabilities; however, little is known about the way in which disadvantage is patterned by gender and type of impairment. OBJECTIVES: 1. To describe whether socio-economic circumstances vary according to type of impairment (sensory and speech, intellectual, physical, psychological and acquired brain injury). 2. To compare levels of socio-economic disadvantage for women and men with the same impairment type. METHODS: We used a large population-based disability-focused survey of Australians, analyzing data from 33,101 participants aged 25-64. Indicators of socio-economic disadvantage included education, income, employment, housing vulnerability, and multiple disadvantage. Stratified by impairment type, we estimated: the population weighted prevalence of socio-economic disadvantage; the relative odds of disadvantage compared to people without disabilities; and the relative odds of disadvantage between women and men. RESULTS: With few exceptions, people with disabilities fared worse for every indicator compared to people without disability; those with intellectual and psychological impairments and acquired brain injuries were most disadvantaged. While overall women with disabilities were more disadvantaged than men, the magnitude of the relative differences was lower than the same comparisons between women and men without disabilities, and there were few differences between women and men with the same impairment types. CONCLUSIONS: Crude comparisons between people with and without disabilities obscure how disadvantage is patterned according to impairment type and gender. The results emphasize the need to unpack how gender and disability intersect to shape socio-economic disadvantage. PMID- 25278488 TI - Patient-rated tennis elbow evaluation questionnaire. PMID- 25278489 TI - Neuroprotective effects of apelin-13 on experimental ischemic stroke through suppression of inflammation. AB - Acute inflammation plays an important role in the pathogenic progression of post ischemic neuronal damage. Apelin-13 has been investigated as a neuropeptide for various neurological disorders. The present study was performed to evaluate the effects of apelin-13 on the inflammation of cerebral ischemia/reperfusion (I/R) injury. Transient focal I/R model in male Wistar rats were induced by 2h middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Rats then received treatment with apelin-13 or vehicle after ischemia at the onset of reperfusion. The neurological deficit was evaluated and the infarct volume was measured by TTC staining. The activity of myeloperoxidase (MPO) was measured. The expression of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and intercellular adhesion molecule-1 (ICAM-1) were measured using real-time PCR. And the expression of apelin receptor (APJ), ionized calcium-binding adapter molecule-1 (Iba1), glial fibrillary acidic protein (GFAP) and high mobility group box 1 (HMGB1) were measured by immunohistochemistry and western blot. Our results demonstrated that treatment with apelin-13 in I/R rats markedly reduced neurological deficits and the infarct volume. The increase of MPO activity induced by I/R was inhibited by apelin-13 treatment. The real-time PCR showed that apelin-13 decreased the expression of inflammatory cytokines such as IL-1beta, TNF-alpha and ICAM-1 in I/R rats. The expression of APJ in I/R rats was increased. And the expression of Iba1, GFAP and HMGB1 in I/R rats was decreased by apelin-13 treatment indicating the inhibition of microglia, astrocytes and other inflammatory cells. In conclusion, apelin-13 is neuroprotective for neurons against I/R through inhibiting the neuroinflammation. PMID- 25278490 TI - New roles of the multidimensional adipokine: chemerin. AB - The discovery of several adipokines with diverse activities and their involvement in regulation of various pathophysiological functions of human body has challenged the researchers. In the family of adipokine, chemerin is a novel and unique addition. Ever since the first report on chemerin as a chemo-attractant protein, there are numerous studies showing a multitasking capacity of chemerin in the maintenance of homeostasis, for the activation of natural killer cells, macrophages and dendritic cells in both innate and adaptive immunity. Its diversity ranges from generalized inflammatory cascades to being explicitly involved in the manifestation of arthritis, psoriasis and peritonitis. Its association with certain cancerous tissue may render it as a potential tumor marker. In present review, we aim to consolidate recent data of investigations on chemerin in context to functional characteristics with a special reference to its role as a metabolic signal in inflammation and non-metabolic syndromes. PMID- 25278491 TI - Study of NAP adsorption and assembly on the surface of HOPG. AB - NAP is an octapeptide that has demonstrated a neuroprotective/therapeutic efficacy at very low concentrations in preclinical studies and in a number of clinical trials. Yet little is known about its structural organization at low concentrations. Here, we have employed atomic force microscopy to investigate NAP peptide assembly on graphite in aqueous media at nanomolar concentration. High spatial resolution scans of NAP assemblies reveal their fine structure with clearly resolved single NAP units. This observation leads us to conclude that NAP molecules do not form complex self-assembled structures at nanomolar concentration when adsorbed on graphite surface. PMID- 25278493 TI - [Necrotizing external otitis: interest imaging]. PMID- 25278492 TI - Alpha synuclein is transported into and out of the brain by the blood-brain barrier. AB - Alpha-synuclein (alpha-Syn), a small protein with multiple physiological and pathological functions, is one of the dominant proteins found in Lewy Bodies, a pathological hallmark of Lewy body disorders, including Parkinson's disease (PD). More recently, alpha-Syn has been found in body fluids, including blood and cerebrospinal fluid, and is likely produced by both peripheral tissues and the central nervous system. Exchange of alpha-Syn between the brain and peripheral tissues could have important pathophysiologic and therapeutic implications. However, little is known about the ability of alpha-Syn to cross the blood-brain barrier (BBB). Here, we found that radioactively labeled alpha-Syn crossed the BBB in both the brain-to-blood and the blood-to-brain directions at rates consistent with saturable mechanisms. Low-density lipoprotein receptor-related protein-1 (LRP-1), but not p-glycoprotein, may be involved in alpha-Syn efflux and lipopolysaccharide (LPS)-induced inflammation could increase alpha-Syn uptake by the brain by disrupting the BBB. PMID- 25278494 TI - Effect of butyrate on immune response of a chicken macrophage cell line. AB - Butyric acid is a major short chain fatty acid (SCFA), produced in the gastrointestinal tract by anaerobic bacterial fermentation, that has beneficial health effects in many species including poultry. To understand the immunomodulating effects of butyrate on avian macrophage, we treated a naturally transformed line of chicken macrophage cells named HTC with Na-butyrate in the absence or presence of Salmonella typhimurium lipopolysaccharide (LPS) or phorbol 12-myristate-13-acetate (PMA), a metabolic activator, evaluating its various functional parameters. The results demonstrate that, butyrate by itself had no significant effect on variables such as nitric oxide (NO) production and the expression of genes associated with various inflammatory cytokines but it inhibited NO production, and reduced the expression of cytokines such as IL 1beta, IL-6, IFN-gamma, and IL-10 in LPS-stimulated cells. Butyrate decreased the expression of TGF-beta3 in the presence or absence of LPS, while it had no effect on IL-4, Tbeta4, and MMP2 gene expression. In addition, butyrate augmented PMA induced oxidative burst indicated by DCF-DA oxidation and restored LPS induced attenuation of tartrate resistant acid phosphatase (TRAP) activity. Although butyrate had no significant effect on phagocytosis or matrix metalloproteinase (MMP) activities of resting macrophages, it significantly suppressed the effects induced by their respective stimulants such as LPS induced phagocytosis and PMA induced MMP expression. These results suggest that butyrate has immunomodulatory property in the presence of agents that incite the cells thus, has potential to control inflammation and restore immune homeostasis. PMID- 25278495 TI - Lung cancer screening as a predictor of future alternative payment models. PMID- 25278496 TI - ACR appropriateness criteria follow-up of Hodgkin lymphoma. AB - The main objectives of follow-up studies after completion of treatment for Hodgkin lymphoma are detection of recurrence for salvage therapy and monitoring for sequelae of treatment. The focus of the follow-up shifts, with time after treatment, from detection of recurrence to long-term sequelae. A majority of recurrence is detected by history and physical examination. The yield for routine imaging studies and blood tests is low. Although routine surveillance CT scan can detect recurrence not detected by history and physical examination, its benefit in ultimate survival and cost-effectiveness is not well defined. Although PET scan is a useful tool in assessing response to treatment, its routine use for follow-up is not recommended. Long-term sequelae of treatment include secondary malignancy, cardiovascular disease, pneumonitis, reproductive dysfunction, and hypothyroidism. Follow-up strategies for these sequelae need to be individualized, as their risks in general depend on the dose and volume of radiation to these organs, chemotherapy, age at treatment, and predisposing factors for each sequela. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is either lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25278497 TI - Development and validation of a high-throughput anti-Wolbachia whole-cell screen: a route to macrofilaricidal drugs against onchocerciasis and lymphatic filariasis. AB - There is an urgent need to develop new, safe, and affordable macrofilaricidal drugs for onchocerciasis and lymphatic filariasis treatment and control. The Anti Wolbachia Consortium (A.WOL) aims to provide a novel treatment with macrofilaricidal activity by targeting the essential bacterial symbiont Wolbachia. The consortium is currently screening a diverse range of compounds to find new chemical space to drive this drug discovery initiative and address this unmet demand. To increase the throughput and capacity of the A.WOL cell-based screen, we have developed a 384-well format assay using a high-content imaging system (Operetta) in conjunction with optimized Wolbachia growth dynamics in the C6/36 Aedes albopictus mosquito cell line. This assay uses texture analysis of cells stained with SYTO 11 as a direct measure of bacterial load. This validated assay has dramatically increased the capacity and throughput of the A.WOL compound library screening program 25-fold, enriching the number of new anti Wolbachia hits identified for further development as potential macrofilaricides for onchocerciasis and lymphatic filariasis. PMID- 25278498 TI - Validation and optimization of novel high-throughput assays for human epithelial sodium channels. AB - The epithelial sodium channel (ENaC) plays a crucial role in salt and water homeostasis and is primarily involved in sodium reabsorption in the kidney and lung. Modulators of ENaC function, particularly within lung epithelia, could offer potential treatments for a number of diseases. As a constitutively active sodium channel, ENaC expression at the cell membrane is highly regulated through rapid turnover. This short half-life of the channel at the membrane and cytotoxicity from overexpression pose a problem for reagent generation and assay development in drug discovery. We have generated an HEK293 stable cell line expressing ENaC beta and gamma subunits containing the PY motif trafficking mutations found in Liddle's syndrome to overcome rapid channel turnover at the membrane. A BacMam virus was used to transiently express the ENaC alpha subunit to reconstitute channel function to reduce the toxicity associated with long-term overexpression. We have configured a 384-well FLIPR membrane potential antagonist assay for high-throughput screening and an IonWorks Quattro electrophysiology antagonist assay that is predictive of potency values derived from primary lung epithelial cell short-circuit measurements. The triage strategy for compound screening and profiling against this target using these assays has resulted in the discovery of novel chemotypes. PMID- 25278500 TI - MALDI-TOF MS for the diagnosis of infectious diseases. AB - BACKGROUND: First introduced into clinical microbiology laboratories in Europe, MALDI-TOF MS is being rapidly embraced by laboratories around the globe. Although it has multiple applications, its widespread adoption in clinical microbiology relates to its use as an inexpensive, easy, fast, and accurate method for identification of grown bacteria and fungi based on automated analysis of the mass distribution of bacterial proteins. CONTENT: This review provides a historical perspective on this new technology. Modern applications in the clinical microbiology laboratory are reviewed with a focus on the most recent publications in the field. Identification of aerobic and anaerobic bacteria, mycobacteria, and fungi are discussed, as are applications for testing urine and positive blood culture bottles. The strengths and limitations of MALDI-TOF MS applications in clinical microbiology are also addressed. SUMMARY: MALDI-TOF MS is a tool for rapid, accurate, and cost-effective identification of cultured bacteria and fungi in clinical microbiology. The technology is automated, high throughput, and applicable to a broad range of common as well as esoteric bacteria and fungi. MALDI-TOF MS is an incontrovertibly beneficial technology for the clinical microbiology laboratory. PMID- 25278501 TI - Increased rheumatoid factor and deep venous thrombosis: 2 cohort studies of 54628 individuals from the general population. AB - BACKGROUND: The risk of deep venous thrombosis is increased in patients with rheumatoid arthritis. We tested the hypothesis that increased concentrations of rheumatoid factor are associated with increased risk of deep venous thrombosis in individuals without autoimmune rheumatic disease in the general population. METHODS: We included 54628 participants from the Copenhagen City Heart Study (1981-83) and the Copenhagen General Population Study (2004-12), all with a measured concentration of IgM rheumatoid factor and without autoimmune rheumatic disease or venous thromboembolism. The main outcome was incident deep venous thrombosis. There were no losses to follow-up. RESULTS: During 368381 person years, 670 individuals developed deep venous thrombosis. A rheumatoid factor concentration >= vs <110 IU/mL showed the strongest association with deep venous thrombosis, with multivariable adjusted hazard ratios of 9.0 (95% CI 3.1-26) for 1-year follow-up, 4.3 (2.2-8.5) for 5-year follow-up, and 3.1 (1.7-5.6) for up to 32 years of follow-up. Compared with rheumatoid factor concentrations <15 IU/mL, the multivariable adjusted hazard ratios for deep venous thrombosis during maximum follow-up were 1.3 (1.0-1.5) for 15-29 IU/mL, 1.7 (1.0-2.8) for 30-59 IU/mL, 2.4 (1.3-4.3) for 60-119 IU/mL, and 3.0 (1.6-5.6) for >=120 IU/mL (trend P = 6 * 10(-7)). Results were similar in the 2 studies separately. Obese men and women age >60 years with rheumatoid factor concentrations >=120 IU/mL had 10% and 8% 5-year risk of deep venous thrombosis. CONCLUSIONS: Increased rheumatoid factor in the general population was associated with up to 3-fold increased long term risk and up to 9-fold increased 1-year risk of deep venous thrombosis. PMID- 25278499 TI - Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice. AB - Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12alpha-OH/non12alpha-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7alpha-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na+/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine. PMID- 25278502 TI - Validation of a model-based measurement of the minimum insert thickness of knee prostheses: a retrieval study. AB - INTRODUCTION: Wear of polyethylene inserts plays an important role in failure of total knee replacement and can be monitored in vivo by measuring the minimum joint space width in anteroposterior radiographs. The objective of this retrospective cross-sectional study was to compare the accuracy and precision of a new model-based method with the conventional method by analysing the difference between the minimum joint space width measurements and the actual thickness of retrieved polyethylene tibial inserts. METHOD: Before revision, the minimum joint space width values and their locations on the insert were measured in 15 fully weight-bearing radiographs. These measurements were compared with the actual minimum thickness values and locations of the retrieved tibial inserts after revision. RESULTS: The mean error in the model-based minimum joint space width measurement was significantly smaller than the conventional method for medial condyles (0.50 vs 0.94 mm, p < 0.01) and for lateral condyles (0.06 vs 0.34 mm, p = 0.02). The precision (standard deviation of the error) of the methods was similar (0.84 vs 0.79 mm medially and both 0.46 mm laterally). The distance between the true minimum joint space width locations and the locations from the model-based measurements was less than 10 mm in the medial direction in 12 cases and less in the lateral direction in 13 cases. CONCLUSION: The model-based minimum joint space width measurement method is more accurate than the conventional measurement with the same precision. Cite this article: Bone Joint Res 2014;3:289-96. PMID- 25278505 TI - Structural basis for organohalide respiration. AB - Organohalide-respiring microorganisms can use a variety of persistent pollutants, including trichloroethene (TCE), as terminal electron acceptors. The final two electron transfer step in organohalide respiration is catalyzed by reductive dehalogenases. Here we report the x-ray crystal structure of PceA, an archetypal dehalogenase from Sulfurospirillum multivorans, as well as structures of PceA in complex with TCE and product analogs. The active site harbors a deeply buried norpseudo-B12 cofactor within a nitroreductase fold, also found in a mammalian B12 chaperone. The structures of PceA reveal how a cobalamin supports a reductive haloelimination exploiting a conserved B12-binding scaffold capped by a highly variable substrate-capturing region. PMID- 25278503 TI - Structure of the large ribosomal subunit from human mitochondria. AB - Human mitochondrial ribosomes are highly divergent from all other known ribosomes and are specialized to exclusively translate membrane proteins. They are linked with hereditary mitochondrial diseases and are often the unintended targets of various clinically useful antibiotics. Using single-particle cryogenic electron microscopy, we have determined the structure of its large subunit to 3.4 angstrom resolution, revealing 48 proteins, 21 of which are specific to mitochondria. The structure unveils an adaptation of the exit tunnel for hydrophobic nascent peptides, extensive remodeling of the central protuberance, including recruitment of mitochondrial valine transfer RNA (tRNA(Val)) to play an integral structural role, and changes in the tRNA binding sites related to the unusual characteristics of mitochondrial tRNAs. PMID- 25278506 TI - Conservation. Taking the measure of change. PMID- 25278504 TI - A mid-term analysis of progress toward international biodiversity targets. AB - In 2010, the international community, under the auspices of the Convention on Biological Diversity, agreed on 20 biodiversity-related "Aichi Targets" to be achieved within a decade. We provide a comprehensive mid-term assessment of progress toward these global targets using 55 indicator data sets. We projected indicator trends to 2020 using an adaptive statistical framework that incorporated the specific properties of individual time series. On current trajectories, results suggest that despite accelerating policy and management responses to the biodiversity crisis, the impacts of these efforts are unlikely to be reflected in improved trends in the state of biodiversity by 2020. We highlight areas of societal endeavor requiring additional efforts to achieve the Aichi Targets, and provide a baseline against which to assess future progress. PMID- 25278507 TI - Topological matter. Observation of Majorana fermions in ferromagnetic atomic chains on a superconductor. AB - Majorana fermions are predicted to localize at the edge of a topological superconductor, a state of matter that can form when a ferromagnetic system is placed in proximity to a conventional superconductor with strong spin-orbit interaction. With the goal of realizing a one-dimensional topological superconductor, we have fabricated ferromagnetic iron (Fe) atomic chains on the surface of superconducting lead (Pb). Using high-resolution spectroscopic imaging techniques, we show that the onset of superconductivity, which gaps the electronic density of states in the bulk of the Fe chains, is accompanied by the appearance of zero-energy end-states. This spatially resolved signature provides strong evidence, corroborated by other observations, for the formation of a topological phase and edge-bound Majorana fermions in our atomic chains. PMID- 25278508 TI - Cavity quantum electrodynamics with many-body states of a two-dimensional electron gas. AB - Light-matter interaction has played a central role in understanding as well as engineering new states of matter. Reversible coupling of excitons and photons enabled groundbreaking results in condensation and superfluidity of nonequilibrium quasiparticles with a photonic component. We investigated such cavity-polaritons in the presence of a high-mobility two-dimensional electron gas, exhibiting strongly correlated phases. When the cavity was on resonance with the Fermi level, we observed previously unknown many-body physics associated with a dynamical hole-scattering potential. In finite magnetic fields, polaritons show distinct signatures of integer and fractional quantum Hall ground states. Our results lay the groundwork for probing nonequilibrium dynamics of quantum Hall states and exploiting the electron density dependence of polariton splitting so as to obtain ultrastrong optical nonlinearities. PMID- 25278509 TI - Effect of oral bisphosphonates for osteoporosis on development of skeletal metastases in women with breast cancer: results from a pharmaco-epidemiological study. AB - BACKGROUND: Treatment with bisphosphonates in women with breast cancer and established bone metastasis delays further skeletal-related events. Evidence is emerging that bisphosphonates are beneficial for secondary prevention of bone metastasis. The study aimed to estimate the effect of oral bisphosphonates for treatment or prevention of osteoporosis on development of bone metastasis in a population of women with breast cancer. METHODS: A historical cohort of 21664 women diagnosed with breast cancer was created from health administrative data in Quebec, Canada. The primary outcome was time to develop bone metastasis; exposure was bisphosphonate use prediagnosis, postdiagnosis, both, or neither and a cumulative index of drug exposure. The sample was stratified according to stage (0-II or III) at time of diagnosis. Cox proportional hazards tested the effect of bisphosphonate use on time to develop bone metastases. RESULTS: Taking bisphosphonates postdiagnosis of breast cancer only or continuing bisphosphonates started prior to diagnosis after diagnosis was associated with a reduction in risk of bone metastasis from 45% to 28% in women with local disease at diagnosis. In women with regional disease, postdiagnosis bisphosphonate use, with or without prediagnosis use, reduced risk by almost 50%. A statistically significant dose response trend was observed relating increased use to lower risk (slope = 0.94, 95% confidence interval = 0.90 to 0.99). Bisphosphonates were also associated with a decreased risk of all-cause mortality similar to that of the development of bone metastasis. CONCLUSION: Low-dose oral bisphosphonates administered for prevention or treatment of postmenopausal osteoporosis were associated with lower risk of skeletal metastasis in patients with early- or more advanced-stage breast cancer. PMID- 25278511 TI - Should the threshold for a generalised HIV epidemic be 1% or 5%? PMID- 25278510 TI - High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - High-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predict heart failure (HF) in the general population. However, the interpretation of levels of these biomarkers as predictors of HF is uncertain among patients with CKD. Here, we investigated whether hsTnT and NT proBNP are associated with incident HF among patients with CKD. In a prospective cohort analysis, we studied 3483 people with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study recruited from June of 2003 to August of 2008 who were free of HF at baseline. We used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident HF after adjustment for demographic factors, traditional cardiovascular risk factors, markers of kidney disease, pertinent medication use, and mineral metabolism markers. At baseline, hsTnT levels ranged from <=5.0 to 738.7 pg/ml, and NT proBNP levels ranged from <=5 to 35,000 pg/ml. Compared with those who had undetectable hsTnT, participants in the highest quartile (>26.5 pg/ml) had a significantly higher rate of HF (hazard ratio, 4.77; 95% confidence interval, 2.49 to 9.14). Similarly, compared with those in the lowest NT-proBNP quintile (<47.6 pg/ml), participants in the highest quintile (>433.0 pg/ml) experienced a substantially higher rate of HF (hazard ratio, 9.57; 95% confidence interval, 4.40 to 20.83) [corrected]. In conclusion, hsTnT and NT-proBNP were strongly associated with incident HF among a diverse cohort of individuals with mild to severe CKD. Elevations in these biomarkers may indicate subclinical changes in volume and myocardial stress that subsequently contribute to clinical HF. PMID- 25278513 TI - Chemical and biological processes for multi-metal extraction from waste printed circuit boards of computers and mobile phones. AB - E-waste printed circuit boards (PCB) of computers, mobile-phones, televisions, LX (LongXiang) PCB in LED lights and bulbs, and tube-lights were crushed to >=250 um particle size and 16 different metals were analysed. A comparative study has been carried out to evaluate the extraction of Cu-Zn-Ni from computer printed circuit boards (c-PCB) and mobile-phone printed circuit boards (m-PCB) by chemical and biological methods. Chemical process showed the extraction of Cu-Zn-Ni by ferric sulphate was best among the studied chemical lixiviants. Bioleaching experiments were carried out with the iron oxidising consortium, which showed that when E waste and inoculum were added simultaneously in the medium (one-step process); 60.33% and 87.50% Cu, 75.67% and 85.67% Zn and 71.09% and 81.87% Ni were extracted from 10 g L(-1) of c-PCB and m-PCB, respectively, within 10-15 days of reaction time. Whereas, E-waste added after the complete oxidation of Fe(2+) to Fe(3+) iron containing medium (two-step process) showed 85.26% and 99.99% Cu, 96.75% and 99.49% Zn and 93.23% and 84.21% Ni extraction from c-PCB and m-PCB, respectively, only in 6-8 days. Influence of varying biogenerated Fe(3+) and c PCB concentrations showed that 16.5 g L(-1) of Fe(3+) iron was optimum up to 100 g L(-1) of c-PCB. Changes in pH, acid consumed and redox potential during the process were also studied. The present study shows the ability of an eco-friendly process for the recovery of multi-metals from E-waste even at 100 g L(-1) printed circuit boards concentration. PMID- 25278512 TI - How do mobile phone diabetes programs drive behavior change? Evidence from a mixed methods observational cohort study. AB - PURPOSE: The purpose of this study was to investigate the behavioral effects of a theory-driven, mobile phone-based intervention that combines automated text messaging and remote nursing, using an automated, interactive text messaging system. METHODS: This was a mixed methods observational cohort study. Study participants were members of the University of Chicago Health Plan (UCHP) who largely reside in a working-class, urban African American community. Surveys were conducted at baseline, 3 months (mid-intervention), and 6 months (postintervention) to test the hypothesis that the intervention would be associated with improvements in self-efficacy, social support, health beliefs, and self-care. In addition, in-depth individual interviews were conducted with 14 participants and then analyzed using the constant comparative method to identify new behavioral constructs affected by the intervention. RESULTS: The intervention was associated with improvements in 5 of 6 domains of self-care (medication taking, glucose monitoring, foot care, exercise, and healthy eating) and improvements in 1 or more measures of self-efficacy, social support, and health beliefs (perceived control). Qualitatively, participants reported that knowledge, attitudes, and ownership were also affected by the program. Together these findings were used to construct a new behavioral model. CONCLUSIONS: This study's findings challenge the prevailing assumption that mobile phones largely affect behavior change through reminders and support the idea that behaviorally driven mobile health interventions can address multiple behavioral pathways associated with sustained behavior change. PMID- 25278514 TI - Does imaging alphavbeta3 integrin expression with PET detect changes in angiogenesis during bevacizumab therapy? AB - In recent years, there has been a growing interest in molecular imaging markers of tumor-induced angiogenesis. Several radiolabeled RGD (arginine, glycine, aspartate) peptides have been developed for PET imaging of alphavbeta3 integrins in the tumor vasculature, but there are only limited data on how angiogenesis inhibitors affect the tumor uptake of these peptides. METHODS: Changes in (68)Ga NODAGA-c(RGDfK) peptide uptake were measured using PET during bevacizumab therapy of 2 alphavbeta3-negative squamous cell carcinoma cell lines (A-431 and FaDu) that induce alphavbeta3-positive neovasculature when transplanted into nude mice. Tumor uptake of (68)Ga-NODAGA-c(RGDfK) was correlated to microvascular density, vascular morphology, and permeability as well as alphavbeta3 integrin expression. RESULTS: Bevacizumab significantly inhibited growth of A-431 tumors and caused a significant reduction in microvascular density and alphavbeta3 integrin expression within 7 d after start of therapy. Bevacizumab also caused a normalization of blood vessel morphology and decreased tumor necrosis. However, (68)Ga-NODAGA-c(RGDfK) uptake was significantly increased at day 7 of therapy and did not decrease until after 3 wk of treatment. In Fadu xenografts, bevacizumab therapy caused only a minor inhibition of tumor growth and minor changes in (68)Ga-NODAGA-c(RGDfK) uptake. CONCLUSION: Uptake of radiolabeled RGD peptides is not necessarily decreased by effective antiangiogenic therapy. Early in the course of therapy a decrease in the expression of alphavbeta3 integrins may not be reflected by a decrease in the uptake of RGD peptides. PMID- 25278517 TI - Draft Genome Sequence of a Psychrophilic Bacterium, Sphingomonas antarcticum, Isolated from the Soils of Schirmacher Oasis, Antarctica. AB - We report the 4.5-Mbp genome sequences of Sphingobacterium antarcticum 4BY, a psychrophilic bacterium isolated from the soils of Schirmacher Oasis, Antarctica. The draft genome of S. antarcticum strain 4BY consists of 4,566,318 bp with 40.4% G+C content, 4,234 protein coding genes, and 52 RNAs. PMID- 25278518 TI - Draft Genome Sequences of Brucella suis Biovar 4 Strain NCTC 10385, Brucella ceti Strain NCTC 12891T, Brucella inopinata Strain CAMP 6436T, and Brucella neotomae Strain ATCC 23459T. AB - With the aim of developing quantitative PCR methods for the detection and differentiation of Brucella species, the genomes of Brucella ceti, Brucella inopinata, Brucella netotomae, and Brucella suis biovar 4 were sequenced and analyzed. PMID- 25278515 TI - An SPM8-based approach for attenuation correction combining segmentation and nonrigid template formation: application to simultaneous PET/MR brain imaging. AB - We present an approach for head MR-based attenuation correction (AC) based on the Statistical Parametric Mapping 8 (SPM8) software, which combines segmentation- and atlas-based features to provide a robust technique to generate attenuation maps (MU maps) from MR data in integrated PET/MR scanners. METHODS: Coregistered anatomic MR and CT images of 15 glioblastoma subjects were used to generate the templates. The MR images from these subjects were first segmented into 6 tissue classes (gray matter, white matter, cerebrospinal fluid, bone, soft tissue, and air), which were then nonrigidly coregistered using a diffeomorphic approach. A similar procedure was used to coregister the anatomic MR data for a new subject to the template. Finally, the CT-like images obtained by applying the inverse transformations were converted to linear attenuation coefficients to be used for AC of PET data. The method was validated on 16 new subjects with brain tumors (n = 12) or mild cognitive impairment (n = 4) who underwent CT and PET/MR scans. The MU maps and corresponding reconstructed PET images were compared with those obtained using the gold standard CT-based approach and the Dixon-based method available on the Biograph mMR scanner. Relative change (RC) images were generated in each case, and voxel- and region-of-interest-based analyses were performed. RESULTS: The leave-one-out cross-validation analysis of the data from the 15 atlas-generation subjects showed small errors in brain linear attenuation coefficients (RC, 1.38% +/- 4.52%) compared with the gold standard. Similar results (RC, 1.86% +/- 4.06%) were obtained from the analysis of the atlas validation datasets. The voxel- and region-of-interest-based analysis of the corresponding reconstructed PET images revealed quantification errors of 3.87% +/ 5.0% and 2.74% +/- 2.28%, respectively. The Dixon-based method performed substantially worse (the mean RC values were 13.0% +/- 10.25% and 9.38% +/- 4.97%, respectively). Areas closer to the skull showed the largest improvement. CONCLUSION: We have presented an SPM8-based approach for deriving the head MU map from MR data to be used for PET AC in integrated PET/MR scanners. Its implementation is straightforward and requires only the morphologic data acquired with a single MR sequence. The method is accurate and robust, combining the strengths of both segmentation- and atlas-based approaches while minimizing their drawbacks. PMID- 25278516 TI - 188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2 expressing tumors: preclinical assessment. AB - Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors. METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment. RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 +/- 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 +/- 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 +/- 2, 12 +/- 2, 5 +/- 2, and 1.8 +/- 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 +/- 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible. CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits. PMID- 25278519 TI - Complete genome sequence of equid herpesvirus 3. AB - Equid herpesvirus 3 (EHV-3) is a member of the subfamily Alphaherpesvirinae that causes equine coital exanthema. Here, we report the first complete genome sequence of EHV-3. The 151,601-nt genome encodes 76 distinct genes like other equine alphaherpesviruses, but genetically, EHV-3 is significantly more divergent. PMID- 25278521 TI - Draft Genome Sequence of Pseudomonas savastanoi pv. savastanoi Strain DAPP-PG 722, Isolated in Italy from an Olive Plant Affected by Knot Disease. AB - Olive knot disease, caused by the bacterium Pseudomonas savastanoi pv. savastanoi, seriously affects olive trees in the Mediterranean basin. Here, we report the draft genome sequence of P. savastanoi pv. savastanoi DAPP-PG 722, a strain isolated in Italy from an olive plant affected by knot disease. PMID- 25278520 TI - Genetic Instability of Influenza pH1N1 Viruses. AB - Here, we report full-length genome sequences of influenza pH1N1 viruses obtained prior to and after propagation in MDCK cells. Paired comparisons of the genomes showed that each strain acquired 1.0 to 18.8 mutations per genome per replication cycle, which corresponds to 0.5 to 5.8 mutations per virus proteome per replication cycle. Our analysis indicates that pH1N1 viruses accumulated adaptive mutations among others in response to propagation in cell culture. These results could be important for vaccine and drug-sensitivity surveillance studies, as well as for vaccine and antiviral drug development programs where cell cultures are used for influenza propagation. PMID- 25278522 TI - Complete genome sequence of an Indian field isolate of classical Swine Fever virus belonging to subgenotype 1.1. AB - We report the complete genome sequence of an Indian field isolate of classical swine fever virus (CSFV) belonging to predominant subgenotype 1.1 prevalent in India. This report will help in understanding the molecular diversity of CSFV strains circulating worldwide and to select and develop a suitable vaccine candidate for classical swine fever (CSF) control in India. PMID- 25278523 TI - Draft Genome Sequence of Polychlorinated Biphenyl-Dechlorinating Dehalococcoides mccartyi Strain SG1, Which Carries a Circular Putative Plasmid. AB - Dehalococcoides mccartyi strain SG1, isolated from digester sludge, dechlorinates polychlorinated biphenyls (PCBs) to lower congeners. Here we report the draft genome sequence of SG1, which carries a 22.65 kbp circular putative plasmid. PMID- 25278525 TI - Draft Genome Sequence of Geotrichum candidum Strain 3C. AB - We report here the draft genome sequence of Geotrichum candidum strain 3C, which is a filamentous yeast-like fungus that holds great promise for biotechnology. The genome was sequenced using Ion Torrent and 454 platforms. The estimated genome size was 41.4 Mb, and 14,579 protein-coding genes were predicted ab initio. PMID- 25278524 TI - Draft Genome Sequences of Campylobacter fetus subsp. venerealis bv. venerealis Strain B6 and bv. intermedius Strain 642-21. AB - Campylobacter fetus subsp. venerealis is an important venereal pathogen. We sequenced the genomes of Campylobacter fetus subsp. venerealis bv. venerealis strain B6 and bv. intermedius strain 642-21. The genetic variability of these Australian strains will facilitate the study of mechanisms of geographical adaptation of these pathogens that impact livestock. PMID- 25278526 TI - Draft Genome Assembly of Pseudomonas aeruginosa Quality Control Reference Strain Boston 41501. AB - We present the scaffolded genome assembly of Pseudomonas aeruginosa Boston 41501, now publicly available in GenBank (JOVK00000000) in 10 contigs placed into a single scaffold. The 6.82-Mbp genome contains 66.1% G+C content and 6,295 coding sequences, including type 4 pilus and type 3 secretion system production genes. PMID- 25278527 TI - Genome Assembly of Methicillin-Resistant Quality Control Strain Staphylococcus aureus CDC73-57501 (ATCC 29247). AB - Staphylococcus aureus is a major cause of bacterial infections in the United States, with high percentages of serious infections resistant to a variety of beta-lactam antibiotics. Here, we present the scaffolded genome assembly into 16 contigs of S. aureus CDC73-57501 (ATCC 29247), a methicillin-resistant quality control strain. PMID- 25278528 TI - Genome Sequence of Coxiella burnetii Strain AuQ01 (Arandale) from an Australian Patient with Acute Q Fever. AB - Coxiella burnetii strain AuQ01 was isolated from the serum of an Australian acute Q fever patient and represents the first whole genome from this historical Q fever country. This new genome shows distinct differences from existing genomic data and will enhance the understanding of this query pathogen. PMID- 25278530 TI - Draft Genome Sequence of a Deep-Sea Bacterium, Bacillus niacini Strain JAM F8, Involved in the Degradation of Glycosaminoglycans. AB - Here, we report the draft genome sequence of Bacillus niacini JAM F8, which was newly isolated from deep-sea sediment at a depth of 2,759 m from the Izu Ogasawara Trench. An array of genes related to degradation of glycosaminoglycans in this bacterium was identified by whole-genome analysis. PMID- 25278529 TI - Genome Sequence of Lactococcus lactis subsp. lactis NCDO 2118, a GABA-Producing Strain. AB - Lactococcus lactis subsp. lactis NCDO 2118 is a nondairy lactic acid bacterium, a xylose fermenter, and a gamma-aminobutyric acid (GABA) producer isolated from frozen peas. Here, we report the complete genome sequence of L. lactis NCDO 2118, a strain with probiotic potential activity. PMID- 25278531 TI - Complete Genome Sequence of Mycoplasma canadense Strain HAZ 360_1 from Bovine Mastitic Milk in Japan. AB - Bovine mycoplasmal mastitis is spreading quickly among cows. Mycoplasma canadense, a causal species of bovine mastitis, reduces milk quality and quantity via the infiltration of numerous inflammatory cells. Presented here is the complete 693,241-bp genome sequence of M. canadense strain HAZ 360_1, which was isolated in Japan. PMID- 25278532 TI - First Complete Genome Sequence of Salmonella enterica subsp. enterica Serovar Typhimurium Strain ATCC 13311 (NCTC 74), a Reference Strain of Multidrug Resistance, as Achieved by Use of PacBio Single-Molecule Real-Time Technology. AB - We report the first complete genomic sequence of Salmonella enterica subsp. enterica serovar Typhimurium strain ATCC 13311, the leading food-borne pathogen and a reference strain used in drug resistance studies. De novo assembly with PacBio sequencing completed its chromosome and one plasmid. They will accelerate the investigation into multidrug resistance in Salmonella Typhimurium. PMID- 25278533 TI - Draft Genome Sequence of the Pathogenic Fungus Scedosporium apiospermum. AB - The first genome of one species of the Scedosporium apiospermum complex, responsible for localized to severe disseminated infections according to the immune status of the host, will contribute to a better understanding of the pathogenicity of these fungi and also to the discovery of the mechanisms underlying their low susceptibility to current antifungals. PMID- 25278534 TI - Draft Genome Sequence of Bacillus subtilis Strain D7XPN1, Isolated from Commercial Bioreactor-Degrading Food Waste. AB - The analysis of the 4.1-Mb draft genome sequence of a moderately thermophilic, heterotrophic, and facultatively anaerobic bacterium, Bacillus subtilis strain D7XPN1, identified genes for a range of enzymes with potential in the biodegradation of food waste, a property consistent with the ecological habitat of the isolate. PMID- 25278535 TI - Draft Genome Sequence of Burkholderia pyrrocinia Lyc2, a Biological Control Strain That Can Suppress Multiple Plant Microbial Pathogens. AB - Burkholderia pyrrocinia strain Lyc2 was isolated from the tobacco rhizosphere in China. This bacterium exhibits a remarkable capacity to inhibit the growth of multiple pathogens and shows strong suppression of cotton seedling damping-off. Here, we present the draft genome sequence of Burkholderia pyrrocinia strain Lyc2. PMID- 25278536 TI - Draft Genome Sequence of the Organophosphorus-Degrading Bacterium Pseudomonas sp. Strain 1-7, Isolated from Organophosphorus-Polluted Sludge. AB - Pseudomonas sp. strain 1-7, isolated from organophosphorus-polluted sludge, is able to degrade many organophosphorus compounds. Here, we report the draft genome sequence of Pseudomonas sp. strain 1-7. PMID- 25278537 TI - Draft Genome Sequences of Devosia sp. Strain 17-2-E-8 and Devosia riboflavina Strain IFO13584. AB - Here we report the draft genome of Devosia sp. strain 17-2-E-8, isolated from Ontario agricultural soil (Canada) with promising deoxynivalenol biotransformation capabilities. In addition, we report the draft genome of Devosia riboflavina strain IFO13584, used as a control strain in our studies aimed at highlighting unique gene clusters involved in deoxynivalenol epimerization. PMID- 25278538 TI - High-Quality Draft Genome Sequence of Pseudomonas sp. BRG100, a Strain with Bioherbicidal Properties against Setaria viridis (Green Foxtail) and Other Pests of Agricultural Significance. AB - Pseudomonas sp. BRG100 inhibits the growth of certain agricultural pests and is a potentially useful biopesticide for weeds and plant diseases. We have sequenced the 6.25-Mbp genome of this strain and assembled it into 4 scaffolds. Genome sequence comparisons revealed that this strain may represent a novel species of Pseudomonas. PMID- 25278539 TI - Genome Sequence of Maribius sp. Strain MOLA 401, a Marine Roseobacter with a Quorum-Sensing Cell-Dependent Physiology. AB - Maribius sp. strain MOLA401 is an alphaproteobacterium isolated from a coral reef lagoon located in New Caledonia, France. We report the genome sequence and its annotation which, interestingly, reveals the presence of genes involved in quorum sensing. This is the first report of a full genome within the genus Maribius. PMID- 25278540 TI - Draft Genome Sequence of "Candidatus Liberibacter asiaticus" from California. AB - We report here the draft genome sequence of "Candidatus Liberibacter asiaticus" strain HHCA, collected from a lemon tree in California. The HHCA strain has a genome size of 1,150,620 bp, 36.5% G+C content, 1,119 predicted open reading frames, and 51 RNA genes. PMID- 25278541 TI - Complete Genome Sequence of Vibrio vulnificus 93U204, a Bacterium Isolated from Diseased Tilapia in Taiwan. AB - Vibrio vulnificus 93U204 is a bacterium isolated from a moribund tilapia collected in Kaohsiung, Taiwan. Here, we report the complete genome sequence of this bacterium to facilitate the investigation of its pathogenicity and for comparative analyses with human-pathogenic strains within the same species. PMID- 25278542 TI - Draft Genome Sequence of the Oyster Larval Probiotic Bacterium Vibrio sp. Strain OY15. AB - We report the draft genome sequence of Vibrio sp. strain OY15, a Gram-negative marine bacterium isolated from an oyster (Crassostrea virginica) digestive tract and shown to possess probiotic activity. The availability of this genome sequence will facilitate the study of the mechanisms of probiotic activity as well as virulence capacity. PMID- 25278543 TI - Complete Genome Sequences of H3N2 Canine Influenza Virus with the Matrix Gene from the Pandemic A/H1N1 Virus. AB - We analyzed the complete genome sequence containing the 3' and 5' noncoding regions (NCRs) of H3N2 canine influenza virus (CIV) with the matrix gene from the pandemic A/H1N1 virus, which will provide a better understanding of the pathogenesis, transmission, and evolution of variant CIV. PMID- 25278544 TI - Lower physical activity and depression are associated with hospitalization and shorter survival in CKD. PMID- 25278545 TI - CKD and hypertension during long-term follow-up in children and adolescents previously treated with extracorporeal membrane oxygenation. AB - BACKGROUND AND OBJECTIVES: Many children receiving extracorporeal membrane oxygenation develop AKI. If AKI leads to permanent nephron loss, it may increase the risk of developing CKD. The prevalence of CKD and hypertension and its predictive factors during long-term follow-up of children and adolescents previously treated with neonatal extracorporeal membrane oxygenation were determined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between November of 2010 and February of 2014, neonatal survivors of extracorporeal membrane oxygenation who visited the prospective follow-up program at 1, 2, 5, 8, 12, and 18 years of age were screened for CKD and hypertension (BP>=95th percentile of reference values). CKD was suspected in children with either an eGFR<90 ml/min per 1.73 m(2) or proteinuria (urinary protein-to-creatinine ratio >0.50 for children ages <=24 months and >0.20 at >24 months). The RIFLE classification (risk, injury, or failure as 150%, 200%, or 300% of serum creatinine reference values) was used to define AKI during extracorporeal membrane oxygenation without preemptive hemofiltration. RESULTS: Median follow-up of 169 screened participants was 8.2 years (interquartile range=5.2-12.1 years). Nine children had a lower eGFR, but all rates were >60 ml/min per 1.73 m(2). Proteinuria was observed in 20 children (median=0.26 mg protein/mg creatinine; interquartile range=0.23-0.32 mg protein/mg creatinine), and 32 children had hypertension. Only history of AKI was associated with CKD (P=0.004). Children with RIFLE scores injury and failure had 4.3 times higher odds of CKD signs or hypertension than those without AKI (95% confidence interval, 1.6 to 12.1; P=0.004). CONCLUSIONS: Altogether, 54 participants (32%) had at least one sign of CKD and/or hypertension. However, most values were marginally abnormal, with no immediate consequences for clinical care. Nevertheless, a prevalence of 32% clearly indicates that survivors of neonatal extracorporeal membrane oxygenation, especially those with AKI, are at risk of a more rapid decline of kidney function with increasing age. Therefore, screening for CKD development in adulthood is recommended. PMID- 25278547 TI - Screening for CKD: a pro and con debate. PMID- 25278546 TI - Depressive affect and hospitalization risk in incident hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Recent studies demonstrated an association between depressive affect and higher mortality risk in incident hemodialysis patients. This study sought to determine whether an association also exists with hospitalization risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All 8776 adult incident hemodialysis patients with Medical Outcomes Study Short Form 36 survey results treated in Fresenius Medical Care North America facilities in 2006 were followed for 1 year from the date of survey, and all hospitalization events lasting >24 hours were tracked. A depressive affect score was derived from responses to two Medical Outcomes Study Short Form 36 questions ("down in the dumps" and "downhearted and blue"). A high depressive affect score corresponded with an average response of "some of the time" or more frequent occurrence. Cox and Poisson models were constructed to determine associations of depressive affect scores with risk for time to first hospitalization and risk for hospitalization events, as well as total days spent in the hospital, respectively. RESULTS: Incident patients with high depressive affect score made up 41% of the cohort and had a median (interquartile range) hospitalization event rate of one (0, 3) and 4 (0, 15) total hospital days; the values for patients with low depressive affect scores were one (0, 2) event and 2 (0, 11) days, respectively. For high-scoring patients, the adjusted hazard ratio for first hospitalization was 1.12 (1.04, 1.20). When multiple hospital events were considered, the adjusted risk ratio was 1.13 (1.02, 1.25) and the corresponding risk ratio for total hospital days was 1.20 (1.07, 1.35). High depressive affect score was generally associated with lower physical and mental component scores, but these covariates were adjusted for in the models. CONCLUSIONS: Depressive affect in incident hemodialysis patients was associated with higher risk of hospitalization and more hospital days. Future studies are needed to investigate the effect of therapeutic interventions to address depressive affect in this high risk population. PMID- 25278548 TI - Associations of self-reported physical activity types and levels with quality of life, depression symptoms, and mortality in hemodialysis patients: the DOPPS. AB - BACKGROUND AND OBJECTIVES: Physical activity has been associated with better health status in diverse populations, but the association in patients on maintenance hemodialysis is less established. Patient-reported physical activities and associations with mortality, health-related quality of life, and depression symptoms in patients on maintenance hemodialysis in 12 countries were examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 5763 patients enrolled in phase 4 of the Dialysis Outcomes and Practice Patterns Study (2009 2011) were classified into five aerobic physical activity categories (never/rarely active to very active) and by muscle strength/flexibility activity using the Rapid Assessment of Physical Activity questionnaire. The Kidney Disease Quality of Life scale was used for health-related quality of life. The Center for Epidemiologic Studies Depression scale was used for depression symptoms. Linear regression was used for associations of physical activity with health-related quality of life and depression symptoms scores. Cox regression was used for association of physical activity with mortality. RESULTS: The median (interquartile range) of follow-up was 1.6 (0.9-2.5) years; 29% of patients were classified as never/rarely active, 20% of patients were classified as very active, and 20.5% of patients reported strength/flexibility activities. Percentages of very active patients were greater in clinics offering exercise programs. Aerobic activity, but not strength/flexibility activity, was associated positively with health-related quality of life and inversely with depression symptoms and mortality (adjusted hazard ratio of death for very active versus never/rarely active, 0.60; 95% confidence interval, 0.47 to 0.77). Similar associations with aerobic activity were observed in strata of age, sex, time on dialysis, and diabetes status. CONCLUSIONS: The findings are consistent with the health benefits of aerobic physical activity for patients on maintenance hemodialysis. Greater physical activity was observed in facilities providing exercise programs, suggesting a possible opportunity for improving patient outcomes. PMID- 25278549 TI - Stone composition as a function of age and sex. AB - BACKGROUND AND OBJECTIVES: Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (>=50%) calcium oxalate, or majority (>=50%) hydroxyapatite. RESULTS: Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones were the most common type of stone overall, hydroxyapatite stones were the second most common before age 55 years, whereas uric acid stones were the second most common after age 55 years. More calcium oxalate and uric acid stones were submitted in the summer months (July and August; P<0.001), whereas the season did not influence other stone types. CONCLUSIONS: It is well known that calcium oxalate stones are the most common stone type. However, age and sex have a marked influence on the type of stone formed. The higher number of stones submitted by women compared with men between the ages of 10 and 29 years old and the change in composition among the elderly favoring uric acid have not been widely appreciated. These data also suggest increases in stone risk during the summer, although this is restricted to calcium oxalate and uric acid stones. PMID- 25278550 TI - The evolving role of the medical director of a dialysis facility. AB - The medical director has been a part of the fabric of Medicare's ESRD program since entitlement was extended under Section 299I of Public Law 92-603, passed on October 30, 1972, and implemented with the Conditions for Coverage that set out rules for administration and oversight of the care provided in the dialysis facility. The role of the medical director has progressively increased over time to effectively extend to the physicians serving in this role both the responsibility and accountability for the performance and reliability related to the care provided in the dialysis facility. This commentary provides context to the nature and expected competencies and behaviors of these medical director roles that remain central to the delivery of high-quality, safe, and efficient delivery of RRT, which has become much more intensive as the dialysis industry has matured. PMID- 25278551 TI - Nondisease-specific problems and all-cause mortality among older adults with CKD: the REGARDS Study. AB - BACKGROUND AND OBJECTIVES: The term "nondisease-specific" has been used to describe problems that cross multiple domains of health and are not necessarily the result of a single underlying disease. Although individuals with reduced eGFR and elevated albumin-to-creatinine ratio have many comorbidities, the prevalence of and outcomes associated with nondisease-specific problems have not been well studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants included 3557 black and white United States adults >=75 years of age from the Reasons for Geographic and Racial Differences in Stroke Study. Nondisease-specific problems included cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy. Hazard ratios for mortality over a median (interquartile range) of 5.4 (4.2-6.9) years of follow-up associated with one, two, or three to six nondisease-specific problems were calculated and stratified by eGFR (>=60, 45-59, and <45 ml/min per 1.73 m(2)) and separately, albumin-to creatinine ratio (<30, 30-299, and >=300 mg/g). Secondary outcomes included hospitalizations and emergency department visits over 1.8 (0.7-4.0) and 2.3 (0.9 4.7) years of follow-up, respectively. RESULTS: The prevalence of nondisease specific problems was more common at lower eGFR and higher albumin-to-creatinine ratio levels. Within each eGFR and albumin-to-creatinine ratio strata, the risk for mortality was higher among those with a greater number of nondisease-specific problems. For example, among those with an eGFR=45-59 ml/min per 1.73 m(2), the multivariable adjusted hazard ratios (95% confidence intervals) for mortality associated with one, two, or three to six nondisease-specific problems were 1.17 (0.78 to 1.76), 1.95 (1.24 to 3.07), and 2.44 (1.39 to 4.27; P trend <0.001). Risk for hospitalization and emergency department visits was higher among those with more nondisease-specific problems within eGFR and albumin-to-creatinine ratio strata. CONCLUSIONS: Among older adults, nondisease-specific problems commonly co-occur with reduced eGFR and elevated albumin-to-creatinine ratio. Identification of nondisease-specific problems may provide mortality risk information independent of measures of kidney function. PMID- 25278553 TI - A high-throughput siRNA screen identifies genes that regulate mannose 6-phosphate receptor trafficking. AB - The delivery of newly synthesized soluble lysosomal hydrolases to the endosomal system is essential for lysosome function and cell homeostasis. This process relies on the proper trafficking of the mannose 6-phosphate receptors (MPRs) between the trans-Golgi network (TGN), endosomes and the plasma membrane. Many transmembrane proteins regulating diverse biological processes ranging from virus production to the development of multicellular organisms also use these pathways. To explore how cell signaling modulates MPR trafficking, we used high-throughput RNA interference (RNAi) to target the human kinome and phosphatome. Using high content image analysis, we identified 127 kinases and phosphatases belonging to different signaling networks that regulate MPR trafficking and/or the dynamic states of the subcellular compartments encountered by the MPRs. Our analysis maps the MPR trafficking pathways based on enzymes regulating phosphatidylinositol phosphate metabolism. Furthermore, it reveals how cell signaling controls the biogenesis of post-Golgi tubular carriers destined to enter the endosomal system through a SRC-dependent pathway regulating ARF1 and RAC1 signaling and myosin II activity. PMID- 25278552 TI - Identification of molecular heterogeneity in SNX27-retromer-mediated endosome-to plasma-membrane recycling. AB - Retromer is a protein assembly that orchestrates the sorting of transmembrane cargo proteins into endosome-to-Golgi and endosome-to-plasma-membrane transport pathways. Here, we have employed quantitative proteomics to define the interactome of human VPS35, the core retromer component. This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3) and VPS9-ankyrin-repeat protein (VARP, also known as ANKRD27). Depletion of these proteins resulted in trafficking defects of retromer-dependent cargo, but differential and cargo specific effects suggested a surprising degree of functional heterogeneity in retromer-mediated endosome-to-plasma-membrane sorting. Extending this, suppression of the retromer-associated WASH complex did not uniformly affect retromer cargo, thereby confirming cargo-specific functions for retromer interacting proteins. Further analysis of the retromer-VARP interaction identified a role for retromer in endosome-to-melanosome transport. Suppression of VPS35 led to mistrafficking of the melanogenic enzymes, tyrosinase and tryrosine-related protein 1 (Tyrp1), establishing that retromer acts in concert with VARP in this trafficking pathway. Overall, these data reveal hidden complexities in retromer-mediated sorting and open up new directions in our molecular understanding of this essential sorting complex. PMID- 25278554 TI - Crossover formation during rice meiosis relies on interaction of OsMSH4 and OsMSH5. AB - MSH4 encodes a MutS protein that plays a specialized role in meiosis. In eukaryotic species, such as budding yeast, mice, Caenorhabditis elegans, and Arabidopsis, msh4 mutants display meiotic defects with a reduced number of chiasmata. Here, we characterized rice MSH4 by map-based cloning. In Osmsh4 mutants, the chiasma frequency was dramatically decreased to ~10% of the wild type, but the synaptonemal complex was normally installed. The double mutant analysis showed that in the Osmsh4 Osmsh5 mutant, the reduction of chiasmata was greater than other zmm mutants. This was consistent with the absence of localization for OsZIP4 and OsMER3 in Osmsh4 and suggests an earlier role for OsMSH4 and OsMSH5 than other ZMM proteins where they may be required to stabilize progenitor Holliday junctions. Using yeast two-hybrid and pull-down assays, we verified the direct physical association between OsMSH4 and OsMSH5 and OsMSH5 and HEI10 in plants for the first time. The MSH4-MSH5 heterodimer has been demonstrated in mammals to stabilize the formation of progenitor and double Holliday junctions that may be resolved as crossovers (COs). We propose that OsMSH4 interacts with OsMSH5 to promote formation of the majority of COs in rice. PMID- 25278555 TI - A multivariate analysis of genetic constraints to life history evolution in a wild population of red deer. AB - Evolutionary theory predicts that genetic constraints should be widespread, but empirical support for their existence is surprisingly rare. Commonly applied univariate and bivariate approaches to detecting genetic constraints can underestimate their prevalence, with important aspects potentially tractable only within a multivariate framework. However, multivariate genetic analyses of data from natural populations are challenging because of modest sample sizes, incomplete pedigrees, and missing data. Here we present results from a study of a comprehensive set of life history traits (juvenile survival, age at first breeding, annual fecundity, and longevity) for both males and females in a wild, pedigreed, population of red deer (Cervus elaphus). We use factor analytic modeling of the genetic variance-covariance matrix ( G: ) to reduce the dimensionality of the problem and take a multivariate approach to estimating genetic constraints. We consider a range of metrics designed to assess the effect of G: on the deflection of a predicted response to selection away from the direction of fastest adaptation and on the evolvability of the traits. We found limited support for genetic constraint through genetic covariances between traits, both within sex and between sexes. We discuss these results with respect to other recent findings and to the problems of estimating these parameters for natural populations. PMID- 25278556 TI - Increased prevalence of posttraumatic stress disorder in patients after transient ischemic attack. AB - BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) involves temporary neurological symptoms but leaves a patient symptom-free. Patients are faced with an increased risk for future stroke, and the manifestation of the TIA itself might be experienced as traumatizing. We aimed to investigate the prevalence of posttraumatic stress disorder (PTSD) after TIA and its relation to patients' psychosocial outcome. METHODS: Patients with TIA were prospectively studied, and 3 months after the diagnosis, PTSD, anxiety, depression, quality of life, coping strategies, and medical knowledge were assessed via self-rating instruments. RESULTS: Of 211 patients with TIA, data of 108 patients were complete and only those are reported. Thirty-two (29.6%) patients were classified as having PTSD. This rate is 10* as high as in the general German population. Patients with TIA with PTSD were more likely to show signs of anxiety and depression. PTSD was associated with the use of maladaptive coping strategies, subjectively rated high stroke risk, as well as with younger age. Finally, PTSD and anxiety were associated with decreased mental quality of life. CONCLUSIONS: The experience of TIA increases the risk for PTSD and associated anxiety, depression, and reduced mental quality of life. Because a maladaptive coping style and a subjectively overestimated stroke risk seem to play a crucial role in this adverse progression, the training of adaptive coping strategies and cautious briefing about the realistic stroke risk associated with TIA might be a promising approach. Despite the great loss of patients to follow-up, the results indicate that PTSD after TIA requires increased attention. PMID- 25278558 TI - Posttraumatic stress disorder after cerebrovascular events: broadening the landscape of psychological assessment in stroke and transient ischemic attack. PMID- 25278559 TI - Quantitative T2'-mapping in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Quantitative T2'-mapping detects regional changes in the relation of oxygenated and deoxygenated haemoglobine and might reflect areas with increased oxygen extraction. T2'-mapping in conjunction with an elaborate algorithm for motion correction was performed in patients with acute large-vessel stroke, and quantitative T2'-values were determined within the diffusion-weighted imaging lesion and perfusion-restricted tissue. METHODS: Eleven patients (median age, 71 years) with acute middle cerebral or internal carotid artery occlusion underwent MRI before scheduled endovascular treatment. MR-examination included diffusion- and perfusion-weighted imaging and quantitative, motion-corrected mapping of T2'. Time-to-peak maps were thresholded for different degrees of perfusion delays (eg, >=0 s, >= 2s) when compared with a reference time-to-peak value from healthy contralateral tissue. Mean T2'-values in areas with reduced apparent diffusion coefficient and in areas with impaired perfusion were compared with T2'-values in corresponding contralateral areas. RESULTS: Median time between symptom onset and MRI was 238 minutes. T2'-values were significantly reduced within the apparent diffusion coefficient -lesion when compared with contralateral healthy tissue (83 ms [67, 97] versus 97 ms [91, 111]; P<0.003). In perfusion-restricted tissue, T2'-values were also significantly lower when compared with contralateral healthy tissue (ie, for time to peak, >=0 s 93 ms [86, 102] versus 104 [90, 110]; P=0.008) but were significantly higher than within the apparent diffusion coefficient lesion. The severity of the perfusion impairment had no influence on median T2'-values. CONCLUSIONS: Motion-corrected T2'-mapping reveals significant and gradually declining values from healthy to perfusion-disturbed to apparent diffusion coefficient-restricted tissue. Current T2'-mapping can differentiate between the ischemic core and the perfusion impaired areas but not on its own between penumbral and oligemic tissue. PMID- 25278557 TI - RNF213 rare variants in an ethnically diverse population with Moyamoya disease. AB - BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States. METHODS: We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families. RESULTS: RNF213 p.R4810K was identified in 56% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant. CONCLUSIONS: These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD. PMID- 25278560 TI - Desulfoprunum benzoelyticum gen. nov., sp. nov., a Gram-stain-negative, benzoate degrading, sulfate-reducing bacterium isolated from a wastewater treatment plant. AB - A strictly anaerobic, mesophilic, sulfate-reducing bacterium, strain KoBa311(T), isolated from the wastewater treatment plant at Konstanz, Germany, was characterized phenotypically and phylogenetically. Cells were Gram-stain negative, non-motile, oval to short rods, 3-5 um long and 0.8-1.0 um wide with rounded ends, dividing by binary fission and occurring singly or in pairs. The strain grew optimally in freshwater medium and the optimum temperature was 30 degrees C. Strain KoBa311(T) showed optimum growth at pH 7.3-7.6. Organic electron donors were oxidized completely to carbon dioxide concomitant with sulfate reduction to sulfide. At excess substrate supply, substrates were oxidized incompletely and acetate (mainly) and/or propionate accumulated. The strain utilized short-chain fatty acids, alcohols (except methanol) and benzoate. Sulfate and DMSO were used as terminal electron acceptors for growth. The genomic DNA G+C content was 52.3 mol% and the respiratory quinone was menaquinone MK-5 (V H2). The major fatty acids were C16:0, C16:1omega7c/omega6c and C18:1omega7c. Phylogenetic analysis based on 16S rRNA gene sequences placed strain KoBa311(T) within the family Desulfobulbaceae in the class Deltaproteobacteria. Its closest related bacterial species on the basis of the distance matrix were Desulfobacterium catecholicum DSM 3882(T) (93.0% similarity), Desulfocapsa thiozymogenes (93.1%), Desulforhopalus singaporensis (92.9%), Desulfopila aestuarii (92.4%), Desulfopila inferna JS_SRB250Lac(T) (92.3%) and Desulfofustis glycolicus (92.3%). On the basis of phylogenetic, physiological and chemotaxonomic characteristics, strain KoBa311(T) was distinct from any related type species. Therefore, strain KoBa311(T) is considered to represent a novel species of a new genus, for which the name Desulfoprunum benzoelyticum gen. nov., sp. nov. is proposed. The type strain of Desulfoprunum benzoelyticum is KoBa311(T) ( =DSM 28570(T) =KCTC 15441(T)). PMID- 25278561 TI - Sulfitobacter pseudonitzschiae sp. nov., isolated from the toxic marine diatom Pseudo-nitzschia multiseries. AB - A taxonomic study was carried out on bacterial strain H3(T), which was isolated from the toxic marine diatom Pseudo-nitzschia multiseries. Cells of strain H3(T) were Gram-stain-negative, rod-shaped, non-motile and capable of reducing nitrate to nitrite, but not denitrification. Growth was observed at NaCl concentrations of 1-9%, pH 6-12 and 10-37 degrees C. It was unable to degrade aesculin or gelatin. The dominant fatty acids (>10 %) were C18:1omega7c/omega6c (summed feature 8) and C16:0. The respiratory ubiquinone was Q10. The major lipids were phosphatidylethanolamine, phosphatidylglycerol, an aminolipid and one unknown lipid, and the minor lipids were two phospholipids and three unknown lipids. The G+C content of the chromosomal DNA was 61.7 mol%. 16S rRNA gene sequence comparison showed that strain H3(T) was related most closely to Sulfitobacter donghicola DSW-25(T) (97.3% similarity) and levels of similarity with other species of the genus Sulfitobacter were 95.1-96.9%. The mean (+/- sd) DNA-DNA hybridization value between strain H3(T) and Sulfitobacter donghicola DSW-25(T) was 18.0 +/- 2.25%. The average nucleotide identity between strain H3(T) and Sulfitobacter donghicola DSW-25(T) was 70.45%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain H3(T) formed a separate clade close to the genus Sulfitobacter and was distinguishable from phylogenetically related species by differences in several phenotypic properties. On the basis of the phenotypic and phylogenetic data, strain H3(T) represents a novel species of the genus Sulfitobacter, for which the name Sulfitobacter pseudonitzschiae is proposed (type strain H3(T) =DSM 26824(T) =MCCC 1A00686(T)). PMID- 25278562 TI - Platelet microparticles are not created equal. PMID- 25278563 TI - A key to the quest? PMID- 25278564 TI - PP2A inactivation by ROS accumulation. PMID- 25278565 TI - The SOX11-PDGFA axis in mantle cell lymphoma. PMID- 25278566 TI - Platelet 12-LOX scores a HIT. PMID- 25278567 TI - Less Jak2 makes more platelets. PMID- 25278568 TI - Exosome complex and erythropoiesis. PMID- 25278569 TI - Warfarin pharmacogenetics: it matters if you're black or white. PMID- 25278570 TI - Population-based epidemiology and microbiology of community-onset bloodstream infections. AB - Bloodstream infection (BSI) is a major cause of infectious disease morbidity and mortality worldwide. While a positive blood culture is mandatory for establishment of the presence of a BSI, there are a number of determinants that must be considered for establishment of this entity. Community-onset BSIs are those that occur in outpatients or are first identified <48 h after admission to hospital, and they may be subclassified further as health care associated, when they occur in patients with significant prior health care exposure, or community associated, in other cases. The most common causes of community-onset BSI include Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrobial-resistant organisms, including methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase/metallo-beta-lactamase/carbapenemase producing Enterobacteriaceae, have emerged as important etiologies of community onset BSI. PMID- 25278571 TI - Controlling hospital-acquired infection: focus on the role of the environment and new technologies for decontamination. AB - There is increasing interest in the role of cleaning for managing hospital acquired infections (HAI). Pathogens such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), multiresistant Gram negative bacilli, norovirus, and Clostridium difficile persist in the health care environment for days. Both detergent- and disinfectant-based cleaning can help control these pathogens, although difficulties with measuring cleanliness have compromised the quality of published evidence. Traditional cleaning methods are notoriously inefficient for decontamination, and new approaches have been proposed, including disinfectants, steam, automated dispersal systems, and antimicrobial surfaces. These methods are difficult to evaluate for cost effectiveness because environmental data are not usually modeled against patient outcome. Recent studies have reported the value of physically removing soil using detergent, compared with more expensive (and toxic) disinfectants. Simple cleaning methods should be evaluated against nonmanual disinfection using standardized sampling and surveillance. Given worldwide concern over escalating antimicrobial resistance, it is clear that more studies on health care decontamination are required. Cleaning schedules should be adapted to reflect clinical risk, location, type of site, and hand touch frequency and should be evaluated for cost versus benefit for both routine and outbreak situations. Forthcoming evidence on the role of antimicrobial surfaces could supplement infection prevention strategies for health care environments, including those targeting multidrug-resistant pathogens. PMID- 25278573 TI - Microbiological features and clinical relevance of new species of the genus Mycobacterium. AB - Nontuberculous mycobacteria (NTM) are present in the environment, mainly in water, and are occasionally responsible for opportunistic infections in humans. Despite the fact that NTM are characterized by a moderate pathogenicity, the diseases caused by NTM at various body sites are increasing on a worldwide level. Among over 150 officially recognized NTM species, only two or three dozen are familiar to clinicians, and even to most microbiologists. In this paper, approximately 50 new species described in the last 8 years are reviewed, and their role in human infections is assessed on the basis of reported clinical cases. The small number of reports concerning most of the "new" mycobacterial species is responsible for the widespread conviction that they are very rare. Their role is actually largely underestimated, mainly because they often remain unrecognized and misidentified. Aiming to minimize such bias, emphasis has been placed on more common identification pitfalls. Together with new NTM, new members of the Mycobacterium tuberculosis complex described in the last few years are also an object of the present review. PMID- 25278575 TI - Emerging technologies for the clinical microbiology laboratory. AB - In this review we examine the literature related to emerging technologies that will help to reshape the clinical microbiology laboratory. These topics include nucleic acid amplification tests such as isothermal and point-of-care molecular diagnostics, multiplexed panels for syndromic diagnosis, digital PCR, next generation sequencing, and automation of molecular tests. We also review matrix assisted laser desorption ionization-time of flight (MALDI-TOF) and electrospray ionization (ESI) mass spectrometry methods and their role in identification of microorganisms. Lastly, we review the shift to liquid-based microbiology and the integration of partial and full laboratory automation that are beginning to impact the clinical microbiology laboratory. PMID- 25278572 TI - Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. AB - The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis. PMID- 25278574 TI - Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients. AB - Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced. PMID- 25278578 TI - Microbiology, genomics, and clinical significance of the Pseudomonas fluorescens species complex, an unappreciated colonizer of humans. AB - Pseudomonas fluorescens is not generally considered a bacterial pathogen in humans; however, multiple culture-based and culture-independent studies have identified it at low levels in the indigenous microbiota of various body sites. With recent advances in comparative genomics, many isolates originally identified as the "species" P. fluorescens are now being reclassified as novel Pseudomonas species within the P. fluorescens "species complex." Although most widely studied for its role in the soil and the rhizosphere, P. fluorescens possesses a number of functional traits that provide it with the capability to grow and thrive in mammalian hosts. While significantly less virulent than P. aeruginosa, P. fluorescens can cause bacteremia in humans, with most reported cases being attributable either to transfusion of contaminated blood products or to use of contaminated equipment associated with intravenous infusions. Although not suspected of being an etiologic agent of pulmonary disease, there are a number of reports identifying it in respiratory samples. There is also an intriguing association between P. fluorescens and human disease, in that approximately 50% of Crohn's disease patients develop serum antibodies to P. fluorescens. Altogether, these reports are beginning to highlight a far more common, intriguing, and potentially complex association between humans and P. fluorescens during health and disease. PMID- 25278584 TI - How I treat polycythemia vera. AB - Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with JAK2 mutations (V617F or exon 12) in almost all cases. The World Health Organization has defined the criteria for diagnosis, but it is still unclear which parameter (hemoglobin or hematocrit) is the most reliable for demonstrating increased red cell volume and for monitoring response to therapy; also, the role of bone marrow biopsy is being revisited. PV is associated with reduced survival because of cardiovascular complications and progression to post-PV myelofibrosis or leukemia. Criteria for risk-adapted treatment rely on the likelihood of thrombosis. Controlled trials have demonstrated that incidence of cardiovascular events is reduced by sustained control of hematocrit with phlebotomies (low-risk patients) and/or cytotoxic agents (high-risk patients) and antiplatelet therapy with aspirin. Hydroxyurea and interferon may be used as first-line treatments, whereas busulfan is reserved for patients that are refractory or resistant to first-line agents. However, there is no evidence that therapy improves survival, and the significance of reduction of JAK2 mutated allele burden produced by interferon is unknown. PV is also associated with a plethora of symptoms that are poorly controlled by conventional therapy. This article summarizes my approach to the management of PV in daily clinical practice. PMID- 25278586 TI - Building agricultural research. PMID- 25278581 TI - Clinical microbiology informatics. AB - The clinical microbiology laboratory has responsibilities ranging from characterizing the causative agent in a patient's infection to helping detect global disease outbreaks. All of these processes are increasingly becoming partnered more intimately with informatics. Effective application of informatics tools can increase the accuracy, timeliness, and completeness of microbiology testing while decreasing the laboratory workload, which can lead to optimized laboratory workflow and decreased costs. Informatics is poised to be increasingly relevant in clinical microbiology, with the advent of total laboratory automation, complex instrument interfaces, electronic health records, clinical decision support tools, and the clinical implementation of microbial genome sequencing. This review discusses the diverse informatics aspects that are relevant to the clinical microbiology laboratory, including the following: the microbiology laboratory information system, decision support tools, expert systems, instrument interfaces, total laboratory automation, telemicrobiology, automated image analysis, nucleic acid sequence databases, electronic reporting of infectious agents to public health agencies, and disease outbreak surveillance. The breadth and utility of informatics tools used in clinical microbiology have made them indispensable to contemporary clinical and laboratory practice. Continued advances in technology and development of these informatics tools will further improve patient and public health care in the future. PMID- 25278576 TI - Pathogenesis of human diffusely adhering Escherichia coli expressing Afa/Dr adhesins (Afa/Dr DAEC): current insights and future challenges. AB - The pathogenicity and clinical pertinence of diffusely adhering Escherichia coli expressing the Afa/Dr adhesins (Afa/Dr DAEC) in urinary tract infections (UTIs) and pregnancy complications are well established. In contrast, the implication of intestinal Afa/Dr DAEC in diarrhea is still under debate. These strains are age dependently involved in diarrhea in children, are apparently not involved in diarrhea in adults, and can also be asymptomatic intestinal microbiota strains in children and adult. This comprehensive review analyzes the epidemiology and diagnosis and highlights recent progress which has improved the understanding of Afa/Dr DAEC pathogenesis. Here, I summarize the roles of Afa/Dr DAEC virulence factors, including Afa/Dr adhesins, flagella, Sat toxin, and pks island products, in the development of specific mechanisms of pathogenicity. In intestinal epithelial polarized cells, the Afa/Dr adhesins trigger cell membrane receptor clustering and activation of the linked cell signaling pathways, promote structural and functional cell lesions and injuries in intestinal barrier, induce proinflammatory responses, create angiogenesis, instigate epithelial-mesenchymal transition-like events, and lead to pks-dependent DNA damage. UTI-associated Afa/Dr DAEC strains, following adhesin-membrane receptor cell interactions and activation of associated lipid raft-dependent cell signaling pathways, internalize in a microtubule-dependent manner within urinary tract epithelial cells, develop a particular intracellular lifestyle, and trigger a toxin dependent cell detachment. In response to Afa/Dr DAEC infection, the host epithelial cells generate antibacterial defense responses. Finally, I discuss a hypothetical role of intestinal Afa/Dr DAEC strains that can act as "silent pathogens" with the capacity to emerge as "pathobionts" for the development of inflammatory bowel disease and intestinal carcinogenesis. PMID- 25278588 TI - Infectious diseases. When Ebola protection fails. PMID- 25278579 TI - Emerging and reemerging neglected tropical diseases: a review of key characteristics, risk factors, and the policy and innovation environment. AB - In global health, critical challenges have arisen from infectious diseases, including the emergence and reemergence of old and new infectious diseases. Emergence and reemergence are accelerated by rapid human development, including numerous changes in demographics, populations, and the environment. This has also led to zoonoses in the changing human-animal ecosystem, which are impacted by a growing globalized society where pathogens do not recognize geopolitical borders. Within this context, neglected tropical infectious diseases have historically lacked adequate attention in international public health efforts, leading to insufficient prevention and treatment options. This subset of 17 infectious tropical diseases disproportionately impacts the world's poorest, represents a significant and underappreciated global disease burden, and is a major barrier to development efforts to alleviate poverty and improve human health. Neglected tropical diseases that are also categorized as emerging or reemerging infectious diseases are an even more serious threat and have not been adequately examined or discussed in terms of their unique risk characteristics. This review sets out to identify emerging and reemerging neglected tropical diseases and explore the policy and innovation environment that could hamper or enable control efforts. Through this examination, we hope to raise awareness and guide potential approaches to addressing this global health concern. PMID- 25278585 TI - Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin alpha3beta1-dependent. AB - Integrin-mediated migration of neutrophils to infected tissue sites is vital for pathogen clearance and therefore host survival. Although beta2 integrins have been shown to mediate neutrophil transendothelial migration during systemic and local inflammation, relatively little information is available regarding neutrophil migration in sepsis beyond the endothelial cell layer. In this study, we report that integrin alpha3beta1 (VLA-3; CD49c/CD29) is dramatically upregulated on neutrophils isolated from both human septic patients and in mouse models of sepsis. Compared with the alpha3beta1 (low) granulocytes, alpha3beta1 (high) cells from septic animals displayed hyperinflammatory phenotypes. Administration of a alpha3beta1 blocking peptide and conditional deletion of alpha3 in granulocytes significantly reduced the number of extravasating neutrophils and improved survival in septic mice. In addition, expression of alpha3beta1 on neutrophils was associated with Toll-like receptor-induced inflammatory responses and cytokine productions. Thus, our results show that alpha3beta1 is a novel marker of tissue homing and hyperresponsive neutrophil subtypes in sepsis, and blocking of alpha3beta1 may represent a new therapeutic approach in sepsis treatment. PMID- 25278589 TI - Geoscience. Double-whammy tsunami? PMID- 25278590 TI - Planetary science. Intruder from the Oort cloud will graze Mars. PMID- 25278592 TI - Quantum mechanics. Breakthrough lost in coin toss? PMID- 25278591 TI - Virology. Early AIDS virus may have ridden Africa's rails. PMID- 25278580 TI - Cryptococcus gattii infections. AB - Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans, although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended. PMID- 25278593 TI - The littlest patient. PMID- 25278577 TI - Coagulase-negative staphylococci. AB - The definition of the heterogeneous group of coagulase-negative staphylococci (CoNS) is still based on diagnostic procedures that fulfill the clinical need to differentiate between Staphylococcus aureus and those staphylococci classified historically as being less or nonpathogenic. Due to patient- and procedure related changes, CoNS now represent one of the major nosocomial pathogens, with S. epidermidis and S. haemolyticus being the most significant species. They account substantially for foreign body-related infections and infections in preterm newborns. While S. saprophyticus has been associated with acute urethritis, S. lugdunensis has a unique status, in some aspects resembling S. aureus in causing infectious endocarditis. In addition to CoNS found as food associated saprophytes, many other CoNS species colonize the skin and mucous membranes of humans and animals and are less frequently involved in clinically manifested infections. This blurred gradation in terms of pathogenicity is reflected by species- and strain-specific virulence factors and the development of different host-defending strategies. Clearly, CoNS possess fewer virulence properties than S. aureus, with a respectively different disease spectrum. In this regard, host susceptibility is much more important. Therapeutically, CoNS are challenging due to the large proportion of methicillin-resistant strains and increasing numbers of isolates with less susceptibility to glycopeptides. PMID- 25278582 TI - Human astroviruses. AB - Human astroviruses (HAtVs) are positive-sense single-stranded RNA viruses that were discovered in 1975. Astroviruses infecting other species, particularly mammalian and avian, were identified and classified into the genera Mamastrovirus and Avastrovirus. Through next-generation sequencing, many new astroviruses infecting different species, including humans, have been described, and the Astroviridae family shows a high diversity and zoonotic potential. Three divergent groups of HAstVs are recognized: the classic (MAstV 1), HAstV-MLB (MAstV 6), and HAstV-VA/HMO (MAstV 8 and MAstV 9) groups. Classic HAstVs contain 8 serotypes and account for 2 to 9% of all acute nonbacterial gastroenteritis in children worldwide. Infections are usually self-limiting but can also spread systemically and cause severe infections in immunocompromised patients. The other groups have also been identified in children with gastroenteritis, but extraintestinal pathologies have been suggested for them as well. Classic HAstVs may be grown in cells, allowing the study of their cell cycle, which is similar to that of caliciviruses. The continuous emergence of new astroviruses with a potential zoonotic transmission highlights the need to gain insights on their biology in order to prevent future health threats. This review focuses on the basic virology, pathogenesis, host response, epidemiology, diagnostic assays, and prevention strategies for HAstVs. PMID- 25278594 TI - Hope in a mouse. PMID- 25278595 TI - Photochemistry. Hot molecules--off the beaten path. PMID- 25278596 TI - Geophysics. Seafloor secrets revealed. PMID- 25278597 TI - Ecology. How large predators manage the cost of hunting. PMID- 25278598 TI - Microbiology. How to survive being hot and inebriated. PMID- 25278599 TI - Physiology. Good barriers make good neighbors. PMID- 25278600 TI - Conservation. A double-edged sword for tropical forests. PMID- 25278601 TI - Immunology. A neighborhood watch upholds local immune protection. PMID- 25278602 TI - Psychology and economics. Progress in measuring subjective well-being. PMID- 25278605 TI - Photochemistry. Evidence for direct molecular oxygen production in CO2 photodissociation. AB - Photodissociation of carbon dioxide (CO2) has long been assumed to proceed exclusively to carbon monoxide (CO) and oxygen atom (O) primary products. However, recent theoretical calculations suggested that an exit channel to produce C + O2 should also be energetically accessible. Here we report the direct experimental evidence for the C + O2 channel in CO2 photodissociation near the energetic threshold of the C((3)P) + O2(X(3)Sigma(g)(-)) channel with a yield of 5 +/- 2% using vacuum ultraviolet laser pump-probe spectroscopy and velocity-map imaging detection of the C((3)PJ) product between 101.5 and 107.2 nanometers. Our results may have implications for nonbiological oxygen production in CO2-heavy atmospheres. PMID- 25278604 TI - HIV epidemiology. The early spread and epidemic ignition of HIV-1 in human populations. AB - Thirty years after the discovery of HIV-1, the early transmission, dissemination, and establishment of the virus in human populations remain unclear. Using statistical approaches applied to HIV-1 sequence data from central Africa, we show that from the 1920s Kinshasa (in what is now the Democratic Republic of Congo) was the focus of early transmission and the source of pre-1960 pandemic viruses elsewhere. Location and dating estimates were validated using the earliest HIV-1 archival sample, also from Kinshasa. The epidemic histories of HIV 1 group M and nonpandemic group O were similar until ~1960, after which group M underwent an epidemiological transition and outpaced regional population growth. Our results reconstruct the early dynamics of HIV-1 and emphasize the role of social changes and transport networks in the establishment of this virus in human populations. PMID- 25278606 TI - Marine geophysics. New global marine gravity model from CryoSat-2 and Jason-1 reveals buried tectonic structure. AB - Gravity models are powerful tools for mapping tectonic structures, especially in the deep ocean basins where the topography remains unmapped by ships or is buried by thick sediment. We combined new radar altimeter measurements from satellites CryoSat-2 and Jason-1 with existing data to construct a global marine gravity model that is two times more accurate than previous models. We found an extinct spreading ridge in the Gulf of Mexico, a major propagating rift in the South Atlantic Ocean, abyssal hill fabric on slow-spreading ridges, and thousands of previously uncharted seamounts. These discoveries allow us to understand regional tectonic processes and highlight the importance of satellite-derived gravity models as one of the primary tools for the investigation of remote ocean basins. PMID- 25278607 TI - Biofuels. Engineering alcohol tolerance in yeast. AB - Ethanol toxicity in the yeast Saccharomyces cerevisiae limits titer and productivity in the industrial production of transportation bioethanol. We show that strengthening the opposing potassium and proton electrochemical membrane gradients is a mechanism that enhances general resistance to multiple alcohols. The elevation of extracellular potassium and pH physically bolsters these gradients, increasing tolerance to higher alcohols and ethanol fermentation in commercial and laboratory strains (including a xylose-fermenting strain) under industrial-like conditions. Production per cell remains largely unchanged, with improvements deriving from heightened population viability. Likewise, up regulation of the potassium and proton pumps in the laboratory strain enhances performance to levels exceeding those of industrial strains. Although genetically complex, alcohol tolerance can thus be dominated by a single cellular process, one controlled by a major physicochemical component but amenable to biological augmentation. PMID- 25278608 TI - Biofuels. Altered sterol composition renders yeast thermotolerant. AB - Ethanol production for use as a biofuel is mainly achieved through simultaneous saccharification and fermentation by yeast. Operating at >=40 degrees C would be beneficial in terms of increasing efficiency of the process and reducing costs, but yeast does not grow efficiently at those temperatures. We used adaptive laboratory evolution to select yeast strains with improved growth and ethanol production at >=40 degrees C. Sequencing of the whole genome, genome-wide gene expression, and metabolic-flux analyses revealed a change in sterol composition, from ergosterol to fecosterol, caused by mutations in the C-5 sterol desaturase gene, and increased expression of genes involved in sterol biosynthesis. Additionally, large chromosome III rearrangements and mutations in genes associated with DNA damage and respiration were found, but contributed less to the thermotolerant phenotype. PMID- 25278609 TI - Mammalian energetics. Flexible energetics of cheetah hunting strategies provide resistance against kleptoparasitism. AB - Population viability is driven by individual survival, which in turn depends on individuals balancing energy budgets. As carnivores may function close to maximum sustained power outputs, decreased food availability or increased activity may render some populations energetically vulnerable. Prey theft may compromise energetic budgets of mesopredators, such as cheetahs and wild dogs, which are susceptible to competition from larger carnivores. We show that daily energy expenditure (DEE) of cheetahs was similar to size-based predictions and positively related to distance traveled. Theft at 25% only requires cheetahs to hunt for an extra 1.1 hour per day, increasing DEE by just 12%. Therefore, not all mesopredators are energetically constrained by direct competition. Other factors that increase DEE, such as those that increase travel, may be more important for population viability. PMID- 25278610 TI - Mammalian energetics. Instantaneous energetics of puma kills reveal advantage of felid sneak attacks. AB - Pumas (Puma concolor) live in diverse, often rugged, complex habitats. The energy they expend for hunting must account for this complexity but is difficult to measure for this and other large, cryptic carnivores. We developed and deployed a physiological SMART (species movement, acceleration, and radio tracking) collar that used accelerometry to continuously monitor energetics, movements, and behavior of free-ranging pumas. This felid species displayed marked individuality in predatory activities, ranging from low-cost sit-and-wait behaviors to constant movements with energetic costs averaging 2.3 times those predicted for running mammals. Pumas reduce these costs by remaining cryptic and precisely matching maximum pouncing force (overall dynamic body acceleration = 5.3 to 16.1g) to prey size. Such instantaneous energetics help to explain why most felids stalk and pounce, and their analysis represents a powerful approach for accurately forecasting resource demands required for survival by large, mobile predators. PMID- 25278612 TI - T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. AB - After an infection, pathogen-specific tissue-resident memory T cells (T(RM) cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create T(RM) cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how T(RM) cells provide such pathogen protection. Here, we demonstrate that activated T(RM) cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This "pathogen alert" allows skin T(RM) cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8(+) T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants. PMID- 25278611 TI - Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. AB - Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation. PMID- 25278613 TI - A detour for love. PMID- 25278614 TI - Bionanotechnology. Colloidal nanoparticles as advanced biological sensors. AB - Colloidal nanoparticle biosensors have received intense scientific attention and offer promising applications in both research and medicine. We review the state of the art in nanoparticle development, surface chemistry, and biosensing mechanisms, discussing how a range of technologies are contributing toward commercial and clinical translation. Recent examples of success include the ultrasensitive detection of cancer biomarkers in human serum and in vivo sensing of methyl mercury. We identify five key materials challenges, including the development of robust mass-scale nanoparticle synthesis methods, and five broader challenges, including the use of simulations and bioinformatics-driven experimental approaches for predictive modeling of biosensor performance. The resultant generation of nanoparticle biosensors will form the basis of high performance analytical assays, effective multiplexed intracellular sensors, and sophisticated in vivo probes. PMID- 25278615 TI - Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. AB - Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals emanating from the niche can act as self-renewal factors for stem cells in multiple mammalian tissues. Wnt proteins are lipid-modified, which constrains them to act as short-range cellular signals. The locality of Wnt signaling dictates that stem cells exiting the Wnt signaling domain differentiate, spatially delimiting the niche in certain tissues. In some instances, stem cells may act as or generate their own niche, enabling the self organization of patterned tissues. In this Review, we discuss the various ways by which Wnt operates in stem cell control and, in doing so, identify an integral program for tissue renewal and regeneration. PMID- 25278616 TI - Tracking cancer drugs in living cells by thermal profiling of the proteome. AB - The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity. PMID- 25278618 TI - Low-density plasma formation in aqueous biological media using sub-nanosecond laser pulses. AB - We demonstrate the formation of low- and high-density plasmas in aqueous media using sub-nanosecond laser pulses delivered at low numerical aperture (NA = 0.25). We observe two distinct regimes of plasma formation in deionized water, phosphate buffered saline, Minimum Essential Medium (MEM), and MEM supplemented with phenol red. Optical breakdown is first initiated in a low-energy regime and characterized by bubble formation without plasma luminescence with threshold pulse energies in the range of Ep ~ 4-5 MUJ, depending on media formulation. The onset of this regime occurs over a very narrow interval of pulse energies and produces small bubbles (Rmax = 2-20 MUm) due to a tiny conversion (eta < 0.01%) of laser energy to bubble energy EB. The lack of visible plasma luminescence, sharp energy onset, and low bubble energy conversion are all hallmarks of low density plasma (LDP) formation. At higher pulse energies (Ep = 11-20 MUJ), the process transitions to a second regime characterized by plasma luminescence and large bubble formation. Bubbles formed in this regime are 1-2 orders of magnitude larger in size [Formula: see text] due to a roughly two-order-of-magnitude increase in bubble energy conversion (eta ? 3%). These characteristics are consistent with high-density plasma formation produced by avalanche ionization and thermal runaway. Additionally, we show that supplementation of MEM with fetal bovine serum (FBS) limits optical breakdown to this high-energy regime. The ability to produce LDPs using sub-nanosecond pulses focused at low NA in a variety of cell culture media formulations without FBS can provide for cellular manipulation at high throughput with precision approaching that of femtosecond pulses delivered at high NA. PMID- 25278617 TI - Alcohol consumption and prevalence of human papillomavirus (HPV) infection among US men in the HPV in Men (HIM) study. AB - OBJECTIVES: Moderate alcohol consumption can impair host defence against viral infections. The objective of this cross-sectional analysis was to assess the association between alcohol intake and prevalent human papillomavirus (HPV) infection among US men enrolled in the HPV in Men (HIM) study using quantitative alcohol intake measured from a Food Frequency Questionnaire. METHODS: The HIM study is a prospective, multinational study of the natural history of HPV infection. For this report, we restricted our analyses to men from the US cohort (N = 1313). Samples from the corona of glans penis, penile shaft and scrotum were combined for HPV DNA testing. Self-reported alcohol intake was quantified by grams of alcohol intake per day. Multivariable prevalence ratios (mPRs) were used to assess the association between alcohol intake and HPV infections. RESULTS: Prevalent infections were significantly higher among men in the highest quartile of alcohol intake and multivariable models revealed that the highest quartile of alcohol intake was associated with significantly increased risks for any (mPR = 1.13; 95% CI 1.00 to 1.27) HPV types and oncogenic (mPR = 1.35; 95% CI 1.08 to 1.68) HPV types. The fourth quartile of alcohol intake was associated with elevated risks for prevalent HPV infection across all strata of number of sexual partners and among never-smokers and current smokers, but not among former smokers. CONCLUSIONS: These results demonstrate that high intake of alcohol is associated with an increased risk for prevalent HPV infections among men. The biological role that alcohol plays in genital HPV infection remains understudied and limited epidemiological data exist, especially among men. PMID- 25278619 TI - Pre-Column Derivatization HPLC Procedure for the Quantitation of Aluminium Chlorohydrate in Antiperspirant Creams Using Quercetin as Chromogenic Reagent. AB - This article describes the development and validation of a selective high performance liquid chromatography method that allows, after liquid-liquid extraction and pre-column derivatization reaction with quercetin, the quantification of aluminium chlorohydrate in antiperspirant creams. Chromatographic separation was achieved on an XTerra MS C18 analytical column (150 * 3.0 mm i.d., particle size 5 MUm) using a mobile phase of acetonitrile:water (15:85, v/v) containing 0.08 % trifluoroacetic acid at a flow rate of 0.30 mL min-1. Ultraviolet spectrophotometric detection at 415 nm was used. The assay was linear over a concentration range of 3.7-30.6 MUg mL-1 for aluminium with a limit of quantitation of 3.74 MUg mL-1. Quality control samples (4.4, 17.1 and 30.6 MUg mL-1) in five replicates from five different runs of analysis demonstrated intra-assay precision (% coefficient of variation <3.8 %), inter-assay precision (% coefficient of variation <5.4 %) and an overall accuracy (% recovery) between 96 and 101 %. The method was used to quantify aluminium in antiperspirant creams containing 11.0, 13.0 and 16.0 % (w/w) aluminium chlorohydrate, respectively. PMID- 25278620 TI - Transvaginal Ultrasound for Endometrial Carcinoma Screening - Current Evidence based Data. AB - The value of transvaginal ultrasound in gynaecological examinations is beyond dispute. But it is of particular forensic importance that the validity of this type of imaging with regard to the reliable detection of early-stage malignancy is properly understood. Vaginal ultrasound screening in asymptomatic patients for the early detection of endometrial carcinoma is not useful from a medical point of view, nor is it cost-efficient. However, even though the validity of transvaginal ultrasound for screening has currently not been proven, the method should still be an integral part of gynaecological examinations. PMID- 25278621 TI - Vaginal Vault Suspension at Hysterectomy for Prolapse - Myths and Facts, Anatomical Requirements, Fixation Techniques, Documentation and Cost Accounting. AB - Vaginal vault suspension during hysterectomy for prolapse is both a therapy for apical insufficiency and helps prevent recurrence. Numerous techniques exist, with different anatomical results and differing complications. The description of the different approaches together with a description of the vaginal vault suspension technique used at the Department for Urogynaecology at St. Hedwig Hospital could serve as a basis for reassessment and for recommendations by scientific associations regarding general standards. PMID- 25278622 TI - Normal Pressure Hydrocephalus as Cause of Urinary Incontinence - A Shunt for Incontinence. AB - Normal pressure hydrocephalus is a frequently missed clinical entity with the typical symptom triad of gait disturbance, urinary incontinence and dementia (Hakim's triad) and occurs mostly from the 6th decade of life onwards. Early therapy can lead to a complete reversal of the symptoms. The present case report is intended to draw attention to the clinical entity normal pressure hydrocephalus (NPH) since the afflicted patients often primarily consult a gynaecologist on account of the urinary bladder disorders. PMID- 25278623 TI - 18-Year-Old Woman with an Embryonal Rhabdomyosarcoma of the Uterus in Statu Nascendi. AB - Background: We report a case of an 18-year-old woman with an embryonal rhabdomyosarcoma in statu nascendi. Case: A fist-sized embryonal rhabdomyosarcoma of the uterus filling the vaginal vault was diagnosed in an adolescent with virgo intacta suffering from therapy resistant vaginal discharge, bleeding and bulging mass for six months. Further imaging revealed one suspicious pelvine lymph node. Excision of the tumour including the intracervical stalk was performed and followed by systemic multiagent chemotherapy. PET-CT scan presented a complete response after the third cycle. Histological complete response was shown by laparoscopic dissection of regional pelvic lymph nodes and curettage. Conclusion: Uterine Rhabdomyosarcoma should be considered as differential diagnosis of therapy resistant vaginal flour and bleeding in young women. Fertility-sparing therapy is possible in selected exceptional cases. PMID- 25278624 TI - Prenatal Foetal Non-invasive ECG instead of Doppler CTG - A Better Alternative? AB - Introduction: This study aimed to evaluate foetal signal quality obtained using an antenatal foetal ECG system (Monica 24TM) and compare it with Doppler ultrasound CTG monitoring (Corometrics(r) 250 series). Material and Methods: Seventy pregnant women (gestational age: between 20 + 0 weeks and 40 + 0 weeks) were examined using the Monica AN24TM system and also underwent Doppler CTG. The signal quality of both methods was compared and correlated with gestational age and pre-pregnancy body mass index (BMI). Results: Overall, ECG had a signal quality of 77.4 % and CTG had a signal quality of 73.1 % (p > 0.05). In gestational weeks (GW) 20-26, the signal quality of ECG was significantly better compared to that obtained with CTG (75.5 vs. 45.3 %; p = 0.003), while in GW 27 36, the signal quality was better with CTG (72.3 vs. 83.0 %, p = 0.001). No difference in signal quality was found between the two methods after the 37th GW (87.7 vs. 86.1 %; p > 0.05). CTG showed a statistically significant correlation with BMI (rho 0.25, p < 0.05) while ECG showed no such correlation. Conclusion: The use of non-invasive ECG is particularly indicated in the early weeks of pregnancy, while CTG offers superior results during the vernix period. There was no difference in signal quality after the vernix period. The signal quality with ECG was found to be independent of BMI, while the signal quality of CTG deteriorated with increasing BMI. PMID- 25278625 TI - Twin Birth Considering the Current Results of the "Twin Birth Study" AB - The rate of caesarean sections in multiple births has grown sharply worldwide. The reason for this may be the results of large retrospective cohort studies from the 1990s, which displayed an increased risk of mortality and morbidity, especially for the second twin, in the case of vaginal births. Multiple monocentric analyses have not been able to confirm this. As a prospective, multi centre randomised study, the Twin Birth Study published in 2013, in which 105 clinics in 25 countries took part, showed that, under optimum conditions, there was no difference in neonatal and maternal mortality and morbidity if the birth was planned to be vaginal or via caesarean. Detailed analyses, which would be helpful in choosing the type of birth method and obstetric management in the event of vaginal birth, have not previously been published. Retrospective studies must be referred to for this. PMID- 25278626 TI - Folate Metabolism and Human Reproduction. AB - Folate metabolism affects ovarian function, implantation, embryogenesis and the entire process of pregnancy. In addition to its well-established effect on the incidence of neural tube defects, associations have been found between reduced folic acid levels and increased homocysteine concentrations on the one hand, and recurrent spontaneous abortions and other complications of pregnancy on the other. In infertility patients undergoing IVF/ICSI treatment, a clear correlation was found between plasma folate concentrations and the incidence of dichorionic twin pregnancies. In patients supplemented with 0.4 mg/d folic acid undergoing ovarian hyperstimulation and oocyte pick-up, carriers of the MTHFR 677T mutation were found to have lower serum estradiol concentrations at ovulation and fewer oocytes could be retrieved from them. It appears that these negative effects can be compensated for in full by increasing the daily dose of folic acid to at least 0.8 mg. In carriers of the MTHFR 677TT genotype who receive appropriate supplementation, AMH concentrations were found to be significantly increased, which could indicate a compensatory mechanism. AMH concentrations in homozygous carriers of the MTHFR 677TT genotype could even be overestimated, as almost 20 % fewer oocytes are retrieved from these patients per AMH unit compared to MTHFR 677CC wild-type individuals. PMID- 25278628 TI - Establishment of the Certification System "Gynaecological Dysplasia" in Germany. AB - Gynaecological cancer centres have been established nationwide in Germany since 2008 according to the certification system of the German Cancer Society (Deutsche Krebsgesellschaft e. V. [DKG]) and the German Society for Gynaecology and Obstetrics (Deutsche Gesellschaft fur Gynakologie und Geburtshilfe e. V. [DGGG]). However, patient access to the certified gynaecological cancer centres is currently only possible through direct referrals. A longitudinal structure with the corresponding long-term documentation of both the high-grade precursors as well as the cancers does not exist as yet. According to the aims of the National Cancer Plan, a corresponding structure for the cancer entity "cervix carcinoma" should be established. The foundations for such a structure are appropriate diagnostic units that are responsible, after nationwide screening, for clarification according to guideline-conform principles. On the basis of the vote of the certification commission for gynaecological cancer centres under the chairmanship of the DKG, the Working Group for Gynaecological Oncology (Arbeitsgemeinschaft Gynakologische Onkologie e. V. [AGO]), the Committee on Cervical Pathology and Colposcopy (Arbeitsgemeinschaft Zervixpathologie & Kolposkopie [AG-CPC]) and the DGGG the certification system for gynaecological dysplasia has been established. As a general principle, a distinction is made between the certification of a consulting practice for gynaecological dysplasia and a gynaecological dysplasia facility in order to integrate both outpatient and inpatient health-care facilities into the certification system. In analogy to the further catalogue of requirements from the DKG, quantitative and qualitative minimum numbers are demanded. Furthermore, the requirements of the certification process include a summary of patient information, the applied guidelines, continuing and further training, interdisciplinary cooperation in tumour boards, contents or, respectively, procedure descriptions for consulting practices and the trial participations. Central components of the questionnaire are quality indicators that can be used as specific and measurable elements to evaluate the quality of treatment. After successful pilot certification, finalisation of the updated version of the questionnaire and a completed specialist auditor training course for the certification of gynaecological dysplasia, it will be possible to establish a nationwide treatment system for dysplasia within certified structures. PMID- 25278627 TI - Current and Future Status of Laparoscopy in Gynecologic Oncology. AB - Laparoscopy is playing an increasingly important role in gynecologic oncology. The benefits of minimally invasive surgery for oncology patients and the quality of this treatment are well documented. Outcomes and quality of minimally invasive surgical procedures to treat cervical cancer were evaluated based on retrospective and case-control studies; outcomes and quality after minimally invasive treatment fur early-stage low-risk endometrial cancer were also assessed in prospective randomized studies. If indicated, laparoscopic lymphadenectomy is both technically feasible and oncologically safe. Adipose patients in particular benefit from minimally invasive procedures, where feasible. The potential role of laparoscopy in neoadjuvant therapy for ovarian cancer and in surgery for early stage ovarian carcinoma is still controversially discussed and is currently being assessed in further studies. Using a minimally invasive approach in gynecologic oncology procedures demands strict adherence to oncological principles and requires considerable surgical skill. PMID- 25278629 TI - Quality Assurance for Patients with Breast Cancer - the Impact of Clinical Cancer Registries. AB - Introduction: Since 2000 all service providers in the German healthcare system are legally obliged to take part in quality assurance (QA) procedures as stipulated in Book Five of the German Social Code. Clinical cancer registries provide methodological tools to assess the quality of structures, processes and outcomes. The aim of this study was to analyze the consequences of guideline concordant treatment using two examples of quality indicators: endocrine therapy (adjuvant hormonal therapy, AHT) to treat patients with steroid hormone receptor (SHR)-positive breast cancer and trastuzumab therapy to treat patients with HER2 positive breast cancer. Material and Methods: Data from the Tumor Center Regensburg (Bavaria, Germany) included all female patients listed in the registry with primary, non-metastatic invasive breast cancer diagnosed between 2000 and 2012. Results: A total of 6164 patients with invasive breast cancer and known HER2 status were analyzed. 1134 patients (18.4 %) had HER2-positive and 5346 patients (86.7 %) had SHR-positive breast cancer. Premenopausal patients with HER2-positive breast cancer receiving trastuzumab had a 7-year OS rate of 93.8 % compared to 86.8 % of patients who did not receive trastuzumab (p = 0.079). Similarly, postmenopausal patients with HER2-positive breast cancer treated with trastuzumab had better 7-year OS rates (87.3 %) than patients who did not receive the antibody (76.7 %) (p < 0.001). Premenopausal patients with SHR-positive breast cancer receiving AHT had a 7-year OS rate of 95.2 % compared to 75.9 % of patients who did not receive AHT (p < 0.001). Equally, postmenopausal patients treated with AHT had a 7-year OS rate of 83.8 % compared to 64.1 % without AHT (p < 0.001). Conclusion: Clinical cancer registries depend on the cooperation of the various health service providers to generate data that are essential for QA for breast cancer patients. PMID- 25278630 TI - "Pregnant and Operating": Evaluation of a Germany-wide Survey Among Female Gynaecologists and Surgeons. AB - The current law on the protection of expectant and nursing mothers largely rules out surgical activities during pregnancy for female doctors who perform surgical roles in hospitals. The proportion of female junior staff in gynaecology amounts to 80 %, and, for many of these women, surgical further training is not possible following official notification of an existing pregnancy. In a Germany-wide survey of female gynaecologists and surgeons using a questionnaire, it was determined to what extent female doctors worked in surgery during pregnancy, whether it led to complications in the pregnancy, when the employer was notified about the pregnancy, and what desire for change there is with regard to the law on the protection of expectant and nursing mothers. The data from 164 female doctors, of which 136 are gynaecologists and 28 surgeons, was evaluated. On average, the pregnancy was announced during the 14th week of pregnancy (WOP), and the doctor was not allowed to perform surgical activities in the 21st WOP. Female doctors in higher professional roles tended to announce the pregnancy later and ended their surgical activities later. There was no link between the time of ceasing surgical activities and an increased occurrence of complaints or complications during the pregnancy. In total, only 53 % of respondents had an appraisal during pregnancy and 75 % wanted a change in the law on the protection of expectant and nursing mothers. PMID- 25278631 TI - Phase Diagrams of Instabilities in Compressed Film-Substrate Systems. AB - Subject to a compressive membrane stress, an elastic film bonded on a substrate can become unstable, forming wrinkles, creases or delaminated buckles. Further increasing the compressive stress can induce advanced modes of instabilities including period-doubles, folds, localized ridges, delamination, and coexistent instabilities. While various instabilities in film-substrate systems under compression have been analyzed separately, a systematic and quantitative understanding of these instabilities is still elusive. Here we present a joint experimental and theoretical study to systematically explore the instabilities in elastic film-substrate systems under uniaxial compression. We use the Maxwell stability criterion to analyze the occurrence and evolution of instabilities analogous to phase transitions in thermodynamic systems. We show that the moduli of the film and the substrate, the film-substrate adhesion strength, the film thickness, and the prestretch in the substrate determine various modes of instabilities. Defects in the film-substrate system can facilitate it to overcome energy barriers during occurrence and evolution of instabilities. We provide a set of phase diagrams to predict both initial and advanced modes of instabilities in compressed film-substrate systems. The phase diagrams can be used to guide the design of film-substrate systems to achieve desired modes of instabilities. PMID- 25278632 TI - Symmetries and the u-condition in Hom-Yetter-Drinfeld categories. AB - Let (H, S, alpha) be a monoidal Hom-Hopf algebra and [Formula: see text] the Hom Yetter-Drinfeld category over (H, alpha). Then in this paper, we first find sufficient and necessary conditions for [Formula: see text] to be symmetric and pseudosymmetric, respectively. Second, we study the u-condition in [Formula: see text] and show that the Hom-Yetter-Drinfeld module (H, adjoint, Delta, alpha) (resp., (H, m, coadjoint, alpha)) satisfies the u-condition if and only if S2 = id. Finally, we prove that [Formula: see text] over a triangular (resp., cotriangular) Hom-Hopf algebra contains a rich symmetric subcategory. PMID- 25278633 TI - An Asymmetric Organocatalytic Quadruple Cascade to Tetraaryl-Substituted 2 Azabicyclo[3.3.0]octadienones. AB - A new asymmetric organocatalytic three-component quadruple cascade of alpha ketoamides with alpha,beta-unsaturated aldehydes is described. The reaction is catalyzed by the (S)-diphenylprolinol TMS ether catalyst and proceeds via an aza Michael/aldol condensation/vinylogous Michael/aldol condensation sequence to yield tetraaryl-substituted 2-azabicyclo[3.3.0]octadienone derivatives. The cascade products are obtained with good to very good yields (34-71%), virtually complete diastereoselectivities (>20:1), and very good enantioselectivities (84 97%). PMID- 25278634 TI - Organocatalytic Asymmetric Synthesis of Functionalized 1,3,5-Triarylpyrrolidin-2 ones via an Aza-Michael/Aldol Domino Reaction. AB - The organocatalytic asymmetric synthesis of functionalized 1,3,5 triarylpyrrolidin-2-ones bearing three contiguous stereocenters through an aza Michael/aldol domino reaction of alpha-ketoamides with alpha,beta-unsaturated aldehydes is described. The domino products were further derivatized by aldehyde olefination under one-pot conditions. The reaction proceeds with excellent diastereoselectivities (>20:1) and good to excellent enantioselectivities (60-96% ee). PMID- 25278635 TI - Regioselectivity of Diels-Alder Reactions Between 6,7-Dehydrobenzofuran and 2 Substituted Furans. AB - We describe the first report of the generation of 6,7-dehydrobenzofuran (6,7 benzofuranyne) from 6,7-dihalobenzofurans via metal-halogen exchange and elimination, in a manner similar to our previous work with 6,7-indole arynes. This benzofuranyne undergoes highly regioselective Diels-Alder cycloadditions with 2-substituted furans. PMID- 25278636 TI - Total Synthesis of (+/-)-Cis-Trikentrin B via Intermolecular 6,7-Indole Aryne Cycloaddition and Stille Cross-Coupling. AB - An efficient total synthesis of the annulated indole natural product (+/-)-cis trikentrin B was accomplished by means of a regioselectively generated 6,7-indole aryne cycloaddition via selective metal-halogen exchange from a 5,6,7 tribromoindole. The unaffected C-5 bromine was subsequently used for a Stille cross-coupling to install the butenyl side chain and complete the synthesis. This strategy provides rapid access into the trikentrins and the related herbindoles, and represents another application of this methodology to natural products total synthesis. The required 5,6,7-indole aryne precursor was prepared using the Leimgruber-Batcho indole synthesis. PMID- 25278637 TI - Low Mass-Damping Vortex-Induced Vibrations of a Single Cylinder at Moderate Reynolds Number. AB - The feasibility and accuracy of large eddy simulation is investigated for the case of three-dimensional unsteady flows past an elastically mounted cylinder at moderate Reynolds number. Although these flow problems are unconfined, complex wake flow patterns may be observed depending on the elastic properties of the structure. An iterative procedure is used to solve the structural dynamic equation to be coupled with the Navier-Stokes system formulated in a pseudo Eulerian way. A moving mesh method is involved to deform the computational domain according to the motion of the fluid structure interface. Numerical simulations of vortex-induced vibrations are performed for a freely vibrating cylinder at Reynolds number 3900 in the subcritical regime under two low mass-damping conditions. A detailed physical analysis is provided for a wide range of reduced velocities, and the typical three-branch response of the amplitude behavior usually reported in the experiments is exhibited and reproduced by numerical simulation. PMID- 25278638 TI - Analytical Study of Cavitation Surge in a Hydraulic System. AB - In order to clarify effects of an accumulator, pipe lengths and gradients of pressure and suction performances on cavitation surge, one-dimensional stability analyses of cavitation surge were performed in hydraulic systems consisting of an upstream tank, an inlet pipe, a cavitating pump, a downstream pipe, and a downstream tank. An accumulator located upstream or downstream of the cavitating pump was included in the analysis. Increasing the distance between the upstream accumulator and the cavitating pump enlarged the stable region. On the other hand, decreasing the distance between the downstream accumulator and the cavitating pump enlarged the stable region. Furthermore, the negative gradient of a suction performance curve and the positive gradient of a pressure performance curve cause cavitation surge. PMID- 25278639 TI - Religiosity is negatively associated with later-life intelligence, but not with age-related cognitive decline. AB - A well-replicated finding in the psychological literature is the negative correlation between religiosity and intelligence. However, several studies also conclude that one form of religiosity, church attendance, is protective against later-life cognitive decline. No effects of religious belief per se on cognitive decline have been found, potentially due to the restricted measures of belief used in previous studies. Here, we examined the associations between religiosity, intelligence, and cognitive change in a cohort of individuals (initial n = 550) with high-quality measures of religious belief taken at age 83 and multiple cognitive measures taken in childhood and at four waves between age 79 and 90. We found that religious belief, but not attendance, was negatively related to intelligence. The effect size was smaller than in previous studies of younger participants. Longitudinal analyses showed no effect of either religious belief or attendance on cognitive change either from childhood to old age, or across the ninth decade of life. We discuss differences between our cohort and those in previous studies - including in age and location - that may have led to our non replication of the association between religious attendance and cognitive decline. PMID- 25278640 TI - Intelligence, creativity, and cognitive control: The common and differential involvement of executive functions in intelligence and creativity. AB - Intelligence and creativity are known to be correlated constructs suggesting that they share a common cognitive basis. The present study assessed three specific executive abilities - updating, shifting, and inhibition - and examined their common and differential relations to fluid intelligence and creativity (i.e., divergent thinking ability) within a latent variable model approach. Additionally, it was tested whether the correlation of fluid intelligence and creativity can be explained by a common executive involvement. As expected, fluid intelligence was strongly predicted by updating, but not by shifting or inhibition. Creativity was predicted by updating and inhibition, but not by shifting. Moreover, updating (and the personality factor openness) was found to explain a relevant part of the shared variance between intelligence and creativity. The findings provide direct support for the executive involvement in creative thought and shed further light on the functional relationship between intelligence and creativity. PMID- 25278642 TI - Response to Can the Study of Female Rats Help Our Understanding of Women? PMID- 25278643 TI - If The Sky Were The Limit, What Would You Do In Technology Transfer? PMID- 25278644 TI - The Birth of Social Intelligence. AB - The ability to make sense out of the actions of others is critical to people's daily functioning. Adults are social experts: They understand that people's actions are directed at goals and are driven by intentions. In this article, the authors highlight key findings from studies examining infants' understanding of human action. These findings suggest that infants come to understand that intentions and attention guide human action within the first few months of their lives. By 13 months, infants understand that intentions are specific to individuals, yet there are some actions that are shared by all individuals within a group. Taken together, the evidence suggests that infants are well on their way to becoming social experts by their second birthdays. PMID- 25278641 TI - Correlational structure of 'frontal' tests and intelligence tests indicates two components with asymmetrical neurostructural correlates in old age. AB - Both general fluid intelligence (gf) and performance on some 'frontal tests' of cognition decline with age. Both types of ability are at least partially dependent on the integrity of the frontal lobes, which also deteriorate with age. Overlap between these two methods of assessing complex cognition in older age remains unclear. Such overlap could be investigated using inter-test correlations alone, as in previous studies, but this would be enhanced by ascertaining whether frontal test performance and gf share neurobiological variance. To this end, we examined relationships between gf and 6 frontal tests (Tower, Self-Ordered Pointing, Simon, Moral Dilemmas, Reversal Learning and Faux Pas tests) in 90 healthy males, aged ~ 73 years. We interpreted their correlational structure using principal component analysis, and in relation to MRI-derived regional frontal lobe volumes (relative to maximal healthy brain size). gf correlated significantly and positively (.24 <= r <= .53) with the majority of frontal test scores. Some frontal test scores also exhibited shared variance after controlling for gf. Principal component analysis of test scores identified units of gf-common and gf-independent variance. The former was associated with variance in the left dorsolateral (DL) and anterior cingulate (AC) regions, and the latter with variance in the right DL and AC regions. Thus, we identify two biologically meaningful components of variance in complex cognitive performance in older age and suggest that age-related changes to DL and AC have the greatest cognitive impact. PMID- 25278645 TI - Practice-Based Knowledge Discovery for Comparative Effectiveness Research: An Organizing Framework. AB - Electronic health information systems can increase the ability of health-care organizations to investigate the effects of clinical interventions. The authors present an organizing framework that integrates outcomes and informatics research paradigms to guide knowledge discovery in electronic clinical databases. They illustrate its application using the example of hospital acquired pressure ulcers (HAPU). The Knowledge Discovery through Informatics for Comparative Effectiveness Research (KDI-CER) framework was conceived as a heuristic to conceptualize study designs and address potential methodological limitations imposed by using a single research perspective. Advances in informatics research can play a complementary role in advancing the field of outcomes research including CER. The KDI-CER framework can be used to facilitate knowledge discovery from routinely collected electronic clinical data. PMID- 25278646 TI - Experimental and Numerical Investigations of Effects of Flow Control Devices Upon Flat-Plate Film Cooling Performance. AB - This study deals with the experimental and numerical studies of the effect of flow control devices (FCDs) on the film cooling performance of a circular cooling hole on a flat plate. Two types of FCDs with different heights are examined in this study, where each of them is mounted to the flat plate upstream of the cooling hole by changing its lateral position with respect to the hole centerline. In order to measure the film effectiveness as well as heat transfer downstream of the cooling hole with upstream FCD, a transient method using a high resolution infrared camera is adopted. The velocity field downstream of the cooling hole is captured by 3D laser Doppler velocimeter (LDV). Furthermore, the aerodynamic loss associated with the cooling hole with/without FCD is measured by a total pressure probe rake. The experiments are carried out at blowing ratios ranging from 0.5 to 1.0. In addition, numerical simulations are also made to have a better understanding of the flow field. LES approach is employed to solve the flow field and visualize the vortex structure around the cooling hole with FCD. When a taller FCD is mounted to the plate, the film effectiveness tends to increase due to the vortex structure generated by the FCD. As FCD is laterally shifted from the centerline, the film effectiveness increases, while the lift-off of cooling air is also promoted when FCD is put on the center line. PMID- 25278647 TI - Review of 9 cases of diaphragmatic injury following blunt trauma chest; 3 years experience. AB - Diaphragmatic injuries can occur with both blunt and penetrating trauma which can be associated with herniation of abdominal viscera into the thoracic cavity. Diaphragmatic injuries can occur with blunt trauma chest in 1-7 % of patients. Retrospectively for last 3 years all cases blunt trauma chest admitted to surgery were reviewed and a study of cases of diaphragmatic rupture was done. We analysed 496 patients of blunt trauma chest retrospectively for period of three years. Nine patients have diaphragmatic injuries, all were males, six presented acutely three were chronic. In six patients laparotomy was done, four subcostal and two midline incisions were preferred. In chronic cases thoracotomy was done. Left sided injury predominates and rib fractures are most common associated finding. Diagnosis in majority of cases is made by Computerised tomography scan. Subcostal incision may be used in patients with isolated diaphragmatic injury in acute presentation while thoracotomy is preferred in late cases. Most common morbidity is pulmonary complications. PMID- 25278648 TI - Trends in trauma: a rural experience. AB - In last 20 years a progressive increase in the cases of road traffic accidents is seen in the institution. In this study efforts have been made to study epidemiology of trauma & how to help the trauma victims in a better way. To study the changing trends in incidence & presentation of trauma victims. To recommend preventive measures based on the analysis. The present study was carried out in MGIMS, Sewagram, Wardha from 2001 to 2003. For this study which is retrospective and prospective, a total of 986 cases of surgical trauma were studied. Present study showed that in this rural area accidents account for maximum trauma admissions & major trauma only in 20 %. Out of 986 patients, 78.8 % required repair of wounds, 3.8 % required exploratory laparotomy and 16.3 % had orthopedic interventions. Overall mortality rate was 2.9 %. It was found that general care in wards was good in terms of trauma results of rural areas. These results may vary when compared with specialized trauma centers in cities; however after a period of few years cost effectiveness of trauma centers in terms of benefits needs an assessment*. PMID- 25278649 TI - Interrupted abdominal closure prevents burst: randomized controlled trial comparing interrupted-x and conventional continuous closures in surgical and gynecological patients. AB - Reduction in the risk of abdominal dehiscence with application of interrupted method of laparotomy closure and comparison with risk of burst with continuous method of closure. Three hundred forty eight patients undergoing laparotomy (114 elective gynecology, 114-emergency gynecology, 120-emergency surgery) were randomized into three arms to undergo closure with continuous, interrupted-X, and Modified Smead-Jones suturing techniques. Burst abdomen occurring up to 4 weeks of operation. Twenty-nine (8.33 %) of 348 patients developed burst in the post operative period. 19 (15.70 %) of 121 patients in continuous arm developed burst. Five of 110 (4.55 %) patients in Interrupted-X arm and 5 of 117 (4.27 %) patients in Modified Smead-Jones arm developed burst. Interrupted suturing was associated with significant reduction in risk of burst when compared with continuous closure. Important predictors of burst were Intraperitoneal sepsis, cough, uremia, and surgical site infection. PMID- 25278650 TI - Clinical experience of frame ring utilization in applying interintestinal anastomoses in urgent surgery. AB - The problem of restoration of intestinal integrity preserves its importance as the intestinal suture is a basis for digestive tract surgery. Tightness failure in the intestinal suture during gastrointestinal surgery is a threatening and, unfortunately, frequent complication, and it gets especial importance in emergency patients and those with severe concomitant pathologies. The research is carried out on utilization of a metal frame ring in applying interintestinal anastomoses. Clinical utilization of the method developed was preceded with a series of experiments on animals with morphological researches with the use of the device. Seventy operations were performed with utilization of a frame metal ring during application of interintestinal anastomoses. After performing an operation, intestinal peristalsis restored faster. In the postoperative period, all patients undertook study of abdominal exudates to determine for early diagnostics of development of intestinal suture failure. In clinical practice, utilization of a frame ring is indicated in applying primary interintestinal anastomoses in adverse conditions, namely, peritonitis and intestinal obstruction. PMID- 25278651 TI - A comparative study of paediatric thermal burns treated with topical heparin and without heparin. AB - Following reports of heparin use in burn treatment, an ethics-committee-approved prospective randomized study with controls compared results obtained using traditional usual burn treatment without heparin with results in similar patients similarly treated with heparin added topically. The subjects were 100 consecutive burn patients (age <15 years) with second-degree superficial and deep burns of 5 45 % total body surface area size. Two largely similar cohort groups-a control group (C) and a heparin group (H) with 50 subjects per group-were randomly treated. The 50 control group patients received traditional routine treatment, including topical antimicrobial cream, debridement, and, when needed, skin grafts in the early postburn period. The 50 heparin group patients, without topical cream, were additionally treated, starting on day 1 postburn, with 200 IU/ml sodium aqueous heparin solution USP (heparin) dripped on the burn surfaces and inserted into the blisters two to four times a day for 1-2 days, and then only on burn surfaces for a total of 5-7 days, before skin grafting, when needed. Thereafter, control and heparin group treatment was similar. It was found that the heparin patients complained of less pain and received less pain medicine than the control patients. The heparin group needed fewer dressings and oral antibiotics than the control group. The 50 heparin group patients had 4 skin graftings (8 %), while the 50 control group patients had 10 (20 %). Five control group patients died (mortality 10 %). No heparin group patients died. The number of days in hospital for the heparin group versus control group was significantly less (overall P < 0.0001): 58 % of heparin group patients were discharged within 10 days versus 6 % of control group patients; 82 % of heparin group patients were out in 20 days versus 14 % of control group patients; 98 % of the heparin group versus 44 % of the control group were out in 30 days; and while 100 % of heparin group patients were discharged by day 40, 56 % of the control group required up to another 10 days. Burns in heparin group patients healed on average in 15 days (maximum period 37 days) versus an average of 25 days (maximum >48 days) in control group patients (P < 0.0006). Procedures and costs in the heparin group were much reduced compared with the control group. Differences between the heparin and control groups are presented for the sake of comparison. It was concluded that heparin applied topically for 5-7 days improved burn treatment: it reduced pain, pain medicine, dressings, and use of antibiotics; it significantly reduced IV fluids (P < 0.04), days in hospital (P < 0.0001), and healing time (P < 0.0006); and it reduced skin grafts, mortality, and costs. PMID- 25278652 TI - Anatomical variations of the profunda femoris artery and its branches-a cadaveric study in South Indian population. AB - The variations of the profunda and its branches are numerous, and, to a considerable extent, largely associated with one another. In occlusion of the Superficial femoral artery, the profunda femoris artery forms an effective collateral bed between the ileo-femoral segment and the popliteal artery and its branches. This study based on dissections performed on 40 properly embalmed human cadaver specimens. The position, source and the point of origin of the profunda and its circumflex branches were studied and compared with earlier literature. We found that profunda femoris was originated from the posterolateral surface of the common femoral artery with a mean distance of 3.56 cms from the midinguinal point. An absence of profunda femoris was noted in one (5 %) case. Medial circumflex femoral artery (in 40 % on right side and 60 % on left side) originated from the profunda femoris; whereas in 50 % on right and 35 % on left side, it begins from the femoral artery. On the otherhand, the lateral circumflex femoral in 80 % on right and 70 % on left sides sprungs from profunda femoris with 20 % and 25 % from common femoral arteries of right and left limb specimens respectively. Knowledge of variations in profunda femoris and its branches helps surgeons during preoperative clinical evaluation for surgical and interventional revascularization of the ileo-femoral and femoro-popliteal segments, in open canulation of femoral artery for cardiopulmonary bypasss, in radiological interventions for A-V malformations, and in salvage operations for traumatic limb ischemia. PMID- 25278653 TI - Differentiated thyroid cancer and pregnancy. AB - Thyroid cancer is second most common malignancy diagnosed during pregnancy. Differentiated thyroid cancer (DTC) is more common in reproductive age group due to its association with oestrogen and human chorionic gonadotropin. Evaluation and management of DTC has changed from an aggressive approach, now, to a more conservative approach. Management of DTC must be coordinated among the different specialists which include the surgeon, endocrinologist, radiologist, pathologist and, in pregnant patients, the obstetrician. Generally, DTC can be postponed till delivery, but exceptions include airway compromise, aggressive cytologic features, invasion of surrounding tissue, extracapsular spread and poor prognostic factors. PMID- 25278654 TI - Management of severe thoracic impalement trauma against two-wheeled horse carriage: a case report and literature review. AB - Thoracic injuries in general are of great importance due to their high incidence and high mortality. Thoracic impalement injuries are rare but severe due to the combination of cause, effect and result. This study's primary objective is to report the case of a young man who was impaled by a two-wheeled horse carriage shaft while crashing his motorcycle in a rural zone. An EMT-B ferry was called at the crash scene and a conscious patient was found, sustaining a severe impalement injury to the left hemithorax, suspended over the floor by the axial skeleton with the carriage shaft coming across his left chest. As a secondary objective, a literature review of thoracic impalement injuries is performed. Cases of thoracic impalement injury require unique and individualized care based on injury severity and affected organs. Reported protocols for managing impalement injuries are entirely anecdotal, with no uniformity on impaled patient's approach and management. In penetrating trauma, it is essential not to remove the impaled object, so that possible vascular lesions remain buffered by the object, avoiding major bleeding and exsanguination haemorrhage. Severed impaled thoracic patients should be transferred to a specialist centre for trauma care, as these lesions typically require complex multidisciplinary treatment. High-energy thoracic impalement injuries are rare and hold a high mortality rate, due to the complexity of trauma and associated injuries such as thoracic wall and lung lesions. Modern medicine still seems limited in cases of such seriousness, not always with satisfactory results. PMID- 25278655 TI - Extrahepatic duct injury in blunt trauma: two case reports and a literature review. AB - Traumatic injuries of the extrahepatic biliary tract are rare. Associated injuries are usually responsible for immediate indication for surgical treatment, the time when an injury to the extrahepatic biliary ducts may be diagnosed. However, missed injuries are often common. The primary aim of this paper is to describe the clinical features, diagnosis, treatment, and outcome of two patients with left hepatic duct injury after blunt abdominal trauma. As a secondary objective, a literature review is presented. The two cases presented in this study are as follows: (1) A young male, involved in a motor vehicle crash, was admitted with blunt hepatic trauma in a general hospital. Endoscopic retrograde cholangiography was conducted 3 weeks later and revealed a large leakage at the left hepatic duct. Exploratory laparotomy was performed 26 days after the initial traumatic event and identified a complete section of the left hepatic duct, treated with anastomosis. (2) A male fell from a height. On exploratory laparotomy, a 30 % partial injury of the left hepatic duct was found in addition to hemoperitoneum, liver injury, gallbladder detachment together with cystic duct rupture, retroperitoneal hematoma to the right, and cecum hematoma. A high level of suspicion is necessary to identify injuries to the hepatic ducts. Early diagnosis that occurs during laparotomy due to associated injuries is important to reduce complications. PMID- 25278656 TI - Surgical treatment of primary hyperparathyroidism: description of techniques and advances in the field. AB - Primary hyperparathyroidism is a disease commonly seen in patients above 60 years of age. It is the most common cause of asymptomatic or symptomatic hypercalcemia, usually found incidentally on routine check-ups. Surgical treatment is the only definitive treatment of choice in the symptomatic patient; however, it can also be employed in asymptomatic patients. First described in 1925, bilateral neck exploration is the gold standard of treatment for primary hyperparathyroidism. The recent interest in minimally invasive surgeries has led to better and improved techniques of neck exploration with improved cosmetic results and lesser chances of transient or permanent hypoparathyroidism due to inadvertent removal of normally functioning parathyroid tissue. These include unilateral neck explorations, minimally invasive parathyroidectomies and minimally invasive radio guided parathyroidectomy. The intact parathyroid hormone assays have greatly added to the detection of normal and abnormal functioning glands, hence better surgical outcomes. PMID- 25278657 TI - Sarcomatoid carcinoma of penis with bilateral inguinal metastases-a case report and review of literature. AB - Sarcomatoid carcinoma or carcinosarcoma of the penis is a rare entity with 36 cases reported in the literature. A 61-year-old male presented with swelling in the glans and shaft of the penis with bilateral inguinal lymph node metastases. He underwent total penectomy with bilateral inguinal block dissection. Histopathology revealed sarcomatoid carcinoma of the Penis with bilateral inguinal lymph node metastases. The patient later developed bilateral lung metastases in 6 months and was succumbed to death. Sarcomatoid carcinoma or carcinosarcoma is a rare malignancy with poor prognosis. PMID- 25278658 TI - Neonatal gastric perforations: are they really spontaneous? AB - CASE REPORT: We report a case of 4-day-old male infant who developed rapid abdominal distension with progression to shock. Abdominal radiography showed free gas under diaphragm for which emergency laparotomy was done revealing a perforation in the greater curvature of the stomach that was sutured after excising surrounding ischemic stomach wall. PMID- 25278659 TI - Asymptomatic uterine torsion in a pregnant woman. AB - Some degree rotation of the gravid uterus in the third trimester of pregnancy is not an abnormal finding. However, extreme uterine torsion of 180 degrees around its cervical junction is a relatively rare event in obstetrical practice. We report here such a case that detected at laparotomy for an emergency cesarean section due to rapture of amniotic membrane. PMID- 25278660 TI - Internal hernias: surgeons dilemma-unravelled by imaging. AB - Internal hernias may present as intestinal obstruction and account for 0.5 to 4.1 % of all cases. Clinical diagnosis of internal hernias is often difficult and thus imaging studies plays an important role in the early diagnosis. It is vital for the radiologist to be familiar with the various types of internal hernias and their radiological features so that prompt diagnosis and early intervention can be made. PMID- 25278661 TI - Papilloma of the umbilicus. AB - We present an interesting and rare case of umbilical papilloma associated with Carcinoma cervix. PMID- 25278662 TI - An intra-arterial knotted guide wire. AB - Central access is essentially an integral part of critical care, both for invasive monitoring and therapeutic interventions. Seldinger technique is the method for the insertion of a central line. It requires the following steps: cannulation of vessel followed by guide wire insertion, dilation of the tract and the vessel and the insertion and securing of the central line followed its maintenance-each of this step has its own complication. PMID- 25278663 TI - Redefining anatomy in a case of midline subhyoid ectopic thyroid. AB - Ectopic thyroid is an uncommon embryological aberration of the thyroid descent. Subhyoid median ectopic thyroid gland is a result of incomplete descent of the thyroid anlage and is characterized by a cosmetically unacceptable ovoid mass of thyroid tissue in the midline overlying the thyroid cartilage and thyrohyoid membrane. A normally placed thyroid gland is not detectable and in most cases all functioning thyroid tissue is located within the mass. Most of the ectopic thyroids are usually mistaken for a thyroglossal cyst and excised. Severe myxedema follows removal. Many cases have been reported in the literature, none of which was recognized prior to operation. All patients were operated upon for removal of a thyroglossal duct cyst. The diagnosis was missed at operation and in these cases severe myxedema was universal. The cause of the myxedema was not always immediately recognized. Therefore, many diagnostic tests including thyroid function test, ultrasound of the neck, and thyroid scanning had been recommended in the preoperative evaluation of a thyroglossal cyst. Here, we present a case of ectopic thyroid mass which was the only thyroid tissue present in the neck. So, division and repositioning of the thyroid mass thereby redefining the anatomy was done with good cosmetic results. PMID- 25278664 TI - Surgical rehabilitation of free fibula graft fracture under local anesthesia with posteriorly directed vertical alveolar distractor. AB - Reconstruction of the mandible with a free fibular graft is one of the most common treatment choices following tumor resection. But as the graft is often vertically deficient, pathological fracture may occur because of occlusal forces after prosthetic rehabilitation. Distraction osteogenesis can be a good choice for the repair of the fibular flap. In this report, a case of fractured fibula flap after 7 years, rehabilitated with a posteriorly directed vertical distractor, will be presented. PMID- 25278665 TI - Role and feasibility of Intraoperative Rapid Parathormone Assay for Enabling Parathyroid Excision. PMID- 25278666 TI - Ideal technique of incisional hernia repair: the quest continues. PMID- 25278667 TI - Pharmaceutical care outcomes in an outpatient human immunodeficiency virus treatment center in Jos, Nigeria. AB - RATIONALE: Pharmacotherapy for patients infected with human immunodeficiency virus (HIV) is complex and increases the potential for drug therapy problems (DTPs). We described the frequency and type of DTPs in a Nigerian cohort of HIV infected patients on antiretroviral therapy (ART), as well as the changes in HIV clinical outcomes after pharmacists' intervention. METHODS: A prospective 1-year descriptive study was conducted from July 2010 to June 2011, at the adult HIV clinic of Jos University Teaching Hospital, Nigeria. DTPs and the associated pharmacist-initiated interventions were documented. Chi-square and Wilcoxon signed ranks test was used as appropriate, to compare the main outcome measures of pre- and post-intervention levels of viral load and CD+ cell count. RESULTS: A total of 64,839 prescriptions were dispensed to 9320 patients. Interventions were documented for 85 unique patients (incidence of 1.31 interventions/1000 prescriptions), of which 62 (73%) and 3 (3.5%) were on first- and second-line ART, respectively, while 20 (23.5%) were yet to commence ART. Reasons for pharmacist intervention included failure to initiate therapy for HIV or hepatitis B infection; therapeutic failure (25.9%); and drug toxicity (24.7%). After intervention, the percentage of patients with HIV ribonucleic acid level <400 copies/mL rose from 29.4% to 67.1% (P < 0.001), while median (interquartile range) CD4+ cell count increased from 200 (123-351) to 361 (221-470) cells/mm(3) (P < 0.001). CONCLUSION: Pharmacist intervention resulted in clinically significant improvements in patients HIV virological and immunological outcomes. This highlights an important role for the pharmacist in the treatment and care of HIV-infected patients, in a multidisciplinary team. PMID- 25278668 TI - Alteration of glucose lowering effect of glibenclamide on single and multiple treatments with fenofibrate in experimental rats and rabbit models. AB - OBJECTIVE: Diabetes mellitus is a syndrome of multiple etiologies. Both type 1 and type 2 diabetes lead to multiple abnormalities of lipid and lipoprotein metabolism. The aim of this investigation was to study the influence of fenofibrate on the blood glucose lowering effect of glibenclamide. MATERIALS AND METHODS: Glibenclamide (0.45, 0.23 mg/kg) and fenofibrate (18.1, 9.38 mg/kg) was treated to normal, diabetic rats, and normal rabbits. Blood samples were collected at various time intervals and were analyzed for blood glucose levels using a glucometer. RESULTS: Co-administration of fenofibrate with glibenclamide significantly elevated the blood glucose reduction exhibited by glibenclamide. CONCLUSION: The results obtained from single and multiple dose treatments clearly demonstrated the existence of drug-drug interaction at the dose tested in animal models. Hence, this investigation would serve as a preclinical evidence for the effect of fenofibrate on the therapeutic efficacy of glibenclamide. PMID- 25278669 TI - Drug utilization in pediatric neurology outpatient department: A prospective study at a tertiary care teaching hospital. AB - BACKGROUND: Neurological disorders are a significant cause of morbidity, mortality and adversely affect quality of life among pediatric patients. In India, more than 30% population is under 20 years of age, many of whom present late during the course of illness. Several drugs prescribed to pediatric population suffering from neurological disorders may be off label or unlicensed. AIMS AND OBJECTIVES: To study drug use pattern, identify off-label/unlicensed drug use and to check potential for drug-drug interactions in patients attending outpatient department of pediatric neurology at a tertiary care teaching hospital. METHODOLOGY: Prescriptions of patients attending pediatric neurology outpatient department were collected prospectively for 8 weeks. They were analyzed for prescribing pattern, WHO core prescribing indicators, off label/unlicensed drug use and potential for drug-drug interactions. RESULT: A total of 140 prescriptions were collected, male female ratio being 2:1. Epilepsy was the most common diagnosis (73.57%) followed by breath holding spells, migraine and developmental disorders. Partial seizure was the most common type of epilepsy (52.42%). Average number of drugs prescribed per patient was 1.56. Most commonly prescribed drug was sodium valproate (25.11%) followed by phenytoin (11.41%). About 16% of the prescriptions contained newer antiepileptic drugs. More than 60% of the drugs were prescribed from WHO essential drug list. In 8.57% of cases drugs were prescribed in off-label/unlicensed manner. Twenty-six percent prescriptions showed potential for drug interactions. CONCLUSION: Epilepsy is the most common neurological disease among children and adolescents. Sodium valproate is the most commonly prescribed drug. A few prescriptions contained off label/unlicensed drugs. PMID- 25278670 TI - Awareness and attitudes regarding breast cancer and breast self-examination among female Jordanian students. AB - BACKGROUND: Despite huge efforts to increase the level of breast cancer awareness, breast self-examination (BSE) is still poorly practiced across Jordan. This baseline study aimed to assess the awareness of female Jordanian students about breast cancer and their practice of BSE. MATERIALS AND METHODS: Using a cross-sectional research design, a self-administered survey was used, via a pre validated pre-piloted questionnaire was distributed to 900 female students aged between 18 and 37 years recruited from the University of Jordan in Amman. The questionnaire was divided into four domains: Socio-demographic characteristics; the respondent's knowledge of breast cancer and BSE; their attitude towards risk factors for breast cancer; their experience of breast cancer screening and BSE. Statistical analysis was performed using Epi-Info version 6.4 statistical Software. RESULTS: The overall response rate was 93.3%. Approximately half of the respondents 435 (51.8%) were aware of breast cancer. Of these, 99 (22.7%) believed that it was caused by a medical condition, followed by old age (71; 16.4%), lack of breastfeeding (58; 13.3%), heredity (56; 12.8%), late marriage (44; 10.3%), pregnancies in older women (33; 7.5%), the use of brassieres (18; 4.1%), excessive breastfeeding (17; 3.9%), being unmarried (14; 3.2%), and spirituality (11; 2.6%). Overall, 152 participants (34.9%) were aware of BSE, but only 93 (11%) had performed it. CONCLUSIONS: The current status of awareness of breast cancer in Jordanian students and their use of BSE are insufficient. Women need to be encouraged to self-monitor in order to detect abnormalities in their breasts. Appropriate educational interventions are urgently required to encourage women to engage in regular BSE. PMID- 25278671 TI - Prescribing pattern and efficacy of anti-diabetic drugs in maintaining optimal glycemic levels in diabetic patients. AB - CONTEXT: Despite the availability of efficacious anti-diabetic drugs, which act by different mechanisms to reduce the blood-glucose, the majority of people with diabetes on anti-diabetic drug therapy, have poor glycemic control and diabetic vascular complications. AIM AND OBJECTIVES: The aim was to study the prescribing pattern and efficacy of anti-diabetic drugs in maintaining optimal glycemic levels in diabetic patients attending tertiary care teaching hospital in Navi Mumbai. MATERIALS AND METHODS: A prospective, cross-sectional, observational survey was carried out in 100 patients of diabetes mellitus attending diabetes outpatient/medicine outpatient departments, to assess their prescribing pattern of anti-diabetic drugs, and their blood-glucose level was measured by Accu-Chek Active glucometer to determine their glycemic control. RESULTS: Average number of anti-diabetic drugs per prescription was 1.4. Sulfonylureas were the most commonly prescribed class, but metformin (biguanide) was the commonest prescribed individual drug among oral hypoglycemic agents (OHA). Fixed dose combination of biguanide and sulfonylurea was prescribed commonly. Monotherapy dominated over polytherapy and there was a higher percentage of use of insulin in Type 2 diabetics. Only 41% of patients on anti-diabetic therapy had optimal glycemic control. The association between anti-diabetic therapy along with lifestyle modification and glycemic control was statistically significant (P = 0.0011). CONCLUSIONS: OHAs still dominate the prescribing pattern, but there was a shifting trend toward the use of insulin preparations in the management of Type 2 diabetes mellitus. In achieving optimal glycemic control, the efficacy of the anti-diabetic drugs was only 41%; therefore intensification of current drug treatment as well as planning multiple drug interventions with lifestyle modification is necessary. PMID- 25278672 TI - Postoperative pharmacodynamic interaction of ondansetron; a 5-HT3 antagonist and paracetamol in patients operated in the ENT department under local anesthesia. PMID- 25278673 TI - Contribution of TLR signaling to the pathogenesis of colitis-associated cancer in inflammatory bowel disease. AB - In the intestine a balance between proinflammatory and repair signals of the immune system is essential for the maintenance of intestinal homeostasis. The innate immunity ensures a primary host response to microbial invasion, which induces an inflammatory process to localize the infection and prevent systemic dissemination of pathogens. The key elements of this process are the germline encoded pattern recognition receptors including Toll-like receptors (TLRs). If pathogens cannot be eliminated, they may elicit chronic inflammation, which may be partly mediated via TLRs. Additionally, chronic inflammation has long been suggested to trigger tissue tumorous transformation. Inflammation, the seventh hallmark of cancer, may affect all phases of tumor development, and evade the immune system. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability. Furthermore, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Colorectal cancers in inflammatory bowel disease patients are considered typical examples of inflammation-related cancers. Although data regarding the role of TLRs in the pathomechanism of cancer-associated colitis are rather conflicting, functionally these molecules can be classified as "largely antitumorigenic" and "largely pro-tumorigenic" with the caveat that the underlying signaling pathways are mainly context (i.e., organ-, tissue-, cell-) and ligand-dependent. PMID- 25278674 TI - Eligibility of persons who inject drugs for treatment of hepatitis C virus infection. AB - In this decade, an increase is expected in end-stage liver disease and hepatocellular carcinoma, most commonly caused by hepatitis C virus (HCV) infection. Although people who inject drugs (PWID) are the major source for HCV infection, they were excluded from antiviral treatments until recently. Nowadays there is incontrovertible evidence in favor of treating these patients, and substitution therapy and active substance use are no longer contraindications for antiviral treatment. The viral clearance in PWID after HCV antiviral treatment with interferon or pegylated interferon combined with ribavirin is comparable to the viral clearance in non-substance users. Furthermore, multidisciplinary approaches to delivering treatment to PWID are advised, and their treatment should be considered on an individualized basis. To prevent the spread of HCV in the PWID community, recent active PWID are eligible for treatment in combination with needle exchange programs and substitution therapy. As the rate of HCV reinfection is low after HCV antiviral treatment, there is no need to withhold HCV treatment due to concerns about reinfection alone. Despite the advances in treatment efficacies and data supporting their success, HCV assessment of PWID and initiation of antiviral treatment remains low. However, the proportion of PWID assessed and treated for HCV is increasing, which can be further enhanced by understanding the barriers to and facilitators of HCV care. Removing stigmatization and implementing peer support and group treatment strategies, in conjunction with greater involvement by nurse educators/practitioners, will promote greater treatment seeking and adherence by PWID. Moreover, screening can be facilitated by noninvasive methods for detecting HCV antibodies and assessing liver fibrosis stages. Recently, HCV clearance has become a major endpoint in the war against drugs for the Global Commission on Drug Policy. This review highlights the most recent evidence concerning HCV infection and treatment strategies in PWID. PMID- 25278676 TI - Immune evasion strategies used by Helicobacter pylori. AB - Helicobacter pylori (H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immune response elements, uses gastric epithelial cells as mediators to manipulate host T cell responses and uses virulence factors to avoid adaptive immune responses by T cells to establish a persistent infection. We also discuss in this review how the genetic diversity of this pathogen helps for its survival. PMID- 25278677 TI - Effect of Helicobacter pylori on gastric epithelial cells. AB - The gastrointestinal epithelium has cells with features that make them a powerful line of defense in innate mucosal immunity. Features that allow gastrointestinal epithelial cells to contribute in innate defense include cell barrier integrity, cell turnover, autophagy, and innate immune responses. Helicobacter pylori (H. pylori) is a spiral shape gram negative bacterium that selectively colonizes the gastric epithelium of more than half of the world's population. The infection invariably becomes persistent due to highly specialized mechanisms that facilitate H. pylori's avoidance of this initial line of host defense as well as adaptive immune mechanisms. The host response is thus unsuccessful in clearing the infection and as a result becomes established as a persistent infection promoting chronic inflammation. In some individuals the associated inflammation contributes to ulcerogenesis or neoplasia. H. pylori has an array of different strategies to interact intimately with epithelial cells and manipulate their cellular processes and functions. Among the multiple aspects that H. pylori affects in gastric epithelial cells are their distribution of epithelial junctions, DNA damage, apoptosis, proliferation, stimulation of cytokine production, and cell transformation. Some of these processes are initiated as a result of the activation of signaling mechanisms activated on binding of H. pylori to cell surface receptors or via soluble virulence factors that gain access to the epithelium. The multiple responses by the epithelium to the infection contribute to pathogenesis associated with H. pylori. PMID- 25278675 TI - Potential for human immunodeficiency virus parenteral transmission in the Middle East and North Africa: an analysis using hepatitis C virus as a proxy biomarker. AB - The Middle East and North Africa (MENA) region has endured several major events of infection parenteral transmission. Recent work has established the utility of using hepatitis C virus (HCV) as a proxy biomarker for assessing the epidemic potential for human immunodeficiency virus (HIV) parenteral transmission. In this review, we use data on the prevalence of HCV infection antibody (seroprevalence) among general population and high risk population groups to assess the potential for HIV parenteral transmission in MENA. Relatively low prevalence of HCV infection in the general population groups was reported in most MENA countries indicating that parenteral HIV transmission at endemic levels does not appear to be a cause for concern. Nonetheless, there could be opportunities for localized HIV outbreaks and transmission of other blood-borne infections in some settings such as healthcare facilities. Though there have been steady improvements in safety measures related to parenteral modes of transmission in the region, these improvements have not been uniform across all countries. More precautions, including infection control training programs, surveillance systems for nosocomial infections and wider coverage and evaluation of hepatitis B virus immunization programs need to be implemented to avoid the unnecessary spread of HIV, HCV, and other blood-borne pathogens along the parenteral modes of transmission. PMID- 25278679 TI - Role of Helicobacter pylori infection on nutrition and metabolism. AB - Helicobacter pylori (H. pylori) is a gram-negative pathogen that is widespread all over the world, infecting more than 50% of the world's population. It is etiologically associated with non-atrophic and atrophic gastritis, peptic ulcer and shows a deep association with primary gastric B-cell lymphoma and gastric adenocarcinoma. Recently, the medical research focused on the modification of the gastric environment induced by H. pylori infection, possibly affecting the absorption of nutrients and drugs as well as the production of hormones strongly implicated in the regulation of appetite and growth. Interestingly, the absorption of iron and vitamin B12 is impaired by H. pylori infection, while infected subjects have lower basal and fasting serum levels of ghrelin and higher concentration of leptin compared to controls. Since leptin is an anorexigenic hormone, and ghrelin stimulates powerfully the release of growth hormone in humans, H. pylori infection may finally induce growth retardation if acquired very early in the childhood and in malnourished children. This review is focused on the nutritional effects of H. pylori infection, such as the reduced bioavailability or the malabsorbption of essential nutrients, and of gastrointestinal hormones, as well as on the relationship between H. pylori and the metabolic syndrome. PMID- 25278681 TI - Role of Helicobacter pylori infection in autoimmune systemic rheumatic diseases. AB - The relationship between infection and autoimmunity has been increasingly defined over the last 20 years. The systemic rheumatic diseases are characterized by dysregulation of the immune system resulting in a loss of tolerance to self antigen. The exact etiology for the majority of these diseases is unknown; however, a complex combination of host and environmental factors are believed to play a pivotal role. Helicobacter pylori (H. pylori) is one of the most widely studied infectious agents proposed as agents triggering autoimmune response. The persistent presence of H. pylori in the gastric mucosa results in chronic immune system activation with ongoing cytokine signaling, infiltration of gastric mucosa by neutrophils, macrophages, lymphocytes, as well as production of antibodies and effector T-cells. Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: molecular mimicry, endothelial cell damage, superantigens and microchimerism. I performed a systematic literature review using the keywords "rheumatoid arthritis", "Sjogren's syndrome", "systemic sclerosis", "systemic lupus erythematosus", "Helicobacter pylori" and "pathogenesis". A systematic literature search was carried out in MEDLINE; EMBASE; Cochrane Library and ACR/EULAR meeting abstracts. In systemic rheumatic diseases H. pylori infection prevalence alone should not be expected to provide sufficient evidence for or against a pathologic role in the disease. In this article I review studies examining the potential involvement of H. pylori infection in autoimmune systemic rheumatic diseases. Further studies of the immunological response to H. pylori and its role in the pathogenesis of systemic rheumatic diseases are warranted. PMID- 25278678 TI - Beyond the stomach: an updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment. AB - Helicobacter pylori (H. pylori) is an extremely common, yet underappreciated, pathogen that is able to alter host physiology and subvert the host immune response, allowing it to persist for the life of the host. H. pylori is the primary cause of peptic ulcers and gastric cancer. In the United States, the annual cost associated with peptic ulcer disease is estimated to be $6 billion and gastric cancer kills over 700000 people per year globally. The prevalence of H. pylori infection remains high (> 50%) in much of the world, although the infection rates are dropping in some developed nations. The drop in H. pylori prevalence could be a double-edged sword, reducing the incidence of gastric diseases while increasing the risk of allergies and esophageal diseases. The list of diseases potentially caused by H. pylori continues to grow; however, mechanistic explanations of how H. pylori could contribute to extragastric diseases lag far behind clinical studies. A number of host factors and H. pylori virulence factors act in concert to determine which individuals are at the highest risk of disease. These include bacterial cytotoxins and polymorphisms in host genes responsible for directing the immune response. This review discusses the latest advances in H. pylori pathogenesis, diagnosis, and treatment. Up-to date information on correlations between H. pylori and extragastric diseases is also provided. PMID- 25278680 TI - Hematologic manifestations of Helicobacter pylori infection. AB - Helicobacter pylori (H. pylori) is the most common infection in humans, with a marked disparity between developed and developing countries. Although H. pylori infections are asymptomatic in most infected individuals, they are intimately related to malignant gastric conditions such as gastric cancer and gastric mucosa associated lymphoid tissue (MALT) lymphoma and to benign diseases such as gastritis and duodenal and gastric peptic ulcers. Since it was learned that bacteria could colonize the gastric mucosa, there have been reports in the medical literature of over 50 extragastric manifestations involving a variety medical areas of specialization. These areas include cardiology, dermatology, endocrinology, gynecology and obstetrics, hematology, pneumology, odontology, ophthalmology, otorhinolaryngology and pediatrics, and they encompass conditions with a range of clear evidence between the H. pylori infection and development of the disease. This literature review covers extragastric manifestations of H. pylori infection in the hematology field. It focuses on conditions that are included in international consensus and management guides for H. pylori infection, specifically iron deficiency, vitamin B12 (cobalamin) deficiency, immune thrombocytopenia, and MALT lymphoma. In addition, there is discussion of other conditions that are not included in international consensus and management guides on H. pylori, including auto-immune neutropenia, antiphospholipid syndrome, plasma cell dyscrasias, and other hematologic diseases. PMID- 25278684 TI - Potential role of metabolomics in diagnosis and surveillance of gastric cancer. AB - Gastric cancer is one of the deadliest cancers worldwide, and is especially prevalent in Asian countries. With such high morbidity and mortality, early diagnosis is essential to achieving curative intent treatment and long term survival. Metabolomics is a new field of study that analyzes metabolites from biofluids and tissue samples. While metabolomics is still in its infancy, there are numerous potential applications in oncology, specifically early diagnosis. Only a few studies in the literature have examined metabolomics' role in gastric cancer. Various fatty acid, carbohydrate, nucleic acid, and amino acid metabolites have been identified that distinguish gastric cancer from normal tissue and benign gastric disease. However, findings from these few studies are at times conflicting. Most studies demonstrate some relationship of cancer cells to the Warburg Effect, in that glycolysis predominates with conversion of pyruvate to lactate. This is one of the most consistent findings across the literature. There is less consistency in metabolomic signature with respect to nucleic acids, lipids and amino acids. In spite of this, metabolomics holds some promise for cancer surveillance but further studies are necessary to achieve consistency and validation before it can be widely employed as a clinical tool. PMID- 25278683 TI - Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis. AB - Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX 2 in H. pylori-infected patients and their possible association with gastric cancer risk. PMID- 25278686 TI - Multimodality treatment of potentially curative gastric cancer: geographical variations and future prospects. AB - After much controversy, multimodality therapy is now accepted worldwide as the gold standard for treatment of resectable bulky localized gastric cancer. There is significant regional variation in the style of multimodality treatment with adjuvant chemoradiation the North American standard, neoadjuvant chemotherapy preferred in Europe and Australasia, whilst adjuvant chemotherapy is preferred in Asia. With further standardization of surgery and D1+/D2 resections increasingly accepted world wide, and in particular in the West, as the surgical standard of care for potentially curable disease, it is timely to reassess the multimodality regimes being used. The challenge in the use of multimodality therapy is how current outcomes can be standardized and improved further. Recent studies indicate that mere intensification of the regime in time, dosage or addition of further agents does not improve localized gastric cancer outcomes. More novel strategies including early commencement of adjuvant therapies, intra-peritoneal chemotherapy or assessing neoadjuvant response with positron emission tomography scanning may give improvements in outcomes. The introduction of targeted therapies means that the adjuvant use of biological agents needs to be explored. By proper assessment of the patient's co-morbidities, full tumour staging, and a better understanding of the tumour's molecular pathology, multimodality therapy for gastric adenocarcinoma may be individualized to optimize the likelihood of cure. PMID- 25278682 TI - Diagnosis of Helicobacter pylori: what should be the gold standard? AB - Since the discovery of Helicobacter pylori (H. pylori) in 1983, numerous detection methods for the presence of the bacterium have been developed. Each one of them has been associated with advantages and disadvantages. Noninvasive tests such as serology, (13)C urea breath test (UBT) and stool antigen tests are usually preferred by the clinicians. Serology has its own limitation especially in endemic areas while (13)C UBT is technically very demanding. The stool antigen detection method, although specific, is usually associated with poor sensitivity. The (13)C UBT is believed to be specific, but with present revelation of the fact that stomach is colonized by many other urease producing bacteria makes it questionable. Histology, culture, rapid urease test and polymerase chain reaction (PCR) are the tests which are carried out on antral biopsies collected by invasive means. Histology has been proposed to be very sensitive and specific but the question is how by simply looking the morphology of the bacteria in the microscope, one can claim that the curved bacterium is exclusively H. pylori. Rapid urease test (RUT), the doctor's test, is also challenged because the presence of other urease producing bacteria in the stomach cannot be denied. Moreover, RUT has been reported with poor sensitivity specially, when density of the bacterium is low. Isolation of H. pylori is essential to investigate its growth requirements, antibiotic susceptibility testing, studying virulence factor to develop vaccine and many more explorations. It has also got several disadvantages i.e., special condition for transporting, media, incubation and few days waiting for the colonies to appear, apart from the speed essentially needed to process the specimens. Till date, majority of the microbiological laboratories in the world are not equipped and trained to isolate such fastidious bacterium. The option left is PCR methods to detect H. pylori's DNA in gastric mucosa, gastric juice, saliva, dental plaques and environmental specimens. There are speculations for false positivity due to detection of non-pylori Helicobacters due to genetic sharing; and false negativity due to low bacterial counts and presence of PCR inhibitors. However, specimen collection, transportation and processing do not require speed and special conditions. PCR based diagnosis may be considered as gold standard by designing primers extremely specific to H. pylori and targeting at least more than one conserved genes. Similarly specificity of PCR may be improved by use of internal Primers. Further, nested PCR will take care of false negatives by countering the effect of PCR inhibitors and low bacterial counts. Therefore, nested PCR based methods if performed properly, may be proposed as gold standard test. PMID- 25278685 TI - Problems faced by evidence-based medicine in evaluating lymphadenectomy for gastric cancer. AB - Gastric cancer surgical management differs between Eastern Asia and Western countries. Extended lymphadenectomy (D2) is the standard of care in Japan and South Korea since decades, while the majority of United States patients receive at most a limited lymphadenectomy (D1). United States and Northern Europe are considered the scientific leaders in medicine and evidence-based procedures are the cornerstone of their clinical practice. However, surgeons in Eastern Asia are more experienced, as there are more new cases of gastric cancer in Japan (107898 in 2012) than in the entire European Union (81592), or in South Korea (31269) than in the entire United States (21155). For quite a long time evidence-based medicine (EBM) did not solve the question whether D2 improves long-term prognosis with respect to D1. Indeed, eastern surgeons were reluctant to perform D1 even in the frame of a clinical trial, as their patients had a very good prognosis after D2. Evidence-based surgical indications provided by Western trials were questioned, as surgical procedures could not be properly standardized. In the present study we analyzed indications about the optimal extension of lymphadenectomy in gastric cancer according to current scientific literature (2008-2012) and surgical guidelines. We searched PubMed for papers using the key words "lymphadenectomy or D1 or D2" AND "gastric cancer" from 2008 to 2012. Moreover, we reviewed national guidelines for gastric cancer management. The support to D2 lymphadenectomy increased progressively from 2008 to 2012: since 2010 papers supporting D2 have achieved a higher overall impact factor than the other papers. Till 2011, D2 was the procedure of choice according to experts' opinion, while three meta-analyses found no survival advantage after D2 with respect to D1. In 2012-2013, however, two meta-analyses reported that D2 improves prognosis with respect to D1. D2 lymphadenectomy was proposed as the standard of care for advanced gastric cancer by Japanese National Guidelines since 1981 and was adopted as the standard procedure by the Italian Research Group for Gastric Cancer since the Nineties. D2 is now indicated as the standard of surgical treatment with curative intent by the German, British and ESMO-ESSO-ESTRO guidelines. At variance American NCCN guidelines recommend a D1(+) or a modified D2 lymph node dissection. In conclusion, D2 lymphadenectomy, originally developed by Eastern surgeons, is now becoming the procedure of choice also in the West. In gastric cancer surgery EBM is lagging behind national guidelines, rather than preceding and orienting them. To eliminate this lag, EBM should value to a larger extent Eastern Asian literature and should evaluate not only the quality of the study design but also the quality of surgical procedures. PMID- 25278687 TI - Postoperative adjuvant chemoradiotherapy in D2-dissected gastric cancer: is radiotherapy necessary after D2-dissection? AB - Studies from the Far East have demonstrated that D2-dissection is superior to D0/1-dissection. The effect of postoperative chemoradiotherapy (CRT) after D2 dissection has not been accepted due to the lack of D2-dissection in Western countries, as well as the potential harmful effect of radiotherapy. In the current NCCN guideline, adjuvant chemotherapy alone is recommended in D2 dissected patients. However, three recent prospective randomized controlled trials in South Korea and China (ARTIST, NCC and Multicenter IMRT Trials) demonstrated that adjuvant CRT can be safely administered to D2-dissected patients with notable benefits. To identify the role of radiotherapy (RT) in the D2-dissected postoperative setting, clinical research attempts should include (1) identification of high-risk patients for loco-regional recurrence who might benefit from CRT; (2) modification of RT target volume based on the findings that failure patterns should be different after D1- and D2-dissection; and (3) integration of new RT techniques to decrease treatment-related toxicity. The present paper is a review of recent studies addressing these fields. Well designed prospective randomized studies are needed to clearly define the role of adjuvant CRT in D2-dissected gastric cancer, however, future clinical studies should also focus on answering these questions. PMID- 25278689 TI - Alcoholic liver disease: treatment. AB - The excess consumption of alcohol is associated with alcoholic liver diseases (ALD). ALD is a major healthcare problem, personal and social burden, and significant reason for economic loss worldwide. The ALD spectrum includes alcoholic fatty liver, alcoholic hepatitis, cirrhosis, and the development of hepatocellular carcinoma. The diagnosis of ALD is based on a combination of clinical features, including a history of significant alcohol intake, evidence of liver disease, and laboratory findings. Abstinence is the most important treatment for ALD and the treatment plan varies according to the stage of the disease. Various treatments including abstinence, nutritional therapy, pharmacological therapy, psychotherapy, and surgery are currently available. For severe alcoholic hepatitis, corticosteroid or pentoxifylline are recommended based on the guidelines. In addition, new therapeutic targets are being under investigation. PMID- 25278688 TI - New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. AB - Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1beta, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1alpha. PMID- 25278690 TI - Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. AB - Hepatocellular carcinoma (HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease (NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools. PMID- 25278692 TI - Laparoscopic natural orifice specimen extraction-colectomy: a systematic review. AB - Over the last 20 years, laparoscopic colorectal surgery has shown equal efficacy for benign and malignant colorectal diseases when compared to open surgery. However, a laparoscopic approach reduces postoperative morbidity and shortens hospital stay. In the quest to optimize outcomes after laparoscopic colorectal surgery, reduction of access trauma could be a way to improve recovery. To date, one method to reduce access trauma is natural orifice specimen extraction (NOSE). NOSE aims to reduce access trauma in laparoscopic colorectal surgery. The specimen is delivered via a natural orifice and the anastomosis is created intracorporeally. Different methods are used to extract the specimen and to create a bowel anastomosis. Currently, specimens are delivered transcolonically, transrectally, transanally, or transvaginally. Each of these NOSE-procedures raises specific issues with regard to operative technique and application. The presumed benefits of NOSE-procedures are less pain, lower analgesia requirements, faster recovery, shorter hospital stay, better cosmetic results, and lower incisional hernia rates. Avoidance of extraction site laparotomy is the most important characteristic of NOSE. Concerns associated with the NOSE-technique include bacterial contamination of the peritoneal cavity, inflammatory response, and postoperative outcomes, including postoperative pain and the functional and oncologic outcomes. These issues need to be studied in prospective randomized controlled trials. The aim of this systematic review is to describe the role of NOSE in minimally invasive colorectal surgery. PMID- 25278694 TI - Is there a role for colon capsule endoscopy beyond colorectal cancer screening? A literature review. AB - Colon capsule endoscopy is recommended in Europe alternatively to colonoscopy for colorectal cancer screening in average risk individuals. The procedure has also been proposed to complete colon examination in cases of incomplete colonoscopy or when colonoscopy is contraindicated or refused by the patient. As tissue samples cannot be obtained with the current capsule device, colon capsule endoscopy has no place in diagnosing ulcerative colitis or in dysplasia surveillance. Nevertheless, data are accumulating regarding its feasibility to examine ulcerative colitis disease extent and to monitor disease activity and mucosal healing, even though reported results on the capsule's performance in this field vary greatly. In this review we present the currently available evidence for the use of colon capsule endoscopy to complement colonoscopy failure to reach the cecum and its use to evaluate ulcerative colitis disease activity and extent. Moreover, we provide an outlook on issues requiring further investigation before the capsule becomes a mainstream alternative to colonoscopy in such cases. PMID- 25278695 TI - Endoscopic treatment of esophageal varices in patients with liver cirrhosis. AB - Variceal bleeding is a life-threatening complication of portal hypertension with a six-week mortality rate of approximately 20%. Patients with medium- or large sized varices can be treated for primary prophylaxis of variceal bleeding using two strategies: non-selective beta-blockers (NSBBs) or endoscopic variceal ligation (EVL). Both treatments are equally effective. Patients with acute variceal bleeding are critically ill patients. The available data suggest that vasoactive drugs, combined with endoscopic therapy and antibiotics, are the best treatment strategy with EVL being the endoscopic procedure of choice. In cases of uncontrolled bleeding, transjugular intrahepatic portosystemic shunt (TIPS) with polytetrafluoroethylene (PTFE)-covered stents are recommended. Approximately 60% of the patients experience rebleeding, with a mortality rate of 30%. Secondary prophylaxis should start on day six following the initial bleeding episode. The combination of NSBBs and EVL is the recommended management, whereas TIPS with PTFE-covered stents are the preferred option in patients who fail endoscopic and pharmacologic treatment. Apart from injection sclerotherapy and EVL, other endoscopic procedures, including tissue adhesives, endoloops, endoscopic clipping and argon plasma coagulation, have been used in the management of esophageal varices. However, their efficacy and safety, compared to standard endoscopic treatment, remain to be further elucidated. There are safety issues accompanying endoscopic techniques with aspiration pneumonia occurring at a rate of approximately 2.5%. In conclusion, future research is needed to improve treatment strategies, including novel endoscopic techniques with better efficacy, lower cost, and fewer adverse events. PMID- 25278696 TI - Improving quality measures in colonoscopy and its therapeutic intervention. AB - Colonoscopy with polypectomy has been shown to reduce the risk of colon cancer. The critical element in the quality of colonoscopy in terms of polyp detection and removal continues to be the performance of the endoscopist, independent of patient-related factors. Improved results in terms of polyp detection and complete removal have implications regarding the development of screening and surveillance intervals and the reduction of interval cancers after negative colonoscopy. Advances in colonoscopy techniques such as high-definition colonoscopy, hood-assisted colonoscopy and dye-based chromoendoscopy have improved the detection of small and flat-type colorectal polyps. Virtual chromoendoscopy has not proven to improve polyp detection but may be useful to predict polyp pathology. The majority of polyps can be removed endoscopically. Available polypectomy techniques include cold forceps polypectomy, cold snare polypectomy, conventional polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection. The preferred choice depends on the polyp size and characteristics. Other useful techniques include colonoscopic hemostasis for acute colonic diverticular bleeding, endoscopic decompression using colonoscopic stenting, and transanal tube placement for colorectal obstruction. Here we review the current knowledge concerning the improvement of quality measures in colonoscopy and colonoscopy-related therapeutic interventions. PMID- 25278693 TI - Endoscopic features of gastro-intestinal lymphomas: from diagnosis to follow-up. AB - Many progresses have been done in the management of gastrointestinal (GI) lymphomas during last decades, especially after the discovery of Helicobacter pylori-dependent lymphoma development. The stepwise implementation of new endoscopic techniques, by means of echoendoscopy or double-balloon enteroscopy, enabled us to more precisely describe the endoscopic features of GI lymphomas with substantial contribution in patient management and in tailoring the treatment strategy with organ preserving approaches. In this review, we describe the recent progresses in GI lymphoma management from disease diagnosis to follow up with a specific focus on the endoscopic presentation according to the involved site and the lymphoma subtype. Additionally, new or emerging endoscopic technologies that have an impact on the management of gastrointestinal lymphomas are reported. We here discuss the two most common subtypes of GI lymphomas: the mucosa-associated lymphoid tissue and the diffuse large B cell lymphoma. A general outline on the state-of-the-art of the disease and on the role of endoscopy in both diagnosis and follow-up will be performed. PMID- 25278698 TI - Capsule endoscopy in Crohn's disease: are we seeing any better? AB - Crohn's disease (CD) is a complex, immune-mediated disorder that often requires a multi-modality approach for optimal diagnosis and management. While traditional methods include ileocolonoscopy and radiologic modalities, increasingly, capsule endoscopy (CE) has been incorporated into the algorithm for both the diagnosis and monitoring of CD. Multiple studies have examined the utility of this emerging technology in the management of CD, and have compared it to other available modalities. CE offers a noninvasive approach to evaluate areas of the small bowel that are difficult to reach with traditional endoscopy. Furthermore, CE maybe favored in specific sub segments of patients with inflammatory bowel disease (IBD), such as those with IBD unclassified (IBD-U), pediatric patients and patients with CD who have previously undergone surgery. PMID- 25278697 TI - Minimally invasive surgery for submucosal (subepithelial) tumors of the stomach. AB - Minimally invasive surgery has become common in the surgical resection of gastrointestinal submucosal tumors (SMTs). The purpose of this article is to review recent trends in minimally invasive surgery for gastric SMTs. Although laparoscopic resection has been main stream of minimally invasive surgery for gastrointestinal SMTs, recent advances in endoscopic procedures now provide various treatment modalities for gastric SMTs. Moreover, investigators have developed several hybrid techniques that include the advantages of both laparoscopic and endoscopic procedure. In addition, several types of reduced port surgeries, modification of conventional laparoscopic procedures, have been recently applied to the surgical resection of SMTs. Meanwhile, robotic surgery for SMTs requires further evidence and improvement. PMID- 25278699 TI - Anal squamous cell carcinoma: an evolution in disease and management. AB - Anal cancer represents less than 1% of all new cancers diagnosed annually in the United States. Yet, despite the relative paucity of cases, the incidence of anal cancer has seen a steady about 2% rise each year over the last decade. As such, all healthcare providers need to be cognizant of the evaluation and treatment of anal squamous cell carcinoma. While chemoradiation remains the mainstay of therapy for most patients with anal cancer, surgery may still be required in recurrent, recalcitrant and palliative disease. In this manuscript, we will explore the diagnosis and management of squamous cell carcinoma of the anus. PMID- 25278700 TI - Mycobacterium avium subspecies paratuberculosis in the etiology of Crohn's disease, cause or epiphenomenon? AB - The origin of inflammatory bowel disease is unknown. Attempts have been made to isolate a microorganism that could explain the onset of inflammation, but no pathological agent has ever been identified. Johne's disease is a granulomatous chronic enteritis of cattle and sheep caused by Mycobacterium avium subspecies paratuberculosis (MAP) and shows some analogies with Crohn's disease (CD). Several studies have tried to clarify if MAP has a role in the etiology of CD. The present article provides an overview of the evidence in favor and against the "MAP-hypothesis", analyzing the methods commonly adopted to detect MAP and the role of antimycobacterial therapy in patients with inflammatory bowel disease. Studies were identified through the electronic database, MEDLINE, and were selected based on their relevance to the objective of the review. The presence of MAP was investigated using multiple diagnostic methods for MAP detection and in different tissue samples from patients affected by CD or ulcerative colitis and in healthy controls. On the basis of their studies, several authors support a close relationship between MAP and CD. Although increasing evidence of MAP detection in CD patients is unquestionable, a clear etiological link still needs to be proven. PMID- 25278691 TI - Non-alcoholic fatty liver disease: what the clinician needs to know. AB - Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment. PMID- 25278701 TI - NANOG: a promising target for digestive malignant tumors. AB - NANOG has been extensively researched since its discovery by Chambers et al. NANOG is a homeodomain transcription factor and an essential regulator of embryonic stem cell (ESC) self-renewal, which inhibits differentiation. Cancer stem cells (CSCs) are a small subset of cells that are thought to drive uncontrolled tumor growth; CSCs retain the tumor capabilities of self-renewal and propagation. The existence of CSCs was recently shown by direct experimental evidence. NANOG is expressed in CSCs and ESCs, although it remains unclear whether ESCs and CSCs share similar mechanisms in the regulation of physical and biological processes. Several studies suggest that the expression level of NANOG is high in cancer tissues and low or absent in normal tissues. High levels of NANOG expression are associated with advanced stages of cancer and a poor prognosis, indicating that it plays a vital role in tumor transformation, tumorigenesis, and tumor metastasis. NANOG is part of a complex regulatory network that controls cell fate determination, proliferation, and apoptosis. NANOG cooperates with other regulators, such as microflora, transcription factors, and kinases, in cancer cells. NANOG might have a promising future in anti-cancer and other therapeutic treatments, which could improve human health. PMID- 25278702 TI - Role of Nrf2 in chronic liver disease. AB - Nuclear erythroid 2-related factor 2 (Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases. PMID- 25278703 TI - Osteopontin is an important mediator of alcoholic liver disease via hepatic stellate cell activation. AB - AIM: To investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models. METHODS: OPN pathway was evaluated in livers from patients with progressive stages of human ALD and serum from drinkers with and without liver cirrhosis. In vitro stellate LX2 cells exposed to acute alcohol and in vivo in acute alcoholic steatosis mouse models were also investigated for OPN pathway expression and function. WT and OPN(-/-) mice were administered an acute dose of alcohol and extent of liver injury was examined by histopathology and liver biochemistry after 16-24 h. The causative role of OPN was studied in OPN knockout animals and in vitro in stellate LX2 cells, utilizing siRNA, aptamer and neutralizing antibodies to block OPN and OPN pathway. OPN pathway expression and downstream functional consequences were measured for signaling by Western blotting, plasmin activation by spectrophotometric assays and cell migration by confocal imaging and quantitation. RESULTS: OPN expression positively correlated with disease severity in patients with progressive stages of ALD. In vivo, associated with alcoholic steatosis, a single dose of acute alcohol significantly increased hepatic OPN mRNA and protein, and a cleaved OPN form in a dose dependent manner. OPN mRNA and secreted OPN also increased in parallel with activation of LX2 stellate cells within 4 h of a single dose of alcohol. Expression of OPN receptors, alphavbeta3-integrin and CD44, increased in human ALD, and in vivo and in vitro with alcohol administration. This was accompanied by downstream phosphorylation of Akt and Erk, increased mRNA expression of several fibrogenesis, fibrinolysis and extracellular matrix pathway genes, plasmin activation and hepatic stellate cell (HSC) migration. Inhibition of OPN and OPN-receptor mediated signaling partially inhibited alcohol-induced HSC activation, plasmin activity and cell migration. CONCLUSION: OPN is a key mediator of the alcohol-induced effects on hepatic stellate cell functions and liver fibrogenesis. PMID- 25278705 TI - Reversible immortalization of human hepatocytes mediated by retroviral transfer and site-specific recombination. AB - AIM: To establish a method for the reversible immortalization of human hepatocytes, which may offer a good and safe source of hepatocytes for practical applications. METHODS: We successfully isolated primary human hepatocytes from surgically resected liver tissue taken from a patient with liver hemangiomas. The freshly isolated cells were then immortalized with retroviral vector SSR#69 expressing simian virus 40 large T antigen (SV40T) and hygromycin-resistance genes flanked by paired loxP recombination targets. RESULTS: The freshly isolated hepatocytes with high viability (85%) were successfully immortalized using retroviral gene transfer of SV40T. SV40T in the immortalized cells was then excised by Cre/loxP site-specific recombination. This cell population exhibited the characteristics of differentiated hepatocytes. CONCLUSION: We successfully established reversibly immortalized human hepatocytes, which will provide an unlimited supply of cells for practical applications. PMID- 25278704 TI - Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1 regulated proliferation of gastric cancer stem-like cells. AB - AIM: To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs). METHODS: The gastric cancer cell line MKN-45 line was selected and sorted by FACS using the cancer stem cell marker CD44; the stemness of these cells was checked in our previous study. In an in vitro study, the expression of Notch-1, Hes1, Vascular endothelial growth factor (VEGF), and Ki-67 in both CD44-positive gastric cancer stem-like cells (GCSCs) and CD44-negative cells was measured by Western blot. The effect of XTSJ serum on cell viability and on the above markers was measured by MTT assay and Western blot, respectively. In an in vivo study, the ability to induce angiogenesis and maintenance of GCSCs in CD44-positive-MKN-45- and CD44 negative-engrafted mice were detected by immunohistochemical staining using markers for CD34 and CD44, respectively. The role of XTSJ decoction in regulating the expression of Notch-1, Hes1, VEGF and Ki-67 was measured by Western blot and real-time polymerase chain reaction. RESULTS: CD44(+) GCSCs showed more cell proliferation and VEGF secretion than CD44-negative cells in vitro, which were accompanied by the high expression of Notch-1 and Hes1 and positively associated with tumor growth (GCSCs vs CD44-negative cells, 2.72 +/- 0.25 vs 1.46 +/- 0.16, P < 0.05) and microvessel density (MVD) (GCSCs vs CD44-negative cells, 8.15 +/- 0.42 vs 3.83 +/- 0.49, P < 0.001) in vivo. XTSJ decoction inhibited the viability of both cell types in a dose-dependent manner in vitro. Specifically, a significant difference in the medium- (82.87% +/- 6.53%) and high-dose XTSJ groups (77.43% +/- 7.34%) was detected at 24 h in the CD44(+) GCSCs group compared with the saline group (95.42% +/- 5.76%) and the low-dose XTSJ group (90.74% +/- 6.57%) (P < 0.05). However, the efficacy of XTSJ decoction was reduced in the CD44(-) groups; significant differences were only detected in the high-dose XTSJ group at 48 h (78.57% +/- 6.94%) and 72 h (72.12% +/- 7.68%) when compared with the other CD44- groups (P < 0.05). Notably, these differences were highly consistent with the Notch-1, Hes1, VEGF and Ki-67 expression in these cells. Similarly, in vivo, XTSJ decoction inhibited tumor growth in a dose dependent manner. A significant difference was observed in the medium- (1.76 +/- 0.15) and high-dose XTSJ (1.33 +/- 0.081) groups compared with the GCSCs control group (2.72 +/- 0.25) and the low-dose XTSJ group (2.51 +/- 0.25) (P < 0.05). We also detected a remarkable decrease of MVD in the medium- (7.10 +/- 0.60) and high-dose XTSJ (5.99 +/- 0.47) groups compared with the GCSC control group (8.15 +/- 0.42) and the low-dose XTSJ group (8.14 +/- 0.46) (P < 0.05). Additionally, CD44 expression was decreased in these groups [medium- (4.43 +/- 0.45) and high dose XTSJ groups (3.56 +/- 0.31) vs the GCSC control (5.96 +/- 0.46) and low dose XTSJ groups (5.91 +/- 0.38)] (P < 0.05). The significant differences in Notch-1, Hes1, VEGF and Ki-67 expression highly mirrored the results of XTSJ decoction in inhibiting tumor growth, MVD and CD44 expression. CONCLUSION: Notch-1 may play an important role in regulating the proliferation of GCSCs; XTSJ decoction could attenuate tumor angiogenesis, at least partially, by inhibiting Notch-1. PMID- 25278706 TI - Decreased serum platelet derived growth factor BB levels in acute and increased in chronic pancreatitis. AB - AIM: To examine circulating growth factor concentrations in patients with acute pancreatitis (AP) and chronic pancreatitis (CP), and walled-off pancreatic necrosis (WOPN). METHODS: Forty patients with mild AP, 40 patients with alcoholic CP, 33 patients with WOPN and 40 healthy subjects were examined. Serum concentrations of platelet derived growth factor BB (PDGF-BB), transforming growth factor beta-1 (TGFbeta-1), chemerin and high-mobility group box chromosomal protein 1 (HMBG1) were assayed by enzyme linked immunosorbent assay. RESULTS: Patients with mild AP and those with WOPN had significantly lower serum levels of PDGF-BB compared to healthy subjects (4.0 +/- 0.61 ng/mL vs 6.2 +/- 0.76 ng/mL, P = 0.027, and 1.60 +/- 0.31 ng/mL vs 6.2 +/- 0.76 ng/mL, P < 0.001, respectively), while CP was associated with higher serum levels of PDGF-BB (12 +/ 1.3 ng/mL vs 6.2 +/- 0.76 ng/mL, P < 0.001). Circulating TGFbeta-1 and chemerin levels were elevated in CP patients (57 +/- 3.6 ng/mL vs 39 +/- 3.6 ng/mL, P < 0.001 and 73 +/- 7.2 ng/mL vs 48 +/- 2.3 ng/mL, P < 0.001, respectively), but not in patients with AP and WOPN. No significant changes in serum HMBG1 levels were found either in patients with AP, WOPN or CP. CONCLUSION: The serum levels of some growth factors and cytokines differ significantly in AP, WOPN and CP. These data suggest that selected growth factors and cytokines may be considered as potential diagnostic biomarkers in patients with pancreatic diseases. PMID- 25278707 TI - Small-bowel mucosal injuries in low-dose aspirin users with obscure gastrointestinal bleeding. AB - AIM: To investigate the clinical differences between small intestinal injuries in low-dose aspirin (LDA) users and in non-steroidal anti-inflammatory drug (NSAID) users who were examined by capsule endoscopy (CE) for obscure gastrointestinal bleeding (OGIB). METHODS: A total of 181 patients who underwent CE for OGIB were included in this study. Based on clinical records, laboratory data such as hemoglobin levels, major symptoms, underlying diseases, the types and duration of LDA and NSAID use, and endoscopic characteristics of CE were reviewed. RESULTS: Out of a total of 45 cases of erosive lesions, 27 cases were taking LDA or NSAIDs (7 were on NSAIDs, 9 were on LDA alone, 9 were on LDA and thienopyridine, and 2 were on LDA and warfarin).The prevalence of ulcers or erosion during chronic use of LDA, LDA and the anti-platelet drug thienopyridine (clopidogrel or ticlopidine), and NSAIDs were 64.3%, 80.0%, and 75.0%, respectively. Erosive lesions were observed predominantly in chronic LDA users, while ulcerative lesions were detected mainly in NSAID users. However, concomitant use of thienopyridine such as clopidogrel with LDA increased the proportion of ulcers. The erosive lesions were located in the whole of the small intestine (jejunum and ileum), whereas ulcerative lesions were mainly observed in the ileum (P < 0.05). CONCLUSION: Our CE findings indicate that chronic LDA users and NSAID users show different types and locations of small-bowel mucosal injuries. The concomitant use of anti-platelet drugs with LDA tends to exacerbate the injuries from LDA type to NSAID-type injuries. PMID- 25278708 TI - Identification of pathologic features associated with "ulcerative colitis-like" Crohn's disease. AB - AIM: To identify pathologic features associated with this "ulcerative colitis (UC)-like" subgroup of Crohn's disease (CD). METHODS: Seventeen subjects diagnosed as having UC who underwent proctocolectomy (RPC) from 2003-2007 and subsequently developed CD of the ileal pouch were identified. UC was diagnosed based on pre-operative clinical, endoscopic, and pathologic studies. Eighteen patients who underwent RPC for UC within the same time period without subsequently developing CD were randomly selected and used as controls. Pathology reports and histological slides were reviewed for a wide range of gross and microscopic pathological features, as well as extent of disease. The demographics, gross description and histopathology of the resection specimens were reviewed and compared between the two groups. RESULTS: Patients with "UC like" CD were on average 13 years younger than those with "true" UC (P < 0.01). More severe disease in the proximal involved region and active ileitis with/without architectural distortion were observed in 6 of 17 (35%) and 7 of 17 (41%) "UC-like" CD cases, respectively, but in none of the "true" UC cases (P < 0.05). Active appendicitis occurred in 8 of 16 (50%) "UC-like" CD cases but in only two (11%) "true" UC cases (P < 0.05). Conspicuous lamina propria neutrophils were more specific for "UC-like" CD (76% vs 22%, P < 0.05). In addition, prominent lymphoid aggregates tended to be more common in "UC-like" CD (P = 0.07). The "true" UC group contained a greater number of cases with severe activity (78% vs 47%). Therefore, the features more commonly seen in "UC-like" CD were not due to a more severe disease process. Crohn's granulomas and transmural inflammation in non-ulcerated areas were absent in both groups. CONCLUSION: More severe disease in the proximal involved region, terminal ileum involvement, active appendicitis, and prominent lamina propria neutrophils may be morphological factors associated with "UC-like" CD. PMID- 25278709 TI - IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients. AB - AIM: To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response. METHODS: A cohort of 118 Caucasian treatment-naive HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response. RESULTS: Twenty-six out of 118 patients (22%) had no HCV RNA decline >= 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G)/rs1297860 in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction >= log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis. CONCLUSION: Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness. PMID- 25278710 TI - Repeat endoscopic retrograde cholangiopancreaticography after failed initial precut sphincterotomy for biliary cannulation. AB - AIM: To investigate the outcome of repeating endoscopic retrograde cholangiopancreaticography (ERCP) after initially failed precut sphincterotomy to achieve biliary cannulation. METHODS: In this retrospective study, consecutive ERCPs performed between January 2009 and September 2012 were included. Data from our endoscopy and radiology reporting databases were analysed for use of precut sphincterotomy, biliary access rate, repeat ERCP rate and complications. Patients with initially failed precut sphincterotomy were identified. RESULTS: From 1839 consecutive ERCPs, 187 (10%) patients underwent a precut sphincterotomy during the initial ERCP in attempts to cannulate a native papilla. The initial precut was successful in 79/187 (42%). ERCP was repeated in 89/108 (82%) of patients with failed initial precut sphincterotomy after a median interval of 4 d, leading to successful biliary cannulation in 69/89 (78%). In 5 patients a third ERCP was attempted (successful in 4 cases). Overall, repeat ERCP after failed precut at the index ERCP was successful in 73/89 patients (82%). Complications after precut sphincterotomy were observed in 32/187 (17%) patients including pancreatitis (13%), retroperitoneal perforations (1%), biliary sepsis (0.5%) and haemorrhage (3%). CONCLUSION: The high success rate of biliary cannulation in a second attempt ERCP justifies repeating ERCP within 2-7 d after unsuccessful precut sphincterotomy before more invasive approaches should be considered. PMID- 25278711 TI - Risk factors for de novo hepatitis B infection in pediatric living donor liver transplantation. AB - AIM: To investigate the incidence of de novo hepatitis B virus (HBV) infection after pediatric living donor liver transplantation (LDLT) and to analyze the risk factors associated with this de novo HBV infection. METHODS: The clinical and laboratory data of children who underwent LDLT from June 2010 to September 2012 in First Center Hospital in Tianjin, China, were retrospectively included in the study. Intrahepatic HBV DNA in donors and recipients was quantified by real-time polymerase chain reaction using DNA extracted from formalin-fixed, paraffin embedded tissues. RESULTS: Between June 2010 to September 2012, 32 consecutive pediatric patients underwent LDLT in our institute. Thirty LDLT patients (13 girls and 17 boys) were followed up for a median of 15 mo, of whom 53.3% (16/30) were hepatitis B core antibody (HBcAb) positive and 36.7% (11/30) were hepatitis B surface antibody (HBsAb)/HBcAb positive before transplantation. Sixteen of the children received HBcAb-positive allografts, and 43.7% (7/16) of the grafts were found to be intrahepatic HBV DNA positive. De novo HBV infection developed in 16.1% (5/30) of the children within a median of 11 mo after transplantation. All five of the HBV-infected children had received HBcAb-positive allografts, four of which were intrahepatic HBV DNA positive. Two of the children developed de novo HBV infection despite the preoperative presence of both HBsAb and HBcAb CONCLUSION: In pediatric recipients, positive intrahepatic HBV DNA in allografts could be a risk factor for de novo HBV infection from HBcAb-positive allografts. HBsAb/HBcAb positivity in pediatric LDLT patients before transplantation exhibited only weak effectiveness in protecting them against de novo HBV infection from HBcAb-positive allografts. PMID- 25278712 TI - Preoperative high level of D-dimers predicts unresectability of pancreatic head cancer. AB - AIM: To assess the value of D-dimer level in determining resectability of pancreatic cancer. METHODS: Preoperative prediction of pancreatic head cancer resectability remains inaccurate. The use of hemostatic factors may be of potential help, since D-dimers correlate with tumor stage. Single center clinical trial study comprised patients with potentially resectable pancreatic head tumor and without detectable venous thrombosis (n = 64). Resectability was defined as no evidence of nodal involvement, distant spread and no invasion of mesenteric vessels. Final decision of resectability was confirmed intraoperatively. Experienced pancreatic surgeon performed all surgeries. Following the dissection of hepatoduodenal ligament, samples of portal blood and bile were taken. Peripheral blood via central line and urine via Foley catheter were sampled. D dimer levels were further measured. RESULTS: At laparotomy only 29 (45.3%) tumors were found to be resectable. Our analysis showed higher by 57.5% (P < 0.001) mean D-dimer values in peripheral and 43.7% (P = 0.035) in portal blood of patients with unresectable pancreatic cancer. Significant differences were not observed when analyzing D-dimer levels in bile and urine. Peripheral D-dimer level correlated with pancreatic cancer resectability. When cut-off D-dimer value of 570.6 MUg/L was used, the sensitivity for assessment of tumor unresectability was 82.8%. Furthermore, D-dimer level in peripheral blood of metastatic disease (n = 15) was significantly higher when compared to locally advanced (n = 20) pancreatic cancer (2470 vs 1168, P = 0.029). The area under ROC curve for this subgroup of patients was 0.87; for determination of unresectable disease when threshold of 769.8 MUg/L was used, sensitivity and specificity was 86.6% and 80%, respectively. CONCLUSION: Patients with resectable pancreatic head cancer based on preoperative imaging studies and high D-dimer level may be considered unresectable due to occult hepatic metastases. These patients may benefit from diagnostic laparoscopy to avoid exploratory laparotomy. PMID- 25278713 TI - Negative methylation status of vimentin predicts improved prognosis in pancreatic carcinoma. AB - AIM: To determine the existence of a potential relationship between the methylation state of the Vimentin gene and its prognostic value in pancreatic cancer. METHODS: Sixty-four primary tumor specimens and normal tissues were collected consecutively from pancreatic cancer patients during surgery at Hangzhou First People's Hospital and Affiliated Hospital of the Logistics University of the Chinese People's Armed Police Force. DNA was extracted from the samples and subsequently quantitative methylation-specific polymerase chain reaction was used to detect the Vimentin methylation status of the samples. All of the patients were followed up to December 2012. chi(2) test, Kaplan-Meier survival and Cox regression statistical models were used. RESULTS: Out of 64 pancreatic cancer tissues, 21 were marked as Vimentin methylation-positive, and 43 were marked as Vimentin methylation-negative. The location of pancreatic carcinoma was related to the Vimentin methylation state. The pathological T staging (P < 0.001), adjuvant chemotherapy (P = 0.003) and the Vimentin methylation state (P = 0.037) were independent prognostic factors. CONCLUSION: In our study, Vimentin methylation status can predict the prognosis of pancreatic cancer patients. However, additional experiments and clinical trials are needed to accurately validate this observation. PMID- 25278714 TI - Magnetic imaging-assisted colonoscopy vs conventional colonoscopy: a randomized controlled trial. AB - AIM: To compare magnetic imaging-assisted colonoscopy (MIC) with conventional colonoscopy (CC). METHODS: Magnetic imaging technology provides a computer generated image of the shape and position of the colonoscope onto a monitor to give visual guidance to the endoscopist. It is designed to improve colonoscopy performance and tolerability for patients by enabling visualization of loop formation and endoscope position. Recently, a new version of MIC technology was developed for which there are limited data.To evaluate this latest generation of MIC among experienced rather than inexperienced or trainee endoscopists, a prospective randomized trial was performed using only gastroenterologists with therapeutic endoscopy training. Consecutive patients undergoing elective outpatient colonoscopy were randomized to MIC or CC, with patients blinded to their group assignment. Endoscopic procedural metrics and quantities of conscious sedation medications were recorded during the procedures. The procedure was classified as "usual" or "difficult" by the endoscopist at the conclusion of each case based on the need for adjunctive maneuvers to facilitate endoscope advancement. After more than one hour post-procedure, patients completed a 10 cm visual analogue pain scale to reflect the degree of discomfort experienced during their colonoscopy. The primary outcome was patient comfort expressed by the visual analogue pain score. Secondary outcomes consisted of endoscopic procedural metrics as well as a sedation score derived from standardized dose increments of the conscious sedation medications. RESULTS: Two hundred fifty-three patients were randomized and underwent MIC or CC between September 2011 and October 2012. The groups were similar in terms of the indications for colonoscopy and patient characteristics. There were no differences in cecal intubation rates (100% vs 99%), insertion distance-to-cecum (82 cm vs 83 cm), time-to-cecum (6.5 min vs 7.2 min), or polyp detection rate (47% vs 52%) between the MIC and CC groups. The primary outcome of mean pain score (1.0 vs 0.9 out of 10, P = 0.41) did not differ between MIC and CC groups, nor did the mean sedation score (8.2 vs 8.5, P = 0.34). Within the subgroup of cases considered more challenging or difficult, time-to-cecum was significantly faster with MIC compared to CC, 10.1 min vs 13.4 min respectively (P = 0.01). Sensitivity analyses confirmed a similar pattern of overall findings when each endoscopist was considered separately, demonstrating that the mean results for the entire group were not unduly influenced by outlier results from any one endoscopist. CONCLUSION: Although the latest version of MIC resulted in faster times-to-cecum within a subgroup of more challenging cases, overall it was no better than CC in terms of patient comfort, sedation requirements and endoscopic procedural metrics, when performed in experienced hands. PMID- 25278715 TI - Clinical features, outcomes and treatment-related pneumonitis in elderly patients with esophageal carcinoma. AB - AIM: To investigate the clinical features and prognoses of elderly patients with esophageal carcinoma and to compare the effects of radiotherapy and rates of treatment-related pneumonitis (TRP) between elderly and non-elderly patients. METHODS: A total of 236 patients with esophageal carcinoma who received radiotherapy between 2002 and 2012 were enrolled. The patients were divided into two groups: an elderly group (age >= 65 years) and a non-elderly group (age < 65 years). The tumor position and stage, lymph node and distant metastases, and incidence and severity of TRP were compared. Multivariate analysis was applied to identify independent prognostic factors. RESULTS: The median overall survival times after radiotherapy in the elderly and non-elderly groups were 18.5 and 20.5 mo, respectively. Cox regression analysis showed that TRP grade and tumor-node metastasis (TNM) stage were independent prognostic factors in the elderly group. High-dose radiotherapy (> 60 Gy) was associated with a high incidence of TRP. Tumor TNM staging was significantly different between the two groups in which TRP occurred. Multivariate analysis showed that TNM stage was an independent prognostic factor. Esophageal carcinoma in elderly patients was relatively less malignant compared with that in non-elderly patients. CONCLUSION: An appropriate dose should be used to decrease the incidence of TRP in radiotherapy, and intensity modulated radiation therapy should be selected if possible. PMID- 25278716 TI - Ileal intussusception due to a parasite egg: a case report. AB - Ileal intussusception is the invagination of the small intestine within itself and accounts for 1% of cases of acute obstruction. However, physicians do not initially consider intussusception as a possible diagnosis of obstruction due to its rarity in adults. Herein, we report the case of a 22-year-old male who was admitted to the Emergency Department with continuous abdominal pain. Ultrasonography and computed tomography revealed an ileal intussusception. The patient underwent surgical removal of the segment of the small bowel. Unexpectedly, pathology revealed that the invagination occurred due to a parasite egg, with features suggestive of Schistosoma species. Schistosomiasis, although considered a parasitic disease in tropical countries, is not absent from Europe and though it is highly improbable, it may be responsible for cases of intussusception in adults. PMID- 25278717 TI - Adrenal lymphangioma masquerading as a pancreatic tail cyst. AB - Cystic lymphangiomas of the adrenal gland are rare. A 79-year-old female presented in the emergency room with epigastric discomfort, and an immovable mass was palpated in her abdomen upon physical examination. Imaging studies revealed a large cystic lesion in the pancreatic tail. The radiologic impression ruled out the possibility of a mucinous cystic neoplasm, or a pseudocyst in the pancreas. The operative findings demonstrated that the cystic mass originated in the left adrenal gland. A laparoscopic excision of the cystic mass was performed, and immunohistochemistry confirmed that this mass was a lymphangioma of the adrenal gland. Several prior reports have suggested that lymphangioma can mimic renal or splenic cysts. However, lymphangioma cases mimicking pancreatic cysts are very rare. PMID- 25278718 TI - Pancreaticojejunostomy, hepaticojejunostomy and double Roux-en-Y digestive tract reconstruction for benign pancreatic diseases. AB - Surgery such as digestive tract reconstruction is usually required for pancreatic trauma and severe pancreatitis as well as malignant pancreatic lesions. The most common digestive tract reconstruction techniques (e.g., Child's type reconstruction) for neoplastic diseases of the pancreatic head often encompass pancreaticojejunostomy, choledochojejunostomy and then gastrojejunostomy with pancreaticoduodenectomy, whereas these techniques may not be applicable in benign pancreatic diseases due to an integrated stomach and duodenum in these patients. In benign pancreatic diseases, the aforementioned reconstruction will not only increase the distance between the pancreaticojejunostomy and choledochojejunostomy, but also the risks of traction, twisting and angularity of the jejunal loop. In addition, postoperative complications such as mixed fistula are refractory and life-threatening after common reconstruction procedures. We here introduce a novel pancreaticojejunostomy, hepaticojejunostomy and double Roux-en-Y digestive tract reconstruction in two cases of benign pancreatic disease, thus decreasing not only the distance between the pancreaticojejunostomy and choledochojejunostomy, but also the possibility of postoperative complications compared to common reconstruction methods. Postoperatively, the recovery of these patients was uneventful and complications such as bile leakage, pancreatic leakage and digestive tract obstruction were not observed during the follow-up period. PMID- 25278719 TI - Which statin worked best to achieve lipid level targets in a European registry? A post-hoc analysis of the EUROASPIRE III for coronary heart disease patients. AB - OBJECTIVE: The objective of the study is to determine the proportion of patients within the subsample reaching the target lipid levels defined in the European guidelines, stratified according to type and dose of statin used. BACKGROUND: Many factors affect the attainment of lipid level targets including gender, age, compliance, statin type, and dosage. This study aimed to determine the percentage of post-interventional coronary heart disease (CHD) patients who met the lipid level targets recommended by the Joint European Societies Guidelines, the medications used, and their doses. METHODS: A post-hoc analysis of a subsample of 2,000 patients from EUROASPIRE III database was selected randomly from patients who attended the interviews (between six months to three years after event). Further stratification according to type and dose of statin was performed. RESULTS: The sample comprised 74.5% males, and two thirds (63.8%) of the entire sample were over 60 years of age. More women than men showed elevated total cholesterol (>4.5 mmol/l and >4.0 mmol/l), LDL-cholesterol (>2.5 mmol/l and >2.0 mmol/l), and triglycerides (>1.7 mmol/l). Atorvastatin was the most widely used at both discharge and interview (47.1% and 45.4%) than simvastatin (37.7% and 39.4%). A dose of 20 mg atorvastatin was used by 44.10% of patients, while those on fluvastatin used a higher dose: ?40 mg in 88.31%. Patients who achieved targeted total cholesterol levels for atorvastatin, fluvastatin, lovastatin and simvastatin showed a trend in dose increase. Pravastatin users who achieved the target were taking a dose of 10 mg (75%) and less were in the 20 mg group (33.33%). Rosuvastatin users who consumed 10 mg and ?40 mg dose achieved the lipid level targets by 61.82% and 66.67%, respectively. CONCLUSION: Compliance with medications was high after a CHD incident in this European sample and the increase of the atorvastatin and simvastatin doses enabled the attainment of the target levels recommended. PMID- 25278720 TI - Value of N-terminal pro brain natriuretic peptide in predicting prognosis and severity of coronary artery disease in acute coronary syndrome. AB - BACKGROUND: Measurement of N-terminal pro brain natriuretic peptide (NT-proBNP) in the evaluation of patients with acute coronary syndrome has appeared to be a useful prognostic marker of cardiovascular risk. AIM OF THE WORK: To assess the in-hospital prognostic value of NT-proBNP in patients with acute coronary syndrome (ACS) and its relation to the severity of coronary artery disease. PATIENTS AND METHODS: This study included 132 consecutive patients with ACS, 64 patients with unstable angina (UA), 46 patients with non-ST segment elevation myocardial infarction (NSTEMI), and 22 patients with ST segment elevation myocardial infarction (STEMI). ECG, echocardiography and pre and post coronary angiography measurement of troponin I, creatine kinase (Ck), C-reactive protein (CRP) and NT-proBNP were done. Patients were divided into two groups: Group A with NT-proBNP less than 474 pg/ml and Group B with NT-proBNP equal or more than 474 pg/ml. RESULTS: There was a significant negative correlation between NT proBNP and ejection fraction. Incidence of heart failure and duration of hospital stay were significantly higher in Group B (with NT-proBNP equal or more than 474 pg/ml) than Group A (with NT-proBNP less than 474 pg/ml). Moreover, there was a trend to an increased incidence of cardiogenic shock and mortality in Group B compared to Group A. The number of coronary vessels affected, severity of stenosis and proximal left anterior descending artery (LAD) disease were higher in Group B than in Group A. TIMI flow grade was significantly higher in Group A than in Group B. CONCLUSION: NT-proBNP is a valuable marker for predicting prognosis and severity of coronary artery disease in patients with acute coronary syndrome. PMID- 25278721 TI - Ultrasound guided vascular access in pediatric cardiac critical care. AB - INTRODUCTION: Safely obtaining vascular access in the pediatric population is challenging. This report highlights our real-world experience in developing a safer approach to obtaining vascular access using ultrasound guidance in children and infants with congenital heart disease. METHODS: As part of a quality initiative, we prospectively monitored outcomes of all vascular access attempts guided by ultrasound from January 2010 to September 2010. Variables monitored included age, weight, the time from first needle puncture to wire insertion, site of insertion, number of attempts, type of line, and complications. RESULTS: There were 77 attempts (15 arterial and 62 venous) to obtain vascular access in 43 patients. The mean age was 15 months (6 days-11 years; median 2.5 months). The mean weight was 7.2 kg (2-46 kg, median 3.8). Success rates were 93% and 95% for arterial and venous cannulation, respectively. Mean time from first needle puncture to wire insertion was 3.9 min (0.5-15 min, median 2 min). Fifty-five (75%) central line cannulations were successful from the first puncture; 17(23%) were successful from the second puncture; and one case (2%) required three punctures. Thirty patients (45%) weighed less than 3.5 kg. This lower body weight did not affect success rate, which was unexpectedly high (96.6%). There were no associated complications. CONCLUSION: Ultrasound guided vascular cannulation in critically ill pediatric patients is safe, effective and efficient. This approach had a high success rate, and was associated with zero complications in our setting. PMID- 25278722 TI - Comparative study between real time three dimensional echocardiogram and angiography in evaluation of patent ductus arteriosus, single center experience. AB - In this study we compared the real time three dimensional echocardiogram data in evaluation of patent ductus arteriosus with the gold standard angiography. METHODS: This study included 25 patients with PDA referred to Tanta University Hospital for elective cardiac catheterization. The patients comprised seven males and 18 females, with a mean age of 3.7 +/- 0.36 years. The study duration was six months. All patients underwent full 2D echocardiogram as well as real time three dimensional echocardiogram (RT3DE). Essential measurements included the pulmonary end of the duct, duct length, aortic end and aortic ampulla as well as the anatomical type of the PDA. Data obtained by RT3DE were compared against 2D echocardiogram and angiography. RESULTS: There was no significant difference between 3D echocardiogram and angiography (P = 0.001) in the pulmonary end of the duct measurement. Neither were there any significant differences between the length of the duct or the aortic end measured by 3D echocardiogram and by angiography (P = 0.001 in both). While there was adequate agreement between both 2D and 3D echocardiogram and angiography in determining the anatomical type of the PDA, 3D echocardiogram determined type A and type E ductus more accurately than 2D echocardiogram. The feasibility of Q lab analysis of PDA was 96%, while the feasibility of gated color flow 3D acquisitions in determining anatomical types was 64%. CONCLUSION: There was complete agreement on location, size, morphology and surrounding structure of PDA between 2D and 3D echocardiogram, and angiography. This result illustrates the need for the proper placement of the device in catheterization laboratories. PMID- 25278723 TI - The cardiac patient during Ramadan and Hajj. AB - The holy month of Ramadan is one of the five pillars of Islam. During this month, fasting Muslims refrain from eating, drinking, smoking, and sex from dawn until sunset. Although the Quran exempts sick people from the duty of fasting, it is not uncommon for many heart disease patients to fast during Ramadan. Despite the fact that more than a billion Muslims worldwide fast during Ramadan, there is no clear consensus on its effects on cardiac disease. Some studies have shown that the effects of fasting on stable patients with cardiac disease are minimal and the majority of patients with stable cardiac illness can endure Ramadan fasting with no clinical deterioration. Fasting during Ramadan does not seem to increase hospitalizations for congestive heart failure. However, patients with decompensated heart failure or those requiring large doses of diuretics are strongly advised not to fast, particularly when Ramadan falls in summer. Patients with controlled hypertension can safely fast. However, patients with resistant hypertension should be advised not to fast until their blood pressure is reasonably controlled. Patients with recent myocardial infarction, unstable angina, recent cardiac intervention or cardiac surgery should avoid fasting. Physician advice should be individualized and patients are encouraged to seek medical advice before fasting in order to adjust their medications, if required. The performance of the Hajj pilgrimage is another pillar of Islam and is obligatory once in the lifetime for all adult Muslims who are in good health and can afford to undertake the journey. Hajj is a physically, mentally, emotionally, and spiritually demanding experience. Medical checkups one or two months before leaving for Hajj is warranted, especially for those with chronic illnesses such as cardiovascular disease. Patients with heart failure, uncontrolled hypertension, serious arrhythmias, unstable angina, recent myocardial infarction, or cardiac surgery should be considered unfit for undertaking the Hajj pilgrimage. PMID- 25278724 TI - Severe reversible myocardial injury associated with aluminium phosphide toxicity: A case report and review of literature. AB - Aluminium phosphide is commonly used as an insecticide and can be toxic to humans at the cellular level by interfering with mitochondrial energy metabolism. We report on three cases of severe aluminium phosphide cardio-toxicity, resulting in severe decrease in both ventricular heart functions. The first case succumbed to intractable ventricular arrhythmias complicated by multi-organ failure before she died; while the other two cases required invasive hemodynamic support and eventually improved over the course of 10-14 days. We describe our experience and the challenges faced while managing one of them. PMID- 25278725 TI - The innovation of composite core dual coil coronary guide-wire technology: A didactic coronary chronic total occlusion revascularization case report. AB - The treatment of coronary chronic total occlusions (CTO) continues to solicit technical innovations. As success primarily depends on crossing the lesion with a wire, all aspects regarding tip shape retention, torque precision, and penetration ability of the guide-wire have greatly influenced new techniques and strategies. The world of interventional cardiology has to look carefully at these developments, and to use them accordingly to improve the success rate in ordinary percutaneous coronary interventions. We present a didactical case report of a CTO revascularization treated with a new 'dual core' technology guide-wire. PMID- 25278727 TI - The QT measurements after biventricular pacing, is it reliable? PMID- 25278726 TI - Neo-atherosclerosis in very late stent thrombosis of drug eluting stent. AB - BACKGROUND: Recent studies have described neo-atherosclerosis, developing inside the stent, as cause of very late stent thrombosis. CASE REPORT: A 59-year-old man, with family history of coronary artery disease, presented to our Department because of anterior ST-segment elevation myocardial infarction. Two years before he had underwent percutaneous coronary intervention with multiple drug-eluting stents (DES) implantation on proximal-mid left anterior descending artery (LAD), and mid-right coronary artery (RCA), respectively. The angiogram revealed stent thrombosis with total occlusion of proximal LAD. Multiple passages with manual thrombus-aspiration catheter were successfully performed with improvement in TIMI flow. Optical Coherence Tomography (OCT) imaging revealed fully expanded stents without areas of inappropriate apposition to vessel wall; and mild to moderate intimal hyperplasia throughout the stented segment, with full covered stent struts; areas of ulcerated and ruptured plaque within the proximal struts of stented segment was depicted with intraluminal protruding material. Thus, an additional bare metal stent (BMS) was deployed inside and overlapping the previous in order to seal this plaque. OCT post procedure revealed optimal stent expansion and apposition, without residual protruding material. At 9-month follow up patient was alive and free from symptoms. Coronary angiogram revealed patency of implanted stents without significant restenosis. CONCLUSIONS: Neo atherosclerosis with thrombosis on top of ruptured necrotic plaque core may play a role in the pathophysiology of very late stent thrombosis in both BMS and DES. Our report highlights the role OCT to assess the mechanism of VLST. PMID- 25278728 TI - Reply to: The QT measurements after biventricular pacing, is it reliable? PMID- 25278730 TI - Reply to "Congenital right lung hypoplasia associated with dextrocardia". PMID- 25278729 TI - Congenital right lung hypoplasia associated with dextrocardia. PMID- 25278731 TI - A heart on the wrong side. PMID- 25278732 TI - Harm reduction. AB - The "Harm Reduction" session was chaired by Dr. Jacques Normand, Director of the AIDS Research Program of the U.S. National Institute on Drug Abuse. The three presenters (and their presentation topics) were: Dr. Don Des Jarlais (High Coverage Needle/Syringe Programs for People Who Inject Drugs in Low and Middle Income Countries: A Systematic Review), Dr. Nicholas Thomson (Harm Reduction History, Response, and Current Trends in Asia), and Dr. Jih-Heng Li (Harm Reduction Strategies in Taiwan). PMID- 25278733 TI - Introduction to the Special Issue: Promoting global health-treatment and prevention of substance abuse and HIV in Asia. PMID- 25278734 TI - Current status of substance abuse and HIV infection in Japan. AB - Japan has experienced an epidemic of methamphetamine (MAP) abuse three times: The first epidemic was from 1951 to 1957, the second epidemic was from 1970 to 1994, and the third epidemic started in 1995 and continues today. Fortunately, HIV infection is not as serious a problem in Japan as it is in other countries. The major route of HIV infection in Japan has been through male homosexual transmission. In cumulative number, homosexual transmission accounted for 63% of the 11,146 HIV-positive patients and 40% of 5,158 AIDS patients as of December 30, 2011. Intravenous drug use accounted for 0.3% and 0.4% of these cases, respectively. Drug abuse has changed during the past 20 years in Japan. The changes are summarized as follows: There has been (1) a remarkable decrease in solvent abuse, (2) a stabilization of MAP abuse, (3) a penetration of cannabis abuse, (4) an emergence of evasive drug abuse, and (5) a silent increase in medical drug dependence. This implies that (1) there has been a change from a "solvent dominant type" of use to a "cannabis dominant type," that is, from a "Japanese type" to a "Western type," (2) a shift to drugs which do not have a high potential to cause drug-induced psychosis, and (3) a shift from conduct that leads to arrest to conduct that does not lead to arrest. Regardless of whether the drug use is illicit or not, drug dependence is a mental disorder. Japan is urged to deal with drug abuse and dependence using not only the criminal model but also the medical model. PMID- 25278735 TI - HIV: seek, test, treat, and retain. AB - The "HIV: Seek, Test, Treat, and Retain" session was chaired by Dr. Jacques Normand, the Director of AIDS Research at the U.S. National Institute on Drug Abuse. Dr. Yi-Ming Chen served as the discussant. The three presenters (and their presentation topics) were: Dr. Julio Montaner (Treatment as Prevention-The Key to an AIDS-free Generation), Dr. Chi-Tai Fang (Population-level Effect of Free Access to HAART on Reducing HIV Transmission in Taiwan), and Dr. Zunyou Wu (Challenges in Promoting HIV Test & Treat Strategy in China). PMID- 25278736 TI - Substance use disorders and HIV in Vietnam since Doi Moi (Renovation): an overview. AB - Drawing from published and gray literature, this manuscript focuses on the following topics: (1) changing patterns of substance use and abuse in Vietnam since the early 1990s; (2) the roles of substance use in the HIV epidemic; (3) the responses of the Vietnamese government and other entities (both domestic and international) to substance use disorders (SUDs) and HIV; and (4) the current research capacity in Vietnam and ways in which furthering research in Vietnam could enrich our knowledge of the linkages between SUDs and HIV and of effective measures to reduce their public health consequences. A growing number of studies during the past two decades show dynamic and still evolving twin epidemics of SUDs and HIV in Vietnam, including a shift from consumption of opium to heroin and amphetamine-type stimulants, the concurrent use of drugs, and the increasing embrace by the government of internationally recognized effective responses (including harm reduction and methadone substitution therapy). And yet, remaining issues, such as the rapid ascendance of amphetamine-type stimulant use among the country's most vulnerable populations, the lack of effective integration of SUD and HIV services for HIV-infected drug users, and the reliance on international resources for maintaining quality services, among others, are posing challenges for building sustainable Vietnamese responses. Therefore, building local research and training capacity is a crucial foundation to meet these challenges. PMID- 25278737 TI - Substance Abuse and the HIV Situation in Malaysia. AB - Heroin continues to be the main drug used in Malaysia, while amphetamine-type stimulants (ATS) have been recently identified as a growing problem. A cumulative total of 300,241 drug users were detected between 1988 and 2006. It is also estimated that Malaysia has 170,000 injecting drug users. HIV prevalence among drug users in the country ranges from 25% to 45%. Currently, there are approximately 380 general medical practice offices that offer agonist maintenance treatments for approximately 10,000 patients. There are 27,756 active patients in 333 general medical practice offices and government-run methadone maintenance treatment (MMT) centers. The Needle Syringe Exchange Program (NSEP) reached out to 34,244 injection drug users (IDUs) in 2011. In the last 2 years (2011 and 2012) the number of detected drug addicts decreased from 11,194 to 9015. The arrests made by the police related to opiate and cannabis use increased from 41,363 to 63,466 between the years 2008 and 2010, but decreased since 2010. An almost four-fold increase in the number of ATS and ketamine users was detected from 2006 (21,653 users) 2012 (76,812). Between 2004 and 2010, the yearly seizures for heroin ranged between 156 to 270 kg. However, in 2010 and 2011, heroin seizures showed a significant increase of 445kg and 410.02 kg, respectively. There has been a seizure of between 600 to 1000kg of syabu yearly from 2009 to 2012. Similar to heroin, increased seizures for Yaba have also been observed over the last 2 years. A significant increase has also been recorded for the seizures of ecstasy pills from 2011 (47,761 pills) to 2012 (634,573 pills). The cumulative number of reported HIV infections since 1986 is 94,841. In 2011, sexual activity superseded injection drug use as the main transmission factor for the epidemic. HIV in the country mainly involves males, as they constitute 90% of cumulative HIV cases and a majority of those individuals are IDUs. However, HIV infection trends are shifting from males to females. There are 37,306 people living with HIV (PLHIV) who are eligible for treatment, and 14,002 PLHIV were receiving antiretroviral treatment (ART) in 2011. The decreasing trend of heroin users who have been detected and arrested could be due to the introduction of medical treatments and harm reduction approaches for drug users, resulting in fewer drug users being arrested. However, we are unable to say with certainty why there has been an increase in heroin seizures in the country. There has been an increasing trend in both ATS users and seizures. A new trend of co-occurring opiate dependence and ATS underscores the need to develop and implement effective treatments for ATS, co-occurring opiate and ATS, and polysubstance abuse disorders. The low numbers of NSEP clients being tested for HIV underscores our caution in interpreting the decline of HIV infections among drug users and the importance of focusing on providing education, prevention, treatment, and outreach to those who are not in treatment. PMID- 25278738 TI - Pharmacogenomics study in a Taiwan methadone maintenance cohort. AB - Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future methadone dosage adjustment and to reduce adverse reactions. PMID- 25278739 TI - Attenuated Fractional Wave Equations With Anisotropy. AB - This paper develops new fractional calculus models for wave propagation. These models permit a different attenuation index in each coordinate to fully capture the anisotropic nature of wave propagation in complex media. Analytical expressions that describe power law attenuation and anomalous dispersion in each direction are derived for these fractional calculus models. PMID- 25278740 TI - Comparison of Poroviscoelastic Models for Sound and Vibration in the Lungs. AB - Noninvasive measurement of mechanical wave motion (sound and vibration) in the lungs may be of diagnostic value, as it can provide information about the mechanical properties of the lungs, which in turn are affected by disease and injury. In this study, two previously derived theoretical models of the vibroacoustic behavior of the lung parenchyma are compared: (1) a Biot theory of poroviscoelasticity and (2) an effective medium theory for compression wave behavior (also known as a "bubble swarm" model). A fractional derivative formulation of shear viscoelasticity is integrated into both models. A measurable "fast" compression wave speed predicted by the Biot theory formulation has a significant frequency dependence that is not predicted by the effective medium theory. Biot theory also predicts a slow compression wave. The experimentally measured fast compression wave speed and attenuation in a pig lung ex vivo model agreed well with the Biot theory. To obtain the parameters for the Biot theory prediction, the following experiments were undertaken: quasistatic mechanical indentation measurements were performed to estimate the lung static shear modulus; surface wave measurements were performed to estimate lung tissue shear viscoelasticity; and flow permeability was measured on dried lung specimens. This study suggests that the Biot theory may provide a more robust and accurate model than the effective medium theory for wave propagation in the lungs over a wider frequency range. PMID- 25278741 TI - In The Best Interest Of The (Adult) Child: Ideas About Kinship Care Of Older Adults. AB - This article uses a qualitative, ethnographic approach to examine the experiences older adults and their kin, as the older adult engages in relocation. Studies looking at caregiving by kin for older adults highlight burdens for the adult child. This study offers a life course perspective on kinship care, analyzing older adults' decisions' to move. It was found that many older adults are strongly influenced by the desire to not be cared for by their kin as well as to select housing near their existing social network, which might exclude kin. In conclusion, policy implications are discussed. PMID- 25278742 TI - Random walks based multi-image segmentation: Quasiconvexity results and GPU-based solutions. AB - We recast the Cosegmentation problem using Random Walker (RW) segmentation as the core segmentation algorithm, rather than the traditional MRF approach adopted in the literature so far. Our formulation is similar to previous approaches in the sense that it also permits Cosegmentation constraints (which impose consistency between the extracted objects from >= 2 images) using a nonparametric model. However, several previous nonparametric cosegmentation methods have the serious limitation that they require adding one auxiliary node (or variable) for every pair of pixels that are similar (which effectively limits such methods to describing only those objects that have high entropy appearance models). In contrast, our proposed model completely eliminates this restrictive dependence the resulting improvements are quite significant. Our model further allows an optimization scheme exploiting quasiconvexity for model-based segmentation with no dependence on the scale of the segmented foreground. Finally, we show that the optimization can be expressed in terms of linear algebra operations on sparse matrices which are easily mapped to GPU architecture. We provide a highly specialized CUDA library for Cosegmentation exploiting this special structure, and report experimental results showing these advantages. PMID- 25278743 TI - An open letter to the FDA and other regulatory agencies: Preclinical drug development must consider the impact on metastasis. PMID- 25278744 TI - Surgical treatment for medically refractory myasthenic blepharoptosis. AB - PURPOSE: Currently, only a few reports have recommended surgery as a suitable treatment for blepharoptosis associated with myasthenia gravis. The present study aims to introduce our surgical criteria, surgical options, outcomes, and precautions for medically refractory myasthenic blepharoptosis. PATIENTS AND METHODS: Eight patients who failed to respond to at least 2 years of medical treatment and who underwent blepharoptosis surgery, from January 2008 to December 2011, were enrolled in this study. Medical records, photographs, and questionnaire results regarding postoperative status were evaluated. Of the eleven procedures performed, four involved frontal suspension, four involved external levator advancement, one involved nonincisional transconjunctival levator advancement, and two involved subbrow blepharoplasty with orbicularis oculi muscle tucking. The margin reflex distance improved postoperatively in seven patients. RESULTS: Seven patients had very minimal scarring, and one had minimal scarring. Five patients showed no eyelid asymmetry, one had subtle asymmetry, and two had obvious asymmetry. Seven patients were very satisfied, and one patient was satisfied with the overall result. Postoperative complications included mild lid lag with incomplete eyelid closure, prolonged scar redness, and worsened heterophoria. No patient experienced postoperative exposure keratitis or recurrent blepharoptosis during the study period. CONCLUSION: Our results indicate that blepharoptosis surgery is effective for patients with myasthenia gravis, especially those with residual blepharoptosis despite multiple sessions of medical treatments. We recommend that neurologists and surgeons collaborate more systematically and discuss comprehensive treatment plans to increase the quality of life for patients with myasthenia gravis. PMID- 25278745 TI - Time and dose relationships between schisandrin B- and schisandrae fructus oil induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice. AB - BACKGROUND: Schisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice. METHODS: Institute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125-2 g/kg) or SFO (0.3-5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6-120 hours postdosing. RESULTS: Serum ALT activity was elevated by 60%, with maximum effect (E(max)) = 45.77 U/L and affinity (K(D)) = 1.25 g/kg at 48-96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (E(max) =2.30 nmol/mg protein and K(D) =0.41 g/kg) and 22% (E(max) = 1.42 nmol/mg protein and K D = 2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%-60% (E max = 11.01, K(D) = 0.68 g/kg) and 8%-32% (E(max) = 9.88, K D = 4.47 g/kg) at 12-120 hours and 24-120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%-158% and 35%-85%, respectively, at 12-96 hours and 6 48 hours after Sch B and SFO treatment, respectively. The values of E max and K D for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 MUmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of E(max) = 5.50/4.60 mmol/L and K D = 0.43/2.84 g/kg, respectively. CONCLUSION: The findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The E max and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO. PMID- 25278748 TI - A cross-sectional study to assess the feasibility of a short message service to improve adherence of outpatients undergoing sedation gastrointestinal endoscopy in the People's Republic of China. AB - BACKGROUND: Adherence to the prescribed preparation regimen for patients scheduled for sedation gastrointestinal endoscopy (SGIE) often fails to meet health care providers' expectations. Therefore, the feasibility of using mobile phones to improve the adherence of outpatients was assessed among outpatients scheduled for SGIE. METHODS: The study was designed as a cross-sectional study using survey questionnaires. Outpatients who would be undergoing SGIE were enrolled. The main outcomes included proportions of outpatients who have access to mobile phones, and the use of text-messaging among outpatients. Willingness to receive text messages and personal opinions about short message service (SMS) were also investigated. Characteristics of outpatients, including socio demographic factors, with a mobile phone (or those who could receive and read messages) compared with those without a mobile phone (or those who could not receive and read messages) were compared using the chi-square test. Logistic regression was used to analyze significant contributing factors associated with mobile phone ownership and the use of text messages. RESULTS: A large majority of outpatients owned personal mobile phones (94.9%) and could receive and read the messages (78.9%). Most of the outpatients were willing to receive a pre-procedure education via text message (81.9%). Outpatients aged 16-39 years old and those with a college education or higher were more likely to use mobile phones and read SMS than outpatients aged 60-80 years old and those with only a primary education level (P<0.0001). Outpatients who lived in an urban setting were more likely to own a mobile phone than outpatients who lived in a rural setting (P=0.002). CONCLUSION: The accessibility of mobile phones and the frequent use of message functions on mobile phones provide support for the initiation of an SMS reminder system for outpatients who will undergo SGIE in the People's Republic of China. In addition, the characteristics of the target study population should be considered when carrying out an SMS intervention. PMID- 25278747 TI - Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands. AB - A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6 triaminopyrimidine (compounds 2-7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Galphai2 and Gbeta1gamma2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N (4)-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N benzylamine and substitution of an amine group at the 2-position of the 2 aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N (4)-benzyl-N (2)-(4-(3-(piperidin-1 yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (k(i) =4.49 +/- 1.25 nM) and H3R receptor subtype selectivity of more than 6,500*. Moreover, initial metric analyses were conducted based on their target oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5-650 nM), moderate to low hH4R affinity (4,500-30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8-6,500), and promising calculated drug-likeness properties. PMID- 25278746 TI - Ferulago angulata activates intrinsic pathway of apoptosis in MCF-7 cells associated with G1 cell cycle arrest via involvement of p21/p27. AB - Ferulago angulata is a medicinal plant that is traditionally known for its anti inflammatory and antiulcer properties. The present study was aimed to evaluate its anticancer activity and the possible mechanism of action using MCF-7 as an in vitro model. F. angulata leaf extracts were prepared using solvents in the order of increasing polarity. As determined by MTT assay, F. angulata leaves hexane extract (FALHE) revealed the strongest cytotoxicity against MCF-7 cells with the half maximal inhibitory concentration (IC50) value of 5.3 +/- 0.82 MUg/mL. The acute toxicity study of FALHE provided evidence of the safety of the plant extract. Microscopic and flow cytometric analysis using annexin-V probe showed an induction of apoptosis in MCF-7 by FALHE. Treatment of MCF-7 cells with FALHE encouraged the intrinsic pathway of apoptosis, with cell death transducing signals that reduced the mitochondrial membrane potential with cytochrome c release from mitochondria to cytosol. The released cytochrome c triggered the activation of caspase-9. Meanwhile, the overexpression of caspase-8 suggested the involvement of an extrinsic pathway in the induced apoptosis at the late stage of treatment. Moreover, flow cytometric analysis showed that FALHE treatment significantly arrested MCF-7 cells in the G1 phase, which was associated with upregulation of p21 and p27 assessed by quantitative polymerase chain reaction. Immunofluorescence and the quantitative polymerase chain reaction analysis of MCF 7 cells after treatment with FALHE revealed an upregulation of Bax and a downregulation of Bcl-2 proteins. These findings proposed that FALHE suppressed the proliferation of MCF-7 cells via cell cycle arrest and the induction of apoptosis through intrinsic pathway. PMID- 25278749 TI - Comparison of one-year clinical outcomes between intravascular ultrasound-guided versus angiography-guided implantation of drug-eluting stents for left main lesions: a single-center analysis of a 1,016-patient cohort. AB - BACKGROUND: The importance of intravascular ultrasound (IVUS)-guided stenting of the unprotected left main coronary artery (ULMCA) remains controversial and has not been fully studied in the subset of patients with ULMCA. This study evaluated the clinical outcome of IVUS-guided stenting using a drug-eluting stent for ULMCA. METHODS: A total of 1,016 consecutive patients with ULMCA stenosis who underwent drug-eluting stent implantation from January 2006 to December 2011 were prospectively registered. The primary endpoint of this nonrandomized registry was the rate of one-year major adverse cardiac events (MACE, including cardiac death, myocardial infarction, and target vessel revascularization). Stent thrombosis served as the safety endpoint. Propensity score matching was used to calculate the adjusted event rate. RESULTS: The unadjusted one-year MACE rate was 14.8% in the IVUS-guided group (n=337, 33.2%), significantly different from the 27.7% (P<0.001) in the angiography-guided group (n=679, 66.8%). After propensity score matching, 291 paired patients were matched between the two groups, and the difference in one-year MACE between IVUS-guided (16.2%) versus angiography-guided (24.4%) groups was still significant (P=0.014), mainly driven by decreased rates of cardiac death (1.7%) and target vessel revascularization (3.4%) in the IVUS guided group when compared with 5.2% (P=0.023) and 10.0% (P=0.002) in the angiography-guided group, respectively. Although it did not reach significance (P=0.075), the adjusted one-year rate of stent thrombosis in the angiography guided group was higher than in the IVUS-guided group. CONCLUSION: Compared with angiography guidance, IVUS-guided treatment of ULMCA using a drug-eluting stent was associated with a significant reduction of one-year cardiac death and target vessel revascularization, resulting in less frequent one-year MACE after propensity score matching. PMID- 25278750 TI - Predicting adverse drug reactions in older adults; a systematic review of the risk prediction models. AB - Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR. PMID- 25278751 TI - Antimicrobial nanocapsules: from new solvent-free process to in vitro efficiency. AB - Skin and mucosal infections constitute recurrent pathologies resulting from either inappropriate antiseptic procedures or a lack of efficacy of antimicrobial products. In this field, nanomaterials offer interesting antimicrobial properties (eg, long-lasting activity; intracellular and tissular penetration) as compared to conventional products. The aim of this work was to produce, by a new solvent free process, a stable and easily freeze-dryable chlorhexidine-loaded polymeric nanocapsule (CHX-NC) suspension, and then to assess the antimicrobial properties of nanomaterials. The relevance of the process and the physicochemical properties of the CHX-NCs were examined by the assessment of encapsulation efficiency, stability of the nanomaterial suspension after 1 month of storage, and by analysis of granulometry and surface electric charge of nanocapsules. In vitro antimicrobial activities of the CHX-NCs and chlorhexidine digluconate solution were compared by measuring the inhibition diameters of two bacterial strains (Escherichia coli and Staphylococcus aureus) and one fungal strain (Candida albicans) cultured onto appropriate media. Based on the findings of this study, we report a new solvent-free process for the production of nanomaterials exhibiting antimicrobial activity, suitable stability, and easily incorporable as a new ingredient in various pharmaceutical products. PMID- 25278752 TI - Nanoencapsulation of the sasanquasaponin from Camellia oleifera, its photo responsiveness and neuroprotective effects. AB - Sasanquasaponin, a bioactive compound isolated from seeds of Camellia oleifera, shows central effects in our previous research. In order to investigate its neuroprotective effects, a new kind of nanocapsule with photo responsiveness was designed to deliver sasanquasaponin into the brain and adjusted by red light. The nanocapsule was prepared using sasanquasaponin emulsified with soybean lecithin and cholesterol solution. The natural phaeophorbide from silkworm excrement as a photosensitizer was added in the lipid phase to make the nanocapsules photo responsive. The physicochemical properties of encapsulation efficiency, size distribution, morphology and stability were measured using high-performance liquid chromatography, particle size analyzer, transmission electron microscope, differential scanning calorimetry and thermogravimetry. Photo responsiveness was determined by the sasanquasaponin release in pH 7.5 phosphate buffer under the laser at 670 nm. The neuroprotective effects were evaluated by the expression of tyrosine hydroxylase (TH), decrease of inflammatory cytokines TNF-alpha and IL 1beta in the brain, and amelioration of kainic acid-induced behavioral disorder in mice. The nanocapsules had higher encapsulation efficiency and stability when the phaeophorbide content was 2% of lecithin weight. The average size was 172.2 nm, distributed in the range of 142-220 nm. The phaeophorbide was scattered sufficiently in the outer lecithin layer of the nanocapsules and increased the drug release after irradiation. TH expression in brain tissues and locomotive activities in mice were reduced by kainic acid, but could be improved by the sasanquasaponin nanocapsules after tail vein injection with 15 minutes of irradiation at the nasal cavity. The sasanquasaponin took effect through inflammatory alleviation in central tissues. The sasanquasaponin nanocapsules with phaeophorbide have photo responsiveness and neuroprotective effects under the irradiation of red light. This preparation presents a new approach to brain neuroprotection, and has potential for clinical application. PMID- 25278753 TI - Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer. AB - The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers. PMID- 25278754 TI - No change in N-acetyl aspartate in first episode of moderate depression after antidepressant treatment: (1)H magnetic spectroscopy study of left amygdala and left dorsolateral prefrontal cortex. AB - BACKGROUND: The role of brain metabolites as biological correlates of the intensity, symptoms, and course of major depression has not been determined. It has also been inconclusive whether the change in brain metabolites, measured with proton magnetic spectroscopy, could be correlated with the treatment outcome. METHODS: Proton magnetic spectroscopy was performed in 29 participants with a first episode of moderate depression occurring in the left dorsolateral prefrontal cortex and left amygdala at baseline and after 8 weeks of antidepressant treatment with escitalopram. The Montgomery-Asberg Depression Rating Scale, the Hamilton Rating Scale for Depression, and the Beck Depression Inventory were used to assess the intensity of depression at baseline and at the endpoint of the study. At endpoint, the participants were identified as responders (n=17) or nonresponders (n=12) to the antidepressant therapy. RESULTS: There was no significant change in the N-acetyl aspartate/creatine ratio (NAA/Cr) after treatment with antidepressant medication. The baseline and endpoint NAA/Cr ratios were not significantly different between the responder and nonresponder groups. The correlation between NAA/Cr and changes in the scores of clinical scales were not significant in either group. CONCLUSION: This study could not confirm any significant changes in NAA after antidepressant treatment in the first episode of moderate depression, or in regard to therapy response in the left dorsolateral prefrontal cortex or left amygdala. Further research is necessary to conclude whether NAA alterations in the first episode of depression could possibly be different from chronic or late-onset depression, and whether NAA alterations in stress-induced (reactive) depression are different from endogenous depression. The potential role of NAA as a biomarker of a treatment effect has yet to be established. PMID- 25278755 TI - Altered intrinsic regional brain activity in male patients with severe obstructive sleep apnea: a resting-state functional magnetic resonance imaging study. AB - BACKGROUND: Previous studies have demonstrated that obstructive sleep apnea (OSA) is associated with abnormal brain structural deficits. However, little is known about the changes in local synchronization of spontaneous activity in patients with OSA. The primary aim of the present study was to investigate spontaneous brain activity in patients with OSA compared with good sleepers (GSs) using regional homogeneity (ReHo) analysis based on resting-state functional magnetic resonance imaging (MRI). METHODS: Twenty-five untreated male patients with severe OSA and 25 male GSs matched for age and years of education were included in this study. The ReHo method was calculated to assess the strength of local signal synchrony and was compared between the two groups. The observed mean ReHo values were entered into Statistical Package for the Social Sciences software to assess their correlation with behavioral performance. RESULTS: Compared with GSs, patients with OSA showed significantly lower ReHo in the right medial frontal gyrus (BA11), right superior frontal gyrus (BA10), right cluster of the precuneus and angular gyrus (BA39), and left superior parietal lobule (BA7), and higher ReHo in the right posterior lobe of the cerebellum, right cingulate gyrus (BA23), and bilateral cluster covering the lentiform nucleus, putamen, and insula (BA13). The lower mean ReHo value in the right cluster of the precuneus and angular gyrus had a significant negative correlation with sleep time (r=-0.430, P=0.032), and higher ReHo in the right posterior lobe of the cerebellum showed a significant positive correlation with stage 3 sleep (r=0.458, P=0.021) and in the right cingulate gyrus showed a significant positive correlation with percent rapid eye movement sleep (r=0.405, P=0.045). CONCLUSION: Patients with OSA showed significant regional spontaneous activity deficits in default mode network areas. The ReHo method is a useful noninvasive imaging tool for detection of early changes in cerebral ReHo in patients with OSA. PMID- 25278756 TI - End-of-Life Decisions about Withholding or Withdrawing Therapy: Medical, Ethical, and Religio-Cultural Considerations. AB - Towards the end of life, physicians face dilemmas of discontinuing life sustaining treatments or interventions. In some circumstances, these treatments are no longer of benefit, while in others the patient or family no longer want them. The physician plays an essential role in clarifying the goals of medical treatment, defining the care plan, initiating discussions about life-sustaining therapy, educating patients and families, helping them deliberate, making recommendations, and implementing the treatment plan. Communication is key. It should be clarified that when inevitable death is imminent, it is legitimate to refuse or limit forms of treatment that would only secure a precarious and burdensome prolongation of life, for as long as basic humane, compassionate care is not interrupted. Agreement to DNR status does not preclude supportive measures that keep patients free from pain and suffering as possible. Acceptable clinical practice on withdrawing or withholding treatment is based on an understanding of the medical, ethical, cultural, and religious issues. There is a need to individualize care option discussions to illness status, and patient and family preferences, beliefs, values, and cultures. The process of shared decision making between the patient, the family, and the clinicians should continue as goals evolve and change over time. PMID- 25278757 TI - Program assessment framework for a rural palliative supportive service. AB - Although there are a number of quality frameworks available for evaluating palliative services, it is necessary to adapt these frameworks to models of care designed for the rural context. The purpose of this paper was to describe the development of a program assessment framework for evaluating a rural palliative supportive service as part of a community-based research project designed to enhance the quality of care for patients and families living with life-limiting chronic illness. A review of key documents from electronic databases and grey literature resulted in the identification of general principles for high-quality palliative care in rural contexts. These principles were then adapted to provide an assessment framework for the evaluation of the rural palliative supportive service. This framework was evaluated and refined using a community-based advisory committee guiding the development of the service. The resulting program assessment framework includes 48 criteria organized under seven themes: embedded within community; palliative care is timely, comprehensive, and continuous; access to palliative care education and experts; effective teamwork and communication; family partnerships; policies and services that support rural capacity and values; and systematic approach for measuring and improving outcomes of care. It is important to identify essential elements for assessing the quality of services designed to improve rural palliative care, taking into account the strengths of rural communities and addressing common challenges. The program assessment framework has potential to increase the likelihood of desired outcomes in palliative care provisions in rural settings and requires further validation. PMID- 25278758 TI - Grief and palliative care: mutuality. AB - Grief and palliative care are interrelated and perhaps mutually inclusive. Conceptually and practically, grief intimately relates to palliative care, as both domains regard the phenomena of loss, suffering, and a desire for abatement of pain burden. Moreover, the notions of palliative care and grief may be construed as being mutually inclusive in terms of one cueing the other. As such, the discussions in this article will center on the conceptualizations of the mutuality between grief and palliative care related to end-of-life circumstances. Specifically, the complementarity of grief and palliative care, as well as a controvertible view thereof, will be considered. PMID- 25278759 TI - Situational analysis of palliative care education in thai medical schools. AB - OBJECTIVE: The Thai Medical School Palliative Care Network conducted this study to establish the current state of palliative care education in Thai medical schools. METHODS: A questionnaire survey was given to 2 groups that included final year medical students and instructors in 16 Thai medical schools. The questionnaire covered 4 areas related to palliative care education. RESULTS: An insufficient proportion of students (defined as fewer than 60%) learned nonpain symptoms control (50.0%), goal setting and care planning (39.0%), teamwork (38.7%), and pain management (32.7%). Both medical students and instructors reflected that palliative care education was important as it helps to improve quality of care and professional competence. The percentage of students confident to provide palliative care services under supervision of their senior, those able to provide services on their own, and those not confident to provide palliative care services were 57.3%, 33.3%, and 9.4%, respectively. CONCLUSIONS: The lack of knowledge in palliative care in students may lower their level of confidence to practice palliative care. In order to prepare students to achieve a basic level of competency in palliative care, each medical school has to carefully put palliative care content into the undergraduate curriculum. PMID- 25278760 TI - Pediatric palliative care: a reflection on terminology. AB - The definition of palliative care is the cornerstone of a medical subspecialty that plays a particular role for all who need it, for all who practice it, and increasingly for those who try to understand it. The difficulties around the definition and terminology arise from problems in separating it from other concepts such as supportive care, constructs such as "palliative care is only about dying", or, in children, the rather vague use of terms like life threatening and life-limiting diseases. These weaknesses have been recognized and important steps have been taken. This review discusses current definitions as well as efforts to overcome their weaknesses and make the term palliative care for both children and adults-more intelligible. PMID- 25278761 TI - Psychiatric issues in palliative care: assessing mental capacity. AB - Issues surrounding capacity to consent to or refuse treatment are increasingly receiving clinical and legal attention. Through the use of 3 case vignettes that involve different aspects of mental health care in palliative care settings, mental capacity issues are discussed. The vignettes tackle capacity in a patient with newly developed mental illness consequent to physical illness, capacity in a patient with mental illness but without delirium and capacity in a patient with known impairment of the mind. These discussions give credence to best practice position where physicians act in the best interests of their patients at all times. It is important to emphasize that capacity decisions have to be made on a case by case basis, within the remit of legal protection. This is a fundamental requirement of the Mental Capacity Act 2005, England & Wales (MCA). The later is used as the legal basis for these discussions. The psychiatric liaison service is a useful resource to provide consultation, advice and or joint assessment to clinicians encountering complex dilemmas involving decision-making capacity. PMID- 25278762 TI - Examining Do-Not-Resuscitate Orders Among Newly Admitted Residents of Long-term Care Facilities. AB - Do-not-resuscitate (DNR) orders are an important part of advance directives. To date, little is known about DNR orders in Ontario's long-term care (LTC) facilities. The Canadian Institute for Health Information (CIHI) stated that in between 2011 and 2012, there were more than 32,000 discharges from Ontario's LTC facilities, 44% of which resulted from death. This study examined DNR orders in LTC homes in Ontario. The sample includes all LTC residents receiving care between 2010 and 2012. Data provided by the CIHI were collected using the Canadian version of the Resident Assessment Instrument. The data included administrative assessments on health of 112,746 residents. The average age of LTC residents in this study was 84.5 years, and about 70% were female residents. Results showed that residents admitted from home were less likely to have a DNR order on file during assessment and three months later. Residents whose families were responsible for care were more likely to have DNR orders when admitted, but this effect was not found at three-month follow-up. Residents who were in end stage diseases were more likely to have completed DNR orders upon admission to LTC facilities. The presence of a health condition (eg frailty, depression, heart condition, pulmonary or psychiatric condition) increased the likelihood of residents having DNR orders when admitted to LTC facilities. Residents whose conditions were deteriorating were more likely to have completed DNR orders before the three-month follow-up. In conclusion, this study represents an important step in identifying issues related to DNR orders in LTC facilities. The factors that influence whether residents have DNR orders on file upon admission depend on the presence of family members, whether the residents are designated as end-of-life cases (six months or less), older age, and health. Discussions about resuscitation are an important part of care plans. PMID- 25278763 TI - Levorphanol: revisiting an underutilized analgesic. AB - Levorphanol (levo-3-hydroxy-N-methylmorphinan) is a step 3 opioid first developed in the 1940s as an alternative to morphine. Levorphanol belongs to the morphinan opioid series. Levorphanol has greater potency than morphine and is a potent N methyl-d aspartate (NMDA) antagonist. Levorphanol interferes with the uptake of norepinephrine and serotonin, which makes it potentially useful for neuropathic pain. Glucuronidation changes Levorphanol to Levorphanol-3-glucuronide with excretion by the kidney. Levorphanol has a long half-life and may accumulate with repeated dosing. Levorphanol can be administered orally, intravenously, and subcutaneously. This article provides an update regarding the pharmacodynamics, pharmacology, and clinical efficacy of this often overlooked step 3 opioid. PMID- 25278764 TI - Obesity and insulin resistance: an abridged molecular correlation. AB - A relationship between obesity and type 2 diabetes is now generally well accepted. This relationship represents several major health hazards including morbid obesity and cardiovascular complications worldwide. Diabetes mellitus is a complex metabolic disorder characterized by impaired insulin release and insulin resistance. Lipids play an important physiological role in skeletal muscle, heart, liver and pancreas. Deregulation of fatty acid metabolism is the main culprit for developing insulin resistance and type 2 diabetes. A predominant predisposing factor to developing obesity, insulin resistance and type 2 diabetes is the permanent elevation of free fatty acids in plasma followed by impaired utilization of lipids by muscle. Diabetes-induced inflammation and oxidative stress have also vital role for development of insulin resistance in diabetic patients. The present review is intended to describe the correlation between lipids, obesity and insulin resistance based on current literature, in order to elucidate involved molecular mechanisms in depth. PMID- 25278765 TI - Do omega-3 polyunsaturated Fatty acids prevent cardiovascular disease? A review of the randomized clinical trials. AB - Fish oil is rich in the omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Numerous epidemiological studies and several large randomized clinical trials have shown that modest doses of omega-3 PUFAs significantly reduce the risk of unstable angina, myocardial infarction, and sudden cardiac death as well as death in coronary artery disease and heart failure patients. Based on the scientific evidence, the American Heart Association (AHA) has recommended all individuals eat fish at least twice a week to prevent cardiovascular disease. For individuals with coronary artery disease, the recommended dose of omega-3 PUFAs is 1 g of EPA and DHA daily. To lower triglyceride levels, much higher doses are needed. However, more recent randomized clinical trials have questioned the cardiovascular benefits of fish oil. These studies have contributed to the uncertainty health care providers face when recommending omega-3 PUFA supplementation according to clinical guidelines. The purpose of this review is to examine the randomized clinical trials and scientific evidence between omega-3 PUFAs and cardiovascular outcomes to better understand the current role of omega 3 PUFAs in improving cardiovascular health. PMID- 25278766 TI - Mass spectrometric analysis of oxidized eicosapentaenoic Acid sodium salt. AB - Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid (PUFA) with 20 carbon atoms and 5 carbon-carbon double bonds. Mammalian cells cannot synthesize long chain PUFAs such as EPA de novo, and, thus, the most effective way to enrich cells in EPA is by dietary intake of fish oils. EPA supplementation causes an increase in its concentration in plasma lipids and in cell membrane phospholipids. Many beneficial effects of EPA supplementation have been noted, including (1) the potential to sensitize cancerous tumors towards chemotherapy, (2) the promotion of cardiovascular health, and (3) the alleviation of some mental disorders, but results from clinical trials have sometimes been disparate. In this study, we report the use of mass spectrometry to investigate the autoxidation of EPA, thereby demonstrating the formation of a variety of oxidized products. The oxidative stress of the patient may affect the response to EPA and may, in part, explain divergent results from clinical trials. PMID- 25278768 TI - Stimulation of Hepatic Apolipoprotein A-I Production by Novel Thieno Triazolodiazepines: Roles of the Classical Benzodiazepine Receptor, PAF Receptor, and Bromodomain Binding. AB - Expression and secretion of apolipoprotein A-I (apoA-I) by cultured liver cells can be markedly stimulated by triazolodiazepines (TZDs). It has been shown previously that the thieno-TZD Ro 11-1464 increases plasma levels of apoA-I and in vivomacrophage reverse cholesterol transport in mice. However, these effects were only seen at high doses, at which the compound could act on central benzodiazepine (BZD) receptors or platelet activating factor (PAF) receptors, interfering with its potential utility. In this work, we describe 2 new thieno TZDs MDCO-3770 and MDCO-3783, both derived from Ro 11-1464. These compounds display the same high efficacy on apoA-I production, metabolic stability, and lack of cytotoxicity in cultured hepatocytes as Ro 11-1464, but they do not bind to the central BZD receptor and PAF receptor. The quinazoline RVX-208 was less efficacious in stimulating apoA-I production and displayed signs of cytotoxicity. Certain TZDs stimulating apoA-I production are now known to be inhibitors of bromodomain (BRD) extra-terminal (BET) proteins BRDT, BRD2, BRD3, and BRD4, and this inhibition was inferred as a main molecular mechanism for their effect on apoA-I expression. We show here that the thieno-TZD (+)-JQ1, a potent BET inhibitor, strongly stimulated apoA-I production in Hep-G2 cells, but that its enantiomer (-)-JQ1, which has no BET inhibitor activity, also showed considerable effect on apoA-I production. MDCO-3770 and MDCO-3783 also inhibited BRD3 and BRD4 in vitro, with potency somewhat below that of (+)-JQ1. We conclude that the effect of thieno-TZDs on apoA-I expression is not due to inhibition of the BZD or PAF receptors and is not completely explained by transcriptional repression by BET proteins. PMID- 25278767 TI - Diet, obesity, and cancer progression: are adipocytes the link? AB - Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment. PMID- 25278769 TI - Lack of Association between Polymorphisms of Hepatic Lipase with Lipid Profile in Young Jordanian Adults. AB - The human hepatic lipase (LIPC) gene encodes hepatic lipase, an enzyme involved in lipoprotein metabolism and regulation. Therefore, variants in LIPC gene may influence plasma lipoprotein levels. In this study, the association of LIPC C 514T and G-250A polymorphisms with plasma lipid profiles in 348 young Jordanians was investigated. Genotyping of C-514T and G-250A was performed by polymerase chain reaction and subsequent digestion with DraI and NiaIII restriction enzymes, respectively, while Roche analyzer was used to determine plasma total cholesterol, triglycerides, low-and high-density lipoprotein. The G-250 and C-514 alleles were most abundant in Jordanians with 79 and 80% frequencies, respectively. Additionally, no difference was found in the lipid-lipoprotein profile between the different genotype groups of C-514T or G-250A polymorphisms, even when males and females were examined separately (P > 0.05). In young Jordanian adults, the examined LIPC polymorphisms seem to play a limited role in determining the lipid profile. PMID- 25278770 TI - Profile of selumetinib and its potential in the treatment of melanoma. AB - The mitogen-activated protein kinase (MAPK) pathway is a critical oncogenic driver signal in a number of malignancies. The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors. Selumetinib is a potent and selective inhibitor of MEK1 and MEK2, which are essential downstream molecules in the MAPK pathway. Several preclinical and clinical studies have demonstrated the promising antitumor activity of selumetinib. In this review, we discuss the MAPK pathway in melanoma and summarized data from preclinical and clinical studies of selumetinib for advanced melanoma. PMID- 25278771 TI - The effect of a lifestyle intervention on metabolic health in young women. AB - With the increasing obesity rates in Western countries, an effective lifestyle intervention for fat reduction and metabolic benefits is needed. High-intensity intermittent exercise (HIIE), Mediterranean eating habits (Mediet), and fish oil (omega-3) consumption positively impact metabolic health and adiposity, although the combined effect has yet to be determined. A 12-week lifestyle intervention on adiposity, insulin resistance, and interleukin-6 (IL-6) levels of young overweight women was administered. Thirty women with a body mass index of 26.6+/ 0.5 kg/m(2), blood pressure of 114/66+/-1.9/1.5 mmHg, and age of 22+/-0.8 years were randomly assigned to either an intervention group receiving Mediet advice, daily omega-3 supplementation, and HIIE 3 days/week for 12 weeks or a control group. The group receiving Mediet advice, daily omega-3 supplementation, and HIIE experienced a significant reduction in total body fat mass (P<0.001), abdominal adiposity (P<0.05), waist circumference (P<0.001), systolic blood pressure (P<0.05), fasting plasma insulin (P<0.05), IL-6 (P<0.001), and triglycerides (P<0.05). The greatest decreases in fasting plasma insulin (P<0.05) and IL-6 (P<0.001) occurred by week 6 of the intervention. Significant improvements in eating habits (P<0.05) and aerobic fitness (P<0.001) were also found following the intervention. A multifaceted 12-week lifestyle program comprising a Mediet, omega-3 supplementation, and HIIE induced significant improvements in fat loss, aerobic fitness, and insulin and IL-6 levels, positively influencing metabolic health. PMID- 25278773 TI - Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer. AB - The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%-30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10-13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma. PMID- 25278772 TI - Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction. AB - Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, MU-opioid receptor antagonists (PAMORAs) that selectively target MU-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol's pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD. PMID- 25278774 TI - Omega-3 fatty acid supplementation and cognitive function: are smaller dosages more beneficial? AB - As longevity increases, so does the global prevalence of cognitive dysfunction. Numerous lifestyle and/or dietary interventions such as omega-3 fatty acids have been suggested to improve memory. Therefore, this study examined the consistency and strength of the impact of supplementation of omega-3 fatty acids on overall cognitive function using systematic reviews and meta-analytic methods. Of 905 studies retrieved from all searches, 12 randomized controlled trials were included in the meta-analysis. There were differences between studies reporting outcomes for single memory function parameters. Subgroup analysis of doses used (low versus high) indicated that subjects receiving low (<1.73 g/day) doses of omega-3 fatty acids had a significant reduction in cognitive decline rate (-0.07, 95% confidence interval -0.01, -0.02) but there was no evidence for beneficial effects at higher doses (+0.04, 95% confidence interval -0.06, +0.14) compared with the placebo group. This study suggests that omega-3 fatty acids may be beneficial in preventing memory decline at lower doses. PMID- 25278775 TI - Optimal perioperative management of arterial blood pressure. AB - Perioperative blood pressure management is a key factor of patient care for anesthetists, as perioperative hemodynamic instability is associated with cardiovascular complications. Hypertension is an independent predictive factor of cardiac adverse events in noncardiac surgery. Intraoperative hypotension is one of the most encountered factors associated with death related to anesthesia. In the preoperative setting, the majority of antihypertensive medications should be continued until surgery. Only renin-angiotensin system antagonists may be stopped. Hypertension, especially in the case of mild to moderate hypertension, is not a cause for delaying surgery. During the intraoperative period, anesthesia leads to hypotension. Hypotension episodes should be promptly treated by intravenous vasopressors, and according to their etiology. In the postoperative setting, hypertension predominates. Continuation of antihypertensive medications and postoperative care may be insufficient. In these cases, intravenous antihypertensive treatments are used to control blood pressure elevation. PMID- 25278777 TI - Eosinophil apoptosis and clearance in asthma. AB - Asthma is an increasingly common respiratory condition characterized by reversible airway obstruction, bronchial hyper-responsiveness and airway inflammation with a clear unmet need for more effective therapy. Eosinophilic asthma is a phenotype of the condition that features increased blood or sputum eosinophils whose numbers correlate with disease severity. Several lines of evidence are now emerging, which implicate increased persistence of eosinophils in the lungs of patients with asthma as a consequence of inhibition of and defects in the apoptotic process, together with impaired apoptotic cell removal mechanisms. This article will update our knowledge of the mechanisms controlling eosinophil apoptosis and clearance, together with evidence implicating defects in apoptosis and pro-inflammatory cell removal in asthma. Recent developments in novel therapies for asthma that target eosinophil apoptotic and/or clearance pathways will also be discussed. PMID- 25278776 TI - Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis. AB - alpha-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV 1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV 1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts. PMID- 25278780 TI - Increased Lysosomal Membrane Permeabilization in Oxidant-exposed Macrophages of Human Fibrotic Lungs. AB - A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding. PMID- 25278779 TI - Current understanding of the mechanisms for clearance of apoptotic cells-a fine balance. AB - Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called 'eat me' and 'don't eat me' signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies. PMID- 25278778 TI - Crosstalk between apoptosis and autophagy: molecular mechanisms and therapeutic strategies in cancer. AB - Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches. PMID- 25278782 TI - Regulation of ku70-bax complex in cells. AB - Ku70, a DNA repair factor in the nucleus, also regulates cell death by binding to the apoptotic protein Bax in the cytoplasm. Acetylation of Ku70 triggers Bax release resulting in Bax dependent cell death. Thus dissociating Bax from Ku70, either by inhibiting histone deacetylase 6 (HDAC6) that deacetylates Ku70 or by increasing Ku70 acetylation induces cell death. Our results showed that in neuroblastoma cells, the depletion of Ku70 results in Bax-dependent cell death. This model provides a rationale for screening Ku70 acetylation modulators that can be tested in clinical trials, either alone or in combination with radiotherapy or DNA-damaging agents for the treatment of cancer. PMID- 25278781 TI - Regulation of spontaneous eosinophil apoptosis-a neglected area of importance. AB - Asthma is characterized by the accumulation of eosinophils in the airways in most phenotypes. Eosinophils are inflammatory cells that require an external survival prolonging stimulus such as granulocyte macrophage-colony-stimulating factor (GM CSF), interleukin (IL)-5, or IL-3 for survival. In their absence, eosinophils are programmed to die by spontaneous apoptosis in a few days. Eosinophil apoptosis can be accelerated by Fas ligation or by pharmacological agents such as glucocorticoids. Evidence exists for the relevance of these survival-prolonging and pro-apoptotic agents in the regulation of eosinophilic inflammation in inflamed airways. Much less is known about the physiological significance and mechanisms of spontaneous eosinophil apoptosis even though it forms the basis of regulation of eosinophil longevity by pathophysiological factors and pharmacological agents. This review concentrates on discussing the mechanisms of spontaneous eosinophil apoptosis compared to those of glucocorticoid- and Fas induced apoptosis. We aim to answer the question whether the external apoptotic stimuli only augment the ongoing pathway of spontaneous apoptosis or truly activate a specific pathway. PMID- 25278783 TI - Regulation of human neutrophil apoptosis and lifespan in health and disease. AB - Neutrophils (also called polymorphonuclear leukocytes, PMNs) are the most abundant white blood cells in humans and play a central role in innate host defense. Another distinguishing feature of PMNs is their short lifespan. Specifically, these cells survive for less than 24 hours in the bloodstream and are inherently pre-programed to die by constitutive apoptosis. Recent data indicate that this process is regulated by intracellular signaling and changes in gene expression that define an "apoptosis differentiation program." Infection typically accelerates neutrophil turnover, and as such, phagocytosis-induced cell death (PICD) and subsequent clearance of the corpses by macrophages are essential for control of infection and resolution of the inflammatory response. Herein we reprise recent advances in our understanding of the molecular mechanisms of neutrophil apoptosis with a focus on regulatory factors and pathway intermediates that are specific to this cell type. In addition, we summarize mechanisms whereby perturbation of PMN death contributes directly to the pathogenesis of many infectious and inflammatory disease states. PMID- 25278784 TI - Interpreting overall survival results when progression-free survival benefits exist in today's oncology landscape: a metastatic renal cell carcinoma case study. AB - BACKGROUND: The debate surrounding the acceptance of progression-free survival (PFS) as an intermediate endpoint to overall survival (OS) has grown in recent years, due to the challenges in demonstrating an OS benefit within clinical trials today. PFS is generally a good predictor of OS for cases where survival post-progression (SPP) is short, and less so when SPP is long. SPP depends on multiple factors, including residual effect from experimental treatment and effect from crossover or other subsequent therapies, posing unique challenges into the translation of PFS benefit into OS. METHODS: The objective of this analysis was to conduct simulations investigating how increasing SPP impacts PFS translation to OS, utilizing data from the AXIS (axitinib versus sorafenib in advanced metastatic renal cell carcinoma) trial. The underlying assumption was a treatment benefit in PFS (the PFS distribution parameters were chosen to be equal to median PFS in the AXIS trial) but no treatment effect on SPP, implying that PFS improvement is directly reflected in OS improvement. RESULTS: The probability of a statistically significant difference between arms for OS decreased from 54.7% to 6.1% when median SPP was increased from one to 20 months. The probability of the hazard ratio of OS being >=0.9 was similarly increased from 24.3% to 72.6%, even though the hazard ratio for PFS was 0.69. CONCLUSION: The present study shows that when simulated SPP is added to trial PFS data, the existing PFS benefit is diluted. Knowing that the AXIS treatment arms are well balanced with respect to post-trial treatments, we conclude that the PFS to OS benefit translation is primarily obscured by random variability largely unrelated to the true outcomes. The implications for drug development are not insignificant, as there would be a need to include more patients in studies or utilize a longer follow-up time to overcome the SPP variability issue. PMID- 25278786 TI - The relationship between red blood cell distribution width and blood pressure in patients with type 2 diabetes mellitus in Lagos, Nigeria. AB - BACKGROUND: High red blood cell distribution width (RDW) is related to impairment of erythropoiesis, reflecting chronic inflammation and increased levels of oxidative stress, both of which are telltale signs of type 2 diabetics. The aim of this study was to evaluate the relationship between the RDW and fasting blood sugar/blood pressure, and compare the results from diabetics with nondiabetic controls. METHODS: This was an unmatched case-control study involving 200 participants consisting of 100 diabetics and 100 nondiabetic controls. Blood (4.5 mL) was collected from all of the diabetics and nondiabetic controls, and placed into EDTA anticoagulant tubes. A full blood count was performed using the Sysmex KX-21N, a three-part auto analyzer able to run 19 parameters per sample, including RDW. Blood pressure was measured during sample collection and in a sitting position. RESULTS: The mean fasting blood sugar level was 95.20+/-30.10 mg/dL in the controls, and 147.85+/-72.54 mg/dL in the diabetics. The mean blood pressures for diabetics was 138/90 mmHg and for non-diabetics 120/80 mmHg. The mean RDW-SD (RDW standard deviation) was 46.44+/-4.64 fl in the controls, and 46.84+/-3.18 in the diabetics. The mean RDW-CV (RDW coefficient of variation) was 14.74%+/-1.94% in controls, and 14.80+/-0.71 for diabetics. No statistically significant correlation was found between the RDW-SD and fasting blood sugar/blood pressure in the diabetics. A statistically significant positive correlation was found between the RDW-CV and blood pressure in the diabetics. CONCLUSION: A positive correlation between the RDW-CV and blood pressure was established in the diabetics in this study. PMID- 25278785 TI - Global prevalence and incidence of traumatic spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) is a traumatic event that impacts a patient's physical, psychological, and social well-being and places substantial financial burden on health care systems. To determine the true impact of SCI, this systematic review aims to summarize literature reporting on either the incidence or prevalence of SCI. METHODS: A systematic search was conducted using PubMed, MEDLINE, MEDLINE in process, EMBASE, Cochrane Controlled Trial Register, and Cochrane Database of Systematic Reviews to identify relevant literature published through June 2013. We sought studies that provided regional, provincial/state, or national data on the incidence of SCI or reported estimates of disease prevalence. The level of evidence of each study was rated using a scale that evaluated study design, methodology, sampling bias, and precision of estimates. RESULTS: The initial search yielded 5,874 articles, 48 of which met the inclusion criteria. Forty-four studies estimated the incidence of SCI and nine reported the prevalence, with five discussing both. Of the incidence studies, 14 provided figures at a regional, ten at a state or provincial level and 21 at a national level. The prevalence of SCI was highest in the United States of America (906 per million) and lowest in the Rhone-Alpes region, France (250 per million) and Helsinki, Finland (280 per million). With respect to states and provinces in North America, the crude annual incidence of SCI was highest in Alaska (83 per million) and Mississippi (77 per million) and lowest in Alabama (29.4 per million), despite a large percentage of violence injuries (21.2%). Annual incidences were above 50 per million in the Hualien County in Taiwan (56.1 per million), the central Portugal region (58 per million), and Olmsted County in Minnesota (54.8 per million) and were lower than 20 per million in Taipei, Taiwan (14.6 per million), the Rhone-Alpes region in France (12.7 per million), Aragon, Spain (12.1 per million), Southeast Turkey (16.9 per million), and Stockholm, Sweden (19.5 per million). The highest national incidence was 49.1 per million in New Zealand, and the lowest incidences were in Fiji (10.0 per million) and Spain (8.0 per million). The majority of studies showed a high male-to-female ratio and an age of peak incidence of younger than 30 years old. Traffic accidents were typically the most common cause of SCI, followed by falls in the elderly population. CONCLUSION: This review demonstrates that the incidence, prevalence, and causation of SCI differs between developing and developed countries and suggests that management and preventative strategies need to be tailored to regional trends. The rising aging population in westernized countries also indicates that traumatic SCI secondary to falls may become an increasing public health challenge and that incidence among the elderly may rise with increasing life expectancy. PMID- 25278787 TI - Training medical students in the social determinants of health: the Health Scholars Program at Puentes de Salud. AB - PURPOSE: Given the large influence of social conditions on health, physicians may be more effective if they are trained to identify and address social factors that impact health. Despite increasing interest in teaching the social determinants of health in undergraduate medical education, few models exist. PARTICIPANTS AND METHODS: We present a 9-month pilot course on the social determinants of health for medical and other health professional students, which is based at Puentes de Salud, Philadelphia, PA, USA, a community health center serving a Latino immigrant population. This service-learning course, called the Health Scholars Program (HSP), was developed and implemented by volunteer medical and public health faculty in partnership with the community-based clinic. The HSP curriculum combines didactic instruction with service experiences at Puentes de Salud and opportunities for critical reflection. The HSP curriculum also includes a longitudinal project where students develop, implement, and evaluate an intervention to address a community-defined need. RESULTS: In our quantitative evaluation, students reported high levels of agreement with the HSP meeting stated course goals, including developing an understanding of the social determinants of health and working effectively with peers to implement community based projects. Qualitative assessments revealed students' perception of learning more about this topic in the HSP than in their formal medical training and of developing a long-term desire to serve vulnerable communities as a result. CONCLUSION: Our experience with the HSP suggests that partnerships between academic medical centers and community-based organizations can create a feasible, effective, and sustainable platform for teaching medical students about the social determinants of health. Similar medical education programs in the future should seek to achieve a larger scale and to evaluate both students' educational experiences and community-defined outcomes. PMID- 25278788 TI - Evaluation of the orthopedic residency training program in Saudi Arabia and comparison with a selected Canadian residency program. AB - OBJECTIVE: The primary aim of the present study was to assess the quality of the Saudi Orthopedic Residency Program. METHODOLOGY: As a comparator, a cross sectional survey involving 76 Saudi residents from different training centers in Saudi Arabia namely; Riyadh, Jeddah, Medina, Abha, and Dammam and 15 Canadian. RESULTS: The results showed that Canadian residents read more peer-reviewed, scholarly articles compared with Saudi residents (P=0.002). The primary surgical role for residents was to hold retractors during surgery. The survey respondents strongly supported the ability to recommend removal of incompetent trainers. Saudi trainees were more apprehensive of examinations than Canadian trainees (P<0.0001). Most residents preferred studying multiple-choice questions before examinations. Saudi and Canadian participants considered their programs to be overcrowded. Unlike Canadian participants, Saudi trainees reported an inadequate level of training (P<0.0001). CONCLUSION: Educational resources should be readily accessible and a mentorship system monitoring residents' progress should be developed. The role of the resident must be clearly defined and resident feedback should not be ignored. Given the importance of mastering basic orthopedic operative skills for residents, meaningful remedial action should be taken with incompetent trainers. PMID- 25278790 TI - Dry eye and ocular surface disease. PMID- 25278789 TI - Cross-year peer tutoring on internal medicine wards: results of a qualitative focus group analysis. AB - BACKGROUND: Peer-assisted learning (PAL) has become a well-accepted teaching method within medical education. However, descriptions of on-ward PAL programs are rare. A focus group analysis of a newly established PAL program on an internal medicine ward was conducted to provide insights into PAL teaching from a student perspective. PURPOSE: To provide insights into students' experiences regarding their on-ward training with and without accompanying PAL tutors. METHODS: A total of N=168 medical students in their sixth semester participated in the investigation (intervention group: N=88; control group: N=80). The intervention group took part in the PAL program, while the control group received standard on-ward training. There were seven focus groups with N=43 participants (intervention group: four focus groups, N=28 participants; control group: three focus groups, N=15 participants). The discussions were analyzed using content analysis. RESULTS: The intervention group emphasized the role of the tutors as competent and well-trained teachers, most beneficial in supervising clinical skills. Tutors motivate students, help them to integrate into the ward team, and provide a non-fear-based working relationship whereby students' anxiety regarding working on ward decreases. The control group had to rely on autodidactic learning strategies when neither supervising physicians nor final-year students were available. CONCLUSION: On-ward PAL programs represent a particularly valuable tool for students' support in training clinical competencies on ward. The tutor student working alliance acts through its flat hierarchy. Nevertheless, tutors cannot represent an adequate substitute for experienced physicians. PMID- 25278791 TI - Cataract surgery in patients with ocular surface disease: An update in clinical diagnosis and treatment. AB - In this article we review essentials of diagnosis and management of ocular surface disease in patients who undergo cataract surgery. It is clearly shown that dry eye disease worsens following the cataract surgery in patients with prior history of ocular surface disease, Also new cases of dry eye might appear. Current strategies for the timely diagnosis and proper management of dry eye syndrome in the face of cataract surgery patients are mainly emphasized. To achieve the best outcome in cataract surgery, a healthy ocular surface is crucial. While ocular surface preparation is indispensable in patients with established ocular surface disease, it is also helpful in those with minimal signs or symptoms of surface disease. The current approach begins with early diagnosis and drastic management of ocular surface disease before cataract surgery using a stepwise regimen customized to each patient and disease severity. These measures are continued throughout and after the surgery. PMID- 25278792 TI - Management strategies for persistent epithelial defects of the cornea. AB - Management of patients with persistent epithelial defects of the cornea can be challenging to even the seasoned ophthalmologist. It is essential that one understands not only the pathophysiology of the failure of the epithelium to migrate and close a wound appropriately, but also the mechanism of action of the available treatment modalities at one's disposal. This article serves as a review of current standard therapies, recently introduced alternative therapies gaining in popularity, and a look into the newest developments that may change the way we manage corneal surface disease. PMID- 25278794 TI - Balancing antimicrobial efficacy and toxicity of currently available topical ophthalmic preservatives. AB - Medical treatment of ophthalmic diseases relies primarily on the use of multidose drugs. Short term use is highly effective usually with little local toxicity. However, chronic use of these preparations not only increases the likelihood of microbial contamination and secondary ocular infection, but also of toxicity from the drug formulation itself. Increasing awareness of the toxicity of ophthalmic preservatives has led to an increasing variety of preservative schemes ranging from "self-preservation" to ionic buffer systems. Beyond outdated testing methods, the anti-microbial efficacy of most of these systems is poorly defined, potentially placing these preparations at an unknown risk of contamination by unmonitored, untested organisms. No uniformity in toxicity testing exists which further complicates the clinician's judgment of the risk-benefit of using a particular drug formulation. In this manuscript we examine in detail each of the current employed ophthalmic preservative regimens with respect to their known antimicrobial activity and potential toxicity, where known. We also survey the most popular ophthalmic preparations, detailing their preservation schemes as well as concentrations to help the clinician in choosing an appropriate formulation for the treatment of various ophthalmic diseases. PMID- 25278793 TI - Dry eye disease: A review of diagnostic approaches and treatments. AB - Dry eye (DE) is a common ocular disease that results in eye discomfort, visual disturbance and substantially affects the quality of life. It has a multifactorial etiology involving tear film instability, increased osmolarity of the tear film and inflammation of the ocular surface with potential damage to the ocular surface. This review discusses the classification, diagnostic approaches and treatments of DE. PMID- 25278796 TI - Essential fatty acids in the treatment of dry eye syndrome: A myth or reality? AB - Dry eye is a common condition that can severely impair the quality of life. Systemic and topical omega-3 fatty acids and omega-6 fatty acids have been used as treatment for patients with dry eye disease and showed promising results. Further multicenter randomized controlled trials are required in order to establish a standardized protocol for the treatment of dry eye syndrome with those essential fatty acids. PMID- 25278795 TI - Stem cell-based therapy for treating limbal stem cells deficiency: A review of different strategies. AB - The self renewal capability of limbal epithelial stem (LEST) cells is fundamental to the maintenance and healing of corneal epithelium. Limbal stem cell deficiency (LSCD), due to dysfunction or loss of LEST cells, therefore presents as persistent epithelial defects, corneal vascularization, conjunctivalization etc. Stem cell-based therapy, in its simplest form - limbal autograft, has been used successfully for more than a decade. For bilateral LSCD, similar approaches with limbal allografts have been unsuccessful largely due to strong immune rejection. Therefore, as an alternate strategy for treating bilateral LSCD, ex vivo expansion of the remaining LEST cells or autologous stem cells sourced from other potential sites is being explored. Different culture systems (with and without xenobiotic supplements) using substrates like amniotic membrane or fibrin gels have been used successfully for ex vivo LEST cell maintenance and reproduction by imitating the stem cell niche. This paper is organized into sections reviewing the LEST cells, LSCD and various stem cell-based approaches for treating LSCD and discussing future direction and challenges. PMID- 25278797 TI - Ocular surface rehabilitation: Application of human amniotic membrane in high risk penetrating keratoplasties. AB - BACKGROUND: Human amniotic membrane is a versatile tool for management of ocular surface disorders. This study evaluates the effect of cryopreserved human amniotic membrane (hAM) on one-year survival of penetrating keratoplasties (PKP) in high-risk recipients. METHOD: This is a retrospective noncomparative cohort study of 58 consecutive eyes undergoing PKP with concurrent placement of a self retained cryopreserved hAM (PROKERA(r)) at a tertiary care center from January 2009 to July 2010. RESULTS: Mean patient age was 66.7 +/- 17.2 years and 30 (54%) were males. 51 eyes were pseudophakic and one aphakic. 27 eyes were glaucomatous; 24 had glaucoma drainage device and 2 had previous endocyclophotocoagulation. 12 patients had PKP for the first time and 46 had repeat PKP (average number of prior PKP = 1.63 +/- 1.1, range: 1-5). Risk factors for graft failure included repeat PKP (79.3%), corneal neovascularization (51.7%), preexisting glaucoma (46.6%), and presence of anterior synechiae (37.9%). Both First Transplant and Repeat Transplant groups had similar survival rates until 6 months after transplant (75% vs 74%, odds ratio = 1.06, p = 1.00). At 12 months, First Transplant group showed a better survival rate (67% vs 43%, odds ratio = 2.60, p = 0.20). Eyes with >3 risk factors had a higher graft failure rate (odds ratio = 5.81, p = 0.003). CONCLUSION: Survey of the literature suggests that high-risk PKP with concurrent hAM placement demonstrate comparable graft survival. Presence of multiple risk factors is associated with poor survival. PMID- 25278798 TI - Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) scleral lens for Salzmann's nodular degeneration. AB - PURPOSE: To evaluate the use of Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) scleral lens treatment as an alternative to keratectomy in patients with symptomatic Salzmann's nodular degeneration (SND). METHODS: A retrospective chart review from July 2009 to May 2013 identified 9 SND patients who were referred for PROSE evaluation. Patients who did not complete PROSE fitting or had other corneal comorbidities affecting vision were excluded from the study, and 7 eyes of 4 patients were included. Three patients were pseudophakic and 1 patient was phakic, and the lens status of our cohort did not change during the study. RESULTS: Visual acuity improved from 0.19 +/- 0.084 logMAR (approximately 20/31) pre PROSE to 0.028 +/- 0.047 logMAR (approximately 20/21) post PROSE in patients with Salzmann's nodular degeneration (p = 0.002). OSDI scores improved from 46.9 +/- 26.6 pre PROSE to 21.5 +/- 18.7 post PROSE in the same cohort (p = 0.02). CONCLUSION: The results of this study show that PROSE can provide improvements in visual acuity and function in patients with Salzmann's nodular degeneration and offer an alternative to superficial keratectomy. PMID- 25278800 TI - Comparison of LASEK, mechanical microkeratome LASIK and Femtosecond LASIK in low and moderate myopia. AB - PURPOSE: We conducted a prospective study to determine the best treatment option for patients with low-to-moderate spherical myopia or myopic astigmatism who are considered equally eligible for LASEK with mitomycin-C (MMC) and LASIK with either mechanical microkeratome or femtosecond laser flap creation. METHODS: Forty-six adult patients (86 eyes) who underwent LASEK with MMC (16 patients, 31 eyes), and mechanical microkeratome LASIK (13 patients, 23 eyes) or Femtosecond LASIK (17 patients, 32 eyes) were assessed for clinical outcomes 1, 3 and 6 months post-operatively. RESULTS: Six months after surgery, all eyes in all three groups were within 1 D of the intended refractive change. UCVA 20/20 or better was achieved in 96% of eyes undergoing LASEK with MMC 88% of eyes in the mechanical microkeratome LASIK and 72% of eyes in the Femtosecond LASIK group at 6 months. Mean spherical equivalent was -0.12 +/- 0.22 D, -0.09 +/- 0.28 D and 0.25 +/- 0.28 D in the three groups, respectively (p = 0.077). Patients in the LASEK with MMC group had less high order aberrations at 3 and 6 months compared to the two LASIK groups. None of the three procedures were associated with early- or late-onset complications or loss of 2 or more lines after surgery. CONCLUSIONS: After an initially slower visual improvement, LASEK with MMC, and to lesser extent, LASIK with mechanical microkeratome, produced better visual acuity and less corneal aberrations compared to Femtosecond LASIK at 3 and 6 months after surgery. These observations deserve further investigation in a randomized controlled trial. PMID- 25278799 TI - Corneal spherical aberration in Saudi population. AB - PURPOSE: To find out the mean corneal spherical aberration and its changes with age in Saudi population. SETTING: AlHokama Eye Specialist Center, Riyadh, Saudi Arabia. METHODS: Three hundred (300) eyes of 185 Saudi subjects (97 men and 88 women), whose age ranged from 15 to 85 years old, with matched refractive errors, were divided into three groups according to their age, 100 for each. All the subjects were included in measuring the spherical aberration (SA) using pentacam HR (OCULUS, Germany) at the 6-mm optical zone. RESULTS: The mean corneal spherical aberration (CSA) of the fourth order (Z4 (0)) of the whole groups was 0.252 +/- 0.1154 MUm. Patients from 15 to 35 years old have root mean square (RMS) of CSA of 0.2068 +/- 0.07151 MUm, 0.2370 +/- 0.08023 MUm was the RMS of CSA of the patients from 35 to 50 years old, while those from 50 to 85 years old have a CSA-RMS of 0.31511 +/- 0.1503 MUm (P < 0.0001). A positive correlation was found between the spherical aberration (Z4 (0)) and the progress of age (r = 0.3429, P < 0.0001). The high order aberration (HOA) presented 28.1% of the total corneal aberrations. While the fourth order corneal spherical aberration constituted 57% of the HOA and 16% of the total aberration. The pupil diameter shows a negative correlation with the increase in age (P = 0.0012). CONCLUSION: Our results showed a CSA (Z4 (0)) that is varied among the population, comparable to other studies, and significantly correlates to the progress of age. PMID- 25278802 TI - A peculiar case of a retained inert piece of fireworks as an intraocular foreign body in the anterior chamber. AB - This is a descriptive case report of a seven-year-old boy presented in January 2007 with decreased vision in the right eye, for 2 months after sustaining a trauma while he was playing with fireworks during the Eid holiday. He was treated in a suburban hospital for corneal laceration and was prescribed a topical antibiotic and a topical steroid. When the child presented to us, a slit lamp examination revealed a thread in the anterior chamber, his un-aided visual acuity was 6/60 on a Snellen chart. Surgery to remove the foreign body was scheduled, but the patient never attended. The patient was lost to follow-up and returned in January 2011 with an un-aided visual acuity of 6/12, although the foreign body was retained in the anterior chamber (AC) with a quiet eye and good vision. At that time, we decided to follow the patient without any surgical intervention. Again, the patient was lost to follow-up and returned with almost full vision in September 2012, with a visual acuity of 6/6 without correction. Thus, we concluded that thread like IOFBs in the AC can be considered inert materials that may not need any surgical intervention in a quiet eye that does not show any signs of inflammation and where the IOFB is non-mobile and located away from the endothelium. PMID- 25278801 TI - Three dimensional MRI study: Safety of short versus long needle peribulbar anesthesia. AB - BACKGROUND: The standard technique of Peribulbar block is to use 25 g 25 mm needle at the junction between the lateral one third and medial two third of the lower orbital rim in the infero-temporal quadrant of the orbit. Theoretically, insertion of longer needles increases the potential of injury to important structure; however, safety of the shorter needle had never been demonstrated. This study describes the anatomy of the orbital structures with magnetic resonance imaging (MRI) using the three-dimensional constructive interference in steady state (3D CISS) sequence to present a morphological basis for needle entry at 12.5 and 25 mm lengths. Statistical comparisons were performed at the 12.5 versus 25 mm depths. Statistical significance was indicated by P < 0.05. METHOD: Fifty patients free of orbital pathology with normal axial length were selected for MRI with the 3D CISS sequence. Original axial and multiplanar image reconstruction (MPR) images were selected for image interpretation. Orbital structures were identified at 12.5 and 25 mm depths from the orbital rim to compare significant differences in anatomy between the two imaging planes at the expected needle depth and to assess the size of the globe and the orbit. RESULTS: The cross sectional area of the extraocular muscles were statistically significantly smaller at the 12.5 mm plane (P = 0.001). The area of inferotemporal fat was statistically significantly larger at the 12.5 mm plane (P = 0.033). There was no statistical difference in the inferonasal and superonasal fat areas at different depths (P = 0.34, P = 0.35 respectively). The size of the orbit and globe was significantly larger at 12.5 mm (P = 0.001). There was no difference between depths in the presence or absence of neurovascular bundles and supporting structures including the intramuscular septae. CONCLUSION: There is a larger structure-free space at a depth of 12.5 mm than at 25 mm. Therefore, the inference is that a needle inserted in the infero-temporal zone to a depth of 12.5 mm is less likely to injure the eyeball or extra-ocular muscles than one advanced to 25 mm. PMID- 25278803 TI - Retained periorbital and intracranial air-gun pellets causing sclopetaria and visual loss. AB - Three healthy males presented on separate occasions to the emergency room at the King Khaled Eye Specialist Hospital (KKESH) after sustaining trauma by air-gun pellets. Clinical examination indicated sclopetaria in all the cases. The foreign bodies (air-gun pellets) were imbedded in different locations (subconjunctival, intraorbital, and intracranial). All cases resulted in a profound and permanent visual loss. The management of this traumatic injury is discussed and concurs with the published literature. PMID- 25278804 TI - Peripheral ulcerative keratitis: Our challenging experience. AB - A 52 year old male presented with peripheral ulcerative keratitis in the right eye. Patient's history included retinitis pigmentosa, pseudophakia (right eye), cataract (left eye), bilateral partial deafness, ischemic heart disease, hypertension, type 1 diabetes mellitus, depression, hyperparathyroidism, hypertriglycemia and renal failure. The patient was on weekly hemodialysis. The peripheral corneal ulceration remained stable until he developed sudden and rapid thinning after eight months of regular follow up and management. Laboratory investigations including immunological studies were negative and we had to rely on treatment based on clinical signs, including the visual acuity, size, depth and staining of the ulcer and perilimbal, episcleral, scleral, corneal and anterior chamber reactions. The patient was treated with medical and conservative approaches and the eye was protected with a plastic shield to avoid injury. Despite our efforts, the patient perforated his eye due to a trivial trauma during sleep. He was managed successfully with cyanoacrylate glue and a bandage contact lens. The anterior chamber reformed after the perforation was sealed and the patient is on a regular follow up with a multidisciplinary approach. PMID- 25278805 TI - Headache as an initial manifestation of Vogt-Koyanagi-Harada disease. AB - A 29 year-old healthy Saudi female presented with a 1 week history of headache followed by decreased vision in both eyes. Biomicroscopy revealed anterior uveitis without hypopyon, posterior synechia or keratic precipitate. Fundus examinations were remarkable for serous retinal detachment and hyperemic discs. Fundus fluorescein angiogram showed a hot disc with multiple pinpoint leakage in both eyes. CT scan and MRI were normal, all uveitis workups were negative. Five months later, the patient presented with complete criteria of Vogt-Koyanagi Harada disease including a 2 weeks history of tinnitus, alopecia, poliosis and vitiligo. Headache alone followed by decreased vision before the onset of neurological and auditory symptoms can be an initial presentation of VKH disease. VKH should be considered in the differential diagnosis of atypical presentation of symptoms. PMID- 25278806 TI - Good visual outcome in an immunocompromised patient with bilateral acute retinal necrosis syndrome: A case report. AB - Acute retinal necrosis (ARN) is an uncommon necrotizing, fulminant retinopathy caused by the herpes simplex virus types 1 or 2 or by the varicella zoster virus with visually devastating consequences. Generally it occurs in patients who are systemically healthy, but occasionally occurs in immunocompromised host. We report a case of bilateral ARN in a patient with AIDS with a good final visual outcome. PMID- 25278807 TI - Pigmented malignant teratoid medulloepithelioma of ciliary body - An extremely rare intraocular tumor in adult. AB - Malignant teratoid medulloepithelioma of ciliary body is an extremely rare tumor usually occurring in children younger than 5 years of age and is usually amelanotic. Here, we report a very rare case of pigmented malignant teratoid medulloepithelioma in a 20-year old male patient who presented initially with pain, redness and proptosis of right eyeball. The right eyeball was enucleated. A histopathological diagnosis of orbital teratoma was made and no further treatment was given. Four months later, the patient developed another swelling in the same area. A review of the previous histopathology slides revealed a pigmented malignant teratoid medulloepithelioma. No nerve involvement was seen. MRI did not show any intracranial extension. The mass along with rest of the orbital tissue was removed. No adjuvant chemotherapy or radiotherapy was given due to the lack of intracranial extension. The patient was symptom free at 2-year follow-up and the repeat MRI also showed no evidence of recurrence. PMID- 25278808 TI - Supplemental plant sterols and stanols for serum cholesterol and cardiovascular disease. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effects of phytosterols, phytostanols or their esters, ingested in supplemented foods, on blood cholesterol concentrations and cardiovascular disease;To look for adverse effects e.g. on nutritional status or physiological function;To study/comment on, possible effects of cost. PMID- 25278809 TI - Humanistic therapies versus other psychological therapies for depression. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To examine the effectiveness and acceptability of all humanistic therapies compared with all other psychological therapy approaches for acute depression.To examine the effectiveness and acceptability of different humanistic therapy models (person-centred, gestalt, process-experiential, transactional analysis, existential and non-directive therapies) compared with all other psychological therapy approaches for acute depression.To examine the effectiveness and acceptability of all humanistic therapies compared with different psychological therapy approaches (psychodynamic, behavioural, humanistic, integrative, cognitive-behavioural) for acute depression. PMID- 25278810 TI - Gastric tube insertion under direct vision using the King VisionTM video laryngoscope: a randomized, prospective, clinical trial. AB - BACKGROUND: The frequency of malpositioning of gastric tubes in the trachea has been reported to be 0.3-15%, which may cause severe complications, such as pneumonia, if not detected promptly. If a gastric tube can be guided into the esophagus under direct vision with a video laryngoscope, misplacement of the gastric tube into the trachea can be avoided. We compared gastric tube insertion under direct vision using a video laryngoscope with the conventional method of blind insertion. METHODS: We enrolled 60 patients who required a transnasal gastric tube to facilitate elective abdominal surgery under general anesthesia. The participants were recruited consecutively into one of two groups, a group of 30 patients in whom a gastric tube was inserted using a King VisionTM video laryngoscope (KV group), and a group of 30 patients who underwent conventional blind insertion of the gastric tube (Blind group). The success rate, the time taken to insert the gastric tube, and the incidence of complications were compared. RESULTS: In the KV group, the time required for gastric tube placement was 52.5 +/- 17.1 seconds, with a success rate of 100%. Slight oral hemorrhage occurred in two participants and slight epistaxis in one participant. In the Blind group, the time required for gastric tube placement was 65.9 +/- 39.9 seconds, with a success rate of 90% (27 out of 30 patients). Slight oral hemorrhage occurred in two participants, slight epistaxis occurred in two participants, and tracheal malposition occurred in one participant but was detected promptly and corrected using the video laryngoscope. There were no significant differences in the time required for placing the gastric tube, the success rate, or the incidence of complications between the groups. CONCLUSIONS: Gastric tube insertion using a King Vision video laryngoscope was straightforward, and was particularly useful for detecting and correcting tracheal malpositioning. TRIAL REGISTRATION: TRIAL REGISTRY NUMBER: UMIN000011014. PMID- 25278811 TI - TGF-beta isoforms induce EMT independent migration of ovarian cancer cells. AB - BACKGROUND: Transforming growth factor beta (TGF-beta) plays major roles in tumorigenesis by regulating cell growth, epithelial-to-mesenchymal transition (EMT), migration/invasion and metastasis. The epithelial markers E-cadherin, claudin-3 and claudin-4, commonly decreased in human adenocarcinomas are actually up regulated during ovarian carcinogenesis. In human ovarian cancer TGF-beta1 may either suppress or promote tumor progression, but whether other TGF-beta isoforms (TGF-beta2 and TGF-beta3) exert similar effects is not known. METHODS: In this study we investigated the ability of the TGF-beta isoforms (TGF-beta1-3) to induce proliferation and migration by BrdU labeling, scratch wound and trans filter migration assays in the human serous adenocarcinoma cell-line NIH-OVCAR3. Transepithelial resistance was measured and EMT observed by light-microscopy. Expression of adherens-, tight-junction and EMT-related transcription factors was analyzed by qRT-PCR and immunoblotting. RESULTS: All TGF-beta isoforms dose dependently inhibited NIH-OVCAR3 cell growth, stimulated tumor cell migration with similar efficiency. The mesenchymal marker N-cadherin and claudin-1 expression was induced and occludin down regulated. However, migrating cells retained an epithelial shape and E-cadherin expression. The E-cadherin repressor SNAIL mRNA levels remained low independently of TGF-beta1-3 treatment while ZEB1 expression was enhanced. CONCLUSIONS: TGF-beta1, TGF-beta2 and TGF-beta3 promote migration of NIH-OVCAR3 ovarian cancer cells independently of cell proliferation and without conversion to a complete EMT phenotype. Epithelial ovarian cancer commonly metastasis to the surrounding tissue or inside the peritoneum rather than invading blood vessels to set distance metastasis. Our result raises the question whether ovarian cancer primarily spread via collective migration than via single cell invasion. PMID- 25278813 TI - Successful thrombolysis following enoxaparin therapy in two pediatric patients with congenital heart disease presenting with intracardiac and cerebral thrombosis. AB - Enoxaparin displays fibrinolytic activity through stimulation of endothelial release of tissue plasminogen activator. Moreover, enoxaparin increases the release of tissue factor pathway inhibitor, which inhibits coagulation activity. However, there are only few reports regarding the use of enoxaparin for the treatment of children with thrombosis complicating congenital heart disease. We report the clinical findings from two patients, one child with an A. cerebri media infarction and another with a left ventricular thrombus. In both cases successful thrombolysis was obtained by intravenous administration of enoxaparin. The first patient was a 12-year-old girl with an atrioventricular septal defect, who underwent biventricular repair at the age of 8 months. She presented with right-sided middle cerebral artery infarction. Thrombolysis was contraindicated, because she was beyond the therapeutic window recommended by accepted guidelines. Enoxaparin 2.5 mg/kg/d was administered as a continuous intravenous infusion (CII). The MRI 10 days later revealed a reopened middle cerebral artery and she experienced complete remission of the neurological signs. The second patient was a 16-year-old boy who had tetralogy of Fallot corrected in late infancy. He presented with severe heart failure and a mural thrombus in the left ventricular apex. Enoxaparin was administered and resulted in complete disappearance of the thrombus within a week. According to our experience, CII of enoxaparin was safe and well tolerated without secondary bleeding and resulted in complete dissolution of the thrombi without secondary embolization. Therefore, CII of enoxaparin may be a possible alternative for the treatment of thrombotic complications in children with contraindications against conventional thrombolytic therapy. PMID- 25278812 TI - CD28-, CD45RA(null/dim) and natural killer-like CD8+ T cells are increased in peripheral blood of women with low-grade cervical lesions. AB - BACKGROUND: In response to antigen naive CD8+, T cells differentiate into effector cells, which express Natural killer (NK) receptors, lose CD28 expression, and die by apoptosis. However, in smaller quantities, the cells are retained for subsequent exposure to the same antigen. Knowledge is limited regarding whether the percentages of CD28-, Effector memory (EMRA(null/dim)), and the CD16+/CD56 + CD8+ T cells of women with low-grade cervical lesions are altered at a systemic level. METHODS: We enrolled in this study women controls and women with Human papilloma virus infection (HPV-I) without associated cellular neoplastic changes and with Cervical Intraepithelial Neoplastic-I (CIN I). Flow cytometry (FC) was performed for measurement of CD28-, memory subset, and NK-like CD8 + T cells, and IL-17, IFN-gamma, Tumor necrosis factor (TNF) alpha, Interleukin (IL)-10, IL-6, IL-4, and IL-2. Finally, we genotyped the HPV. RESULTS: The CIN-I group increased the CD8 + CD28- and CD16+/56+ T cell percentage compared with that of HPV-I and controls (p <0.01), and CD8 + CCR7 CD45RA(null/dim) (EMRA(null/dim)) T cells were also increased in the CIN-I group compared with the controls (p <0.01). These two study groups were HPV- genotyped; 49% were HPV18+, and we did not observe differences in cytokine levels among all groups. CONCLUSIONS: Increased levels of CD28-, EMRA(null/dim), and CD16+/CD56 + CD8+ T cells of peripheral blood in women with CIN-I may be associated with persistent HPV infection and could exert an influence on progression to cervical cancer. PMID- 25278814 TI - Cost-utility of ferric carboxymaltose (Ferinject(r)) for iron-deficiency anemia patients with chronic heart failure in South Korea. AB - BACKGROUND: Iron-deficiency anemia (IDA) is prevalent in patients with advanced chronic heart failure (CHF). It affects the patients' overall physical condition and is suggested as a strong outcome predictor in CHF. Recent clinical trials suggested that intravenous iron supplementation improves CHF functional status and quality of life. The aim of this study was to assess the cost-effectiveness of ferric carboxymaltose(FCM) in CHF patients with IDA. METHODS: Ferric carboxymaltose, an intravenous iron preparation, was compared with placebo. The target population comprised CHF patients with IDA in hospital and outpatient care settings. We conducted this study from the Korean healthcare payers' perspective with a time horizon of 24 weeks. One clinical trial provided the clinical outcomes of ferric carboxymaltose therapy. The improvement rates of the New York Heart Association (NYHA) functional class in the placebo and ferric carboxymaltose groups were used to estimate effectiveness in the base-case model. We also conducted a scenario 2 analysis using quality of life investigated in the clinical trial. A panel survey was conducted to obtain the ratio of healthcare resource use based on NYHA class in Korea. Cost-effectiveness was expressed as incremental cost (US dollars) per quality-adjusted life-year (QALY) gained. RESULTS: In the base-case analysis, the incremental cost-effectiveness ratio (ICER) of ferric carboxymaltose compared with placebo was $22,192 (?25,010,451) per QALY gained. The sensitivity analysis showed robust results, with the ICERs of ferric carboxymaltose ranging from $5,156 to $29,796 per QALY gained. In the scenario 2 analysis, ICER decreased to $12,598 (?14,198,501) per QALY gained. CONCLUSIONS: Iron repletion with ferric carboxymaltose for IDA in CHF patients was cost-effective compared with placebo. PMID- 25278815 TI - Proprioceptive acuity into knee hypermobile range in children with joint hypermobility syndrome. AB - BACKGROUND: Children with Joint Hypermobility Syndrome (JHS) have reduced knee joint proprioceptive acuity compared to peers. Altered proprioception at end of range in individuals with JHS is hypothesised to contribute to recurrent joint injuries and instability. This study aims to provide the first objective comparison of functional knee joint proprioceptive acuity in hyperextension range compared to early flexion range in children with JHS. METHODS: Active, weight bearing knee joint proprioceptive acuity in both hyperextension and early flexion range was tested with a purpose-built device. Proprioceptive acuity was measured using the psychophysical method of constant stimuli to determine ability to discriminate between the extents of paired active movements made to physical stops. The smallest difference in knee range of motion that the child is able to correctly judge on at least 75% of occasions, the Just Noticeable Difference (JND), was calculated using Probit analysis. Knee pain, muscle strength, amount of physical activity and patient demographic data were collected. RESULTS: Twenty children aged 8-16 years with JHS and hypermobile knees participated. Eleven children demonstrated better proprioceptive acuity in flexion, and 9 in hyperextension (z = 0.45, p = 0.63). Matched pairs t-test found no significant difference in children's ability to discriminate between the same extents of movement in the hyperextension or flexion directions (mean JND difference 0.11 degrees , 95% CI -0.26 degrees - 0.47 degrees , p = 0.545). However, 3 children could not discriminate movements in hyperextension better than chance. Proprioceptive acuity scores were positively correlated between the two directions of movement (r = 0.55, p = 0.02), with no significant correlations found between proprioceptive acuity and age, degree of hypermobility, muscle strength, pain level, amount of physical activity or body mass index centile (r = -0.35 to -0.03, all p >= 0.13). CONCLUSION: For a group of children with JHS involving hypermobile knees, there was no significant difference between knee joint proprioceptive acuity in early flexion and in hypermobile range when measured by a functional, active, weight-bearing test. Therefore, when implementing a proprioceptive training programme, clinicians should focus training throughout knee range, including into hyperextension. Further research is needed to determine factors contributing to pain and instability in hypermobile range. PMID- 25278816 TI - Mutations in CECR1 associated with a neutrophil signature in peripheral blood. AB - BACKGROUND: A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis. METHODS: Considering the phenotypic overlap of ADA2 deficiency with the type I interferonopathy Aicardi-Goutieres syndrome due to mutations in SAMHD1, we looked for the presence of an interferon signature in the peripheral blood of two newly ascertained ADA2-deficient patients. RESULTS: We identified biallelic CECR1 mutations in two patients consistent with ADA2 deficiency. Both patients demonstrated an upregulation of interferon stimulated gene transcripts in peripheral blood. More strikingly however, genome-wide analysis revealed a marked overexpression of neutrophil-derived genes, suggesting that the vasculitis seen in ADA2 deficiency may be an indirect effect resulting from chronic and marked activity of neutrophils. CONCLUSIONS: We hypothesise that ADA2 may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process. PMID- 25278817 TI - Colistimethate sodium for the treatment of chronic pulmonary infection in cystic fibrosis: an evidence-based review of its place in therapy. AB - Chronic bacterial respiratory-tract infections are a major driving force in the pathogenesis of cystic fibrosis (CF) lung disease and promote chronic lung function decline, destruction, and progression to respiratory failure at a premature age. Gram-negative bacteria colonizing the airways in CF are a major problem in CF therapy due to their tendency to develop a high degree of resistance to antibiotic agents over time. Pseudomonas aeruginosa is the dominating bacterial strain infecting the CF lung from early childhood on, and multiresistant strains frequently develop after years of therapy. Colistin has been used for treating pulmonary bacterial infections in CF for decades due to its very good Gram-negative activity. However, drawbacks include concerns regarding toxicity when being applied systemically, and the lack of approval for application by inhalation in the USA for many years. Other antibiotic substances for systemic use are available with good to excellent Gram-negative and anti Pseudomonas activity, while there are only three substances approved for inhalation use in the treatment of chronic pulmonary infection with proven benefit in CF. The emergence of multiresistant strains leaving nearly no antibiotic substance as a treatment option, the limited number of antibiotics with high activity against P. aeruginosa, the concerns about increasing the risk of antibiotic resistance by continuous antibiotic therapy, the development of new drug formulations and drug-delivery devices, and, finally, the differing treatment strategies used in CF centers call for defining the place of this "old" drug, colistimethate, in today's CF therapy. This article reviews the available evidence to reflect on the place of colistimethate sodium in the therapy of chronic pulmonary infection in CF. PMID- 25278819 TI - Synthesis and high sensing properties of a single Pd-doped SnO2 nanoribbon. AB - Monocrystal SnO2 and Pd-SnO2 nanoribbons have been successfully synthesized by thermal evaporation, and novel ethanol sensors based on a single Pd-SnO2 nanoribbon and a single SnO2 nanoribbon were fabricated. The sensing properties of SnO2 nanoribbon (SnO2 NB) and Pd-doped SnO2 nanoribbon (Pd-SnO2 NB) sensors were investigated. The results indicated that the SnO2 NB showed a high sensitivity to ethanol and the Pd-SnO2 NB has a much higher sensitivity of 4.3 at 1,000 ppm of ethanol at 230 degrees C, which is the highest sensitivity for a SnO2-based NB. Pd-SnO2 NB can detect ethanol in a wide range of concentration (1 ~ 1,000 ppm) with a relatively quick response (recovery) time of 8 s (9 s) at a temperature from 100 degrees C to 300 degrees C. In the meantime, the sensing capabilities of the Pd-SnO2 NB under 1 ppm of ethanol at 230 degrees C will help to promote the sensitivity of a single nanoribbon sensor. Excellent performances of such a sensor make it a promising candidate for a device design toward ever shrinking dimensions because a single nanoribbon device is easily integrated in the electronic devices. PMID- 25278818 TI - Efficient perovskite solar cells based on low-temperature solution-processed (CH3NH3)PbI3 perovskite/CuInS2 planar heterojunctions. AB - In this work, the solution-processed CH3NH3PbI3 perovskite/copper indium disulfide (CuInS2) planar heterojunction solar cells with Al2O3 as a scaffold were fabricated at a temperature as low as 250 degrees C for the first time, in which the indium tin oxide (ITO)-coated glass instead of the fluorine-doped tin oxide (FTO)-coated glass was used as the light-incidence electrode and the solution-processed CuInS2 layer was prepared to replace the commonly used TiO2 layer in previously reported perovskite-based solar cells. The influence of the thickness of the as-prepared CuInS2 film on the performance of the ITO/CuInS2(n)/Al2O3/(CH3NH3)PbI3/Ag cells was investigated. The ITO/CuInS2(2)/Al2O3/(CH3NH3)PbI3/Ag cell showed the best performance and achieved power conversion efficiency up to 5.30%. PMID- 25278820 TI - Overview of emerging nonvolatile memory technologies. AB - Nonvolatile memory technologies in Si-based electronics date back to the 1990s. Ferroelectric field-effect transistor (FeFET) was one of the most promising devices replacing the conventional Flash memory facing physical scaling limitations at those times. A variant of charge storage memory referred to as Flash memory is widely used in consumer electronic products such as cell phones and music players while NAND Flash-based solid-state disks (SSDs) are increasingly displacing hard disk drives as the primary storage device in laptops, desktops, and even data centers. The integration limit of Flash memories is approaching, and many new types of memory to replace conventional Flash memories have been proposed. Emerging memory technologies promise new memories to store more data at less cost than the expensive-to-build silicon chips used by popular consumer gadgets including digital cameras, cell phones and portable music players. They are being investigated and lead to the future as potential alternatives to existing memories in future computing systems. Emerging nonvolatile memory technologies such as magnetic random-access memory (MRAM), spin-transfer torque random-access memory (STT-RAM), ferroelectric random-access memory (FeRAM), phase-change memory (PCM), and resistive random-access memory (RRAM) combine the speed of static random-access memory (SRAM), the density of dynamic random-access memory (DRAM), and the nonvolatility of Flash memory and so become very attractive as another possibility for future memory hierarchies. Many other new classes of emerging memory technologies such as transparent and plastic, three-dimensional (3-D), and quantum dot memory technologies have also gained tremendous popularity in recent years. Subsequently, not an exaggeration to say that computer memory could soon earn the ultimate commercial validation for commercial scale-up and production the cheap plastic knockoff. Therefore, this review is devoted to the rapidly developing new class of memory technologies and scaling of scientific procedures based on an investigation of recent progress in advanced Flash memory devices. PMID- 25278821 TI - Comparative analysis of barium titanate thin films dry etching using inductively coupled plasmas by different fluorine-based mixture gas. AB - In this work, the inductively coupled plasma etching technique was applied to etch the barium titanate thin film. A comparative study of etch characteristics of the barium titanate thin film has been investigated in fluorine-based (CF4/O2, C4F8/O2 and SF6/O2) plasmas. The etch rates were measured using focused ion beam in order to ensure the accuracy of measurement. The surface morphology of etched barium titanate thin film was characterized by atomic force microscope. The chemical state of the etched surfaces was investigated by X-ray photoelectron spectroscopy. According to the experimental result, we monitored that a higher barium titanate thin film etch rate was achieved with SF6/O2 due to minimum amount of necessary ion energy and its higher volatility of etching byproducts as compared with CF4/O2 and C4F8/O2. Low-volatile C-F compound etching byproducts from C4F8/O2 were observed on the etched surface and resulted in the reduction of etch rate. As a result, the barium titanate films can be effectively etched by the plasma with the composition of SF6/O2, which has an etch rate of over than 46.7 nm/min at RF power/inductively coupled plasma (ICP) power of 150/1,000 W under gas pressure of 7.5 mTorr with a better surface morphology. PMID- 25278823 TI - Association of mid-pregnancy antioxidative vitamin and oxidative stress levels with infant growth during the first 3 years of life. AB - OBJECTIVE: Numerous studies have revealed the impacts of maternal nutritional status on subsequent birth outcome, but much less is known about the long-term impacts on infant growth after birth. We investigated the association between maternal micronutrient levels/oxidative stress status in pregnancy and infant growth during the first 3 years of life. DESIGN: Prospective cohort study. SETTING: The Ewha Birth & Growth Cohort study was constructed for women who had been recruited between 24 and 28 weeks' gestation and their offspring at Ewha Womans University Hospital. SUBJECTS: Maternal serum vitamin and urinary oxidative stress levels were measured, and infant weight, height, and head circumference were measured repeatedly at birth and at 6, 12, 18, 24, and 36 months of age. RESULTS: Maternal vitamins A and C were positively associated with infant head circumference and infant weight, respectively, during the first 3 years of life, even after controlling for potential confounding factors. But, maternal oxidative stress was not related to infant growth. CONCLUSIONS: The effects of maternal vitamin levels on subsequent infant growth during the first 3 years of life necessitate interventions to supplement antioxidative vitamins during pregnancy. PMID- 25278822 TI - Bread consumption patterns in a Swedish national dietary survey focusing particularly on whole-grain and rye bread. AB - BACKGROUND: Bread types with high contents of whole grains and rye are associated with beneficial health effects. Consumer characteristics of different bread consumption patterns are however not well known. OBJECTIVE: To compare bread consumption patterns among Swedish adults in relation to selected socio demographic, geographic, and lifestyle-related factors. For selected consumer groups, the further aim is to investigate the intake of whole grains and the context of bread consumption, that is, where and when it is consumed. DESIGN: Secondary analysis was performed on bread consumption data from a national dietary survey (n=1,435). Respondents were segmented into consumer groups according to the type and amount of bread consumed. Multiple logistic regressions were performed to study how selected socio-demographic, geographic, and lifestyle related factors were associated with the consumer groups. Selected consumption groups were compared in terms of whole-grain intake and consumption context. Consumption in different age groups was analysed more in detail. RESULTS: One third of the respondents consumed mainly white bread. Socio-demographic, geographic, and healthy-lifestyle-related factors were associated with the bread type consumed. White bread consumption was associated with younger age groups, less education, children in the family, eating less fruit and vegetables, and more candy and snacks; the opposite was seen for mainly whole-grain bread consumers. Older age groups more often reported eating dry crisp bread, whole grain bread, and whole-grain rye bread with sourdough whereas younger respondents reported eating bread outside the home, something that also mainly white bread eaters did. Low consumers of bread also consumed less whole grain in total. CONCLUSIONS: Traditional bread consumption structures were observed, as was a transition among young consumers who more often consumed fast food bread and bread outside the home, as well as less rye and whole-grain bread. Target groups for communication strategies and product development of more sensorily attractive rye or whole-grain-rich bread should be younger age groups (18-30 years), families with children, and groups with lower educational levels. PMID- 25278824 TI - The fast and the slow sides of cortisol's effects on emotional interference and sustained attention. PMID- 25278826 TI - Anterograde transport blockade precedes deficits in retrograde transport in the visual projection of the DBA/2J mouse model of glaucoma. AB - Axonal transport deficits have been reported as an early pathology in several neurodegenerative disorders, including glaucoma. However, the progression and mechanisms of these deficits are poorly understood. Previous work suggests that anterograde transport is affected earlier and to a larger degree than retrograde transport, yet this has never been examined directly in vivo. Using combined anterograde and retrograde tract tracing methods, we examined the time-course of anterograde and retrograde transport deficits in the retinofugal projection in pre-glaucomatous (3 month-old) and glaucomatous (9-13 month old) DBA/2J mice. DBA/2J-Gpnmb (+) mice were used as a control strain and were shown to have similar retinal ganglion cell densities as C57BL/6J control mice-a strain commonly investigated in the field of vision research. Using cholera toxin-B injections into the eye and FluoroGold injections into the superior colliculus (SC), we were able to measure anterograde and retrograde transport in the primary visual projection. In DBA/2J, anterograde transport from the retina to SC was decreased by 69% in the 9-10 month-old age group, while retrograde transport was only reduced by 23% from levels seen in pre-glaucomatous mice. Despite this minor reduction, retrograde transport remained largely intact in these glaucomatous age groups until 13-months of age. These findings indicate that axonal transport deficits occur in semi-functional axons that are still connected to their brain targets. Structural persistence as determined by presence of estrogen-related receptor beta label in the superficial SC was maintained beyond time-points where reductions in retrograde transport occurred, also supporting that transport deficits may be due to physiological or functional abnormalities as opposed to overt structural loss. PMID- 25278827 TI - The evolution of music and human social capability. AB - Music is a core human experience and generative processes reflect cognitive capabilities. Music is often functional because it is something that can promote human well-being by facilitating human contact, human meaning, and human imagination of possibilities, tying it to our social instincts. Cognitive systems also underlie musical performance and sensibilities. Music is one of those things that we do spontaneously, reflecting brain machinery linked to communicative functions, enlarged and diversified across a broad array of human activities. Music cuts across diverse cognitive capabilities and resources, including numeracy, language, and space perception. In the same way, music intersects with cultural boundaries, facilitating our "social self" by linking our shared experiences and intentions. This paper focuses on the intersection between the neuroscience of music, and human social functioning to illustrate the importance of music to human behaviors. PMID- 25278828 TI - Rapid shape detection signals in area V4. AB - Vision in foveate animals is an active process that requires rapid and constant decision-making. For example, when a new object appears in the visual field, we can quickly decide to inspect it by directing our eyes to the object's location. We studied the contribution of primate area V4 to these types of rapid foveation decisions. Animals performed a reaction time task that required them to report when any shape appeared within a peripherally-located noisy stimulus by making a saccade to the stimulus location. We found that about half of the randomly sampled V4 neurons not only rapidly and precisely represented the appearance of this shape, but they were also predictive of the animal's saccades. A neuron's ability to predict the animal's saccades was not related to the specificity with which the cell represented a single type of shape but rather to its ability to signal whether any shape was present. This relationship between sensory sensitivity and behavioral predictiveness was not due to global effects such as alertness, as it was equally likely to be observed for cells with increases and decreases in firing rate. Careful analysis of the timescales of reliability in these neurons implies that they reflect both feedforward and feedback shape detecting processes. In approximately 7% of our recorded sample, individual neurons were able to predict both the delay and precision of the animal's shape detection performance. This suggests that a subset of V4 neurons may have been directly and causally contributing to task performance and that area V4 likely plays a critical role in guiding rapid, form-based foveation decisions. PMID- 25278829 TI - Visual attention for social information and salivary oxytocin levels in preschool children with autism spectrum disorders: an eye-tracking study. AB - This study was designed to ascertain the relationship between visual attention for social information and oxytocin (OT) levels in Japanese preschool children with autism spectrum disorder (ASD). We hypothesized that poor visual attention for social information and low OT levels are crucially important risk factors associated with ASD. We measured the pattern of gaze fixation for social information using an eye-tracking system, and salivary OT levels by the Enzyme Linked Immunosorbent Assay (ELISA). There was a positive association between salivary OT levels and fixation duration for an indicated object area in a finger pointing movie in typically developing (TD) children. However, no association was found between these variables in children with ASD. Moreover, age decreased an individual's attention to people moving and pointed-at objects, but increased attention for mouth-in-the-face recognition, geometric patterns, and biological motions. Thus, OT levels likely vary during visual attention for social information between TD children and those with ASD. Further, aging in preschool children has considerable effect on visual attention for social information. PMID- 25278825 TI - Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders. AB - Peptides synthesized in endocrine cells in the gastrointestinal tract and neurons are traditionally considered regulators of metabolism, energy intake, and appetite. However, recent work has demonstrated that many of these peptides act on corticostriatal-limbic circuitry and, in turn, regulate addictive behaviors. Given that alcohol is a source of energy and an addictive substance, it is not surprising that increasing evidence supports a role for gut-brain peptides specifically in alcohol use disorders (AUD). In this review, we discuss the effects of several gut-brain peptides on alcohol-related behaviors and the potential mechanisms by which these gut-brain peptides may interfere with alcohol induced changes in corticostriatal-limbic circuitry. This review provides a summary of current knowledge on gut-brain peptides focusing on five peptides: neurotensin, glucagon-like peptide 1, ghrelin, substance P, and neuropeptide Y. Our review will be helpful to develop novel therapeutic targets for AUD. PMID- 25278831 TI - Hearing impairment in the P23H-1 retinal degeneration rat model. AB - The transgenic P23H line 1 (P23H-1) rat expresses a variant of rhodopsin with a mutation that leads to loss of visual function. This rat strain is an experimental model usually employed to study photoreceptor degeneration. Although the mutated protein should not interfere with other sensory functions, observing severe loss of auditory reflexes in response to natural sounds led us to study auditory brain response (ABR) recording. Animals were separated into different hearing levels following the response to natural stimuli (hand clapping and kissing sounds). Of all the analyzed animals, 25.9% presented auditory loss before 50 days of age (P50) and 45% were totally deaf by P200. ABR recordings showed that all the rats had a higher hearing threshold than the control Sprague Dawley (SD) rats, which was also higher than any other rat strains. The integrity of the central and peripheral auditory pathway was analyzed by histology and immunocytochemistry. In the cochlear nucleus (CN), statistical differences were found between SD and P23H-1 rats in VGluT1 distribution, but none were found when labeling all the CN synapses with anti-Syntaxin. This finding suggests anatomical and/or molecular abnormalities in the auditory downstream pathway. The inner ear of the hypoacusic P23H-1 rats showed several anatomical defects, including loss and disruption of hair cells and spiral ganglion neurons. All these results can explain, at least in part, how hearing impairment can occur in a high percentage of P23H-1 rats. P23H-1 rats may be considered an experimental model with visual and auditory dysfunctions in future research. PMID- 25278833 TI - Abnormal yawning in stroke patients: the role of brain thermoregulation. PMID- 25278832 TI - Neuroanatomy and sex differences of the lordosis-inhibiting system in the lateral septum. AB - Female sexual behavior in rodents, termed lordosis, is controlled by facilitatory and inhibitory systems in the brain. It has been well demonstrated that a neural pathway from the ventromedial hypothalamic nucleus (VMN) to the midbrain central gray (MCG) is essential for facilitatory regulation of lordosis. The neural pathway from the arcuate nucleus to the VMN, via the medial preoptic nucleus, in female rats mediates transient suppression of lordosis, until female sexual receptivity is induced. In addition to this pathway, other regions are involved in inhibitory regulation of lordosis in female rats. The lordosis-inhibiting systems exist not only in the female brain but also in the male brain. The systems contribute to suppression of heterotypical sexual behavior in male rats, although they have the potential ability to display lordosis. The lateral septum (LS) exerts an inhibitory influence on lordosis in both female and male rats. This review focuses on the neuroanatomy and sex differences of the lordosis inhibiting system in the LS. The LS functionally and anatomically links to the MCG to exert suppression of lordosis. Neurons of the intermediate part of the LS (LSi) serve as lordosis-inhibiting neurons and project axons to the MCG. The LSi MCG neural connection is sexually dimorphic, and formation of the male-like LSi MCG neural connection is affected by aromatized testosterone originating from the testes in the postnatal period. The sexually dimorphic LSi-MCG neural connection may reflect the morphological basis of sex differences in the inhibitory regulation of lordosis in rats. PMID- 25278834 TI - The brain correlates of the effects of monetary and verbal rewards on intrinsic motivation. AB - Apart from everyday duties, such as doing the laundry or cleaning the house, there are tasks we do for pleasure and enjoyment. We do such tasks, like solving crossword puzzles or reading novels, without any external pressure or force; instead, we are intrinsically motivated: we do the tasks because we enjoy doing them. Previous studies suggest that external rewards, i.e., rewards from the outside, affect the intrinsic motivation to engage in a task: while performance based monetary rewards are perceived as controlling and induce a business contract framing, verbal rewards praising one's competence can enhance the perceived self-determination. Accordingly, the former have been shown to decrease intrinsic motivation, whereas the latter have been shown to increase intrinsic motivation. The present study investigated the neural processes underlying the effects of monetary and verbal rewards on intrinsic motivation in a group of 64 subjects applying functional magnetic resonance imaging (fMRI). We found that, when participants received positive performance feedback, activation in the anterior striatum and midbrain was affected by the nature of the reward; compared to a non-rewarded control group, activation was higher while monetary rewards were administered. However, we did not find a decrease in activation after reward withdrawal. In contrast, we found an increase in activation for verbal rewards: after verbal rewards had been withdrawn, participants showed a higher activation in the aforementioned brain areas when they received success compared to failure feedback. We further found that, while participants worked on the task, activation in the lateral prefrontal cortex was enhanced after the verbal rewards were administered and withdrawn. PMID- 25278830 TI - Restoration of motor function following spinal cord injury via optimal control of intraspinal microstimulation: toward a next generation closed-loop neural prosthesis. AB - Movement is planned and coordinated by the brain and carried out by contracting muscles acting on specific joints. Motor commands initiated in the brain travel through descending pathways in the spinal cord to effector motor neurons before reaching target muscles. Damage to these pathways by spinal cord injury (SCI) can result in paralysis below the injury level. However, the planning and coordination centers of the brain, as well as peripheral nerves and the muscles that they act upon, remain functional. Neuroprosthetic devices can restore motor function following SCI by direct electrical stimulation of the neuromuscular system. Unfortunately, conventional neuroprosthetic techniques are limited by a myriad of factors that include, but are not limited to, a lack of characterization of non-linear input/output system dynamics, mechanical coupling, limited number of degrees of freedom, high power consumption, large device size, and rapid onset of muscle fatigue. Wireless multi-channel closed-loop neuroprostheses that integrate command signals from the brain with sensor-based feedback from the environment and the system's state offer the possibility of increasing device performance, ultimately improving quality of life for people with SCI. In this manuscript, we review neuroprosthetic technology for improving functional restoration following SCI and describe brain-machine interfaces suitable for control of neuroprosthetic systems with multiple degrees of freedom. Additionally, we discuss novel stimulation paradigms that can improve synergy with higher planning centers and improve fatigue-resistant activation of paralyzed muscles. In the near future, integration of these technologies will provide SCI survivors with versatile closed-loop neuroprosthetic systems for restoring function to paralyzed muscles. PMID- 25278836 TI - A fast BK-type KCa current acts as a postsynaptic modulator of temporal selectivity for communication signals. AB - Temporal patterns of spiking often convey behaviorally relevant information. Various synaptic mechanisms and intrinsic membrane properties can influence neuronal selectivity to temporal patterns of input. However, little is known about how synaptic mechanisms and intrinsic properties together determine the temporal selectivity of neuronal output. We tackled this question by recording from midbrain electrosensory neurons in mormyrid fish, in which the processing of temporal intervals between communication signals can be studied in a reduced in vitro preparation. Mormyrids communicate by varying interpulse intervals (IPIs) between electric pulses. Within the midbrain posterior exterolateral nucleus (ELp), the temporal patterns of afferent spike trains are filtered to establish single-neuron IPI tuning. We performed whole-cell recording from ELp neurons in a whole-brain preparation and examined the relationship between intrinsic excitability and IPI tuning. We found that spike frequency adaptation of ELp neurons was highly variable. Postsynaptic potentials (PSPs) of strongly adapting (phasic) neurons were more sharply tuned to IPIs than weakly adapting (tonic) neurons. Further, the synaptic filtering of IPIs by tonic neurons was more faithfully converted into variation in spiking output, particularly at short IPIs. Pharmacological manipulation under current- and voltage-clamp revealed that tonic firing is mediated by a fast, large-conductance Ca(2+)-activated K(+) (KCa) current (BK) that speeds up action potential repolarization. These results suggest that BK currents can shape the temporal filtering of sensory inputs by modifying both synaptic responses and PSP-to-spike conversion. Slow SK-type KCa currents have previously been implicated in temporal processing. Thus, both fast and slow KCa currents can fine-tune temporal selectivity. PMID- 25278835 TI - In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period. AB - Aminoglycoside-induced cochlear ototoxicity causes hair cell (HC) loss and results in hearing impairment in patients. Previous studies have developed the concept of an ototoxicity-sensitive period during which the cochleae of young mice are more vulnerable to auditory trauma than adults. Here, we compared neomycin-induced ototoxicity at the following four developmental ages in mice: postnatal day (P)1-P7, P8-P14, P15-P21, and P60-P66. We found that when neomycin was administered between P8 and P14, the auditory brainstem response threshold increase was significantly higher at low frequencies and HC loss was significantly greater in the apical turn of the cochlea compared to neomycin administration during the other age ranges. Quantitative real-time PCR (qPCR) data revealed that the expression of apoptotic markers, including Casp3 and Casp9, was significantly higher when neomycin was injected from P8 to P14, while the expression of the X-linked inhibitor of apoptosis protein (XIAP) gene was significantly higher when neomycin was injected from P60 to P66. Because XIAP expression was low during the neomycin-sensitive period, we overexpressed XIAP in mice and found that it could protect against neomycin-induced hearing loss at low frequencies and HC loss in the apical turn of the cochlea. Altogether, our findings demonstrate a protective role for XIAP against neomycin-induced hearing loss and HC loss in the apical turn of the cochlea during the ototoxic-sensitive period, and suggest that apoptotic factors mediate the effect of neomycin during the ototoxic-sensitive period. PMID- 25278837 TI - A simulation study on the effects of dendritic morphology on layer V prefrontal pyramidal cell firing behavior. AB - Pyramidal cells, the most abundant neurons in neocortex, exhibit significant structural variability across different brain areas and layers in different species. Moreover, in response to a somatic step current, these cells display a range of firing behaviors, the most common being (1) repetitive action potentials (Regular Spiking-RS), and (2) an initial cluster of 2-5 action potentials with short interspike interval (ISIs) followed by single spikes (Intrinsic Bursting IB). A correlation between firing behavior and dendritic morphology has recently been reported. In this work we use computational modeling to investigate quantitatively the effects of the basal dendritic tree morphology on the firing behavior of 112 three-dimensional reconstructions of layer V PFC rat pyramidal cells. Particularly, we focus on how different morphological (diameter, total length, volume, and branch number) and passive [Mean Electrotonic Path length (MEP)] features of basal dendritic trees shape somatic firing when the spatial distribution of ionic mechanisms in the basal dendritic trees is uniform or non uniform. Our results suggest that total length, volume and branch number are the best morphological parameters to discriminate the cells as RS or IB, regardless of the distribution of ionic mechanisms in basal trees. The discriminatory power of total length, volume, and branch number remains high in the presence of different apical dendrites. These results suggest that morphological variations in the basal dendritic trees of layer V pyramidal neurons in the PFC influence their firing patterns in a predictive manner and may in turn influence the information processing capabilities of these neurons. PMID- 25278838 TI - Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics. AB - The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory gamma-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCR (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the alpha2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence. PMID- 25278840 TI - Neural precursor cells in the ischemic brain - integration, cellular crosstalk, and consequences for stroke recovery. AB - After an ischemic stroke, neural precursor cells (NPCs) proliferate within major germinal niches of the brain. Endogenous NPCs subsequently migrate toward the ischemic lesion where they promote tissue remodeling and neural repair. Unfortunately, this restorative process is generally insufficient and thus unable to support a full recovery of lost neurological functions. Supported by solid experimental and preclinical data, the transplantation of exogenous NPCs has emerged as a potential tool for stroke treatment. Transplanted NPCs are thought to act mainly via trophic and immune modulatory effects, thereby complementing the restorative responses initially executed by the endogenous NPC population. Recent studies have attempted to elucidate how the therapeutic properties of transplanted NPCs vary depending on the route of transplantation. Systemic NPC delivery leads to potent immune modulatory actions, which prevent secondary neuronal degeneration, reduces glial scar formation, diminishes oxidative stress and stabilizes blood-brain barrier integrity. On the contrary, local stem cell delivery allows for the accumulation of large numbers of transplanted NPCs in the brain, thus achieving high levels of locally available tissue trophic factors, which may better induce a strong endogenous NPC proliferative response. Herein we describe the diverse capabilities of exogenous (systemically vs. locally transplanted) NPCs in enhancing the endogenous neurogenic response after stroke, and how the route of transplantation may affect migration, survival, bystander effects and integration of the cellular graft. It is the authors' claim that understanding these aspects will be of pivotal importance in discerning how transplanted NPCs exert their therapeutic effects in stroke. PMID- 25278841 TI - Spiny neurons of amygdala, striatum, and cortex use dendritic plateau potentials to detect network UP states. AB - SPINY NEURONS OF AMYGDALA, STRIATUM, AND CEREBRAL CORTEX SHARE FOUR INTERESTING FEATURES: (1) they are the most abundant cell type within their respective brain area, (2) covered by thousands of thorny protrusions (dendritic spines), (3) possess high levels of dendritic NMDA conductances, and (4) experience sustained somatic depolarizations in vivo and in vitro (UP states). In all spiny neurons of the forebrain, adequate glutamatergic inputs generate dendritic plateau potentials ("dendritic UP states") characterized by (i) fast rise, (ii) plateau phase lasting several hundred milliseconds, and (iii) abrupt decline at the end of the plateau phase. The dendritic plateau potential propagates toward the cell body decrementally to induce a long-lasting (longer than 100 ms, most often 200 800 ms) steady depolarization (~20 mV amplitude), which resembles a neuronal UP state. Based on voltage-sensitive dye imaging, the plateau depolarization in the soma is precisely time-locked to the regenerative plateau potential taking place in the dendrite. The somatic plateau rises after the onset of the dendritic voltage transient and collapses with the breakdown of the dendritic plateau depolarization. We hypothesize that neuronal UP states in vivo reflect the occurrence of dendritic plateau potentials (dendritic UP states). We propose that the somatic voltage waveform during a neuronal UP state is determined by dendritic plateau potentials. A mammalian spiny neuron uses dendritic plateau potentials to detect and transform coherent network activity into a ubiquitous neuronal UP state. The biophysical properties of dendritic plateau potentials allow neurons to quickly attune to the ongoing network activity, as well as secure the stable amplitudes of successive UP states. PMID- 25278839 TI - A synaptic mechanism for network synchrony. AB - Within neural networks, synchronization of activity is dependent upon the synaptic connectivity of embedded microcircuits and the intrinsic membrane properties of their constituent neurons. Synaptic integration, dendritic Ca(2+) signaling, and non-linear interactions are crucial cellular attributes that dictate single neuron computation, but their roles promoting synchrony and the generation of network oscillations are not well understood, especially within the context of a defined behavior. In this regard, the lamprey spinal central pattern generator (CPG) stands out as a well-characterized, conserved vertebrate model of a neural network (Smith et al., 2013a), which produces synchronized oscillations in which neural elements from the systems to cellular level that control rhythmic locomotion have been determined. We review the current evidence for the synaptic basis of oscillation generation with a particular emphasis on the linkage between synaptic communication and its cellular coupling to membrane processes that control oscillatory behavior of neurons within the locomotor network. We seek to relate dendritic function found in many vertebrate systems to the accessible lamprey central nervous system in which the relationship between neural network activity and behavior is well understood. This enables us to address how Ca(2+) signaling in spinal neuron dendrites orchestrate oscillations that drive network behavior. PMID- 25278843 TI - Simultaneous visualization of extrinsic and intrinsic axon collaterals in Golgi like detail for mouse corticothalamic and corticocortical cells: a double viral infection method. AB - Here we present a novel tracing technique to stain projection neurons in Golgi like detail by double viral infection. We used retrograde lentiviral vectors and adeno-associated viral vectors (AAV) to drive "TET-ON/TET-OFF system" in neurons connecting two regions. Using this method, we successfully labeled the corticothalamic (CT) cells of the mouse somatosensory barrel field (S1BF) and motor cortex (M1) in their entirety. We also labeled contra- and ipsilaterally projecting corticocortical (CC) cells of M1 by targeting contralateral M1 or ipsilateral S1 for retrograde infection. The strength of this method is that we can observe the morphology of specific projection neuron subtypes en masse. We found that the group of CT cells extends their dendrites and intrinsic axons extensively below but not within the thalamorecipient layer in both S1BF and M1, suggesting that the primary target of this cell type is not layer 4. We also found that both ipsi- and contralateral targeting CC cells in M1 commonly exhibit widespread collateral extensions to contralateral M1 (layers 1-6), bilateral S1 and S2 (layers 1, 5 and 6), perirhinal cortex (layers 1, 2/3, 5, and 6), striatum and claustrum. These findings not only strengthened the previous findings of single cell tracings but also extended them by enabling cross-area comparison of CT cells or comparison of CC cells of two different labeling. PMID- 25278844 TI - Network analysis of time-lapse microscopy recordings. AB - Multicellular organisms rely on intercellular communication to regulate important cellular processes critical to life. To further our understanding of those processes there is a need to scrutinize dynamical signaling events and their functions in both cells and organisms. Here, we report a method and provide MATLAB code that analyzes time-lapse microscopy recordings to identify and characterize network structures within large cell populations, such as interconnected neurons. The approach is demonstrated using intracellular calcium (Ca(2+)) recordings in neural progenitors and cardiac myocytes, but could be applied to a wide variety of biosensors employed in diverse cell types and organisms. In this method, network structures are analyzed by applying cross correlation signal processing and graph theory to single-cell recordings. The goal of the analysis is to determine if the single cell activity constitutes a network of interconnected cells and to decipher the properties of this network. The method can be applied in many fields of biology in which biosensors are used to monitor signaling events in living cells. Analyzing intercellular communication in cell ensembles can reveal essential network structures that provide important biological insights. PMID- 25278842 TI - Swimming against the tide: investigations of the C-bouton synapse. AB - C-boutons are important cholinergic modulatory loci for state-dependent alterations in motoneuron firing rate. m2 receptors are concentrated postsynaptic to C-boutons, and m2 receptor activation increases motoneuron excitability by reducing the action potential afterhyperpolarization. Here, using an intensive review of the current literature as well as data from our laboratory, we illustrate that C-bouton postsynaptic sites comprise a unique structural/functional domain containing appropriate cellular machinery (a "signaling ensemble") for cholinergic regulation of outward K(+) currents. Moreover, synaptic reorganization at these critical sites has been observed in a variety of pathologic states. Yet despite recent advances, there are still great challenges for understanding the role of C-bouton regulation and dysregulation in human health and disease. The development of new therapeutic interventions for devastating neurological conditions will rely on a complete understanding of the molecular mechanisms that underlie these complex synapses. Therefore, to close this review, we propose a comprehensive hypothetical mechanism for the cholinergic modification of alpha-MN excitability at C-bouton synapses, based on findings in several well-characterized neuronal systems. PMID- 25278845 TI - Optical suppression of drug-evoked phasic dopamine release. AB - Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior. PMID- 25278846 TI - Regulatory effects of intermittent noxious stimulation on spinal cord injury sensitive microRNAs and their presumptive targets following spinal cord contusion. AB - Uncontrollable nociceptive stimulation adversely affects recovery in spinally contused rats. Spinal cord injury (SCI) results in altered microRNA (miRNA) expression both at, and distal to the lesion site. We hypothesized that uncontrollable nociception further influences SCI-sensitive miRNAs and associated gene targets, potentially explaining the progression of maladaptive plasticity. Our data validated previously described sensitivity of miRNAs to SCI alone. Moreover, following SCI, intermittent noxious stimulation decreased expression of miR124 in dorsal spinal cord 24 h after stimulation and increased expression of miR129-2 in dorsal, and miR1 in ventral spinal cord at 7 days. We also found that brain-derived neurotrophic factor (BDNF) mRNA expression was significantly down regulated 1 day after SCI alone, and significantly more so, after SCI followed by tailshock. Insulin-like growth factor-1 (IGF-1) mRNA expression was significantly increased at both 1 and 7 days post-SCI, and significantly more so, 7 days post SCI with shock. MiR1 expression was positively and significantly correlated with IGF-1, but not BDNF mRNA expression. Further, stepwise linear regression analysis indicated that a significant proportion of the changes in BDNF and IGF-1 mRNA expression were explained by variance in two groups of miRNAs, implying co regulation. Collectively, these data show that uncontrollable nociception which activates sensorimotor circuits distal to the injury site, influences SCI-miRNAs and target mRNAs within the lesion site. SCI-sensitive miRNAs may well mediate adverse consequences of uncontrolled sensorimotor activation on functional recovery. However, their sensitivity to distal sensory input also implicates these miRNAs as candidate targets for the management of SCI and neuropathic pain. PMID- 25278849 TI - Mice and rats achieve similar levels of performance in an adaptive decision making task. AB - Two opposing constraints exist when choosing a model organism for studying the neural basis of adaptive decision-making: (1) experimental access and (2) behavioral complexity. Available molecular and genetic approaches for studying neural circuits in the mouse fulfill the first requirement. In contrast, it is still under debate if mice can perform cognitive tasks of sufficient complexity. Here we compare learning and performance of mice and rats, the preferred behavioral rodent model, during an acoustic flexible categorization two alternative choice task. The task required animals to switch between two categorization definitions several times within a behavioral session. We found that both species achieved similarly high performance levels. On average, rats learned the task faster than mice, although some mice were as fast as the average rat. No major differences in subjective categorization boundaries or the speed of adaptation between the two species were found. Our results demonstrate that mice are an appropriate model for the study of the neural mechanisms underlying adaptive decision-making, and suggest they might be suitable for other cognitive tasks as well. PMID- 25278850 TI - The topology of connections between rat prefrontal, motor and sensory cortices. AB - The connections of prefrontal cortex (PFC) were investigated in the rat brain to determine the order and location of input and output connections to motor and somatosensory cortex. Retrograde (100 nl Fluoro-Gold) and anterograde (100 nl Biotinylated Dextran Amines, BDA; Fluorescein and Texas Red) neuronanatomical tracers were injected into the subdivisions of the PFC (prelimbic, ventral orbital, ventrolateral orbital, dorsolateral orbital) and their projections studied. We found clear evidence for organized input projections from the motor and somatosensory cortices to the PFC, with distinct areas of motor and cingulate cortex projecting in an ordered arrangement to the subdivisions of PFC. As injection location of retrograde tracer was moved from medial to lateral in PFC, we observed an ordered arrangement of projections occurring in sensory-motor cortex. There was a significant effect of retrograde injection location on the position of labelled cells occurring in sensory-motor cortex (dorsoventral, anterior-posterior and mediolateral axes p < 0.001). The arrangement of output projections from PFC also displayed a significant ordered projection to sensory motor cortex (dorsoventral p < 0.001, anterior-posterior p = 0.002 and mediolateral axes p < 0.001). Statistical analysis also showed that the locations of input and output labels vary with respect to one another (in the dorsal ventral and medial-lateral axes, p < 0.001). Taken together, the findings show that regions of PFC display an ordered arrangement of connections with sensory motor cortex, with clear laminar organization of input connections. These results also show that input and output connections to PFC are not located in exactly the same sites and reveal a circuit between sensory-motor and PFC. PMID- 25278847 TI - Neural rhythmic symphony of human walking observation: Upside-down and Uncoordinated condition on cortical theta, alpha, beta and gamma oscillations. AB - Biological motion observation has been recognized to produce dynamic change in sensorimotor activation according to the observed kinematics. Physical plausibility of the spatial-kinematic relationship of human movement may play a major role in the top-down processing of human motion recognition. Here, we investigated the time course of scalp activation during observation of human gait in order to extract and use it on future integrated brain-computer interface using virtual reality (VR). We analyzed event related potentials (ERP), the event related spectral perturbation (ERSP) and the inter-trial coherence (ITC) from high-density EEG recording during video display onset (-200-600 ms) and the steady state visual evoked potentials (SSVEP) inside the video of human walking 3D-animation in three conditions: Normal; Upside-down (inverted images); and Uncoordinated (pseudo-randomly mixed images). We found that early visual evoked response P120 was decreased in Upside-down condition. The N170 and P300b amplitudes were decreased in Uncoordinated condition. In Upside-down and Uncoordinated conditions, we found decreased alpha power and theta phase-locking. As regards gamma oscillation, power was increased during the Upside-down animation and decreased during the Uncoordinated animation. An SSVEP-like response oscillating at about 10 Hz was also described showing that the oscillating pattern is enhanced 300 ms after the heel strike event only in the Normal but not in the Upside-down condition. Our results are consistent with most of previous point-light display studies, further supporting possible use of virtual reality for neurofeedback applications. PMID- 25278851 TI - Down-regulation of amygdala activation with real-time fMRI neurofeedback in a healthy female sample. AB - Psychiatric conditions of emotion dysregulation are often characterized by difficulties in regulating the activity of limbic regions such as the amygdala. Real-time functional magnetic resonance imaging (rt-fMRI) allows to feedback brain activation and opens the possibility to establish a neurofeedback (NF) training of amygdala activation, e.g., for subjects suffering from emotion dysregulation. As a first step, we investigated whether feedback of the amygdala response to aversive scenes can improve down-regulation of amygdala activation. One group of healthy female participants received amygdala feedback (N = 16) and a control group was presented with feedback from a control region located in the basal ganglia [N(sum) = 32]. Subjects completed a one-session rt-fMRI-NF training where they viewed aversive pictures and received continuous visual feedback on brain activation (REGULATE condition). In a control condition, subjects were advised to respond naturally to aversive pictures (VIEW), and a neutral condition served as the non-affective control (NEUTRAL). In an adjacent run, subjects were presented with aversive pictures without feedback to test for transfer effects of learning. In a region of interest (ROI) analysis, the VIEW and the REGULATE conditions were contrasted to estimate brain regulation success. The ROI analysis was complemented by an exploratory analysis of activations at the whole-brain level. Both groups showed down-regulation of the amygdala response during training. Feedback from the amygdala but not from the control region was associated with down-regulation of the right amygdala in the transfer test. The whole-brain analysis did not detect significant group interactions. Results of the group whole-brain analyses are discussed. We present a proof-of-concept study using rt-fMRI-NF for amygdala down-regulation in the presence of aversive scenes. Results are in line with a potential benefit of NF training for amygdala regulation. PMID- 25278848 TI - Boosting visual cortex function and plasticity with acetylcholine to enhance visual perception. AB - The cholinergic system is a potent neuromodulatory system that plays critical roles in cortical plasticity, attention and learning. In this review, we propose that the cellular effects of acetylcholine (ACh) in the primary visual cortex during the processing of visual inputs might induce perceptual learning; i.e., long-term changes in visual perception. Specifically, the pairing of cholinergic activation with visual stimulation increases the signal-to-noise ratio, cue detection ability and long-term facilitation in the primary visual cortex. This cholinergic enhancement would increase the strength of thalamocortical afferents to facilitate the treatment of a novel stimulus while decreasing the cortico cortical signaling to reduce recurrent or top-down modulation. This balance would be mediated by different cholinergic receptor subtypes that are located on both glutamatergic and GABAergic neurons of the different cortical layers. The mechanisms of cholinergic enhancement are closely linked to attentional processes, long-term potentiation (LTP) and modulation of the excitatory/inhibitory balance. Recently, it was found that boosting the cholinergic system during visual training robustly enhances sensory perception in a long-term manner. Our hypothesis is that repetitive pairing of cholinergic and sensory stimulation over a long period of time induces long-term changes in the processing of trained stimuli that might improve perceptual ability. Various non invasive approaches to the activation of the cholinergic neurons have strong potential to improve visual perception. PMID- 25278852 TI - Chronic immobilization stress occludes in vivo cortical activation in an animal model of panic induced by carbon dioxide inhalation. AB - Breathing high concentrations of carbon dioxide (CO2) can trigger panic and anxiety in humans. CO2 inhalation has been hypothesized to activate neural systems similar to those underlying fear learning, especially those involving the amygdala. Amygdala activity is also upregulated by stress. Recently, however, a separate pathway has been proposed for interoceptive panic and anxiety signals, as patients exhibited CO2-inhalation induced panic responses despite bilateral lesions of the amygdala. This paradoxical observation has raised the possibility that cortical circuits may underlie these responses. We sought to examine these divergent models by comparing in vivo brain activation in unstressed and chronically-stressed rats breathing CO2. Regional cerebral blood flow measurements using functional Magnetic Resonance Imaging (fMRI) in lightly anaesthetized rats showed especially strong activation of the somatosensory cortex by CO2 inhalation in the unstressed group. Strikingly, prior exposure to chronic stress occluded this effect on cortical activity. This lends support to recent clinical observations and highlights the importance of looking beyond the traditional focus on limbic structures, such as the hippocampus and amygdala, to investigate a role for cortical areas in panic and anxiety in humans. PMID- 25278853 TI - Display of individuality in avoidance behavior and risk assessment of inbred mice. AB - Factors determining individuality are still poorly understood. Rodents are excellent model organisms to study individuality, due to a rich behavioral repertoire and the availability of well-characterized isogenic populations. However, most current behavioral assays for rodents have short test duration in novel test environments and require human interference, which introduce coercion, thereby limiting the assessment of naturally occurring individuality. Thus, we developed an automated behavior system to longitudinally monitor conditioned fear for assessing PTSD-like behavior in individual mice. The system consists of a safe home compartment connected to a risk-prone test compartment (TC). Entry and exploration of the TC is solely based on deliberate choice determined by individual fear responsiveness and fear extinction. In this novel ethological assay, C57BL/6J mice show homogeneous responses after shock exposure (innate fear), but striking variation in long-lasting fear responses based on avoidance and risk assessment (learned fear), including automated stretch-attend posture quantification. TC entry (retention) latencies after foot shock differed >24 h and the re-explored TC area differed >50% among inbred mice. Next, we compared two closely related C57BL/6 substrains. Despite substantial individual differences, previously observed higher fear of C57BL/6N vs. C57BL/6J mice was reconfirmed, whereas fear extinction was fast and did not differ. The observed variation in fear expression in isogenic mice suggests individual differences in coping style with PTSD-like avoidance. Investigating the assumed epigenetic mechanisms, with reduced interpretational ambiguity and enhanced translational value in this assay, may help improve understanding of personality type-dependent susceptibility and resilience to neuropsychiatric disorders such as PTSD. PMID- 25278854 TI - Balancing the excitability of M1 circuitry during movement observation without overt replication. AB - Although observation of a movement increases the excitability of the motor system of the observer, it does not induce a motor replica. What is the mechanism for replica suppression? We performed a series of experiments, involving a total of 66 healthy humans, to explore the excitability of different M1 circuits and the spinal cord during observation of simple movements. Several strategies were used. In the first and second experimental blocks, we used several delay times from movement onset to evaluate the time-course modulation of the cortico-spinal excitability (CSE), and its potential dependency on the duration of the movement observed; in order to do this single pulse transcranial magnetic stimulation (TMS) over M1 was used. In subsequent experiments, at selected delay times from movement-onset, we probed the excitability of the cortico-spinal circuits using three different approaches: (i) electric cervicomedullary stimulation (CMS), to test spinal excitability, (ii) paired-pulse TMS over M1, to evaluate the cortical inhibitory-excitatory balance (short intracortical inhibition (SICI) and intracortical facilitation (ICF)], and (iii) continuous theta-burst stimulation (cTBS), to modulate the excitability of M1 cortical circuits. We observed a stereotyped response in the modulation of CSE. At 500 ms after movement-onset the ICF was increased; although the most clear-cut effect was a decrease of CSE. The compensatory mechanism was not explained by changes in SICI, but by M1 intracortical circuits targeted by cTBS. Meanwhile, the spinal cord maintained the elevated level of excitability induced when expecting to observe movements, potentially useful to facilitate any required response to the movement observed. PMID- 25278855 TI - Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease. AB - Intraneuronal accumulation of amyloid beta (iAbeta) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg(+/-)) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Abeta accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Abeta by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Abeta peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS resistant Abeta oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg(+/-) rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg(+/-) rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Abeta burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in early AD. PMID- 25278857 TI - Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala. AB - Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations. Subjects with posttraumatic stress disorder (PTSD) show impaired extinction of conditioned fear, which is associated with decreased ventromedial prefrontal cortex (vmPFC) control over amygdala activity. Vagus nerve stimulation (VNS) enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here we investigated whether pairing VNS with extinction learning facilitates plasticity between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA). Rats were trained on an auditory fear conditioning task, which was followed by a retention test and 1 day of extinction training. Vagus nerve stimulation or sham-stimulation was administered concurrently with exposure to the fear-conditioned stimulus and retention of fear conditioning was tested again 24 h later. Vagus nerve stimulation-treated rats demonstrated a significant reduction in freezing after a single extinction training session similar to animals that received 5* the number of extinction pairings. To study plasticity in the IL-BLA pathway, we recorded evoked field potentials (EFPs) in the BLA in anesthetized animals 24 h after retention testing. Brief burst stimulation in the IL produced LTD in the BLA field response in fear-conditioned and sham-treated animals. In contrast, the same stimulation resulted in potentiation of the IL-BLA pathway in the VNS-treated group. The present findings suggest that VNS promotes plasticity in the IL-BLA pathway to facilitate extinction of conditioned fear responses (CFRs). PMID- 25278856 TI - Modulation of olfactory sensitivity and glucose-sensing by the feeding state in obese Zucker rats. AB - The Zucker fa/fa rat has been widely used as an animal model to study obesity, since it recapitulates most of its behavioral and metabolic dysfunctions, such as hyperphagia, hyperglycemia and insulin resistance. Although it is well established that olfaction is under nutritional and hormonal influences, little is known about the impact of metabolic dysfunctions on olfactory performances and glucose-sensing in the olfactory system of the obese Zucker rat. In the present study, using a behavioral paradigm based on a conditioned olfactory aversion, we have shown that both obese and lean Zucker rats have a better olfactory sensitivity when they are fasted than when they are satiated. Interestingly, the obese Zucker rats displayed a higher olfactory sensitivity than their lean controls. By investigating the molecular mechanisms involved in glucose-sensing in the olfactory system, we demonstrated that sodium-coupled glucose transporters 1 (SGLT1) and insulin dependent glucose transporters 4 (GLUT4) are both expressed in the olfactory bulb (OB). By comparing the expression of GLUT4 and SGLT1 in OB of obese and lean Zucker rats, we found that only SGLT1 is regulated in genotype dependent manner. Next, we used glucose oxidase biosensors to simultaneously measure in vivo the extracellular fluid glucose concentrations ([Gluc]ECF) in the OB and the cortex. Under metabolic steady state, we have determined that the OB contained twice the amount of glucose found in the cortex. In both regions, the [Gluc]ECF was 2 fold higher in obese rats compared to their lean controls. Under induced dynamic glycemia conditions, insulin injection produced a greater decrease of [Gluc]ECF in the OB than in the cortex. Glucose injection did not affect OB [Gluc]ECF in Zucker fa/fa rats. In conclusion, these results emphasize the importance of glucose for the OB network function and provide strong arguments towards establishing the OB glucose-sensing as a key factor for sensory olfactory processing. PMID- 25278858 TI - Medial amygdala lesions selectively block aversive pavlovian-instrumental transfer in rats. AB - Pavlovian conditioned stimuli (CSs) play an important role in the reinforcement and motivation of instrumental active avoidance (AA). Conditioned threats can also invigorate ongoing AA responding [aversive Pavlovian-instrumental transfer (PIT)]. The neural circuits mediating AA are poorly understood, although lesion studies suggest that lateral, basal, and central amygdala nuclei, as well as infralimbic prefrontal cortex, make key, and sometimes opposing, contributions. We recently completed an extensive analysis of brain c-Fos expression in good vs. poor avoiders following an AA test (Martinez et al., 2013, Learning and Memory). This analysis identified medial amygdala (MeA) as a potentially important region for Pavlovian motivation of instrumental actions. MeA is known to mediate defensive responding to innate threats as well as social behaviors, but its role in mediating aversive Pavlovian-instrumental interactions is unknown. We evaluated the effect of MeA lesions on Pavlovian conditioning, Sidman two-way AA conditioning (shuttling) and aversive PIT in rats. Mild footshocks served as the unconditioned stimulus in all conditioning phases. MeA lesions had no effect on AA but blocked the expression of aversive PIT and 22 kHz ultrasonic vocalizations in the AA context. Interestingly, MeA lesions failed to affect Pavlovian freezing to discrete threats but reduced freezing to contextual threats when assessed outside of the AA chamber. These findings differentiate MeA from lateral and central amygdala, as lesions of these nuclei disrupt Pavlovian freezing and aversive PIT, but have opposite effects on AA performance. Taken together, these results suggest that MeA plays a selective role in the motivation of instrumental avoidance by general or uncertain Pavlovian threats. PMID- 25278860 TI - Examining the role of the temporo-parietal network in memory, imagery, and viewpoint transformations. AB - The traditional view of the medial temporal lobe (MTL) focuses on its role in episodic memory. However, some of the underlying functions of the MTL can be ascertained from its wider role in supporting spatial cognition in concert with parietal and prefrontal regions. The MTL is strongly implicated in the formation of enduring allocentric representations (e.g., O'Keefe, 1976; King et al., 2002; Ekstrom et al., 2003). According to our BBB model (Byrne et al., 2007), these representations must interact with head-centered and body-centered representations in posterior parietal cortex via a transformation circuit involving retrosplenial areas. Egocentric sensory representations in parietal areas can then cue the recall of allocentric spatial representations in long-term memory and, conversely, the products of retrieval in MTL can generate mental imagery within a parietal "window." Such imagery is necessarily egocentric and forms part of visuospatial working memory, in which it can be manipulated for the purpose of planning/imagining the future. Recent fMRI evidence (Lambrey et al., 2012; Zhang et al., 2012) supports the BBB model. To further test the model, we had participants learn the locations of objects in a virtual scene and tested their spatial memory under conditions that impose varying demands on the transformation circuit. We analyzed how brain activity correlated with accuracy in judging the direction of an object (1) from visuospatial working memory (we assume transient working memory due to the order of tasks and the absence of change in viewpoint, but long-term memory retrieval is also possible), (2) after a rotation of viewpoint, or (3) after a rotation and translation of viewpoint (judgment of relative direction). We found performance-related activity in both tasks requiring viewpoint rotation (ROT and JRD, i.e., conditions 2 and 3) in the core medial temporal to medial parietal circuit identified by the BBB model. These results are consistent with the predictions of the BBB model, and shed further light on the neural mechanisms underlying spatial memory, mental imagery and viewpoint transformations. PMID- 25278861 TI - Tickle me, I think I might be dreaming! Sensory attenuation, self-other distinction, and predictive processing in lucid dreams. AB - The contrast between self- and other-produced tickles, as a special case of sensory attenuation for self-produced actions, has long been a target of empirical research. While in standard wake states it is nearly impossible to tickle oneself, there are interesting exceptions. Notably, participants awakened from REM (rapid eye movement-) sleep dreams are able to tickle themselves. So far, however, the question of whether it is possible to tickle oneself and be tickled by another in the dream state has not been investigated empirically or addressed from a theoretical perspective. Here, we report the results of an explorative web-based study in which participants were asked to rate their sensations during self-tickling and being tickled during wakefulness, imagination, and lucid dreaming. Our results, though highly preliminary, indicate that in the special case of lucid control dreams, the difference between self tickling and being tickled by another is obliterated, with both self- and other produced tickles receiving similar ratings as self-tickling during wakefulness. This leads us to the speculative conclusion that in lucid control dreams, sensory attenuation for self-produced tickles spreads to those produced by non-self dream characters. These preliminary results provide the backdrop for a more general theoretical and metatheoretical discussion of tickling in lucid dreams in a predictive processing framework. We argue that the primary value of our study lies not so much in our results, which are subject to important limitations, but rather in the fact that they enable a new theoretical perspective on the relationship between sensory attenuation, the self-other distinction and agency, as well as suggest new questions for future research. In particular, the example of tickling during lucid dreaming raises the question of whether sensory attenuation and the self-other distinction can be simulated largely independently of external sensory input. PMID- 25278862 TI - Correlations between social-emotional feelings and anterior insula activity are independent from visceral states but influenced by culture. AB - The anterior insula (AI) maps visceral states and is active during emotional experiences, a functional confluence that is central to neurobiological accounts of feelings. Yet, it is unclear how AI activity correlates with feelings during social emotions, and whether this correlation may be influenced by culture, as studies correlating real-time AI activity with visceral states and feelings have focused on Western subjects feeling physical pain or basic disgust. Given psychological evidence that social-emotional feelings are cognitively constructed within cultural frames, we asked Chinese and American participants to report their feeling strength to admiration and compassion-inducing narratives during fMRI with simultaneous electrocardiogram recording. Trial-by-trial, cardiac arousal and feeling strength correlated with ventral and dorsal AI activity bilaterally but predicted different variance, suggesting that interoception and social-emotional feeling construction are concurrent but dissociable AI functions. Further, although the variance that correlated with cardiac arousal did not show cultural effects, the variance that correlated with feelings did. Feeling strength was especially associated with ventral AI activity (the autonomic modulatory sector) in the Chinese group but with dorsal AI activity (the visceral-somatosensory/cognitive sector) in an American group not of Asian descent. This cultural group difference held after controlling for posterior insula (PI) activity and was replicated. A bi-cultural East-Asian American group showed intermediate results. The findings help elucidate how the AI supports feelings and suggest that previous reports that dorsal AI activation reflects feeling strength are culture related. More broadly, the results suggest that the brain's ability to construct conscious experiences of social emotion is less closely tied to visceral processes than neurobiological models predict and at least partly open to cultural influence and learning. PMID- 25278863 TI - Processing of acoustic and phonological information of lexical tones in Mandarin Chinese revealed by mismatch negativity. AB - The accurate perception of lexical tones in tonal languages involves the processing of both acoustic information and phonological information carried by the tonal signal. In this study we evaluated the relative role of the two types of information in native Chinese speaker's processing of tones at a preattentive stage with event-related potentials (ERPs), particularly the mismatch negativity (MNN). Specifically, we distinguished the acoustic from the phonological information by manipulating phonological category and acoustic interval of the stimulus materials. We found a significant main effect of phonological category for the peak latency of MMN, but a main effect of both phonological category and acoustic interval for the mean amplitude of MMN. The results indicated that the two types of information, acoustic and phonological, play different roles in the processing of Chinese lexical tones: acoustic information only impacts the extent of tonal processing, while phonological information affects both the extent and the time course of tonal processing. Implications of these findings are discussed in light of neurocognitive processes of phonological processing. PMID- 25278864 TI - A critical reflection on the technological development of deep brain stimulation (DBS). AB - Since the translational research findings of Benabid and colleagues which partly led to their seminal paper regarding the treatment of mainly tremor-dominant Parkinson patients through thalamic high-frequency-stimulation (HFS) in 1987, we still struggle with identifying a satisfactory mechanistic explanation of the underlying principles of deep brain stimulation (DBS). Furthermore, the technological advance of DBS devices (electrodes and implantable pulse generators, IPG's) has shown a distinct lack of dynamic progression. In light of this we argue that it is time to leave the paleolithic age and enter hellenistic times: the device-manufacturing industry and the medical community together should put more emphasis on advancing the technology rather than resting on their laurels. PMID- 25278859 TI - Visual mismatch negativity: a predictive coding view. AB - An increasing number of studies investigate the visual mismatch negativity (vMMN) or use the vMMN as a tool to probe various aspects of human cognition. This paper reviews the theoretical underpinnings of vMMN in the light of methodological considerations and provides recommendations for measuring and interpreting the vMMN. The following key issues are discussed from the experimentalist's point of view in a predictive coding framework: (1) experimental protocols and procedures to control "refractoriness" effects; (2) methods to control attention; (3) vMMN and veridical perception. PMID- 25278865 TI - Is the philosophical construct of "habitus operativus bonus" compatible with the modern neuroscience concept of human flourishing through neuroplasticity? A consideration of prudence as a multidimensional regulator of virtue. PMID- 25278866 TI - Processing of proprioceptive and vestibular body signals and self-transcendence in Ashtanga yoga practitioners. AB - In the rod and frame test (RFT), participants are asked to set a tilted visual linear marker (i.e., a rod), embedded in a square, to the subjective vertical, irrespective of the surrounding frame. People not influenced by the frame tilt are defined as field-independent, while people biased in their rod verticality perception are field-dependent. Performing RFT requires the integration of proprioceptive, vestibular and visual signals with the latter accounting for field-dependency. Studies indicate that motor experts in body-related, balance improving disciplines tend to be field-independent, i.e., better at verticality perception, suggesting that proprioceptive and vestibular expertise acquired by such exercise may weaken the influence of irrelevant visual signals. What remains unknown is whether the effect of body-related expertise in weighting perceptual information might also be mediated by personality traits, in particular those indexing self-focusing abilities. To explore this issue, we tested field dependency in a class of body experts, namely yoga practitioners and in non expert participants. Moreover we explored any link between performance on RFT and self-transcendence (ST), a complex personality construct, which refers to tendency to experience spiritual feelings and ideas. As expected, yoga practitioners (i) were more accurate in assessing the rod's verticality on the RFT, and (ii) expressed significantly higher ST. Interestingly, the performance in these two tests was negatively correlated. More specifically, when asked to provide verticality judgments, highly self-transcendent yoga practitioners were significantly less influenced by a misleading visual context. Our results suggest that being highly self-transcendent may enable yoga practitioners to optimize verticality judgment tasks by relying more on internal (vestibular and proprioceptive) signals coming from their own body, rather than on exteroceptive, visual cues. PMID- 25278867 TI - Mechanical knowledge, but not manipulation knowledge, might support action prediction. PMID- 25278868 TI - Physiological modules for generating discrete and rhythmic movements: action identification by a dynamic recurrent neural network. AB - In this study we employed a dynamic recurrent neural network (DRNN) in a novel fashion to reveal characteristics of control modules underlying the generation of muscle activations when drawing figures with the outstretched arm. We asked healthy human subjects to perform four different figure-eight movements in each of two workspaces (frontal plane and sagittal plane). We then trained a DRNN to predict the movement of the wrist from information in the EMG signals from seven different muscles. We trained different instances of the same network on a single movement direction, on all four movement directions in a single movement plane, or on all eight possible movement patterns and looked at the ability of the DRNN to generalize and predict movements for trials that were not included in the training set. Within a single movement plane, a DRNN trained on one movement direction was not able to predict movements of the hand for trials in the other three directions, but a DRNN trained simultaneously on all four movement directions could generalize across movement directions within the same plane. Similarly, the DRNN was able to reproduce the kinematics of the hand for both movement planes, but only if it was trained on examples performed in each one. As we will discuss, these results indicate that there are important dynamical constraints on the mapping of EMG to hand movement that depend on both the time sequence of the movement and on the anatomical constraints of the musculoskeletal system. In a second step, we injected EMG signals constructed from different synergies derived by the PCA in order to identify the mechanical significance of each of these components. From these results, one can surmise that discrete rhythmic movements may be constructed from three different fundamental modules, one regulating the co-activation of all muscles over the time span of the movement and two others elliciting patterns of reciprocal activation operating in orthogonal directions. PMID- 25278869 TI - Self-consistent determination of the spike-train power spectrum in a neural network with sparse connectivity. AB - A major source of random variability in cortical networks is the quasi-random arrival of presynaptic action potentials from many other cells. In network studies as well as in the study of the response properties of single cells embedded in a network, synaptic background input is often approximated by Poissonian spike trains. However, the output statistics of the cells is in most cases far from being Poisson. This is inconsistent with the assumption of similar spike-train statistics for pre- and postsynaptic cells in a recurrent network. Here we tackle this problem for the popular class of integrate-and-fire neurons and study a self-consistent statistics of input and output spectra of neural spike trains. Instead of actually using a large network, we use an iterative scheme, in which we simulate a single neuron over several generations. In each of these generations, the neuron is stimulated with surrogate stochastic input that has a similar statistics as the output of the previous generation. For the surrogate input, we employ two distinct approximations: (i) a superposition of renewal spike trains with the same interspike interval density as observed in the previous generation and (ii) a Gaussian current with a power spectrum proportional to that observed in the previous generation. For input parameters that correspond to balanced input in the network, both the renewal and the Gaussian iteration procedure converge quickly and yield comparable results for the self-consistent spike-train power spectrum. We compare our results to large scale simulations of a random sparsely connected network of leaky integrate-and fire neurons (Brunel, 2000) and show that in the asynchronous regime close to a state of balanced synaptic input from the network, our iterative schemes provide an excellent approximations to the autocorrelation of spike trains in the recurrent network. PMID- 25278870 TI - A network that performs brute-force conversion of a temporal sequence to a spatial pattern: relevance to odor recognition. AB - A classic problem in neuroscience is how temporal sequences (TSs) can be recognized. This problem is exemplified in the olfactory system, where an odor is defined by the TS of olfactory bulb (OB) output that occurs during a sniff. This sequence is discrete because the output is subdivided by gamma frequency oscillations. Here we propose a new class of "brute-force" solutions to recognition of discrete sequences. We demonstrate a network architecture in which there are a small number of modules, each of which provides a persistent snapshot of what occurs in a different gamma cycle. The collection of these snapshots forms a spatial pattern (SP) that can be recognized by standard attractor-based network mechanisms. We will discuss the implications of this strategy for recognizing odor-specific sequences generated by the OB. PMID- 25278871 TI - Task constraints and minimization of muscle effort result in a small number of muscle synergies during gait. AB - Finding muscle activity generating a given motion is a redundant problem, since there are many more muscles than degrees of freedom. The control strategies determining muscle recruitment from a redundant set are still poorly understood. One theory of motor control suggests that motion is produced through activating a small number of muscle synergies, i.e., muscle groups that are activated in a fixed ratio by a single input signal. Because of the reduced number of input signals, synergy-based control is low dimensional. But a major criticism on the theory of synergy-based control of muscles is that muscle synergies might reflect task constraints rather than a neural control strategy. Another theory of motor control suggests that muscles are recruited by optimizing performance. Optimization of performance has been widely used to calculate muscle recruitment underlying a given motion while assuming independent recruitment of muscles. If synergies indeed determine muscle recruitment underlying a given motion, optimization approaches that do not model synergy-based control could result in muscle activations that do not show the synergistic muscle action observed through electromyography (EMG). If, however, synergistic muscle action results from performance optimization and task constraints (joint kinematics and external forces), such optimization approaches are expected to result in low-dimensional synergistic muscle activations that are similar to EMG-based synergies. We calculated muscle recruitment underlying experimentally measured gait patterns by optimizing performance assuming independent recruitment of muscles. We found that the muscle activations calculated without any reference to synergies can be accurately explained by on average four synergies. These synergies are similar to EMG-based synergies. We therefore conclude that task constraints and performance optimization explain synergistic muscle recruitment from a redundant set of muscles. PMID- 25278872 TI - Analytical approximations of the firing rate of an adaptive exponential integrate and-fire neuron in the presence of synaptic noise. AB - Computational models offer a unique tool for understanding the network-dynamical mechanisms which mediate between physiological and biophysical properties, and behavioral function. A traditional challenge in computational neuroscience is, however, that simple neuronal models which can be studied analytically fail to reproduce the diversity of electrophysiological behaviors seen in real neurons, while detailed neuronal models which do reproduce such diversity are intractable analytically and computationally expensive. A number of intermediate models have been proposed whose aim is to capture the diversity of firing behaviors and spike times of real neurons while entailing the simplest possible mathematical description. One such model is the exponential integrate-and-fire neuron with spike rate adaptation (aEIF) which consists of two differential equations for the membrane potential (V) and an adaptation current (w). Despite its simplicity, it can reproduce a wide variety of physiologically observed spiking patterns, can be fit to physiological recordings quantitatively, and, once done so, is able to predict spike times on traces not used for model fitting. Here we compute the steady-state firing rate of aEIF in the presence of Gaussian synaptic noise, using two approaches. The first approach is based on the 2-dimensional Fokker Planck equation that describes the (V,w)-probability distribution, which is solved using an expansion in the ratio between the time constants of the two variables. The second is based on the firing rate of the EIF model, which is averaged over the distribution of the w variable. These analytically derived closed-form expressions were tested on simulations from a large variety of model cells quantitatively fitted to in vitro electrophysiological recordings from pyramidal cells and interneurons. Theoretical predictions closely agreed with the firing rate of the simulated cells fed with in-vivo-like synaptic noise. PMID- 25278874 TI - Acetylcholine release and inhibitory interneuron activity in hippocampal CA1. AB - Acetylcholine release in the central nervous system (CNS) has an important role in attention, recall, and memory formation. One region influenced by acetylcholine is the hippocampus, which receives inputs from the medial septum and diagonal band of Broca complex (MS/DBB). Release of acetylcholine from the MS/DBB can directly affect several elements of the hippocampus including glutamatergic and GABAergic neurons, presynaptic terminals, postsynaptic receptors, and astrocytes. A significant portion of acetylcholine's effect likely results from the modulation of GABAergic inhibitory interneurons, which have crucial roles in controlling excitatory inputs, synaptic integration, rhythmic coordination of principal neurons, and outputs in the hippocampus. Acetylcholine affects interneuron function in large part by altering their membrane potential via muscarinic and nicotinic receptor activation. This minireview describes recent data from mouse hippocampus that investigated changes in CA1 interneuron membrane potentials following acetylcholine release. The interneuron subtypes affected, the receptor subtypes activated, and the potential outcome on hippocampal CA1 network function is discussed. PMID- 25278876 TI - Reward components of feeding behavior are preserved during mouse aging. AB - Eating behavior depends on associations between the sensory and energetic properties of foods. Healthful balance of these factors is a challenge for industrialized societies that have an abundance of food, food choices and food related cues. Here, we were interested in whether appetitive conditioning changes as a function of age. Operant and pavlovian conditioning experiments (rewarding stimulus was a palatable food) in male mice (aged 3, 6, and 15 months) showed that implicit (non-declarative) memory remains intact during aging. Two other essential components of eating behavior, motivation and hedonic preference for rewarding foods, were also found not to be altered in aging mice. Specifically, hedonic responding by satiated mice to isocaloric foods of differing sensory properties (sucrose, milk) was similar in all age groups; importantly, however, this paradigm disclosed that older animals adjust their energy intake according to energetic need. Based on the assumption that the mechanisms that control feeding are conserved across species, it would appear that overeating and obesity in humans reflects a mismatch between ancient physiological mechanisms and today's cue-laden environment. The implication of the present results showing that aging does not impair the ability to learn stimulus-food associations is that the risk of overeating in response to food cues is maintained through to old age. PMID- 25278879 TI - How to prove the value proposition of spine surgery. PMID- 25278875 TI - Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer's disease. AB - Abnormal elevation of amyloid beta-peptide (Abeta) levels in the brain is the primary trigger for neuronal cell death specific to Alzheimer's disease (AD). It is now evident that Abeta levels in the brain are manipulable due to a dynamic equilibrium between its production from the amyloid precursor protein (APP) and removal by amyloid clearance proteins. Clearance can be either enzymic or non enzymic (binding/transport proteins). Intriguingly several of the main amyloid degrading enzymes (ADEs) are members of the M13 peptidase family (neprilysin (NEP), NEP2 and the endothelin converting enzymes (ECE-1 and -2)). A distinct metallopeptidase, insulin-degrading enzyme (IDE), also contributes to Abeta degradation in the brain. The ADE family currently embraces more than 20 members, both membrane-bound and soluble, and of differing cellular locations. NEP plays an important role in brain function terminating neuropeptide signals. Its decrease in specific brain areas with age or after hypoxia, ischaemia or stroke contribute significantly to the development of AD pathology. The recently discovered mechanism of epigenetic regulation of NEP (and other genes) by the APP intracellular domain (AICD) and its dependence on the cell type and APP isoform expression suggest possibilities for selective manipulation of NEP gene expression in neuronal cells. We have also observed that another amyloid-clearing protein, namely transthyretin (TTR), is also regulated in the neuronal cell by a mechanism similar to NEP. Dependence of amyloid clearance proteins on histone deacetylases and the ability of HDAC inhibitors to up-regulate their expression in the brain opens new avenues for developing preventive strategies in AD. PMID- 25278880 TI - Administrative database studies: goldmine or goose chase? PMID- 25278878 TI - Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer's disease: evidence for a pro-amyloidogenic role of MT1-MMP. AB - Matrix metalloproteinases (MMPs) are pleiotropic endopeptidases involved in a variety of neurodegenerative/neuroinflammatory processes through their interactions with a large number of substrates. Among those, the amyloid precursor protein (APP) and the beta amyloid peptide (Abeta) are largely associated with the development of Alzheimer's disease (AD). However, the regulation and potential contribution of MMPs to AD remains unclear. In this study, we investigated the evolution of the expression of MMP-2, MMP-9, and membrane-type 1-MMP (MT1-MMP) in the hippocampus at different stages of the pathology (asymptomatic, prodromal-like and symptomatic) in the 5xFAD transgenic mouse AD model. In parallel we also followed the expression of functionally associated factors. Overall, the expression of MMP-2, MMP-9, and MT1-MMP was upregulated concomitantly with the tissue inhibitor of MMPs-1 (TIMP-1) and several markers of inflammatory/glial response. The three MMPs exhibited age- and cell-dependent upregulation of their expression, with MMP-2 and MMP-9 being primarily located to astrocytes, and MT1-MMP to neurons. MMP-9 and MT1-MMP were also prominently present in amyloid plaques. The levels of active MT1-MMP were highly upregulated in membrane-enriched fractions of hippocampus at 6 months of age (symptomatic phase), when the levels of APP, its metabolites APP C-terminal fragments (CTFs), and Abeta trimers were the highest. Overexpression of MT1-MMP in HEK cells carrying the human APP Swedish mutation (HEKswe) strongly increased beta-secretase derived C-terminal APP fragment (C99) and Abeta levels, whereas MMP-2 overexpression nearly abolished Abeta production without affecting C99. Our data consolidate the emerging idea of a regulatory interplay between MMPs and the APP/Abeta system, and demonstrate for the first time the pro-amyloidogenic features of MT1-MMP. Further investigation will be justified to evaluate this MMP as a novel potential therapeutic target in AD. PMID- 25278881 TI - Microdiscectomy for the treatment of lumbar disc herniation: an evaluation of reoperations and long-term outcomes. AB - Design Retrospective case series. Objective The objective of this study was to assess the reoperation rate after microdiscectomy for the treatment of lumbar disc herniation (LDH) in patients with >= 5-year follow-up and identify demographic, perioperative, and outcome-related differences between patients with and without a reoperation. Methods The medical records, operative reports, and office notes of patients who had undergone microdiscectomy at a single institution between March 1994 and December 2007 were reviewed and long-term follow-up was assessed via a telephone questionnaire. Results Forty patients (M:24, F:16) with an average age at surgery of 39.9 +/- 12.5 years (range: 18-80) underwent microdiscectomy at the levels L5-S1 (n = 28, 70%), L4-L5 (n = 9, 22.5%), L3-L4 (n = 2, 5.0%), and L1-L2 (n = 1, 2.5%). After an average of 40.4 +/ 40.1 months (range: 1-128), 25% of patients (10/40) required further spine surgery related to the initial microdiscectomy. At an average postoperative follow-up of 11.1 +/- 4.0 years (range: 5-19), additional symptoms apart from back and leg pain were reported more frequently by patients who underwent a reoperation (p = 0.005). Patient satisfaction was significantly higher in patients who did not undergo a reoperation (p = 0.041). For the Oswestry disability index, pain intensity (p = 0.036), and pain-related sleep disturbances (p = 0.006) were reported to be more severe in the reoperation group. Conclusions Microdiscectomy for the treatment of LDH results in a favorable long-term outcome in the majority of cases. The reoperation rate was higher in our series than reported in previous investigations with shorter follow-up. Although there were no statistically significant pre-/perioperative differences between patients with and without reoperation, our findings suggest a difference in self-reported long term outcome measures. PMID- 25278882 TI - Electrical stimulation to enhance spinal fusion: a systematic review. AB - Study Design Systematic review. Clinical Questions Compared with no stimulation, does electrical stimulation promote bone fusion after lumbar spinal fusion procedures? Does the effect differ based on the type of electrical stimulation used? Methods Electronic databases and reference lists of key articles were searched up to October 15, 2013, to identify randomized controlled trials (RCTs) comparing the effect of electrical stimulation to no electrical stimulation on fusion rates after lumbar spinal fusion for the treatment of degenerative disease. Two independent reviewers assessed the strength of evidence using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) criteria. Results Six RCTs met the inclusion criteria. The following types of electrical stimulation were investigated: direct current (three studies), pulsed electromagnetic field (three studies), and capacitive coupling (one study). The control groups consisted of no stimulation (two studies) or placebo (four studies). Marked heterogeneity in study populations, characteristics, and design prevented a meta-analysis. Regardless of the type of electrical stimulation used, cumulative incidences of fusion varied widely across the RCTs, ranging from 35.4 to 90.6% in the intervention groups and from 33.3 to 81.9% in the control groups across 9 to 24 months of follow-up. Similarly, when stratified by the type of electrical stimulation used, fusion outcomes from individual studies varied, leading to inconsistent and conflicting results. Conclusion Given the inconsistency in study results, possibly due to heterogeneity in study populations/characteristics and quality, we are unable to conclude that electrical stimulation results in better fusion outcomes compared with no stimulation. The overall strength of evidence for the conclusions is low. PMID- 25278884 TI - Outpatient surgery in the cervical spine: is it safe? AB - Study Design Systematic review. Study Rationale As the length of stay after cervical spine surgery has decreased substantially, the feasibility and safety of outpatient cervical spine surgery come into question. Although minimal length of stay is a targeted metric for quality and costs for medical centers, the safety of outpatient cervical spine surgery has not been clearly defined. Objective The objective of this article is to evaluate the safety of inpatient versus outpatient surgery in the cervical spine for adult patients with symptomatic or asymptomatic degenerative disc disease. Methods A systematic review of the literature was undertaken for articles published through February 19, 2014. Electronic databases and the bibliographies of key articles were searched to identify comparative studies evaluating the safety of inpatient versus outpatient surgery in the cervical spine. Spinal cord stimulation, spinal injections, and diagnostic procedures were excluded. Two independent reviewers assessed the strength of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system, and disagreements were resolved by consensus. Results Five studies that met the inclusion criteria were identified. One study reported low risk of hematoma (0% of outpatients and 1.6% of inpatients). Two studies reported on mortality and both reported no deaths in either group following surgery. Dysphagia risks ranged from 0 to 10% of outpatients and 1.6 to 5% of inpatients, and infection risks ranged from 0 to 1% of outpatients and 2 to 2.8% of inpatients. One study reported that no (0) outpatients were readmitted to the hospital due to a complication, compared with four inpatients (7%). The overall strength of evidence was insufficient for all safety outcomes examined. Conclusion Though the studies in our systematic review did not suggest an increased risk of complication with outpatient cervical spine surgery, the strength of evidence to make a recommendation was insufficient. Further study is needed to more clearly define the role of outpatient cervical spine surgery. PMID- 25278885 TI - Commentary on: "To the Occiput or Not? C1-C2 Ligamentous Laxity in Children with Down Syndrome". PMID- 25278883 TI - Incidental findings on magnetic resonance imaging of the spine in the asymptomatic pediatric population: a systematic review. AB - Study Design Systematic review. Clinical Question What is the prevalence of incidental magnetic resonance imaging (MRI) findings of the spine in asymptomatic pediatric patients? Methods Electronic databases and reference lists of key articles were searched up to December 15, 2013, to identify studies reporting the incidence or prevalence of incidental findings on MRI in asymptomatic pediatric patients. Athletes or children with a known history of trauma, infection, or congenital abnormalities were excluded. Results Seven publications, one prospective cohort, and six cross-sectional studies met the inclusion criteria. The most commonly reported findings on MRI were disc-related and included degenerative disc disease (seven studies, prevalence 19.6%), disc herniation/protrusion (four studies, 2.9%), disc height/narrowed disc space (two studies, 33.7%), and endplate changes (two studies, 5.3%). Other disc-related findings, reported by one study each, included bulging disc, abnormal nucleus shape, annular tear, high intensity zone, and nerve root compression, with prevalences ranging from 4.5 to 51.6%. Spondylolisthesis and spondylolysis were reported by one study each with a prevalence of 2.3 and 0%, respectively. Other findings reported included tumors and infections (one study, 0% for both) and Scheuermann-type changes (one study, 7.7%). Conclusions The prevalence of positive MRI findings in the asymptomatic pediatric population is higher than previously assumed, particularly in regard to disc morphology, highlighting the importance of correlating the history and physical examination to the MRI findings to avoid misdiagnosis or over-treatment in the pediatric population. PMID- 25278886 TI - Commentary on: "Vertebral Artery Anomalies at the Craniovertebral Junction: A Case Report and Review of the Literature". PMID- 25278887 TI - Commentary on: "Sterile Seroma Resulting from Multilevel XLIF Procedure as Possible Adverse Effect of Prophylactic Vancomycin Powder: A Case Report". PMID- 25278888 TI - Commentary on: "Hydrocephalus Following Bilateral Dumbbell-Shaped C2 Spinal Neurofibromas Resection and Postoperative Cervical Pseudomeningocele in a Patient with Neurofibromatosis Type 1: A Case Report". PMID- 25278889 TI - Commentary on: "Lumbar Intervertebral Discal Cyst: A Rare Cause of Low Back Pain and Radiculopathy. Case Report and Review of the Current Evidences on Diagnosis and Management". PMID- 25278890 TI - Commentary on: "L4 and L5 Spondylectomy for En Bloc Resection of Giant Cell Tumor and Review of the Literature". PMID- 25278877 TI - Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. AB - Pericytes are perivascular cells that envelop and make intimate connections with adjacent capillary endothelial cells. Recent studies show that they may have a profound impact in skeletal muscle regeneration, innervation, vessel formation, fibrosis, fat accumulation, and ectopic bone formation throughout life. In this review, we summarize and evaluate recent advances in our understanding of pericytes' influence on adult skeletal muscle pathophysiology. We also discuss how further elucidating their biology may offer new approaches to the treatment of conditions characterized by muscle wasting. PMID- 25278891 TI - Predictive factors for acute proximal junctional failure after adult deformity surgery with upper instrumented vertebrae in the thoracolumbar spine. AB - Study Type Retrospective cohort study. Introduction Acute proximal junctional failure (APJF) was recently defined by the International Spine Study Group as: postoperative fracture of the upper instrumented vertebrae (UIV) or UIV + 1; UIV implant failure; proximal junctional kyphosis (PJK) increase > 15 degrees; or need for proximal extension of the fusion within 6 months of surgery.1 The incidence and revision rates of APJF have been reported to be higher when the UIV is located in the lower thoracolumbar (TL) spine mostly because of high incidence of UIV or UIV + 1 fractures.2 Sagittal deformity overcorrection has been considered as a potential risk factor.34 Objective The purpose of this study is to assess independent predictive factors and timing for revisions of APJF in adult deformity patients with UIV in the TL (T9-L2) spine. Methods Retrospective review of 135 consecutive patients with minimum 2-year follow-up, treated at a single institution for adult spinal deformity, all with UIV in the TL spine (T9 L2). Fusions were divided into three cohorts based on the UIV location (T9-T10 vs. T11-T12 vs. L1-L2). Demographic data were reviewed and radiographic parameters were measured preoperatively, immediately postoperatively, at 6 months and at the final follow-up. Incidence and failure modes of APJF, as well as timing for APJF revision are reported. Risk factors for APJF were assessed with univariate and multivariate regression analysis models. Results A total of 135 consecutive patients were reviewed, with mean follow-up 42 months (24-126). Mean age was 66 years (24-86). There were no differences in the preoperative radiographic parameters between patients in any of the three cohorts with APJF. The incidence of APJF was 38.5%, with a trend toward higher APJF in the T9-T10 group (p = 0.07) (Table 1). When UIV was at T10, the incidence of APJF was 57.1%, significantly higher than the adjacent vertebrae, T9 and T11 (p = 0.03 and p = 0.01, respectively). The overall revision rate for APJF was 17%, most often for UIV fracture, while PJK > 15 degrees alone had the highest 2 and 5 years survival (100%) (Fig. 1). Univariate analysis revealed preoperative sagittal vertical axis > 5 cm, postoperative PJA > 5 degrees and thoracic kyphosis > 30 degrees, and instrumentation to the pelvis as risk factors for APJF (Table 2). Multivariate regression analysis confirmed postoperative PJA > 5 degrees, and greater correction of lumbar lordosis (LL) as independent risk factors for APJF (Table 3). Conclusion The incidence of APJF in adult deformity patients is high if the UIV is in the lower thoracic or lumbar spine, with a trend toward higher rates when the UIV is at T10. Fracture at the UIV lead to the highest revision rate, while PJK > 15 degrees without fracture or hardware failure had the longest revision-free survival. Postoperative PJA > 5 degrees and greater correction of LL are independent risk factors for APJF. PMID- 25278892 TI - Correlation of posterior occipitocervical angle and surgical outcomes for occipitocervical fusion. AB - Study Type Retrospective cohort study. Introduction Craniocervical instability is a surgical disease, most commonly due to rheumatoid arthritis, trauma, erosive pathologies such as tumors and infection, and advanced degeneration. Treatment involves stabilization of the craniovertebral junction by occipitocervical instrumentation and fusion. However, the impact of the fixed occipitocervical angle on surgical outcomes, in particular the need for revision surgery and the incidence of dysphagia, remains unknown. Occipitocervical fusions (OCFs) at a single institution were reviewed to evaluate the relationships between postoperative neck alignment, the need for revision surgery, and dysphagia. Objective The objective of this study is to determine whether an increased posterior occipital cervical angle results in an increase in the need for revision surgery, and secondary, dysphagia. Methods A retrospective review of spinal surgery patients from January 2007 to June 2013 was conducted searching for patients who underwent an occipitocervical instrumented fusion utilizing diagnostic and procedural codes. Specifically, a current procedural code of 22590 (arthrodesis, posterior technique [craniocervical]) was queried, as well those with a description of "craniocervical" or "occipitocervical" arthrodesis. Ideal neck alignment before rod placement was judged by the attending surgeon. A review of all cases for revision surgery or evidence of dysphagia was then conducted. Results From January 2007 to June 2013, 107 patients were identified (31 male, 76 female, mean age 63). Rheumatoid arthritis causing myelopathy was the most common indication for OCF, followed by trauma. Twenty of the patients were lost to follow-up and seven died within the perioperative period. Average follow-up for the remaining 80 patients was 16.4 months. The mean posterior occipitocervical angle (POCA), defined as the angle formed by the intersection of a line drawn tangential to the posterior aspect of the occipital protuberance and a line determined by the posterior aspect of the facets of the third and fourth cervical vertebrae, calculated after stabilization, was 107.1 degrees (range, 72-140 degrees). Reoperation was required in 11 patients (11/107, 10.3%). The mean POCA for the reoperation group was 109.5 degrees (range, 72-123) and was not significantly different than patients not requiring reoperation (106.5, p > 0.05). However, for all pathologies excluding infection as a cause for reoperation, the mean POCA was significantly higher, 115.14 degrees (p = 0.039) (Table 1). Seven patients (6.5%) complained of dysphagia postoperatively with a significantly higher POCA of 115 degrees (p = 0.039). Of these seven patients, six underwent posterior-only procedures. One patient underwent anterior and posterior procedures for a severe kyphotic deformity. The dysphagia resolved in six patients over a mean of 3 weeks (range, 2-4 weeks). One patient, whose surgery was posterior only, required the insertion of a gastrostomy tube. Conclusions An elevated POCA may result in need for reoperation due to increased biomechanical stress upon adjacent segments or the construct itself due to flexion in an attempt to maintain forward gaze. Further, an elevated POCA seems to also correlate with a higher incidence of dysphagia. Further investigation is necessary to determine the ideal craniocervical angle which is likely individualized to a particular patient based on global and regional spinal alignments. PMID- 25278893 TI - Definition of Levels of Evidence (LoE) and Overall Strength of Evidence (SoE). PMID- 25278894 TI - Strategies for developing novel therapeutics for sensorineural hearing loss. AB - Sensorineural hearing loss (SNHL) is a common disability in the world; however, at present, options for the pharmacological treatment of SNHL are very limited. Previous studies involving human temporal bone analyses have revealed that the degeneration of the cochlea is a common mechanism of SNHL. A major problem for the development of novel pharmacotherapy for SNHL has been the limited regeneration capacity in mammalian cochlear cells. However, recent progress in basic studies has led to several effective strategies for the induction of regeneration in the mammalian cochlea, in accordance with the stage of degeneration. In addition, recent advances in the identification of human deafness genes and their characterization in mouse models have elucidated cellular and/or molecular mechanisms of SNHL, which will contribute to clarify molecular targets of pharmacotherapy for treatment of SNHL. PMID- 25278897 TI - Pain-novel targets and new technologies. PMID- 25278896 TI - The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study. AB - Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed. PMID- 25278895 TI - Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation. AB - Physiological vascular function regulation is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the main risk factors of cardiovascular pathology, where the imbalance between the synthesis of vasodilator and vasoconstrictor molecules is common in the development of vascular disorders in systemic and placental circulation. In the placenta, an organ without autonomic innervations, the local control of vascular tone is critical for maintenance of fetal growth and mechanisms that underlie shear stress response induced by blood flow are essential during pregnancy. In this field, shear stress induced by moderate exercise is one of the most important mechanisms to improve vascular function through nitric oxide synthesis and stimulation of mechanical response of endothelial cells triggered by ion channels, caveolae, endothelial NO synthase, and vascular endothelial growth factor, among others. The demand for oxygen and nutrients by tissues and organs, especially in placentation and pregnancy, determines blood flow parameters, and physiological adaptations of vascular beds for covering metabolic requirements. In this regard, moderate exercise versus sedentarism shows potential benefits for improving vascular function associated with the enhancement of molecular mechanisms induced by shear stress. In this review, we collect evidence about molecular bases of physiological response to shear stress in order to highlight the relevance of moderate exercise-training for vascular health in adult and fetal life. PMID- 25278898 TI - New frontiers in the neuropsychopharmacology of mental illness. PMID- 25278899 TI - Cell-based interventions in utero: time to reconsider. PMID- 25278900 TI - Analysis of enamel development using murine model systems: approaches and limitations. AB - A primary goal of enamel research is to understand and potentially treat or prevent enamel defects related to amelogenesis imperfecta (AI). Rodents are ideal models to assist our understanding of how enamel is formed because they are easily genetically modified, and their continuously erupting incisors display all stages of enamel development and mineralization. While numerous methods have been developed to generate and analyze genetically modified rodent enamel, it is crucial to understand the limitations and challenges associated with these methods in order to draw appropriate conclusions that can be applied translationally, to AI patient care. We have highlighted methods involved in generating and analyzing rodent enamel and potential approaches to overcoming limitations of these methods: (1) generating transgenic, knockout, and knockin mouse models, and (2) analyzing rodent enamel mineral density and functional properties (structure and mechanics) of mature enamel. There is a need for a standardized workflow to analyze enamel phenotypes in rodent models so that investigators can compare data from different studies. These methods include analyses of gene and protein expression, developing enamel histology, enamel pigment, degree of mineralization, enamel structure, and mechanical properties. Standardization of these methods with regard to stage of enamel development and sample preparation is crucial, and ideally investigators can use correlative and complementary techniques with the understanding that developing mouse enamel is dynamic and complex. PMID- 25278901 TI - Is CRT pro-arrhythmic? A comparative analysis of the occurrence of ventricular arrhythmias between patients implanted with CRTs and ICDs. AB - Aim and Hypothesis: Despite the proven symptomatic and mortality benefit of cardiac resynchronization therapy (CRT), there is anecdotal evidence it may be pro-arrhythmic in some patients. We aimed to identify if there were significant differences in the incidence of ventricular arrhythmias (VAs) in patients undergoing CRT-D and implantable cardioverter-defibrillators (ICD) implantation for primary prevention indication. We hypothesized that CRT is unlikely to be pro arrhythmic based on the positive mortality and morbidity data from large randomized trials. METHODS AND RESULTS: A retrospective analysis of device therapies for VA in a primary prevention device cohort was performed. Patients with ischemic (IHD) and non-ischemic (DCM) cardiomyopathy and ICD or CRT+ICD devices (CRT-D) implanted between 2005 and 2007 without prior history of sustained VA were included for analysis. VA episodes were identified from stored electrograms and defined as sustained (VT/VF) if therapy [anti-tachycardia pacing (ATP) or shocks] was delivered or non-sustained (NSVT) if not. Of a total of 180 patients, 117 (68% male) were in the CRT-D group, 42% IHD, ejection fraction (EF) 24.5 +/- 8.2% and mean follow-up 23.9 +/- 9.8 months. 63 patients (84% male) were in the ICD group, 60% IHD, EF 27.7 +/- 7.2% and mean follow-up 24.6 +/- 10.8 months. Overall, there was no significant difference in the incidence of VA (35.0 vs. 38.1%, p = 0.74), sustained VT (21.3 vs. 28.5%, p = 0.36) or NSVT (12.8 vs. 9.5%, p = 0.63) and no significant difference in type of therapy received for VT/VF: ATP (68 vs. 66.6%, p = 0.73) and shocks (32 vs. 33.3%, p = 0.71) between the CRT-D and ICD groups, respectively. CONCLUSION: In patients with cardiomyopathy receiving CRT-D and ICDs for primary prophylaxis, there was no significant difference in the incidence of VA. From this single center retrospective analysis, there is no evidence to support cardiac resynchronization causing pro-arrhythmia. PMID- 25278903 TI - Time-domain analysis of scrotal thermoregulatory impairment in varicocele. AB - Varicocele is a common male disease defined as the pathological dilatation of the pampiniform plexus and scrotal veins with venous blood reflux. Varicocele usually impairs the scrotal thermoregulation via a hemodynamic alteration, thus inducing an increase in cutaneous temperature. The investigation of altered scrotal thermoregulation by means of thermal infrared imaging has been proved to be useful in the study of the functional thermal impairment. In this study, we use the Control System Theory to analyze the time-domain dynamics of the scrotal thermoregulation in response to a mild cold challenge. Four standard time-domain dynamic parameters of a prototype second order control system (Delay Time, Rise Time, closed poles locations, steady state error) and the static basal temperatures were directly estimated from thermal recovery curves. Thermal infrared imaging data from 31 healthy controls (HCS) and 95 varicocele patients were processed. True-positive predictions, by comparison with standard echo color Doppler findings, higher than 87% were achieved into the proper classification of the disease stage. The proposed approach could help to understand at which specific level the presence of the disease impacts the scrotal thermoregulation, which is also involved into normal spermatogenesis process. PMID- 25278905 TI - The adrenergic system in cardiovascular pathophysiology: a translational science point of view. PMID- 25278902 TI - Mitochondrial targets for volatile anesthetics against cardiac ischemia reperfusion injury. AB - Mitochondria are critical modulators of cell function and are increasingly recognized as proximal sensors and effectors that ultimately determine the balance between cell survival and cell death. Volatile anesthetics (VA) are long known for their cardioprotective effects, as demonstrated by improved mitochondrial and cellular functions, and by reduced necrotic and apoptotic cell death during cardiac ischemia and reperfusion (IR) injury. The molecular mechanisms by which VA impart cardioprotection are still poorly understood. Because of the emerging role of mitochondria as therapeutic targets in diseases, including ischemic heart disease, it is important to know if VA-induced cytoprotective mechanisms are mediated at the mitochondrial level. In recent years, considerable evidence points to direct effects of VA on mitochondrial channel/transporter protein functions and electron transport chain (ETC) complexes as potential targets in mediating cardioprotection. This review furnishes an integrated overview of targets that VA impart on mitochondrial channels/transporters and ETC proteins that could provide a basis for cation regulation and homeostasis, mitochondrial bioenergetics, and reactive oxygen species (ROS) emission in redox signaling for cardiac cell protection during IR injury. PMID- 25278904 TI - Bcl-xL in neuroprotection and plasticity. AB - Accepted features of neurodegenerative disease include mitochondrial and protein folding dysfunction and activation of pro-death factors. Neurons that experience high metabolic demand or those found in organisms with genetic mutations in proteins that control cell stress may be more susceptible to aging and neurodegenerative disease. In neurons, events that normally promote growth, synapse formation, and plasticity are also often deployed to control neurotoxicity. Such protective strategies are coordinated by master stress fighting proteins. One such specialized protein is the anti-cell death Bcl-2 family member Bcl-xL, whose myriad death-protecting functions include enhancement of bioenergetic efficiency, prevention of mitochondrial permeability transition channel activity, protection from mitochondrial outer membrane permeabilization (MOMP) to pro-apoptotic factors, and improvement in the rate of vesicular trafficking. Synapse formation and normal neuronal activity provide protection from neuronal death. Therefore, Bcl-xL brings about synapse formation as a neuroprotective strategy. In this review we will consider how this multi functional master regulator protein uses many strategies to enhance synaptic and neuronal function and thus counteracts neurodegenerative stimuli. PMID- 25278907 TI - The heart cannot pump blood that it does not receive. PMID- 25278908 TI - In vitro Models of the Human Blood-Brain Barrier and the Impact of Efflux Transporters on Neurological Disorders: The Work of Cioni et al. (2012). PMID- 25278910 TI - Invisibility and interpretation. AB - Invisibility is often thought to occur because of the low-level limitations of the visual system. For example, it is often assumed that backward masking renders a target invisible because the visual system is simply too slow to resolve the target and the mask separately. Here, we propose an alternative explanation in which invisibility is a goal rather than a limitation and occurs naturally when making sense out of the plethora of incoming information. For example, we present evidence that (in)visibility of an element can strongly depend on how it groups with other elements. Changing grouping changes visibility. In addition, we will show that features often just appear to be invisible but are in fact visible in a way the experimenter is not aware of. PMID- 25278911 TI - The consequences of ignoring measurement invariance for path coefficients in structural equation models. AB - We report a Monte Carlo study examining the effects of two strategies for handling measurement non-invariance - modeling and ignoring non-invariant items - on structural regression coefficients between latent variables measured with item response theory models for categorical indicators. These strategies were examined across four levels and three types of non-invariance - non-invariant loadings, non-invariant thresholds, and combined non-invariance on loadings and thresholds in simple, partial, mediated and moderated regression models where the non invariant latent variable occupied predictor, mediator, and criterion positions in the structural regression models. When non-invariance is ignored in the latent predictor, the focal group regression parameters are biased in the opposite direction to the difference in loadings and thresholds relative to the referent group (i.e., lower loadings and thresholds for the focal group lead to overestimated regression parameters). With criterion non-invariance, the focal group regression parameters are biased in the same direction as the difference in loadings and thresholds relative to the referent group. While unacceptable levels of parameter bias were confined to the focal group, bias occurred at considerably lower levels of ignored non-invariance than was previously recognized in referent and focal groups. PMID- 25278906 TI - The "Goldilocks Zone" from a redox perspective-Adaptive vs. deleterious responses to oxidative stress in striated muscle. AB - Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the "hormetic curve" is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome). PMID- 25278912 TI - To schedule or not to schedule? Agentic and cooperative teams at call centers. PMID- 25278909 TI - Dopamine and glucose, obesity, and reward deficiency syndrome. AB - Obesity as a result of overeating as well as a number of well described eating disorders has been accurately considered to be a world-wide epidemic. Recently a number of theories backed by a plethora of scientifically sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Our laboratory has published on the concept known as Reward Deficiency Syndrome (RDS) which is a genetic and epigenetic phenomena leading to impairment of the brain reward circuitry resulting in a hypo dopaminergic function. RDS involves the interactions of powerful neurotransmitters and results in abnormal craving behavior. A number of important facts which could help translate to potential therapeutic targets espoused in this focused review include: (1) consumption of alcohol in large quantities or carbohydrates binging stimulates the brain's production of and utilization of dopamine; (2) in the meso-limbic system the enkephalinergic neurons are in close proximity, to glucose receptors; (3) highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; (4) a significant correlation between blood glucose and cerebrospinal fluid concentrations of homovanillic acid the dopamine metabolite; (5) 2-deoxyglucose (2DG), the glucose analog, in pharmacological doses is associated with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and fMRI in humans support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and for the most part, implicate the involvement of DA-modulated reward circuits in pathologic eating behaviors. Based on a consensus of neuroscience research treatment of both glucose and drug like cocaine, opiates should incorporate dopamine agonist therapy in contrast to current theories and practices that utilizes dopamine antagonistic therapy. Considering that up until now clinical utilization of powerful dopamine D2 agonists have failed due to chronic down regulation of D2 receptors newer targets based on novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of reward deficiency. PMID- 25278913 TI - An experimental examination of catastrophizing-related interpretation bias for ambiguous facial expressions of pain using an incidental learning task. AB - Individuals with pain-related concerns are likely to interpret ambiguous pain related information in a threatening manner. It is unknown whether this interpretation bias also occurs for ambiguous pain-related facial expressions. This study examined whether individuals who habitually attach a catastrophic meaning to pain are characterized by negative interpretation bias for ambiguous pain-related facial expressions. Sixty-four female undergraduates completed an incidental learning task during which pictures of faces were presented, each followed by a visual target at one of two locations. Participants indicated target location by pressing one of two response keys. During the learning phase, happy and painful facial expressions predicted target location. During two test phases, morphed facial expressions of pain and happiness were added, equally often followed by a target at either location. Faster responses following morphs to targets at the location predicted by painful expressions compared to targets at the location predicted by happy expressions were taken to reflect pain-related interpretation bias. During one test phase, faces were preceded by either a safe or threatening context cue. High, but not low, pain-catastrophizers responded faster following morphs to targets at the location predicted by painful expressions than to targets at the other location (when participants were aware of the contingency between expression type and target location). When context cues were presented, there was no indication of interpretation bias. Participants were also asked to directly classify the facial expressions that were presented during the incidental learning task. Participants classified morphs more often as happy than as painful, independent of their level of pain catastrophizing. This observation is discussed in terms of differences between indirect and direct measures of interpretation bias. PMID- 25278915 TI - Agent-patient similarity affects sentence structure in language production: evidence from subject omissions in Mandarin. AB - Interference effects from semantically similar items are well-known in studies of single word production, where the presence of semantically similar distractor words slows picture naming. This article examines the consequences of this interference in sentence production and tests the hypothesis that in situations of high similarity-based interference, producers are more likely to omit one of the interfering elements than when there is low semantic similarity and thus low interference. This work investigated language production in Mandarin, which allows subject noun phrases to be omitted in discourse contexts in which the subject entity has been previously mentioned in the discourse. We hypothesize that Mandarin speakers omit the subject more often when the subject and the object entities are conceptually similar. A corpus analysis of simple transitive sentences found higher rates of subject omission when both the subject and object were animate (potentially yielding similarity-based interference) than when the subject was animate and object was inanimate. A second study manipulated subject object animacy in a picture description task and replicated this result: participants omitted the animate subject more often when the object was also animate than when it was inanimate. These results suggest that similarity-based interference affects sentence forms, particularly when the agent of the action is mentioned in the sentence. Alternatives and mechanisms for this effect are discussed. PMID- 25278914 TI - The roles of shared vs. distinctive conceptual features in lexical access. AB - Contemporary models of spoken word production assume conceptual feature sharing determines the speed with which objects are named in categorically-related contexts. However, statistical models of concept representation have also identified a role for feature distinctiveness, i.e., features that identify a single concept and serve to distinguish it quickly from other similar concepts. In three experiments we investigated whether distinctive features might explain reports of counter-intuitive semantic facilitation effects in the picture word interference (PWI) paradigm. In Experiment 1, categorically-related distractors matched in terms of semantic similarity ratings (e.g., zebra and pony) and manipulated with respect to feature distinctiveness (e.g., a zebra has stripes unlike other equine species) elicited interference effects of comparable magnitude. Experiments 2 and 3 investigated the role of feature distinctiveness with respect to reports of facilitated naming with part-whole distractor-target relations (e.g., a hump is a distinguishing part of a CAMEL, whereas knee is not, vs. an unrelated part such as plug). Related part distractors did not influence target picture naming latencies significantly when the part denoted by the related distractor was not visible in the target picture (whether distinctive or not; Experiment 2). When the part denoted by the related distractor was visible in the target picture, non-distinctive part distractors slowed target naming significantly at SOA of -150 ms (Experiment 3). Thus, our results show that semantic interference does occur for part-whole distractor-target relations in PWI, but only when distractors denote features shared with the target and other category exemplars. We discuss the implications of these results for some recently developed, novel accounts of lexical access in spoken word production. PMID- 25278917 TI - What is a "sense of foreshortened future?" A phenomenological study of trauma, trust, and time. AB - One of the symptoms of trauma is said to be a "sense of foreshortened future." Without further qualification, it is not clear how to interpret this. In this paper, we offer a phenomenological account of what the experience consists of. To do so, we focus on the effects of torture. We describe how traumatic events, especially those that are deliberately inflicted by other people, can lead to a loss of "trust" or "confidence" in the world. This undermines the intelligibility of one's projects, cares, and commitments, in a way that amounts to a change in the structure of temporal experience. The paper concludes by briefly addressing the implications of this for how we respond to trauma, as well as offering some remarks on the relationship between trauma and psychosis. PMID- 25278916 TI - Temporal dynamics of categorization: forgetting as the basis of abstraction and generalization. AB - Historically, models of categorization have focused on how learners track frequencies and co-occurrence information to abstract relevant category features for generalization. The current study takes a different approach by examining how the temporal dynamics of categorization affect abstraction and generalization. In the learning phase of the experiment, all relevant category features were presented an equal number of times across category exemplars. However, the relevant features were presented on one of two learning schedules: massed or interleaved. At a series of immediate and delayed tests, learners were asked to generalize to novel exemplars that contained massed features, interleaved features, or all novel features. The results of this experiment revealed that, at an immediate test, learners more readily generalized based upon features presented on a massed schedule. Conversely, at a delayed test, learners more readily generalized based upon features presented on an interleaved schedule, until information was no longer readily retrievable from memory. These findings suggest that forgetting and retrieval processes engendered by the temporal dynamics of learning are used as a basis of abstraction, implicating forgetting as a central mechanism of generalization. PMID- 25278918 TI - It's time to take the psychology of biological time into account: speed of driving affects a trip's subjective duration. PMID- 25278919 TI - Do dimensional psychopathology measures relate to creative achievement or divergent thinking? AB - Previous research provides disparate accounts of the putative association between creativity and psychopathology, including schizotypy, psychoticism, hypomania, bipolar disorder, ADHD, and autism spectrum disorders. To examine these association, healthy, non-clinical participants completed several psychopathology spectrum measures, often postulated to associate with creativity: the Schizotypal Personality Questionnaire, the Psychoticism scale, the Personality Inventory for DSM-5, the Hypomanic Personality Scale, the Attention Deficit/Hyperactivity Disorder scale, the Beck Depression Inventory, and the Autism-Spectrum Quotient. The goal of Study 1 was to evaluate the factor structure of these dimensional psychopathology measures and, in particular, to evaluate the case for a strong general factor(s). None of the factor solutions between 1 and 10 factors provided a strong fit with the data based on the most commonly used metrics. The goal of Study 2 was to determine whether these psychopathology scales predict, independently, two measures of creativity: 1. a measure of participants' real world creative achievements, and 2. divergent thinking, a laboratory measure of creative cognition. After controlling for academic achievement, psychoticism and hypomania reliably predicted real-world creative achievement and divergent thinking scored with the consensual assessment technique. None of the psychopathology-spectrum scales reliably predicted divergent thinking scored with the manual scoring method. Implications for the potential links between several putative creative processes and risk factors for psychopathology are discussed. PMID- 25278921 TI - The concepts of representation and information in explanatory theories of human behavior. AB - Focusing in experimental study of human behavior, this article discusses the concepts of information and mental representation aiming the integration of their biological, computational, and semantic aspects. Assuming that the objective of any communication process is ultimately to modify the receiver's state, the term correlational information is proposed as a measure of how changes occurring in external world correlate with changes occurring inside an individual. Mental representations are conceptualized as a special case of information processing in which correlational information is received, recorded, but also modified by a complex emergent process of associating new elements. In humans, the acquisition of information and creation of mental representations occurs in a two-step process. First, a sufficiently complex brain structure is necessary to establishing internal states capable to co-vary with external events. Second, the validity or meaning of these representations must be gradually achieved by confronting them with the environment. This contextualization can be considered as part of the process of ascribing meaning to information and representations. The hypothesis introduced here is that the sophisticated psychological constructs classically associated with the concept of mental representation are essentially of the same nature of simple interactive behaviors. The capacity of generating elaborated mental phenomena like beliefs and desires emerges gradually during evolution and, in a given individual, by learning and social interaction. PMID- 25278920 TI - The philosophy of psychiatry and biologism. PMID- 25278922 TI - Can race really be erased? A pre-registered replication study. AB - WHEN ENCOUNTERING AN UNKNOWN INDIVIDUAL, SOCIAL CATEGORIZATION OF THE INDIVIDUAL HAS BEEN SHOWN TO AUTOMATICALLY PROCEED ON THE BASIS OF THREE FUNDAMENTAL DIMENSIONS: People seem to mandatorily encode race, sex and age. In contradiction to this general finding, Kurzban et al. (2001) showed that race encoding is not automatic and inevitable, but rather a byproduct of categorization in terms of coalitions. In particular, they argue and empirically support that when other coalitional information is present, the encoding of race is spectacularly reduced. In the present contribution, we present a replication of the race-erased effect reported by Kurzban et al. First, we give a detailed overview of the hypotheses, the experimental methodology, the derivation of the sample size required to achieve a power of 95%, and the criteria that need to be met for a successful replication. Then we present the findings of an empirical test that met the requirements of our power analyses. Our results indicate that the encoding of race is indeed reduced when another coalitional cue is available, yet this reduction is less marked than in the original study. This experiment was preregistered before data collection at Open Science Framework, osf.io/vnhrm/. PMID- 25278923 TI - Syncopation creates the sensation of groove in synthesized music examples. AB - In order to better understand the musical properties which elicit an increased sensation of wanting to move when listening to music-groove-we investigate the effect of adding syncopation to simple piano melodies, under the hypothesis that syncopation is correlated to groove. Across two experiments we examine listeners' experience of groove to synthesized musical stimuli covering a range of syncopation levels and densities of musical events, according to formal rules implemented by a computer algorithm that shifts musical events from strong to weak metrical positions. Results indicate that moderate levels of syncopation lead to significantly higher groove ratings than melodies without any syncopation or with maximum possible syncopation. A comparison between the various transformations and the way they were rated shows that there is no simple relation between syncopation magnitude and groove. PMID- 25278924 TI - The impact of the perception of rhythmic music on self-paced oscillatory movements. AB - Inspired by theories of perception-action coupling and embodied music cognition, we investigated how rhythmic music perception impacts self-paced oscillatory movements. In a pilot study, we examined the kinematic parameters of self-paced oscillatory movements, walking and finger tapping using optical motion capture. In accordance with biomechanical constraints accounts of motion, we found that movements followed a hierarchical organization depending on the proximal/distal characteristic of the limb used. Based on these findings, we were interested in knowing how and when the perception of rhythmic music could resonate with the motor system in the context of these constrained oscillatory movements. In order to test this, we conducted an experiment where participants performed four different effector-specific movements (lower leg, whole arm and forearm oscillation and finger tapping) while rhythmic music was playing in the background. Musical stimuli consisted of computer-generated MIDI musical pieces with a 4/4 metrical structure. The musical tempo of each song increased from 60 BPM to 120 BPM by 6 BPM increments. A specific tempo was maintained for 20 s before a 2 s transition to the higher tempo. The task of the participant was to maintain a comfortable pace for the four movements (self-paced) while not paying attention to the music. No instruction on whether to synchronize with the music was given. Results showed that participants were distinctively influenced by the background music depending on the movement used with the tapping task being consistently the most influenced. Furthermore, eight strategies put in place by participants to cope with the task were unveiled. Despite not instructed to do so, participants also occasionally synchronized with music. Results are discussed in terms of the link between perception and action (i.e., motor/perceptual resonance). In general, our results give support to the notion that rhythmic music is processed in a motoric fashion. PMID- 25278925 TI - Seeing emotions in the eyes - inverse priming effects induced by eyes expressing mental states. AB - OBJECTIVE: Automatic emotional processing of faces and facial expressions gain more and more of relevance in terms of social communication. Among a variety of different primes, targets and tasks, whole face images and facial expressions have been used to affectively prime emotional responses. This study investigates whether emotional information provided solely in eye regions that display mental states can also trigger affective priming. METHODS: Sixteen subjects answered a lexical decision task (LDT) coupled with an affective priming paradigm. Emotion associated eye regions were extracted from photographs of faces and acted as primes, whereas targets were either words or pseudo-words. Participants had to decide whether the targets were real German words or generated pseudo-words. Primes and targets belonged to the emotional categories "fear," "disgust," "happiness," and "neutral." RESULTS: A general valence effect for positive words was observed: responses in the LDT were faster for target words of the emotional category happiness when compared to other categories. Importantly, pictures of emotional eye regions preceding the target words affected their subsequent classification. While we show a classical priming effect for neutral target words - with shorter RT for congruent compared to incongruent prime-target pairs- , we observed an inverse priming effect for fearful and happy target words - with shorter RT for incongruent compared to congruent prime-target pairs. These inverse priming effects were driven exclusively by specific prime-target pairs. CONCLUSION: Reduced facial emotional information is sufficient to induce automatic implicit emotional processing. The emotional-associated eye regions were processed with respect to their emotional valence and affected the performance on the LDT. PMID- 25278926 TI - Even with time, conflict adaptation is not made of expectancies. AB - In conflict tasks, congruency effects are modulated by the sequence of preceding trials. This modulation has been interpreted as a strategic reconfiguration of cognitive control, depending on the amount of conflict encountered on the very last trial, and occurring unconditionally whenever there is time to produce it (Notebaert et al., 2006). Jimenez and Mendez (2013) arranged a 4-choice Stroop task with a response-to-stimulus interval (RSI) of 0 ms, and they found that, under these conditions, congruency effects may become dissociated from the explicit expectancies assessed over analogous, but independent, trials. The present study generalizes this phenomenon to a condition with larger RSI, and it shows that participants' performance does not rely on expectancies unless the task includes a specific requirement to generate and report on these expectancies. The results are interpreted as providing new insights with respect to the status of conflict adaptation effects. PMID- 25278928 TI - Personality moderates the links of social identity with work motivation and job searching. AB - Work motivation is critical for successful school-to-work transitions, but little is known about its determinants among labor market entrants. Applying a social identity framework, we examined whether work motivation and job searching are social-contextually determined. We expected that some job seekers are more sensitive to contextual influence, depending on their personality. Mediation analyses on 591 Dutch vocational training students indicate that the perception of more positive work norms in someone's social context was related to higher levels of intrinsic motivation, which in turn predicted higher preparatory job search behavior and job search intentions. Multi-group analysis shows that perceived work norms more strongly predict work motivation among overcontrollers compared to resilients and undercontrollers. In conclusion, work motivation and job searching appear contextually determined: especially among those sensitive to contextual influence, people seem to work when they believe that is what people like them do. PMID- 25278927 TI - Early influence of auditory stimuli on upper-limb movements in young human infants: an overview. AB - Given that the auditory system is rather well developed at the end of the third trimester of pregnancy, it is likely that couplings between acoustics and motor activity can be integrated as early as at the beginning of postnatal life. The aim of the present mini-review was to summarize and discuss studies on early auditory-motor integration, focusing particularly on upper-limb movements (one of the most crucial means to interact with the environment) in association with auditory stimuli, to develop further understanding of their significance with regard to early infant development. Many studies have investigated the relationship between various infant behaviors (e.g., sucking, visual fixation, head turning) and auditory stimuli, and established that human infants can be observed displaying couplings between action and environmental sensory stimulation already from just after birth, clearly indicating a propensity for intentional behavior. Surprisingly few studies, however, have investigated the associations between upper-limb movements and different auditory stimuli in newborns and young infants, infants born at risk for developmental disorders/delays in particular. Findings from studies of early auditory-motor interaction support that the developing integration of sensory and motor systems is a fundamental part of the process guiding the development of goal-directed action in infancy, of great importance for continued motor, perceptual, and cognitive development. At-risk infants (e.g., those born preterm) may display increasing central auditory processing disorders, negatively affecting early sensory-motor integration, and resulting in long-term consequences on gesturing, language development, and social communication. Consequently, there is a need for more studies on such implications. PMID- 25278930 TI - The antibody genetics of multiple sclerosis: comparing next-generation sequencing to sanger sequencing. AB - We previously identified a distinct mutation pattern in the antibody genes of B cells isolated from cerebrospinal fluid (CSF) that can identify patients who have relapsing-remitting multiple sclerosis (RRMS) and patients with clinically isolated syndromes who will convert to RRMS. This antibody gene signature (AGS) was developed using Sanger sequencing of single B cells. While potentially helpful to patients, Sanger sequencing is not an assay that can be practically deployed in clinical settings. In order to provide AGS evaluations to patients as part of their diagnostic workup, we developed protocols to generate AGS scores using next-generation DNA sequencing (NGS) on CSF-derived cell pellets without the need to isolate single cells. This approach has the potential to increase the coverage of the B-cell population being analyzed, reduce the time needed to generate AGS scores, and may improve the overall performance of the AGS approach as a diagnostic test in the future. However, no investigations have focused on whether NGS-based repertoires will properly reflect antibody gene frequencies and somatic hypermutation patterns defined by Sanger sequencing. To address this issue, we isolated paired CSF samples from eight patients who either had MS or were at risk to develop MS. Here, we present data that antibody gene frequencies and somatic hypermutation patterns are similar in Sanger and NGS-based antibody repertoires from these paired CSF samples. In addition, AGS scores derived from the NGS database correctly identified the patients who initially had or subsequently converted to RRMS, with precision similar to that of the Sanger sequencing approach. Further investigation of the utility of the AGS in predicting conversion to MS using NGS-derived antibody repertoires in a larger cohort of patients is warranted. PMID- 25278929 TI - Rhythm perception, production, and synchronization during the perinatal period. AB - Sensori-motor synchronization (SMS) is the coordination of rhythmic movement with an external rhythm. It plays a central role in motor, cognitive, and social behavior. SMS is commonly studied in adults and in children from four years of age onward. Prior to this age, the ability has rarely been investigated due to a lack of available methods. The present paper reviews what is known about SMS in young children, infants, newborns, and fetuses. The review highlights fetal and infant perception of rhythm and cross modal perception of rhythm, fetal, and infant production of rhythm and cross modal production of rhythm, and the contexts in which production of rhythm can be observed in infants. A primary question is whether infants, even newborns, can modify their spontaneous rhythmical motor behavior in response to external rhythmical stimulation. Spontaneous sucking, crying, and leg movements have been studied in the presence or absence of rhythmical auditory stimulation. Findings suggest that the interaction between movement and sound is present at birth and that SMS can be observed in special conditions and within a narrow range of tempi, particularly near the infant's own spontaneous motor tempo. The discussion centers on the fundamental role of SMS in interaction and communication at the beginning of life. PMID- 25278931 TI - Behavioral models of tinnitus and hyperacusis in animals. AB - The phantom perception of tinnitus and reduced sound-level tolerance associated with hyperacusis have a high comorbidity and can be debilitating conditions for which there are no widely accepted treatments. One factor limiting the development of treatments for tinnitus and hyperacusis is the lack of reliable animal behavioral models of these disorders. Therefore, the purpose of this review is to highlight the current animal models of tinnitus and hyperacusis, and to detail the advantages and disadvantages of each paradigm. To date, this is the first review to include models of both tinnitus and hyperacusis. PMID- 25278932 TI - Understanding the patterns of antibiotic susceptibility of bacteria causing urinary tract infection in West Bengal, India. AB - Urinary tract infection (UTI) is one of the most common infectious diseases at the community level. In order to assess the adequacy of empirical therapy, the susceptibility of antibiotics and resistance pattern of bacteria responsible for UTI in West Bengal, India, were evaluated throughout the period of 2008-2013. The infection reports belonging to all age groups and both sexes were considered. Escherichia coli was the most abundant uropathogen with a prevalence rate of 67.1%, followed by Klebsiella spp. (22%) and Pseudomonas spp. (6%). Penicillin was least effective against UTI-causing E. coli and maximum susceptibility was recorded for the drugs belonging to fourth generation cephalosporins. Other abundant uropathogens, Klebsiella spp., were maximally resistant to broad spectrum penicillin, followed by aminoglycosides and third generation cephalosporin. The antibiotic resistance pattern of two principal UTI pathogens, E. coli and Klebsiella spp. in West Bengal, appears in general to be similar to that found in other parts of the Globe. Higher than 50% resistance were observed for broad-spectrum penicillin. Fourth generation cephalosporin and macrolides seems to be the choice of drug in treating UTIs in Eastern India. Furthermore, improved maintenance of infection incident logs is needed in Eastern Indian hospitals in order to facilitate regular surveillance of the occurrence of antibiotic resistance patterns, since such levels continue to change. PMID- 25278934 TI - The plant microbiome and its importance for plant and human health. PMID- 25278933 TI - Insights into novel antimicrobial compounds and antibiotic resistance genes from soil metagenomes. AB - In recent years a major worldwide problem has arisen with regard to infectious diseases caused by resistant bacteria. Resistant pathogens are related to high mortality and also to enormous healthcare costs. In this field, cultured microorganisms have been commonly focused in attempts to isolate antibiotic resistance genes or to identify antimicrobial compounds. Although this strategy has been successful in many cases, most of the microbial diversity and related antimicrobial molecules have been completely lost. As an alternative, metagenomics has been used as a reliable approach to reveal the prospective reservoir of antimicrobial compounds and antibiotic resistance genes in the uncultured microbial community that inhabits a number of environments. In this context, this review will focus on resistance genes as well as on novel antibiotics revealed by a metagenomics approach from the soil environment. Biotechnology prospects are also discussed, opening new frontiers for antibiotic development. PMID- 25278935 TI - Cross-phosphorylation of bacterial serine/threonine and tyrosine protein kinases on key regulatory residues. AB - Bacteria possess protein serine/threonine and tyrosine kinases which resemble eukaryal kinases in their capacity to phosphorylate multiple substrates. We hypothesized that the analogy might extend further, and bacterial kinases may also undergo mutual phosphorylation and activation, which is currently considered as a hallmark of eukaryal kinase networks. In order to test this hypothesis, we explored the capacity of all members of four different classes of serine/threonine and tyrosine kinases present in the firmicute model organism Bacillus subtilis to phosphorylate each other in vitro and interact with each other in vivo. The interactomics data suggested a high degree of connectivity among all types of kinases, while phosphorylation assays revealed equally wide spread cross-phosphorylation events. Our findings suggest that the Hanks-type kinases PrkC, PrkD, and YabT exhibit the highest capacity to phosphorylate other B. subtilis kinases, while the BY-kinase PtkA and the two-component-like kinases RsbW and SpoIIAB show the highest propensity to be phosphorylated by other kinases. Analysis of phosphorylated residues on several selected recipient kinases suggests that most cross-phosphorylation events concern key regulatory residues. Therefore, cross-phosphorylation events are very likely to influence the capacity of recipient kinases to phosphorylate substrates downstream in the signal transduction cascade. We therefore conclude that bacterial serine/threonine and tyrosine kinases probably engage in a network-type behavior previously described only in eukaryal cells. PMID- 25278939 TI - The role of the lys628 (192) residue of the complement protease, c1s, in interacting with Peptide and protein substrates. AB - The C1s protease of the classical complement pathway propagates the initial activation of this pathway of the system by cleaving and thereby activating the C4 and C2 complement components. This facilitates the formation of the classical pathway C3 convertase (C4bC2a). C1s has a Lys residue located at position 628 (192 in chymotrypsin numbering) of the SP domain that has the potential to partially occlude the S2-S2' positions of the active site. The 192 residue of serine proteases generally plays an important role in interactions with substrates. We therefore investigated the role of Lys628 (192) in interactions with C4 by altering the Lys residue to either a Gln (found in many other serine proteases) or an Ala residue. The mutant enzymes had altered specificity profiles for a combinatorial peptide substrate library, suggesting that this residue does influence the active site specificity of the protease. Generally, the K628Q mutant had greater activity than wild type enzyme against peptide substrates, while the K628A residue had lowered activity, although this was not always the case. Against peptide substrates containing physiological substrate sequences, the K628Q mutant once again had generally higher activity, but the activity of the wild type and mutant enzymes against a C4 P4-P4' substrate were similar. Interestingly, alteration of the K628 residue in C1s had a marked effect on the cleavage of C4, reducing cleavage efficiency for both mutants about fivefold. This indicates that this residue plays a different role in cleaving protein versus peptide substrates and that the Lys residue found in the wild type enzyme plays an important role in interacting with the C4 substrate. Understanding the basis of the interaction between C1s and its physiological substrates is likely to lead to insights that can be used to design efficient inhibitors of the enzyme for use in treating diseases caused by inflammation as result of over-activity of the classical complement pathway. PMID- 25278936 TI - Tolerance in organ transplantation: from conventional immunosuppression to extracellular vesicles. AB - Organ transplantation is often the unique solution for organ failure. However, rejection is still an unsolved problem. Although acute rejection is well controlled, the chronic use of immunosuppressive drugs for allograft acceptance causes numerous side effects in the recipient and do not prevent chronic allograft dysfunction. Different alternative therapies have been proposed to replace the classical treatment for allograft rejection. The alternative therapies are mainly based in pre-infusions of different types of regulatory cells, including DCs, MSCs, and Tregs. Nevertheless, these approaches lack full efficiency and have many problems related to availability and applicability. In this context, the use of extracellular vesicles, and in particular exosomes, may represent a cell-free alternative approach in inducing transplant tolerance and survival. Preliminary approaches in vitro and in vivo have demonstrated the efficient alloantigen presentation and immunomodulation abilities of exosomes, leading to alloantigen-specific tolerance and allograft acceptance in rodent models. Donor exosomes have been used alone, processed by recipient antigen presenting cells, or administered together with suboptimal doses of immunosuppressive drugs, achieving specific allograft tolerance and infinite transplant survival. In this review, we gathered the latest exosome-based strategies for graft acceptance and discuss the tolerance mechanisms involved in organ tolerance mediated by the administration of exosomes. We will also deal with the feasibility and difficulties that arise from the application of this strategy into the clinic. PMID- 25278940 TI - Phagocytosis by Thrombocytes is a Conserved Innate Immune Mechanism in Lower Vertebrates. AB - Thrombocytes, nucleated hemostatic blood cells of non-mammalian vertebrates, are regarded as the functional equivalent of anucleated mammalian platelets. Additional immune functions, including phagocytosis, have also been suggested for thrombocytes, but no conclusive molecular or cellular experimental evidence for their potential ingestion and clearance of infiltrating microbes has been provided till date. In the present study, we demonstrate the active phagocytic ability of thrombocytes in lower vertebrates using teleost fishes and amphibian models. Ex vivo, common carp thrombocytes were able to ingest live bacteria as well as latex beads (0.5-3 MUm in diameter) and kill the bacteria. In vivo, we found that thrombocytes represented nearly half of the phagocyte population in the common carp total peripheral blood leukocyte pool. Phagocytosis efficiency was further enhanced by serum opsonization. Particle internalization led to phagolysosome fusion and killing of internalized bacteria, pointing to a robust ability for microbe elimination. We find that this potent phagocytic activity is shared across teleost (Paralichthys olivaceus) and amphibian (Xenopus laevis) models examined, implying its conservation throughout the lower vertebrate lineage. Our results provide novel insights into the dual nature of thrombocytes in the immune and homeostatic response and further provide a deeper understanding of the potential immune function of mammalian platelets based on the conserved and vestigial functions. PMID- 25278937 TI - Tetraspanins in extracellular vesicle formation and function. AB - Extracellular vesicles (EVs) represent a novel mechanism of intercellular communication as vehicles for intercellular transfer of functional membrane and cytosolic proteins, lipids, and RNAs. Microvesicles, ectosomes, shedding vesicles, microparticles, and exosomes are the most common terms to refer to the different kinds of EVs based on their origin, composition, size, and density. Exosomes have an endosomal origin and are released by many different cell types, participating in different physiological and/or pathological processes. Depending on their origin, they can alter the fate of recipient cells according to the information transferred. In the last two decades, EVs have become the focus of many studies because of their putative use as non-invasive biomarkers and their potential in bioengineering and clinical applications. In order to exploit this ability of EVs many aspects of their biology should be deciphered. Here, we review the mechanisms involved in EV biogenesis, assembly, recruitment of selected proteins, and genetic material as well as the uptake mechanisms by target cells in an effort to understand EV functions and their utility in clinical applications. In these contexts, the role of proteins from the tetraspanin superfamily, which are among the most abundant membrane proteins of EVs, will be highlighted. PMID- 25278942 TI - Regulation of fc receptor endocytic trafficking by ubiquitination. AB - Most immune cells, particularly phagocytes, express various receptors for the Fc portion of the different immunoglobulin isotypes (Fc receptors, FcRs). By binding to the antibody, they provide a link between the adaptive immune system and the powerful effector functions triggered by innate immune cells such as mast cells, neutrophils, macrophages, and NK cells. Upon ligation of the immune complexes, the downstream signaling pathways initiated by the different receptors are quite similar for different FcR classes leading to the secretion of preformed and de novo synthesized pro-inflammatory mediators. FcR engagement also promotes negative signals through the combined action of several molecules that limit the extent and duration of positive signaling. To this regard, ligand-induced ubiquitination of FcRs for IgE (FcepsilonR) and IgG (FcgammaR) has become recognized as a key modification that generates signals for the internalization and/or delivery of engaged receptor complexes to lysosomes or cytoplasmic proteasomes for degradation, providing negative-feedback regulation of Fc receptor activity. In this review, we discuss recent advances in our understanding of the molecular mechanisms that ensure the clearance of engaged Fcepsilon and Fcgamma receptor complexes from the cell surface with an emphasis given to the cooperation between the ubiquitin pathway and endosomal adaptors including the endosomal sorting complex required for transport (ESCRT) in controlling receptor internalization and sorting along the endocytic compartments. PMID- 25278943 TI - Transcriptional and metabolic signatures of Arabidopsis responses to chewing damage by an insect herbivore and bacterial infection and the consequences of their interaction. AB - Plants use multiple interacting signaling systems to identify and respond to biotic stresses. Although it is often assumed that there is specificity in signaling responses to specific pests, this is rarely examined outside of the gene-for-gene relationships of plant-pathogen interactions. In this study, we first compared early events in gene expression and later events in metabolite profiles of Arabidopsis thaliana following attack by either the caterpillar Spodoptera exigua or avirulent (DC3000 avrRpm1) Pseudomonas syringae pv. tomato at three time points. Transcriptional responses of the plant to caterpillar feeding were rapid, occurring within 1 h of feeding, and then decreased at 6 and 24 h. In contrast, plant response to the pathogen was undetectable at 1 h but grew larger and more significant at 6 and 24 h. There was a surprisingly large amount of overlap in jasmonate and salicylate signaling in responses to the insect and pathogen, including levels of gene expression and individual hormones. The caterpillar and pathogen treatments induced different patterns of expression of glucosinolate biosynthesis genes and levels of glucosinolates. This suggests that when specific responses develop, their regulation is complex and best understood by characterizing expression of many genes and metabolites. We then examined the effect of feeding by the caterpillar Spodoptera exigua on Arabidopsis susceptibility to virulent (DC3000) and avirulent (DC3000 avrRpm1) P. syringae pv. tomato, and found that caterpillar feeding enhanced Arabidopsis resistance to the avirulent pathogen and lowered resistance to the virulent strain. We conclude that efforts to improve plant resistance to bacterial pathogens are likely to influence resistance to insects and vice versa. Studies explicitly comparing plant responses to multiple stresses, including the role of elicitors at early time points, are critical to understanding how plants organize responses in natural settings. PMID- 25278941 TI - Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies. AB - Neonates have an immature immune system, which cannot adequately protect against infectious diseases. Early in life, immune protection is accomplished by maternal antibodies transferred from mother to offspring. However, decaying maternal antibodies inhibit vaccination as is exemplified by the inhibition of seroconversion after measles vaccination. This phenomenon has been described in both human and veterinary medicine and is independent of the type of vaccine being used. This review will discuss the use of animal models for vaccine research. I will review clinical solutions for inhibition of vaccination by maternal antibodies, and the testing and development of potentially effective vaccines. These are based on new mechanistic insight about the inhibitory mechanism of maternal antibodies. Maternal antibodies inhibit the generation of antibodies whereas the T cell response is usually unaffected. B cell inhibition is mediated through a cross-link between B cell receptor (BCR) with the Fcgamma receptor IIB by a vaccine-antibody complex. In animal experiments, this inhibition can be partially overcome by injection of a vaccine-specific monoclonal IgM antibody. IgM stimulates the B cell directly through cross-linking the BCR via complement protein C3d and antigen to the complement receptor 2 (CR2) signaling complex. In addition, it was shown that interferon alpha binds to the CD21 chain of CR2 as well as the interferon receptor and that this dual receptor usage drives B cell responses in the presence of maternal antibodies. In lieu of immunizing the infant, the concept of maternal immunization as a strategy to protect neonates has been proposed. This approach would still not solve the question of how to immunize in the presence of maternal antibodies but would defer the time of infection to an age where infection might not have such a detrimental outcome as in neonates. I will review successful examples and potential challenges of implementing this concept. PMID- 25278944 TI - Florigen and anti-florigen - a systemic mechanism for coordinating growth and termination in flowering plants. AB - Genetic studies in Arabidopsis established FLOWERING LOCUS T (FT) as a key flower promoting gene in photoperiodic systems. Grafting experiments established unequivocal one-to-one relations between SINGLE FLOWER TRUSS (SFT), a tomato homolog of FT, and the hypothetical florigen, in all flowering plants. Additional studies of SFT and SELF PRUNING (SP, homolog of TFL1), two antagonistic genes regulating the architecture of the sympodial shoot system, have suggested that transition to flowering in the day-neutral and perennial tomato is synonymous with "termination." Dosage manipulation of its endogenous and mobile, graft transmissible levels demonstrated that florigen regulates termination and transition to flowering in an SP-dependent manner and, by the same token, that high florigen levels induce growth arrest and termination in meristems across the tomato shoot system. It was thus proposed that growth balances, and consequently the patterning of the shoot systems in all plants, are mediated by endogenous, meristem-specific dynamic SFT/SP ratios and that shifts to termination by changing SFT/SP ratios are triggered by the imported florigen, the mobile form of SFT. Florigen is a universal plant growth hormone inherently checked by a complementary antagonistic systemic system. Thus, an examination of the endogenous functions of FT-like genes, or of the systemic roles of the mobile florigen in any plant species, that fails to pay careful attention to the balancing antagonistic systems, or to consider its functions in day-neutral or perennial plants, would be incomplete. PMID- 25278945 TI - Tomato ACS4 is necessary for timely start of and progression through the climacteric phase of fruit ripening. AB - Climacteric fruit ripening, as it occurs in many fruit crops, depends on a rapid, autocatalytic increase in ethylene production. This agriculturally important process has been studied extensively, with tomato simultaneously acting both as a model species and target crop for modification. In tomato, the ethylene biosynthetic genes ACC SYNTHASE2 (ACS2) and ACS4 are highly expressed during fruit ripening, with a combined loss of both ACS2 and ACS4 activity preventing generation of the ethylene burst necessary for fruit ripening. However, the individual roles and importance of ACS2 and ACS4 have not been determined. In this study, we examined specifically the role of ACS4 by comparing the phenotype of an acs4 mutant firstly with that of the wild-type, and secondly with two novel ripening-inhibitor (rin) mutants. Ethylene production during ripening was significantly reduced in both acs4-1, and rin lines, with rin genotypes showing the weaker ethylene burst. Also i) the time between anthesis and the start of fruit ripening and ii) the time required to progress through ripening were significantly longer in acs4-1 than in the wild type, but shorter than in the strongest rin mutant. The delay in ripening was reflected in the lower expression of ripening-related transcripts during the mature green and light red ripening stages. Furthermore, expression of ACS2 and ACS4 was strongly dependent on a functional RIN gene, while ACS2 expression was largely independent of ACS4. Altogether, we show that ACS4 is necessary for normal progression of tomato fruit ripening and that mutation of this gene may provide a useful means for altering ripening traits. PMID- 25278947 TI - Belowground plant development measured with magnetic resonance imaging (MRI): exploiting the potential for non-invasive trait quantification using sugar beet as a proxy. AB - Both structural and functional properties of belowground plant organs are critical for the development and yield of plants but, compared to the shoot, much more difficult to observe due to soil opacity. Many processes concerning the belowground plant performance are not fully understood, in particular spatial and temporal dynamics and their interrelation with environmental factors. We used Magnetic Resonance Imaging (MRI) as a noninvasive method to evaluate which traits can be measured when a complex plant organ is monitored in-vivo while growing in the soil. We chose sugar beet (Beta vulgaris ssp. vulgaris) as a model system. The beet consists mainly of root tissues, is rather complex regarding tissue structure and responses to environmental factors, and thereby a good object to test the applicability of MRI for 3D phenotyping approaches. Over a time period of up to 3 months, traits such as beet morphology or anatomy were followed in the soil and the effect of differently sized pots on beet fresh weight calculated from MRI data was studied. There was a clear positive correlation between the pot size and the increase in fresh weight of a sugar beet over time. Since knowledge of the development of internal beet structures with several concentric cambia, vascular and parenchyma rings is still limited, we consecutively acquired 3D volumetric images on individual plants using the MRI contrast parameter T2 to map the development of rings at the tissue level. This demonstrates that MRI provides versatile protocols to non-invasively measure plant traits in the soil. It opens new avenues to investigate belowground plant performance under adverse environmental conditions such as drought, nutrient shortage, or soil compaction to seek for traits of belowground organs making plants more resilient to stress. PMID- 25278946 TI - Regulation of Na(+) fluxes in plants. AB - When exposed to salt, every plant takes up Na(+) from the environment. Once in the symplast, Na(+) is distributed within cells and between different tissues and organs. There it can help to lower the cellular water potential but also exert potentially toxic effects. Control of Na(+) fluxes is therefore crucial and indeed, research shows that the divergence between salt tolerant and salt sensitive plants is not due to a variation in transporter types but rather originates in the control of uptake and internal Na(+) fluxes. A number of regulatory mechanisms has been identified based on signaling of Ca(2+), cyclic nucleotides, reactive oxygen species, hormones, or on transcriptional and post translational changes of gene and protein expression. This review will give an overview of intra- and intercellular movement of Na(+) in plants and will summarize our current ideas of how these fluxes are controlled and regulated in the early stages of salt stress. PMID- 25278949 TI - Brown algal morphogenesis: atomic force microscopy as a tool to study the role of mechanical forces. AB - Over the last few years, a growing interest has been directed toward the use of macroalgae as a source of energy, food and molecules for the cosmetic and pharmaceutical industries. Besides this, macroalgal development remains poorly understood compared to other multicellular organisms. Brown algae (Phaeophyceae) form a monophyletic lineage of usually large multicellular algae which evolved independently from land plants. In their environment, they are subjected to strong mechanical forces (current, waves, and tide), in response to which they modify rapidly and reversibly their morphology. Because of their specific cellular features (cell wall composition, cytoskeleton organization), deciphering how they cope with these forces might help discover new control mechanisms of cell wall softening and cellulose synthesis. Despite the current scarcity in knowledge on brown algal cell wall dynamics and protein composition, we will illustrate, in the light of methods adapted to Ectocarpus siliculosus, to what extent atomic force microscopy can contribute to advance this field of investigation. PMID- 25278951 TI - Silicon, endophytes and secondary metabolites as grass defenses against mammalian herbivores. AB - Grasses have been considered to primarily employ tolerance in lieu of defense in mitigating damage caused by herbivory. Yet a number of mechanisms have been identified in grasses, which may deter feeding by grazers. These include enhanced silicon uptake, hosting of toxin-producing endophytic fungi and induction of secondary metabolites. While these mechanisms have been individually studied, their synergistic responses to grazing, as well as their effects on grazers, are poorly known. A field experiment was carried out in 5 * 5 m outdoor enclosures to quantify phytochemical changes of either endophyte-infected (E+) or endophyte free (E-) meadow fescue (Schedonorus pratensis) in response to medium intensity (corresponding with densities of ca. 1200 voles/ha for 5 weeks during 3 months) or heavy intensity (ca. 1200 voles/ha for 8 weeks during 3 months) grazing by a mammalian herbivore, the field vole (Microtus agrestis). A laboratory experiment was then conducted to evaluate the effects of endophyte infection status and grazing history of the grass diet on vole performance. As predicted, grazing increased foliar silicon content, by up to 13%. Grazing also increased foliar levels of phosphorous and several phenolic compounds, most notably those of the flavonols isorhamnetin-diglycoside and rhamnetin derivative. Silicon concentrations were consistently circa 16% higher in E+ grasses than in E grasses, at all levels of grazing. Similarly, concentrations of chlorogenic acid derivative were found to be consistently higher in E+ than in E- grasses. Female voles maintained on heavily grazed grasses suffered higher mortality rates in the laboratory than female voles fed ungrazed grass, regardless of endophyte infection status. Our results conclusively demonstrate that, in addition to tolerance, grasses employ multi-tiered, effective defenses against mammalian grazers. PMID- 25278952 TI - Enzymes involved in organellar DNA replication in photosynthetic eukaryotes. AB - Plastids and mitochondria possess their own genomes. Although the replication mechanisms of these organellar genomes remain unclear in photosynthetic eukaryotes, several organelle-localized enzymes related to genome replication, including DNA polymerase, DNA primase, DNA helicase, DNA topoisomerase, single stranded DNA maintenance protein, DNA ligase, primer removal enzyme, and several DNA recombination-related enzymes, have been identified. In the reference Eudicot plant Arabidopsis thaliana, the replication-related enzymes of plastids and mitochondria are similar because many of them are dual targeted to both organelles, whereas in the red alga Cyanidioschyzon merolae, plastids and mitochondria contain different replication machinery components. The enzymes involved in organellar genome replication in green plants and red algae were derived from different origins, including proteobacterial, cyanobacterial, and eukaryotic lineages. In the present review, we summarize the available data for enzymes related to organellar genome replication in green plants and red algae. In addition, based on the type and distribution of replication enzymes in photosynthetic eukaryotes, we discuss the transitional history of replication enzymes in the organelles of plants. PMID- 25278948 TI - Wounding in the plant tissue: the defense of a dangerous passage. AB - Plants are continuously exposed to agents such as herbivores and environmental mechanical stresses that cause wounding and open the way to the invasion by microbial pathogens. Wounding provides nutrients to pathogens and facilitates their entry into the tissue and subsequent infection. Plants have evolved constitutive and induced defense mechanisms to properly respond to wounding and prevent infection. The constitutive defenses are represented by physical barriers, i.e., the presence of cuticle or lignin, or by metabolites that act as toxins or deterrents for herbivores. Plants are also able to sense the injured tissue as an altered self and induce responses similar to those activated by pathogen infection. Endogenous molecules released from wounded tissue may act as Damage-Associated Molecular Patterns (DAMPs) that activate the plant innate immunity. Wound-induced responses are both rapid, such as the oxidative burst and the expression of defense-related genes, and late, such as the callose deposition, the accumulation of proteinase inhibitors and of hydrolytic enzymes (i.e., chitinases and gluganases). Typical examples of DAMPs involved in the response to wounding are the peptide systemin, and the oligogalacturonides, which are oligosaccharides released from the pectic component of the cell wall. Responses to wounding take place both at the site of damage (local response) and systemically (systemic response) and are mediated by hormones such as jasmonic acid, ethylene, salicylic acid, and abscisic acid. PMID- 25278950 TI - Footprints of the sun: memory of UV and light stress in plants. AB - Sunlight provides the necessary energy for plant growth via photosynthesis but high light and particular its integral ultraviolet (UV) part causes stress potentially leading to serious damage to DNA, proteins, and other cellular components. Plants show adaptation to environmental stresses, sometimes referred to as "plant memory." There is growing evidence that plants memorize exposure to biotic or abiotic stresses through epigenetic mechanisms at the cellular level. UV target genes such as CHALCONE SYNTHASE (CHS) respond immediately to UV treatment and studies of the recently identified UV-B receptor UV RESISTANCE LOCUS 8 (UVR8) confirm the expedite nature of UV signaling. Considering these findings, an UV memory seems redundant. However, several lines of evidence suggest that plants may develop an epigenetic memory of UV and light stress, but in comparison to other abiotic stresses there has been relatively little investigation. Here we summarize the state of knowledge about acclimation and adaptation of plants to UV light and discuss the possibility of chromatin based epigenetic memory. PMID- 25278953 TI - Chemical and structural analysis of Eucalyptus globulus and E. camaldulensis leaf cuticles: a lipidized cell wall region. AB - The plant cuticle has traditionally been conceived as an independent hydrophobic layer that covers the external epidermal cell wall. Due to its complexity, the existing relationship between cuticle chemical composition and ultra-structure remains unclear to date. This study aimed to examine the link between chemical composition and structure of isolated, adaxial leaf cuticles of Eucalyptus camaldulensis and E. globulus by the gradual extraction and identification of lipid constituents (cutin and soluble lipids), coupled to spectroscopic and microscopic analyses. The soluble compounds and cutin monomers identified could not be assigned to a concrete internal cuticle ultra-structure. After cutin depolymerization, a cellulose network resembling the cell wall was observed, with different structural patterns in the regions ascribed to the cuticle proper and cuticular layer, respectively. Our results suggest that the current cuticle model should be revised, stressing the presence and major role of cell wall polysaccharides. It is concluded that the cuticle may be interpreted as a modified cell wall region which contains additional lipids. The major heterogeneity of the plant cuticle makes it difficult to establish a direct link between cuticle chemistry and structure with the existing methodologies. PMID- 25278954 TI - Border control: selectivity of chloroplast protein import and regulation at the TOC-complex. AB - Plants have evolved complex and sophisticated molecular mechanisms to regulate their development and adapt to their surrounding environment. Particularly the development of their specific organelles, chloroplasts and other plastid-types, is finely tuned in accordance with the metabolic needs of the cell. The normal development and functioning of plastids require import of particular subsets of nuclear encoded proteins. Most preproteins contain a cleavable sequence at their N terminal (transit peptide) serving as a signal for targeting to the organelle and recognition by the translocation machinery TOC-TIC (translocon of outer membrane complex-translocon of inner membrane complex) spanning the dual membrane envelope. The plastid proteome needs constant remodeling in response to developmental and environmental factors. Therefore selective regulation of preprotein import plays a crucial role in plant development. In this review we describe the diversity of transit peptides and TOC receptor complexes, and summarize the current knowledge and potential directions for future research concerning regulation of the different Toc isoforms. PMID- 25278956 TI - A Vavilovian approach to discovering crop-associated microbes with potential to enhance plant immunity. AB - Through active associations with a diverse community of largely non-pathogenic microbes, a plant may be thought of as possessing an "extended genotype," an interactive cross-organismal genome with potential, exploitable implications for plant immunity. The successful enrichment of plant microbiomes with beneficial species has led to numerous commercial applications, and the hunt for new biocontrol organisms continues. Increasingly flexible and affordable sequencing technologies, supported by increasingly comprehensive taxonomic databases, make the characterization of non-model crop-associated microbiomes a widely accessible research method toward this end; and such studies are becoming more frequent. A summary of this emerging literature reveals, however, the need for a more systematic research lens in the face of what is already a metagenomics data deluge. Considering the processes and consequences of crop evolution and domestication, we assert that the judicious integration of in situ crop wild relatives into phytobiome research efforts presents a singularly powerful tool for separating signal from noise, thereby facilitating a more efficient means of identifying candidate plant-associated microbes with the potential for enhancing the immunity and fitness of crop species. PMID- 25278955 TI - Isolation and functional analysis of CONSTANS-LIKE genes suggests that a central role for CONSTANS in flowering time control is not evolutionarily conserved in Medicago truncatula. AB - The zinc finger transcription factor CONSTANS has a well-established central role in the mechanism for photoperiod sensing in Arabidopsis, integrating light and circadian clock signals to upregulate the florigen gene FT under long-day but not short-day conditions. Although CONSTANS-LIKE (COL) genes in other species have also been shown to regulate flowering time, it is not clear how widely this central role in photoperiod sensing is conserved. Legumes are a major plant group and various legume species show significant natural variation for photoperiod responsive flowering. Orthologs of several Arabidopsis genes have been shown to participate in photoperiodic flowering in legumes, but the possible function of COL genes as integrators of the photoperiod response has not yet been examined in detail. Here we characterize the COL family in the temperate long-day legume Medicago truncatula, using expression analyses, reverse genetics, transient activation assays and Arabidopsis transformation. Our results provide several lines of evidence suggesting that COL genes are unlikely to have a central role in the photoperiod response mechanism in this species. PMID- 25278958 TI - Next generation genetics. PMID- 25278957 TI - Clinical and molecular implications of mosaicism in FMR1 full mutations. AB - Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome. PMID- 25278960 TI - DaVIE: Database for the Visualization and Integration of Epigenetic data. AB - One of the challenges in the analysis of large data sets, particularly in a population-based setting, is the ability to perform comparisons across projects. This has to be done in such a way that the integrity of each individual project is maintained, while ensuring that the data are comparable across projects. These issues are beginning to be observed in human DNA methylation studies, as the Illumina 450k platform and next generation sequencing-based assays grow in popularity and decrease in price. This increase in productivity is enabling new insights into epigenetics, but also requires the development of pipelines and software capable of handling the large volumes of data. The specific problems inherent in creating a platform for the storage, comparison, integration, and visualization of DNA methylation data include data storage, algorithm efficiency and ability to interpret the results to derive biological meaning from them. Databases provide a ready-made solution to these issues, but as yet no tools exist that that leverage these advantages while providing an intuitive user interface for interpreting results in a genomic context. We have addressed this void by integrating a database to store DNA methylation data with a web interface to query and visualize the database and a set of libraries for more complex analysis. The resulting platform is called DaVIE: Database for the Visualization and Integration of Epigenetics data. DaVIE can use data culled from a variety of sources, and the web interface includes the ability to group samples by sub-type, compare multiple projects and visualize genomic features in relation to sites of interest. We have used DaVIE to identify patterns of DNA methylation in specific projects and across different projects, identify outlier samples, and cross-check differentially methylated CpG sites identified in specific projects across large numbers of samples. A demonstration server has been setup using GEO data at http://echelon.cmmt.ubc.ca/dbaccess/, with login "guest" and password "guest." Groups may download and install their own version of the server following the instructions on the project's wiki. PMID- 25278959 TI - Statistical methods for detecting differentially methylated loci and regions. AB - DNA methylation, the reversible addition of methyl groups at CpG dinucleotides, represents an important regulatory layer associated with gene expression. Changed methylation status has been noted across diverse pathological states, including cancer. The rapid development and uptake of microarrays and large scale DNA sequencing has prompted an explosion of data analytic methods for processing and discovering changes in DNA methylation across varied data types. In this mini review, we present a compact and accessible discussion of many of the salient challenges, such as experimental design, statistical methods for differential methylation detection, critical considerations such as cell type composition and the potential confounding that can arise from batch effects. From a statistical perspective, our main interests include the use of empirical Bayes or hierarchical models, which have proved immensely powerful in genomics, and the procedures by which false discovery control is achieved. PMID- 25278961 TI - Ecological and evolutionary implications of genomic structural variations. PMID- 25278963 TI - Should we consider patent foramen ovale and secundum atrial septal defect as different steps of a single anatomo-clinical continuum? PMID- 25278962 TI - Sperm epigenomics: challenges and opportunities. AB - Sperm is a highly differentiated cell type whose function is to deliver a haploid genome to the oocyte. The sperm "epigenomes" were traditionally considered to be insignificant - the sperm is transcriptionally inactive, its genome is packaged in sperm-specific protamine toroids instead of nucleosomes, and its DNA methylation profile is erased immediately post-fertilization. Yet, in recent years there has been an increase in the number of reported cases of apparent epigenetic inheritance through the male germline, suggesting that the sperm epigenome may transmit information between generations. At the same time, technical advances have made the genome-wide profiling of different layers of the sperm epigenome feasible. As a result, a large number of datasets have been recently generated and analyzed with the aim to better understand what non genetic material is contained within the sperm and whether it has any function post-fertilization. Here, we provide an overview of the current knowledge of the sperm epigenomes as well as the challenges in analysing them and the opportunities in understanding the potential non-genetic carriers of information in sperm. PMID- 25278964 TI - Intermediate-term mortality and incidence of ICD therapy in octogenarians after cardiac resynchronization therapy. AB - BACKGROUND: Clinical outcomes of cardiac resynchronization therapy (CRT) in patients over the age of 80 have not been well described. METHODS: We retrospectively identified 96 consecutive patients >= 80 years old who underwent an initial implant or an upgrade to CRT, with or without defibrillator (CRT-D vs. CRT-P), at our institution between January 2003 and July 2008. The control cohort consisted of 177 randomly selected patients < 80 years old undergoing CRT implant during the same time period. The primary efficacy endpoint was all-cause mortality at 36 months, assessed by Kaplan-Meier time to first event curves. RESULTS: In the octogenarian cohort, mean age at CRT implant was 83.1 +/- 2.9 years vs. 60.1 +/- 8.8 years among controls (P < 0.001). Across both groups, 70% were male, mean left ventricular ejection fraction (LVEF) was 24.8% +/- 14.1% and QRS duration was 154 +/- 24.8 ms, without significant differences between groups. Octogenarians were more likely to have ischemic cardiomyopathy (74% vs. 37%, P < 0.001) and more likely to undergo upgrade to CRT instead of an initial implant (42% vs. 19%, P < 0.001). The rate of appropriate defibrillator shocks was lower among octogenarians (14% vs. 27%, P = 0.02) whereas the rate of inappropriate shocks was similar (3% vs. 6%, P = 0.55). At 36 months, there was no significant difference in the rate of all-cause mortality between octogenarians (11%) and controls (8%, P = 0.381). CONCLUSION: Appropriately selected octogenarians who are candidates for CRT have similar intermediate-term mortality compared to younger patients receiving CRT. PMID- 25278965 TI - Clinical features of coronary artery ectasia in the elderly. AB - OBJECTIVE: To investigate the incidence, imaging and clinical characteristics in elderly patients with coronary artery ectasia (CAE). METHODS: A retrospective analysis was conducted on patients with CAE who underwent coronary angiography between January 2006 and December 2012. According to age, the enrolled patients were divided into two groups (elderly group, age >= 65 years; non-elderly group, age < 65 years). The clinical feature, imaging characteristics and the 5-year survival rate of the two groups were compared. RESULTS: The prevalence of CAE in elderly patients was 0.33%. Patients in elderly group were found to have significantly higher proportion of female (30.1% vs. 10.1%, P < 0.001), three vessel disease (60.5% vs. 45.2%, P = 0.003) and localized ectasia (55.0% vs. 40.2%, P = 0.003). In addition, body mass index (20.90 +/- 2.71 kg/m(2) vs. 22.31 +/- 2.98 kg/m(2), P < 0.001) and percentage of current smokers (45.0% vs. 64.6%, P < 0.001) were significantly lower in elderly group. Cumulative survival curves demonstrated reduced 5-year cumulative survival at the follow-up in the elderly group compared with the non-elderly group (88.0% vs. 96.0%, P = 0.002). But the 5 year event free survival rate failed to show a significant difference between the two groups (31.0% vs. 35.0%, P = 0.311). CONCLUSION: The prevalence of CAE in elderly patients was 0.33%, which was about 1/3 of the entire numbers of CAE patients. There were significant differences between the elderly and the non elderly patients with CAE in terms of coronary artery disease risk factors and coronary artery ectatic characteristics. CAE might be associated with increased mortality risk in the elderly. PMID- 25278967 TI - Incidence of pocket hematoma after electrophysiological device placement: dual antiplatelet therapy versus low-molecular-weight heparin regimen. AB - BACKGROUND: Given the increasing number of patients who require dual antiplatelet (DAP) therapy and electrophysiological device (EPD) placement, perioperative antiplatelet management is a current challenge. In this study, we investigated the incidence of pocket hematoma formation after EPD placement in patients undergoing DAP therapy or an alternative low-molecular-weight heparin (LMWH) regimen. METHODS: This clinical observational study was performed from July 2010 to July 2012. In total, 171 patients were enrolled in the analysis after meeting the inclusion criteria. These patients were divided into two groups: 86 patients were treated with DAP therapy at the time of device implantation, and the DAP therapy was discontinued for 5 to 7 days and replaced with enoxaparin before device implantation in the other 85 patients. Adenosine phosphate (ADP)-mediated platelet aggregation and arachidonic acid-induced platelet aggregation were tested preoperatively. We compared the incidence of pocket hematoma between the two groups and the association of pocket hematoma development with ADP-mediated platelet aggregation and arachidonic acid-induced platelet aggregation. RESULTS: The incidence of pocket hematoma in the patients who continued DAP was lower than that in the patients who replaced the dual antiplatelet regimen with LMWH (3.49% vs. 16.47%, respectively; X (2) = 6.66, P < 0.01). Among the patients who continued DAP therapies, the rate of ADP-mediated platelet aggregation inhibition in patients with pocket hematomas was higher than that in patients without pocket hematomas. None of the patients undergoing DAP or enoxaparin therapy developed pocket infection, thromboembolic events, or other serious complications. Multiple logistic regression analysis revealed that LMWH therapy was an independent risk factor for the development of pocket hematoma (RR = 0.054, 95%CI = 0.012-0.251). Furthermore, patients undergoing LMWH therapy were 5.1-fold more likely to develop pocket hematomas than were DAP-treated individuals. CONCLUSION: Continuance of DAP therapy does not increase the risk of pocket hematoma formation after EPD placement. PMID- 25278966 TI - Relationship between lipids levels and right ventricular volume overload in congestive heart failure. AB - BACKGROUND: The relationship between lipids and coronary artery disease has been well established. However, this is not the case between lipids and heart failure. Ironically, high lipid levels are associated with better outcomes in heart failure, but the mechanisms underlying the phenomenon are not fully understood. This study was performed to test the hypothesis that reduced intestinal lipid absorption due to venous congestion may lead to low lipid levels. METHODS: We collected data of clinical characteristics, echocardiograph, and lipid profile in 442 unselected patients with congestive heart failure. Correlations between lipid levels [including total cholesterol (TCL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)] and right ventricle end diastolic diameter (RVEDD), left ventricle end diastolic diameter (LVEDD), right atrium diameter (RA), left atrium diameter (LA), or left ventricle ejection fraction (LVEF) were analyzed using Pearson correlation and partial correlation. RVEDD, LVEDD, RA, and LA were indexed to the body surface area. RESULTS: There was a significantly inverse correlation between TCL levels and RVEDD (r = -0.34, P < 0.001) and RA (r = -0.36, P < 0.001). Other lipids such as LDL-C, HDL-C, and TG had a similar inverse correlation with RVEDD and RA. All these correlations remained unchanged after adjusting for age, gender, smoking status, physical activity levels, comorbidities, and medication use. CONCLUSIONS: Lipid levels were inversely correlated to RVEDD in patients with congestive heart failure; however, because this was an observational study, further investigation is needed to verify our results as well as identify a causal relationship, if any. PMID- 25278968 TI - Impact of invasive treatment strategy on health-related quality of life six months after non-ST-elevation acute coronary syndrome. AB - BACKGROUND: Few studies have compared change in the health-related quality of life (HRQL) following treatment of non-ST-elevation acute coronary syndrome (NSTE ACS) with either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). This study is to compare changes in HRQL six months after hospital discharge between NSTE-ACS patients who underwent either PCI or CABG. METHODS: HRQL was assessed using the Seattle angina questionnaire at admission and six months after discharge in 1012 consecutive patients with NSTE-ACS. To assess associations of PCI and CABG with HRQL changes, logistic regression models were constructed treating changes in the score of each dimension of the Seattle angina questionnaire as dependent variables. RESULTS: Although both the PCI and CABG groups experienced angina relief and other improvements at 6-month follow-up (P < 0.001), the CABG relative to PCI group showed more significant improvements in angina frequency (P = 0.044) and quality of life (P = 0.028). In multivariable logistic analysis, CABG also was an independent predictor for both improvement of angina frequency (OR: 1.62, 95%CI: 1.09-4.63, P = 0.042) and quality of life (OR: 2.04, 95%CI: 1.26-6.92, P = 0.038) relative to PCI. CONCLUSIONS: In patients with NSTE-ACS, both PCI and CABG provide great improvement in disease-specific health status at six months, with that of CABG being more prominent in terms of angina frequency and quality of life. PMID- 25278969 TI - Impact of body mass index on the development of pocket hematoma: A retrospective study in Chinese people. AB - BACKGROUND: Pocket hematoma is one of the major complications associated with cardiovascular implantable electronic devices (CIEDs) implantation. The aim of this study is to evaluate the impact of body mass index (BMI) on the occurrence of pocket hematoma after CIEDs implantation. METHODS: The study is a retrospective review of 972 patients receiving CIEDs implantation between 2008 and 2012 in a tertiary hospital. RESULTS: Twenty two patients (2.2%) developed severe pocket hematoma requiring re-intervention. The hematoma rate (4.6%, n = 15) of patients with a BMI of < 23 kg/m(2) was significantly higher compared with that of patients with a BMI of >= 23 kg/m(2) (1.1%, n = 7, P < 0.001). In multivariate regression analysis, a BMI < 23.0 kg/m(2) may be associated with the development of severe pocket hematoma. An increase of 1.0 kg/m(2) in BMI was associated with lower incidence of hematoma formation (OR: 0.84; 95% CI: 0.74 0.95; P = 0.006). CONCLUSION: BMI < 23 kg/m(2) was associated with a higher incidence of pocket hematoma, requiring re-intervention. The data support that great care must be taken when patients were with a lower BMI received CIEDs implantation. PMID- 25278970 TI - Long-term follow-up study of elderly patients with covered stent implantation after coronary perforation. AB - OBJECTIVE: To evaluate the long-term efficacy of covered stent implantation in the treatment of elderly patients with coronary perforation while undergoing percutaneous coronary intervention (PCI). METHODS: From June 2004 to June 2012, our center has followed ten elderly patients (age >= 60 years) who sustained coronary perforation during PCI. The major adverse cardiac events (MACE) were observed as well. The patients were advised to take 75 mg/day Clopidogrel for two years, and indefinite use of 100 mg/day enteric-coated aspirin. RESULTS: Six out of the 10 patients aged from 60 to 76 years old (mean 68.6 +/- 5.2 years) were male, four were female. The average diameter of the implanted stents was 3.3 +/- 0.3 mm, and the average length was 22.1 +/- 3.7 mm. All the ruptures were successfully sealed without intra-procedural death. The follow-up duration ranged from 0.6 to 67 months (mean 31.7 +/- 24.5 months). One patient died of multiple organ failure due to lung infection in 19 days after PCI; one died of cardiac sudden death in 13 months after PCI; one had angina pectoris in 53 months after PCI; one underwent multi-slice CT examination in six months after PCI, and no in stent restenosis was found. The other four patients received angiography follow up, and the results showed that three patients had no intra-stent restenosis, while one had left anterior descending (LAD) restenosis in the covered stent in 67 months after PCI. The in-hospital mortality was 10% (1/10). The MACE rate in 12 months after PCI was 10% (1/10). During the entire followed-up period, the restenosis rate in target vessels was 20% (1/5), mortality was 20% (2/10), and the MACE rate was 40% (4/10). CONCLUSION: Treatment of coronary perforation by using covered stents can achieve favorable long-term results; a two-year dual antiplatelet therapy (DAPT) after PCI can effectively prevent intra-stent thrombosis. PMID- 25278971 TI - Resistin might not be a risk factor for carotid artery atherosclerosis in elderly Chinese males. AB - OBJECTIVE: To investigate the correlation between the serum resistin level and carotid artery atherosclerosis in elderly Chinese males. METHODS: The study enrolled 235 elderly Chinese males [median age 76 (range 60-97) years] scheduled for ultrasound examination of carotid artery plaque and determination of carotid artery intima-media thickness (CIMT). They were divided into carotid atherosclerotic plaque (CAP) and carotid atherosclerotic plaque-free (CAP-free) groups according to the ultrasound results. Their clinical profiles were collected, and the serum resistin and other blood biochemistry levels were determined. RESULTS: The CAP group was older and had a thicker mean CIMT than the CAP-free group. However, there was no difference in the serum resistin level between the groups. CIMT was positively correlated with age (r = 0.299, P < 0.001). The serum resistin level was not correlated with CIMT, even after controlling for age. Multiple linear regression analysis revealed that age (beta = 0.001, P < 0.001) and body mass index (beta = 0.002, P = 0.015) were significantly and positively correlated with the mean CIMT. Only age [odds ratio (OR): 1.159; 95% confidence interval (CI): 1.078-1.183, P < 0.001] was associated with the presence of carotid artery atherosclerotic plaque. The serum resistin level was not correlated with the mean CIMT or associated with the presence of carotid artery atherosclerotic plaque. CONCLUSION: The results suggest that resistin might not be a risk factor for atherosclerosis in elderly Chinese males. PMID- 25278972 TI - Diagnostic value of (18)F-FDG PET in the assessment of myocardial viability in coronary artery disease: A comparative study with (99m)Tc SPECT and echocardiography. AB - OBJECTIVE: To investigate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in the assessment of myocardial viability in patients with known coronary artery disease (CAD) when compared to (99m)Tc single photon emission computed tomography (SPECT) and echocardiography, with invasive coronary angiography as the gold standard. METHODS: Thirty patients with diagnosed CAD met the selection criteria, with 10 of them (9 men, mean age 59.5 +/- 10.5 years) undergoing all of these imaging procedures consisting of SPECT and PET, echocardiography and invasive angiography. Diagnostic sensitivity of these less invasive modalities for detection of myocardial viability was compared to invasive coronary angiography. Inter- and intra-observer agreement was assessed for diagnostic performance of SPECT and PET. RESULTS: Of all patients with proven CAD, 50% had triple vessel disease. Diagnostic sensitivity of SPECT, PET and echocardiography was 90%, 100% and 80% at patient-based assessment, respectively. Excellent agreement was achieved between inter-observer and intra observer agreement of the diagnostic value of SPECT and PET in myocardial viability (k = 0.9). CONCLUSION: (18)F-FDG PET has high diagnostic value in the assessment of myocardial viability in patients with known CAD when compared to SPECT and echocardiography. Further studies based on a large cohort with incorporation of (18)F-FDG PET into patient management are warranted. PMID- 25278973 TI - Hypoxia training attenuates left ventricular remodeling in rabbit with myocardial infarction. AB - OBJECTIVE: Previous studies showed that hypoxia preconditioning could protect cardiac function against subsequent myocardial infarction injury. However, the effect of hypoxia on left ventricular after myocardial infarction is still unclear. This study therefore aims to investigate the effects of hypoxia training on left ventricular remodeling in rabbits post myocardial infarction. METHODS: ADULT MALE RABBITS WERE RANDOMLY DIVIDED INTO THREE GROUPS: group SO (sham operated), group MI (myocardial infarction only) and group MI-HT (myocardial infarction plus hypoxia training). Myocardial infarction was induced by left ventricular branch ligation. Hypoxia training was performed in a hypobaric chamber (having equivalent condition at an altitude of 4000 m, FiO214.9%) for 1 h/day, 5 days/week for four weeks. At the endpoints, vascular endothelial growth factor (VEGF) in the plasma was measured. Infarct size and capillary density were detected by histology. Left ventricular remodeling and function were assessed by echocardiography. RESULTS: After the 4-week experiment, compared with the group SO, plasma VEGF levels in groups MI (130.27 +/- 18.58 pg/mL, P < 0.01) and MI-HT (181.93 +/- 20.29 pg/mL, P < 0.01) were significantly increased. Infarct size in Group MI-HT (29.67% +/- 7.73%) was deceased remarkably, while its capillary density (816.0 +/- 122.2/mm(2)) was significantly increased. For both groups MI and MI-HT, left ventricular end-diastolic and end-systolic dimensions were increased whereas left ventricular ejection fraction was decreased. However, compared with group MI, group MI-HT diminished left ventricular end-diastolic (15.86 +/- 1.09 mm, P < 0.05) and end-systolic dimensions (12.10 +/- 1.20 mm, P < 0.01) significantly and improved left ventricular ejection fraction (54.39 +/- 12.74 mm, P < 0.05). CONCLUSION: Hypoxia training may improve left ventricular function and reduce remodeling via angiogenesis in rabbits with MI. PMID- 25278974 TI - Impact of estimated HDL particle size via the ratio of HDL-C and apoprotein A-I on short-term prognosis of diabetic patients with stable coronary artery disease. AB - BACKGROUND: Revascularization and statin therapy are routinely used in the management of stable coronary artery disease. However, it is unclear whether the estimated high-density lipoprotein (HDL) particle size (eHDL-S), the ratio of HDL cholesterol (HDL-C) to apoprotein A-I (apoA-I), is associated with the clinical outcomes of diabetic patients with stable coronary artery disease (CAD). METHODS: We performed a prospective cohort study of 328 patients diagnosed with stable CAD by coronary angiography. Patients were followed up for a mean duration of 12 months. The patients were divided into three groups by the tertiles of eHDL-S: low eHDL-S (< 0.71, n = 118); intermediate eHDL-S (0.71-0.79, n = 111); and high eHDL-S (> 0.79, n = 99). The associations between the baseline eHDL-S and short term outcomes were evaluated using the Kaplan-Meier method and Cox proportional regression. RESULTS: The low eHDL-S group had higher triglyceride, hemoglobin A1c, uric acid, and leukocyte count than the other groups. During the follow-up period, 47/328 patients experienced a pre-specified outcome. According to the Kaplan-Meier analysis, the incidence of pre-specified outcomes was lower in the high eHDL-S group (P = 0.04). However, eHDL-S was not independently associated with adverse outcomes in Cox proportional hazards regression (hazard ratio (HR): 0.23, 95% confidence interval (95% CI): 0.01-11.24, P = 0.493). CONCLUSION: Although the eHDL-S was associated with inflammatory biomarkers, it was not independently associated with the short-term prognosis of diabetic patients with stable CAD in the era of revascularization and potent statin therapy. PMID- 25278975 TI - The cardiovascular action of hexarelin. AB - Hexarelin, a synthetic growth hormone-releasing peptide, can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects. Furthermore, the non-GHSR CD36 had been demonstrated to be a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. When compared with ghrelin, hexarelin is chemically more stable and functionally more potent. Therefore, it may be a promising therapeutic agent for some cardiovascular conditions. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin. PMID- 25278978 TI - Acute myocardial infarction triggering Takotsubo syndrome, and the need to search for its prevalence. PMID- 25278977 TI - Should antiplatelet therapy be interrupted in drug eluting stent recipients throughout the periendoscopic period? A very late stent thrombosis case report and review of the literature. AB - In-stent thrombosis after cessation of antiplatelet medications in patients with drug-eluting stents (DES) is a significant problem in medical practice, particularly in the perioperative period. We report a case of an 87-year-old man with a medical history of hypertension, coronary artery disease and chronic atrophic gastritis. Very late thrombosis of a sirolimus-eluting stent occurred 1207 days after implantation, seven months after discontinuation of clopidogrel, and the interruption of aspirin 13 days in preparation of an elective endoscopic gastrointestinal procedure presented with acute myocardial infarction. The patient was treated with thrombectomy and successfully revascularized with superimposition of two sirolimus-eluting stents. Medications administered in the catheterization laboratory included low molecular weight heparin and nitroglycerin. Flow was defined as grade 2 according to the thrombolysis in myocardial infarction scale. Electrocardiogram after the procedure revealed persistent, but decreased, ST-segment elevation in the anterolateral leads. The patient recovered and was discharged on aspirin and clopidogrel indefinitely. There was no cardiac event during the two year follow-up period. This case underlines the importance of maintaining the balance of thrombosis and bleeding during perioperation of non-cardiac procedure and the possible need for continuation of aspirin therapy during periendoscopic procedures among patients with low bleeding risks who received DES. PMID- 25278976 TI - Molecular imaging of plaques in coronary arteries with PET and SPECT. AB - Coronary artery disease remains a major cause of mortality. Presence of atherosclerotic plaques in the coronary artery is responsible for lumen stenosis which is often used as an indicator for determining the severity of coronary artery disease. However, the degree of coronary lumen stenosis is not often related to compromising myocardial blood flow, as most of the cardiac events that are caused by atherosclerotic plaques are the result of vulnerable plaques which are prone to rupture. Thus, identification of vulnerable plaques in coronary arteries has become increasingly important to assist identify patients with high cardiovascular risks. Molecular imaging with use of positron emission tomography (PET) and single photon emission computed tomography (SPECT) has fulfilled this goal by providing functional information about plaque activity which enables accurate assessment of plaque stability. This review article provides an overview of diagnostic applications of molecular imaging techniques in the detection of plaques in coronary arteries with PET and SPECT. New radiopharmaceuticals used in the molecular imaging of coronary plaques and diagnostic applications of integrated PET/CT and PET/MRI in coronary plaques are also discussed. PMID- 25278979 TI - Detection of antibodies to Toxoplasma gondii in wild animals in Brazil. AB - BACKGROUND: Toxoplasmosis is a worldwide zoonosis caused by an obligate intracellular protozoan parasite, Toxoplasma gondii, that affects all warm blooded animals, including wild animals. The increased number of cases of parasitic infections is mainly due to the destruction of environmental conservation areas, which is driving wild animals out of their habitats and towards urban areas. In this study, the occurrence of T. gondii infection was investigated by the modified agglutination test (MAT) in 26 different species of run over and injured wild animals that were treated at a Brazilian university veterinary hospital, from June 2007 to August 2008. FINDINGS: Of the studied animals, six (23.1%; CI95% 11.1-42.2%) had T. gondii antibodies, with titers equal to 10 (4; 66.7%) and 40 (2; 33.3%). The species Pseudalopex vetulus, Cerdocyon thous, Hydrochoerus hydrochaeris and Tapyrus terrestris had titers of 10, while Alouatta caraya and Puma concolor had titers of 40. There was no significant association regarding age, gender or purpose of care (p > 0.05). CONCLUSIONS: Carnivorous, herbivorous and omnivorous wild animals are potential sentinels of human toxoplasmosis, especially when wild felids are present, maintaining the environmental contamination. PMID- 25278980 TI - Stroke and bleeding risk in atrial fibrillation. AB - Non-valvular atrial fibrillation (AF) is the most common cardiac arrhythmia in the clinical setting. AF increases both the risk and severity of strokes, and is associated with substantial morbidity and mortality. Despite the clear net clinical benefit of oral anticoagulants (OACs) in patients with AF at risk for stroke, major bleeding events, especially intracranial bleeds, may be devastating. In the last decade, four new OACs have been approved for stroke prevention in patients with AF and are at least as effective as warfarin with better bleeding profiles. These new agents have changed and simplified our approach to stroke prevention because the threshold for initiation of OACs is lowered. An important clinical practice shift is the initial identification of "low-risk" patients who do not need antithrombotic therapy, with low-risk comprising CHA2DS2-VASc {Congestive heart failure, Hypertension, Age >=75 years (double), Diabetes mellitus, previous Stroke/transient ischemic attack/thromboembolism (double), Vascular disease, Age 65-74 years, and female gender (score of 0 for males and 1 for female)}. Subsequent to this step, effective stroke prevention consisting of OACs can be offered to patients with one or more stroke risk factors. Apart from stroke risk, another consideration is bleeding risk assessment, with a focus on the use of the validated HAS-BLED {Hypertension, Abnormal renal/liver function, Stroke, Bleeding history, Labile international normalized ratio (INR), Elderly (age >65 years), drugs or alcohol concomitantly} score. A high HAS-BLED score can flag patients potentially at risk for bleeding, and alert clinicians to the need for careful review and follow up, and the need to consider potentially correctable bleeding risk factors that include uncontrolled hypertension, labile INRs, concomitant aspirin use, and alcohol excess. PMID- 25278982 TI - Effect of High Dose Rosuvastatin Loading before Percutaneous Coronary Intervention on Contrast-Induced Nephropathy. AB - BACKGROUND AND OBJECTIVES: Contrast-induced nephropathy (CIN) is associated with increased morbidity and mortality. This observational, non-randomized study evaluated the effect of rosuvastatin loading before percutaneous coronary intervention (PCI) on the incidence of CIN in patients with acute coronary syndrome (ACS). SUBJECTS AND METHODS: A total of 824 patients who underwent PCI for ACS were studied (408 patients in the statin group=40 mg rosuvastatin loading before PCI; 416 patients of control group=no statin pretreatment). Serum creatinine concentrations were measured before and 24 and 48 hours after PCI. The primary endpoint was development of CIN defined as an increase in serum creatinine concentration of >=0.5 mg/dL or >=25% above baseline within 72 hours after PCI. RESULTS: The incidence of CIN was significantly lower in the statin group than that in the control group (18.8% vs. 13.5%, p=0.040). The maximum percent changes in serum creatinine and estimated glomerular filtration rate in the statin group within 48 hours were significantly lower than those in the control group (5.84+/-22.59% vs. 2.43+/-24.49%, p=0.038; -11.44+/-14.00 vs. 9.51+/-13.89, p=0.048, respectively). The effect of rosuvastatin on preventing CIN was greater in the subgroups of patients with diabetes, high-dose contrast medium, multivessel stents, high baseline C-reactive protein, and myocardial infarction. A multivariate analysis revealed that rosuvastatin loading was independently associated with a decreased risk for CIN (odds ratio, 0.64; 95% confidence interval, 0.43-0.95, p=0.026). CONCLUSION: High-dose rosuvastatin loading before PCI was associated with a significantly lower incidence of CIN in patients with ACS. PMID- 25278981 TI - How to Achieve Complete and Permanent Pulmonary Vein Isolation without Complications. AB - The efficacy and safety of catheter ablation for the management of atrial fibrillation (AF) has been improved in recent years. Radiofrequency (RF) catheter ablation for maintaining sinus rhythm is superior to the current antiarrhythmic drug therapy in selected patients. Pulmonary vein isolation (PVI) is the cornerstone of various catheter ablation strategies. It is well recognized that pulmonary vein (PV) antrum contributes to the AF initiation and/or perpetuation. Since PV stenosis is a complication of ablation within a PV, the ablation site for PVI has shifted to the junction between the left atrium and the PV rather than the ostium of the PV. However, PV reconnection after ablation is the major cause of recurrence of AF. The recovery of PV conduction could be caused by anatomical variations such as the failure to produce complete transmural lesion or gaps at the ablation line due to the transient electrophysiologic effects from the RF ablation. In this review, we discussed several factors to be considered for the achievement of the best PVI, including clinical aspects and technical aspects. PMID- 25278983 TI - The Presence of Fragmented QRS on 12-Lead Electrocardiography in Patients with Coronary Artery Ectasia. AB - BACKGROUND AND OBJECTIVES: Coronary artery ectasia (CAE) is an angiographic finding characterized by dilation of an arterial segment with a diameter at least 1.5 times that of its adjacent normal coronary artery. Fragmented QRS (fQRS) complexes are electrocardiographic signals which reflect altered ventricular conduction around regions of a myocardial scar and/or ischaemia. In the present study, we aimed to evaluate the presence of fQRS in patients with CAE. SUBJECTS AND METHODS: The study population included 100 patients with isolated CAE without coronary artery disease (CAD) and 80 angiographically normal controls. fQRS was defined as the presence of an additional R wave or notching of R or S wave or the presence of fragmentation in two contiguous leads corresponding to a major coronary artery territory. RESULTS: The two groups were similar in terms of age, sex, hypertension, dyslipidemia, and family history of CAD. The presence of fQRS was significantly (p<0.05) higher in the CAE group than that in the normal coronary artery group (29% vs. 6.2%, p=0.008). Isolated CAE were detected most commonly in the right coronary artery (61%), followed by left anterior descending artery (52%), left circumflex artery (36%), and left main artery (9%). Multivariate stepwise logistic regression analysis showed that CAE {odds ratio (OR) 1.412; 95% confidence interval (CI) 1.085-1.541; p=0.003} and diabetes (OR 1.310; 95% CI 1.025-1.482; p=0.041) were independently associated with fQRS. CONCLUSION: The presence of fragmented QRS associated with increased risk for arrhythmias and cardiovascular mortality was significantly higher in patients with CAE than in patient with normal coronary artery. Further studies are needed to determine whether the presence of fragmented QRS is a possible new risk factor for patients with CAE. PMID- 25278984 TI - Late gadolinium enhancement in cardiac MRI in patients with severe aortic stenosis and preserved left ventricular systolic function is related to attenuated improvement of left ventricular geometry and filling pressure after aortic valve replacement. AB - BACKGROUND AND OBJECTIVES: WE INVESTIGATED ECHOCARDIOGRAPHIC PREDICTORS: left ventricular (LV) geometric changes following aortic valve replacement (AVR) according to the late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) in patients with severe aortic stenosis (AS) and preserved LV systolic function. SUBJECTS AND METHODS: We analyzed 41 patients (24 males, 63.1+/-8.7 years) with preserved LV systolic function who were scheduled to undergo AVR for severe AS. All patients were examined with transthoracic echocardiography (TTE), CMR before and after AVR (in the hospital) and serial TTEs (at 6 and 12 months) were repeated. RESULTS: The group with LGE (LGE+) showed greater wall thickness (septum, 14.3+/-2.6 mm vs. 11.5+/-2.0 mm, p=0.001, posterior; 14.3+/-2.5 mm vs. 11.4+/-1.6 mm, p<0.001), lower tissue Doppler image (TDIS', 4.4+/-1.4 cm/s vs. 5.5+/-1.2 cm/s, p=0.021; TDI E', 3.2+/-0.9 cm/s vs. 4.8+/-1.4 cm/s, p=0.002), and greater E/e' (21.8+/-10.3 vs. 15.4+/-6.3, p=0.066) than those without LGE (LGE-). Multivariate analysis show that TDI e' (odds ratio=0.078, 95% confidence interval=0.007-0.888, p=0.040) was an independent determinant of LGE+. In an analysis of the 6- and 12-month follow-up compared with pre-AVR, LGE- showed decreased LV end-diastolic diameter (48.3+/-5.0 mm vs. 45.8+/-3.6 mm, p=0.027; 48.3+/-5.0 mm vs. 46.5+/-3.4 mm, p=0.019). Moreover, E/e' (at 12 months) showed further improved LV filling pressure (16.0+/-6.6 vs. 12.3+/ 4.3, p=0.001) compared with pre-AVR. However, LGE+ showed no significant improvement. CONCLUSION: The absence of LGE is associated with favorable improvements in LV geometry and filling pressure. TDI E' is an independent determinant of LGE in patients with severe AS and preserved LV systolic function. PMID- 25278985 TI - Safety and efficacy of the off-label use of milrinone in pediatric patients with heart diseases. AB - BACKGROUND AND OBJECTIVES: Milrinone is often used in children to treat acute heart failure and prevent low cardiac output syndrome after cardiac surgery. Due to the lack of studies on the long-term milrinone use in children, the objective of this study was to assess the safety and efficacy of the current patterns of milrinone use for >=3 days in infants and children with heart diseases. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of patients aged <13 years who received milrinone for >=3 days from January 2005 to December 2012. Patients' characteristics including age, sex, height, weight, and body surface area were recorded. The following parameters were analyzed to identify the clinical application of milrinone: initial infusion rate, maintenance continuous infusion rate, total duration of milrinone therapy, and concomitantly infused inotropes. The safety of milrinone was determined based on the occurrence of adverse events such as hypotension, arrhythmia, chest pain, headache, hypokalemia, and thrombocytopenia. RESULTS: We assessed 730 admissions (684 patients) during this period. Ventricular septal defects were the most common diagnosis (42.4%) in these patients. Milrinone was primarily used after cardiac surgery in 715 admissions (97.9%). The duration of milrinone treatment varied from 3 to 64.4 days (>=7 days in 149 admissions). Ejection fraction and fractional shortening of the left ventricle improved in patients receiving milrinone after cardiac surgery. Dose reduction of milrinone due to hypotension occurred in only 4 admissions (0.5%). Although diverse arrhythmias occurred in 75 admissions (10.3%), modification of milrinone infusion to manage arrhythmia occurred in only 3 admissions (0.4%). Multivariate analysis indicated that the development of arrhythmia was not influenced by the pattern of milrinone use. CONCLUSION: Milrinone was generally administered for >=3 days in children with heart diseases. The use of milrinone for >=3 days was effective in preventing low cardiac output after cardiac surgery when combined with other inotropes, suggesting that milrinone could be safely employed in pediatric patients with heart diseases. PMID- 25278986 TI - Clinically useful predictors of resistance to intravenous immunoglobulin and prognosis of coronary artery lesions in patients with incomplete kawasaki disease. AB - BACKGROUND AND OBJECTIVES: The prevalence of incomplete Kawasaki disease (iKD) is progressively increasing. We aimed to retrospectively investigate the predictors of intravenous immunoglobulin (IVIG) resistance in iKD patients and compare them with those of IVIG resistance in complete Kawasaki disease (cKD) patients. We also compared the prognosis of coronary artery lesions (CALs) between the IVIG non-responders and responders in both iKD and cKD groups. SUBJECTS AND METHODS: A total of 234 cKD and 77 iKD patients were treated with IVIG between February 2009 and April 2012. Among these 311 patients, we reviewed the data of 77 iKD patients and 75 age-matched cKD patients. RESULTS: Patients with iKD having an elevated neutrophil count {percentage of segmented neutrophils (SEG%) >=79.0} were at risk of IVIG resistance, while patients with cKD having SEG% >=79.25 and serum total bilirubin (TB) >=0.56 mg/dL were at risk of IVIG resistance as shown by multivariable logistic regression analysis. Fractional changes of laboratory data before and after IVIG treatment showed that Creactive protein (CRP) and N terminal B type natriuretic peptide (NT-proBNP) levels were significantly elevated in IVIG non-responders of the iKD group, whereas erythrocyte sedimentation rate was significantly elevated in IVIG non-responders of the cKD group. Among the patients who had CALs at 10 months after the start of illness, the z scores of coronary arteries were higher in IVIG non-responders of the iKD group, when compared with IVIG non-responders of the cKD group. CONCLUSION: Elevated SEG%, changes in CRP and NT-proBNP levels may help in early detection of IVIG resistance in patients of the iKD group, which may aid in predicting the prognosis of CALs in these patients. Further studies with a larger number of patients are warranted. PMID- 25278987 TI - Bilirubin Level is Associated with Left Ventricular Hypertrophy Independent of Blood Pressure in Previously Untreated Hypertensive Patients. AB - BACKGROUND AND OBJECTIVES: Left ventricular hypertrophy (LVH), a sign of subclinical cardiovascular disease, is an important predictor of cardiovascular morbidity and mortality. The aim of our study was to determine the association of left ventricular mass (LVM) with possible causative anthropometric and biochemical parameters as well as carotid intima-media thickness (CIMT) and brachial flow-mediated dilation (FMD) as surrogates of atherosclerosis and endothelial dysfunction, respectively, in previously untreated hypertensive patients. SUBJECTS AND METHODS: Our study included 114 consecutive previously untreated hypertensive patients who underwent echocardiography and ultrasonography to evaluate their vascular status and function via brachial artery CIMT and FMD. RESULTS: Among all study parameters, age, systolic blood pressure (BP), diastolic BP, pulse pressure, plasma glucose, uric acid, total bilirubin, direct bilirubin, hemoglobin, and CIMT were positively correlated with the LVM index. Multiple logistic regression analysis revealed that office systolic BP, age, male gender, and total bilirubin were independent predictors of LVH. CONCLUSION: Bilirubin seems to be related to LVM and LVH. The positive association of bilirubin with these parameters is novel and requires further research. PMID- 25278988 TI - Transcatheter aortic valve implantation in a patient with previous mitral valve replacement. AB - Transcatheter aortic valve implantation (TAVI) has shown favorable outcomes in patients with severe symptomatic aortic valve stenosis who are at high surgical risk or are unsuitable candidates for open heart surgery. However, concerns exist over treating patients who have previously undergone mitral valve surgery due to the potential interference between the mitral prosthetic valve or ring and the TAVI device. In this case report, we present a patient with symptomatic severe aortic stenosis and previous mechanical mitral valve replacement who was successfully treated with TAVI using a CoreValve. PMID- 25278989 TI - Intermittent pre-excitation-syndrome in facio-scapulo-humeral muscular dystrophy. AB - Pre-excitation-syndrome has not been reported as a phenotypic feature of facio scapulo-humeral muscular dystrophy (FSH-MD). In a 39-year-old male with FSH-MD due to a reduced tandem repeat size in the D4Z4-locus on chromosome 4q35, cardiac involvement, manifesting as an incomplete right bundle-branch-block, tall T-waves in V 3-5, ST-elevation in V 2-4, and mild thickening of the left ventricular myocardium, was first recognised 10 years earlier. Follow-up at age 39 years revealed mild myocardial thickening, two intra-ventricular aberrant bands, and, surprisingly, intermittent pre-excitation on a routine electrocardiography. Cardiac involvement in FSH-MD may manifest as hypertrophic cardiomyopathy or various arrhythmias, of which one may be pre-excitation-syndrome. PMID- 25278990 TI - Successful Stent Implantation for Aortoiliac Bifurcation Stenosis in a Young Patient with Behcet's Disease. AB - Behcet's disease (BD) is a multisystem vascular inflammatory disease. BD can affect blood vessels of nearly all sizes and types. Arterial involvement is a rare but serious condition in the course of BD. Here, we report a case of stenosis at the iliac artery bifurcation which was treated with percutaneous balloon angioplasty and stent implantation in a 37-year-old patient with BD. PMID- 25278991 TI - Prasugrel-induced hypersensitivity skin reaction. AB - We report a case of hypersensitivity skin reaction to prasugrel. The patient exhibited a generalized skin rash after treatment with prasugrel, which was resolved after discontinuation of prasugrel and substitution to clopidogrel. Clopidogrel was successfully administered as an alternative to prasugrel without any signs of further hypersensitivity. PMID- 25278992 TI - Inverse takotsubo syndrome resulting from a fall, malleolar fracture, anesthesia, surgery, or complicating pulmonary embolism? PMID- 25278993 TI - Differential expression of centrosome regulators in Her2+ breast cancer cells versus non-tumorigenic MCF10A cells. AB - Centrosome amplification (CA) amongst particular breast cancer subtypes (Her2+ subtype) is associated with genomic instability and aggressive tumor phenotypes. However, changes in signaling pathways associated with centrosome biology have not been fully explored in subtype specific models. Novel centrosome regulatory genes that are selectively altered in Her2+ breast cancer cells are of interest in discerning why CA is more prevalent in this subtype. To determine centrosome/cell cycle genes that are altered in Her2+ cells that display CA (HCC1954) versus non-tumorigenic cells (MCF10A), we carried out a gene microarray. Expression differences were validated by real-time PCR and Western blotting. After the microarray validation, we pursued a panel of upregulated and downregulated genes based on novelty/relevance to centrosome duplication. Functional experiments measuring CA and BrdU incorporation were completed after genetic manipulation of targets (TTK, SGOL1, MDM2 and SFRP1). Amongst genes that were downregulated in HCC1954 cells, knockdown of MDM2 and SFRP1 in MCF10A cells did not consistently induce CA or impaired BrdU incorporation. Conversely, amongst upregulated genes in HCC1954 cells, knockdown of SGOL1 and TTK decreased CA in breast cancer cells, while BrdU incorporation was only altered by SGOL1 knockdown. We also explored the Kaplan Meier Plot resource and noted that MDM2 and SFRP1 are positively associated with relapse free survival in all breast cancer subtypes, while TTK is negatively correlated with overall survival of Luminal A patients. Based on this functional screen, we conclude that SGOL1 and TTK are important modulators of centrosome function in a breast cancer specific model. PMID- 25278995 TI - The correlation between the enzymatic saccharification and the multidimensional structure of cellulose changed by different pretreatments. AB - BACKGROUND: The bioconversion of cellulose into simple sugars or chemicals has attracted extensive attention in recent decades. The crystal allomorphs of cellulose are key factor affecting cellulose saccharification. However, due to the influence of lignin, hemicelluloses, and different characterization methods in the literature, the effect of cellulose allomorphs on cellulose saccharification is still unresolved. Thus, a systematic research on the effect of different cellulose allomorphs on enzymatic saccharification was required. RESULTS: Multiple approaches, including the use of ionic liquid (IL), ethylenediamine (EDA), glycerol, and sodium hydroxide, were used to pretreat alpha-cellulose in this work. The properties of the obtained cellulose (crystallinity, lattice spacing, specific surface area, and wettability) were characterized by X-ray diffraction, Brunauer, Emmett, and Teller (BET) specific surface area analysis, and water contact angle analysis, respectively. The distance of the lattice spacing of cellulose III was longer than that of other cellulose samples. The crystallinity and water contact angles of the cellulose samples were ranked in the following order: cellulose treated with IL < cellulose treated with NaOH < cellulose treated with EDA < cellulose without treatment < cellulose treated with glycerol. Cellulose treated with IL, with a crystallinity index value of 20%, was very close to amorphous cellulose. After 72 h hydrolysis, the cellulose conversion ratio ranged from 43% to 99%. Cellulose treated with IL exhibited the best hydrolysis profile, followed by cellulose treated with EDA. CONCLUSION: Ionic liquid pretreatment significantly altered the ultrastructure and morphology of cellulose samples, making cellulose much easier for enzymes to digest due to its significantly high amorphous content. However, when the impact of amorphous content was not considered, the allomorph easiest for enzymes to digest was cellulose III, followed by cellulose II, cellulose Ialpha, and cellulose Ibeta. When the cellulose crystallinity index was similar, the allomorph type was the dominant factor. The amorphous content had a strong positive influence on cellulose digestibility. Water contact angle was also an important factor in evaluating the enzymatic hydrolysis efficiency of cellulose except for cellulose III. A high wettability of cellulose enhanced the enzymatic hydrolysis when the crystal allomorph of all the cellulosic samples was the same. PMID- 25278996 TI - Revealing the factors influencing a fermentative biohydrogen production process using industrial wastewater as fermentation substrate. AB - BACKGROUND: Biohydrogen production through dark fermentation using organic waste as a substrate has gained increasing attention in recent years, mostly because of the economic advantages of coupling renewable, clean energy production with biological waste treatment. An ideal approach is the use of selected microbial inocula that are able to degrade complex organic substrates with simultaneous biohydrogen generation. Unfortunately, even with a specifically designed starting inoculum, there is still a number of parameters, mostly with regard to the fermentation conditions, that need to be improved in order to achieve a viable, large-scale, and technologically feasible solution. In this study, statistics based factorial experimental design methods were applied to investigate the impact of various biological, physical, and chemical parameters, as well as the interactions between them on the biohydrogen production rates. RESULTS: By developing and applying a central composite experimental design strategy, the effects of the independent variables on biohydrogen production were determined. The initial pH value was shown to have the largest effect on the biohydrogen production process. High-throughput sequencing-based metagenomic assessments of microbial communities revealed a clear shift towards a Clostridium sp.-dominated environment, as the responses of the variables investigated were maximized towards the highest H2-producing potential. Mass spectrometry analysis suggested that the microbial consortium largely followed hydrogen-generating metabolic pathways, with the simultaneous degradation of complex organic compounds, and thus also performed a biological treatment of the beer brewing industry wastewater used as a fermentation substrate. CONCLUSIONS: Therefore, we have developed a complex optimization strategy for batch-mode biohydrogen production using a defined microbial consortium as the starting inoculum and beer brewery wastewater as the fermentation substrate. These results have the potential to bring us closer to an optimized, industrial-scale system which will serve the dual purpose of wastewater pre-treatment and concomitant biohydrogen production. PMID- 25278997 TI - Lessons from aviation safety: "plan your operation - and operate your plan!". PMID- 25278998 TI - Cardiac autonomic responses induced by a single bout of exercise with flexible pole. AB - BACKGROUND: Flexible poles are tools used to provide rapid eccentric and concentric muscle contractions. It lacks in the literature studies that analyze acute cardiovascular responses in different exercises performed with this instrument. It was investigated the acute effects of exercise with flexible poles on heart period in healthy women. METHODS: The study was performed on 32 women between 18 and 25 years old. It was evaluated the heart rate variability (HRV) in the time (SDNN, RMSSD and pNN50) and frequency domain (HF, LF and LF/HF ratio). The subjects remained at rest for 10 minutes. After the rest period, the volunteers performed the exercises with the flexible poles. Immediately after the exercise protocol, the volunteers remained seated at rest for 60 minutes and HRV were analyzed. RESULTS: It was observed no significance changes in the time domain (SDNN: p = 0.14; RMSSD: p = 0.8 and pNN50: p = 0.86) and frequency domain indices (LF (nu): 0.4; LF (ms(2)): p = 0.34; HF (nu): p = 0.4; HF (ms(2)): p = 0.8 and LF/HF ratio: p = 0.3) between before and after single bout of exercise with flexible pole. CONCLUSION: A single bout of exercise with flexible pole did not significantly change cardiac autonomic regulation in healthy women. PMID- 25278999 TI - Association of type IV spinal muscular atrophy (SMA) with myoclonic epilepsy within a single family. AB - BACKGROUND: Spinal muscular atrophies (SMAs) are a group of disorders characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. It is transmitted by autosomal recessive inheritance and most of these conditions are linked to SMN gene. Even if the clinical picture is mainly dominated by the diffuse muscular atrophy, some patients can also show atypical clinical features such as myoclonic epilepsy ("SMA plus"), which may be related to other genes. In particular, the association of SMA and progressive myoclonic epilepsy (PME) has been previously described. CASE PRESENTATION: We present a case of two brothers with late onset SMA associated with a unique form of non progressive myoclonic epilepsy without cognitive impairment or ataxia. They had identical clinical and electrophysiological features. CONCLUSIONS: The association of SMA with myoclonic epilepsy may constitute a separate and genetically independent syndrome with unique clinical and electrophysiological findings. Collection of similar cases with genetic studies is needed to define the phenotype clearly and to identify new genes and molecular pathogenetic mechanisms involved in this condition. PMID- 25279000 TI - A novel insertion ins(18;5)(q21.1;q31.2q35.1) in acute myeloid leukemia associated with microdeletions at 5q31.2, 5q35.1q35.2 and 18q12.3q21.1 detected by oligobased array comparative genomic hybridization. AB - BACKGROUND: Nonrandom clonal chromosomal aberrations can be detected in approximately 55% of adult patients with acute myeloid leukemia (AML). Recurrent cytogenetic abnormalities play an important role in diagnosis, classification and prognosis of AML. However, several chromosomal abnormalities have not been completely determined or characterized, primarily because of their low incidence and limited amount of data. RESULTS: We characterized an AML patient with a novel apparently balanced insertion ins(18;5)(q21;q31.2q35.1) that was cryptic by G banding. The rearrangement was further examined by molecular cytogenetic methods and oligobased high-resolution array CGH (oaCGH) analysis. We show that an approximately 31.8 Mb large segment from chromosome 5 bands q31.2 to q35.1 has been inserted, by a direct mechanism, into chromosome 18 between bands q12.3 and q21.1. The insertion was unbalanced with concurrent submicroscopic deletions at 5q31.2 (approximately 0.37 Mb in size), 5q35.1q35.2 (approximately 1.98 Mb in size), and 18q12.3q21.1 (approximately 2.07 Mb in size). The microdeletions affect genes on 5q and 18q that have been associated with hematological malignancy and other cancers. A novel juxtaposition of the genes NPM1 and HAUS1 at 5q35.1 and 18q21.1, respectively, was detected by FISH analysis. Searching the literature and the Mitelman database revealed no previously reported ins(18;5) cases. Interestingly, however, two AML patients with translocation t(5;18)(q35;q21) encompassing the 5q35 and 18q21 breakpoint regions as detected in our present ins(18;5) patient have been reported. CONCLUSIONS: It is well known that cytogenetic abnormalities on the long arm of chromosome 5 affect hematopoiesis. However, the precise mechanism of their involvement in myeloid transformation is elusive. Our present data shed new light onto the frequent abnormalities on 5q as well as to the less frequent abnormalities observed on 18q in myeloid malignancies. In addition, we show that oaCGH analysis is a useful adjunct to revealing submicroscopic aberrations in regions of clinical importance. Reporting rare and nonrandom chromosomal abnormalities contribute to the identification of the whole spectrum of cytogenetic abnormalities in AML and their prognostic significance. PMID- 25279002 TI - Characteristics of diabetic foot ulcers in Western Sydney, Australia. AB - BACKGROUND: Australia is ranked ninth of 39 countries in the Western Pacific region most affected by diabetes. Patients with diabetes are at high risk of developing foot ulcerations that can develop into non-healing wounds. Recent studies suggest that the lifetime risk of developing a diabetic foot ulcer is as high as 25%. Few studies have reported the prevalence of, risk factors and socioeconomic status associated with, diabetic foot ulcers in Australia. The aim of this study was to evaluate the characteristics of diabetic foot ulcers in a tertiary referral outpatient hospital setting in Western Sydney, Australia. METHODS: From January-December 2011, a total of 195 outpatients with diabetes were retrospectively extracted for analysis from the Westmead Hospital's Foot Wound Clinic Registry. Data on demographics, socioeconomic status, co morbidities, foot ulcer characteristics and treatment were recorded on a standardised form. RESULTS: Demographics and physical characteristics were: 66.2% male, median age 67 years (IQR: 56-76), median body mass index (BMI) of 28 kg/m(2) (IQR: 25.2-34.1), 75.4% had peripheral neuropathy and the median postcode score for socioeconomic status was 996 (IQR: 897-1022). Diabetic foot ulcer characteristics were: median cross sectional area of 1.5 cm(2) (IQR: 0.5-7.0), median volume of 0.4 cm(3) (IQR: 0.11-3.0), 45.1% on the plantar aspect of the foot, 16.6% UT Wound Grade of 0C to 3C (with ischaemia) and 11.8% with a Grade 0D to 3D (with infection and ischaemia) and 25.6% with osteomyelitis. Five patients required an amputation: 1 major and 4 minor amputations. CONCLUSIONS: In accordance with other international studies, foot ulcers are more likely to present on the plantar surface of the foot and largely affect overweight older males with a long standing history diabetes in our outpatient hospital in Western Sydney. PMID- 25279001 TI - The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder: an explorative study. AB - BACKGROUND: Genetic contributions to major depressive disorder (MDD) are thought to result from multiple genes interacting with each other. Different procedures have been proposed to detect such interactions. Which approach is best for explaining the risk of developing disease is unclear. This study sought to elucidate the genetic interaction landscape in candidate genes for MDD by conducting a SNP-SNP interaction analysis using an exhaustive search through 3,704 SNP-markers in 1,732 cases and 1,783 controls provided from the GAIN MDD study. We used three different methods to detect interactions, two logistic regressions models (multiplicative and additive) and one data mining and machine learning (MDR) approach. RESULTS: Although none of the interaction survived correction for multiple comparisons, the results provide important information for future genetic interaction studies in complex disorders. Among the 0.5% most significant observations, none had been reported previously for risk to MDD. Within this group of interactions, less than 0.03% would have been detectable based on main effect approach or an a priori algorithm. We evaluated correlations among the three different models and conclude that all three algorithms detected the same interactions to a low degree. Although the top interactions had a surprisingly large effect size for MDD (e.g. additive dominant model Puncorrected = 9.10E-9 with attributable proportion (AP) value = 0.58 and multiplicative recessive model with Puncorrected = 6.95E-5 with odds ratio (OR estimated from beta3) value = 4.99) the area under the curve (AUC) estimates were low (< 0.54). Moreover, the population attributable fraction (PAF) estimates were also low (< 0.15). CONCLUSIONS: We conclude that the top interactions on their own did not explain much of the genetic variance of MDD. The different statistical interaction methods we used in the present study did not identify the same pairs of interacting markers. Genetic interaction studies may uncover previously unsuspected effects that could provide novel insights into MDD risk, but much larger sample sizes are needed before this strategy can be powerfully applied. PMID- 25279003 TI - Does flip-flop style footwear modify ankle biomechanics and foot loading patterns? AB - BACKGROUND: Flip-flops are an item of footwear, which are rubber and loosely secured across the dorsal fore-foot. These are popular in warm climates; however are widely criticised for being detrimental to foot health and potentially modifying walking gait. Contemporary alternatives exist including FitFlop, which has a wider strap positioned closer to the ankle and a thicker, ergonomic, multi density midsole. Therefore the current study investigated gait modifications when wearing flip-flop style footwear compared to barefoot walking. Additionally walking in a flip-flop was compared to that FitFlop alternative. METHODS: Testing was undertaken on 40 participants (20 male and 20 female, mean +/- 1 SD age 35.2 +/- 10.2 years, B.M.I 24.8 +/- 4.7 kg.m(-2)). Kinematic, kinetic and electromyographic gait parameters were collected while participants walked through a 3D capture volume over a force plate with the lower limbs defined using retro-reflective markers. Ankle angle in swing, frontal plane motion in stance and force loading rates at initial contact were compared. Statistical analysis utilised ANOVA to compare differences between experimental conditions. RESULTS: The flip-flop footwear conditions altered gait parameters when compared to barefoot. Maximum ankle dorsiflexion in swing was greater in the flip-flop (7.6 +/- 2.6 degrees , p = 0.004) and FitFlop (8.5 +/- 3.4 degrees , p < 0.001) than barefoot (6.7 +/- 2.6 degrees ). Significantly higher tibialis anterior activation was measured in terminal swing in FitFlop (32.6%, p < 0.001) and flip flop (31.2%, p < 0.001) compared to barefoot. A faster heel velocity toward the floor was evident in the FitFlop (-.326 +/- .068 m.s(-1), p < 0.001) and flip flop (-.342 +/- .074 m.s(-1), p < 0.001) compared to barefoot (-.170 +/- .065 m.s(-1)). The FitFlop reduced frontal plane ankle peak eversion during stance ( 3.5 +/- 2.2 degrees ) compared to walking in the flip-flop (-4.4 +/- 1.9 degrees , p = 0.008) and barefoot (-4.3 +/- 2.1 degrees , p = 0.032). The FitFlop more effectively attenuated impact compared to the flip-flop, reducing the maximal instantaneous loading rate by 19% (p < 0.001). CONCLUSIONS: Modifications to the sagittal plane ankle angle, frontal plane motion and characteristics of initial contact observed in barefoot walking occur in flip-flop footwear. The FitFlop may reduce risks traditionally associated with flip-flop footwear by reducing loading rate at heel strike and frontal plane motion at the ankle during stance. PMID- 25279004 TI - Genome sequencing and genomic characterization of a tigecycline-resistant Klebsiella pneumoniae strain isolated from the bile samples of a cholangiocarcinoma patient. AB - BACKGROUND: The relationship between Klebsiella pneumoniae and nosocomial and community-acquired infections is well known, and K. pneumoniae resistance to most antibiotics is increasing worldwide. In contrast, tigecycline remains active against many bacterial strains, and serves as a last resort for treating multi drug resistant bacterial infections. That tigecycline nonsusceptibility among K. pneumoniae isolates has been reported worldwide is worrying. However, the mechanisms of tigecycline resistance in K. pneumoniae are less well known. We report the genome sequence and genomic characterization of tigecycline-resistant K. pneumoniae strain 5422 isolated from the bile samples of a patient with cholangiocarcinoma. RESULTS: We sequenced the K. pneumoniae strain 5422 genome using next-generation sequencing technologies. Sequence data assembly revealed a 5,432,440-bp draft genome and 57.1% G + C content, which contained 5397 coding sequences. The genome has extensive similarity to other sequenced K. pneumoniae genomes, but also has several resistance-nodulation-cell division (RND) efflux pump genes that may be related to tigecycline resistance. CONCLUSIONS: K. pneumoniae strain 5422 is resistant to multiple antibiotics. The genome sequence of the isolate and comparative analysis with other K. pneumoniae strains presented in this paper are important for better understanding of K. pneumoniae multi-drug resistance. The RND efflux pump genes identified in the genome indicate the presence of an antibiotic resistance mechanism prior to antibiotics overuse. The availability of the genome sequence forms the basis for further comparative analyses and studies addressing the evolution of the K. pneumoniae drug resistance mechanism and the K. pneumoniae transcriptome. PMID- 25279005 TI - Association between Helicobacter pylori genotypes and severity of chronic gastritis, peptic ulcer disease and gastric mucosal interleukin-8 levels: Evidence from a study in the Middle East. AB - BACKGROUND: The varied clinical presentations of Helicobacter pylori (H. pylori) infection are most likely due to differences in the virulence of individual strains, which determines its ability to induce production of interleukin-8 (IL 8) in the gastric mucosa. The aim of this study was to examine association between cagA, vacA-s1 and vacA-s2 genotypes of H. pylori and severity of chronic gastritis and presence of peptic ulcer disease (PUD), and to correlate these with IL-8 levels in the gastric mucosa. METHODS: Gastric mucosal biopsies were obtained from patients during esophagogastroduodenoscopy. The severity of chronic gastritis was documented using the updated Sydney system. H. pylori cagA and vacA genotypes were detected by PCR. The IL-8 levels in the gastric mucosa were measured by ELISA. RESULTS: H. pylori cagA and/or vacA genotypes were detected in 99 patients (mean age 38.4+/-12.9; 72 males), of whom 52.5% were positive for cagA, 44.4% for vacA-s1 and 39.4% for vacA-s2; and 70.7% patients had PUD. The severity of inflammation in gastric mucosa was increased with vacA-s1 (p=0.017) and decreased with vacA-s2 (p=0.025), while cagA had no association. The degree of neutrophil activity was not associated with either cagA or vacA-s1, while vacA s2 was significantly associated with decreased neutrophil activity (p=0.027). PUD was significantly increased in patients with cagA (p=0.002) and vacA-s1 (p=0.031), and decreased in those with vacA-s2 (p=0.011). The level of IL-8 was significantly increased in patients with cagA (p=0.011) and vacA-s1 (p=0.024), and lower with vacA-s2 (p=0.004). Higher levels of IL-8 were also found in patients with a more severe chronic inflammation (p=0.001), neutrophil activity (p=0.007) and those with PUD (p=0.001). CONCLUSIONS: Presence of vacA-s1 genotype of H. pylori is associated with more severe chronic inflammation and higher levels of IL-8 in the gastric mucosa, as well as higher frequency of PUD. Patients with vacA-s2 have less severe gastritis, lower levels of IL-8, and lower rates of PUD. The presence of cagA genotype is not associated with the severity of gastritis or IL-8 induction in the gastric mucosa. The association of cagA with PUD may be a reflection of its presence with vacA-s1 genotype. PMID- 25279006 TI - Atorvastatin inhibits the expression of RAGE induced by advanced glycation end products on aortas in healthy Sprague-Dawley rats. AB - BACKGROUND: Atorvastatin can downregulate the expression of receptor for advanced glycation end products (RAGE) in the aortas of diabetic rats. However, its effect on healthy rats remains unclear. The aim of this study was to observe the direct impact of atorvastatin on advanced glycation end products- (AGEs) induced RAGE expression in healthy Sprague Dawley (SD) rats. METHODS: SD rats received AGE-BSA (20 mg/kg/day or 40 mg/kg/day), dual treatment (AGE-BSA 40 mg/kg/day and atorvastatin 20 mg/kg/day) or no treatment for 12 and 24 weeks, respectively. The deposition of AGEs and expression of RAGE in the animals' aortas were assessed by Quantitative RT-PCR, immunohistochemistry, and western-blot tests. Serum levels of AGEs were measured using ELISA. RESULTS: AGE-BSA upregulated the serum level of AGEs, deposition of AGEs, and expression of RAGE in aortas in a time- and dose dependent way that can accelerate the development and progression of atherosclerosis. These upregulations could be significantly attenuated by atorvastatin in the absence of its lipid-lowering effects. These data provide further evidence for the novo mechanism of atorvastatin's pleiotropic effect. CONCLUSION: Atorvastatin has a direct inhibitory effect on AGEs-RAGE expression in healthy SD rats. These potential pleiotropic vasculoprotective effects are independent of effects on glucose and lipid control. PMID- 25279007 TI - NK/T cell lymphoma with inverted papilloma: A rare coexistence. AB - Natural killer/T-cell (NK/T) lymphomas are an infrequent tumour type of NK and NK T cells commonly occurring in the upper aero-digestive tract. Most reported cases in the literature are random solitary cases of NK/T-cell lymphoma. A 35-year-old male farmer from Sikkim reported to our institution with NK/T-cell lymphoma (nasal type) with coexistent inverted papilloma of the nose. This case is being reported due to the unique and unusual simultaneous occurrence of these two tumour entities. PMID- 25279008 TI - Factors associated with non-attendance in a general practice super clinic population in regional Australia: A retrospective cohort study. AB - BACKGROUND: Non-attendance at medical appointments is associated with increased patient morbidity and is a significant drain on health service resources. Australian studies have focused on secondary healthcare settings, screening, and interventions to reduce non-attendance. AIMS: To explore factors associated with non-attendance in a regional primary care setting. METHOD: A retrospective cohort of all patients with a scheduled appointment between October 2011 and October 2013 at a regional, primary care clinic providing medical and allied health services in a region of New South Wales (NSW) serving a large Aboriginal population (10.7 per cent). Using multivariate logistic regression, non attendance was regressed on a range of covariates, including number of appointments per person, gender and ethnicity, and day of the week. RESULTS: The overall proportion of missed appointments was 7.6 per cent. Risk factors for non attendance were day of the week [Mondays (8.1 per cent), Fridays (8.0 per cent), and Thursdays (7.9 per cent), (chi2(4)= 20.208, p<0.0005], having fewer scheduled appointments [<=5 appointments resulted in 19.1 per cent greater risk of failure to attend (FTA) (95% CI: 11-28%)]; Aboriginality (OR=4.022, 95% CI: 3.263, 4.956), and female gender (OR=1.077; 95% CI 1.024, 1.132). There was a trend toward an interaction between gender and Aboriginality, with Aboriginal females being the group most likely to miss appointments (OR=1.272, 95% CI: 0.949, 1.705). CONCLUSION: This is the largest study of non-attendance in an Australian primary healthcare setting. While not a typical setting, the study had the advantage of a large, mixed population. The suggested high rates of non attendance by Aboriginal females have potentially important policy implications. PMID- 25279010 TI - Paraneoplastic polyarthritis in association with metastatic neuroendocrince tumour of the adrenal gland. AB - Paraneoplastic polyarthritis is a rare manifestation described in association with various solid tumours. We describe the clinical presentation, diagnostic evaluation, differential diagnosis, and management of a 28-year-old woman who presented with fever, weight loss, and symmetrical polyarthritis, subsequently diagnosed to have a metastatic neuroendocrine tumour of the adrenal gland with paraneoplastic polyarthritis. Paraneoplastic polyarthritis must be considered in polyarthritis unexplained by common aetiologies. The unusual presentation of this case, alerts us about the atypical presentation of these tumours. To the best of our knowledge, this is the first case study of a neuroendocrine tumour presenting as paraneoplastic polyarthritis. PMID- 25279009 TI - Ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a type of nosocomial pneumonia that occurs in patients who receive mechanical ventilation (MV). According to the International Nosocomial Infection Control Consortium (INICC), the overall rate of VAP is 13.6 per 1,000 ventilator days. The incidence varies according to the patient group and hospital setting. The incidence of VAP ranges from 13-51 per 1,000 ventilation days. Early diagnosis of VAP with appropriate antibiotic therapy can reduce the emergence of resistant organisms. METHOD: The aim of this review was to provide an overview of the incidence, risk factors, aetiology, pathogenesis, treatment, and prevention of VAP. A literature search for VAP was done through the PUBMED/MEDLINE database. This review outlines VAP's risk factors, diagnostic methods, associated organisms, and treatment modalities. CONCLUSION: VAP is a common nosocomial infection associated with ventilated patients. The mortality associated with VAP is high. The organisms associated with VAP and their resistance pattern varies depending on the patient group and hospital setting. The diagnostic methods available for VAP are not universal; however, a proper infection control policy with appropriate antibiotic usage can reduce the mortality rate among ventilated patients. PMID- 25279011 TI - A win for the patient: Direct patient notification improves treatment rates of active Helicobacter pylori infection. AB - BACKGROUND: Current international guidelines recommend the commencement of effective eradication therapy as soon as active Helicobacter pylori (H. pylori) infection is confirmed. At our institution, all positive Campylobacter-like Organism (CLO) test results were automatically communicated to general practitioners (GPs) via a standardised letter, which also advised the commencement of eradication therapy. Despite this endeavour, a clinical audit conducted in 2011 demonstrated that only 66 per cent of confirmed H. pylori positive South Auckland patients received eradication treatment and only 83 per cent of these patients received treatment within one month. AIMS: Improve the timely initiation of H. pylori eradication therapy through direct patient notification. METHOD: A prospective clinical audit of 109 consecutive outpatients with a positive CLO test identified at gastroscopy. In addition to standard general practitioner notification, patients were also directly notified of their positive CLO test result via a standardised letter, which provided information about H. pylori and its disease associations as well as advising patients to seek consultation with their GP to commence eradication therapy. Dispensing data was examined using Test Safe electronic records to determine the total uptake and timing of treatment compared to data from a preliminary 2011 audit. RESULTS: Ninety-five per cent of H. pylori-positive patients received standard triple therapy; therefore, treatment of active H. pylori infection was significantly higher when patients were directly notified in addition to standard GP notification, when compared to GP notification alone (95 per cent vs 66 per cent, p<0.001). All patients who received eradication therapy did so within one month of notification, a significant improvement compared to data from the previous audit in 2011 (100 per cent vs. 83 per cent, p<0.001). CONCLUSION: Direct patient notification using a standardised letter is a simple and economical strategy that significantly improves the timely initiation of eradication therapy for active H. pylori infection. This has since been integrated into standard practice at our District Health Board (DHB). PMID- 25279012 TI - Potential cost to Western Australia of proposed patient co-payments according to healthcare organisational structure: A preliminary analysis. AB - BACKGROUND: The Australian federal government has proposed an AUD $7 patient co payment for a general practitioner (GP) consultation. One effect of the co payment may be that patients will seek assistance at public hospital emergency departments (EDs), where currently there is no user charge. AIMS: We studied the possible financial impact of patient diversion on the Western Australia (WA) health budget. METHOD: We constructed a spreadsheet model of changes in annual cash flows including the co-payment, GP fees for service, and rates of diversion to emergency departments with additional marginal costs for ED attendance. RESULTS: Changes in WA cash flows are the aggregate of marginal ED costs of treating diverted patients and added expenditure in fees paid to rural doctors who also man local emergency centres. The estimated costs to WA are AUD $6.3 million, $35.9 million and $87.4 million at 1, 5, and 10 per cent diversion, respectively. Commonwealth receipts increase and expenditure on Medicare benefits declines. CONCLUSION: A diversion of patients from GP surgeries to ED in WA caused by the co-payment will result in increased costs to the state, which may be substantial, and will reduce net costs to the Commonwealth. PMID- 25279013 TI - Genomic medicine and the future of physiotherapy. PMID- 25279014 TI - Pre-pulse inhibition and antisaccade performance indicate impaired attention modulation of cognitive inhibition in 22q11.2 deletion syndrome (22q11DS). AB - BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is associated with a number of physical anomalies and neuropsychological deficits including impairments in executive and sensorimotor function. It is estimated that 25% of children with 22q11DS will develop schizophrenia and other psychotic disorders later in life. Evidence of genetic transmission of information processing deficits in schizophrenia suggests performance in 22q11DS individuals will enhance understanding of the neurobiological and genetic substrates associated with information processing. In this report, we examine information processing in 22q11DS using measures of startle eyeblink modification and antisaccade inhibition to explore similarities with schizophrenia and associations with neurocognitive performance. METHODS: Startle modification (passive and active tasks; 120- and 480-ms pre-pulse intervals) and antisaccade inhibition were measured in 25 individuals with genetically confirmed 22q11DS and 30 healthy control subjects. RESULTS: Individuals with 22q11DS exhibited increased antisaccade error as well as some evidence (trend-level effect) of impaired sensorimotor gating during the active condition, suggesting a dysfunction in controlled attentional processing, rather than a pre-attentive dysfunction using this paradigm. CONCLUSIONS: The findings from the present study show similarities with previous studies in clinical populations associated with 22q11DS such as schizophrenia that may indicate shared dysfunction of inhibition pathways in these groups. PMID- 25279015 TI - Macular retinal and choroidal thickness in unilateral relentless placoid chorioretinitis analyzed by swept-source optical coherence tomography. AB - BACKGROUND: The purpose of this study is to evaluate the retinal and choroidal thickness of the macular region in patients with unilateral relentless placoid chorioretinitis (RPC) and macular involvement. Patients diagnosed with RPC affecting only one eye underwent a comprehensive ophthalmologic examination including best-corrected visual acuity (BCVA), axial length (AL) measurement, slit-lamp examination, and color fundus and autofluorescence photography. The macular region was scanned by swept-source optical coherence tomography in the 1,050-nm wavelength. Automated segmentations of the retina and the choroid were used to obtain the corresponding thickness values. RESULTS: A total number of three patients (two men and one woman; age range 17 to 62 years) were included. Eyes with clinically evident RPC had a mean AL of 24.62 +/- 0.11 mm, whereas in the clinically healthy fellow eyes, the mean AL was 24.65 +/- 0.03 (p = 0.70). The mean BCVA was 0.93 +/- 0.16 in eyes with RPC, and 1.0 in all the fellow eyes (p = 0.70). Slit-lamp examination did not reveal any sign of vitreous inflammation in any cases. The mean macular retinal thickness was 288.10 +/- 10.22 MUm in eyes with RPC, and 300.30 +/- 7.17 MUm in the healthy fellow eyes (p = 0.20). The mean central choroidal thickness was 260.70 +/- 140.60 MUm in eyes with RPC, and 262.30 +/- 123.10 MUm in the fellow eyes (p = 0.99). The mean macular choroidal thickness was 248.60 +/- 128.40 and 255.10 +/- 123.60 MUm, respectively (p = 0.99). CONCLUSIONS: The pathogenesis of RPC remains unknown. No changes in the retinal and choroidal thickness were observed in the macular area of eyes diagnosed with RPC with macular involvement compared with the asymptomatic healthy fellow eyes. Further prospective studies are warranted in order to investigate the role of the choroid in cases of RPC. PMID- 25279016 TI - Impact of 3 Common ABCA1 Gene Polymorphisms on Optimal vs Non-Optimal Lipid Profile in Greek Young Nurses. AB - OBJECTIVE: This study is in line with two previous ones from our group. They evaluated the influence of ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms [such as rs2230806 (R219K), rs2230808 (R1587K) and rs4149313 (I883M)] on the human lipid profile (defined as Optimal and Non-Optimal). METHODS: The present study included 447 unrelated young women and men self reported as being healthy and that attended the University of Nursing of Technological and Educational Institution. All subjects were genotyped and the ABCA1 polymorphisms (R219K, R1587K and I883M) were recorded. According to lipid profile [total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C)] the subjects were separated into those with optimal lipid profile (Optimal Group, n=209) and Non-Optimal Group (n=238). RESULTS: No statistical differences were observed in the distribution of R219K, R1587K and I883M polymorphisms according to the lipid profile (p>0.05 in all cases). No statistical differences were observed in the distribution of R219K, R1587K and I883M polymorphisms according to sex (p>0.05 in all cases). However, Logistic Regression revealed that subjects with RK (R1587K polymorphism) genotype had 69% increased risk on average of having LDL-C above normal limits as compared with those with RR genotype. Similarly, subjects with K allele (R1587K polymorphism) had 59% increased risk on average of having LDL-C above normal limits compared with those with R allele. CONCLUSION: These findings suggest that R1587K polymorphism of ABCA1 gene may influence the lipid profile. However, this needs to be confirmed by larger studies. PMID- 25279018 TI - Serum Adenosine Deaminase Level is High But Not Related with Disease Activity Parameters in Patients with Rheumatoid Arthritis. AB - Serum adenosine deaminase (ADA) has been previously proposed to predict disease activity in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the level of serum ADA, and the relationship between ADA and disease activity markers, in a group of patients with RA. A hundred and 10 patients with a diagnosis of RA were recruited from outpatient clinic of Rheumatology Unit. Demographic properties comprising age, gender, disease duration and drugs were recorded. Disease activity based on disease activity score (DAS)28-erythrocyte sedimentation rate (ESR) and DAS28- C reactive protein (CRP,) ESR, CRP levels, as well as pain by visual analog scale and rheumatoid factor (RF) were recorded. Serum ADA levels (IU/L) were determined in all RA patients and in 55 age and sex similar healthy control subjects. Ninety-six female and 14 male RA patients with a mean age of 54.32+/-11.51, and with a mean disease duration of 11.5+/-9.13 years were included to the study. The control group comprised of 48 female and 7 male healthy subjects. 35.5% of the patients were on methotrexate (MTX) and 64.5% of patients were on combined DMARDs or combined MTX and anti-TNF therapies. The mean serum ADA level was statistically higher in RA patients than in control subjects (27.01+/-10.6 IU/L vs 21.8 +/-9.9 IU/L). The mean values of ESR (23.2+/ 14.8 mm/h), CRP (1.71+/-1.11mg/dL), pain by VAS (37.2+/-27.1), DAS28-ESR (2.72+/ 0.77), DAS28 CRP (1.37+/-0.5) were not correlated with ADA levels (p>0.05). Our results have shown that serum ADA levels are higher in RA patients than in controls but were not related with any of the disease activity markers. We conclude that ADA in the serum may not be a reliable biochemical marker to predict disease activity in patients with RA. PMID- 25279017 TI - The Use of MALDI-TOF Mass Spectrometry, Ribotyping and Phenotypic Tests to Identify Lactic Acid Bacteria from Fermented Cereal Foods in Abidjan (Cote d'Ivoire). AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) protein analysis, automated ribotyping, and phenotypic tests (e.g., cell morphology, gas production from glucose, growth and acid production on homofermemtative-heterofermentative differential (HHD) agar medium, sugar fermentation patterns) were used to identify 23 lactic acid bacteria (LAB) isolated from fermented cereal foods available in Abidjan, Cote d'Ivoire. Pediococcus acidilactici (56.5%), Lactobacillus fermentum (30.4%), L. salivarius (4.3%), P. pentosaceus (4.3%) and L. plantarum subsp. plantarum (4.3%) were the species and subspecies identified. Protein based identification was confirmed by automated ribotyping for selected isolates and was similar to that provided by the phenotypic characterization. MALDI-TOF MS protein analysis provided a high level of discrimination among the isolates and could be used for the rapid screening of LAB starter cultures. PMID- 25279019 TI - Reverse Total Shoulder Replacement with Minimal ACJ Excision Arthroplasty for Management of Massive ACJ Cyst - A Case Report. AB - Massive acromioclavicular joint (ACJ) cysts are an extremely rare cause of shoulder impairment and with limited consensus in its management. We present the first published case report of a patient with a massive ACJ cyst treated with a reverse total shoulder replacement with minimal ACJ excision arthroplasty. PMID- 25279020 TI - Intraocular lens subluxation in marfan syndrome. AB - PURPOSE: Ectopia lentis (EL) is a major criteria for the diagnosis of Marfan syndrome, it may vary from an asymptomatic mild displacement to a significant subluxation that places the equator of the lens in the pupillary axis. The purpose of this work is to present the case of a patient with Marfan syndrome who received treatment for subluxation at our institution. CASE REPORT: A 51-year-old female diagnosed with Marfan syndrome presented to the emergency department with bilateral eye redness, foreign body sensation and crusting around the eyes on awakening. She had the following history of cardiac and ophthalmologic complications, including: 1. Lens subluxation 2. High myopia 3. Aortic root dilation, 4. Mitral valve prolapse and 5. Tricuspid insufficiency. CONCLUSION: The ophthalmological management of Marfan patients is challenging and periodical follow-up is needed. Surgical versus conservative management is controversial, each case needs to be evaluated individually to analyze the risks and benefits of the procedures. PMID- 25279021 TI - A framework for integration of heterogeneous medical imaging networks. AB - Medical imaging is increasing its importance in matters of medical diagnosis and in treatment support. Much is due to computers that have revolutionized medical imaging not only in acquisition process but also in the way it is visualized, stored, exchanged and managed. Picture Archiving and Communication Systems (PACS) is an example of how medical imaging takes advantage of computers. To solve problems of interoperability of PACS and medical imaging equipment, the Digital Imaging and Communications in Medicine (DICOM) standard was defined and widely implemented in current solutions. More recently, the need to exchange medical data between distinct institutions resulted in Integrating the Healthcare Enterprise (IHE) initiative that contains a content profile especially conceived for medical imaging exchange: Cross Enterprise Document Sharing for imaging (XDS i). Moreover, due to application requirements, many solutions developed private networks to support their services. For instance, some applications support enhanced query and retrieve over DICOM objects metadata. This paper proposes anintegration framework to medical imaging networks that provides protocols interoperability and data federation services. It is an extensible plugin system that supports standard approaches (DICOM and XDS-I), but is also capable of supporting private protocols. The framework is being used in the Dicoogle Open Source PACS. PMID- 25279022 TI - Creating Statistically Literate Global Citizens: The Use of IPUMS-International Integrated Census Microdata in Teaching. AB - Census microdata are ideal for developing statistical literacy of university students. Access, particularly to internationally comparable microdata, has been a significant obstacle. The IPUMS-International project offers a uniform solution to providing access for policy analysts, researchers, and students to integrated microdata and metadata, while protecting statistical confidentiality. Eighty-five official statistical agencies have endorsed IPUMS-I dissemination principles and entrusted microdata for 249 censuses to the project. From June 2010, 159 integrated samples, representing 55 countries and totaling over 325 million person records, are available at no cost to researchers and their students. The database is being expanded with the addition of samples for 5-10 countries per year as well as samples for the 2010 round of censuses. This paper illustrates two approaches to using IPUMS-I census microdata in the university curriculum to promote statistical literacy among undergraduates. PMID- 25279024 TI - The evaluability bias in charitable giving: Saving administration costs or saving lives? AB - We describe the "evaluability bias": the tendency to weight the importance of an attribute in proportion to its ease of evaluation. We propose that the evaluability bias influences decision making in the context of charitable giving: people tend to have a strong preference for charities with low overhead ratios (lower administrative expenses) but not for charities with high cost effectiveness (greater number of saved lives per dollar), because the former attribute is easier to evaluate than the latter. In line with this hypothesis, we report the results of four studies showing that, when presented with a single charity, people are willing to donate more to a charity with low overhead ratio, regardless of cost-effectiveness. However, when people are presented with two charities simultaneously-thereby enabling comparative evaluation-they base their donation behavior on cost-effectiveness (Study 1). This suggests that people primarily value cost-effectiveness but manifest the evaluability bias in cases where they find it difficult to evaluate. However, people seem also to value a low overhead ratio for its own sake (Study 2). The evaluability bias effect applies to charities of different domains (Study 3). We also show that overhead ratio is easier to evaluate when its presentation format is a ratio, suggesting an inherent reference point that allows meaningful interpretation (Study 4). PMID- 25279023 TI - Covered stent-graft treatment of a postoperative common carotid artery pseudoaneurysm. AB - BACKGROUND: Extracranial carotid artery pseudoaneurysms are rare cases resulting from trauma, mycotic infection, head and neck carcinomas or complications related to their treatment. Trauma is the most common cause of carotid artery pseudoaneurysms. They can also present after surgery, most commonly following endarterectomy, which is a rare cause with an estimated incidence of 0.3-0.6%. CASE REPORT: A 26-year-old male patient was admitted with swelling in his left neck after left carotid endarterectomy. Angiography confirmed pseudoaneursym in the left carotid bulb and it was treated successfully with two heparin-bonded covered stent grafts. CONCLUSIONS: Endovascular treatment of carotid pseudoaneurysms with covered stent-grafts is a safe and efficient method providing definitive arterial reconstruction. But series with longer follow-up periods are needed to evaluate patient compatibility to lifelong antiplatelet theraphy. PMID- 25279025 TI - Amputee Subject Testing Protocol, Results, and Analysis of a Powered Transtibial Prosthetic Device. AB - A powered ankle-foot prothesis and its control system were previously designed and built. To evaluate this prosthesis, amputee subject testing was performed. The testing results are analyzed and compared between the powered prosthesis, passive prosthesis, and able-bodied gait. Qualitative comparison showed the prosthesis achieved the design objectives. During stance phase, active ankle moment was generated in the powered prosthesis before push-off to help the amputee walk more naturally. During swing phase, the powered prosthesis was able to move to natural position to achieve foot clearance. However, the prosthesis is slightly under powered compared with the able-bodied ankle. PMID- 25279027 TI - Factors predicting late collapse of distal radius fractures. AB - ABSTRACT: BACKGROUND: Although fractures of the distal radius are a common clinical presentation, many factors affect instability of these injuries. The aim of this study was to assess the influence of age, sex, distal radial ulnar joint injury (DRUJ), ulnar styloid fracture, and dorsal displacement in late collapse of distal radius fractures. METHODS: Three hundred twenty-nine patient fractures were measured for dorsal tilt, radial inclination and ulnar variance after reduction and 2 months later. Reduction loss was analysed statistically against variables like DRUJ involvement, ulnar styloid fractures, age, sex, and AO classification. RESULTS: After two months there was loss of reduction in 171(51.9%) cases. Loss of reduction was related to age, AO classification, involvement of DRUJ, ulnar styloid fractures and initial displacement. CONCLUSIONS: Factors such as age, associated DRUJ injury, ulnar styloid fracture are predictive of loss of reduction. Knowing these predictor factors, can aid in decision regarding treatment methods. KEY WORDS: Distal Radius Fracture, Radial Tilt, Ulnar Variance, Volar Tilt, Ulnar Styloid Fracture, DRUJ. PMID- 25279026 TI - Rice and cold stress: methods for its evaluation and summary of cold tolerance related quantitative trait loci. AB - Cold stress adversely affects rice (Oryza sativa L.) growth and productivity, and has so far determined its geographical distribution. Dissecting cold stress mediated physiological changes and understanding their genetic causes will facilitate the breeding of rice for cold tolerance. Here, we review recent progress in research on cold stress-mediated physiological traits and metabolites, and indicate their roles in the cold-response network and cold tolerance evaluation. We also discuss criteria for evaluating cold tolerance and evaluate the scope and shortcomings of each application. Moreover, we summarize research on quantitative trait loci (QTL) related to cold stress at the germination, seedling, and reproductive stages that should provide useful information to accelerate progress in breeding cold-tolerant rice. PMID- 25279028 TI - Glomus tumour: a retrospective review of 15 years experience in a single institution. AB - ABSTRACT: Glomus tumours (GT), neoplasms of the glomus body comprise 4.5% of upper limb tumours. Seventy-five per cent of these occur in the hand, and most are subungual (50%). We performed a literature review and retrospective search of histopathologically confirmed GT seen from 1995 to 2009. Fifteen patients were identified, with an average age of 49.6 years. Eight were in the hand, 2 in the upper limb, 2 lower limb and 3 in the ear. Eighty-six per cent presented with pain and 50% underwent radiological investigation. Most diagnoses followed biopsy findings. Surgical excision resulted in a recurrence rate of 13%. The average time to diagnosis was 3.3 years. The average duration of symptoms was 7 to 11 years with an average of 2 to 3 consultations prediagnosis. MRI remains the most useful imaging modality (82 to 90% sensitivity). Excision biopsy is the most common treatment. Greater awareness is needed for quicker diagnosis. KEY WORDS: Glomus Tumour, Presentation, Imaging, Recurrence. PMID- 25279029 TI - Developmental dysplasia of hip screening using ortolani and barlow testing on breech delivered neonates. AB - ABSTRACT: INTRODUCTION: We conducted this study to compare the specificity and sensitivity of the Ortolani and Barlow tests performed by dedicated examiners, and to ascertain the incidence of developmental dysplasia of the hip (DDH) in breech babies. METHODS: A dedicated examiner underwent specific training and testing by a paediatric orthopaedic surgeon. Routine examiners were medical officers who had basic training in medical school and were briefly trained by their superiors. The dedicated examiner examined 170 babies. Thirty babies including 5 babies with positive tests (according to the dedicated examiner) were examined by a blinded routine examiner. RESULTS of Ortolani and Barlow tests on 30 babies were compared with ultrasound examination by blinded radiologist. RESULTS: Five babies had positive Ortolani and Barlow tests. The routine examiner did not detect positive Ortolani and Barlow tests. CONCLUSION: The incidence of positive Ortolani and Barlow tests among breech babies was 2.8%. Result of Ortolani and Barlow tests by dedicated hip screener were better than results performed by routine examiner. KEY WORDS: Ortolani and Barlow, Dedicated Examiner, Routine Examiner, Breech, Ultrasound. PMID- 25279030 TI - Giant epidermoid cyst of the thigh. AB - ABSTRACT: Epidermoid cyst is a common benign cutaneous swelling frequently encountered in surgical practice. It usually presents as a painless lump frequently occurring in hairbearing areas of the body particularly the scalp, scrotum, neck, shoulder and back. Giant epidermoid cysts commonly occur in hairy areas such as the scalp. We present here the case of a rare occurrence of a giant epidermoid cyst in the less hairy area of the right upper thigh mimicking a soft tissue sarcoma. Steps are highlighted for the management of this unusual cyst. KEY WORDS: Cystic Lesion, Epidermoid Cyst, Giant, Thigh. PMID- 25279031 TI - A technique of distal clavicle fracture fixation using the tightrope procedure. AB - ABSTRACT: We present here a technique of fracture stabilization using the Tightrope procedure in a patient with a widely displaced Neer type IIB distal clavicle fracture. The Tightrope system, typically used for stabilization of acromioclavicular joint dislocation, has not been widely described for distal clavicle fractures. The patient achieved satisfactory results after surgery; we feel that this technique is appealing as it is simple, reproducible and avoids the complications associated with extensive metalwork. This technique may also appeal to the arthroscopic surgeon. KEY WORDS: Neer Type Ii Distal Clavicle Fracture, Tightrope Procedure, Arthroscopy. PMID- 25279032 TI - Two-stage surgery for a large cervical dumbbell tumour in neurofibromatosis 1: a case report. AB - ABSTRACT: Spinal neurofibromas occur sporadically and typically occur in association with neurofibromatosis 1. Patients afflicted with neurofibromatosis 1 usually present with involvement of several nerve roots. This report describes the case of a 14- year-old child with a large intraspinal, but extradural tumour with paraspinal extension, dumbbell neurofibroma of the cervical region extending from the C2 to C4 vertebrae. The lesions were readily detected by MR imaging and were successfully resected in a two-stage surgery. The time interval between the first and second surgery was one month. We provide a brief review of the literature regarding various surgical approaches, emphasising the utility of anterior and posterior approaches. KEY WORDS: Neurofibromatosis 1, Dumbbell Neurofibroma, Spinal Tumour, Cervical Spine, Surgical Approach. PMID- 25279033 TI - Langerhans cell histiocytosis with extensive spinal and thyroid gland involvement presenting with quadriparesis: an unusual case in an adult patient. AB - ABSTRACT: Langerhans cell histiocytosis of the spine frequently presents as a solitary lesion and rarely results in neurological deficit. Involvement of thyroid tissue is also rare, even in multifocal disease presentations. We present an unusual variant of Langerhans cell histiocytosis in a 37-year-old man presenting with profound quadriparesis and incidental thyroid involvement. MR imaging and skeletal radiographs revealed widespread involvement of the spine. The patient underwent surgical resection of the tumour and stabilization of the spine. Diagnosis was confirmed by histological and immunohistochemistry analysis. Langerhans cell histiocytosis should be included in the differential diagnosis of radiolucent lesions of the spine in adults. KEY WORDS: Langerhans Cell Histiocytosis, Spine Tumours, Thyroid Mass, Cord Compression With Quadriparesis, Adult. PMID- 25279034 TI - The great mimic again? A case of tuberculosis knee. AB - ABSTRACT: Tuberculosis (TB), once a disease confined to undeveloped or developing nations is currently in resurgence due to pandemic human immunodeficiency virus infection and immigration from endemic areas. TB is also known as the 'great mimicker'. Extra-pulmonary tuberculosis affecting the knee is rare in all forms of TB (0.1-0.3%). Here, we report a case of isolated highly erosive TB knee in a previously fit Burmese migrant worker. He presented with after a history of fall into a drain. The patient also reported pain and swelling over his left knee for the previous three years. He had been treated for a bacterial infection of the knee in another hospital but defaulted due to financial constraints. Arthrotomy of the knee was performed including washout. Diagnosis of TB of the knee was made based on the synovial fluid and tissue culture. Treatment with antituberculosis drugs was then initiated. KEY WORDS: Tuberculosis Of The Knee, Extrapulmonary Tuberculosis. PMID- 25279035 TI - Comparison of outcomes of operatively treated bicondylar tibial plateau fractures by external fixation and internal fixation. AB - ABSTRACT: The outcome of bicondylar tibial plateau fractures treated with either external fixation (35 patients) or internal fixation (24 patients) was reviewed. Outcome measures included the Rasmussen score, clinical complications, development of osteoarthritis and the requirement for total knee replacement (TKR). Twenty-two (92%) anatomical reductions were achieved in the internal fixation group compared to 27 (77%) in the external fixation group. Infective complications were more common in the external fixation group (9 patients, 26%) due to pin tract infection. There were no deep infections in the internal fixation group. The mean Rasmussen score was not significantly different (mean score 32 in external fixation and 29 in internal fixation) between the two groups and the incidence of osteoarthritis was the same in both groups. Four patients in the external fixation group underwent a TKR compared to 5 patients in the internal fixation group. Bicondylar tibial plateau fractures have similar outcomes following external or internal fixation. KEY WORDS: bicondylar, tibial, plateau, external, internal, fixation, outcome. PMID- 25279036 TI - Management of intraarticular calcaneal fractures by minimally invasive sinus tarsi approach-early results. AB - ABSTRACT: The operative treatment of displaced intraarticular calcaneal fractures has been a controversial topic. Soft tissue conditions and concomitant disease must be considered in these patients. The minimally invasive sinus tarsi approach is a valid therapeutic solution that guarantees stability, anatomic reduction of the fracture and soft tissue preservation. Twenty-five closed calcaneal fractures in 20 patients were treated with open reduction and internal fixation using the sinus tarsi approach (including fixation with cannulated screws). All fractures healed by the time of final follow-up at 18 months. The time to union judged both clinically and radiographically, averaged 3 months. Mean Maryland foot scores were: 95 in type II; 91 in type III; and 83 in type IV fractures. Advantages offered by this new approach include a less invasive incision while still permitting good visualization and anatomic reduction of articular surfaces and with few complications. KEY WORDS: Intraarticular calcaneal fractures, sinus tarsi approach, Sanders classification. PMID- 25279037 TI - Minimal Invasive Plate Osteosynthesis (MIPO) Technique Using Anterolateral Approach for Treating Closed Proximal Humerus Fracture. AB - ABSTRACT: Proximal humerus fracture is the second most common fracture of the upper extremity and presents several unique problems such as anatomical complexity, high risk of avascular necrosis, minimal bone stock for purchase, significant morbidity, and lack of a universally accepted treatment. Recent treatments for proximal humerus fractures include use of minimally invasive plate osteosynthysis (MIPO). The aim of this cross-sectional study was to evaluate the outcomes of our less invasive technique using a modified anterolateral approach for treatment of proximal humerus fractures. Ten such operative procedures were performed in patients of varying age and with varied mechanism of injury from 2002-2011. All cases were conducted in an acute setting. There were no cases of infection and the functional outcome scores were good. This approach represents an alternative treatment for closed proximal humerus fracture but more extensive studies are needed. KEY WORDS: Proximal humerus fracture, MIPO, less invasive,anterolateral approach. PMID- 25279038 TI - Minimal Invasive Plate Osteosynthesis (MIPO) Technique Using Anterolateral Approach for Treating Closed Proximal Humerus Fracture. AB - ABSTRACT: AIM: To analyse the early complications following the use of PFN in subtrochanteric fractures. BACKGROUND: Osteosynthesis with PFN in subtrochanteric fracture features the advantages of high rotational stability of the head-neck fragment, an unreamed implantation technique and the possibility of static or dynamic distal locking. However, the use of the nail requires technical expertise and is accompanied by some risks of error which can lead to osteosynthesis failure. METHODS: Between May 2009 and May 2011, 50 consecutive patients with PFN fixations for subtrochanteric fractures were observed for intraoperative and postoperative complications. RESULTS: We identified intraoperative technical difficulties in four patients and six patients showed postoperative complications. CONCLUSION: When subtrochanteric fractures are to be stabilised with a PFN, the precise and expert technical performance of implantation is the basic surgical requirement. Good reduction with minimal dissection and the use of an appropriate implant is necessary to avoid treatment failure. KEY WORDS: Subtrochanteric fractures, trochanteric fractures, proximal femoral nail, PFN. PMID- 25279039 TI - Outcome of cloverleaf locking plate fixation for femoral neck fractures in young adults. AB - ABSTRACT: Femoral neck fractures in young adults remain a major problem in orthopaedics. Although treatments using cannulated screws and sliding hip screws are widely accepted, they pose significant clinical challenges. In the present study, we evaluated the outcome of treatment using cloverleaf locking plate fixation (augmented with the addition of addition of nonvascularised autologous bone grafts for neglected fracture). Fourteen patients were investigated in this cross-sectional study. Union times and Harris hip scores were analysed by independent T-test based on displacement (displaced vs. nondisplaced) and type (acute vs. neglected) of fracture. No difference in union time was found between acute and neglected groups and between nondisplaced and displaced fractures. Harris hip scores were similar between acute and neglected groups and between non and displaced group. Cloverleaf locking plate fixation is a viable alternative method for stable fixation of femoral neck fractures in young adults. KEY WORDS: Femoral neck fracture, young adult, cloverleaf locking plate, Harris hip score, union rate. PMID- 25279040 TI - Performance of Osteoporosis Self-assessment Tool for Asian (OSTA) for Primary Osteoporosis in Post-menopausal Malay Women. AB - ABSTRACT: The Osteoporosis Self-Assessment Tool for Asians (OSTA) score has been developed to identify women at risk of osteoporosis. It can be used as a screening tool for patients at risk who would benefit from bone mineral density measurement and treatment. It was developed based on data from eight countries including Malaysia. However, most subjects were of Chinese (59%). This study evaluated the performance of OSTA among 152 post-menopausal Malay women. OSTA score calculation and DEXA scan were performed. Our results showed that the OSTA score is a good predictor of patients at risk of osteoporosis based on BMD measurements at the proximal femur. Instrument sensitivity was 87.5%, specificity was 95.8%, positive predictive value (PPV) was 0.538, negative predictive value (NPV) was 0.993, and the area under the receiver operating characteristic curve (ROC) was 0.895. We conclude that use of the OSTA score in postmenopausal Malay women is effective and has adequate sensitivity and specificity. KEY WORDS: Osteoporosis; post menopause; Malay; screening; OSTA. PMID- 25279041 TI - Open anterior hip dislocation in a young adult with exposed femoral head and no neurovascular damage. AB - ABSTRACT: Anterior hip dislocation is common in younger adults and is the result of severe, high energy trauma such as high-velocity motor vehicle accidents or falls from great heights. A similar mechanism of injury would cause a femur neck fracture in older patients. Of these, open anterior hip dislocations are extremely rare and are usually associated with other soft tissue and bony injuries. We report a case of an open anterior hip dislocation with normal neurovascular status in a third world setting. KEY WORDS: trauma, open anterior, dislocation, hip, femoral head, osteonecrosis. PMID- 25279042 TI - Ipsilateral shoulder and elbow dislocation: a case report. AB - ABSTRACT: Simultaneous ipsilateral shoulder and elbow joint dislocation is a rare injury. In most reported cases, shoulder joint dislocation was missed and diagnosed at a later time. We present the case of a 30-year-old male who dislocated his ipsilateral shoulder and elbow joint following a motor vehicle accident. Keeping a high index of suspicion, radiographs of both joints were obtained. Under general anaesthesia, the elbow joint was reduced before the shoulder joint. In the final follow up after 1.5 years, the patient had returned to his occupation and enjoyed a full range of motion. The purpose of this report is to describe a very rare injury and to emphasise the importance of maintaining a high index of suspicion in such cases. KEY WORDS: Dislocation, shoulder, elbow, ipsilateral. PMID- 25279043 TI - Simultaneous double interphalangeal joints dislocation in a finger in a teenager. AB - ABSTRACT: The English literature reports a mere handful of cases involving simultaneous dislocation of two joints in the same finger. To our knowledge, all cases reported to date have been in skeletally mature individuals. We report a case of simultaneous proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints dislocations in one finger in a 14-year-old rugby player, managed by closed reduction and early mobilization, with excellent outcome. KEY WORDS: Proximal interphalangeal joint, Distal interphalangeal joint, Dislocation, Skeletally immature. PMID- 25279044 TI - Intraosseous synovial sarcoma of the proximal femur: Case report. AB - ABSTRACT: Synovial sarcoma is primarily a soft tissue malignancy that most often affects adolescents and young adults. It very rarely presents as a primary bone tumour and has only been reported in nine other cases to date. We report a case of primary synovial sarcoma arising from the proximal femur in a 57-year-old man. KEY WORDS: Synovial sarcoma, primary bone tumour. PMID- 25279045 TI - Soft Tissue Osteochondroma in Elbow Joint: A case report. AB - ABSTRACT: A case of histopathologically verified soft tissue osteochondroma of the elbow joint is presented along with clinical and radiographic findings. The unique feature of this case is that the joint capsule was intact and the tumour was entirely extra-articular. A diagnosis of extraskeletal osteochondroma should be considered when a discrete ossified mass is localized in the soft tissue. Excision and biopsy were performed with complete resolution of the symptoms. KEY WORDS: soft tissue tumour, chondroma, osteochondroma. PMID- 25279046 TI - Non-bacterial chronic recurrent osteomyelitis of the clavicle. AB - ABSTRACT: This report details the case of a 12-year-old girl with a painful, progressive swelling of the medial portion of the clavicle with no history of trauma or other constitutional symptoms. All laboratory investigations were normal except for an elevated erythrocyte sedimentation rate (ESR). Initial plain radiographs showed a destructive lesion with magnetic resonance imaging showing features of malignancy. Biopsies revealed osteomyelitis, but with negative bacterial cultures and no evidence of malignancy. Treatment with antibiotics did not result in a favourable response. Over time, the swelling increased in size with episodic exacerbations of pain. Follow-up radiographs showed sclerosis and hyperostosis. After five years, this was recognized as non-bacterial chronic recurrent osteomyelitis of the clavicle. KEY WORDS: Nonbacterial, chronic recurrent, osteomyelitis, clavicle. PMID- 25279047 TI - The efficacy of flavonoid antioxidant from chocolate: bean extract: prevention of myocyte damage caused by reperfusion injury in predominantly anaerobic sports. AB - ABSTRACT: Background : Use of predominantly anaerobic energy systems such as that seen in 800-meter athlete runners disrupts mitochondrial function as an energy source. Furthermore, it produces free radical substances and causes myocyte damage. Malondialdehyde (MDA) plasma concentrations correlate with free radical levels and are therefore predictive of cell damage. OBJECTIVE: To analyse the effect of flavonoid antioxidant from chocolate bean extract for prevention of lipid peroxidation of myocyte membranes caused by free radical substances in athletes partaking in predominantly anaerobic sports. MATERIALS AND METHODS: The study of population consisted of 16 junior athletes who compete in 800-meter races. This was a randomized experimental study. Subjects were divided into two groups, chocolate bean extracts and placebo groups, and then practiced regularly for 14 days. All subjects were assessed on day 15. RESULTS were analysed statistically using paired t test, ANOVA and Duncan tests. RESULTS: Concentrations of MDA were reduced in flavonoid group. CONCLUSION: Flavonoid antioxidant from chocolate bean extract may prevent myocyte damage was caused by reperfusion injury. PMID- 25279048 TI - Results of Closed Intramedullary Nailing using Talwarkar Square Nail in Adult Forearm Fractures. AB - ABSTRACT: The aim of the study was to evaluate results of closed intramedullary nailing using Talwarkar square nails in adult forearm fractures. We prospectively evaluated 34 patients with both bone forearm fractures. The average time to union was 12.8 (SD +3.2) weeks with cast support for a mean of 8.2 weeks. Union was achieved in 31 out of 34 patients. Using the Grace and Eversmann rating system, 17 patients were excellent, 10 were good, and 4 had an acceptable result. Three patients had non-unions, 2 for the radius and one for the ulna. There were two cases of superficial infection, one subject had olecranon bursitis, and one case of radio-ulnar synostosis. Complication rates associated with the use of square nails were lower compared to plate osteosynthesis and locked intramedullary nails. To control rotation postoperatively, there is a need for application of an above-elbow cast after nailing. KEY WORDS: Adult radius-ulna fractures, square nail, closed intramedullary nailing, radius-ulna nailing. PMID- 25279049 TI - Primary unreamed and unlocked intramedullary nailing of femoral shaft fractures. AB - ABSTRACT: In this retrospective study, we present our experience using open Kuntscher nailing (K-nailing) which is still performed in developing countries for femoral fractures. Of 157 acute fractures treated between January 2003 and December 2009, 100 were stable (63.7%) and 135 were located within the middle third of the shaft (86%). Comminution was absent or minimal in 135 (86%) cases. Fracture union was achieved at an average of 14 weeks (range, 10 - 25). The duration of follow-up was 17 months (range, 6 - 36). Final evaluation showed that 129 (82.2%) patients had a good result according to modified Kempf's criteria. The predominant complications were infection (n=5; 3.2%), nonunion (n=9; 5.5%), implant failure (n=11; 7%), and malunion (n=27; 17.3%). Open reduction and fixation with a tight fitting Knail can give good results in selected acute femoral shaft fractures but knowledge of potential complications is needed. KEY WORDS: femoral shaft fracture, Intramedullary nailing, Open reduction. PMID- 25279050 TI - Morphometric Study of the Atlas Vertebra using Manual Method. AB - ABSTRACT: The atlas (first cervical vertebra) has undergone many structural modifications. It is critically located and close to the 'life centres'. For this study, one hundred dried intact human atlas vertebrae from the Indian population were measured using a digital Vernier calliper that provides accurate resolution up to 0.01 mm. The distance between the tips of the transverse process, the outer and the inner distance between the foramen transversaria and various diameters of vertebral foramen were measured. The mean width of the measured atlases was 69.37 mm. The mean distance between the lateral margins of foramen transversaria was 55.66 mm and the inner distance was 45.93 mm. The mean thickness of vertebral artery grooves was 3.72 +/- 1.06 mm. The observations made in the present study may help in improving understanding of various bony dimensions while operating close to important structures like nerve roots and the vertebral artery. KEY WORDS: Atlas, Atypical cervical vertebra, C1, morphology. PMID- 25279051 TI - A Prospective Comparative Study of Reamed vs. Unreamed Nailing in Fractures Shaft of Tibia. AB - ABSTRACT: BACKGROUND: Although the tibia is one of the most commonly fractured long bones in the body, there are two accepted management techniques: reamed and unreamed nailing. There is not a general consensus as to which technique is more advantageous to the patient. PATIENTS AND METHODS: This was a single centre prospective randomized trial of 38 adults with a tibial shaft fracture who were treated with either reamed or unreamed nailing. RESULTS: Overall fracture healing time was 23 weeks in the reamed group and 25 weeks in the unreamed group. Differences in rate of clinical union, clinical outcome, time for weight bearing and complications in both the groups were not statistically significant. CONCLUSION: There are no clear indications or contraindications to favour either reamed or unreamed nailing over the other. Technique, fracture union, functional outcome and complications are similar in both groups. Considering the ease of technique application and the decreased operative time, unreamed interlocking nailing has an edge over reamed interlocking nailing. KEY WORDS: Reamed, unreamed, interlocking nailing, fracture shaft of tibia. PMID- 25279052 TI - Tibial torsion among filipinos: a cadaveric study. AB - ABSTRACT: Tibial torsion, the twisting of the tibia about its long axis, can affect rotational positioning in total knee replacement. This angle varies depending on the ethnicity of the subject. There are no published studies to date to determine the tibial torsion among Filipinos. In this study, 28 cadaveric limbs were examined. Our results show that the average tibial torsion among adult Filipinos is 28.9 degrees . KEY WORDS: Tibial torsion, Filipinos, cadaveric. PMID- 25279053 TI - A comparison between subvastus and midvastus approaches for staged bilateral total knee arthroplasty:a prospective, randomised study. AB - ABSTRACT: This prospective randomised study was undertaken to compare surgical parameters as well as clinical and radiological outcomes of subvastus (SV) to midvastus (MV) approaches in staged bilateral total knee arthroplasty (TKA). Twenty-three patients, aged 55-76 years, who underwent staged bilateral TKAs, were followed up for 6 months. The SV approach was used on one knee and MV approach on the other. We found similar lateral retinacular release rates and patellar resurfacing rates between the two approaches .The SV approached knees had a more significant blood loss and increased operative time compared to the MV approached knees but they achieved significantly earlier active straightleg raises (SLR) postoperatively (p<0.05 for all). The average postoperative pain, flexion, and Knee Society scores were comparable for both approaches. TKA via SV vs. MV approaches provides comparable satisfactory short-term clinical and radiological outcomes, even though there was slightly more difficulty, more blood loss and longer operative times with the SV approach. KEY WORDS: Total knee arthroplasty, Subvastus approach, Midvastus approach. PMID- 25279054 TI - Traumatic hemipelvectomy with free gluteus maximus fillet flap covers: a case report. AB - ABSTRACT: Traumatic hemipelvectomy is an uncommon and life threatening injury. We report a case of a 16-year-old boy involved in a traffic accident who presented with an almost circumferential pelvic wound with wide diastasis of the right sacroiliac joint and symphysis pubis. The injury was associated with complete avulsion of external and internal iliac vessels as well as the femoral and sciatic nerves. He also had ipsilateral open comminuted fractures of the femur and tibia. Emergency debridement and completion of amputation with preservation of the posterior gluteal flap and primary anastomosis of the inferior gluteal vessels to the internal iliac artery stump were performed. A free fillet flap was used to close the massive exposed area. KEY WORDS: traumatic hemipelvectomy, amputation, and free gluteus maximus fillet flap. PMID- 25279055 TI - Chronic osteomyelitis secondary to human bite: a case report. AB - ABSTRACT: We report a case of a human bite that was initially inadequately treated and progressed to chronic osteomyelitis, finally resulting in digital amputation. Human bites are seemingly innocuous, but if neglected, may lead to subsequent infection and morbidity. Persistence of symptoms should alert the practitioner to the possibility of infection extending to the soft tissue or bone. Bacteriological studies commonly yield mixed aerobic and anaerobic flora. Early debridement and antibiotic treatment may prevent development of severe soft tissue or bone infection. KEY WORDS: human bite, osteomyelitis, amputation. PMID- 25279056 TI - Broken Bioabsorbable Tibial Interference Screw after Anterior Cruciate Ligament (ACL) Reconstruction using a Semitendinosus-gracilis Graft: A Case Report. AB - ABSTRACT: When a patient presents with knee pain and locking after an anterior cruciate ligament (ACL) reconstruction, a new meniscal injury or an osteochondral loose body are usually considered for differential diagnosis. We present the case of a 22-year-old female with just these complaints 6 months after ACL reconstruction surgery. Magnetic resonance imaging (MRI) of the knee showed a broken screw tip which was later arthroscopically removed. At arthroscopy, an 11mm long broken bioabsorbable interference screw tip was found lying in the intercondylar notch; this resulted in a 0.5cm Outerbridge grade II chondral ulcer located at midpatella. Both menisci and cruciate ligaments were intact and no other loose bodies were found in the knee joint. KEY WORDS: ACL reconstruction, bioabsorbable interference screw, chondral ulcer. PMID- 25279057 TI - Retained intraspinal bullet: a rare case in a visitor to malaysia - a case report. AB - ABSTRACT: Firearm injuries to the spine commonly present with acute neurology caused by direct penetration or indirectly from concussive effects of bullet impact on the vertebral column. We report a case of delayed neurologic presentation of retained intra-spinal bullet in a 42 year-old African who had chronic low back pain and sciatica with a past history of gunshot injury to the spine and radiograph revealed a bullet at the L4-5 disc level. Intra-operative exploration showed a fibrous mass around the bullet compressing on the L4 existing nerve root and L5 traversing nerve root. Removal of the retained bullet resulted in a good clinical outcome with complete resolution of symptoms. KEY WORDS: Intra-spinal bullet, gunshot injury. PMID- 25279058 TI - A rare case of heterotopic ossification in a newborn: a case report. AB - ABSTRACT: Heterotopic ossification (HO) is the growth of bone in soft tissue, and can be broadly classified into neurogenic, genetic and traumatic causes. The pathophysiology of HO remains unknown. This disorder is extremely rare in infants and can mimic or coexist with thrombophlebitis, cellulitis or osteomyelitis. Most importantly, HO has to be differentiated from bone-forming tumours such as osteosarcoma and osteochondroma. We report a case of traumatic HO in a fiveday- old newborn following intravenous cannulation of the right wrist and left ankle, with the latter complicated with osteomyelitis. We highlight the clinical and radiological features of HO and differential diagnoses of soft tissue ossification in early childhood. KEY WORDS: Heterotopic ossification, newborn. PMID- 25279059 TI - Multifocal skeletal tuberculosis involving the lumbar spine and iliac bone, mimicking a malignant bone tumour: a case report. AB - ABSTRACT: Multifocal osteoarticular tuberculosis is uncommon and accounts for approximately10% of all cases of osteoarticular tuberculosis. Concomitant vertebral and iliac bone tuberculosis has not been reported in the literature to date. We report one such case for its unusual clinical and radiological presentation, which had presentation more similar to a malignant bone tumour than an infection. KEY WORDS: Skeletal tuberculosis, multifocal osteoarticular tuberculosis. PMID- 25279060 TI - Multiple atraumatic osteoporotic vertebral fractures in an adolescent with suprasellar germinoma: a case report. AB - ABSTRACT: We present the case of a patient with multiple atraumatic osteoporotic vertebral fractures in an adolescent with suprasellar germinoma and also review of relevant literature. The patient suffered from a rare adolescent brain tumour with common complications which are often overlooked and give rise to significant morbidity. Suprasellar germinoma is an intracranial neoplasm, that in addition to its rarity, has variable clinical presentation. Despite appropriate treatment and good outcome, tumour related morbidity is still of concern for these patients. KEY WORDS: Secondary osteoporosis, suprasellar germinoma, panhypopituitarism. PMID- 25279061 TI - Traumatic floating clavicle: a case report. AB - ABSTRACT: Shoulder girdle injuries after high energy traumatic impacts to the shoulder have been well documented. Based on the series of 1603 injuries of the shoulder girdle reported by Cave and colleagues, 85% of the dislocations were glenohumeral, 12% acromioclavicular and 3% sternoclavicular (1). Less frequently described are injuries involving both the sternoclavicular and acromioclavicular joints simultaneously in one extremity. The present report discusses a case of traumatic floating clavicle associated with ipsilateral forearm and wrist injury which was treated surgically. KEY WORDS: Floating clavicle, bipolar dislocation, sternoclavicular. PMID- 25279062 TI - Open total talus dislocation: a case report. AB - ABSTRACT: Total talus dislocation is a rare injury and is commonly accompanied by associated fractures. Common worrisome sequelae are infection, avascular necrosis and post-traumatic arthritis. We report here on a patient who sustained an open total talus dislocation with an ipsilateral medial malleolus fracture. Following early debridement, reduction and a combination of internal and external fixations, early recovery was good with no evidence of avascular necrosis. KEY WORDS: Total talus dislocation, avascular necrosis, infection, outcome. PMID- 25279063 TI - Transverse sacral fracture-dislocation with anterior displacement: a case report. AB - ABSTRACT: Transverse sacral fracture is a very rare injury and frequently missed or delayed in diagnosis. We present a case with this injury and discuss its management. KEY WORDS: Transverse, sacral fracture- dislocation, displacement. PMID- 25279064 TI - A simple method for removal of the distal segment of a broken femoral intramedullary nail: a case report. AB - ABSTRACT: We report a method for removing the distal segment of a broken locked intramedullary nail secondary to nonunion of the femur following radiotherapy for fibromatosis. A Kirschner wire with one tip fashioned into a hook was used to remove the distal segment without opening with the nonunion site. Details of the procedure are described. KEY WORDS: Broken intramedullary nail, removal of distal segment. PMID- 25279065 TI - Rare Presentation of a Rare Disease (Erdheim-Chester disease): A Case Report. AB - ABSTRACT: Erdheim-Chester disease (ECD) was first reported by J. Erdheim and W. Chester, in 1930. There are less than 250 reported cases till date. We report a case of ECD in a 16- year-old Malay male, who initially presented with elusive anemic symptoms with more specific symptoms of bony pain, cardiorespiratory and hepatic involvement evolving as the disease progressed. KEY WORDS: Erdheim Chester disease. PMID- 25279066 TI - Clubfoot: the treatment outcome using quantitative assessment of deformity. AB - ABSTRACT: INTRODUCTION: The recent trend in management of congenital idiopathic clubfoot tends towards conservative treatment. This study reviews the outcomes of treatment in our practice using the quantitative clubfoot assessment of the deformity (QCAD). METHODS: Thirty patients (38 cases of clubfoot) with congenital idiopathic clubfoot treated at Sarawak General Hospital were followed-up for a mean of 3.6 years. The quantitative assessment consists of limb anthropometric measurement and the Pirani deformity severity score. RESULTS: There were 15 boys and 15 girls, with a mean age of 4.4 years (range, 13m - 8y). Most patients were of the Malay race (67%), followed by Chinese (23%) and others (10%). Eight patients suffered from bilateral congenital idiopathic clubfoot (33%), 12 were left unilateral (40%) and 10 were right unilateral (27%). Out of the total of 30 patients, 12 were treated conservatively with serial casting and 18 patients were treated surgically after resistance to serial casting at the age of nine months. At follow-up, there were significant differences between the surgical group (2.57 +/- 1.45); (0.86 +/- 0.36) and conservative group (0.7 +/- 0.81); (0.34 +/- 0.35) respectively (p < 0.05) regarding the mean difference in mid-leg circumference and foot length discrepancy in patients with unilateral clubfoot. There were no significant difference noted between groups with regards to results of the Pirani score, leg length discrepancy and mean difference of mid-foot circumference. CONCLUSION: There were significant differences in calf atrophy and foot length discrepancy when comparing surgically treated clubfoot patient compared to conservatively treated patients. Conservative treatment of clubfoot is the preferred method of treatment while surgical treatment may be necessary in more resistant cases. KEY WORDS: Clubfoot, outcome, treatment, quantitative assessment, deformity. PMID- 25279067 TI - Osteoporotic compression fracture of spine treated with posterior instrumentation and transpedicular bone grafting. AB - ABSTRACT: A series of 11 patients with osteoporotic compression fracture of the spine who underwent posterior instrumentation and transpedicular bone drafting in Siriraj Hospital Bangkok was analysed retrospectively. The indications for surgery were neurological deficit, kyphotic deformity and intractable pain. The mean follow up period was 10.1 months (range, 2.1 - 25.5 months). On follow up, all patients indicated recovery from pain. Most patients (7/11) regained one Frankel grade and one patient who was Frankel grade D preoperatively remained grade D postoperatively. Daily functionality improved in nine patients, but two patients still required aid for walking and standing. There was no pedicle screw loosening, pull-out or implant breakage as of the last date of follow up. Adjacent vertebrae also did not show any fracture or reduction in height. We conclude that this operative method is acceptable for osteoporotic fracture of the spine, although a longer period of follow up is needed to further evaluate its efficacy. PMID- 25279068 TI - Pre-injury demographic patterns of patients sustaining hip fractures in malaysia. AB - ABSTRACT: INTRODUCTION: Hip fractures entail a growing economic burden on the health care system. Study is warranted to further our understanding of its patterns and to create increased awareness in health care providers and the public. MATERIALS AND METHODS: Data was extracted from the ongoing National Orthopaedic Registry of Malaysia (NORM), for the period June 2008 till December 2009. Patients aged 50 years and above without previous pathological fracture hip fractures were included in the study. RESULTS: Most hip fracture patients were 70 years and above (69.5%) with a mean (SD) age of 73.8 (10.3) years. Females represented the majority of the patients in this study (68.4%). Low energy trauma (i.e. trivial fall) was to the main mechanism of hip fractures in this study (81.3%). CONCLUSIONS: Aging adults should be made aware of timely preventive strategies (including osteoporosis prevention) fall prevention measures, and encouraged to maintain physically active lifestyles. KEY WORDS: Hip fracture, pre fracture status. PMID- 25279069 TI - Minimally invasive plate osteosynthesis in the treatment of isolated ulnar bone fractures. AB - ABSTRACT: BACKGROUND: Minimally invasive internal fixation is also called "biological internal fixation". This concept is used widely in the treatment of various fractures but to date, there have been no report about such application in the repair of isolated ulnar bone fractures. METHODS: Eleven patients with fracture of isolated ulnar bone (four AO type 22A11 and seven AO type 22A12), mean age 43.16 (range, 24- 59y), were treated using closed reduction and locking compression plate with minimally invasive plate osteosynthesis (MIPO) with the aim of minimising soft tissue damage. RESULTS: Fractures healed at an average of 7.8 weeks with good to excellent clinical outcomes. There were no complications such as nonunion, implant failure or neurovascular injuries. CONCLUSIONS: MIPO seems to be advantageous for soft tissue and bone biology. Good union was seen and fracture complications were also prevented by early mobilisation. KEY WORDS: Locking compression plate (LCP), closed reduction, isolated ulnar bone fracture, minimally invasive plate osteosynthesis (MIPO). PMID- 25279070 TI - Comparison of lateral mass screw fixation technique and hartshill rectangle technique in the treatment of sub-axial cervical spine fractures. AB - ABSTRACT: INTRODUCTION: Cervical injury in a polytrauma patient is one of the most critical injuries. The aim of this study was to compare the lateral mass screw technique with the Hartshill rectangle technique for treatment of such cases. MATERIALS AND METHODS: This prospective study consisted of 40 patients. Both groups were followed for three years clinically and radiologically. RESULTS: In the lateral mass technique, there were no cases of vertebral artery injury, radiculopathy, screw pullout, dural tears, residual kyphosis or persistent pain. In the Hartshill technique 3 patients experienced intraoperative dural tears, 1 case of wire breakage at the six months follow up, 6 patients with persistent neck pain and 1 with worsening neurological status. One hundred per cent fusion was achieved in both groups. There was significant radiation exposure in the lateral mass group. Post-operative immobilisation was required only in the Hartshill. CONCLUSION: Lateral mass screw technique is definitely a relatively better procedure. But Hartshill rectangle still stands out in certain practical situations. KEY WORDS: lateral mass, Hartshill. PMID- 25279071 TI - Outcome of calcaneoplasty in insertional achilles tendinopathy. AB - ABSTRACT: BACKGROUND: Insertional Achilles tendinopathy may be associated with Haglund's deformity and result in chronic pain. It is usually refractory to conservative management. The aim of this study was to assess the outcome of calcaneoplasty performed in our hospital. METHODS: Eight patients were prospectively evaluated pre- and postoperatively using the American Orthopaedic Foot and Ankle Society (AOFAS) Hindfoot Score, Visual Analogue Scale (VAS) and Short Form (SF) 36, as well as satisfaction rate. Average follow-up duration was 12.4 months. RESULTS: The mean pre and post-operative AOFAS scores were significantly improved at three and six months. SF 36 improved in most parameters. The postoperative VAS score improved significantly and was 0 at 2 years. The procedure was rated as good to excellent by seven of the subjects. CONCLUSION: We recommend calcaneoplasty for the treatment of insertional Achilles tendinopathy. KEY WORDS: Calcaneoplasty, Insertional Achilles tendinopathy, Haglund's deformity. PMID- 25279072 TI - Floating shoulder: ipsilateral clavicle, scapular body and glenoid fracture. A case report. AB - ABSTRACT: We present a case of shoulder instability following a traffic accident. Allman Type I midshaft clavicle, Ideberg Type II glenoid and DeCloux Type I scapular body fractures were diagnosed following radiologic examination. There were no signs of ligamentous injury. Mechanical instability was noted at the shoulder due to breakage of the supportive bony skeleton. The patient was treated surgically with plate and screw fixation. Surgical fixation allowed early postoperative physiotherapy and rehabilitation. This rare injury and its treatment options are discussed in the light of current literature. KEY WORDS: floating shoulder, scapula, clavicle, glenoid, mechanical instability. PMID- 25279073 TI - Early surgical treatment of pectoralis major tendon rupture: a case report. AB - ABSTRACT: Pectoralis major rupture is a relatively uncommon injury. It is often under- or misdiagnosed due to late presentation and the lack of obvious clinical signs. Timely diagnosis and treatment is crucial, as early surgical repair has been shown to improve functional and cosmetic outcomes. We report the case of a young patient who underwent surgical repair of a right pectoralis major rupture sustained during a fall while wakeboarding. At the one-year follow-up, he had achieved full range of right shoulder motion and returned to his previous level of sporting activities. KEY WORDS: Pectoralis major, anterior axillary fold, suture anchor. PMID- 25279074 TI - Congenital humeroradial synostosis: a case report. AB - ABSTRACT: We present here a unique case of humeroradial synostosis. These anomalies are due to longitudinal failure of differentiation. Approximately 150 cases of humeroradial synostosis have been reported worldwide, the majority of which are familial in nature or associated with syndromes. The case presented here involves an infant aged 11/2 months, born with bilateral humeroradial synostosis without familial or syndromic association. To the best of our knowledge, no such case has been reported in Asia. PMID- 25279075 TI - Management of osteonecrosis of the hip complicated with fracture: a case report. AB - ABSTRACT: A 47-year-old gentleman, with underlying seborrhoeic dermatitis that was treated with steroid therapy, and hepatitis B, presented with pain in his right hip. He was diagnosed with stage 2 osteonecrosis of the right hip (Ficat and Arlet classification). Core decompression and bone grafting was performed but recovery was complicated by a surgical site infection. Wound debridement, removal of bone graft and clearance of the bone tunnel were carried out. The patient was allowed to bear weight after surgery. Twelve days later, he developed right hip pain and radiographs showed fractured femur neck; the patient then underwent a two-stage total hip replacement (THR). KEY WORDS: Osteonecrosis, avascular necrosis, hip, core decompression, total hip replacement. PMID- 25279076 TI - SLAP Lesion with Supraglenoid Labral Cyst causing Suprascapular Nerve Compression: A case report. AB - ABSTRACT: We present a case of left suprascapular nerve palsy in a 39- year-old female secondary to compression from a large ganglion cyst. She presented with a two month history of left posterior shoulder pain which affected her work and disturbed her sleep. Clinical examination revealed a positive O'Brien's test. Supraspinatus and infraspinatus strength was mildly weakened. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a superior labral anterior to posterior (SLAP) lesion with a large supraglenoid labral cyst extending posteriorly to the spinoglenoid notch, resulting in compression of the suprascapular nerve. Arthroscopy revealed the SLAP lesion with a haemorrhagic labral cyst at the posterosuperior aspect. Arthroscopic decompression of the cyst and SLAP repair with two suture anchors was performed. At 22 months postoperative follow-up, the patient's left shoulder remained asymptomatic with full range of motion and full strength. KEY WORDS: SLAP lesion; Supraglenoid Labral Cyst; Suprascapular Nerve Compression. PMID- 25279077 TI - Long Term Results of PHILOS Plating and Percutaneous K-Wire Fixation in Proximal Humerus Fractures in The Elderly. AB - ABSTRACT: This is a report of a study on the long term results of PHILOS plating and percutaneous K-wire fixation in a prospective series of proximal humerus fractures in elderly patients. We reviewed a total of 60 patients with proximal humerus fractures in 30 patients (Group 1), who were treated by open reduction and internal fixation with Proximal Humeral Internal Locking System (PHILOS) plate and 30 patients (Group 2) who were treated with percutaneous K-wire fixation. Functional outcome was assessed using Visual Analogue Scale(VAS) and Constant-Murley Score. Mean Constant-Murley score was 84.6 points (range: 61- 100) in Group 1 and - 76.4 points(range:56-100) in Group 2 at final follow up. Values varied depending upon the fracture type with worst in 4-part fractures. Mean VAS Score was 2.6(range:0-10) in Group 1 and 3.8(range:0-10) in Group 2. We obtained satisfactory results in both the groups, with each procedure having its advantages and shortcomings. We found that PHILOS plate fixation provided stable fixation with minimal implant problems and enabled early range-ofmotion exercises to achieve acceptable functional results. Fixation with percutaneous K-wires presented an efficient treatment option with the advantages of minimal invasiveness and soft tissue dissection. KEY WORDS: Proximal humerus fractures, PHILOS plate and K-wires. PMID- 25279078 TI - Open reduction and Internal Fixation of Displaced Proximal Humerus Fractures with AO Stainless Steel T-Plate. AB - ABSTRACT: BACKGROUND: Proximal humeral fractures are considered the last unsolved fractures in orthopaedics. The treatment is controversial and various operative modalities have been reported in the literature. The aim of the present study was to evaluate functional outcome and complication rate after open reduction and internal fixation of displaced proximal humerus fractures by proximal humerus AO stainless steel T-plate. Twenty-five (25) patients with displaced proximal humerus fractures treated with proximal humerus T-plate between May 2005 and June 2008 were included in the study. Fractures were classified according to the Neer classification into displaced 2-part, 3-part, and 4-part fractures. Patients were followed-up for a minimum period of two years. Functional evaluation was done according to the Neer scoring system. Scores were compared with other studies in the literature using similar implant. Twenty patients had 2-part fracture, four had 3-part fracture, and one had 4-part fracture. Eighty-eight [88% (n = 22)] patients had good to excellent result, eight [8% (n = 2)] had fair, and four [4% (n = 1)] had poor result. Difference in Neer's score between 2-part and 3-part fractures was not significant. Complications encountered in this series were screw backout in 8% (n = 2), superficial infection in 12% (n = 3), and avascular necrosis in 4% (n = 1) of cases. We conclude that proximal humerus AO T- plate is a cheap and easily available implant, aspects which are particularly relevant in third world countries like India. It gives reliable fixation for 2-part and 3-part fractures. Its use in more complicated fracture patterns of 4-part fractures is not recommended. KEY WORDS: Proximal humerus fractures, proximal humerus stainless steel T-plate, unstable fracture. PMID- 25279079 TI - The outcomes of salvage surgery for vascular injury in the extremities: a special consideration for delayed revascularization. AB - ABSTRACT: A seven years retrospective study was performed in 45 consecutive vascular injuries in the extremities to investigate the pattern of injuries, managements and outcomes. Motor-vehicle accidents were the leading cause of injuries (80%), followed by industrial injuries (11.1%) and iatrogenic injuries (4.4%). Popliteal and brachial artery injuries were commonly involved (20%). Fifteen (33.3%) patients had fractures, dislocation or fracture dislocation around the knee joint and 6 (13.3%) patients had soft tissue injuries without fracture. Traumatic arterial transection accounted for 34 (75.6%) cases, followed by laceration in 7 (15.6%) and 9 (6.7%) contusions. Associated nerve injuries were seen in 8 (17.8 %) patients using intra-operative findings as the gold standard, both conventional angiogram (CA) and computerized tomography angiogram (CTA) had 100% specificity and 100% sensitivity in determining the site of arterial injuries. The mean ischemic time was 25.31 hours (4 - 278 hours). Thirty three (73.3 %) patients were treated more than 6 hours after injury and 6 patients underwent revascularization after 24 hours; all had good collateral circulation without distal pulses or evidence of ischemic neurological deficit. The mean ischemic time in 39 patients who underwent revascularization within 24 hours was 13.2 hours. Delayed amputation was performed in 5 patients (11.1%). Of the 6 patients who underwent delayed revascularization, one patient had early amputation, one -had delayed amputation following infection and multiple flap procedures while the rest of the patients' limbs survived. Joint stiffness was noted in 10 patients (22.2%) involving the knee joint, elbow and shoulder in two patients each. Infection was also noted in 5 patients (11.1%) with two of them were due to infected implants. Other complications encountered included nonunion (2 patients, 4.4%), delayed union (1 patient, 2.2%),limb length discrepancy (1 patient, 2.2%), hematoma (1 patient, 2.2%) and leaking anastomosis in one patient (2.2%). Volkmann's ischemic contracture occurred in 3 (6.7%) patients. There was no complication noted in 8 (17.8%) patients Three patients (6.7%) died of whom two were not due to vascular causes. We conclude that early detection and revascularization of traumatic vascular injuries is important but delayed revascularization also produced acceptable results. PMID- 25279080 TI - Correlation of psychosocial factor with functional outcome: one year after hip fracture surgery. AB - ABSTRACT: OBJECTIVE: This study investigated the correlation of 8 domains of psychosocial factors with functional outcome one year after hip fracture surgery. A prospective cohort study of patients who had unilateral hip fracture surgery was included. A total of 89 subjects were interviewed between 3rd to 7th day after the hip surgery using the short length Multi-level Assessment Instrument and followed up after 1 year. The functional outcomes were measured through the Harris Hip Score. All of the psychosocial factors have little to no correlation on the functional recovery of the patient but the cognitive domain had a fair correlation in Harris Hip Score (r=0.46) and is significant (p-value<0.0001) The study did not find strong correlation between psychosocial factors and functional outcome one year after unilateral hip surgery. Although statistics have shown little effect on psychosocial factors to functional outcome, it may still be prudent to consider every aspect that may contribute to the whole wellbeing of our patients, which includes their psychosocial background. KEY WORDS: Psychosocial Factors; Hip Fracture Outcome; Biopsychosocial; Hip Surgery; Psychosocial Background. PMID- 25279081 TI - Outcome of surgery for unstable intertrochanteric fractures in octogenarians. AB - ABSTRACT: This study aims to determine pre-morbid parameters as possible predictors of outcome of hip fracture in octogenarians with unstable intertrochanteric fracture treated operatively. Presence of co-morbidities, pre injury level of ambulation, type of surgery, and period of delay in surgery were considered, and their effect on the post-operative outcome was evaluated using the Harris Hip Score. The computed probability of survival of octogenarians who had surgery was approximately 11 months. In patients with two or more co morbidities, there is a significant effect on Harris Hip Score in terms of pain and deformity. Delay in surgery of more than two weeks significantly decreased the distance travelled at one year. The overall recovery is correlated to preinjury level of ambulation and delay in surgery. Patients with intertochanteric fracture in this age group, who have less co-morbidities and with more independent ambulation, are good candidates for timely operative treatment. PMID- 25279082 TI - Revisiting the outcome of displaced two-part fractures of the humeral neck in elderly patients after conservative treatment. AB - ABSTRACT: The aim of this study was to evaluate our experience with regard to the outcome of displaced two-part fractures of the humeral neck in elderly patients that were treated conservatively. Between July 2008 and June 2010, 53 consecutive patients (42 females and 11 males; mean age = 74; range = 60-92) with an acute, displaced, two-part fracture of the humeral neck were treated conservatively using a sling and swathe for two weeks, followed by a standard rehabilitation protocol. The inclusion criteria were a displacement of the shaft >50% of its width and/or angulation of the shaft >45 degrees on standard radiographs. The exclusion criteria were patients younger than 60 years of age and those with cognitive or systemic impairment that would preclude the recommended physiotherapy. Patients were followed-up for one year, and were assessed at 3, 6, and 12 months using the Constant- Murley Score (CMS) and the Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH). Patients were divided into two groups, those below 70 years of age and those above 70-. Two-way repeated measures analysis of variance (ANOVA) was used to determine if there were significant differences between the results at 3, 6 and 12 months for both groups, and if the results were significantly different between the two groups. Forty-eight out of 53 patients (91%) were able to complete the follow-up schedule, while five patients died. The mean CMS improved progressively at three (51.3), six (60.4), and 12 (61.3) months. The mean DASH also improved progressively at three (38.8), six (34.8), and 12 (32.6) months. For both groups, the CSS and DASH improved significantly from three to six months and from three to 12 months. However, the improvements were not significant from just six to 12 months. Between the two groups, the results at three, six, and 12 months were not significantly different from each other. On final follow-up, 42 out of 48 patients (88%) were satisfied with their outcome and reported that they would choose to undergo the same treatment if they had to do everything all over again. Conservative management of displaced two-part fractures of the humeral neck in elderly patients is a safe, efficacious, and acceptable treatment. PMID- 25279083 TI - Tuberculosis of capitate bone in a skeletally immature patient: a case report. AB - ABSTRACT: Primary Tuberculosis of wrist joint and carpal bone is rare, and when occurring it usually affects adults. We present a case of isolated tuberculosis of capitate bone; which was confirmed with intra-osseous tissue histopathological examination in a skeletally immature 12-year old boy. There was no signs of reactivation seen at follow-up 18 months after treatment. PMID- 25279084 TI - Construct Failure in an Atypical Femoral Fracture treated with Intramedullary Nailing: A Case Report. AB - ABSTRACT: The aim of this paper is to document a rare case of construct failure in a 68-year old Filipina who sustained an atypical femoral fracture (AFF) in her left subtrochanteric area. The patient previously had a 40-month history of alendronate 70mg + vitamin D 5600u therapy for osteoporosis and underwent closed intramedullary nailing for the AFF. Six months postoperatively, she began to experience progressive pain in her operated thigh. Radiographs revealed a broken nail at the proximal screw hole and non-union of the AFF. The patient was treated with exposure of the fracture site, removal of the broken device, exchange intramedullary nailing, and iliac bone grafting. She had radiographic and clinical union and was full weight bearing after three months. PMID- 25279085 TI - Displaced mid-shaft clavicle fractures: a subset for surgical treatment. AB - ABSTRACT: Recent studies have shown a high prevalence of symptomatic malunion and nonunion after nonoperative treatment of displaced midshaft clavicle fractures. We sought to study the result of surgical treatment of displaced mid-shaft fracture of clavicle. Forty mid shaft clavicle fractures in adults, displaced with initial shortening of more than 15 mm, were treated with primary internal fixation with plates. The inclusion criteria were displacement, shortening of clavicle of more than 15 mm and/or impending skin penetration. The follow-up period varied from 6 months to 24 months. Fracture union occurred in all patients (average union time 8.5 weeks). Superficial infection developed in one patient and implant was a problem in one patient. The outcome was assessed by complications, constant score and patient satisfaction questionnaire. Constant scores were excellent in the study group and 96% of the patients were satisfied with the operation. Surgical treatment in displaced fractures of the clavicle in our study produces satisfactory results. KEY WORDS: Displaced, clavicle fracture, mid shaft and plating. PMID- 25279086 TI - The Prevalence of Accidental Needle Stick Injury and their Reporting among Healthcare Workers in Orthopaedic Wards in General Hospital Melaka, Malaysia. AB - ABSTRACT: Background :Accidental needle-stick injuries (NSIs) are a hazard for health-care workers and general public health. Orthopaedic surgeons may be more prone to NSIs due to the prevalence of bone spikes in the operative field and the use of sharp orthopaedic instruments such as drills, saws and wires. A hospital based cross sectional study was conducted in the orthopedic wards of Melaka General Hospital. The prevalence of NSIs was 32 (20.9%) and majority of it occurred during assisting in operation theatre 13(37.4%). Among them six (18.8%) were specialist, 12(37.5%) medical officer, 10 (31.2%) house officer and four staff nurses (12.5%). Among the respondents 142 (92.8%) had been immunized against Hepatitis B and 148 (96.7%) participants had knowledge regarding universal precaution. The incidence of NSI among health care workers at orthopaedics ward was not any higher in comparison with the similar studies and it was found out that the prevalence was more in junior doctors compared with specialist and staff nurses and it was statistically significant. KEY WORDS: Needle sticks injury, health care workers, and standard precaution. PMID- 25279087 TI - Cannulated Screw Fixation For Femoral Neck Fractures : A 5-year Experience In A Single Institution. AB - ABSTRACT: Cannulated screw fixation is a widely accepted surgical method for management of fractures of the neck of femur especially in patients with poor premorbid conditions, minimally displaced fractures and those from a younger age group. A five year retrospective study was carried out in 53 consecutive patients between 2006 to 2010 to determine the pattern of injuries, management, outcomes and the associated predictive factors.All the patients underwent cannulated screw fixation, with 37 (69.8%) having had surgery within 24 hours and the remaining 16 (30.2%) 24 hours after the initial injury. All patients were followed up to union of fractures and complications thereafter if any. Good outcome was observed in 43 (81.1%) patients leaving only 10 (18.9%) patients with a poor outcome, of whom nine developed avascular necrosis (90%) and one non-union (10%). We found no significant relationship between the incidence of avascular necrosis and age of patient, fracture displacement, numbers of cannulated screws used, fracture reduction acceptability and anatomical location of the fracture. The time interval from injury to surgery and the presence of posterior comminution did seem to influence the rate of avascular necrosis but due to the small number of patients, was not statistically significant.We conclude that cannulated screw fixation is a viable option of treatment for fractures of the neck of femur. KEY WORDS: femoral neck fractures, screw fixation. PMID- 25279088 TI - The outcome in early cases of treatment of subtrochanteric fractures with proximal femur locking compression plate. AB - ABSTRACT: The objective of this study was to evaluate the outcome in early treatment of subtrochanteric fractures with proximal femur locking compression plate (PF-LCP).The patients included in this study were those with subtrochanteric fractures (AO type 32A-C) treated with PF-LCP (Synthes) between Jan 2009 and Jun 2011. The patient characteristics and details of clinical conditions were obtained from records. Clinical and radiographic follow-ups were done at one, two, four and 6 months intervals, and at one year. The primary outcome studied included fracture union and functional ambulatory status. Twenty six patients were included in the study, 19 of whom were male with a mean age of 42.4 years. Fourteen patients (53.9%) had sustained AO type 32B fractures, the majority in motor vehicle accidents. Twenty-two fractures (84.6%) achieved union, while sixpatients (23.1%) had complications such as broken plate, varus collapse, and broken screw. Four patients (15.4%) underwent a second operation. At the end of the follow-ups, 25 patients (96.2%) were community ambulators. We conclude that PF-LCP is an effective alternative treatment for subtrochanteric fractures when properly performed. KEY WORDS: Subtrochateric fracture, Proximal Femur Locking Compression Plate (PF-LCP), Outcome, Complication, Cerclage wire. PMID- 25279089 TI - Open Reduction and Internal Fixation of displaced Supracondylar Fractures of Humerus with Crossed K-wires via Medial Approach. AB - ABSTRACT: This study aimed at evaluating the medial approach for open reduction and internal fixation of Gartland type 3 displaced supracondylar fractures of humerus in children. A prospective, single centre study of on displaced supracondylar humerus fractures in 42 children was carried out at our institute. All fractures were managed with open reduction and internal fixation with crossed K-wires via medial approach. The mean follow-up was 12 months and patients were assessed according to Flynn's criteria. No patients had post-operative ulnar nerve injury. Cubitus varus was not seen in any patient. Superficial pin tract infection occurred in three patients that subsided with anti-septic dressings and antibiotics. No deep infection occurred. 88.09 % patients showed satisfactory results as per Flynn's criteria. The medial approach provides an excellent view of the supracondylar area. The approach is convenient due to a lower risk for ulnar nerve injury and better acceptability of the medial incisional scar. KEY WORDS: Type 3 supracondylar fracture humerus, medial approach, crossed K-wire fixation, medial column comminution. PMID- 25279090 TI - A Biomechanical Comparison between Taylor's Spatial Frame and Ilizarov External Fixator. AB - ABSTRACT: Taylor's spatial frame (TSF) and Ilizarov external fixators (IEF) are two circular external fixator commonly used to address complex deformity and fractures. There is currently no data available comparing the biomechanical properties of these two external fixators. This study looks into the mechanical characteristics of each system. TSF rings with 6 oblique struts, 4 tube connectors, 4 threaded rods, and 6 threaded rods were compared to a standard IEF rings with 4 threaded rods. Compression and torsional loading was performed to the frame as well as construct with Polyvinylchloride tubes. TSF rings with 4 tube connectors had the highest stiffness (3288 N/mm) while TSF rings with 6 struts was the least stiff. The situation was reversed for torsion where TSF rings with 6 oblique struts had the highest torsional stiffness (82.01 Nm/Degree) and frame Ilizarov rings with 4 threaded rods the least. Standard TSF construct of two ring with 6 oblique struts have better torsional stiffness and lower axial stiffness compared to the standard IEF. KEY WORDS: Taylor's Spatial Frame, Ilizarov External Fixator, Biomechanical properties. PMID- 25279091 TI - Trapezius Rotational Flap for Cervico-thoracic Wound Breakdown in Post radiotherapy Necrosis : A Case Report. AB - ABSTRACT: The management of post-radiation wound breakdown over the posterior cervico thoracic region can be a challenging task for a surgeon. The aim of the treatment is to produce a well vascularized and a low tensile flap which will close a large defect. We describe the use of the lower trapezius flap to reconstruct the wound breakdown and to obtain stable tissue coverage in a patient with postradiation necrosis. This flap minimizes the disruption of the scapula thoracic function while preserving the range of movement over the shoulder. From the literature review, it was noted that the dorsal scapular artery (DSA) and transverse cervical artery (TCA) aid in the blood supply to the trapezius muscle and prevent local necrosis during rotation of the flap. The trapezius flap is widely accepted because of the minor donor site morbidity, large arc of rotation and adequate blood supply. KEY WORDS: lower trapezius flap, scapula-thoracic function, postradiation necrosis. PMID- 25279092 TI - Haemangioma of knee joint: a case report. AB - ABSTRACT: BACKGROUND: Hemagioma arising in the knee is a rare cause of knee swelling. The diagnosis frequently is delayed for long. METHODS: We are presenting the case report of a 12 year old male child who had a swelling on anteromedial knee which remained undiagnosed for more than 1 year. Patient had all baseline blood investigations and plain radiograph of knee which were normal. He also had got his knee aspirated which yielded only blood. CONCLUSION: The aim of presenting this case report is to create awareness about the possibility of a hemangioma arising from a joint which although rare should be kept as a differential diagnosis. KEY WORDS: Haemangioma,knee joint,Swelling. PMID- 25279093 TI - Scapulothoracic dissociation: a rare variant: a case report. AB - ABSTRACT: Scapulothoracic dissociation is a rare injury involving separation of scapula from the thorax along with the upper extremity. Majority of the patients have concomitant neurovascular injury and the prognosis is uniformly poor in such cases. We present a case of scapulothoracic dissociation with comminuted fracture of scapula and acromioclavicular joint disruption without neurovascular deficit. There were associated avulsion fractures of the spinous processes of vertebrae (T3-T5). Such presentation is rare in an already rare scapulothoracic dissociation injury. A discussion regarding the probable mechanism of injury, management and prognosis is presented. KEY WORDS: scapulothoracic dissociation, scapula fracture, brachial plexus injury, vascular injury. PMID- 25279094 TI - Negative Pressure Wound Therapy in Infected Wound following Posterior Spinal Instrumentation using Simple Self-assembled System: A Case Report. AB - ABSTRACT: Postoperative wound infection in an instrumented spine patient is often disastrous. Management includes implant removal leading to spine instability. Negative pressure wound therapy (NPWT) applied to the spine surgical wound is one of the wound care technique with successful results. We report a case of a man who sustained Chance fracture of Lumbar 1 (L1) vertebra treated with long segment posterior instrumentation, who unfortunately developed Extended-spectrum beta lactamase (ESBL) positive E. coli infection one month after the operation. After careful debridement of the wound, the implant became exposed. Three cycles of NPWT were applied and the wound healed with granulation tissue completely covering the implant, and thus negating the need to remove the implant. In conclusion, the NPWT is a good alternative in postoperative wound management especially in an instrumented spine patient. KEY WORDS: vacuum assisted closure, infection, instrumentation, spine. PMID- 25279095 TI - Salmonella Osteomyelitis in a one year old Child without Sickle Cell Disease: A Case Report. AB - ABSTRACT: A one year old boy was admitted with left shoulder pain with reduced range of motion of five days' duration associated. Inflammatory markers were raised and radiograph of the left shoulder revealed widening of the metaphysis of the proximal humerus. Empirically, he was started on intravenous C-penicillin and cloxacillin after initial joint aspiration yielded only synovial fluid with negative culture. Subsequent MRI revealed acute osteomyelitis of the proximal left humerus with concurrent septic arthritis of the shoulder joint. Cultures from the arthrotomy washout grew Salmonella sp, sensitive to ampicillin. He recovered following six weeks of intravenous unasyn ( ampicillin and sulbactum). This rare case of salmonella osteomyelitis in a non-sickle cell disease patient was diagnosed with serial laboratory and radiological studies and was successfully treated with adequate duration of antibiotics and operative intervention. KEY WORDS: salmonella osteomyelitis, non-sickle cell disease, children. PMID- 25279096 TI - Rare presentation of metachronous multicentric pelvic and extracranial chondrosarcoma : a case report. AB - ABSTRACT: Conventional chondrosarcomas rarely metastasize and it is extremely unusual to see multicentric- behaviour in malignant cartilage tumour. We report a 40 year old lady with presentation of two non-contiguous metachronous foci of low to intermediate grade of chondrosarcoma over left pelvic bone and right scalp respectively in the absence of pulmonary or visceral metastasis. KEY WORDS: vacuum assisted closure, infection, instrumentation, spine. PMID- 25279097 TI - Arthroscopic resection of the distal clavicle with concomitant subacromial decompression: a case series. AB - ABSTRACT: Shoulder impingement syndrome and acromioclavicular joint osteoarthritis often occur simultaneously and easily missed. Kay et al. reported excellent results with combined arthroscopic subacromial decompression and resection of the distal end of the clavicle in patients with both disorders(1). Arthroscopic treatment of these disorders produces more favourable results than open procedures. We report two patients who were not responding to conservative management and were treated with direct arthroscopic distal clavicle excision and subacromial decompression in single setting. Both patients gained good postoperative outcome in terms of pain score, function and strength improvement assessed objectively with visual analogue score (VAS) and University of California Los Angeles Score (UCLA). KEY WORDS: Acromioclavicular joint arthritis, distal clavicle excision, Arthroscopy, Mumford operation. PMID- 25279098 TI - Intra-articular nodular fasciitis: an unexpected diagnosis for a joint lesion: a case report. AB - Pathological lesions in and around a joint can arise from underlying dermis, subcutis, deep muscle, bone or synovium. Clinical presentation can include joint pain, joint swelling, palpable masses and mechanical restriction. Whilst giant cell tumour of tendon sheath, pigmented villonodular synovitis, synovial chondromatosis, lipoma arborescens, juxta articular myxomas and inflammatory arthritis are the better-known conditions of the joint. Intra-articular nodular fasciitis, on the other hand, is less well recognized both clinically and radiologically. It is rarely seen in routine practice and is only described in case reports in the literature. Due to the non-specific clinical and radiological findings as well as the unfamiliarity with the entity, the diagnosis of intra articular nodular fasciitis is usually clinched only after histological examination. We present a case of intra-articular nodular fasciitis arising in the knee joint which was not suspected clinically or radiologically. KEY WORDS: Intra-articular, nodular fasciitis, joint, knee, MRI. PMID- 25279099 TI - Reimplantation of an Extruded Femoral Segment After Gamma Sterilization in A Type IIIA Supracondylar Femur Fracture: A Case Report. AB - ABSTRACT: Extruded bone is a rare complication of high energy open fractures, and there is only a handful of literature on reimplantation of the extruded segment. No clear guidelines exist regarding timing of reimplantation, stabilization of extruded bone segments, and also bone disinfection and sterilization techniques. Previous reports describe sterilization using thermal or chemical methods. We present a case of successful reimplantation of an extruded metaphyseal segment of femur after gamma sterilization in a fourteen- year old boy. KEY WORDS: extruded bone, reimplantation, gamma sterilization. PMID- 25279100 TI - Regulation of TRPC6 Channels by Non-Steroidal Anti-Inflammatory Drugs. AB - Family focal segmental glomerulosclerosis (FSGS) is characterized by sclerosis and hyalinosis of particular loops of glomeruli and is one of the causes of the nephrotic syndrome. Certain mutations in the structure of TRPC6 channels are the genetic impetus for FSGS development resulting in podocytes functional abnormalities and various nephropathies. We have recently demonstrated that non steroid anti-inflammatory drugs (NSAID) ibuprofen and diclofenac decrease the activity of endogenous TRPC like cal cium channels in the podocytes of the freshly isolated rat glomeruli. It has also been shown that TRPC6 chan nels are expressed in the podocytes. In the current study we have functionally reconstituted TRPC6 channels in mammalian cells to investigate the effects of diclofenac on the activity of wild type TRPC6 channel and TRPC6P112Q channel containing a mutation in the N-terminus that was described in FSGS patients. Intracellular calcium level measurements in transfected cells revealed a more intensive carbachol induced increase of calcium concentration in HEK 293 cells expressing TRPC6P112Q versus the cells expressing wild-type TRPC6. We also performed patch-clamp experiments to study TRPC6 channels reconstituted in Chinese hamster ovary (CHO) cell line and found that application of diclofenac (500 MUM) acutely reduced single channel activity. Preincubation with diclofenac (100 MUM) also decreased the whole cell current in CHO cells overexpressing TRPC6P112Q. Therefore, our previously published data on the effects of NSAID on TRPC-like channels in the isolated rat glomeruli, along with this current investigation on the cultured overexpressed mammalian cells, allows hypothesizing that TRPC6 channels may be a target for NSAID that can be impor tant in the treatment of FSGS. PMID- 25279101 TI - When the world collapses: changed worldview and social reconstruction in a traumatized community. AB - BACKGROUND: Traumatic experience can affect the individual's basic beliefs about the world as a predictable and safe place. One of the cornerstones in recovery from trauma is reestablishment of safety, connectedness, and the shattered schema of a worldview. OBJECTIVE: This study explored the role of negatively changed worldview in the relationship between war-related traumatization and readiness for social reconstruction of intergroup relations in a post-conflict community measured by three processes: intergroup rapprochement, rebuilding trust, and need for apology. It was hypothesized that more traumatized people are less supportive of social reconstruction and that this relationship is mediated by the changed worldview. METHOD: The study included a community random sample of 333 adults in the city of Vukovar, Croatia, that was most devastated during the 1991-1995 war. Six instruments were administered: Stressful Events Scale, Impact of Event Scale Revised, Changed Worldview Scale, and three scales measuring the post-conflict social reconstruction processes: Intergroup Rapprochement, Intergroup Trust and Need for Apology. RESULTS: Mediation analyses showed that the worldview change fully mediated between traumatization and all three aspects of social reconstruction. CONCLUSIONS: In a population exposed to war traumatization the worldview change mediates post-conflict social recovery of community relations. PMID- 25279102 TI - Predictors of change in mental health and distress among women attending a women's shelter. AB - BACKGROUND: Intimate partner violence (IPV) is detrimental to mental health. The Domestic Violence Survivor Assessment (DVSA), which includes a mental health assessment, is often used to evaluate abuse survivors in a counseling situation. The DVSA seeks to outline the cognitive state of women as per the stages of change as they attempt to move toward a life with no IPV. OBJECTIVE: The objective of this study was to explore predictors of change in mental health and distress among women who entered a women's shelter more than once. METHODS: Women entering a women's shelter more than once over a 3-year period were assessed by a trained social worker using the DVSA. A logistic regression analysis examined relationships between the chosen characteristics and the participants' mental health through the DVSA stages of change. RESULTS: We analyzed complete data for 94 women who entered the shelter a mean of 3.3 times (range 2-8) over a mean period of 16.1 days (range: 1-391). Thirty-six women (36/94; 38.3%) progressed through the stages. The average number of visits among women who progressed through the stages was 4. Our multivariable logistic regression showed women who had more visits to the shelter were almost twice as likely to progress through the stages compared to women who entered the shelter fewer times (OR=1.928; 95% CI=1.292-2.877; p=0.001). In the univariate analysis, only increased number of visits was significantly associated with progressing through the stages of change (OR=1.694; 95% CI=1.237-2.322; p=0.001). The other factors were not significantly associated with a change in mental health and distress (p>0.05). CONCLUSION: Women who enter women's shelters more frequently may be more likely to progress through the DVSA mental health stages compared to other women. Women's shelters may be helpful in assisting progression through the stages of change, thereby improving their mental health after abuse. PMID- 25279104 TI - "It will always continue unless we can change something": consequences of intimate partner violence for indigenous women, children, and families. AB - BACKGROUND: Violence against indigenous women and girls is endemic, yet the absence of research on the consequences of this violence from the perspectives of women presents a profound barrier to the development of knowledge, along with violence prevention and mitigation. Although family is central to many indigenous communities, existing research typically examines the consequences of intimate partner violence (IPV) on women or children in isolation, rather than examining its consequences holistically. OBJECTIVE: The purpose of this article is to identify US indigenous women's perspectives about the impact of IPV on women, children, and families. METHOD: Data were collected with 29 indigenous women affected by violence from a Southeastern tribe in the United States. As part of a larger critical ethnography, pragmatic horizon analysis of life history interviews revealed the consequences of IPV across multiple levels. RESULTS: Women reported profound psychological consequences resulting from IPV. The majority of women had witnessed IPV in their childhood, providing support for an intergenerational cycle of violence. Women reported psychological consequences on children, which paralleled those reported by women, leaving deep impressions on children across their life course. Consequences on children and whole families were extensive, indicating the negative ramifications of IPV transcended personal boundaries and affected children and families across multiple generations. CONCLUSIONS: Given the tight-knit nature of indigenous families and communities, the consequences across individuals and families were noteworthy. However, a dearth in research examining consequences of IPV across levels fails to capture the interconnections of consequences for women, children, and families. Given the centrality of family in many indigenous communities, examining IPV from a holistic perspective that incorporates multiple levels is recommended for IPV research and intervention development. PMID- 25279103 TI - Adult experience of mental health outcomes as a result of intimate partner violence victimisation: a systematic review. AB - BACKGROUND: Intimate partner violence (IPV) has been known to adversely affect the mental health of victims. Research has tended to focus on the mental health impact of physical violence rather than considering other forms of violence. OBJECTIVE: To systematically review the literature in order to identify the impact of all types of IPV victimisation on various mental health outcomes. METHOD: A systematic review of 11 electronic databases (2004-2014) was conducted. Fifty eight papers were identified and later described and reviewed in relation to the main objective. RESULTS: Main findings suggest that IPV can have increasing adverse effects on the mental health of victims in comparison with those who have never experienced IPV or those experiencing other traumatic events. The most significant outcomes were associations between IPV experiences with depression, posttraumatic stress disorder, and anxiety. Findings confirm previous observations that the severity and extent of IPV exposure can increase mental health symptoms. The effect of psychological violence on mental health is more prominent than originally thought. Individual differences such as gender and childhood experience of violence also increase IPV risk and affect mental health outcomes in diverse ways. CONCLUSIONS: Psychological violence should be considered as a more serious form of IPV which can affect the mental health of victims. Experiencing more than one form of IPV can increase severity of outcomes. Researchers should look at IPV as a multi-dimensional experience. A uniformed definition and measure of IPV could help advance knowledge and understanding of this disparaging global issue. PMID- 25279105 TI - Intimate partner violence and mental health-Remarks from two Chief Editors on a joint publishing venture. PMID- 25279106 TI - Assessing the co-occurrence of intimate partner violence domains across the life course: relating typologies to mental health. AB - BACKGROUND: The inter-generational transmission of violence (ITV) hypothesis and polyvictimisation have been studied extensively. The extant evidence suggests that individuals from violent families are at increased risk of subsequent intimate partner violence (IPV) and that a proportion of individuals experience victimisation across multiple rather than single IPV domains. Both ITV and polyvictimisation are shown to increase the risk of psychiatric morbidity, alcohol use, and anger expression. OBJECTIVE: The current study aimed to 1) ascertain if underlying typologies of victimisation across the life-course and over multiple victimisation domains were present and 2) ascertain if groupings differed on mean scores of posttraumatic stress disorder (PTSD), depression, alcohol use, and anger expression. METHOD: University students (N=318) were queried in relation to victimisation experiences and psychological well-being. Responses across multiple domains of IPV spanning the life-course were used in a latent profile analysis. ANOVA was subsequently used to determine if profiles differed in their mean scores on PTSD, depression, alcohol use, and anger expression. RESULTS: Three distinct profiles were identified; one of which comprised individuals who experienced "life-course polyvictimisation," another showing individuals who experienced "witnessing parental victimisation," and one which experienced "psychological victimisation only." Life-course polyvictims scored the highest across most assessed measures. CONCLUSION: Witnessing severe physical aggression and injury in parental relationships as a child has an interesting impact on the ITV into adolescence and adulthood. Life-course polyvictims are shown to experience increased levels of psychiatric morbidity and issues with alcohol misuse and anger expression. PMID- 25279107 TI - Effects of an intervention program for female victims of intimate partner violence on psychological symptoms and perceived social support. AB - BACKGROUND: Research has documented severe mental health problems in female victims of intimate partner violence (IPV). Therefore, providing effective treatment is pivotal. Few studies have investigated the effects of intervention programs on reducing the harmful consequences of IPV. OBJECTIVE: The present study examined the effects of a specific three-phase intervention program for female victims of IPV on psychological symptoms (PTSD, anxiety, and depression) and perceived social support. Given that many of the women dropped out before and during the intervention program, potential differences in initial levels of psychological symptoms, perceived social support, as well as descriptive variables were explored between the women who completed the whole program and the groups of women who dropped out prematurely. METHOD: The initial sample consisted of 212 female victims of IPV. Symptoms of PTSD, depression, anxiety, and level of perceived social support were measured with validated scales before the start of the intervention and after completion of each treatment phase. RESULTS: Results showed a significant effect of the intervention program on reducing psychological symptoms and increasing levels of perceived social support. Effect sizes ranged from medium to very high. Significant positive effects were found for each of the treatment phases. There were no significant differences between the women who completed the whole program and those women who dropped out prematurely in terms of initial level of symptoms and perceived social support as well as descriptive characteristics. CONCLUSIONS: Specifically developed intervention programs for female victims of IPV are effective in reducing the harmful personal consequences of IPV. Future studies should consider employing controlled study designs and address the issue of high drop out rates found in intervention studies. PMID- 25279108 TI - Intimate partner violence and drug-addicted women: from explicative models to gender-oriented treatments. AB - Thanks to studies conducted over the past decades, it has been underlined how harmful consumption of alcohol or other substances and intimate partner violence are intertwined. What has been recognized is, in particular, how the relation between these two factors may be represented as a vicious cycle in which each of them influences the other, reciprocally. The aim of this paper is to offer an overview, firstly, about the global and European scenario of the spread of these constructs, delineating, then, the main explanation models that theorize their connection and those risk factors associated with the environmental settings which may play a significant role. The last part, finally, offers some starting points in order to provide efficient multidisciplinary approaches both to prevent and support victims, increasing their mental, physical, and emotional health. PMID- 25279109 TI - Childhood maltreatment and intimate partner violence in dissociative disorder patients. AB - BACKGROUND: Childhood maltreatment (CM) is a risk factor for subsequent intimate partner violence (IPV) in adulthood, with high rates of retrospectively reported CM among IPV victims and perpetrators. A theorized mechanism of the link between CM and IPV is dissociation. Dissociation may allow perpetrators of violence to remain emotionally distant from their behavior and minimize empathy toward those they victimize, enabling them to commit acts of violence similar to their own experiences. Indeed, elevated rates of dissociation and dissociative disorders (DD) have been found among IPV survivors and perpetrators. In addition, in pilot studies, DD clinicians have reported high levels of violent behavior among DD patients. OBJECTIVE: The present study investigates IPV among DD patients with Dissociative Identity Disorder and Dissociative Disorder Not Otherwise Specified, a group with CM rates of 80-95% and severe dissociative symptoms. METHODS: DD clinicians reported on rates of CM and IPV among 275 DD patients in outpatient treatment. DD patients also completed a self-report measure of dissociation. Analyses assessed the associations between CM typologies and IPV, as well as trait dissociation and IPV. RESULTS: Physical and emotional child abuse were associated with physical IPV, and childhood witnessing of domestic violence (DV) and childhood neglect were associated with emotional IPV. CONCLUSIONS: The present study is the first to provide empirical support for a possible CM to adult IPV developmental trajectory among DD patients. Future research is needed to better understand the link between CM and IPV among those with trauma and DD. PMID- 25279110 TI - Intimate partner violence and mental health. PMID- 25279111 TI - Distinguishing PTSD, Complex PTSD, and Borderline Personality Disorder: A latent class analysis. AB - BACKGROUND: There has been debate regarding whether Complex Posttraumatic Stress Disorder (Complex PTSD) is distinct from Borderline Personality Disorder (BPD) when the latter is comorbid with PTSD. OBJECTIVE: To determine whether the patterns of symptoms endorsed by women seeking treatment for childhood abuse form classes that are consistent with diagnostic criteria for PTSD, Complex PTSD, and BPD. METHOD: A latent class analysis (LCA) was conducted on an archival dataset of 280 women with histories of childhood abuse assessed for enrollment in a clinical trial for PTSD. RESULTS: THE LCA REVEALED FOUR DISTINCT CLASSES OF INDIVIDUALS: a Low Symptom class characterized by low endorsements on all symptoms; a PTSD class characterized by elevated symptoms of PTSD but low endorsement of symptoms that define the Complex PTSD and BPD diagnoses; a Complex PTSD class characterized by elevated symptoms of PTSD and self-organization symptoms that defined the Complex PTSD diagnosis but low on the symptoms of BPD; and a BPD class characterized by symptoms of BPD. Four BPD symptoms were found to greatly increase the odds of being in the BPD compared to the Complex PTSD class: frantic efforts to avoid abandonment, unstable sense of self, unstable and intense interpersonal relationships, and impulsiveness. CONCLUSIONS: Findings supported the construct validity of Complex PTSD as distinguishable from BPD. Key symptoms that distinguished between the disorders were identified, which may aid in differential diagnosis and treatment planning. PMID- 25279112 TI - Reference values and the problem of health as normality: a veterinary attempt in the light of a one health approach. AB - Reference values seem crucial to both veterinary medicine and human medicine. The main critique is that the theoretical connections between the concepts of reference values, normality, and health are weak. In this paper, we analyze especially one attempt in veterinary medicine to establish such a theoretical connection. We find that this attempt fails because it is circular. In conclusion, we would postulate that there are two apparent ways forward: to aim for a definition of health not based on the concept of normality, or to develop the concept of normality as separate from statistical normality. These goals can be reached with a one health perspective. PMID- 25279113 TI - Single-step isolation of extracellular vesicles by size-exclusion chromatography. AB - BACKGROUND: Isolation of extracellular vesicles from plasma is a challenge due to the presence of proteins and lipoproteins. Isolation of vesicles using differential centrifugation or density-gradient ultracentrifugation results in co isolation of contaminants such as protein aggregates and incomplete separation of vesicles from lipoproteins, respectively. AIM: To develop a single-step protocol to isolate vesicles from human body fluids. METHODS: Platelet-free supernatant, derived from platelet concentrates, was loaded on a sepharose CL-2B column to perform size-exclusion chromatography (SEC; n=3). Fractions were collected and analysed by nanoparticle tracking analysis, resistive pulse sensing, flow cytometry and transmission electron microscopy. The concentrations of high density lipoprotein cholesterol (HDL) and protein were measured in each fraction. RESULTS: Fractions 9-12 contained the highest concentrations of particles larger than 70 nm and platelet-derived vesicles (46%+/-6 and 61%+/-2 of totals present in all collected fractions, respectively), but less than 5% of HDL and less than 1% of protein (4.8%+/-1 and 0.65%+/-0.3, respectively). HDL was present mainly in fractions 18-20 (32%+/-2 of total), and protein in fractions 19-21 (36%+/-2 of total). Compared to the starting material, recovery of platelet-derived vesicles was 43%+/-23 in fractions 9-12, with an 8-fold and 70-fold enrichment compared to HDL and protein. CONCLUSIONS: SEC efficiently isolates extracellular vesicles with a diameter larger than 70 nm from platelet-free supernatant of platelet concentrates. Application SEC will improve studies on the dimensional, structural and functional properties of extracellular vesicles. PMID- 25279114 TI - Glaucoma and choroidal thickness. PMID- 25279115 TI - Peripapillary and macular choroidal thickness in glaucoma. AB - PURPOSE: To compare choroidal thickness (CT) between individuals with and without glaucomatous damage and to explore the association of peripapillary and submacular CT with glaucoma severity using spectral domain optical coherence tomography (SD-OCT). METHODS: Ninety-one eyes of 20 normal subjects and 43 glaucoma patients from the UCLA SD-OCT Imaging Study were enrolled. Imaging was performed using Cirrus HD-OCT. Choroidal thickness was measured at four predetermined points in the macular and peripapillary regions, and compared between glaucoma and control groups before and after adjusting for potential confounding variables. RESULTS: The average (+/- standard deviation) mean deviation (MD) on visual fields was -0.3 (+/-2.0) dB in controls and -3.5 (+/ 3.5) dB in glaucoma patients. Age, axial length and their interaction were the most significant factors affecting CT on multivariate analysis. Adjusted average CT (corrected for age, axial length, their interaction, gender and lens status) however, was not different between glaucoma patients and the control group (P=0.083) except in the temporal parafoveal region (P=0.037); nor was choroidal thickness related to glaucoma severity (r=-0.187, P=0.176 for correlation with MD, r=-0.151, P=0.275 for correlation with average nerve fiber layer thickness). CONCLUSIONS: Choroidal thickness of the macular and peripapillary regions is not decreased in glaucoma. Anatomical measurements with SD-OCT do not support the possible influence of the choroid on the pathophysiology of glaucoma. PMID- 25279116 TI - Triamcinolone acetonide as an adjunct to bevacizumab for prevention of corneal neovascularization in a rat model. AB - PURPOSE: To evaluate the short-term effects of a single subconjunctival injection of triamcinolone acetonide as an adjunct to subconjunctival bevacizumab for prevention of corneal neovascularization in rats. METHODS: Chemical cauterization was performed in the central cornea of the right eye in 48 male Sprague-Dawley rats (4 eyes were excluded due to perforation and/or infection). Immediately after the injury, the rats were randomly assigned to four treatment groups: controls (n=10), received subconjunctival injection of 0.02 mL balanced salt solution; group 1 (n=12), received 0.02 mL bevacizumab (25 mg/mL); group 2 (n=11), were treated with 0.02 mL triamcinolone acetonide (40 mg/mL); and group 3 (n=11), received both bevacizumab and triamcinolone acetonide. On days 7 and 14 after cauterization, digital photographs of the corneas were taken and the area of neovascularization was calculated and compared among the study groups. RESULTS: The area of corneal neovascularization in all three treatment groups was less than the controls (P<0.05 for all comparisons). On day 7, the corneal avascular area was largest in group 3 (63%). On day 14, the area of corneal neovascularization in groups 2 and 3 was smaller than that in group 1 (P=0.031 and 0.011, respectively), but the difference between groups 2 and 3 was not statistically significant (P=0.552). Microscopic evaluation of the cornea was compatible with gross findings; inflammation and the number of new vessels was the least in group 3. CONCLUSION: Triamcinolone acetonide was more effective than bevacizumab in inhibiting corneal neovascularization. Its adjunctive administration to bevacizumab resulted in even better prevention of corneal neovascularization. However, the produced combined effect was less than the sum of their separate effects and did not match additive or synergistic interactions. PMID- 25279117 TI - Partial Coherence Laser Interferometry in Highly Myopic versus Emmetropic Eyes. AB - PURPOSE: To investigate the reliability of partial coherence laser interferometry for optical biometry in highly myopic eyes. METHODS: Axial length measurements by the IOLMaster (Carl Zeiss Meditec, Germany) with signal-to-noise ratio (SNR) >=2 were performed in 52 consecutive myopic subjects with axial length >=26.5 mm and 45 emmetropic patients before cataract surgery. Axial length measurements and SNR were analyzed and compared among the two study groups. RESULTS: Axial length measurements were feasible in 46 of 52 (88.5%) highly myopic eyes and in 41 of 45 (91.1%) eyes with normal axial length. To achieve two reliable axial length values with SNR >=2, a mean number of 2.06+/-0.25 measurements was necessary in myopic eyes and 2.10+/-0.37 in emmetropic counterparts. Mean SNR after two measurements was 4.98+/-2.44 in myopic eyes versus 5.56+/-2.32 in control eyes. Even though successful measurement was independent of preoperative visual acuity, patients with visual acuity better than 20/63 showed significantly higher SNR values. CONCLUSIONS: Partial coherence laser interferometry shows satisfying feasibility and good signal quality for axial length determination in highly myopic eyes with stable retinal condition and clear media. PMID- 25279118 TI - Flexible toric iris claw phakic intraocular lens implantation for myopia and astigmatism. AB - PURPOSE: To assess the visual and refractive outcomes of flexible toric iris claw phakic intraocular lens implantation for correction of moderate to high myopia with astigmatism. METHODS: In this non-randomized prospective study, 31 eyes of 18 patients including 8 male and 10 female subjects with mean age of 27.62+/-5.53 (range 19 to 38) years with moderate to high myopia and astigmatism underwent toric Artiflex (Ophtec BV, Groningen, Netherlands) phakic intraocular lens (PIOL) implantation. Uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were measured in logarithm of minimum angle of resolution (logMAR) notations. Manifest refraction, safety, efficacy, predictability and complications were measured 6 months after surgery. RESULTS: Pre-operatively, mean spherical equivalent (SE) refractive error was -9.68+/-1.92 (range -14.00 to -6.00) diopter (D) and mean cylinder was -2.79+/-1.06 (range -4.75 to -1.00) D. After a minimum of 6 months, mean SE was -0.38+/-0.27 (range -0.87 to 0.00) D and mean cylinder was -0.66+/-0.43 (range -1.50 to 0.00) D. SE was within 0.50 D of emmetropia in 63.8% and within 1.0 D of target refraction in 100% of eyes. UDVA was equal or better than 20/20 in 45.1% of eyes while CDVA was equal or better than 20/20 in 67.7%; 83.8% of eyes gained 1 or more Snellen lines of CDVA after surgery. No serious complications occurred in this series of cases. CONCLUSIONS: Implantation of the toric Artiflex PIOL is a safe and effective procedure for correction of moderate to high myopia with astigmatism. PMID- 25279119 TI - Complement Factor H Y402H and LOC387715 A69S Polymorphisms in Association with Age-Related Macular Degeneration in Iran. AB - PURPOSE: To determine the frequency of complement factor H (Y402H) and age related macular degeneration susceptibility gene 2 (A69S) single nucleotide polymorphisms in patients with age-related macular degeneration (AMD) and in matched non-AMD controls in an Iranian population. METHODS: Seventy patients with AMD and 86 age- and sex-matched controls were recruited and examined. Peripheral blood sample was obtained from all subjects for DNA extraction and direct sequencing of Y402H and A69S genes. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association of Y402H and A69S polymorphisms with AMD were determined. RESULTS: The frequencies of both homozygous and heterozygous genotypes were significantly higher in cases than controls for both Y402H and A69S polymorphisms. In comparison to the wild genotypes, OR for AMD associated with Y402H and A69S polymorphisms were 1.9 (95% CI, 1.1-3.2) and 2.2 (95%CI, 1.6 3.1), respectively. Joint risk analysis considering both genes revealed a higher risk of AMD when polymorphisms were present for both genes. CONCLUSION: Y402H and A69S polymorphisms were strongly associated with AMD in this Iranian population. PMID- 25279120 TI - Characteristics of Germline and Non-germline Retinoblastomas. AB - PURPOSE: To discuss the clinical characteristics, treatment and outcomes of germline and non-germline retinoblastoma tumors. METHODS: A retrospective study was performed on retinoblastoma cases from 1979 to 2007. General characteristics of the patients, treatment modalities, histopathological findings and survival were compared in germline versus non-germline cases. RESULTS: We analyzed 557 cases of retinoblastoma with mean age of 32.2+/-22.0 months including 177 and 380 patients with germline and non-germline tumors, respectively. Germline cases were significantly different from non-germline counterparts in terms of mean age (24.7+/-17.7 vs 35.7+/-23.0 months), symptoms (leukocoria in 49.4% vs 62.9%), and outcomes (death in 40.1% vs 13.9%), respectively (P<0.001). In the germline group 66.5% and in non-germline group over 97% of patients had stage Va or higher (ICRB D-E disease). Disease-free survival was 48.6% for germlines cases versus 80.9% for non-germline patients (with mean follow up of 61.9 months, P<0.001). Histopathologically, more invasions to intraocular and extraocular tissues were seen with non-germline tumors of (66% vs 39.8%). Mortality rates in germline cases and non-germline were 40.1% and 13.9%, respectively (P<0.001). CONCLUSION: Despite higher tumor staging in nongermline cases at the time of diagnosis and therefore more aggressive behavior of the tumor, germline cases had a higher rate of mortality during the follow up period. PMID- 25279121 TI - Electroretinogram changes in the sound eye of subjects with unilateral necrotizing herpetic retinitis. AB - PURPOSE: To evaluate electroretinogram (ERG) changes in the contralateral normal appearing eye of patients with unilateral acute necrotizing herpetic retinitis (NHR). METHODS: This interventional case series includes subjects with acute unilateral NHR. All patients were treated with intravenous followed by oral acyclovir and systemic steroids. Main outcome measures were changes in a- and b wave amplitudes of scotopic and photopic full-field ERG in the sound eye, 1 and 3 months after therapy as compared to baseline. Twenty normal subjects served as controls. RESULTS: Forty eyes of 20 patients including 12 male and 8 female subjects with mean age of 44.1+/-11.5 (range 22 to 66) years were studied. Twenty unaffected eyes were the subject of the current study. The retina in all of these eyes remained intact during the course of the study. In the sound eyes, mean b wave amplitude of the maximal combined response ERG before initiation of treatment was 229.5+/-38.8 microvolts which increased to 356.1+/-34.0 (P<0.001) and 365.8+/-32.7 (P<0.001) microvolts 1 and 3 months after treatment, respectively. Corresponding figures for b-wave amplitudes of the cone response ERG were 24.9+/-6.0, 47.0+/-12.9 (P<0.001) and 52.8+/-12.7 (P<0.001) microvolts, respectively. Visual acuity of all sound eyes remained unchanged throughout the study. CONCLUSION: Despite normal retinal appearance and intact visual acuity in the sound eyes of patients with NHR, electrophysiological changes were observed. Prompt diagnosis and management of NHR and continuation of medication for 3 months may reverse subclinical ERG changes and reduce the risk of progression to overt clinical disease. PMID- 25279123 TI - Characteristics and outcomes of pediatric retinal detachment surgery at a tertiary referral center. AB - PURPOSE: To report the clinical features, and anatomic and visual outcomes of pediatric retinal detachment (RD) surgery at a tertiary referral center in Southern Iran. METHODS: In this retrospective, non-comparative, interventional case series, we reviewed the records of 77 patients less than 18 years of age who had undergone primary RD surgery at Khalili Hospital, Shiraz, Iran from 2005 to 2010. All patients had follow-up duration more than 12 months. RESULTS: Seventy seven eyes of 77 patients with mean age of 12.5+/-5 (range, 2-18) years including 56 (73%) male subjects were included. The most common etiologies of RD included trauma (90%) and myopia (6%). Different types of breaks and proliferative viteroretinopathy were present in 75% and 13% of eyes, respectively. The most common primary surgery was deep viterectomy (78%) followed by scleral buckling (19.5%). Single-operation reattachment was accomplished in 55% of cases. At final follow up, functional visual loss [best corrected visual acuity (BCVA) <5/200] occurred in 66.7%, while the rate of anatomical success was 62.3%. Significant predictors of better final BCVA were higher initial BCVA (P=0.015), absence of relative afferent pupillary defect (P=0.002), less extensive RD (P=0.031), and primary RD surgery (P=0.056). Anatomical success was associated with a lower number of procedures (P<0.001) and marginally with phakic lens status (P=0.079). CONCLUSIONS: Trauma was the most prevalent predisposing factor for pediatric RD in our study. The high rates of functional visual loss and low anatomical success may be due to a large proportion of trauma and the complex nature of RD. PMID- 25279122 TI - Retinal biocompatibility of brilliant blue g with deuterated water for chromovitrectomy. AB - PURPOSE: To investigate the retinal biocompatibility of Brilliant Blue G with deuterated water (BBG-D2O) as a vital dye for chromovitrectomy. METHODS: In this animal study, 0.05 mL of 0.25 g/L Brilliant Blue G (BBG) associated with 0.13 mL/mL of deuterium oxide (D2O) was injected intravitreally in the right eye and the same amount of balanced salt solution (BSS) was injected similarly in the left eye of rabbits. Clinical examination and histology with light microscopy were performed after seven days. Retinal cell layers were evaluated for morphologic alterations. Electroretinographic (ERG) changes were also assessed at baseline and 7 days after the injections. RESULTS: A total of 6 rabbits were included in the study. The gross histopathologic appearance of the retina, choroid, sclera and optic nerve was within normal limits without any sign of severe retinal necrosis or cystic degeneration. Light microscopy showed that BBG D2O caused no substantial alterations in retinal layers as compared to control eyes. The injection of BBG-D2O did not induce considerable functional ERG alterations. CONCLUSION: Intravitreal injection of BBG-D2O 0.25 g/L seems to induce no retinal toxicity as documented by lack of functional and histological changes. PMID- 25279124 TI - Histopathologic and electron microscopic features of internal limiting membranes in maculopathies of various etiologies. AB - PURPOSE: To report micro- and ultrastructural features of internal limiting membranes (ILMs) in various maculopathies and to evaluate the effects of indocyanine green (ICG) and triamcinolone acetonide (TA) on epiretinal proliferations associated with ILM and on retinal cleavage plane. METHODS: ILMs from various maculopathies were evaluated regarding presence or absence of membrane-associated cells, type of cells and ILM thickness based on routine histopathology, immunohistochemistry and transmission electron microscopy (TEM). RESULTS: Thirty ILM specimens were enrolled; 25 of which were evaluated by histopathology and immunohistochemistry and 5 by TEM. ICG only had been used in 17 specimens, TA in 4, and both agents in one specimen. The majority of specimens were immunoreactive for glial fibrillary acidic protein and neuron specific enolase. No significant difference in specimen cellularity and alteration of cleavage plane was noted between ICG-stained and non-ICG-stained ILMs or between TA-assisted and non-TA-assisted ones. Excluding central retinal vein occlusion (CRVO) cases, acellularity was not observed in any of ILMs from diabetic macular edema (DME), cystoid macular edema (CME), and traumatic macular hole (TMH) eyes. TEM disclosed ILM thickening and cellularity in DME as compared to CRVO. CONCLUSION: Acellular membranes from CRVO maculopathy may be a sequel of acute retinal ischemia. Thickened diabetic ILMs with high cellularity may be related to chronic activation of Muller cells. No obvious influence of ICG or TA on epiretinal cellularity was detected and the dyes seem to have no significant effect on cleavage plane. PMID- 25279125 TI - Knowledge and awareness of age related eye diseases: a population-based survey. AB - PURPOSE: To determine general awareness and knowledge about cataracts, glaucoma and diabetic retinopathy (DR), as common avoidable causes of blindness in an Iranian population. METHODS: This cross-sectional population-based survey was performed on residents over 45 years of age in Tehran. The sampling frame was the list of all landline phone numbers registered by the Telecommunications Center of Iran, through which systematic random sampling was performed. Data was collected by phone-call interviews and completing a semi-structured questionnaire. Awareness was defined as whether the respondent had ever heard of the disease. Knowledge was assessed by realizing different aspects of each disease. RESULTS: Of a total of 1,084 eligible people including 574 (52.9%) women and 510 (47.1%) men were included and 957 subjects (response rate, 88.3%) completed the interview. Awareness regarding glaucoma, cataract and DR was 46.6% (95% confidence interval [CI]:43.4 -49.8%), 82.9% (95% CI: 80.5 -85.3%) and 86.2% (95% CI: 84-88.4%). In addition, 19.2% (95% CI: 16.7 -21.7%), 57.3% (95% CI: 54.2 60.4%) and 72% (95% CI: 69.2 -74.8%) of respondents could give at least a basic definition of the mentioned diseases, respectively. Only 22.6% (95% CI: 20-25.2%) and 41.6% (95% CI: 38.5-44.7%) realized glaucoma and DR as a treatable condition; in contrast, 77.2% (95% CI: 74.5-79.9%) categorized cataract as treatable. Only 19% and 7.1% knew that DR and glaucoma may commence without any apparent symptoms. CONCLUSION: Compared with cataract and DR, most participants had limited information about glaucoma. In addition, few of the respondents were familiar with the initial symptoms of DR and glaucoma. PMID- 25279126 TI - Prevalence of Refractive Errors among High School Students in Western Iran. AB - PURPOSE: To determine the prevalence of refractive errors among high school students. METHODS: In a cross-sectional study, we applied stratified cluster sampling on high school students of Aligoudarz, Western Iran. Examinations included visual acuity, non-cycloplegic refraction by autorefraction and fine tuning with retinoscopy. Myopia and hyperopia were defined as spherical equivalent of -0.5/+0.5 diopter (D) or worse, respectively; astigmatism was defined as cylindrical error >0.5 D and anisometropia as an interocular difference in spherical equivalent exceeding 1 D. RESULTS: Of 451 selected students, 438 participated in the study (response rate, 97.0%). Data from 434 subjects with mean age of 16+/-1.3 (range, 14 to 21) years including 212 (48.8%) male subjects was analyzed. The prevalence of myopia, hyperopia and astigmatism was 29.3% [95% confidence interval (CI), 25-33.6%], 21.7% (95%CI, 17.8-25.5%), and 20.7% (95%CI, 16.9-24.6%), respectively. The prevalence of myopia increased significantly with age [odds ratio (OR)=1.30, P=0.003] and was higher among boys (OR=3.10, P<0.001). The prevalence of hyperopia was significantly higher in girls (OR=0.49, P=0.003). The prevalence of astigmatism was 25.9% in boys and 15.8% in girls (OR=2.13, P=0.002). The overall prevalence of high myopia and high hyperopia were 0.5% and 1.2%, respectively. The prevalence of with-the-rule, against-the-rule, and oblique astigmatism was 14.5%, 4.8% and 1.4%, respectively. Overall, 4.6% (95%CI, 2.6-6.6%) of subjects were anisometropic. CONCLUSION: More than half of high school students in Aligoudarz had at least one type of refractive error. Compared to similar studies, the prevalence of refractive errors was high in this age group. PMID- 25279127 TI - Dry eye: an inflammatory ocular disease. AB - Keratoconjunctivitis sicca, or dry eye, is a common ocular disease prompting millions of individuals to seek ophthalmological care. Regardless of the underlying etiology, dry eye has been shown to be associated with abnormalities in the pre-corneal tear film and subsequent inflammatory changes in the entire ocular surface including the adnexa, conjunctiva and cornea. Since the recognition of the role of inflammation in dry eye, a number of novel treatments have been investigated designed to inhibit various inflammatory pathways. Current medications that are used, including cyclosporine A, corticosteroids, tacrolimus, tetracycline derivatives and autologous serum, have been effective for management of dry eye and lead to measurable clinical improvement. PMID- 25279128 TI - Chromovitrectomy: an update. AB - Adequate visualization and identification of the posterior hyaloid, epiretinal membranes and the internal limiting membrane are of paramount importance in modern vitreoretinal surgery. "Chromovitrectomy" is a term used for describing the vital dyes use in order to stain these transparent tissues and facilitate their manipulation during vitreous surgery. This article reviews the indications, applications and characteristics of vital dyes in vitreoretinal surgery. Various dyes are currently being used in routine clinical procedures, however the ideal staining agent has not yet been found. Any dye which is injected intravitreally has the potential to become toxic. Triamcinolone acetonide is used to highlight the vitreous and is particularly beneficial in determining the attachment of the posterior hyaloid to the underlying retina. Trypan blue stains epiretinal membranes and facilitates their complete removal. Both indocyanine green and brilliant blue G stain the internal limiting membrane properly, however concerns over indocyanine green toxicity have made surgeons switch to brillliant blue G as a safer alternative. PMID- 25279130 TI - Crystalline subtype of pre-descemetic corneal dystrophy. AB - PURPOSE: To report corneal findings in a familial case of the crystalline subtype of pre-Descemetic corneal dystrophy. CASE REPORT: A 19-year-old girl and her 44 year-old mother were found to have asymptomatic, bilateral, punctiform and multi colored crystalline opacities across the whole posterior layer of the corneas. Endothelial specular microscopy revealed the presence of white round flecks located at different levels anterior to the endothelium. No systemic abnormalities or medications could be related to account for these findings. CONCLUSION: To the best of our knowledge, this is the third familial report of this rare corneal disorder. Differential diagnosis may include Schnyder corneal dystrophy, cystinosis, Bietti's dystrophy and monoclonal gammopathy. PMID- 25279129 TI - The road ahead to continuous 24-hour intraocular pressure monitoring in glaucoma. AB - Intraocular pressure (IOP) is the only treatable risk factor for glaucoma. Yet, current glaucoma management usually relies on single IOP measurements during clinic hours despite the fact that IOP is a dynamic parameter with individual rhythms. Single IOP measurements underpin all major clinical guidelines on treatment of glaucoma. Other potentially informative parameters, such as IOP fluctuations and peak IOP, have been neglected, and effects of IOP-lowering interventions on such measures are largely unknown. The search for continuous 24 hour IOP monitoring started over 50 years ago, but only recent technological advances have provided clinician-researchers with devices for continuous IOP monitoring. Herein, we discuss innovative approaches with permanent and temporary devices for 24-hour IOP monitoring, such as a contact lens sensor. Despite being in their infancy, these devices may soon enable clinicians to use 24-hour IOP data to improve glaucoma management and reduce the glaucoma-related burden of disease. PMID- 25279131 TI - Single cotton wool spot as a late manifestation of head trauma. AB - PURPOSE: To report a patient with a single cotton wool spot (CWS) following head trauma. CASE REPORT: A 37-year-old male electrician presented with painless paracentral blurred vision in his left eye of one month duration together with three transient episodes of obscuration of vision in the same eye lasting for 10 minutes. He reported blunt head trauma due to a fall 40 days before referral. Fundus examination at presentation was normal but after 4 months, revealed the appearance of a white spot along the superotemporal arcade in the absence of other fundus lesions. A comprehensive systemic workup was performed revealing no specific findings. Ophthalmoscopic examination after 6 weeks disclosed resolution of the CWS with no intervention. The patient's complaint of paracentral visual field defect improved and subsequent optical coherence tomography showed retinal thinning in that area. CONCLUSION: Herein, we report a patient with a single CWS near the optic disc four months after head trauma along with normal systemic and paraclinical evaluations. Head trauma may thus be considered as a cause of CWS. PMID- 25279132 TI - A baby with primary congenital glaucoma not responding to trabeculotomy. PMID- 25279133 TI - Unusual presentation of cerebral venous sinus thrombosis associated with contraceptive usage. PMID- 25279134 TI - A Simple Method for Removal of Particles from the Retinal Surface during Vitrectomy. AB - Removal of particulate materials from the retinal surface is somewhat difficult during small gauge vitrectomy. Simple injection of balanced salt solution into the vitreous cavity in a controlled manner using a connector tubing between the syringe and needle can produce enough turbulence to float the deposited material and remove it. PMID- 25279135 TI - Prevention of childhood blindness: strengthening primary health care. PMID- 25279137 TI - Chiropractors' attitudes toward drug prescription rights: a narrative review. AB - BACKGROUND: The right to prescribe drugs remains a contentious issue within the chiropractic profession. Nevertheless, drug prescription by manual therapy providers is currently an important topic. Notably, physiotherapists in the United Kingdom were recently granted limited independent prescribing rights. Reports suggest that physiotherapists in Australia now want those same rights, and as such a review of chiropractors' general attitudes toward drug prescription is needed. OBJECTIVE: To examine the literature concerning chiropractors' attitudes toward drug prescription rights and to compare the opinions of chiropractors currently licensed to prescribe medication with those in the profession who are not. METHODS: This was a narrative review, consisting of a formal literature search and summary of included articles. Electronic databases searched included the Cumulative Index to Nursing and Allied Health Literature, PubMed, and the Index to Chiropractic Literature. Inclusion criteria consisted of prospective studies published in English in peer-reviewed journals. Studies were required to contain data on chiropractors' opinions toward medication prescription rights. RESULTS: Of 33 articles identified, a total of seven surveys were included in the review. Of these, there was a general split in opinion among chiropractors regarding the right to prescribe drugs in chiropractic practice. Those supportive of prescribing rights favoured a limited number of over-the counter and/or prescription-based medications such as analgesics, anti inflammatories, and muscle relaxants. When questioned on full prescribing rights, however, chiropractors were generally opposed. In jurisdictions where chiropractors are currently licensed to prescribe from a limited formulary, such as in Switzerland, the majority perceived this right as an advantage for the profession. Moreover, continuing education in pharmacology was viewed as a necessary component of this privilege. CONCLUSIONS: Based on the literature to date there is a general split in chiropractors' attitudes toward drug prescription rights. This split is most pronounced in countries where chiropractors are not licensed to prescribe medications. Notwithstanding, this is an important topic in chiropractic currently and warrants both further discussion and research to determine future directions and the implications of either pursuit or denial of prescription rights by chiropractors. Future surveys and/or qualitative studies of other chiropractors' opinions toward gaining prescription privileges would be timely. PMID- 25279138 TI - A computerized neuropsychological test battery designed for idiopathic normal pressure hydrocephalus. AB - BACKGROUND: A tool for standardized and repeated neuropsychological assessments in patients with idiopathic normal pressure hydrocephalus (INPH) is needed. The objective of this study was to develop a computerized neuropsychological test battery designed for INPH and to evaluate its reliability, validity and patient's ability to complete the tests. METHODS: Based on a structured review of the literature on neuropsychological testing in INPH, the eight tests most sensitive to the INPH cognitive profile were implemented in a computerized format. The Geriatric Depression Scale (GDS) was also included. Tests were presented on a touch-screen monitor, with animated instructions and speaker sound. The battery was evaluated with the following cohorts: A. Test-retest reliability, 44 healthy elderly; B. Validity against standard pen and pencil testing, 28 patients with various cognitive impairments; C. Ability to complete test battery, defined as completion of at least seven of the eight tests, 40 investigated for INPH. RESULTS: A. All except the figure copy test showed good test-retest reliability, r = 0.67-0.90; B. A high correlation was seen between conventional and computerized tests (r = 0.66-0.85) except for delayed recognition and figure copy task; C. Seventy-eight percent completed the computerized battery; Patients diagnosed with INPH (n = 26) performed worse on all tests, including depression score, compared to healthy controls. CONCLUSIONS: A new computerized neuropsychological test battery designed for patients with communicating hydrocephalus and INPH was introduced. Its reliability, validity for general cognitive impairment and completion rate for INPH was promising. After exclusion of the figure copy task, the battery is ready for clinical evaluation and as a next step we suggest validation for INPH and a comparison before and after shunt surgery. TRIAL REGISTRATION: ClinicalTrials.org NCT01265251. PMID- 25279139 TI - Copper toxicity in a New Zealand dairy herd. AB - Chronic copper toxicity was diagnosed in a Jersey herd in the Waikato region of New Zealand following an investigation into the deaths of six cattle from a herd of 250 dry cows. Clinical signs and post-mortem examination results were consistent with a hepatopathy, and high concentrations of copper in liver and blood samples of clinically affected animals confirmed copper toxicity. Liver copper concentrations and serum gamma-glutamyl transferase activities were both raised in a group of healthy animals sampled at random from the affected herd, indicating an ongoing risk to the remaining cattle; these animals all had serum copper concentrations within normal limits. Serum samples and liver biopsies were also collected and assayed for copper from animals within two other dairy herds on the same farm; combined results from all three herds showed poor correlation between serum and liver copper concentrations. To reduce liver copper concentrations the affected herd was drenched with 0.5 g ammonium molybdate and 1 g sodium sulphate per cow for five days, and the herd was given no supplementary feed or mineral supplements. Liver biopsies were repeated 44 days after the initial biopsies (approximately 1 month after the end of the drenching program); these showed a significant 37.3% decrease in liver copper concentrations (P <0.02). Also there were no further deaths after the start of the drenching program. Since there was no control group it is impossible to quantify the effect of the drenching program in this case, and dietary changes were also made that would have depleted liver copper stores. Historical analysis of the diet was difficult due to poor record keeping, but multiple sources of copper contributed to a long term copper over supplementation of the herd; the biggest source of copper was a mineral supplement. The farmer perceived this herd to have problems with copper deficiency prior to the diagnosis of copper toxicity, so this case demonstrates the importance of monitoring herd copper status regularly. Also the poor correlation between liver and serum copper concentrations in the three herds sampled demonstrates the importance of using liver copper concentration to assess herd copper status. PMID- 25165537 TI - Cytoscape: the network visualization tool for GenomeSpace workflows. AB - Modern genomic analysis often requires workflows incorporating multiple best-of breed tools. GenomeSpace is a web-based visual workbench that combines a selection of these tools with mechanisms that create data flows between them. One such tool is Cytoscape 3, a popular application that enables analysis and visualization of graph-oriented genomic networks. As Cytoscape runs on the desktop, and not in a web browser, integrating it into GenomeSpace required special care in creating a seamless user experience and enabling appropriate data flows. In this paper, we present the design and operation of the Cytoscape GenomeSpace app, which accomplishes this integration, thereby providing critical analysis and visualization functionality for GenomeSpace users. It has been downloaded over 850 times since the release of its first version in September, 2013. PMID- 25279141 TI - In silico analysis of high affinity potassium transporter (HKT) isoforms in different plants. AB - BACKGROUND: High affinity potassium transporters (HKTs) are located in the plasma membrane of the vessels and have significant influence on salt tolerance in some plants. They exclude Na(+) from the parenchyma cells to reduce Na(+) concentration. Despite many studies, the underlying regulatory mechanisms and the exact functions of HKTs within different genomic backgrounds are relatively unknown. In this study, various bioinformatics techniques, including promoter analysis, identification of HKT-surrounding genes, and construction of gene networks, were applied to investigate the HKT regulatory mechanism. RESULTS: Promoter analysis showed that rice HKTs carry ABA response elements. Additionally, jasmonic acid response elements were detected on promoter region of TmHKT1;5. In silico synteny highlighted several unknown and new loci near rice, Arabidopsis thaliana and Physcomitrella patent HKTs, which may play a significant role in salt stress tolerance in concert with HKTs. Gene network prediction unravelled that crosstalk between jasmonate and ethylene reduces AtHKT1;1 expression. Furthermore, antiporter and transferase proteins were found in AtHKT1;1 gene network. Interestingly, regulatory elements on the promoter region of HKT in wild genotype (TmHKT1;5) were more frequent and variable than the ones in cultivated wheat (TaHKT1;5) which provides the possibility of rapid response and better understanding of environmental conditions for wild genotype. CONCLUSION: Detecting ABA and jasmonic acid response elements on promoter regions of HKTs provide valuable clues on underlying regulatory mechanisms of HKTs. In silico synteny and pathway discovery indicated several candidates which act in concert with HKTs in stress condition. We highlighted different arrangement of regulatory elements on promoter region of wild wheat (TmHKT1;5) compared to bread wheat (TaHKT1;5) in this study. PMID- 25279142 TI - Effects of corn gluten feed inclusion at graded levels in a corn-soybean diet on the ileal and fecal digestibility of growing pigs. AB - BACKGROUND: This study aimed to determine the effect of the inclusion of corn gluten feed (CGF) on the apparent and standardized ileal digestibility of protein and amino acids and the apparent ileal and total tract digestibility of energy in growing pigs. The study was performed using 16 barrows (weight, 45.3 +/- 4.5 kg) that were fitted with a T cannula at the terminal ileum. There were four treatments: a corn-soybean diet without CGF and three corn-soybean diets containing increasing levels of CGF (65, 130, and 195 g/kg). Data were analyzed according to a randomized complete block design, four blocks with four pigs each (one pig per treatment). The trend of the response (linear or quadratic) was determined using orthogonal contrasts, and when a linear effect was determined, a linear equation was obtained. RESULTS: The results showed that the inclusion up to 195 g/kg of CGF in the corn-soybean diet did not diminish the ileal digestibility (apparent and standardized) of protein and amino acids (P > 0.05), except that of phenylalanine, cystine, and proline. A linear decrease (P < 0.05) per gram of CGF added to the diet in the apparent and standardized ileal digestibility of phenylalanine (0.011 and 0.015 percentage units, respectively), cystine (0.048 and 0.043 percentage units, respectively), and proline (0.045 and 0.047 percentage units, respectively) was noted. Similarly, ileal digestibility of dry matter and energy were adversely affected (reduced by 0.028 and 0.025 percentage units, respectively, per gram of CGF increment in the diet). A significant (P < 0.05) linear reduction in total tract digestibility with increase in CGF amount in the diet was observed for energy (0.027 percentage units), dry matter (0.027 percentage units), crude protein (0.020 percentage units), and neutral detergent fiber (0.041 percentage units) per gram of CGF added to the diet. CONCLUSION: CGF did not affect the ileal digestibility of protein and most amino acids but reduced the ileal and total tract digestibility of energy. PMID- 25279144 TI - Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review). AB - Inflammation is a key component of atherosclerosis. Genes coding for inflammatory or anti-inflammatory molecules are considered good candidates for estimating the risk of developing atherosclerosis. Cyclin-dependent kinase 9 (CDK9), the kinase of positive transcription elongation factor b (P-TEFb), is crucial in the cell cycle and apoptosis. Previous studies have focused on its inhibition of immune cells for the resolution of inflammation. Considering the effects of inflammation in the pathogenicity of atherosclerosis, decreasing inflammation through the inhibition of CDK9 may be useful for the prognosis of atherosclerosis. The aim of this review was to examine whether inhibition of the CDK9 monocyte may affect the process of inflammation by acting on the cytokine secretion and interacting with endothelial cells (ECs). Thus, CDK9 may be a novel target for the diagnosis and therapy of atherosclerosis. PMID- 25279143 TI - Effects of vitamin D in the elderly population: current status and perspectives. AB - Besides its well-known effect on bone metabolism, recent researches suggest that vitamin D may also play a role in the muscular, immune, endocrine, and central nervous systems. Double-blind RCTs support vitamin D supplementation at a dose of 800 IU per day for the prevention of falls and fractures in the senior population. Ecological, case-control and cohort studies have suggested that high vitamin D levels were associated with a reduced risk of autoimmune diseases, type 2 diabetes, cardio-vascular diseases and cancer but large clinical trials are lacking today to provide solid evidence of a vitamin D benefit beyond bone health. At last, the optimal dose, route of administration, dosing interval and duration of vitamin D supplementation at a specific target dose beyond the prevention of vitamin D deficiency need to be further investigated. PMID- 25279145 TI - Effect of light on global gene expression in the neuroglobin-deficient mouse retina. AB - Several previous studies have raised controversy over the functional role of neuroglobin (Ngb) in the retina. Certain studies indicate a significant impact of Ngb on retinal physiology, whereas others are conflicting. The present is an observational study that tested the effect of Ngb deficiency on gene expression in dark- and light-adapted mouse retinas. Large-scale gene expression profiling was performed using GeneChip(r) Mouse Exon 1.0 ST arrays and the results were compared to publicly available data sets. The lack of Ngb was found to have a minor effect on the light-induced retinal gene expression response. In addition, there was no increase in the expression of marker genes associated with hypoxia, endoplasmic reticulum-stress and oxidative stress in the Ngb-deficient retina. By contrast, several genes were identified that appeared to be differentially expressed between the genotypes when the effect of light was ignored. The present study indicates that Ngb deficiency does not lead to major alternations in light dependent gene expression response, but leads to subtle systemic differences of a currently unknown functional significance. PMID- 25279146 TI - Rho/Rock cross-talks with transforming growth factor-beta/Smad pathway participates in lung fibroblast-myofibroblast differentiation. AB - The differentiation of fibroblasts, which are promoted by transforming growth factor-beta (TGF-beta)/Smad, is involved in the process of pulmonary fibrosis. The Rho/Rho-associated coiled-coil-forming protein kinase (Rock) pathway may regulate the fibroblast differentiation and myofibroblast expression of alpha smooth muscle actin (alpha-SMA), however, the mechanism is not clear. The aim of the present study was to evaluate the role of Rho/Rock and TGF-beta/Smad in TGF beta1-induced lung fibroblasts differentiation. Human embryonic lung fibroblasts were stimulated by TGF-beta1, Y-27632 (inhibitor of Rho/Rock signaling) and staurosporine (inhibitor of TGF-beta/Smad signaling). The alpha-SMA expression, cell cycle progression, content of the extracellular matrix (ECM) in cell culture supernatants and the expression of RhoA, RhoC, Rock1 and Smad2 were detected. The results demonstrated that alpha-SMA-positive cells significantly increased following TGF-beta1 stimulation. Rho/Rock and TGF-beta/Smad inhibitors suppressed TGF-beta1-induced lung fibroblast differentiation. The inhibitors increased G0/G1 and decreased S and G2/M percentages. The concentrations of the ECM proteins in the supernatant were significantly increased by TGF-beta1 stimulation, whereas they were decreased by inhibitor stimulation. RhoA, RhoC, Rock1, Smad2 and tissue inhibitor of metalloproteinase-1 were upregulated by TGF-beta1 stimulation. The Rho/Rock inhibitor downregulated Smad2 expression and the TGF-beta/Smad inhibitor downregulated RhoA, RhoC and Rock1 expression. Therefore, the Rho/Rock pathway and Smad signaling were involved in the process of lung fibroblasts transformation, induced by TGF-beta1, to myofibroblasts. The two pathways may undergo cross-talk in the lung fibroblasts differentiation in vitro. PMID- 25279147 TI - Comparative proteomic analysis of renal tissue in IgA nephropathy with iTRAQ quantitative proteomics. AB - Immunoglobulin (Ig) A nephropathy (IgAN) is the most common form of glomerulonephritis. In clinical practice, it is difficult to monitor the repeating relapse in patients suffering from IgAN, which usually occurs within 10 years of end-stage renal disease. In order to identify and quantify the total protein content in the renal tissue of patients with IgAN, isobaric tags for relative and absolute quantification (iTRAQ) technology was performed. iTRAQ coupled with multiple chromatographic fractionation and tandem mass spectrometry was used to analyze the total protein of normal renal tissue in IgAN and healthy patients. The individual proteins were identified by the Mascot search engine and any that were differentially expressed were monitored. A total of 574 different proteins were identified, and 287 proteins were up- or downregulated by >1 fold alteration in levels. The results showed that iTRAQ-based quantitative proteomic technology for the identification and relative quantitation of the renal tissue proteome is efficiently applicable. The differential expression of the proteome profiles for IgAN patients was determined. Further studies using large cohorts of patient samples with long-term clinical follow-up data should be conducted to evaluate the usefulness of the pathogenesis and novel biomarker candidates of IgAN, which may develop a novel technique for the diagnosis of IgAN. PMID- 25279148 TI - Co-culture of hepatocellular carcinoma cells and human umbilical endothelial cells damaged by SU11274. AB - Mesenchymal-epithelial transition factor (c-Met) is a receptor that binds to the hepatocyte growth factor and is upregulated in hepatocellular carcinoma (HCC). The anti-tumor effects of (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4- methyl piperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-me- thyl-2-oxo-2,3-dihydro 1H-indole-5-sulfonamide (SU11274), a c-Met inhibitor, were investigated in the present study. HCC cells (HLE, HLF, PLC/PRL/5, Hep3B, Huh-6 and HepG2) and human umbilical vein endothelial cells (HUVECs) were used. Quantitative polymerase chain reaction was performed to detect the expression level of c-Met in HCC and HUVECs, and cyclin D1 in HCC. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-car boxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt assay was performed to assess the proliferation of the HCC cells and HUVECs cultured with SU11274. Co-culture of HLF or PLC/PRL/5 cells and HUVECs was established as an in vitro model of HCC tissues. The expression levels of c-Met in HLE, HLF, PLC/PRL/5, Hep3B, Huh-6 and HepG2, adult healthy liver and HUVECs were 4.43+/ 0.50, 1.61+/-0.18, 3.70+/-0.08, 0.81+/-0.18, 6.60+/-1.29, 1.06+/-0.35, 1.00+/ 0.09 and 88.8+/-17.3 (mean +/- standard deviation), respectively. SU11274 (30 MUM) suppressed the proliferation of HLF, PLC/PRL/5 and HUVECs to 11.0+/-9.4, 46.5+/-30.7 and 29.4+/-5.0%, respectively. SU11274 (30 MUM) decreased the expression levels of cyclin D1 in HLF and PLC/PRL/5 cells to 45.1+/-11.6 and 30.1+/-10.3%, respectively. SU11274, at a concentration of 30 MUM damaged the morphology of the co-cultures of HLF or PLC/PRL/5 cells with HUVECs and all the cells died. c-Met is highly expressed in HUVECs and HCC cells, but not in Hep3B. At a 30-MUM concentration, SU11274 suppresses the proliferation of HLF, PLC/PRL/5 and HUVECs. SU11274 (30 MUM) damages the co-cultures of HLF or PLC/PRL/5 cells with HUVECs. PMID- 25279149 TI - DNA profiling in peripheral blood, buccal swabs, hair follicles and semen from a patient following allogeneic hematopoietic stem cells transplantation. AB - Allogeneic peripheral blood stem cells transplantation (allo-PBSCT) or allogeneic bone marrow transplantation (allo-BMT) have been widely used to treat patients exhibiting certain severe illnesses. However, previous studies have shown that the biological materials of allo-PBSCT or allo-BMT recipients may not constitute credible materials for personal identification. In the present study, four types of commonly used samples were collected from a male individual following gender matched allo-BMT. Autosomal short tandem repeat (STR) and Y-STR markers analysis, based on polymerase chain reaction, were used to evaluate the chimerism status. The results showed that the blood sample were all donor type, the buccal swab sample were mixed chimerism, and the sperm and hair follicle samples maintained a recipient origin of 100%. In conclusion, identical results were obtained by the two methods and it was confirmed that DNA extracted from hair follicles and sperm can be used as a reference for the pre-transplant genotype DNA profile of the recipient in the gender-match allo-BMT or -PBSCT. PMID- 25279150 TI - Induction of HLA-A*33-restricted cytotoxic lymphocytes against renal cell carcinoma targeting galectin 9 and PINCH. AB - Galectin 9, a ligand of T cell immunoglobulin and mucin domain 3 (TIM-3), and PINCH, an epithelial-to-mesenchymal transition (EMT)-promoting molecule, are expressed at much higher levels in cancerous lesions of clear cell type renal cell carcinoma (RCC) compared to normal renal tissues, and their expression levels are extremely low in normal tissues, except for galectin 9 in the spleen. Galectin 9- and PINCH-derived peptides have previously been shown to induce human leukocyte antigen (HLA)-A*2402-restricted and HLA-A*0201-restricted cytotoxic lymphocytes (CTLs) with specific and highly cytotoxic activities toward RCC cells. The present study aimed to identify the peptides that induced HLA-A*33 restricted CTLs that exhibited specific and highly cytotoxic activities toward RCC cells. Specific CTLs were induced significantly, as shown by cluster of differentiation 107a degranulation stimulated with VMRC-RCW renal carcinoma cells. Therefore, peptide vaccines targeting galectin 9 and PINCH appear to be promising for clinical application. PMID- 25279151 TI - Expression and significance of transient receptor potential cation channel V5 in articular cartilage cells under exercise loads. AB - The expression of transient receptor potential cation channel V5 (TRPV5) in articular cartilage cells under normal and exercise loading conditions was measured, and the clinical significance, in order to define its role in the formation of articular cartilage tissues was analyzed. In normal and osteoarthritis (OA) Sprague Dawley rats the severity of injury was observed, TRPV5 expression was measured by immunohistochemistry following exercise loading, and its association with clinical pathological characteristics (including articular lesions) was analyzed. The results of the immunohistochemical assay showed that the percentage of positive expression areas in the normal articular cartilage and loading articular cartilage groups was 34.3+/-5.8 and 18.1+/-4.9%, respectively. In the OA articular cartilage and OA loading articular cartilage groups, the positive expression areas were 13.17+/-4.2 and 6.4+/-2.7%, respectively. There was a statistically significant difference in TRPV5 expression levels between the normal articular cartilage and loading articular cartilage groups, and between the OA articular cartilage and OA loading articular cartilage groups (P<0.001). TRPV5 is expressed in all bone cartilage tissues and its expression level depends on the load of the bone and joint. Therefore, this indicates that TRPV5 may play a role in the formation and development processes of cartilage tissues. PMID- 25279152 TI - Association of a butyrophilin, subfamily 2, member A1 gene polymorphism with hypertension. AB - The C->T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 (BTN2A1) gene has been previously identified as a susceptibility locus for myocardial infarction by a genome-wide association study. As hypertension is a major risk factor for myocardial infarction, the association between the BTN2A1 polymorphism, rs6929846, and myocardial infarction may be partly due to its effect on hypertension susceptibility. The aim of the present study was to examine the possible association of rs6929846 with hypertension. The study subjects comprised 5,959 community-dwelling individuals (2,183 subjects with hypertension and 3,776 controls) who were recruited to a population-based cohort study. The rs6929846 genotype was determined by a method that combined polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons between the genotype distributions (P=0.0090) and allele frequencies (P=0.0051) by the chi2 test revealed that rs6929846 was significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs6929846 was significantly associated with hypertension (P=0.0008; odds ratio, 1.29; dominant model), with the minor T allele representing a risk factor for this condition. Among all the individuals, systolic, diastolic and mean blood pressure was significantly higher in the combined group of individuals with the CT or TT genotypes compared to the CC genotype group. BTN2A1 may thus be a susceptibility gene for hypertension. Therefore, determining the genotype for this polymorphism may provide genetic risk assessment information for hypertension. PMID- 25279153 TI - Association of the vascular endothelial growth factor -2578C/A polymorphism with cancer risk: A meta-analysis update. AB - The vascular endothelial growth factor (VEGF) -2578C/A polymorphism has been previously reported to be associated with cancer risk; however, the results have been controversial. Therefore, the aim of the present study was to explore the association between the VEGF -2578C/A polymorphism with the cancer risk. A total of 37 case-control studies were identified. The pooled analysis showed that there was no association between VEGF -2578C/A and the risk of cancer, and the odds ratios (ORs) [with the corresponding 95% confidence intervals (95% CIs)] were 0.97 (0.91-1.04) for C vs. A, 0.94 (0.86-1.02) for CC vs. AA, 0.92 (0.80-1.06) for CA vs. AA, 0.96 (0.89-1.03) for CC/CA vs. AA and 0.97 (0.88-1.08) for CC vs. CA/AA. Subgroup analyses according to ethnicity, source of control and type of cancer showed that the VEGF -2578C/A polymorphism is associated with colorectal and lung cancers. Additionally, the polymorphism may decrease the risk of cancer in the Asian population. This VEGF polymorphism was not associated with a risk of cancer for the Caucasian [0.92 (0.76-1.11) for CC vs. AA] and African populations [1.31 (0.67-2.58) for CC vs. AA], and it was not associated with bladder [1.06 (0.74-1.53) for CC/AA] and breast cancers [1.01 (0.90-1.15) for CC/AA]. Therefore, the present meta-analysis indicates that VEGF -2578C/A may only be associated with the risk of colorectal cancer, lung cancer and the Asian population. More studies with larger sample sizes are required to provide more conclusive evidence. PMID- 25279154 TI - Altered glutamate cysteine ligase expression and activity in renal cell carcinoma. AB - Oxidative stress has been linked to the progression of mutations and cancer. Increased glutathione (GSH) contents have been observed in a number of different human cancer tissues. GSH is synthesized de novo in a two-step process catalyzed by glutamate cysteine ligase (GCL). The present study aimed to investigate whether GCL was associated with renal cell carcinoma (RCC). The protein expression levels of the GCL subunits (catalytic subunit, GCLc; and modulatory subunit, GCLm) and GCL activity were examined in renal cancer tissue. A total of 46 patients fulfilling the RCC criteria of the World Health Organization, revised in 2004, were enrolled. The tumor and adjacent tissues were sampled from all the subjects by surgery. The study demonstrated that GCLc and GCLm protein expression and the GCL activity were significantly increased in the tumor tissue from RCC patients. These results indicate that increased expression and enzymatic activity of GCL is closely associated with RCC and thus, this suggests an important role for GSH in the pathogenesis of RCC. PMID- 25279155 TI - Preliminary analysis of different microRNA expression levels in juvenile angiofibromas. AB - Juvenile angiofibroma (JA) is a rare fibrovascular tumor affecting, almost exclusively, adolescent males. The finding of frequent beta-catenin-mutations in JAs emphasized the significance of the Wnt-signaling pathway in tumor pathogenesis. In the last decade, microRNAs (miRNAs or miRs) have been found to be involved in cancer pathogenesis by post-transcriptional regulation of gene expression and have not been analyzed in JAs thus far. In the present study, the expression of 4 miRNAs (hsa-let-7d, hsa-miR-98, hsa-miR-125a-5p and hsa-miR-218) was analyzed in 13 JAs and 3 deepithelized inferior nasal turbinates that were used as control tissue. The miRNA expression of hsa-let-7d (P=0.158) and hsa-miR 98 (P=0.069) was not statistically different between the two tissue types, however, a significant decrease in expression was observed for hsa-miR-125a-5p (P=0.037) and hsa-miR-218 (P=0.009) in JAs compared to inferior nasal turbinates. As downregulation of miRNA 218 has been recently shown to result in stabilization and nuclear accumulation of beta-catenin, the present data indicates further evidence for the importance of the Wnt-signaling pathway in JAs. PMID- 25279156 TI - Association between fetuin-A levels with insulin resistance and carotid intima media thickness in patients with new-onset type 2 diabetes mellitus. AB - Fetuin-A, which is known to inhibit insulin signaling and pathological calcification, has emerged as a diabetes risk biomarker. In the present study, the association between the fetuin-A levels with insulin resistance (IR) and carotid intima-media thickness (CIMT) was investigated in patients with new-onset type 2 diabetes mellitus (nT2DM). A total of 100 patients with nT2DM (nT2DM group) and 100 normal glucose tolerance (NGT group) controls were evaluated. The serum fetuin-A level was measured by a commercial solid-phase ELISA kit. The estimate of IR was calculated by homeostasis model assessment (HOMA-IR). CIMT was measured by B-mode ultrasound. The association between the serum fetuin-A levels and the metabolic parameters was also analyzed. The serum fetuin-A levels were increased significantly in the nT2DM group compared to the NGT group (368.5+/ 15.6 mg/ml vs. 152.7+/-7.1 mg/ml, P<0.01). Fetuin-A was positively correlated with HOMA-IR, CIMT, glycated hemoglobin, triglyceride, low-density lipoprotein cholesterol, body mass index, systolic blood pressure, fasting blood glucose and 2 h post-glucose load blood glucose (P<0.05 and P<0.01), but negatively correlated with fasting plasma insulin, 2 h plasma insulin after glucose overload, high-density lipoprotein cholesterol and HOMA-beta-cell insulin secretion index (P<0.05 and P<0.01). To the best of our knowledge, the study demonstrated for the first time that there is a significant association between the serum fetuin-A levels with IR and CIMT in nT2DM. These results indicate that serum fetuin-A levels can be used as independent markers in the diagnosis of macroangiopathies in nT2DM. PMID- 25279157 TI - Predictive prognostic role of miR-181a with discrepancy in the liver and serum of genotype 4 hepatitis C virus patients. AB - microRNA (miRNA) expression in organs does not always represent their quantity in serum. A disparity in the expression of miR-181a has been reported in the tissues and serum of hepatocellular carcinoma (HCC) patients. Since hepatitis C virus (HCV) is a major cause of HCC and miR-181a has never been studied in HCV, the present study aimed to investigate the miR-181a expression profile in genotype 4 (GT4)-HCV patients to evaluate whether this pattern is also apparent in HCV. RNA was extracted from liver tissues, peripheral mononuclear cells (PBMCs) and serum samples from GT4-HCV-infected patients and healthy donors to evaluate the relative miR-181a expression using quantitative reverse transcription-polymerase chain reaction. miR-181a was significantly higher in the serum of naive patients compared to controls, and an inverse correlation with the viral load and liver enzymes was apparent. By contrast, no difference in miR-181a expression was observed in the liver tissues and PBMCs of patients compared to controls. This expression observed in HCV is conflicting to that previously reported in HCC. The study also demonstrates a significant upregulation of miR-181a post interferon/ribavirin treatment in the serum of sustained virological responders (SVRs) compared to non-responders and treatment-naive SVRs. In conclusion, miR 181a may be considered to be a possible prognostic marker in GT4-HCV infection. PMID- 25279158 TI - Lack of association between LEPR Lys656Asn or Ser343Ser polymorphisms and cancer susceptibility: A meta-analysis. AB - Previous studies have shown conflicting results between the association of leptin receptor (LEPR) genetic polymorphisms and cancer risk. The frequent LEPR Lys656Asn or Ser343Ser genetic polymorphism has been demonstrated to be functional and may promote genetic susceptibility to cancers. However, the association between the LEPR Lys656Asn or Ser343Ser genetic polymorphism and cancer risk remains to be determined. To improve the understanding of the LEPR Lys656Asn or Ser343Ser genetic polymorphism role in global cancer, a comprehensive meta-analysis was conducted that comprised 2,480 cases and 3,162 controls. The LEPR Lys656Asn or Ser343Ser genetic polymorphism did not significantly affect the cancer risk. In the stratified analysis, there was no significant association of the LEPR Lys656Asn or Ser343Ser variants with any type of cancer under any model. In addition, significantly increased risks were found in the Asian population in heterozygous codominant [odds ratio (OR), 1.24 (1.01 1.53)] and dominant [OR, 1.24 (1.02-1.50)] genetic models. A significantly increased susceptibility to cancer was not found when stratified by study design. There were no significant differences found in genotype method and sample size in cases among the genotypes. These findings indicated a lack of association between LEPR Lys656Asn or Ser343Ser polymorphisms and cancer susceptibility, however, these polymorphisms may increase the cancer susceptibility among the Asian population, particularly in the dominant genetic model. The single-nucleotide polymorphism is also suggested to function as a dominant mutation, which requires verification or association with functional studies. PMID- 25279159 TI - Effects of Chungsinoryungsan, a polyherbal complex, on the pharmacokinetic profiles of perindopril in rats. AB - For sufficient antihypertension with less adverse effects, numerous clinical trials have recommended combination therapy using two or more hypertensive drugs. Chungsinoryungsan (CSORS) is a polyherbal complex based on oriental medicine, which has shown therapeutic potentials for antihypertension and additional renal improvement. Therefore, the affect of CSORS on the pharmacokinetic profiles of perindopril, an antihypertensive drug, was analyzed as a novel combination of hypertensive drugs. Rats received perindopril with CSORS as the combination or distilled water as the control. The co-administration of perindopril with CSORS or distilled water was performed by single dosing or repeated dosing for a week at a 2-h interval. The analyzed pharmacokinetic parameters included peak concentration (Cmax), time to reach the Cmax (Tmax), area under the plasma concentration-time curve, terminal half-life (t1/2) and mean residence time to infinity (MRTinf). In the single oral co-administration within 5 min, the pharmacokinetics of perindopril demonstrated an increased Tmax and MRTinf but reduced t1/2 in the combination compared to the control treatment, indicating drug-drug interactions between perindopril and CSORS. However, in the repeated co administration for a week at a 2-h interval, which was more than perindopril MRTinf in the control treatment (1.5+/-0.1 h), the initial co-administration showed no differences in the pharmacokinetics between the combination and control treatments. Furthermore, the repeated co-administration also showed no differences between the combination and control treatment. The results indicate that CSORS can be co-administered at a 2-h interval that was more than perindopril MRTinf and further clinical studies may provide detailed information for developing a drug regimen that generates enhanced combination effects of CSORS with hypertensive drugs. PMID- 25279160 TI - Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension. AB - The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (chi2=6.658, chi2=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID- 25279161 TI - Early expression of local cytokines during systemic Candida albicans infection in a murine intravenous challenge model. AB - Local cytokine production is a significant indicator for disease pathogenesis or progression. Previous studies on cytokine production during systemic Candida albicans (C. albicans) infection were solely on kidney or single cell type interaction with C. albicans. Therefore, the present study aimed to assess the early cytokine expression of various target organs (kidney, spleen and brain) over a 72-h time course during systemic C. albicans infection. The local cytokine profiles of the target organs during systemic C. albicans infection were measured by cytometric bead array and ELISA analysis. The results demonstrated that interleukin-6 (IL-6) and IL-2 were statistically significant (P<0.05) in the spleen at 24 and 72 h post-infection, whereas in the kidney, IL-6 and tumor necrosis factor-alpha (TNF-alpha) were statistically significant (P<0.05) at 24 and 72 h post-infection and CXCL-1 and transforming growth factor-beta (TGF-beta) were statistically significant (P<0.05) at 72 h post-infection. In the brain, IL 6 and TNF-alpha were statistically significant (P<0.05) at 24 and 72 h post infection, whereas TGF-beta was statistically significant (P<0.05) at 72 h post infection. These findings demonstrate that host immune responses were varied among target organs during systemic C. albicans infection. This could be important for designing targeted immunotherapy against this pathogen through immunomodulatory approaches in future exploratory research. PMID- 25279162 TI - Role of cyclooxygenase-2 in intestinal injury in neonatal rats. AB - Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature neonates. The pathogenesis of NEC remains poorly understood. The present study aimed to investigate the dynamic change and role of cyclooxygenase 2 (COX-2) in neonatal rats with intestinal injury. Wistar rats, <24 h in age, received an intraperitoneal injection with 5 mg/kg lipopolysaccharide (LPS). Ileal tissues were collected at 1, 3, 6, 12 and 24 h following the LPS challenge for histological evaluation of NEC and for measurements of COX-2 mRNA. The correlation between the degree of intestinal injury and expression of COX-2 mRNA was determined. The LPS-injected pups showed a significant increase in injury scores compared to the control, and the most deteriorating change was at 12 h. COX-2 mRNA expression was upregulated following LPS injection. There was a significantly positive correlation between COX-2 mRNA and the grade of intestinal injury within 12 h, whereas COX-2 mRNA expression had a significantly negative correlation with the severity of intestinal injury at 24 h. COX-2 plays an important role in LPS-induced intestinal injury and the repair processes. Caution should be exerted concerning the potential therapeutic uses of COX-2 inhibitors or promoters in NEC. PMID- 25279163 TI - Association between LGALS2 3279C>T and coronary artery disease: A case-control study and a meta-analysis. AB - Coronary artery disease (CAD) has become the main cause of mortality worldwide. Lectin galactoside-binding soluble-2 (LGALS2) is involved in the cytokine lymphotoxin-alpha (LTA) cascade that may influence the progress of CAD. The aim of the present study was to assess the association between the LGALS2 3279C>T (rs7291467) polymorphism and CAD. A total of 562 cases and 572 controls were recruited to examine the association. A systematic meta-analysis was performed to evaluate the contribution of LGALS2 3279C>T polymorphism to the risk of CAD among 12,093 cases and 11,020 controls. There was no significant association found in the present case-control study. However, the meta-analysis showed that LGALS2 3279C>T played a protective role in CAD [P=0.008, odds ratio (OR), 0.90; 95% confidence interval (95% CI), 0.82-0.97] and particularly in the Asian population (P=0.006; OR, 0.82; 95% CI, 0.71-0.94). The present case-control study did not find a significant association between LGALS2 3279C>T and CAD in the Eastern Han Chinese population. However, the meta-analysis indicated that LGALS2 3279C>T played a protective role in CAD, suggesting an ethnic difference in the association of the locus with CAD. PMID- 25279164 TI - Meta-analyses of seven GIGYF2 polymorphisms with Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects ~2% of the global population aged >=65 years. Grb10-interacting GYF protein-2 (GIGYF2) can influence the development of PD through the regulation of insulin-like growth factor-1. The aim of the present meta-analysis study was to establish the contribution of GIGYF2 polymorphisms to PD. The study was conducted based on nine eligible studies consisting of 7,246 PD patients and 7,544 healthy controls. The results indicated that the GIGYF2 C.3630A>G polymorphism increased the risk of PD by 37% [P=0.008; odds ratio (OR), 1.37; 95% confidence interval (CI), 1.08-1.73] and that the GIGYF2 C.167G>A polymorphism was significantly associated with PD (P=0.003; OR, 3.67; 95% CI, 1.56-8.68). The meta-analyses of the other five GIGYF2 polymorphisms (C.1378C>A, C.1554G>A, C.2940A>G, C.1370C>A and C.3651G>A) did not reveal any significant associations. The present meta analyses of the GIGYF2 genetic polymorphisms may provide a comprehensive overview of this PD candidate gene for future studies. PMID- 25279165 TI - Effects of cisplatin on the contractile function of thoracic aorta of Sprague Dawley rats. AB - DNA-damaging agents have been reported to be associated with cardiovascular complications, however, the underlying mechanisms remain to be clarified. In the present study, the possible vascular effects of cisplatin was assessed by measuring its effects on the contractile function of thoracic aortic rings dissected from Sprague-Dawley (SD) rats. Contraction of the aortic ring was induced by 60 mM KCl or 10-6 M phenylephrine (PE) in an ex vivo perfusion system. Cisplatin (200 MUM) counteracted KCl- and PE-induced contraction by 57.6 and 91.8%, respectively, in endothelium-intact aortic rings. Similar results were obtained in endothelium-denuded aortas. Electromicroscopy analysis revealed severe damage to blood vessel walls in vivo by cisplatin. In addition, cisplatin significantly inhibited adenosine triphosphate (ATP)-induced intracellular Ca2+ concentration ([Ca2+]i) increases in human umbilical vein endothelial cells (HUVECs). These results suggested that the DNA-damaging agent cisplatin can affect the contractile function of thoracic aortas. In addition, in accordance with its DNA-damaging properties, the cardiovascular toxicity of cisplatin may be the result of its direct cytotoxicity. PMID- 25279166 TI - Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer. AB - Endostatin, as the most potential antiangiogenic factor, is a naturally occurring fragment of collagen XVIII in bloodstream capable of inhibiting tumor growth and metastasis. This study was conducted to explore the clinical value of endostatin in serum and tumor tissue in patients with operable non-small cell lung cancer (NSCLC). ELISA and immunohistochemistry were applied to detect the expression of endostatin in serum and tumor tissue in 105 patient-matched operable NSCLC patients. The serum level of endostatin was significantly higher in NSCLC patients than healthy individuals (P=0.0018). Cases with poorer differentiation showed a higher endostatin serum level (P=0.008). There was no significant correlation between tumor tissue expression and clinical parameters, such as TNM stage, differentiation degree, histological type and lymph node invasion status. A stronger expression of endostain in tumor tissue was associated with a higher serum level (r=0.223). The univariate and multivariate analyses with Cox proportional hazards model for overall survival showed that tumor stage and node status were independent prognostic factors, whereas neither endostatin levels in serum nor in tumor tissue showed potential in predicting the long-term survival of operable NSCLC patients. In conclusion, the results observed in the present study did not support the prediction of overall survival in operable NSCLC based on the expression levels of endostatin in serum and tumor tissue. PMID- 25279167 TI - Serum beta-human chorionic gonadotropin and interleukin-1 as diagnostic biomarkers for the premature rupture of membranes and chorioamnionitis. AB - Chorioamnionitis is common in females with prematurely ruptured fetal membranes (PROM). The current diagnosis of PROM and preterm PROM (PPROM) is based on vaginal fluid analysis. The present study investigated the value of serum beta human chorionic gonadotropin (beta-hCG) and interleukin-1 (IL-1) levels in diagnosing chorioamnionitis. In total, 150 term-pregnancy patients were included in the prospective study. A total of 50 females had normal pregnancies (control group) and 100 had PROM. One hour before delivery, 3 ml venous blood was collected and analyzed. Fetal membrane and placental tissue underwent histopathological analyses. Of the 100 term-pregnancy females, 56 had PROM and 44 had PROM combined with chorioamnionitis (PROM + C). The serum beta-hCG levels for the control, PROM and PROM + C groups were 7,557.86+/-2,922.06, 636.96+/ 14,379.10 and 50,310.34+/-22,874.82 IU/l, respectively. The receiver operating characteristic (ROC) for PROM and PROM + C groups (beta-hCG >=23,900.50 IU/l) had a sensitivity of 77.5% and a specificity of 78.6%. The level of IL-1 in the PROM + C group was higher compared to the control and PROM groups (0.58+/-0.05, 0.12+/ 0.04 and 0.13+/-0.03 ng/ml, respectively). In conclusion, ROC for the PROM and PROM + C groups (IL-1 >=0.38 ng/ml) had a sensitivity of 76.5% and a specificity of 72.6%. Therefore, serum beta-hCG and IL-1 are potential biomarkers for diagnosing PROM and PROM + C, respectively. PMID- 25279169 TI - Cathepsin K in treatment monitoring following intravenous zoledronic acid. AB - Cathepsin K (CatK) is mainly expressed by osteoclasts and plays an important role in bone resorption. As CatK is expressed and secreted by osteoclasts during active bone resorption, it may be a useful and specific biochemical marker of osteoclastic activity. Therefore, CatK serum levels were studied for monitoring the treatment of females with postmenopausal osteoporosis by zoledronic acid. The serum CatK levels were determined in nine postmenopausal females before and after 3, 6 and 12 months of treatment. The levels were significantly reduced after 3 and 6 months (P<0.05), whereas they returned to baseline after 1 year. Taken together, the serum level of CatK may be suitable for monitoring anti osteoporotic therapy in association with treatment response. PMID- 25279168 TI - beta-catenin knockdown enhances the effects of fluorouracil in the breast cancer cell line MDA-MB-468. AB - Tumor proliferation, drug resistance and cell stemness are major difficulties that are encountered during breast cancer therapy and are often responsible for disease progression and cancer-related mortality. beta-catenin is considered to be an invasion gene in breast cancer. However, how beta-catenin regulates breast cancer cell proliferation and stemness remains unclear. In the present study, beta-catenin knockdown by small interfering RNA in MDA-MB-468, a highly metastatic breast cancer cell line, inhibited the expression of beta-catenin, Oct3/4 (stemness), survivin (anti-apoptosis) and BCRP (drug resistance). Knockdown of beta-catenin enhanced the effects of fluorouracil (5-FU) chemotherapy on the proliferation of MDA-MB-468 cells. Thus, these preliminary results indicate that beta-catenin knockdown enhanced 5-FU-induced proliferation inhibition in the breast cancer cell line MDA-MB-468, and indicate that combining 5-FU with gene silencing could be an advantageous option for enhancing the curative effect of chemotherapy in breast cancer and other malignancies. PMID- 25279170 TI - Differential expression of natural antisense transcripts during liver development in embryonic mice. AB - The mature adult liver is a metabolizing and synthesizing organ consisting of hepatic lobules. The liver development during fetal stages is induced by the interaction between hepatoblast cells derived from the endoderm and stellate cells and/or endothelial cells derived from the mesoderm. Recently, the association of non-coding RNAs, such as microRNAs, in the liver development process has been reported. In the present study, the gene expression changes were investigated of natural antisense transcripts (NATs), a type of non-coding RNA, during the liver development using livers from embryonic day (E) 14, E17, E19 and newborn (NB). The upregulated NATs of 87 genes and the downregulated NATs of 26 genes were identified when the expression was >5.0-fold up/downregulated NATs at E17, E19 or NB compared to those at E14, as examined by microarray analysis. Among these NATs, strand-specific reverse transcription-quantitative polymerase chain reaction analyses validated that the NAT expression of Fga, Fgb, Fgg, F2, Apoa1, Fabp1, C3 and Proc, which have metabolic and synthesizing functions in the adult liver, increased, whereas the NAT expression of Ermap and Tfrc, which function in the hematopoiesis, decreased during the developmental stages. These results indicate that the differential expression of several NATs is induced during the process of liver development, suggesting that these NATs may be involved in the regulation of gene expression and functional conversion from a hematopoietic to a metabolic organ in the developmental stages of the liver. PMID- 25279172 TI - Passive targeting of nanoparticles to cancer: A comprehensive review of the literature. AB - Cancer remains the one of the most common causes of mortality in humans; thus, cancer treatment is currently a major focus of investigation. Researchers worldwide have been searching for the optimal treatment (the 'magic bullet') that will selectively target cancer, without afflicting significant morbidity. Recent advances in cancer nanotechnology have raised exciting opportunities for specific drug delivery by an emerging class of nanotherapeutics that may be targeted to neoplastic cells, thereby offering a major advantage over conventional chemotherapeutic agents. There are two ways by which targeting of nanoparticles may be achieved, namely passive and active targeting. The aim of this study was to provide a comprehensive review of the literature focusing on passive targeting. PMID- 25279171 TI - Utilising proteomic approaches to understand oncogenic human herpesviruses (Review). AB - The gamma-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus are successful pathogens, each infecting a large proportion of the human population. These viruses persist for the life of the host and may each contribute to a number of malignancies, for which there are currently no cures. Large-scale proteomic-based approaches provide an excellent means of increasing the collective understanding of the proteomes of these complex viruses and elucidating their numerous interactions within the infected host cell. These large-scale studies are important for the identification of the intricacies of viral infection and the development of novel therapeutics against these two important pathogens. PMID- 25279173 TI - Features of ovarian cancer in Lynch syndrome (Review). AB - Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but >=80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3 kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome. PMID- 25279174 TI - Management of lymph node metastases from an unknown primary site to the head and neck (Review). AB - Cancer of unknown primary site (CUP) is an intriguing clinical phenomenon found in ~3-9% of all head and neck cancers. It has not yet been determined whether CUP forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is the clinical presentation of metastasis in patients with an undetected primary tumor and no visible clinical signs. The treatment of patients with cervical lymph node metastases from CUP remains controversial, due to the lack of randomized clinical trials comparing different treatment options. Consequently, treatment is currently based on non-randomized data and institutional policy. In the present review, the range and limitations of diagnostic procedures are summarized and an optimal diagnostic work-up is recommended. The initial preferred diagnostic procedures include fine-needle aspiration biopsy (FNAB) and imaging. Although neck dissection followed by postoperative radiotherapy is the the most generally accepted approach, other curative options may be used in certain patients, such as neck dissection alone, nodal excision followed by postoperative radiotherapy, or radiotherapy alone. There remains controversy regarding target radiation volumes, ranging from ipsilateral neck irradiation to prophylactic irradiation of all the potential mucosal sites and both sides of the neck. When no primary lesion is identified with imaging and endoscopy in patients without history of smoking and alcohol abuse, molecular profiling of an FNAB sample for human papillomavirus and/or Epstein-Barr virus is required. PMID- 25279175 TI - Clinical experience with plerixafor as a mobilization regimen for autologous peripheral blood stem cell transplantation in patients with refractory germ cell tumors. AB - The purpose of this study was to report our experience with administration of plerixafor for the mobilization of hematopoietic stem cells (HSCs) in patients with refractory or recurrent germ cell tumors who were candidates for salvage therapy with high-dose chemotherapy and HSC transplantation and for whom mobilization of HSCs had not been achieved by standard therapies. This retrospective and observational study selected patients who were eligible for autologous HSC transplantation (AHSCT) and received plerixafor after failure of HSC mobilization by granulocyte colony-stimulating factor (G-CSF). A total of 5 patients (4 male and 1 female), aged 19-41 years (mean age, 29.6 years) were initially selected. Four patients (80%) achieved an adequate HSC mobilization with plerixafor and subsequently received high-dose chemotherapy followed by HSC transplantation. In these patients, the number of CD34+ cells collected following plerixafor mobilization was 1.8*106-10.3*106 cells/kg, with a peak CD34+ cell count of 7.0-32.0 cells/MUl. Following HSC infusion, these 4 patients achieved a neutrophil count of >0.5*103/mm3 and a platelet count of >20,000/MUl between days 10 and 14. Therefore, patients with high-risk germ cell tumors eligible for AHSCT who are refractory to mobilization by G-CSF, may benefit from the use of plerixafor, possibly to the same extent as patients with lymphoma and multiple myeloma. PMID- 25279176 TI - Time trends of clinical characteristics in hepatocellular carcinoma patients with chronic hepatitis B virus infection: A field survey between 2000 and 2012. AB - The hepatitis B virus (HBV) carrier rate has decreased in Japan; however, the incidence of HBV infection among hepatocellular carcinoma (HCC) patients has not decreased accordingly. In this study, we aimed to assess the time trends of the clinical characteristics in HCC patients with chronic HBV infection. Between 2000 and 2012, we enrolled a total of 156 HCC patients with chronic HBV infection in our field survey. The HCC risk was evaluated using the HCC prediction score, which is constructed from the characteristics of age, presence of liver cirrhosis and serum levels of albumin, bilirubin and HBV DNA. Lifestyle factors and the presence of diabetes mellitus were also evaluated. The time trends of patient characteristics were analyzed using the Jonckheere-Terpstra proportion trend test. Among HCC patients with chronic HBV infection, the proportion of patients at high risk according to the HCC prediction score significantly decreased during the study period (P=0.0005). Similarly, the proportion of patients with liver cirrhosis, <=3.5 g/dl serum albumin level, >4 log copies/ml serum HBV DNA level and >=60 g/day alcohol intake were also significantly decreased. The proportion of male and obese patients was not significantly altered, whereas the proportion of elderly (>=65 years) and diabetic patients tended to increase during the study period (P=0.0654 and P=0.0528, respectively). In this study, we analyzed the time trends of the clinical characteristics in HCC patients with chronic HBV infection and demonstrated that aging and diabetes mellitus may be involved in the hepatocarcinogenesis in patients with chronic HBV infection. PMID- 25279178 TI - Precursor T-cell lymphoblastic lymphoma extensively involving the mediastinum, pleura and pericardium: A case report. AB - Precursor T-cell lymphoblastic lymphoma (T-LBL) is a rare type of malignant lymphoma, with clinical manifestations including diaphragmatic lymph node enlargement, accompanied by local oppression and/or systemic lymphoma symptoms. However, extensive involvement of the mediastinum, pleura and pericardium is rare in T-LBL cases. This is the case report of a T-LBL extensively involving the mediastinum, pleura and pericardium in a 54-year-old woman. The patient complained of anhelation, chest tightness and tiredness for ~3 months. A computed tomography (CT) scan of the chest revealed a diffuse mass of soft tissue density involving the mediastinum, pleura and pericardium. Several thoracocenteses indicated inflammatory changes and cytological examination of the pleural fluid and pleural biopsy under CT guidance identified no heterotypic cells. As 18F fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT imaging revealed a diffused moderate FDG uptake (maximum standard uptake value of 4) by the mediastinum, pleura and cardiac sac, we diagnosed a malignant lymphoma. We subsequently successfully performed needle biopsy under PET/CT guidance according to the PET/CT images and the diagnosis of T-LBL was pathologically confirmed. PMID- 25279177 TI - Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models. AB - CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB 300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives. PMID- 25279179 TI - Double primary hepatic cancer (sarcomatoid carcinoma and hepatocellular carcinoma): A case report. AB - Primary liver sarcomatoid carcinoma (SC) is a rare and aggressive tumor exhibiting rapid growth and a high recurrence rate following resection. To date, there have been no reports of primary liver SC occurring simultaneously with hepatocellular carcinoma (HCC). This is the case report of a 54-year-old man with liver cirrhosis due to hepatitis B virus (HBV) infection and alcoholic hepatitis. The abdominal computed tomography and magnetic resonance imaging revealed two distinct hepatic masses in a background of hepatic cirrhosis and esophageal varices. Following a clinical diagnosis of two HCCs, a right hepatic lobectomy was performed. Grossly, two distinct lesions were identified: the larger mass was gray to white and well-demarcated, sized 2.5*2.0 cm, located in S5-6, whereas the other was a gray to whitish nodule, sized 1.3*1.0 cm, located in S8. The microscopic analysis revealed that the larger mass was a primary liver SC, which was immunoreactive for cytokeratin (CK) and vimentin (VMT) and negative for hepatocyte-specific antigen (HSA). The other nodule was histologically diagnosed as HCC, which was positive for HSA and CK and negative for HSA, VMT, CK7 and CK19. There was no transition or intermingling lesion between the two tumors. To the best of our knowledge, this is the first case report of double primary liver cancer comprising an SC and a HCC. PMID- 25279180 TI - Rechallenge with pemetrexed-based chemotherapy improves the survival of patients with advanced non-squamous non-small-cell lung cancer. AB - Rechallenge chemotherapy with pemetrexed was shown to be efficient in malignant pleural mesothelioma; however, its role in non-small-cell lung cancer (NSCLC) has not been investigated. In this study, we retrospectively enrolled 31 patients with non-squamous NSCLC who had achieved disease control with initial pemetrexed treatment, followed by rechallenge with pemetrexed-based chemotherapy (PBC) upon disease progression. After the rechallenge, 5 patients (16.1%) achieved partial remission (PR), 17 (54.8%) achieved stable disease (SD) and 9 (29.1%) experienced progressive disease. The treatment was generally well tolerated, with a low rate of toxicity. The median progression-free survival (PFS) was 3.8 months with the rechallenge. Patients with a PFS of >=10 months with initial PBC exhibited longer PFS and overall survival (OS) with the rechallenge compared to those with a PFS of <10 months with initial PBC (PFS: 6.2+/-0.33 vs. 3.1+/-0.26 months, respectively; P=0.011; and OS, 19.8+/-3.2 vs. 9.2+/-1.1 months, respectively; P=0.005). The time from the termination of initial PBC to disease progression was also associated with survival after the rechallenge. However, the response to initial PBC (PR vs. SD) did not affect PFS after the rechallenge. No significant differences were observed in thymidylate synthase expression, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene fusion, or epithelial growth factor receptor mutation status between pemetrexed-sensitive and pemetrexed-resistant patients. Our results demonstrated that rechallenge with PBC was well tolerated and survival after the rechallenge was associated with survival during initial PBC. Therefore, patients with a PFS of >=10 months or time-to-disease progression >=3 months may be considered as candidates for pemetrexed rechallenge. PMID- 25279181 TI - Bladder extragastrointestinal stromal tumor in an adolescent patient: A case based review. AB - Extragastrointestinal stromal tumors (EGISTs) are mesenchymal tumors occurring outside the gastrointestinal tract, with histological, immunohistochemical and molecular genetic characteristics similar to those of gastrointestinal stromal tumors (GISTs). The immunohistochemical examination usually demonstrates a positive expression for CD117. GISTs are rare neoplasms and EGISTs are even less common. This is the report of a case of EGIST in the urinary bladder of a 15-year old adolescent female patient who presented with painless gross hematuria. Pelvic computed tomography revealed an irregular soft tissue density mass, sized 5.7*4.8 cm, in the bladder. Partial cystectomy was performed in April, 2011. There was no recurrence during follow-up over the next 35 months, as determined by transabdoninal ultrasonography and cystoscopic examination. The patient in this study did not receive any molecular-targeted drugs. To the best of our knowledge, this is the first reported case of an EGIST of the urinary bladder in an adolescent patient. PMID- 25279182 TI - Lymph node spread of gallbladder cancer from the perspective of embryologically based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery. AB - Lymph node metastasis from gallbladder cancer is often found in the pericholedochal area; however, these regional lymph nodes are not typically accompanied by arteries. We hypothesized that the artery accompanying pericholedochal lymph nodes was either the regressed embryonic right hepatic artery (eRHA) or an aberrant right hepatic artery (aRHA) remaining without regression. This study aimed to determine the artery supplying pericholedochal lymph nodes. We obtained serial tissue sections of resected specimens from 10 patients who underwent pancreaticoduodenectomy with combined resection of the superior mesenteric artery and vein and investigated the association between the distribution of enlarged lymph nodes and the course of blood vessels in each section. In 2 cases with aRHA, enlarged lymph nodes were distributed in the posterosuperior area, pancreaticoduodenal region and retroportal area along this artery. By contrast, no blood vessels accompanied enlarged lymph nodes in 8 patients exhibiting a normal hepatic artery branching pattern, although these nodes exhibited a distribution pattern similar to that of patients with the aRHA. Thus, the artery supplying pericholedochal lymph nodes appears to be either the regressed eRHA or an aRHA persisting without regression. PMID- 25279183 TI - Mechanism underlying the transient increase of serum iron during FOLFOX/FOLFIRI therapy. AB - In patients with advanced colorectal cancer (CRC), a transient significant increase of serum iron is observed during chemotherapy with leucovorin and fluorouracil plus oxaliplatin (FOLFOX) or leucovorin and fluorouracil plus irinotecan (FOLFIRI). Serum iron may be a useful and convenient predictor of the response to chemotherapy; however, the mechanism underlying its increase has not been fully elucidated. Accordingly, the mechanism underlying the elevation of serum iron during chemotherapy was investigated in 20 patients with advanced CRC who were treated between September, 2012 and July, 2013. The levels of iron, ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), hemoglobin (Hb), hepcidin-25, interleukin (IL)-6 and soluble transferrin receptor (sTfR) were measured before and 48 h after chemotherapy. The serum levels of iron and hepcidin-25 were found to be significantly increased after chemotherapy (P<0.0001), whereas those of IL-6 were significantly decreased (P=0.0057). There were no significant changes in any of the other parameters. The lack of significant changes in AST, ALT and Hb suggested that the elevation of serum iron was not due to the destruction of hepatocytes, whereas the stable sTfR level suggested no destruction of erythroblasts. Hepcidin-25 regulates iron metabolism and decreases serum iron levels; it is increased by an iron load and IL-6, but is decreased under anemic or hypoxic conditions. The suppression of erythropoiesis increases serum iron levels and chemotherapy suppresses erythropoiesis. As serum iron and hepcidin-25 were both significantly increased and IL-6 was significantly decreased, with no significant changes in sTfR, it appears that the elevation of serum iron during chemotherapy may be secondary to reduced iron consumption by erythropoiesis, leading to increased expression of hepcidin-25 and suppression of Il-6 via negative feedback. PMID- 25279184 TI - Overexpression of membrane-type 2 matrix metalloproteinase induced by hypoxia inducible factor-1alpha in pancreatic cancer: Implications for tumor progression and prognosis. AB - Membrane-type 2 matrix metalloproteinase (MT2-MMP) has been identified as a powerful modulator of the pericellular environment that promotes tumor invasion and metastasis. In this study, we investigated the association of MT2-MMP and hypoxia-inducible factor-1alpha (HIF-1alpha) expression in pancreatic cancer with regard to their clinical prognostic significance. Of the tissue specimens obtained from the 78 patients included in this study, 46 (59%) were found to be positive for MT2-MMP immunostaining and MT2-MMP expression was colocalized with HIF-1alpha in pancreatic cancer. Using the Spearman's rank analysis, the protein and mRNA expression level of MT2-MMP was found to be significantly correlated with HIF-1alpha and CD34-microvascular density in pancreatic cancer. Furthermore, the expression of MT2-MMP in response to hypoxia was increased in a time dependent manner and the promoter luciferase reporter revealed upregulation of MT2-MMP expression induced by HIF-1alpha in pancreatic cancer cells. Moreover, the Cox regression model indicated that MT2-MMP was an independent prognostic factor in patients with pancreatic cancer. Our results demonstrated that the overexpression of MT2-MMP was induced by HIF-1alpha in response to hypoxia and was an independent prognostic factor for pancreatic cancer progression. PMID- 25279185 TI - Predominance of ERG-negative high-grade prostate cancers in African American men. AB - Erythroblast transformation-specific-related gene (ERG) fusions, the most common and validated prostate cancer (CaP) genome alteration, result in alterations in the expression of the ERG oncoprotein. Significantly lower frequencies of ERG have been reported in tumors of African American (AA) in comparison to Caucasian American (CA) men. Building on our preliminary observations, this study has focused on the increased association of the ERG-negative status with higher-grade prostate tumors in AA men. Representative whole-mount prostate sections from a matched cohort of 63 AA and 63 CA men with Gleason scores of 4+3 and those with Gleason scores of 8-10 were analyzed for ERG oncoprotein by immunohistochemistry. The striking finding of this study was that ERG expression was 3 times more likely to be present in the higher-grade index tumors of CA men compared to AA men (31 of 63 vs. 10 of 63 patients, respectively; P<0.0001). Although the mechanisms underlying these differences have not been elucidated, the present study along with our previous observations underscores that ERG typing may enhance the understanding of ethnic differences and future targeted therapy of CaP. PMID- 25279186 TI - Malignant peripheral nerve sheath tumor in the anterior mediastinum: A case report. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are rare neoplasms, accounting for only 5% of all malignant soft-tissue sarcomas. This is the case report of a 28-year-old male patient with a MPNST located in the anterior mediastinum, originating from the phrenic nerve. The patient presented with an abnormal shadow on chest radiography and a 10-cm mass in the right anterior mediastinum was identified on computed tomography and magnetic resonance imaging. The patient subsequently underwent surgical resection. The tumor originated from the right phrenic nerve and was tightly adherent to the middle and lower lobes of the right lung, the pericardium and the diaphragm. The tumor was completely resected, along with partial resection of the adherent tissues. The histological diagnosis was spindle cell sarcoma and the final diagnosis was MPNST of the anterior mediastinum, based on the characteristic microscopic appearance indicating the nervous origin of the tumor and on the intraoperative findings. The patient remains free of recurrence 1 year after surgery. PMID- 25279187 TI - Phase II study of erlotinib for previously treated patients with EGFR wild-type non-small-cell lung cancer, following EGFR mutation status reevaluation with the Scorpion Amplified Refractory Mutation System. AB - While assessing the efficacy of erlotinib in patients with epidermal growth factor receptor (EGFR) wild-type (WT) non-small-cell lung cancer (NSCLC), the sensitivity of the method used for the EGFR mutation analysis may affect the evaluation of the efficacy. We conducted a phase II study of erlotinib for previously treated patients with EGFR WT NSCLC screened by the peptide nucleic acid-locked nucleic acid (PNA-LNA) polymerase chain reaction (PCR) clamp method, which is known to be highly sensitive. The primary endpoint was the objective response rate (ORR). Preplanned reevaluation of the EGFR genotype as an exploratory endpoint was performed using the Scorpion Amplification Refractory Mutation System (S-ARMS) assay. Erlotinib was administered daily until disease progression or development of unacceptable toxicity. A total of 53 evaluable patients were enrolled. The histological subtypes were adenocarcinoma in 40 patients, squamous cell carcinoma in 9 patients and not otherwise specified NSCLC in 4 patients. Partial response (PR) was achieved in 6 patients (4 with adenocarcinoma and 2 with squamous cell carcinoma). The ORR was 11.3% [95% confidence interval (CI): 4.3-23.0]. The median progression-free survival (PFS) was 1.8 months (95% CI: 1.2-2.3). Samples from 26 of the 53 patients (49.0%) were available for EGFR mutation reanalysis with the S-ARMS assay. Of these 26 samples, only 1 sample of adenocarcinoma was found to be EGFR mutation-positive (exon 19 deletion) and the patient achieved a PR. The EGFR WT genotype was reconfirmed by the S-ARMS assay in the remaining 25 patients and 2 of these patients exhibited a PR. This study did not meet the primary endpoint, although erlotinib was found to be moderately effective in pretreated patients with EGFR WT NSCLC, even when the EGFR mutational status was confirmed by the highly sensitive PNA-LNA clamp PCR method. PMID- 25279188 TI - Long-term outcomes following adjuvant endocrine therapy in breast cancer patients with a positive-to-negative change of hormone receptor status following neoadjuvant chemotherapy. AB - The aim of the present study was to investigate whether breast cancer patients with changes from positive to negative in the hormone receptor following neoadjuvant chemotherapy (NAC) could benefit from adjuvant endocrine therapy (ET). Between December 2000 and November 2010, 97 eligible patients with a positive-to-negative switch of the hormone receptor status following NAC were identified. All the patients were categorized into two groups on the basis of the administration of ET: 57 ET-administered and 40 ET-naive patients. Survival analyses were performed to examine the prognostic value of ET administration, as well as other clinical and pathological variables. The administration of ET was associated with a significantly improved disease-free survival (DFS) (P=0.018) in patients with a positive-to-negative switch of the hormone receptor status. The 5 year DFS rates were 77.0 and 55.5% in ET-administered and ET-naive patients, respectively. The 5-year overall survival (OS) rate for ET-administered was also higher than that of the ET-naive patients (81.3 vs. 72.7%, P=0.053), but the difference between the two groups did not reach a statistical significance. The present study revealed that patients with the hormone receptor that was altered from positive to negative following NAC benefit from ET, and the hormone receptor status should be evaluated not only in specimens obtained during post-NAC surgery, but also in specimens biopsied prior to NAC. PMID- 25279189 TI - Placement of self-expandable metallic stents for tracheal stenosis secondary to thyroid cancer. AB - The indications and suitable approaches for treating upper airway obstruction secondary to thyroid cancer are controversial. Patients with thyroid cancer generally have a good prognosis, but airway stenosis and vocal cord paralysis are not uncommon. Subglottic airway stenting may be challenging, due to stent migration, granulation tissue formation and supraglottic stenosis. In this study, we evaluated the application of covered self-expandable metallic stents to relieve upper airway obstruction. This was a retrospective study of 5 patients with airway stenosis due to thyroid cancer treated in 2009 and 2010. Immediate airway enlargement was achieved in 3 patients with stenosis at the middle mediastinum. Gradual enlargement over 2 months was observed in the remaining 2 patients with stenosis at the cervical level. The performance status was improved in all 5 patients, including a case with anaplastic carcinoma. The follow-up averaged 13 months (range, 8-27 months). Granulation tissue developed at both ends of the stent in 3 patients, sputum was retained in 2 cases and bacterial colonization was detected in all 5 cases. No stent migration was reported. Additional tracheostomy was required in 2 patients, due to proximal tumor growth or progressive bilateral vocal cord paralysis after 10 and 6 months, respectively. In conclusion, stenting for central airway stenosis secondary to thyroid cancer may be beneficial, even in patients with anaplastic carcinoma. Long-term regular bronchoscopic follow-up is required to monitor complications, as patients with thyroid cancer are at high risk of granulation tissue formation, sputum retention and bacterial colonization. PMID- 25279190 TI - Apolipoprotein E genetic polymorphism, serum lipoprotein levels and breast cancer risk: A case-control study. AB - The purpose of this study was to evaluate the association between apolipoprotein E (APOE) allelic frequency, serum lipoproteins and breast cancer (BC). We conducted a nested case-control study within a cohort including 47 cases and 165 controls. Polymerase chain reaction-restriction fragment length polymorphism analyses of the APOE polymorphism were performed. In general, participants with the genotype including alleles e2 and e3 tended to have lower serum triglycerides, total cholesterol and low-density lipoprotein cholesterol levels and higher high-density lipoprotein (HDL) cholesterol levels compared to participants homozygous for the e3 allele and participants heterozygous for the e3 and e4 alleles, respectively. BC patients exhibited higher mean levels of total serum cholesterol (P=0.070), dietary fat intake (P=0.020) and dietary cholesterol intake (P=0.017) compared to control subjects. The allelic distribution between the two groups revealed that the presence of the e2 allele was positively associated with the absence of BC, whereas the e4 allele was positively associated with the BC case group (P=0.019). The distribution of the APOE genotypes was not significantly different between cases and controls (P=0.172). The concomitant presence of the e2 and e4 alleles was positively associated with the absence of BC and e4/e4 homozygosity was positively associated with BC (P=0.021). Our findings suggested that APOE polymorphism plays an important role in the development of BC, particularly when associated with higher serum triglyceride levels. PMID- 25279191 TI - Ritonavir acts synergistically with panobinostat to enhance histone acetylation and inhibit renal cancer growth. AB - There is currently no curative treatment for advanced renal cancer. Enhancing histone acetylation is a promising epigenetic-based therapy for cancer; however, in solid tumors, the efficacy of histone deacetylase (HDAC) inhibitors alone is limited. The human immunodeficiency virus protease inhibitor ritonavir is also a CYP3A4 inhibitor and we hypothesized that combining ritonavir with the HDAC inhibitor panobinostat, one of the substrates of CYP3A4, may effectively eliminate renal cancer cells by enhancing the activity of panobinostat. The combination of ritonavir and panobinostat synergistically inhibited cancer cell growth and cancer cell colony formation, while only slightly inhibiting the growth of renal proximal tubule epithelial cells. This combination significantly induced apoptosis in cancer cells and this apoptosis was considered to be caspase dependent, since the pan-caspase inhibitor Z-VAD-FMK reduced the number of Annexin V-positive cells. In murine subcutaneous xenograft models using Caki-1 cells, a 10-day treatment with the combination of ritonavir and panobinostat significantly inhibited tumor growth. Panobinostat alone increased histone acetylation in a dose-dependent manner and the co-administration of ritonavir synergistically enhanced this acetylation. Furthermore, this combination inhibited the expression of HDACs, which may also play a role in the enhancement of histone acetylation. Thus, the present study may provide a basis for testing the combination of ritonavir and panobinostat for patients with advanced renal cancer. PMID- 25279192 TI - Granulocyte macrophage colony-stimulating factor as a predictor of the response of metastatic renal cell carcinoma to tyrosine kinase inhibitor therapy. AB - This prospective study was conducted to identify predictive markers for the response of metastatic renal cell carcinoma (RCC) to tyrosine kinase inhibitors (TKIs). Patients with histologically proven RCC with at least one measurable metastatic lesion were enrolled in this study. Blood samples were collected prior to treatment and the plasma levels of 27 cytokines were measured. Tumor response was assessed 8-12 weeks after the initiation of TKI treatment. A total of 13 patients (11 men and 2 women) with a median age of 63 years received sunitinib (8 cases), sorafenib (1 case), or axitinib (4 cases). Partial response (PR) was achieved in 5 patients (38%), stable disease (SD) in 4 (30%) and progressive disease (PD) was noted in 4 (30%). The plasma granulocyte macrophage colony stimulating factor (GM-CSF) level in PR cases was significantly higher compared to that in SD or PD cases (P=0.012). Therefore, GM-CSF may be a predictive biomarker of the response of RCC to TKI treatment, suggesting that TKIs may exert clinical effects not only through suppression of the vascular endothelial growth factor, but also through immune system modulation. PMID- 25279193 TI - Comparison of hepatic arterial infusion chemotherapy and sorafenib in elderly patients with advanced hepatocellular carcinoma: A case series. AB - Sorafenib and hepatic arterial infusion chemotherapy (HAIC) are both indicated for unresectable hepatocellular carcinoma (HCC). In this study, we compared the efficacy and safety of HAIC to that of sorafenib in elderly patients with HCC. Eligible patients included those aged >=70 years, with histologically or clinically confirmed advanced HCC. A total of 12 patients received sorafenib (800 mg per day) and 8 patients received HAIC with 5-fluorouracil (300 mg/m2 on days 1 5 and 8-12) with or without cisplatin (20 mg/m2 on days 1 and 8), with interferon alpha (3 times per week for 4 weeks). The response rate was significantly higher in patients treated with HAIC (37.5%) compared to that in patients treated with sorafenib (no response). The median overall survival (18.6 and 11.7 months) and progression-free survival (4.0 and 5.0 months) were similar between the sorafenib and HAIC groups, respectively. In the sorafenib group, 58.3% of the patients discontinued treatment compared to none in the HAIC group. The most frequent adverse event leading to discontinuation of sorafenib was anorexia. Similar to sorafenib, HAIC appears to be a feasible treatment and may also have the advantage of an adequate safety profile for elderly patients with advanced HCC. Further study of HAIC in a larger population of elderly patients is required to assess its potential as an alternative to sorafenib for HCC. PMID- 25279194 TI - PD-1 gene promoter polymorphisms correlate with a poor prognosis in non-small cell lung cancer. AB - An imbalance to the regulation of the immune system changes the tumor-specific T cell immunity in the cancer microenvironment and adjusts the tumor progression and metastasis. Inhibiting the interactions of the immune function mediates the antitumor activity in preclinical models. The programmed death 1 (PD-1) gene -606 G/A polymorphism, which may modify promoter activity and is Asian-specific, was investigated by TaqMan quantitative polymerase chain reaction assay in surgically treated non-small cell lung cancer (NSCLC) cases. In the present study, 583 surgically removed NSCLC cases were included for single-nucleotide polymorphism (SNP) analyses. The PD-1 SNP statuses at the promoter region (rs36084323) were 146 AA (25.0%), 293 GA (50.3%) and 144 GG (24.7%). The ratio was extremely similar to the healthy control in a previous study: 24.9% AA, 47.8% GA and 27.3% GG. The ratio of the GG phenotype was not significantly different for gender (25.1% males and 23.9% female), age (25.2% <=65 years and 24.4% >65 years), smoking status (26.1% smoker and 21.8% non-smoker) and pathological subtypes [25.4% adenocarcinoma (adeno) and 24.2% squamous cell carcinoma (SCC)]. The GG ratio of PD-1 was not significantly different between pathological stage II-IV (25.5%) and stage I cases (24.1%; P=0.6245). The survival time of the patients with the -606 GG phenotype of PD-1 was significantly lower (n=147, 50 succumbed) compared to the patients with -606 GA or -606 AA (n=435, 109 succumbed) (P=0.0183). The GG phenotype patients had a significantly worse prognosis in the SCC population (P=0.009), however, this was not different to the adeno population (P=0.2594). Thus, PD-1 may promote tumor prognosis and provide a candidate for the blockade of its function as a strategy to antagonize the progression process in NSCLC, particularly lung SCC. PMID- 25279195 TI - Ginsenoside Rg3 enhances the inhibitory effects of chemotherapy on esophageal squamous cell carcinoma in mice. AB - The present study was conducted in order to investigate the inhibitory effects of ginsenoside Rg3 combined with chemotherapy on Eca-109 esophageal squamous cell carcinoma (ESCC) in mice. Tumor xenograft models were established in the right forelimb of 20 BALB/c nude mice by subcutaneous injection. The tumor-bearing mice were randomly assigned to 4 treatment groups (n=5 per group) as follows: the control group (saline), the ginsenoside Rg3 alone group (6 mg/kg/day, once a day for 3 weeks), the chemotherapy alone group (paclitaxel 10 mg/kg/day + cisplatin 5 mg/kg/day on days 1, 7, 14 and 21) and the chemotherapy + Rg3 group (combined treatment). The length and width of the tumor were directly measured with calipers at different time points and the tumor volume (cm3) was calculated using the formula 0.52 * length * width2 every other day. The mice were sacrificed by cervical dislocation following completion of therapy, the tumors were removed and weighed and the expression levels of Ki-67 were determined by immunohistochemistry. The results indicated that the coadministration of ginsenoside Rg3 significantly enhanced the inhibitory effects of chemotherapy on tumor growth. In addition, the expression levels of Ki-67 in the chemotherapy + Rg3 group were significantly lower compared to those in the other 3 groups. The chemotherapy + Rg3 group also exhibited the lowest microvascular density among all four groups. These findings suggested that ginsenoside Rg3 may improve the antitumor efficacy of chemotherapy in Eca-109 ESCC in mice. PMID- 25279196 TI - Transarterial chemoembolization vs. conservative treatment for unresectable infiltrating hepatocellular carcinoma: A retrospective comparative study. AB - This study was conducted to compare long-term survival between patients with unresectable infiltrating hepatocellular carcinoma (HCC) who were treated with transarterial chemoembolization (TACE) and those who received conservative treatment (best supportive care). Between January, 2007 and January, 2012, a total of 131 consecutive patients with unresectable infiltrating HCC underwent TACE in a cancer center (TACE group), while 156 similar consecutive HCC patients received conservative treatment in another cancer center (conservative treatment group). The diagnosis of unresectable infiltrating HCC was established by agreement between two radiologists coming from the two centers, who performed an independent review of all the cross-sectional imagings of the patients. The two groups were comparable regarding patient characteristics, preoperative liver function, tumor burden and general condition. In the TACE group, 52 patients received one session and 79 patients received more than one session of TACE (mean, 1.5 and range, 1-4 sessions). There was no reported TACE-related mortality. The 1-month mortality rate was 0.8 and 3.8% in the TACE and the conservative groups, respectively (P=0.134). The median survival for the TACE and conservative treatment groups was 7.0 and 3.0 months, respectively. The 6-, 12- and 24-month overall survival rates for the TACE and conservative treatment groups were 61.7, 18.5 and 2.3% vs. 22.7, 12.1 and 0%, respectively (P<0.001). On multivariate analysis, treatment allocation [odds ratio (OR)=1.777; 95% confidence interval (CI): 1.499-2.107; P<0.001] and portal vein tumor thrombosis (OR=1.721; 95% CI: 1.504-1.907; P<0.001) were independent predictors of overall survival. In conclusion, TACE was found to be a safe and feasible treatment option for patients with unresectable infiltrating HCC and it conferred survival benefit over conservative treatment. PMID- 25279197 TI - Prognostic significance of the co-expression of nucleophosmin and trefoil factor 3 in postoperative gastric cancer patients. AB - Although a number of studies have indicated that the positive expression of nucleophosmin (NPM) and trefoil factor 3 (TFF3) is associated with oncogenesis and poor prognosis in several tumor types, the prognostic value of the co expression of NPM and TFF3 in gastric cancer (GC) has not been fully elucidated. Therefore, in this study, we aimed to investigate the role of NPM and TFF3 in GC and determine their prognostic value. We retrospectively reviewed 108 patients who had undergone radical gastric tumor resection. The expression of NPM and TFF3 was detected by immunohistochemistry and the association of NPM and TFF3 with clinicopathological characteristics was investigated using the Chi-square test. Furthermore, univariate and multivariate analyses were conducted to determine the prognostic value of these markers. Of the 108 samples, NPM was positive in 57 (53%) and TFF3 was positive in 54 samples (50%). The positive expression of NPM was correlated with advanced tumor stage and recurrence (P=0.0333 and P<0.0001, respectively), whereas the expression of TFF3 was associated with larger tumor size (P=0.0005), poor differentiation (P=0.0435), lymph node metastasis (P=0.0116), advanced tumor stage (P=0.0244) and recurrence (P=0.0116). The univariate analysis revealed that the expression of NPM, the expression of TFF3 and the co-expression of the two were associated with poor survival (P=0.0004, 0.0028 and 0.0020, respectively). By multivariate analysis, all three factors were identified as independent prognostic factors in postoperative GC patients (hazard ratio = 1.970, 2.021 and 2.339, respectively). In conclusion, the expression of NPM and TFF3 and, particularly, the co-expression of the two, may serve as independent prognostic factors in postoperative GC patients. PMID- 25279198 TI - Prognostic significance of Ki-67 index value at the primary breast tumor in recurrent breast cancer. AB - The Ki-67 index value is a prognostic factor in primary breast cancer and is a proliferation marker that also distinguishes between luminal type A and type B breast cancer. Moreover, a change in Ki-67 index values due to treatment and recurrence is considered to be important in treating breast cancer. In this study, we investigated whether the baseline Ki-67 value in the primary tumor is useful as a prognostic factor following disease recurrence. Immunohistochemical analysis of the Ki-67 index was performed on 4,701 patients with primary breast cancer from 1987 until March, 2013. Among these patients, there were 666 consecutive cases exhibiting recurrence after primary surgery. The fraction of proliferating cells was based on a count of at least 500 tumor cells in the area including the hot spot. The Ki-67 values were divided into 3 groups, namely <20, >=20 and >=50%. The investigated items included estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), tumor size, nodal status for the primary tumor, recurrence site (soft tissue, bone and viscera) and disease-free interval (DFI). The Cox's proportional hazard model was used to perform univariate and multivariate analyses of the factors associated with overall survival (OS) following recurrence. The median follow-up period was 65.9 months in the surviving group. The median Ki-67 value at baseline was 20% in all the cases and 27% in the recurrent cases. The Ki-67 values were low (24%) in patients with bone metastasis and significantly higher in patients with liver or brain metastasis (38 and 55%, respectively). Moreover, DFI was found to be inversely correlated with the Ki-67 values. Univariate analysis was performed to identify the prognostic factors for OS after recurrence. The significant factors included tumor size, lymph node status, ER, PgR, DFI, recurrence site and Ki-67 index value. Among these factors, a multivariate analysis identified the Ki-67 index value in the primary tumor as an independent significant factor, particularly in luminal type tumors. The Ki-67 index value in the primary tumor was a significant prognostic factor for OS after disease recurrence. It is, therefore, important to take the Ki-67 index value into consideration for the treatment and follow-up of breast cancer patients. PMID- 25279200 TI - Association of a disintegrin and metalloprotease 33 gene polymorphisms with asthma. AB - Various studies reported a disintegrin and metalloprotease 33 (ADAM33) as an important susceptibility gene for asthma, which is frequently detected among certain populations. The aim of the present study was to investigate the association between single-nucleotide polymorphisms (SNPs) of the ADAM33 gene and asthma. Our case-control study included 183 patients (73 male and 110 female, mean age 42.93+/-13.48 years) who were admitted in the First Affiliated Hospital of Xinjiang Medical University between February, 2012 and May, 2013 and 155 healthy controls (66 male and 89 female, mean age 41.14+/-14.10 years). Allele specific polymerase chain reaction technology and DNA testing training methods were applied to detect the T2 and ST+5 polymorphisms of the ADAM33 gene. The data were statistically analyzed to determine whether there exists an association between these genotypes and asthma-related morbidity. The genotypes and allele frequencies of the T2 and ST+5 SNPs of ADAM33 were not found to be significantly associated with asthma risk when compared between asthmatic patients and healthy controls (P>0.05). In addition, there was no association of the investigated SNPs with the severity of asthma. There was no significant difference in the forced vital capacity and the forced expiratory volume between patients with the ADAM33 T2 and ST+5 genotype. In conclusion, our results suggested that the T2 and ST+5 ADAM33 gene polymorphisms do not confer a significant risk of asthma or affect its severity in the population investigated. PMID- 25279199 TI - Survival outcomes and progonostic factors of extrahepatic cholangiocarcinoma patients following surgical resection: Adjuvant therapy is a favorable prognostic factor. AB - This study was conducted to investigate survival and prognostic factors for extrahepatic cholangiocarcinoma (ECC) following surgical resection and evaluate the effects of postoperative adjuvant therapy (AT) on overall survival (OS). We retrospectively collected clinical and pathological data between March, 2008 and December, 2013. The Kaplan-Meier method and the COX regression model were used to evaluate the OS and prognostic factors of 105 postoperative ECC patients, of whom 32 had received AT. The patients were stratified into seven risk subgroups and the survival rates were compared within each subgroup between patients who received AT and those who did not. The results demonstrated a median OS of 17.6 months, with 1- and 3-year survival rates of 67.9 and 19.5%, respectively, for the entire cohort. On univariate analysis, preoperative cholangitis, non-R0 surgical margins, poor differentiation grade, stage 3/4 and lymphatic metastasis were identified as adverse prognostic factors. AT was not significantly associated with improved OS. However, the subgroup analysis revealed that the effect of AT was significant only in the lymphatic metastasis group (median OS, 21.6 vs. 10.4 months; and 3-year OS, 16.6 vs. 0%, respectively; P=0.02). The survival curves of the AT and non-AT groups were significantly different only for node-positive patients. The COX regression model identified lymphatic metastasis, surgical margins and AT as independent prognostic factors for ECC. A negative resection margin may reduce the mortality rate following surgery by 47%. By contrast, lymph node metastasis was associated with a 2.18-fold higher mortality rate for ECC patients. Postoperative AT contributed to a 0.45-fold mortality rate compared to non-AT ECC patients. Therefore, we concluded that AT is a favorable prognostic factor for ECC patients and it may prolong the survival of patients with lymphatic metastasis. Our data suggest that postoperative AT should be recommended for node-positive ECC patients. PMID- 25279201 TI - Expression of enoyl coenzyme A hydratase, short chain, 1, in colorectal cancer and its association with clinicopathological characteristics. AB - This study aimed to investigate the expression and clinical significance of enoyl coenzyme A hydratase, short chain, 1 (ECHS1), in patients with colorectal cancer (CRC). The ECHS1 protein expression as detected by immunohistochemistry in 148 CRC specimens was evaluated and compared by clinical pathology and prognosis; 38 specimens from proximal non-cancerous colorectal tissues were included as controls. The ECHS1 protein expression was also measured by western blot analysis in 46 fresh CRC tissue specimens and 22 normal colorectal tissue specimens. The rate of positive ECHS1 expression differed significantly between the CRC tissues (56.76%, 84/148) and the proximal non-cancerous colorectal tissues (5.26%, 2/38) (P<0.001). The ECHS1 protein expression was confirmed not to be associated with gender or age. However, the positive expression of ECHS1 tended to be positively associated with clinical TNM stage (P=0.015), lymph node metastasis (P=0.011) and histological differentiation (P=0.028). The expression of the ECHS1 protein on western blot analysis was significantly increased in CRC vs. normal tissues. In addition, the overall survival curves estimated with the Kaplan-Meier method demonstrated that CRC patients exhibiting low ECHS1 expression survived significantly longer compared to patients with high ECHS1 levels (P=0.039). Our data suggested that ECHS1 protein expression may contribute to the occurrence, progression and metastasis of CRC, is closely associated with prognosis and may provide useful information for CRC molecular-targeted therapy. PMID- 25279202 TI - Learning curve of endorectal ultrasonography in preoperative staging of rectal carcinoma. AB - Accurate preoperative staging of rectal carcinoma is essential for optimal treatment. This study was designed to evaluate the accuracy and learning curve of endorectal ultrasonography (ERUS) in the preoperative staging of rectal carcinoma. We retrospectively analyzed the records of patients with rectal carcinoma who underwent preoperative ERUS followed by curative surgery at the Shanxi Province Tumor Hospital between January, 2007 and March, 2010. The patients were divided into three groups, namely A, B and C, depending on whether the examination was performed between January and December, 2007, between January and December, 2008 or between January, 2009 and March, 2010, respectively. Five physicians with no prior experience in ERUS performed the examinations. We compared the ERUS staging with the pathological findings using the tumor-node metastasis (TNM) classification. The accuracy of ERUS in T and N staging after each additional consecutive 20 patients was calculated for physicians D, E and F. A total of 319 patients underwent ERUS prior to surgery. There were 38 patients in group A, 135 in group B and 146 in group C. Two of the five physicians performed only 47 of the 319 examinations, whereas the remaining 272 patients were examined by physicians D (n=162), E (n=64) and F (n=46). The overall accuracy in assessing the extent of rectal wall invasion (T) was 67%, with 16% of the cases overstaged and 17% understaged and the accuracy in assessing nodal involvement (N) was 66%, with 11% of the cases overstaged and 23% understaged. The total T and N staging accuracy of physicians D, E and F was 75 and 72%; 59 and 59%; and 50 and 52%, respectively. For physicians D, E and F, the accuracy of T and N staging after each additional 20 patients was calculated and the curve of the accuracy reached a plateau after physician D completed 80 cases. Therefore, ERUS is a valuable tool for assessing the depth of tumor invasion and it appears that after ~80 cases a physician may be considered able to apply it efficiently. PMID- 25279203 TI - Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: A systematic review. AB - The findings of randomized clinical trials (RCTs) regarding the efficacy of adjuvant conventional oral systemic chemotherapy (COSC) for patients with hepatocellular carcinoma (HCC) following curative hepatic resection (HR) are contradictory. Therefore, a systematic review of RCTs is required to evaluate the clinical efficacy of adjuvant COSC. Sources such as Medline, Embase and the Cochrane Library were systematically searched and all the RCTs comparing curative HR alone to HR plus COSC for HCC were identified. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. No treatment-related mortality was reported by the included RCTs and the adverse effects of COSC were generally mild. However, adjuvant COSC did not achieve a statistically significant improvement in the 1-, 3- and 5-year overall survival (OR=1.43, 95% CI: 0.58 3.56, P=0.44; OR=1.39, 95% CI: 0.75-2.55, P=0.29; and OR=1.20, 95% CI: 0.46-3.16, P=0.71, respectively). In addition, adjuvant COSC did not achieve a statistically significant decrease in the incidence of 1-, 3- and 5-year tumor recurrence, with pooled ORs of 0.92 (95% CI: 0.26-1.35, P=0.66); 0.82 (95% CI: 0.66-1.01, P=0.06); and 0.84 (95% CI: 0.71-1.01, P=0.06), respectively. Narrative reviews offer no evidence supporting the use of COSC. Adjuvant COSC has provided marginal benefits for HCC patients following curative HR. Considering the efficacy of sorafenib for advanced HCC and the results of this systematic review, no further trials should be performed to assess the efficacy of adjuvant COSC. PMID- 25279204 TI - Laparoscopic versus open surgery for rectal cancer: Results of a systematic review and meta-analysis on clinical efficacy. AB - Colorectal cancer is one of the main malignant tumors threatening human health. Surgery plays a pivotal role in treating colorectal cancer. The present study aimed to compare the clinical effect in patients with rectal cancer undergoing laparoscopic versus open surgery by meta-analysis of the randomized controlled trials (RCTs) published in the past 20 years. The data showed that 14 RCTs comparing laparoscopic surgery with conventional open surgery for rectal cancer matched the selection criteria and reported on 2,114 subjects, of whom 1,111 underwent laparoscopic surgery and 1,003 underwent open surgery for rectal cancer. Blood loss (P<0.00001), days to passage of flatus (P=0.0003), first bowel movement (P=0.0006), fluids intake (P<0.00001), walking independently (P<0.00001), length of hospital duration (P=0.003) and the rate of wound infection (P=0.04) were all significantly reduced following laparoscopic surgery. The incidence of complications, such as ureteric injury (P=0.33), urinary retention (P=0.43), ileus (P=0.05), anastomotic leakage (P=0.09) and incisional hernia (P=0.88), were not significantly different between the two groups. There were no significant differences in lymph nodes harvested (P=0.88), length of specimen (P=0.60), circumferential resection margin (CRM) (P=0.86), regional recurrence ((P=0.08), port site or wound metastasis (P=0.67), distant metastasis (P=0.12), 3-year overall survival (OS) (P=0.42), 3-year disease-free survival (DFS) (P=0.44), 5-year OS (P=0.60) and 5-year DFS (P=0.70). Therefore, laparoscopy for the treatment of patients with rectal cancer has the advantage of recovery and the same complications and prognosis as laparotomy, which indicates that laparoscopy may provide a potential survival benefit for patients with rectal cancer. PMID- 25279205 TI - Safety of repeated cell-free and concentrated ascites reinfusion therapy for malignant ascites from gastrointestinal cancer. AB - Malignant ascites due to peritoneal metastasis is one of the major problems caused by advanced gastrointestinal cancer. Although drainage of a large amount of ascitic fluid improves symptoms such as abdominal fullness, it may lead to protein loss and renal dysfunction. Cell-free and concentrated ascites reinfusion therapy (CART) may help avoid such complications due to paracentesis. The purpose of this study was to evaluate the safety of CART. We performed a total of 51 sessions of CART in 5 patients, 4 of whom had gastric cancer and 1 appendiceal cancer. We retrospectively evaluated laboratory data immediately prior to CART, on the following day, 1 week later and 2 weeks later. We also measured the amount of total protein and albumin in collected and concentrated ascites. The mean amount of collected ascites was 4,007 ml. All the patients exhibited improvement of symptoms such as abdominal fullness. Four patients developed fever (>38 degrees C) immediately after reinfusion of the concentrated ascites and 3 of these patients required corticosteroid administration. The mean total protein and albumin in the collected ascites were 122 and 64 g, respectively, and those in the concentrated ascites 75 and 39 g, respectively. The serum levels of total protein, albumin and creatinine after CART were almost identical to those prior to CART. Blood hemoglobin concentration was significantly decreased 1 day after CART and returned to baseline levels in 1-2 weeks. CART does not cause renal dysfunction and does not decrease serum albumin; therefore, repeated CART is safe and may be used to improve the symptoms of malignant ascites from gastrointestinal cancer. PMID- 25279207 TI - Pre-chemotherapy preservation of fertility in male patients with high-grade malignant bone and soft tissue tumors. AB - Only a limited number of orthopedic oncologists make arrangements for pre chemotherapy fertility preservation, such as sperm cryopreservation, for their patients. The purpose of this study was to offer fertility preservation to male patients with high-grade malignant bone and soft tissue tumors and assess the outcomes. The study included 14 male patients, aged <45 years, with high-grade bone and soft tissue tumors. The median age at diagnosis was 23.0+/-12.0 years (range, 8-42 years). Following pathological confirmation of high-grade malignant tumor, we informed all the patients and/or their guardians on the issue of chemotherapy-related male infertility. If the patients were interested in preserving fertility, they were referred to a team of reproductive specialists. We documented the patients' clinical characteristics and techniques used for fertility preservation. The majority of unmarried and childless patients were interested in fertility preservation. Four patients (28.5%) selected sperm cryopreservation and 1 patient (7.1%) selected hemi-testicular preservation, as he had developed erectile dysfunction following previous surgery for colon cancer. Married patients and those with children did not wish to preserve fertility. In conclusion, infertility following chemotherapy raises serious concerns for young male patients with high-grade bone and soft tissue tumors. Prior to initiating chemotherapy, the potential risks of chemotherapy should be explained, counseling should be provided and informed consent should be obtained from the patients, ideally without delaying commencement of cancer treatment. Prior to administering cancer chemotherapy, orthopedic oncologists are encouraged to offer sperm banking to young male patients at risk of infertility. PMID- 25279206 TI - Lack of HER-2 gene amplification and association with pathological and clinical characteristics of differentiated thyroid cancer. AB - Human epidermal growth factor receptor 2 (HER-2) is a well recognized prognostic and predictive factor in breast cancer. However, the role of HER-2 in thyroid cancer remains controversial. The aim of this study was to evaluate HER-2 expression in differentiated thyroid cancer (DTC) and determine whether there is an association with other clinical and pathological characteristics. A total of 69 patients with DTC were investigated, 58 of whom had papillary and 11 follicular carcinomas. HER-2 was detected by immunohistochemical examination on sections from formalin-fixed, paraffin-embedded tumor tissues. Tumors with HER-2 expression classed as +1 and +2 were retested with chromogenic in situ hybridization. Clinicopathological data were retrieved from the hospital records of the patients. HER-2 overexpression was found in 4 (6.9%) of the 58 patients with papillary carcinoma, whereas there was no HER-2 overexpression in any of the 11 cases of follicular carcinoma. There was no association of HER-2 expression with tumor size, pathological grade and cervical lymph node metastasis. In conclusion, there were no HER-2 positive cases of follicular carcinoma and the incidence of HER-2 overexpression in papillary carcinoma was very low. Thus, HER 2 cannot be used routinely as a prognostic or predictive factor in DTC. The expression of other epidermal growth factor receptors in DTC merits further investigation. PMID- 25279208 TI - Alcohol consumption and risk of myelodysplastic syndromes: A meta-analysis of epidemiological studies. AB - Previous studies on the association between alcohol intake and the risk of myelodysplastic syndromes (MDS) have been inconclusive. We conducted a meta analysis to evaluate alcohol intake as a risk factor for MDS. We performed a systematic literature search of articles published before March, 2014 using Web of Science, PubMed and the Cochrane Library. Two evaluators independently selected and reviewed studies based on predetermined selection criteria. The fixed- or random-effects models were used to summarize the estimates of odds ratios (ORs) with 95% confidence intervals (CIs). A total of 9 studies (8 case control and 1 cohort) met the inclusion criteria of this meta-analysis. No significant association was observed between alcohol consumption and MDS when comparing drinkers to non-drinkers (OR=1.16, 95% CI: 0.88-1.53) or between subgroups stratified by alcohol history, gender, ethnicity, study design, source of patients or MDS subtypes. However, the data indicated a stronger association of alcohol with MDS in individuals who consumed >=10 g/day (OR=1.55, 95% CI: 1.08 2.21) vs. those who consumed <10 g/day (OR=1.09, 95% CI: 0.78-1.53). This meta analysis suggests that alcohol intake may increase the risk of MDS in a dose dependent manner. However, additional well-designed, prospective cohort studies are required to verify these findings and identify other risk factors associated with MDS. PMID- 25279209 TI - p16 promoter hypermethylation is associated with increased risk of nasopharyngeal carcinoma. AB - The present study aimed to investigate the effects of p16 hypermethylation on the risk of nasopharyngeal carcinoma (NPC) quantitatively, through a meta-analysis of available case-control studies including malignant and normal NPC tissue samples. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of the association between p16 hypermethylation and NPC risk. A total of 9 studies, including 406 NPC and 376 control cases, were identified for meta-analysis. Statistically significant ORs of p16 hypermethylation were obtained from the NPC and control groups (OR=19.53; 95% CI: 9.54-39.97; P=0.685). The meta-analysis indicated that p16 hypermethylation significantly increases NPC risk. PMID- 25279211 TI - Curative effect of stereotactic body radiotherapy on hepatic hilar carcinoma. AB - This study was conducted to investigate the effect of stereotactic body radiotherapy (SBRT) on hepatic hilar tumors. Between October, 2006 and October, 2012, we analyzed 63 unresectable hepatic hilar tumors that were treated by SBRT at the Department of Radiation Oncology, 323 Hospital of the People's Liberation Army, Xi'an, China. The patients received a total radiation dose of 45 Gy (range, 44-48 Gy) with a dose fractionation of 3-6 Gy/fx, administered for a total of 9 12 times, 2-5 times/week. At 1 and 3 months we evaluated therapeutic efficacy and 1- and 2-year survival rate. At 1 month, the patients exhibiting complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were 15 (23.8%), 34 (54.0%), 11 (17.5%) and 3 (4.7%), respectively. At 3 months, the number of cases with CR, PR, SD and PD was 22 (34.9%), 32 (50.8%), 3 (4.8%) and 6 (9.5%), respectively. The total effective rate, defined as CR + PR, was 85.7% (54/63). The number of patients with a tumor diameter of <=5 cm in the CR, PR, SD and PD groups was 13 (72.2%), 4 (22.2%), 1 (5.6%) and 0 (0.0%), respectively. The number of patients with a tumor diameter of >5 cm in the CR, PR, SD and PD groups was 9 (20.0%), 28 (62.2%), 6 (13.3%) and 2 (4.5%), respectively. The 1-year survival rate of patients with a tumor diameter >5 cm was 71.4% (45/63) and the 2-year survival rate was 42.9% (27/63). In conclusion, SBRT appears to be a safe and effective treatment for hepatic hilar tumors. PMID- 25279210 TI - Adjuvant interferon for early or late recurrence of hepatocellular carcinoma and mortality from hepatocellular carcinoma following curative treatment: A meta analysis with comparison of different types of hepatitis. AB - Adjuvant interferon (IFN) therapy following curative treatment for hepatocellular carcinoma (HCC) has been extensively investigated; however, the clinical benefits with different hepatitis backgrounds remain unclear. Medline, Embase, PubMed and the Cochrane Library databases were searched to identify randomized trials and cohort studies that enrolled HCC patients who received curative surgery or ablation therapy followed by IFN and control subjects; the studies were required to include data on early or late recurrence and mortality rates of HCC. Hepatitis B virus (HBV) associated with HCC (HBV-HCC) and hepatitis C virus (HCV) associated with HCC (HCV-HCC) were separately analyzed and recurrence, mortality and clinicopathological factors were compared. A total of 14 studies (9 randomized trials and 5 cohort studies, including 1,385 patients in total) were eligible for meta-analysis. IFN was found to decrease mortality and early recurrence rates, but exerted no effect on late recurrence rate. The effect of IFN differed between HBV-HCC and HCV-HCC cases. In HCV-HCC, IFN significantly reduced mortality as well as recurrence rates. However, in HBV-HCC patients, IFN reduced mortality rather than recurrence rates, although it also reduced the recurrence rate in certain subgroups. In conclusion, the effect of adjuvant IFN on postoperative recurrence differed between HBV-HCC and HCV-HCC cases; therefore, different strategies with adjuvant IFN should be used to treat HCC with different hepatitis backgrounds. PMID- 25279212 TI - Metadherin in prostate, bladder, and kidney cancer: A systematic review. AB - Metadherin (MTDH) has been identified as an important oncogene in carcinogenesis, tumor progression and metastasis in numerous malignancies, through signal transduction pathways. MTDH is a potential biomarker and therapeutic target in cancers. The present systematic review was performed to search for studies regarding MTDH and prostate, bladder and kidney cancer using several databases and the eligible studies were reviewed. MTDH expression was found to significantly increase in prostate, bladder and kidney cancers, not only in clinical tissue samples, but also in cancer cell lines. Reviewing the clinical and statistical analysis revealed that MTDH may be involved in urologic cancer progression, metastasis and prognosis. MTDH may be an independent or one of the cofactors in urologic cancers for prediction of patient survival, and may be involved in potential anticancer strategies. MTDH may be associated with several signal transduction pathways in urologic cancers, indicating latent targets to develop anticancer therapeutic strategy. Further studies are required to confirm these findings. PMID- 25279213 TI - Upgrading and upstaging in prostate cancer: From prostate biopsy to radical prostatectomy. AB - Prostate cancer (CaP) is the most common malignancy in men and the second cause of cancer-related mortality after lung cancer. Several studies have evaluated the correlation between bioptic and pathological Gleason score (GS), documenting a correlation ranging between 30 and 60%. The aim of this study was the evaluation of the association between bioptic and pathological GS in a series of patients undergoing prostate needle biopsy and subsequent radical prostatectomy. We also aimed to evaluate the possible prognostic factors of upgrading and upstaging. We prospectively collected and retrospectively reviewed data from 300 consecutive patients who underwent radical retropubic or robot-assisted prostatectomy at our Institution. Patients who underwent prostate needle biopsy, transrectal or transperineal, with a minimum of 5 samples, were included in this study. Upgrading and downgrading were defined as increase or decrease, respectively, from one prognostic grade group to another, similar to up- or downstaging. The mean age of the patients was 62.97 years and the mean prostate-spesific antigen (PSA) level was 7.83 ng/ml. A total of 51.3% of the population underwent a transperineal prostate biopsy. The most frequently represented bioptic GS was 3+3 (64.0%) followed by 3+4=7 (15.6%); the most frequent pathological Gleason score was 3+4 (44.3%), followed by 3+3 (31.0%). With reagard to the bioptic GS 4-5-6 group, approximately half of the specimens (46.7%) were subsequently upgraded to GS 3+4, and 5.3% to 4+3. With regards to the bioptic GS 3+4 group, 57.4% was confirmed in the surgical specimen. In the 4+3 group, 23.5% of the cases was downgraded to 3+4 and 35.3% was confirmed. With regards to stage, ~39.7% of the patients received an upstaging on the pathological specimen. We evaluated the correlations between preoperative serum PSA level, prostate volume, digital rectal examination and biopsy type and none of the variables considered exhibited a correlation with any upgrading (P>0.05). Moreover, we evaluated the correlations between the aforementioned variables and upstaging and, at the multivariate analysis, only a serum PSA <4 ng/ml was found to be an independent variable predictive of upstaging (P=0.017). Therefore, new tools are required to predict upgrading and upstaging of our patients, in order to ensure better counseling for optimal treatment planning. PMID- 25279214 TI - Radiotherapy and chemoradiotherapy as a novel option for the treatment of locally advanced inoperable gastric adenocarcinoma: A phase II study. AB - This phase II trial aimed to evaluate the tolerance and efficacy of radical radiotherapy or chemoradiotherapy in patients with primarily inoperable gastric cancer. The analysis was based on 13 patients with primarily inoperable gastric cancer. A total of 6 (46.2%) patients refused surgery and 7 (53.8%) had contraindications to anesthesia due to cardiological or respiratory reasons (4 and 3 patients, respectively). The treatment regimen consisted of radiotherapy and chemotherapy based on 5-fluorouracil. Half of the patients were not qualified to receive chemotherapy due to the presence of comorbidities. A total dose of 45 Gy was administered in 25 fractions. Of the 13 patients who started treatment, 12 (92.3%) completed radiotherapy. Local treatment response was observed in 6/12 patients (50%), with 5/12 (41.7%) displaying clinical complete response and 1/12 (8.3%) partial response. The 1- and 3-year overall survival rates and the median survival were 59 and 48% and 17.1 months, respectively. In conclusion, radical radiotherapy, either alone or in combination with chemotherapy, is safe for patients with inoperable locally advanced gastric cancer and may prolong survival. PMID- 25279215 TI - XAGE-1b expression is associated with the diagnosis and early recurrence of hepatocellular carcinoma. AB - XAGE-1b is a 470 bp transcript of the XAGE-1 gene, which belongs to the cancer testis antigens that exhibit a restricted pattern of expression in normal tissues. Recently, the expression of XAGE-1b has been shown to be frequent in patients with hepatocellular carcinoma (HCC). However, the underlying mechanism is not fully understood. To investigate the role of XAGE-1b in HCC diagnosis and postoperative evaluation, the expression level of XAGE-1b was first examined in the tissue and peripheral blood of HCC patients and controls by using quantitative polymerase chain reaction. Subsequently, the associations between XAGE-1b and the clinical variables were assessed using chi2 or Kaplan-Meier tests. The data showed that HCC tissues had increased XAGE-1b expression when compared to paired non-tumorous tissues. The blood samples from the HCC patients showed upregulated XAGE-1b mRNA, as compared to non-HCC patients. The patients with portal vein tumor thrombus or higher tumor-node metastasis stages (II~IV) were more likely to have increased levels of XAGE-1b mRNA. Furthermore, the 1 year recurrence rate of the patients with a high level of XAGE-1b mRNA was significantly greater compared to the patients with a low level. All these findings indicate that XAGE-1b is associated with the aggressive biological behavior of HCC cells and it may be a potential biomarker for HCC diagnosis and prognosis. PMID- 25279216 TI - Expression of acidosis-dependent genes in human cancer nests. AB - Previous studies investigating cancer cells cultured at acidic pH have shown that the expression level of ~700 genes were more than two-fold higher than those of the cells cultured in alkaline medium at pH 7.5. The aim of the present study was to confirm whether these acidosis-induced genes are expressed in human cancer tissues. Therefore, 7 genes were selected from our previous study, which encoded interleukin 32 (IL-32), lysosomal H+ transporting ATPase, V0 subunit d2 (ATP6V0D2), tumor necrosis factor receptor superfamily, member 9 (TNFRSF9), amphiregulin, schwannoma-derived growth factor (AREG), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ErbB3), PRR5-ARHGAP8 (LOC553158) and dimethylglycine dehydrogenase (DMGDH), and their expression was examined in human clinical specimens from patients with cancer. In addition, the expression of the gene encoding manganese superoxide dismutase (MnSOD) was examined. The specimens from patients with colon, stomach and renal cancer showed increased MnSOD, IL-32, and TNFRSF9 transcripts compared to those from non-tumorous regions of the same patients. Notably, an elevated expression of ATP6V0D2 was found in the specimens from patients with stomach cancer, whereas the expression was decreased in those from patients with colon and renal cancer. The expression of LOC553158 was upregulated in colon and stomach cancer specimens. These results indicate that the investigation of gene expression under acidic conditions is useful for the development of novel cancer markers and/or chemotherapeutic targets. PMID- 25279217 TI - Study of the effectiveness of first-line treatment in renal cell carcinoma. AB - The emergence of novel drugs corresponds with the determination of the effectiveness of the current treatments used in clinical practice. A retrospective observational study was conducted to evaluate the effectiveness of first-line treatments and to test the influence of the prognostic factors established using the Memorial Sloan-Kettering Cancer Center (MSKCC) and the analysis of Mekhail's study for two or more metastatic sites. The primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS) times. A total of 65 patients were enrolled and the mPFS and mOS of the patients treated with sunitinib (n=51) were 9.0 and 20.1 months, respectively, and for the patients treated with temsirolimus (n=14) these were 3.0 and 6.2 months, respectively. In the poor-prognosis (PP) group, a difference of 1.2 months (P=0.049) was found in mPFS depending on the first-line treatment. A difference of 4.1 months (P=0.023) was also found in mPFS when classified by histology (clear verses non-clear cell) in the sunitinib-treatment group. When stratified by the prognostic group, differences of >7 months (P<0.001) were found between the groups. Therefore, it was concluded that the effectiveness of the treatments was reduced compared to previous studies and differences were found in the PP group when classified by first-line drug and histology. Additionally, the influence of prognostic factors on OS and the value of stratifying patients using these factors have been confirmed. PMID- 25279218 TI - Efficacy of gemcitabine combined with oxaliplatin, L-asparaginase and dexamethasone in patients with newly-diagnosed extranodal NK/T-cell lymphoma. AB - There is currently no standard first-line regimen for patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL). In this study, we investigated the efficacy and toxicity of gemcitabine (GEM) combined with oxaliplatin (L-OHP), L asparaginase (L-ASP) and dexamethasone (DXM) (GOLD regimen) as a systemic treatment scheme for newly-diagnosed ENKTCL cases. A total of 55 patients were recruited at the Henan Province Cancer Hospital and the Cancer Center of Sun Yat sen University between May, 2008 and August, 2012. The GOLD regimen included a 14 day treatment cycle with GEM (1,000 mg/m2) on day 1, L-OHP (100 mg/m2) on day 1, L-ASP (10,000 U/m2) on days 1-5 and DXM (20 mg b.i.d.) on days 1-4. The response rate, survival rate and treatment toxicity were analyzed. The overall response rate was 91% (48/55) with a complete response in 62% (34/55) and a partial response in 29% (15/55) of the patients. For all patients, the 1-, 2- and 3-year progression-free survival (PFS) rate was 86, 64 and 57% and the overall survival (OS) 91, 80 and 74%, respectively. The 1-year PFS in patients with stage I/II vs. those with III/IV disease was 87 vs. 66% (P<0.001) and the 1-year OS was 98 vs. 75%, respectively (P<0.001). No chemotherapy-related mortality or severe complications were recorded. In conclusion, the GOLD regimen was found to be highly effective and safe for the treatment of patients with newly-diagnosed ENKTCL. PMID- 25279219 TI - Association of xeroderma pigmentosum complementation group G Asp1104His polymorphism with breast cancer risk: A cumulative meta-analysis. AB - The xeroderma pigmentosum complementation group G (XPG) gene plays an important role in the DNA nucleotide excision repair (NER) pathway. Several studies have investigated the association between the XPG Asp1104His polymorphism and breast cancer; however, the results have been inconsistent. Therefore, we conducted a meta-analysis of 8 published articles (10 case-control studies) including a total of 5,235 patients with breast cancer and 5,685 healthy controls. The results demonstrated that the XPG Asp1104His polymorphism was not associated with breast cancer in the overall population [His vs. Asp, odds ratio (OR)=1.00, 95% confidence interval (CI): 0.91-1.08; His/His vs. Asp/Asp, OR=0.96, 95% CI: 0.83 1.11; Asp/His vs. Asp/Asp, OR=1.02, 95% CI: 0.94-1.11; His/His+Asp/His vs. Asp/Asp, OR=1.03, 95% CI: 0.92-1.15; and His/His vs. Asp/Asp+Asp/His, OR=0.93, 95% CI: 0.81-1.06]. In the subgroup analysis by ethnicity, no significant association was observed in European subjects. In conclusion, this meta-analysis suggested that the XPG Asp1104His polymorphism is not associated with breast cancer risk. PMID- 25279220 TI - Docetaxel-based therapy with and without antiangiogenic agents as first-line chemotherapy for castration-resistant prostate cancer: A meta-analysis of nine randomized controlled trials. AB - The aim of this study was to systematically assess the effectiveness and safety of the addition of antiangiogenic agents to docetaxel-based chemotherapy for the treatment of castration-resistant prostate cancer. Computerized electronic databases, including Embase, PubMed and The Cochrane Library were searched for randomized controlled trials (RCTs) on the comparison between docetaxel-based therapy with and without antiangiogenic agents for the treatment of prostate cancer. The search time limit was from the building of the database until July 18, 2013. Following extracting information and conducting a methodological quality evaluation for study inclusion based on inclusion and exclusion criteria, RevMan 5.2 and Stata 12.0 software were used to perform a meta-analysis and the Jadad scale was used for evaluation of study quality. A total of 9 RCTs and 4,681 patients were included in this meta-analysis. The comparison between docetaxel based therapy with and without antiangiogenic agents revealed no statistically significant differences regarding prostate-specific antigen response rate [risk ratio (RR)=0.99, 95% confidence interval (CI): 0.87-1.12, P=0.84], overall survival (OS) [hazard ratio (HR)=0.97, 95%CI: 0.91-1.05)] and progression-free survival (PFS) (HR=0.99, 95%CI: 0.83-1.18); however, the incidence of treatment related mortality was higher in the docetaxel-based therapy with antiangiogenic agents group (RR=1.95, 95%CI: 1.23-3.11, P=0.005), whereas the incidence of thrombus formation was higher in the docetaxel-based therapy without antiangiogenic agents group (RR=0.57, 95%CI: 0.41-0.80, P=0.001). In conclusion, our findings indicated that docetaxel combined with antiangiogenic agents did not increase the OS or the PFS of the patients with castration-resistant prostate cancer, whereas it may increase the risk of treatment-related mortality. However, further RCTs with larger, high-quality patient samples are required to verify these findings. PMID- 25279221 TI - Timing of high-intensity pulses for myocardial cavitation-enabled therapy. AB - BACKGROUND: High-intensity ultrasound pulses intermittently triggered from an ECG signal can interact with circulating contrast agent microbubbles to produce myocardial cavitation microlesions of potential therapeutic value. In this study, the timing of therapy pulses relative to the ECG R wave was investigated to identify the optimal time point for tissue reduction therapy with regard to both the physiological cardiac response and microlesion production. METHODS: Rats were anesthetized, prepared for ultrasound, placed in a heated water bath, and treated with 1.5 MHz focused ultrasound pulses targeted to the left ventricular myocardium with an 8 MHz imaging transducer. Initially, the rats were treated for 1 min at each of six different time points in the ECG while monitoring blood pressure responses to assess cardiac functional effects. Next, groups of rats were treated at three different time points: end diastole, end systole, and mid diastole to assess the impact of timing on microlesion creation. These rats were pretreated with Evans blue injections and were allowed to recover for 1 day until hearts were harvested for scoring of injured cardiomyocytes. RESULTS: The initial results showed a wide range of cardiac premature complexes in the ECG, which corresponded with blood pressure pulses for ultrasound pulses triggered during diastole. However, the microlesion experiment did not reveal any statistically significant variations in cardiomyocyte injury. CONCLUSION: The end of systole (R + RR/3) was identified as an optimal trigger time point which produced identifiable ECG complexes and substantial cardiomyocyte injury but minimal cardiac functional disruption during treatment. PMID- 25279223 TI - Solid-phase microextraction fiber development for sampling and analysis of volatile organohalogen compounds in air. AB - A green, environmental friendly and sensitive method for determination of volatile organohalogen compounds was described in this paper. The method is based on a homemade sol-gel single-walled carbon nanotube/silica composite coated solid phase microextraction to develop for sampling and analysis of Carbon tetrachloride, Benzotrichloride, Chloromethyl methyl ether and Trichloroethylene in air. Application of this method was investigated under different laboratory conditions. Predetermined concentrations of each analytes were prepared in a home made standard chamber and the influences of experimental parameters such as temperature, humidity, extraction time, storage time, desorption temperature, desorption time and the sorbent performance were investigated. Under optimal conditions, the use of single-walled carbon nanotube/silica composite fiber showed good performance, high sensitive and fast sampling of volatile organohalogen compounds from air. For linearity test the regression correlation coefficient was more than 98% for analyte of interest and linear dynamic range for the proposed fiber and the applied Gas Chromatography-Flame Ionization Detector technique was from 1 to 100 ngmL(-1). Method detection limits ranged between 0.09 to 0.2 ngmL(-1) and method quantification limits were between 0.25 and 0.7 ngmL(-1). Single-walled carbon nanotube/silica composite fiber was highly reproducible, relative standard deviations were between 4.3 to 11.7 percent. PMID- 25279222 TI - Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma. AB - BACKGROUND: Histone deacetylase inhibitor romidepsin has demonstrated durable clinical responses and tolerability in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma (PTCL, CTCL). Selection of novel drug therapies for patients with relapsed/refractory aggressive lymphoma requires not only considerations regarding efficacy but also careful evaluation of toxicities as well as overall clinical benefit. The purpose of this analysis was to examine common adverse events (AEs) reported in pivotal trials of romidepsin in relapsed/refractory PTCL or CTCL and to more clearly define the overall AE profile in these populations. METHODS: Patients with relapsed/refractory PTCL or CTCL were treated with romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles for up to 6 cycles; patients with at least stable disease could extend therapy until progressive disease or another withdrawal criterion was met. All enrolled patients who received >= 1 dose of romidepsin were included in the AE analyses. RESULTS: Overall, safety profiles of common AEs were similar, although patients with relapsed/refractory PTCL had more frequent hematologic toxicities and grade >= 3 infections. In both patient populations, the greatest incidence of grade >= 3 AEs and the majority of discontinuations due to AEs occurred during cycles 1-2. Early discontinuations were primarily related to infection, thrombocytopenia, or electrocardiogram abnormalities, confirming the need to closely monitor patients with poor bone marrow reserve or other comorbidities. Despite this, 28% of patients with relapsed/refractory PTCL and 36% of patients with relapsed/refractory CTCL continued on romidepsin treatment for >= 6 cycles. CONCLUSIONS: This study demonstrates that patients with relapsed/refractory PTCL or CTCL have similar AE profiles with romidepsin treatment, although patients with PTCL experienced more frequent and more severe hematologic toxicities and more frequent grade >= 3 infections. The greatest incidence of grade >= 3 AEs and the majority of discontinuations due to AEs occurred during treatment cycles 1-2. Extended dosing of romidepsin can be tolerated in responding patients. TRIAL REGISTRATION: NCT00426764,NCT00106431. PMID- 25279224 TI - Strategy for the customized mass screening of genetic sensorineural hearing loss in koreans. AB - Hearing loss is one of the most common sensorineural disorder. More than half of congenital bilateral profound deafness cases have been estimated to be attributed to genetic cause. Identification of genetic cause can provide valuable information. We developed new diagnostic strategy combining phenotype-driven candidate gene approach and targeted exome sequencing to find out the causative mutation of hearing loss. The causative mutation detection rates of this strategy were 78.1% and 54.8% in Korean multiplex families and sporadic severe to profound hearing loss families, respectively. The most frequent causative genes of Korean multiplex families were SLC26A4 and POU3F4. The other causative genes were MRNR1, WFS1, COCH, TECTA, MYO6, COL11A2, EYA4, GJB3, OTOF, STRC, MYO3A, and GJB2. The most frequent causative gene of Korean sporadic severe to profound hearing loss families was SLC26A4 followed by GJB2, CHD7, and CDH23. Based upon the results, the value of this strategy as a diagnostic tool seems to be promising. Although whole genome and exome sequencing have advanced as the development of next generation sequencing, this new strategy could be a good screening and diagnostic tool to find the causative mutations. PMID- 25279226 TI - Middle ear surgery in only hearing ears and postoperative hearing rehabilitation. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate surgical interventions and hearing rehabilitation in patients with chronic middle ear disease of only hearing ears. SUBJECTS AND METHODS: Thirty-one patients with chronic middle ear disease of only hearing ears were enrolled in this retrospective study. Patients were classified into three groups according to the hearing level: groups A [pure tone audiometry (PTA)<40], B (40<=PTA<70), and C (PTA>=70). We evaluated hearing results and patterns of auditory rehabilitation. RESULTS: The main consideration for a surgical procedure was the presence of recurrent otorrhea and structural destruction. The reasons for surgical intervention in only hearing ears were otorrhea caused by chronic otitis media (68%), cholesteatoma (29%), and cholesterol granuloma (3%). The causes of contralateral deaf ears were chronic otitis media (81%) and sensorineural hearing loss (19%). Although there was hearing deterioration in some patients with severe hearing loss (PTA>=70), all patients achieved dry ears after surgery and functional hearing using auditory rehabilitation. Hearing aids were used in most patients with moderate to moderately severe hearing loss and cochlear implants were used for auditory rehabilitation in patients with severe to profound hearing loss. CONCLUSIONS: Proper evaluation and indications for surgery in only hearing ears are important for successful eradication of inflammation and hearing preservation. Surgical interventions can achieve dry ear and enable further auditory rehabilitations using hearing aids and cochlear implantation. PMID- 25279225 TI - Study of phonological awareness of preschool and school aged children with cochlear implant and normal hearing. AB - BACKGROUND AND OBJECTIVES: The primary purpose of this study was to assess whether very early access to speech sounds provided by the cochlear implant enables children to develop age-appropriate phonological awareness abilities in their preschool and school years. A secondary purpose of this study was to examine whether children who had cochlear implantation before 18 months of age will develop better skills in phonological awareness than children who had cochlear implants in 18-36 months of age. A third purpose of this study was to examine whether some factors like the child's age or sex would have any effects on developing of age-appropriate phonological awareness abilities. SUBJECTS AND METHODS: 48 children with 70 to 95 months of age who had been utilizing their cochlear implant(s) before 36 months of age (CI group) and 30 normal hearing peers (NH group) were enrolled in this study. RESULTS: Child's age had a significant effect on phonological awareness, but sex had absolutely no effect in each group. Children in the cochlear implanted group were outperformed by their normal hearing peers in the area of phonological awareness, especially in phonemic awareness. The age of implantation was another significant variable. CONCLUSIONS: Although children with a younger age at implantation got better scores in phonological awareness test, they were outperformed by their normal hearing peers in this area. PMID- 25279227 TI - Comparison of the effectiveness of monitoring Cisplatin-induced ototoxicity with extended high-frequency pure-tone audiometry or distortion-product otoacoustic emission. AB - BACKGROUND AND OBJECTIVES: To compare the effectiveness of monitoring cisplatin induced ototoxicity in adult patients using extended high-frequency pure-tone audiometry (EHF-PTA) or distortion-product otoacoustic emission (DP-OAE) and to evaluate the concurrence of ototoxicity and nephrotoxicity in cisplatin-treated patients. SUBJECTS AND METHODS: EHF-PTA was measured at frequencies of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 9, 11.2, 12.5, 14, 16, 18, and 20 kHz and DP-OAE at frequencies of 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 kHz in cisplatin-treated patients (n=10). Baseline evaluations were made immediately before chemotherapy and additional tests were performed before each of six cycles of cisplatin treatment. Laboratory tests to monitor nephrotoxicity were included before every cycle of chemotherapy. RESULTS: Four of 10 patients showed threshold changes on EHF-PTA. Five of 10 patients showed reductions in DP-OAE, but one was a false-positive result. The results of EHF-PTA and DP-OAE were consistent in two patients. Only one patient displayed nephrotoxicity on laboratory tests after the third cycle. CONCLUSIONS: In our study, the incidence rate of cisplatin-induced ototoxicity was 40% with EHF-PTA or DP-OAE. Although both EHF-PTA and DP-OAE showed the same sensitivity in detecting ototoxicity, they did not produce the same results in all patients. These two hearing tests could be used to complement one another. Clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity. PMID- 25279229 TI - A case of otogenic brain abscess causing loss of consciousness. AB - Acute or chronic otitis media can cause intracranial complications, one of the most serious being brain abscess. Empirical antibiotic treatment and proper surgical management should be considered to avoid fatal consequences. However, proper extent and optimal timing of surgical intervention are still matters of debate. We present a case of a 31-year-old man who presented with acutely altered mental status, caused by otogenic brain abscess who we treated successfully with antibiotics and otologic surgery and no neurosurgical treatment. PMID- 25279228 TI - A clinical analysis of sudden sensorineural hearing loss cases. AB - BACKGROUND AND OBJECTIVES: High-dose systemic steroid therapy is the mainstay treatment for sudden sensorineural hearing loss (SSNHL). Recovery rates from SSNHL range are about 47-63% and are influenced by various prognostic factors. To evaluate the prognostic value of specific clinical parameters, we reviewed 289 cases by clinical and statistical analysis. SUBJECTS AND METHODS: This study included 289 patients with SSNHL who visited the Department of Otolaryngology at Soonchunhyang University Hospital from January 2005 to December 2012. The cases were reviewed retrospectively based on clinical charts. Hearing improvement was evaluated in relation to pure-tone audiogram results, duration between SSNHL onset and time of initial treatment, seasonal incidence, dizziness, patient age, degree of hearing loss, patterns of initial pure-tone audiogram and presence of underlying disease. RESULTS: Hearing improvement was observed in 196 of 289 (67.8%) patients; such improvement began within 7 days in most patients, followed by rapid hearing recovery. Cases that failed to show improvement within 14 days were unlikely to achieve hearing recovery. The more severe the hearing loss during the early stage, the lower the hearing recovery rates. Patients aged less than 60 years appear to have better prognosis of hearing improvement compared to those who are over 60 years. CONCLUSIONS: Important prognostic factors for recovery in patients with SSNHL include the time of initiating treatment after symptom onset, the degree of early-stage hearing loss, and the age of the affected patient. PMID- 25279230 TI - A case of acute bilateral retrocochlear hearing loss as an initial symptom of unilateral thalamic hemorrhage. AB - A speech discrimination test is a test using a list of 25 phonetically balanced monosyllables. It is often overlooked but significant enough for pure tone audiometry. Many physicians have performed pure tone audiometry but without a speech discrimination test. A 73-year-old woman visited our clinic complaining of sudden bilateral hearing loss. Pure tone audiometry showed only bilateral high frequency loss. However, speech discrimination had decreased markedly. We decided to follow-up after 1 week of Ginexin-F(r) (ginkgo leaf extract) and Nafril(r) (nafronyl oxalate). She felt a gait disturbance within 2 days. Magnetic resonance imaging revealed a left thalamic hemorrhage. After a 1 month hospitalization, the hematoma subsided, and speech discrimination recovered 3 months later. Acute hearing loss due to thalamic hemorrhage that recovered has never been reported. We report the first case of retrocochlear hearing loss that occurred with a thalamic hemorrhage in a patient who recovered. PMID- 25279231 TI - Congenital cholesteatoma localized to the tip of the mastoid bone: a case report and possible etiology. AB - Congenital cholesteatomas of mastoid origin are extremely rare. We reported one in 2007 and experienced an additional case. A male presented with a 5-month history of right-sided ear discharge. Computed tomography of the temporal bone showed a soft tissue density occupying the mastoid tip. At surgery, the cholesteatoma sac was completely isolated from the mastoid antrum and lateral air cell in the mastoid tip area. We now doubt the rarity of this entity. With a brief literature review, we consider how the cholesteatoma localizes to the tip of the mastoid bone. PMID- 25279232 TI - A case of a cholesterol granuloma occluding the external auditory canal in a 12 year-old girl. AB - Cholesterol granulomas are benign granulomatous lesions caused by tissue reaction to a foreign body such as cholesterol crystals. These crystals have been are associated with pathological conditions of pneumatized spaces, including those causing inadequate aeration, obstruction of drainage, and hemorrhage in pneumatized spaces, and where materials trapping materials, such as hemosiderin or cholesterol become trapped, and then forming a cholesterol granuloma. Cholesterol granulomas are frequently found in the temporal bones, with the middle ear, mastoid caverna, and petrous apex being the most commonly affected sites. As there have been few reported cases of cholesterol granulomas presenting as a mass in the external acoustic canal (EAC), a cholesterol granuloma occluding the entire EAC in a pediatric patient is considered quite rare. We encountered a large cholesterol granuloma occupying the entire EAC, resulting in total EAC occlusion in a 12-year-old girl. The granuloma was diagnosed via medical imaging and surgically excised. PMID- 25279233 TI - A case of the vibrant soundbridge stapes coupler in patients with mixed hearing loss. AB - The Vibrant Soundbridge (VSB) with stapes clip coupler placement at the stapes head has been used successfully to treat mixed hearing loss. Coupling between the floating mass transducer of the VSB and the stapes head is technically less demanding than incus vibroplasty and is more likely to generate a positive outcome without significantly changing residual hearing or resulting in medical or surgical complications. A 65-year-old man with bilateral mixed hearing loss and chronic otitis media underwent vibroplasty with a stapes clip coupler. Speech discrimination scores in both quiet and noise environments showed better functional gain with the VSB than with the use of a conventional hearing aid. The results of the present case show the feasibility of implanting a VSB with a stapes coupler in patients with mixed hearing loss due to chronic otitis media. PMID- 25279234 TI - International neurourology journal: get ready for the readers' quest. PMID- 25279235 TI - Metabolomics goes to work for you. PMID- 25279236 TI - Neurourology transforms the drug development experience. PMID- 25279237 TI - Metabolomics insights into pathophysiological mechanisms of interstitial cystitis. AB - Interstitial cystitis (IC), also known as painful bladder syndrome or bladder pain syndrome, is a chronic lower urinary tract syndrome characterized by pelvic pain, urinary urgency, and increased urinary frequency in the absence of bacterial infection or identifiable clinicopathology. IC can lead to long-term adverse effects on the patient's quality of life. Therefore, early diagnosis and better understanding of the mechanisms underlying IC are needed. Metabolomic studies of biofluids have become a powerful method for assessing disease mechanisms and biomarker discovery, which potentially address these important clinical needs. However, limited intensive metabolic profiles have been elucidated in IC. The article is a short review on metabolomic analyses that provide a unique fingerprint of IC with a focus on its use in determining a potential diagnostic biomarker associated with symptoms, a response predictor of therapy, and a prognostic marker. PMID- 25279239 TI - The prevalence of lower urinary tract symptoms in korean men aged 40 years or older: a population-based survey. AB - PURPOSE: The aim of this study was to evaluate the prevalence of lower urinary tract symptoms (LUTS) among Korean men aged >=40 years. METHODS: We performed a population-based, cross-sectional door-to-door survey on a geographically stratified random sample of men aged >=40 years. All respondents were asked about the presence of individual LUTS using a questionnaire based on 2002 International Continence Society definitions. For comparison, we also defined nocturia as two or more nocturnal micturitions per night. The International Prostate Symptom Score (IPSS) questionnaire was used to assess LUTS severity. RESULTS: Responses from 1,842 subjects were analyzed. The overall prevalence of LUTS was 83.4%. Storage LUTS (70.1%) were more prevalent than voiding (60.4%) or postmicturition LUTS (38.3%). When nocturia was defined as two or more nocturnal micturitions per night, voiding symptoms became most prevalent (storage, 39.7%; voiding, 60.4%; and postmicturition, 38.3%). More than 90% of our population described the severity of their urinary symptoms as moderate (8-19) or severe (20-35). The prevalence and severity of LUTS increased with age. CONCLUSIONS: LUTS are highly prevalent among Korean men, and its prevalence increases with age. Increased public awareness and a larger number of treatment options are needed to appropriately manage symptoms and their consequences. PMID- 25279238 TI - Inhibitory Effects of Isoquinoline Alkaloid Berberine on Ischemia-Induced Apoptosis via Activation of Phosphoinositide 3-Kinase/Protein Kinase B Signaling Pathway. AB - PURPOSE: Berberine is a type of isoquinoline alkaloid that has been used to treat various diseases. A neuroprotective effect of berberine against cerebral ischemia has been reported; however, the effects of berberine on apoptosis in relation to reactive astrogliosis and microglia activation under ischemic conditions have not yet been fully evaluated. In the present study, we investigated the effects of berberine on global ischemia-induced apoptosis, and focused on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the hippocampus using gerbils. METHODS: Gerbils received berberine orally once a day for 14 consecutive days, starting one day after surgery. In this study, a step down avoidance task was used to assess short-term memory. Furthermore, we employed the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay to evaluate DNA fragmentation, immunohistochemistry to investigate glial fibriallary acidic protein, CD11b, and caspase-3, and western blot to assess PI3K, Akt, Bax, Bcl-2, and cytochrome c. RESULTS: Our results revealed that berberine treatment alleviated ischemia-induced short-term memory impairment. Treatment with berbeine also attenuated ischemia-induced apoptosis and inhibited reactive astrogliosis and microglia activation. Furthermore, berberine enhanced phospho-PI3K and phospho-Akt expression in the hippocampus of ischemic gerbils. CONCLUSIONS: Berberine exerted a neuroprotective effect against ischemic insult by inhibiting neuronal apoptosis via activation of the PI3K/Akt signaling pathway. The antiapoptotic effect of berberine was achieved through inhibition of reactive astrogliosis and microglia activation. Berberine may therefore serve as a therapeutic agent for stroke-induced neurourological problems. PMID- 25279240 TI - Clinical outcome in male patients with detrusor overactivity with impaired contractility. AB - PURPOSE: To review the clinical outcomes of patients with voiding dysfunction who have detrusor overactivity with impaired contractility (DOIC) diagnosed with urodynamic studies. METHODS: Urodynamic reports from 2005 to 2009 were reviewed, and 54 male patients had findings consistent with DOIC. Patients with acontractile or neuropathic bladders were excluded. Clinical outcomes were obtained from patient records. RESULTS: Of 54 men, 8 presented with voiding symptoms, 17 had storage symptoms, and 29 had mixed symptoms. Twenty-two had a previous transurethral resection of the prostate. The median follow-up was 12 months. Four patients received no intervention. Two patients were taught intermittent self-catheterization. Five patients underwent surgery to reduce outlet resistance and all reported improvement. Forty-three patients were started on pharmacotherapy; symptomatic improvement was reported by 9 of 16 patients commenced on anticholinergics alone, 6 of 16 on alpha-blockers alone, and 4 of 5 treated with a combination of alpha-blockers and anticholinergics. Eleven patients experienced no difference on pharmacotherapy and 2 reported deterioration. One patient developed acute urinary retention (18 months after commencing treatment with alpha-blockers). No patient had urosepsis. CONCLUSIONS: Anticholinergics and alpha-blockers appear to be safe in patients with DOIC. The risk of urinary retention and sepsis is low. The majority of patients report symptomatic benefit from either drugs or surgical treatment. PMID- 25279241 TI - Transurethral surgical anatomy of the arterial bleeder in the enucleated capsular plane of enlarged prostates during holmium laser enucleation of the prostate. AB - PURPOSE: To identify the endoscopic vascular anatomy of the prostate during Holmium laser enucleation of the prostate (HoLEP), and analyze the clinical risk factors associated with significant arterial bleeding. METHODS: We identified 107 consecutive patients with benign prostatic hyperplasia who underwent HoLEP between September 2009 and August 2010, performed by a single surgeon (S.J.O.). Two independent reviewers reviewed the surgery video database and completed a prespecified form. The location of bleeding arteries was marked at the level of the bladder neck, proximal prostate, distal prostate, and verumontanum. Arterial bleeding was classified into one of three grades according to bleeding severity (grades 2 and 3 indicate significant bleeding). RESULTS: The mean prostate volume was 65.1+/-31.5 mL, and the mean prostate-specific antigen (PSA) level was 3.69+/ 3.58 ng/mL. During the HoLEP procedure, the most common locations of significant bleeders were the 2-5 and 7-10 o'clock positions in the proximal prostate. The average number of bleeding arteries was 12.1+/-7.9 per procedure, and 1.93+/-1.20 per 10 mL of prostate volume. Multivariate analysis revealed that prostate volume and serum PSA were significant parameters for estimating the number of bleeding vessels. CONCLUSIONS: During the HoLEP procedure, the most common locations of significant bleeders were the 2-5 and 7-10 o'clock positions in the proximal prostate. Prostate volume was associated with the number of bleeders. A careful approach to the capsular plane of the proximal prostate facilitates early hemostasis during the HoLEP procedure, especially with larger adenomas. PMID- 25279242 TI - The correlation between the treatment efficacy and the sympathetic activity in men with lower urinary tract symptoms. AB - PURPOSE: In this study, we examined the difference in the treatment efficacy depending on the sympathetic activity in men with lower urinary tract symptoms (LUTS). METHODS: In the current single-center, retrospective study, we evaluated a total of 66 male patients aged 40-70 years of age, presenting with LUTS, whose International Prostate Symptom Score (IPSS) exceeded 8 points. They had a past 3 month history of taking alfuzosin XL, and their heart rate variability (HRV) was measured before and after the treatment. In addition, we also recruited 39 healthy volunteers who visited a health promotion center for a regular medical check-up. They were aged between 40 and 70 years and had an IPSS of <8 points. We divided the patients with LUTS into two groups: the groups A and B, based on a low frequency/high frequency (LF/HF) ratio of 1.7, which was the mean value of the LF/HF ratio in the healthy volunteers. After a 3-month treatment with alfuzosin XL, we compared treatment outcomes, based on the IPSS and peak urine flow rate, between the two groups. RESULTS: A 3-month treatment with alfuzosin XL, comprising the measurement of the HRV, was performed for the 23 patients of the group A (23/38) and 17 of the group B (17/28). After a 3-month treatment with alfuzosin XL, total IPSS and IPSS questionnaire 2 and 5 were significantly lower in the group A as compared with the group B. But this was not seen in the group B. Furthermore, there were no significant differences in other parameters, such as maximal flow rate and IPSS storage subscore, between the two groups. CONCLUSIONS: Our results indicate that the treatment efficacy was lower in patients with sympathetic hyperactivity as compared with those with sympathetic hypoactivity. Thus, our results will provide a basis for further studies to clarify causes of LUTS in a clinical setting. PMID- 25279243 TI - Association of urinary urgency and delay time of micturition in women with overactive bladder. AB - PURPOSE: Accurately measuring urinary urgency is important for diagnosing overactive bladder (OAB) and quantifying improvements in treatment outcome. Various methods have been recommended for evaluating urinary urgency, but these methods assess individual perceptions and preferences. To overcome the subjectivity in measuring urinary urgency, we evaluated the relationship between uroflowmetric parameters and urinary urgency in women with OAB. METHODS: Consecutive female patients with lower urinary tract symptoms (n=110) were prospectively enrolled in this study between April 2011 and September 2012. Individuals with a history of using medications that are known to affect bladder function were excluded. All enrolled patients completed uroflowmetry with a delayed time to voiding (T2V). After urination was completed, patients were asked whether they experienced any urinary hesitancy or urgency at that time. RESULTS: The mean patient age was 56.1 years; 70 out of 110 patients reported some degree of urinary urgency. T2V decreased with increased urgency. Several uroflowmetric parameters were observed to have a significant correlation with urinary urgency. T2V had a meaningful correlation coefficient for individuals with urgency, regardless of the voided volume. There was no significant correlation between the presence of urinary hesitancy and T2V. CONCLUSIONS: We believe that T2V would be a complementary tool for diagnosing and determining the degree of urinary urgency in women with OAB. PMID- 25279244 TI - The study about physical activity for subjects with prevention of benign prostate hyperplasia. AB - PURPOSE: The number of benign prostatic hyperplasia (BPH) subjects has been increasing worldwide, and many studies have been conducted to determine the treatment that can delay drug therapy or surgery. Subsequently, most of these studies involved physical activity (PA) and associated factors. Therefore, we aimed to determine factors associated with BPH prevalence based on a review of past and present studies and to investigate the effect of a healthy lifestyle as a protective factor of BPH occurrence. METHODS: We selected 582 subjects aged >=40 years from an initial 779 subjects recruited from Gyeonggi, Yangpyeong, South Korea, during August 2009 to August 2011. Trained investigators surveyed International Prostate Symptom Score and demographic information, including PA and lifestyle questionnaire during face-to-face interviews; further, they performed digital rectal examination, rectal ultrasonography, and measured prostate-specific antigen levels. The statistical association between PA and BPH was analyzed by logistic regression analysis using multivariable regression models which use categorical variables by the Cochran-Mantel-Haenszel test and continuous variables by the general linear model. RESULTS: Seven statistically significant variables for PA were selected. Regular exercise, frequency of exercise, sedentary time, nonsedentary time, leisure time PA (metabolic equivalent, hr/wk) were not statistically associated with prostate volume but sedentary time (hr/day) was the only factor that showed a significant association in the multivariable model, including a linear effect relationship. Subjects with lower levels of sedentary time (4.5-7.0 hr/day) had a significantly lower risk of BPH (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.52-1.67) than those with a higher sedentary time (>7 hr/day) (OR, 1.72; 95% CI, 0.96-3.09) (P for trend=0.05). CONCLUSIONS: Our study showed that reducing sedentary time could have a protective effect and reduce the prevalence of BPH. Further prospective studies with a larger sample size are needed to assess the impact of reducing sedentary time on BPH risk. PMID- 25279246 TI - Comparing Model Selection and Regularization Approaches to Variable Selection in Model-Based Clustering. AB - We compare two major approaches to variable selection in clustering: model selection and regularization. Based on previous results, we select the method of Maugis et al. (2009b), which modified the method of Raftery and Dean (2006), as a current state of the art model selection method. We select the method of Witten and Tibshirani (2010) as a current state of the art regularization method. We compared the methods by simulation in terms of their accuracy in both classification and variable selection. In the first simulation experiment all the variables were conditionally independent given cluster membership. We found that variable selection (of either kind) yielded substantial gains in classification accuracy when the clusters were well separated, but few gains when the clusters were close together. We found that the two variable selection methods had comparable classification accuracy, but that the model selection approach had substantially better accuracy in selecting variables. In our second simulation experiment, there were correlations among the variables given the cluster memberships. We found that the model selection approach was substantially more accurate in terms of both classification and variable selection than the regularization approach, and that both gave more accurate classifications than K means without variable selection. But the model selection approach is not available in a very high dimension context. PMID- 25279245 TI - Pretreatment features to influence effectiveness of intravesical hyaluronic Acid instillation in refractory interstitial cystitis/painful bladder syndrome. AB - PURPOSE: To determine the efficacy of intravesical hyaluronic acid (HA) instillation in treating patients with refractory interstitial cystitis/painful bladder syndrome (IC/PBS) and to identify any related factors that influence its therapeutic effect. METHODS: Thirty-three female IC/PBS patients who demonstrated poor or unsatisfactory responses to previous treatments between December 2010 and October 2012 were enrolled. Despite previous treatments, the enrolled patients had visual analogue scale (VAS) pain scores >=4 and total scores (symptom and bother scores) >=13 on the pelvic pain and urgency/frequency (PUF) questionnaire and >=12 on the O'Leary-Sant interstitial cystitis symptoms index (ICSI)/problems index (ICPI). All patients received once weekly intravesical instillations of 40 mg HA diluted in 50-mL saline for 4 weeks. The efficacy of the HA instillation was evaluated by comparing the mean changes in the scores of the VAS and questionnaires from baseline to 4 weeks after treatment. Improvement was defined as a >=2 decrease in the VAS. Moreover, we investigated the effects of the presence of Hunner's ulcer and previous treatment modalities on the therapeutic outcome of HA instillation. RESULTS: The mean age was 57.0+/-1.8 years (range, 28 75 years). The VAS score significantly decreased from baseline to 4 weeks after treatment (-2.5, P<0.001). The mean changes in the PUF, ICSI, and ICPI from baseline to 4 weeks after the treatment were -3.8 (P<0.001), -2.3 (P<0.001), and 2.7 (P<0.001), respectively. Twenty patients (61%) showed improvements. Previous treatment modalities did not affect the efficacy of HA instillation and the presence of Hunner's ulcer was unrelated to outcomes. No complications were observed. CONCLUSIONS: These results show that intravesical HA instillation is an effective and safe treatment for patients with refractory IC/PBS. Previous treatment modalities and presence of Hunner's ulcer do not affect the efficacy of HA instillation. PMID- 25279247 TI - Estimating Transitional Probabilities with Cross-Sectional Data to Assess Smoking Behavior Progression: A Validation Analysis. AB - BACKGROUND AND OBJECTIVE: New analytical tools are needed to advance tobacco research, tobacco control planning and tobacco use prevention practice. In this study, we validated a method to extract information from cross-sectional survey for quantifying population dynamics of adolescent smoking behavior progression. METHODS: With a 3-stage 7-path model, probabilities of smoking behavior progression were estimated employing the Probabilistic Discrete Event System (PDES) method and the cross-sectional data from 1997-2006 National Survey on Drug Use and Health (NSDUH). Validity of the PDES method was assessed using data from the National Longitudinal Survey of Youth 1997 and trends in smoking transition covering the period during which funding for tobacco control was cut substantively in 2003 in the United States. RESULTS: Probabilities for all seven smoking progression paths were successfully estimated with the PDES method and the NSDUH data. The absolute difference in the estimated probabilities between the two approaches varied from 0.002 to 0.076 (p>0.05 for all) and were highly correlated with each other (R2 =0.998, p<0.01). Changes in the estimated transitional probabilities across the 1997-2006 reflected the 2003 funding cut for tobacco control. CONCLUSIONS: The PDES method has validity in quantifying population dynamics of smoking behavior progression with cross-sectional survey data. The estimated transitional probabilities add new evidence supporting more advanced tobacco research, tobacco control planning and tobacco use prevention practice. This method can be easily extended to study other health risk behaviors. PMID- 25279248 TI - A historical perspective on the lateral diffusion model of GTPase activation and related coupling of membrane signaling proteins. AB - Aspects of our discovery of lateral diffusion of the G protein coupled receptor (GPCR) rhodopsin and that a single activated rhodopsin can non-covalently catalyze GTP binding to thousands of GTPases per second on rod disk membranes via this diffusion are summarized herein. Rapid GTPase coupling to membrane-bound phosphodiesterase (PDE) further amplifies the signal via cGMP hydrolysis, essential to visual transduction. Important generalizations from this work are that biomembranes can uniquely concentrate, orient for reaction and provide a solvent appropriate to rapid, powerful and appropriately controlled sequential interaction of signaling proteins. Of equal importance to function is timely control and termination of such powerful amplification via receptor phosphorylation (quenching) and arrestin binding. Downstream kinetic modulation by GTPase activating proteins (GAPs) and regulators of G protein signaling (RGS) and related mechanisms as well as limitations set by membrane domain fencing, structural protein binding etc. can be essential in relevant systems. PMID- 25279249 TI - Current understanding of signal amplification in phototransduction. AB - The studies of visual signal transduction, or phototransduction, have played a pivotal role in elucidating the most general principles of G protein signaling, particularly in regards to the concept of signal amplification, i.e., the process by which activation of a relatively small number of G protein coupled receptors is transformed into a robust downstream signaling event. In this essay, we summarize our current quantitative understanding of this process in living rods of lower and higher vertebrate animals. An integration of biochemical experiments in vitro with electrophysiological recordings from intact rod photoreceptors indicates that the total number of G protein molecules activated in the course of a light response to a single photon is ~16 in the mouse and ~60 in the frog. This further translates into hydrolysis of ~2000 and ~72 000 molecules of cGMP downstream of G protein, respectively, which represents the total degree of biochemical amplification in the phototransduction cascade. PMID- 25279250 TI - G Protein-coupled receptors: Multi-turnover GDP/GTP exchange catalysis on heterotrimeric G proteins. AB - G protein-coupled receptors and heterotrimeric G proteins can diffuse laterally in the plasma membrane such that one receptor can catalyze the activation (GDP/GTP exchange) of multiple G proteins. In some cases, these processes are fast enough to support molecular signal amplification, where a single receptor maintains the activation of multiple G proteins at steady-state. Amplification in cells is probably highly regulated. It depends upon the identities of the G receptor and G protein - some do and some don't - and upon the activities of GTPase-activating proteins, membrane scaffolds, and other regulatory partners. PMID- 25279251 TI - G protein coupled receptor signaling complexes in live cells. AB - Classical models of receptor (GPCR) and G protein (Galphabetagamma) signaling based on biochemical studies have proposed that receptor stimulation results in G protein activation (Galpha-GTP) and dissociation of the heterotrimer (Galpha-GTP + Gbetagamma) to regulate downstream signaling events. Unclear is whether or not there exists freely diffusible, activated Galpha-GTP on cellular membranes capable of catalytic signal amplification. Recent studies in live cells indicate that GPCRs serve as platforms for the assembly of macromolecular signaling complexes that include G proteins to support a highly efficient and spatially restricted signaling event, with no requirement for full Galpha-GTP and Gbetagamma dissociation and lateral diffusion within the plasma membrane. PMID- 25279253 TI - Ethical considerations in elective amputation after traumatic peripheral nerve injuries. AB - Traumatic peripheral nerve injuries often complicate extremity trauma, and may cause substantial functional deficits. We have encountered patients who request amputation of such injured extremities, with the goal of prosthetic replacement as a means to restore function. Data on long-term outcomes of limb salvage vs amputation are limited and somewhat contradictory, leaving how to respond to such requests in the hands of the treating physician. We present example cases, drawn from our experience with wounded soldiers in a peripheral nerve injury clinic, in order to facilitate discussion of the ways in which these patients stress the system of medical decision-making while identifying ethical questions central to responding to these requests. PMID- 25279254 TI - Corticobasal syndrome: Five new things. AB - Corticobasal syndrome (CBS) is characterized by asymmetric involuntary movements including rigidity, tremor, dystonia, and myoclonus, and often associated with apraxia, cortical sensory deficits, and alien limb phenomena. Additionally, there are various nonmotor (cognitive and language) deficits. CBS is associated with several distinct histopathologies, including corticobasal degeneration, other forms of tau-related frontotemporal lobar degeneration such as progressive supranuclear palsy, and Alzheimer disease. Accurate antemortem diagnosis of underlying pathology in CBS is challenging, though certain clinical and imaging findings may be helpful. Five recent advances in the understanding of CBS are reviewed, including clinical and pathologic features, imaging and CSF biomarkers, the role of specific genes, and the concept of a spectrum of tauopathies. PMID- 25279252 TI - Current Gaps in the Understanding of the Subcellular Distribution of Exogenous and Endogenous Protein TorsinA. AB - BACKGROUND: An in-frame deletion leading to the loss of a single glutamic acid residue in the protein torsinA (DeltaE-torsinA) results in an inherited movement disorder, DYT1 dystonia. This autosomal dominant disease affects the function of the brain without causing neurodegeneration, by a mechanism that remains unknown. METHODS: We evaluated the literature regarding the subcellular localization of torsinA. RESULTS: Efforts to elucidate the pathophysiological basis of DYT1 dystonia have relied partly on examining the subcellular distribution of the wild type and mutated proteins. A typical approach is to introduce the human torsinA gene (TOR1A) into host cells and overexpress the protein therein. In both neurons and non-neuronal cells, exogenous wild-type torsinA introduced in this manner has been found to localize mainly to the endoplasmic reticulum, whereas exogenous DeltaE-torsinA is predominantly in the nuclear envelope or cytoplasmic inclusions. Although these outcomes are relatively consistent, findings for the localization of endogenous torsinA have been variable, leaving its physiological distribution a matter of debate. DISCUSSION: As patients' cells do not overexpress torsinA proteins, it is important to understand why the reported distributions of the endogenous proteins are inconsistent. We propose that careful optimization of experimental methods will be critical in addressing the causes of the differences among the distributions of endogenous (non overexpressed) vs. exogenously introduced (overexpressed) proteins. PMID- 25279255 TI - Professionalism in court: The neurologist as expert witness. AB - Serving as an expert witness can be a rewarding experience. It affords the neurologist the opportunity to contribute expertise to the legal system's pursuit of justice and benefits the public interest. However, serving as an expert witness without understanding and incorporating relevant professional and specialty guidelines concerning expert witness testimony can place the neurologist at risk. The American Academy of Neurology has established standards governing expert witness testimony and a disciplinary process to respond to complaints of violation of its standards. Increased understanding of and adherence to these qualifications and guidelines, coupled with an awareness of how the legal system differs from clinical practice, will better equip neurologists serving as expert witnesses and minimize their professional risk when doing so. PMID- 25279256 TI - Population structure and residency patterns of whale sharks, Rhincodon typus, at a provisioning site in Cebu, Philippines. AB - This study represents the first description of whale sharks, Rhincodon typus, occurring at a provisioning site in Oslob, Cebu, Philippines. Frequent observations of sharks are often difficult, even at tourism sites, giving rise to provisioning activities to attract them. The present study provides repeated longitudinal data at a site where daily provisioning activities took place, and whale sharks were present every day. A total of 158 individual whale sharks were photographically identified between Mar 2012 and Dec 2013, with 129 males (82%), 19 females (12%) and 10 (6%) of undetermined sex. Mean estimated total length was 5.5 m (+/-1.3 m S.D.). Twenty individuals were measured with laser photogrammetry to validate researchers' estimated sizes, yielding a good correlation (r (2) = 0.83). Fifty-four (34%) individuals were observed being hand-fed by local fishermen (provisioned), through in-water behavioural observations. Maximum likelihood methods were used to model mean residency time of 44.9 days (+/-20.6 days S.E.) for provisioned R. typus contrasting with 22.4 days (+/-8.9 days S.E.) for non-provisioned individuals. Propeller scars were observed in 47% of the animals. A mean of 12.7 (+/-4.3 S.D.) R. typus were present in the survey area daily, with a maximum of 26 individuals (Aug 10 2013) and a minimum of 2 (Dec 6 2012). Twelve (8%) individuals were seen on at least 50% of survey days (n = 621), with a maximum residency of 572 days for one individual (P-396). Twenty four individuals were photographically identified across regional hotsposts, highlighting the species' migratory nature and distribution. Extended residency and differences in lagged identification rates suggest behavioural modification on provisioned individuals, underlying the necessity for proper management of this tourism activity. PMID- 25279257 TI - Shared phylogeographic patterns between the ectocommensal flatworm Temnosewellia albata and its host, the endangered freshwater crayfish Euastacus robertsi. AB - Comparative phylogeography of commensal species may show congruent patterns where the species involved share a common history. Temnosewellia is a genus of flatworms, members of which live in commensal relationships with host freshwater crustaceans. By constructing phylogenetic trees based on mitochondrial COI and 28S nuclear ribosomal gene sequences, this study investigated how evolutionary history has shaped patterns of intraspecific molecular variation in two such freshwater commensals. This study concentrates on the flatworm Temnosewellia albata and its critically endangered crayfish host Euastacus robertsi, which have a narrow climatically-restricted distribution on three mountaintops. The genetic data expands upon previous studies of Euastacus that suggested several vicariance events have led to the population subdivision of Euastacus robertsi. Further, our study compared historical phylogeographic patterning of these species. Our results showed that phylogeographic patterns shared among these commensals were largely congruent, featuring a shared history of limited dispersal between the mountaintops. Several hypotheses were proposed to explain the phylogeographic points of differences between the species. This study contributes significantly to understanding evolutionary relationships of commensal freshwater taxa. PMID- 25279258 TI - Nestling activity levels during begging behaviour predicts activity level and body mass in adulthood. AB - Across a range of species including humans, personality traits, or differences in behaviour between individuals that are consistent over time, have been demonstrated. However, few studies have measured whether these consistent differences are evident in very young animals, and whether they persist over an individual's entire lifespan. Here we investigated the begging behaviour of very young cross-fostered zebra finch nestlings and the relationship between that and adult activity levels. We found a link between the nestling activity behaviour head movements during begging, measured at just five and seven days after hatching, and adult activity levels, measured when individuals were between three and three and a half years old. Moreover, body mass was found to be negatively correlated with both nestling and adult activity levels, suggesting that individuals which carry less body fat as adults are less active both as adults and during begging as nestlings. Our work suggests that the personality traits identified here in both very young nestlings and adults may be linked to physiological factors such as metabolism or environmental sources of variation. Moreover, our work suggests it may be possible to predict an individual's future adult personality at a very young age, opening up new avenues for future work to explore the relationship between personality and a number of aspects of individual life history and survival. PMID- 25279259 TI - What's for dinner? Undescribed species of porcini in a commercial packet. AB - Accurate diagnosis of the components of our food and a standard lexicon for clear communication is essential for regulating global food trade and identifying food frauds. Reliable identification of wild collected foods can be particularly difficult, especially when they originate in under-documented regions or belong to poorly known groups such as Fungi. Porcini, one of the most widely traded wild edible mushrooms in the world, are large and conspicuous and they are used as a food both on their own and in processed food products. China is a major exporter of porcini, most of it ending up in Europe. We used DNA-sequencing to identify three species of mushroom contained within a commercial packet of dried Chinese porcini purchased in London. Surprisingly, all three have never been formally described by science and required new scientific names. This demonstrates the ubiquity of unknown fungal diversity even in widely traded commercial food products from one of the most charismatic and least overlooked groups of mushrooms. Our rapid analysis and description makes it possible to reliably identify these species, allowing their harvest to be monitored and their presence tracked in the food chain. PMID- 25279260 TI - Students distracted by electronic devices perform at the same level as those who are focused on the lecture. AB - Background. Little is known about the characteristics of internet distractions that students may engage in during lecture. The objective of this pilot study is to identify some of the internet-based distractions students engage in during in person lectures. The findings will help identify what activities most commonly cause students to be distracted from the lecture and if these activities impact student learning. Methods. This study is a quasi-experimental pilot study of 26 students from a single institution. In the current study, one class of third-year students were surveyed after a lecture on special needs dentistry. The survey identified self-reported utilization patterns of "smart" devices during the lecture. Additionally, twelve quiz-type questions were given to assess the students' recall of important points in the lecture material that had just been covered. Results. The sample was comprised of 26 students. Of these, 17 were distracted in some form (either checking email, sending email, checking Facebook, or sending texts). The overall mean score on the test was 9.85 (9.53 for distracted students and 10.44 for non-distracted students). There were no significant differences in test scores between distracted and non-distracted students (p = 0.652). Gender and types of distractions were not significantly associated with test scores (p > 0.05). All students believed that they understood all the important points from the lecture. Conclusions. Every class member felt that they acquired the important learning points during the lecture. Those who were distracted by electronic devices during the lecture performed similarly to those who were not. However, results should be interpreted with caution as this study was a small quasi-experimental design and further research should examine the influence of different types of distraction on different types of learning. PMID- 25279261 TI - MicroRNAs expression profile in CCR6(+) regulatory T cells. AB - Backgroud. CCR6(+) CD4(+) regulatory T cells (CCR6(+) Tregs), a distinct Tregs subset, played an important role in various immune diseases. Recent evidence showed that microRNAs (miRNAs) are vital regulators in the function of immune cells. However, the potential role of miRNAs in the function of CCR6(+) Tregs remains largely unknown. In this study, we detected the expression profile of miRNAs in CCR6(+) Tregs. Materials and Methods. The expression profile of miRNAs as well as genes in CCR6(+) Tregs or CCR6(-) Tregs from Balb/c mice were detected by microarray. The signaling pathways were analyzed using the Keggs pathway library. Results. We found that there were 58 miRNAs significantly upregulated and 62 downregulated up to 2 fold in CCR6(+) Tregs compared with CCR6(-) Tregs. Moreover, 1,391 genes were observed with 3 fold change and 20 signaling pathways were enriched using the Keggs pathway library. Conclusion. The present data showed CCR6(+) Tregs expressed specific miRNAs pattern, which provides insight into the role of miRNAs in the biological function of distinct Tregs subsets. PMID- 25279262 TI - The impact of atypical early histories on pet or performer chimpanzees. AB - It is widely accepted that an animal's early history, including but not limited to its rearing history, can have a profound impact on later behavior. In the case of captive animals, many studies have used categorical measures such as mother reared or human reared that do not account for both the influence of human and conspecific interaction. In order to account for the influence of both human and conspecific early exposure to later behavior, we collected 1385 h of data on 60 chimpanzees, of which 36 were former pets or performers, currently housed at accredited zoos or sanctuaries. We developed a unique metric, the Chimpanzee Human Interaction (CHI) Index that represented a continuous measure of the proportion of human and chimpanzee exposure subjects experienced and here focused on their exposure during the first four years of life. We found that chimpanzees who experienced less exposure to other chimpanzees as infants showed a lower frequency of grooming and sexual behaviors later in life which can influence social dynamics within groups. We also found chimpanzees who experienced more exposure to other chimpanzees as infants showed a higher frequency of coprophagy, suggesting coprophagy could be a socially-learned behavior. These results help characterize some of the long-term effects borne by chimpanzees maintained as pets and performers and may help inform managers seeking to integrate these types of chimpanzees into larger social groups, as in zoos and sanctuaries. In addition, these results highlight the necessity of taking into account the time weighted influence of human and conspecific interactions when assessing the impact that humans can have on animals living in captivity. PMID- 25279263 TI - Fast and accurate estimation of the covariance between pairwise maximum likelihood distances. AB - Pairwise evolutionary distances are a model-based summary statistic for a set of molecular sequences. They represent the leaf-to-leaf path lengths of the underlying phylogenetic tree. Estimates of pairwise distances with overlapping paths covary because of shared mutation events. It is desirable to take these covariance structure into account to increase precision in any process that compares or combines distances. This paper introduces a fast estimator for the covariance of two pairwise maximum likelihood distances, estimated under general Markov models. The estimator is based on a conjecture (going back to Nei & Jin, 1989) which links the covariance to path lengths. It is proven here under a simple symmetric substitution model. A simulation shows that the estimator outperforms previously published ones in terms of the mean squared error. PMID- 25279264 TI - Anopheles gambiae densovirus (AgDNV) has negligible effects on adult survival and transcriptome of its mosquito host. AB - Mosquito densoviruses (DNVs) are candidate agents for paratransgenic control of malaria and other vector-borne diseases. Unlike other mosquito DNVs, the Anopheles gambiae DNV (AgDNV) is non-pathogenic to larval mosquitoes. However, the cost of infection upon adults and the molecular mechanisms underpinning infection in the mosquito host are unknown. Using life table analysis, we show that AgDNV infection has minimal effects on An. gambiae survival (no significant effect in 2 replicates and a slight 2 day survival decrease in the third replicate). Using microarrays, we show that AgDNV has very minimal effect on the adult mosquito transcriptome, with only 4-15 genes differentially regulated depending on the statistical criteria imposed. The minimal impact upon global transcription provides some mechanistic understanding of lack of virus pathogenicity, suggesting a long co-evolutionary history that has shifted towards avirulence. From an applied standpoint, lack of strong induced fitness costs makes AgDNV an attractive agent for paratransgenic malaria control. PMID- 25279266 TI - A simple non-invasive method for measuring gross brain size in small live fish with semi-transparent heads. AB - This paper describes a non-invasive method for estimating gross brain size in small fish with semi-transparent heads, using system camera equipment. Macro photographs were taken from above on backlit free-swimming fish undergoing light anaesthesia. From the photographs, the width of the optic tectum was measured. This measure (TeO-measure) correlates well with the width of the optic tectum as measured from out-dissected brains in both brown trout fry and zebrafish (Pearson r > 0.90). The TeO-measure also correlates well with overall brain wet weight in brown trout fry (r = 0.90), but less well for zebrafish (r = 0.79). A non invasive measure makes it possible to quickly assess brain size from a large number of individuals, as well as repeatedly measuring brain size of live individuals allowing calculation of brain growth. PMID- 25279265 TI - Culture-independent detection and characterisation of Mycobacterium tuberculosis and M. africanum in sputum samples using shotgun metagenomics on a benchtop sequencer. AB - Tuberculosis remains a major global health problem. Laboratory diagnostic methods that allow effective, early detection of cases are central to management of tuberculosis in the individual patient and in the community. Since the 1880s, laboratory diagnosis of tuberculosis has relied primarily on microscopy and culture. However, microscopy fails to provide species- or lineage-level identification and culture-based workflows for diagnosis of tuberculosis remain complex, expensive, slow, technically demanding and poorly able to handle mixed infections. We therefore explored the potential of shotgun metagenomics, sequencing of DNA from samples without culture or target-specific amplification or capture, to detect and characterise strains from the Mycobacterium tuberculosis complex in smear-positive sputum samples obtained from The Gambia in West Africa. Eight smear- and culture-positive sputum samples were investigated using a differential-lysis protocol followed by a kit-based DNA extraction method, with sequencing performed on a benchtop sequencing instrument, the Illumina MiSeq. The number of sequence reads in each sputum-derived metagenome ranged from 989,442 to 2,818,238. The proportion of reads in each metagenome mapping against the human genome ranged from 20% to 99%. We were able to detect sequences from the M. tuberculosis complex in all eight samples, with coverage of the H37Rv reference genome ranging from 0.002X to 0.7X. By analysing the distribution of large sequence polymorphisms (deletions and the locations of the insertion element IS6110) and single nucleotide polymorphisms (SNPs), we were able to assign seven of eight metagenome-derived genomes to a species and lineage within the M. tuberculosis complex. Two metagenome-derived mycobacterial genomes were assigned to M. africanum, a species largely confined to West Africa; the others that could be assigned belonged to lineages T, H or LAM within the clade of "modern" M. tuberculosis strains. We have provided proof of principle that shotgun metagenomics can be used to detect and characterise M. tuberculosis sequences from sputum samples without culture or target-specific amplification or capture, using an accessible benchtop-sequencing platform, the Illumina MiSeq, and relatively simple DNA extraction, sequencing and bioinformatics protocols. In our hands, sputum metagenomics does not yet deliver sufficient depth of coverage to allow sequence-based sensitivity testing; it remains to be determined whether improvements in DNA extraction protocols alone can deliver this or whether culture, capture or amplification steps will be required. Nonetheless, we can foresee a tipping point when a unified automated metagenomics-based workflow might start to compete with the plethora of methods currently in use in the diagnostic microbiology laboratory. PMID- 25279267 TI - Differences in healthcare expenditures for inflammatory bowel disease by insurance status, income, and clinical care setting. AB - Background. Socioeconomic factors and insurance status have not been correlated with differential use of healthcare services in inflammatory bowel disease (IBD). Aim. To describe IBD-related expenditures based on insurance and household income with the use of inpatient, outpatient, emergency, and office-based services, and prescribed medications in the United States (US). Methods. We evaluated the Medical Expenditure Panel Survey from 1996 to 2011 of individuals with Crohn's disease (CD) or ulcerative colitis (UC). Nationally weighted means, proportions, and multivariate regression models examined the relationships between income and insurance status with expenditures. Results. Annual per capita mean expenditures for CD, UC, and all IBD were $10,364 (N = 238), $7,827 (N = 95), and $9,528, respectively, significantly higher than non-IBD ($4,314, N = 276, 372, p < 0.05). Publicly insured patients incurred the highest costs ($18,067) over privately insured ($8,014, p < 0.05) or uninsured patients ($5,129, p < 0.05). Among all IBD patients, inpatient care composed the highest proportion of costs ($3,392, p < 0.05). Inpatient costs were disproportionately higher for publicly insured patients. Public insurance had higher odds of total costs than private (OR 2.13, CI [1.08-4.19]) or no insurance (OR 4.94, CI [1.26-19.47]), with increased odds for inpatient and emergency care. Private insurance had higher costs associated with outpatient care, office-based care, and prescribed medicines. Low-income patients had lower costs associated with outpatient (OR 0.38, CI [0.15-0.95]) and office-based care (OR 0.21, CI [0.07-0.62]). Conclusions. In the US, high inpatient utilization among publicly insured patients is a previously unrecognized driver of high IBD costs. Bridging this health services gap between SES strata for acute care services may curtail direct IBD-related costs. PMID- 25279268 TI - Bio-inspired design of ice-retardant devices based on benthic marine invertebrates: the effect of surface texture. AB - Growth of ice on surfaces poses a challenge for both organisms and for devices that come into contact with liquids below the freezing point. Resistance of some organisms to ice formation and growth, either in subtidal environments (e.g., Antarctic anchor ice), or in environments with moisture and cold air (e.g., plants, intertidal) begs examination of how this is accomplished. Several factors may be important in promoting or mitigating ice formation. As a start, here we examine the effect of surface texture alone. We tested four candidate surfaces, inspired by hard-shelled marine invertebrates and constructed using a three dimensional printing process. We examined sub-polar marine organisms to develop sample textures and screened them for ice formation and accretion in submerged conditions using previous methods for comparison to data for Antarctic organisms. The sub-polar organisms tested were all found to form ice readily. We also screened artificial 3-D printed samples using the same previous methods, and developed a new test to examine ice formation from surface droplets as might be encountered in environments with moist, cold air. Despite limitations inherent to our techniques, it appears surface texture plays only a small role in delaying the onset of ice formation: a stripe feature (corresponding to patterning found on valves of blue mussels, Mytilus edulis, or on the spines of the Antarctic sea urchin Sterechinus neumayeri) slowed ice formation an average of 25% compared to a grid feature (corresponding to patterning found on sub-polar butterclams, Saxidomas nuttalli). The geometric dimensions of the features have only a small (~6%) effect on ice formation. Surface texture affects ice formation, but does not explain by itself the large variation in ice formation and species-specific ice resistance observed in other work. This suggests future examination of other factors, such as material elastic properties and surface coatings, and their interaction with surface pattern. PMID- 25279269 TI - Synergy as a rationale for phage therapy using phage cocktails. AB - Where phages are used to treat bacterial contaminations and infections, multiple phages are typically applied at once as a cocktail. When two or more phages in the cocktail attack the same bacterium, the combination may produce better killing than any single phage (synergy) or the combination may be worse than the best single phage (interference). Synergy is of obvious utility, especially if it can be predicted a priori, but it remains poorly documented with few examples known. This study addresses synergy in which one phage improves adsorption by a second phage. It first presents evidence of synergy from an experimental system of two phages and a mucoid E. coli host. The synergy likely stems from a tailspike enzyme produced by one of the phages. We then offer mathematical models and simulations to understand the dynamics of synergy and the enhanced magnitude of bacterial control possible. The models and observations complement each other and suggest that synergy may be of widespread utility and may be predictable from easily observed phenotypes. PMID- 25279270 TI - Revision of the Late Jurassic crocodyliform Alligatorellus, and evidence for allopatric speciation driving high diversity in western European atoposaurids. AB - Atoposaurid crocodyliforms represent an important faunal component of Late Jurassic to Early Cretaceous Laurasian semi-aquatic to terrestrial ecosystems, with numerous spatiotemporally contemporaneous atoposaurids known from western Europe. In particular, the Late Jurassic of France and Germany records evidence for high diversity and possible sympatric atoposaurid species belonging to Alligatorellus, Alligatorium and Atoposaurus. However, atoposaurid taxonomy has received little attention, and many species are in need of revision. As such, this potentially high European diversity within a narrow spatiotemporal range might be a taxonomic artefact. Here we provide a taxonomic and anatomical revision of the Late Jurassic atoposaurid Alligatorellus. Initially described as A. beaumonti from the Kimmeridgian of Cerin, eastern France, additional material from the Tithonian of Solnhofen, south-eastern Germany, was subsequently referred to this species, with the two occurrences differentiated as A. beaumonti beaumonti and A. beaumonti bavaricus, respectively. We provide a revised diagnosis for the genus Alligatorellus, and note a number of anatomical differences between the French and German specimens, including osteoderm morphology and the configuration and pattern of sculpting of cranial elements. Consequently, we restrict the name Alligatorellus beaumonti to include only the French remains, and raise the rank of the German material to a distinct species: Alligatorellus bavaricus. A new diagnosis is provided for both species, and we suggest that a recently referred specimen from a coeval German locality cannot be conclusively referred to Alligatorellus. Although it has previously been suggested that Alligatorellus, Alligatorium and Atoposaurus might represent a single growth series of one species, we find no conclusive evidence to support this proposal, and provide a number of morphological differences to distinguish these three taxa that appear to be independent of ontogeny. Consequently, we interpret high atoposaurid diversity in the Late Jurassic island archipelago of western Europe as a genuine biological signal, with closely related species of Alligatorellus, Alligatorium and Atoposaurus in both French and German basins providing evidence for allopatric speciation, potentially driven by fluctuating highstand sea levels. PMID- 25279271 TI - Antidepressants and the Placebo Effect. AB - Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed, their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future. PMID- 25279272 TI - The effect of standing and sitting postures on breathing in brass players. AB - PURPOSE: The object of this study was to examine the effect of posture on breathing in brass players. Breathing when standing was compared with sitting erect on a flat, downward or upward sloping seat, or on a reclining seat. METHODS: Spirometry was used to measure aspects of lung function. Muscle activity and respiratory movements during different playing tasks were recorded using electromyography and inductive plethysmography. RESULTS: Only sitting in a reclining position produced statistically significantly lower values for VC, FVC, FEV1, PEF than standing. When players were asked to produce a note of maximum duration, only a downward sloping seat caused a significant change (an 11% reduction) compared to standing. When seated, the abdominal component of respiratory movement was significantly higher during these long notes than when standing, though maximum activity in abdominal wall muscles was significantly reduced (by 32-44%). On a downward sloping seat, muscle activity was significantly higher (9%) than on a flat seat. Tongued and untongued sforzando notes recruited significantly less abdominal muscle activity (33-67%) when sitting than when standing. When playing a trumpet study, abdominal muscle activity was significantly reduced on a downward sloping seat (by 32%) and on a flat seat (by 40%) in comparison to standing. Muscle activity in the two sitting positions were not significantly different. CONCLUSION: Though brass players are often told to "sit as if standing", abdominal muscle activity is always significantly reduced when sitting on a flat or downward sloping seat, however when greater respiratory effort is required, activity on downward sloping seats may rise closer to that of standing. PMID- 25279273 TI - Comparison of end-diastolic versus end-systolic cardiac-computed tomography reconstruction interval in patient's prior to pulmonary vein isolation. AB - PURPOSE: Aim of the study was to investigate diagnostic accuracy of cardiac computed tomography angiography (CCTA) between left ventricular end-systolic (LVES) and left ventricular end-diastolic (LVED) cardiac phase for thrombus detection in patient's prior to pulmonary vein isolation (PVI). MATERIALS AND METHODS: 182 consecutive Patients with drug refractory AF scheduled for PVI (62.6% male, mean age 64.1 +/- 10.2 years) underwent routine pre-procedural evaluation including transesophageal echocardiography (TEE) and CCTA for evaluation of left atrial (LA)/left atrial appendage (LAA) anatomy and thrombus formation. Qualitative and quantitative analysis (using aorta ascendens (AA)/LAA ratio) was performed. Measurements of the LA/LAA in LVES and LVED cardiac phase were obtained. RESULTS: End-systolic volumes (LA/LAA) measured in 30 patients without filling defects as control group and all 14 with filling defects of 182 patients were significantly larger (p < 0.01) than in end-diastolic phase. Qualitative analysis was inferior to quantitative analysis using LA/LAA ratio (<0.5; accuracy: 100%, 88%,100%, 99% vs 100%). 5 out of 182 patients (2.7%) showed thrombus formation of the LAA in CCTA confirmed by TEE and quantitative analysis. Intra/-interobserver variability was lower in end-systolic vs end diastolic reconstruction interval. CONCLUSION: For evaluating CCTA datasets in patients prior PVI, the LVES reconstruction interval is recommended due to significantly larger LA/LAA volumes and lower intra/- interobserver variability's. PMID- 25279274 TI - Activated and inactivated immune responses in Caenorhabditis elegans against Photorhabdus luminescens TT01. AB - The Gram-negative bacterium Photorhabdus luminescens which symbiotically associates with the entomopathogenic nematode Heterorhabditis bacteriophora, has a broad insecticidal and nematicidal activity. The virulence of P. luminescens toward the non-mutualistic nematode Caenorhabditis elegans has not been described. We showed that when fed on P. luminescens, the intestinal cells of C. elegans worms become delicate and some crystal-like structure was developed within the intestinal lumen. Next, we examined the requirement of the p38 mitogen activated protein kinase (MAPK) and insulin/IGF-1 signaling pathway against P. luminescens. Depletion of pmk-1 by RNAi enhances susceptibility to P. luminescens, and numerous downstream targets regulated by the p38 MAPK pathway were induced when fed on P. luminescens. On the other hand, knockdown of daf-16 has no effects on C. elegans lifespan, but knockdown of daf-2 dramatically increased resistance to P. luminescens in a daf-16-dependent manner. We also revealed one of the daf-2 ligands ins-7 was induced and ins-7 deletion mutant survived longer when fed on P. luminescens. These results suggest the p38 MAPK pathway is activated and required for the host defense against P. luminescens. Insulin/IGF-1 signaling pathway is inactivated by P. luminescens through the overexpression of insulin-like gene. PMID- 25279275 TI - Methylphenidate off-label use and safety. AB - INTRODUCTION: Methylphenidate is a piperidine derivative structurally and pharmacologically similar to amphetamine. Methylphenidate is indicated for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 years of age and over when remedial measures alone prove insufficient. In adults, its indication, except in narcolepsy, is not defined. Methylphenidate received regulatory approval almost sixty years ago with a first registration in Switzerland in October 1954. OBJECTIVE: To evaluate the off-label use of methylphenidate and its characteristics from a database of spontaneous reports. METHODS: This study analysed data from the French Pharmacovigilance Database of adverse drug reactions spontaneously reported by health professionals from 1985 to December 2011. Off-label use was evaluated according to age. RESULTS: In the French Pharmacovigilance database, 181 cases of adverse drug reactions were reported with methylphenidate. Neuropsychiatric effects were the most frequent adverse event reported (41%) followed by cardiovascular and cutaneous side effects (14%). 143 reports concerned children (113 boys, 30 girls, mean age 10.6 +/- 3.3 years) of which 46 (30%) were off-label uses. There were 38 adults (20 men, 18 women), of which 32 (88%) off-label use. In adults, methylphenidate was prescribed for depression, and this practice was associated with serious adverse events of drug dependence, overdose and suicide attempt. Overall, off-label use was detected in 43% (78/181) of all cases reported. CONCLUSION: More than 40% of the patients with drug reactions received methylphenidate for off-label indications. Additional long-term exposures and independent clinical studies are necessary to establish the long-term profile safety of methylphenidate. PMID- 25279276 TI - Human kallikrein-2 gene and protein expression predicts prostate cancer at repeat biopsy. AB - PURPOSE: The human kallikrein-2 (hK2) protein and two single nucleotide polymorphism (SNPs) (rs2664155, rs198977) of the gene are associated with prostate cancer risk. We examined whether hK2 protein and gene SNPs predict prostate cancer at the time of repeat biopsy. METHODS: We prospectively offered a repeat biopsy to men with a negative prostate biopsy performed for a PSA >4.0 ng/mL or abnormal Digital Rectal Exam (DRE) between 2001-2005. We genotyped and measured serum hK2 levels in 941 men who underwent a repeat prostate biopsy. Logistic regression analyses were conducted to determine the significance of KLK2 SNPs and hK2 levels for predicting cancer at repeat biopsy. RESULTS: Of the 941 patients, 180 (19.1%) were found to have cancer. The rs198977 SNP was positively associated with cancer at repeat biopsy (OR variant T allele = 1.8, 95% CI: 1.04 3.13, p = 0.049). When combined, the odds ratio for prostate cancer for patients with high hK2 levels and the variant T-allele of rs198977 was 3.77 (95% CI: 1.94 7.32, p < 0.0001), compared to patients with low hK2 levels and the C-allele. The addition of hK2 levels and KLK2 rs198977 to the baseline predictive model did not significantly increase the area under the curve from a baseline model of 0.67 to 0.69 (p = 0.6). CONCLUSIONS: The KLK2 SNP rs198977 was positively associated with hK2 levels and predicts prostate cancer at the time of repeat prostate biopsy. Further characterization of the KLK2 gene will be needed to determine its clinical utility. PMID- 25279277 TI - Antityphoid and radical scavenging properties of the methanol extracts and compounds from the aerial part of Paullinia pinnata. AB - Paullinia pinnata Linn (Sapindaceae) is a medicinal plant, locally used in the West Region of Cameroon for the treatment of typhoid fever. This work was designed to evaluate the antityphoid and antioxidant activities of the extracts and compounds of P. pinnata. The methanol extracts of the leaves and stems were tested for antityphoid and antioxidant activities. Compounds were isolated, and their structures elucidated by analysis of spectroscopic data in conjuction with literature data and tested for the same activities. The leaf extract was also tested in vivo for its antityphoid potential in a Salmonella typhimurium-induced typhoid fever model in Wistar rats. Seven known compounds: methylinositol (1), beta-sitosterol (2), friedelin (3), 3beta-(beta-D-Glucopyranosyloxy)stigmast-5 ene (4), (3beta)-3-O-(2'-Acetamido-2'-deoxy-beta-D-glucopyranosyl) oleanolic acid (5), (3beta,16alpha-hydroxy)-3-O-(2'-Acetamido-2'-deoxy-beta-D-glucopyranosyl) echinocystic acid (6) and (3beta,)-3-O-[beta-D-glucopyranosyl-(1"-3')-2' acetamido-2'-deoxy-beta-D-galactopyranosyl]oleanolic acid (7) were isolated. Compounds 5 and 1 showed the highest antibacterial (MIC = 0.781-1.562 MUg/ml) and DPPH radical scavenging (RSa50 = 19.27 +/- 4.43 MUg/ml) activities respectively. The maximum extract dose (446.00 mg/kg bw) had comparable activity with ciprofloxacin (7.14 mg/kg bw) and oxytetracycline (5 mg/kg bw). The extract induced significant dose-dependent increase of WBCs and lymphocytes. These results support the ethnomedicinal use of P. pinnata and its isolated Compounds could be useful in the standardization of antityphoid phytomedicine from it. PMID- 25279278 TI - Insect pests of sweetpotato in Uganda: farmers' perceptions of their importance and control practices. AB - Insect pests are among the most important constraints limiting sweetpotato (Ipomoea batatas) production in Africa. However, there is inadequate information about farmers' knowledge, perceptions and practices in the management of key insect pests. This has hindered development of effective pest management approaches for smallholder farmers. A standard questionnaire was used to interview individual sweetpotato farmers (n = 192) about their perception and management practices regarding insect pests in six major sweetpotato producing districts of Uganda. The majority (93%) of farmers perceived insect pests to be a very serious problem. With the exception of Masindi and Wakiso districts where the sweetpotato butterfly (Acraea acerata) was the number one constraint, sweetpotato weevils (Cylas puncticollis and C. brunneus) were ranked as the most important insect pests. Insecticide use in sweetpotato fields was very low being highest (28-38% of households) in districts where A. acerata infestation is the biggest problem. On average, 65% and 87% of the farmers took no action to control A. acerata and Cylas spp., respectively. Farmers were more conversant with the presence of and damage by A. acerata than of Cylas spp. as they thought that Cylas spp. root damage was brought about by a prolonged dry season. Different levels of field resistance (ability of a variety to tolerate damage) of sweetpotato landraces to A. acerata (eight landraces) and Cylas spp. (six landraces) were reported by farmers in all the six districts. This perceived level of resistance to insect damage by landraces needs to be investigated. To improve farmers' capabilities for sweetpotato insect pest management, it is crucial to train them in the basic knowledge of insect pest biology and control. PMID- 25279279 TI - Molecular diversity and functional variability of environmental isolates of Bacillus species. AB - In the present study, out of 264 phosphate (P) solubilizing Bacillus strains isolated from apple rhizosphere, only twelve isolates were found to be efficient (showed most of the plant growth promoting activity) which were further characterized at molecular level using 16S rDNA partial gene sequencing. Out of 12 isolates, MZPSB 207 was found to be most efficient P-solubilizing (864.71 MUg/ml) isolate which also showed indole acetic acid production (51.83 MUg/ml), siderophore production, ammonia production, antagonistic property (against Rhizoctonia solani and Fusarium oxysporum), hydrolytic enzymes productions (protease, chitinase and cellulase), 1-aminocyclopropane-1-carboxylate (ACC) deaminase production (7.7 MUm alphaKB mg(-1) h(-1)). The in-vitro seed germination assay showed that Bacillus (twelve isolates) inoculated seeds showed more seed germination and seedling vigor rate as compared to uninoculated control treatment. For the genetic diversity studies of efficient 12 strains, the polyphasic approach using 16S-rDNA, Repetitive element sequence (rep) based PCR (ERIC-PCR and BOX-PCR) were used. Based on 16S rDNA partial gene sequencing the isolated Bacillus genus was divide into four groups. First group (five isolates), second group (two isolates), third group (three isolates) and fourth group (two isolates) which showed close genetic relatedness to the B. subtilis, B. pumulis, B. megaterium and B. amyloliquefaciens, respectively. The rep PCR fingerprinting showed variability between and within the species. The large variability was showed by ERIC-PCR whereas some variability was showed by BOX-PCR. The results clearly showed that 16S rRNA gene sequencing is unable to discriminate the isolates at strain level. But rep-PCR fingerprinting is excellent tool to characterize and discriminate the strains at the genomic level. PMID- 25279280 TI - Solitary hepatic lymphangioma: a one-case report. AB - Hepatic lymphangiomas, malformations of the liver lymphatic system, are extremely rare conditions in adults. A 41-year-old man presented with right upper abdominal pain for 6 months was introduced in this report. Ultrasound (US) and computed tomography (CT) scan demonstrated a giant cystictumor with a pedunculatedextrahepatic growth pattern. Due to diagnostic uncertainty, a partial hepatectomy was performed and pathological results confirmed the diagnosis of solitary hepatic lymphangioma. In this article, we reviewed the clinical and pathology features, preoperative diagnostic challenges, and treatments of hepaticlymphangiomas. PMID- 25279281 TI - Characterization of Newcastle Disease Virus and poultry-handling practices in live poultry markets, Ethiopia. AB - Newcastle disease represents the most severe poultry disease responsible for marked economic losses in Ethiopia. To provide a molecular characterization of Newcastle disease viruses circulating in this country, a cross sectional survey was conducted at five selected live poultry market sites in Addis Ababa. In addition, baseline data on the live poultry market system were acquired through a detailed questionnaire submitted to poultry traders. We identified 44/146 positive samples, 29 of which were virulent strains belonging to sub-genotype VIf. The very poor biosecurity practices, which have resulted from responses of the participants, suggest that they might have had a heavy impact in the spread of the disease. This study provides important information on epidemiology and control of NDV in Ethiopia and highlights the importance of implementing surveillances and biosecurity practices in live poultry markets. PMID- 25279282 TI - Feature selection and semi-supervised clustering using multiobjective optimization. AB - In this paper we have coupled feature selection problem with semi-supervised clustering. Semi-supervised clustering utilizes the information of unsupervised and supervised learning in order to overcome the problems related to them. But in general all the features present in the data set may not be important for clustering purpose. Thus appropriate selection of features from the set of all features is very much relevant from clustering point of view. In this paper we have solved the problem of automatic feature selection and semi-supervised clustering using multiobjective optimization. A recently created simulated annealing based multiobjective optimization technique titled archived multiobjective simulated annealing (AMOSA) is used as the underlying optimization technique. Here features and cluster centers are encoded in the form of a string. We assume that for each data set for 10% data points class level information are known to us. Two internal cluster validity indices reflecting different data properties, an external cluster validity index measuring the similarity between the obtained partitioning and the true labelling for 10% data points and a measure counting the number of features present in a particular string are optimized using the search capability of AMOSA. AMOSA is utilized to detect the appropriate subset of features, appropriate number of clusters as well as the appropriate partitioning from any given data set. The effectiveness of the proposed semi-supervised feature selection technique as compared to the existing techniques is shown for seven real-life data sets of varying complexities. PMID- 25279283 TI - Resistivity anisotropy of the misfit layer compound (SmS)1.25 TiS2. AB - BACKGROUND: The misfit layer compound (SmS)1.25 TiS2 has a layered structure which consists on an alternating sequence of one |SmS| bi-layer adopting a NaCl distorted structure and one |TiS2| tri-layer with the Ti atoms plane sandwiched by two sulfur ones and the Ti atoms octahedrally coordinated. Stacking is along the c-axis. Each of these two subsystems has its own 3D lattice and space group, and they have a common (b*, c*) plane in the reciprocal lattice so that the a axes are parallel and of irrational ratio. The physical properties of this compound have never been investigated. Accurate resistivity anisotropy measurement down to the liquid nitrogen temperature is presented here. FINDINGS: The in-plane resistivity shows an anomaly at 202 K, and the out-of-plane resistivity shows also anomalies at 202 and 222 K and an upward curvature between 100 and 222 K. Consequently, the resistivity anisotropy shows peculiarities; mainly an important jump at 222 K.This behavior is discussed in the framework of a possible magnetic ordering and/or anisotropic lattices distortions. Although, the role of this work is to draw the attention to these features and further investigations to confirm these results would be of interest. CONCLUSION: Further investigations are needed, mainly magnetic and crystallographic in function of temperature in order to conclude definitely whether there is any phase transition or not. PMID- 25279284 TI - In search of an empowering and motivating personal wellbeing pathway for Finnish heart patients. AB - In this article, motivation for healthy living is discussed, with a special focus on empowerment and responsibility. The individual and his or her needs and preferences are taken as the starting point with an aim to sketch a holistic picture of the elements needed in a health promotive care process from the perspective of the individual, to enhance empowerment and motivation to lead a healthy life. Health and wellbeing related services are presented as an exemplar of a structural element by which society can work as an enabler of wellbeing, taking co-responsibility of the wellbeing of the individual. It is argued that this requires that the services of public, private and third sector service providers from different fields are seamlessly connected and easy to access, with support and information available throughout the personally tailored care pathway. Also the knowhow and attitudes of all the actors must be thought of. These aspects of a good care process have been identified through interviews with heart patients and workshops with actors in a region in southern Finland, as well as based on theoretical background information and prior research. These aspects form the personal wellbeing pathway model that is presented in this article as an ideal type of a service pathway to enhance taking actively charge of one's own wellbeing. PMID- 25279285 TI - Should providers encourage realistic weight expectations and satisfaction with lost weight in commercial weight loss programs? a preliminary study. AB - BACKGROUND: Attrition is a problem among patients who participate in commercial weight loss programs. One possible explanation is that if patients are unable to reach a weight that they expect to achieve, they may be more likely to drop out of treatment. This study investigated variables associated with attrition among 30 obese patients who completed a liquid meal replacement program (LMR) and enrolled in a 52-week Small Changes Maintenance intervention (SCM). Patients lost a median 18% of body weight during LMR and completed assessments about weight expectations and weight satisfaction pre- and post-SCM. FINDINGS: Of the 30 patients who started SCM, 8 (27%) were lost to attrition. Odds of SCM attrition were higher in patients who lost <= 18.2% of pre-LMR weight (OR: 12.25, P = 0.035), had lower satisfaction (<=7) pre-SCM (OR: 10.11, P = 0.040), and who expected further weight loss of 9.1 kg or more pre-SCM (OR: 10.11, P = 0.040). SCM completers significantly increased weight loss expectations by a median of 2.3 kg from pre-SCM to post-SCM (WSR P = 0.049) that paralleled weight regained post-SCM (2.7 kg). CONCLUSIONS: After completion of a medically-supervised commercial weight loss program, patients with the greatest expectations for further weight loss and the lowest weight satisfaction were more likely to drop out of SCM. Failure to participate in maintenance treatment may lead to regain of greater than half of lost weight over the next year. Among SCM completers, lower expectations for further weight loss and greater weight satisfaction appeared to be associated with continued engagement in maintenance treatment. PMID- 25279286 TI - Process evaluation of electron beam irradiation-based biodegradation relevant to lignocellulose bioconversion. AB - In order to solve the inefficient problem of long-term biodegradation by wood decaying fungus, rice straw (RS) was depolymerized using electron beam irradiation-based biodegradation (EBIBB). This environment-friendly program without the use of inhibitory byproducts significantly increased the digestibility and fermentability of RS. Specifically, when irradiated RS was simultaneously biodegraded by Phanerochaete chrysosporium for 10 days, the sugar yield was 65.5% of the theoretical maximum. This value was on the same level as the 64.8% (for 15 days) measured from unirradiated RS. In case of fermentability, similarly, EBIBB program had an effect on time/energy saving. Furthermore, the transcriptomic profiles under different biosystem were analyzed in order to verify possible substrate-specific regulation based on change of lignocellulosic components. Interestingly, the overall correlation based on the bias (upregulation or downregulation) was reasonably analogous, especially lignocellulolysis-related genes. PMID- 25279287 TI - A study of photothermal laser ablation of various polymers on microsecond time scales. AB - To analyze the photothermal ablation of polymers, we designed a temperature measurement setup based on spectral pyrometry. The setup allows to acquire 2D temperature distributions with 1 MUm size and 1 MUs time resolution and therefore the determination of the center temperature of a laser heating process. Finite element simulations were used to verify and understand the heat conversion and heat flow in the process. With this setup, the photothermal ablation of polystyrene, poly(alpha-methylstyrene), a polyimide and a triazene polymer was investigated. The thermal stability, the glass transition temperature Tg and the viscosity above Tg were governing the ablation process. Thermal decomposition for the applied laser pulse of about 10 MUs started at temperatures similar to the start of decomposition in thermogravimetry. Furthermore, for polystyrene and poly(alpha-methylstyrene), both with a Tg in the range between room and decomposition temperature, ablation already occurred at temperatures well below the decomposition temperature, only at 30-40 K above Tg. The mechanism was photomechanical, i.e. a stress due to the thermal expansion of the polymer was responsible for ablation. Low molecular weight polymers showed differences in photomechanical ablation, corresponding to their lower Tg and lower viscosity above the glass transition. However, the difference in ablated volume was only significant at higher temperatures in the temperature regime for thermal decomposition at quasi-equilibrium time scales. PMID- 25279288 TI - Dynamic cluster scheduling for cluster-tree WSNs. AB - While Cluster-Tree network topologies look promising for WSN applications with timeliness and energy-efficiency requirements, we are yet to witness its adoption in commercial and academic solutions. One of the arguments that hinder the use of these topologies concerns the lack of flexibility in adapting to changes in the network, such as in traffic flows. This paper presents a solution to enable these networks with the ability to self-adapt their clusters' duty-cycle and scheduling, to provide increased quality of service to multiple traffic flows. Importantly, our approach enables a network to change its cluster scheduling without requiring long inaccessibility times or the re-association of the nodes. We show how to apply our methodology to the case of IEEE 802.15.4/ZigBee cluster tree WSNs without significant changes to the protocol. Finally, we analyze and demonstrate the validity of our methodology through a comprehensive simulation and experimental validation using commercially available technology on a Structural Health Monitoring application scenario. PMID- 25279289 TI - Non-volatile main memory management methods based on a file system. AB - ABSTRACT: There are upcoming non-volatile (NV) memory technologies that provide byte addressability and high performance. PCM, MRAM, and STT-RAM are such examples. Such NV memory can be used as storage because of its data persistency without power supply while it can be used as main memory because of its high performance that matches up with DRAM. There are a number of researches that investigated its uses for main memory and storage. They were, however, conducted independently. This paper presents the methods that enables the integration of the main memory and file system management for NV memory. Such integration makes NV memory simultaneously utilized as both main memory and storage. The presented methods use a file system as their basis for the NV memory management. We implemented the proposed methods in the Linux kernel, and performed the evaluation on the QEMU system emulator. The evaluation results show that 1) the proposed methods can perform comparably to the existing DRAM memory allocator and significantly better than the page swapping, 2) their performance is affected by the internal data structures of a file system, and 3) the data structures appropriate for traditional hard disk drives do not always work effectively for byte addressable NV memory. We also performed the evaluation of the effects caused by the longer access latency of NV memory by cycle-accurate full-system simulation. The results show that the effect on page allocation cost is limited if the increase of latency is moderate. PMID- 25279290 TI - Investigating the relationship between peak inspiratory flow rate and volume of inhalation from a DiskusTM Inhaler and baseline spirometric parameters: a cross sectional study. AB - Drug delivery from a Dry Powder Inhaler (DPI) is dependent on the peak inspiratory flow rate (PIFR) generated. Currently available methods for estimating PIFR from most DPIs are limited and mainly rely on subjective assessment. We aim to show that spirometric and DiskusTM PIFR and Inspiratory Vital Capacity (IVC) are related to the underlying respiratory condition and that spirometric PIFR can be used to assess whether DiskusTM PIFR will be adequate when using this DPI. Healthy volunteers and patients with asthma, COPD, neuromuscular disease and non-respiratory disorders were recruited (n = 85). Demographics and baseline lung function by spirometry were recorded. Flow and volume readings were taken while patients used a DiskusTM DPI, housed in an airtight container connected to a spirometer. T-tests were performed to compare mean spirometric and DiskusTM PIFR/ IVC between groups. Stepwise regression analysis of DiskusTM PIFR versus spirometric PIFR, spirometric IVC, age, gender, condition, BMI, FEV1 and FVC was performed. The DiskusTM PIFR for the COPD and Neuromuscular Disease group was more than 10 L/min lower than the Healthy or Asthma groups (p < 0.05). The mean spirometric and DiskusTM IVC of the Healthy group was significantly (>0.75 L) higher than the mean for the other three groups (p < 0.05). DiskusTM PIFR was moderately correlated with spirometric PIFR and age (Adjusted R(2) = 0.58, p < 0.0001). PIFR generated using a DiskusTM DPI is dependent on the underlying disease and age. A spirometric PIFR of less than 196 L/min should prompt further investigation into the suitability of a patient for a DiskusTM DPI, with possible consideration of alternate devices. PMID- 25279291 TI - Enzymatic and acid conversion of new starches from improved orphan crops: prospects for renewable materials uses in food and non-food industries. AB - The enzymatic and acid hydrolysis have converted eight new starches into a range of chain lengths mainly including glucose, maltose, and maltodextrins as observed on TLC plates, irrespective to the starch variety and treatment. Results of the enzymatic hydrolysis have highlighted the possibility of the use of V4 and V64, which can be labelled as "dietary fibres", to enhance the organoleptic qualities of foods and for fibre fortification of low-calorie products. Concerning V66 and V69, they have much relevant in food, textile and pharmaceutical applications. The acid hydrolysis showed that V73 is the best starch in the chemical industry for making environment-friendly products such as plastics. Because starch is a natural component that degrade quickly in normal composting condition, the whole studied starches could be advised for various utilizations in the food, textile, paper, biofuel, pharmaceutical and plastic industries for sustainable development. PMID- 25279292 TI - Successful reduction of alopecia induced by anthracycline and taxane containing adjuvant chemotherapy in breast cancer - clinical evaluation of sensor-controlled scalp cooling. AB - BACKGROUND: Scalp cooling is a long known method to reduce chemotherapy-induced alopecia in cancer patients with solid tumors. Due to a progress in this method, a medical device enabling individual feedback-controlled temperature regulation was evaluated. Between June 2011 and December 2012, 83 breast cancer patients were included. Evaluation was focussed on the quantification of alopecia, satisfaction and side effects of the scalp cooling system in (neo-) adjuvant chemotherapy regimens. Alopecia quantification was done by patient evaluation and experts rating. FINDINGS: Based on patient hair loss evaluations, the mean overall success rate of scalp cooling (<50% hair loss) in (neo-) adjuvant chemotherapy was at 52.6%. 51.7% of patients in (neo-) adjuvant CT did not need head covers. In 51.7% of patients in (neo-) adjuvant chemotherapy hair regrowth occurred. Patient satisfaction rate was between VAS 70 and 80 (0-100, where 100 is completely satisfied). CONCLUSION: The evaluation demonstrates that feedback controlled scalp cooling provides a good chance for breast cancer patients to keep their hair even during (neo-)adjuvant chemotherapies, which are known to cause severe to complete alopecia without scalp cooling. PMID- 25279293 TI - Hypouricemic effect and safety of febuxostat used for prevention of tumor lysis syndrome. AB - PURPOSE: We evaluated the efficacy and safety of febuxostat, a non-purine xanthine oxidase inhibitor, used for prevention of hyperuricemia associated with tumor lysis syndrome (TLS). METHODS: Records of adult patients with newly diagnosed or relapsed hematologic malignancies who received febuxostat within 7 days before initiation of chemotherapy were retrieved retrospectively at a single institute. The changes in serum uric acid levels from before and 7 days after initiation of febuxostat were evaluated and compared with the historical control group of patients who received allopurinol. We also evaluated non-hematological adverse events during the study period. RESULTS: A total of 78 patients' records were analyzed, 38 in the febuxostat group and 39 in the allopurinol group. There were no significant differences in the incidence of treatment failure, defined as development of clinical TLS or receiving rasburicase, between the febuxostat and allopurinol group (5.2% vs 5.1%, P>0.99). The mean serum uric acid levels were significantly decreased, compared to the baseline (5.6 +/- 2.1 mg/dL), at 7 days after initiation of febuxostat (3.1 +/- 1.5 mg/dL, last observation carried forward, P<0.001). There were no statistically significant differences in the percent change in the serum uric acid levels between the 40 mg/day febuxostat and the 300 mg/day allopurinol groups (P = 0.57). Grade 3-4 liver dysfunctions were observed in both the febuxostat and allopurinol groups, without significant differences in incidence between the two groups (2.6% vs 5.1%, P>0.99). Neither gout flare nor skin rash occurred in any patients. CONCLUSIONS: Febuxostat is feasible for prevention of hyperuricemia associated with TLS. PMID- 25279294 TI - Tristetraprolin is a novel regulator of BDNF. AB - Brain-derived neurotrophic factor (BDNF) regulates multiple biological processes ranging from central nervous system development and function to neuroinflammation and myogenic differentiation and repair. While coordination of BDNF levels is central in determining the biological outcome, mechanisms involved in controlling BDNF levels are not fully understood. Here we find that both short (BDNF-S) and long (BDNF-L) BDNF 3'UTR isoforms contain conserved adenylate- and uridylate rich elements (AREs) that may serve as binding sites for RNA-binding proteins (ARE BPs). We demonstrate that ARE-BPs tristetraprolin (TTP) and its family members butyrate response factor 1 (BRF1) and 2 (BRF2) negatively regulate expression from both BDNF-S and BDNF-L containing transcripts in several cell-lines and that interaction between TTP and AU-rich region in proximal 5' end of BDNF 3'UTR is direct. In line with the above, endogenous BDNF mRNA co-immunoprecipitates with endogenous TTP in differentiated mouse myoblast C2C12 cells and TTP overexpression destabilizes BDNF-S containing transcript. Finally, RNAi-mediated knock-down of TTP increases the levels of endogenous BDNF protein in C2C12 cells. Our findings uncover TTP as a novel regulator of BDNF assisting future studies in different physiological and pathological contexts. PMID- 25279295 TI - Primary mediastinal goiters. AB - BACKGROUND: Primary mediastinal goiters (PMG) are very uncommon; few cases were reported in the literature. PATIENT DESCRIPTION: We report here two cases of mediastinal goiters that met all criteria of PMG. Transternal approach was necessary for complete removal and pathological diagnoses confirmed their adenomatous goiter nature. The rarity of their occurrence, their clinical characteristics and surgical management were discussed. CONCLUSION: PMG is part of the differential diagnoses of mediastinal masses. Safe excision is ensured through transthoracic approach. PMID- 25279296 TI - Analysis of tennis champions' career: how did top-ranked players perform the previous years? AB - Professional tennis is a highly competitive sport ranked through an objective, merit-based, mathematical system. The objective of this study was to determine and analyze how top 1 degrees -ranked professional tennis players perform in the previous three years. Data of ranking position of all top 1 degrees -ranked female and male players in the professional era and their performance in Grand Slams tournaments were collected from tennis stakeholders' websites and analyzed. Top 1 degrees male players' ranking position averaged 2.17 +/- 1.92 (CI 95%:1.56/2.78), 7.02 +/- 18.073, and 10.73 +/- 29.31, at 1, 2, and 3 previous years, respectively. Top 1 degrees female players' ranking position averaged 2.21 +/- 1.59 (CI 95%:1.61/2.71), 4.78 +/- 4.09, and 14.97 +/- 26.75, at 1, 2, and 3 previous years, respectively. All top 1 degrees male and female players were ranked within the 1 degrees -10 degrees and 1 degrees -6 degrees positions the previous year, respectively; the majority of tennis champions won at least one Grand Slam tournament during the year before reaching the top 1 degrees ranking position (females = 69%; males = 65%), and during the same season (females = 82%; males = 92%). Female and male top 1 degrees -ranked player maintained that position in the following year in 48.7% and 52.5% of cases, respectively. In conclusion, tennis players need to perform at high level during at least three years prior to reach the top 1 degrees position in the professional tennis ranking. Both, male and female champions, showed similar patterns of performance in their professional career. PMID- 25279297 TI - Spatio-temporal diffusion of residential land prices across Taipei regions. AB - ABSTRACT: Past studies have shown that changes in the house price of a region may transmit to its neighbouring regions. The transmission mechanism may follow spatial and temporal diffusion processes. This paper investigates such regional housing market dynamics and interactions among local housing sub-markets in Taipei. The analysis is based on a panel data framework and spatial panel models using annual data on median residential land prices from 41 Taipei sub-markets over the period from 1992 to 2010. The empirical analysis suggests that spatial dependence plays a significant role in interactions among regional housing markets. The results are strongly robust across several model specifications and regions controlling for time fixed effects and space-time covariance. These findings have significant implications for urban spatial planning and efficient use of public resources in mega-urban areas. JEL CLASSIFICATIONS: C21; C23; R12; H50. PMID- 25279298 TI - Individual in vitro effects of ochratoxin A, deoxynivalenol and zearalenone on oxidative stress and acetylcholinesterase in lymphocytes of broiler chickens. AB - The contamination of consumer food and animal feed with toxigenic fungi has resulted in economic losses worldwide in animal industries. Mycotoxins are highly biologically reactive secondary metabolites and can inhibit protein synthesis and cell multiplication. Considering the cytotoxicity of mycotoxins, this experiment was performed to determine the in vitro influence of ochratoxin A, deoxynivalenol and zearalenone on lipid peroxidation in lymphocytes of broiler chickens at different concentrations. This study has also evaluated whether the presence of these mycotoxins changes the acetylcholinesterase activity in lymphocytes, which is involved in the regulation of immune and inflammatory responses. Blood lymphocytes of broiler chickens were isolated through density gradient centrifugation and incubated with the respective mycotoxins at concentrations of 0.001, 0.01, 0.1 and 1 MUg/mL. Lipid peroxidation, which was evaluated through the amount of malondialdehyde measured in a thiobarbituric acid-reactive species test, and the enzymatic activity were analyzed at 24, 48 and 72 h. Results of the lipid peroxidation evaluation showed an increasing cytotoxicity relation: ochratoxin A > deoxynivalenol > zearalenone. Conversely, cytotoxicity was valued as zearalenone > deoxynivalenol > ochratoxin A in relation to the acetylcholinesterase enzymatic activity. At a concentration of 1 MUg/mL, ochratoxin A and deoxynivalenol induced the highest cellular oxidative stress levels and the highest enzymatic activity at the majority of time points. However, the same mycotoxins, except at 1 MUg/mL concentration, induced a reduction of lymphocytic lipid peroxidation 72 h after incubation, suggesting the action of a compensatory mechanism in these cells. PMID- 25279299 TI - Getting out of a wheelchair: an uncommon insertion mutation in exon 19 of EGFR responsive to erlotinib. AB - BACKGROUND: Most patients with non-small cell lung cancer (NSCLC) present with advanced disease and have poor long-term prognosis. Advanced NSCLC that contains characteristic mutations in epidermal growth factor receptor (EGFR) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions mutations are rare, and response to TKIs is still unclear. CASE DESCRIPTION: A young Arab patient was diagnosed with metastatic disease of NSCLC harboring an exon 19 insertion of 18 nucleotides. The patient showed a very impressive clinical and radiological response within few weeks treatment with TKI agent. DISCUSSION AND EVALUATION: To our best knowledge, This case is the first case in Arab woman and one of few cases described in the literature with this rare mutation responding to TKIs. CONCLUSIONS: Treatment with TKIs should be the standard choice in patients with metastatic disease NSCLC. PMID- 25279300 TI - Dothideomycetes and Leotiomycetes sterile mycelia isolated from the Italian seagrass Posidonia oceanica based on rDNA data. AB - Marine fungi represent a group of organisms extremely important from an ecological and biotechnological point of view, but often still neglected. In this work, an in-depth analysis on the systematic and the phylogenetic position of 21 sterile mycelia, isolated from Posidonia oceanica, was performed. The molecular (ITS and LSU sequences) analysis showed that several of them are putative new species belonging to three orders in the Ascomycota phylum: Pleosporales, Capnodiales and Helotiales. Phylogenetic analyses were performed using Bayesian Inference and Maximum Likelihood approaches. Seven sterile mycelia belong to the genera firstly reported from marine environments. The bioinformatic analysis allowed to identify five sterile mycelia at species level and nine at genus level. Some of the analyzed sterile mycelia could belong to new lineages of marine fungi. PMID- 25279301 TI - Rheumatoid arthritis-associated aortitis: a case report and literature review. AB - Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder that primarily affects the synovial joints. Rheumatoid vasculitis (RV) is an extra articular manifestation of RA, and its association with aortitis is rare and not widely recognised. Here, we report the case of a 69-year-old woman with RA associated aortitis and review the literature on rheumatoid aortitis. The mean oral steroid dose administered to RA-associated aortitis patients was 46.3 mg/day prednisolone (PSL). In our patient, the aortitis was also thought to be due to RV because she had findings of RV, such as cutaneous ulceration and a high rheumatoid factor titre, and because a moderate PSL dose dramatically improved the clinical findings. RA-associated aortitis, if left untreated, can be fatal; therefore, early detection and treatment initiation is very important. PMID- 25279302 TI - Creatine metabolism differs between mammals and rainbow trout (Oncorhynchus mykiss). AB - Creatine plays an important role in the cell as an energy buffer. As the energy system is a basic element of the organism it may possibly contribute to differences between rainbow trout strains selected for the traits growth and robustness, respectively. The cDNA sequences of creatine-related genes encoding glycine amidinotransferase (GATM), guanidinoacetate N-methyltransferase (GAMT), creatine kinase muscle-type (CKM) and creatine transporter 1 (CT1, encoded by gene solute carrier family 6, member 8 (SLC6A8)) were characterized in rainbow trout. Transcripts of the respective genes were quantified in kidney, liver, brain and skeletal muscle in both trout strains that had been acclimated to different temperatures. Several differences between the compared trout strains were found as well as between temperatures indicating that the energy system may contribute to differences between both strains. In addition to that, the expression data showed clear differences between the creatine system in rainbow trout and mammals, as the spatial distribution of the enzyme-encoding gene expression was clearly different from the patterns described for mammals. In rainbow trout, creatine synthesis seems to take place to a big extent in the skeletal muscle. PMID- 25279303 TI - Viewing systematic reviews and meta-analysis in social research through different lenses. AB - Systematic reviews and meta-analyses are used to combine results across studies to determine an overall effect. Meta-analysis is especially useful for combining evidence to inform social policy, but meta-analyses of applied social science research may encounter practical issues arising from the nature of the research domain. The current paper identifies potential resolutions to four issues that may be encountered in systematic reviews and meta-analyses in social research. The four issues are: scoping and targeting research questions appropriate for meta-analysis; selecting eligibility criteria where primary studies vary in research design and choice of outcome measures; dealing with inconsistent reporting in primary studies; and identifying sources of heterogeneity with multiple confounded moderators. The paper presents an overview of each issue with a review of potential resolutions, identified from similar issues encountered in meta-analysis in medical and biological sciences. The discussion aims to share and improve methodology in systematic reviews and meta-analysis by promoting cross-disciplinary communication, that is, to encourage 'viewing through different lenses'. PMID- 25279304 TI - An experimental determination of the drag coefficient of a Mens 8+ racing shell. AB - This study centered around an experimental analysis of a Mens Lightweight Eight racing shell and, specifically, determining an approximation for the drag coefficient. A testing procedure was employed that used a Global Positioning System (GPS) unit in order to determine the acceleration and drag force on the shell, and through calculations yield a drag coefficient. The testing was run over several days in numerous conditions, and a 95% confidence interval was established to capture the results. The results obtained, over these varying trials, maintained a successful level of consistency. The significance of this study transcends the determination an approximation for the drag coefficient of the racing shell; it defined a successful means of quantifying performance of the shell itself. The testing procedures outlined in the study represent a uniform means of evaluating the factors that influence drag on the shell, and thus influence speed. PMID- 25279305 TI - A case of pulmonary fibrosis associated with rheumatoid arthritis, scleroderma sine scleroderma and ANCA associated vasculitis. AB - INTRODUCTION: Diffuse parenchymal lung disease (DPLD) may be idiopathic or may be due to known associations such as autoimmune diseases. The prognosis in cases associated with autoimmune diseases depends on many factors such as histopathology, baseline lung function, auto-antibody level, et cetera. DPLD and its prognosis is worse in patients with overlap syndromes. CASE DESCRIPTION: We present a rare case of a 71 year old Caucasian lady with gradually worsening pulmonary fibrosis secondary to an overlap syndrome with rheumatoid arthritis (RA), scleroderma sine scleroderma (SSS) and anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis. DISCUSSION AND EVALUATION: In this paper, we share information from review of literature regarding DPLD associated with RA, systemic sclerosis (SSc) and ANCA associated vasculitis. Details of our discussion include prognostic factors, histology and radiographic features of these individual disease entities. CONCLUSION: Since pulmonary fibrosis in overlap syndromes has a poor prognosis, extensive work up should be performed even when clinical evidence of only one autoimmune disease is present. PMID- 25279306 TI - Changes to signal peptide and the level of transforming growth factor- beta1 due to T869C polymorphism of TGF beta1 associated with lupus renal fibrosis. AB - Lupus Nephritis (LN) is a serious manifestation of lupus that can lead to End Stage Renal Disease (ESRD). Fibrosis is the main feature of ESRD, and it is likely influenced by Transforming Growth Factor Beta1 (TGFbeta1). The T869C gene polymorphism of TGFbeta1 is assumed to change the signal peptide, that has potential to interfere the urine production and renal protein expression of TGFbeta1. The influence of T869C gene polymorphism on TGFbeta1 production and renal fibrosis was evaluated in this study. Subjects were 45 patients LN with renal fibrosis and 45 participants without renal fibrosis as control, that were recruited from 2011 to 2013.Their urinary TGFbeta1 levels and TGFbeta1 gene polymorphisms were examined. All lupus patients underwent renal biopsy to assess their protein expression of TGFbeta1 in the renal tissue by immunohistochemistry and their renal fibrosis by morphometry and chronicity index. Changes in the signal peptide interaction with Signal Recognition Particle (SRP) and translocon of endoplasmic reticulum were analyzed by Bioinformatics. Levels of urinary and protein expression of TGFbeta1 increased in the LN with renal fibrosis group. There were significant differences in levels of urinary TGFbeta1 in T, C allele and TT, TC, CC genotypes between case and control groups. Furthermore, patients with C allele are 3.86 times more at risk of renal fibrosis than T allele. The C allele encodes proline, which stabilizes the interaction of the TGFbeta1 signal peptide with SRP and translocon, resulting in elevation of TGFbeta1 secretion. Our results indicated that T869C gene polymorphism of TGFbeta1 changes the signal peptide, that contributes to the production of urinary TGFbeta1 and affects renal fibrosis in lupus nephritis. PMID- 25279307 TI - Coating of magnetite with mercapto modified rice hull ash silica in a one-pot process. AB - In this research, mercapto-silica coated magnetite (Fe3O4-SiO2-SH) has been prepared in aqueous solution through a simple approach so called a one-pot process. The Fe3O4-SiO2-SH was prepared in nitrogen condition by mixing magnetite, 3-mercaptopropyltrimethoxysilane (MPTMS), and sodium silicate (Na2SiO3) solution extracted from rice hull ash, and adjusting the pH of 7.0 using hydrochloric acid. The residue was washed with deionized water, dried at 150 degrees C and separated with an external magnetic field. In that work, the volume of MPTMS and Na2SiO3 was varied and the total amount of Si represented as silica was kept constant. Characters of the material including the functional group presence, the structure, the porosity, the morphology and stability toward various solvents were identified and evaluated. Results of characterization indicated that mercapto-silica has been coated magnetite particle with a simple one-pot process. Coating mercapto-silica on magnetite increases particle size, surface area, and chemical stability. Additionally, Fe3O4-SiO2-SH also shows high stability toward various organic solvents. The magnetic property of magnetite does not change after coating and the addition of nonmagnetic material still gives high value of maximum saturation magnetization. The presence of mercapto groups effective for interaction with heavy metal ions, the high chemical stability without removing the magnetic property promises the prospective application of Fe3O4-SiO2-SH in the future such as for separation and removal of heavy metal ions from aquatic environments. PMID- 25279308 TI - Comparison of SHF and SSF of wet exploded corn stover and loblolly pine using in house enzymes produced from T. reesei RUT C30 and A. saccharolyticus. AB - The aim of the present study was to compare bioethanol production from wet exploded corn stover (WECS) and loblolly pine (WELP) hydrolyzed with in-house and commercial enzymes and fermented separately (SHF) and simultaneously (SSF). In house enzymes produced from Trichoderma reesei, RUT-C30 and a novel fungal strain, Aspergillus saccharolyticus were loaded as 5 and 15 FPU/g glucan and supplemented with 10 and 30 CBU/g glucan, respectively. For hydrolysis and fermentation, slurries of WECS and WELP at 5 and 10% (w/w) solids loading (SL) were utilized. Saccharomyces cerevisae was used for ethanol fermentation at 33 degrees C. Maximally, 15.6 g/L and 13.4 g/L (corresponding to theoretical ethanol yield of 76% and 67%, respectively) were achieved in SSF process from WECS and WELP, respectively at 5% SL and 15 FPU/g glucan loading of in-house enzymes. Ethanol concentrations in all cases were higher for SSF compared to SHF under same conditions. A cross comparison of SSF with commercial enzymes (Celluclast 1.5 L + Novozym 188) showed highest ethanol concentration of 17.3 g/L and 15.4 g/L (corresponding to theoretical ethanol yield of 84% and 77%, respectively) from WECS and WELP, respectively at 5% SL and 15 FPU/g glucan. These findings demonstrated that in-house enzymes were comparable to commercial enzymes as these fungi produced other lignocellulolytic enzymes beyond cellulase and hence enhanced the overall enzyme activity. PMID- 25279309 TI - Continuous paravertebral block for postoperative pain compared to general anaesthesia and wound infiltration for major oncological breast surgery. AB - We hypothesized that improved acute postoperative pain relief will be achieved using general anaesthesia (GA) either in combination with continuous thoracic paravertebral block (GA-cPVB) or single shot (GA-sPVB) as compared to GA supplemented by local wound infiltration (GA-LWI) after unilateral major breast cancer surgery. A randomised controlled trial was conducted in 46 adult women in a day-care or short-stay hospital setting after major breast cancer surgery. Pain intensity was measured using an 11-point visual analogue scale (VAS) until postoperative day 2. GA-sPVB was stopped due to slow inclusion. No significant difference in VAS score was noted between GA-LWI (VAS median 0.5 (interquartile range 0.18-2.00)) and GA-cPVB, (VAS 0.3 (0.00-1.55, p = 0.195)) 24 hours after surgery or at any point postoperatively until postoperative day 2. We conclude that both GA-LWI and GA-cPVB anaesthetic techniques are equally effective in treatment of acute postoperative pain after major oncological breast surgery. As GA-LWI is easily to perform with fewer complications and it is more cost effective it should be preferred over GA-cPVB. PMID- 25279310 TI - Effect of dietary coenzyme Q10 supplementation on the growth rate, carcass characters and cost effectiveness of broiler fed with three energy levels. AB - The objective of this experiment was to study the effect of dietary supplementation of Coenzyme Q10 on broiler growth rate, carcass characteristics and cost of production. A biological trial was carried out with 270 broiler chicks fed with coenzyme Q10 at 0, 20 and 40 mg/kg of diet at each of the three energy levels. At the end of 42 days growth period the birds were sacrificed and the samples were analysed. Feed intake was comparable in all the energy and CoQ10 combinations, but higher body weight gain and better feed efficiency with less feed cost per kilogram weight gain was observed in high energy group supplemented with 20 mg of CoQ10/kg diet. The dressing percentages, weight of giblet, liver, spleen, abdominal fat, intestinal length were not significantly altered by CoQ10 supplementation. The heart weight, gizzard weight and ascites heart weight (AHI) were significantly decreased due to CoQ10 supplementation. Hence, birds fed with high energy diet supplemented with 20 mg CoQ10 per kg of diet had higher production performance. PMID- 25279311 TI - The role of transcavitary ultrasonography in diagnosis and staging of nonmuscle invasive bladder cancer: a prospective non-randomized clinical study. AB - To evaluate the efficacy of cystoscopy, computed tomography (CT), transcavitary ultrasound (TCUS) and cytology, separately and in combination, for the diagnosis and evaluation of superficial bladder cancer. Initial cystoscopy and wash-out cytology were performed for 1548 patients. Of these, 206 with proven bladder tumors were included in this prospective study. CT and TCUS were performed for patients with bladder tumors without knowledge of their cystoscopy results. The lesions were classified as low- (pTa) and high- (pT1) risk superficial tumors according to multiplicity and size. Patients were divided into three categories according to their cystoscopically evaluated tumor size: <=1 cm (88 patients, 42.7%), 1-3 cm (51 patients, 24.8%) and >=3 cm (67 patients, 32.5%). TCUS identified 46 (22.3%) high-risk patients with/without invasion and 160 (77.7%) low-risk patients with no invasion. Overall, the sensitivity, specificity, positive predictive value and negative predictive value of TCUS for tumor detection were 77.4%, 60%, 94.7% and 22.2%, respectively. Cystoscopy remains the most widely used technique for the diagnosis of bladder cancer. The combined use of CT, TCUS and cytology detected 72% of cystoscopically proven tumors. Among the three, TCUS findings exhibited the strongest correlation with cystoscopy findings. PMID- 25279312 TI - Comparison of total lipids and fatty acids from liver, heart and abdominal muscle of scalloped (Sphyrna lewini) and smooth (Sphyrna zygaena) hammerhead sharks. AB - Liver, heart and abdominal muscle samples from scalloped (Sphyrna lewini) and smooth (Sphyrna zygaena) hammerhead sharks were analysed to characterise their lipid and fatty acid profiles. Samples were compared both between and within species, but there were no significant differences in total lipids for either comparison, although much greater total amounts were found in the liver samples. Within the individual fatty acids, the only significant differences were greater amounts of 22:6n-3, total n-3 polyunsaturates and total polyunsaturates in smooth, when compared to scalloped, hammerhead liver. This may reflect the more wide spread distribution of this species into cooler waters. Within both species the liver levels of the same fatty acid fractions decreased from spring to summer, which may correlate with changes in fatty acid profile to adapt to any differences in amount or species of prey consumed, or other considerations, eg. buoyancy, however there was no data to clarify this. PMID- 25279313 TI - Absence of the appendix discovered during childhood. AB - Absence of the appendix is rare. Isolated cases are usually discovered in adult patients or cadavers. We report the case of a 14 year old boy who was found to have no appendix on laparotomy for assumed acute appendicitis and use this opportunity to highlight the growing surgical uses of this vestigial structure. PMID- 25279315 TI - Herpes simplex encephalitis in Iceland 1987-2011. AB - Herpes simplex encephalitis (HSE) is a serious disease with 10-20% mortality and high rate of neuropsychiatric sequelae. This study is a long-term, nationwide study in a single country, Iceland. Clinical data were obtained from patient records and from DNA PCR and antibody assays of CSF. Diagnosis of HSE was classified as definite, possible or rejected based on symptoms, as well as virological, laboratory and brain imaging criteria. A total of 30 definite cases of HSE were identified during the 25 year period 1987-2011 corresponding to incidence of 4.3 cases/106 inhabitants/year. Males were 57% of all patients, median age 50 years (range, 0-85). Fever (97%), cognitive deficits (79%), impaired consciousness (79% with GCS < 13), headache (55%) and seizures (55%) were the most common symptoms. Brain lesions were found in 24 patients (80%) by MRI or CT. All patients received intravenous acyclovir for a mean duration of 20 days. Three patients (10%) died within one year and 21/28 pts (75%) had a Karnofsky performance score of <70% with memory loss (59%), dysphasia (44%), frontal symptoms (44%) and seizures (30%) as the most frequent sequelae. Mean delay from onset of symptoms to treatment was 6 days; this was associated with adverse outcome. In conclusion, the incidence of 'HSE is higher than recently reported in a national registry study from Sweden. Despite advances in rapid diagnosis and availability of treatment of HSE, approximately three of every four patients die or are left with serious neurological impairment. PMID- 25279314 TI - Cardiac taurine and principal amino acids in right and left ventricles of patients with either aortic valve stenosis or coronary artery disease: the importance of diabetes and gender. AB - Free intracellular taurine and principal alpha-amino acids (glutamate, glutamine, aspartate, asparagine and alanine) are abundant in human heart. They are cellular regulators and their concentration can change in response to disease and cardiac insults and have been shown to differ between hypertrophic left ventricle (LV) and the relatively "normal" right ventricle (RV) in patients with aortic valve stenosis (AVS). This difference has not been shown for coronary artery disease (CAD) and there are no studies that have simultaneously compared amino acid content in LV and RV from different pathologies. In this study we investigated the effect of disease on taurine and principal amino acids in both LV and RV, measured in myocardial biopsies collected from patients with either AVS (n = 22) or CAD (n = 36). Amino acids were extracted and measured using HPLC. Intra- and inter-group analysis was performed as well as subgroup analysis focusing on gender in AVS and type 2 diabetes in CAD. LV of both groups has significantly higher levels of taurine compared to RV. This difference disappears in both diabetic CAD patients and in male AVS patients. Alanine was the only alpha-amino acid to be altered by diabetes. LV of female AVS patients had significantly more glutamate, aspartate and asparagine than corresponding RV, whilst no difference was seen between LV and RV in males. LV of females has higher glutamate and glutamine and less metabolic stress than LV of males. This work shows that in contrast to LV, RV responds differently to disease which can be modulated by gender and diabetes. PMID- 25279316 TI - Sibling relationships as a resource for coping with traumatic events. AB - The study investigated the correlation between the perception of sibling relationship to cope an adverse occurrence - the partial collapse of a primary school - and the indicators related to the traumatic impact set off by the event, by soliciting the child's reminiscence of the catastrophic experience. One hundred trauma-exposed children were recruited from a Sicilian primary school and were administered the following research instruments: the Trauma Symptom Checklist for Children (TSCC-A), to investigate the traumatized response that can be triggered in the children involved; the Brother as a Resource Questionnaire (BRQ), to delve into the perception of sibling relationship as a resource. The outcomes showed statistically significant negative correlations between the Anxiety scale of the TSCC-A and the Scaffolding factors (r = -.260, p < .05) and Decision making process (r = -.315, p < 05) of the BRQ; between the Depression scale and the Scaffolding factors (r = -.147, p < .05), Emotional sharing (r = .168, p < .05) and Decision making process (r = -.281, p < .05). The Anger scale correlated negatively with the Emotional sharing (r = -187, p < .05), the Decision making process (r = -.182, p < .05) and the Scaffolding factors (r = .279, p < .05); the Post-traumatic Stress correlated negatively with the Scaffolding factors (r = -.203, p < .05) and the Decision making process (r = .238, p < .05). Lastly, the Dissociation correlated negatively with the Decision making process (r = -.270, p < .05). PMID- 25279317 TI - Significance of propolis administration for homeostasis of CD4(+)CD25(+) immunoregulatory T cells controlling hyperglycemia. AB - In the present study, we examined the effect of ethanolic soluble derivative of propolis (EEP) extract on immunological function in diabetic mouse models with the aim of highlighting the role of regulatory T cell, the change of cell surface molecule, and in vivo productions of IFN-gamma. Murine models of diabetes mellitus (DM) were created by injecting normal mice with S961 peptide. Normal BALB/c mice were injected intraperitoneally with peptide S961 300 mg/kg body weight (BW) twice a day for eight days. On day 15, the spleen was isolated; then, cell surface molecules and regulatory T cells were analyzed using flow cytometry. The histopathological changes were monitored in the liver of treated and control mice. Afterward, we tested the ability of propolis as an immunomodulator that initiate normality metabolism and homeostasis. The propolis decreased blood sugar levels and increased the number of naive T cells expressing CD62L molecule by suppressing the development of effector cells in diabetic mice. However, the propolis stimulated development of effector cells, which was indicated by increasing the number of CD4(+)CD25(+) T cells in normal mice. Moreover, the propolis increased the production of IFN-gamma in normal mice, whereas in mouse models of diabetes mellitus propolis tends to suppress the production of IFN gamma. The histological analysis of the liver shows that at a dose of 50-200 mg/kg BW propolis does not show a toxic effect so that the dose is categorized safe. Therefore, the ethanolic soluble derivative of propolis (EEP) extract warrant for further exploited as an antidiabetic agent that safe for human. PMID- 25279318 TI - Glucocorticoids promote neural progenitor cell proliferation derived from human induced pluripotent stem cells. AB - Glucocorticoids (GCs) are frequently used for treating and preventing chronic lung disease and circulatory dysfunction in premature infants. However, there is growing concern about the detrimental effects of systemic GC administration on neurodevelopment. The first choice of GCs to minimize the adverse effects on the developing brain is still under debate. We investigated the effect of commonly used GCs such as dexamethasone (DEX), betamethasone (BET) and hydrocortisone (HDC) on the proliferation of human-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs). In this study, NPCs were treated with various concentrations of GCs and subjected to cell proliferation assays. Furthermore, we quantified the number of microtubule-associated protein 2 (MAP2) positive neurons in NPCs by immunostaining. All GCs promoted NPC proliferation in a dose-dependent manner. We also confirmed that MAP2-positive neurons in NPCs increased upon GC treatment. However, differential effects of GCs on MAP2 positive neurons were observed when we treated NPCs with H2O2. The total numbers of NPCs increased upon any GC treatment even under oxidative conditions but the numbers of MAP2 positive neurons increased only by HDC treatment. GCs promoted human iPSCsa?"derived NPC proliferation and the differential effects of GCs became apparent under oxidative stress. Our results may support HDC as the preferred choice over DEX and BET to prevent adverse effects on the developing human brain. PMID- 25279319 TI - The sheep KAP8-2 gene, a new KAP8 family member that is absent in humans. AB - The keratin-associated proteins (KAPs) are fundamental components of hair and wool fibres, and are believed to in part be responsible for some of the properties of these fibres. KAPs can be divided into three groups: the high sulphur (HS) KAPs, the ultra-high sulphur (UHS) KAPs and the high glycine tyrosine (HGT) KAPs. KAP8 is a HGT-KAP family and was believed to be coded for by a single gene in both humans and sheep. However, the recent identification of a KAP8-2 gene in goats led us to investigate whether a KAP8-2 gene exists in sheep. A BLAST search of the Ovine Genome Assembly v2.0 using the coding sequence of caprine KRTAP8-2 identified a homologous region on sheep chromosome 1 (OAR1:123005473_123005664; E = e(-101)). This region was clustered with a number of previously identified KAP genes including (in order from the centromere) KRTAP11-1, KRTAP7-1, KRTAP8-1, KRTAP6-2, KRTAP6-1, KRTAP13-3 and KRTAP24-1. PCR SSCP analysis of the notional gene revealed two dissimilar PCR-SSCP banding patterns, representing two DNA sequences. A single nucleotide difference 21 bp upstream of the TATA box was identified. The two sequences did not have great homology with known ovine KRTAP sequences, but high sequence identity was found with KRTAP8-2 from goats and reindeer. These results suggest that sheep possess a KAP8-2 gene and that this gene is polymorphic. The notional KAP8-2 protein is comprised of 63 amino acid residues and is rich in glycine and tyrosine, but has a low cysteine content. In contrast to other HGT-KAPs, ovine KAP8-2 contains more acidic amino acid residues, and this would likely result in a lower isoelectric point (pI) of 6.3. PMID- 25279320 TI - Pre-service ultrasonic and manual evaluation of the reproductive organs of dairy cows presumed to be in estrus. AB - Manual and ultrasonic evaluation of the the reproductive organs of 62 dairy cows and heifers belonging to smallholder farms was conducted. The objective was to assess the efficiency of visual estrus detection method in the dairy animals that were presented for artificial insemination. Data were collected on reproductive status, body condition, estrus signs, and findings of rectal examination. Thirty three animals were inseminated after ultrasonic evaluation while 29 animals were inseminated after manual evaluation through rectal palpation. Pregnancy diagnosis was performed using ultrasound 30 days post insemination. The most frequently observed estrus signs by the dairy owners were mucus discharge (83.9%) and mounting (67.7%) while the most frequently confirmed physical signs of estrus by rectal examination were cervical opening (88.7%), and uterine turgidity (82.3%). The overall mean (+/-SD) diameter of the largest follicle was 12.9 +/- 3.4 mm with an average number of 3.5 follicles per ovary. The overall pregnancy rate was 29%. Evaluation of post-insemination records showed a significant difference (P < 0.05) in the diameter of largest follicle between the pregnant (14.7 mm) and non pregnant (12.1 mm) animals. The mean (+/-SD) time interval between the first observed estrus sign to service were 10.5 +/- 7.0 hrs and 14.5 +/- 10.0 hrs for pregnant and non-pregnant, respectively. The low pregnancy rate, delayed time of insemination, and the difference in the size of dominant follicle indicate the incompatibility between visual estrus detection and optimal time of insemination. This confirms the significance of improving estrus detection and the need for combining estrus signs with pre-service evaluation of the reproductive organs either manually or using ultrasound. PMID- 25279321 TI - Population distribution and household conditions in Saudi Arabia: reflections from the 2010 Census. AB - The Kingdom of Saudi Arabia, the largest nation in the Arabian Peninsula is divided into 13 regions, which are of different development levels in terms of both population and public utility infrastructure. More than the other regions, population is high in Al-Riyadh, Makkah Al-Mokarramah, and the Eastern Region, due to urbanization. The current analysis of census results is aimed at understanding (i) regional variations in population and households and (ii) house ownership, type of housing, and housing infrastructure. Saudi Arabia's population is 26,090,555, living in 4,655,127 households with higher concentration in Al Riyadh, Makkah Al-Mokarramah, and the Eastern Region. One-fourth of the households are in Makkah Al-Mokarrammah while another one-fourth in Al-Riyadh. Households are small with 6 persons in each. The proportion of households in own houses is less than half - mostly Saudi households. Households in the Kingdom live in apartments, traditional houses, villas or floor in a villa with differing proportions across regions and between Saudi and non-Saudi. While apartments are the major type of housing (major regions), traditional houses (Jazan, Al-Baha, Hail, and Aseer regions) and villas (Al-Riyadh region) still exist that are built by concrete (less than four-fifths), block/brick (less than one-fifth), mud (rare), and stone (rare) with varying regional proportions. Infrastructure - electricity, water, and sewage - vary across regions. The major source of electricity is public station followed by private station and private generators. Water source is mainly the public water inside the pipe unit but catchment tank water and well water are used. Three types of sewage system are prevalent in the Kingdom - public sewage, ditch sewage, and private sewage. An inequitable distribution of population across regions shows urbanization, causing an emergence of the modern housing sector influencing house ownership. Developed regions have less ownership, more rentals and office quarters, thus, presuming that development level and migration status are driving house ownership. The impact of infrastructural variations is difficult to interpret as such variations affect the interest of the public sector and customers. A lesser dependence on the public sector requires caution when assessing the situation and when creating policies and provisions to improve quality of life. PMID- 25279322 TI - Fault lines in forensic medical toxicology in Ireland exposed through replies of pathologists and coroners to anonymous questionnaires. AB - The attitudes and experiences of pathologists and coroners to the provision of biochemical forensic toxicology in the Republic of Ireland were determined using separate questionnaires to each group anonymously. Replies were received from 36/88 (41%) of pathologists and 19/71 (27%) of coroners. 37% of coroners considered that histopathologists give an adequate opinion in forensic toxicology yet 58% of pathologists reported that they did not have adequate access to expert medical interpretative toxicological opinion. For drug-drug interactions and metabolic diseases, 69% of pathologists were unhappy with the processes and 68% of coroner replies did not know if vitreous samples were used appropriately. There is a clear requirement for retraining of coroners and for the appointment of medical toxicology expertise to improve the quality of service for coroners. PMID- 25279323 TI - Formulation of Trichoderma sp. SL2 inoculants using different carriers for soil treatment in rice seedling growth. AB - BACKGROUND: Trichoderma sp. SL2 has been previously reported to enhance rice germination, vigour, growth and physiological characteristics. The use of Potato Dextrose Agar as carrier of Trichoderma sp. SL2 inoculant is not practical for field application due to its short shelf life and high cost. This study focuses on the use of corn and sugarcane bagasse as potential carriers for Trichoderma sp. SL2 inoculants. FINDINGS: A completely randomized design was applied for this study. Trichoderma sp. SL2 suspension mixed with corn and sugarcane bagasse were used as treatment mixture in soil. Growth parameters including rice seedling height, root length, wet weight, leaf number and biomass were measured and compared to control. The results showed that Trichoderma sp. SL2 mixed with corn significantly enhanced rice seedlings root length, wet weight and biomass compared to Trichoderma sp. SL2 mixed with sugarcane bagasse and control. CONCLUSION: Corn can be a potential carrier for Trichoderma spp. inoculants for field application. PMID- 25279325 TI - Do we protect freshwater eels or do we drive them to extinction? AB - Freshwater eels are important animals because they have a unique catadromous life history and are used as food resources. European, American and Japanese eel populations now are considered to be outside the safe biological limits and are seriously threatened with extinction. Therefore, the European eel was recently categorised as critically endangered by the European Union and the United Nations. One of the reasons for the drastic decline in eel populations is overfishing, which has caused a high demand for eel aquaculture; eel aquaculture completely depends on wild juveniles, and in contrast to animals, artificial propagation has not yet succeeded for the eels. Therefore, commercial eel industries are now considering tropical eels as possible replacement for European and Japanese eels to compensate for declining stocks. In this study, I attempt to examine the present status of the biology and stock of tropical eels. However, useful scientific research and information on the biology and stock assessments of tropical eels are lacking, a situation quite different from that for other temperate freshwater eels, which have been well studied for several decades with trends and recruitment patterns being on record. Nevertheless, the present tropical eel catch has been reported as being less than half that of 20 years ago. The present trends in eel stocks and utilization for human consumption suggest that all eel populations will decline to numbers that fall outside safe biological limits and will be seriously threatened with extinction without protection and conservation from strict enforcement of local and international laws. PMID- 25279324 TI - Association of hypertension with coronary artery disease onset in the Lebanese population. AB - The onset of coronary artery disease (CAD) is influenced by cardiovascular risk factors that often occur in clusters and may build on one another. The objective of this study is to examine the relationship between hypertension and CAD age of onset in the Lebanese population. This retrospective analysis was performed on data extracted from Lebanese patients (n = 3,753). Logistic regression examined the association of hypertension with the age at CAD diagnosis after controlling for other traditional risk factors. The effect of antihypertensive drugs and lifestyle changes on the onset of CAD was also investigated. Results showed that hypertension is associated with late onset CAD (OR=0.656, 95% CI=0.504-0.853, p=0.001). Use of antihypertensive drugs showed a similar association with delayed CAD onset. When comparing age of onset in CAD patients with traditional risk factors such as hypertension, diabetes, hyperlipidemia, obesity, smoking and family history of CAD, the age of onset was significantly higher for patients with hypertension compared to those with any of the other risk factors studied (p < 0.001). In conclusion, hypertension and its treatment are associated with late coronary atherosclerotic manifestations in Lebanese population. This observation is currently under investigation to clarify its genetic and/or environmental mechanisms. PMID- 25279326 TI - Metastatic breast cancer: prolongation of survival in routine care is restricted to hormone-receptor- and Her2-positive tumors. AB - 18,000 women die due to metastatic breast cancer in Germany per year. Median survival is 20-28 months after diagnosis. The question we wanted to answer was whether survival has improved in routine care? For this purpose we conducted a retrospective analysis of all patients with metastatic breast cancer who were treated between 06/1995-06/2013 in a community-based oncology group practice in Germany. 716 patients were analyzed with a median age of 61 (31-93). Localizations of metastases were distributed as follows: 47% visceral, 36% bone, 9% lymphatic, 4% CNS, 4% others. 79% were hormone-receptor-positive, 20% Her2 positive, 9% triple-negative. Median overall survival was 34 months (95% Confidence Interval: 31-37), median disease-specific survival 36.8 months and disease-specific survival after 5 years 34%. Survival was significantly correlated with localizations of metastases, number of metastasized organs, disease free survival since initial diagnosis, hormone-receptor status and age. Patients with hormone-receptor-positive tumors had a median overall survival of 37 months, Her2-positive patients of 34 months and triple-negative patients of 13 months. 86% of hormone-receptor-positive patients received antihormonal therapy. 81% of Her2-positive patients received anti-Her2 therapy. In summary, longer survival is strongly restricted to hormone receptor- and Her2-positive tumors most likely due to targeted therapies directed against the estrogen-receptor and Her2. PMID- 25279327 TI - Penicillium sp. as an organism that degrades endosulfan and reduces its genotoxic effects. AB - Endosulfan is an organochloride and persistent pesticide that has caused concern because of its impact in the environment and its toxicity to and bioaccumulation in living organisms. In this study, we isolated an endosulfan-degrading fungus from the activated sludge from an industrial wastewater treatment plant. Through repetitive enrichment and successive subculture in media containing endosulfan as the sole carbon source, a fungus designated CHE 23 was isolated. Based on a phylogenetic analysis, strain CHE 23 was assigned to the genus Penicillium sp. In a mineral salt medium with 50 mg/l endosulfan as the sole source carbon, CHE 23 removed the added endosulfan in a period of six days. To verify the decrease in endosulfan toxicity due to the activity of the fungus, we performed genotoxicity tests trough the single cell gel electrophoresis assay or comet assay, with Eisenia fetida as the bioindicator species. This organism was exposed to the supernatants of the culture of the fungus and endosulfan. Our results indicated that the genotoxicity of endosulfan was completely reduced due the activity of this fungus. These results suggest that the Penicillium sp. CHE 23 strain can be used to degrade endosulfan residues and/or for water and soil bioremediation processes without causing toxicity problems, which are probably due to the generation of no-toxic metabolites during biodegradation. PMID- 25279328 TI - Modeling of HIV/AIDS dynamic evolution using non-homogeneous semi-markov process. AB - The purpose of this study is to model the progression of HIV/AIDS disease of an individual patient under ART follow-up using non-homogeneous semi-Markov processes. The model focuses on the patient's age as a relevant factor to forecast the transitions among the different levels of seriousness of the disease. A sample of 1456 patients was taken from a hospital record at Amhara Referral Hospitals, Amhara Region, Ethiopia, who were under ART follow up from June 2006 to August 2013. The states of disease progression adopted in the model were defined based on of the following CD4 cell counts: >500 cells/mm(3) (SI); 349 to 500 cells/mm(3) (SII); 199 to 350 cells/mm(3)(SIII); <=200 cells/mm(3) (SIV); and death (D). The first four states are referred as living states. The probability that an HIV/AIDS patient with any one of the living states will transition to the death state is greater with increasing age, irrespective of the current state and age of the patient. More generally, the probability of dying decreases with increasing CD4 counts over time. For an HIV/AIDS patient in a specific state of the disease, the probability of remaining in the same state decreases with increasing age. Within the living states, the results show that the probability of being in a better state is non-zero, but less than the probability of being in a worse state for all ages. A reliability analysis also revealed that the survival probabilities are all declining over time. Computed conditional probabilities show differential subject response that depends on the age of the patient. The dynamic nature of AIDS progression is confirmed with particular findings that patients are more likely to be in a worse state than a better one unless interventions are made. Our findings suggest that ongoing ART treatment services could be provided more effectively with careful consideration of the recent disease status of patients. PMID- 25279329 TI - The best triathletes are older in longer race distances - a comparison between Olympic, Half-Ironman and Ironman distance triathlon. AB - The purpose of this study was (i) to determine the age of peak triathlon performance for world class athletes competing in Olympic, Half-Ironman and Ironman distance races and (ii) to investigate a potential change in the age of the annual fastest athletes across years. Data of ages and race times of all finishers in the international top races over the three distances between 2003 and 2013 were collected and the annual top ten women and men were analysed using linear, non-linear and hierarchical multivariate regression analyses. The age of peak male performance was 27.1 +/- 4.9 years in the Olympic, 28.0 +/- 3.8 years in the Half-Ironman and 35.1 +/- 3.6 years in the Ironman distance and the age of peak male performance was higher in the Ironman compared to the Olympic (p < 0.05) and the Half-Ironman distance (p < 0.05) triathlon. The age of peak female performance was 26.6 +/- 4.4 years in the Olympic, 31.6 +/- 3.4 years in the Half Ironman and 34.4 +/- 4.4 years in the Ironman distance and the age of peak female performance was lower in the Olympic compared to the Half-Ironman (p < 0.05) and Ironman distance (p < 0.05) triathlon. The age of the annual top ten women and men remained unchanged over the last decade in the Half-Ironman and the Ironman distance. In the Olympic distance, however, the age of the annual top ten men decreased slightly. To summarize, the age of peak triathlon performance was higher in the longer triathlon race distances (i.e. Ironman) and the age of the annual top triathletes remained mainly stable over the last decade. With these findings top athletes competing at world class level can plan their career more precisely as they are able to determine the right time in life to switch from the shorter (i.e. Olympic distance) to the longer triathlon race distances (i.e. Half Ironman and Ironman) in order to continuously compete in triathlon races at world class level. PMID- 25279330 TI - Cloning, phylogeny, and expression analysis of the Broad-Complex gene in the longicorn beetle Psacothea hilaris. AB - Seven isoforms of Broad-Complex (PhBR-C), in which the sequence of the zinc finger domain differed (referred to as Z1, Z2, Z3, Z2/Z3, Z4, Z5/Z6, and Z6, respectively), were cloned from the yellow-spotted longicorn beetle Psacothea hilaris. The Z1-Z4 sequences were highly conserved among insect species. The Z5/Z6 isoform was aberrant in that it contained a premature stop codon. Z6 had previously only been detected in a hemimetabola, the German cockroach Blattella germanica. The presence of Z6 in P. hilaris, and not in other holometabolous model insects such as Drosophila melanogaster or Tribolium castaneum, suggests that Z6 was lost multiple times in holometabolous insects during the course of evolution. PhBR-C expression levels in the brain, salivary gland, and epidermis of larvae grown under different feeding regimens were subsequently investigated. PhBR-C expression levels increased in every tissue examined after the gut purge, and high expression levels were observed in prepupae. A low level of PhBR-C expression was continuously observed in the brain. An increase was noted in PhBR C expression levels in the epidermis when 4th instar larvae were starved after 4 days of feeding, which induced precocious pupation. No significant changes were observed in expression levels in any tissues of larvae starved immediately after ecdysis into 4th instar, which did not grow and eventually died. PMID- 25279331 TI - Age effects on tinnitus and hearing loss in CBA/CaJ mice following sound exposure. AB - Tinnitus is a maladaptive neuropathic condition that develops in humans and laboratory animals following auditory insult. In our previous study we demonstrated that sound exposure leads to development of behavioral evidence of tinnitus in a sample of exposed mice. However, this tinnitus mouse model did not account for long-term maladaptive plasticity or aging, factors that are commonly linked to the human tinnitus population. Therefore the same group of mice was monitored for tinnitus for 360 days post exposure. Tinnitus was assessed behaviorally by measuring gap-induced pre-pulse suppression of the acoustic startle (GPIAS). Cochlear histology was performed on both control (unexposed) and experimental mice to determine whether sound exposure caused any evident cochlear damage. We found that 360 days after exposure the vast majority of exposed mice exhibited similar gap detection deficits as detected at 84 days post exposure. These mice did not demonstrate significant loss of inner/outer hair cells or spiral ganglion neurons compared to the control sample. Lastly, we demonstrated that GPIAS deficits observed in exposed animals were unlikely exclusively caused by cochlear damage, but could be a result of central auditory maladaptive plasticity. We conclude that CBA/CaJ mice can be considered a good animal model to study the possible contribution of age effects on tinnitus development following auditory insult. PMID- 25279332 TI - Prognostic significance of histological invasion in high grade soft tissue sarcomas. AB - High grade soft tissue sarcomas often show histological invasion to adjacent compartment including bone and vessel. This study aimed to evaluate histological invasion in high grade soft tissue sarcomas, clarify its impact on prognosis and devise treatment strategies. We retrospectively reviewed 133 patients with non small round cell high grade soft tissue sarcomas surgically treated between 2001 and 2011. Clinical and histological factors examined for prognostic value included age, gender, size, depth, location, adjuvant therapy and invasion to adjacent compartment. Study endpoints included overall survival rate, event free survival rate and local recurrence free survival rate, estimated by the Kaplan Meier method. Univariate and multivariate analyses were performed using the log rank test and Cox proportional hazards model. Local recurrence was recognized in 14 cases (11%). The 5-year overall survival rate and 5-year event free survival rate were 82.2% and 63.6% respectively. The metastasis-free survival rate at 5 years and local recurrence-free survival rate at 5 years were 69.8% and 86.8% respectively. Histological invasion to adjacent compartment was noted in 52 cases (39%), and was significantly correlated with histological type (p = 0.01), tumor size (p = 0.009), and depth (p < 0.05). In multivariate analyses, we showed that tumor size and histological invasion were significant independent predictors of OS (hazard ratio 8.1/2.5) and EFS (hazard ratio 5.5/2.2), while only tumor size was a significant independent predictor of LRFS (hazard ratio 4.0). We evaluated the relation between histological invasion and the oncological outcomes of high grade soft tissue sarcomas. In multivariate analyses, histological invasion was found to be an independent adverse prognostic factor with hazard ratios of 2.2 2.5, suggesting that a detailed assessment of these factors is essential. Histological invasion showed a correlation with tumor size and histological type, and the surgical margin should be decided based on these factors. PMID- 25279333 TI - Relationships between priming and subsequent recognition memory. AB - A discrepancy exists among previous studies regarding whether priming and subsequent recognition memory are positively or negatively correlated. We consider that the difference in recognition memory measures used in these studies accounts for the discrepancy. To examine this, we introduced three different recognition measures and reexamined the relationship between priming and subsequent recognition. Participants learned stimulus words in the first encoding block while performing an abstract/concrete decision task. In the second encoding block, a priming test was conducted, followed by a surprise recognition memory test. Results showed that the hit rate and hit rate (pHit)-false-alarm rate (pFA) positively correlated with priming. However, the difference between hit rates for the twice- and once-encoded stimuli, which can reflect the representations acquired at the second exposure in particular, did not significantly correlate with priming. These results suggest that priming and subsequent recognition relate positively because of the common representations acquired at the initial encoding. Furthermore, the present results are consistent with a previous study that failed to reproduce the negative correlation between priming and subsequent recognition. PMID- 25279334 TI - Location of alpha-tocopherol and alpha-tocotrienol to heterogeneous cell membranes and inhibition of production of peroxidized cholesterol in mouse fibroblasts. AB - BACKGROUND: alpha-Tocopherol (alpha-T) and alpha-tocotrienol (alpha-T3) are well recognized as lipophilic antioxidants. Nevertheless, there is limited knowledge on their location in heterogeneous cell membranes. We first investigated the distribution of alpha-T and alpha-T3 to the cholesterol-rich microdomains (lipid rafts and caveolae) of heterogeneous cell membranes by incubating these antioxidants with cultured mouse fibroblasts. FINDINGS: Levels of cellular uptake for alpha-T and alpha-T3 were adjusted to the same order, as that of the latter was much more efficient than that of the former in the cultured cells. After ultracentrifugation, alpha-T and alpha-T3 were partitioned to the microdomain fractions. When the distribution of alpha-T and alpha-T3 was further confirmed by using methyl-beta-cyclodextrin (which removes cholesterol from membranes), alpha T was suggested to be distributed to the microdomains (approx. 9% of the total uptake). The same treatment did not affect alpha-T3 content in the microdomain fractions, indicating that alpha-T3 is not located in these cholesterol-rich domains. However, alpha-T and alpha-T3 significantly inhibited the production of peroxidized cholesterol when cells were exposed to ultraviolet-A light. CONCLUSIONS: These results suggest that alpha-T and alpha-T3 can act as membranous antioxidants against photo-irradiated cholesterol peroxidation irrespective of their distribution to cholesterol-rich microdomains. PMID- 25279335 TI - Towards institutionalised regionalism: the role of institutions and prospects for institutionalisation in ASEAN. AB - This paper provides concrete understanding of the role of institutions and prospects for institutionalisation in ASEAN. It highlights the significant roles of institutions in the integrating Southeast Asia and demonstrates three main areas of institutional deficiency in the association. However, although ASEAN institutions meet the expectations, by and large, in terms of serving the national governments and upholding the association's norms, along with theoretical explanation, this paper argues that ASEAN should focus on strengthening its existing institutional structure by providing them with a mandate and sufficient financial and human resources in order to support its administration and growing activities. Finally, the paper suggests a revision of the current financial contribution system, a seeking of alternative sources of income and some institutional inventions such as a research wing and a mechanism that can get non-state actors involved in the process. PMID- 25279336 TI - Convergence of nanotechnology with radiation therapy-insights and implications for clinical translation. AB - Improvements in accuracy and efficacy in treating tumors with radiation therapy (RT) over the years have been fueled by parallel technological and conceptual advances in imaging and image-guidance techniques, radiation treatment machines, computational methods, and the understanding of the biology of tumor response to RT. Recent advances in our understanding of the hallmarks of cancer and the emergence of strategies to combat these traits of cancer have resulted in an expanding repertoire of targeted therapeutics, many of which can be exploited for enhancing the efficacy of RT. Complementing this advent of new treatment options is the evolution of our knowledge of the interaction between nanoscale materials and human tissues (nanomedicine). As with the changes in RT paradigms when the field has encountered newer and maturing disciplines, the incorporation of nanotechnology innovations into radiation oncology has the potential to refine or redefine its principles and revolutionize its practice. This review provides a summary of the principles, applications, challenges and outlook for the use of metallic nanoparticles in RT. PMID- 25279338 TI - Radiographic evaluation of third molar development in 6- to 24-year-olds. AB - PURPOSE: This study investigated the developmental stages of third molars in relation to chronological age and compared third molar development according to location and gender. MATERIALS AND METHODS: A retrospective analysis of panoramic radiographs of 2490 patients aged between 6 and 24 years was conducted, and the developmental stages of the third molars were evaluated using the modified Demirjian's classification. The mean age, standard deviation, minimal and maximal age, and percentile distributions were recorded for each stage of development. A Mann-Whitney U test was performed to test the developmental differences in the third molars between the maxillary and mandibular arches and between genders. A linear regression analysis was used for assessing the correlation between the third molar development and chronological age. RESULTS: The developmental stages of the third molars were more advanced in the maxillary arch than the mandibular arch. Males reached the developmental stages earlier than females. The average age of the initial mineralization of the third molars was 8.57 years, and the average age at apex closure was 21.96 years. The mean age of crown completion was 14.52 and 15.04 years for the maxillary and the mandibular third molars, respectively. CONCLUSION: The developmental stages of the third molars clearly showed a strong correlation with age. The third molars developed earlier in the upper arch than the lower arch; further, they developed earlier in males than in females. PMID- 25279337 TI - Three-dimensional imaging modalities in endodontics. AB - Recent research in endodontics has highlighted the need for three-dimensional imaging in the clinical arena as well as in research. Three-dimensional imaging using computed tomography (CT) has been used in endodontics over the past decade. Three types of CT scans have been studied in endodontics, namely cone-beam CT, spiral CT, and peripheral quantitative CT. Contemporary endodontics places an emphasis on the use of cone-beam CT for an accurate diagnosis of parameters that cannot be visualized on a two-dimensional image. This review discusses the role of CT in endodontics, pertaining to its importance in the diagnosis of root canal anatomy, detection of peri-radicular lesions, diagnosis of trauma and resorption, presurgical assessment, and evaluation of the treatment outcome. PMID- 25279339 TI - Correlation of morphological variants of the soft palate and Need's ratio in normal individuals: A digital cephalometric study. AB - PURPOSE: The present study was aimed to investigate the variation of soft palate morphology in different age and gender groups. The correlations of radiographic velar length (VL), velar width (VW), pharyngeal depth (PD), and Need's ratio with soft palate variants were also studied in the North Indian subpopulation. MATERIALS AND METHODS: The study sample consisted of 300 subjects aged between 15 and 45 (mean: 31.32) years. The velar morphology on lateral cephalograms was examined and grouped into six types. The results obtained were subjected to a statistical analysis to find the correlation between variants of the soft palate with gender and different age groups. RESULTS: The most frequent type of soft palate was leaf shaped (48.7%), and the least common was crook shaped (3.0%) among both the genders and various age groups, showing a significant correlation. The mean VL, VW, and PD values were significantly higher in males and significantly correlated with the types of soft palate. A significant correlation was observed between the mean VL, VW, PD, and Need's ratio with various age groups, showing an inconsistent pattern with an increase in age. The types of soft palate, gender, and Need's ratio were also significantly correlated, with an overall higher mean value of the Need's ratio among female subjects and the S shaped soft palate. CONCLUSION: The knowledge of a varied spectrum of velar morphology and the variants of the soft palate help in a better understanding of the velopharyngeal closure and craniofacial anomalies. PMID- 25279341 TI - Deviation of landmarks in accordance with methods of establishing reference planes in three-dimensional facial CT evaluation. AB - PURPOSE: This study aimed to investigate the deviation of landmarks from horizontal or midsagittal reference planes according to the methods of establishing reference planes. MATERIALS AND METHODS: Computed tomography (CT) scans of 18 patients who received orthodontic and orthognathic surgical treatment were reviewed. Each CT scan was reconstructed by three methods for establishing three orthogonal reference planes (namely, the horizontal, midsagittal, and coronal reference planes). The horizontal (bilateral porions and bilateral orbitales) and midsagittal (crista galli, nasion, prechiasmatic point, opisthion, and anterior nasal spine) landmarks were identified on each CT scan. Vertical deviation of the horizontal landmarks and horizontal deviation of the midsagittal landmarks were measured. RESULTS: The porion and orbitale, which were not involved in establishing the horizontal reference plane, were found to deviate vertically from the horizontal reference plane in the three methods. The midsagittal landmarks, which were not used for the midsagittal reference plane, deviated horizontally from the midsagittal reference plane in the three methods. CONCLUSION: In a three-dimensional facial analysis, the vertical and horizontal deviations of the landmarks from the horizontal and midsagittal reference planes could vary depending on the methods of establishing reference planes. PMID- 25279340 TI - Effect of changing the kilovoltage peak on radiographic caries assessment in digital and conventional radiography. AB - PURPOSE: This study aimed to investigate the effect of changing the kilovoltage peak (kVp) on the radiographic assessment of dental caries. MATERIALS AND METHODS: Seventy-five extracted posterior teeth with proximal caries or apparently sound proximal surfaces were radiographed with conventional E-speed films and a photostimulable phosphor system using 60 kVp and 70 kVp for the caries assessment. The images were evaluated by three oral radiologists and compared with the results of the stereomicroscope analysis. RESULTS: No statistically significant difference was found between 60 kVp and 70 kVp for the caries detection, determination of caries extension into dentin, and caries severity in either the conventional or the digital images. Good to very good inter-observer and intra-observer agreements were found for both kilovoltage values on the conventional and digital images. CONCLUSION: Changing the kilovoltage between 60 kVp and 70 kVp had no obvious effect on the detection of proximal caries or determination of its extension or severity. PMID- 25279342 TI - Preoperative implant planning considering alveolar bone grafting needs and complication prediction using panoramic versus CBCT images. AB - PURPOSE: This study was performed to determine the efficacy of observers' prediction for the need of bone grafting and presence of perioperative complications on the basis of cone-beam computed tomography (CBCT) and panoramic radiographic (PAN) planning as compared to the surgical outcome. MATERIALS AND METHODS: One hundred and eight partially edentulous patients with a need for implant rehabilitation were referred for preoperative imaging. Imaging consisted of PAN and CBCT images. Four observers carried out implant planning using PAN image datasets, and at least one month later, using CBCT image datasets. Based on their own planning, the observers assessed the need for bone graft augmentation as well as complication prediction. The implant length and diameter, the need for bone graft augmentation, and the occurrence of anatomical complications during planning and implant placement were statistically compared. RESULTS: In the 108 patients, 365 implants were installed. Receiver operating characteristic analyses of both PAN and CBCT preoperative planning showed that CBCT performed better than PAN-based planning with respect to the need for bone graft augmentation and perioperative complications. The sensitivity and the specificity of CBCT for implant complications were 96.5% and 90.5%, respectively, and for bone graft augmentation, they were 95.2% and 96.3%, respectively. Significant differences were found between PAN-based planning and the surgery of posterior implant lengths. CONCLUSION: Our findings indicated that CBCT-based preoperative implant planning enabled treatment planning with a higher degree of prediction and agreement as compared to the surgical standard. In PAN-based surgery, the prediction of implant length was poor. PMID- 25279343 TI - Cone-beam computed tomography analysis of root and canal morphology of mandibular premolars in a Spanish population. AB - PURPOSE: This study aimed to investigate the clinical anatomy of lower premolar roots in a Spanish population by using cone-beam computed tomography (CBCT), correlating findings with patient gender and tooth type. MATERIALS AND METHODS: Using 70 CBCT images, we evaluated 126 healthy, untreated, well-developed lower premolars. The number and morphology of roots and root canals, and the foramina number were assessed. Results for gender and tooth type were compared using the chi-squared and ANOVA tests. RESULTS: The average length of teeth and roots was significantly higher in men (p=0.00). All 126 premolars had a single root. One canal was found in 83.3% of the premolars, with no gender or tooth type differences; Vertucci configuration types I and V were the most prevalent. The first premolars showed significantly greater variability than the second premolars (p=0.03). A single apical foramen was found in 89.7% of the premolars, with no differences by tooth type. Women had a significantly higher prevalence of two apical foramina than men (p=0.04). Some degree of curvature was observed in 65% of the premolars, with no differences by gender or tooth type. A root angle of more than 20 degrees was found in 12.98% of the premolars, without any differences by gender or tooth. CONCLUSION: All premolars were single-rooted. One canal had the most prevalent morphology. More variability in canal anatomy was found in the first premolars. Curvatures greater than 20 degrees were found at less than 5 mm from the apex. PMID- 25279344 TI - Assessment of bifid and trifid mandibular canals using cone-beam computed tomography. AB - PURPOSE: To investigate the prevalence of bifid and trifid mandibular canals using cone-beam computed tomography (CBCT) images, and to measure their length, diameter, and angle. MATERIALS AND METHODS: CBCT images of 500 patients, involving 755 hemi-mandibles, were used for this study. The presence and type of bifid mandibular canal was evaluated according to a modified classification of Naitoh et al. Prevalence rates were determined according to age group, gender, and type. Further, their diameter, length, and angles were measured using PACSPLUS Viewer and ImageJ 1.46r. Statistical analysis with chi-squared and analysis of variance (ANOVA) tests was performed. RESULTS: Bifid and trifid mandibular canals were found in 22.6% of the 500 patients and 16.2% of the 755 sides. There was no significant difference between genders and among age groups. The retromolar canal type accounted for 71.3% of the identified canals; the dental canal type, 18.8%; the forward canal type, 4.1%; and the trifid canal type, 5.8%. Interestingly, seven cases of the trifid canal type, which has been rarely reported, were observed. The mean diameter of the bifid and trifid mandibular canals was 2.2 mm and that of the main mandibular canal was 4.3 mm. Their mean length was 16.9 mm; the mean superior angle was 149.2 degrees , and the mean inferior angle was 37.7 degrees . CONCLUSION: Bifid and trifid mandibular canals in the Korean population were observed at a relatively high rate through a CBCT evaluation, and the most common type was the retromolar canal. CBCT is suggested for a detailed evaluation of bifid and trifid mandibular canals before mandibular surgery. PMID- 25279345 TI - Multiple fibromyxomas of the jaws: A case report. AB - Fibromyxoma of the jaw is a rare benign mesenchymal odontogenic tumor with locally aggressive behavior. In the present report, a 13-year-old female patient presented to our university hospital with delayed eruption of some of her teeth. A panoramic radiograph taken at the initial examination revealed four pericoronal radiolucencies related to the four third molars. Thereafter, a magnetic resonance imaging (MRI) examination was performed. After the surgical removal of these molars, the microscopic examination diagnosed the four lesions as fibromyxomas. Here, we have discussed the clinical, panoramic radiography, MRI, and histopathological findings of the case. PMID- 25279346 TI - Chronic osteitic rhinosinusitis as a manifestation of cystic fibrosis: A case report. AB - A 28-year-old male patient with a history of cystic fibrosis (CF) was referred to the University of Connecticut School of Dental Medicine for an evaluation of a cystic lesion in the right maxilla using cone-beam computed tomography (CBCT). CF is an autosomal recessive disease characterized by an abnormal production of viscous mucus, affecting the mucociliary clearance. The CBCT scan revealed a large cystic lesion in the right maxilla extending from the right maxillary second molar to the midline in the region of the right central incisor with a significant buccal expansion. Further evaluation revealed complete opacification of the paranasal sinuses with medial bulging of the lateral maxillary sinus walls. The maxillary and sphenoid sinuses also appeared hypoplastic. The peculiar finding seen in this case was the presence of marked sclerosis and an increase in the thickness of the adjacent bony framework. This report aimed to describe the common sinonasal findings associated with CF and its underlying pathophysiology. PMID- 25279347 TI - Glandular odontogenic cyst mimicking ameloblastoma in a 78-year-old female: A case report. AB - Glandular odontogenic cyst (GOC) is a rare, potentially aggressive jaw lesion. The common radiographic features include a well-defined radiolucency with distinct borders, presenting a uni- or multilocular appearance. A cystic lesion in the posterior mandible of a 78-year-old female was incidentally found. Radiographs showed a unilocular lesion with a scalloped margin, external root resorption of the adjacent tooth, and cortical perforation. This lesion had changed from a small ovoid shape to a more expanded lesion in a period of four years. The small lesion showed unilocularity with a smooth margin and a well defined border, but the expanded lesion produced cortical perforation and a lobulated margin. The provisional diagnosis was an ameloblastoma, whereas the histopathological examination revealed a GOC. This was a quite rare case, given that this radiographic change was observed in the posterior mandible of an elderly female. This case showed that a GOC can grow even in people in their seventies, changing from the unilocular form to an expanded, lobulated lesion. Here, we report a case of GOC with characteristic radiographic features. PMID- 25279348 TI - Laser-guided intraoral radiography: A future focus. PMID- 25279350 TI - Management of Common Toxicities in Metastatic NSCLC Related to Anti-Lung Cancer Therapies with EGFR-TKIs. AB - Tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor (EGFR) are the standard of care treatment in non-small cell lung cancer (NSCLC). TKIs are used first line in EGFR mutation-positive NSCLC; erlotinib is the only TKI approved for subsequent lines of treatment in EGFR wild-type NSCLC. As promising as TKIs are in helping patients avoid some of the side effects of traditional cytotoxic chemotherapy, they do come with a variety of side effects. This article will describe the most common adverse events associated with the epidermal EGFR family of TKIs including diarrhea, rash, mucositis, and paronychia. The objective of this paper is to provide simple guidelines to assist oncologists in managing these common toxicities. As patient survival is often directly correlated with successful therapeutic drug delivery, the management of TKI-induced adverse events ensures proper treatment and may avoid discontinuation or reduction of the therapeutic. PMID- 25279351 TI - Is DHT Production by 5alpha-Reductase Friend or Foe in Prostate Cancer? AB - The first advance in the history of studies on prostate cancer (PCa) and androgens was the development of treatment with castration and administration of estrogen by Charles B. Huggins, who won the Nobel Prize in Physiology and Medicine. Since then, and for 70 years, androgen deprivation therapy has been the standard therapy for advanced PCa and the center of studies on PCa. However, recent advances have shed light on the relationship between androgens and the development or the progression of PCa. The use of 5AR inhibitors to prevent progression of PCa continues to be widely discussed. Discussion has been fueled by the findings of two large randomized, placebo-controlled trials: the Prostate Cancer Prevention Trial with finasteride and the Reduction by Dutasteride of Prostate Cancer Events trial. Does the development of PCa or progression to castration-resistant PCa depend on dihydrotestosterone (DHT)? Here, we summarize and discuss recent topics of local androgen production of DHT in PCa. PMID- 25279354 TI - Mycobacterial glycoproteins: a novel subset of vaccine candidates. PMID- 25279352 TI - Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells may Sensitize Them to Extracellular Ascorbate. AB - Low millimolar concentrations of ascorbate are capable of inflicting lethal damage on a high proportion of cancer cells lines, yet leave non-transformed cell lines unscathed. Extracellular generation of hydrogen peroxide, reflecting reduction of molecular oxygen by ascorbate, has been shown to mediate this effect. Although some cancer cell lines express low catalase activity, this cannot fully explain the selective sensitivity of cancer cells to hydrogen peroxide. Ranzato and colleagues have presented evidence for a plausible new explanation of this sensitivity - a high proportion of cancers, via NADPH oxidase complexes or dysfunctional mitochondria, produce elevated amounts of superoxide. This superoxide, via a transition metal-catalyzed transfer of an electron to the hydrogen peroxide produced by ascorbate, can generate deadly hydroxyl radical (Haber-Weiss reaction). It thus can be predicted that concurrent measures which somewhat selectively boost superoxide production in cancers will enhance their sensitivity to i.v. ascorbate therapy. One way to achieve this is to increase the provision of substrate to cancer mitochondria. Measures which inhibit the constitutive hypoxia-inducible factor-1 (HIF-1) activity in cancers (such as salsalate and mTORC1 inhibitors, or an improvement of tumor oxygenation), or that inhibit the HIF-1-inducible pyruvate dehydrogenase kinase (such as dichloroacetate), can be expected to increase pyruvate oxidation. A ketogenic diet should provide more lipid substrate for tumor mitochondria. The cancer killing activity of 42 degrees C hyperthermia is to some degree contingent on an increase in oxidative stress, likely of mitochondrial origin; reports that hydrogen peroxide synergizes with hyperthermia in killing cancer cells suggest that hyperthermia and i.v. ascorbate could potentiate each other's efficacy. A concurrent enhancement of tumor oxygenation might improve results by decreasing HIF-1 activity while increasing the interaction of ascorbic acid with oxygen. An increased pool of labile iron in cancer cells may contribute to the selective susceptibility of many cancers to i.v. ascorbate; antagonism of NF-kappaB activity with salicylate, and intravenous iron administration, could be employed to further elevate free iron in cancers. PMID- 25279356 TI - A comprehensive approach to refractory cardiac arrest: saving more lives one way or another. PMID- 25279353 TI - How to find RNA thermometers. AB - Temperature is one of the decisive signals that a mammalian pathogen has entered its warm-blooded host. Among the many ways to register temperature changes, bacteria often use temperature-modulated structures in the untranslated region of mRNAs. In this article, we describe how such RNA thermometers (RNATs) have been discovered one by one upstream of heat shock and virulence genes in the past, and how next-generation sequencing approaches are able to reveal novel temperature responsive RNA structures on a global scale. PMID- 25279355 TI - Decentralized nursing education in northern Norway: a basis for continuing education to meet competence needs in rural Arctic healthcare services. AB - BACKGROUND: Ensuring a sufficient nursing workforce, with respect to both number and relevant professional competencies, is crucial in rural Arctic regions in Norway. This study examines the continuing education (CE) of nurses who graduated from a decentralized nursing programme between 1994 and 2011. OBJECTIVE: This study aims to measure the extent to which the decentralized nursing education (DNE) in question has served as a basis for CE that is adapted to current and future community health care service needs in rural Arctic regions in northern Norway. More specifically, the study aims to investigate the frequency and scope of CE courses among the graduates of a DNE, the choice of study model and the degree of employment with respect to the relevant CE. DESIGN: This study is a quantitative survey providing descriptive statistics. RESULTS: The primary finding in this study is that 56% of the participants had engaged in CE and that they were employed in positions related to their education. The majority of students with decentralized bachelor's degrees engaged in CE that was part time and/or decentralized. CONCLUSIONS: More than half of the population in this study had completed CE despite no mandatory obligation in order to maintain licensure. Furthermore, 31% of the participants had completed more than one CE programme. The findings show that the participants preferred CE organized as part time and or decentralized studies. PMID- 25279357 TI - A simplified minimally invasive approach to mitral valve surgery - optimal access under direct vision. AB - With increasing enthusiasm in minimally invasive surgery, several approaches and access are being performed with great precision. In this report, we illustrate and describe a minimal invasive approach to mitral valve surgery with optimal access under direct vision, the indications and patient selection, the surgical techniques, its advantages over the other approaches, and its simplicity and reproducibility. PMID- 25279359 TI - Atrial fibrillation after isolated coronary surgery. Incidence, long term effects and relation with operative technique. AB - INTRODUCTION: Postoperative atrial fibrillation after isolated coronary revascularization has been associated with increased morbidity and mortality. Aim of present investigation was to evaluate incidence of postoperative atrial fibrillation and its prognostic role in patients undergoing isolated coronary artery by-pass and disclose possible differences between off-pump and cardiopulmonary assisted revascularization. METHODS: Prospective cohort study of 229 patients undergoing isolated coronary artery by-pass at a tertiary heart surgery Centre. Off-pump treated patients were significantly older (70.5 vs 64.9 years, p<0.001). No other baseline differences were found. Patients who developed postoperative atrial fibrillation were followed up for an average period of 2 years. RESULTS: Post-operative occurred in 56/229 (24.1% after cardiopulmonary and 24.6% after off-pump coronary artery by-pass). Left atrium diameter was the only independent predictive factor (odds ratio =1.15, 95% confidence interval 1.02-1.30, p<0.001). All patients with postoperative atrial fibrillation were treated and discharged in sinus rhythm, in 6/56 recurred, only in one persisted. One patient died during follow up. No stroke was recorded. CONCLUSIONS: After isolated surgical revascularization, atrial fibrillation occurred in 24% without differences related to operative technique. Recurrence of atrial fibrillation occurred in 6/56 patients (10.7%) however only in 1 persisted. Early and late mortality did not show relation with post-operative atrial fibrillation probably due to immediate treatment with recovery of sinus rhythm before discharge. PMID- 25279358 TI - Acute right heart syndrome in the critically ill patient. AB - Acute right heart syndrome is a sudden deterioration in right ventricular performance, resulting in right ventricular failure and confers significant in hospital morbidity and mortality. In critically ill patients, the syndrome is often undiagnosed and untreated, as these patients do not usually exhibit the common clinical manifestations of the condition, making the diagnosis challenging for the intensivist. In this narrative review we focus on the pathophysiology of acute right heart syndrome, in critical illness, diagnostic modalities used to assess right ventricular function and management of acute right heart syndrome, including mechanical ventilation strategies and circulatory support. PMID- 25279360 TI - Acute myocardial infarction associated to DPP-4 inhibitors. AB - INTRODUCTION: Diabetes mellitus is associated with cardiovascular disease. Anti diabetic therapy has a limited capability (if any) of changing the incidence of either death or major cardiovascular disease, and cardiovascular safety concerns have been raised. We aimed at identifying episodes of acute myocardial infarction associated to a relatively new class of drugs, dipeptidyl peptidase-4 inhibitors. METHODS: Retrospective study: from 954 admissions (15 month period) in the coronary care unit, we selected 200 admissions corresponding to 196 patients with myocardial infarction and diabetes. 35 of these patients were receiving therapy with dipeptidyl peptidase-4 inhibitors (the vast majority, in association to metformin). We evaluated the peak plasma cardiac troponin I as the main study parameter. RESULTS: Patients on dipeptidyl peptidase-4 inhibitors therapy had a mean peak cardiac troponin plasma level of 50.2+/-121.3 ng/ml (n=35), the corresponding value for insulin being 39.2+/-108.4 ng/ml (n=56), for metformin the value was 45.8+/-97.3 ng/ml (n=93) and for sulfonylureas, 42.4+/-77.7 ng/ml (n=52). None of these values differed significantly from the corresponding control group of patients not taking each class of drug. The linear regression study also yielded a negative result relating therapy with dipeptidyl peptidase-4 inhibitors and peak troponin values. Acute myocardial infarctions associated to dipeptidyl peptidase-4 inhibitors varied widely in the clinical characteristics of the patients. CONCLUSIONS: We found no evidence that peak plasma troponin I was different between patient with acute myocardial infarction and use of dipeptidyl peptidase-4 inhibitors when compared to cases not under such therapy. PMID- 25279361 TI - Agglutinins and cardiac surgery: a web based survey of cardiac anaesthetic practice; questions raised and possible solutions. AB - INTRODUCTION: Cardiac surgery involves cardiopulmonary bypass during which the core temperature is generally lowered to hypothermic levels. Patients presenting for cardiac surgery are sometimes reported to have cold or warm autoantibodies at the time of blood screening. It is known that cold agglutinins may cause potentially life-threatening haemolysis, intracoronary haemagglutination leading to inadequate cardioplegia distribution, thrombosis, embolism, ischaemia or infarction. The risk (if any) posed by warm autoantibodies is less clear. Because of the absence of hospital policies and of clear UK guidelines that explain how to manage such cases, we decided to conduct a web-based survey regarding standard anaesthesia practice in patients with both cold and warm autoantibodies presenting for cardiac surgery. METHODS: We devised a short electronic survey asking for responses to 8 questions on cold auto-antibodies and 2 on warm auto antibodies. This was sent to all members of the Association of Cardiothoracic Anaesthetists. Responses were collated and expressed as percentages. Free text responses were analysed for trend or reported verbatim. RESULTS: The results of our survey demonstrate that there is no consensus on the appropriate management of such patients, with responses ranging from cancelling surgery to proceeding without additional precautions. CONCLUSIONS: In collaboration with haematologists and taking into account the available evidence, our institution has now developed a management strategy for cardiac patients with cold autoantibodies. Further studies will be required to determine the usefulness of our algorithm in daily practice. PMID- 25279362 TI - Direct comparison between cerebral oximetry by INVOS(TM) and EQUANOX(TM) during cardiac surgery: a pilot study. AB - INTRODUCTION: Several near-infrared spectroscopy oximeters are commercially available for clinical use, with lack of standardization among them. Accordingly, cerebral oxygen saturation thresholds for hypoxia/ischemia identified in studies conducted with INVOS(TM) models do not necessarily apply to other devices. In this study, the measurements made with both INVOS(TM) and EQUANOX(TM) oximeters on the forehead of 10 patients during conventional cardiac surgery are directly compared, in order to evaluate the interchangeability of these two devices in clinical practice. METHODS: Cerebral oxygen saturation measurements were collected from both INVOS(TM) 5100C and EQUANOX(TM) 7600 before anesthetic induction (baseline), two minutes after tracheal intubation, at cardiopulmonary bypass onset/offset, at aortic cross-clamping/unclamping, at the end of surgery and whenever at least one of the two devices measured a reduction in cerebral oxygen saturation equal to or greater than 20% of the baseline value. Bland Altman analysis was used to compare the bias and limits of agreement between the two devices. RESULTS: A total of 140 paired measurements were recorded. The mean bias between INVOS(TM) and EQUANOX(TM) was -5.1%, and limits of agreement were +/ 16.37%. Considering the values as percent of baseline, the mean bias was -1.43% and limits of agreement were +/-16.47. A proportional bias was observed for both absolute values and changes from baseline. CONCLUSIONS: INVOS(TM) and EQUANOX(TM) do not seem to be interchangeable in measuring both absolute values and dynamic changes of cerebral oxygen saturation during cardiac surgery. Large investigations, with appropriate design, are needed in order to identify any device-specific threshold. PMID- 25279363 TI - Life threatening tension pneumothorax during cardiac surgery. A case report. AB - Tension pneumothorax is a life threatening condition that occurs when the intrapleural pressure exceeds atmospheric pressure. It requires prompt diagnosis and immediate treatment. Tension pneumothorax developing postoperatively after cardiac surgery is not uncommon but occurrence in the operating room during cardiac surgery is rare. We report a case of tension pneumothorax intraoperatively during off pump coronary artery bypass grafting. PMID- 25279364 TI - Coronary to extra-cardiac anastomosis. PMID- 25279365 TI - Internal thoracic vein: friend or foe? PMID- 25279366 TI - Can we improve patient safety? AB - Despite greater awareness of patient safety issues especially in the operating room and the widespread implementation of surgical time out World Health Organization (WHO), errors, especially wrong site surgery, continue. Most such errors are due to lapses in communication where decision makers fail to consult or confirm operative findings but worryingly where parental concerns over the planned procedure are ignored or not followed through. The WHO Surgical Pause/Time Out aims to capture these errors and prevent them, but the combination of human error and complex hospital environments can overwhelm even robust safety structures and simple common sense. Parents are the ultimate repository of information on their child's condition and planned surgery but are traditionally excluded from the process of Surgical Pause and Time Out, perhaps to avoid additional stress. In addition, surgeons, like pilots, are subject to the phenomenon of "plan-continue-fail" with potentially disastrous outcomes. If we wish to improve patient safety during surgery and avoid wrong site errors then we must include parents in the Surgical Pause/Time Out. A recent pilot study has shown that neither staff nor parents found it added to their stress, but, moreover, 100% of parents considered that it should be a mandatory component of the Surgical Pause nor does it add to the stress of surgery. Surgeons should be required to confirm that the planned procedure is in keeping with the operative findings especially in extirpative surgery and this "step back" should be incorporated into the standard Surgical Pause. It is clear that we must improve patient safety further and these simple measures should add to that potential. PMID- 25279367 TI - Hirschsprung's Disease and Associated Congenital Heart Defects: A Prospective Observational Study from a Single Institution. AB - OBJECTIVE: To define the prevalence and characteristics of associated congenital heart diseases (CHDs) in patients with Hirschsprung's disease (HSCR). METHOD: All patients with a histological diagnosis of HSCR admitted to our hospital between January 2010 and December 2013 were included in this prospective observational study and underwent cardiovascular screening. Cardiac anatomy was assessed by a segmental echocardiographic approach. Measurements of aortic root and left ventricular dimensions, wall thickness, and function were obtained. CHDs requiring a percutaneous or surgical intervention were described as major heart diseases. RESULTS: One hundred thirty-three consecutive patients were enrolled at median age of 2.3 years. Eleven patients (8.3%) presented an associated heart disease. Moreover, five patients had mild dilatation of aortic root. Six out of 11 (4.5%) patients had a major CHDs requiring surgical repair. CONCLUSION: Prevalence of associated CHDs was slightly higher than in previous papers, and mostly represented by septal defects. Four out of six patients with major heart disease had also a chromosomal anomaly. If we do not consider the subpopulation of patients with a chromosomal anomaly, cardiac defects were present in 3.8% of the patients. Based on these results, we suggest to perform routine echocardiogram in all Hirschsprung patients, with or without associated chromosomal syndromes. PMID- 25279368 TI - Antipodal biosecurity? Oversight of dual use research in the United States and australia. PMID- 25279369 TI - The antimicrobial resistance crisis: causes, consequences, and management. AB - The antimicrobial resistance (AMR) crisis is the increasing global incidence of infectious diseases affecting the human population, which are untreatable with any known antimicrobial agent. This crisis will have a devastating cost on human society as both debilitating and lethal diseases increase in frequency and scope. Three major factors determine this crisis: (1) the increasing frequency of AMR phenotypes among microbes is an evolutionary response to the widespread use of antimicrobials; (2) the large and globally connected human population allows pathogens in any environment access to all of humanity; and (3) the extensive and often unnecessary use of antimicrobials by humanity provides the strong selective pressure that is driving the evolutionary response in the microbial world. Of these factors, the size of the human population is least amenable to rapid change. In contrast, the remaining two factors may be affected, so offering a means of managing the crisis: the rate at which AMR, as well as virulence factors evolve in microbial world may be slowed by reducing the applied selective pressure. This may be accomplished by radically reducing the global use of current and prospective antimicrobials. Current management measures to legislate the use of antimicrobials and to educate the healthcare world in the issues, while useful, have not comprehensively addressed the problem of achieving an overall reduction in the human use of antimicrobials. We propose that in addition to current measures and increased research into new antimicrobials and diagnostics, a comprehensive education program will be required to change the public paradigm of antimicrobial usage from that of a first line treatment to that of a last resort when all other therapeutic options have failed. PMID- 25279370 TI - The Australian Public is Still Vulnerable to Emerging Virulent Strains of West Nile Virus. AB - The mosquito-borne West Nile virus (WNV) is responsible for outbreaks of viral encephalitis in humans and horses with particularly virulent strains causing recent outbreaks in Eastern Europe, the Middle East, and North America. In Australia, a strain of WNV, Kunjin (WNVKUN), is endemic in the north and infection with this virus is generally asymptomatic. However, in early 2011, following extensive flooding, an unprecedented outbreak of WNVKUN encephalitis in horses occurred in South-Eastern Australia, resulting in more than 1,000 cases and a mortality of 10-15%. Despite widespread evidence of equine infections, there was only a single mild human case reported during this outbreak. To understand why clinical disease was seen in horses without similar observations in the human population, a serosurvey was conducted using blood donor samples from areas where equine cases were reported to assess level of flavivirus exposure. The seroprevalence to WNVKUN in humans was low before the outbreak (0.7%), and no significant increase was demonstrated after the outbreak period (0.6%). Due to unusual epidemiological features during this outbreak, a serosurvey was also conducted in rabbits, a potential reservoir host. Out of 675 animals, sampled across Australia between April 2011 and November 2012, 86 (12.7%) were seropositive for WNVKUN, with the highest prevalence during February of 2012 (28/145; 19.3%). As this is the first serological survey for WNVKUN in Australian feral rabbits, it remains to be determined whether wild rabbits are able to develop a high enough viremia to actively participate in WNV transmission in Australia. However, they may constitute a sentinel species for arbovirus activity, and this is the focus of on-going studies. Collectively, this study provides little evidence of human exposure to WNVKUN during the 2011 outbreak and indicates that the Australian population remains susceptible to the emergence of virulent strains of WNV. PMID- 25279371 TI - Larvicidal, Repellent, and Irritant Potential of the Seed-Derived Essential oil of Apium graveolens Against Dengue Vector, Aedes aegypti L. (Diptera: Culicidae). AB - Aedes aegypti L. is one of the primary disease vectors spreading various dreadful diseases throughout the world, specifically over tropics and subtropics. Keeping in view the adverse effects of chemical insecticides-based intervention measures, the eco-friendly and bio-degradable essential oil extracted from the seeds of celery, Apium graveolens were investigated for its efficacy against Ae. aegypti. Larvicidal bioassay carried out with the seed oil against early fourth instars of Ae. aegypti caused an LC50 and LC90 values of 16.10 and 29.08 ppm, respectively, after an exposure to 24 h. The cidal effect of the celery seed oil augmented by 1.2-fold; after an exposure to 48 h; revealing an LC50 value of 13.22 ppm. Interestingly, the seed oil did not cause immediate larval mortality, suggesting a delayed toxicity against the larval stage. Present investigations also revealed remarkable effective repellency of the oil leading to 100% protection till 165 min as compared to control that did not result in any repellency against adult Ae. aegypti. Interestingly, only one bite was recorded in the 165th-min after which only two bites were scored until 180 min of exposure of the adult mosquitoes to the oil. An exciting observation was that the knocked-down effect in adults exposed to 10% oil-impregnated papers. The contact irritancy assays with paper impregnated with 1% celery seed oil caused first flight only after 4 s resulting in an average of 63.66 flights during 15 min of exposure revealing the relative irritability of 26.97. The qualitative phytochemical analysis of the seed oil showed the presence of flavonoids, lactones, and terpenoids as the major constituents suggesting their probable role in the toxicity. Our results confirmed that celery seed essential oil can be used as an efficient larvicide and repellent against Ae. aegypti. The identification of the bioactive components, their mode of action, and studying effects on non-target organisms and the environment would help in devising mosquito-management strategies. PMID- 25279372 TI - Development of ricehusk ash reinforced bismaleimide toughened epoxy nanocomposites. AB - Recent past decades have witnessed remarkable advances in composites with potential applications in biomedical devices, aerospace, textiles, civil engineering, energy, electronic engineering, and household products. Thermoset polymer composites have further enhanced and broadened the area of applications of composites. In the present work epoxy-BMI toughened-silica hybrid (RHA/DGEBA BMI) was prepared using bismaleimide as toughener, bisphenol-A as matrix and a silica precursor derived from rice husk ash as reinforcement with glycidoxypropyltrimethoxysilane as coupling agent. Differential scanning calorimetry, electron microscopy, thermogravimetric analysis, and goniometry were used to characterize RHA/DGEBA-BMI composites developed in the present work. Tensile, impact and flexural strength, tensile and flexural modulus, hardness, dielectric properties were also studied and discussed. The hybrid nanocomposites possess the higher values of the glass transition temperature (Tg) and mechanical properties than those of neat epoxy matrix. PMID- 25279373 TI - Covalent modification of a ten-residue cationic antimicrobial peptide with levofloxacin. AB - The rampant spread of antibiotic resistant bacteria has spurred interest in alternative strategies for developing next-generation antibacterial therapies. As such, there has been growing interest in cationic antimicrobial peptides (CAMPs) and their therapeutic applications. Modification of CAMPs via conjugation to auxiliary compounds, including small molecule drugs, is a new approach to developing effective, broad-spectrum antibacterial agents with novel physicochemical properties and versatile antibacterial mechanisms. Here, we've explored design parameters for engineering CAMPs conjugated to small molecules with favorable physicochemical and antibacterial properties by covalently affixing a fluoroquinolone antibiotic, levofloxacin, to the ten-residue CAMP Pep 4. Relative to the unmodified Pep-4, the conjugate was found to demonstrate substantially increased antibacterial potency under high salt concentrations. Historically, it has been observed that most CAMPs lose antibacterial effectiveness in such high ionic strength environments, a fact that has presented a challenge to their development as therapeutics. Physicochemical studies revealed that P4LC was more hydrophobic than Pep-4, while mechanistic findings indicated that the conjugate was more effective at disrupting bacterial membrane integrity. Although the inherent antibacterial effect of the incorporated levofloxacin molecules did not appear to be substantially realized in this conjugate, these findings nevertheless suggest that covalent attachment of small molecule antibiotics with favorable physicochemical properties to CAMPs could be a promising strategy for enhancing peptide performance and overall therapeutic potential. These results have broader applicability to the development of future CAMP-antibiotic conjugates for potential therapeutic applications. PMID- 25279374 TI - Grand challenges for biosafety and biosecurity. PMID- 25279376 TI - Secondary structures involving the poly(A) tail and other 3' sequences are major determinants of mRNA isoform stability in yeast. AB - In Saccharomyces cerevisiae, previous measurements of mRNA stabilities have been determined on a per-gene basis. We and others have recently shown that yeast genes give rise to a highly heterogeneous population of mRNAs thanks to extensive alternative 3' end formation. Typical genes can have fifty or more distinct mRNA isoforms with 3' endpoints differing by as little as one and as many as hundreds of nucleotides. In our recent paper [Geisberg et al. Cell (2014) 156: 812-824] we measured half-lives of individual mRNA isoforms in Saccharomyces cerevisiae by using the anchor away method for the rapid removal of Rpb1, the largest subunit of RNA Polymerase II, from the nucleus, followed by direct RNA sequencing of the cellular mRNA population over time. Combining these two methods allowed us to determine half-lives for more than 20,000 individual mRNA isoforms originating from nearly 5000 yeast genes. We discovered that different 3' mRNA isoforms arising from the same gene can have widely different stabilities, and that such half-life variability across mRNA isoforms from a single gene is highly prevalent in yeast cells. Determining half-lives for many different mRNA isoforms from the same genes allowed us to identify hundreds of RNA sequence elements involved in the stabilization and destabilization of individual isoforms. In many cases, the poly(A) tail is likely to participate in the formation of stability-enhancing secondary structures at mRNA 3' ends. Our results point to an important role for mRNA structure at 3' termini in governing transcript stability, likely by reducing the interaction of the mRNA with the degradation apparatus. PMID- 25279375 TI - Synechocystis: Not Just a Plug-Bug for CO2, but a Green E. coli. AB - Following multiple reports warning for threats posed by raising levels of atmospheric CO2, it is of paramount importance that human society rapidly evolves to be sustainable. Processes relying on photosynthetic microorganisms, converting CO2 and water into compounds of interest, fueled by light, are very pertinent, particularly if not directly competing for arable land. Here, we identify specific research questions that remain to be targeted to exploit the full potential of cyanobacterial cell factories. We argue that this approach will be more likely to be successful if organisms such as Synechocystis are not perceived as mere chassis for CO2 fixation, but rather considered as the "green" E. coli. PMID- 25279377 TI - Inequities in the freedom to lead a flourishing and healthy life: issues for healthy public policy. AB - There are many reasons for the health inequities that we see around the world today. Public policy and the way society organises its affairs affects the economic, social and physical factors that influence the conditions in which people are born, grow, live, work and age - the social determinants of health. Tackling health inequities is a political issue that requires leadership, political courage, progressive public policy, social struggle and action, and a sound evidence base. PMID- 25279378 TI - Fetus, fasting, and festival: the persistent effects of in utero social shocks. AB - The Fetal Origins Hypothesis (FOH), put forward in the epidemiological literature and later flourished in the economics literature, suggests that the time in utero is a critical period for human development. However, much attention has been paid to the consequences of fetal exposures to more extreme natural shocks, while less is known about fetal exposures to milder but more commonly experienced social shocks. Using two examples of under-nutrition due to mild social shocks, i.e. Ramadan fasting and festival overspending, this paper summarizes our current knowledge, especially the contribution from economics, and key challenges in exploring fetal exposures to milder social shocks. I also discuss the salient added value of identifying milder versus more extreme fetal shocks. Finally, implications are drawn on individual decisions and public policy to improve children's well-being before they are born or even before their mothers realize that they are pregnant. PMID- 25279379 TI - Preventing injuries in workers: the role of management practices in decreasing injuries reporting. AB - BACKGROUND: Researchers have found that management safety practices may predict occupational injuries and psychological distresses in the workplace. The present study examined the perception of management safety practices related to injuries reporting and its dimensions among workers of Isfahan Steel Company (ESCO). METHODS: A self-administered anonymous survey was distributed to 189 workers. The survey included demographic factors, management safety perception, injuries reporting and its components (physical symptoms, psychological symptoms, and injuries). The data were analyzed by Multivariate and correlation techniques. RESULTS: The results showed that: 1) there were significant correlations between management safety perception with injuries reporting and its two dimensions namely physical and psychological symptoms; 2) there was no significant relationship between management safety perception and injury; 3) in Multivariate analysis, management safety perception significantly predicted about 26%, 19%, and 28% of the variances of variables of injuries reporting, physical symptoms, and psychological symptoms respectively (P< 0.01). CONCLUSION: Improving employees' perception of management safety practices can be important to prevent the development of job injuries and to promote workers' safety and well-being. PMID- 25279380 TI - Assessing performance of Botswana's public hospital system: the use of the World Health Organization Health System Performance Assessment Framework. AB - BACKGROUND: Very few studies have assessed performance of Botswana public hospitals. We draw from a large research study assessing performance of the Botswana Ministry of Health (MoH) to evaluate the performance of public hospital system using the World Health Organization Health Systems Performance Assessment Framework (WHO HSPAF). We aimed to evaluate performance of Botswana public hospital system; relate findings of the assessment to the potential for improvements in hospital performance; and determine the usefulness of the WHO HSPAF in assessing performance of hospital systems in a developing country. METHODS: This article is based on data collected from document analysis, 54 key informants comprising senior managers and staff of the MoH (N= 40) and senior officers from stakeholder organizations (N= 14), and surveys of 42 hospital managers and 389 health workers. Data from documents and transcripts were analyzed using content and thematic analysis while data analysis for surveys was descriptive determining proportions and percentages. RESULTS: The organizational structure of the Botswana's public hospital system, authority and decision-making are highly centralized. Overall physical access to health services is high. However, challenges in the distribution of facilities and inpatient beds create inequities and inefficiencies. Capacity of the hospitals to deliver services is limited by inadequate resources. There are significant challenges with the quality of care. CONCLUSION: While Botswana invested considerably in building hospitals around the country resulting in high physical access to services, the organization and governance of the hospital system, and inadequate resources limit service delivery. The ongoing efforts to decentralize management of hospitals to district level entities should be expedited. The WHO HSPAF enabled us to conduct a comprehensive assessment of the public hospital system. Though relatively new, this approach proved useful in this study. PMID- 25279381 TI - Potential pros and cons of external healthcare performance evaluation systems: real-life perspectives on Iranian hospital evaluation and accreditation program. AB - BACKGROUND: Performance evaluation is essential to quality improvement in healthcare. The current study has identified the potential pros and cons of external healthcare evaluation programs, utilizing them subsequently to look into the merits of a similar case in a developing country. METHODS: A mixed method study employing both qualitative and quantitative data collection and analysis techniques was adopted to achieve the study end. Subject Matter Experts (SMEs) and professionals were approached for two-stage process of data collection. RESULTS: Potential advantages included greater attractiveness of high accreditation rank healthcare organizations to their customers/purchasers and boosted morale of their personnel. Downsides, as such, comprised the programs' over-reliance on value judgment of surveyors, routinization and incurring undue cost on the organizations. In addition, the improved, standardized care processes as well as the judgmental nature of program survey were associated, as pros and cons, to the program investigated by the professionals. CONCLUSION: Besides rendering a tentative assessment of Iranian hospital evaluation program, the study provides those running external performance evaluations with a lens to scrutinize the virtues of their own evaluation systems through identifying the potential advantages and drawbacks of such programs. Moreover, the approach followed could be utilized for performance assessment of similar evaluation programs. PMID- 25279382 TI - Social determinants of equity in access to healthcare for tuberculosis patients in Republic of Macedonia - results from a case-control study. AB - BACKGROUND: Health is a complex phenomenon and equity as a basic human right an integral part of constitutions in almost all countries in the world. In Republic of Macedonia (RM), Tuberculosis (TB) is clustered regionally and in certain ethnic groups. The main objective of this study was to analyze Social Determinants of Health (SDH) and equity in access to healthcare services for TB patients in RM, aimed at complex analysis of factors that cause inequities. METHODS: Case-control study was conducted in the period March-December, 2013; "cases" are households of TB patients registered in the period July, 2012-June, 2013 and controls are households with no TB patients in their immediate vicinity. World Health Organization (WHO) World Health Survey questionnaire was used to collect data. RESULTS: Analysis of SDH of TB patients shows that patients are mostly males, of lower socio-economic status, are less educated, unemployed and TB is clustered in certain ethnic groups. Analysis of access has identified these determinants as important barriers in access to health services. CONCLUSION: The study has documented the basic SDH of TB patients in RM, as well as barriers in access to healthcare, providing useful baseline information to facilitate determination where to concentrate future efforts. PMID- 25279383 TI - Local stakeholders' perceptions about the introduction of performance-based financing in Benin: a case study in two health districts. AB - BACKGROUND: Performance-Based Financing (PBF) has been advanced as a solution to contribute to improving the performance of health systems in developing countries. This is the case in Benin. This study aims to analyse how two PBF approaches, piloted in Benin, behave during implementation and what effects they produce, through investigating how local stakeholders perceive the introduction of PBF, how they adapt the different approaches during implementation, and the behavioural interactions induced by PBF. METHODS: The research rests on a socio anthropological approach and qualitative methods. The design is a case study in two health districts selected on purpose. The selection of health facilities was also done on purpose, until we reached saturation of information. Information was collected through observation and semi-directive interviews supported by an interview guide. Data was analysed through contents and discourse analysis. RESULTS: The Ministry of Health (MoH) strongly supports PBF, but it is not well integrated with other ongoing reforms and processes. Field actors welcome PBF but still do not have a sense of ownership about it. The two PBF approaches differ notably as for the organs in charge of verification. Performance premiums are granted according to a limited number of quantitative indicators plus an extensive qualitative checklist. PBF matrices and verification missions come in addition to routine monitoring. Local stakeholders accommodate theoretical approaches. Globally, staff is satisfied with PBF and welcomes additional supervision and training. Health providers reckon that PBF forces them to depart from routine, to be more professional and to respect national norms. A major issue is the perceived unfairness in premium distribution. Even if health staff often refer to financial premiums, actually the latter are probably too weak-and 'blurred'-to have a lasting inciting effect. It rather seems that PBF motivates health workers through other elements of its 'package', especially formative supervisions. CONCLUSION: If the global picture is quite positive, several issues could jeopardise the success of PBF. It appears crucial to reduce the perceived unfairness in the system, notably through enhancing all facilities' capacities to ensure they are in line with national norms, as well as to ensure financial and institutional sustainability of the system. PMID- 25279384 TI - A single competency-based education and training and competency-based career framework for the Australian health workforce: discussing the potential value add. AB - This brief discusses the policy implications of a research study commissioned by Health Workforce Australia (HWA) within its health workforce innovation and reform work program. The project explored conceptually complex and operationally problematic concepts related to developing a whole-of-workforce competency-based education and training and competency-based career framework for the Australian health workforce and culminated with the production of three reports published by HWA. The project raised important queries as to whether such a concept is desirable, feasible or implementable - in short what is the potential value add and is it achievable? In setting the scene for discussion, the foundation of the project's genesis and focus of the study are highlighted. A summary of key definitions related to competency-based education and training frameworks and competency-based career frameworks are provided to further readers' commonality of understanding. The nature of the problem to be solved is explored and the potential value-add for the Australian health workforce and its key constituents proposed. The paper concludes by discussing relevance and feasibility issues within Australia's current and changing healthcare context along with the essential steps and implementation realities that would need to be considered and actioned if whole-of-workforce frameworks were to be developed and implemented. PMID- 25279385 TI - Inequities in the freedom to lead a flourishing and healthy life: time for a progressive social protections framework : Comment on "Inequities in the freedom to lead a flourishing and healthy life: issues for healthy public policy". AB - Evidence now shows that the key drivers of poor health are social factors, such as education, employment, housing and urban environments. Variations in these social factors-or the conditions in which we live our lives-have lead to a growth in health inequalities within and between countries. One of the key challenges facing those concerned with health equity is how to effect change across the broad policy areas that impact these social. PMID- 25279387 TI - Topic Modeling with Nonparametric Markov Tree. AB - A new hierarchical tree-based topic model is developed, based on nonparametric Bayesian techniques. The model has two unique attributes: (i) a child node in the tree may have more than one parent, with the goal of eliminating redundant sub topics deep in the tree; and (ii) parsimonious sub-topics are manifested, by removing redundant usage of words at multiple scales. The depth and width of the tree are unbounded within the prior, with a retrospective sampler employed to adaptively infer the appropriate tree size based upon the corpus under study. Excellent quantitative results are manifested on five standard data sets, and the inferred tree structure is also found to be highly interpretable. PMID- 25279386 TI - Evaluation of gene delivery strategies to efficiently overexpress functional HLA G on human bone marrow stromal cells. AB - Mesenchymal stromal cells (MSC) constitutively express low levels of human leukocyte antigen-G (HLA-G), which has been shown to contribute to their immunomodulatory and anti-inflammatory properties. Here, we hypothesized that overexpression of HLA-G on bone marrow-derived MSC would improve their immunomodulatory function, thus increasing their therapeutic potential. Therefore, we investigated which gene transfer system is best suited for delivering this molecule while maintaining its immuno-modulatory effects. We performed a side-by-side comparison between three nonviral plasmid-based platforms (pmax-HLA-G1; MC-HLA-G1; pEP-HLA-G1) and a viral system (Lv-HLA-G1) using gene transfer parameters that yielded similar levels of HLA-G1-expressing MSC. Natural killer (NK) cell-mediated lysis assays and T cell proliferation assays showed that MSC modified with the HLA-G1 expressing viral vector had significantly lower susceptibility to NK-lysis and significantly reduced T cell proliferation when compared to nonmodified cells or MSC modified with plasmid. We also show that, in plasmid-modified MSC, an increase in Toll-like receptor (TLR)9 expression is the mechanism responsible for the abrogation of HLA-G1's immunomodulatory effect. Although MSC can be efficiently modified to overexpress HLA-G1 using viral and nonviral strategies, only viral-based delivery of HLA-G1 is suitable for improvement of MSC's immunomodulatory properties. PMID- 25279388 TI - TEXTING WHILE DRIVING: EVALUATION OF GLANCE DISTRIBUTIONS FOR FREQUENT/INFREQUENT TEXTERS AND KEYPAD/TOUCHPAD TEXTERS. AB - The threat that cell-phones pose to driving has been a well researched topic. There are fewer studies of the threat that texting creates for drivers, but the risks are obvious and the few existing studies confirm this. What is not obvious is whether frequent texters will expose themselves to the same risks as infrequent texters. This is important to know because many texters, especially teens who text frequently, may consider themselves immune to the dangers of texting while driving. As such, a comparison of frequent and infrequent texters was undertaken on a driving simulator. It is also not immediately clear what effects the different types of interfaces have on driving performance while text messaging. The interfaces under evaluation included keypad or "qwerty" phones (e.g., Blackberries) and touchpad phones (iPhone). It was found that the frequent and infrequent texters were equally likely to glance at least once for more than 2s inside the vehicle while sending a text message. It was also found that touchpad texters had a larger number of glances above the 2s threshold than keypad users, though this difference was not significant. The implications of this for future public policy are discussed. PMID- 25279389 TI - Tree-Structured Infinite Sparse Factor Model. AB - A tree-structured multiplicative gamma process (TMGP) is developed, for inferring the depth of a tree-based factor-analysis model. This new model is coupled with the nested Chinese restaurant process, to nonparametrically infer the depth and width (structure) of the tree. In addition to developing the model, theoretical properties of the TMGP are addressed, and a novel MCMC sampler is developed. The structure of the inferred tree is used to learn relationships between high dimensional data, and the model is also applied to compressive sensing and interpolation of incomplete images. PMID- 25279390 TI - Children's Sleep, Sleepiness, and Performance on Cognitive Tasks. AB - While causal connections between sleep deprivation and attention, learning, and memory have been well established in adults, much less research has been done with children. Relations between the amount and quality of sleep and daytime sleepiness have been found for a number of cognitive and academic tasks in several groups of children. These relations have been found for children who have sleep disorders, for children with disorders involving cognitive impairment, and for typically developing children with no known disorders. The research is reviewed here with a focus on the types of cognitive and academic tasks that have been related to insufficient sleep. A series of studies is described that relates sleep parameters to the Woodcock-Johnson(r) III Tests of Cognitive Abilities and other, similar measures. Implications for educators and psychologists who work with children are discussed. PMID- 25279391 TI - Lognormal and Gamma Mixed Negative Binomial Regression. AB - In regression analysis of counts, a lack of simple and efficient algorithms for posterior computation has made Bayesian approaches appear unattractive and thus underdeveloped. We propose a lognormal and gamma mixed negative binomial (NB) regression model for counts, and present efficient closed-form Bayesian inference; unlike conventional Poisson models, the proposed approach has two free parameters to include two different kinds of random effects, and allows the incorporation of prior information, such as sparsity in the regression coefficients. By placing a gamma distribution prior on the NB dispersion parameter r, and connecting a lognormal distribution prior with the logit of the NB probability parameter p, efficient Gibbs sampling and variational Bayes inference are both developed. The closed-form updates are obtained by exploiting conditional conjugacy via both a compound Poisson representation and a Polya Gamma distribution based data augmentation approach. The proposed Bayesian inference can be implemented routinely, while being easily generalizable to more complex settings involving multivariate dependence structures. The algorithms are illustrated using real examples. PMID- 25279392 TI - Learning Statistical Correlation of Prostate Deformations for Fast Registration. AB - This paper presents a novel fast registration method for aligning the planning image onto each treatment image of a patient for adaptive radiation therapy of the prostate cancer. Specifically, an online correspondence interpolation method is presented to learn the statistical correlation of the deformations between prostate boundary and non-boundary regions from a population of training patients, as well as from the online-collected treatment images of the same patient. With this learned statistical correlation, the estimated boundary deformations can be used to rapidly predict regional deformations between prostates in the planning and treatment images. In particular, the population based correlation can be initially used to interpolate the dense correspondences when the number of available treatment images from the current patient is small. With the acquisition of more treatment images from the current patient, the patient-specific information gradually plays a more important role to reflect the prostate shape changes of the current patient during the treatment. Eventually, only the patient-specific correlation is used to guide the regional correspondence prediction, once a sufficient number of treatment images have been acquired and segmented from the current patient. Experimental results show that the proposed method can achieve much faster registration speed yet with comparable registration accuracy compared with the thin plate spline (TPS) based interpolation approach. PMID- 25279393 TI - Survival of porcelain laminate veneers with different degrees of dentin exposure: 2-year clinical results. AB - PURPOSE: To evaluate the clinical performance of porcelain laminate veneers (PLVs) after 2 years. MATERIALS AND METHODS: Twenty-eight patients were treated with 125 PLVs. The experimental variables were preparation design (incisal overlap [IO] and incisal bevel [IB]) and adhesion surface (enamel [E], enamel with minimal dentin exposure [MDE], and enamel with severe dentin exposure (SDE)]. Marginal adaptation, marginal discoloration, secondary caries, postoperative sensitivity, and patient satisfaction were assessed according to the modified United States Public Health Service criteria. Each restoration was examined for fractures and debonding. In addition, gingival tissue health by gingival plaque, bleeding, and recession was recorded. An experienced clinician evaluated the restorations at baseline and after 6, 12, and 24 months, and survival rates evaluating relative and absolute failures were calculated (p = 0.05). RESULTS: Eleven (8.8%) veneers failed, and the overall cumulative survival rate was 91.2% after 2 years of followup. IB and IO preparation designs exhibited survival rates of 94% and 85.7%, respectively, but this difference was not statistically significant (p > 0.05). PLVs bonded to SDE were more likely to fail than those bonded to E and MDE (p < 0.05). There was no significant difference between the failure rate of PLVs bonded to E and those bonded to MDE (p > 0.05). CONCLUSIONS: PLVs have high survival rates when bonded to enamel only, as well as to enamel with minimal dentin exposure. However, extensive dentin exposure should be avoided during the preparation. PMID- 25279394 TI - Association of periodontal pathogenesis and cardiovascular diseases: a literature review. AB - PURPOSE: To present a short review of recent literature available on the association of periodontal and cardiovascular diseases (CVD) and the role of peridontal disease as a risk factor to exacerbate CVD. MATERIALS AND METHODS: A thorough search of articles was carried out on the databases PUBMED and MEDLINE on the association of periodontal and cardiovascular diseases (CVD). The selected literature included review articles, observational and case-control studies as well as randomised control trials. While selecting articles, priority was placed on papers published within the last 12 years. A brief description of periodontal diseases, atherosclerosis, underlying pathophysiology and oral bacteria has been included. RESULTS AND CONCLUSION: There is growing evidence of the association of periodontal diseases and CVD, as reviewed by the epidemiological studies. The in vitro studies also highlight a potential link between oral bacteria and atherosclerosis. Thus, there is urgent need for proper case controls and efficient interventional trials to analyse how such interventions can produce a positive outcome on cardiovascular diseases. Some recent interventional trials have shown that periodontal treatment can decrease markers of systemic inflammation. The relationship between periodontal diseases and CVD deserves further research because of its consequences for public health. PMID- 25279395 TI - Dental plaque, gingival inflammation and tooth -discolouration with different commercial -formulations of 0.2% chlorhexidine rinse: a double-blind randomised controlled clinical trial. AB - PURPOSE: To investigate the efficacy of various formulations of chlorhexidine 0.2% (CHX) in terms of plaque and gingival bleeding control compared to each other and to saline rinse (CTRL) over a 35-day rinsing period. MATERIALS AND METHODS: Seventy subjects were randomly allocated to one of 4 groups rinsing twice daily for 35 days. The different groups used CHX 0.2% rinse with alcohol (CHX1) and without alcohol (CHX2), with an antidiscolouration system (CHX3) or saline rinse (CTRL). Clinical examinations to evaluate full-mouth plaque scores (FMPS) and periodontal parameters were performed at baseline, 7, 21 and 35 days. Tooth discolouration (TD) was measured at each time point using digital photographs and spectrophotometric analysis. RESULTS: At 35 days, CTRL showed the highest levels of plaque. The mean changes in FMPS from baseline were 69.8% +/- 6.8 for CHX1, 57.5% +/- 9.8 for CHX2, 43.7% +/- 9.8 for CHX3 and 25.8% +/- 7.7 for CTRL. Statistically significant differences were demonstrated between CHX1 and CHX3 (p = 0.02), CHX2 vs CHX3 (p <= 0.05) and CHX1/CHX2 vs CHX3 (p < 0.05). In contrast, CHX3 appeared more effective in reducing inflammatory indexes. TD increased over time in 60% to 70% of participants, although lighter staining was found in the CHX3 group. Greater FMPS reduction was observed in participants with staining vs without staining (26.0% +/- 12.3, p = 0.04). CONCLUSION: Conventional CHX appeared more effective in terms of plaque reduction. Interestingly, the newest formulation showed a higher control of gingival inflammation. Staining was associated with lower plaque levels. PMID- 25279396 TI - Connective tissue graft combined with autogenous bone graft in the treatment of peri-implant soft and hard tissue defect. AB - The use of dental implants to improve functional and esthetic demands of dentition has increased significantly over the past two decades. Soft and hard tissue management is one of the factors contributing to improved esthetic results. This report describes the correction of an esthetic problem in a single implant combined connective tissue graft and autogenous bone graft. Four months after the surgical procedure, it could be observed that the combination of connective tissue graft and autogenous bone graft resulted in the augmentation of hard and soft tissue in the peri-implant area with favorable esthetic outcomes. PMID- 25279397 TI - Antibiotic prophylaxis for third molar extraction in healthy patients: Current scientific evidence. AB - Third molar extraction is one of the most frequently performed procedures in the dental clinic, and it is associated with innumerable trans- and postoperative complications, such as pain, trismus, edema, localized alveolar osteitis, and surgical site infection. Some authors advocate the use of local or systemic antibiotics to reduce the incidence of these postoperative complications. However, several studies have revealed an insignificant gain after using antibiotics. Despite the risks of allergic reactions, toxicity, and the development of resistant microorganisms, about 50% of dentists routinely prescribe the use of prophylactic antibiotics for this purpose. The goal of this paper is to evaluate the scientific evidence that justifies antibiotic prescription to healthy patients undergoing third molar extraction. PMID- 25279398 TI - Assessment of the soft tissue volumetric changes following acellular dermal matrix grafts with cone beam computerized tomography. AB - OBJECTIVE: The aim of this study was to use cone beam computerized tomography (CBCT), which consistently allowed the determination of the dimensions of the soft tissue, to evaluate acellular dermal matrix grafts (ADMG) used to increase gingival soft tissue thickness (GSTT). METHOD AND MATERIALS: In total, 90 gingival defects were included in the study. Surgical procedures were performed to augment the gingival tissue with ADMG. While GSTT measurements were assessed at baseline and 6, 12, and 18 months post-surgery, ADMG measurements were performed with CBCT at 6, 12, and 18 months post-surgery. RESULTS: All parameters showed statistically significant differences between time intervals. In the ADMG treated sites, the baseline GSTT was 1.00 +/- 0.37 mm and the final thickness was 1.66 +/- 0.34 mm. The 6-month measurement of ADMG was 0.79 +/- 0.08 mm, and the final measurement was 0.11 +/- 0.09 mm. CONCLUSION: High-quality images of the GSTT and ADMG can be consistently obtained with CBCT. The present findings indicate that soft tissue augmentation can be achieved in gingival defects with the use of ADMG. PMID- 25279399 TI - Tailoring recognition clefts from non-specific recognition matrices in mixed molecular arrays. AB - Multi-component organic interfaces with molecular-level mixing were prepared by integrating benzoic acid appended thiophene amphiphile [4-(6-(thiophene-3 carbonyloxy)hexyloxy)benzoic acid] (T6BA) and (+/-)-alpha-lipoic acid onto the Au surface. On a flat surface with infinite radii of curvature, T6BA and (+/-)-alpha lipoic acid, endowed with chemically distinct end-groups, provided sufficient length mismatch to gain conformational entropy leading to stripe-like patterns when the immiscible ligands co-adsorbed. Good quality multi-component organic interfaces and molecular islands could be fabricated via composition variation of the participating ligands. Host-guest chemistry between benzoic acids and beta cyclodextrin was used to confirm the molecular-level mixing. T6BA and (+/-)-alpha lipoic acid, each being a non-specific recognition matrix for dopamine, could thus be organized into mixed molecular arrays having well defined cavities for guest inclusion. This mixed molecular array behaved as a 'recognition matrix' for dopamine (DA, 15 nm) in the presence of ascorbic acid (AA). The surface patterns described here on a flat surface should in principle be applicable to other geometrical structures like spheres and cylinders. Further, charge transfer through the T6BA self-assembled monolayers depended on the anion type present in the supporting electrolyte, monitored through cyclic voltammetry. PMID- 25279401 TI - Response to Pasquale Santangeli, MD, Luigi Di Biase, MD, PhD, Andrea Natale, MD. PMID- 25279400 TI - Nanocoaxes for optical and electronic devices. AB - The evolution of micro/nanoelectronics technology, including the shrinking of devices and integrated circuit components, has included the miniaturization of linear and coaxial structures to micro/nanoscale dimensions. This reduction in the size of coaxial structures may offer advantages to existing technologies and benefit the exploration and development of new technologies. The reduction in the size of coaxial structures has been realized with various permutations between metals, semiconductors and dielectrics for the core, shield, and annulus. This review will focus on fabrication schemes of arrays of metal - nonmetal - metal nanocoax structures using non-template and template methods, followed by possible applications. The performance and scientific advantages associated with nanocoax based optical devices including waveguides, negative refractive index materials, light emitting diodes, and photovoltaics are presented. In addition, benefits and challenges that accrue from the application of novel nanocoax structures in energy storage, electronic and sensing devices are summarized. PMID- 25279402 TI - Response to Colleen M. Hanley, MD, Douglas Esberg, MD, FACC, FHRS, Peter R. Kowey, MD, FAHA, FHRS. PMID- 25279403 TI - A journey from CABG to drug-eluting balloon. AB - A middle aged male underwent series of percutaneous coronary intervention (PCI) of left main stenosis for Canadian cardiovascular society (CCS) IV angina. He developed recurrent severe proliferative in-stent restenosis which was treated with different available options including drug-eluting stents and finally with drug-eluting balloons. During his treatment, challenges of PCI including left main chronic total occlusion PCI, complications like coronary perforation were encountered and treated successfully. PMID- 25279405 TI - Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling. AB - AIMS: The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. METHODS: Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. RESULTS: Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h-1 [95% CI 12.6, 18.0 l h-1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of -1.2% (95% CI 3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. CONCLUSION: A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation. PMID- 25279407 TI - Wojciech A. Rowicski, M.D., Ph.D. (1935Y2014): humanist, transplant surgeon and scientist. PMID- 25279406 TI - Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. AB - AIMS: The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. METHODS: We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. RESULTS: The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). CONCLUSIONS: MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis. PMID- 25279408 TI - Assessing the harms of polypharmacy requires careful interpretation and consistent definitions. PMID- 25279409 TI - Response to: assessing the harms of polypharmacy requires careful interpretation and consistent definitions. PMID- 25279404 TI - Oxidative stress, redox signalling and endothelial dysfunction in ageing related neurodegenerative diseases: a role of NADPH oxidase 2. AB - Chronic oxidative stress and oxidative damage of the cerebral microvasculature and brain cells has become one of the most convincing theories in neurodegenerative pathology. Controlled oxidative metabolism and redox signalling in the central nervous system are crucial for maintaining brain function; however, excessive production of reactive oxygen species and enhanced redox signalling damage neurons. While several enzymes and metabolic processes can generate intracellular reactive oxygen species in the brain, recently an O2- generating enzyme, NADPH oxidase 2 (Nox2), has emerged as a major source of oxidative stress in ageing-related vascular endothelial dysfunction and neurodegenerative diseases. The currently available inhibitors of Nox2 are not specific, and general antioxidant therapy is not effective in the clinic; therefore, insights into the mechanism of Nox2 activation and its signalling pathways are needed for the discovery of novel drug targets to prevent or treat these neurodegenerative diseases. This review summarizes the recent developments in understanding the mechanisms of Nox2 activation and redox-sensitive signalling pathways and biomarkers involved in the pathophysiology of the most common neurodegenerative diseases, such as ageing-related mild cognitive impairment, Alzheimer's disease and Parkinson's disease. PMID- 25279410 TI - Knowledge is only rumour, until it is in the muscle. PMID- 25279411 TI - Author's reply: To PMID 25003681. PMID- 25279412 TI - Don't stop yearly appointments. PMID- 25279413 TI - 'Let food be thy medicine, and medicine be thy food': Hippocrates revisited. PMID- 25279414 TI - A short historical review of SCNP with special reference to the UKU. AB - OBJECTIVE: To give a review of the history of SCNP since the first meeting in 1960 with specific focus on UKU. METHODS: Consulting the appropriate minutes from the meetings. RESULTS: One of the major goals of the SCNP was the standardization of clinical trials with psychotropic drugs. In 1969, the SCNP established a Committee for Clinical Investigations (UKU) with the representation of clinical investigators and the drug industry; moreover, during the 1970s and '80s, the UKU initiated clinical trials and contributed to the methodology of clinical investigations with psychotropic drugs. With the decrease in governmental funding and increasing influence of the US Food and Drug Administration on the methodology of clinical investigations around the world in the 1990s, the UKU was dissolved. The changes had a detrimental effect on the developments on the methodology of clinical investigations, and the lack of clinical feedback led to an impasse in psychotropic drug development with some pharmaceutical companies abandoning research in the central nervous system area. CONCLUSION: It is suggested that a revival of UKU to provide a platform for dialogue among government, industry, and academia could help break the impasse. PMID- 25279415 TI - Memory impairment in chronic pain patients and the related neuropsychological mechanisms: a review. AB - OBJECTIVE: This study provides a comprehensive review of the literature on memory impairment and the potential effective factors in patients with chronic pain. METHODS: A literature search of databases PubMed, EMBASE, SpringerLink, and PsycINFO until September 2012 was conducted using the keywords 'memory' and 'chronic pain'. The study emphasises on publications over the past 20 years. RESULTS: Memory impairment in chronic pain patients is substantial, but the aspects of memory (e.g. working memory, long-term memory, and autobiographical memory) in chronic pain patients and the potentially related factors (e.g. age, level of education, pain conditions, emotion, neural network, and use of analgesics) are modest. Memory impairment is interpreted with the attention narrowing hypothesis and the capacity-reduction hypothesis. CONCLUSIONS: The currently available data and theory have explained memory impairment in chronic pain patients, but many controversies remain. Future research should focus on the subclinical characteristics of chronic pain, enlarging the sample size, and emphasise on the experimental intervention method and the cognitive neuroscience method. PMID- 25279416 TI - Treatment-resistant depression: a challenge for future research. PMID- 25279417 TI - Mental health care in China: review on the delivery and policy issues in 1949 2009 and the outlook for the next decade. AB - Using qualitative and quantitative methodologies, delivery models and policies on mental health care in China during the period of 1949-2009 were reviewed and characteristics of different stages of the mental health-care development were also analysed in this period. Recent studies demonstrate that mental health-care services in China are being transformed from large mental hospital-based pattern to community-based pattern in the past six decades. Combining the international experiences with current strategies and situations of Chinese health care, we provided the outlook for mental health-care services in the next decade in China. In addition, we proposed relevant policy recommendations that mainly focus on the equity and availability of mental health-care services with the purpose of promoting community-based health services. PMID- 25279418 TI - Building a better community medic. An improved curriculum is helping the new CP profession grow up. PMID- 25279419 TI - The role of data in care. A roundup of what's new and next from the annual ZOLL user summit. PMID- 25279420 TI - Electrical injury and burn care: a review of best practices. PMID- 25279421 TI - Activation of nitrogen Bronsted acids: synthesis and reactivity of a new class of nitrogen acid complexes. AB - The nitrogen acids RC(O)NHNO2, N-nitroamide, R = CH3 (1), C2H5 (2) and N nitrocarbamate, R'OC(O)NHNO2, R' = CH3 (3), C2H5 (4) are a class of primary N nitrocarboxamide compounds that oxidatively add to trans-Ir((I))(Cl)(N2)(PPh3)2 to give six-coordinate Ir((III))(eta(2)-(NO2)-nitrogen acid)(H)(Cl)(PPh3)2 complexes 5-8. Unexpected fluxional behavior of the complexes in solution is observed by (1)H NMR spectroscopy. Reaction intermediates of the oxidative addition reactions were also observed and monitored using (31)P and (1)H NMR and solution IR spectroscopies. Complex 5 reacts with methyl triflate in CH3CN to generate bis(acetonitrile) complex (9) from a net loss of the nitrogen acid anion. P(CH3)2Ph reacts with 5 to give phosphine-substituted and P(CH3)2Ph addition isomers (10). Reactivity studies of 5 with CO gave metastable CO adduct isomer 11, which loses CO on prolonged standing in solution. PMID- 25279422 TI - Evidence-based alternatives for autogenous grafts around teeth: outcomes, attachment, and stability. AB - Although the use of autogenous harvested tissues has proven to be the gold standard for soft tissue augmentation procedures involving root coverage or generation of keratinized tissue, harvest site morbidity and limited supply have prompted clinicians to seek graft alternatives. Using a hierarchy of evidence, the author reviews both clinical and patient-reported results for harvest graft substitutes and, considering his own research experience, reviews autogenous graft substitute outcomes, attachment, and stability over time. Overall, when the goal is keratinized-tissue generation, living cellular constructs and xenogeneic collagen matrices have provided acceptable clinical results, but with better esthetics and patient preference than autogenous free gingival grafts. For root coverage therapy, enamel matrix derivatives, platelet-derived growth factors, and xenogeneic collagen matrices have provided acceptable results with equivalent esthetics to autogenous connective tissue grafts, while also being preferred by patients. Longterm results for enamel matrix derivatives, platelet-derived growth factors, and xenogeneic collagen matrices indicate root coverage can be maintained over time. In the author's hands, xenogeneic collagen matrices have been the only harvest graft alternatives that can be used either covered or uncovered by soft tissue. PMID- 25279423 TI - Examining prescribed rest as treatment for adolescents who are slow to recover from concussion. AB - OBJECTIVE: Rest is a widely recommended treatment for concussion, but its utility is unclear following the acute stage of recovery. This study examined the effects of 1-week of prescribed rest in concussed adolescent athletes. METHOD: Participants were 13 adolescent athletes with persistent symptoms following a concussion. More than three-quarters (77%) had self-reported ADHD, learning disability or two prior concussions. All completed ImPACT at another facility, but none completed a period of comprehensive rest prior to examination at a specialty practice. Three time points of test data were compared, to control for possible spontaneous recovery: Test 1 (external facility), Test 2 (before prescribed rest) and Test 3 (following prescribed rest). RESULTS: Repeated measures ANOVAs revealed a significant effect of prescribed rest on all ImPACT composite scores and the total symptom score. Post-hoc analyses revealed no significant differences between Time 1 and Time 2, whereas significant differences were present after prescribed rest. Following prescribed rest, having two or more reliably improved cognitive test scores or having improved symptoms was present in eight of the 13 patients (61.5%). CONCLUSIONS: A substantial percentage of adolescents with persistent symptoms following concussion showed improvement in symptoms and cognitive functioning following education, reassurance and 1-week of prescribed rest. PMID- 25279424 TI - TGF-beta & BMP receptors endoglin and ALK1: overview of their functional role and status as antiangiogenic targets. AB - The formation of new blood vessels from existing vasculature, angiogenesis, is facilitated through a host of different signaling processes. Members of the TGF beta superfamily, TGF-beta1, TGF-beta3, and BMP9, are key propagators of both inhibition and initiation of angiogenesis. HHT, characterized by AVM and capillary bed defects, is caused by germline mutations in the ENG and ACVRL1/ALK1 genes, respectively. Clinical symptoms include epistaxis and GI hemorrhage. The membranous receptors endoglin and ALK1 activate proliferation and migration of endothelial cells during the angiogenic process via the downstream intracellular SMAD signaling pathway. Endothelial cell senescence or activation is dependent on the type of cytokine, ligand concentration, cell-cell interaction, and a multitude of other signaling molecules. Endoglin and ALK1 receptor levels in tumor vasculature correlate inversely with prognosis in humans, whereas in mice, endoglin deficiency decelerates tumor progression. Therefore, endoglin and ALK1 have been identified as potential therapeutic targets for antibody treatment in various cancers. Early phase clinical trials in humans are currently underway to evaluate the efficacy and safety of biological therapy targeting endoglin/ALK1 mediated cells signaling. PMID- 25279427 TI - The dynamic changes of capillary permeability and upregulation of VEGF in rats following radiation-induced brain injury. AB - OBJECTIVE: To explore the dynamic changes of capillary permeability and the expression of VEGF in cerebral cortex after RIBI. METHODS: Male SD rats were randomly divided into the RIBI group and control group, and the RIBI group was randomly subdivided into five groups for analysis on day 1, 3, 7, 14, and 28, respectively. We established an RIBI model, and then evaluated BBB permeability by EB. We also measured the expression of VEGF with IHC stain and western blot. RESULTS: EB extravasation in injured cortex of RIBI group was increased at five time points compared with the control group. The western blot results and IHC revealed that the levels of VEGF expression in the RIBI groups was significantly increased at day 1 compared with the control group, then rose to a maximum at day 7, and subsequently the levels of expression recovered from day 14 to 28. CONCLUSIONS: The increases in both BBB permeability and VEGF expression in the brain cortex of RIBI groups at same time period confirmed the possibility of brain injury following irradiation of 6 Gy. PMID- 25279426 TI - Three-dimensional reconstruction of neovasculature in solid tumors and basement membrane matrix using ex vivo X-ray microcomputed tomography. AB - OBJECTIVE: To create accurate, high-resolution 3D reconstructions of neovasculature structures in xenografted tumors and Matrigel plugs for quantitative analyses in angiogenesis studies in animal models. METHODS: The competent neovasculature within xenografted solid tumors or Matrigel plugs in mice was perfused with Microfil, a radioopaque, hydrophilic polymerizing contrast agent, by systemic perfusion of the blood circulation via the heart. The perfused tumors and plugs were resected and scanned by X-ray micro-CT to generate stacks of 2D images showing the radioopaque material. A nonbiased, precise postprocessing scheme was employed to eliminate background X-ray absorbance from the extravascular tissue. The revised binary image stacks were compiled to reveal the Microfil-casted neovasculature as 3D reconstructions. Vascular structural parameters were calculated from the refined 3D reconstructions using the scanner software. RESULTS: Clarified 3D reconstructions were sufficiently precise to allow measurements of vascular architecture to a diametric limit of resolution of 3 MUm in tumors and plugs. CONCLUSIONS: Ex vivo micro-CT can be used for 3D reconstruction and quantitative analysis of neovasculature including microcirculation in solid tumors and Matrigel plugs. This method can be generally applied for reconstructing and measuring vascular structures in three dimensions. PMID- 25279428 TI - Advanced glycation end products activate the miRNA/RhoA/ROCK2 pathway in endothelial cells. AB - OBJECTIVE: AGEs induce endothelial cell dysfunction in HUVECs, resulting in ROS production and triggering apoptosis. This study sought to identify miRNAs involved in AGE-induced endothelial cell injury. METHODS: Microarray analysis to identify miRNAs altered with AGE stimulation was undertaken, and results were confirmed using real-time quantitative polymerase chain reaction. The interaction of miRNAs with the RhoA and ROCK2 genes was confirmed using luciferase assays, and their effects on expression were determined using Western blot analysis. The effects of AGEs and miRNAs on endothelial cell permeability were assessed. RESULTS: AGEs induced ROS production and apoptosis of HUVECs (p < 0.05). AGE induced miR-200b and miR-200c downregulation led to increased expression of their target genes, RhoA and ROCK, respectively. AGE-induced endothelial cell permeability and F-actin expression were significantly reduced with both miR-200b and miR-200c mimics (p < 0.05). Furthermore, AGE-induced stress fiber formation was reduced in cells treated with miR-200b mimics. CONCLUSION: miR-200b and miR 200c are suppressed in AGE-induced endothelial cell injury, resulting in unregulated RhoA/ROCK2 signaling. Further studies are necessary to evaluate the therapeutic value of targeting miRNAs or their target genes for treatment of vascular diseases. PMID- 25279429 TI - I2-mediated oxidative C-N bond formation for metal-free one-pot synthesis of di-, tri-, and tetrasubstituted pyrazoles from alpha,beta-unsaturated aldehydes/ketones and hydrazines. AB - An I2-mediated metal-free oxidative C-N bond formation methodology has been established for the regioselective pyrazole synthesis. This practical and eco friendly one-pot protocol requires no isolation of the less stable intermediates hydrazones and provides a facile access to a variety of di-, tri-, and tetrasubstituted (aryl, alkyl, and/or vinyl) pyrazoles from readily available alpha,beta-unsaturated aldehydes/ketones and hydrazine salts. PMID- 25279425 TI - In vivo microscopy reveals extensive embedding of capillaries within the sarcolemma of skeletal muscle fibers. AB - OBJECTIVE: To provide insight into mitochondrial function in vivo, we evaluated the 3D spatial relationship between capillaries, mitochondria, and muscle fibers in live mice. METHODS: 3D volumes of in vivo murine TA muscles were imaged by MPM. Muscle fiber type, mitochondrial distribution, number of capillaries, and capillary-to-fiber contact were assessed. The role of Mb-facilitated diffusion was examined in Mb KO mice. Distribution of GLUT4 was also evaluated in the context of the capillary and mitochondrial network. RESULTS: MPM revealed that 43.6 +/- 3.3% of oxidative fiber capillaries had >=50% of their circumference embedded in a groove in the sarcolemma, in vivo. Embedded capillaries were tightly associated with dense mitochondrial populations lateral to capillary grooves and nearly absent below the groove. Mitochondrial distribution, number of embedded capillaries, and capillary-to-fiber contact were proportional to fiber oxidative capacity and unaffected by Mb KO. GLUT4 did not preferentially localize to embedded capillaries. CONCLUSIONS: Embedding capillaries in the sarcolemma may provide a regulatory mechanism to optimize delivery of oxygen to heterogeneous groups of muscle fibers. We hypothesize that mitochondria locate to PV regions due to myofibril voids created by embedded capillaries, not to enhance the delivery of oxygen to the mitochondria. PMID- 25279430 TI - Synthetic tunable amplifying buffer circuit in E. coli. AB - While predictable design of a genetic circuit's output is a major goal of synthetic biology, it remains a significant challenge because DNA binding sites in the cell affect the concentration of available transcription factors (TF). To mitigate this problem, we propose to use a TF that results from the (reversible) phosphorylation of protein substrate as a circuit's output. We demonstrate that by comparatively increasing the amounts of substrate and phosphatase, the TF concentration becomes robust to the presence of DNA binding sites and can be kept at a desired value. The circuit's input/output gain can, in turn, be tuned by changing the relative amounts of the substrate and phosphatase, realizing an amplifying buffer circuit with tunable gain. In our experiments in E. coli, we employ phospho-NRI as the output TF, phosphorylated by the NRII kinase, and dephosphorylated by the NRII phosphatase. Amplifying buffer circuits such as ours could be used to insulate a circuit's output from the context, bringing synthetic biology one step closer to modular design. PMID- 25279432 TI - Use of antidepressant medication and suicidal ideation-the Northern Finland Birth Cohort 1966. AB - OBJECTIVE: The aim was to study the association between use of antidepressant medication and suicidal ideation in different diagnostic groups in a large population-based cohort. METHODS: Information on prescribed drugs within the Northern Finland Birth Cohort 1966 was collected at the age of 31 years with postal questionnaire (N= 8218). The presence of suicidal ideation was assessed via the Hopkins Symptom Checklist-25 questionnaire. We studied associations between suicidal ideation and antidepressant medication in various diagnostic and symptom groups, and it adjusted for symptoms of depression and anxiety. RESULTS: Suicidal ideation was associated with the use of antidepressant medication in all diagnostic groups, but the association disappeared with adjustment for other symptoms of depression and anxiety. Subjects who reported insomnia and used antidepressants had suicidal ideation more commonly than did subjects who were not using antidepressants even when other symptoms were adjusted for (p = 0.02). There were no statistically significant differences between antidepressant groups or doses. CONCLUSION: In a large unselected cohort, antidepressant medication was not associated with increased suicidal ideation when other symptoms of depression and anxiety were taken into account. The assessment of insomnia might be useful for identifying individuals liable to have increased suicidal ideation while on antidepressant medication. PMID- 25279433 TI - Indication-specific pricing for cancer drugs. PMID- 25279431 TI - Synthetic polymers active against Clostridium difficile vegetative cell growth and spore outgrowth. AB - Nylon-3 polymers (poly-beta-peptides) have been investigated as synthetic mimics of host-defense peptides in recent years. These polymers are attractive because they are much easier to synthesize than are the peptides themselves, and the polymers resist proteolysis. Here we describe in vitro analysis of selected nylon 3 copolymers against Clostridium difficile, an important nosocomial pathogen that causes highly infectious diarrheal disease. The best polymers match the human host-defense peptide LL-37 in blocking vegetative cell growth and inhibiting spore outgrowth. The polymers and LL-37 were effective against both the epidemic 027 ribotype and the 012 ribotype. In contrast, neither vancomycin nor nisin inhibited outgrowth for the 012 ribotype. The best polymer was less hemolytic than LL-37. Overall, these findings suggest that nylon-3 copolymers may be useful for combatting C. difficle. PMID- 25279434 TI - Question format shifts bias away from the emphasised response in tests of recognition memory. AB - The question asked to interrogate memory has potential to influence response bias at retrieval, yet has not been systematically investigated. According to framing effects in the field of eyewitness testimony, retrieval cueing effects in cognitive psychology and the acquiescence bias in questionnaire responding, the question should establish a confirmatory bias. Conversely, according to findings from the rewarded decision-making literature involving mixed incentives, the question should establish a disconfirmatory bias. Across three experiments (ns=90 [online], 29 [laboratory] and 29 [laboratory]) we demonstrate a disconfirmatory bias - "old?" decreased old responding. This bias is underpinned by a goal-driven mechanism wherein participants seek to maximise emphasised response accuracy at the expense of frequency. Moreover, we demonstrate that disconfirmatory biases can be generated without explicit reference to the goal state. We conclude that subtle aspects of the test environment influence retrieval to a greater extent than has been previously considered. PMID- 25279435 TI - Muscle changes detected with diffusion-tensor imaging after long-distance running. AB - PURPOSE: To develop a protocol for diffusion-tensor imaging (DTI) of the complete upper legs and to demonstrate feasibility of detection of subclinical sports related muscle changes in athletes after strenuous exercise, which remain undetected by using conventional T2-weighted magnetic resonance (MR) imaging with fat suppression. MATERIALS AND METHODS: The research was approved by the institutional ethics committee review board, and the volunteers provided written consent before the study. Five male amateur long-distance runners underwent an MR examination (DTI, T1-weighted MR imaging, and T2-weighted MR imaging with fat suppression) of both upper legs 1 week before, 2 days after, and 3 weeks after they participated in a marathon. The tensor eigenvalues (lambda1, lambda2, and lambda3), the mean diffusivity, and the fractional anisotropy (FA) were derived from the DTI data. Data per muscle from the three time-points were compared by using a two-way mixed-design analysis of variance with a Bonferroni posthoc test. RESULTS: The DTI protocol allowed imaging of both complete upper legs with adequate signal-to-noise ratio and within a 20-minute imaging time. After the marathon, T2-weighted MR imaging revealed grade 1 muscle strains in nine of the 180 investigated muscles. The three eigenvalues, mean diffusivity, and FA were significantly increased (P < .05) in the biceps femoris muscle 2 days after running. Mean diffusivity and eigenvalues lambda1 and lambda2 were significantly (P < .05) increased in the semitendinosus and gracilis muscles 2 days after the marathon. CONCLUSION: A feasible method for DTI measurements of the upper legs was developed that fully included frequently injured muscles, such as hamstrings, in one single imaging session. This study also revealed changes in DTI parameters that over time were not revealed by qualitative T2-weighted MR imaging with fat suppression. PMID- 25279437 TI - Young children's developing sensitivity to discourse continuity as a cue for inferring reference. AB - Children encounter many opportunities for word learning where a novel word (e.g., "chinchilla") coincides in time with the presence of its referent (e.g., a parent pointing at a fuzzy rodent). These two ingredients are not always paired simultaneously, but they sometimes still occur in succession within a discourse. We investigated children's ability to apply their knowledge of discourse structure to infer the referent of a novel word in the absence of social cues such as pointing and eye gaze. In Experiment 1A, we introduced 2- to 6-year-old children and adults to two novel toys and described each using two sentences. We embedded the introduction of a novel label ("Have you seen a toma before?") between the two sentences about one of the toys, with no cues implying the label's referent other than its position in the discourse. Children older than 3 years and adults were more likely to attribute the label to the toy whose descriptions surrounded the naming event. In Experiment 1B, we tested whether participants made their selections based on temporal associations-choosing the toy that was described closest in time to the naming event-rather than inferences about discourse. Participants heard the novel label introduced after the two descriptions of a toy rather than embedded between them. Both children and adults responded close to chance in this experiment, indicating that temporal proximity alone did not guide their selections. Together, these results suggest that children can use discourse position to make inferences about reference in word learning situations. PMID- 25279436 TI - Can structural joint damage measured with MR imaging be used to predict knee replacement in the following year? AB - PURPOSE: To assess whether magnetic resonance (MR) imaging-based cross-sectional measures of structural joint damage can be used to predict knee replacement during the following year. MATERIALS AND METHODS: Participants were drawn from the Osteoarthritis Initiative, a longitudinal observational study that includes 4796 participants who have knee osteoarthritis or are at risk. The HIPAA compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all participants. During the 5 years of follow-up, 199 knees underwent knee replacement and were matched with 199 control knees that did not undergo knee replacement. Knees were matched according to radiographic disease stage and patient sex and age. All knees that underwent knee replacement and had MR images available from the year before surgery were included. MR images were assessed for cartilage damage, bone marrow lesions, meniscal damage, meniscal extrusion, synovitis, and effusion prior to reported knee replacement. Conditional logistic regression was applied to assess the risk of knee replacement. Analyses were performed on a compartmental and knee level. RESULTS: Participants had a mean age +/- standard deviation of 64.2 years +/- 8.4 (range, 47-82 years) and were predominantly women (232 of 398 participants, 58.3%). Risk for knee replacement was significantly increased for knees that exhibited two or more subregions with severe cartilage loss (odds ratio [OR], 16.5; 95% confidence interval [CI]: 3.96, 68.76), more than two subregions with bone marrow lesions (OR, 4.00; 95% CI: 1.75, 9.16), medial meniscal maceration (OR, 1.84; 95% CI: 1.13, 2.99), effusion (OR, 4.75; 95% CI: 2.55, 8.85), or synovitis (OR, 2.17; 95% CI: 1.33, 3.56), but not extrusion (OR, 1.00; 95% CI: 0.60,1.67), when compared with knees that did not exhibit these features as the reference standard. CONCLUSION: Apart from meniscal extrusion, all features of tissue abnormalities at MR imaging were related to clinical prognosis and could be used to predict knee replacement in the following year. PMID- 25279438 TI - Reproducibility of LCA models of crude oil production. AB - Scientific models are ideally reproducible, with results that converge despite varying methods. In practice, divergence between models often remains due to varied assumptions, incompleteness, or simply because of avoidable flaws. We examine LCA greenhouse gas (GHG) emissions models to test the reproducibility of their estimates for well-to-refinery inlet gate (WTR) GHG emissions. We use the Oil Production Greenhouse gas Emissions Estimator (OPGEE), an open source engineering-based life cycle assessment (LCA) model, as the reference model for this analysis. We study seven previous studies based on six models. We examine the reproducibility of prior results by successive experiments that align model assumptions and boundaries. The root-mean-square error (RMSE) between results varies between ~1 and 8 g CO2 eq/MJ LHV when model inputs are not aligned. After model alignment, RMSE generally decreases only slightly. The proprietary nature of some of the models hinders explanations for divergence between the results. Because verification of the results of LCA GHG emissions is often not possible by direct measurement, we recommend the development of open source models for use in energy policy. Such practice will lead to iterative scientific review, improvement of models, and more reliable understanding of emissions. PMID- 25279439 TI - Fluorescence-based ion-sensing with colloidal particles. AB - Particle-based fluorescence sensors for the quantification of specific ions can be made by coupling ion-sensitive fluorophores to carrier particles, or by using intrinsically fluorescent particles whose fluorescence properties depend on the concentration of the ions. Despite the advantages of such particle-based sensors for the quantitative detection of ions, such as the possibility to tune the surface chemistry and thus entry portal of the sensor particles to cells, they have also some associated problems. Problems involve for example crosstalk of the ion-sensitive fluorescence read-out with pH, or spectral overlap of the emission spectra of different fluorescent particles in multiplexing formats. Here the benefits of using particle-based fluorescence sensors, their limitations and strategies to overcome these limitations will be described and exemplified with selected examples. PMID- 25279441 TI - C-Reactive Protein at Discharge, Diabetes Mellitus and >= 1 Hospitalization During Previous Year Predict Early Readmission in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - Recurrent hospitalizations in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients have clinical and economic consequences; particularly those readmitted soon after discharge. The aim of our observational study was to determine predictors of early readmission to hospital (30 days from discharge). Prospective data on 125 hospitalized AECOPD patients were collected over a 30 month period at two Spanish university hospitals. Based on readmission after discharge, patients were divided into non-readmitted (n = 96) and readmitted (n = 29). Measures of serum inflammatory biomarkers were recorded on admission to hospital, at day 3 and at discharge; data on clinical, laboratory, microbiological and severity features were also recorded. In a multivariate model, C-reactive protein (CRP) at discharge >= 7.6 mg/L, presence of diabetes and >= 1 hospitalization for AECOPD during previous year were significant risk factors for predicting readmission. Presence of all 3 risk factors perfectly identified the readmitted patients (positive and negative predictive values of 1.000; 95% CI, 1.00-1.00). A combination of 3 readily available clinical and biochemical parameters is accurate in identifying hospitalized AECOPD patients at risk for early readmission. PMID- 25279440 TI - Modelling central metabolic fluxes by constraint-based optimization reveals metabolic reprogramming of developing Solanum lycopersicum (tomato) fruit. AB - Modelling of metabolic networks is a powerful tool to analyse the behaviour of developing plant organs, including fruits. Guided by our current understanding of heterotrophic metabolism of plant cells, a medium-scale stoichiometric model, including the balance of co-factors and energy, was constructed in order to describe metabolic shifts that occur through the nine sequential stages of Solanum lycopersicum (tomato) fruit development. The measured concentrations of the main biomass components and the accumulated metabolites in the pericarp, determined at each stage, were fitted in order to calculate, by derivation, the corresponding external fluxes. They were used as constraints to solve the model by minimizing the internal fluxes. The distribution of the calculated fluxes of central metabolism were then analysed and compared with known metabolic behaviours. For instance, the partition of the main metabolic pathways (glycolysis, pentose phosphate pathway, etc.) was relevant throughout fruit development. We also predicted a valid import of carbon and nitrogen by the fruit, as well as a consistent CO2 release. Interestingly, the energetic balance indicates that excess ATP is dissipated just before the onset of ripening, supporting the concept of the climacteric crisis. Finally, the apparent contradiction between calculated fluxes with low values compared with measured enzyme capacities suggest a complex reprogramming of the metabolic machinery during fruit development. With a powerful set of experimental data and an accurate definition of the metabolic system, this work provides important insight into the metabolic and physiological requirements of the developing tomato fruits. PMID- 25279442 TI - Racial and ethnic differences in the risk of postpartum venous thromboembolism: a population-based, case-control study. AB - BACKGROUND: Venous thromboembolism (VTE) is a major contributor of maternal morbidity and mortality. Whether maternal race/ethnicity is associated with the risk of postpartum VTE remains unclear. METHODS AND RESULTS: We conducted a population-based, case-control study in Washington State, from 1987 through 2011. Cases comprised all women with selected International Classification of Diseases, Ninth Edition, Clinical Modification codes for hospitalized VTE within 3 months post-delivery. Controls were randomly selected postpartum women who did not experience a VTE. Characteristics of women and their deliveries were abstracted from birth certificates. Using logistic regression models, we compared the risk of postpartum VTE in black, Asian, and Hispanic women with that in non-Hispanic white women, after adjustment for maternal characteristics (age, body mass index, parity, education), pregnancy complications, and delivery methods. RESULTS: Our study comprised 688 cases and 10 246 controls. Among controls, the mean age and body mass index were 27.5 years and 26.3 kg m(-2) , respectively. Compared with white women, black and Asian women had a greater and lower risk of postpartum VTE (adjusted odds ratio [OR] 1.50, 95% confidence interval [CI] 1.10-2.04 and OR 0.67, 95%CI 0.48-0.94, respectively). A lower risk was present in Hispanic women (adjusted OR 0.80, 95% CI 0.61-1.06) but was not statistically significant. In subgroup analyses, we observed an increased risk for black compared with white women among women who delivered via cesarean section (OR 2.03, 95% CI 1.34-3.07) but not among vaginal deliveries (OR 1.03, 95% CI 0.61-1.74). CONCLUSIONS: Maternal race/ethnicity is associated with the risk of postpartum VTE, independently of other risk factors, and should be considered when assessing the use of thromboprophylaxis after delivery. PMID- 25279443 TI - False vs True rupture of membranes. AB - New medical nomenclature: False rupture of membranes or False ROM and Double rupture of membranes or Double ROM are being introduced into the English language. A single caregiver found about 1% of term births and 10% of term PROM involved False ROM, in which the chorion breaks while the amnion remains intact. Diagnostically, if meconium or vernix is observed, then both the chorionic and amniotic sacs have broken. In the absence of detection of vernix or meconium, an immediate accurate diagnostic test for False ROM is lacking and differentiating between True ROM from False ROM is possible only after leaking stops, which takes hours to days. The obvious benefit of differentiating between 'True' and 'False' ROM, is that in the case of False ROM, the amnion is intact and ascending infections are likely not at increased risk, although research is lacking as to whether False ROM is associated with an increased rate of ascending infection. Three cases of False ROM are presented and avenues for future research are enumerated. PMID- 25279444 TI - Synthesis and preclinical evaluation of 2-(2-furanyl)-7-[2-[4-[4-(2 [11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3 e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine ([11C]Preladenant) as a PET tracer for the imaging of cerebral adenosine A2A receptors. AB - 2-(2-Furanyl)-7-[2-[4-[4-(2-[(11)C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [(11)C]-3 ([(11)C]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiography (ARG) experiments. Regional brain uptake of [(11)C]-3 was consistent with known A2ARs distribution, with highest uptake in striatum. The results indicate that [(11)C]-3 has favorable brain kinetics and exhibits suitable characteristics as an A2AR PET tracer. PMID- 25279445 TI - Cyclooctane metathesis catalyzed by silica-supported tungsten pentamethyl [(=SiO)W(Me)5]: distribution of macrocyclic alkanes. AB - Metathesis of cyclic alkanes catalyzed by the new surface complex [(=SiO)W(Me)5] affords a wide distribution of cyclic and macrocyclic alkanes. The major products with the formula C(n)H(2n) are the result of either a ring contraction or ring expansion of cyclooctane leading to lower unsubstituted cyclic alkanes (5<=n<=7) and to an unprecedented distribution of unsubstituted macrocyclic alkanes (12<=n<=40), respectively, identified by GC/MS and by NMR spectroscopies. PMID- 25279446 TI - Amino-modified tetraphenylethene derivatives as nucleic acid stain: relationship between the structure and sensitivity. AB - A series of new amino-functionalized tetraphenylethene (TPE) derivatives were designed and synthesized to study the effect of molecular structures on the detection of nucleic acid. Contrastive studies revealed that the number of binding groups, the length of hydrophobic linking arm and the configuration of TPE molecule all play important roles on the sensitivity of the probes in nucleic acid detection. Z-TPE3 with two binding amino groups, long linking arms, and cis configuration was found to be the most sensitive dye in both solution and gel matrix. Z-TPE3 is able to stain dsDNA with the lowest amount of 1 ng and exclusively stain 40 ng of short oligonucleotide with only 10 nt. This work is of important significance for the further design of TPE probes as biosensors with higher sensitivity. PMID- 25279447 TI - Integration of heterogeneous molecular networks to unravel gene-regulation in Mycobacterium tuberculosis. AB - BACKGROUND: Different methods have been developed to infer regulatory networks from heterogeneous omics datasets and to construct co-expression networks. Each algorithm produces different networks and efforts have been devoted to automatically integrate them into consensus sets. However each separate set has an intrinsic value that is diluted and partly lost when building a consensus network. Here we present a methodology to generate co-expression networks and, instead of a consensus network, we propose an integration framework where the different networks are kept and analysed with additional tools to efficiently combine the information extracted from each network. RESULTS: We developed a workflow to efficiently analyse information generated by different inference and prediction methods. Our methodology relies on providing the user the means to simultaneously visualise and analyse the coexisting networks generated by different algorithms, heterogeneous datasets, and a suite of analysis tools. As a show case, we have analysed the gene co-expression networks of Mycobacterium tuberculosis generated using over 600 expression experiments. Regarding DNA damage repair, we identified SigC as a key control element, 12 new targets for LexA, an updated LexA binding motif, and a potential mismatch repair system. We expanded the DevR regulon with 27 genes while identifying 9 targets wrongly assigned to this regulon. We discovered 10 new genes linked to zinc uptake and a new regulatory mechanism for ZuR. The use of co-expression networks to perform system level analysis allows the development of custom made methodologies. As show cases we implemented a pipeline to integrate ChIP-seq data and another method to uncover multiple regulatory layers. CONCLUSIONS: Our workflow is based on representing the multiple types of information as network representations and presenting these networks in a synchronous framework that allows their simultaneous visualization while keeping specific associations from the different networks. By simultaneously exploring these networks and metadata, we gained insights into regulatory mechanisms in M. tuberculosis that could not be obtained through the separate analysis of each data type. PMID- 25279449 TI - Vitamin D pathway gene variants and HCV-2/3 therapy outcomes. AB - BACKGROUND: The combination of ribavirin and pegylated interferon-alpha is considered the standard of care for HCV-2/3 genotypes. The immune system plays a key role in the achievement of a sustained virological response (SVR). Vitamin D seems to influence antiviral response in chronic hepatitis C and its pathway is controlled by polymorphic genes such as CYP27B1, CYP24A1 and VDR. In this study, we have investigated the correlation among the treatment outcomes and single nucleotide polymorphisms (SNPs) in the above-mentioned genes and IL28B genes. METHODS: A total of 112 HCV-2/3 patients treated with interferon plus ribavirin were retrospectively studied; allelic discrimination was performed by real-time PCR. RESULTS: CYP24A1rs2585428, IL28Brs12979860 and rs8099917 SNPs affected treatment failure and body mass index (BMI), Metavir score, IL28Brs8099917TT and CYP24A1rs2585428GG were the only factors able to predict it. SVR was predicted by Metavir score, HCV RNA at baseline and early virological response (EVR). IL28Brs12979860 SNP and HCV RNA were also related to rapid virological response. EVR was predicted by BMI, Metavir score and CYP24A1rs2585428 SNP. IL28Brs8099917TT and FokITT were relapse prediction factors. CONCLUSIONS: In addition to non-genetic factors, SNPs in the vitamin D pathway seem to have a role in HCV-2/3 therapy outcomes. This study reveals the likely usefulness of pharmacogenetic-based ribavirin and interferon therapy to help identify patients for whom therapy could be successful or not, also considering new future expensive therapy options. To date, no similar data were published on these viral genotypes, but further studies in different and bigger cohorts are needed. PMID- 25279448 TI - E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity. AB - The transcription factor E2F1 activates gene targets required for G1 -S phase progression and for apoptosis, and exhibits increased expression levels in neurons in several CNS diseases including HIV encephalitis, Alzheimer disease, and Parkinson's Disease. While E2F1 is known to regulate cell viability through activation of caspases, here we present evidence supporting the involvement of E2F1 in N-methyl-d-aspartate (NMDA) receptor-dependent, HIV-induced neuronal death mediated by calpains. Using an in vitro model of HIV-induced neurotoxicity that is dependent on NMDA receptor and calpain activation, we have shown that cortical neurons lacking functional E2F1 are less susceptible to neuronal death. In addition, we report that neuronal E2F1 is cleaved by calpain to a stable 55 kiloDalton fragment following NR2B-dependent NMDA receptor stimulation. This cleavage of E2F1 is protein conformation-dependent and involves at least two cleavage events, one at each terminus of the protein. Intriguingly, the stabilized E2F1 cleavage product is produced in post-mitotic neurons of all ages, but fails to be stabilized in cycling cells. Finally, we show that a matching E2F1 cleavage product is produced in human fetal neurons, suggesting that calpain cleavage of E2F1 may be produced in human cortical tissue. These results suggest neuronal E2F1 is processed in a novel manner in response to NMDA receptor mediated toxicity, a mechanism implicated in HIV-associated neurocognitive disorders pathogenesis as well as several other diseases of the CNS. After crossing the blood-brain barrier, HIV-infected monocytes differentiate into macrophages and release excitotoxins and inflammatory factors including glutamate into the brain parenchyma (1). These factors stimulate neuronal N-Methyl-d aspartate (NMDA) receptors (2), causing calcium influx (3) and subsequent activation of the cysteine protease calpain (4). Activated calpain cleaves multiple substrates including E2F1, producing a stabilized protein fragment with truncations at the N- and C-terminus (5). Calpain-cleaved E2F1 may contribute to calpain-mediated neuronal damage observed in NMDA receptor-mediated neurotoxicity (6). PMID- 25279450 TI - Rapidly growing mycobacteria associated with laparoscopic gastric banding, Australia, 2005-2011. AB - Laparoscopic gastric banding is a common bariatric procedure worldwide. Rapidly growing mycobacteria are environmental organisms increasingly seen as pathogens,often in infected prosthetic material. We report 18 cases of infection associated with laparoscopic gastric banding caused by Mycobacterium fortuitum and M. abscessus in Australia during 2005-2011. We identified cases by reviewing positive cultures at the Queensland state reference laboratory or through correspondence with clinicians, and we obtained clinical and epidemiologic data. Eleven cases of M. fortuitum and 7 cases of M. abscessus infection were identified. The port was thought to be the primary site of infection in 10 of these cases. Complications included peritonitis,band erosion, and chronic ulceration at the port site.Rapidly growing mycobacteria can infect both port and band and can occur as either an early perioperative or late infection.Combination antimicrobial therapy is used on the basis of in vitro susceptibilities. Device removal seems to be vital to successful therapy. PMID- 25279453 TI - Nursing care process for releasing psychiatric inpatients from long-term seclusion in Japan: modified grounded theory approach. AB - Based on a modified grounded theory approach, in this study, we sought to elucidate the nursing care process used to guide psychiatric inpatients in long term seclusion towards release from seclusion. Participant observations and interviews were conducted with a total of 18 nurses from three long-term psychiatric wards at two institutions from September 2011 to November 2012, to collect data on the nursing care they provided for psychiatric patients in long term seclusion. Consequently, four categories and 15 concepts were extracted. The nurses viewed "a mature therapeutic environment that utilizes flexible apportionment of care" as the foundation (i.e. the core category) in guiding psychiatric inpatients towards release from long-term seclusion. The results revealed a care structure in which nurses in such a treatment environment provided care by flexible apportionment of three types of care: care aimed at avoiding mental and physical exhaustion, standardized care that does not confer a disadvantage to patients, and immediately responding to prevent problematic behaviors. PMID- 25279454 TI - Doing the month in a Taiwanese postpartum nursing center: an ethnographic study. AB - Traditionally Chinese and Taiwanese postpartum women conducted postpartum ritual practices, called "doing the month," at home. Today, many Taiwanese women undertake this ritual in postpartum nursing centers. However, little is known about how the traditional practices are being transformed in relation to contemporary health care in Taiwan. In this ethnographic study observations were carried out in a large post-partum center attached to a major hospital in Taipei for nine months, and 27 postpartum women were interviewed. Data were analyzed using ethnographic approaches to extract codes and categories. Doing the month was reshaped by being relocated from the home to a healthcare setting. Midwives took on roles traditionally taken by family members, which had an impact on family roles and relationships. Some postpartum practices were maintained, based on traditional explanations. However, many were modified or challenged, based on explanations from contemporary scientific knowledge. Midwives need to be aware that there could be differences between their culture of care and the cultural values of the women they care for. This study informs culturally appropriate postpartum care and support for women with traditional and contemporary cultural beliefs and attitudes to doing the month in a range of healthcare contexts. PMID- 25279452 TI - From Human Papillomavirus (HPV) Detection to Cervical Cancer Prevention in Clinical Practice. AB - The newly gained knowledge of the viral etiology in cervical carcinogenesis has prompted industrial interests in developing virology-based tools for cervical cancer prevention. Due to the long incubation period from viral infection to developing an invasive cancer, a process whose outcome is influenced by numerous life-style and genetic factors, the true efficacy of the genotype-specific human papillomavirus (HPV) vaccines in cervical cancer prevention cannot be determined for another 30 years. Most HPV DNA test kits designed to replace the traditional Papanicolaou (Pap) smears for precancer detection lack the analytical sensitivity and specificity to comprehensively detect all potentially carcinogenic HPVs and to perform reliable genotyping. The authors implemented the classic nested PCR and Sanger DNA-sequencing technology for routine HPV testing. The results showed a true negative HPV PCR invariably indicates the absence of precancerous cells in the cytology samples. However, 80.5% of single positive HPV-16 tests and 97.3% of single positive HPV-18 tests were associated with a negative or a largely self reversible Pap cytology. Routine sensitive and reliable HPV type-specific or perhaps even variant-specific methods are needed to address the issues of persistence of HPV infection if a virology-based primary cervical screen is used to replace the Pap cytology screening paradigm. PMID- 25279451 TI - Situational awareness: regulation of the myb transcription factor in differentiation, the cell cycle and oncogenesis. AB - This review summarizes the mechanisms that control the activity of the c-Myb transcription factor in normal cells and tumors, and discusses how c-Myb plays a role in the regulation of the cell cycle. Oncogenic versions of c-Myb contribute to the development of leukemias and solid tumors such as adenoid cystic carcinoma, breast cancer and colon cancer. The activity and specificity of the c Myb protein seems to be controlled through changes in protein-protein interactions, so understanding how it is regulated could lead to the development of novel therapeutic strategies. PMID- 25279455 TI - Distinct chromatin organization in the germ line founder cell of the Caenorhabditis elegans embryo. AB - Cells belonging to the germ lineage segregate physically and molecularly from their somatic neighbors during embryogenesis. While germ line-specific chromatin modifications have been identified at later stages in the Caenorhabditis elegans nematode, none have been found in the single P4 germ line founder cell that arises at the beginning of gastrulation. Using light and electron microscopy, we now report that the chromatin organization in the germ line founder cell of the early C. elegans embryo is distinct from that in the neighboring somatic cells. This unique organization is characterized by a greater chromatin compaction and an expansion of the interchromatin compartment. The ultrastructure of individual chromatin domains does not differ between germ line and somatic cells, pointing to a specific organization mainly at the level of the whole nucleus. We show that this higher order reorganization of chromatin is not a consequence of the P4 nucleus being smaller than somatic nuclei or having initiated mitosis. Imaging of living embryos expressing fluorescent markers for both chromatin and P granules revealed that the appearance of a distinct chromatin organization in the P4 cell occurs approximately 10 min after its birth and coincides with the aggregation of P granules around the nucleus, suggesting a possible link between these two events. The higher order reorganization of chromatin that is reported here occurs during the establishment of definitive germ cell identity. The changes we have observed could therefore be a prerequisite for the programming of chromatin totipotency. PMID- 25279456 TI - A modified chronic infection model for testing treatment of Staphylococcus aureus biofilms on implants. AB - Bacterial biofilms causing implant-associated osteomyelitis is a severe complication with limited antimicrobial therapy options. We designed an animal model, in which implant associated osteomyelitis arise from a Staphylococcus aureus biofilm on a tibia implant. Two bioluminescently engineered (luxA-E transformed), strains of S. aureus were utilized, Xen29 and Xen31. Biofilm formation was assessed with epifluorescence microscopy. Quantitative measurements were performed day 4, 6, 8, 11 and 15 post-surgery. Bacteria were extracted from the biofilm by sonication and the bacterial load quantified by culturing. Biofilm formation was evident from day 6 post-implantation. Mean bacterial load from implants was ~1*10(4) CFU/implant, while mean bacterial load from infected tibias were 1*10(6) CFU/bone. Bioluminesence imaging revealed decreasing activity throughout the 15-day observation period, with signal intensity for both strains reaching that of the negative control by day 15 while there was no significant reduction in bacterial load. The model is suitable for testing antimicrobial treatment options for implant associated OM, as treatment efficacy on both biofilm and viable counts can be assessed. PMID- 25279457 TI - Cortical response variation with different sound pressure levels: a combined event-related potentials and FMRI study. AB - INTRODUCTION: Simultaneous recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) provides high spatial and temporal resolution. In this study we combined EEG and fMRI to investigate the structures involved in the processing of different sound pressure levels (SPLs). METHODS: EEG data were recorded simultaneously with fMRI from 16 healthy volunteers using MR compatible devices at 3 T. Tones with different SPLs were delivered to the volunteers and the N1/P2 amplitudes were included as covariates in the fMRI data analysis in order to compare the structures activated with high and low SPLs. Analysis of variance (ANOVA) and ROI analysis were also performed. Additionally, source localisation analysis was performed on the EEG data. RESULTS: The integration of averaged ERP parameters into the fMRI analysis showed an extended map of areas exhibiting covariation with the BOLD signal related to the auditory stimuli. The ANOVA and ROI analyses also revealed additional brain areas other than the primary auditory cortex (PAC) which were active with the auditory stimulation at different SPLs. The source localisation analyses showed additional sources apart from the PAC which were active with the high SPLs. DISCUSSION: The PAC and the insula play an important role in the processing of different SPLs. In the fMRI analysis, additional activation was found in the anterior cingulate cortex, opercular and orbito-frontal cortices with high SPLs. A strong response of the visual cortex was also found with the high SPLs, suggesting the presence of cross-modal effects. PMID- 25279458 TI - Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study. AB - BACKGROUND: COPD exacerbations accelerate disease progression. AIMS: To examine if COPD characteristics and systemic inflammatory markers predict the risk for acute COPD exacerbation (AECOPD) frequency and duration. METHODS: 403 COPD patients, GOLD stage II-IV, aged 44-76 years were included in the Bergen COPD Cohort Study in 2006/07, and followed for 3 years. Examined baseline predictors were sex, age, body composition, smoking, AECOPD the last year, GOLD stage, Charlson comorbidity score (CCS), hypoxemia (PaO2<8 kPa), cough, use of inhaled steroids, and the inflammatory markers leucocytes, C-reactive protein (CRP), neutrophil gelatinase associated lipocalin (NGAL), soluble tumor necrosis factor receptor 1 (sTNF-R1), and osteoprotegrin (OPG). Negative binomial models with random effects were fitted to estimate the annual incidence rate ratios (IRR). For analysis of AECOPD duration, a generalized estimation equation logistic regression model was fitted, also adjusting for season, time since inclusion and AECOPD severity. RESULTS: After multivariate adjustment, significant predictors of AECOPD were: female sex [IRR 1.45 (1.14-1.84)], age per 10 year increase [1.23 (1.03-1.47)], >1 AECOPD last year before baseline [1.65 (1.24-2.21)], GOLD III [1.36 (1.07-1.74)], GOLD IV [2.90 (1.98-4.25)], chronic cough [1.64 (1.30-2.06)] and use of inhaled steroids [1.57 (1.21-2.05)]. For AECOPD duration more than three weeks, significant predictors after adjustment were: hypoxemia [0.60 (0.39 0.92)], years since inclusion [1.19 (1.03-1.37)], AECOPD severity; moderate [OR 1.58 (1.14-2.18)] and severe [2.34 (1.58-3.49)], season; winter [1.51 (1.08 2.12)], spring [1.45 (1.02-2.05)] and sTNF-R1 per SD increase [1.16 (1.00-1.35)]. CONCLUSION: Several COPD characteristics were independent predictors of both AECOPD frequency and duration. PMID- 25279459 TI - Paricalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production. AB - Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice. PMID- 25279460 TI - The associations of serum serotonin with bone traits are age- and gender specific. AB - CONTEXT: Serotonin plays a potential role in bone metabolism, but the nature and extent of this relationship is unclear and human studies directly addressing the skeletal effect of circulating serotonin are rare. OBJECTIVE: The study aimed to investigate the associations between serum serotonin and bone traits at multiple skeletal sites in women and men. SUBJECTS AND METHODS: Subjects were part of the CALEX-family study and comprised 235 young women, 121 premenopausal women, 124 postmenopausal women, and 168 men. Body composition was assessed using DXA, as was areal bone mineral density (aBMD) of spine, femur and whole body. In addition, pQCT was used to determine bone properties at tibial midshaft and distal radius. Fasting serum serotonin concentration was assessed using a competitive enzyme-linked immunosorbent assay. RESULTS: Serum serotonin declined with advancing age both in females and males (all p<0.01). Serotonin was negatively correlated with weight, BMI, lean and fat mass in women (r = -0.22 to 0.39, all p<0.001), but positively with height and lean mass in men (all p<0.01). In the premenopausal women, serotonin was negatively correlated with lumbar spine aBMD (r = -0.23, p<0.05) but the statistical significance disappeared after adjustment for weight. Conversely, in postmenopausal women, serotonin was positively correlated with whole body and femur aBMD, as well as with distal radius bone mineral content and volumetric BMD (r = 0.20 to 0.30, all p<0.05), and these associations remained significant after adjustment for weight. In men, no significant associations were found between serotonin and bone traits. CONCLUSION: Serum serotonin is positively associated with bone traits in postmenopausal women, but not in premenopausal women or men. This partially supports the idea of circulating serotonin playing a role in the regulation of bone metabolism, but also indicates the importance of gender and age specific factors. PMID- 25279461 TI - A miRNA signature for defining aggressive phenotype and prognosis in gliomas. AB - Gliomas represent a disparate group of tumours for which there are to date no cure. Thus, there is a recognized need for new diagnostic and therapeutic approaches based on increased understanding of their molecular nature. We performed the comparison of the microRNA (miRNA) profile of 8 WHO grade II gliomas and 24 higher grade tumours (2 WHO grade III and 22 glioblastomas) by using the Affymetrix GeneChip miRNA Array v. 1.0. A relative quantification method (RT-qPCR) with standard curve was used to confirm the 22 miRNA signature resulted by array analysis. The prognostic performances of the confirmed miRNAs were estimated on the Tumor Cancer Genome Atlas (TCGA) datasets. We identified 22 miRNAs distinguishing grade II gliomas from higher grade tumours. RT-qPCR confirmed the differential expression in the two patients' groups for 13 out of the 22 miRNAs. The analysis of the Glioblastoma Multiforme (GBM) and Lower Grade Glioma (LGG) datasets from TCGA demonstrated the association with prognosis for 6 of those miRNAs. Moreover, in the GBM dataset miR-21 and miR-210 were predictors of worse prognosis in both univariable and multivariable Cox regression analyses (HR 1.19, p = 0.04, and HR 1.18, p = 0.029 respectively). Our results support a direct contribution of miRNAs to glioma cancerogenesis and suggest that miR-21 and miR-210 may play a role in the aggressive clinical behaviour of glioblastomas. PMID- 25279463 TI - A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery. AB - Central nervous system (CNS) diseases are difficult to treat because of the blood brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (i.n.) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+i.n.) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After i.n. administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (i.v.) drug injection is employed, FUS was also applied after i.v. injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+i.n. enhanced drug delivery within the targeted region compared with that achieved by i.n. only. Despite the fact that the i.n. route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+i.n. was not significantly different from that of FUS+i.v.. As a new drug delivery platform, the FUS+i.n. technique is potentially useful for treating CNS diseases. PMID- 25279462 TI - Identification and molecular characterization of MYB Transcription Factor Superfamily in C4 model plant foxtail millet (Setaria italica L.). AB - MYB proteins represent one of the largest transcription factor families in plants, playing important roles in diverse developmental and stress-responsive processes. Considering its significance, several genome-wide analyses have been conducted in almost all land plants except foxtail millet. Foxtail millet (Setaria italica L.) is a model crop for investigating systems biology of millets and bioenergy grasses. Further, the crop is also known for its potential abiotic stress-tolerance. In this context, a comprehensive genome-wide survey was conducted and 209 MYB protein-encoding genes were identified in foxtail millet. All 209 S. italica MYB (SiMYB) genes were physically mapped onto nine chromosomes of foxtail millet. Gene duplication study showed that segmental- and tandem duplication have occurred in genome resulting in expansion of this gene family. The protein domain investigation classified SiMYB proteins into three classes according to number of MYB repeats present. The phylogenetic analysis categorized SiMYBs into ten groups (I-X). SiMYB-based comparative mapping revealed a maximum orthology between foxtail millet and sorghum, followed by maize, rice and Brachypodium. Heat map analysis showed tissue-specific expression pattern of predominant SiMYB genes. Expression profiling of candidate MYB genes against abiotic stresses and hormone treatments using qRT-PCR revealed specific and/or overlapping expression patterns of SiMYBs. Taken together, the present study provides a foundation for evolutionary and functional characterization of MYB TFs in foxtail millet to dissect their functions in response to environmental stimuli. PMID- 25279464 TI - The involvement of Nek2 and Notch in the proliferation of rat adrenal cortex triggered by POMC-derived peptides. AB - The adrenal gland is a dynamic organ that undergoes constant cell turnover. This allows for rapid organ remodeling in response to the physiological demands of the HPA axis, which is controlled by proopiomelanocortin (POMC)-derived peptides, such as adrenocorticotropic hormone (ACTH) and N-Terminal peptides (N-POMC). In the rat adrenal cortex, POMC-derived peptides trigger a mitogenic effect, and this process increases cyclins D and E, while inhibiting p27Kip1. The goal of the present study was to further explore the mitogenic effect of ACTH and synthetic N POMC1-28 peptides by investigating the differences in the expression of key genes involved in the cell cycle of the rat adrenal cortex, following inhibition of the HPA axis. Moreover, we evaluated the differences between the inner and outer fractions of the adrenal cortex (ZF-fraction and ZG-fraction) in terms of their response patterns to different stimuli. In the current study, the inhibition of the HPA axis repressed the expression of Ccnb2, Camk2a, and Nek2 genes throughout the adrenal cortex, while treatments with POMC-derived peptides stimulated Nek2, gene and protein expression, and Notch2 gene expression. Furthermore, Notch1 protein expression was restricted to the subcapsular region of the cortex, an area of the adrenal cortex that is well-known for proliferation. We also showed that different regions of the adrenal cortex respond to HPA-axis inhibition and to induction with POMC-derived peptides at different times. These results suggest that cells in the ZG and ZF fractions could be at different phases of the cell cycle. Our results contribute to the understanding of the mechanisms involved in cell cycle regulation in adrenocortical cells triggered by N-POMC peptides and ACTH, and highlight the involvement of genes such as Nek2 and Notch. PMID- 25279465 TI - Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial. AB - The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25.1, 55.6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2.64, 95% CI 1.32, 5.31, p = 0.006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN45724312. PMID- 25279466 TI - A study of remitted and treatment-resistant depression using MMPI and including pessimism and optimism scales. AB - BACKGROUND: The psychological aspects of treatment-resistant and remitted depression are not well documented. METHODS: We administered the Minnesota Multiphasic Personality Inventory (MMPI) to patients with treatment-resistant depression (n = 34), remitted depression (n = 25), acute depression (n = 21), and healthy controls (n = 64). Pessimism and optimism were also evaluated by MMPI. RESULTS: ANOVA and post-hoc tests demonstrated that patients with treatment resistant and acute depression showed similarly high scores for frequent scale (F), hypochondriasis, depression, conversion hysteria, psychopathic device, paranoia, psychasthenia and schizophrenia on the MMPI compared with normal controls. Patients with treatment-resistant depression, but not acute depression registered high on the scale for cannot say answer. Using Student's t-test, patients with remitted depression registered higher on depression and social introversion scales, compared with normal controls. For pessimism and optimism, patients with treatment-resistant depression demonstrated similar changes to acutely depressed patients. Remitted depression patients showed lower optimism than normal controls by Student's t-test, even though these patients were deemed recovered from depression using HAM-D. CONCLUSIONS: The patients with remitted depression and treatment-resistant depression showed subtle alterations on the MMPI, which may explain the hidden psychological features in these cohorts. PMID- 25279467 TI - Appraisal of artificial screening techniques of tomato to accurately reflect field performance of the late blight resistance. AB - Late blight (LB) caused by the oomycete Phytophthora infestans continues to thwart global tomato production, while only few resistant cultivars have been introduced locally. In order to gain from the released tomato germplasm with LB resistance, we compared the 5-year field performance of LB resistance in several tomato cultigens, with the results of controlled conditions testing (i.e., detached leaflet/leaf, whole plant). In case of these artificial screening techniques, the effects of plant age and inoculum concentration were additionally considered. In the field trials, LA 1033, L 3707, L 3708 displayed the highest LB resistance, and could be used for cultivar development under Polish conditions. Of the three methods using controlled conditions, the detached leaf and the whole plant tests had the highest correlation with the field experiments. The plant age effect on LB resistance in tomato reported here, irrespective of the cultigen tested or inoculum concentration used, makes it important to standardize the test parameters when screening for resistance. Our results help show why other reports disagree on LB resistance in tomato. PMID- 25279469 TI - Under pressure. PMID- 25279470 TI - Allergic contact dermatitis from ketoconazole. AB - Ketoconazole is a widely used imidazole antifungal agent. True contact allergy to topical ketoconazole is rare, and few cases of patients with contact allergy to ketoconazole have been reported. We present the case of a patient with a history of undiagnosed recurrent dermatitis who developed acute facial swelling and pruritus after using ketoconazole cream and shampoo for the treatment of seborrheic dermatitis. Patch testing revealed true contact allergy to ketoconazole without cross-reactivity to 4 other imidazole antifungals. Review of the patient's medical record suggested that prior incidences of dermatitis might have been due to ketoconazole exposure. When the patient avoided this imidazole agent, the dermatitis resolved. PMID- 25279468 TI - PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. AB - Immunology-based interventions have been proposed as a promising curative chance to effectively attack postoperative minimal residual disease and distant metastatic localizations of prostate tumors. We developed a chimeric antigen receptor (CAR) construct targeting the human prostate-specific membrane antigen (hPSMA), based on a novel and high affinity specific mAb. As a transfer method, we employed last-generation lentiviral vectors (LV) carrying a synthetic bidirectional promoter capable of robust and coordinated expression of the CAR molecule, and a bioluminescent reporter gene to allow the tracking of transgenic T cells after in vivo adoptive transfer. Overall, we demonstrated that CAR expressing LV efficiently transduced short-term activated PBMC, which in turn were readily stimulated to produce cytokines and to exert a relevant cytotoxic activity by engagement with PSMA+ prostate tumor cells. Upon in vivo transfer in tumor-bearing mice, CAR-transduced T cells were capable to completely eradicate a disseminated neoplasia in the majority of treated animals, thus supporting the translation of such approach in the clinical setting. PMID- 25279471 TI - Dermatology: the last refuge for private practice? PMID- 25279472 TI - Rupioid psoriasis and other skin diseases with rupioid manifestations. AB - The term rupioid has been used to describe well-demarcated, cone-shaped plaques with thick, dark, lamellate, and adherent crusts on the skin that somewhat resemble oyster or limpet shells. We present a case of rupioid psoriasis that was treated with methotrexate, topical steroids, and intralesional steroid injections. Rupioid manifestations have been clinically observed in a variety of disease settings, including rupioid psoriasis, reactive arthritis, disseminated histoplasmosis, keratotic scabies, secondary syphilis, and photosensitive skin lesions in association with aminoaciduria. To diagnose the underlying infectious or inflammatory diseases beneath the thick crusts, skin biopsy and a blood test for syphilis may be necessary. Our aim is to familiarize clinicians with the differential diagnoses for skin diseases with rupioid manifestations. PMID- 25279473 TI - Facial rejuvenation: combining cosmeceuticals with cosmetic procedures. AB - Cosmetic patients are looking for a more youthful appearance without spending a lot of money, feeling any pain, or experiencing any postprocedure downtime. New cosmeceutical therapies can be used adjuvant to chemical peels, lasers, and injectables, making antiaging regimens less painful and requiring less postprocedural healing time. Adjunctive agents can be used to enhance chemical peels and decrease postinflammatory hyperpigmentation (PIH). Topical retinoids used prior to ablative laser treatments can aid in faster postprocedure healing and reepithelialization. Cosmeceuticals that contain both antioxidants and anti inflammatories can help reduce postprocedure inflammation. Acetyl hexapeptide-3 is an effective topical agent for decreasing wrinkles and can be used as an adjunct to intramuscular botulinum neurotoxin, which may reduce the number of injections needed. Topical hyaluronic acid also would help patients who are averse to needles or are just starting to get wrinkles and are looking for noninvasive therapy. This article reviews combinations of cosmeceuticals with cosmetic procedures that dermatologists may want to consider discussing with their cosmetic patients. PMID- 25279474 TI - Calcipotriene-betamethasone dipropionate topical suspension in the management of psoriasis: a status report on available data with an overview of practical clinical application. AB - Psoriasis is a multifactorial process associated with immunologic dysregulation. Chronic plaque psoriasis (PP) is the most common clinical presentation. Plaque psoriasis is characteristically a chronic disease associated with periods of persistence and episodes of flaring; therefore, intermittent use of topical corticosteroid (TC) therapy along with concurrent or sequential use of a nonsteroidal topical agent is commonly employed to achieve and sustain control of the disorder. Calcipotriene 0.005%-betamethasone dipropionate 0.064% topical suspension (C/Bd-TS) is a rational option for the treatment of PP in patients with localized disease or in patients treated systemically or with phototherapy for more extensive disease who exhibit persistence or recurrence of scattered areas of PP. This article provides a review of a patented topical suspension combination formulation of C/Bd-TS, including formulation characteristics, perspectives on modes of action, outcomes from pivotal trials, and efficacy and safety data reported from additional studies. PMID- 25279475 TI - UV radiation transmittance: regular clothing versus sun-protective clothing. AB - There are many clothing options available for patients who are interested in limiting their exposure to UV radiation; however, these options can be confusing for patients. For dermatologists, there is limited clinical data regarding the advantages, if any, of sun-protective clothing. In this study, we examined the UV radiation transmittance of regular clothing versus sun-protective clothing. We found that regular clothing may match or even exceed sun-protective clothing in blocking the transmittance of UV radiation. These data will help dermatologists better counsel their patients on clothing options for sun protection. PMID- 25279477 TI - Palmoplantar pustular psoriasis following initiation of a beta-blocker: disease control with low-dose methotrexate. AB - Palmoplantar pustular psoriasis is a debilitating chronic disease that can have a serious impact on patients' quality of life. There currently is no therapeutics standard for controlling palmoplantar pustular psoriasis, but various treatments, many of which have serious toxic side effects, have been used to treat this disease, including methotrexate. We report a case of palmoplantar pustular psoriasis in a 76-year-old woman that was triggered by initiation of a beta blocker. The patient's condition was controlled with a low-dose regimen of methotrexate. It is important for dermatologists to recognize that pustular psoriasis can be treated with low-dose methotrexate to avoid potentially toxic effects of higher doses of methotrexate, which is especially true in cases of drug-induced disease, as seen in our patient. PMID- 25279476 TI - A rare case of segmental neurofibromatosis with multiple blue-red pseudoatrophic plaques. AB - We report the case of a 5-year-old girl who presented with 2 blue-red atrophic plaques on the left leg as well as subcutaneous nodules that were present since infancy. Although the clinical criteria of neurofibromatosis (NF) were absent, microscopic examination revealed features of a blue-red neurofibroma. PMID- 25279478 TI - Hypereosinophilia in erythrodermic psoriasis: superimposed scabies. AB - Scabies is a common ectoparasitic disease that can be diagnosed based on the presence of pruritus and typical clinical signs including burrows, vesicles, and erythematous papules. If a desquamative disease such as psoriasis precedes scabies, then the disease course may be altered. Pruritus may be absent and typical scabies lesions may be concealed due to the preexisting disease, resulting in delayed diagnosis. We present 2 cases of scabies in a brother and sister with erythrodermic psoriasis. In both cases peripheral hypereosinophilia suggested scabies. In patients with erythematous scaly inflammatory skin diseases who are treated with immunosuppressive agents, peripheral eosinophilia also could suggest scabies; therefore, a search for sarcoptic mites in skin scrapings should be undertaken. PMID- 25279479 TI - What is your diagnosis? verruciform xanthoma. PMID- 25279480 TI - Subcutaneous panniculitislike T-cell lymphoma. PMID- 25279481 TI - Narrow-toed shoes and the toe-to-toe sign. PMID- 25279482 TI - Successful treatment of Schnitzler syndrome with canakinumab. PMID- 25279483 TI - Glomus tumor of uncertain malignant potential on the forehead. AB - Malignant glomus tumors (GTs) are rare, and diagnosis requires consideration of specific histologic criteria. Glomus tumors that do not fulfill the histologic criteria for malignancy but show at least 1 feature other than nuclear atypia should be classified as GTs of uncertain malignant potential (GTUMPs). We report the case of a 74-year-old man with a slowly progressing, painful, 2.5-cm nodule on the forehead that was successfully treated via wide surgical excision and was later diagnosed as a GTUMP. Three-year follow-up showed no local recurrence or distant metastasis. Malignant GTs and GTUMPs are rare, and the nomenclature and classification of these tumors is controversial. These findings and the difficulty of differential diagnosis in a continuum between benignity and malignancy prompted our report. PMID- 25279484 TI - Adult-type Langerhans cell histiocytosis: minimal treatment for maximal results. PMID- 25279485 TI - Papular eruption following excessive tanning bed use. PMID- 25279486 TI - Rapidly enlarging noduloulcerative lesions. Lues maligna. PMID- 25279487 TI - Basics of lasers in dermatology. AB - Lasers have become a critical part of the dermatologist's armamentarium for modulating cutaneous biology, both in treating skin disorders and providing tangible cosmetic alterations to the skin. Although modern lasers are relatively straightforward to use, they are powerful tools that are capable of considerable damage when used incorrectly. Developing an understanding of how these lasers function is essential to their safe and responsible use. This article will discuss the fundamental concepts of lasers in dermatology and the cutaneous interactions they cause. PMID- 25279488 TI - Fungal melanonychia caused by Trichophyton rubrum and the value of dermoscopy. PMID- 25279489 TI - Yellowish papulonodular periorbital eruption. PMID- 25279490 TI - Mechanochemical preparation of hydantoins from amino esters: application to the synthesis of the antiepileptic drug phenytoin. AB - The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of alpha and beta-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent. PMID- 25279491 TI - Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL): a possible pathogenic role in chronic plaque psoriasis. AB - BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine member of the tumour necrosis factor (TNF) family. Its role has been investigated in skin cancers and some inflammatory and/or immune-mediated skin diseases. An involvement of TRAIL in psoriasis pathogenesis has recently been hypothesized. We investigated the expression and localization of TRAIL and its receptors in psoriatic skin and measured serum TRAIL. The intracellular pathways activated by TRAIL were assessed to investigate its potential role in the pathogenesis of psoriasis. METHODS: Twenty-four consecutive patients with plaque psoriasis and age- and sex-matched healthy subjects were recruited. Serum TRAIL was measured by means of an enzyme-linked immunosorbent assay (ELISA). TRAIL and TRAIL receptors were evaluated by reverse transcription - polymerase chain reaction (RT-PCR) (RNA of lesional and non-lesional psoriatic skin) and by immunohistochemistry (lesional skin). Caspase 8 and NF-kB immunoexpression were also evaluated by immunohistochemistry. RESULTS: RT-PCR demonstrated increased synthesis of TRAIL and its receptors in lesional vs. non-lesional skin. Immunohistochemistry showed a strong staining of TRAIL and TRAIL receptors both in the epidermis and in the dermal infiltrate. Finally, a correlation emerged between caspase 8 and TRAIL immunoexpression in the dermis. CONCLUSIONS: Our findings suggest an involvement of TRAIL in psoriasis pathogenesis, probably through an action at the site of the inflammatory infiltrate, likely via caspase 8. PMID- 25279492 TI - Novel inflammatory markers in psoriasis vulgaris: vaspin, vascular adhesion protein-1 (VAP-1), and YKL-40. AB - BACKGROUND: Psoriasis is a chronic relapsing inflammatory skin disease. Vaspin, vascular adhesion protein-1 (VAP-1), chitinase-3-like protein 1 (also known as YKL-40), and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers. However, with the exception of hs-CRP, the role of these markers in the pathogenesis of psoriasis is yet to be elucidated. This study investigated vaspin, VAP-1, YKL-40, and hs-CRP levels in the serum of psoriatic patients and healthy controls. METHODS: A total of 56 patients suffering from psoriasis and 34 age-matched controls were included in the study. Vaspin, VAP-1, YKL-40, and hs CRP serum levels were evaluated by ELISA. The psoriasis area severity index (PASI) was calculated in all psoriatic patients and patients were divided in two groups according to PASI <10 or >=10. RESULTS: The serum concentration of soluble vaspin was significantly lower in psoriatic patients compared to healthy controls (1.33+/-0.32 pg/mL, 1.72+/-0.39 pg/mL, respectively; P<0.001). The serum concentrations of soluble VAP-1 and hs-CRP were significantly higher in psoriatic patients compared to healthy controls (VAP-1: 2.05+/-0.46 pg/mL, 1.82+/-0.46 pg/mL, hs-CRP: 4.97+/-3.53 mg/L, 3.48+/-0.08 mg/L, respectively; P<0.05). There was no significant difference in the serum concentration of soluble YKL-40 between psoriatic patients and the control group (1.37+/-0.55 ng/mL, 1.54+/-0.79 ng/mL, respectively; P>0.05). The mean PASI score was 9.1+/-8.2 in the patient group. A total of 36 patients had PASI<10 and 20 patients had PASI>=10. The serum concentration of vaspin was the only marker to exhibit a significant difference between the low and high PASI groups (1.40+/-0.27 pg/mL and 1.20+/-0.37 pg/mL, respectively; P<0.05). CONCLUSIONS: These findings suggest that vaspin and VAP-1 may play a role in the pathogenesis of psoriasis and can be used as markers of the disease. Furthermore, vaspin levels may reflect the severity of disease. PMID- 25279493 TI - Daylight photodynamic therapy with methyl aminolaevulinate in patients with actinic keratoses: a preliminary experience in Southern Italy. AB - BACKGROUND: Daylight photodynamic therapy (D-PDT) is a novel modality of PDT in which the activation of the topical photosensitizer is mediated by the exposure to daylight instead of artificial light sources without the need of preliminary occlusion. This simplified modality has been found to be well tolerated. We report our experience with D-PDT in patients with actinic keratoses (AK). METHODS: The data relative to 53 patients consecutively treated for AK with a single session of D-PDT using methyl aminolaevulinate cream were retrospectively reviewed. Most patients had grade I and/or II AK on the face and/or the scalp. Some patients had additional cutaneous lesions, including non-melanoma skin cancers, in the AK-associated field, that were simultaneously treated with D-PDT. RESULTS: At 3 months, a complete response (AK number=0) was achieved by 54.7% of patients, and the lesion clearance rate was 82.7%. Treatment was more effective in thinner lesions, with complete clearance involving 93% of grade I AK. At 6-9 months after treatment, response was maintained in 85.7% of the lesions previously cleared, and 72.4% of the initial complete responders did not relapse. No relevant effect of D-PDT was instead observed on senile lentigo, nodular basal cell carcinoma and squamous cell carcinoma, whereas a complete response was seen in 7 of the 9 superficial basal cell carcinomas treated. Local skin reactions mostly consisted in slight erythema. Mild symptoms (burning and tingling sensations) were reported by 12 patients. CONCLUSIONS: These preliminary results support the favorable efficacy and tolerability profile of D-PDT, which seems to be an interesting, valid, and convenient therapeutic option for AK, and possibly also for superficial basal cell carcinomas. PMID- 25279494 TI - Inherited epidermolysis bullosa. AB - Inherited epidermolysis bullosa (EB) refers to a clinically and genetically heterogeneous group of rare disorders characterized by fragility of the skin and mucous membranes. Despite the preclinical development of different molecular and cell-based treatment strategies, no cure is still available for EB. Therefore it is important to establish the management of EB patient since neonatal age in order to ensure an early diagnosis and contribute to prevent complications and to improve quality of life. A review of literature was performed underlining the specific attention to coordinated multidisciplinary approach. The major topics treated comprise the multidisciplinary approach to EB patients, global skin care including wound care, management of itching and pain, and early diagnosis of squamous cell carcinoma. The rarity of EB and the variable involvement of several organs and systems challenge the appropriate treatment of these patients. The care of EB requires a coordinated multidisciplinary approach. The team should be specifically trained and a regular follow-up is required to prevent cutaneous and systemic complications. A well-organized and structured continuity of care is important in EB like in all chronic and rare diseases. The management of EB patients is very important because a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection. The center of expertise stays as the main structure offering specialized care to EB patients and also helps patients and their families to understand and deal with the disease and to ensure an adequate liaison with the community healthcare system. PMID- 25279495 TI - Childhood granuloma annulare: a review. AB - Granuloma annulare (GA) is a self-limited benign inflammatory dermatosis of unknown origin characterized by the development of papules arranged in an annular, circinate pattern, mainly involving the extensor surfaces of lower and upper extremities. The diagnosis depends on clinical and histological features. There are four main variants of GA: localized GA (LGA), subcutaneous GA (SGA), generalized GA (GGA) and perforating GA (PGA) and 2 uncommon subtypes: papular umbilicated GA and linear or segmental GA. Children most commonly present with the localized and subcutaneous forms. The aim of this review was to provide an update on the etiology, diagnosis and management of GA focusing on the pediatric age. PMID- 25279496 TI - Spitz nevi: defining features and management in children. AB - We reviewed literature data in order to better define clinical features of Spitz nevi (SNi) in children. Lots of interest has been given in the past decade to these neoplasms that due the clinical course and sometime the rapid onset, may often cause worrisome consultations. Dermoscopy has played an important role in the improved diagnostic capability of clinicians, regarding all melanocytic neoplasms and also SNi. The description of specific and typical dermoscopic patterns is largely reviewed as well as the new laboratory diagnostic tools in the field of dermatopathology. PMID- 25279497 TI - Celiac disease and bone fractures: a systematic review and meta-analysis. AB - CONTEXT: Celiac disease, an autoimmune disease induced by dietary gluten, is associated with metabolic bone disorders, such as low bone mineral density. However, it is unclear whether this translates into an association between celiac disease and such hard clinical outcomes as bone fractures. OBJECTIVE: To systematically review and pool the evidence for the relationship of celiac disease with prevalence and incidence of bone fractures. DATA SOURCES: We systematically searched Pubmed, Scopus, Web of Science, and Cochrane Library in January 2014 for studies of celiac disease and bone fractures. STUDY SELECTION: Observational studies of any design, in which bone fracture outcomes were compared in individuals with and without celiac disease were included. DATA EXTRACTION: Two investigators independently extracted results from eligible studies. DATA SYNTHESIS: In the meta-analyses of case-control and cross-sectional studies, bone fractures were almost twice as common in individuals with a clinically diagnosed celiac disease as in those without the disease. In the meta analyses of prospective studies, celiac disease at baseline was associated with a 30% increase (95% confidence interval [CI]: 1.14, 1.50) in the risk of any fracture and a 69% increase in the risk of hip fracture (95% CI: 1.10, 2.59). The two studies of unrecognized celiac disease (elevated circulating concentrations of celiac disease-specific autoantibodies but no celiac disease diagnosis) had contradicting findings. CONCLUSION: Our findings suggest that clinically diagnosed celiac disease and bone fractures co-occur and that celiac disease was associated with an increased risk of hip fractures as well as fractures in general. Further research would be needed to determine whether unrecognized celiac disease is associated with the risk of bone fractures. PMID- 25279499 TI - Incidence of hypocalcemic seizures due to vitamin D deficiency in children in the United Kingdom and Ireland. AB - CONTEXT: Anecdotal reports suggest that increasing numbers of children in the UK are presenting with clinical manifestations of vitamin D deficiency (VDD). However, the epidemiology of symptomatic VDD is largely undetermined; existing studies are limited to local case series, and national incidence estimates of disease burden are lacking. OBJECTIVE: To estimate the incidence of hypocalcaemic seizures secondary to VDD in children in the UK and Ireland, and describe the demographic and clinical features of cases. DESIGN AND SETTING: Prospective, population-based active surveillance study using the established British Paediatric Surveillance Unit (BPSU) methodology. POPULATION: Children aged 0-15 years, resident in the UK and Ireland, who developed a hypocalcaemic seizure due to VDD between September 2011 and September 2013. MAIN OUTCOME MEASURE: Overall incidence of hypocalcaemic seizures due to VDD in children age 0-15, and incidence stratified by age, sex, and ethnicity. RESULTS: Ninety one confirmed or probable cases were reported, equating to an overall annual incidence of 3.49 per million children age 0-15 years (95% CI: 2.81-4.26). Incidence was significantly greater in males compared to females, in infants compared to older children, and in children of South Asian or Black ethnicity compared to children from white ethnic backgrounds. CONCLUSIONS: Current implementation of public health policy in the UK is not successful in preventing children from developing one of the severe manifestations of VDD. Further studies are required to evaluate the epidemiology of symptomatic VDD more broadly in order to guide future public health policy decisions. PMID- 25279498 TI - Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma. AB - CONTEXT: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear. OBJECTIVE: The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias. PATIENTS AND METHODS: Whole-genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analyzed for accompanying somatic mutations in the identified target genes. RESULTS: PMAH presenting either as overt or subclinical Cushing's syndrome was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) located on chromosome 16. Analysis of tumor tissue showed different somatic ARMC5 mutations in adrenal nodules supporting a second hit hypothesis with inactivation of a tumor suppressor gene. A damaging somatic ARMC5 mutation was also found in a concomitant meningioma (p.R502fs) but not in a pancreatic tumor, suggesting biallelic inactivation of ARMC5 as causal also for the intracranial meningioma. CONCLUSIONS: Our analysis further confirms inherited inactivating ARMC5 mutations as a cause of familial PMAH and suggests an additional role for the development of concomitant intracranial meningiomas. PMID- 25279501 TI - Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism: analysis of three Italian cohorts. AB - CONTEXT: Glial cells missing-2 (GCM2) is key for parathyroid gland organogenesis. Its persistent expression in the adult parathyroid raises the possibility that overactive forms play a role in the evolution of parathyroid hyperactivity or tumorigenesis. A GCM2 c.844T -> G; p.Y282D missense variant has been described within a transactivation inhibitory domain (amino acids 263-352). OBJECTIVE: The aims of the study were to 1) assess the frequency of Y282D in Italian primary hyperparathyroidism (PHPT) and control (C) populations, 2) test for association of 282D with PHPT and its phenotypic features, and 3) compare the transactivation potency of GCM2 282D relative to wild-type Y282. SUBJECTS AND METHODS: Subjects included a large southern Italian cohort (310 PHPT and 433 C) and 2 replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. An in vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells. RESULTS: 282D was significantly increased in the PHPT group, with a minor allele frequency of 0.066 compared with 0.029 in the C group (P = .0008), in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (510 PHPT and 665 C) yielded a likelihood ratio of 2.27 (95% confidence interval = 1.50-3.42; P < .0001). The 282D variant was not associated with serum calcium, phosphate, creatinine, or PTH levels or with bone mineral density, fractures, or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17* basal vs 12* basal; P < 0.05). CONCLUSION: The higher frequency of GCM2 282D in PHPT and enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis. PMID- 25279500 TI - Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin-sensitive subjects without altering brain structure. AB - CONTEXT: Leptin is a key regulator of energy intake and expenditure. Individuals with congenital leptin deficiency demonstrate structural and functional brain changes when given leptin. However, whether acquired leptin deficiency may operate similarly is unclear. OBJECTIVE: We set out to determine whether the brains of individuals with acquired leptin deficiency may react to leptin in a similar manner. DESIGN: We used functional magnetic resonance imaging before and after short- and long-term metreleptin treatment in three leptin-sensitive patients with acquired hypoleptinemia. Nine healthy women were scanned as normoleptinemic controls. SETTING: The setting was an academic medical center. PATIENTS OR OTHER PARTICIPANTS: The participants were 3 hypoleptinemic women and nine normoleptinemic, matched women. INTERVENTIONS: We used metreleptin, recombinant leptin, therapy for 24 weeks in hypoleptinemic women only. MAIN OUTCOME MEASURE: We measured neural changes in response to viewing food as compared to nonfood images. We hypothesized that metreleptin treatment would increase brain activity in areas related to cognitive control and inhibition and would decrease brain activity in areas related to reward processing, as compared to the normoleptinemic counterparts. RESULTS: Unlike patients with congenital leptin deficiency, hypoleptinemic patients demonstrated no structural brain differences from healthy controls and/or structural changes in response to treatment. Short-term metreleptin treatment in leptin-sensitive hypoleptinemic subjects enhances areas involved in detecting the salience and rewarding value of food during fasting, whereas long-term treatment decreases attention to food and the rewarding value of food after feeding. Furthermore, hypothalamic activity is modulated by metreleptin treatment, and leptin decreases functional connectivity of the hypothalamus to key feeding-related areas in these hypoleptinemic subjects. CONCLUSIONS: Leptin replacement in acutely hypoleptinemic women did not alter brain structure but did alter functional cortical activity to food cues in key feeding and reward-related areas. PMID- 25279502 TI - Increased mortality in patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. AB - CONTEXT: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. OBJECTIVE: This study sought to study mortality and causes of death in CAH. DESIGN, SETTING, AND PARTICIPANTS: We studied patients with CAH (21 hydroxylase deficiency, n = 588; CYP21A2 mutations known, >80%), and compared them with controls (n = 58 800). Data were derived through linkage of national population-based registers. MAIN OUTCOME MEASURES: Mortality and causes of death. RESULTS: Mean age of death was 41.2 +/- 26.9 years in patients with CAH and 47.7 +/- 27.7 years in controls (P < .001). Among patients with CAH, 23 (3.9%) had deceased compared with 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3 (1.2-4.3) in CAH males and 3.5 (2.0-6.0) in CAH females. Including only patients born 1952-2009, gave similar total results but only patients with salt wasting (SW) or with unclear phenotype had an increased mortality. The causes of death in patients with CAH were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter, all except one were deceased before the introduction of neonatal screening in 1986, and most of them in the first weeks of life, probably in an adrenal crisis. CONCLUSIONS: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The SW phenotype also seemed to have worse outcome in children and adults due to adrenal crisis and not only before the introduction of neonatal screening. PMID- 25279503 TI - Bioenergetic differences between MCF-7 and T47D breast cancer cells and their regulation by oestradiol and tamoxifen. AB - Oestrogen receptor alpha (ERalpha+) breast tumours rely on mitochondria (mt) to generate ATP. The goal of the present study was to determine how oestradiol (E2) and 4-hydroxytamoxifen (4-OHT) affect cellular bioenergetic function in MCF-7 and T47D ERalpha+ breast cancer cells in serum-replete compared with dextran-coated charcoal (DCC)-stripped foetal bovine serum (FBS)-containing medium ('serum starved'). Serum-starvation reduced oxygen consumption rate (OCR), extracellular acidification rate (ECAR), ATP-linked OCR and maximum mt capacity, reflecting lower ATP demand and mt respiration. Cellular respiratory stateapparent was unchanged by serum deprivation. 4-OHT reduced OCR independent of serum status. Despite having a higher mt DNA/nuclear DNA ratio than MCF-7 cells, T47D cells have a lower OCR and ATP levels and higher proton leak. T47D express higher nuclear respiratory factor-1 (NRF-1) and NRF-1-regulated, nuclear-encoded mitochondrial transcription factor TFAM and cytochrome c, but lower levels of cytochrome c oxidase, subunit IV, isoform 1 (COX4, COX4I1). Mitochondrial reserve capacity, reflecting tolerance to cellular stress, was higher in serum-starved T47D cells and was increased by 4-OHT, but was decreased by 4-OHT in MCF-7 cells. These data demonstrate critical differences in cellular energetics and responses to 4-OHT in these two ERalpha+ cell lines, likely reflecting cancer cell avoidance of apoptosis. PMID- 25279504 TI - Percutaneous extrusion of an implanted spinal cord stimulator. PMID- 25279505 TI - Room temperature growth of ultrathin Au nanowires with high areal density over large areas by in situ functionalization of substrate. AB - Although ultrathin Au nanowires (~2 nm diameter) are expected to demonstrate several interesting properties, their extreme fragility has hampered their use in potential applications. One way to improve the stability is to grow them on substrates; however, there is no general method to grow these wires over large areas. The existing methods suffer from poor coverage and associated formation of larger nanoparticles on the substrate. Herein, we demonstrate a room temperature method for growth of these nanowires with high coverage over large areas by in situ functionalization of the substrate. Using control experiments, we demonstrate that an in situ functionalization of the substrate is the key step in controlling the areal density of the wires on the substrate. We show that this strategy works for a variety of substrates ranging like graphene, borosil glass, Kapton, and oxide supports. We present initial results on catalysis using the wires grown on alumina and silica beads and also extend the method to lithography free device fabrication. This method is general and may be extended to grow ultrathin Au nanowires on a variety of substrates for other applications. PMID- 25279506 TI - Magnet supporting patient safety. PMID- 25279507 TI - A new mindset for quality and safety: the QSEN competencies redefine nurses' roles in practice. AB - Preventable errors are a major issue in health care. The complexity of health care requires interactions among numerous providers for any patient multiple times a day. Nurses are the constant presence with patients and have an important role in coordinating the contributions of the myriad of caregivers. Nurses are also the last line of defense. Increasingly, it is recognized that nurses need to be better prepared with quality and safety competencies to have a leading role in making our healthcare system safer.This article presents evidence related to quality and safety, describes the six core competencies from the Quality and Safety Education for Nurses (QSEN) project for integration in nursing practice, describes a practice based on inquiry and engagement, and presents a toolkit for developing a new mindset based on new quality and safety science. PMID- 25279508 TI - The effect of critical care nursing and organizational characteristics on pediatric cardiac surgery mortality in the United States. AB - OBJECTIVE: This study explored pediatric critical care nursing and organizational factors that impact in-hospital mortality for cardiac surgery patients across children's hospitals in the United States. BACKGROUND: Congenital heart disease is the most common birth defect and the no. 1 cause of death for infants with a congenital defect. Little is known about the impact of pediatric critical care nursing and organizational factors on pediatric mortality. METHODS: Nursing leaders from 38 children's hospitals that contribute data to the Pediatric Health Information System data set completed an organizational assessment for years 2009 and 2010. These data were linked with patient-level data. The Risk Adjustment for Congenital Heart Surgery method was used to adjust for baseline patient differences in patients younger than 18 years. RESULTS: The odds of death increased as the institutional percentage of pediatric critical care unit nurses with 2 years' clinical experience or less increased. The odds of mortality were highest when the percentage of RNs with 2 years' clinical experience or less was 20% or greater. The odds of death decreased as the institutional percentage of critical care nurses with 11 years' clinical experience or more increased and for hospitals participating in national quality metric benchmarking. Clinical experience was independently associated with in-hospital mortality. CONCLUSIONS: These data are the 1st to link clinical nursing experience with pediatric patient outcomes. A cut point of 20% RNs or greater with 2 years' clinical experience or less was determined to significantly affect inpatient mortality. Participation in national quality metric benchmarking programs was significantly associated with improved mortality. PMID- 25279510 TI - Patient safety is the foundation. PMID- 25279509 TI - Leadership, safety climate, and continuous quality improvement: impact on process quality and patient safety. AB - BACKGROUND: Successful amelioration of medical errors represents a significant problem in the health care industry. There is a need for greater understanding of the factors that lead to improved process quality and patient safety outcomes in hospitals. PURPOSE: We present a research model that shows how transformational leadership, safety climate, and continuous quality improvement (CQI) initiatives are related to objective quality and patient safety outcome measures. METHODOLOGY/APPROACH: The proposed framework is tested using structural equation modeling, based on data collected for 204 hospitals, and supplemented with objective outcome data from the Centers for Medicare and Medicaid Services. FINDINGS: The results provide empirical evidence that a safety climate, which is connected to the chief executive officer's transformational leadership style, is related to CQI initiatives, which are linked to improved process quality. A unique finding of this study is that, although CQI initiatives are positively associated with improved process quality, they are also associated with higher hospital-acquired condition rates, a measure of patient safety. Likewise, safety climate is directly related to improved patient safety outcomes. PRACTICAL IMPLICATIONS: The notion that patient safety climate and CQI initiatives are not interchangeable or universally beneficial is an important contribution to the literature. The results confirm the importance of using CQI to effectively enhance process quality in hospitals, and patient safety climate to improve patient safety outcomes. The overall pattern of findings suggests that simultaneous implementation of CQI initiatives and patient safety climate produces greater combined benefits. PMID- 25279512 TI - Techniques to improve patient safety in hospitals: what nurse administrators need to know. AB - Nurse administrators are challenged to determine the best use of limited resources to support organizational patient safety improvement efforts. This article reviews the literature on techniques to reduce errors and improve patient safety in hospitals with a focus on team training initiatives. Implications for nurse administrators are discussed. PMID- 25279511 TI - How hospital leaders contribute to patient safety through the development of trust. AB - OBJECTIVE: The aim of this study was to explore the associations between hospital management support for patient safety, registered nurses' trust in hospital management, and their overall perception of patient safety, considering aspects of safety communication as possible mediating variables. BACKGROUND: Limited research exists regarding how key elements of a patient safety culture, that is, leadership, safety communication, and trust, are interrelated. METHODS: This study used cross-sectional nurse survey data from 1,633 registered nurses working in 35 acute care hospitals participating in the Swiss arm of the RN4CAST (Nurse Forecasting in Europe) study. RESULTS: A path analysis revealed that the indirect associations between "management support for patient safety" and "overall perception of patient safety" were more prominent than the direct association. CONCLUSION: Our findings confirm that safety communication plays a partially mediating role between "management support for patient safety" and nursing professionals' assessments of patient safety. This suggests that hospital leader unit exchanges might improve patient safety. PMID- 25279513 TI - Exploring relationships between patient safety culture and patients' assessments of hospital care. AB - OBJECTIVES: The purpose of this study was to examine relationships among 2 Agency for Healthcare Research and Quality measures of hospital patient safety and quality, which reflect different perspectives on hospital performance: the Hospital Survey on Patient Safety Culture (Hospital SOPS)--a hospital employee patient safety culture survey--and the Consumer Assessment of Healthcare Providers and Systems Hospital Survey (CAHPS Hospital Survey)--a survey of the experiences of adult inpatients with hospital care and services. Our hypothesis was that these 2 measures would be positively related. METHODS: We performed multiple regressions to examine the relationships between the Hospital SOPS measures and CAHPS Hospital Survey measures, controlling for hospital bed size and ownership. Analyses were conducted at the hospital level with each survey's measures using data from 73 hospitals that administered both surveys during similar periods. RESULTS: Higher overall Hospital SOPS composite average scores were associated with higher overall CAHPS Hospital Survey composite average scores (r = 0.41, P G 0.01). Twelve of 15 Hospital SOPS measures were positively related to the CAHPS Hospital Survey composite average score after controlling for bed size and ownership, with significant standardized regression coefficients ranging from 0.25 to 0.38. None of the Hospital SOPS measures were significantly correlated with either of the two single-item CAHPS Hospital Survey measures (hospital rating and willingness to recommend). CONCLUSIONS: This study found that hospitals where staff have more positive perceptions of patient safety culture tend to have more positive assessments of care from patients. This finding helps validate both surveys and suggests that improvements in patient safety culture may lead to improved patient experience with care. Further research is needed to determine the generalizability of these results to larger sets of hospitals, to hospital units, and to other settings of care. PMID- 25279515 TI - Metallo-cryptophanes decorated with bis-N-heterocyclic carbene ligands: self assembly and guest uptake into a nonporous crystalline lattice. AB - Pd3L2 metallo-cryptophane cages with cyclotriveratrylene-type L ligands can be stabilized by use of a bis-N-heterocyclic carbene as an auxiliary cis-protecting ligand, while use of more common protecting chelating ligands such as ethylenediamine saw a Pd3L2 to Pd6L8 rearrangement occur in solution. The crystalline Pd3L2 complexes act as sponges, taking up 1,2-dichorobenzene or iodine in a single-crystal-to-single-crystal fashion despite not exhibiting conventional porosity. PMID- 25279514 TI - Niche-partitioning of edaphic microbial communities in the Namib Desert gravel plain Fairy Circles. AB - Endemic to the Namib Desert, Fairy Circles (FCs) are vegetation-free circular patterns surrounded and delineated by grass species. Since first reported the 1970's, many theories have been proposed to explain their appearance, but none provide a fully satisfactory explanation of their origin(s) and/or causative agent(s). In this study, we have evaluated an early hypothesis stating that edaphic microorganisms could be involved in their formation and/or maintenance. Surface soils (0-5 cm) from three different zones (FC center, FC margin and external, grass-covered soils) of five independent FCs were collected in April 2013 in the Namib Desert gravel plains. T-RFLP fingerprinting of the bacterial (16S rRNA gene) and fungal (ITS region) communities, in parallel with two-way crossed ANOSIM, showed that FC communities were significantly different to those of external control vegetated soil and that each FC was also characterized by significantly different communities. Intra-FC communities (margin and centre) presented higher variability than the controls. Together, these results provide clear evidence that edaphic microorganisms are involved in the Namib Desert FC phenomenon. However, we are, as yet, unable to confirm whether bacteria and/or fungi communities are responsible for the appearance and development of FCs or are a general consequence of the presence of the grass-free circles. PMID- 25279516 TI - Internationalization. PMID- 25279518 TI - How sample size influences research outcomes. AB - Sample size calculation is part of the early stages of conducting an epidemiological, clinical or laboratory study. In preparing a scientific paper, there are ethical and methodological indications for its use. Two investigations conducted with the same methodology and achieving equivalent results, but different only in terms of sample size, may point the researcher in different directions when it comes to making clinical decisions. Therefore, ideally, samples should not be small and, contrary to what one might think, should not be excessive. The aim of this paper is to discuss in clinical language the main implications of the sample size when interpreting a study. PMID- 25279517 TI - The use of bisphosphonates does not contraindicate orthodontic and other types of treatment! AB - Bisphosphonates have been increasingly used not only to treat bone diseases as well as conditions such as osteopenia and osteoporosis, but also in oncotherapy. The use of bisphosphonates induces clinicians to fear and care. These reactions are associated with controversy resulting from lack of in-depth knowledge on the mechanisms of action as well as lack of a more accurate assessment of side effects. Scientific and clinical knowledge disclosure greatly contributes to professionals' discernment and inner balance, especially orthodontists. Fear does not lead to awareness. For these reasons, we present an article that focuses on that matter. This article was adapted from different journals of different dental specialties, as mentioned on footnote. There is no scientific evidence demonstrating that bisphosphonates are directly involved with etiopathogenic mechanisms of osteonecrosis and jaw osteomyelitis. Their use is contraindicated and limited in cases of dental treatment involving bone tissue. Nevertheless, such fact is based on professional opinion, case reports, and personal experience or trials with flaws in experimental methods. Additional studies will always be necessary; however, in-depth knowledge on bone biology is of paramount importance to offer an opinion about the clinical use of bisphosphonates and their further implications. Based on bone biopathology, this article aims at contributing to lay people the groundwork for this matter. PMID- 25279519 TI - An interview with Nigel Harradine. PMID- 25279520 TI - Influence of initial occlusal severity on time and efficiency of Class I malocclusion treatment carried out with and without premolar extractions. AB - INTRODUCTION: The aim of this retrospective study was to compare the occlusal outcomes, duration and efficiency of Class I malocclusion treatment carried out with and without premolar extractions in patients with different degrees of initial malocclusion severity. METHODS: Complete records of 111 patients were obtained and divided into two groups: Group 1 consisted of 65 patients at an initial mean age of 13.82 years old treated with four premolar extractions; whereas Group 2 consisted of 46 patients at an initial mean age of 14.01 years old treated without extractions. Two subgroups were obtained from each group (1A, 1B, 2A and 2B) with different degrees of malocclusion severity according to the initial values of PAR index. Compatibility was assessed using chi-square and t tests. The subgroups were compared by means of Analysis of Variance (ANOVA). The variables that might be related to treatment duration and efficiency were assessed using the multiple linear regression analysis. RESULTS: Initial malocclusion severity was positively related to the amount of occlusal correction and consequently to a higher efficiency index. Moreover, extraction protocol showed a positive relationship with treatment duration and a negative relationship with treatment efficiency. CONCLUSION: Extraction and non-extraction protocols for correction of Class I malocclusion provide similar satisfactory results; however, the extraction protocol increases the overall treatment duration. Orthodontic treatment is more efficient in cases with high initial malocclusion severity treated with a non-extraction protocol. PMID- 25279521 TI - Comparative study of dental cephalometric patterns of Japanese-Brazilian, Caucasian and Mongoloid patients. AB - INTRODUCTION: The objective of this study was to identify the patterns of dental variables of adolescent Japanese-Brazilian descendants with normal occlusion, and also to compare them with a similar Caucasian and Mongoloid sample. METHODS: Lateral cephalometric radiographs were used to compare the groups: Caucasian (n = 40), Japanese-Brazilian (n = 32) and Mongoloid (n = 33). The statistical tests used were one-way ANOVA and ANCOVA. The cephalometric measurements used followed the analyses of Steiner, Tweed and McNamara Jr. RESULTS: Statistical differences (P < 0.05) indicated a smaller interincisal angle and overbite for the Japanese Brazilian sample, when compared to the Caucasian sample, although with similar values to the Mongoloid group. CONCLUSION: The dental patterns found for the Japanese-Brazilian descendants were, in general, more similar to those of the Mongoloid sample. PMID- 25279522 TI - Skeletal maturation in individuals with Down's syndrome: comparison between PGS curve, cervical vertebrae and bones of the hand and wrist. AB - INTRODUCTION: This study was conducted with the aim of adapting the methods developed by Martins and Sakima to assess skeletal maturation by cervical vertebrae in the pubertal growth spurt (PGS) curve. It also aimed to test the reliability and agreement between those methods and the method of hand and wrist radiograph when compared two by two and all together. METHODS: The sample comprised 72 radiographs, with 36 lateral radiographs of the head and 36 hand wrist radiographs of 36 subjects with Down's syndrome (DS), 13 female and 23 male, aged between 8 years and 6 months and 18 years and 7 months, with an average age of 13 years and 10 months. RESULTS AND CONCLUSIONS: Results revealed that adapting the methods developed by Martins and Sakima to assess skeletal maturation by cervical vertebrae in the PGS curve is practical and useful in determining the stage of growth and development of individuals. The stages of maturation evaluated by cervical vertebrae and ossification centers observed in radiographs of the hand and wrist were considered reliable, with excellent level of agreement between the methods by Hassel and Farman as well as Baccetti, Franchi and McNamara Jr and Martins and Sakima. Additionally, results revealed an agreement that ranged between reasonable to good for the three methods used to assess the skeletal maturation, showing statistical significance. PMID- 25279523 TI - In vitro cytotoxicity of self-curing acrylic resins of different colors. AB - OBJECTIVE: The aim of this study was to assess the in vitro cytotoxicity of acrylic resins of different colors over time. METHODS: Specimens were divided into 4 groups (n = 6) according to the color of the acrylic resin (Orto Class, Classico, Campinas, Sao Paulo, Brazil): Group 1, clear acrylic resin; Group 2, pink acrylic resin; Group 3, blue acrylic resin; and Group 4, green acrylic resin. All specimens were fabricated according to the mass manipulation technique and submitted to mechanical polishing protocol. The control was performed with an amalgam specimen (C+), a glass specimen (C-) and cell control (CC). Specimens were immersed in Minimum Eagle's Medium (MEM) and incubated for 24 h at 37oC. The extracts from the experimental material were filtered and mixed with L929 fibroblast. Cytotoxicity was evaluated at four different times, 24, 48, 72 and 168 h. After contact, cells were incubated for 24 h and added to 100 u of 0.01% neutral red dye. The cells were incubated for 3 h for pigment incorporation and fixed. Cells viability was determined by a spectroscopic (BioTek, Winooski, Vermont, USA) with a 492-nm wavelength lambda=492 nm). RESULTS: There were no statistical differences between the experimental groups and the CC and C- groups. CONCLUSION: Clear, pink, blue and green self-curing acrylic resins fabricated by means of the mass manipulation technique and mechanically polished are not cytotoxic. Neither the pigment added to the self-curing acrylic resin nor the factor of time influenced the cytotoxicity of the material. PMID- 25279524 TI - Three-dimensional dental arch changes of patients submitted to orthodontic surgical treatment for correction of Class II malocclusion. AB - INTRODUCTION: This study assessed the three-dimensional changes in the dental arch of patients submitted to orthodontic-surgical treatment for correction of Class II malocclusions at three different periods. METHODS: Landmarks previously identified on upper and lower dental casts were digitized on a three-dimensional digitizer MicroScribe-3DX and stored in Excel worksheets in order to assess the width, length and depth of patient's dental arches. RESULTS: During orthodontic preparation, the maxillary and mandibular transverse dimensions measured at the premolar regions were increased and maintained throughout the follow-up period. Intercanine width was increased only in the upper arch during orthodontic preparation. Maxillary arch length was reduced during orthodontic finalization, only. Upper and lower arch depths were stable in the study periods. Differences between changes in centroid and gingival points suggested that upper and lower premolars buccaly proclined during the pre-surgical period. CONCLUSIONS: Maxillary and mandibular dental arches presented transverse expansion at premolar regions during preoperative orthodontic preparation, with a tendency towards buccal tipping. The transverse dimensions were not altered after surgery. No sagittal or vertical changes were observed during the follow-up periods. PMID- 25279525 TI - Lateral cephalometric diagnosis of asymmetry in Angle Class II subdivision compared to Class I and II. AB - INTRODUCTION: Lateral cephalometric radiographs are traditionally required for orthodontic treatment, yet rarely used to assess asymmetries. OBJECTIVE: The objective of the present study was to use lateral cephalometric radiographs to identify existing skeletal and dentoalveolar morphological alterations in Class II subdivision and to compare them with the existing morphology in Class I and II relationship. MATERIAL AND METHODS: Ninety initial lateral cephalometric radiographs of male and female Brazilian children aged between 12 to 15 years old were randomly and proportionally divided into three groups: Group 1 (Class I), Group 2 (Class II) and Group 3 (Class II subdivision). Analysis of lateral cephalometric radiographs included angular measurements, horizontal linear measurements and two indexes of asymmetry that were prepared for this study. RESULTS: In accordance with an Index of Dental Asymmetry (IDA), greater mandibular dental asymmetry was identified in Group 3. An Index of Mandibular Asymmetry (IMA) revealed less skeletal and dental mandibular asymmetry in Group 2, greater skeletal mandibular asymmetry in Group 1, and greater mandibular dental asymmetry in Group 3. CONCLUSION: Both IDA and IMA revealed greater mandibular dental asymmetry for Group 3 in comparison to Groups 1 and 2. These results are in accordance with those found by other diagnostic methods, showing that lateral cephalometric radiography is an acceptable method to identify existing skeletal and dentoalveolar morphological alterations in malocclusions. PMID- 25279526 TI - Lateral cephalometric radiograph versus lateral nasopharyngeal radiograph for quantitative evaluation of nasopharyngeal airway space. AB - OBJECTIVE: This study compared lateral radiographs of the nasopharynx (LN) and lateral cephalometric radiographs (LC) used to assess nasopharyngeal airway space in children. MATERIAL AND METHODS: One examiner measured the nasopharyngeal space of 15 oral breathing patients aged between 5 and 11 years old by using LN and LC. Both assessments were made twice with a 15-day interval in between. Intergroup comparison was performed with t-tests (P < 0.05). RESULTS: Comparison between LN and LC measurements showed no significant differences. CONCLUSION: Lateral cephalometric radiograph is an acceptable method used to assess nasopharyngeal airway space. PMID- 25279527 TI - Effectiveness of orofacial myofunctional therapy in orthodontic patients: a systematic review. AB - OBJECTIVE: The aim of the present systematic review was to determine the existence of scientific evidence demonstrating the effectiveness of orofacial myofunctional therapy (OMT) as an adjuvant to orthodontic treatment in individuals with orofacial disorders. A further aim was to assess the methodological quality of the studies included in the review. METHODS: An electronic search was performed in eight databases (Medline, BBO, LILACS, Web of Science, EMBASE, BIREME, Cochrane Library and SciELO) for papers published between January 1965 and March 2011, with no language restrictions. Selection of articles and data extraction were performed by two independent researchers. The quality of the selected articles was also assessed. RESULTS: Search strategy resulted in the retrieval of 355 publications, of which only 4 fulfilled the eligibility criteria and qualified for final analysis. All papers selected had a high risk of bias. CONCLUSIONS: The findings of the present systematic review demonstrate the scarcity of consistent studies and scientific evidence supporting the use of OMT in combination with orthodontic treatment to achieve better results in the correction of dentofacial disorders in individuals with orofacial abnormalities. PMID- 25279528 TI - Orthodontic post-adjustment pain control with acupuncture. AB - OBJECTIVE: This study aimed to evaluate the analgesic efficacy of systemic acupuncture therapy on the pain caused after orthodontic adjustments. METHODS: An initial sample of 30 orthodontic patients with fixed appliances monthly adjusted was selected; however, only 11 participants completed the study. For this reason, final sample comprised these patients' data only. Initially, average pain levels were assessed at different periods by means of an analogue visual scale (VAS) for three months without acupuncture. In the following three months, the volunteers were submitted to systemic acupuncture sessions on Hegu (LI4) and Jiache (St6) points, before orthodontic adjustments were carried out. RESULTS: Results revealed statistically significant reduction in pain level indexes both for men (P = 0.030) and women (P = 0.028) when acupuncture therapy was performed prior to orthodontic adjustment. Patients did not present any side effects. CONCLUSION: Acupuncture is a safe and effective method in reducing orthodontic post adjustment pain. PMID- 25279529 TI - Tooth-size discrepancy: a comparison between manual and digital methods. AB - INTRODUCTION: Technological advances in Dentistry have emerged primarily in the area of diagnostic tools. One example is the 3D scanner, which can transform plaster models into three-dimensional digital models. OBJECTIVE: This study aimed to assess the reliability of tooth size-arch length discrepancy analysis measurements performed on three-dimensional digital models, and compare these measurements with those obtained from plaster models. MATERIAL AND METHODS: To this end, plaster models of lower dental arches and their corresponding three dimensional digital models acquired with a 3Shape R700T scanner were used. All of them had lower permanent dentition. Four different tooth size-arch length discrepancy calculations were performed on each model, two of which by manual methods using calipers and brass wire, and two by digital methods using linear measurements and parabolas. RESULTS: Data were statistically assessed using Friedman test and no statistically significant differences were found between the two methods (P > 0.05), except for values found by the linear digital method which revealed a slight, non-significant statistical difference. CONCLUSIONS: Based on the results, it is reasonable to assert that any of these resources used by orthodontists to clinically assess tooth size-arch length discrepancy can be considered reliable. PMID- 25279530 TI - In vitro study of color stability of polycrystalline and monocrystalline ceramic brackets. AB - OBJECTIVE: The aim of this in vitro study was to analyze color stability of monocrystalline and polycrystalline ceramic brackets after immersion in dye solutions. METHODS: Seven ceramic brackets of four commercial brands were tested: Two monocrystalline and two polycrystalline. The brackets were immersed in four dye solutions (coffee, red wine, Coke and black tea) and in artificial saliva for the following times: 24 hours, 7, 14 and 21 days, respectively. Color changes were measured by a spectrophotometer. Data were assessed by Multivariate Profile Analysis, Analysis of Variance (ANOVA) and Multiple Comparison Tests of means. RESULTS: There was a perceptible change of color in all ceramic brackets immersed in coffee (DeltaE* Allure = 7.61, Inspire Ice = 6.09, Radiance = 6.69, Transcend = 7.44), black tea (DeltaE* Allure = 6.24, Inspire Ice = 5.21, Radiance = 6.51, Transcend = 6.14) and red wine (DeltaE* Allure = 6.49, Inspire Ice = 4.76, Radiance = 5.19, Transcend = 5.64), but no change was noticed in Coke and artificial saliva (DeltaE < 3.7). CONCLUSION: Ceramic brackets undergo color change when exposed to solutions of coffee, black tea and red wine. However, the same crystalline structure, either monocrystalline or polycrystalline, do not follow the same or a similar pattern in color change, varying according to the bracket fabrication, which shows a lack of standardization in the manufacturing process. Coffee dye produced the most marked color changes after 21 days of immersion for most ceramic brackets evaluated. PMID- 25279531 TI - Two-phase treatment of patients with crossbite and tendency toward skeletal Class III malocclusion. AB - Angle Class III malocclusion is characterized by an inadequate anteroposterior dental relationship which may or may not be accompanied by skeletal changes. In general, patients are distressed by a significantly compromised facial aspect which, when associated with a deficient middle third, encourages patients to seek treatment. This article reports a two-phase treatment carried out in a female patient aged six years and six months with a tendency towards a Class III skeletal pattern. This case was presented to the Brazilian Board of Orthodontics and Facial Orthopedics (BBO). It is representative of the category with Discrepancy Index (DI) equal or greater than 10, and fulfills part of the requirements for obtaining BBO Diploma. PMID- 25279532 TI - 10 commandments of smile esthetics. AB - The search for esthetic treatment has persisted in the routine of dental professionals. Following this trend, dental patients have sought treatment with the primary aim of improving smile esthetics. The aim of this article is to present a protocol to assess patient's smile: The 10 Commandments of smile esthetics. PMID- 25279533 TI - Traumatic ossicular disruption with isolated fracture of the stapes suprastructure: comparison with incudostapedial joint dislocation. AB - CONCLUSION: More severe high frequency hearing loss, especially at 8 kHz, occurs with fracture of the stapes suprastructure (SSF) compared with isolated incudostapedial joint dislocation (ISD). Successful hearing gain can be achieved in the speech range with appropriate ossicular reconstruction. OBJECTIVES: Traumatic SSF is a rare consequence of head trauma. This study aimed to demonstrate the characteristic features of SSF compared with traumatic ISD. METHODS: Eighteen patients who suffered from conductive hearing loss after head trauma and were operated from 2000 to 2012 were enrolled. Eight and 10 patients were confirmed to have a traumatic SSF (SSF group) and ISD (ISD group), respectively. The etiology of ossicular disruption, preoperative CT scan of the temporal bone, and intraoperative findings were retrospectively reviewed. Pre- and postoperative hearing was analyzed by both pure tone averages and thresholds at each frequency (0.5-8 kHz). RESULTS: The most common etiologies in the SSF group were fall (n = 3) and direct ear trauma (n = 3), and for those in the ISD group, the most common etiology was traffic accident (n = 6). CT scan showed no evidence of fracture in the SSF group, whereas findings of ossicular dislocation were found in 70% of patients in the ISD group. Hearing outcomes according to the frequencies demonstrated that pre- and postoperative hearing loss at 8 kHz was more severe in the SSF group than in the ISD group. In a comparison of hearing outcomes at each frequency, the postoperative hearing threshold at 8 kHz was higher than for other frequencies. Postoperatively, 63% of the SSF group and 70% of the ISD group obtained an air-bone gap of within 15 dB. PMID- 25279534 TI - Maintenance: the key to successful periodontal and implant therapy. AB - The management of periodontal diseases requires an effective treatment and maintenance program, as well as collaboration among clinicians. Having a better understanding of the factors contributing to periodontal maintenance is key. The components of a maintenance program and determining proper intervals ensure that patients increase their chances for maintaining their teeth and implants in an optimal state of health. PMID- 25279535 TI - Traditional and emerging diagnostic strategies for identifying risk. AB - Like other healthcare professionals, dentists are in a position to not only treat but also prevent chronic diseases using individualized treatment plans that address disease risk and preventive measures that can be initiated prior to the appearance of symptoms. Such measures start with assessment of risk based on the patient's past history of disease and risk factors. PMID- 25279536 TI - Contingency, priority, and risk (CPR) protocol: a roadmap for designing successful and long-lasting implant therapy. AB - Poorly planned implant-supported restorations not only cause discomfort for patients, but they can also seriously damage the intraoral cavity. Sometimes clinicians inherit cases with poorly planned implant-supported restorations, while other times they may create this problem by not addressing a patient's overall condition prior to treatment planning. Clinicians require a realistic approach for designing prostheses in a comprehensive way. The CPR--ie, contingency, priority, and risk treatment planning--technique aids in identifying potential problems and creating a practical treatment option. By addressing the treatment-planning process in this manner, clinicians are better equipped to design successful and long-lasting implant restorations. PMID- 25279537 TI - Intraoral digital impressions to enhance implant esthetics. AB - Providing an accurate soft-tissue transfer for anterior implants is not a new concept; however, it is currently an especially relevant one. There are numerous documented cases in which residual excess cement with cement-retained implant restorations was a contributing cause in periimplantitis. In 2012, Wadhwani et al reported the importance of placing the crown abutment margins supragingivally for ease of cement removal as a possible solution to address this important issue. Therefore, if placement of the crown abutment margin location is imperative, making an impression that reproduces the soft tissue is equally critical. In 1997, this author introduced the "custom impression coping" to achieve such an accurate transfer. Given the wide use of intraoral digital impressions in 2014, this discussion describes how to fabricate a "custom scan body" using that technology to replicate the transition zone in the virtual environment. PMID- 25279538 TI - Laser-induced fluorescence detection of hot molecular oxygen in flames using an alexandrite laser. AB - The use of an alexandrite laser for laser-induced fluorescence (LIF) spectroscopy and imaging of molecular oxygen in thermally excited vibrational states is demonstrated. The laser radiation after the third harmonic generation was used to excite the B-X (0-7) band at 257 nm in the Schumann-Runge system of oxygen. LIF emission was detected between 270 and 380 nm, revealing distinct bands of the transitions from B(0) to highly excited vibrational states in the electronic ground state, X (v > 7). At higher spectral resolution, these bands reveal the common P- and R-branch line splitting. Eventually, the proposed LIF approach was used for single-shot imaging of the two-dimensional distribution of hot oxygen molecules in flames. PMID- 25279539 TI - An effective and practical immunohistochemical protocol for bone specimens characterized by hyaluronidase and pepsin predigestion combined with alkaline phosphatase-mediated chromogenic detection. AB - The aim of this study was to provide an effective procedure for immunohistochemistry (IHC) investigations of bone specimens. Samples from rat femoral and human vertebral bone were processed with a detailed and effective IHC protocol summarized here. First, a novel antigen retrieval (AR) method of hyaluronidase combined pepsin predigestion (H+P) was established and the optimal concentration and pH value for AR of bone specimens were determined. Second, the newly developed method was compared with existing AR methods (boiling in sodium citrate, hyaluronidase predigestion (H) and pepsin predigestion (P), with PBS only as the negative control) using two chromogenic detection systems (horseradish peroxidase (HRP) and alkaline phosphatase (AP)) to evaluate their efficacy in obtaining the best IHC results for bone samples. Considering the drawbacks of significant shrinking and detachment from slide for heat retrieval methods and the only moderate immunolabeling for H and P, H+P was the optimal AR method for IHC of bone specimens with the advantages of both good morphological preservation and strong immunoreactivity. Moreover, AP-mediated chromogenic detection was superior to HRP-labeled chromogenic detection due to significantly less non-specific staining. In conclusion, we presented an effective and practical IHC protocol for bone specimens characterized by H+P predigestion combined with AP-mediated chromogenic detection. Finally, a detailed troubleshooting guide was provided for common mistakes that occur during IHC processing of the bone tissue samples. PMID- 25279540 TI - Implantable photonic devices for improved medical treatments. AB - An evolving area of biomedical research is related to the creation of implantable units that provide various possibilities for imaging, measurement, and the monitoring of a wide range of diseases and intrabody phototherapy. The units can be autonomic or built-in in some kind of clinically applicable implants. Because of specific working conditions in the live body, such implants must have a number of features requiring further development. This topic can cause wide interest among developers of optical, mechanical, and electronic solutions in biomedicine. We introduce preliminary clinical trials obtained with an implantable pill and devices that we have developed. The pill and devices are capable of applying in body phototherapy, low-level laser therapy, blue light (450 nm) for sterilization, and controlled injection of chemicals. The pill is also capable of communicating with an external control box, including the transmission of images from inside the patient's body. In this work, our pill was utilized for illumination of the sinus-carotid zone in dog and red light influence on arterial pressure and heart rate was demonstrated. Intrabody liver tissue laser ablation and nanoparticle-assisted laser ablation was investigated. Sterilization effect of intrabody blue light illumination was applied during a maxillofacial phlegmon treatment. PMID- 25279541 TI - Different doses of low-level laser irradiation modulate the in vitro response of osteoblast-like cells. AB - Because osteoblasts play a key role in bone remodeling and the influence of low level laser therapy on this process is not clear, Saos-2 human osteoblast-like cells were irradiated by a gallium-aluminum-arsenide diode laser (915 nm) for 10, 48, 96, 193, and 482 s using doses 1, 5, 10, 20, and 50 J/cm2, respectively. A control group was not irradiated. Morphology, viability, and cytotoxicity analyses were carried out after 1 hr, 1 day, and 3 days. Deoxyribose nucleic acid (DNA) content and release of vascular endothelial growth factor (VEGF), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were evaluated. Viability was modulated by laser irradiation in a dose-dependent manner, with 10 J/cm2 inducing a biostimulatory response and 20 to 50 J/cm2 determining a bioinhibitory and cytotoxic effect. Accordingly, DNA content was generally increased for the 10 J/cm2 dose and decreased for the 50 J/cm2 dose. A rapid and transitory trend toward increased RANKL/OPG ratio and a tendency toward a delayed increase in VEGF release for doses of 1 to 10 J/cm2 was found. Further investigations using the biostimulatory dose of 10 J/cm2 emerged from this study are needed to establish the ideal treatment regimens in the laboratory as well as in clinical practice. PMID- 25279542 TI - CpG oligodeoxynucleotide inhibits HBV replication in a hydrodynamic injection murine model. AB - BACKGROUND: Chronic HBV infection is a significant public health problem and one major cause of liver cirrhosis and hepatocellular carcinoma (HCC). HBV impairs the host immune system and results in immunotolerance, which is a major obstacle to HBV therapy. CpG oligodeoxynucleotide (ODN) is a strong immunostimulant which activates the innate immune response rapidly and has been shown to be an efficient therapy agent in viral infection treatment. Here, we report the anti HBV activity of CpG-1826 in a hydrodynamic injection murine model. METHODS: CpG 1826 was administrated intraperitoneally every other day in HBV carrier mice established by tail vein hydrodynamic injection of HBV plasmids. The serum concentrations of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), HBV surface antibody (HBsAb), HBV core antibody (HBcAb), interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) were measured by enzyme-linked immunosorbent assay (ELISA). The activities of alanine aminotransferase (ALT) were determined by ALT kit using a Spectramax Plus spectrophotometer. Hepatic HBV DNA was quantified by quantitative real-time PCR. The expression of HBV core antigen (HBcAg) in liver was detected by immunohistochemistry. Drug toxicity of CpG-1826 was evaluated by body weighting and liver histopathology confirmation. RESULTS: CpG-1826 administration inhibited HBV replication efficiently with significant reduction of serum HBsAg and HBeAg, hepatic HBcAg and HBV DNA levels. The serum levels of IFN-alpha, IFN-gamma and HBsAb increased but the HBcAb level declined in the CpG 1826 group compared to CpG-1982 and PBS control groups. Results of ALT activity indicated no significant difference among CpG-1826 group, CpG-1982 and PBS control groups. Body weighting and histopathology examination showed no obvious toxicity. CONCLUSIONS: Given the stimulation activity of a host immune system, CpG ODN is a promising strategy for HBV therapy with more relevant research needed. PMID- 25279543 TI - Ongoing epidemic of cutaneous leishmaniasis among Syrian refugees, Lebanon. AB - In September 2012, a cutaneous leishmaniasis outbreak began among Syrian refugees in Lebanon. For 948 patients in whom leishmaniasis was not confirmed, we obtained samples for microscopic confirmation and molecular speciation. We identified Leishmania tropica in 85% and L. major in 15% of patients. After 3 months of megulamine antimonite therapy, patients initial cure rate was 82%. PMID- 25279544 TI - A health impact assessment of a proposed bill to decrease speed limits on local roads in Massachusetts (U.S.A.). AB - Decreasing traffic speeds increases the amount of time drivers have to react to road hazards, potentially averting collisions, and makes crashes that do happen less severe. Boston's regional planning agency, the Metropolitan Area Planning Council (MAPC), in partnership with the Massachusetts Department of Public Health (MDPH), conducted a Health Impact Assessment (HIA) that examined the potential health impacts of a proposed bill in the state legislature to lower the default speed limits on local roads from 30 miles per hour (mph) to 25 mph. The aim was to reduce vehicle speeds on local roads to a limit that is safer for pedestrians, cyclists, and children. The passage of this proposed legislation could have had far-reaching and potentially important public health impacts. Lower default speed limits may prevent around 18 fatalities and 1200 serious injuries to motorists, cyclists and pedestrians each year, as well as promote active transportation by making local roads feel more hospitable to cyclists and pedestrians. While a lower speed limit would increase congestion and slightly worsen air quality, the benefits outweigh the costs from both a health and economic perspective and would save the state approximately $62 million annually from prevented fatalities and injuries. PMID- 25279547 TI - Targeted communication intervention using nursing crew resource management principles. PMID- 25279545 TI - Ecohealth approach to urban waste management: exposure to environmental pollutants and health risks in Yamoussoukro, Cote d'Ivoire. AB - Poor waste management is a key driver of ill-health in urban settlements of developing countries. The current study aimed at assessing environmental and human health risks related to urban waste management in Yamoussoukro, the political capital of Cote d'Ivoire. We undertook trans-disciplinary research within an Ecohealth approach, comprised of a participatory workshop with stakeholders and mapping of exposure patterns. A total of 492 randomly selected households participated in a cross-sectional survey. Waste deposit sites were characterised and 108 wastewater samples were subjected to laboratory examinations. The physico-chemical parameters of the surface water (temperature, pH, conductivity, potential oxidise reduction, BOD5, COD, dissolved oxygen, nitrates, ammonia and total Kendal nitrogen) did not comply with World Health Organization standards of surface water quality. Questionnaire results showed that malaria was the most commonly reported disease. Diarrhoea and malaria were associated with poor sanitation. Households having dry latrines had a higher risk of diarrhoea (odds ratio (OR) = 1.8, 95% confidence interval (CI) 1.2-2.7) compared to latrines with septic tanks and also a higher risk for malaria (OR = 1.9, 95% (CI) 1.1-3.3). Our research showed that combining health and environmental assessments enables a deeper understanding of environmental threats and disease burdens linked to poor waste management. Further study should investigate the sanitation strategy aspects that could reduce the environmental and health risks in the study area. PMID- 25279548 TI - Baseline drug resistance mutations are detectable in HCV genes NS3 and NS5A but not NS5B in acute and chronic HIV-coinfected patients. PMID- 25279549 TI - High expression of hTERT and stemness genes in BORIS/CTCFL positive cells isolated from embryonic cancer cells. AB - BORIS/CTCFL is a member of cancer testis antigen family normally expressed in germ cells. In tumors, it is aberrantly expressed although its functions are not completely well-defined. To better understand the functions of BORIS in cancer, we selected the embryonic cancer cells as a model. Using a molecular beacon, which specifically targets BORIS mRNA, we demonstrated that BORIS positive cells are a small subpopulation of tumor cells (3-5% of total). The BORIS-positive cells isolated using BORIS-molecular beacon, expressed higher telomerase hTERT, stem cell (NANOG, OCT4, SOX2) and cancer stem cell marker genes (CD44 and ALDH1) compared to the BORIS-negative tumor cells. In order to define the functional role of BORIS, stable BORIS-depleted embryonic cancer cells were generated. BORIS silencing strongly down-regulated the expression of hTERT, stem cell and cancer stem cell marker genes. Moreover, the BORIS knockdown increased cellular senescence in embryonic cancer cells, revealing a putative role of BORIS in the senescence biological program. Our data indicate an association of BORIS expressing cells subpopulation with the expression of stemness genes, highlighting the critical role played by BORIS in embryonic neoplastic disease. PMID- 25279550 TI - Hydroxytyrosol prevents increase of osteoarthritis markers in human chondrocytes treated with hydrogen peroxide or growth-related oncogene alpha. AB - Hydroxytyrosol (HT), a phenolic compound mainly derived from olives, has been proposed as a nutraceutical useful in prevention or treatment of degenerative diseases. In the present study we have evaluated the ability of HT to counteract the appearance of osteoarthritis (OA) features in human chondrocytes. Pre treatment of monolayer cultures of chondrocytes with HT was effective in preventing accumulation of reactive oxidant species (ROS), DNA damage and cell death induced by H2O2 exposure, as well as the increase in the mRNA level of pro inflammatory, matrix-degrading and hypertrophy marker genes, such as iNOS, COX-2, MMP-13, RUNX-2 and VEGF. HT alone slightly enhanced ROS production, but did not enhance cell damage and death or the expression of OA-related genes. Moreover HT was tested in an in vitro model of OA, i.e. three-dimensional micromass cultures of chondrocytes stimulated with growth-related oncogene alpha (GROalpha), a chemokine involved in OA pathogenesis and known to promote hypertrophy and terminal differentiation of chondrocytes. In micromass constructs, HT pre treatment inhibited the increases in caspase activity and the level of the messengers for iNOS, COX-2, MMP-13, RUNX-2 and VEGF elicited by GROalpha. In addition, HT significantly increased the level of SIRT-1 mRNA in the presence of GROalpha. In conclusion, the present study shows that HT reduces oxidative stress and damage, exerts pro-survival and anti-apoptotic actions and favourably influences the expression of critical OA-related genes in human chondrocytes treated with stressors promoting OA-like features. PMID- 25279551 TI - Involvement of trigeminal transition zone and laminated subnucleus caudalis in masseter muscle hypersensitivity associated with tooth inflammation. AB - A rat model of pulpitis/periapical periodontitis was used to study mechanisms underlying extraterritorial enhancement of masseter response associated with tooth inflammation. Periapical bone loss gradually increased and peaked at 6 weeks after complete Freund's adjuvant (CFA) application to the upper molar tooth pulp (M1). On day 3, the number of Fos-immunoreactive (IR) cells was significantly larger in M1 CFA rats compared with M1 vehicle (veh) rats in the trigeminal subnucleus interpolaris/caudalis transition zone (Vi/Vc). The number of Fos-IR cells was significantly larger in M1 CFA and masseter (Mass) capsaicin applied (M1 CFA/Mass cap) rats compared with M1 veh/Mass veh rats in the contralateral Vc and Vi/Vc. The number of phosphorylated extracellular signal regulated kinase (pERK)-IR cells was significantly larger in M1 CFA/Mass cap and M1 veh/Mass cap rats compared to Mass-vehicle applied rats with M1 vehicle or CFA in the Vi/Vc. Pulpal CFA application caused significant increase in the number of Fos-IR cells in the Vi/Vc but not Vc on week 6. The number of pERK-IR cells was significantly lager in the rats with capsaicin application to the Mass compared to Mass-vehicle treated rats after pulpal CFA- or vehicle-application. However, capsaicin application to the Mass did not further affect the number of Fos-IR cells in the Vi/Vc in pulpal CFA-applied rats. The digastric electromyographic (d EMG) activity after Mass-capsaicin application was significantly increased on day 3 and lasted longer at 6 weeks after pulpal CFA application, and these increase and duration were significantly attenuated by i.t. PD98059, a MEK1 inhibitor. These findings suggest that Vi/Vc and Vc neuronal excitation is involved in the facilitation of extraterritorial hyperalgesia for Mass primed with periapical periodontitis or acute pulpal-inflammation. Furthermore, phosphorylation of ERK in the Vi/Vc and Vc play pivotal roles in masseter hyperalgesia after pulpitis or periapical periodontitis. PMID- 25279553 TI - Ruminal paramphistomosis in cattle from northeastern Algeria: prevalence, parasite burdens and species identification. AB - Slaughterhouse samples were analysed over a two-year period (September 2010 August 2012) in Jijel (northeastern Algeria) in order to determine seasonal variations in the prevalence and intensity of bovine paramphistomosis in a Mediterranean climate and identify paramphistome species using molecular biology. In spring and summer, significantly higher prevalences and lower parasite burdens were noted in bull calves, thus indicating an effect of season on these parameters. In contrast, the differences among seasonal prevalences or among seasonal parasite burdens were not significant in the case of old cows. Eleven adult worms from the slaughterhouses of Jijel and three neighbouring departments (Constantine, El Tarf and Setif) were analysed using molecular markers for species identification. Two different species, Calicophoron daubneyi and C. microbothrium, were found. The presence of these two paramphistomids raises the question of their respective frequency in the definitive host and local intermediate hosts. PMID- 25279552 TI - Clathrin assembly protein CALM plays a critical role in KIT signaling by regulating its cellular transport from early to late endosomes in hematopoietic cells. AB - CALM is implicated in the formation of clathrin-coated vesicles, which mediate endocytosis and intracellular trafficking of growth factor receptors and nutrients. We previously found that CALM-deficient mice suffer from severe anemia due to the impaired clathrin-mediated endocytosis of transferrin receptor in immature erythroblast. However, CALM has been supposed to regulate the growth and survival of hematopoietic stem/progenitor cells. So, in this study, we focused on the function of CALM in these cells. We here show that the number of Linage-Sca 1+KIT+ (LSK) cells decreased in the fetal liver of CALM-/- mice. Also, colony forming activity was impaired in CALM-/- LSK cells. In addition, SCF, FLT3, and TPO-dependent growth was severely impaired in CALM-/- LSK cells, while they can normally proliferate in response to IL-3 and IL-6. We also examined the intracellular trafficking of KIT using CALM-/- murine embryonic fibroblasts (MEFs) engineered to express KIT. At first, we confirmed that endocytosis of SCF bound KIT was not impaired in CALM-/- MEFs by the internalization assay. However, SCF-induced KIT trafficking from early to late endosome was severely impaired in CALM-/- MEFs. As a result, although intracellular KIT disappeared 30 min after SCF stimulation in wild-type (WT) MEFs, it was retained in CALM-/- MEFs. Furthermore, SCF-induced phosphorylation of cytosolic KIT was enhanced and prolonged in CALM-/- MEFs compared with that in WT MEFs, leading to the excessive activation of Akt. Similar hyperactivation of Akt was observed in CALM-/- KIT+ cells. These results indicate that CALM is essential for the intracellular trafficking of KIT and its normal functions. Also, our data demonstrate that KIT located in the early endosome can activate downstream molecules as a signaling endosome. Because KIT activation is involved in the pathogenesis of some malignancies, the manipulation of CALM function would be an attractive therapeutic strategy. PMID- 25279554 TI - Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor. AB - Human cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Although its collagenase activity is unique, CatK also exerts a potent elastolytic activity that is shared with human cathepsins V and S. Other members of the cysteine cathepsin family, which are structurally similar, do not exhibit significant collagen and elastin degrading activities. This raises the question of the presence of specific structural elements, exosites, that are required for these activities. CatK has two exosites that control its collagenolytic and elastolytic activity. Modifications of exosites 1 and 2 block the elastase activity of CatK, whereas only exosite-1 alterations prevent collagenolysis. Neither exosite affects the catalytic activity, protease stability, subsite specificity of CatK or the degradation of other biological substrates by this protease. A low-molecular-mass inhibitor that docks into exosite-1 inhibits the elastase and collagenase activity of CatK without interfering with the degradation of other protein substrates. The identification of CatK exosites opens up the prospect of designing highly potent inhibitors that selectively inhibit the degradation of therapeutically relevant substrates by this multifunctional protease. PMID- 25279555 TI - Interactions between medical residents and drug companies: a national survey after the Mediator(r) affair. AB - BACKGROUND: The present study aimed to describe exposure and attitudes of French medical residents towards pharmaceutical industry. The study was performed shortly after the Mediator affair which revealed several serious conflicts of interest inside the French health system. METHODS AND FINDINGS: A cross-sectional study was implemented among residents from 6 French medical faculties. Independent education in pharmacology, attitudes towards the practices of pharmaceutical sales representatives, opinions concerning the pharmaceutical industry, quality of information provided by the pharmaceutical industry, and opinions about pharmaceutical company sponsorship were investigated through a web based questionnaire. We also assessed potential changes in resident attitudes following the Mediator affair. The mean value of exposure to drug companies was 1.9 times per month. Global opinions towards drug company information were negative for 42.7% of the residents and positive for only 8.2%. Surprisingly, 81.6% of residents claimed that they had not changed their practices regarding drug information since the Mediator affair. Multivariate analyses found that residents in anesthesiology were less likely to be exposed than others (OR = 0.17 CI95% [0.05-0.61]), exposure was significantly higher at the beginning of residence (p<0.001) and residents who had a more positive opinion were more frequently exposed to drug companies (OR = 2.12 CI95% [1.07-4.22]). CONCLUSIONS: Resident exposure to drug companies is around 1 contact every 2 weeks. Global opinion towards drug information provided by pharmaceutical companies was negative for around 1 out of 2 residents. In contrast, residents tend to consider the influences of the Mediator affair on their practice as relatively low. This survey enabled us to identify profiles of residents who are obviously less exposed to pharmaceutical industry. Current regulatory provisions are not sufficient, indicating that further efforts are necessary to develop a culture of disclosure of conflict of interest and of transparency in residents. PMID- 25279556 TI - Inactivation of the anterior cingulate reveals enhanced reliance on cortical networks for remote spatial memory retrieval after sequential memory processing. AB - One system consolidation model suggests that as time passes, ensembles of cortical neurons form strong connections to represent remote memories. In this model, the anterior cingulate cortex (ACC) serves as a cortical region that represents remote memories. However, there is debate as to whether remote spatial memories go through this systems consolidation process and come to rely on the ACC. The present experiment examined whether increasing the processing demand on the hippocampus, by sequential training on two spatial tasks, would more fully engage the ACC during retrieval of a remote spatial memory. In this scenario, inactivation of the ACC at a remote time point was hypothesized to produce a severe memory deficit if rats had been trained on two, sequential spatial tasks. Rats were trained on a water maze (WM) task only or a WM task followed by a radial arm maze task. A WM probe test was given recently or remotely to all rats. Prior to the probe test, rats received an injection of saline or muscimol into the ACC. A subtle deficit in probe performance was found at the remote time point in the group trained on only one spatial task and treated with muscimol. In the group trained on two spatial tasks and treated with muscimol, a subtle deficit in probe performance was noted at the recent time point and a substantial deficit in probe performance was observed at the remote time point. c-Fos labeling in the hippocampus revealed more labeling in the CA1 region in all remotely tested groups than recently tested groups. Findings suggest that spatial remote memories come to rely more fully on the ACC when hippocampal processing requirements are increased. Results also suggest continued involvement of the hippocampus in spatial memory retrieval along with a progressive strengthening of cortical connections as time progresses. PMID- 25279557 TI - Reduced topological efficiency in cortical-basal Ganglia motor network of Parkinson's disease: a resting state fMRI study. AB - Parkinson's disease (PD) is mainly characterized by dopamine depletion of the cortico-basal ganglia (CBG) motor circuit. Given that dopamine dysfunction could affect functional brain network efficiency, the present study utilized resting state fMRI (rs-fMRI) and graph theoretical approach to investigate the topological efficiency changes of the CBG motor network in patients with PD during a relatively hypodopaminergic state (12 hours after a last dose of dopamimetic treatment). We found that PD compared with controls had remarkable decreased efficiency in the CBG motor network, with the most pronounced changes observed in rostral supplementary motor area (pre-SMA), caudal SMA (SMA-proper), primary motor cortex (M1), primary somatosensory cortex (S1), thalamus (THA), globus pallidus (GP), and putamen (PUT). Furthermore, reduced efficiency in pre SMA, M1, THA and GP was significantly correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in PD patients. Together, our results demonstrate that individuals with PD appear to be less effective at information transfer within the CBG motor pathway, which provides a novel perspective on neurobiological explanation for the motor symptoms in patients. These findings are in line with the pathophysiology of PD, suggesting that network efficiency metrics may be used to identify and track the pathology of PD. PMID- 25279558 TI - JMY functions as actin nucleation-promoting factor and mediator for p53-mediated DNA damage in porcine oocytes. AB - Junction-mediating and regulatory protein(JMY) is a multifunctional protein with roles in the transcriptional co-activation of p53 and the regulation of actin nucleation promoting factors and, hence, cell migration; however, its role in the maturation of porcine oocytes is unclear. In the current study, we investigated functional roles of JMY in porcine oocytes. Porcine oocytes expressed JMY mRNA and protein, and the mRNA expression level decreased during oocyte maturation. Knockdown of JMY by RNA interference decreased the rate of polar body extrusion, validating its role in the asymmetric division of porcine oocytes. JMY knockdown also down-regulated the mRNA and protein levels of actin and Arp2/3. Furthermore, JMY accumulated in the nucleus in response to DNA damage, and JMY knockdown suppressed DNA damage-mediated p53 activation. In conclusion, our results show that JMY has important roles in oocyte maturation as a regulator of actin nucleation-promoting factors and an activator of p53 during DNA damage during DNA damages in porcine oocytes. PMID- 25279559 TI - Caspr4 interaction with LNX2 modulates the proliferation and neuronal differentiation of mouse neural progenitor cells. AB - Contactin-associated protein 4 (Caspr4), also known as contactin-associated protein-like protein (CNTNAP4), is expressed in various regions of the brain. Recent reports suggest that CNTNAP4 is a susceptibility gene of autism spectrum disorders (ASDs). However, the molecular function of Caspr4 in the brain has yet to be identified. In this study, we show an essential role of Caspr4 in neural progenitor cells (NPCs). Caspr4 is expressed in NPCs in the subventricular zone (SVZ), a neurogenic region in the developing cortex. Knocking down of Caspr4 enhances the proliferation of NPCs derived from the SVZ of embryonic day 14 mouse. Neuronal differentiation is increased by overexpression of Caspr4, but decreased by knocking down of Caspr4 in cultured mouse NPCs. Transfection of the intracellular domain of Caspr4 (C4ICD) rescues the abnormal decreased neuronal differentiation of Caspr4-knocking down NPCs. Ligand of Numb protein X2 (LNX2), a binding partner of Numb, interacts with Caspr4 in a PDZ domain-dependent manner and plays a similar role to Caspr4 in NPCs. Moreover, transfection of LNX2 rescues the decreased neuronal differentiation in Caspr4-knocking down NPCs. In contrast, transfection of C4ICD fails to do so in LNX2-knocking down NPCs. These results indicate that Caspr4 inhibits neuronal differentiation in a LNX-dependent manner. Therefore, this study reveals a novel role of Caspr4 through LNX2 in NPCs, which may link to the pathogenesis of ASDs. PMID- 25279560 TI - A dynamic study of protein secretion and aggregation in the secretory pathway. AB - Precise coordination of protein biogenesis, traffic and homeostasis within the early secretory compartment (ESC) is key for cell physiology. As a consequence, disturbances in these processes underlie many genetic and chronic diseases. Dynamic imaging methods are needed to follow the fate of cargo proteins and their interactions with resident enzymes and folding assistants. Here we applied the Halotag labelling system to study the behavior of proteins with different fates and roles in ESC: a chaperone, an ERAD substrate and an aggregation-prone molecule. Exploiting the Halo property of binding covalently ligands labelled with different fluorochromes, we developed and performed non-radioactive pulse and chase assays to follow sequential waves of proteins in ESC, discriminating between young and old molecules at the single cell level. In this way, we could monitor secretion and degradation of ER proteins in living cells. We can also follow the biogenesis, growth, accumulation and movements of protein aggregates in the ESC. Our data show that protein deposits within ESC grow by sequential apposition of molecules up to a given size, after which novel seeds are detected. The possibility of using ligands with distinct optical and physical properties offers a novel possibility to dynamically follow the fate of proteins in the ESC. PMID- 25279561 TI - Experimental comparison of the reproductive outcomes and early development of the offspring of rats given five common types of drinking water. AB - Tap water (unfiltered), filtered tap water and processed bottled water (purified water, artificial mineralized water, or natural water) are now the five most widely consumed types of drinking water in China. However, the constituents (organic chemicals and inorganic ingredients) of the five waters differ, which may cause them to have different long-term health effects on those who drink them, especially sensitive children. In order to determine which type of water among the five waters is the most beneficial regarding reproductive outcomes and the developmental behaviors of offspring, two generations of Sprague-Dawley rats were given these five waters separately, and their reproductive outcomes and the developmental behaviors of their offspring were observed and compared. The results showed that the unfiltered tap water group had the lowest values for the maternal gestation index (MGI) and offspring's learning and memory abilities (OLMA); the lowest offspring survival rate was found in the purified water group; and the highest OLMA were found in the filtered tap water group. Thus, the best reproductive and offspring early developmental outcomes were found in the group that drank filtered tap water, which had the lowest levels of pollutants and the richest minerals. Therefore, thoroughly removing toxic contaminants and retaining the beneficial minerals in drinking water may be important for both pregnant women and children, and the best way to treat water may be with granular activated carbon and ion exchange by copper zinc alloy. PMID- 25279562 TI - Spinal autofluorescent flavoprotein imaging in a rat model of nerve injury induced pain and the effect of spinal cord stimulation. AB - Nerve injury may cause neuropathic pain, which involves hyperexcitability of spinal dorsal horn neurons. The mechanisms of action of spinal cord stimulation (SCS), an established treatment for intractable neuropathic pain, are only partially understood. We used Autofluorescent Flavoprotein Imaging (AFI) to study changes in spinal dorsal horn metabolic activity. In the Seltzer model of nerve injury induced pain, hypersensitivity was confirmed using the von Frey and hotplate test. 14 Days after nerve-injury, rats were anesthetized, a bipolar electrode was placed around the affected sciatic nerve and the spinal cord was exposed by a laminectomy at T13. AFI recordings were obtained in neuropathic rats and a control group of naive rats following 10 seconds of electrical stimulation of the sciatic nerve at C-fiber strength, or following non-noxious palpation. Neuropathic rats were then treated with 30 minutes of SCS or sham stimulation and AFI recordings were obtained for up to 60 minutes after cessation of SCS/sham. Although AFI responses to noxious electrical stimulation were similar in neuropathic and naive rats, only neuropathic rats demonstrated an AFI-response to palpation. Secondly, an immediate, short-lasting, but strong reduction in AFI intensity and area of excitation occurred following SCS, but not following sham stimulation. Our data confirm that AFI can be used to directly visualize changes in spinal metabolic activity following nerve injury and they imply that SCS acts through rapid modulation of nociceptive processing at the spinal level. PMID- 25279563 TI - Prevalence and risk factors for depressive reaction among resident survivors after the tsunami following the Great East Japan Earthquake, March 11, 2011. AB - OBJECTIVES: The Great East Japan Earthquake caused a gigantic tsunami which devastated coastal areas of northern Japan on 11 March 2011. Despite the large number of 'resident survivors' who continued to reside in their damaged houses on the second or upper floors, research on the mental health of these individuals has been limited. This study explored the prevalence of depressive reaction and risk factors for depressive reaction among these resident survivors. METHODS: A cross-sectional household health support needs screening was conducted for resident survivors in Higashi-Matsushima city, Miyagi prefecture, two to four months after the tsunami. The health interview that was conducted including mental status, assessed by the Patient Health Questionnaire-2 (PHQ-2). RESULTS: Of 5,454 respondents, 8.1% had depressive reaction. After adjustment by the number of weeks from the tsunami and the mortality rate at each respondent's place of residence, depressive reaction was significantly associated with house flooding below or above the ground floor (odds ratios of 1.92, 2.36, respectively), the unavailability of gas supply (odds ratio, 1.67), being female (odds ratio, 1.47), middle aged or elderly (odds ratios of 2.41, 2.42, respectively), regular intake of psychotropic medicine(s) since before the tsunami (odds ratio, 2.53) and the presence of one to five or more than six cohabiters (odds ratios of 0.61, 0.52, respectively). CONCLUSIONS: The results suggest a considerable psychological burden (depressive reaction) following the tsunami among resident survivors. Special supports for families with psychiatric problems need to be considered among resident survivors. Restoration of lifeline utilities and the strengthening of social ties of persons living alone may help prevent depressive reaction among resident survivors after a tsunami. PMID- 25279564 TI - Protein NMR structures refined without NOE data. AB - The refinement of low-quality structures is an important challenge in protein structure prediction. Many studies have been conducted on protein structure refinement; the refinement of structures derived from NMR spectroscopy has been especially intensively studied. In this study, we generated flat-bottom distance potential instead of NOE data because NOE data have ambiguity and uncertainty. The potential was derived from distance information from given structures and prevented structural dislocation during the refinement process. A simulated annealing protocol was used to minimize the potential energy of the structure. The protocol was tested on 134 NMR structures in the Protein Data Bank (PDB) that also have X-ray structures. Among them, 50 structures were used as a training set to find the optimal "width" parameter in the flat-bottom distance potential functions. In the validation set (the other 84 structures), most of the 12 quality assessment scores of the refined structures were significantly improved (total score increased from 1.215 to 2.044). Moreover, the secondary structure similarity of the refined structure was improved over that of the original structure. Finally, we demonstrate that the combination of two energy potentials, statistical torsion angle potential (STAP) and the flat-bottom distance potential, can drive the refinement of NMR structures. PMID- 25279565 TI - Clinical usefulness of nonhyperemic baseline Pd/Pa as a hybrid baseline Pd/Pa fractional flow reserve strategy. AB - OBJECTIVE: The ratio of basal distal intracoronary pressure (Pd) and aortic pressure (Pa) is a nonhyperemic index for the severity of coronary artery stenosis. The aim of the current study was to evaluate the clinical usefulness of a hybrid baseline Pd/Pa-fractional flow reserve (FFR) strategy in reducing the need for hyperemia. METHODS: In this study, 570 lesions from 527 consecutive patients who had both baseline Pd/Pa and FFR determined were evaluated retrospectively. To evaluate the hybrid baseline Pd/Pa-FFR approach, patients were categorized into treatment, deferral, and undetermined groups on the basis of their baseline Pd/Pa. Thereafter, patients in the undetermined group were assigned to FFR-guided treatment or deferral on the basis of an FFR cutoff value of 0.80 or lower. Major adverse cardiac events were evaluated in a median of 48.8 months (interquartile range, 35.0-66.4). RESULTS: A hybrid strategy using a deferral baseline Pd/Pa value of 1.00 (negative predictive value of 100%) and a treatment baseline Pd/Pa value of 0.86 or lower (positive predictive value of 100%), and limiting adenosine to a baseline Pd/Pa value between 0.87 and 0.99 would prevent the need for vasodilator drugs in 14.6% of lesions (14.0% patients), maintaining 100% agreement with an FFR-only strategy. However, adenosine-free lesions are increased to 59.6%, with 91% agreement. There was no difference in the major adverse cardiac event-free survival rate at 5 years between baseline Pd/Pa-guided and FFR-guided treatment patients (70.8 vs. 76.3%, P=0.63), or between baseline Pd/Pa-guided and FFR-guided deferral patients (71.3 vs. 82.4%, P=0.99). CONCLUSION: The current study reports a range of baseline Pd/Pa values that can predict myocardial ischemia without the need for inducing hyperemia. Adoption of this hybrid baseline Pd/Pa-FFR approach can reduce the need for drug-induced hyperemia. PMID- 25279566 TI - A regional pharmacoinvasive PCI strategy incorporating selected bleeding avoidance strategies. AB - BACKGROUND: Pharmacoinvasive therapy (PIT) is a potential treatment for ST segment elevation myocardial infarction patients who are not able to achieve primary percutaneous intervention (PCI) within guideline-recommended time limits. The risk for bleeding complications with PIT has not been studied in the setting of routine use of two selected bleeding avoidance strategies (BAS): bivalirudin and vascular closure devices. METHODS: We analyzed a contemporary multicenter registry (2009-2013) of consecutive patients undergoing PCI as part of a 10 hospital regional algorithm involving one PCI center and nine transfer centers: PIT for hospitals greater than 60 min (N=140), and primary PCI if less than 60 min travel time to the PCI center (N=346). We compared the risk for Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS) major bleeding among patients undergoing PIT versus primary PCI in the setting of routine use of selected BAS and determined the independent predictors of major bleeding in the entire cohort. RESULTS: The PIT patients had a median travel time of 103+/-49 min, were more frequently female, had a higher incidence of renal failure, and had a lower frequency of cardiogenic shock compared with the primary PCI group. BAS were routine and similar in both groups. Rates of death, stroke, and ischemic and major bleeding outcomes were similar between the two groups, and the length of stay was shorter in the PIT group. Multivariate logistic models indicated that two independent predictors of major bleeding were cardiac arrest [odds ratio (OR)=3.89, 95% confidence interval (CI): 1.2-12.1, P=0.02] and bailout glycoprotein IIb/IIIa inhibitor utilization (OR=3.29, 95% CI: 1.1-9.6, P=0.03). The PIT strategy in conjunction with selected BAS did not predict major bleeding (OR=2.1, 95% CI: 0.85-5.44, P=0.11). CONCLUSION: Bleeding and ischemia rates were similar between the PIT and primary PCI strategies in the setting of routine use of selected BAS; further study on a broader range of BAS including the radial approach may be warranted. Cardiac arrest and bailout glycoprotein IIb/IIIa inhibitor, but not PIT in conjunction with selected BAS, are independent predictors of bleeding risk in a regional ST-segment elevation myocardial infarction population. PMID- 25279567 TI - Comparison of phenology models for predicting the onset of growing season over the Northern Hemisphere. AB - Vegetation phenology models are important for examining the impact of climate change on the length of the growing season and carbon cycles in terrestrial ecosystems. However, large uncertainties in present phenology models make accurate assessment of the beginning of the growing season (BGS) a challenge. In this study, based on the satellite-based phenology product (i.e. the V005 MODIS Land Cover Dynamics (MCD12Q2) product), we calibrated four phenology models, compared their relative strength to predict vegetation phenology; and assessed the spatial pattern and interannual variability of BGS in the Northern Hemisphere. The results indicated that parameter calibration significantly influences the models' accuracy. All models showed good performance in cool regions but poor performance in warm regions. On average, they explained about 67% (the Growing Degree Day model), 79% (the Biome-BGC phenology model), 73% (the Number of Growing Days model) and 68% (the Number of Chilling Days-Growing Degree Day model) of the BGS variations over the Northern Hemisphere. There were substantial differences in BGS simulations among the four phenology models. Overall, the Biome-BGC phenology model performed best in predicting the BGS, and showed low biases in most boreal and cool regions. Compared with the other three models, the two-phase phenology model (NCD-GDD) showed the lowest correlation and largest biases with the MODIS phenology product, although it could catch the interannual variations well for some vegetation types. Our study highlights the need for further improvements by integrating the effects of water availability, especially for plants growing in low latitudes, and the physiological adaptation of plants into phenology models. PMID- 25279568 TI - Procyanidins protects against oxidative damage and cognitive deficits after traumatic brain injury. AB - PRIMARY OBJECTIVE: Oxidative stress is the principal factor in traumatic brain injury (TBI) that initiates the events that result in protracted neuronal dysfunction and remodeling. Importantly, antioxidants can protect the brain against oxidative damage and modulate the capacity of the brain to cope with synaptic dysfunction and cognitive impairment. RESEARCH DESIGN: To date, however, no studies have investigated the effects of procyanidins (PC) on cognitive deficits after TBI. METHODS AND PROCEDURES: In the present study, rats with controlled cortical impact (CCI) were used to investigate the protective effects of procyanidins. MAIN OUTCOMES AND RESULTS: The results showed that procyanidins reduced the level of malondialdehyde (MDA) and elevated the level of glutathione (GSH) and the activity of superoxide dismutase (SOD). In addition, treatment with procyanidins, which elevated the levels of brain-derived neurotropic factor (BDNF), phosphorylation-cAMP-response element binding protein (pCREB), total CREB, and cyclic AMP (cAMP), improved cognitive performance in the Morris water maze after TBI. CONCLUSIONS: These results suggest that procyanidins appear to counteract oxidative damage and behavioral dysfunction after TBI through antioxidant activity and the up-regulation of cAMP/CREB signaling. PMID- 25279569 TI - In memoriam, Dr. E. Chester Ridgway, 1942-2014. PMID- 25279570 TI - Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. AB - OBJECTIVE: To update practice guidelines for the therapeutic use of androgens in women. PARTICIPANTS: A Task Force appointed by the Endocrine Society, American Congress of Obestricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), European Society of Endocrinology (ESE), and International Menopause Society (IMS) consisting of six experts, a methodologist, and a medical writer. EVIDENCE: The Task Force commissioned two systematic reviews of published data and considered several other existing meta-analyses and trials. The GRADE methodology was used; the strength of a recommendation is indicated by a number "1" (strong recommendation, we recommend) or "2" (weak recommendation, we suggest). CONSENSUS PROCESS: Multiple e-mail communications and conference calls determined consensus. Committees of the Endocrine Society, ASRM, ACOG, ESE, and IMS reviewed and commented on the drafts of the guidelines. CONCLUSIONS: We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable. We recommend against the general use of T for the following indications: infertility; sexual dysfunction other than hypoactive sexual desire disorder; cognitive, cardiovascular, metabolic, or bone health; or general well being. We recommend against the routine use of dehydroepiandrosterone due to limited data concerning its effectiveness and safety in normal women or those with adrenal insufficiency. We recommend against the routine prescription of T or dehydroepiandrosterone for the treatment of women with low androgen levels due to hypopituitarism, adrenal insufficiency, surgical menopause, pharmacological glucocorticoid administration, or other conditions associated with low androgen levels because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk. Evidence supports the short-term efficacy and safety of high physiological doses of T treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder. Importantly, endogenous T levels did not predict response to therapy. At present, physiological T preparations for use in women are not available in many countries including the United States, and long-term safety data are lacking. We recommend that any woman receiving T therapy be monitored for signs and symptoms of androgen excess. We outline areas for future research. Ongoing improvement in androgen assays will allow a redefinition of normal ranges across the lifespan; this may help to clarify the impact of varying concentrations of plasma androgens on the biology, physiology, and psychology in women and lead to indications for therapeutic interventions. PMID- 25279571 TI - Clinical review: The benefits and harms of systemic dehydroepiandrosterone (DHEA) in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. AB - CONTEXT: Exogenous dehydroepiandrosterone (DHEA) therapy has been proposed to replenish the depletion of endogenous DHEA and its sulfate form, which occurs with advancing age and is thought to be associated with loss of libido and menopausal symptoms. OBJECTIVE: We conducted a systematic review and meta analysis to summarize the evidence supporting the use of systemic DHEA in postmenopausal women with normal adrenal function. METHODS: We searched MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through January 2014. Pairs of reviewers, working independently, selected studies and extracted data from eligible randomized controlled trials (RCTs). We used the random-effects model to pool across studies and evaluated heterogeneity using the I(2) statistic. RESULTS: We included 23 RCTs with moderate to high risk of bias enrolling 1188 women. DHEA use was not associated with significant improvement in libido or sexual function (standardized mean difference, 0.35; 95% confidence interval, 0.02 to 0.73; P value = .06; I(2) = 62%). There was also no significant effect of DHEA on serious adverse effects, serum lipids, serum glucose, weight, body mass index, or bone mineral density. This evidence warranted low confidence in the results, mostly due to imprecision, risk of bias, and inconsistency across RCTs. CONCLUSIONS: Evidence warranting low confidence suggests that DHEA administration does not significantly impact sexual symptoms or selected metabolic markers in postmenopausal women with normal adrenal function. PMID- 25279572 TI - Clinical review: The benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta analysis. AB - CONTEXT: The use of T has been suggested to improve women's health during the postmenopausal period. OBJECTIVE: We conducted a systematic review and meta analysis of randomized trials to summarize the best available evidence regarding the benefits and harms of systemic T in postmenopausal women with normal adrenal function. METHODS: A comprehensive search of MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, EBSCO CINAHL, and Scopus was conducted through January 2014. We conducted study selection, data extraction, and appraisal in duplicate. Random-effects meta analysis was used to pool results. RESULTS: We identified 35 randomized trials (n = 5053) at a moderate risk of bias. T use was associated with statistically significant improvement in various domains of sexual function and personal distress in postmenopausal women, although the majority of the trials did not have specific or contemporary diagnostic criteria for androgen deficiency in women. T use was also associated with a reduction in total cholesterol, triglyceride, and high-density lipoprotein and an increase in low-density lipoprotein and in the incidence of acne and hirsutism. No significant effect was noted on anthropometric measures and bone density. Long-term safety data were sparse, and the quality of such evidence was low. CONCLUSION: Despite the improvement in sexual function associated with T use in postmenopausal women, long-term safety data are lacking. PMID- 25279573 TI - Endocytic cycling of glucose transporters and insulin resistance due to immunosuppressive agents. PMID- 25279574 TI - Myostatin inhibition: a new treatment for androgen deprivation-induced sarcopenia? PMID- 25279579 TI - Male menopause: myth vs. fact. PMID- 25279575 TI - E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors. PMID- 25279580 TI - Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes. AB - BACKGROUND: Fetal assessment following preterm prelabour rupture of membranes (PPROM) may result in earlier delivery due to earlier detection of fetal compromise. However, early delivery may not always be in the fetal or maternal interest, and the effectiveness of different fetal assessment methods in improving neonatal and maternal outcomes is uncertain. OBJECTIVES: To study the effectiveness of fetal assessment methods for improving neonatal and maternal outcomes in PPROM. Examples of fetal assessment methods that would be eligible for inclusion in this review include fetal cardiotocography, fetal movement counting and Doppler ultrasound. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing any fetal assessment methods, or comparing one fetal assessment method to no assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion into the review. The same two review authors independently assessed trial quality and independently extracted data. Data were checked for accuracy. MAIN RESULTS: We included three studies involving 275 women (data reported for 271) with PPROM at up to 34 weeks' gestation. All three studies were conducted in the United States. Each study investigated different methods of fetal assessment. One study compared weekly endovaginal ultrasound scans with no assessment (n = 93), one compared amniocentesis with no assessment (n = 47), and one compared daily nonstress testing with daily modified biophysical profiling (n = 135). We were unable to perform a meta-analysis, but were able to report data from individual studies.There was no convincing evidence of increased risk of neonatal death in the group receiving endovaginal ultrasound scans compared with the group receiving no assessment (risk ratio (RR) 7.30, 95% confidence interval (CI) 0.39 to 137.54; one study, 92 women), or in the group receiving amniocentesis compared with the group receiving no amniocentesis (RR 1.00, 95% CI 0.07 to 15.00; one study, 44 women). For both these interventions, we inferred that there were no fetal deaths in the intervention or control groups. The study comparing daily nonstress testing with daily modified biophysical profiling did not report fetal or neonatal death. Primary outcomes of maternal death and serious maternal morbidity were not reported in any study. Overall, there were few statistically significant differences in outcomes between the comparisons.The overall quality of evidence is poor, because participant blinding was not possible for any study. AUTHORS' CONCLUSIONS: There is insufficient evidence on the benefits and harms of fetal assessment methods for improving neonatal and maternal outcomes in women with PPROM to draw firm conclusions. The overall quality of evidence that does exist is poor.Further high quality randomised controlled trials are required to guide clinical practice. PMID- 25279581 TI - Biomarker correlates of survival in pediatric patients with Ebola virus disease. AB - Outbreaks of Ebola virus disease (EVD) occur sporadically in Africa and are associated with high case-fatality rates. Historically, children have been less affected than adults. The 2000-2001 Sudan virus-associated EVD outbreak in the Gulu district of Uganda resulted in 55 pediatric and 161 adult laboratory confirmed cases. We used a series of multiplex assays to measure the concentrations of 55 serum analytes in specimens from patients from that outbreak to identify biomarkers specific to pediatric disease. Pediatric patients who survived had higher levels of the chemokine regulated on activation, normal T cell expressed and secreted marker and lower levels of plasminogen activator inhibitor 1, soluble intracellular adhesion molecule, and soluble vascular cell adhesion molecule than did pediatric patients who died. Adult patients had similar levels of these analytes regardless of outcome. Our findings suggest that children with EVD may benefit from different treatment regimens than those for adults. PMID- 25279582 TI - The association of the microcystic, elongated and fragmented (MELF) invasion pattern in endometrial carcinomas with deep myometrial invasion, lymphovascular space invasion and lymph node metastasis. AB - The purpose of this study was to investigate the frequency of microcystic, elongated and fragmented (MELF) pattern of invasion in endometrioid endometrial adenocarcinomas (EA) and its association with prognostic factors. Stained tissue sections from 121 cases of EA (total hysterectomy and pelvic, with or without para-aortic, lymphadenectomy specimens) were reviewed to identify cases showing MELF-type invasion. The prognostic factors of low tumour grade, deep myometrial invasion (MI), cervical stromal involvement, lymphovascular space invasion (LVSI), lymph node (LN) metastasis and advanced clinical stage were more frequently observed in MELF-positive cases (p < 0.05). Thus, MELF-positive cases had an increased frequency (28/121) of these prognostic factors, which has implications in routine clinical practice, as it signals the importance of recognising MELF pattern invasion. In univariate analysis, MELF positivity, deep MI, cervical stroma involvement and LVSI were significantly related to LN metastasis (p < 0.05). However, in multivariate analysis, only MELF pattern invasion and cervical stroma involvement were independent factors for LN metastasis. Nevertheless, further studies are needed to evaluate the clinical significance of MELF pattern of invasion in endometrial adenocarcinoma. PMID- 25279583 TI - Chewing lice in Azorean Blackcaps ( Sylvia atricapilla ): a contribution to parasite island syndromes. AB - Focusing upon chewing lice (Phthiraptera: Amblycera, Ischnocera) parasitizing blackcaps ( Sylvia atricapilla ) in the Azores (Portugal), we found a lower number of louse species in the Azores compared to mainland Europe. Only chewing lice host specific to blackcaps were found in the Azores. Louse prevalences were much higher in blackcaps from the Azores compared to those of various mainland populations. Chewing lice are permanent parasites of birds, and for such parasites the parasite island syndrome could be characterized by higher parasite prevalence on the islands compared to the mainland. PMID- 25279584 TI - Clomipramine demethylation rate is important on the outcome of obsessive compulsive disorder treatment. AB - The aim of this study was to investigate the influence of demethylation rate on the outcome of obsessive-compulsive disorder patients treated with clomipramine. Eighteen patients meeting the DSM-IV criteria for obsessive-compulsive disorder received 150-300 mg of clomipramine daily in a single-blind design for 12 weeks. The patients were evaluated with the Clinical Global Impression scale and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Clinical assessment and serum measurements of clomipramine and desmethylclomipramine were carried out at baseline and after 3, 6, 8, 10, and 12 weeks. A greater improvement in Clinical Global Impression scale rating was associated with a lower desmethylclomipramine/daily dose and the total clomipramine and desmethylclomipramine/daily dose. Moreover, an improved response on the YBOCS obsession score was associated with higher serum levels of clomipramine and the total clomipramine and desmethylclomipramine/daily dose. Patients with a greater reduction in baseline YBOCS rating had a lower desmethylclomipramine/clomipramine ratio. These data suggest that a lower demethylation rate correlates with better clinical outcome. PMID- 25279586 TI - Electric and magnetic field-assisted orientational transitions in the ensembles of domains in a nematic liquid crystal on the polymer surface. AB - Using electro- and magneto-optical techniques, we investigated orientational transitions in the ensembles of domains in a nematic liquid crystal on the polycarbonate film surface under the conditions of competing surface forces that favor radial and uniform planar alignment of nematic molecules. Having analyzed field dependences of the intensity of light passed through a sample, we established the threshold character of the orientational effects, plotted the calculated intensity versus magnetic coherence length, and compared the latter with the equilibrium length that characterizes the balance of forces on the polymer surface. PMID- 25279585 TI - Insulin induces an increase in cytosolic glucose levels in 3T3-L1 cells with inhibited glycogen synthase activation. AB - Glucose is an important source of energy for mammalian cells and enters the cytosol via glucose transporters. It has been thought for a long time that glucose entering the cytosol is swiftly phosphorylated in most cell types; hence the levels of free glucose are very low, beyond the detection level. However, the introduction of new fluorescence resonance energy transfer-based glucose nanosensors has made it possible to measure intracellular glucose more accurately. Here, we used the fluorescent indicator protein (FLIPglu-600u) to monitor cytosolic glucose dynamics in mouse 3T3-L1 cells in which glucose utilization for glycogen synthesis was inhibited. The results show that cells exhibit a low resting cytosolic glucose concentration. However, in cells with inhibited glycogen synthase activation, insulin induced a robust increase in cytosolic free glucose. The insulin-induced increase in cytosolic glucose in these cells is due to an imbalance between the glucose transported into the cytosol and the use of glucose in the cytosol. In untreated cells with sensitive glycogen synthase activation, insulin stimulation did not result in a change in the cytosolic glucose level. This is the first report of dynamic measurements of cytosolic glucose levels in cells devoid of the glycogen synthesis pathway. PMID- 25279587 TI - Bilateral Alveolar Distraction for Large Alveolar Defects: Case Report. AB - Distraction osteogenesis has become a very popular technique, as the ability to reconstruct combined deficiencies in bone and soft tissue makes this process unique and invaluable to all types of reconstructive surgeons. We document a case in which an intraoral tooth-borne distractor was designed and segmental alveolar distraction was performed in a large alveolar defect in a patient with bilateral cleft lip and palate. Cosmetic dentistry was performed to attain a pleasing result. This article aims at highlighting the use of distraction in large defects in which bone grafting only is not a suitable procedure. PMID- 25279588 TI - Creatine kinase as predictor of blood pressure and hypertension. Is it all about body mass index? A follow-up study of 250 patients. AB - The correlation between creatine kinase (CK) and blood pressure (BP) was examined prospectively in 120 patients with persistent high CK and 130 individuals with normal CK. Hypertension was defined as systolic BP (SBP) >= 140 mm Hg or diastolic BP (DBP) >= 90 mm Hg or current use of antihypertensive medication. Baseline CK was weakly correlated with SBP (r = 0.11, P = .07) and DBP (r = 0.16, P = .01) at follow-up. Persons with persistent high CK had higher SBP (140.8 mm Hg vs 138.2 mm Hg) and DBP (83.2 mm Hg vs 81.0 mm Hg, P = .06) values and were more likely to have hypertension (66.7% vs 55.5%, P = .05) than individuals with normal CK. In age- and sex-adjusted analysis, a 1-unit change in logCK was associated with a 4.9-mm Hg higher SBP, a 3.3-mm Hg higher DBP, and a 2.2-higher odds for having hypertension at follow-up (P = .1, .07, and .06, respectively). When including body mass index (BMI) to the model, BMI was a strong and independent predictor for SBP, DBP, and hypertension at follow-up and the CK effect on blood pressure was substantially attenuated. This study showed that the CK effect on blood pressure is clearly modified by BMI. PMID- 25279589 TI - Comparison of the hydrogen-bond patterns in 2-amino-1,3,4-thiadiazolium hydrogen oxalate, 2-amino-1,3,4-thiadiazole-succinic acid (1/2), 2-amino-1,3,4-thiadiazole glutaric acid (1/1) and 2-amino-1,3,4-thiadiazole-adipic acid (1/1). AB - The X-ray single-crystal structure determinations of the chemically related compounds 2-amino-1,3,4-thiadiazolium hydrogen oxalate, C2H4N3S(+).C2HO4(-), (I), 2-amino-1,3,4-thiadiazole-succinic acid (1/2), C2H3N3S.2C4H6O4, (II), 2-amino 1,3,4-thiadiazole-glutaric acid (1/1), C2H3N3S.C5H8O4, (III), and 2-amino-1,3,4 thiadiazole-adipic acid (1/1), C2H3N3S.C6H10O4, (IV), are reported and their hydrogen-bonding patterns are compared. The hydrogen bonds are of the types N H...O or O-H...N and are of moderate strength. In some cases, weak C-H...O interactions are also present. Compound (II) differs from the others not only in the molar ratio of base and acid (1:2), but also in its hydrogen-bonding pattern, which is based on chain motifs. In (I), (III) and (IV), the most prominent feature is the presence of an R2(2)(8) graph-set motif formed by N-H...O and O H...N hydrogen bonds, which are present in all structures except for (I), where only a pair of N-H...O hydrogen bonds is present, in agreement with the greater acidity of oxalic acid. There are nonbonding S...O interactions present in all four structures. The difference electron-density maps show a lack of electron density about the S atom along the S...O vector. In all four structures, the carboxylic acid H atoms are present in a rare configuration with a C-C-O-H torsion angle of ~0 degrees . In the structures of (II)-(IV), the C-C-O-H torsion angle of the second carboxylic acid group has the more common value of ~|180| degrees . The dicarboxylic acid molecules are situated on crystallographic inversion centres in (II). The Raman and IR spectra of the title compounds are presented and analysed. PMID- 25279590 TI - The three-dimensional coordination polymer poly[[aqua[MU4-2,2'-(diazene-1,2 diyl)dibenzoato]lead(II)] 1,2-bis(pyridin-4-yl)ethylene hemisolvate]. AB - A novel three-dimensional coordination polymer, {[Pb(C14H8N2O4)(H2O)].0.5C12H10N2}n, has been synthesized by hydrothermal reaction of Pb(OAc)2.3H2O (OAc is acetate), 2,2'-(diazene-1,2-diyl)dibenzoic acid (H2L) and 1,2-bis(pyridin-4-yl)ethylene (bpe). The asymmetric unit contains a crystallographically independent Pb(II) cation, one L(2-) ligand, an aqua ligand and half a bpe molecule. Each Pb(II) centre is seven-coordinated by six O atoms of bridging-chelating carboxylate groups from L(2-) ligands and by one O atom from a coordinated water molecule. The Pb(II) cations are bridged by L(2-) ligands, forming [PbO2]n chains along the a axis. These chains are further connected by L(2-) ligands along the b and c axes to give a three-dimensional framework with a 4(12)6(3) topology. The channel voids are occupied by bpe molecules. PMID- 25279591 TI - Monomolecular sheets of propeller-shaped triethyl 4,4',4''-[benzene-1,3,5 triyltris(ethyne-2,1-diyl)]tribenzoate deuterochloroform monosolvate. AB - The title compound, C39H30O6.CDCl3, has a chemical threefold axis and an approximately planar structure, with an ethoxycarbonyl substituent on each of the terminal benzenes oriented in the same direction, thus forming a propeller-shaped molecule. This molecule is of particular interest in the field of metal-organic frameworks (MOFs), where its hydrolyzed analogue forms MOF structures with high surface areas. The benzene ring which occupies the centre of the molecule forms pi-pi interactions to the equivalent benzene ring at a perpendicular distance of 3.32 (1) A. Centrosymmetric dimers formed in this way are interconnected by intermolecular C-H...pi interactions with a rather short H...CgA distance of 2.51 A (CgA is the centroid of the central benzene ring). The molecules are arranged in regular parallel sheets. Within a sheet, molecules are interconnected via C H...O interactions where all carbonyl O atoms participate in weak hydrogen bonds as hydrogen-bond acceptors. Neighbouring sheets are connected through the above mentioned pi-pi and C-H...pi interactions. PMID- 25279592 TI - Two precatalysts for application in asymmetric homogeneous hydrogenation. AB - The title compounds, [(1R,1'R,2R,2'R)-2,2'-bis(diphenylphosphanyl)-1,1' dicyclopentane](eta(4)-norbornadiene)rhodium(I) tetrafluoridoborate, [Rh(C34H36P2)(C7H8)]BF4, (I), and [(1R,1'R,2R,2'R)-2,2'-bis(diphenylphosphanyl) 1,1'-dicyclopentane][eta(4)-(Z,Z)-cycloocta-1,5-diene]rhodium(I) tetrafluoridoborate dichloromethane monosolvate, [Rh(C34H36P2)(C8H12)]BF4.CH2Cl2, (II), are applied as precatalysts in asymmetric homogeneous hydrogenation, e.g. in the reduction of dehydroamino acids, affording excellent enantiomeric excesses [Zhu, Cao, Jiang & Zhang (1997). J. Am. Chem. Soc. 119, 1799-1800]. PMID- 25279593 TI - Synthesis and crystal structures of RE7Zn(21+x)Si(2-x) [RE = Ce, Pr, and Nd; 0.09 (1) < x < 0.95 (1)]. AB - The focus of this paper is on the synthesis and crystal structures of three Zn rich compounds with the general formula RE7Zn(21+x)Si(2-x), where RE = Ce [x = 0.95 (1); heptacerium docosazinc silicon], Pr [x = 0.09 (1); heptapraseodymium henicosazinc disilicon], and Nd [x = 0.53 (1); heptaneodymium docosazinc silicon]. The compounds were obtained by high-temperature reactions, using the respective elements as starting materials. The structures were determined by single-crystal X-ray diffraction. The title compounds crystalize in the orthorhombic space group Pbam (No. 55, Pearson symbol oP60) and are isostructural with about a dozen RE7Zn(21+x)Tt(2-x) (RE = La-Nd; Tt = Ge, Sn, and Pb) compounds previously reported by our group. The results from the present refinements confirm the previously published data on RE7Zn(21+x)Si(2-x) (RE = La and Ce; x ? 1.45) [Malik et al. (2013). Intermetallics, 36, 118-126]. Additionally, magnetic susceptibility measurements on the corresponding bulk samples show Curie-Weiss paramagnetic behavior from 5 to 300 K, consistent with RE(3+) ground states and local-moment magnetism due to the core 4f electrons. PMID- 25279594 TI - Glycyl-L-alanine: a multi-temperature neutron study. AB - Neutron diffraction data have been collected at 12, 50, 150 and 295 K for the dipeptide glycyl-L-alanine, C5H10N2O3, in order to obtain accurate positional and anisotropic displacement parameters for the H atoms. The values of these parameters serve as a benchmark for assessing the equivalent parameters obtained from a so-called Hirshfeld-atom refinement of X-ray diffraction data described elsewhere [Capelli et al. (2014). IUCrJ, 1, 361-379]. The flexibility of the glycyl-L-alanine molecule in the solid and the hydrogen-bonding interactions as a function of temperature are also considered. PMID- 25279595 TI - Three closely-related cyclohexanols (C35H27X2N3O3; X = F, Cl or Br): similar molecular structures but different crystal structures. AB - Three highly-substituted cyclohexanol derivatives have been prepared from 2 acetylpyridine and 4-halogenobenzaldehydes under mild conditions. (1RS,2SR,3SR,4RS,5RS)-3,5-Bis(4-fluorophenyl)-2,4-bis(pyridine-2-carbonyl)-1 (pyridin-2-yl)cyclohexanol, C35H27F2N3O3, (I), (1RS,2SR,3SR,4RS,5RS)-3,5-bis(4 chlorophenyl)-2,4-bis(pyridine-2-carbonyl)-1-(pyridin-2-yl)cyclohexanol acetone 0.951-solvate, C35H27Cl2N3O3.0.951C3H6O, (II), and (1RS,2SR,3SR,4RS,5RS)-3,5 bis(4-bromophenyl)-2,4-bis(pyridine-2-carbonyl)-1-(pyridin-2-yl)cyclohexanol, C35H27Br2N3O3, (III), all crystallize in different space groups, viz. Pbca, Fdd2 and P1, respectively. In compound (II), the acetone molecule is disordered over two sets of atomic sites having occupancies of 0.690 (13) and 0.261 (13). Each of the cyclohexanol molecules contains an intramolecular O-H...N hydrogen bond and their overall molecular conformations are fairly similar. The molecules of (I) are linked by two independent C-H...O hydrogen bonds to form a C(5)C(10)[R2(2)(15)] chain of rings, and those of (III) are linked by a combination of C-H...O and C-H...N hydrogen bonds, forming a chain of alternating R2(2)(16) and R2(2)(18) rings. The cyclohexanol molecules in (II) are linked by a single C-H...N hydrogen bond to form simple C(4) chains and these chains are linked by a pi-pi stacking interaction to form sheets, to which the disordered acetone molecules are weakly linked via a number of C-H...O contacts. PMID- 25279596 TI - Three p-xylene-solvated pseudopolymorphs of bis[1,3-bis(pentafluorophenyl)propane 1,3-dionato]copper(II). AB - The Cu(2+) ions in the title compounds, namely bis[1,3 bis(pentafluorophenyl)propane-1,3-dionato-kappa(2)O,O']copper(II) p-xylene n solvate, [Cu(C15HF10O2)2].nC8H10, with n = 1, (I), n = 2, (II), and n = 4, (III), are coordinated by two 1,3-bis(pentafluorophenyl)propane-1,3-dionate ligands. The coordination complexes of (I) and (II) have crystallographic inversion symmetry at the Cu atom and the p-xylene molecule in (I) also lies across an inversion centre. The p-xylene molecules in (I) and (II) interact with the pentafluorophenyl groups of the complex via arene-perfluoroarene interactions. In the crystal of (III), two of the p-xylene molecules interact with the pentafluorophenyl groups via arene-perfluoroarene interactions. The other two p xylene molecules are located on the CuO4 coordination plane, forming a uniform cavity produced by metal...pi interactions. PMID- 25279597 TI - NMR analysis of a series of 1,2-bis(1-R-5-oxo-2,3-dihydro-1H-pyrrol-4 ylidene)ethanes and X-ray crystal structure analysis of the R = mesityl compound. AB - Four tetramethyl 4,4'-(ethane-1,2-diylidene)bis[1-R-5-oxo-4,5-dihydro-1H-pyrrole 2,3-dicarboxylate] compounds, denoted class (1), are a series of conjugated buta 1,3-dienes substituted with a heterocyclic group. The compounds can be used as dyes and pigments due to their long-range conjugated systems. Four structures were studied using (1)H NMR, (13)C NMR and mass spectroscopy, viz. with R = 2,4,6 trimethylphenyl, (1a), R = cyclohexyl, (1b), R = tert-butyl, (1c), and R = isopropyl, (1d). A detailed discussion is presented regarding the characteristics of the three-dimensional structures based on NMR analysis and the X-ray crystal structure of (1a), namely tetramethyl 4,4'-(ethane-1,2-diylidene)bis[5-oxo-1 (2,4,6-trimethylphenyl)-4,5-dihydro-1H-pyrrole-2,3-dicarboxylate], C36H36N2O10. The conjugation plane and stability were also studied via quantum chemical calculations. PMID- 25279598 TI - The polyoctahedral silsesquioxane (POSS) 1,3,5,7,9,11,13,15 octaphenylpentacyclo[9.5.1.1(3,9).1(5,15).1(7,13)]octasiloxane (octaphenyl-POSS). AB - Solvent-free single crystals of 1,3,5,7,9,11,13,15 octaphenylpentacyclo[9.5.1.1(3,9).1(5,15).1(7,13)]octasiloxane (abbreviated as octaphenyl-POSS), C48H40O12Si8, were obtained by dehydration/condensation of the tetrol Si4O4(Ph)4(OH)4. The powder pattern generated from the single-crystal data matches well with the experimentally measured powder pattern of commercial octaphenyl-POSS. The geometry of the centrosymmetric molecule in the crystal was compared with that in the gas phase, and had shorter Si-O bond lengths and a broader range of Si-O-Si bond angles. The average Si-O bond length [1.621 (3) A], and Si-O-Si and O-Si-O bond angles [149 (5) and 109 (1) degrees , respectively] were within the same range measured previously for octaphenyl-POSS solvates. PMID- 25279599 TI - Two organophosphorus pesticides: methyl parathion and dicapthon. AB - Structural studies performed in this laboratory of organophosphorus pesticides continue with these related compounds. The -NO2 groups of methyl parathion (systematic name: dimethyl 4-nitrophenyl phosphorothioate, C8H10NO5PS) and dicapthon (systematic name: 2-chloro-4-nitrophenyl dimethyl phosphorothioate, C8H9ClNO5PS) make dihedral angles of 10.67 (8) and 5.8 (1) degrees , respectively, with the planes of their attached rings, which accompanies angular distortion at the ring C atoms to which the -NO2 groups are attached. Similar distortions are observed at the C atom to which the thiophosphate groups are attached. Significant differences in distances and angles around the phenolic O, versus the -OMe groups, explain why it is the site of hydrolysis for these compounds. A comparison of a torsion angle involving the thiophosphate group and phenolic O atom with similar pesticide structures is given and indicates steric influences on that angle. PMID- 25279600 TI - The topotactic dehydration of monoclinic {[Co(pht)(bpy)(H2O)2].2H2O}n into orthorhombic [Co(pht)(bpy)(H2O)2]n (pht is phthalate and bpy is 4,4'-bipyridine). AB - Controlled heating of single crystals of the previously reported [Koferstein & Robl (2007). Z. Anorg. Allg. Chem. 633, 1127-1130] dihydrate {[Co(pht)(bpy)(H2O)2].2H2O}n, (II) [where pht is phthalate (C8H4O4) and bpy is 4,4'-bipyridine (C10H8N2)], produced a topotactic transformation into an unreported diaqua anhydrate, namely poly[diaqua(MU2-benzene-1,2-dicarboxylato kappa(2)O(1):O(2))(MU2-4,4'-bipyridine-kappa(2)N:N')cobalt(II)], [Co(C8H4O4)(C10H8N2)(H2O)2]n, (IIa). The structural change consists of the loss of the two solvent water molecules linking the original two-dimensional covalent substructures which are the 'main frame' of the monoclinic P2/n hydrate (strictly preserved during the transformation), with further reaccommodation of the latter. The anhydrate organizes itself in the orthorhombic system (space group Pmn2(1)) in a disordered fashion, where the space-group-symmetry restrictions are achieved only in a statistical sense, with mirror-related two-dimensional planar substructures, mirrored in a plane perpendicular to [100]. Thus, the asymmetric unit in the refined model is composed of two superimposed mirror-related 'ghosts' of half-occupancy each. Similarities and differences with the parent dihydrate and some other related structures in the literature are discussed. PMID- 25279601 TI - A pillared framework coordination polymer based on the Cd3(MU3-OH) unit: poly[[(MU4-5-aminotetrazolato-kappa(4)N(1):N(2):N(3):N(4))chlorido-MU3-hydroxido (MU3-isonicotinato-kappa(3)N:O:O')dicadmium(II)] 0.14-hydrate]. AB - The title coordination polymer, {[Cd2(CH2N5)(C6H4NO2)Cl(OH)].0.14H2O}n, (I), was synthesized by the reaction of cadmium acetate and N-(1H-tetrazol-5 yl)isonicotinamide in aqueous ammonia, using hydrochloric acid to adjust the pH. Under hydrothermal conditions, N-(1H-tetrazol-5-yl)isonicotinamide slowly hydrolyzes to form isonicotinic acid (Hisonic) and 5-aminotetrazole (Hatz). The deprotonated form of isonicotinic acid (denoted isonic) acts as a bridging ligand in the structure. The polymer crystallizes in the monoclinic space group C2/m. In the structure, there is one Cd3(MU3-OH) unit of Cs symmetry, with one of the Cd(II) atoms and the O and H atoms located on a mirror plane. The other crystallographically independent Cd(II) cation is located on an inversion centre. Each edge of the Cd3(MU3-OH) isosceles triangle is bridged by an atz ligand in a MU1,2 or MU2,3/MU3,4 mode. The Cd3(MU3-OH) units are laced around with a belt of chloride ligands. The belts are further connected into undulating layers via weak inter-belt Cd-Cl bonds. The two organic ligands reside across mirror planes. The construction of a three-dimensional framework is completed by the pillaring isonic ligand. Water molecules partially occupy the voids of the framework. PMID- 25279602 TI - Substituent effects in nitro derivatives of carbazoles investigated by comparison of low-temperature crystallographic studies with density functional theory (DFT) calculations. AB - The crystal structure of 9H-carbazole, C12H9N, (I), has been redetermined at low temperature for use as a reference structure in a comparative study with the structures of 1-nitro-9H-carbazole, C12H8N2O2, (II), and 9-nitrocarbazole, C12H8N2O2, (III). The molecule of (I) has crystallographically imposed mirror symmetry (Z' = 0.5). All three solid-state structures are slightly nonplanar, the dihedral angles between the planes of the arene and pyrrole rings ranging from 0.40 (7) degrees in (III) to 1.82 (18) degrees in (II). Nevertheless, a density functional theory (DFT) study predicts completely planar conformations for the isolated molecules. To estimate the influence of nitro-group substitution on aromaticity, the HOMA (harmonic oscillator model of aromaticity) descriptor of pi electron delocalization has been calculated in each case. The HOMA indices for the isolated and solid-state molecules are relatively consistent and decrease in value for aromatic rings that are substituted with a pi-electron-withdrawing nitro group. Substitution of the arene ring influences the pi-electron delocalization in the ring only weakly, showing strong resistance to a perturbation of its geometry, contrary to what is observed for nitro substitution of the five-membered heterocyclic pyrrole ring. In (II), the molecules are arranged in near-planar dimers connected to each other by strong N-H...O hydrogen bonds that stack parallel to the crystallographic b axis. A similar stacking arrangement is observed in (III), although here the stacked structure is formed by stand-alone molecules. PMID- 25279603 TI - One- and two-dimensional Cd(II) coordination polymers constructed from 2-(2 methyl-1H-benzimidazol-1-yl)acetate ligands. AB - The one- and two-dimensional polymorphic cadmium polycarboxylate coordination polymers, catena-poly[bis[MU2-2-(2-methyl-1H-benzimidazol-1-yl)acetato kappa(3)N(3):O,O']cadmium(II)], [Cd(C10H9N2O2)2]n, and poly[bis[MU2-2-(2-methyl 1H-benzimidazol-1-yl)acetato-kappa(3)N(3):O,O']cadmium(II)], also [Cd(C10H9N2O2)2]n, were prepared under solvothermal conditions. In each structure, each Cd(II) atom is coordinated by four O atoms and two N atoms from four different ligands. In the former structure, two crystallographically independent Cd(II) atoms are located on twofold symmetry axes and doubly bridged in a MU2-N:O,O'-mode by the ligands into correspondingly independent chains that run in the [100] and [010] directions. Chains containing crystallographically related Cd(II) atoms are linked into sheets via pi-pi stacking interactions. Sheets containing one of the distinct types of Cd(II) atom are stacked perpendicular to [001] and alternate with sheets containing the other type of Cd(II) atom. The second complex is a two-dimensional homometallic Cd(II) (4,4) net structure in which each Cd(II) atom is singly bridged to four neighbouring Cd(II) atoms by four ligands also acting in a MU2-N:O,O'-mode. A square-grid network results and the three-dimensional supramolecular framework is completed by pi-pi stacking interactions between the aromatic ring systems. PMID- 25279604 TI - Three new phosphoric triamides with a [C(O)NH]P(O)[N(C)(C)]2 skeleton: a database analysis of C-N-C and P-N-C bond angles. AB - In N,N,N',N'-tetraethyl-N''-(4-fluorobenzoyl)phosphoric triamide, C15H25FN3O2P, (I), and N-(2,6-difluorobenzoyl)-N',N''-bis(4-methylpiperidin-1-yl)phosphoric triamide, C19H28F2N3O2P, (II), the C-N-C angle at each tertiary N atom is significantly smaller than the two P-N-C angles. For the other new structure, N,N'-dicyclohexyl-N''-(2-fluorobenzoyl)-N,N'-dimethylphosphoric triamide, C21H33FN3O2P, (III), one C-N-C angle [117.08 (12) degrees ] has a greater value than the related P-N-C angle [115.59 (9) degrees ] at the same N atom. Furthermore, for most of the analogous structures with a [C(=O)NH]P(=O)[N(C)(C)]2 skeleton deposited in the Cambridge Structural Database [CSD; Allen (2002). Acta Cryst. B58, 380-388], the C-N-C angle is significantly smaller than the two P-N-C angles; exceptions were found for four structures with the N methylcyclohexylamide substituent, similar to (III), one structure with the seven membered cyclic amide azepan-1-yl substituent and one structure with an N methylbenzylamide substituent. The asymmetric units of (I), (II) and (III) contain one molecule, and in the crystal structures, adjacent molecules are linked via pairs of N-H...O=P hydrogen bonds to form dimers. PMID- 25279605 TI - Lung-homing of endothelial progenitor cells and airway vascularization is only partially dependant on eosinophils in a house dust mite-exposed mouse model of allergic asthma. AB - BACKGROUND: Asthmatic responses involve a systemic component where activation of the bone marrow leads to mobilization and lung-homing of progenitor cells. This traffic may be driven by stromal cell derived factor-1 (SDF-1), a potent progenitor chemoattractant. We have previously shown that airway angiogenesis, an early remodeling event, can be inhibited by preventing the migration of endothelial progenitor cells (EPC) to the lungs. Given intranasally, AMD3100, a CXCR4 antagonist that inhibits SDF-1 mediated effects, attenuated allergen induced lung-homing of EPC, vascularization of pulmonary tissue, airway eosinophilia and development of airway hyperresponsiveness. Since SDF-1 is also an eosinophil chemoattractant, we investigated, using a transgenic eosinophil deficient mouse strain (PHIL) whether EPC lung accumulation and lung vascularization in allergic airway responses is dependent on eosinophilic inflammation. METHODS: Wild-type (WT) BALB/c and eosinophil deficient (PHIL) mice were sensitized to house dust mite (HDM) using a chronic exposure protocol and treated with AMD3100 to modulate SDF-1 stimulated progenitor traffic. Following HDM challenge, lung-extracted EPCs were enumerated along with airway inflammation, microvessel density (MVD) and airway methacholine responsiveness (AHR). RESULTS: Following Ag sensitization, both WT and PHIL mice exhibited HDM induced increase in airway inflammation, EPC lung-accumulation, lung angiogenesis and AHR. Treatment with AMD3100 significantly attenuated outcome measures in both groups of mice. Significantly lower levels of EPC and a trend for lower vascularization were detected in PHIL versus WT mice. CONCLUSIONS: This study shows that while allergen-induced lung-homing of endothelial progenitor cells, increased tissue vascularization and development lung dysfunction can occur in the absence of eosinophils, the presence of these cells worsens the pathology of the allergic response. PMID- 25279607 TI - Focusing in Arthurs-Kelly-type joint measurements with correlated probes. AB - Joint approximate measurement schemes of position and momentum provide us with a means of inferring pieces of complementary information if we allow for the irreducible noise required by quantum theory. One such scheme is given by the Arthurs-Kelly model, where information about a system is extracted via indirect probe measurements, assuming separable uncorrelated probes. Here, following Di Lorenzo [Phys. Rev. Lett. 110, 120403 (2013)], we extend this model to both entangled and classically correlated probes, achieving full generality. We show that correlated probes can produce more precise joint measurement outcomes than the same probes can achieve if applied alone to realize a position or momentum measurement. This phenomenon of focusing may be useful where one tries to optimize measurements with limited physical resources. Contrary to Di Lorenzo's claim, we find that there are no violations of Heisenberg's error-disturbance relation in these generalized Arthurs-Kelly models. This is simply due to the fact that, as we show, the measured observable of the system under consideration is covariant under phase space translations and as such is known to obey a tight joint measurement error relation. PMID- 25279606 TI - Potential association between rosuvastatin use and high atazanavir trough concentrations in ritonavir-treated HIV-infected patients. AB - BACKGROUND: Emerging evidence shows that standard atazanavir (ATV) dosages are associated with considerable interindividual variability in plasma drug concentrations. Given the potential impact of ATV exposure on clinical outcome, in this retrospective study we sought to assess demographic and clinical factors influencing ATV plasma concentrations in a large cohort of HIV-infected patients. METHODS: HIV-infected patients treated with ATV for at least 3 months and with at least one assessment of ATV trough concentrations were enrolled. Blood trough samples were collected from all patients immediately before the next drug intake. Plasma ATV and ritonavir concentrations were quantified by a validated chromatographic method coupled with tandem mass spectrometric detection. Univariate and multivariate regression analyses were performed using ATV plasma concentrations as the dependent variable, with demographic and clinical characteristics as the independent ones. RESULTS: A total of 273 HIV-infected adult patients were included in the present study. Factors significantly associated with increased ATV concentrations by univariate analysis were ATV dosage, number of concomitant drugs, ritonavir or statin use. However, with multivariate regression analysis, the only factors independently and significantly associated with ATV concentrations were ritonavir use (r=0.291, P<0.0001) and concomitant rosuvastatin therapy (r=0.315, P<0.0001). CONCLUSIONS: We found that patients on ATV/ritonavir given rosuvastatin concomitantly have ATV concentrations that exceed the upper therapeutic threshold of 800 ng/ml known to be associated with a high risk of experiencing ATV-related side effects. In agreement with previous findings we confirmed the lack of association between other demographic and clinical characteristics such as age, gender, body weight and ATV exposure. PMID- 25279608 TI - Direct observation of coherent interorbital spin-exchange dynamics. AB - We report on the first direct observation of fast spin-exchange coherent oscillations between different long-lived electronic orbitals of ultracold 173Yb fermions. We measure, in a model-independent way, the strength of the exchange interaction driving this coherent process. This observation allows us to retrieve important information on the interorbital collisional properties of 173Yb atoms and paves the way to novel quantum simulations of paradigmatic models of two orbital quantum magnetism. PMID- 25279609 TI - Nonrelativistic Nambu-Goldstone modes associated with spontaneously broken space time and internal symmetries. AB - We show that a momentum operator of a translational symmetry may not commute with an internal symmetry operator in the presence of a topological soliton in nonrelativistic theories. As a striking consequence, there appears a coupled Nambu-Goldstone mode with a quadratic dispersion consisting of translational and internal zero modes in the vicinity of a domain wall in an O(3) sigma model, a magnetic domain wall in ferromagnets with an easy axis. PMID- 25279610 TI - How the result of a single coin toss can turn out to be 100 heads. AB - We show that the phenomenon of anomalous weak values is not limited to quantum theory. In particular, we show that the same features occur in a simple model of a coin subject to a form of classical backaction with pre- and postselection. This provides evidence that weak values are not inherently quantum but rather a purely statistical feature of pre- and postselection with disturbance. PMID- 25279612 TI - Nonclassical paths in quantum interference experiments. AB - In a double slit interference experiment, the wave function at the screen with both slits open is not exactly equal to the sum of the wave functions with the slits individually open one at a time. The three scenarios represent three different boundary conditions and as such, the superposition principle should not be applicable. However, most well-known text books in quantum mechanics implicitly and/or explicitly use this assumption that is only approximately true. In our present study, we have used the Feynman path integral formalism to quantify contributions from nonclassical paths in quantum interference experiments that provide a measurable deviation from a naive application of the superposition principle. A direct experimental demonstration for the existence of these nonclassical paths is difficult to present. We find that contributions from such paths can be significant and we propose simple three-slit interference experiments to directly confirm their existence. PMID- 25279611 TI - Test of time dilation using stored Li+ ions as clocks at relativistic speed. AB - We present the concluding result from an Ives-Stilwell-type time dilation experiment using 7Li+ ions confined at a velocity of beta=v/c=0.338 in the storage ring ESR at Darmstadt. A Lambda-type three-level system within the hyperfine structure of the 7Li+3S1 ->3P2 line is driven by two laser beams aligned parallel and antiparallel relative to the ion beam. The lasers' Doppler shifted frequencies required for resonance are measured with an accuracy of <4*10(-9) using optical-optical double resonance spectroscopy. This allows us to verify the special relativity relation between the time dilation factor gamma and the velocity beta, gamma?1-beta2=1 to within +/-2.3*10(-9) at this velocity. The result, which is singled out by a high boost velocity beta, is also interpreted within Lorentz invariance violating test theories. PMID- 25279613 TI - Scalable boson sampling with time-bin encoding using a loop-based architecture. AB - We present an architecture for arbitrarily scalable boson sampling using two nested fiber loops. The architecture has fixed experimental complexity, irrespective of the size of the desired interferometer, whose scale is limited only by fiber and switch loss rates. The architecture employs time-bin encoding, whereby the incident photons form a pulse train, which enters the loops. Dynamically controlled loop coupling ratios allow the construction of the arbitrary linear optics interferometers required for boson sampling. The architecture employs only a single point of interference and may thus be easier to stabilize than other approaches. The scheme has polynomial complexity and could be realized using demonstrated present-day technologies. PMID- 25279614 TI - Universal large deviations for the tagged particle in single-file motion. AB - We consider a gas of point particles moving in a one-dimensional channel with a hard-core interparticle interaction that prevents particle crossings--this is called single-file motion. Starting from equilibrium initial conditions we observe the motion of a tagged particle. It is well known that if the individual particle dynamics is diffusive, then the tagged particle motion is subdiffusive, while for ballistic particle dynamics, the tagged particle motion is diffusive. Here we compute the exact large deviation function for the tagged particle displacement and show that this is universal, independent of the individual dynamics. PMID- 25279615 TI - Phase transitions on random lattices: how random is topological disorder? AB - We study the effects of topological (connectivity) disorder on phase transitions. We identify a broad class of random lattices whose disorder fluctuations decay much faster with increasing length scale than those of generic random systems, yielding a wandering exponent of omega=(d-1)/(2d) in d dimensions. The stability of clean critical points is thus governed by the criterion (d+1)nu>2 rather than the usual Harris criterion dnu>2, making topological disorder less relevant than generic randomness. The Imry-Ma criterion is also modified, allowing first-order transitions to survive in all dimensions d>1. These results explain a host of puzzling violations of the original criteria for equilibrium and nonequilibrium phase transitions on random lattices. We discuss applications, and we illustrate our theory by computer simulations of random Voronoi and other lattices. PMID- 25279619 TI - Exact slope and interpolating functions in N=6 supersymmetric Chern-Simons theory. AB - Using the quantum spectral curve approach we compute, exactly, an observable (called slope function) in the planar Aharony-Bergman-Jafferis-Maldacena theory in terms of an unknown interpolating function h(lambda) which plays the role of the coupling in any integrability based calculation in this theory. We verified our results with known weak coupling expansion in the gauge theory and with the results of semiclassical string calculations. Quite surprisingly at strong coupling the result is given by an explicit rational function of h(lambda) to all orders. By comparing the structure of our result with that of an exact localization based calculation for a similar observable in Marino and Putrov [J. High Energy Phys. 06 (2010) 011], we conjecture an exact expression for h(lambda). PMID- 25279620 TI - Holographic signatures of cosmological singularities. AB - To gain insight into the quantum nature of cosmological singularities, we study anisotropic Kasner solutions in gauge-gravity duality. The dual description of the bulk evolution towards the singularity involves N=4 super Yang-Mills theory on the expanding branch of deformed de Sitter space and is well defined. We compute two-point correlators of Yang-Mills operators of large dimensions using spacelike geodesics anchored on the boundary. The correlators show a strong signature of the singularity around horizon scales and decay at large boundary separation at different rates in different directions. More generally, the boundary evolution exhibits a process of particle creation similar to that in inflation. This leads us to conjecture that information on the quantum nature of cosmological singularities is encoded in long-wavelength features of the boundary wave function. PMID- 25279618 TI - Search for bosonic superweakly interacting massive dark matter particles with the XMASS-I detector. AB - Bosonic superweakly interacting massive particles (super-WIMPs) are a candidate for warm dark matter. With the absorption of such a boson by a xenon atom, these dark matter candidates would deposit an energy equivalent to their rest mass in the detector. This is the first direct detection experiment exploring the vector super-WIMPs in the mass range between 40 and 120 keV. With the use of 165.9 day of data, no significant excess above background was observed in the fiducial mass of 41 kg. The present limit for the vector super-WIMPs excludes the possibility that such particles constitute all of dark matter. The absence of a signal also provides the most stringent direct constraint on the coupling constant of pseudoscalar super-WIMPs to electrons. The unprecedented sensitivity was achieved exploiting the low background at a level 10(-4) kg-1 keVee-1 day-1 in the detector. PMID- 25279621 TI - Cosmological signatures of a UV-conformal standard model. AB - Quantum scale invariance in the UV has been recently advocated as an attractive way of solving the gauge hierarchy problem arising in the standard model. We explore the cosmological signatures at the electroweak scale when the breaking of scale invariance originates from a hidden sector and is mediated to the standard model by gauge interactions (gauge mediation). These scenarios, while being hard to distinguish from the standard model at LHC, can give rise to a strong electroweak phase transition leading to the generation of a large stochastic gravitational wave signal in possible reach of future space-based detectors such as eLISA and BBO. This relic would be the cosmological imprint of the breaking of scale invariance in nature. PMID- 25279623 TI - Confirming a predicted selection rule in inelastic neutron scattering spectroscopy: the quantum translator-rotator H2 entrapped inside C60. AB - We report an inelastic neutron scattering (INS) study of a H2 molecule encapsulated inside the fullerene C60 which confirms the recently predicted selection rule, the first to be established for the INS spectroscopy of aperiodic, discrete molecular compounds. Several transitions from the ground state of para-H2 to certain excited translation-rotation states, forbidden according to the selection rule, are systematically absent from the INS spectra, thus validating the selection rule with a high degree of confidence. Its confirmation sets a precedent, as it runs counter to the widely held view that the INS spectroscopy of molecular compounds is not subject to any selection rules. PMID- 25279624 TI - Limits on a gravitational field dependence of the proton-electron mass ratio from H2 in white dwarf stars. AB - Spectra of molecular hydrogen (H2) are employed to search for a possible proton to-electron mass ratio (MU) dependence on gravity. The Lyman transitions of H2, observed with the Hubble Space Telescope towards white dwarf stars that underwent a gravitational collapse, are compared to accurate laboratory spectra taking into account the high temperature conditions (T~13 000 K) of their photospheres. We derive sensitivity coefficients Ki which define how the individual H2 transitions shift due to MU dependence. The spectrum of white dwarf star GD133 yields a DeltaMU/MU constraint of (-2.7+/-4.7stat+/-0.2syst)*10(-5) for a local environment of a gravitational potential phi~10(4) phiEarth, while that of G29-38 yields DeltaMU/MU=(-5.8+/-3.8stat+/-0.3syst)*10(-5) for a potential of 2*10(4) phiEarth. PMID- 25279625 TI - Binding potentials and interaction gates between microwave-dressed Rydberg atoms. AB - We demonstrate finite range binding potentials between pairs of Rydberg atoms interacting with each other via attractive and repulsive van der Waals potentials and driven by a microwave field. We show that, using destructive quantum interference to cancel single-atom Rydberg excitation, the Rydberg-dimer states can be selectively and coherently populated from the two-atom ground state. This can be used to realize a two-qubit interaction gate which is not susceptible to mechanical forces between the atoms and is therefore immune to motional decoherence. PMID- 25279626 TI - Non-Hermitian degeneracies and unidirectional reflectionless atomic lattices. AB - Light propagation in optical lattices of driven cold atoms exhibits non-Hermitian degeneracies when the first-order modulation amplitudes of real and imaginary parts of the probe susceptibility are manipulated to be balanced. At these degeneracies, one may observe complete unidirectional reflectionless light propagation. This strictly occurs with no gain and can be easily tuned and fully reversed as supported by the transfer-matrix calculations and explained via a coupled-mode analysis. PMID- 25279627 TI - Coupled electronic and structural relaxation pathways in the postexcitation dynamics of Rydberg states of BaArN clusters. AB - We investigate, theoretically, the joint relaxation of orbital and structure in postexcitation dynamics of Rydberg states of cluster BaArN (N=250). Mixed quantum classical dynamics is used to account for the nonadiabatic transitions among more than 160 electronic states, represented via a diatomics-in-molecules Hamiltonian. The simulation illustrates the complex multistep relaxation processes and provides detailed insight in the mechanisms contributing to the final-time experimental photoelectron spectrum. PMID- 25279622 TI - Search for nucleon decay via n->nu[over -]pi0 and p->nu[over -]pi+ in Super Kamiokande. AB - We present the results of searches for nucleon decay via n->nu[over -]pi0 and p >nu[over -]pi+ using data from a combined 172.8 kt.yr exposure of Super Kamiokande-I,-II, and-III. We set lower limits on the partial lifetime for each of these modes: taun->nu[over -]pi0>1.1*10(33) years and taup->nu[over ]pi+>3.9*10(32) years at a 90% confidence level. PMID- 25279628 TI - Flux qubits with long coherence times for hybrid quantum circuits. AB - We present measurements of superconducting flux qubits embedded in a three dimensional copper cavity. The qubits are fabricated on a sapphire substrate and are measured by coupling them inductively to an on-chip superconducting resonator located in the middle of the cavity. At their flux-insensitive point, all measured qubits reach an intrinsic energy relaxation time in the 6-20 MUs range and a pure dephasing time comprised between 3 and 10 MUs. This significant improvement over previous works opens the way to the coherent coupling of a flux qubit to individual spins. PMID- 25279629 TI - All-electromagnetic control of broadband quantum excitations using gradient photon echoes. AB - A broadband photon echo effect in a three level Lambda-type system interacting with two laser fields is investigated theoretically. Inspired by the emerging field of nuclear quantum optics which typically deals with very narrow resonances, we consider broadband probe pulses that couple to the system in the presence of an inhomogeneous control field. We show that such a setup provides an all-electromagnetic-field solution to implement high bandwidth photon echoes, which are easy to control, store and shape on a short time scale and, therefore, may speed up future photonic information processing. The time compression of the echo signal and possible applications for quantum memories are discussed. PMID- 25279616 TI - High statistics measurement of the positron fraction in primary cosmic rays of 0.5-500 GeV with the alpha magnetic spectrometer on the international space station. AB - A precision measurement by AMS of the positron fraction in primary cosmic rays in the energy range from 0.5 to 500 GeV based on 10.9 million positron and electron events is presented. This measurement extends the energy range of our previous observation and increases its precision. The new results show, for the first time, that above ~200 GeV the positron fraction no longer exhibits an increase with energy. PMID- 25279630 TI - Mode spectrum and temporal soliton formation in optical microresonators. AB - The formation of temporal dissipative solitons in optical microresonators enables compact, high-repetition rate sources of ultrashort pulses as well as low noise, broadband optical frequency combs with smooth spectral envelopes. Here we study the influence of the microresonator mode spectrum on temporal soliton formation in a crystalline MgF2 microresonator. While an overall anomalous group velocity dispersion is required, it is found that higher order dispersion can be tolerated as long as it does not dominate the resonator's mode structure. Avoided mode crossings induced by linear mode coupling in the resonator mode spectrum are found to prevent soliton formation when affecting resonator modes close to the pump laser frequency. The experimental observations are in excellent agreement with numerical simulations based on the nonlinear coupled mode equations. The presented results provide for the first time design criteria for the generation of temporal solitons in optical microresonators. PMID- 25279631 TI - Rapidly accelerating Mathieu and Weber surface plasmon beams. AB - We report the generation of two types of self-accelerating surface plasmon beams which are solutions of the nonparaxial Helmholtz equation in two dimensions. These beams preserve their shape while propagating along either elliptic (Mathieu beam) or parabolic (Weber beam) trajectories. We show that owing to the nonparaxial nature of the Weber beam, it maintains its shape over a much larger distance along the parabolic trajectory, with respect to the corresponding solution of the paraxial equation-the Airy beam. Dynamic control of the trajectory is realized by translating the position of the illuminating free-space beam. Finally, the ability of these beams to self-heal after blocking obstacles is demonstrated as well. PMID- 25279617 TI - Electron and positron fluxes in primary cosmic rays measured with the alpha magnetic spectrometer on the international space station. AB - Precision measurements by the Alpha Magnetic Spectrometer on the International Space Station of the primary cosmic-ray electron flux in the range 0.5 to 700 GeV and the positron flux in the range 0.5 to 500 GeV are presented. The electron flux and the positron flux each require a description beyond a single power-law spectrum. Both the electron flux and the positron flux change their behavior at ~30 GeV but the fluxes are significantly different in their magnitude and energy dependence. Between 20 and 200 GeV the positron spectral index is significantly harder than the electron spectral index. The determination of the differing behavior of the spectral indices versus energy is a new observation and provides important information on the origins of cosmic-ray electrons and positrons. PMID- 25279633 TI - Thermal transport along the dislocation line in silicon carbide. AB - We elucidate thermal conductivity along the screw dislocation line, which represents a transport direction inaccessible to classical theories. By using equilibrium molecular dynamics simulations, we uncover a Burgers vector dependent thermal conductivity reduction in silicon carbide. The effect is uncorrelated with the classical modeling and originates in the highly deformed core region, which represents a significant source of anharmonic phonon-phonon scattering. High strain reduces the phonon relaxation time, especially in the longitudinal acoustic branches, and creates an effective internal thermal resistance around the dislocation axis. Our results have implications for designing materials useful for high-temperature electronics and thermoelectric applications. PMID- 25279632 TI - Impact of loss on the wave dynamics in photonic waveguide lattices. AB - We analyze the impact of loss in lattices of coupled optical waveguides and find that, in such a case, the hopping between adjacent waveguides is necessarily complex. This results not only in a transition of the light spreading from ballistic to diffusive, but also in a new kind of diffraction that is caused by loss dispersion. We prove our theoretical results with experimental observations. PMID- 25279634 TI - Phase imprinting in equilibrating Fermi gases: the transience of vortex rings and other defects. AB - We present numerical simulations of phase imprinting experiments in ultracold trapped Fermi gases, which were obtained independently and are in good agreement with recent experimental results. Our focus is on the sequence and evolution of defects using the fermionic time-dependent Ginzburg-Landau equation, which contains dissipation necessary for equilibration. In contrast to other simulations, we introduce small, experimentally unavoidable symmetry breaking, particularly that associated with thermal fluctuations and with the phase imprinting tilt angle, and we illustrate their dramatic effects. As appears consistent with experiment, the former causes vortex rings in confined geometries to move to the trap surface and rapidly decay into more stable vortex lines. The latter aligns the precessing and relatively long-lived vortex filaments, rendering them difficult to distinguish from solitons. PMID- 25279635 TI - Reconnections of quantized vortex rings in superfluid 4He at very low temperatures. AB - Collisions in a beam of unidirectional quantized vortex rings of nearly identical radii R in superfluid 4He in the limit of zero temperature (0.05 K) were studied using time-of-flight spectroscopy. Reconnections between two primary rings result in secondary vortex loops of both smaller and larger radii. Discrete steps in the distribution of flight times, due to the limits on the earliest possible arrival times of secondary loops created after either one or two consecutive reconnections, are observed. The density of primary rings was found to be capped at the value 500 cm-2R-1 independent of the injected density. This is due to collisions between rings causing the piling up of many other vortex rings. Both observations are in quantitative agreement with our theory. PMID- 25279637 TI - Limitations to carrier mobility and phase-coherent transport in bilayer graphene. AB - We present transport measurements on high-mobility bilayer graphene fully encapsulated in hexagonal boron nitride. We show two terminal quantum Hall effect measurements which exhibit full symmetry broken Landau levels at low magnetic fields. From weak localization measurements, we extract gate-tunable phase coherence times tauphi as well as the inter- and intravalley scattering times taui and tau*, respectively. While tauphi is in qualitative agreement with an electron-electron interaction-mediated dephasing mechanism, electron spin-flip scattering processes are limiting tauphi at low temperatures. The analysis of taui and tau* points to local strain fluctuation as the most probable mechanism for limiting the mobility in high-quality bilayer graphene. PMID- 25279636 TI - Transmission phase in the Kondo regime revealed in a two-path interferometer. AB - We report on the direct observation of the transmission phase shift through a Kondo correlated quantum dot by employing a new type of two-path interferometer. We observed a clear pi/2-phase shift, which persists up to the Kondo temperature TK. Above this temperature, the phase shifts by more than pi/2 at each Coulomb peak, approaching the behavior observed for the standard Coulomb blockade regime. These observations are in remarkable agreement with two-level numerical renormalization group calculations. The unique combination of experimental and theoretical results presented here fully elucidates the phase evolution in the Kondo regime. PMID- 25279638 TI - Emergent defect states as a source of resistivity anisotropy in the nematic phase of iron pnictides. AB - We consider the role of potential scatterers in the nematic phase of Fe-based superconductors above the transition temperature to the (pi, 0) magnetic state but below the orthorhombic structural transition. The anisotropic spin fluctuations in this region can be frozen by disorder, to create elongated magnetic droplets whose anisotropy grows as the magnetic transition is approached. Such states act as strong anisotropic defect potentials that scatter with much higher probability perpendicular to their length than parallel, although the actual crystal symmetry breaking is tiny. We calculate the scattering potentials, relaxation rates, and conductivity in this region and show that such emergent defect states are essential for the transport anisotropy observed in experiments. PMID- 25279639 TI - Tuning ferromagnetism at interfaces between insulating perovskite oxides. AB - We use density functional theory calculations to show that the LaAlO3|SrTiO3 interface between insulating perovskite oxides is borderline in satisfying the Stoner criterion for itinerant ferromagnetism and explore other oxide combinations with a view to satisfying it more amply. The larger lattice parameter of a LaScO3|BaTiO3 interface is found to be less favorable than the greater interface distortion of LaAlO3|CaTiO3. Compared to LaAlO3|SrTiO3, the latter is predicted to exhibit robust magnetism with a larger saturation moment and a higher Curie temperature. Our results provide support for a "two phase" picture of coexistent superconductivity and ferromagnetism. PMID- 25279640 TI - New anomalous Lieb-Robinson bounds in quasiperiodic XY chains. AB - We announce and sketch the rigorous proof of a new kind of anomalous (or sub ballistic) Lieb-Robinson (LR) bound for an isotropic XY chain in a quasiperiodic transversal magnetic field. Instead of the usual effective light cone |x|<=v|t|, we obtain |x|<=v|t|alpha for some 0G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. RESULTS: Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp- carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp- carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp- alleles were associated with non-response to MTX. Regarding MTX related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. CONCLUSION: Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences. PMID- 25279665 TI - Variations in mouthguard thickness according to fabrication method. AB - AIM: The purpose of this study was to examine differences in mouthguard thickness according to the method used to form the mouthguard sheet in a combination vacuum pressure former. MATERIALS AND METHODS: The material used in this study was a mouthguard sheet of 3.8-mm ethylene vinyl acetate. Three forming methods were used: vacuum-forming, vacuum-pressure-forming, and pressure-forming. The sheets were formed when heating causing them to displace 15 mm from baseline. We measured mouthguard thickness at the labial surface of the central incisor, the buccal surface of the first molar, and the occlusal surface of the first molar. Differences in thickness in different regions of mouthguards formed under different conditions were analyzed by two-way analysis of variance and the Bonferroni method. RESULTS: We found that mouthguard thickness differed in different regions of the central incisors and the first molars (P < 0.01). The incisal (cusp) region was thinner than the cervical region. There were significant differences in the thicknesses of vacuum-formed mouthguards and vacuum-pressure-formed mouthguards (P < 0.05), with the vacuum-forming method resulting in thinner guards than the vacuum-pressure-forming method. Mouthguard thickness at the first molar did not differ according to the forming method. CONCLUSIONS: Our results suggest that mouthguard thickness at the anterior teeth varies with different forming methods. This information is important when selecting a mouthguard-forming method. PMID- 25279664 TI - Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis. AB - We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7+/-2.2 days (range of days 2 10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain. PMID- 25279666 TI - Dental prophylaxis decreases the risk of esophageal cancer in males; a nationwide population-based study in Taiwan. AB - BACKGROUND: Periodontal disease (PD) is one of the most common chronic inflammatory diseases. Esophageal cancer (EC) is also a common cause of death due to cancer among males. Systemic inflammatory processes have been shown to increase the risk of cancer. We conducted a retrospective cohort study to investigate the association between PD and EC. METHODS: A total of 718,409 subjects were recruited from the Taiwan National Health Insurance Research Database (NHIRD) and followed from January 1, 2000 to December 31, 2010. Of these, 519,831 subjects were diagnosed with PD and were grouped according to the most advanced treatment they received: dental prophylaxis, intensive treatment, or no treatment. The IRs of EC were compared among groups. RESULTS: A total of 682 patients developed EC, resulting in an overall IR of 0.11 case-number per 1000 person-years (0/00/y). The dental prophylaxis group had a significantly lower IR of EC (0.060/00/y) than other groups (p<0.001). Multivariable Cox regression analysis further revealed that male subjects [hazard ratio (HR) = 10.04, 95% confidence interval (CI) = 7.58-13.30], as well as a history of esophageal ulcers (HR = 7.10, 95% CI = 5.03-10.01), alcohol abuse (HR = 5.46, 95% CI = 2.26-13.18), or esophageal reflux (HR = 1.86, 95% CI = 1.02-3.52), were factors associated with a higher risk of EC. And the dental prophylaxis group showed a significantly lower risk for EC (HR = 0.53, 95% CI = 0.44-0.65). Further subgroup analysis showed that the dental prophylaxis group among males had a significant lower risk (HR = 0.54, 95% CI = 0.44-0.66) for EC, while that of the females did not has statistically significant difference. CONCLUSION: For this cohort, subjects received dental prophylaxis reduced the risk of EC compared to all PD and no PD groups among males. PMID- 25279667 TI - Listening in on the past: what can otolith delta18O values really tell us about the environmental history of fishes? AB - Oxygen isotope ratios from fish otoliths are used to discriminate marine stocks and reconstruct past climate, assuming that variations in otolith delta18O values closely reflect differences in temperature history of fish when accounting for salinity induced variability in water delta18O. To investigate this, we exploited the environmental and migratory data gathered from a decade using archival tags to study the behaviour of adult plaice (Pleuronectes platessa L.) in the North Sea. Based on the tag-derived monthly distributions of the fish and corresponding temperature and salinity estimates modelled across three consecutive years, we first predicted annual otolith delta18O values for three geographically discrete offshore sub-stocks, using three alternative plausible scenarios for otolith growth. Comparison of predicted vs. measured annual delta18O values demonstrated >96% correct prediction of sub-stock membership, irrespective of the otolith growth scenario. Pronounced inter-stock differences in delta18O values, notably in summer, provide a robust marker for reconstructing broad-scale plaice distribution in the North Sea. However, although largely congruent, measured and predicted annual delta18O values did not fully match [ corrected]. Small, but consistent, offsets were also observed between individual high-resolution otolith delta18O values measured during tag recording time and corresponding delta18O predictions using concomitant tag-recorded temperatures and location-specific salinity estimates. The nature of the shifts differed among sub-stocks, suggesting specific vital effects linked to variation in physiological response to temperature. Therefore, although otolith delta18O in free-ranging fish largely reflects environmental temperature and salinity, we counsel prudence when interpreting otolith delta18O data for stock discrimination or temperature reconstruction until the mechanisms underpinning otolith delta18O signature acquisition, and associated variation, are clarified. PMID- 25279668 TI - Identification of small molecules that protect pancreatic beta cells against endoplasmic reticulum stress-induced cell death. AB - Endoplasmic reticulum (ER) stress plays an important role in the decline in pancreatic beta cell function and mass observed in type 2 diabetes. Here, we developed a novel beta cell-based high-throughput screening assay to identify small molecules that protect beta cells against ER stress-induced cell death. Mouse betaTC6 cells were treated with the ER stressor tunicamycin to induce ER stress, and cell death was measured as a reduction in cellular ATP. A collection of 17600 compounds was screened for molecules that promote beta cell survival. Of the approximately 80 positive hits, two selected compounds were able to increase the survival of human primary beta cells and rodent beta cell lines subjected to ER stressors including palmitate, a free fatty acid of pathological relevance to diabetes. These compounds also restored ER stress-impaired glucose-stimulated insulin secretion responses. We show that the compounds promote beta cell survival by reducing the expression of key genes of the unfolded protein response and apoptosis, thus alleviating ER stress. Identification of small molecules that prevent ER stress-induced beta cell dysfunction and death may provide a new modality for the treatment of diabetes. PMID- 25279669 TI - Polypeptide-functionalized NaYF4:Yb(3+),Er(3+) nanoparticles: red-emission biomarkers for high quality bioimaging using a 915 nm laser. AB - We prepared poly-L-aspartic acid (PASP) functionalized NaYF4:Yb(3+),Er(3+) upconversion nanoparticles (UCNP-PASP). These nanoparticles can give red upconversion emission under excitation at 915 nm, whose wavelength of emission and excitation is located in the optical window of biological tissue. Dynamic laser scatting and zeta potentials of UCNP-PASP were used to study their stabilities in different aqueous solution. To understand the mechanism of the red emission of UCNP-PASP, photoluminescence spectra of samples were recorded before and after modification with PASP, poly acrylic acid (PAA), and poly(ether imide) (PEI) ligands under excitation at 915 and 980 nm, respectively. The cytotoxicity of the UCNP-PASP was also examined on a A549 cell and KB cell by 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. Moreover, the PASP-functionalized UCNP was employed as a potential biomarker for in vitro and in vivo experiments of upconversion luminescence imaging. PMID- 25279670 TI - Risk factors associated with HIV infection among male homosexuals and bisexuals followed in an open cohort study: Project Horizonte, Brazil (1994-2010). AB - BACKGROUND: There has recently been an increase in HIV infection rates among men who have sex with men (MSM). This study aimed at investigating risk factors associated with incident HIV infection in a MSM cohort-Project Horizonte, Belo Horizonte, Minas Gerais, Brazil. METHODOLOGY: This is a nested case-control study in an ongoing open cohort of homosexual and bisexual men, carried out in 1994 2010, during which 1,085 volunteers were enrolled. Each HIV seroconverted volunteer (case) was compared with three randomly selected HIV negative controls, matched by admission date and age (+/-3 years). During follow-up, 93 volunteers seroconverted and were compared with 279 controls. PRINCIPAL FINDINGS: The risk factors associated with HIV seroconversion were: contact with partner's blood during sexual relations (OR 3.7; 95% CI 1.2-11.6), attendance at gay saunas in search for sexual partners (OR 2.6; 95% CI 1.3-5.4), occasional intake of alcohol when flirting and engaging in sexual activity (OR 2.5; 95% CI 1.3-5.1), inconsistent use of condoms in receptive anal sex (OR 2.4; 95% CI 1.1-5.4), little interest to look up information about AIDS (OR 2.6; 95% CI 1.0-6.7) particularly in newspapers (OR 3.4; 95% CI 1.4-8.1). CONCLUSIONS: This study shows that MSM are still engaging in risk behavior, such as unprotected anal intercourse, despite taking part in a cohort study on various preventive measures. New preventive strategies in touch with the epidemic's development and the specificities of this particular population are needed. PMID- 25279671 TI - Relationship of temperament and character in remitted depressed patients with suicidal ideation and suicide attempts--results from the CRESCEND study. AB - The aim of this study was to evaluate the Temperament and Character Inventory (TCI) scores of a sample of Korean patients with remitted depression who had attempted suicide and reported suicidal ideation and to compare their scores with those of remitted depressed patients without suicidal ideation. Adult depression patients who had completed 12 weeks of follow-up (N = 138) were divided into three groups: patients with a history of suicide attempts (N = 23); patients with current suicidal ideation (N = 59); and patients without current suicidal ideation (N = 56). After controlling for covariates, no significant differences were found among the three groups on any measure of temperament or character except self-directedness and self-transcendence. The self-transcendence scores of the lifetime suicide-attempt group were significantly higher compared with those of the suicidal-ideation group; post hoc analysis revealed that self-directedness was significantly lower in the suicide-attempt group compared with the non suicidal group. The results from the present study suggest that remitted depression patients with a history of suicide attempts do not differ from non attempters in temperament, but do differ in certain character traits. PMID- 25279672 TI - The influence of partner-specific memory associations on picture naming: a failure to replicate Horton (2007). AB - The results of two experiments by Horton (2007) show that speakers name a pictured object faster when in the presence of another person with whom the speaker has previously associated that object name. The first of those two experiments (Horton, 2007, Experiment 1) is the focus of the present research. This paper presents the results of three experiments designed to replicate and extend Horton's (2007) Experiment 1. The original findings were not replicated. These findings do not support the hypothesis that partner-specific memory associations facilitate object naming. PMID- 25279673 TI - Comparison of the abiotic preferences of macroinvertebrates in tropical river basins. AB - We assessed and compared abiotic preferences of aquatic macroinvertebrates in three river basins located in Ecuador, Ethiopia and Vietnam. Upon using logistic regression models we analyzed the relationship between the probability of occurrence of five macroinvertebrate families, ranging from pollution tolerant to pollution sensitive, (Chironomidae, Baetidae, Hydroptilidae, Libellulidae and Leptophlebiidae) and physical-chemical water quality conditions. Within the investigated physical-chemical ranges, nine out of twenty-five interaction effects were significant. Our analyses suggested river basin dependent associations between the macroinvertebrate families and the corresponding physical-chemical conditions. It was found that pollution tolerant families showed no clear abiotic preference and occurred at most sampling locations, i.e. Chironomidae were present in 91%, 84% and 93% of the samples taken in Ecuador, Ethiopia and Vietnam. Pollution sensitive families were strongly associated with dissolved oxygen and stream velocity, e.g. Leptophlebiidae were only present in 48%, 2% and 18% of the samples in Ecuador, Ethiopia and Vietnam. Despite some limitations in the study design, we concluded that associations between macroinvertebrates and abiotic conditions can be river basin-specific and hence are not automatically transferable across river basins in the tropics. PMID- 25279674 TI - Temperature-triggered reversible dielectric and nonlinear optical switch based on the one-dimensional organic-inorganic hybrid phase transition compound [C6H11NH3]2CdCl4. AB - The one-dimensional organic-inorganic hybrid compound bis(cyclohexylammonium) tetrachlorocadmate(II) (1), in which the adjacent infinite [CdCl4]n(-) chains are connected to each other though Cd...Cl weak interactions to form perovskite-type layers of corner-sharing CdCl6 octahedra separated by cyclohexylammonium cation bilayers, was synthesized. It undergoes two successive structural phase transitions, at 215 and 367 K, which were confirmed by systematic characterizations including differential scanning calorimetry (DSC) measurements, variable-temperature structural analyses, and dielectric and second harmonic generation (SHG) measurements. A precise structural analysis discloses that the phase transition at 215 K is induced by the disorder-order transition of cyclohexylammonium cations, while the phase transition at 367 K derives from changes in the relative location of Cd atoms. Emphatically, both the dielectric constant and SHG intensity of 1 show a striking change between low and high states at around 367 K, which reveals that 1 might be considered as a potential dielectric and nonlinear optical (NLO) switch with high-temperature response characterization, excellent reversibility, and obvious change of states. PMID- 25279675 TI - How to Macguyver an epidural dressing for patients with spica casts. PMID- 25279676 TI - The addition of tramadol to a standard i.v. acetaminophen/morphine analgesia protocol in neonates: purposeful or just polypharmacy? PMID- 25279677 TI - Bispectral index monitoring of propofol anesthesia in pediatric patients with hydrocephalus. A prospective observational study. PMID- 25279678 TI - Clinical evidence of Brody's effect in infants undergoing Kasai's portoenterostomy for biliary atresia. PMID- 25279679 TI - The depth of the tip of the endotracheal tube in children. PMID- 25279680 TI - Response to Dr Sen et al.: Pediatric airway surgery under spontaneous breathing. PMID- 25279681 TI - The Miller and Macintosh blades in young children. PMID- 25279682 TI - Comment on Varghese and Kundu, Does the Miller blade truly provide a better laryngoscopic view and intubating conditions than the Macintosh blade in small children? PMID- 25279684 TI - Does adherence therapy improve medication adherence among patients with schizophrenia? A systematic review. AB - Non-adherence to medication is highly prevalent in patients with schizophrenia. Adherence therapy aims to improve medication adherence of these patients by applying techniques of cognitive behavioural therapy, psycho-education, and motivational interviewing. Even though adherence therapy is frequently discussed and researched, its effectiveness is still uncertain. This paper aims to review the effectiveness of adherence therapy on the medication adherence of patients with schizophrenia. To this end, six electronic databases were systematically searched for randomized, controlled trials on adherence therapy from January 2002 to March 2013. Four trials met the inclusion criteria and were incorporated into the review. The findings suggest that adherence therapy does not improve patients' medication adherence in comparison to treatment as usual or a control intervention. However, all the studies reviewed showed high-adherence ratings at baseline. Thus, further well-designed studies that target adherence therapy to patients who are non-adherent to their medication are needed for a more profound understanding of its effectiveness. In addition, if adherence therapy is aimed not only at improving medication adherence, but also to reach an agreement whereby the patient's decision not to take his medication is accepted, the shared decision-making process needs to be assessed as well. PMID- 25279685 TI - Redox and Lewis acid relay catalysis: a titanocene/zinc catalytic platform in the development of multicomponent coupling reactions. AB - A titanocene-catalyzed multicomponent coupling is described herein. Using catalytic titanocene, phosphine, and zinc dust, zinc acetylides can be generated from the corresponding iodoalkynes to affect sequential nucleophilic additions to aromatic aldehydes. The intermediate propargylic alkoxides are trapped in situ with acetic anhydride, which are susceptible to a second nucleophilic displacement upon treatment with a variety of electron-rich species, including acetylides, allyl silanes, electron-rich aromatics, silyl enol ethers, and silyl ketene acetals. Additionally, employing cyclopropane carboxaldehydes led to ring opened products resulting from iodine incorporation. Taken together, these results form the basis for a new mode of three-component coupling reactions, which allows for rapid access to value added products in a single synthetic operation. PMID- 25279683 TI - Prediction of long-term segmental and global functional recovery of hibernating myocardium after revascularisation based on low dose dobutamine and late gadolinium enhancement cardiovascular magnetic resonance. AB - BACKGROUND: This study sought to evaluate the relation between long-term segmental and global functional outcome after revascularisation in patients with chronic ischaemic left ventricular dysfunction (LVD) and baseline markers of viability: late gadolinium enhancement (LGE) transmurality and contractile reserve (CR). METHODS: Forty-two patients with chronic ischaemic LVD underwent low-dose dobutamine- (LDD) and late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) before surgical or percutaneous revascularisation. Regional and global left ventricular (LV) functions and LGE were repeatedly assessed 6 +/- 1 and 35 +/- 6 months after revascularisation. In total, 319 at baseline dysfunctional and successfully revascularised segments were available for statistical analysis. RESULTS: The likelihood of long-term functional improvement was directly related to the presence of CR and inversely related to both the LGE and the degree of contractile dysfunction at baseline. The time course of functional improvement was protracted, with significantly more delay in segments with more extensive LGE (p = 0.005) and more severe contractile dysfunction at baseline (p = 0.002). The presence of CR was the predictor of earlier functional improvement (p < 0.0001). Using a definition of viable segment as a segment without any LGE or with any LGE and producing CR during LDD stimulation, >= 55% of viable segments from all dysfunctional and revascularised segments in a patient was the only independent predictor of significant improvement (>= 5%) in the left ventricular ejection fraction (LVEF) after revascularisation, with a 72% sensitivity and an 80% specificity (AUC 0.76, p = 0.014). Reverse LV remodelling was observed in patients who had a significant amount of viable myocardium successfully revascularised. CONCLUSIONS: In patients with chronic ischaemic LVD, improvement of dysfunctional but viable myocardium can be considerably delayed. Both the likelihood and the time course of functional improvement are related to the LGE, CR and the degree of contractile dysfunction at baseline. At 35 +/- 6 months after revascularisation, patients with >=55% of viable segments from all dysfunctional and revascularised segments significantly improve LVEF and experience reverse LV remodelling. A combination of LDD-CMR and LGE-CMR is a simple and powerful tool for identifying which patients with impaired LV function will benefit from revascularisation. PMID- 25279686 TI - Feature selection for speech emotion recognition in Spanish and Basque: on the use of machine learning to improve human-computer interaction. AB - Study of emotions in human-computer interaction is a growing research area. This paper shows an attempt to select the most significant features for emotion recognition in spoken Basque and Spanish Languages using different methods for feature selection. RekEmozio database was used as the experimental data set. Several Machine Learning paradigms were used for the emotion classification task. Experiments were executed in three phases, using different sets of features as classification variables in each phase. Moreover, feature subset selection was applied at each phase in order to seek for the most relevant feature subset. The three phases approach was selected to check the validity of the proposed approach. Achieved results show that an instance-based learning algorithm using feature subset selection techniques based on evolutionary algorithms is the best Machine Learning paradigm in automatic emotion recognition, with all different feature sets, obtaining a mean of 80,05% emotion recognition rate in Basque and a 74,82% in Spanish. In order to check the goodness of the proposed process, a greedy searching approach (FSS-Forward) has been applied and a comparison between them is provided. Based on achieved results, a set of most relevant non-speaker dependent features is proposed for both languages and new perspectives are suggested. PMID- 25279688 TI - Structure-function relationship of PAMAM dendrimers as robust oil dispersants. AB - PAMAM dendrimers have recently been investigated as efficient and biocompatible oil dispersants utilizing their encapsulation capacity; however, their high cationic charge density has been shown to be cytotoxic. It is therefore imperative to mitigate cationic charge-induced toxicity and understand the effects of such changes. Presented here is a synergistic experimental and computational approach to examine the effects of varying terminal surface charge on the capacity of dendrimers to disperse model liner, polycyclic aromatic, and hybrid hydrocarbons. Uncharged dendrimers collapse by forming intramolecular hydrogen bonds, which reduce the hosting capability. On the other hand, changing the surface charges from positive to negative greatly shifts the pKa of tertiary amines of the PAMAM dendrimer interior. As a result, the negatively charged dendrimers have a significant percentage of tertiary amines protonated, ~30%. This unexpected change in the interior protonation state causes electrostatic interactions with the anionic terminal groups, leading to contraction and a marked decrease in hydrocarbon hosting capacity. The present work highlights the robust nature of dendrimer oil dispersion and also illuminates potentially unintended or unanticipated effects of varying dendrimer surface chemistry on their encapsulation or hosting efficacy, which is important for their environmental, industrial, and biomedical applications. PMID- 25279687 TI - The pisiform growth plate is lost in humans and supports a role for Hox in growth plate formation. AB - The human pisiform is a small, nodular, although functionally significant, bone of the wrist. In most other mammals, including apes and Australopithecus afarensis, pisiforms are elongate. An underappreciated fact is that the typical mammalian pisiform forms from two ossification centers. We hypothesize that: (i) the presence of a secondary ossification center in mammalian pisiforms indicates the existence of a growth plate; and (ii) human pisiform reduction results from growth plate loss. To address these hypotheses, we surveyed African ape pisiform ossification and confirmed the presence of a late-forming secondary ossification center in chimpanzees and gorillas. Identification of the initial ossification center occurs substantially earlier in apes relative to humans, raising questions concerning the homology of the human pisiform and the two mammalian ossification centers. Second, we conducted histological and immunohistochemical analyses of pisiform ossification in mice. We confirm the presence of two ossification centers separated by organized columnar and hypertrophic chondrocyte zones. Flattened chondrocytes were highly mitotic, indicating the presence of a growth plate. Hox genes have been proposed to play a fundamental role in growth plate patterning. The existence of a pisiform growth plate presents an interesting test case for the association between Hox expression and growth plate formation, and could explain the severe effects on the pisiform observed in Hoxa11 and Hoxd11 knockout mice. Consistent with this hypothesis, we show that Hoxd11 is expressed adjacent to the pisiform in late-stage embryonic mouse limbs supporting a role for Hox genes in growth plate specification. This raises questions concerning the mechanisms regulating Hox expression in the developing carpus. PMID- 25279689 TI - Effect of aerobic exercise on premenstrual symptoms, haematological and hormonal parameters in young women. AB - The objective of this study was to investigate the effect of aerobic exercise on premenstrual symptoms, haematological and hormonal parameters in young women. A total of 30 participants aged 16-20 years and complaining of premenstrual syndrome (PMS) were randomly assigned into two groups: a control group received vitamin B6 and Ca supplements once daily and a study group received the same medical treatment and participated in treadmill training three times per week for 3 months. A premenstrual syndrome questionnaire (MSQ), complete blood picture and hormone assays were performed for the assessment of all participants at the start and after the end of the treatment course. The study group showed a significant decrease in all post-treatment subscale symptoms, scores and total score. Haemoglobin, haematocrit, red cell count and platelet count were significantly increased, while mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC) and white blood cell count showed no significant differences. There was also a significant decrease in prolactin, oestradiol and progesterone levels. In conclusion, aerobic exercise increases haemoglobin, haematocrit, red cell count and platelet count, and decreases levels of prolactin, oestradiol and progesterone, resulting in improvement of fatigue, impaired concentration, confusion and most premenstrual symptoms. PMID- 25279690 TI - No association between gender inequality and peak HIV prevalence in developing countries - an ecological study. AB - The prevalence of both gender inequality and HIV prevalence vary considerably both within all developing countries and within those in sub-Saharan Africa. We test the hypothesis that the extent of gender inequality is associated with national peak HIV prevalence. Linear regression was used to test the association between national peak HIV prevalence and three markers of gender equality - the gender-related development index (GDI), the gender empowerment measure (GEM), and the gender inequality index (GII). No evidence was found of a positive relationship between gender inequality and HIV prevalence, either in the analyses of all developing countries or those limited to Africa. In the bivariate analyses limited to Africa, there was a positive association between the two measures of gender "equality" and peak HIV prevalence (GDI: coefficient 28, 95% confidence interval (CI) 9.1-46.8; GEM: coefficient 54.8, 95% CI 20.5-89.1). There was also a negative association between the marker of gender "inequality" and peak HIV prevalence (GII: coefficient -66.9, 95% CI -112.8 to -21.0). These associations all disappeared on multivariate analyses. We could not find any evidence to support the hypothesis that variations in the extent of gender inequality explain variations in HIV prevalence in developing countries. PMID- 25279691 TI - Factors influencing patients' preferences and perceived involvement in shared decision-making in mental health care. AB - BACKGROUND: Although research has suggested that patients desire to participate in shared decision-making, recent studies show that most patients take a passive role in their treatment decisions. The discrepancy between patients' expressed desire and actual behaviors underscores the need to better understand how patients perceive shared decision-making and what factors influence their participation. AIMS: To investigate patients' preferences and appraisals of their involvement in treatment decisions. METHODS: Fifty-four qualitative interviews were conducted with veterans receiving outpatient mental health care at a U.S. Veterans Affairs Medical Center. Interviews were analyzed using thematic analysis. RESULTS: Participants outlined several factors that influence their preferences and involvement in treatment decisions. These include the patient provider relationship, fear of being judged, perceived inadequacy, and a history of substance abuse. CONCLUSION: Patients' preferences and willingness to engage in shared decision-making fluctuate over time and are context dependent. A better understanding of these factors and a strong patient-provider relationship will facilitate better measurement and implementation of shared decision-making. PMID- 25279692 TI - Do sensation differences exist between dental implants and natural teeth?: a meta analysis. AB - OBJECTIVE: The purpose of this systematic review was to survey evidence pertaining to the sensation differences between natural teeth and osseointegrated dental implants. MATERIAL AND METHODS: Using the MEDLINE (online PubMed) database, Cochrane Library, and Scientific Citation index, we performed a systematic search of articles. We used the following search terms: "perception or sensation and dental implant." The systematic review of the extracted articles was performed to see the sensation differences between natural teeth and dental implants. RESULTS: A total of six studies on oral sensation, "tactile sensibility," and "thickness discrimination" were included in the meta-analysis. As to the "tactile sensibility", all studies indicated the threshold levels of the implants were about 4-20 times higher than that of natural teeth. The tactile sensibility of an implant was significantly higher than that of a natural tooth, with an standardized mean difference (SMD) of 8.3619 (95% CI, 6.3920-10.3317) and a P < 0.0001. As to the "thickness discrimination", all studies indicated the threshold levels of implants were about 1.2-2.3 times higher than that of natural teeth. The thickness discrimination was significantly higher than that of natural teeth with an SMD of 1.2368 (95% CI, 0.8699-1.6038) and a P < 0.0001. CONCLUSION: This meta-analysis suggested that both tactile sensibility and thickness discrimination thresholds of implants were significantly higher than those of natural teeth. This meta-analysis reconfirms that sensation differences between dental implants and natural teeth exist. PMID- 25279693 TI - A new, simple approximation for the deconvolution of instrumental broadening in spectroscopic band profiles. AB - A robust empirical correction formula has been developed for the approximation of Lorentzian widths, using a known spectrometer bandpass, in instrument-broadened Voigt bands in optical spectra. The relationship between analytically calculated [(w(Voigt) - w(Lorentz))/w(Gauss)] and [w(Voigt)/w(Gauss) - 1] values (where w is the full width at half-maximum [FWHM]) is analyzed to derive the formula for the approximation of the (w(Voigt) - w(Lorentz)) difference. The precision of the method is demonstrated by comparing its performance to several previously published numerical correction approaches. The fraction of the Lorentzian contribution in Voigt FWHMs is evaluated in terms of the Gaussian FWHM to assess the conditions under which the deconvolution of instrumental broadening is necessary. PMID- 25279694 TI - Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies. AB - Tau and its aggregates are linked to the pathology of Alzheimer's disease (AD) and other tauopathies and, therefore, are explored as therapeutic targets for such disorders. Tau belongs to a family of microtubule-associated proteins that promote microtubule assembly. When hyperphosphorylated, tau becomes prone to forming aggregates. Increased brain levels of hyperphosphorylated tau correlate with dementia. Specificity protein 1 (Sp1), a transcription factor elevated in AD, is responsible for the transcription of AD-related proteins including the amyloid precursor protein, tau, and its cyclin-dependent kinase-5 (CDK5) activators. Tolfenamic acid promotes the degradation of Sp1, our previous studies demonstrated its ability to down-regulate transcriptional targets of Sp1 like amyloid precursor protein and reduce amyloid beta (Abeta), the main component of AD plaques. In this study, we administered tolfenamic acid daily to hemizygous R1.40 transgenic mice for 34 days, and examined tau and CDK5 gene and protein expression within the brain. Our results demonstrate that tolfenamic acid lowers tau mRNA and protein, as well as the levels of its phosphorylated form and CDK5. Thus, we present a drug candidate that inhibits the transcription of multiple major intermediates in AD pathology, thereby helping uncover a new mechanism based approach for targeting AD. A new approach for targeting Alzheimer's disease through a transcriptional based mechanism is presented. Tolfenamic acid lowers the levels of tau, which forms pathological aggregates in Alzheimer's disease and other tauopathies, by promoting the degradation of the transcription factor specificity protein 1 which regulates tau transcription. PMID- 25279695 TI - Faecal microbiota of cats with insulin-treated diabetes mellitus. AB - Microorganisms within the gastrointestinal tract significantly influence metabolic processes within their mammalian host, and recently several groups have sought to characterise the gastrointestinal microbiota of individuals affected by metabolic disease. Differences in the composition of the gastrointestinal microbiota have been reported in mouse models of type 2 diabetes mellitus, as well as in human patients. Diabetes mellitus in cats has many similarities to type 2 diabetes in humans. No studies of the gastrointestinal microbiota of diabetic cats have been previously published. The objectives of this study were to compare the composition of the faecal microbiota of diabetic and non-diabetic cats, and secondarily to determine if host signalment and dietary factors influence the composition of the faecal microbiota in cats. Faecal samples were collected from insulin-treated diabetic and non-diabetic cats, and Illumina sequencing of the 16S rRNA gene and quantitative PCR were performed on each sample. ANOSIM based on the unweighted UniFrac distance metric identified no difference in the composition of the faecal microbiota between diabetic and non diabetic cats, and no significant differences in the proportions of dominant bacteria by phylum, class, order, family or genus as determined by 16S rRNA gene sequencing were identified between diabetic and non-diabetic cats. qPCR identified a decrease in Faecalibacterium spp. in cats aged over ten years. Cat breed or gender, dietary carbohydrate, protein or fat content, and dietary formulation (wet versus dry food) did not affect the composition of the faecal microbiota. In conclusion, the composition of the faecal microbiota was not altered by the presence of diabetes mellitus in cats. Additional studies that compare the functional products of the microbiota in diabetic and non-diabetic cats are warranted to further investigate the potential impact of the gastrointestinal microbiota on metabolic diseases such as diabetes mellitus in cats. PMID- 25279696 TI - A protein with an inactive pterin-4a-carbinolamine dehydratase domain is required for Rubisco biogenesis in plants. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) plays a critical role in sustaining life by catalysis of carbon fixation in the Calvin-Benson pathway. Incomplete knowledge of the assembly pathway of chloroplast Rubisco has hampered efforts to fully delineate the enzyme's properties, or seek improved catalytic characteristics via directed evolution. Here we report that a Mu transposon insertion in the Zea mays (maize) gene encoding a chloroplast dimerization co factor of hepatocyte nuclear factor 1 (DCoH)/pterin-4alpha-carbinolamine dehydratases (PCD)-like protein is the causative mutation in a seedling-lethal, Rubisco-deficient mutant named Rubisco accumulation factor 2 (raf2-1). In raf2 mutants newly synthesized Rubisco large subunit accumulates in a high-molecular weight complex, the formation of which requires a specific chaperonin 60-kDa isoform. Analogous observations had been made previously with maize mutants lacking the Rubisco biogenesis proteins RAF1 and BSD2. Chemical cross-linking of maize leaves followed by immunoprecipitation with antibodies to RAF2, RAF1 or BSD2 demonstrated co-immunoprecipitation of each with Rubisco small subunit, and to a lesser extent, co-immunoprecipitation with Rubisco large subunit. We propose that RAF2, RAF1 and BSD2 form transient complexes with the Rubisco small subunit, which in turn assembles with the large subunit as it is released from chaperonins. PMID- 25279697 TI - B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of alpha-dystroglycan. AB - Recent studies demonstrated that mutations in B3GNT1, an enzyme proposed to be involved in poly-N-acetyllactosamine synthesis, were causal for congenital muscular dystrophy with hypoglycosylation of alpha-dystroglycan (secondary dystroglycanopathies). Since defects in the O-mannosylation protein glycosylation pathway are primarily responsible for dystroglycanopathies and with no established O-mannose initiated structures containing a beta3 linked GlcNAc known, we biochemically interrogated this human enzyme. Here we report this enzyme is not a beta-1,3-N-acetylglucosaminyltransferase with catalytic activity towards beta-galactose but rather a beta-1,4-glucuronyltransferase, designated B4GAT1, towards both alpha- and beta-anomers of xylose. The dual-activity LARGE enzyme is capable of extending products of B4GAT1 and we provide experimental evidence that B4GAT1 is the priming enzyme for LARGE. Our results further define the functional O-mannosylated glycan structure and indicate that B4GAT1 is involved in the initiation of the LARGE-dependent repeating disaccharide that is necessary for extracellular matrix protein binding to O-mannosylated alpha dystroglycan that is lacking in secondary dystroglycanopathies. PMID- 25279698 TI - Adaptability of non-genetic diversity in bacterial chemotaxis. AB - Bacterial chemotaxis systems are as diverse as the environments that bacteria inhabit, but how much environmental variation can cells tolerate with a single system? Diversification of a single chemotaxis system could serve as an alternative, or even evolutionary stepping-stone, to switching between multiple systems. We hypothesized that mutations in gene regulation could lead to heritable control of chemotactic diversity. By simulating foraging and colonization of E. coli using a single-cell chemotaxis model, we found that different environments selected for different behaviors. The resulting trade-offs show that populations facing diverse environments would ideally diversify behaviors when time for navigation is limited. We show that advantageous diversity can arise from changes in the distribution of protein levels among individuals, which could occur through mutations in gene regulation. We propose experiments to test our prediction that chemotactic diversity in a clonal population could be a selectable trait that enables adaptation to environmental variability. PMID- 25279701 TI - Intrinsic Bauschinger effect and recoverable plasticity in pentatwinned silver nanowires tested in tension. AB - Silver nanowires are promising components of flexible electronics such as interconnects and touch displays. Despite the expected cyclic loading in these applications, characterization of the cyclic mechanical behavior of chemically synthesized high-quality nanowires has not been reported. Here, we combine in situ TEM tensile tests and atomistic simulations to characterize the cyclic stress-strain behavior and plasticity mechanisms of pentatwinned silver nanowires with diameters thinner than 120 nm. The experimental measurements were enabled by a novel system allowing displacement-controlled tensile testing of nanowires, which also affords higher resolution for capturing stress-strain curves. We observe the Bauschinger effect, that is, asymmetric plastic flow, and partial recovery of the plastic deformation upon unloading. TEM observations and atomistic simulations reveal that these processes occur due to the pentatwinned structure and emerge from reversible dislocation activity. While the incipient plastic mechanism through the nucleation of stacking fault decahedrons (SFDs) is fully reversible, plasticity becomes only partially reversible as intersecting SFDs lead to dislocation reactions and entanglements. The observed plastic recovery is expected to have implications to the fatigue life and the application of silver nanowires to flexible electronics. PMID- 25279699 TI - The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated alpha-dystroglycan functional glycosylation. AB - Dystroglycan is a cell membrane receptor that organizes the basement membrane by binding ligands in the extracellular matrix. Proper glycosylation of the alpha dystroglycan (alpha-DG) subunit is essential for these activities, and lack thereof results in neuromuscular disease. Currently, neither the glycan synthesis pathway nor the roles of many known or putative glycosyltransferases that are essential for this process are well understood. Here we show that FKRP, FKTN, TMEM5 and B4GAT1 (formerly known as B3GNT1) localize to the Golgi and contribute to the O-mannosyl post-phosphorylation modification of alpha-DG. Moreover, we assigned B4GAT1 a function as a xylose beta1,4-glucuronyltransferase. Nuclear magnetic resonance studies confirmed that a glucuronic acid beta1,4-xylose disaccharide synthesized by B4GAT1 acts as an acceptor primer that can be elongated by LARGE with the ligand-binding heteropolysaccharide. Our findings greatly broaden the understanding of alpha-DG glycosylation and provide mechanistic insight into why mutations in B4GAT1 disrupt dystroglycan function and cause disease. PMID- 25279702 TI - Stereoselective synthesis and cytoselective toxicity of monoterpene-fused 2-imino 1,3-thiazines. AB - Starting from pinane-, apopinane- and carane-based 1,3-amino alcohols obtained from monoterpene-based beta-amino acids, a library of monoterpene-fused 2-imino 1,3-thiazines as main products and 2-thioxo-1,3-oxazines as side-products were prepared via two- or three-step syntheses. When thiourea adducts prepared from 1,3-amino alcohols and aryl isothiocyanates were reacted with CDI under mild conditions, O-imidazolylcarbonyl intermediates were isolated which could be transformed to the desired 1,3-thiazines under microwave conditions. 1,3 Thiazines and 2-thioxo-1,3-oxazine side-products could also be prepared in one step reactions through the application of CDI and microwave irradiation. The ring closure process was extended to cycloalkane-based gamma-hydroxythioureas. The carane- and apopinane-based derivatives exhibited marked antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, A2780, MCF7 and A431). PMID- 25279703 TI - Lower aldosterone-renin ratio is a risk factor for total and cancer death in Japanese individuals: the Takahata study. AB - OBJECTIVE: A higher plasma aldosterone-renin ratio (ARR) is an established marker for screening for primary aldosteronism (PA). The association between higher ARR and mortality in a general population has not been fully explored. We here examined whether higher ARR is a risk factor for total and cause-specific mortality in a Japanese population. SUBJECTS AND METHODS: A population-based, longitudinal study of 1,310 Japanese individuals (age: 63.9 +/- 9.8 years) enrolled in the Takahata study between 2004 and 2006 and followed for up to 8 years. The incidence and causes of death were monitored annually until 10 January 2012 (median follow-up: 2691 days). RESULTS: During the follow-up period, 64 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total and cancer mortality in subjects with lower ARR (log-rank P < 0.001). Cox's proportional hazard model analyses with adjustment for age and gender showed that lower ARR was associated with increased total and cancer mortality in subjects with low (?72) vs high (>72) ARR (hazard ratios and 95% confidential intervals: 2.56, 1.44-4.56 and 2.78, 1.16-6.65, respectively). CONCLUSIONS: Lower ARR was a significant and independent risk factor for increased total and cancer mortality in this Japanese population. Subjects with higher ARR were not-at-risk for total death in general. These findings increase the necessity for identifying people with PA from those with higher ARR. People with higher ARR without PA may be at very low risk for total and cancer death. PMID- 25279700 TI - TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. AB - Plasma membrane lipid composition must be maintained during growth and under environmental insult. In yeast, signaling mediated by TOR Complex 2 (TORC2) dependent protein kinase Ypk1 controls lipid abundance and distribution in response to membrane stress. Ypk1, among other actions, alleviates negative regulation of L-serine:palmitoyl-CoA acyltransferase, upregulating production of long-chain base precursors to sphingolipids. To explore other roles for TORC2 Ypk1 signaling in membrane homeostasis, we devised a three-tiered genome-wide screen to identify additional Ypk1 substrates, which pinpointed both catalytic subunits of the ceramide synthase complex. Ypk1-dependent phosphorylation of both proteins increased upon either sphingolipid depletion or heat shock and was important for cell survival. Sphingolipidomics, other biochemical measurements and genetic analysis demonstrated that these modifications of ceramide synthase increased its specific activity and stimulated channeling of long-chain base precursors into sphingolipid end-products. Control at this branch point also prevents accumulation of intermediates that could compromise cell growth by stimulating autophagy. PMID- 25279704 TI - Nanocatalyst superior to Pt for oxygen reduction reactions: the case of core/shell Ag(Au)/CuPd nanoparticles. AB - Controlling the electronic structure and surface strain of a nanoparticle catalyst has become an important strategy to tune and to optimize its catalytic efficiency for a chemical reaction. Using density functional theory (DFT) calculations, we predicted that core/shell M/CuPd (M = Ag, Au) NPs with a 0.8 or 1.2 nm CuPd2 shell have similar but optimal surface strain and composition and may surpass Pt in catalyzing oxygen reduction reactions. We synthesized monodisperse M/CuPd NPs by the coreduction of palladium acetylacetonate and copper acetylacetonate in the presence of Ag (or Au) nanoparticles with controlled shell thicknesses of 0.4, 0.75, and 1.1 nm and CuPd compositions and evaluated their catalysis for the oxygen reduction reaction in 0.1 M KOH solution. As predicted, our Ag/Cu37Pd63 and Au/Cu40Pd60 catalysts with 0.75 and 1.1 nm shells were more efficient catalysts than the commercial Pt catalyst (Fuel Cells Store), with their mass activity reaching 0.20 A/mg of noble metal at -0.1 V vs Ag/AgCl (4 M KCl); this was over 3 times higher than that (0.06 A/mg Pt) from the commercial Pt. These Ag(Au)/CuPd nanoparticles are promising non-Pt catalysts for oxygen reduction reactions. PMID- 25279706 TI - Benzodiazepine use among chronic pain patients prescribed opioids: associations with pain, physical and mental health, and health service utilization. AB - OBJECTIVE: Benzodiazepines (BZDs) are commonly used by chronic pain patients, despite limited evidence of any long-term benefits and concerns regarding adverse events and drug interactions, particularly in older patients. This article aims to: describe patterns of BZDs use; the demographic, physical, and mental health correlates of BZD use; and examine if negative health outcomes are associated with BZD use after controlling for confounders. SUBJECTS: A national sample of 1,220 chronic noncancer pain (CNCP) patients prescribed long-term opioids. METHODS: We report on baseline data from a prospective cohort study comparing four groups based on their current BZD use patterns. General demographics, pain, mental and physical comorbidity, and health service utilization were examined. RESULTS: One-third (N = 398, 33%) of participants reported BZD use in the past month, and 17% (N = 212) reported daily BZD use. BZD use was associated with: 1) greater pain severity, pain interference with life, and lower feelings of self efficacy with respect to their pain; 2) being prescribed "higher-risk" (>200 mg oral morphine equivalent) doses of opioids; 3) using antidepressant and/or antipsychotic medications; 4) substance use (including more illicit and injection drug use, alcohol use disorder, and daily nicotine use); and 5) greater mental health comorbidity. After controlling for differences in demographic characteristics, physical and mental health, substance use, and opioid dose, BZD use was independently associated with greater past-month use of emergency health care such as ambulance or accident and emergency services. CONCLUSIONS: CNCP patients using BZDs daily represent a high-risk group with multiple comorbid mental health conditions and higher rates of emergency health care use. The high prevalence of BZD use is inconsistent with guidelines for the management of CNCP or chronic mental health conditions. PMID- 25279707 TI - Intrathecal opioids for chronic pain: a call for evidence. PMID- 25279705 TI - Histone deacetylase 1/Sp1/microRNA-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma. AB - The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR 200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells. PMID- 25279708 TI - Metabolic effects of pulmonary obstruction on myocardial functioning: a pilot study using multiple time-point 18F-FDG-PET imaging. AB - RATIONALE: The aim of this study was to evaluate fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the right ventricle (RV) of patients with chronic obstructive pulmonary disease (COPD) and to characterize the variability of 18F-FDG uptake in the RV at different time points following radiotracer administration using PET/computerized tomography (CT). Impaired RV systolic function, RV hypertrophy, and RV dilation are associated with increases in mean pulmonary arterial pressure in patients with COPD. Metabolic changes in the RV using 18F-FDG-PET images 2 and 3 h after tracer injection have not yet been investigated. METHODS: Twenty-five patients with clinical suspicion of lung cancer underwent 18F-FDG-PET/CT imaging at 1, 2, and 3 h after tracer injection. Standardized uptake values (SUVs) and volumes of RV were recorded from transaxial sections to quantify the metabolic activity. RESULTS: The SUV of RV was higher in patients with COPD stages 1-3 as compared with that in patients with COPD stage 0. RV SUV was inversely correlated with FEV1/FVC pack-years of smoking at 1 h after 18F-FDG injection. In the majority of patients, 18F-FDG activity in RV decreased over time. There was no significant difference in the RV myocardial free wall and chamber volume on the basis of COPD status. CONCLUSION: The severity of lung obstruction and pack-years of smoking correlate with the level of 18F-FDG uptake in the RV myocardium, suggesting that there may be metabolic changes in the RV associated with lung obstruction that can be detected noninvasively using 18F-FDG-PET/CT. Multiple time-point images of the RV did not yield any additional value in this study. PMID- 25279709 TI - Is computed tomography attenuation correction more efficient than gated single photon emission computed tomography analysis in improving the diagnostic performance of myocardial perfusion imaging in patients with low prevalence of ischemic heart disease? AB - OBJECTIVE: The purpose of this study was to compare computed tomography (CT) based attenuation correction (AC) using a hybrid single photon emission computed tomography (SPECT)-CT system and quantitative analysis of wall thickening using gated SPECT with regard to the diagnostic accuracy of myocardial perfusion imaging. MATERIALS AND METHODS: We prospectively included 70 patients with low prevalence of acute coronary artery disease who underwent a myocardial stress rest SPECT study. Interpretation was based on supine nongated SPECT data with (AC) or without (NC) CT-based attenuation correction, and on gated SPECT data without attenuation correction (GNC). The scintigraphic diagnosis was obtained using standard automated quantitative analysis software and compared with a 23+/ 14 months' clinical follow-up for 57 patients or with the results of a coronary angiography for 13 patients. RESULTS: The sensitivity, specificity, and overall accuracy were, respectively, 77, 60, and 63% for NC SPECT, 67, 81, and 79% for AC SPECT, and 69, 98, and 93% for GNC SPECT. The initial diagnosis was modified in about one-third of the cases for both AC and GNC, this rate being independent of any clinical parameter (including BMI) except sex (two to four times more artifact correction in men). CONCLUSION: Its widespread availability, cost effectiveness, safety in terms of radiation exposure, and ability to significantly improve myocardial perfusion imaging specificity and accuracy make gated SPECT a self-sufficient modality for coronary artery disease screening and follow-up, whereas CT-AC should be discussed on a case-by-case basis. PMID- 25279710 TI - Estimation of patient attenuation factor for iodine-131 based on direct dose rate measurements from radioiodine therapy patients. AB - The aim of the study was to measure the actual dose at 1 m from the patients per unit activity with the aim of providing a more accurate prediction of the dose levels around radioiodine patients in the hospital, as well as to compare our results with the literature. In this work the demonstration of a patient body tissue attenuation factor is verified by comparing the dose rates measured from the patients with those measured from the unshielded radioiodine capsules immediately after administration of the radioactivity. The normalized dose rate per unit activity is therefore proposed as an operational quantity that can be used to predict exposure rates to staff and patients' relatives. The average dose rate measured from our patient per unit activity was 38.4+/-11.8 MUSv/h/GBq. The calculated attenuation correction factor based on our measurements was 0.55+/ 0.17. The calculated dose rate from a radioiodine therapy patient should normally include a factor accounting for patient body tissue attenuation and scatter. The attenuation factor is currently neglected and not applied in operational radiation protection. Realistic estimation of radiation dose levels from radioiodine therapy patients when properly performed will reduce the operational cost and optimize institutional radiation protection practice. It is recommended to include patient attenuation factors in risk assessment exercises - in particular, when accurate estimates of total effective doses to exposed individuals are required when direct measurements are not possible. The information provided about patient attenuation might benefit radiation protection specialists and regulators. PMID- 25279711 TI - Directed Evolution of a Panel of Orthogonal T7 RNA Polymerase Variants for in Vivo or in Vitro Synthetic Circuitry. AB - T7 RNA polymerase is the foundation of synthetic biological circuitry both in vivo and in vitro due to its robust and specific control of transcription from its cognate promoter. Here we present the directed evolution of a panel of orthogonal T7 RNA polymerase:promoter pairs that each specifically recognizes a synthetic promoter. These newly described pairs can be used to independently control up to six circuits in parallel. PMID- 25279712 TI - Immunohistochemical distinction of renal cell carcinoma from other carcinomas with clear-cell histomorphology: utility of CD10 and CA-125 in addition to PAX-2, PAX-8, RCCma, and adipophilin. AB - Clear-cell renal cell carcinoma (CC-RCC) is the most common primary kidney malignancy, yet this morphology is not unique to renal primary tumors, as clear cell variants of numerous nonrenal carcinomas of varying lineages exist. Therefore, because of CC-RCC's ability to metastasize to nearly any anatomic location, ancillary studies such as immunohistochemistry are often needed to establish the diagnosis. Despite CD10 and renal cell carcinoma monoclonal antibody (RCCma) being touted as sensitive and specific markers, some have suggested that more recent stains including PAX-2, PAX-8, or adipophilin (ADP) are more robust markers of CC-RCC. In this study, 26 cases of CC-RCC, and 51 nonrenal carcinomas with clear-cell histomorphology (CCM) were stained with CD10, RCCma, PAX-2, PAX-8, and ADP. CA-125 was also included to help distinguish CC-RCC from Mullerian clear-cell carcinomas, due the known expression of PAX-2 and PAX-8 in both these entities. RCCma highlighted 77% of CC-RCC and 27% of the CCM group, whereas CD10 was positive in 85% and 25%, respectively. ADP highlighted all CC RCC and 45% of CCMs. PAX-2 was positive in 81% of CC-RCC and 24% of CCM, whereas PAX-8 stained 100% of CC-RCC and 39% of CCM. Mullerian-derived tumors (clear-cell carcinomas of the ovary, vagina, and cervix) were positive with PAX-2 and PAX-8 in 69% and 100% of cases, respectively. No cases of CC-RCC stained with CA-125, whereas 88% of the Mullerian-derived tumors were positive. In summary, although new markers such as PAX-2 and PAX-8 tend to be more sensitive markers of CC-RCC, they lose specificity when Mullerian tumors are included. Inclusion of a classic renal marker such as CD10 or RCCma in the immunohistochemical panel, as well as CA-125 obviates this difficulty. PMID- 25279713 TI - IMP3 expression in serous tumors of the ovary. AB - Insulin-like growth factor II mRNA-binding protein (IMP3) is an oncofetal protein involved in embryogenesis, which is expressed in a variety of malignant neoplasms. It is rarely expressed in normal adult tissue and benign tumors. The aim of this study was to evaluate the expression of IMP3 in benign and malignant serous tumors of the ovary. Seventy-nine ovarian tumors were examined for IMP3 expression by immunohistochemical analysis, comprising 16 benign serous tumors, 19 borderline serous tumors, and 44 serous carcinomas. Positive staining was defined as brown staining in the cytoplasm. Negative staining was defined as absent staining or staining of <5% of tumor cells. The intensity of staining (weak, moderate, and strong) and percentage (0% to 100%) of neoplastic cells staining positive for cytoplasmic IMP3 staining were recorded in each case. Moderate to strong cytoplasmic staining for IMP3 was observed in 30 of 44 (68%) serous carcinomas of the ovary; in contrast, <5% of the borderline and benign serous tumors expressed IMP3 ranging from weak to strong cytoplasmic staining. Statistically, the difference in IMP3 expression between these groups of tumors was highly significant (P<0.0001). Our findings demonstrate moderate to strong expression of IMP3 in the majority of ovarian serous carcinomas as compared with benign/borderline serous tumors, which demonstrated weak to strong expression in a small minority (<5%) of the tumors. Thus, IMP3 may be a useful adjunctive tool in the pathologic evaluation of ovarian serous tumors. PMID- 25279714 TI - Cytoplasmic EGFR staining and gene amplification in glottic cancer: a better indicator of EGFR-driven signaling? AB - Although enhanced epidermal growth factor receptor (EGFR) signaling has been connected with glottic cancerogenesis, the precise mechanisms of its activation still remain unclear. The aim of the present study was to examine EGFR on protein level, confronting cellular pattern of expression and EGFR gene amplification in glottic carcinomas. Tissue microarray technology was applied for uniformity of results. Biopsy specimens of patients with glottic squamous cell carcinoma and simple hyperplasia (control samples) were immunostained for EGFR. Immunohistochemical EGFR reaction was analyzed as membrane and cytoplasm positive and compared with the presence of gene amplification obtained by fluorescent in situ hybridization (FISH) analysis, obtained previously on a large group of patients. The cytoplasmic distribution of the EGFR staining appeared as a primary property of some squamous carcinoma cells; different from the membranous reaction, the reactions were mutually exclusive. Significantly higher scores of cytoplasmic EGFR staining were found in carcinomas with gene amplification when the cell reaction was examined in the basal and suprabasal layer. Our results suggest that EGFR expression in squamous cell carcinoma is different with regard to tumor cell position in carcinoma with ERGF gene amplification, which could be a new indicator of differently driven EGFR signaling in glottic cancer. Such results with cellular pattern distribution of EGFR protein are worthy of further research. PMID- 25279715 TI - Resistance mutations are rare among protease inhibitor treatment-naive hepatitis C genotype-1 patients with or without HIV coinfection. AB - BACKGROUND: HCV has a high replication rate and a lack of proofreading activity, leading to a greatly diverse viral population. This diversity may lead to emergence of resistant strains in direct-acting antiviral therapy. The frequency of naturally occurring HCV protease inhibitor (PI) mutations has been addressed in many countries, but there are few data on the prevalence of these mutations in Brazilian patients. METHODS: We evaluated the sequence of HCV NS3 protease gene in 247 patients (135 HCV-monoinfected and 112 HIV-HCV-coinfected patients). HCV RNA was extracted from plasma and a fragment of 765 base pairs from the NS3 region was amplified and sequenced with Sanger-based technology. RESULTS: HIV-HCV coinfected patients were more likely to be older than 40 years and have an HCV subtype-1a infection. Overall, 21.9% of patients had at least one amino acid substitution in the NS3 region; 14 patients (5.7%) harboured at least one resistance mutation (T54S, V55A, Q80R) and the Q80K mutation was not found in our case series. There was no difference between monoinfected and coinfected patients regarding the frequency of natural polymorphisms and resistance mutations. CONCLUSIONS: Baseline HCV NS3 amino acid substitutions identified herein are considered mostly natural polymorphisms with no clinical impact on PI-based therapy. The identified resistance mutations may be associated with low-level resistance to PIs in vitro. Q80K substitution seems to be a rare event in Brazil. HIV coinfection was not associated with a greater frequency of such substitutions in the studied sample. PMID- 25279716 TI - The effect of glassy carbon surface oxides in non-aqueous voltammetry: the case of quinones in acetonitrile. AB - Glassy carbon (GC) electrodes are well-known to contain oxygenated functional groups such as phenols, carbonyls, and carboxylic acids on their surface. The effects of these groups on voltammetry in aqueous solution are well-studied, but there has been little discussion of their possible effects in nonaqueous solution. In this study, we show that the acidic functional groups, particularly phenols, are likely causes of anomalous features often seen in the voltammetry of quinones in nonaqueous solution. These features, a too small second cyclic voltammetric wave and extra current between the two waves that sometimes appears to be a small, broad third voltammetric wave, have previously been attributed to different types of dimerization. In this work, concentration-dependent voltammetry in acetonitrile rules out dimerization with a series of alkyl benzoquinones because the anomalous features get larger as the concentration decreases. At low concentrations, solution bimolecular reactions will be relatively less important than reactions with surface groups. Addition of substoichiometric amounts of naphthol at higher quinone concentrations produces almost identical behavior as seen at low quinone concentrations with no added naphthol. This implicates hydrogen bonding and proton transfer from the surface phenolic groups as the cause of the anomalous features in quinone voltammetry at GC electrodes. This conclusion is supported by the perturbation of surface oxide coverage on GC electrodes through different electrode pretreatments. PMID- 25279719 TI - Long-term stabilization of organic solar cells using hindered phenols as additives. AB - We report on the improvement of long-term stability of organic solar cells (OPV) using hindered phenol based antioxidants as stabilizing additives. A set of seven commercially available hindered phenols are investigated for use in bulk heterojunction OPV. Polymer:fullerene films based on poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) are characterized with respect to the initial power conversion efficiency and the long-term stability improvement under illumination in ambient conditions. FTIR spectroscopy is used to trace chemical degradation over time. OPV performance is recorded under ISOS-3 conditions, and an improved long-term performance of OPV devices, manifested in increased accumulated power generation (APG), is found for octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. Using this additive, APG is increased by a factor of 3 compared to the reference. Observed differences in the stabilization of tested additives are discussed in terms of energetic trap states formation within the HOMO/LUMO gap of the photoactive material, morphological changes, and chemical structure. PMID- 25279717 TI - 1,25-Dihydroxyvitamin D3 and its analog TX527 promote a stable regulatory T cell phenotype in T cells from type 1 diabetes patients. AB - The emergence of regulatory T cells (Tregs) as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4+ CD25high CD127low regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4+ CD25high CD127low regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX 40. Also, 1,25(OH)2D3 and TX527 treatment inhibit the production of effector cytokines IFN-gamma, IL-9, and IL-17. Importantly, 1,25(OH)2D3 and TX527 promote the induction of IL-10-producing CD4+ CD25high CD127low T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes. PMID- 25279718 TI - Early versus deferred treatment for smoldering multiple myeloma: a meta-analysis of randomized, controlled trials. AB - PURPOSE: Whether patients with smoldering multiple myeloma (SMM) needed to receive early interventional treatment remains controversial. Herein, we conducted a meta-analysis comparing the efficacy and safety of early treatment over deferred treatment for patients with SMM. METHODS: MEDLINE and Cochrane Library were searched to May 2014 for randomized controlled trials (RCTs) that assessed the effect of early treatment over deferred treatment. Primary outcome measure was mortality, and secondary outcome measures were progression, response rate, and adverse events. RESULTS: Overall, 5 trials including 449 patients were identified. There was a markedly reduced risk of disease progression with early treatment (Odds Ratio [OR] = 0.13, 95% confidence interval [CI] = 0.07 to 0.24). There were no significant differences in mortality and response rate (OR = 0.85, 95% CI = 0.45 to 1.60, and OR = 0.63, 95% CI = 0.32 to 1.23, respectively). More patients in the early treatment arm experienced gastrointestinal toxicities (OR = 10.02, 95%CI = 4.32 to 23.23), constipation (OR = 8.58, 95%CI = 3.20 to 23.00) and fatigue or asthenia (OR = 2.72, 95%CI = 1.30 to 5.67). No significant differences were seen with the development of acute leukemia (OR = 2.80, 95%CI = 0.42 to 18.81), hematologic cancer (OR = 2.07, 95%CI = 0.43 to 10.01), second primary tumors (OR = 3.45, 95%CI = 0.81 to 14.68), nor vertebral compression (OR = 0.18, 95%CI = 0.02 to 1.59). CONCLUSIONS: Early treatment delayed disease progression but increased the risk of gastrointestinal toxicities, constipation and fatigue or asthenia. The differences on vertebral compression, acute leukemia, hematological cancer and second primary tumors were not statistically significant. Based on the current evidence, early treatment didn't significantly affect mortality and response rate. However, further much larger trials were needed to provide more evidence. PMID- 25279720 TI - Diatom cell size, coloniality and motility: trade-offs between temperature, salinity and nutrient supply with climate change. AB - Reduction in body size has been proposed as a universal response of organisms, both to warming and to decreased salinity. However, it is still controversial if size reduction is caused by temperature or salinity on their own, or if other factors interfere as well. We used natural benthic diatom communities to explore how "body size" (cells and colonies) and motility change along temperature (2-26 degrees C) and salinity (0.5-7.8) gradients in the brackish Baltic Sea. Fourth corner analysis confirmed that small cell and colony sizes were associated with high temperature in summer. Average community cell volume decreased linearly with 2.2% per degrees C. However, cells were larger with artificial warming when nutrient concentrations were high in the cold season. Average community cell volume increased by 5.2% per degrees C of artificial warming from 0 to 8.5 degrees C and simultaneously there was a selection for motility, which probably helped to optimize growth rates by trade-offs between nutrient supply and irradiation. Along the Baltic Sea salinity gradient cell size decreased with decreasing salinity, apparently mediated by nutrient stoichiometry. Altogether, our results suggest that climate change in this century may polarize seasonality by creating two new niches, with elevated temperature at high nutrient concentrations in the cold season (increasing cell size) and elevated temperature at low nutrient concentrations in the warm season (decreasing cell size). Higher temperature in summer and lower salinity by increased land-runoff are expected to decrease the average cell size of primary producers, which is likely to affect the transfer of energy to higher trophic levels. PMID- 25279721 TI - Substrate-selective catalysis. AB - Substrate selectivity is an important output function for the validation of different enzyme models, catalytic cavity compounds, and reaction mechanisms as demonstrated in this review. In contrast to stereo-, regio-, and chemoselective catalysis, the field of substrate-selective catalysis is under-researched and has to date generated only a few, but important, industrial applications. This review points out the broad spectrum of different reaction types that have been investigated in substrate-selective catalysis. The present review is the first one covering substrate-selective catalysis and deals with reactions in which the substrates involved have the same reacting functionality and the catalysts is used in catalytic or in stoichiometric amounts. The review covers real substrate selective catalysis, thus only including cases in which substrate-selective catalysis has been observed in competition between substrates. PMID- 25279722 TI - Distinct characteristics and complex evolution of PEDV strains, North America, May 2013-February 2014. AB - Porcine epidemic diarrhea virus (PEDV), which emerged in the United States in 2013, has spread throughout North America. Limited availability of PEDV complete genomes worldwide has impeded our understanding of PEDV introduction into the United States. To determine the relationship between the North American strains and global emerging and historic PEDV strains, we sequenced and analyzed complete genomes of 74 strains from North America; the strains clustered into 2 distinct clades. Compared with the initially reported virulent US PEDV strains, 7 (9.7%) strains from 4 states contained insertions and deletions in the spike gene (S INDELs). These S INDEL strains share 99.8%-100% nt identity with each other and 96.2%-96.7% nt identity with the initial US strains. Furthermore, the S INDEL strains form a distinct cluster within North American clade II, sharing 98.6% 100% nt identity overall. In the United States, the S INDEL and original PEDV strains are co-circulating and could have been introduced simultaneously. PMID- 25279723 TI - Comparison of personality traits, attitude toward orthodontic treatment, and pain perception and experience before and after orthodontic treatment. AB - OBJECTIVE: To compare personality traits, attitude toward orthodontic treatment, and pain perception and experience before and after orthodontic treatment. MATERIALS AND METHODS: One hundred subjects (50 male and 50 female) were included in this study. The mean (SD) age was 17.5 (2.05) years at T1 and 19.15 (2.32) years at T2. The instruments for data collection were questionnaires that included assessment of patients' personality traits, attitudes toward orthodontic treatment, and pain perception/experience. Subjects completed the questionnaires at two different times: before orthodontic treatment (T1) and after fixed orthodontic treatment (T2). Subjects were treated by fixed orthodontic appliances for an average (SD) period of 18.64 (0.35) months. Paired sample t-test and chi square test were used to detect any differences. RESULTS: Significant changes in personality traits were detected after orthodontic treatment irrespective of gender. Neuroticism, openness, agreeableness, and conscientiousness scores were improved (P < .001). A positive attitude toward orthodontic treatment was reported at T1 (4.31 [+/-1.26]) and improved at T2 (3.98 [+/-1.16]) irrespective of gender (P < .05). The average (SD) expected pain score (T1) was 4.73 (1.88) and the average (SD) experienced pain score (T2) was 4.63 (1.58). Significant difference in the expected and experienced pain scores was not detected (P = .11). CONCLUSIONS: Personality traits and attitude toward orthodontic treatment improved after orthodontic treatment. Reported actual pain experience during orthodontic treatment was similar to that expected before treatment. PMID- 25279724 TI - Evaluation of the effects of skeletal anchoraged Forsus FRD using miniplates inserted on mandibular symphysis: A new approach for the treatment of Class II malocclusion. AB - OBJECTIVE: To evaluate the skeletal, dentoalveolar, and soft tissue effects of the Forsus Fatigue Resistant Device (FRD) appliance with miniplate anchorage for the treatment of skeletal Class II malocclusion. MATERIAL AND METHODS: The prospective clinical study group included 17 patients (11 girls and 6 boys; mean age 12.96 +/- 1.23 years) with Class II malocclusion due to mandibular retrusion and treated with skeletal anchoraged Forsus FRD. After 0.019 * 0.025-inch stainless steel archwire was inserted and cinched back in the maxillary arch, two miniplates were placed bilaterally on the mandibular symphysis. Then, the Forsus FRD EZ2 appliance was adjusted to the miniplates without leveling the mandibular arch. The changes in the leveling and skeletal anchoraged Forsus FRD phases were evaluated by means of the Paired and Student's t-tests using the cephalometric lateral films. RESULTS: The success rate of the miniplates was found to be 91.5% (38 of 42 miniplates). The mandible significantly moved forward (P < .001) and caused a significant restraint in the sagittal position of the maxilla (P < .001). The overjet correction (-5.11 mm) was found to be mainly by skeletal changes (A-VRL, -1.16 mm and Pog-VRL, 2.62 mm; approximately 74%); the remaining changes were due to the dentoalveolar contributions. The maxillary and mandibular incisors were significantly retruded (P < .001). CONCLUSION: This new approach was an effective method for treating skeletal Class II malocclusion due to the mandibular retrusion via a combination of skeletal and dentoalveolar changes. PMID- 25279725 TI - Finding my own way: an fMRI single case study of a subject with developmental topographical disorientation. AB - Developmental topographical disorientation (DTD) causes impaired spatial orientation and navigation from early childhood with no evidence of cerebral damage. Using fMRI and a landmark sequencing task, we investigated the hypothesis that Dr Wai's abnormal cerebral activation pattern was related to his peculiar behavioral profile. Although Dr Wai was able to correctly perform landmark sequencing, he showed a lack of activity in regions activated in all control subjects and activity in areas that were not activated in any control subject. These results are discussed in light of cognitive and functional model of navigation, with relevant implications for DTD physiology. PMID- 25279726 TI - Role of CRS plus HIPEC in gastric cancer peritoneal carcinomatosis. PMID- 25279727 TI - Leaping forward in amphibian health and nutrition. AB - The Epidemiology Working Group, a subgroup of the participants of the Disney's Animal Kingdom Workshop on "Ex situ Amphibian Medicine and Nutrition," identified a critical need to design and implement approaches that will facilitate the assessment and evaluation of factors impacting amphibian health. In this manuscript, we describe and summarize the outcomes of this workshop with regards (a) the identified gaps in knowledge, (b) identified priorities for closing these gaps, and (c) compile a list of actions to address these priorities. Four general areas of improvement were identified in relation to how measurements are currently being taken to evaluate ex situ amphibian health: nutrition, infectious diseases, husbandry, and integrated biology including genetics and endocrinology. The proposed actions that will be taken in order to address the identified gaps include: (1) identify and quantify major health issues affecting ex situ amphibian populations, (2) identify and coordinate laboratories to conduct analyses using standardized and validated protocols to measure nutritional, infectious diseases, genetic, and hormonal parameters, (3) determine in situ baseline distribution of parameters related to amphibian health, and (4) establish an inter-disciplinary research approach to target specific hypotheses related to amphibian health such as the effects of population genetics (e.g., relatedness, inbreeding) on disease susceptibility, or how environmental parameters are related to chronic stress and hormone production. We think is important to address current gaps in knowledge regarding amphibian health in order to increase the probability to succeed in addressing the issues faced by in situ and ex situ amphibians populations. We are confident that the recommendations provided in this manuscript will facilitate to address these challenges and could have a positive impact in both the health of in situ and ex situ amphibian populations, worldwide. PMID- 25279728 TI - A comparison of next generation sequencing technologies for transcriptome assembly and utility for RNA-Seq in a non-model bird. AB - De novo assembled transcriptomes, in combination with RNA-Seq, are powerful tools to explore gene sequence and expression level in organisms without reference genomes. Investigators must first choose which high throughput sequencing platforms will provide data most suitable for their experimental goals. In this study, we explore the utility of 454 and Illumina sequences for de novo transcriptome assembly and downstream RNA-Seq applications in a reproductive gland from a non-model bird species, the Japanese quail (Coturnix japonica). Four transcriptomes composed of either pure 454 or Illumina reads or mixtures of read types were assembled and evaluated for the same cost. Illumina assemblies performed best for de novo transcriptome characterization in terms of contig length, transcriptome coverage, and complete assembly of gene transcripts. Improvements over the Hybrid assembly were marginal, with the exception that the addition of 454 data significantly increased the number of genes annotated. The Illumina assembly provided the best reference to align an independent set of RNA Seq data as ~84% of reads mapped to single genes in the transcriptome. Contigs constructed solely from 454 data may impose problems for RNA-Seq as our 454 transcriptome revealed a high number of indels and many ambiguously mapped reads. Correcting the 454 transcriptome with Illumina reads was an effective strategy to deal with indel and frameshift errors inherent to the 454 transcriptome, but at the cost of transcriptome coverage. In the absence of a reference genome, we find that Illumina reads alone produced a high quality transcriptome appropriate for RNA-Seq gene expression analyses. PMID- 25279729 TI - Reduced right frontal fractional anisotropy correlated with early elevated plasma LDL levels in obese young adults. AB - OBJECTIVE: To investigate the underlying physiological mechanisms of the structural differences in gray matter (GM) and white matter (WM) associated with obesity in young Chinese adults. MATERIALS AND METHODS: A total of 49 right handed obese or overweight (n = 22, mean age 31.72+/-8.04 years) and normal weight (n = 27, mean age 29.04+/-7.32 years) Han Chinese individuals were recruited. All participants underwent voxel-based morphometry analysis of T1 weighted MRI and tract-based spatial statistics analysis of diffusion tensor imaging. Partial correlation analysis was performed between the physiological data obtained and the abnormal structural alterations. RESULTS: In the OO group, GM atrophy occurred in the left prefrontal cortex, bilateral cingulate gyrus, and the right temporal lobe, while enlargement was observed in the bilateral putamen. WM atrophy was observed predominantly in the regions that regulate food intake, such as the bilateral basal ganglia, the right amygdala, and the left insula. The OO group exhibited lower fractional anisotropy (FA) in bilateral frontal corticospinal tracts and the right brainstem. Significant negative correlations were observed between FA values of those three clusters and BMI, and waist circumference, while the volume of bilateral putamen positively correlated with both BMI and waist circumference. High plasma LDL levels were correlated with low FA values in the right frontal corticospinal tract. Interestingly, the negative correlation was limited to male participants. CONCLUSIONS: Obesity-related alterations of GM and WM volumes were observed predominantly in food reward circuit, which may motivate abnormal dietary intake. Further, early elevated plasma LDL might contribute to low right frontal FA values of male adults, which requires further demonstration by larger-scale and longitudinal studies. PMID- 25279730 TI - Colorimetric aptasensor using unmodified gold nanoparticles for homogeneous multiplex detection. AB - Colorimetric aptasensors using unmodified gold nanoparticles (AuNPs) have attracted much attention because of their low cost, simplicity, and practicality, and they have been developed for various targets in the past several years. However, previous research has focused on developing single-target assays. Here, we report the development of a homogeneous multiplex aptasensor by using more than one class of aptamers to stabilize AuNPs. Using sulfadimethoxine (SDM), kanamycin (KAN) and adenosine (ADE) as example targets, a KAN aptamer (750 nM), an SDM aptamer (250 nM) and an ADE aptamer (500 nM) were mixed at a 1?1?1 volume ratio and adsorbed directly onto the surface of unmodified AuNPs by electrostatic interaction. Upon the addition of any of the three targets, the conformation of the corresponding aptamer changed from a random coil structure to a rigid folded structure, which could not adsorb and stabilize AuNPs. The AuNPs aggregated in a specific reaction buffer (20 mM Tris-HCl containing 20 mM NaCl and 5 mM KCl), which led to a color change from red to purple/blue. These results demonstrate that the multiplex colorimetric aptasensor detected three targets simultaneously while maintaining the same sensitivity as a single-target aptasensor for each individual target. The multiplex aptasensor could be extended to other aptamers for various molecular detection events. Due to its simple design, easy operation, fast response, cost effectiveness and lack of need for sophisticated instrumentation, the proposed strategy provides a powerful tool to examine large numbers of samples to screen for a small number of potentially positive samples containing more than one analyte, which can be further validated using sophisticated instruments. PMID- 25279732 TI - Multiporphyrin arrays on cyclotriphosphazene scaffolds. AB - We report the synthesis of first examples of hexaporphyrin and dodecaporphyrin assemblies on cyclotriphosphazene scaffold by adopting two different approaches based on Ru-pyridyl "N" coordination in decent yields. The multiporphyrin assemblies were confirmed by (31)P, (13)C, (1)H, (1)H-(1)H COSY, and NOESY NMR spectroscopic studies. The absorption studies showed 2-fold intensity enhancement with negligible changes in peak maxima compared to porphyrin monomers. The redox potentials of multiporphyrin assemblies showed the redox features of the constituted porphyrin monomers and supported weak interactions among the porphyrin units in noncovalent hexaporphyrin and dodecaporphyrin arrays. PMID- 25279731 TI - Peripheral blood mitochondrial DNA copy number is associated with prostate cancer risk and tumor burden. AB - Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of prostate cancer (PCa) has not been investigated. In a case-control study of 196 PCa patients and 196 age-paired healthy controls in a Chinese Han population, the association between mtDNA copy number in PBLs and PCa risk was evaluated. The relative mtDNA copy number was measured using quantitative real-time PCR; samples from three cases and two controls could not be assayed, leaving 193 cases and 194 controls for analysis. PCa patients had significantly higher mtDNA copy numbers than controls (medians 0.91 and 0.82, respectively; P<0.001). Dichotomized at the median value of mtDNA copy number in the controls, high mtDNA copy number was significantly associated with an increased risk of PCa (adjusted odds ratio= 1.85, 95% confidence interval: 1.21-2.83). A significant dose-response relationship was observed between mtDNA copy number and risk of PCa in quartile analysis (Ptrend = 0.011). Clinicopathological analysis showed that high mtDNA copy numbers in PCa patients were significantly associated with high Gleason score and advanced tumor stage, but not serum prostate-specific antigen level (P = 0.002, 0.012 and 0.544, respectively). These findings of the present study indicate that increased mtDNA copy number in PBLs is significantly associated with an increased risk of PCa and may be a reflection of tumor burden. PMID- 25279733 TI - Flow characterization of a spinner flask for induced pluripotent stem cell culture application. AB - We present detailed quantitative measurement analyses for flow in a spinner flask with spinning rates between 20 to 45 RPM, utilizing the optical velocimetry measurement technique of Particle Image Velocimetry (PIV). A partial section of the impeller was immersed in the working fluid to reduce the shear forces induced on the cells cultured on microcarriers. Higher rotational speeds improved the mixing effect in the medium at the expense of a higher shear environment. It was found that the mouse induced pluripotent stem (iPS) cells achieved the optimum number of cells over 7 days in 25 RPM suspension culture. This condition translates to 0.0984 Pa of maximum shear stress caused by the interaction of the fluid flow with the bottom surface. However, inverse cell growth was obtained at 28 RPM culture condition. Such a narrow margin demonstrated that mouse iPS cells cultured on microcarriers are very sensitive to mechanical forces. This study provides insight to biomechanical parameters, specifically the shear stress distribution, for a commercially available spinner flask over a wide range of Reynolds number. PMID- 25279735 TI - Copper-catalyzed, C-C coupling-based one-pot tandem reactions for the synthesis of benzofurans using o-iodophenols, acyl chlorides, and phosphorus ylides. AB - One-pot reactions involving acyl chlorides, phosphorus ylides, and o-iodophenols with copper catalysis have been established for the rapid synthesis of functionalized benzofurans. With all of these easily available and stable reactants, the construction of the target products has been accomplished via tandem transformations involving a key C-C coupling, leading to the formation of one C(sp(2))-C bond, one C(sp(2))-O bond, and one C ? C bond. PMID- 25279734 TI - In vivo time-related evaluation of a therapeutic neutralization monoclonal antibody against lethal enterovirus 71 infection in a mouse model. AB - Enterovirus 71 (EV71) is a neurotropic virus capable of inducing severe neurological symptoms and death. No direct targeting antivirals are useful in the treatment of severe EV71 infection. Because of low toxicity and good specificity, monoclonal antibodies (MAb) are a potential candidate for the treatment of viral infections. Therefore, we developed an EV71-specific conformational MAb with high in vitro cross-neutralization activity to heterologous EV71 subgenotypes. The in vivo treatment experiment at different days post-infection indicated that a single treatment of MAb CT11F9 within day 3 post-infection fully protected mice from morbidity and mortality (0% PBS vs. 100% at 10 ug/g per body weight ***P<0.0001). Immunohistochemical and histological analysis confirmed that CT11F9 significantly prohibited EV71 VP1 expression in various tissues and prevented EV71-induced myonecrosis. Moreover, thrice-treatment at day 4, 5, 6 post infection was associated with an increased survival rate (18.2% single vs. 50% thrice at 20 ug/g per body weight), and the mice recovered from limb paralysis. Competitive ELISA also confirmed that CT11F9-recognized epitopes were immunodominant in humans. In conclusion, MAb CT11F9 is an ideal candidate to be humanized and used in severe EV71 infection. PMID- 25279736 TI - Simple approach to derivatization of alcohols and phenols for the analysis by matrix(surface)-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - RATIONALE: Direct analysis of hydroxyl-containing compounds by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) methods is not always possible due to the neutral character of analytes. The suggested fixed-charge derivatization may increase the ionization efficiency for various alcohols and phenols in specific matrix- and surface-activated LDI conditions. METHODS: Aliphatic and steroid alcohols, as well as chlorophenols, were converted into various ammonioacetyl derivatives, containing a covalently bonded charged group, by reaction with bromoacetyl chloride and amine-type compounds such as triethylamine, pyridine or quinoline. The derivatives are suitable for MALDI-time of-flight (TOF)MS analysis. RESULTS: Triethylammoniumacetyl, pyridyliumacetyl and quinoliniumacetyl derivatives were prepared from aliphatic alcohols, some sterols and chlorinated phenols in one stage with quantitative yields. The derivatives produced characteristic MALDI and SALDI mass spectra. CONCLUSIONS: The suggested derivatization approach for the modification of alcohols is simple and does not require any expensive reagents. The derivatives include a fixed charge and produce intense signals in MALDI (preferentially non-acidic matrices) and matrix free SALDI (nanostructured target) conditions. Corresponding mass spectra are suitable for the determination of molecular mass and profiling of alcohols. PMID- 25279737 TI - Identification of the chemical components of Saussurea involucrata by high resolution mass spectrometry and the mass spectral trees similarity filter technique. AB - RATIONALE: Saussurea involucrata is a rare traditional Chinese medicine (TCM) that displays anti-fatigue, anti-inflammatory and anti-tumor effects. In this paper, the different chemical components of Saussurea involucrata were characterized and identified over a wide dynamic range by high-performance liquid chromatography coupled with high-resolution hybrid mass spectrometry (HPLC/HRMS/MS(n)) and the mass spectral trees similarity filter (MTSF) technique. METHODS: The aerial parts of Saussurea involucrata were extracted with 75% ethanol. The partial extract was separated on a chromatography column to concentrate the low-concentration compounds. Mass data were acquired using full scan mass analysis (resolving power 50,000) with data-dependent incorporation of dynamic exclusion analysis. The identified compounds were used as templates to construct a database of mass spectral trees. Data for the unknown compounds were matched with those templates and matching candidate structures were obtained. RESULTS: The detected compounds were characterized based on matching to candidate structures by the MTSF technique and were further identified by their accurate mass weight, multiple-stage analysis and fragmentation patterns and through comparison with literature data. A total of 38 compounds were identified including 19 flavones, 11 phenylpropanoids and 8 sphingolipids. Among them, 7 flavonoids, 8 phenylpropanoids and 8 sphingolipids were identified for the first time in Saussurea involucrata. CONCLUSIONS: HPLC/HRMS/MS(n) combined with MTSF was successfully used to discover and identify the chemical compounds in Saussurea involucrata. The results indicated that this combined technique was extremely useful for the rapid detection and identification of the chemical components in TCMs. PMID- 25279738 TI - Mass resolution of linear quadrupole ion traps with round rods. AB - RATIONALE: Auxiliary dipole excitation is widely used to eject ions from linear radio-frequency quadrupole ion traps for mass analysis. Linear quadrupoles are often constructed with round rod electrodes. The higher multipoles introduced to the electric potential by round rods might be expected to change the ion ejection process. We have therefore investigated the optimum ratio of rod radius, r, to field radius, r0, for excitation and ejection of ions. METHODS: Trajectory calculations are used to determine the excitation contour, S(q), the fraction of ions ejected when trapped at q values close to the ejection (or excitation) q. Initial conditions are randomly selected from Gaussian distributions of the x and y coordinates and a thermal distribution of velocities. The N = 6 (12 pole) and N = 10 (20 pole) multipoles are added to the quadrupole potential. Peak shapes and resolution were calculated for ratios r/r0 from 1.09 to 1.20 with an excitation time of 1000 cycles of the trapping radio-frequency. RESULTS: Ratios r/r0 in the range 1.140 to 1.160 give the highest resolution and peaks with little tailing. Ratios outside this range give lower resolution and peaks with tails on either the low-mass side or the high-mass side of the peaks. This contrasts with the optimum ratio of 1.126-1.130 for a quadrupole mass filter operated conventionally at the tip of the first stability region. With the optimum geometry the resolution is 2.7 times greater than with an ideal quadrupole field. Adding only a 2.0% hexapole field to a quadrupole field increases the resolution by a factor of 1.6 compared with an ideal quadrupole field. Addition of a 2.0% octopole lowers resolution and degrades peak shape. With the optimum value of r/r0 , the resolution increases with the ejection time (measured in cycles of the trapping rf, n) approximately as R0.5 = 6.64n, in contrast to a pure quadrupole field where R0.5 = 1.94n. CONCLUSIONS: Adding weak nonlinear fields to a quadrupole field can improve the resolution with mass-selective ejection of ions by up to a factor of 2.7. The optimum ratio r/r0 is 1.14 to 1.16, which differs from the optimum ratio for a mass filter of 1.128-1.130. PMID- 25279739 TI - Sample matrix effects on measured carbon and oxygen isotope ratios during continuous-flow isotope-ratio mass spectrometry. AB - RATIONALE: Continuous-flow isotope-ratio mass spectrometry (CF-IRMS) is frequently used to analyze CO2 found in media such as air, breath, and soil pore space gas with the aid of a sample preparation and transfer device such as a Gasbench II. This study investigated the effect that matrices other than helium (He) have on the measured delta(13)C and delta(18)O isotope ratios of CO2. METHODS: Identical CO2 was added to sample vials with matrices of pure He, pure N2, or a 21:79 mixture of O2/N2 and analyzed by a ThermoFinnigan Delta(Plus) XP isotope-ratio mass spectrometer coupled to a ThermoFinnigan Gasbench II. Variables such as CO2 concentration, sample analysis sequence, and sample matrix removal ('blanking') through manipulation of an injection and dilution open split were tested to identify systematic isotope ratio offsets between the different matrix types. RESULTS: The process of blanking induced a delta(13)C and delta(18)O offset of <=0.20/00 between otherwise identical populations of CO2 samples in He. The (13)C/(12)C and (18)O/(16)O isotope ratios of CO2 sampled from pure N2 or a mixture of O2/N2 were found to be within 0.1 to 0.20/00 of those of an identical CO2 sampled from a He matrix when N2 or O2/N2 was removed prior to transport to the mass spectrometer. The measured oxygen isotope ratios of CO2 sampled from N2 and O2/N2 varied by as much as 0.60/00 and 40/00, respectively, if matrix gas was not removed prior to ionization. CONCLUSIONS: Sampling CO2 from matrices similar to air does not significantly affect the measured (13)C/(12)C and (18)O/(16)O isotope ratios of CO2 when a gas-handling procedure that includes the removal of matrix gas is utilized. This procedure is much preferable to introducing matrix gas and potentially isobaric interference to the ion source. PMID- 25279740 TI - Evaluation of the photooxidation of galactosyl- and lactosylceramide by electrospray ionization mass spectrometry. AB - RATIONALE: Glycosphingolipids are important lipid molecules namely as constituents of the plasma membrane organized in lipid rafts, in signal transduction, and cell-cell communication. Although many human diseases are associated with oxidative stress and lipid oxidation, a link between oxidative stress and modification of glycosphingolipids has never been addressed. METHODS: In this study, the structural changes caused by UVA-induced photooxidation of galactosyl- (GalCer) and lactosylceramide (LacCer) molecular species were studied by electrospray ionization mass spectrometry (ESI-MS and MS/MS), using a quadrupole time-of-flight (QTOF) mass spectrometer and high-performance liquid chromatography/tandem mass spectrometry with a C5 stationary phase (C5 HPLC/MS/MS) using a linear ion trap. RESULTS: ESI-MS spectra of GalCer and LacCer after photooxidation showed new ions with a mass shift of +32 Da when compared with the ions of the non-modified glycosphingolipids. These new species were assigned as hydroperoxyl derivatives, confirmed by HPLC/MS/MS and through FOX 2 assay. In the ESI-MS and LC/MS of lactosylceramide a new ion with lower m/z value, assigned as glucosylceramide (GlcCer) + 32 Da, was also detected and proposed to be formed due to oxidative cleavage of lactosyl moieties. ESI-MS/MS of the oxidized species allowed us to infer the presence of isomeric hydroperoxyl derivatives, with the hydroperoxyl moiety either linked to the sphingosine backbone or in the unsaturated acyl chain. Oxidation in the sugar moieties was observed in the case of LacCer, suggesting an oxidation via radical reactive oxygen species that can induce the oxidative cleavage of the lactosyl moiety. CONCLUSIONS: This study shows that glycosphingolipids are prone to oxidation and the identified mass spectrometry fingerprint of oxidized galactosyl- and lactosylceramide species will support their future identification in lipidomic studies of biological samples under oxidative conditions. PMID- 25279741 TI - Ambient analysis of leachable compounds from single-use bioreactors with desorption electrospray ionization time-of-flight mass spectrometry. AB - RATIONALE: Trace levels of bis(2,4-di-tert-butylphenyl)phosphate (BdtbPP) leaching from single-use bioreactors (SUBs) were recently found to be highly detrimental to mammalian cell growth. The traditional approach to detect the leachable requires time-consuming solvent extraction of SUBs. To assist the qualification of SUBs and/or their manufacturing raw materials in biopharmaceutical development and manufacturing, it is essential to develop a rapid and sensitive analytical approach for detecting this leachable and related compounds, which is described in this study. METHODS: Native films from several commercially available SUBs were directly examined by desorption electrospray ionization (DESI) time-of-flight mass spectrometry (TOFMS) without sample preparation. As a comparison, the same SUBs were also analyzed by high performance liquid chromatography (HPLC)/ultraviolet (UV) following the solvent extraction. RESULTS: With a suitable spray solvent selected in this study, DESI TOFMS enabled rapid and sensitive detection of leachable compounds directly from SUBs. Accurate mass measurement from TOFMS allowed ready identification of BdtbPP, its parent analog compound, and other polymer components in the SUBs from their protonated surrogates. The relative abundances of BdtbPP in different SUBs measured by DESI-TOFMS exhibited good correlation with those from the traditional extraction-based approach with HPLC/UV. CONCLUSIONS: A rapid and sensitive approach was developed for direct detection of BdtbPP and other leachables from SUBs using DESI-TOFMS. The results are in high accordance with those from conventional approaches, which indicates the usefulness of the proposed method as a qualification tool for SUBs in biopharmaceutical development and also its great potential in the analysis of extractables/leachables in a wide variety of materials, process components, devices and containers used in the pharmaceutical industry. PMID- 25279742 TI - Species-related difference between limonin and obacunone among five liver microsomes and zebrafish using ultra-high-performance liquid chromatography coupled with a LTQ-Orbitrap mass spectrometer. AB - RATIONALE: Limonin and obacunone are two major limonoids distributed in the Rutaceae and Meliaceae families. Their defined anti-tumor activity is closely connected with the furan ring and the multi-carbonyls in their structures. In vivo and in vitro biotransformations may influence their structures and further change their effects. The metabolic profiles of limonin and obacunone have not been studied previously. In order to clarify their in vivo and in vitro metabolism, a comparative investigation of their metabolic pathways in five different species of liver microsomes and zebrafish was carried out. METHODS: In the present study, ultra-high-performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC/HRMS) and related electrospray ionization (ESI) tandem mass spectrometric (MS/MS) dissociation of limonin and obacunone were applied for the analysis. Each metabolite was identified by its accurate mass data. Human liver microsomes (HLMs), monkey liver microsomes (MLMs), dog liver microsomes (DLMs), rat liver microsomes (RLMs), mice liver microsomes (XLMs) and zebrafish were included in the biotransformations. RESULTS: One phase I metabolite of limonin (M1-1) and two phase I metabolites of obacunone (M2-1, M2 2) were identified by accurate mass measurement and MS/MS fragmentation behaviors. A reduction reaction was regarded as the major metabolic pathway of limonoids in liver microsomes. The reduction reaction site of M1-1 and M2-1 was at the C-16 carbonyl, while for M2-2 it was at C-7. M1-1 was the major and unique metabolite of limonin and the metabolic rate of limonin varied from 11.5% to 17.8% in liver microsomes (LMs). M2-2 was the main metabolite of obacunone in LMs and zebrafish. M1-1 and M2-1 were only detected in LMs while M2-2 was found in both LMs and zebrafish incubation systems. The metabolic rate of obacunone varied from 2.5% to 19.1% and the content of M2-2 was about five times higher than that of M2-1. CONCLUSIONS: The ESI-HR-MS/MS fragmentation behaviors of limonin and obacunone were investigated for the first time. A qualitative and semi quantitative method was developed for the in vivo and in vitro metabolic analysis of limonin and obacunone. The results demonstrated that the metabolic processes of limonin and obacunone were different between LMs and zebrafish. However, both of these two parent compounds presented similar metabolic processes in five species of LMs. This was caused by the metabolic difference between mammals and fish or because limonin probably cannot be absorbed in zebrafish. PMID- 25279743 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of small volatile molecules using a parylene-matrix chip. AB - RATIONALE: In matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) mass spectrometry (MS), volatile small molecules have been nearly impossible to analyze because (1) such molecules evaporate under drying and vacuum conditions and (2) the organic matrix creates matrix peaks in the low mass-to charge (m/z) range (m/z <500). In this work, the analysis of volatile small molecules using MALDI-TOFMS was realized using (1) a parylene-matrix chip to eliminate the matrix peaks of the organic matrix and (2) graphene for the effective adsorption of the small volatile molecules. METHODS: The parylene matrix chip was produced by deposition of a partially porous parylene-N thin film on a dried organic matrix array. The sample solution of volatile small molecules was mixed with the graphene and then placed on the parylene-matrix chip for MALDI TOFMS. Analogs of chemical agents called dimethyl methyl phosphonate (DMMP) and 2 chloroethylethylsulfide (CEES) were used as model compounds for the small volatile molecules, and the sensing parameters were estimated, such as the limit of detection (LOD) and the detection range. RESULTS: MALDI-TOFMS based on the parylene-matrix chip and graphene as the adsorbent could achieve a LOD of approximately 1 ppb in the detection range of 1 ppm-1 ppb for the highly volatile DMMP and CEES. CONCLUSIONS: The parylene-matrix chip with graphene can be applied for the detection of volatile small molecule analytes in the m/z ratio range of small molecules (m/z <500) using graphene as an effective adsorbent. PMID- 25279744 TI - GUMBOS matrices of variable hydrophobicity for matrix-assisted laser desorption/ionization mass spectrometry. AB - RATIONALE: Detection of hydrophobic peptides remains a major obstacle for matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). This stems from the fact that most matrices for MALDI are hydrophilic and therefore have low affinities for hydrophobic peptides. Herein, 1-aminopyrene (AP) and AP-derived group of uniform materials based on organic salts (GUMBOS) as novel matrices for MALDI-MS analyses of peptides were investigated for hydrophobic and hydrophilic peptides. METHODS: A number of solid-phase AP-based GUMBOS are synthesized with variable hydrophobicity simply by changing the counterions. Structures were confirmed by use of (1)H NMR and electrospray ionization mass spectrometry (ESI MS). 1-Octanol/water partition coefficients (Ko/w) were used to measure the hydrophobicity of the matrices. A dried-droplet method was used for sample preparation. All spectra were obtained using a MALDI-TOF mass spectrometer in positive ion reflectron mode. RESULTS: A series of AP-based GUMBOS was synthesized including [AP][chloride] ([AP][Cl]), [AP][ascorbate] ([AP][Asc]) and [AP][bis(trifluoromethane)sulfonimide] ([AP][NTf2]). The relative hydrophobicities of these compounds and alpha-cyano-4-hydroxycinnamic acid (CHCA, a common MALDI matrix) indicated that AP-based GUMBOS can be tuned to be much more hydrophobic than CHCA. A clear trend is observed between the signal intensities of hydrophobic peptides and hydrophobicity of the matrix. CONCLUSIONS: MALDI matrices of GUMBOS with tunable hydrophobicities are easily obtained simply by varying the counterion. We have found that hydrophobic matrix materials are very effective for MALDI determination of hydrophobic peptides and, similarly, the more hydrophilic peptides displayed greater intensity in the more hydrophilic matrix. PMID- 25279745 TI - Fully automated, high-throughput instrumentation for measuring the delta13C value of methane and application of the instrumentation to rice paddy samples. AB - RATIONALE: The stable carbon isotope ratio ((13)C/(12)C or delta(13)C value) of methane (CH4) produced in methanogenic environments contains information about primary source material, CH4 production pathways, degree of oxidation, and transport. However, the availability of delta(13)C-CH4 data is severely limited because isotope analysis methods are low throughput, owing primarily to the need for manual processing steps. High-throughput, fully automated measurement is necessary to facilitate the use of the delta(13)C signature in understanding CH4 biogeochemistry. METHODS: We modified a conventional continuous-flow (CF) gas chromatography/combustion/isotope ratio mass spectrometry (IRMS) instrument system by incorporating (i) automated sample injection, (ii) a newly developed temperature-control unit for preconcentration and cryofocus traps, and (iii) an automatic system for liquid-nitrogen refilling. The system, which could run unattended for 1 day, was used to obtain delta(13)C-CH4 data for CH4 samples collected from an irrigated rice paddy with an automated closed-chamber system. RESULTS: Using the fully automated CF-IRMS system, we measured delta(13)C-CH4 data for 77 samples during a 21.5-h continuous run (17 min per sample) with high precision (1sigma = 0.110/00, reproducibility) and moderate consumption of liquid nitrogen (11 L). Application of the system to CH4 samples obtained from the rice paddy revealed distinct seasonal and diurnal variations in delta(13)C values with the highest temporal resolution ever reported. CONCLUSIONS: A fully automated, high-throughput system for the measurement of delta(13)C-CH4 values was developed and used to analyze air samples obtained from a rice paddy. Our results demonstrate the high potential of this system for obtaining delta(13)C data useful for process-level understanding of CH4 biogeochemistry with respect to spatiotemporal variation of CH4 sources and how that variation is affected by environmental and management factors. PMID- 25279746 TI - Desorption atmospheric pressure photoionization and direct analysis in real time coupled with travelling wave ion mobility mass spectrometry. AB - RATIONALE: Ambient mass spectrometry (MS) is a tool for screening analytes directly from sample surfaces. However, background impurities may complicate the spectra and therefore fast separation techniques are needed. Here, we demonstrate the use of travelling wave ion mobility spectrometry in a comparative study of two ambient MS techniques. METHODS: Desorption atmospheric pressure photoionization (DAPPI) and direct analysis in real time (DART) were coupled with travelling wave ion mobility mass spectrometry (TWIM-MS) for highly selective surface analysis. The ionization efficiencies of DAPPI and DART were compared. Test compounds were: bisphenol A, benzo[a]pyrene, ranitidine, cortisol and alpha tocopherol. DAPPI-MS and DART-TWIM-MS were also applied to the analysis of chloroquine from dried blood spots, and alpha-tocopherol from almond surface, and DAPPI-TWIM-MS was applied to analysis of pharmaceuticals and multivitamin tablets. RESULTS: DAPPI was approximately 100 times more sensitive than DART for bisphenol A and 10-20 times more sensitive for the other compounds. The limits of detection were between 30-290 and 330-8200 fmol for DAPPI and DART, respectively. Also, from the authentic samples, DAPPI ionized chloroquine and alpha-tocopherol more efficiently than DART. The mobility separation enabled the detection of species with low signal intensities, e.g. thiamine and cholecalciferol, in the DAPPI-TWIM-MS analysis of multivitamin tablets. CONCLUSIONS: DAPPI ionized the studied compounds of interest more efficiently than DART. For both DAPPI and DART, the mobility separation prior to MS analysis reduced the amount of chemical noise in the mass spectrum and significantly increased the signal-to-noise ratio for the analytes. PMID- 25279747 TI - Effects of soil mineral matrix on the analysis of plant- and soil-derived polysaccharides after acid hydrolysis. AB - RATIONALE: The efficiency of extraction procedures for the determination of organic compounds in soil may be affected by the presence of the mineral phase. Our aim was to analyse the magnitude of such an effect on both total polysaccharide content and (13)C-isotopic signature of the polysaccharides. METHODS: After acid hydrolysis of (13)C-labelled wheat, soil and a mixture of these, sugars were quantified and analysed isotopically. Measured values were compared with theoretical contents. RESULTS: No matrix effect was apparent for total sugar-C content of the mixture. However, a matrix effect was observed for the contribution of (13)C-labelled wheat sugars. For the soil+plant mixture (13)C labelled wheat sugar contribution was overestimated. Soil-derived sugar-C contribution to the mixture was underestimated. CONCLUSIONS: Studies using stable isotopes to follow the fate of added plant-derived compounds in soil need to take into account matrix effects. Further studies have to elaborate on correction procedures and/or the development of extraction procedures to overcome the influence of matrix effects and/or acid hydrolysis extraction on sugar-C contents. PMID- 25279748 TI - Minimising methodological biases to improve the accuracy of partitioning soil respiration using natural abundance 13C. AB - RATIONALE: Microbial degradation of soil organic matter (heterotrophic respiration) is a key determinant of net ecosystem exchange of carbon, but it is difficult to measure because the CO2 efflux from the soil surface is derived not only from heterotrophic respiration, but also from plant root and rhizosphere respiration (autotrophic). Partitioning total CO2 efflux can be achieved using the different natural abundance stable isotope ratios (delta(13)C) of root and soil CO2. Successful partitioning requires very accurate measurements of total soil efflux delta(13)CO2 and the delta(13)CO2 of the autotrophic and heterotrophic sources, which typically differ by just 2-80/00. METHODS: In Scottish moorland and grass mesocosm studies we systematically tested some of the most commonly used techniques in order to identify and minimise methodological errors. Typical partitioning methods are to sample the total soil-surface CO2 efflux using a chamber, then to sample CO2 from incubated soil-free roots and root-free soil. We investigated the effect of collar depth on chamber measurements of surface efflux delta(13)CO2 and the effect of incubation time on estimates of end-member delta(13)CO2. RESULTS: (1) a 5 cm increase in collar depth affects the measurement of surface efflux delta(13)CO2 by -1.50/00 and there are fundamental inconsistencies between modelled and measured biases; (2) the heterotrophic delta(13)CO2 changes by up to -40/00 within minutes of sampling; we recommend using regression to estimate the in situ delta(13)CO2 values; (3) autotrophic delta(13)CO2 measurements are reliable if root CO2 is sampled within an hour of excavation; (4) correction factors should be used to account for instrument drift of up to 30/00 and concentration-dependent non linearity of CRDS (cavity ringdown spectroscopy) analysis. CONCLUSIONS: Methodological biases can lead to large inaccuracies in partitioning estimates. The utility of stable isotope partitioning of soil CO2 efflux will be enhanced by consensus on the optimum measurement protocols and by minimising disturbance, particularly during chamber measurements. PMID- 25279749 TI - Mass spectral characterisation of a polar, esterified fraction of an organic extract of an oil sands process water. AB - RATIONALE: Characterising complex mixtures of organic compounds in polar fractions of heavy petroleum is challenging, but is important for pollution studies and for exploration and production geochemistry. Oil sands process affected water (OSPW) stored in large tailings ponds by Canadian oil sands industries contains such mixtures. METHODS: A polar OSPW fraction was obtained by silver ion solid-phase extraction with methanol elution. This was examined by numerous methods, including electrospray ionisation (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS) and ultra-high-pressure liquid chromatography (uHPLC)/Orbitrap MS, in multiple ionisation and MS/MS modes. Compounds were also synthesised for comparison. RESULTS: The major ESI ionisable compounds detected (+ion mode) were C15-28 SO3 species with 3-7 double bond equivalents (DBE) and C27-28 SO5 species with 5 DBE. ESI-MS/MS collision-induced losses were due to water, methanol, water plus methanol and water plus methyl formate, typical of methyl esters of hydroxy acids. Once the fraction was re saponified, species originally detected by positive ion MS, could be detected only by negative ion MS, consistent with their assignment as sulphur-containing hydroxy carboxylic acids. The free acid of a keto dibenzothiophene alkanoic acid was added to an unesterified acid extract of OSPW in known concentrations as a putative internal standard, but attempted quantification in this way proved unreliable. CONCLUSIONS: The results suggest the more polar acidic organic SO3 constituents of OSPW include C15-28 S-containing, alicyclic and aromatic hydroxy carboxylic acids. SO5 species are possibly sulphone analogues of these. The origin of such compounds is probably via further biotransformation (hydroxylation) of the related S-containing carboxylic acids identified previously in a less polar OSPW fraction. The environmental risks, corrosivity and oil flow assurance effects should be easier to assess, given that partial structures are now known, although further identification is still needed. PMID- 25279750 TI - Tandem mass spectrometric fragmentation behavior of lignans, flavonoids and triterpenoids in Streblus asper. AB - RATIONALE: An unambiguous identification of compounds can be achieved by comparison of known fragmentation patterns. While the literature about fragmentation mechanisms of lignans, flavonoids and triterpenoids is few. So the present study analyses the fragmentation mechanisms of these compounds isolated from Streblus asper. METHODS: Electrospray ionization ion trap mass spectrometry (ESI-ITMS) and atmospheric pressure chemical ionization ion trap mass spectrometry (APCI-ITMS) were used to obtain the MS(n) spectra of the compounds. By analyzing the differences between the ions, the fragmentation mechanisms of these compounds were explored. RESULTS: Of the 29 compounds detected, 17, 7, and 5 were lignans, flavonoids and triterpenoids, respectively. The majority of lignans were found to give [M - H](-) ions of sufficient abundance for MS(n) analyses. The flavonoids were prone to the loss of CO and H2O. The triterpenoids always lost one formic acid molecule and two hydrogens, or one H2O from [M - H]( ) to form the most abundant product ion in the MS(n) spectrum. CONCLUSIONS: ESI/APCI-ITMS were demonstrated to be fast, effective and practical tools to characterize the structures of flavonoids, triterpenoids and lignans. Results of the present study can help identify the analogous constituents by analyzing their MS(n) spectra. PMID- 25279751 TI - Clumped isotope measurements of small carbonate samples using a high-efficiency dual-reservoir technique. AB - RATIONALE: The measurement of multiply substituted isotopologues of CO2 derived from carbonate has allowed the reconstruction of paleotemperatures from a single phase (CaCO3 ), circumventing uncertainty inherent in other isotopic paleothermometers. Traditional analytical techniques require relatively large amounts of carbonate (3-8 mg per replicate), which limits the applicability of the clumped isotope proxy to certain geological materials such as marine microfossils, commonly used for paleoclimate reconstructions. METHODS: Clumped isotope ratio measurements of small samples were made on a new, high-efficiency, dual-reservoir sample-preparation inlet system attached to a Thermo-Finnigan MAT 253 mass spectrometer. Sample gas produced on the inlet is introduced from a 10 mL reservoir directly into the source via a capillary. Reference gas fills an identical 10 mL reservoir installed between the reference bellows and the capillary. The gas pressures in the two reservoirs are initially balanced, and are allowed to decrease together over the run. RESULTS: Carbonate samples from 1 mg to 2.6 mg produced Delta47 values equivalent to those from the traditional two bellows method with identical single-sample precision (1 SE = 0.005-0.0150/00) and external standard error (SE = 0.006-0.0150/00, n = 4-6). The size of sample needed to achieve good precision is controlled by the sensitivity of the mass spectrometer and the size of the fixed reservoirs and adjacent U-trap installed on our inlet. CONCLUSIONS: The high-precision clumped isotope measurements of small aliquots of carbonate obtained in this method allows for the application of this proxy to a wider range of geological sample materials, such as marine microfossils, that until now have been nearly impossible to analyze given sample size limitation. PMID- 25279752 TI - Ambient laser ablation sample transfer with nanostructure-assisted laser desorption ionization mass spectrometry for bacteria analysis. PMID- 25279753 TI - Early cleavage of ethylene glycol bis(succinimidylsuccinate) (EGS)-linker moieties during enzymatic digestion of cross-linked proteins. PMID- 25279754 TI - Prevalence and trends of sunscreen use and sunburn among Norwegian women. AB - BACKGROUND: Sunscreen is recommended to prevent sunburn and skin cancer. OBJECTIVES: To investigate sunscreen use in relation to demographic and phenotypic characteristics among women in Norway, as well as solar UV exposure, sunburn experience in different decades of life, and temporal trends in sunscreen use. METHODS: We used data from the Norwegian Women and Cancer Study, a large population-based prospective cohort study. Log-binomial regression was used to estimate the association between sunscreen use and personal characteristics. Results are presented as prevalence ratios (PRs) and 99% confidence intervals (CIs). RESULTS: The study sample consisted of 148,869 women, with a mean age, when answering the questionnaire, of 53 years (range 41-75). Sixty-five per cent of the women used sunscreen during the Easter holiday, 73% in northern latitudes and 87% in bathing vacations in southern latitudes. Sunscreen with sun protection factor (SPF) >= 15 was used by 25,156 (18%) at Easter, 18,118 (13%) in northern latitudes and 22,678 (30%) in southern latitudes. The prevalence of sunscreen use increased from 1997 to 2007, and this increase was associated with age. In 1997, 39% of women reported at least one sunburn per year in the recent decade, compared with 46% in 2007 (Ptrend = 0.001). Women who experienced at least four sunburns per year during adolescence reported more sunscreen use in adulthood (PREaster 1.54, 99% CI 1.30-1.83; PRnorthern latitudes 1.49, 99% CI 1.20-1.84; PRsouthern latitudes 1.37, 99% CI 1.14-1.65). CONCLUSIONS: The prevalence of sunscreen use increased from 1997 to 2007. However, this increase has not been accompanied by a decrease in sunburn. Moreover, use of sunscreen with the recommended SPF was not common among Norwegian women. PMID- 25279755 TI - Different patterns of punctate white matter lesions in serially scanned preterm infants. AB - BACKGROUND AND PURPOSE: With the increased use of MRI in preterm infants, punctate white matter lesions (PWML) are more often recognized. The aim of this study was to describe the incidence and characteristics of these lesions as well as short-term outcome in a cohort of serially scanned preterm infants, using both conventional imaging, diffusion (DWI) and susceptibility (SWI) weighted imaging. MATERIALS AND METHODS: 112 preterm infants with 2 MRIs in the neonatal period, with evidence of punctate white matter lesions, were included. Appearance, lesion load, location, and abnormalities on DWI and SWI were scored and outcome data were collected. RESULTS: Different patterns of punctate white matter lesions did appear: a linear appearance associated with signal loss on SWI, and a cluster appearance associated with restricted diffusion on DWI on the first MRI. Cluster and mixed lesions on the first scan changed in appearance in over 50% on the second scan, whereas linear lesions generally kept their appearance. Lesions were only visible on the early scan in 33%, and were only seen at term equivalent age in 20%. Nine infants developed cerebral palsy, due to additional overt white matter lesions in six. CONCLUSION: Two patterns of punctate white matter lesions were identified: one with loss of signal on SWI in a linear appearance, and the other with DWI lesions with restricted diffusion in a cluster appearance. These different patterns are suggestive of a difference in underlying pathophysiology. To reliably classify PWML in the preterm infant in either pattern, an early MRI with DWI and SWI sequences is required. PMID- 25279757 TI - The effect of salinity, redox mediators and temperature on anaerobic biodegradation of petroleum hydrocarbons in microbial fuel cells. AB - Microbial fuel cells (MFCs) need to be robust if they are to be applied in the field for bioremediation. This study investigated the effect of temperature (20 50 degrees C), salinity (0.5-2.5% (w/v) as sodium chloride), the use of redox mediators (riboflavin and anthraquinone-2-sulphonate, AQS) and prolonged fed batch operation (60 days) on biodegradation of a petroleum hydrocarbon mix (i.e. phenanthrene and benzene) in MFCs. The performance criteria were degradation efficiency, % COD removal and electrochemical performance. Good electrochemical and degradation performance were maintained up to a salinity of 1.5% (w/v) but deteriorated by 35-fold and 4-fold respectively as salinity was raised to 2.5%w/v. Degradation rates and maximum power density were both improved by approximately 2-fold at 40 degrees C compared to MFC performance at 30 degrees C but decreased sharply by 4-fold when operating temperature was raised to 50 degrees C. The optimum reactor performance obtained at 40 degrees C was 1.15 mW/m(2) maximum power density, 89.1% COD removal and a degradation efficiency of 97.10%; at moderately saline (1% w/v) conditions the maximum power density was 1.06 mW/m(2), 79.1% COD removal and 91.6% degradation efficiency. This work suggests the possible application of MFC technology in the effective treatment of petroleum hydrocarbons contaminated site and refinery effluents. PMID- 25279756 TI - Network analysis identifies SOD2 mRNA as a potential biomarker for Parkinson's disease. AB - Increasing evidence indicates that Parkinson's disease (PD) and type 2 diabetes (T2DM) share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2), is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE). The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted. PMID- 25279758 TI - Formation of trichloronitromethane and dichloroacetonitrile in natural waters: precursor characterization, kinetics and interpretation. AB - During the chloramination of natural waters, both chloramines and dissolved organic nitrogen (DON) can serve as nitrogen sources for the formation of trichloronitromethane (TCNM) and dichloroacetonitrile (DCAN). The present study investigated the formation kinetics and precursor characteristics of TCNM and DCAN. (15)N-Isotopic monochloramination of the organic fractions produced both (15)N- and (14)N-DCAN and TCNM. Nitrogenous disinfection byproduct (N-DBP) formation, in which the nitrogen precursor originated from DON ((14)N-DCAN and (14)N-TCNM), followed a second-order reaction kinetics (k=3.2*10(-5) to 9.4*10( 5)MUM(-1)h(-1)). The formation of N-DBP where the nitrogen atoms originated from chloramines (e.g. (15)N-DCAN and (15)N-TCNM) correlated linearly with chloramine exposure. The discrepancy in formation kinetics results in that the (14)N-DCAN concentrations were two to ten times higher than (15)N-DCAN in the beginning of the reaction (<12h). Possible rate equations are proposed in this study. The results of a model compound study support the results of the chloramination of natural waters. In addition, 4-hydroxybenzaldehyde, an oxidative product commonly found during chlorination/chloramination of natural organic matters, gave a 10 fold greater yield of DCAN than that produced from tyrosine; 4 hydroxybenzaldehyde is thus an important precursor in DCAN formation by chloramine incorporation during the chloramination of natural waters. PMID- 25279759 TI - Compensation of missing wedge effects with sequential statistical reconstruction in electron tomography. AB - Electron tomography (ET) of biological samples is used to study the organization and the structure of the whole cell and subcellular complexes in great detail. However, projections cannot be acquired over full tilt angle range with biological samples in electron microscopy. ET image reconstruction can be considered an ill-posed problem because of this missing information. This results in artifacts, seen as the loss of three-dimensional (3D) resolution in the reconstructed images. The goal of this study was to achieve isotropic resolution with a statistical reconstruction method, sequential maximum a posteriori expectation maximization (sMAP-EM), using no prior morphological knowledge about the specimen. The missing wedge effects on sMAP-EM were examined with a synthetic cell phantom to assess the effects of noise. An experimental dataset of a multivesicular body was evaluated with a number of gold particles. An ellipsoid fitting based method was developed to realize the quantitative measures elongation and contrast in an automated, objective, and reliable way. The method statistically evaluates the sub-volumes containing gold particles randomly located in various parts of the whole volume, thus giving information about the robustness of the volume reconstruction. The quantitative results were also compared with reconstructions made with widely-used weighted backprojection and simultaneous iterative reconstruction technique methods. The results showed that the proposed sMAP-EM method significantly suppresses the effects of the missing information producing isotropic resolution. Furthermore, this method improves the contrast ratio, enhancing the applicability of further automatic and semi automatic analysis. These improvements in ET reconstruction by sMAP-EM enable analysis of subcellular structures with higher three-dimensional resolution and contrast than conventional methods. PMID- 25279760 TI - Selection of functional lactic acid bacteria as starter cultures for the fermentation of Korean leek (Allium tuberosum Rottler ex Sprengel.). AB - The purpose of this research was to find safe and suitable starter cultures for the fermentation of Korean leek (Allium tuberosum Rottler), also known as garlic chives or Oriental garlic. This traditional herb has several functional properties and a strong flavour; its leaves are used as food material. Eighteen strains of lactic acid bacteria (LAB) were isolated from well-fermented leek kimchi. Controlled fermentation of the leek leaves was conducted with 2 strains (Weissella confusa LK4 and Lactobacillus plantarum LK8), selected as potential starter cultures on the basis of their safety properties, and on the pH, total titratable acidity (TTA), and viable cell numbers [colony forming units (CFUml( 1))] achieved during the fermentation. Microbial dynamics was also followed during fermentation by using PCR-DGGE (Denaturing Gradient Gel Electrophoresis) on DNA level. To analyse bioactive compounds such as thiols and allicin (diallyl thiosulfinates), the total flavonoid and polyphenolic contents were determined by colorimetric methods. Functional properties were assessed on the basis of anti oxidative capacities by determining the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging effect, and ferric reducing antioxidant power (FRAP). W. confusa LK4 rapidly increased during the first stage of leek fermentation, and was mainly responsible for accelerated fermentation during the early period in contrast to L. plantarum LK8, a stronger acid producer during the later stages of fermentation. After 48 h fermentation, leeks fermented with W. confusa LK4 showed the highest radical scavenging effects and reducing ability. The detectable amount of allicin of fermented leeks decreased relative to the change in pH, whereas the concentration of thiols significantly increased. Total flavonoid and poly-phenolic contents changed during fermentation and showed correlation with anti-oxidant effects. We therefore suggest the suitability of W. confusa LK4 as a potential starter culture for fermentation of leeks. PMID- 25279762 TI - Pain in children--are we accomplishing the optimal pain treatment? AB - Morphine, paracetamol and local anesthetics have for a long time been the foremost used analgesics in the pediatric patient by tradition but not always enough effective and associated with side effects. The purpose with this article is to propose alternative approaches in pain management, not always supported up by substantial scientific work but from a combination of science and clinical experience in the field. The scientific literature has been reviewed in parts regarding different aspects of pain assessment and analgesics used for treatment of diverse pain conditions with focus on procedural and acute pain. Clinical experience has been added to form the suggested improvements in accomplishing an improved pain management in pediatric patients. The aim with pain management in children should be a tailored analgesic medication with an individual acceptable pain level and optimal degree of mobilization with as little side effects as possible. Simple techniques of pain control are as effective as and complex techniques in pediatrics but the technique used is not of the highest importance in achieving a good pain management. Increased interest and improved education of the doctors prescribing analgesics is important in accomplishing a better pain management. The optimal treatment with analgesics is depending on the analysis of pain origin and analgesics used should be adjusted thereafter. A multimodal treatment regime is advocated for optimal analgesic effect. PMID- 25279761 TI - Effect of pioglitazone on in-stent restenosis after coronary drug-eluting stent implantation: a meta-analysis of randomized controlled trials. AB - BACKGROUND: In-stent restenosis (ISR) remains a common life-threatening complication and some studies have shown that pioglitazone can reduce the incidence of ISR in patients with drug-eluting stents (DES) implantation. We conducted a meta-analysis to assess the effect of pioglitazone in preventing ISR after DES implantation. METHODS: Randomized controlled trials (RCTs) investigating the effects of pioglitazone for ISR after DES implantation were identified by systematic searches of multiple online databases and manual searches of related reference lists of identified trials through May 2014. The primary endpoint was the rate of ISR. Secondary endpoints included minimum lumen diameter, percentage stenosis of stented vessels, late loss, in-stent neointimal volume, target vessel revascularization (TVR), target lesion revascularization, myocardial infarction, stent thrombosis and death. RESULTS: Five studies, comprising 255 pioglitazone-treated patients and 245 controls, were identified in the current meta-analysis. Pioglitazone did not significantly reduce the rate of ISR (P = 0.20) with low heterogeneity (I2 = 13.3%, P = 0.32). For the secondary outcomes, pioglitazone did not substantially affect the pooled estimates of these endpoints except late loss (P = 0.01) and TVR (P = 0.04). CONCLUSIONS: The limited evidence indicates that pioglitazone does not demonstrate markedly beneficial effect in patients subjected to coronary DES implantation. However, the results should be interpreted with care given the small sample size. Further large-scale RCTs are needed. PMID- 25279763 TI - Releasing dentate nucleus cells from Purkinje cell inhibition generates output from the cerebrocerebellum. AB - The cerebellum generates its vast amount of output to the cerebral cortex through the dentate nucleus (DN) that is essential for precise limb movements in primates. Nuclear cells in DN generate burst activity prior to limb movement, and inactivation of DN results in cerebellar ataxia. The question is how DN cells become active under intensive inhibitory drive from Purkinje cells (PCs). There are two excitatory inputs to DN, mossy fiber and climbing fiber collaterals, but neither of them appears to have sufficient strength for generation of burst activity in DN. Therefore, we can assume two possible mechanisms: post-inhibitory rebound excitation and disinhibition. If rebound excitation works, phasic excitation of PCs and a concomitant inhibition of DN cells should precede the excitation of DN cells. On the other hand, if disinhibition plays a primary role, phasic suppression of PCs and activation of DN cells should be observed at the same timing. To examine these two hypotheses, we compared the activity patterns of PCs in the cerebrocerebellum and DN cells during step-tracking wrist movements in three Japanese monkeys. As a result, we found that the majority of wrist movement-related PCs were suppressed prior to movement onset and the majority of wrist-movement-related DN cells showed concurrent burst activity without prior suppression. In a minority of PCs and DN cells, movement-related increases and decreases in activity, respectively, developed later. These activity patterns suggest that the initial burst activity in DN cells is generated by reduced inhibition from PCs, i.e., by disinhibition. Our results indicate that suppression of PCs, which has been considered secondary to facilitation, plays the primary role in generating outputs from DN. Our findings provide a new perspective on the mechanisms used by PCs to influence limb motor control and on the plastic changes that underlie motor learning in the cerebrocerebellum. PMID- 25279764 TI - Towards a model for understanding the development of post-traumatic stress and general distress in mental health nurses. AB - In their daily work, mental health nurses (MHN) are often exposed to stressful events, including patient-perpetrated aggression and violence. Personal safety and health concerns, as well as concern for the physical and psychological well being of patients, dominate; these concerns have a profound impact on nurses. This cross-sectional study explored and compared the psychological well-being of 196 hospital-based MHN (97 forensic and 99 mainstream registered psychiatric nurses or psychiatric state enrolled nurses). The aim was to examine exposure to inpatient aggression and work stress, and identify factors contributing to the development of post-traumatic stress reactions and general distress. Multiple regression analyses indicated that working in a mainstream setting is associated with increased work stress; however, mainstream and forensic nurses experienced similar psychological well-being. As a group, 14-17% of mainstream and forensic nurses met the diagnostic criteria for post-traumatic stress disorder, and 36% scored above the threshold for psychiatric caseness. A tentative model of post traumatic stress and general distress in nurses was developed, illustrating the impact of aggression and stress on well-being. The present study affirms that mental health nursing is a challenging and stressful occupation. Implications for organizations, managers, and individual nurses are discussed. PMID- 25279765 TI - Analysis of palmitoyl apo-astaxanthinals, apo-astaxanthinones, and their epoxides by UHPLC-PDA-ESI-MS. AB - Food products enriched with fatty acid-esterified xanthophylls may result in deviating dietary apo-carotenoids. Therefore, free astaxanthin and its mono- and dipalmitate esters were subjected to two degradation processes in a methanolic model system: light-accelerated autoxidation and hypochlorous acid/hypochlorite (HOCl/OCl(-)) bleaching. Reversed phase ultrahigh-performance liquid chromatography photodiode array with in-line electrospray ionization mass spectrometry (RP-UHPLC-PDA-ESI-MS) was used for assessment of degradation products. Apo-astaxanthinals and -astaxanthinones containing 3 (apo-9) to 10 (apo 8') conjugated double bonds were found upon autoxidation for all three types of astaxanthin (except free apo-8'-astaxanthinal). Fragmentation of [M + H](+) and [M + Na](+) parent masses of apo-astaxanthins from dipalmitate astaxanthin indicated palmitate esterification. Astaxanthin monopalmitate degradation resulted in a mixture of free and palmitate apo-astaxanthins. HOCl/OCl(-) rapidly converted the astaxanthins into a mixture of epoxy-apo-9- and epoxy-apo-13 astaxanthinones. The palmitate ester bond was hardly affected by autoxidation, whereas for HOCl/OCl(-) the ester bond of the apo-astaxanthin palmitoyl esters was degraded. PMID- 25279766 TI - Injectable in situ self-cross-linking hydrogels based on poly(L-glutamic acid) and alginate for cartilage tissue engineering. AB - Injectable hydrogels as an important biomaterial class have been widely used in regenerative medicine. A series of injectable poly(l-glutamic acid)/alginate (PLGA/ALG) hydrogels were fabricated by self-cross-linking of hydrazide-modified poly(l-glutamic acid) (PLGA-ADH) and aldehyde-modified alginate (ALG-CHO). Both the degree of PLGA modification and the oxidation degree of ALG-CHO could be adjusted by the amount of activators and sodium periodate, respectively. The effect of the solid content of the hydrogels and oxidation degree of ALG-CHO on the gelation time, equilibrium swelling, mechanical properties, microscopic morphology, and in vitro degradation of the hydrogels was examined. Encapsulation of rabbit chondrocytes within hydrogels showed viability of the entrapped cells and good biocompatibility of the injectable hydrogels. A preliminary study exhibited injectability and rapid in vivo gel formation, as well as mechanical stability, cell ingrowth, and ectopic cartilage formation. The injectable PLGA/ALG hydrogels demonstrated attractive properties for future application in a variety of pharmaceutical delivery and tissue engineering, especially in cartilage tissue engineering. PMID- 25279767 TI - Switching of the triplet excited state of styryl 2,6-diiodo-bodipy and its application in acid-activatable singlet oxygen photosensitizing. AB - IodoBodipy-styrylBodipy dyads triplet photosensitizers were prepared (B-1 and B 2) which contain acid-responsive moiety. Both compounds show broadband visible light absorption, due to the resonance energy transfer (RET) between the two different visible light-harvesting Bodipy units. The photophysical properties of the dyads were studied with steady-state and nanosecond time-resolved transient absorption spectroscopy. The production of triplet excited state is switched ON or OFF by protonation/deprotonation of the amino group in the dyads. In the neutral form, the excited state is short-lived (<10 ns) and no singlet oxygen ((1)O2) photosensitizing was observed. Upon protonation, a long-lived triplet excited state was observed (tauT = 3.1 MUs) and the (1)O2 quantum yield (PhiDelta) is up to 73.8%. The energy levels of the components of the dyads were changed upon protonation and this energy level tuning exerts significant influence on the triplet state property of the dyad. Acid-activated shuffling of the localization of the triplet excited state between two components of a dyad was observed. Furthermore, we observed a rare example that a chromophore giving shorter absorption wavelength is acting as the singlet energy acceptor in RET. The experimental results were rationalized by density functional theory (DFT) and time-dependent DFT (TDDFT) calculations. PMID- 25279768 TI - A mammalian cell based FACS-panning platform for the selection of HIV-1 envelopes for vaccine development. AB - An increasing number of broadly neutralizing monoclonal antibodies (bnMAb) against the HIV-1 envelope (Env) protein has been discovered recently. Despite this progress, vaccination efforts with the aim to re-elicit bnMAbs that provide protective immunity have failed so far. Herein, we describe the development of a mammalian cell based FACS-panning method in which bnMAbs are used as tools to select surface-exposed envelope variants according to their binding affinity. For that purpose, an HIV-1 derived lentiviral vector was developed to infect HEK293T cells at low multiplicity of infection (MOI) in order to link Env phenotype and genotype. For proof of principle, a gp145 Env model-library was established in which the complete V3 domain was substituted by five strain specific V3 loop sequences with known binding affinities to nMAb 447-52D, respectively. Env genes were recovered from selected cells by PCR, subcloned into a lentiviral vector (i) to determine and quantify the enrichment nMAb binders and (ii) to generate a new batch of transduction competent particles. After 2 selection cycles the Env variant with highest affinity was enriched 20-fold and represented 80% of the remaining Env population. Exploiting the recently described bnMAbs, this procedure might prove useful in selecting Env proteins from large Env libraries with the potential to elicit bnMAbs when used as vaccine candidates. PMID- 25279771 TI - Is induction of labour by Propess((r)) safe? A comparison of midwife-led versus obstetrician-led labour management. AB - This retrospective study compared maternal and fetal outcomes after labour induction, using a dinoprostone vaginal pessary (Propess((r))) in midwife-led and obstetrician-led labour management. Labour induction outcomes, delivery mode and rates of admission to the neonatal intensive care unit were compared. A total of 405 women, 40.5% (n = 164) from midwife-led units and 59.5% (n = 241) from an obstetrician-led unit, participated. There was no statistically significant difference between the two groups in caesarean section rate or neonatal intensive care unit admission rates (p = 0.789 and 0.769, respectively). Non-reassuring fetal non-stress test and uterine hyperstimulation risks were higher in the obstetrician-led unit (p = 0.003 and 0.001, respectively, and odds ratio (OR) 0.165, 95% CI: 0.117-0.232 and OR 0.218, 95% CI: 0.078-0.611, respectively). Postpartum blood transfusion rate was higher in the midwife-led units (p = 0.002, OR 8.082, 95% CI: 1.879-39.292). Labour induction with Propess((r)) is safe during both midwife-led and obstetrician-led labour management. PMID- 25279769 TI - Impact of miR-21, miR-126 and miR-221 as prognostic factors of clear cell renal cell carcinoma with tumor thrombus of the inferior vena cava. AB - Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR 221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients. PMID- 25279773 TI - Shear and friction between carbon nanotubes in bundles and yarns. AB - We perform a detailed density functional theory assessment of the factors that determine shear interactions between carbon nanotubes (CNTs) within bundles and in related CNT and graphene structures including yarns, providing an explanation for the shear force measured in recent experiments (Filleter, T. etal. Nano Lett. 2012, 12, 73). The potential energy barriers separating AB stacked structures are found to be irrelevant to the shear analysis for bundles and yarns due to turbostratic stacking, and as a result, the tube-tube shear strength for pristine CNTs is estimated to be <0.24 MPa, that is, extremely small. Instead, it is pinning due to the presence of defects and functional groups at the tube ends that primarily cause resistance to shear when bundles are fractured in weak vacuum (~10(-5) Torr). Such defects and groups are estimated to involve 0.55 eV interaction energies on average, which is much larger than single-atom vacancy defects (approximately 0.039 eV). Furthermore, because graphitic materials are stiff they have large coherence lengths, and this means that push-pull effects result in force cancellation for vacancy and other defects that are internal to the CNTs. Another important factor is the softness of cantilever structures relative to the stiff CNTs in the experiments, as this contributes to elastic instability transitions that account for significant dissipation during shear that has been observed. The application of these results to the mechanical behavior of yarns is discussed, providing general guidelines for the manufacture of strong yarns composed of CNTs. PMID- 25279772 TI - Human intracranial high-frequency activity during memory processing: neural oscillations or stochastic volatility? AB - Intracranial high-frequency activity (HFA), which refers to fast fluctuations in electrophysiological recordings, increases during memory processing. Two views have emerged to explain this effect: (1) HFA reflects a synchronous signal, related to underlying gamma oscillations, that plays a mechanistic role in human memory and (2) HFA reflects an asynchronous signal that is a non-specific marker of brain activation. We review recent data supporting each of these views and conclude that HFA during memory processing is more consistent with an asynchronous signal. Memory-related HFA is therefore best conceptualized as a biomarker of neural activation that can functionally map memory with high spatial and temporal precision. PMID- 25279774 TI - Bone suppression increases the visibility of invasive pulmonary aspergillosis in chest radiographs. AB - OBJECTIVE: Chest radiographs (CXR) are an important diagnostic tool for the detection of invasive pulmonary aspergillosis (IPA) in critically ill patients, but their diagnostic value is limited by a poor sensitivity. By using advanced image processing, the aim of this study was to increase the value of chest radiographs in the diagnostic work up of neutropenic patients who are suspected of IPA. METHODS: The frontal CXRs of 105 suspected cases of IPA were collected from four institutions. Radiographs could contain single or multiple sites of infection. CT was used as reference standard. Five radiologists and two residents participated in an observer study for the detection of IPA on CXRs with and without bone suppressed images (ClearRead BSI 3.2; Riverain Technologies). The evaluation was performed separately for the right and left lung, resulting in 78 diseased cases (or lungs) and 132 normal cases (or lungs). For each image, observers scored the likelihood of focal infectious lesions being present on a continuous scale (0-100). The area under the receiver operating characteristics curve (AUC) served as the performance measure. Sensitivity and specificity were calculated by considering only the lungs with a suspiciousness score of greater than 50 to be positive. RESULTS: The average AUC for only CXRs was 0.815. Performance significantly increased, to 0.853, when evaluation was aided with BSI (p = 0.01). Sensitivity increased from 49% to 66% with BSI, while specificity decreased from 95% to 90%. CONCLUSION: The detection of IPA in CXRs can be improved when their evaluation is aided by bone suppressed images. BSI improved the sensitivity of the CXR examination, outweighing a small loss in specificity. PMID- 25279775 TI - Selectivity and isotope effects in hydronation of a naked aryl anion. AB - An aryl anion is produced by rapid addition of iodide to the p-benzyne diradical formed by cycloaromatization of an enediyne. The aryl anion is then hydronated (protonated or deuteronated) to form 1-iodotetrahydronaphthalene. Hydrons can be incorporated not only from water but also from such weak acids as dimethyl sulfoxide and acetonitrile. The relative reactivity of each pair of hydron donors is evaluated from competition experiments. A low selectivity is observed and taken as evidence for a high basicity of the aryl anion. Moreover, the same relative reactivities are obtained with Bu4NI as with LiI; therefore the species that undergoes hydronation is not an aryllithium but a naked aryl anion. These studies thus characterize the reactivity of a naked aryl anion in solution and contrast it with the reactivity of an aryllithium or an aryl Grignard. PMID- 25279777 TI - Evaluation of reading, writing, and watching TV using the Dutch ICF Activity Inventory. AB - PURPOSE: To investigate the longitudinal outcomes of rehabilitation (from baseline to 4 and 12 months) at a multidisciplinary rehabilitation center. The three goals ("Reading," "Writing," and "Watching TV") were measured with the Dutch ICF Activity Inventory (D-AI). In addition, outcomes were compared with the Low Vision Quality-of-Life questionnaire (LVQOL) for better insight into the (longitudinal) interpretation. METHODS: In a cohort of 241 visually impaired persons, corrected and uncorrected linear mixed models were used to determine longitudinal rehabilitation outcomes for the D-AI goals "Reading," "Writing," and "Watching TV," and difficulty and underlying tasks, as well as for the LVQOL scales "Basic aspects" and "Reading and fine work." At baseline, Spearman correlations were determined for similar scales of the D-AI and LVQOL. RESULTS: Importance scores of goals were stable over time. Difficulty scores decreased over time, but the differences were not significant at each measurement moment. For reading, difficulty of underlying tasks seemed to reflect the (change in) difficulty at the goal level; however, change in writing tasks did not reflect the change in the umbrella goal. Each of the three subscales of underlying tasks of the goal "Watching TV" changed in a different way. Changes in similar LVQOL scales were comparable, although less pronounced and more influenced by depression. Prescription or advice of low-vision aids and training in visual devices was not related (p > 0.01) with any of the outcome measures. CONCLUSIONS: It seems reasonable to conclude that the decrease in perceived difficulty was an effect of rehabilitation. The D-AI goal scores for difficulty were less influenced by depression and may be more sensitive to measure change over time compared with the LVQOL. Importance scores may not be useful for evaluation purposes. PMID- 25279776 TI - Ischemia-related subcellular redistribution of sodium channels enhances the proarrhythmic effect of class I antiarrhythmic drugs: a simulation study. AB - BACKGROUND: Cardiomyocytes located at the ischemic border zone of infarcted ventricle are accompanied by redistribution of gap junctions, which mediate electrical transmission between cardiomyocytes. This ischemic border zone provides an arrhythmogenic substrate. It was also shown that sodium (Na+) channels are redistributed within myocytes located in the ischemic border zone. However, the roles of the subcellular redistribution of Na+ channels in the arrhythmogenicity under ischemia remain unclear. METHODS: Computer simulations of excitation conduction were performed in a myofiber model incorporating both subcellular Na+ channel redistribution and the electric field mechanism, taking into account the intercellular cleft potentials. RESULTS: We found in the myofiber model that the subcellular redistribution of the Na+ channels under myocardial ischemia, decreasing in Na+ channel expression of the lateral cell membrane of each myocyte, decreased the tissue excitability, resulting in conduction slowing even without any ischemia-related electrophysiological change. The conventional model (i.e., without the electric field mechanism) did not reproduce the conduction slowing caused by the subcellular Na+ channel redistribution. Furthermore, Na+ channel blockade with the coexistence of a non ischemic zone with an ischemic border zone expanded the vulnerable period for reentrant tachyarrhythmias compared to the model without the ischemic border zone. Na+ channel blockade tended to cause unidirectional conduction block at sites near the ischemic border zone. Thus, such a unidirectional conduction block induced by a premature stimulus at sites near the ischemic border zone is associated with the initiation of reentrant tachyarrhythmias. CONCLUSIONS: Proarrhythmia of Na+ channel blockade in patients with old myocardial infarction might be partly attributable to the ischemia-related subcellular Na+ channel redistribution. PMID- 25279778 TI - Severe primary ocular surface involvement in Behcet disease. AB - PURPOSE: Behcet disease (BD) is a chronic, relapsing inflammatory disorder of unknown etiology characterized by obstructive vasculitis. Ocular surface involvement is a less frequent anterior segment finding. We report a patient with BD whose ocular presentation was severe surface involvement. CASE REPORT: A 26 year-old Chinese woman, who was diagnosed as having BD by a dermatologist because of oral and genital ulceration and erythema nodosum in the upper extremities 1 month ago, presented with dry eye syndrome, corneal ulceration, and conjunctival lesions. Both clinical and confocal microscope examination revealed bilateral severe inflammatory ocular surface disease. However, she did not have the common clinical ocular manifestations such as iridocyclitis, vitritis, retinal perivasculitis, or retinitis for BD. In addition to oral methylprednisolone and thalidomide, topical 1% prednisolone acetate ophthalmic suspension, tacrolimus ophthalmic suspension, and artificial tears were used. We observed for the first time histopathological changes of the eyelid in BD by confocal microscopy. CONCLUSIONS: Ocular surface lesions should be noted as an uncommon but possible manifestation of BD. Such severe ocular surface lesions without uveitis require a thorough medical history, dermatological examination, and serological testing to arrive at a diagnosis of BD. Accordingly, routine examination of the ocular surface is recommended in patients with BD, and BD should be included in a list of differential diagnoses for patients with ocular surface lesions. PMID- 25279780 TI - Treatment of Valsalva retinopathy. AB - PURPOSE: To report a case of Valsalva retinopathy treated by neodymium-doped yttrium aluminum garnet (Nd:YAG) laser and discuss the previously reported treatments for Valsalva retinopathy. CASE REPORT: A 35-year-old-woman experienced a sudden painless visual loss in her left eye after lifting heavy bags of manure on the farm. The patient was diagnosed as having Valsalva retinopathy. The examination revealed a macular preretinal hemorrhage. An Nd:YAG laser was used on the patient after conservative management afforded no resolution. After treatment, visual acuity improved. CONCLUSIONS: Valsalva retinopathy can be treated by conservative management, Nd:YAG laser, and vitrectomy, but each treatment must be evaluated in regard to the duration, the location, and the amount of the hemorrhage. PMID- 25279779 TI - Assessment of corneal epithelial thickness in dry eye patients. AB - PURPOSE: To investigate the features of corneal epithelial thickness topography with Fourier-domain optical coherence tomography (OCT) in dry eye patients. METHODS: In this cross-sectional study, 100 symptomatic dry eye patients and 35 normal subjects were enrolled. All participants answered the ocular surface disease index questionnaire and were subjected to OCT, corneal fluorescein staining, tear breakup time, Schirmer 1 test without anesthetic (S1t), and meibomian morphology. Several epithelium statistics for each eye, including central, superior, inferior, minimum, maximum, minimum - maximum, and map standard deviation, were averaged. Correlations of epithelial thickness with the symptoms of dry eye were calculated. RESULTS: The mean (+/-SD) central, superior, and inferior corneal epithelial thickness was 53.57 (+/-3.31) MUm, 52.00 (+/ 3.39) MUm, and 53.03 (+/-3.67) MUm in normal eyes and 52.71 (+/-2.83) MUm, 50.58 (+/-3.44) MUm, and 52.53 (+/-3.36) MUm in dry eyes, respectively. The superior corneal epithelium was thinner in dry eye patients compared with normal subjects (p = 0.037), whereas central and inferior epithelium were not statistically different. In the dry eye group, patients with higher severity grades had thinner superior (p = 0.017) and minimum (p < 0.001) epithelial thickness, more wide range (p = 0.032), and greater deviation (p = 0.003). The average central epithelial thickness had no correlation with tear breakup time, S1t, or the severity of meibomian glands, whereas average superior epithelial thickness positively correlated with S1t (r = 0.238, p = 0.017). CONCLUSIONS: Fourier domain OCT demonstrated that the thickness map of the dry eye corneal epithelium was thinner than normal eyes in the superior region. In more severe dry eye disease patients, the superior and minimum epithelium was much thinner, with a greater range of map standard deviation. PMID- 25279781 TI - A comparison of the short-term settling of three scleral lens designs. AB - PURPOSE: Scleral gas-permeable lenses are rapidly gaining international popularity. Unlike corneal gas-permeable lenses, scleral lenses are fitted to the bulbar conjunctiva and settle into the tissue after insertion. To date, we are unaware of any studies examining the settling behavior of three varying scleral lens designs. The purpose of this study was to quantify the mean total settling and mean rates of settling for three scleral lens designs: Onefit P&A (Blanchard Contact Lens, Inc), Mini Scleral Design (msd) (Blanchard Contact Lens, Inc), and Jupiter (Visionary Optics). METHODS: A randomized, repeated-measures study of Onefit P&A, msd, and Jupiter was performed. Subjects were fitted from a trial lens set, according to the manufacturer's guidelines. After insertion, lens settling was measured at 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours. Statistical analyses were performed using analysis of variance and two-stage, nonlinear regression analyses of settling over time. RESULTS: On average, the Onefit P&A, msd, and Jupiter lenses settled a total of 113.7, 133.7, and 88.1 MUm, respectively. Although the rates of settling were not linear, analysis of variance revealed a significant difference in the average settling rates (p < 0.05) among the groups. Tukey analyses revealed a significant difference in the settling rates for msd and Jupiter comparison (p < 0.05). Nonlinear regression analyses predicted that the lenses settled to about 80% of the final estimated values for the Onefit P&A lens, 90% for msd, and 99% for the Jupiter, after 8 hours. CONCLUSION: We concluded that the amount of settling varied significantly among the three lens designs. Settling rates were greatest shortly after insertion. Larger lenses were estimated to be settled by 8 hours. Based on the results of this short-term study, careful consideration to the settling patterns of individual scleral lens designs should be given. PMID- 25279782 TI - Effects of contact lens solution disinfectants against filamentous fungi. AB - PURPOSE: To assess and compare the antifungal activity of polyhexamethylene biguanide (PHMB), thimerosal, cetylpyridinium chloride, and chlorhexidine, which are disinfectants used in multipurpose disinfectant solutions (MPDSs) against ocular pathogenic Fusarium solani and Aspergillus flavus isolates in vitro. METHODS: The in vitro activity of PHMB, thimerosal, cetylpyridinium chloride, and chlorhexidine was assessed against 40 isolates of ocular pathogenic fungi that included 24 F. solani and 16 A. flavus isolates. The strains were tested by broth dilution antifungal susceptibility testing of filamentous fungi approved by the CLSI (Clinical and Laboratory Standards Institute) M38-A document. RESULTS: MIC90 (minimum inhibitory concentration for 90% of the organisms) values of PHMB were 4 and 16 MUg/mL for F. solani and A. flavus, respectively. MIC90 values of thimerosal were 0.0313 and 0.0625 MUg/mL for F. solani and A. flavus, respectively. MIC90 values of cetylpyridinium chloride were 2 and 2 MUg/mL for F. solani and A. flavus, respectively. MIC90 values of chlorhexidine were 32 and 32 MUg/mL for F. solani and A. flavus, respectively. CONCLUSIONS: As a disinfectant used in MPDSs, thimerosal showed the highest levels of antimicrobial activity against ocular pathogenic F. solani and A. flavus isolates. The concentrations of PHMB (0.0001%), cetylpyridinium chloride (0.00014%), and chlorhexidine (0.003%) in MPDSs are sublethal levels for ocular pathogenic F. solani and A. flavus isolates. Although multiple ingredients within MPDSs play a role in antimicrobial efficacy, antimicrobial activity may be significantly influenced by the disinfectants used in the solution formulations. PMID- 25279783 TI - Optical coherence tomography and histopathology of macular uveitis. AB - PURPOSE: Spectral-domain optical coherence tomography (SD-OCT) is a noninvasive technique that can provide high-resolution images of macular morphology. The purpose of this study was to examine the pathological mechanism of uveitis and compare the changes in the macula of uveitis patients and the histopathological features of experimentally induced uveitis in mice. METHODS: Macular OCT was performed on 78 eyes of 51 patients of the Eye Hospital of Shandong University of Traditional Chinese Medicine, China, with apparent uveitis changes. C57BL/6 mice were injected with interphotoreceptor retinoid-binding protein (IRBP)-specific T cells from naive mice immunized with complete Freund adjuvant IRBP(1-20) to induce uveitis. The disease was monitored by indirect fundoscopy. The eyes of the mice with experimental autoimmune uveitis (EAU) were enucleated 18 days after injection and classified according to pathological characteristics. RESULTS: The characteristics of uveitis were classified into six categories. Macular edema was detected in 48 eyes (61.5%); macular epiretinal membrane in 22 eyes (28.2%); choroidal neovascularization and macular lamellar holes in 4 eyes (5.1%), respectively; macular atrophy in 10 eyes (12.8%); and serous neuroepithelium detachment in 22 eyes (28.2%). As in human patients, pathological examinations of mouse EAU showed inflammation, folds, and atrophy of the outer part of the neuroretina, choroidal neovascularization with hemorrhagic retinal detachment, serous neuroepithelium detachment, and epiretinal membrane formation. CONCLUSIONS: Macular OCT of uveitis patients can display different morphological characteristics. Mouse EAU can simulate human uveitis. The comparative analysis of macular OCT in human uveitis and transfer EAU histopathology changes could provide important information on the pathogenesis of human uveitis. PMID- 25279784 TI - Visual fields and OCT role in diagnosis of glaucoma. AB - PURPOSE: To evaluate the clinical performance of visual field (VF) tests and optical coherence tomography (OCT) in diagnosing glaucoma. METHODS: One hundred sets of disc photographs, red-free fundus photographs, VF tests, and OCT images were presented progressively to seven ophthalmologists. Each set was provided in three steps: (1) the disc and red-free fundus photographs were shown first; (2) then, VF tests were also provided; and (3) finally, the OCT results were provided. The same process was repeated on another day. Kappa statistics were used to assess the intraobserver and interobserver agreement, as well as the agreement with the reference standard. RESULTS: The intraobserver agreement was almost perfect in this study and did not change markedly with the addition of diagnostic tools. The interobserver agreement increased from 0.54 to 0.61 when VF was added and increased slightly to 0.63 with OCT. The agreement with the reference standard also increased significantly from 0.48 to 0.61 after adding VF and increased slightly with additional OCT. CONCLUSIONS: An optic disc evaluation and VF test are sufficient to diagnose glaucoma in most cases. However, OCT can play an important role in detecting glaucoma in cases in which it cannot be identified by optic disc examination and VF. PMID- 25279785 TI - Traumatic intracranial hemorrhage correlates with preinjury brain atrophy, but not with antithrombotic agent use: a retrospective study. AB - BACKGROUND: The impact of antithrombotic agents (warfarin, clopidogrel, ASA) on traumatic brain injury outcomes is highly controversial. Although cerebral atrophy is speculated as a risk for acute intracranial hemorrhage, there is no objective literature evidence. MATERIALS AND METHODS: This is a retrospective, consecutive investigation of patients with signs of external head trauma and age >=60 years. Outcomes were correlated with antithrombotic-agent status, coagulation test results, admission neurologic function, and CT-based cerebral atrophy dimensions. RESULTS: Of 198 consecutive patients, 36% were antithrombotic negative and 64% antithrombotic-positive. ASA patients had higher arachidonic acid inhibition (p = 0.04) and warfarin patients had higher INR (p<0.001), compared to antithrombotic-negative patients. Antithrombotic-positive intracranial hemorrhage rate (38.9%) was similar to the antithrombotic-negative rate (31.9%; p = 0.3285). Coagulopathy was not present on the ten standard coagulation, thromboelastography, and platelet mapping tests with intracranial hemorrhage and results were similar to those without hemorrhage (p>=0.1354). Hemorrhagic-neurologic complication (intracranial hemorrhage progression, need for craniotomy, neurologic deterioration, or death) rates were similar for antithrombotic-negative (6.9%) and antithrombotic-positive (8.7%; p = 0.6574) patients. The hemorrhagic-neurologic complication rate was increased when admission major neurologic dysfunction was present (63.2% versus 2.2%; RR = 28.3; p<0.001). Age correlated inversely with brain parenchymal width (p<0.001) and positively with lateral ventricular width (p = 0.047) and cortical atrophy (p<0.001). Intracranial hemorrhage correlated with cortical atrophy (p<0.001) and ventricular width (p<0.001). CONCLUSIONS: Intracranial hemorrhage is not associated with antithrombotic agent use. Intracranial hemorrhage patients have no demonstrable coagulopathy. The association of preinjury brain atrophy with acute intracranial hemorrhage is a novel finding. Contrary to antithrombotic agent status, admission neurologic abnormality is a predictor of adverse post admission outcomes. Study findings indicate that effective hemostasis is maintained with antithrombotic therapy. PMID- 25279786 TI - Stable-isotope probing and metagenomics reveal predation by protozoa drives E. coli removal in slow sand filters. AB - Stable-isotope probing and metagenomics were applied to study samples taken from laboratory-scale slow sand filters 0.5, 1, 2, 3 and 4 h after challenging with (13)C-labelled Escherichia coli to determine the mechanisms and organisms responsible for coliform removal. Before spiking, the filters had been continuously operated for 7 weeks using water from the River Kelvin, Glasgow as their influent source. Direct counts and quantitative PCR assays revealed a clear predator-prey response between protozoa and E. coli. The importance of top-down trophic-interactions was confirmed by metagenomic analysis, identifying several protozoan and viral species connected to E. coli attrition, with protozoan grazing responsible for the majority of the removal. In addition to top-down mechanisms, indirect mechanisms, such as algal reactive oxygen species-induced lysis, and mutualistic interactions between algae and fungi, were also associated with coliform removal. The findings significantly further our understanding of the processes and trophic interactions underpinning E. coli removal. This study provides an example for similar studies, and the opportunity to better understand, manage and enhance E. coli removal by allowing the creation of more complex trophic interaction models. PMID- 25279787 TI - Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula. AB - The gut microbiota is hypothesized to have a critical role in metabolic diseases, including type 2 diabetes (T2D). A traditional Chinese herbal formula, Gegen Qinlian Decoction (GQD), can alleviate T2D. To find out whether GQD modulates the composition of the gut microbiota during T2D treatment, 187 T2D patients were randomly allocated to receive high (HD, n=44), moderate (MD, n=52), low dose GQD (LD, n=50) or the placebo (n=41) for 12 weeks in a double-blinded trial. Patients who received the HD or MD demonstrated significant reductions in adjusted mean changes from baseline of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) compared with the placebo and LD groups. Pyrosequencing of the V3 regions of 16S rRNA genes revealed a dose-dependent deviation of gut microbiota in response to GQD treatment. This deviation occurred before significant improvement of T2D symptoms was observed. Redundancy analysis identified 47 GQD-enriched species level phylotypes, 17 of which were negatively correlated with FBG and 9 with HbA1c. Real-time quantitative PCR confirmed that GQD significantly enriched Faecalibacterium prausnitzii, which was negatively correlated with FBG, HbA1c and 2-h postprandial blood glucose levels and positively correlated with homeostasis model assessment of beta-cell function. Therefore, these data indicate that structural changes of gut microbiota are induced by Chinese herbal formula GQD. Specifically, GQD treatment may enrich the amounts of beneficial bacteria, such as Faecalibacterium spp. In conclusion, changes in the gut microbiota are associated with the anti-diabetic effects of GQD. PMID- 25279788 TI - Patterns of brain activation when mothers view their own child and dog: an fMRI study. AB - Neural substrates underlying the human-pet relationship are largely unknown. We examined fMRI brain activation patterns as mothers viewed images of their own child and dog and an unfamiliar child and dog. There was a common network of brain regions involved in emotion, reward, affiliation, visual processing and social cognition when mothers viewed images of both their child and dog. Viewing images of their child resulted in brain activity in the midbrain (ventral tegmental area/substantia nigra involved in reward/affiliation), while a more posterior cortical brain activation pattern involving fusiform gyrus (visual processing of faces and social cognition) characterized a mother's response to her dog. Mothers also rated images of their child and dog as eliciting similar levels of excitement (arousal) and pleasantness (valence), although the difference in the own vs. unfamiliar child comparison was larger than the own vs. unfamiliar dog comparison for arousal. Valence ratings of their dog were also positively correlated with ratings of the attachment to their dog. Although there are similarities in the perceived emotional experience and brain function associated with the mother-child and mother-dog bond, there are also key differences that may reflect variance in the evolutionary course and function of these relationships. PMID- 25279789 TI - Abiotic determinants of the historical buildings biodeterioration in the former Auschwitz II-Birkenau concentration and extermination camp. AB - The paper presents the results of a study conducted at the Auschwitz-Birkenau State Museum in Oswiecim on the occurrence of biodeterioration. Visual assessment of the buildings revealed signs of deterioration of the buildings in the form of dampness, bulging and crumbling plaster, and wood fiber splitting. The external surfaces, and especially the concrete strips and ground immediately adjoining the buildings, were colonized by bryophytes, lichens, and algae. These organisms developed most intensively close to the ground on the northern sides of the buildings. Inside the buildings, molds and bacteria were not found to develop actively, while algae and wood-decaying fungi occurred locally. The factors conducive to biological corrosion in the studied buildings were excessive dampness of structural partitions close to the ground and a relative air humidity of above 70%, which was connected to ineffective moisture insulation. The influence of temperature was smaller, as it mostly affected the quantitative composition of the microorganisms and the qualitative composition of the algae. Also the impact of light was not very strong, but it was conducive to algae growth. PMID- 25279790 TI - Community profiling of culturable fluorescent pseudomonads in the rhizosphere of green gram (Vigna radiata L.). AB - Study on microbial diversity in the unexplored rhizosphere is important to understand their community structure, biology and ecological interaction with the host plant. This research assessed the genetic and functional diversity of fluorescent pseudomonads [FP] in the green gram rhizophere. One hundred and twenty types of morphologically distinct fluorescent pseudomonads were isolated during vegetative as well as reproductive growth phase of green gram. Rep PCR, ARDRA and RISA revealed two distinct clusters in each case at 75, 61 and 70% similarity coefficient index respectively. 16S rRNA partial sequencing analysis of 85 distantly related fluorescent pseudomonads depicted Pseudomonas aeruginosa as the dominant group. Out of 120 isolates, 23 (19%) showed antagonistic activity towards phytopathogenic fungi. These bacterial isolates showed varied production of salicylic acid, HCN and chitinase, 2, 4-diacetylphloroglucinol (DAPG), phenazine-1-carboxylic acid (PCA) and pyoluteorin (PLT). Production efficiency of inherent level of plant growth promoting (PGP) traits among the 120 isolates demonstrated that 10 (8%) solubilised inorganic phosphates, 25 (20%) produced indoles and 5 (4%) retained ACC deaminase activity. Pseudomonas aeruginosa GGRJ21 showed the highest production of all antagonistic and plant growth promoting (PGP) traits. In a greenhouse experiment, GGRJ21 suppressed root rot disease of green gram by 28-93% (p = 0.05). Consistent up regulation of three important stress responsive genes, i.e., acdS, KatA and gbsA and elevated production efficiency of different PGP traits could promote GGRJ21 as a potent plant growth regulator. PMID- 25279792 TI - Maternal high-fat diet and offspring expression levels of vitamin K-dependent proteins. AB - Studies suggest that bone growth and development and susceptibility to vascular disease in later life are influenced by maternal nutrition during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including osteocalcin, matrix Gla protein, periostin, and growth arrest specific- protein 6, in both bone and vascular development. We have examined whether there are alterations in these VKDPs in bone and vascular tissue from offspring of mothers subjected to a nutritional challenge: a high-fat diet during pregnancy and postnatally, using 6-week-old mouse offspring. Bone site specific and sex-specific differences across femoral and vertebral bone in male and female offspring were observed. Overall a high-fat maternal diet and offspring diet exacerbated the bone changes observed. Sex-specific differences and tissue-specific differences were observed in VKDP levels in aorta tissue from high-fat diet-fed female offspring from high-fat diet-fed mothers displaying increased levels of Gas6 and Ggcx compared with those of female controls. In contrast, differences were seen in VKDP levels in femoral bone of female offspring with lower expression levels of Mgp in offspring of mothers fed a high fat diet compared with those of controls. We observed a significant correlation in Mgp expression levels within the femur to measures of bone structure of the femur and vertebra, particularly in the male offspring cohort. In summary, the current study has highlighted the importance of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure. PMID- 25279791 TI - Wistar rats resistant to the hypertensive effects of ouabain exhibit enhanced cardiac vagal activity and elevated plasma levels of calcitonin gene-related peptide. AB - Ouabain is a cardiac glycoside produced in the adrenal glands and hypothalamus. It affects the function of all cells by binding to Na+/K+-ATPase. Several lines of evidence suggest that endogenous ouabain could be involved in the pathogenesis of essential (particularly, salt-sensitive) hypertension. However, information regarding the postulated hypertensive effect of the long-term administration of low-dose exogenous ouabain is inconsistent. This study was designed to help settle this controversy through the use of telemetric monitoring of arterial blood pressure and to elucidate the ouabain-induced alterations that could either promote or prevent hypertension. Ouabain (63 and 324 ug/kg/day) was administered subcutaneously to male Wistar rats. Radiotelemetry was used to monitor blood pressure, heart rate and measures of cardiovascular variability and baroreflex sensitivity. The continuous administration of ouabain for 3 months did not elevate arterial blood pressure. The low-frequency power of systolic pressure variability, urinary excretion of catecholamines, and cardiovascular response to restraint stress and a high-salt diet as well as the responsiveness to alpha1 adrenergic stimulation were all unaltered by ouabain administration, suggesting that the activity of the sympathetic nervous system was not increased. However, surrogate indices of cardiac vagal nerve activity based on heart rate variability were elevated. Molecular remodeling in mesenteric arteries that could support the development of hypertension (increased expression of the genes for the Na+/Ca2+ exchanger and Na+/K+-ATPase alpha2 isoform) was not evident. Instead, the plasma level of vasodilatory calcitonin gene-related peptide (CGRP) significantly rose from 55 (11, SD) in the control group to 89 (20, SD) pg/ml in the ouabain-treated rats (PTukey's = 18.10(-5)). These data show that long-term administration of exogenous ouabain does not necessarily cause hypertension in rodents. The augmented parasympathetic activity and elevated plasma level of CGRP could be linked to the missing hypertensive effect of ouabain administration. PMID- 25279793 TI - A balance theory of peripheral corticotropin-releasing factor receptor type 1 and type 2 signaling to induce colonic contractions and visceral hyperalgesia in rats. AB - Several recent studies suggest that peripheral corticotropin-releasing factor (CRF) receptor type 1 (CRF1) and CRF2 have a counter regulatory action on gastrointestinal functions. We hypothesized that the activity balance of each CRF subtype signaling may determine the changes in colonic motility and visceral sensation. Colonic contractions were assessed by the perfused manometry, and contractions of colonic muscle strips were measured in vitro in rats. Visceromotor response was determined by measuring contractions of abdominal muscle in response to colorectal distensions (CRDs) (60 mm Hg for 10 min twice with a 30-min rest). All drugs were administered through ip route in in vivo studies. CRF increased colonic contractions. Pretreatment with astressin, a nonselective CRF antagonist, blocked the CRF-induced response, but astressin2-B, a selective CRF2 antagonist, enhanced the response by CRF. Cortagine, a selective CRF1 agonist, increased colonic contractions. In in vitro study, CRF increased contractions of muscle strips. Urocortin 2, a selective CRF2 agonist, itself did not alter the contractions but blocked this increased response by CRF. Visceromotor response to the second CRD was significantly higher than that of the first. Astressin blocked this CRD-induced sensitization, but astressin2-B or CRF did not affect it. Meanwhile, astressin2-B together with CRF significantly enhanced the sensitization. Urocortin 2 blocked, but cortagine significantly enhanced, the sensitization. These results indicated that peripheral CRF1 signaling enhanced colonic contractility and induced visceral sensitization, and these responses were modulated by peripheral CRF2 signaling. The activity balance of each subtype signaling may determine the colonic functions in response to stress. PMID- 25279794 TI - Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. AB - Nonalcoholic fatty liver disease, particularly its more aggressive form, nonalcoholic steatohepatitis (NASH), is associated with hepatic insulin resistance. Osteocalcin, a protein secreted by osteoblast cells in bone, has recently emerged as an important metabolic regulator with insulin-sensitizing properties. In humans, osteocalcin levels are inversely associated with liver disease. We thus hypothesized that osteocalcin may attenuate NASH and examined the effects of osteocalcin treatment in middle-aged (12-mo-old) male Ldlr(-/-) mice, which were fed a Western-style high-fat, high-cholesterol diet for 12 weeks to induce metabolic syndrome and NASH. Mice were treated with osteocalcin (4.5 ng/h) or vehicle for the diet duration. Osteocalcin treatment not only protected against Western-style high-fat, high-cholesterol diet-induced insulin resistance but substantially reduced multiple NASH components, including steatosis, ballooning degeneration, and fibrosis, with an overall reduction in nonalcoholic fatty liver disease activity scores. Further, osteocalcin robustly reduced expression of proinflammatory and profibrotic genes (Cd68, Mcp1, Spp1, and Col1a2) in liver and suppressed inflammatory gene expression in white adipose tissue. In conclusion, these results suggest osteocalcin inhibits NASH development by targeting inflammatory and fibrotic processes. PMID- 25279795 TI - Functional diversification of vitamin D receptor paralogs in teleost fish after a whole genome duplication event. AB - The diversity and success of teleost fishes (Actinopterygii) has been attributed to three successive rounds of whole-genome duplication (WGD). WGDs provide a source of raw genetic material for evolutionary forces to act upon, resulting in the divergence of genes with altered or novel functions. The retention of multiple gene pairs (paralogs) in teleosts provides a unique opportunity to study how genes diversify and evolve after a WGD. This study examines the hypothesis that vitamin D receptor (VDR) paralogs (VDRalpha and VDRbeta) from two distantly related teleost orders have undergone functional divergence subsequent to the teleost-specific WGD. VDRalpha and VDRbeta paralogs were cloned from the Japanese medaka (Beloniformes) and the zebrafish (Cypriniformes). Initial transactivation studies using 1alpha, 25-dihydroxyvitamin D3 revealed that although VDRalpha and VDRbeta maintain similar ligand potency, the maximum efficacy of VDRbeta was significantly attenuated compared with VDRalpha in both species. Subsequent analyses revealed that VDRalpha and VDRbeta maintain highly similar ligand affinities; however, VDRalpha demonstrated preferential DNA binding compared with VDRbeta. Protein-protein interactions between the VDR paralogs and essential nuclear receptor coactivators were investigated using transactivation and mammalian two-hybrid assays. Our results imply that functional differences between VDRalpha and VDRbeta occurred early in teleost evolution because they are conserved between distantly related species. Our results further suggest that the observed differences may be associated with differential protein-protein interactions between the VDR paralogs and coactivators. We speculate that the observed functional differences are due to subtle ligand-induced conformational differences between the two paralogs, leading to divergent downstream functions. PMID- 25279797 TI - Efficacy of do-it-yourself whitening as compared to conventional tooth whitening modalities: an in vitro study. AB - AIM: To evaluate the efficacy of do-it-yourself (DIY) whitening as compared to conventional tooth whitening modalities using different shade assessment tools. METHODS AND MATERIALS: Extracted human molars (120) were randomly distributed to six groups (n=20). Whitening was performed according to manufacturer's directions for over-the-counter, dentist-dispensed for home use, and in-office whitening. DIY whitening consisted of a strawberry and baking soda mix. Additionally, negative and positive controls were used. Two evaluators used the Vita Classical (VC) and Vita Bleachedguide 3D-Master with interpolated numbers (BGi) for visual assessment at baseline and one-week, one-month, and three-month postwhitening. Instrumental measurements were performed with a spectrophotometer. Kruskal-Wallis procedure was used to assess color changes among groups and intraclass correlation (ICC) to evaluate agreement between evaluators. RESULTS: DIY exhibited lower color change (DeltaSGUVC, DeltaSGUBGi, DeltaE*, where SGU = shade guide unit and E = overall color change) compared to other whitening groups at all time points (p<0.05). ICC demonstrated very good agreement between evaluators with VC and BGi at each time point. Both shade guides were related with each other and strongly related to instrumental measurements (p<0.05). CONCLUSIONS: DIY whitening was the least effective whitening modality. Both VC and BGi are related with each other and have good correlation with instrumental measurements. PMID- 25279796 TI - Impaired musculoskeletal response to age and exercise in PPARbeta(-/-) diabetic mice. AB - Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes in which the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARbeta(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARbeta(-/ ) mice and investigated both the mechanism behind those changes with age as well as their response to exercise. Compared with their wild type, PPARbeta(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation, and increased resorption. In addition, mesenchymal cells from PPARbeta(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARgamma, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARbeta(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARbeta controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARbeta deficiency leads to glucose intolerance, decreased muscle function, and reduced bone strength. On a molecular level, PPARbeta appears to regulate myostatin and PPARgamma expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances. PMID- 25279798 TI - Oxidative potential and inflammatory impacts of source apportioned ambient air pollution in Beijing. AB - Air pollution exposure is associated with a range of adverse health impacts. Knowledge of the chemical components and sources of air pollution most responsible for these health effects could lead to an improved understanding of the mechanisms of such effects and more targeted risk reduction strategies. We measured daily ambient fine particulate matter (<2.5 MUm in aerodynamic diameter; PM2.5) for 2 months in peri-urban and central Beijing, and assessed the contribution of its chemical components to the oxidative potential of ambient air pollution using the dithiothreitol (DTT) assay. The composition data were applied to a multivariate source apportionment model to determine the PM contributions of six sources or factors: a zinc factor, an aluminum factor, a lead point factor, a secondary source (e.g., SO4(2-), NO3(2-)), an iron source, and a soil dust source. Finally, we assessed the relationship between reactive oxygen species (ROS) activity-related PM sources and inflammatory responses in human bronchial epithelial cells. In peri-urban Beijing, the soil dust source accounted for the largest fraction (47%) of measured ROS variability. In central Beijing, a secondary source explained the greatest fraction (29%) of measured ROS variability. The ROS activities of PM collected in central Beijing were exponentially associated with in vivo inflammatory responses in epithelial cells (R2=0.65-0.89). We also observed a high correlation between three ROS-related PM sources (a lead point factor, a zinc factor, and a secondary source) and expression of an inflammatory marker (r=0.45-0.80). Our results suggest large differences in the contribution of different PM sources to ROS variability at the central versus peri-urban study sites in Beijing and that secondary sources may play an important role in PM2.5-related oxidative potential and inflammatory health impacts. PMID- 25279799 TI - Quantitative analysis of motifs contributing to the interaction between PLS subfamily members and their target RNA sequences in plastid RNA editing. AB - In plant organelles, RNA editing alters specific cytidine residues to uridine in transcripts. Target cytidines are specifically recognized by pentatricopeptide repeat (PPR) proteins of the PLS subfamily, which have additional C-terminal E or E-DYW motifs. Recent in silico analysis proposed a model for site recognition by PLS-subfamily PPR proteins, with a correspondence of one PPR motif to one nucleotide, and with the C-terminal last S motif aligning with the nucleotide at position -4 with respect to the editing site. Here, we present quantitative biochemical data on site recognition by four PLS-subfamily proteins: CRR28 and OTP85 are DYW-class members, whereas CRR21 and OTP80 are E-class members. The minimal RNA segments required for high-affinity binding by these PPR proteins were experimentally determined. The results were generally consistent with the in silico-based model; however, we clarified that several PPR motifs, including the C-terminal L2 and S motifs of CRR21 and OTP80, are dispensable for the RNA binding, suggesting distinct contributions of each PPR motif to site recognition. We also demonstrate that the DYW motif interacts with the target C and its 5' proximal region (from -3 to 0), whereas the E motif is not involved in binding. PMID- 25279800 TI - Two-minute training for improving neonatal bag and mask ventilation. AB - OBJECTIVES: To test effectivity of a two-minute training consisting of a few key points in ventilation using the self-inflating bag (SIB). STUDY DESIGN: Experienced and inexperienced caregivers were asked to mask ventilate a leak free manikin using the SIB before and after the training. Mask leak and pressures were measured using respiratory function monitoring. Pressures above 35 cm H2O were considered excessive. Parameters were compared using a Wilcoxon non-parametric test. RESULTS: Before and after the short training, experienced caregivers had minimal median (IQR) mask leak (14 (3-75) vs. 3 (0-53)%; p<0.01). Inexperienced users had large leak which reduced from 51 (7-91)% before to 11 (2-71)% after training (p<0.01). Pressures above 35 cm H2O hardly occurred in experienced caregivers (0 (0-5) vs. 0 (0-0)%; ns). In inexperienced caregivers this frequently occurred but decreased considerably after training (94 (46-100) vs. 2 (0-70)%; p<0.01). CONCLUSION: A two-minute training of bag and mask ventilation was effective. This training could be incorporated into any training program. PMID- 25279801 TI - Peripapillary retinal nerve fiber layer assessment of spectral domain optical coherence tomography and scanning laser polarimetry to diagnose preperimetric glaucoma. AB - PURPOSE: To compare the abilities of peripapillary retinal nerve fiber layer (RNFL) parameters of spectral domain optical coherence tomograph (SDOCT) and scanning laser polarimeter (GDx enhanced corneal compensation; ECC) in detecting preperimetric glaucoma. METHODS: In a cross-sectional study, 35 preperimetric glaucoma eyes (32 subjects) and 94 control eyes (74 subjects) underwent digital optic disc photography and RNFL imaging with SDOCT and GDx ECC. Ability of RNFL parameters of SDOCT and GDx ECC to discriminate preperimetric glaucoma eyes from control eyes was compared using area under receiver operating characteristic curves (AUC), sensitivities at fixed specificities and likelihood ratios (LR). RESULTS: AUC of the global average RNFL thickness of SDOCT (0.786) was significantly greater (p<0.001) than that of GDx ECC (0.627). Sensitivities at 95% specificity of the corresponding parameters were 20% and 8.6% respectively. AUCs of the inferior, superior and temporal quadrant RNFL thickness parameters of SDOCT were also significantly (p<0.05) greater than the respective RNFL parameters of GDx ECC. LRs of outside normal limits category of SDOCT parameters ranged between 3.3 and 4.0 while the same of GDx ECC parameters ranged between 1.2 and 2.1. LRs of within normal limits category of SDOCT parameters ranged between 0.4 and 0.7 while the same of GDx ECC parameters ranged between 0.7 and 1.0. CONCLUSIONS: Abilities of the RNFL parameters of SDOCT and GDx ECC to diagnose preperimetric glaucoma were only moderate. Diagnostic abilities of the RNFL parameters of SDOCT were significantly better than that of GDx ECC in preperimetric glaucoma. PMID- 25279802 TI - Common source identification of images in large databases. AB - Photo-response non-uniformity noise patterns are a robust way to identify the source of an image. However, identifying a common source of images in a large database may be impractical due to long computation times. In this paper a solution for large volume digital camera identification is proposed, which combines, and sometimes slightly modifies, existing methods for a 500 times improvement in the speed of common source identification. Single image comparisons are often plagued by considerable noise contamination from scene content and random noise, which makes it harder to accomplish reliable common source identification. Therefore a new method is introduced that can increase true positive rates by more than 45% at very low computation costs. Analysis of real data from a fraud case shows the effectiveness of the proposed method. As a whole the proposed solution makes it possible to analyze a large database in forensically relevant time, without resorting to large and expensive computer clusters. PMID- 25279803 TI - Using the fibre structure of paper to determine authenticity of the documents: analysis of transmitted light images of stamps and banknotes. AB - A novel method is presented for distinguishing postal stamp forgeries and counterfeit banknotes from genuine samples. The method is based on analyzing differences in paper fibre networks. The main tool is a curvelet-based algorithm for measuring overall fibre orientation distribution and quantifying anisotropy. Using a couple of more appropriate parameters makes it possible to distinguish forgeries from genuine originals as concentrated point clouds in two- or three dimensional parameter space. PMID- 25279804 TI - Accuracy of the Alberta Infant Motor Scale (AIMS) to detect developmental delay of gross motor skills in preterm infants: a systematic review. AB - OBJECTIVE: To assess, through a systematic review, the ability of Alberta Infant Motor Scale (AIMS) to diagnose delayed motor development in preterm infants. METHODS: Systematic searches identified five studies meeting inclusion criteria. These studies were evaluated in terms of: participants' characteristics, main results and risk of bias. The risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies--second edition (QUADAS-2). RESULTS: All five studies included a high risk of bias in at least one of the assessed fields. The most frequent biases included were presented in patient selection and lost follow up. All studies used the Pearson correlation coefficient to assess the diagnostic capability of the Alberta Infant Motor Scale. None of the assessed studies used psychometric measures to analyze the data. CONCLUSION: Given the evidence, the research supporting the ability of Alberta Infant Motor Scale to diagnose delayed motor development in preterm infants presents limitations. Further studies are suggested in order to avoid the above-mentioned biases to assess the Alberta Infant Motor Scale accuracy in preterm babies. PMID- 25279806 TI - A novel and effective surface design: conducting polymer/beta-cyclodextrin host guest system for cholesterol biosensor. AB - The combination of supramolecules and conducting polymers (CPs) has gained much attention for the development of new immobilization matrices for biomolecules. Herein, an amperometric biosensor based on a novel conducting polymer, poly(2-(2 octyldodecyl)-4,7-di(selenoph-2-yl)-2H-benzo[d][1,2,3]triazole)) (PSBTz) and beta cyclodextrin (beta-CD) for the detection of cholesterol, was constructed. The PSBTz film with beta-CD was deposited on a graphite electrode by electropolymerization technique to achieve a suitable matrix for enzyme immobilization. Moreover, to justify the immobilization, alkyl chain containing conducting polymer (PSBTz) was designed, synthesized and electrochemically polymerized on the transducer surface. Alkyl chains in the structure of SBTz and hydroxyl groups of beta-CD contributed to effective immobilization while protecting the suitable orientation of the biomolecule. Cholesterol oxidase (ChOx) was covalently immobilized onto the modified surface using N,N' carbonyldiimidazole (CDI) as the cross-linking agent. After successful immobilization, amperometric biosensor responses were recorded at -0.7 V vs Ag/AgCl in phosphate buffer (pH 7.0). The apparent Michaelis-Menten constant (KM(app)), maximum current (Imax), limit of detection (LOD), and sensitivity values were determined: 28.9 MUM, 12.1 MUA, 0.005 MUM, and 5.77 MUA/MUM cm(2), respectively. The fabricated biosensor was characterized using scanning electron microscopy (SEM) and cyclic voltammetry (CV) techniques. Finally, the prepared biosensor was successfully applied for the determination of cholesterol in blood samples. PMID- 25279805 TI - Efferent pathways in sodium overload-induced renal vasodilation in rats. AB - Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. The present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280-350 g) were anesthetized with sodium thiopental (40 mg. kg(-1), i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 ug * kg(-1), i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml * kg( 1) b.wt., i.v.) was infused over 60 s. In sham rats (n = 6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; atosiban, 40 ug * kg(-1) * h(-1), i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. The combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia. PMID- 25279807 TI - Comparative effects of morning vs. evening dosing of extended-release hydromorphone on sleep physiology in patients with low back pain: a pilot study. AB - OBJECTIVE: To investigate effects of extended-release (ER) hydromorphone dosing time (morning, QAM; evening, QPM) on sleep physiology in patients with chronic low back pain. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Clinical research site. PATIENTS: Fifteen patients with moderate to-severe chronic low back pain requiring long-term opioid analgesia. INTERVENTIONS: Following an open-label immediate-release (IR) hydromorphone titration phase, patients received once-daily ER hydromorphone QAM or QPM for at least 14 days and then crossed over to the alternate regimen. Overnight polysomnographic sleep studies were performed at baseline, following IR hydromorphone titration, and following each ER hydromorphone dosing period. OUTCOME MEASURES: The primary outcome measure was prevalence of nocturnal apnea hypopnea index (AHI). Other evaluations included central apnea index and obstructive apnea index; Short-Form McGill Pain Questionnaire; a modified Medical Outcomes Study sleep scale, patient responses in a daily diary, and adverse event safety profiles. RESULTS: Mean AHI scores were lower following QAM rather than QPM dosing, but not significantly (12.9 vs. 17.1, P > 0.05). Secondarily, QAM dosing resulted in numerically fewer apnea episodes and improvements in pulse oximetry measures; however, these differences were not significant (P > 0.05). Sleep quality/quantity and pain measures were improved with opioid therapy overall, particularly QPM dosing, without significantly compromising safety. CONCLUSIONS: ER hydromorphone QAM dosing may be preferred if sleep-disordered breathing associated with ongoing opioid therapy is of concern; however, QPM dosing may be advantageous in terms of pain relief and quality/quantity of sleep. Further research is recommended to provide more definitive clinical guidance. PMID- 25279808 TI - Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations. AB - BACKGROUND: Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC. METHODS: Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively. RESULTS: Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria. CONCLUSIONS: This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid. PMID- 25279810 TI - Quaternary ammonium promoted ultra selective and sensitive fluorescence detection of fluoride ion in water and living cells. AB - Highly selective and sensitive fluorescent probes with a quaternary ammonium moiety have been rationally designed and developed for fast and sensitive fluorescence detection of fluoride ion (F(-) from NaF, not TBAF) in aqueous solution and living cells. With the sequestration effect of quaternary ammonium, the detection time was less than 2 min and the detection limit of fluoride ion was as low as 0.57 ppm that is among the lowest detection limits in aqueous solutions of many fluoride fluorescence probes in the literature. PMID- 25279809 TI - Biogenesis of C-glycosyl flavones and profiling of flavonoid glycosides in lotus (Nelumbo nucifera). AB - Flavonoids in nine tissues of Nelumbo nucifera Gaertner were identified and quantified by high-performance liquid chromatography with diode array detector (HPLC-DAD) and HPLC-electrospray ionization-mass spectrometry (HPLC-ESI-MSn). Thirty-eight flavonoids were identified; eleven C-glycosides and five O glycosides were discovered for the first time in N. nucifera. Most importantly, the C-glycosyl apigenin or luteolin detected in lotus plumules proved valuable for deep elucidation of flavonoid composition in lotus tissues and for further utilization as functional tea and medicine materials. Lotus leaves possessed the significantly highest amount of flavonoids (2.06E3+/-0.08 mg 100 g(-1) FW) and separating and purifying the bioactive compound, quercetin 3-O-glucuronide, from leaves showed great potential. In contrast, flavonoids in flower stalks, seed coats and kernels were extremely low. Simultaneously, the optimal picking time was confirmed by comparing the compound contents in five developmental phases. Finally, we proposed the putative flavonoid biosynthesis pathway in N. nucifera. PMID- 25279811 TI - How to spot a narcissist: Mental health literacy with respect to Narcissistic Personality Disorder. AB - Lay people were asked to read one Depression, one Schizophrenia, and three Narcissistic Personality Disorder (NPD) vignettes. After each, they were asked what they thought the problem was for the individuals concerned and to make various ratings. Half of each of the five vignettes were of male, and the other of female, characters. The results demonstrated that laypeople are less likely to suggest help for, and have more difficulty identifying NPD compared to Depression and Schizophrenia. There were differences in the likeliness to suggest help between all three NPD vignettes and differences in the identification of two NPD vignettes possible due to the length and details in different vignettes. The gender of the person in the vignette had no effect on identification. The participants NPI scores were not correlated with the Narcissism literacy suggesting no relationship between having, and spotting, the disorder. Implications and limitations of the research are considered. PMID- 25279812 TI - Breast cancer risk in MEN1 - a cancer genetics perspective. AB - The tumour spectrum associated with multiple endocrine neoplasia type 1 (MEN1) has been known for many years. New data suggest that females with MEN1 may face an additional, hitherto unrecognized, risk of early-onset breast cancer. The menin protein is certainly known to have a role in regulating oestrogen receptor activity; but how robust are the data linking MEN1 to breast cancer? This article examines the published data from the viewpoint of a cancer geneticist and considers whether there really is a justifiable indication for enhanced breast surveillance in women with MEN1. PMID- 25279813 TI - Imported malaria in China, 2012. PMID- 25279816 TI - Using plain English and behaviourally specific language to increase the implementation of clinical guidelines for psychological treatments in schizophrenia. AB - BACKGROUND: Inequalities in the implementation of recommended psychological interventions for schizophrenia persist. Writing guidance in a particular style has been shown to improve service user intention to implement the recommendations. This current study explored this further in healthcare staff members. AIMS: Can behaviourally specific and plain English language improve healthcare intentions to perform actions in line with guidance for schizophrenia. METHOD: An independent measure, single blind, randomised control trial. Guidance was written and disseminated in two formats, the "original" and "alternative". Self-report measures were administered to assess the cognitive determents of behaviour as described by the Theory of Planned Behaviour, actual behaviour consistent with the guidance, comprehension and satisfaction with the guidance. RESULTS: No significant results were found when comparing the original guidance to the alternative for the cognitive determinants of behaviour, actual behaviour, comprehension or satisfaction. CONCLUSIONS: Behaviourally specific and plain English language does not affect healthcare professionals' intentions or behaviour to implement recommended guidance for the provision of psychological interventions for schizophrenia. A more multi-factorial approach including organisational culture may be required. PMID- 25279815 TI - Phototransformation of amlodipine: degradation kinetics and identification of its photoproducts. AB - Nowadays, monitoring focuses on the primary compounds and does not include degradation products formed during various biological and chemical processes. Transformation products may have the same effects to human health and the environment or sometimes they can be more toxic than the parent compound. Unfortunately, knowledge about the formation of degradation products is still limited, however, can be very important for the environmental risk assessment. Firstly, the photodegradation kinetic of amlodipine was investigated in two experimental conditions: during the exposure to solar radiation and during the exposure to the light emitted by the xenon lamp. In all cases degradation of amlodipine followed a pseudo-first-order kinetics. In the next step, identification of transformation products of amlodipine formed during the exposure to xenon lamp irradiation was performed using ultra high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). As a result sixteen photoproducts were identified, their structures were elucidated and ultimately the transformation pathway was proposed. Fifteen compounds (out of 16 photoproducts) were newly identified and reported here for the first time; some of those compounds were formed from the first photoproduct, amlodipine pyridine derivative. Several analytes were formed only in acidic or basic conditions. Furthermore, the occurrence of amlodipine and its identified degradation products was investigated in environmental waters. Only one out of 16 compounds was found in wastewater effluent. The possibility of the sorption of examined analytes to sewage sludge particles was discussed based on QSAR. PMID- 25279817 TI - Unmanned aerial survey of fallen trees in a deciduous broadleaved forest in eastern Japan. AB - Since fallen trees are a key factor in biodiversity and biogeochemical cycling, information about their spatial distribution is of use in determining species distribution and nutrient and carbon cycling in forest ecosystems. Ground-based surveys are both time consuming and labour intensive. Remote-sensing technology can reduce these costs. Here, we used high-spatial-resolution aerial photographs (0.5-1.0 cm per pixel) taken from an unmanned aerial vehicle (UAV) to survey fallen trees in a deciduous broadleaved forest in eastern Japan. In nine sub plots we found a total of 44 fallen trees by ground survey. From the aerial photographs, we identified 80% to 90% of fallen trees that were >30 cm in diameter or >10 m in length, but missed many that were narrower or shorter. This failure may be due to the similarity of fallen trees to trunks and branches of standing trees or masking by standing trees. Views of the same point from different angles may improve the detection rate because they would provide more opportunity to detect fallen trees hidden by standing trees. Our results suggest that UAV surveys will make it possible to monitor the spatial and temporal variations in forest structure and function at lower cost. PMID- 25279814 TI - Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways. AB - As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue specific gene control. PMID- 25279818 TI - Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability. AB - Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. PMID- 25279821 TI - Workplace interventions: a challenge for promoting long-term health among shift workers. PMID- 25279820 TI - Molecular modeling of prion transmission to humans. AB - Using different prion strains, such as the variant Creutzfeldt-Jakob disease agent and the atypical bovine spongiform encephalopathy agents, and using transgenic mice expressing human or bovine prion protein, we assessed the reliability of protein misfolding cyclic amplification (PMCA) to model interspecies and genetic barriers to prion transmission. We compared our PMCA results with in vivo transmission data characterized by attack rates, i.e., the percentage of inoculated mice that developed the disease. Using 19 seed/substrate combinations, we observed that a significant PMCA amplification was only obtained when the mouse line used as substrate is susceptible to the corresponding strain. Our results suggest that PMCA provides a useful tool to study genetic barriers to transmission and to study the zoonotic potential of emerging prion strains. PMID- 25279822 TI - Insight into the reactivity and electronic structure of dinuclear dinitrosyl iron complexes. AB - A combination of N/S/Fe K-edge X-ray absorption spectroscopy (XAS), X-ray diffraction data, and density functional theory (DFT) calculations provides an efficient way to unambiguously delineate the electronic structures and bonding characters of Fe-S, N-O, and Fe-N bonds among the direduced-form Roussin's red ester (RRE) [Fe2(MU-SPh)2(NO)4](2-)(1) with {Fe(NO)2}(10)-{Fe(NO)2}(10) core, the reduced-form RRE [Fe2(MU-SPh)2(NO)4](-)(3) with {Fe(NO)2}(9)-{Fe(NO)2}(10) core, and RRE [Fe2(MU-SPh)2(NO)4] (4) with {Fe(NO)2}(9)-{Fe(NO)2}(9) core. The major contributions of highest occupied molecular orbital (HOMO) 113alpha/beta in complex 1 is related to the antibonding character between Fe(d) and Fe(d), Fe(d), and S atoms, and bonding character between Fe(d) and NO(pi*). The effective nuclear charge (Zeff) of Fe site can be increased by removing electrons from HOMO to shorten the distances of Fe...Fe and Fe-S from 1 to 3 to 4 or, in contrast, to increase the Fe-N bond lengths from 1 to 3 to 4. The higher IR nuNO stretching frequencies (1761, 1720 cm(-1) (4), 1680, 1665 cm(-1) (3), and 1646, 1611, 1603 cm(-1) (1)) associated with the higher transition energy of N1s ->sigma*(NO) (412.6 eV (4), 412.3 eV (3), and 412.2 eV (1)) and the higher Zeff of Fe derived from the transition energy of Fe1s -> Fe3d (7113.8 eV (4), 7113.5 eV (3), and 7113.3 eV (1)) indicate that the N-O bond distances of these complexes are in the order of 1 > 3 > 4. The N/S/Fe K-edge XAS spectra as well as DFT computations reveal the reduction of complex 4 yielding complex 3 occurs at Fe, S, and NO; in contrast, reduction mainly occurs at Fe site from complex 3 to complex 1. PMID- 25279819 TI - Mutation of the highly conserved Ser-40 of the HIV-1 p6 gag protein to Phe causes the formation of a hydrophobic patch, enhances membrane association, and polyubiquitination of Gag. AB - The HIV-1 p6 Gag protein contains two late assembly (l-) domains that recruit proteins of the endosomal sorting complex required for transport (ESCRT) pathway to mediate membrane fission between the nascent virion and the cell membrane. It was recently demonstrated that mutation of the highly conserved Ser-40 to Phe (S40F) disturbs CA-SP1 processing, virus morphogenesis, and infectivity. It also causes the formation of filopodia-like structures, while virus release remains unaffected. Here, we show that the mutation S40F, but not the conservative mutation to Asp (S40D) or Asn (S40N), augments membrane association, K48-linked polyubiquitination, entry into the 26S proteasome, and, consequently, enhances MHC-I antigen presentation of Gag derived epitopes. Nuclear magnetic resonance (NMR) structure analyses revealed that the newly introduced Phe-40, together with Tyr-36, causes the formation of a hydrophobic patch at the C-terminal alpha-helix of p6, providing a molecular rationale for the enhanced membrane association of Gag observed in vitro and in HIV-1 expressing cells. The extended exposure of the S40F mutant to unidentified membrane-resident ubiquitin E3-ligases might trigger the polyubiquitination of Gag. The cumulative data support a previous model of a so far undefined property of p6, which, in addition to MA, acts as membrane targeting domain of Gag. PMID- 25279824 TI - Visible-light-induced CO release from a therapeutically viable tryptophan-derived manganese(I) carbonyl (TryptoCORM) exhibiting potent inhibition against E. coli. AB - The first visible-light-activated carbon-monoxide-releasing molecule (CO-RM) to exhibit a potent effect against Escherichia coli is described. The easily prepared tryptophan-derived manganese-containing complex (TryptoCORM) released 1.4 moles of CO at 465 nm, and 2 moles at 400 nm. A comprehensive synthetic, mechanistic and microbiological study into the behaviour of TryptoCORM is reported. The complex is thermally stable (i.e., does not release CO in solution in the absence of light), shows low toxicity against mammalian cells and releases tryptophan on photoinduced degradation, all of which point to TryptoCORM being therapeutically viable. PMID- 25279825 TI - Suppression of phase and amplitude J(HH) modulations in HSQC experiments. AB - The amplitude and the phase of cross peaks in conventional 2D HSQC experiments are modulated by both proton-proton, J(HH), and proton-carbon, (1)J(CH), coupling constants. It is shown by spectral simulation and experimentally that J(HH) interferences are suppressed in a novel perfect-HSQC pulse scheme that incorporates perfect-echo INEPT periods. The improved 2D spectra afford pure in phase cross peaks with respect to (1)J(CH) and J(HH), irrespective of the experiment delay optimization. In addition, peak volumes are not attenuated by the influence of J(HH), rendering practical issues such as phase correction, multiplet analysis, and signal integration more appropriate. PMID- 25279826 TI - Intramolecular oxonium ylide formation-[2,3] sigmatropic rearrangement of diazocarbonyl-substituted cyclic unsaturated acetals: a formal synthesis of hyperolactone C. AB - Rh(II)-catalyzed oxonium ylide formation-[2,3] sigmatropic rearrangement of alpha diazo-beta-ketoesters possessing gamma-cyclic unsaturated acetal substitution, followed by acid-catalyzed elimination-lactonization, provides a concise approach to 1,7-dioxaspiro[4.4]non-2-ene-4,6-diones. The process creates adjacent quaternary stereocenters with full control of the relative stereochemistry. An unsymmetrical monomethylated cyclic unsaturated acetal leads to hyperolactone C, where ylide formation-rearrangement proceeds with high selectivity between subtly nonequivalent acetal oxygen atoms. PMID- 25279827 TI - Deep sequencing analysis of microRNAs in bovine sperm. AB - microRNAs (miRNAs) are small non-coding RNAs that participates in the regulation of many physiological pathways, but a role for spermatozoon-delivered miRNAs in fertilization and embryonic development remains controversial. A library of miRNAs in bovine sperm was constructed using Illumina high-throughput sequencing technology, along with the predication and the pathway analysis of target genes. miRNAs in mammalian spermatozoon were systematically investigated, and a protocol for RNA isolation from the cauda region of an epididymal biopsy was established. Unique sequences that were 18-26 nucleotides in length were mapped to specific precursors in miRBase 20.0 using BLAST. A total of 951 known miRNAs and 8 novel, highly expressed miRNA candidates were identified. The search for endogenous sperm miRNAs will contribute to a preliminary database for functional and molecular mechanistic studies in embryonic development and sperm epigenetic programming. PMID- 25279828 TI - Regulation of emotional memory by hydrogen sulfide: role of GluN2B-containing NMDA receptor in the amygdala. AB - As an endogenous gaseous molecule, hydrogen sulfide (H2 S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2 S on amygdala-mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2 S could regulate emotional memory. It was shown that the H2 S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2 S markedly enhanced amygdala-dependent cued fear memory in rats. Moreover, it was found that H2 S selectively increased the surface expression and currents of NMDA-type glutamate receptor subunit 2B (GluN2B)-containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B-containing NMDARs in lateral amygdala eliminated the effects of H2 S to enhance amygdalar long-term potentiation and cued fear memory. These results demonstrate that H2 S can regulate amygdala-dependent emotional memory by promoting the function of GluN2B-containing NMDARs in amygdala, suggesting that H2 S-associated signaling may hold potential as a new target for the treatment of emotional disorders. In our study, the effect of hydrogen sulfide (H2 S) on amygdala-mediated emotional memory was investigated. It was found that H2 S could enhance amygdala-dependent emotional memory and long-term potentiation (LTP) in rats by selectively increasing the function of GluN2B-containing NMDA receptors in the amygdala. These results suggest that H2 S-associated signaling may be a new target for the treatment of emotional disorders. PMID- 25279829 TI - The effect of C. burnetii infection on the cytokine response of PBMCs from pregnant goats. AB - In humans, infection with Coxiella burnetii, the causative agent of Q fever, leads to acute or chronic infection, both associated with specific clinical symptoms. In contrast, no symptoms are observed in goats during C. burnetii infection, although infection of the placenta eventually leads to premature delivery, stillbirth and abortion. It is unknown whether these differences in clinical outcome are due to the early immune responses of the goats. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from pregnant goats. In total, 17 goats were included in the study. Six goats remained naive, while eleven goats were infected with C. burnetii. Toll-like receptor (TLR) and cytokine mRNA expression were measured after in vitro stimulation with heat killed C. burnetii at different time points (prior infection, day 7, 35 and 56 after infection). In naive goats an increased expression of interleukin (IL) 1beta, tumor necrosis factor (TNF)-alpha, IL-10 and interferon (IFN)-gamma mRNA upon C. burnetii stimulation was detected. In addition, TLR2 expression was strongly up-regulated. In goats infected with C. burnetii, PBMCs re-stimulated in vitro with C. burnetii, expressed significantly more TNF-alpha mRNA and IFN-gamma mRNA compared to naive goats. In contrast, IL-10 mRNA production capacity was down-regulated during C. burnetii infection. Interestingly, at day 7 after inoculation a decreased IFN-gamma protein level was observed in stimulated leukocytes in whole blood from infected goats, whereas at other time-points increased production of IFN-gamma protein was seen. Our study shows that goats initiate a robust pro-inflammatory immune response against C. burnetii in vitro. Furthermore, PBMCs from C. burnetii infected goats show augmented pro inflammatory cytokine responses compared to PBMCs from non-infected goats. However, despite this pro-inflammatory response, goats are not capable of clearing the C. burnetii infection. PMID- 25279831 TI - Deformative transition of the Menschutkin reaction and helical atropisomers in a congested polyheterocyclic system. AB - A 4,7-phenanthroline polycyclic 1A designed for probing the limits of the Menschutkin reaction was synthesized in a six-step sequence. The rotational barrier of the phenyl ring nearby the N-methyl group in rac-2A was estimated to be ? 18.1 kcal/mol from VT-NMR experiments, making them a new type of helical atropisomer. The methylation rate constants of 9 and 1A with MeI was found to be 2.22 * 10(-4) and 9.62 * 10(-6) s(-1) mol(-1) L, respectively; thus, the formation rate of (P/M)-2A is one of the slowest rates ever reported for a Menschutkin reaction. The N-methyl protons in (P/M)-2A exhibit a significant upfield shift (Deltadelta 1.0 ppm) in its (1)H NMR, compared to those without a nearby phenyl, indicating a strong CH-pi interaction is involved. Conformational flexibility in dipyridylethene 9 is clearly shown by its complexation with BH3 to form helical atropisomers (P,P/M,M)-10. The pKa values of the conjugate acids of 1A and 9 in acetonitrile were determined to be 4.65 and 5.07, respectively, which are much smaller compared to that of pyridine 14a (pKa = 12.33), implying that the basicity, nucleophilicity, and amine alkylation rates of 1A and 9 are markedly decreased by the severe steric hindrance of the flanking phenyl rings in the polyheterocycles. PMID- 25279830 TI - Highly adaptable triple-negative breast cancer cells as a functional model for testing anticancer agents. AB - A major obstacle in developing effective therapies against solid tumors stems from an inability to adequately model the rare subpopulation of panresistant cancer cells that may often drive the disease. We describe a strategy for optimally modeling highly abnormal and highly adaptable human triple-negative breast cancer cells, and evaluating therapies for their ability to eradicate such cells. To overcome the shortcomings often associated with cell culture models, we incorporated several features in our model including a selection of highly adaptable cancer cells based on their ability to survive a metabolic challenge. We have previously shown that metabolically adaptable cancer cells efficiently metastasize to multiple organs in nude mice. Here we show that the cancer cells modeled in our system feature an embryo-like gene expression and amplification of the fat mass and obesity associated gene FTO. We also provide evidence of upregulation of ZEB1 and downregulation of GRHL2 indicating increased epithelial to mesenchymal transition in metabolically adaptable cancer cells. Our results obtained with a variety of anticancer agents support the validity of the model of realistic panresistance and suggest that it could be used for developing anticancer agents that would overcome panresistance. PMID- 25279832 TI - Towards an age-dependent transmission model of acquired and sporadic Creutzfeldt Jakob disease. AB - INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) might be transmitted by surgery. The purpose of this study was to investigate potential susceptibility to sCJD from surgery at juvenile age and in early adulthood. METHODS: From Danish and Swedish national registries we identified 167 definite and probable sCJD cases with onset from 1987 through 2003, and 835 age-, sex- and residence-matched controls along with their surgical histories. Main, anatomically or etiologically classified surgical procedures followed by a >=20-year lag were analyzed using logistic regression, and stratified by age at first-registered surgical discharge. RESULTS: The risk of having a diagnosis of CJD depended strongly on age at first surgery with odds ratio (OR) of 12.80 (95% CI 2.56-64.0) in patients <30 years, 3.04 (95% 1.26-7.33) in 30-39 years, and 1.75 (95% CI 0.89-3.45) in >=40 years, for anatomically classified surgical procedures. Similar figures were obtained for etiologically classified surgical procedures. CONCLUSIONS: Risk of surgical-acquired sCJD depends on age at exposure; this pattern is similar to age specific profiles reported for CJD accidentally transmitted by human pituitary derived growth hormone and susceptibility curves for variant CJD estimated after adjustment for dietary exposure to bovine spongiform encephalopathy. There might be an age-at-exposure-related susceptibility to acquire all CJD forms, including sCJD from routine surgery. PMID- 25279833 TI - Physical activity and bone mineral accrual in boys with different body mass parameters during puberty: a longitudinal study. AB - The aim of our longitudinal study was to investigate the relationships between physical activity and bone mass in boys with different body mass status during the years surrounding pubertal growth spurt. Two hundred and six boys entering puberty took part in this study. The subjects were divided into underweight (BMI < 15.35), normal weight (BMI >= 15.35-21.22), overweight (BMI >= 21.22-26.02) and obese (BMI > 26.02) groups at baseline according to age related categories. Whole body DXA scans were performed at baseline, after 12 and 24 months to assess body composition (lean body mass, fat mass), and total body (TB), lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) parameters. Physical activity was measured by 7-day accelerometry. For longitudinal analysis, multilevel fixed effects regression models were constructed. Biological age, height and lean body mass had an effect for explanation of TB BMD, FN BMD and LS BMD. Moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA) and sedentary time (SED) had the significant effect only on FN BMD. Being an underweight boy at the baseline indicated greater chance (p<0.01) to have lower TB BMD in the future (2 years at follow up) development, compared to normal weight (estimates = 0.038), overweight (estimates = -0.061) and obese boys (estimates = -0.106). PMID- 25279836 TI - Phylogenetic diversity and co-evolutionary signals among trophic levels change across a habitat edge. AB - Incorporating the evolutionary history of species into community ecology enhances understanding of community composition, ecosystem functioning and responses to environmental changes. Phylogenetic history might partly explain the impact of fragmentation and land-use change on assemblages of interacting organisms and even determine potential cascading effects across trophic levels. However, it remains unclear whether phylogenetic diversity of basal resources is reflected at higher trophic levels in the food web. In particular, phylogenetic determinants of community structure have never been incorporated into habitat edge studies, even though edges are recognized as key factors affecting communities in fragmented landscapes. Here, we test whether phylogenetic diversity at different trophic levels (plants, herbivores and parasitoids) and signals of co-evolution (i.e. phylogenetic congruence) among interacting trophic levels change across an edge gradient between native and plantation forests. To ascertain whether there is a signal of co-evolution across trophic levels, we test whether related consumer species generally feed on related resource species. We found differences across trophic levels in how their phylogenetic diversity responded to the habitat edge gradient. Plant and native parasitoid phylogenetic diversity changed markedly across habitats, while phylogenetic variability of herbivores (which were predominantly native) did not change across habitats, though phylogenetic evenness declined in plantation interiors. Related herbivore species did not appear to feed disproportionately on related plant species (i.e. there was no signal of co-evolution) even when considering only native species, potentially due to the high trophic generality of herbivores. However, related native parasitoid species tended to feed on related herbivore species, suggesting the presence of a co-evolutionary signal at higher trophic levels. Moreover, this signal was stronger in plantation forests, indicating that this habitat may impose stresses on parasitoids that constrain them to attack only host species for which they are best adapted. Overall, changes in land use across native to plantation forest edges differentially affected phylogenetic diversity across trophic levels, and may also exert a strong selective pressure for particular co evolved herbivore-parasitoid interactions. PMID- 25279834 TI - Gene expression during the generation and activation of mouse neutrophils: implication of novel functional and regulatory pathways. AB - As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1alpha, MIP-1beta, and TNF-alpha by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions. PMID- 25279835 TI - The structure, stability and pheromone binding of the male mouse protein sex pheromone darcin. AB - Mouse urine contains highly polymorphic major urinary proteins that have multiple functions in scent communication through their abilities to bind, transport and release hydrophobic volatile pheromones. The mouse genome encodes for about 20 of these proteins and are classified, based on amino acid sequence similarity and tissue expression patterns, as either central or peripheral major urinary proteins. Darcin is a male specific peripheral major urinary protein and is distinctive in its role in inherent female attraction. A comparison of the structure and biophysical properties of darcin with MUP11, which belongs to the central class, highlights similarity in the overall structure between the two proteins. The thermodynamic stability, however, differs between the two proteins, with darcin being much more stable. Furthermore, the affinity of a small pheromone mimetic is higher for darcin, although darcin is more discriminatory, being unable to bind bulkier ligands. These attributes are due to the hydrophobic ligand binding cavity of darcin being smaller, caused by the presence of larger amino acid side chains. Thus, the physical and chemical characteristics of the binding cavity, together with its extreme stability, are consistent with darcin being able to exert its function after release into the environment. PMID- 25279837 TI - Propionibacterium species and follicular keratinocyte activation in acneic and normal skin. AB - BACKGROUND: The pathogenesis of acne vulgaris is multifactorial with increased sebum production, alteration in the quality of sebum lipids, dysregulation of the hormone microenvironment, follicular hyperkeratinization and Propionibacterium acnes-driven inflammation as major contributory factors. Hyperproliferation of keratinocytes is believed to contribute to hypercornification and eventually leads to comedone development. While the distribution of P. acnes is relatively well documented in acneic and healthy skin, little is known about P. granulosum and P. avidum. OBJECTIVES: To visualize directly the three major Propionibacterium in 117 control and 26 acneic skin samples. In addition, keratinocyte proliferation was evaluated. METHODS: Propionibacteria were visualized by immunofluorescence microscopy, and keratinocyte proliferation was assessed by Ki67, keratin (K) 16 and p63 immunochemistry. RESULTS: P. acnes was identified in 68 samples (48%), while P. granulosum was identified in 12 (8%) samples; P. avidum was not detected at all. Unexpectedly, acne samples did not show higher keratinocyte proliferation than controls, nor was there any association between bacterial colonization and expression of Ki67/K16/p63. CONCLUSIONS: Our findings do not support earlier notions of follicular keratinocyte hyperproliferation as a cause of ductal hypercornification in acneic facial skin. Further studies on the mechanisms underlying hypercornification in acne pathogenesis are needed. PMID- 25279839 TI - The medial pterygoid tubercle in the Atapuerca Early and Middle Pleistocene mandibles: evolutionary implications. AB - Numerous studies have attempted to identify the presence of uniquely derived (autoapomorphic) Neandertal features. Here, we deal with the medial pterygoid tubercle (MTP), which is usually present on the internal face of the ascending ramus of Neandertal specimens. Our study stems from the identification of a hypertrophied tubercle in ATD6-96, an Early Pleistocene mandible recovered from the TD6 level of the Atapuerca-Gran Dolina site and attributed to Homo antecessor. Our review of the literature and study of numerous original fossil specimens and high quality replicas confirm that the MTP occurs at a high frequency in Neandertals (ca. 89%) and is also present in over half (ca. 55%) of the Middle Pleistocene Sima de los Huesos (SH) hominins. In contrast, it is generally absent or minimally developed in other extinct hominins, but can be found in variable frequencies (=11 in these ICU patients with AKI. CONCLUSIONS: For patients coexisting with AKI admitted to ICU, this work recommends application of SOFA by physicians to assess ICU mortality because of its practicality and low cost. A SOFA score of >= "11" on ICU day 1 should be considered an indicator of negative short-term outcome. PMID- 25279845 TI - Anatomic-functional (perfusion-based) magnetic resonance imaging follow-up in patients with rheumatoid arthritis treated with anti-interleukin 6 antibodies: a comparison with clinical scores and serologic data. AB - OBJECTIVE: On a 3-T magnetic resonance scanner, morphologic and perfusion changes of 9 patients with rheumatoid arthritis were evaluated after start of anti interleukin 6 receptor antibody Tocilizumab (TCZ) treatment. METHODS: Morphologic and perfusion-based magnetic resonance imaging (MRI) parameters were assessed before and 4, 12, and 24 after the start of TCZ treatment. Furthermore, serologic biomarkers and clinical assessment scores were evaluated 4, 12, 24, and 52 weeks after treatment initiation. RESULTS: Results of MRI parameters showed significant group differences between responders and nonresponders for synovial volume, transfer constant, and blood plasma volume fraction already at week 12 as well as relative enhancement and rate of early enhancement at week 24. CONCLUSIONS: Considering the temporal change of perfusion-derived MRI parameters (transfer constant, blood plasma volume fraction, relative enhancement, and rate of early enhancement) as well as morphologic MRI parameters (synovial volume measurements), a quantifiable assessment of response to TCZ therapy in rheumatoid arthritis seems possible at an even earlier time point compared with clinical assessment scores, whereas serologic biomarkers proved nonspecific in this respect. PMID- 25279846 TI - Arterial pseudoaneurysms complicating pancreatitis: literature review. AB - Arterial pseudoaneurysm formation of visceral arteries as a vascular complication of pancreatitis, either acute or chronic, is an uncommon phenomenon. This review article discusses the incidence, pathophysiology, imaging, treatment strategies, and prognosis of mesenteric pseudoaneurysms complicating pancreatitis. PMID- 25279847 TI - Material characterization of dual-energy computed tomographic data using polar coordinates. AB - The purpose of this study was to evaluate a new dual-energy computed tomographic postprocessing approach on the basis of the transformation of dual-energy radiodensity data into polar coordinates. Given 2 corresponding dual-energy computed tomographic images, the attenuation data D(U1), D(U2) in Hounsfield units of both tube voltages (U1,U2) were transformed for each voxel to polar coordinates: r (distance to the radiodensity coordinate origin) is an approximate measure of electron density and phi (angle to the abscissa) differentiates between materials. PMID- 25279848 TI - Lung cancer associated with cystic airspaces. AB - OBJECTIVE: This study aimed to define computed tomographic morphologic features of lung cancer associated with cystic airspaces, their modifications in serial computed tomographic scans, and 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography uptake. METHODS: Computed tomographic scans and 18F-FDG positron emission tomography in 24 patients with lung cancer (17 adenocarcinomas, 7 squamous cell carcinomas, 12 stage I and 12 stage II to IV) associated with cystic airspaces were reviewed. RESULTS: Mean diameter of airspace was initially 17.6 mm (range, 5-30 mm), and 4 morphologic patterns were recognized: solid nodule protruding externally (type I, n = 5) or internally (type II, n = 4) from the cyst wall; circumferential thickening of the cyst wall (type III, n = 8); and tissue intermixed within clusters of cysts (type IV, n = 7). With tumor growth, airspace size decreased in 9, increased in 6, and was unchanged in 9 cases. Five cases evolved from type III to type I, and 5 lesions became completely solid. 18F fluoro-2-deoxy-D-glucose uptake was initially absent to mild in 7 and moderate to marked in 14 lesions. CONCLUSIONS: Progressive wall thickening or appearance/increase of a nodule inside or outside a cystic airspace should raise suspicion of lung cancer irrespective of FDG uptake. PMID- 25279849 TI - Myocardial and hepatic iron overload assessment by region-based and pixel-wise T2* mapping analysis: technical pitfalls and clinical warnings. AB - OBJECTIVE: The aim of this study was to compare myocardial T2* assessment with region-based (RB) T2* multiecho technique (CMRtools) with the pixel-wise (PW) inline myocardial T2* mapping (Siemens) in patients with thalassemia major for myocardial iron characterization. MATERIALS AND METHODS: Forty-three thalassemia major patients were examined on a 1.5-T scanner using conventional gradient multiecho sequence. All the images were analyzed using both RB and PW T2* mapping. Coefficients of reproducibility (CRs) were used to assess the interoperator and intraobserver variability of each software. RESULTS: The mean (SD) myocardial T2* values using RB and PW software resulted significantly different (30.7 [15] milliseconds [range, 4.8-52.6 milliseconds] vs 24.3 [10.5] milliseconds [range 4.6-38.2 milliseconds]; P < 0.0001). Interestingly, we found that SD had exponential relationship with T2* with evidence of increase in SD for T2* values greater than 20 milliseconds. For myocardial T2* values less than 20 milliseconds, intraobserver CR was 1.2 milliseconds for RB and 1.8 milliseconds for PW T2* mapping, and the interoperator CR was 3.4 and 1.6 milliseconds for RB and PW T2* mapping, respectively. Comparing iron overload classification by both software, we found that 7 patients (16%) were differently categorized using the standard T2* thresholds. CONCLUSIONS: Our data show that RB and PW T2* mapping can be used interchangeably to measure severe myocardial and hepatic iron overload, whereas for borderline T2* values, we observed differences among the 2 methods causing different categorization. PMID- 25279850 TI - Procedure-oriented sectional anatomy of the foot. AB - This is the seventh and last in a series of studies related to procedure-oriented joint anatomy. This article reviews the anatomy of the foot and its relationship to procedures in the clinical setting with or without ultrasound guidance. Anatomically correct axial schematics allow injections to be envisioned relative to clinically important anatomy for common forefoot procedures. Cross-sectional schematics for the ankle were drawn as they appear in imaging projections. The levels and planes of cross section were selected to highlight important anatomic landmarks for injection. It is hoped that these schematics allow for safer and more accurate needle procedures in the foot area. PMID- 25279851 TI - Bioaccumulation of cadmium and lead and its effects on hepatopancreas morphology in three terrestrial isopod crustacean species. AB - This study was designed to compare cadmium (Cd) and lead (Pb) bioaccumulation in three species of oniscidean isopods - Armadillidium granulatum Brandt, Armadillidium vulgare (Latreille) and Porcellio laevis Latreille which were exposed for three weeks to a contaminated diet, and to determine the morphological and ultrastructural changes in hepatopancreas. Metal accumulation, determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), was linearly associated with the exposed concentration and was a function of the metal and the species tested. All three species accumulated lower levels of Pb than Cd. A. vulgare accumulated the largest concentration of Pb, especially at the higher doses, whereas P. laevis showed the greatest Cd accumulation, and the highest Cd concentration was lethal for all exposed species. The highest concentrations of Pb and Cd induced significant changes both in the general morphology of tubules and in the ultrastructural organization of epithelial cells in hepatopancreas. Some Pb/Cd induced alterations include: brush border disorganization; reduction of the basal labyrinth formed by the plasma membrane; condensation of some cytoplasm areas and of chromatin; rough endoplasmic reticulum and mitochondrial alterations; increase of secondary lysosomes and of type B granules in S cells. Some of the ultrastructural changes observed overlap with those induced by prolonged starvation, whereas others can be useful biomarkers of heavy metal toxicity. This study has confirmed that in terrestrial isopods, the accumulation of the different metals occurs in a species-specific manner; therefore ecological monitoring and assessment studies should consider each species individually. The research has confirmed that in the terrestrial isopods the accumulation of the different metals occurs in a species-specific way; therefore each species should first be evaluated in view of its employ in biomonitoring programs. PMID- 25279852 TI - Association of angiopoietin-2 with renal outcome in chronic kidney disease. AB - BACKGROUND: The pathophysiological mechanisms of renal function progression in chronic kidney disease (CKD) have still not been completely explored. In addition to well-known traditional risk factors, non-traditional risk factors, such as endothelial dysfunction, have gradually attracted physicians' attention. Angiopoietin-2 (Ang-2) impairs endothelial function through preventing angiopoietin-1 from binding to Tie2 receptor. Whether Ang-2 is associated with renal function progression in CKD is unknown. METHODS: This study enrolled 621 patients with stages 3-5 CKD to assess the association of circulating Ang-2 with commencing dialysis, doubling creatinine and rapid decline in renal function (the slope of estimated glomerular filtration rate (eGFR) greater than 5 ml/min per 1.73 m2/y) over follow-up of more than 3 years. RESULTS: Of all patients, 224 patients (36.1%) progressed to commencing dialysis and 165 (26.6%) reached doubling creatinine. 85 subjects (13.9%) had rapid decline in renal function. Ang 2 quartile was divided at 1494.1, 1948.8, and 2593.1 pg/ml. The adjusted HR of composite outcomes, either commencing dialysis or doubling creatinine was 1.53 (95% CI: 1.06-2.23) for subjects of quartile 4 compared with those of quartile 1. The adjusted OR for rapid decline in renal function was 2.96 (95% CI: 1.13-7.76) for subjects of quartile 4 compared with those of quartile 1. The linear mixed effects model shows a more rapid decrease in eGFR over time in patients with quartile 3 or more of Ang-2 than those with the lowest quartile of Ang-2. CONCLUSIONS: Ang-2 is an independent predictor of adverse renal outcome in CKD. Further study is needed to identify the pathogenic role of Ang-2 in CKD progression. PMID- 25279853 TI - Bayesian analysis using a simple likelihood model outperforms parsimony for estimation of phylogeny from discrete morphological data. AB - Despite the introduction of likelihood-based methods for estimating phylogenetic trees from phenotypic data, parsimony remains the most widely-used optimality criterion for building trees from discrete morphological data. However, it has been known for decades that there are regions of solution space in which parsimony is a poor estimator of tree topology. Numerous software implementations of likelihood-based models for the estimation of phylogeny from discrete morphological data exist, especially for the Mk model of discrete character evolution. Here we explore the efficacy of Bayesian estimation of phylogeny, using the Mk model, under conditions that are commonly encountered in paleontological studies. Using simulated data, we describe the relative performances of parsimony and the Mk model under a range of realistic conditions that include common scenarios of missing data and rate heterogeneity. PMID- 25279854 TI - The influence of executive functions on spatial biases varies during the lifespan. AB - Many perceptual processes, such as language or face perception, are asymmetrically organised in the hemispheres already in childhood. These asymmetries induce behaviourally observable spatial biases in which the observer perceives stimuli in one of the hemispaces more efficiently or more frequently than in the other one. Another source for spatial biases is spatial attention which is also asymmetrically organised in the hemispheres. The bias induced by attention is directed towards the right side, which is clearly demonstrated by patients with neglect but also in lesser degree by healthy observers in cognitively loading situations. Recent findings indicate that children and older adults show stronger spatial biases than young adults. We discuss how the development of executive functions might contribute to the manifestation of spatial biases during the lifespan. We present a model in which the interaction between the asymmetrical perceptual processes, the age-related development of the lateralised spatial attention and the development of the executive functions influence spatial perceptual performance and in which the development and decline of the executive processes during the lifespan modify the spatial biases. PMID- 25279855 TI - Neural processing of moral violations among incarcerated adolescents with psychopathic traits. AB - Neuroimaging studies have found that adult male psychopaths show reduced engagement of limbic and paralimbic circuitry while making moral judgments. The goal of this study was to investigate whether these findings extend to adolescent males with psychopathic traits. Functional MRI was used to record hemodynamic activity in 111 incarcerated male adolescents while they viewed unpleasant pictures that did or did not depict moral transgressions and rated each on "moral violation severity". Adolescents were assessed for psychopathic traits using the Psychopathy Checklist-Youth Version (PCL-YV), Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (KSADS-PL) Conduct Disorder supplement, and Inventory of Callous and Unemotional Traits-Youth Version (ICU-Y). While viewing pictures depicting moral transgressions, CD scores were negatively correlated with hemodynamic responses in the anterior temporal cortex. Adolescents scoring low on the ICU-Y showed a positive correlation between right amygdala responses and severity of violation ratings; those with high ICU-Y scores showed a negative correlation. While viewing unpleasant pictures with and without moral transgressions, PCL-YV scores were negatively correlated with hemodynamic responses in the left amygdala. Overall, the results are consistent with those previously found in adult male psychopaths, but vary depending on the type of psychopathy assessment. PMID- 25279856 TI - Cyclization of eta3-benzylpalladium intermediates derived from carbene insertion. AB - Migratory insertion of benzylidene carbene ligands into arylpalladium(II) species generates eta(3)-benzylpalladium intermediates that can cyclize to generate five- and six-membered rings with new sp(3) centers. The reaction tolerates a range of arene functional groups and stabilized enolates. The products generated through this reaction are 1-arylindanes and 1-aryltetralins that are common to a range of natural products. PMID- 25279858 TI - Oxidative stress induces the biosynthesis of citrinin by Penicillium verrucosum at the expense of ochratoxin. AB - Penicillium verrucosum is a fungus that can produce ochratoxin A and citrinin, two structurally related nephrotoxic mycotoxins. P. verrucosum usually occurs on wheat but can occasionally also be found in NaCl rich habitats such as salted cheeses or olives, indicating that this fungus can adapt to different environments. The ratio of ochratoxin A to citrinin produced by P. verrucosum is shifted to one of either mycotoxin at the expense of the other dependent on the environmental conditions. High NaCl concentrations shift secondary metabolite biosynthesis towards ochratoxin A production. P. verrucosum copes with NaCl stress by increased ochratoxin A biosynthesis, ensuring chloride homeostasis. Ochratoxin A carries chlorine in its molecule and can excrete chlorine from the cell. It was further shown that the regulation of ochratoxin A by high NaCl conditions is mediated by the HOG MAP kinase signal transduction pathway. Here it is shown that high oxidative stress conditions, evoked for example by increasing concentrations of Cu(2+) cations in the growth medium, shift secondary metabolite biosynthesis of P. verrucosum from ochratoxin A to citrinin. The production of citrinin normalizes the oxidative status of the fungal cell under oxidative stress conditions leading to an adaptation to these environmental conditions and protects against increased oxidative stress caused by increased Cu(2+) concentrations. Moreover citrinin also protects against light of short wavelength, which may also increase the oxidative status of the environment. The biosynthesis of citrinin is apparently regulated by a cAMP/PKA signaling pathway, because increasing amounts of external cAMP reduce citrinin biosynthesis in a concentration dependent manner. These conditions lead to the cross-regulation of the ochratoxin A/citrinin secondary metabolite pair and support the adaptation of P. verrucosum to different environments. PMID- 25279857 TI - Involvement of the iron regulatory protein from Eisenia andrei earthworms in the regulation of cellular iron homeostasis. AB - Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs) that exist in different organisms. IRPs are cytosolic proteins that bind to iron responsive elements (IREs) of the 5'- or 3'-untranslated regions (UTR) of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP). The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant. PMID- 25279859 TI - Glutaminase-producing Meyerozyma (Pichia) guilliermondii isolated from Thai soy sauce fermentation. AB - In this study, 34 yeast isolates were obtained from koji and moromi samples of Thai soy sauce fermentation. However, the most interesting yeast strain was isolated from the enriched 2 month-old (M2) moromi sample and identified as Meyerozyma (Pichia) guilliermondii EM2Y61. This strain is a salt-tolerant yeast that could tolerate up to 20% (w/v) NaCl and produce extracellular and cell-bound glutaminases. Interestingly, its glutaminases were more active in 18% (w/v) NaCl which is a salt concentration in moromi. The extracellular glutaminase's activity was found to be much higher than that of cell-bound glutaminase. The highest specific activity and stability of the extracellular glutaminase were found in 18% (w/v) NaCl at pH4.5 and 37 degrees C. A challenge test by adding partially purified extracellular glutaminase from M. guilliermondii EM2Y61 into 1 month-old (M1) moromi sample showed an increased conversion of L-glutamine to L-glutamic acid. This is the first report of glutaminase producing M. guilliermondii isolated from the moromi of Thai soy sauce fermentation. The results suggested the potential application of M. guilliermondii EM2Y61 as starter yeast culture to increase l-glutamic acid during soy sauce fermentation. PMID- 25279861 TI - Short-term mesh exposure after robotic sacrocolpopexy with and without concomitant hysterectomy. AB - OBJECTIVES: The primary objective of this study was to compare the short-term rate of mesh exposure after a robotic sacrocolpopexy (RSCP) compared with those after RSCP with a concomitant hysterectomy. Secondary objectives included a comparison of mesh exposure from total hysterectomies (TH) versus supracervical hysterectomies (SCH) and determination of risk factors for mesh exposure. METHODS: This was a retrospective cohort study of women who underwent RSCP between January 2009 and December 2011 at one academic center. The primary outcome was mesh exposure at 6 weeks postoperation. Subjects were divided into two groups: those with concomitant hysterectomy and those with RSCP alone. The hysterectomy group was subdivided into TH versus SCH. Mesh exposures and mesh revision procedures were identified using International Classification of Diseases-9 and CPT codes, respectively, and confirmed by chart review. RESULTS: There were 230 eligible women who underwent RSCP during the study period and were followed up at a 6-week postoperative visit; 118 (51.7%) had RSCP only and 112 (48.7%) had a concomitant hysterectomy. Of those who underwent hysterectomy, 79 patients (70.5%) had TH and 33 (29.5%) had SCH. There were nine (3.9%) mesh exposures attributed to RSCP. The difference between the RSCP + hysterectomy group and the RSCP-only group was 2.7% versus 5.1% (P = 0.50). The 2.7% of mesh exposures in the hysterectomy group were associated with TH and none with SCH, but this difference was not significant (P = 0.55). CONCLUSIONS: Although mesh exposure with RSCP is low, serious morbidity can be associated with mesh use and appropriate preoperative counseling is critical. PMID- 25279860 TI - Changes in compact bone microstructure of rats subchronically exposed to cadmium. AB - BACKGROUND: Chronic exposure to cadmium (Cd), even at low concentrations, has an adverse impact on the skeletal system. Histologically, primary and secondary osteons as basic structural elements of compact bone can also be affected by several toxicants leading to changes in bone vascularization and mechanical properties of the bone. The current study was designed to investigate the effect of subchronic peroral exposure to Cd on femoral bone structure including histomorphometry of the osteons in adult male rats. In our study, 20 one-month old male Wistar rats were randomly divided into two experimental groups. In the first group, young males received a drinking water containing 30 mg of CdCl2/L, for 90 days. Ten one-month-old males without Cd intoxication served as a control group. After 90 days of daily peroral exposure, body weight, femoral weight, femoral length, cortical bone thickness and histological structure of the femora were analysed. RESULTS: We found that subchronic peroral application of Cd had no significant effect on body weight, femoral length and cortical bone thickness in adult rats. On the other hand, femoral weight was significantly increased (P < 0.05) in Cd-intoxicated rats. These rats also displayed different microstructure in the middle part of the compact bone where vascular canals expanded into central area of substantia compacta and supplied primary and secondary osteons. Additionally, a few resorption lacunae which are connected with an early stage of osteoporosis were identified in these individuals. Histomorphometrical evaluations showed that all variables (area, perimeter, maximum and minimum diameter) of the primary osteons' vascular canals, Haversian canals and secondary osteons were significantly decreased (P < 0.05) in the Cd group rats. This fact points to alterations in bone vascularization. CONCLUSIONS: Subchronic peroral exposure to Cd significantly influences femoral weight and histological structure of compact bone in adult male rats. It induces an early stage of osteoporosis and causes reduced bone vascularization. Histomorphometrical changes of primary and secondary osteons allow for the conclusion that the bone mechanical properties could be weakened in the Cd group rats. The current study significantly expands the knowledge on damaging action of Cd on the bone. PMID- 25279862 TI - Cardiovascular risk in Gullah African Americans with high familial risk of type 2 diabetes mellitus: project SuGAR. AB - OBJECTIVES: To determine the prevalence of cardiovascular disease, levels of cardiovascular risk factors, and extent of preventive care in Gullah African Americans with a high familial risk of type 2 diabetes mellitus. METHODS: Between 1995 and 2003, 1321 Gullah African Americans with a high prevalence of diabetes mellitus from the South Carolina Sea Islands consented to and enrolled in the Sea Islands Genetic African American Registry (Project SuGAR). A cross-sectional analysis of cardiometabolic risk, preventive care, and self-reported cardiovascular disease was conducted. RESULTS: Cardiometabolic risk factor levels were high and vascular disease was prevalent. Among the subjects with diabetes mellitus, the mean disease duration was 10.5 years; approximately one-third reported reduced vision or blindness; and >80% reported numbness, pain, or burning in their feet. Preventive diabetes care was limited, with <60%, <25%, and <40% seeing an ophthalmologist, podiatrist, and dentist, respectively, within the past year. Only 54.4% of women and 39.3% of men reported daily glucose monitoring. CONCLUSIONS: As the largest existing study of Gullah individuals, our study offers insight into not only the level of cardiovascular risk in this population but also the pathophysiological mechanisms central to ancestral differences in cardiometabolic risk in the broader African American population. PMID- 25279863 TI - Endoscopic mucosal resection recurrence rate for colorectal lesions. AB - OBJECTIVES: We aimed to evaluate the polyp recurrence rate after endoscopic mucosal resection (EMR) and factors contributing to increased recurrence. METHODS: MEDLINE (from 1966 to 2013), the Cochrane Central Register of Controlled Trials, and the Scopus database were searched in December 2013. Studies evaluating the polyp recurrence rate after colonic EMR were included. All of the articles were assigned a quality score. Standard forms were used to extract data regarding study design, outcome measures, and adverse effects by two independent reviewers. We performed a meta-analysis with a random effects model. Separate analyses were performed for each main outcome by using odds ratio (OR) and risk difference. Heterogeneity was assessed by I(2) measure of inconsistency. RESULTS: For the recurrence rate of colorectal lesions, 30 articles were included, with a total of 3404 patients. The polyp recurrence rate after EMR was 13.1%. Piecemeal resection was associated with a higher recurrence rate compared with en bloc resection (OR 4.39, 95% confidence interval 2.05-9.41; 14 studies). The use of argon plasma coagulation did not affect the polyp recurrence rate (OR 1.23, 95% confidence interval 0.39-3.88). Significant heterogeneity was present among studies. CONCLUSIONS: The recurrence rate of colorectal polyps after EMR is reasonably low; however, piecemeal resection was associated with a higher recurrence rate than en bloc resection after EMR. PMID- 25279864 TI - Commentary on "endoscopic mucosal resection recurrence rate for colorectal lesion". PMID- 25279865 TI - Burden of elective early-term births in rural Appalachia. AB - OBJECTIVES: Infants delivered at >= 37 weeks' gestation are considered full term, but research has demonstrated those born at 37 to 38 weeks (early term) have a higher risk for poor birth outcomes than deliveries at 39 to 41 weeks (full term). Despite this, many deliveries occur electively (scheduled, no medical indication) before 39 weeks. This study examined the risks of elective early-term delivery in a disadvantaged, rural sample and compared these results with national findings. METHODS: Data were available for 638 rural women, recruited prenatally from three counties in rural southern Appalachia, who delivered electively at >= 37 weeks. RESULTS: Compared with electively delivered full-term infants, those delivered electively at early term were 7.7 times more likely to be low birth weight, 4.4 times more likely to have a neonatal intensive care unit admission, and 2.5 times more likely to develop jaundice. Those living furthest from the hospital were most likely to deliver electively at <39 weeks. Although rates of elective deliveries <39 weeks were no higher than national rates, adjusted odds ratios (aOR) of associated admission to a neonatal intensive care unit doubled (aOR 4.4 vs aOR 2.2). CONCLUSIONS: Results demonstrate that initiatives targeting early-term elective deliveries are needed in rural, disadvantaged regions. PMID- 25279866 TI - Electronic cigarettes: a perspective for the primary care physician. PMID- 25279867 TI - Association of body mass index and waist circumference with subclinical atherosclerosis in retired NFL players. AB - OBJECTIVES: It is unknown which measure of adiposity (body mass index [BMI] or waist circumference [WC]) is associated with subclinical atherosclerosis in retired National Football League (NFL) players and whether this relation is attenuated after adjusting for components of the metabolic syndrome (elevated triglycerides, fasting glucose, and low levels of high-density lipoprotein cholesterol [HDL-C]) that frequently coexist with obesity. METHODS: Coronary artery calcium (CAC) was measured in 926 retired NFL players. BMI was calculated as weight (in kilograms)/height (in meters)(2) and WC was measured in inches. Logistic regression analyses adjusting for age, race, systolic blood pressure, high sensitivity C-reactive protein, triglycerides, HDL-C, and fasting blood glucose were performed to evaluate whether BMI or WC was independently associated with the presence of CAC (CAC score >0). RESULTS: The median age, BMI and WC were 54 years, 31 kg/m(2), and 40 inches, respectively. CAC was present in 61% (n = 562) of retired players. Adjusting for age, race, systolic blood pressure, high sensitivity C-reactive protein, triglycerides, HDL-C, and fasting blood glucose, each standard deviation increase in BMI (4.85 kg/m(2)) was significantly associated with CAC (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.03 1.50), but each standard deviation increase in WC (10.53 inches) was not significantly associated with CAC (OR 1.18, 95% CI 0.96-1.45). There was a significant association for the presence of CAC for highest versus lowest quartiles of both BMI (OR 1.93, 95% CI 1.13-3.28) and WC (OR 1.75, 95% CI 1.05 2.92), although the trend for the presence of CAC was significant only across increasing BMI quartiles, even in models that included WC. CONCLUSIONS: In retired NFL players both BMI and WC were associated with CAC. Higher BMI may be associated with an increasing trend for the presence of CAC independent of WC. PMID- 25279868 TI - Commentary on "association of body mass index and waist circumference with subclinical atherosclerosis in retired NFL players". PMID- 25279869 TI - Aerococcal infection at three US Tertiary Care Hospitals. AB - OBJECTIVES: The aim of the present study was to determine clinical features of Aerococcus infections and the significance of the Aerococcus species isolated from any clinical samples. METHODS: Electronic records of all cultures yielding Aerococcus species from 2002 to 2012 were obtained from three tertiary care hospitals. We performed an in-depth review of medical records. RESULTS: Aerococcus was isolated from >= 1 site in 93 patients. Blood cultures were positive in 64 patients; 15 with definite bacteremia, including 3 with endocarditis, 7 with urinary tract infections, 13 with probable bacteremia, and 36 in which Aerococcus was judged to be a possible contaminant. Of 19 urine isolates, 10 were from patients with symptomatic urinary tract infections and 7 were from patients with asymptomatic bacteriuria; in 2 cases, urine isolates were regarded as possible contaminants. Most patients with urinary isolates had underlying urological abnormalities. Other sources for Aerococcus included synovial fluid, bile, bone, intraabdominal abscess, and ovarian abscess. All of the isolates tested with ampicillin, cefazolin, clindamycin, and vancomycin were susceptible. A total of two patients with definite Aerococcus infection died, but all of the others responded to antibiotic therapy. CONCLUSIONS: Aerococcus often is considered a contaminant; however, in our case series, 35% of cases in which Aerococcus was isolated from any site indicated a definite infection. In patients with positive blood cultures for Aerococcus, at least 23% were associated with infection. Appropriate attention needs to be directed to Aerococcus when it is isolated from a normally sterile site. PMID- 25279870 TI - Emergency department orthopedics observation unit as an alternative to admission. AB - OBJECTIVES: Inclusion of select orthopedic problems in the orthopedics observation unit (OOU) may reduce hospital admissions. Our system allows OOU status for 24 hours, but the effect on admissions is unknown. Our primary hypothesis was that we could predict which OOU patients required admission based on the presence of uncontrolled pain. METHODS: Data were prospectively collected for all OOU patients in this prospective observational study, including data on extremity cellulitis, fractures, and spine injuries awaiting brace placement.The primary outcome variable was admission to the hospital versus discharge home. The a priori hypotheses were that patients with more persistent or worsening pain would require admission more often and that the OOU would result in fewer patients needing a costlier inpatient admission to the hospital. An a priori power analysis showed adequate power of 80% to detect a difference between admitted and discharged patients. RESULTS: Data were prospectively collected from August 2011 to August 2012 for 199 consecutive OOU patients, 62% of whom were men. Diagnoses included infection (cellulitis or abscess of extremity) in 76%, fracture in 15% and other in 9% of the patients. Sixty-two patients (31%) were admitted and 7 patients (4%) made return visits for the same problem within a 30 day period. No significant relations existed between any of the independent variables and admission on bivariate analysis. Multivariable logistic regression found no significant predictors of hospital admission. Logistic regression was not performed on 30-day returns because of the low event rate (4%). CONCLUSIONS: An OOU prevented 138 of 199 (69%) patients from being admitted to a hospital. There were no significant predictors of which patients would require admission. Pain was not a predictor of need for admission. The lack of significant predictors is important in suggesting that without the ability to predict which patients require admission, a system using an OOU can reduce admissions by more than two-thirds. PMID- 25279871 TI - Commentary on "emergency department orthopedics observation unit as an alternative to admission". PMID- 25279872 TI - Hepatitis B screening practice among older Chinese in the Greater Washington, DC, area. AB - OBJECTIVES: Older Chinese Americans are at greater risk of contracting hepatitis B virus (HBV) because they were born before the implementation of universal childhood vaccination policies. This study examined the prevalence of HBV screening, test results, and predictors of HBV screening among older Chinese. METHODS: Two hundred fifty-two Chinese immigrants (older than 50 years) recruited from Chinese-speaking physicians' offices in the Washington, DC, area participated in a cancer screening questionnaire. Descriptive statistics and hierarchical logistic regressions were conducted. RESULTS: Among the 164 participants (65%) who underwent HBV screening, 66% reported that they were susceptible to HBV infection. Stronger self-care beliefs, longer US residency, lower HBV knowledge, and lack of physician recommendations were independently and negatively associated with HBV screening. CONCLUSIONS: Many older Chinese did not adhere to HBV screening guidelines because of cultural views and information deficiency. Culturally appropriate interventions aimed to enhance their knowledge and communication with physicians about HBV are needed for promoting screening. PMID- 25279873 TI - VHA chaplaincy contact with veterans at increased risk of suicide. AB - OBJECTIVES: To examine the extent to which chaplains interact with military veterans at increased risk of suicide and select characteristics related to those at-risk veterans who present for chaplaincy services. METHODS: The nationwide network of chaplains affiliated with the Veterans Health Administration (n = 990) was e-mailed a letter inviting those who have contact with at-risk veterans to complete a survey. This letter included an Internet link, connecting respondents to an online survey collection service. One hundred eighteen chaplains (11.91%) responded to the survey. RESULTS: More than half of the respondents reported that veterans at increased risk of suicide constitute either <5% or 5% to 10% of the overall population of veterans under their care. At-risk veterans are most often identified based on open admission of suicidal behavior or red flags in their treatment file. Veterans typically do not look for chaplains from their own faith tradition, will seek care from >1 chaplain, and present at a moderate-to-high level of risk. CONCLUSIONS: The present study finds that some at-risk veterans look to chaplains for supportive services. The findings also allow for opportunities for future research. PMID- 25279874 TI - Commentary on "VHA chaplaincy contact with veterans at increased risk of suicide". PMID- 25279875 TI - Screening for connective tissue disease in pulmonary arterial hypertension. AB - OBJECTIVES: To evaluate the utility of anti-nuclear antibody (ANA) levels in distinguishing the cause of pulmonary arterial hypertension as idiopathic (IPAH) or connective tissue disease related (CTD-PAH). METHODS: We retrospectively identified patients with IPAH or CTD-PAH seen between 2010 and 2012 at our institution. Medical records were reviewed for demographic and clinical data and laboratory values. RESULTS: Of 115 patients identified, 65 (56%) had IPAH and 50 (44%) had CTD-PAH. The mean age was 59 years and most of the patients (76%) were women. Most patients (64%) were in World Health Organization functional class III or IV. Compared with the IPAH group, the CTD-PAH group had significantly increased B-type natriuretic peptide levels (635 vs 325 pg/mL; P = 0.02) and decreased pulmonary vascular resistance (6 vs 9 WU; P = 0.04). The median ANA level was significantly higher in the CTD-PAH group than the IPAH group (7 vs 0 U; P < 0.001). The area under the receiver operating characteristic curve for a positive ANA to predict CTD-PAH was 0.91 (P < 0.001). A cutoff of 5 U for predicting ANA provided an optimal specificity of 94% and a sensitivity of 70%. The resulting likelihood ratio using the same cutoff was 12 (P < 0.001), or a positive predictive value of 91% with a negative predictive value of 79%. CONCLUSIONS: In this selected cohort of patients, a quantitative ANA value >5 U may be useful in distinguishing CTD-PAH from IPAH, but a lower level does not confidently exclude CTD-PAH. PMID- 25279877 TI - Giant cervical polyps: Three cases with different pathologies. PMID- 25279878 TI - Warming up. PMID- 25279879 TI - Retraction challenges. PMID- 25279880 TI - BRAIN gain. PMID- 25279881 TI - Water politics must adapt to a warming world. PMID- 25279893 TI - Fast genetic sequencing saves newborn lives. PMID- 25279894 TI - Biopiracy ban stirs red-tape fears. PMID- 25279895 TI - Ebola obstructs malaria control. PMID- 25279896 TI - Tibetan plateau gets wired up for monsoon prediction. PMID- 25279897 TI - Forensic chemistry could stop African-plant thieves. PMID- 25279899 TI - Data bounty spurs debate. PMID- 25279900 TI - Astronomy: To catch a cosmic ray. PMID- 25279901 TI - The first South Americans: Extreme living. PMID- 25279902 TI - Resources: Curb vast water use in central Asia. PMID- 25279903 TI - Climate policy: Ditch the 2 degrees C warming goal. PMID- 25279907 TI - Preventative care: Lung-cancer screens now worth the cost. PMID- 25279908 TI - Scientific misconduct: Research integrity guidelines in Japan. PMID- 25279909 TI - Psychosocial models: Focus on positive features of ageing. PMID- 25279910 TI - Society: Protect privacy of mobile data. PMID- 25279911 TI - Environment: Invest in renewable energy in Tibet. PMID- 25279912 TI - Geoscience: The plumbing of Greenland's ice. PMID- 25279913 TI - Solar system: Not just a storm in a teacup. PMID- 25279915 TI - Astronomy: The age of the quasars. PMID- 25279916 TI - Microbiology: An integrated view of the skin microbiome. PMID- 25279918 TI - HCN ice in Titan's high-altitude southern polar cloud. AB - Titan's middle atmosphere is currently experiencing a rapid change of season after northern spring arrived in 2009 (refs 1, 2). A large cloud was observed for the first time above Titan's southern pole in May 2012, at an altitude of 300 kilometres. A temperature maximum was previously observed there, and condensation was not expected for any of Titan's atmospheric gases. Here we report that this cloud is composed of micrometre-sized particles of frozen hydrogen cyanide (HCN ice). The presence of HCN particles at this altitude, together with temperature determinations from mid-infrared observations, indicate a dramatic cooling of Titan's atmosphere inside the winter polar vortex in early 2012. Such cooling is in contrast to previously measured high-altitude warming in the polar vortex, and temperatures are a hundred degrees colder than predicted by circulation models. These results show that post-equinox cooling at the winter pole of Titan is much more efficient than previously thought. PMID- 25279919 TI - Structure and evolution of the lunar Procellarum region as revealed by GRAIL gravity data. AB - The Procellarum region is a broad area on the nearside of the Moon that is characterized by low elevations, thin crust, and high surface concentrations of the heat-producing elements uranium, thorium, and potassium. The region has been interpreted as an ancient impact basin approximately 3,200 kilometres in diameter, although supporting evidence at the surface would have been largely obscured as a result of the great antiquity and poor preservation of any diagnostic features. Here we use data from the Gravity Recovery and Interior Laboratory (GRAIL) mission to examine the subsurface structure of Procellarum. The Bouguer gravity anomalies and gravity gradients reveal a pattern of narrow linear anomalies that border Procellarum and are interpreted to be the frozen remnants of lava-filled rifts and the underlying feeder dykes that served as the magma plumbing system for much of the nearside mare volcanism. The discontinuous surface structures that were earlier interpreted as remnants of an impact basin rim are shown in GRAIL data to be a part of this continuous set of border structures in a quasi-rectangular pattern with angular intersections, contrary to the expected circular or elliptical shape of an impact basin. The spatial pattern of magmatic-tectonic structures bounding Procellarum is consistent with their formation in response to thermal stresses produced by the differential cooling of the province relative to its surroundings, coupled with magmatic activity driven by the greater-than-average heat flux in the region. PMID- 25279920 TI - Experimental realization of universal geometric quantum gates with solid-state spins. AB - Experimental realization of a universal set of quantum logic gates is the central requirement for the implementation of a quantum computer. In an 'all-geometric' approach to quantum computation, the quantum gates are implemented using Berry phases and their non-Abelian extensions, holonomies, from geometric transformation of quantum states in the Hilbert space. Apart from its fundamental interest and rich mathematical structure, the geometric approach has some built in noise-resilience features. On the experimental side, geometric phases and holonomies have been observed in thermal ensembles of liquid molecules using nuclear magnetic resonance; however, such systems are known to be non-scalable for the purposes of quantum computing. There are proposals to implement geometric quantum computation in scalable experimental platforms such as trapped ions, superconducting quantum bits and quantum dots, and a recent experiment has realized geometric single-bit gates in a superconducting system. Here we report the experimental realization of a universal set of geometric quantum gates using the solid-state spins of diamond nitrogen-vacancy centres. These diamond defects provide a scalable experimental platform with the potential for room-temperature quantum computing, which has attracted strong interest in recent years. Our experiment shows that all-geometric and potentially robust quantum computation can be realized with solid-state spin quantum bits, making use of recent advances in the coherent control of this system. PMID- 25279917 TI - Biogeography and individuality shape function in the human skin metagenome. AB - The varied topography of human skin offers a unique opportunity to study how the body's microenvironments influence the functional and taxonomic composition of microbial communities. Phylogenetic marker gene-based studies have identified many bacteria and fungi that colonize distinct skin niches. Here metagenomic analyses of diverse body sites in healthy humans demonstrate that local biogeography and strong individuality define the skin microbiome. We developed a relational analysis of bacterial, fungal and viral communities, which showed not only site specificity but also individual signatures. We further identified strain-level variation of dominant species as heterogeneous and multiphyletic. Reference-free analyses captured the uncharacterized metagenome through the development of a multi-kingdom gene catalogue, which was used to uncover genetic signatures of species lacking reference genomes. This work is foundational for human disease studies investigating inter-kingdom interactions, metabolic changes and strain tracking, and defines the dual influence of biogeography and individuality on microbial composition and function. PMID- 25279921 TI - Direct observations of evolving subglacial drainage beneath the Greenland Ice Sheet. AB - Seasonal acceleration of the Greenland Ice Sheet is influenced by the dynamic response of the subglacial hydrologic system to variability in meltwater delivery to the bed via crevasses and moulins (vertical conduits connecting supraglacial water to the bed of the ice sheet). As the melt season progresses, the subglacial hydrologic system drains supraglacial meltwater more efficiently, decreasing basal water pressure and moderating the ice velocity response to surface melting. However, limited direct observations of subglacial water pressure mean that the spatiotemporal evolution of the subglacial hydrologic system remains poorly understood. Here we show that ice velocity is well correlated with moulin hydraulic head but is out of phase with that of nearby (0.3-2 kilometres away) boreholes, indicating that moulins connect to an efficient, channelized component of the subglacial hydrologic system, which exerts the primary control on diurnal and multi-day changes in ice velocity. Our simultaneous measurements of moulin and borehole hydraulic head and ice velocity in the Paakitsoq region of western Greenland show that decreasing trends in ice velocity during the latter part of the melt season cannot be explained by changes in the ability of moulin-connected channels to convey supraglacial melt. Instead, these observations suggest that decreasing late-season ice velocity may be caused by changes in connectivity in unchannelized regions of the subglacial hydrologic system. Understanding this spatiotemporal variability in subglacial pressures is increasingly important because melt-season dynamics affect ice velocity beyond the conclusion of the melt season. PMID- 25279924 TI - Scientific writing: the online cooperative. PMID- 25279926 TI - Inhibition of demethylases by GSK-J1/J4. PMID- 25279927 TI - Kruidenier et al. reply. PMID- 25279928 TI - Another explanation for apparent epistasis. PMID- 25279929 TI - Hemani et al. reply. PMID- 25279930 TI - Sedation monitoring during open muscle biopsy in children by Comfort Score and Bispectral Index - a prospective analysis. AB - BACKGROUND: Open muscle biopsies in children are generally performed under general anesthesia. Alternatively, deep sedation and analgesia may be required. OBJECTIVES: The aim of our study was to compare the Bispectral Index (BIS) and Comfort Score (CS) with respect to their clinical significance for sedation/analgesia in children undergoing open muscle biopsy. METHODS: Thirty pediatric patients subjected to open muscle biopsy for diagnosis of their underlying disease were prospectively enrolled. Sedation/analgesia was performed in all patients using remifentanil and propofol. The patients were simultaneously monitored using the CS and BIS. RESULTS: All sedations and muscle biopsies were performed uneventfully. The CS and BIS were significantly correlated (R = 0.589; P < 0.01). Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.918 with a maximum cut-off point of BIS 70.5 (sensitivity 0.9; specificity 0.785) for adequate sedation. Sensitivity of 100% was achieved at BIS 60. Accordingly, all patients with BIS <=60 had CS within the target range of 10-14. The BIS showed substantial intra- and interindividual variability (30 points and 58 points, respectively) during sedation, whereas CS varied only within close ranges during sedation. In 25 patients, sedatives were reduced according to low BIS values (<60). No unintended anesthesia awareness was noted during the study period. CONCLUSION: Bispectral Index provides an additional helpful tool to guide sedation/analgesia in minor surgical procedures in children. BIS values <=60 correlated with sufficient depth of sedation and prevented unintended awareness. Additionally, BIS measurement allowed for distinct regulation of depth of sedation without prolonged sedation/analgesia due to unintended overdose. PMID- 25279932 TI - Influence of different light-dark cycles on motility and photosynthesis of Euglena gracilis in closed bioreactors. AB - Abstract The unicellular photosynthetic freshwater flagellate Euglena gracilis is a promising candidate as an oxygen producer in biological life-support systems. In this study, the capacity of Euglena gracilis to cope with different light regimes was determined. Cultures of Euglena gracilis in closed bioreactors were exposed to different dark-light cycles (40 W/m(2) light intensity on the surface of the 20 L reactor; cool white fluorescent lamps in combination with a 100 W filament bulb): 1 h-1 h, 2 h-2 h, 4 h-4 h, 6 h-6 h, and 8 h-16 h, respectively. Motility and oxygen development in the reactors were measured constantly. It was found that, during exposure to light-dark cycles of 1 h-1 h, 2 h-2 h, 4 h-4 h, and 6 h-6 h, precision of gravitaxis as well as the number of motile cells increased during the dark phase, while velocity increased in the light phase. Oxygen concentration did not yet reach a plateau phase. During dark-light cycles of 8 h-16 h, fast changes of movement behavior in the cells were detected. The cells showed an initial decrease of graviorientation after onset of light and an increase after the start of the dark period. In the course of the light phase, graviorientation increased, while motility and velocity decreased after some hours of illumination. In all light profiles, Euglena gracilis was able to produce sufficient oxygen in the light phase to maintain the oxygen concentration above zero in the subsequent dark phase. PMID- 25279933 TI - Produced water exposure alters bacterial response to biocides. AB - Microbial activity during the holding and reuse of wastewater from hydraulic fracturing operations, termed produced water, may lead to issues with corrosion, sulfide release, and fouling. Biocides are applied to control biological activity, often with limited efficacy, which is typically attributed to chemical interactions with the produced water. However, it is unknown whether there is a biologically driven mechanism to biocide tolerance in produced water. Here, we demonstrate that produced water exposure results in an enhanced tolerance against the typically used biocide glutaraldehyde and increased susceptibility to the oxidative biocide hypochlorite in a native and a model bacteria and that this altered resistance is due to the salinity of the produced water. In addition, we elucidate the genetic response of the model organism Pseudomonas fluorescens to produced water exposure to provide a mechanistic interpretation of the altered biocide resistance. The RNA-seq data demonstrated the induction of genes involved in osmotic stress, energy production and conversion, membrane integrity, and protein transport following produced water exposure, which facilitates bacterial survival and alters biocide tolerance. Efforts to fundamentally understand biocide resistance mechanisms, which enable the optimization of biocide application, hold significant implications for greening of the fracturing process through encouraging produced water recycling. Specifically, these results suggest the necessity of optimizing biocide application at the level of individual shale plays, rather than historical experience, based upon produced water characteristics and salinity. PMID- 25279934 TI - Irreversible trimer to monomer transition of thermophilic rhodopsin upon thermal stimulation. AB - Assembly is one of the keys to understand biological molecules, and it takes place in spatial and temporal domains upon stimulation. Microbial rhodopsin (also called retinal protein) is a membrane-embedded protein that has a retinal chromophore within seven-transmembrane alpha-helices and shows homo-, di-, tri-, penta-, and hexameric assemblies. Those assemblies are closely related to critical physiological properties such as stabilizing the protein structure and regulating their photoreaction dynamics. Here we investigated the assembly and disassembly of thermophilic rhodopsin (TR), which is a novel proton-pumping rhodopsin derived from a thermophile living at 75 degrees C. TR was characterized using size-exclusion chromatography and circular dichroism spectroscopy, and formed a trimer at 25 degrees C, but irreversibly dissociated into monomers upon thermal stimulation. The transition temperature was estimated to be 68 degrees C. The irreversible nature made it possible to investigate the photochemical properties of both the trimer and the monomer independently. Compared with the trimer, the absorption maximum of the monomer is blue-shifted by 6 nm without any changes in the retinal composition, pKa value for the counterion or the sequence of the proton movement. The photocycling rate of the monomeric TR was similar to that of the trimeric TR. A similar trimer-monomer transition upon thermal stimulation was observed for another eubacterial rhodopsin GR but not for the archaeal rhodopsins AR3 and HwBR, suggesting that the transition is conserved in bacterial rhodopsins. Thus, the thermal stimulation of TR induces the irreversible disassembly of the trimer. PMID- 25279936 TI - Curved adjustable fiberoptic laser for endoscopic cholesteatoma surgery. AB - OBJECTIVE: To determine whether endoscopic cholesteatoma removal can be performed efficiently and safely using a curved fiberoptic-based laser. BACKGROUND: Angled instruments are required in endoscopic ear surgery to access recesses of the middle ear without extra drilling. Lasers are effective at ablating visible and microscopic cholesteatoma matrix and removing granulation tissue. STUDY DESIGN: Retrospective case review from 2006 to 2013. SETTING: Single tertiary care center. PATIENTS: Patients who underwent cholesteatoma surgery with otoendoscopy. INTERVENTION: Residual cholesteatoma that could not be reached by conventional microinstruments was identified using an endoscope. This residual cholesteatoma was ablated in a contactless manner using a fiberoptic-based curved laser carrier with an argon laser. The laser tip through the carrier probe has a 45-degree curve, and the length of the tip is adjustable, allowing it to be used in recesses or around corners, such as in the sinus tympani, around the stapes suprastructure, in the oval window, or in the Eustachian tube orifice. MAIN OUTCOME MEASURES: Presence or absence of residual cholesteatoma after laser ablation and complications. RESULTS: In 7 cases, the fiberoptic curved laser was used to ablate cholesteatoma completely with no injury to surrounding structures and with no evidence of recidivism with a mean follow-up period of 19 months. There were no cases of sensorineural hearing loss or perilymphatic fistula. CONCLUSION: The curved laser probe allows for precise removal of cholesteatoma endoscopically. PMID- 25279935 TI - Prevalence and use of complementary health approaches among women with chronic pelvic pain in a prospective cohort study. AB - OBJECTIVE: The aim of this study was to examine the prevalence of and factors associated with use of complementary health approaches among women with chronic pelvic pain (CPP). DESIGN: We analyzed data from the Study of Pelvic Problems, Hysterectomy, and Intervention Alternatives, a prospective cohort study of women seeking care for noncancerous pelvic problems with intact uteri at enrollment. Among a subset of 699 participants who reported having CPP, we analyzed the prevalence of complementary health approaches used and associated patient sociodemographic and clinical characteristics, health-related quality of life, attitudes and beliefs, and conventional health care practices. RESULTS: At baseline, slightly over one-half (51%) of women with CPP used at least one complementary health approach in the past year, including acupuncture (8%), special foods or diets (22%), herbs (27%), and vitamins and minerals (29%). During follow-up surveys conducted annually for 4 years, a substantial proportion of women (44.8%) used complementary health approaches at more than half of the assessments. Users of complementary health approaches were more likely to undergo a hysterectomy or oophorectomy or to use gonadotropin-releasing hormone agonists or opioids during the study compared with nonusers. Women with CPP who used complementary health approaches also had more optimal health-related quality of life measured by the Pelvic Problem Impact Questionnaire (31.6 vs 25.6, P < 0.001). CONCLUSION(S): Many women with CPP consistently use complementary health approaches. The substantial interest in and high prevalence of complementary health approaches used alongside conventional medical approaches highlight the need for better understanding of multimodal approaches to address the complex condition of CPP. PMID- 25279937 TI - A method to quantitate the neutralizing capacity of anti-therapeutic protein antibodies in serum and their correlation to clinical impact. AB - A robust, quantitative method for assessing the neutralizing capacity of anti therapeutic protein antibodies was developed and tested using 4 analytical assay platforms typically used for detection of anti-drug neutralizing antibodies. The method described here utilized titration of increasing concentrations of therapeutic protein into serum containing anti-therapeutic protein antibodies, either positive control antibodies or clinical samples. Neutralizing capacities were calculated by determining the EC50 from the titration curves. The neutralizing capacity of purified anti therapeutic protein antibodies was expressed in terms of "MUg of drug neutralized per MUg of anti-TP antibody" present. In the case of serum originating from clinical study subjects, the neutralizing capacity of the samples was expressed as "MUg of drug neutralized per mL of serum". A relative shift in EC50 values was observed as the amount of serum or antibody was changed resulting in a proportional shift of the calculated neutralizing capacity. Application of this approach using different assay platforms was consistent providing evidence for its potential to be a useful approach to characterize, qualify and compare neutralizing positive control antibody preparations or clinical samples. Using this methodology, we were able to draw a clear correlation between the neutralizing capacity and the effect of these antibodies on a clinical pharmacodynamic (PD) marker. Determination of the neutralizing capacity of antibody positive samples from subjects in a clinical study indicated direct correlation of pharmacodynamic results with non-response, partial response and response to high, mid and low neutralizing capacities respectively. PMID- 25279940 TI - Photocatalytic metal-organic framework from CdS quantum dot incubated luminescent metallohydrogel. AB - Cadmium sulfide (CdS) quantum dots (<10 nm in size) have been successfully synthesized in situ without any capping agent in a Zn(II)-based low-molecular weight metallohydrogel (ZAVA). Pristine ZAVA hydrogel shows blue luminescence, but the emission can be tuned upon encapsulation of the CdS quantum dots. Time dependent tunable emission (white to yellow to orange) of the CdS incubated gel (CdS@ZAVA gel) can be attributed to sluggish growth of the quantum dots inside the gel matrix. Once CdS quantum dots are entrapped, their augmentation can be stopped by converting the gel into xerogel, wherein the quantum dots remains embedded in the solid xerogel matrix. Similar size stabilization of CdS quantum dots can be achieved by means of a unique room-temperature conversion of the CdS incubated ZAVA gel to CdS incubated MOF (CdS@ZAVCl) crystals. This in turn arrests the tunability in emission owing to the restriction in the growth of CdS quantum dots inside xerogel and MOF. These CdS embedded MOFs have been utilized as a catalyst for water splitting under visible light. PMID- 25279939 TI - Sleep quality during exam stress: the role of alcohol, caffeine and nicotine. AB - Academic exam stress is known to compromise sleep quality and alter drug consumption in university students. Here we evaluated if sleeping problems and changes in legal drug consumption during exam stress are interrelated. We used the Pittsburgh Sleep Quality Index (PSQI) to survey sleep quality before, during, and after an academic exam period in 150 university students in a longitudinal questionnaire study. Self-reports of alcohol, caffeine, and nicotine consumption were obtained. The Perceived Stress Questionnaire (PSQ-20) was used as a measure of stress. Sleep quality and alcohol consumption significantly decreased, while perceived stress and caffeine consumption significantly increased during the exam period. No significant change in nicotine consumption was observed. In particular, students shortened their time in bed and showed symptoms of insomnia. Mixed model analysis indicated that sex, age, health status, as well as the amounts of alcohol and caffeine consumed had no significant influence on global sleep quality. The amount of nicotine consumed and perceived stress were identified as significant predictors of diminished sleep quality. Nicotine consumption had a small-to-very-small effect on sleep quality; perceived stress had a small-to-moderate effect. In conclusion, diminished sleep quality during exam periods was mainly predicted by perceived stress, while legal drug consumption played a minor role. Exam periods may pose an interesting model for the study of stress-induced sleeping problems and their mechanisms. PMID- 25279938 TI - Psychosocial assessments for HIV+ African adolescents: establishing construct validity and exploring under-appreciated correlates of adherence. AB - STUDY OBJECTIVES: Psychosocial factors such as outcome expectancy, perceived stigma, socio-emotional support, consideration of future consequences, and psychological reactance likely influence adolescent adherence to antiretroviral treatments. Culturally-adapted and validated tools for measuring these factors in African adolescents are lacking. We aimed to identify culturally-specific factors of importance to establishing local construct validity in Botswana. METHODS: Using in-depth interviews of 34 HIV+ adolescents, we explored how the psychosocial factors listed above are perceived in this cultural context. We evaluated six scales that have been validated in other contexts. We also probed for additional factors that the adolescents considered important to their HIV medication adherence. Analyses were conducted with an analytic framework approach using NVivo9 software. RESULTS: While the construct validity of some Western derived assessment tools was confirmed, other tools were poorly representative of their constructs in this cultural context. Tools chosen to evaluate HIV-related outcome expectancy and perceived stigma were well-understood and relevant to the adolescents. Feedback from the adolescents suggested that tools to measure all other constructs need major modifications to obtain construct validity in Botswana. The scale regarding future consequences was poorly understood and contained several items that lacked relevance for the Batswana adolescents. They thought psychological reactance played an important role in adherence, but did not relate well to many components of the reactance scale. Measurement of socio emotional support needs to focus on the adolescent-parent relationship, rather than peer-support in this cultural context. Denial of being HIV-infected was an unexpectedly common theme. Ambivalence about taking medicines was also expressed. DISCUSSION: In-depth interviews of Batswana adolescents confirmed the construct validity of some Western-developed psychosocial assessment tools, but demonstrated limitations in others. Previously underappreciated factors related to HIV medication adherence, such as denial and ambivalence, should be further explored. PMID- 25279941 TI - A sensitive method for the analysis of glutathione in porcine hepatocytes. AB - BACKGROUND: Reduced glutathione (gamma-glutamylcysteinylglycine), GSH, is essential when protecting cells from oxidative stress and also an indicator of disease risk. Reported concentrations of GSH and its oxidized form, glutathione disulfide (GSSG), varies considerably, primarily due to the instability of GSH and various analytical methods. METHODS: We designed a sensitive method to analyze GSH and GSSG in porcine hepatocytes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) after stabilization with N-ethylmaleimide (NEM). This method includes stable isotope labeled internal standards and simple synthesis of labeled GSSG which commercial sources rarely offer. GSH and GSSG were analyzed in porcine liver biopsies giving a reference interval based on a large number of samples (26 pigs; 3 parallels). RESULTS: The LC-MS/MS results revealed excellent linearity for both GSH and GSSG, with interday coefficient of variation (%CV) for GSH-NEM and GSSG <10 %. Accuracy for recovery tests was between 95.6% and 106.7% (n = 3) for GSH and between 92.3% and 107.7% (n = 3) for GSSG. The limits of quantification were 0.1 MUM for GSH-NEM and 0.08 MUM for GSSG. The mean concentration of GSH was 3.5 (95% CI = 1.5-8.1) mmol/liter and of GSSG 0.0023 (95% CI = 0.0003-0.019) mmol/liter. CONCLUSION: For the first time GSH and GSSG are analyzed in porcine hepatocytes by LC-MS/MS yielding a reference level of GSH and GSSG. The method is reproducible in any laboratory with LC-MS/MS service and will probably be applicable in all soft tissues and cell suspensions, essentially with no modification. PMID- 25279942 TI - The polycomb group gene EMF2B is essential for maintenance of floral meristem determinacy in rice. AB - Polycomb Repressive Complex 2 (PRC2) represses the transcriptional activity of target genes through trimethylation of lysine 27 of histone H3. The functions of plant PRC2 have been chiefly described in Arabidopsis, but specific functions in other plant species, especially cereals, are still largely unknown. Here we characterize mutants in the rice EMF2B gene, an ortholog of the Arabidopsis EMBRYONIC FLOWER2 (EMF2) gene. Loss of EMF2B in rice results in complete sterility, and mutant flowers have severe floral organ defects and indeterminacy that resemble loss-of-function mutants in E-function floral organ specification genes. Transcriptome analysis identified the E-function genes OsMADS1, OsMADS6 and OsMADS34 as differentially expressed in the emf2b mutant compared with wild type. OsMADS1 and OsMADS6, known to be required for meristem determinacy in rice, have reduced expression in the emf2b mutant, whereas OsMADS34 which interacts genetically with OsMADS1 was ectopically expressed. Chromatin immunoprecipitation for H3K27me3 followed by quantitative (q)RT-PCR showed that all three genes are presumptive targets of PRC2 in the meristem. Therefore, in rice, and possibly other cereals, PRC2 appears to play a major role in floral meristem determinacy through modulation of the expression of E-function genes. PMID- 25279943 TI - Biohybrid polymer-antimicrobial peptide medium against Enterococcus faecalis. AB - Antimicrobial peptides (AMPs) are conserved evolutionary components of the innate immune system that are being tested as alternatives to antibiotics. Slow release of AMPs using biodegradable polymers can be advantageous in maintaining high peptide levels for topical treatment, especially in the oral environment in which dosage retention is challenged by drug dilution with saliva flow and by drug inactivation by salivary enzymatic activity. Enterococcus faecalis is a multidrug resistant nosocomial pathogen and a persistent pathogen in root canal infections. In this study, four ultra-short lipopeptides (C16-KGGK, C16-KLLK, C16-KAAK and C16-KKK) and an amphipathic alpha-helical antimicrobial peptide (Amp-1D) were tested against E. faecalis. The antibacterial effect was determined against planktonic bacteria and bacteria grown in biofilm. Of the five tested AMPs, C16 KGGK was the most effective. Next C16-KGGK was formulated with one of two polymers poly (lactic acid co castor oil) (DLLA) or ricinoleic acid-based poly (ester-anhydride) P(SA-RA). Peptide-synthetic polymer conjugates, also referred to as biohybrid mediums were tested for antibacterial activity against E. faecalis grown in suspension and in biofilms. The new formulations exhibited strong and improved anti-E. faecalis activity. PMID- 25279945 TI - Hair pigmentation disorders or 50 years of German-Polish alliance for study on a severe side effect of chemotherapy: Kostanecki's legacy. PMID- 25279944 TI - Transcriptional responses of olive flounder (Paralichthys olivaceus) to low temperature. AB - The olive flounder (Paralichthys olivaceus) is an economically important flatfish in marine aquaculture with a broad thermal tolerance ranging from 14 to 23 degrees C. Cold-tolerant flounder that can survive during the winter season at a temperature of less than 14 degrees C might facilitate the understanding of the mechanisms underlying the response to cold stress. In this study, the transcriptional response of flounder to cold stress (0.7+/-0.05 degrees C) was characterized using RNA sequencing. Transcriptome sequencing was performed using the Illumina MiSeq platform for the cold-tolerant (CT) group, which survived under the cold stress; the cold-sensitive (CS) group, which could barely survive at the low temperature; and control group, which was not subjected to cold treatment. In all, 29,021 unigenes were generated. Compared with the unigene expression profile of the control group, 410 unigenes were up-regulated and 255 unigenes were down-regulated in the CT group, whereas 593 unigenes were up regulated and 289 unigenes were down-regulated in the CS group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that signal transduction, lipid metabolism, digestive system, and signaling molecules and interaction were the most highly enriched pathways for the genes that were differentially expressed under cold stress. All these pathways could be assigned to the following four biological functions for flounder that can survive under cold stress: signal response to cold stress, cell repair/regeneration, energy production, and cell membrane construction and fluidity. PMID- 25279946 TI - Stable isotopes in fish eye lenses as potential recorders of trophic and geographic history. AB - We evaluated eye lenses as potential recorders of stable isotope histories in fish because they consist of metabolically inert optical proteins that are deposited in successive, concentric circles (laminae) much like otolith circuli and tree rings. We conducted four different tests on lenses from red snapper, red grouper, gag, and white grunt. The first test was a low-resolution screening of multiple individuals (4-5 radial groups of laminae per lens, all species except white grunt). Along the radial axis, all individuals exhibited substantial isotopic variability. Red snapper individuals separated into two groups based on delta15N and gag separated into two groups based on delta13C. Two gag with the greatest variation were chosen for high-resolution temporal analysis using individual laminae from their second eye lenses. The first-order patterns from the high-resolution analysis generally mimicked patterns from the low-resolution screening of grouped laminae, yet the high-resolution plots revealed early-life details that were not apparent in the low-resolution screenings. For the third test, left- versus right-eye variation was compared using high-resolution methods. White grunt left- and right-eye radial isotopic patterns were almost identical for both delta13C and delta15N, suggesting the variations observed among individual fish were not artifacts. The final test evaluated intra-laminar variation; multiple samples were analyzed from different parts of the same lamina. Seven laminae from three individuals of two species were analyzed in this manner; variations among laminae were found to be much higher than variations within laminae. However, nominal intra-laminar variations were comparable to nominal differences between left and right lenses, suggesting intra-laminar variation established measurement precision. Eye lens isotopes appear to be useful for reconstructing the isotopic histories of individual fish; these histories can be compared with spatially-derived isoscapes to reconstruct individual histories for site fidelity, movement and trophic position. PMID- 25279948 TI - Complex reaction dynamics in the cerium-bromate-2-methyl-1,4-hydroquinone photoreaction. AB - Spontaneous oscillations with a long induction time were observed in the bromate 2-methyl-1,4-hydroquinone photoreaction in a batch reactor, where removal of illumination effectively quenched any reactivity. A substantial lengthening of the oscillatory window and a dramatic increase in the complexity of the reaction behavior arose upon the addition of cerium ions, in which separate bifurcation regions and mixed mode oscillations were present. The complexity has a strong dependence on the intensity of illumination supplied to the system and on the initial concentrations of the reactants. (1)H NMR spectroscopy measurements show that the photoreduction of 2-methyl-1,4-benzoquinone leads to the formation of 2 methyl-1,4-hydroquinone and the compound 2-hydroxy-3-methyl-1,4-benzoquinone. Spectroscopic investigation also indicates that the presence of methyl group hinders the bromination of the studied organic substrate 2-methyl-1,4 hydroquinone, resulting in the formation of 2-methyl-1,4-benzoquinone. PMID- 25279947 TI - Cost trend analysis of initial cancer treatment in Taiwan. AB - BACKGROUND: Despite the high cost of initial cancer care, that is, care in the first year after diagnosis, limited information is available for specific categories of cancer-related costs, especially costs for specific services. This study purposed to identify causes of change in cancer treatment costs over time and to perform trend analyses of the percentage of cancer patients who had received a specific treatment type and the mean cost of care for patients who had received that treatment. METHODOLOGY/PRINCIPAL FINDINGS: The analysis of trends in initial treatment costs focused on cancer-related surgery, chemotherapy, radiation therapy, and treatments other than active treatments. For each cancer specific trend, slopes were calculated for regression models with 95% confidence intervals. Analyses of patients diagnosed in 2007 showed that the National Health Insurance (NHI) system paid, on average, $10,780 for initial care of a gastric cancer patient and $10,681 for initial care of a lung cancer patient, which were inflation-adjusted increases of $6,234 and $5,522, respectively, over the 1996 care costs. During the same interval, the mean NHI payment for initial care for the five specific cancers increased significantly (p<0.05). Hospitalization costs comprised the largest portion of payments for all cancers. During 1996-2007, the use of chemotherapy and radiation therapy significantly increased in all cancer types (p<0.05). In 2007, NHI payments for initial care for these five cancers exceeded $12 billion, and gastric and lung cancers accounted for the largest share. CONCLUSIONS/SIGNIFICANCE: In addition to the growing number of NHI beneficiaries with cancer, treatment costs and the percentage of patients who undergo treatment are growing. Therefore, the NHI must accurately predict the economic burden of new chemotherapy agents and radiation therapies and may need to develop programs for stratifying patients according to their potential benefit from these expensive treatments. PMID- 25279950 TI - Intracellular Na(+) inhibits volume-regulated anion channel in rat cortical astrocytes. AB - Accumulating evidence indicates that increased intracellular Na(+) concentration ([Na(+) ]i ) in astroglial cells is associated with the development of brain edema under ischemic conditions, but the underlying mechanisms are still elusive. Here, we report that in primary cultured rat cortical astrocytes, elevations of [Na(+) ]i reflecting those achieved during ischemia cause a marked decrease in hypotonicity-evoked current mediated by volume-regulated anion channel (VRAC). Pharmacological manipulations revealed that VRAC inhibition was not due to the reverse mode of the plasma membrane sodium/calcium exchanger. The negative modulation of VRAC was also observed in an astrocytic cell line lacking the predominant astrocyte water channel aquaporin 4, indicating that [Na(+) ]i effect was not mediated by the regulation of aquaporin 4 activity. The inward rectifier Cl(-) current, which is also expressed by cultured astrocytes, was not affected by [Na(+) ]i increase. VRAC depression by high [Na(+) ]i was confirmed in adult astrocytes, suggesting that it was not developmentally regulated. Altogether, these results provide the first evidence that intracellular Na(+) dynamics can modulate astrocytic membrane conductance that controls functional processes linked to cell volume regulation and add further support to the concept that limiting astrocyte intracellular Na(+) accumulation might be a favorable strategy to counteract the development of brain edema. PMID- 25279949 TI - Characterization of the Neurospora crassa cell fusion proteins, HAM-6, HAM-7, HAM 8, HAM-9, HAM-10, AMPH-1 and WHI-2. AB - Intercellular communication of vegetative cells and their subsequent cell fusion is vital for different aspects of growth, fitness, and differentiation of filamentous fungi. Cell fusion between germinating spores is important for early colony establishment, while hyphal fusion in the mature colony facilitates the movement of resources and organelles throughout an established colony. Approximately 50 proteins have been shown to be important for somatic cell-cell communication and fusion in the model filamentous fungus Neurospora crassa. Genetic, biochemical, and microscopic techniques were used to characterize the functions of seven previously poorly characterized cell fusion proteins. HAM-6, HAM-7 and HAM-8 share functional characteristics and are proposed to function in the same signaling network. Our data suggest that these proteins may form a sensor complex at the cell wall/plasma membrane for the MAK-1 cell wall integrity mitogen-activated protein kinase (MAPK) pathway. We also demonstrate that HAM-9, HAM-10, AMPH-1 and WHI-2 have more general functions and are required for normal growth and development. The activation status of the MAK-1 and MAK-2 MAPK pathways are altered in mutants lacking these proteins. We propose that these proteins may function to coordinate the activities of the two MAPK modules with other signaling pathways during cell fusion. PMID- 25279951 TI - Synthesis and characterization of a trisheteroleptic Ru(II) -based molecular switch. AB - The synthesis of a trisheteroleptic ruthenium complex [Ru(tb)(dppz)(tmbiH2 )][PF6 ]2 (tb=4,4'-di-tert-butyl-2,2'-bipyridine, dppz=dipyrido[3,2-a:2',3'-c]phenazin, tmbiH2 =5,6,5',6'-tetramethyl-2,2'-bibenzimidazole) is described. In addition, the structural characterisation by means of 1D, 2D (1) H NMR spectroscopy, and mass spectrometry, along with determination of the solid-state structure of the important precursor Ru(tb)(dppz)Cl2 , supports the proposed octahedral coordination geometry. The capability of tmbiH2 to form hydrogen bonds is corroborated by the solid-state structure. The photochemical characteristics of this complex can be described as a combination of the "light switch" effects, which are either attributed to the dppz or to the tmbiH2 ligand. To illustrate the molecule's double switchable features, steady-state absorption and emission measurements were performed, which include the determination of the quantum yield and the pKa values of the acidic protons of the tmbiH2 ligand. Notably, the emission lifetimes are sensitive to the solvents used. This phenomenon is due to a proton-coupled deactivation of the excited metal-to-ligand charge transfer (MLCT) state of the complex. PMID- 25279952 TI - Synthesis of a novel core-shell nanocomposite Ag@SiO2@Lu2O3:Gd/Yb/Er for large enhancing upconversion luminescence and bioimaging. AB - Upconversion nanocrystals have many advantages over other fluorescent materials. However, their upconversion luminescence intensities are not desirable, limiting their applications for highly sensitive detection. Therefore, it is really important to enhance upconversion luminescent intensities of upconversion nanocrystals. In the present study, a novel Ag core and upconversion nanocrystal shell based nanocomposite Ag@SiO2@Lu2O3:Gd/Yb/Er for metal-enhanced upconversion luminescence was fabricated successfully, and its morphology, crystalline phase, composition, optical property, and cell imaging application were investigated. It was found that a maximum upconversion luminescence enhancement of 30-fold was obtained in comparison with the control without a silver core, and the nanocomposite exhibited bright upconversion luminescence when it was used for imaging with HeLa cells. This enhancement potentially increases the overall upconversion nanocrystal detectability, endowing the nanocomposite with a potential capability for highly sensitive biological, medical, and optical detection. PMID- 25279953 TI - Selective and sensitive platform for function-based screening of potentially harmful furans. AB - Many furan-containing compounds have been reported to be toxic and/or carcinogenic. Furanoids have been found in a wide range of fruits, herbs, foods, and beverages. The risks for intake of toxic furans have been rising, due to the rapid growth of globe-wide consumption of natural products. The objective of the study was to develop an analytical platform to screen cis-enediones (cis-enedials or gamma-ketoenals) resulting from metabolic activation of potentially harmful furans. 2,5-Dimethylfuran (DMF), a model furan compound, was incubated with rat liver microsomes supplemented with glutathione (GSH) and 4-bromobenzylamine (BBA) as trapping agents, to produce a GSH/BBA-derived pyrrole. The incubation mixture was monitored by acquiring neutral loss scan of 129 Da and precursor ion scans of m/z 272, 169, and 171 in polarity switch mode. Four individual chromatograms showed the respective peak with the same retention time. An additional six furan containing compounds were tested by the same approach, and similar observation was obtained. The system also showed its extremely high sensitivity, and an estimate of the limit of detection for DMF bioactivated in rat liver microsomes was <100 fmol. We also applied inductively coupled plasma mass spectrometry (ICP MS) to monitor the formation of the bromine-tagged pyrrole derivatives. Crude extracts obtained from traditional Chinese medicine Dioscorea bulbifera L., known to contain furanoditerpenoids, were analyzed by the approach. In conclusion, the platform has been proven selective, sensitive, effective, and reliable, and ICP MS allows us to estimate the resulting bromine-labeled pyrroles without authentic standards. PMID- 25279954 TI - Evolutionary strategies of viruses, bacteria and archaea in hydrothermal vent ecosystems revealed through metagenomics. AB - The deep-sea hydrothermal vent habitat hosts a diverse community of archaea and bacteria that withstand extreme fluctuations in environmental conditions. Abundant viruses in these systems, a high proportion of which are lysogenic, must also withstand these environmental extremes. Here, we explore the evolutionary strategies of both microorganisms and viruses in hydrothermal systems through comparative analysis of a cellular and viral metagenome, collected by size fractionation of high temperature fluids from a diffuse flow hydrothermal vent. We detected a high enrichment of mobile elements and proviruses in the cellular fraction relative to microorganisms in other environments. We observed a relatively high abundance of genes related to energy metabolism as well as cofactors and vitamins in the viral fraction compared to the cellular fraction, which suggest encoding of auxiliary metabolic genes on viral genomes. Moreover, the observation of stronger purifying selection in the viral versus cellular gene pool suggests viral strategies that promote prolonged host integration. Our results demonstrate that there is great potential for hydrothermal vent viruses to integrate into hosts, facilitate horizontal gene transfer, and express or transfer genes that manipulate the hosts' functional capabilities. PMID- 25279955 TI - Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals. AB - Chronic immune activation that persists despite anti-retroviral therapy (ART) is the strongest predictor of disease progression in HIV infection. Monocyte/macrophages in HIV-infected individuals are known to spontaneously secrete cytokines, although neither the mechanism nor the molecules involved are known. Here we show that overexpression of the newly described co-stimulatory molecule, PD1 homologue (PD-1H) in human monocyte/macrophages is sufficient to induce spontaneous secretion of multiple cytokines. The process requires signaling via PD-1H as cytokine secretion could be abrogated by deletion of the cytoplasmic domain. Such overexpression of PD-1H, associated with spontaneous cytokine expression is seen in monocytes from chronically HIV-infected individuals and this correlates with immune activation and CD4 depletion, but not viral load. Moreover, antigen presentation by PD-1H-overexpressing monocytes results in enhanced cytokine secretion by HIV-specific T cells. These results suggest that PD-1H might play a crucial role in modulating immune activation and immune response in HIV infection. PMID- 25279956 TI - A metastatic relapse associated with hippocampal dose sparing after whole-brain radiotherapy. PMID- 25279957 TI - Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. AB - BACKGROUND: Proton therapy offers superior low and intermediate radiation dose distribution compared with photon-based radiation for brain and skull base tumors; yet tissue within and adjacent to the target volume may receive a comparable radiation dose. We investigated the tolerance of the pediatric brainstem to proton therapy and identified prognostic variables. MATERIAL AND METHODS: All patients < 18 years old with tumors of the brain or skull base treated from 2007 to 2013 were reviewed; 313 who received > 50.4 CGE to the brainstem were included in this study. Brainstem toxicity was graded according to the NCI Common Terminology Criteria for Adverse Events v4.0. RESULTS: The three most common histologies were ependymoma, craniopharyngioma, and low-grade glioma. Median patient age was 5.9 years (range 0.5-17.9 years) and median prescribed dose was 54 CGE (range 48.6-75.6 CGE). The two-year cumulative incidence of toxicity was 3.8% +/- 1.1%. The two-year cumulative incidence of grade 3 + toxicity was 2.1% +/- 0.9%. Univariate analysis identified age < 5 years, posterior fossa tumor location and specific dosimetric parameters as factors associated with an increased risk of toxicity. CONCLUSION: Utilization of current national brainstem dose guidelines is associated with a low risk of brainstem toxicity in pediatric patients. For young patients with posterior fossa tumors, particularly those who undergo aggressive surgery, our data suggest more conservative dosimetric guidelines should be considered. PMID- 25279958 TI - Auto-segmentation of the brachial plexus assessed with TaCTICS - a software platform for rapid multiple-metric quantitative evaluation of contours. PMID- 25279960 TI - 'Tu quoque Brute fili mihi!' (Julius Caesar, Ides of March, 44 BC): role of tumor microenvironment and immune system in breast cancer progression. PMID- 25279959 TI - Dose intensified hypofractionated intensity-modulated radiotherapy with synchronous cetuximab for intermediate stage head and neck squamous cell carcinoma. AB - BACKGROUND: For stage II and III head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy alone, loco-regional recurrence is the main cause of treatment failure. Strategies to improve loco-regional control should not be at the expense of increased late normal tissue toxicity. We investigated dose intensified hypofractionated intensity-modulated radiotherapy (IMRT) with synchronous cetuximab. MATERIAL AND METHODS: In a phase I/II trial, 27 patients with stage III or high risk stage II HNSCC were recruited. They received three dose level simultaneous integrated boost IMRT, 62.5 Gy in 25 daily fractions to planning target volume one over five weeks with synchronous cetuximab. The primary endpoint was acute toxicity. Secondary endpoints included: late toxicity and quality of life; loco-regional control, cause-specific and overall survival. RESULTS: Radiotherapy was completed by 26/27 patients; for one (4%) the final fraction was omitted due to skin toxicity. All cycles of cetuximab were received by 23/27 patients. Grade 3 acute toxicities included: pain (81%), oral mucositis (78%) and dysphagia (41%). There were few grade 3 physician-recorded late toxicities, including: pain (11%), problems with teeth (8%) and weight loss (4%). At 12 months, only one (4%) patient required a feeding tube, inserted prior to treatment due to dysphagia. The maximal/peak rates of patient-reported late toxicities included: severe pain (11%), any dry mouth (89%) and swallowing dysfunction that required a soft/liquid diet (23%). At 12 months, all quality of life and most symptoms mean scores had resolved to baseline or were only a little worse; dry mouth, sticky saliva and dentition scores remained very much worse. At a median follow-up of 47 months, there were five (18.5%) loco-regional recurrences and the overall cause-specific survival was 79% (95% CI 53-92). CONCLUSIONS: This regimen is safe with acceptable acute toxicity, low rates of late toxicity and impact on quality of life at 12 months following treatment. Further evaluation is recommended. PMID- 25279961 TI - Obesity, proinflammatory mediators, adipose tissue progenitors, and breast cancer. AB - PURPOSE OF REVIEW: There is emerging evidence that obesity is associated with an increase in the incidence, severity, and mortality from different types of cancer, including postmenopausal breast cancer. Here, we discuss the role of white adipose tissue (WAT) cells and of related soluble factors in the local and metastatic growth of this neoplastic disease. Moreover, we discuss the recent increase in the use of WAT-derived progenitor cells in breast cancer patients to enhance the quality of breast reconstruction and the related risks. RECENT FINDINGS: In several murine models, WAT cells and progenitors were found to have cooperative roles in promoting local breast cancer. Moreover, they were found to contribute to adipocytes and pericytes supporting the cancer vasculature, and stimulated the metastatic progression of breast cancer. There are some clinically retrospective data showing a significant increase in the frequency of intraepithelial neoplasia in patients who received a lipofilling procedure for breast reconstruction compared with controls. SUMMARY: Preclinical models and clinical studies are urgently needed to investigate how to inhibit the tumor promoting activity of WAT cells and progenitors. The risks associated with the use of WAT cells for breast reconstructions should be better investigated retrospectively and prospectively. PMID- 25279962 TI - Tumor-stroma crosstalk: targeting stroma in breast cancer. AB - PURPOSE OF REVIEW: Combinatorial strategies in cancer medicine will not only target cancer cell-intrinsic pathways, but also cancer cell-extrinsic cells, pathways, and mediators of the tumor microenvironment. The aim of the present review is to define the roles of the tumor microenvironment in primary and metastatic breast cancer progression. RECENT FINDINGS: The cancer microenvironment is composed of nontransformed host stromal cells, such as endothelial cells, fibroblasts, various immune cells, and a complex extracellular matrix secreted by both the normal and neoplastic cells embedded in it. The stromal constituents contribute to the core and emergent hallmarks of cancer. In particular, they can boost sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. SUMMARY: The stromal cells play a role in enabling or enhancing multiple hallmark capabilities in tumor microenvironment. This is a background for therapeutic-targeting strategies aimed to abrogate the stroma's contribution. Targeting tumor-associated fibroblasts, macrophages, angiogenesis and enhancing immune response may represent a paradigm shifting approach to treating human cancer in the near future. PMID- 25279963 TI - Low-grade glioma management: a contemporary surgical approach. AB - PURPOSE OF REVIEW: The primary treatment of low-grade gliomas is still claimed to lack robust supporting evidence. Yet, several investigations were performed in the last 2 decades. To critically review these studies could help in further clarifying the role of surgery aimed at maximal resection. RECENT FINDINGS: Despite the lack of randomized clinical trials hampering the performance of appropriate meta-analyses, the increasing amount of evidence pointed toward an aggressive surgical strategy to low-grade glioma. Low-grade glioma surgery has to be performed with the appropriate armamentarium, which is the availability of intraoperative stimulation mapping, especially for those lesions occurring in cortical and subcortical eloquent sites. SUMMARY: According to the recently published guidelines, surgical treatment has been increasingly recognized as the initial therapeutic act of choice for patients diagnosed with a presumed low grade glioma, given that total resection can improve seizure control, progression free survival and overall survival, while reducing the risk of malignant transformation and preserving patients' functional status. PMID- 25279964 TI - Prevalence of comorbidities and their impact on hospital management and short term outcomes in Vietnamese patients hospitalized with a first acute myocardial infarction. AB - BACKGROUND: Cardiovascular disease is one of the leading causes of morbidity and mortality in Vietnam. We conducted a pilot study of Hanoi residents hospitalized with a first acute myocardial infarction (AMI) at the Vietnam National Heart Institute in Hanoi for purposes of describing the prevalence of cardiovascular (CVD) and non-CVD comorbidities and their impact on hospital management, in hospital clinical complications, and short-term mortality in these patients. METHODS: The study population consisted of 302 Hanoi residents hospitalized with a first AMI at the largest tertiary care medical center in Hanoi in 2010. RESULTS: The average age of study patients was 66 years and one third were women. The proportions of patients with none, any 1, and >= 2 CVD comorbidities were 34%, 42%, and 24%, respectively. Among the CVD comorbidities, hypertension was the most commonly reported (59%). There were decreasing trends in the proportion of patients who were treated with effective cardiac medications and coronary interventions as the number of CVD comorbidities increased. Patients with multiple CVD comorbidities tended to develop acute clinical complications and die at higher rates during hospitalization compared with patients with no CVD comorbidities (Odds Ratio: 1.40; 95% Confidence Interval: 0.40-4.84). CONCLUSIONS: Our data suggest that patients with multiple cardiac comorbidities tended to experience high in-hospital death rates in the setting of AMI. Full scale surveillance of Hanoi residents hospitalized with AMI at all Hanoi hospitals is needed to confirm these findings. Effective strategies to manage Vietnamese patients hospitalized with AMI who have multiple comorbidities are warranted to improve their short-term prognosis. PMID- 25279965 TI - Increased pyrethroid resistance in malaria vectors and decreased bed net effectiveness, Burkina Faso. AB - Malaria control is dependent on insecticides. Increases in prevalence of insecticide resistance in malaria vectors across Africa are well-documented. However, few attempts have been made to quantify the strength of this resistance and link it to the effectiveness of control tools. Using quantitative bioassays, we show that in Burkina Faso pyrethroid resistance in Anopheles gambiae mosquitoes has increased in intensity in recent years and now exceeds 1,000-fold. In laboratory assays, this level of resistance renders insecticides used to impregnate bed nets ineffective. Thus, the level of personal and community protection afforded by long-lasting insecticide-treated net campaigns will probably be reduced. Standardized methods are needed to quantify resistance levels in malaria vectors and link these levels to failure of vector control methods. PMID- 25279966 TI - Mechanical properties of cranial bones and sutures in 1-2-year-old infants. AB - BACKGROUND: The mechanical properties of 1-2-year-old pediatric cranial bones and sutures and their influential factors were studied to better understand how the pediatric calvarium reacts to loading. MATERIAL AND METHODS: Cranial bone and suture specimens were extracted from seven fresh-frozen human infant cadavers (1.5+/-0.5 years old). Eight specimens were obtained from each subject: two frontal bones, two parietal bones, two sagittal suture samples, and two coronal suture samples. The specimens were tested in a three-point bend setup at 1.5 mm/s. The mechanical properties, such as ultimate stress, elastic modulus, and ultimate strain, were calculated for each specimen. RESULTS: The ultimate stress and elastic modulus of the frontal bone were higher than those of the parietal bone (P<0.05). No differences were found between the coronal and sagittal sutures in ultimate stress, elastic modulus, or ultimate strain (P>0.05). The ultimate stress and elastic modulus of the frontal and parietal bones were higher than those of the sagittal and coronal sutures (P<0.05), whereas the opposite ultimate strain findings were revealed (P<0.05). CONCLUSIONS: There was no significant difference in ultimate stress, elastic modulus, or ultimate strain between the sagittal and coronal sutures. However, there were significant differences in ultimate stress, elastic modulus, and ultimate strain between the frontal and parietal bones as well as between the cranial bones and sutures. PMID- 25279967 TI - Aryl bromides as inexpensive starting materials in the catalytic enantioselective arylation of aryl aldehydes: the additive TMEDA enhances the enantioselectivity. AB - We used aryl bromides as inexpensive starting materials to enantioselectively arylate aldehydes in one pot. Aryl bromides readily transfer aryls to aryllithiums with n-butyllithium, successively to triarylaluminums with aluminum chloride, and then to aryltitaniums with titanium isopropoxide. Finally aryltitaniums arylate aldehydes catalyzed by (S)-H8-BINOL-Ti(Oi-Pr)2 in excellent yields and enantioselectivities. The additive TMEDA evidently suppresses the racemic background reaction promoted by LiCl generated from salt metathesis. This procedure represents a cost-effective and operationally convenient method for enantioenriched diarylmethanols. PMID- 25279968 TI - Undergraduates' perceptions of three augmentative and alternative communication modes. AB - OBJECTIVE: To assess undergraduates' perceptions of three augmentative and alternative communication (AAC) modes. METHOD: We showed 104 undergraduates a video clip of a person using each of the three AAC modes and asked them to rate each option in terms of perceived (a) intelligibility, (b) ease of acquisition, (c) effectiveness/acceptability, and (d) preference. The three AAC modes shown were (a) manual signing, (b) picture exchange, and (c) speech-generating device. RESULTS: Mean ratings for perceived intelligibility and effectiveness/acceptability were significantly higher for the speech-generating device. The speech-generating device and manual signing options were rated as being more preferred over picture exchange. Picture exchange was rated significantly higher on perceived ease of acquisition. CONCLUSION: Speech generating devices were perceived to have greater social validity than manual signing and picture exchange. PMID- 25279969 TI - Relationships of serum lipid profiles and bone mineral density in postmenopausal Chinese women. AB - OBJECTIVES: Recent studies suggest that serum lipid profiles are related to bone mineral density (BMD). But data about this relationship on Chinese population are scarce. We investigated the relationships between serum lipid and BMD in postmenopausal Chinese women. METHODS: A cross-sectional study was conducted in 790 Chinese postmenopausal women. BMDs were measured by dual X-ray absorptiometry. Serum lipid profiles were obtained after a 12-h fasting. RESULTS: Women with serum high-density lipoprotein cholesterol (HDL-C) levels of at least 1.55 mmol/l had a greater prevalence of osteoporosis compared with women with lower HDL-C (<=1.54 mmol/l). After controlling for age, menopausal duration, body mass index, serum creatinine levels, outdoor activity, smoking and alcohol intake, high HDL-C levels were associated with osteoporosis (OR = 1.64, 95%CI 1.16-2.33, P < 0.01). BMD at femoral neck and total hip was significantly lower in the higher HDL-C class than the lower class (0.722 +/- 0.118 vs 0.744 +/- 0.120 g/cm(2) , P < 0.01; 0.800 +/- 0.126 vs 0.824 +/- 0.125 g/cm(2) , P < 0.01, respectively). No association was found between total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) with BMD. CONCLUSIONS: In Chinese postmenopausal women, elevated levels of serum HDL-C had a greater probability of being osteoporosis than the lower HDL-C levels. Our analysis showed higher HDL-C level that is favourable for cardiovascular diseases should be regarded as a risk factor for osteoporosis. PMID- 25279970 TI - si-RNA-Mediated Silencing of ADRBK1 Gene Attenuates Breast Cancer Cell Proliferation. AB - Abstract Breast cancer is the most prominent cause of cancer-related deaths among women worldwide. It has been found that genetic mutations play distinct roles in the onset and progression of breast cancer. Androgenic, beta, receptor kinase 1 (ADRBK1) has been reported to possess oncogenic characteristics vital for cancer cell viability. This study was designed to investigate the effects of small interference RNA (si-RNA)-mediated ADRBK1 knockdown on breast cancer cell growth in vitro. High-expression levels of ADRBK1 were observed in all tested breast cancer cell lines (MDA-MB-231, MCF-7, T-47D, and BT-474). ADRBK1 si-RNA was delivered to breast cancer cells using lentivirus delivery system. Depletion of ADRBK1 significantly attenuated the cell viability and colony-formation ability. Flow cytometry analysis further demonstrated that ADRBK1 silencing led to MDA-MB 231 cell arrest in the G0/G1 phase. Collectively, these results indicate that knockdown of ADRBK1 gene has detrimental effects on breast cancer cell growth, which may be a potential therapeutic approach for the treatment of breast cancer. PMID- 25279971 TI - Chloride intracellular channel 1 regulates prostate cancer cell proliferation and migration through the MAPK/ERK pathway. AB - Abstract Aims: To investigate the effect of chloride intracellular channel 1 (CLIC1) on the proliferation, migration, and apoptosis of prostate cancer cell lines PC-3 and DU145 and the possible molecular mechanisms. MATERIALS AND METHODS: Using the technique of RNA interference, the expression of CLIC1 was downregulated in the PC-3 and DU145 cell lines. MTT assay, Transwell chamber, and flow cytometry were used to determine the effect of CLIC1 on the proliferation, migration, and apoptosis ability of PC-3 and DU145 cells. The levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), ERK1/2, matrix metalloproteinase (MMP)-2, and MMP-9 were examined by western blotting. RESULTS: The results showed that the knockdown of CLIC1 exerts inhibitory effects on the proliferation and migration of PC-3 and DU145 cells. At the same time, the authors found that the knockdown of CLIC1 has no effect on the apoptosis in PC-3 and DU145 cells. Meanwhile, the levels of p-ERK1/2, MMP-2, and MMP-9 were decreased in the CLIC1 small interfering RNA (siRNA) group compared with the control and vector groups. CONCLUSION: These results indicate that CLIC1 could regulate prostate cancer cell proliferation and migration by regulating the mitogen-activated protein kinase (MAPK)/ERK pathway and offers a candidate molecular target for prostate cancer prevention and therapy. PMID- 25279972 TI - Highlights from Faraday Discussion 168: astrochemistry of dust, ice and gas, Leiden, The Netherlands, April 2014. PMID- 25279973 TI - The complete sequence of a West Nile virus lineage 2 strain detected in a Hyalomma marginatum marginatum tick collected from a song thrush (Turdus philomelos) in eastern Romania in 2013 revealed closest genetic relationship to strain Volgograd 2007. AB - In this study the first complete sequence of the West Nile virus (WNV) lineage 2 strain currently circulating in Romania was determined. The virus was detected in a Hyalomma marginatum marginatum tick collected from a juvenile song thrush (Turdus philomelos) in the Romanian Danube Delta close to the city of Tulcea, end of August 2013. Our finding emphasizes the role of ticks in introduction and maintenance of WNV infections. Sequence analyses revealed close genetic relationship of the Romanian WNV strain to strain Reb_Volgograd_07_H, which was isolated from human brain tissue during an outbreak of West Nile neuroinvasive disease (WNND) in Russia in 2007. In 2010 the Eastern European lineage 2 WNV caused an outbreak of human WNND in Romania. Partial sequences from subsequent years demonstrated that this WNV strain became endemic in Eastern Europe and has been causing outbreaks of varying sizes in southern Russia since 2007 and in Romania since 2010. PMID- 25279975 TI - Percentiles and regional distribution of skinfold thickness among children and adolescents in Shandong, China. AB - OBJECTIVE: Skinfold thicknesses (SFT) have long been considered important and valid measurements of subcutaneous fat. The present study reported the percentiles and regional distribution of SFT among children and adolescents in Shandong, China. METHODS: Data for this study were obtained from a large cross sectional survey of schoolchildren. A total of 42,268 students (21,200 boys and 21,068 girls) aged 7-18 years from 16 districts participated in this study. Triceps, subscapular, and abdomen SFT of all subjects were measured. RESULTS: Shandong children and adolescents had a high SFT level and substantial regional disparities in SFT were observed. Boys and girls resident in high socioeconomic status (SES) districts had higher SFT level than those living in moderate and low SES districts. CONCLUSION: The SFT level of children and adolescents is associated with regional SES in Shandong, China. This may be interpreted as a result of geographic variation between the districts in the process of urbanization, living standards, nutritional conditions, dietary patterns, and public health. PMID- 25279974 TI - Role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy of rocuronium in Chinese patients. AB - This study explored the role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy and duration of action of rocuronium in Chinese patients. Two hundred seven unrelated Chinese patients scheduled for elective surgery were recruited, and 200 completed the study. Their ABCB1, SLCO1B1, and CHRNA1 genotypes were determined. Demographic and clinical non-genetic data also were collected. The SLCO1B1, ABCB1, and CHRNA1 variants did not affect the onset time of rocuronium. Clinical duration and recovery time of rocuronium were prolonged in patients with the ABCB1 rs1128503TT and SLCO1B1 rs2306283 AG and GG genotypes. We demonstrate that the SLCO1B1 and ABCB1 gene variants could affect the pharmacodynamics of rocuronium. The ABCB1 rs1128503 C>T genotype was the most important factor on the efficacy of rocuronium. PMID- 25279977 TI - Identification of cytolytic vaginosis versus vulvovaginal candidiasis. AB - OBJECTIVE: This study aimed to observe the morphological characteristic of vaginal discharge in patients with cytolytic vaginosis (CV) under the microscope and to identify it in patients with CV and in patients with vulvovaginal candidiasis (VVC). METHODS: A total of 108 subjects including 21 healthy women, 33 patients with CV, and 54 patients with VVC were enrolled in the present morphological study. Vaginal discharge was collected and made into smear. The morphological characteristics of these vaginal smears with Gram staining were observed under the microscope. The smears were assessed for the quantity of lactobacilli, epithelial cell morphology, and the absence or presence of Candida species, Trichomonas vaginalis, and clue sells. RESULTS: First, the age, the level of education, and especially the status of pregnancy of patients with CV were significantly different from those of the patients with VVC. Second, the morphological characteristics of patients with CV consisted of overgrowth of lactobacilli, the presence of naked nuclei and fragments of the epithelial cells, a paucity of leukocytes, and the absence of Candida species and other pathogens. However, the morphological characteristic of patients with VVC consisted of the presence or absence of lactobacilli and the presence of normal epithelial cells, candidal spores, blastospores, hyphae, or other pathogens such as T. vaginalis and Gardnerella vaginalis. CONCLUSIONS: Both CV and VVC can be identified based on the quantity of lactobacilli, the morphology of the epithelial cells, and the absence or presence of Candida species and other pathogens, and the misdiagnosis of CV as VVC can be avoided. PMID- 25279978 TI - The Influence of Human Papillomavirus Genotypes on Visual Screening and Diagnosis of Cervical Precancer and Cancer. AB - OBJECTIVE: To examine the influence of human papillomavirus (HPV) genotypes on the sensitivity of visual inspection with acetic acid (VIA) for screening, and colposcopy for diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+). MATERIALS AND METHODS: Women aged 25 to 65 years from China (n = 7,541) were screened with 6 tests (careHPV and Hybrid Capture 2 on self- and clinician-collected specimens; HPV-16, HPV-18, HPV-45 E6 detection; and VIA). Biopsies from women with a diagnosis of CIN2+ underwent testing for 25 HPV genotypes using SPF10/LiPA. Human papillomavirus genotyping results were classified according to broad categories of cancer risk. RESULTS: Among the 143 women with a diagnosis of CIN2+, the percentage who were HPV16 positive increased with increasing severity of diagnosis: 33.3% for CIN2 (n = 39), 69.1% for CIN3 (n = 94), and 90% for cancer (n = 10). There was a higher percentage of HPV-16 in women with abnormal colposcopic impression (p = .007) and positive VIA (p = .02) than normal colposcopy and negative VIA, respectively. Colposcopy and VIA were more sensitive to detect CIN2+ among HPV-16- and/or HPV-18-positive women than HPV-16-/HPV-18-negative women (67.4% vs 43.1%, p = .008, for colposcopy; and 53.3% vs 37.3%, p = .08, for VIA). CONCLUSIONS: Human papillomavirus type 16 is related to more clear visual acetowhite changes in the epithelium. Therefore, we should expect a reduction of the performance of VIA for cervical cancer screening to identify women with CIN2+, and reduction of the performance of colposcopy to diagnose CIN2+, in vaccinated populations. PMID- 25279979 TI - Preference for human papillomavirus-based cervical cancer screening: results of a choice-based conjoint study in Zambia. AB - OBJECTIVE: The objective of this study was to assess the conditions under which Zambian women with a history of cervical cancer screening by visual inspection with acetic acid might switch to human papillomavirus-based testing in the future. MATERIALS AND METHODS: We conducted a choice-based conjoint survey in a sample of women recently screened by visual inspection in Lusaka, Zambia. The screening attribute considered in hypothetical-choice scenarios included screening modality, sex and age of the examiner, whether screening results would be presented visually, distance from home to the clinic, and wait time for results. RESULTS: Of 238 women in the sample, 208 (87.4%) provided responses sufficiently reliable for analysis. Laboratory testing on a urine sample was the preferred screening modality, followed by visual screening, laboratory testing on a self-collected vaginal specimen, and laboratory testing on a nurse-collected cervical specimen. Market simulation suggested that only 39.7% (95% CI = 33.8 45.6) of the respondents would prefer urine testing offered by a female nurse in her 30s over visual inspection of the cervix conducted by a male nurse in his 20s if extra wait time were as short as 1 hour and the option of viewing how their cervix looks like were not available. CONCLUSIONS: Our study suggests that, for some women, the level of preference for human papillomavirus-based screening strategies may depend highly on the process and conditions of service delivery. PMID- 25279980 TI - Management of "Atypical Endocervical Cells" Compared to "Atypical Glandular Cells". AB - OBJECTIVE: To assess adherence to management guidelines based on the terminology used to describe atypical glandular cells (AGC) on cytology reports. MATERIALS AND METHODS: We analyzed AGC pathology reports from Hartford Hospital, 2004-2007, and identified cases of AGC with the terminology atypical glandular cells or atypical endocervical cells (AEC). We calculated rates of clinical evaluations based on the terminology used to describe the AGC. Statistical analysis was performed using the chi test. RESULTS: Seventy-eight reports contained the terminology AEC and 97 reports contained the terminology AGC. The rate of histologic sampling in women with AEC was lower than in women with AGC (52.6% vs 83.5%; p < .01). Similarly, the rate of comprehensive evaluations was lower (33.3% vs 71.1%; p < .01). Fewer endocervical curettages (47.4% vs 77.3%; p < .01) and fewer endometrial biopsies in women 35 years or older were performed (26.9% vs 69.1%; p < .01) in women with AEC than in women with AGC. CONCLUSIONS: Women with AGC reports containing the term AEC were managed less optimally than those with AGC. These results suggest that the terminology used to describe the finding of atypical glandular cells may influence the clinical evaluation. Clinicians may not recognize AEC as AGCs. Ours results suggest that the terminology atypical endocervical cells should be avoided or accompanied by the terminology atypical glandular cells. PMID- 25279982 TI - Effective genetic-risk prediction using mixed models. AB - For predicting genetic risk, we propose a statistical approach that is specifically adapted to dealing with the challenges imposed by disease phenotypes and case-control sampling. Our approach (termed Genetic Risk Scores Inference [GeRSI]), combines the power of fixed-effects models (which estimate and aggregate the effects of single SNPs) and random-effects models (which rely primarily on whole-genome similarities between individuals) within the framework of the widely used liability-threshold model. We demonstrate in extensive simulation that GeRSI produces predictions that are consistently superior to current state-of-the-art approaches. When applying GeRSI to seven phenotypes from the Wellcome Trust Case Control Consortium (WTCCC) study, we confirm that the use of random effects is most beneficial for diseases that are known to be highly polygenic: hypertension (HT) and bipolar disorder (BD). For HT, there are no significant associations in the WTCCC data. The fixed-effects model yields an area under the ROC curve (AUC) of 54%, whereas GeRSI improves it to 59%. For BD, using GeRSI improves the AUC from 55% to 62%. For individuals ranked at the top 10% of BD risk predictions, using GeRSI substantially increases the BD relative risk from 1.4 to 2.5. PMID- 25279981 TI - Ascertainment bias causes false signal of anticipation in genetic prion disease. AB - Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested. PMID- 25279983 TI - Biased gene conversion skews allele frequencies in human populations, increasing the disease burden of recessive alleles. AB - Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ~ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications. PMID- 25279984 TI - Characteristics of neutral and deleterious protein-coding variation among individuals and populations. AB - Whole-genome and exome data sets continue to be produced at a frenetic pace, resulting in massively large catalogs of human genomic variation. However, a clear picture of the characteristics and patterns of neutral and deleterious variation within and between populations has yet to emerge, given that recent large-scale sequencing studies have often emphasized different aspects of the data and sometimes appear to have conflicting conclusions. Here, we comprehensively studied characteristics of protein-coding variation in high coverage exome sequence data from 6,515 European American (EA) and African American (AA) individuals. We developed an unbiased approach to identify putatively deleterious variants and investigated patterns of neutral and deleterious single-nucleotide variants and alleles between individuals and populations. We show that there are substantial differences in the composition of genotypes between EA and AA populations and that small but statistically significant differences exist in the average number of deleterious alleles carried by EA and AA individuals. Furthermore, we performed extensive simulations to delineate the temporal dynamics of deleterious alleles for a broad range of demographic models and use these data to inform the interpretation of empirical patterns of deleterious variation. Finally, we illustrate that the effects of demographic perturbations, such as bottlenecks and expansions, often manifest in opposing patterns of neutral and deleterious variation depending on whether the focus is on populations or individuals. Our results clarify seemingly disparate empirical characteristics of protein-coding variation and provide substantial insights into how natural selection and demographic history have patterned neutral and deleterious variation within and between populations. PMID- 25279985 TI - Cryptic and complex chromosomal aberrations in early-onset neuropsychiatric disorders. AB - Structural variation (SV) is a significant component of the genetic etiology of both neurodevelopmental and psychiatric disorders; however, routine guidelines for clinical genetic screening have been established only in the former category. Genome-wide chromosomal microarray (CMA) can detect genomic imbalances such as copy-number variants (CNVs), but balanced chromosomal abnormalities (BCAs) still require karyotyping for clinical detection. Moreover, submicroscopic BCAs and subarray threshold CNVs are intractable, or cryptic, to both CMA and karyotyping. Here, we performed whole-genome sequencing using large-insert jumping libraries to delineate both cytogenetically visible and cryptic SVs in a single test among 30 clinically referred youth representing a range of severe neuropsychiatric conditions. We detected 96 SVs per person on average that passed filtering criteria above our highest-confidence resolution (6,305 bp) and an additional 111 SVs per genome below this resolution. These SVs rearranged 3.8 Mb of genomic sequence and resulted in 42 putative loss-of-function (LoF) or gain-of-function mutations per person. We estimate that 80% of the LoF variants were cryptic to clinical CMA. We found myriad complex and cryptic rearrangements, including a "paired" duplication (360 kb, 169 kb) that flanks a 5.25 Mb inversion that appears in 7 additional cases from clinical CNV data among 47,562 individuals. Following convergent genomic profiling of these independent clinical CNV data, we interpreted three SVs to be of potential clinical significance. These data indicate that sequence-based delineation of the full SV mutational spectrum warrants exploration in youth referred for neuropsychiatric evaluation and clinical diagnostic SV screening more broadly. PMID- 25279987 TI - Respiratory inductance plethysmography calibration for pediatric upper airway obstruction: an animal model. AB - BACKGROUND: We sought to determine optimal methods of respiratory inductance plethysmography (RIP) flow calibration for application to pediatric postextubation upper airway obstruction. METHODS: We measured RIP, spirometry, and esophageal manometry in spontaneously breathing, intubated Rhesus monkeys with increasing inspiratory resistance. RIP calibration was based on: DeltauV(ao) ~ M[DeltauV(RC) + K(DeltauV(AB))] where K establishes the relationship between the uncalibrated rib cage (DeltauV(RC)) and abdominal (DeltauV(AB)) RIP signals. We calculated K during (i) isovolume maneuvers during a negative inspiratory force (NIF), (ii) quantitative diagnostic calibration (QDC) during (a) tidal breathing, (b) continuous positive airway pressure (CPAP), and (c) increasing degrees of upper airway obstruction (UAO). We compared the calibrated RIP flow waveform to spirometry quantitatively and qualitatively. RESULTS: Isovolume calibrated RIP flow tracings were more accurate (against spirometry) both quantitatively and qualitatively than those from QDC (P < 0.0001), with bigger differences as UAO worsened. Isovolume calibration yielded nearly identical clinical interpretation of inspiratory flow limitation as spirometry. CONCLUSION: In an animal model of pediatric UAO, isovolume calibrated RIP flow tracings are accurate against spirometry. QDC during tidal breathing yields poor RIP flow calibration, particularly as UAO worsens. Routine use of a NIF maneuver before extubation affords the opportunity to use RIP to study postextubation UAO in children. PMID- 25279988 TI - Impaired epithelial Na+ channel activity contributes to cystogenesis and development of autosomal recessive polycystic kidney disease in PCK rats. AB - BACKGROUND: Autosomal recessive polycystic kidney disease is a genetic disorder characterized by the development of renal cysts of tubular epithelial cell origin. Epithelial Na(+) channel (ENaC) is responsible for sodium reabsorption in the aldosterone-sensitive distal nephron. Here, we investigated the ENaC expression and activity in cystic tissue taken from rats with autosomal recessive polycystic kidney disease. METHODS: Polycystic kidney (PCK) rats were treated with the selective ENaC inhibitor benzamil given in the drinking water, and after 4 or 12 wk, the severity of morphological malformations in the kidneys was assessed. ENaC and aquaporin-2 expression and ENaC activity were tested with immunohistochemistry and patch-clamp electrophysiology, respectively. RESULTS: Treatment with benzamil exacerbated development of cysts compared with the vehicle-treated animals. In contrast, the 12 wk of treatment with the loop diuretic furosemide had no effect on cystogenesis. Single-channel patch-clamp analysis revealed that ENaC activity in the freshly isolated cystic epithelium was significantly lower than that in the noncystic collecting ducts isolated from PCK or normal Sprague-Dawley rats. Immunohistochemical analysis confirmed that beta-ENaC and aquaporin-2 expressions in cysts are decreased compared with nondilated tubules from PCK rat kidneys. CONCLUSION: We demonstrated that cystic epithelium exhibits low ENaC activity and this phenomenon can contribute to cyst progression. PMID- 25279989 TI - Upper and lower esophageal sphincter kinetics are modified during maturation: effect of pharyngeal stimulus in premature infants. AB - BACKGROUND: We hypothesized that changes in proximal and distal esophageal sphincter kinetics evoked upon pharyngeal provocation undergo longitudinal maturation. METHODS: Pharyngeal stimulation-induced reflexes were characterized using novel pharyngo-esophageal motility methods in 19 healthy premature neonates, studied at 34.7 +/- 0.8 wk (time-1) and 39.3 +/- 1.1 wk postmenstrual age (time-2). Graded volumes of air (290 infusions) and sterile water (172 infusions) were infused to define sensory-motor characteristics of upstream (pharyngeal reflexive swallow, PRS) and downstream (pharyngo-lower esophageal sphincter relaxation reflex, PLESRR) esophageal reflexes. Data displayed as mean +/- SE. RESULTS: Threshold volumes were similar with air and water for PRS and PLESRR at time-1 and time-2. Multiple PRS responses were noted with water stimulus and were different between the media (time-1 vs. air, P < 0.0001; time-2 vs. air, P = 0.0003). Dose-response relationships for water were significant (P < 0.01 for PRS and PLESRR time-1 and time-2), but not with air. CONCLUSION: Significantly, the recruitment frequency of PRS and PLESRR increases with maturation, liquid is a superior medium for evoking such swallowing reflexes, and stimulus-response relationships for these reflexes are evident. These changes in aerodigestive protective reflexive activity may indicate differences in modulation of excitatory and inhibitory pathways during longitudinal postnatal maturation. PMID- 25279990 TI - Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain. AB - BACKGROUND: Prolonged hypoglycemia leads to brain injury, despite treatment with 10% dextrose. Whether induction of hyperglycemia or ketonemia achieves better neuroprotection is unknown. Hyperglycemia is neuroprotective in other brain injuries during development; however, it worsens hypoglycemia-induced injury in the adult brain via poly(ADP-ribose)polymerase-1 (PARP-1) overactivation. METHODS: Three-week-old rats were subjected to insulin-induced hypoglycemia and treated with 10% dextrose or 50% dextrose. Neuronal injury, PARP-1, and brain derived neurotrophic factor (BDNF) III/TrkB/p75(NTR) expressions were determined. In the second experiment, ketonemia was induced by administering beta hydroxybutyrate during hypoglycemia and its effect on neuronal injury was compared with those conventionally treated using 10% dextrose. RESULTS: Both 10 and 50% dextrose administration led to hyperglycemia (50% dextrose > 10% dextrose). Compared with the 10% dextrose group, neuronal injury was greater in the 50% dextrose group and was accompanied by PARP-1 overactivation. BDNF III and p75(NTR), but not TrkBFL, mRNA expressions were upregulated. Neuronal injury was less severe in the rats subjected to ketonemia, compared with those conventionally treated using 10% dextrose. CONCLUSION: Hyperglycemia accentuated hypoglycemia-induced neuronal injury, likely via PARP-1 overactivation. Although BDNF was upregulated, it was not neuroprotective and potentially exaggerated injury by binding to p75(NTR) receptor. Conversely, ketonemia during hypoglycemia attenuated neuronal injury. PMID- 25279992 TI - Wood anatomy reveals high theoretical hydraulic conductivity and low resistance to vessel implosion in a Cretaceous fossil forest from northern Mexico. AB - The Olmos Formation (upper Campanian), with over 60 angiosperm leaf morphotypes, is Mexico's richest Cretaceous flora. Paleoclimate leaf physiognomy estimates indicate that the Olmos paleoforest grew under wet and warm conditions, similar to those present in modern tropical rainforests. Leaf surface area, tree size and climate reconstructions suggest that this was a highly productive system. Efficient carbon fixation requires hydraulic efficiency to meet the evaporative demands of the photosynthetic surface, but it comes at the expense of increased risk of drought-induced cavitation. Here we tested the hypothesis that the Olmos paleoforest had high hydraulic efficiency, but was prone to cavitation. We characterized the hydraulic properties of the Olmos paleoforest using theoretical conductivity (Ks), vessel composition (S) and vessel fraction (F), and measured drought resistance using vessel implosion resistance (t/b)h(2) and the water potential at which there is 50% loss of hydraulic conductivity (P50). We found that the Olmos paleoforest had high hydraulic efficiency, similar to that present in several extant tropical-wet or semi-deciduous forest communities. Remarkably, the fossil flora had the lowest (t/b)h(2), which, together with low median P50 ( 1.9 MPa), indicate that the Olmos paleoforest species were extremely vulnerable to drought-induced cavitation. Our findings support paleoclimate inferences from leaf physiognomy and paleoclimatic models suggesting it represented a highly productive wet tropical rainforest. Our results also indicate that the Olmos Formation plants had a large range of water conduction strategies, but more restricted variation in cavitation resistance. These straightforward methods for measuring hydraulic properties, used herein for the first time, can provide useful information on the ecological strategies of paleofloras and on temporal shifts in ecological function of fossil forests chronosequences. PMID- 25279991 TI - Maternal nicotine exposure during gestation and lactation induces kidney injury and fibrosis in rat offspring. AB - BACKGROUND: Maternal tobacco smoke exposure adversely affected fetal kidney development. Nicotine stimulates epithelial-mesenchymal transition and connective tissue growth factor (CTGF) expression in the renal epithelium. We hypothesized that maternal nicotine exposure would induce kidney fibrosis and involve CTGF in newborn rats. METHODS: Nicotine was administered to pregnant Sprague-Dawley rats at a dose of 6 mg/kg/d from gestational days 7-21 and gestational day 7 to postnatal day 14. A control group was injected with normal saline. Neonatal kidney tissues underwent histological analysis, collagen measurement, and western blot analysis. RESULTS: Tubular injury scores and total collagen contents were significantly higher in rats born to nicotine-treated dams than in rats born to normal saline-treated dams on postnatal days 7 and 21. Masson's trichrome staining further verified the presence of kidney fibrosis. Prenatal and/or postnatal nicotine exposure increased CTGF expression on postnatal days 7 and 21. CONCLUSION: Maternal nicotine exposure during gestation and lactation induces neonatal kidney fibrosis, and CTGF may be involved in the pathogenesis of kidney fibrosis. These results may be relevant to premature low-birth-weight infants who are conveyed a high risk of developing chronic kidney disease and exposed to breast milk of smoking mothers during the neonatal period. PMID- 25279993 TI - Autism spectrum disorders and coexisting disorders in a nationwide Swedish twin study. AB - BACKGROUND: Evidence from twin and molecular genetic studies is accumulating that Autism Spectrum Disorder (ASD) shares substantial etiological factors with other disorders. This is mirrored in clinical practice where ASD without coexisting disorders is rare. The present study aims to examine the range of coexisting disorders in ASD in a genetically informative cohort. METHODS: Parents of all Swedish 9-year-old twins born between 1992 and 2001 (n = 19,130) underwent a telephone interview designed to screen for child psychiatric disorders, including ASD. To ensure full coverage of child psychiatric disorders, data were also retrieved from population-based health registers. We investigated the coexistence of eight psychiatric disorders known to coexist with ASDs in probands and their co-twins. RESULTS: Half of the individuals with ASDs (50.3%) had four or more coexisting disorders and only 4% did not have any concomitant disorder. The 'healthy co-twin' in ASD discordant monozygotic twin pairs was very often (79% of boys and 50% of girls) affected by at least one non-ASD disorder. The corresponding figures for ASD discordant dizygotic twin pairs were significantly lower (46% of males and 30% of females). CONCLUSIONS: Detailed phenotypic descriptions including symptoms of problems associated with a wide range of child psychiatric disorders may aid in unraveling the genetic architecture of ASD and should guide the development of intervention strategies addressing each problem type specifically. PMID- 25279986 TI - Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region. AB - Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 * 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 * 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 * 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 * 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 * 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRbeta1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 * 10(-67) to 2.67 * 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 * 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 * 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. PMID- 25279994 TI - Proton NMR investigations on 6-alkylamino-2-alkylthioadenosine derivatives. PMID- 25279995 TI - Non-invasive bedside assessment of central venous pressure: scanning into the future. AB - BACKGROUND: Noninvasive evaluation of central venous pressure (CVP) can be achieved by assessing the Jugular Venous Pressure (JVP), Peripheral Venous Collapse (PVC), and ultrasound visualization of the inferior vena cava. The relative accuracy of these techniques compared to one another and their application by trainees of varying experience remains uncertain. We compare the application and utility of the JVP, PVC, and handheld Mini Echo amongst trainees of varying experience including a medical student, internal medicine resident, and cardiology fellow. We also introduce and validate a new physical exam technique to assess central venous pressures, the Anthem sign. METHODS: Patients presenting for their regularly scheduled echocardiograms at the hospital echo department had clinical evaluations of their CVP using these non-invasive bedside techniques. The examiners were blinded to the echo results, each other's assessments, and patient history; their CVP estimates were compared to the gold standard level 3 echo-cardiographer's estimates at the completion of the study. RESULTS: 325 patients combined were examined (mean age 65, s.d. 16 years). When compared to the gold standard of central venous pressure by a level 3 echocardiographer, the JVP was the most sensitive at 86%, improving with clinical experience (p<0.01). The classic PVC technique and Anthem sign had better specificity compared to the JVP. Mini Echo estimates were comparable to physical exam assessments. CONCLUSIONS: JVP evaluation is the most sensitive physical examination technique in CVP assessments. The PVC techniques along with the newly described Anthem sign may be of value for the early learner who still has not mastered the art of JVP assessment and in obese patients in whom JVP evaluation is problematic. Mini Echo estimates of CVPs are comparable to physical examination by trained clinicians and require less instruction. The use of Mini Echo in medical training should be further evaluated and encouraged. PMID- 25279997 TI - The participatory design of a performance oriented monitoring and evaluation system in an international development environment. AB - This article illustrates the application of the impact monitoring and evaluation process for the design and development of a performance monitoring and evaluation framework in the context of human and institutional capacity development. This participative process facilitated stakeholder ownership in several areas including the design, development, and use of a new monitoring and evaluation system, as well their targeted results and accomplishments through the use of timely performance data gathered through ongoing monitoring and evaluation. The process produced a performance indicator map, a comprehensive monitoring and evaluation framework, and data collection templates to promote the development, implementation, and sustainability of the monitoring and evaluation system of a farmer's trade union in an African country. PMID- 25279999 TI - Structural evolution of homoleptic heterodinuclear copper-nickel carbonyl anions revealed using photoelectron velocity-map imaging. AB - The homoleptic heterodinuclear copper-nickel carbonyl anions CuNi(CO)n(-) (n = 2 4) were generated in a pulsed-laser vaporization source and investigated using photoelectron velocity-map imaging spectroscopy. The electron affinities of CuNi(CO)2 (2.15 +/- 0.03 eV), CuNi(CO)3 (2.30 +/- 0.03 eV), and CuNi(CO)4 (1.90 +/- 0.04 eV) were deduced from the photoelectron spectra. Theoretical calculations at the B3LYP level were carried out to elucidate the structures and the electronic properties of CuNi(CO)n(0/1-) (n = 1-4) and to support the experimental observations. Comprehensive comparisons between experiments and calculations suggest that there is a turnover point of the absorption site during the progressive carbonylation process. The carbonyl groups are determined to be preferentially bonded to the nickel atom. When the nickel center satisfies the 18 electron configuration, the copper atom starts to adsorb additional CO molecules. These results will shed light on the bonding mechanisms of the heterometallic carbonyl clusters. PMID- 25279998 TI - Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons. AB - Aldo-keto reductases (AKRs) are promiscuous NAD(P)(H) dependent oxidoreductases implicated in the metabolic activation of polycyclic aromatic hydrocarbons (PAH). These enzymes catalyze the oxidation of non-K-region trans-dihydrodiols to the corresponding o-quinones with the concomitant production of reactive oxygen species (ROS). The PAH o-quinones are Michael acceptors and can form adducts but are also redox-active and enter into futile redox cycles to amplify ROS formation. Evidence exists to support this metabolic pathway in humans. The human recombinant AKR1A1 and AKR1C1-AKR1C4 enzymes all catalyze the oxidation of PAH trans-dihydrodiols to PAH o-quinones. Many human AKRs also catalyze the NADPH dependent reduction of the o-quinone products to air-sensitive catechols, exacerbating ROS formation. Moreover, this pathway of PAH activation occurs in a panel of human lung cell lines, resulting in the production of ROS and oxidative DNA damage in the form of 8-oxo-2'-deoxyguanosine. Using stable-isotope dilution liquid chromatography tandem mass spectrometry, this pathway of benzo[a]pyrene (B[a]P) metabolism was found to contribute equally with the diol-epoxide pathway to the activation of this human carcinogen in human lung cells. Evaluation of the mutagenicity of anti-B[a]P-diol epoxide with B[a]P-7,8-dione on p53 showed that the o-quinone produced by AKRs was the more potent mutagen, provided that it was permitted to redox cycle, and that the mutations observed were G to T transversions, reminiscent of those observed in human lung cancer. It is concluded that there is sufficient evidence to support the role of human AKRs in the metabolic activation of PAH in human lung cell lines and that they may contribute to the causation of human lung cancer. PMID- 25280000 TI - Functional dynamic contrast-enhanced magnetic resonance imaging in an animal model of brain metastases: a pilot study. AB - BACKGROUND: Brain metastasis is a common disease with a poor prognosis. The purpose of this study is to test feasibility and safety of the animal models for brain metastases and to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to enhance detection of brain metastases. METHODS: With approval from the institutional animal ethics committee, 18 New Zealand rabbits were randomly divided into three groups: Group A received an intra-carotid infusion (ICI) of mannitol followed by VX2 cells; group B received successive ICI of mannitol and heparin followed by VX2 cells; and group C received an ICI of normal saline. The survival rate and clinical symptoms were recorded after inoculation. After two weeks, conventional MRI and DCE-MRI were performed using 3.0 Tesla scanner. The number of tumors and detection rate were analyzed. After MRI measurements, the tumors were stained with hematoxylin-eosin. RESULTS: No rabbits died during the procedure. The rabbits had common symptoms, including loss of appetite, lassitude and lethargy, etc. at 10.8+/-1.8 days and 8.4+/-1.5 days post-inoculation in group A and B, respectively. Each animal in groups A and B re-gained the lost weight within 14 days. Brain metastases could be detected by MRI at 14 days post inoculation in both groups A and B, with metastases manifesting as nodules in the brain parenchyma and thickening in the meninges. DCE-MRI increased the total detection of tumors compared to non-contrast MRI (P<0.05). The detection rates of T1-weighted image, T2-weighted image and DCE-MRI were 12%, 32% and 100%, respectively (P<0.05). Necropsy revealed nodules or thickening meninges in the gross samples and VX2 tumor cytomorphologic features in the slides, which were consistent with the MRI results. CONCLUSIONS: The VX2 rabbit model of brain metastases is feasible, as verified by MRI and pathologic findings, and may be a suitable platform for future studies of brain metastases. Functional DCE-MRI can be used to evaluate brain metastases in a rabbit model. PMID- 25280002 TI - Can balance trampoline training promote motor coordination and balance performance in children with developmental coordination disorder? AB - The present study aimed to examine movement difficulties among typically developing 8- to 9-year-old elementary students in Greece and to investigate the possible effects of a balance training program to those children assessed with Developmental Coordination Disorder (DCD). The Body Coordination Test for Children (BCTC; Korperkoordinationstest fur Kinder, KTK, Kiphard & Schilling, 1974) was chosen for the purposes of this study and 20 children out of the total number of 200, exhibited motor difficulties indicating a probable DCD disorder. The 20 students diagnosed with DCD were equally separated into two groups where each individual of the experimental group was paired with an individual of the control group. The intervention group attended a 12-week balance training program while students of the second - control group followed the regular school schedule. All participants were tested prior to the start and after the end of the 12-week period by performing static balance control tasks while standing on an EPS pressure platform and structured observation of trampoline exercises while videotaping. The results indicated that after a 12-week balance training circuit including a trampoline station program, the intervention group improved both factors that were examined. In conclusion, balance training with the use of attractive equipment such as trampoline can be an effective intervention for improving functional outcomes and can be recommended as an alternative mode of physical activity. PMID- 25280003 TI - Perioperative pulmonary aspiration is infrequent and low risk in pediatric anesthetic practice. AB - Recent studies have reported perioperative pulmonary aspiration in pediatric practice to be an uncommon problem associated with low morbidity and mortality. This paper examines the recent publications in both the adult and pediatric literature and looks at some of the potential risk factors involved, both patient and anesthetic, in the development of aspiration of gastric contents. We also look at the risk of severe morbidity following pulmonary aspiration and speculate on possible reasons behind the assertion that pulmonary aspiration in pediatric anesthetic practice is rare and a low-risk event. PMID- 25280001 TI - The gene expression response of chronic lymphocytic leukemia cells to IL-4 is specific, depends on ZAP-70 status and is differentially affected by an NFkappaB inhibitor. AB - Interleukin 4 (IL-4), an essential mediator of B cell development, plays a role in survival of chronic lymphocytic leukemia (CLL) cells. To obtain new insights into the function of the IL-4 pathway in CLL, we analyzed the gene expression response to IL-4 in CLL and in normal B cells (NBC) by oligonucleotide microarrays, resulting in the identification of 232 non-redundant entities in CLL and 146 in NBC (95 common, 283 altogether), of which 189 were well-defined genes in CLL and 123 in NBC (83 common, 229 altogether) (p<0.05, 2-fold cut-off). To the best of our knowledge, most of them were novel IL-4 targets for CLL (98%), B cells of any source (83%), or any cell type (70%). Responses were significantly higher for 54 and 11 genes in CLL and NBC compared to each other, respectively. In CLL, ZAP-70 status had an impact on IL-4 response, since different sets of IL 4 targets correlated positively or negatively with baseline expression of ZAP-70. In addition, the NFkappaB inhibitor 6-Amino-4-(4 phenoxyphenethylamino)quinazoline, which reversed the anti-apoptotic effect of IL 4, preferentially blocked the response of genes positively correlated with ZAP-70 (e.g. CCR2, SUSD2), but enhanced the response of genes negatively correlated with ZAP-70 (e.g. AUH, BCL6, LY75, NFIL3). Dissection of the gene expression response to IL-4 in CLL and NBC contributes to the understanding of the anti-apoptotic response. Initial evidence of a connection between ZAP-70 and NFkappaB supports further exploration of targeting NFkappaB in the context of the assessment of inhibition of the IL-4 pathway as a therapeutic strategy in CLL, especially in patients expressing bad prognostic markers. PMID- 25280004 TI - Thermal energy harvesting plasmonic based chemical sensors. AB - Detection of gases such as H2, CO, and NO2 at 500 degrees C or greater requires materials with thermal stability and reliability. One of the major barriers toward integration of plasmonic-based chemical sensors is the requirement of multiple components such as light sources and spectrometers. In this work, plasmonic sensing results are presented where thermal energy is harvested using lithographically patterned Au nanorods, replacing the need for an external incident light source. Gas sensing results using the harvested thermal energy are in good agreement with sensing experiments, which used an external incident light source. Principal Component Analysis (PCA) was used to reduce the wavelength parameter space from 665 variables down to 4 variables with similar levels of demonstrated selectivity. The combination of a plasmonic-based energy harvesting sensing paradigm with PCA analysis offers a novel path toward simplification and integration of plasmonic-based sensing methods. PMID- 25280006 TI - Palladium-catalyzed oxidative rearrangement of tertiary allylic alcohols to enones with oxygen in aqueous solvent. AB - A one-pot procedure for Pd(TFA)2-catalyzed 1,3-isomerization of tertiary allylic alcohols to secondary allylic alcohols followed by a Pd(TFA)2/neocuproine catalyzed oxidative reaction to beta-disubstituted-alpha,beta-unsaturated kenones was developed. PMID- 25280005 TI - PDGF-D expression is down-regulated by TGFbeta in fibroblasts. AB - Transforming growth factor-beta (TGFbeta) is a key mediator of fibrogenesis. TGFbeta is overexpressed and activated in fibrotic diseases, regulates fibroblast differentiation into myofibroblasts and induces extracellular matrix deposition. Platelet-derived growth factor (PDGF) is also a regulator of fibrogenesis. Some studies showed a link between TGFbeta and PDGF in certain fibrotic diseases. TGFbeta induces PDGF receptor alpha expression in scleroderma fibroblasts. PDGF-C and -D are the most recently discovered ligands and also play a role in fibrosis. In this study, we report the first link between TGFbeta and PDGF-D and -C ligands. In normal fibroblasts, TGFbeta down-regulated PDGF-D expression and up regulated PDGF-C expression at the mRNA and protein levels. This phenomenon is not limited to TGFbeta since other growth factors implicated in fibrosis, such as FGF, EGF and PDGF-B, also regulated PDGF-D and PDGF-C expression. Among different kinase inhibitors, only TGFbeta receptor inhibitors and the IkappaB kinase (IKK) inhibitor BMS-345541 blocked the effect of TGFbeta. However, activation of the classical NF-kappaB pathway was not involved. Interestingly, in a model of lung fibrosis induced by either bleomycin or silica, PDGF-D was down-regulated, which correlates with the production of TGFbeta and other fibrotic growth factors. In conclusion, the down-regulation of PDGF-D by TGFbeta and other growth factors may serve as a negative feedback in the network of cytokines that control fibrosis. PMID- 25280007 TI - Andrographis paniculata leaf extract prevents thioacetamide-induced liver cirrhosis in rats. AB - This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result from the reduction of thioacetamide-induced toxicity, normalizing reactive oxygen species levels, inhibiting cellular proliferation, and inducing apoptosis in HepG2 cells. PMID- 25280008 TI - VGF changes during the estrous cycle: a novel endocrine role for TLQP peptides? AB - Although the VGF derived peptide TLQP-21 stimulates gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, available data on VGF peptides and reproduction are limited. We used antibodies specific for the two ends of the VGF precursor, and for two VGF derived peptides namely TLQP and PGH, to be used in immunohistochemistry and enzyme-linked immunosorbent assay complemented with gel chromatography. In cycling female rats, VGF C-/N-terminus and PGH peptide antibodies selectively labelled neurones containing either GnRH, or kisspeptin (VGF N-terminus only), pituitary gonadotrophs and lactotrophs, or oocytes (PGH peptides only). Conversely, TLQP peptides were restricted to somatostatin neurones, gonadotrophs, and ovarian granulosa, interstitial and theca cells. TLQP levels were highest, especially in plasma and ovary, with several molecular forms shown in chromatography including one compatible with TLQP-21. Among the cycle phases, TLQP levels were higher during metestrus-diestrus in median eminence and pituitary, while increased in the ovary and decreased in plasma during proestrus. VGF N- and C-terminus peptides also showed modulations over the estrous cycle, in median eminence, pituitary and plasma, while PGH peptides did not. In ovariectomised rats, plasmatic TLQP peptide levels showed distinct reduction suggestive of a major origin from the ovary, while the estrogen-progesterone treatment modulated VGF C-terminus and TLQP peptides in the hypothalamus pituitary complex. In in vitro hypothalamus, TLQP-21 stimulated release of growth hormone releasing hormone but not of somatostatin. In conclusion, various VGF peptides may regulate the hypothalamus-pituitary complex via specific neuroendocrine mechanisms while TLQP peptides may act at further, multiple levels via endocrine mechanisms involving the ovary. PMID- 25280011 TI - Applications of polyparameter linear free energy relationships in environmental chemistry. AB - Partitioning behavior of organic chemicals has tremendous influences on their environmental distribution, reaction rates, bioaccumulation, and toxic effects. Polyparameter linear free energy relationships (PP-LFERs) have been proven to be useful to characterize the equilibrium partitioning of organic chemicals in various environmental and technical partitioning systems and predict the respective partition coefficients. Over the past decade, PP-LFER solute descriptors for numerous environmentally relevant organic chemicals and system parameters for environmentally important partitioning systems have been determined, extending substantially the applicability of the PP-LFER approaches. However, the information needed for the use of PP-LFERs including descriptors and parameters is scattered over a large number of publications. In this work, we review the state of the art of the PP-LFER approaches in environmental chemical applications. The solute descriptors and system parameters reported in the literature and the availability of their database are summarized, and their calibration and prediction methods are overviewed. We also describe tips and pitfalls associated with the use of the PP-LFER approaches and identify research needs to improve further the usefulness of PP-LFERs for environmental chemistry. PMID- 25280010 TI - Prolonged instability prior to a regime shift. AB - Regime shifts are generally defined as the point of 'abrupt' change in the state of a system. However, a seemingly abrupt transition can be the product of a system reorganization that has been ongoing much longer than is evident in statistical analysis of a single component of the system. Using both univariate and multivariate statistical methods, we tested a long-term high-resolution paleoecological dataset with a known change in species assemblage for a regime shift. Analysis of this dataset with Fisher Information and multivariate time series modeling showed that there was a~2000 year period of instability prior to the regime shift. This period of instability and the subsequent regime shift coincide with regional climate change, indicating that the system is undergoing extrinsic forcing. Paleoecological records offer a unique opportunity to test tools for the detection of thresholds and stable-states, and thus to examine the long-term stability of ecosystems over periods of multiple millennia. PMID- 25280009 TI - Sequence and annotation of the apicoplast genome of the human pathogen Babesia microti. AB - The apicomplexan intraerythrocytic parasite Babesia microti is an emerging human pathogen and the primary cause of human babesiosis, a malaria-like illness endemic in the United States. The pathogen is transmitted to humans by the tick vector, Ixodes scapularis, and by transfusion of blood from asymptomatic B. microti-infected donors. Whereas the nuclear and mitochondrial genomes of this parasite have been sequenced, assembled and annotated, its apicoplast genome remained incomplete, mainly due to its low representation and high A+T content. Here we report the complete sequence and annotation of the apicoplast genome of the B. microti R1 isolate. The genome consists of a 28.7 kb circular molecule encoding primarily functions important for maintenance of the apicoplast DNA, transcription, translation and maturation of organellar proteins. Genome analysis and annotation revealed a unique gene structure and organization of the B. microti apicoplast genome and suggest that all metabolic and non-housekeeping functions in this organelle are nuclear-encoded. B. microti apicoplast functions are significantly different from those of the host, suggesting that they might be useful as targets for development of potent and safe therapies for the treatment of human babesiosis. PMID- 25280012 TI - Confined phase diagram of binary n-alkane mixtures within three-dimensional microcapsules. AB - The confined phase behaviors of microencapsulated normal hexadecane/octadecane mixtures (abbreviated as m-C16/C18) have been investigated by combination of differential scanning calorimetry and in situ wide-angle X-ray scattering. The binary alkane mixtures confined in three-dimensional geometrical space demonstrate two novel crystallization features. The surface freezing is significantly enhanced after C16/C18 mixtures being encapsulated, and the surface monolayer formed is proved to be an ideal solid solution composed by C16 and C18. Furthermore, m-C16/C18 mixtures are trapped into a stabilized rotator phase below the crystallization temperatures, whereas C16/C18 mixtures with certain compositions form the low-temperature crystalline structure directly. These confined crystallization features originate from the jointed effects of spatial confinement and chain mixing of the components. Moreover, the phase diagram of the confined binary alkane mixtures (m-C16/C18) is successfully established for the first time, which enlightens the crystallization features of other spatially confined soft-matter binary systems. PMID- 25280013 TI - 'Imperfect' conjugated polymer nanoparticles from MEH-PPV for bioimaging and Fe(III) sensing. AB - A simple and effective method was reported for the preparation from MEH-PPV of conjugated polymer nanoparticles (Pdots) that are water-soluble and well dispersed. The as-prepared Pdots show bright orange fluorescence at a quantum yield up to 32.37%. The fluorescence intensity of Pdots can be quenched with good selectively by the successive addition of Fe(3+) . In addition, the as-obtained Pdots were applied to the imaging of HeLa cells, and exhibited low cytotoxicity and excellent biocompatibility. PMID- 25280014 TI - CD147 in cardiovascular disease and thrombosis. AB - Thrombotic and inflammatory pathways play a key role in coronary artery disease (CAD) development. Extracellular matrix metalloproteinase (aka CD147) is a member of the immunoglobulin superfamily that is expressed on many cell types including hematopoietic, endothelial cells, leukocytes, keratinocytes, platelets, and others. The binding partners of CD147 are numerous and diverse, and give some indication to the various roles that CD147 can play; these include homophilic interactions, integrins, cyclophilins, glycoprotein VI (GPVI), caveolin 1, and monocarboxylate transporters. Recent evidence suggests a role for CD147 in both thrombosis and inflammation, as well as involvement in CAD and cancer. In this review, we summarize the role of CD147 and its binding partners in platelets, thrombosis, and arterial disease and assess mechanistic aspects of CD147 biology. PMID- 25280015 TI - Venous thromboembolism in tropical Australia and in Indigenous Australians. AB - There is a paucity of data on the incidence of venous thromboembolism (VTE) in Australia, particularly amongst Indigenous Australians. We have therefore conducted a retrospective review of all cases of deep vein thrombosis and pulmonary embolism over a 24 months' period in two major hospitals of the Northern Territory (NT). A total of 429 VTE diagnoses were recorded over a 2-year period and 71 of 429 (17%) patients were Indigenous Australians. The overall incidence rate was 0.9 per 1,000 person-year for the population of the NT with a rate of 0.5 per 1,000 person-year for Indigenous Australians versus 1 per 1,000 person-year for non-Indigenous Australians. Of the 71, 39 (55%) of the VTE cases in the Indigenous group occurred in patients younger than 50 years and almost half of these (n = 18) were younger than 29 years. Hospitalization was found to be a major risk factor for VTE in 20 (38%) of the 54 Indigenous Australians of whom 10 (26%) patients were younger than 50 years. Although the rate of VTE in Indigenous Australians was low, its onset was significantly earlier in life and it was often triggered by prolonged hospitalization. VTE therefore should be added to the list of adverse outcomes of poor health and chronic diseases, which cause disproportional high rates of hospitalization amongst Indigenous Australians. The low number of VTE observed in older Indigenous patients in our study possibly reflects on the lower life expectancy and ongoing wide gap in life expectancy between Indigenous and non-Indigenous Australians. PMID- 25280017 TI - Nitrite reduction mechanism on a Pd surface. AB - Nitrate (NO3-) is one of the most harmful contaminants in the groundwater, and it causes various health problems. Bimetallic catalysts, usually palladium (Pd) coupled with secondary metallic catalyst, are found to properly treat nitrate containing wastewaters; however, the selectivity toward N2 production over ammonia (NH3) production still requires further improvement. Because the N2 selectivity is determined at the nitrite (NO2-) reduction step on the Pd surface, which occurs after NO3- is decomposed into NO2- on the secondary metallic catalyst, we here performed density functional theory (DFT) calculations and experiments to investigate the NO2- reduction pathway on the Pd surface activated by hydrogen. Based on extensive DFT calculations on the relative energetics among ~100 possible intermediates, we found that NO2- is easily reduced to NO* on the Pd surface, followed by either sequential hydrogenation steps to yield NH3 or a decomposition step to N* and O* (an adsorbate on Pd is denoted using an asterisk). Based on the calculated high migration barrier of N*, we further discussed that the direct combination of two N* to yield N2 is kinetically less favorable than the combination of a highly mobile H* with N* to yield NH3. Instead, the reduction of NO2- in the vicinity of the N* can yield N2O* that can be preferentially transformed into N2 via diverse reaction pathways. Our DFT results suggest that enhancing the likelihood of N* encountering NO2- in the solution phase before combination with surface H* is important for maximizing the N2 selectivity. This is further supported by our experiments on NO2- reduction by Pd/TiO2, showing that both a decreased H2 flow rate and an increased NO2- concentration increased the N2 selectivity (78.6-93.6% and 57.8-90.9%, respectively). PMID- 25280016 TI - Nuclear import of transcription factor BR-C is mediated by its interaction with RACK1. AB - The transcription factor Broad Complex (BR-C) is an early ecdysone response gene in insects and contains two types of domains: two zinc finger domains for the activation of gene transcription and a Bric-a-brac/Tramtrack/Broad complex (BTB) domain for protein-protein interaction. Although the mechanism of zinc finger mediated gene transcription is well studied, the partners interacting with the BTB domain of BR-C has not been elucidated until now. Here, we performed a yeast two-hybrid screen using the BTB domain of silkworm BR-C as bait and identified the receptor for activated C-kinase 1 (RACK1), a scaffolding/anchoring protein, as the novel partner capable of interacting with BR-C. The interaction between BR C and RACK1 was further confirmed by far-western blotting and pull-down assays. Importantly, the disruption of this interaction, via RNAi against the endogenous RACK1 gene or deletion of the BTB domain, abolished the nuclear import of BR-C in BmN4 cells. In addition, RNAi against the endogenous PKC gene as well as phosphorylation-deficient mutation of the predicted PKC phosphorylation sites at either Ser373 or Thr406 in BR-C phenocopied RACK1 RNAi and altered the nuclear localization of BR-C. However, when BTB domain was deleted, phosphorylation mimics of either Ser373 or Thr406 had no effect on the nuclear import of BR-C. Moreover, mutating the PKC phosphorylation sites at Ser373 and Thr406 or deleting the BTB domain significantly decreased the transcriptional activation of a BR-C target gene. Given that RACK1 is necessary for recruiting PKC to close and phosphorylate target proteins, we suggest that the PKC-mediated phosphorylation and nuclear import of BR-C is determined by its interaction with RACK1. This novel finding will be helpful for further deciphering the mechanism underlying the role of BR-C proteins during insect development. PMID- 25280019 TI - Vesicles protect activated acetic acid. AB - Abstract Methyl thioacetate, or activated acetic acid, has been proposed to be central to the origin of life and an important energy currency molecule in early cellular evolution. We have investigated the hydrolysis of methyl thioacetate under various conditions. Its uncatalyzed rate of hydrolysis is about 3 orders of magnitude faster (K=0.00663 s(-1); 100 degrees C, pH 7.5, concentration=0.33 mM) than published rates for its catalyzed production, making it unlikely to accumulate under prebiotic conditions. However, our experiments showed that methyl thioacetate was protected from hydrolysis when inside its own hydrophobic droplets. Further, we found that methyl thioacetate protection from hydrolysis was also possible in droplets of hexane and in the membranes of nonanoic acid vesicles. Thus, the hydrophobic regions of prebiotic vesicles and early cell membranes could have offered a refuge for this energetic molecule, increasing its lifetime in close proximity to the reactions for which it would be needed. This model of early energy storage evokes an additional critical function for the earliest cell membranes. PMID- 25280018 TI - Critical role of exogenous nitric oxide in ROCK activity in vascular smooth muscle cells. AB - OBJECTIVE: Rho-associated kinase (ROCK) signaling pathway has been shown to mediate various cellular functions including cell proliferation, migration, adhesion, apoptosis, and contraction, all of which may be involved in pathogenesis of atherosclerosis. Endogenous nitric oxide (NO) is well known to have an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in vascular smooth muscle cells (VSMCs) in vitro and in vivo. METHODS: VSMCs migration was evaluated using a modified Boyden chamber assay. ROCK activities were measured by Western blot analysis in murine and human VSMCs and aorta of mice treated with or without angiotensin II (Ang II) and/or sodium nitroprusside (SNP), an NO donor. RESULTS: Co-treatment with SNP inhibited the Ang II-induced cell migration and increases in ROCK activity in murine and human VSMCs. Similarly, the increased ROCK activity 2 weeks after Ang II infusion in the mouse aorta was substantially inhibited by subcutaneous injection of SNP. CONCLUSIONS: These findings suggest that administration of exogenous NO can inhibit ROCK activity in VSMCs in vitro and in vivo. PMID- 25280021 TI - Matrix-assisted laser desorption/ionization mass spectrometry imaging: a powerful tool for probing the molecular topology of plant cutin polymer. AB - The cutin polymers of different fruit cuticles (tomato, apple, nectarine) were examined using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) after in situ release of the lipid monomers by alkaline hydrolysis. The mass spectra were acquired from each coordinate with a lateral spatial resolution of approximately 100 MUm. Specific monomers were released at their original location in the tissue, suggesting that post-hydrolysis diffusion can be neglected. Relative quantification of the species was achieved by introducing an internal standard, and the collection of data was subjected to non supervised and supervised statistical treatments. The molecular images obtained showed a specific distribution of ions that could unambiguously be ascribed to cutinized and suberized regions observed at the surface of fruit cuticles, thus demonstrating that the method is able to probe some structural changes that affect hydrophobic cuticle polymers. Subsequent chemical assignment of the differentiating ions was performed, and all of these ions could be matched to cutin and suberin molecular markers. Therefore, this MALDI-MSI procedure provides a powerful tool for probing the surface heterogeneity of plant lipid polymers. This method should facilitate rapid investigation of the relationships between cuticle phenotypes and the structure of cutin within a large population of mutants. PMID- 25280020 TI - Oncogenic GNAQ and GNA11 mutations in uveal melanoma in Chinese. AB - PURPOSE: To examine whether GNAQ and GNA11 somatic mutations previously identified in uveal melanomas of Caucasians are associated with uveal melanomas in Chinese patients. METHODS: Uveal melanomas treated by primary enucleation in Chinese patients underwent a mutation analysis of GNAQ and GNA11 with sequencing of exon 5 and exon 4. RESULTS: The study included 50 patients with uveal melanoma and with a mean age of 47.6+/-13.0 years. During the follow-up of at least 3 years, 20 (40%) patients developed extraocular metastases. The frequencies of GNAQ and GNA11 somatic mutations in uveal melanoma were 18% (9/50) and 20% (10/50), respectively. The mutations occurred exclusively in codon 209 of exon 5. No mutations were detected in exon 4. Mutations affecting codon 209 in GNAQ were c.626A>C(Q209P) (78%) and c.626A>T(Q209L) (22%). Mutations affecting codon 209 in GNA11 were exclusively c.626A>T(Q209L) (100%). In none of the tumors, mutations of BRAF and NRAS were detected. GNAQ/11 mutations were marginally (P = 0.045) associated with optic disc involvement. In Kaplan-Meier analysis, metastasis-free survival was not significantly (P = 0.94) associated with GNAQ/11 mutations. CONCLUSIONS: Mutations of GNAQ and GNA11 can be found in Chinese patients as in Caucasian patients with uveal melanoma, with a higher frequency reported for Caucasian patients. PMID- 25280022 TI - Review on medicinal uses, pharmacological, phytochemistry and immunomodulatory activity of plants. AB - Since ancient times, plants have been an exemplary source of medicine. Researchers have discovered some important compounds from plants. The present work constitutes a review of the medicinal plants whose immunomodulant activity has been proven. We performed PUBMED, EMBASE, Google scholar searches for research papers of medicinal plants having immunomodulant activity. Medicinal plants used by traditional physicians or reported as having immunomodulant activity include Acacia concocinna, Camellia sinensis, Lawsonia inermis Linn, Piper longum Linn, Gelidium amansii, Petroselinum crispum, Plantago major and Allium sativum. Immunomodulant activities of some of these medicinal plants have been investigated. The medicinal plants documented have immunomodulant activity and should be further investigated via clinical trial. PMID- 25280023 TI - The "mystery" of cutaneous sarcoidosis: facts and controversies. AB - The reason why the cutaneous form of sarcoidosis is well known in the literature is because of its spectrum of manifestations granting it the fame of a Great Imitator. The mystery shrouding the pathogenesis of this rare cutaneous disease is still there (in spite of the fundamental progress of the various diagnostic methods in current day medicine). The production of the morphological substrate - the epithelioid cell granuloma - which is considered to be characteristic of skin sarcoidosis, could, however, also be the end result of a reaction to i) various specific infectious agents such as Leishmaniasis cutis, coccidioidomycosis, etc., ii) certain residual bacterial or other mycobacterial antigens which, at the moment of setting the diagnosis are - by definition - non-infectious but still immunogenic, as well as iii) different tumor antigens in lesional tissue or other location. Often, differentiating between sarcodiosis and a sarcoid-like reaction, based on the updated criteria for cutaneous sarcoidosis, is problematic to downright impossible. A future characterization of the genetic signature of the two conditions, as well as the implementation of additional mandatory panels for i) the identification of certain infectious or ii) non-infectious but immunogenic and iii) tumor antigens in the epithelioid cell granuloma (or in another location in the organism), could be a considerable contribution to the process of differentiating between the two above-mentioned conditions. This will create conditions for greater accuracy when setting the subsequent therapeutic approaches. PMID- 25280024 TI - Impact of mast cells on multiple sclerosis: inhibitory effect of natalizumab. AB - Mast cells (MCs) derive from a distinct precursor in the bone marrow and are predominantly found in tissues at the interface between the host and the external environment where they can secrete mediators without overt degranulation. Mast cells mature under local tissue microenvironmental factors and are necessary for the development of allergic reactions, through crosslinking of their surface receptors for IgE (FcepsilonRI), leading to degranulation and the release of vasoactive, pro-inflammatory and nociceptive mediators that include histamine, pro-inflammatory and anti-inflammatory cytokines and proteolytic enzymes. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demylination within the central nervous system. MCs are involved in the pathogenesis of MS by generating various vasoactive mediators and cytokines and participate in the destruction of the myelin sheath and the neuronal cells. The process of the development of demyelinating plaques in MS is probably linked with the rupture of the blood-brain barrier by MC products. The effects of natalizumab, which is a very effective drug in reducing the annualized relapse rate and other relapse-based endpoints, are discussed. Here, we report the relationship between MCs and MS. PMID- 25280025 TI - Evaluation of CD44 variant expression in oral, head and neck squamous cell carcinomas using a triple approach and its clinical significance. AB - Cancer stem cells possess the qualities of self-renewal, tumorigenesis and the ability to recapitulate a heterogeneous tumor. Our group was the first to isolate head and neck squamous cell carcinoma (HNSCC) stem cells using the cell surface marker CD44. CD44 is a trans-membrane glycoprotein with a multitude of key functions that regulate cancer cell proliferation and metastasis. The variety of CD44 functions is due to tissue-specific patterns of glycosylation of the extracellular portion, and to the multiple protein isoforms (CD44 variants, CD44v) generated by alternative splicing. This study investigates the expression pattern of CD44 variants in HNSCC. Ten cell lines from the most common HNSCC locations and representative of various clinical outcomes were assayed by quantitative realtime PCR, flow cytometry and immunofluorescence comparatively with normal oral keratinocytes. The CD44 v4 and v6 were exclusively abundant in HNSCC while the isoform v1,2 was expressed in normal oral keratinocytes. Of interest, the highest level of CD44v6 expression was detected in advanced metastatic HNSCC, suggesting a link between CD44v6 expression and HNSCC metastasis, while the highest CD44v4 was detected in a stage IV HNSCC refractory to chemotherapy which developed recurrence. Oral-derived HNSCC expressed the highest CD44v4 and v6, and levels corresponded with staging, showing also an increasing tendency with recurrence and metastasis. CD44v were detected predominantly in smaller cells (a characteristic that has been associated with stem cell properties) or cells with mesenchymal morphology (a characteristic that has been associated with the migratory and invasive potential of epithelial tumor cells), suggesting that CD44v differential expression in HNSCC may be representative of the morphological changes inherent during tumor progression towards a more aggressive potential, and thus contributing to the individual tumor biology. The mechanism of CD44 variant involvement in HNSCC progression and metastasis is under investigation. PMID- 25280026 TI - Effect of an educational program in primary care: the case of lipid control in cardio-cerebrovascular prevention. AB - Lowering blood cholesterol levels reduces the risk of coronary heart disease. However, the effect of interventions depends on the patients' adherence to treatment. Primary care plays an important role in the detection, treatment and monitoring of disease, therefore different educational programs (EP) have been implemented to improve disease management in general practice. The present study is aimed to assess whether a general practitioner auditing and feedback EP may improve dyslipidaemia management in a primary care setting and to evaluate patients' adherence to prescribed lipid-lowering treatment. The quality of cardiovascular and cerebrovascular disease prevention before and after the implementation of an EP offered to 25 general practitioners (GPs), was evaluated. Clinical and prescription data on patients receiving at least one lipid-lowering treatment was collected. To evaluate the quality of the healthcare service provided, clinical and biochemical outcomes, and drug-utilization, process indicators were set up. Adherence was evaluated before and after the EP as the "Medication Possession Ratio" (MPR). A correlation analysis was carried out to estimate the effect of the MPR in achieving pre-defined clinical end-points. Prescription data for lipid-lowering drugs was collected in a sample of 839 patients. While no differences in the achievement of blood lipid targets were observed, a slight but significant improvement of the MPR was registered after the EP (MPR >0.8=64.2% vs 60.6%, p=0.0426). Moreover, high levels of statin adherence were associated with the achievement of total blood cholesterol target (OR=3.3 for MPR >0.8 vs MPR <0.5, 95% CI:1.7-6.7) or LDL therapeutic goal (OR=3.3 for MPR >0.8 vs MPR <0.5, 95% CI:1.5-7.2). The EP partially improved the defined clinical targets; probably, a more patient-based approach could be more appropriate to achieve the defined target. Further studies are needed to identify how healthcare services can be improved. PMID- 25280027 TI - Changes in extra- and intracellular pH in hepatocytes exposed to gabexate mesilate. AB - Gabexate mesilate (GM) is a synthetic inhibitor of plasmatic and pancreatic serine proteases licensed for the treatment of pancreatitis. Here we show that in suspensions of isolated hepatocytes, profound changes in extracellular, cytoplasmic, and vesicular pH occur after addition of GM. Isolated hepatocytes obtained by collagenase perfusion of rat liver were pre-incubated with 1, 2, and 4 mM GM. Extracellular pH (pH in the incubation medium) was measured by a conventional pH electrode, cytosolic and vesicular pH were measured by fluorescence changes of 2',7'-biscarboxyethyl-5,6-carboxyfluorescein acetoxymethyl ester (BCECF-AM) and fluorescein dextran, respectively. Incubation of hepatocytes with GM resulted in a dose-dependent decrease of extracellular pH. Cytosolic pH decreased rapidly and markedly in a dose-dependent manner during the first minutes and gradually returned towards baseline. Simultaneously, GM induced a rapid alkalinization of acidic vesicles. The presence of bis-(p-nitrophelyl) phosphate (BNPP), an esterase inhibitor, reduced the extent of extracellular acidification. Incubation of hepatocytes in the presence of dimethylamiloride, an Na+/H+ exchanger inhibitor, or in a sodium-free medium, did not modify the rate and extent of extracellular acidification. GM, a commercially available pharmacological agent, could be useful to manipulate extra- and intracellular pH. PMID- 25280028 TI - Pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection: the role of surgical treatment. AB - Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive compulsive disorders (OCD) consistently exacerbate in temporal correlation to a Group A beta-haemolytic streptococcal infection. In children with PANDAS, there is speculation about whether tonsillectomy or adenotonsillectomy might improve the neuropsychiatric course. Our objective was to examine whether such surgery impacted remission or, in patients without remission, modified clinical course of the disease, streptococcal antibody titers, neuronal antibodies or clinical severity of Obsessive-Compulsive Disorder (OCD) and/or tics. Study participants (n = 120) with positive PANDAS criteria were recruited, examined, and divided into surgical or non-surgery groups. The surgical group consisted of children with tonsillectomy or adenotonsillectomy (n=56). The remaining children were categorized as non-surgery (n=64). Clinical follow-up was made every 2 months for more than 2 years. Surgery did not affect symptomatology progression, streptococcal and neuronal antibodies, or the clinical severity of neuropsychiatric symptoms in these children. In conclusion, in our series clinical progression, antibody production, and neuropsychiatric symptom severity did not differ on the basis of surgical status. We cannot uphold surgical management as likely to impact positive remission rates, course of OCD/tics, or antibody concentrations in children with PANDAS. PMID- 25280029 TI - Ozone autohemotherapy induces long-term cerebral metabolic changes in multiple sclerosis patients. AB - Ozone autohemotherapy is an emerging therapeutic technique that is gaining increasing importance in treating neurological disorders. A validated and standard methodology to assess the effect of such therapy on brain metabolism and circulation is however still lacking. We used a near-infrared spectroscopy (NIRS) system to monitor the cerebral metabolism and a transcranial Doppler (TCD) to monitor the blood flow velocity in the middle cerebral arteries. Fifty-four subjects (32 neurological patients and 22 controls) were tested before, during, and after ozone autohemotherapy. We monitored the concentration changes in the level of oxygenated and deoxygenated haemoglobin, and in the level of the Cytochrome-c-oxidase (CYT-c). As a primary endpoint of the work, we showed the changes in the brain metabolism and circulation of the entire population. The concentration of oxygenated haemoglobin increased after the reinjection of the ozoned blood and remained higher than the beginning for another 1.5 hours. The concentration of the deoxygenated haemoglobin decreased during the therapy and the CYT-c concentration markedly increased about 1 hour after the reinjection. No significant changes were observed on the blood flow velocity. As secondary endpoint, we compared the NIRS metabolic pattern of 20 remitting-relapsing multiple sclerosis (MS) patients against 20 controls. We showed that by using only 7 NIRS variables it was possible to characterize the metabolic brain pattern of the two groups of subjects. The MS subjects showed a marked increase of the CYT-c activity and concentration about 40 minutes after the end of the autohemotherapy, possibly revealing a reduction of the chronic oxidative stress level typical of MS sufferers. From a technical point of view, this preliminary study showed that NIRS could be useful to show the effects of ozone autohemotherapy at cerebral level, in a long-term monitoring. The clinical result of this study is the quantitative measurement of the CYT-c level changes in MS induced by ozone autohemotherapy. PMID- 25280030 TI - Human mesenchymal stem cells produce bioactive neurotrophic factors: source, individual variability and differentiation issues. AB - The possible use of cell therapies for neurological lesions and disorders is regarded as a very promising strategy. However, many issues related to cell type, tissue donor, expected biological action etc., are still open. In this study human mesenchymal stem cells derived from different fetal and adult tissues were examined in order to explore growth and neurotrophic factor synthesis and biological action, also considering the individual variability of the donors. Cells were derived from different human tissues and characterized according to the guidelines of the International Society for Cellular Therapy. Growth and neurotrophic factor synthesis was evaluated by real time PCR, biological assays and ELISA. It was found that human mesenchymal stem cells produce vascular endothelial-, nerve-growth factor (VEGF, NGF), brain-derived-, ciliary- and glial derived neurotrophic factors (BDNF, CDGF, GDNF), which are neuroprotective molecules, but the source and the donor influence the synthesis rate. Accordingly, it is suggested that the source and the individual variability are key issues to be considered in the perspective of the clinical use of mesenchymal stem cells in neurological disorders. PMID- 25280031 TI - An antibody reactivity-based assay for diagnosis of invasive candidiasis using protein array. AB - The increased incidence of invasive candidiasis and of patients at risk requires early diagnosis and treatment to improve prognosis and survival. The aim of this study was to set up a ten-protein array-based immunoassay to assess the IgG antibody responses against ten well-known immunogenic C. albicans proteins (Bgl2, Eno1, Pgk1, Pdc11, Fba1, Adh1, Als3, Hwp1, Hsp90 and Grp2) in 51 patients with invasive candidiasis (IC) and in 38 culture-negative controls (non-IC). Antibody levels were higher against Bgl2, Eno1, Pgk1, Als3, Hwp1 and Grp2, than against Adh1, Pdc11, Fba1 and Hsp90, irrespectively of the patient group considered. Moreover, the IgG levels against Bgl2, Eno1, Pgk1 and Grp2 were significantly higher in IC than in non-IC patients. Furthermore, the ROC curves generated by the analysis of the antibody responses against Bgl2, Grp2 and Pgk1 displayed AUC values above 0.7, thus discriminating IC and non-IC patients. According to these results, the employment of the microarray immunoassay (a rapid, sensitive and multiparametric system), in parallel with conventional diagnostics, can help to spot IC patients. This ultimately will allow to initiate an early, focused and optimized antifungal therapy. PMID- 25280032 TI - Efficacy and safety of pidotimod in the prevention of recurrent respiratory infections in children: a multicentre study. AB - Acute respiratory infections (ARI) still represent a big challenge for paediatricians, especially in those children defined as "ailed" as they are more susceptible to such kinds of disease. In this paediatric population, the immune system is still under-developed with an evident alteration in cytokine levels. A clinical study was carried out in 5 sites in Russia with the intention to enroll children particularly susceptible to contract respiratory infections (defined as "ailing"), assigning them to a treatment group with pidotimod in comparison with a control group, treating them for 30 days and observing the reduction in the number of ARI episodes throughout the follow-up period (6 months). Moreover, changes in serum immunological markers were evaluated at baseline and 30 days after treatment discontinuation. One hundred and fifty-seven ailing children were enrolled and assigned to two arms: a main pidotimod treatment group or a control group. The percentage of incidence of ARIs in the observation period at three different time points was statistically significant (p < 0.05). At the end of the follow-up period (after 6 months), ARIs had developed in 72 children (92.3%) in the main group and in 79 patients (100%) in the control group. Concerning changes of the immunological markers, the treatment group showed a better profile of normalization compared to the control group. The 30-day pidotimod therapy course led to improvement/reduction in the rate of acute respiratory infection recurrence in ailing children within a 3-month period, with a quick elimination of symptoms and signs of infection and, as a result, a faster recovery. The normalisation of the content of the pro-inflammatory cytokine interleukin-8 confirmed the immune-modulatory effect of the investigational drug, underlying its prophylactic effect. PMID- 25280033 TI - Do elevated serum IgM levels have to be included in probable diagnosis criteria of patients with ataxia-telangiectasia? AB - Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder that is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency. Delay in diagnosis or misdiagnosis is probable due to its wide clinical heterogeneity in infancy. Recurrent sinopulmonary infections are often the only presenting symptom and usually patients have decreased immunoglobulins. A total 10% of patients who present with decreased serum immunoglobulin G and A and with normal or elevated immunoglobulin M levels are often misdiagnosed as hyperimmunoglobulin M syndrome. Definitive diagnosis is made if a patient with progressive cerebellar ataxia has a disease causing mutation on the ATM gene. Ataxia-telangiectasia guideline of the European Society for Immunodeficiencies defines the probable diagnosis criteria. We evaluated twenty ataxia-telangiectasia patients (mean age 13.8+/-4.1 years) retrospectively who were followed-up for a mean of 38.6+/-27.0 months. Twelve patients had a family history of consanguinity. A total of 80% patients suffered from various infections. Neoplasms occurred in three of them. Patients showed immunological abnormalities as low IgG (45%), low IgA (65%) and elevated IgM (60%) levels. CD3+CD4+ T lymphocyte frequency was low in 45% patients. The mean AFP concentration at the diagnosis was 191.9+/-140.1 ng/mL and the raised IgM values did not show any statistically significant relationship with high AFP concentrations. Frequency of the elevated IgM concentrations in (60%) patients raises the concerns about thinking this finding has to be accepted as a probable diagnosis criterium. PMID- 25280034 TI - Recurrent miscarriages in women not fulfilling classification criteria for antiphospholipid antibody syndrome. AB - Obstetric antiphospholipid antibody syndrome (APS), is well defined by classification criteria. It is well known that women with APS should receive prophylactic anticoagulation therapy with subcutaneous low weight heparin all throughout pregnancy and in the first 6 weeks postpartum. However, the optimal treatment for pregnant women having positive anti-phospholipid antibodies, but not fulfilling classification criteria for APS is still unclear. In this retrospective study we report pregnancy outcomes of 10 patients affected by recurrent miscarriages and positive anti-cardiolipin or abeta2GP1 antibodies with titers ranging from 10 to 20 GPL/MPL demonstrated at least twice before pregnancy. PMID- 25280035 TI - Gut hormones and endothelial dysfunction in patients with obesity and diabetes. AB - Overweight and obesity are the fifth leading risk for global deaths and its prevalence has doubled since 1980. At least 2.8 million adults, worldwide, die each year as a result of being overweight or obese. The deleterious effects of obesity are tightly related to diabetes, as they are often clinically present in combination to confer increased cardiovascular mortality. Thus, patients with diabetes and obesity are known to develop accelerated atherosclerosis characterized by a dysfunctional endothelium and decreased nitric oxide bioavailability. Recent clinical studies support, indeed, the use of incretin based antidiabetic therapies for vascular protection. Thus, attention has been focusing on gut hormones and their role, not only in the regulation of appetite but also in vascular health. Intervention directed at modulating these molecules has the potential to decrease mortality of patients with diabetes and obesity. This review will cover part of the ongoing research to understand the role of gut hormones on endothelial function and vascular health. PMID- 25280036 TI - Novel hydroxyapatite biomaterial covalently linked to raloxifene. AB - Since raloxifene, a drug used in osteoporosis therapy, inhibits osteoclast, but not osteoblast functions, it has been suggested to improve recovery during implant surgery. The present paper describes an effective method to link raloxifene, through a covalent bond, to a nano-Hydroxyapatite-based biomaterial by interfacing with (3-aminopropyl)-Triethoxysilane as assessed by Infra Red Fourier Transformed (IR-FT) spectroscopy and Scanning Electron Microscope (SEM). To evaluate the safety of this modified new material, the vitality of osteoblast like cells cultured with the new biomaterial was then investigated. Raloxifene conjugated HAbiomaterial has been shown to be a safe material easy to obtain which could be an interesting starting point for the use of a new functional biomaterial suitable in bone regeneration procedures. PMID- 25280037 TI - An incomplete form of childhood Behcet's disease treated with infliximab. AB - Behcet's disease (BD) is a multi-systemic vasculitis characterized by the possible presence of cutaneous, ocular, articular and neurological manifestations. In this report, we examine the case of a fifteen-year old boy with an incomplete form of juvenile Behcet's disease which began with joint involvement and developed into a complete form only after several years. The patient showed a rapid response to anti-TNF-alpha (infliximab) with an improvement of mucocutaneous lesions (oral and genital ulcers, pseudofolliculitis) and arthritis. PMID- 25280038 TI - Serum resistin levels in children with primary snoring. AB - Primary Snoring (PS) has been positioned at the milder end of the Sleep Disordered Breathing severity continuum characterized by snoring and it is usually underestimated. PS is defined as snoring without apnea, frequent arousals, or gas exchange abnormalities and recent studies demonstrated that children with PS have increased blood pressure and reduced arterial distensibility. The association between adipokines and SDB has been recently investigated, though most of the studies were focused on OSAS where intermittent hypoxia characterizing the disease may lead to an inflammatory cascade and to the release of several adipokines, contributing to oxidative stress. Resistin, initially described s an adipokine increasing insulin resistance, has been recently identified as a novel important member of the cytokine family involved in the regulation of inflammation. The aim of our study was to investigate circulating resistin levels in normal weight children with PS. Sixty-five children of normal weight aged between 4 and 14 years of age were selected for habitual snoring. Children with positive polysomnography were excluded from the study. Serum resistin levels were detected in all children with PS. Thirty-three healthy non-snorer children with similar age, sex and BMI were selected as a control group. A significantly higher level of resistin was observed in patients with PS compared to the control group (4.67+/-1.91 ng/ml vs 3.98+/-1.58 ng/ml; p<0.01). Patients with inconclusive pulse oximetry showed significantly higher resistin levels than those with negative recordings recordings (5.29+/-1.91 ng/ml vs 4.20+/-1.93 ng/ml; p<0.008). Moreover, there was a significant increasing trend between sieric adipokine level and the frequency of snoring (p<0.006). Our results suggest that systemic inflammation and oxidative stress may also play a significant role in the pathophysiology of PS. PMID- 25280039 TI - Retrospective observational study to investigate Sinerga, a multifactorial nutritional product, and bacterial extracts in the prevention of recurrent respiratory infections in children. AB - In this retrospective observational clinical study, 167 children, aged 3 to 7 years, of both sexes, with a clinical history of recurrent respiratory infections, administered with bacterial extracts of first and second generation or Sinerga a nutritional product containing palmitoylethanolamide, bovine colostrum, phenylethylamine and the new generation of probiotic kluyveromyces FM B0399, were observed. The goal of the study was to compare the supplementation with Sinerga with the supplementation with bacterial extracts, for the effect on the frequency of episodes of respiratory infection that had resulted in a prescription for antibiotics. The study focused retrospectively on the months from March 2013 to November 2012. The results showed a greater reduction in the frequency of respiratory infections with antibiotic therapy in the group of children supplemented with Sinerga than in the group treated with bacterial extracts. In particular, it was observed that 49.3% of the children supplemented with Sinerga, against 5% of those supplemented with extracts, had no infectious episodes requiring the administration of an antibiotic. 100% of subjects supplemented with Sinerga have had no more than two episodes of respiratory infection, while this condition, in the cohort treated with bacterial extracts, was observed in only 51% of cases. PMID- 25280040 TI - Subglotic malt-lymphoma of the larynx: an unusual presentation of chronic cough. AB - Extranodal non-Hodgkin lymphomas limited to the larynx are rare, accounting for less than 1% of all laryngeal neoplasms. The most common site of development of primary laryngeal lymphomas is the supraglottic region. In most cases, the presenting symptoms are hoarseness, dysphagia, dyspnea, and cervical lymphadenopathy. They consist mainly of non-Hodgkin lymphoma, especially of diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue. We report a case of a primary extranodal marginal zone of mucosa-associated lymphoid tissue (Malt Lymphoma) of the larynx in a 73-year-old non-smoker woman, presented as chronic cough, unresponsive to oral corticosteroid. We present a detailed report of her clinical and paraclinical data as well as treatment options. In patients with chronic cough, uncommon causes should be considered when the cough persists after evaluation for common causes. If a cough persists after consideration of the most common causes, CT scan and a bronchoscopic evaluation are fundamental for the diagnosis of tumors of the upper and lower respiratory tract. PMID- 25280041 TI - Effects of a nutrient additive on the density of functional bacteria and the microbial community structure of bioorganic fertilizer. AB - In this study, a secondary composting experiment was conducted to investigate the effects of concentrated monosodium glutamate wastewater (CMGW) as a nutrient additive on enhancing the density of functional bacteria in bioorganic fertilizer (BOF). The results showed that, as the CMGW was added, the composting mixture temperature rose more quickly and strongly, and the functional bacteria Bacillus subtilis F2 percentage in spores increased significantly. Furthermore, both the highest species richness value (Rs) of a given sample and similarity coefficient value (Cs) between a sample and strain F2 based on DGGE analysis were also observed in the treatment with CMGW. A similar effect of CMGW on the microbial community structure was verified by means of illumine-MiSeq sequencing. It may thus be concluded that CMGW is a recommendable nutrient additive for F2 predominating in the secondary composting process. PMID- 25280042 TI - The effect of trace element addition to mono-digestion of grass silage at high organic loading rates. AB - This study investigated the effect of trace element addition to mono-digestion of grass silage at high organic loading rates. Two continuous reactors were compared. The first mono-digested grass silage whilst the second operated in co digestion, 80% grass silage with 20% dairy slurry (VS basis). The reactors were run for 65weeks with a further 5weeks taken for trace element supplementation for the mono-digestion of grass silage. The co-digestion reactor reported a higher biomethane efficiency (1.01) than mono-digestion (0.90) at an OLR of 4.0kgVSm( 3)d(-1) prior to addition of trace elements. Addition of cobalt, iron and nickel, led to an increase in the SMY in mono-digestion of grass silage by 12% to 404LCH4kg(-1)VS and attained a biomethane efficiency of 1.01. PMID- 25280043 TI - Integration of denitrifying phosphorus removal via nitrite pathway, simultaneous nitritation-denitritation and anammox treating carbon-limited municipal sewage. AB - High nutrients removal above 90% from carbon-limited municipal sewage was obtained without adding external carbon source. Achieving nitritation was a prerequisite to improve nutrients removal. Denitrifying phosphorus (P) removal using nitrite as electron acceptor was the key pathway in anoxic zone, where nitrogen removal reached above 60% and average denitrifying P removal was 88%. Simultaneous nitritation/denitritation and anaerobic ammonia oxidation (anammox) possibly contributed to nitrogen removal of 26-36% in aerobic zone. Quantitative PCR assays presented that the abundance of anammox bacteria under nitritation was more than that under complete nitrification. The largest amount of anammox bacteria was 1.32*10(6)copies/gVSS, about 5.6 times increase over a period of 255days. Nitrite concentration of 17mg/L in aerobic zone inhibited anammox bacteria. Quantitative results suggested possible occurrence of anammox. Based on performance of nitritation, combining heterotrophic denitrification with autotrophic nitrogen removal is an effective strategy to improve nutrients removal from carbon-limited wastewater. PMID- 25280044 TI - Intermittent load implementation in microbial fuel cells improves power performance. AB - This study reports on the response of small-scale MFCs to intermittent loading, in terms of power output over time. The aim was to understand the evolution with time of power output under different duty cycles, in conditions close to practical implementation. Inexpensive ceramic membranes were compared to cation exchange membranes, under continuous flow and with a pre-digester connected. Results show that at the minute-scale, all the duty cycles investigated, produced 78% higher power bursts from the MFCs (500MUW) than when under continuous loading (280MUW). These results were recorded from MFCs employing ceramic membranes, whereas the difference in performance for MFCs employing commercially available cation-exchange-membranes was insignificant. When normalising to daily energy production, only specific duty cycles produced more power than continuous loading. Furthermore, the introduction of a pre-digester increased the MFC power outputs 10-fold, thus confirming that separating fermentation from electro-active respiration, significantly enhances the system performance. PMID- 25280045 TI - Sequential in situ hydrotalcite precipitation and biological denitrification for the treatment of high-nitrate industrial effluent. AB - A sequential process using hydrotalcite precipitation and biological denitrification was evaluated for the treatment of a magnesium nitrate (Mg(NO3)2) rich effluent (17,000mgNO3(-)-N/L, 13,100mgMg/L) generated from an industrial nickel-mining process. The hydrotalcite precipitation removed 41% of the nitrate (7000mgNO3(-)-N/L) as an interlayer anion with an approximate formula of Mg5Al2(OH)14(NO3)2.6H2O. The resultant solute chemistry was a Na-NO3-Cl type with low trace element concentrations. The partially treated effluent was continuously fed (hydraulic retention time of 24h) into a biological fluidised bed reactor (FBR) with sodium acetate as a carbon source for 33days (1:1 v/v dilution). The FBR enabled >70% nitrate removal and a maximal NOx (nitrate+nitrite) removal rate of 97mg NOx-N/Lh under alkaline conditions (pH 9.3). Overall, this sequential process reduced the nitrate concentration of the industrial effluent by >90% and thus represents an efficient method to treat Mg(NO3)2-rich effluents on an industrial scale. PMID- 25280046 TI - Effect of short-time hydrothermal pretreatment of kitchen waste on biohydrogen production: fluorescence spectroscopy coupled with parallel factor analysis. AB - The enhancement of bio-hydrogen production from kitchen waste by a short-time hydrothermal pretreatment at different temperatures (i.e., 90 degrees C, 120 degrees C, 150 degrees C and 200 degrees C) was evaluated. The effects of temperature for the short-time hydrothermal pretreatment on kitchen waste protein conversion and dissolved organic matter characteristics were investigated in this study. A maximum bio-hydrogen yield of 81.27mL/g VS was acquired at 200 degrees C by the short-time hydrothermal pretreatment during the anaerobic fermentative hydrogen production. Analysis of the dissolved organic matter composition showed that the protein-like peak dominated and that three fluorescent components were separated using fluorescence excitation-emission matrix spectra coupled with the parallel factor model. The maximum fluorescence intensities of protein-like components decomposed through the parallel factor analysis has a significant correlation with the raw protein concentration, showed by further correlation analysis. This directly impacted the hydrogen production ability. PMID- 25280047 TI - Fe2 O3 -TiO2 nanocomposites for enhanced charge separation and photocatalytic activity. AB - Photocatalysis provides a cost effective method for both renewable energy synthesis and environmental purification. Photocatalytic activity is dominated by the material design strategy and synthesis methods. Here, for the first time, we report very mild and effective photo-deposition procedures for the synthesis of novel Fe2 O3 -TiO2 nanocomposites. Their photocatalytic activities have been found to be dramatically enhanced for both contaminant decomposition and photoelectrochemical water splitting. When used to decompose a model contaminant herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), monitored by both UV/Vis and total organic carbon (TOC) analysis, 10% Fe-TiO2 -H2 O displayed a remarkable enhancement of more than 200 % in the kinetics of complete mineralisation in comparison to the commercial material P25 TiO2 photocatalyst. Furthermore, the photocurrent is nearly double that of P25. The mechanism for this improvement in activity was determined using density functional theory (DFT) and photoluminescence. These approaches ultimately reveal that the photoelectron transfer is from TiO2 to Fe2 O3 . This favours O2 reduction which is the rate determining step in photocatalytic environmental purification. This in situ charge separation also allows for facile migration of holes from the valence band of TiO2 to the surface for the expected oxidation reactions, leading to higher photocurrent and better photocatalytic activity. PMID- 25280048 TI - In vitro pharmacological screening of three newly synthesised pyrimidine derivatives. AB - The antibacterial and antifungal activities of three new pyrimidine derivatives, namely, 2,6-bis(4,6-dimethylpyrimidin-2-ylthio)benzene-1,4-diol (1),3,5-bis(4,6 dimethylpyrimidin-2-ylthio)-2-methylbenzene-1,4-diol (2) and 3,5-bis(4,6 dimethylpyrimidin-2-ylthio)-2-methoxybenzene-1,4-diol (3), synthesised by electrochemical method are presented here. The compounds were screened for their activities against Gram-positive and Gram-negative bacteria, Bacillus subtilis, Staphylococcusaureus, Escherichia coli and a pathogenic fungus Aspergillus niger. The results show that these compounds have significant activity against these bacteria and fungus. The minimum inhibitory concentration of compound 1 was determined as 62.5 MUg/mL against B. subtilis, 125 MUg/mL against E. coli and 250 MUg/mL against S. aureus establishing its promising activities higher than susceptible ranges. PMID- 25280049 TI - The association of lacrimal gland inflammation with alopecia areata. AB - PURPOSE: To describe the association of lacrimal gland inflammation with alopecia areata. METHODS: We reviewed the medical records of 4 patients diagnosed with lacrimal gland inflammation who had an antecedent or subsequent episode of alopecia. Data was collected on the presentation age, gender, medical history, disease onset, symptoms and signs, imaging, histopathology, systemic evaluation, management and outcome. Pathology and imaging results were correlated with clinical findings. RESULTS: Three patients were Asian and one Caucasian. Two developed alopecia after presentation for lacrimal inflammation. The remaining two had a history of alopecia totalis (2 years and 10 years). Three of the 4 patients presented or developed other systemic disorders, including seizures, thrombocytopenia, optic neuritis, ulcerative colitis, allergic rhinitis, lymphadenopathy, vasculitic rash and positive p-ANCA values. All received oral corticosteroids, with the addition of methotrexate therapy in one for relapsing inflammation. CONCLUSIONS: Lacrimal gland inflammation and alopecia areata are autoimmune processes that can be seen in association with each other. PMID- 25280050 TI - Diagnosing type 1 von Willebrand disease: good for patient's health or for doctor's prestige? reply. PMID- 25280051 TI - Reverberation time influences musical enjoyment with cochlear implants. AB - OBJECTIVE: To identify factors that enhance the enjoyment of music in cochlear implant (CI) recipients. Specifically, we assessed the hypothesis that variations in reverberation time (RT60) may be linked to variations in the level of musical enjoyment in CI users. STUDY DESIGN: Prospective analysis of music enjoyment in normal-hearing individuals. SETTING: Single tertiary academic medical center. PATIENTS: Normal-hearing adults (N = 20) were asked to rate a novel 20-second melody on three enjoyment modalities: musicality, pleasantness, and naturalness. INTERVENTION: Subjective rating of music excerpts. MAIN OUTCOME MEASURES: Participants listened to seven different instruments play the melody, each with five levels (0.2, 1.6, 3.0, 5.0, 10.0 s) of RT60, both with and without CI simulation processing. Linear regression analysis with analysis of variance was used to assess the impact of RT60 on music enjoyment. RESULTS: Without CI simulation, music samples with RT60 = 3.0 seconds were ranked most pleasant and most musical, whereas those with RT60 = 1.6 seconds and RT60 = 3.0 seconds were ranked equally most natural (all p < 0.05). With CI simulation, music samples with RT60 = 0.2 seconds were ranked most pleasant, most musical, and most natural (all p < 0.05). Samples without CI simulation show a preference for middle-range RT60, whereas samples with CI simulation show a negative linear relationship between RT60 and musical enjoyment, with preference for minimal reverberation. CONCLUSION: Minimization of RT60 may be a useful strategy for increasing musical enjoyment under CI conditions, both in altering existing music as well as in composition of new music. PMID- 25280052 TI - Effect of cochlear nerve electrocautery on the adult cochlear nucleus. AB - HYPOTHESIS: Electrocauterization and subsequent transection of the cochlear nerve induce greater injury to the cochlear nucleus than sharp transection alone. BACKGROUND: Some studies show that neurofibromatosis Type 2 (NF2) patients fit with auditory brainstem implants (ABIs) fail to achieve speech perception abilities similar to ABI recipients without NF2. Reasons for these differences remain speculative. One hypothesis posits poorer performance to surgically induced trauma to the cochlear nucleus from electrocautery. Sustained electrosurgical depolarization of the cochlear nerve may cause excitotoxic induced postsynaptic nuclear injury. Equally plausible is that cautery in the vicinity of the cochlear nucleus induces necrosis. METHODS: The cochlear nerve was transected in anesthetized adult gerbils sharply with or without bipolar electrocautery at varying intensities. Gerbils were perfused at 1, 3, 5, and 7 days postoperatively; their brainstem and cochleas were embedded in paraffin and sectioned at 10 MUm. Alternate sections were stained with flourescent markers for neuronal injury or Nissl substance. In additional experiments, anterograde tracers were applied directly to a sectioned eighth nerve to verify that fluorescent-labeled profiles seen were terminating auditory nerve fibers. RESULTS: Cochlear nerve injury was observed from 72 hours postoperatively and was identical across cases regardless of surgical technique. Postsynaptic cochlear nucleus injury was not seen after distal transection of the nerve. By contrast, proximal transection was associated with trauma to the cochlear nucleus. CONCLUSION: Distal application of bipolar electrocautery seems safe for the cochlear nucleus. Application near the root entry zone must be used cautiously because this may compromise nuclear viability needed to support ABI stimulation. PMID- 25280053 TI - Fibrous dysplasia of the temporal bone: systematic review of management and hearing outcomes. AB - OBJECTIVES: The management options for otologic symptoms (i.e., hearing loss, otorrhea) in patients with fibrous dysplasia of the temporal bone (FDTB) include either observation or otologic surgery. The objective of this review is to describe the hearing outcomes in patients with FDTB to compare surgical intervention and conservative management to determine an evidence-based approach to patient management. DATA SOURCES: Cochrane Central Register of Controlled Trials (1995-April 5, 2013), MEDLINE (January 1948-April 5, 2013), EMBASE (January 1974-April 5, 2013), conference proceedings, and the reference lists of articles. STUDY SELECTION: Studies describing interventions or no intervention in patients with FDTB were included. Studies failing to report hearing outcomes were excluded. DATA EXTRACTION: Two authors independently reviewed titles and abstracts, read full-text articles, assessed quality, and extracted data. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were followed. DATA SYNTHESIS: Seventy-two studies involving 215 patients were included. Thirty-one studies (n = 49 patients), including three case series and 28 case reports, had sufficient information for analysis of hearing outcomes (Level 4 evidence). The surgical intervention showing the best hearing outcomes was canaloplasty, with improvement in 84% of patients (n = 16 patients) and stable hearing thresholds in 18% (n = 3 patients). CONCLUSION: The literature lacks consistent reporting of hearing outcomes after otologic surgery in FDTB. Level 4 evidence suggests that an improvement in hearing thresholds is achievable in most patients when the disease involves the external ear canal. A management algorithm is proposed using the available evidence. PMID- 25280054 TI - Polypharmacy and chronic pain: harm exposure is not all about the opioids. AB - OBJECTIVE AND DESIGN: Individuals seeking treatment for chronic pain in multidisciplinary pain management services are typically already on high doses of pain medications. This cross-sectional cohort study of patients with long-term chronic pain examined profiles of polypharmacy and pain medication-related harm exposure. SETTING: Multidisciplinary pain management service. SUBJECTS: The cohort comprised 224 patients taking medications for their pain (1-9 medications; mean = 3.19) with an average pain duration of 10.33 years. METHODS: The Medication Quantification Scale III (MQS-III) was used to examine potential harm exposure. We generated detriment scores for simple analgesics, adjunctive therapies (e.g., anticonvulsants), opioids, and benzodiazepines. RESULTS: The total MQS-III score was correlated with the total number of medications, but not with age. Almost 10% of patients took medications from all four categories, with most taking medications from two (37%) to three (35%) classes. Eighty percent of patients were taking opioids, accounting for 41% of total MQS scores. Five primary profiles of potential medication-related harms were identified: high harm from all medication categories (N = 12); above average harm from single category simple analgesics (N = 76), adjunctive analgesics (N = 59), or opioids (N = 46); and above average opioid and benzodiazepine harm (N = 31). CONCLUSIONS: While treatment with multiple medications for synergistic or adjunctive effects may assist in medical management of chronic pain, this approach generates increased potential harm exposure. We show that the majority of detriment comes from medications other than opioids and highlight the importance of profiling all pain medications contributing to polypharmacy in clinical pain studies. PMID- 25280056 TI - Advancements in waste water characterization through NMR spectroscopy: review. AB - There are numerous organic pollutants that lead to several types of ecosystem damage and threaten human health. Wastewater treatment plants are responsible for the removal of natural and anthropogenic pollutants from the sewage, and because of this function, they play an important role in the protection of human health and the environment. Nuclear magnetic resonance (NMR) has proven to be a valuable analytical tool as a result of its versatility in characterizing both overall chemical composition as well as individual species in a wide range of mixtures. In addition, NMR can provide physical information (rigidity, dynamics, etc.) as well as permit in depth quantification. Hyphenation with other techniques such as liquid chromatography, solid phase extraction and mass spectrometry creates unprecedented capabilities for the identification of novel and unknown chemical species. Thus, NMR is widely used in the study of different components of wastewater, such as complex organic matter (fulvic and humic acids), sludge and wastewater. This review article summarizes the NMR spectroscopy methods applied in studies of organic pollutants from wastewater to provide an exhaustive review of the literature as well as a guide for readers interested in this topic. PMID- 25280055 TI - Toxicity of topical antifungal agents to stratified human cultivated corneal epithelial sheets. AB - PURPOSE: Prolonged use of topical antifungal agents may compromise corneal epithelial integrity. Here, we used an in vitro model of human stratified corneal epithelium to compare the ocular toxicity profiles of 4 different antifungal eye drops. METHODS: Human corneal epithelial cell sheets were cultured in a serum free medium containing 0.1% micafungin, 1% voriconazole, 5% pimaricin, 0.1% amphotericin B, or controls (saline or 5% glucose). Cell viability and barrier function were measured by WST-1 assay and carboxyfluorescein permeability assay, respectively. Cell migration was measured on a wound healing assay. RESULTS: WST 1 assay and carboxyfluorescein permeability assay revealed that amphotericin B was the most toxic drug, followed by pimaricin, micafungin, and voriconazole. Cell migration on a wound healing assay was decreased in the following order, amphotericin B, pimaricin, micafungin, and voriconazole. CONCLUSIONS: Topical micafungin and voriconazole appeared to be the least toxic to the corneal epithelium. Drug prescription should consider not only fungal species and susceptibility but also ocular toxicity and stage of treatment. PMID- 25280057 TI - An infrared scanning and tracking system for detecting mid-wave infrared spectral characteristics of moving targets. AB - This paper presents the design and fabrication of an infrared scanning and tracking system for detecting mid-wave infrared (MWIR) spectral characteristics of moving targets. The infrared spectra and infrared image are integrated in this system, which is mainly composed of a two-dimensional (2D) scanning mirror, dual band infrared lens, long-wave infrared imaging unit, MWIR spectrum-measuring unit, and processing-controlling unit. After describing the design specifications of this system, this paper analyzes the detection method and then describes how the tracking was realized by controlling the 2D scanning mirror. Experiments were carried out to verify its feasibility. PMID- 25280058 TI - Improving natural products identification through targeted LC-MS/MS in an untargeted secondary metabolomics workflow. AB - Tandem mass spectrometry is a widely applied and highly sensitive technique for the discovery and characterization of microbial natural products such as secondary metabolites from myxobacteria. Here, a data mining workflow based on MS/MS precursor lists targeting only signals related to bacterial metabolism is established using LC-MS data of crude extracts from shaking flask fermentations. The devised method is not biased toward specific compound classes or structural features and is capable of increasing the information content of LC-MS/MS analyses by directing fragmentation events to signals of interest. The approach is thus contrary to typical auto-MS(2) setups where precursor ions are usually selected according to signal intensity, which is regarded as a drawback for metabolite discovery applications when samples contain many overlapping signals and the most intense signals do not necessarily represent compounds of interest. In line with this, the method described here achieves improved MS/MS scan coverage for low-abundance precursor ions not captured by auto-MS(2) experiments and thereby facilitates the search for new secondary metabolites in complex biological samples. To underpin the effectiveness of the approach, the identification and structure elucidation of two new myxobacterial secondary metabolite classes is reported. PMID- 25280059 TI - Cerebellopontine angle mass mimicking lingual nerve injury after dental implant placement: a case report. AB - This is a rare case report of a cerebellopontine angle (CPA) mass mimicking lingual nerve injury after a dental implant placement. Lingual nerve injury is a common complication following dental implant placement. CPA masses are likely to cause symptomatic trigeminal neuralgia, and thus can mimic and be easily confused with oral diseases. We experienced a case of CPA mass mimicking lingual nerve injury after dental implant placement. The patient was a 57-year-old Japanese female who complained of glossalgia. She underwent dental implant placement in the mandible before visiting our clinic. Panoramic x-ray radiography revealed no abnormalities; the salivary flow rate by gum test was 7.0 ml/10 min. She was diagnosed with lingual nerve injury and secondary burning mouth syndrome. Vitamin B12 and oral moisturizer did not provide relief; furthermore, numbness in the lower lip emerged. A Semmes Weinstein test demonstrated elevation of her sensitivity threshold. Finally, magnetic resonance imaging revealed a 20-mm diameter mass in the CPA. The patient is now being followed under conservative management. Our experience underscores the importance of including CPA mass in the differential diagnosis of dental diseases. PMID- 25280060 TI - A new way to interpret perturbation-correlation moving-window two-dimensional correlation spectroscopy: probing the dynamic interaction of ionic liquid 1-ethyl 3-methylimidazolium acetate to absorb atmospheric water. AB - A rule to interpret perturbation-correlation moving-window two-dimensional correlation spectroscopy (PCMW2D) was developed. Compared with Morita's rule, this proposed rule retains the ability to obtain interval features (i.e., monotonicity, concavity, and convexity) and adds the function to quickly and accurately determine both tipping points (i.e., local extrema and inflection points). It could be described as follows: the local extrema and inflection point could be determined by the zero point with an opposite sign on its left and right side in PiPhi (synchronous PCMW2D) and PiPsi (asynchronous PCMW2D), respectively. Specifically, a negative left (right) side and a positive right (left) side of point indicates a local minimal (maximal) value. By using the rule to interpret PiIR (PCMW2D infrared spectroscopy) of 1-ethyl-3-methyl-imidazolium acetate [EMIM][Ac]-atmospheric water (H2O) as a function of time, we found that the atmospheric water was absorbed only into the bulk of [EMIM][Ac] before 150 min by hydrogen-bonding interaction, only onto the surface of [EMIM][Ac] after 330 min by van der Waals force, and both to the bulk and surface of [EMIM][Ac] between 150 and 330 min by hydrogen-boding and van der Waals force simultaneously. The proportion of bulk water sorption and surface water sorption to [EMIM][Ac] was about 4 and 96%, respectively. PMID- 25280061 TI - Cytotoxic activity of novel palladium-based compounds on leukemia cell lines. AB - Effective treatment methods for human leukemia are under development, but so far none of them have been found to be completely satisfactory. It was recently reported that palladium complexes have significant anticancer activity as well as lower toxicity compared with some clinically used chemotherapeutics. The anticancer activities of two novel palladium(II) complexes, [Pd(sac)(terpy)](sac).4H2O and [PdCl(terpy)](sac).2H2O, were tested against three human leukemia cell lines, Jurkat, MOLT-4, and THP-1, in comparison with cisplatin and adriamycin. The cytotoxic effect of the drugs was determined using the MTT assay. Cell death was assessed using fluorescein isothiocyanate annexin/propidium iodide staining for flow cytometry. Furthermore, p53 phosphorylation, poly(ADP-ribose) polymerase cleavage, and Bax and Bcl-2 mRNA levels were examined to elucidate the mechanism of cell death induction. Both complexes exhibited a significant dose-dependent antigrowth effect in vitro. The complexes predominately induced apoptosis, but necrosis was also observed. In vitro results have shown that palladium(II) complexes may be regarded as potential anticancer agents for treating human leukemia. Therefore, further analysis to determine the putative mechanism of action and in-vivo studies on animal models are warranted. PMID- 25280062 TI - Pharmacokinetics of low molecular weight heparin in patients with malignant tumors. AB - Cancer patients have an increased risk for venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is the mainstay of VTE treatment in these patients. Heparanase, which degrades heparin and LMWH, is an enzyme secreted from a variety of malignant tumors. The objective of this study was to elucidate the pharmacokinetics of LMWH in patients with locally advanced or metastatic cancer. A total of 10 cancer patients with VTE treated with the LMWH enoxaparin at a standard dose of 1 mg/kg every 12 h were enrolled. Blood samples were obtained before the injection of LMWH and at 1, 2, 3, 4, 6, and 8 h after LMWH administration, and they were tested for anti-factor Xa activity and heparanase levels. Peak anti-Xa activity was achieved 2-8 h after subcutaneous administration of LMWH. Six patients did not reach a therapeutic anti-Xa activity target (0.6-1.2 IU/ml) at 4 h after LMWH administration. Four patients did not reach anti-factor Xa values of 0.6 IU/ml throughout the trial. The median anti-Xa activity before LMWH injection was 0.24 IU/ml (range 0.07-0.7 IU/ml), as opposed to 0.52 IU/ml in historical controls. The median anti-Xa activity 4 h after LMWH injection was 0.58 IU/ml (range 0.22-1.23 IU/ml), as opposed to 1.2 IU/ml in historical controls. The blood level of heparanase in patients with malignancy and VTE was 6.24 +/- 4.3 ng/ml, compared with 2.67 +/- 1.09 ng/ml in cancer-free, age-matched, normal controls. In this pilot study, a substantial proportion of cancer patients suffering from VTE and treated with LMWH had subtherapeutic anti Xa activity. PMID- 25280063 TI - Effect of androgen replacement therapy on atherosclerotic risk markers in young to-middle-aged men with idiopathic hypogonadotropic hypogonadism. AB - OBJECTIVE: Idiopathic hypogonadotropic hypogonadism is a rare disorder. This study evaluated the effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with this disorder. DESIGN AND METHODS: Forty-three male patients aged 30 (range: 24-39 years) who were newly diagnosed with idiopathic hypogonadotropic hypogonadism and 20 age-, sex- and weight matched controls (range: 26-39 years) were included in the study. Androgen replacement therapy was given according to the Algorithm of Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes (2010; Journal of Clinical Endocrinology and Metabolism, 95, 2536). The patients were assessed at a pretreatment visit and 3 and 6 months after the treatment. Inflammatory markers and lipid parameters were evaluated. Endothelial function was assessed with brachial flow-mediated dilation of a brachial artery and high-resolution ultrasonography of the carotid intima-media thickness. RESULTS: The carotid intima-media thickness (P < 0.001) was higher and the brachial flow-mediated diameter (P = 0.002) was lower in patients with idiopathic hypogonadotropic hypogonadism compared to the control subjects at the pretreatment visit. There was a negative correlation between the total testosterone level and carotid intima-media thickness (r = -0.556, P = <0.001). The carotid intima-media thickness and per cent flow-mediated diameter were significantly improved in the patient group 6 months after the androgen replacement therapy (P = 0.002 and 0.026, respectively). CONCLUSIONS: This study indicated that low total testosterone levels can be considered a significant marker of atherosclerosis in patients with idiopathic hypogonadotropic hypogonadism and that androgen replacement therapy significantly reduces atherosclerotic risk markers in these patients after 6 months. PMID- 25280064 TI - Docking ligands into flexible and solvated macromolecules. 7. Impact of protein flexibility and water molecules on docking-based virtual screening accuracy. AB - The use of predictive computational methods in the drug discovery process is in a state of continual growth. Over the last two decades, an increasingly large number of docking tools have been developed to identify hits or optimize lead molecules through in-silico screening of chemical libraries to proteins. In recent years, the focus has been on implementing protein flexibility and water molecules. Our efforts led to the development of Fitted first reported in 2007 and further developed since then. In this study, we wished to evaluate the impact of protein flexibility and occurrence of water molecules on the accuracy of the Fitted docking program to discriminate active compounds from inactive compounds in virtual screening (VS) campaigns. For this purpose, a total of 171 proteins cocrystallized with small molecules representing 40 unique enzymes and receptors as well as sets of known ligands and decoys were selected from the Protein Data Bank (PDB) and the Directory of Useful Decoys (DUD), respectively. This study revealed that implementing displaceable crystallographic or computationally placed particle water molecules and protein flexibility can improve the enrichment in active compounds. In addition, an informed decision based on library diversity or research objectives (hit discovery vs lead optimization) on which implementation to use may lead to significant improvements. PMID- 25280066 TI - Double perovskite Sr(2)FeMoO(6) films prepared by electrophoretic deposition. AB - The present work reports on the new approach to create metal-supported Sr2FeMoO6 (SFMO)-based electrodes that have high potential to be applied in solid oxide fuel cells. The SFMO films were formed on stainless steel substrates by electrophoretic deposition (EPD) method. Ethyl alcohol with phosphate ester as a dispersant and isopropyl alcohol with I2-acetone mixture as a charge additive were considered as an effective medium for EPD of SFMO particles. The synthesis of SFMO powder as well as suspension preparation and deposition kinetics were systematically studied. The effect of applied voltage on the thickness and morphology of SFMO films was established. The microstructure of the deposits was examined by electron microscopy. The thickness, morphology and porosity of the SFMO layers can be fine-tuned by varying solvent, charging additives, deposition time, and applied voltage. According to X-ray photoelectron spectroscopy analysis, it was found that Fe(3+)-Mo(5+) and Fe(2+)-Mo(6+) pairs coexist, whereas the valent balance shifts toward an Fe(2+)-Mo(6+) configuration. PMID- 25280065 TI - Approach to analyze the diversity of myxobacteria in soil by semi-nested PCR denaturing gradient gel electrophoresis (DGGE) based on taxon-specific gene. AB - The genotypic diversity of insoluble macromolecules degraded myxobacteria, provided an opportunity to discover new bacterial resources and find new ecological functions. In this study, we developed a semi-nested-PCR-denaturing gradient gel electrophoresis (DGGE) strategy to determine the presence and genotypic diversity of myxobacteria in soil. After two rounds of PCR with myxobacteria-specific primers, an 194 bp fragment of mglA, a key gene involved in gliding motility, suitable for DGGE was obtained. A large number of bands were observed in DGGE patterns, indicating diverse myxobacteria inhabiting in soils. Furthermore, sequencing and BLAST revealed that most of the bands belonged to the myxobacteria-group, and only three of the twenty-eight bands belonged to other group, i.e., Deinococcus maricopensis. The results verified that myxobacterial strains with discrepant sequence compositions of gene mglA could be discriminated by DGGE with myxobacteria-specific primers. Collectively, the developed semi nested-PCR-DGGE strategy is a useful tool for studying the diversity of myxobacteria. PMID- 25280067 TI - KATNB1 in the human testis and its genetic variants in fertile and oligoasthenoteratozoospermic infertile men. AB - Oligoasthenoteratozoospermia (OAT) is a phenotype frequently observed in infertile men, and is defined by low spermatozoa number, abnormal spermatozoa morphology and poor motility. We previously showed that a mutation in the Katnb1 gene in mice causes infertility because of OAT. The KATNB1 gene encodes an accessory subunit of the katanin microtubule-severing enzyme complex; this accessory subunit is thought to modulate microtubule-severing location and activity. We hypothesized that KATNB1 may play a role in human spermatogenesis and that genetic variants in KATNB1 could be associated with OAT in humans. Using immunostaining, we defined the localization of the KATNB1 protein in human testes. KATNB1 was present during spermatid development, and in particular localized to the microtubules of the manchette, a structure required for sperm head shaping. To assess a potential association between genetic variants in the KATNB1 gene and infertile men with OAT, we performed direct sequencing of genomic DNA samples from 100 OAT infertile and 100 proven fertile men. Thirty-seven KATNB1 variants were observed, five of which had not previously been described. Ten variants were present only in OAT men, however, statistical analysis did not reveal a significant association with fertility status. Our results suggest that variants in the KATNB1 gene are not commonly associated with OAT infertility in Australian men. PMID- 25280068 TI - Vitamin D and muscle strength throughout the life course: a review of epidemiological and intervention studies. AB - The putative role of vitamin D in muscle function and strength throughout the life course is of interest because muscle strength is required for engagement in physical activity at all ages. As vitamin D deficiency is widely reported in the population, especially in countries at high latitude, the potential importance of vitamin D in muscle function throughout life, and the potential impacts on growth and development, participation in physical activity, and effects on skeletal and cardio-metabolic health, comprise an important topic for discussion. This review provides an overview of muscle function and summarises the role of the vitamin D receptor and the proposed molecular mechanisms of action of vitamin D in muscle cells. In addition, the review provides a comprehensive assessment of the clinical evidence surrounding the association between vitamin D and muscle strength. Among adults, particularly older adults, cross-sectional and cohort studies reported a positive association between vitamin D status and muscle strength. These associations have been largely confirmed by intervention studies. Limited research has been carried out in adolescents and children; two cross sectional studies in adolescents have suggested an association between serum 25 hydroxyvitamin D concentrations and muscle strength. However, the two intervention studies in adolescents have yielded conflicting results. Other than a single observational study, data in young children are very limited and further investigation in under 12-year-olds is warranted. PMID- 25280070 TI - Statin treatment patterns and clinical profile of patients with risk factors for coronary heart disease defined by National Cholesterol Education Program Adult Treatment Panel III. AB - OBJECTIVE: To compare clinical characteristics, statin treatment patterns and adherence among patients at different risk for coronary heart disease (CHD) as defined by National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines. METHODS: Patients >= 18 years old with >= 1 claim for dyslipidemia, >= 1 statin claim, or >= 1 LDL-C value >= 100 mg/dL were identified from 1 January 2007 to 31 July 2012. Patients were classified as low risk (LR) (0 1 risk factor: hypertension, age >= 45 years [men] or >= 55 years [women], or low HDL-C), moderate/moderately high risk (MR) (>= 2 risk factors), high risk (HR) (CHD or CHD risk equivalent), or very high risk (VHR) (acute coronary syndrome, or established cardiovascular disease plus diabetes or metabolic syndrome). Medication use and lipid levels during the 12 months before and statin use during the 6 months after index were compared across risk groups. RESULTS: There were 1,524,351 LR, 242,357 MR, 188,222 HR, and 57,469 VHR patients identified. Statin use was observed in 15% of all patients, but was higher in the VHR group (45%) versus LR (12%), MR (18%), and HR (29%) groups. Simvastatin accounted for 50%-52% of all statin use, and average statin dose was higher among VHR patients compared with all other groups. Adherence was low overall (mean proportion of days covered [PDC]: 0.57), but higher among VHR (0.69) versus others (mean PDC: 0.55, 0.59, and 0.59 in LR, MR, and HR groups, respectively). CONCLUSIONS: Statin treatment was low across all risk groups, and VHR patients had higher doses and better adherence compared with other risk groups. However, adherence was not optimal, indicating a potential limited benefit from statin treatment. PMID- 25280072 TI - The benefits of integrating a statistician into a nursing research department. AB - In today's competitive healthcare market, more hospitals are seeking Magnet(r) designation. To meet the expectations for evidence-based practice and research, many organizations are considering the addition of statistical expertise to their team. The authors discuss the benefits of analytical support and integration of a statistician on the team. PMID- 25280069 TI - Neurocognitive abilities in the general population and composite genetic risk scores for attention-deficit hyperactivity disorder. AB - BACKGROUND: The genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population. METHODS: Children (N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure. RESULTS: The results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ (beta = -.05, p < .001) and working memory performance (beta = -.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition (p > .05). CONCLUSIONS: These findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level. PMID- 25280073 TI - The influence of emerging administrative scientists: an interview with Matthew McHugh. PMID- 25280074 TI - An assessment of the alignment between graduate nursing leadership education and established standards. AB - The increasing complexity of healthcare systems is driving changes in the academic preparation of nurse leaders. The number of doctorate of nursing practice programs has increased. Leaders in the Council on Graduate Education for Administration in Nursing (CGEAN) were interested in learning how graduate nursing leadership programs have responded. An electronic survey was administered to CGEAN members to understand the emphasis of their graduate curricula. Results demonstrate good alignment between academic programs, American Association of College of Nursing essentials, and American Organization of Nurse Executives competencies. PMID- 25280075 TI - Effects of a national safe patient handling program on nursing injury incidence rates. AB - OBJECTIVE: The objective of the study was to identify which components of a system-wide safe patient handling (SPH) program reduced musculoskeletal injury (MSI) due to patient handling among nurses. METHODS: The 3-year longitudinal study from 2008 to 2011 used a pretest-posttest design. The study was conducted in the Veterans Health Administration, and all medical centers participated. The outcome was 2011 MSI incidence rates due to patient-related handling for nurses, expressed as injuries per 10 000 full-time employees. RESULTS: Three organizational risk factors, bed days of care, facility complexity level, and baseline MSI incidence rate, were significantly associated with MSI incidence rate and explained 21% of its variation. Five SPH components, including deployment of ceiling lifts and other new technologies, peer leader effectiveness, competency in SPH equipment use, facility coordinator link with safety committee, and peer leader training, uniquely accounted for an additional 23% of the total variation. CONCLUSIONS: Findings provide evidence to support the effectiveness of a multicomponent approach to SPH programs given contextual considerations. PMID- 25280076 TI - Virtual education: is it effective for preparing nurses for a hospital move? AB - OBJECTIVE: The objective of this study was to compare the effectiveness of using a virtual environment (VE) versus traditional paper floor plans (FPs) to prepare nurses for wayfinding in a new hospital building. BACKGROUND: This study was designed to control for variables such as task complexity and individual ability that have been missed in other media comparison studies. METHODS: Thirty nurses were assigned to the VE or FP condition using a randomized block experimental design. Subjects were blocked by alternate ranks on spatial/navigational ability and computer attitude/experience and randomly assigned to conditions. Nurses received instruction with either a VE or FP condition. Wayfinding tasks were then completed with trained observers at the new hospital under construction. RESULTS: The investigators found no significant differences between the wayfinding performance or postintervention confidence levels of subjects. Instruction using both media improved wayfinding and navigation skills. Qualitative findings suggest that interactions of the instructional style, media, and learner influence information retention and transfer. CONCLUSIONS: Although the virtual media did not prove to be more effective than FPs, it was equally effective for learning wayfinding and navigation skills in a new hospital. Nursing leaders may want to consider use of 3-dimensional VEs as an early method to provide repetitive practice for learning how to navigate a new large-scale space. PMID- 25280077 TI - Experienced nurses' level of engagement: priority areas for nurse executives. AB - OBJECTIVE: This study examined the engagement level of direct care nurses 45 years or older with at least 10 years' experience to create a baseline for action to increase engagement among these seasoned nurses. BACKGROUND: Assessing an organization's level of nursing engagement and designing strategies to improve engagement are crucial to support decreased turnover and increased levels of quality outcomes. METHODS: The Health Care Advisory Board's Nurse Engagement Survey was distributed via SurveyMonkey to direct care nurses meeting the study criteria. RESULTS: Thirty-seven percent of participants were engaged, 47% content, 12% ambivalent, 4% disengaged, and 98.6% of respondents were proud to be a nurse. CONCLUSION: Nursing leaders should assess the level of engagement of their nursing workforce and use this information to prioritize strategies designed to retain, reenergize, and engage experienced nurses. PMID- 25280078 TI - Viewpoints on driving of individuals with and without autism spectrum disorder. AB - OBJECTIVE: Understanding the viewpoints of drivers with autism spectrum disorder (ASD) is crucial in the development of mobility support and driver training that is responsive to their needs. METHODS: Fifty young adults with ASD and fifty seven typically developed adults participated in the study to form a contrasting group. Q-methodology was used to understand viewpoints on driving as a main mode of transportation. Data were analysed using a PQ by-person varimax rotation factor analysis. RESULTS: Although some ASD participants perceived themselves as confident and independent drivers, others preferred other modes of transportation such as public transport and walking. Anxiety was also found to be a barrier to driving. The contrast group revealed consistent viewpoints on their driving ability. They preferred driving as their main mode of transportation and believed that they were competent, safe and independent drivers. CONCLUSION: These results are important in the planning of transport policies and driver training for individuals with ASD. Driver training manuals can be developed to address anxiety issues, hazard perception and navigation problems in the ASD population. Their use of public transport could be further facilitated through more inclusive transport policies. PMID- 25280079 TI - Morphology modulating the wettability of a diamond film. AB - Control of the wetting property of diamond surface has been a challenge because of its maximal hardness and good chemical inertness. In this work, the micro/nanoarray structures etched into diamond film surfaces by a maskless plasma method are shown to fix a surface's wettability characteristics, and this means that the change in morphology is able to modulate the wettability of a diamond film from weakly hydrophilic to either superhydrophilic or superhydrophobic. It can be seen that the etched diamond surface with a mushroom-shaped array is superhydrophobic following the Cassie mode, whereas the etched surface with nanocone arrays is superhydrophilic in accordance with the hemiwicking mechnism. In addition, the difference in cone densities of superhydrophilic nanocone surfaces has a significant effect on water spreading, which is mainly derived from different driving forces. This low-cost and convenient means of altering the wetting properties of diamond surfaces can be further applied to underlying wetting phenomena and expand the applications of diamond in various fields. PMID- 25280080 TI - Axial diffusion barriers in near-infrared nanopillar LEDs. AB - The growth of GaAs/GaAsP axial heterostructures is demonstrated and implemented as diffusion current barriers in nanopillar light-emitting diodes at near infrared wavelengths. The nanopillar light-emitting diodes utilize an n-GaAs/i InGaAs/p-GaAs axial heterostructure for current injection. Axial GaAsP segments are inserted into the n- and p-GaAs portions of the nanopillars surrounding the InGaAs emitter region, acting as diffusion barriers to provide enhanced carrier confinement. Detailed characterization of growth of the GaAsP inserts and electronic band-offset measurements are used to effectively implement the GaAsP inserts as diffusion barriers. The implementation of these barriers in nanopillar light-emitting diodes provides a 5-fold increase in output intensity, making this a promising approach to high-efficiency pillar-based emitters in the near infrared wavelength range. PMID- 25280086 TI - Effects of chemical aging on the ice nucleation activity of soot and polycyclic aromatic hydrocarbon aerosols. AB - The role of soot particles as ice nuclei (IN) in heterogeneous freezing processes in the atmosphere remains uncertain. Determination of the freezing efficiency of soot is complicated by the changing properties of soot particles undergoing atmospheric aging processes. In this study, the heterogeneous freezing temperatures of droplets in contact with fresh and oxidized soot particles were determined using an optical microscope apparatus equipped with a sealed cooling stage and a CCD video camera. Experiments were also conducted using fresh and oxidized polycyclic aromatic hydrocarbons (PAHs), including anthracene, pyrene, and phenanthrene, as potential ice nuclei. Chemical changes at the surface of the aerosols caused by exposure to ozone were characterized using Fourier transform infrared spectroscopy with horizontal attenuated total reflectance (FTIR-HATR). In addition, Brunauer-Emmett-Teller (BET) measurements were used to determine the specific surface areas of the soot particles. Mean freezing temperatures on fresh particles ranged from -19 to -24 degrees C, depending on the IN composition and size. In all cases, exposure to ozone facilitated ice nucleation at warmer temperatures, by 2-3 degrees C, on average. In addition, nucleation rate coefficients for a single temperature and IN type increased by as much as 4 orders of magnitude because of oxidation. Furthermore, a fraction of the oxidized soot particles froze at temperatures above -10 degrees C. A modified version of classical nucleation theory that accounts for a range of contact angles on nucleation sites within an IN population was used to derive the probability of freezing as a function of temperature for each type of IN. In summary, our results suggest that atmospheric oxidation processes may both extend the range over which particles can act as ice nuclei to warmer temperatures and increase heterogeneous nucleation rates on soot and pollutant aerosols. PMID- 25280087 TI - Contrasting physiological responses of ozone-tolerant Phaseolus vulgaris and Nicotiana tobaccum varieties to ozone and nitric acid. AB - Ozone (O3) and nitric acid (HNO3) are synthesized by the same atmospheric photochemical processes and are almost always co-pollutants. Effects of O3 on plants have been well-elucidated, yet less is known about the effects of HNO3 on plants. We investigated the physiological effects of experimental O3 and HNO3 fumigation on Phaseolus vulgaris (snap bean) and Nicotiana tobaccum (tobacco) varieties with known sensitivity to O3, but unknown responses to HNO3. Responses were measured as leaf absorptance, aboveground plant biomass, and photosynthetic CO2-response curve parameters. Our results demonstrate that O3 reduced absorptance, stomatal conductance and plant biomass in both species, and maximum photosynthetic rate in P. vulgaris, whereas the main effect of HNO3 was an increase in mesophyll conductance. Overall, the results suggest that HNO3 affects mesophyll conductance through increased nitrogen absorbed by leaves during HNO3 deposition which in turn increases photosynthetic demand for CO2, or that damage to epicuticular waxes on leaves increased diffusion of CO2 to sites of carboxylation. PMID- 25280085 TI - Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose selection in patients with rheumatoid arthritis (RA). AB - R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation. PMID- 25280088 TI - Investigation of diastereoselective acyclic alpha-alkoxydithioacetal substitutions involving thiacarbenium intermediates. AB - Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic alpha-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the alpha-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The DeltaDeltaG(?) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn alpha,beta-bis alkoxydithioacetals. PMID- 25280089 TI - Prognostic value of intrathecal heme oxygenase-1 concentration in patients with Fisher Grade III aneurysmal subarachnoid hemorrhage. AB - OBJECT: Experimental studies have demonstrated the crucial role of posthemorrhagic erythrocyte catabolism in the pathogenesis of subarachnoid hemorrhage (SAH). The authors of this study aimed to investigate the prognostic value of a series of CSF biomarkers linked to heme metabolism in SAH patients. METHODS: Patients with Fisher Grade III aneurysmal SAH undergoing early aneurysm obliteration were enrolled. The levels of heme oxygenase-1 (HO-1), oxyhemoglobin, ferritin, and bilirubin in intrathecal CSF were measured on the 7th day posthemorrhage. The associations of functional outcome with clinical and CSF parameters were analyzed. RESULTS: The study included 41 patients (mean age 59 +/ 14 years; 16 male, 25 female), 17 (41.5%) of whom had an unfavorable outcome (Glasgow Outcome Scale score <= 3) 3 months after SAH. In terms of the clinical data, age > 60 years, admission World Federation of Neurosurgical Societies Grade >= III, and the presence of acute hydrocephalus were independent factors associated with an unfavorable outcome. After adjusting for clinical parameters, a higher level of HO-1 appeared to be the most significant CSF parameter related to an unfavorable outcome among all tested CSF molecules (OR 0.934, 95% CI 0.883 0.989, p = 0.018). Further analysis using a generalized additive model identified a cutoff HO-1 value of 81.2 MUM, with higher values predicting unfavorable outcome (82.4% accuracy). CONCLUSIONS: The authors propose that the level of intrathecal CSF HO-1 at Day 7 post-SAH can be an effective outcome indicator in patients with Fisher Grade III aneurysmal SAH. PMID- 25280090 TI - Low-energy extracorporeal shock wave therapy promotes vascular endothelial growth factor expression and improves locomotor recovery after spinal cord injury. AB - OBJECT: Extracorporeal shock wave therapy (ESWT) is widely used for the clinical treatment of various human diseases. Recent studies have demonstrated that low energy ESWT upregulates the expression of vascular endothelial growth factor (VEGF) and promotes angiogenesis and functional recovery in myocardial infarction and peripheral artery disease. Many previous reports suggested that VEGF produces a neuroprotective effect to reduce secondary neural tissue damage after spinal cord injury (SCI). The purpose of the present study was to investigate whether low-energy ESWT promotes VEGF expression and neuroprotection and improves locomotor recovery after SCI. METHODS: Sixty adult female Sprague-Dawley rats were randomly divided into 4 groups: sham group (laminectomy only), sham-SW group (low-energy ESWT applied after laminectomy), SCI group (SCI only), and SCI-SW group (low-energy ESWT applied after SCI). Thoracic spinal cord contusion injury was inflicted using an impactor. Low-energy ESWT was applied to the injured spinal cord 3 times a week for 3 weeks. Locomotor function was evaluated using the Basso, Beattie, and Bresnahan (BBB) Scale (open field locomotor score) at different time points over 42 days after SCI. Hematoxylin and eosin staining was performed to assess neural tissue damage in the spinal cord. Neuronal loss was investigated by immunostaining for NeuN. The mRNA expressions of VEGF and its receptor, Flt-1, in the spinal cord were assessed using real-time polymerase chain reaction. Immunostaining for VEGF was performed to evaluate VEGF protein expression in the spinal cord. RESULTS: In both the sham and sham-SW groups, no animals showed locomotor impairment on BBB scoring. Histological analysis of H & E and NeuN stainings in the sham-SW group confirmed that no neural tissue damage was induced by the low-energy ESWT. Importantly, animals in the SCI-SW group demonstrated significantly better locomotor improvement than those in the SCI group at 7, 35, and 42 days after injury (p < 0.05). The number of NeuN-positive cells in the SCI-SW group was significantly higher than that in the SCI group at 42 days after injury (p < 0.05). In addition, mRNA expressions of VEGF and Flt-1 were significantly increased in the SCI-SW group compared with the SCI group at 7 days after injury (p < 0.05). The expression of VEGF protein in the SCI-SW group was significantly higher than that in the SCI group at 7 days (p < 0.01). CONCLUSIONS: The present study showed that low-energy ESWT significantly increased expressions of VEGF and Flt-1 in the spinal cord without any detrimental effect. Furthermore, it significantly reduced neuronal loss in damaged neural tissue and improved locomotor function after SCI. These results suggested that low-energy ESWT enhances the neuroprotective effect of VEGF in reducing secondary injury and leads to better locomotor recovery following SCI. This study provides the first evidence that low-energy ESWT can be a safe and promising therapeutic strategy for SCI. PMID- 25280092 TI - Use of sensory and motor action potentials to identify the position of trigeminal nerve divisions for radiofrequency thermocoagulation. AB - OBJECT: The objective of this study was to develop an electrophysiological method for intraoperative localization of the trigeminal nerve branches during radiofrequency thermocoagulation (RFTC). METHODS: Twenty-three patients who were scheduled to undergo RFTC were included. The trigeminal nerve root was stimulated through the foramen ovale using the radiofrequency cannula. Antidromic responses were recorded from the target division through supraorbital, infraorbital, and mental foramina electrodes, and an additional electrode at the masseter muscle. Sensory and motor action responses, as well as verbal and masseter contraction responses, were recorded and correlated. RESULTS: The antidromic responses were easily recorded in the target division in all 23 patients, and they were invariably correlated with the patient's verbal responses. The potentials were recorded successively from V1 to V3. The amplitude in each division before and after RFTC showed little difference in response to electrical stimulation with the same current. The motor trigeminal nerve action potentials were recorded in 10 patients; 7 of these patients had postoperative masseter muscle weakness, while the remaining 3 had normal masseter muscle function. Potentials with low amplitudes were usually obtained from neighboring divisions, but no unexpected denervation of any branches was observed. All the patients experienced immediate pain relief after the procedure. CONCLUSIONS: This technique is sensitive and easy to apply. The sensory and motor potentials matched the verbal responses and the complications. Although it cannot completely substitute for the patient's verbal response, this approach is helpful in uncooperative patients, and it predicts and reduces the incidence of masseter muscle weakness. The use of these complementary techniques could increase the chances of treatment success. PMID- 25280091 TI - The Sport Concussion Education Project. A brief report on an educational initiative: from concept to curriculum. AB - Current research on concussion is primarily focused on injury identification and treatment. Prevention initiatives are, however, important for reducing the incidence of brain injury. This report examines the development and implementation of an interactive electronic teaching program (an e-module) that is designed specifically for concussion education within an adolescent population. This learning tool and the accompanying consolidation rubric demonstrate that significant engagement occurs in addition to the knowledge gained among participants when it is used in a school curriculum setting. PMID- 25280094 TI - Surgical outcomes following encephaloduroarteriosynangiosis in North American adults with moyamoya. AB - OBJECT: Moyamoya disease/syndrome (MMD/S) is a progressive, occlusive vasculopathy of the intracranial vasculature that leads to ischemic and hemorrhagic strokes. Significant debate exists regarding the role of indirect cerebrovascular bypass surgery in its management. The authors review their institution's experience with indirect bypass in the surgical management of patients with MMD/S. METHODS: The authors conducted a retrospective review of patients with MMD/S who underwent encephaloduroarteriosynangiosis (EDAS), a form of indirect bypass, from 1996 to 2013. RESULTS: A total of 37 patients (52 hemispheres) underwent an EDAS procedure for MMD/S; 21 patients received revascularization of both hemispheres. Patients presented with the following: 49% with stroke, 35% with transient ischemic attack, 13% with hemorrhage, and 3% with seizure. The mean Suzuki grade was 3.46. The number of patients with a modified Rankin Scale score of 0-1 improved from 21 to 29 (p = 0.002) from the time of surgery to the time of last follow-up. The number of neurological events (i.e., transient ischemic attacks, strokes, and hemorrhages) decreased from a mean of 1.7 events per patient to 0.14 (p < 0.001). The mean length of follow-up was 32.8 months. CONCLUSIONS: This series demonstrates that EDAS is an effective procedure for MMD/S in a North American cohort of patients. PMID- 25280093 TI - Sex differences in the effect of progesterone after controlled cortical impact in adolescent mice: a preliminary study. AB - OBJECT: While progesterone has been well studied in experimental models of adult traumatic brain injury (TBI), it has not been evaluated in pediatric models. The study of promising interventions in pediatric TBI is important because children have the highest public health burden of such injuries. Therapies that are beneficial in adults may not necessarily be effective in the pediatric population. The purpose of this study was to evaluate whether progesterone treatment improves outcomes in an experimental model of pediatric TBI. METHODS: The authors determined whether progesterone administered after controlled cortical impact (CCI) improves functional and histopathological outcomes in 4 week-old mice. Both male and female mice (58 mice total) were included in this study, as the majority of prior studies have used only male and/or reproductively senescent females. Mice were randomized to treatment with progesterone or vehicle and to CCI injury or sham injury. Motor (wire grip test) and memory (Morris water maze) testing were performed to determine the effect of progesterone on TBI. Lesion volume was also assessed. RESULTS: Compared with their vehicle-treated counterparts, the progesterone-treated CCI-injured male mice had improved motor performance (p < 0.001). In contrast, progesterone-treated CCI-injured female mice had a worse performance than their vehicle-treated counterparts (p = 0.001). Progesterone treatment had no effect on spatial memory performance or lesion volume in injured male or female mice. CONCLUSIONS: These data suggest a sex specific effect of progesterone treatment after CCI in adolescent mice and could inform clinical trials in children. PMID- 25280095 TI - Trends and outcome predictors after traumatic brain injury surgery: a nationwide population-based study in Taiwan. AB - OBJECT: The authors sought to analyze trends in hospital resource utilization and mortality rates in a population of patients who had received traumatic brain injury (TBI) surgery. METHODS: This nationwide population-based cohort study retrospectively analyzed 18,286 patients who had received surgical treatment for TBI between 1998 and 2010. The multiple linear regression model and Cox proportional hazards model were used for multivariate assessment of outcome predictors. RESULTS: The prevalence rate of surgical treatment for patients with TBI gradually but significantly (p < 0.001) increased by 47.6% from 5.0 per 100,000 persons in 1998 to 7.4 per 100,000 persons in 2010. Age, sex, Deyo Charlson comorbidity index score, hospital volume, and surgeon volume were significantly associated with TBI surgery outcomes (p < 0.05). Over the 12-year period analyzed, the estimated mean hospital treatment cost increased 19.06%, whereas the in-hospital mortality rate decreased 10.9%. The estimated mean time of overall survival after TBI surgery (+/- SD) was 83.0 +/- 4.2 months, and the overall in-hospital and 1-, 3-, and 5-year survival rates were 74.5%, 67.3%, 61.1%, and 57.8%, respectively. CONCLUSIONS: These data reveal an increased prevalence of TBI, especially in older patients, and an increased hospital treatment cost but a decreased in-hospital mortality rate. Health care providers and patients should recognize that attributes of the patient and of the hospital may affect hospital resource utilization and the mortality rate. These results are relevant not only to other countries with similar population sizes but also to countries with larger populations. PMID- 25280097 TI - Endoscopic pituitary surgery. PMID- 25280096 TI - Widening of the basilar bifurcation angle: association with presence of intracranial aneurysm, age, and female sex. AB - OBJECT: Arterial bifurcations represent preferred locations for aneurysm formation, especially when they are associated with variations in divider geometry. The authors hypothesized a link between basilar apex aneurysms and basilar bifurcation (alpha) and vertebrobasilar junction (VBJ) angles. METHODS: The alpha and VBJ angles were measured in 3D MR and rotational angiographic volumes using a coplanar 3-point technique. Angle alpha was compared between age matched cohorts in 45 patients with basilar artery (BA) aneurysms, 65 patients with aneurysms in other locations (non-BA), and 103 nonaneurysmal controls. Additional analysis was performed in 273 nonaneurysmal controls. Computational fluid dynamics (CFD) simulations were performed on parametric BA models with increasing angles. RESULTS: Angle alpha was significantly wider in patients with BA aneurysms (146.7 degrees +/- 20.5 degrees ) than in those with non-BA aneurysms (111.7 degrees +/- 18 degrees ) and in controls (103 degrees +/- 20.6 degrees ) (p < 0.0001), whereas no difference was observed for the VBJ angle. A wider angle alpha correlated with BA aneurysm neck width but not dome size, which is consistent with CFD results showing a widening of the impingement zone at the bifurcation apex. BA bifurcations hosting even small aneurysms (< 5 mm) had a significantly larger alpha angle compared with matched controls (p < 0.0001). In nonaneurysmal controls, alpha increased with age (p < 0.0001), with a threshold effect above 35 years of age and a steeper dependence in females (p = 0.002) than males (p = 0.04). CONCLUSIONS: The alpha angle widens with age during adulthood, especially in females. This angular widening is associated with basilar bifurcation aneurysms and may predispose individuals to aneurysm initiation by diffusing the flow impingement zone away from the protective medial band region of the flow divider. PMID- 25280098 TI - GET two for one. AB - In this issue, Voth et al. (2014) reveal that Get3, the GET pathway targeting factor shuttling TA-proteins from the ribosome to the ER membrane, moonlights as a chaperone under oxidizing conditions in a manner reminiscent of bacterial Hsp33. PMID- 25280099 TI - eRNAs lure NELF from paused polymerases. AB - RNAs transcribed from enhancers (eRNAs) have been linked to enhancer function. In this issue of Molecular Cell, Schaukowitch et al. (2014) show that upon activation, eRNAs can bind NELF and are necessary for its transient removal from promoters to release paused RNA polymerase II and drive expression of immediate early genes in neurons. PMID- 25280100 TI - Dynamic RNA modifications in posttranscriptional regulation. AB - Cellular RNAs can be chemically modified over a hundred different ways. These modifications were once thought to be static, discrete, and utilized to fine-tune RNA structure and function. However, recent studies have revealed that some modifications, like mRNA methylation, can be reversed, and these reversible modifications may play active roles in regulating diverse biological processes. In this perspective, we summarize examples of dynamic RNA modifications that affect biological functions. We further propose that reversible modifications might occur on tRNA, rRNA, and other noncoding RNAs to regulate gene expression analogous to the reversible mRNA methylation. PMID- 25280101 TI - Looking at LncRNAs with the ribozyme toolkit. AB - A diverse population of large RNA molecules controls every aspect of cellular function, and yet we know very little about their molecular structures. However, robust technologies developed for visualizing ribozymes and riboswitches, together with new approaches for mapping RNA inside cells, provide the foundation for visualizing the structures of long noncoding RNAs, mRNAs, and viral RNAs, thereby facilitating new mechanistic insights. PMID- 25280103 TI - Structural model of a CRISPR RNA-silencing complex reveals the RNA-target cleavage activity in Cmr4. AB - The Cmr complex is an RNA-guided endonuclease that cleaves foreign RNA targets as part of the CRISPR prokaryotic defense system. We investigated the molecular architecture of the P. furiosus Cmr complex using an integrative structural biology approach. We determined crystal structures of P. furiosus Cmr1, Cmr2, Cmr4, and Cmr6 and combined them with known structural information to interpret the cryo-EM map of the complex. To support structure determination, we obtained residue-specific interaction data using protein crosslinking and mass spectrometry. The resulting pseudoatomic model reveals how the superhelical backbone of the complex is defined by the polymerizing principles of Cmr4 and Cmr5 and how it is capped at the extremities by proteins of similar folds. The inner surface of the superhelix exposes conserved residues of Cmr4 that we show are required for target-cleavage activity. The structural and biochemical data thus identify Cmr4 as the conserved endoribonuclease of the Cmr complex. PMID- 25280102 TI - Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs. AB - Piwi proteins and Piwi-interacting RNAs (piRNAs) are essential for gametogenesis, embryogenesis, and stem cell maintenance in animals. Piwi proteins act on transposon RNAs by cleaving the RNAs and by interacting with factors involved in RNA regulation. Additionally, piRNAs generated from transposons and psuedogenes can be used by Piwi proteins to regulate mRNAs at the posttranscriptional level. Here we discuss piRNA biogenesis, recent findings on posttranscriptional regulation of mRNAs by the piRNA pathway, and the potential importance of this posttranscriptional regulation for a variety of biological processes such as gametogenesis, developmental transitions, and sex determination. PMID- 25280104 TI - MicroRNAs block assembly of eIF4F translation initiation complex in Drosophila. AB - miRNAs silence their complementary target mRNAs by translational repression as well as by poly(A) shortening and mRNA decay. In Drosophila, miRNAs are typically incorporated into Argonaute1 (Ago1) to form the effector complex called RNA induced silencing complex (RISC). Ago1-RISC associates with a scaffold protein GW182, which recruits additional silencing factors. We have previously shown that miRNAs repress translation initiation by blocking formation of the 48S and 80S ribosomal complexes. However, it remains unclear how ribosome recruitment is impeded. Here, we examined the assembly of translation initiation factors on the target mRNA under repression. We show that Ago1-RISC induces dissociation of eIF4A, a DEAD-box RNA helicase, from the target mRNA without affecting 5' cap recognition by eIF4E in a manner independent of GW182. In contrast, direct tethering of GW182 promotes dissociation of both eIF4E and eIF4A. We propose that miRNAs act to block the assembly of the eIF4F complex during translation initiation. PMID- 25280105 TI - MicroRNAs trigger dissociation of eIF4AI and eIF4AII from target mRNAs in humans. AB - In animals, key functions of microRNA-induced silencing complex (miRISC) are translational repression and deadenylation followed by mRNA decay. While miRISC represses translation initiation, it is poorly understood how miRISC exerts this function. Here we assessed the effect of miRISC on synergistic recruitment of translation initiation factors to target mRNAs by using direct biochemical assays. We show that miRISC promotes eIF4AI and eIF4AII release from target mRNAs prior to dissociation of eIF4E and eIF4G in a deadenylation-independent manner. Strikingly, miRISC-induced release of eIF4AI and eIF4AII from target mRNAs and miRISC-induced inhibition of cap-dependent translation can both be counteracted by the RNA-binding protein HuD via a direct interaction of HuD with eIF4A. Furthermore, the pharmacological eIF4A inhibitor silvestrol, which locks eIF4A on mRNAs, conferred resistance to miRNA-mediated translational repression. In summary, we propose that both eIF4AI and eIF4AII are functionally important targets in miRISC-mediated translation control. PMID- 25280108 TI - Noble metal catalyzed aqueous phase hydrogenation and hydrodeoxygenation of lignin-derived pyrolysis oil and related model compounds. AB - Aqueous phase hydrodeoxygenation of lignin pyrolysis oil and related model compounds were investigated using four noble metals supported on activated carbon. The hydrodeoxygenation of guaiacol has three major reaction pathways and the demethylation reaction, mainly catalyzed by Pd, Pt and Rh, produces catechol as the products. The presence of catechol and guaiacol in the reaction is responsible for the coke formation and the catalysts deactivation. As expected, there was a significant decrease in the specific surface area of Pd, Pt and Rh catalysts during the catalytic reaction because of the coke deposition. In contrast, no catechol was produced from guaiacol when Ru was used so a completely hydrogenation was accomplished. The lignin pyrolysis oil upgrading with Pt and Ru catalysts further validated the reaction mechanism deduced from model compounds. Fully hydrogenated bio-oil was produced with Ru catalyst. PMID- 25280107 TI - Neighborhood socioeconomic status and food environment: a 20-year longitudinal latent class analysis among CARDIA participants. AB - Cross-sectional studies suggest that neighborhood socioeconomic (SES) disadvantage is associated with obesogenic food environments. Yet, it is unknown how exposure to neighborhood SES patterning through adulthood corresponds to food environments that also change over time. We used latent class analysis (LCA) to classify participants in the U.S.-based Coronary Artery Risk Development in Young Adults study [n=5,114 at baseline 1985-1986 to 2005-2006] according to their longitudinal neighborhood SES residency patterns (upward, downward, stable high and stable low). For most classes of residents, the availability of fast food and non-fast food restaurants and supermarkets and convenience stores increased (p<0.001). Yet, socioeconomically disadvantaged neighborhood residents had fewer fast food and non-fast food restaurants, more convenience stores, and the same number of supermarkets in their neighborhoods than the advantaged residents. In addition to targeting the pervasive fast food restaurant and convenient store retail growth, improving neighborhood restaurant options for disadvantaged residents may reduce food environment disparities. PMID- 25280109 TI - Interaction and its induced inhibiting or synergistic effects during co gasification of coal char and biomass char. AB - Co-gasification of coal char and biomass char was conducted to investigate the interactions between them. And random pore model (RPM) and modified random pore model (MRPM) were applied to describe the gasification behaviors of the samples. The results show that inhibiting effect was observed during co-gasification of corn stalk char with Hulunbeier lignite coal char, while synergistic effects were observed during co-gasification of corn stalk char with Shenmu bituminous coal char and Jincheng anthracite coal char. The inhibiting effect was attributed to the intimate contact and comparable gasification rate between biomass char and coal char, and the loss of the active form of potassium caused by the formation of KAlSiO4, which was proved to be inactive during gasification. While the synergistic effect was caused by the high potassium content of biomass char and the significant difference of reaction rate between coal char and biomass char during gasification. PMID- 25280110 TI - A dynamic growth model of Dunaliella salina: parameter identification and profile likelihood analysis. AB - In this work, a photoautotrophic growth model incorporating light and nutrient effects on growth and pigmentation of Dunaliella salina was formulated. The model equations were taken from literature and modified according to the experimental setup with special emphasis on model reduction. The proposed model has been evaluated with experimental data of D. salina cultivated in a flat-plate photobioreactor under stressed and non-stressed conditions. Simulation results show that the model can represent the experimental data accurately. The identifiability of the model parameters was studied using the profile likelihood method. This analysis revealed that three model parameters are practically non identifiable. However, some of these non-identifiabilities can be resolved by model reduction and additional measurements. As a conclusion, our results suggest that the proposed model equations result in a predictive growth model for D. salina. PMID- 25280111 TI - Enhancing the functional and economical efficiency of a novel combined thermo chemical disperser disintegration of waste activated sludge for biogas production. AB - In this investigation, an effort was made to pretreat surplus waste activated sludge (WAS) inexpensively by a novel combined process involving thermo chemical disperser pretreatment. This pretreatment was found to be efficient at a specific energy (SE) consumption of 3360.94 kJ/kg TS, with the chemical oxygen demand (COD) solubilization of 20%. This was comparatively higher than thermo chemically treated sludge where the solubilization was found to be 15.5% at a specific energy consumption of 10,330 kJ/kg TS respectively. Higher production of volatile fatty acids (VFA) (675 mg/L) in anaerobic fermentation of pretreated WAS indicates better hydrolysis performance. The biogas production potential of sludge pretreated through this combined technique was found to be 0.455 (L/gVS) and comparatively higher than thermo chemically pretreated sludge. Economic investigation provides 90% net energy savings in this combined pretreatment. Therefore, this combined process was considered to be potentially effective and economical in sludge disintegration. PMID- 25280112 TI - Ethanol production from cotton gin trash using optimised dilute acid pretreatment and whole slurry fermentation processes. AB - Cotton ginning trash (CGT) collected from Australian cotton gins was evaluated for bioethanol production. CGT composition varied between ginning operations and contained high levels of extractives (26-28%), acid-insoluble material (17-22%) and holocellulose (42-50%). Pretreatment conditions of time (4-20 min), temperature (160-220 degrees C) and sulfuric acid concentration (0-2%) were optimised using a central composite design. Response surface modelling revealed that CGT fibre pretreated at 180 degrees C in 0.8% H2SO4 for 12 min was optimal for maximising enzymatic glucose recoveries and achieved yields of 89% theoretical, whilst the total accumulated levels of furans and acetic acid remained relatively low at <1 and 2 g/L respectively. Response surface modelling also estimated maximum xylose recovery in pretreated liquors (87% theoretical) under the set conditions of 150 degrees C in 1.9% H2SO4 for 23.8 min. Yeast fermentations yielded high ethanol titres of 85%, 88% and 70% theoretical from glucose generated from: (a) enzymatic hydrolysis of washed pretreated fibres, (b) enzymatic hydrolysis of whole pretreated slurries and (c) simultaneous saccharification fermentations, respectively. PMID- 25280113 TI - Role of axial base coordination in isonitrile binding and chalcogen atom transfer to vanadium(III) complexes. AB - The enthalpy of oxygen atom transfer (OAT) to V[(Me3SiNCH2CH2)3N], 1, forming OV[(Me3SiNCH2CH2)3N], 1-O, and the enthalpies of sulfur atom transfer (SAT) to 1 and V(N[t-Bu]Ar)3, 2 (Ar = 3,5-C6H3Me2), forming the corresponding sulfides SV[(Me3SiNCH2CH2)3N], 1-S, and SV(N[t-Bu]Ar)3, 2-S, have been measured by solution calorimetry in toluene solution using dbabhNO (dbabhNO = 7-nitroso 2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene) and Ph3SbS as chalcogen atom transfer reagents. The V-O BDE in 1-O is 6.3 +/- 3.2 kcal.mol(-1) lower than the previously reported value for 2-O and the V-S BDE in 1-S is 3.3 +/- 3.1 kcal.mol( 1) lower than that in 2-S. These differences are attributed primarily to a weakening of the V-Naxial bond present in complexes of 1 upon oxidation. The rate of reaction of 1 with dbabhNO has been studied by low temperature stopped-flow kinetics. Rate constants for OAT are over 20 times greater than those reported for 2. Adamantyl isonitrile (AdNC) binds rapidly and quantitatively to both 1 and 2 forming high spin adducts of V(III). The enthalpies of ligand addition to 1 and 2 in toluene solution are -19.9 +/- 0.6 and -17.1 +/- 0.7 kcal.mol(-1), respectively. The more exothermic ligand addition to 1 as compared to 2 is opposite to what was observed for OAT and SAT. This is attributed to less weakening of the V-Naxial bond in ligand binding as opposed to chalcogen atom transfer and is in keeping with structural data and computations. The structures of 1, 1-O, 1-S, 1-CNAd, and 2-CNAd have been determined by X-ray crystallography and are reported. PMID- 25280114 TI - Is 17alpha-hydroxyprogesterone caproate contraindicated in twin gestations? PMID- 25280115 TI - The influence of contextual variables on judgments about patients and their pain. AB - OBJECTIVE: Professional judgments about persistent pain are influenced by contextual variables, which are features relating to the patient, the assessor, or the broader situation. Such judgments directly inform assessment and treatment and therefore represent an important area of research. While current formulations of persistent pain adopt a biopsychosocial framework, contextual variables relating to psychosocial information have not been well examined in the literature. DESIGN: We employed a within-subjects experimental vignette paradigm to investigate the influence of four contextual variables, 2 (medical evidence: present vs absent) * 2 (pain behavior: present vs absent) * 2 (referral to a psychologist: yes vs no) * 2 (responsibility: onset controllable vs onset uncontrollable), on perceptions of pain. Judgments about patients with chronic low back pain were made across several dimensions. SUBJECTS: One hundred sixteen medical and nursing students. RESULTS: Main findings revealed that identifiable pain pathology led to increased ratings of pain intensity and emotional distress, and decreased perceived likelihood of malingering. Pain behavior and referral to a psychologist were also found to increase ratings of pain intensity and emotional distress. Encouragingly, psychological referral was not found to increase the perceived likelihood of malingering. Responsibility for the initial injury was found to influence judgments, but this occurred in interaction with medical evidence as well as pain behavior. CONCLUSIONS: These findings suggest that contextual variables have an important influence on medical and nursing students' perceptions of patients and their pain. Theoretical and practical implications for provider training and community education are discussed. PMID- 25280116 TI - Trading height for education in the marriage market. AB - OBJECTIVES: Several empirical studies point out the relevance of individuals' physical attributes-such as height, weight, beauty-in the labor market. In the same way, physical characteristics may affect lifetime prospects through their impact on the selection of a partner in the marriage market. We analyzed to what extent an individual's height and weight (arguably affecting physical attractiveness, as documented in many studies) are related to lifetime economic outcomes through the marriage market, investigating whether individual height and weight affect the probability of marrying with a "high-quality partner," measuring quality as the partner's educational attainment or as the partner's prospective labor income. METHODS: Using a large Italian dataset of married (and cohabiting) couples-the 2005 Italian Health Conditions Survey which provides information on health conditions, individual characteristics, and socioeconomic variables-we estimated separate OLS and Ordered Probit regressions for females and males. Since weight might be endogenously determined, to avoid any estimation bias we also estimated a reduced form equation in which predetermined height affects directly and indirectly (through BMI) physical attractiveness and, as a consequence, the choice of a partner with a given educational attainment. RESULTS: Our findings suggest that height is a desirable trait in mating selection affecting the partner's socioeconomic characteristics: we found that taller individuals tended to mate with more educated partners, controlling for their own educational level-to take into account the tendency for assortative mating for education-and for other personal traits such as age, geographical residence, city size, and the presence of health problems. On the other hand, we showed that individuals with higher BMI were married to partners with lower levels of education. The results also provide evidence of non-linearity in the relationship between height and educational attainment of the partner. These findings are confirmed for both males and females, but being taller seems to be more relevant for males, while being thinner is more important for females. We have also found that taller and thinner females and males tend to be married with partners earning higher labor incomes. These findings were robust to a number of checks. CONCLUSIONS: Our findings confirm that the physical characteristics that an individual brings to the marriage market influences the outcome in this market: physical attractiveness is exchanged in the marriage market for a higher educational attainment and the ability to earn a higher labor income. PMID- 25280117 TI - Computerized delineation of nuclei in liquid-based pap smears stained with immunohistochemical biomarkers. AB - BACKGROUND: Infection with high-risk human papillomaviruses (hrHPVs) is a frequent cause of cervical intraepithelial neoplasias and carcinomas. The recently developed p16/Ki67 dual stain of cytologic preparations possesses superior specificity over current HPV testing for detecting moderate- and high grade dysplasias and can potentially be applied in routine cytology screening. Image analysis can possibly improve the efficiency of evaluating Papanicolaou (Pap) smears, if dual-stained nuclei are accurately localized and reliably distinguished from the background of other cells. METHODS: Here, we describe a technique comprising color deconvolution, radial symmetry detector, and a superpixel-based segmentation for computerized delineation of nuclei in Pap smears stained with p16/Ki67. RESULTS: The performance of the method was determined by the precision and recall in 99 images (n = 19,323 cells) and reached 0.952 and 0.958, respectively. The accuracy of delineation, assessed by the Jaccard index (n = 1,080 cells), was 0.794. In single cells the precision and recall was higher than in clumps (P = 0.005). CONCLUSIONS: In summary, the new technique delineates large and small nuclei irrespectively of coloration with a significantly better performance than a method solely involving the radial symmetry detector. Therefore, it is suited to automatically define nuclear areas for quantification of nuclear biomarkers in smears. PMID- 25280118 TI - Ten years of a model of aesthetic appreciation and aesthetic judgments : The aesthetic episode - Developments and challenges in empirical aesthetics. AB - About a decade ago, psychology of the arts started to gain momentum owing to a number of drives: technological progress improved the conditions under which art could be studied in the laboratory, neuroscience discovered the arts as an area of interest, and new theories offered a more comprehensive look at aesthetic experiences. Ten years ago, Leder, Belke, Oeberst, and Augustin (2004) proposed a descriptive information-processing model of the components that integrate an aesthetic episode. This theory offered explanations for modern art's large number of individualized styles, innovativeness, and for the diverse aesthetic experiences it can stimulate. In addition, it described how information is processed over the time course of an aesthetic episode, within and over perceptual, cognitive and emotional components. Here, we review the current state of the model, and its relation to the major topics in empirical aesthetics today, including the nature of aesthetic emotions, the role of context, and the neural and evolutionary foundations of art and aesthetics. PMID- 25280119 TI - Scientific aesthetics: three steps forward. AB - Leder and Nadal (2014, this issue) examine the current state of scientific aesthetics through the lens of a prescient psychological model proposed 10 years ago. These retrospective points to several future directions of which I touch on three: the nature of aesthetic emotions, the time course of emotions in aesthetic episodes, and the relationship of art and evolution. PMID- 25280121 TI - Domain specificity and mental chronometry in empirical aesthetics. AB - This article is a commentary on 'Ten years of a model of aesthetic appreciation and aesthetic judgments: The aesthetic episode - developments and challenges in empirical aesthetics' (Leder & Nadal, 2014, this issue). It focuses on domain specificity and mental chronometry in empirical aesthetics. PMID- 25280120 TI - Beauty: neglected, but alive and kicking. AB - This article is a commentary on 'Ten years of a model of aesthetic appreciation and aesthetic judgments: The aesthetic episode - developments and challenges in empirical aesthetics' (Leder & Nadal, 2014, this issue). It focuses on the importance of beauty in aesthetic appreciation and aesthetic judgments. Beauty is considered as a formal inherent property of visual stimuli that has the potential to elicit visual pleasure by direct sensory stimulation. It is argued that any comprehensive model of aesthetic experience must account fully for cognitive aspects of aesthetics (cultural, conceptual, psychological, and individual factors) as well as intrinsic properties of beautiful visual stimuli and how they relate to basic mechanisms of visual perception, which are universal among humans. PMID- 25280122 TI - The effect of psychological stress and expectation on auditory perception: A signal detection analysis. AB - Both psychological stress and predictive signals relating to expected sensory input are believed to influence perception, an influence which, when disrupted, may contribute to the generation of auditory hallucinations. The effect of stress and semantic expectation on auditory perception was therefore examined in healthy participants using an auditory signal detection task requiring the detection of speech from within white noise. Trait anxiety was found to predict the extent to which stress influenced response bias, resulting in more anxious participants adopting a more liberal criterion, and therefore experiencing more false positives, when under stress. While semantic expectation was found to increase sensitivity, its presence also generated a shift in response bias towards reporting a signal, suggesting that the erroneous perception of speech became more likely. These findings provide a potential cognitive mechanism that may explain the impact of stress on hallucination-proneness, by suggesting that stress has the tendency to alter response bias in highly anxious individuals. These results also provide support for the idea that top-down processes such as those relating to semantic expectation may contribute to the generation of auditory hallucinations. PMID- 25280123 TI - Polymer nanopillar-gold arrays as surface-enhanced Raman spectroscopy substrate for the simultaneous detection of multiple genes. AB - In our study, 2D nanopillar arrays with plasmonic crystal properties are optimized for surface-enhanced Raman spectroscopy (SERS) application and tested in a biochemical assay for the simultaneous detection of multiple genetic leukemia biomarkers. The special fabrication process combining soft lithography and plasma deposition techniques allows tailoring of the structural and chemical parameters of the crystal surfaces. In this way, it has been possible to tune the plasmonic resonance spectral position close to the excitation wavelength of the monochromatic laser light source in order to maximize the enhancing properties of the substrate. Samples are characterized by scanning electron microscopy and reflectance measurements and tested for SERS activity using malachite green. Besides, as the developed substrate had been prepared on a simple glass slide, SERS detection from the support side is also demonstrated. The optimized substrate is functionalized with thiol-modified capture oligonucleotides, and concentration-dependent signal of the target nucleotide is detected in a sandwich assay with labeled gold nanoparticles. Gold nanoparticles functionalized with different DNA and various Raman reporters are applied in a microarray-based assay recognizing a disease biomarker (Wilms tumor gene) and housekeeping gene expressions in the same time on spatially separated microspots. The multiplexing performance of the SERS-based bioassay is illustrated by distinguishing Raman dyes based on their complex spectral fingerprints. PMID- 25280124 TI - Venous thromboembolism incidence in the Cooperative Study of Sickle Cell Disease. AB - BACKGROUND: Venous thromboembolism (VTE) has been recently recognized as a complication of sickle cell disease (SCD); however, the incidence of VTE in SCD is unknown. OBJECTIVES: The primary objective of this study was to determine the incidence of first VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), among SCD patients age >= 15 years. We also evaluated genotypic differences in VTE risk and determined the relationship between VTE and mortality. PATIENTS/METHODS: In this retrospective cohort study, we used data from the Cooperative Study of Sickle Cell Disease (CSSCD) to calculate incidence rates for first VTE. We used Cox proportional hazard models to estimate hazard ratios (HRs) for time to VTE by genotype and time to death by VTE status. RESULTS: We included 1523 SCD patients aged >= 15 years with 8862 years of follow up in this analysis. The incidence rate for first VTE was 5.2 events/1000 person years (95% confidence interval [CI] 3.8-6.9) with a cumulative incidence of 11.3% (95% CI 8.3-15.3) by age 40 years. Individuals with the SS/Sbeta(0) -thalassemia genotype had the highest rate of VTE (7.6 events/1000 person-years [95% CI 5.3 10.6]). The incidence of PE exceeded that of isolated DVT (3.6 [95% CI 2.5-5.1] events/1000 person-years vs. 1.6 [95% CI 0.9-2.7] events/1000 person-years), although this difference was not statistically significant. SCD patients with VTE had a higher mortality rate (adjusted HR 2.32 [95% CI 1.20-4.46]) than those without VTE. CONCLUSIONS: Patients with SCD are at substantial risk for VTE, and individuals with VTE are at higher risk of death than those without VTE. PMID- 25280125 TI - Prenatal exposure to phthalate esters and behavioral syndromes in children at 8 years of age: Taiwan Maternal and Infant Cohort Study. AB - BACKGROUND: Few studies have shown an association between prenatal phthalate exposure and adverse effects on neurodevelopment and behavior in young children. OBJECTIVES: We aimed to assess the relationship between prenatal exposure to phthalate esters and behavior syndromes in children at 8 years of age. METHODS: A total of 122 mother-child pairs from the general population in central Taiwan were studied from 2000 to 2009. Mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three di-(2 ethylhexyl) phthalate (DEHP) metabolites-mono-2-ethylhexyl, mono-2-ethyl-5 hydroxyhexyl, and mono-2-ethyl-5-oxohexyl phthalates (MEHP, MEHHP, and MEOHP)- were measured in maternal urine collected during the third trimester of pregnancy using liquid chromatography-electrospray ionization-tandem mass spectrometry. Behavioral syndromes of children at 8 years of age were evaluated using the Child Behavior Checklist (CBCL). Associations between log10-transformed creatinine corrected phthalate concentrations and standardized scores of the CBCL were estimated using linear regression models or multinomial logistic regressions with adjustments for potential confounders. RESULTS: Externalizing problem scores were significantly higher in association with a 1-unit increase in log10-transformed creatinine-corrected concentrations of maternal MBP (beta = 4.29; 95% CI: 0.59, 7.99), MEOHP (beta = 3.74; 95% CI: 1.33, 6.15), and MEHP (beta = 4.28 ; 95% CI: 0.03, 8.26) after adjusting for the child's sex, intelligence, and family income. Meanwhile, MBP and MEOHP were significantly associated with Delinquent Behavior and Aggressive Behavior scores. The same pattern was found for borderline and/or clinical ranges. CONCLUSIONS: Our findings suggest positive associations between maternal DEHP and dibutyl phthalate (DBP) exposure and externalizing domain behavior problems in 8-year-old children. PMID- 25280126 TI - Agreement of urine specific gravity measurements between manual and digital refractometers. AB - CONTEXT: Urine specific gravity (Usg), measured by a handheld manual refractometer (MAN), has been recognized as a valid and practical means of assessing hydration status. Newer, digital refractometers are faster and more user friendly but have not been validated against the traditional MAN. OBJECTIVE: To compare the reliability and validity of 2 digital refractometer models and a MAN. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Sample of convenience was recruited from the local university and surrounding community (n = 82). INTERVENTION(S): Participants provided multiple urine samples (n = 124) over a 5-month period under various hydration conditions. MAIN OUTCOME MEASURE(S): Urine specific gravity was compared among a MAN, a digital refractometer requiring the prism to be dipped (DIP) into a urine sample, and a digital refractometer that requires urine to be pipetted (PIP) onto its prism for analysis. RESULTS: The MAN measurements were strongly correlated with the DIP (r = 0.99, P < .001) and PIP (r = 0.97, P < .001) measurements. Bland-Altman analyses revealed slight mean underestimation (95% upper and lower levels of agreement) between MAN and DIP (-0.0012 [0.0028] and PIP -0.0011 [0.0035], respectively) and trends toward increased underestimation at higher Usg. Measurement error >= .005 was greater for PIP (4/124, 3.2%) than for DIP (2/124, 1.6%). CONCLUSIONS: Negligible differences were exhibited between PIP and DIP, with both displaying acceptable reliability and validity compared with the MAN. However, the Bland-Altman analysis suggests underestimation bias for the DIP and PIP as Usg increases, with the potential for rare but substantial underestimation when using PIP that should be recognized by clinicians, particularly when used as a screening measure in weight-class sports. PMID- 25280127 TI - Competitive incorporation of perrhenate and nitrate into sodalite. AB - Nuclear waste storage tanks at the Hanford site in southeastern Washington have released highly alkaline solutions, containing radioactive and other contaminants, into subsurface sediments. When this waste reacts with subsurface sediments, feldspathoid minerals (sodalite, cancrinite) can form, sequestering pertechnetate (99TcO4-) and other ions. This study investigates the potential for incorporation of perrhenate (ReO4-), a chemical surrogate for 99TcO4-, into mixed perrhenate/nitrate (ReO4-/NO3-) sodalite. Mixed-anion sodalites were hydrothermally synthesized in the laboratory from zeolite A in sodium hydroxide, nitrate, and perrhenate solutions at 90 degrees C for 24 h. The resulting solids were characterized by bulk chemical analysis, X-ray diffraction, scanning electron microscopy, and X-ray absorption near edge structure spectroscopy (XANES) to determine the products' chemical composition, structure, morphology, and Re oxidation state. The XANES data indicated that nearly all rhenium (Re) was incorporated as Re(VII)O4-. The nonlinear increase of the unit cell parameter with ReO4-/NO3- ratios suggests formation of two separate sodalite phases in lieu of a mixed-anion sodalite. The results reveal that the sodalite cage is highly selective toward NO3- over ReO4-. Calculated enthalpy and Gibbs free energy of formation at 298 K for NO3- and ReO4-sodalite suggest that NO3- incorporation into the cage is favored over the incorporation of the larger ReO4-, due to the smaller ionic radius of NO3-. Based on these results, it is expected that NO3-, which is present at significantly higher concentrations in alkaline waste solutions than 99TcO4-, will be strongly preferred for incorporation into the sodalite cage. PMID- 25280128 TI - Effect of molecular orientation on monolayer and multilayer formations of fluorocarbon alcohol and fluorocarbon-alpha,omega-diol mixture at the hexane/water interface. AB - The effect of molecular orientation on the miscibility and structure of the adsorbed film of the 1H,1H,10H,10H-perfluorodecane-1,10-diol (FC10diol) 1H,1H,2H,2H-perfluorodecanol (FC10OH) mixture at the hexane/water interface were examined by interfacial tension and X-ray reflectivity measurements. The interfacial tension and X-ray reflectivity at the hexane solution/water interface were measured as a function of total molality m and composition of FC10OH in the mixture X2 under atmospheric pressure at 298.15 K. The interfacial pressure vs mean area per molecule curves showed that two kinds of condensed monolayers (C1 and C2) and multilayer (M) states appeared depending on m and X2. In the pure component systems, it was found that FC10OH forms condensed monolayer in which the molecules orient almost normally to the interface, and FC10diol orients parallel and is densely packed in the condensed monolayer and then piles spontaneously to form multilayer. In the mixed system, the phase diagram of adsorption indicated that FC10OH molecules are richer in C2 than in C1 state. The X-ray reflectivity measurements manifest that the condensed monolayer below X2 = 0.985 is heterogeneous in which the normal- and parallel-oriented domains coexist at the interface (C1 state), and that above X2 = 0.985 seems to be homogeneous with normal molecular orientation (C2 state). The structure of M state depends on those of condensed monolayers, on which the molecules pile spontaneously. The heterogeneous structure in C1 state is compared to that previously observed in the mixed system of FC10diol-FC12OH (1H,1H,2H,2H-perfluorododecanol), where FC12OH has longer fluorocarbon chain length than FC10OH and is discussed in terms of domain line tension. PMID- 25280129 TI - Egg yolk identification and aging in mixed paint binding media by NMR spectroscopy. AB - NMR spectroscopy is a powerful analytical tool for the identification and quantitative analysis of organic materials in a cultural heritage context. In this report, we present an analytical NMR protocol for the identification and semiquantification of egg yolk binders and mixed binding media that also contain a drying oil, namely linseed oil. The samples studied have been artificially and/or naturally aged in order to simulate the composition of organic materials in paintings. Analysis of the 1D and 2D NMR spectra showed that egg yolk can be identified even in binding media of considerable age via signals originating from cholesterol and/or cholesterol oxidation products present in the aged binding medium. Based on cholesterol-related and other lipid signals in the NMR spectra of egg yolk binders, a molecular marker (R/F) that suggests the presence of egg yolk in paint binders is proposed. Via this marker, the presence of egg yolk in the organic material obtained from an early 18th century Greek icon is confirmed, and this is further verified by 2D NMR spectroscopy. It is demonstrated that NMR molecular markers developed to estimate the hydrolysis/oxidation state of oil paintings are also suitable for the analysis of egg yolk and mixed medium (egg yolk-linseed oil) binders, indicating the generality of the NMR methodological approach in the analysis of organic materials in a cultural heritage context. PMID- 25280130 TI - A robust method for iodine status determination in epidemiological studies by capillary electrophoresis. AB - Iodine deficiency is the most common preventable cause of intellectual disabilities in children. Global health initiatives to ensure optimum nutrition thus require continuous monitoring of population-wide iodine intake as determined by urinary excretion of iodide. Current methods to analyze urinary iodide are limited by complicated sample pretreatment, costly infrastructure, and/or poor selectivity, posing restrictions to large-scale epidemiological studies. We describe a simple yet selective method to analyze iodide in volume-restricted human urine specimens stored in biorepositories by capillary electrophoresis (CE) with UV detection. Excellent selectivity is achieved when using an acidic background electrolyte in conjunction with dynamic complexation via alpha cyclodextrin in an unmodified fused-silica capillary under reversed polarity. Sample self-stacking is developed as a novel online sample preconcentration method to boost sensitivity with submicromolar detection limits for iodide (S/N ~ 3, 0.06 MUM) directly in urine. This assay also allows for simultaneous analysis of environmental iodide uptake inhibitors, including thiocyanate and nitrate. Rigorous method validation confirmed good linearity (R(2) = 0.9998), dynamic range (0.20 to 4.0 MUM), accuracy (average recovery of 93% at three concentration levels) and precision for reliable iodide determination in pooled urine specimens over 29 days of analysis (RSD = 11%, n = 87). PMID- 25280131 TI - A positive viewpoint regarding arthroscopy for degenerative knee conditions. PMID- 25280132 TI - Mobile- vs. fixed-bearing total knee replacement. AB - BACKGROUND AND PURPOSE: It is unclear whether mobile-bearing (MB) total knee arthroplasties reduce the risk of tibial component loosening compared to fixed bearing (FB) designs. This randomized study investigated implant migration, periprosthetic bone mineral density (BMD), and patient-reported outcomes (Oxford knee score)-all at 2 years-for the P.F.C. Sigma Cruciate Retaining total knee arthroplasty. PATIENTS AND METHODS: 50 osteoarthritis patients were allocated to either FB or MB tibial articulation. RESULTS AND INTERPRETATION: At 2 years, the mean total translation (implant migration) was higher for the FB implant (0.30 mm, SD 0.22) than for the MB implant (0.17 mm, SD 0.09) (p = 0.04). BMD decreased between baseline and 1-year follow-up. At 2-year follow-up, BMD was close to the baseline level. The knee scores of both groups improved equally well. The FB tibial implant migrated more than the MB, but this was not clinically significant. The mobile polyethylene presumably partly absorbs the force transmitted to the metal tibial tray, thereby reducing micromotion. PMID- 25280134 TI - Enantioselective one-pot synthesis of ring-fused tetrahydroquinolines via aerobic oxidation and 1,5-hydride transfer/cyclization sequences. AB - Enantioselective organocatalytic synthesis of tetrahydroquinolines has been achieved via an aerobic oxidation and a 1,5-hydride transfer/cyclization sequence. The feature of this research is a one-pot transformation of 3-arylprop 2-en-1-ol derivatives into tetrahydroquinolines using a Ru(VII)-catalyzed aerobic oxidation and highly efficient internal redox reactions. The synthetically useful ring-fused tetrahydroquinoline derivatives are obtained in moderate yields and high levels of enantioselectivity. PMID- 25280133 TI - High risk of early periprosthetic fractures after primary hip arthroplasty in elderly patients using a cemented, tapered, polished stem. AB - BACKGROUND AND PURPOSE: Postoperative periprosthetic femoral fracture (PPF) after hip arthroplasty is associated with considerable morbidity and mortality. We assessed the incidence and characteristics of periprosthetic fractures in a consecutive cohort of elderly patients treated with a cemented, collarless, polished and tapered femoral stem (CPT). PATIENTS AND METHODS: In this single center prospective cohort study, we included 1,403 hips in 1,357 patients (mean age 82 (range 52-102) years, 72% women) with primary osteoarthritis (OA) or a femoral neck fracture (FNF) as indication for surgery (367 hips and 1,036 hips, respectively). 64% of patients were ASA class 3 or 4. Hip-related complications and need for repeat surgery were assessed at a mean follow-up time of 4 (1-7) years. A Cox regression analysis was used to evaluate risk factors associated with PPF. RESULTS: 47 hips (3.3%) sustained a periprosthetic fracture at median 7 (2-79) months postoperatively; 41 were comminute Vancouver B2 or complex C-type fractures. The fracture rate was 3.8% for FNF patients and 2.2% for OA patients (hazard ratio (HR) = 4; 95% CI: 1.3-12). Patients > 80 years of age also had a higher risk of fracture (HR = 2; 95% CI: 1.1-4.5). INTERPRETATION: We found a high incidence of early PPF associated with the CPT stem in this old and frail patient group. A possible explanation may be that the polished tapered stem acts as a wedge, splitting the femur after a direct hip contusion. Our results should be confirmed in larger, registry-based studies, but we advise caution when using this stem for this particular patient group. PMID- 25280135 TI - User involvement in structured violence risk management within forensic mental health facilities -- a systematic literature review. AB - AIMS AND OBJECTIVES: To examine empirical literature on user involvement in collaboration between patients and nurses. The scope of the review was limited to structured violence risk management interventions in forensic mental health settings. BACKGROUND: Violence in forensic mental health settings represents a significant problem for patients and staff. Structured violence risk management interventions in forensic mental health have been reported to ignore patient participation, despite the growing attention on user involvement in clinical practice. DESIGN: A systematic review. METHOD: Searches were conducted in six databases: the Cochrane Systematic Reviews, MEDLINE, CINAHL, ProQuest, ScienceDirect and PsycINFO. Papers were assessed according to a predetermined set of inclusion and exclusion criteria. RESULTS: After searches of the reference lists of retrieved articles were conducted, only three papers met the inclusion criteria. CONCLUSIONS: This review has shown that empirical research on the topic of risk management interventions in which patients are involved is scarce. RELEVANCE TO CLINICAL PRACTICE: There is barely any research evidence of the clinical effect of user involvement approaches on violence risk management in forensic mental health practice. Therefore, we suggest that clinicians may learn from positive experiences concerning user involvement in general psychiatry and carefully adapt and test them out in the forensic treatment context. PMID- 25280136 TI - Experiences of mothers with substance dependence: Informing the development of parenting support. AB - AIMS AND OBJECTIVES: To understand the experiences of women with a history of substance dependence when they attempted to gain parenting support. BACKGROUND: Becoming a mother provides a window of opportunity to support women with a substance dependence make changes to their lives and the way they will parent their infants and young children. Yet there are many barriers and a constant fear of the removal of their children from their care. DESIGN: Focus groups were conducted using a qualitative interpretive descriptive approach to enable exploration of the women's experiences as mothers with infants and young children. METHOD: A series of three focus groups were facilitated with three to six women per group. Thirteen women who were substance dependent participated in this study. Semi-structured interviews guided the collection of data. Thematic content analysis was used to work with the data. RESULTS: Four themes were identified: (1) feelings of guilt, (2) judged by others, (3) normalising and (4) support and learning to be a mother. CONCLUSION: The mothers expressed alienation from mainstream health services. Providing parenting and child health services, which avoid mothers feeling judged by the staff and other mothers, is an important step to enabling these women to appropriately and sensitively care for their infants and young children. RELEVANCE TO CLINICAL PRACTICE: Midwives and nurses working with mothers and their infants and young children are well positioned to support women who are or have experienced substance dependence. Working with this group of mothers requires the development of a therapeutic relationship to provide optimum support, education and, if necessary, intervention. PMID- 25280137 TI - Vital exhaustion and anxiety are related to subjective quality of life in patients with acute myocardial infarct before cardiac rehabilitation. AB - AIMS AND OBJECTIVES: To examine psychological risk factors and somatic factors in patients after myocardial infarction. To study the relationship between somatic and psychological factors, their influence on subjective quality of life (well being) and also to examine possible gender differences. BACKGROUND: There has been a growing body of evidence that psychosocial factors are risk factors for incident and recurrent myocardial infarction. DESIGN: Descriptive correlational and cross-sectional survey design. METHODS: In patients (n = 97, 67 men), the level of depression and anxiety, vital exhaustion, sleep disturbances and well being were assessed. Left ventricular ejection fraction, left ventricular diastolic diameter, body mass index, metabolic equivalents and the number of diseased vessels were retrieved from medical records. RESULTS: Anxiety, vital exhaustion and sleep disturbances were significantly higher in women than in men. Well-being showed a significant linear correlation with body mass index, anxiety, depression, vital exhaustion and sleep disturbances scores. After adjustment for psychological risk factors and somatic parameters, only vital exhaustion and anxiety correlated significantly with well-being. However, there were gender differences in predictive variables of well-being. Anxiety in men and vital exhaustion in women showed a linear correlation with the subjective quality of life. CONCLUSION: Our study revealed that only vital exhaustion and anxiety showed a significant correlation with well-being in patients. RELEVANCE TO CLINICAL PRACTICE: During cardiac rehabilitation, it is important to detect and treat not only depression but also vital exhaustion and anxiety, because by reducing these psychological conditions, we can improve well-being. PMID- 25280138 TI - How clinical nurse and midwifery consultants optimise patient care in a tertiary referral hospital. AB - AIMS AND OBJECTIVES: To develop new insights into the phenomenon of clinical nurse/midwifery consultant clinical effectiveness in a tertiary referral hospital. BACKGROUND: International studies identify the pivotal role clinical nurse/midwifery consultants play in patient outcomes. There remains, however, a significant deficit in our knowledge of how these, or other advanced practice nurses and midwives, apply their extensive experience, ontological understandings and tacit knowledge to the enhancement of patient outcomes in complex healthcare environments. DESIGN: This study was underpinned by the principles of Heideggerian hermeneutic phenomenology. METHODS: Recruitment involved expressions of interest distributed hospital-wide to clinical nurse/midwifery consultants. Inclusion criteria specified a minimum of three years' experience. Fifteen clinical nurse/midwifery consultants, representing a broad range of specialties, were interviewed. Preliminary descriptive analysis of transcribed data was followed by in-depth hermeneutic analysis. RESULTS: The findings comprise four themes: walking beside the patient, anticipating the unexpected, pushing through barriers and leading within a complex system. These themes highlight how clinical nurse/midwifery consultants significantly influence pre-existing trajectories of patient care delivery through context-appropriate strategies. CONCLUSION: This study introduces new insights into the meanings advanced practice nurses and midwives develop from their engagements with patients and how these meanings inform clinical decisions. The paper accomplishes this by drawing on Heideggerian philosophical concepts such as ontological understandings, authenticity and care. It also casts light on the participants' shared understandings of how to synergise expectations within the team. RELEVANCE TO CLINICAL PRACTICE: The significance of this paper lies in the uncovering of ontological understandings and tacit knowledge of how consultant nurses and midwives optimise patient care delivery in challenging situations. The findings indicate, however, that the value of these internationally established roles is yet to be fully realised. The paper concludes by recommending strategies to assist newly appointed clinical nurse/midwifery consultants transition into these demanding autonomous roles. PMID- 25280139 TI - Childhood obesity: an observational study. PMID- 25280140 TI - Randomized controlled pilot trial of the rigid and flexing laryngoscope versus the fiberoptic bronchoscope for intubation of potentially difficult airway. AB - BACKGROUND: The flexible fiberoptic bronchoscope (FOB) is viewed as the gold standard device for awake intubation in the difficult airway. The newer rigid flexible laryngoscope (RIFL) was developed for similar indications. In this study we compare these two devices for management of potentially difficult airways after induction of general anesthesia. METHODS: Adult surgical patients requiring endotracheal intubation and having a predicted difficult airway based on airway examination, BMI>=35, and/or history of prior difficult intubation were randomized to undergo endotracheal intubation with either the RIFL or FOB. Induction was performed in usual manner, and intubation was performed by providers proficient with both airway devices after induction of general anesthesia. The primary outcomes measured were intubation success, time to intubation, number of attempts, and the need for airway assist maneuvers. The lowest observed oxygen saturation and airway trauma were also recorded. RESULTS: A total of 41 patients were enrolled, with 20 randomized to each group and 1 withdrawal. Intubation was successful in all patients with both devices. The median time for successful intubation was significantly shorter in the RIFL group compared to the FOB group (49 vs. 64 seconds; P=0.048). Airway assist maneuvers were required in 2 (10%) intubations with the RIFL compared to 16 (80%) intubations with the FOB (P<0.001). There were no significant differences in lowest oxygen saturation or airway trauma. CONCLUSION: The RIFL required significantly less time and fewer airway assist maneuvers for successful endotracheal intubation compared to FOB when used by experienced providers in patients with anticipated difficult airways. PMID- 25280141 TI - Levosimendan in lung transplant recipients with difficult weaning from ECMO. PMID- 25280142 TI - Relationship of ECMO duration with outcomes after pediatric cardiac surgery: a multi-institutional analysis. AB - BACKGROUND: There are very sparse data on the outcomes of children receiving prolonged extracorporeal membrane oxygenation (ECMO) after cardiac surgery. This study was aimed to evaluate the association of ECMO duration with outcomes in children undergoing surgery for congenital heart disease using the Pediatric Health Information System (PHIS) database. METHODS: Patients aged <=18 years receiving ECMO after pediatric cardiac surgery (with or without cardiopulmonary bypass) at a PHIS-participating hospital (2004-2013) were included. De-identified data obtained from retrospective, observational dataset included demographic information, baseline characteristics, pre-ECMO risk factors, operation details, patient diagnoses, and center data. Outcomes evaluated included in-hospital mortality, length of mechanical ventilation, length of ICU stay, length of hospital stay, and hospital charges. Cox proportional hazards models were fitted to study the probability of study outcomes as a function of ECMO duration. RESULTS: Nine hundred ninety-eight patients from 37 hospitals qualified for inclusion. The median duration of ECMO run was 4 days (IQR: 1.7). After adjusting for patient and center characteristics, there was 12% increase in the odds of mortality for every 24 hours increase in ECMO duration (OR: 1.12, 95% CI: 1.07 1.18, P<0.001). Patients receiving longer duration of ECMO were associated with longer length of mechanical ventilation, longer length of ICU stay, longer length of hospital stay, and higher hospital charges. CONCLUSION: Data from this large multicenter database suggest that longer duration of ECMO support after pediatric cardiac surgery is associated with worsening outcomes. PMID- 25280143 TI - Predictors of acute symptomatic seizures after intracranial hemorrhage in infants. AB - OBJECTIVE: To determine the prevalence of acute symptomatic seizures in infants with supratentorial intracranial hemorrhage, to identify potential risk factors, and to determine the effect of acute seizures on long-term morbidity and mortality. DESIGN: Children less than 24 months with intracranial hemorrhage were identified from a neurocritical care database. All patients who received seizure prophylaxis beginning at admission were included in the study. Risk factors studied were gender, etiology, location of hemorrhage, seizure(s) on presentation, and the presence of parenchymal injury. Acute clinical and electrographic seizures were identified from hospital medical records. Subsequent development of late seizures was determined based on clinical information from patients' latest follow-up. SETTING AND PATIENTS: Patients with idiopathic neonatal intracranial hemorrhage, premature infants, and those with prior history of seizures were excluded from analysis. Seventy-two infants met inclusion criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty percent of infants had acute symptomatic seizures. The prevalence was similar regardless of whether etiology of hemorrhage was traumatic or nontraumatic. Seizures on presentation and parenchymal injury were independent risk factors of acute seizures (p = 0.001 and p = 0.006, respectively). Younger children and women were also at higher risk (p < 0.05). Twenty percent had electrographic-only seizures, and those with parenchymal injury trended toward an increased risk (p < 0.1). Acute seizures were not predictive of mortality, but nearly twice as many patients with acute seizures developed late seizures when compared with those without. Electrographic seizures and parenchymal injury were also predictive of development of late seizures (p < 0.001 and p = 0.013, respectively). CONCLUSIONS: Despite seizure prophylaxis, infants with supratentorial intracranial hemorrhage are at high risk for acute symptomatic seizures. This is regardless of the etiology of hemorrhage. Younger patients, women, patients with parenchymal injury, and patients presenting with seizure are most likely to develop acute seizures. Although the benefits of seizure prophylaxis have not been studied in this specific population, these results suggest that it is an important component of acute care following intracranial hemorrhage. PMID- 25280144 TI - Helping children tolerate the cardiac ICU: where do we start? PMID- 25280145 TI - Identifying critically ill patients who may benefit from adjunctive corticosteroids: not as easy as we thought. PMID- 25280146 TI - Long-term dexmedetomidine use for pediatric critical care sedation: no need to sleep on it. PMID- 25280147 TI - Overtesting and overtreatment: the role of tracheal aspirate cultures in the diagnosis and management of ventilator-associated infections. PMID- 25280148 TI - What is my child's outcome? A simple question with a complex answer. PMID- 25280149 TI - Neonatal single-ventricle palliative surgery: lost in (dead) space? PMID- 25280150 TI - Cerebrovascular autoregulation in diabetic ketoacidosis: time to go with the (microvascular cerebral blood) flow! PMID- 25280151 TI - An ounce of prevention but less than a pound of cure: seizure prophylaxis after intracranial hemorrhage. PMID- 25280152 TI - Moving beyond mortality: preservation of value, but at what cost? PMID- 25280153 TI - Palliative care in the ICU: together we can make a greater difference. PMID- 25280154 TI - How we measure anticoagulation is just as important (maybe more important) as how we anticoagulate. PMID- 25280155 TI - Do you smell something burning? Could it be you? PMID- 25280156 TI - Commercial aviation: are there unrecognized risks for infants and toddlers? PMID- 25280157 TI - How to monitor and how to decrease protein hypercatabolism in critically ill children? PMID- 25280158 TI - The authors reply. PMID- 25280159 TI - Vasopressin versus terlipressin and low-dose versus high-dose steroids. PMID- 25280160 TI - The authors reply. PMID- 25280161 TI - Silver corrole complexes: unusual oxidation states and near-IR-absorbing dyes. AB - Macrocycles such as porphyrins and corroles have important functions in chemistry and biology, including light absorption for photosynthesis. Generation of near-IR (NIR)-absorbing dyes based on metal complexes of these macrocycles for mimicking natural photosynthesis still remains a challenging task. Herein, the syntheses of four new Ag(III) corrolato complexes with differently substituted corrolato ligands are presented. A combination of structural, electrochemical, UV/Vis/NIR EPR spectroelectrochemical, and DFT studies was used to decipher the geometric and electronic properties of these complexes in their various redox states. This combined approach established the neutral compounds as stable Ag(III) complexes, and the one-electron reduced species of all the compounds as unusual, stable Ag(II) complexes. The one-electron oxidized forms of two of the complexes display absorptions in the NIR region, and thus they are rare examples of mononuclear complexes of corroles that absorb in the NIR region. The appearance of this NIR band, which has mixed intraligand charge transfer/intraligand character, is strongly dependent on the substituents of the corrole rings. Hence, the present work revolves round the design principles for the generation of corrole-based NIR absorbing dyes and shows the potential of corroles for stabilizing unusual metal oxidation states. These findings thus further contribute to the generation of functional metal complexes based on such macrocyclic ligands. PMID- 25280162 TI - The study of binding of methyl tert-butyl ether to human telomeric G-quadruplex and calf thymus DNA by gas chromatography, a thermodynamic discussion. AB - Methyl-tert-butyl ether (MTBE) is widely used as an antiknock additive for increasing octane number of gasoline. Recently, the in vivo studies demonstrated that MTBE has genotoxic potential and able to form adducts with DNA. In the work, the interactions of MTBE with calf thymus DNA (ct-DNA) and the Na(+) form of G quadruplex DNA (wtTel22) were studied by using of head space-solid phase microextraction technique coupled to gas chromatography. The binding equilibrium constants were measured through the equilibriums of a four phase system. In addition, the MTBE Henry's law constants for two different buffers in the temperature range of 283-303K were measured. Thermodynamic studies revealed that the complexation of MTBE to both DNAs is enthalpy favored and entropy disfavored. The thermodynamic results revealed that MTBE may have interaction with ct-DNA via the minor groove of DNA. Also, MTBE may be complexed into the basket of G quadruplex structure. In addition, the low difference in the binding constants of MTBE for both different DNA targets may confirm that MTBE is poorly selective for different conformations of DNA. PMID- 25280163 TI - Radical scavenging and antimicrobial activities of Croton zehntneri, Pterodon emarginatus and Schinopsis brasiliensis essential oils and their major constituents: estragole, trans-anethole, beta-caryophyllene and myrcene. AB - The essential oils (EOs) from the Brazilian species Croton zehntneri, Pterodon emarginatus and Schinopsis brasiliensis were examined for their chemical constituents, and antioxidant and antimicrobial activities. The composition of EOs was determined by using gas chromatography coupled with mass spectrometry analysis, while the antioxidant activity was evaluated through the 1,1-diphenyl-2 picrylhydrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) assays. Furthermore, the antimicrobial activity was investigated against Escherichia coli and Pseudomonas aeruginosa (both Gram-negative), Staphylococcus aureus (Gram positive) and Candida parapsilosis (fungus). The main components of C. zehntneri, P. emarginatus and S. brasiliensis were identified as estragole, trans-anethole, beta-caryophyllene and myrcene. Among the EOs, P. emarginatus showed the highest antioxidant activity, with an IC50 of 7.36 mg/mL and a Trolox equivalent antioxidant capacity of 3748 MUmol/g determined by DPPH and ORAC assays, respectively. All EOs showed low activities against the bacterial strains tested, whereas the C. zehntneri oil and its main constituent estragole exhibited an appreciable antifungal activity against C. parapsilosis. PMID- 25280164 TI - Gender and theory of mind in preschoolers' group effort: evidence for timing differences behind children's earliest social loafing. AB - This study explored mental state reasoning within the context of group effort and possible differences in development between boys and girls. Preschool children (59 girls, 47 boys) were assessed for theory of mind (ToM) ability using classic false belief tests. Children participated in group effort conditions that alternated from one condition, where individual effort was transparent and obvious, to one where individual effort remained anonymous. The aim was to investigate if emergent mental state reasoning, after controlling for age, was associated with the well-known phenomenon of reduced effort in group tasks ("social loafing"). Girls had slightly higher ToM scores and social loafing than boys. Hierarchical regression, controlling for age, indicated that understanding of others' false beliefs uniquely predicted social loafing and interacted weakly with gender status. PMID- 25280165 TI - Authoritarianism, cognitive rigidity, and the processing of ambiguous visual information. AB - Intolerance of ambiguity and cognitive rigidity are unifying aspects of authoritarianism as defined by Adorno, Frenkel-Brunswik, Levinson, and Sanford (1982/1950), who hypothesized that authoritarians view the world in absolute terms (e.g., good or evil). Past studies have documented the relationship between authoritarianism and intolerance of ambiguity and rigidity. Frenkel-Brunswik (1949) hypothesized that this desire for absolutism was rooted in perceptual processes. We present a study with three samples that directly tests the relationship between right wing authoritarianism (RWA) and the processing of ideologically neutral but ambiguous visual stimuli. As hypothesized, in all three samples we found that RWA was related to the slower processing of visual information that required participants to recategorize objects. In a fourth sample, RWA was unrelated to speed of processing visual information that did not require recategorization. Overall, results suggest a relationship between RWA and rigidity in categorization. PMID- 25280166 TI - Unanswered prayers: religiosity and the god-serving bias. AB - Two self-report experiments examined how religiosity affects attributions made for a target person's death. Online adults (Study 1, N = 427) and undergraduate students (Study 2, N = 326) read about Chris who had a heart attack, used religious or health behaviors, and lived or died. Participants made attributions to Chris and God (both studies), and reported their emotions (Study 2). Participants made more attributions to Chris when he lived than when he died, but only when he used health behaviors. The highly religious made more attributions to God, but not when Chris used religious behaviors and died (the God-serving bias); they reported the most positive emotions when Chris lived after using religious behaviors (the Hallelujah effect). Directions for future research in terms of implicit religious beliefs and normative evaluations of religion are discussed. PMID- 25280167 TI - The effect of effort and weight controllability on perceptions of obese individuals. AB - We examined the impact of offset controllability (capability of losing weight) and offset effort (efforts to lose weight) on judgments of an obese target. Participants (n = 216) read about an obese person whose body weight was controllable/uncontrollable, and who did/did not put in effort to eat healthily and exercise. Effort played a more important role than controllability in evaluations of the target. Targets who put in effort to be healthy were ascribed fewer obesity stereotypes, evoked less disgust, and were considered to have a more acceptable lifestyle. These findings extend attribution theory and have implications for strategies to reduce weight bias. PMID- 25280168 TI - A bright side, facet analysis of histrionic personality disorder: the relationship between the HDS Colourful factor and the NEO-PI-R facets in a large adult sample. AB - This study looks at "bright-side," Big Five Personality trait correlates of a "dark-side" Personality Disorder, namely Histrionic Personality Disorder (HPD). More than 5000 British adults completed the Neuroticism Extraversion Openness Personality Inventory-Revised (Costa & McCrae, 1985), which measures the Big Five Personality factors at the Domain (Super Factor) and the Facet (Factor) level, as well as the Hogan Development Survey (HDS; Hogan & Hogan, 2009), which has a measure of HPD, exclusively called "Colourful" in the HDS terminology. Correlation and regression results confirmed many of the associations between these "bright" and "dark" side individual difference variables. The Colourful (HPD) score from the HDS was the criterion variable in all analyses. Colourful individuals are high on Extraversion and Openness, but also Stable and disagreeable. The Facet analysis identified Assertiveness and Immodesty as particularly characteristic of that type. The study confirmed work on HPD using different population groups and different measures, showing that personality traits are predictable and correlated with various personality disorders. PMID- 25280169 TI - Embracing humanity in the face of death: why do existential concerns moderate ingroup humanization? AB - People humanize their ingroup to address existential concerns about their mortality, but the reasons why they do so remain ambiguous. One explanation is that people humanize their ingroup to bolster their social identity in the face of their mortality. Alternatively, people might be motivated to see their ingroup as more uniquely human (UH) to distance themselves from their corporeal "animal" nature. These explanations were tested in Australia, where social identity is tied less to UH and more to human nature (HN) which does not distinguish humans from animals. Australians attributed more HN traits to the ingroup when mortality was salient, while the attribution of UH traits remained unchanged. This indicates that the mortality-buffering function of ingroup humanization lies in reinforcing the humanness of our social identity, rather than just distancing ourselves from our animal nature. Implications for (de)humanization in intergroup relations are discussed. PMID- 25280170 TI - Gendered mental disorders: masculine and feminine stereotypes about mental disorders and their relation to stigma. AB - Research indicates that stereotypes can intersect. For example, the intersection of stereotypes about gender and mental disorders could result in perceptions of gendered mental disorders. In the current research, Studies 1 and 2 showed that people view specific disorders as being masculine or feminine. The masculine stereotype included antisocial personality disorder, addictions, and paraphilias. The feminine stereotype included eating disorders, histrionic personality disorder, body dysmorphia, and orgasmic disorder. In both studies, the perception of disorders as masculine was positively correlated with stigma. Study 3 showed that the positive correlation between masculinity and stigma also occurred when examining specific symptoms rather than full mental disorders. The findings provide further evidence for the intersection of stereotypes and indicate a novel factor in the understanding of stigma. PMID- 25280174 TI - Eyes on new product development. PMID- 25280175 TI - Potential therapeutic effects of baicalein, baicalin, and wogonin in ocular disorders. AB - Ocular diseases such as cataract, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy are the leading causes of blindness. The elderly population is at particular risk of developing one or more of these age-related ocular diseases. By virtue of multiple bioactivities, effort has been made to develop dietary flavonoids as complimentary therapies for ocular disorders. Dietary intake of flavonoids has been reported to reduce the risk of cataract and AMD. This review focuses on the main flavones baicalein, baicalin, and wogonin isolated from the Chinese medicinal herb, Scutellariae radix (SR), which has been widely used in Asian countries for the treatment of many diseases. Interest in SR has grown recently following new findings that suggest multiple routes of therapeutic action. This review will summarize the diverse pharmacological properties, therapeutic roles, and mechanisms of these flavones of SR in cellular and animal models of ocular diseases. PMID- 25280176 TI - Dimethylamine biodegradation by mixed culture enriched from drinking water biofilter. AB - Dimethylamine (DMA) is one of the important precursors of drinking water disinfection by-product N-nitrosodimethylamine (NDMA). Reduction of DMA to minimize the formation of carcinogenic NDMA in drinking water is of practical importance. Biodegradation plays a major role in elimination of DMA pollution in the environment, yet information on DMA removal by drinking water biofilter is still lacking. In this study, microcosms with different treatments were constructed to investigate the potential of DMA removal by a mixed culture enriched from a drinking water biofilter and the effects of carbon and nitrogen sources. DMA could be quickly mineralized by the enrichment culture. Amendment of a carbon source, instead of a nitrogen source, had a profound impact on DMA removal. A shift in bacterial community structure was observed with DMA biodegradation, affected by carbon and nitrogen sources. Proteobacteria was the predominant phylum group in DMA-degrading microcosms. Microorganisms from a variety of bacterial genera might be responsible for the rapid DMA mineralization. PMID- 25280178 TI - Extracorporeal Septoplasty Combined With Valve Surgery in Rhinoplasty Patients. AB - External nasal deviation is caused primarily by severely a deformed septum. The nose functions as a whole composed of the septum, valve systems, and mucosal structures. Patients with severely deviated septums also have deformed nasal valve systems. Extracorporeal septoplasty is advocated for an extremely deviated nasal septum. Nasal valve dysfunctions can be resolved successfully with spreader grafts. Application of extracorporeal septoplasty in combination with spreader grafts in patients with nasal valve dysfunction not only enables nasal respiration but also supports aesthetic appearance. The 19 patients in our study had undergone aesthetic rhinoplasty and presented with breathing problems and septal deviations. The patients were treated with extracorporeal septoplasty and spreader grafts. The patients were followed with clinical measures and computed tomographic scanning. No complications such as relapse, perforation, or saddling were encountered during follow-up. Aesthetically and functionally satisfactory results were obtained. PMID- 25280177 TI - Neonatal thyroid function born to mothers living with long-term excessive iodine intake from drinking water. AB - OBJECTIVE: The effects of long-term excessive maternal iodine intake on neonatal thyroid function are less known. This study aimed to assess the effects of maternal excessive iodine intake from drinking water on thyroid functions of both mothers and their neonates. DESIGN AND METHODS: This observational study was performed in high iodine (HI) areas and adequate iodine (AI) intake areas, including 384 healthy pregnant women in late gestation (mean week 39.3 +/- 1.6 weeks) and their newborns. Blood and urine samples were obtained from pregnant women, while cord blood samples were obtained from neonates. Urinary iodine concentration (UIC) and thyroid function were evaluated. RESULTS: The median maternal UIC was 1241 and 217 MUg/l in HI and AI areas, respectively (P < 0.001). The concentrations of serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) in neonates in HI areas were 7.33 mIU/l (range 5.47, 11.06 mIU/l), 2.93 +/- 0.59 and 15.03 +/- 1.92 pmol/l, respectively, while that were 4.71 mIU/l (range 3.96, 6.04 mIU/l), 2.31 +/- 0.28 and 16.50 +/- 1.35 pmol/l in AI neonates (P < 0.05). Similar changes were also observed in neonates in HI areas when excluding the effect of maternal thyroid autoimmunity. Cord blood TSH concentration (r = 0.31, P = 0.001) and FT3 concentration (r = 0.43, P = 0.001) were positively correlated with maternal UIC. Cord blood FT4 concentration was negatively correlated with maternal UIC (r = 0.25, P = 0.001). Mothers living in HI areas (beta = 0.296, 95% CI: 0.163, 0.255) and with subclinical hypothyroidism (beta = 0.360, 95% CI: 0.034, 0.175) contributed to elevated cord blood TSH concentration in neonates, while male neonates were more likely to present with higher TSH concentration compared with female infants (beta = -0.760, 95% CI: -0.119, -0.033). CONCLUSIONS: Excessive iodine intake during pregnancy was associated with an increased rate of hyperthyrotropinaemia in neonates and their mothers, especially in male neonates. PMID- 25280180 TI - Highly alloyed PtRu nanoparticles confined in porous carbon structure as a durable electrocatalyst for methanol oxidation. AB - The state-of-the-art carbon-supported PtRu catalysts are widely used as the anode catalysts in polymer electrolyte fuel cells (PEMFCs) but suffer from instability issues. Severe ruthenium dissolution occurring at potentials higher than 0.5 V vs NHE would result in a loss of catalytic activity of PtRu hence a worse performance of the fuel cell. In this work, we report an ultrastable PtRu electrocatalyst for methanol oxidation by confining highly alloyed PtRu nanoparticles in a hierarchical porous carbon structure. The structural characteristics, e.g., the surface composition and the morphology evolution, of the catalyst during the accelerated degradation test were characterized by the Cu stripping voltammetry and the TEM/SEM observations. From the various characterization results, it is revealed that both the high alloying degree and the pore confinement of PtRu nanoalloys play significant roles in suppressing the degradation processes, including Ru dissolution and particle agglomeration/migration. This report provides an opportunity for efficient design and fabrication of highly stable bimetallic or trimetallic electrocatalysts in a large variety of applications. PMID- 25280179 TI - Attention regulates anger and fear to predict changes in adolescent risk-taking behaviors. AB - BACKGROUND: Regulation of negative affect is critical to healthy development in childhood and adolescence. We conducted a longitudinal study examining the moderating role of attention control in the effects of anger and fear on changes in risk-taking behaviors from early to middle adolescence. METHOD: The sample involved participants from the Study of Early Child Care and Youth Development (SECCYD), assessed at 9, 11, and 15 years of age. Composite scores for anger, fear, and attention control were computed using indicators from multiple informants, and risk-taking behaviors were assessed based on adolescents' self reports. RESULTS: Latent difference score analysis indicated significant moderating effects of attention control showing that increased anger between 9 and 11 years was related to increases in risk-taking behaviors between 11 and 15 years only for adolescents with low attention control but not for adolescents with high attention control. In contrast, significant moderating effects of attention control for the link between fear and risk-taking behaviors suggested increased fear between 9 and 11 years tended to be associated with decreases in risk-taking behaviors between 11 and 15 years only for adolescents with high attention control, but not for adolescents with low attention control. CONCLUSIONS: Attention control regulates the connections between negative affect such as anger and fear with changes in adolescent risk-taking behaviors. Our data suggest the protective role of strong attention control against the development of risk-taking behaviors in adolescence as it demotes the effects of anger and promotes the effects of fear. PMID- 25280181 TI - Sources of vitamin D and calcium in the diets of preschool children in the UK and the theoretical effect of food fortification. AB - BACKGROUND: Dietary intakes of vitamin D are very low in the UK. Dietary calcium is also necessary to promote bone health. The fortification of foods with vitamin D could be a safe and effective way of increasing intake. METHODS: Diets of preschool children, 755 at 18 months and 3.5 years, from the Avon Longitudinal Study of Parents and Children were assessed using dietary records completed by parents. Energy, vitamin D and calcium intakes were calculated. Multinomial logistic regression was used to estimate the odds ratio for being in the highest/lowest quartile of intake. Intakes were recalculated to test different fortification regimes. RESULTS: Vitamin D intakes were low; all children were below the UK and US dietary recommendations. Calcium intakes decreased between the two ages as a result of reduced milk consumption. Children in the lowest quartile for vitamin D intake at 18 months were twice as likely to remain in that quartile at 3.5 years (odds ratio = 2.35; 95% confidence interval = 1.56-3.55). The majority of foods provide no vitamin D with fat spreads and milk as the main sources. The contribution from breakfast cereals increased, from 6% to 12%, as a result of the increased consumption of fortified cereals. Dairy foods provided the highest contribution to calcium at 18 months but were less important at 3.5 years. Theoretical intakes from different fortification regimens suggest that milk fortified at 2 MUg 100 g(-1) vitamin D would provide most children with adequate but not excessive intakes. CONCLUSIONS: Dietary vitamin D intakes were very low and calcium intakes were mostly adequate. Fortification of milk with vitamin D could be a good way to boost intakes. PMID- 25280182 TI - DNA repair and redox activities and inhibitors of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1): a comparative analysis and their scope and limitations toward anticancer drug development. AB - The apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme involved in DNA repair and activation of transcription factors through its redox function. The evolutionarily conserved C- and N-termini are involved in these functions independently. It is also reported that the activity of APE1/Ref-1 abruptly increases several-fold in various human cancers. The control over the outcomes of these two functions is emerging as a new strategy to combine enhanced DNA damage and chemotherapy in order to tackle the major hurdle of increased cancer cell growth and proliferation. Studies have targeted these two domains individually for the design and development of inhibitors for APE1/Ref-1. Here, we have made, for the first time, an attempt at a comparative analysis of APE1/Ref-1 inhibitors that target both DNA repair and redox activities simultaneously. We further discuss their scope and limitations with respect to the development of potential anticancer agents. PMID- 25280183 TI - Google unveils a glimpse of allergic rhinitis in the real world. AB - Google Trends (GT) is a Web-based surveillance tool used to explore the searching trends of specific queries on Google. Recent studies have suggested the utility of GT in predicting outbreaks of influenza and other diseases. However, this utility has not been thoroughly evaluated for allergic diseases. Therefore, we investigated the utility of GT for predicting the epidemiology of allergic rhinitis. In the USA, GT for allergic rhinitis showed repetitive seasonality that peaked in late April and early May and then rapidly decreased, and a second small peak occurred in September. These trends are highly correlated with the searching trends for other queries such as 'pollen count', antihistamines such as loratadine and cetirizine (all r > 0.88 and all P < 0.001), and even the total pollen count collected from 21 pollen counters across the USA (r = 0.928, P < 0.001). Google Trends for allergic rhinitis was similar to the monthly changes in rhinitis symptoms according to the US National Health and Nutrition Examination Survey III, sales for Claritin((r)) and all over-the-counter antihistamines, and the number of monthly page views of 'claritin.com'. In conclusion, GT closely reflects the real-world epidemiology of allergic rhinitis in the USA and could potentially be used as a monitoring tool for allergic rhinitis. PMID- 25280184 TI - Single-shot digital holography using a spectral estimation technique. AB - We demonstrate a technique capable of obtaining spectral information and a three dimensional (3D) profile of an object with a single-shot exposure. This technique is based on digital holography and the spectral estimation technique. In the demonstration of this technique, we simultaneously use three laser lines operating at 473, 532, and 633 nm to record the multiple complex amplitudes of the object corresponding to the wavelengths and obtain reconstructed monochrome images of each wavelength. A spectral estimation technique is applied to estimate the spectral reflectance of the object from the reconstructed monochrome images. We experimentally succeed in estimating the spectral reflectance of a lemon by using the technique. PMID- 25280185 TI - Lung Function and CT Densitometry in Subjects with alpha-1-Antitrypsin Deficiency and Healthy Controls at 35 Years of Age. AB - Alpha-1-antitrypsin (AAT) deficiency is a genetic risk factor for pulmonary emphysema. In 1972-74 all 200,000 Swedish new-born infants were screened for AAT deficiency. The aim of the present study was to investigate whether the PiZZ and PiSZ individuals identified by this screening have signs of emphysema and the role of smoking in this, compared with a random sample of control subjects at 35 years of age. The study participants underwent complete pulmonary function tests (PFT) and CT densitometry. The fifteenth percentile density (PD15) and the relative area below -910 HU (RA-910) were analyzed. Fifty-four PiZZ, 21 PiSZ and 66 PiMM control subjects participated in the study. No significant differences were found in lung function between the never-smoking AAT-deficient and control subjects. The 16 PiZZ ever-smokers had significantly lower carbon monoxide transfer coefficient (KCO) than the 20 PiSZ never-smokers (p = 0.014) and the 44 PiMM never-smokers (p = 0.005). After correction for the CT derived lung volume, the PiZZ ever-smokers had significantly lower PD15 (p = 0.046) than the ever smoking controls. We conclude that 35-year-old PiZZ and PiSZ never-smokers have normal lung function when compared with never-smoking control subjects. The differences in KCO and CT densitometric parameters between the PiZZ ever-smokers and the control subjects may indicate early signs of emphysema. PMID- 25280186 TI - Intensity-value corrections for integrating sphere measurements of solid samples measured behind glass. AB - Accurate and calibrated directional-hemispherical reflectance spectra of solids are important for both in situ and remote sensing. Many solids are in the form of powders or granules and to measure their diffuse reflectance spectra in the laboratory, it is often necessary to place the samples behind a transparent medium such as glass for the ultraviolet (UV), visible, or near-infrared spectral regions. Using both experimental methods and a simple optical model, we demonstrate that glass (fused quartz in our case) leads to artifacts in the reflectance values. We report our observations that the measured reflectance values, for both hemispherical and diffuse reflectance, are distorted by the additional reflections arising at the air-quartz and sample-quartz interfaces. The values are dependent on the sample reflectance and are offset in intensity in the hemispherical case, leading to measured values up to ~6% too high for a 2% reflectance surface, ~3.8% too high for 10% reflecting surfaces, approximately correct for 40-60% diffuse-reflecting surfaces, and ~1.5% too low for 99% reflecting Spectralon(r) surfaces. For the case of diffuse-only reflectance, the measured values are uniformly too low due to the polished glass, with differences of nearly 6% for a 99% reflecting matte surface. The deviations arise from the added reflections from the quartz surfaces, as verified by both theory and experiment, and depend on sphere design. Empirical correction factors were implemented into post-processing software to redress the artifact for hemispherical and diffuse reflectance data across the 300-2300 nm range. PMID- 25280187 TI - Reflections as content. PMID- 25280188 TI - Ensuring content integrity when using commercial support. AB - Preventing continuing education program bias when commercial support is used can be challenging. Standards have been developed by health care professional accreditation organizations that focus on independence, conflict of interest, appropriate management of commercial funds, content integrity, and disclosure to learners. Implementation of these standards can significantly reduce the risk of bias and improve dissemination of balanced clinical information. PMID- 25280189 TI - Hypoglycemia and diabetes: an update of current trends and treatment. AB - Iatrogenic hypoglycemia is a complication of diabetes treatment that can cause harm and prevent optimal glycemic control. The problem can be minimized through the identification of risk factors, use of tools, appropriate drug regimens, and education. Every effort needs to be made to help minimize the risk and prevent the associated complications. PMID- 25280190 TI - The power of relationships in leading. AB - A key component of successful leadership is the network of relationships that create the foundation for influence, support, and capacity for change. This article presents a four-step formula developed by Al Ritter for approaching relationships. PMID- 25280191 TI - Synthesizing learning in a workshop or conference. AB - With an increased emphasis on elevating the level of learning in all settings, continuing educators have the opportunity to facilitate learners achieving more from workshops. Using the recommended assessment strategy of The Big Point/Big Question allows educators to respond to pending questions, clarify major learning points, and help learners actively engage in processing information presented in workshops or conferences. PMID- 25280194 TI - Perinatal nurses' perceptions of competency assessments. AB - Competency assessment should be a changing and continuing process. In addition, it should be appropriate for the organization and the nursing staff. Nursing educators are challenged to provide a competency assessment process that is relevant and meaningful. This qualitative research study describes perinatal nurses' perceptions of a change from a traditional testing competency assessment to a hands-on competency assessment. The setting was a medical center in southeastern Alabama. Thirteen nurses participated in the study. Focus groups were used to explore the new assessment method. Three themes were identified: I am learning, multidimensional learning together, and increasing professional confidence. As the medical center perinatal nursing competency assessment program continues to improve, the expectation is for other departments to assess and revise their competency assessment program. PMID- 25280192 TI - Factors influencing job satisfaction of new graduate nurses participating in nurse residency programs: a systematic review. AB - Nurse residency programs are designed to increase competence and skill, and ease the transition from student to new graduate nurse. These programs also offer the possibility to positively influence the job satisfaction of new graduate nurses, which could decrease poor nursing outcomes. However, little is known about the impact of participation in a nurse residency program on new graduate nurses' satisfaction. This review examines factors that influence job satisfaction of nurse residency program participants. Eleven studies were selected for inclusion, and seven domains influencing new graduate nurses' satisfaction during participation in nurse residency programs were identified: extrinsic rewards, scheduling, interactions and support, praise and recognition, professional opportunities, work environment, and hospital system. Within these domains, the evidence for improved satisfaction with nurse residency program participation was mixed. Further research is necessary to understand how nurse residency programs can be designed to improve satisfaction and increase positive nurse outcomes. PMID- 25280195 TI - Bibliometric evaluation of pediatric neurosurgery in North America. AB - OBJECT: The application of bibliometric techniques to academic neurosurgery has been the focus of several recent publications. The authors provide here a detailed analysis of all active pediatric neurosurgeons in North America and their respective departments. METHODS: Using Scopus and Google Scholar, a bibliometric profile for every known active pediatric neurosurgeon in North America was created using the following citation metrics: h-, contemporary h-, g , and e-indices and the m-quotient. Various subgroups were compared. Departmental productivity from 2008 through 2013 was measured, and departments were ranked on the basis of cumulative h- and e-indices and the total number of publications and citations. Lorenz curves were created, and Gini coefficients were calculated for all departments with 4 or more members. RESULTS: Three hundred twelve pediatric neurosurgeons (260 male, 52 female) were included for analysis. For the entire group, the median h-index, m-quotient, contemporary h-, g-, and e-indices, and the corrected g- and e-indices were 10, 0.59, 7, 18, 17, 1.14, and 1.01, respectively; the range for each index varied widely. Academic pediatric neurosurgeons associated with fellowship programs (compared with unassociated neurosurgeons), academic practitioners (compared with private practitioners), and men (compared with women) had superior measurements. There was no significant difference between American and Canadian pediatric neurosurgeons. The mean Gini coefficient for publications was 0.45 (range 0.18-0.70) and for citations was 0.53 (range 0.25-0.80). CONCLUSIONS: This study represents the most exhaustive evaluation of academic productivity for pediatric neurosurgeons in North America to date. These results should serve as benchmarks for future studies. PMID- 25280196 TI - A conversation for the holidays: the Conversation Project. PMID- 25280197 TI - Serum neuron-specific enolase predicting neurological outcomes post-cardiac arrest: a review of the literature. AB - BACKGROUND: Coronary artery disease is a major problem in the United States, affecting 785 000 individuals, with the most serious event being a cardiopulmonary arrest. Families of post-cardiac arrest patients are left with difficult decisions to be made. OBJECTIVE: This article is a comprehensive literature review examining the current research available to health care professionals about the biomarker serum neuron-specific enolase (NSE) and its use in predicting neurological outcomes in comatose post-cardiac arrest patients. METHODS: Using the bibliographic databases CINAHL, Plus, EBSCOhost, MEDLINE, PubMed, Google Scholar, H. W. Wilson, Cochrane, and NEXUS, from the period 2003 to 2013, revealed there is minimal research or literature on NSE predicting neurological outcomes post-cardiac arrest. RESULTS: Research on this particular biomarker is relatively new, and more research is necessary to establish an adequate amount of support. At this time, an exact NSE cutoff value or its exact ability to help predict neurological outcomes is unable to be established, and further research is necessary. DISCUSSION: This literature review should provide a basic understanding of NSE and its ability to help predict neurological outcomes of post-cardiac arrest patients earlier. The research provides evidence that NSE should be considered in determining outcomes. However, more research is necessary before nursing practice is changed and implemented into patient care. PMID- 25280198 TI - Better pain management for elders in the intensive care unit. AB - By 2040, there will be 70 million people older than 65 years in the United States. Approximately 50% have pain on a daily basis, and research shows that their pain is often underdiagnosed and undertreated. Nurses have an obligation to provide state-of-the-art care and advocate for vulnerable older adults in the intensive care unit (ICU). Untreated pain can complicate an ICU stay and delay discharge. This article briefly reviews difficulties in managing pain in ICU patients, suggests creative methods to properly assess pain, and discusses approaches for encouraging elders in ICU to manage their pain effectively. PMID- 25280199 TI - Factors affecting nurses' intent to assess for depression in heart failure patients. AB - The association between depression and cardiovascular disease has been well established and has been shown to decrease patients' quality of life and increase the risk of mortality, frequency and duration of hospitalization, and health care costs. The inpatient setting provides a potentially valuable opportunity to assess and treat depression among patients with acute cardiac illness, allowing for daily monitoring of treatment side effects. Although systematic depression screening appears to be feasible, efficient, and well accepted on inpatient cardiac units, the current lack of consistent inpatient assessment for depression in heart failure patients suggests the presence of barriers influencing the effective diagnosis and treatment of depression among inpatients with heart failure. The theory of planned behavior describes the cognitive mechanism by which behavioral intent is formed, giving some insight into how nurses' attitudes and beliefs affect their performance of routine depression screening. In addition, application of this cognitive theory suggests that nurses may be influenced to adopt more positive attitudes and beliefs about depression through educational intervention, leading to greater likelihood of routine assessment for depression, ultimately leading to more timely diagnosis and treatment and improved patient outcomes. PMID- 25280201 TI - Infective endocarditis: a review for nurses. AB - Infective endocarditis (IE) is a relatively uncommon condition that can present with a variety of noncardiac symptoms, making diagnosis of this condition challenging. Although IE is no longer uniformly fatal as it was in the preantibiotic era, it still has a high mortality rate. The major risk factor for IE, rheumatic fever, has decreased significantly in the industrialized west, but the incidence of IE remains as high as it was in the preantibiotic era. Today, IE has changed from a disease primarily of the young to one of the elderly. The increase in frequency of IE seems to be related to the fact that individuals are now living longer with chronic heart diseases and are having invasive medical procedures performed more often. The 2 main approaches to treating IE are the use of antibiotics and cardiac surgery. This article provides an overview of IE, epidemiology, pathogenesis, clinical manifestations, diagnosis criteria, and treatment options for IE. PMID- 25280202 TI - Guide to nurse specialty organizations. PMID- 25280203 TI - Lateral hostilities among nurses employed in intensive care units, emergency departments, operating rooms, and emergency medical services. A national survey in Italy. AB - BACKGROUND: Lateral hostilities (LHs) are "nasty, unkind, aggressive behavior between colleagues working at comparable organizational levels." When LHs occur "at least once a week for a period of not less than 6 months," they become "bullying." The frequency of lateral violence in health care literature varies from 5.7% to 65%. OBJECTIVES: The aim of this study was to explore the extent of LH and the effects on the quality of lives of Italian nurses working in prehospital emergency medical system, emergency department, intensive care unit, and operating rooms. METHODS: A descriptive study was conducted through an online survey in the Web site of the National Italian Association of Critical Care Nurses (ANIARTI). RESULTS: A total of 1504 nurses filled up the questionnaire, with 1202 valid data entries (79.9%). Of this group, 739 (61.5%) were women and 951 (79.1%) had experienced some form of LH at least once in the last 12 months, whereas 269 (22.4%) felt to be victims of bullying. The number of transfers to other departments/services due to LH was 43 cases (3.6%), and 829 (69%) experienced psychophysical disorders attributed to LH experienced in the span of the year. DISCUSSION: Lateral hostility is a frequent occurrence that calls for implementation of management policies to achieving an overall improvement of the work environment climate. PMID- 25280205 TI - Closing word: a gift of time and knowledge for this holiday season. PMID- 25280206 TI - Influence of lipid coatings on surface wettability characteristics of silicone hydrogels. AB - Insoluble lipids serve vital functions in our bodies and interact with biomedical devices, e.g., the tear film on a contact lens. Over a period of time, these naturally occurring lipids form interfacial coatings that modify the wettability characteristics of these foreign synthetic surfaces. In this study, we examine the deposition and consequences of tear film lipids on silicone hydrogel (SiHy) contact lenses. We use bovine meibum, which is a complex mixture of waxy esters, cholesterol esters, and lipids that is secreted from the meibomian glands located on the upper and lower eyelids of mammals. For comparison, we study two commercially available model materials: dipalmitoylphosphatidylcholine (DPPC) and cholesterol. Upon deposition, we find that DPPC and meibum remain closer to the SiHy surface than cholesterol, which diffuses further into the porous SiHy matrix. In addition, we also monitor the fate of unstable thin liquid films that consequently rupture and dewet on these lipid-decorated surfaces. This dewetting provides valuable qualitative and quantitative information about the wetting characteristics of these SiHy substrates. We observe that decorating the SiHy surface with simple model lipids such as DPPC and cholesterol increases the hydrophilicity, which consequently inhibits dewetting, whereas meibum behaves conversely. PMID- 25280207 TI - Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer's disease? AB - Alzheimer's disease is the most common cause of dementia in the United States. A better understanding of the disease's underlying pathways may provide novel treatment and/or prevention strategies for this progressive chronic neurodegenerative disorder. In recent years, there has been a growing interest in the possible links between insulin and Alzheimer's disease. Insulin-induced hypoglycemia causes adaptive changes in the brain, including an improved ability to use alternative fuels. Insulin has been shown to facilitate reduction of intracellular amyloid plaque and downregulation of amyloid-beta-derived diffusible ligand-binding sites. Insulin also promotes tau hypophosphorylation, which stabilizes microtubules and promotes tubulin polymerization. Excess exogenous insulin may also play a role in overcoming the decreased utilization and transport of glucose in patients with Alzheimer's disease. Intranasal insulin therapy may have beneficial effects on cognition and function in patients with Alzheimer's disease, as well as having only minor adverse effects, and this route of administration been the focus in clinical trials. These data support the mechanistic pathways that might link excess exogenous insulin administered to patients with type 1 diabetes mellitus to possible protection from Alzheimer's disease and provide a rationale for using insulin to prevent the disease in high risk patients. PMID- 25280208 TI - Bridging and caging in mixed suspensions of microsphere and adsorptive microgel. AB - Gelation and glass transition in a mixed suspension of polystyrene (PS) microsphere and poly(N-isopropylacrylamide) (PNIPAM) microgel were studied as a function of the total colloid volume fraction and mixing ratio of these two components. The PNIPAM microgel, which is adsorbable on the PS microsphere surface, can induce bridging or stabilizing effect between microspheres depending on whether the volume fraction of microgel (PhiMG) is smaller or larger than the saturated adsorption concentration (Phi*MG) for a given volume fraction of the microsphere (PhiMS). Phi*MG is in a linear relationship with PhiMS, and the value of PhiMG/Phi*MG can be taken as an approximate measure of surface coverage. A state diagram of gelation and glass transition is constructed with the short ranged attractive interaction, resulting from the well-defined bridging bonding. Keeping PhiMG/Phi*MG = 0.20 and increasing PhiMS from 0.25 to 0.55, the mixed suspension transforms from a bridging gel into an attractive glass; moreover, while keeping PhiMS = 0.45 and increasing PhiMG/Phi*MG from 0.20 to 1.2, the mixed suspension changes from a bridging gel into an attractive glass, and then to a repulsive glass. The bridging effect and the cage effect can be distinguished by the yielding behaviors in rheological measurements. In the nonlinear dynamic rheological experiments, one-step yielding, corresponding to the disconnecting of bridge network, is observed in the bridging gel, and one step yielding, corresponding to the breaking of cage, is observed in the repulsive glass. However, a two-step yielding behavior is found in the bridging induced attractive glass, which is attributed to the bridging effect of microgels and the caging effect of the dense environment. PMID- 25280209 TI - Palladium-catalyzed carbonylative synthesis of benzoxazinones from N-(o bromoaryl)amides using paraformaldehyde as the carbonyl source. AB - Carbonylation reactions have been widely used in organic synthesis. However, the manipulation of toxic and pressurized carbon monoxide limited their applications in organic laboratories. The search for alternative carbonyl sources as an important method for carbonylative organic synthesis is spreading. Herein, a series of substituted benzoxazinones were synthesized from N-(o-bromoaryl)amides by palladium-catalyzed carbonylation with paraformaldehyde as the carbonyl source, which is inexpensive, stable, and easy to use. Notably, this is the first example of using paraformaldehyde as the CO source in palladium-catalyzed carbonylative synthesis of heterocycles. PMID- 25280210 TI - Antioxidant status and serum levels of selectins in pre-eclampsia. AB - A cross-sectional study was conducted in a university hospital, enrolling 40 patients with pre-eclampsia (case group) and 40 healthy normotensive pregnant women (control group). Plasma activity of antioxidants and some adhesion molecules involved in oxidative stress were measured and compared between the two groups, according to the patients' age. In patients over the age of 30 years, serum levels of L-selectin and E-selectin were lower in pre-eclamptic patients (p < 0.05); antioxidants, catalase and superoxide dismutase did not significantly differ between the two groups, while glutathione peroxidase was significantly higher in the normotensive group (p < 0.05). In patients under the age of 30 years, E-selectin was significantly higher in the pre-eclampsia group (p < 0.05), while P-selectin, catalase and superoxide dismutase were not significantly different between the two groups (p > 0.05). Total antioxidative activity was similar between pre-eclamptic and normotensive patients (p > 0.05). This study revealed no relationship between total antioxidant activity and pre-eclampsia. PMID- 25280211 TI - A big surprise in the little zygote: the curious business of losing methylated cytosines. AB - In stem cell biology, the dynamic addition and removal of 5-methylcytosines (5mCs) are necessary for lineage differentiation, nuclear reprogramming, and embryonic development. Recent investigations have sought to understand the mechanisms of how 5mCs are added and in particular how 5mCs are removed from DNA during embryogenesis. PMID- 25280212 TI - A knockout Combo: eradicating AML Stem Cells with TKI plus SIRT1 inhibition. AB - SIRT1 inhibition facilitates elimination of CML stem cells by Imatinib, in part via p53 activation. In this issue of Cell Stem Cell, Li et al. (2014) demonstrate a similar role for SIRT1 inhibition in eradicating FLT3-ITD AML stem cells, potentially through a positive feedback loop with c-MYC, highlighting SIRT1 as a potential target in combination cancer therapy. PMID- 25280213 TI - Reinventing the neural crest: direct reprogramming makes iNCCs. AB - Aberrant neural crest (NC) development is at the origin of many congenital diseases. Given the limitations in human NC cell isolation and expansion, the development of new strategies for NC generation is crucial. In this issue of Cell Stem Cell, Kim et al. (2014) report the direct reprogramming of postnatal fibroblasts into multipotent NC cells. PMID- 25280214 TI - When old hematopoietic stem cells get damaged. AB - Hematopoietic stem cells (HSCs) functionally decline and are prone to lineage bias and myeloid malignancies upon aging. Two recent studies (Beerman et al., 2014; Flach et al., 2014) investigate the underlying mechanisms associated with aged HSC phenotypes and highlight DNA damage, replication stress, and ribosomal stress in the process. PMID- 25280215 TI - Inflamm-aging: STAT3 signaling pushes muscle stem cells off balance. AB - Two recent studies shed light on mechanisms underlying muscle dysfunction in age and disease. They reveal that JAK-STAT signaling regulates myogenic differentiation, leading to a reduced reservoir of muscle stem cells. Both genetic and pharmacologic inhibition of STAT3 signaling improve stem cell homeostasis and physiology of aged and dystrophic muscles. PMID- 25280216 TI - Revisiting the flight of Icarus: making human organs from PSCs with large animal chimeras. AB - While cell therapies hold great potential for treating many conditions, their utility for treating patients that require whole organ replacement is unclear. To address this challenge, we propose using genetically engineered "organ niches" in large animals to generate human organs from pluripotent stem cells and discuss the hurdles facing such strategies. PMID- 25280217 TI - The naive state of human pluripotent stem cells: a synthesis of stem cell and preimplantation embryo transcriptome analyses. AB - Here we use a systems biology approach to comprehensively assess the conservation of gene networks in naive pluripotent stem cells (PSCs) with preimplantation embryos. While gene networks in murine naive and primed pluripotent states are reproducible across data sets, different sources of human stem cells display high degrees of variation, partly reflecting disparities in culture conditions. Finally, naive gene networks between human and mouse PSCs are not well conserved and better resemble their respective blastocysts. PMID- 25280218 TI - Regulatory principles of pluripotency: from the ground state up. AB - Pluripotency is the remarkable capacity of a single cell to engender all the specialized cell types of an adult organism. This property can be captured indefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent an invaluable platform to investigate cell fate decisions and disease. Recent advances have revealed that manipulation of distinct signaling cues can render ESCs in a uniform "ground state" of pluripotency, which more closely recapitulates the pluripotent naive epiblast. Here we discuss the extrinsic and intrinsic regulatory principles that underpin the nature of pluripotency and consider the emerging spectrum of pluripotent states. PMID- 25280219 TI - SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. AB - The FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and is associated with poor prognosis. In such patients, FLT3 tyrosine kinase inhibitors (TKIs) are only partially effective and do not eliminate the leukemia stem cells (LSCs) that are assumed to be the source of treatment failure. Here, we show that the NAD-dependent SIRT1 deacetylase is selectively overexpressed in primary human FLT3-ITD AML LSCs. This SIRT1 overexpression is related to enhanced expression of the USP22 deubiquitinase induced by c-MYC, leading to reduced SIRT1 ubiquitination and enhanced stability. Inhibition of SIRT1 expression or activity reduced the growth of FLT3-ITD AML LSCs and significantly enhanced TKI-mediated killing of the cells. Therefore, these results identify a c-MYC-related network that enhances SIRT1 protein expression in human FLT3-ITD AML LSCs and contributes to their maintenance. Inhibition of this oncogenic network could be an attractive approach for targeting FLT3-ITD AML LSCs to improve treatment outcomes. PMID- 25280220 TI - Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. AB - With the exception of imprinted genes and certain repeats, DNA methylation is globally erased during preimplantation development. Recent studies have suggested that Tet3-mediated oxidation of 5-methylcytosine (5mC) and DNA replication dependent dilution both contribute to global paternal DNA demethylation, but demethylation of the maternal genome occurs via replication. Here we present genome-scale DNA methylation maps for both the paternal and maternal genomes of Tet3-depleted and/or DNA replication-inhibited zygotes. In both genomes, we found that inhibition of DNA replication blocks DNA demethylation independently from Tet3 function and that Tet3 facilitates DNA demethylation largely by coupling with DNA replication. For both genomes, our data indicate that replication dependent dilution is the major contributor to demethylation, but Tet3 plays an important role, particularly at certain loci. Our study thus defines the respective functions of Tet3 and DNA replication in paternal DNA demethylation and reveals an unexpected contribution of Tet3 to demethylation of the maternal genome. PMID- 25280222 TI - The antibiotic resistome: what's new? AB - The antibiotic resistome is dynamic and ever expanding, yet its foundations were laid long before the introduction of antibiotics into clinical practice. Here, we revisit our theoretical framework for the resistome concept and consider the many factors that influence the evolution of novel resistance genes, the spread of mobile resistance elements, and the ramifications of these processes for clinical practice. Observing the trends and prevalence of genes within the antibiotic resistome is key to maintaining the efficacy of antibiotics in the clinic. PMID- 25280223 TI - Molecular characterization of edestin gene family in Cannabis sativa L. AB - Globulins are the predominant class of seed storage proteins in a wide variety of plants. In many plant species globulins are present in several isoforms encoded by gene families. The major seed storage protein of Cannabis sativa L. is the globulin edestin, widely known for its nutritional potential. In this work, we report the isolation of seven cDNAs encoding for edestin from the C. sativa variety Carmagnola. Southern blot hybridization is in agreement with the number of identified edestin genes. All seven sequences showed the characteristic globulin features, but they result to be divergent members/forms of two edestin types. According to their sequence similarity four forms named CsEde1A, CsEde1B, CsEde1C, CsEde1D have been assigned to the edestin type 1 and the three forms CsEde2A, CsEde2B, CsEde2C to the edestin type 2. Analysis of the coding sequences revealed a high percentage of similarity (98-99%) among the different forms belonging to the same type, which decreased significantly to approximately 64% between the forms belonging to different types. Quantitative RT-PCR analysis revealed that both edestin types are expressed in developing hemp seeds and the amount of CsEde1 was 4.44 +/- 0.10 higher than CsEde2. Both edestin types exhibited a high percentage of arginine (11-12%), but CsEde2 resulted particularly rich in methionine residues (2.36%) respect to CsEde1 (0.82%). The amino acid composition determined in CsEde1 and CsEde2 types suggests that these seed proteins can be used to improve the nutritional quality of plant food stuffs. PMID- 25280221 TI - Generation of naive induced pluripotent stem cells from rhesus monkey fibroblasts. AB - Conventional embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) derived from primates resemble mouse epiblast stem cells, raising an intriguing question regarding whether the naive pluripotent state resembling mouse embryonic stem cells (mESCs) exists in primates and how to capture it in vitro. Here we identified several specific signaling modulators that are sufficient to generate rhesus monkey fibroblast-derived iPSCs with the features of naive pluripotency in terms of growth properties, gene expression profiles, self-renewal signaling, X-reactivation, and the potential to generate cross species chimeric embryos. Interestingly, together with recent reports of naive human pluripotent stem cells, our findings suggest several conserved signaling pathways shared with rodents and specific to primates, providing significant insights for acquiring naive pluripotency from other species. In addition, the derivation of rhesus monkey naive iPSCs also provides a valuable cell source for use in preclinical research and disease modeling. PMID- 25280224 TI - Electronic structure of open-shell tetrahedral {Fe(NO)2}(9) dinitrosyliron complexes. AB - High-level ab initio excited-state theory is employed to investigate the electronic structure of doublet {Fe(NO)2}(9) species in the ground state and compared with the results obtained by density functional theory. Both of the approaches consistently suggest that the linear NO ligands in dinitrosyliron complexes (DNICs) feature a radical character. Theoretical calculations also predict that the cyanide-supported DNIC anion of [(NC)2Fe(NO)2](-) features C2v symmetry with a Fe-C-N bonding motif, and multireference theories suggest a minimal active space of CAS(9,9) to describe these {Fe(NO)2}(9) compounds, while larger CAS(13,13) calculations do not tend to significantly improve the geometries. Experimental vibration modes of NO ligands are also accurately assigned due to second-order n-electron valence state perturbation theory. PMID- 25280225 TI - A Survey of Scientist and Policy Makers' Attitudes Toward Research on Stored Human Biological Materials in Sri Lanka. AB - INTRODUCTION: Stored human samples and the establishment of biobanks are increasing in the world. Along with this there are the questions of ethics that arise such as the correct method of obtaining informed consent for research on stored samples and the policies involved in collaborative research using collected samples. This study is an attempt to evaluate the researchers, academics and policy makers' views on these ethical aspects. METHODS: This was an anonymised study involving a Sri Lankan population of researchers, ethics committee members, and policy makers. A self administered questionnaire was utilised as the study instrument. The questionnaire captured four major areas of interest: demographic characteristics of respondents, their attitudes on informed consent policy, their opinion on rights of collaborating researchers, their attitudes on dealing with international differences in regulatory frameworks. RESULTS: The study included 55 responders with 40/55 (73%) agreeing that donors should receive the option of giving informed consent for future research, with 31/55 (56%) considering multiple- type consent options most appropriate. Regarding the issue of shared samples in collaborative research majority agreed that source country ethics review committee approval was necessary 53/55 (96%). CONCLUSION: The study concludes that sample donors should be given the option of giving advance consent to unspecified future research provided that future research is approved by an ethics committee. In collaborative research, it is necessary to involve ethics committees from donor countries in the research approval process. PMID- 25280226 TI - Assessment of pain intensity in clinical trials: individual ratings vs composite scores. AB - OBJECTIVES: To evaluate the reliability of findings suggesting that composite scores made up of just two ratings of recalled pain may be adequately reliable and valid for assessing outcome in pain clinical trials. DESIGN: Secondary analyses of data from a study where the responsivity of the outcome measures was a critical concern; that is, a study with few subjects testing the effects of a treatment that had only modest effects. Ten adults with spinal cord injury rated four domains of pain intensity (current pain and 24-hour recalled worst, least, and average pain) on four occasions before and after 12 sessions of neurofeedback treatment. We evaluated the reliability and validity of four single ratings and 16 different composite scores. RESULTS: None of the single-item scales performed adequately. However, composite scores made up of two items or more yielded consistent effect size estimates. CONCLUSIONS: The findings provide additional evidence that two-item composite scores may be adequate for assessing the primary outcome of pain intensity in chronic pain clinical trials. Additional research is needed to further establish the generalizability of these findings. PMID- 25280227 TI - Genomic alterations as mediators of miRNA dysregulation in ovarian cancer. AB - Ovarian cancer is the fifth most common cause of cancer death in women worldwide. Serous epithelial ovarian cancer (SEOC) is the most common and aggressive histological subtype. Widespread genomic alterations go hand-in-hand with aberrant DNA damage signaling and are a hallmark of high-grade SEOC. MicroRNAs (miRNAs) are a class of small noncoding RNA molecules that are nonrandomly distributed in the genome. They are frequently located in chromosomal regions susceptible to copy number variation (CNV) associated with malignancy that can influence their expression. Widespread changes in miRNA expression have been reported in multiple cancer types including ovarian cancer. This review examines CNV and single nucleotide polymorphisms, two common types of genomic alterations that occur in ovarian cancer, in the context of their influence on the expression of miRNA and the ability of miRNA to bind to and regulate their target genes. This includes genes encoding proteins involved in DNA repair and the maintenance of genomic stability. Improved understanding of mechanisms of miRNA dysregulation and the role of miRNA in ovarian cancer will provide further insight into the pathogenesis and treatment of this disease. PMID- 25280228 TI - Capillary electrophoresis separation of aminoalkanol derivatives of 1,7-dimethyl 8,9-diphenyl-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5,10-trione as potential anticancer drugs. AB - The purpose of this study, the direct separation of aminoalkanol derivatives I and II of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.0(2,6) ]dec-8-ene-3,5,10 trione, which was found in earlier studies as potential anticancer drugs, were performed. Capillary electrophoresis offers the possibility of fast, cheap, and reproducible separations for compounds I and II. In this paper, the simultaneous separation of I and II by capillary zone electrophoresis has been achieved within 8 min by use of 50 mM phosphate buffer of pH 2.5. Analysis of the two compounds in the serum plasma standards was conducted. Limits of detection of I and II by UV absorbance at 200 nm were achieved in the range of 156.3-156.6 ng/mL. The method was validated for linearity, accuracy, precision, limits of detection, and quantification. The calibration equation revealed a good linear relationship (r(2) = 0.998-0.999). Sufficient recovery was observed in the range of 96.3 99.5%. The method showed good reproducibility with intra- and interday precision of 0.97 and 1.76%, respectively. The quantification limits for the compounds were in the range of 477.0-479.8 ng/mL. The proposed method was applied to the analysis of real serum samples. PMID- 25280230 TI - Watchful waiting: role of disease progression on uncertainty and depressive symptoms in patients with chronic hepatitis C. AB - BACKGROUND AND AIMS: New therapies for HCV are rapidly emerging and providers are advising select patients to defer treatment and elect 'watchful waiting'. During the watchful waiting period, patients have been shown to have high rates of illness uncertainty and depression. We sought to answer the question of whether reassuring histological data (showing minimal fibrosis or no fibrosis progression over time) is associated with less illness uncertainty and depressive symptoms. METHODS: This was a single-centre outpatient prospective cohort study to determine whether stage of fibrosis, fibrosis progression and reasons for treatment deferral were related to illness uncertainty and depressive symptoms in patients following watchful waiting. RESULTS: Illness uncertainty was significantly related to depressive symptoms (r = 0.49, P < 0.01). More than half of the participants (54%) had moderate levels of uncertainty. About 40% of the participants were at risk for clinical depression (21.7% at mild to moderate risk and 18.5% at high risk). Treatment naive subjects had lower mean scores on both the CES-D (depressive symptoms measure) and the MUIS-A (illness uncertainty measure) total score, MUIS-A Ambiguity subscale and MUIS-A Inconsistency subscale than subjects who failed treatment or were interferon intolerant or ineligible. Surprisingly, liver fibrosis stage and progression were not significantly associated with overall illness uncertainty or depressive symptoms. CONCLUSION: Patients with chronic hepatitis C on watchful waiting are at high risk for significant illness uncertainty and depressive symptoms. Reassuring histological data does not seem to correlate with less uncertainty or depressive symptoms. PMID- 25280229 TI - Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men. AB - We examined the characteristics associated with hepatitis C virus (HCV) antibody (anti-HCV) prevalence and HCV clearance between injection drug using (IDU) and non-IDU men who have sex with men (MSM). Stored serum and plasma samples were tested for anti-HCV and HCV RNA to determine the HCV status of 6925 MSM at enrolment into the Multicentre AIDS Cohort Study (MACS). Prevalence and clearance ratios were calculated to determine the characteristics associated with HCV prevalence and clearance. Multivariable analyses were performed using Poisson regression methods with robust variance estimation. Anti-HCV prevalence was significantly higher among IDU than among non-IDU MSM (42.9% vs 4.0%), while clearance was significantly lower among IDU MSM (11.5% vs 34.5% among non-IDU MSM). HIV infection, Black race, and older age were independently associated with higher prevalence in both groups, while smoking, transfusion history, and syphilis were significantly associated with prevalence only among non-IDU MSM. The rs12979860-C/C genotype was the only characteristic independently associated with HCV clearance in both groups, but the effects of both rs12979860-C/C genotype [clearance ratio (CR) = 4.16 IDUs vs 1.71 non-IDUs; P = 0.03] and HBsAg positivity (CR = 5.06 IDUs vs 1.62 non-IDUs; P = 0.03) were significantly larger among IDU MSM. HIV infection was independently associated with lower HCV clearance only among non-IDU MSM (CR = 0.59, 95% CI = 0.40-0.87). IDU MSM have higher anti-HCV prevalence and lower HCV clearance than non-IDU MSM. Differences in the factors associated with HCV clearance suggest that the mechanisms driving the response to HCV may differ according to the mode of acquisition. PMID- 25280231 TI - Effect of FGFR inhibitors on chicken limb development. AB - Fibroblast growth factor (FGF) signalling appears essential for the regulation of limb development, but a full complexity of this regulation remains unclear. Here, we addressed the effect of three different chemical inhibitors of FGF receptor tyrosine kinases (FGFR) on growth and patterning of the chicken wings. The inhibitor PD173074 caused shorter and thinner wing when using lower concentration. Microinjection of higher PD173074 concentrations (25 and 50 mmol/L) into the wing bud at stage 20 resulted in the development of small wing rudiment or the total absence of the wing. Skeletal analysis revealed the absence of the radius but not ulna, deformation of metacarpal bones and/or a reduction of digits. Treatment with PD161570 resembled the effects of PD173074. NF449 induced shortening and deformation of the developing wing with reduced autopodium. These malformed embryos mostly died at the stage HH25-29. PD173074 reduced chondrogenesis also in the limb micromass cultures together with early inhibition of cartilaginous nodule formation, evidenced by lack of sulphated proteoglycan and peanut agglutinin expression. The effect of FGFR inhibition on limb development observed here was unlikely mediated by excessive cell death as none of the inhibitors caused massive apoptosis at low concentrations. More probably, FGFR inhibition decreased both the proliferation and adhesion of mesenchymal chondroprogenitors. We conclude that FGFR signalling contributes to the regulation of the anterior-posterior patterning of zeugopod during chicken limb development. PMID- 25280232 TI - Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis: comment. PMID- 25280234 TI - Kinetics of Hg(II) exchange between organic ligands, goethite, and natural organic matter studied with an enriched stable isotope approach. AB - The mobility and bioavailability of toxic Hg(II) in the environment strongly depends on its interactions with natural organic matter (NOM) and mineral surfaces. Using an enriched stable isotope approach, we investigated the exchange of Hg(II) between dissolved species (inorganically complexed or cysteine-, EDTA-, or NOM-bound) and solid-bound Hg(II) (carboxyl-/thiol-resin or goethite) over 30 days under constant conditions (pH, Hg and ligand concentrations). The Hg(II) exchange was initially fast, followed by a slower phase, and depended on the properties of the dissolved ligands and sorbents. The results were described by a kinetic model allowing the simultaneous determination of adsorption and desorption rate coefficients. The time scales required to reach equilibrium with the carboxyl-resin varied greatly from 1.2 days for Hg(OH)2 to 16 days for Hg(II) cysteine complexes and approximately 250 days for EDTA-bound Hg(II). Other experiments could not be described by an equilibrium model, suggesting that a significant fraction of total-bound Hg was present in a non-exchangeable form (thiol-resin and NOM: 53-58%; goethite: 22-29%). Based on the slow and incomplete exchange of Hg(II) described in this study, we suggest that kinetic effects must be considered to a greater extent in the assessment of the fate of Hg in the environment and the design of experimental studies, for example, for stability constant determination or metal isotope fractionation during sorption. PMID- 25280233 TI - Environmental lead exposure and attention deficit/hyperactivity disorder symptom domains in a community sample of South Korean school-age children. AB - BACKGROUND: Low-level environmental exposure to lead has been associated with both reduced intelligence and symptoms of attention deficit/hyperactivity disorder (ADHD). However, few studies have estimated the association of lead and intelligence independent of ADHD, and it is not clear from previous studies whether lead is associated with both inattention and impulsivity ADHD symptoms. OBJECTIVES: We estimated mutually adjusted associations of environmental lead exposure with both intelligence and ADHD symptoms, and associations between lead and specific ADHD-related domains. METHODS: Blood lead concentrations were measured in a general population of 1,001 children 8-11 years of age. We used multivariable linear regression models to estimate associations of blood lead concentrations with IQ scores, teacher and parent ratings of ADHD symptoms, and measures of inattention and impulsivity. Models were adjusted for demographic variables and other environmental exposures (blood levels of mercury and manganese, urinary concentrations of cotinine, phthalate metabolites, and bisphenol A). RESULTS: Associations of blood lead with lower IQ and higher impulsivity were robust to adjustment for a variety of covariates. When adjusted for demographic characteristics, other environmental exposures, and ADHD symptoms or IQ, a 10-fold increase in blood lead concentration was associated with lower Full-Scale IQ (-7.23; 95% CI: -13.39, -1.07) and higher parent- and teacher-rated hyperactivity/impulsivity scores (ADHD Rating Scale, 1.99; 95% CI: 0.17, 3.81 and 3.66; 95% CI: 1.18, 6.13, respectively) and commission errors (Continuous Performance Test, 12.27; 95% CI: -0.08, 24.62). Blood lead was not significantly associated with inattention in adjusted models. CONCLUSIONS: Low-level lead exposure was adversely associated with intelligence in school-age children independent of ADHD, and environmental lead exposure was selectively associated with impulsivity among the clinical features of ADHD. PMID- 25280235 TI - Metallization of single-stranded polyI by Zn(2+) ions in neutral solutions. AB - Metallization of single-stranded polyinosinic acid (polyI) by Zn(2+) ions at pH 7.0 was studied by differential UV spectroscopy at different temperatures. It was found that polyI is metallized at N7 and N1 atoms of hypoxanthine. The concentration dependence of the degree of binding of Zn(2+) ions to both N7 and N1 sites was obtained, and the corresponding binding constants were determined. Metallization of N1 occurs due to Zn(2+) substituting the imino protons and is effective not only at alkaline but also at neutral pH. This makes multistranded polyI-based systems more promising candidates for use in nanoelectronics than natural DNA sequences, metallization of which can be achieved only at alkaline pH. PMID- 25280236 TI - Social determinants of health in selected slum areas in Jordan: challenges and policy directions. AB - BACKGROUND: The unplanned urbanization in Jordan has over time created many informal settlements "slums" around big cities as Amman, Zerka and Aqaba. The purpose of this study was to highlight the most common challenges related to social determinants of health in two selected slum areas in Amman and Aqaba and suggest policy directions and interventions to meet these challenges. METHODS: In addition to a prestructured interview with all household heads living in the two slum sites, focus group meetings with a purposefully selected sample of 12 slum dwellers in each site were used to assess the structural and intermediary determinants of health as perceived by slum residents in the two study locations. RESULTS: The study found that slum residents in the two locations suffer from many challenges as severe poverty; unemployment; illiteracy and low education attainments; gender discrimination; insufficient and poor diet; social and official exclusion; unhealthy environment; lack of water supply, electricity and basic sanitation facilities; high prevalence of diseases; and insufficient and inappropriate health services. Specific policy directions to meet these challenges were recommended and grouped into three main clusters: social protection, social inclusion and empowerment. CONCLUSION: New plans and tools should be developed by local authorities in Jordan to understand, protect, include and empower those vulnerable people who are forced to live in these unhealthy and inhuman environments. PMID- 25280237 TI - Stochasticity in gene expression in a cell-sized compartment. AB - The gene expression in a clonal cell population fluctuates significantly, and its relevance to various cellular functions is under intensive debate. A fundamental question is whether the fluctuation is a consequence of the complexity and redundancy in living cells or an inevitable attribute of the minute microreactor nature of cells. To answer this question, we constructed an artificial cell, which consists of only necessary components for the gene expression (in vitro transcription and translation system) and its boundary as a microreactor (cell sized lipid vesicle), and investigated the gene expression noise. The variation in the expression of two fluorescent proteins was decomposed into the components that were correlated and uncorrelated between the two proteins using a method similar to the one used by Elowitz and co-workers to analyze the expression noise in E. coli. The observed fluctuation was compared with a theoretical model that expresses the amplitude of noise as a function of the average number of intermediate molecules and products. With the assumption that the transcripts are partly active, the theoretical model was able to well describe the noise in the artificial system. Furthermore, the same measurement for E. coli cells harboring an identical plasmid revealed that the E. coli exhibited a similar level of expression noise. Our results demonstrated that the level of fluctuation found in bacterial cells is mostly an intrinsic property that arises even in a primitive form of the cell. PMID- 25280238 TI - Common risky behaviours checklist: a tool to assist nurse supervisors to assess unsafe practice. AB - AIM: To describe the development of the Common Risky Behaviour Checklist, a tool to aid nurse supervisors in determining when a nurse may be questionably fit to perform, particularly in cases of substance abuse. BACKGROUND: A significant number of nurses may have substance use disorders that could manifest as unsafe performance at work, and nurse supervisors lack the tools to assess a nurse's fitness to perform at work. METHOD: Job analysis techniques were used to identify the critical impairment behaviours for the tool. Job analysis is a legally defensible, multi-stage process used in the organisational psychology field to develop work performance assessments. RESULTS: A screening tool was developed for nurse supervisors to assess when a nurse may be questionably fit to perform. CONCLUSION: The development of this checklist is one of several needed advancements in order to address the issue of fitness to perform and patient safety. IMPLICATIONS FOR NURSING MANAGEMENT: The Common Risky Behaviour Checklist offers nurse managers assistance in protecting patient safety by providing a quick (one-page), systematic, behaviour-based method to collect information that can inform urgent decisions, trigger performance corrections and can complement formal organisational documentation processes in cases of unsafe practice due to substance abuse. PMID- 25280239 TI - Novel PTM-TEMPO biradical for fast dissolution dynamic nuclear polarization. AB - The synthesis and characterization of a novel trityl-TEMPO biradical and the investigation of its properties as Dynamic Nuclear Polarization (DNP) polarizing agent are reported. Comparison with a structurally related monoradical (PTM TEMPE) or mixtures of the two monoradical components reveals that the biradical has a much higher polarization efficiency and a faster polarization buildup. This offers the possibility of faster recycling further contributing to its efficiency as a polarizing agent. PMID- 25280240 TI - Effect of olive mill wastewater phenol compounds on reactive carbonyl species and Maillard reaction end-products in ultrahigh-temperature-treated milk. AB - Thermal processing and Maillard reaction (MR) affect the nutritional and sensorial qualities of milk. In this paper an olive mill wastewater phenolic powder (OMW) was tested as a functional ingredient for inhibiting MR development in ultrahigh-temperature (UHT)-treated milk. OMW was added to milk at 0.1 and 0.05% w/v before UHT treatment, and the concentration of MR products was monitored to verify the effect of OMW phenols in controlling the MR. Results revealed that OMW is able to trap the reactive carbonyl species such as hydroxycarbonyls and dicarbonyls, which in turn led to the increase of Maillard derived off-flavor development. The effect of OMW on the formation of Amadori products and N-epsilon-(carboxymethyl)-lysine (CML) showed that oxidative cleavage, C2-C6 cyclization, and the consequent reactive carbonyl species formation were also inhibited by OMW. Data indicated that OMW is a functional ingredient able to control the MR and to improve the nutritional and sensorial attributes of milk. PMID- 25280241 TI - Physiological, structural and molecular traits activated in strawberry plants after inoculation with the plant growth-promoting bacterium Azospirillum brasilense REC3. AB - The plant growth-promoting strain REC3 of Azospirillum brasilense, isolated from strawberry roots, prompts growth promotion and systemic protection against anthracnose disease in this crop. Hence, we hypothesised that A. brasilense REC3 can induce different physiological, structural and molecular responses in strawberry plants. Therefore, the aim of this work was to study these traits activated in Azospirillum-colonised strawberry plants, which have not been assessed until now. Healthy, in vitro micropropagated plants were root-inoculated with REC3 under hydroponic conditions; root and leaf tissues were sampled at different times, and oxidative burst, phenolic compound content, malondialdehyde (MDA) concentration, callose deposition, cell wall fortification and gene expression were evaluated. Azospirillum inoculation enhanced levels of soluble phenolic compounds after 12 h post-inoculation (hpi), while amounts of cell wall bound phenolics were similar in inoculated and control plants. Other early responses activated by REC3 (at 24 hpi) were a decline of lipid peroxidation and up-regulation of strawberry genes involved in defence (FaPR1), bacterial recognition (FaFLS2) and H2O2 depuration (FaCAT and FaAPXc). The last may explain the apparent absence of oxidative burst in leaves after bacterial inoculation. Also, REC3 inoculation induced delayed structural responses such as callose deposition and cell wall fortification (at 72 hpi). Results showed that A. brasilense REC3 is capable of exerting beneficial effects on strawberry plants, reinforcing their physiological and cellular characteristics, which in turns contribute to improve plant performance. PMID- 25280242 TI - Designing foldamer-foldamer interactions in solution: the roles of helix length and terminus functionality in promoting the self-association of aminoisobutyric acid oligomers. AB - The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure-activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen-bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D6]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X-ray crystallography studies of two oligomers allowed a comparison of the inter- and intramolecular hydrogen-bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer-foldamer interactions. These solution-based and solid-state studies indicated that the preferred geometry for aggregation is through head-to-tail interactions between the N and C termini of adjacent Aib oligomers. PMID- 25280243 TI - Differentiating the levels of risk for muscle dysmorphia among Hungarian male weightlifters: a factor mixture modeling approach. AB - Muscle dysmorphia (MD) is a body image disturbance characterized by a pathological preoccupation with muscularity. The study aimed to differentiate the levels of risk for MD among weightlifters and to define a tentative cut-off score for the Muscle Appearance Satisfaction Scale (MASS) for the identification of high risk MD cases. Hungarian male weightlifters (n=304) completed the MASS, the Exercise Addiction Inventory, and specific exercise and body image related questions. For the differentiation of MD, factor mixture modeling was performed, resulting in three independent groups: low-, moderate-, and high risk MD groups. The estimated prevalence of high risk MD in this sample of weightlifters was 15.1%. To determine a cut-off score for the MASS, sensitivity and specificity analyses were performed and a cut-off point of 63 was suggested. The proposed cut off score for the MASS can be useful for the early detection of high risk MD. PMID- 25280244 TI - Using guided individualised feedback to review self-reported quality of life in health and its importance. AB - This pilot study investigated the effects of providing guided, individualised feedback on subjective quality of life (QoL), using results from the multidimensional WHOQOL-BREF profile. Participants (n = 129; 85 chronically ill) were recruited in the community, and primary care. They were randomised to receive written or verbal guidance on interpreting a new graphical summary profile, which simultaneously presented (a) their individual self-ratings of QoL and (b) the importance attributed to each QoL dimension. Before and after feedback, participants completed health status, subjective QoL, QoL Importance, goal-oriented QoL and mood measures. Receiving individualised feedback was associated with increased psychological QoL, with modest effect size. No effects were found for physical, social or environmental QoL or QoL importance, health status, mood or goal-oriented QoL. There were no differences between modes of delivering guidance, indicating equal effectiveness. Chronic illness participants reported poorer QoL, moved more slowly towards their QoL goals, and had larger differences between core QoL and QoL Importance than healthy participants. Guided individualised empirical feedback about QoL judgements could be used to promote psychological well-being. Although professional interpretation of feedback is unnecessary, if shared, patients' profiled WHOQOL information could support self monitoring, self-management and clinical decision-making. PMID- 25280246 TI - Diagnostic laparoscopy for intraabdominal evaluation and ventriculoperitoneal shunt placement in children: a means to avoid ventriculoatrial shunting. AB - BACKGROUND: Laparoscopic assistance for the placement of a ventriculoperitoneal shunt (VPS) has been shown to be a safe, effective, and minimally invasive approach for distal peritoneal shunt placement. The purpose of our study was to review our experience with laparoscopy for VPS placement in patients with a potential hostile abdomen. MATERIALS AND METHODS: After institutional review board approval, a retrospective analysis of all patients who underwent diagnostic laparoscopy for VPS placement from March 2009 to March 2013 was performed. Patient demographics and outcomes were analyzed. RESULTS: Twenty-seven patients underwent diagnostic laparoscopy for VPS placement at a mean age of 7.7 +/- 6.8 years. Twenty-five patients had previous shunts placed in the peritoneum, whereas 2 underwent initial placement. Sixteen patients (59%) had undergone previous non shunt abdominal operations. Twenty-three patients (85%) had successful peritoneal shunt placement. Distal peritoneal shunt placement was unsuccessful at the time of laparoscopy in 4 patients (15%) secondary to adhesions. Of the 23 patients who had successful peritoneal shunt placement, 57% did not require further shunt intervention, 22% underwent conversion to a ventriculoatrial shunt, 17% underwent re-externalization, and 4% required distal shunt revision. Of the 4 patients who required externalization, 3 underwent a second laparoscopic procedure with successful peritoneal shunt placement. CONCLUSIONS: Diagnostic laparoscopy eliminated the need for ventriculoatrial shunt placement in 85% of patients with a potentially hostile abdomen. Sixty percent required no further shunt revision. Laparoscopic-assisted peritoneal shunt insertion is a safe, minimally invasive technique in children with the added benefit of allowing full exploration and adhesiolysis. PMID- 25280245 TI - Causal pathways between impulsiveness, cocaine use consequences, and depression. AB - AIMS: The present study examined whether lifetime cocaine use consequences mediate the relationship between trait impulsiveness and current depression symptoms among regular cocaine users. METHODS: Regular cocaine users (N=108) were assessed using: Barratt Impulsiveness Scale subscales (non-planning, attentional, motor sub-scales) to measure trait impulsiveness; a standardized Drug History and Use Questionnaire to measure cocaine use and related consequences; and Beck Depression Inventory to measure current depression symptoms. RESULTS: All impulsiveness subscales were positively associated with an earlier age of first cocaine use, a higher degree of current depression symptoms and a greater number of lifetime cocaine use consequences. In three separate simple mediation tests, lifetime cocaine use consequences partially mediated the relationship between each of the impulsiveness subscales (non-planning: R(2)=.42; attentional: R(2)=.40; motor: R(2)=.24) and current depression symptoms. Separate moderated mediation analyses failed to demonstrate an interaction between lifetime cocaine use and cocaine-related consequences predicting depression symptoms for the mediation models. CONCLUSIONS: Cocaine-related consequences function in a more nuanced manner than just an outcome of impulsiveness or cocaine use, but as a pathway between trait impulsiveness and current depression symptoms. PMID- 25280247 TI - In vitro effects of nonylphenol on motility, mitochondrial, acrosomal and chromatin integrity of ram and boar spermatozoa. AB - The objective of this study was to determine the effects of nonylphenol (NP) on viability of ram and boar sperm in vitro. Ram or boar spermatozoa were exposed to 1, 10, 100, 250 and 500 MUg NP ml(-1) for 1, 2, 3 or 4 h. Computer-assisted sperm motility analysis (CASA) system was used to evaluate sperm motility characteristics. Flow cytometry was used to determine mitochondrial membrane potential (MMP) and chromatin integrity, while epifluorescent microscopy was used to determine sperm acrosomal status. Exposure of both species spermatozoa to 250 and 500 MUg NP ml(-1) was detrimental to progressive motility (P < 0.05), and its adverse effect was significant at lower (100 MUg NP ml(-1) ) concentration (P < 0.05). The percentages of ram and boar spermatozoa with high MMP declined drastically after exposures to >=250 MUg ml(-1) NP (P < 0.05). Unlike chromatin integrity, which did not appear to be altered by NP exposure, there were dose dependent NP effects (P < 0.05) on acrosomal integrity of both species at as low as 1 MUg ml(-1) NP for boar spermatozoa and 10 MUg ml(-1) NP for ram spermatozoa. These data show adverse effects of NP on ram and boar spermatozoa and thus its potential harmful effects on male reproduction as NP is found in fruits, vegetables, human milk, fish and livestock products. PMID- 25280248 TI - Quantifying chemical reactions by using mixing analysis. AB - This work is motivated by a sound understanding of the chemical processes that affect the organic pollutants in an urban aquifer. We propose an approach to quantify such processes using mixing calculations. The methodology consists of the following steps: (1) identification of the recharge sources (end-members) and selection of the species (conservative and non-conservative) to be used, (2) identification of the chemical processes and (3) evaluation of mixing ratios including the chemical processes. This methodology has been applied in the Besos River Delta (NE Barcelona, Spain), where the River Besos is the main aquifer recharge source. A total number of 51 groundwater samples were collected from July 2007 to May 2010 during four field campaigns. Three river end-members were necessary to explain the temporal variability of the River Besos: one river end member is from the wet periods (W1) and two are from dry periods (D1 and D2). This methodology has proved to be useful not only to compute the mixing ratios but also to quantify processes such as calcite and magnesite dissolution, aerobic respiration and denitrification undergone at each observation point. PMID- 25280250 TI - "Choose-a-size" approach in dynamic combinatorial chemistry: a single substrate dynamic combinatorial library of oligomacrocycles that adapts to the size and shape of carboxylates. AB - A neutral anion binding receptor based on dipicolinic acid diamide was equipped with thiol groups in the amidic side arms. After the thiol was oxidized to disulfide groups with I2, a mixture of cyclic oligomers (a library) was obtained. The distribution of macrocycles can be controlled kinetically during the oxidation process or thermodynamically at basic conditions via disulfide bond exchange. The library proved to be very sensitive to templation with various carboxylates in DMSO. The amplification pattern reflects the structural features of the anionic template and is sensitive to changes in the template's geometry. The application of carboxylates with multiple functional groups resulted in very strong amplification of the large penta- and hexameric macrocycles. The thermodynamic parameters of some templation effects were rationalized using a simple model and confirmed using competitive NMR titration. PMID- 25280251 TI - Proton-insertion-enhanced pseudocapacitance based on the assembly structure of tungsten oxide. AB - The capacitances of supercapacitors with carbon and metal oxides as electrodes are usually associated with the available surface areas of the electrode materials. However, in this paper, we report that proton insertion, an unusual capacitive mechanism, may effectively enhance the capacitance of metal oxides with low surface area but specific structures. Tungsten trioxide (WO3) as the electrode material for supercapacitors has always suffered from low capacitance. Nevertheless, enhanced by the proton insertion mechanism, we demonstrate that electrodes fabricated by an assembly structure of hexagonal-phase WO3 (h-WO3) nanopillars achieve a high capacitance of up to 421.8 F g(-1) under the current density of 0.5 A g(-1), which is the highest capacitance achieved with pure WO3 as the electrodes so far, to the best of our knowledge. Detailed analyses indicate that proton insertion dominates the electrochemical behavior of h-WO3 and plays the key role in reaching high capacitance by excluding other mechanisms. In addition, a thorough investigation on the temperature-dependent electrochemical performance reveals excellent performance stability at different temperatures. This study provides a new approach to achieving high capacitance by effective proton insertion into ordered tunnels in crystallized metal oxides, which is primarily important for the fabrication of compact high-performance energy storage devices. PMID- 25280249 TI - Understanding cadherin EGF LAG seven-pass G-type receptors. AB - The cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors, which are pivotal regulators of many biologic processes such as neuronal/endocrine cell differentiation, vessel valve formation, and the control of planar cell polarity during embryonic development. All three members of the CELSR family (CELSR1-3) have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Mutations in the ecto-domain or other gene locations of CELSRs are associated with neural tube defects and other diseases in humans. Celsr knockout (KO) animals have many developmental defects. Therefore, specific agonists or antagonists of CELSR members may have therapeutic potential. Although significant progress has been made regarding the functions and biochemical properties of CELSRs, our knowledge of these receptors is still lacking, especially considering that they are broadly distributed but have few characterized functions in a limited number of tissues. The dynamic activation and inactivation of CELSRs and the presence of endogenous ligands beyond homophilic interactions remain elusive, as do the regulatory mechanisms and downstream signaling of these receptors. Given this motivation, future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CELSR-targeted therapeutic reagents. The cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors (GPCRs), which have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Recent studies have revealed that CELSRs are pivotal regulators of many biological processes, such as neuronal/endocrine cell differentiation, vessel valve formation and the control of planar cell polarity during embryonic development. PMID- 25280252 TI - The spatial clustering of obesity: does the built environment matter? AB - BACKGROUND: Obesity rates in the USA show distinct geographical patterns. The present study used spatial cluster detection methods and individual-level data to locate obesity clusters and to analyse them in relation to the neighbourhood built environment. METHODS: The 2008-2009 Seattle Obesity Study provided data on the self-reported height, weight, and sociodemographic characteristics of 1602 King County adults. Home addresses were geocoded. Clusters of high or low body mass index were identified using Anselin's Local Moran's I and a spatial scan statistic with regression models that searched for unmeasured neighbourhood-level factors from residuals, adjusting for measured individual-level covariates. Spatially continuous values of objectively measured features of the local neighbourhood built environment (SmartMaps) were constructed for seven variables obtained from tax rolls and commercial databases. RESULTS: Both the Local Moran's I and a spatial scan statistic identified similar spatial concentrations of obesity. High and low obesity clusters were attenuated after adjusting for age, gender, race, education and income, and they disappeared once neighbourhood residential property values and residential density were included in the model. CONCLUSIONS: Using individual-level data to detect obesity clusters with two cluster detection methods, the present study showed that the spatial concentration of obesity was wholly explained by neighbourhood composition and socioeconomic characteristics. These characteristics may serve to more precisely locate obesity prevention and intervention programmes. PMID- 25280253 TI - Rhenium and technetium tricarbonyl complexes of N-heterocyclic carbene ligands. AB - A strategy for the conjugation of N-heterocyclic carbene (NHC) ligands to biomolecules via amide bond formation is described. Both 1-(2-pyridyl)imidazolium or 1-(2-pyridyl)benzimidazolium salts functionalized with a pendant carboxylic acid group were prepared and coupled to glycine benzyl ester using 1-ethyl-3-(3 (dimethylamino)propyl)carbodiimide. A series of 10 rhenium(I) tricarbonyl complexes of the form [ReX(CO)3(CN)] (CN is a bidentate NHC ligand, and X is a monodentate anionic ligand: Cl(-), RCO2(-)) were synthesized via a Ag2O transmetalation protocol from the Re(I) precursor compound Re(CO)5Cl. The synthesized azolium salts and Re(I) complexes were characterized by elemental analysis and by (1)H and (13)C NMR spectroscopy, and the molecular structures for one imidazolium salt and seven Re(I) complexes were determined by single-crystal X-ray diffraction. (1)H NMR and mass spectrometry studies for an acetonitrile-d3 solution of [ReCl(CO)3(1-(2-pyridyl)-3-methylimidazolylidene)] show that the monodentate chloride ligand is labile and exchanges with this solvent yielding a cationic acetonitrile adduct. For the first time the labeling of an NHC ligand with technetium-99m is reported. Rapid Tc-99m labeling was achieved by heating the imidazolium salt 1-(2-pyridyl)-3-methylimidazolium iodide and Ag2O in methanol, followed by the addition of fac-[(99m)Tc(OH2)3(CO)3](+). To confirm the structure of the (99m)Tc-labeled complex, the equivalent (99)Tc complex was prepared, and mass spectrometric studies showed that the formed Tc complexes are of the form [(99m/99)Tc(CH3CN)(CO)3(1-(2-pyridyl)-3-methylimidazolylidene)](+) with an acetonitrile molecule coordinated to the metal center. PMID- 25280254 TI - Editorial: hyponatremia - a possible but forgotten consequence of bowel preparation for colonoscopy. PMID- 25280256 TI - Editorial: patients' preferences and health utility assessment in those with HCV treated with sofosbuvir - stating the obvious? PMID- 25280255 TI - Editorial: hyponatremia - a possible but forgotten consequence of bowel preparation for colonoscopy; authors' reply. PMID- 25280257 TI - Editorial: patients' preferences and health utility assessment in those with HCV treated with sofosbuvir - stating the obvious? Authors' reply. PMID- 25280258 TI - Editorial: abnormal permeability and altered mucosal serotonin metabolism in the irritable bowel syndrome - is there a link? PMID- 25280259 TI - Letter: inverse correlation between Helicobacter pylori and obesity - a conclusion too early? PMID- 25280260 TI - Letter: predictors of severe disease in ulcerative colitis - the same or different in Crohn's disease? PMID- 25280261 TI - Letter: inverse correlation between Helicobacter pylori and obesity - a conclusion too early? Authors' reply. PMID- 25280262 TI - Letter: predictors of severe disease in ulcerative colitis - the same or different in Crohn's disease? Authors' reply. PMID- 25280263 TI - Psychiatric disorders and left-handedness in children living in an urban environment. AB - The objective of this study was to conduct an analysis of left-handed children treated in an urban mental health clinic to investigate the frequency and severity of psychiatric disorders compared to right-handed peers. Data on handedness, diagnoses, hospitalizations and severity of mental disorders were collected on 692 consecutive children, 4-18 years old (M=10.1, SD=3.2), referred for psychiatric evaluation. Left-handed children were 18.2% of patients in the study, a rate significantly higher than left-hand dominance in the USA (p<.05). Compared to children with right-handedness, logistic regression analysis yielded 31% [odds ratio (OR)=1.31, 95% confidence interval (CI): 1.15-1.50] higher odds of having more psychiatric diagnosis, 70% (OR=1.70, 95% CI: 1.10-2.62) increased odds of anxiety, 53% (OR=1.53, 95% CI: 1.03-2.27) increased odds of depression and 78% (OR=1.78, 95% CI: 1.21-2.62) increased odds of oppositional defiant disorder for children who were left-handed. Left-handed children had increased odds of being prescribed antipsychotic and anxiolytic medication uses, 53% and 86% increased odds, respectively, and 66% (OR=1.66, 95% CI: 1.08-2.55) increased odds of psychiatric hospitalizations. Left-handedness was a phenotypic risk factor for psychiatric disorders and increased severity of psychiatric disorders. PMID- 25280264 TI - In situ synthesis of MOF membranes on ZnAl-CO3 LDH buffer layer-modified substrates. AB - We develop here a urea hydrolysis method to in situ prepare asymmetric ZnAl-CO3 layered double hydroxide (LDH) buffer layers with various stable equilibrium morphology on porous Al2O3 substrates. In particular it is found that well intergrown ZIF-8 membranes can be directly synthesized on the ZnAl-CO3 LDH buffer layer-modified substrates, owing to the specific metal-imidazole interaction between ZnAl-CO3 LDHs and ZIF-8. Other Zn-based MOF membranes, like ZIF-7 and ZIF 90, can also be synthesized with this method. Our finding demonstrates that LDH buffer layer represents a new concept for substrate modification. PMID- 25280265 TI - Conformations and effective interactions of polymer-coated nanoparticles at liquid interfaces. AB - We investigate conformations and effective interactions of polymer-coated nanoparticles adsorbed at a model liquid-liquid interface via molecular dynamics simulations. The polymer shells strongly deform at the interface, with the shape governed by a balance between maximizing the decrease in interfacial area between the two solvent components, minimizing unfavorable contact between polymer and solvent, and maximizing the conformational entropy of the polymers. Using potential of mean force calculations, we compute the effective interaction between the nanoparticles at the liquid-liquid interface. We find that it differs quantitatively from the bulk and is significantly affected by the length of the polymer chains and by the solvent quality. Under good solvent conditions, the effective interactions are always repulsive and soft for long chains. The repulsion range decreases as the solvent quality decreases. In particular, under poor solvent conditions, short chains may fail to induce steric repulsion, leading to a net attraction between the nanoparticles, whereas with long-enough chains the effective interaction potential may feature an additional repulsive shoulder at intermediate distances. PMID- 25280266 TI - Enhanced performance from a hybrid quenchometric deoxyribonucleic acid (DNA) silica xerogel gaseous oxygen sensing platform. AB - A complex of salmon milt deoxyribonucleic acid (DNA) and the cationic surfactant cetyltrimethylammonium (CTMA) forms an organic-soluble biomaterial that can be readily incorporated within an organically modified silane-based xerogel. The photoluminescence (PL) intensity and excited-state luminescence lifetime of tris(4,7'-diphenyl-1,10'-phenanathroline) ruthenium(II) [(Ru(dpp)3](2+), a common O2 responsive luminophore, increases in the presence of DNA-CTMA within the xerogel. The increase in the [Ru(dpp)3](2+)excited-state lifetime in the presence of DNA-CTMA arises from DNA intercalation that attenuates one or more non radiative processes, leading to an increase in the [Ru(dpp)3](2+) excited-state lifetime. Prospects for the use of these materials in an oxygen sensor are demonstrated. PMID- 25280267 TI - Minoxidil-associated anorexia in an infant with refractory hypertension. AB - Minoxidil is a potent antihypertensive used as an adjunctive agent in refractory hypertension. It exerts an antihypertensive effect through two mechanisms: selective arterial vasodilation by activation of potassium channels in the vascular smooth muscle and stimulation of carotid and aortic baroreceptors, leading to downstream release of renin and norepinephrine. Although frequently cited in reviews of antihypertensive agents, limited data about the use of minoxidil in neonates are available. We describe an infant girl, born at 35 weeks of gestation, who was diagnosed with idiopathic hypertension after extensive diagnostic evaluation. Adequate blood pressure control was not achieved with captopril, amlodipine, and clonidine. Oliguria secondary to captopril and rapid onset congestive heart failure due to persistent hypertension led to the introduction of intravenous agents labetalol and nitroprusside. Although adequate blood pressure control was achieved, attempts to transition back to oral agents were unsuccessful, prompting the use of minoxidil as an alternative agent. Although good blood pressure control was achieved, the infant's oral intake plummeted from 210 to 63 ml/kg/day. The anorexia quickly resolved after stopping minoxidil, and she was discharged home at 5 months of age receiving propranolol, amlodipine, and doxazosin. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 10) between the patient's development of anorexia and minoxidil therapy. To our knowledge, there have been no previous reports of minoxidil-associated anorexia in preterm or term infants. Clinicians should be aware that anorexia is a possible adverse effect of minoxidil in this patient population when initiating the drug in similar patients. PMID- 25280268 TI - Unique multiple soluble-insoluble phase transitions in aqueous two-phase copolymerization of acrylamide and a weakly charged comonomer. AB - A unique phenomenon of multiple soluble-insoluble phase transitions was found in the two-phase copolymerization of acrylamide (AM) and a weakly charged comonomer, N,N-dimethylaminoethyl methacrylate (DMAEMA), in the aqueous solution of poly(ethylene glycol) (PEG). As the DMAEMA molar fraction increased from 0 to 0.30, the insoluble-soluble (I-S) phase transition first appeared and then disappeared. Varying the PEG concentration, the salt concentration, or the pH of reaction mixture, the phase transitions were tuned dependently. The volume fractions and refractive indices of continuous and disperse phases, as well as the viscosity change in the phase transitions were investigated, and the results showed that phase reentrance had occurred in the I-S phase transition. The transitional conversion for the first S-I phase transition increased with the DMAEMA molar fraction, indicating the solubility enhancement of charged polyelectrolytes. The content of DMAEMA in the resulting copolymer first increased and then decreased as the polymerization progressed. Accordingly, the droplet size increased in the two S-I phase transitions and decreased in the I-S phase transition. And it was proved that the copolymers were molecularly solubilized after the I-S phase transition. The multiple soluble-insoluble phase transitions were ascribed to the synergistic effect of polymer concentration, solubility enhancement of charged copolymers, and the salting-out effect of ionic comonomers. A generalized mechanism for the multiple soluble-insoluble phase transitions was proposed, which showed that the effects of polymer concentration were dominant in the two S-I phase transitions, while the effects of solubility enhancement played a key role in the I-S phase transition. PMID- 25280270 TI - Selective formation of a Z-trisubstituted double bond using a 1-(tert butyl)tetrazolyl sulfone. AB - In our effort to gain further insight into the enantioselective synthesis of the structural core of phormidolides B and C, we have discovered the formation of a Z trisubstituted double bond. Here, we describe a highly selective process that can be applied to our target following a strategy that is based on Julia-Kocienski olefination. The use of 1-(tert-butyl)tetrazolyl sulfone affords the construction of the Z-trisubstituted alkene with high efficiency and stereoselectivity. PMID- 25280269 TI - Catalytic core of human topoisomerase IIalpha: insights into enzyme-DNA interactions and drug mechanism. AB - Coordination between the N-terminal gate and the catalytic core of topoisomerase II allows the proper capture, cleavage, and transport of DNA during the catalytic cycle. Because the activities of these domains are tightly linked, it has been difficult to discern their individual contributions to enzyme-DNA interactions and drug mechanism. To further address the roles of these domains, we analyzed the activity of the catalytic core of human topoisomerase IIalpha. The catalytic core and the wild-type enzyme both maintained higher levels of cleavage with negatively (as compared to positively) supercoiled plasmid, indicating that the ability to distinguish supercoil handedness is embedded within the catalytic core. However, the catalytic core alone displayed little ability to cleave DNA substrates that did not intrinsically provide the enzyme with a transport segment (i.e., substrates that did not contain crossovers). Finally, in contrast to interfacial topoisomerase II poisons, covalent poisons did not enhance DNA cleavage mediated by the catalytic core. This distinction allowed us to further characterize the mechanism of etoposide quinone, a drug metabolite that functions primarily as a covalent poison. Etoposide quinone retained some ability to enhance DNA cleavage mediated by the catalytic core, indicating that it still can function as an interfacial poison. These results further define the distinct contributions of the N-terminal gate and the catalytic core to topoisomerase II function. The catalytic core senses the handedness of DNA supercoils during cleavage, while the N-terminal gate is critical for capturing the transport segment and for the activity of covalent poisons. PMID- 25280272 TI - Marie-Paule Pileni text. PMID- 25280271 TI - Oligonucleotide analogues as modulators of the expression and function of noncoding RNAs (ncRNAs): emerging therapeutics applications. AB - ncRNAs are emerging as key regulators of physiological and pathological processes and therefore have been identified as pharmacological targets and as markers for some diseases. Oligonucleotide analogues represent so far the most widely employed tool for the modulation of the expression of ncRNAs. In this perspective we briefly describe most of the known classes of ncRNAs and then we discuss the design and the applications of oligonucleotide analogues for their targeting. The effects of modifications of the chemical structure of the oligonucleotides on properties such as the binding affinity toward targets and off targets, and the stability to degradation and their biological effects (when known) are discussed. Examples of molecules currently used in clinical trials are also reported. PMID- 25280273 TI - Re: systematic review of adrenalectomy and lymph node dissection in locally advanced renal cell carcinoma. PMID- 25280274 TI - Re: overall survival and development of stage iv chronic kidney disease in patients undergoing partial and radical nephrectomy for benign renal tumors. PMID- 25280275 TI - Re: efficacy of imaging-guided percutaneous radiofrequency ablation for the treatment of biopsy-proven malignant cystic renal masses. PMID- 25280277 TI - Re: current clinical practice gaps in the treatment of intermediate- and high risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guerin (BCG): results of an international individual patient data survey (IPDS). PMID- 25280279 TI - Re: robotic-assisted radical cystectomy with extracorporeal urinary diversion for urothelial carcinoma of the bladder: analysis of complications and oncologic outcomes in 175 patients with a median follow-up of 3 years. PMID- 25280280 TI - Re: metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. PMID- 25280281 TI - Re: marital status and survival in patients with cancer. PMID- 25280282 TI - Re: cigarette smoking is associated with an increased risk of biochemical disease recurrence, metastasis, castration-resistant prostate cancer, and mortality after radical prostatectomy: results from the SEARCH database. PMID- 25280283 TI - Re: does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? PMID- 25280284 TI - Re: lymph node management in patients with paratesticular rhabdomyosarcoma: a population-based analysis. PMID- 25280285 TI - Re: prostatic biopsies in selected men aged 75 years and older guide key clinical management decisions. PMID- 25280286 TI - Re: histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (PSA) concentration in the Finnish Prostate Cancer Screening Trial. PMID- 25280287 TI - Re: Th1-Th17 cells contribute to the development of uropathogenic Escherichia coli-induced chronic pelvic pain. PMID- 25280288 TI - Re: metabolic disturbances and renal stone promotion on treatment with topiramate: a systematic review. PMID- 25280289 TI - Re: dietary hyperoxaluria is not reduced by treatment with lactic acid bacteria. PMID- 25280290 TI - Re: body fat content and distribution and urinary risk factors for nephrolithiasis. PMID- 25280291 TI - Re: defining variation in urinary oxalate in hyperoxaluric stone formers. PMID- 25280292 TI - Re: prospective randomized trial comparing shock wave lithotripsy and flexible ureterorenoscopy for lower pole stones smaller than 1 cm. PMID- 25280293 TI - Re: comparison of serum and urinary calcium profile of immobilized and ambulant trauma patients. PMID- 25280294 TI - Re: a prospective, randomized, single-blind trial of 5-mm versus 3-mm ports for laparoscopic cholecystectomy: is smaller better? PMID- 25280295 TI - Re: anatomy of the dorsal nerve of the penis, clinical implications. PMID- 25280296 TI - Re: prospective evaluation of a new visual prostate symptom score, the International Prostate Symptom Score, and uroflowmetry in men with urethral stricture disease. PMID- 25280297 TI - Re: outcome of 1-stage urethroplasty using oral mucosal grafts for the treatment of urethral strictures associated with genital lichen sclerosus. PMID- 25280298 TI - Re: postanastomotic transplant renal artery stenosis: association with de novo class II donor-specific antibodies. PMID- 25280299 TI - Re: risk of kidney stones with surgical intervention in living kidney donors. PMID- 25280300 TI - Re: risk factors for the failure of antimuscarinic treatment with solifenacin in women with overactive bladder. PMID- 25280301 TI - Re: long-term results of artificial urinary sphincter for women with type III stress urinary incontinence. PMID- 25280302 TI - Re: cystectomy for ulcerative interstitial cystitis: sequelae and patients' perceptions of improvement. PMID- 25280303 TI - Re: the artificial urinary sphincter after a quarter of a century: a critical systematic review of its use in male non-neurogenic incontinence. PMID- 25280304 TI - Re: transcorporal artificial urinary sphincter implantation as a salvage surgical procedure for challenging cases of male stress urinary incontinence: surgical technique and functional outcomes in a contemporary series. PMID- 25280305 TI - Re: genetic variants in 2q31 and 5p15 are associated with aggressive benign prostatic hyperplasia in a Chinese population. PMID- 25280306 TI - Re: effect of selective alpha-blocker tamsulosin on erectile function in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. PMID- 25280307 TI - Re: bipolar vs monopolar transurethral resection of the prostate: evaluation of the impact on overall sexual function in an international randomized controlled trial setting. PMID- 25280308 TI - Re: the risk of adverse outcomes in association with use of testosterone products: a cohort study using the UK-based General Practice Research Database. PMID- 25280309 TI - Re: hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. PMID- 25280310 TI - Re: management of ED under the "severe distress" criteria in the NHS: a real-life study. PMID- 25280314 TI - Re: bigger is not always better: the effect of obesity on sexual satisfaction and behavior of adult men in the United States. PMID- 25280315 TI - Re: functional and nutritional state in elderly men with compensated hypogonadism. PMID- 25280316 TI - Re: the association of physical and mental health with sexual activity in older adults in a retirement community. PMID- 25280317 TI - Re: cancer risk among children born after assisted conception. PMID- 25280318 TI - Re: testicular cell transplantation into the human testes. PMID- 25280319 TI - Re: impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: a multicenter prospective study from the CECOS Network. PMID- 25280320 TI - Re: increased risk of cancer among azoospermic men. PMID- 25280321 TI - Re: a novel cell-processing method 'AgarCytos' in conjunction with OCT3/4 and PLAP to detect intratubular germ cell neoplasia in non-obstructive azoospermia using remnants of testicular sperm extraction specimens. PMID- 25280322 TI - Re: germ cell tumor in an adolescent with extensive testicular microlithiasis: concerns regarding future management, and re: clinical aspects of testicular microlithiasis in boys: a review. PMID- 25280323 TI - Re: adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients. PMID- 25280324 TI - Re: penile duplication: is it necessary to excise one of the penises? PMID- 25280325 TI - Re: single- vs. multi-stage repair of proximal hypospadias: the dilemma continues. PMID- 25280326 TI - Re: TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer. PMID- 25280327 TI - Re: bispecific small molecule-antibody conjugate targeting prostate cancer. PMID- 25280328 TI - Re: leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function. PMID- 25280329 TI - Re: focused ultrasonic propulsion of kidney stones: review and update of preclinical technology. PMID- 25280331 TI - Vibrational spectroscopic study of poldervaartite CaCa[SiO3(OH)(OH)]. AB - We have studied the mineral poldervaartite CaCa[SiO3(OH)(OH)] which forms a series with its manganese analogue olmiite CaMn[SiO3(OH)](OH) using a range of techniques including scanning electron microscopy, thermogravimetric analysis, Raman and infrared spectroscopy. Chemical analysis shows the mineral is reasonably pure and contains only calcium and manganese with low amounts of Al and F. Thermogravimetric analysis proves the mineral decomposes at 485 degrees C with a mass loss of 7.6% compared with the theoretical mass loss of 7.7%. A strong Raman band at 852 cm(-1) is assigned to the SiO stretching vibration of the SiO3(OH) units. Two Raman bands at 914 and 953 cm(-1) are attributed to the antisymmetric vibrations. Intense prominent peaks observed at 3487, 3502, 3509, 3521 and 3547 cm(-1) are assigned to the OH stretching vibration of the SiO3(OH) units. The observation of multiple OH bands supports the concept of the non equivalence of the OH units. Vibrational spectroscopy enables a detailed assessment of the molecular structure of poldervaartite. PMID- 25280332 TI - Spectroscopic properties of a series of Co(II) coordination polymers and the influence of Co(II) coordination environment on photoelectric property. AB - Four Co(II) coordination polymers, [Co(suc)]n 1, [Co(pdc)]n 2, {[Co7(suc)4(OH)6(H2O)3].8H2O}n 3, {[Co(bdc)(phen)(H2O)].H2O}n 4 (H2suc=succinic acid, H2pdc=pyridine-3,4-dicarboxylic acid, H2bdc=1,2-benzenedicarboxylic acid, phen=1,10-phenanthroline) were hydrothermally synthesized and characterized by X ray single-crystal diffraction, surface photovoltage spectroscopy (SPS), electrical conductivity, thermogravimetric analysis (TG), ultraviolet visible and near-infrared absorption spectrum (UV-Vis-NIR), infrared spectrum (IR), and elemental analysis. The structural analyses indicate that the coordination numbers of the Co(II) ions are 4, 5, 6 and 6 for the polymers 1-4, respectively. And polymers 1 and 2 exhibit 3D structure formed by suc(2-) and pdc(2-) anions bridging Co(II) ions, respectively. Polymer 3 exhibits a 2D structure with suc(2 ) anions bridging seven-nuclear [Co7(OH)6(H2O)3](3-) unit and polymer 4 is a 1D structure bridged by bdc(2-) anions. The surface photoelectric properties of the cobalt polymers were mainly studied by SPS. The results of SPS reveal that all polymers possess certain photoelectric conversion property in the range of 300 800 nm. The influences of the structure, coordination micro-environment of central metal ion and structural dimensionality on response bands of SPS were discussed. PMID- 25280334 TI - Luminescence and energy transfer of tunable emission phosphor Ca2PO4Cl:Ce(3+), Mn(2+). AB - A series of Ca2PO4Cl:Ce(3+), Mn(2+) phosphors are synthesized by a high temperature solid state reaction method, and their luminescent properties are investigated. Ca2PO4Cl:Ce(3+), Mn(2+) has an obvious absorption in the region of 300-350 nm, and energy transfer from Ce(3+) to Mn(2+) in Ca2PO4Cl has been validated, and proved to be a resonant type via a dipole-dipole interaction. Orange red emission intensity of Mn(2+) can be obviously enhanced via the efficient energy transfer from Ce(3+) to Mn(2+), and critical distance of energy transfer is also calculated by concentration quenching method, and about 14.1 A. The results show that Ce(3+) ion may be an available sensitizer for Ca2PO4Cl:Mn(2+), and Ca2PO4Cl:Ce(3+), Mn(2+) may have potential application in white light emitting diodes. PMID- 25280333 TI - Structures and spectroscopic characterization of calcium chloride-nicotinamide, isonicotinamide, -picolinamide and praseodymium bromide-nicotinamide complexes. AB - The coordination structures formed by calcium complexes with nicotinamide (na), isonicotinamide (ina) and picolinamide (pa) and praseodymium bromide-na are reported. The structures of CaCl2.(C6H6N2O)2.2H2O (Ca-na), CaCl2.(C6H6N2O)2.4H2O (Ca-ina), CaCl2.(C6H6N2O)2.5H2O (Ca-pa) and PrBr3.(C6H6N2O)2.6H2O (PrBr-na) in the solid state have been characterized by X-ray single crystal diffraction, FTIR, FIR, THz and Raman spectroscopies. Carbonyl oxygen of nicotinamide is coordinated to Ca(2+), but it is O-monodentate (carbonyl oxygen) and N,O bidentate ligand (pyridyl nitrogen and carbonyl oxygen) for Pr(3+) to form a chain structure in PrBr-na. For isonicotinamide, only carbonyl oxygen atom is coordinated to Ca(2+). Pyridyl nitrogen and carbonyl oxygen of picolinamide are coordinated to Ca(2+) to form a five-membered ring structure. The crystal structure and spectroscopic results indicate the differences of the coordination of Ca and Pr ions, the changes of hydrogen bonds and conformation of the ligands induced by complexation. Unlike transition metal ions, Sr(2+) or lanthanide ions, Ca(2+) is inclined to coordinate to carbonyl oxygen atoms of the ligands. PMID- 25280335 TI - Temperature controlled ionic liquid-based dispersive micro-extraction using two ligands, for determination of aluminium in scalp hair samples of Alzheimer's patients: a multivariate study. AB - A green and sensitive temperature controlled dispersive liquid-liquid microextraction (TIL-DLLME) methodology based on the application of ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [C4mim][PF6], as an extractant solvent was proposed for the preconcentration of trace levels of aluminium (Al(3+)) in scalp hair samples of Alzheimer's (AD) patients, prior to analyzing by flame atomic absorption spectrometry (FAAS). The Al(3+) was complexed with 8 hydrooxyquinoline (oxine) (L1) and 3,5,7,2'-4' pentahydroxy flavone (morin) (L2) separately and then extracted by IL at temperature (50+/-2.0 degrees C). Some effective factors that influence the TIL-DLLME efficiency such as pH, ligands concentrations, volume of IL, ionic strength, and incubation time were investigated and optimized by multivariate analysis. In the optimum experimental conditions, the limit of detection (3s) and enhancement factor were 0.56 MUg L( 1), 0.64 MUg L(-1) and 85, 73 for both ligands, respectively. The relative standard deviation (RSD) for six replicate determinations of 100 MUg L(-1) Al(3+) complexed with oxine and morin were found to be 3.88% and 4.74%, respectively. The developed method was validated by the analysis of certified reference material of human hair (NCSZC81002).and applied satisfactorily to the determination of Al(3+) in acid digested scalp hair samples of AD patients and healthy controls. The resulted data shows significant higher level in scalp hair samples of AD male patients with related to referents of same age and socioeconomic status. PMID- 25280336 TI - Plectranthus amboinicus leaf extract mediated synthesis of zinc oxide nanoparticles and its control of methicillin resistant Staphylococcus aureus biofilm and blood sucking mosquito larvae. AB - In this study, zinc oxide nanoparticles were biologically synthesized using the leaf extract of Plectranthus amboinicus (Pam-ZnO NPs). The synthesized Pam-ZnO NPs were characterized by UV-Vis spectrophotometer, FTIR, TEM and XRD analysis. TEM analysis of Pam-ZnO NPs showed the average size of about 20-50 nm. Pam-ZnO NPs control the growth of methicillin-resistant Staphylococcus aureus biofilms (MRSA ATCC 33591) at the concentration of 8-10 MUg/ml. Confocal laser scanning microscope (CLSM) images revealed that Pam-ZnO NPs strongly inhibited the biofilm forming ability of S. aureus. In addition, Pam-ZnO NPs showed 100% mortality of fourth instar mosquito larvae of Anopheles stephensi, Culex quinquefasciatus and Culex tritaeniorhynchus at the concentration of 8 and 10 MUg/ml. The histopathological studies of Pam-ZnO NPs treated A. stephensi and C. quinquefasciatus larvae revealed the presence of damaged cells and tissues in the mid-gut. The damaged tissues suffered major changes including rupture and disintegration of epithelial layer and cellular vacuolization. The present study conclude that Pam-ZnO NPs showed effective control of S. aureus biofilms and mosquito larvae by damaging the mid gut cells. PMID- 25280337 TI - Experimental and theoretical studies on the vibrational spectra of trans-3 phenylacryloyl chloride. AB - The infrared and Raman spectra of trans-3-phenylacryloyl chloride (TPC) were reported and compared with the theoretical results calculating at B3LYP/6-311++G (d, p) level. Both wavenumbers and intensities obtained from the experimental and theoretical spectra were in good agreement. A complete spectral assignment was made with the aid of potential energy distribution (PED) based on the scaled quantum mechanical (SQM) force field method. This study provided valuable insight for understanding the observed spectral features of TPC. Additionally, the HOMO LUMO gap, molecular electrostatic potential (MEP) atomic charge distribution, and natural bond orbitals (NBO) were studied theoretically on the same basis set. PMID- 25280338 TI - Quantum chemical calculations and interpretation of electronic transitions and spectroscopic characteristics belonging to 1-(3-Mesityl-3-methylcyclobutyl)-2 (naphthalene-1-yloxy)ethanone. AB - This comprehensive study reports the synthesis of the title compound, 1-(3 Mesityl-3-methylcyclobutyl)-2-(naphthalene-1-yloxy)ethanone (C26H28O2), and identification of the molecule by means of the standard experimental methods such as single-crystal X-ray diffraction, ultra violet-visible (UV-vis) spectra, Fourier transform infrared (FTIR) spectra, (13)C and (1)H NMR chemical shifts and quantum chemical calculations using density functional theory (B3LYP) method for the first time. The experimental results observed display that the synthesis of the C26H28O2 compound is perfectly conducted without any impurities. Additionally, the little deviations are noticed on the bond lengths and bond angles, confirming that the strong intra-molecular charge transfers appear in the due to the presence of the electron engagements and conjugative effects (bond weakening). Besides, the intermolecular C-H?O distance presents the interaction between the methylcyclobutyl C-H group and oxygen atom in the ethanone group. At the same time, the absorption wavelength (lambdamax) appears at 292 nm and interval 297-269 nm in the solvent of chloroform and THF as a consequence of the presence of effective pi-pi(*) conjugated segments in the molecule studied. Besides, optical band gap energy of 3.22/3.25 eV (chloroform/THF), verifies the existence of the strong electronic donating groups in the structure. As for the quantum chemical computations, the determination of the optimized molecular structures, vibrational frequencies including infrared intensities, vibrational wavenumbers, thermodynamic properties, atomic charges, electronic transitions, dipole moment (charge distribution), optical band gap energy, (1)H and (13)C NMR chemical shifts are conducted using density functional theory/Becke-3-Lee-Yang Parr (DFT/B3LYP) method with the standard 6-311++G(2d,2p) level of theory. The results obtained show that the strong intra-molecular charge transfer (ICT) appears between the donor and acceptor in the title compound due to the existence of the strong electronic donating groups and effective pi-pi(*) conjugated segments with high electronic donor ability for the electrophilic attack (intermolecular interactions). Additionally, the presence of the non-uniform charge distributions (polar behavior) on the various atoms makes the title compound be useful to bond metallically. PMID- 25280339 TI - Analysis of microRNA-203 function in CREB/MITF/RAB27a pathway: comparison between canine and human melanoma cells. AB - MicroRNA (miR)-203 is downregulated and acts as an anti-oncomir in melanoma cells. Here, using human and canine melanoma cells, we elucidated the effects of miR-203 on cyclic adenosine monophosphate response element binding protein (CREB)/microphthalmia-associated transcription factor (MITF)/RAB27a pathway, which is known to be important for the development and progression of human melanoma. In this study, we showed that miR-203 directly targeted CREB1 and regulated its downstream targets, MITF and RAB27a. miR-203 significantly suppressed the growth of human and canine melanoma cells and inhibited melanosome transport through the suppression of the signalling pathway. In conclusion, miR 203 was shown to be a common tumour-suppressive miRNA in human and canine melanoma and thus to play a crucial role in the biological mechanisms of melanoma development. PMID- 25280340 TI - Dynamic range extension of hybridization sensors. AB - In hybridization based nucleic acid sensors the stringency of hybridization poses a challenge to design and experiment. For a given set of experimental parameters the affinity window of probe-target interaction is always limited and vice versa for a given probe set design, changes in experimental conditions can easily bring some measurements out of detection range. In this paper we introduce and apply a strategy to extend this dynamic range for affinity sensors, sensors which measure the amount of hybridized molecules after equilibrium is reached. The method relies on concepts of additivity of nucleic acids hybridization free energies and on equilibrium isotherms. It consists in combining the measurements from probes with different lengths, by appropriately rescaling the measured signals. We test the validity of the approach on experiments and show that by combining probes with hybridizing regions of length 21, 23 and 25 nucleotides we manage to extend the dynamic range of the intensity signals by a factor of 25. The presented concept is easy to extend, platform free and applies to any hybridization based affinity sensor. PMID- 25280341 TI - Electrochemical sensor for chloramphenicol based on novel multiwalled carbon nanotubes@molecularly imprinted polymer. AB - Herein, we present a novel electrochemical sensor for the determination of chloramphenicol (CAP), which is based on multiwalled carbon nanotubes@molecularly imprinted polymer (MWCNTs@MIP), mesoporous carbon (CKM-3) and three-dimensional porous graphene (P-r-GO). Firstly, 3-hexadecyl-1-vinylimidazolium chloride (C16VimCl) was synthetized by using 1-vinylimidazole and 1-chlorohexadecane as precursors. Then, C16VImCl was used to improve the dispersion of MWCNT and as monomer to prepare MIP on MWCNT surface to obtain MWCNTs@MIP. After that, the obtained MWCNTs@MIP was coated on the CKM-3 and P-r-GO modified glassy carbon electrode to construct an electrochemical sensor for the determination of CAP. The parameters concerning this assay strategy were carefully considered. Under the optimal conditions, the electrochemical sensor offered an excellent response for CAP. The linear response ranges were 5.0 * 10(-9)-5 * 10(-7)mol L(-1) and 5.0 * 10(-7)-4.0 * 10(-6), respectively, and the detection limit was 1.0 * 10(-10)mol L(-1). The electrochemical sensor was applied to determine CAP in real samples with satisfactory results. PMID- 25280342 TI - An electrochemical aptasensor for thrombin using synergetic catalysis of enzyme and porous Au@Pd core-shell nanostructures for signal amplification. AB - In this work, a sensitive electrochemical aptasensor for thrombin (TB) based on synergetic catalysis of enzyme and porous Au@Pd core-shell nanostructure has been constructed. With the advantages of large surface area and outstanding catalytic performance, porous Au@Pd core-shell nanostructures were firstly employed as the nanocarrier for the immobilization of electroactive toluidine blue (Tb), hemin/G quadruplex formed by intercalating hemin into the TB aptamer (TBA) and glucose oxidase (GOx). As a certain amount of glucose was added into the detection cell, GOx rapidly catalyzed the oxidation of glucose, coupling with the local generation of H2O2 in the presence of dissolved O2. Then, porous Au@Pd nanoparticles and hemin/G-quadruplex as the peroxidase mimics efficiently catalyzed the reduction of H2O2, amplifying the electrochemical signal and improving the sensitivity. Finally, a detection limit of 0.037pM for TB was achieved. The excellent performance of the aptasensor indicated its promising prospect as a valuable tool in simple and cost-effective TB detection in clinical application. PMID- 25280343 TI - Development and validation of an ultra high performance liquid chromatography electrospray ionization tandem mass spectrometry method for the simultaneous determination of selected flavonoids in Ginkgo biloba. AB - A rapid and sensitive ultra high performance liquid chromatography electrospray ionization tandem mass spectrometry method was developed and validated for the simultaneous determination of 13 flavonoids in leaf, stem, and fruit extracts of male and female trees of Ginkgo biloba to investigate gender- and age-related variations of flavonoids content. Chromatographic separation was accomplished on an Acquity UPLC BEH C18 column (50 mm * 2.1 mm id, 1.7 MUm) in 5 min. Quantitation was performed using negative electrospray ionization mass spectrometry in multiple reaction monitoring mode. The calibration curves of all analytes showed a good linear relationship (r(2) >= 0.9977) over the concentration range of 1-1000 ng/mL. The precision evaluated by an intra- and interday study showed RSD <= 1.98% and good accuracy with overall recovery in the range from 97.90 to 101.09% (RSD <= 1.67%) for all analytes. The method sensitivity expressed as the limit of quantitation was typically 0.25-3.57 ng/mL. The results showed that the total content of 13 flavonoids was higher in the leaf extract of an old male Ginkgo tree compared to young female Ginkgo trees. PMID- 25280344 TI - Electron backscatter diffraction applied to lithium sheets prepared by broad ion beam milling. AB - Due to its very low hardness and atomic number, pure lithium cannot be prepared by conventional methods prior to scanning electron microscopy analysis. Here, we report on the characterization of pure lithium metallic sheets used as base electrodes in the lithium-ion battery technology using electron backscatter diffraction (EBSD) and X-ray microanalysis using energy dispersive spectroscopy (EDS) after the sheet surface was polished by broad argon ion milling (IM). No grinding and polishing were necessary to achieve the sufficiently damage free necessary for surface analysis. Based on EDS results the impurities could be characterized and EBSD revealed the microsctructure and microtexture of this material with accuracy. The beam damage and oxidation/hydration resulting from the intensive use of IM and the transfer of the sample into the microscope chamber was estimated to be <50 nm. Despite the fact that the IM process generates an increase of temperature at the specimen surface, it was assumed that the milling parameters were sufficient to minimize the heating effect on the surface temperature. However, a cryo-stage should be used if available during milling to guaranty a heating artefact free surface after the milling process. PMID- 25280345 TI - PRDM1 expression on the epithelial component but not on ectopic lymphoid tissues of Warthin tumour. AB - OBJECTIVE: To determine the role of PRDM1, a key molecule for modulating the immune cells, in Warthin tumour (WT) pathogenesis. SUBJECTS AND METHODS: Forty paraffin-embedded parotid tissues of patients (mean age: 62.08 +/- 11.90) with WT were retrieved from the pathology archives of Qindu Hospital from January 2012 to December 2012. The PRDM1 expression was investigated in a cohort of WT by immunohistochemistry. RESULTS: PRDM1 was expressed only on the epithelial component but not on ectopic lymphoid tissue of the tumour. Statistically, PRDM1 expression rates between WT glandular epithelial cells (40/40 cases) and the tumour-adjacent tissues (0/9 cases), and WT germinal centres (0/34 cases) and tonsil tissues (10/10 cases) were significantly different (P < 0.001), respectively. CONCLUSIONS: The PRDM1 expression appeared to play an essential role in WT pathogenesis. A better understanding of it might give options for revealing possible novel management strategies. PMID- 25280346 TI - Sulfur-doped graphene quantum dots as a novel fluorescent probe for highly selective and sensitive detection of Fe(3+). AB - Sulfur-doped graphene quantum dots (S-GQDs) with stable blue-green fluorescence were synthesized by one-step electrolysis of graphite in sodium p toluenesulfonate aqueous solution. Compared with GQDs, the S-GQDs drastically improved the electronic properties and surface chemical reactivities, which exhibited a sensitive response to Fe(3+). Therefore, the S-GQDs were used as an efficient fluorescent probe for highly selective detection of Fe(3+). Upon increasing of Fe(3+) concentration ranging from 0.01 to 0.70 MUM, the fluorescence intensity of S-GQDs gradually decreased and reached a plateau at 0.90 MUM. The difference in the fluorescence intensity of S-GQDs before and after adding Fe(3+) was proportional to the concentration of Fe(3+), and the calibration curve displayed linear regions over the range of 0-0.70 MUM. The detection limit was 4.2 nM. Finally, this novel fluorescent probe was successfully applied to the direct analysis of Fe(3+) in human serum, which presents potential applications in clinical diagnosis and may open a new way to the design of effective fluorescence probes for other biologically related targets. PMID- 25280347 TI - Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: comment. PMID- 25280348 TI - The impact of an incentive on the use of an online self-directed wellness and self-management program. AB - BACKGROUND: Those who pay for health care are increasingly looking for strategies to influence individuals to take a more active role in managing their health. Incenting health plan members and/or employees to participate in wellness programs is a widely used approach. OBJECTIVE: In this study, we examine financial incentives to health plan members to participate in an online self management/wellness program-US $20 for completing the patient activation measure (PAM) and an additional US $40 for completing 8 learning modules. We examined whether the characteristics of plan members differed by the degree to which they responded to the incentives. Further, we examined whether participation in the wellness program was associated with improvements in PAM scores and changes in health care utilization. METHODS: This retrospective study compared demographic characteristics and change in PAM scores and health utilization for 144,625 health plan members in 2011. Four groups were compared: (1) those who were offered the incentives but chose not to participate (n=128,634), (2) those who received the initial incentive (PAM only) but did not complete 8 topics (n=7099), (3) those who received both incentives (completing 8 topics but no more) (n=2693), and (4) those who received both incentives and continued using the online program beyond what was required by the incentives (n=6249). RESULTS: The vast majority of health plan members did not participate in the program (88.91%, 128,634/144,675). Of those who participated, only 7099 of 16,041 (44.25%) completed the PAM for the first incentive, 2693 (16.79%) completed 8 topics for the second incentive, and 6249 (38.96%) received both incentives and continued using the program beyond the incentive requirements. Nonparticipants were more likely to be men and to have lower health risk scores on average than the other three groups of participants (P<.001). In multivariate regression models, those who used the online program (8 topics or beyond) increased their PAM score by approximately 1 point more than those who only took the PAM and did not use the wellness program (P<.03). In addition, emergency department visits were lower for all groups who responded to any level of the incentive as compared to those who did not (P<.01). No differences were found in other types of utilization. CONCLUSIONS: The incentive was not sufficient to spark most health plan members to use the wellness program. However, the fact that many program participants went beyond the incentive in their use of the online wellness program suggests that the users of the online program found value in using it, and it was their own internal motivation that stimulated this additional use. Providing an incentive for program participation may be an effective pathway for working with less activated patients, particularly if the program is tailored to the needs of the less activated. PMID- 25280349 TI - The 21st-century landscape of adult fractures: cohort study of a complete adult regional population. AB - Recent reports on adult fracture epidemiology have focused mainly on the hip in the elderly, in whom increasing rates lately have changed to a decline. New reports of the preponderance of nonhip fractures in health expenditure call for a wider scope. We therefore examined current overall and site-specific fracture epidemiology in adults. We ascertained all fractures diagnosed in inpatient and outpatient care in all men and women aged 20 years or older in Skane County, Sweden, from 1999 to 2010 (10 million person-years). For each fracture type, we estimated age-specific and sex-specific rates and evaluated potential time trends. We found 205,908 fractures yielding an overall fracture rate of 192 per 10,000 person-years. The age-standardized overall fracture rate increased by 1.2 per 10,000 and year (95% confidence interval, 0.8 to 1.5), but time trends were different for different fracture types, age strata, and for men and women. For example, in both women and men aged >=50 years the rates of proximal humerus fracture increased (0.6 and 0.2 per 10,000 and year, respectively) while hip fracture rates declined (-1.0 and -0.3 per 10,000/year, respectively). Overall age-specific number of fractures increased with age in women but was stable in men. The increasing overall fracture rate is a major concern in the context of a growing and aging population. Effective and affordable preventive strategies and treatments should be an urgent priority to meet the challenges, especially in older women in whom most fractures occur. Comprehensive current detailed data, as provided in this study, may serve as reference for projections and for cost calculations of fracture care in other settings before results of similar examinations are available there. PMID- 25280350 TI - Nurses' working time use - how value adding it is? AB - AIM: To investigate registered nurses' (RN) and licensed practical nurses' (LPN) working time use in adult inpatient units. BACKGROUND: There is only scarce information about value-adding patient care. Nursing care can be divided into three major categories: value-adding care (direct care, indirect care, patient documentation), necessary activities (indirect work, unit-related work) and non value-adding work (personal time, miscellaneous work). METHOD: A cross-sectional quantitative work sampling study. Total of 11,029 nursing activities were collected from two Finnish tertiary hospitals using registered nurses' (n = 66) and licensed practical nurses' (n = 12) self-reporting. RESULTS: Nearly three quarters of nurses' work was value-adding care (71%). The working time division was almost identical for necessary activities and non-value-adding work. Registered nurses spent more time carrying out unit-related work, while licensed practical nurses' spent more time on direct care. Nurses' working time use was divided nearly identically in somatic units but there were differences when compared with psychiatric units. CONCLUSION AND IMPLICATIONS FOR NURSING MANAGEMENT: Nurses' work seemed to concentrate on value-adding care. The results of working time use studies can be used when developing nursing work for more value-adding care for the patients. PMID- 25280351 TI - Design, synthesis, and antiviral, fungicidal, and insecticidal activities of tetrahydro-beta-carboline-3-carbohydrazide derivatives. AB - According to our previous research on the antiviral activity of beta-carboline and tetrahydro-beta-carboline derivatives, using (1S,3S)-1-methyl-2,3,4,9 tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (1) as a lead compound, series of novel tetrahydro-beta-carboline derivatives containing acylhydrazone moiety were designed, synthesized, and first evaluated for their biological activities. Most of these compounds exhibited excellent antiviral activity both in vitro and in vivo. The in vivo inactivation, curative, and protection activities of compounds 8, 9, 12, 16, 28, 29, and 30 were much higher than that of ribavirin (37.6%, 39.4%, and 37.9% at 500 MUg/mL) and the lead compound (40.0%, 42.3%, and 39.6% at 500 MUg/mL). Especially, the in vitro and in vivo activities of compound 16 (36.9%, 33.6%, 30.2%, and 35.8%) at 100 MUg/mL, which were very close to that of ribavirin (40.0% for in vitro activity) at 500 MUg/mL. Compounds 9 and 29 were chosen for the field trials of antiviral efficacy against TMV (tobacco mosaic virus); the results exhibited that both compounds, especially compound 29, showed better activities than control plant virus inhibitors. At the same time, the fungicidal results showed that compounds 6, 9, and 11 exhibited good fungicidal activities against 14 kinds of phytopathogens. Additionally, compounds 3 and 23 exhibited moderate insecticidal activity against the four tested species of insects. PMID- 25280352 TI - Mutation of the rice ASL2 gene encoding plastid ribosomal protein L21 causes chloroplast developmental defects and seedling death. AB - The plastid ribosome proteins (PRPs) play important roles in plastid protein biosynthesis, chloroplast differentiation and early chloroplast development. However, the specialised functions of individual protein components of the chloroplast ribosome in rice (Oryza sativa) remain unresolved. In this paper, we identified a novel rice PRP mutant named asl2 (Albino seedling lethality 2) exhibiting an albino, seedling death phenotype. In asl2 mutants, the alteration of leaf colour was associated with chlorophyll (Chl) content and abnormal chloroplast development. Through map-based cloning and complementation, the mutated ASL2 gene was isolated and found to encode the chloroplast 50S ribosome protein L21 (RPL21c), a component of the chloroplast ribosome large subunit, which was localised in chloroplasts. ASL2 was expressed at a higher level in the plumule and leaves, implying its tissue-specific expression. Additionally, the expression of ASL2 was regulated by light. The transcript levels of the majority of genes for Chl biosynthesis, photosynthesis and chloroplast development were strongly affected in asl2 mutants. Collectively, the absence of functional ASL2 caused chloroplast developmental defects and seedling death. This report establishes the important role of RPL21c in chloroplast development in rice. PMID- 25280353 TI - Comprehensive analysis of aerobic and anaerobic bacteria found on dental bib clips. AB - Multiple-use dental bib clips are considered to present relatively low risks for transmitting infections and, thus, are thought to only require disinfection between patient visits. This study was designed to: 1) determine the presence and composition of bacterial contaminants on reusable rubber-faced metal bib clips after dental treatment at the hygiene clinic at Tufts University School of Dental Medicine and 2) evaluate the effectiveness of the disinfection for this clip type. Aerobic and anaerobic bacterial contaminant loads on the surfaces of the clips were investigated immediately after hygiene treatments were rendered and again after clips were disinfected. The species and strains of bacterial isolates were identified using 16S rDNA sequencing and Human Oral Microbe Identification Microarray analyses. The results demonstrated that although the use of disinfection proved to be significantly effective, some clips retained at least one bacterium on their surfaces after disinfection. Although the bacterial species present on disinfected clips were typical skin or environmental isolates, some were oral in origin. In the study's settings, bacterial presence on the clips did not indicate an infectious disease problem. The different bacterial loads on clips suggest that cross-contamination risks may not be the same for all clinics, and that this difference may be related to the type of treatments and services performed. PMID- 25280354 TI - 2-Methoxy-4-methylsulfinylbenzyl: a backbone amide safety-catch protecting group for the synthesis and purification of difficult peptide sequences. AB - The use of 2-methoxy-4-methylsulfinylbenzyl (Mmsb) as a new backbone amide protecting group that acts as a safety-catch structure is proposed. Mmsb, which is stable during the elongation of the sequence and trifluoroacetic acid-mediated cleavage from the resin, improves the synthetic process as well as the properties of the quasi-unprotected peptide. Mmsb offers the possibility of purifying and characterizing complex peptide sequences, and renders the target peptide after NH4 I/TFA treatment and subsequent ether precipitation to remove the cleaved Mmsb moiety. First, the "difficult peptide" sequence H-(Ala)10-NH2 was selected as a model to optimize the new protecting group strategy. Second, the complex, bioactive Ac-(RADA)4-NH2 sequence was chosen to validate this methodology. The improvements in solid-phase peptide synthesis combined with the enhanced solubility of the quasi-unprotected peptides, as compared with standard sequences, made it possible to obtain purified Ac-(RADA)4-NH2. To extend the scope of the approach, the challenging Abeta(1-42) peptide was synthesized and purified in a similar manner. The proposed Mmsb strategy opens up the possibility of synthesizing other challenging small proteins. PMID- 25280355 TI - Enhancement of the mechanical properties of hydroxyapatite by SiC addition. AB - Improvements of mechanical and anticorrosive properties, as well as superior osseointegration of the hydroxyapatite coated titanium alloy were reported in the last years by the addition of different elements (Si or Ti) into hydroxyapatite structure. The aim of this work was to prepare and to investigate the hydroxyapatite (HAP) coatings enriched with SiC in order to enhance the mechanical properties of HAP films. The coatings were deposited on Ti6Al4V alloy substrates by co-sputtering of HAP and SiC targets, using a magnetron sputtering system. The films were characterized in terms of elemental and phase composition, chemical binding, morphology and mechanical properties by EDS, XRD, FTIR, SEM, AFM, and nanoindentation. Overall, improved mechanical properties were found by adding SiC to the basic HAP structure. PMID- 25280356 TI - Fatty acid composition of subcutaneous adipose tissue from entire male pigs with extremely divergent levels of boar taint compounds--an exploratory study. AB - This exploratory study investigated the variability of fatty acid composition in entire male pigs with extremely divergent levels of boar taint compounds. Fatty acids were quantified in back fat samples from 20 selected carcasses of Pietrain*F1 sired boars (average carcass weight 84 kg) with extremely low (LL) or extremely high (HH) levels of androstenone, skatole, and indole. Concentrations of polyunsaturated fatty acids (PUFA) were significantly (p<0.05) increased in LL boars (23.4%) compared to HH boars (19.7%). This was mainly due to increased levels of linoleic acid (C18:2 n-6) and alpha-linolenic acid (C18:3 n-3). Correspondingly, unsaturated fatty acids (SFA) were significantly lower (p<0.05) in LL boars (35.2%) compared to HH boars (37.7%). The findings are discussed with respect to potential effects on flavor formation in boar fat and meat. Further research is needed to study the gender specificity and the interplay of the synthesis and the metabolism of steroids, lipids, and the clearance of skatole in pigs. PMID- 25280357 TI - Nitrite spray treatment to promote red color stability of vacuum packaged beef. AB - Sodium nitrite solutions were sprayed on select grade boneless rib (M. longissimus thoracis) and bottom round (mainly M. biceps femoris) steaks individually, to form bright red nitric oxide myoglobin (NO-Mb) in vacuum packages. Our objective was to determine the optimum level of nitrite in spray for stable raw steak redness, low or no residual nitrite, and low surface pinking (ham-like cured color) after cooking. Results showed that steaks sprayed with 100 350 ppm nitrite solutions had 3.0-3.6g weight gain and a calculated level of 1.3 5.3mg nitrite added/kg steak, but very low (<1 ppm) residual nitrite. Nitrite sprays of 250-350 ppm were optimum for raw steak color during 21 days of storage at 1 degrees C (a*>10; chroma C*>16). Raw steak redness was less stable in round than rib. Visual scores for pinkness after cooking were low, indicating that cooked color at even the highest nitrite treatment (350 ppm) was acceptable. PMID- 25280359 TI - Activity and expression of nitric oxide synthase in pork skeletal muscles. AB - The objective of this study was to investigate the biochemical changes of nitric oxide synthase (NOS) in pork skeletal muscles during postmortem storage. Longissimus thoracis (LT), psoas major (PM) and semimembranosus (SM) muscles of pork were removed immediately after slaughter and stored under vacuum condition at 4 degrees C for 0, 1 and 3d. Results showed that all three muscles exhibited NOS activity until 1d while SM muscle retained NOS activity after 3d of storage. The content of nNOS in SM muscle was stable across 3d of storage while decreased intensity of nNOS was detected at 1 and 3d of aging in PM and LT muscles due to the degradation of calpain. Immunostaining showed that nNOS was located at not only sarcolemma but also cytoplasm at 0 and 1d of storage. Our data suggest that postmortem muscles possess NOS activity and nNOS expression depends on muscle type. PMID- 25280358 TI - Effects of acerola fruit extract on sensory and shelf-life of salted beef patties from grinds differing in fatty acid composition. AB - The effects of added acerola fruit extract on sensory and shelf-life of beef patties were evaluated. Ground beef was obtained from young bulls fed one of four diets (CON: control, LIN: linseed, CLA: conjugated linoleic acid, LINCLA: LIN plus CLA). Pre-salted (1.8% w/w) beef patties (7.7% fat) with (0.15% w/w) or without acerola were packed in modified atmosphere (80%O2:20%CO2) and displayed in a retail case for 8days. There were no interactions between diet and antioxidant treatments. LIN and/or CLA had no effect on color and lipid stability during display. However, LIN increased n-3 fatty acids in beef and tended to increase intensity of rancid flavor. Addition of acerola extended shelf-life by at least 3 days by improving color and lipid stability and a decreased trend in intensity of rancid flavor of patties without affecting microbial counts. Thus, the use of acerola as a natural antioxidant can be considered an effective method to retard color and lipid oxidation in beef patties. PMID- 25280360 TI - Microbial effect of steam vacuum pasteurisation implemented after slaughtering and dressing of sheep and lamb. AB - The main objective of the study was to assess the effect of steam vacuum pasteurisation on carcass contamination with focus on Escherichia coli, Enterobacteriaceae and total plate count (TPC). Additionally, the effect of an additional tryptone soy agar (TSA) step for resuscitation of Enterobacteriaceae after steam vacuum pasteurisation was investigated. Steam vacuum pasteurisation was applied at a temperature of >82 degrees C for a duration of 10s on sheep and lamb carcasses (n=120). Samples were taken immediately: i) after trimming just before the use of steam vacuum and ii) after use of steam vacuum. Nordic Committee on Food Analysis methods were used in microbial analyses. The differences in log reduction were found significant for all of the three microorganisms (p<0.05). For TPC, the general reduction was a 0.65 log10 in the number of colony forming units (CFU) per cm(2). For E. coli, the median reduction effect on carcasses positive before decontamination was 1.1 log10 CFU/cm(2). A large variability of the effect was however found, with 50% of the figures ranging from a 0.24 to 1.62 log10 CFU/cm(2) reduction and a 10-90% range of 0 2.1. The number of positive carcasses with Enterobacteriaceae after steam vacuum pasteurisation was higher in samples where TSA+violet red bile glucose agar (VRBGA) was used compared to samples where only VRBGA was used (p<0.01). Steam vacuum pasteurisation was found efficient in reducing the total count, read as TPC, as well as the level of E. coli and Enterobacteriaceae. PMID- 25280361 TI - Influence of household cooking methods on amino acids and minerals of Barrosa-PDO veal. AB - The effect of commonly household cooking methods (boiling, microwaving and grilling) on amino acid and mineral (Fe, Mg, K and Zn) contents was investigated in the longissimus lumborum muscle of Barrosa-PDO veal. Fifteen Barrosa purebred calves at 7-8 months of age and an average weight of 177+/-37 kg were slaughtered. Cooking had a strong effect (P<0.05) on yield, being higher (67.5%) in boiling compared to microwave and grilling (64.0% and 64.5%, respectively). Grilling increased most of the percentage retention of individual amino acids (>100%), in particular for leucine. No significant differences (P>0.05) were observed for iron and zinc retentions among the cooking methods, while the retention of magnesium and potassium was strongly affected, mainly after boiling. Our findings indicate that the different cooking methods clearly affect the chemical composition and nutritional value of meat, which may have a strong impact on the intake of essential nutrients. PMID- 25280362 TI - Changes in physico-chemical properties and volatile compounds throughout the manufacturing process of dry-cured foal loin. AB - Physico-chemical, textural, lipolytic and volatile compound changes that occur during the manufacture of dry-cured foal loin were studied. Hardness and chewiness increased significantly (P<0.001) from 1.67 kg and 0.48 kg * mm to 18.33 kg and 5.01 kg*mm, respectively during ripening process. The total average content of free fatty acid increased significantly (P<0.001), from 768.8 mg/100g of fat in the loins immediately after the seasoning period to 1271.1mg/100g of fat at the end of the drying-ripening period. In the final product, aldehydes became the dominant volatile compounds. PMID- 25280363 TI - Modifying fatty acid profiles through a new cytokinin-based plastid transformation system. AB - The widespread use of herbicides and antibiotics for selection of transgenic plants has not been very successful with regard to commercialization and public acceptance. Hence, alternative selection systems are required. In this study, we describe the use of ipt, the bacterial gene encoding the enzyme isopentenyl transferase from Agrobacterium tumefaciens, as a positive selectable marker for plastid transformation. A comparison between the traditional spectinomycin-based aadA selection system and the ipt selection system demonstrated that selection of transplastomic plants on medium lacking cytokinin was as effective as selection on medium containing spectinomycin. Proof of principle was demonstrated by transformation of the kasIII gene encoding 3-ketoacyl acyl carrier protein synthase III into tobacco plastids. Transplastomic tobacco plants were readily obtained using the ipt selection system, and were phenotypically normal despite over-expression of isopentenyl transferase. Over-expression of KASIII resulted in a significant increase in 16:0 fatty acid levels, and a significant decrease in the levels of 18:0 and 18:1 fatty acids. Our study demonstrates use of a novel positive plastid transformation system that may be used for selection of transplastomic plants without affecting the expression of transgenes within the integrated vector cassette or the resulting activity of the encoded protein. This system has the potential to be applied to monocots, which are typically not amenable to traditional antibiotic-based selection systems, and may be used in combination with a negative selectable marker as part of a two-step selection system to obtain homoplasmic plant lines. PMID- 25280364 TI - Homoatomic clustering in T4Ga5 (T = Ta, Nb, Ta/Mo): a story of reluctant intermetallics crystallizing in a new binary structure type. AB - In the formation of binary compounds, heteroatomic interactions are generally expected to play the leading role in providing stability. In this Article, we present a series of gallides, T(4)Ga(5) (T = Ta, Nb, and Ta/Mo), which appear to defy this expectation. Their complex crystal structures represent a new binary structure type (to the best of our knowledge),, which can be visualized in terms of a host lattice of T@T(8) body centered cubic (bcc) clusters linked through face-capping Ga(2) dumbbells to form a primitive cubic framework. The cubic spaces that result are alternately filled by distorted T pentagonal dodecahedra (sharing atoms with the host lattice) and dimers of bcc fragments, leading to a ?2 * ?2 * 2 supercell of the host framework structure. Ga tetrahedra and icosahedral units fill the remaining void spaces. Underlying these structural features is a strong tendency for homoatomic clustering of Ta and Ga, which is evident in all of the coordination polyhedra. Electronic structure calculations using density functional theory (DFT) and DFT-calibrated Huckel models reveal possible origins for this elemental segregation and the factors stabilizing the structure as a whole. A deep pseudogap is present at the Fermi energy of Ta(4)Ga(5) (as well as at that of Nb(4)Ga(5)), corresponding to the near optimization of Ta-Ta and Ta-Ga interactions. This pseudogap emerges as a result of the ability of extensive Ta-Ta bonding to provide local 18-electron configurations to the Ta atoms, despite the electron concentration being only 8.75 electrons per Ta atom. Support for these Ta-Ta interactions is provided by Ga bridging atoms, whose valence orbitals' low number of angular nodes confers preferential stabilization to Ta-Ta bonding functions over antibonding ones. The observed spatial separation of the structure into Ta and Ga domains occurs as a consequence of the Ga atoms being pushed toward the periphery of the Ta clusters to play this supporting role. PMID- 25280365 TI - Reporting and interpreting red blood cell morphology: is there discordance between clinical pathologists and clinicians? AB - BACKGROUND: Clinical pathologists (CPs) report RBC morphologic (RBC-M) changes to assist clinicians in prioritizing differential diagnoses. However, reporting is subjective, semiquantitative, and potentially biased. Reporting decisions vary among CPs, and reports may not be interpreted by clinicians as intended. OBJECTIVES: The aims of this study were to survey clinicians and CPs about RBC-M terms and their clinical value, and identify areas of agreement and discordance. METHODS: Online surveys were distributed to small animal clinicians via the Veterinary Information Network and to CPs via the ASVCP listserv. A quiz assessed understanding of RBC-M terms among respondent groups. Descriptive statistics were used to analyze responses to survey questions, and quiz scores were compared among groups. RESULTS: Analyzable responses were obtained from 1662 clinicians and 82 CPs. Both clinicians and CPs considered some terms, e.g., agglutination, useful, whereas only CPs considered other terms, e.g., ghost cells, useful. All groups interpreted certain terms, e.g., Heinz bodies, correctly, whereas some clinicians misinterpreted others, e.g., eccentrocytes. Responses revealed that CPs often do not report RBC-M they consider insignificant, when present in low numbers. Twenty-eight percent of clinicians think CPs review all blood smears while only 19% of CPs report reviewing all smears. CONCLUSIONS: Important differences about the clinical relevance of certain RBC-M terms exist between clinicians and CPs. Inclusion of interpretive comments on CBC reports is the clearest way to ensure that RBC-M changes are interpreted as intended by the CP. Reporting practices should be examined critically to improve communication, transparency, and ultimately medical decisions. PMID- 25280366 TI - Prevalence of Borrelia miyamotoi in Ixodes ticks in Europe and the United States. AB - Borrelia miyamotoi, a relapsing fever-related spirochete transmitted by Ixodes ticks, has been recently shown to be a human pathogen. To characterize the prevalence of this organism in questing Ixodes ticks, we tested 2,754 ticks for a variety of tickborne pathogens by PCR and electrospray-ionization mass spectrometry. Ticks were collected from California, New York, Connecticut, Pennsylvania, and Indiana in the United States and from Germany and the Czech Republic in Europe from 2008 through 2012. In addition, an isolate from Japan was characterized. We found 3 distinct genotypes, 1 for North America, 1 for Europe, and 1 for Japan. We found B. miyamotoi infection in ticks in 16 of the 26 sites surveyed, with infection prevalence as high as 15.4%. These results show the widespread distribution of the pathogen, indicating an exposure risk to humans in areas where Ixodes ticks reside. PMID- 25280368 TI - Raman spectroscopy study of calcium oxalate extracted from cacti stems. AB - To find markers that distinguish the different Cactaceae species, by using near infrared Raman spectroscopy and scanning electron microscopy, we studied the occurrence, in the stem, of solid deposits in five Cactaceae species (Coryphantha clavata, Ferocactus latispinus, Opuntia ficus-indica, O. robusta, and O. strepthacantha) collected from their natural habitats from a region of Mexico. The deposits in the tissues usually occurred as spheroidal aggregates, druses, or prismatic crystals. From the Raman spectra, the crystals were identified either as calcium oxalate monohydrate (CaC2O4.H2O) or calcium oxalate dihydrate (CaC2O4.2H2O). Opuntia species (subfamily Opuntioideae) showed the presence of CaC2O4.H2O, and the deposition of CaC2O4.2H2O was present in C. clavata and F. latispinus (subfamily Cactoideae, Cacteae tribe). As a punctual technique, Raman spectroscopy seems to be a useful tool to identify crystal composition. In addition to allowing the analysis of crystal morphology, this spectroscopic technique can be used to identify Cactaceae species and their chemotaxonomy. PMID- 25280369 TI - Design, synthesis, and antibacterial properties of dual-ligand inhibitors of acetyl-CoA carboxylase. AB - There is an urgent demand for the development of new antibiotics due to the increase in drug-resistant pathogenic bacteria. A novel target is the multifunctional enzyme acetyl-CoA carboxylase (ACC), which catalyzes the first committed step in fatty acid synthesis and consists of two enzymes: biotin carboxylase and carboxyltransferase. Covalently attaching known inhibitors against these enzymes with saturated hydrocarbon linkers of different lengths generated dual-ligand inhibitors. Kinetic results revealed that the dual-ligands inhibited the ACC complex in the nanomolar range. Microbiology assays showed that the dual-ligand with a 15-carbon linker did not exhibit any antibacterial activity, while the dual-ligand with a 7-carbon linker displayed broad-spectrum antibacterial activity as well as a decreased susceptibility in the development of bacterial resistance. These results suggest that the properties of the linker are vital for antibacterial activity and show how inhibiting two different enzymes with the same compound increases the overall potency while also impeding the development of resistance. PMID- 25280370 TI - Ultrasonic Fenton-like catalytic degradation of bisphenol A by ferroferric oxide (Fe3O4) nanoparticles prepared from steel pickling waste liquor. AB - In this study, Fe3O4 NPs (named as Fe3O4 NPs-PO) were prepared by steel pickling waste liquor to reduce the cost of preparation, and were compared with those obtained by the common co-precipitation method (named as Fe3O4 NPs-CP) which prepared from chemical reagent using BET, XRD, XPS, TEM and SEM techniques. The results indicated that Fe3O4 NPs-PO nanoparticles mainly existed in the form of Fe3O4 and appeared to be roughly spherical in shape with a size range of 20-50 nm. The heterogeneous Fenton-like catalytic capacity of Fe3O4 NPs-PO in US+Fe3O4+H2O2 system was comprehensively investigated. BPA could be degraded within a wide pH range of 7-10. The removal efficiencies of BPA were close to 100% and about 45% total organic carbon (TOC) in solution was eliminated at the optimized conditions. It was found that .OH radicals which mainly caused the degradation of BPA were promptly generated due to the catalysis of the Fe3O4 NPs PO. Furthermore, the comparative study of catalytic activity, stability and reusability between Fe3O4 NPs-PO and Fe3O4 NPs-CP showed that the two catalysts both remained good activity after several reaction cycles and no significant change in composition and structure was observed, the loss of catalyst was negligible, which demonstrated that Fe3O4 NPs-PO were promising in ultrasonic Fenton-like process to treat refractory organics. PMID- 25280371 TI - Construction of doxorubicin-loading magnetic nanocarriers for assaying apoptosis of glioblastoma cells. AB - Magnetic nanoparticles (MNPs), in comparison with traditional drug solutions or suspensions, represent a promising vehicle to achieve the controlled drug delivery to targeted cell/tissue regions in cancer treatment. In this study, the biodegradable chitosan-modified magnetite (Fe3O4) NPs (CS-MNPs) are firstly synthesized using as nanocarriers, and then encapsulated with anti-tumor drug doxorubicin (DOX) to construct DOX-loaded CS-MNPs (DOX-CS-MNPs), which are further applied to assay apoptosis of glioblastoma multiforme U251 cells. The properties of the DOX-CS-MNPs including particle size, shape and magnetization, are characterized. The stability, drug release, magnetic response and redispersion of the DOX-CS-MNPs within an external magnetic field are evaluated. Furthermore, the biological effects of the DOX-CS-MNPs on U251 glioblastoma cells, particularly cytotoxicity, cell viability, actin cytoskeleton and apoptosis rate, are subsequently investigated. The data show that the prepared DOX-CS-MNPs are spherical in shape with average diameter of 60 nm approximately. The fabricated DOX-CS-MNPs also exhibit specific properties including low aggregation, high saturation magnetization, satisfactory magnetic-responsive aggregation, and redispersion in water, etc. The biological assays show that the DOX-CS-MNPs can efficiently enter the cells, reduce cell viability, and inhibit cell proliferation in a dose-dependent manner, and a high rate of cell apoptosis is induced in U251 glioblastoma cells after DOX-CS-MNPs treatment. Therefore, the present results indicate that the constructed DOX-CS-MNPs may be a promising vehicle for efficiently inhibiting proliferation of human U251 glioblastoma cells. PMID- 25280367 TI - Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state nuclear magnetic resonance. AB - In Huntington's disease, expansion of a polyglutamine (polyQ) domain in the huntingtin (htt) protein leads to misfolding and aggregation. There is much interest in the molecular features that distinguish monomeric, oligomeric, and fibrillar species that populate the aggregation pathway and likely differ in cytotoxicity. The mechanism and rate of aggregation are greatly affected by the domains flanking the polyQ segment within exon 1 of htt. A "protective" C terminal proline-rich flanking domain inhibits aggregation by inducing polyproline II structure (PPII) within an extended portion of polyQ. The N terminal flanking segment (htt(NT)) adopts an alpha-helical structure as it drives aggregation, helps stabilize oligomers and fibrils, and is seemingly integral to their supramolecular assembly. Via solid-state nuclear magnetic resonance (ssNMR), we probe how, in the mature fibrils, the htt flanking domains impact the polyQ domain and in particular the localization of the beta-structured amyloid core. Using residue-specific and uniformly labeled samples, we find that the amyloid core occupies most of the polyQ domain but ends just prior to the prolines. We probe the structural and dynamical features of the remarkably abrupt beta-sheet to PPII transition and discuss the potential connections to certain htt-binding proteins. We also examine the htt(NT) alpha-helix outside the polyQ amyloid core. Despite its presumed structural and demonstrated stabilizing roles in the fibrils, quantitative ssNMR measurements of residue-specific dynamics show that it undergoes distinct solvent-coupled motion. This dynamical feature seems reminiscent of molten-globule-like alpha-helix-rich features attributed to the nonfibrillar oligomeric species of various amyloidogenic proteins. PMID- 25280372 TI - Removal of the antibiotic metronidazole by adsorption on various carbon materials from aqueous phase. AB - The adsorption of the antibiotic metronidazole (MNZ) on activated carbon (F400), activated carbon cloth (ACF), mesoporous activated carbon (CMK-3), and carbon nanotubes (MWCNT) was investigated in this work. The effect of the adsorbent adsorbate interactions as well as the operating conditions (ionic strength, solution pH, temperature, chemical modification of the adsorbents by HNO3 treatment, and water matrix) on the adsorption capacity were analyzed to substantiate the adsorption mechanism. The adsorption capacity markedly varied as function of the carbon material, decreasing in the following order: F400>ACF>F400 HNO3>CMK-3>MWCNT>MWCNT-HNO3, and depended not only on their surface area and pore size distribution, but also on their chemical nature. The adsorption of MNZ was influenced by the solution pH, but was not significantly affected by the ionic strength and temperature. The adsorption of MNZ was enhanced when the MNZ solutions were prepared using wastewater. Therefore, the electrolytes present in the wastewater cooperated rather than competed with the MNZ molecules for the adsorption sites. Desorption equilibrium data of MNZ on all carbon materials demonstrated that the adsorption was reversible corroborating the weakness of the adsorbent-adsorbate interactions. PMID- 25280373 TI - Using plate mapping to examine portion size and plate composition for large and small divided plates. AB - Does the size of a plate influence the serving of all items equally, or does it influence the serving of some foods - such as meat versus vegetables - differently? To examine this question, we used the new method of plate mapping, where people drew a meal on a paper plate to examine sensitivity to small versus large three-compartment divided plates in portion size and meal composition in a sample of 109 university students. The total drawn meal area was 37% bigger on large plates than small plates, which showed that the portion of plate coverage did not differ by plate size. Men and women drew bigger vegetable portions and men drew bigger meat portions on large plates when compared to small plates. These results suggest that men and women are differentially sensitive to plate size for overall meal size and for meal composition. Implications for decreasing portion size and improving meal balance are that plate size may influence portion size and change the proportions of foods served. PMID- 25280374 TI - Elemental analysis in biotechnology. AB - This article focuses on analytical strategies integrating atomic spectroscopy in biotechnology. The rationale behind developing such methods is inherently linked to unique features of the key technique in elemental analysis, which is inductively coupled plasma mass spectrometry: (1) the high sensitivity and selectivity of state of the art instrumentation, (2) the possibility of accurate absolute quantification even in complex matrices, (3) the capability of combining elemental detectors with chromatographic separation methods and the versatility of the latter approach, (4) the complementarity of inorganic and organic mass spectrometry, (5) the multi-element capability and finally (6) the capability of isotopic analysis. The article highlights the most recent bio-analytical developments exploiting these methodological advantages and shows the potential in biotechnological applications. PMID- 25280375 TI - Autologous resurfacing. AB - BACKGROUND: There is a discrepancy between the interest in joint-reconstructions and the current knowledge about the healing-processes involved. Major reconstructions are performed with osteosynthesized allografts and fresh allografts for cartilage. OBJECTIVES: The main question to be answered is: what do we know about metaphyseal and epiphyseal cancellous bone healing, contact healing of the subchondral bone and its influence on cartilage healing? Can we achieve healing of all four compartments in contact? PURPOSE: The purpose is to systematically investigate through animal testing the healing processes of metaphyseal and epiphyseal bone, including the subchondral bone and the healing of cartilage of press-fit-inserted grafts, considering nondemineralized high resolution histology. MATERIAL AND METHODS: Primary cancellous-bone healing of osteosynthesized hemi-osteotomies was studied in 13 canine tibial heads, the contact healing was investigated in 7 dogs and 18 giant-rabbits comparing contact healing of press-fit-inserted autologs cylindrical grafts with empty defects applying the wet-grinding diamond-technology. Bench-experiments on the epiphyseal bones of swine including pullout-tests of cylindrical grafts formed the basis for validation of that press-fit diamond technology. RESULTS: Primary metaphyseal and epiphyseal contact healing, including hyaline cartilage, was found in all compartments of the meta-and epiphysis in the precisely performed experiments. The press-fit principle, which employs cylindrical grafts and diamond instrumentation featuring a difference of 15/100 mm between graft and recipient bed, achieved high loads between 73.48 and 178.95 N (mean value 118.16 and standard deviation 32.79) in the pullout tests. CONCLUSION: Autologous press-fit grafting with alignment of the bony baseplate using wet-grinding precision has attained promising histo-morphological results. PMID- 25280376 TI - Carbon-, binder-, and precious metal-free cathodes for non-aqueous lithium-oxygen batteries: nanoflake-decorated nanoneedle oxide arrays. AB - Rechargeable lithium-oxygen (Li-O2) batteries have higher theoretical energy densities than today's lithium-ion batteries and are consequently considered to be an attractive energy storage technology to enable long-range electric vehicles. The main constituents comprising a cathode of a lithium-oxygen (Li-O2) battery, such as carbon and binders, suffer from irreversible decomposition, leading to significant performance degradation. Here, carbon- and binder-free cathodes based on nonprecious metal oxides are designed and fabricated for Li-O2 batteries. A novel structure of the oxide-only cathode having a high porosity and a large surface area is proposed that consists of numerous one-dimensional nanoneedle arrays decorated with thin nanoflakes. These oxide-only cathodes with the tailored architecture show high specific capacities and remarkably reduced charge potentials (in comparison with a carbon-only cathode) as well as excellent cyclability (250 cycles). PMID- 25280377 TI - Forensic miRNA: potential biomarker for body fluids? AB - In forensic investigation, body fluids represent an important support to professionals when detected, collected and correctly identified. Through many years, various approaches were used, namely serology-based methodologies however, their lack of sensitivity and specificity became difficult to set aside. In order to sidetrack the problem, miRNA profiling surged with a real potential to be used to identify evidences like urine, blood, menstrual blood, saliva, semen and vaginal secretions. MiRNAs are small RNA structures with 20-25 nt whose proprieties makes them less prone to degradation processes when compared to mRNA which is extremely important once, in a crime scene, biological evidences might be exposed to several unfavorable environmental factors. Recently, published studies were able to identify some specific miRNAs, however their results were not always reproducible by others which can possibly be the reflection of different workflow strategies for their profiling studies. Given the current blast of interest in miRNAs, it is important to acknowledge potential limitations of miRNA profiling, yet, the lack of such studies are evident. This review pretends to gather all the information to date and assessed a multitude of factors that have a potential aptitude to discrediting miRNA profiling, such as: methodological approaches, environmental factors, physiological conditions, gender, pathologies and samples storage. It can be asserted that much has yet to be made, but we pretend to highlight a potential answer for the ultimate question: Can miRNA profiling be used as the forensic biomarker for body fluids identification? PMID- 25280378 TI - Robust detection of individual forensic profiles in DNA mixtures. AB - For a forensic identification method to be admissible in international courts, the probability of false match must be quantified. For comparison of individuals against complex mixtures using a panel of single nucleotide polymorphisms (SNPs), the probability of a random man not excluded, P(RMNE) is one admissible standard. While the P(RMNE) of SNP alleles has been previously studied, it remains to be rigorously defined and calculated for experimentally genotyped mixtures. In this report, exact P(RMNE) values were calculated for a range of complex mixtures, verified with Monte Carlo simulations, and compared alongside experimentally determined detection probabilities. PMID- 25280379 TI - Long D13S317 variant allele: a cautionary case report. AB - Exclusion at locus D13S317 between a father and child was observed in a kinship case, which at first glance appeared as a silent allele. However, a closer inspection using three commercial kits showed that the observed pattern is due to a long variant allele overlapping with different loci in different kits. Sequencing of the variant revealed a duplication within D13S317, that had also created an additional binding site for short amplicon reverse primer. If ignored, genotyping results including this variant may be wrongly interpreted. PMID- 25280380 TI - Risk factors for human lice and bartonellosis among the homeless, San Francisco, California, USA. AB - Homeless persons in San Francisco, California, USA,have been shown to have head and body lice infestations and Bartonella quintana infections. We surveyed a self selected population of homeless persons in San Francisco to assess infestations of head and body lice, risks of having body lice, and presence of B. quintana in lice. A total of 203 persons who reported itching were surveyed during 2008-2010 and 2012: 60 (30%) had body lice, 10 (4.9%)had head lice, and 6 (3.0%) had both. B. quintana was detected in 10 (15.9%) of 63 body lice pools and in 6 (37.5%)of 16 head lice pools. Variables significantly associated(p<0.05) with having body lice in this homeless population included male sex, African-American ethnicity, and sleeping outdoors. Our study findings suggest that specific segments of the homeless population would benefit from information on preventing body lice infestations and louse borne diseases. PMID- 25280381 TI - Floating growth of large-scale freestanding TiO2 nanorod films at the gas-liquid interface for additive-free Li-ion battery applications. AB - The floating growth process of large-scale freestanding TiO2 nanorod films at the gas-liquid interface was investigated. On the basis of the experiments, a self templated growth scenario was developed to account for the self-assembly process. In the scenario, titanium complexes function not only as the Ti source for the growth of TiO2 but also as a soft template provider for the floating growth. According to the scenario, several new recipes of preparing freestanding TiO2 nanorod films at the gas-liquid interface were developed. The freestanding film was applied to a lithium ion battery as a binder-free and conducting agent-free anode, and good cyclability was obtained. This work may pave a new way to floating and freestanding TiO2 and other semiconductor materials, which has great potential not only in basic science but also in the applications such as materials engineering, Li-ion battery, photocatalyst, dye-sensitized solar cell, and flexible electronics. PMID- 25280382 TI - Hollow Co(0.85)Se nanowire array on carbon fiber paper for high rate pseudocapacitor. AB - A supercapacitor electrode is fabricated with Co0.85Se hollow nanowires (HNW) array, which is synthesized by wet chemical hydrothermal selenization of initially grown cobalt hydroxyl carbonate nanowires on conductive CFP. The dense self-organized morphology of Co0.85Se HNWs is revealed by scanning/transmission electron microscopy. The as-synthesized Co0.85Se HNWs possess high pseudocapacitive property with high capacitance retention and high durability. The areal capacitance value is seen to vary from 929.5 to 600 mF cm(-2) (60% retention) as the current density is increased from 1 to 15 mA cm(-2), an increase of a factor of 15. Based on mass loading, this corresponds to a very high gravimetric capacitance of 674 (for 2 mA cm(-2) or 1.48 Ag(-1)) and 444 Fg(1 ) (for 15 mA cm(-2) or 11 A g(-1)) in a full-cell configuration with the Co0.85Se HNWs as cathode and activated carbon as anode (asymmetric configuration) promising results are obtained. PMID- 25280383 TI - Case report: Time of death estimation of a buried body by modeling a decomposition matrix for a pig carcass. AB - Estimating time of death of buried human bodies is a very difficult task. Casper's rule from 1860 is still widely used which illustrates the lack of suitable methods. In this case study excavations in an arbor revealed the crouching body of a human being, dressed only in boxer shorts and socks. Witnesses were not able to generate a concise answer as to when the person in question was last seen alive; the pieces of information opened a window of 2-6 weeks for the possible time of death. To determine the post mortem interval (PMI) an experiment using a pig carcass was conducted to set up a decomposition matrix. Fitting the autopsy findings of the victim into the decomposition matrix yielded a time of death estimation of 2-3 weeks. This time frame was later confirmed by a new witness. The authors feel confident that a widespread conduction of decomposition matrices using pig carcasses can lead to a great increase of experience and knowledge in PMI estimation of buried bodies and will eventually lead to applicable new methods. PMID- 25280384 TI - Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways. AB - BACKGROUND: Diabetes mellitus is the most common chronic endocrine disorder, affecting an estimated population of 382 million people worldwide. It is associated with microvascular and macrovascular complications, including diabetic nephropathy (DN); primary cause of end-stage renal disease. Different inflammatory and angiogenic molecules in various pathways are important modulators in the pathogenesis and progression of diabetic nephropathy. Differential disease risk in DN may be partly attributable to genetic susceptibility. In this meta-analysis, we aimed to determine which of the previously investigated genetic variants in these pathways are significantly associated with the development of DN and to examine the functional role of these genes. METHODS: A systematic search was conducted to collect and analyze all studies published till June 2013; that investigated the association between genetic variants involved in inflammatory cytokines and angiogenesis and diabetic nephropathy. Genetic variants associated with DN were selected and analyzed by using Comprehensive Meta Analysis software. Pathway analysis of the genes with variants showing significant positive association with DN was performed using Genomatix Genome Analyzer (Genomatix, Munich, Germany). RESULTS: After the inclusion and exclusion criteria for this analysis, 34 studies were included in this meta-analysis. 11 genetic variants showed significant positive association with DN in a random-effects meta-analysis. These included genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10. rs1800871 (T) genetic variant in IL-10 showed protective effect for DN. Most of these eleven genetic variants were involved in GPCR signaling and receptor binding pathways whereas four were involved in chronic kidney failure. rs833061 [OR 2.08 (95% CI 1.63-2.66)] in the VEGFA gene and rs3917887 [OR 2.04 (95% CI 1.64-2.54)] in the CCL2 gene showed the most significant association with the risk of diabetic nephropathy. CONCLUSIONS: Our results indicate that 11 genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10 showed significant positive association with diabetic nephropathy. Gene Ontology or pathway analysis showed that these genes may contribute to the pathophysiology of DN. The functional relevance of the variants and their pathways can lead to increased biological insights and development of new therapeutic targets. PMID- 25280385 TI - Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations. AB - BACKGROUND: Anaphylaxis-related deaths in the United States have not been well characterized in recent years. OBJECTIVES: We sought to define epidemiologic features and time trends of fatal anaphylaxis in the United States from 1999 to 2010. METHODS: Anaphylaxis-related deaths were identified by using the 10th clinical modification of the International Classification of Diseases system diagnostic codes on death certificates from the US National Mortality Database. Rates were calculated by using census population estimates. RESULTS: There were a total of 2458 anaphylaxis-related deaths in the United States from 1999 to 2010. Medications were the most common cause (58.8%), followed by "unspecified" (19.3%), venom (15.2%), and food (6.7%). There was a significant increase in fatal drug-induced anaphylaxis over 12 years: from 0.27 (95% CI, 0.23-0.30) per million in 1999 to 2001 to 0.51 (95% CI, 0.47-0.56) per million in 2008 to 2010 (P < .001). Fatal anaphylaxis caused by medications, food, and unspecified allergens was significantly associated with African American race and older age (P < .001). Fatal anaphylaxis to venom was significantly associated with white race, older age, and male sex (P < .001). The rates of fatal anaphylaxis to foods in male African American subjects increased from 0.06 (95% CI, 0.01-0.17) per million in 1999 to 2001 to 0.21 (95% CI, 0.11-0.37) per million in 2008 to 2010 (P < .001). The rates of unspecified fatal anaphylaxis decreased over time from 0.30 (95% CI, 0.26-0.34) per million in 1999 to 2001 to 0.09 (95% CI, 0.07-0.11) per million in 2008 to 2010 (P < .001). CONCLUSION: There are strong and disparate associations between race and specific classes of anaphylaxis-related mortality in the United States. The increase in medication-related deaths caused by anaphylaxis likely relates to increased medication and radiocontrast use, enhanced diagnosis, and coding changes. PMID- 25280386 TI - Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. AB - OBJECTIVE: More tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC. MATERIALS AND METHODS: From December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (<75 years, 75-84 years, >=85 years). Kaplan Meier methodology was used to estimate median progression-free survival (PFS). Safety data were collected with a focus on interstitial lung disease (ILD). RESULTS: A total of 9907 patients were eligible for safety assessment (<75 years, n=7848; 75-84 years, n=1911; >=85 years, n=148) and 9651 for efficacy assessment (<75 years, n=7701; 75-84 years, n=1815; >=85 years, n=135). Other baseline characteristics were balanced. The incidence of ILD (all grades) was 4.2% (<75 years), 5.1% (75-84 years), and 3.4% (>=85 years). The mortality rate due to ILD was <=1.7% in all age groups. Other toxicities (including rash) were similar between age groups. The median PFS was 65 days (95% confidence interval [CI], 62 68) for patients aged <75 years, 74 days (95% CI, 69-82) for patients aged 75-84 years, and 72 days (95% CI, 56-93) for patients aged >=85 years. CONCLUSIONS: Efficacy and tolerability of erlotinib for elderly patients was not numerically inferior to that reported in younger patients. Erlotinib could be considered for elderly patients with recurrent/advanced NSCLC. PMID- 25280387 TI - Potentially avoidable blood transfusion during trauma resuscitation. AB - INTRODUCTION: Red blood cell (RBC) transfusion is often essential during trauma resuscitation but is associated with high cost and potential adverse outcomes. This study aimed to determine the incidence of potentially avoidable RBC transfusions (PAT) among adult major trauma patients. MATERIALS AND METHODS: A retrospective review of data collected by Registry on patients presenting between Jan 2006 and Dec 2011 was conducted. Eligible patients received at least 1 unit of RBC in the first 24h following presentation to the Emergency Department (ED). Episodes of PAT were determined according to haemodynamic stability and post-transfusion haemoglobin levels. RESULTS: There were 621 patients included, of whom 224 (36.1%; 95% CI: 32.3-40.0) received PAT. Of them, 132 (58.9%) were haemodynamically stable on arrival and did not require a surgical procedure. Patients with PAT had significantly lower injury severity scores (30 vs 34, p<0.01), higher presenting systolic blood pressure (129 vs 112mm Hg, p<0.01) and a lower frequency of a shock index >=1 (24.1 vs 65.0%, p<0.01), compared to those without PAT. They also had a significantly lower mortality (13.4 vs 21.7%, p<0.01). CONCLUSIONS: PAT after trauma was common and often delivered to haemodynamically stable patients who did not require surgical procedures. Clinical decision pathways for trauma resuscitation should aim to limit PAT. PMID- 25280388 TI - The power of positive messages. PMID- 25280389 TI - How to evaluate a private practice radiology job offer. PMID- 25280390 TI - Impact of psychosocial factors on cardiovascular morbimortality: a prospective cohort study. AB - BACKGROUND: Whilst it is well known that psychosocial determinants may contribute to cardiovascular diseases (CVD), data from specific groups are scarce. The present study aims to determine the contribution of psychosocial determinants in increasing the risk of cardiovascular events (myocardial infarction and stroke), and death from CVD, in a high risk adult population. METHODS: Longitudinal prospective study of 7263 patients (57.5% women), mean age 67.0 (SD 6.2) free from CVD but at high risk, with a median follow-up of 4.8 years (from October 2003 to December 2010). The Hazard Ratios (HRs) of cardiovascular events (myocardial infarction, stroke, and death from cardiovascular causes) related to educational attainment, diagnosed depression (based on medical records), and low social support (number of people living in the household) were estimated by multivariate Cox regression models. RESULTS: Stroke incidence was associated with low educational level in the whole population (HR: 1.83, 95% CI: 1.09-3.09), and especially in men (HR: 2.11, 95% CI 1.09-4.06). Myocardial infarction and CVD mortality were not associated with any of the psychosocial factors considered. CONCLUSION: Adults with low educational level had a higher risk of stroke. Depression and low social support were not associated with CVD incidence. TRIAL REGISTRATION: Clinical trial registration information unique identifier: ISRCTN35739639. PMID- 25280391 TI - Retrospective study of canine heartworm disease with caval syndrome in Grenada, West Indies. AB - Canine heartworm disease caused by Dirofilaria immitis is an important disease of dogs. The aim of this retrospective study was to estimate the prevalence of canine heartworm disease and evaluate cases of caval syndrome in dogs submitted for necropsy in Grenada. Out of 1617 dogs necropsied over a period of 13 years (2001-2013), 249 were found to be infected with D. immitis; giving an overall prevalence of 15.4% (95% confidence interval, 13.6% to 17.1%). There was no significant difference between male and female dogs with respect to canine heartworm infection (p = 0.3). During this period, the annual prevalence of canine heartworm disease was 22% in 2001 before slightly declining to an average of 18% in 2002-2003 and peaking at 26.8% in 2004-2005. From 2006 onwards, annual prevalence rates have steadily been decreasing; reaching the lowest (9%) in 2013. Among the 249 positive cases, 33 (13.2%) of the dogs had caval syndrome. Caval syndrome cases presented with concurrent clinical signs and were associated with cardio-pulmonary and hepatic gross lesions at necropsy. Aberrant migration of D. immitis was also noted in 2 dogs with caval syndrome. This is the first report which presents the findings of canine heartworm disease with caval syndrome in Grenada. PMID- 25280393 TI - Structural investigation of the cold-adapted acylaminoacyl peptidase from Sporosarcina psychrophila by atomistic simulations and biophysical methods. AB - Protein structure and dynamics are crucial for protein function. Thus, the study of conformational properties can be very informative for characterizing new proteins and to rationalize how residue substitutions at specific protein sites affect its dynamics, activity and thermal stability. Here, we investigate the structure and dynamics of the recently isolated cold-adapted acylaminoacyl peptidase from Sporosarcina psychrophila (SpAAP) by the integration of simulations, circular dichroism, mass spectrometry and other experimental data. Our study notes traits of cold-adaptation, such as lysine-to-arginine substitutions and a lack of disulphide bridges. Cold-adapted enzymes are generally characterized by a higher number of glycine residues with respect to their warm-adapted counterparts. Conversely, the SpAAP glycine content is lower than that in the warm-adapted variants. Nevertheless, glycine residues are strategically located in proximity to the functional sites in SpAAP, such as the active site and the linker between the two domains.. In particular, G457 reduces the steric hindrance around the nucleophile elbow. Our results suggest a local weakening of the intramolecular interactions in the cold-adapted enzyme. This study offers a basis for the experimental mutagenesis of SpAAP and related enzymes. The approaches employed in this study may also provide a more general framework to characterize new protein structures in the absence of X-ray or NMR data. PMID- 25280394 TI - Simultaneous characterization of sequence polymorphisms, glycosylation and phosphorylation of fibrinogen in a direct analysis by LC-MS. AB - Fibrinogen is an abundant plasma glycoprotein involved in pathologically important processes like blood clotting, hemostasis and angiogenesis. Sequence polymorphisms and posttranslational modification (PTM) status of fibrinogen are important factors of cardiovascular disease. We aim for the simultaneous analysis of fibrinogen subunits for sequence polymorphisms (SNPs), phosphorylation and glycosylation by top-down mass spectrometry. Fibrinogen was isolated from human plasma of twelve individuals and subunits of fibrinogen were separated by RP-HPLC and subsequently analyzed by high resolution ESI mass spectrometry. Two coding single nucleotide polymorphisms on the Aalpha- and Bbeta-subunit could be identified on the basis of their mass shifts: Three individuals are heterozygous and two are homozygous for Thr312Ala on the Aalpha-subunit, three individuals are heterozygous for Arg448Lys on the Bbeta-subunit. For the Aalpha-subunit we find mono- and diphosphorylation amounting to about 55% to 71% and O-glycosylation (likely sialyl-T-antigen) from 10% to 17%. N-glycosylation is present with one or two sialic acids in a ratio of about 3:2 and 3:1 for the Bbeta and the gamma subunit, respectively. Both SNPs and the PTMs are associated with fibrinogen levels, clotting behavior and thus the risk for cardiovascular diseases. The homozygosity of the SNP at position 312 in the alpha chain for example nearly doubles the risk for ischemic stroke. Isolation and analysis of fibrinogen can be achieved in a few hours from only one drop of blood plasma, and thus the method presented here should assist in a quick assessment and prevention of stroke and infarction. PMID- 25280395 TI - Revision of type III and type IVB acetabular defects with Burch-Schneider anti Protrusio cages. AB - Extensive bone loss in severe acetabular deficiencies can make repair with acetabular shells impossible. We retrospectively analyzed mid-term to long-term results of acetabular revision with Burch-Schneider reinforcement cages in 33 hips in patients with a mean age of 59.03years after a mean follow-up period of 6.19years. Under the American Academy of Orthopaedic Surgeons classification, 9 patients had type III acetabular bone defects and 24 had type IVB. Merle D'Aubigne scores improved by a mean of 9.3 points. The prosthesis failure rate was 15.1%, the series complication rate was 21.2%, and the mean survivorship was 11.57years. The Burch-Schneider cage is useful for reconstruction in massive acetabular deficiency, but complication rates are high and long-term mechanical failure is a concern. PMID- 25280392 TI - Risk of neuroblastoma, maternal characteristics and perinatal exposures: the SETIL study. AB - PURPOSE: Neuroblastoma (NB) is the most common extra-cranial paediatric solid tumour. Incidence peaks in infancy, suggesting a role of in-utero and neonatal exposures but its aetiology is largely unknown. The aim of the present study is to evaluate the association between maternal characteristics and perinatal factors with the risk of NB, using data from the SETIL database. METHODS: SETIL is a large Italian population-based case-control study established to evaluate several potential cancer risk factors in 0-10 year olds. Information about maternal characteristics, reproductive history, environmental and occupational exposures during pregnancy, as well as newborns' characteristics were obtained using a structured questionnaire. Extremely low frequency magnetic field (ELF-MF) home exposure was measured. The study included 1044 healthy controls and 153 NB cases, diagnosed between 1998 and 2001. RESULTS: A twofold risk was associated to exposure in pregnancy to chemical products for domestic work and to hair dye. The risk associated with the latter was higher among 0-17 month old children (OR = 5.5, 95%CI: 1.0-29.3). Risk was increased for children whose mothers had suffered work related exposure in the preconception period to solvents (OR = 2.0 95%CI: 1.0-4.1) and in particular to aromatic hydrocarbons (OR = 9.2, 95%CI: 2.4-34.3). No association was observed with ELF-MF exposure. A higher risk was found among children with congenital malformations (OR = 4.9, 95%CI: 1.8-13.6) or neurofibromatosis (2 cases and 0 controls, p = 0.016). CONCLUSIONS: Our study suggests maternal exposure to hair dyes and aromatic hydrocarbons plays a role and deserves further investigation. The association with congenital malformations might also be explained by over-diagnosis. External exposure, in particular during and before pregnancy might contribute to NB occurrence. PMID- 25280396 TI - Changes in bone mineral density and femoral neck narrowing in the proximal femur three to five years after hip resurfacing versus conventional total hip arthroplasty. AB - We studied whether bone mineral density (BMD) is preserved without significant femoral neck narrowing (FNN) after hip resurfacing (RHA) (n=42) versus small diameter metal-on-metal total hip arthroplasty (MoM THA) (n=40). In this three to five year randomized trial BMD was measured in the calcar with dual energy absorptiometry (DXA) preoperatively, at three and six months, one, two, three and five years postoperatively. Four additional BMD regions of interest (ROIs) and femoral neck narrowing (FNN) were measured after RHA. BMD in the calcar increased to 107% (P<0.001) at one year and remained stable. Additional ROIs in the femoral neck and trochanter-area BMD changes fluctuated between 99.9% and 104.1%. FNN was minimal with a mean of 1.3% at three years. After THA BMD decreased in the calcar to 80% at one year (P<0.001) and stabilized. This bone stock preserving nature of RHA must be weighed against potential disadvantages caused by specific metal-on metal bearing problems. PMID- 25280397 TI - Fed-batch fermentation for enhanced lactic acid production from glucose/xylose mixture without carbon catabolite repression. AB - There has been tremendous growth in the production of optically pure l-lactic acid from lignocellulose-derived sugars. In this study, Enterococcus mundtii QU 25 was used to ferment a glucose/xylose mixture to l-lactic acid. Maintenance of the xylose concentration at greater than 10 g/L achieved homo-lactic acid fermentation and reduced the formation of byproducts. Furthermore, carbon catabolite repression (CCR) was avoided by maintaining the glucose concentration below 25 g/L; therefore, initial concentrations of 25 g/L glucose and 50 g/L xylose were selected. Supplementation with 5 g/L yeast extract enhanced the maximum xylose consumption rate and consequently increased lactic acid production and productivity. Finally, a 129 g/L lactic acid without byproducts was obtained with a maximum lactic acid productivity of 5.60 g/(L.h) in fed-batch fermentation with feeding a glucose/xylose mixture using ammonium hydroxide as the neutralizing agent. These results indicate a potential for lactic acid production from glucose and xylose as the main components of lignocellulosic biomasses. PMID- 25280398 TI - Pioglitazone reduces lipid droplets in cholesterolosis of the gallbladder by increasing ABCA1 and NCEH1 expression. AB - As a cholesterol-induced metabolic disease, cholesterolosis of the gallbladder is often resected clinically, which could lead to many complications. The histopathology of cholesterolosis is due to excessive lipid droplet accumulation in epithelial and subcutaneous tissues. The main components of lipid droplets are cholesterol esters (CEs). Removal of CEs from gallbladder epithelial cells (GBECs) is very important for maintaining intracellular cholesterol homeostasis and for treating cholesterol-related diseases. In this study, pioglitazone was used to reduce intracellular CEs. To further elucidate the mechanism, cholesterolosis GBECs were treated with pioglitazone, 22-(R)-hydroxycholesterol (a liver X receptor alpha (LXRalpha) agonist), or peroxisome proliferator activated receptor gamma (PPARgamma) siRNA. Western blotting for PPARgamma, LXRalpha, ATP-binding cassette transporter A1 (ABCA1), and neutral cholesteryl ester hydrolase 1 (NCEH1) was performed. At length, cholesterol efflux to apoA-I was measured, and oil red O staining was used to visualize lipid droplet variations in cells. In conclusion, we observed that pioglitazone increased ABCA1 expression in an LXR-dependent manner and NCEH1 expression in an LXRalpha independent manner, which mobilized CE hydrolysis and cholesterol efflux to reduce lipid droplet content in cholesterolosis GBECs. Our data provide a plausible alternative to human gallbladder cholesterolosis. PMID- 25280399 TI - Transcript expression of the freeze responsive gene fr10 in Rana sylvatica during freezing, anoxia, dehydration, and development. AB - Freeze tolerance is a critical winter survival strategy for the wood frog, Rana sylvatica. In response to freezing, a number of genes are upregulated to facilitate the survival response. This includes fr10, a novel freeze-responsive gene first identified in R. sylvatica. This study analyzes the transcriptional expression of fr10 in seven tissues in response to freezing, anoxia, and dehydration stress, and throughout the Gosner stages of tadpole development. Transcription of fr10 increased overall in response to 24 h of freezing, with significant increases in expression detected in testes, heart, brain, and lung when compared to control tissues. When exposed to anoxia; heart, lung, and kidney tissues experienced a significant increase, while the transcription of fr10 in response to 40% dehydration was found to significantly increase in both heart and brain tissues. An analysis of the transcription of fr10 throughout the development of the wood frog showed a relatively constant expression; with slightly lower transcription levels observed in two of the seven Gosner stages. Based on these results, it is predicted that fr10 has multiple roles depending on the needs and stresses experienced by the wood frog. It has conclusively been shown to act as a cryoprotectant, with possible additional roles in anoxia, dehydration, and development. In the future, it is hoped that further knowledge of the mechanism of action of FR10 will allow for increased stress tolerance in human cells and tissues. PMID- 25280400 TI - Transcriptional and antioxidative responses to endogenous polyunsaturated fatty acid accumulation in yeast. AB - Pathophysiology of polyunsaturated fatty acids (PUFAs) is associated with aberrant lipid and oxygen metabolism. In particular, under oxidative stress, PUFAs are prone to autocatalytic degradation via peroxidation, leading to formation of reactive aldehydes with numerous potentially harmful effects. However, the pathological and compensatory mechanisms induced by lipid peroxidation are very complex and not sufficiently understood. In our study, we have used yeast capable of endogenous PUFA synthesis in order to understand the effects triggered by PUFA accumulation on cellular physiology of a eukaryotic organism. The mechanisms induced by PUFA accumulation in S. cerevisiae expressing Hevea brasiliensis Delta12-fatty acid desaturase include down-regulation of components of electron transport chain in mitochondria as well as up-regulation of pentose-phosphate pathway and fatty acid beta-oxidation at the transcriptional level. Interestingly, while no changes were observed at the transcriptional level, activities of two important enzymatic antioxidants, catalase and glutathione-S-transferase, were altered in response to PUFA accumulation. Increased intracellular glutathione levels further suggest an endogenous oxidative stress and activation of antioxidative defense mechanisms under conditions of PUFA accumulation. Finally, our data suggest that PUFA in cell membrane causes metabolic changes which in turn lead to adaptation to endogenous oxidative stress. PMID- 25280401 TI - Investigation of bn-44 peptide fragments using high resolution mass spectrometry and isotope labeling. AB - An N-terminal deuterohemin-containing hexapeptide (DhHP-6) was designed as a short peptide cytochrome c (Cyt c) mimetic to study the effect of N-terminal charge on peptide fragmentation pathways. This peptide gave different dissociation patterns than normal tryptic peptides. Upon collision-induced dissociation (CID) with an ion trap mass spectrometer, the singly charged peptide ion containing no added proton generated abundant and characteristic bn-44 ions instead of bn-28 (an) ions. Studies by high resolution mass spectrometry (HRMS) and isotope labeling indicate that elimination of 44 Da fragments from b ions occurs via two different pathways: (1) loss of CH3CHO (44.0262) from a Thr side chain; (2) loss of CO2 (43.9898) from the oxazolone structure in the C-terminus. A series of analogues were designed and analyzed. The experimental results combined with Density Functional Theory (DFT) calculations on the proton affinity of the deuteroporphyrin demonstrate that the production of these novel bn-44 ions is related to the N-terminal charge via a charge-remote rather than radical directed fragmentation pathway. PMID- 25280402 TI - A co-culture model with brain tumor-specific bioluminescence demonstrates astrocyte-induced drug resistance in glioblastoma. AB - BACKGROUND: Although several studies suggest that stromal fibroblasts mediate treatment resistance in several cancer types, little is known about how tumor associated astrocytes modulate the treatment response in brain tumors. Since traditionally used metabolic assays do not distinguish metabolic activity between stromal and tumor cells, and since 2-dimensional co-culture system does not recreate the formidable complexity of the microenvironment within 3-dimensional structures such as solid tumor tissue, we instead established a glioblastoma (GBM) cell-specific bioluminescent assay for direct measurements of tumor cell viability in the treatment of clinical relevant drugs. METHODS: Using lentiviral transfection, we established a panel of human GBM cell lines constitutively expressing a fusion transgene encoding luciferase and the enhanced green fluorescence protein (eGFP). We then initiated co-cultures with immortalized astrocytes, TNC-1, and the eGFP/Luc GBM cell lines. Next, we treated all eGFP/Luc GBM cell lines with Temozolomide (TMZ) or Doxorubicin, comparing co-cultures of glioblastoma (GBM) cells and TNC-1 astrocytes with mono-cultures of eGFP/Luc GBM cells. Cell viability was quantitated by measuring the luciferase expression. RESULTS: Titration experiments demonstrated that luciferase expression was proportional to the number of eGFP/Luc GBM cells, whereas it was not influenced by the number of TNC-1 cells present. Notably, the presence of TNC-1 astrocytes mediated significantly higher cell survival after TMZ treatment in the U251, C6, A172 cell lines as well as the in vivo propagated primary GBM tumor cell line (P3). Moreover, TNC-1 astrocytes mediated significantly higher survival after Doxorubicin treatment in the U251, and LN18 glioma cell lines. CONCLUSION: Glioma cell-specific bioluminescent assay is a reliable tool for assessment of cell viability in the brain tumor cell compartment following drug treatment. Moreover, we have applied this assay to demonstrate that astrocytes can modulate chemo sensitivity of GBM tumor cells. These effects varied both with the cell line and cytotoxic drug that were used, suggesting that several mechanisms may be involved. PMID- 25280403 TI - Does maternal diet during pregnancy and lactation affect outcomes in offspring? A systematic review of food-based approaches. AB - OBJECTIVES: The aim of this study was to investigate the relationship between maternal diet during pregnancy and lactation and development of atopic disorders in childhood. METHODS: We included studies published up to August 2011 that assessed food-based maternal dietary interventions or that examined associations between maternal dietary intake during pregnancy and/or lactation and allergic outcomes (eczema, asthma, hay fever, and sensitization) in their children. RESULTS: We included 42 studies (>40 000 children): 11 intervention studies (including 7 randomized control trials), 26 prospective cohort studies, 4 retrospective cohort studies, and 1 case-control study. In the randomized control trials, no significant difference was noted overall in the prevalence of eczema and asthma in the offspring of women on diets free from common food allergens during pregnancy. The prospective cohorts investigated a large number of potential associations, but reported few significant associations between maternal dietary intake and development of allergy. Maternal diets rich in fruits and vegetables, fish, and foods containing vitamin D and Mediterranean dietary patterns were among the few consistent associations with lower risk for allergic disease in their children. Foods associated with higher risk included vegetable oils and margarine, nuts, and fast food. CONCLUSION: This review did not find widespread or consistent links between mothers' dietary intake and atopic outcomes in their children. However, maternal consumption of Mediterranean dietary patterns, diets rich in fruits and vegetables, fish, and vitamin D containing foods were suggestive of benefit, requiring further evaluation. PMID- 25280405 TI - Quercetin bioavailability is associated with inadequate plasma vitamin C status and greater plasma endotoxin in adults. AB - OBJECTIVE: Quercetin bioavailability exhibits high interindividual variation for reasons that remain unclear. We conducted a 24-h pharmacokinetic study to investigate whether individual differences in circulating antioxidants, oxidative stress and inflammation, and intestinal permeability affect quercetin bioavailability. METHODS: Healthy adults (n = 9 M/7 F; 34.3 +/- 4.5 y; 27.0 +/- 1.7 kg/m(2)) ingested 1095 mg quercetin aglycone with a standardized meal. Plasma antioxidants, biomarkers of oxidative stress and inflammation, and endotoxin were measured at baseline (0 h), and quercetin and its methylated metabolites isorhamnetin and tamarixetin were measured at timed intervals for 24 h. RESULTS: Plasma pharmacokinetics of quercetin, isorhamnetin and tamarixetin were highly variable between participants (CVinter = 37-96%). Plasma vitamin C concentrations (34.6 +/- 2.5 MUmol/L), but no other antioxidants, were inversely correlated to the Cmax and AUC0 to 24 h of total quercetin (Qtotal; sum of quercetin, isorhamnetin and tamarixetin; r = -0.52 to -0.53; P < 0.05). Plasma endotoxin (0.13 +/- 0.01 EU/mL), a surrogate marker of intestinal permeability, was correlated to Qtotal Cmax (r = 0.45; P < 0.05) and tended to be correlated to Qtotal AUC0 to 24 h (r = 0.38; P = 0.07). Additionally, vitamin C was inversely related to C-reactive protein, myeloperoxidase, and endotoxin (r = -0.46 to 0.55; P < 0.05), whereas endotoxin was positively correlated to C-reactive protein (r = 0.73; P < 0.05). CONCLUSIONS: These findings suggest that vitamin C status and plasma endotoxin may be associated with interindividual variations in quercetin bioavailability. Greater quercetin absorption and bioavailability may be associated with poor vitamin C status and increased intestinal permeability in healthy adults. PMID- 25280404 TI - Colon carcinogenesis: influence of Western diet-induced obesity and targeting stem cells using dietary bioactive compounds. AB - Colon cancer strikes more than 1 million people annually and is responsible for more than 500,000 cancer deaths worldwide. Recent evidence suggests that the majority of malignancies, including colon cancer are driven by cancer stem cells (CSCs) that are resistant to current chemotherapeutic approaches leading to cancer relapse. Wnt signaling plays a critical role in colon stem cell renewal and carcinogenesis. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a Wnt target gene, and aldehyde dehydrogenase 1 B1 (ALDH1B1) are good markers for normal and malignant human colon stem cells. Diet contributes to 20% to 42% of all human cancers and 50% to 90% of colon cancer. Recent evidence shows that the Western diet has a causative link to colon cancer; however, mechanisms of action are not fully elucidated. Western diet-induced obesity elevates systemic insulin-like growth factor-1 and insulin levels, which could lead to elevated proliferation and suppressed apoptosis of CSCs through PI3K/AKT/Wnt pathway. Although conventional chemotherapy targets the PI3K/AKT pathways and can significantly reduce tumor size, it fails to eliminate CSCs and has serious side effects. Dietary bioactive compounds such as grape seed extract, curcumin, lycopene, and resveratrol have promising chemopreventive effects, without serious side effects on various types of cancers due to their direct and indirect actions on CSC self-renewal pathways such as the Wnt pathway. Understanding the role of CSCs in diet-induced colon cancer will aid in development of evidence-based dietary chemopreventive strategies and/or therapeutic agents targeting CSCs. PMID- 25280406 TI - Design and validation of a program to identify inadequate intake of iron, zinc, and vitamin A. AB - OBJECTIVE: The aim of this study was to create an innovative, easy-to-use, and informative web-based application system to calculate the iron, zinc, and vitamin A intake in comparison to the recommended nutrient intake (RNI). METHODS: Food survey data on commonly consumed Indonesian foods (122 foods) were recorded from 68,800 households. The data were used to extract 13 relevant food groups representing typical Indonesian dietary patterns and were incorporated into the development of new software called the Calculator of Inadequate Micronutrient Intake (CIMI). To validate, 24-h dietary recall data of children (n = 118) and adult women (n = 124) from Indonesia were collected and analyzed using CIMI and Nutrisurvey (NS) and the results were analyzed. RESULTS: CIMI calculates the absolute intake of energy, macronutrients, retinol, beta-carotene, retinol equivalents, iron, and zinc. The percentages of RNI fulfillment with regard to age and sex are presented. The bioavailability levels of iron and zinc are considered. Validation showed that results of CIMI and NS were comparable with regard to the average intake and range of data distribution ratio. Due to bioavailability factors, more participants who had intake of iron (adult group) and zinc (both groups) below the cutoff were detected by CIMI. The range of correlation coefficient of NS and CIMI were from 0.889 (energy) to 0.713 (iron) in the children's group and from 0.919 (protein) to 0.686 (vitamin A) in the adult group. CONCLUSION: CIMI is a simple and rapid tool that calculates energy and nutrient intake, and also the percentage of nutrient fulfillment in comparison with the dietary recommendation. PMID- 25280407 TI - Role of metabolic syndrome and antiretroviral therapy in adiponectin levels and oxidative stress in HIV-1 infected patients. AB - OBJECTIVE: HIV-1 infection is accompanied by severe metabolic and immune dysfunction. The aim of this study was to evaluate the role of metabolic syndrome (MetS) and antiretroviral therapy (ART) utilization on the adiponectin levels and oxidative stress in patients infected with HIV-1. METHODS: We allocated 285 patients into four groups: group 1: patients without MetS who were not using ART; group 2: patients without MetS using ART; group 3: patients with MetS who were not using ART; and group 4: patients with MetS using ART. Biochemical, immunologic, and oxidative stress parameters were measured. RESULTS: Group 4 exhibited higher lipoperoxides when compared with group 1 (P < 0.0001) and higher advanced oxidation protein products (AOPP) compared with group 2 or group 1 (P < 0.0001). Group 3 also presented higher AOPP than group 2 (P < 0.05). Group 4 showed lower adiponectin levels compared with groups 1 or 2 (P < 0.0001). Similarly, group 3 presented lower adiponectin levels compared with group 2 (P < 0.05) or group 1 (P < 0.0001). Multivariate analysis showed that both an increase in AOPP and a decrease in total radical-trapping antioxidant parameter/uric acid were independently associated with MetS in HIV-1 patients. Regarding immunologic markers of HIV-1 disease progression and viral replication, group 4 exhibited significantly higher CD45(+), CD3(+), and CD4(+) T cells count compared with group 2 (P < 0.01). CONCLUSION: HIV-1-infected patients with MetS exhibited hypoadiponectinemia and increased oxidative stress, and these findings were not influenced by ART use. The findings of the present study allow the suggestion that MetS and inflammation might be mainly responsible for the aforementioned features. More studies are needed to verify whether drugs or food, which yield increased adiponectinemia and decreased oxidative stress, could reduce cardiovascular risk in HIV-infected patients. PMID- 25280408 TI - Carbohydrate and glutamine supplementation modulates the Th1/Th2 balance after exercise performed at a simulated altitude of 4500 m. AB - OBJECTIVE: The aim of this study was to evaluate the effect of carbohydrate or glutamine supplementation, or a combination of the two, on the immune system and inflammatory parameters after exercise in simulated hypoxic conditions at 4500 m. METHODS: Nine men underwent three sessions of exercise at 70% VO2peak until exhaustion as follows: 1) hypoxia with a placebo; 2) hypoxia with 8% maltodextrin (200 mL/20 min) during exercise and for 2 h after; and 3) hypoxia after 6 d of glutamine supplementation (20 g/d) and supplementation with 8% maltodextrin (200 mL/20 min) during exercise and for 2 h after. All procedures were randomized and double blind. Blood was collected at rest, immediately before exercise, after the completion of exercise, and 2 h after recovery. Glutamine, cortisol, cytokines, glucose, heat shock protein-70, and erythropoietin were measured in serum, and the cytokine production from lymphocytes was measured. RESULTS: Erythropoietin and interleukin (IL)-6 increased after exercise in the hypoxia group compared with baseline. IL-6 was higher in the hypoxia group than pre-exercise after exercise and after 2 h recovery. Cortisol did not change, whereas glucose was elevated post-exercise in the three groups compared with baseline and pre exercise. Glutamine increased in the hypoxia + carbohydrate + glutamine group after exercise compared with baseline. Heat shock protein-70 increased post exercise compared with baseline and pre-exercise and after recovery compared with pre-exercise, in the hypoxia + carbohydrate group. No difference was observed in IL-2 and IL-6 production from lymphocytes. IL-4 was reduced in the supplemented groups. CONCLUSION: Carbohydrate or glutamine supplementation shifts the T helper (Th)1/Th2 balance toward Th1 responses after exercise at a simulated altitude of 4500 m. The nutritional strategies increased in IL-6, suggesting an important anti-inflammatory effect. PMID- 25280409 TI - Effect of replacing bread, egg, milk, and yogurt with equivalent omega-3 enriched foods on omega-3 LCPUFA intake of Australian children. AB - OBJECTIVE: In countries with traditionally low fish consumption such as Australia, foods enriched with omega-3 long-chain polyunsaturated fatty acids (omega-3 LCPUFA) may play a role in meeting omega-3 LCPUFA intakes for optimal health. The aim of this study was to assess the effect of replacing bread, egg, milk, and yogurt with omega-3 LCPUFA enrichment of these foods on total omega-3 LCPUFA intake in Australian children's diets. METHODS: Dietary modeling was undertaken using survey data from a nationally representative sample of 4487 children (2249 boys, 2238 girls) ages 2 to 16 y in whom the Multiple Source Method was used to estimate usual omega-3 LPUFA intakes distributions from two 24 h dietary recalls, corrected for within-person variation; 15 models were constructed. RESULTS: The adjusted mean +/- SD and median and interquartile range (IQR) of usual dietary intakes of omega-3 LCPUFA gradually increased from 2.5 +/- 0.8 to 7.1 +/- 4.9 mg/d and 2.3 (1.9-2.9) to 5.4 (3.6-9.2), respectively, after the modeling (P = 0.001 for each model). Median (IQR) intake of total omega-3 LCPUFAs in non-fish eaters and fish eaters was 1.4 (0.8-2.3) and 2.3 (1.0-6.1) mg/d, respectively, which increased threefold to 4.3 (2.6-7.8) and 7.5 (3.9-13) mg/d, respectively, after replacement of all four omega-3 enriched foods. CONCLUSION: Replacement of four core foods with omega-3 enriched alternatives resulted in improved simulated omega-3 LCPUFA intakes in Australian children but not to optimal levels of intake. Increased fish consumption is still the most effective strategy for increasing omega-3 LCPUFA intake. PMID- 25280410 TI - Short-term dietary supplementation with fructose accelerates gastric emptying of a fructose but not a glucose solution. AB - OBJECTIVE: Short-term dietary glucose supplementation has been shown to accelerate the gastric emptying rate of both glucose and fructose solutions. The aim of this study was to examine gastric emptying rate responses to monosaccharide ingestion following short-term dietary fructose supplementation. METHODS: The gastric emptying rate of a fructose solution containing 36 g of fructose and an equicaloric glucose solution containing 39.6 g glucose monohydrate were measured in 10 healthy non-smoking men with and without prior fructose supplementation (water control) using a randomized crossover design. Gastric emptying rate was assessed for a period of 1 h using the [(13)C]breath test with sample collections at baseline and 10-min intervals following drink ingestion. Additionally, appetite ratings of hunger, fullness, and prospective food consumption were recorded at baseline and every 10 min using visual analog scales. RESULTS: Increased dietary fructose ingestion resulted in significantly accelerated half-emptying time of a fructose solution (mean = 48, SD = 6 versus 58, SD = 14 min control; P = 0.037), whereas the emptying of a glucose solution remained unchanged (mean = 85, SD = 31 versus 78, SD = 27 min control; P = 0.273). Time of maximal emptying rate of fructose was also significantly accelerated following increased dietary fructose intake (mean = 33, SD = 6 versus 38, SD = 9 min control; P = 0.042), while it remained unchanged for glucose (mean = 45, SD = 14 versus 44, SD = 14 min control; P = 0.757). No effects of supplementation were observed for appetite measures. CONCLUSION: Three d of supplementation with 120 g/d of fructose resulted in an acceleration of gastric emptying rate of a fructose solution but not a glucose solution. PMID- 25280411 TI - Low energy and carbohydrate intake associated with higher total antioxidant capacity in apparently healthy adults. AB - OBJECTIVES: The aim of this study was to investigate the associations between plasma total antioxidant capacity (TAC) and anthropometric, biochemical, clinical, and dietary measurements in young and apparently healthy individuals. METHODS: We evaluated 156 individuals (91 women and 65 men; ages 23.1 +/- 3.5 y; body mass index 22 +/- 2.9 kg/m(2)) for anthropometrics, biochemical markers, clinical, dietary, and some components of the antioxidant defense system, including the plasma TAC. Statistical analyses were performed to detect differences between individuals with TAC higher and lower than the mean value and to screen the associations between TAC and variables of interest. A linear regression model was fitted to identify TAC predictors. RESULTS: Daily caloric intake and macronutrient consumption were lower in individuals who exhibited the highest TAC values (P < 0.05). Linear regression analysis showed that daily calories and carbohydrate intake was a possible negative TAC predictor (P < 0.05). Nevertheless, there was no difference in the values of oxidized low density lipoprotein in the individuals separated by means of TAC. In contrast, individuals whose plasma TAC values were above the mean showed higher low-density lipoprotein cholesterol concentrations, total cholesterol/high-density lipoprotein cholesterol values, and selenium in nails (P < 0.05). CONCLUSIONS: In physiological conditions, the caloric intake level seems to be an important factor to act in the modulation of plasma TAC, before establishing anthropometric impairments of body or metabolic composition, or both. Additionally, the plasma TAC increase may be able to act as a compensatory mechanism. PMID- 25280412 TI - Number of days required for assessing usual nutrient and antioxidant intakes in a sample from a U.S. healthy college population. AB - OBJECTIVE: The primary aim of this study was to determine the number of days required to assess usual antioxidant intake with a defined level of accuracy in a sample of healthy college students. The secondary aim of this study was to increase the validity of the calculation of days by first determining the prevalence of misreporting energy intake in 30-d food records (FRs). METHOD: We examined the percentage of misreporting, the within- and between-person variations of nutrient intake, and the minimum days required to estimate a person's true intake with a correlation coefficient r >= 0.9. Sixty students from the University of Connecticut completed a 30-d FR, which was analyzed using the Nutrition Data System for Research software combined with Flavonoid and Proanthocyanidin Provisional Table. RESULTS: Twenty-seven percent (44 average reporters) included in the dietary analysis misreported after applying the Goldberg cutoff equation. The within-person variation was greater than the between-person variation with the variance ratios ranging from 1.10 to 10.51. After adjusting for energy and sex, a 7-d FR was adequate to achieve r >= 0.9 for fat, carbohydrate, protein, lycopene, and proanthocyanidin, whereas alpha tocopherol, total carotenoids, and flavonoids required 8 d. The remaining antioxidants required between 10 and 45 d. CONCLUSIONS: Overall, micronutrients and antioxidants had a greater daily variation than macronutrients and the majority required more than 7 d to assess usual intakes for this population. PMID- 25280413 TI - Effect of traditional food supplements on nutritional status of lactating mothers and growth of their infants. AB - OBJECTIVES: During lactation, traditional food supplements (TFS) are commonly consumed in India to increase lactation performance and health of mothers. TFS are rich in fats, nuts, dry fruits, and sugars and indulging in such supplements for 3 to 6 mo postpartum may put the mother at risk for obesity. The aim of this study was to assess the nutrient quality of TFS and its effect on nutritional status of lactating mothers and infant's weight gain in first 6 mo after delivery. METHODS: A random sample of 125 Indian urban lactating mothers (28.9 +/ 3.2 y) was assessed within 6 mo postpartum for anthropometry, diet by 24-h recall on 3 random days, along with socioeconomic factors, lactation history, and infant's birth weight and current weight. RESULTS: Among 18 different TFS, 50% TFS were rich in calcium, 33% rich in iron, 38% in zinc, and only 13% were good sources of vitamins. Mothers consuming TFS (n = 75) had significantly higher fat intakes than mothers consuming no TFS Supplements (NTS; n = 50). A higher weight gain was seen in TFS mothers (10.5%) than NTS mothers (8.8%) after adjusting for number of days after delivery, parity, mother's age, and breast-feeding practices (P < 0.05). Percent weight gain in infants of TFS mothers (120.7% +/- 7.3%) was higher than in infants of NTS mothers (96.2% +/- 7.8%; P = 0.024) after adjusting for infant's age and mother's breast-feeding practices. CONCLUSION: TFS may be modified to increase its micronutrient quality and to reduce fat contents with the goal of reducing the risk for obesity in mothers, while still benefiting infant growth. PMID- 25280414 TI - Dietary fatty acids intake and mortality in patients with heart failure. AB - OBJECTIVE: Dietary strategies in heart failure (HF) are focused on sodium and fluid restriction to minimize the risk for acute volume overload episodes. However, the importance of dietary factors beyond sodium intake in the prognosis of the disease is uncertain. The purpose of this study was to evaluate the association of macro- and micronutrients intake on 1-y mortality in patients with HF. METHODS: A secondary analysis of 203 patients with chronic HF enrolled in a randomized trial of sodium reduction was completed. Patients with a complete 3-d food record at baseline were included in this analysis (N = 118); both control and intervention arms were combined. Three-d mean dietary intake was estimated. Cox multivariable regression analysis was used to evaluate the association between dietary factors and 1-y mortality. RESULTS: Among the 118 included patients, 54% were men, median (25th-75th percentiles) age 66 y (52-75 y), median ejection fraction 45% (30%-60%), and ischemic etiology present in 49% of patients. The association with 1-y mortality was significant for both polyunsaturated fatty acids (PUFA; adjusted hazard ratio [HR], 0.67; 95% confidence interval [CI]. 0.51-0.86 for intake as percentage of daily energy) and saturated fatty acids (SFA; adjusted HR, 1.15; 95% CI, 1.03-1.30 for intake as percentage of daily energy). Median of intake as percentage of daily energy was 5.3% for PUFAs and 8.2% for SFAs. CONCLUSIONS: Intake of PUFAs and SFAs was independently associated with 1-y all-cause mortality in patients with chronic HF. Limiting dietary SFA and increasing PUFA intake may be advisable in this population. PMID- 25280415 TI - Management of patients during hunger strike and refeeding phase. AB - OBJECTIVE: Hunger strikers resuming nutritional intake may develop a life threatening refeeding syndrome (RFS). Consequently, hunger strikers represent a core challenge for the medical staff. The objective of the study was to test the effectiveness and safety of evidence-based recommendations for prevention and management of RFS during the refeeding phase. METHODS: This was a retrospective, observational data analysis of 37 consecutive, unselected cases of prisoners on a hunger strike during a 5-y period. The sample consisted of 37 cases representing 33 individual patients. RESULTS: In seven cases (18.9%), the hunger strike was continued during the hospital stay, in 16 episodes (43.2%) cessation of the hunger strike occurred immediately after admission to the security ward, and in 14 episodes (37.9%) during hospital stay. In the refeed cases (n = 30), nutritional replenishment occurred orally, and in 25 (83.3%) micronutrients substitutions were made based on the recommendations. The gradual refeeding with fluid restriction occurred over 10 d. Uncomplicated dyselectrolytemia was documented in 12 cases (40%) within the refeeding phase. One case (3.3%) presented bilateral ankle edemas as a clinical manifestation of moderate RFS. Intensive medical treatment was not necessary and none of the patients died. Seven episodes of continued hunger strike were observed during the entire hospital stay without medical complications. CONCLUSIONS: Our data suggested that seriousness and rate of medical complications during the refeeding phase can be kept at a minimum in a hunger strike population. This study supported use of recommendations to optimize risk management and to improve treatment quality and patient safety in this vulnerable population. PMID- 25280416 TI - Adherence to Mediterranean diet in a sample of Tuscan adolescents. AB - OBJECTIVE: The aim of this study was to estimate the level of adherence to the Mediterranean diet in a group of Italian high school students, in relation to their lifestyles and social and family contexts, and to compare the nutrition habits of the sample with other similar groups. METHODS: The KIDMED index and an ad hoc questionnaire were administered to 1127 students (mean age 16.8 +/- 1.6 y) in the province of Florence. Any significant associations between the level of adherence to the Mediterranean diet and the aforementioned variables were assessed by the chi(2) test and by logistic regression analysis. RESULTS: The adherence to the Mediterranean diet was good in 16.5%, average in 60.5%, and poor in 23% of the students. The students attending technical high schools, those who played sports less than "almost every day", those who spent >3 h/d in sedentary activities, those who defined their school performance as worse than "more than sufficient," and those who referred to use of a car/moped as the most frequent mode of transportation, had significantly higher odds of poor rather than average or good adherence to Mediterranean diet. Moreover, being normal weight or overweight/obese, and referring to health workers as source of information on diet, seem to be protective factors against poor adherence to Mediterranean diet. CONCLUSIONS: Our sample presents a departure from the Mediterranean dietary pattern. It is certainly necessary to implement public health policies targeting teenagers to promote healthier lifestyle choices; the nutritional patterns of the Mediterranean diet should be among these choices. PMID- 25280417 TI - Do structural quality indicators of nutritional care influence malnutrition prevalence in Dutch, German, and Austrian nursing homes? AB - OBJECTIVE: The aim of this study was to explore whether structural quality indicators for nutritional care influence malnutrition prevalence in the Netherlands, Germany, and Austria. Furthermore, differences in malnutrition prevalence and structural quality indicators for nutritional care nursing homes in the three countries were examined. METHODS: This was a cross-sectional, multicenter study using a standardized questionnaire at the patient, ward, and institutional levels. Malnutrition was assessed by low body mass index, undesired weight loss, and reduced intake. Structural quality indicators of nutritional care were measured at the ward and institutional levels. RESULTS: The prevalence of malnutrition differed significantly between the three countries (Netherlands 18%, Germany 20%, and Austria 22.7%). Structural quality indicators related to nutritional care as having a guideline of prevention and treatment of malnutrition were related to malnutrition and explained malnutrition prevalence variance between the Netherlands and Germany. Differences between the Netherlands and Austria in malnutrition prevalence still existed after controlling for these quality structural indicators. CONCLUSIONS: Structural quality indicators of nutritional care are important in explaining malnutrition variance between the Netherlands and Germany. However, they did not explain the difference in malnutrition prevalence between the Netherlands and Austria. Investigating the role of process indicators may provide insight in the role of structural quality indicators of nutritional care in explaining the malnutrition prevalence differences between the Netherlands and Austria. PMID- 25280418 TI - Association between junk food consumption and mental health in a national sample of Iranian children and adolescents: the CASPIAN-IV study. AB - OBJECTIVES: The consumption of high energy and low nutritional content foods, which are known as junk foods, has increased. The aim of this study was to evaluate the association between junk food intake and mental health in a national sample of Iranian children and adolescents. METHOD: Data were obtained from a surveillance system entitled CASPIAN-IV (Childhood and Adolescence Surveillance and Prevention of Adult Non communicable Disease) study of school students, ages 6 to 18 y in Iran. The students and their parents completed two sets of reliable questionnaires obtained from Global School Health Survey translated to Persian. The student questionnaire comprised several questions such as psychiatric distress (worry, depression, confusion, insomnia, anxiety, aggression, and worthless) and violent behaviors (physical fighting, being a victim, and bullying). The junk foods consisted of sweets, sweetened beverages, fast foods, and salty snacks. RESULTS: In the sample of 13 486 children and adolescents, the frequency of junk food consumption was significantly associated with psychiatric distress (P < 0.001). There was a significant association between violent behaviors and intake of junk foods (P < 0.001) except for sweets, whereas the association between sweetened beverages consumption and being a victim was not significant (P > 0.05). Additionally, the results of logistic regression showed that daily consumption of sweetened beverages and snacks significantly increased the odds of self-reported psychiatric distress. Also, daily consumption of salty snacks was significantly associated with violent behavior, including physical fighting (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.21-1.60), being a victim (OR, 1.19; 95% CI, 1.04-1.37), and bullying (OR, 1.55; 95% CI, 1.32 1.82). CONCLUSION: Junk food consumption may increase the risk for psychiatric distress and violent behaviors in children and adolescents. Improvement of eating habits toward healthier diets may be an effective approach for improving mental health. PMID- 25280419 TI - Estimated dietary intake and major food sources of polyphenols in the Polish arm of the HAPIEE study. AB - OBJECTIVE: The aim of this study was to estimate the intake of known individual polyphenols and their major dietary sources in the Polish arm of the HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) study. METHODS: A total of 10,477 random sample (45-69 y) of urban population of Krakow, Poland, completed a validated 148-item food frequency questionnaire. Polyphenol intake was calculated by matching food consumption data with the recently developed Phenol-Explorer database. RESULTS: The mean intake of polyphenols was 1756.5 +/- 695.8 mg/d (median = 1662.5 mg/d). The main polyphenol groups were flavonoids (897 mg/d) and phenolic acids (800 mg/d). A total of 347 polyphenols from 19 polyphenol subclasses were found. The individual compounds with the highest intakes were isomers of chlorogenic acid (i.e., 5-caffeoylquinic acid and 4 caffeoylquinic acid) among hydroxycinnamic acids (average intake 150 mg/d), that largely originated from coffee, and compounds belonging to the catechin chemical family (i.e., [+]-gallocatechin, [-]-epigallocatechin 3-O-gallate, and [-] epicatechin) among flavanols (average intake 50 mg/d), that mostly originated from tea and cocoa products. CONCLUSIONS: The current study provides the most updated data for individual polyphenols intake in the diet of a well-established nutritional cohort. These findings will be useful to assess potential beneficial role on health of specific foods with high polyphenol content and characterize the effects of individual phenolic compounds. PMID- 25280420 TI - Erythrocyte saturated fatty acids and systemic inflammation in adults. AB - OBJECTIVE: The role of saturated fatty acids (SFAs) in chronic disease remains controversial; inflammation is one pathway by which SFAs influence the risk for chronic disease. The aim of this study was to investigate the associations between red blood cell (RBC) phospholipid SFAs and systemic inflammation. METHODS: As part of a randomized controlled trial, we measured RBC phospholipid FA composition in 55 generally healthy adults twice at 3-mo intervals. We estimated associations of RBC total SFAs and two major SFA subtypes, palmitic and stearic acids, with C-reactive protein (CRP), interleukin (IL)-6, white blood count (WBC), and a composite inflammation measure using generalized estimating equations in multivariable FA substitution models. RESULTS: Mean (+/-SD) SFA level across both visits was 45% +/- 3% of the total RBC FAs, mainly palmitic (21% +/- 1%) and stearic (17% +/- 3%) acids. In models adjusted for age, sex, race, smoking, body mass index, statin use, aspirin use, transunsaturated FAs, and omega-3 FAs, SFAs were significantly associated with IL-6 (20% increase per 1 SD increment; 95% confidence interval [CI], 0.03%-43%; P = 0.05) and the composite inflammation measure (P = 0.05) and marginally associated with CRP (34% increase; 95% CI, -1% to 81%; P = 0.06), but not associated with WBC. Stearic acid was positively associated with CRP (35% increase; 95% CI, 2%-79%; P = 0.04). Palmitic acid was marginally associated with the composite inflammation measure (P = 0.06) and, upon additional omega-6 FA adjustment, significantly associated with IL-6 (15% increase; 95% CI, 0.4%-27%; P = 0.006). CONCLUSIONS: RBC SFAs, which represent longer-term dietary intake, are positively associated with inflammation. In particular, palmitic acid was associated with IL-6, and stearic acid was associated with CRP after multivariable adjustment. PMID- 25280421 TI - Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial. AB - OBJECTIVE: To our knowledge, no randomized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis; therefore, we performed a double-blind, placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy. METHODS: Patients with liver cirrhosis and hyperammonemia (at or above the institutional reference value) and hypozincemia (<=65 MUg/dL) were enrolled in the outpatient units of the participating institutions and were randomly divided to receive placebo (P group) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d (Z group) by the envelope method. Of the 18 enrolled patients, 6 dropped out; thus, the analyses included 12 patients (5 in the P group and 7 in the Z group). Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared. RESULTS: Blood zinc levels significantly increased in the Z group (P = 0.0037; Friedman test) but not the P group. Blood ammonia levels significantly decreased in the Z group (P = 0.0114; Friedman test) but not the P group. The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group (P = 0.0188: Mann-Whitney test). No serious adverse events attributable to the zinc preparation were noted. CONCLUSION: Although this study is preliminary and includes a small sample, it is, to our knowledge, the first randomized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis. Studies with a larger sample size are needed to confirm our findings. PMID- 25280422 TI - Protective effect of hesperidin in a model of Parkinson's disease induced by 6 hydroxydopamine in aged mice. AB - OBJECTIVE: Parkinson's disease (PD) may be caused by the interaction of a number of factors, including genetics, toxins, oxidative stress, mitochondrial abnormalities, and aging. Studies have shown that consumption of an antioxidant rich diet may reduce the incidence of neurodegenerative diseases. The aim of this study was to evaluate the role of the flavonoid hesperidin in an animal model of PD induced by 6-hidroxidopamine (6-OHDA). METHODS: Aged mice were treated with hesperidin (50 mg/kg) during 28 d after an intracerebroventricular injection of 6 OHDA. The enzymatic activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, the levels of glutathione, reactive oxygen species, total reactive antioxidant potential, dopamine and its levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, was analyzed in the striatum. The behavioral parameters (depressive-like, memory, and locomotor) were measured. RESULTS: This study demonstrated that hesperidin (50 mg/kg) treatment was effective in preventing memory impairment in the Morris water maze test, as well as, depressive-like behavior in the tail suspension test. Hesperidin attenuated the 6-OHDA-induced reduction in glutathione peroxidase and catalase activity, total reactive antioxidant potential and the dopamine and its metabolite levels in the striatum of aged mice. 6-OHDA increased reactive oxygen species levels and glutathione reductase activity in the striatum, and these alterations were mitigated by chronic administration of hesperidin. CONCLUSION: This study demonstrated a protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD. PMID- 25280424 TI - Lysophospholipid profile in serum and liver by high-fat diet and tumor induction in obesity-resistant BALB/c mice. AB - OBJECTIVE: Our previous study revealed that chronic consumption of a high-fat diet (HFD) stimulates colon cancer progression in obesity-resistant BALB/c mice. The aim of the present study was to investigate the significant alteration of metabolites caused by tumor progression and an HFD in the serum and liver in the same mouse model. METHODS: Male BALB/c mice were fed either a control diet or a HFD for 20.5 wk. The syngeneic CT26 colon carcinoma cells were injected into the right rear flank of mice after 16 wk of feeding. Metabolites in serum and liver samples were analyzed by ultra-performance liquid chromatography-quadrupole-time of-flight-mass spectrometry-based metabolomics. RESULTS: HFD feeding and tumor injection induced changes in the choline-containing phospholipids, namely, phosphatidylcholines and lysophosphatidylcholines (lysoPCs), and lysophosphatidylethanolamines in the serum and liver. The majority of these metabolite changes were due to HFD feeding (11 in sera and 5 in livers) rather than tumors (3 in sera and 1 in livers). CONCLUSION: The HFD- and tumor-related metabolite alterations of phospholipids, especially lysoPCs, in the liver and serum of obesity-resistant mice, suggesting that the lysoPCs are potential biomarkers for the chronic consumption of HFD in nonobese individuals. PMID- 25280423 TI - Evaluation of immune response, microbiota, and blood markers after probiotic bacteria administration in obese mice induced by a high-fat diet. AB - OBJECTIVE: Obesity is associated with alterations in intestinal microbiota and immunity. The aim of this study was to determine the effect of probiotic Lactobacillus casei CRL 431 administration on intestinal and humoral immune response, clinical parameters, and gut microbiota was evaluated using a high-fat diet to induce obesity in a mouse model. METHODS: Adult mice received a conventional balanced diet or a high-fat diet supplemented with milk, milk fermented by Lactobacillus casei (FM), L. casei as suspension, or water over 60 d. Histology of liver and small intestine (SI), immunoglobulin A-positive cells and macrophages in SI, phagocytic activity of spleen and peritoneal macrophages, and humoral immune response to ovalbumin were studied. Clinical parameters in serum and gut microbiota were also analyzed. RESULTS: FM was the most effective supplement for decreasing body weight and clinical parameters in serum. The histology of liver and SI was also improved in obese mice given FM. These animals had increased numbers of immunoglobulin A-positive cells and macrophages in SI. The gut microbiota showed that obese mice given probiotics had increased Bacteroides and bifidobacteria. Administration of FM or L. casei as suspension enhanced the phagocytic activity of macrophages. The anti-ovalbumin specific immune response was not increased by any supplement assayed. CONCLUSION: Administration of probiotics to obese hosts improved the gut microbiota and the mucosal immunity altered by obesity, down-regulated some biochemical parameters in blood associated with metabolic syndrome, and decreased liver steatosis. These results demonstrate the potential use of probiotics in obese individuals to decrease the body weight and to improve the biochemical and immunologic parameters altered by obesity. PMID- 25280425 TI - Effects of maternal over- and undernutrition on intestinal morphology, enzyme activity, and gene expression of nutrient transporters in newborn and weaned pigs. AB - OBJECTIVES: It has been suggested that maternal nutrition during gestation is involved in the offspring's intestinal development. The aim of this study was to evaluate the effects of maternal nutrition on digestive and absorptive function of offspring at both birth and weaning with pig as model. METHODS: Eighteen primiparous Landrace * Yorkshire gilts (ages 253 +/- 9 d; body weight 148.6 +/- 6.9 kg) were allocated to a normal nutrition (control) group as recommended by the National Research Council (NRC; 1998), an undernutrition (UN) group (75% of NRC recommendations), and an overnutrition (ON) group (150% of NRC recommendations); the nutritional treatments were introduced from day 1 of gestation to farrowing. RESULTS: By comparison, the small intestine weight (+33%; P < 0.01) and the ratio of small intestine weight to length (+25%; P < 0.05) for the ON group were higher than those for the control group. Meanwhile, the maternal ON treatment had significant effect on the activity of brush border lactase in the jejunum (+125%; P < 0.05) at birth. Expression of mRNA for SGLT1, GLUT2, PEPT1, and GLP2R were significantly increased (+1.7~9.6-fold; P < 0.05) in jejunum of newborn or weaned piglets from the ON group; whereas maternal UN significantly affected small intestine weight (-28%; P < 0.01), length, and the ratio of weight to length (-11% and -19%; P < 0.05, respectively), and villus height (-29% and -22%; P < 0.05, respectively) in jejunum and ileum. Furthermore, maternal UN enhanced the activity of brush border lactase in the jejunum of newborn piglets (P < 0.05). CONCLUSIONS: Maternal ON enhanced intestinal function via up-regulating digestive enzyme activities and gene expression of transporters in both newborn and weaning piglets. Maternal UN impaired fetal intestinal development that could be partially compensated during the neonatal period. PMID- 25280426 TI - Refeeding syndrome: problems with definition and management. AB - Refeeding syndrome (RFS) broadly encompasses a severe electrolyte disturbance (principally low serum concentrations of intracellular ions such as phosphate, magnesium, and potassium) and metabolic abnormalities in undernourished patients undergoing refeeding whether orally, enterally, or parenterally. RFS reflects the change from catabolic to anabolic metabolism. RFS sometimes is undiagnosed and unfortunately some clinicians remain oblivious to its presence. This is particularly concerning as RFS is a life-threatening condition, although it need not be so and early recognition reduces morbidity and mortality. Careful patient monitoring and multidiscipline nutrition team management may help to achieve this goal. The diagnosis of RFS is not facilitated by the fact that there is no universal agreement as to its definition. The presence of hypophosphatemia alone does not necessarily mean that RFS is present as there are many other causes for this, as discussed later in this article. RFS is increasingly being recognized in neonates and children. An optimal refeeding regimen for RFS is not universally agreed on due to the paucity of randomized controlled trials in the field. PMID- 25280427 TI - Successful nutritional support for a dysphagic patient with massive cirrhotic ascites and intrathoracic stomach using percutaneous endoscopic gastrostomy (PEG). AB - Although massive cirrhotic ascites is generally considered a contraindication for the placement of percutaneous endoscopic gastrostomy (PEG), such patients are usually poorly nourished. Preceding paracentesis of ascites is one method for controlling ascites and allowing the safe placement of PEG, but it often results in overuse of albumin. Preceding peritoneal-venous (P-V) shunting can avoid excessive use of albumin, but this introduces the risk of infectious contamination. We encountered an 88-y-old woman with massive cirrhotic ascites, a giant esophageal hernia with dislocation of the proximal stomach into the mediastinum, hypertrophy of the lateral segment of the liver, and malnutrition who had suffered from appetite loss and a swallowing disorder for 4 mo. She underwent PEG using a staged sequential introduction method using a Funada-style gastric wall fixation kit as follows: 1) full stretching and pushing out of the stomach from the mediastinum into the peritoneal cavity by deep insertion and a turning-over procedure of the endoscope, 2) full distention by air to adhere the gastric wall to the peritoneal wall without migration of the colon, 3) four-point square fixation under gastroenterological endoscopy without migration of the visceral organ, and 4) puncture of the needle introducer of the PEG tube in the center of the fixations under repeated gastroenterological endoscopy 3 d after the fixation. She underwent P-V shunting under local anesthesia on the 28th day after placement of PEG and enteral nutrition. Her case shows that we can achieve proper enteral nutritional support even for patients with massive cirrhotic ascites. PMID- 25280428 TI - Elevated preoperative peripheral blood monocyte count predicts poor prognosis for hepatocellular carcinoma after curative resection. AB - BACKGROUND: Peripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection. METHODS: We retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed. RESULTS: On univariate and multivariate analysis, elevated monocyte counts (>= 545/mm(3)), tumor size >= 5 cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1 , 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm(3), and 36%, 23% and 21% for patients with monocyte counts >= 545/mm(3). Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm(3), and 64%, 36% and 29% for monocyte counts >= 545/mm(3). Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm(3), but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm(3), whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors. CONCLUSIONS: Elevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts. PMID- 25280429 TI - Efficacy of lurasidone across five symptom dimensions of schizophrenia: pooled analysis of short-term, placebo-controlled studies. AB - OBJECTIVE: To evaluate the efficacy of lurasidone for schizophrenia using an established five-factor model of the Positive and Negative Syndrome Scale (PANSS). METHODS: Patient-level data were pooled from five randomized, double blind, placebo-controlled, 6-week studies of lurasidone (fixed doses, 40-160mg/d) for patients with an acute exacerbation of schizophrenia. Changes in five established PANSS factors were assessed using mixed-model repeated measures analysis. RESULTS: Compared with placebo (n=496), lurasidone (n=1029, dose groups pooled) significantly improved the PANSS total score at Week 6 (-22.6 vs. -12.8; P<0.001; effect size, 0.45), as well as all factor scores (P<0.001 for each): positive symptoms (-8.4 vs. -6.0; effect size, 0.43), negative symptoms (-5.2 vs. -3.3; effect size, 0.33), disorganized thought (-4.9 vs. -2.8; effect size, 0.42), hostility/excitement (-2.7 vs. -1.6; effect size, 0.31), and depression/anxiety (-3.2 vs. -2.3; effect size, 0.31). Separation from placebo occurred at Week 1 for the positive symptoms, disorganized thought, and hostility/excitement factors and at Week 2 for the other factors. CONCLUSIONS: In this pooled analysis of short-term studies in patients with acute schizophrenia, lurasidone demonstrated significant improvement for each of the five PANSS factor scores, indicating effectiveness across the spectrum of schizophrenia symptoms. PMID- 25280430 TI - Bipolar I and II versus unipolar depression: clinical differences and impulsivity/aggression traits. AB - OBJECTIVE: To investigate distinguishing features between bipolar I, II and unipolar depression, and impulsivity/aggression traits in particular. METHODS: Six hundred and eighty-five (n=685) patients in a major depressive episode with lifetime Unipolar (UP) depression (n=455), Bipolar I (BP-I) disorder (n=151), and Bipolar II (BP-II) (n=79) disorder were compared in terms of their socio demographic and clinical characteristics. RESULTS: Compared to unipolar patients, BP-I and BP-II depressed patients were significantly younger at onset of their first depressive episode, and were more likely to experience their first depressive episode before/at age of 15. They also had more previous affective episodes, more first- and second-degree relatives with history of mania, more current psychotic and subsyndromal manic symptoms, and received psychopharmacological and psychotherapy treatment at an earlier age. Furthermore, BP-I and BP-II depressed patients had higher lifetime impulsivity, aggression, and hostility scores. With regard to bipolar subtypes, BP-I patients had more trait-impulsivity and lifetime aggression than BP-II patients whereas the latter had more hostility than BP-I patients. As for co-morbid disorders, Cluster A and B Personality Disorders, alcohol and substance abuse/dependence and anxiety disorders were more prevalent in BP-I and BP-II than in unipolar patients. Whereas the three groups did not differ on other socio-demographic variables, BP I patients were significantly more often unemployed that UP patients. CONCLUSION: Our findings comport with major previous findings on differences between bipolar and unipolar depression. As for trait characteristics, bipolar I and II depressed patients had more life-time impulsivity and aggression/hostility than unipolar patients. In addition, bipolar I and II patients also differed on these trait characteristics. PMID- 25280431 TI - Fox- and raccoon-dog-associated rabies outbreaks in northern China. PMID- 25280433 TI - The case for ILI surveillance. PMID- 25280432 TI - Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain. AB - Endometriosis, the most common cause of chronic pelvic pain, is an estrogen dependent disease in which classic estrogen receptors (ERalpha, ERbeta) play an important role. Although recent evidence suggests that the novel G protein coupled estrogen receptor (GPR30) also plays a key role in the progression of endometriosis, whether it is also involved in endometriosis pain is still unknown. Here we tested the hypothesis that GPR30 expressed by nociceptors contributes to endometriosis pain. Intramuscular injection of the GPR30 agonists raloxifene or 17beta-estradiol produced a fast-onset, persistent, mechanical hyperalgesia at the site of the injection. Intrathecal antisense (AS) oligodeoxynucleotides (ODN), but not mismatch (MM) ODN, targeting mRNA for GPR30 markedly inhibited its protein expression in nociceptors and attenuated the mechanical hyperalgesia induced by local raloxifene or 17beta-estradiol. Pretreatment with the GPR30 antagonist G-36 also inhibited the hyperalgesia induced by raloxifene or 17beta-estradiol in naive control rats. Surgical implant of autologous uterine tissue onto the gastrocnemius muscle, which induces endometriosis-like lesions, produced local mechanical hyperalgesia. Intrathecal AS, but not MM, ODN targeting GPR30 mRNA reversibly inhibited the mechanical hyperalgesia at the site of endometriotic lesions. Finally, intralesional injection of the GPR30 antagonist G-36 also inhibited the mechanical hyperalgesia at the site of ectopic uterine tissue. We conclude that local GPR30 agonists produce persistent mechanical hyperalgesia in naive female rats, whereas local GPR30 antagonists inhibit mechanical hyperalgesia in a model of endometriosis pain. Thus, GPR30 expressed by nociceptors innervating ectopic uterine lesions might play a major role in endometriosis pain. PMID- 25280434 TI - Relative timing of influenza disease by age group. AB - A detailed understanding of influenza movement in communities during yearly epidemics is needed to inform improved influenza control programs. We sought to determine the relative timing of influenza presentation and symptom onset by age group and influenza strain. Prospective, laboratory-confirmed surveillance was performed over three moderate influenza seasons in emergency departments and inpatient settings of both medical centers in Winston-Salem, NC. Influenza disease presented first in school age children through community epidemics of influenza A(H1N1)pdm09 and influenza B, and first in persons 5-49 years old for influenza A(H3N2). This finding indicates that influenza prevention in persons 5 49 years of age may be particularly important in influenza epidemic control. PMID- 25280435 TI - Vaccination with liposomal poly(I:C) induces discordant maturation of migratory dendritic cell subsets and anti-viral gene signatures in afferent lymph cells. AB - Vaccine formulations administered in the periphery must activate naive immune cells within the lymph node. In this study, we have directly cannulated the ovine lymphatic vessels to investigate the cellular and molecular mechanisms that transfer information from the periphery into the local draining lymph node via the afferent lymph. Inclusion of poly(I:C) into a liposomal vaccine formulation enhances the neutrophil-associated inflammatory immune response in afferent lymph and increases antigen uptake by migratory dendritic cells (DCs). Interestingly, antigen positive migratory DCs undergo discordant maturation, with peak expression of CD86 at 4 h and CD80 at 48-72 h post vaccination. Afferent lymph monocytes up-regulate expression of genes related to inflammatory and anti-viral immune phenotypes following vaccination however show no differentiation into APCs prior to their migration to the local lymph node as measured by surface MHC II expression. Finally, this study reveals the addition of poly(I:C) increases systemic antigen-specific humoral immunity. These findings provide a detailed understanding of the real time in vivo immune response induced by liposomes incorporating the innate immune agonist poly(I:C) utilising a vaccination setting comparable to that administered in humans. PMID- 25280436 TI - Mapping vaccine hesitancy--country-specific characteristics of a global phenomenon. AB - The term vaccine hesitancy refers to delay in acceptance or refusal of vaccines despite the availability of vaccination services. Different factors influence vaccine hesitancy and these are context-specific, varying across time and place and with different vaccines. Factors such as complacency, convenience and confidence are involved. Acceptance of vaccines may be decreasing and several explanations for this trend have been proposed. The WHO Strategic Advisory Group of Experts (SAGE) on Immunization has recognized the global importance of vaccine hesitancy and recommended an interview study with immunization managers (IMs) to better understand the range of vaccine hesitancy determinants that are encountered in different settings. Interviews with IMs in 13 selected countries were conducted between September and December 2013 and various factors that discourage vaccine acceptance were identified. Vaccine hesitancy was not defined consistently by the IMs and most interpreted the term as meaning vaccine refusal. Although vaccine hesitancy existed in all 13 countries, some IMs considered its impact on immunization programmes to be a minor problem. The causes of vaccine hesitancy varied in the different countries and were context-specific, indicating a need to strengthen the capacity of national programmes to identify the locally relevant causal factors and to develop adapted strategies to address them. PMID- 25280437 TI - Survey of pediatricians in Germany reveals important challenges for possible implementation of meningococcal B vaccination. AB - Incidence of invasive meningococcal disease is low in Germany at 0.5 cases/100,000 inhabitants. Serogroup B (MenB) is most common, causing 70% of cases, with highest incidence in infants (5.9/100,000). In 2013, a MenB vaccine was licensed in Europe. To assess pediatricians' attitudes towards MenB vaccination and its potential use in Germany we conducted a nationwide cross sectional survey among 5677 pediatricians. Of 3107 participants (response: 55%), 79.1% would recommend a MenB vaccination to parents, with 66.7% favoring a schedule at 6, 8 and 12 months over 2, 3, 4 and 12 months (13.4%). Administration separately from other vaccines was preferred (63.2%); 38.5% feared that a recommendation would lead to refusal of other recommended vaccinations. In conclusion, pediatricians showed distinct preferences regarding possible integration of MenB vaccination into the existent immunization schedule. As physicians play a crucial role in the implementation, findings will be useful in decision-making regarding potential introduction. PMID- 25280438 TI - Hepatitis B: are at-risk individuals vaccinated if screened and found negative for HBV? Results of an online survey conducted in six EU countries. AB - INTRODUCTION: Vaccination is the best way to prevent hepatitis B infection and its consequences. The aim of the present study is to analyze the current vaccination practices within various population subgroups who are offered screening for hepatitis B, when found negative, in Germany, Hungary, Italy, the Netherlands, Spain and the UK. METHODS: Online surveys were conducted in the six countries. In total, 1181 experts from six different health professions were invited to participate. Descriptive analyses of data were performed. RESULTS: Less than half of the respondents in the Netherlands, only about 1/4 in Germany and none in Hungary reported that the vaccine is commonly offered to people who inject drugs. Less than half of the respondents in Germany reported vaccinating sex workers or HIV positive patients against hepatitis B as common practice. None in Hungary stated that vaccinating sex workers is common practice, and only according to a minority (17%) HIV patients are commonly vaccinated. 1/4 to 1/3 of respondents in Germany, the Netherlands, Italy, Hungary and the UK, indicated that HCV positive patients are only sporadically immunized. Only in Spain almost half of the respondents reported that migrants from hepatitis B endemic areas who are screened negative are commonly vaccinated. Widespread uncertainty about vaccination practices for asylum seekers was reported. CONCLUSIONS: By showing the gaps between current practices and policies in place, our findings can help to increase the success of future vaccination programmes. Implementation of training for health care professional, e.g. introducing vaccinology and vaccination policy courses in the medical and paramedical curriculum, could contribute to a more homogenous application of the recommendations regarding immunization against hepatitis B. Our results show, nonetheless, that the universal vaccination approach, coupled with targeted programmes for immigrants, represents the only way to make the elimination of hepatitis B a foreseeable, realistic objective. PMID- 25280439 TI - Young adult social smokers: their co-use of tobacco and alcohol, tobacco-related attitudes, and quitting efforts. AB - OBJECTIVE: Young adults frequently report social smoking. This study examined the relationship between different social smoking definitions and the co-use of cigarettes and alcohol, tobacco-related attitudes, and quitting efforts. METHOD: Cross-sectional data were collected at bars using randomized time location sampling among young adults aged 21-26 in San Diego, California from 2010 to 2011 (73% response rate). Multivariable logistic regression examined if current smoking and quit attempts were associated with tobacco-related attitudes, and whether social smoking self-identification or behavior was associated with cigarette-and-alcohol co-use, tobacco-related attitudes, quit attempts, or quitline use. RESULTS: Among 537 current smokers, 80% self-identified and 49% behaved as social smokers. Social smoking self-identification was positively associated with cigarette-and-alcohol co-use, and quit attempts. Social smoking behavior was negatively associated with tobacco marketing receptivity, quit attempts, and quitline use. Tobacco-related attitudes were associated with smoking but did not generally differ by social smoking status. CONCLUSION: Identification and behavior as a social smoker have opposing associations with co use of cigarettes and alcohol and quit attempts. Tobacco cessation programs for self-identified social smokers should address co-use. Interventions denormalizing the tobacco industry or emphasizing the health effects of temporary smoking and secondhand smoke may address smoking among young adult bar patrons regardless of social smoking status. PMID- 25280440 TI - Is an index of co-occurring unhealthy lifestyles suitable for understanding migrant health? AB - OBJECTIVE: This study investigated variation in unhealthy lifestyles within Australia according to where people were born. METHOD: Multilevel linear regression models were used to explore variation in co-occurring unhealthy lifestyles (from 0 to 8) constructed from responses to tobacco smoking, alcohol consumption, moderate-to-vigorous physical activity and a range of dietary indicators for 217,498 adults born in 22 different countries now living in Australia. Models were adjusted for socio-economic variables. Data was from the 45 and Up Study (2006-2009). Further analyses involved multilevel logistic regression to examine country-of-birth patterning of each individual unhealthy lifestyle. RESULTS: Small differences in the co-occurrence of unhealthy lifestyles were observed by country of birth, ranging from 3.1 (Philippines) to 3.8 (Russia). More substantial variation was observed for each individual unhealthy lifestyle. Smoking and alcohol ranged from 7.3% and 4.2% (both China) to 28.5% (Lebanon) and 30.8% (Ireland) respectively. Non-adherence to physical activity guidelines was joint-highest among participants born in Japan and China (both 74.5%), but lowest among those born in Scandinavian countries (52.5%). Substantial variation in meeting national dietary guidelines was also evident between participants born in different countries. CONCLUSION: The growing trend for constructing unhealthy lifestyle indices can hide important variation in individual unhealthy lifestyles by country of birth. PMID- 25280441 TI - Associations between the GNB3 C825T polymorphism and obesity-related metabolic risk factors in Korean obese women. AB - PURPOSE: It is important to identify a 'metabolically unhealthy obese' subset with higher cardiovascular risk among obese individuals. We investigated the associations between the GNB3 C825T polymorphism and obesity-related metabolic risk factors among Korean obese women. METHODS: This study was a sub investigation of a double-blind randomized controlled trial that examined the additive effect of or list at on weight loss with sibutramine. A sample of 111 obese women were divided into T-carriers (CT/TT) or a homozygous CC group, according to the presence of the 825T allele at GNB3. These groups were compared to determine their associations with obesity-related metabolic risk factors, i.e., fasting plasma glucose, serum lipids, serum insulin/insulin resistance, and abdominal fat amounts. RESULTS: The allele frequencies of the GNB3 polymorphism were C allele = 59.5% and T allele = 40.5%. The T allele was found to be significantly associated with greater visceral fat and higher serum lipids, and these significances remained robust after adjusting for potential covariates. CONCLUSIONS: The GNB3 825T polymorphism is significantly associated with greater visceral fat and higher serum lipids in Korean obese women and it suggests that the GNB3 C825T is a determinant of obesity-related metabolic traits in this population. PMID- 25280442 TI - A Mixture Cure-Rate Model for Responses and Response Times in Time-Limit Tests. AB - Many large-scale standardized tests are intended to measure skills related to ability rather than the rate at which examinees can work. Time limits imposed on these tests make it difficult to distinguish between the effect of low proficiency and the effect of lack of time. This paper proposes a mixture cure rate model approach to address this issue. Maximum likelihood estimation is proposed for parameter and variance estimation for three cases: when examinee parameters are to be estimated given precalibrated item parameters, when item parameters are to be calibrated given known examinee parameters, and when item parameters are to be estimated without assuming known examinee parameters. Large sample properties are established for the cases under suitable regularity conditions. Simulation studies suggest that the proposed approach is appropriate for inferences concerning model parameters. In addition, not distinguishing between the effect of low proficiency and the effect of lack of time is shown to have considerable consequences for parameter estimation. A real data example is presented to demonstrate the new model. Choice of survival models for the latent power times is also discussed. PMID- 25280444 TI - Subcallosal artery stroke: infarction of the fornix and the genu of the corpus callosum. The importance of the anterior communicating artery complex. Case series and review of the literature. AB - INTRODUCTION: Despite the variable anatomy of the anterior communicating artery (AcoA) complex, three main perforating branches can be typically identified the largest of which being the subcallosal artery (ScA). We present a case series of infarction in the vascular territory of the ScA to highlight the anatomy, the clinical symptomatology, and the presumed pathophysiology as it pertains to endovascular and surgical management of vascular pathology in this region. METHODS: In this retrospective multicenter case series study of patients who were diagnosed with symptomatic ScA stroke, we analyzed all available clinical records, MRI, and angiographic details. Additionally, a review of the literature is provided. RESULTS: We identified five different cases of ScA stroke, leading to a subsequent infarction of the fornix and the genu of the corpus callosum. The presumed pathophysiology in non-iatrogenic cases is microangiopathy, rather than embolic events; iatrogenic SCA occlusion can present after both surgical and endovascular treatment of AcoA aneurysms that may occur with or without occlusion of the AcoA. CONCLUSION: Stroke in the vascular territory of the ScA leads to a characteristic imaging and clinical pattern. Ischemia involves the anterior columns of the fornix and the genu of the corpus callosum, and patients present with a Korsakoff's syndrome including disturbances of short-term memory and cognitive changes. We conclude that despite its small size, the ScA is an important artery to watch out for during surgical or endovascular treatment of AcoA aneurysms. PMID- 25280443 TI - Association between molecular subtypes of colorectal cancer and patient survival. AB - BACKGROUND AND AIMS: Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. METHODS: Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. RESULTS: Compared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47 3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality. CONCLUSIONS: Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC. PMID- 25280445 TI - EVIDENCE trial: design of a phase 2, randomized, controlled, multicenter study comparing flow diversion and traditional endovascular strategy in unruptured saccular wide-necked intracranial aneurysms. AB - INTRODUCTION: Endovascular treatment of large, wide-necked intracranial aneurysms with coils is associated with low rates of initial angiographic occlusion and high rates of recurrence. The PipelineTM Embolization Device has shown high rates of complete occlusion in uncontrolled clinical series. METHODS: The study is a prospective, controlled, randomized, multicenter, phase 2 open-label trial. Intention-to-treat population includes age >=18, unruptured saccular aneurysm located in the intra-dural area, neck diameter >=4 and <=10 mm, sac diameter >=7 mm and <=20 mm, "dome/neck" ratio is >=1, diameter of the parent artery >=2 mm and <=5 mm, and no prior treatment of the aneurysm. Site can only participate if five patients have been previously treated with the Pipeline device. The primary end point of the study is complete occlusion of the aneurysm on angiogram performed 12 months after the endovascular procedure. Complete aneurysm occlusion is defined as the absence of visible blood flow, grade 1 according to the Raymond scale for the standard procedure group and grade 4 according to the grading scale of Kamran for the flow diverter group. RESULTS: The trial is currently enrolling and results of the data are pending the completion of enrollment and follow-up. CONCLUSION: This paper details the trial design of the French EVIDENCE phase 2 trial, a blinded, controlled randomized trial of wide-neck intra-dural aneurysms amenable to either traditional endovascular strategy or flow diversion with Pipeline device. PMID- 25280446 TI - High HIV prevalence in a respondent-driven sampling survey of injection drug users in Tehran, Iran. AB - Iran is facing unprecedented dual drug use and HIV epidemics. We conducted a cross-sectional survey to obtain HIV prevalence and risk behavior data from injection drug users (IDU) in Tehran. We used respondent-driven sampling (RDS) to recruit IDU through successive waves starting with 24 "seeds," conducted anonymous face-to-face interviews and HIV testing and counseling, and used RDSAT to adjust data. During 44 weeks, 1,726 study referral coupons resulted in 645 (37 %) IDU referrals, of whom 548 (85 %) were enrolled. From those enrolled, 84 % were incarcerated, 47 % employed, 55 % single, 27 % under 30 years of age, and 26 % homeless. The adjusted HIV prevalence was 26.6 % (95 % confidence interval 21.3 32.1), and was higher among certain IDU subgroups (e.g., those who sharing injection paraphernalia). Our estimates of HIV prevalence were higher than some other estimates; however, repeated surveys using similar methodology are needed to monitor the trend of HIV epidemic over time. PMID- 25280447 TI - The validity of self-reported medication adherence as an outcome in clinical trials of adherence-promotion interventions: Findings from the MACH14 study. AB - In medication adherence-promotion trials, participants in the intervention arm are often cognizant of the researcher's aim to improve adherence; this may lead to their inflating reports of their own adherence compared to control arm participants. Using data from 1,247 HIV-positive participants across eight U.S. Studies in the Multi-site Adherence Collaboration on HIV (MACH14) collaboration, we evaluated the validity of self-reported adherence by examining whether its association with two more objective outcomes [1], electronically monitored adherence and [2] viral load, varied by study arm. After adjusting for potential confounders, there was no evidence of greater overestimation of self-reported adherence among intervention arm participants, supporting its potential as a trial outcome indicator. PMID- 25280448 TI - Correlates of Use of Timed Unprotected Intercourse to Reduce Horizontal Transmission Among Ugandan HIV Clients with Fertility Intentions. AB - We examined the correlates of use of safer conception methods (SCM) in a sample of 400 Ugandan HIV clients (75 % female; 61 % on antiretroviral therapy; 61 % with HIV-negative or unknown status partners) in heterosexual relationships with fertility intentions. SCM assessed included timed unprotected intercourse, manual self-insemination, sperm washing, and pre-exposure prophylaxis (PrEP). In the 6 months prior to baseline, 47 (12 %) reported using timed unprotected intercourse to reduce risk of HIV infection (or re-infection), none had used manual self insemination or sperm washing, and two had used PrEP. In multiple regression analysis, correlates of use of timed unprotected intercourse included greater perceptions of partner's willingness to use SCM and providers' stigma of childbearing among people living with HIV, higher SCM knowledge, and desire for a child within the next 6 months. These findings highlight the need for policy and provider training regarding integration of couples' safer conception counselling into HIV care. PMID- 25280450 TI - Effects of background suppression on the sensitivity of dual-echo arterial spin labeling MRI for BOLD and CBF signal changes. AB - Dual-echo arterial spin labeling (DE-ASL) enables the simultaneous acquisition of BOLD and CBF fMRI data and is often used for calibrated BOLD and cerebrovascular CO2 reactivity measurements. DE-ASL, like all ASL techniques, suffers from a low intrinsic CBF SNR, which can be improved by suppressing the background signal via the inclusion of additional inversion pulses. However, until now this approach has been considered to be undesirable for DE-ASL, because the BOLD signal is extracted from the background signal and attenuating the background signal could decrease the sensitivity of DE-ASL scans for BOLD changes. In this study, the effect of background suppression on the sensitivity of DE-ASL MRI for BOLD and CBF signal changes with a visual stimulation paradigm was studied. Results showed that with an average background suppression level of 70% the BOLD sensitivity of DE-ASL MRI decreases slightly (15%), while the CBF sensitivity of the scans increased by almost a factor-of-two (81%). These findings support the conclusion that the gains in CBF sensitivity of DE-ASL MRI due to background suppression outweigh the slight decrease in sensitivity of these scans for BOLD changes, and thus that background suppression is highly recommended for DE-ASL. PMID- 25280449 TI - Use of incisional negative pressure wound therapy on closed median sternal incisions after cardiothoracic surgery: clinical evidence and consensus recommendations. AB - Negative pressure wound therapy is a concept introduced initially to assist in the treatment of chronic open wounds. Recently, there has been growing interest in using the technique on closed incisions after surgery to prevent potentially severe surgical site infections and other wound complications in high-risk patients. Negative pressure wound therapy uses a negative pressure unit and specific dressings that help to hold the incision edges together, redistribute lateral tension, reduce edema, stimulate perfusion, and protect the surgical site from external infectious sources. Randomized, controlled studies of negative pressure wound therapy for closed incisions in orthopedic settings (which also is a clean surgical procedure in absence of an open fracture) have shown the technology can reduce the risk of wound infection, wound dehiscence, and seroma, and there is accumulating evidence that it also improves wound outcomes after cardiothoracic surgery. Identifying at-risk individuals for whom prophylactic use of negative pressure wound therapy would be most cost-effective remains a challenge; however, several risk-stratification systems have been proposed and should be evaluated more fully. The recent availability of a single-use, closed incision management system offers surgeons a convenient and practical means of delivering negative pressure wound therapy to their high-risk patients, with excellent wound outcomes reported to date. Although larger, randomized, controlled studies will help to clarify the precise role and benefits of such a system in cardiothoracic surgery, limited initial evidence from clinical studies and from the authors' own experiences appears promising. In light of the growing interest in this technology among cardiothoracic surgeons, a consensus meeting, which was attended by a group of international experts, was held to review existing evidence for negative pressure wound therapy in the prevention of wound complications after surgery and to provide recommendations on the optimal use of negative pressure wound therapy on closed median sternal incisions after cardiothoracic surgery. PMID- 25280451 TI - Crossmodal plasticity in the fusiform gyrus of late blind individuals during voice recognition. AB - Blind individuals are trained in identifying other people through voices. In congenitally blind adults the anterior fusiform gyrus has been shown to be active during voice recognition. Such crossmodal changes have been associated with a superiority of blind adults in voice perception. The key question of the present functional magnetic resonance imaging (fMRI) study was whether visual deprivation that occurs in adulthood is followed by similar adaptive changes of the voice identification system. Late blind individuals and matched sighted participants were tested in a priming paradigm, in which two voice stimuli were subsequently presented. The prime (S1) and the target (S2) were either from the same speaker (person-congruent voices) or from two different speakers (person-incongruent voices). Participants had to classify the S2 as either coming from an old or a young person. Only in late blind but not in matched sighted controls, the activation in the anterior fusiform gyrus was modulated by voice identity: late blind volunteers showed an increase of the BOLD signal in response to person incongruent compared with person-congruent trials. These results suggest that the fusiform gyrus adapts to input of a new modality even in the mature brain and thus demonstrate an adult type of crossmodal plasticity. PMID- 25280452 TI - Analysis and characterization of the novel psychoactive drug 4 chloromethcathinone (clephedrone). AB - Novel psychoactive drugs, such as amphetamine-, cathinone-, benzofury- and tryptamine derivatives, gained high popularity on the global drug market in the last years. These drugs are sold via the Internet as for example "research chemicals", "room odorizers" or "lawn fertilizers" by different online suppliers. They are also known as "Legal Highs", among them, cathinone derivatives play an important role. Well known substituted cathinone derivatives are mephedrone, brephedrone and flephedrone. Since a couple of weeks, a chlorine substituted methcathinone derivative, namely clephedrone (4-chloromethcathinone), is commercially available via the Internet from www.deboralabs.com. The goal of this study was to confirm identity of this substance, which was done successfully by GC-MS and NMR. Since all cathinone derivatives are chiral, it was found out, whether the purchased sample was present as a racemic mixture. For this purpose, methods for enantioseparation by GC and CE were developed and applied successfully. In case of CE a chiral selector was added, whereas chiral separation with GC-MS was done indirectly, after derivatization of clephedrone with trifluoroacetyl-l-prolyl chloride. PMID- 25280453 TI - Self-perceptions and their Prediction of Aggression in Male Juvenile Offenders. AB - This study evaluated multiple facets of self-perceptions that have been theorized and shown to play a contributory role in the development of aggression for less clinically severe populations in a sample of youths from the juvenile justice system. Independent and unique associations of low self-esteem and inflated self perceptions with aggression were examined in a sample of male juvenile offenders (N = 119; Mean age = 16.74 years) using a longitudinal study design. Latent growth curve modeling analyses revealed that self-esteem, adaptive and maladaptive narcissism independently predicted juvenile offenders' initial levels of aggression. It was also found that perceptual bias independently predicted changes in aggression over time. With the inclusion of all variables in the same model, self-esteem was no longer associated with aggression; however, all other relationships remained significant. The implications of these findings as well as the importance of interventions targeting self-perceptions to decrease aggression among high-risk youths are discussed. PMID- 25280454 TI - Predictors of mortality in children with typhoid ileal perforation in a Nigerian tertiary hospital. AB - PURPOSE: Childhood typhoid ileal perforation is associated with high morbidity and mortality. Our aim was to ascertain the predictors of survival in children. MATERIALS AND METHODS: This is a tertiary hospital-based retrospective review of patients aged <=15 years managed for typhoid ileal perforations between January 2005 and December 2013. The details of their biodata, potential risk factors and outcome were evaluated. RESULTS: Forty-five children out of a total of 97 with typhoid fever had typhoid ileal perforation. The age range was 2-15 years, mean (+/-SD) = 9.3 (+/-3.31) years, median = 10 years. There were more males than females (26:19). Thirty-nine (86.7%) patients were >5 years old. There were nine deaths (20% mortality). The mean (+/-SD) age of survivors was 9.8 (+/-2.9) years and 7.1 (+/-4.2) for non-survivors (p = 0.026). The duration of illness at presentation, gender, admission temperature, nutritional status and packed cell volume, perforation-operation interval, number of perforations, surgical procedure, and the duration of surgery did not statistically influence survival (p > 0.05). The age of the patients and burst abdomen attained statistical significance (p < 0.05). CONCLUSION: The patients' age and postoperative burst abdomen were significant determinants of survival in children with typhoid ileal perforation. PMID- 25280455 TI - Suitability of skin integrity tests for dermal absorption studies in vitro. AB - Skin absorption testing in vitro is a regulatory accepted alternative method (OECD Guideline 428). Different tests can be applied to evaluate the integrity of the skin samples. Here, we compared the pre- or post-run integrity tests (transepidermal electrical resistance, TEER; transepidermal water loss, TEWL; absorption of the reference compounds water, TWF, or methylene blue, BLUE) and additionally focused on co-absorption of a (3)H-labeled internal reference standard (ISTD) as integrity parameter. The results were correlated to absorption profiles of various test compounds. Limit values of 2kOmega, 10 gm(-2)h(-1) and 4.5*10(-3)cmh(-1) for the standard methods TEER, TEWL and TWF, respectively, allowed distinguishing between impaired and intact human skin samples in general. Single skin samples did, however, not, poorly and even inversely correlate with the test-compound absorption. In contrast, results with ISTD (e.g. (3)H testosterone) were highly correlated to the absorption of (14)C-labeled test compounds. Importantly, ISTD did not influence analytics or absorption of test compounds. Therefore, ISTD, especially when adjusted to the physico-chemical properties of test compounds, is a promising concept to assess the integrity of skin samples during the whole course of absorption experiments. However, a historical control dataset is yet necessary for a potential routine application. PMID- 25280456 TI - American Society of Biomechanics Clinical Biomechanics Award 2013: tibiofemoral contact location changes associated with lateral heel wedging--a weight bearing MRI study. AB - BACKGROUND: Vertically open magnetic resonance imaging permits study of knee joint contact during weight bearing. Lateral wedging is a low cost intervention for knee osteoarthritis that may influence load distribution and contact. This study assessed the ability of feedback-assisted weight bearing magnetic resonance imaging to detect changes in tibiofemoral contact associated with lateral wedging. METHODS: One knee in each of fourteen subjects with symptomatic knee osteoarthritis was studied, without specification of compartmental involvement. Knees were imaged during upright standing and at 20 degrees knee flexion. Bilateral external heel wedges were used to provide non-wedged and 5 degrees lateral wedging conditions. Computer modeling was used to measure the medial and lateral compartment contact patch center coordinates on the tibial plateau and the respective contact areas. FINDINGS: Lateral heel wedging in flexion was associated with a significant anterior shift of the contact patch of the lateral femoral condyle. Changes with knee flexion were similar to previous reports: both medial and lateral contact centers moved posteriorly with flexion, and lateral condyle contact also moved laterally. Lateral condyle contact area significantly reduced with flexion, while lateral wedging did not significantly affect contact areas. INTERPRETATION: In symptomatic knee osteoarthritis patients standing in knee flexion, weight bearing magnetic resonance imaging recorded an anterior shift of lateral condyle contact in response to lateral heel wedging. Future studies may investigate lateral wedging effects more specifically in candidates for this clinical intervention. PMID- 25280457 TI - Evaluation of cytotoxic properties of a cyclopamine glucuronide prodrug in rat glioblastoma cells and tumors. AB - Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Activation of the developmental hedgehog (Hh) pathway is observed in GBM, particularly in the so-called glioma stem cells (GSCs). An inhibitor of this pathway is the steroidal alkaloid cyclopamine, an antagonist of the Hh coreceptor Smoothened (SMO). To limit the toxicity of cyclopamine toward Hh-dependent non tumor cells, our group previously reported the synthesis of a prodrug (called 1b), designed to deliver cyclopamine in the presence of beta-glucuronidase, an enzyme found in the necrotic area of GBM. Here, we aimed to analyze the in vitro, ex vivo, and in vivo cytotoxic properties of this prodrug in the C6 rat GBM cells. In the presence of beta-glucuronidase, the activated prodrug 1b was toxic and downregulated expression of Gli1, a Hh target gene, in C6 cells and C6-GSCs, but not in normal rat astrocytes in which the Hh pathway is weakly activated. In the absence of beta-glucuronidase, prodrug 1b displayed no obvious toxicity toward rat brain tissue explants while cyclopamine clearly affected brain tissue viability. When administered to rats bearing fluorescent C6-derived GBM, the prodrug 1b reduced the tumor density more efficiently than cyclopamine. Prodrug 1b thus appears as a promising concept to optimize confinement of cyclopamine cytotoxicity within the tumors, with more limited effects in the surrounding normal brain tissue. PMID- 25280458 TI - Occupational low back pain in primary and high school teachers: prevalence and associated factors. AB - OBJECTIVE: The purposes of this study were to investigate the prevalence of and risk factors for low back pain (LBP) in teachers and to evaluate the association of individual and occupational characteristics with the prevalence of LBP. METHODS: In this cross-sectional study, 586 asymptomatic teachers were randomly selected from 22 primary and high schools in Semnan city of Iran. Data on the personal, occupational characteristics, pain intensity, and functional disability as well as the prevalence and risk factors of LBP were collected using different questionnaires. RESULTS: Point, last month, last 6 months, annual, and lifetime prevalence rates of LBP were 21.8%, 26.3%, 29.6%, 31.1%, and 36.5%, respectively. The highest prevalence was obtained for the high school teachers. The prevalence of LBP was significantly associated with age, body mass index, job satisfaction, and length of employment (P < .05 in all instances). Prolonged sitting and standing, working hours with computer, and correcting examination papers were the most aggravating factors, respectively. Rest and participation in physical activity were found to be the most relieving factors. CONCLUSION: The prevalence of LBP in teachers appears to be high. High school teachers were more likely to experience LBP than primary school teachers. Factors such as age, body mass index, length of employment, job satisfaction, and work-related activities were significant factors associated with LBP in this teacher population. PMID- 25280459 TI - Description and prediction of the development of metabolic syndrome in Dongying City: a longitudinal analysis using the Markov model. AB - BACKGROUND: Metabolic Syndrome (MS) is increasingly becoming a major worldwide clinical and public health issue. Thus it is extremely important to study the history of MS and search for the most likely component contributing to start the cascade of confusions of MS. METHODS: A longitudinal cohort was involved which included the data of 7510 individuals who had at least two routine health check ups in a six-year follow-up. Based on the data, a Markov model with each chain containing seven states (no component state, four isolated states, 2-component state, and MS state) was built. Annual transition probability was the mean of five probabilities for the transition between the given states between each pair of consecutive years. RESULTS: The transition probabilities from the no component state to MS were higher in men than that in women in four age groups. In the young people (men <60 years and women <50 years), the probabilities to the overweight or obesity state and dyslipidemia state were the first two biggest probabilities in transition from no component to the rest six states. However, in the elderly population, the probabilities to hypertension state and 2-component state increased, even surpassed the above two states. The individuals initiating with 2-component states and the isolated hyperglycemia state were more likely to develop MS than the others. CONCLUSIONS: The Markov model was able to give a better description of the evolutionary history of MS, and to predict the future course based on past evidence. The occurrence of the MS process mostly began with overweight or obesity and dyslipidemia in young people. In the elderly population, many individuals initiating with hypertension or 2 components besides the above two states. Individuals with the isolated hyperglycemia had greater chances to develop MS than other isolated MS' components. PMID- 25280460 TI - Ribosomal protein P2 localizes to the parasite zoite-surface and is a target for invasion inhibitory antibodies in Toxoplasma gondii and Plasmodium falciparum. AB - In the malarial parasite Plasmodium falciparum, the conserved ribosomal stalk protein P2 (PfP2) exhibits extra-ribosomal stage-specific oligomerization and trafficking to the host red cell membrane. Antibodies directed against PfP2 arrested cell division. We sought to examine whether P2 from a closely related Apicomplexan parasite, Toxoplasma gondii, exhibits similar properties in terms of its oligomeric status as well as such unique host-cell localization. Circular dichroism spectroscopy of recombinant P2 from T. gondii (TgP2) showed a structure similar to that of PfP2, but unlike PfP2, which forms SDS- and DTT-resistant oligomers, TgP2 exhibited only a weak SDS-resistant dimerization. Also, unlike PfP2 localization to the infected erythrocyte surface, TgP2 did not localize to the host membrane in T. gondii infected human foreskin fibroblast cells. However, P2 protein was detected on the free tachyzoite surface, corroborated by localization of epitope-tagged P2 transfected in T. gondii. The presence of P2 on the surface of P. falciparum merozoites was also observed, and specific antibodies raised against the P2 protein blocked both T. gondii and P. falciparum zoite invasion of the host cells. Thus, although certain moonlighting functions of the acidic ribosomal protein P2 are different amongst P. falciparum and T. gondii, the P2 protein localizes to the surface of the invasive zoite form, and appears to constitute a potential target for host cell invasion inhibition in both the Apicomplexan infections. PMID- 25280461 TI - JMY protein, a regulator of P53 and cytoplasmic actin filaments, is expressed in normal and neoplastic tissues. AB - JMY is a p300-binding protein with dual action: by enhancing P53 transcription in the nucleus, it plays an important role in the cellular response to DNA damage, while by promoting actin filament assembly in the cytoplasm; it induces cell motility in vitro. Therefore, it has been argued that, depending of the cellular setting, it might act either as tumor suppressor or as oncogene. In order to further determine its relevance to human cancer, we produced the monoclonal antibody HMY 117 against a synthetic peptide from the N-terminus region and characterized it on two JMY positive cell lines, MCF7 and HeLa, wild type and after transfection with siRNA to switch off JMY expression. JMY was expressed in normal tissues and heterogeneously in different tumor types, with close correlation between cytoplasmic and nuclear expression. Most noticeable was the loss of expression in some infiltrating carcinomas compared to normal tissue and in in situ carcinomas of the breast, which is consistent with a putative suppressor role. However, as in lymph node metastases, expression of JMY was higher than in primary colorectal and head and neck carcinomas, it might also have oncogenic properties depending on the cellular context by increasing motility and metastatic potential. PMID- 25280462 TI - L-Glutamine enhances enterocyte growth via activation of the mTOR signaling pathway independently of AMPK. AB - Neonates (including human infants) require L-glutamine (Gln) for optimal intestinal health. This study tested the hypothesis that Gln enhances enterocyte growth via both mammalian target of rapamycin (mTOR) and AMP-activated kinase (AMPK) signaling pathways. Intestinal porcine epithelial cells (IPEC-1) were cultured for 3 days in Gln-free Dulbecco's modified Eagle medium containing 0 or 2 mM Gln. To determine the role of mTOR and AMPK on cell growth, additional experiments were conducted where medium contained 2 mM Gln and 10 nM rapamycin (Rap, an inhibitor of mTOR) or 1 MUM compound C (an inhibitor of AMPK). IPEC-1 cell growth increased with increasing concentrations of Gln from 0 to 2 mM. Compared with 0 mM Gln, 2 mM Gln increased (P < 0.05) the amounts of phosphorylated 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (p70S6 kinase) proteins but did not affect abundances of total or phosphorylated AMPK protein. Gln also increased mRNA levels for Bcl-2, mTOR, p70S6 kinase, 4E BP1, COX7C, ASCT2, ODC, SGLT-1, CFTR, Na(+)/K(+)-ATPase, HSP70, and ZO-1. Similarly, cells cultured with Rap and Gln exhibited higher (P < 0.05) abundances of phosphorylated 4E-BP1 and p70S6 kinase proteins than the Rap-only group, whereas abundances of phosphorylated mTOR and 4E-BP1 proteins were increased when AMPK was inhibited by compound C. Conversely, the amount of phosphorylated AMPK increased when mTOR was inhibited by Rap, suggesting a negative cross-talk between mTOR and AMPK. Collectively, these results indicate that Gln stimulates enterocyte growth by activating the mTOR signaling pathway independently of AMPK. PMID- 25280463 TI - A new lexicon for polypharmacy: Implications for research, practice, and education. AB - Previous research suggests that polypharmacy is a significant challenge for health care systems. However, polypharmacy has been defined in at least 24 distinct ways, which has understandably caused confusion among researchers, educators, and students in health care. Previous definitions of polypharmacy capture what could be both inappropriate therapy, i.e. too many medications, as well as evidence-based therapy that is appropriate. Previous research has tried to focus on the number of medications a patient is prescribed to define polypharmacy; however only focusing on the number of medications a patient is taking may be of limited value in determining whether that patient will experience an adverse event. This paper proposes a lexicon change for polypharmacy. It suggests that in future research, polypharmacy be defined as patients going to more than one pharmacy for their prescriptions. The authors also proffer a new term, 'extraordinary prescribing,' to define patients who are taking medications that are either grossly excessive or not beneficial for that patient. This definition is different than the current use of polypharmacy because the number of medications a patient is taking is irrelevant, especially if that patient has multiple chronic diseases. This paper is meant to start a dialog within the health services research community to inform future research that examines why inefficient prescribing may harm patients and the broader health care system. PMID- 25280464 TI - Angioedema deaths in the United States, 1979-2010. AB - BACKGROUND: Hospital admission data indicate that the angioedema incidence has increased during the past several decades. Little is known about mortality trends. OBJECTIVES: To count the number of deaths associated with angioedema in the United States, investigate correlations with age, sex, race, and other contributory causes, and analyze trends from 1979 to 2010. METHODS: All US death certificates in which angioedema was listed as an underlying or contributing cause of death during 1979 to 2010 were analyzed. Age-adjusted mortality rates were analyzed by age, sex, and race. Other conditions designated as the underlying cause of death were investigated. RESULTS: From 1979 to 2010, there were 5,758 deaths in which angioedema was listed as a contributing cause. The age adjusted death rate for hereditary angioedema decreased from 0.28 (95% confidence interval [CI] 0.25-0.32) to 0.06 (95% CI 0.05-0.08) per million persons per year. Conversely, mortality for angioedema increased from 0.24 (95% CI 0.21-0.27) to 0.34 (95% CI 0.31-0.37) per million. Blacks constituted 55% of angioedema deaths that were associated with use of angiotensin-converting enzyme inhibitors. On death certificates that listed hereditary angioedema as the underlying cause of death, cancer (frequently lymphoma or leukemia) was the second most commonly listed cause. CONCLUSION: Angioedema-associated deaths were very rare from 1979 to 2010. Hereditary angioedema deaths became even more so, whereas nonhereditary angioedema deaths increased. Risks associated with angiotensin-converting enzyme inhibitors were higher in blacks. Lack of specific coding for acquired angioedema most likely explains the observed association between cancer and hereditary angioedema. In the future, more granular coding systems may help distinguish hereditary from acquired angioedema. PMID- 25280465 TI - Responsiveness to inhaled corticosteroid treatment in patients with asthma chronic obstructive pulmonary disease overlap syndrome. AB - BACKGROUND: Inhaled corticosteroid (ICS) is recommended in the management of patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS), but its effectiveness has not been clearly proved. OBJECTIVE: To evaluate whether ICS has effects on outcomes of ACOS. METHODS: In this observational 12 year retrospective cohort study involving 125 patients with ACOS from Seoul National University Hospital, the annual rate of decrease in forced expiration volume in 1 second, the incidence rate of severe exacerbation, and overall mortality in an ICS-treated group were compared with those in a non-ICS-treated group. RESULTS: Of 125 patients with ACOS, 90 and 35 were categorized to the ICS and non-ICS treatment groups, respectively. There were no significant differences between the 2 groups in the annual rate of decrease in forced expiration volume in 1 second (9.61 mL/year in ICS treatment group vs 15.68 mL/year in non-ICS treatment group, P = .598). Compared with the non-ICS treatment group, the ICS treatment group did not show a decrease in the risk of severe exacerbation (adjusted incidence rate ratio 1.24, 95% confidence interval 0.44-3.46). Time to death also did not differ between the 2 groups. Even when analyses with propensity score matching were performed, the results were similar. CONCLUSION: In the management of ACOS, the use of ICS was not significantly associated with improvements in the annual rate of decrease in forced expiration volume in 1 second, the incidence of severe exacerbations, and overall mortality compared with the non-ICS treatment group. PMID- 25280466 TI - MicroRNA-23a-3p attenuates oxidative stress injury in a mouse model of focal cerebral ischemia-reperfusion. AB - The present study was designed to investigate the potential role of miR-23a-3p in experimental brain ischemia-reperfusion injury. Cerebral ischemia reperfusion was induced by transient middle cerebral artery occlusion (MCAO) for 1h in C57/BL6 mice. And miR-23a-3p angomir was transfected to upregulate the miR-23a-3p level. Our results showed that miR-23a-3p levels were transiently increased at 4h after reperfusion in the peri-infarction area, while markedly increased in the infarction core at reperfusion 4h and 24h. Importantly, in vivo study demonstrated that miR-23a-3p angomir treatment through intracerebroventricular injection markedly decreased cerebral infarction volume after MCAO. Simultaneously, miR-23a-3p reduced peroxidative production nitric oxide (NO) and 3-nitrotyrosine (3-NT), and increased the expression of manganese superoxide dismutase (MnSOD). In vitro study demonstrated that miR-23a-3p decreased hydrogen peroxide (H2O2)-induced lactate dehydrogenase (LDH) leakage dose-dependently, and reduced protein levels of activated caspase-3 in neuro-2a cells. In addition, miR 23a-3p reduced H2O2-induced production of NO and 3-NT dose-dependently, and reversed the decreased activity of total SOD and MnSOD in neuro-2a cells. Our study indicated that miR-23a-3p suppressed oxidative stress and lessened cerebral ischemia-reperfusion injury. PMID- 25280468 TI - Mood disorder as a manifestation of primary hypoparathyroidism: a case report. AB - INTRODUCTION: Primary hypoparathyroidism is a rare condition caused by parathyroid hormone deficiency and characterized by hypocalcemia. The clinical manifestations of primary hypoparathyroidism include tetany, seizures, paresthesias, dementia, and parkinsonism. Psychiatric manifestations such as mood disorders are unusual and may constitute a major diagnostic challenge, especially if the typical manifestations caused by hypocalcemia are absent. CASE PRESENTATION: The patient was a 22-year-old Caucasian man with a history of chronic omeprazole use and periodic seizures, who presented to the emergency department of a secondary hospital in Southern Brazil with symptoms of major depression (sadness, anhedonia, loss of appetite, insomnia, and fatigue) associated with paresthesias affecting his toes. The initial electrocardiogram revealed a prolonged QTc interval. A computed tomography scan of his brain revealed bilateral, nonenhancing hyperdense calcifications involving the putamen and caudate nucleus. An electroencephalogram showed generalized bursts of slow spikes. Blood laboratory study results indicated serum hypocalcemia, hypomagnesemia, and hyperphosphatemia associated with a low parathyroid hormone level. His serum levels of albumin, 25-hydroxyvitamin D, thyroid-stimulating hormone, T3 and T4 thyroid hormones, as well as the results of kidney function tests, were normal. The definitive diagnosis was primary hypoparathyroidism with psychiatric manifestations due to chronic hypomagnesemia induced by proton pump inhibitor use. CONCLUSIONS: In some cases, to differentiate between a primary psychiatric disorder and primary hypoparathyroidism with neuropsychiatric symptoms may represent a challenge given that the classical manifestations of hypocalcemia, especially tetany, may be absent in the setting of chronic hypoparathyroidism. Clinicians and psychiatrists should consider primary hypoparathyroidism part of the differential diagnosis during the evaluation of patients with mood symptoms, especially in the context of atypical presentations associated with hypocalcemia. PMID- 25280467 TI - Exploring the relationship between governance mechanisms in healthcare and health workforce outcomes: a systematic review. AB - BACKGROUND: The objective of this systematic review of diverse evidence was to examine the relationship between health system governance and workforce outcomes. Particular attention was paid to how governance mechanisms facilitate change in the workforce to ensure the effective use of all health providers. METHODS: In accordance with standard systematic review procedures, the research team independently screened over 4300 abstracts found in database searches, website searches, and bibliographies. Searches were limited to 2001-2012, included only publications from Canada, the United Kingdom, the Netherlands, New Zealand, Australia, and the United States. Peer- reviewed papers and grey literature were considered. Two reviewers independently rated articles on quality and relevance and classified them into themes identified by the team. One hundred and thirteen articles that discussed both workforce and governance were retained and extracted into narrative summary tables for synthesis. RESULTS: Six types of governance mechanisms emerged from our analysis. Shared governance, Magnet accreditation, and professional development initiatives were all associated with improved outcomes for the health workforce (e.g., decreased turnover, increased job satisfaction, increased empowerment, etc.). Implementation of quality-focused initiatives was associated with apprehension among providers, but opportunities for provider training on these initiatives increased quality and improved work attitudes. Research on reorganization of healthcare delivery suggests that changing to team-based care is accompanied by stress and concerns about role clarity, that outcomes vary for providers in private versus public organizations, and that co-operative clinics are beneficial for physicians. Funding schemes required a supplementary search to achieve adequate depth and coverage. Those findings are reported elsewhere. CONCLUSIONS: The results of the review show that while there are governance mechanisms that consider workforce impacts, it is not to the extent one might expect given the importance of the workforce for improving patient outcomes. Furthermore, to successfully implement governance mechanisms in this domain, there are key strategies recommended to support change and achieve desired outcomes. The most important of these are: to build trust by clearly articulating the organization's goal; considering the workforce through planning, implementation, and evaluation phases; and providing strong leadership. PMID- 25280469 TI - Combined double tarsal wedge osteotomy and transcuneiform osteotomy for correction of resistant clubfoot deformity (the "bean-shaped" foot). AB - PURPOSE: The "bean-shaped foot" exhibits forefoot adduction and midfoot supination, which interfere with function because of poor foot placement. The purpose of the study is a retrospective evaluation of patients who underwent a combined double tarsal wedge osteotomy and transcuneiform osteotomy to correct such a deformity. METHODS: Twenty-seven children with 35 idiopathic clubfeet were treated surgically by combined double tarsal wedge osteotomy (closing wedge cuboid osteotomy and opening wedge medial cuneiform osteotomy) and transcuneiform osteotomy between 2008 and 2012. The age of children at surgery ranged from 4 to 9 years. There were 19 boys and 8 girls. Pre- and postoperative X-rays were used, considering: on the AP radiograph, the calcaneo-fifth metatarsal angle and the talo-first metatarsal angle (indicators of forefoot adduction); on the lateral radiograph, the talo-first metatarsal angle (an indication of supination deformity) and calcaneo-first metatarsal angles (an indication of cavus deformity). These radiological parameters were compared with the clinical results. RESULTS: Follow-up was conducted for 24-79 months following surgery. Clinical and radiographic improvements in forefoot position were achieved in all cases. An average improvement in the anteroposterior talo-first metatarsal angle of 21 degrees , calcaneo-fifth metatarsal angle of 14 degrees , lateral talo first metatarsal angle of 10 degrees , and lateral calcaneo-first metatarsal of 12 degrees confirmed the clinically satisfactory correction in all feet. One patient had a wound infection postoperatively, which resolved with removal of the wires and administration of oral antibiotics. Eight patients followed up for more than 5 years had no deterioration of results. CONCLUSIONS: Combined double tarsal wedge osteotomy as well as transcuneiform osteotomy is an effective and safe procedure for lasting correction of the bean-shaped foot. PMID- 25280470 TI - Reference point indentation is not indicative of whole mouse bone measures of stress intensity fracture toughness. AB - Bone fragility is a concern for aged and diseased bone. Measuring bone toughness and understanding fracture properties of the bone are critical for predicting fracture risk associated with age and disease and for preclinical testing of therapies. A reference point indentation technique (BioDent) has recently been developed to determine bone's resistance to fracture in a minimally invasive way by measuring the indentation distance increase (IDI) between the first and last indentations over cyclic indentations in the same position. In this study, we investigate the relationship between fracture toughness KC and reference point indentation parameters (i.e. IDI, total indentation distance (TID) and creep indentation distance (CID)) in bones from 38 mice from six types (C57Bl/6, Balb, oim/oim, oim/+, Phospho1(-/-) and Phospho1 wild type counterpart). These mice bone are models of healthy and diseased bone spanning a range of fracture toughness from very brittle (oim/oim) to ductile (Phospho1(-/-)). Left femora were dissected, notched and tested in 3-point bending until complete failure. Contralateral femora were dissected and indented in 10 sites of their anterior and posterior shaft surface over 10 indentation cycles. IDI, TID and CID were measured. Results from this study suggest that reference point indentation parameters are not indicative of stress intensity fracture toughness in mouse bone. In particular, the IDI values at the anterior mid-diaphysis across mouse types overlapped, making it difficult to discern differences between mouse types, despite having extreme differences in stress intensity based toughness measures. When more locations of indentation were considered, the normalised IDIs could distinguish between mouse types. Future studies should investigate the relationship of the reference point indentation parameters for mouse bone in other material properties of the bone tissue in order to determine their use for measuring bone quality. PMID- 25280471 TI - Targeting myeloid cells using nanoparticles to improve cancer immunotherapy. AB - While nanoparticles have traditionally been used to deliver cytotoxic drugs directly to tumors to induce cancer cell death, emerging data suggest that nanoparticles are likely to generate a larger impact on oncology through the delivery of agents that can stimulate antitumor immunity. Tumor-targeted nanocarriers have generally been used to localize chemotherapeutics to tumors and thus decrease off-target toxicity while enhancing efficacy. Challengingly, tumor heterogeneity and evolution render tumor-intrinsic approaches likely to succumb to relapse. The immune system offers exquisite specificity, cytocidal potency, and long-term activity that leverage an adaptive memory response. For this reason, the ability to manipulate immune cell specificity and function would be desirable, and nanoparticles represent an exciting means by which to perform such manipulation. Dendritic cells and tumor-associated macrophages are cells of the myeloid lineage that function as natural phagocytes, so they naturally take up nanoparticles. Dendritic cells direct the specificity and potency of cellular immune responses that can be targeted for cancer vaccines. Herein, we discuss the specific criteria needed for efficient vaccine design, including but not limited to the route of administration, size, morphology, surface charge, targeting ligands, and nanoparticle composition. In contrast, tumor-associated macrophages are critical mediators of immunosuppression whose trans-migratory abilities can be exploited to localize therapeutics to the tumor core and which can be directly targeted for elimination or for repolarization to a tumor suppressive phenotype. It is likely that a combination of targeting dendritic cells to stimulate antitumor immunity and tumor-associated macrophages to reduce immune suppression will impart significant benefits and result in durable antitumor responses. PMID- 25280472 TI - Acquired heterotopic ossification in hips and knees following encephalitis: case report and literature review. AB - BACKGROUND: Heterotopic ossification (HO) is a rare and potentially detrimental complication of soft-tissue trauma, amputations, central nervous system injury (traumatic brain injuries, spinal cord lesions, tumors, encephalitis), vasculopathies, arthroplasties and burn injury, characterized by lamellar bone growth in non-osseous tissues such as the muscle and the joint capsule. Heterotopic ossification associated with encephalitis is rare and the occurrence of excessive, symptomatic heterotopic ossification around bilateral hips and bilateral knees is rarely described in the literature. CASE PRESENTATION: We present a 47-year-old man with heterotopic ossification in the bilateral hips and bilateral knees that prevented him from walking after being attacked by encephalitis as the case study. He developed severe pain and significantly impaired range of motion of bilateral hips and bilateral knees. Research so far revealed that the management of heterotopic ossification is controversial. After requiring revision surgery resection of heterotopic ossification, reconstruction of the medial collateral ligament and adjunctive pharmacotherapy of 200 mg Celecoxib for 8 weeks after operation, he regained mobility of his joints. On review of X-ray, there was no recurrence of HO and no loosening of rivets which were used in the reconstruction of medial collateral ligament. CONCLUSION: Heterotopic ossification in the bilateral hip joints and bilateral knee joints associated with encephalitis have never been reported previously. Daily functions of heterotopic ossification patients can be hampered by pain, inflammation, reduced mobility, the loss of normal posture and other complications. Further studies of presumptive root causes, the early diagnosis, preventability and optimal therapeutic measures for heterotopic ossification following encephalitis are required. Different patient should be managed with different appropriated protocol based on the risk of individual patient and the institutional experience. PMID- 25280474 TI - Economist intelligence unit democracy index in relation to health services accessibility: a regression analysis. AB - BACKGROUND: The relationship between political environment and health services accessibility (HSA) has not been the focus of any specific studies. The purpose of this study was to address this gap in the literature by examining the relationship between political environment and HSA. METHODS: This relationship that HSA indicators (physicians, nurses and hospital beds per 10 000 people) has with political environment was analyzed with multiple least-squares regression using the components of democracy (electoral processes and pluralism, functioning of government, political participation, political culture, and civil liberties). The components of democracy were represented by the 2011 Economist Intelligence Unit Democracy Index (EIUDI) sub-scores. The EIUDI sub-scores and the HSA indicators were evaluated for significant relationships with multiple least squares regression. RESULTS: While controlling for a country's geographic location and level of democracy, we found that two components of a nation's political environment: functioning of government and political participation, and their interaction had significant relationships with the three HSA indicators. CONCLUSIONS: These study findings are of significance to health professionals because they examine the political contexts in which citizens access health services, they come from research that is the first of its kind, and they help explain the effect political environment has on health. PMID- 25280473 TI - Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. AB - BACKGROUND: Variation in hippocampal volume has been linked to significant differences in memory, behavior, and cognition among individuals. To identify genetic variants underlying such differences and associated disease phenotypes, multinational consortia such as ENIGMA have used large magnetic resonance imaging (MRI) data sets in human GWAS studies. In addition, mapping studies in mouse model systems have identified genetic variants for brain structure variation with great power. A key challenge is to understand how genetically based differences in brain structure lead to the propensity to develop specific neurological disorders. RESULTS: We combine the largest human GWAS of brain structure with the largest mammalian model system, the BXD recombinant inbred mouse population, to identify novel genetic targets influencing brain structure variation that are linked to increased risk for neurological disorders. We first use a novel cross species, comparative analysis using mouse and human genetic data to identify a candidate gene, MGST3, associated with adult hippocampus size in both systems. We then establish the coregulation and function of this gene in a comprehensive systems-analysis. CONCLUSIONS: We find that MGST3 is associated with hippocampus size and is linked to a group of neurodegenerative disorders, such as Alzheimer's. PMID- 25280475 TI - A review of the documentation in the British Armed Forces electronic patient record following discharge from the Role 3 Hospital in Camp Bastion. AB - INTRODUCTION: The British Role 3 Hospital in Camp Bastion, Afghanistan, uses a different electronic patient record (EPR) to Defence Primary Health Care and the two cannot directly communicate. Consequently, hospital discharge information is transferred by printed letter to primary care, introducing a step where information can be lost. This study was designed to test the hypothesis that the primary care EPR contained an accurate summary of the secondary care admission. METHODS: Cross-sectional information on consecutive General Internal Medicine patients at the hospital was collected and compared with the primary care EPR. RESULTS: From April 2011 the hospital records of 270 patients were reviewed. 239 primary care records were available for comparison. Of 185 patients discharged back to their unit the EPR of 43.8% contained a comprehensive summary, 23.2% contained the scanned discharge letter and 50.8% contained an account of their hospital admission but not necessarily a comprehensive summary. Of the 54 patients evacuated to the UK, the EPRs of 48.1% contained a summary, 68.1% contained the scanned discharge letter and 75.9% contained some account of their hospital admission. More of the evacuated group had their admission documented in the primary care EPR (p=0.001). Only 56.5% of all primary care records contained some account of the hospital admission. DISCUSSION: The primary care record is not a reliable record of operational hospital admission and presents an unrecognised potential patient safety issue. The systems responsible for the transfer of discharge summary data need to be appraised to prevent it continuing. Retrospective action should be considered to rectify this problem in former hospital patients. PMID- 25280476 TI - Automated breast ultrasound system (ABUS): reproducibility of mass localization, size measurement, and characterization on serial examinations. AB - BACKGROUND: Automated breast ultrasound (ABUS) is gaining popularity for breast cancer detection and diagnosis with its high reproducibility. Consistent recognition of breast lesions on serial exams is critical, and high reproducibility for lesion characterization is expected with ABUS, but not well reported. PURPOSE: To retrospectively evaluate the reproducibility of ABUS for mass localization, size measurement, and characterization. MATERIAL AND METHODS: Bilateral whole breast US images were obtained twice using a commercially available ABUS within a mean interval of 1.3 days. In total, 24 patients were imaged before biopsy or surgery. There were 24 breast cancers and nine benign diagnoses. Two breast radiologists reviewed every paired three-dimensional dataset with regard to lesion visibility, reproducibility of documented location (clockface location, distance from nipple, and lesion depth), size of the lesions, and similarity for lesion characteristics. Lesion similarity was classified as being identical, similar, or different by consensus reading using the SomoVu workstation. Intraclass correlation coefficients (ICCs) and the Bland Altman method were used to determine the amount of agreement between assessments of lesion location and size. RESULTS: Among 33 breast lesions, 31 lesions were depicted in both serial examinations. ICCs for the displayed lesion location (clock face location, distance from nipple), and the individual size of detected lesions were 0.994, 0.926, and 0.980, indicating excellent reliability. However, the ICC for lesion depth from the skin was 0.342 showing low reliability. For lesion similarity, 16 cancers and five benign lesions were classified as being identical, and six cancers and two benign lesions were classified as being similar. Two benign lesions were assessed to have different lesion characteristics and final assessment categories. CONCLUSION: The ABUS provided reproducible images for mass localization, size measurement, and characterization, which may be useful for follow-up studies. PMID- 25280478 TI - Hospitals could run general practice services in underserved areas. PMID- 25280479 TI - Glasgow Coma Scale is unreliable for the prediction of severe head injury in elderly trauma patients. AB - OBJECTIVES AND BACKGROUND: Elderly patients comprise an ever-increasing proportion of major trauma patients. The presenting GCS in elderly patients with traumatic brain injury (TBI) may not reflect the severity of injury as accurately as it does in the younger patient population. However, GCS is often used as part of the decision tool to define the population transferred directly to a major trauma centre. The aim of this study was to explore the relationship between age and presenting GCS in patients with isolated TBI. METHODS: A retrospective database review was undertaken using the Trauma Audit and Research Network database. All patients presenting to Derriford Hospital, Plymouth, between 1 January 2009 and 31 May 2014 with isolated TBI were included. Demographic, mechanistic, physiological, resource use and outcome data were collected. Abbreviated injury scale (AIS) was recorded for all patients. Patients were categorised into those older and younger than 65 years on presentation. Distribution of GCS, categorised into severe (GCS 3-8), moderate (GCS 9-12) and mild TBI (13-15), was compared between the age groups. Median GCS at each AIS level was also compared. RESULTS: The distribution of GCS differed between young and old patients with TBI (22.1% vs 9.8% had a GCS 3-8, respectively) despite a higher burden of anatomical injury in the elderly group. Presenting GCS was higher in the elderly at each level of AIS. The difference was more apparent in the presence of more severe injury (AIS 5). CONCLUSIONS: Elderly patients who have sustained isolated severe TBI may present with a higher GCS than younger patients. Triage tools using GCS may need to be modified and validated for use in elderly patients with TBI. PMID- 25280477 TI - Hot spots of DNA double-strand breaks and genomic contacts of human rDNA units are involved in epigenetic regulation. AB - DNA double-strand breaks (DSBs) are involved in many cellular mechanisms, including replication, transcription, and genome rearrangements. The recent observation that hot spots of DSBs in human chromosomes delimit DNA domains that possess coordinately expressed genes suggests a strong relationship between the organization of transcription patterns and hot spots of DSBs. In this study, we performed mapping of hot spots of DSBs in a human 43-kb ribosomal DNA (rDNA) repeated unit. We observed that rDNA units corresponded to the most fragile sites in human chromosomes and that these units possessed at least nine specific regions containing clusters of extremely frequently occurring DSBs, which were located exclusively in non-coding intergenic spacer (IGS) regions. The hot spots of DSBs corresponded to only a specific subset of DNase-hypersensitive sites, and coincided with CTCF, PARP1, and HNRNPA2B1 binding sites, and H3K4me3 marks. Our rDNA-4C data indicate that the regions of IGS containing the hot spots of DSBs often form contacts with specific regions in different chromosomes, including the pericentromeric regions, as well as regions that are characterized by H3K27ac and H3K4me3 marks, CTCF binding sites, ChIA-PET and RIP signals, and high levels of DSBs. The data suggest a strong link between chromosome breakage and several different mechanisms of epigenetic regulation of gene expression. PMID- 25280480 TI - Spectral correction factors for conventional neutron dosemeters used in high energy neutron environments. AB - High-energy neutrons (>10 MeV) contribute substantially to the dose fraction but result in only a small or negligible response in most conventional moderated-type neutron detectors. Neutron dosemeters used for radiation protection purpose are commonly calibrated with (252)Cf neutron sources and are used in various workplace. A workplace-specific correction factor is suggested. In this study, the effect of the neutron spectrum on the accuracy of dose measurements was investigated. A set of neutron spectra representing various neutron environments was selected to study the dose responses of a series of Bonner spheres, including standard and extended-range spheres. By comparing (252)Cf-calibrated dose responses with reference values based on fluence-to-dose conversion coefficients, this paper presents recommendations for neutron field characterisation and appropriate correction factors for responses of conventional neutron dosemeters used in environments with high-energy neutrons. The correction depends on the estimated percentage of high-energy neutrons in the spectrum or the ratio between the measured responses of two Bonner spheres (the 4P6_8 extended-range sphere versus the 6" standard sphere). PMID- 25280481 TI - Tissue depletion of quinocetone and its five major metabolites in pigs, broilers, and carp fed quinocetone premix. AB - A residue depletion study was performed to investigate the tissue kinetics of quinocetone (1) and its major metabolites. Quinocetone and its major metabolites were simultaneously quantitated with a high-performance liquid chromatography ultraviolet (HPLC-UV) method. A total of 25 pigs, 30 broilers, and 50 carp were fed 100 mg/kg quinocetone for 90, 42, and 60 days, respectively. Liver, kidney, muscle, and fat (skin) tissues were collected at five different withdrawal times for analysis. Results revealed that quinocetone, 1-desoxyquinocetone (2), carbonyl-reduced 4-desoxyquinocetone (4), 3-methylquinoxaline-2-carboxylic acid (5), and carbonyl-reduced dideoxyquinocetone (6) could be depleted quickly in tissues; by contrast, dideoxyquinocetone, 3, persisted for a long time in the liver. Therefore, the liver is possibly the target tissue of quinocetone, and 3 is the residual marker; the recommended withdrawal times (WDTs) are 0 days in pigs and carp and 3 days in broilers. These results provided clear monitoring tools and technical standards to evaluate the food safety of quinocetone. PMID- 25280483 TI - Growth factor-eluting cochlear implant electrode: impact on residual auditory function, insertional trauma, and fibrosis. AB - BACKGROUND: A cochlear implant (CI) is an artificial hearing device that can replace a damaged cochlea. The present study examined the use of growth factor eluting gelatin hydrogel coatings on the electrodes to minimize inner ear trauma during electrode insertion. Insulin-like growth factor 1 (IGF1) and/or hepatocyte growth factor (HGF) were chosen as the agents to be administered. METHODS: Silicone CI electrode analogs were prepared and coated with gelatin hydrogels. Adsorption/release profile of the hydrogel was measured using (125)I-radiolabeled IGF. Hydrogel-coated electrodes were absorbed with IGF1, HGF, IGF1 plus HGF, or saline (control) and implanted into the basal turns of guinea pig cochleae (n = 5). Auditory sensitivity was determined pre-operatively, immediately after, and 3, 7, 14, 21, and 28 days post-operatively by using auditory brainstem response (ABR; 4-16 kHz). In addition, histological analysis was performed and auditory hair cell (HC) survival, spiral ganglion neuron (SGN) densities, and fibrous tissue thickness were measured. RESULTS: Compared to non-coated arrays, hydrogel coated electrodes adsorbed significantly greater amounts of IGF1 and continuously released it for 48 h. Residual hearing measured by ABR thresholds after surgery were elevated by 50-70 dB in all of the electrode-implanted animals, and was maximal immediately after operation. Thresholds were less elevated after hydrogel treatment, and the hearing protection improved when IGF1 or HGF was applied. Histopathologically, hair cell survival, spiral ganglion cell survival, and fibrous tissue thickness were not different between the experimental groups. No serious adverse events were observed during the 4-week observation period. CONCLUSIONS: Our findings provide the first evidence that hydrogel-coated, growth factor-releasing CI electrodes could attenuate insertional trauma and promote recovery from it, suggesting that this combination might be a new drug delivery strategy not only in cochlear implantation but also in treating clinical conditions characterized by inner ear damage. PMID- 25280484 TI - The GC + CC genotype at position -418 in TIMP-2 promoter and the -1575GA/-1306CC genotype in MMP-2 is genetic predisposing factors for prevalence of moyamoya disease. AB - BACKGROUND: To investigate the association of single-nucleotide polymorphisms (SNPs) in matrix metalloproteinases (MMPs)-2, -3, and -9 and tissue inhibitor of metalloproteinase (TIMP)-2 with moyamoya disease (MMD). We conducted a case control study of MMD patients by assessing the prevalence of six SNPs of MMP-2 1575G > A [rs243866], MMP-2 -1306C > T [rs243865], MMP-3 -1171 5a/6a [rs3025058], MMP-9 -1562C > T [rs3918242], MMP-9 Q279R [rs17576], and TIMP-2 -418G > C [rs8179090]. METHODS: Korean patients with MMD (n = 107, mean age, 20.9 +/- 15.9 years; 66.4% female) and 243 healthy control subjects (mean age, 23.0 +/- 16.1 years; 56.8% female) were included. The subjects were divided into pediatric and adult groups. The genotyping of six well-known SNPs (MMP-2 -1575G > A, MMP-2 1306C > T, MMP-3 -1171 5a/6a, MMP-9 -1562C > T, MMP-9 Q279R, and TIMP-2 -418G > C) in MMP and TIMP genes was performed by polymerase chain reaction-restriction fragment length polymorphism assays. RESULTS: A significantly higher frequency of the GC genotype for TIMP-2 -418 G > C was found in MMD patients. The MMP-9 Q279R GA + AA genotype showed a protective effect for MMD. The GA/CC MMP-2 -1575/-1306 genotype was significantly more prevalent in MMD patients. CONCLUSIONS: Our findings demonstrate that TIMP-2 -418 GC + CC and MMP-2 -1575GA/-1306CC genotypes could be genetic predisposing factors for MMD development. PMID- 25280485 TI - Study protocol for the PHANTOM study: prehospital assessment of noninvasive tissue oximetry monitoring. AB - BACKGROUND: Traumatic brain injury is a major cause of mortality and morbidity worldwide. It can be worsened by secondary injury particularly with hypoxia or hypotension. Current prehospital guidelines emphasise regular measurement of peripheral oxygen saturation and blood pressure but there is no monitor in use to provide direct information relating to blood flow or oxygen delivery to the brain tissue. This prospective cohort study will assess the utility of near-infrared spectroscopy monitoring in prehospital medicine in demonstrating injury, pathophysiology and associations with long-term functional outcomes. METHODS/DESIGN: A prospective cohort study will be conducted in prehospital services where physician/paramedic teams respond rapidly to patients suffering significant traumatic injuries. A study observer accompanying the clinical team will apply non-invasive near-infrared spectroscopy tissue oximetry using a Nonin EQUANOX 7610 Regional Oximetry monitor (TM Nonin Medical, Inc.). This will be applied to patients with traumatic injuries less than 30 minutes old requiring transport. Measurements will be taken at two sites on the forehead and one on the forearm. Clinical teams will be blinded to all monitoring values. Near-infrared spectroscopy tissue oximetry parameters of oxyhaemoglobin%, deoxyhaemoglobin%, total tissue haemoglobin index and regional oxygen saturation will be recorded. Separate statistical analysis relating to time spent with cerebral regional oxygen saturation values < 45% and time series analysis will be performed to demonstrate associations with acute phase outcomes including injuries seen on cerebral imaging, and long-term functional outcomes measured by Glasgow Outcome Score and Extended Glasgow Outcome Score will then be undertaken. DISCUSSION: This prospective cohort study will demonstrate associations evident from the earliest stages of prehospital treatment between near-infrared spectroscopy tissue oximetry values and both acute and long-term outcomes of patients suffering traumatic injuries. This may provide the basis for future interventional studies utilising near-infrared spectroscopy tissue oximetry to guide prehospital trauma care. TRIAL REGISTRATION: This trial is registered with the Australian and New Zealand Clinical Trials Registry. The registration number is ACTRN12611001124921 . PMID- 25280486 TI - In vivo dual targeting of the oncogenic Ether-a-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors. AB - BACKGROUND: The oncogenic ether-a-go-go-1 potassium channel (EAG1) activity and expression are necessary for cell cycle progression and tumorigenesis. The active vitamin D metabolite, calcitriol, and astemizole, a promising antineoplastic drug, target EAG1 by inhibiting its expression and blocking ion currents, respectively. We have previously shown a synergistic antiproliferative effect of calcitriol and astemizole in breast cancer cells in vitro, but the effect of this dual therapy in vivo has not been studied. METHODS: In the present study, we explored the combined antineoplastic effect of both drugs in vivo using mice xenografted with the human breast cancer cell line T-47D and a primary breast cancer-derived cell culture (MBCDF). Tumor-bearing athymic female mice were treated with oral astemizole (50 mg/kg/day) and/or intraperitoneal injections of calcitriol (0.03 MUg/g body weight twice a week) during 3 weeks. Tumor sizes were measured thrice weekly. For mechanistic insights, we studied EAG1 expression by qPCR and Western blot. The expression of Ki-67 and the relative tumor volume were used as indicators of therapeutic efficacy. RESULTS: Compared to untreated controls, astemizole and calcitriol significantly reduced, while the coadministration of both drugs further suppressed, tumor growth (P < 0.05). In addition, the combined therapy significantly downregulated tumoral EAG1 and Ki-67 expression. CONCLUSIONS: The concomitant administration of calcitriol and astemizole inhibited tumor growth more efficiently than each drug alone, which may be explained by the blocking of EAG1. These results provide the bases for further studies aimed at testing EAG1-dual targeting in breast cancer tumors expressing both EAG1 and the vitamin D receptor. PMID- 25280487 TI - Prevalence and risk factors of abnormal left ventricular geometrical patterns in untreated hypertensive patients. AB - BACKGROUND: The various prevalence of LVH and abnormal LV geometry have been reported in different populations. So far, only a few reports are available on the prevalence of LV geometric patterns in a large Chinese untreated hypertensive population. METHODS: A total of 9,286 subjects (5167 men and 4119 women) completed the survey and 1641 untreated hypertensive patients (1044 males and 597 females) enrolled in the present study. The LV geometry was classified into four patterns: normal; abnormal,defined as concentric remodeling;concentric or eccentric hypertrophy based on the values of left ventricular mass index (LVMI) and relative wall thickness (RWT). Logistic regression model was applied to determine the odds ratio (OR) and 95% confidence intervals (CI) of the risk factors of left ventricular hypertrophy. RESULTS: The prevalence of LVH was 20.2% in untreated hypertensive patients, much higher in women (30.8%) than in men (14.2%) (P < 0.01). The prevalence of LV geometrical patterns was 34.9%, 11.1%, 9.1% for concentric remodeling, concentric and eccentric hypertrophy,respectively. After adjustment by using Logistic regression model, the risk factors for LVH and abnormal LV geometry were age, female, systolic blood pressure, and body mass index. And low high density lipoprotein maybe a positive factor. CONCLUSIONS: The prevalence of LVH and abnormal LV geometric patterns was higher in women than in men and increased with age. It is crucial to improve the awareness rate of hypertension and control the risk factors of CV complications in untreated hypertensive population. PMID- 25280482 TI - Metabolic control of oocyte development: linking maternal nutrition and reproductive outcomes. AB - Obesity, diabetes, and related metabolic disorders are major health issues worldwide. As the epidemic of metabolic disorders continues, the associated medical co-morbidities, including the detrimental impact on reproduction, increase as well. Emerging evidence suggests that the effects of maternal nutrition on reproductive outcomes are likely to be mediated, at least in part, by oocyte metabolism. Well-balanced and timed energy metabolism is critical for optimal development of oocytes. To date, much of our understanding of oocyte metabolism comes from the effects of extrinsic nutrients on oocyte maturation. In contrast, intrinsic regulation of oocyte development by metabolic enzymes, intracellular mediators, and transport systems is less characterized. Specifically, decreased acid transport proteins levels, increased glucose/lipid content and elevated reactive oxygen species in oocytes have been implicated in meiotic defects, organelle dysfunction and epigenetic alteration. Therefore, metabolic disturbances in oocytes may contribute to the diminished reproductive potential experienced by women with metabolic disorders. In-depth research is needed to further explore the underlying mechanisms. This review also discusses several approaches for metabolic analysis. Metabolomic profiling of oocytes, the surrounding granulosa cells, and follicular fluid will uncover the metabolic networks regulating oocyte development, potentially leading to the identification of oocyte quality markers and prevention of reproductive disease and poor outcomes in offspring. PMID- 25280488 TI - A phase II study of ifosfamide, methotrexate, etoposide, and prednisolone for previously untreated stage I/II extranodal natural killer/T-cell lymphoma, nasal type: a multicenter trial of the Korean Cancer Study Group. AB - BACKGROUND: Combination chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) was active as first-line and second-line treatment for extranodal natural killer/T-cell lymphoma (NTCL). METHODS: Forty four patients with chemo-naive stage I/II NTCL were enrolled in a prospective, multicenter, phase II study and received six cycles of IMEP (ifosfamide 1.5 g/m(2) on days 1-3; methotrextate 30 mg/m(2) on days 3 and 10; etoposide 100 mg/m(2) on days 1-3; and prednisolone 60 mg/m(2) per day on days 1-5) followed by involved field radiotherapy (IFRT). RESULTS: Overall response rates were 73% (complete remission [CR] in 11 of 41 evaluable patients [27%]) after IMEP chemotherapy and 78% (CR 18 of 27 evaluable patients [67%]) after IMEP followed by IFRT. Neutropenia and thrombocytopenia were documented in 33 patients (75%) and 7 patients (16%), respectively. Only 8 patients (18%) experienced febrile neutropenia. Three-year progression-free survival (PFS) and overall survival (OS) were 66% and 56%, respectively. High Ki-67 (>=70%) and Ann Arbor stage II independently reduced PFS (p = .004) and OS (p = .001), respectively. CONCLUSION: Due to the high rate of progression during IMEP chemotherapy, IFRT needs to be introduced earlier. Moreover, active chemotherapy including an l-asparaginase based regimen should be use to reduce systemic treatment failure in stage I/II NTCL. PMID- 25280489 TI - A phase I/II study of XELIRI plus bevacizumab as second-line chemotherapy for Japanese patients with metastatic colorectal cancer (BIX study). AB - BACKGROUND: Capecitabine is used mainly with oxaliplatin to treat metastatic colorectal cancer (mCRC). Results from capecitabine plus irinotecan (XELIRI) with or without bevacizumab (BV) have been reported in Europe but not in Japan. Consequently, the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC were assessed in a single-arm phase II study. METHODS: Eligible patients had had prior chemotherapy containing BV for mCRC and wild-type or heterozygous UGT1A1. Therapy in each 21-day treatment cycle consisted of capecitabine (800 mg/m(2) twice daily on days 1-15), irinotecan (200 mg/m(2) on day 1), and BV (7.5 mg/kg on day 1). The primary endpoint was dose-limiting toxicity in phase I and progression-free survival (PFS) in phase II. RESULTS: A total of 34 patients (6 in phase I, 28 in phase II) were enrolled from May 2010 to June 2011. Baseline characteristics included a median age of 60 years (range: 22-74 years) for 24 men and 10 women. No dose-limiting toxicities appeared in phase I. Median PFS was 240 days (95% confidence interval: 179-311 days). Overall response rate was 18.1%, and the disease-control rate was 90.9%. The incidence of adverse events frequently associated with irinotecan and capecitabine were neutropenia (any grade, 55.9%; grade 3 or 4, 11.8%), diarrhea (any grade, 50%; grade 3 or 4, 5.9%), and hand-foot syndrome (any grade, 61.8%; grade 3 or 4, 5.9%). CONCLUSION: Our results suggest that XELIRI plus BV is well tolerated and effective as a second-line treatment for mCRC in Japanese patients. This regimen could be especially appropriate for patients resistant to oxaliplatin-based regimens. PMID- 25280490 TI - Updated product label allows home administration of omacetaxine mepesuccinate. PMID- 25280491 TI - A revised interview for deterioration in daily living activities in dementia reveals the relationship between social activities and well-being. AB - BACKGROUND: The ability to perform instrumental activities of daily living deteriorates early in dementia and affects people with dementia and their carers. However, little is known about individual instrumental activities of daily living impairments. This study therefore investigated instrumental activities of daily living deficits in mild dementia by exploring the relationship between instrumental activities of daily living initiative and performance and general cognition, people with dementia quality of life and carer stress. Moreover, this study explored the contribution of social instrumental activities of daily livings, which to date have received little or no attention. METHODS: Twenty carers were administered a revised Interview for Deterioration for Daily Living Activities in Dementia and measures of carer stress (General Health Questionnaire 12) and quality of life in dementia (Quality of Life in Alzheimer's Disease). The people with dementia completed measures of general cognition (Mini-Mental State Examination and Montreal Cognitive Assessment). Data were analysed using frequency and bivariate correlation analyses and basic thematic analysis was employed to the qualitative data on carer stress. RESULTS: Carer interviews showed that instrumental activities of daily living impairments were associated more with performance than with initiative deficits. Increased social isolation and reluctance to engage in hobbies were particularly stressful to carers and impacted negatively on the people with dementia quality of life, yet were not reported as critical in the qualitative assessment. CONCLUSIONS: This study shows that people with mild dementia are impaired to different degrees on their initiative and performance of instrumental activities of daily livings and that impairments relating to social activities particularly relate to well-being. The revised Interview for Deterioration for Daily Living Activities in Dementia with its social instrumental activities of daily livings can help shift the focus of interventions to address those activities that are frequently impaired in mild dementia and relate to people with dementia and carer well-being. PMID- 25280492 TI - Beginning to explore the experience of managing a direct payment for someone with dementia: The perspectives of suitable people and adult social care practitioners. AB - Following legal improvements made around mental capacity together with the Health and Social Care Act, it is now possible for a direct payment to be paid to a 'Suitable Person' to manage on someone's behalf to purchase directly care and support services. People with dementia are a key group affected by this change in England of adult social care. We interviewed nine social care practitioners and seven Suitable People for people with dementia across five English local authorities to begin to examine their experiences of this new method of social care provision. Findings from thematic analyses suggest positive outcomes and multiple beneficiaries, but some challenges: potentially inappropriate processes, support planning, divergence in attitudes towards care and support outcomes. Implications for practice include obfuscation of recipients' and Suitable People's best interests and supporting practitioners to explore fully clients' aspirations for care and support. PMID- 25280493 TI - The Thoughts Questionnaire (TQ) for family caregivers of people with dementia. AB - OBJECTIVES: To develop a new measure of dysfunctional thoughts for family caregivers of people living with dementia. These thoughts can contribute to negative outcomes, but they may be modifiable. METHOD: A stepwise process was used to develop the Thoughts Questionnaire, commencing with item generation, concept mapping, and pilot testing in a sample of professional and nonprofessional caregivers of people with dementia (n = 18). Next, an independent sample of 35 family caregivers of people with dementia (30 female; Mage = 64.30, standard deviation = 10.65) completed: (a) the Thoughts Questionnaire; (b) an existing measure of dysfunctional thoughts, the Dementia Thoughts Caregivers Questionnaire; and (c) separate validated measures of depressive symptoms, caregiver stress, and coping, respectively. RESULTS: The level of agreement with dysfunctional thought statements from the Dementia Thoughts Caregivers Questionnaire and Thoughts Questionnaire was low. However, a small number of Thoughts Questionnaire statements were strongly endorsed by over 85% of the sample. Both dysfunctional thought measures had adequate reliability, but total scores were not significantly intercorrelated (r = .287, p = .095). Only the Thoughts Questionnaire was significantly, positively correlated with most caregiver stress measures. Thoughts Questionnaire items required a much lower reading level than the Dementia Thoughts Caregivers Questionnaire items. DISCUSSION: This study provides preliminary data on a tool for assessing the negative role-related thoughts that family caregivers of people with dementia may experience. Given that these thoughts are implicated in depression but they may be modified, the capacity to identify dysfunctional thoughts may prove useful in caregiver support programs. PMID- 25280494 TI - Functional somatic syndromes: asking about exclusionary medical conditions results in decreased prevalence and overlap rates. AB - BACKGROUND: The diagnosis of functional somatic syndromes (FSS) requires 1) presence of somatic symptoms, and 2) absence of medical conditions potentially accounting for these symptoms. Due to the limited feasibility of medical examinations, epidemiological research on FSS has neglected to assess the second criterion. Our objective was therefore to evaluate the implications of considering information on exclusionary medical conditions in epidemiological research on FSS. METHODS: A survey among 3'054 students was conducted. We compared prevalence rates and overlap of 17 FSS obtained by: 1) a symptom-based strategy and 2) a symptom-and-exclusion-based strategy including information on exclusionary medical conditions. RESULTS: The symptom-and-exclusion-based strategy led to a marked decrease in prevalence rates compared to the symptom based strategy. Furthermore, it resulted in fewer individuals who were affected by multiple FSS. CONCLUSIONS: Adding self-reported information on exclusionary medical conditions leads to a significant decrease in the prevalence and overlap of FSS. More rigorous approaches to studying FSS should be adopted. PMID- 25280496 TI - Dietary fiber, kidney function, inflammation, and mortality risk. AB - BACKGROUND AND OBJECTIVES: In the United States population, high dietary fiber intake has been associated with a lower risk of inflammation and mortality in individuals with kidney dysfunction. This study aimed to expand such findings to a Northern European population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Dietary fiber intake was calculated from 7-day dietary records in 1110 participants aged 70-71 years from the Uppsala Longitudinal Study of Adult Men (examinations performed during 1991-1995). Dietary fiber was adjusted for total energy intake by the residual method. Renal function was estimated from the concentration of serum cystatin C, and deaths were registered prospectively during a median follow-up of 10.0 years. RESULTS: Dietary fiber independently and directly associated with eGFR (adjusted difference, 2.6 ml/min per 1.73 m(2) per 10 g/d higher; 95% confidence interval [95% CI], 0.3 to 4.9). The odds of C reactive protein >3 mg/L were lower (linear trend, P=0.002) with higher fiber quartiles. During follow-up, 300 participants died (incidence rate of 2.87 per 100 person-years at risk). Multiplicative interactions were observed between dietary fiber intake and kidney dysfunction in the prediction of mortality. Higher dietary fiber was associated with lower mortality in unadjusted analysis. These associations were stronger in participants with kidney dysfunction (eGFR<60 ml/min per 1.73 m(2)) (hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.98) than in those without (HR, 1.30; 95% CI, 0.76 to 2.22; P value for interaction, P=0.04), and were mainly explained by a lower incidence of cancer-related deaths (0.25; 95% CI, 0.10 to 0.65) in individuals with kidney dysfunction versus individuals with an eGFR>=60 ml/min per 1.73 m(2) (1.61; 95% CI, 0.69 to 3.74; P value for interaction, P=0.01). CONCLUSIONS: High dietary fiber was associated with better kidney function and lower inflammation in community-dwelling elderly men from Sweden. High dietary fiber was also associated with lower (cancer) mortality risk, especially in individuals with kidney dysfunction. PMID- 25280495 TI - Chemical and Physical Sensors in the Regulation of Renal Function. AB - In order to assess the status of the volume and composition of the body fluid compartment, the kidney monitors a wide variety of chemical and physical parameters. It has recently become clear that the kidney's sensory capacity extends well beyond its ability to sense ion concentrations in the forming urine. The kidney also keeps track of organic metabolites derived from a surprising variety of sources and uses a complex interplay of physical and chemical sensing mechanisms to measure the rate of fluid flow in the nephron. Recent research has provided new insights into the nature of these sensory mechanisms and their relevance to renal function. PMID- 25280497 TI - Recognition and reporting of AKI in very low birth weight infants. AB - BACKGROUND AND OBJECTIVES: AKI is associated with both increased short-term morbidity and mortality and greater long-term risk for CKD. This study determined the prevalence of AKI among very low birth weight infants using a modern study definition, evaluated the frequency of AKI diagnosis reporting in the discharge summary, and determined whether infants were referred to a pediatric nephrologist for AKI follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Records of very low birth weight infants admitted to a level IV neonatal intensive care unit from 2008 to 2011 were reviewed. AKI was classified using the Kidney Disease: Improving Global Outcomes definition modified to include only serum creatinine. RESULTS: AKI occurred in 39.8% of 455 infants; 75 (16.5%) infants experienced multiple episodes of AKI, and 8 (2%) infants were discharged with an abnormal last creatinine. Updated clinical risk index for babies score >10 (odds ratio, 12.9; 95% confidence interval, 7.8 to 21.4) and gestational age <28 weeks (odds ratio, 10.6; 95% confidence interval, 6.8 to 16.7) were strongly associated with AKI in univariate analyses. AKI was associated with increased mortality (odds ratio, 4.0; 95% confidence interval, 1.4 to 11.5) and length of stay (11.7 hospital days; 95% confidence interval, 5.1 to 18.4), even after accounting for gestational age, birth weight, and updated clinical risk index for babies score. AKI was recorded in the discharge summary for only 13.5% of AKI survivors. No infants were referred to a nephrologist for AKI follow-up. CONCLUSIONS: AKI occurred in 40% of very low birth weight infants and was concentrated in the most premature and severely ill infants. One in six infants experienced multiple episodes of AKI, and a small number of infants was discharged with an elevated serum creatinine. Reporting a history of AKI in the discharge summary occurred infrequently, and referral to a nephrologist for AKI follow-up did not occur, highlighting areas for quality improvement. PMID- 25280498 TI - Prevalence and antibiotic resistance pattern of urinary tract bacterial infections in Dessie area, North-East Ethiopia. AB - BACKGROUND: Different studies have indicated that urinary tract infections frequently occur in both community and hospital environments and are of the most common bacterial infections in humans. the outcomes of urinary tract infections are increased hospitalization, increased direct patient costs and mortality. In Dessie, the prevalence of the commmon pathogens and antibiotic susceptibility pattern is not well studied sofar. Thus, the aim of this study is to address these gaps in the study area. METHODS: Retrospective study was conducted in Dessie regional health reseacrh laboratory from January 1-March 31, 2012. All culture and antibiotic susceptibility test results of patients' diagnosed with UTI from September 2002 to September 2011 G.C were included in the study. Data were abstracted using structured questionnaires and finally, entered into SPSS Windows version 16.0, and descriptive statistics was generated to meet the study objective. RESULTS: During the last ten years 680 (27.35%) bacteria were isolated in the regional laboratory. The most commonly isolated were E. coli 410 (60.29%), Pseudomonas species 59 (8.68%), Proteus species 53 (7.79%), S. aurous 50 (7.35%) and Klebsiella species 40 (5.88%). The E.coli were susceptible to Nitrofurantoin 43 (89.6%), furantoin 124 (87.3%), Nalidixic acid 91 (86.7%), kanamycin 116 (80%) & ciprofloxacin 66 (71.7%) but were almost resistant to Ampicillin, tetracycline, & trimethoprim-sulfamethoxazole. Similarly Pseudomonas and proteus species were resistant to almost all antibiotics except Gentamycin. CONCLUSION: The E.coli, pseudomonas and proteus species were the commonly isolated bacteria in the regional health research laboratory. A majority of isolated bacterial microbes were resistant to antibiotics commonly used in clinical practices and generally available in the local economy without prescription. Culture results are necessary before initiating antibiotics. PMID- 25280499 TI - Comparing multilevel and Bayesian spatial random effects survival models to assess geographical inequalities in colorectal cancer survival: a case study. AB - BACKGROUND: Multilevel and spatial models are being increasingly used to obtain substantive information on area-level inequalities in cancer survival. Multilevel models assume independent geographical areas, whereas spatial models explicitly incorporate geographical correlation, often via a conditional autoregressive prior. However the relative merits of these methods for large population-based studies have not been explored. Using a case-study approach, we report on the implications of using multilevel and spatial survival models to study geographical inequalities in all-cause survival. METHODS: Multilevel discrete time and Bayesian spatial survival models were used to study geographical inequalities in all-cause survival for a population-based colorectal cancer cohort of 22,727 cases aged 20-84 years diagnosed during 1997-2007 from Queensland, Australia. RESULTS: Both approaches were viable on this large dataset, and produced similar estimates of the fixed effects. After adding area level covariates, the between-area variability in survival using multilevel discrete-time models was no longer significant. Spatial inequalities in survival were also markedly reduced after adjusting for aggregated area-level covariates. Only the multilevel approach however, provided an estimation of the contribution of geographical variation to the total variation in survival between individual patients. CONCLUSIONS: With little difference observed between the two approaches in the estimation of fixed effects, multilevel models should be favored if there is a clear hierarchical data structure and measuring the independent impact of individual- and area-level effects on survival differences is of primary interest. Bayesian spatial analyses may be preferred if spatial correlation between areas is important and if the priority is to assess small-area variations in survival and map spatial patterns. Both approaches can be readily fitted to geographically enabled survival data from international settings. PMID- 25280500 TI - Impact of endometriosis on women's lives: a qualitative study. AB - BACKGROUND: This study aimed to explore women's experiences of the impact of endometriosis and whether there are differences across three age groups. METHODS: A qualitative descriptive design was conducted using semi-structured focus group discussions with 35 Australian women with endometriosis, in three age groups. All tape-recorded discussions were transcribed verbatim and read line by line to extract meaningful codes and categories using NVivo 9 software through a thematic analysis approach. Categories were then clustered into meaningful themes. RESULTS: Participants' ages ranged from 17 to 53 years and had a history of 2 to 40 years living with endometriosis, with an average delay time to diagnosis of 8.1 years. Two main themes emerged: (1) experiences of living with endometriosis, and (2) impact of endometriosis on women's lives, with 14 discrete categories. The results showed similarities and differences of the impact between the three age groups. The most highlighted impacts were on marital/sexual relationships, social life, and on physical and psychological aspects in all three age groups, but with different orders of priority. Education was the second most highlighted for the 16-24 years, life opportunities and employment for the 25-34 years; and financial impact for those 35 years and above. CONCLUSIONS: Our findings show that endometriosis impacts negatively on different aspects of women's lives. A better understanding of these findings could help to decrease the negative impact of endometriosis by guiding service delivery and future research to meet more effectively the needs of women and teenagers with this condition. PMID- 25280501 TI - Comparative and genetic analysis of the four sequenced Paenibacillus polymyxa genomes reveals a diverse metabolism and conservation of genes relevant to plant growth promotion and competitiveness. AB - BACKGROUND: Members of the genus Paenibacillus are important plant growth promoting rhizobacteria that can serve as bio-reactors. Paenibacillus polymyxa promotes the growth of a variety of economically important crops. Our lab recently completed the genome sequence of Paenibacillus polymyxa CR1. As of January 2014, four P. polymyxa genomes have been completely sequenced but no comparative genomic analyses have been reported. RESULTS: Here we report the comparative and genetic analyses of four sequenced P. polymyxa genomes, which revealed a significantly conserved core genome. Complex metabolic pathways and regulatory networks were highly conserved and allow P. polymyxa to rapidly respond to dynamic environmental cues. Genes responsible for phytohormone synthesis, phosphate solubilization, iron acquisition, transcriptional regulation, sigma-factors, stress responses, transporters and biomass degradation were well conserved, indicating an intimate association with plant hosts and the rhizosphere niche. In addition, genes responsible for antimicrobial resistance and non-ribosomal peptide/polyketide synthesis are present in both the core and accessory genome of each strain. Comparative analyses also reveal variations in the accessory genome, including large plasmids present in strains M1 and SC2. Furthermore, a considerable number of strain-specific genes and genomic islands are irregularly distributed throughout each genome. Although a variety of plant growth promoting traits are encoded by all strains, only P. polymyxa CR1 encodes the unique nitrogen fixation cluster found in other Paenibacillus sp. CONCLUSIONS: Our study revealed that genomic loci relevant to host interaction and ecological fitness are highly conserved within the P. polymyxa genomes analysed, despite variations in the accessory genome. This work suggets that plant-growth promotion by P. polymyxa is mediated largely through phytohormone production, increased nutrient availability and bio-control mechanisms. This study provides an in-depth understanding of the genome architecture of this species, thus facilitating future genetic engineering and applications in agriculture, industry and medicine. Furthermore, this study highlights the current gap in our understanding of complex plant biomass metabolism in Gram positive bacteria. PMID- 25280503 TI - The dynamics of low-chlorinated benzenes in a pilot-scale constructed wetland and a hydroponic plant root mat treating sulfate-rich groundwater. AB - A rarely used hydroponic plant root mat filter (PRMF, of 6 m(2)) and a horizontal subsurface flow constructed wetland (HSSF CW, of 6 m(2)), operating in continuous flow and discontinuous outflow flushing modes, were investigated for treating sulfate-rich and organic carbon-lean groundwater contaminated with monochlorobenzene (MCB); 1,2-dichlorobenzene (1,2-DCB); 1,4-dichlorobenzene (1,4 DCB); and 2-chlorotoluene. Whereas the mean inflow loads ranged from 1 to 247 mg m(-2) days(-1), the range of mean inflow concentrations of the chlorobenzenes recorded over a period of 7 months was within 0.04 and 8 mg L(-1). A hydraulic surface loading rate of 30 L m(-2) days(-1) was obtained in both systems. The mean load removal efficiencies were found to vary between 87 and 93 % in the PRMF after a flow path of 4 m, while the removal efficiencies were found to range between 46 and 70 % and 71 to 73 % in the HSSF CW operating in a continuous flow mode and a discontinuous outflow flushing mode, respectively. Seasonal variations in the removal efficiencies were observed for all low-chlorinated hydrocarbons both in the PRMF and the HSSF CW, whereby the highest removal efficiencies were reached during the summer months. Sulfide formation occurred in the organic carbon-lean groundwater particularly in summer, which is probably due to the plant-derived organic carbon that fostered the microbial dissimilatory sulfate reduction. Higher redox potential in water was observed in the PRMF. In conclusion, the PRMF could be an option for the treatment of water contaminated with compounds which in particular need oxic conditions for their microbial degradation, such as in the case of low-chlorinated benzenes. PMID- 25280502 TI - Application of molecularly imprinted polymers in wastewater treatment: a review. AB - Molecularly imprinted polymers are synthetic polymers possessing specific cavities designed for target molecules. They are prepared by copolymerization of a cross-linking agent with the complex formed from a template and monomers that have functional groups specifically interacting with the template through covalent or noncovalent bonds. Subsequent removal of the imprint template leaves specific cavities whose shape, size, and functional groups are complementary to the template molecule. Because of their predetermined selectivity, molecularly imprinted polymers (MIPs) can be used as ideal materials in wastewater treatment. Especially, MIP-based composites offer a wide range of potentialities in wastewater treatment. This paper reviews the latest applications of MIPs in wastewater treatment, highlights the development of MIP-based composites in wastewater, and offers suggestions for future success in the field of MIPs. PMID- 25280504 TI - Polycyclic aromatic hydrocarbons (PAHs) in sea sediments of the Turkish Mediterranean coast, composition and sources. AB - The concentrations of polycyclic aromatic hydrocarbons (PAHs) were determined in 25 surface sediment samples from five sites located at Oludeniz Lagoon of the Turkish Mediterranean coast. The total concentration of the PAHs (1.85 +/- 1.39 mg/kg) was lower than the sediments from highly urbanized areas, while it was comparable with the sediments from similar locations. Acenaphthene and chrysene were dominant ones with the concentrations of 0.620 and 0.515 mg/kg, respectively. The isomeric ratios indicated that combustion is the predominant source of PAHs in the sediments. Factor analysis solution supports the same finding with three major factors accounting for 71.7% of the variability in the data. Factor 1 with 43.4% of the total variance identified as a pyrogenic source (coal combustion; 4 rings PAH and traffic related pollution; 5-6 rings PAHs). Factor 2 (explains 39% of the total variance) represents PAHs originating from traffic, and factor 3 (explains 12% of the total variance) represents petrogenic source. Our results suggest that combustion of fossil fuels affects most of the points, followed by combustion of biomass and human activity. PMID- 25280506 TI - Study on emission characteristics and reduction strategy of nitrous oxide during wastewater treatment by different processes. AB - Given the inexorable increase in global wastewater treatment, increasing amounts of nitrous oxide are expected to be emitted from wastewater treatment plants and released to the atmosphere. It has become imperative to study the emission and control of nitrous oxide in the various wastewater treatment processes currently in use. In the present investigation, the emission characteristics and the factors affecting the release of nitrous oxide were studied via full- and pilot scale experiments in anoxic-oxic, sequencing batch reactor and oxidation ditch processes. We propose an optimal treatment process and relative strategy for nitrous oxide reduction. Our results show that both the bio-nitrifying and bio denitrifying treatment units in wastewater treatment plants are the predominant sites for nitrous oxide production in each process, while the aerated treatment units are the critical sources for nitrous oxide emission. Compared with the emission of nitrous oxide from the anoxic-oxic (1.37% of N-influent) and sequencing batch reactor (2.69% of N-influent) processes, much less nitrous oxide (0.25% of N-influent) is emitted from the oxidation ditch process, which we determined as the optimal wastewater treatment process for nitrous oxide reduction, given the current technologies. Nitrous oxide emissions differed with various operating parameters. Controlling the dissolved oxygen concentration at a proper level during nitrification and denitrification and enhancing the utilization rate of organic carbon in the influent for denitrification are the two critical methods for nitrous oxide reduction in the various processes considered. PMID- 25280507 TI - Artificial neural network modelling of biological oxygen demand in rivers at the national level with input selection based on Monte Carlo simulations. AB - Biological oxygen demand (BOD) is the most significant water quality parameter and indicates water pollution with respect to the present biodegradable organic matter content. European countries are therefore obliged to report annual BOD values to Eurostat; however, BOD data at the national level is only available for 28 of 35 listed European countries for the period prior to 2008, among which 46% of data is missing. This paper describes the development of an artificial neural network model for the forecasting of annual BOD values at the national level, using widely available sustainability and economical/industrial parameters as inputs. The initial general regression neural network (GRNN) model was trained, validated and tested utilizing 20 inputs. The number of inputs was reduced to 15 using the Monte Carlo simulation technique as the input selection method. The best results were achieved with the GRNN model utilizing 25% less inputs than the initial model and a comparison with a multiple linear regression model trained and tested using the same input variables using multiple statistical performance indicators confirmed the advantage of the GRNN model. Sensitivity analysis has shown that inputs with the greatest effect on the GRNN model were (in descending order) precipitation, rural population with access to improved water sources, treatment capacity of wastewater treatment plants (urban) and treatment of municipal waste, with the last two having an equal effect. Finally, it was concluded that the developed GRNN model can be useful as a tool to support the decision-making process on sustainable development at a regional, national and international level. PMID- 25280509 TI - Erratum to: TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF. PMID- 25280508 TI - E2 potentializes benzo(a)pyrene-induced hepatic cytochrome P450 enzyme activities in Nile tilapia at high concentrations. AB - In the aquatic environment, biotransformation enzymes are established biomarkers for assessing PAH exposure in fish, but little is known about the effect of 17beta-estradiol (E2) on these enzymes during exposure to benzo(a)pyrene (BaP). In this study, Nile tilapia (Oreochromis niloticus) were exposed for 3, 5, and 10 days to BaP (300 MUg L(-1)) and E2 (5 MUg L(-1)). These substances were applied isolated or mixed. In the mixture experiment, fish were analyzed pre- and postexposure in order to better understand whether preexposure to the hormone masks the responses activated by PAH or vice versa. Phase I enzymes ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin-O-depenthylase (PROD), and benzyloxyresorufin-O-debenzylase (BROD) activities as well as the phase II enzyme glutathione S-transferase (GST) were analyzed. Isolated E2 treatment decreased EROD activity after 3 days, but this enzyme activity returned to control values after 5 and 10 days of exposure. Isolated BaP treatment significantly induced EROD activity after 3 and 5 days, and the activity returned to control levels after ten exposure days. Combined treatment (E2 + Bap) significantly increased EROD activity, both in the pre- and postexposure. This increase was even higher than in the isolated BaP treatment, suggesting a synergism between these two compounds. When E2 and BaP were used singly, they did not change BROD and PROD activities. However, combined treatment (E2 + Bap) significantly increased PROD activity. Isolated BaP treatment increased GST activity after 10 days. However, this response was not observed in the mixture treatment, suggesting that E2 suppressed the GST induction modulated by BaP. The results put together indicated that E2 altered the biotransformation pathway regarding enzymes activated by BaP in Nile tilapia. PMID- 25280510 TI - Connective tissue graft as a biological barrier for guided tissue regeneration in intrabony defects: a histological study in dogs. AB - BACKGROUND: The use of the autogenous periosteal graft as biological barrier has been proposed for periodontal regeneration. The aim of this study was to evaluate the histometric findings of the subepithelial connective tissue graft as barrier in intrabony defects compared to a bioabsorbable membrane. METHODS: Three-walled intrabony defects were created surgically in the mesial aspect of the right and left maxillary canines in five healthy mongrel dogs. The defects were chronified, and two types of barriers were randomly carried out for guided tissue regeneration in a split-mouth design: the test group with a subepithelial connective tissue graft and the control group with a bioabsorbable membrane. The specimens were processed for histometric analyses of the epithelium (E), connective tissue (CT), newly formed cementum (NC), new bone (NB), and total newly formed tissues (NFT). RESULTS: The test side showed smaller mean of NC (3.6 +/- 1.2), NB (2.1 +/- 0.7), and NFT (7.7 +/- 0.8) than the control group (NC 7.3 +/- 0.5; NB 5.3 +/- 1.3; NFT 10.1 +/- 2.2; P < 0.05). No statistically significant differences were verified for E (test 3.1 +/- 2.0; control 2.8 +/- 2.1; P > 0.05) and CT (test 2.5 +/- 1.1; control 2.0 +/- 0.5; P > 0.05) between groups. CONCLUSION: The bioabsorbable membrane was more effective in maintaining the space for periodontal regeneration than periosteal connective graft when used as barrier. CLINICAL RELEVANCE: The bioabsorbable membrane showed more favorable regenerative results in intrabony defects in dogs than the subepithelial connective tissue graft as biological barrier. PMID- 25280511 TI - Post-endodontic treatment of incisors and premolars among dental practitioners in Saarland: an interactive Web-based survey. AB - OBJECTIVES: The aim of the present study was to evaluate the trend of dental practitioners in the federal state of Saarland in Germany in regard to restoring endodontically treated teeth using a Web-based survey. MATERIALS AND METHODS: An interactive Web-based survey instrument was developed, including seven clinical scenarios, presented by photographs of natural incisor and premolar with different types of cavities. Following a decision tree adapted to the clinical treatment, questions on different aspects of the post-endodontic treatment were asked. All 615 members of the Saarland Dental Association (SDA) were asked to participate in the survey. RESULTS: A total of 33 % completed the survey. The majority of the participants believed in the reinforcement effect of the ferrule design, as well as the post placement. The vast majority of the responding practitioners (92 %) adapted their treatment strategies to a high extent to the destruction degree of the endodontically treated tooth. Fiber-reinforced composite (FRC) posts are the most popular prefabricated post type, regardless of the cavity size and tooth localization. Significant differences between the dentists according to the degree of experience were detected only for the use of glass-ionomer cements as core buildup material. CONCLUSIONS: The predominant post endodontic treatment strategies of German dental practitioners are only partly in agreement with the current literature. There is a clear trend toward the increasing use of metal-free post and core materials. CLINICAL SIGNIFICANCE: Although the participants showed a general adoption of modern materials and techniques, different patterns of post-endodontic treatment were revealed that were not consistent with approaches supported by the literature. PMID- 25280513 TI - Introduction to pediatric congenital heart disease. PMID- 25280512 TI - Clobazam monotherapy for partial-onset or generalized-onset seizures. AB - BACKGROUND: There is a need to expand monotherapy options available to a clinician for the treatment of new partial-onset or generalized-onset seizures. A Cochrane systematic review for clobazam monotherapy is expected to define its place in the treatment of new-onset or untreated seizures and highlight gaps in evidence. OBJECTIVES: To evaluate the efficacy, effectiveness, tolerability and safety of clobazam as monotherapy in people with new-onset partial or generalized seizures. SEARCH METHODS: We searched the following databases: Cochrane Epilepsy Group Specialized Register (5 March 2013), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, January 2013, Issue 1), MEDLINE (Ovid, 1946 to July 1, 2014), Database of Abstracts of Reviews of Effectiveness (DARE, January 2013, Issue 1), BIOSIS Previews (all years, searched on 5 March 2013). There were no language restrictions. SELECTION CRITERIA: Randomized or quasi-randomised controlled trials comparing clobazam monotherapy versus placebo or other anti-seizure medication in people with two or more unprovoked seizures or single acute symptomatic seizure requiring short-term continuous anti-seizure medication, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Primary outcome measure was time on allocated treatment (retention time), reflecting both efficacy and tolerability. Secondary outcomes included short- and long-term effectiveness measures, tolerability, quality of life, and tolerance measures. Two authors independently extracted the data. MAIN RESULTS: We identified two trials fulfilling the review criteria, which included 163 participants. None of the identified studies reported the preselected primary outcome measure. A meta analysis was not possible. Lack of detail regarding concealment of allocation and a high risk of performance and detection bias in one study prompted us to downgrade the quality of evidence for some of our results due to risk of bias.Regarding retention at 12 months, we detected no evidence of a statistically significant difference between clobazam and carbamazepine (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.61 to 1.12); low quality evidence. There was low quality evidence that clobazam led to better retention compared with phenytoin (RR 1.43, 95% CI 1.08 to 1.90). We could not determine whether participants receiving clobazam were found to be less likely to discontinue it due to adverse effects as compared to phenytoin (RR 0.10, 95% CI 0.01 to 1.65, low quality evidence). AUTHORS' CONCLUSIONS: We found no advantage for clobazam over carbamazepine for retention at 12 months in drug-naive children and a slight advantage of clobazam over phenytoin for retention at six months in adolescents and adults with neurocysticercosis in a single clinical trial each. At present, the available evidence is insufficient to inform clinical practice. PMID- 25280514 TI - Degree of associations among vectors of the genus Culicoides (Diptera: Ceratopogonidae) and host bird species with respect to haemosporidian parasites in NE Bulgaria. AB - The occurrence of haemosporidians in biting midges of the genus Culicoides is examined in North-East Bulgaria in order to reveal their potential role for parasite transmission. A PCR-based technique amplifying part of the mitochondrial cytochrome b gene of the parasite is applied on naturally infected biting midges. Totally, 640 parous individuals of four species and 95 blood-fed individuals of six species of Culicoides are examined for the presence of DNA of haemosporidians. Haemosporidian genetic lineages are identified in individuals of three insect species: Culicoides alazanicus (12 lineages, nine lineages of Haemoproteus and three lineages of Plasmodium), Culicoides festivipennis and Culicoides circumscriptus (with two and one lineages of Haemoproteus, respectively). Two genetic lineages of Haemoproteus are recorded in more than one vector species. These results demonstrate variations in the specificity of Haemoproteus genetic lineages to their potential vectors, since some lineages are recorded in a single vector species and others occur in two or more vector species. PMID- 25280515 TI - Activity of ivermectin long-acting injectable (IVOMEC((r)) GOLD) in first-season grazing cattle exposed to natural challenge conditions in Germany. AB - The persistent activity of ivermectin long-acting injection (IVM LAI; IVOMEC(r) GOLD, Merial; 3.15% ivermectin w/v) against nematode infections of cattle was evaluated under natural challenge conditions. Seventy nematode-free Brown Swiss calves were blocked by pre-treatment bodyweight and allocated randomly to seven groups of 10 animals each: saline (control) at 1 mL/50 kg bodyweight once on day 0 or IVM LAI at 1 mL/50 kg bodyweight (630 mcg IVM/kg) on either days 0, 7, 14, 21, 28, or 35. After housing until day 35, calves were grazed as one herd on a naturally contaminated pasture for 42 days. Calves were then weighed and housed for 4 weeks before being necropsied for parasite counting. Treatment with IVM LAI prevented the establishment (>90%, p < 0.05) of Dictyocaulus viviparus (100%), Bunostomum phlebotomum (100 %), Haemonchus contortus (98.6%), Ostertagia ostertagi/lyrata (94.9%), and Oesophagostomum radiatum (93.3%) for at least 77 days; Ostertagia leptospicularis (99.1%) for 63 days; Cooperia punctata (97.7%), Trichostrongylus axei (96.5%), and Ostertagia spp. inhibited larvae 4 (93.3%) for 56 days; Cooperia oncophora/surnabada (96.9%), Trichuris discolor (93.6%), and Cooperia spp. inhibited larvae 4 (98.8%); and Nematodirus spp. inhibited larvae 4 (97.1%) for 42 days. Calves of groups treated with IVM LAI had significantly (p < 0.001) higher days 0 to 77 weight gains than the saline-treated controls (28.40 39.25 vs 2.60 kg); the weight gains of the IVM LAI-treated groups, however, were not different from one another (p > 0.3). This study demonstrated a very high efficacy of IVOMEC(r) GOLD in preventing the establishment of a wide range of bovine nematodes for extended periods of time which was associated with a significant benefit to productivity in terms of weight gain. PMID- 25280516 TI - Piroplasmosis in an endemic area: analysis of the risk factors and their implications in the control of Theileriosis and Babesiosis in horses. AB - Theileria equi (Laveran 1901) and Babesia caballi (Nuttall and Strickland 1910) are the causative agents of Equine Piroplasmosis (EP), a severe and problematic disease compromising international movement of horses. Infected horses usually become asymptomatic carriers and, for this reason, their movement across borders may become restricted. The aim of this study was to assess the seroprevalence of EP in Southern France and to evaluate risk factors associated with these parasites. In 2002, we performed a complement fixation test (CF) with blood samples from 443 horses stabled at 95 different farms located in the region of Camargue. Two epidemiological questionnaires have been used: one for each single horse (individual and management factors) and one for each place where horses were sampled (environment, presence of other species, etc.) to identify risk factors for seropositivity. T. equi and B. caballi had a seroprevalence of 58 % and 12.9%, respectively. For T. equi, sex, age, activity, management, and living with or near cattle were identified as risk factors, while for B. caballi, only living in wetlands was recognized as a risk factor in the bivariate analysis. In the multivariate analysis, the best model for T. equi included as variables age, breed, and deworming, while the best model for B. caballi included the type of housing during day and the contact with cows. PMID- 25280517 TI - Combined downregulation of microRNA-133a and microRNA-133b predicts chemosensitivity of patients with esophageal squamous cell carcinoma undergoing paclitaxel-based chemotherapy. AB - microRNA-133a (miR-133a) and miR-133b, located on chromosome 18 in the same bicistronic unit, have been commonly identified as being downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the correlation of miR-133a/b expression with efficacy of paclitaxel based chemotherapy and clinical outcome of ESCC patients. miR-133a expression and miR-133b expression were examined in 100 newly diagnosed ESCC patients prior to treatment by quantitative real-time PCR. Then, the patients received four cycles of paclitaxel-based chemotherapy, the short-term treatment efficacy was evaluated, and a 3-year follow-up was performed. Expression levels of miR-133a and miR-133b were both significantly lower in ESCC tissues compared to adjacent noncancerous tissues (both P < 0.001). In addition, combined miR-133a/b downregulation was found to be closely correlated with advanced tumor stage (P = 0.02) and poor differentiation (P = 0.01). Moreover, the response rate of ESCC patients to paclitaxel-based chemotherapy was significantly higher in combined miR-133a/b downregulation group compared with other groups (P = 0.02). Furthermore, univariate and multivariate Cox analyses revealed that tumor stage and combined expression of miR-133a/b were independent prognosis factors in ESCC patients. Our data offer the convincing evidence that combined expression of miR 133a and miR-133b may predict chemosensitivity of patients with ESCC undergoing paclitaxel-based chemotherapy, implying its importance in applying 'personalized cancer medicine' in the clinical treatment of ESCC. We also identified combined expression of miR-133a and miR-133b as an effective prognostic marker of this malignancy. PMID- 25280518 TI - Triptolide induces apoptosis of gastric cancer cells via inhibiting the overexpression of MDM2. AB - Triptolide has been reported to exhibit antitumor effects in several cancers. This study investigates the mechanism by which triptolide induces apoptosis of gastric cancer cells. Gastric biopsies were collected for histological evaluation and detection of murine double minute 2 (MDM2) expression. Gastric cancer cells were cultured and treated with different concentrations of triptolide at indicated time points. The expression of MDM2, p53 protein, and target proteins including p21, PUMA, and X-linked inhibitor of apoptosis protein (XIAP) was detected. Apoptosis of cells treated with or without triptolide was evaluated. Our results showed that MDM2 protein was overexpressed in gastric cancer (p < 0.01, resp.). Triptolide induced significant apoptosis of gastric cancer cells in a dose- and time-dependent manner (p < 0.05). In addition, treatment with triptolide strongly inhibited the overexpression of MDM2 in gastric cancer cells, and this MDM2 inhibition led to increased levels of p53 protein and inhibition of XIAP (p < 0.05). However, triptolide failed to increase the expression of p53 target protein p21 and PUMA (p > 0.05). In conclusion, triptolide may induce apoptosis of gastric cancer cells via the inhibition of MDM2 overexpression in a p53-independent manner. PMID- 25280520 TI - Media multitasking and behavioral measures of sustained attention. AB - In a series of four studies, self-reported media multitasking (using the media multitasking index; MMI) and general sustained-attention ability, through performance on three sustained-attention tasks: the metronome response task (MRT), the sustained-attention-to-response task (SART), and a vigilance task (here, a modified version of the SART). In Study 1, we found that higher reports of media multitasking were associated with increased response variability (i.e., poor performance) on the MRT. However, in Study 2, no association between reported media multitasking and performance on the SART was observed. These findings were replicated in Studies 3a and 3b, in which we again assessed the relation between media multitasking and performance on both the MRT and SART in two large online samples. Finally, in Study 4, using a large online sample, we tested whether media multitasking was associated with performance on a vigilance task. Although standard vigilance decrements were observed in both sensitivity (A') and response times, media multitasking was not associated with the size of these decrements, nor was media multitasking associated with overall performance, in terms of either sensitivity or response times. Taken together, the results of the studies reported here failed to demonstrate a relation between habitual engagement in media multitasking in everyday life and a general deficit in sustained-attention processes. PMID- 25280519 TI - EZH2 elevates the proliferation of human cholangiocarcinoma cells through the downregulation of RUNX3. AB - To investigate the impact of histone methyltransferase enhancer of zeste homolog 2 (EZH2) on the proliferation and apoptosis of human cholangiocarcinoma cells as well as its related mechanisms. Immunohistochemistry and Western blot analyses were used to examine the expression of EZH2 in 40 cases of human cholangiocarcinoma tissues and four strains of human cholangiocarcinoma cells. The influence of EZH2 on cell growth and apoptosis were assessed by knockdown experiments, and a xenograft experiment in nude mice was performed to evaluate the impact of siEZH2 on the tumorigenicity of tumor cells. The correlation of EZH2, clinic pathological features and overall survival rates was also analyzed. EZH2 was highly expressed in human cholangiocarcinoma tissues and cells. Silencing of EZH2 could significantly reduce the methylation level of RUNX3 DNA in human cholangiocarcinoma cells and improve its protein expression as well as inhibit cell proliferation, induce apoptosis and slow down the growth of tumor in nude mice. In addition, the expression of EZH2 was associated with the tumor stage, lymph node positivity and poor prognoses. Overexpression of EZH2 can promote the proliferation of cholangiocarcinoma cells and inhibit their apoptosis. It is associated with poor prognoses in patients with cholangiocarcinoma. Therefore, EZH2 could be a potential clinical therapeutic target for the treatment of cholangiocarcinoma. PMID- 25280521 TI - Sensorimotor adaptation modifies action effects on sensory binding. AB - Previous studies have shown that performing a motor action toward a target decreases the perceptual asynchrony observed in a temporal order judgment (TOJ) of a change in the target's visual attributes. We examined the temporal limit of this effect and whether this temporal limit can be extended through sensorimotor adaptation. Participants performed a TOJ task related to changes of the position and color of a visual stimulus in a perceptual and a motor task. A fixed change (color or position) occurred 250 or 500 ms following an auditory cue (perceptual task) or the end of a manual reaching action (motor task), whereas the variable change (position or color) occurred randomly within a time window of +/-200 ms locked to the fixed change. The points of subjective simultaneity (PSSs) revealed that performing a voluntary action decreased the temporal asynchrony observed in the perceptual task, but only in the 250-ms delay condition. In Experiment 2, the fixed change occurred 1 s after either an auditory cue or the end of a manual reaching action, and the variable change occurred either simultaneously (new sensorimotor contingencies, 60 % of trials) or within a time window of +/-200 ms (40 % of trials). The PSSs revealed that temporal asynchrony decreased in the motor task, but only after adaptation to the 1-s delay. Taken together, these data show that voluntary motor action affects the temporal binding of visual attributes for a period of less than 500 ms after the end of the action. Sensorimotor adaptation can nevertheless extend this time interval, at least up to 1 s. PMID- 25280522 TI - Color-motion asynchrony assessed along the chromatic axes and with luminance variation. AB - Color-motion asynchrony was fist reported by Moutoussis and Zeki (Proceedings of the Royal Society B, 264, 393-399, 1997), who showed that a motion direction change needs to precede a color change by approximately 80-120 ms in order for humans to perceive change as synchronous when a visual stimulus changes its direction of motion and color rapidly and repetitively. This phenomenon was investigated with stimuli with a single change of color and a single change of motion. The stimulus was varied along the L/(L+M) axis, along the S/(L+M) axis, or in luminance at a constant chromaticity. The psychophysical task was either a correspondence task or a temporal judgment task. The results showed that all three of the variations in color or luminance produced similar color-motion asynchronies, but the correspondence task consistently showed greater asynchrony (80-110 ms) than did the temporal order judgment task (45-70 ms). The results indicated that color-motion asynchrony is processed at cortical areas after cone specific chromatic signals and luminance signals are integrated. PMID- 25280523 TI - Listening to music reduces eye movements. AB - Listening to music can change the way that people visually experience the environment, probably as a result of an inwardly directed shift of attention. We investigated whether this attentional shift can be demonstrated by reduced eye movement activity, and if so, whether that reduction depends on absorption. Participants listened to their preferred music, to unknown neutral music, or to no music while viewing a visual stimulus (a picture or a film clip). Preference and absorption were significantly higher for the preferred music than for the unknown music. Participants exhibited longer fixations, fewer saccades, and more blinks when they listened to music than when they sat in silence. However, no differences emerged between the preferred music condition and the neutral music condition. Thus, music significantly reduces eye movement activity, but an attentional shift from the outer to the inner world (i.e., to the emotions and memories evoked by the music) emerged as only one potential explanation. Other explanations, such as a shift of attention from visual to auditory input, are discussed. PMID- 25280524 TI - Use of controlled diaphragmatic breathing for the management of motion sickness in a virtual reality environment. AB - Evidence indicates that activation of the parasympathetic nervous system (PNS) suppresses physiological responses associated with motion sickness. Research also shows paced breathing increases PNS activation; the current study examines the use of paced diaphragmatic breathing (DB) training to quell motion sickness symptoms. Healthy participants (N = 60) were pre-screened for motion sickness susceptibility. Participants were then randomly assigned to either a control condition, focusing on environmental awareness, or to an experimental condition implementing paced DB. Following this, participants were exposed to a virtual reality (VR) motion sickness experience, while heart rate variability, breathing rate (RPM), and motion sickness ratings were collected. Results demonstrated participants in the DB condition had higher PNS activation and reported fewer motion sickness symptoms during the VR experience than the participants in the control condition. Results suggest that the DB protocol can be used to significantly increase PNS tone and decrease the development of motion sickness symptoms. PMID- 25280525 TI - Evidence of MAPK-JNK1/2 activation by hepatitis E virus ORF3 protein in cultured hepatoma cells. AB - Hepatitis E virus (HEV) has recently emerged to cause chronic infection in some immunosuppressed individuals, including extrahepatic manifestations in acute and chronic patients. Mammalian MAPK-JNK1/2 is expressed in hepatocytes, which is known to be involved in anti-apoptotic signaling pathway for the establishment of persistent infection. Though in vitro modulation of cellular MAPK-ERK cascade by HEV-ORF3 protein is suggested to have a role in host pathobiology, activation of the JNK module has not been studied so far. In this report, we have shown for the first time, evidence of MAPK-JNK1/2 activation by HEV-ORF3, using viral replicon as well as expression vector in human hepatoma cells. Phospho-ELISA based relative quantitaion has demonstrated ~54% and ~66% phosphorylation of JNK1/2 in replicon-RNA and ORF3-vector DNA transfected cells, respectively. Our finding however, suggests further molecular studies to validate a role of JNK1/2 in HEV pathogenesis. PMID- 25280526 TI - Cardiovascular risk factor trends in the Eastern Mediterranean region: evidence from four countries is alarming. AB - OBJECTIVES: Many Eastern Mediterranean countries are undergoing dramatic socioeconomic, demographic and life style changes and face noncommunicable disease (NCD) epidemics. We evaluated recent trends in major NCD risk factors in occupied Palestinian territories (OPT), Turkey, Syria and Tunisia. METHODS: We searched published and unpublished sources for systolic blood pressure (SBP), diabetes, smoking, body mass index (BMI), and cholesterol trends for both men and women aged 35-84 in each country from 1995 to 2009. RESULTS: Smoking prevalence was stable over time in Tunisia and Syria, but decreasing in Turkey (annual change -0.9%) and OPT (annual change -0.7%). Mean BMI (annual change of 0.1% for Turkey, 0.2% for OPT and Tunisia and 0.3% in Syria) and diabetes (annual change of 0.3% for Turkey, 0.4% for OPT and Tunisia and 0.7% in Syria) prevalence increased in each country. SBP levels increased slightly in Tunisia and Syria but decreased in OPT and Turkey. CONCLUSIONS: Recent risk factor trends are worrying. Good quality data on the extent and determinants of NCDs are essential to respond the changing health needs of populations with burgeoning NCD epidemics. PMID- 25280527 TI - Temperature variation between neighboring days and mortality: a distributed lag non-linear analysis. AB - OBJECTIVES: To investigate whether a sudden temperature change between neighboring days has significant impact on mortality. METHODS: A Poisson generalized linear regression model combined with a distributed lag non-linear models was used to estimate the association of temperature change between neighboring days with mortality in a subtropical Chinese city during 2008-2012. Temperature change was calculated as the current day's temperature minus the previous day's temperature. RESULTS: A significant effect of temperature change between neighboring days on mortality was observed. Temperature increase was significantly associated with elevated mortality from non-accidental and cardiovascular diseases, while temperature decrease had a protective effect on non-accidental mortality and cardiovascular mortality. Males and people aged 65 years or older appeared to be more vulnerable to the impact of temperature change. CONCLUSIONS: Temperature increase between neighboring days has a significant adverse impact on mortality. Further health mitigation strategies as a response to climate change should take into account temperature variation between neighboring days. PMID- 25280528 TI - Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation. AB - Although ceramide accumulation in the heart is considered a major factor in promoting apoptosis and cardiac disorders, including heart failure, lipotoxicity and ischemia-reperfusion injury, little is known about ceramide's role in mediating changes in contractility. In the present study, we measured the functional consequences of acute exposure of isolated field-stimulated adult rat cardiomyocytes to C6-ceramide. Exogenous ceramide treatment depressed the peak amplitude and the maximal velocity of shortening without altering intracellular calcium levels or kinetics. The inactive ceramide analog C6-dihydroceramide had no effect on myocyte shortening or [Ca(2+)]i transients. Experiments testing a potential role for C6-ceramide-mediated effects on activation of protein kinase C (PKC) demonstrated evidence for signaling through the calcium-independent isoform, PKCepsilon. We employed 2-dimensional electrophoresis and anti-phospho peptide antibodies to test whether treatment of the cardiomyocytes with C6 ceramide altered myocyte shortening via PKC-dependent phosphorylation of myofilament proteins. Compared to controls, myocytes treated with ceramide exhibited increased phosphorylation of myosin binding protein-C (cMyBP-C), specifically at Ser273 and Ser302, and troponin I (cTnI) at sites apart from Ser23/24, which could be attenuated with PKC inhibition. We conclude that the altered myofilament response to calcium resulting from multiple sites of PKC dependent phosphorylation contributes to contractile dysfunction that is associated with cardiac diseases in which elevations in ceramides are present. PMID- 25280529 TI - Endogenous lentivirus in Malayan colugo (Galeopterus variegatus), a close relative of primates. AB - BACKGROUND: A significant fraction of mammalian genomes is composed of endogenous retroviral (ERV) sequences that are formed by germline infiltration of various retroviruses. In contrast to other retroviral genera, lentiviruses only rarely form ERV copies. We performed a computational search aimed at identification of novel endogenous lentiviruses in vertebrate genomes. FINDINGS: Using the in silico strategy, we have screened 104 publicly available vertebrate genomes for the presence of endogenous lentivirus sequences. In addition to the previously described cases, the search revealed the presence of endogenous lentivirus in the genome of Malayan colugo (Galeopterus variegatus). At least three complete copies of this virus, denoted ELVgv, were detected in the colugo genome, and approximately one hundred solo LTR sequences. The assembled consensus sequence of ELVgv had typical lentivirus genome organization including three predicted accessory genes. Phylogenetic analysis placed this virus as a distinct subgroup within the lentivirus genus. The time of insertion into the dermopteran lineage was estimated to be more than thirteen million years ago. CONCLUSIONS: We report the discovery of the first endogenous lentivirus in the mammalian order Dermoptera, which is a taxon close to the Primates. Lentiviruses have infiltrated the mammalian germline several times across millions of years. The colugo virus described here represents possibly the oldest documented endogenization event and its discovery can lead to new insights into lentivirus evolution. This is also the first report of an endogenous lentivirus in an Asian mammal, indicating a long-term presence of this retrovirus family in Asian continent. PMID- 25280530 TI - Mutation rates and evolution of multiple coding in RNA-based protocells. AB - RNA has a myriad of biological roles in contemporary life. We use the RNA paradigm for genotype-phenotype mappings to study the evolution of multiple coding in dependence to mutation rates. We study three different one-to-many genotype-phenotype mappings which have the potential to encode the information for multiple functions on a single sequence. These three different maps are (i) cofolding, where two sequences can bind and "cofold," (ii) suboptimal folding, where the alternative foldings within a certain range of the native state of sequences are considered, and (iii) adapter-based folding, in which protocells can evolve adapter-mediated alternative foldings. We study how protocells with a set of sequences can code for a set of predefined functional structures, while avoiding all other structures, which are considered to be misfoldings. Note that such misfolded structures are far more prevalent than functional ones. Our results highlight the flexibility of the RNA sequence to secondary structure mapping and the power of evolution to shape the genotype-phenotype mapping. We show that high fitness can be achieved even at high mutation rates. Mutation rates affect genome size, but differently depending on which folding method is used. We observe that cofolding limits the possibility to avoid misfolded structures and that adapters are always beneficial for fitness, but even more beneficial at low mutation rates. In all cases, the evolution procedure selects for molecules that can form additional structures. Our results indicate that inherent properties of RNA molecules and their interactions allow the evolution of complexity even at high mutation rates. PMID- 25280531 TI - Optimizing the use of expert panel reference diagnoses in diagnostic studies of multidimensional syndromes. AB - BACKGROUND: In the absence of a gold standard, a panel of experts can be invited to assign a reference diagnosis for use in research. Available literature offers limited guidance on assembling and working with an expert panel for this purpose. We aimed to develop a protocol for an expert panel consensus diagnosis and evaluated its applicability in a pilot project. METHODS: An adjusted Delphi method was used, which started with the assessment of clinical vignettes by 3 experts individually, followed by a consensus discussion meeting to solve diagnostic discrepancies. A panel facilitator ensured that all experts were able to express their views, and encouraged the use of argumentation to arrive at a specific diagnosis, until consensus was reached by all experts. Eleven vignettes of patients suspected of having a primary neurodegenerative disease were presented to the experts. Clinical information was provided stepwise and included medical history, neurological, physical and cognitive function, brain MRI scan, and follow-up assessments over 2 years. After the consensus discussion meeting, the procedure was evaluated by the experts. RESULTS: The average degree of consensus for the reference diagnosis increased from 52% after individual assessment of the vignettes to 94% after the consensus discussion meeting. Average confidence in the diagnosis after individual assessment was 85%. This did not increase after the consensus discussion meeting. The process evaluation led to several recommendations for improvement of the protocol. CONCLUSION: A protocol for attaining a reference diagnosis based on expert panel consensus was shown feasible in research practice. PMID- 25280533 TI - Efficacy, predictability, and safety of small incision lenticule extraction: 6 months prospective cohort study. AB - BACKGROUND: To report our experience with small incision lenticule extraction ("SMILE") for myopia treatment. METHODS: In this prospective clinical study, we evaluated 447 eyes from 224 patients with myopia, with and without astigmatism. We followed the patients for 6 months after SMILE. RESULTS: The mean (+/-standard deviation, SD) spherical equivalent was -6.75 +/- 1.65 diopters (D) preoperatively and -0.21 +/- 0.37 D at 6 months postoperatively. Our data showed that 97.9% of eyes were within +/-1.0 D and 86.1% were within +/-0.5 D of the intended correction. Furthermore, 79.8% had an uncorrected distance visual acuity (UDVA) of 0 logMAR or less (20/20 or better in the Snellen equivalent) 6 months after surgery. Additionally, 48.5% remained unchanged, 41% gained one line of corrected distance visual acuity (CDVA), 7.2% gained two lines of CDVA, 3.3% lost one line of CDVA, and 0.3% lost two or more lines of CDVA. Age was the only predictor for worsening UDVA at 6 months postoperatively in linear regression analyses (0.07 decrease logMAR per increased 10 years of age; P < 0.05). No predictor showed an association with error in spherical equivalent refraction at 6 months postoperatively. CONCLUSIONS: SMILE is an effective and safe refractive surgery. Age was the only predictor that influenced visual outcome, but its effect appeared clinically insignificant. Faster visual recovery is also expected with improved surgical technique. PMID- 25280532 TI - Attenuated transforming growth factor beta signaling promotes metastasis in a model of HER2 mammary carcinogenesis. AB - INTRODUCTION: Transforming growth factor beta (TGFbeta) plays a major role in the regulation of tumor initiation, progression, and metastasis. It is depended on the type II TGFbeta receptor (TbetaRII) for signaling. Previously, we have shown that deletion of TbetaRII in mammary epithelial of MMTV-PyMT mice results in shortened tumor latency and increased lung metastases. However, active TGFbeta signaling increased the number of circulating tumor cells and metastases in MMTV Neu mice. In the current study, we describe a newly discovered connection between attenuated TGFbeta signaling and human epidermal growth factor receptor 2 (HER2) signaling in mammary tumor progression. METHODS: All studies were performed on MMTV-Neu mice with and without dominant-negative TbetaRII (DNIIR) in mammary epithelium. Mammary tumors were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence staining. The levels of secreted proteins were measured by enzyme-linked immunosorbent assay. Whole-lung mount staining was used to quantitate lung metastasis. The Cancer Genome Atlas (TCGA) datasets were used to determine the relevance of our findings to human breast cancer. RESULTS: Attenuated TGFbeta signaling led to a delay tumor onset, but increased the number of metastases in MMTVNeu/DNIIR mice. The DNIIR tumors were characterized by increased vasculogenesis, vessel leakage, and increased expression of vascular endothelial growth factor (VEGF). During DNIIR tumor progression, both the levels of CXCL1/5 and the number of CD11b+Gr1+ cells and T cells decreased. Analysis of TCGA datasets demonstrated a significant negative correlation between TGFBR2 and VEGF genes expression. Higher VEGFA expression correlated with shorter distant metastasis-free survival only in HER2+ patients with no differences in HER2-, estrogen receptor +/- or progesterone receptor +/- breast cancer patients. CONCLUSION: Our studies provide insights into a novel mechanism by which epithelial TGFbeta signaling modulates the tumor microenvironment, and by which it is involved in lung metastasis in HER2+ breast cancer patients. The effects of pharmacological targeting of the TGFbeta pathway in vivo during tumor progression remain controversial. The targeting of TGFbeta signaling should be a viable option, but because VEGF has a protumorigenic effect on HER2+ tumors, the targeting of this protein could be considered when it is associated with attenuated TGFbeta signaling. PMID- 25280534 TI - Association between appropriateness of coronary revascularization and quality of life in patients with stable ischemic heart disease. AB - BACKGROUND: The relationship between appropriateness score, treatment strategy and quality of life (QOL) among patients with stable ischemic heart disease (SIHD) is not known. In this prospective cohort study, we evaluated changes in generic and cardiac-specific quality of life in patients with documented SIHD, comparing patients with revascularization versus those with medical therapy alone, stratified by their appropriateness scores. METHODS: Consecutive patients with SIHD undergoing elective coronary angiogram from November 1st 2008 to December 1st 2009 completed the Seattle Angina Questionnaire (SAQ) and EQ-5D at the time of procedure and at 1 year. The appropriateness for coronary revascularization was determined at the time of coronary angiography. RESULTS: Our final cohort consisted of 425 patients, 69.4% of whom underwent revascularization. In the overall cohort, 272 (64.0%) had appropriate indications for revascularization, while 57 (13.4%) had inappropriate indications and 96 (22.6%) had uncertain indications. On average, patients improved in most QOL domains, regardless of treatment strategy and appropriateness score. In patients with appropriate indications, revascularized patients had greater improvements in both generic (0.073; 95% CI 0.003-0.144; p-value 0.04) and disease-specific indices, including angina stability (14.6; 95% CI 0.85-28.3; p-value 0.04), physical limitation (9.3; 95% CI 0.71-17.8; p-value 0.03) and disease perception (12.7; 95% CI4.3-21.1; p-value 0.003) compared to medically treated patients. However, patients with uncertain and inappropriate indications also had improvements in physical limitation and disease perception with revascularization compared to medical therapy. CONCLUSIONS: Patients who had appropriate revascularization derived the greatest improvement in QOL compared with medical therapy. PMID- 25280535 TI - Pharmacy refill adherence outperforms self-reported methods in predicting HIV therapy outcome in resource-limited settings. AB - BACKGROUND: Optimal adherence to antiretroviral therapy is critical to prevent HIV drug resistance (HIVDR) epidemic. The objective of the study was to investigate the best performing adherence assessment method for predicting virological failure in resource-limited settings (RLS). METHOD: This study was a single-centre prospective cohort, enrolling 220 HIV-infected adult patients attending an HIV/AIDS Care and Treatment Centre in Dar es Salaam, Tanzania, in 2010. Pharmacy refill, self-report (via visual analog scale [VAS] and the Swiss HIV Cohort study-adherence questionnaire), pill count, and appointment keeping adherence measurements were taken. Univariate logistic regression (LR) was done to explore a cut-off that gives a better trade-off between sensitivity and specificity, and a higher area under the curve (AUC) based on receiver operating characteristic curve in predicting virological failure. Additionally, the adherence models were evaluated by fitting multivariate LR with stepwise functions, decision trees, and random forests models, assessing 10-fold multiple cross validation (MCV). Patient factors associated with virological failure were determined using LR. RESULTS: Viral load measurements at baseline and one year after recruitment were available for 162 patients, of whom 55 (34%) had detectable viral load and 17 (10.5%) had immunological failure at one year after recruitment. The optimal cut-off points significantly predictive of virological failure were 95%, 80%, 95% and 90% for VAS, appointment keeping, pharmacy refill, and pill count adherence respectively. The AUC for these methods ranged from 0.52 to 0.61, with pharmacy refill giving the best performance at AUC 0.61. Multivariate logistic regression with boost stepwise MCV had higher AUC (0.64) compared to all univariate adherence models, except pharmacy refill adherence univariate model, which was comparable to the multivariate model (AUC = 0.64). Decision trees and random forests models were inferior to boost stepwise model. Pharmacy refill adherence (<95%) emerged as the best method for predicting virological failure. Other significant predictors in multivariate LR were having a baseline CD4 T lymphocytes count < 200 cells/MUl, being unable to recall the diagnosis date, and a higher weight. CONCLUSION: Pharmacy refill has the potential to predict virological failure and to identify patients to be considered for viral load monitoring and HIVDR testing in RLS. PMID- 25280536 TI - A novel procedure for transtracheal resection for recurrent thyroid cancer involving a trachea and esophagus. AB - BACKGROUND: Surgery remains the main treatment for locally advanced thyroid cancers invading the trachea, esophagus, and recurrent laryngeal nerve. However, extensive resection of such tumors can sometimes involve difficulties and may result in the deterioration of the patient's quality of life. The surgeon should consider not only the patient's prognosis but also the preservation of postoperative function. METHODS: This report describes a minimally invasive surgical procedure for recurrent poorly differentiated papillary thyroid carcinoma involving the trachea and esophagus. To decrease the potential for recurrent laryngeal nerve injuries and to preserve both the tracheal and esophageal blood supply, we adapted a transtracheal approach; the recurrent tumor was safely and completely removed without causing a dysfunction. After a tracheotomy to the right, the tumor was easily detected through the tracheostoma and delineated by palpation. The mucous membrane of the trachea was minimally incised along the right-hand border of the tumor and a mucosal flap was elevated. The left side of the trachea including the membranous wall and cartilage of the tracheal mucosa was maximally preserved, to maintain the vascular supply to the trachea. Finally, the membranous wall of the trachea was preserved to within one third of the left-hand side. Furthermore, the risk of bleeding from major lateral vessels was reduced. A sternocleidomastoid muscle flap was elevated and inserted into the cavity resulting from the tumor resection and sutured between the esophagus and trachea. The membranous wall of the tracheal mucosa was also sutured submucosally. RESULTS: The tumor was removed completely with the muscular layer of the esophagus without injury to the intact recurrent laryngeal nerve and lateral major vessels. The patient started oral nutritional intake on the first postoperative day and was discharged without any significant postoperative complications. CONCLUSIONS: This new procedure for transtracheal resection for recurrent thyroid cancer involving the trachea and esophagus was useful and safe. PMID- 25280537 TI - Creatine kinase elevation caused by a combination of fluvastatin and telmisartan in a patient heterozygous for the CYP2C9*3 and ABCC2 -24C > T variants: a case report. AB - BACKGROUND: Genetic factors as predictor of the individual outcome of drug therapy is one aim of personalized medicine approaches. CASE PRESENTATION: We report a drug metabolism based analysis of genetic polymorphisms in a Caucasian patient receiving fluvastatin and telmisartan experiencing myotoxicity (myalgia and moderate creatine kinase elevation). CONCLUSIONS: The obtained findings suggest that heterocygocity of cytochrome P450 CYP2C9*3 variant in combination with multidrug resistance-associated protein MRP2-24C > T functions as risk factor predisposing to experience drug-drug interaction combing those drugs. PMID- 25280538 TI - Study of ZHENG differentiation in hepatitis B-caused cirrhosis: a transcriptional profiling analysis. AB - BACKGROUND: In traditional Chinese medicine (TCM) clinical practice, ZHENG (also known as TCM syndrome) helps to understand the human homeostasis and guide individualized treatment. However, the scientific basis of ZHENG remains unclear due to limitations of current reductionist approaches. METHODS: We collected the leukocyte samples of three hepatitis B-caused cirrhosis (HBC) patients with dampness-heat accumulation syndrome (DHAS) and three HBC patients with liver depression and spleen deficiency syndrome (LDSDS) for microarray analysis. We generated Gene-Regulatory-Networks (GeneRelNet) from the differentially expressed genes (DEGs) of microarray date. Core genes were validated using anther independent cohort of 40 HBC patients (20 DHAS, 20 LDSDS) with RT-PCR. RESULTS: There were 2457 mapped genes were differentially expressed between DHAS and LDSDS (Fold change >= 2.0, P < 0.05). There were markedly different genes co-expression patterns in DHAS and LDSDS. Furthermore, three differential co-expression genes including purine nucleoside phosphorylase (PNP); aquaporin 7 (AQP7) and proteasome 26S subunit, non-ATPase 2 (PSMD2) were screened by GeneRelNets, and their mRNA expressions were further validated by real time RT-PCR. The results were consistent with microarray. The PNP (P = 0.007), AQP7 (P = 0.038) and PSMD2 (P = 0.009) mRNA expression is significant difference between DHAS and LDSDS using the non-parametric test. Furthermore, we constructed an mRNA panel of PNP, AQP7 and PSMD2 (PAP panel) by logistic regression model, and evaluated the PAP panel to distinguish DHAS from LDSDS by area under the receiver operating characteristic curve (AUC) analysis, which showed a higher accuracy (AUC = 0.835). Gene ontology (GO) analysis indicated that the DHAS is most likely related to system process while the functions overrepresented by LDSDS most related to the response to stimulus. CONCLUSIONS: This study suggested that there are particular transcriptional profiles, genes co-expressions patterns and functional properties of DHAS and LDSDS, and PNP, AQP7, and PSMD2 may be involved in ZHENG differentiation of DHAS and LDSDS in HBC. PMID- 25280540 TI - Self-organized nanoparticles based on chitosan-folic acid and dextran succinate doxorubicin conjugates for drug targeting. AB - Folic acid-decorated self-organized nanoparticles were fabricated to target folate receptor of cancer cells. Doxorubicin (DOX) was conjugated with carboxyl group of dextran backbone using succinic anhydride (DexSU-DOX). DOX-loaded self organized nanoparticles were prepared by complexation with folic acid-grafted chitosan (ChitoFA) and DexSU-DOX. Nanoparticles in the aqueous environment have spherical shapes with average size less than 100 nm and their sizes were increased by coated with ChitoPEG or ChitoFA. At cell culture study with KB cells, ChitoFA coated nanoparticles (FADex NP) revealed folate-receptor mediated endocytosis to cancer cells and cell viability was significantly changed by folate receptor targeting. Tumor xenograft model of KB cells also showed similar results, i.e. FAdex NP efficiently inhibited growth of tumor compared to the treatment group with blocking of folate receptor. These results indicated that DOX-loaded nanoparticles of FADex NP are promising vehicle for anticancer drug targeting. PMID- 25280539 TI - Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models. AB - BACKGROUND: Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans. RESULTS: We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans. CONCLUSIONS: We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury. PMID- 25280541 TI - Genome-wide identification and evolutionary analysis of algal LPAT genes involved in TAG biosynthesis using bioinformatic approaches. AB - Lysophosphatidyl acyltransferase (LPAT) is one of the major triacylglycerol synthesis enzymes, controlling the metabolic flow of lysophosphatidic acid to phosphatidic acid. Experimental studies in Arabidopsis have shown that LPAT activity is exhibited primarily by three distinct isoforms, namely the plastid located LPAT1, the endoplasmic reticulum-located LPAT2, and the soluble isoform of LPAT (solLPAT). In this study, 24 putative genes representing all LPAT isoforms were identified from the analysis of 11 complete genomes including green algae, red algae, diatoms and higher plants. We observed LPAT1 and solLPAT genes to be ubiquitously present in nearly all genomes examined, whereas LPAT2 genes to have evolved more recently in the plant lineage. Phylogenetic analysis indicated that LPAT1, LPAT2 and solLPAT have convergently evolved through separate evolutionary paths and belong to three different gene families, which was further evidenced by their wide divergence at gene structure and sequence level. The genome distribution supports the hypothesis that each gene encoding a LPAT is not duplicated. Mapping of exon-intron structure of LPAT genes to the domain structure of proteins across different algal and plant species indicates that exon shuffling plays no role in the evolution of LPAT genes. Besides the previously defined motifs, several conserved consensus sequences were discovered which could be useful to distinguish different LPAT isoforms. Taken together, this study will enable the generation of experimental approximations to better understand the functional role of algal LPAT in lipid accumulation. PMID- 25280542 TI - A novel SMAD family protein, SMAD9 is involved in follicular initiation and changes egg yield of geese via synonymous mutations in exon1 and intron2. AB - Elevation of egg performance is vital to goose farming. Many poultry scientists are seeking for efficient molecular genetic markers associated with egg yield. In this study, mRNA differential display was adopted to investigate gene expression profiling in the follicular development of goose. For the first time, a novel SMAD family protein SMAD9 (EST CJ111007) was found to be involved in follicular initiation and used to be a candidate gene. Functional regions analysis of Smad9 indicated that SMAD9 protein is highly conserved in MH1 and MH2 domains, and the connection area is highly variable region. 6 pairs of primers (p1-p6) were designed to detect the SNPs of Smad9 by PCR-SSCP method. The results revealed that polymorphisms were discovered in the PCR products amplified with P1 primers in exon1 and P3 primers in intron2. In Smad9 exon1, 5 genotypes were found: FK, FF, JJ, JK and KK, including 2 SNPs: 243 bp G -> A, 309 bp T -> G, the mutations did not result in amino acid mutations; In intron2, 3 genotypes were found: AA, BB and AB, only 1 SNP (C -> T). The annual egg yield of FK genotype geese or allele gene A in intron2 are significantly more than those of other genotypes on the average (p < 0.05). Taken together, it is suggested that Smad9 is a promising candidate gene affecting egg performance in goose. PMID- 25280543 TI - Association between glutathione S-transferases P1 Ile105Val polymorphism and susceptibility to esophageal cancer: evidence from 20 case-control studies. AB - Available epidemiological studies had estimated the correlation between glutathione S-transferases P1 (GSTP1) Ile105Val polymorphism and esophageal cancer (EC) risk. However, the conclusions were controversial and inconclusive. An updated meta-analysis was conducted to explore whether GSTP1 polymorphism could be contributed to the EC risk. Ultimately, a total of 2,992 cases and 4,758 controls from 20 previous studies were included. Crude odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were used to assess the strength of the associations. Pooled results suggested that GSTP1 Ile105Val polymorphism significantly increased the risk of developing EC in Caucasians under three genetic models (G vs. A, OR 1.146, 95 % CI 1.031-1.275, P = 0.012, I(2) = 30.40 %; GA vs. AA, OR 1.208, 95 % CI 1.036-1.408, P = 0.016, I(2) = 50.30 %; GG+GA vs. AA, OR 1.219, 95 % CI 1.053-1.410, P = 0.008, I(2) = 44.50 %). However, no significant correlation was found in Asians, African and mixed ethnicities analyses. Moreover, similar results were detected for any genetic model in esophageal squamous cell carcinoma and esophageal adenocarcinoma when stratifying for pathologic types. This meta-analysis provides new evidences that GSTP1 Ile105Val gene polymorphism contributes to EC susceptibility in Caucasians. PMID- 25280544 TI - Association of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms with the risk of COPD: an updated meta-analysis of 2,644 cases and 4,804 controls. AB - A series of observational studies have been made to investigate the association of the ADAM33 gene polymorphisms with the risk of COPD, but their results were conflicting. Therefore, we performed an updated meta-analysis to quantitatively summarize the associations of ADAM33 gene polymorphisms with the risk of COPD. Thirteen case-control studies referring to nine SNPs were identified: V4 (rs2787094), T+1 (rs2280089), T2 (rs2280090), T1 (rs2280091), S2 (rs528557), S1 (rs3918396), Q-1 (rs612709), F+1 (rs511898) and ST+5 (rs597980). A dominant model (AA+Aa vs. aa), recessive model (AA vs. Aa+aa), additive model (AA vs. aa) and allelic model (A vs. a) were used to evaluate the association of ADAM33 polymorphism with the risk of COPD. The results indicated that significant associations were found for ADAM33 T1, T2, S1, Q-1, F+1 and ST+5 polymorphisms associated with the risk of COPD in different populations. However, no significant associations were found for V4, T+1 and S2 polymorphisms with the risk of COPD in all genetic models, even in the subgroup analysis by ethnicity. This meta-analysis provided evidence that the ADAM33 T1, T2, S1, Q-1, F+1 and ST+5 six locus polymorphisms association with the risk of COPD. Furthermore, T2, Q-1 and ST+5 indicated an association with the risk of COPD in the European populations, whereas T1, T2, S1, F+1 and Q-1 indicated an association with the risk of COPD in the Asian populations. PMID- 25280545 TI - Data for action: the use of formative research to design a school-based intervention programme to increase physical activity in adolescents. AB - Formative research is a critical step for the development of interventions aimed at changing behaviours, as is the case of physical activity. This process permits obtaining detailed information about the programme application context. 'Follow the Footstep' is a quasi-experimental and longitudinal study in secondary schools, the aim of which is to increase levels of physical activity among adolescents. To inform the design of the intervention programme, formative research has been carried out to analyse the perceptions of parents, teachers and students, through six focus groups.The social-ecological model was used both to carry out the formative research and then to design the programme, including five levels of influence on behaviour (individual, interpersonal, organizational, community and political), which are important when it comes to adopting a comprehensive intervention approach. The authors describe how the results of formative research were transferred to guide the design and development of the intervention. As results indicate, parents, teachers and students agreed on a need to intervene by engaging adolescents and their close social environment. The school centre is the key organizational structure to implement this intervention, supported by professionals and the community. PMID- 25280546 TI - Colorectal cancer in Jordan: prevention and care. AB - The aim of this study was to describe the knowledge, attitudes, and practices toward colorectal cancer prevention and care in Jordan. A survey was designed to produce reliable estimates for the population's knowledge, attitudes, and practices in all 12 governorates of Jordan by using stratified random sampling. A representative sample of the adult population in Jordan completed a comprehensive tool which explored participants' knowledge about the risk factors associated with colorectal cancer, cancer prevention through lifestyle changes, and early cancer diagnosis and screening. According to the participants (n = 3196), colorectal cancer had the second highest percentage of screening recommendation (12.6%) after breast cancer (57.3%). Only 340 individuals (11%) reported ever screening for cancer. About 20% of the participants had heard of one of the screening tests for colorectal cancer. In fact, only 290 (9.1%) participants had performed the colorectal cancer screening tests. This study provides data that will help colorectal cancer prevention and treatment programs and may enhance the efficiency of colorectal cancer-controlling programs. The findings confirm the necessity of starting colorectal screening intervention that targets the most vulnerable individuals. PMID- 25280547 TI - Effectiveness of a school-based nutrition and food safety education program among primary and junior high school students in Chongqing, China. AB - BACKGROUND: Health behavioral patterns, especially eating patterns, established in childhood often carry over into adulthood, and some of the unhealthy ones are later associated with adult morbidity and mortality. Recently, a few nutrition and food safety education programs have been implemented in primary and junior high schools in China. PURPOSE: This study aims to examine the effectiveness of a school-based nutrition and food safety education program among primary and junior high school students in China. METHODS: A mixed study design incorporating an intervention study and a quantitative survey was conducted for this research. With stratified cluster sampling, students from the 5(th) and 6(th) grade in one primary school and the 7(th) and 8(th) grade in one junior high school in Chongqing, China, were all selected and separated randomly into an intervention group (n = 501) and a control group (n = 522). Effectiveness evaluation investigations were performed at the initial time and nine-month follow-up (n = 472), respectively. Effectiveness of pre-/post-intervention and nine-month follow up changes in scores of nutrition knowledge and food safety was assessed using a two-tailed t-test and analysis of variance. RESULTS: Nutrition knowledge scores for the intervention group were mean 9.03, SD+/-2.75 at the baseline, and 14.70+/ 3.28 after intervention. There was a significant improvement (t = 29.78, p < 0.01). The nine-month follow-up knowledge scores of the intervention group were 12.35+/-2.89, which were lower than the immediately after the intervention group (t = 12.40, p<0.01), but higher than those of the baseline level (t = 18.04, p < 0.01). Food safety scores of the post-intervention were higher (p < 0.01) than that of the control group in both pre-intervention and nine-month follow-up. The control group had no significant change in the pre-post intervention. CONCLUSIONS: It is feasible and effective to improve nutrition and food safety knowledge among primary and junior high school students through school-based nutrition and food safety education programs. PMID- 25280548 TI - Exploring the potential for internet-based interventions for treatment of overweight and obesity in college students. AB - OBJECTIVE: To assess the use of internet-enabled technology for seeking health information and resources in overweight/obese college students. PARTICIPANTS: College students (N = 706) in Vancouver, Canada surveyed in April 2012. METHODS: An online survey assessed socio-demographics, health behaviors, and use of internet-enabled technology. RESULTS: Eating habits, dieting and/or exercising to lose weight, and weight satisfaction differed by weight status (all p < 0.05). Of overweight/obese participants, 48% reported they would use online student health resources. When seeking general health information, 91% would use websites; 45% would use online videos; and 75% trusted information from government or health organizations. CONCLUSIONS: Overweight/obesity is prevalent among college students. The majority of overweight/obese students reported trying to lose weight and would use the internet for health information, especially if a website is associated with a health organization. The internet is a cost-effective channel for screening coupled with the delivery of tailored, evidence-based interventions for college students. PMID- 25280549 TI - Comparison of quadriceps strength and handgrip strength in their association with health outcomes in older adults in primary care. AB - Sarcopenia is thought to play a major role in the functional impairment that occurs with old age. In clinical practice, sarcopenia is often determined by measuring handgrip strength. Here, we compared the lower limb quadriceps strength to the handgrip strength in their association with health outcomes in older adults in primary care. Our study population consisted of older adults (n = 764, 68.2% women, median age 83) that participated in the Integrated Systemic Care for Older People (ISCOPE) study. Participants were visited at baseline to measure quadriceps strength and handgrip strength. Data on health outcomes were obtained at baseline and after 12 months (including life satisfaction, disability in daily living, GP contact-time and hospitalization). Quadriceps strength and handgrip strength showed a weak association (beta = 0.42 [95% CI 0.33-0.50]; R (2) = 0.17). Quadriceps strength and handgrip strength were independently associated with health outcomes at baseline, including quality of life, disability in daily living, GP contact-time, hospitalization, and gait speed. Combined weakness of the quadriceps and handgrip distinguished a most vulnerable subpopulation that presented with the poorest health outcomes. At follow-up, handgrip strength showed an association with quality of life (beta = 0.05; P = 0.002) and disability in daily living (beta = -0.5; P = 0.004). Quadriceps weakness did not further contribute to the prediction of the measured health outcomes. We conclude that quadriceps strength is only moderately associated with handgrip strength in an older population and that the combination of quadriceps strength and handgrip strength measurements may aid in the identification of older adults in primary care with the poorest health outcomes. In the prediction of poor health outcomes, quadriceps strength measurements do not show an added value to the handgrip strength. PMID- 25280550 TI - What is the age for the fastest ultra-marathon performance in time-limited races from 6 h to 10 days? AB - Recent findings suggested that the age of peak ultra-marathon performance seemed to increase with increasing race distance. The present study investigated the age of peak ultra-marathon performance for runners competing in time-limited ultra marathons held from 6 to 240 h (i.e. 10 days) during 1975-2013. Age and running performance in 20,238 (21%) female and 76,888 (79%) male finishes (6,863 women and 24,725 men, 22 and 78%, respectively) were analysed using mixed-effects regression analyses. The annual number of finishes increased for both women and men in all races. About one half of the finishers completed at least one race and the other half completed more than one race. Most of the finishes were achieved in the fourth decade of life. The age of the best ultra-marathon performance increased with increasing race duration, also when only one or at least five successful finishes were considered. The lowest age of peak ultra-marathon performance was in 6 h (33.7 years, 95% CI 32.5-34.9 years) and the highest in 48 h (46.8 years, 95% CI 46.1-47.5). With increasing number of finishes, the athletes improved performance. Across years, performance decreased, the age of peak performance increased, and the age of peak ultra-marathon performance increased with increasing number of finishes. In summary, the age of peak ultra marathon performance increased and performance decreased in time-limited ultra marathons. The age of peak ultra-marathon performance increased with increasing race duration and with increasing number of finishes. These athletes improved race performance with increasing number of finishes. PMID- 25280551 TI - Discovery of bacterial polyhydroxyalkanoate synthase (PhaC)-encoding genes from seasonal Baltic Sea ice and cold estuarine waters. AB - Polyhydroxyalkanoates (PHAs) are macromolecules produced by bacteria as means for storing carbon and energy in intracellular granules. PHAs have physical properties similar to those of plastics and have become of interest to industry as materials for environmentally friendly bioplastic production. There is an ongoing search for new PHA-producing bacterial strains and PHA-synthesizing enzymes tolerating extreme conditions to find ways of producing PHAs at cold temperatures and high solute concentrations. Moreover, the study of PHA producers in the sea-ice biome can aid in understanding the microbial ecology of carbon cycling in ice-associated ecosystems. In this study, PHA producers and PHA synthase genes were examined under the extreme environmental conditions of sea ice and cold seawater to find evidence of PHA production in an environment requiring adaptation to high salinity and cold temperatures. Sea ice and cold estuarine water samples were collected from the northern Baltic Sea and evidence of PHA production was gathered, using microscopy with Nile Blue A staining of PHA granules and PCR assays detecting PHA-synthesis genes. The PHA granules and PHA synthases were found at all sampling locations, in both sea ice and water, and throughout the sampling period spanning over 10 years. Our study shows, for the first time, that PHA synthesis occurs in Baltic Sea cold-adapted bacteria in their natural environment, which makes the Baltic Sea and its cold environments an interesting choice in the quest for PHA-synthesizing bacteria and synthesis genes. PMID- 25280552 TI - Patients with greater symptom intensity and more disability are more likely to be surprised by a hand surgeon's advice. AB - BACKGROUND: A clash between a patient's assumptions and a doctor's advice can feel adversarial which might influence satisfaction ratings and compliance with treatment recommendations. A better understanding of sources of patients' bewilderment might lead to improved strategies for conveying counterintuitive information that improve patient comfort and wellbeing. QUESTIONS/PURPOSES: This study addressed the following questions: (1) Are magnitude of disability, pain intensity, symptoms of depression, or health anxiety associated with a higher level of surprise when a patient is presented with diagnostic information and/or therapeutic recommendations? (2) Does the surgeon accurately perceive the patient's bewilderment? (3) Does the surgeon's perception of patient bewilderment correlate with diagnosis or a patient's magnitude of disability, pain intensity, symptoms of depression, or health anxiety? PATIENTS AND METHODS: In this prospective cohort study, we invited new patients who met prespecified criteria during a 3-month period in one hand-surgery practice to enroll; of 93 patients invited, 84 (90%) agreed to participate. Patients reported demographics and completed the short versions of the DASH questionnaire (QuickDASH), the Patient Health Questionnaire, the Pain Self-Efficacy Questionnaire, and the Short Health Anxiety Inventory; rated their pain intensity; and rated the degree to which the information given by the surgeon was unexpected or surprising on an 11-point ordinal scale. The surgeon also rated his impression of the patient's surprise on an 11-point ordinal scale. RESULTS: Only greater symptom intensity and magnitude of disability (QuickDASH) correlated with greater unexpected information when rated by the patient (beta = 0.058; p < 0.001). There was a correlation between patient surprise and the surgeon's perception of the patient's surprise (r = 0.58; p < 0.001). Greater surgeon-perceived patient surprise correlated with nonspecific illness (p = 0.007; beta = 3.0). CONCLUSIONS: Patients with greater symptom intensity and magnitude of disability, and perhaps also patients with nonspecific diagnoses, are more likely to be surprised by a hand surgeon's advice. Future research might address the ability of previsit preparation (using decision aids or other alternative means of education) to ameliorate the discordance between patient assumptions and hand surgeon advice. PMID- 25280554 TI - Letter to the editor: Editorial: words hurt - avoiding dehumanizing language in orthopaedic research and practice. PMID- 25280553 TI - Patients with knee osteoarthritis have a phenotype with higher bone mass, higher fat mass, and lower lean body mass. AB - BACKGROUND: Although knee osteoarthritis (OA) is common, its etiology is poorly understood. Specifically, it is not known whether knee OA is associated with abnormal anthropometric and musculoskeletal characteristics known to be associated with OA in general. We recently studied this topic for patients with hip arthritis; however, it is important to evaluate it for knee OA separately, because there are reports indicating that patients with primary OA in different joints may have a different phenotype. QUESTIONS/PURPOSES: Do patients with primary knee OA have a phenotype with higher bone mineral density (BMD), higher body mass index (BMI), larger skeletal size, lower lean body mass, and higher fat content? METHODS: We included 38 women and 74 men (mean age, 61 years; range, 34 85 years) with primary knee OA and 122 women and 121 men as control subjects. We used dual-energy x-ray absorptiometry to measure total body BMD (g/cm2), femoral neck width (cm), fat and lean mass (%), and BMI (kg/m2). Z scores were calculated for each individual. Data are presented as means with 95% confidence intervals. RESULTS: Women with knee OA had the following Z scores: total body BMD 0.8 (0.5 1.0); BMI 1.6 (1.1-2.0); femoral neck width 0.1 (-0.3 to 0.4); proportion of lean mass -1.0 (-1.5 to -0.6); and proportion of fat mass 1.0 (0.6-1.4). Men with knee OA had the following Z scores: total body BMD 0.5 (0.3-0.7); BMI 0.9 (0.6-1.1); femoral neck width 0.3 (0.1-0.7); proportion of lean mass -0.9 (-1.1 to -0.8); and proportion of fat mass 0.7 (0.5-0.9). CONCLUSIONS: Women and men with idiopathic knee OA have a phenotype with higher BMD, higher BMI, proportionally higher fat mass, and proportionally lower lean body mass. Men also have a larger skeletal size. CLINICAL RELEVANCE: A higher BMD may lead to stiffer bone, a higher BMI to a greater joint load, and a proportionally lower lean body (muscle) mass to lower joint-protective ability, and all trait deviations probably predispose for knee OA. PMID- 25280555 TI - CORR Insights: Comorbidities in patients undergoing total knee arthroplasty: do they influence hospital costs and length of stay? PMID- 25280557 TI - Comparison of conventional and integrated programs for control of Tetranychus urticae (Acari: Tetranychidae). AB - The twospotted spider mite (TSSM), Tetranychus urticae Koch, is one of the main pests on strawberry crops in Brazil. TSSM can be difficult to control due to acaricide resistance. The objective of this work was to compare the effect of conventional and integrated strawberry production (ISP) systems on mite abundance and acaricide resistance. The control of TSSM in ISP was based on the release of Neoseiulus californicus (McGregor) or application of a selective acaricide (propargite), when TSSM monitoring indicated the timing for the release of predaceous mites (1-3 mites per leaflet on 30% leaflets) or chemical intervention (>10 mites per leaflet). Only acaricides (abamectin, fenpyroximate) were applied in the conventional system. Integrated control of TSSM were sufficient to maintain a significantly lower pest infestation level, resulting in a sixfold reduction in the frequency of acaricide applications, and consequently, a lower selection pressure for acaricide resistance. Strategies for the management of TSSM in strawberry fields are described and discussed. PMID- 25280556 TI - Development of a single-replicon miniBYV vector for co-expression of heterologous proteins. AB - In planta production of recombinant proteins, including vaccine antigens and monoclonal antibodies, continues gaining acceptance. With the broadening range of target proteins, the need for vectors with higher performance is increasing. Here, we have developed a single-replicon vector based on beet yellows virus (BYV) that enables co-delivery of two target genes into the same host cell, resulting in transient expression of each target. This BYV vector maintained genetic stability during systemic spread throughout the host plant, Nicotiana benthamiana. Furthermore, we have engineered a miniBYV vector carrying the sequences encoding heavy and light chains of a monoclonal antibody (mAb) against protective antigen (PA) of Bacillius anthracis, and achieved the expression of the full-length functional anti-PA mAb at ~300 mg/kg of fresh leaf tissue. To demonstrate co-expression and functionality of two independent proteins, we cloned the sequences of the Pfs48/45 protein of Plasmodium falciparum and endoglycosidase F (PNGase F) from Flavobacterium meningosepticum into the miniBYV vector under the control of two subgenomic RNA promoters. Agroinfiltration of N. benthamiana with this miniBYV vector resulted in accumulation of biologically active Pfs48/45 that was devoid of N-linked glycosylation and had correct conformation and epitope display. Overall, our findings demonstrate that the new BYV-based vector is capable of co-expressing two functionally active recombinant proteins within the same host cell. PMID- 25280558 TI - The risk of colorectal cancer in patients with ulcerative colitis. AB - BACKGROUND AND AIM: Ulcerative colitis increases the risk of developing dysplasia and colitis-associated cancer (CAC). The purpose of this study was to determine the risk factors as well as protective measures for disease burden, need for colectomy and the development of CAC in ulcerative colitis (UC) patients. METHODS: A cohort of n = 434 UC patients was evaluated. Data analysis was performed by univariate and multivariate logistic regression. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated, and significance was assessed by the likelihood ratio test. RESULTS: Mean patient age at UC diagnosis was 45.7 +/- 15.1 years which manifested mainly as pancolitis (47 %) or left-sided colitis (45.2 %). CAC was detected in ten patients (2.3 %). UC disease duration was strongly associated with the risk of CAC (P < 0.0014); disease duration between 9 and 15 years: OR of 2.5 (95 % CI 0.2-41.1), more than 15 years: OR of 21.4 (95 % CI 2.6-173.6). The risk of developing dysplasia (low-grade intraepithelial neoplasia, LGIEN and high-grade intraepithelial neoplasia, HGIEN) or the need to undergo colectomy was also significantly related to disease duration (P = 0.006, P = 0.002, respectively). Established anti-inflammatory medication (e.g., 5-ASA, anti-TNF-alpha) significantly reduced the risk of both dysplasia and CAC (P = 0.02). CONCLUSIONS: Despite the use of modern therapies for UC, CAC rates remain high. In our study, risk factors included disease duration while anti inflammatory therapies reduced the risk. Effective control of the intestinal inflammation also reduced the disease burden as indicated by decreased risk of requiring colectomy, underscoring the need for sufficient surveillance and anti inflammatory therapies. PMID- 25280559 TI - Environmental effects on the shape variation of male ultraviolet patterns in the Brimstone butterfly (Gonepteryx rhamni, Pieridae, Lepidoptera). AB - The males of the Brimstone butterfly (Gonepteryx rhamni) have ultraviolet pattern on the dorsal surfaces of their wings. Using geometric morphometrics, we have analysed correlations between environmental variables (climate, productivity) and shape variability of the ultraviolet pattern and the forewing in 110 male specimens of G. rhamni collected in the Palaearctic zone. To start with, we subjected the environmental variables to principal component analysis (PCA). The first PCA axis (precipitation, temperature, latitude) significantly correlated with shape variation of the ultraviolet patterns across the Palaearctic. Additionally, we have performed two-block partial least squares (PLS) analysis to assess co-variation between intraspecific shape variation and the variation of 11 environmental variables. The first PLS axis explained 93% of variability and represented the effect of precipitation, temperature and latitude. Along this axis, we observed a systematic increase in the relative area of ultraviolet colouration with increasing temperature and precipitation and decreasing latitude. We conclude that the shape variation of ultraviolet patterns on the forewings of male Brimstones is correlated with large-scale environmental factors. PMID- 25280560 TI - Association between Catechol-O-methyltransferase rs4680 (G>A) polymorphism and lung cancer risk. AB - BACKGROUND: The association between the Val158Met polymorphism in the catechol-O methyltransferase (COMT) gene and lung cancer risk remains controversial and inconclusive. Therefore, the meta-analysis was performed to provide a quality reevaluation of the association between the COMT Val158Met polymorphism and the risk of lung cancer. METHODS: Two major public databases (Pubmed and Embase) and several Chinese databases were searched for eligible studies. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the strength of the association. RESULTS: Five publications, including six individual studies with a total of 4,043 subjects (1,796 cases and 2,247 controls) regarding the association of COMT Val158Met polymorphism with lung cancer susceptibility were included in this meta-analysis. Overall, pooled analysis indicated that there was no significant association between COMT Val158Met polymorphism and lung cancer susceptibility under all genetic models. Likewise, no association was observed in the stratified analysis by ethnicity and control source, either. However, Val158Met polymorphism was shown to increase lung cancer risk among women (AG vs. GG, OR=1.190, 95% CI=1.001-1.422, p=0.049). CONCLUSION: These findings suggested that the COMT l58Val/Met polymorphism confer genetic susceptibility to lung cancer among women. However, no evidence was found for the association with lung cancer risk in ethnicity and smoking status. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_192. PMID- 25280561 TI - Motivational and emotional influences on cognitive control in depression: A pupillometry study. AB - Depressed people perform poorly on cognitive tasks; however, under certain conditions they show intact cognitive performance, with physiological reactivity consistent with needing to recruit additional cognitive control. We hypothesized that this apparent compensation is driven by the presence of affective processes (e.g., state anxiety), which in turn are moderated by the depressed individual's motivational state. Clarifying these processes may help researchers identify targets for treatment that if addressed may improve depressed patients' cognitive functioning. To test this hypothesis, 36 participants with unipolar depression and 36 never-depressed controls completed a problem-solving task that was modified to elicit anxiety. The participants completed measures of motivation, anxiety, sadness, and rumination, while pupillary responses were continuously measured during problem-solving, as an index of cognitive control. Anxiety increased throughout the task for all participants, whereas both sadness and rumination were decreased during the task. In addition, anxiety more strongly affected planning accuracy in depressed participants than in controls, regardless of the participants' levels of motivation. In contrast, differential effects of anxiety on pupillary responses were observed as a function of depressed participants' levels of motivation. Consistent with the behavioral results, less motivated and anxious depressed participants demonstrated smaller pupillary responses, whereas more highly motivated and anxious depressed participants demonstrated larger pupillary responses than did controls. Strong effects of sadness and rumination on cognitive control in depression were not observed. Thus, we conclude that anxiety inhibits the recruitment of cognitive control in depression and that a depressed individual's motivational state determines, in part, whether he or she is able to compensate by recruiting additional cognitive control. PMID- 25280562 TI - Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. AB - Sporadic and non-hereditary mutations account for the majority of colorectal cancers (CRC). After the loss of adenomatous polyposis coli (APC) function and activation of the beta-catenin/LEF signaling pathway, activating mutations in Kras are major drivers of sporadic CRC. Preventing the outgrowth of cells that develop sporadic mutations will decrease CRC. Resveratrol, a naturally occurring polyphenolic compound has anti-inflammatory, anti-oxidant and anti-cancer activities. We used a genetically engineered mouse model for sporadic CRC where the APC locus is knocked out and Kras is activated specifically in the distal colon to determine the effects of resveratrol on preventing and treating CRC. Feeding mice a diet supplemented with 150 or 300 ppm resveratrol (105 and 210mg daily human equivalent dose, respectively) before tumors were visible by colonoscopy resulted in a 60% inhibition of tumor production. In the 40% of mice that did develop tumors Kras expression was lost in the tumors. In a therapeutic assay where tumors were allowed to develop prior to treatment, feeding tumor bearing mice with resveratrol resulted in a complete remission in 33% of the mice and a 97% decrease in tumor size in the remaining mice. Analysis of miRNA expression in non-tumoral and tumoral colonic tissue of resveratrol treated mice showed an increased expression of miR-96, a miRNA previously shown to regulate Kras translation. These data indicate that resveratrol can prevent the formation and growth of colorectal tumors by downregulating Kras expression. PMID- 25280563 TI - MicroRNA-105 suppresses cell proliferation and inhibits PI3K/AKT signaling in human hepatocellular carcinoma. AB - A growing amount of evidence supports that microRNA (miRNA) dysregulation is involved in cancer progression by directly downregulating multiple targets. Elucidating the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In the current study, we found that miR-105 expression was markedly downregulated in both hepatocellular carcinoma (HCC) cell lines and clinical HCC tissues, compared with normal human hepatocyte and adjacent non-cancerous tissues, respectively. Ectopic miR-105 expression suppressed, whereas inhibiting miR-105 promoted the proliferation and tumorigenicity of HCC cells both in vitro and in vivo. Furthermore, we demonstrated that miR-105 could deactivated the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway by downregulating insulin receptor substrate-1, 3 phosphoinositide-dependent protein kinase-1 and AKT1 directly, resulting in increasing cyclin-dependent kinase inhibitors 1A and 1B (p21(Cip1) and p27(Kip1)) and decreasing cyclin D1 expression in HCC. Therefore, our results suggest that miR-105 functions as a potential tumor suppressor by inhibiting the PI3K/AKT signaling pathway and might represent a potential therapeutic target for HCC patients. PMID- 25280566 TI - Focal, transient mechanical narrowing of a pipeline embolization device following treatment of an internal carotid artery aneurysm. AB - Flow diversion is a promising technique for cerebral aneurysm treatment but presents new and sometimes unique challenges. Transient reversible narrowing due to device reconfiguration of the pipeline embolization device (PED) has not been previously described. Here we describe a patient with dolichoectasia of the distal right internal carotid artery with an associated saccular sidewall aneurysm who developed asymptomatic circumferential narrowing of the proximal aspect of the PED in the first month following deployment. The patient was followed conservatively and demonstrated partial resolution of device narrowing on 6 month follow-up imaging. PMID- 25280565 TI - Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis. AB - The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia. PMID- 25280567 TI - Intra-aneurysmal flow rates are reduced by two flow diverters: an experiment using tomographic particle image velocimetry in an aneurysm model. AB - BACKGROUND: Limitations on treating large, giant, and wide-necked aneurysms with coiling have made flow diverters a promising alternative to current practice by supporting reconstruction of the parent artery. OBJECTIVE: To assess the changes to fluid dynamics within an aneurysm by studying two different endoluminal flow diverters on a simple aneurysm model, using tomographic particle image velocimetry to determine which device would better minimize fluid flow into an aneurysm and observe any significant changes in aneurysm fluid structures. METHODS: Steady velocity fields of the model's aneurysm dome and neck were measured at three inlet velocities (18, 39, and 59 cm/s) for two flow diverter diameters with different porosities and compared against a baseline case with no flow diverter. RESULTS: In the baseline case a large vortex was present inside the dome for all flow rates. However, both devices eliminated this main vortex at all flow rates and reduced the peak aneurysmal velocities by about 90%. A strong correlation between flow diverter porosity and flow reduction was found. In each case the inflow to the aneurysm shifted from the distal neck to the mid- or proximal neck after flow diverter placement. CONCLUSIONS: Even with this relatively simple experimental setup, we were able to observe the major flow field changes, which occurred immediately after the deployment of each flow diverter. Limitations of the study included a simplified geometry and steady state flow. Constraints included model making and limited availability of flow diverters. PMID- 25280564 TI - Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma. AB - Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility. PMID- 25280568 TI - New Pipeline Flex device: initial experience and technical nuances. AB - BACKGROUND: Flow diverter stents (FDS) have been described as a breakthrough in the treatment of intracranial aneurysms. Of the various flow diverter models, the Pipeline device has been the main approved and used device, with established and good long-term results. OBJECTIVE: To present the first series of patients treated with its new version, the Pipeline Flex device. This has kept the same device design and configuration but redesigned and completely modified the delivery system. METHODS: In this technical report, we include 10 consecutive patients harboring 12 saccular aneurysms of the anterior circulation. We report the main changes on the system, immediate results, and technical nuances with illustrative cases. RESULTS: We implanted 12 devices, including 11 Pipeline Flex and one Pipeline device. We used the old version in one case that required a second layer with a short length not available in the Pipeline Flex size range. All attempts at treatment were successful and no device was discharged or removed. Recovery was required or used in half of the cases with good or excellent performance, except in one case that presented with multiple proximal loops and tight curves. We had two transitory events without ischemic lesions on MRI that recovered 1 and 4 h after all patients were discharged home asymptomatic. CONCLUSIONS: Pipeline Flex represents a major advance in FDS technology. The redesigned system has significantly improved the deployment of the Pipeline stent, by enabling the operator to resheath the device. It has the potential to continue revolutionizing the endovascular approach for intracranial aneurysms. PMID- 25280570 TI - Periconal arterial anastomotic circle and posterior lumbosacral watershed zone of the spinal cord. AB - BACKGROUND: The existence of spinal cord watershed territories was suggested in the 1950s. Segmental infarcts within the junctional territories of adjacent radiculomedullary contributors and isolated spinal gray matter ischemia constitute two well-recognized types of watershed injury. This report describes the existence of another watershed territory related to the particular configuration of the spinal vasculature in the region of the conus medullaris. METHODS: The anatomical bases underlying the concept of a posterior lumbosacral watershed zone are demonstrated with angiographic images obtained in a 16-year old child. The clinical importance of this watershed zone is illustrated with MRI and angiographic data of three patients with a conus medullaris infarction. RESULTS: In all three cases of spinal ischemia an intersegmental artery providing a significant radiculomedullary contribution for the lower cord was compromised by a compressive mechanism responsible for decreased spinal cord perfusion (diaphragmatic crus syndrome in two cases, disk herniation in one). The ischemic injury, located at the junction of the anterior and posterior spinal artery territories along the dorsal aspect of the conus medullaris, was consistent with a watershed mechanism. This zone is at risk because of the caudocranial direction of flow within the most caudal segment of the posterior spinal arterial network which, from a functional standpoint, depends on the anterior spinal artery. CONCLUSIONS: The posterior thoracolumbar watershed zone of the spinal cord represents an area at increased risk of ischemic injury, particularly in the context of partial flow impairment related to arterial compression mechanisms. PMID- 25280569 TI - Multimodal angiographic assessment of cerebral arteriovenous malformations: a pilot study. AB - PURPOSE: We describe our protocol of three-dimensional (3D) Roadmap intracranial navigation and image fusion for analysis of the angioarchitecture and endovascular treatment of brain arteriovenous malformations (AVMs). METHODS: We performed superselective catheterization of brain AVMs feeders under 3D-Roadmap navigation. Angiograms of each catheterized artery on two registered orthogonal views were transferred to the imaging workstations, and dedicated postprocessing imaging software allowed automated multiple overlays of the arterial supply of the AVM superselective acquisitions on the global angiogram in angiographic or 3D views and on coregistered MRI datasets. RESULTS: 11 untreated brain AVMs (4 with hemorrhagic presentation) were explored. The superselective acquisitions were performed under 3D-Roadmap navigation in 74 arteries, for a total of 79 targeted arteries. Imaging analysis was available at table side or postoperatively for discussion of the therapeutic strategy. No complications occurred during superselective catheterization. The accuracy of the coregistration of angiogram and MRI was submillimetric after automated mutual information coregistration, with manual re-registration by the physicians. CONCLUSIONS: Superselective angiograms acquired under 3D-Roadmap navigation can be postprocessed with multiple overlays. The fluoroscopic navigation under 3D-Roadmapping and the coregistration of 3D rotational angiography, selective angiography, and 3D MR datasets appears reliable with millimeter accuracy, and could be implemented in the critical brain AVM embolization setting to allow refined analysis of AVM angioarchitecture. PMID- 25280571 TI - Assessment of intra-aneurysmal flow modification after flow diverter stent placement with four-dimensional flow MRI: a feasibility study. AB - BACKGROUND: Flow diverter stents (FDS) have been effectively used for the endovascular treatment of sidewall intracranial aneurysms (IAs). Unlike standard endovascular treatments used to exclude directly the aneurysm bulge from the parent vessel, FDS induce reduction in the intra-aneurysmal flow and promote progressive and stable thrombosis therein. The advent of FDS has therefore increased the need for understanding of IA hemodynamics. METHODS: We proposed the use of the most recently evolved four-dimensional (4D) flow MRI technique to evaluate qualitatively and quantitatively post-FDS flow modification in 10 patients. We report intra-aneurysmal velocity measurements and the influence of metal artifacts induced by the stent. RESULTS: An index was defined to quantitatively measure flow changes-namely, the proportional velocity reduction ratio (PVRR)-with ranges from 34.6% to 71.1%. Furthermore, we could compare streamlines characterizing the post-stent flow patterns in five patients in whom the intra-aneurysmal velocity was beyond the visualization threshold of 7.69 cm/s. CONCLUSIONS: Despite metal artifacts and the low velocities involved, 4D flow MRI could be of interest to measure qualitatively and quantitatively flow changes in stented aneurysms. However, further enhancements are required together with further validation work before it can be considered for clinical use. PMID- 25280572 TI - Transvaginal single-incision mesh reconstruction for recurrent or advanced anterior vaginal wall prolapse. AB - AIMS: Single-incision transvaginal mesh for reconstruction of Level I and II prolapses in women with recurrent or advanced prolapse. We evaluated functional, anatomical, sonomorphological and quality-of-life outcome. METHODS: Data were collected retrospectively for preoperative parameters and at follow-up visits. Anatomical cure was assessed with vaginal examination using the ICS-POP-Q system; introital-ultrasound scan for postvoidal residual and description of mesh characteristics was performed. We applied a visual analogue scale (VAS) and the German Pelvic Floor Questionnaire to assess quality-of-life. RESULTS: Seventy women with cystocele (III: 61.3%/IV: 16%), all post-hysterectomy and in majority (81.4%) after previous cystocele repair, were operated using a single-incision transvaginal technique. Overall anatomical success rate was 95.7% with significant improvement in quality-of-life (p < 0.0001). Mesh erosion occurred in 5.7%, one patient presented symptomatic vaginal vault prolapse. Postvoidal residual declined significantly (58 vs. 2.9%). Sonographic mesh length was 55.7% of implanted mesh with a wide range of mesh position, but no signs of mesh dislocation. There was no de novo dyspareunia reported, one case of preoperative existing dyspareunia worsened. No severe adverse event was observed. CONCLUSIONS: We hereby present a trial of a high-risk group of patients requiring reconstruction of anterior and apical vaginal wall in mostly recurrent prolapse situation. Our data support the hypothesis of improved anatomical and functional results and less mesh shrinkage caused by the single-incision technique with fixation in sacrospinous ligament in combination with modification in mesh quality compared to former multi-incision techniques. PMID- 25280573 TI - Adenomyosis and accompanying gynecological pathologies. AB - OBJECTIVE: The aim of the present study is to determine the potential risk factors for adenomyosis and to investigate its relationship with accompanying gynecological pathologies and clinical characteristics. MATERIALS AND METHOD: This study is a retrospective analysis of 945 patients who underwent hysterectomy between May 2005 and January 2013 at the Sifa University Medical Faculty Hospital, Clinic of Obstetrics and Gynecology. The study included 327 patients with adenomyosis and 618 patients without adenomyosis by histopathological examination of the uterus. RESULTS: There was a significant positive correlation between development of adenomyosis and presence of leiomyoma (p < 0.0001), history of previous abortion (p < 0.0001), history of previous pregnancy (p = 0.0002), and normal body mass index (p < 0.0001). However, no significant relationship existed between development of adenomyosis and smoking (p > 0.4300), normal delivery (p = 0.9600), cesarean delivery (p = 0.5705), endometrial hyperplasia (p = 0.1721), or ovarian endometriosis (p = 0.8595). CONCLUSION: Women who are multiparous have leiomyoma, a previous history of abortion, and a normal body mass index are at increased risk for development of adenomyosis. Adenomyosis might be one cause of unexplained recurrent spontaneous abortion during pregnancy. PMID- 25280574 TI - No relationship between osteoprotegerin concentrations and endothelial dysfunction in non-obese women with and without polycystic ovary syndrome. AB - PURPOSE: To investigate the relationships of osteoprotegerin (OPG) concentrations to brachial artery flow-mediated vasodilation (FMD) and the carotid artery intima media thickness (CIMT) in polycystic ovary syndrome (PCOS). METHODS: Thirty-seven women with PCOS and 41 controls matched for body mass index (BMI) and age were included in study. The serum OPG concentrations, hormonal and metabolic profiles were measured in women with PCOS and in control group. The CIMT and brachial artery FMD were evaluated in both groups. RESULTS: The mean serum concentrations of all hormones were comparable, except LH, which was higher in women with PCOS. Lipid parameters were similar between groups. There were no differences between groups with respect to fasting glucose, 2-h glucose, fasting insulin, HbA1c and HOMA-IR. The mean osteoprotogerin concentrations were higher in PCOS group (11.39 +/- 2.29 vs. 10.22 +/- 2.25 pmol/L, P = 0.026). The mean CIMT was higher in PCOS group than control group (0.52 +/- 0.058 vs. 0.45 +/- 0.059 mm, P < 0.01). The mean brachial artery FMD was lower in PCOS group (0.068 +/- 0.022 vs. 0.055 +/- 0.029, P = 0.017). CONCLUSIONS: We found high osteoprotogerin concentrations, increased CIMT and decreased FMD, in women with PCOS. However, there was no correlation between osteoprotegerin and cardiovascular risk markers. PMID- 25280575 TI - Factors predicting one-year mortality in amyotrophic lateral sclerosis patients- data from a population-based registry. AB - BACKGROUND: Survival in amyotrophic lateral sclerosis varies considerably. About one third of the patients die within 12 months after first diagnosis. The early recognition of fast progression is essential for patients and neurologists to weigh up invasive therapeutic interventions. In a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany, we identified significant prognostic factors at time of diagnosis that allow prediction of early death within first 12 months. METHODS: Incident cases, diagnosed between October 2009 and September 2012 were enrolled and followed up at regular intervals of 3 to 6 months. Univariate analysis utilized the Log-Rank Test to identify association between candidate demographic and disease variables and one year mortality. In a second step we investigated a multiple logistic regression model for the optimal prediction of one-year mortality rate. RESULTS: In the cohort of 176 ALS patients (mean age 66.2 years; follow-up 100%) one-year mortality rate from diagnosis was 34.1%. Multivariate analysis revealed that age over 75 years, interval between symptom onset and diagnosis below 7 months, decline of body weight before diagnosis exceeding 2 BMI units and Functional Rating Score below 31 points were independent factors predicting early death. CONCLUSIONS: Probability of early death within 12 months from diagnosis is predicted by advanced age, short interval between symptom onset and first diagnosis, rapid decline of body weight before diagnosis and advanced functional impairment. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01955369, registered September 28, 2013). PMID- 25280576 TI - Population genetics of neotropical Culex quinquefasciatus (Diptera: Culicidae). AB - BACKGROUND: Culex quinquefasciatus mosquitoes can be found in almost every major city of Brazil and are vectors of filariasis and several arboviruses. Microsatellite markers have been widely used to uncover the genetic structure of various groups of insect populations. The aim of this study was to glimpse the genetic structure of Cx. quinquefasciatus in Brazil. METHODS: Nine populations were sampled across Brazil (one of them from a laboratory colony - COL) and another one from Argentina and process regarding the variability of six microsatellite loci. RESULTS: The analyzed loci revealed moderate population genetic structure (mean Fst = 0.12). Dendrograms of genetic distances evidenced two major population clusters, respectively corresponding to the northern and southern populations. The hybrid population Cx. pipiens/quinquefasciatus (from La Plata, Argentina) and the colony population fell outside the major clusters. Those clusters were substructured and there was a significant correlation between genetic and geographic distances and environmental variables (r = 0.51; p > 0.001 and r = 0.46; p > 0.004). CONCLUSIONS: Multilocus cluster Bayesian analysis confirmed that populations are mutually distinct, and the set of results point to genetic differences among populations. The presumable low gene flow among them may be due to the large geographic distances (>1000 km) and to the environmental heterogeneity of the sampled areas. The genetic structure observed in this study may lead to the best understanding of Cx. quinquefasciatus demographical diversity as well as their genetic variations patterns in Brazil so far unknown. PMID- 25280577 TI - Predictors of positive and negative parenting behaviours: evidence from the ALSPAC cohort. AB - BACKGROUND: This study aimed to establish the predictors of positive and negative parenting behaviours in a United Kingdom population. The majority of previous research has focused on specific risk factors and has used a variety of outcome measures. This study used a single assessment of parenting behaviours and started with a wide range of potential pre- and post-natal variables; such an approach might be used to identify families who might benefit from parenting interventions. METHODS: Using a case-control subsample of 160 subjects from the Avon Longitudinal Study of Parents and Children (ALSPAC), regression analysis was undertaken to model parenting behaviours at 12 months as measured by the Mellow Parenting Observational System. RESULTS: Positive parenting increased with maternal age at delivery, levels of education and with prenatal anxiety. More negative interactions were observed among younger mothers, mothers with male infants, with prenatal non-smokers and among mothers who perceived they had a poor support structure. CONCLUSIONS: This study indicates two factors which may be important in identifying families most at risk of negative parenting: younger maternal age at delivery and lack of social support during pregnancy. Such factors could be taken into account when planning provision of services such as parenting interventions. We also established that male children were significantly more likely to be negatively parented, a novel finding which may suggest an area for future research. However the findings have to be accepted cautiously and have to be replicated, as the measures used do not have established psychometric validity and reliability data. PMID- 25280578 TI - An intervention to reassure patients about test results in rapid access chest pain clinic: a pilot randomised controlled trial. AB - BACKGROUND: Most people referred to rapid access chest pain clinics have non cardiac chest pain, and in those diagnosed with stable coronary heart disease, guidance recommends that first-line treatment is usually medication rather than revascularisation. Consequently, many patients are not reassured they have the correct diagnosis or treatment. A previous trial reported that, in people with non-cardiac chest pain, a brief discussion with a health psychologist before the tests about the meaning of potential results led to people being significantly more reassured. The aim of this pilot was to test study procedures and inform sample size for a future multi-centre trial and to gain initial estimates of effectiveness of the discussion intervention. METHODS: This was a two-arm pilot randomised controlled trial in outpatient rapid access chest pain clinic in 120 people undergoing investigation for new onset, non-urgent chest pain. Eligible participants were randomised to receive either: a discussion about the meaning and implication of test results, delivered by a nurse before tests in clinic, plus a pre-test pamphlet covering the same information (Discussion arm) or the pre-test pamphlet alone (Pamphlet arm). Main outcome measures were recruitment rate and feasibility for a future multi-centre trial, with an estimate of reassurance in the groups at month 1 and 6 using a 5-item patient-reported scale. RESULTS: Two hundred and seventy people attended rapid access chest pain clinic during recruitment and 120/270 participants (44%) were randomised, 60 to each arm. There was no evidence of a difference between the Discussion and Pamphlet arms in the mean reassurance score at month 1 (34.2 vs 33.7) or at month 6 (35.3 vs 35.9). Patient-reported chest pain and use of heart medications were also similar between the two arms. CONCLUSIONS: A larger trial of the discussion intervention in the UK would not be warranted. Patients reported high levels of reassurance which were similar in patients receiving the discussion with a nurse and in those receiving a pamphlet alone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN60618114 (assigned 27.05.2011). PMID- 25280579 TI - Perceptions on healthy eating, physical activity and lifestyle advice: opportunities for adapting lifestyle interventions to individuals with low socioeconomic status. AB - BACKGROUND: Individuals with low socioeconomic status (SES) are generally less well reached through lifestyle interventions than individuals with higher SES. The aim of this study was to identify opportunities for adapting lifestyle interventions in such a way that they are more appealing for individuals with low SES. To this end, the study provides insight into perspectives of groups with different socioeconomic positions regarding their current eating and physical activity behaviour; triggers for lifestyle change; and ways to support lifestyle change. METHODS: Data were gathered in semi-structured focus group interviews among low SES (four groups) and high SES (five groups) adults. The group size varied between four and nine participants. The main themes discussed were perceptions and experiences of healthy eating, physical activity and lifestyle advice. Interviews were transcribed verbatim and a thematic approach was used to analyse the data. RESULTS: In general, three key topics were identified, namely: current lifestyle is logical for participants given their personal situation; lifestyle change is prompted by feedback from their body; and support for lifestyle change should include individually tailored advice and could profit from involving others. The perceptions of the low SES participants were generally comparable to the perceptions shared by the high SES participants. Some perceptions were, however, especially shared in the low SES groups. Low SES participants indicated that their current eating behaviour was sometimes affected by cost concerns. They seemed to be especially motivated to change their lifestyle when they experienced health complaints, but were rather hesitant to change their lifestyle for preventive purposes. Regarding support for lifestyle change, low SES participants preferred to receive advice in a group rather than on their own. For physical activities, groups should preferably consist of persons of the same age, gender or physical condition. CONCLUSIONS: To motivate individuals with low SES to change their lifestyle, it may be useful to (visually) raise their awareness of their current weight or health status. Lifestyle interventions targeting individuals with low SES should take possible cost concerns into account and should harness the supportive effect of (peer) groups. PMID- 25280581 TI - Distribution and content of lipid droplets and mitochondria in pig parthenogenetically activated embryos after delipation. AB - The present study examines the effect of delipation on developmental competence and the distribution pattern of lipid droplets (LDs) and mitochondria in parthenogenetically activated (PA) pig embryos. Mature oocytes were delipated by centrifugation after partial digestion of the zonae pellucidae, subjected to parthenogenetic activation after total removal of zonae pellucidae by pronase, and then cultured in vitro up to the blastocyst stage. The contents and distributions of LDs and mitochondria in the oocytes and/or embryos were observed by staining with Oil Red O and MitoTracker Red CMXRos, respectively. The LD and mitochondrial contents were significantly reduced by the delipation process, and only smaller LDs remained in the delipated oocytes and/or embryos. Their content remained constant from the metaphase II oocyte to the blastocyst stage, but they became gradually smaller as the oocytes and/or embryos developed. The distribution pattern of the LDs in the delipated embryos changed over time and in a manner different to that seen in the controls. In the early developmental stages (1- to 4-cell stages), they were distributed peripherally and formed a ring around the nucleus. However, by the blastocyst stage, a homogeneous distribution of LDs was observed in both the inner cell mass and trophectoderm. The distribution pattern of mitochondria also changed with the development of the delipated PA embryos and again, in ways different to those seen in the controls. In the early 1- to 4-cell stages, a peripheral distribution of mitochondrial foci was observed in each blastomere. However, in blastocysts, the mitochondria were homogeneously distributed throughout the inner cell mass and trophectoderm. Although the cleavage rate at the 2- and 4-cell stages of the PA embryos was not affected by delipation (95.83 +/- 2.25% vs. 97.44 +/- 0.67%; 79.17 +/- 4.47% vs. 84.62 +/- 1.19%), it was reduced significantly in the blastocyst compared with the controls (21.67 +/- 3.78% vs. 49.36 +/- 1.77%). The distribution pattern of the LDs in oocytes and/or embryos at different developmental stages, and that of the mitochondria in metaphase II oocytes, was affected by delipation. The developmental competence of porcine PA embryos would appear to be affected by delipation. PMID- 25280580 TI - A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology. AB - Gonadotropins extracted from the urine of post-menopausal women have traditionally been used to stimulate folliculogenesis in the treatment of infertility and in assisted reproductive technology (ART). Products, such as human menopausal gonadotropin (hMG), consist not only of a mixture of the hormones, follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG), but also other biologically active contaminants, such as growth factors, binding proteins and prion proteins. The actual amount of molecular LH in hMG preparations varies considerably due to the purification process, thus hCG, mimicking LH action, is added to standardise the product. However, unlike LH, hCG plays a different role during the natural human menstrual cycle. It is secreted by the embryo and placenta, and its main role is to support implantation and pregnancy. More recently, recombinant gonadotropins (r-hFSH and r-hLH) have become available for ART therapies. Recombinant LH contains only LH molecules. In the field of reproduction there has been controversy in recent years over whether r-hLH or hCG should be used for ART. This review examines the existing evidence for molecular and functional differences between LH and hCG and assesses the clinical implications of hCG-supplemented urinary therapy compared with recombinant therapies used for ART. PMID- 25280582 TI - A novel system for automatic classification of upper limb motor function after stroke: an exploratory study. AB - In the early post-stroke phase, when clinicians attempt to evaluate interventions and accurately measure motor performance, reliable tools are needed. Therefore, the development of a system capable of independent, repeated and automatic assessment of motor function is of increased importance. This manuscript explores the potential of a newly designed device for automatic assessment of motor impairment after stroke. A portable motion capture system was developed to acquire three-dimensional kinematics data of upper limb movements. These were then computed through an automatic decision tree classifier, with features inferred from the Functional Ability Score (FAS) of the Wolf Motor Function Test (WMFT). Five stroke patients were tested on both sides across five selected tasks. The system was compared against a trained clinician, operating simultaneously and blinded. Regarding performance time, the mean difference (system vs clinician) was 0.17s (sd=0.14s). For FAS evaluation, there was agreement in 4 out of 5 patients in the two tasks evaluated. The prototype tested was able to automatically classify upper limb movement, according to a widely used functional motor scale (WMFT) in a relevant clinical setting. These results represent an important step towards a system capable of precise and independent motor evaluation after stroke. The portability and low-cost design will contribute for its usability in ambulatory clinical settings and research trials. PMID- 25280584 TI - Creating the patient centered medical home. PMID- 25280583 TI - BCG and infection with Mycobacterium tuberculosis. PMID- 25280585 TI - Mesenchymal stem cells as a potential therapeutic tool for spinocerebellar ataxia. AB - Spinocerebellar ataxia (SCA) is a devastating progressive neurodegenerative disorder, for which no effective treatments have been developed. However, some studies have shown that an intracerebellar or intrathecal injection of mesenchymal stem cells (MSCs) was partially effective in some genetic mouse models of cerebellar ataxia such as SCA1 and Lurcher mutant. MSCs likely exert their therapeutic efficacy by secreting innate factors to induce neuronal growth and synaptic connection and reduce apoptosis. In this review, we introduce the therapeutic influence of MSCs on each mouse model for cerebellar ataxia and the possible mechanisms underlying the action of MSCs. We also introduce studies on the safety and effectiveness of umbilical cord MSCs for patients with SCA. PMID- 25280586 TI - Clinical and forensic signs related to chemical burns: a mechanistic approach. AB - This manuscript highlights and critically analyses clinical and forensic signs related to chemical burns. Signs that may lead to suspicion of a particular chemical are thoroughly discussed regarding its underlying mechanisms. Burns due to sulfuric, hydrofluoric, nitric, hydrochloric (muriatic) and acetic (including derivatives) acids, hydrogen sulphide, sodium (caustic soda) and calcium (cement) hydroxides, paraquat, burns after inflation and rupture of airbags, povidone iodine, chlorhexidine/alcohol (in preterm infants), laxatives, and vesicants (warfare agents), will be reviewed since these are the most common agents found in daily practice, for which relevant and timed information may be helpful in formulating an emergency treatment protocols and toxicological analysis. PMID- 25280588 TI - Organising evidence for environmental management decisions: a '4S' hierarchy. AB - Making decisions informed by the best-available science is an objective for many organisations managing the environment or natural resources. Yet, available science is still not widely used in environmental policy and practice. We describe a '4S' hierarchy for organising relevant science to inform decisions. This hierarchy has already revolutionised clinical practice. It is beginning to emerge for environmental management, although all four levels need substantial development before environmental decision-makers can reliably and efficiently find the evidence they need. We expose common bypass routes that currently lead to poor or biased representation of scientific knowledge. We argue that the least developed level of the hierarchy is that closest to decision-makers, placing synthesised scientific knowledge into environmental decision support systems. PMID- 25280589 TI - Extended blood group molecular typing and next-generation sequencing. AB - Several high-throughput multiplex blood group molecular typing platforms have been developed to predict blood group antigen phenotypes. These molecular systems support extended donor/patient matching by detecting commonly encountered blood group polymorphisms as well as rare alleles that determine the expression of blood group antigens. Extended molecular typing of a large number of blood donors by high-throughput platforms can increase the likelihood of identifying donor red blood cells that match those of recipients. This is especially important in the management of multiply-transfused patients who may have developed several alloantibodies. Nevertheless, current molecular techniques have limitations. For example, they detect only predefined genetic variants. In contrast, target enrichment next-generation sequencing (NGS) is an emerging technology that provides comprehensive sequence information, focusing on specified genomic regions. Target enrichment NGS is able to assess genetic variations that cannot be achieved by traditional Sanger sequencing or other genotyping platforms. Target enrichment NGS has been used to detect both known and de novo genetic polymorphisms, including single-nucleotide polymorphisms, indels (insertions/deletions), and structural variations. This review discusses the methodology, advantages, and limitations of the current blood group genotyping techniques and describes various target enrichment NGS approaches that can be used to develop an extended blood group genotyping assay system. PMID- 25280587 TI - Dohaekseunggi-tang extract inhibits obesity, hyperlipidemia, and hypertension in high-fat diet-induced obese mice. AB - BACKGROUND: Dohaekseunggi-tang (DHSGT) is a traditional plant-based medicine prescribed to promote blood circulation and to treat obesity and hypertension. The present study aimed to identify potential anti-obesity activities of DHSGT extract. METHODS: Anti-obesity, anti-hyperlipidemic, and anti-hypertensive effects of orally-administered DHSGT extract were evaluated in high-fat diet- (HFD)-induced obese mice. Serum biochemistry profiles and expression of diverse metabolic regulatory gene mRNAs in mouse visceral fat were assessed by RT-PCR. The effects of DHSGT on angiotensin-1 converting enzyme (ACE) and pancreatic lipase activities were determined using in vitro inhibition assays. RESULTS: Oral DHSGT treatment reduced obese HFD C57BL/6 J mouse body weight, liver and adipose tissue mass, adipocyte size, and blood pressure versus untreated HFD mice. DHSGT also decreased serum total cholesterol, LDL-cholesterol, triglyceride, glucose, and leptin concentrations, and increased HDL-cholesterol and adiponectin levels in HFD mice. Furthermore, DHSGT markedly increased mRNA expression of peroxisome proliferator activated receptor-gamma, uncoupling protein-2, and adiponectin in visceral adipose tissue of HFD mice. In vitro tests revealed that DHSGT effectively inhibited porcine pancreatic lipase and ACE activities, with IC50 values of 7.58 mg/ml and 0.56 mg/ml, respectively. CONCLUSIONS: These results validate traditional knowledge and suggest that DHSGT may be potentially useful for managing hyperlipidemia, hyperglycemia, hypertension, and obesity. PMID- 25280590 TI - A mechanistic approach to the diagnosis and management of atypical hemolytic uremic syndrome. AB - Until recently, atypical hemolytic uremic syndrome (aHUS), conventionally defined in the pediatric literature as a syndrome of the triad of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia without a prodrome of hemorrhagic diarrhea, has received little attention in adult practice because the patients are commonly given the diagnosis of thrombotic thrombocytopenic purpura (TTP) or TTP/HUS and treated as TTP with plasma exchange, augmented in refractory cases with rituximab and sometimes even splenectomy. Molecular studies have shown that the regulation of the alternative complement pathway is defective in many patients with conventionally defined aHUS. With this new knowledge and the findings of ADAMTS13 autoinhibitors or mutations in TTP, it is time to redefine aHUS as a disorder with propensity to the development of thrombotic microangiopathy due to defective regulation of the alternative complement pathway and TTP as a disorder with propensity to arteriolar and capillary thrombosis due to ADAMTS13 deficiency. This new definition provides a clear distinction of aHUS from TTP, encompasses patients without all 3 components of the triad, and provides the rationale for management with anticomplement therapy. PMID- 25280592 TI - Unresectable isolated hepatic metastases from solid pseudopapillary neoplasm of the pancreas: a case report of chemosaturation with high-dose melphalan. AB - BACKGROUND/OBJECTIVES: Solid pseudopapillary neoplasms of the pancreas (SPN) are rare tumors. For patients with unresectable liver metastases of SPN, no standard treatment has been defined so far. Here we report a case of a 40-year-old woman with SPN and metastases confirmed to the liver, and disease progression in the liver after primary tumor resection and chemotherapy with gemcitabine and cisplatin. METHODS: Chemosaturation with percutaneous hepatic perfusions is a minimally invasive, repeatable regional therapy which delivers chemotherapy directly to the liver while limiting systemic toxicity. As an individual treatment approach, the patient was treated with chemosaturation with percutaneous hepatic perfusions of melphalan. RESULTS: The procedure was performed twice within 8 weeks after which the liver metastases showed a marked reduction in size and vascularization (partial response). Grade 3 leukopenia after the second procedure was managed effectively with granulocyte colony stimulating factor. No other toxicities were observed. Ten months after initiating treatment, the patient had a good performance status and remained stable. CONCLUSIONS: For SPN with unresectable liver metastases and progression despite systemic treatment, repeat chemosaturation with high-dose melphalan may also offer an effective regional treatment option. PMID- 25280591 TI - Cyclic nucleotide-gated ion channel gene family in rice, identification, characterization and experimental analysis of expression response to plant hormones, biotic and abiotic stresses. AB - BACKGROUND: Cyclic nucleotide-gated channels (CNGCs) are Ca2+-permeable cation transport channels, which are present in both animal and plant systems. They have been implicated in the uptake of both essential and toxic cations, Ca2+ signaling, pathogen defense, and thermotolerance in plants. To date there has not been a genome-wide overview of the CNGC gene family in any economically important crop, including rice (Oryza sativa L.). There is an urgent need for a thorough genome-wide analysis and experimental verification of this gene family in rice. RESULTS: In this study, a total of 16 full length rice CNGC genes distributed on chromosomes 1-6, 9 and 12, were identified by employing comprehensive bioinformatics analyses. Based on phylogeny, the family of OsCNGCs was classified into four major groups (I-IV) and two sub-groups (IV-A and IV- B). Likewise, the CNGCs from all plant lineages clustered into four groups (I-IV), where group II was conserved in all land plants. Gene duplication analysis revealed that both chromosomal segmentation (OsCNGC1 and 2, 10 and 11, 15 and 16) and tandem duplications (OsCNGC1 and 2) significantly contributed to the expansion of this gene family. Motif composition and protein sequence analysis revealed that the CNGC specific domain "cyclic nucleotide-binding domain (CNBD)" comprises a "phosphate binding cassette" (PBC) and a "hinge" region that is highly conserved among the OsCNGCs. In addition, OsCNGC proteins also contain various other functional motifs and post-translational modification sites. We successively built a stringent motif: (LI-X(2)-[GS]-X-[FV]-X-G-[1]-ELL-X-W-X(12,22)-SA-X(2)-T X(7)-[EQ]-AF-X-L) that recognizes the rice CNGCs specifically. Prediction of cis acting regulatory elements in 5' upstream sequences and expression analyses through quantitative qPCR demonstrated that OsCNGC genes were highly responsive to multiple stimuli including hormonal (abscisic acid, indoleacetic acid, kinetin and ethylene), biotic (Pseudomonas fuscovaginae and Xanthomonas oryzae pv. oryzae) and abiotic (cold) stress. CONCLUSIONS: There are 16 CNGC genes in rice, which were probably expanded through chromosomal segmentation and tandem duplications and comprise a PBC and a "hinge" region in the CNBD domain, featured by a stringent motif. The various cis-acting regulatory elements in the upstream sequences may be responsible for responding to multiple stimuli, including hormonal, biotic and abiotic stresses. PMID- 25280593 TI - Electron-microscopic evidence of mitochondriae containing macroautophagy in experimental acute pancreatitis: implications for cell death. AB - BACKGROUND: Dysfunctional autophagy and necrosis are characteristic features of severe acute pancreatitis. OBJECTIVE: To unravel the cellular mechanisms underlying the pathogenesis of acute pancreatitis. METHODS: We studied the ultrastructural pancreatic morphology using electron microscopy in experimental acute pancreatitis. The control group of animals received intraperitoneal injections of normal saline. Different severity of acute pancreatitis was induced by low and high doses of caerulein in Swiss albino mice. In the low dose group, pancreatitis was induced by 4 injections of caerulein given hourly [50 MUg/kg/dose - total of 200 MUg/kg] and in the high dose group by 8 injections given hourly (total of 400 MUg/kg). The experiments were repeated in Na taurocholate model of acute pancreatitis in rats. The pancreatic tissue was processed and studied by transmission electron microscopy for ultrastructural changes. RESULTS: The acinar cells of the pancreatitis animals revealed autophagosomes that contained cellular organelles, including mitochondria. The animals that received a higher dose of caerulein had numerous cells showing a necrotic morphology, whereas the animals in the low dose group showed a predominantly apoptotic cell morphology. The Na-taurocholate model in rats also showed similar features of severe pancreatitis with cellular necrosis and macroautophagy. CONCLUSIONS: Dysfunctional mitochondria in the injured pancreatic acinar cells are degraded by macroautophagy. These observations are not model specific. Mitochondrial dysfunction and consequent energy deficit in the cells might be causally related to cellular necrosis. PMID- 25280594 TI - Clinical and historical aspects of the Elephant Man: exploring the facts and the myths. AB - Joseph Merrick, the Elephant Man, presented to the Royal London Hospital in 1884 with an obscure condition that puzzled his contemporaries, and fascinates clinicians to this day. Throughout the 1900s, a number of theories were advanced to explain the numerous growths that covered his body: neurofibromatosis, Proteus syndrome, and a combination of childhood injury, fibrous dysplasia, and pyarthrosis. The debate continued throughout the 20th century without resolution. Today, new consensus on the genetic and clinical diagnosis of neurofibromatosis and Proteus syndrome has allowed advancements in the Elephant Man's diagnosis. Using recent clinical diagnostic criteria it is now possible to conclude that Joseph Merrick was in all likelihood suffering from Proteus syndrome. Nevertheless, details of his genotype remain unknown. Obtaining intact DNA from the Elephant Man's skeleton is challenging, yet it is possible that sequencing Merrick's genome could provide genetic confirmation of his clinical diagnosis, and shed light on the process of tumourigenesis. PMID- 25280595 TI - Pycnodysostosis and the making of an artist. AB - Henri de Toulouse-Lautrec, a 19th century artist celebrated for his depictions of the Moulin Rouge and Parisian nightlife, suffered from an unknown disorder. His symptoms were not only rare, but also difficult to determine. Both during his lifetime and following his death potential diagnoses have proved controversial, including the most popularly supported suggestion of pycnodysostosis. Addressing the ongoing debate of Toulouse-Lautrec's diagnosis, this article reconsiders the evidence. It summarises multiple perspectives and draws on more recent medical research, while acknowledging that the available sources are often unreliable. Ultimately, while there may be no definitive solution to the mystery of Toulouse Lautrec's diagnosis, it is possible to draw one conclusion. Observing its impact on his life and work, it is clear that the condition formed the foundation of Toulouse-Lautrec's artistic career, shaping the way he perceived the world and defining the artworks that are now so widely admired. PMID- 25280597 TI - Training in proctologic surgery: How and for whom? PMID- 25280596 TI - The role of beta3 integrin gene variants in Autism Spectrum Disorders--diagnosis and symptomatology. AB - Autism Spectrum Disorders (ASDs) represent a group of very complex early-onset neurodevelopmental diseases. In this study, we analyzed 5 SNPs (rs2317385, rs5918, rs15908, rs12603582, rs3809865) at the beta3 integrin locus (ITGB3), which has been suggested as a possible susceptibility gene, both as single markers and as part of haplotypes in 209 ASD children and their biological parents. We tested for association with the following: a) DSM-IV ASD diagnosis; b) clinical symptoms common in ASD patients (repetitive behaviors, echolalia, seizures and epilepsy, mood instability, aggression, psychomotor agitation, sleep disorders); and c) dimensional scores obtained with the Autism Screening Questionnaire and the Childhood Autism Rating Scale. These hypotheses were investigated using family-based tests, logistic regression models and analysis of covariance. The family-based tests showed an association with the H5 haplotype (composed by GTCGA alleles, the order of SNPs as above), which was transmitted less often than expected by chance (P=0.006; Pcorr=0.036). The analyses of the clinical symptoms showed a trend for an association with rs12603582 (P=0.008; Pcorr=0.064) and positive results for the haplotype composed of rs15908 and rs12603582 (Pglcorr=0.048; Pindcorr=0.015), both in symptoms of echolalia. Other nominal associations with different variants were found and involved epilepsy/seizures, aggression symptoms and higher ASQ scores. Although our positive results are not definitive, they suggest small effect associations of the ITGB3 gene with both ASD diagnosis and symptoms of echolalia. Other studies are nonetheless needed to fully understand the involvement of this locus on the etiology of ASDs and its different clinical aspects. PMID- 25280598 TI - Sphincter-sparing techniques for fistulas-in-ano. AB - Anal fistulas require surgical treatment to cure the fistula. Fistulotomy is the treatment of choice because of its high success rate, but it also carries a risk of postoperative incontinence. Different methods have been proposed to overcome the need for dividing part or all of the sphincter, so-called "sphincter saving techniques" (SST), such as flap advancement, intrafistular injection of glue, or the insertion of a bio-prosthesis (collagen plug). However, the success rate of SSTs is lower than that of fistulotomy. Ligation of the Intersphincteric Fistula Tract (LIFT) is one of the most recent SSTs. It aims to ligate and transect the fistula by an approach through the intersphincteric space. The methodological quality of most published studies has been only average, but several studies have reported attractive success rates of 70 to 95% without postoperative incontinence. Other techniques such as endo-anal clip or injection of autologous stem cells are still anecdotal. PMID- 25280599 TI - Anaerobic digestion of municipal wastewater sludges using anaerobic fluidized bed bioreactor. AB - The anaerobic digestion of primary sludge (PS) and thickened waste activated sludge (TWAS) using an anaerobic fluidized bed bioreactor (AnFBR) employing zeolite particles as the carrier media was investigated at different organic loading rates (OLRs). PS was tested at OLRs from 4.2 to 39kgCOD/m(3)-d corresponding to hydraulic retention times (HRTs) from 1.0 to 8.9days. The highest COD removal and VSS destruction efficiencies for primary sludge of 85% and 88%, respectively, were achieved at an HRT of 8.9days and OLR of 4.2kgCOD/m(3)-d. For TWAS, VSS destruction efficiencies varied from 42% at an HRT of 2.6days and OLR of 13.1kgCOD/m(3)-d to 69% at an HRT of 8.8days and an OLR of 4.2kgCOD/m(3)-d. The first-order COD biodegradation rates in the AnFBR for PS and TWAS were 0.4d(-1) and 0.1d(-1), respectively, almost double the rates in conventional high-rate digesters. PMID- 25280600 TI - Effects of pH control and concentration on microbial oil production from Chlorella vulgaris cultivated in the effluent of a low-cost organic waste fermentation system producing volatile fatty acids. AB - The objective of this study was to investigate the feasibility of applying volatile fatty acids (VFAs) produced from low-cost organic waste to the major carbon sources of microalgae cultivation for highly efficient biofuel production. An integrated process that consists of a sewage sludge fermentation system producing VFAs (SSFV) and mixotrophic cultivation of Chlorella vulgaris (C. vulgaris) was operated to produce microbial lipids economically. The effluents from the SSFV diluted to different concentrations at the level of 100%, 50%, and 15% were prepared for the C. vulgaris cultivation and the highest biomass productivity (433+/-11.9 mg/L/d) was achieved in the 100% culture controlling pH at 7.0. The harvested biomass included lipid contents ranging from 12.87% to 20.01% under the three different effluent concentrations with and without pH control. The composition of fatty acids from C. vulgaris grown on the effluents from the SSFV complied with the requirements of high-quality biodiesel. These results demonstrated that VFAs produced from the SSFV are favorable carbon sources for cultivating C. vulgaris. PMID- 25280601 TI - Flexible biogas production for demand-driven energy supply--feeding strategies and types of substrates. AB - Purpose of this work was the evaluation of demand driven biogas production. In laboratory-scale experiments it could be demonstrated that with diurnal flexible feeding and specific combination of substrates with different degradation kinetics biogas can be produced highly flexible in CSTR systems. Corresponding to the feedings the diurnal variation leads to alternations of the methane, carbon dioxide and acid concentrations as well as the pH-value. The long-time process stability was not negatively affected by the dynamic feeding regime at high OLRs of up to 6 kg VS m(-3) d(-1). It is concluded that the flexible gas production can give the opportunity to minimize the necessary gas storage capacity which can save investments for non-required gas storage at site. PMID- 25280602 TI - Mild disintegration of the green microalgae Chlorella vulgaris using bead milling. AB - In this work, the mild disintegration of the microalgae Chlorella vulgaris for the release of intracellular products has been studied. By means of bead milling the microalgae suspensions were successfully disintegrated at different biomass concentrations (25-145 gDW kg(-1)) over a range of agitator speeds (6-12 m s( 1)). In all cases over 97% of cell disintegration was achieved resulting in a release of water soluble proteins. A clear optimum rate of disintegration and protein release was observed at an agitator speed of 9-10 m s(-1) regardless of the biomass concentration. Selective extraction of water soluble proteins was observed as proteins released sooner than cell disintegration took place. Proteins could be released at 85% lower energy input than for cell disintegration resulting in specific energy consumptions well below 2.5 kWh kgDW(-1). PMID- 25280603 TI - Novel continuous passive motion device for self-treatment of chronic lower back pain: a randomised controlled study. AB - OBJECTIVE: To evaluate the efficacy of a novel, angular, continuous passive motion device for self-treatment at home in patients with mild-to-moderate, non specific, chronic low back pain (LBP). DESIGN: Prospective, randomised, waiting list-controlled (WLC) trial. SETTING: Recruitment and assessment were conducted at the Koren Centre for Physical Therapy. Self-treatment was performed at home. PARTICIPANTS: Thirty-six patients with a score <=6 on the numeric rating scale (NRS) for pain were enrolled. Twenty-eight patients completed treatment. INTERVENTIONS: Participants were randomised to receive the Kyrobak (Radiancy, Hod hasharon, Israel) at enrolment [immediate treatment (IT) group] or 3 weeks later (WLC group). Self-treatment was prescribed for 10minutes, one to three times per day, for 3 weeks. The treatment period was followed by a 3-week follow-up period. MAIN OUTCOME MEASURES: Primary outcome was self-reported pain level (NRS). RESULTS: Three weeks of self-treatment with the Kyrobak reduced pain levels significantly in the IT group compared with the WLC group {mean [standard deviation (SD)] DeltaNRS score from baseline to post-treatment: IT group, 1.4 (1.5), 95% confidence interval (CI) 0.5 to 2.3; WLC group, -0.1 (2.2), 95% CI 1.1 to 1.2; effect mean difference 1.5}. This benefit was maintained over the follow-up period [from baseline to end of follow-up, mean (SD) DeltaNRS score 1.1 (1.8), 95% CI 0.4 to 1.8]. Multi-linear regression analysis found that higher baseline pain resulted in greater pain reduction (P=0.003). Eighty-three percent of participants with a baseline NRS score >4.35 (threshold determined by logistic regression, P=0.01) achieved the minimal important change criterion of DeltaNRS score >=2. Daily NRS score reduced gradually over the treatment period [regression slope -0.052 (0.01), 95% CI -0.07 to -0.03]. CONCLUSIONS: Preliminary evidence suggests that the Kyrobak may be beneficial for short-term relief of non specific, chronic LBP, particularly in participants with a moderate level of pain. A longer treatment period may lead to a further reduction in pain. PMID- 25280604 TI - Improvement in upper leg muscle strength underlies beneficial effects of exercise therapy in knee osteoarthritis: secondary analysis from a randomised controlled trial. AB - OBJECTIVES: Although exercise therapy is effective for reducing pain and activity limitations in patients with knee osteoarthritis (OA), the underlying mechanisms are unclear. This study aimed to evaluate if improvements in neuromuscular factors (i.e. upper leg muscle strength and knee proprioception) underlie the beneficial effects of exercise therapy in patients with knee OA. DESIGN: Secondary analyses from a randomised controlled trial, with measurements at baseline, 6 weeks, 12 weeks and 38 weeks. SETTING: Rehabilitation centre. PARTICIPANTS: One hundred and fifty-nine patients diagnosed with knee OA. INTERVENTION: Exercise therapy. MAIN OUTCOME MEASURES: Changes in pain [numeric rating scale (NRS)] and activity limitations [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale and get-up and-go test] during the study period. Independent variables were changes in upper leg muscle strength and knee joint proprioception (i.e. motion sense) during the study period. Longitudinal regression analyses (generalised estimating equation) were performed to analyse associations between changes in upper leg muscle strength and knee proprioception with changes in pain and activity limitations. RESULTS: Improved muscle strength was significantly associated with reductions in NRS pain {B coefficient -2.5 [95% confidence interval (CI) -3.7 to -1.4], meaning that every change of 1 unit of strength was linked to a change of -2.5 units of pain}, WOMAC physical function (-8.8, 95% CI -13.4 to -4.2) and get-up-and-go test (-1.7, 95% CI -2.4 to -1.0). Improved proprioception was not significantly associated with better outcomes of exercise therapy (P>0.05). CONCLUSIONS: Upper leg muscle strengthening is one of the mechanisms underlying the beneficial effects of exercise therapy in patients with knee OA. PMID- 25280606 TI - Precise manipulation of cell behaviors on surfaces for construction of tissue/organs. AB - The use of micro/nanotechnology has become an indispensable strategy to manipulating cell microenvironments. By employing key elements of soft lithographical technologies including self-assembled monolayers (SAMs), microcontact printing (MUCP), and microfluidic pattering (MUFP) and a number of switchable surfaces such as electrochemical active, photosensitive, and thermosensitive surfaces, scientists can control the adhesion, proliferation, migration and differentiation of cells. By combining essential in vivo conditions, various physical or pathological processes such as cell-cell interaction in wound healing and tumor metastasis could be studied on well defined surfaces and interfaces. By integrating key elements in live tissues, in vitro models mimicking basic structure and function of vital organs such as lung, heart, blood vessel, liver, kidney, and brain have been developed and greatly increased our knowledge of these important life processes. In this review, we will focus on the recent development of these interfacial methods and their application in fundamental biology research. PMID- 25280605 TI - Cerebral aspergillosis in a patient with leprosy and diabetes: a case report. AB - BACKGROUND: Opportunistic fungi are dispersed as airborne, ground and decaying matter. The second most frequent extra-pulmonary disease by Aspergillus is in the central nervous system. CASE PRESENTATION: The case subject was 55 years old, male, mulatto, and an assistant surveyor residing in Teresina, Piaui. He presented with headache, seizures, confusion, fever and left hemiparesis upon hospitalization in 2006 at Hospital Sao Marcos. Five years previously, he was diagnosed with diabetes mellitus, and 17 months previously he had acne margined by hyperpigmented areas and was diagnosed with leprosy. Laboratory tests indicated leukocytosis and magnetic resonance imaging showed an infarction in the right cerebral hemisphere. Cerebrospinal fluid examination showed 120 cells/mm(3) and was alcohol-resistant bacilli negative. Trans-sphenoidal surgery with biopsy showed inflammation was caused by infection with Aspergillus fumigatus. We initiated use of parenteral amphotericin B, but his condition worsened. He underwent another surgery to implant a reservoir of Ommaya-Hickmann, a subcutaneous catheter. We started liposomal amphotericin B 5 mg/kg in the reservoir on alternate days. He was discharged with a prescription of tegretol and fluconazole. CONCLUSION: This report has scientific interest because of the occurrence of angioinvasive cerebral aspergillosis in a diabetic patient, which is rarely reported. In conclusion, we suggest a definitive diagnosis of cerebral aspergillosis should not postpone quick effective treatment. PMID- 25280607 TI - Quantitative description of the parameters affecting the adsorption behaviour of globular proteins. AB - The adsorption behaviour of proteins depends significantly on their molecular properties and system conditions. To study this relation, the effect of relative exposed hydrophobicity, protein concentration and ionic strength on the adsorption rate and adsorbed amount is studied using beta-lactoglobulin, ovalbumin and lysozyme. The curves of surface elastic modulus versus surface pressure of all three proteins, under different conditions (i.e. concentration and ionic strength) superimposed. This showed that the interactions between the adsorbed proteins are similar and that the adsorbed proteins retain their native state. In addition, the adsorption rate (kadsorb) was shown to scale with the relative hydrophobicity and ionic strength. Moreover, the adsorbed amount was shown to be dependent on the protein charge and the ionic strength. Based on these results, a model is proposed to predict the maximum adsorbed amount (Gammamax). The model approximates the adsorbed amount as a close-packed monolayer using a hard-sphere approximation with an effective protein radius which depends on the electrostatic repulsion. The theoretical adsorbed amount was in agreement with experimental Gammamax (+/-10%). PMID- 25280608 TI - Enzyme-responsive multifunctional surfaces for controlled uptake/release of (bio)molecules. AB - The current trend in the development of biomaterials is towards bioactive and biodegradable systems. In particular, enzyme-responsive structures are useful tools to realize biodegradable surfaces for the controlled delivery of biomolecules/drugs through a triggered surface erosion process. Up to now, enzyme responsive structures have been designed by covalent linkage between synthetic polymers and biodegradable functionalities that are responsive to chemical and biological cues (i.e. proteases or pH) [1-4]. Here, we present a novel approach to achieve enzyme-responsive surface-attached networks by exploiting the non covalent interaction between streptavidin and biotin. The functional component of this three-dimensional (3D) structure is a layer of biotinylated peptides that are degraded by the action of specific proteases. The system was stable under typical physiological conditions; however, it was efficiently degraded upon enzyme exposure. Further, the controlled release of biomolecules and drugs- previously entrapped into the surface-attached network--was demonstrated to occur as a consequence of the enzymatic cleavage. This versatile approach does not require complex chemical procedures. Interestingly, it can be easily adapted to different enzyme-peptide partners and therefore is very attractive for tissue replacement, drug delivery and biosensing. PMID- 25280609 TI - Liposomes as carriers of hydrophilic small molecule drugs: strategies to enhance encapsulation and delivery. AB - Although hydrophilic small molecule drugs are widely used in the clinic, their rapid clearance, suboptimal biodistribution, low intracellular absorption and toxicity can limit their therapeutic efficacy. These drawbacks can potentially be overcome by loading the drug into delivery systems, particularly liposomes; however, low encapsulation efficiency usually results. Many strategies are available to improve both the drug encapsulation efficiency and delivery to the target site to reduce side effects. For encapsulation, passive and active strategies are available. Passive strategies encompass the proper selection of the composition of the formulation, zeta potential, particle size and preparation method. Moreover, many weak acids and bases, such as doxorubicin, can be actively loaded with high efficiency. It is highly desirable that once the drug is encapsulated, it should be released preferentially at the target site, resulting in an optimal therapeutic effect devoid of side effects. For this purpose, targeted and triggered delivery approaches are available. The rapidly increasing knowledge of the many overexpressed biochemical makers in pathological sites, reviewed herein, has enabled the development of liposomes decorated with ligands for cell-surface receptors and active delivery. Furthermore, many liposomal formulations have been designed to actively release their content in response to specific stimuli, such as a pH decrease, heat, external alternating magnetic field, ultrasound or light. More than half a century after the discovery of liposomes, some hydrophilic small molecule drugs loaded in liposomes with high encapsulation efficiency are available on the market. However, targeted liposomes or formulations able to deliver the drug after a stimulus are not yet a reality in the clinic and are still awaited. PMID- 25280610 TI - The burden and management of sports-related musculoskeletal injuries and conditions within the US military. AB - Military service members comprise a young and physically active population who are at increased risk for musculoskeletal injuries and conditions related to sports and physical training. Even during times of war, musculoskeletal injuries and conditions related to sports and physical training, not associated with combat, are the leading cause of medical evacuation from theater. As a result, these injuries significantly compromise military readiness, and they can lead to an increased risk for reinjury and long-term disability among military service members. Regardless of the mechanism of injury, the large volume and types of musculoskeletal injuries and conditions that affect soldiers are similar to those that are commonly seen and treated in sports medicine clinics and practices. Recently, the US Marine Corps, Navy, and Army have recognized the value of the sports medicine model of care to improve the access, efficiency, and effectiveness of care for solders who experience musculoskeletal injuries related to sports and training. A highly skilled sports medicine team of providers and allied health care professionals (eg, athletic trainers, physical therapists), with expertise in the prevention, assessment, diagnosis, and management of musculoskeletal injuries and conditions, will continue to be an integral cog in the effective management of these types of injuries into the future, as the sports medicine model continues to expand across the military health system. PMID- 25280611 TI - Lower extremity stress fractures in the military. AB - Stress fractures of the lower extremities are common among the military population and, more specifically, military recruits who partake in basic training. Both intrinsic and extrinsic factors play a role in the development of these injuries, and it is important to identify those individuals at risk early in their military careers. Some of these factors are modifiable, so they may become preventable injuries. It is important to reiterate that one stress fracture places the soldier at risk for future stress fractures; but the first injury should not be reason enough for separation from the military, as literature would support no long-term deficits from properly treated stress fractures. Early in the process, radiographic analysis is typically normal; continued pain may warrant advanced imaging, such as scintigraphy or MRI. Most stress fractures that are caught early are amendable to nonoperative management consisting of a period of immobilization and NWB followed by progressive rehabilitation to preinjury levels. Complete or displaced fractures may require operative intervention as do tension-sided FNSF. Improving dietary and preaccession physical fitness levels may play a role in reducing the incidence of stress fractures in the active-duty military population. It is important to keep in mind when evaluating soldiers and athletes who present with activity-related pain that stress fractures are not uncommon and should be given significant consideration. PMID- 25280613 TI - ACL injury and posttraumatic osteoarthritis. AB - Continued development and validation of quantitative imaging and biochemical assessment techniques are critical research priorities to lead to improved diagnosis and treatment of PTOA. There is also a compelling need to advance understanding of how mechanical joint injuries lead to joint degeneration, and to define the roles of acute joint damage and post-joint injury incongruity and instability as etiologic factors leading to development of OA.22 As OA occurs more frequently in the military population and ACL tears are endemic to the military, it is essential that the military become more active in funding research and seeking novel research cohorts to help solve some of the most fundamental problems in PTOA. The military population, while deeply affected by PTOA, may also prove to be pivotal in determining improved diagnostic techniques and treatment interventions to help minimize the long-term effects of this disease. PMID- 25280612 TI - Seven steps for developing and implementing a preventive training program: lessons learned from JUMP-ACL and beyond. PMID- 25280614 TI - Meniscal repair and transplantation in the military active-duty population. PMID- 25280615 TI - Intra-articular hip disorders in the military population: evaluation and management. AB - The physical demands of the military expose the hip to extreme forces and stresses and generate a high incidence of hip disorders within this population. Fundamental to the pathophysiology of hip injuries is the underlying anatomy of the joint because problematic femoroacetabular mechanics predispose to injury. FAI is increasingly recognized as the underlying cause of hip disorders and should be considered when assessing a patient with hip complaints. Young, male patients are at increased risk of FAI, especially cam impingement, and high levels of athletic activity during skeletal growth may contribute to the development of cam morphology. A complete evaluation requires a careful history and physical examination combined with multiple imaging modalities. Conservative treatment is indicated for acute hip injury to allow alleviation of inflammation and restoration of normal gait and range of motion. Surgery should be considered for refractory dysfunction, mechanical symptoms, or significant deformities. Arthroscopy has revolutionized the treatment of hip injuries in young, active patients, and is likely to continue to expand in use. PMID- 25280616 TI - Management of chronic lateral ankle instability in military service members. AB - Chronic lateral ankle instability is a condition frequently encountered by orthopedic surgeons treating highly active patient populations, particularly military service members. Providers treating military service members must have a high index of suspicion for this condition when signs and symptoms of functional or mechanical instability exist. Stress testing and ankle MRI, although not definitive in sensitivity for detecting instability or other concomitant injuries, should be considered during the treatment decision-making process. Appropriate nonoperative treatment should be attempted initially; however, when nonoperative treatment fails, surgical management is warranted to prevent untoward long-term sequelae. Proper surgical treatment and subsequent postoperative management are at the discretion of the individual surgeon but must account for the concomitant diseases frequently associated with chronic lateral ankle instability. Low recurrence of lateral instability can be achieved even in high-demand military patient populations with a focused treatment plan. PMID- 25280617 TI - Chronic exertional compartment syndrome of the leg in the military. AB - CECS is a common source of lower extremity disability among young athletic cohorts and military personnel. The five cardinal symptoms are pain, tightness, cramps, weakness, and diminished sensation. History and clinical examination remain the hallmarks for identifying CECS, although ICP measurements during exercise stress testing may be used to confirm diagnosis. Nonsurgical management is generally unsuccessful, although gait retraining may have benefits in selected individuals. When conservative measures have failed, operative management may be considered with fascial release of all affected compartments. Although clinical success has been documented in civilian cohorts, the results of surgical treatment in military service members have been far less reliable. Only approximately half of the military service members experience complete resolution of symptoms and at least 25% are unable to return to full duty. PMID- 25280618 TI - Shoulder instability in the military. AB - Shoulder instability is common in military populations, and this demographic represents individuals at high risk for recurrence. Surgical management is often indicated, especially in high-demand young individuals, and provides a predictable return to military duties. Accurate recognition of glenoid bone loss and other associated anatomic lesions is of importance for appropriate selection between arthroscopic capsulolabral repair and bony reconstruction procedures. A thorough understanding of underlying pathology, diagnostic testing, and available treatment options provides for optimal care of the unstable shoulder. PMID- 25280619 TI - Surgical management of acromioclavicular dislocations. AB - AC injuries are common in the military population. Many AC injuries can be treated conservatively with good success. Due to requirements of a military population, however, conservative management may fail at a higher rate than in civilian populations. Surgical management is indicated for high-grade injuries and those that are refractory to nonoperative treatment, as well as in those patients at high risk for failure of conservative management. Many techniques exist and there is no single superior technique. The anatomic reconstruction is evolving into a more consistent procedure with good biomechanical support. However, complication rates and failures are higher than ideal; thus, the surgeon must approach this injury with meticulous attention to detail and technique. PMID- 25280620 TI - Pectoralis major injuries: evaluation and treatment. AB - PM tears most commonly occur in the young athletic male while performing weight lifting exercises, but can result from any activity whereby the arm is maximally contracted in an extended and externally rotated position. Patients typically present with acute pain, swelling, ecchymosis, deformity, and weakness with adduction and internal rotation. Diagnosis of PM tears can usually be made by history and physical examination, but MRI can be helpful in identifying the extent and location of injury. Most tears occur near the tendon insertion. Nonoperative treatment is generally reserved for proximal tears, low-grade partial tears, and tears in sedentary patients. In most cases these patients will resume full activities of daily living. For all other tears, especially in the young, active athlete, acute (<6 weeks) repair is recommended to return the patient to full strength and function. PMID- 25280621 TI - Snapping scapula syndrome in the military. AB - Snapping scapula syndrome is a rare condition resulting in painful crepitus of the scapulothoracic articulation that may be more common in a military population because of significant upper extremity load-bearing activities. Conservative management is the first-line therapy and is successful in up to 80% of patients. For those patients who fail conservative management, arthroscopic bursectomy and partial scapulectomy is a reasonable option, but is technically demanding and requires an in-depth understanding of the complex anatomy of the scapulothoracic region. PMID- 25280622 TI - Foreword. Clinics in Sports Medicine featuring military authors. PMID- 25280623 TI - Preface. Athletic injuries in the military. PMID- 25280625 TI - [Septoplasties and associated procedures]. AB - Observing a morphological alteration of the nasal septum should in no way automatically lead to a septoplasty. Only poorly tolerated septal deviations creating a mechanical nasal obstruction are a surgical indication. This delicate operation requires meticulousness to preserve the muco-perichondrial envelope. The statement follows a rigorous clinical assessment where endoscopy is important because it points out the septal deformities, the size of the inferior turbinates and possible valvate problems. Performing a rhinomanometry and sometimes a CAT scan will complete the preoperative assessment. PMID- 25280626 TI - Grass carp SARM1 and its two splice variants negatively regulate IFN-I response and promote cell death upon GCRV infection at different subcellular locations. AB - Sterile alpha and Toll/IL-1R motif containing 1 (SARM1) negatively regulates TRIF dependent TLR signaling in mammals. However, its immune function remains unclear in teleost. Here, a grass carp Ctenopharyngodon idella SARM1 (CiSARM1) gene and its two novel splice variants (CiSARM1s1 and CiSARM1s2) were identified. CiSARM1s1 and CiSARM1s2 are generated by intron retention mechanism, and they only retain N-terminal HEAT/armadillo motifs. In C. idella kidney (CIK) cells, CiSARM1 and CiSARM1s1 are located in mitochondria, whereas CiSARM1s2 distributes in the whole cell. All the three transcripts are ubiquitously expressed in 15 investigated tissues. They were responsive to GCRV in vivo and in vitro and to viral/bacterial PAMPs in vitro, implying they participate in both antiviral and antibacterial immune responses. By overexpression experiment, CiSARM1 and its two isoforms affected each other's expression in CIK cells. CiSARM1 inhibited GCRV triggered IFN-I response by affecting the expressions of CiTRIF, CiMyD88, CiIPS 1, CiTRAF6, CiTBK1, CiIRF3 and CiIRF7 in TRIF-, MyD88- and IPS-1-dependent pathways; CiSARM1s1 and CiSARM1s2 inhibited GCRV-triggered IFN-I production through suppressing the expressions of CiMyD88, CiIPS-1, CiTRAF6, CiTBK1, CiIRF3 and CiIRF7 in MyD88- and IPS-1-dependent pathways. Moreover, antiviral activity assays indicated that all the three genes promote GCRV-induced cell death. These results were further verified by RNAi experiments. Thus, CiSARM1 and its two splice variants jointly prevent excessive activation of the host immune response. These findings uncover the regulatory mechanisms of SARM1 in teleost and lay a foundation for further functional and evolutionary researches on SARM1. PMID- 25280627 TI - Molecular characterization of porcine Siglec-10 and analysis of its expression in blood and tissues. AB - Siglecs are sialic acid binding Ig-like proteins involved in the control of leukocyte responses. In this study we describe the characterization of a porcine orthologue of Siglec-10. A cDNA clone was obtained from a porcine library which encodes a protein with sequence homology to human Siglec-10. This cDNA codes for a type I transmembrane protein containing four Ig-like domains, a transmembrane region, and a cytoplasmic tail with three tyrosine-based motifs, including a membrane-proximal Grb2-binding motif, and two ITIM motifs. When expressed on transfected cells, porcine Siglec-10 was able to bind red blood cells in a sialic acid-dependent manner. Monoclonal antibodies were developed against this protein and used to examine its cell and tissue distribution in the pig. Siglec-10 was found to be expressed on blood B cells and B cell areas of the spleen and lymph nodes. A weak expression was also detected on monocytes. PMID- 25280628 TI - Alteration in substrate specificity of horse liver alcohol dehydrogenase by an acyclic nicotinamide analog of NAD(+). AB - A new, acyclic NAD-analog, acycloNAD(+) has been synthesized where the nicotinamide ribosyl moiety has been replaced by the nicotinamide (2 hydroxyethoxy)methyl moiety. The chemical properties of this analog are comparable to those of beta-NAD(+) with a redox potential of -324mV and a 341nm lambdamax for the reduced form. Both yeast alcohol dehydrogenase (YADH) and horse liver alcohol dehydrogenase (HLADH) catalyze the reduction of acycloNAD(+) by primary alcohols. With HLADH 1-butanol has the highest Vmax at 49% that of beta NAD(+). The primary deuterium kinetic isotope effect is greater than 3 indicating a significant contribution to the rate limiting step from cleavage of the carbon hydrogen bond. The stereochemistry of the hydride transfer in the oxidation of stereospecifically deuterium labeled n-butanol is identical to that for the reaction with beta-NAD(+). In contrast to the activity toward primary alcohols there is no detectable reduction of acycloNAD(+) by secondary alcohols with HLADH although these alcohols serve as competitive inhibitors. The net effect is that acycloNAD(+) has converted horse liver ADH from a broad spectrum alcohol dehydrogenase, capable of utilizing either primary or secondary alcohols, into an exclusively primary alcohol dehydrogenase. This is the first example of an NAD analog that alters the substrate specificity of a dehydrogenase and, like site directed mutagenesis of proteins, establishes that modifications of the coenzyme distance from the active site can be used to alter enzyme function and substrate specificity. These and other results, including the activity with alpha-NADH, clearly demonstrate the promiscuity of the binding interactions between dehydrogenases and the riboside phosphate of the nicotinamide moiety, thus greatly expanding the possibilities for the design of analogs and inhibitors of specific dehydrogenases. PMID- 25280629 TI - A central role for intermolecular dityrosine cross-linking of fibrinogen in high molecular weight advanced oxidation protein product (AOPP) formation. AB - BACKGROUND: Advanced oxidation protein products (AOPPs) are dityrosine cross linked and carbonyl-containing protein products formed by the reaction of plasma proteins with chlorinated oxidants, such as hypochlorous acid (HOCl). Most studies consider human serum albumin (HSA) as the main protein responsible for AOPP formation, although the molecular composition of AOPPs has not yet been elucidated. Here, we investigated the relative contribution of HSA and fibrinogen to generation of AOPPs. METHODS: AOPP formation was explored by SDS-PAGE, under both reducing and non-reducing conditions, as well as by analytical gel filtration HPLC coupled to fluorescence detection to determine dityrosine and pentosidine formation. RESULTS: Following exposure to different concentrations of HOCl, HSA resulted to be carbonylated but did not form dityrosine cross-linked high molecular weight aggregates. Differently, incubation of fibrinogen or HSA/fibrinogen mixtures with HOCl at concentrations higher than 150 MUM induced the formation of pentosidine and high molecular weight (HMW)-AOPPs (>200 k Da), resulting from intermolecular dityrosine cross-linking. Dityrosine fluorescence increased in parallel with increasing HMW-AOPP formation and increasing fibrinogen concentration in HSA/fibrinogen mixtures exposed to HOCl. This conclusion is corroborated by experiments where dityrosine fluorescence was measured in HOCl-treated human plasma samples containing physiological or supra physiological fibrinogen concentrations or selectively depleted of fibrinogen, which highlighted that fibrinogen is responsible for the highest fluorescence from dityrosine. CONCLUSIONS: A central role for intermolecular dityrosine cross linking of fibrinogen in HMW-AOPP formation is shown. GENERAL SIGNIFICANCE: These results highlight that oxidized fibrinogen, instead of HSA, is the key protein for intermolecular dityrosine formation in human plasma. PMID- 25280630 TI - Hunger is the best spice: effects of starvation in the antennal responses of the blood-sucking bug Rhodnius prolixus. AB - Blood-sucking insects strongly rely on olfactory cues to find their vertebrate hosts. As in other insects with different lifestyles, it has been shown that endogenous and exogenous factors modulate olfactory responses. The triatomine bug Rhodnius prolixus is an important vector of Chagas disease and a classical model for studies of physiology and behavior. In this species, the behavioral response to host-derived odorants is modulated by both the time of the day and the starvation. Here I investigated the peripheral neural mechanisms underlying these modulatory effects. For this, I measured the electroantennogram (EAG) responses of insects towards different concentrations (from 0.5% to 75% vol/vol) of an attractive host-odorant, ammonia. I tested the responses of starved and fed animals during the middle of the day (when insects are inactive and aggregated in refuges) and at the beginning of the night (when insects become active and search for hosts). Regardless of the time of the day and the starvation status, EAG responses systematically increased with odorant concentration, thus accurately reflecting the response of olfactory receptor cells. Interestingly, the EAG responses of starved insects were larger than those of fed insects only during the night, with larger differences (6-7 times) observed at low-middle concentrations. This study is the first reporting modulation of sensory responses at the neural level in triatomines. This modulation, considering that triatomine hosts are mostly diurnal and are also potential predators, has an important adaptive value, ensuring that insects search for hosts only when they are hungry and at appropriate times. PMID- 25280632 TI - An extracellular chitinase from Streptomyces sp. CS147 releases N-acetyl-D glucosamine (GlcNAc) as principal product. AB - Streptomyces sp. CS147 grown on chitin liquid medium incorporating 0.5 % colloidal chitin as a sole carbon source produced an extracellular chitinase (Ch147). The enzyme (Ch147) was purified using Sepharose CL-6B column chromatography and biochemically characterized. The enzymatic reaction products, analyzed using high-performance liquid chromatography and thin layer chromatography clearly indicates the production of N-acetyl-D-glucosamine (GlcNAc) as principal product which can be further hydrolyzed for the production of alcohol, a second generation biofuel. Ch147 hydrolyzed colloidal chitin to 0.278, 0.817, and 1.058 mg/mL of (GlcNAc) as a major product, at retention time of 4.3, respectively, when incubated for 8, 16, and 24 h at 50 degrees C. GlcNAc is a monosaccharide that usually polymerize linearly through (1, 4) beta linkage. The 41 kDa molecular mass chitinase, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), has the amino acid sequences DINGGGATLPQKLYL significantly different from other chitinase. Ch147 had K m and V max values of 2.05 +/- 5.3 mg/mL and 467.2 +/- 2.4 mmol/min, respectively. Further, the purified enzyme (5 U) inhibits the fungal phytopathogens belonging to the genera Fusarium and Aspergillus. We believe that Ch147 is a potential candidate for the conversion of waste materials into simple sugar for productions of biofuels and also can be used as an alternative option for biological control of plant pathogens being unfriendly to chemicals. PMID- 25280631 TI - Uptake and degradation of protease-sensitive and -resistant forms of abnormal human prion protein aggregates by human astrocytes. AB - Sporadic Creutzfeldt-Jakob disease is the most common of the human prion diseases, a group of rare, transmissible, and fatal neurologic diseases associated with the accumulation of an abnormal form (PrP(Sc)) of the host prion protein. In sporadic Creutzfeldt-Jakob disease, disease-associated PrP(Sc) is present not only as an aggregated, protease-resistant form but also as an aggregated protease-sensitive form (sPrP(Sc)). Although evidence suggests that sPrP(Sc) may play a role in prion pathogenesis, little is known about how it interacts with cells during prion infection. Here, we show that protease sensitive abnormal PrP aggregates derived from patients with sporadic Creutzfeldt Jakob disease are taken up and degraded by immortalized human astrocytes similarly to abnormal PrP aggregates that are resistant to proteases. Our data suggest that relative proteinase K resistance does not significantly influence the astrocyte's ability to degrade PrP(Sc). Furthermore, the cell does not appear to distinguish between sPrP(Sc) and protease-resistant PrP(Sc), suggesting that sPrP(Sc) could contribute to prion infection. PMID- 25280633 TI - Functional characterisation of novel enantioselective lipase TALipA from Trichosporon asahii MSR54: sequence comparison revealed new signature sequence AXSXG among yeast lipases. AB - A gene encoding lipase TALipA from Trichosporon asahii MSR54 was successfully isolated, cloned and expressed in Pichia pastoris X-33. It was purified to homogeneity by affinity chromatography with 1.7 purification fold. SDS-PAGE revealed it as a monomeric 27-kDa protein. Sequence comparison showed that it has close affinity with bacterial and actinobacterial lipases. It has unique oxyanion hole "GL" and conserved pentapeptide AHSMG where alanine is present instead of glycine, which is unique to yeast lipase database. The temperature and pH optima for activity were 60 degrees C and pH 8.0, respectively. It is thermostable with t1/2 of 68 min at 70 degrees C. It hydrolyzed p-np esters with better specificity on p-np palmitate, which was again confirmed during hydrolysis of triacylglyceride mixture. The enzyme was found to be regioselective during hydrolysis of triolein. It exhibited enantio preference during esterification of phenylethanol depending upon solvent used. It was S-enantioselective in 1,4 dioxane and R-selective in isopropanol and hexane. It is a magnesium-activated metalloenzyme inhibited by 10-mM EDTA. It was stable towards most of the polar and non-polar solvents. PMID- 25280634 TI - Re: do rigid dressings reduce the time from amputation to prosthetic fitting? A systematic review and meta-analysis. PMID- 25280635 TI - Patient with spinal muscular atrophy with respiratory distress type 1 presenting initially with hypertonia. AB - Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene and characterized by life-threatening respiratory distress due to irreversible diaphragmatic paralysis between 6weeks and 6months of age. In this study, we describe a two-month-old boy who presented with hypertonia at first and developed to hypotonia progressively, which was in contrast to the manifestations reported previously. Bone tissue compromise was also observed as one of the unique symptoms. Muscle biopsy indicated mild myogenic changes. He was misdiagnosed until genetic screening to be confirmed as SMARD1. SMARD1 is a clinical heterogeneous disease and this case broadens our perception of its phenotypes. PMID- 25280636 TI - Cryptic species of hairworm parasites revealed by molecular data and crowdsourcing of specimen collections. AB - Recognizing cryptic species promotes a better understanding of biodiversity, systematics, evolutionary biology, and biogeography. When cryptic species are disease-causing organisms, such as parasites, their correct recognition has important implications for the study of epidemiology, disease ecology, and host parasite relationships. Freshwater nematomorphs (Nematomorpha: Gordiida) or hairworms, are an enigmatic yet fascinating group of parasites that are known to manipulate host behavior to aid transition from the parasitic phase, within terrestrial insects, to the free-living aquatic stage. Hairworm taxonomy has been hampered by a paucity of informative diagnostic characters and it has long been suspected that this group contains numerous cryptic species. Study of single hairworm species over large geographical areas has been difficult due to extremely rare encounters and unreliable methods of collecting adult worms. Here we report that by using crowdsourcing, citizen scientists have collected and submitted samples of Gordius cf. robustus from throughout its range in North America making its genetic study possible. Combined with our own collections, we examined samples from 28 localities within the USA; despite the collection of numerous hairworms from Canada and Mexico, G. cf. robustus were not collected outside of the contiguous United States. Mitochondrial CO1 genetic distances revealed that specimens grouped into 8 clades separated by 8-24.3%. In addition, molecular evidence from mitochondrial (CO1 and cytB) and nuclear (partial 28S, ITS1, 5.8S and ITS2) DNA suggests that these 8 clades are distinct species and that this group of species is paraphyletic, since the North American species G. attoni and the European species G. aquaticus and G. balticus group among the G. robustus lineages. Furthermore, there was a significant correlation between genetic (CO1) and geographic distance between the 8 Gordius species. This study demonstrates the value of involving the general public in biodiversity studies and highlights the feasibility of using the mitochondrial CO1 gene as a taxonomic marker for genetic barcoding and species identification within the phylum Nematomorpha. PMID- 25280638 TI - Plant phosphoinositides-complex networks controlling growth and adaptation. AB - Plants differ in many ways from mammals or yeast. However, plants employ phosphoinositides for the regulation of essential cellular functions as do all other eukaryotes. In recent years the plant phosphoinositide system has been linked to the control of cell polarity. Phosphoinositides are also implicated in plant adaptive responses to changing environmental conditions. The current understanding is that plant phosphoinositides control membrane trafficking, ion channels and the cytoskeleton in similar ways as in other eukaryotic systems, but adapted to meet plant cellular requirements and with some plant-specific features. In addition, the formation of soluble inositol polyphosphates from phosphoinositides is important for the perception of important phytohormones, as the relevant receptor proteins contain such molecules as structural cofactors. Overall, the essential nature of phosphoinositides in plants has been established. Still, the complexity of the phosphoinositide networks in plant cells is only emerging and invites further study of its molecular details. This article is part of a special issue entitled Phosphoinositides. PMID- 25280639 TI - Cardiac functions of voltage-gated Ca(2+) channels: role of the pharmacoresistant type (E-/R-Type) in cardiac modulation and putative implication in sudden unexpected death in epilepsy (SUDEP). AB - Voltage-gated Ca(2+) channels (VGCCs) are ubiquitous in excitable cells. These channels play key roles in many physiological events like cardiac regulation/pacemaker activity due to intracellular Ca(2+) transients. In the myocardium, the Cav1 subfamily (L-type: Cav1.2 and Cav1.3) is the main contributor to excitation-contraction coupling and/or pacemaking, whereas the Cav3 subfamily (T-type: Cav3.1 and Cav3.2) is important in rhythmically firing of the cardiac nodal cells. No established cardiac function has been attributed to the Cav2 family (E-/R-type: Cav2.3) despite accumulating evidence of cardiac dysregulation observed upon deletion of the Cav2.3 gene, the only member of this family so far detected in cardiomyocytes. In this review, we summarize the pathophysiological changes observed after ablation of the E-/R-type VGCC and propose a cardiac mechanism of action for this channel. Also, considering the role played by this channel in epilepsy and its reported sensitivity to antiepileptic drugs, a putative involvement of this channel in the cardiac mechanism of sudden unexpected death in epilepsy is also discussed. PMID- 25280640 TI - Use of gel-based separator tubes to stabilise phosphate in mailed blood samples. PMID- 25280641 TI - Optimal criteria for microscopic review of urinalysis following use of automated urine analyzer. AB - BACKGROUND: The Sysmex UX-2000 is a new, fully automated integrated urine analyzer. This device analyzes all physical and chemical characteristics of urine and sediments in urine on single platform. Because sediment analysis by fluorescent flow cytometry has limited ability to classify some formed elements present in urine (e.g., casts), laboratories should develop criteria for manual microscopic examination of urinalysis following the use of the automated urine analyzer. METHODS: 399 urine samples were collected from routine workload. All samples were analyzed on the automated analyzer and were then compared to the results of the manual microscopic method to establish optimal criteria. Another set of 599 samples was then used to validate the optimized criteria. The efficiency of criteria and review rate were calculated. The false-positive and false-negative cases were enumerated and clarified. RESULTS: We can set 11 rules which are related to the parameters categorized by the UX-2000, including cells, casts, crystals, organisms, sperm, and flags. After optimizing the rules, the review rate was 54.1% and the false-negative rate was 2.8%. CONCLUSIONS: The combination of both UX-2000 and manual microscopic method obtain the best results. The UX-2000 improves efficiency by reducing the time and labor associated with the specimen analysis process. PMID- 25280637 TI - PI(4,5)P2-binding effector proteins for vesicle exocytosis. AB - PI(4,5)P2participates directly in priming and possibly in fusion steps of Ca2+ triggered vesicle exocytosis. High concentration nanodomains of PI(4,5)P2reside on the plasma membrane of neuroendocrine cells. A subset of vesicles that co localize with PI(4,5)P2 domains appear to undergo preferential exocytosis in stimulated cells. PI(4,5)P2directly regulates vesicle exocytosis by recruiting and activating PI(4,5)P2-binding proteins that regulate SNARE protein function including CAPS, Munc13-1/2, synaptotagmin-1, and other C2 domain-containing proteins. These PI(4,5)P2effector proteins are coincidence detectors that engage in multiple interactions at vesicle exocytic sites. The SNARE protein syntaxin-1 also binds to PI(4,5)P2, which promotes clustering, but an activating role for PI(4,5)P2in syntaxin-1 function remains to be fully characterized. Similar principles underlie polarized constitutive vesicle fusion mediated in part by the PI(4,5)P2-binding subunits of the exocyst complex (Sec3, Exo70). Overall, focal vesicle exocytosis occurs at sites landmarked by PI(4,5)P2, which serves to recruit and/or activate multifunctional PI(4,5)P2-binding proteins. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25280642 TI - Admixture mapping identifies a locus at 15q21.2-22.3 associated with keloid formation in African Americans. AB - Keloids are benign dermal tumors that occur ~20 times more often in African versus Caucasian descent individuals. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and the large differences in risk among populations. Yet, no well-established genetic risk factors for keloids have been identified. In this study, we conducted admixture mapping and whole-exome association using 478 African Americans (AAs) samples (122 cases, 356 controls) with exome genotyping data to identify regions where local ancestry associated with keloid risk. Logistic regression was used to evaluate associations under admixture peaks. A significant mapping peak was observed on chr15q21.2-22.3. This peak included NEDD4, a gene previously implicated in a keloid genome-wide association study (GWAS) of Japanese individuals later validated in a Chinese cohort. While we observed modest evidence for association with NEDD4, a more significant association was observed at (myosin 1E) MYO1E. A genome scan not including the 15q21-22 region also identified associations at MYO7A (rs35641839, odds ratio [OR] = 4.71, 95% confidence interval [CI] 2.38-9.32, p = 8.34 * 10(-6)) at 11q13.5. The identification of SNPs in two myosin genes strongly associated with keloid formation suggests that an altered cytoskeleton contributes to the enhanced migratory and invasive properties of keloid fibroblasts. Our findings support the admixture mapping approach for the study of keloid risk, and indicate potentially common genetic elements on chr15q21.2-22.3 in causation of keloids in AAs, Japanese, and Chinese populations. PMID- 25280643 TI - Extracorporeal fetal support: a new animal model with preservation of the placenta. AB - BACKGROUND: Previous models of support for premature sheep fetuses have consisted of cesarean delivery followed by catheterization of umbilical or central vessels and support with extracorporeal membrane oxygenation (ECMO). The limitations of these models have been insufficient blood flow, significant fetal edema, and hemorrhage related to anticoagulation. METHODS: We performed a gravid hysterectomy on 13 ewes between 135 and 145days gestational age. The uterine vessels were cannulated bilaterally and circulatory support was provided via ECMO. Successful transition was defined as maintenance of fetal heart rate for 30minutes after establishing full extracorporeal support. Circuit flow was titrated to maintain mixed venous oxygen saturation (SvO2) of 70-75%. RESULTS: Seven experiments were successfully transitioned to ECMO, with an average survival time of 2hours 9minutes. The longest recorded time from cannulation to death was 6hours 14minutes. By delivering a circuit flow of up to 2120ml/min, all but one of the transitioned uteri were maintained within the desired SvO2 range. CONCLUSION: We report a novel animal model of fetal ECMO support that preserves the placenta, mitigates the effects of heparin, and allows for increased circuit flow compared to prior techniques. This approach may provide insight into a technique for future studies of fetal physiology. PMID- 25280644 TI - Serum levels of interleukin-8 and gut-associated biomarkers in diagnosing necrotizing enterocolitis in preterm infants. AB - BACKGROUND: In recent years several potential biochemical markers have been evaluated to facilitate a reliable diagnosis of necrotizing enterocolitis (NEC), but none have made progress to clinical routine. We performed a comparative assessment in premature infants to evaluate the diagnostic value of the routinely available cytokine interleukin (IL)-8, and two promising experimental biomarkers, the gut barrier proteins liver fatty acid binding protein (L-FABP) and intestinal fatty acid binding protein (I-FABP), respectively, for the diagnosis of NEC. METHODS: IL-8, L-FABP, and I-FABP concentrations were analyzed in the serum of 15 infants with NEC and compared with 14 gestational age-matched infants serving as a control group. RESULTS: Serum concentrations of I-FABP, L-FABP and IL-8 were significantly higher in infants with NEC compared with controls. IL-8 showed the highest diagnostic value with an area under the curve of 0.99, followed by L-FABP and I-FABP. In addition we found a significant correlation between IL-8 and both FABPs in infants with NEC. CONCLUSION: Our results further advocate the possible role of IL-8 as a specific marker for NEC. The diagnostic value of IL-8 seems to be superior to I-FABP, and similar to L-FABP. The routinely availability facilitates IL-8 as a possible candidate for further clinical investigations. PMID- 25280645 TI - Outcomes comparing dual-lumen to multisite venovenous ECMO in the pediatric population: the Extracorporeal Life Support Registry experience. AB - PURPOSE: The purpose of this study is to evaluate outcomes associated with single site dual-lumen venovenous cannulas (VVDL) and to compare them to those associated with multisite VV ECMO (VVMS) cannulation. METHODS: The Extracorporeal Life Support (ELSO) Registry was reviewed to identify all children 31days to 18years treated with venovenous ECMO from 1998 to 2011 using either VVDL or VVMS techniques. Patient demographics, cannula type, ECMO variables, complications, and patient survival were analyzed. RESULTS: From 1998 to 2011, 1323 children underwent venovenous ECMO. The annual utilization of VVDL cannulas has increased and recently surpassed VVMS. Fifty-four percent (n=717) of patients had VVDL cannulation. This group was significantly younger and weighed less than the VVMS group. VVDL cannulas demonstrated improved weight-adjusted flow performance than traditional cannulation. Overall survival was comparable, 64.4% and 68.6%, for VVMS and VVDL respectively. VVDL cannulas experienced higher mechanical (26.2% vs. 22.5%; p=0.004) and cardiovascular complications rates (24.4% vs. 21.7%; p=0.03) than VVMS cannulas, but when stratified by VVDL cannula type, there were no differences between wire-reinforced and non-wire reinforced cannulas. CONCLUSIONS: VVDL cannulation has become the preferred modality for ECMO therapy in children with respiratory failure and it is mainly utilized in younger patients. The use of newer VVDL cannulas may provide improved pump flow performance without substantial additional risk. PMID- 25280646 TI - Full thickness abdominal wall defect in growing rats as a model for congenital diaphragmatic hernia prosthetic repair. AB - BACKGROUND: Large congenital diaphragmatic hernia may require prosthetic correction. Acellular collagen matrices were introduced to avoid complications owing to the use of synthetic patches. We tested 3 different ACM for reconstruction of an abdominal wall defect in an animal model that mimics the fast growth during infancy. METHODS: Pelvisoft(r) (CR Bard, Covington, GA) and 2 investigational ACM were used for primary reconstruction of a full thickness abdominal wall defect. 3months-old rats (n=26) were allowed to survive for 90days after implantation. Anatomical, tensiometric and histological analyses were performed. Based on good outcomes, we did the same with 1month-old rats (n=54). Unoperated rats were used for obtaining reference tensiometric values of selected native tissues. RESULTS: Major wound complications were exclusively observed in 1month-old rats. All explants in both groups thinned significantly (p<0.03) and had an elastic modulus increasing over time, far above that from native tissues at 90days of life. Both investigational ACM induced a more vigorous foreign body reaction than Pelvisoft((r)). CONCLUSIONS: The shift from 3 to 1month-old rats was associated with wound complications. Pelvisoft(r) showed a better biocompatibility than the 2 investigational ACM. Passive biomechanical properties of all explants were still not comparable to that of native tissues. PMID- 25280647 TI - The long term physical consequences of gastroschisis. AB - PURPOSE: To determine the progress, physical and metabolic outcomes of gastroschisis survivors. METHODS: Fifty children born with gastroschisis were assessed with a health questionnaire, physical assessment, bone density and nutritional blood parameters at a median age of 9years (range 5-17). RESULTS: After initial abdominal closure, 27/50 (54%) required additional surgical interventions. Ten (20%) children had complex gastroschisis (CG). Abdominal pain was common: weekly in 41%; and requiring hospitalization in 30%. The weight, length and head circumference z-scores improved by a median 0.88 (p=0.001), 0.56 (p=0.006) and 0.74 (p=0.018) of a standard deviation (SD) respectively from birth; 24% were overweight or obese at follow up. However, those with CG had significantly lower median weight z-scores (-0.43 v 0.49, p=0.0004) and body mass index (BMI) (-0.48 v 0.42, p=0.001) at follow up compared to children with simple gastroschisis. Cholesterol levels were elevated in 24% of children. Bone mineral density was reassuring. There were 15 instances of low blood vitamin and mineral levels. CONCLUSIONS: Although gastroschisis survival levels are high, many children have significant ongoing morbidity. Children with simple gastroschisis showed significant catch up growth and a quarter had become overweight. PMID- 25280648 TI - The effect of colchicine and low-dose methotrexate on intestinal ischemia/reperfusion injury in an experimental model. AB - AIM: Intestinal ischemia/reperfusion (I/R) injury is a serious clinical condition. Colchicine and low-dose methotrexate have anti-inflammatory features. An experimental model was conducted to investigate the effect of colchicine and methotrexate on intestinal I/R injury. METHODS: Twenty-four rats were included. Only laparotomy was done in control group (CG, n=6). In experimental groups, superior mesenteric artery was occluded. After 1h ischemia, reperfusion (1h) was started by de-occlusion. 30min before reperfusion, saline in sham group (SG, n:6), colchicine (1mg/kg) in colchicine group (CNG, n:6), and methotrexate (0.1mg/kg) in methotrexate group (MTXG, n:6) were infused intraperitoneally. Small intestines were harvested for evaluation of intestinal mucosal injury (Chiu score) and oxidative stress markers (nitric oxide: NO, malondialdehyde: MDA, superoxide dismutase: SOD). RESULTS: Biochemically, MDA levels were significantly low in CG compared to SG, CNG, and MTXG (p<0.05). NO levels were significantly low and SOD levels were significantly high in CG compared to MTXG (p<0.05). Histopathologically, Chiu score was significantly low in CG compared to SG, CNG, and MTXG (p<0.05), and significantly high in MTXG compared to SG and CNG (p<0.05). CONCLUSION: The present experimental model caused I/R injury in rat intestines. Contrary to literature, it was found that methotrexate worsens and colchicine does not attenuate intestinal I/R injury. PMID- 25280649 TI - Pediatric surgeons' attitudes toward regionalization of neonatal surgical care. AB - BACKGROUND/PURPOSE: Research has suggested that high-risk pediatric surgical patients have better outcomes when treated in resource-rich children's environments. Surgical neonates are a particularly high-risk population and some suggest that regionalization might be a strategy to improve clinical outcomes in neonatal surgical patients. We conducted a national survey of pediatric surgeons in the United States to explore their attitudes toward regionalization of neonatal surgical care. METHODS: Members of the American Pediatric Surgical Association were asked to participate in an anonymous online survey to assess both attitudes toward regionalization, as well as perceptions of the importance of various resources in providing optimal care for surgical neonates. RESULTS: Overall, 56.2% of participants favored regionalization. Surgeons whose practice was part of a training program tended to favor regionalization more, as did those from larger group practices and those who practiced at free-standing children's hospital. In addition, surgeons from larger groups and those involved with training programs more strongly favored the premise that a higher level of resource commitment should be available to treat surgical neonates. CONCLUSIONS: The impact of any national strategy to improve neonatal surgical outcomes will be large and multi-faceted. While the majority of pediatric surgeons favor regionalization, our findings demonstrate variation in this view and highlight the necessity for surgeon involvement and education that will be critical in this effort. PMID- 25280650 TI - Locally increased concentrations of inflammatory cytokines in an experimental intraabdominal adhesion model. AB - BACKGROUND: Peritoneal adhesions may cause bowel obstruction, infertility, and pain. This study investigated cytokines, proteins and growth factors thought to promote formation of adhesions in an experimental intraabdominal adhesion model. METHODS: Male Sprague-Dawley rats were subjected to laparotomy, cecal abrasion, and construction of a small bowel anastomosis and examined at various time points after surgery. Concentrations of cytokines and growth factors in plasma and peritoneal fluid were analyzed using electrochemoluminescence and quantitative sandwich enzyme immunoassay technique. RESULTS: Concentrations of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha) increased in peritoneal fluid from 6h after incision. Plasma concentrations of IL 6 increased at 6h, but plasma concentrations of IL-1beta and TNF-alpha remained low. Peritoneal fluid concentrations of platelet-derived growth factor-BB (PDGF BB), transforming growth factor beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were below detection levels at all time points. CONCLUSION: Early elevations of IL-6, IL-1beta, and TNF-alpha concentrations in peritoneal fluid correlated to adhesion formation in this rodent model. Our model is relevant and reproducible, suitable for intervention, and indicates that antiadhesion strategies should be early, local and not systemic. PMID- 25280651 TI - Feasibility of laparoscopic pyloromyotomy under spinal anesthesia. AB - BACKGROUND: Most agents used for GA are considered to be neurotoxins and affect developing brains in experimental models, leading to a push for spinal anesthesia (SA). There are no reports of laparoscopic pyloromyotomy (LP) performed under SA. We present our experience with LP and SA and discuss feasibility. METHODS: A retrospective analysis was performed on a consecutive series of patients who underwent an LP. An 'intent to treat' analysis was utilized, and GA was compared to SA. Data regarding patient characteristics, operative intervention, complications, and postoperative course were collected. RESULTS: Twelve cases had attempted SA for the LP, 9 were successful. During the same time, 12 cases underwent LP under GA. We found no difference for length of procedure, time to the first feed, or the postoperative LOS. The time to leave the OR after conclusion of the procedure was significantly shorter for the SA group (14min vs. 28min, p<0.001). There were no complications from the SA, however three cases had to be converted to GA. CONCLUSIONS: It is feasible and safe to perform laparoscopic pyloromyotomy under spinal anesthesia. Given the increasing concern over the use of GA in infants, consideration may be given to use of SA for LP. PMID- 25280652 TI - Dyssynergic defecation may play an important role in postoperative Hirschsprung's disease patients with severe persistent constipation: analysis of a case series. AB - BACKGROUND: After surgery for Hirschsprung's disease (HD) the majority of patients have satisfactory clinical outcomes. Nevertheless, a substantial number of patients remain who suffer from severe persistent constipation. Current consensus attributes these complaints to the hallmarks of HD. In non-HD patients a cause for severe constipation is dyssynergic defecation. METHODS: Retrospectively, we reviewed the medical records of ten postoperative HD patients with severe persistent constipation who had undergone extensive anorectal function tests to diagnose the reason for the constipation. We analyzed the results of these tests. RESULTS: During the last three years, ten postoperative HD patients with severe persistent constipation were given extensive anorectal function tests. All ten patients were diagnosed with dyssynergic defecation. The ages at the time of diagnosis ranged from 7 to 19years with a median age of 12years. Signs of an enlarged rectum were seen in all ten patients, with a maximum measured value of 845mL. CONCLUSIONS: Patients with HD may also suffer from dyssynergic defecation. It is important to consider this possibility when dealing with severe persistent constipation in postoperative HD patients. Viable options for treating dyssynergic defecation are available that could prevent irreversible long-term complications. PMID- 25280653 TI - Is routine chest radiograph necessary after chest tube removal? AB - BACKGROUND: Obtaining a chest radiograph (CXR) after chest tube (CT) removal to rule out a pneumothorax is a universal practice. However, the yield of this CXR has not been well documented. Additionally, most iatrogenic pneumothoraces resulting from CT removal are atmospheric in origin, asymptomatic, and can be observed. Recently, we have begun to discontinue routine CXR for CT removal. We evaluated our experience with CT removal to clarify the usefulness of routine post CT removal CXR. METHODS: After IRB approval, a retrospective study was conducted on patients who had a CT placed in the past decade. Cardiac patients requiring a CT were excluded. Patient demographics, diagnosis, treatments, and outcomes were collected. Patients were divided into two groups, those with a CXR after CT removal (Group 1) and those without (Group 2). Percentages were compared with Chi square with Yates correction. RESULTS: 462 patients were identified (group 1=327, group 2=135). Indications for CT included; empyema (n=176), lung resection (n=146), pneumothorax (n=71), pleural effusion (n=26), spinal fusion (n=20), trauma (n=16), and miscellaneous (n=7). Seven patients (2.1%) in group 1 required reinsertion for pneumothorax (n=4), empyema (n=2), and pleural effusion (n=1) compared to 1 patient (0.7%) in group 2 who required reinsertion for pleural effusion. This difference was not significant (P=0.2). CONCLUSIONS: In non-cardiac patients with a CT, tube reinsertion is uncommon and tube replacement is secondary to symptoms. Therefore, routine post CT removal CXR is not necessary. CXR in these patients should be obtained based upon clinical indications after CT removal. PMID- 25280654 TI - Impact of pelvic osteotomy on the incidence of inguinal hernias in classic bladder exstrophy. AB - BACKGROUND/PURPOSE: The high prevalence of inguinal hernias in the bladder exstrophy population is well documented. The authors' aim is to determine whether pelvic osteotomy reduces the incidence of primary and recurrent inguinal hernias in patients with classic bladder exstrophy. METHODS: Using an institutionally approved database, patients who underwent immediate or delayed primary bladder closure between 1974 and 2012 were identified and stratified by the use of pelvic osteotomy at the time of closure. Data were analyzed using Fisher's exact test and multivariate logistic regression analysis. RESULTS: One hundred thirty-six patients were identified with a median follow up of 8years. The incidence of inguinal hernias following closure was 25% in the osteotomy group versus 46% in the non-osteotomy group (p=0.017). Osteotomy was associated with a significant decrease in recurrence of inguinal hernias amongst patients who underwent previous repair (17% versus 47%, osteotomy versus non-osteotomy, p=0.027) and the development of primary inguinal hernias in whom initial groin exploration was negative (20% versus 39%, p=0.029). Osteotomy and female sex were associated with a decreased rate of inguinal hernia development after bladder closure while age at closure was not. CONCLUSIONS: Pelvic osteotomy at the time of exstrophy closure decreases the likelihood of primary or recurrent inguinal hernia development. PMID- 25280655 TI - Internal hemipelvectomy in the management of pelvic Ewing sarcoma - are outcomes better than with radiation therapy? AB - BACKGROUND: Pelvic Ewing sarcoma (ES) is commonly associated with a worse prognosis. Large size and location limit local control options to radiation therapy, and local recurrences are common. We evaluated the impact of hemipelvectomy and radiation on outcomes, including function. MATERIALS AND METHODS: Thirty-nine patients (median age 13.5years) with ES of the pelvis and sacral bones were treated during the period 2000-2012. Fifteen were treated with definitive radiotherapy (RT), 9 patients underwent hemipelvectomy alone, and 15 were treated with combined hemipelvectomy and RT. RESULTS: Twenty patients (51.2%) are alive with a median follow-up 3.2years from diagnosis. Median time from diagnosis to relapse was 1.3years. Three-year estimates of EFS and OS were 47% and 61%, respectively. Patients treated with surgery or surgery with RT had better outcome than patients treated with RT only (3-year OS 78% or 81% vs. 36%, respectively, p=0.00083). The outcome of patients with pelvic ES treated with hemipelvectomy was not significantly different from the outcome of all patients with Ewing sarcoma treated on the national Polish protocol. CONCLUSIONS: Internal hemipelvectomy offers good chances of cure for patients with pelvic ES, with a reasonable rate of complications and good function. PMID- 25280656 TI - Open versus needle biopsy in diagnosing neuroblastoma. AB - BACKGROUND: Open surgical biopsy is traditionally advocated prior to initiating therapy in UKCCLG neuroblastoma protocols. We report a single centre experience comparing the utility of open biopsy vs image guided needle biopsy in aiding the definitive diagnosis and risk stratification of neuroblastoma - (Shimada classification, MYCN expression, cytogenetics - 1p 11q, 17 q). METHODS: Medical records of all new cases of neuroblastoma presenting to a single UKCCLG centre during January 2002-July 2013 were examined. RESULTS: Thirty nine patients underwent a biopsy of primary tumour for neuroblastoma during the study. Twenty one children had open biopsy and eighteen cases had a needle biopsy. Staging of neuroblastoma revealed - stage 4 (n=26), stage 3 (n=7), stage 2 (n=3) and stage 4S (n=3). Sites of primary tumour were adrenal gland (n=20), abdomen (n=12), thoracic (n=4), abdomino-thoracic (n=2) and abdomino pelvic regions (n=1). All patients (open vs needle) had adequate tissue retrieved for histological diagnosis of neuroblastoma. One needle and one open biopsy case did not have MYCN status determined despite adequate tissue sampling. Seventeen patients (7 open and 10 needle biopsies) had 1p and 17q status reported in MLPA testing (Multiplex Ligation-dependent Probe Amplification). No single patient required a repeat tumour biopsy. Morbidity in the series was minimal with only one child - open biopsy group, requiring emergent laparotomy to control bleeding from an abdominal primary tumour. No complications were recorded with needle biopsy. CONCLUSIONS: Open and image guided needle biopsy appear to yield adequate tissue sampling for diagnosis, risk classification and staging of neuroblastoma. Further larger co operative studies may usefully guide national and international protocols. PMID- 25280657 TI - Transumbilical laparoscopic-assisted appendectomy is associated with lower costs compared to multiport laparoscopic appendectomy. AB - BACKGROUND/PURPOSE: Single-incision laparoscopic appendectomy has been associated with improved cosmetic benefits, and decreased postoperative pain. Less is known about costs and other outcomes. Our aim was to evaluate the costs and outcomes between transumbilical laparoscopic-assisted appendectomy (TULAA) and multiport laparoscopic appendectomy (MLA). METHODS: IRB-approved retrospective review (September 2010-July 2013) of institutional medical records identified 372 pediatric patients undergoing laparoscopic appendectomy. Outcomes included costs, LOS and readmission. Costs were fully loaded operating costs from the hospital's cost accounting database. Generalized linear regression was used to assess costs of MLA and TULAA. A subgroup analysis was performed using only patients with non perforated appendicitis. RESULTS: There were 132 patients (35.5%) that underwent TULAA while 240 patients (65.5%) underwent MLA. Compared to MLA, TULAA was associated with decreased operative time (0.6 vs. 1.0h, p<0.0001), used in comparable proportions of interval appendectomies, but was performed less often for perforated appendicitis (9.8% vs. 22.9%, p=0.002). Readmission and postoperative complications were similar between both groups. In the setting of non-perforated appendicitis, TULAA was associated with lower costs of $1378 relative to MLA (p=0.009). CONCLUSIONS: In non-perforated appendicitis, TULAA is associated with lower costs and comparable rates of readmission and postoperative complications. PMID- 25280658 TI - Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience. AB - BACKGROUND: Neuroendocrine tumours (NET) of the appendix are rare histopathological neoplasms detected following operation for appendicitis in childhood. The role (if any) for radical surgery notably right hemicolectomy (RHC) has often reflected the 'expert opinion' of adult general surgeons with wider experience of managing NET lesions of the gastrointestinal tract. Critical decisions have focused on (a) tumour size, (b) histology, (c) tumour location/invasion and (d) positive lymph nodes. Against this background we report the clinical outcome of children with 'incidental' appendix carcinoid tumours managed at two regional UK paediatric surgery centres. A critical review of the literature is additionally provided in an effort to define contemporary patterns of care in paediatric surgical practice. METHODS: Hospital records and pathology database(s) identified 27 patients at two UK centres with a confirmed histological diagnosis of appendix NET lesions during January 1997-January 2013. A PUBMED and EMBASE search strategy-(English language publications only), 1975 present, was performed to gather information on all patients younger than 20years at primary diagnosis with NET appendix tumours to review their management and outcomes. RESULTS: All 27 patients treated at the two institutions had acute appendicitis including 3 cases presenting with an appendix mass. Twenty-five underwent appendicectomy with two having interval operations. Tumours had a maximum diameter of 2-18mm (median 9mm) with 73% of lesions located at the appendix tip. Fourteen (52%) had tumour invading the mesoappendix. All patients underwent appendicectomy only with no single case having RHC or additional surgery. Surveillance studies (5HIAA, chromogranin-A) and imaging including ultrasound or CT were deployed in a minority of patients revealing no abnormality. All 27 cases are alive and well-(mean follow up 5years; range: 9months-16years). The literature highlights varied management strategies and no recorded fatalities with radical surgery in children largely evolving from adult surgical practice. CONCLUSIONS: This study confirms that paediatric patients with 'incidental' NET tumours of the appendix have an excellent prognosis. Consensus guidelines should ideally be developed by paediatric oncology surgeons to avoid unnecessary radical surgery in many otherwise healthy children. PMID- 25280659 TI - A new simplified technique of arterial reconstruction in pediatric living-donor liver transplantation: a comparison with the classical technique. AB - BACKGROUND/AIM: Hepatic artery anastomosis (HAA) is the most important aspect of living donor liver transplantation (LDLT), and it is currently performed by a specialized microsurgeon using micro surgical techniques, with interrupted sutures and the aid of an operative microscope. To simplify the procedure, we studied a new, simpler technique performed by pediatric transplant surgeons with continuous sutures and the same 3.5* magnification loupe used during other transplant procedures. The aim of this study was to compare these two hepatic artery reconstruction techniques in two pediatric LDLT series. METHODS: This study was initiated in January 2010 and finished in June 2013. In the first period, the arterial reconstruction was performed with an operating microscope and the classical technique of 9-0 separate sutures. In the second period, the arterial reconstruction was performed using a simpler technique, with surgical loupe and continuous 8-0 Prolene sutures. The incidences and outcomes of complications within the two periods were analyzed and compared. RESULTS: A total of 82 LDLTs were performed, 38 in the first period and 44 in the second period. There were no differences between the periods, except for the arterial ischemia time, which was lower in the second period. CONCLUSION: Hepatic artery anastomosis can be safely performed with low complication rates by a pediatric transplant surgeon using continuous sutures with a 3.5* magnifying loupe. This technique is simpler, less time consuming and simplifies the complex pediatric LDLT procedure. PMID- 25280660 TI - International attitudes of early adopters to current and future robotic technologies in pediatric surgery. AB - BACKGROUND: Perceptions toward surgical innovations are critical to the social processes that drive technology adoption. This study aims to capture attitudes of early adopter pediatric surgeons toward robotic technologies in order to clarify 1) specific features that are driving appeal, 2) limiting factors that are acting as diffusion barriers, and 3) future needs. METHODS: Electronic surveys were distributed to pediatric surgeons with personal experience or exposure in robotic surgery. Participants were classified as experts or nonexperts for subgroup analysis. Coded Likert scale responses were analyzed using the Friedman or Mann Whitney test. RESULTS: A total of 48 responses were received (22 experts, 26 nonexperts), with 14 countries represented. The most highly rated benefits of robot assistance were wristed instruments, stereoscopic vision, and magnified view. The most highly rated limitations were capital outlay expense, instrument size, and consumables/maintenance expenses. Future technologies of greatest interest were microbots, image guidance, and flexible snake robots. CONCLUSIONS: Putative benefits and limitations of robotic surgery are perceived with widely varied weightings. Insight provided by these responses will inform relevant clinical, engineering, and industry groups such that unambiguous goals and priorities may be assigned for the future. Pediatric surgeons seem most receptive toward technology that is smaller, less expensive, more intelligent and flexible. PMID- 25280661 TI - Complex gastroschisis is a different entity to simple gastroschisis affecting morbidity and mortality-a systematic review and meta-analysis. AB - BACKGROUND: Comparison of the outcome of newborns with simple (sGS) and complex gastroschisis (cGS: gastroschisis with atresia, necrosis, perforation or volvulus). MATERIALS AND METHODS: We conducted a systematic database search, quality assessment and meta-analyzed relevant articles which evaluated the mortality and morbidity of newborns with cGS versus sGS. Risk ratios (RR) with 95% confidence interval (CI) were reported for categorical data, and the mean difference (MD) was calculated for continuous data. Pooled estimates of RR and MD were computed using generic inverse variance and a random-effects model. RESULTS: Of 19 identified reports, 13 eligible studies were included. The mortality of infants with cGS (16.67%) was significantly higher than sGS (2.18%, RR: 5.39 [2.42, 12.01], p<0.0001). Significantly different outcome was found for the following parameters: Infants with cGS are started on enteral feedings later and they take longer to full enteral feedings with a subsequent longer duration of parenteral nutrition. Their risk of sepsis, short bowel syndrome and necrotizing enterocolitis is higher. They stay longer in hospital and are more likely to be sent home with enteral tube feedings and parenteral nutrition. DISCUSSION: Occurring in 17% of infants born with gastroschisis, complex gastroschisis is associated with a significantly increased morbidity and mortality. More research should be focused on this special subgroup of patients, not only on postnatal management, but additionally directing efforts to improve diagnosing and predicting complex gastroschisis prenatally as well as implement any probable fetal intervention to alleviate its disastrous outcome. PMID- 25280662 TI - Laparoscopic Ladd's procedure for superior mesenteric artery syndrome. AB - Superior mesenteric artery (SMA) syndrome is an uncommon condition where the third portion of the duodenum is compressed and obstructed between the SMA and the aorta. An otherwise healthy 17-year-old female presented with a 2-month history of postprandial abdominal pain and weight loss. Upper gastrointestinal (UGI) series demonstrated SMA obstruction of the third portion of the duodenum. Despite nasojejunal tube feedings over 4months with appropriate weight gain, symptoms continued and repeat UGI demonstrated persistent SMA syndrome. A laparoscopic Ladd's procedure served as definitive treatment. The steps of the procedure include mobilization of the Ligament of Treitz, mobilization of the right colon, complete derotation of the duodenum, delivery of the small bowel to the right upper quadrant, and appendectomy. Following the procedure, a postoperative UGI showed complete resolution of SMA compression of the duodenum. The patient had an uneventful postoperative course with immediate resolution of symptoms. She was discharged home tolerating a regular diet. PMID- 25280663 TI - The role of bowel preparation to optimize working space in laparoscopic inguinal hernia repair in infants. PMID- 25280664 TI - Effectiveness of collateral vein embolization for salvage of immature native arteriovenous fistulas. AB - PURPOSE: To investigate the value of collateral vein embolization (CVE) as a salvage treatment for nonmaturing native arteriovenous fistulae (AVFs) in patients requiring hemodialysis. MATERIALS AND METHODS: A total of 49 patients undergoing CVE (N = 65) for immature native AVFs at a single institution were reviewed. The study included 42 patients treated by 56 embolizations. Average fistula age at time of intervention was 18.2 weeks. Each patient underwent angiographic evaluation for fistula immaturity, with clinical success defined by initiation of single-session hemodialysis through the native fistula. RESULTS: Fistula maturity was achieved in 32 of 42 patients (76.2%). No major complications occurred. Average time from CVE to fistula maturity was 38.4 days. Angioplasty done with CVE was found in a statistically higher percentage of patients with fistula success versus failure (31.3% vs 8.3%; P = .039). Radiocephalic fistulae were seen in a higher percentage of fistula failures compared with successes, but the results were not statistically significant (83.3% vs 59.4%; P = .054). Thirty-four patients underwent CVE without angioplasty, which resulted in successful fistula maturation in 22 cases (64.7%). Radiocephalic fistulae were again seen in a higher percentage of fistula failures compared with successes, but the findings did not meet statistical significance (81.8% vs 54.5%; P = .052). CONCLUSIONS: Coil embolization of competing collateral vessels as a salvage treatment for nonfunctioning autologous AVFs is a viable treatment option in the majority of patients. Patients with radiocephalic fistulae may be at higher risk for primary fistula failure, but the present data are inconclusive. PMID- 25280666 TI - Data identification for improving gene network inference using computational algebra. AB - Identification of models of gene regulatory networks is sensitive to the amount of data used as input. Considering the substantial costs in conducting experiments, it is of value to have an estimate of the amount of data required to infer the network structure. To minimize wasted resources, it is also beneficial to know which data are necessary to identify the network. Knowledge of the data and knowledge of the terms in polynomial models are often required a priori in model identification. In applications, it is unlikely that the structure of a polynomial model will be known, which may force data sets to be unnecessarily large in order to identify a model. Furthermore, none of the known results provides any strategy for constructing data sets to uniquely identify a model. We provide a specialization of an existing criterion for deciding when a set of data points identifies a minimal polynomial model when its monomial terms have been specified. Then, we relax the requirement of the knowledge of the monomials and present results for model identification given only the data. Finally, we present a method for constructing data sets that identify minimal polynomial models. PMID- 25280665 TI - The role of mathematical models in understanding pattern formation in developmental biology. AB - In a Wall Street Journal article published on April 5, 2013, E. O. Wilson attempted to make the case that biologists do not really need to learn any mathematics-whenever they run into difficulty with numerical issues, they can find a technician (aka mathematician) to help them out of their difficulty. He formalizes this in Wilsons Principle No. 1: "It is far easier for scientists to acquire needed collaboration from mathematicians and statisticians than it is for mathematicians and statisticians to find scientists able to make use of their equations." This reflects a complete misunderstanding of the role of mathematics in all sciences throughout history. To Wilson, mathematics is mere number crunching, but as Galileo said long ago, "The laws of Nature are written in the language of mathematics[Formula: see text] the symbols are triangles, circles and other geometrical figures, without whose help it is impossible to comprehend a single word." Mathematics has moved beyond the geometry-based model of Galileo's time, and in a rebuttal to Wilson, E. Frenkel has pointed out the role of mathematics in synthesizing the general principles in science (Both point and counter-point are available in Wilson and Frenkel in Notices Am Math Soc 60(7):837-838, 2013). We will take this a step further and show how mathematics has been used to make new and experimentally verified discoveries in developmental biology and how mathematics is essential for understanding a problem that has puzzled experimentalists for decades-that of how organisms can scale in size. Mathematical analysis alone cannot "solve" these problems since the validation lies at the molecular level, but conversely, a growing number of questions in biology cannot be solved without mathematical analysis and modeling. Herein, we discuss a few examples of the productive intercourse between mathematics and biology. PMID- 25280669 TI - Liquid marbles stabilized by charged polymer latexes: how does the drying of the latex particles affect the properties of liquid marbles? AB - The coating of solid particles on the surface of liquid in air makes liquid marbles a promising approach in the transportation of a small amount of liquid. The stabilization of liquid marbles by polymeric latex particles imparts extra triggers such as pH and temperature, leading to the remote manipulation of droplets for many potential applications. Because the functionalized polymeric latexes can exist either as colloidally stable latex or as flocculated latex in a dispersion, the drying of latex dispersions under different conditions may play a significant role in the stabilization of subsequent liquid marbles. This article presents the investigation of liquid marbles stabilized by poly(styrene-co methacrylic acid) (PS-co-MAA) particles drying under varied conditions. Protonation of the particles before freeze drying makes the particles excellent liquid marble stabilizers, but it is hard to stabilize liquid marbles for particles dried in their deprotonated states. The static properties of liquid marbles with increasing concentrations of protonating reagent revealed that the liquid marbles are gradually undermined by protonating the stabilizers. Furthermore, the liquid marbles stabilized by different particles showed distinct behaviors in separation and merging manipulated by tweezers. This study shows that the initial state of the particles should be carefully taken into account in formulating liquid marbles. PMID- 25280668 TI - Changes in Brain 14-3-3 Proteins in Response to Insulin Resistance Induced by a High Palatable Diet. AB - The 14-3-3 protein family takes part in a wide range of cellular processes and is expressed in all eukaryotic organisms. In mammals, seven isoforms (beta, epsilon, eta, gamma, tau, zeta, and sigma) have been identified. 14-3-3 proteins are suggested to modulate the insulin-signaling cascade in the brain. The aim of this study was to investigate whether insulin resistance state induced by high palatable diet modulates expression of the 14-3-3 proteins in brain. Wistar male rats (n = 8) were divided into two experimental groups: insulin resistant (IR), induced by high palatable diet, and control (CO) group. Biochemical parameters (glucose tolerance test and plasma lipid profile) were evaluated after 130 days. Brain structures (cortex and hippocampus) were dissected for evaluation of messenger RNA (mRNA) and protein levels of different 14-3-3 proteins. Statistical analyses included Student t test and Pearson correlation. Significant decrease was observed in Ywhah and in Ywahq mRNA levels in the cortex of IR group, while no changes were observed in the hippocampus. Significant increase of theta isoform was observed in hippocampus IR group by immunodetection, while no differences were detected in the remaining isoforms. Inverse correlation was observed between blood glucose levels in cortex IR group and both Ywhah and Ywhaq mRNA levels. Protein levels of Creb and phosphatidylinositide 3-kinases (PI3K) showed to be increased in the hippocampus. These alterations may be due to a compensatory effect of impaired insulin signaling. We demonstrated differential expression of 14-3-3 isoforms throughout brain regions of rats with IR. As a whole, our results indicate that brain 14-3-3 levels are influenced by different diets. PMID- 25280667 TI - Tinospora cordifolia Induces Differentiation and Senescence Pathways in Neuroblastoma Cells. AB - Children diagnosed with neuroblastomas often suffer from severe side as well as late effects of conventional treatments like chemotherapy and radiotherapy. Recent advances in understanding of molecular pathways involved in cellular differentiation and apoptosis have helped in the development of new therapeutic approach based on differentiation-based therapy of malignant tumours. Natural medicines with their holistic therapeutic approach are known to selectively eliminate cancer cells thus provide a better substitute for the conventional treatment modes. The current study was aimed to investigate the anti-cancer potential of aqueous ethanolic extract of Tinospora cordifolia (TCE) using IMR-32 human neuroblastoma cell line as a model system. TCE is highly recommended in Ayurveda for its general body and metal health-promoting properties. TCE treatment was seen to arrest the majority of cells in G0/G1 phase and modulated the expression of DNA clamp sliding protein (PCNA) and cyclin D1. Further, TCE treated cells showed differentiation as revealed by their morphology and the expression of neuronal cell specific differentiation markers NF200, MAP-2 and NeuN in neuroblastoma cells. The differentiated phenotype was associated with induction of senescence and pro-apoptosis pathways by enhancing expression of senescence marker mortalin and Rel A subunit of nuclear factor kappa beta (NFkB) along with decreased expression of anti-apoptotic marker, Bcl-xl. TCE exhibited anti-metastatic activity and significantly reduced cell migration in the scratched area along with downregulation of neural cell adhesion molecule (NCAM) polysialylation and secretion of matrix metalloproteinases (MMPs). Our data suggest that crude extract or active phytochemicals from this plant may be a potential candidate for differentiation-based therapy of malignant neuroblastoma cells. PMID- 25280671 TI - Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. PMID- 25280672 TI - Feeling happy and thinking about food. Counteractive effects of mood and memory on food consumption. AB - Separate lines of research have demonstrated the role of mood and memory in the amount of food we consume. However, no work has examined these factors in a single study and given their combined effects beyond food research, this would seem important. In this study, the interactive effect of these factors was investigated. Unrestrained female participants (n = 64) were randomly assigned to either a positive or neutral mood induction, and were subject to a lunch cue (recalling their previously eaten meal) or no lunch cue, followed by a snack taste/intake test. We found that in line with prediction that food intake was lower in the lunch cue versus no cue condition and in contrast, food intake was higher in the positive versus neutral mood condition. We also found that more food was consumed in the lunch cue/positive mood compared to lunch cue/neutral mood condition. This suggests that positive mood places additional demands on attentional resources and thereby reduces the inhibitory effect of memory on food consumption. These findings confirm that memory cue and positive mood exert opposing effects on food consumption and highlight the importance of both factors in weight control interventions. PMID- 25280670 TI - Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. AB - This review focuses on two paralogue Rab GTPase activating proteins known as TBC1D1 Tre-2/BUB2/cdc 1 domain family (TBC1D) 1 and TBC1D4 (also called Akt Substrate of 160 kDa, AS160) and their roles in controlling skeletal muscle glucose transport in response to the independent and combined effects of insulin and exercise. Convincing evidence implicates Akt2-dependent TBC1D4 phosphorylation on T642 as a key part of the mechanism for insulin-stimulated glucose uptake by skeletal muscle. TBC1D1 phosphorylation on several insulin responsive sites (including T596, a site corresponding to T642 in TBC1D4) does not appear to be essential for in vivo insulin-stimulated glucose uptake by skeletal muscle. In vivo exercise or ex vivo contraction of muscle result in greater TBC1D1 phosphorylation on S237 that is likely to be secondary to increased AMP-activated protein kinase activity and potentially important for contraction-stimulated glucose uptake. Several studies that evaluated both normal and insulin-resistant skeletal muscle stimulated with a physiological insulin concentration after a single exercise session found that greater post-exercise insulin-stimulated glucose uptake was accompanied by greater TBC1D4 phosphorylation on several sites. In contrast, enhanced post-exercise insulin sensitivity was not accompanied by greater insulin-stimulated TBC1D1 phosphorylation. The mechanism for greater TBC1D4 phosphorylation in insulin stimulated muscles after acute exercise is uncertain, and a causal link between enhanced TBC1D4 phosphorylation and increased post-exercise insulin sensitivity has yet to be established. In summary, TBC1D1 and TBC1D4 have important, but distinct roles in regulating muscle glucose transport in response to insulin and exercise. PMID- 25280673 TI - Ruthenium (II) complexes of thiosemicarbazone: synthesis, biosensor applications and evaluation as antimicrobial agents. AB - A conformationally rigid half-sandwich organoruthenium (II) complex [(eta(6)-p cymene)RuClTSC(N-S)]Cl, (1) and carbonyl complex [Ru(CO)Cl(PPh3)2TSC(N-S)] (2) have been synthesized from the reaction of [{(eta(6)-p-cymene)RuCl}2(MU-Cl)2] and [Ru(H)(Cl)(CO)(PPh3)3] with thiophene-2-carboxaldehyde thiosemicarbazon (TSC) respectively and both novel ruthenium (II) complexes have been characterized by elemental analysis, FT-IR and NMR spectroscopy. The peripheral TSC in the complexes acts as an electrochemical coupling unit providing the ability to carry out electrochemical deposition (ED) and to form an electro-deposited film on a graphite electrode surface. The biosensing applicability of complexes 1 and 2 was investigated by using glucose oxidase (GOx) as a model enzyme. Electrochemical measurements at -0.9V versus Ag/AgCl electrode by following the ED Ru(II) reduction/oxidation due to from the enzyme activity, in the presence of glucose substrate. The designed biosensor showed a very good linearity for 0.01-0.5mM glucose. The in vitro antimicrobial activities of complexes 1 and 2 were also investigated against nine bacterial strains and one fungus by the disc diffusion test method. No activity was observed against the Gram-negative strains and fungus, whereas complex 1 showed moderate antibacterial activities against Gram positive bacterial strains. PMID- 25280674 TI - One step poly(rutin) particle preparation as biocolloid and its characterization. AB - Poly(rutin) p(RT) particles were prepared for the first time via a simple microemulsion polymerization/crosslinking method using l-alpha lecithin as surfactant, cyclohexane as organic phase and glycerol diglycidyl ether (GDE) as a crosslinking agent. Highly negatively charged p(RT) particles, -48.2 mV, were obtained due to phenolic groups on the particles. It was also confirmed that p(RT) particles are thermally more stable than RT and degradable in PBS at pH7.4., e.g., 11 wt.% can degrade in 1 day and little further degradation was observed over 9 days. The prepared p(RT) particles showed insignificant antibacterial characteristics against common bacteria such as Escherichia coli ATCC8739, Staphylococcus aureus ATCC6538, and Bacillus subtilis ATCC6633 whereas the RT molecules showed significantly better antibacterial characteristics even at low concentrations. Moreover, p(RT) particles were demonstrated for use as drug delivery devices by loading rosmarinic acid (RA) as model drug and showed release capability for up to 6 days by releasing 85% of the loaded RA. Intriguingly, p(RT) particles illustrated enhanced fluorescent properties providing great potential for fluorescent active antioxidant and antibacterial materials in biomedical use. PMID- 25280675 TI - Aqueous synthesis of highly luminescent glutathione-capped Mn2+-doped ZnS quantum dots. AB - In this paper, an aqueous-based route has been developed to prepare highly luminescent glutathione (GSH)-capped Mn-doped ZnS quantum dots (QDs). The dots obtained have an average diameter of 4.3 nm and exhibit the Mn(2+)-related orange luminescence with very low surface defect density. The highest photoluminescence was observed for a Mn(2+) to Zn(2+) molar ratio of 3%. Consecutive overcoating of the Mn:ZnS@GSH QDs by a ZnS shell was done, and the core/shell structured QDs exhibit a PL quantum yield of 23%. Transmission electron microscopy, X-ray powder diffraction, electron spin resonance, X-ray photoelectron spectroscopy, UV visible spectroscopy and spectrofluorometry have been used to characterize the crystal structure, the doping status, and the optical properties of the doped QDs. Our systematic investigation shows that Mn:ZnS/ZnS@GSH QDs are highly promising fluorescent labels in biological applications. PMID- 25280676 TI - Synthesis, characterization and antioxidant activity of a novel electroactive and biodegradable polyurethane for cardiac tissue engineering application. AB - There has been a growing trend towards applying conducting polymers for electrically excitable cells to increase electrical signal propagation within the cell-loaded substrates. A novel biodegradable electroactive polyurethane containing aniline pentamer (AP-PU) was synthesized and fully characterized by spectroscopic methods. To tune the physico-chemical properties and biocompatibility, the AP-PU was blended with polycaprolactone (PCL). The presence of electroactive moieties and the electroactivity behavior of the prepared films were confirmed by UV-visible spectroscopy and cyclic voltammetry. A conventional four probe analysis demonstrated the electrical conductivity of the films in the semiconductor range (~10(-5)S/cm). MTT assays using L929 mouse fibroblast and human umbilical vein endothelial cells (HUVECs) showed that the prepared blend (PB) displayed more cytocompatibility compared with AP-PU due to the introduction of a biocompatible PCL moiety. The in vitro cell culture also confirmed that PB was as supportive as tissue culture plate. The antioxidant activity of the AP-PU was proved using 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay by employing UV-vis spectroscopy. In vitro degradation tests conducted in phosphate buffered saline, pH7.4 and pH5.5, proved that the films were also biodegradable. The results of this study have highlighted the potential application of this bioelectroactive polyurethane as a platform substrate to study the effect of electrical signals on cell activities and to direct desirable cell function for tissue engineering applications. PMID- 25280677 TI - Improved cell activity on biodegradable photopolymer scaffolds using titanate nanotube coatings. AB - The development of bioactive materials is in the premise of tissue engineering. For several years, surface functionalization of scaffolds has been one of the most promising approaches to stimulate cellular activity and finally improve implant success. Herein, we describe the development of a bioactive composite scaffold composed of a biodegradable photopolymer scaffold and titanate nanotubes (TNTs). The biodegradable photopolymer scaffolds were fabricated by applying mask projection excimer laser photocuring at 308 nm. TNTs were synthesized and then spin-coated on the porous scaffolds. Upon culturing fibroblast cells on scaffolds, we found that nanotubes coating affects cell viability and proliferation demonstrating that TNT coatings enhance cell growth on the scaffolds by further improving their surface topography. PMID- 25280678 TI - Effect of polydopamine on the biomimetic mineralization of mussel-inspired calcium phosphate cement in vitro. AB - Inspired by the excellent adhesive property of mussel adhesive protein, we added polydopamine (PDA) to calcium phosphate cement (PDA-CPC) to enhance its compressive strength previously. The mineralization and mechanism on PDA-CPC were investigated by soaking it in simulated body fluid in this study. The results indicated that PDA promoted the conversion of dicalcium phosphate dihydrate and alpha-tricalcium phosphate to hydroxyapatite (HA) in the early stage but inhibited this conversion subsequently. PDA promoted the rapid mineralization on PDA-CPC to form a layer of nanoscale calcium phosphate (CaP) whereas there was no CaP formation on the control-CPC after 1d of soaking. This layer of nanoscale CaP was similar to that of natural bone, which was always observed during soaking. X ray photoelectron spectroscopy showed that the peak of CO of PDA existed in the newly formed CaP on PDA-CPC, indicating the co-precipitation of CaP with PDA. Furthermore, the newly formed CaP on PDA-CPC was HA confirmed by transmission electron microscopy, which the newly formed HA was in association with PDA. Therefore, PDA increased the capacity of mineralization of CPC and induced the formation of nanoscale bone-like apatite on PDA-CPC. Thus, this provides the feasible route for surface modification on CPC. PMID- 25280679 TI - Electrospun propolis/polyurethane composite nanofibers for biomedical applications. AB - Tissue engineering requires functional polymeric membrane for adequate space for cell migration and attachment within the nanostructure. Therefore, biocompatible propolis loaded polyurethane (propolis/PU) nanofibers were successfully prepared using electrospinning of propolis/PU blend solution. Here, composite nanofibers were subjected to detailed analysis using electron microscopy, FT-IR spectroscopy, thermal gravimetric analysis (TGA), and mechanical properties and water contact angle measurement. FE-SEM images revealed that the composite nanofibers became point-bonded with increasing amounts of propolis in the blend due to its adhesive properties. Incorporation of small amount of propolis through PU matrix could improve the hydrophilicity and mechanical strength of the fibrous membrane. In order to assay the cytocompatibility and cell behavior on the composite scaffolds, fibroblast cells were seeded on the matrix. Results suggest that the incorporation of propolis into PU fibers could increase its cell compatibility. Moreover, composite nanofibers have effective antibacterial activity. Therefore, as-synthesized nanocomposite fibrous mat has great potentiality in wound dressing and skin tissue engineering. PMID- 25280680 TI - Optimization of modified carbon paste electrode with multiwalled carbon nanotube/ionic liquid/cauliflower-like gold nanostructures for simultaneous determination of ascorbic acid, dopamine and uric acid. AB - We describe the modification of a carbon paste electrode (CPE) with multiwalled carbon nanotubes (MWCNTs) and an ionic liquid (IL). Electrochemical studies by using a D-optimal mixture design in Design-Expert software revealed an optimized composition of 60% graphite, 14.2% paraffin, 10.8% MWCNT and 15% IL. The optimal modified CPE shows good electrochemical properties that are well matched with model prediction parameters. In the next step, the optimized CPE was modified with gold nanostructures by applying a double-pulse electrochemical technique. The resulting electrode was characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, and electrochemical impedance spectroscopy. It gives three sharp and well-separated oxidation peaks for ascorbic acid (AA), dopamine (DA), and uric acid (UA). The sensor enables simultaneous determination of AA, DA and UA with linear responses from 0.3 to 285, 0.08 to 200, and 0.1 to 450 MUM, respectively, and with 120, 30 and 30 nM detection limits (at an S/N of 3). The method was successfully applied to the determination of AA, DA, and UA in spiked samples of human serum and urine. PMID- 25280681 TI - Molecularly imprinted solid-phase extraction of glutathione from urine samples. AB - Molecularly imprinted polymer (MIP) particles for glutathione were synthesized through iniferter-controlled living radical precipitation polymerization (IRPP) under ultraviolet radiation at ambient temperature. Static adsorption, solid phase extraction, and high-performance liquid chromatography were carried out to evaluate the adsorption properties and selective recognition characteristics of the polymers for glutathione and its structural analogs. The obtained IRPP-MIP particles exhibited a regularly spherical shape, rapid binding kinetics, high imprinting factor, and high selectivity compared with the MIP particles prepared using traditional free-radical precipitation polymerization. The selective separation and enrichment of glutathione from the mixture of glycyl-glycine and glutathione disulfide could be achieved on the IRPP-MIP cartridge. The recoveries of glutathione, glycyl-glycine, and glutathione disulfide were 95.6% +/- 3.65%, 29.5% +/- 1.26%, and 49.9% +/- 1.71%, respectively. The detection limit (S/N=3) of glutathione was 0.5 mg.L(-1). The relative standard deviations (RSDs) for 10 replicate detections of 50 mg.L(-1) of glutathione were 5.76%, and the linear range of the calibration curve was 0.5 mg.L(-1) to 200 mg.L(-1) under optimized conditions. The proposed approach was successfully applied to determine glutathione in spiked human urine samples with recoveries of 90.24% to 96.20% and RSDs of 0.48% to 5.67%. PMID- 25280682 TI - Effect of thermomechanical treatment on the superelasticity of Ti-7.5Nb-4Mo-2Sn biomedical alloy. AB - Effects of thermomechanical treatment on the microstructure and superelasticity of Ti-7.5Nb-4Mo-2Sn biomedical alloy were investigated by using XRD measurement, optical microscope (OM), transmission electron microscope (TEM) and tensile tests. The titanium alloy samples were prepared by annealing at a temperature in the range of 600 to 1000 degrees C after severe cold rolling; and the samples that were annealed at 800 degrees C were further aged at 600 and 700 degrees C. The volume fraction of alpha phases decreased while that of omega phases increase with increasing annealing temperature. The alpha->beta transformation temperature of the alloy was determined to be between 700 and 800 degrees C. The alloy that was annealed at 700 degrees C exhibited a high level of superelasticity with relatively high first yield stress (sigmaSIM) at room temperature because it contained a fine alpha phase. A certain amount of omega phases also resulted in an increase in sigmaSIM, leading to an improvement in the superelasticity of the alloys that were annealed at 900 and 1000 degrees C. Aging treatment led to the precipitations of alpha and omega phases in the alloy after annealing at 800 degrees C; and the volume fraction of alpha phases decreased while that of omega phases increased with increasing aging temperature. Excellent superelasticity with high recovered strain (epsilonrecoverable) and strain recovery rate (eta) were obtained in the aged alloy due to the reinforcement of alpha and omega phases induced by aging treatment. The alloy annealed at 700 degrees C for 0.5h exhibited the best superelasticity in all the thermomechanically treated alloys due to the strengthening from the subgrain refining and the precipitating of fine alpha phases. PMID- 25280683 TI - Synthesis of silver nanoparticles in aqueous aminopolycarboxylic acid solutions via gamma-irradiation and hydrogen reduction. AB - Formation of silver nanoparticles in the presence of various aminipolycarboxylic acids (APCAs) such as iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and N,N,N',N",N''',N'''-triethylenetetraminehexaacetic acid (TTHA) was studied. Monodispersed silver nanoparticles capped by carboxylate groups of APCAs were prepared by the reduction of Ag(+) ions induced by either gamma-radiolytic or H2 reduction at room temperature. APCAs act as stabilizer to avoid the aggregation of silver nanoparticles. It has been shown that H2-induced reduction of Ag(+) is possible at room temperature in the presence of APCAs. TTHA stabilized gamma reduced particles showed reactivity towards oxygen. The formed particles were characterized by UV-vis absorption, X-ray diffraction, zetasizer and transmission electron microscopy. PMID- 25280684 TI - Biogenic gold nano-triangles: cargos for anticancer drug delivery. AB - We present synthesis of biogenic gold nano triangles (GNTs) using Azadirachta indica leaf extract at inherent pH (5.89) and its application in efficient drug delivery of doxorubicin (DOX) (anticancer drug). The main idea was to take advantage of large surface area of GNTs which has 3 dimensions and use the plant peptides coated on these triangles as natural linkers for the attachment of DOX. Sucrose density gradient centrifugation (SDGC) and dialysis methods were used for separation of the GNT from mixture of GNPs. Flocculation parameter (FP) was used to check stability of GNT which was found to be exceptionally high (0-0.75) due to the biological capping agents. DOX attachment to GNT was verified using Fourier transformed infra-red (FTIR) spectroscopy. The complex thus formed was found to be less toxic to normal cells (MDCK cells) and significantly toxic for the cancerous cells (HeLa cells). Drug loading efficiency was found to be 99.81% and DOX release followed first order release kinetics. Percentage drug release was found to be more than 4.5% in both acidic (5.8) as well as physiological pH (7.2) which is suitable for tumor targeting. PMID- 25280685 TI - Improved selective cholesterol adsorption by molecularly imprinted poly(methacrylic acid)/silica (PMAA-SiO2) hybrid material synthesized with different molar ratios. AB - The present paper describes the synthesis of molecularly imprinted polymer - poly(methacrylic acid)/silica and reports its performance feasibility with desired adsorption capacity and selectivity for cholesterol extraction. Two imprinted hybrid materials were synthesized at different methacrylic acid (MAA)/tetraethoxysilane (TEOS) molar ratios (6:1 and 1:5) and characterized by FT IR, TGA, SEM and textural data. Cholesterol adsorption on hybrid materials took place preferably in apolar solvent medium, especially in chloroform. From the kinetic data, the equilibrium time was reached quickly, being 12 and 20 min for the polymers synthesized at MAA/TEOS molar ratio of 6:1 and 1:5, respectively. The pseudo-second-order model provided the best fit for cholesterol adsorption on polymers, confirming the chemical nature of the adsorption process, while the dual-site Langmuir-Freundlich equation presented the best fit to the experimental data, suggesting the existence of two kinds of adsorption sites on both polymers. The maximum adsorption capacities obtained for the polymers synthesized at MAA/TEOS molar ratios of 6:1 and 1:5 were found to be 214.8 and 166.4 mg g(-1), respectively. The results from isotherm data also indicated higher adsorption capacity for both imprinted polymers regarding to corresponding non-imprinted polymers. Nevertheless, taking into account the retention parameters and selectivity of cholesterol in the presence of structurally analogue compounds (5 alpha-cholestane and 7-dehydrocholesterol), it was observed that the polymer synthesized at the MAA/TEOS molar ratio of 6:1 was much more selective for cholesterol than the one prepared at the ratio of 1:5, thus suggesting that selective binding sites ascribed to the carboxyl group from MAA play a central role in the imprinting effect created on MIP. PMID- 25280686 TI - A novel multiple drug release system in vitro based on adjusting swelling core of emulsion electrospun nanofibers with core-sheath structure. AB - We have developed a novel drug delivery system with the swelling core for differential release of multiple drugs by emulsion electrospinning, in which the aqueous phase is composed of polyvinyl alcohol and the oil phase consists of poly(epsilon-caprolactone). The microscopy images indicate that the W/O nanofibers with swelling core structure are successfully prepared and the model drugs, Rhodamine B and bovine serum albumin, were encapsulated in the fibers. In vitro drug release study demonstrated that this core-sheath structure could significantly alleviate the initial drug burst release and provided a differential diffusion pathway to release. It could be found that the postponement of the maximum accumulated release of bovine serum albumin was found due to the presence of sodium citrate and different types of polyvinyl alcohol. This study would provide a basis for optimization of encapsulation conditions to control the release of multiple agents and ultimately be applied in cancer chemotherapy. PMID- 25280687 TI - Control of the properties of porous chitosan-alginate membranes through the addition of different proportions of Pluronic F68. AB - This work addresses the development and characterization of porous chitosan alginate based polyelectrolyte complexes, obtained by using two different proportions of the biocompatible surfactant Pluronic F68. These biomaterials are proposed for applications as biodegradable and biocompatible wound dressing and/or scaffolds. The results indicate that thickness, roughness, porosity and liquid uptake of the membranes increase with the amount of surfactant used, while their mechanical properties and stability in aqueous media decrease. Other important properties such as color and surface hydrophilicity (water contact angle) are not significantly altered or did not present a clear tendency of variation with the increase of the amount of surfactant added to the polyelectrolyte complexes, such as real density, average pore diameter, total pore volume and surface area. The prepared biomaterials were not cytotoxic to L929 cells. In conclusion, it is possible to tune the physicochemical properties of chitosan-alginate polyelectrolyte complexes, through the variation of the proportion of surfactant (Pluronic F68) added to the mixture, so as to enable the desired application of these biomaterials. PMID- 25280688 TI - Physical and chemical characterization of Ag-doped Ti coatings produced by magnetron sputtering of modular targets. AB - Silver-doped Ti films were produced using a single magnetron sputtering source equipped with a titanium target containing implemented silver modules under variation of bias voltage and substrate temperature. The Ti(Ag) films were characterized regarding their morphology, contact angle, phase composition, silver content and distribution as well as the elution of Ag(+) ions into cell media. SEM and AFM pictures showed that substrate heating during film deposition supported the formation of even and dense surface layers with small roughness values, an effect that could even be enforced, when a substrate bias voltage was applied instead. The deposition of both Ti and Ag was confirmed by X-ray diffraction. ICP-MS and EDX showed a clear correlation between the applied sputtering parameters and the silver content of the coatings. Surface-sensitive XPS measurements revealed that higher substrate temperatures led to an accumulation of Ag in the near-surface region, while the application of a bias voltage had the opposite effect. Additional elution measurements using ICP-MS showed that the release kinetics depended on the amount of silver located at the film surface and hence could be tailored by variation of the sputter parameters. PMID- 25280689 TI - Swelling, diffusion, network parameters and adsorption properties of IPN hydrogel of chitosan and acrylic copolymer. AB - Interpenetrating network (IPN) type hydrogels of a biopolymer and a synthetic polymer were prepared from chitosan and crosslink copolymer of acrylic acid, sodium acrylate and hydroxyethyl methacrylate. Acrylic acid, sodium acrylate, hydroxyethyl methacrylate and N'N'-methylenebisacrylamide (MBA) monomers were free radically copolymerized and crosslinked in aqueous solution of chitosan. Several IPN hydrogels were prepared by varying concentrations of initiator, crosslinker (MBA) and weight% of chitosan . These hydrogels were characterized by free acid content, pH at point of zero charge (PZC), FTIR, DTA-TGA, SEM and XRD. The swelling and diffusion characteristics, network parameters and adsorption of cationic methyl violet (MV) and anionic congo red (CR) dyes by these hydrogels were studied. The hydrogels showed high adsorption (9.5-119 mg/g for CR and 9.2 98 mg/g for MV) and removal% (98-73% for CR and 94-66% for MV) over the feed concentration of 10-140 mg/l dye in water. The isotherms and kinetics of dye adsorption by the hydrogels were also studied. PMID- 25280690 TI - Glassy carbon electrode modified with a graphene oxide/poly(o-phenylenediamine) composite for the chemical detection of hydrogen peroxide. AB - Conducting poly(o-phenylenediamine) (POPD)/graphene oxide (GO) composites were prepared using a facile and efficient method involving the in-situ polymerization of OPD in the presence of GO in an aqueous medium. Copper sulfate was used as an oxidative initiator for the polymerization of OPD. Scanning electron microscopy and transmission electron microscopy images showed that POPD microfibrils were formed and distributed relatively uniformly with GO sheets in the obtained composites. X-ray diffraction results revealed the highly crystal structure of POPD. This composite exhibited good catalytic activity and stability. These results highlight the potential applications of POPD/GO composites as excellent electrochemical sensors. The composites were used to modify glass carbon electrodes for the chemical detection of hydrogen peroxide in aqueous media. PMID- 25280691 TI - Preparation and characterization of novel carbopol based bigels for topical delivery of metronidazole for the treatment of bacterial vaginosis. AB - The current study reports the development of bigels using sorbitan monostearate sesame oil organogel and carbopol 934 hydrogel. The microstructures and physicochemical properties were investigated by microscopy, viscosity measurement, mechanical analysis and differential scanning calorimetry analysis. Fluorescence microscopy confirmed the formation of oil-in-water type of emulsion gel. There was an increase in the strength of the bigels as the proportion of the organogel was increased in the bigels. The developed bigels showed shear-thinning flow behavior. The stress relaxation study suggested viscoelastic nature of the bigels. The developed bigels were biocompatible. Metronidazole, drug of choice for the treatment of bacterial vaginosis, loaded bigels showed diffusion-mediated drug release. The drug loaded gels showed good antimicrobial efficiency against Escherichia coli. In gist, the developed bigels may be used as delivery vehicles for the vaginal delivery of the drugs. PMID- 25280692 TI - Structure, biodegradation behavior and cytotoxicity of alkali-containing alkaline earth phosphosilicate glasses. AB - We report on the effect of sodium on the structure, chemical degradation and bioactivity of glasses in the CaO-MgO-SiO2-P2O5-CaF2 system. The (29)Si and (31)P magic angle spinning-nuclear magnetic resonance spectroscopy of melt-quenched glasses with varying Na2O/MgO ratios exhibit a silicate glass network with the dominance of Q(2)(Si) units and phosphorus mainly forming orthophosphate species. Sodium incorporation in the glasses did not induce a significant structural change in the silicate network, while it did influence the phosphate environment due to its lower ionic field strength in comparison with that of magnesium. The apatite forming ability of glasses has been investigated by immersion of glass powders in simulated body fluid (SBF) for time durations varying between 1h and 7 days while their chemical degradation has been studied in Tris-HCl in accordance with ISO-10993-14. Increasing Na(+)/Mg(2+) ratio caused a decrease in the chemical durability of glasses and in the apatite forming ability especially during initial steps of interaction between glass and SBF solution. The cellular responses were observed in vitro on bulk glass samples using mouse-derived pre osteoblastic MC3T3-E1 cell line. The preliminary study suggested that the increasing alkali-concentration in glasses led to cytotoxicity in the cell culture medium. PMID- 25280693 TI - Silk fibroin nanoparticles prepared by electrospray as controlled release carriers of cisplatin. AB - To maintain the anti-tumor activity of cis-dichlorodiamminoplatinum (CDDP) while avoiding its cytotoxicity and negative influence on normal tissue, CDDP-loaded silk fibroin nanoparticles approximately 59 nm in diameter were successfully prepared by electrospray without using organic solvent. CDDP was incorporated into nanoparticles through metal-polymer coordination bond exchange. In vitro release tests showed that the cisplatin in the nanoparticles could be slowly and sustainably released for more than 15 days. In vitro anti-cancer experiments and intracellular Pt content testing indicated that CDDP-loaded silk fibroin nanoparticles were easily internalized by A549 lung cancer cells, transferring CDDP into cancer cells and then triggering their apoptosis. In contrast, the particles were not easily internalized by L929 mouse fibroblast cells and hence showed weaker cell growth inhibition. The CDDP-loaded silk fibroin nanoparticles showed sustained and efficient killing of tumor cells but weaker inhibition of normal cells. In general, this study provides not only a novel method for preparing CDDP-loaded silk fibroin nanoparticles but also a new carrier system for clinical therapeutic drugs against lung cancers and other tumors. PMID- 25280694 TI - Voltammetric behavior of tiopronin on carbon paste electrode modified with nanocrystalline Fe50Ni50 alloys. AB - A simple and sensitive sensor was proposed for the rapid determination of tiopronin (TP) using a carbon paste electrode (CPE) modified with synthesized nanocrystalline Ni50-Fe50 alloys (nano-Ni50-Fe50) and ferrocene carboxylic acid (FcCa). The synthesized nano-Ni50-Fe50 was characterized by different methods such as TEM, SEM and XRD. The electrochemical oxidation of TP on the nano-Ni50 Fe50/FcCa carbon paste electrode (nano-Ni50-Fe50/FcCa/CPE) was studied. The nano Ni50-Fe50/FcCa/CPE exhibited good electrocatalytic properties towards oxidation of TP in phosphate buffer solution (pH7.0) with an overpotential of about 500 mV lower than that of the bare electrode. The rate constant for the catalytic oxidation of TP was evaluated by rotating disk voltammetry and the value of kc was found to be 3.2 * 10(7) cm(3)mol(-1)s(-1). Using differential pulse voltammetry (DPV), the determination of TP was explored at the modified electrode. The results indicated that the differential pulse response of TP was linear with its concentration in the range of 0.01-50.0 MUM. The detection limit was 7.46 nM (S/N=3). The proposed sensor was successfully applied for the determination of TP in tablet and urine samples. PMID- 25280695 TI - Electrospun gelatin/poly(epsilon-caprolactone) fibrous scaffold modified with calcium phosphate for bone tissue engineering. AB - In this study gelatin (Gel) modified with calcium phosphate nanoparticles (SG5) and polycaprolactone (PCL) were used to prepare a 3D bi-layer scaffold by collecting electrospun PCL and gelatin/SG5 fibers separately in the same collector. The objective of this study was to combine the desired properties of PCL and Gel/SG5 in the same scaffold in order to enhance mineralization, thus improving the ability of the scaffold to bond to the bone tissue. The scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and the wide angle X-ray diffraction (WAXD) measurements confirmed that SG5 nanoparticles were successfully incorporated into the fibrous gelatin matrix. The composite Gel/SG5/PCL scaffold exhibited more enhanced mechanical properties than individual Gel and Gel/SG5 scaffolds. The presence of SG5 nanoparticles accelerated the nucleation and growth of apatite crystals on the surface of the composite Gel/SG5/PCL scaffold in simulated body fluid (SBF). The osteoblast response in vitro to developed electrospun scaffolds (PCL and Gel/SG5/PCL) was investigated by using normal human primary NHOst cell lines. NHOst cell culture studies showed that higher alkaline phosphatase (ALP) activity and better mineralization were obtained in the case of composite materials than in pure PCL scaffolds. The mechanically strong PCL scaffold served as a skeleton, while the Gel/SG5 fibers facilitated cell spreading and mineralization of the scaffold. PMID- 25280697 TI - Fabrication of polycaprolactone nanofibrous scaffolds by facile phase separation approach. AB - Three-dimensional polycaprolactone (PCL) scaffolds with spherulite and nanofibrous structures were fabricated for the first time by thermally induced phase separation from a ternary PCL/dioxane/water system. Moreover, the effects of polymer concentration, aging temperature and the ratio of dioxane to water on the morphology of nanofibrous scaffolds were investigated. The result revealed that gelation, aging temperature, and ratio of solvents significantly influenced the formation of the unique spherulite and nanofibrous structures. The apatite formation ability test showed relatively rapid growth of carbonate hydroxyapatite in the nanofibrous PCL scaffold with macropore compared to the other two scaffolds with smooth structure and nanofibrous structure without macropore, respectively, indicating good apatite-formation ability of the macroporous and nanofibrous PCL scaffolds. PMID- 25280696 TI - Surface microcracks signal osteoblasts to regulate alignment and bone formation. AB - Microcracks are present in bone and can result from fatigue damage due to repeated, cyclically applied stresses. From a mechanical point, microcracks can dissipate strain energy at the advancing tip of a crack to improve overall bone toughness. Physiologically, microcracks are thought to trigger bone remodeling. Here, we examine the effect of microcracks specifically on osteoblasts, which are bone-forming cells, by comparing cell responses on microcracked versus non microcracked hydroxyapatite (HA) specimens. Osteoblast attachment was found to be greater on microcracked HA specimens (p<0.05). More importantly, we identified the preferential alignment of osteoblasts in the direction of the microcracks on HA. Cells also displayed a preferential attachment that was 75 to 90 MUm away from the microcrack indent. After 21 days of culture, osteoblast maturation was notably enhanced on the HA with microcracks, as indicated by increased alkaline phosphatase activity and gene expression. Furthermore, examination of bone deposition by confocal laser scanning microscopy indicated preferential mineralization at microcrack indentation sites. Dissolution studies indicate that the microcracks increase calcium release, which could contribute to osteoblast responses. Our findings suggest that microcracks signal osteoblast attachment and bone formation/healing. PMID- 25280698 TI - Sunflower oil mediated biomimetic synthesis and cytotoxicity of monodisperse hexagonal silver nanoparticles. AB - In this work, sunflower oil was utilized for the biomimetic synthesis of silver (Ag) nanoparticles (NPs), leading to highly mono-dispersed hexagonal-shaped silver nanoparticles (NPs) at various concentrations. It was found that the biomolecules of the oil not only have the capability to reduce silver ions, due to its extended phenolic system, but also appear to recognize and affect the Ag nanocrystal growth on the (110) face, leading to hexagonal growth of the NPs of 50 nm size. Initially, some spherical AgNPs of less than 10nm diameter were observed; however, over a longer period of time, a majority of hexagonal-shaped nanocrystals were formed. The one step synthesis can be extended for other metals. The as prepared sunflower oil capped AgNPs being completely free of toxic chemicals can be directly utilized for in vitro studies and offer a more rational approach for cellular applications. The NP solution exhibited dose-dependent cytotoxicity in human lung carcinoma cells and physiologically relevant cell model (3T3L1 cells). PMID- 25280699 TI - Research on the formation mechanism of composites from lignocelluloses and CaCO3. AB - The purpose of this work is to explore the formation mechanism of lignocellulose composites in ionic liquids, which is very important for the potential applications of lignocellulose composites. In this study, the lignocellulose/CaCO3 composites have been synthesized using different concentrations of CaCO3 by a rapid and green microwave-ionic liquid method. In view of the experimental results and literature, the formation mechanism of the composites from lignocelluloses and CaCO3 was proposed. It is suggested that lignocelluloses accumulated Ca(2+) ions due to the complexation of the Ca(2+) ions and the highly anionic polysaccharide groups of lignocelluloses, and CaCO3 was obtained by the strong electrostatic interactions between carbonate anions and calcium cations. When the content of CaCO3 reached a certain level, the activity of CaCO3 in the composites was mainly as aggregation. Using lignocelluloses instead of cellulose as a template to synthesize the organic inorganic composites was a facile method, which does not need to separate the lignocelluloses and can utilize all the main components of lignocelluloses. PMID- 25280700 TI - Production and characterization of cornstarch/cellulose acetate/silver sulfadiazine extrudate matrices. AB - The production and evaluation of cornstarch/cellulose acetate/silver sulfadiazine extrudate matrices are reported herein. The matrices were melt extruded under nine different conditions, altering the temperature and the screw speed values. The surface morphology of the matrices was examined by scanning electron microscopy. The micrographs revealed the presence of non-melted silver sulfadiazine microparticles in the matrices extruded at lower temperature and screw speed values. The thermal properties were evaluated and the results for both the biopolymer and the drug indicated no thermal degradation during the melt extrusion process. The differential scanning analysis of the extrudate matrices showed a shift to lower temperatures for the silver sulfadiazine melting point compared with the non-extruded drug. The starch/cellulose acetate matrices containing silver sulfadiazine demonstrated significant inhibition of the growth of Pseudomonas aeruginosa and Staphylococcus aureus. In vivo inflammatory response tests showed that the extrudate matrices, with or without silver sulfadiazine, did not trigger chronic inflammatory processes. PMID- 25280701 TI - Anticancer activity of Ficus religiosa engineered copper oxide nanoparticles. AB - The design, synthesis, characterization and application of biologically synthesized nanomaterials have become a vital branch of nanotechnology. There is a budding need to develop a method for environmentally benign metal nanoparticle synthesis, that do not use toxic chemicals in the synthesis protocols to avoid adverse effects in medical applications. Here, it is a report on an eco-friendly process for rapid synthesis of copper oxide nanoparticles using Ficus religiosa leaf extract as reducing and protecting agent. The synthesized copper oxide nanoparticles were confirmed by UV-vis spectrophotometer, absorbance peaks at 285 nm. The copper oxide nanoparticles were analyzed with field emission-scanning electron microscope (FE-SEM), Fourier transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS) and X-ray diffraction (XRD) spectrum. The FE-SEM and DLS analyses exposed that copper oxide nanoparticles are spherical in shape with an average particle size of 577 nm. FT-IR spectral analysis elucidates the occurrence of biomolecules required for the reduction of copper oxide ions. Zeta potential studies showed that the surface charge of the formed nanoparticles was highly negative. The XRD pattern revealed that synthesized nanoparticles are crystalline in nature. Further, biological activities of the synthesized nanoparticles were confirmed based on its stable anti-cancer effects. The apoptotic effect of copper oxide nanoparticles is mediated by the generation of reactive oxygen species (ROS) involving the disruption of mitochondrial membrane potential (Deltapsim) in A549 cells. The observed characteristics and results obtained in our in vitro assays suggest that the copper nanoparticles might be a potential anticancer agent. PMID- 25280702 TI - On-line solid-phase separation/preconcentration for the determination of copper in urine by flame atomic absorption spectrometry. AB - A new on-line separation/preconcentration system was developed for the determination of Cu(II) ions by flame atomic absorption spectrometry in urine samples. A newly synthesized chelating resin, by anchoring eriochrome blue black R reagent to Amberlite XAD-16 resin, was used as a packing material for the selective separation/preconcentration of Cu(II) ions. The influence of the parameters on the determination of Cu(II) ions such as pH of sample solution, amount of the resin, eluent type, interfering ions and flow variables was studied. The detection limit of the method was 1.0 MUg L(-1) while precision was 2.3% (n=15) at 50 MUg L(-1) Cu(II) level. The adsorption capacity of the resin was 217 MUg g(-1) Cu(II). The accuracy of the method was proven using TMDA-64 standard lake water and synthetic urine sample. The developed method has been applied successfully to the determination of copper in urine with satisfactory results. PMID- 25280703 TI - Boron containing poly-(lactide-co-glycolide) (PLGA) scaffolds for bone tissue engineering. AB - Scaffold-based bone defect reconstructions still face many challenges due to their inadequate osteoinductive and osteoconductive properties. Various biocompatible and biodegradable scaffolds, combined with proper cell type and biochemical signal molecules, have attracted significant interest in hard tissue engineering approaches. In the present study, we have evaluated the effects of boron incorporation into poly-(lactide-co-glycolide-acid) (PLGA) scaffolds, with or without rat adipose-derived stem cells (rADSCs), on bone healing in vitro and in vivo. The results revealed that boron containing scaffolds increased in vitro proliferation, attachment and calcium mineralization of rADSCs. In addition, boron containing scaffold application resulted in increased bone regeneration by enhancing osteocalcin, VEGF and collagen type I protein levels in a femur defect model. Bone mineralization density (BMD) and computed tomography (CT) analysis proved that boron incorporated scaffold administration increased the healing rate of bone defects. Transplanting stem cells into boron containing scaffolds was found to further improve bone-related outcomes compared to control groups. Additional studies are highly warranted for the investigation of the mechanical properties of these scaffolds in order to address their potential use in clinics. The study proposes that boron serves as a promising innovative approach in manufacturing scaffold systems for functional bone tissue engineering. PMID- 25280704 TI - Zirconia coated titanium for implants and their interactions with osteoblast cells. AB - The anodic plasma-electrochemical oxidation in aqueous electrolytes of Zr(SO4)2 was used to prepare new zirconia/titania-based surfaces M1 (Ti, Zr and O: 7-10, 22-27 and 65-69 at.%) and M2 (Ti, Zr and O: 11-13, 20-23 and 64-69 at.%). The chemical composition and the microstructure of these coatings were characterized by surface and solid state techniques such as scanning electron microscopy, electron probe microanalysis, Raman spectroscopy and X-ray diffraction. These mixed oxides of ZrO2/TiO2 surfaces consist up to 84% (m/m) of ZrO2 and 16% (m/m) of TiO2. Monoclinic zirconia was detected as the dominant microcrystalline phase. In vitro studies were conducted on primary human osteoblast cells. MTT and DAPI assays were used for assessment on cell proliferation. Immunohistochemical analyses of morphology, cell cluster formation and expression of bone sialoprotein (BSP) and osteocalcin (OC) were performed. Novel surfaces M1 and M2 induced proliferation and expression of OC and BSP similarly to Ticer, used in clinical practice. Furthermore, the presence of zirconia on titanium surface has a higher beneficial effect on the osteoblast morphological changes and cell cluster formation. PMID- 25280705 TI - Synthesis of novel core-shell structured dual-mesoporous silica nanospheres and their application for enhancing the dissolution rate of poorly water-soluble drugs. AB - Novel core-shell dual-mesoporous silica nanospheres (DMSS) with a tunable pore size were synthesized successfully using a styrene monomer as a channel template for the core and cetyltrimethyl ammonium bromide (CTAB) as a channel template for the shell in order to improve the dissolution rate of poorly water-soluble drugs. Simvastatin was used as a model drug and loaded into DMSS and the mesoporous core without the shell (MSC) by the solvent evaporation method. The drug loading efficiency of DMSS and MSC were determined by thermogravimetric analysis (TGA) and ultraviolet spectroscopy (UV). Characterization, using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) showed that simvastatin adsorbed in DMSS and MSC was in an amorphous state, and in vitro release test results demonstrated that both DMSS and MSC increased the water solubility and dissolution rate of simvastatin. The shell structure of DMSS was able to regulate the release of simvastatin compared with MSC. It is worth noting that DMSS has significant potential as a carrier for improving the dissolution of poorly water soluble drugs and reducing the rapid release. PMID- 25280706 TI - Biologically improved nanofibrous scaffolds for cardiac tissue engineering. AB - Nanofibrous structure developed by electrospinning technology provides attractive extracellular matrix conditions for the anchorage, migration and differentiation of stem cells, including those responsible for regenerative medicine. Recently, biocomposite nanofibers consisting of two or more polymeric blends are electrospun more tidily in order to obtain scaffolds with desired functional and mechanical properties depending on their applications. The study focuses on one such an attempt of using copolymer Poly(l-lactic acid)-co-poly (epsilon caprolactone) (PLACL), silk fibroin (SF) and Aloe Vera (AV) for fabricating biocomposite nanofibrous scaffolds for cardiac tissue engineering. SEM micrographs of fabricated electrospun PLACL, PLACL/SF and PLACL/SF/AV nanofibrous scaffolds are porous, beadless, uniform nanofibers with interconnected pores and obtained fibre diameter in the range of 459 +/- 22 nm, 202 +/- 12 nm and 188 +/- 16 nm respectively. PLACL, PLACL/SF and PLACL/SF/AV electrospun mats obtained at room temperature with an elastic modulus of 14.1 +/- 0.7, 9.96 +/- 2.5 and 7.0 +/ 0.9 MPa respectively. PLACL/SF/AV nanofibers have more desirable properties to act as flexible cell supporting scaffolds compared to PLACL for the repair of myocardial infarction (MI). The PLACL/SF and PLACL/SF/AV nanofibers had a contact angle of 51 +/- 12 degrees compared to that of 133 +/- 15 degrees of PLACL alone. Cardiac cell proliferation was increased by 21% in PLACL/SF/AV nanofibers compared to PLACL by day 6 and further increased to 42% by day 9. Confocal analysis for cardiac expression proteins myosin and connexin 43 was observed better by day 9 compared to all other nanofibrous scaffolds. The results proved that the fabricated PLACL/SF/AV nanofibrous scaffolds have good potentiality for the regeneration of infarcted myocardium in cardiac tissue engineering. PMID- 25280707 TI - Antimicrobial activity of the metals and metal oxide nanoparticles. AB - The ever increasing resistance of pathogens towards antibiotics has caused serious health problems in the recent years. It has been shown that by combining modern technologies such as nanotechnology and material science with intrinsic antimicrobial activity of the metals, novel applications for these substances could be identified. According to the reports, metal and metal oxide nanoparticles represent a group of materials which were investigated in respect to their antimicrobial effects. In the present review, we focused on the recent research works concerning antimicrobial activity of metal and metal oxide nanoparticles together with their mechanism of action. Reviewed literature indicated that the particle size was the essential parameter which determined the antimicrobial effectiveness of the metal nanoparticles. Combination therapy with the metal nanoparticles might be one of the possible strategies to overcome the current bacterial resistance to the antibacterial agents. However, further studies should be performed to minimize the toxicity of metal and metal oxide nanoparticles to apply as proper alternatives for antibiotics and disinfectants especially in biomedical applications. PMID- 25280708 TI - Degradation behavior of Ca-Mg-Zn intermetallic compounds for use as biodegradable implant materials. AB - With the goal of developing new biodegradable implant materials, we have investigated the degradation behavior of (Ca, Mg)-based intermetallic compounds. The degradation behavior of the compounds within the Ca-Mg-Zn system was roughly classified into four groups, and their behaviors were strongly influenced by the compositions of the compounds. For example, the Ca3MgxZn(15-x) compound exhibited a large solubility region with varying the Mg/Zn ratio, and the Ca3Mg12Zn3 phase alloy with the lowest Zn content was rapidly broken apart within 6h of immersion. Alternatively, the Ca3Mg4.6Zn10.4 phase alloy with the highest Zn content retained the bulk shape even after 250 h of immersion. These varying degradation behaviors were ascribed to the difference in the formability of Zn oxide as a protective layer against corrosion on the specimen surfaces, depending on the Zn content. The gained results suggest that there is a feasibility on developing new biodegradable materials based on intermetallic compounds in which the degradation rate can be controlled by their compositions. PMID- 25280710 TI - Biomimetic apatite-coated porous PVA scaffolds promote the growth of breast cancer cells. AB - Recapitulating the native environment of bone tissue is essential to develop in vitro models of breast cancer bone metastasis. The bone is a composite material consisting of organic matrix and inorganic mineral phase, primarily hydroxyapatite. In this study, we report the mineralization of porous poly vinyl alcohol (PVA) scaffolds upon incubation in modified Hanks' Balanced Salt Solution (HBSS) for 14 days. Scanning electron microscopy, energy dispersive X-ray analysis, and X-ray diffraction analysis revealed that the deposited minerals have composition similar to hydroxyapatite. The study demonstrated that the rate of nucleation and growth of minerals was faster on surfaces of less porous scaffolds. However, upon prolonged incubation, formation of mineral layer was observed on the surface of all the scaffolds. In addition, the study also demonstrated that 3D mineralization only occurred for scaffolds with highly interconnected porous networks. The mineralization of the scaffolds promoted the adsorption of serum proteins and consequently, the adhesion and proliferation of breast cancer cells. PMID- 25280709 TI - Magnetic glass ceramics for sustained 5-fluorouracil delivery: characterization and evaluation of drug release kinetics. AB - In the present study, magnetic glass ceramics in the system Fe2O3 ? TiO2 ? P2O5 ? SiO2 ? MO (M=Mg, Ca, Mn, Cu, Zn or Ce) are prepared. The effect of adding different cations on the thermal behavior, developed phases, microstructure and magnetic properties is studied using differental thermal analysis (DTA), X-ray diffraction analysis (XRD), transmission electron microscope (TEM), FT-infrared transmission (FT-IR) and vibrating sample magnetometer (VSM) respectively. The magnetic glass ceramics are tested as delivery systems for 5-fluorouracil. Modeling and analysis of release kinetics are addressed. The application of Higuchi square root of time model and the first order release model indicated that, 5-FU is released by diffusion controlled mechanisms, and that its released rate depends greatly on the concentration of loaded drug during the loading stage. The obtained results suggested that, the prepared magnetic glass ceramics can be used for cancer treatment by hyperthermia and/or by localized delivery of therapeutic doses of 5-fluorouracil. PMID- 25280711 TI - Corrosion behaviour of Nitinol alloy coated with alkylsilanes and polypyrrole. AB - Nitinol (equiatomic Ni and Ti alloy (NiTi)) substrate was modified using a coating system formed by a self-assembled film of alkylsilane compounds (propyltrichlorosilane (C3H7SiCl3) or octadecyltrichlorosilane (C18H37SiCl3)) and polypyrrole (PPy) doped with sodium bis(2-ethylhexyl) sulfosuccinate (Aerosol OT or AOT). The combination of alkylsilanes and the presence of a voluminous molecule like AOT entrapped into the PPy films improve the pitting corrosion resistance of the substrate in chloride solution. The best performance was achieved with the longest alkylsilane chains, where the PPy film remains adhered to the underlying coating after a pitting corrosion test. PMID- 25280712 TI - Enhanced healing of rabbit segmental radius defects with surface-coated calcium phosphate cement/bone morphogenetic protein-2 scaffolds. AB - Large osseous defects remain a difficult clinical problem in orthopedic surgery owing to the limited effective therapeutic options, and bone morphogenetic protein-2 (BMP-2) is useful for its potent osteoinductive properties in bone regeneration. Here we build a strategy to achieve prolonged duration time and help inducting new bone formation by using water-soluble polymers as a protective film. In this study, calcium phosphate cement (CPC) scaffolds were prepared as the matrix and combined with sodium carboxymethyl cellulose (CMC-Na), hydroxypropylmethyl cellulose (HPMC), and polyvinyl alcohol (PVA) respectively to protect from the digestion of rhBMP-2. After being implanted in the mouse thigh muscles, the surface-modified composite scaffolds evidently induced ectopic bone formation. In addition, we further evaluated the in vivo effects of surface modified scaffolds in a rabbit radius critical defect by radiography, three dimensional micro-computed tomographic (MUCT) imaging, synchrotron radiation based micro-computed tomographic (SRMUCT) imaging, histological analysis, and biomechanical measurement. The HPMC-modified CPC scaffold was regarded as the best combination for segmental bone regeneration in rabbit radius. PMID- 25280713 TI - Fabrication, nanomechanical characterization, and cytocompatibility of gold reinforced chitosan bio-nanocomposites. AB - Chitosan, a naturally derived polymer represents one of the most technologically important classes of active materials with applications in a variety of industrial and biomedical fields. Gold nanoparticles (~32 nm) were synthesized via a citrate reduction method from chloroauric acid and incorporated in Chitosan matrix. Bio-nanocomposite films with varying concentrations of gold nanoparticles were prepared through solution casting process. Uniform distribution of gold nanoparticles was achieved throughout the chitosan matrix and was confirmed with SEM. Synthesis outcomes and prepared nanocomposites were characterized using SEM, TEM, EDX, SAED, UV-vis, XRD, DLS, and Zeta potential for their physical, morphological and structural properties. Nanoscale properties of materials under the influence of temperature were characterized through nanoindentation techniques. From quasi-static nanoindentation, it was observed that hardness and reduced modulus of the nanocomposites were increased significantly in direct proportion to the gold nanoparticle concentration. Gold nanoparticle concentration also showed positive impact on storage modulus and thermal stability of the material. The obtained films were confirmed to be biocompatible by their ability to support growth of human cells in vitro. In summary, the results show enhanced mechanical properties with increasing gold nanoparticle concentration, and provide better understanding of the structure-property relationships of such biocompatible materials for potential biomedical applications. PMID- 25280714 TI - Magnetic microparticles post-synthetically coated by hyaluronic acid as an enhanced carrier for microfluidic bioanalysis. AB - Iron oxide based particles functionalized by bioactive molecules have been utilized extensively in biotechnology and biomedicine. Despite their already proven advantages, instability under changing reaction conditions, non-specific sorption of biomolecules on the particles' surfaces, and iron oxide leakage from the naked particles can greatly limit their application. As confirmed many times, surface treatment with an appropriate stabilizer helps to minimize these disadvantages. In this work, we describe enhanced post-synthetic surface modification of superparamagnetic microparticles varying in materials and size using hyaluronic acid (HA) in various chain lengths. Scanning electron microscopy, atomic force microscopy, phase analysis light scattering and laser diffraction are the methods used for characterization of HA-coated particles. The zeta potential and thickness of HA-layer of HA-coated Dynabeads M270 Amine were 50 mV and 85 nm, respectively, and of HA-coated p(GMA-MOEAA)-NH2 were -38 mV and 140 nm, respectively. The electrochemical analysis confirmed the zero leakage of magnetic material and no reactivity of particles with hydrogen peroxide. The rate of non-specific sorption of bovine serum albumin was reduced up to 50% of the naked ones. The coating efficiency and suitability of biopolymer-based microparticles for magnetically active microfluidic devices were confirmed. PMID- 25280715 TI - Controlled release of folic acid through liquid-crystalline folate nanoparticles. AB - The present study explores folate nanoparticles as nano-carriers for controlled drug delivery. Cross-linked nanoparticles of liquid crystalline folates are composed of ordered stacks. This paper shows that the folate nanoparticles can be made with less than 5% loss in folate ions. In addition, this study shows that folate nanoparticles can disintegrate in a controlled fashion resulting in controlled release of the folate ions. Release can be controlled by the size of nanoparticles, the extent of cross-linking and the choice of cross-linking cation. The effect of different factors like agitation, pH, and temperature on folate release was also studied. Studies were also carried out to show the effect of release medium and role of ions in the release medium on disruption of folate assembly. PMID- 25280716 TI - Potentiality of the "Gum Metal" titanium-based alloy for biomedical applications. AB - In this study, the "Gum Metal" titanium-based alloy (Ti-23Nb-0.7Ta-2Zr-1.2O) was synthesized by melting and then characterized in order to evaluate its potential for biomedical applications. Thus, the mechanical properties, the corrosion resistance in simulated body fluid and the in vitro cell response were investigated. It was shown that this alloy presents a very high strength, a low Young's modulus and a high recoverable strain by comparison with the titanium alloys currently used in medicine. On the other hand, all electrochemical and corrosion parameters exhibited more favorable values showing a nobler behavior and negligible toxicity in comparison with the commercially pure Ti taken as reference. Furthermore, the biocompatibility tests showed that this alloy induced an excellent response of MC3T3-E1 pre-osteoblasts in terms of attachment, spreading, viability, proliferation and differentiation. Consequently, the "Gum Metal" titanium-based alloy processes useful characteristics for the manufacturing of highly biocompatible medical devices. PMID- 25280717 TI - An investigation into environment dependent nanomechanical properties of shallow water shrimp (Pandalus platyceros) exoskeleton. AB - The present investigation focuses on understanding the influence of change from wet to dry environment on nanomechanical properties of shallow water shrimp exoskeleton. Scanning Electron Microscopy (SEM) based measurements suggest that the shrimp exoskeleton has Bouligand structure, a key characteristic of the crustaceans. As expected, wet samples are found to be softer than dry samples. Reduced modulus values of dry samples are found to be 24.90 +/- 1.14 GPa as compared to the corresponding values of 3.79 +/- 0.69 GPa in the case of wet samples. Hardness values are found to be 0.86 +/- 0.06 GPa in the case of dry samples as compared to the corresponding values of 0.17 +/- 0.02 GPa in the case of wet samples. In order to simulate the influence of underwater pressure on the exoskeleton strength, constant load creep experiments as a function of wet and dry environments are performed. The switch in deformation mechanism as a function of environment is explained based on the role played by water molecules in assisting interface slip and increased ductility of matrix material in wet environment in comparison to the dry environment. PMID- 25280718 TI - Iontophoresis with gold nanoparticles improves mitochondrial activity and oxidative stress markers of burn wounds. AB - The aim of this study was to analyse the effects of microcurrent and gold nanoparticles on oxidative stress parameters and the mitochondrial respiratory chain in the healing of skin wounds. Thirty 60-day old male Wistar rats (250-300 g) were divided into five groups (N=6): Control; Burn wounds; Microcurrent (MIC); Gold nanoparticle gel (GNP gel) and Microcurrent+Gold nanoparticle gel (MIC+GNP gel). The microcurrent treatment was applied for five consecutive days at a dose of 300 MUA. The results demonstrate a significant decrease in the activity of complexes I, II-III and IV in the Burn Wounds group compared to the control, and the MIC+GNP gel group was able to reverse this inhibition in complexes I, III and IV. Furthermore, a significant reduction in oxidative damage parameters and a significant increase in the levels of antioxidant defence enzymes were induced in the MIC+GNP gel group compared to the Burn Wounds group. The data strongly indicate that the group receiving treatment with MIC+GNP gel had improved mitochondrial functioning and oxidative stress parameters, which contributed to tissue repair. PMID- 25280719 TI - Polymerizable disulfide paclitaxel prodrug for controlled drug delivery. AB - A polymerizable disulfide paclitaxel (PTX) prodrug was synthesized by the consequential esterification reactions of 3,3'-dithiodipropionic acid (DTPA), a disulfide compound containing two active carboxyl groups, with 2-hydroxyethyl methacrylate (HEMA) and PTX. The structure of the prodrug was confirmed by (1)H NMR characterization. Then, the polymerizable prodrug was copolymerized with poly(ethylene glycol) methyl ether methacrylate (PEGMEA) to obtain a copolymer with hydrophilic PEG side chains and PTX covalently linked onto the backbone via disulfide bonds. The loading content of PTX was 23%. In aqueous solution, this copolymer prodrug could self-assemble into micelles, with hydrophobic PTX as the cores and hydrophilic PEG-segment as the shells. In vitro cell assay demonstrated that this copolymer prodrug showed more apparent cytotoxicity to cancer cells than to human normal cells. After incubation for 48 h, the cell viability of HEK 293 cells (human embryo kidney cells) at 0.1 MUg/mL PTX still remained more than 90%, however, that of HeLa cells (human cervical cancer cells) decreased to 52%. PMID- 25280720 TI - Synthesis and properties of ternary (K, NH4, H3O)-jarosites precipitated from Acidithiobacillus ferrooxidans cultures in simulated bioleaching solutions. AB - The purpose of this study was to synthesize a series of solid solution jarosites by biological oxidation of ferrous iron at pH2.2-4.4 and ambient temperature in media containing mixtures of K(+) (0, 1, 4, 6, 12, 31 mM) and NH4(+) (6.1, 80, 160, 320 mM). The starting material was a liquid medium for Acidithiobacillus ferrooxidans comprised of 120 mM FeSO4 solution and mineral salts at pH2.2. Following inoculation with A. ferrooxidans, the cultures were incubated in shake flasks at 22 degrees C. As bacteria oxidized ferrous iron, ferric iron hydrolyzed and precipitated as jarosite-group minerals (AFe3(SO4)2(OH)6) and/or schwertmannite (idealized formula Fe8O8(OH)6(SO4).nH2O). The precipitates were characterized by X-ray diffraction (XRD), elemental analysis, and Munsell color. Schwertmannite was the dominant mineral product at low combinations of K(+) (<= 4 mM) and NH4(+) (<= 80 mM) in the media. At higher single or combined concentrations, yellowish jarosite phases were produced, and Munsell hue provided a sensitive means of detecting minor schwertmannite in the oxidation products. Although the hydrated ionic radii of K(+) and NH4(+) are similar, K(+) greatly facilitated the formation of a jarosite phase compared to NH4(+). Unit cell and cell volume calculations from refinements of the powder XRD patterns indicated that the jarosite phases produced were mostly ternary (K, NH4, H3O)-solid solutions that were also deficient in structural Fe, especially at low NH4 contents. Thus, ferric iron precipitation from the simulated bioleaching systems yielded solid solutions of jarosite with chemical compositions that were dependent on the relative concentrations of K(+) and NH4(+) in the synthesis media. No phase separations involving discrete, end-member K-jarosite or NH4 jarosite were detected in the un-aged precipitates. PMID- 25280721 TI - Biocompatible Ni-free Zr-based bulk metallic glasses with high-Zr-content: compositional optimization for potential biomedical applications. AB - The present study designs and prepares Ni-free Zr60+xTi2.5Al10Fe12.5-xCu10Ag5 (at.%, x=0, 2.5, 5) bulk metallic glasses (BMGs) by copper mold casting for potential biomedical application. The effects of Zr content on the in vitro biocompatibility of the Zr-based BMGs are evaluated by investigating mechanical properties, bio-corrosion behavior, and cellular responses. It is found that increasing the content of Zr is favorable for the mechanical compatibility with a combination of low Young's modulus, large plasticity, and high notch toughness. Electrochemical measurements demonstrate that the Zr-based BMGs are corrosion resistant in a phosphate buffered saline solution. The bio-corrosion resistance of BMGs is improved with the increase in Zr content, which is attributed to the enrichment in Zr and decrease in Al concentration in the surface passive film of alloys. Regular cell responses of mouse MC3T3-E1 cells, including cell adhesion and proliferation, are observed on the Zr-Ti-Al-Fe-Cu-Ag BMGs, which reveals their general biosafety. The high-Zr-based BMGs exhibit a higher cell proliferation activity in comparison with that of pure Zr and Ti-6Al-4V alloy. The effects of Zr content on the in vitro biocompatibility can be used to guide the future design of biocompatible Zr-based BMGs. PMID- 25280722 TI - A novel thiolated human-like collage zinc complex as a promising zinc supplement: physicochemical characteristics and biocompatibility. AB - To improve zinc binding ability to human-like collagen (HLC) and stability of metal complex, HLC was thiolated by mercaptosuccinylation reaction with S acetylmercaptosuccinic anhydride (S-AMSA) at pH8.0. One mole of thiolated HLC-Zn (SHLC-Zn) complex possessed 24.3mol zinc ions when pH was 8.0 and zinc concentration was 15 mM. The physicochemical properties and biocompatibility of thiolated HLC-Zn (SHLC-Zn) complex were investigated by UV-vis, CD, electrophoresis analysis, differential scanning calorimetry (DSC) and cell viability assay, respectively. The results showed that SHLC-Zn complex(1) exhibited higher zinc ions than that of native HLC and still maintained the secondary structure of HLC though interaction occurred between SHLC and zinc ions, (2) increased the apparent molecular weight when compared with native HLC, (3) exhibited greater thermal stability than native HLC, and (4) presented toxicity free for BHK cells. This study suggests that the SHLC-Zn complex is a potential nutrition as well as zinc supplement in the medical application. PMID- 25280723 TI - The study of structural properties of carbon nanotubes decorated with NiFe2O4 nanoparticles and application of nano-composite thin film as H2S gas sensor. AB - Nano-composite of multiwall carbon nanotube, decorated with NiFe2O4 nanoparticles (NiFe2O4-MWCNT), was synthesized using the sol-gel method. NiFe2O4-MWCNTs were characterized using different methods such as X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), atomic force microscopy (AFM) and vibrating sample magnetometer (VSM). The average size of the crystallites is 23.93 nm. The values of the saturation magnetization (MS), coercivity (HC) and retentivity (MR) of NiFe2O4-MWCNTs are obtained as 15 emu g(-1), 21Oe and 5 emu g(-1), respectively. In this research, NiFe2O4-MWCNT thin films were prepared with the spin-coating method. These thin films were used as the H2S gas sensor. The results suggest the possibility of the utilization of NiFe2O4-MWCNT nano-composite, as the H2S detector. The sensor shows appropriate response towards 100 ppm of H2S at 300 degrees C. PMID- 25280724 TI - Determination of the relaxation characteristics of sugar glasses embedded in microfiber substrates. AB - Recently there has been considerable interest in developing sugar glasses that enable storage of biologics without refrigeration. Microfiber filter papers are good substrates for drying biologics in the presence of sugar glass-formers, providing for an even distribution of samples and an enhanced surface area for drying, but the opaqueness prevents macroscopic observation of the sample and can introduce complexities that impede physical characterization. Because drying kinetics and processing conditions can impact the relaxation dynamics (e.g., alpha- and beta-relaxation), which can influence the efficacy of the glass as a stabilizer, methods are needed that can enable a determination of relaxation phenomena of sugar glasses in such complex environments. In this study we present a method which provides verification of the absence of crystallinity following drying on glass fiber filter paper and also enables the determination of relaxation characteristics of amorphous sugar compositions embedded within these filter substrates. Using material pockets to contain the sugar glass-embedded microfiber paper, the alpha-relaxation temperature, Talpha, was determined as a function of the water content in trehalose and sucrose samples using Dynamic Mechanical Analysis (DMA). Results were verified by comparison with previous calorimetric and spectroscopic studies. The data also demonstrated the plasticizing effects of water, as Talpha was shown to correlate with water content via a Gordon-Taylor-like relationship. Our findings validate a new approach for determining the relaxation characteristics of microfiber embedded sugar glasses, and offer new insights into the relaxation characteristics of glasses prepared by microwave-assisted drying on filter papers. PMID- 25280725 TI - Cationic micellar nanoparticles for DNA and doxorubicin co-delivery. AB - Cationic micellar nanoparticles for chemotherapeutic drugs and therapeutic gene co-delivery were prepared based on a poly-(N-epsilon-carbobenzyloxy-l-lysine) (PZLL) and dendritic polyamidoamine (PAMAM) block copolymer (PZLL-D3). PZLL-D3 was synthesized by a copper-catalyzed azide alkyne cyclization (click) reaction between alpha-alkyne-PZLL and azide focal point PAMAM dendrons. Its structure was characterized by (1)H NMR and FTIR, and its buffering capability was determined by acid-base titration. MTT, agarose gel electrophoresis and flow cytometry studies showed that PZLL-D3 revealed low in vitro cytotoxicity, strong pDNA condensation ability, protection of pDNA against deoxyribonuclease I degradation and high gene transfection efficiency in 293T and HeLa cells. In addition, the micellar nanoparticles delivered pDNA and anticancer drug doxorubicin (DOX) simultaneously and efficiently to tumor cells, and the DOX loaded nanoparticles showed sustained in vitro release at pH=7.4 and 5.8. PMID- 25280726 TI - Enhancement of skin wound healing with decellularized scaffolds loaded with hyaluronic acid and epidermal growth factor. AB - Current therapy for skin wound healing still relies on skin transplantation. Many studies were done to try to find out ways to replace skin transplantation, but there is still no effective alternative therapy. In this study, decellularized scaffolds were prepared from pig peritoneum by a series of physical and chemical treatments, and scaffolds loaded with hyaluronic acid (HA) and epidermal growth factor (EGF) were tested for their effect on wound healing. MTT assay showed that EGF increased NIH3T3 cell viability and confirmed that EGF used in this study was biologically active in vitro. Scanning electron microscope (SEM) showed that HA stably attached to scaffolds even after soaking in PBS for 48 h. ELISA assay showed that HA increased the adsorption of EGF to scaffolds and sustained the release of EGF from scaffolds. Animal study showed that the wounds covered with scaffolds containing HA and EGF recovered best among all 4 groups and had wound healing rates of 49.86%, 70.94% and 87.41% respectively for days 10, 15 and 20 post-surgery compared to scaffolds alone with wound healing rates of 29.26%, 42.80% and 70.14%. In addition, the wounds covered with scaffolds containing EGF alone were smaller than no EGF scaffolds on days 10, 15 and 20 post-surgery. Hematoxylin-Eosin (HE) staining confirmed these results by showing that on days 10, 15 and 20 post-surgery, the thicker epidermis and dermis layers were observed in the wounds covered with scaffolds containing HA and EGF than scaffolds alone. In addition, the thicker epidermis and dermis layers were also observed in the wounds covered with scaffolds containing EGF than scaffolds alone. Skin appendages were observed on day 20 only in the wound covered with scaffolds containing HA and EGF. These results demonstrate that the scaffolds containing HA and EGF can enhance wound healing. PMID- 25280727 TI - Molecular cloning and functional characterization of the hepcidin gene from the convict cichlid (Amatitlania nigrofasciata) and its expression pattern in response to lipopolysaccharide challenge. AB - The hepcidin gene is widely expressed in many fish species and functions as an antimicrobial peptide, suggesting that it plays an important role in the innate immune system of fish. In the present study, the Amatitlania nigrofasciata hepcidin gene (AN-hepc) was cloned from the liver and its expression during an immune response was characterized. The results of quantitative PCR and RT-PCR showed that the AN-hepc transcript was most abundant in the liver. The expression of AN-hepc mRNA was significantly increased in the liver, stomach, heart, intestine, gill and muscle but was not significantly altered in the spleen, kidney, brain or skin after lipopolysaccharide challenge. The synthetic AN-hepc peptide showed a wide spectrum of antimicrobial activity in vitro toward gram positive and gram-negative bacteria. In particular, this peptide demonstrated potent antimicrobial activity against the aquatic pathogens Vibrio alginolyticus, V. parahaemolyticus, V. vulnificus, Aeromonas hydrophila and Streptococcus agalactiae. The in vivo bacterial challenge results demonstrated that the synthetic AN-hepc peptide significantly improved the survival rate of S. agalactiae- and V. vulnificus-infected zebrafish. Taken together, these data indicate an important role for AN-hepc in the innate immunity of A. nigrofasciata and suggest its potential application in aquaculture for increasing resistance to disease. PMID- 25280728 TI - Confirmatory Factor Analysis of the System for Evaluation of Teaching Qualities (SETQ) in Graduate Medical Training. AB - The System for Evaluation of Teaching Qualities (SETQ) was developed as a formative system for the continuous evaluation and development of physicians' teaching performance in graduate medical training. It has been seven years since the introduction and initial exploratory psychometric analysis of the SETQ questionnaires. This study investigates the validity and reliability of the SETQ questionnaires across hospitals and medical specialties using confirmatory factor analyses (CFAs), reliability analysis, and generalizability analysis. The SETQ questionnaires were tested in a sample of 3,025 physicians and 2,848 trainees in 46 hospitals. The CFA revealed acceptable fit of the data to the previously identified five-factor model. The high internal consistency estimates suggest satisfactory reliability of the subscales. These results provide robust evidence for the validity and reliability of the SETQ questionnaires for evaluating physicians' teaching performance. PMID- 25280729 TI - A suicidal zinc finger nuclease expression coupled with a surrogate reporter for efficient genome engineering. AB - Genome editing with engineered nucleases, such as zinc-finger nucleases (ZFNs) and TALE nucleases, remains confronted with a high risk of cellular toxicity induced by off-targeting. Here we describe the construction of a suicidal nuclease expression vector in which a pair of ZFNs genes were flanked of its target sites. To further enrich the targeted cells, the suicidal ZFN expression cassette was also inserted within an eGFP reporter, to disrupt the ORF of eGFP gene. ZFN-associated toxicity was reduced by ~40 % with this new system, and the activities of ZFNs were ~4.5 % lower. We conclude that using this new suicidal ZFN expression and surrogate reporter system represents an improvement for genomic editing by reducing toxicity and allowing easy detection of edited cells by eGFP analysis. PMID- 25280730 TI - Identification of functional cis-elements required for repression of the Taka amylase A gene under secretion stress in Aspergillus oryzae. AB - The expression of secreted proteins in filamentous fungi is down-regulated by a transcriptional feedback mechanism under endoplasmic reticulum stress, termed repression under secretion stress (RESS). To investigate the RESS mechanism, we analyzed the expression of the Taka-amylase A gene (amyB) in Aspergillus oryzae, which was depressed under secreted protein stress. We conducted a truncation and deletion analysis of the amyB promoter to identify cis-elements required for RESS. A nucleotide sequence (positions -378 to -291) without any binding sites for the transcriptional activator AmyR, which is involved in amylolytic gene expression, was required for RESS. The octamer sequence TCACGGGC (positions -307 to -300) constituted the core sequence of the upstream activating element essential for amyB down-regulation under secretion stress. Both the inactivation of AmyR and RESS contributed to the down-regulation of amyB expression under ER stress. PMID- 25280731 TI - Comparison of chloromethyl-dialkylcarbocyanine and green fluorescent protein for labeling human umbilical mesenchymal stem cells. AB - To investigate the effectiveness of chloromethyl-dialkylcarbocyanine (CM-Dil) and green florescent protein (GFP) for tracking transplanted stem human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), hUC-MSCs were labeled with CM-Dil or GFP and transplanted into guinea pigs with nasal mucosa radiation injury. In vitro and in vivo labeling efficiency was investigated by flow cytometry and fluorescence microscopy. Proliferation and multi-lineage differentiation potential of labeled hUC-MSCs were assessed via cell quantification and specific staining. In vitro CM-Dil and GFP labeling efficiency was 95 +/- 12.2 and 90 +/- 8 % at first passage, respectively. Labeled hUC-MSCs were detected by fluorescence microscopy 10 days (CM-Dil) or 20 days (GFP) after transplantation. Neither type of cell labeling affected the multi-differentiation potential but GFP labeling inhibited hUC-MSC proliferation due to virus toxicity. hUC-MSCs can be labeled with either CM-Dil or GFP with high efficiency without impacting multi differentiation potential. PMID- 25280732 TI - Bio-electrospraying is a safe technology for delivering human adipose-derived stem cells. AB - Bio-electrospraying (BES) is a technique for directly jetting living cells that has significant implications for tissue engineering and regenerative medicine. However, the effect of BES on human adipose-derived stem cells (hASCs) remains unknown. Here, we show that an hASC suspension was successfully electrosprayed via a continuous, stable and linearly directed electrospray at 10 kV and at 3 ml/h. Morphological observations and Trypan Blue and CCK-8 assays revealed that the cells remained viable and proliferated at a rate similar to that of the controls (0 kV). However, at 20 kV, BES became unstable and cell viability was reduced. Moreover, hASCs electrosprayed at 10 kV retained their multilineage potential, successfully differentiating into chondrogenic, osteogenic and neurogenic lineages. Thus, BES does not significantly affect cell morphology, viability or multipotency. PMID- 25280734 TI - Training and deployment of lay refugee/internally displaced persons to provide basic health services in camps: a systematic review. AB - BACKGROUND: Training of lay refugees/internally displaced persons (IDPs) and deploying them to provide basic health services to other women, children, and families in camps is perceived to be associated with public health benefits. However, there is limited evidence to support this hypothesis. OBJECTIVES: To assess the effects of interventions to train and deploy lay refugees and/or IDPs for the provision of basic health service to other women, children, and families in camps. METHODS: PubMed, Science and Social Science Citation Indices, PsycINFO, EMBASE, POPLINE, CINAHL, and reference lists of relevant articles were searched (from inception to June 30, 2014) with the aim of identifying studies that reported the effects of interventions that trained and deployed lay refugees and/or IDPs for the provision of basic health service to other women, children, and families in camps. Two investigators independently reviewed all titles and abstracts to identify potentially relevant articles. Discrepancies were resolved by repeated review, discussion, and consensus. Study quality assessment was undertaken using standard protocols. RESULTS: Ten studies (five cross-sectional, four pre-post, and one post-test only) conducted in Africa (Guinea and Tanzania), Central America (Belize), and Asia (Myanmar) were included. The studies demonstrated some positive impact on population health associated with training and deployment of trained lay refugees/IDPs as health workers in camps. Reported effects included increased service coverage, increased knowledge about disease symptoms and prevention, increased adoption of improved treatment seeking and protective behaviors, increased uptake of services, and improved access to reproductive health information. One study, which assessed the effect of peer refugee health education on sexual and reproductive health, did not demonstrate a marked reduction in unintended pregnancies among refugee/IDP women. CONCLUSION: Although available evidence suggests a positive impact of training and deployment of lay refugees/IDPs as health workers in camps, existing body of evidence is weak, and calls for a re-examination of current practices. Interventions that promote training and deployment of lay refugees/IDPs as health workers in camps should include strong evaluation components in order to facilitate assessment of effects on population health. PMID- 25280733 TI - A matter of emphasis: Linguistic stress habits modulate serial recall. AB - Models of short-term memory for sequential information rely on item-level, feature-based descriptions to account for errors in serial recall. Transposition errors within alternating similar/dissimilar letter sequences derive from interactions between overlapping features. However, in two experiments, we demonstrated that the characteristics of the sequence are what determine the fates of items, rather than the properties ascribed to the items themselves. Performance in alternating sequences is determined by the way that the sequences themselves induce particular prosodic rehearsal patterns, and not by the nature of the items per se. In a serial recall task, the shapes of the canonical "saw tooth" serial position curves and transposition error probabilities at successive input-output distances were modulated by subvocal rehearsal strategies, despite all item-based parameters being held constant. We replicated this finding using nonalternating lists, thus demonstrating that transpositions are substantially influenced by prosodic features-such as stress-that emerge during subvocal rehearsal. PMID- 25280735 TI - Impact of HIV on and the constructions of masculinities among HIV-positive men in South Africa: implications for secondary prevention programs. AB - BACKGROUND: To date, whilst there have been many published studies exploring the links between masculinity and HIV, not much work has been done to explore how an HIV-positive diagnosis impacts men's sense of masculinity and contextualizing the masculinities as fluid and changing. OBJECTIVE: To explore how human immunodeficiency virus (HIV) impacts the lives of men and their constructions of masculinity through interviews with 18 men living with HIV. DESIGN: Qualitative study involving conveniently and purposively selected black South African adult men who lived with HIV. In-depth interviews were conducted with 18 men who resided in Johannesburg and Mthatha, South Africa. RESULTS: Our analysis suggests that the performance of risky masculinity may influence the acquisition of HIV. Yet, it also reveals that HIV can have a significant effect on men and their masculinities. Men's constructions of harmful notions of hegemonic masculinity pre-HIV diagnosis negatively affected their help-seeking behavior and coping and adjustment to living with HIV, post-diagnosis. The dominant discourse that men are strong and healthy visibly presented challenges for men when faced with an HIV-positive status. They interpreted HIV diagnosis as a loss, a sign of failure as a man, and evidence of an inability to retain control. Being sick undermined their ability to perform roles expected of them, and this led to feelings of powerlessness, worthlessness, and distress. CONCLUSIONS: Interventions with men living with HIV need to provide safe spaces for men to critically explore gender and constructions of social identities and the pressures these place on men and implications for their health. With this approach, harmful constructions of masculinities may be challenged and mitigated, and this process may render men amenable to change. PMID- 25280736 TI - Understanding reasons for treatment interruption amongst patients on antiretroviral therapy--a qualitative study at the Lighthouse Clinic, Lilongwe, Malawi. AB - BACKGROUND: In recent years, scaling up of antiretroviral therapy (ART) in resource-limited settings moved impressively towards universal access. Along with these achievements, public health HIV programs are facing a number of challenges including the support of patients on lifelong therapy and the prevention of temporary/permanent loss of patients in care. Understanding reasons for treatment interruption (TI) can inform strategies for improving drug adherence and retention in care. OBJECTIVE: To evaluate key characteristics of patients resuming ART after TI at the Lighthouse Clinic in Lilongwe, Malawi, and to identify their reasons for interrupting ART. DESIGN: This study uses a mixed methods design to evaluate patients resuming ART after TI. We analysed an assessment form for patients with TI using pre-defined categories and a comments field to identify frequently stated reasons for TI. Additionally, we conducted 26 in-depth interviews to deepen our understanding of common reasons for TI. In depth interviews also included the patients' knowledge about ART and presence of social support systems. Qualitative data analysis was based on a thematic framework approach. RESULTS: A total of 347 patients (58.2% female, average age 35.1+/-11.3 years) with TI were identified. Despite the presence of social support and sufficient knowledge of possible consequences of TI, all patients experienced situations that resulted in TI. Analysis of in-depth interviews led to new and distinct categories for TI. The most common reason for TI was travel (54.5%, n=80/147), which further differentiated into work- or family-related travel. Patients also stated transport costs and health-care-provider-related reasons, which included perceived/enacted discrimination by health care workers. Other drivers of TI were treatment fatigue/forgetfulness, the patients' health status, adverse drug effects, pregnancy/delivery, religious belief or perceived/enacted stigma. CONCLUSIONS: To adequately address patients' needs on a lifelong therapy, adherence-counselling sessions require provision of problem solving strategies for common barriers to continuous care. PMID- 25280737 TI - Human resources for health: task shifting to promote basic health service delivery among internally displaced people in ethnic health program service areas in eastern Burma/Myanmar. AB - BACKGROUND: Burma/Myanmar was controlled by a military regime for over 50 years. Many basic social and protection services have been neglected, specifically in the ethnic areas. Development in these areas was led by the ethnic non-state actors to ensure care and the availability of health services for the communities living in the border ethnic-controlled areas. Political changes in Burma/Myanmar have been ongoing since the end of 2010. Given the ethnic diversity of Burma/Myanmar, many challenges in ensuring health service coverage among all ethnic groups lie ahead. METHODS: A case study method was used to document how existing human resources for health (HRH) reach the vulnerable population in the ethnic health organizations' (EHOs) and community-based organizations' (CBHOs) service areas, and their related information on training and services delivered. Mixed methods were used. Survey data on HRH, service provision, and training were collected from clinic-in-charges in 110 clinics in 14 Karen/Kayin townships through a rapid-mapping exercise. We also reviewed 7 organizational and policy documents and conducted 10 interviews and discussions with clinic-in-charges. FINDINGS: Despite the lack of skilled medical professionals, the EHOs and CBHOs have been serving the population along the border through task shifting to less specialized health workers. Clinics and mobile teams work in partnership, focusing on primary care with some aspects of secondary care. The rapid-mapping exercise showed that the aggregate HRH density in Karen/Kayin state is 2.8 per 1,000 population. Every mobile team has 1.8 health workers per 1,000 population, whereas each clinic has between 2.5 and 3.9 health workers per 1,000 population. By reorganizing and training the workforce with a rigorous and up-to-date curriculum, EHOs and CBHOs present a viable solution for improving health service coverage to the underserved population. CONCLUSION: Despite the chronic conflict in Burma/Myanmar, this report provides evidence of the substantive system of health care provision and access in the Karen/Kayin State over the past 20 years. It underscores the climate of vulnerability of the EHOs and CBHOs due to lack of regional and international understanding of the political complexities in Burma/Myanmar. As Association of Southeast Asian Nations (ASEAN) integration gathers pace, this case study highlights potential issues relating to migration and health access. The case also documents the challenge of integrating indigenous and/or cross-border health systems, with the ongoing risk of deepening ethnic conflicts in Burma/Myanmar as the peace process is negotiated. PMID- 25280738 TI - Moving data off the shelf and into action: an intervention to improve data informed decision making in Cote d'Ivoire. AB - BACKGROUND: Improving a health system requires data, but too often they are unused or under-used by decision makers. Without interventions to improve the use of data in decision making, health systems cannot meet the needs of the populations they serve. In 2008, in Cote d'Ivoire, data were largely unused in health decision-making processes. OBJECTIVE: To implement and evaluate an intervention to improve the use of data in decision making in Cote d'Ivoire. DESIGN: From 2008 to 2012, Cote d'Ivoire sought to improve the use of national health data through an intervention that broadens participation in and builds links between data collection and decision-making processes; identifies information needs; improves data quality; builds capacity to analyze, synthesize, and interpret data; and develops policies to support data use. To assess the results, a Performance of Routine Information System Management Assessment was conducted before and after the intervention using a combination of purposeful and random sampling. In 2008, the sample consisted of the central level, 12 districts, and 119 facilities, and in 2012, the sample consisted of the central level, 20 districts, and 190 health facilities. To assess data use, we developed dichotomous indicators: discussions of analysis findings, decisions taken based on the analysis, and decisions referred to upper management for action. We aggregated the indicators to generate a composite, continuous index of data use. RESULTS: From 2008 to 2012, the district data-use score increased from 40 to 70%; the facility score remained the same - 38%. The central score is not reported, because of a methodological difference in the two assessments. CONCLUSIONS: The intervention improved the use of data in decision making at the district level in Cote d'Ivoire. This study provides an example of, and guidance for, implementing a large-scale intervention to improve data-informed decision making. PMID- 25280739 TI - Sharing perspectives and experiences of doctoral fellows in the first cohort of Consortium for Advanced Research Training in Africa: 2011-2014. AB - BACKGROUND: Resolution of public health problems in Africa remains a challenge because of insufficient skilled human resource capacity. The Consortium for Advanced Research Training in Africa (CARTA) was established to enhance capacity in multi-disciplinary health research that will make a positive impact on population health in Africa. OBJECTIVE: The first cohort of the CARTA program describes their perspectives and experiences during the 4 years of fellowship and puts forward suggestions for future progress and direction of research in Africa. CONCLUSIONS: The model of training as shown by the CARTA program is an effective model of research capacity building in African academic institutions. An expansion of the program is therefore warranted to reach out to more African academics in search of advanced research training. PMID- 25280740 TI - Global mental health: perspectives from Ethiopia. AB - BACKGROUND: Global mental health (GMH) advocates for access to and the equitable provision of mental health care. Although the treatment gap is a useful construct to measure access and equitability of care, it fails to communicate the real-life consequences of the treatment gap and the urgent need to address care disparities. OBJECTIVE: The aim of this article is to present a perspective on the practical application of the principles of GMH to understand the real-life impact of the treatment gap and the approaches taken to improve treatment coverage in Ethiopia. DESIGN: A case study method is used. RESULTS: Multiple international collaborations undertaken in Ethiopia and facilitated by GMH to improve care, capacity, and the evidence base for increased treatment coverage are described briefly. A series of steps taken at the local and national levels to address the treatment gap are highlighted. The stories of two patients are also presented to illustrate the real-life consequences of the treatment gap and the potential transformational impact of addressing the treatment gap on patients, families, and communities. CONCLUSIONS: GMH has a key role to play in addressing the treatment gap, which improves the life of people with mental disorders, their families, and their communities. However, national-level policy support and coordination are essential for any realistic improvement in treatment coverage. The reflections offered through the case examples may have utility in similar low-income settings. PMID- 25280741 TI - Factors associated with mortality in HIV-infected people in rural and urban South Africa. AB - BACKGROUND: Factors associated with mortality in HIV-infected people in sub Saharan Africa are widely reported. However rural-urban disparities and their association with all-cause mortality remain unclear. Furthermore, commonly used classical Cox regression ignores unmeasured variables and frailty. OBJECTIVE: To incorporate frailty in assessing factors associated with mortality in HIV infected people in rural and urban South Africa. DESIGN: Using data from a prospective cohort following 6,690 HIV-infected participants from Soweto (urban) and Mpumalanga (rural) enrolled from 2003 to 2010; covariates of mortality were assessed by the integrated nested Laplace approximation method. RESULTS: We enrolled 2,221 (33%) rural and 4,469 (67%) urban participants of whom 1,555 (70%) and 3,480 (78%) were females respectively. Median age (IQR) was 36.4 (31.0-44.1) in rural and 32.7 (28.2-38.1) in the urban participants. The mortality rate per 100 person-years was 11 (9.7-12.5) and 4 (3.6-4.5) in the rural and urban participants, respectively. Compared to those not on HAART, rural participants had a reduced risk of mortality if on HAART for 6-12 (HR: 0.20, 95% CI: 0.10 0.39) and >12 months (HR: 0.10, 95% CI: 0.05-0.18). Relative to those not on HAART, urban participants had a lower risk if on HAART >12 months (HR: 0.35, 95% CI: 0.27-0.46). The frailty variance was significant and >1 in rural participants indicating more heterogeneity. Similarly it was significant but <1 in the urban participants indicating less heterogeneity. CONCLUSION: The frailty model findings suggest an elevated risk of mortality in rural participants relative to the urban participants potentially due to unmeasured variables that could be biological, socio-economic, or healthcare related. Use of robust methods that optimise data and account for unmeasured variables could be helpful in assessing the effect of unknown risk factors thus improving patient management and care in South Africa and elsewhere. PMID- 25280743 TI - Chemostat cultivation and transcriptional analyses of Clostridium acetobutylicum mutants with defects in the acid and acetone biosynthetic pathways. AB - Clostridium acetobutylicum is a model organism for the biotechnologically important acetone-butanol-ethanol (ABE) fermentation. With the objective to rationally develop strains with improved butanol production, detailed insights into the physiological and genetic mechanisms of solvent production are required. Therefore, pH-controlled phosphate-limited chemostat cultivation and DNA microarray technology were employed for an in-depth analysis of knockout mutants with defects in the central fermentative metabolism. The set of studied mutants included strains with inactivated phosphotransacetylase (pta), phosphotransbutyrylase (ptb), and acetoacetate decarboxylase (adc) encoding genes, as well as an adc/pta double knockout mutant. A comprehensive physiological characterization of the mutants was performed by continuous cultivation, allowing for a well-defined separation of acidogenic and solventogenic growth, combined with the advantage of the high reproducibility of steady-state conditions. The ptb-negative strain C. acetobutylicum ptb::int(87) exhibited the most striking metabolite profile: Sizable amounts of butanol (29 +/ 1.3 mM) were already produced during acidogenic growth. The product patterns of the mutants as well as accompanying transcriptomic data are presented and discussed. PMID- 25280742 TI - Evidence summaries (decision boxes) to prepare clinicians for shared decision making with patients: a mixed methods implementation study. AB - BACKGROUND: Decision boxes (Dboxes) provide clinicians with research evidence about management options for medical questions that have no single best answer. Dboxes fulfil a need for rapid clinical training tools to prepare clinicians for clinician-patient communication and shared decision-making. We studied the barriers and facilitators to using the Dbox information in clinical practice. METHODS: We used a mixed methods study with sequential explanatory design. We recruited family physicians, residents, and nurses from six primary health-care clinics. Participants received eight Dboxes covering various questions by email (one per week). For each Dbox, they completed a web questionnaire to rate clinical relevance and cognitive impact and to assess the determinants of their intention to use what they learned from the Dbox to explain to their patients the advantages and disadvantages of the options, based on the theory of planned behaviour (TPB). Following the 8-week delivery period, we conducted focus groups with clinicians and interviews with clinic administrators to explore contextual factors influencing the use of the Dbox information. RESULTS: One hundred clinicians completed the web surveys. In 54% of the 496 questionnaires completed, they reported that their practice would be improved after having read the Dboxes, and in 40%, they stated that they would use this information for their patients. Of those who would use the information for their patients, 89% expected it would benefit their patients, especially in that it would allow the patient to make a decision more in keeping with his/her personal circumstances, values, and preferences. They intended to use the Dboxes in practice (mean 5.6+/-1.2, scale 1 7, with 7 being "high"), and their intention was significantly related to social norm, perceived behavioural control, and attitude according to the TPB (P<0.0001). In focus groups, clinicians mentioned that co-interventions such as patient decision aids and training in shared decision-making would facilitate the use of the Dbox information. Some participants would have liked a clear "bottom line" statement for each Dbox and access to printed Dboxes in consultation rooms. CONCLUSIONS: Dboxes are valued by clinicians. Tailoring of Dboxes to their needs would facilitate their implementation in practice. PMID- 25280744 TI - L-Arabinose isomerase and its use for biotechnological production of rare sugars. AB - L-Arabinose isomerase (AI), a key enzyme in the microbial pentose phosphate pathway, has been regarded as an important biological catalyst in rare sugar production. This enzyme could isomerize L-arabinose into L-ribulose, as well as D galactose into D-tagatose. Both the two monosaccharides show excellent commercial values in food and pharmaceutical industries. With the identification of novel AI family members, some of them have exhibited remarkable potential in industrial applications. The biological production processes for D-tagatose and L-ribose (or L-ribulose) using AI have been developed and improved in recent years. Meanwhile, protein engineering techniques involving rational design has effectively enhanced the catalytic properties of various AIs. Moreover, the crystal structure of AI has been disclosed, which sheds light on the understanding of AI structure and catalytic mechanism at molecular levels. This article reports recent developments in (i) novel AI screening, (ii) AI-mediated rare sugar production processes, (iii) molecular modification of AI, and (iv) structural biology study of AI. Based on previous reports, an analysis of the future development has also been initiated. PMID- 25280745 TI - Metabolic engineering of Saccharomyces cerevisiae for the production of isobutanol and 3-methyl-1-butanol. AB - Saccharomyces cerevisiae naturally produces small amounts of isobutanol and 3 methyl-1-butanol via Ehrlich pathway from the catabolism of valine and leucine, respectively. In this study, we engineered CEN.PK2-1C, a leucine auxotrophic strain having a LEU2 gene mutation, for the production of isobutanol and 3-methyl 1-butanol. First, ALD6 encoding aldehyde dehydrogenase and BAT1 involved in valine synthesis were deleted to eliminate competing pathways. We also increased transcription of endogenous genes in the valine and leucine biosynthetic pathways by expressing Leu3Delta601, a constitutively active form of Leu3 transcriptional activator. For the production of isobutanol, genes involved in isobutanol production (ILV2, ILV3, ILV5, ARO10, and ADH2) were additionally overexpressed in ald6Deltabat1Delta strain expressing LEU3Delta601, resulting in 376.9 mg/L isobutanol production from 100 g/L glucose. To increase 3-methyl-1-butanol production, leucine biosynthetic genes were additionally overexpressed in the final isobutanol-production strain. The resulting strain overexpressing LEU2 and LEU4 (D578Y) , a feedback inhibition-insensitive mutant of LEU4, showed a 34-fold increase in 3-methyl-1-butanol synthesis compared with CEN.PK2-1C control strain, producing 765.7 mg/L 3-methyl-1-butanol. PMID- 25280746 TI - Influence of manufacturing processes on cell surface properties of probiotic strain Lactobacillus rhamnosus Lcr35(r). AB - The influence of the industrial process on the properties of probiotics, administered as complex manufactured products, has been poorly investigated. In the present study, we comparatively assessed the cell wall characteristics of the probiotic strain Lactobacillus rhamnosus Lcr35(r) together with three of its commercial formulations with intestinal applications. Putative secreted and transmembrane-protein-encoding genes were initially searched in silico in the genome of L. rhamnosus Lcr35(r). A total of 369 candidate genes were identified which expressions were followed using a custom Lactobacillus DNA chip. Among them, 60 or 67 genes had their expression either upregulated or downregulated in the Lcr Restituo(r) packet or capsule formulations, compared to the native Lcr35(r) strain. Moreover, our data showed that the probiotic formulations (Lcr Lenio(r), Lcr restituo(r) capsule and packet) showed a better capacity to adhere to intestinal epithelial Caco-2 cells than the native Lcr35(r) strain. Microbial (MATS) tests showed that the probiotic was an electron donor and that they were more hydrophilic than the native strain. The enhanced adhesion capacity of the active pharmaceutical ingredients (APIs) to epithelial Caco-2 cells and their antipathogen effect could be due to this greater surface hydrophilic character. These findings suggest that the manufacturing process influences the protein composition and the chemical properties of the cell wall. It is therefore likely that the antipathogen effect of the formulation is modulated by the industrial process. Screening of the manufactured products' properties would therefore represent an essential step in evaluating the effects of probiotic strains. PMID- 25280747 TI - Elderly patients at higher risk of laryngeal carcinoma recurrence could be identified by a panel of two biomarkers (nm23-H1 and CD105) and pN+ status. AB - Laryngeal squamous cell carcinoma (LSCC) recurrences are very difficult to manage in elderly patients (age >=65 years), because treatment carries significant morbidity and mortality. The aim of this study was to develop a panel of parameters (clinicopathological variables or biomarkers) to improve our ability to detect elderly patients at higher risk of LSCC recurrence. Maspin, nm23-H1, and CD105 were investigated using immunohistochemistry on surgical specimens from 46 elderly patients treated for LSCC. After univariate analysis identified parameters associated with LSCC recurrence, a multivariate prognostic model was constructed. At univariate analysis, a higher recurrence rate was significantly associated with nm23-H1 nuclear expression in carcinoma cells <=2.0% (p = 0.01), CD105 expression in intratumoral vascular endothelial cells >=5.28% (p = 0.04), and pN+ status (p = 0.04). Multivariate modeling confirmed that nuclear nm23-H1 <=2.0% (p = 0.009) and CD105 >=5.28% (p = 0.013) had a negative prognostic significance in terms of disease recurrence, while pN+ status showed a trend toward significance (p = 0.05). We thus obtained a panel comprising two biomarkers and neck lymph node status that revealed an excellent discriminatory power [AUC (ROC) of 0.81] in terms of the risk of LSCC recurrence. The panel achieved a specificity of 96% and a positive predictive value of 93%. We identified a panel with an excellent discriminatory power in identifying elderly patients at higher risk of recurrence after treatment for LSCC. These patients would benefit from a more aggressive primary treatment. PMID- 25280748 TI - Stroke, multimorbidity and polypharmacy in a nationally representative sample of 1,424,378 patients in Scotland: implications for treatment burden. AB - BACKGROUND: The prevalence of multimorbidity (the presence of two or more long term conditions) is rising internationally. Multimorbidity affects patients by increasing their burden of symptoms, but is also likely to increase the self-care demands, or treatment burden, that they experience. Treatment burden refers to the effort expended in operationalising treatments, navigating healthcare systems and managing relations with healthcare providers. This is an important problem for people with chronic illness such as stroke. Polypharmacy is an important marker of both multimorbidity and burden of treatment. In this study, we examined the prevalence of multimorbidity and polypharmacy in a large, nationally representative population of primary care patients with and without stroke, adjusting for age, sex and deprivation. METHODS: A cross-sectional study of 1,424,378 participants aged 18 years and over, from 314 primary care practices in Scotland that were known to be demographically representative of the Scottish adult population. Data included information on the presence of stroke and another 39 long-term conditions, plus prescriptions for regular medications. RESULTS: In total, 35,690 people (2.5%) had a diagnosis of stroke. Of the 39 comorbidities examined, 35 were significantly more common in people with stroke. Of the people with a stroke, the proportion that had one or more additional morbidities present (94.2%) was almost twice that in the control group (48%) (odds ratio (OR) adjusted for age, sex and socioeconomic deprivation 5.18; 95% confidence interval (CI) 4.95 to 5.43). In the stroke group, 12.6% had a record of 11 or more repeat prescriptions compared with only 1.5% of the control group (OR adjusted for age, sex, deprivation and morbidity count 15.84; 95% CI 14.86 to 16.88). Limitations include the use of data collected for clinical rather than research purposes, a lack of consensus in the literature on the definition of certain long-term conditions, and the absence of statistical weighting in the measurement of multimorbidity, although the latter was deemed suitable for descriptive analyses. CONCLUSIONS: Multimorbidity and polypharmacy were strikingly more common in those with a diagnosis of stroke compared with those without. This has important implications for clinical guidelines and the design of health services. PMID- 25280749 TI - Serum sclerostin in high-activity adult patients with juvenile idiopathic arthritis. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a disease associated with loss of bone mass, deterioration in bone mass quality and an increased risk of fractures. The objective of this study was to evaluate factors that predict bone mineral density (BMD) alterations in young adult patients with active JIA before and during therapy with tumour necrosis factor alpha (TNFalpha) inhibitors. METHODS: Thirty-one patients (twelve males and nineteen females; mean age =25.1 +/- 6.1 years) with active JIA (mean Disease Activity Score in 28 joints (DAS28) =6.36 +/- 0.64; mean high-sensitivity C-reactive protein (hsCRP) =18.36 +/- 16.95 mg/L) were investigated. The control group consisted of 84 healthy individuals matched by sex and age. BMD, bone turnover markers and serum concentrations of soluble receptor activator of nuclear factor kappaB ligand, osteoprotegerin, dickkopf Wnt signalling pathway inhibitor 1 (Dkk1) and sclerostin were evaluated. RESULTS: Baseline BMD values in the lumbar spine, proximal femur, femoral neck and distal radius were significantly lower in patients with JIA compared to healthy control participants. Baseline sclerostin serum concentrations were significantly higher in patients with JIA compared to control participants. After 2 years of treatment with TNFalpha inhibitors, BMD was significantly increased in the lumbar spine. This increase correlated with a drop in DAS28 score. A statistically significant correlation between hsCRP and Dkk1 was found at baseline, as well as during the 2-year follow-up period. A significant reduction in serum sclerostin after 1 year of therapy was predictive of a drop in DAS28 score observed with a 1-year delay after reduction of serum sclerostin. CONCLUSION: A significant correlation between the sclerostin serum concentration and the number of tender and swollen joints, but not BMD, supports the hypothesis that chondrocytes and cells of the subchondral bone may contribute to circulating sclerostin in JIA. PMID- 25280750 TI - Clinical interpretation of CNVs with cross-species phenotype data. AB - BACKGROUND: Clinical evaluation of CNVs identified via techniques such as array comparative genome hybridisation (aCGH) involves the inspection of lists of known and unknown duplications and deletions with the goal of distinguishing pathogenic from benign CNVs. A key step in this process is the comparison of the individual's phenotypic abnormalities with those associated with Mendelian disorders of the genes affected by the CNV. However, because often there is not much known about these human genes, an additional source of data that could be used is model organism phenotype data. Currently, almost 6000 genes in mouse and zebrafish are, when knocked out, associated with a phenotype in the model organism, but no disease is known to be caused by mutations in the human ortholog. Yet, searching model organism databases and comparing model organism phenotypes with patient phenotypes for identifying novel disease genes and medical evaluation of CNVs is hindered by the difficulty in integrating phenotype information across species and the lack of appropriate software tools. METHODS: Here, we present an integrated ranking scheme based on phenotypic matching, degree of overlap with known benign or pathogenic CNVs and the haploinsufficiency score for the prioritisation of CNVs responsible for a patient's clinical findings. RESULTS: We show that this scheme leads to significant improvements compared with rankings that do not exploit phenotypic information. We provide a software tool called PhenogramViz, which supports phenotype-driven interpretation of aCGH findings based on multiple data sources, including the integrated cross species phenotype ontology Uberpheno, in order to visualise gene-to-phenotype relations. CONCLUSIONS: Integrating and visualising cross-species phenotype information on the affected genes may help in routine diagnostics of CNVs. PMID- 25280751 TI - Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC). AB - BACKGROUND AND AIMS: Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. METHODS: Tumour DNA was extracted (formalin fixed, paraffin embedded, FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. FINDINGSS: Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2% to 98.4%), specificity 87.7% (95% CI 77.9% to 94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7% to 76.5%), specificity 98.6% (95% CI 92.4% to 100.0%) for the identification of those with pathogenic MLH1 mutations. CONCLUSIONS: Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours. PMID- 25280752 TI - Comparison of genes required for H2O2 resistance in Streptococcus gordonii and Streptococcus sanguinis. AB - Hydrogen peroxide (H2O2) is produced by several members of the genus Streptococcus mainly through the pyruvate oxidase SpxB under aerobic growth conditions. The acute toxic nature of H2O2 raises the interesting question of how streptococci cope with intrinsically produced H2O2, which subsequently accumulates in the microenvironment and threatens the closely surrounding population. Here, we investigate the H2O2 susceptibility of oral Streptococcus gordonii and Streptococcus sanguinis and elucidate potential mechanisms of how they protect themselves from the deleterious effect of H2O2. Both organisms are considered primary colonizers and occupy the same intraoral niche making them potential targets for H2O2 produced by other species. We demonstrate that S. gordonii produces relatively more H2O2 and has a greater ability for resistance to H2O2 stress. Functional studies show that, unlike in Streptococcus pneumoniae, H2O2 resistance is not dependent on a functional SpxB and confirms the important role of the ferritin-like DNA-binding protein Dps. However, the observed increased H2O2 resistance of S. gordonii over S. sanguinis is likely to be caused by an oxidative stress protection machinery present even under anaerobic conditions, while S. sanguinis requires a longer period of time for adaptation. The ability to produce more H2O2 and be more resistant to H2O2 might aid S. gordonii in the competitive oral biofilm environment, since it is lower in abundance yet manages to survive quite efficiently in the oral biofilm. PMID- 25280753 TI - Coordinated response of phospholipids and acyl components of membrane lipids in Pseudomonas putida A (ATCC 12633) under stress caused by cationic surfactants. AB - The present study assessed the role of membrane components of Pseudomonas putida A (ATCC 12633) under chemical stress conditions originated by treatment with tetradecyltrimethylammonium bromide (TTAB), a cationic surfactant. We examined changes in fatty acid composition and in the fluidity of the membranes of cells exposed to TTAB at a specific point of growth as well as of cells growing with TTAB. The addition of 10-50 mg TTAB l(-1) promoted an increase in the saturated/unsaturated fatty acid ratio. By using fluorescence polarization techniques, we found that TTAB exerted a fluidizing effect on P. putida A (ATCC 12633) membranes. However, a complete reversal of induced membrane fluidification was detected after 15 min of incubation with TTAB. Consistently, the proportion of unsaturated fatty acids was lower in TTAB-treated cells as compared with non treated cells. In the presence of TTAB, the content of phosphatidylglycerol increased (120 %), whilst that of cardiolipin decreased (60 %). Analysis of the fatty acid composition of P. putida A (ATCC 12633) showed that phosphatidylglycerol carried the major proportion of saturated fatty acids (89 %), whilst cardiolipin carried an elevated proportion of unsaturated fatty acids (18 %). The increase in phosphatidylglycerol and consequently in saturated fatty acids, together with a decrease in cardiolipin content, enabled greater membrane resistance, reversing the fluidizing effect of TTAB. Therefore, results obtained in the present study point to changes in the fatty acid profile as an adaptive response of P. putida A (ATCC 12633) cells to stress caused by a cationic surfactant. PMID- 25280754 TI - Utility of qualitative C- reactive protein assay and white blood cells counts in the diagnosis of neonatal septicaemia at Bugando Medical Centre, Tanzania. AB - BACKGROUND: Neonatal septicaemia diagnosis based on clinical features alone is non-specific leading to the initiation of unnecessary antibiotic treatment posing a danger of increased antibiotic resistance. In the present study the utility of serial qualitative C-reactive protein (CRP) assay and white blood cells count (WBC) in the diagnosis of neonatal septicaemia was investigated using blood culture as gold standard. METHODS: A total of 305 neonates admitted at Bugando Medical Centre (BMC) neonatal units between September 2013 and April 2014 were enrolled. Demographic and clinical data were collected using standardized data collection tool. Blood specimens were collected for blood culture, WBC count and qualitative CRP assay. RESULTS: Of 305 neonates; 224 (73.4%) were <= 72 hrs of age and 91(29.8%) had low birth weight. The positive CRP assay was observed in 67 (22.0%), 80 (26.2%) and 88 (28.9%) of neonates on day 1, 2 and 3 respectively; with any CRP positive occurred in 104 (34.1%) of neonates. The sensitivities of CRP assay in the diagnosis of septicaemia using culture as gold standard on day 1, 2, 3 and any positive were 40.4%, 53.2%, 54.8% and 62.9% respectively. While specificities were 82.7%, 80.7%, 77.8% and 73.3% respectively. Higher sensitivity of 75% was observed when CRP was used to diagnose gram negative septicaemia compared to 50% that was observed in the diagnosis of gram positive septicaemia. WBC count of >=13 * 109 /L had sensitivity and specificity of 64.5% and 66.7% respectively with area under the curve of 0.694. When the any positive CRP and WBC of >=13 * 109 /L were used the sensitivity increased to 90.3% with specificity of 50%. Neonates with septicaemia due to gram negative bacteria were significantly found to have higher rates of positive CRP than neonates with gram positive septicaemia and with negative culture (p < 0.001, OR 8.2, 95 CI; 2.9 26). CONCLUSION: In place where blood culture is limited neonates having clinical features of neonatal sepsis with positive qualitative CRP assay and increased WBC should urgently be initiated on appropriate sepsis management in order to reduce morbidity and mortality associated with neonatal sepsis. PMID- 25280755 TI - Glucagon-Like Peptide 2 Improves Cholestasis in Parenteral Nutrition--Associated Liver Disease. AB - BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon-like peptide-2 (GLP-2) is being advanced as therapy, the effect of GLP-2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP-2 administration on hepatic function in a neonatal piglet model of PNALD. METHODS: Neonatal piglets (aged 2-6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP-2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age-matched sow-reared control piglets (group 3, n = 8) were used for comparison. RESULTS: Both groups 1 and 2 receiving PN developed cholestasis relative to sow-reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 uL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 umol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens. CONCLUSIONS: The exogenous administration of GLP 2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP-2 in improving PNALD in the setting of prolonged PN duration. PMID- 25280756 TI - Risk factors for early and delayed post-operative bleeding after endoscopic submucosal dissection of gastric neoplasms, including patients with continued use of antithrombotic agents. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has become widely accepted as a standard treatment for gastric epithelial neoplasms. Antithrombotic agents are widely used to prevent thromboembolic disease. However, the feasibility of endoscopic procedures for patients using such agents has been rarely investigated. The aim of this study was to identify risk factors for post operative bleeding after gastric ESD and to evaluate the relationship between the use of antithrombotic agents and post-operative bleeding. METHODS: From June 2005 to March 2014, 413 patients with 425 gastric neoplasms were treated by ESD. The demographic and clinical parameters associated with post-operative bleeding were investigated. 83 patients receiving antithrombotic agents were separately assessed using various methods of administration during the ESD procedure. Post operative bleeding that occurred within 5 days of ESD was defined as early post operative bleeding, whereas subsequent bleeding was defined as delayed bleeding. RESULTS: The overall post-operative bleeding rate was 4.7%. In patients with continued low-dose aspirin (LDA), heparin replacement (HR), or continued LDA along with HR, post-operative bleeding rates were 9.5%, 23.8%, and 25.0%, respectively. On multivariate analysis, a specimen size of >=40 mm was a risk factor for early post-operative bleeding [odds ratio (OR) 6.08, 95% CI: 1.74 21.27], and HR and chronic kidney disease (CKD) requiring hemodialysis were risk factors for delayed bleeding (OR 12.23, 95% CI: 2.63-56.77 and OR 28.35, 95% CI: 4.67-172.11, respectively). Continued LDA was not a risk factor for post operative bleeding. CONCLUSIONS: Large specimen size is a risk factor for early post-operative bleeding, and HR and CKD requiring hemodialysis are risk factors for delayed bleeding. Patients with risk factors should be carefully watched, allowing for the timing of post-operative bleeding after ESD. PMID- 25280758 TI - Triage challenges: recognizing intimate partner violence. PMID- 25280757 TI - Intestinal current measurement versus nasal potential difference measurements for diagnosis of cystic fibrosis: a case-control study. AB - BACKGROUND: Nasal potential difference (NPD) and intestinal current measurement (ICM) are functional CFTR tests that are used as adjunctive diagnostic tools for cystic fibrosis (CF). Smoking has a systemic negative impact on CFTR function. A diagnostic comparison between NPD and ICM and the impact of smoking on both CFTR tests has not been done. METHODS: The sweat chloride test, NPD, and ICM were performed in 18 patients with CF (sweat chloride >60 mmol/l), including 6 pancreatic sufficient (PS) patients, and 13 healthy controls, including 8 smokers. The NPD CFTR response to Cl-free and isoproterenol perfusion (Delta0Cl- + Iso) was compared to the ICM CFTR response to forskolin/IBMX, carbachol, and histamine (DeltaIsc, forskolin/IBMX+ carbachol+histamine). RESULTS: The mean NPD CFTR response and ICM CFTR response between patients with CF and healthy controls was significantly different (p <0.001), but not between patients with CF who were PS and those who were pancreatic insufficient (PI). Smokers have a decreased CFTR response measured by NPD (p = 0.049). For ICM there is a trend towards decreased CFTR response (NS). Three healthy control smokers had NPD responses within the CF range. In contrast to NPD, there was no overlap of the ICM response between patients with CF and controls. CONCLUSIONS: ICM is superior to NPD in distinguishing between patients with CF who have a sweat chloride > 60 mmol/l and healthy controls, including smokers. Neither NPD nor ICM differentiated between patients with CF who were PS from those who were PI. Smoking has a negative impact on CFTR function in healthy controls measured by NPD and challenges the diagnostic interpretation of NPD, but not ICM. PMID- 25280759 TI - European Society of Biomechanics S.M. Perren Award 2014: Safety factor of the proximal femur during gait: a population-based finite element study. AB - It has been suggested that the mechanical competence of the proximal femur is preserved with respect to physiological loading conditions rather than accidental overloading, but the consequences of this adaptation for fracture risk in the elderly remain unclear. The goal of the present study was to analyse the safety factor of the human femur in the two most frequent daily activities, level walking and stair climbing, and to understand the dependence, if any, of this safety factor on age, volumetric bone mineral density (vBMD), and gender. To this aim, a finite element study was performed on 200 subjects (116 women and 84 men), spanning a large range of age (23-84 years) and vBMD levels (T-score from 0 to 3.59). For the first time, finite element models that included a subject-specific description of the anatomy and mineral density distribution of each bone were coupled with a personalisation of the loads acting on the proximal femur during movement, including the action of the muscles and their variability across the population. The results demonstrate that the human proximal femur is characterised by a high safety factor (on average five, never reaching fracture threshold), even in the presence of advanced age and low mineral content. These results corroborate the hypothesis that the relationship between loading and mechanical competence is generally preserved in the elderly population for the most frequent motor activities, walking and stair climbing. Interestingly, a decrease of the safety factor was observed with increasing lifespan and reduced mineral content in women but not in men. PMID- 25280760 TI - Use of efficacy probability maps for the post-operative programming of deep brain stimulation in essential tremor. AB - INTRODUCTION: Post-operative programming of deep brain stimulation for movement disorders can be both time consuming and difficult, which can delay the optimal symptom control for the patient. Probabilistic maps of stimulation response could improve programming efficiency and optimization. METHODS: The clinically selected contacts of patients who had undergone ventral intermediate nucleus deep brain stimulation for the treatment of essential tremor at our institution were compared against contacts selected based on a probability map of symptom reduction built by populating data from a number of patients using non-rigid image registration. A subgroup of patients whose clinical contacts did not match the map-based selections prospectively underwent a tremor rating scale evaluation to compare the symptom relief achieved by the two options. Both the patient and video reviewer were blinded to the selection. RESULTS: 54% of the map-based and clinical contacts were an exact match retrospectively and were within one contact 83% of the time. In 5 of the 8 mismatched leads that were evaluated prospectively in a double blind fashion, the map-based contact showed equivalent or better tremor improvement than the clinically active contact. CONCLUSIONS: This study suggests that probability maps of stimulation responses can assist in selecting the clinically optimal contact and increase the efficiency of programming. PMID- 25280762 TI - Myocardial blood flow quantification with SPECT and conventional tracers: a critical appraisal. PMID- 25280761 TI - Feasibility and operator variability of myocardial blood flow and reserve measurements with 99mTc-sestamibi quantitative dynamic SPECT/CT imaging. AB - PURPOSE: Myocardial blood flow (MBF) quantification with dynamic SPECT could lead to widespread utilization of MBF imaging in clinical practice with little cost increase over current standard SPECT myocardial perfusion imaging. This work evaluates the feasibility and operator-dependent variability of MBF and flow reserve measurements with (99m)Tc-sestamibi (MIBI) dynamic SPECT imaging using a standard dual-head SPECT camera. METHODS: Twenty-eight patients underwent dipyridamole-stress and rest imaging with dynamic SPECT/CT acquisition. Quantitative images were iteratively reconstructed with all physical corrections and then myocardial and arterial blood regions of interest (ROI) were defined semi-automatically. A compartmental model was fitted to these ROI-sampled time activity-curves, and flow-dependent MIBI extraction correction was applied to derive regional MBF values. Myocardial flow reserve (MFR) was estimated as stress/rest MBF ratio. MBF and MFR in low and high risk populations were evaluated for ability to detect disease. Images were each processed twice (>=7 days apart) by one expert and one novice operator to evaluate intra- and inter operator variability of MBF and MFR measurement in the three coronary artery vascular territories. RESULTS: Mean rest flow, stress flow, and MFR values were 0.83, 1.82 mL.minute(-1).g(-1), and 2.45, respectively. For stress/rest MFR, the inter-operator reproducibility was r(2) = 0.86 with RPC = 1.1. Stress MBF and MFR were significantly reduced (P < .05) in high risk (n = 9) vs low risk populations (n = 19), indicating ability to detect disease. For expert and novice operators very good intra-operator correlations of r(2) = 0.98 and 0.95 (n = 168, P < .001) were observed for combined rest and stress regional flow values. Bland-Altman reproducibility coefficients (RPC) were 0.25 and 0.47 mL.minute(-1).g(-1) for the expert and novice operators, respectively (P < .001). Inter-operator correlation was r(2) = 0.91 and Bland-Altman RPC = 0.58 mL.minute(-1).g(-1) (n = 336). CONCLUSIONS: MBF and reserve measurements using (99m)Tc-sestamibi on a traditional, two-headed camera with fast rotation and with quantitative dynamic SPECT appears to be feasible, warranting further investigation. PMID- 25280763 TI - Gastroprotective effect of the traditional herbal medicine, Sipjeondaebo-tang water extract, against ethanol-induced gastric mucosal injury. AB - BACKGROUND: Sipjeondaebo-tang, a traditional herbal medicine, has been reported to activate the immune response. Although, most research has focused on its anticancer activity. The purpose of this study was to determine whether Sipjeondaebo-tang exerts antioxidant activity against ethanol-induced gastric injury. METHODS: Gastric mucosal injury was induced by the oral administration of absolute ethanol at 5 mL/kg to rats after 18 h fast. Sipjeondaebo-tang water extract (SDTW; 200 mg/kg of body weight) was administered to rats 2 h before the oral administration of absolute ethanol. Gastric mucosal injury was evaluated by measuring the gastric injury, such as extent of lesions, malondialdehyde (MDA) concentration, glutathione (GSH) content and activities of antioxidant enzymes including catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase, and superoxide dismutase in stomach tissue. RESULTS: Oral administration of SDTW markedly decreased the damage by conditioning the gastric mucosa such as hemorrhage, hyperemia. Pretreatment with SDTW significantly reduced MDA concentration and significantly increased GSH content and the activities of antioxidant enzymes. In an acute toxicity study, no adverse effects of SDTW were observed at doses up to 5000 mg/kg/day. CONCLUSIONS: SDTW may protect the gastric mucosa against ethanol-induced gastric mucosa injury. These results suggested that SDTW might also play an important role in the gastroprotection based on their antioxidant effect. PMID- 25280764 TI - Bacterial influences on animal origins. AB - Animals evolved in seas teeming with bacteria, yet the influences of bacteria on animal origins are poorly understood. Comparisons among modern animals and their closest living relatives, the choanoflagellates, suggest that the first animals used flagellated collar cells to capture bacterial prey. The cell biology of prey capture, such as cell adhesion between predator and prey, involves mechanisms that may have been co-opted to mediate intercellular interactions during the evolution of animal multicellularity. Moreover, a history of bacterivory may have influenced the evolution of animal genomes by driving the evolution of genetic pathways for immunity and facilitating lateral gene transfer. Understanding the interactions between bacteria and the progenitors of animals may help to explain the myriad ways in which bacteria shape the biology of modern animals, including ourselves. PMID- 25280765 TI - Conflict on the sex chromosomes: cause, effect, and complexity. AB - Intralocus sexual conflict and intragenomic conflict both affect sex chromosome evolution and can in extreme cases even cause the complete turnover of sex chromosomes. Additionally, established sex chromosomes often become the focus of heightened conflict. This creates a tangled relationship between sex chromosomes and conflict with respect to cause and effect. To further complicate matters, sexual and intragenomic conflict may exacerbate one another and thereby further fuel sex chromosome change. Different magnitudes and foci of conflict offer potential explanations for lineage-specific variation in sex chromosome evolution and answer long-standing questions as to why some sex chromosomes are remarkably stable, whereas others show rapid rates of evolutionary change. PMID- 25280767 TI - Spectral transmission of the pig lens: effect of ultraviolet A+B radiation. AB - OBJECTIVE: To determine the spectral transmission curve of the crystalline lens of the pig. To analyse how this curve changes when the crystalline lens is irradiated with ultraviolet A+B radiation similar to that of the sun. To compare these results with literature data from the human crystalline lens. PROCEDURES: We used crystalline lenses of the common pig from a slaughterhouse, i.e. genetically similar pigs, fed with the same diet, and slaughtered at six months old. Spectral transmission was measured with a Perkin-Elmer Lambda 35 UV/VIS spectrometer. The lenses were irradiated using an Asahi Spectra Lax-C100 ultraviolet source, which made it possible to select the spectral emission band as well as the intensity and exposure time. RESULTS: The pig lens transmits all the visible spectrum (95%) and lets part of the ultraviolet A through (15%). Exposure to acute UV (A+B) irradiation causes a decrease in its transmission as the intensity or exposure time increases: this decrease is considerable in the UV region. CONCLUSIONS: We were able to determine the mean spectral transmission curve of the pig lens. It appears to be similar to that of the human lens in the visible spectrum, but different in the ultraviolet. Pig lens transmission is reduced by UV (A+B) irradiation and its transmission in the UV region can even disappear as the intensity or exposure time increases. An adequate exposure intensity and time of UV (A+B) radiation always causes an anterior subcapsular cataract (ASC). PMID- 25280768 TI - [Proptosis in a child secondary to an isolated orbital hydatid cyst]. PMID- 25280766 TI - Endocytic accessory factors and regulation of clathrin-mediated endocytosis. AB - Up to 60 different proteins are recruited to the site of clathrin-mediated endocytosis in an ordered sequence. These accessory proteins have roles during all the different stages of clathrin-mediated endocytosis. First, they participate in the initiation of the endocytic event, thereby determining when and where endocytic vesicles are made; later they are involved in the maturation of the clathrin coat, recruitment of specific cargo molecules, bending of the membrane, and finally in scission and uncoating of the nascent vesicle. In addition, many of the accessory components are involved in regulating and coupling the actin cytoskeleton to the endocytic membrane. We will discuss the different accessory components and their various roles. Most of the data comes from studies performed with cultured mammalian cells or yeast cells. The process of endocytosis is well conserved between these different organisms, but there are also many interesting differences that may shed light on the mechanistic principles of endocytosis. PMID- 25280769 TI - Antiretroviral interventions for preventing breast milk transmission of HIV. AB - BACKGROUND: An estimated 260,000 children under the age of 15 years acquired HIV infection in 2012. As much as 42% of mother-to-child transmission is related to breastfeeding. Antiretroviral prophylaxis for mothers or infants has the potential to prevent mother-to-child transmission of HIV through breast milk. OBJECTIVES: To determine which antiretroviral prophylactic regimens are efficacious and safe for reducing mother-to-child transmission of HIV through breastfeeding and thereby avert child morbidity and mortality. SEARCH METHODS: Using Cochrane Collaboration search methods in conjunction with appropriate search terms, we identified relevant studies from January 1, 1994 to January 14, 2014 by searching databases including Cochrane CENTRAL, EMBASE and PubMed, LILACS, and Web of Science/Web of Social Science. SELECTION CRITERIA: Randomized controlled trials in which HIV-infected mothers breastfed their infants, and in which the mothers used antiretroviral prophylaxis while breastfeeding their children or their children received antiretroviral prophylaxis for at least four weeks while breastfeeding, were included. DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified were examined independently by two authors. We identified 15,922 references and examined 81 in detail. Data were abstracted independently using a standardized form. MAIN RESULTS: Seven RCTs were included in the review.One trial compared triple antiretroviral prophylaxis during pregnancy and breastfeeding with short antiretroviral prophylaxis to given to the mother to prevent mother-to-child transmission of HIV. At 12 months, the risks of HIV transmission, and of HIV transmission or death, were lower, but there was no difference in infant mortality alone in the triple arm versus the short arm. Using the GRADE methodology, evidence quality for outcomes in this trial was generally low to moderate.One trial compared six months of breastfeeding using zidovudine, lamivudine, and lopinavir/ritonavir versus zidovudine, lamivudine, and abacavir from 26-34 weeks gestation. At six months, there was no difference in risk of infant HIV infection, infant death, or infant HIV infection or death between the two groups. Evidence quality for outcomes in this trial was generally very low to low.One trial of single dose nevirapine versus six weeks of infant zidovudine found the risk of HIV infection at 12 weeks to be greater in the zidovudine arm than in the single dose nevirapine arm. Evidence quality for outcomes in this trial was generally very low.One multi-country trial compared single dose nevirapine and six weeks of infant nevirapine. After 12 months, infants in the extended nevirapine group had a lower risk of infant mortality compared with the control. There was no difference in the risk of HIV infection or death or in HIV transmission alone in the extended nevirapine group compared with the control. Evidence quality for outcomes in this trial was generally low to moderate.One trial compared single dose nevirapine plus one week zidovudine; the control regimen plus nevirapine up to 14 weeks; or the control regimen with dual prophylaxis up to 14 weeks. At 24 months, the extended nevirapine regimen group had a lower risk of HIV transmission and of HIV transmission or death vs. the control. There was no difference in infant mortality alone. Compared with controls, the dual prophylaxis group had a lower risk of HIV transmission and of HIV transmission or death, but no difference in infant mortality alone. There was no difference in these outcomes between the two intervention arms. Evidence quality for outcomes in this trial was generally moderate to high.One trial compared six weeks of nevirapine with six months of nevirapine. Among infants of mothers not using highly active antiretroviral therapy, there was no difference in risk of HIV infection among the six month nevirapine group versus the six week nevirapine group. Evidence quality for outcomes in this trial was generally low to moderate.One trial compared a maternal triple-drug antiretroviral regimen, infant nevirapine, or neither intervention. Infants in the maternal prophylaxis arm were at lower risk for HIV, and HIV infection or death when compared with the control group. There was no difference in the risk of infant mortality alone. Infants with extended prophylaxis had a lower risk of HIV infection and of HIV infection or death versus the control group infants. There was no difference in the risk of infant mortality alone in the extended infant nevirapine group versus the control. There was no difference in HIV infection, infant mortality, and HIV infection or death between the maternal and extended infant prophylaxis groups. Evidence quality for outcomes in this trial was generally low to moderate. AUTHORS' CONCLUSIONS: Antiretroviral prophylaxis, whether used by the HIV infected mother or the HIV-exposed infant while breastfeeding, is efficacious in preventing mother-to-child transmission of HIV. Further research is needed regarding maternal resistance and response to subsequent antiretroviral therapy after maternal prophylaxis. An ongoing trial (IMPAACT 1077BF) compares the efficacy and safety of maternal triple antiretroviral prophylaxis versus daily infant nevirapine for prevention of mother-to-child transmission through breastfeeding. PMID- 25280770 TI - Recent advances in antibody engineering. PMID- 25280772 TI - Gestational exposure to di(2-ethylhexyl) phthalate (DEHP) impairs pancreatic beta cell function in F1 rat offspring. AB - Di(2-ethylhexyl) phthalate, a distinctive endocrine-disrupting chemical (EDC), is widely used as plasticizer. Gestational exposure to EDCs like DEHP may program a permanent diabetes disposition. We investigated whether gestational DEHP exposure disrupts glucose homeostasis in the rat F1 offspring as a result of early impairment in the functions of endocrine pancreas. Pregnant Wistar rats were administered with DEHP (1, 10 and 100mgkg-(1)day-(1)) or olive oil from gestational day 9-21 by oral gavage. DEHP-exposed offspring exhibited elevated blood glucose, impaired insulin, glucose tolerance, glucose-stimulated insulin secretion and decreased pancreatic insulin content at postnatal day 60 (PND60). Global DNA methylation level was increased while the expression of genes involved in the development and function of beta-cells were down regulated in islets in DEHP exposed groups. Gestational exposure to DEHP favours beta-cell dysfunction and the whole body glucometabolic abnormalities in the F1 offspring by down regulating the expression of critical genes. Further, DEHP-induced epigenetic changes in genes involved in beta-cell development and function appear to play a significant role. PMID- 25280771 TI - Transcriptome analysis of Gossypium hirsutum flower buds infested by cotton boll weevil (Anthonomus grandis) larvae. AB - BACKGROUND: Cotton is a major fibre crop grown worldwide that suffers extensive damage from chewing insects, including the cotton boll weevil larvae (Anthonomus grandis). Transcriptome analysis was performed to understand the molecular interactions between Gossypium hirsutum L. and cotton boll weevil larvae. The Illumina HiSeq 2000 platform was used to sequence the transcriptome of cotton flower buds infested with boll weevil larvae. RESULTS: The analysis generated a total of 327,489,418 sequence reads that were aligned to the G. hirsutum reference transcriptome. The total number of expressed genes was over 21,697 per sample with an average length of 1,063 bp. The DEGseq analysis identified 443 differentially expressed genes (DEG) in cotton flower buds infected with boll weevil larvae. Among them, 402 (90.7%) were up-regulated, 41 (9.3%) were down regulated and 432 (97.5%) were identified as orthologues of A. thaliana genes using Blastx. Mapman analysis of DEG indicated that many genes were involved in the biotic stress response spanning a range of functions, from a gene encoding a receptor-like kinase to genes involved in triggering defensive responses such as MAPK, transcription factors (WRKY and ERF) and signalling by ethylene (ET) and jasmonic acid (JA) hormones. Furthermore, the spatial expression pattern of 32 of the genes responsive to boll weevil larvae feeding was determined by "in situ" qPCR analysis from RNA isolated from two flower structures, the stamen and the carpel, by laser microdissection (LMD). CONCLUSION: A large number of cotton transcripts were significantly altered upon infestation by larvae. Among the changes in gene expression, we highlighted the transcription of receptors/sensors that recognise chitin or insect oral secretions; the altered regulation of transcripts encoding enzymes related to kinase cascades, transcription factors, Ca2+ influxes, and reactive oxygen species; and the modulation of transcripts encoding enzymes from phytohormone signalling pathways. These data will aid in the selection of target genes to genetically engineer cotton to control the cotton boll weevil. PMID- 25280773 TI - Hyaluronan regulates chemical allergen-induced IL-18 production in human keratinocytes. AB - Interleukin-18 (IL-18) has been shown to play a key proximal role in the induction of allergic contact dermatitis. Low molecular weight hyaluronan (LMWHA), an endogenous molecule and a member of the so-called damage associated molecular patterns (DAMPs), has been suggested to elicit immune-stimulatory effects. The purpose of this study was to examine the role of hyaluronan (HA) degradation in IL-18 production in human keratinocytes following stimulation with the contact sensitizers 2,4-dinitrochlorobenzene (DNCB) and PPD. IL-18 production in the human keratinocyte cell line NCTC2544 was measured by ELISA, whereas changes in HA metabolism were determined by Real-time PCR and immunofluorescence. Both contact allergens were able to enhance hyaluronidase (HYAL) 1 and 2 expression inducing HA degradation. Modulation of HA production, by HYAL or aristolochic acid pre-treatment, resulted in a significant reduction of contact allergen-induced IL-18 production. Oxidative stress appears to be the initial step in KC activation, as all the sequels of events can be blocked using antioxidants. This is the first indication that LMWHA can act as a DAMP in keratinocytes. In conclusion LMWHA fragments are important mediators in the process of contact sensitisation leading to IL-18 dependent responses. PMID- 25280774 TI - 17-beta estradiol inhibits oxidative stress-induced accumulation of AIF into nucleolus and PARP1-dependent cell death via estrogen receptor alpha. AB - Oxidative stress-induced DNA damage results in over-activation of poly(ADP ribose) polymerase 1 (PARP1), leading to parthanatos, a newly discovered cell elimination pathway. Inhibition of PARP1-dependent cell death has shown to improve the outcome of diseases, including stroke, heart ischemia, and neurodegenerative diseases. In the present study we aimed to detect whether estrogen plays a protective role in inhibiting parthanatos. We utilized human mammary adenocarcinoma cells (MCF7) that abundantly express the estrogen receptor alpha and beta (ERalpha and ERbeta). Parthanatos was induced by challenging the cells with hydrogen peroxide (H2O2). Microscopic imaging and molecular biological techniques, such as Western blot analysis and RNA interference, were performed. The results showed 17beta estradiol (E2) protected MCF7 cells from PARP1 dependent cell death by decreasing protein PARylation, and AIF translocation into nuclei/nucleoli. Down-regulation of ERalpha expression by siRNA before E2 addition resulted in the failure of the E2-mediated inhibition of H2O2-induced protein PARylation and AIF nucleolar translocation. Together these data suggest that estrogen via its alpha-type receptor inhibits oxidative stress-induced, PARP1-dependent cell death. The present study provided us insight into how to apply hormone therapy in intervention of parthanatos-implicated ischemic and degenerative diseases. PMID- 25280776 TI - Assessment of inbreeding resulting from selection for scrapie resistance: a model for rare sheep breeds. AB - Inbreeding in a small population of Chios sheep undergoing intense selection for the PrP gene was assessed 10 years after the beginning of a scrapie resistance selection programme. Inbreeding in this stock, already under selection for production traits, was analysed by using pedigree records containing 10,492 animals from 1968 to 2008, and also by genotyping 192 individuals with a panel of 15 microsatellites. Genetic markers indicated a loss of heterozygosity (FIS over all loci was 0.059) and allelic diversity (mean effective number of alleles was 3.075+/-0.275). The annual rate of inbreeding increased significantly after the start of the scrapie resistance programme, DeltaF=0.005 compared with DeltaF=0.001 before 1999, and was subjected to several genetic bottlenecks, mainly due to the low initial frequency of resistant animals. However, the mean individual inbreeding coefficient estimated from the pedigree - in this closed stock resembling the case of a rare breed - stood at the level of 4.5 per cent, five generations after the implementation of selection for the PrP gene. The inbreeding coefficient estimated by genetic markers was 4.37 per cent, implying that such a marker panel could be a useful and cost-effective tool for estimating inbreeding in unrecorded populations. PMID- 25280775 TI - Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2. AB - This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5mg/kg, sc for 4 days) and the genetic alteration of Nrf2 (Nrf2-null, wild type, and Keap1-HKO mice) to examine the role of Nrf2 in protection against phalloidin hepatotoxicity. Mice were given phalloidin (1.5mg/kg, ip for 8h) to examine liver injury and the expression of toxicity-related genes. Phalloidin increased serum enzyme activities and caused extensive hepatic hemorrhage and necrosis in Nrf2-null and wild-type mice, but less injury was seen in Keap1-HKO mice and OA-pretreated mice. Phalloidin increased the expression of neutrophil specific chemokine mKC and MIP-2 in Nrf2-null and WT mice, but such increases were attenuated in Keap1-HKO and OA-pretreated mice. Phalloidin increased, while Nrf2 activation attenuated, the expression of genes involved in acute-phase response (Ho-1) and DNA-damage response genes (Gadd45 and Chop10). Phalloidin is taken up by hepatocytes through Oatp1b2, but there was no difference in basal and phalloidin-induced Oatp1b2 expression among Nrf2-null, wild-type, and Keap1-HKO mice. In contrast, OA decreased phalloidin-induced Oatp1b2. Phalloidin activated MAPK signaling (p-JNK), which was attenuated by activation of Nrf2. In conclusion, this study demonstrates that protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2. PMID- 25280777 TI - Flipping healthcare: an essay by Maureen Bisognano and Dan Schummers. PMID- 25280778 TI - Age differences in the impact of peers on adolescents' and adults' neural response to reward. AB - Prior research suggests that increased adolescent risk-taking in the presence of peers may be linked to the influence of peers on the valuation and processing of rewards during decision-making. The current study explores this idea by examining how peer observation impacts the processing of rewards when such processing is isolated from other facets of risky decision-making (e.g. risk-perception and preference, inhibitory processing, etc.). In an fMRI paradigm, a sample of adolescents (ages 14-19) and adults (ages 25-35) completed a modified High/Low Card Guessing Task that included rewarded and un-rewarded trials. Social context was manipulated by having participants complete the task both alone and while being observed by two, same-age, same-sex peers. Results indicated an interaction of age and social context on the activation of reward circuitry during the receipt of reward; when observed by peers adolescents exhibited greater ventral striatal activation than adults, but no age-related differences were evinced when the task was completed alone. These findings suggest that, during adolescence, peers influence recruitment of reward-related regions even when they are engaged outside of the context of risk-taking. Implications for engagement in prosocial, as well as risky, behaviors during adolescence are discussed. PMID- 25280779 TI - An eco-friendly and water mediated product selective synthesis of 2 aminopyrimidines and their in vitro anti-bacterial evaluation. AB - A greener water mediated protocol for the efficient synthesis of a library of 2 amino-6-styryl pyrimidines (4) and their dihydro analogues (3) has been reported. Most of the saturated compounds (3) rather than their unsaturated analogues (4) showed better anti-bacterial (in vitro) activity against three human pathogens viz. Staphylococcus aureus, Klebsiella pneumonia and Escherichia coli. In particular, three of them (3 b, 3 i &3 k) exhibited high inhibition against the growth of all the three pathogens comparable with that of the reference drug, tetracycline. PMID- 25280780 TI - Neosartorya pseudofischeri cellulitis in an extremely low birth weight preterm baby. PMID- 25280781 TI - Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy. AB - The mechanisms linking the expression of sarcomeric mutant proteins to the development of pathological hypertrophy in hypertrophic cardiomyopathy (HCM) remain poorly understood. We investigated the role of the plasma membrane Ca(2+) ATPase PMCA4 in the HCM phenotype using a transgenic model that expresses mutant (Glu180Gly) alpha-tropomyosin (Tm180) in heart. Immunoblot analysis revealed that cardiac PMCA4 expression was upregulated early in Tm180 disease pathogenesis. This was accompanied by an increase in levels of the L-type Ca(2+)-channel, which is implicated in pathological hypertrophy. When Tm180 mice were crossed with a PMCA4-null line, loss of PMCA4 caused the abrogation of hypertrophy in Tm180/PMCA4-null double mutant mice. RT-PCR analysis of Tm180/PMCA4-null hearts revealed blunting of the fetal program and reversion of pro-fibrotic Col1a1 and Col3a1 gene expression to wild-type levels. This was accompanied by evidence of reduced L-type Ca(2+)-channel expression, and diminished calcineurin activity. Expression of the metabolic substrate transporters glucose transporter 4 and carnitine palmitoyltransferase 1b was preserved and Tm180-related changes in mRNA levels of various contractile stress-related proteins including the cardiac ankyrin protein CARP and the N2B isoform of titin were reversed in Tm180/PMCA4 null hearts. cGMP levels were increased and phosphorylation of vasodilator stimulated phosphoprotein was elevated in Tm180/PMCA4-null hearts. These changes were associated with a sharp reduction in left ventricular end-diastolic pressure in Tm180/PMCA4-null hearts, which occurred despite persistence of Tm180-related impairment of relaxation dynamics. These results reveal a novel and specific role for PMCA4 in the Tm180 hypertrophic phenotype, with the "protective" effects of PMCA4 deficiency encompassing multiple determinants of HCM-related hypertrophy. PMID- 25280782 TI - Three-dimensional finite element analysis and comparison of a new intramedullary fixation with interlocking intramedullary nail. AB - This study was set to introduce a new intramedullary fixation, explore its biomechanical properties, and provide guidance for further biomechanical experiments. With the help of CT scans and finite element modeling software, finite element model was established for a new intramedullary fixation and intramedullary nailing of femoral shaft fractures in a volunteer adult. By finite element analysis software ANSYS 10.0, we conducted 235-2,100 N axial load, 200 1,000 N bending loads and 2-15 Nm torsional loading, respectively, and analyzed maximum stress distribution, size, and displacement of the fracture fragments of the femur and intramedullary nail. During the loading process, the maximum stress of our new intramedullary fixation were within the normal range, and the displacement of the fracture fragments was less than 1 mm. Our new intramedullary fixation exhibited mechanical reliability and unique advantages of anti-rotation, which provides effective supports during fracture recovery. PMID- 25280783 TI - Pin1 is overexpressed and correlates with poor prognosis in gastric cancer. AB - The prolyl isomerase Pin1, which isomerizes the p-Ser/Thr-Pro peptide bonds and effects conformational and functional changes of the bound proteins, has been identified as a regulator of phosphorylation signaling in several diseases including cancer. The aim of this study is to determine the expression status of Pin1 in gastric cancer, its relationship between clinicopathologic features and patients' outcome. The mRNA levels of Pin1 in human normal and gastric cancer tissues were analyzed using the datasets from the publicly available Oncomine database ( www.oncomine.org ). Pin1 protein levels in human gastric cancer cells and tissues were analyzed by Western blot and immunohistochemistry staining, respectively. The Pin1 protein expression levels and its clinicopathologic correlations were investigated using tumor tissue microarray including 182 cases of human gastric cancer samples with survival information. Pin1 mRNA expression was found to be overexpressed in gastric cancer by using several datasets of Oncomine database analyzing. Pin1 protein expression is higher in 10 gastric cancer cell lines than that in normal gastric epithelial cell line GES-1. Pin1 positive expression was observed in 109 of 182 (59.9 %) gastric cancer samples and in 55 of 182 (30.2 %) normal gastric tissues (P < 0.001). Correlation analysis showed that high expression of Pin1 was significantly associated with pT (P = 0.017), pN (P = 0.043), TNM staging (P = 0.027), Lauren's classification (P < 0.001), as well as shorter overall survival in gastric cancer patients (29 mos vs. 47 mos. P = 0.048). Moreover, Pin1 expression, pT, and differentiation were independent prognostic factors of gastric cancer in Cox regression analysis. Pin1 is overexpressed in gastric cancer and correlates with clinicopathologic features, which might predict poor prognosis of gastric cancer patients. PMID- 25280784 TI - Construction and in vivo evaluation of a mammary gland-specific expression vector for human lysozyme. AB - A mammary gland-specific expression vector p205C3 was constructed with the 5'- and 3'-flanking regions of beta-lactoglobulin gene and the first intron of beta casein gene of Chinese dairy goat as regulatory sequences. Human lysozyme (hLYZ) cDNA from mammary gland was cloned into p205C3 and the recombinant vector was used to generate transgenic mice by microinjection. Based on the lysoplate assay, four female offspring of one male founder were detected expressing recombinant hLYZ in their milk at the levels of 5-200 mg/l, and the expressed protein had the same molecular weight as that of normal hLYZ. Besides mammary glands, ectopic expressions were also found in the spleens and the small intestines of the transgenic mice. Among the offspring, the female transgenic mice maintained and expressed the transgene stably with a highest expression level of 750 mg/l. Therefore, p205C3 could be used to develop animal mammary gland bioreactors expressing hLYZ. PMID- 25280785 TI - Cystic fibrosis (cf) and ovarian reserve: A cross-sectional study examining serum anti-mullerian hormone (amh) in young women. AB - BACKGROUND: Reduced female fertility in CF is believed to be due to thick cervical mucous, poor nutritional status, functional hypogonadotropic hypogonadism and possibly increased inflammation. Literature suggests that reduced ovarian reserve may also play a role. METHODS: 20 women with CF and 20 controls age 18-35 years were recruited. Serum anti-mullerian hormone (AMH), estradiol and follicle stimulating hormone (FSH) were assessed as well as antral follicle count (AFC) using transvaginal ultrasound. RESULTS: Women with CF had significantly lower AMH levels than controls (17.8+/-4.7 vs. 33.2+/-21.0 pmol/L respectively; p=0.004). There were no differences in estradiol, FSH or AFC. CONCLUSIONS: Women with CF have reduced ovarian reserve which may contribute to sub-fertility. CF care providers should consider referring women with CF to fertility specialists early to optimize chances of pregnancy. PMID- 25280787 TI - Nitric oxide plays a dual role in the oxidative injury of cultured rat microglia but not astroglia. AB - Nitric oxide (NO) and oxidative stress caused by reactive oxygen species (ROS) accumulation are two important factors that lead to the progression of human neurological diseases. NO can be detrimental or protective to neurons under oxidative toxicity; however, in the case of brain exposure to oxidative stress, in addition to neurons, the existence of glia may also be disturbed by toxic ROS. The influence NO will have on ROS-mediated glial injury remains unclear. Here, we examined the effects of NO on cell viability under oxidative stress induced by hydrogen peroxide (H2O2) in rat primary mixed glia cultures, as well as pure astroglia and microglia cultures. We found that in mixed glia cultures, both H2O2 and NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) elicited cell death in a concentration-dependent manner. Combinations of H2O2 and SNAP at sublytic concentrations were sufficient to damage mixed glia, and sublytic concentrations of SNAP could reduce the insults that resulted from toxic H2O2. Furthermore, in microglia or astroglia, sublytic concentrations of H2O2 were toxic when combined with SNAP, and the potency was increased with an increased SNAP concentration. In microglia but not astroglia, a toxic H2O2-induced apoptotic injury was attenuated by a sublytic level of SNAP. H2O2 at toxic levels activated p38 mitogen-activated protein kinases (MAPK) and p53 pathways and increased DNA double strand breaks (DSBs) in microglia, whereas the rescue exerted by sublytic SNAP against toxic H2O2 occurred via the activation of both Akt and extracellular-signal-regulated kinase (ERK) cascades and decreased DNA DSBs. Moreover, a sublytic concentration of SNAP induced both heat shock protein 70 and heme oxygenase-1, which may be involved in decreasing the susceptibility of microglia to H2O2 toxicity. These results suggest that NO exhibits a concentration-dependent dual action of weakening or enhancing oxidative injury in mixed glia, particularly microglia. PMID- 25280786 TI - Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression. AB - P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus (SE) or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. SE was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18-24h after severe SE by immunohistochemistry. Co-localization with neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP) and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro. CYP2E1 expression was investigated in brain resections from a cohort of drug-resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro, ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain. PMID- 25280788 TI - Repeated restraint stress-induced atrophy of glutamatergic pyramidal neurons and decreases in glutamatergic efflux in the rat amygdala are prevented by the antidepressant agomelatine. AB - Major depressive illness is among the most prevalent neuropsychiatric disorders and is associated with neuroplasticity deficits in limbic structures such as the amygdala. Since exposure to stressful life events is proposed to contribute to depressive illness, our recent studies examined the effects of stress on amygdalar neuroplasticity. These studies determined that repeated stress elicits deficits in glutamatergic activity in the amygdala, neuroplasticity deficits that can be prevented by some but not all antidepressants. In view of these observations, the goal of the current study was to determine the effects of repeated restraint stress (RRS) on the dendritic architecture of pyramidal neurons in the rat basolateral nucleus of the amygdala (CBL), as well as glutamate efflux in the CBL and central nucleus of the amygdala (CMX) via in vivo microdialysis. We also examined the ability of the antidepressant agomelatine to prevent RRS-induced neuroplasticity deficits. Compared with control rats, rats subjected to RRS exhibited atrophy of CBL pyramidal neurons, including decreases in total dendritic length, branch points, and dendritic complexity index. In addition, glutamate efflux was significantly reduced in the CMX of rats subjected to RRS, thereby identifying a potential neurochemical consequence of stress induced dendritic atrophy of CBL pyramidal neurons. Lastly, an acute stress challenge increased corticosterone (CORT) levels in the CBL, suggesting that stress-induced increases in CORT levels may contribute to the neuroanatomical and neurochemical effects of RRS in the CBL. Importantly, these RRS-induced changes were prevented by daily agomelatine administration. These results demonstrate that the neuroanatomical and neurochemical properties of glutamatergic neurons in the rat amygdala are adversely affected by repeated stress and suggest that the therapeutic effects of agomelatine may include protection of structural and neurochemical plasticity in limbic structures like the amygdala. PMID- 25280789 TI - The neural basis of image segmentation in the primate brain. AB - Image segmentation is a fundamental aspect of vision and a critical part of scene understanding. Our visual system rapidly and effortlessly segments scenes into component objects but the underlying neural basis is unknown. We studied single neurons in area V4 while monkeys discriminated partially occluded shapes. We found that many neurons tuned to boundary curvature maintained their shape selectivity over a large range of occlusion levels as compared to neurons that are not tuned to boundary curvature. This lends support to the hypothesis that segmentation in the face of occlusion may be solved by contour grouping. PMID- 25280790 TI - Maternal nicotine exposure during gestation and lactation induces cardiac remodeling in rat offspring. AB - The aim of this study was to evaluate the effects of maternal nicotine exposure on heart morphology and fibrosis in rat offspring. Nicotine was administered to pregnant Sprague-Dawley rats by using a subcutaneous osmotic mini-pump at a dose of 6 mg/kg/day from Gestational Days 7-21 or Gestational Day 7 to Postnatal Day 14. A control group received an equal volume of saline by the same route as nicotine. Rats born to prenatal nicotine-treated dams exhibited significantly greater cell width of cardiomyocytes, fewer cardiomyocyte nuclei number, higher beta-myosin heavy chain and transforming growth factor (TGF-beta1) expression, and higher collagen deposition in heart compared with rats born to normal saline treated dams on Postnatal Days 7 and 21. Postnatal nicotine exposure further enhances these effects. We conclude that TGF-beta1 may be involved in the pathogenesis of cardiac remodeling induced by maternal nicotine exposure during gestation and lactation in rat offspring. PMID- 25280791 TI - Neuroleptic malignant syndrome in an elderly patient with normal pressure hydrocephalus overlapping corticobasal degeneration. AB - In this case report, neuroleptic malignant syndrome (NMS) in an elderly patient with normal pressure hydrocephalus overlapping corticobasal degeneration was reported. The case highlights the need for clinicians to be cautious when using dopaminergic medication in the elderly patients, since these agents have risks for NMS which is a life-threatening complication. Additionally, co-occurrence of primary and secondary parkinsonian dementia syndromes should be kept in mind to avoid additional complications in the elderly patients. PMID- 25280792 TI - The Peripheral Sympathetic Neuron is Intact in Alzheimer's Disease and Behavioral Variant of Frontotemporal Dementia. AB - INTRODUCTION: The study was undertaken to evaluate the postganglionic sympathetic sudomotor function employing the quantitative sudomotor axon reflex test (QSART) in tauopathies Alzheimer's disease (AD) and behavioral variant of frontotemporal dementia (bvFTD). METHODS: Patients were recruited in a prospective pilot study. A structured history was taken and QSART was recorded. RESULTS: In all, 15 patients with AD (7 female) and 14 patients with bvFTD (9 female) were included. Mean age (+/-standard deviation) of patients with AD and bvFTD was 74 +/- 9 and 71 +/- 10 years, respectively. Severe sudomotor dysfunction (Composite Autonomic Severity sudomotor score 3) was present in 3 (20%) patients with AD and 0 (0%) patients with bvFTD (P = .037). The upper extremity was only involved in 1 patient with AD and 1 patient with bvFTD. Sweat results of the 4 recording sites did not differ between both groups. Patients' history correlated with severe autonomic symptoms as assessed with QSART. CONCLUSION: Postganglionic sudomotor involvement in AD and bvFTD is most likely not part of the disease. PMID- 25280793 TI - A novel function of interferon regulatory factor-1: inhibition of Th2 cells by down-regulating the Il4 gene during Listeria infection. AB - Infection with certain pathogens induces a shift of the Th subset balance to a Th1 dominant state. This, in turn, results in the suppression of Th2 responses. We focused on the involvement of interferon regulatory factor-1 (IRF-1) in the suppression of Th2 cells during Listeria infection. We found that the inhibition of IL-4 production by Th2 cells is mediated by a soluble factor (LmSN) produced by Listeria-infected antigen-presenting cells. The inhibition is not observed with T cells from Irf1 gene-targeted mice. IRF-1 suppresses transcription of the Il4 gene in Th2 cells. Under the influence of the LmSN, IRF-1 binds to the 3' untranslated region (UTR) region of the Il4 gene and down-regulates Il4 gene transcription. Finally, we identified IL-1alpha and IL-1beta as the mediator of the LmSN activity. Signaling through IL-1R induces the stabilization and/or nuclear translocation of IRF-1. We propose that IRF-1 functions to induce the T cell subset shift via a novel mechanism. Under the influence of IL-1, IRF-1 translocates into the nucleus and acts on the 3'UTR region of the Il4 gene, thus inhibiting its transcription in Th2 cells. As a result, the immune system shifts predominantly to a Th1 response during Listeria infection, resulting in effective protection of the host. PMID- 25280795 TI - Depressive symptoms are more strongly related to executive functioning and episodic memory among African American compared with non-Hispanic White older adults. AB - We examined whether the reserve capacity model can be extended to cognitive outcomes among older African Americans. Two hundred and ninety-two non-Hispanic Whites and 37 African Americans over age 54 participated in the normative study for the NIH Toolbox for the Assessment of Neurological and Behavioral Function. Multiple-group path analysis showed that associations between depressive symptoms and cognition differed by race, independent of age, education, reading level, income, health, and recruitment site. Depressive symptoms were associated with slowed processing speed among Whites and worse task-switching, inhibition, and episodic memory among African Americans. African Americans may be more vulnerable to negative effects of depression on cognition than non-Hispanic Whites. Further research is needed to explicate the psychological and neurobiological underpinnings of this greater vulnerability. PMID- 25280794 TI - Test validity and performance validity: considerations in providing a framework for development of an ability-focused neuropsychological test battery. AB - Literature on test validity and performance validity is reviewed to propose a framework for specification of an ability-focused battery (AFB). Factor analysis supports six domains of ability: first, verbal symbolic; secondly, visuoperceptual and visuospatial judgment and problem solving; thirdly, sensorimotor skills; fourthly, attention/working memory; fifthly, processing speed; finally, learning and memory (which can be divided into verbal and visual subdomains). The AFB should include at least three measures for each of the six domains, selected based on various criteria for validity including sensitivity to presence of disorder, sensitivity to severity of disorder, correlation with important activities of daily living, and containing embedded/derived measures of performance validity. Criterion groups should include moderate and severe traumatic brain injury, and Alzheimer's disease. Validation groups should also include patients with left and right hemisphere stroke, to determine measures sensitive to lateralized cognitive impairment and so that the moderating effects of auditory comprehension impairment and neglect can be analyzed on AFB measures. PMID- 25280796 TI - Ganser-like syndrome after loss of psychic self-activation syndrome: psychogenic or organic? AB - Very few data are available on the long-term changes in the cognitive abilities of patients with loss of psychic self-activation syndrome (LPSAS). Here, we present a 25-year follow-up study on a case of LPSAS resulting from bilateral pallidal lesions caused by carbon monoxide intoxication. Typical signs of LPSAS were observed, showing no changes in severity, but Ganser syndrome (GS) gradually developed and worsened during the follow-up period. GS is generally assumed to be a psychogenic syndrome, but an organic etiology has been suspected by the authors of several case reports. Here, atypical features of GS plead against the independence of GS and LPSAS. DaTSCAN and brain 18FDG-PET were performed. Since left hippocampal hypometabolism has been previously described in patients with functional amnesia, it is possible that long periods of mental inactivity may have psychological consequences, but the atypical features of GS also suggest that an organic mechanism may be involved. PMID- 25280798 TI - The clypeal gland: a new exocrine gland in termite imagoes (Isoptera: Serritermitidae, Rhinotermitidae, Termitidae). AB - Social insects possess a rich set of exocrine organs producing diverse pheromones and defensive compounds. This is especially true for termite imagoes, which are equipped with several glands producing, among others, sex pheromones and defensive compounds protecting imagoes during the dispersal flight and colony foundation. Here, we describe the clypeal gland, a new termite exocrine organ occurring in the labro-clypeal region of imagoes of most Rhinotermitidae, Serritermitidae and Termitidae species. The clypeal gland of Coptotermes testaceus consists of class 1 (modified epidermal cell) and class 3 (bicellular gland unit) secretory cells. Ultrastructural features suggest that the gland secretes volatile compounds and proteins, probably after starting the reproduction. One peculiar feature of the gland is the presence of multiple secretory canals in a single canal cell, a feature never observed before in other insect glands. Although the function of the gland remains unknown, we hypothesize that it could produce secretion signalling the presence of functional reproductives or their need to be fed. PMID- 25280797 TI - Reliable quantification of mRNA in archived formalin-fixed tissue with or without paraffin embedding. AB - INTRODUCTION: Formalin fixation and paraffin embedding (FFPE) is a standard method for tissue sample storage and preservation in pathology archives. The Reverse Transcriptase Quantitative Polymerase Chain Reaction (RT-qPCR) is a useful method for gene expression analysis, but its sensitivity is significantly decreased in FFPE tissue due to the fixation process. This process results in chemical modifications of RNA, cross-links proteins to RNA, and degrades RNA in these archived samples, hindering the reverse transcription step of the conventional RT-pPCR method and preventing generation of a cDNA that is long enough for the subsequent quantitative PCR step. METHODS: In this study, we used a multi-species RT-qPCR method originally developed to detect mRNA in tissue homogenate samples (Wang et al., 2011) and applied it to effectively detect a specific mRNA in formalin-fixed tissues with or without paraffin-embedding by targeting mRNA sequences as short as 24 nucleotides. RESULTS: Target sizes ranging from 24 to 91 nucleotides were evaluated using this multi-species RT-qPCR assay. Data generated with FFPE tissues demonstrated that use of short target sequences relieved the dependence on RNA quality and could reliably quantify mRNA. This method was highly sensitive, reproducible, and had a dynamic range of five orders of magnitude. Importantly, this method could quantify mRNA in prolonged formalin-fixed and FFPE tissue, where conventional RT-qPCR assays failed. Moreover, a similar result for small interfering RNA (siRNA)-mediated Apob mRNA knockdown was obtained from tissues fixed in formalin solution for 3months to 4years, and was found to be comparable to results obtained with frozen liver tissues. DISCUSSION: Therefore, the method presented here allows for preclinical and clinical retrospective and prospective studies on mRNA derived from archived FFPE and prolonged formalin-fixed tissue. PMID- 25280799 TI - Pseudologia fantastica: forensic and clinical treatment implications. AB - Pseudologia fantastica, also known as mythomania, or pathological lying, is a psychiatric phenomenon that is a mixture of fact and fiction involving fantasized events and self aggrandizing personal roles. It has been recognized in the field for over a century. In this case report we discuss three different cases, two of them presented in the acute inpatient setting and one outpatient setting. All three presented with the common theme of extensive and 'pathological lying' in a manner that was notably very destructive to them and posing significant challenges to the treatment team. In an attempt to shed light into some of the clinical and legal/forensic challenges it creates when faced in the clinical settings, we also raise the need for a better definition and classification of this symptom in the DSM. PMID- 25280800 TI - A comparison of peritoneal fluid values in mares following bilateral laparoscopic ovariectomy using a vessel sealing and dividing device versus placement of two ligating loops. AB - The objective of this study was to determine the effect of bilateral laparoscopic ovariectomy on peritoneal fluid values in mares and compare how this effect was modified by the method of ovarian vessel hemostasis used. Ten mares undergoing standing bilateral laparoscopic ovariectomy were used in a randomized clinical study. During surgery, blood vessels within the mesovarium were either: (1) sealed and transected with a vessel sealing and dividing device (VSDD), or (2) ligated using two loops placed proximal to each ovary and then the mesovarium transected using laparoscopic scissors. The ovaries were removed through the ipsilateral body wall. Abdominocentesis was performed before surgery and 24 h and 72 h after surgery. Markers of peritoneal inflammation, as measured by total nucleated cell count, total protein (TP) and red blood cell count via abdominocentesis, were consistently increased for all groups compared to pre operative values. The mean (range) of TP for the VSDD group was 4.14 (3.9-4.5) g/dL, and that for the ligating loop group was 3.18 (2.7-3.5) g/dL. Use of the VSDD resulted in significantly greater TP concentrations in the abdominal fluid at 24 h and 72 h post-operatively when compared to a ligating loop (P <0.001 and 0.04, respectively). PMID- 25280801 TI - Stroke knowledge in Italy. AB - Stroke knowledge improves public behavior in terms of prevention, symptom recognition, and timely response. Contemporary data on stroke awareness in the Italian general population are lacking. This study surveyed public knowledge of risk factors, warning signs, and proper reactions to stroke among Italian adults. A population-based telephone survey was carried out in a sample of 1,000 residents aged >=18 years in May-June 2010. The questionnaire included close ended questions focused on stroke symptoms, risk factors, and treatment options. We examined the prevalence and distribution of stroke knowledge in the community and generated multivariable logistic regression models. Among the 1,000 participants (481 men, mean age 48.8 +/- 17.2), only the 55.8 % correctly identified the brain as the affected organ in stroke. The most common risk factor for stroke identified by respondents was hypertension (67.6 %), the most common warning sign was hemiparesis (68.7 %), the 43.5 % could list >1 warning sign. Multivariate analyses indicate that education and previous stroke experience are the only independent predictors of stroke knowledge. Only 26.2 % reported to know about the availability of t-PA treatment. An ambulance would be called by 59 % of respondents in the event of a stroke. Respondents with a high level of education are more likely to call an ambulance in case of stroke. This study provides the first comprehensive data describing stroke knowledge among Italian adults: the general level is suboptimal and is associated only with education and previous family experience of stroke. Public education could potentially improve treatment and prevention. PMID- 25280802 TI - A pilot study of a wearable apnoea detection device. AB - RATIONALE: Current techniques for monitoring patients for apnoea suffer from significant limitations. These include insufficient availability to meet diagnostic needs, cost, accuracy of results in the presence of artefacts and difficulty of use in unsupervised conditions. OBJECTIVES: We created and clinically tested a novel miniature medical device that targets overcoming these limitations. METHODS: We studied 20 healthy control participants and 10 patients who had been referred for sleep apnoea diagnosis. The performances of the new system and also of the Food and Drug Administration (FDA) approved SOMNO clinical system, conventionally used for sleep apnoea diagnosis were evaluated under the same conditions. Both systems were tested during a normal night of sleep in controls and patients. Their performances were quantified in terms of detection of apnoea and hypopnoea in individual 10 s epochs, which were compared with scoring of signals by a blinded clinician. MAIN RESULTS: For spontaneous apnoeas during natural sleep and considering the clinician scorer as the gold standard, the new wearable apnoea detection device had 88.6% sensitivity and 99.6% specificity. In comparison the SOMNO system had 14.3% sensitivity and 99.3% specificity. The novel device had been specifically designed to detect apnoea, but if apnoea and hypopnoea during sleep were both considered in the assessment, the sensitivity and specificity were 77.1% and 99.7%, respectively, versus 54% and 98.5%, respectively, for the SOMNO. CONCLUSIONS: The performance of the novel device compares very well to the scoring by an experienced clinician even in the presence of breathing artefacts, in this small pilot study. This can potentially make it a real solution for apnoea home monitoring. PMID- 25280803 TI - Association between serum gamma-glutamyltranspeptidase and atherosclerosis: a population-based cross-sectional study. AB - OBJECTIVE: The purpose of this study was to determine the relationship between serum gamma-glutamyltranspeptidase (GGT) and brachial-ankle pulse wave velocity (baPWV) as an indicator for atherosclerosis in Japanese men and women after adjusting for fatty liver. DESIGN: A cross-sectional study. SETTING: A health check-up centre in Japan. PARTICIPANTS: 912 Japanese men and women aged 24-84 years recruited from people who received a medical health check-up programme with a standardised questionnaire and an automatic waveform analyser to measure baPWV. MAIN OUTCOME MEASURES: We measured serum GGT concentrations and baPWV. Fatty liver was diagnosed by standardised criteria using abdominal ultrasonography. The postmenopausal state was defined as beginning 1 year after the cessation of menses. RESULTS: In women, log2 GGT was positively associated with baPWV (beta=0.11, 95% CI 0.02 to 0.19, p<0.05), independent of age, body mass index, systolic blood pressure, fasting plasma glucose, triglycerides, estimated glomerular filtration rate, fatty liver, menopausal state and parameters of lifestyles. However, in men, the positive association of log2 GGT with baPWV was not significant (beta=-0.04, 95% CI -0.10 to 0.03, p=0.28) in multivariable linear regression analyses. CONCLUSIONS: The serum GGT level was associated with baPWV, independently of covariates including fatty liver or menopausal state just in women, but not in men. PMID- 25280804 TI - The effect of an interdisciplinary rehabilitation intervention comparing HRQoL, symptom burden and physical function among patients with primary glioma: an RCT study protocol. AB - INTRODUCTION: Gliomas are among the biggest challenges in neurological and oncology rehabilitation and optimising treatment is of major clinical importance in this population. Although inpatient rehabilitation among glioma patients' results in improved functional measures, rehabilitation efforts are still not emphasised in this patient group and the literature lacks studies investigating the impact of outpatient rehabilitation. METHOD: This protocol describes a randomised 6-week parallel group rehabilitation study investigating an outpatient interdisciplinary rehabilitation programme. The intervention consists of 6 weeks intensive physiotherapy as groups exercise in conjunction with 0-6 weeks of individual occupational therapy if a need is present. The aim of this study is to describe the design of the upcoming randomised control trial (RCT). The results of the RCT will add to the growing body of literature investigating the potential role of exercise as a supportive therapeutic intervention for a patient with cancer. ETHICS AND DISSEMINATION: The project is approved by the Regional Scientific Ethical Committees for Southern Denmark under Project-ID: (S-20140108) and by the Danish Data Protection Agency (J. no.2008-58-0035). Dissemination will occur through presentation and findings will be published in peer-reviewed journals. The key strength of this study is its randomised design and it is the first study to investigate a standardised outpatient interdisciplinary rehabilitation programme among patients with glioma. A potential limitation is the uncertainty and risk of side effects to the concomitant treatment, which enhances the risk of dropout. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier NCT02221986. PMID- 25280805 TI - Assessing bias in osteoarthritis trials included in Cochrane reviews: protocol for a meta-epidemiological study. AB - INTRODUCTION: The validity of systematic reviews and meta-analysis depends on methodological quality and unbiased dissemination of trials. Our objective is to evaluate the association of estimates of treatment effects with different bias related study characteristics in meta-analyses of interventions used for treating pain in osteoarthritis (OA). From the findings, we hope to consolidate guidance on interpreting OA trials in systematic reviews based on empirical evidence from Cochrane reviews. METHODS AND ANALYSIS: Only systematic reviews that compare experimental interventions with sham, placebo or no intervention control will be considered eligible. Bias will be assessed with the risk of bias tool, used according to the Cochrane Collaboration's recommendations. Furthermore, center status, trial size and funding will be assessed. The primary outcome (pain) will be abstracted from the first appearing forest plot for overall pain in the Cochrane review. Treatment effect sizes will be expressed as standardised mean differences (SMDs), where the difference in mean values available from the forest plots is divided by the pooled SD. To empirically assess the risk of bias in treatment benefits, we will perform stratified analyses of the trials from the included meta-analyses and assess the interaction between trial characteristics and treatment effect. A relevant study-level covariate is defined as one that decreases the between-study variance (tau(2), estimated as Tau-squared) as a consequence of inclusion in the mixed effects statistical model. ETHICS AND DISSEMINATION: Meta-analyses and randomised controlled trials provide the most reliable basis for treatment of patients with OA, but the actual impact of bias is unclear. This study will systematically examine the methodological quality in OA Cochrane reviews and explore the effect estimates behind possible bias. Since our study does not collect primary data, no formal ethical assessment and informed consent are required. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42013006924). PMID- 25280806 TI - Rate of venous thromboembolism among surgical patients in Australian hospitals: a multicentre retrospective cohort study. AB - OBJECTIVES: Despite the burden of venous thromboembolism (VTE) among surgical patients on health systems in Australia, data on VTE incidence and its variation within Australia are lacking. We aim to explore VTE and subsequent mortality rates, trends and variations across Australian acute public hospitals. SETTING: A large retrospective cohort study using all elective surgical patients in 82 acute public hospitals during 2002-2009 in New South Wales, Australia. PARTICIPANTS: Patients underwent elective surgery within 2 days of admission, aged between 18 and 90 years, and who were not transferred to another acute care facility; 4 362 624 patients were included. OUTCOME MEASURES: VTE incidents were identified by secondary diagnostic codes. Poisson mixed models were used to derive adjusted incidence rates and rate ratios (IRR). RESULTS: 2/1000 patients developed postoperative VTE. VTE increased by 30% (IRR=1.30, CI 1.19 to 1.42) over the study period. Differences in the VTE rates, trends between hospital peer groups and between hospitals with the highest and those with the lowest rates were significant (between-hospital variation). Smaller hospitals, accommodated in two peer groups, had the lowest overall VTE rates (IRR=0.56:0.33 to 0.95; IRR=0.37:0.23 to 0.61) and exhibited a greater increase (64% and 237% vs 19%) overtime and greater between-hospital variations compared to larger hospitals (IRR=8.64:6.23 to 11.98; IRR=8.92:5.49 to 14.49 vs IRR=3.70:3.32 to 4.12). Mortality among patients with postoperative VTE was 8% and remained stable overtime. No differences in post-VTE death rates and trends were seen between hospital groups; however, larger hospitals exhibited less between-hospital variations (IRR=1.78:1.30 to 2.44) compared to small hospitals (IRR>23). Hospitals performed differently in prevention versus treatment of postoperative VTE. CONCLUSIONS: VTE incidence is increasing and there is large variation between-hospital and within-hospital peer groups suggesting a varied compliance with VTE preventative strategies and the potential for targeted interventions and quality improvement opportunities. PMID- 25280807 TI - Early life-course socioeconomic position, adult work-related factors and oral health disparities: cross-sectional analysis of the J-SHINE study. AB - OBJECTIVES: We examined the association between socioeconomic position (SEP) and oral health, and the associations of economic difficulties in childhood and workplace-related factors on these parameters. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 3201 workers aged 25-50 years, living in and around Tokyo, Japan, from the J-SHINE (Japanese study of Stratification, Health, Income, and Neighborhood) study. The response rate was 31.6%. OUTCOME MEASURES: Self rated oral health (SROH)-A logistic regression model was used to estimate ORs for the association between poor SROH and each indicator of SEP (annual household income, wealth, educational attainment, occupation and economic situation in childhood). Multiple imputation was used to address missing values. RESULTS: Each indicator of SEP, including childhood SEP, was significantly inversely associated with SROH, and all of the workplace-related factors (social support in the workplace, job stress, working hours and type of employment) were also significantly associated with SROH. Compared with professionals, blue-collar workers had a significantly higher OR of poor SROH and the association was substantially explained by the workplace-related factors; ORs ranged from 1.44 in the age-adjusted and sex-adjusted model to 1.18 in the multivariate model. Poverty during childhood at age 5 and at age 15 was associated with poorer SROH, and these two factors seemed to be independently associated with SROH. CONCLUSIONS: We found oral health disparity across SEP among workers in Japan. Approximately 60% of the association between occupation and SROH was explained by job-related factors. Economic difficulties during childhood appear to affect SROH in adulthood separately from sex, age and the current workplace-related factors. PMID- 25280808 TI - A comparison of calls subjected to a malpractice claim versus 'normal calls' within the Swedish healthcare direct: a case-control study. AB - OBJECTIVES: The purpose of this study is to compare communication patterns in calls subjected to a malpractice claim with matched controls. SETTING: In many countries, telephone advice nursing is patients' first contact with healthcare. Telenurses' assessment of callers' symptoms and needs are based on verbal communication only, and problems with over-triage and under-triage have been reported. PARTICIPANTS: A total sample of all reported medical errors (n=33) during the period 2003-2010 within Swedish Healthcare Direct was retrieved. Corresponding calls were thereafter identified and collected as sound files from the manager in charge at the respective call centres. For technical reasons, calls from four of the cases were not possible to retrieve. For the present study, matched control calls (n=26) based on the patient's age, gender and main symptom presented by the caller were collected. RESULTS: Male patients were in majority (n=16), and the most common reasons for calling were abdominal pain (n=10) and chest pain (n=5). There were statistically significant differences between the communication in the cases and controls: telenurses used fewer open ended medical questions (p<0.001) in the cases compared to the control calls; callers provided telenurses with more medical information in the control calls compared to the cases (p=0.001); and telenurses used more facilitation and patient activation activities in the control calls (p=0.034), such as back channel response (p=0.001), compared to the cases. CONCLUSIONS: The present study shows that telenurses in malpractice claimed calls used more closed-ended questioning compared to those in control calls, who used more open-ended questioning and back-channel response, which provided them with richer medical descriptions and more information from the caller. Hence, these communicative techniques are important in addition to solid medical and nursing competence and sound decision aid systems. PMID- 25280809 TI - Implementing family involvement in the treatment of patients with psychosis: a systematic review of facilitating and hindering factors. AB - OBJECTIVE: To synthesise the evidence on implementing family involvement in the treatment of patients with psychosis with a focus on barriers, problems and facilitating factors. DESIGN: Systematic review of studies evaluating the involvement of families in tripartite communication between health professionals, 'families' (or other unpaid carers) and adult patients, in a single-family context. A theoretical thematic analysis approach and thematic synthesis were used. DATA SOURCES: A systematic electronic search was carried out in seven databases, using database-specific search strategies and controlled vocabulary. A secondary manual search of grey literature was performed as well as using forwards and backwards snowballing techniques. RESULTS: A total of 43 studies were included. The majority featured qualitative data (n=42), focused solely on staff perspectives (n=32) and were carried out in the UK (n=23). Facilitating the training and ongoing supervision needs of staff are necessary but not sufficient conditions for a consistent involvement of families. Organisational cultures and paradigms can work to limit family involvement, and effective implementation appears to operate via a whole team coordinated effort at every level of the organisation, supported by strong leadership. Reservations about family involvement regarding power relations, fear of negative outcomes and the need for an exclusive patient-professional relationship may be explored and addressed through mutually trusting relationships. CONCLUSIONS: Implementing family involvement carries additional challenges beyond those generally associated with translating research to practice. Implementation may require a cultural and organisational shift towards working with families. Family work can only be implemented if this is considered a shared goal of all members of a clinical team and/or mental health service, including the leaders of the organisation. This may imply a change in the ethos and practices of clinical teams, as well as the establishment of working routines that facilitate family involvement approaches. PMID- 25280810 TI - Protocol for economic evaluation alongside a cluster-randomised controlled trial of a psychoeducational intervention for the primary prevention of postnatal mental health problems in first-time mothers. AB - INTRODUCTION: Postnatal mental health problems, which are an international public health priority, are a suitable target for preventive approaches. The financial burden of these disorders is borne across sectors in society, including health, early childhood, education, justice and the workforce. This paper describes the planned economic evaluation of What Were We Thinking, a psychoeducational intervention for the prevention of postnatal mental health problems in first-time mothers. METHODS AND ANALYSIS: The evaluation will be conducted alongside a cluster-randomised controlled trial of its clinical effectiveness. Cost effectiveness and costs-utility analyses will be conducted, resulting in estimates of cost per percentage point reduction in combined 30-day prevalence of depression, anxiety and adjustment disorders and cost per quality-adjusted life year gained. Uncertainty surrounding these estimates will be addressed using non parametric bootstrapping and represented using cost-effectiveness acceptability curves. Additional cost analyses relevant for implementation will also be conducted. Modelling will be employed to estimate longer term cost-effectiveness if the intervention is found to be clinically effective during the period of the trial. ETHICS AND DISSEMINATION: Approval to conduct the study was granted by the Southern Health (now Monash Health) Human Research Ethics Committee (24 April 2013; 11388B). The study was registered with the Monash University Human Research Ethics Committee (30 April 2013; CF12/1022-2012000474). The Education and Policy Research Committee, Victorian Government Department of Education and Early Childhood Development approved the study (22 March 2012; 2012_001472). Use of the EuroQol was registered with the EuroQol Group; 16 August 2012. TRIAL REGISTRATION NUMBER: The trial was registered with the Australian New Zealand Clinical Trials Registry on 7 May 2012 (registration number ACTRN12613000506796). PMID- 25280811 TI - Evaluation of long-term clinical and health service outcomes following coronary artery revascularisation in Western Australia (WACARP): a population-based cohort study protocol. AB - INTRODUCTION: Coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI) are procedures commonly performed on patients with significant obstructive coronary artery disease to relieve symptoms of ischaemia, improve survival or both. Although the efficacy of both procedures at the individual level has been established, the impact of advances in coronary artery revascularisation procedures (CARP) on long-term outcomes and cost-effectiveness at the population level are yet to be assessed. Our aim is to evaluate a minimum of 6-year outcomes and costs for the total population of patients who had CARP in Western Australia (WA) in 2000-2005. METHODS AND ANALYSIS: This retrospective population cohort study will link clinical and administrative health data for a previously defined cohort including all patients in WA who had a CARP in the period 2000-2005. The cohort consists of 19,014 patients who had 21,175 procedures (15,429 PCI and 5746 CABG). We are now collecting a minimum of 6 years follow-up of morbidity and mortality data for the cohort using the WA Data Linkage System, clinical registries and hospital records, with 12 years follow-up for cases in the year 2000. Comparison of long-term outcomes for different CARP will be reported (PCI vs CABG; bare metal stents vs drug-eluting stents vs CABG). Cost-effectiveness analysis of CARP from the perspective of the healthcare sector will be performed using individual level cost data and average costs from Australian Refined Diagnosis Related Groups. ETHICS AND DISSEMINATION: This study has received ethics approval from the University of Western Australia, the Western Australian Department of Health and all participating hospitals. Being a large population cohort study, approval included a waiver of informed consent. All findings will be presented at local, national and international healthcare/academic conferences and published in peer-reviewed journals. PMID- 25280812 TI - C60 carboxyfullerene-based functionalised nanohybrids as signal-amplifying tags for the ultrasensitive electrochemical detection of procalcitonin. AB - BACKGROUND AND OBJECTIVES: Electrochemical immunosensors have attracted much interest recently. Some researches on electrochemical PCT measurement have been reported but improvements are still needed to enhance detection performance for the clinical determination of PCT. DESIGN AND METHODS: In this work, a novel signal amplification strategy was developed by fabricating an electrochemical immunosensor for the sensitive detection of procalcitonin (PCT). Amino group functionalised C(60) nanoparticles were used as a matrix to immobilise a redox probe, ferrocene carboxylic acid (Fc), and were subsequently coated with platinum nanoparticles (PtNPs) to form PtNP-Fc-C(60) nanocomposites. RESULTS: The experimental results demonstrated that the multi-labelled PtNP-Fc-C(60) nanocomposites displayed satisfactory electrochemical redox activity and high electrocatalytic activity from the PtNPs and glucose oxidase, consequently resulting in high sensitivity for the detection of PCT. The linear range of PCT was 0.01-10 ng/mL, with a detection limit of 6p g/mL (S/N = 3). CONCLUSION: Although the proposed immunosensor was only to determine PCT in this study, we expect that this immunosensor should be suitable for the determination of other targets in similar signal-enhanced immunoassays. PMID- 25280813 TI - Inhibition of heat shock protein 90 decreases ACTH production and cell proliferation in AtT-20 cells. AB - PURPOSE: Cushing's disease is primarily caused by adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. If excision of the tumor from the pituitary, which is the primary treatment for Cushing's disease, is unsuccessful, further medical therapy is needed to treat the resultant hypercortisolism. Some of the drugs used to treat this condition have shown potential therapeutic benefits, but a more effective treatment should be explored for the treatment of Cushing's disease. In the present study, we determined the effect of heat shock protein 90 inhibitors on ACTH production and cell proliferation of AtT-20 corticotroph tumor cells. METHODS: AtT-20 pituitary corticotroph tumor cells were cultured. The expression levels of mouse proopiomelanocortin (POMC) and pituitary tumor transforming gene 1 (PTTG1) mRNA were evaluated using quantitative real-time PCR. Cellular DNA content was analyzed with fluorescence-activated cell sorting (FACS) analysis. The protein levels were determined by Western blot analysis. RESULTS: Both 17-allylamino-17-demethoxygeldanamycin and CCT018159 decreased POMC mRNA levels in AtT-20 cells and ACTH levels in the culture medium of these cells, suggesting that both drugs suppress ACTH synthesis and secretion in corticotroph tumor cells. Both drugs also decreased cell proliferation and induced apoptosis. FACS analyses revealed that both agents increased the percentage of AtT-20 cells in the G2/M phase. These drugs decreased cell proliferation, presumably due to the induction of cell death and arrest of the cell cycle in AtT-20 cells. Tumor weight in mice xenografted with AtT-20 cells and treated with CCT018159 was lower than in AtT-20-xenografted control mice. CCT018159 also decreased plasma ACTH levels, and POMC and PTTG1 mRNA levels in the tumor cells. CONCLUSIONS: CCT018159 inhibits ACTH production and corticotroph tumor cell proliferation in vitro and in vivo. PMID- 25280814 TI - A systematic review of self-reported swallowing assessments in progressive neurological disorders. AB - Dysphagia experienced as a consequence of neurodegenerative disease can have severe consequences on a patient's health and well-being. Regular assessment of swallowing function can assist to achieve adequate nutrition and hydration. Here we review subjective swallowing assessments currently available are suitable for use in people with neurodegenerative disease. Measurement properties were reviewed for each tool and coverage of the World Health Organization's International Classification of Functioning, Disability and Health (WHO ICF) was considered. Assessments were identified following a review of the published literature Instruments were reviewed on the basis of reliability and validity, as well as administrative properties, such an interpretability, acceptability, and feasibility. Tools were also evaluated according to the WHO ICF framework. In total, 19 studies were identified for full-text review from 13,315 abstracts. Nine self-reported dysphagia assessment tools suitable for use in progressive neurological disorders were identified. The Swallowing Quality of Life Questionnaire (SWAL-QOL) yields the strongest combination of reliability (including internal consistency and test-retest reliability) and convergent validity while simultaneously covering all WHO ICF domains. Lengthy administration time was identified as a limitation of the SWAL-QOL. The review highlights a relative lack of well-validated self-report questionnaires in dysphagia for people with progressive neurological disease. Additional validation and evaluation of the clinical utility of the tools currently available is required to further promote an informed selection of available assessments. PMID- 25280815 TI - Hammondia hammondi harbors functional orthologs of the host-modulating effectors GRA15 and ROP16 but is distinguished from Toxoplasma gondii by a unique transcriptional profile. AB - Toxoplasma gondii and its nearest extant relative, Hammondia hammondi, are phenotypically distinct despite their remarkable similarity in gene content, synteny, and functionality. To begin to identify genetic differences that might drive distinct infection phenotypes of T. gondii and H. hammondi, in the present study we (i) determined whether two known host-interacting proteins, dense granule protein 15 (GRA15) and rhoptry protein 16 (ROP16), were functionally conserved in H. hammondi and (ii) performed the first comparative transcriptional analysis of H. hammondi and T. gondii sporulated oocysts. We found that GRA15 and ROP16 from H. hammondi (HhGRA15 and HhROP16) modulate the host NF-kappaB and STAT6 pathways, respectively, when expressed heterologously in T. gondii. We also found the transcriptomes of H. hammondi and T. gondii to be highly distinct. Consistent with the spontaneous conversion of H. hammondi tachyzoites into bradyzoites both in vitro and in vivo, H. hammondi high-abundance transcripts are enriched for genes that are of greater abundance in T. gondii bradyzoites. We also identified genes that are of high transcript abundance in H. hammondi but are poorly expressed in multiple T. gondii life stages, suggesting that these genes are uniquely expressed in H. hammondi. Taken together, these data confirm the functional conservation of known T. gondii virulence effectors in H. hammondi and point to transcriptional differences as a potential source of the phenotypic differences between these species. PMID- 25280816 TI - Protein phosphatase 2A (PP2A) regulatory subunits ParA and PabA orchestrate septation and conidiation and are essential for PP2A activity in Aspergillus nidulans. AB - Protein phosphatase 2A (PP2A) is a major intracellular protein phosphatase that regulates multiple aspects of cell growth and metabolism. Different activities of PP2A and subcellular localization are determined by its regulatory subunits. Here we identified and characterized the functions of two protein phosphatase regulatory subunit homologs, ParA and PabA, in Aspergillus nidulans. Our results demonstrate that ParA localizes to the septum site and that deletion of parA causes hyperseptation, while overexpression of parA abolishes septum formation; this suggests that ParA may function as a negative regulator of septation. In comparison, PabA displays a clear colocalization pattern with 4',6-diamidino-2 phenylindole (DAPI)-stained nuclei, and deletion of pabA induces a remarkable delayed-septation phenotype. Both parA and pabA are required for hyphal growth, conidiation, and self-fertilization, likely to maintain normal levels of PP2A activity. Most interestingly, parA deletion is capable of suppressing septation defects in pabA mutants, suggesting that ParA counteracts PabA during the septation process. In contrast, double mutants of parA and pabA led to synthetic defects in colony growth, indicating that ParA functions synthetically with PabA during hyphal growth. Moreover, unlike the case for PP2A-Par1 and PP2A-Pab1 in yeast (which are negative regulators that inactivate the septation initiation network [SIN]), loss of ParA or PabA fails to suppress defects of temperature sensitive mutants of the SEPH kinase of the SIN. Thus, our findings support the previously unrealized evidence that the B-family subunits of PP2A have comprehensive functions as partners of heterotrimeric enzyme complexes of PP2A, both spatially and temporally, in A. nidulans. PMID- 25280817 TI - Factors associated with severity of leukoaraiosis in first-ever lacunar stroke and atherosclerotic ischemic stroke patients. AB - BACKGROUND: Leukoaraiosis (LA) is an indicator of small vessel disease, but little is known about the relationship between the severity of LA and etiologic subtype of ischemic stroke. Our study aimed to investigate the factors associated with the severity of LA and the relationship between the severity of LA and etiologic subtype of ischemic stroke. METHODS: A total of 791 patients with first ever ischemic stroke within 7 days were enrolled in our study. We evaluated cranial magnetic resonance imagings including severity of LA in periventricular and deep white matter, severity of silent lacunar infarcts (SLIs), etiologic subtype of ischemic stroke, and topographic patterns of acute cerebral infarcts. Severity of LA was graded as grade 0 when Fazekas scores = 0, grade 1 when Fazekas scores ranged from 1 to 2, and grade 2 when Fazekas scores were greater than or equal to 3. Multivariable ordinal logistic regression was used to analyze the factors associated with the severity of LA. RESULTS: A total of 748 patients (94.6%) had LA, the numbers and proportions of grade 0, grade 1, and grade 2 LA were 43 patients (5.4%), 413 patients (52.2%), and 335 patients (42.4%), respectively. In multivariable ordinal logistic regression analysis, increasing age, higher diastolic blood pressure, admission National Institutes of Health Stroke Scale scores less than or equal to 3, presence of SLIs, and small artery occlusion (SAO) subtype of ischemic stroke were found to be independently associated with higher grade of LA. CONCLUSIONS: LA is prevalent in first-ever ischemic stroke patients. Severe LA is more frequently associated with higher grades of SLIs and ischemic stroke due to SAO. PMID- 25280818 TI - Research article: clinical characteristics of isolated anterior cerebral artery territory infarction due to arterial dissection. AB - BACKGROUND: Isolated brain infarction in the anterior cerebral artery (ACA) territory is rare, and its etiology has not yet been fully elucidated. Thus, we aimed to determine the etiologic and clinical characteristics of patients with isolated ACA territory infarction due to arterial dissection. METHODS: Of 2315 patients with acute cerebral infarction admitted to our hospital between April 2007 and September 2013, 34 patients (1.5%; 28 men, 6 women; mean age, 65 +/- 15 years) suffered isolated ACA territory infarction. We performed cranial magnetic resonance (MR) imaging and MR angiography for all the patients. Whenever possible, we also performed 3-dimensional computed tomography angiography, digital subtraction angiography, and MR cisternography to diagnose the stroke subtype. RESULTS: The stroke subtypes of the 34 patients with isolated ACA territory infarction were atherothrombotic infarction, cardioembolic infarction, arterial dissection, and unclassified in 11 patients (32%), 11 patients (32%), 11 patients (32%), and 1 patient (3%), respectively. The mean ages at onset were 48 +/- 9 and 72 +/- 11 years in the dissection and nondissection groups, respectively (P < .001). Headaches were present at onset in 4 patients (36%) and 1 patient (4%) with and without dissection, respectively (P = .026). Blood pressure at onset was significantly higher among patients with dissection (systolic, 179 +/- 34 mm Hg; diastolic, 102 +/- 17 mm Hg) than among patients without dissection (systolic, 155 +/- 30 mm Hg; diastolic, 86 +/- 21 mm Hg; P < .05), and d-dimer values were significantly lower among patients with dissection (P = .034). Favorable clinical outcome (modified Rankin Scale score, 0-2) at discharge was achieved in 9 patients (82%) and 10 patients (43%) with and without dissection, respectively (P = .035). CONCLUSIONS: Patients with isolated ACA territory infarction demonstrated a relatively high frequency of dissection (32%). Patients with dissection were younger, had a higher frequency of headaches, and demonstrated more favorable prognoses than patients without dissection. PMID- 25280819 TI - Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban. AB - As limited amounts of data are available regarding thrombolytic therapy for patients taking novel oral anticoagulants, thrombolytic therapy is not recommended in such cases. Here, we report an acute stroke patient taking rivaroxaban who received intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). An 80-year-old man with a history of nonvalvular atrial fibrillation, who had been receiving 10 mg of rivaroxaban showed abrupt onset of aphasia and right hemiparesis. National Institutes of Health Stroke Scale score was 10. Onset of neurologic deficits occurred 4 hours after the last dose of rivaroxaban. Clinical data on admission were as follows: blood pressure, 170/90 mm Hg; prothrombin time (PT), 22.6 seconds (control, 12.9 seconds); international normalized ratio, 2.03; activated partial thromboplastin time, 46 seconds (normal, 23-32 seconds); and creatinine level, 1.11 mg/dL. Magnetic resonance angiography revealed occlusion of the superior trunk of the left middle cerebral artery. Intravenous infusion of .6 mg/kg of rt-PA (total dose, 36 mg) was performed 6 hours after the last rivaroxaban administration with informed consent. The neurologic deficit improved during infusion of rt-PA. Repeat brain computed tomography showed left frontal cortical infarction without hemorrhagic changes. In the case of rivaroxaban, it is difficult to accurately determine the drug activity. As the anticoagulant activity of rivaroxaban can be estimated from its pharmacokinetics and PT, it is clinically important to obtain accurate information about the timing of medication and blood sampling. PMID- 25280820 TI - Treatment strategy for bilateral carotid stenosis: 2 cases of carotid endarterectomy for the symptomatic side followed by carotid stenting. AB - Since the introduction of carotid stenting (CAS), a combined treatment for bilateral lesions using carotid endarterectomy (CEA) and CAS has been developed. However, there has been only 1 report about CEA then CAS. Herein we describe 2 patients with bilateral severe carotid stenosis who were treated by CEA for the symptomatic side and CAS for the contralateral asymptomatic side. A 71-year-old man underwent CEA for the symptomatic side. Although the patient suffered hyperperfusion syndrome after CEA, he recovered fully after 3 weeks of rehabilitation. Two months later, CAS was performed for the asymptomatic side, and he was discharged with no deficit. A 67-year-old man underwent CEA for the symptomatic side. The patient developed no postoperative neurologic deficits except for hoarseness. Four weeks later, CAS was performed for the contralateral asymptomatic side. After the procedure, however, severe hypotension occurred, and treatment by continuous injection of catecholamine was necessary to maintain systematic blood pressure. The patient was ultimately discharged with no deficit. The combined therapy of CAS for the asymptomatic side and then CEA for the symptomatic side has been recommended by several authors. However, one of the problems of this strategy is the higher incidence of postprocedural hemodynamic complications, and hypotension after CAS may be dangerous for the symptomatic hemisphere. We suggest a combined therapy using CEA for the symptomatic side and then CAS for the asymptomatic side can be 1 beneficial treatment option for patients with bilateral carotid stenosis without coronary artery disease. PMID- 25280821 TI - Do characteristics of dissection differ between the posterior inferior cerebellar artery and the vertebral artery? AB - OBJECTIVE: The purpose of this study was to clarify the features of posterior inferior cerebellar artery (PICA) dissection. MATERIALS AND METHODS: We prospectively registered 93 consecutive patients and 108 arteries with confirmed diagnoses of dissection in the vertebral artery (VA) or PICA between February 2007 and January 2014. Patients were diagnosed with arterial dissection when they had both acute symptoms and radiological characteristics in magnetic resonance imaging or digital subtraction angiography. Patients were divided into 2 groups depending on whether the site of dissection was VA (VA group) or PICA (PICA group). We compared the clinical and radiological characteristics and clinical outcomes of PICA versus VA dissection. RESULTS: Of the 93 patients included in this study, 83 were in the VA group, and 10 had arterial dissection in the PICA. Patients with PICA dissection more frequently suffered from SAH (P < .001), whereas nonstroke symptom was often the initial symptom in the VA group. Pearl sign was seen most frequently at the dissection site of PICA. Surgical or endovascular treatment was performed in 9 of 10 PICA dissections, whereas more than half of the VA dissections were treated conservatively (P < .001). SAH was significantly more severe in the patients with PICA dissection compared with those in the VA group (P = .049). CONCLUSION: Patients with PICA dissection suffered from subarachnoid hemorrhage more frequently than those with VA dissection. PICA dissection was treated with surgical intervention, whereas VA dissection was treated conservatively. PMID- 25280822 TI - Anti-inflammatory and antiapoptotic effects of mesenchymal stem cells transplantation in rat brain with cerebral ischemia. AB - BACKGROUND: Excessive inflammation and apoptosis contribute to the pathogenesis of ischemic brain damage. Nuclear factor-kappa B (NF-kappaB) is considered to be a key protein complex involved in this cascade of events. The aim of the present study was to clarify the protection mechanism of the mesenchymal stem cells (MSCs). METHODS: Lewis rats (N = 90) were randomly assigned to three groups: (1) the sham-operated group; (2) the saline group, in which the animals underwent rat transient middle cerebral artery occlusion (tMCAO, for 2 hours) and were treated with saline through the tail vein; and (3) the MSCs group, in which the animals underwent tMCAO (for 2 hours) and were infused with cultured human MSCs (4 * 10(6)/0.4 ml PBS) through the tail vein. At days 1 and 3 post-MSCs infusion, real time PCR, and Western blot, immunohistochemical analyses were applied for tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and P-IKKbeta, p53, and B-cell lymphoma 2 (Bcl-2) expression levels. RESULTS: TNF-alpha, IL 1beta messenger RNA (mRNA) and P-IkappaB-alpha, P-IKKbeta, p53 protein expression levels were significantly increased in the saline group compared with the sham group. However, IkappaB-alpha and Bcl-2 protein expression levels were markedly decreased in the saline group. After injection of BrdU(+) MSCs, the expression levels of TNF-alpha, IL-1beta mRNA and P-IkappaB-alpha, P-IKKbeta, p53 protein were significantly decreased. Contrary to these findings, IkappaB-alpha, Bcl-2 protein expression levels were markedly increased. In addition, we found that infarct area was significantly reduced in MSCs group. CONCLUSIONS: These results suggest that MSCs' neuroprotection is attributable to its anti-inflammatory and antiapoptotic effect through inhibition of NF-kappaB. PMID- 25280823 TI - Randomized controlled trial of interpersonal psychotherapy versus enhanced treatment as usual for women with co-occurring depression and pelvic pain. AB - OBJECTIVE: Our study assessed the effectiveness of Interpersonal Psychotherapy (IPT) tailored for biomedical patients with depression and pain. IPT was compared to enhanced treatment as usual (E-TAU) among women with co-occurring depression and chronic pain presenting for care at a women's health or family medicine practice. We hypothesized that women presenting to urban medical practices with depression and chronic pain would benefit from IPT tailored to address their needs to a greater degree than from E-TAU. METHODS: We conducted a randomized controlled psychotherapy trial of 61 women from 2 urban medical practices who met criteria for major depressive disorder and chronic pelvic pain. Participants were assigned to receive either 8 sessions of IPT or a facilitated psychotherapy referral to a community mental health center, and assessed for depression, social interactions, and pain at 0-, 12-, 24-, and 36-weeks, with score on the Hamilton Rating Scale for Depression as the primary outcome. Both intent-to-treat (ITT) and causal modeling analyses correcting for treatment attendance were conducted. RESULTS: ITT analyses were not significant. In causal modeling analyses, participants assigned to IPT showed significantly more improvement for depression and social interactions, but not for pain. CONCLUSION: IPT may be a viable option as part of a comprehensive treatment program for women in medical practices with depression and chronic pain. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT00895999. PMID- 25280824 TI - Complex regional pain syndrome, alexithymia, and psychological distress. AB - OBJECTIVE: This study aims to elucidate the relationships between alexithymia, psychological distress, and pain in persons with complex regional pain syndrome (CRPS). METHODS: Participants were 60 Israeli adults ages 19-65. This is a cross sectional study with a comparison group. Alexithymia, psychological distress, and pain were assessed in 30 individuals with CRPS in comparison to 30 gender- and age-matched persons with lower back pain (LBP). Assessments included the Toronto Alexithymia Scale, Hospital Anxiety and Depression Scale, and two subscales of the McGill Pain Questionnaire. RESULTS: Persons with CRPS had significantly higher ratings of psychological distress and of alexithymia when compared to LBP controls. Pain severity was significantly associated with higher levels of alexithymia and psychological distress among persons with CRPS, but not among controls. Alexithymia and pain severity correlations were significantly different between the two groups. In persons with CRPS, the relationships between alexithymia and pain severity and between difficulty identifying feelings and pain were not confounded by psychological distress. CONCLUSIONS: To our knowledge, this is the first cross sectional study providing empirical evidence on the relationship between alexithymia and CRPS. From the perspective of conceptualizing alexithymia as an outcome of CRPS, findings highlight the importance of early CRPS diagnosis and support the provision of care that addresses pain-related psychological distress and alexithymia among CRPS patients. Also, findings underscore the need to generate alternative, non physical avenues, such as learning to identify feelings for processing pain, in order to reduce pain among persons with CRPS. PMID- 25280825 TI - Anxiety sensitivity and medication nonadherence in patients with uncontrolled hypertension. AB - OBJECTIVE: Anxiety sensitivity-fear of the negative social, physical, or cognitive consequences of anxiety related sensations-has been linked to cardiovascular disease and adverse cardiovascular health behaviors. Medication nonadherence may account for this association. We examined whether anxiety sensitivity was independently associated with objectively measured medication nonadherence in a multi-ethnic primary care sample. METHODS: Eighty-eight patients with uncontrolled hypertension completed the Anxiety Sensitivity Index and had their adherence to blood pressure (BP) medications measured during the interval between two primary care visits using an electronic pillbox (MedSignals(r)). Multivariable Poisson regressions were conducted to determine the relative risks of medication nonadherence associated with anxiety sensitivity after adjustment for age, gender, Hispanic/Latino ethnicity, education, total number of prescribed medications, and depressive and posttraumatic stress disorder (PTSD) symptoms. RESULTS: Nearly twice as many patients with high anxiety sensitivity were nonadherent to BP medications compared to patients with low anxiety sensitivity (65.0% vs. 36.8%; p=0.03). Patients with high anxiety sensitivity had higher relative risks of medication nonadherence than their low anxiety sensitivity counterparts (adjusted relative risk [RR]=1.76; 95% CI: 1.03 3.03). CONCLUSIONS: In this first study of the association between anxiety sensitivity and medication adherence, we found that high anxiety sensitivity was strongly associated with BP medication nonadherence, even after adjustment for known confounders. Our results suggest that teaching patients who have uncontrolled hypertension adaptive strategies to manage their anxiety sensitivity may help improve their medication adherence, and thereby lower their cardiovascular risk. PMID- 25280826 TI - Intention and planning predicting medication adherence following coronary artery bypass graft surgery. AB - OBJECTIVE: Medication adherence rates after coronary artery bypass graft (CABG) surgery are low due to intentional (e.g., deliberately choosing not to take medication) and unintentional (e.g., forgetting to take the medication) person related factors. There is a lack of studies examining the psychological factors related to non-adherence in CABG patients. Intentions to take medication and planning when, where, and how to take medication and to overcome unintentional forgetting to take medication were hypothesized to be independently related to medication adherence. Furthermore, planning to overcome forgetting was hypothesized to be more strongly associated with medication adherence in patients who have stronger intentions to take medication, reflecting the idea that planning is a factor that specifically helps in patients who are willing to take medication, but fail to do so. METHODS: Measures of medication adherence, intention and planning were collected in a sample of (N=197) post-CABG surgery patients followed from discharge (baseline; Time 1) over a 12-month period (Time 2) in Boo-Ali Hospital in Qazvin, Iran. A series of hierarchical multiple regression analyses were performed in which medication adherence at Time 2 was regressed onto socio-demographic and clinical factors, the hypothesized psychological variables (adherence-related intention and planning), and interaction terms. RESULTS: Intentions to take medication (B=.30, P<.01), action planning when, where, and how to take the medication (B=.19, P<.01), and coping planning how to avoid forgetting to take the medication (B=.16, P<.01) were independently related to medication adherence. Beyond that, action planning * intention to take medication (B=.06, P<.05) and coping planning * intention (B=.07, P<.01) interaction also significantly predicted adherence. CONCLUSION: Intention to take medication was associated with better medication adherence and action and coping planning strategies to avoid forgetting to take the medication added significantly to the prediction of adherence in the year following CABG discharge. This is in line with theory and evidence about the independent roles of intentional and unintentional predictors of non-adherence. As hypothesized, planning to overcome unintentional forgetting to take the medication was more predictive of medication adherence in those patients who reported higher intentions to take medication, reflecting the idea that planning helps patients overcome unintentional reasons of being non-adherent. PMID- 25280828 TI - The Common Sense Model in early adolescents with asthma: longitudinal relations between illness perceptions, asthma control and emotional problems mediated by coping. AB - OBJECTIVE: The present study examined the longitudinal relations between illness perceptions and asthma control and emotional problems (i.e., anxiety, depression, stress), respectively, in adolescents with asthma. Furthermore, the mediating effects of asthma-specific coping strategies on these relations were examined, as specified in the Common Sense Model (CSM). METHODS: In 2011, 2012, and 2013, adolescents (aged 10-15) with asthma were visited at home (N=253) and completed questionnaires about their illness perceptions, asthma-specific coping strategies, asthma control, symptoms of anxiety and depression, and perceived stress. Path analyses were used to examine the direct relations of illness perceptions with asthma control and emotional problems and the mediating effects of coping strategies cross-sectionally and longitudinally. RESULTS: Perceptions of less perceived control and attributing more complaints to asthma were associated with better asthma control. Perceptions of more concern, less coherence, and increased influence of asthma on emotional well-being were associated with more emotional problems. Longitudinally, perceptions of more treatment control and fewer concerns predicted less emotional problems over time. More worrying mediated the cross-sectional relation between perceiving more concern about asthma and less asthma control and the longitudinal relation between perceiving more concern about asthma and more emotional problems. CONCLUSION: Illness perceptions were associated with asthma control and emotional problems; however, over time, illness perceptions only predicted changes in emotional problems. Most coping strategies did not mediate the relation between illness perceptions and outcomes. Interventions aimed to change illness perceptions in adolescents with asthma could decrease emotional problems. PMID- 25280827 TI - Asthma and odors: the role of risk perception in asthma exacerbation. AB - OBJECTIVE: Fragrances and strong odors have been characterized as putative triggers that may exacerbate asthma symptoms and many asthmatics readily avoid odors and fragranced products. However, the mechanism by which exposure to pure, non-irritating odorants can elicit an adverse reaction in asthmatic patients is still unclear and may involve both physiological and psychological processes. The aim of this study was to investigate how beliefs about an odor's relationship to asthmatic symptoms could affect the physiological and psychological responses of asthmatics. METHODS: Asthmatics classified as 'moderate-persistent', according to NIH criteria, were exposed for 15 min to a fragrance which was described either as eliciting or alleviating asthma symptoms. During exposure, participants were asked to rate odor intensity, perceived irritation and subjective annoyance while physiological parameters such as electrocardiogram, respiratory rate, and end tidal carbon dioxide (etCO2) were recorded. Before, immediately after, and at 2 and 24h post-exposure, participants were required to subjectively assess their asthma symptom status using a standardized questionnaire. We also measured asthma status at each of those time points using objective parameters of broncho constriction (spirometry) and measures of airway inflammation (exhaled nitric oxide, FeNO). RESULTS: Predictably, manipulations of perceived risk altered both the quality ratings of the fragrance as well as the reported levels of asthma symptoms. Perceived risk also modulated the inflammatory airway response. CONCLUSIONS: Expectations elicited by smelling a perceived harmful odor may affect airway physiology and impact asthma exacerbations. PMID- 25280830 TI - Can quick first step bio-psycho-social screening, COMPRI (COMplexity PRediction Instrument), predict length of hospital stay in a general hospital in Japan? PMID- 25280829 TI - Is atopy in early childhood a risk factor for ADHD and ASD? a longitudinal study. AB - OBJECTIVE: Previous studies have found a temporal concordance in the increased prevalence of atopic diathesis/atopic diseases, attention-deficit hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD) worldwide. But, the temporal association among these 3 distinct diseases is unknown. METHOD: 14,812 atopic subjects diagnosed with any atopic disease (asthma, atopic dermatitis, allergic rhinitis, or allergic conjunctivitis) before the age of 3 (atopic cohort) and 6944 non-atopic subjects with no lifetime atopic disease (non-atopic cohort), born between 1997 and 2000, were enrolled and followed to December 31, 2010 to identify the development of ADHD and ASD. RESULTS: The presence of any atopic disease in early childhood increased the risk of developing ADHD (hazard ratio [HR]: 1.97) and ASD (HR: 3.40) in later life. Greater numbers of atopic comorbidities (4 comorbidities: ADHD: HR: 2.53; ASD: HR: 4.29) were significantly related to a greater risk of developing ADHD and ASD. DISCUSSION: Atopic diathesis in early childhood elevated the risk of developing ADHD and ASD in later life, with the dose-dependent relationship of more atopic comorbidities with a greater likelihood of ADHD and ASD. PMID- 25280832 TI - Cervicofacial actinomycosis. PMID- 25280831 TI - Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death. AB - Stress adaptation effect provides cell protection against ischemia induced apoptosis. Whether this mechanism prevents other types of cell death in stroke is not well studied. This is an important question for regenerative medicine to treat stroke since other types of cell death such as necrosis are also prominent in the stroke brain apart from apoptosis. We report here that treatment with 17-N Allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, protected neural progenitor cells (NPCs) against oxygen glucose deprivation (OGD) induced cell death in a dose dependent fashion. Cell death assays indicated that 17AAG not only ameliorated apoptosis, but also necrosis mediated by OGD. This NPC protection was confirmed by exposing cells to oxidative stress, a major stress signal prevalent in the stroke brain. Mechanistic studies demonstrated that 17AAG activated PI3K/Akt and MAPK cell protective pathways. More interestingly, these two pathways were activated in vivo by 17AAG and 17AAG treatment reduced infarct volume in a middle cerebral artery occlusion (MCAO) stroke model. These data suggest that 17AAG protects cells against major cell death pathways and thus might be used as a pharmacological conditioning agent for regenerative medicine for stroke. PMID- 25280834 TI - Signaling mechanism of protease activated receptor 1-induced proliferation of astrocytes: stabilization of hypoxia inducible factor-1alpha triggers glucose metabolism and accumulation of cyclin D1. AB - Thrombin was found to stimulate astrocytes proliferation. In this study, we want to clarify whether thrombin-activated protease-activated receptor will affect the glucose metabolism signaling pathways to accelerate the proliferation of astrocytes. In addition, we study if thrombin has effects on cell cycle transition to promote astrocytes proliferation. We firstly observed that thrombin activated protease-activated receptor 1 (PAR-1) inducing the increases of intracellular Ca(2+) and ROS production, which contribute to the astrocytes' proliferation. We further confirmed that ROS stabilized HIF-1alpha, the latter subsequently accelerated glucose uptake in astrocytes. On the other hand, we demonstrated that thrombin triggered PI3K/Akt/cyclin D1 signal transduction, which may promote the cell cycle transition to enhance astrocytes proliferation. As a result, we discovered three signaling pathways mainly accounting for cell proliferation induced by thrombin: (1) thrombin-stimulated ERK, JNK/ROS/HIF 1alpha and (2) PI3K/Akt/ROS/HIF-1alpha pathways to increase expression of hexokinase 2 which mediated glucose metabolism in astrocytes, and (3) thrombin stimulates PAR-1/PI3K/Akt/cyclin D1 to promote the cell cycle transition and finally to increase cell proliferation. PMID- 25280833 TI - Further evidence for the neuroprotective role of oleanolic acid in a model of focal brain hypoxia in rats. AB - Ischemic brain injury is a dynamic process involving oxidative stress, inflammation, cell death and the activation of endogenous adaptive and regenerative mechanisms depending on the activation of transcription factors such as hypoxia-inducible factor 1-alpha. Accordingly, we have previously described a new focal hypoxia model by direct intracerebral cobalt chloride injection. In turn, oleanolic acid, a plant-derived triterpenoid, has been extensively used in Asian countries for its anti-inflammatory and anti-tumor properties. A variety of novel pharmacological effects have been attributed to this triterpenoid, including beneficial effects on neurodegenerative disorders--including experimental autoimmune encephalomyelitis--due to its immunomodulatory activities at systemic level, as well as within the central nervous system. In this context, we hypothesize that this triterpenoid may be capable of exerting neuroprotective effects in ischemic brain, suppressing glial activities that contribute to neurotoxicity while promoting those that support neuronal survival. In order to test this hypothesis, we used the intraperitoneal administration of oleanoic acid in adult rats for seven days previous to focal cortical hypoxia induced by cobalt chloride brain injection. We analyzed the neuroprotective effect of oleanoic acid from a morphological point of view, focusing on neuronal survival and glial reaction. PMID- 25280837 TI - Impact of a lung-protective ventilatory strategy on systemic and pulmonary inflammatory responses during laparoscopic surgery: is it really helpful? AB - Laparoscopic surgery is performed by carbon dioxide (CO2) insufflation, but this may induce stress responses. The aim of this study is to compare the level of inflammatory mediators in patients receiving low tidal volume (VT) versus traditional VT during gynecological laparoscopic surgery. Forty American Society of Anesthesiologists (ASA) physical status 1 and 2 subjects older than 18 years old undergoing laparoscopic gynecological surgery were included. Systemic inflammatory response was assessed with serum IL-6, TNF-alpha, IL-8, and IL-1beta in patients receiving intraoperative low VT and traditional VT during laparoscopic surgery [within the first 5 min after endotracheal intubation (T1), 60 min after the initiation of mechanical ventilation (T2), and in the postanesthesia care unit 30 min after tracheal extubation (T3)]. Additionally, inflammatory response was assessed with bronchoalveolar lavage (BAL) at T1 and T3 periods. An increase in the serum levels of IL-6, TNF-alpha, IL-8, and IL-1beta was observed in both groups during the time periods of T1, T2, and T3. No significant differences were found in the serum and BAL levels of inflammatory mediators during time periods between groups. The results of the present study suggested that the lung-protective ventilation and traditional strategies are not different in terms of lung injury and inflammatory response during conventional laparoscopic gynecological surgery. PMID- 25280838 TI - Bench-scale biodegradation tests to assess natural attenuation potential of 1,4 dioxane at three sites in California. AB - 1,4-Dioxane (dioxane) is relatively recalcitrant to biodegradation, and its physicochemical properties preclude effective removal from contaminated groundwater by volatilization or adsorption. Through this microcosm study, we assessed the biodegradation potential of dioxane for three sites in California. Groundwater and sediment samples were collected at various locations at each site, including the presumed source zone, middle and leading edge of the plume. A total of 16 monitoring wells were sampled to prepare the microcosms. Biodegradation of dioxane was observed in 12 of 16 microcosms mimicking natural attenuation within 28 weeks. Rates varied from as high as 3,449 +/- 459 ug/L/week in source-zone microcosms to a low of 0.3 +/- 0.1 ug/L/week in microcosms with trace level of dioxane (<10 ug/L as initial concentration). The microcosms were spiked with (14)C-labeled dioxane to assess the fate of dioxane. Biological oxidizer-liquid scintillation analysis of bound residue infers that 14C-dioxane was assimilated into cell material only in microcosms exhibiting significant dioxane biodegradation. Mineralization was also observed per (14)CO2 recovery (up to 44% of the amount degraded in 28 weeks of incubation). Degradation and mineralization activity significantly decreased with increasing distance from the contaminant source area (p < 0.05), possibly due to less acclimation. Furthermore, both respiked and repeated microcosms prepared with source-zone samples from Site 1 confirmed relatively rapid dioxane degradation (i.e., 100 % removal by 20 weeks). These results show that indigenous microorganisms capable of degrading dioxane are present at these three sites, and suggest that monitored natural attenuation should be considered as a remedial response. PMID- 25280839 TI - Childhood income volatility and adult outcomes. AB - Using data linked across generations in the Panel Study of Income Dynamics, I estimate the relationship between exposure to volatile income during childhood and a set of socioeconomic outcomes in adulthood. The empirical framework is an augmented intergenerational income mobility model that includes controls for income volatility. I measure income volatility at the family level in two ways: (1) instability as measured by squared deviations around a family-specific mean; and (2) instability as percentage changes of 25 % or more. Volatility enters the model both separately and interacted with income level. I find that family income volatility during childhood has a modest negative association with educational attainment. Volatility has a smaller descriptive role in explaining intergenerational outcomes relative to permanent income. Across the income distribution, the negative association between volatility exposure and educational attainment is largest for young adults from moderate-income families. PMID- 25280841 TI - Physicochemical perspective on "polydopamine" and "poly(catecholamine)" films for their applications in biomaterial coatings. AB - Bioinspired poly(catecholamine) based coatings, mostly "polydopamine," were conceived based on the chemistry used by mussels to adhere strongly to the surface of stones and wood in water and to remain attached to their substrates even under conditions of strong shear stresses. These kinds of films can in turn be easily modified with a plethora of molecules and inorganic (nano)materials. This review shows that poly(catecholamine) based coatings are an ideal film forming method for applications in the field of biomaterials. It is written from a physicochemical and a materials science perspective and discusses optical, chemical, electrochemical, and mechanical properties of polydopamine films. It further demonstrates that a better understanding of the polydopamine film deposition mechanism is warranted to improve the properties of these coatings even further. PMID- 25280840 TI - When does time matter? maternal employment, children's time with parents, and child development. AB - This study tests the two assumptions underlying popularly held notions that maternal employment negatively affects children because it reduces time spent with parents: (1) that maternal employment reduces children's time with parents, and (2) that time with parents affects child outcomes. We analyze children's time diary data from the Child Development Supplement of the Panel Study of Income Dynamics and use child fixed-effects and IV estimations to account for unobserved heterogeneity. We find that working mothers trade quantity of time for better "quality" of time. On average, maternal work has no effect on time in activities that positively influence children's development, but it reduces time in types of activities that may be detrimental to children's development. Stratification by mothers' education reveals that although all children, regardless of mother's education, benefit from spending educational and structured time with their mothers, mothers who are high school graduates have the greatest difficulty balancing work and child care. We find some evidence that fathers compensate for maternal employment by increasing types of activities that can foster child development as well as types of activities that may be detrimental. Overall, we find that the effects of maternal employment are ambiguous because (1) employment does not necessarily reduce children's time with parents, and (2) not all types of parental time benefit child development. PMID- 25280842 TI - Grafting titanium nitride surfaces with sodium styrene sulfonate thin films. AB - The importance of titanium nitride lies in its high hardness and its remarkable resistance to wear and corrosion, which has led to its use as a coating for the heads of hip prostheses, dental implants and dental surgery tools. However, the usefulness of titanium nitride coatings for biomedical applications could be significantly enhanced by modifying their surface with a bioactive polymer film. The main focus of the present work was to graft a bioactive poly(sodium styrene sulfonate) (pNaSS) thin film from titanium nitride surfaces via a two-step procedure: first modifying the surface with 3-methacryloxypropyltrimethoxysilane (MPS) and then grafting the pNaSS film from the MPS modified titanium through free radical polymerization. X-ray photoelectron spectroscopy (XPS) and time-of flight secondary ion mass spectrometry (ToF-SIMS) were used after each step to characterize success and completeness of each reaction. The surface region of the titanium nitride prior to MPS functionalization and NaSS grafting contained a mixture of titanium nitride, oxy-nitride, oxide species as well as adventitious surface contaminants. After MPS functionalization, Si was detected by XPS, and characteristic MPS fragments were detected by ToF-SIMS. After NaSS grafting, Na and S were detected by XPS and characteristic NaSS fragments were detected by ToF SIMS. The XPS determined thicknesses of the MPS and NaSS overlayers were ~1.5 and ~1.7 nm, respectively. The pNaSS film density was estimated by the toluidine blue colorimetric assay to be 260 +/- 70 ng/cm(2). PMID- 25280843 TI - Microbiological investigation of an antibacterial sandwich layer system. AB - To allow medical application of an artificial bladder made of biocompatible polyurethane, a long-term stable antibacterial coating is required. Alone, the artificial bladder exhibits no defense against microorganisms. Silver coating provides long-term antibacterial protection by the continuous release of silver ions into aqueous solutions. To control and to prolong the rate of silver ion release, the deposited silver film has to be protected by an inert film of biocompatible polyparylene by means of chemical vapor deposition. In this study, an antibacterial artificial bladder surface was developed by the formation of a sandwich structure consisting of silver and a biocompatible polymer (polyparylene) as a diffusion barrier. Specifically, this study analyzed the correlation between polyparylene thickness and silver release to determine optimal concentrations to combat common bacteria in vitro. The release of silver from sandwich structures was investigated in vitro by testing different thicknesses of polyparylene (0, 190, 540, and 1000 nm) as a diffusion barrier. The best result was demonstrated with a thickness of 190 nm of polyparylene, which yielded a silver dispense rate of 650 pg/(cm(2)?min), which would yield bacteriozidal concentrations above 30 MUg/l in the bladder volume. The authors confirmed the antibacterial effect in vitro against common urinary tract infection pathogens, namely, Escherichia coli and Staphylococcus cohnii. Inhibition of bacterial growth could be detected within 8 h. A diffusion assay with spherical silver spots showed concentric zones free of bacterial growth. Our results suggest the possible utility of silver-polyparylene coatings as antibacterial agents. PMID- 25280844 TI - Comparative assessment of the stability of nonfouling poly(2-methyl-2-oxazoline) and poly(ethylene glycol) surface films: an in vitro cell culture study. AB - Poly(ethylene glycol) (PEG) has been the most frequently reported and commercially used polymer for surface coatings to convey nonfouling properties. PEGylated surfaces are known to exhibit limited chemical stability, particularly due to oxidative degradation, which limits long-term applications. In view of excellent anti-adhesive properties in the brush conformation and resistance to oxidative degradation, poly(2-methyl-2-oxazoline) (PMOXA) has been proposed recently as an alternative to PEG. In this study, the authors systematically compare the (bio)chemical stability of PEG- and PMOXA-based polymer brush monolayer thin films when exposed to cultures of human umbilical vein endothelial cells (HUVECs) and human foreskin fibroblasts (HFFs). To this end, the authors used cell-adhesive protein micropatterns in a background of the nonfouling PEG and PMOXA brushes, respectively, and monitored the outgrowth of HUVECs and HFFs for up to 21 days and 1.5 months. Our results demonstrate that cellular micropatterns spaced by PMOXA brushes are significantly more stable under serum containing cell culture conditions in terms of confinement of cells to the adhesive patterns, when compared to corresponding micropatterns generated by PEG brushes. Moreover, homogeneous PEG and PMOXA-based brush monolayers on Nb2O5 surfaces were investigated after immersion in endothelial cell medium using ellipsometry and x-ray photoelectron spectroscopy. PMID- 25280845 TI - Biodegradation performance of a chitosan coated magnesium-zinc-tricalcium phosphate composite as an implant. AB - A Mg-Zn-tricalcium phosphate composite with a chitosan coating was prepared in this investigation to study its biodegradation performance both in vitro and in vivo conditions. The in vitro test results show that the immersion corrosion rate, the pH values of the simulated body fluids and the released metal ion concentration of the chitosan coated composite are all lower than those of the uncoated composite. The in vitro cytotoxicity test shows that the chitosan coated specimens is safe for cellular applications. When the chitosan coated composite is tested in vivo, the concentration of metal ions from the composite observed in the venous blood of Zelanian rabbits is less than the uncoated composite specimens. The chitosan coating slows down the in vivo degradation of the composite after surgery. In vivo testing also indicates that the chitosan coated composite is harmless to important visceral organs, including the heart, kidneys, and liver of the rabbits. The new bone formation surrounding the chitosan coated composite implant shows that the composite improves the concrescence of the bone tissues. The chitosan coating is an effective corrosion resistant layer that reduces the hydrogen release of the implant composite, thereby decreasing the subcutaneous gas bubbles formed. PMID- 25280846 TI - Dynamic 3D cell culture via a chemoselective photoactuated ligand. AB - A new strategy to create a dynamic scaffold for three-dimensional (3D) cell experiments based on a photo-activated cell adhesive peptide ligand is described. After polymerization, the inert matrix becomes cell adhesive by chemoselective modification through the conjugation of oxyamine-terminated ligands. Furthermore, spatial and temporal control of cell culture within the 3D matrix was achieved by the use of a biospecific photoprotected peptide and visualized by confocal microscopy. PMID- 25280847 TI - Atomistic modeling of peptide adsorption on rutile (100) in the presence of water and of contamination by low molecular weight alcohols. AB - Previous models for the interface between titanium implants and biosystems take into account the oxide passivation layer and the hydroxylation, but omit the hydrocarbon contamination on air-exposed samples. The authors develop a consistent model for the contamination of the rutile (100) surface by small alcohols, which are known to be present in ambient atmosphere, and use this approach in molecular dynamics calculations. Contact angle evaluation reveals that hydrophobic surfaces can be generated. During molecular dynamics simulations with three peptides (RPRGFGMSRERQ, WFCLLGCDAGCW, and RKLPDA), polar side chains penetrate the hydrocarbons and become immobilized on the titanium dioxide. In the carbon layer, the peptide recognizes a hydrophobic environment, which was not present on the clean surface, and the authors attribute changes in the secondary structure in one case to this interaction. The authors further include the popular Matsui-Akaogi approach [M. Matsui and M. Akaogi, Mol. Simul. 6, 239 (1991)] into the frame of the AMBER force field and quote van der Waals parameters for fitting the original Buckingham part. With the new potential, the authors evaluated lattice parameters, thermal fluctuation, and bulk modulus. Translational diffusion coefficients and dipole autocorrelation functions of water on the surface are discussed in relation to surface properties, and it is shown that the water layers are more rigid than on earlier titanium dioxide models, and that contacts between peptide and surface are less direct. PMID- 25280848 TI - Role of hyaluronic acid and phospholipid in the lubrication of a cobalt-chromium head for total hip arthroplasty. AB - The tribological performance of total hip arthroplasty has an important influence on its success rate. This study examined the concentration-dependent role of hyaluronic acid (HA) and phospholipid (dipalmitoylphosphatidylcholine, DPPC) in the boundary lubricating ability of retrieved cobalt-chromium femoral heads. The microscale frictional coefficients (MU) were measured by atomic force microscopy using a rectangular silicon cantilever integrated with sharp silicon tips. In the case of HA lubricant, the frictional coefficients decreased significantly at concentrations of 2.0 (0.16 +/- 0.03) and 3.5 mg/ml (0.11 +/- 0.01) while increased at 5.0 mg/ml (0.15 +/- 0.01), compared to that with phosphate buffer saline (0.25 +/- 0.03). The concentration-dependent lubrication behavior of DPPC was most effective when DPPC was in the physiological concentration range, showing MU = 0.16 +/- 0.01 in polypropylene glycol, and 0.05 +/- 0.01, 0.02 +/- 0.01, and 0.03 +/- 0.01 at a DPPC concentration of 0.05, 0.2, and 3.0 mg/ml, respectively. Results obtained show significant differences between the DPPC concentration groups. Conclusively, the microscale frictional response of the retrieved CoCr femoral head has a significant dependence on the concentrations of HA and DPPC. Moreover, observed optimal concentration of HA and DPPC for effective lubrication is similar to that observed in normal human synovial fluid. Therefore, a retrieval of the synovia may be considered during total hip replacement surgeries in an effort for reduction of friction between head and liner of total hip replacement implants. PMID- 25280849 TI - Preparation and bioactive properties of nanocrystalline hydroxyapatite thin films obtained by conversion of atomic layer deposited calcium carbonate. AB - Nanocrystalline hydroxyapatite thin films were fabricated on silicon and titanium by atomic layer deposition (ALD) of CaCO3 and its subsequent conversion to hydroxyapatite by diammonium hydrogen phosphate (DAP) solution. The effects of conversion process parameters to crystallinity and morphology of the films were examined. DAP concentration was found to be critical in controlling the crystal size and homogeneity of the films. The hydroxyapatite phase was identified by XRD. ToF-elastic recoil detection analysis studies revealed that the films are calcium deficient in relation to hydroxyapatite with a Ca/P ratio of 1.39 for films converted with 0.2 M DAP at 95 degrees C. The coatings prepared on titanium conformally follow the rough surface topography of the substrate, verifying that the good step coverage of the ALD method was maintained in the conversion process. The dissolution tests revealed that the coating was nondissolvable in the cell culture medium. Annealing the coated sample at 700 degrees C for 1 h seemed to enhance its bonding properties to the substrate. Also, the biocompatibility of the coatings was confirmed by human bone marrow derived cells in vitro. The developed method provides a new possibility to produce thin film coatings on titanium implants with bone-type hydroxyapatite that is biocompatible with human osteoblasts and osteoclasts. PMID- 25280850 TI - Effect of current density on the microstructure and corrosion resistance of microarc oxidized ZK60 magnesium alloy. AB - The application of magnesium alloys as biomaterials is limited by their poor corrosion behavior. Microarc oxidation (MAO) treatment was used to prepare ceramic coatings on ZK60 magnesium alloys in order to overcome the poor corrosion resistance. The process was conducted at different current densities (3.5 and 9.0 A/dm(2)), and the effect of current density on the process was studied. The microstructure, elemental distribution, and phase composition of the MAO coatings were characterized by scanning electron microscopy, energy-dispersive x-ray spectrometry, and x-ray diffraction, respectively. The increment of current density contributes to the increase of thickness. A new phase Mg2SiO4 was detected as the current density increased to 9.0 A/dm(2). A homogeneous distribution of micropores could be observed in the coating produced at 3.5 A/dm(2), while the surface morphology of the coating formed at 9.0 A/dm(2) was more rough and apparent microcracks could be observed. The coating obtained at 3.5 A/dm(2) possessed a better anticorrosion behavior. PMID- 25280851 TI - Preventing infection of osseointegrated transcutaneous implants: Incorporation of silver into preconditioned fibronectin-functionalized hydroxyapatite coatings suppresses Staphylococcus aureus colonization while promoting viable fibroblast growth in vitro. AB - The success of transcutaneous implants depends on the achievement of a soft tissue seal by enabling fibroblasts to win the race for the surface against bacteria. Fibronectin-functionalized hydroxyapatite coatings (HAFn) have been shown to improve dermal tissue ingrowth and attachment. However, during the early postoperative period before a soft tissue seal has formed, bacterial colonization may occur. This study explored the incorporation of silver, a broad spectrum antimicrobial agent, into HAFn coatings with the aim of reducing bacterial colonization. Silver is known to have dose-dependent cytotoxic effects. Therefore, the effects of silver incorporation into HAFn coatings on both in vitro human dermal fibroblast viability and Staphylococcus aureus colonization were assessed. An electrochemical deposition technique was used to codeposit hydroxyapatite and silver (HAAg) and fibronectin was adsorbed onto this to produce HAAgFn coatings. Surfaces were preconditioned with serum to mimic the in vivo environment. Nonpreconditioned HAAg and HAAgFn coatings suppressed bacterial colonization but were cytotoxic. After serum-preconditioning, more than 90% of fibroblasts that grew on all HAAg and HAAgFn coatings were viable. The highest silver content coatings tested (HAAg100 and HAAgFn100) resulted in a greater than 99% reduction in biofilm and planktonic bacterial numbers compared to HA and HAFn controls. Although HAAg100 had greater antibacterial activity than HAAgFn100, the findings of this study indicate that fibroblasts would win the race for the surface against S aureus on both HAAg100 and HAAgFn100 after serum preconditioning. PMID- 25280852 TI - Nanoceria based electrochemical sensor for hydrogen peroxide detection. AB - Oxidative stress is a condition when the concentration of free radicals and reactive molecular species rise above certain level in living systems. This condition not only perturbs the normal physiology of the system but also has been implicated in many diseases in humans and other animals. Hydrogen peroxide (H2O2) is known to be involved in induction of oxidative stress and has also been linked to a variety of ailments such as inflammation, rheumatoid arthritis, diabetes, and cancer in humans. It is one of the more stable reactive molecular species present in living systems. Because of its stability and links with various diseases, sensing the level of H2O2 can be of great help in diagnosing these diseases, thereby easing disease management and amelioration. Nanoceria is a potent candidate in free radical scavenging as well as sensing because of its unique redox properties. These properties have been exploited, in the reported work, to sense and quantify peroxide levels. Nanoceria has been synthesized using different capping agents: Hexamethylene-tetra-amine (HMTA) and fructose. CeO2 HMTA show rhombohedral and cubic 6.4 nm particles whereas CeO2-fructose are found to be spherical with average particle diameter size 5.8 nm. CeO2-HMTA, due to the better exposure of the active (200) and (220) planes relative to (111) plane, exhibits superior electrocatalytic activity toward H2O2 reduction. Amperometric responses were measured by increasing H2O2 concentration. The authors observed a sensitivity of 21.13 and 9.6 MUA cm(-2) mM(-1) for CeO2-HMTA and CeO2-fructose, respectively. The response time of 4.8 and 6.5 s was observed for CeO2-HMTA and CeO2-fructose, respectively. The limit of detection is as low as 0.6 and 2.0 MUM at S/N ratio 3 for CeO2-HMTA and CeO2-fructose, respectively. Ceria-HMTA was further tested for its antioxidant activity in an animal cell line in vitro and the results confirmed its activity. PMID- 25280853 TI - Epithelial cell morphology and adhesion on diamond films deposited and chemically modified by plasma processes. AB - The authors show that nanocrystalline diamond (NCD) thin films prepared by microwave plasma enhanced chemical vapor deposition apparatus with a linear antenna delivery system are well compatible with epithelial cells (5637 human bladder carcinoma) and significantly improve the cell adhesion compared to reference glass substrates. This is attributed to better adhesion of adsorbed layers to diamond as observed by atomic force microscopy (AFM) beneath the cells. Moreover, the cell morphology can be adjusted by appropriate surface treatment of diamond by using hydrogen and oxygen plasma. Cell bodies, cytoplasmic rims, and filopodia were characterized by Peakforce AFM. Oxidized NCD films perform better than other substrates under all conditions (96% of cells adhered well). A thin adsorbed layer formed from culture medium and supplemented with fetal bovine serum (FBS) covered the diamond surface and played an important role in the cell adhesion. Nevertheless, 50-100 nm large aggregates formed from the RPMI medium without FBS facilitated cell adhesion also on hydrophobic hydrogenated NCD (increase from 23% to 61%). The authors discuss applicability for biomedical uses. PMID- 25280854 TI - Cocoon of the silkworm Antheraea pernyi as an example of a thermally insulating biological interface. AB - Biological materials are hierarchically organized complex composites, which embrace multiple practical functionalities. As an example, the wild silkworm cocoon provides multiple protective functions against environmental and physical hazards, promoting the survival chance of moth pupae that resides inside. In the present investigation, the microstructure and thermal property of the Chinese tussah silkworm (Antheraea pernyi) cocoon in both warm and cold environments under windy conditions have been studied by experimental and numerical methods. A new computational fluid dynamics model has been developed according to the original fibrous structure of the Antheraea pernyi cocoon to simulate the unique heat transfer process through the cocoon wall. The structure of the Antheraea pernyi cocoon wall can promote the disorderness of the interior air, which increases the wind resistance by stopping most of the air flowing into the cocoon. The Antheraea pernyi cocoon is wind-proof due to the mineral crystals deposited on the outer layer surface and its hierarchical structure with low porosity and high tortuosity. The research findings have important implications to enhancing the thermal function of biomimetic protective textiles and clothing. PMID- 25280855 TI - Influence of heat treatments upon the mechanical properties and in vitro bioactivity of ZrO2-toughened MgO-CaO-SiO2-P2O5-CaF2 glass-ceramics. AB - Zirconia-toughened MgO-CaO-SiO2-P2O5-CaF2 glass-ceramics are prepared using sintering techniques, and a series of heat treatment procedures are designed to obtain a glass-ceramic with improved properties. The crystallization behavior, phase composition, and morphology of the glass-ceramics are characterized. The bending strength, elastic modulus, fracture toughness, and microhardness of the glass-ceramics are investigated, and the effect mechanism of heat treatments upon the mechanical properties is discussed. The bioactivity of glass-ceramics is then evaluated using the in vitro simulated body fluid (SBF) soaking test, and the mechanism whereby apatite forms on the glass-ceramic surfaces in the SBF solution is discussed. The results indicate that the main crystal phase of the G-24 sample undergoing two heat treatment procedures is Ca5(PO4)3F (fluorapatite), and those of the G-2444 sample undergoing four heat treatment procedures are Ca5(PO4)3F and beta-CaSiO3 (beta-wollastonite). The heat treatment procedures are found to greatly influence the mechanical properties of the glass-ceramic, and an apatite layer is induced on the glass-ceramic surface after soaking in the SBF solution. PMID- 25280856 TI - Influence of surface coatings of poly(d,l-lactide-co-glycolide) particles on HepG2 cell behavior and particle fate. AB - This study is focused on the intracellular fate of poly(d,l-lactide-co-glycolide) (PLGA) particles with different surface coatings after cellular uptake, and their influence on the functions of human liver cancer cells (HepG2 cells). The PLGA particles coated with polyethyleneimine (PEI) and bovine serum albumin (BSA) with a similar diameter of ~400 nm but different surface chemistry were prepared. The intracellular distribution of the PLGA particles was also largely dependent on their surface coatings. The PLGA-PEI particles were removed from cells by exocytosis with a slower rate compared to the PLGA-BSA particles. In general, uptake of both types of the PLGA particles did not cause apparent impedance on cell viability and cell cycle, but uptake of the PLGA-PEI particles did have certain influence on cell functions such as intracellular level of reactive oxygen species, cytoskeleton organization, cell migration, and secretion levels of triglyceride. PMID- 25280858 TI - Plasmon resonance based analysis of a single protein conjugated Au nanoshell. AB - The authors perform a numerical calculation of a gold nanoshell, having either a silica core or a hollow one, interacting with incident electromagnetic radiation and aggregated with a single protein on its surface, by using the discrete dipole approximation. The protein model accounts for a tertiary structure that may contain internal cavities, while the entire structure is placed either in vacuum or a uniform host medium. The authors further analyze the near field pattern by a spherical harmonic transform. Our results identify the interactions that account for the observed extinction peak and wavelength shift in related optical experiments. The theoretical basis provided in this work may be used not only to identify a single protein conjugated nanoparticle, but also to determine the cavity content of the protein by its refractive index properties, determined from optical measurements. PMID- 25280857 TI - Effect of low-intensity pulsed ultrasound on biocompatibility and cellular uptake of chitosan-tripolyphosphate nanoparticles. AB - Using low molecular weight chitosan nanoparticles (CNPs) prepared by an ionic gelation method, the authors report the effect of low-intensity pulsed ultrasound (US) on cell viability and nanoparticle uptake in cultured murine preosteoblasts. Particle size and zeta potential are measured using dynamic light scattering, and cell viability is evaluated using the of [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] assay. Results show that 30 min delivery of CNPs at 0.5 mg/mL is able to prevent loss of cell viability due to either serum starvation or subsequent exposure to US (1 W/cm(2) or 2 W/cm(2), up to 1 min). Additionally, flow cytometry data suggest that there is a close association between cellular membrane integrity and the presence of CNPs when US at 2 W/cm(2) is administered. PMID- 25280859 TI - Selective covalent immobilization of ferritin on alumina. AB - Selective and specific covalent immobilization and simultaneous suppression of nonspecific adsorption of the protein ferritin (FN) on the surfaces of polycrystalline alpha-alumina colloidal particles and single alpha-alumina crystals is demonstrated. FN immobilization is obtained by using a classical immobilization route and by combining either the organic silane 3 (triethoxysilyl)propylsuccinic anhydride (TESPSA) or (3 aminopropyl)triethoxysilane (APTES) with the zero-length cross linking system N (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)/N hydroxysuccinimide (NHS). The combination of APTES or TESPSA with EDC/NHS leads to a stable FN binding via amide bonds. However, the authors demonstrate that the TESPSA-EDC/NHS system enables an overall higher amount of covalent immobilization and a simultaneous suppression of nonspecific FN adsorption. After TESPSA functionalization negatively charged carboxylic groups are formed and can at the same time both electrostatically repel the overall negatively charged FN proteins and react with EDC/NHS for FN covalent immobilization. Moreover, the authors show that by specifically controlling the FN concentration during the immobilization reaction, the molecule distribution and density of bound FN can be easily tuned. The approach presented enables to selectively immobilize FN at mild conditions on substrates with different geometries and is therefore relevant for the fabrication of biomimetic nanomaterials and two-dimensional FN arrays. PMID- 25280860 TI - A treatment study of canine symmetrical onychomadesis (symmetrical lupoid onychodystrophy) comparing fish oil and cyclosporine supplementation in addition to a diet rich in omega-3 fatty acids. AB - BACKGROUND: Treatment of symmetrical onychomadesis (symmetrical lupoid onychodystrophy) is a challenging task for dermatologists. The acute phase is characterized by sloughing of claw plates and loose claws have to be removed and secondary infections treated. The goal of long-term treatment is to allow claws to re-grow with normal quality and to achieve life-long lack of recurrence. The aim of this randomized treatment trial was to see if adding fish oil or cyclosporine to a diet rich in omega-3 could improve the treatment outcome of symmetrical onychomadesis in Gordon and English setters. All dogs were fed Eukanuba Veterinary Diets Dermatosis(r) exclusively during the six month treatment trial. The treatment outcome was measured as the change in number of healthy claws during treatment, as well as the long-term effect on hunting ability and recurrence of onychomadesis. The hypothesis was that cyclosporine provides a stronger and different immune modulating property than fish oil and therefore would give a better treatment outcome in dogs with symmetrical onychomadesis eating a diet rich in omega-3 fatty acids. RESULTS: Six Gordon setters and one English setter were treated with 5 mg/kg cyclosporine once daily for six months and seven Gordon setters were treated with 10 ml Dr Baddaky fish oil(r) once daily for six months. All dogs were evaluated every month and the numbers of healthy claws were recorded. CONCLUSION: Cyclosporine and fish oil appeared to be equally effective in treating symmetrical onychomadesis when the dog is fed a diet high in omega-3. PMID- 25280861 TI - The dopaminergic system in upper limb motor blocks (ULMB) investigated during bimanual coordination in Parkinson's disease (PD). AB - Upper limb motor blocks (ULMB) (inability to initiate or sudden discontinue in voluntary movements) have been identified in both unimanual and bimanual tasks in individuals with Parkinson's disease (PD). In particular, ULMB have been observed during rhythmic bimanual coordination when switching between phase patterns which is required (e.g. between in-phase and anti-phase). While sensory-perceptual mechanisms have recently been suggested to be involved in lower limb freezing, there has been no consensus on the mechanism that evokes ULMB or whether motor blocks respond to dopamine replacement like other motor symptoms of PD. The current study investigated the occurrence of ULMB in PD participants without ('off') and with ('on') dopamine replacement using bimanual wrist flexion extension with external auditory cues. In Experiment 1, coordination was performed in either in-phase (simultaneous flexion and extension) or anti-phase (asymmetrical flexion and extension between the limbs) in one of three sensory conditions: no vision, normal vision or augmented vision. Cycle frequency was increased within each trial across seven cycle frequencies (0.75-2 Hz). In Experiment 2, coordination was initiated in either phase pattern and participants were cued to make an intentional switch between phases in the middle of trials. Trials were performed at one of two cycle frequencies (1 or 2 Hz) and one of two sensory conditions: no vision or normal vision. Healthy age-matched control participants were also investigated in both experiments for the occurrence of motor blocks that were measured using automated detection from a computer algorithm. The results from Experiment 1 indicated that increasing cycle frequency resulted in more ULMB in individuals with PD during continuous coordinated movement, regardless of dopaminergic status, phase pattern or sensory condition. Experiment 2 also confirmed an increased occurrence of ULMB with increased cycle frequency. Furthermore, a large amount of ULMB were observed when initiating anti-phase coordination at 2 Hz, as well as after both externally-cued switches and in 'catch trials' with distracting auditory cues when no switch was required. Dopamine replacement was not found to influence the frequency of ULMB in either experiment. Therefore, ULMB likely result from non-hypodopaminergic impairments associated with PD. Specifically, ULMB may be caused by an inability to shift attentional control under increased cognitive demand that could be associated with hypoactivation in motor and prefrontal areas. PMID- 25280862 TI - Taste in Parkinson's disease. AB - Parkinson's disease is now considered a complex systemic disease also characterized by the occurrence of a variety of non-motor symptoms. Among them, a chemosensory impairment defined as a deficient olfactory performance is now acknowledged to be one of the prevalent symptoms since the early stages of the disease. Less clear are the incidence, extent and pathophysiology of taste function. The purpose of the present review is to summarize the state of the art in taste literature. To provide a better understanding of the available results, we will also discuss the different methods for taste evaluation and the other potential confounders to be addressed by future research. PMID- 25280863 TI - Should hip fractures be operated upon only by specialist hip unit surgeons in order to lower rates of surgical site infection? AB - PURPOSE: The purpose of this study was to compare outcomes of hip fractures treated by orthopaedic surgeons, performed by specialist vs. non-specialist surgeons. The rate of surgical site infection (SSI) obtained is taken as the main variable. METHODS: This was a prospective controlled cohort study of 814 patients presenting with hip fractures, operated on by a group of orthopaedic surgeons within the same hospital department. Patients were classified according to whether the surgeons belonged to a specialist hip unit (group A = 212 cases) or not (group B = 602 cases). RESULTS: Multivariate logistic regression showed that there was no relation between gender, SSI, Charlson's index, preoperative period, surgical technique or study groups (A or B). Only age was a determinant factor (rank-sum test p = 0.03; OR 95% CI = 1.07, p = 0.005). CONCLUSIONS: Since there were no differences in the SSI outcome between surgeons working in a specialist hip unit and the general orthopaedic surgeons, delaying operative treatment for hip fractures to enable treatment in such a unit or creating a new unit of this type is not necessary. In this respect, the only significant variable is the patient's age. PMID- 25280864 TI - Innovative uses of communication technology for HIV programming for men who have sex with men and transgender persons. AB - Globally, overall rates of HIV are on the decline; however, rates among gay men and other men who have sex with men (MSM) and transgender persons are increasing. Meanwhile, there has been exponential growth in access to communication technology over the last decade. More innovative prevention and care technology based programmes are needed to help address the growing numbers of MSM and transgender persons living with HIV and those at risk for infection. To address this need, a meeting was hosted by the U.S. Agency for International Development (USAID) through the President's Emergency Plan for AIDS Relief (PEPFAR) and co sponsored by amfAR, The Foundation for AIDS Research and the National Institute of Mental Health (NIMH). The meeting brought together researchers, community implementers, advocates and federal partners to discuss the current landscape of technology-based interventions for MSM and transgender persons and to discuss key considerations. Presentations and discussions focused on the research gaps, facilitators and barriers to programme implementation and public-private partnerships. This article summarizes the meeting proceedings and outlines key considerations for future work in this area. PMID- 25280865 TI - Protease inhibitor monotherapy is associated with a higher level of monocyte activation, bacterial translocation and inflammation. AB - INTRODUCTION: Monotherapy with protease-inhibitors (MPI) may be an alternative to cART for HIV treatment. We assessed the impact of this strategy on immune activation, bacterial translocation and inflammation. METHODS: We performed a cross-sectional study comparing patients on successful MPI (n=40) with patients on cART (n=20). Activation, senescence, exhaustion and differentiation stage in CD4+ and CD8+ T lymphocyte subsets, markers of monocyte activation, microbial translocation, inflammation, coagulation and low-level viremia were assessed. RESULTS: CD4+ or CD8+ T lymphocyte subset parameters were not significantly different between both groups. Conversely, as compared with triple cART, MPI patients showed a higher proportion of activated monocytes (CD14+ CD16-CD163+ cells, p=0.031), soluble markers of monocyte activation (sCD14 p=0.004, sCD163 p=0.002), microbial translocation (lipopolysaccharide (LPS)-binding protein; LBP p=0.07), inflammation (IL-6 p=0.04) and low-level viremia (p=0.035). In a multivariate model, a higher level of CD14+ CD16-CD163+ cells and sCD14, and presence of very low-level viremia were independently associated with MPI. Monocyte activation was independently associated with markers of inflammation (IL 6, p=0.006), microbial translocation (LBP, p=0.01) and low-level viremia (p=0.01). CONCLUSIONS: Patients on MPI showed a higher level of monocyte activation than patients on standard therapy. Microbial translocation and low level viremia were associated with the high level of monocyte activation observed in patients on MPI. The long-term clinical consequences of these findings should be assessed. PMID- 25280867 TI - Autoimmune pancreatitis with colonic stenosis: an unusual complication and atypical pancreatographic finding. AB - BACKGROUND: Type 1 autoimmune pancreatitis (AIP) often accompanies various systematic disorders such as sclerosing cholangitis, sialoadenitis, retroperitoneal fibrosis, interstitial pneumonitis and nephritis. Although rarely reported in acute pancreatitis, colonic stenosis is an uncommon complication in cases with AIP. CASE PRESENTATION: A 69-year-old Japanese man complained of abdominal pain and continuous diarrhea, resistant to intake of antimuscarinic and probiotic agents. A colonoscopy demonstrated a stenosis at the splenic flexure. Computed tomography revealed a focal enlargement of the pancreatic tail with a capsule-like rim, contacting with the descending colon. Endoscopic retrograde pancreatography (ERP) was unable to visualize the main pancreatic duct (MPD) at the pancreatic tail, despite a full contrast injection. A high serum IgG4 level (1060 mg/dL) and exclusion of pancreatic cancer by endoscopic ultrasound guided fine needle aspiration suggested AIP, but did not fulfill the diagnostic criteria, and steroid therapy was initiated. One month after starting steroid intake, pancreatic swelling was minimized and the MPD was visualized by ERP, fulfilling the international consensus diagnostic criteria (ICDC) of AIP. Colonic stenosis was relieved and the patient's symptoms disappeared. CONCLUSION: The present case is the first report of AIP developing colonic stenosis by the inflammatory infiltration. In this case, steroid therapy was effective for the diagnosis and treatment of pancreatic mass involving the descending colon. PMID- 25280866 TI - Focal adhesion kinase is required for synovial fibroblast invasion, but not murine inflammatory arthritis. AB - INTRODUCTION: Synovial fibroblasts invade cartilage and bone, leading to joint destruction in rheumatoid arthritis. However, the mechanisms that regulate synovial fibroblast invasion are not well understood. Focal adhesion kinase (FAK) has been implicated in cellular invasion in several cell types, and FAK inhibitors are in clinical trials for cancer treatment. Little is known about the role of FAK in inflammatory arthritis, but, given its expression in synovial tissue, its known role in invasion in other cells and the potential clinical availability of FAK inhibitors, it is important to determine if FAK contributes to synovial fibroblast invasion and inflammatory arthritis. METHODS: After treatment with FAK inhibitors, invasiveness of human rheumatoid synovial fibroblasts was determined with Matrigel invasion chambers. Migration and focal matrix degradation, two components of cellular invasion, were assessed in FAK inhibited rheumatoid synovial fibroblasts by transwell assay and microscopic examination of fluorescent gelatin degradation, respectively. Using mice with tumor necrosis factor alpha (TNFalpha)-induced arthritis in which fak could be inducibly deleted, invasion and migration by FAK-deficient murine arthritic synovial fibroblasts were determined as described above and arthritis was clinically and pathologically scored in FAK-deficient mice. RESULTS: Inhibition of FAK in human rheumatoid synovial fibroblasts impaired cellular invasion and migration. Focal matrix degradation occurred both centrally and at focal adhesions, the latter being a novel site for matrix degradation in synovial fibroblasts, but degradation was unaltered with FAK inhibitors. Loss of FAK reduced invasion in murine arthritic synovial fibroblasts, but not migration or TNFalpha-induced arthritis severity and joint erosions. CONCLUSIONS: FAK inhibitors reduce synovial fibroblast invasion and migration, but synovial fibroblast migration and TNFalpha-induced arthritis do not rely on FAK itself. Thus, inhibition of FAK alone is unlikely to be sufficient to treat inflammatory arthritis, but current drugs that inhibit FAK may inhibit multiple factors, which could increase their efficacy in rheumatoid arthritis. PMID- 25280868 TI - Bioelectrical impedance analysis to estimate body composition, and change in adiposity, in overweight and obese adolescents: comparison with dual-energy x-ray absorptiometry. AB - BACKGROUND: There is a need for a practical, inexpensive method to assess body composition in obese adolescents. This study aimed to 1) compare body composition parameters estimated by a stand-on, multi-frequency bioelectrical impendence (BIA) device, using a) the manufacturers' equations, and b) published and derived equations with body composition measured by dual-energy x-ray absorptiometry (DXA) and 2) assess percentage body fat (%BF) change after a weight loss intervention. METHODS: Participants were 66 obese adolescents, mean age (SD) 12.9 (2.0) years. Body composition was measured by Tanita BIA MC-180MA (Tanita BIA8) and DXA (GE-Lunar Prodigy). BIA resistance and reactance data at frequencies of 5, 50, 250 and 500 kHz, were used in published equations, and to generate a new prediction equation for fat-free mass (FFM) using a split-sample method. Approximately half (n = 34) of the adolescents had their body composition measured by DXA and BIA on two occasions, three to nine months apart. RESULTS: The correlations between FFM (kg), fat mass (kg) and %BF measured by BIA and DXA were 0.92, 0.93 and 0.78, respectively. The Tanita BIA8 manufacturers equations significantly (P < 0.001) overestimated FFM (4.3 kg [-5.3 to 13.9]) and underestimated %BF (-5.0% [-15 to 5.0]) compared to DXA. The mean differences between BIA derived equations and DXA measured body composition parameters were small (0.4 to 2.1%), not significant, but had large limits of agreements (~ +/ 15% for FFM). After the intervention mean %BF loss was similar by both methods (~1.5%), but with wide limits of agreement. CONCLUSION: The Tanita BIA8 could be a valuable clinical tool to measure body composition at the group level, but is inaccurate for the individual obese adolescent. PMID- 25280870 TI - Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. AB - BACKGROUND: Trend data for causes of child death are crucial to inform priorities for improving child survival by and beyond 2015. We report child mortality by cause estimates in 2000-13, and cause-specific mortality scenarios to 2030 and 2035. METHODS: We estimated the distributions of causes of child mortality separately for neonates and children aged 1-59 months. To generate cause-specific mortality fractions, we included new vital registration and verbal autopsy data. We used vital registration data in countries with adequate registration systems. We applied vital registration-based multicause models for countries with low under-5 mortality but inadequate vital registration, and updated verbal autopsy based multicause models for high mortality countries. We used updated numbers of child deaths to derive numbers of deaths by causes. We applied two scenarios to derive cause-specific mortality in 2030 and 2035. FINDINGS: Of the 6.3 million children who died before age 5 years in 2013, 51.8% (3.257 million) died of infectious causes and 44% (2.761 million) died in the neonatal period. The three leading causes are preterm birth complications (0.965 million [15.4%, uncertainty range (UR) 9.8-24.5]; UR 0.615-1.537 million), pneumonia (0.935 million [14.9%, 13.0-16.8]; 0.817-1.057 million), and intrapartum-related complications (0.662 million [10.5%, 6.7-16.8]; 0.421-1.054 million). Reductions in pneumonia, diarrhoea, and measles collectively were responsible for half of the 3.6 million fewer deaths recorded in 2013 versus 2000. Causes with the slowest progress were congenital, preterm, neonatal sepsis, injury, and other causes. If present trends continue, 4.4 million children younger than 5 years will still die in 2030. Furthermore, sub-Saharan Africa will have 33% of the births and 60% of the deaths in 2030, compared with 25% and 50% in 2013, respectively. INTERPRETATION: Our projection results provide concrete examples of how the distribution of child causes of deaths could look in 15-20 years to inform priority setting in the post 2015 era. More evidence is needed about shifts in timing, causes, and places of under-5 deaths to inform child survival agendas by and beyond 2015, to end preventable child deaths in a generation, and to count and account for every newborn and every child. FUNDING: Bill & Melinda Gates Foundation. PMID- 25280871 TI - An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders. AB - Recently, growing evidence has demonstrated that nuclear factor erythroid 2 related factor 2 (Nrf2) is a pivotal regulator of endogenous defense systems that function via the activation of a set of protective genes, and this is particularly clear in the central nervous system (CNS). Therefore, it is highly useful to summarize the current literature on the molecular mechanisms and role of Nrf2 in the CNS. In this review, we first briefly introduce the molecular features of Nrf2. We then discuss the regulation, cerebral actions, upstream modulators and downstream targets of Nrf2 pathway. Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis. Lastly, we discuss some potential future directions. The information reviewed here may be significant in the design of further experimental research and increase the potential of Nrf2 as a therapeutic target in the future. PMID- 25280869 TI - TargetCOPD: a pragmatic randomised controlled trial of targeted case finding for COPD versus routine practice in primary care: protocol. AB - BACKGROUND: Many people with clinically significant chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. There are a number of small studies which have examined possible methods of case finding through primary care, but no large RCTs that have adequately assessed the most cost-effective approach. METHODS/DESIGN: In this study, using a cluster randomised controlled trial (RCT) in 56 general practices in the West Midlands, we plan to investigate the effectiveness and cost-effectiveness of a Targeted approach to case finding for COPD compared with routine practice. Using an individual patient RCT nested in the Targeted arm, we plan also to compare the effectiveness and cost effectiveness of Active case finding using a postal questionnaire (with supplementary opportunistic questionnaires), and Opportunistic-only case finding during routine surgery consultations.All ever-smoking patients aged 40-79 years, without a current diagnosis of COPD and registered with participating practices will be eligible. Patients in the Targeted arm who report positive respiratory symptoms (chronic cough or phlegm, wheeze or dyspnoea) using a brief questionnaire will be invited for further spirometric assessment to ascertain whether they have COPD or not. Post-bronchodilator spirometry will be conducted to ATS standards using an Easy One spirometer by trained research assistants.The primary outcomes will be new cases of COPD and cost per new case identified, comparing targeted case finding with routine care, and two types of targeted case finding (active versus opportunistic). A multilevel logistic regression model will be used to model the probability of detecting a new case of COPD for each treatment arm, with clustering of patients (by practice and household) accounted for using a multi-level structure.A trial-based analysis will be undertaken using costs and outcomes collected during the trial. Secondary outcomes include the feasibility, efficiency, long-term cost-effectiveness, patient and primary care staff views of each approach. DISCUSSION: This will be the largest RCT of its kind, and should inform how best to identify undiagnosed patients with COPD in the UK and other similar healthcare systems. Sensitivity analyses will help local policy-makers decide which sub-groups of the population to target first. TRIAL REGISTRATION: Current controlled trials ISRCTN14930255. PMID- 25280872 TI - Dynamical crises, multistability and the influence of the duration of immunity in a seasonally-forced model of disease transmission. AB - BACKGROUND: Highly successful strategies to make populations more resilient to infectious diseases, such as childhood vaccinations programs, may nonetheless lead to unpredictable outcomes due to the interplay between seasonal variations in transmission and a population's immune status. METHODS: Motivated by the study of diseases such as pertussis we introduce a seasonally-forced susceptible infectious-recovered model of disease transmission with waning and boosting of immunity. We study the system's dynamical properties using a combination of numerical simulations and bifurcation techniques, paying particular attention to the properties of the initial condition space. RESULTS: We find that highly unpredictable behaviour can be triggered by changes in biologically relevant model parameters such as the duration of immunity. In the particular system we analyse--used in the literature to study pertussis dynamics--we identify the presence of an initial-condition landscape containing three coexisting attractors. The system's response to interventions which perturb population immunity (e.g. vaccination "catch-up" campaigns) is therefore difficult to predict. CONCLUSION: Given the increasing use of models to inform policy decisions regarding vaccine introduction and scheduling and infectious diseases intervention policy more generally, our findings highlight the importance of thoroughly investigating the dynamical properties of those models to identify key areas of uncertainty. Our findings suggest that the often stated tension between capturing biological complexity and utilising mathematically simple models is perhaps more nuanced than generally suggested. Simple dynamical models, particularly those which include forcing terms, can give rise to incredibly complex behaviour. PMID- 25280873 TI - Characterization of aqueous two phase systems by combining lab-on-a-chip technology with robotic liquid handling stations. AB - Over the last decade, the use of design of experiment approaches in combination with fully automated high throughput (HTP) compatible screenings supported by robotic liquid handling stations (LHS), adequate fast analytics and data processing has been developed in the biopharmaceutical industry into a strategy of high throughput process development (HTPD) resulting in lower experimental effort, sample reduction and an overall higher degree of process optimization. Apart from HTP technologies, lab-on-a-chip technology has experienced an enormous growth in the last years and allows further reduction of sample consumption. A combination of LHS and lab-on-a-chip technology is highly desirable and realized in the present work to characterize aqueous two phase systems with respect to tie lines. In particular, a new high throughput compatible approach for the characterization of aqueous two phase systems regarding tie lines by exploiting differences in phase densities is presented. Densities were measured by a standalone micro fluidic liquid density sensor, which was integrated into a liquid handling station by means of a developed generic Tip2World interface. This combination of liquid handling stations and lab-on-a-chip technology enables fast, fully automated, and highly accurate density measurements. The presented approach was used to determine the phase diagram of ATPSs composed of potassium phosphate (pH 7) and polyethylene glycol (PEG) with a molecular weight of 300, 400, 600 and 1000 Da respectively in the presence and in the absence of 3% (w/w) sodium chloride. Considering the whole ATPS characterization process, two complete ATPSs could be characterized within 24h, including four runs per ATPS for binodal curve determination (less than 45 min/run), and tie line determination (less than 45 min/run for ATPS preparation and 8h for density determination), which can be performed fully automated over night without requiring man power. The presented methodology provides a cost, time and material effective approach for characterization of ATPS phase diagram on base on highly accurate and comprehensive data. By this means the derived data opens the door for a more detailed description of ATPS towards generating mechanistic based models, since molecular approaches such as MD simulations or molecular descriptions along the line of QSAR heavily rely on accurate and comprehensive data. PMID- 25280874 TI - Coated capillaries with highly charged polyelectrolytes and carbon nanotubes co aggregated with sodium dodecyl sulphate for the analysis of sulfonylureas by capillary electrophoresis. AB - Sulfonylureas (SUs) are one of the most widely used herbicides to control weeds in crops. Herein, capillary electrophoresis (CE) was used to determine four sulfonylureas in natural waters, namely chlorsulfuron (CS), iodosulfuron methyl (IM), metsulfuron methyl (MSM) and mesosulfuron methyl (MSS). First of all, a bare silica capillary was chosen with 10mM of 1-butyl-3-methylimidazolium tetrafluoroborate (bminBF4) as electrophoretic buffer (pH 9.6) containing 2 mg L( 1) of surfactant-coated single-wall carbon nanotubes (SC-SWCNTs). A dramatic deviation in migration times was observed. Therefore, a poly(diallyldimethylammonium) chloride (PDADMAC) statically coated cationic capillary was used to improve repeatability and to alter the selectivity of the separation. The electroosmotic flow (EOF) measurement revealed that the SC-SWCNTs were strongly adsorbed at the surface of the PDADMAC coating even in the absence of the surfactant-coated nanotubes in the electrolyte buffer. Consequently, a stable strong cathodic EOF and excellent repeatabilities were obtained with relative standard deviations (RSDs) on migration times and on corrected peak areas below 0.9 and 1.5%, respectively. The separation of the SUs was conducted in only 6 min. No regeneration of the coating between analyses was necessary, and high peak efficiencies up to 173,000 theoretical plates were obtained. The bi layer coating was subsequently used to analyze sulfonylureas in tap water, in several mineral waters as well as in underground waters spiked with SUs and directly injected into the CE capillary. PMID- 25280875 TI - Headspace generation coupled to gas chromatography-mass spectrometry for the automated determination and quantification of endogenous compounds in urine. Aldehydes as possible markers of oxidative stress. AB - A methodology for the determination of five aldehydes in urine has been developed based on the coupling of a headspace generation sampler with a gas chromatography mass spectrometry system equipped with a programmed temperature vaporizer. This instrumental configuration minimizes sample manipulation and allows the determination of these compounds without the need for a derivatization step so that the methodology is largely shortened and simplified. An experimental design was carried out in order to optimize the headspace sampling. Sample matrix effect was eliminated by means of dilution of urine samples. The calibration models displayed good linearity (0.1-10 MUg/L) and their validity was checked using ANOVA, and it was observed that they did not exhibit any lack of fit. The LODs obtained ranged between 0.04 and 0.08 MUg/L and the LOQs between 0.12 and 0.24 MUg/L. The accuracy of the method was evaluated in terms of apparent recoveries which were between 86 and 120%. The method developed was applied to the analysis of 17 samples of urine from different subjects in order to quantify these endogenous compounds. PMID- 25280876 TI - Lingual traction to aid fibreoptic orotracheal intubation. PMID- 25280877 TI - Use of Complementary and Alternative Medicines (CAMs) among type 2 diabetes patients in Sri Lanka: a cross sectional survey. AB - BACKGROUND: The incidence of chronic illnesses has increased worldwide. Diabetes is one such illness and 80% of the diabetic population lives in the developing world. There is a rapidly growing trend towards the use of Complementary and Alternative Medical practices in Diabetes. Sri Lanka is a developing Asian nation with a rich culture of Ayurvedic and native medical culture. The objective of this study was to find the prevalence of use of CAMs in a diabetic population attending a large multiethnic diabetes facility in a University unit and to assess whether there is an increase in the incidence of hypoglycaemic episodes among users of CAMs. METHODS: A cross sectional study was performed at Teaching Hospital Peradeniya between April and August 2012. Following verbal consent, 254 type 2 adult diabetic patients attending the diabetes facility were interviewed regarding the use of CAM and hypoglycaemia using an interviewer-administered questionnaire. RESULTS: Of the 252 valid results, 192 patients (76%) admitted to the use of a CAM to reduce blood glucose. Bitter gourd, ivy gourd and crepe ginger were used by 128, 113 and 92 individuals. While 19% used a single agent, 34%, 21% and 2.4% used 2,3 and more than 3 agents. The incidence of hypoglycaemia in CAM users was 21% and 16.6% in non-users. The difference was statistically not significant. (p = 0.57) Ingestion of Costus speciosus (Crepe ginger) was associated with higher incidence of hypoglycaemia (P = 0.01).Female gender was significantly associated with CAM use (p = 0.01), while the age, duration of diabetes, presence of co-morbidities and complications of diabetes failed to show a significant association. CONCLUSION: Sri Lanka has a very high use of herbal supplementation in type 2 diabetes patients. Although the overall incidence of hypoglycaemia is not increased among CAM users, crepe ginger is associated with significant hypoglycaemia and warrants further research. PMID- 25280878 TI - Perfusion techniques for minimally invasive valve procedures. AB - In this paper, we present, in detail, the simplified perfusion technique that we have adopted since January 2009 and that we have utilized in 200 cases for cardiac minimally invasive valvular procedures that were performed through a right lateral mini-thoracotomy in the 3(rd)-4(th) intercostal space. Cardiopulmonary bypass was achieved by means of the direct cannulation of the ascending aorta and the insertion of a percutaneous venous cannula in the femoral vein. A flexible aortic cross-clamp was applied through the skin incision and cardioplegic arrest was obtained with the antegrade delivery of a crystalloid solution. Gravity drainage was enhanced by vacuum-assisted aspiration. There were no technical complications related to this perfusion technique that we have adopted in minimally invasive surgical procedures. PMID- 25280879 TI - What may be lurking in the hospital undergrowth? Inapparent cross-transmission of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae pose an increasing challenge in hospitals. AIM: To describe the benefits of using molecular techniques to investigate the spread of ESBL-producing Klebsiella pneumoniae (ESBL-KP) within a tertiary referral centre. METHODS: Following the identification of a cluster of five ESBL-KP on one ward, a hospital-wide retrospective epidemiological investigation was undertaken into the incidence and spread of these organisms. Variable number tandem repeat (VNTR) profiles were used to assign patients to possible clusters. Patient outcome and length of hospital stay were reviewed. Locations of patients assigned to each cluster were investigated as possible sources of spread. Antimicrobial prescribing practices and hand hygiene compliance on affected wards were also reviewed. FINDINGS: Twenty-four ESBL-KP isolates were characterized by VNTR. The mean length of stay was 102.5 days for patients with ESBL-KP, which was significantly longer compared with the mean length of stay for all patients (10.1 days, P < 0.01). Nineteen patients were assigned to clusters with shared VNTR profiles. Review of patient transfer histories identified two instances where cross-transmission may have occurred. In both cases, compliance with good hand hygiene practice and antimicrobial prescribing was suboptimal. CONCLUSION: Molecular typing provided a valuable insight into the clones of ESBL-KP circulating within the study institution. Increased surveillance to identify colonization among patients and routine typing of isolates should be considered, but the resource implications for patient isolation are considerable. PMID- 25280880 TI - A case of popliteal artery entrapment syndrome presenting with acute limb ischaemia. AB - Popliteal artery entrapment syndrome (PAES) is caused by an anomalous anatomic relationship between the popliteal artery and the musculotendinous structures in the popliteal fossa. In the early stage of PAES, patients most commonly present with intermittent claudication. If we don't perform appropriate investigation, the diagnosis of PAES is easily missed and may lead to irreversible arterial damage. Thrombus formation in the damaged popliteal artery can cause complete obstruction of the popliteal artery leading to acute limb-threatening ischaemia. PMID- 25280882 TI - Nanostructured lipid carriers versus microemulsions for delivery of the poorly water-soluble drug luteolin. AB - OBJECTIVE: Nanostructured lipid carriers and microemulsions effectively deliver poorly water-soluble drugs. However, few studies have investigated their ability and difference in improving drug bioavailability, especially the factors contributed to the difference. Thus, this study was aimed at investigating their efficiency in bioavailability enhancement based on studying two key processes that occur in NLC and ME during traverse along the intestinal tract: the solubilization process and the intestinal permeability process. METHODS: The nanostructured lipid carriers and microemulsions had the same composition except that the former were prepared with solid lipids and the latter with liquid lipids; both were evaluated for particle size and zeta potential. Transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction were performed to characterize their properties. Furthermore, in vitro drug release, in situ intestinal absorption, and in vitro lipolysis were studied. The bioavailability of luteolin delivered using nanostructured lipid carriers in rats was compared with that delivered using microemulsions and suspensions. RESULTS: The in vitro analysis revealed different release mechanisms for luteolin in nanostructured lipid carriers and microemulsions, although the in situ intestinal absorption was similar. The in vitro lipolysis data indicated that digestion speed and extent were higher for microemulsions than for nanostructured lipid carriers, and that more of the former partitioned to the aqueous phase. The in vivo bioavailability analysis in rats indicated that the oral absorption and bioavailability of luteolin delivered using nanostructured lipid carriers and microemulsions were higher than those of luteolin suspensions. CONCLUSION: Nanostructured lipid carriers and microemulsions improved luteolin's oral bioavailability in rats. The rapid lipid digestion and much more drug solubilized available for absorption in microemulsions may contribute to better absorption and higher bioavailability. PMID- 25280881 TI - Genomic comparison of 93 Bacillus phages reveals 12 clusters, 14 singletons and remarkable diversity. AB - BACKGROUND: The Bacillus genus of Firmicutes bacteria is ubiquitous in nature and includes one of the best characterized model organisms, B. subtilis, as well as medically significant human pathogens, the most notorious being B. anthracis and B. cereus. As the most abundant living entities on the planet, bacteriophages are known to heavily influence the ecology and evolution of their hosts, including providing virulence factors. Thus, the identification and analysis of Bacillus phages is critical to understanding the evolution of Bacillus species, including pathogenic strains. RESULTS: Whole genome nucleotide and proteome comparison of the 93 extant Bacillus phages revealed 12 distinct clusters, 28 subclusters and 14 singleton phages. Host analysis of these clusters supports host boundaries at the subcluster level and suggests phages as vectors for genetic transfer within the Bacillus cereus group, with B. anthracis as a distant member of the group. Analysis of the proteins conserved among these phages reveals enormous diversity and the uncharacterized nature of these phages, with a total of 4,922 protein families (phams) of which only 951 (19%) had a predicted function. In addition, 3,058 (62%) of phams were orphams (phams containing a gene product from a single phage). The most populated phams were those encoding proteins involved in DNA metabolism, virion structure and assembly, cell lysis, or host function. These included several genes that may contribute to the pathogenicity of Bacillus strains. CONCLUSIONS: This analysis provides a basis for understanding and characterizing Bacillus phages and other related phages as well as their contributions to the evolution and pathogenicity of Bacillus cereus group bacteria. The presence of sparsely populated clusters, the high ratio of singletons to clusters, and the large number of uncharacterized, conserved proteins confirms the need for more Bacillus phage isolation in order to understand the full extent of their diversity as well as their impact on host evolution. PMID- 25280883 TI - Prolonged local retention of subcutaneously injected polymers monitored by noninvasive SPECT imaging. AB - Polymers are widely applied to drug delivery systems because polymers are generally excreted from the body more slowly than small molecules. Subcutaneous injection is one plausible means of administration. In this study, the in vivo behaviors of subcutaneously injected polymers, linear poly(glutamic acid) (Poly Glu), acetylated dendrimer (Ac-den) and collagen peptide-conjugated dendrimer (CP den), were investigated. Single photon emission computed tomography (SPECT) imaging was used to noninvasively monitor the in vivo behaviors. Diethylenetriaminepentaacetic acid (DTPA) was conjugated to these polymers, which were labeled with radioactive (111)In. These (111)In-DTPA-bearing polymers (Poly Glu-DTPA, Ac-den-DTPA and CP-den-DTPA) and unconjugated DTPA were subcutaneously injected into tumor-bearing mice, which were subjected to SPECT imaging. These (111)In-DTPA-bearing polymers were largely retained at the injection site for at least 1 day, whereas the unconjugated DTPA was rapidly cleared from the whole body through excretion. Poly-Glu-DTPA and Ac-den-DTPA were partly accumulated in the kidney (and the liver), but the CP-den-DTPA was not. However, these (111)In DTPA-bearing polymers were accumulated in the liver and the kidney following intravenous administration. These results indicate that the subcutaneously injected polymers did not largely gain substantial access to the systemic circulation, which is useful for a depot of drug around the injection site. PMID- 25280884 TI - Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin. AB - We recently demonstrated that Doxil loses its long-circulating properties when injected repeatedly at doses below 2 mg/m(2) in dogs. In studies using other animal species, PEGylated liposomal doxorubicin has been reported not to induce the accelerated blood clearance (ABC) phenomenon. We investigated the issue of whether Doxil can elicit the ABC phenomenon in several species. In minipigs, the ABC phenomenon was induced at 2 mg/m(2). In other animal species, the ABC phenomenon was not observed at higher doses (>2 mg/m(2)), but was observed at much lower doses (0.2 mg/m(2)). The pharmacokinetic profile of a second dose of Doxil reflected the circulating anti-PEG IgM level induced by the first dose. The ABC phenomenon was not observed at the clinically recommended DXR dose (20 mg/m(2)) in any animal species. These results indicate that Doxil can cause the ABC phenomenon in all animals tested, the extent of induction was dependent on the first dose of Doxil, and a higher Doxil dose lessened the ABC phenomenon. The current study results suggest that a careful study design including selection of animal species is important for preclinical studies using PEGylated liposomal formulations even if they contain anticancer drugs that suppress the host immune response. PMID- 25280885 TI - Sustained release of antibiotic complexed by multivalent ion: in vitro and in vivo study for the treatment of peritonitis. AB - The main aims of this study are (i) the development of an antibiotic complexed with multivalent ion, which can allow sustained release of the antibiotic without any additional matrix or difficult process and (ii) the feasibility study of the ion-complexed antibiotic as a therapeutic technique for peritonitis treatment. An ion-complexed antibiotic is prepared by simple mixing of two aqueous solutions containing an ionized (water-soluble) drug (tetracycline) and a multivalent counter ionic compound. The ion-complexed antibiotic shows a continuous release of the antibiotic up to 21 days, and thus prolonged anti-bacterial effect by gradual ionic exchange between the multivalent ions in the complex and same charged monovalent ions in surrounding medium. From the in vivo animal study using a cecum perforated peritonitis mouse model, the ion-complexed antibiotic group shows sufficient anti-bacterial effect and thus effectively treat the peritonitis because of the extermination of the contaminated enteric bacteria in the peritoneum during wound healing of injury cecum (by the sustained release of antibiotic from the ion complex). These results suggest that the ion-complexed antibiotic system may be promising for the effective treatment of the peritonitis caused by frequent gastrointestinal defect in clinical fields. PMID- 25280886 TI - Sore throat in women after intubation with 6.5 or 7.0 mm endotracheal tube: a quantitative study. AB - BACKGROUND: Women experience more sore throats than men after endotracheal intubation. AIM: The aim of this study was to investigate the incidence of self rated sore throat immediately, and 2-4 hours postoperatively, in women after elective gynaecological surgery under general anaesthesia using an endotracheal tube (ETT) size 6.5 or 7.0mm in inner diameter. METHOD: Eighty-two female participants who had undergone elective gynaecological surgery participated, 44 and 38 were intubated with size 6.5 mm ETT and 7.0mm ETT respectively. They estimated the occurrence of sore throat preoperatively and postoperatively, according to a 4-point Likert scale. Statistical data were analysed using the Package for Social Science (SPSS) 19. RESULTS: Sore throat was present in 29.5% of participants who were intubated with size 6.5 mm ETT immediately postoperatively and in 39.5% of those who were intubated with size 7.0 mm ETT. CONCLUSION: Nurses specialising in the supervision of daily care specific to the intubated patient should note and alleviate sore throat as part of their nursing care. PMID- 25280887 TI - Spanish Implantable Cardioverter-defibrillator Registry. Tenth Official Report of the Spanish Society of Cardiology Electrophysiology and Arrhythmias Section (2013). AB - INTRODUCTION AND OBJECTIVES: To present the findings of the Spanish Implantable Cardioverter-defibrillator Registry for 2013 compiled by the Electrophysiology and Arrhythmias Section of the Spanish Society of Cardiology. METHODS: Prospective data were voluntarily recorded on a data collection form and sent to the Spanish Society of Cardiology by each implantation team. RESULTS: Overall, 4772 device implantations were reported, representing 85% of the estimated total number of implantations. The reported implantation rate was 102 per million population and the estimated total implantation rate was 120 per million. The proportion of first implantations was 68.8%. Data were received from 154 hospitals (4 fewer than in 2012). Most implantable cardioverter-defibrillator recipients were men (83.3%). The mean age was 62.5 (13.4) years. Most patients had severe or moderate-to-severe ventricular dysfunction and were in New York Heart Association functional class II. The most frequent underlying cardiac condition was ischemic heart disease, followed by dilated cardiomyopathy. Indications for primary prevention accounted for 53.0% of first implantations, consolidating the decrease first observed in 2012. Overall, 79.8% of devices were implanted by cardiac electrophysiologists. CONCLUSIONS: The 2013 Spanish Implantable Cardioverter-defibrillator Registry includes information on 85% of the devices implanted in Spain. The total number of implantations increased compared with the previous 2 years. The percentage of implantations for primary prevention indications decreased compared with the previous year. PMID- 25280888 TI - Evolution of cardiac imaging according to the number of scientific articles in medical journals: a long and fruitful journey. AB - The use of cardiac imaging techniques as a diagnostic method in the understanding of physiopathology, as well as in cardiology research has been one of the most important revolutions in the management of cardiac patients, our understanding of physiopathology, and basic research in almost all heart diseases. This article analyzes the literature on echocardiography, cardiovascular magnetic resonance imaging, computed tomography, and nuclear medicine during the last 60 years and provides an overview of how these techniques have developed and how their introduction into daily practice has changed attitudes among cardiologists. The literature not only shows that the implementation of these techniques in daily practice requires an immense amount of research and effort by many working groups throughout the scientific world, but also that techniques that once seemed promising may finally be discarded. PMID- 25280889 TI - Permanent draft genome sequence of Geobacillus thermocatenulatus strain GS-1. AB - Geobacillus thermocatenulatus strain GS-1 is a thermophilic bacillus having a growth optimum at 60 degrees C, capable of degrading alkanes. It was isolated from the formation water of a high-temperature deep oil reservoir in Qinghai oilfield, China. Here, we report the draft genome sequence with an estimated assembly size of 3.5Mb. A total of 3371 protein-coding sequences, including monooxygenase, alcohol dehydrogenase, aldehyde dehydrogenase, fatty acid-CoA ligase, acyl-CoA dehydrogenase, enoyl-CoA hydrogenase, hydroxyacyl-CoA dehydrogenase and thiolase, were detected in the genome, which are involved in the alkane degradation pathway. Our results may provide insights into the genetic basis of the adaptation of this strain to high-temperature oilfield ecosystems. PMID- 25280890 TI - Draft genome sequence of Halapricum salinum CBA1105(T), an extremely halophilic archaeon isolated from solar salt. AB - Halapricum salinum CBA1105(T) (=KCTC 4202(T), JCM 19729(T)) is an extremely halophilic archaeon isolated from solar salt in the Republic of Korea. We present the draft genome of CBA1105(T), which is assembled into 3 contigs containing 3,451,492bp with a G+C content of 63.7%. This is the first genome that has been sequenced in the genus Halapricum. PMID- 25280891 TI - Automated marker tracking using noisy X-ray images degraded by the treatment beam. AB - This study demonstrates the feasibility of automated marker tracking for the real time detection of intrafractional target motion using noisy kilovoltage (kV) X ray images degraded by the megavoltage (MV) treatment beam. The authors previously introduced the in-line imaging geometry, in which the flat-panel detector (FPD) is mounted directly underneath the treatment head of the linear accelerator. They found that the 121 kVp image quality was severely compromised by the 6 MV beam passing through the FPD at the same time. Specific MV-induced artefacts present a considerable challenge for automated marker detection algorithms. For this study, the authors developed a new imaging geometry by re positioning the FPD and the X-ray tube. This improved the contrast-to-noise-ratio between 40% and 72% at the 1.2 mAs/image exposure setting. The increase in image quality clearly facilitates the quick and stable detection of motion with the aid of a template matching algorithm. The setup was tested with an anthropomorphic lung phantom (including an artificial lung tumour). In the tumour one or three Calypso beacons were embedded to achieve better contrast during MV radiation. For a single beacon, image acquisition and automated marker detection typically took around 76 +/- 6 ms. The success rate was found to be highly dependent on imaging dose and gantry angle. To eliminate possible false detections, the authors implemented a training phase prior to treatment beam irradiation and also introduced speed limits for motion between subsequent images. PMID- 25280892 TI - Non-voltage-gated Ca2+ entry pathways in the heart: the untold STOrai? PMID- 25280893 TI - Novel ligands for zipping and unzipping the intercalated disk: today's experimental tools, tomorrow's therapies? PMID- 25280895 TI - Health secretary will commission review to pinpoint GP shortages. PMID- 25280896 TI - Chromatin-driven behavior of topologically associating domains. AB - Metazoan genomes are highly organized inside the cell nucleus. Topologically associating domains (TADs) represent the building blocks of genome organization, but their linear modularity does not explain alone their spatial organization. Indeed, the chromatin type adorning a TAD can shape its structure and drives its nuclear positioning and its function. Genome-wide association studies revealed mainly four chromatin types: active chromatin, Polycomb-repressed chromatin, null chromatin and constitutive heterochromatin. In this review, we will describe the main three-dimensional features of each chromatin type and finally their relationships with TAD organization and epigenetic memory. PMID- 25280897 TI - Structural determinants in prion protein folding and stability. AB - Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases, involving post-translational modifications of the cellular prion protein. Epidemiological studies on Creutzfeldt-Jakob disease, a prototype prion disorder, show a majority of cases being sporadic, while the remaining occurrences are either genetic or iatrogenic. The molecular mechanisms by which PrP(C) is converted into its pathological isoform have not yet been established. While point mutations and seeds trigger the protein to cross the energy barriers, thus causing genetic and infectious transmissible spongiform encephalopathies, respectively, the mechanism responsible for sporadic forms remains unclear. Since prion diseases are protein-misfolding disorders, we investigated prion protein folding and stability as functions of different milieus. Using spectroscopic techniques and atomistic simulations, we dissected the contribution of major structural determinants, also defining the energy landscape of prion protein. In particular, we elucidated (i) the essential role of the octapeptide region in prion protein folding and stability, (ii) the presence of a very enthalpically stable intermediate in prion-susceptible species, and (iii) the role of the disulfide bridge in prion protein folding. PMID- 25280894 TI - A diagnostic approach for cerebral palsy in the genomic era. AB - An ongoing challenge in children presenting with motor delay/impairment early in life is to identify neurogenetic disorders with a clinical phenotype, which can be misdiagnosed as cerebral palsy (CP). To help distinguish patients in these two groups, conventional magnetic resonance imaging of the brain has been of great benefit in "unmasking" many of these genetic etiologies and has provided important clues to differential diagnosis in others. Recent advances in molecular genetics such as chromosomal microarray and next-generation sequencing have further revolutionized the understanding of etiology by more precisely classifying these disorders with a molecular cause. In this paper, we present a review of neurogenetic disorders masquerading as cerebral palsy evaluated at one institution. We have included representative case examples children presenting with dyskinetic, spastic, and ataxic phenotypes, with the intent to highlight the time-honored approach of using clinical tools of history and examination to focus the subsequent etiologic search with advanced neuroimaging modalities and molecular genetic tools. A precise diagnosis of these masqueraders and their differentiation from CP is important in terms of therapy, prognosis, and family counseling. In summary, this review serves as a continued call to remain vigilant for current and other to-be-discovered neurogenetic masqueraders of cerebral palsy, thereby optimizing care for patients and their families. PMID- 25280898 TI - Difference in ability of hospitalized patients to identify their attending physician from surgical and nonsurgical service lines: an academic medical center study. PMID- 25280901 TI - Decoding gene patents in Australia. AB - Patents directed to naturally occurring genetic material, such as DNA, RNA, chromosomes, and genes, in an isolated or purified form have been granted in Australia for many years. This review provides scientists with a summary of the gene patent debate from an Australian perspective and specifically reviews how the various levels of the legal system as they apply to patents-the Australian Patent Office, Australian courts, and Australian government-have dealt with the issue of whether genetic material is proper subject matter for a patent. PMID- 25280899 TI - Genetic networks governing heart development. AB - Animal genomes contain a code for construction of the body plan from a fertilized egg. Understanding how genome information is deciphered to create the complex multilayered regulatory systems that drive organismal development, and which become altered in disease, is one of the greatest challenges in the biological sciences. The development of methods that effectively represent and communicate the complexity inherent in gene regulatory networks remains a major barrier. This review introduces the philosophy of systems biology and discusses recent progress in understanding the development of the heart at a systems biology level. PMID- 25280903 TI - HIV infection: a new risk factor for intracerebral hemorrhage? PMID- 25280902 TI - Elevated rates of intracerebral hemorrhage in individuals from a US clinical care HIV cohort. AB - OBJECTIVE: To compare rates of intracerebral hemorrhage (ICH) in HIV-infected and uninfected individuals in a large clinical care cohort and to assess risk factors associated with ICH. METHODS: We identified incident ICH in HIV-infected and uninfected control cohorts from the Partners Health Care system using ICD-9-CM codes. We constructed Cox proportional hazards models to estimate adjusted hazard ratios for HIV infection and other predictors of ICH. RESULTS: The incidence rate of ICH was 2.29 per 1,000 person-years in HIV-infected individuals compared with 1.23 per 1,000 person-years in uninfected individuals, with an unadjusted incidence rate ratio of 1.85 (95% confidence interval 1.37-2.47, p < 0.001). In a multivariable model, HIV infection was independently associated with a higher hazard of ICH, although its effect diminished with increasing age. Female sex was associated with a lower hazard of ICH in the uninfected cohort but not in the HIV cohort. CD4 count <200 * 10(6) cells/L and anticoagulant use were predictive of ICH. CONCLUSIONS: HIV infection conferred an increased adjusted hazard of ICH, which was more pronounced in young patients and in women. PMID- 25280900 TI - Clinical characteristics and current treatment of age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a multifactorial degeneration of photoreceptors and retinal pigment epithelium. The societal impact is significant, with more than 2 million individuals in the United States alone affected by advanced stages of AMD. Recent progress in our understanding of this complex disease and parallel developments in therapeutics and imaging have translated into new management paradigms in recent years. However, there are many unanswered questions, and diagnostic and prognostic precision and treatment outcomes can still be improved. In this article, we discuss the clinical features of AMD, provide correlations with modern imaging and histopathology, and present an overview of treatment strategies. PMID- 25280905 TI - Doctors can withdraw treatment from brain damaged baby, High Court rules. PMID- 25280904 TI - Maternal buffering of human amygdala-prefrontal circuitry during childhood but not during adolescence. AB - Mature amygdala-prefrontal circuitry regulates affect in adulthood but shows protracted development. In altricial and semialtricial species, caregivers provide potent affect regulation when mature neurocircuitry is absent. The present investigation examined a potential mechanism through which caregivers provide regulatory influences in childhood. Children, but not adolescents, showed evidence of maternal buffering, such that maternal stimuli suppressed amygdala reactivity. In the absence of maternal stimuli, children exhibited immature amygdala-prefrontal connectivity. However, in the presence of maternal stimuli, children's connectivity was more mature, resembling adolescents' connectivity. Children showed improved affect-related regulation in the presence of their mothers. Individual differences emerged, with greater maternal influence on amygdala-prefrontal circuitry associated with stronger mother-child relationships and maternal modulation of behavioral regulation. These findings suggest a neural mechanism through which caregivers modulate children's regulatory behavior by inducing more mature connectivity and buffering against heightened reactivity. Maternal buffering in childhood, but not adolescence, suggests that childhood may be a sensitive period for amygdala-prefrontal development. PMID- 25280906 TI - Molecular mechanisms of memory in imprinting. AB - Converging evidence implicates the intermediate and medial mesopallium (IMM) of the domestic chick forebrain in memory for a visual imprinting stimulus. During and after imprinting training, neuronal responsiveness in the IMM to the familiar stimulus exhibits a distinct temporal profile, suggesting several memory phases. We discuss the temporal progression of learning-related biochemical changes in the IMM, relative to the start of this electrophysiological profile. c-fos gene expression increases <15 min after training onset, followed by a learning-related increase in Fos expression, in neurons immunopositive for GABA, taurine and parvalbumin (not calbindin). Approximately simultaneously or shortly after, there are increases in phosphorylation level of glutamate (AMPA) receptor subunits and in releasable neurotransmitter pools of GABA and taurine. Later, the mean area of spine synapse post-synaptic densities, N-methyl-D-aspartate receptor number and phosphorylation level of further synaptic proteins are elevated. After ~ 15 h, learning-related changes in amounts of several synaptic proteins are observed. The results indicate progression from transient/labile to trophic synaptic modification, culminating in stable recognition memory. PMID- 25280907 TI - The opportunities and challenges of large-scale molecular approaches to songbird neurobiology. AB - High-throughput methods for analyzing genome structure and function are having a large impact in songbird neurobiology. Methods include genome sequencing and annotation, comparative genomics, DNA microarrays and transcriptomics, and the development of a brain atlas of gene expression. Key emerging findings include the identification of complex transcriptional programs active during singing, the robust brain expression of non-coding RNAs, evidence of profound variations in gene expression across brain regions, and the identification of molecular specializations within song production and learning circuits. Current challenges include the statistical analysis of large datasets, effective genome curations, the efficient localization of gene expression changes to specific neuronal circuits and cells, and the dissection of behavioral and environmental factors that influence brain gene expression. The field requires efficient methods for comparisons with organisms like chicken, which offer important anatomical, functional and behavioral contrasts. As sequencing costs plummet, opportunities emerge for comparative approaches that may help reveal evolutionary transitions contributing to vocal learning, social behavior and other properties that make songbirds such compelling research subjects. PMID- 25280909 TI - The trap of sex in social insects: from the female to the male perspective. AB - The phenotype of male Hymenoptera and the peculiar role of males has been neglected and greatly understudied, given the spectacular cooperative behavior of female social insects. In social insects there has been considerable progress in understanding the molecular mechanisms behind haplodiploid sex determination but, beyond that, very little is known concerning the neural, endocrine, and genetic correlates of sexual selection in males. An opportunity is being missed: the male phenotype in Hymenoptera is a natural experiment to compare the drives of natural versus sexual selection. In contrast to females, males do not work, they usually display far from the nest to gain mates, compete among rivals in nuptial flights or for a symbolic territory at leks, and engage in direct or ritualized conflicts. By comparing the available data on male paper wasps with studies on other social Hymenoptera, we summarize what we currently know about the physical, hormonal, neural and behavioral traits in a model system appropriate to examine current paradigms on sexual selection. Here we review male behavior in social Hymenoptera beyond sex stereotypes: the subtle role of "drones" in the colony, the lack of armaments and ornaments, the explosive mating crowds, the "endurance" race, the cognitive bases of the "choosy" male and his immune defense. Social insect males are not just simple-minded mating machines, they are shaped, constrained and perhaps trapped by sexual selection. PMID- 25280910 TI - Higher contact-force values associated with better mid-term outcome of paroxysmal atrial fibrillation ablation using the SmartTouchTM catheter. AB - AIMS: Real-time measurement of contact force (CF) during catheter ablation of atrial fibrillation (AF) has been recently suggested to potentially impact procedural outcome. However, the role of CF intensity on mid-term results using the SmartTouchTM catheter has not been investigated so far. METHODS AND RESULTS: Pulmonary vein isolation (PVI) using the SmartTouchTM catheter was performed in 100 eligible patients (age 62 +/- 8; 79% men) undergoing a first procedure of paroxysmal AF catheter ablation. Continuous CF monitoring during catheter ablation allowed calculation of mean CF per patient. Patients were dichotomized into high CF (>=22 g, upper quartile) and low CF (<22 g, remaining) and enroled in a standardized follow-up programme (after a 3-month blanking period), free from antiarrhythmic therapy, with regular evaluations including 24 h Holter recordings at 1, 3, 6, 9, 12, 18, and 24 months. Atrial fibrillation relapse was defined as any symptomatic or asymptomatic atrial arrhythmia lasting >30 s. The average CF among all procedures was 19.6 +/- 3.7 g. Though complete PVI was eventually achieved in all cases in both groups, success using an exclusively anatomical approach was higher in the high CF group (92.0 vs. 72.0%; P = 0.04). During a mean follow-up of 19 +/- 5 months, a lower incidence of AF relapse was observed in higher CF patients (4.0 vs. 20.0%; log rank P = 0.04). Pericardial tamponade occurred in one patient in the higher CF group. No thromboembolism or procedure-associated deaths were observed. CONCLUSION: Higher values of CF overall during antral PVI appear to be associated with a higher likelihood of sinus rhythm maintenance without significantly increasing the complication rate. PMID- 25280911 TI - Old drug tipepidine as new hope for children with ADHD. PMID- 25280912 TI - India's health assurance plan will offer free medicines, diagnostics, insurance, and traditional medicine. PMID- 25280913 TI - The network topology of aneurysmal subarachnoid haemorrhage. AB - OBJECTIVE: Network analysis is an emerging tool for the study of complex systems. In the current report, the cascade of physiological and neurological changes following aneurysmal subarachnoid haemorrhage (SAH) was modelled as a complex system of interacting parameters. Graph theoretical analysis was then applied to identify parameters at critical topological junctions of the network, which may represent the most effective therapeutic targets. METHODS: Correlation matrices were calculated using a combination of Pearson, polyserial and polychoric regressions among 50 variables collected from 120 participants (38 male; mean age 51 years) included in the CONSCIOUS-1 trial. Graph theoretical analysis was performed to identify important topological features within the network formed by the interactions among these variables. Non-parametric resampling was applied to determine thresholds for significance. RESULTS: Several critical network hubs were identified, including the incidence of delayed ischaemic neurological deficit (DIND), anaemia and hypoalbuminaemia/hypoproteinaemia. While not significant hubs, World Federation of Neurosurgical Societies (WFNS) score and use of rescue therapy had widespread connections within the network. Patient sex and history of hypertension also strongly clustered with other variables. A subnetwork (module) was also identified, which was related to neurological outcomes including WFNS score, angiographic vasospasm, DIND, use of rescue therapy and hydrocephalus. INTERPRETATION: Using graph theoretical analysis, we identify critical network topologies following SAH, which may serve as useful therapeutic targets. Importantly, we demonstrate that network analysis is a robust method to model complex interactions following SAH. TRIAL REGISTRATION NUMBER: URL: http://www.clinicaltrials.gov; Identifier: NCT00111085. PMID- 25280908 TI - In search of a recognition memory engram. AB - A large body of data from human and animal studies using psychological, recording, imaging, and lesion techniques indicates that recognition memory involves at least two separable processes: familiarity discrimination and recollection. Familiarity discrimination for individual visual stimuli seems to be effected by a system centred on the perirhinal cortex of the temporal lobe. The fundamental change that encodes prior occurrence within the perirhinal cortex is a reduction in the responses of neurones when a stimulus is repeated. Neuronal network modelling indicates that a system based on such a change in responsiveness is potentially highly efficient in information theoretic terms. A review is given of findings indicating that perirhinal cortex acts as a storage site for recognition memory of objects and that such storage depends upon processes producing synaptic weakening. PMID- 25280914 TI - Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation. AB - OBJECTIVES: To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinson's disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. RESULTS: Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. CONCLUSIONS: Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects. PMID- 25280915 TI - Parkinson's disease beyond 20 years. AB - BACKGROUND: A very limited number of studies report data on the clinical features of Parkinson's disease (PD) 20 years after onset and beyond. OBJECTIVE: To characterise PD 20 years after onset, investigating the impact of age at onset and disease duration on the clinical picture and the predictors of outcomes in patients reaching the 20-year time point. METHODS: We conducted a retrospective, cross-sectional study and a longitudinal study. All case visits of patients with a disease duration >=20 years (N=401) were stratified by disease duration (20-22, 23-25, >=26 years) and by age at onset (cut-off, 50 years). Patients with a disease duration of 20-22 years (N=320) were prospectively followed up for a median of 45 months (IQR 23-89) for the new occurrence of fracture, percutaneous endoscopic gastrostomy, institutionalisation, confinement to a wheelchair or bed and death. RESULTS: Older age at onset and longer disease duration were independently associated with a higher prevalence of major motor and non-motor milestones of disease disability (no interaction observed). In the longitudinal study, the most frequent outcomes were death (N=92), confinement to a wheelchair or bed (N=67) and fracture (N=52). Mortality was associated with the gender: male, older age, dysphagia, orthostatic hypotension, postural instability, fractures and institutionalisation. Fracture was associated with postural instability. Predictors of permanent confinement to a wheelchair or bed were older age, postural instability and institutionalisation. Comorbid dementia at the 20-year examination did not predict any of the outcomes. CONCLUSIONS: Age at onset and disease duration are independent determinants of the clinical features of PD beyond 20 years. Non-motor symptoms depend more on age at onset rather than the disease duration itself. Non-levodopa-responsive axial symptoms are the main predictors of all relevant outcomes. PMID- 25280916 TI - VSARICHS: a simple grading scale for vascular structural abnormality-related intracerebral haemorrhage. AB - BACKGROUND AND PURPOSE: Vascular structural abnormality-related intracerebral haemorrhage (VSARICH) accounts for 10-20% of cases of intracerebral haemorrhage (ICH), but none of the grading scales for primary ICH are reliable for VSARICH. This study aimed to propose a grading scale based on clinical and anatomical parameters to predict short-term clinical outcome. METHODS: Data were prospectively collected from patients with ICH recruited consecutively from 50 secondary and tertiary hospitals in China. Demographic and clinicopathological factors associated with mortality and good clinical outcome were identified and used to develop a grading scale for VSARICH. RESULTS: The VSARICH was 10.8% and 13% in the derivation (n=335) and validation (n=109) cohorts, respectively. Data from 307 patients with VSARICH in the derivation cohort were used to generate a VSARICH score (VSARICHS) system ranging from 0 to 9. Points were assigned based on the Glasgow Coma Scale (GCS) score on admission (GCS 3-4=4 points; 5-12=2 points; 13-15=0 points), age (>=80 years=2 points; 79-60=1 point; <=59=0 points), presence of subarachnoid haemorrhage (yes=1 point; no=0 points) and presence of herniation (yes=2 points; no=0 points). VSARICHS showed good discrimination in the derivation cohort (area under the receiver operating characteristic curves, AUCs)AUCs 0.837 for good clinical outcome; 0.942 for mortality) and validation cohort (AUCs 0.813 for good clinical outcome; 0.930 for mortality). CONCLUSIONS: VSARICHS appears to be a reliable clinical scoring system that may prove useful for guiding risk stratification, clinical treatment and research. PMID- 25280917 TI - Glioma trials and viral tribulations: can anything be concluded from non controlled trials? PMID- 25280918 TI - Comparison of expectations and beliefs about good teaching in an academic day release medical education program: a qualitative study. AB - BACKGROUND: In a professional learner-centered(ness) educational environment, communication and alignment of expectations about teaching are indispensable. Professional education of residents could benefit from an analysis and comparison of teachers' and residents' educational expectations and beliefs. Our purpose is to identify success factors and barriers related to aligning expectations and beliefs and building a supportive professional learner-centered educational environment. METHODS: We conducted semi-structured individual interviews with teachers and semi-structured focus groups with residents. A single interview format was used to make it possible to compare the results. Data were analysed using a qualitative software package (AtlasTi). Data analysis steps were followed by the author team, which identified four domains of good teaching: personal traits, knowledge, relationships and teaching qualities. RESULTS: Teachers and residents agreed about the importance of personal professional characteristics like being a role model and having an open and enthusiastic attitude. They all thought that having a specific knowledge base was essential for teaching. Approaching residents as adult learners was found to be an important element of the learner-centred environment and it was agreed that teachers should take practical experiences to a higher level. However, teachers and residents had different expectations about the practical consequences of being a role model, adult learning, coaching and openness, and the type of knowledge that was needed in the professional development program. Communication about different expectations appeared to be difficult. CONCLUSIONS: Teachers and residents agreed on a conceptual level about expectations and beliefs regarding good teaching, but disagreed on an executive level. According to the residents, the disagreement about good teaching was not the biggest barrier to creating alignment and a supportive professional relationship; instead, it was the absence of a proper dialogue regarding issues about expectations and beliefs. PMID- 25280919 TI - Quantifying subtle locomotion phenotypes of Drosophila larvae using internal structures based on FIM images. AB - Quantitative analysis of behavioral traits requires precise image acquisition and sophisticated image analysis to detect subtle locomotion phenotypes. In the past, we have established Frustrated Total Internal Reflection (FTIR) to improve the measurability of small animals like insects. This FTIR-based Imaging Method (FIM) results in an excellent foreground/background contrast and even internal organs and other structures are visible without any complicated imaging or labeling techniques. For example, the trachea and muscle organizations are detectable in FIM images. Here these morphological details are incorporated into phenotyping by performing cluster analysis using histogram-based statistics for the first time. We demonstrate that FIM enables the precise quantification of locomotion features namely rolling behavior or muscle contractions. Both were impossible to quantify automatically before. This approach extends the range of FIM applications by enabling advanced automatic phenotyping for particular locomotion patterns. PMID- 25280920 TI - Hydrogen sulfide production from subgingival plaque samples. AB - Periodontitis is a polymicrobial anaerobe infection. Little is known about the dysbiotic microbiota and the role of bacterial metabolites in the disease process. It is suggested that the production of certain waste products in the proteolytic metabolism may work as markers for disease severity. Hydrogen sulfide (H2S) is a gas produced by degradation of proteins in the subgingival pocket. It is highly toxic and believed to have pro-inflammatory properties. We aimed to study H2S production from subgingival plaque samples in relation to disease severity in subjects with natural development of the disease, using a colorimetric method based on bismuth precipitation. In remote areas of northern Thailand, adults with poor oral hygiene habits and a natural development of periodontal disease were examined for their oral health status. H2S production was measured with the bismuth method and subgingival plaque samples were analyzed for the presence of 20 bacterial species with the checkerboard DNA-DNA hybridization technique. In total, 43 subjects were examined (age 40-60 years, mean PI 95 +/- 6.6%). Fifty-six percent had moderate periodontal breakdown (CAL > 3 < 7 mm) and 35% had severe periodontal breakdown (CAL > 7 mm) on at least one site. Parvimonas micra, Filifactor alocis, Porphyromonas endodontalis and Fusobacterium nucleatum were frequently detected. H2S production could not be correlated to periodontal disease severity (PPD or CAL at sampled sites) or to a specific bacterial composition. Site 21 had statistically lower production of H2S (p = 0.02) compared to 16 and 46. Betel nut chewers had statistically significant lower H2S production (p = 0.01) than non-chewers. Rapid detection and estimation of subgingival H2S production capacity was easily and reliably tested by the colorimetric bismuth sulfide precipitation method. H2S may be a valuable clinical marker for degradation of proteins in the subgingival pocket. PMID- 25280921 TI - The influence of Lactobacillus casei DN 114 001 on the activity of faecal enzymes and genotoxicity of faecal water in the presence of heterocyclic aromatic amines. AB - High activity of bacterial enzymes in human colon and genotoxicity of faecal water (FW) are biomarkers of the harmful action of microbiota. The aim of the present study was to assess the activity of beta-glucuronidase and beta glucosidase and the genotoxicity of FW in vitro after incubation with 2-amino-3 methyl-3H-imidazo[4,5-f]quinoline (IQ) or 2-amino-1-methyl-6-phenyl-1H imidazo[4,5-b]pyridine (PhIP) and probiotic Lactobacillus casei DN 114 001 (Actimel). Our results indicate, that IQ and PhIP greatly increased the activity of faecal enzymes (it was up to four times higher, as measured by spectrophotometric methods) and the genotoxicity of FW (% DNA in the tail was up to 3.2 times higher, as evaluated by the comet assay on Caco-2 cells) in 15 individuals from three age-dependent groups (breast-fed children, adults aged 30 40 years, elderly aged 75-85 years). Lb. casei DN 114 001 decreased the activity of faecal enzymes and the genotoxicity of FW exposed to PhIP and IQ mostly to control values. The activity of faecal enzymes after incubation with IQ was reduced by 71.8% in the FW of children, 37.5% in adults and 64.2% in elderly (beta-glucuronidase); as well as by 59.9% in children and 87.9% in elderly (beta glucosidase). For PhIP the reduction was by 59.0% in the FW of children, 50.0% in adults and 81.2% in elderly (beta-glucuronidase) and by 20.2% in children, 20.7% in adults and 84.1% in elderly (beta-glucosidase). Lb. casei DN 114 001 also decreased the genotoxicity of FW to the greatest extent in adults after incubation with IQ (by 65.4%) and PhIP (by 69.6%) and it was found to correlate positively with the decrease in faecal enzymes activity. In conclusion, Lb. casei DN 114 001 may exert the protective effects against genotoxic and possibly pro carcinogenic effects of food processing-derived chemicals present in faecal water. PMID- 25280922 TI - Evaluation of four alpha-diketones for toll-like receptor-4 (TLR-4) activation in a human transfected cell line. AB - Toll-like receptor-4 (TLR-4) activity is upregulated in persons with fibrotic lung diseases secondary to chronic inflammatory conditions like Crohn's disease and rheumatoid arthritis. We hypothesized that alpha-diketones associated with fixed obstructive lung disease may activate TLR-4. We utilized a human embryonic kidney cell assay (HEK293) with human TLR-4 receptors to test for potential activation effects of 2,3-butandeione, 2,3-pentanedione, 2,3-hexanedione, and 2,3 heptanedione at test concentrations of 1, 10, 100, and 1000 uM. The assay detects NF-kappaB-induced expression of secreted alkaline phosphatase measured after 16 h incubation by a UV-VIS Spectrometer at 650 nm. Escherichia coli K12 lipopolysaccharide (LPS) at 0.5 ng/mL served as a positive control and was added with each test compound to evaluate combined effects. None of the tested alpha diketones were found to exhibit cytotoxicity, agonism, or synergistic effects with LPS in the human TLR-4 assay up to 1000 uM. Screening of 2,3-butanedione for agonist activity using the HEK assay with mouse TLR-4 receptors exhibited cytotoxicity at 1000 uM, but no agonist activity. We conclude that the tested alpha-diketones at relatively high concentrations in vitro do not exhibit TLR-4 agonist or synergistic activity and, therefore, apparently do not directly induce inflammasome activation through this pathway in humans or mice. PMID- 25280923 TI - Fumonisin B1 contamination in breast milk and its exposure in infants under 6 months of age in Rombo, Northern Tanzania. AB - The carry-over of fumonisin B1 from contaminated feed into dairy milk also suggests its carry-over from contaminated food into breast milk. This study assessed fumonisin B1 contamination in breast milk and associated exposures of infants under 6 months of age. Breast milk samples were collected from 131 lactating mothers and the weight of their infants was measured during the first month of lactation. Fumonisin B1 was extracted using methanol:acetone, cleaned up with Strong Anion Exchange columns and quantified by HPLC. Fumonisin B1 exposure in each child was estimated using deterministic approach. Out of the 131 samples, 58 (44.3%) contained fumonisin B1 at levels ranging from 6.57 to 471.05 ng/ml. Of the contaminated samples, 10.3% had fumonisin B1 levels above the EU limit of 200 ppb for fumonisins in infants' food. Exposure in the infants ranged from 0.78 to 64.93 ug/kg body weight (bw) per day (median, 3 ug/kg bw/day) and exceeded the provisional maximum tolerable limit of 2 ug/kg bw/day in 29% of the infants. In conclusion, breast milk from mothers in Northern Tanzania is contaminated with fumonisins at levels that lead to unacceptable exposures in infants. Strategies to prevent lactating mothers from fumonisin exposure are urgently needed to minimise fumonisin exposure in infants. PMID- 25280924 TI - A European model and case studies for aggregate exposure assessment of pesticides. AB - Exposures to plant protection products (PPPs) are assessed using risk analysis methods to protect public health. Traditionally, single sources, such as food or individual occupational sources, have been addressed. In reality, individuals can be exposed simultaneously to multiple sources. Improved regulation therefore requires the development of new tools for estimating the population distribution of exposures aggregated within an individual. A new aggregate model is described, which allows individual users to include as much, or as little, information as is available or relevant for their particular scenario. Depending on the inputs provided by the user, the outputs can range from simple deterministic values through to probabilistic analyses including characterisations of variability and uncertainty. Exposures can be calculated for multiple compounds, routes and sources of exposure. The aggregate model links to the cumulative dietary exposure model developed in parallel and is implemented in the web-based software tool MCRA. Case studies are presented to illustrate the potential of this model, with inputs drawn from existing European data sources and models. These cover exposures to UK arable spray operators, Italian vineyard spray operators, Netherlands users of a consumer spray and UK bystanders/residents. The model could also be adapted to handle non-PPP compounds. PMID- 25280925 TI - Corneal injuries from liquid detergent pods. AB - Laundry and dishwasher detergent "pods" were introduced to the United States market in 2010 and are sold by several manufacturers. They represent a high percentage of household cleaning product exposure in the United Kingdom. We present a consecutive case series of 10 children seen in a 9-month period with corneal injuries from exposure to liquid detergent pods. PMID- 25280926 TI - The distribution of incubation and relapse times in experimental human infections with the malaria parasite Plasmodium vivax. AB - BACKGROUND: The distributions of incubation and relapse periods are key components of infectious disease models for the malaria parasite Plasmodium vivax; however, detailed distributions based upon experimental data are lacking. METHODS: Using a range of historical, experimental mosquito-transmitted human infections, Bayesian estimation with non-informative priors was used to determine parametric distributions that can be readily implemented for the incubation period and time-to-first relapse in P. vivax infections, including global subregions by parasite source. These analyses were complemented with a pooled analysis of observational human infection data with infections that included malaria chemoprophylaxis and long-latencies. The epidemiological impact of these distributional assumptions was explored using stochastic epidemic simulations at a fixed reproductive number while varying the underlying distribution of incubation periods. RESULTS: Using the Deviance Information Criteria to compare parameterizations, experimental incubation periods are most closely modeled with a shifted log-logistic distribution; a log-logistic mixture is the best fit for incubations in observational studies. The mixture Gompertz distribution was the best fit for experimental times-to-relapse among the tested parameterizations, with some variation by geographic subregions. Simulations suggest underlying distributional assumptions have critically important impacts on both the time scale and total case counts within epidemics. CONCLUSIONS: These results suggest that the exponential and gamma distributions commonly used for modeling incubation periods and relapse times inadequately capture the complexity in the distributions of event times in P. vivax malaria infections. In future models, log-logistic and Gompertz distributions should be utilized for general incubation periods and relapse times respectively, and region-specific distributions should be considered to accurately model and predict the epidemiology of this important human pathogen. PMID- 25280927 TI - Childhood tuberculosis in general practice. AB - Tuberculosis (TB) in children is a common cause of morbidity. Diagnosis is difficult because of paucibacillary nature of illness and difficulty in obtaining appropriate samples. Children presenting with poor weight gain, fever with or without cough for more than two weeks or contact with an adult in family with pulmonary tuberculosis should be investigated for TB. In all suspected cases of tuberculosis initial investigations include radiograph of chest (CXR) and Mantoux test. If CXR is suggestive of TB, an ambulatory gastric aspirate and induced sputum for acid fast bacilli (AFB) smear may be carried out in two days. Children with AFB positive or abnormal CXR with positive Mantoux test should be started on Antitubercular therapy (ATT). Rest of the patients require more investigations and should be referred to a specialist. All children with newly diagnosed tuberculosis should be treated with 6 mo of ATT (two months with 4 drugs, followed by four months with 2 drugs). Children on ATT should be monitored for improvement in symptoms and weight gain along with side effects of medications. CXR should be done after completion of treatment. PMID- 25280928 TI - Swelling of a lumbar spinal nerve root mimicking an intraspinal mass lesion on preoperative magnetic resonance imaging. PMID- 25280929 TI - A rare case of extramedullary myxopapillary ependymoma. PMID- 25280930 TI - Test-retest reliability of seven common clinical tests for assessing lower extremity muscle flexibility in futsal and handball players. AB - OBJECTIVE: To determine the inter-session reliability of seven lower limb muscle flexibility measures obtained from the passive hip extension test (PHE), passive hip flexion test (PHF), passive hip abduction test (PHA), passive straight leg raise test (PSLR), modified Thomas test (MTh), the ankle dorsi-flexion with knee extended (ADFKE) and flexed (ADFKF) tests. DESIGN: Repeated measures design. SETTING: Controlled laboratory environment. PARTICIPANTS: 60 futsal and 30 handball players. MAIN OUTCOME MEASURES: Reliability was examined through the change in the mean (ChM), standard error of measurement expressed in absolute values (SEM) and as a percentage of the mean score (%SEM), minimal detectable change (MDC95), and intraclass correlation coefficient (ICC2,k). RESULTS: The findings showed negligible ChM values for all the flexibility measures analysed (<1 degrees ). Furthermore, the SEM and MDC95 for each flexibility measure ranged from 1.3 degrees to 2.5 degrees and from 3.8 degrees to 6.9 degrees , respectively, with %SEM scores lower than 10% and ICC scores higher than 0.88. CONCLUSIONS: Clinicians can be 95% confident that an observed change between 2 measures larger than 3.7 degrees , 6.2 degrees , 5.5 degrees , 6.1 degrees , 6.9 degrees , 4.7 degrees , and 5.0 degrees for the flexibility measures obtained from the PHE, PHF, PHA, PSLR, MTh, ADFKE and ADFKF, respectively, likely indicates a real change in muscle flexibility. PMID- 25280931 TI - The acute effects of spinal manipulation on neuromuscular function in asymptomatic individuals: A preliminary study. AB - OBJECTIVES: To analyse the acute effects of spinal manipulation on neuromuscular function in asymptomatic individuals. DESIGN: Randomised controlled, cross-over trial. SETTINGS: Spinal manipulation (SM) is used as therapeutic modality for various neuromuscular disorders and also in sport with asymptomatic individuals to improve range of motion and/or facilitate motor control. Experimental evidence of its effectiveness is lacking. PARTICIPANTS: 27 asymptomatic participants (15 males and 12 females) [age (mean +/- standard deviation) 24 +/- 3 years] were exposed to three separate treatments in random order: 1) Spinal Manipulation of the lumbar spine (MAN); 2) Stretching of the Lumbar spine (STR); 3) sham manipulation (SHA). MAIN OUTCOME MEASURES: Before (PRE), after (POST) and 15 min after (15_MIN) each treatment, the participants were asked to perform three tasks always in the same order: 1) force fluctuation task; 2) Modified Sorensen's test; 3) sit and reach. Surface EMG was recorded from Gastrocnemius medialis and Erector Spinae muscles using linear arrays during task 1 and 2. RESULTS: MAN was not shown to determine improvements superior to other treatments in the control of force output and sEMG parameters. CONCLUSIONS: Studies with larger populations are needed in order to ascertain the effectiveness of SM on neuromuscular function. PMID- 25280932 TI - Cardiovascular effects of levosimendan during rewarming from hypothermia in rat. AB - BACKGROUND: Previous research aimed at ameliorating hypothermia-induced cardiac dysfunction has shown that inotropic drugs, that stimulate the cAMP, - PKA pathway via the sarcolemmal beta-receptor, have a decreased inotropic effect during hypothermia. We therefore wanted to test whether levosimendan, a calcium sensitizer and dose-dependent phosphodiesterase 3 (PDE3) inhibitor, is able to elevate stroke volume during rewarming from experimental hypothermia. METHODS: A rat model designed for circulatory studies during experimental hypothermia (4h at 15 degrees C) and rewarming was used. The following three groups were included: (1) A normothermic group receiving levosimendan, (2) a hypothermic group receiving levosimendan the last hour of stable hypothermia and during rewarming, and (3) a hypothermic placebo control group. Hemodynamic variables were monitored using a Millar conductance catheter in the left ventricle (LV), and a pressure transducer connected to the left femoral artery. In order to investigate the level of PKA stimulation by PDE3 inhibition, myocardial Ser23/24-cTnI phosphorylation was measured using Western-blot. RESULTS: After rewarming, stroke volume (SV), cardiac output (CO) and preload recruitable stroke work (PRSW) were restored to within pre-hypothermic values in the levosimendan-treated animals. Compared to the placebo group after rewarming, SV, CO, PRSW, as well as levels of Ser23/24-cTnI phosphorylation, were significantly higher in the levosimendan treated animals. CONCLUSION: The present data shows that levosimendan ameliorates hypothermia-induced systolic dysfunction by elevating SV during rewarming from 15 degrees C. Inotropic treatment during rewarming from hypothermia in the present rat model is therefore better achieved through calcium sensitizing and PDE3 inhibition, than beta-receptor stimulation. PMID- 25280933 TI - 13 C flux analysis of cyanobacterial metabolism. AB - (13)C metabolic flux analysis (MFA) has made important contributions to our understanding of the physiology of model strains of E. coli and yeast, and it has been widely used to guide metabolic engineering efforts in these microorganisms. Recent advancements in (13)C MFA methodology combined with publicly available software tools are creating new opportunities to extend this approach to examine less characterized microbes. In particular, growing interest in the use of cyanobacteria as industrial hosts for photosynthetic production of biofuels and biochemicals has led to a critical need to better understand how cyanobacterial metabolic fluxes are regulated in response to changes in growth conditions or introduction of heterologous pathways. In this contribution, we review several prior studies that have applied isotopic steady-state (13)C MFA to examine heterotrophic or mixotrophic growth of cyanobacteria, as well as recent studies that have pioneered the use of isotopically nonstationary MFA (INST-MFA) to study autotrophic cultures. We also provide recommendations for the design and analysis of INST-MFA experiments in cyanobacteria, based on our previous experience and a series of simulation studies used to assess the selection of measurements and sample time points. We anticipate that this emerging knowledgebase of prior (13)C MFA studies, optimized experimental protocols, and public software tools will catalyze increasing use of (13)C MFA techniques by the cyanobacteria research community. PMID- 25280935 TI - Identical inferences about correlated evolution arise from ancestral state reconstruction and independent contrasts. AB - Inferences about the evolution of continuous traits based on reconstruction of ancestral states have often been considered more error-prone than analysis of independent contrasts. Here we show that both methods in fact yield identical estimators for the correlation coefficient and regression gradient of correlated traits, indicating that reconstructed ancestral states are a valid source of information about correlated evolution. We show that the independent contrast associated with a pair of sibling nodes on a phylogenetic tree can be expressed in terms of the maximum likelihood ancestral state function at those nodes and their common parent. This expression gives rise to novel formulae for independent contrasts for any model of evolution admitting of a local likelihood function. We thus derive new formulae for independent contrasts applicable to traits evolving under directional drift, and use simulated data to show that these directional contrasts provide better estimates of evolutionary model parameters than standard independent contrasts, when traits in fact evolve with a directional tendency. PMID- 25280934 TI - Indacaterol improves lung hyperinflation and physical activity in patients with moderate chronic obstructive pulmonary disease--a randomized, multicenter, double blind, placebo-controlled study. AB - BACKGROUND: Indacaterol is a long-acting beta-2 agonist for once-daily treatment of COPD. We evaluated the effects of indacaterol 150 MUg on lung hyperinflation compared with placebo and open-label tiotropium 18 MUg. We measured physical activity during treatment with indacaterol 150 MUg and matched placebo. METHODS: We performed a randomized, three-period, cross-over study (21 days of treatment separated by two wash-out periods of 13 days) with indacaterol 150 MUg or matching placebo and tiotropium 18 MUg. Lung function was assessed by body plethysmography and spirometry. Physical activity was measured for one week by a multisensory armband at the end of both treatment periods with indacaterol/matched placebo. The primary endpoint was peak inspiratory capacity at the end of each treatment period. RESULTS: 129 patients (mean age, 61 years; mean post-bronchodilator FEV1, 64%), were randomized and 110 patients completed the study. Peak inspiratory capacity was 0.22 L greater with Indacaterol at day 21 compared to placebo (p < 0.001). Similar results were observed for tiotropium. Both bronchodilators also significantly improved other parameters of lung hyperinflation compared with placebo. All parameters of physical activity were significantly increased during treatment with indacaterol versus placebo. CONCLUSIONS: Indacaterol 150 MUg improved lung hyperinflation in patients with moderate COPD, which was associated with an increase of physical activity. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01012765. PMID- 25280936 TI - fabp4 is central to eight obesity associated genes: a functional gene network based polymorphic study. AB - Network study on genes and proteins offers functional basics of the complexity of gene and protein, and its interacting partners. The gene fatty acid-binding protein 4 (fabp4) is found to be highly expressed in adipose tissue, and is one of the most abundant proteins in mature adipocytes. Our investigations on functional modules of fabp4 provide useful information on the functional genes interacting with fabp4, their biochemical properties and their regulatory functions. The present study shows that there are eight set of candidate genes: acp1, ext2, insr, lipe, ostf1, sncg, usp15, and vim that are strongly and functionally linked up with fabp4. Gene ontological analysis of network modules of fabp4 provides an explicit idea on the functional aspect of fabp4 and its interacting nodes. The hierarchal mapping on gene ontology indicates gene specific processes and functions as well as their compartmentalization in tissues. The fabp4 along with its interacting genes are involved in lipid metabolic activity and are integrated in multi-cellular processes of tissues and organs. They also have important protein/enzyme binding activity. Our study elucidated disease-associated nsSNP prediction for fabp4 and it is interesting to note that there are four rsID's (rs1051231, rs3204631, rs140925685 and rs141169989) with disease allelic variation (T104P, T126P, G27D and G90V respectively). On the whole, our gene network analysis presents a clear insight about the interactions and functions associated with fabp4 gene network. PMID- 25280937 TI - Analysis of ethylene biosynthesis and perception during postharvest cold storage of Marsh and Star Ruby grapefruits. AB - Grapefruits are among the citrus species more sensitive to cold and develop chilling injury symptoms during prolonged postharvest storage at temperatures lower than 8 C-10 C. The plant hormone ethylene has been described either to protect or potentiate chilling injury development in citrus whereas little is known about transcriptional regulation of ethylene biosynthesis, perception and response during cold storage and how the hormone is regulating its own perception and signaling cascade. Then, the objective of the present study was to explore the transcriptional changes in the expression of ethylene biosynthesis, receptors and response genes during cold storage of the white Marsh and the red Star Ruby grapefruits. The effect of the ethylene action inhibitor, 1-MCP, was evaluated to investigate the involvement of ethylene in the regulation of the genes of its own biosynthesis and perception pathway. Ethylene production was very low at the harvest time in fruits of both varieties and experienced only minor changes during storage. By contrast, inhibition of ethylene perception by 1-MCP markedly induced ethylene production, and this increase was highly stimulated during shelf life at 20 C, as well as transcription of ACS and ACO. These results support the auto-inhibitory regulation of ethylene in grapefruits, which acts mainly at the transcriptional level of ACS and ACO genes. Moreover, ethylene receptor1 and ethylene receptor3 were induced by cold while no clear role of ethylene was observed in the induction of ethylene receptors. However, ethylene appears to be implicated in the transcriptional regulation of ERFs both under cold storage and shelf-life. PMID- 25280938 TI - Antimicrobial activity of essential oils against Staphylococcus aureus biofilms. AB - The present study was aimed to evaluate the potential of essential oils to remove the foodborne pathogen Staphylococcus aureus from food-processing facilities. The effectiveness of 19 essential oils against planktonic cells of S. aureus was firstly assessed by minimal inhibitory concentration. Planktonic cells showed a wide variability in resistance to essential oils, with thyme oil as the most effective, followed by lemongrass oil and then vetiver oil. The eight essential oils most effective against planktonic cells were subsequently tested against 48 h-old biofilms formed on stainless steel. All essential oils reduced significantly (p < 0.01) the number of viable biofilm cells, but none of them could remove biofilms completely. Thyme and patchouli oils were the most effective, but high concentrations were needed to achieve logarithmic reductions over 4 log CFU/cm(2) after 30 min exposure. Alternatively, the use of sub-lethal doses of thyme oil allowed to slow down biofilm formation and to enhance the efficiency of thyme oil and benzalkonium chloride against biofilms. However, some cellular adaptation to thyme oil was detected. Therefore, essential oil-based treatments should be based on the rotation and combination of different essential oils or with other biocides to prevent the emergence of antimicrobial-resistant strains. PMID- 25280940 TI - Gax inhibits perivascular preadipocyte biofunction mediated by IGF-1 induced FAK/Pyk2 and ERK2 cooperative pathways. AB - Perivascular adipocyte (PVAC) biofunctions were closely related to cardiovascular diseases; its specific biological mechanisms remained unclear. How to adjust PVAC functions of vascular cells is an important topic. The present study was designed to investigate whether FAK/Pyk2 and ERK1/2 MAPK signaling pathways participate in PVAC functions, which is activated by insulin-like growth factor 1(IGF-1) and inhibited by Gax. PVACs isolated from perivascular adipocyte were cultured, dedifferentiated, and stimulated with 10nM IGF-I. Cellular function experiments showed that IGF-1 promoted PVAC proliferation, adhesion, and migration. However Gax weakened IGF-1-mediated these function. Flow cytometry demonstrated that IGF 1 increased PVACs percent of S phase and decreased the percent of G0/G1 phase and apoptotic cells. While, Gax decreased the percent of S phase cells and increased those of G0-G1 phase and apoptotic cells. Western blotting and RT-PCR revealed that IGF-1 activated FAK/Pyk2 and ERK1/2 signaling pathways, upregulated the mRNA and protein expression of FAK, Pyk2, and ERK1/2, and suppressed p53 expression. Reversely, Gax lowered the expression of these signaling proteins and increased p53 expression. Therefore, IGF-1 mediated FAK/Pyk2 and ERK1/2 pathways to augment PVAC functions; Gax effectively counteracted these effects of IGF-1, repressed PVAC activities, and increased the cell apoptosis. Our findings suggested that FAK/Pyk2 and ERK1/2 cooperative activation mediated by IGF-1 is essential for PVAC functions, and Gax is a promising candidate gene to interfere with these signaling pathways and inhibit PVAC functions. PMID- 25280939 TI - Deficit irrigation strategies combined with controlled atmosphere preserve quality in early peaches. AB - Due to the water scarcity in the Mediterranean countries, irrigation must be optimized while keeping fruit quality. The effect of deficit irrigation strategies on changes in quality parameters of the early "Flordastar" peaches was studied. The deficit irrigation was programmed according to signal intensity of the maximum daily trunk shrinkage; deficit irrigation plants were irrigated to maintain maximum daily trunk shrinkage signal intensity values close to 1.4 or 1.3 in the case of DI1 or DI2 plants, respectively. Results were compared to a control watered at 150% crop evapotranspiration. Fruits were stored up to 14 days at 0 C and 95% Relative Humidity (RH) in air or in controlled atmosphere (controlled atmosphere; 3-4 kPa O2 and 12-14 kPa CO2), followed by a retail sale period of 4 days at 15 C and 90-95% Relative Humidity in air. Weight losses were lower in controlled atmosphere stored peaches from deficit irrigation. Air-stored fruits developed a more intense red color due to a faster ripening, which was not affected by the type of watering. At harvest, deficit irrigation peaches showed higher soluble solids content, which provided a better sensory evaluation. The soluble phenolic content was initially higher (55.26 +/- 0.18 mg gallic acid equivalents/100 g fresh weight) and more stable throughout postharvest life in DI1 fruits than in those from the other irrigation treatments. Concerning vitamin C, control fruits at harvest showed higher ascorbic acid than dehydroascorbic acid content (5.43 versus 2.43 mg/100 g fresh weight, respectively), while water stressed peaches showed the opposite results. The combination of DI2 and controlled atmosphere storage allowed saving a significant amount of water and provided peaches with good overall quality, maintaining the bioactive compounds analyzed. PMID- 25280941 TI - XBP1 induces snail expression to promote epithelial- to-mesenchymal transition and invasion of breast cancer cells. AB - Breast cancer is highly metastatic disease and the most lethal of the gynecologic malignancies. Epithelial-to-mesenchymal is a crucial process for the invasion of epithelial tumors. Recent studies revealed that breast cancer cells that have undergone EMT acquire aggressive malignant properties, but the molecular mechanisms underlying this transition are not well-understood. In this study, we report findings that human X-box binding protein1 (XBP1) acts as a novel regulator of EMT. We found that increased expression of XBP1 was associated with the progression of breast cancer and that XBP1 protein was significantly over expressed in matched metastatic tumor. High XBP1 protein also predicts shorter overall survival of breast cancer patients. RNA interference-mediated knockdown of XBP1 expression restored E-cadherin expression and cell-cell junction formation in breast cancer cells, suppressing cell invasion, and tumor formation. In contrast, overexpression of XBP1 decreased the expression of the epithelial marker E-cadherin but increased the mesenchymal markers in breast cancer cells. Our finding demonstrates the upregulated expression of the key EMT regulator Snail and that it mediated EMT activation and cell invasion by XBP1. PMID- 25280943 TI - TRAF6 is a novel regulator of Notch signaling in Drosophila melanogaster. AB - Notch signaling pathway unravels a fundamental cellular communication system that plays an elemental role in development. It is evident from different studies that the outcome of Notch signaling depends on signal strength, timing, cell type, and cellular context. Since Notch signaling affects a spectrum of cellular activity at various developmental stages by reorganizing itself in more than one way to produce different intensities in the signaling output, it is important to understand the context dependent complexity of Notch signaling and different routes of its regulation. We identified, TRAF6 (Drosophila homolog of mammalian TRAF6) as an interacting partner of Notch intracellular domain (Notch-ICD). TRAF6 genetically interacts with Notch pathway components in trans-heterozygous combinations. Immunocytochemical analysis shows that TRAF6 co-localizes with Notch in Drosophila third instar larval tissues. Our genetic interaction data suggests that the loss-of-function of TRAF6 leads to the rescue of previously identified Kurtz-Deltex mediated wing notching phenotype and enhances Notch protein survival. Co-expression of TRAF6 and Deltex results in depletion of Notch in the larval wing discs and down-regulates Notch targets, Wingless and Cut. Taken together, our results suggest that TRAF6 may function as a negative regulator of Notch signaling. PMID- 25280942 TI - IL-32theta downregulates CCL5 expression through its interaction with PKCdelta and STAT3. AB - Interleukin-32 (IL-32) exists in several isoforms and plays an important role in inflammatory response. Recently, we identified a new isoform, IL-32theta, and performed a microarray analysis to identify IL-32theta-regulated genes in THP-1 myelomonocytic cells. Upon stimulating IL-32theta-expressing THP-1 cells with phorbol myristate acetate (PMA), we found that the CCL5 transcript level was significantly reduced. We confirmed the downregulation of CCL5 protein expression by using an enzyme-linked immunosorbent assay (ELISA). Because STAT3 phosphorylation on Ser727 by PKCdelta is reported to suppress CCL5 protein expression, we examined whether IL-32theta-mediated STAT3 Ser727 phosphorylation occurs through an interaction with PKCdelta. In this study, we first demonstrate that IL-32theta interacts with PKCdelta and STAT3 using co-immunoprecipitation (Co-IP) and pulldown assay. Moreover, STAT3 was rarely phosphorylated on Ser727 in the absence of IL-32theta, leading to the binding of STAT3 to the CCL5 promoter. These results indicate that IL-32theta, through its interaction with PKCdelta, downregulates CCL5 expression by mediating the phosphorylation of STAT3 on Ser727 to render it transcriptionally inactive. Therefore, similar to what we have reported for IL-32alpha and IL-32beta, our data from this study suggests that the newly identified IL-32theta isoform also acts as an intracellular modulator of inflammation. PMID- 25280944 TI - Aberrantly expressed long noncoding RNAs in human intervertebral disc degeneration: a microarray related study. AB - INTRODUCTION: In addition to the well-known short noncoding RNAs such as microRNAs (miRNAs), increasing evidence suggests that long noncoding RNAs (lncRNAs) act as key regulators in a wide aspect of biologic processes. Dysregulated expression of lncRNAs has been demonstrated being implicated in a variety of human diseases. However, little is known regarding the role of lncRNAs with regards to intervertebral disc degeneration (IDD). In the present study we aimed to determine whether lncRNAs are differentially expressed in IDD. METHODS: An lncRNA-mRNA microarray analysis of human nucleus pulposus (NP) was employed. Bioinformatics prediction was also applied to delineate the functional roles of the differentially expressed lncRNAs. Several lncRNAs and mRNAs were chosen for quantitative real-time PCR (qRT-PCR) validation. RESULTS: Microarray data profiling indicated that 116 lncRNAs (67 up and 49 down) and 260 mRNAs were highly differentially expressed with an absolute fold change greater than ten. Moreover, 1,052 lncRNAs and 1,314 mRNAs were differentially expressed in the same direction in at least four of the five degenerative samples with fold change greater than two. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the differentially expressed mRNAs indicated a number of pathways, such as extracellular matrix (ECM)-receptor interaction. A coding-noncoding gene co expression (CNC) network was constructed for the ten most significantly changed lncRNAs. Annotation terms of the coexpressed mRNAs were related to several known degenerative alterations, such as chondrocyte differentiation. Moreover, lncRNAs belonging to a particular subgroup were identified. Functional annotation for the corresponding nearby coding genes showed that these lncRNAs were mainly associated with cell migration and phosphorylation. Interestingly, we found that Fas-associated protein factor-1 (FAF1), which potentiates the Fas-mediated apoptosis and its nearby enhancer-like lncRNA RP11-296A18.3, were highly expressed in the degenerative discs. Subsequent qRT-PCR results confirmed the changes. CONCLUSIONS: This is the first study to demonstrate that aberrantly expressed lncRNAs play a role in the development of IDD. Our study noted that up regulated RP11-296A18.3 highly likely induced the over-expression of FAF1, which eventually promoted the aberrant apoptosis of disc cells. Such findings further broaden the understanding of the etiology of IDD. PMID- 25280945 TI - Complementary/alternative therapies use in older women with arthritis: Information sources and factors influencing dialog with health care providers. AB - The purpose of this study was to describe the information sources older women with arthritis use to make decisions about complementary/alternative therapies (C/AT), and factors that influence C/AT dialog with their HCP. The purposive sample included 50 community-dwelling older women (mean age = 77.8, SD = 7.6, range 66-101) who were using C/AT for arthritis management. Eight focus groups were conducted. Qualitative data were analyzed using both manual and computer based (Atlas.ti) methods. Participants used a variety of C/AT for arthritis management. Most did not seek C/AT information from their health care provider (HCP) but primarily relied on family and friends as resources. Common themes that influenced C/AT dialog included collaborative patient relationship with HCP, HCP unsupportive attitudes toward C/AT and lack of C/AT knowledge, and time-limited clinic visits. Clinical implications include fostering shared decision making clinical relationships, increasing HCP knowledge about C/AT, initiating C/AT dialog and offering credible C/AT information sources. PMID- 25280946 TI - Multiple presentations reduce the behavioral impact of protected predator exposure in rats. AB - Exposure of rats to a predator species, such as a cat, or stimuli associated with a predator species has been used to model the effects of traumatic stress. We further investigated this procedure to determine if the behavioral effects from such exposure could be increased by multiple exposures. In rats (n=8 for each treatment group), we evaluated single (1*) and multiple (1*/day for 3 consecutive days [3*] and 2*/day for 3 consecutive days [6*]) exposures using cats and soiled cat litter. All exposures were 15min in duration and the rats were directly exposed to the cats but in a protected fashion that did not allow the predator to physically injure the rat. Sham exposures were conducted using similar conditions without the presence of the predator or litter. The effects of the exposures were evaluated using an elevated plus maze (EPM). Sessions on the EPM were conducted before the exposures and at various times after the exposure. Difference scores (post-pre) were calculated for dependent measures from the EPM, and statistical analyses compared the slopes and intercept values derived from regression functions from these scores over the post-exposure sessions. During the first 30 days after exposure, a significant reduction in activity on the EPM was observed for the 1* treatment and a smaller reduction was observed for the 3* treatment, but no reduction was observed for the 6* and sham control treatments. Thus, increasing the number of exposures did not increase the magnitude of the effect but, instead, resulted in a decrease. These results show that adaptation to the effects of the predator exposure occurred with repeated sessions. PMID- 25280947 TI - Genome sequence of Erinnyis ello granulovirus (ErelGV), a natural cassava hornworm pesticide and the first sequenced sphingid-infecting betabaculovirus. AB - BACKGROUND: Cassava (Manihot esculenta) is the basic source for dietary energy of 500 million people in the world. In Brazil, Erinnyis ello ello (Lepidoptera: Sphingidae) is a major pest of cassava crops and a bottleneck for its production. In the 1980s, a naturally occurring baculovirus was isolated from E. ello larva and successfully applied as a bio-pesticide in the field. Here, we described the structure, the complete genome sequence, and the phylogenetic relationships of the first sphingid-infecting betabaculovirus. RESULTS: The baculovirus isolated from the cassava hornworm cadavers is a betabaculovirus designated Erinnyis ello granulovirus (ErelGV). The 102,759 bp long genome has a G + C content of 38.7%. We found 130 putative ORFs coding for polypeptides of at least 50 amino acid residues. Only eight genes were found to be unique. ErelGV is closely related to ChocGV and PiraGV isolates. We did not find typical homologous regions and cathepsin and chitinase homologous genes are lacked. The presence of he65 and p43 homologous genes suggests horizontal gene transfer from Alphabaculovirus. Moreover, we found a nucleotide metabolism-related gene and two genes that could be acquired probably from Densovirus. CONCLUSIONS: The ErelGV represents a new virus species from the genus Betabaculovirus and is the closest relative of ChocGV. It contains a dUTPase-like, a he65-like, p43-like genes, which are also found in several other alpha- and betabaculovirus genomes, and two Densovirus related genes. Importantly, recombination events between insect viruses from unrelated families and genera might drive baculovirus genomic evolution. PMID- 25280949 TI - Bilingualism as a potential strategy to improve executive function in preterm infants: a review. AB - Preterm birth is associated with long-term deficits in executive functioning and cognitive performance. Using the model of brain plasticity as a theoretical framework, it is possible that preterm infants' neurodevelopmental sequelae can be altered. Evidence suggests that bilingualism confers cognitive advantages on executive functioning, so it is possible that bilingualism may improve preterm infants' neurodevelopment. However, bilingualism has only been studied in term children. This review examined literature that compared the performance of preterm-born children to term children and bilingual children to monolingual children on executive function tasks. To address cognitive disparities in preterm born children, studies investigating the effect of bilingualism on preterm infants' executive functioning is warranted. PMID- 25280948 TI - Is early treatment of cam-type femoroacetabular impingement the key to avoiding associated full thickness isolated chondral defects? AB - PURPOSE: Hip arthroscopy is a safe and reproducible method for treating femoroacetabular impingement (FAI) and has evolved greatly in recent years. But little is known about the influences on the outcome after surgery. The aims of the current study were to elucidate (1) which parameters can be used as a marker for the presence of chondral and labral lesions, (2) the postoperative clinical outcome, and (3) at which time after surgery recovery occurs. METHODS: A prospective study was performed with 177 patients who underwent hip arthroscopy because of cam-type FAI. The patients were examined preoperatively as well as 6 weeks and 6 months postoperatively, and their condition was rated according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Non Arthritic Hip Score (NAHS). Statistical analyses were performed to evaluate the influence of independent factors such as "patient age," "pain duration before surgery" on the clinical outcome, and the appearance of chondral or labral defects. RESULTS: The NAHS and WOMAC scores showed a significant enhancement 6 weeks after surgery. Only the NAHS showed a further improvement after 6 months. A positive correlation with the dependent variable "chondral lesion" was evaluated for the independent variables "pain duration before surgery," "preoperative NAHS," and "labrum lesion". Using ROC analysis, the optimal cutoff value of "pain duration before surgery" as a predictor was 9.5 months, for the NAHS 42.5 points. For the dependent variable, "6-month postoperative NAHS" significant correlations for the independent variables "age" and "pain duration before surgery" were revealed with a cutoff value of 55.5 years, respectively, 23.5 months. CONCLUSIONS: It was concluded from the results that the date of surgery is relevant for the appearance of chondral defects. Patient age is a further relevant factor for clinical outcome. Recovery after hip arthroscopy takes place mainly in the first 6 weeks after surgery. LEVEL OF EVIDENCE: Therapeutic study, Level III. PMID- 25280950 TI - Management of natural health products in pediatrics: a provider-focused quality improvement project. AB - INTRODUCTION: The use of natural health products by pediatric patients is common, yet health care providers often do not provide management guidance. The purpose of this project was to improve management of natural health products by pediatric nurse practitioners. METHOD: Pediatric nurse practitioners from large metropolitan city were recruited (n = 32). A paired pretest-posttest design was used. Study participants were engaged to improve knowledge of natural health products, and a management toolkit was created and tested. RESULTS: Mean knowledge scores increased from 59.19 to 76.3 (p < .01). Management practices improved with regard to patient guidance (p < .01) and resource utilization (p < .01). Assessments of product use (p = .51) and drug/herb interactions (p = .35) were not significant. DISCUSSION: This investigation is the first known study to improve knowledge and management of natural health products in pediatric clinical practice. PMID- 25280952 TI - Comparative study on "long-dan", "qin-jiao" and their adulterants by HPLC analysis. AB - "Long-Dan" and "Qin-Jiao" are two important TCM herbs since ancient times in China. In the Chinese Pharmacopoeia, the dried roots and rhizomes of four species from the genus Gentiana, e.g. Gentiana manshurica, G. scabra, G. triflora and G. rigescens, are recorded under the name of Gentianae Radix et Rhizoma ("Long-Dan" in Chinese), while the other four species from the same genus including G. macrophylla, G. crassicaulis, G. straminea and G. duhurica are recorded and used as the raw materials of Gentianae Macrophyllae Radix ("Qin-Jiao" in Chinese). On the basis of the establishment of a validated HPLC-UV method for quantifying simultaneously, five iridoid glycosides, e.g. loganic acid (1), swertiamarinin (2), gentiopicroside (3), sweroside (4) and 2'-(o,m-dihydroxybenzyl)sweroside (5) have been used successfully as chemical markers for the comparison of the species used as "Long-Dan", "Qin-Jiao" and their adulterants in the present study. The results suggested that four iridoid glycosides 1-4 commonly existed in both "Long Dan" and "Qin-Jiao", while 2'-(o,m-dihydroxybenzyl)sweroside (5) also existed as one of the major components in "Dian-Long-Dan" species. Moreover, the contents of compounds 1-5 were various in different "Long-Dan" and "Qin-Jiao" species. Herein, we profiled and compared three "Long-Dan" species, four "Qin-Jiao" species and five adulterants by applying multivariate statistical techniques to their HPLC data sets to establish the differences and/or similarities. PMID- 25280951 TI - In vitro heme and non-heme iron capture from hemoglobin, myoglobin and ferritin by bovine lactoferrin and implications for suppression of reactive oxygen species in vivo. AB - Lactoferrin (Lf), present in colostrum and milk is a member of the transferrin family of iron-binding glyco-proteins, with stronger binding capacity to ferric iron than hemoglobin, myoglobin or transferrin. Unlike hemoglobin and myoglobin, iron-bound Lf is reasonably stable to gastric and duodenal digestive conditions. Unlike ferrous iron, ferric iron is not directly reactive with oxygen supporting the capacity of Lf capture of heme iron to suppress reactive oxygen species (ROS) production. We therefore hypothesized that bovine Lf could capture and thereby terminate the cycle of ROS production by heme iron. The transfer of heme iron from either intact or digested forms of hemoglobin and myoglobin and from intact ferritin was demonstrated by in vitro methods, monitoring Fe-saturation status of Lf by changes in absorptivity at 465 nm. The results are discussed in the context of new proposed opportunities for orally administered Lf to regulate oxidative damage associated with heme iron. In addition to potentially suppressing oxidative heme-iron-mediated tissue damage in the lumen, Lf is expected to also reverse the overload of ferritin-bound iron, that accompanies chronic inflammation and aging. These new proposed uses of Lf are additional to known host defense functions that include anti-microbial, anti-viral properties, immune and cancer cell growth regulation. The findings and interpretations presented require clinical substantiation and may support important additional protective and therapeutic uses for Lf in the future. PMID- 25280953 TI - An ice block: a novel technique of successful prevention of cement leakage using an ice ball. AB - We report three cases of painful bone metastases with extraosseous invasion treated with cementoplasty and cryoablation. Due to significant cortical loss in all cases, the ice ball was used simultaneously during cementoplasty to deter potential cement leakage. This was achieved by direct application of the ice ball against the cortical surface, resulting in adequate consolidation and successful containment of the cement within the treated bones. To the authors' knowledge, this is the first report to describe such a combined technique. PMID- 25280954 TI - Efficacy of a radiation absorbing shield in reducing dose to the interventionalist during peripheral endovascular procedures: a single centre pilot study. AB - PURPOSE: This prospective pilot study was undertaken to evaluate the feasibility and effectiveness of using a radiation absorbing shield to reduce operator dose from scatter during lower limb endovascular procedures. MATERIALS AND METHODS: A commercially available bismuth shield system (RADPAD) was used. Sixty consecutive patients undergoing lower limb angioplasty were included. Thirty procedures were performed without the RADPAD (control group) and thirty with the RADPAD (study group). Two separate methods were used to measure dose to a single operator. Thermoluminescent dosimeter (TLD) badges were used to measure hand, eye, and unshielded body dose. A direct dosimeter with digital readout was also used to measure eye and unshielded body dose. To allow for variation between control and study groups, dose per unit time was calculated. RESULTS: TLD results demonstrated a significant reduction in median body dose per unit time for the study group compared with controls (p = 0.001), corresponding to a mean dose reduction rate of 65 %. Median eye and hand dose per unit time were also reduced in the study group compared with control group, however, this was not statistically significant (p = 0.081 for eye, p = 0.628 for hand). Direct dosimeter readings also showed statistically significant reduction in median unshielded body dose rate for the study group compared with controls (p = 0.037). Eye dose rate was reduced for the study group but this was not statistically significant (p = 0.142). CONCLUSION: Initial results are encouraging. Use of the shield resulted in a statistically significant reduction in unshielded dose to the operator's body. Measured dose to the eye and hand of operator were also reduced but did not reach statistical significance in this pilot study. PMID- 25280955 TI - Biological monitoring of exposure and effects in workers employed in a selenium processing plant. AB - PURPOSE: The aim of the study was to assess external and internal selenium exposure and potential biological effects in employees working in a selenium processing plant. METHODS: Twenty male employees of a selenium-processing plant (exposed) and 20 age-matched male individuals without occupational selenium exposure (controls) participated in the study. Exposure to selenium at the workplace was determined by personal air sampling. Internal exposure was assessed by measuring total selenium concentration in plasma after a workshift and after holidays as well as by measuring the selenium concentration in urine before and after shift and after holidays. The activity of glutathione peroxidase (GPx) in blood and the prothrombin time were determined as biological effect parameters. RESULTS: The exposure to selenium in the workplace air ranged from 8 to 950 ug/m(3) and exceeded in a large part current occupational exposure limits. The selenium levels in plasma samples of the exposed ranged from 49 to 182 ug/L during exposure and were significantly higher than the plasma levels observed after holidays as well as in the control group. The selenium concentration in pre and post-shift urine samples did not differ significantly, and the average urinary selenium levels of the employees (18-1,104 ug/g creatinine) were significantly higher than those measured after holidays or determined in controls. Both the concentration of selenium in plasma and in urine did not correlate with the current external exposure of the employees at the workplace. However, we found a strong and significant association between the two biomonitoring parameters. In spite of the considerable high external exposure to elemental selenium, we did not find any effect on the GPx activity in blood as well as on the prothrombin time. CONCLUSIONS: Both the selenium levels in plasma and urine may be used as biological monitoring parameters for the assessment of chronic occupational exposure to selenium. Nevertheless, the toxicokinetics of the urinary excretion of selenium remain still unclear and require further investigations. Moreover, our findings emphasise the necessity of a re-evaluation of occupational exposure limits for elemental selenium and inorganic selenium compounds. PMID- 25280956 TI - Gardnerella vaginalis triggers NLRP3 inflammasome recruitment in THP-1 monocytes. AB - Gardnerella vaginalis is a Gram-positive bacterium associated with bacterial vaginosis (BV), pelvic inflammatory disease, and preterm birth. BV is the most prevalent vaginal dysbiosis in women of childbearing age characterized by the absence of normal lactobacilli and an overgrowth of G. vaginalis and other bacteria. Although mucosal fluids from BV patients exhibit increases in proinflammatory cytokines and Toll-like receptor 2 and 4 mRNA, G. vaginalis has not been demonstrated to directly induce an inflammatory response. This study tested the hypothesis that G. vaginalis induces an inflammatory response in the human monocyte cell line, THP-1. The objectives of the study were to measure proinflammatory cytokine production, molecular mechanisms by which cytokines are produced, and whether G. vaginalis results in death of the monocytic cells. We found that G. vaginalis induced significant increases in the inflammasome dependent cytokines IL-1beta, IL-18, as well as TNF-alpha in treated cells. G. vaginalis caused significant cell death by 24h post-treatment compared with untreated controls, but cells remained 66% viable. Caspase-1 cleavage in treated cells confirmed the inflammatory cell death, and NLRP3 knockdown confirmed its involvement through reduction of IL-1beta secretion. Using a stably expressing YFP-ASC THP-1 cell model with immunofluorescent staining, YFP-ASC colocalized with NLRP3 in G. vaginalis-treated cells and the addition of a caspase-1 inhibitor wholly ameliorated IL-1beta secretion. Our study provides new insight into the role of G. vaginalis in inflammatory conditions in the genital tract. PMID- 25280957 TI - Effect of liraglutide administration and a calorie-restricted diet on lipoprotein profile in overweight/obese persons with prediabetes. AB - BACKGROUND AND AIMS: To evaluate the effects of 14 weeks of liraglutide plus modest caloric restriction on lipid/lipoprotein metabolism in overweight/obese persons with prediabetes. METHODS AND RESULTS: Volunteers with prediabetes followed a calorie-restricted diet (-500 Kcal/day) plus liraglutide (n = 23) or placebo (n = 27) for 14 weeks. The groups were similar in age (58 +/- 7 vs. 58 +/ 8 years) and body mass index (31.9 +/- 2.8 vs. 31.9 +/- 3.5 kg/m(2)). A comprehensive lipid/lipoprotein profile was obtained before and after intervention using vertical auto profile (VAP). Weight loss was greater in the liraglutide group than in the placebo group (6.9 vs. 3.3 kg, p < 0.001), as was the fall in fasting plasma glucose concentration (9.9 mg/dL vs. 0.3 mg/dL, p < 0.001). VAP analysis revealed multiple improvements in lipid/lipoprotein metabolism in liraglutide-treated compared with placebo-treated volunteers, including decreases in concentrations of total cholesterol, low-density lipoprotein cholesterol and several of its subclasses, triglyceride, and non-high density cholesterol. The liraglutide-treated group also had a significant shift away from small, dense low-density lipoprotein-particles, as well as decreases in apolipoprotein B concentration and ratio of apolipoprotein B/apolipoprotein A-1. There were no significant changes in the lipoprotein profile in the placebo treated group. CONCLUSION: Treatment with liraglutide plus modest calorie restriction led to enhanced weight loss, a decrease in fasting plasma glucose concentration, and improvement in multiple aspects of lipid/lipoprotein metabolism associated with increased cardiovascular disease (CVD) risk. The significant clinical benefit associated with liraglutide-assisted weight loss in a group at high risk for CVD - obese/overweight individuals with prediabetes - as seen in our pilot study, suggests that this approach deserves further study. PMID- 25280958 TI - [Health in Africa, dynamics and socio-territorial challenges]. AB - Because health is the product of a combination of political, economic, social, cultural, technical factors, the values of the indicators of health are an observatory of the African continent and its billion people in all their dimensions. So, the reading of the program of the 9(th) French-speaking international Congress of the Society of Exotic Pathology is significant of the state of Africa in this second decade of the 21(th) century. The age-old infectious plagues go alongside to emergent fevers there, but the program also dedicates a wide time to the chronic pathologies. This kaleidoscope invites to discuss the concept of epidemiological transition chosen by the Congress. What is its meaning when the order of magnitude of the values of the indicators of health was distended never also and became the most contrasted by the world, in all the scales of observation? Which is its meaning when, in Black Africa, unlike the processes observed in the countries which formed the Third World in 1950, the evolution observed for the last five decades is chaotic, made by a succession of advances, by a progress, by blockings, even by walking back, original expression of the health transition, the process which includes the evolution of the health and the answers of States and societies. The geography of the values of indicators shows the socio-territorial dynamics in process, which place societies in more or less protective systems for their health. More than ever, diverse worlds are next to a sum of challenges, of which that to improve the knowledge of the needs for health, in relatively fine scale to avoid generalizations and amalgams, and target priorities of health according to the socio-territorial contexts. PMID- 25280961 TI - Effect of loading parameters on motor performance during a dynamic weight-shift task. AB - Controlling weight shift (WS) is essential to performing motions safely and smoothly during daily and athletic activities. This study investigated the impact of loading parameters on the motor performance and difficulty level of a dynamic WS task performed while standing. Twelve healthy young adults (21.2 +/- 0.9 years, 53.5 +/- 7.4 kg) were asked to match the target and their weight loads using visual feedback displayed on a computer monitor. Motor performance was estimated by assessment of loading accuracy and pace of motor skill acquisition, measured as a proxy of difficulty level, was estimated by assessment of learning rate. As predicted, both loading accuracy values decreased with increasing target frequency. Notably, the interaction of loading size and frequency had a significant effect on loading accuracy, which was increasingly impaired as the weight load increased at frequencies greater than 0.5 Hz. Moreover, the pace of motor skill acquisition in a dynamic WS task while standing was affected by the weight-load speed independently of the weight-load size. These results indicate that loading accuracy is affected by both the weight-load size and frequency and that 0.5 Hz is a critical frequency at which the difficulty level increases during dynamic WS tasks while standing in healthy youths. These findings suggest that the adequacy of the initial settings used regarding loading size and frequency is an important consideration in rehabilitative and athletic training aimed at evaluating and improving WS while standing. PMID- 25280960 TI - Visceral adiposity index and risks of cardiovascular events and mortality in prevalent hemodialysis patients. AB - BACKGROUND: The visceral adiposity index (VAI) is a newly-derived measure of visceral adiposity with well-validated predictive power for cardiovascular (CV) outcomes in the general population. However, this predictability has not been investigated in hemodialysis patients, and whether VAI is superior to waist circumference (WC) and waist-to-height ratio (WHtR) in predicting CV outcomes and survival in hemodialysis patients remains unknown. METHODS: We performed a prospective study including 464 prevalent hemodialysis patients. The composite outcome was the occurrence of death and CV events during follow-up. Using multivariate Cox regression analysis, VAI, WC and WHtR were tested for the predictive power of outcomes. To evaluate the predictive performance of the VAI, WC and WHtR, time-dependent receiver operating characteristic curve (ROC) analysis was performed. RESULTS: VAI, WC and WHtR positively correlated with each other. Patients with a higher VAI (tertile 3 vs. tertile 1, adjusted hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.12-2.42; tertile 2 vs. tertile 1, adjusted HR, 1.52; 95% CI, 1.1-2.18) had more composite outcomes. VAI had a similar predictive power of all-cause mortality to WC and WHtR, but superior predictive power of composite and CV outcomes to WC when analyzed by a stepwise forward likelihood ratio test. In time-dependent ROC analysis, VAI, WC and WHtR showed similar predictive performance for outcomes. CONCLUSION: VAI is an optimal method to measure visceral adiposity to assess long-term CV outcomes and all cause mortality in prevalent hemodialysis patients. VAI may provide a superior predictive power of CV outcomes to WC and WHtR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01457625. PMID- 25280959 TI - Clinical applications of remote ischaemic preconditioning in native and transplant acute kidney injury. AB - Ischaemia-reperfusion (IR) injury is a composite of the injury sustained during a period of reduced or absent blood flow to a tissue or organ and the additional insult sustained upon reperfusion that limits the amount of tissue that can be salvaged. IR injury plays a central role in both native and transplant acute kidney injury (AKI). Native AKI is associated with increased morbidity and mortality in hospital inpatients, and transplant AKI contributes to graft dysfunction, ultimately limiting graft longevity. In this review, we discuss the potential therapeutic benefits of a cost-effective and low-risk intervention, remote ischaemic preconditioning (RIPC), and its applicability in the prevention and reduction of AKI. PMID- 25280963 TI - HCV core and NS3 proteins mediate toll like receptor induced innate immune response in corneal epithelium. AB - Direct association of dry eye syndrome and hepatitis C virus (HCV) infection is a well established fact. In this context, the current study examines the in vitro corneal inflammatory response with respect to HCV core and NS3 antigens. Toll like receptors (TLRs) are pattern recognition receptors which can mediate innate immune response. In the present study, corneal epithelial cells responded to HCV core and NS3 proteins by secreting pro-inflammatory cytokines IL-8, IL-6 and TNF alpha via TLR1, TLR2 and TLR6 mediated innate immune response. MyD88/NF-kB signalling was involved in pro-inflammatory cytokine production. Corneal epithelium synthesised nitric oxide (NO) via iNOS during HCV core and NS3 exposure. On later stages of inflammation, cells underwent apoptosis which lead to cell death. SiRNA mediated silencing of TLR1, TLR2 and TLR6 resulted in a significant down regulation of IL-8 and NO. In conclusion, this study indicates that HCV core and NS3 proteins are capable of inducing immune response in corneal epithelium which can potentiate the pathology of HCV associated dry eye condition. Blocking specific TLR response can have therapeutic application in controlling the inflammatory response associated with this dry eye condition. PMID- 25280962 TI - Depressive symptoms, negative urgency and substance use initiation in adolescents. AB - BACKGROUND: Studies show depressive symptoms are associated with substance use in adolescents, but the mechanism underlying this association is still unclear. This study investigated negative urgency - the disposition to rash action during emotional states - as a factor explaining relations between depressive symptoms and use of several substances. METHODS: In this cross-sectional study, 476 adolescents (mean age 14.5 years) completed self-report surveys. Regression models and products of coefficient analyses examined the overall relation of depressive symptoms to substance use and negative urgency as a statistical mediator of this association. RESULTS: Depression levels associated with increased likelihood of lifetime use of cigarettes, other forms of tobacco, marijuana, alcohol, inhalants, prescription painkillers, and any substance. Relations between depression levels and lifetime use of alcohol, inhalants, and any substance were accounted for (i.e., statistically mediated) by negative urgency. In adolescents endorsing lifetime use, depression levels associated with younger age of first use of other forms of tobacco and alcohol as well as use frequency of cigarette, alcohol, and composite frequency. Negative urgency accounted for the covariance between depression level and age of first use of alcohol, but did not for other forms of tobacco or frequency of use of any substances. CONCLUSIONS: Depression levels are associated with lifetime use of a variety of substances in early adolescence and targeting this risk factor with preventive efforts may be useful in reducing risk. Negative urgency may be an important target for interventions aimed at alcohol and inhalant use. PMID- 25280964 TI - A comprehensive score to diagnose Hashimoto's thyroiditis: a proposal. AB - The heterogeneity of diagnostic criteria of Hashimoto's thyroiditis leads to overdiagnosis and prevents strong conclusions from being drawn in clinical studies. The aim of this study is to propose a comprehensive scoring system. A case-control study compared a set of presurgical features of patients with lymphocytic infiltration of the thyroid (Hashimoto's thyroiditis) and controls, in order to design a multi-criteria scoring system. Given a dichotomous outcome (lymphocytic infiltration of the thyroid), a set of covariates was analyzed in 180 patients after total thyroidectomy. A different validation cohort of 1,171 patients was reviewed and classified according to the score. Variables associated with the diagnosis of Hashimoto's thyroiditis were first assessed by univariate analysis. Analysis showed that TPOAb (area under the ROC curve (AUC), 0.67; 95 % CI 0.57-0.77) and TgAb (0.63; 95 % CI 0.54-0.74) were univariate predictors of the diagnosis of HT, which is largely recognized. Combined covariates were then tested using stepwise logistic regression analysis. The final regression model included TPOAb, TgAb, and thyroid vascularity (AUC 0.72; 95 % CI 0.62-0.81). A scoring system was developed, which has a sensitivity of 45.5 % and a specificity of 89.0 %, with a cutoff of 1.7. The likelihood of incident hypothyroidism was higher (OR 2.30; p = 0.004) in the positive (>=1.7) score group. A scoring system has a better performance than any single predictor and is able to identify the subgroup of individuals at higher risk to develop subsequent hypothyroidism. PMID- 25280965 TI - Framing expectations in early HIV cure research. AB - Language used to describe clinical research represents a powerful opportunity to educate volunteers. In the case of HIV cure research there is an emerging need to manage expectations by using the term 'experiment'. Cure experiments are proof-of concept studies designed to evaluate novel paradigms to reduce persistent HIV-1 reservoirs, without any expectation of medical benefit. PMID- 25280967 TI - Pre-ART retention in care and prevalence of tuberculosis among HIV-infected children at a district hospital in southern Ethiopia. AB - BACKGROUND: The Ethiopian epidemic is currently on the wane. However, the situation for infected children is in some ways lagging behind due to low treatment coverage and deficient prevention of mother-to-child transmission. Too few studies have examined HIV infected children presenting to care in low-income countries in general. Considering the presence of local variations in the nature of the epidemic a study in Ethiopia could be of special value for the continuing fight against HIV. The aim of this study is to describe the main characteristics of children with HIV presenting to care at a district hospital in a resource limited area in southern Ethiopia. The aim was also to analyse factors affecting pre-ART loss to follow-up, time to ART-initiation and disease stage upon presentation. METHODS: This was a prospective cohort study. The data analysed were collected in 2009 for the period January 2003 through December 2008 at Arba Minch Hospital and additional data on the ART-need in the region were obtained from official reports. RESULTS: The pre-ART loss to follow-up rate was 29.7%. Older children (10-14 years) presented in a later stage of their disease than younger children (76.9% vs. 45.0% in 0-4 year olds, chi-square test, chi2 = 8.8, P = 0.01). Older girls presented later than boys (100.0% vs. 57.1%, Fisher's exact test, P = 0.02). Children aged 0-4 years were more likely to be lost to follow-up (40.0 vs. 21.8%, chi-square test, chi2 = 5.4, P = 0.02) and had a longer time to initiate ART (Cox regression analysis, HR: 0.50, 95% CI: 0.25 0.97, P = 0.04, controlling for sex, place of residence, enrollment phase and WHO clinical stage upon presentation). Neither sex was overrepresented in the sample. Tuberculosis prevalence upon presentation and previous history of tubercolosis were 14.5% and 8% respectively. CONCLUSIONS: The loss to follow-up is alarmingly high and children present too late. Further research is needed to explore specific causes and possible solutions. PMID- 25280966 TI - Development of kinomic analyses to identify dysregulated signaling pathways in cells expressing cytoplasmic PrP. AB - BACKGROUND: Dysregulated protein kinase signaling is involved in the pathogenesis of many chronic diseases. However, the dysregulated signaling pathways critical to prion pathogenesis remain incompletely characterized. Global analyses of signaling pathways may be useful to better characterize these pathways. We therefore set out to develop such global assays. To this end, we used as a model cytoplasmic mutants of the cellular prion protein (PrPC), which are toxic to N2a neuroblastoma cells. We tested the global assays for their sensitivity to detect changes in signaling pathways in cells expressing cytoplasmic PrP mutants. METHODS: We developed a targeted proteomics (kinomics) approach using multiplex Western blots to identify signaling pathways dysregulated in chronic neurological pathologies. We tested the approach for its potential ability to detect signaling changes in N2a cells expressing cytoplasmic PrP mutants. RESULTS: Multiplex Western blots were designed to quantitate the expression levels of 137 protein kinases in a single membrane and using only 1.2 mg of sample. The response of the blots was sensitive and linear to changes of 6% in protein levels. Hierarchical and functional clustering of the relative expression levels identified an mTOR signaling pathway as potentially dysregulated in N2a cells expressing cytoplasmic PrP. The mTOR signaling pathway regulates global protein synthesis, which is inhibited in cells expressing cytoplasmic PrP. The levels of proteins involved in the Akt1/p70S6K branch of mTOR signaling changed in synchrony with time of cytoplasmic PrP expression. Three kinases in this pathway, Akt, p70S6K, and eIF4B were in their inactive states, as evaluated by phosphorylation of their regulatory sites. CONCLUSION: The results presented are consistent with the previously reported inhibition of Akt/p70S6K/eIF4B signaling as mediating pathogenesis of cytoplasmic PrP. We conclude that the kinomic analyses are sensitive and specific to detect signaling pathways dysregulated in a simple in vitro model of PrP pathogenesis. PMID- 25280968 TI - Matrix stiffening and beta1 integrin drive subtype-specific fibroblast accumulation in lung cancer. AB - The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by beta1 integrin mechano-sensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in beta1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), beta1 expression, and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or beta1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs. IMPLICATIONS: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells. PMID- 25280969 TI - WHSC1 promotes oncogenesis through regulation of NIMA-related kinase-7 in squamous cell carcinoma of the head and neck. AB - Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN. Immunohistochemical analysis of locoregionally advanced SCCHN, dysplastic, and normal epithelial tissue specimens revealed that WHSC1 expression and dimethylation of histone H3 lysine 36 (H3K36me2) were significantly higher in SCCHN tissues than in normal epithelium. Both WHSC1 expression and H3K36me2 levels were significantly correlated with histologic grade. WHSC1 knockdown in multiple SCCHN cell lines resulted in significant growth suppression, induction of apoptosis, and delay of the cell-cycle progression. Immunoblot and immunocytochemical analyses in SCCHN cells demonstrated that WHSC1 induced H3K36me2 and H3K36me3. Microarray expression profile analysis revealed NIMA-related kinase-7 (NEK7) to be a downstream target gene of WHSC1, and chromatin immunoprecipitation (ChIP) assays showed that NEK7 was directly regulated by WHSC1 through H3K36me2. Furthermore, similar to WHSC1, NEK7 knockdown significantly reduced cell-cycle progression, indicating that NEK7 is a key player in the molecular pathway regulated by WHSC1. IMPLICATIONS: WHSC1 possesses oncogenic functions in SCCHN and represents a potential molecular target for the treatment of SCCHN. PMID- 25280971 TI - Effects of reaction time variability and age on brain activity during Stroop task performance. AB - Variability in reaction time during task performance may reflect fluctuations in attention and cause reduced performance in goal-directed tasks, yet it is unclear whether the mechanisms behind this phenomenon change with age. Using fMRI, we tested young and cognitively healthy older adults with the Stroop task to determine whether aging affects the neural mechanisms underlying intra-individual reaction time variability. We found significant between-group differences in BOLD activity modulated by reaction time. In older adults, longer reaction times were associated with greater activity in frontoparietal attentional areas, while in younger adults longer reaction times were associated with greater activity in default mode network areas. Our results suggest that the neural correlates of reaction time variability change with healthy aging, reinforcing the concept of functional plasticity to maintain high cognitive function throughout the lifespan. PMID- 25280972 TI - Tensile strain increased COX-2 expression and PGE2 release leading to weakening of the human amniotic membrane. AB - INTRODUCTION: There is evidence that premature rupture of the fetal membrane at term/preterm is a result of stretch and tissue weakening due to enhanced prostaglandin E2 (PGE2) production. However, the effect of tensile strain on inflammatory mediators and the stretch sensitive protein connexin-43 (Cx43) has not been examined. We determined whether the inflammatory environment influenced tissue composition and response of the tissue to tensile strain. METHODS: Human amniotic membranes isolated from the cervix (CAM) or placenta regions (PAM) were examined by second harmonic generation to identify collagen orientation and subjected to tensile testing to failure. In separate experiments, specimens were subjected to cyclic tensile strain (2%, 1 Hz) for 24 h. Specimens were examined for Cx43 by immunofluorescence confocal microscopy and expression of COX-2 and Cx43 by RT-qPCR. PGE2, collagen, elastin and glycosaminoglycan (GAG) levels were analysed by biochemical assay. RESULTS: Values for tensile strength were significantly higher in PAM than CAM with mechanical parameters dependent on collagen orientation. Gene expression for Cx43 and COX-2 was enhanced by tensile strain leading to increased PGE2 release and GAG levels in PAM and CAM when compared to unstrained controls. In contrast, collagen and elastin content was reduced by tensile strain in PAM and CAM. DISCUSSION: Fibre orientation has a significant effect on amniotic strength. Tensile strain increased Cx43/COX-2 expression and PGE2 release resulting in tissue softening mediated by enhanced GAG levels and a reduction in collagen/elastin content. CONCLUSION: A combination of inflammatory and mechanical factors may disrupt amniotic membrane biomechanics and matrix composition. PMID- 25280973 TI - Trans-placental passage and anti-inflammatory effects of solithromycin in the human placenta. AB - INTRODUCTION: Solithromycin is a 4th generation macrolide/fluoroketolide antibiotic that has potential applications in the treatment and prevention of intrauterine and fetal infections in pregnancy; it has also been reported to exert anti-inflammatory effects. The objective of the present study was to determine its ability to cross the human placenta and inhibit cytokine production by placental and decidual cells in culture. METHODS: Maternal-to-fetal passage of solithromycin was determined using the dual recycling ex vivo placental perfusion model; normal healthy term placentas delivered by Caesarean section were employed for the study. Creatinine transfer was also assessed as a diffusion-limited perfusion control. Purified primary decidual and trophoblast cells were treated in vitro for 20 h with solithromycin (0-100 MUg/mL) and cytokine production and cell viability were assessed. RESULTS: The mean +/- SD maternal-to-fetal transfer ratio (TRf: concentration in maternal / fetal circuit) of solithromycin after 3 h perfusion was 40.3 +/- 23.6% (n = 4 placentas), with values from individual experiments ranging from 18 to 65%. The peak TRf of creatinine was 54%, and the clearance index for solithromycin (TRfsoli/TRfcreat) was 87% at 3 h. Solithromycin did not inhibit production of IL-6 and TNF-alpha by trophoblasts and decidual cells at non-toxic pharmacological concentrations (<= 11 MUg/mL). DISCUSSION: Solithromycin is the first antibiotic of its class to exhibit efficient maternal-to-fetal transfer across the human placenta and is thus an ideal candidate for evaluation for the treatment of intrauterine and fetal infections in pregnancy. At pharmacological concentrations it does not appear to inhibit pro-inflammatory cytokine production by placental cells. PMID- 25280974 TI - Response to letter to the editor concerning "Quantitative evaluation of mechanical properties in tissue-engineered auricular cartilage". PMID- 25280975 TI - Comparative persistence on beta-blockers versus calcium channel blockers for ventricular rate control in nonelderly patients with atrial fibrillation. AB - BACKGROUND: For patients with atrial fibrillation (AF), early treatment is essential to prevent serious complications such as stroke. Several randomized clinical trials have shown that rate-control may be as effective as rhythm control medications, whereas the latter have serious side effects. Little evidence exists, however, about which class of rate-control medication-beta blockers (BBs) or calcium channel blockers (CCBs)-may be superior. OBJECTIVE: The objective was to compare the long-term persistence on BBs versus CCBs in nonelderly adult patients with AF. METHODS: A longitudinal retrospective cohort study for patients 40 to 60 years old with newly diagnosed AF (identified by ICD 9 code 427.31) was performed using data from Ohio Medicaid physician, institutional, and pharmacy claims from January 2006 through June 2011. A Cox proportional hazard regression, with time to change out of rate-control therapy as the dependent variable, was estimated to compare persistence on (proxy for effectiveness of) rate-control medication across drug classes. A propensity-score analysis was used to control for selection bias. Additional covariates included age, development of heart failure, and medication adherence. RESULTS: Out of 1239 patients included in the cohort, 1016 received a BB; 223 received a CCB. Over time, patients on CCBs were significantly more likely to switch out of rate control therapy (hazard ratio = 1.89; 95% CI = 1.14-3.09) than patients on BBs. CONCLUSIONS: Evidence suggests that nonelderly AF patients, when prescribed rate control therapy, persist longer on BBs than CCBs. Because this is the first long term study comparing the 2 drug classes in the nonelderly population, further research is suggested. PMID- 25280970 TI - Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease. AB - Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance. PMID- 25280977 TI - Identification of multidrug-resistant bacteria and Bacillus cereus from healthcare workers and environmental surfaces in a hospital. PMID- 25280978 TI - GP leader warns of hundreds of practice closures. PMID- 25280976 TI - Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children. AB - BACKGROUND: Cyclosporine (CsA) is frequently responsible for hypertension in bone marrow transplant children. Calcium channel blockers (CCBs) are considered to be the best treatment for CsA-induced hypertension, but they may alter the exposure and the effect of CsA by inhibiting the CYP3A4 pathway of CsA metabolism or P-gp. However, the inhibitory effect on CYP3A4 may vary among CCBs. METHODS: This study aimed to quantify the pharmacokinetic drug-drug interaction between CsA and nicardipine, amlodipine, and lacidipine. In all, 51 children who received CsA and CCB concomitantly were included. RESULTS: Dose-normalized CsA trough blood concentrations significantly increased in patients treated with nicardipine and amlodipine, whereas they remained stable in patients treated with lacidipine. CONCLUSIONS: Because lacidipine appears to have no effect on CsA exposure, it may be the best option among CCBs for treating high blood pressure caused by CsA in children. PMID- 25280979 TI - The impact of an algorithm on the optimization of beta-blockers after cardiac surgery. AB - OBJECTIVE: To evaluate the impact of a simple written algorithm of early postoperative beta-blocker administration on daily practices. DESIGN: A prospective, single center observational study. SETTING: A 16-bed cardiac surgical intensive care unit in a university teaching hospital. PATIENTS: One hundred twenty-five consecutive adult patients chronically treated with beta blockers and scheduled for conventional cardiac surgery. INTERVENTIONS: Two successive 4-month phases: Phase 1 = uncontrolled early postoperative beta blocker administration (n = 73) and phase 2 = beta-blocker administration by an institutional written algorithm using incremental doses of bisoprolol and/or esmolol (n = 52). MEASUREMENTS AND MAIN RESULTS: The main endpoint was the number of patients receiving beta-blockers on the morning of postoperative day 1. Secondary endpoints were the number of patients receiving beta-blockers on the morning of postoperative day 1 and reaching the targeted therapeutic goal and the incidence of postoperative atrial fibrillation in the intensive care unit. A 79% increase in the number of patients receiving beta-blockers on the morning of postoperative day 1 (42% v 75%, p<0.001) was observed during the second phase of the study. The number of patients receiving beta-blockers on the morning of postoperative day 1 and reaching the targeted therapeutic goal was increased significantly by 127% (33% v 75%, p<0.001). The incidence of atrial fibrillation was similar between both phases of the study: 37% versus 31%, p = 0.567. CONCLUSIONS: A simple written algorithm markedly improved early postoperative continuation of beta-blockers in chronically treated patients undergoing conventional cardiac surgery. PMID- 25280980 TI - [Editorial]. PMID- 25280981 TI - Status of the effectiveness of contact lens solutions against keratitis-causing pathogens. AB - PURPOSE: The aim of this study was to assess the antimicrobial effects of marketed contact lens disinfecting solutions. METHODS: Using ISO 14729 Stand Alone Test for disinfecting solutions, bactericidal, fungicidal and amoebicidal assays of eight different contact lens solutions including: ReNu MultiPlus, DuraPlus, Ultimate Plus, OptiFree Express, Kontex Clean, Kontex Normal, Kontex Multisol extra(+), Kontex Soak were performed. The efficacy of contact lens solutions was determined against keratitis-causing microbes, namely: Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus, Fusarium solani and Acanthamoeba castellanii. RESULTS: The results revealed that ReNu MultiPlus, DuraPlus and OptiFree Express were effective in killing bacterial and fungal pathogens as per manufacturer's minimum recommended disinfection time. Ultimate Plus was effective against F. solani and MRSA but ineffective against P. aeruginosa, S. marcescens and S. aureus. Of concern however, is that none of the locally formulated contact lens disinfecting solutions from Pakistan, i.e., Kontex Clean, Kontex Normal, Kontex Multisol extra(+) and Kontex Soak were effective against any of the keratitis-causing organisms tested. All eight contact lens disinfecting solutions were unable to destroy Acanthamoeba cysts. CONCLUSIONS: Because such ineffective contact lens disinfection solutions present a major risk to public health, these findings are of great concern to the health officials and to the manufacturers of the contact lens disinfection solutions and effective solutions are needed, along with emphasis on proper hygiene for contact lens care and special guidelines for developing countries regarding the manufacture and storage of contact lens disinfecting solutions. PMID- 25280982 TI - Comments on "Modern scleral contact lenses: a review" [van der Worp et al. (2014)]. PMID- 25280983 TI - T-pattern analysis for the study of temporal structure of animal and human behavior: a comprehensive review. AB - A basic tenet in the realm of modern behavioral sciences is that behavior consists of patterns in time. For this reason, investigations of behavior deal with sequences that are not easily perceivable by the unaided observer. This problem calls for improved means of detection, data handling and analysis. This review focuses on the analysis of the temporal structure of behavior carried out by means of a multivariate approach known as T-pattern analysis. Using this technique, recurring sequences of behavioral events, usually hard to detect, can be unveiled and carefully described. T-pattern analysis has been successfully applied in the study of various aspects of human or animal behavior such as behavioral modifications in neuro-psychiatric diseases, route-tracing stereotypy in mice, interaction between human subjects and animal or artificial agents, hormonal-behavioral interactions, patterns of behavior associated with emesis and, in our laboratories, exploration and anxiety-related behaviors in rodents. After describing the theory and concepts of T-pattern analysis, this review will focus on the application of the analysis to the study of the temporal characteristics of behavior in different species from rodents to human beings. This work could represent a useful background for researchers who intend to employ such a refined multivariate approach to the study of behavior. PMID- 25280985 TI - Reward breaks through the inhibitory region around attentional focus. AB - It is well known that directing attention to a location in space enhances the processing efficiency of stimuli presented at that location. Research has also shown that around this area of enhanced processing, there is an inhibitory region within which processing of information is suppressed. In this study, we investigated whether a reward-associated stimulus can break through the inhibitory surround. A distractor that was previously associated with high or low reward was presented near the target with a variable distance between them. For low-reward distractors, only the distractor very close to the target caused interference to target processing; for high-reward distractors, both near and relatively far distractors caused interference, demonstrating that task irrelevant reward-associated stimuli can capture attention even when presented within the inhibitory surround. PMID- 25280984 TI - Identification of functional synaptic plasticity from spiking activities using nonlinear dynamical modeling. AB - This paper presents a systems identification approach for studying the long-term synaptic plasticity using natural spiking activities. This approach consists of three modeling steps. First, a multi-input, single-output (MISO), nonlinear dynamical spiking neuron model is formulated to estimate and represent the synaptic strength in means of functional connectivity between input and output neurons. Second, this MISO model is extended to a nonstationary form to track the time-varying properties of the synaptic strength. Finally, a Volterra modeling method is used to extract the synaptic learning rule, e.g., spike-timing dependent plasticity, for the explanation of the input-output nonstationarity as the consequence of the past input-output spiking patterns. This framework is developed to study the underlying mechanisms of learning and memory formation in behaving animals, and may serve as the computational basis for building the next generation adaptive cortical prostheses. PMID- 25280987 TI - A divided and sliding postauricular myocutaneous flap for anterior auricular reconstruction. PMID- 25280986 TI - The best interests of the child and the return of results in genetic research: international comparative perspectives. AB - BACKGROUND: Paediatric genomic research raises particularly challenging questions on whether and under what circumstances to return research results. In the paediatric context, decision-making is guided by the best interests of the child framework, as enshrined in the 1989 international Convention on the Rights of the Child. According to this Convention, rights and responsibilities are shared between children, parents, researchers, and the state. These "relational" obligations are further complicated in the context of genetic research. DISCUSSION: A comparative review of international, regional and national documents on the return of research results reveals that there is a dearth of normative documents in the paediatric context. The best interests of the child framework is increasingly complicated by a growing appreciation of pediatric autonomy and the development thereof; parental rights (particularly when parents are affected by the genomic information of their children); and the right not to know. SUMMARY: This comparative analysis reveals that policy-makers and legislators have responded to the above challenges in different ways. Nevertheless, in Europe as well as in Canada, there is an emerging trend towards making the return of certain results mandatory in the paediatric context, should this course of action prove to be in the best interests of the child. PMID- 25280988 TI - Clinical verification of patients with obstructive sleep apnea provided with a customized cushion for continuous positive airway pressure. AB - STATEMENT OF PROBLEM: Patients with obstructive sleep apnea may stop breathing momentarily during sleep because of a narrow upper respiratory tract. One of the main treatments for obstructive sleep apnea is continuous positive airway pressure. However, after long-term treatment, patients tend to complain about the leakage, inconvenience, and discomfort of the nasal mask. PURPOSE: The purpose of the study was to develop customized cushions and compare the clinical performance of the customized cushion with the conventional one. MATERIAL AND METHODS: Each participant's face was replicated by using a 3-dimensional scanner and reverse engineering technology, and computer numerical control techniques were used to design and manufacture customized cushions. Forty participants were randomly divided into 2 groups, a control group with conventional cushions and an experimental group with customized cushions. The saturation level of peripheral oxygen, apnea-hypopnea index, leakage data, and answers to a comfort questionnaire were examined. RESULTS: Customized and conventional cushions were compared with independent sampling t tests and relational analyses. A significant difference was found in the apnea-hypopnea index (P=.001) of participants with the customized cushion and those with the conventional cushion. Participants with the conventional cushion had a lower apnea-hypopnea index. The customized cushion applied less headgear force and fit better than the conventional cushion. The leakage volume, saturation of peripheral oxygen (SpO2), treatment compliance, and degree of comfort were not significantly different between the groups. CONCLUSIONS: Customized nasal mask cushions fit better and reduce the force applied by the headgear. Participants using a customized cushion showed an improved apnea-hypopnea index. PMID- 25280989 TI - Bending strength of zirconia/porcelain functionally graded materials prepared using spark plasma sintering. AB - OBJECTIVES: The purpose of this study was to fabricate functionally graded materials (FGMs) consisting of yttria-stabilised tetragonal zirconia polycrystal (Y-TZP) and porcelain using spark plasma sintering (SPS) and examine the influence of their microstructures and thermal stress on their bending strengths. METHODS: Two types of four-layered Y-TZP/porcelain FGMs having a constant layer thickness and a varying layer thickness, Y-TZP/porcelain composite materials having a microstructure corresponding to each layer in FGMs and monolithic materials of Y-TZP and porcelain were fabricated by SPS. The Y-TZP/porcelain volume fraction of each layer in FGMs was varied over 100/0-70/30. Three-point bending test, X-ray diffraction, density measurement, microstructure observation, and thermal stress estimation were performed to characterise the materials. RESULTS: The bending strength of the Y-TZP/porcelain composite materials decreased with the volume fraction of the porcelain. About FGMs, when the 100%Y TZP layer was on the tensile stress side during the bending test, the bending strength was almost the same as that of the 100%Y-TZP monolithic material. On the other hand, when the 100%Y-TZP layer was on the compressive stress side, the bending strength of FGM having a constant layer thickness was almost the same as that of the 70%Y-TZP+30%porcelain composite material, while the bending strength of FGM with a varying layer thickness was significantly higher than that of the 70%Y-TZP+30%porcelain composite material. CLINICAL SIGNIFICANCE: The FGMs prepared and analyzed in this research can potentially be used for crowns and bridges as well as for inlays and onlays. CONCLUSION: The SPS method could effectively fabricate the Y-TZP/porcelain FGMs, and the bending strength results revealed that the graded structure was very efficient to raise the bending strength. PMID- 25280990 TI - Determination of thimerosal in pharmaceutical industry effluents and river waters by HPLC coupled to atomic fluorescence spectrometry through post-column UV assisted vapor generation. AB - A high performance liquid chromatography coupled with atomic fluorescence spectrometry method for the determination of thimerosal (sodium ethylmercury thiosalicylate, C9H9HgNaO2S), ethylmercury, and inorganic mercury is proposed. Mercury vapor is generated by the post-column reduction of mercury species in formic acid media using UV-radiation. Thimerosal is quantitatively converted to Hg(II) followed by the reduction of Hg(II) to Hg(0). This method is applied to the determination of thimerosal (THM), ethylmercury (EtHg) and inorganic Hg in samples of a pharmaceutical industry effluent, and in waters of the San Luis River situated in the west side of San Luis city (Middle West, Argentine) where the effluents are dumped. The limit of detections, calculated on the basis of the 3sigma criterion, where 0.09, 0.09 and 0.07 MUg L(-1) for THM, EtHg(II) and for Hg(II), respectively. Linearity was attained from levels close to the detection limit up to at least 100 MUg L(-1). PMID- 25280992 TI - Renal amyloidosis. PMID- 25280993 TI - Avoiding postnatal undernutrition of VLBW infants during neonatal intensive care: evidence and personal view in the absence of evidence. AB - Inadequate nutrient intakes in the first postnatal weeks play a crucial role in the aetiology of postnatal growth restriction of very low birthweight (VLBW) infants. Efforts to improve early nutrition in these infants led to a significant reduction in postnatal growth failure. Initiation of enhanced parenteral nutrition immediately after birth and utilisation of the large potential of early enteral nutrition seem pivotal. Nevertheless, it remains challenging to further reduce the initial drop in weight and head circumference z-score and to improve body composition and linear growth. This review will summarise data on how near fetal postnatal weight gain in VLBW infants can be achieved and makes suggestions for early nutrition of VLBW infants. PMID- 25280991 TI - Microvascular oxygen pressures in muscles comprised of different fiber types: Impact of dietary nitrate supplementation. AB - Nitrate (NO3(-)) supplementation via beetroot juice (BR) preferentially improves vascular conductance and O2 delivery to contracting skeletal muscles comprised predominantly of type IIb + d/x (i.e. highly glycolytic) fibers following its reduction to nitrite and nitric oxide (NO). To address the mechanistic basis for NO3(-) to improve metabolic control we tested the hypothesis that BR supplementation would elevate microvascular PO2 (PO2mv) in fast twitch but not slow twitch muscle. Twelve young adult male Sprague-Dawley rats were administered BR ([NO3(-)] 1 mmol/kg/day, n = 6) or water (control, n = 6) for 5 days. PO2mv (phosphorescence quenching) was measured at rest and during 180 s of electrically induced 1-Hz twitch contractions (6-8 V) of the soleus (9% type IIb +d/x) and mixed portion of the gastrocnemius (MG, 91% type IIb + d/x) muscles. In the MG, but not the soleus, BR elevated contracting steady state PO2mv by ~43% (control: 14 +/- 1, BR: 19 +/- 2 mmHg (P < 0.05)). This higher PO2mv represents a greater blood-myocyte O2 driving force during muscle contractions thus providing a potential mechanism by which NO3(-) supplementation via BR improves metabolic control in fast twitch muscle. Recruitment of higher order type II muscle fibers is thought to play a role in the development of the VO2 slow component which is inextricably linked to the fatigue process. These data therefore provide a putative mechanism for the BR-induced improvements in high-intensity exercise performance seen in humans. PMID- 25280994 TI - Inhibition of maintenance DNA methylation by Stella. AB - DNA methylation is a key epigenetic regulator in mammals, and the dynamic balance between methylation and demethylation impacts various processes, from development to disease. DNA methylation is erased during replication when DNA methyltransferase 1 (DNMT1) fails to methylate the daughter strand, in a process known as passive DNA demethylation. We found that the enforced expression of Stella (also known as PGC7, Dppa3), a maternal factor required for the maintenance of DNA methylation in early embryos, induced global DNA demethylation in NIH3T3 cells. This demethylation was caused by the binding of Stella to Np95 (also known as Uhrf1, ICBP90) and the subsequent inhibition of DNMT1 recruitment. Considering that impaired DNA methylation profiles are associated with various developmental or disease phenomena, Stella may be a powerful tool with which to study the biological effects of global DNA hypomethylation. PMID- 25280995 TI - Heat shock factor 1 regulates hsa-miR-432 expression in human cervical cancer cell line. AB - Heat shock response pathway is a conserved defense mechanism of mammalian cells to maintain protein homeostasis against proteotoxic environmental conditions. This is characterized by robust synthesis of molecular chaperones mostly by stress-induced activation of heat shock factor 1 (HSF1). MicroRNAs (miRNAs) are a family of small non-coding RNAs that negatively regulate expression of protein coding genes. Here we report altered expression of a set of miRNAs by thermal stress in HeLa cells. We also show that HSF1 regulates hsa-miR-432 expression in heat shock-dependent manner through its cognate binding site present in hsa-miR 432 upstream sequence. Our report uncovers a novel function of HSF1 and indicates involvement of miRNAs in HSF1-mediated protection of cellular proteome. PMID- 25280996 TI - bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche. AB - The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche. PMID- 25280997 TI - IL-33/ST2 pathway contributes to metastasis of human colorectal cancer. AB - Interleukin-33 (IL-33) was recently implicated in cancer pathogenesis. However, the possible effect of IL-33 on tumor progression of colorectal cancer (CRC), which is one of the most commonly diagnosed and lethal cancers worldwide, was still unclear. Here we evaluated the potential role of IL-33/ST2 pathway in metastasis of human CRC. We found an elevated expression of IL-33 and ST2 in tumor tissues of CRC patients. Higher expressions of IL-33 and ST2 were observed in poor-differentiated human CRC cells. Of note, IL-33 stimulation promoted the invasion of human CRC cells in a dose dependent manner. Enhanced IL-33/ST2 signaling promoted CRC metastasis, while attenuated IL-33/ST2 signaling decreased CRC metastasis. In consistent, enforced IL-33 expression in human CRC cells enhanced their growth, metastasis and reduced the survival time in nude mice, while decreased IL-33 expression in human CRC cells inhibited their growth, metastasis and prolonged the survival time in nude mice. Finally, we observed an increased expression of IL-6, CXCR4, MMP2 and MMP9 in response to IL-33/ST2 signaling in human CRC cells, which were crucial for the enhanced metastasis by IL-33 stimulation. Collectively, our findings demonstrated that IL-33/ST2 pathway could contribute to the metastasis of human CRC, which could enlarge the understanding of CRC pathogenesis and provide clues for developing new CRC therapeutics. PMID- 25280998 TI - Restoration of cellular ubiquitin reverses impairments in neuronal development caused by disruption of the polyubiquitin gene Ubb. AB - Disruption of the polyubiquitin gene Ubb leads to hypothalamic neurodegeneration and metabolic disorders, including obesity and sleep abnormalities, in mice. However, it has yet to be determined whether or not these neural phenotypes in Ubb(-/-) mice are directly caused by cell autonomous defects in maintaining proper levels of ubiquitin (Ub). To directly demonstrate that reduced levels of Ub are sufficient to cause neuronal abnormalities, we investigated the characteristics of cultured neurons isolated from Ubb(-/-) mouse embryonic brains. We found that neuronal morphology, neurite outgrowth, and synaptic development were significantly impaired in Ubb(-/-) neurons. Furthermore, we observed the growth of astrocytes in Ubb(-/-) cell cultures despite the fact that cells were cultured under conditions promoting neuronal growth. When the reduced levels of free Ub, but not Ub conjugates, in Ubb(-/-) cells were restored to those of wild-type cells by providing exogenous Ub via lentivirus-mediated delivery, the increased apoptosis observed in Ubb(-/-) cells was almost completely abolished. Ectopic expression of Ub also improved neuronal and glial phenotypes observed in Ubb(-/-) cells. Therefore, our study suggests that Ub homeostasis, or the maintenance of cellular free Ub above certain threshold levels, is essential for proper neuronal development and survival. PMID- 25280999 TI - Establishment of a mouse melanoma model system for the efficient infection and replication of human adenovirus type 5-based oncolytic virus. AB - Due to poor adenoviral infectivity and replication in mouse tumor cell types compared with human tumor cell types, use of human-type adenoviral vectors in mouse animal model systems was limited. Here, we demonstrate enhanced infectivity and productive replication of adenovirus in mouse melanoma cells following introduction of both the Coxsackievirus and adenovirus receptor (CAR) and E1B-55K genes. Introduction of CAR into B16BL6 or B16F10 cells increased the infectivity of GFP-expressing adenovirus; however, viral replication was unaffected. We demonstrated a dramatic increase of adenoviral replication (up to 100-fold) in mouse cells via E1B-55K expression and subsequent viral spreading in mouse tissue. These results reveal for the first time that human adenovirus type 5 (Ad5)-based oncolytic virus can be applied to immunocompetent mouse with the introduction of CAR and E1B-55K to syngenic mouse cell line. PMID- 25281001 TI - Backbone and side chain NMR assignment, along with the secondary structure prediction of RRM2 domain of La protein from a lower eukaryote exhibiting identical structural organization with its human homolog. AB - The La protein (Lupus antigen), a key mediator during biogenesis of RNA polymerase III transcripts, contains a characteristic La motif and one or two RNA recognition motif (RRM) domains, depending on the organism of origin. The RRM1 domain is conserved in higher eukaryotes and located in the N-terminal region, whereas the C-terminal RRM2 domain is absent in most lower eukaryotes and its specific role remains, so far, uncharacterized. Here, we present the backbone and side-chain assignment of the (1)H, (13)C and (15)N resonances of RRM2 of La protein from Dictyostelium discoideum. Interestingly, the La protein in this lower eukaryote, exhibits high homology to its human counterpart. Moreover, it contains two RRM domains, instead of one, raising questions on its evolutionary origin and the putative role of RRM2 in vivo. We also provide its secondary structure as predicted by the TALOS+ online tool. PMID- 25281000 TI - Evolutionary profiling reveals the heterogeneous origins of classes of human disease genes: implications for modeling disease genetics in animals. AB - BACKGROUND: The recent expansion of whole-genome sequence data available from diverse animal lineages provides an opportunity to investigate the evolutionary origins of specific classes of human disease genes. Previous studies have observed that human disease genes are of particularly ancient origin. While this suggests that many animal species have the potential to serve as feasible models for research on genes responsible for human disease, it is unclear whether this pattern has meaningful implications and whether it prevails for every class of human disease. RESULTS: We used a comparative genomics approach encompassing a broad phylogenetic range of animals with sequenced genomes to determine the evolutionary patterns exhibited by human genes associated with different classes of disease. Our results support previous claims that most human disease genes are of ancient origin but, more importantly, we also demonstrate that several specific disease classes have a significantly large proportion of genes that emerged relatively recently within the metazoans and/or vertebrates. An independent assessment of the synonymous to non-synonymous substitution rates of human disease genes found in mammals reveals that disease classes that arose more recently also display unexpected rates of purifying selection between their mammalian and human counterparts. CONCLUSIONS: Our results reveal the heterogeneity underlying the evolutionary origins of (and selective pressures on) different classes of human disease genes. For example, some disease gene classes appear to be of uncommonly recent (i.e., vertebrate-specific) origin and, as a whole, have been evolving at a faster rate within mammals than the majority of disease classes having more ancient origins. The novel patterns that we have identified may provide new insight into cases where studies using traditional animal models were unable to produce results that translated to humans. Conversely, we note that the larger set of disease classes do have ancient origins, suggesting that many non-traditional animal models have the potential to be useful for studying many human disease genes. Taken together, these findings emphasize why model organism selection should be done on a disease-by-disease basis, with evolutionary profiles in mind. PMID- 25281003 TI - Chemical shift assignments of DRB4 (1-153), a dsRNA binding protein in A. thaliana RNAi pathway. AB - RNA interference (RNAi) is a conserved biological response to dsRNA and regulates the expression of protein-coding genes to mediate resistance to both endogenous parasitic and exogenous pathogenic nucleic acids. In RNAi pathway, dsRNA binding proteins assists Dicer at various stages of RNAi. In plants, DRB4, is a multidomain protein containing two dsRNA binding domains that recognizes the long exogenous/endogenous dsRNA and presents it to Ribonuclease enzyme, Dicer like 4, resulting in the production of 21 nt small interfering RNA. Here, we report nearly complete backbone and sidechain chemical shift assignments of N-terminus of DRB4 (1-153, ~18 kDa), containing both double stranded RNA binding domains and the linker. PMID- 25281002 TI - Backbone assignments of mini-RecA intein with short native exteins and an active N-terminal catalytic cysteine. AB - The backbone resonance assignments of an engineered splicing-inactive mini-RecA intein based on triple resonance experiments with [(13)C,(15)N]-labeled protein are reported. The construct contains inactivating mutations specifically designed to retain most catalytic residues, especially those that are potentially metal coordinating. The assignments are essential for protein structure determination of a precursor with an active N-terminal catalytic cysteine and for investigation of the atomic details of splicing. PMID- 25281004 TI - High levels of mannose-binding lectin are associated with lower pulse wave velocity in uraemic patients. AB - BACKGROUND: Uraemia is associated with a highly increased risk of cardiovascular disease. Mannose-binding lectin (MBL) has been shown to be involved in cardiovascular pathophysiology and a protective effect of MBL is suggested. The purpose of the present study was to evaluate a potential impact of MBL on vascular parameters in uraemic patients. METHODS: A cohort of 98 patients with end stage renal disease (ESRD) awaiting kidney transplantation had pulse wave velocity (PWV) and augmentation index (AIX) examined by tonometry and endothelial dependent flow-mediated (FMD) and endothelial independent nitroglycerin-induced (NID) dilatory capacities of the brachial artery measured by ultrasound. An oral glucose tolerance test (OGTT) was performed and serum levels of MBL were measured using Luminex xMAP bead array technology. RESULTS: The cohort was divided in two groups according to MBL-concentration below or above the median concentration. These groups were comparable regarding age, BMI, and duration of ESRD. PWV was significantly lower in the group with high MBL levels compared to the group with low MBL levels and trends toward better AIX and higher insulin sensitivity (ISI) was also seen in the group with high MBL levels. No difference was seen in FMD and NID. CONCLUSIONS: High levels of MBL are associated with lower PWV and the use of antihypertensive drugs in a cohort of patients with ESRD awaiting kidney transplantation suggesting a beneficial role of high levels of MBL on arterial stiffness in uraemia. PMID- 25281005 TI - Impact of left atrial appendage exclusion using an epicardial ligation system (LARIAT) on atrial fibrillation burden in patients with cardiac implantable electronic devices. AB - BACKGROUND: The left atrial appendage (LAA) is a well-known source of atrial arrhythmia and atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to determine whether LAA exclusion using the LARIAT device would decrease AF burden. METHODS: A total of 50 patients with AF and cardiac implantable electronic devices who underwent successful LAA exclusion were enrolled in this prospective observational study. AF burden before LAA exclusion (baseline) and 3 and 12 months after exclusion was assessed by device interrogation. RESULTS: AF burden at 3-month follow-up (42% +/- 34%) was significantly lower compared to baseline (76% +/- 33%, P < .0001). The reduction in AF burden was sustained at 12 months (59% +/- 26%, P < .001). Subgroup analysis revealed that AF burden at 3 month follow-up was similarly reduced in both paroxysmal AF (n = 19) and nonparoxysmal AF (n = 31). However, there was no reduction in AF burden in patients with paroxysmal AF at 12 months. AF burden in patients with known AF triggers in the LAA (n = 9) was significantly reduced at 3 months (52% +/- 35%) and 12 months (42% +/- 19%) compared to respective baseline (84 +/- 31%, P < .0001). CONCLUSION: LAA exclusion appears to reduce AF burden. The presence of AF triggers in the LAA appears to be the strongest predictor of AF reduction. The study underscores the role of the LAA in arrhythmogenesis for AF and highlights the complementary role of LAA exclusion in restoration of normal sinus rhythm. PMID- 25281007 TI - Is the eGFR formula adequate for evaluating renal function before chemotherapy in patients with urogenital cancer? A suggestion for clinical application of eGFR formula. AB - BACKGROUND: Accurate evaluation of renal function is required before cancer chemotherapy. Various kinds of formula have been developed for estimating creatinine clearance (Ccr) or glomerular filtration rate (GFR) conveniently. We retrospectively examined the reliability of the GFR estimating formula using the renal function data in cancer chemotherapy. METHODS: Clinical data of 12 patients with urogenital cancer from 1998 to 2013 in Saga University Hospital were reviewed. Patients were treated with 6-21 (median 10.5) courses of chemotherapy and those patients underwent 9-29 (median 14.5) times of 24hrCcr tests before and during chemotherapy. We compared estimated GFR (eGFR) with 24hrCcr. In addition, we developed a novel method to estimate the Ccr using the patient-inherent 24hrCcr/eGFR ratio, which is calculated from initial 3 or 4 determinations of 24hrCcr and the corresponding eGFR. Those estimated Ccrs were also compared with 24hrCcr. RESULTS: The dissociation between 24hrCcr and eGFR was not constant, and a large dissociation was observed in some cases. The newly devised estimated Ccr demonstrated less dissociation from 24hrCcr compared with eGFR. CONCLUSIONS: The eGFR formula is not adequate for the clinical use in cancer chemotherapy. The absolute value of eGFR is not reliable, but clinical use of eGFR as relative value seems to be acceptable. To avoid troublesome 24hrCcr measurement in long term cancer chemotherapy, eGFR formula can be used for estimating Ccr in combination with the specific inherent 24hrCcr/eGFR ratio, which is obtained from 3 or 4 times of actual 24hrCcr measurements. PMID- 25281008 TI - Effects of serum albumin and glycated albumin levels on performance of the Japanese GFR equation based on serum cystatin C. AB - BACKGROUND: We reported that both serum albumin (Alb) and glycated albumin (GA) levels influenced the performance of the Japanese GFR equation based on serum creatinine. In the present study, we studied the effects of both markers on the estimated GFR by Japanese GFR equation based on serum cystatin C (Eq-cys). METHODS: 715 Japanese subjects were included. GFR was measured by inulin renal clearance (Cin). Correlations between estimated GFR by Eq-cys (eGFRcys) and Cin were evaluated in subjects stratified by GA (GA-1: GA <= 16.3 % and GA-2: GA >= 16.4 %) and Alb levels (Alb-1: Alb <= 3.5 g/dl and Alb-2: Alb >= 3.6 g/dl). RESULTS: Correlation coefficients between eGFRcys and Cin were 0.863, 0.919, 0.948 and 0.974 in GA-1, GA-2, Alb-1 and Alb-2, respectively. Slopes (95 % confidential interval) of the regression lines with zero intercepts were 1.014 (0.993-1.035), 0.989 (0.944-1.033), 1.019 (0.970-1.068) and 1.011 (0.990-1.031), respectively. The slopes were not significantly different from 1.0, suggesting that Eq-cys performed well in subjects at wide spectrum of GA and Alb levels. Single regression analysis of GA on eGFRcys/GFR was not significant in total subjects and subjects with GA > 12.4 %. Single regression analysis of Alb on eGFRcys/GFR was significant in total subjects, but the correlation coefficient was very low (r = 0.08, p = 0.03). Multiple regression analysis showed that Alb and GA were not significantly associated with eGFRcys/Cin in subjects with GA > 12.4 %. These results suggested that both parameters were not important factors affecting the performance of Eq-cys. CONCLUSION: Performance of Eq-cys was well irrespective of GA and Alb levels. Both parameters were not important factors affecting the estimated GFR by Eq-cys. PMID- 25281006 TI - Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating mmachc expression. AB - Mutations in HCFC1 (MIM300019), have been recently associated with cblX (MIM309541), an X-linked, recessive disorder characterized by multiple congenital anomalies including craniofacial abnormalities. HCFC1 is a transcriptional co regulator that modulates the expression of numerous downstream target genes including MMACHC, but it is not clear how these HCFC1 targets play a role in the clinical manifestations of cblX. To begin to elucidate the mechanism by which HCFC1 modulates disease phenotypes, we have carried out loss of function analyses in the developing zebrafish. Of the two HCFC1 orthologs in zebrafish, hcfc1a and hcfc1b, the loss of hcfc1b specifically results in defects in craniofacial development. Subsequent analysis revealed that hcfc1b regulates cranial neural crest cell differentiation and proliferation within the posterior pharyngeal arches. Further, the hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, a downstream target of HCFC1 that is aberrantly expressed in cblX. Furthermore, we tested distinct human HCFC1 mutations for their role in craniofacial development and demonstrated variable effects on MMACHC expression in humans and craniofacial development in zebrafish. Notably, several individuals with mutations in either HCFC1 or MMACHC have been reported to have mild to moderate facial dysmorphia. Thus, our data demonstrates that HCFC1 plays a role in craniofacial development, which is in part mediated through the regulation of MMACHC expression. PMID- 25281009 TI - Cross-cultural adaptation and validation of the Italian Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ). AB - PURPOSE: To validate and cross-culturally adapt the Italian version of the Psychological Impact of Dental Aesthetics Questionnaire (PIDAQ) among Italian young adults. METHODS: After translation, back translation, and cross-cultural adaptation of the English PIDAQ, a first version of the Italian questionnaire was pretested. The final Italian PIDAQ was administered to 598 subjects aged 18-30 years, along with two other instruments: the aesthetic component of the index of orthodontic treatment need (IOTN-AC) and the perception of occlusion scale (POS), which identified the self-reporting grade of malocclusion. Structural validity was assessed by means of factorial analysis, internal consistency was measured with Cronbach's alpha coefficient (alpha), convergent validity was assessed by means of Spearman correlation, and test-retest reliability was calculated with intra-class correlation coefficient (ICC) and standard measurement error. Criterion validity was evaluated by multivariate and univariate analysis of variance with Bonferroni post hoc tests. RESULTS: The alpha of the Italian PIDAQ domains ranged between 0.79 and 0.92. The ICC was between 0.81 and 0.90. The mean scores of each PIDAQ domain showed a statistically significant difference when analysed according to the IOTN-AC and POS scores. CONCLUSION: The satisfactory psychometric properties make PIDAQ a usable tool for future studies on oral health-related quality of life among Italian young adults. PMID- 25281011 TI - Intraobserver and interobserver reliability of measures of cervical sagittal rotation. AB - BACKGROUND: Diagnosis and treatment decisions of cervical instability are made, in part, based on the clinician's assessment of sagittal rotation on flexion and extension radiographs. The objective of this study is to evaluate the intraobserver and interobserver reliability of three measurement techniques in assessing cervical sagittal rotation. METHODS: Fifty lateral radiographs of patients with single-level cervical degenerative disc were selected and measured on two separate occasions by three spine surgeons using three different measurement techniques. Cervical sagittal rotation was measured using three different techniques. RESULTS: Intraclass correlation coefficients were most consistent for Method 2 (ICC 0.93-0.96) followed by Method 1 (ICC 0.88-0.91) and Method 3 (ICC 0.81-0.87). Intraobserver agreement (% of repeated measures within 0.5 degrees of the original measurement) ranged between 76% and 96% for all techniques, with Method 2 showing the best agreement (92%-96%). Paired comparisons between observers varied considerably with interobserver reliability correlation coefficients ranging from 0.54 to 0.89. Method 2 showed the highest interobserver reliability coefficient (0.82, range 0.73-0.88). Method 2 was also more reliable for the classification of "instability". Intraobserver percent agreements ranged from 94 to 98% for Method 2 versus 84% to 90% for Method 1 and 78% to 86% for Method 3, while interobserver percent agreements ranged from 90% to 98% for Method 2 versus 86% to 94% for Method 1 and 74% to 84% for Method 3. CONCLUSIONS: Method 2 (measuring the angle from the inferior endplate of the vertebra above the degenerative disc and the inferior endplate of the vertebra below the degenerative disc) showed the best intraobserver and interobserver reliability overall in assessing cervical sagittal rotation. PMID- 25281010 TI - Validation of clinical symptom IRT scores for diagnosis and severity assessment of common mental disorders. AB - PURPOSE: We studied the validity and responsiveness of an item response theory (IRT) scoring method for assessing major depressive episode (MDE) and generalized anxiety disorder (GAD) severity based on direct assessment of DSM-IV-TR symptoms. METHODS: Prospective cohort study (baseline, 1-month, 3-months assessments) of patients seeking help for incident or aggravated mood or anxiety symptoms from primary, outpatient and inpatient mental health centers (N = 244; 67.81 % active cases - 100 % under psychiatric treatment). The drop-out rate at 3 months was 24.89 %. Patients were assessed at each follow-up for presence/absence of DSM-IV symptoms of MDE (nine symptoms) and GAD (eight symptoms). IRT scores for depression (INS-D) and anxiety (INS-G), based on response patterns, were obtained by means of a 2-parameter model. Diagnostic accuracy was assessed with receiver operating characteristic analysis, using a blinded MINI interview as gold standard. Scores' construct validity was compared with external clinician administered (Hamilton Depression Rating Scale, HRSD; Hamilton Anxiety Rating Scale, HAM-A) and self-reported severity measures (PHQ-9; Beck Anxiety Inventory Subjective Aspects, BAI-Sub). Responsiveness was analyzed based on the evolution of HRSD and HAM-A scores. RESULTS: Both severity scores showed excellent reliability (INS-D: 0.92; INS-G: 0.93) and yielded high diagnostic accuracy (INS D: AUC = 0.96; INS-G: AUC = 0.91) with respect to MINI diagnoses. INS-D and INS-G had higher correlations with clinician-administered measures of the same disorder (INS-D-HRSD: 0.73; INS-G-HAM-A: 0.53) than with self-reported measures (INS-D-PHQ 9: 0.69; INS-G-BAI-Sub: 0.49). Patients who recovered during follow-up showed important decreases in severity (Cohen's d INS-D:-1.38; INS-G: -1.75). About 90 % variance of INS-D and INS-G score changes over time was associated with changes in clinical status. CONCLUSIONS: INS-D and INS-G are short reliable, valid, and responsive measures that can be used for diagnostic and severity assessment of mood and anxiety disorders in outpatient care. PMID- 25281012 TI - To reheat, or to not reheat: that is the question: the efficacy of a local reheating protocol on mechanisms of cutaneous vasodilatation. AB - The aim of this study is to determine the effect of repeated bouts of local skin heating on the roles of nitric oxide synthase (NOS) and sympathetic nerves in cutaneous vasodilatation. In 3 repeated-heating protocols skin blood flux of the forearm and leg was measured using laser-Doppler flowmetry and data are presented as cutaneous vascular conductance (CVC; flux/blood pressure). Local heating was performed from 33 degrees C (thermoneutral) to 42 degrees C at 0.5 degrees C.10s( 1), allowed to cool passively for ~60-min, then reheated at the same rate. In protocol 1, CVC was measured in response to repeated heating. In protocol 2, NOS was inhibited with N(G)-nitro-l-arginine methyl ester (L-NAME) and in protocol 3, sympathetic nerve blockade was achieved with bretylium tosylate (BT), both infused via intradermal microdialysis. In protocol 1, there were no differences (P>0.05) in CVC at either the forearm (88+/-4 vs. 86+/-4%max) or the leg (97+/-4 vs. 96+/-6%max) between heating bouts. In protocol 2, no differences (P>0.05) in CVC were observed between heating bouts at L-NAME treated sites at either the forearm (55+/-3 vs. 51+/-4%max) or the leg (71+/-3 vs. 70+/-4%max) . In protocol 3, there were differences (P<0.001) between BT treated sites when comparing the first and second bouts of heating for both the forearm (75+/-3 vs. 88+/-4%max) and the leg (79+/-3 vs. 97+/-4%max). The effect of sympathetic blockade on CVC responses to local heating was abolished following repeated bouts of heating. Consequently, it is our suggestion that when examining mechanisms of skin blood flow control, investigators use single bouts of local heating. PMID- 25281013 TI - Improvement of neuronal bioenergetics by neurosteroids: implications for age related neurodegenerative disorders. AB - The brain has high energy requirements to maintain neuronal activity. Consequently impaired mitochondrial function will lead to disease. Normal aging is associated with several alterations in neurosteroid production and secretion. Decreases in neurosteroid levels might contribute to brain aging and loss of important nervous functions, such as memory. Up to now, extensive studies only focused on estradiol as a promising neurosteroid compound that is able to ameliorate cellular bioenergetics, while the effects of other steroids on brain mitochondria are poorly understood or not investigated at all. Thus, we aimed to characterize the bioenergetic modulating profile of a panel of seven structurally diverse neurosteroids (progesterone, estradiol, estrone, testosterone, 3alpha androstanediol, DHEA and allopregnanolone), known to be involved in brain function regulation. Of note, most of the steroids tested were able to improve bioenergetic activity in neuronal cells by increasing ATP levels, mitochondrial membrane potential and basal mitochondrial respiration. In parallel, they modulated redox homeostasis by increasing antioxidant activity, probably as a compensatory mechanism to a slight enhancement of ROS which might result from the rise in oxygen consumption. Thereby, neurosteroids appeared to act via their corresponding receptors and exhibited specific bioenergetic profiles. Taken together, our results indicate that the ability to boost mitochondria is not unique to estradiol, but seems to be a rather common mechanism of different steroids in the brain. Thus, neurosteroids may act upon neuronal bioenergetics in a delicate balance and an age-related steroid disturbance might be involved in mitochondrial dysfunction underlying neurodegenerative disorders. PMID- 25281014 TI - Genomic characterisation of two virulent Newcastle disease viruses isolated from crested ibis (Nipponia nippon) in China. AB - This paper describes the complete genomic sequences of two virulent Newcastle disease virus (NDV) isolates, Shaanxi06 (prevalent genotype VIId) and Shaanxi10 (novel sub-genotype VIi), from sick crested ibises. The genomes of both isolates were 15,192 nt long and consisted of six genes in the order of 3'-NP-P-M-F-HN-L 5'. The genomes of the two isolates were highly similar to other reference NDV strains. However, some unique features were found in the HN protein of Shaanxi06 and the F gene end of Shaanxi10. Shaanxi06 and Shaanxi10 shared the same virulent motif (112-)R-R-Q-K-R-F(-117) at the F protein cleavage site, which coincided with previous pathogenicity test results. Phylogenetic analysis revealed that both isolates were clustered within class II NDV, with Shaanxi06 in genotype VII and Shaanxi10 in genotype VI. Both isolates shared high homology with the prevalent genotype NDV strains that circulate in fowls and waterfowls. This study is the first to provide genomic information about a novel sub-genotype VIi NDV strain and another genotype VIId virus, which will be useful for subsequent investigations. PMID- 25281015 TI - Analysis of methylation microarray for tissue specific detection. AB - The role of human DNA methylation has been extensively studied in genomic imprinting, X-inactivation, and disease. However, studies of tissue-specific methylation remain limited. In this study, we use bioinformatics methods to analyze methylation data and reveal loci that are exclusively methylated or unmethylated in individual tissues. We collect 39 previously published DNA methylation profiles using an Illumina(r) HumanMethylation 27 BeadChip Kit containing 22 common tissues and involving 27,578 CpG loci across the human genome. We found 86 positions of tissue specific methylation CpG (TSM) that encompass 34 hypermethylated TSMs (31 genes) and 52 hypomethylated TSMs (47 genes). Tissues were found to contain 1 to 25 TSM loci, with the majority in the liver (25), testis (18), and brain (16). Fewer TSM loci were found in the muscle (8), ovary (7), adrenal gland (3), pancreas (2-4), kidney, spleen, and stomach (1 each). TSMs are predominantly located 0-300 base pairs in the 3' direction after the transcription start site. Similar to known promoters of methylation, hypermethylated TSM genes suppress transcription, while hypomethylated TSMs allow gene transcription. The majority of hypermethylated TSM genes encode membrane proteins and receptors, while hypomethylated TSM genes primarily encode signal peptides and tissue-specific proteins. In summary, the database of TSM loci produced herein is useful for the selection of tissue-specific DNA markers as diagnostic tools, as well as for the further study of the mechanisms and roles of TSM. PMID- 25281016 TI - Six newly sequenced chloroplast genomes from prasinophyte green algae provide insights into the relationships among prasinophyte lineages and the diversity of streamlined genome architecture in picoplanktonic species. AB - BACKGROUND: Because they represent the earliest divergences of the Chlorophyta, the morphologically diverse unicellular green algae making up the prasinophytes hold the key to understanding the nature of the first viridiplants and the evolutionary patterns that accompanied the radiation of chlorophytes. Nuclear encoded 18S rDNA phylogenies unveiled nine prasinophyte clades (clades I through IX) but their branching order is still uncertain. We present here the newly sequenced chloroplast genomes of Nephroselmis astigmatica (clade III) and of five picoplanktonic species from clade VI (Prasinococcus sp. CCMP 1194, Prasinophyceae sp. MBIC 106222 and Prasinoderma coloniale) and clade VII (Picocystis salinarum and Prasinophyceae sp. CCMP 1205). These chloroplast DNAs (cpDNAs) were compared with those of the six previously sampled prasinophytes (clades I, II, III and V) in order to gain information both on the relationships among prasinophyte lineages and on chloroplast genome evolution. RESULTS: Varying from 64.3 to 85.6 kb in size and encoding 100 to 115 conserved genes, the cpDNAs of the newly investigated picoplanktonic species are substantially smaller than those observed for larger-size prasinophytes, are economically packed and contain a reduced gene content. Although the Nephroselmis and Picocystis cpDNAs feature a large inverted repeat encoding the rRNA operon, gene partitioning among the single copy regions is remarkably different. Unexpectedly, we found that all three species from clade VI (Prasinococcales) harbor chloroplast genes not previously documented for chlorophytes (ndhJ, rbcR, rpl21, rps15, rps16 and ycf66) and that Picocystis contains a trans-spliced group II intron. The phylogenies inferred from cpDNA encoded proteins are essentially congruent with 18S rDNA trees, resolving with robust support all six examined prasinophyte lineages, with the exception of the Pycnococcaceae. CONCLUSIONS: Our results underscore the high variability in genome architecture among prasinophyte lineages, highlighting the strong pressure to maintain a small and compact chloroplast genome in picoplanktonic species. The unique set of six chloroplast genes found in the Prasinococcales supports the ancestral status of this lineage within the prasinophytes. The widely diverging traits uncovered for the clade-VII members (Picocystis and Prasinophyceae sp. CCMP 1205) are consistent with their resolution as separate lineages in the chloroplast phylogeny. PMID- 25281017 TI - Multiple system atrophy is not caused by C9orf72 hexanucleotide repeat expansions. AB - Multiple system atrophy (MSA) is a fatal neurodegenerative disorder of unknown etiology that presents with variable combinations of progressive ataxia, parkinsonism, and autonomic instability. Pathologic expansion of a hexanucleotide repeat in the C9orf72 gene has been demonstrated to cause neurodegeneration with diverse neurologic presentations. To test the hypothesis whether pathologic expansions in C9orf72 are a cause of MSA, we undertook genetic screening in 100 neuropathologically confirmed cases. No pathologic repeat expansions were detected suggesting that MSA is not a C9orf72-related neurodegenerative disease. PMID- 25281018 TI - Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models. AB - In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-beta positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well established AD-related factors, such as alpha-, beta-, and gamma-secretase activities, brain amyloid-beta42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between beta-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-beta positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-beta-secretase interaction, increased amyloid-beta40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis. PMID- 25281019 TI - Subcortical structures in amyotrophic lateral sclerosis. AB - The aim of this study was to assess the involvement of deep gray matter, hippocampal subfields, and ventricular changes in patients with amyotrophic lateral sclerosis (ALS). A total of 112 ALS patients and 60 healthy subjects participated. High-resolution T1-weighted images were acquired using a 3T MRI scanner. Thirty-nine patients underwent a follow-up scan. Volumetric and shape analyses of subcortical structures were performed, measures were correlated with clinical parameters, and longitudinal changes were assessed. At baseline, reduced hippocampal volumes (left: p = 0.007; right: p = 0.011) and larger inferior lateral ventricles (left: p = 0.013; right: p = 0.041) were found in patients compared to healthy controls. Longitudinal analyses demonstrated a significant decrease in volume of the right cornu ammonis 2/3 and 4/dentate gyrus and left presubiculum (p = 0.002, p = 0.045, p < 0.001), and a significant increase in the ventricular volume in the lateral (left: p < 0.001; right: p < 0.001), 3rd (p < 0.001) and 4th (p = 0.001) ventricles. Larger ventricles were associated with a lower ALSFRS-R score (p = 0.021). In conclusion, ALS patients show signs of neurodegeneration of subcortical structures and ventricular enlargement. Subcortical involvement is progressive and correlates with clinical parameters, highlighting its role in the neurodegenerative process in ALS. PMID- 25281020 TI - Structure-activity relationships of thiostrepton derivatives: implications for rational drug design. AB - The bacterial ribosome is a major target of naturally occurring thiopeptides antibiotics. Studying thiopeptide (e.g. thiostrepton) binding to the GAR's 23S.L11 ribosomal subunit using docking methods is challenging. Regarding the target, the binding site is composed of a flexible protein-RNA nonbonded interface whose available crystal structure is of medium resolution. Regarding the ligands, the thiopeptides are chemically complex, flexible, and contain macrocycles. In this study we developed a combined MD-docking-MD workflow that allows us to study thiopeptide-23S.L11 binding. It is shown that docking thiostrepton-like ligands to an MD-refined receptor structure instead of the medium resolution crystal leads to better convergence to the native-like docking pose and a better reproduction of experimental binding affinities. By applying an energy decomposition analysis, we identify key structural binding elements within GAR's rRNA-protein binding site and within the ligand structures. PMID- 25281021 TI - Coaching during a trauma surgery team training: perceptions versus structured observations. AB - BACKGROUND: Using the concept perception to quantify coaching skills during surgical training is questionable. This study compared the perceptions reported by the trainees and the faculty members following an emergency surgery team training with structured observations made on the basis of video registrations. METHODS: For each faculty member, we scored 45 minutes of identical scenarios to enable the quantitative assessment of the use of positive feedback, corrective feedback, as well as instruction and in particular comments containing how and why explanations. We compared the values determined from the video scores with the perceptions reported by the trainees and faculty on questionnaires. RESULTS: The trainee and faculty ratings for the coaching differed, with trainees generally giving a higher rating. While both the trainees and the faculty gave high ratings for the non-technical skills, corrective and complimenting feedback, and explanations why, the structured video observations showed lower scores in these categories. CONCLUSIONS: Both the trainees and the faculty overrated the coaching. Trainee questionnaires and faculty self-reports neither reflected the actual coaching activities nor identified coaching skill deficits. PMID- 25281022 TI - Point-Process Deconvolution of fMRI BOLD Signal Reveals Effective Connectivity Alterations in Chronic Pain Patients. AB - It is now recognized that important information can be extracted from the brain spontaneous activity, as exposed by recent analysis using a repertoire of computational methods. In this context a novel method, based on a blind deconvolution technique, is used to analyze potential changes due to chronic pain in the brain pain matrix's effective connectivity. The approach is able to deconvolve the hemodynamic response function from spontaneous neural events, i.e., in the absence of explicit onset timings, and to evaluate information transfer between two regions as a joint probability of the occurrence of such spontaneous events. The method revealed that the chronic pain patients exhibit important changes in the insula's effective connectivity which can be relevant to understand the overall impact of chronic pain on brain function. PMID- 25281023 TI - Introduction for the special edition. PMID- 25281025 TI - Cutaneous presentation of an aggressive plasmablastic neoplasm indiscriminate between lymphoma and myeloma. PMID- 25281024 TI - Influence of nocturnal and daytime sleep on initial orthostatic hypotension. AB - PURPOSE: The incidence of vasovagal syncope is more common in the morning. Previous researchers have reported negligible diurnal variation in the physiological responses associated with initial orthostatic hypotension (IOH). Nevertheless, physical activity and sleep prior to morning and afternoon test times have not been controlled and may influence the findings. We designed a semi constant routine protocol to examine diurnal variation in cardiorespiratory and cerebrovascular responses to active standing. METHODS: At 06:00 and 16:00 hours, nine males (27 +/- 9 years) completed an upright-stand protocol. Altimetry measured sleep durations were 3.3 +/- 0.4 and 3.2 +/- 0.6 h immediately prior to the morning and afternoon test times. Continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv), mean arterial blood pressure (MAP), heart rate (HR), and end-tidal carbon dioxide were obtained. Intestinal body temperature and salivary melatonin concentrations were also measured. RESULTS: Compared with the afternoon, resting HR and body temperature were 4 +/- 2 beats min(-1) and 0.45 +/- 0.2 degrees C lower, respectively, whereas melatonin concentration was 28.7 +/- 3.2 pg ml(-1) higher in the morning (P <= 0.02). Although all individuals experienced IOH at both times of the day, the initial decline in MAP during standing was 13 +/- 4 mmHg greater in the afternoon (P = 0.01). Nevertheless, the decline in MCAv was comparable at both times of day (mean difference: 2 +/- 3 cm s(-1); P = 0.5). CONCLUSION: These findings indicate that a bout of sleep in the afternoon in healthy young individuals results in greater IOH that is compensated for by effective cerebral blood flow regulation. PMID- 25281026 TI - Ovarian Brenner tumors and Walthard nests: a histologic and immunohistochemical study. AB - Brenner tumors are composed of urothelial/transitional-type epithelium and, hence, are morphologically similar to Walthard nests and tubal/mesothelial transitional metaplasia. In this study, we analyzed immunohistochemical markers on Brenner tumors to explore Mullerian as well as Wolffian and germ cell derivation. We also attempted to explore their possible association with tubal/paratubal Walthard nests/transitional metaplasia, using the same immunostains. Thirty-two consecutive cases of Brenner tumors were identified. Thirteen (43%) of the patients had Walthard nests in the tubal/periovarian soft tissue. All Brenner tumors were diffusely positive for GATA3 (strongly positive in 30/32 and weakly positive in the remaining 2) and negative for PAX8, PAX2, and SALL4. Similarly, all Walthard nests were positive for GATA3, whereas only 3 (23%) of 13 showed occasional PAX8 expression; all were negative for PAX2 and SALL4. In our study, more than 40% of Brenner tumors had associated Walthard nests. The similar morphology and immunoprofile of Brenner tumors and Walthard nests suggest a probable link between Brenner tumors and Walthard nests. Two additional cases presented highlight small transitional lesions involving the ovary: a possible precursor lesion or the initial steps of Brenner tumor formation. Brenner tumors and most Walthard nests lacked staining for Mullerian (PAX8 and PAX2) and germ cell tumor markers (SALL4). PMID- 25281027 TI - Chromosome 20q13.2 ZNF217 locus amplification correlates with decreased E cadherin expression in ovarian clear cell carcinoma with PI3K-Akt pathway alterations. AB - This study aims to evaluate the relationships between chromosome 20q13.2 zinc finger protein 217 (ZNF217) locus amplification, ZNF217 expression, E-cadherin expression, and PI3K-Akt pathway alterations (activating PIK3CA mutations or loss of phosphatase and tensin homolog [PTEN] expression), and whether these molecular alterations can predict the clinical survival data in ovarian clear cell carcinoma (OCCC) patients. Samples and clinical data of 72 OCCC patients were collected. Chromosome 20q13.2 ZNF217 locus amplification was detected by fluorescence in situ hybridization. ZNF217, E-cadherin and PTEN expression were assessed using immunohistochemical stain. PIK3CA mutation was identified by PCR amplified gene sequencing. Cox proportional hazard regression model was used to estimate the adjusted hazard ratios of survival. Chromosome 20q13.2 ZNF217 locus amplification was detected in 31% (22/72) of cases, and ZNF217 expression was increased in 40% (27/68) of cases. E-cadherin and PTEN expressions were decreased or lost in 44% (32/72) and 14% (10/72) of cases, respectively. Activating PIK3CA mutations were present in 35% (25/72) of cases. Thirty-three OCCC patients (46%) showed activating PI3K-Akt pathway alterations. Chromosome 20q13.2 ZNF217 locus amplification was significantly associated with decreased E-cadherin expression (P = .001). In contrast, ZNF217 expression was not related to ZNF217 amplification or E-cadherin expression. In OCCC patients with activating PI3k-Akt pathway, decreased E-cadherin expression (P = .033) and advanced Federation of Gynecology and Obstetrics stage (P = .014) predicted shorter overall survival. Two conclusions were raised in our study. First, ZNF217 plays a role in down regulating E-cadherin expression and is a potential therapeutic target for OCCC patients. Second, E-cadherin expression is a prognostic marker for OCCC patients with activating PI3K-Akt pathway. PMID- 25281028 TI - Overexpression of the cell adhesion molecule claudin-9 is associated with invasion in pituitary oncocytomas. AB - Pituitary oncocytoma is a subtype of nonfunctioning pituitary adenomas with the potential to be locally invasive. Currently, surgery is the most effective treatment, whereas functional pituitary adenomas can be treated by drugs. We analyzed the invasiveness of pituitary oncocytomas to identify biomarkers that may be useful for guiding future therapeutic decision making. To identify important biomarkers of pituitary oncocytomas, 20 oncocytomas that were negative for hormone-specific immunostaining were confirmed by anti-mitochondria antibody immunostaining and electron microscopy. Our clinical phenotype data showed a prominent male predilection (85%). These tumors were classified as invasive or noninvasive based on preoperative magnetic resonance imaging, intraoperative records, and pathology slide. We observed significantly different expression profiles between pituitary oncocytomas (n = 3) and normal pituitary glands (n = 3). A total of 1937 genes were differentially expressed between the pituitary oncocytomas and normal pituitary glands. Among these 1937 genes, 954 were up regulated and 983 were down-regulated in pituitary oncocytomas. The most significantly altered gene, claudin-9 (CLDN9), was further confirmed by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining in 10 invasive pituitary oncocytoma samples and 10 noninvasive pituitary oncocytoma samples. High levels of CLDN9 were found in the pituitary oncocytomas, whereas low levels were detected in normal pituitary glands. In addition, the CLDN9 expression level was higher in invasive oncocytomas compared with noninvasive oncocytomas. Bioinformatics Gene Ontology analysis was performed to better understand the critical role of CLDN9 in the development and progression of oncocytomas. Consequently, CLDN9 may be an important biomarker for invasive pituitary oncocytomas. PMID- 25281029 TI - Plant-water relationships in the Great Basin Desert of North America derived from Pinus monophylla hourly dendrometer records. AB - Water is the main limiting resource for natural and human systems, but the effect of hydroclimatic variability on woody species in water-limited environments at sub-monthly time scales is not fully understood. Plant-water relationships of single-leaf pinyon pine (Pinus monophylla) were investigated using hourly dendrometer and environmental data from May 2006 to October 2011 in the Great Basin Desert, one of the driest regions of North America. Average radial stem increments showed an annual range of variation below 1.0 mm, with a monotonic steep increase from May to July that yielded a stem enlargement of about 0.5 mm. Stem shrinkage up to 0.2 mm occurred in late summer, followed by an abrupt expansion of up to 0.5 mm in the fall, at the arrival of the new water year precipitation. Subsequent winter shrinkage and enlargement were less than 0.3 mm each. Based on 4 years with continuous data, diel cycles varied in both timing and amplitude between months and years. Phase shifts in circadian stem changes were observed between the growing season and the dormant one, with stem size being linked to precipitation more than to other water-related indices, such as relative humidity or soil moisture. During May-October, the amplitude of the phases of stem contraction, expansion, and increment was positively related to their duration in a nonlinear fashion. Changes in precipitation regime, which affected the diel phases especially when lasting more than 5-6 h, could substantially influence the dynamics of water depletion and replenishment in single-leaf pinyon pine. PMID- 25281030 TI - Pathways to social anxiety: the role of reinforcement sensitivities and emotion regulation. AB - Past research has demonstrated a strong relationship between threat sensitivity and social anxiety; however, the relationship between reward sensitivity and social anxiety is less clear. Further, the role that emotion regulation (ER) may play in the expression of social anxiety disorder (SAD) is rarely considered. The current study tested whether two emotion regulation strategies (emotional suppression and cognitive reappraisal) mediated associations between threat sensitivity and reward sensitivity and social anxiety in a community sample (402 adults, 78% female; Mage=32.49, S.D.age=11.53). Path analyses indicated that low reappraisal mediated the relationship between high threat sensitivity and high social anxiety; and both low reappraisal and high suppression mediated the relationship between low reward sensitivity and high social anxiety. These results highlight the potential role that emotion regulation plays in the relationship between trait motivation and social anxiety. PMID- 25281031 TI - Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment. AB - Menkes disease is an X-linked recessive disorder of brain copper metabolism caused by mutations in an essential mammalian copper transport gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. Death by age three years is typical. While provision of working copies of ATP7A to the brain by viral vectors is a promising strategy under development, the only treatment currently available is subcutaneous copper injections. These can normalize circulating blood levels and may replete brain copper depending on the molecular context, e.g., the severity of ATP7A mutation and potential presence of mosaicism. In this paper, we summarize somatic growth and neurodevelopmental outcomes for 60 subjects enrolled in a recently concluded phase I/II clinical trial of copper histidine for Menkes disease (ClinicalTrials.gov Identifier: NCT00001262). Primary outcomes indicate highly statistically significant improvements in gross motor, fine motor/adaptive, personal-social, and language neurodevelopment in the cohort of subjects who received early treatment prior to onset of symptoms (n=35). Correlating with these findings, quantitative parameters of somatic growth indicated statistically significant greater growth in head circumference for the initially asymptomatic group, whereas weight and height/length at age three years (or at time of death) did not differ significantly. Mortality at age 3 was higher (50%) in subjects older and symptomatic when treatment commenced compared to the asymptomatic group (28.6%). We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation. PMID- 25281032 TI - Biomarkers of endothelial dysfunction in relation to impaired carbohydrate metabolism following pregnancy with gestational diabetes mellitus. AB - BACKGROUND: History of gestational diabetes mellitus (GDM) identifies a very young population of females predisposed for type 2 diabetes and cardiovascular disease. Endothelial dysfunction might represent a shared precursor of both disorders. Hence, this study aimed to characterize endothelial biomarkers in relation to impaired insulin sensitivity and progression to overt diabetes early after index pregnancy. METHODS: 108 women with previous GDM and 40 controls were included three to six months after delivery and underwent specific metabolic assessments including a frequently sampled intravenous glucose tolerance test and an oral glucose tolerance test. Diabetes progression was assessed in females with pGDM over 10 years of follow-up. Circulating sICAM-1 (intracellular-adhesion molecule-1), sVCAM-1 (vascular-cell-adhesion-molecule-1) and sE-selectin, representing biomarkers of endothelial dysfunction were assessed at baseline and annually over five years. RESULTS: Endothelial biomarkers were significantly associated with insulin sensitivity (sICAM-1: r = -0.23, p = 0.009; sVCAM-1: r = 0.22, p = 0.011; sE-selectin: r = -0.21, p = 0.018) as well as with GDM status and parameters of subtle inflammation. Analysis of long-term trajectories revealed constantly elevated sICAM-1 (p = 0.033) and sE-selectin (p = 0.007) in 25 subjects with diabetes progression. Accordingly, sE-selectin levels at the early post partum visit predicted a later development of the disease (HR =1.02 95%CI 1.01 to 1.04, p = 0.013), however, this was attenuated after adjustment for BMI. CONCLUSIONS: Elevated circulating markers of endothelial dysfunction in young females with GDM history might reflect an early stage on the pathway to the manifestation of future cardiometabolic disorders. Timely identification of women at high risk and optimization of follow-up management might provide an opportunity to prevent disease progression. PMID- 25281034 TI - Dural-based Rosai-Dorfman disease: differential diagnostic considerations. AB - Extranodal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a non-neoplastic condition that has rarely been reported to involve the central nervous system. This report documents a 28-year-old man with Rosai Dorfman disease who presented with a seizure and a dural-based mass that was thought to represent a meningioma. Resection showed a lesion marked by large, S 100 protein immunoreactive histiocytic cells with intermixed benign lymphocytes and plasma cells. Emperipolesis with intracytoplasmic lymphocytes and plasma cells was present. Differential diagnostic considerations will be discussed. PMID- 25281033 TI - Treatment-related fatigue with everolimus and temsirolimus in patients with cancer-a meta-analysis of clinical trials. AB - Mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are approved for the treatment of a variety of malignancies. Fatigue has been described with these agents as a common side effect, although the overall incidence and risk remain unclear. We performed a meta-analysis to calculate the overall incidence of fatigue in cancer patients treated with everolimus and temsirolimus and to compare the differences in incidence with placebo. The electronic databases PubMed, Embase, Web of Science, and Cochrane databases were searched for studies to include in the meta-analysis. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with single drug everolimus or temsirolimus with toxicity data on fatigue. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included studies. A total of 9,760 patients with a variety of malignancies from 56 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade fatigue in cancer patients treated with mTOR inhibitor (everolimus or temsirolimus) were 45.4% (95% CI 36.9-55.8%) and 8.7% (95% CI 7.2-10.4%), respectively. The relative risks of fatigue of mTOR inhibitor compared to placebo were increased for all-grade (RR = 1.22, 95% CI 1.08-1.38, P = 0.002) and high-grade (RR = 1.82, 95% CI 1.24-2.69, P = 0.002) fatigue. The incidence of all-grade fatigue of patients treated with everolimus was higher than those with temsirolimus (RR = 1.85, 95% CI 1.71-2.01, P < 0.001). No significant difference was detected with between everolimus and temsirolimus in terms of high-grade fatigue (RR = 1.15, 95% CI 0.94-1.41, P = 0.18). Treatment with mTOR inhibitor, everolimus and temsirolimus, is associated with an increased incidence of fatigue in patients with cancer. Early detection and management of fatigue is needed. PMID- 25281035 TI - Digital photography improves estimates of dietary intake in adolescents with intellectual and developmental disabilities. AB - BACKGROUND: Dietary assessment of adolescents with intellectual and developmental disabilities (IDD) is challenging due to the limited cognitive abilities of this population. OBJECTIVE: The purpose of this study was to determine the feasibility of using of digital images to improve the estimates of energy and macronutrient intake from proxy-assisted 3-day food records in adolescents with IDD. METHOD: Participants used a mobile device to take photos of all food and beverages consumed over a three-day period and simultaneously completed a standard parent assisted 3-day food record at two separate time points. A registered dietitian reviewed and recorded the differences between the standard record and the images. The proxy-assisted records and the photo-assisted records were analyzed separately. RESULTS: One hundred and thirty eating occasions were entered (20 participants (age = 14.9 +/- 2.2 yrs, 45.0% female)). Photo-assisted records captured significantly higher estimates of energy intake per eating occasion than regular proxy-assisted records (P = 0.001) as well as significantly greater grams of fat (P = 0.011), carbohydrates (P = 0.003), and protein (P = 0.004). CONCLUSION: The use of photo-assisted diet records appears to be a feasible method to obtain substantial additional details about dietary intake that consequently may improve the overall estimates of energy and macronutrient intake when using proxy-assisted diet records in adolescents with IDD. PMID- 25281036 TI - Medicaid managed care: issues for beneficiaries with disabilities. AB - BACKGROUND: States are increasingly turning to managed care arrangements to control costs in their Medicaid programs. Historically, such arrangements have excluded people with disabilities who use long-term services and supports (LTSS) due to their complex needs. Now, however, some states are also moving this population to managed care. Little is known about the experiences of people with disabilities during and after this transition. OBJECTIVE: To document experiences of Medicaid enrollees with disabilities using long-term services and supports during transition to Medicaid managed care in Kansas. METHODS: During the spring of 2013, 105 Kansans with disabilities using Medicaid long-term services and supports (LTSS) were surveyed via telephone or in-person as they transitioned to managed care. Qualitative data analysis of survey responses was conducted to learn more about the issues encountered by people with disabilities under Medicaid managed care. RESULTS: Respondents encountered numerous disability related difficulties, particularly with transportation, durable medical equipment, care coordination, communication, increased out of pocket costs, and access to care. CONCLUSIONS: As more states move people with disabilities to Medicaid managed care, it is critically important to address these identified issues for a population that often experiences substantial health disparities and a smaller margin of health. It is hoped that the early experiences reported here can inform policy-makers in other states as they contemplate and design similar programs. PMID- 25281038 TI - Hemodynamic transesophageal echocardiography in left ventricular assist device care: a complementary technology. PMID- 25281037 TI - Imported pediatric malaria at the Hospital for Sick Children, Toronto, Canada: a 16 year review. AB - BACKGROUND: Children under 5 represent 86% of annual malaria deaths in the world. Following increasing trends in international travel, cases of imported malaria are rising in North America. We describe the epidemiology of malaria diagnosed at a tertiary care pediatric center in the multicultural city of Toronto. METHOD: Retrospective chart review of all laboratory confirmed malaria from birth to <18 years between July 1, 1997 and June 30, 2013. Epidemiological data, travel history, chemoprophylaxis history, as well as clinical presentation, diagnosis and treatment were extracted. RESULTS: In total 107 children were diagnosed with malaria in the 16 year time period. Plasmodium falciparum malaria was identified in 76 (71%), Plasmodium vivax in 28 (26%). Median age of infected children was 6.7 years where 35% of children were born in Canada, 63% were recent or previous immigrants. Of those who resided in Canada, reason for travel included visiting friends or relatives (VFR) 95% and tourism or education (5%). Most common countries of infection were Ghana (22%), Nigeria (20%) and India (14%). Median parasitemia at presentation to our institution was 0.4% (IQR 0.1-2.3) with a maximum parasitemia of 31%. Nineteen (18%) met the WHO criteria for severe malaria due to hyperparasitemia, with 3 of these cases also meeting clinical criteria for severe malaria. One third of patients had a delay in treatment of 2 or more days. Ten percent of children had seen two or more primary health care professionals prior to admission. Prophylaxis was documented in 22 (21%), and out of those, 6 (27%) were appropriate for the region of travel and only 1 case was documented as adherent to their prescription. There were no cases of fatality. CONCLUSION: Malaria continues to be a significant disease in returning travelers and immigrant or refugee populations. An increase in physician awareness is required. Appropriate pre-travel advice, insect protection measures, effective chemoprophylaxis is needed to reduce the incidence and improve the management of imported pediatric malaria. PMID- 25281039 TI - Impact of intraoperative transesophageal echocardiography on acute type-A aortic dissection. AB - OBJECTIVE: To evaluate the impact of intraoperative transesophageal echocardiography on type-A acute aortic dissection. DESIGN: Retrospective observational study. SETTING: Tertiary care hospital. PARTICIPANTS: Sixty-four consecutive patients with type-A aortic dissection. INTERVENTIONS: Surgeons interviewed regarding how transesophageal echocardiography changed the surgical procedure. MEASUREMENTS AND MAIN RESULTS: Transesophageal echocardiography confirmed an ascending aorta intimal flap in 53 (83%) patients and an intramural hematoma in 9 (14%) patients. The aortic valve was bicuspid in 5 (8%) cases and a prior prosthetic valve was present in 4 (6%) patients. Aortic insufficiency was moderate in 12 (19%) cases and severe in 18 (28%) patients. Additionally, transesophageal echocardiography was useful in defining the size of pericardial effusion in 18 (28%) patients, 8 with large effusions and/or tamponade. Altogether, transesophageal echocardiography added data beyond prior imaging in 41 (64%) patients, including moderate or severe mitral regurgitation, right ventricular dysfunction, and atrial septal defects. The findings from intraoperative transesophageal echocardiography led directly to a change in planned surgery in 25 (39%) patients. Transesophageal echocardiography verified suitability of the repair in all cases of interposition graft or valve repair. CONCLUSIONS: Intraoperative transesophageal echocardiography provides incremental information to the original imaging examination in the management of type-A acute aortic dissection in nearly two-thirds of patients, leading to a change in the planned surgery in 39% of patients, thus supporting its role as suggested in recent guidelines. PMID- 25281040 TI - Factor VIII inhibitor bypass activity and recombinant activated factor VII in cardiac surgery. AB - OBJECTIVE: Postcardiopulmonary bypass hemorrhage remains a serious complication of cardiac surgery. Given concerns regarding adverse effects of blood product transfusion and limited efficacy of current antifibrinolytics, procoagulant medications, including recombinant factor VIIa (rFVIIa) and factor eight inhibitor bypass activity (FEIBA), increasingly have been used in managing refractory bleeding. While effective, these medications are associated with thromboembolic complications. This study compared the efficacy and risk of adverse events of rFVIIa and FEIBA in cardiac surgical patients with refractory bleeding. DESIGN: This retrospective study evaluated 168 patients who underwent cardiac surgery and received either FEIBA or rFVIIa to manage postbypass hemorrhage. Demographic, clinical, and outcomes data were collected and statistical analysis performed to compare thromboembolic event rates, relative efficacy, and 30-day mortality following administration of these medications. SETTING: Single university hospital. PARTICIPANTS: Patients undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULT: Sixty-one patients received rFVIIa, and 107 received FEIBA. Demographics, surgical procedures, and preoperative anticoagulation were similar between the cohorts; however, the rFVIIa cohort had longer durations of cardiopulmonary bypass (305.1 v 243.8 min, p<0.01). There were no significant differences in the number of thromboembolic events, 30-day mortality, or rates of revision surgery. Neither group demonstrated a clear relationship between dosage and occurrence of thromboembolic events. The rFVIIa cohort received more platelets than the FEIBA cohort (3.13 v 1.67 units, p = 0.01), but transfusion rates of other blood products were similar. CONCLUSIONS: This study suggests that rFVIIa and FEIBA have similar efficacy and adverse event profiles in managing intractable postbypass hemorrhage in cardiac surgical patients. Further prospective studies are required. PMID- 25281041 TI - Protamine requirements in cardiac surgery: effect of changes in the heparin reference standard. AB - OBJECTIVE: UFH (unfractionated heparin) and protamine are integral to cardiac surgery, and inappropriate dosing can predispose to coagulopathy and hemorrhage. The FDA (Food and Drug Administration) recently has instituted changes to UFH formulation and it is not known if this has influenced its susceptibility to neutralization by protamine. Hence, the authors sought to compare 2 commercial preparations of UFH (old and new) with regard to their neutralization by protamine in patients undergoing cardiopulmonary bypass (CPB). DESIGN: Prospective, observational, cohort study. SETTING: Tertiary care university hospital and associated research laboratory PARTICIPANTS: Twenty adult patients undergoing elective cardiac surgery with CPB. INTERVENTIONS: Blood samples were drawn preinduction, prior to, and 5 and 30 minutes following protamine, and 0 and 2 hours after ICU admission. Protamine titration assays were conducted in vitro on samples drawn prior to and following protamine administration. Anti-IIa and anti-Xa activity were assayed in all samples. RESULTS: Anti-IIa and anti-Xa activity were detected ubiquitously at all time points following CPB, and there were no differences in susceptibility to protamine neutralization between the 2 groups. In vitro protamine titration studies revealed that anti-IIa was more resistant to protamine neutralization compared to anti-Xa activity. CONCLUSIONS: The 'old' and 'new' formulations of UFH evaluated in this study were similar in their susceptibility to protamine neutralization. Circulating UFH is detected as early as 5 minutes after protamine administration and anti-IIa is more resistant to protamine neutralization as compared to anti-Xa activity. Further studies are required to quantify the precise dose of protamine following CPB. PMID- 25281042 TI - Levosimendan increases bleeding risk after heart valve surgery: a retrospective analysis of a randomized trial. AB - OBJECTIVE: To investigate whether levosimendan, an inotrope with cardioprotective properties, increases postoperative bleeding after cardiac surgery. DESIGN: Retrospective analysis of a randomized, prospective clinical study. SETTING: Post anesthesia care unit (PACU) and surgical ward in a university hospital. PARTICIPANTS: Two hundred heart valve surgery patients. INTERVENTIONS: The patients were randomized to receive either a 24-hour intravenous infusion of levosimendan or placebo. Infusion was administered as a 24 ug/kg bolus over 30 minutes and then continued at a dose of 0.2 ug/kg/min. MEASUREMENTS AND MAIN RESULTS: Postoperative bleeding was approximately 31% greater in the levosimendan group (1050 mL) compared to the placebo group (880 mL, p = 0.008). Serious bleeding exceeding 1000 mL was more common in the levosimendan group than the placebo group (51 v 38 patients, p = 0.044, risk ratio (RR) 1.37, 95% CI 1.00 1.87). However, the risk of reoperation for bleeding did not increase if patients received levosimendan (RR 1.52, 95% CI 0.77-2.97, p = 0.309). This result did not change after excluding patients who received clopidogrel preoperatively (RR 2.13, 95% CI 0.98-4.65, p = 0.145). The groups did not differ regarding transfused blood products. Eight patients, including seven from the levosimendan group, had delayed (diagnosed>48 hours after the surgery) cardiac tamponade and underwent re exploration (7 v 1, p = 0.031). CONCLUSIONS: Levosimendan increased the risk of postoperative bleeding after cardiac valve surgery. In addition, the risk of postoperative cardiac tamponade was increased in patients who received levosimendan compared to placebo. PMID- 25281043 TI - Glasgow Coma Scale for outcome prediction after cardiac surgery: is it applicable? AB - OBJECTIVES: The Glasgow Coma Scale (GCS) is used commonly for assessing patients' neurologic condition and outcome in intensive care units (ICUs); however, its reliability in cardiac surgical patients has been questioned. It has been claimed that active sedation is the cause of its unsuitability for these patients. This study aimed to compare the accuracy of GCS in cardiac surgical patients with and without active sedation to find out if the inapplicability of GCS in surgical patients is related to active sedation. DESIGN: This was an observational cohort study. SETTING: The study was conducted in a cardiac surgical intensive care unit between January 1, 2007 and December 31, 2009. PARTICIPANTS: All consecutive adult cardiac surgical patients were included in this study. INTERVENTIONS: All types of cardiac surgical procedures performed during the study period were included without any exceptions. The study population was divided into 2 groups: sedated and non-sedated. MEASUREMENTS AND MAIN RESULTS: GCS was calculated daily for the first 7 postoperative days. The authors developed a new 4-point neurologic descriptor (ND): (1) neurologically free, (2) ICU psychosis, (3) actively sedated, and (4) documented focal neurologic deficits. The accuracy of both scales (GCS and ND) at predicting ICU mortality was compared by replacing the GCS in the Sequential Organ Failure Assessment (SOFA) score with the new ND, producing a modified SOFA. GCS was not an accurate outcome predictor in non sedated or sedated patients. The ND was superior to GCS. Correspondingly, the modified SOFA showed a significantly higher accuracy of ICU-mortality prediction than the original SOFA. CONCLUSIONS: Regardless of active sedation, GCS is not accurate at outcome prediction for cardiac surgical patients. The suggested ND is a simple and more accurate risk stratification variable in cardiac surgical ICUs. PMID- 25281044 TI - Perioperative glycemic control with a computerized algorithm versus conventional glycemic control in cardiac surgical patients undergoing cardiopulmonary bypass with blood cardioplegia. AB - OBJECTIVE: In critical illness, hypoglycemia and hyperglycemia seem to influence outcome. While hypoglycemia can lead to organ dysfunction, hyperglycemia can lead to surgical site infections (SSI). In cardiac surgery, the use of blood cardioplegia is associated with high blood glucose levels. A computer-based algorithm (CBA) for guiding insulin towards normoglycemia might be beneficial. The authors' primary study end-point was the duration in a predefined blood glucose target range of 80 mg/dL to 150 mg/dL. Patients with conventional therapy served as controls. DESIGN: Prospective, randomized trial. SETTING: University hospital. PARTICIPANTS: Seventy-five patients. INTERVENTIONS: The start of therapy was the beginning of cardiopulmonary bypass. Group A: Therapy with CBA and measurement of blood glucose every 30 minutes. Group B: Measurement of blood glucose every 15 minutes using the identical CBA. Group C: Conventional therapy using a fixed insulin dosing scheme. End of therapy was defined as discharge from ICU. MEASUREMENT AND MAIN RESULTS: Glucose administration during cardioplegia did not differ between groups (A: 33 +/- 12 g; B: 32 +/- 12 g; C: 38 +/- 20 g). Glucose levels in groups A and B stayed significantly longer in the target interval compared with group C (A: 75 +/- 20%; B: 72 +/- 19%; C: 50 +/- 34%, p < 0.01 n = 25, respectively). There were no significant differences regarding ICU stay and SSI rates. CONCLUSIONS: Early computer-based insulin therapy allows practitioners to better achieve normoglycemia in patients undergoing major cardiac surgery with the use of blood cardioplegia. PMID- 25281045 TI - Remote ischemic preconditioning does not affect the incidence of acute kidney injury after elective abdominal aortic aneurysm repair. AB - OBJECTIVE: Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair. DESIGN: Prospective, randomized double-blinded control trial. SETTING: Tertiary referral hospital. PARTICIPANTS: Sixty-two patients undergoing elective open AAA repair. INTERVENTION: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). MEASUREMENTS: Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase associated lipocalin (NGAL), occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC. CONCLUSION: RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors' results do not support the introduction of this technique to routine clinical practice. PMID- 25281047 TI - Improving the quality and safety of patient care in cardiac anesthesia. PMID- 25281048 TI - Postoperative delirium: risk factors, prevention, and treatment. PMID- 25281049 TI - Simulation of cardiopulmonary bypass management: an approach to resident training. PMID- 25281046 TI - Early removal of urinary catheter after surgery requiring thoracic epidural: a prospective trial. AB - OBJECTIVES: To prevent urinary retention, urinary catheters commonly are removed only after thoracic epidural discontinuation after thoracotomy. However, prolonged catheterization increases the risk of infection. The purpose of this study was to determine the rates of urinary retention and catheter-associated infection after early catheter removal. DESIGN: This study described a prospective trial instituting an early urinary catheter removal protocol compared with a historic control group of patients. SETTING: The protocol was instituted at a single, academic thoracic surgery unit. PARTICIPANTS: The study group was comprised of patients undergoing surgery requiring thoracotomy who received an intraoperative epidural for postoperative pain control. INTERVENTIONS: An early urinary catheter removal protocol was instituted prospectively, with all catheters removed on or before postoperative day 2. Urinary retention was determined by bladder ultrasound and treated with recatheterization. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were urinary retention rate, defined as bladder volume>400 mL, and urinary tract infection rate. Results were compared with a retrospective cohort of 210 consecutive patients who underwent surgery before protocol initiation. Among the 101 prospectively enrolled patients, urinary retention rate was higher (26.7% v 12.4%, p = 0.003), while urinary tract infection rate improved moderately (1% v 3.8%, p = 0.280). CONCLUSIONS: Early removal of urinary catheters with thoracic epidurals in place is associated with a high incidence of urinary retention. However, an early catheter removal protocol may play a role in a multifaceted approach to reducing the incidence of catheter-associated urinary tract infections. PMID- 25281050 TI - Three-dimensional printing of the mitral annulus using echocardiographic data: science fiction or in the operating room next door? PMID- 25281051 TI - Pro: Simulation training in transesophageal echocardiography. PMID- 25281052 TI - Con: Simulation training in transesophageal echocardiography. PMID- 25281053 TI - Use of multimodal imaging in the management of tumor embolism from the inferior vena cava through the right heart in a patient with renal cell carcinoma. PMID- 25281054 TI - Caval thrombosis: imaging and managing a moving target. PMID- 25281055 TI - "Nothing's gonna change my world": Why? PMID- 25281056 TI - Pre-hospital/emergency department handover in Italy. AB - In Italy, emergency department (ED) triage is a complex and delicate interface in which different emergency healthcare providers interact: physicians, nurses, and pre-hospital rescuers. There are significant differences in the communication, training, and abilities of these providers. Communication failures during the pre hospital/hospital interface have been identified as a major preventable cause of patient harm. We previously evaluated handover in simulated scenarios, and developed specialized handover training for pre-hospital emergency rescuers. The purpose of this study is to evaluate communication during the clinical handover between pre-hospital to ED staff, using realistic scenarios. A nurse, trained through high-fidelity simulation handover scenarios, used our adapted ISBAR tool to evaluate inter-professional communication at triage. We evaluated and statistically analyzed 240 handovers performed by pre-hospital rescuers over nine observing shifts. On the whole, the data analysis highlights a lack of communication standards, a lack of formal transfer of responsibility of patient care, and a marked inconsistency in information communicated by every professional group examined. Only those rescuers who were previously trained in handover performed 100% of the ISBAR tool items. The information most often communicated was the reason for the call, (85%) and the information least often communicated was the complete ABCDE patient survey (1%). Currently, ED personnel receive poor verbal information from pre-hospital providers. The general habit of pre-hospital providers is to give different written reports to the triage nurses without a true shared transfer of responsibility. This lack of standardization in communication presumably has an adverse impact upon patient care. PMID- 25281057 TI - Targeting CHK1 inhibits cell proliferation in FLT3-ITD positive acute myeloid leukemia. AB - CHK1 Ser/Thr kinase, a well characterized regulator of DNA damage response, is also involved in normal cell cycle progression. In this study, we investigate how CHK1 participates to proliferation of acute myeloid leukemia cells expressing the mutated FLT3-ITD tyrosine kinase receptor. Pharmacological inhibition of CHK1 as well as its shRNA mediated down regulation reduced the proliferation rate of FLT ITD expressing leukemic cell lines in a cytostatic manner. Flow cytometry analysis revealed no accumulation in a specific phase of the cell cycle upon CHK1 inhibition. Accordingly, lentiviral-mediated CHK1 overexpression increased the proliferation rate of FLT3-ITD expressing cells, as judged by cell viability and [3H] thymidine incorporation experiments. By contrast, expression of a ser280 mutant did not, suggesting that phosphorylation of this residue is an important determinant of CHK1 proliferative function. Clonogenic growth of primary leukemic cells from patients in semi-solid medium was reduced upon CHK1 inhibition, confirming the data obtained with leukemic established cell lines. Surprisingly, 3 out of 4 CHK1 inhibitory compounds tested in this study were also potent inhibitors of the FLT3-ITD tyrosine kinase receptor. Altogether, these data identify CHK1 as a regulator of FLT3-ITD-positive leukemic cells proliferation, and they open interesting perspectives in terms of new therapeutic strategies for these pathologies. PMID- 25281058 TI - Acute postoperative seizures and long-term seizure outcome after surgery for hippocampal sclerosis. AB - PURPOSE: To assess the incidence and the prognostic value of acute postoperative seizures (APOS) in patients surgically treated for drug-resistant temporal lobe epilepsy due to hippocampal sclerosis (TLE-HS). METHODS: We studied 139 consecutive patients with TLE-HS who underwent epilepsy surgery and were followed up for at least 5 years (mean duration of follow-up 9.1 years, range 5-15). Medical charts were reviewed to identify APOS, defined as ictal events with the exception of auras occurring within the first 7 days after surgery. Seizure outcome was determined at annual intervals. Patients who were in Engel Class Ia at the last contact were classified as having a favorable outcome. RESULTS: Seizure outcome was favorable in 99 patients (71%). Six patients (4%) experienced APOS and in all cases their clinical manifestations were similar to the habitual preoperative seizures. All patients with APOS had unfavorable long-term outcome, as compared with 35 (26%) of 133 in whom APOS did not occur (p<0.001). CONCLUSIONS: Our study suggests that APOS, despite being relatively uncommon in patients undergoing resective surgery for TLE-HS, are associated with a worse long-term seizure outcome. Given some study limitations, our findings should be regarded as preliminary and need confirmation from future larger, prospective, multicenter studies. PMID- 25281059 TI - Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7 H1 interactions. AB - Mesenchymal stem cells (MSCs) exert a suppressive role toward T cells which has been widely studied in recent decades. However, the underlying mechanisms utilized by MSCs are still not fully elucidated. Herein, we performed traditional suppressive assays using co-cultured MSCs and conventional CD4(+)CD25(-) T cells (Tconv) with and without transwell systems. We showed that the expression of programmed cell death-1 receptor (PD-1) on activated Tconv was significantly elevated after they were exposed to MSCs. And we demonstrated that PD-1/B7-H1 pathway was involved in the suppression of MSCs on activated Tconv. Further analysis revealed that the up-regulation of PD-1 was related to an increasing apoptosis of activated Tconv. Finally, we demonstrated that the PD-1/B7-H1 pathway was not related to the elevated immunosuppressive cytokines including IL 10 and TGF-beta1 which in turn played dispensable roles in the up-regulation of PD-1 on activated Tconv in MSC-Tconv co-culture systems. PMID- 25281060 TI - Comment on "A spectroscopic comparison of selected Chinese kaolinite, coal bearing kaolinite and halloysite--a mid-infrared and near-infrared study" and "Infrared and infrared emission spectroscopic study of typical Chinese kaolinite and halloysite" by Hongfei Cheng et al. (2010). AB - In two papers Cheng et al. (2010) reported in this journal on the mid-infrared, near-infrared and infrared emission spectroscopy of a halloysite from Hunan Xianrenwan, China. This halloysite contains around 8% of quartz (SiO2) and nearly 9% gibbsite (Al(OH)3). In their interpretation of the spectra these impurities were completely ignored. Careful comparison with a phase pure halloysite from Southern Belgium, synthetic gibbsite, gibbsite from Minas Gerais, and quartz show that these impurities do have a marked influence on the mid-infrared and infrared emission spectra. In the near-infrared, the effect is much less pronounced. Quartz does not show bands in this region and the gibbsite bands will be very weak. Comparison still show that the presence of gibbsite does contribute to the overall spectrum and bands that were ascribed to the halloysite alone do coincide with those of gibbsite. PMID- 25281061 TI - Maintenance interventions for overweight or obese children and adolescents who participated in a treatment program: study protocol for a systematic review. AB - BACKGROUND: Childhood overweight and obesity are associated with significant health consequences. Early and successful treatment of this public health issue is necessary. Although several intervention programs for children result in weight loss or stabilisation in the short term, preventing relapse after weight loss remains an important challenge. Weight loss maintenance approaches in childhood are thought to be promising, but a structured overview of these maintenance interventions is lacking. The aim of the systematic review described in this protocol is to provide an overview of reports published about maintenance interventions in childhood overweight and obesity following initial treatment, in order to guide future directions in the development of maintenance programs for childhood obesity. METHODS/DESIGN: The electronic databases PubMed, Embase, Cochrane Library, CINAHL, Web of Science, PsycINFO, Scopus, and SocINDEX will be searched for this review. Reference lists of eligible study reports will be scanned for relevant references. Article selection including risk of bias assessment will be performed independently in an unblinded standardised manner by three authors. All reports describing a maintenance intervention in overweight or obese children with a mean or median age of <18 years who have followed a treatment program, regardless of the type of intervention, will be included. Data extraction will be performed using a predesigned pilot-tested data extraction sheet that covers participant characteristics, details about the treatment preceding the maintenance intervention, and the maintenance intervention itself. Body mass index standard deviation score (BMI-SDS or BMI-Z-score) will be used to compare studies. If possible, a meta-analysis will be performed using the inverse variance random-effects method. Studies that are not included in the meta analysis will be described in a narrative way in tables and/or in the text. DISCUSSION: This systematic review will give an overview of the existing knowledge on programs and initiatives aimed at long-term maintenance of a healthy or reduced weight in children and adolescents following initial treatment of overweight. It will form a basis for future research and practice in this area, a topic on which studies are scarce but highly necessary. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014008698. PMID- 25281062 TI - Complete resolution of avascular necrosis of the human femoral head treated with adipose tissue-derived stem cells and platelet-rich plasma. AB - We report a case of a 43-year-old man with early stage (stage 1) avascular necrosis (AVN) of the femoral head treated with adipose tissue-derived stem cells (ASCs) and platelet-rich plasma (PRP). ASC-containing stromal vascular fraction was mixed with PRP and hyaluronic acid. This mixture was then injected into the diseased hip under ultrasound guidance. The affected hip was reinjected weekly with additional PRP for 4 weeks. The patient was followed-up with sequential magnetic resonance imaging (MRI) scans at 3, 18, and 21 months after treatment, together with Visual Analogue Scale (VAS) Walking Index, Functional Rating Index, Harris Hip Score, and Range of Motion (ROM) assessments. The patient's severe hip pain was considerably improved at 3 months after treatment, with pain scores, ROM and MRI showing near complete resolution of AVN. Pain scores, ROM and MRI at 18 and 21 months after treatment indicated complete resolution of AVN. This case represents the first evidence of complete resolution of early stage AVN of the hip following treatment with ASCs/PRP. PMID- 25281063 TI - Interleukin-10 gene -1082 G/A polymorphism in cervical cancer and cervical intraepithelial neoplasia: meta-analysis. AB - OBJECTIVES: To assess the association between polymorphism in the interleukin (IL)-10 promoter region of 1082 G/A and the risk of cervical cancer and/or cervical intraepithelial neoplasia (CIN), using meta-analysis. METHODS: The electronic literature databases PubMed(r), Embase(r), Web of Science, CBMdisc and CNKI were searched for relevant studies. The strength of association between IL 10 gene -1082 G/A polymorphism and cervical cancer and/or CIN was measured using pooled odds ratios with 95% confidence intervals in four genetic models: allelic model (A allele versus G allele); additive model (A/A versus G/G); recessive model (A/A versus G/A+G/G); dominant model (A/A+G/A versus G/G). RESULTS: Eight studies involving 1983 cases and 1618 controls were identified and included in the meta-analysis. No significant associations were found between IL-10 gene 1082 G/A polymorphism and cervical cancer and/or CIN in any of the genetic models. CONCLUSIONS: IL-10 gene -1082 G/A polymorphism does not appear to be associated with the risk of cervical cancer and/or CIN. PMID- 25281064 TI - Better health outcomes at lower costs: the benefits of primary care utilisation for chronic disease management in remote Indigenous communities in Australia's Northern Territory. AB - BACKGROUND: Indigenous residents living in remote communities in Australia's Northern Territory experience higher rates of preventable chronic disease and have poorer access to appropriate health services compared to other Australians. This study compared health outcomes and costs at different levels of primary care utilisation to determine if primary care represents an efficient use of resources for Indigenous patients with common chronic diseases namely hypertension, diabetes, ischaemic heart disease, chronic obstructive pulmonary disease and renal disease. METHODS: This was an historical cohort study involving a total of 14,184 Indigenous residents, aged 15 years and over, who lived in remote communities and used a remote clinic or public hospital from 2002 to 2011. Individual level demographic and clinical data were drawn from primary care and hospital care information systems using a unique patient identifier. A propensity score was used to improve comparability between high, medium and low primary care utilisation groups. Incremental cost-effectiveness ratios and acceptability curves were used to analyse four health outcome measures: total and, avoidable hospital admissions, deaths and years of life lost. RESULTS: Compared to the low utilisation group, medium and high levels of primary care utilisation were associated with decreases in total and avoidable hospitalisations, deaths and years of life lost. Higher levels of primary care utilisation for renal disease reduced avoidable hospitalisations by 82-85%, deaths 72-75%, and years of life lost 78-81%. For patients with ischaemic heart disease, the reduction in avoidable hospitalisations was 63-78%, deaths 63-66% and years of life lost 69 73%. In terms of cost-effectiveness, primary care for renal disease and diabetes ranked as more cost-effective, followed by hypertension and ischaemic heart disease. Primary care for chronic obstructive pulmonary disease was the least cost-effective of the five conditions. CONCLUSION: Primary care in remote Indigenous communities was shown to be associated with cost-savings to public hospitals and health benefits to individual patients. Investing $1 in primary care in remote Indigenous communities could save $3.95-$11.75 in hospital costs, in addition to health benefits for individual patients. These findings may have wider applicability in strengthening primary care in the face of high chronic disease prevalence globally. PMID- 25281065 TI - Analysis of pesticide and veterinary drug residues in baby food by liquid chromatography coupled to Orbitrap high resolution mass spectrometry. AB - Pesticide and veterinary drug residues have been simultaneously determined in several baby foods as meat, fish and vegetable-based baby food. A generic extraction method without clean-up step was applied. Moreover, the use of a representative matrix for proper quantification of all target compounds was studied and the best results were obtained when vegetable-based baby food was used as representative matrix, allowing the reliable quantification of more than 300 compounds. The method was validated and good recoveries were obtained for most of compounds at concentrations higher than 50 ug kg(-1). Limits of detection (LOD) ranged from 0.5 to 50 ug kg(-1), whereas limits of quantification (LOQ) were established between 10 and 100 ug kg(-1). Limits of identification (LOIs) ranged from 0.5 to 50 ug kg(-1). This method was applied to the analysis of 46 different baby food samples and no positive samples were found. PMID- 25281066 TI - Detection of trace microcystin-LR on a 20 MHz QCM sensor coated with in situ self assembled MIPs. AB - A 20 MHz quartz crystal microbalance (QCM) sensor coated with in situ self assembled molecularly imprinted polymers (MIPs) was presented for the detection of trace microcystin-LR (MC-LR) in drinking water. The sensor performance obtained using the in situ self-assembled MIPs was compared with traditionally synthesized MIPs on 20 MHz and normal 10 MHz QCM chip. The results show that the response increases by more than 60% when using the in situ self-assembly method compared using the traditionally method while the 20 MHz QCM chip provides four fold higher response than the 10 MHz one. Therefore, the in situ self-assembled MIPs coated on a high frequency QCM chip was used in the sensor performance test to detect MC-LR in tap water. It showed a limit of detection (LOD) of 0.04 nM which is lower than the safety guideline level (1 nM MC-LR) of drinking water in China. The low sensor response to other analogs indicated the high specificity of the sensor to MC-LR. The sensor showed high stability and low signal variation less than 2.58% after regeneration. The lake water sample analysis shows the sensor is possible for practical use. The combination of the higher frequency QCM with the in situ self-assembled MIPs provides a good candidate for the detection of other small molecules. PMID- 25281067 TI - Quantitative evaluation by attenuated total reflectance infrared (ATR-FTIR) spectroscopy of the chemical composition of decayed wood preserved in waterlogged conditions. AB - This paper reports on the assessment of lignin and holocellulose by means of ATR FTIR analysis and multivariate PLS regression. The analysis was conducted on 59 samples coming from different excavations where wood had been preserved in waterlogged conditions. A range of results from different wood species (Alnus sp.p., Cupressus sempervirens, Larix decidua, Picea abies, Pinus sp.p., Quercus sp.p., Ulmus sp.p.), states of preservation, waterlogged environments, and burial times are presented. A calibration model was selected after comparing different reference data (samples extracted and not-extracted, and ash-rich and ash-free bases of calculation for the calibration values), and two different post acquisition spectroscopic manipulations (both in terms of normalisation procedures and of spectral ranges used for the calibration). Results showed that the best models were different depending on which considered component (lignin or holocellulose) was measured and to which data set (softwood or hardwood) the samples belonged. It is shown that the predictive ability of the models is affected by high ash content (too contaminated samples had to be excluded in order to attain good results, because of excessive overlapping of bands related to the inorganic fraction) but not by the preliminary extraction of sample. Furthermore, the stability of best models is also demonstrated and a procedure of external validation carried out on an external set of samples confirmed the general validity of the identified models. PMID- 25281068 TI - An air carrier flow system for the spectrophotometric determination of water in biodiesel exploiting bleaching of the cobalt chloride complex. AB - Water content is an important parameter in biodiesel quality control, as excess of this substance may lead to biofuel hydrolysis, microorganism proliferation, and alterations in the oxidative stability of the biofuel. The threshold limit is established as 200 mg kg(-1) and the determination is usually based on Karl Fischer titration. In this work, a simple, reliable and environmentally friendly procedure is proposed for water determination in biodiesel by exploiting a multicommuted flow system with air carrier stream. The method relies on the color fading of the cobalt chlorocomplex in the presence of the analyte, which is monitored by spectrophotometry. A linear response was observed from 100 to 5000 mg kg(-1) water, with detection limit, coefficient of variation (n=20) and sampling rate estimated as 25 mg kg(-1), 0.7% and 30 h(-1), respectively. The procedure consumes only 3.5 ug of CoCl2 and generates 750 uL of waste per determination. Results obtained by using the standard additions method agreed with those attained by the Karl Fischer titration at the 95% confidence level. PMID- 25281069 TI - Combination of electrochemistry with chemometrics to introduce an efficient analytical method for simultaneous quantification of five opium alkaloids in complex matrices. AB - For the first time, an analytical methodology based on differential pulse voltammetry (DPV) at a glassy carbon electrode (GCE) and integration of three efficient strategies including variable selection based on ant colony optimization (ACO), mathematical pre-processing selection by genetic algorithm (GA), and sample selection (SS) through a distance-based procedure to improve partial least squares-1 (PLS-1, ACO-GA-SS-PLS-1) multivariate calibration (MVC) for the simultaneous determination of five opium alkaloids including morphine (MOP), noscapine (NOP), thebaine (TEB), codeine (COD), and papaverine (PAP) was used and validated. The baselines of the DPV signals were modeled as a smooth curve, using P-splines, a combination of B-splines and a discrete roughness penalty. After subtraction of the baseline we got a signal with a two-component probability density. One component was for the peaks and it was approximated by a uniform distribution on the potential axis. The other component was for the observed noise around the baseline. Some sources of bi-linearity deviation for electrochemical data were discussed and analyzed. The lack of bi-linearity was tackled by potential shift correction using correlation optimized warping (COW) algorithm. The MVC model was developed as a quinternary calibration model in a blank human serum sample (drug-free) provided by a healthy volunteer to regard the presence of a strong matrix effect which may be caused by the possible interferents present in the serum, and it was validated and tested with two independent sets of analytes mixtures in the blank and actual human serum samples, respectively. Fortunately, the proposed methodology was successful in simultaneous determination of MOP, NOP, TEB, COD, and PAP in both blank and actual human serum samples and its results were satisfactory comparable to those obtained by applying the reference method based on high performance liquid chromatography-ultraviolet detection (HPLC-UV). PMID- 25281070 TI - Degradation of phenolic compounds by laccase immobilized on carbon nanomaterials: diffusional limitation investigation. AB - Carbon nanoparticles are promising candidates for enzyme immobilization. We investigated enzyme loading and laccase activity on various carbon nanoparticles, fullerene (C60), multi-walled carbon nanotubes (MWNTs), oxidized-MWNTs (O-MWNTs), and graphene oxide (GO). The loading capacity was highest for O-MWNTs and lowest for C60. The activity of laccase on various nanomatrices using 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTs) as a substrate decreased in the following order: GO>MWNTs>O-MWNTs>C60. We speculated that aggregation of the nanoparticles influenced enzyme loading and activity by reducing the available adsorption space and substrate accessibility. The nanoparticle-immobilized laccase was then used for removal of bisphenol and catechol substrates. Compared to free laccase, the immobilized enzymes had significantly reduced reaction rates. For example, the reaction rate of GO-laccase conjugated with bisphenol or catechol substrates was only 10.28% or 12.33%, respectively, of that of the free enzyme. Considering that there was no obvious structural change observed after enzyme immobilization, nanomatrix-induced diffusional limitation most likely caused the low reaction rates. These results demonstrate that the diffusional limitation induced by the aggregation of carbon nanoparticles cannot be ignored because it can lead to increased reaction times, low efficiency, and high economic costs. Furthermore, this problem is exacerbated when low concentrations of environmental contaminants are used. PMID- 25281071 TI - Determination of acrylamide and glycidamide in various biological matrices by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. AB - Acrylamide (AA) is a heat-generated food toxicant formed when starchy foods are fried or baked. This study describes a simple and sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous quantification of AA and its active metabolite, glycidamide (GA) in rat plasma, urine, and 14 different tissues. The assay utilized a simple method of protein precipitation and achieved a lower limit of quantification of 5, 10 and 25 ng/mL of AA and 10, 20 and 100 ng/mL of GA for plasma, tissues and urine, respectively. The assay was fully validated to demonstrate the linearity, sensitivity, accuracy, precision, process recovery, and stability using matrix matched quality control samples. The mean intra- and inter-day assay accuracy was 91.6-110% for AA and 92.0-109% for GA, and the mean intra- and inter-day assay precisions were <= 10.9% for AA and <= 8.60% for GA. The developed method was successfully applied to a pharmacokinetic study of AA and GA following intravenous and oral administration of AA in rats. Tissue distribution characteristics of AA and GA were also determined under steady-state conditions. PMID- 25281072 TI - Determination of cmc of imidazolium based surface active ionic liquids through probe-less UV-vis spectrophotometry. AB - In the first of its kind we herein report the results of our studies undertaken on the micellization behaviour of imidazolium based surface active ionic liquids (SAILs) to prove that their critical micelle concentration (cmc) can be estimated through ultraviolet-visible (UV-vis) spectroscopy without using any external probe. Tensiometric and spectrophotometric investigations of a series of freshly prepared SAILs viz. 1-octyl-3-methylimidazolium chloride ([OMIM][Cl]), 1-octyl-3 methylimidazolium dodecylsulphate ([OMIM][DS]), 1-octyl-3-methylimidazolium benzoate ([OMIM][Bz]), 1-octyl-3-methylimidazolium salicylate ([OMIM][Sc]), 1 octyl-3-methylimidazolium acetate ([OMIM][Ac]) are presented as a case study in support of the said claim. The cmcs estimated through spectrophotometric method were found to be close to the values estimated through tensiometry for the said SAILs. The cmcs for the investigated SAILS were found to vary in order of [OMIM][Cl]>[OMIM][Ac]>[OMIM][Bz]>[OMIM][Sc]>[OMIM][DS]. To the best of our knowledge the present communication will be the first report about the synthesis, characterization and micellization behaviour of [OMIM][Bz] and [OMIM][Sc]. PMID- 25281073 TI - Label-free detection of exonuclease III by using dsDNA-templated copper nanoparticles as fluorescent probe. AB - 3'-5' Exonuclease activities play key roles in maintaining genome stability, so the detection of 3'-5' exonuclease activity is very important for diseases diagnosis and drug development. In this paper, we established a simple, sensitive, low-cost and label-free method to detect the activity of exonuclease III (Exo III) by using double-strand DNA (dsDNA)-templated copper nanoparticles as fluorescent probe. Fluorescent Cu nanoparticles (NPs ) with maximum emission wavelength of 575 nm are formed by using double-strand DNA (dsDNA) as templates. Upon the addition of Exo III, the dsDNA templates would be digested from 3' to 5', and the formation of fluorescent Cu NPs would be inhibited. Thus, the fluorescence intensity of dsDNA-Cu NPs would decrease. This method exhibits a low detection limit of 0.02 U mL(-1) for Exo III. Compared with the previous reports, this method does not need complex DNA sequence design, fluorescence dye label and sophisticated experimental techniques. PMID- 25281074 TI - Synthesis of a mixed-model stationary phase derived from glutamine for HPLC separation of structurally different biologically active compounds: HILIC and reversed-phase applications. AB - A novel mixed-mode stationary phase was synthesised starting from N-Boc glutamine, aniline and spherical silica gel (4 um, 60 A). The prepared stationary phase was characterized by IR and elemental analysis. The new stationary phase bears an embedded amide group into phenyl ring, highly polar a terminal amide group and non-polar groups (phenyl and alkyl groups). At first, this new mixed mode stationary phase was used for HILIC separation of four nucleotides and five nucleosides. The effects of different separation conditions, such as pH value, mobile phase and temperature, on the separation process were investigated. The optimum separation for nucleotides was achieved using HILIC isocratic elution with aqueous mobile phase and acetonitrile with 20 degrees C column temperature. Under these conditions, the four nucleotides could be separated and detected at 265 nm within 14 min. Five nucleosides were separated under HILIC isocratic elution with aqueous mobile phase containing pH=3.25 phosphate buffer (10mM) and acetonitrile with 20 degrees C column temperature and detected at 265 nm within 14 min. Chromatographic parameters as retention factor, selectivity, theoretical plate number and peak asymmetry factor were calculated for the effect of temperature and water content in mobile phase on the separation process. The new column was also tested for nucleotides and nucleosides mixture and six analytes were separated in 10min. The chromatographic behaviours of these polar analytes on the new mixed-model stationary phase were compared with those of HILIC columns under similar conditions. Further, phytohormones and phenolic compounds were separated in order to see influence of the new stationary phase in reverse phase conditions. Eleven plant phytohormones were separated within 13 min using RP-HPLC gradient elution with aqueous mobile phase containing pH=2.5 phosphate buffer (10mM) and acetonitrile with 20 degrees C column temperature and detected at 230 or 278 nm. The best separation conditions for seven phenolic compounds was also achieved using reversed-phase HPLC gradient elution with aqueous mobile phase containing pH=2.5 phosphate buffer (10mM) and acetonitrile with 20 degrees C column temperature and seven phenolic compounds could be separated and detected at 230 nm within 16 min. PMID- 25281075 TI - Analyzing the biosensor signal in flows: studies with glucose optrodes. AB - Responses of enzymatic bio-optrodes in flow regime were studied and an original model was proposed with the aim of establishing a reliable method for a quick determination of biosensor signal parameters, applicable for biosensor calibration. A dual-optrode glucose biosensor, comprising of a glucose bio optrode and a reference oxygen optrode, both placed into identical flow channels, was developed and used as a model system. The signal parameters of this biosensor at different substrate concentrations were not dependent on the speed of the probe flow and could be determined from the initial part of the biosensor transient phase signal, providing a valuable tool for rapid analysis. In addition, the model helped to design the biosensor system with reduced impact of enzyme inactivation to the system stability (20% decrease of the enzyme activity lead to only a 1% decrease of the slope of the calibration curve) and hence significantly prolong the effective lifetime of bio-optrodes. PMID- 25281076 TI - An innovative approach to the recovery of phenolic compounds and volatile terpenes from the same fresh foliar sample of Rosmarinus officinalis L. AB - Rosmarinus officinalis L. is a plant of relevant commercial interest because of its volatile fraction and also its phenolic constituents which are both well known for their numerous properties. Nevertheless, an extractive method suitable to recovering both the aromatic and phenolic fractions from the same fresh foliar tissue has not yet been reported. In this work we have optimized a two-step procedure able to recover first the phenolic compounds and successively the volatile terpenes from the same foliar sample. The recovery of the whole phenolic fraction, partially degraded using a traditional extractive method, was guaranteed and we observed a significant increment in the amount of volatile terpenes compared to a traditional extraction procedure. We also highlight crucial information on the enzymatic activity of the endogenous oxidases that rapidly transform the phenolic substrates, mainly the rosmarinic acid. Our results suggest that this extractive procedure could also be used for other aromatic plants, thus providing a useful tool for more complete analyses of the main phytochemicals available in fresh foliar samples and creating the possibility of incrementing yields of volatile compounds. PMID- 25281077 TI - A novel fluorescence probing strategy for the determination of parathion-methyl. AB - A sensitive fluorescence probing strategy for parathion-methyl (PM) detection was developed based on electron transfer (ET) between p-nitrophenol (the hydrolysate of PM) and CdTe quantum dots (QDs) in cetyltrimethylammonium bromide (CTAB). PM was hydrolyzed by organophosphorus hydrolase (OPH) to form p-nitrophenol. P nitrophenol is a typically electron-deficient compound due to the strong electron withdrawing effect of the nitro groups. The positive charge of CTAB which make it assemble with electronegative mercaptopropionic acid-capped QDs, could be used as an absorbent for p-nitrophenol due to the strong hydrophobic interaction between the long alkyl chain of CTAB and aromatic ring of p-nitrophenol. Thus, the fluorescence intensity of CdTe QDs/CTAB probe could be quenched by p-nitrophenol due to the ET mechanism. The fluorescence intensity of the QD/CTAB system was proportional to PM concentration in the range of 25-3000 ng mL(-1), with a detection limit of 18 ng mL(-1). Furthermore, the proposed method was simple in design and fast in operation, and has been successfully used for PM detection in environmental and agricultural samples with satisfactory recovery. PMID- 25281078 TI - Determination of L-canavanine and other free amino acids in Vicia disperma (Fabaceae) seeds by precolumn derivatization using diethyl ethoxymethylenemalonate and reversed-phase high-performance liquid chromatography. AB - A method for determination of the non-protein amino acid l-alpha-amino-gamma (guanidinooxy)-n-butyric acid (L-canavanine) and other free amino acids in Vicia disperma is presented. Seed extracts were derivatized by reaction with diethyl ethoxymethylenemalonate and analyzed by reverse-phase high-performance liquid chromatography. Calibration curves showed very good linearity of the response. The limit of detection and quantification were 0.15 and 0.50 MUM, respectively. The method has a high intra- (RSD=0.35%) and inter-repeatability (RSD=2.86%), and a remarkable accuracy with a 99% recovery in spiked samples. The method is very easy to carry out and allows for ready analysis of large number of samples using very basic HPLC equipment because the derivatized samples are very stable and have very good chromatographic properties. PMID- 25281079 TI - Preparation and application of sulfaguanidine-imprinted polymer on solid-phase extraction of pharmaceuticals from water. AB - The molecularly imprinted polymers (MIPs) with sulfaguanidine as a template, methacrylic acid, 4-vinylpyridine, and 2-hydroxyethyl methacrylate as functional monomers, ethylene glycol dimethacrylate as a cross-linker and 2,2'-azobis isobutyronitrile as an initiator have been prepared through the cross-link reaction of polymerization. Solid-phase extraction (SPE) procedure for the extraction of sulfaguanidine from water samples using the prepared MIPs and non imprinted (NIPs) was evaluated. The best MIP in combination with commercial sorbents was applied for simultaneous extraction of eight pharmaceuticals. New SPE cartridges were prepared by combination of optimal produced MIP and Oasis HLB in 6 mL of polypropilene SPE reservoir. The developed method which includes new SPE cartridge (MIPMAA-Oasis HLB, 400mg/6 mL) and thin-layer chromatography was validated. The method provides a linear response over the concentration range of 0.5-150 MUg/L, depending on the pharmaceutical with the correlation coefficients>0.9843 in all cases except for norfloxacin (0.9770) and penicillin G procaine (0.9801). Also, the method has revealed low limits of detection (0.25-20 MUg/L), good precision (intra and inter-day), a relative standard deviation below 15% and recoveries above 95% for all eight pharmaceuticals. The developed method by using newly prepared SPE cartridge has been successfully applied to the analysis of production wastewater samples from pharmaceutical industry. PMID- 25281080 TI - Novel flow injection analysis methods for the determination of total iron in blood serum and water. AB - This work describes rapid, sensitive and highly precise methods for the determination of total iron in blood serum and water samples, using batch, nFIA and rFIA techniques. The proposed methods are based on the selective oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) by iron(III). The absorbance of the resultant green solution of radical cation (ABTS(.+)) was monitored spectrophotometrically at lambda max=415 nm. The reaction is stoichiometric with a ratio of 1:1 (Fe(III):ABTS) as determined by Job's and molar ratio methods. The proposed methods allow for the determination of Fe(III) in the ranges 0-4.5 mg L(-1) (LOD 25.5 ug L(-1), %RSD 0.97%, n=7); 0 to 4.5 mg L( 1) (LOD 370 ug L(-1), %RSD 1.28%, n=7) and 0 to 2.7 mg L(-1) (81.6 ug L(-1), %RSD 0.76%, n=6) for batch, nFIA and rFIA techniques, respectively. The proposed methods show high selectivity to Fe(III), as indicated by the high tolerance limits for common interfering ions. The nFIA method was applied in total iron assay in camel blood serum, whereas batch and rFIA methods were successful in the determination of total iron in municipal pipeline water and spiked groundwater. Statistical analysis indicated insignificant differences in accuracy and precision between the results obtained by the developed methods and ICP-AES or phenanthroline methods. PMID- 25281081 TI - A new label-free and turn-on strategy for endonuclease detection using a DNA silver nanocluster probe. AB - Endonuclease plays a vital role in a variety of biological processes and the assay of endonuclease activity and inhibitors is of high importance in the fields ranging from biotechnology to pharmacology. Howerer, traditional techniques usually suffer from time intensive, laborious, and cost-expensive. This work aims to develop a facile and sensitive method for endonuclease activity assay by making use of the fluorescence enhancement effect when DNA-silver nanoclusters (DNA-Ag NCs) are in proximity to guanine-rich DNA sequences. The system mainly consists of block DNA (B-DNA), G-DNA and Ag-DNA. B-DNA serves as the substrate of the endonuclease (S1 nuclease as the model enzyme). G-DNA, which is predesigned entirely complementary to B strand, contains a guanine-rich overhang sequence and hybridization part at the 5'-end. Ag-DNA involves a sequence for Ag NCs synthesis and a sequence complementary to the hybridization part of the G-DNA. In the "off" state, B-DNA plays the role as a blocker that inhibit the proximity between Ag NCs and guanine-rich DNA sequences, resulting in a low fluorescence readout. However, if S1 nuclease is introduced into the system, B-DNA was cleaved into mono- or short-oligonucleotides fragments, which could not hybridize with G-DNA. As a result, the subsequent addition of DNA-Ag NCs could bring guanine-rich DNA sequences close to the Ag NCs, accompanied by a significant fluorescence enhancement. Therefore, endonuclease activity could be successfully quantified by monitoring the variation in fluorescence intensity. In addition, this approach can also be applied for inhibitor screening of endonuclease. This label-free and turn-on fluorescent assays employing the mechanism proposed here for the detection of nuclease and inhibitors turn out to be sensitive, selective, and convenient. PMID- 25281082 TI - Electrochemical OFF-ON ratiometric chemodosimeters for the selective and rapid detection of fluoride. AB - We have described two "OFF-ON electrochemical latent ratiometric redox chemodosimeters", 1,4-Bis(tert-butyldimethylsiloxy)benzene (H2Q') and 1,4-Bis (tert-butyldimet hylsiloxy)-2-methoxybenzene (MH2Q') for the selective detection of inorganic fluoride. The electrochemical signals of hydroquinone (H2Q) and o methoxy hydroquinone (MH2Q) within this latent redox probes (H2Q' and MH2Q') were completely masked by protecting their hydroxyl group as silylether (OFF state). The externally added fluoride ions triggered the deprotection of H2Q' and MH2Q' and unmasked the electrochemical properties of H2Q and MH2Q respectively. The electrochemical reporters (H2Q and MH2Q) presented a pair of redox peaks at the electrode surface (ON state) and the peak currents are linearly dependent with the concentration of fluoride which leading to the ratiometric detection of fluoride. The limit of detection (signal-to-noise ratio=3) observed for the probes are 23.8 uM and 2.38 uM for H2Q' and MH2Q' respectively. The deprotection is highly selective for fluoride over other anions investigated. The probes are highly stable and the proposed approach offers rapid response time and promising practical applicability. The proposed strategy holds great promise for the commencement of new H2Q based electrochemical probes by tuning the electrochemical behavior of H2Q. PMID- 25281083 TI - Acrylamide-modified graphene for online micro-solid-phase extraction coupled to high-performance liquid chromatography for sensitive analysis of heterocyclic amines in food samples. AB - Heterocyclic amines (HAs) are considered as potential mutagens and carcinogens, and are found in trace quantities (ng/g level) in food samples. Therefore, it is important to develop a selective and effective method to determine trace HAs in complex matrices. In this study, acrylamide-modified graphene (AMG) was successfully synthesised and showed good stability and permeability in aqueous and organic phases. AMG was used as an efficient adsorbent in the online micro solid-phase extraction (MU-SPE) of trace HAs. The enrichment factors of the AMG MU-SPE column were determined as 78-166 for six HAs. An online method based on AMG MU-SPE coupled to high-performance liquid chromatography was developed. The limits of detection ranged from 0.70 to 2.5 ng/L. Trace HAs in spicy salted duck, baked fish, and fried chicken samples were determined and the concentrations of 2 amino-3-methylimidazo[4,5-f]quinoine, 2-amino-3,4-dimethylimidazo[4,5-f]quinoine, and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in these samples were 4.7-37.3, 8.1-15.4, and 43.3-109 ng/g, respectively. The recoveries for the six HAs ranged from 65.9% to 118%, and the relative standard deviation (RSDs) were less than 10.8%. The proposed online method was sensitive, reliable, and convenient for the analysis of trace HAs in food samples. PMID- 25281084 TI - Application of curcumin nanoparticles in a lab-on-paper device as a simple and green pH probe. AB - This article describes the design and fabrication of a novel lab-on-paper device for pH sensing using curcumin nanoparticles (CURNs). In order to fabricate the lab-on-paper, the wax dipping method was used. The color of loaded paper with CURNs changed from yellow to orange and red to brown in the pH range of 7-13. The image of the lab-on-paper was taken by a digital camera and the picture was processed and analyzed using Adobe Photoshop software. The change in mean color intensity with pH was recorded and employed as an analytical signal for quantitative sensing of pH. The parameters affecting the pH sensor were optimized to enhance the selectivity and sensitivity of the method. Under optimum conditions, the mean color intensity was linearly proportional to the pH in the range of 8-13. The relative standard deviations of 10 replicate measurements of pH 9 and pH 12 were 2.3% and 1.5%, respectively. The developed sensor was successfully applied to the determination of pH in different water samples with satisfactory results. PMID- 25281085 TI - Graphene packed needle trap device as a novel field sampler for determination of perchloroethylene in the air of dry cleaning establishments. AB - In this paper we describe the application of a needle trap microextraction device packed with graphene nanoplatelets for the sampling and analysis of perchloroethylene in dry cleaning. The study was carried out in two phases. First the parameters for the sampling and analysis of perchloroethylene by NTD were evaluated and optimized in the laboratory. Then the sampler was used to determine the levels of perchloroethylene in a dry-cleaning shop. In the laboratory phase of the study the performance of the NTD packed with the proposed sorbent was examined in a variety of sampling conditions to evaluate the technique. The technique was also compared with NTDs packed with PDMS as well as SPME with Carboxen/PDMS-coated fibers. Both the NTDs and SPME performed better at lower sampling temperatures and relative humidity levels. The post-sampling storage times for a 95% recovery of the analyte were 5, 5 and 3 days for NTD-graphene, NTD-PDMS and SPME-CAR/PDMS respectively. The optimum desorption time was 3 min for NTDs packed with either graphene or PDMS and 1 min for SPME-CAR/PDMS. The limits of detection for the GC/MS detection system were 0.023 and 0.25 ng mL(-1) for NTDs packed with graphene and PDMS and 0.014 ng mL(-1) for SPME coated with CAR/PDMS. In the second stage of the study the evaluated technique was applied to the sampling and analysis of perchloroethylene in dry cleaning. In this environment the performance of the NTD-graphene as a field sampler for PCE was similar to that of the SPME-CA/PDMS, and better than the NIOSH 1003 method which had greater measurement variations. The results show that a NTD packed with carbonic graphene nanoplatelets and used as an active exhaustive sampling technique is effective for determination of VOC and HVOC occupational/environmental pollutants in air. PMID- 25281086 TI - Determination of atropine sulfate using a novel sensitive DNA-biosensor based on its interaction on a modified pencil graphite electrode. AB - A novel, selective, rapid and simple electrochemical method is developed for the determination of atropine sulfate. UV-Vis and differential pulse voltammetry are used to study the interaction of atropine sulfate with salmon sperm ds-DNA on the surface of salmon sperm ds-DNA modified-pencil graphite electrode (PGE). For this purpose, a pencil graphite electrode (PGE) modified with multiwall carbon nanotubes (MWCNTs), titanium dioxide nanoparticles (TiO2NPs), and poly dialyldimethylammonium chloride (PDDA) decorated with ds-DNA is tested for the determination of atropine sulfate. The electrochemical oxidation peak current of adenine and guanine bonded on the surface of ds-DNA/PDDA-TiO2NPs-MWCNTs/PGE is used to obtain the analytical signal. Decreases in the intensities of guanine and adenine oxidation signals after their interaction with atropine sulfate are used as indicator signals for the sensitive determination of atropine sulfate. Using ds-DNA/PDDA-TiO2NPs-MWCNTs/PGE and based on the guanine signal, linear calibration curves were obtained in the range of 0.6 to 30.0 MUmol L(-1) and 30.0 to 600.0 MUmol L(-1) atropine sulfate with low detection limits of 30.0 nmol L( 1). The biosensor shows a good selectivity for the determination of atropine sulfate. Finally, the applicability of the biosensor is evaluated by measuring atropine sulfate in real samples with good accuracy. PMID- 25281087 TI - Electrochemical magnetoimmunosensing platform for determination of the milk allergen beta-lactoglobulin. AB - A very sensitive magnetoimmunosensor for the determination of beta-lactoglobulin (beta-LG) is reported in this work. A sandwich configuration involving covalent immobilization of the capture antibody (antibeta-LG) onto activated carboxylic modified magnetic beads (HOOC-MBs) and incubation of the modified MBs with a horseradish peroxidase labeled antibody (HRP-antibeta-LG), is used. The resulting modified MBs are captured by a magnet placed under the surface of a disposable carbon screen-printed electrode (SPCE) and the amperometric responses are measured at -0.20 V (vs. Ag pseudo-reference electrode), upon addition of hydroquinone (HQ) as electron transfer mediator and H2O2 as the enzyme substrate. The beta-LG magnetoimmunosensor exhibited a wide range of linearity (2.8-100 ng mL(-1)) and a low detection limit of 0.8 ng mL(-1) (20 pg in 25 MUL sample). The magnetoimmunosensing platform was successfully applied for the detection of beta LG in different types of milk without any matrix effect after just a sample dilution. The results correlated properly with those provided by a commercial ELISA method offering a truthful analytical screening tool. These features make the developed methodology a promising alternative in the development of user friendly devices for on-site determination of beta-LG in dairy products. PMID- 25281089 TI - Multilevel analysis of temperature dependent near-infrared spectra. AB - Quantitative spectra-temperature relationship (QSTR) between near-infrared (NIR) spectra and temperature has been used for quantitative determination of the compositions in mixtures. In this work, QSTR is studied using multilevel simultaneous component analysis (MSCA) and the spectral data of the samples with different concentrations measured at different temperatures. MSCA model contains a between-individual model describing the differences between the individuals and a within-individual model capturing the differences within the data of all the individuals. NIR spectra of five different compositions (water-ethanol isopropanol) measured at seven temperatures were analyzed. A between-temperature model describing the effect of temperature and a within-temperature model describing the variation of concentration were obtained, from which QSTR model is established and quantitative analysis is achieved. Furthermore, the difference between the between-temperature or within-temperature models of different mixtures is used to study the composition of the solvent. PMID- 25281088 TI - Determination of alpha- and beta-boldenone sulfate, glucuronide and free forms, and androstadienedione in bovine urine using immunoaffinity columns clean-up and liquid chromatography tandem mass spectrometry analysis. AB - The debate about the origins of boldenone in bovine urine is ongoing for two decades in Europe. Despite the fact that its use as a growth promoter has been banned in the European Union (EU) since 1981, its detection in bovine urine, in the form of alpha-boldenone conjugate, is considered fully compliant up to 2 ng mL(-1). The conjugated form of beta-boldenone must be absent. In recent years, the literature about boldenone has focused on the identification of biomarkers that can indicate an illicit treatment. beta-boldenone sulfate is a candidate molecule, even if the only studies currently available have taken place in small populations. In this study, a method for the determination of sulfate and glucuronate conjugates of beta-boldenone was developed and validated according to the European Commission Decision 2002/657/EC and applied to alpha-boldenone sulfate and glucuronide, alpha- and beta-boldenone free forms and androstadienedione (ADD), too. The clean-up with immunoaffinity columns enabled the direct determination of the conjugates and free forms and allowed specific and sensitive analyses of urine samples randomly selected to verify this method. The decision limits (CCalpha) ranged between 0.07 and 0.08 ng mL(-1), the detection capabilities (CCbeta) between 0.08 and 0.1 ng mL(-1). Recovery was higher than 92% for all the analytes. Intra-day repeatability was between 5.8% and 17.2%, and inter-day repeatability was between 6.0% and 21.8% for the studied free and conjugated forms. This method has been developed as a powerful tool with the aim to study the origin of boldenone in a trial on a significant number of animals. PMID- 25281090 TI - Atmospheric pressure solid analysis probe coupled to quadrupole-time of flight mass spectrometry as a tool for screening and semi-quantitative approach of polycyclic aromatic hydrocarbons, nitro-polycyclic aromatic hydrocarbons and oxo polycyclic aromatic hydrocarbons in complex matrices. AB - A new screening and semi-quantitative approach has been developed for direct analysis of polycyclic aromatic hydrocarbons (PAHs) and their nitro and oxo derivatives in environmental and biological matrices using atmospheric pressure solid analysis probe (ASAP) quadrupole-time of flight mass spectrometry (Q-TOF MS). The instrumental parameters were optimized for the analysis of all these compounds, without previous sample treatment, in soil, motor oil, atmospheric particles (ashes) and biological samples such as urine and saliva of smokers and non-smokers. Ion source parameters in the MS were found to be the key parameters, with little variation within PAHs families. The optimized corona current was 4 uA, sample cone voltage 80 V for PAHs, nitro-PAHs and oxo-PAHs, while the desolvation temperatures varied from 300 degrees C to 500 degrees C. The analytical method performance was checked using a certified reference material. Two deuterated compounds were used as internal standards for semi-quantitative purposes together with the pure individual standard for each compound and the corresponding calibration plot. The compounds nitro PAH 9-nitroanthracene and oxo PAH 1,4-naphthalenedione, were found in saliva and urine in a range below 1 ug/g while the range of PAHs in these samples was below 2 ug/g. Environmental samples provided higher concentration of all pollutants than urine and saliva. PMID- 25281091 TI - Dispersive liquid-liquid microextraction for the determination of flavonoid aglycone compounds in honey using liquid chromatography with diode array detection and time-of-flight mass spectrometry. AB - A rapid approach for the determination of eight flavonoid aglycone compounds, baicalein, hesperitin, fisetin, naringenin, chrysin, myricetin, quercetin and kaempferol, in honey samples and related products has been optimized and validated. The enriched extracts obtained by dispersive liquid-liquid microextraction (DLLME) were analyzed by liquid chromatography with diode array detection coupled to electrospray ionization and time-of-flight mass spectrometry (LC-DAD-ESI-ToFMS). For DLLME, using acetonitrile and chloroform as disperser and extractant solvents, respectively, a Taguchi experimental method was applied to find the optimal combination of following six factors: disperser and extractant solvent volumes, sodium chloride concentration, pH of the aqueous phase, honey mass and centrifugation time. The sedimented organic phase obtained after centrifugation was evaporated, reconstituted in acetonitrile and submitted to LC. The matrix effect was evaluated, and it was concluded that sample quantification can be carried out against aqueous external standards when using DAD and by matrix-matched calibration in the case of ToFMS. Detection limits in the ranges of 0.4-4 and 0.01-0.5 ng g(-1) were obtained for DAD and ToFMS, respectively. Satisfactory recovery values between 80 and 111% were obtained for three spiked samples. Honeys and related products were analyzed and flavonoids were found within a wide range. PMID- 25281092 TI - A novel solid-state Ru(bpy)3(2+) electrochemiluminescence immunosensor based on poly(ethylenimine) and polyamidoamine dendrimers as co-reactants. AB - In this study, a novel solid-state Ru(bpy)3(2+) electrochemiluminescence (ECL) sandwiched immunosensor for sensitive detection of alpha-fetoprotein (AFP) was constructed based on poly(ethylenimine) (PEI) functionalized reduced graphene oxide (PEI-rGO) and Au nanoparticles (AuNPs) decorated polyamidoamine (PAMAM) dendrimers. Both PEI and PAMAM are polymers with a lot of amino groups, which are able to serve as good co-reactant to remarkably enhance the ECL signal of Ru(bpy)3(2+). For improving the poor conductivity of PAMAM, the AuNPs were decorated on the amino groups of PAMAM. Through Au-N bonds, the formed AuNPs PAMAM was decorated on the PEI-rGO. The obtained AuNPs-PAMAM/PEI-rGO was introduced to immobilize the detection antibody (Ab2). Then, the Ab2 labeled AuNPs-PAMAM/PEI-rGO was modified onto the glass carbon electrode surface via sandwiched immunoreactions. The ECL substrate was prepared by mixing nafion and the complex (Ru-PtNPs) of Pt nanoparticles (PtNPs) and Ru(bpy)3(2+), which could reduce the consumption of Ru complex, simplify the operation and enhance the ECL efficiency. The experimental results demonstrated that the proposed immunosensor had good response to AFP. The linear range was from 0.01 pg mL(-1) to 10 ng mL( 1) with a low detection limit of 3.3 fg mL(-1). Meanwhile, with satisfying stability, selectivity and reproducibility, the proposed sandwiched immunosensor was presented to possess good potential in clinical detection. PMID- 25281093 TI - Determination of trace uranyl ion by thermoresponsive porphyrin-terminated polymeric sensor. AB - Uranyl ion exists at trace levels in the environment and can cause severe adverse effects to human health. Therefore, it is desirable to develop analytical methods that can determine the trace uranyl ion in aqueous medium. We report here a new method using a thermo-responsive polymeric fluorescent sensor. Specifically, 5,10,15,20-tetrakis(4-carboxyphenyl)-porphyrin terminated poly(N isopropylacrylamide) (TCPP-PNIPAM) was synthesized by controlled free radical polymerization for the detection of uranyl ion. The maximum fluorescence intensity at ~ 658 nm of TCPP-PNIPAM increases with molecular weights and is also closely related to the temperature. The polymeric sensor is sensitive to pH (1.0 ~ 5.0) with a fast responsive time (~ 3 min). Under optimized experimental conditions, the sensor exhibits a stable response for uranyl ion with high selectivity over a concentration range from 1.0 * 10(-3) to 1.0 * 10(-7)mol/L. For the trace uranyl ion (such as 1.0 * 10(-8) or 10(-9)mol/L), the determination could be successfully achieved after concentrating 100 times by centrifugation above 32 degrees C. The properties enable the polymeric sensor to have great potential for environmental application. PMID- 25281094 TI - Simple SPE-HPLC determination of some common drugs and herbicides of environmental concern by pulsed amperometry. AB - In this work the electrochemical behavior of substances of environmental concern [bentazone, atrazine, carbamazepine, phenytoin and its metabolite 5-(4 hydroxyphenyl)-5-phenylhydantoin, HPPH] on a glassy carbon working electrode (Ag/AgCl reference electrode) was studied with the aim to develop a HPLC method coupled with amperometric detection. Constant potential (DC), pulsed amperometric detection modes were studied. For the pulsed mode, several waveforms were set and investigated. Detection conditions were optimized as a function of eluent pH. In order to reduce the limits of detection and to analyze natural water samples, a SPE protocol was optimized to be coupled to the developed procedure. For this aim, five sorbents of different physico-chemical characteristics were tested optimizing a recovery procedure for each of the cartridge evaluated. At the optimized SPE conditions, recoveries were included in the range (R=90.2-100.5% for all the analytes, with excellent reproducibility (<%, n=3). The method detection limits obtained by pulsed amperometry after the SPE protocol (preconcentration factor 100) were 113 ng L(-1) (0.47 nmol L(-1)), 67 ng L(-1) (0.25 nmol L(-1)), 234 ng L(-1) (1.1 nmol L(-1)), for bentazone, HPPH and carbamazepine, respectively. Robustness of the method was assessed for each analyte at a concentration level corresponding to about three times the limit of detection, through the evaluation of intra-day (n=13) and inter-day tests (4 days, n=52). Finally the method was successfully applied for the analysis of a river sample (Po River, Turin, Italy). PMID- 25281095 TI - Restricted access carbon nanotubes for direct extraction of cadmium from human serum samples followed by atomic absorption spectrometry analysis. AB - In this paper, we propose a new sorbent that is able to extract metal ions directly from untreated biological fluids, simultaneously excluding all proteins from these samples. The sorbent was obtained through the modification of carbon nanotubes (CNTs) with an external bovine serum albumin (BSA) layer, resulting in restricted access carbon nanotubes (RACNTs). The BSA layer was fixed through the interconnection between the amine groups of the BSA using glutaraldehyde as cross linker. When a protein sample is percolated through a cartridge containing RACNTs and the sample pH is higher than the isoelectric point of the proteins, both proteins from the sample and the BSA layer are negatively ionized. Thus, an electrostatic repulsion prevents the interaction between the proteins from the sample on the RACNTs surface. At the same time, metal ions are adsorbed in the CNTs (core) after their passage through the chains of proteins. The Cd(2+) ion was selected for a proof-of-principle case to test the suitability of the RACNTs due to its toxicological relevance. RACNTs were able to extract Cd(2+) and exclude almost 100% of the proteins from the human serum samples in an online solid-phase extraction system coupled with thermospray flame furnace atomic absorption spectrometry. The limits of detection and quantification were 0.24 and 0.80 MUg L(-1), respectively. The sampling frequency was 8.6h(-1), and the intra- and inter-day precisions at the 0.80, 15.0, and 30.0 MUg L(-1) Cd(2+) levels were all lower than 10.1% (RSD). The recoveries obtained for human blood serum samples fortified with Cd(2+) ranged from 85.0% to 112.0%. The method was successfully applied to analyze Cd(2+) directly from six human blood serum samples without any pretreatment, and the observed concentrations ranged from 3) and quantification (S/N>10) limits varied between 0.001 ng and 2.5 ng and between 0.005 and 10 ng respectively with a reproducibility varied between 14% (bifenthrin) and 39% (permethrin). The method was used for the comparison indoor air contamination after low-pressure spraying and fumigation application in a rubbish chute situated in the basement of a building. PMID- 25281108 TI - Exploring petroleum hydrocarbons in groundwater by double solid phase extraction coupled to gas chromatography-flame ionization detector. AB - This work proposes an analytical procedure for measuring aliphatic and aromatic hydrocarbons fractions present in groundwater. In this method, hydrocarbons are solid phase extracted (SPE) twice from the groundwater and the resulting fractions are analyzed by gas chromatography with flame ionization detection. The first SPE disposes the hydrocarbons present in groundwater in organic solvents and the second SPE divides them into aliphatic and aromatic hydrocarbons. The validation study is carried out and its uncertainties are discussed. Identifying the main sources of uncertainty is evaluated through applying the bottom-up approach. Limits of detection for hydrocarbons ranges are below 5 ug L(-1), precision is not above of 30%, and acceptable recoveries are reached for aliphatic and aromatic fractions studied. The uncertainty due to volume of the sample, factor of calibration and recovery are the highest contributions. The expanded uncertainty range from 13% to 26% for the aliphatic hydrocarbons ranges and from 14% to 23% for the aromatic hydrocarbons ranges. As application, the proposed method is satisfactorily applied to a set of groundwater samples collected in a polluted area where there is evidence to present a high degree of hydrocarbons. The results have shown the range of aliphatic hydrocarbons >C21-C35 is the most abundant, with values ranging from 215 ug L(-1) to 354 ug L(-1), which it is associated to a contamination due to diesel. PMID- 25281109 TI - Removal of copper and iron by polyurethane foam column in FIA system for the determination of nickel in pierced ring. AB - Polyurethane foam (PUF) mini-column was used to eliminate copper and iron for the determination of nickel in pierced rings. The PUF mini-column was connected to FIA system for on-line sorption of copper and iron in complexes form of CuSCN(+) and FeSCN(2+). For this season, the acid solution containing a mixture of Ni(II), Fe(III), Cu(II) and SCN(-) ions was firstly flew into the PUF column. Then, the percolated solution which Fe(III) and Cu(II) ions is separated from analysis was injected into FIA system to react with 4-(2-pyridylazo) resorcinol (PAR) reagent in basic condition which this method is called pH gradient technique. The Ni-PAR complexes obtained were measured theirs absorbance at 500 nm by UV visible spectrophotometer. In this study, it was found that Cu(II) and Fe(III) were completely to form complexes with 400 mmol/L KSCN and entirely to eliminate in acidic condition at pH 3.0. In the optimum condition of these experiments, the method provided the linear relationship between absorbance and the concentration of Ni(II) in the range from 5.00 to 30.00 mg/L. Linear equation is y=0.0134x+0.0033 (R(2)=0.9948). Precision, assessed in the term of the relative standard deviation, RSD, and accuracy for multiple determinations obtained in values of 0.77-1.73% and 97.4%, respectively. The level of an average amount of Ni(II) in six piercing rings was evaluated to be 14.78 mg/g. PMID- 25281110 TI - Combination of poly(diallyldimethylammonium chloride) and hydroxypropyl-gamma cyclodextrin for high-speed enantioseparation of phenothiazines by capillary electrophoresis. AB - High-speed capillary electrophoresis (CE) enables the simple, rapid, and inexpensive analysis of large sets of chiral samples in the pharmaceutical industry. Hence, we developed a novel method for separating enantiomers of d,L phenothiazines simply and rapidly, based on using poly(diallyldimethylammonium chloride) (PDDAC) as an additive and hydroxypropyl-gamma-cyclodextrin (Hp-gamma CD) as a chiral selector in capillary electrophoresis. Adding 0.9% PDDAC to the background electrolyte generated a stable, high, and reversed electroosmotic flow (EOF). Hp-gamma-CD not only worked as a complexing agent to increase the chiral resolution between d,L-phenothiazines but also decreased the effective electrophoretic mobility of these drugs. Combining PDDAC and Hp-gamma-CD as buffer additives enabled CE to achieve a high-speed enantioseparation of five pairs of d,L-phenothiazines. A decrease in capillary length and an increase in the intensity of the electric field further shortened the separation time. When the background electrolyte contained 0.9% PDDAC, 5mM Hp-gamma-CD, and 75 mM formic acid (pH 3.0), enantioseparation of the d,L-phenothiazines was attained within 230 s by applying a capillary length of 32.5 cm and an electric field of 292 V cm(-1). The limit of detection (LOD) of the d,L-phenothiazines at a signal to-noise ratio of 3 ranged from 2 to 8 MUM. We demonstrated the feasibility of this method by detecting the five pairs of d,L-phenothiazines in urine samples. PMID- 25281111 TI - Investigating the performance of in situ quantitative nuclear magnetic resonance analysis and applying the method to determine the distribution of saccharides in various parts of carrot roots (Daucus carota L.). AB - In order to explore the performance of the analytical method called in situ quantitative nuclear magnetic resonance spectroscopy - is q NMR - the distribution of glucose, fructose and sucrose in various parts of a carrot root (Daucus carota L.) - primary xylem, secondary xylem, phloem, cortex; top part and lower part - was determined. The influence on the quality of spectra of drying samples before analysis was studied, as well as the influence of the length of strips of tissue used in analysis. Finally samples as small as 240 mm(3) could be studied directly, with minimum prior treatment (only drying), along with deuterated water for locking and a sealed capillary tube containing a solution of 0.5% of the sodium salt of (trimethylsilyl)propionic-2,2,3,3-d4 acid, used both as an internal reference and for quantification. With optimized parameters, the coefficients of variation for measurements were observed to have an average value of 0.038, with a standard deviation of 0.047. PMID- 25281112 TI - A fluorescence method for detection of DNA and DNA methylation based on graphene oxide and restriction endonuclease HpaII. AB - DNA methylation plays an important role in many biological events and is associated with various diseases. Most traditional methods for detection of DNA methylation are based on the complex and expensive bisulfite method. In this paper, we report a novel fluorescence method to detect DNA and DNA methylation based on graphene oxide (GO) and restriction endonuclease HpaII. The skillfully designed probe DNA labeled with 5-carboxyfluorescein (FAM) and optimized GO concentration keep the probe/target DNA still adsorbed on the GO. After the cleavage action of HpaII the labeled FAM is released from the GO surface and its fluorescence recovers, which could be used to detect DNA in the linear range of 50 pM-50 nM with a detection limit of 43 pM. DNA methylation induced by transmethylase (Mtase) or other chemical reagents prevents HpaII from recognizing and cleaving the specific site; as a result, fluorescence cannot recover. The fluorescence recovery efficiency is closely related to the DNA methylation level, which can be used to detect DNA methylation by comparing it with the fluorescence in the presence of intact target DNA. The method for detection of DNA and DNA methylation is simple, reliable and accurate. PMID- 25281113 TI - Dispersive liquid-liquid microextraction for metals enrichment: a useful strategy for improving sensitivity of laser-induced breakdown spectroscopy in liquid samples analysis. AB - A rapid and efficient Dispersive Liquid-Liquid Microextraction (DLLME) followed by Laser-Induced Breakdown Spectroscopy detection (LIBS) was evaluated for simultaneous determination of Cr, Cu, Mn, Ni and Zn in water samples. Metals in the samples were extracted with tetrachloromethane as pyrrolidinedithiocarbamate (APDC) complexes, using vortex agitation to achieve dispersion of the extractant solvent. Several DLLME experimental factors affecting extraction efficiency were optimized with a multivariate approach. Under optimum DLLME conditions, DLLME LIBS method was found to be of about 4.0-5.5 times more sensitive than LIBS, achieving limits of detection of about 3.7-5.6 times lower. To assess accuracy of the proposed DLLME-LIBS procedure, a certified reference material of estuarine water was analyzed. PMID- 25281114 TI - Electrochemical sensor based on magnetic graphene oxide@gold nanoparticles molecular imprinted polymers for determination of dibutyl phthalate. AB - A novel composite of magnetic graphene oxide @ gold nanoparticles-molecular imprinted polymers (MGO@AuNPs-MIPs) was synthesized and applied as a molecular recognition element to construct dibutyl phthalate (DBP) electrochemical sensor. The composite of MGO@AuNPs was first synthesized using coprecipitation and self assembly technique. Then the template molecules (DBP) were absorbed at the MGO@AuNPs surface due to their excellent affinity, and subsequently, selective copolymerization of methacrylic acid and ethylene glycol dimethacrylate was further achieved at the MGO@AuNPs surface. Potential scanning was presented to extract DBP molecules from the imprinted polymers film rapidly and completely. As a consequence, an electrochemical sensor for highly sensitive and selective detection of DBP was successfully constructed as demonstration based on the synthesized MGO@AuNPs-MIPs composite. Under optimal experimental conditions, selective detection of DBP in a linear concentration range of 2.5 * 10(-9)-5.0 * 10(-6)mol/L was obtained. The new DBP electrochemical sensor also exhibited excellent repeatability, which expressed as relative standard deviation (RSD) was about 2.50% for 30 repeated analyses of 2.0 * 10(-6)mol/L DBP. PMID- 25281115 TI - Separation-preconcentration of nickel and lead in food samples by a combination of solid-liquid-solid dispersive extraction using SiO2 nanoparticles, ionic liquid-based dispersive liquid-liquid micro-extraction. AB - A microextraction method for the determination of nickel and lead using solid liquid-solid dispersive extraction followed by ionic liquid-based dispersive liquid-liquid microextraction (SLSDE-ILDLLME) was presented. It was applied to the extraction of nickel and lead from food samples. Ammonium pyrrolidine dithiocarbamate (APDC) as complexing agent, [C4MIM][PF6] as ionic liquid, SiO2 as nanoparticles and 2 mol L(-1) HNO3 as eluent were used. Several important parameters such as amount of IL, extraction time, pH and volume of the complexing agent were investigated. The quantitative recoveries were obtained at pH 7.0 for analytes. Under the optimum conditions, the limits of detection (LODs) calculated using 3(Sd)blank/m were 0.17 for Ni(II) and 0.79 ug L(-1) for Pb(II) for aqueous solutions with 125 enrichment factor (EF). The limit of detections of the analyte ions (3(Sd)blank/m) for solid samples were 0.09 ug g(-1) (Ni) and 0.40 ug g(-1) (Pb). The accuracy of the proposed method was confirmed by the analysis of standard reference material (1577c bovine liver) and spiked recovery test. The proposed method was applied to determine nickel and lead levels in chicken, fish and meat samples. PMID- 25281116 TI - Capillary electrophoresis with laser-induced fluorescence detection for studying amino acid uptake by yeast during beer fermentation. AB - The amino acid composition of cultivation broth is known to affect the biomass accumulation, productivity, and vitality of yeast during cultivation. A separation method based on capillary electrophoresis with laser-induced fluorescence (LIF) detection was developed for the determination of amino acid consumption by Saccharomyces cerevisiae during beer fermentation. Intraday relative standard deviations were less than 2.1% for migration times and between 2.9% and 9.9% for peak areas. Interday relative standard deviations were less than 2.5% for migration times and between 4.4% and 18.9% for peak areas. The quantification limit was even as low as 62.5 pM which equals to below attomole level detection. The method was applied to study the rate of amino acid utilization during beer fermentation. PMID- 25281117 TI - Metals in boat paint fragments from slipways, repair facilities and abandoned vessels: an evaluation using field portable XRF. AB - Paint flaking off abandoned vessels or generated during boat repair is hazardous to human health and wildlife. In this study, a means of screening paint fragments using a field portable-X-ray fluorescence (FP-XRF) spectrometer is described. The technique is capable of delivering rapid, surficial measurements of Ba, Cu, Pb and Zn down to concentrations less than 150 MUg g(-1), and Sn and Cr to concentrations of a few hundred MUg g(-1). Application of the technique to fragments collected from slipways, yards, hardstandings, abandoned boats and ships undergoing maintenance throughout the EU reveal highly variable concentrations of metals among samples from the same environment or from the same region of a given boat; in many cases, variability is also evident in different areas or on different surfaces of the same fragment. Of particular concern are elevated concentrations of substances that have been restricted or banned (e.g. Sn, an indicator of organotin, and up to concentrations of 40,000 MUg g(-1), and Pb up to concentrations of 200,000 MUg g(-1)). Although FP-XRF can rapidly screen samples whose composition and origin are unknown and can assist in instantaneous decision making, a full risk assessment will rely on additional analyses of the precise species (including organo-forms) of the metals present. PMID- 25281118 TI - Electrochemiluminescence immunosensor for highly sensitive detection of 8-hydroxy 2'-deoxyguanosine based on carbon quantum dot coated Au/SiO2 core-shell nanoparticles. AB - An electrochemiluminescence (ECL) immunosensor using Pt electrode modified with carbon quantum dot (CQDs) coated Au/SiO2 core-shell nanoparticles was proposed for sensitive detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in this work. Rabbit anti-8-OHdG antibody was covalently bound to CQDs on the surface of Au/SiO2 core-shell nanoparticles. Through signal amplification of Au/SiO2 core shell nanoparticles, 8-fold enhancement of the ECL signals was achieved. Under optimal conditions, a good linear range from 0.2 to 200 ng mL(-1) with a low detection limit of 0.085 ng mL(-1) (S/N=3) for 8-OHdG detection was obtained. Interfering substances tests showed that the corresponding ECL intensity (DeltaECL) of 8-OHdG is 8-18 times higher than that of guanine, uric acid (UA) and ascorbic acid, demonstrating its good selectivity for 8-OHdG detection. The ECL immunosensor exhibits long-term stability with a relative standard deviation (RSD) of 8.5% even after 16 cycles of continuous potential scans. The result of analytical detection of 8-OHdG in real samples was satisfactory. The proposed ECL immunosensor shows good performance with high sensitivity, specificity, repeatability, stability and provided a powerful tool for 8-OHdG monitoring in clinical samples. PMID- 25281119 TI - An analytical method coupling accelerated solvent extraction and HPLC fluorescence for the quantification of particle-bound PAHs in indoor air sampled with a 3-stages cascade impactor. AB - Most of Polycyclic Aromatic Hydrocarbons (PAHs) are associated to airborne particles and their health impact depends on the particle size where they are bound. This work aims to develop a high sensitive analytical technique to quantify particulate PAHs sampled with a 3-stages cascade impactor in order to derive simultaneously their individual concentration in PM1, PM2.5 and PM10. Three key steps of the method were evaluated separately in order to avoid any PAHs loss during the global sample preparation procedure: (1) the accelerated solvent extraction of PAHs from the filter; (2) the primary concentration of the extract until 1 mL by means of a rotary evaporator at 45 degrees C and 220 mbar and (3) the final concentration of the pre-concentrated extract to about 100-150 uL under a gentle nitrogen stream. Each recovery experiment was realized in triplicates. All these steps evaluated independently show that the overall PAHs loss, even for those with a low molecular weight, should not exceed more than a few percent. Extracts were then analyzed by using a HPLC coupled to fluorescence and Diode Array Detectors with the external standard method. The resulting calibration curves containing between 9 and 12 points were plotted in the concentration range of 0.05-45 ug L(-1) for most of the 16 US-EPA priority PAHs and were fully linear (R(2)>0.999). Limits Of Quantification were in the range 0.05-0.47 ug L(-1) corresponding to 0.75-7.05 pg m(-3) for 20 m(3) of pumped air. Finally, taking into account the average PAHs concentrations previously reported in typical European indoor environments, and considering the use of a 3-stages cascade impactor to collect simultaneously PM>10 um, 2.5 um99% and the recoveries of analytes were in the range 92 97%. The limits of detection for As, B, Bi, Ga, Ge, P, Pb, Sb, Se, Si and Te were found to be 0.18, 0.21, 0.07, 0.06, 0.25, 0.11, 0.09, 0.10, 0.17, 0.20 and 0.07 MUg g(-1) respectively. The procedure was applied for the analysis of a standard reference material nickel oxide (SRM 761, Nickel Oxide No.1, NBS, USA) and the values obtained are in close agreement with the certified values. PMID- 25281134 TI - Development and analytical comparison of microflow and nanoflow liquid chromatography/mass spectrometry procedures for quantification of cardiac troponin T in mouse hearts. AB - Three procedures for the quantification of cardiac troponin T (cTnT) based on liquid chromatography/mass spectrometry (LC/MS) were developed, validated and compared. The procedures were applied to estimate the cTnT content in the hearts of wild type mice C57BL/6J (WT) and double knock-outs for apolipoprotein E and receptor for LDL (AL KO). Three variants of the procedure proposed include microflow, direct injection nanoflow and preconcentration nanoflow LC/MS. Troponin T tryptic peptide YEINVLR and its analog (internal standard) were monitored in a multiple reaction monitoring mode using triple quadrupole mass detector with electrospray (ESI) ion sources. The preconcentration nanoflow LC/MS method offered the best sensitivity with a lower limit of quantification (LLOQ) of 0.25 fg uL(-1) and a minimal matrix effect. The LLOQ value was 8 times better, compared with that in direct injection nanoflow LC/MS and 200 times better than in microflow LC/MS. The accuracy or precision for all three methods were not different. Separation time in the direct injection nanoflow (8 min) was equivalent to the microflow method (6 min). The cTnT contents in the mice hearts measured by the methods developed by the present authors were not different between the WT and AL KO. We conclude that nanoflow LC/MS based quantitative proteomics offers fundamentally better sensitivities while maintaining analytical quality and separation times equivalent to microflow procedures. PMID- 25281135 TI - Enzymatic amplification detection of peanut allergen Ara h1 using a stem-loop DNA biosensor modified with a chitosan-mutiwalled carbon nanotube nanocomposite and spongy gold film. AB - In this paper, a highly sensitive biosensor was constructed for peanut allergen Ara h1 detection. The biosensor was constructed by coating a glassy carbon electrode with a chitosan-mutiwalled carbon nanotube nanocomposite and then adding a spongy gold film via electro-deposition to increase the effective area. The probe switched from an "on" to an "off" state in the presence of target DNA, which detached biotin from the electrode surface. This also detached streptavidin horseradish peroxidase (HRP-SA), which was bound to the electrode via specific interaction with biotin. The HRP-SA catalyzed chemical oxidation of hydroquinone by H2O2 to form benzoquinone, and when it was detached, electrochemical reduction of the signal of benzoquinone could be used to monitor DNA hybridization via chronoamperometry. Under optimum conditions, a wide dynamic detection range (3.91 * 10(-17)-1.25 * 10(-15) mol L(-1)) and a low detection limit (1.3 * 10(-17) mol L(-1)) were achieved for the complementary sequence. Furthermore, the DNA biosensor exhibited an excellent ability to discriminate between a complementary target and a one-base mismatch or non-complementary sequence. The sensor was successfully applied to Ara h1 analysis in peanuts. PMID- 25281136 TI - Evaluation of sequential injection chromatography for reversed phase separation of triazine herbicides exploiting monolithic and core-shell columns. AB - This paper describes the development of reversed phase sequential injection chromatography (SIC) methods for separation of simazine (SIM) and atrazine (AT), as well as their metabolites deethylatrazine (DEA), deisopropylatrazine (DIA) and hydroxyatrazine (HAT) exploiting silica based monolithic (50 * 4.6 mm) and core shell (30 * 4.6 mm, 2.7 um particles) columns. The separation was made by stepwise elution with two mobile phases: MP1 composed of 15:85 (v/v) acetonitrile: 2.5 mmol L(-1) acetic acid/ammonium acetate buffer (pH 4.2), and MP2, composed of 35:65 (v/v) acetonitrile: 2.5 mmol L(-1) acetic acid/ammonium acetate buffer (pH 4.2).The less hydrophobic compounds (DIA, HAT and DEA) eluted with MP1, whereas SIM and AT eluted with MP2. The method using core-shell column exhibited better chromatographic efficiency compared with monolithic column for separation of SIM and AT, but failed to provide base line separation of DIA and HAT. The proposed composition of mobile phases enabled the monolithic column to separate all the studied compounds with resolution >2.3 at flow rate of 35 uL s( 1) and sampling throughput of 8 analyses per hour, whereas in the core-shell the maximum flow rate allowed in the SIC system was 8 uL s(-1) (sampling throughput of 3 analyses per hour). The limits of detection were between 24 ug L(-1) (AT) and 40 ug L(-1) (DEA) using the monolithic column, and between 20 ug L(-1) (SIM) and 38 ug L(-1) (DEA) with the core-shell. Ultrasound-assisted extraction (80:20 v/v acetonitrile:water) of a soil sample enriched with the five triazines (250, 500 and 1000 ug kg(-1)) resulted recoveries between 51% and 121% of the spiked concentrations. PMID- 25281137 TI - Determination of tamoxifen and its main metabolites in plasma samples from breast cancer patients by micellar liquid chromatography. AB - A method was developed for the analysis of tamoxifen and its main derivatives (4 hydroxytamoxifen, N-desmethyl-tamoxifen, tamoxifen-N-oxide and endoxifen) in human plasma, using micellar liquid chromatography coupled with fluorescence detection. Analytes were off-line derivatized by sample UV-irradiation for 20 min to form the photocycled fluorescent derivatives. Then samples were diluted, filtered and directly injected, thus avoiding extraction steps. The analytes were resolved using a mobile phase containing 0.08 M SDS-4.5% butanol at pH 3 running at 1.5 mL/min through a C18 column at 40 degrees C, without interferences from endogenous compounds in plasma. Excitation and emission wavelengths were 260 and 380 nm, respectively. The chromatographic analysis time was less than 40 min. The analytical methodology was validated following the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines in terms of: selectivity, linear range (0.3-15 MUg/mL), linearity (r(2)>0.999), sensitivity (LOD, 65-80 ng/mL; LOQ, 165-200 ng/mL), intra- and interday accuracy (-12.2-11.5%) and precision (<9.2%) and robustness (<6.3%). The method was used to quantify the tamoxifen and tamoxifen derivatives in several breast cancer patients from a local hospital, in order to study the correlation between the genotype of the patient and the ability to metabolize tamoxifen. PMID- 25281138 TI - Influence of Pluronic F127 on the distribution and functionality of inkjet printed biomolecules in porous nitrocellulose substrates. AB - The distribution of inkjet-printed biomolecules in porous nitrocellulose substrates often results in a non-homogeneous spot morphology commonly referred to as 'doughnut-shaped' spots. We have studied the influence of Pluronic F127 (an amphiphilic surfactant) on the functionality of inkjet-printed primary antibody molecules and on the final assay result by performing a one-step antibody binding assay in the nitrocellulose substrate. The primary antibody was printed with and without Pluronic, followed by the addition of double-labelled amplicons as antigen molecules and a fluorophore-labelled streptavidin as detection conjugate. The distribution of the fluorescence intensity down into the nitrocellulose substrate was investigated by confocal laser scanning microscopy in 'Z' stacking mode. Each horizontal slice was further analysed by applying a concentric ring format and the fluorescence intensity in each slice was represented in a colour coded way. The mean and total fluorescence intensity of the antibody binding assay (fluorescent streptavidin) showed a peak at 0.2% (w/v) Pluronic F127. In addition, an improved spot morphology was observed also peaking at the same Pluronic concentration. Subsequently, we investigated the direct influence of Pluronic F127 on the location of the primary antibody molecules by labelling these molecules with the fluorophore Alexa-488. Our results show that upon increasing the concentration of Pluronic F127 in the printing buffer, the spot diameter increased and the number of primary antibody molecules bound in the spot area gradually decreased. This was confirmed by analysing the distribution of fluorescently labelled primary antibody molecules down into the membrane layers. We conclude that a particular ratio between primary antibody and Pluronic F127 molecules in combination with available substrate binding capacity results in an optimal orientation, that is Fab-UP, of the primary antibody molecules. Consequently, an increased number of antigen molecules (in our case the labelled amplicons) and of the fluorescent detection conjugate (streptavidin) will give an optimal signal. Moreover, distribution of the primary antibody molecules was more homogeneous at the optimal Pluronic F127 concentration, contributing to the better spot morphology observed. PMID- 25281139 TI - New nano-composite potentiometric sensor composed of graphene nanosheets/thionine/molecular wire for nanomolar detection of silver ion in various real samples. AB - A novel nanographene carbon composite potentiometric sensor for the determination of trace amounts of silver(I) ion was fabricated. Its sensing layer was prepared with the addition of graphene nanosheets into the matrix consisting of graphite powder, diphenylacetylene "a typically molecular wire (MW) as the conductive binder" and thionine as an efficient ionophore. For investigation of the ion-to electron transducing ability of graphene nanosheets and molecular wire on the electrode surface, the electrochemical impedance spectroscopy measurements were done and the morphology and properties of the electrode surfaces were characterized by scanning electron microscopy. Under the optimized experimental conditions, the suggested potentiometric silver(I) sensor exhibited an excellent Nernstian slope of 59.70 mV decade(-1) with a rapid response to silver(I) ion within ~ 6s. The response was linear in the range 8.00 * 10(-9) to 1.00 * 10(-2) mol L(-1) and calculated detection limit was 4.17 * 10(-9) mol L(-1). The suggested sensor was successfully applied to the determination of silver in radiological film, environmental and drug samples with satisfactory results. PMID- 25281140 TI - Determination of urine ionic composition with potentiometric multisensor system. AB - The ionic composition of urine is a good indicator of patient's general condition and allows for diagnostics of certain medical problems such as e.g., urolithiasis. Due to environmental factors and malnutrition the number of registered urinary tract cases continuously increases. Most of the methods currently used for urine analysis are expensive, quite laborious and require skilled personnel. The present work deals with feasibility study of potentiometric multisensor system of 18 ion-selective and cross-sensitive sensors as an analytical tool for determination of urine ionic composition. In total 136 samples from patients of Urolithiasis Laboratory and healthy people were analyzed by the multisensor system as well as by capillary electrophoresis as a reference method. Various chemometric approaches were implemented to relate the data from electrochemical measurements with the reference data. Logistic regression (LR) was applied for classification of samples into healthy and unhealthy producing reasonable misclassification rates. Projection on Latent Structures (PLS) regression was applied for quantitative analysis of ionic composition from potentiometric data. Mean relative errors of simultaneous prediction of sodium, potassium, ammonium, calcium, magnesium, chloride, sulfate, phosphate, urate and creatinine from multisensor system response were in the range 3-13% for independent test sets. This shows a good promise for development of a fast and inexpensive alternative method for urine analysis. PMID- 25281141 TI - A direct competitive assay-based aptasensor for sensitive determination of tetracycline residue in honey. AB - Tetracycline (TC) is a common antibacterial agent used for prevention and control of animal diseases. The increasing concern about TC residue in food demands high performing analytical techniques for food quality assessment. Biosensors represent a promising tool for food safety analysis as they can fulfill some demand that the conventional methods do not attain. In this study, a novel colorimetric aptasensor was developed for sensitive detection of TC in honey. The aptasensor was based on a modified direct competitive enzyme-linked aptamer assay (dc-ELAA) scheme utilizing a 76 mer single-stranded DNA (ssDNA) aptamer selected by Systematic Evolution of Ligands by Exponential Enrichment (SELEX). The optimized aptasensor showed a good limit of detection (LOD of 0.0978 ng/mL), a wide linear range (0.1-1000 ng/mL) toward TC in honey, with good recoveries (92.09-109.7%) in TC-spiked honey, and was compared with an indirect competitive assay-based aptasensor and validated with a standard ELISA. The biosensor based on dc-ELAA with good limit of detection and simplicity can be applied for high throughput detection of TC in food. PMID- 25281142 TI - Resonance Rayleigh scattering method for determination of ethion using silver nanoparticles as probe. AB - A simple, novel and sensitive method was developed to determine ethion insecticide in water samples. This method was based on the interaction of ethion with silver nanoparticles (AgNPs) and quenching of the resonance Rayleigh scattering (RRS) intensity. The change in RRS intensity (DeltaIRRS) was linearly correlated to the concentration of ethion over the range of 10.0-900.0 ug L(-1). Ethion can be measured in a short time (3 min) without any complicated or time consuming sample pretreatment process. Parameters that affect the RRS intensities such as pH, concentration of AgNPs, standing time, electrolyte concentration, and coexisting substances were systematically investigated and optimized. Interference tests showed that the developed method has a very good selectivity and could be used conveniently for determination of ethion. The limit of detection (LOD) and limit of quantification (LOQ) were 3.7 and 11.0 ug L(-1), respectively. Relative standard deviations (RSD) for 15.0 and 60.0 ug L(-1) of ethion were 4.1 and 0.2, respectively. Possible mechanisms for the quenching of RRS of AgNPs were discussed and the method was successfully applied for the analysis of spiked real water samples. PMID- 25281143 TI - Coulometric differential FFT admittance voltammetry determination of Amlodipine in pharmaceutical formulation by nano-composite electrode. AB - An electrochemical detection technique based on combination of was coulometric differential fast Fourier transformation admittance voltammetry (CDFFTAV) and nano-composite film modified glassy carbon electrode was successfully applied for sensitive determination of Amlodipine. The nano-composite film was made by a mixture of ionic liquid, 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIMBF4), multiwall carbon nanotube and Au nanoparticles as electrochemical mediators. Studies reveal that the irreversible oxidation of Amlodipine was highly facile on the electrode surface. The electrochemical response was established on calculation of the charge under the admittance peak, which was obtained by discrete integration of the admittance response in a selected potential range, obtained in a flow injection analysis. Once established the best operative optimum conditions, the resulting nano-composite film electrode showed a catalytic effect on the oxidation of the analyte. The response is linear in the Amlodipine concentration range of 1.0 * 10(-9) to 2.0 * 10(-7)M with a detection limit of 1.25 * 10(-10)M. Moreover, the proposed technique exhibited high sensitivity, fast response time (less than 6s) and long-term stability and reproducibility around 96%, and it was successfully used to the determination of Amlodipine content in the pharmaceutical formulation. PMID- 25281144 TI - Determination of trace elements in medicinal activated charcoal using slurry sampling electrothermal vaporization inductively coupled plasma mass spectrometry with low vaporization temperature. AB - The determination of Cd, Sb, Te, Hg, Tl and Pb in medicinal activated charcoal by ultrasonic slurry sampling electrothermal vaporization inductively coupled plasma mass spectrometry (USS-ETV-ICP-MS) was described. EDTA was used as the modifier to enhance the volatility of elements studied. The influences of instrument operating conditions and slurry preparation on the ion signals were studied. A relatively low vaporization temperature of 1000 degrees C was used, which separated the analyte from the major matrix components that improved ion signals. The method has been applied to determine Cd, Sb, Te, Hg, Tl and Pb in an NIST SRM 1633b Coal Fly Ash reference material and three brands of medicinal activated charcoal capsules using isotope dilution and standard addition calibration methods. The concentrations that are in ng g(-1) levels were in good agreement between different calibration methods. The precision between sample replicates was better than 7% with USS-ETV-ICP-MS technique. The method detection limit estimated from standard addition curves was 0.4, 0.3, 0.3, 0.3, 0.04 and 0.9 ng g(-1) for Cd, Sb, Te, Hg, Tl and Pb, respectively, in original medicinal activated charcoal. PMID- 25281145 TI - Sequential hollow-fiber liquid phase microextraction for the determination of rosiglitazone and metformin hydrochloride (anti-diabetic drugs) in biological fluids. AB - A new analytical method for the simultaneous determination of the antidiabetic drugs rosiglitazone (ROS) and metformin hydrochloride (MH) with marked differences in their affinity towards organic solvents (log P of 2.4 and -1.43, respectively) was developed. Prior to the HPLC separation, the drugs were subjected to a sequential hollow fiber liquid phase microextraction (HF-LPME) procedure. Two sequential HF-LPME approaches were considered, the preferred one involves the use of two vials containing solution mixtures for the extraction of ROS (vial 1) and MH (vial 2), respectively, but using the same fiber and acceptor phase. Important parameters that affect the extraction efficiency such as extracting solvent, donor phase conditions, HCl concentration, agitation, extraction time, addition of salt, etc. were studied. Under the optimum conditions, good enrichment factors (EF, 471 and 86.6 for ROS and MH, respectively) were achieved. Calibration curves were linear over the range 1-500 (r(2)=0.998) and 5-2500 ng mL(-1) (r(2)=0.999) for ROS and MH, respectively. The relative standard deviation values (RSD%) for six replicates were below 8.4%. Detection and quantitation limits based on S/N ratio of 3 and 10 were 0.12, 1.0 and 0.36, 3.0 ng mL(-1) for ROS and MH, respectively. The proposed method is simple, sensitive and opens up new opportunities for the microextraction of analytes with contrasting properties. PMID- 25281146 TI - Ratiometric fluorescence detection of fluoride ion by indole-based receptor. AB - A novel artificial receptor 1 containing the indolocarbazole-NH moieties as the recognition sites exhibited high selectivity and sensitivity toward F(-) over other typical anionic species in DMSO solution. Upon addition of F(-) into the solution, receptor 1 showed a remarkable ratiometric shift of the fluorescence maximum from 535 to 590 nm, and also a prominent color change from light yellow to orange, which was observable by the naked eye. The recognition properties of receptor 1 were investigated by (1)H NMR, UV-vis, and fluorescence titration experiments, with the results suggesting a two-step strategy of binding with F( ). In addition, the theoretical calculations were carried out to reveal the role of intramolecular charge transfer in the ratiometric fluorescence recognition process. PMID- 25281147 TI - Dispersive solvent-free ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction coupled with HPLC for determination of ulipristal acetate. AB - In this paper, a simple and efficient ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction (UA IL-DLLME) coupled with high-performance liquid chromatography for the analysis of ulipristal acetate (UPA) was developed. UPA could be easily migrated into 1-octyl-3-methylimidazolium hexafluorophosphate [C8mimPF6] IL phase without dispersive solvent. The research of extraction mechanism showed that hydrophobic interaction force played a key role in the IL DLLME. Several important parameters affecting the extraction recovery were optimized. Under the optimized conditions, 25-fold enrichment factor was obtained and the limit of detection (LOD) was 6.8 ng mL(-1) (tablet) or 9.3 ng mL(-1) (serum) at a signal-to-noise ratio of 3. The calibration curve was linear over the range of 0.03-6.0 ug mL(-1). The proposed method was successfully applied to the UPA tablets and the real mice serum samples. PMID- 25281148 TI - On the feasibility of near infrared spectroscopy to detect contaminants in water using single salt solutions as model systems. AB - This research work evaluates the feasibility of NIRS to detect contaminants in water using single salt solutions as model systems. Previous research has indicated the potential of near infrared spectroscopy (NIRS) for detecting solutes in water; however, a comprehensive investigation of the limit of detection of this technique has not been carried out. Near infrared transmittance spectra of aqueous salt solutions in the concentration range 0.002-0.1 mol L(-1) (equivalent to 117-13,334 ppm or 0.0001-0.01% mass/mass) were investigated. The first overtone region of the near infrared spectrum (1300-1600 nm) was found to be the most effective wavelength range for prediction of salt concentration in aqueous solutions. Calibration models built using this wavelength range and employing the extended multiplicative scatter spectral pre-treatment resulted in root mean squared error of prediction values ranging from 0.004 to 0.01 mol L( 1). The limit of detection (LOD) was estimated to be of the order of 0.1% (mass/mass) or 1000 ppm. Within the framework of Aquaphotomics, it was possible to examine the effect of different salts on the NIR spectra of water in the first overtone range. Our results were confirmed through test experiments at various geographical locations employing dispersive and Fourier transform type NIRS instruments. PMID- 25281149 TI - Electrocatalytic determination of chloramphenicol based on molybdenum disulfide nanosheets and self-doped polyaniline. AB - In this paper, a novel molybdenum disulfide (MoS2) intercalated by self-doped polyaniline (SPAN) via ultrasonic exfoliating method was prepared to show outstanding conductivity and synergistic electrocatalytic activity using chloramphenicol (CAP) as a case. In the ultrasonic process, due to the strong pi pi(*) stacking interaction and electrostatic repulsion, the negatively charged SPAN served as an intercalator to result in few-layers MoS2 nanosheets, which were exfoliated from bulk MoS2. This nanocomposite was characterized by scanning electron microscopy, transmission electron microscopy and differential pulse voltammetry. The obtained nanocomposite owns large conjugated structure and rich negative charge, which can improve the adsorption of conjugate structured CAP with the detection range from 0.1 to 1000 MUmol L(-1). The results also showed that the electrocatalytic responses were further affected by the mass ratio of SPAN-MoS2 and the ultrasonication time. Our electrocatalytic platform could be further applied in the adsorption and detection of other positively charged biomolecules or aromatic molecules. PMID- 25281150 TI - Sensitive analysis of amino acids and vitamin B3 in functional drinks via field amplified stacking with reversed-field stacking in microchip electrophoresis. AB - An on-line preconcentration strategy combining field-amplified stacking and reversed-field stacking was developed for efficient and sensitive analysis of amino acids and vitamin B3 including lysine (Lys), taurine (Tau), and niacinamide (NA) by microchip electrophoresis with LIF detection. In this technique, the addition of a reversed-polarity step termed reversed-field stacking could enhance the preconcentration effect of field-amplified stacking and push most of the sample matrix out of the separation channel, thus greatly improving the sensitivity enhancement by 1-2 orders of magnitude over the classical MCE-LIF methods. The related mechanism as well as important parameters governing preconcentration and separation have been investigated in order to obtain strongest sensitivity amplification and maximum resolution. Under optimal conditions, all analytes were successfully focused and completely separated within 4 min. The limits of detection for Lys, Tau, and NA were 0.25, 0.50, and 0.20 nM (S/N=3), respectively, and enhancement factors of 165-, 285-, and 236 fold were obtained for Lys, Tau, and NA as compared to using the no concentration step. Other validation parameters such as linearity and precision were considered as satisfactory. The proposed method also gave accurate and reliable results in the analysis of these functional ingredients in eight functional drink samples. PMID- 25281151 TI - High-performance liquid chromatography coupled with mass spectrometry for analysis of ultrasmall palladium nanoparticles. AB - Metal nanoparticles (NPs) have recently attracted considerable attention in many areas of research including bioscience, chemistry and material science. Regrettably, most current and past work usually focuses on studies of multi component NPs mixture where there is a plethora of NPs species co-existing. This work highlights the merits of reverse-phase high-performance liquid chromatography (RP-HPLC) for disclosing the genuine properties of individual palladium nanoparticles (PdNPs) species present in an as-synthesized N,N' dimethylformamide-stabilized PdNPs product (DMF-PdNPs) which might have been previously hidden or misinterpreted. DMF-PdNPs is successfully separated by RP HPLC that smaller DMF-PdNPs are approximately eluted first and then follow by the large ones on a C18 column. The separation fractions are further collected and determined their chemical compositions by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The results unambiguously reveal that the as-synthesized DMF-PdNPs product is indeed a complex mixture of ultrasmall PdxNPs (x=10-20) stabilized with different numbers of DMF ligands. It is anticipated that the separated fractions afforded by RP-HPLC will offer more accurate determinations of the catalytic, electronic, optical and toxicological properties of metal NPs which might have been previously misinterpreted. PMID- 25281153 TI - Use of switchable solvents in the microextraction context. AB - In this article, a new homogeneous liquid-liquid microextraction alternative, based on the use of switchable hydrophilicity solvents (SHS), is presented for the first time. The extraction technique makes use of a water-immiscible solvent (N,N-Dimethylcyclohexylamine) that can be solubilised in 1:1 ratio using CO2 as reagent. After the extraction, phases' separation is induced by the addition of sodium hydroxide, which produces a change on the ionisation state of the amine, centrifugation not being necessary. The extraction technique has been optimised and characterised using the determination of benz[a]anthracene by fluorimetric measurements in water samples as model analytical problem. Although the native fluorescence of the compound is quenched in the organic phase, this attenuation is reduced by diluting the extractant (1:1) in acetic acid. The fluorescence intensity is 35% higher in the SHS-acetic acid mixture than that obtained in pure methanol. The proposed method allows the determination of the target analyte with limit of detection of 0.08 MUg/L and good precision (relative standard deviation of 6.7% at the limit of quantification level). The recoveries were in the range of 72-100% fulfilling the Environmental Protection Agency criterion. Finally, the potential use of this microextraction technique in combination with gas chromatography is shown for several polycyclic aromatic hydrocarbons. PMID- 25281152 TI - Peptidomics study of anthocyanin-rich juice of elderberry. AB - Biologically active peptides play a role in plant signaling and defense. Elderberry juice is known to contain a variety of anthocyanin compounds, a sub set of polyphenols, which are responsible for the deep purple color of the juice. In this paper, we describe a method utilizing solid phase extraction (SPE) to remove anthocyanins from peptides. Liquid chromatography coupled with tandem mass spectrometry was used to separate and identify the peptides. The results showed that the use of SPE was an effective method to separate peptides from anthocyanins and other background compounds including high polyphenol content in the juice samples. More than 1000 peptides present in elderberry juice were successfully identified. PMID- 25281154 TI - Investigation of nonylphenol and nonylphenol ethoxylates in sewage sludge samples from a metropolitan wastewater treatment plant in Turkey. AB - Nonylphenol ethoxylates (NPEOs) have drawn significant attention within the last decade for both scientific and legislative reasons. In Turkey, the Regulation Regarding the Use of Domestic and Urban Sludges on Land states a limit value for the sum of nonylphenol (NP), nonylphenol monoethoxylate (NP1EO) and nonylphenol diethoxylate (NP2EO) as NPE (NPE=NP+NP1EO+NP2EO). Unfortunately a standard method for the determination of these chemicals has not been yet set by the authorities and no data exists about the concentrations of NP and NPEOs in sewage sludge in Turkey. The aim of this study is to propose simple and easily applicable extraction and measurement techniques for 4-n-nonylphenol (4-n-NP), NP, NP1EO and NP2EO in sewage sludge samples and investigate the year round concentrations in a Metropolitan Wastewater Treatment Plant (WWTP) in Turkey. Different extraction techniques and GC/MS methods for sewage sludge were tested. The best extraction method for these compounds was found to be ultrasonication (5 min) using acetone as the solvent with acceptable recovery of analytes suggested by USEPA and other studies. The optimized extraction method showed good repeatability with relative standard deviations (RSDs) less than 6%. The recovery of analytes were within acceptable limits suggested by USEPA and other studies. The limits of detection (LODs) were 6 ug kg(-1) for NP and NP1EO, 12 ug kg(-1) for NP2EO and 0.03 ug kg( 1) for 4-n-NP. The developed method was applied to sewage sludge samples obtained from the Central WWTP in Ankara, Turkey. The sum NPE (NP+NP1EO+NP2EO) was found to be in between 5.5 ug kg(-1) and 19.5 ug kg(-1), values which are in compliance with Turkish and European regulations. PMID- 25281155 TI - Development of a LC-MS/MS methodology for the monitoring of the antichagasic drug benznidazole in human urine. AB - Monitoring the drug benznidazole in biological fluids is a powerful tool for clinical diagnostic and pharmacological studies in chagasic patients. However, research in this concern needs to be done. The accurate quantitation of this drug in complex matrices represents a highly challenging task complicated by the absence of sensitive analytical methods. It follows that sample processing strategies, preparation/cleanup procedures, and chromatographic/ionization/detection parameters, were evaluated for method optimization. The summation of this work generated a rapid, selective, sensitive methodology based on reversed-phase chromatography-tandem mass spectrometry for the analysis of benznidazole in urine samples. To the best of our knowledge, this is a first report of a LC-MS/MS platform employed for this application. Matrix effect was determined; a 90% of signal suppression was observed. The limits of detection and quantification were 0.75 and 4.85 MUg L(-1); respectively. The latter allowed the method's application to the detection of benznidazole in clinical studies and pharmacological monitoring analysis. PMID- 25281156 TI - Characterization of Fe3O4/SiO2/Gd2O(CO3)2 core/shell/shell nanoparticles as T1 and T2 dual mode MRI contrast agent. AB - Core/shell/shell structured Fe3O4/SiO2/Gd2O(CO3)2 nanoparticles were successfully synthesized. Their properties as a new type of T1-T2 dual model contrast agent for magnetic resonance imaging were investigated. Due to the introduce of a separating SiO2 layer, the magnetic coupling between Gd2O(CO3)2 and Fe3O4 could be modulated by the thickness of SiO2 layer and produce appropriate T1 and T2 signal. Additionally, the existence of Gd(3+) enhances the transverse relaxivity of Fe3O4 possibly because of the magnetic coupling between Gd(3+) and Fe3O4. The Fe3O4/SiO2/Gd2O(CO3)2 nanoparticles exhibit good biocompatibility, showing great potential for biomedical applications. PMID- 25281157 TI - A profluorescent ratiometric probe for intracellular pH imaging. AB - A ratiometric pH probe composed of a fluorescein moiety and an ionic near infrared-emitting phosphorescent cyclometalated iridium(III) complex bis(6 (benzo[b]thien-2-yl)phenanthridinato)(4-(3-carboxypropyl)-4'-methyl-2,2' bipyridine)iridium(III) was synthesized. With good cell permeability, the probe demonstrated a linear ratiometric response to the pH variation in the physiological range in HeLa cell assay. PMID- 25281158 TI - Determination of free tryptophan in serum with aptamer--comparison of two aptasensors. AB - Two aptasensors based on graphene oxide (GO) and molecular beacon were designed for the detection of L-tryptophan (L-Trp) using L-Trp aptamer (Trp3a-1). The fluorescein (FAM) labeled Trp3a-1 was absorbed by GO, which resulted in the fluorescence quenching, and exhibiting minimal background fluorescence. Upon the addition of L-Trp, Trp3a-1 was not absorbed quickly. This effect allows for a quantitative assay of L-Trp over the concentration range of 10-500 MUM and with a detection limit of 6.84 MUM. However, due to the unspecific adsorption of GO, the GO based aptasensor can't be applied in complex matrixes. In respect of molecular beacon based aptasensor, FRET between Trp3a-1 labeled with FAM and CS-Trp3a-1 labeled with BHQ-1(black hole quencher-1) which is partially complementary with the aptamer was used to detect L-Trp. L-Trp binding could induce the disassociation of CS-Trp3a-1, resulted in the enhancement of fluorescence in solution. With an excellent linear relationship in 10-500 MUM and a detection limit of 6.97 MUM in 25% serum, the aptasensor is expected to be improved for the detection of free L-Trp in other complex samples. PMID- 25281159 TI - Conjugated polyelectrolyte-stabilized silver nanoparticles coupled with pyrene derivative for ultrasensitive fluorescent detection of iodide. AB - A new sensing system is developed for selective and ultrasensitive detection of iodide based on the inner filter effect (IFE) between conjugated polyelectrolyte stabilized silver nanoparticles (P1-AgNPs) and 4-oxo-4-(pyren-1-ylmethoxy) butanoic acid (probe 1). P1-AgNPs are designed to be capable of functioning as a composite light-absorber. Meanwhile, probe 1 is selected as an ideal fluorophore because its emission spectrum can perfectly overlap with the absorption band of P1-AgNPs. The intense fluorescence of probe 1 quenched by P1-AgNPs can be efficiently recovered after adding H2O2 and I(-) via the oxidation-etching and regeneration of P1-AgNPs. Under the optimum conditions, this facile IFE-based approach allows the sensitive and selective determination of I(-) in tap water, iodized salt and urine with the detection limit as low as 0.3 nM (S/N=3). Interestingly, the regenerated AgNPs is in smaller size and well-dispersed perhaps due to the particular role of P1 as a polymer localizer containing pyridinyl and sulfonate groups. PMID- 25281160 TI - Synthesis and characterization of ester-bonded stationary phases for liquid chromatography. AB - The new type of stationary bonded phases for liquid chromatography with immobilized artificial membrane properties was synthesized. Based on the modification of diol-bonded silica gel the cholesterol-ester and alkyl-ester stationary phases were obtained. The structures of synthesized material were confirmed by different physico-chemical techniques such as elemental analysis, infrared spectroscopy (FTIR), (13)C CP/MAS NMR and chromatography. Synthesized stationary phases were characterized and visualized by computer modeling that indicates the regions of potential hydrophobic and polar interactions. Synthesized material possess residual hydroxyl groups that reduce the hydrophobicity of the material and causes better stability at high water concentration. Due to surface properties these materials are became polar embedded stationary phases. PMID- 25281161 TI - Nanoparticles applied to plant science: a review. AB - The present review addresses certain important aspects regarding nanoparticles and the environment, with an emphasis on plant science. The production and characterization of nanoparticles is the focus of this review, providing an idea of the range and the consolidation of these aspects in the literature, with modifications on the routes of synthesis and the application of the analytical techniques for characterization of the nanoparticles (NPs). Additionally, aspects related to the interaction between the NPs and plants, their toxicities, and the phytoremediation process, among others, are also discussed. Future trends are also presented, supplying evidence for certain possibilities regarding new research involving nanoparticles and plants. PMID- 25281162 TI - Electrochemical biotin detection based on magnetic beads and a new magnetic flow cell for screen printed electrode. AB - The use of the first flow-cell for magnetic assays with an integrated magnet is reported here. The flow injection analysis system (FIA) is used for biotin determination. The reaction scheme is based on a one step competitive assay between free biotin and biotin labeled with horseradish peroxidase (B-HRP). The mixture of magnetic beads modified with streptavidin (Strep-MB), biotin and B-HRP is left 15 min under stirring and then a washing step is performed. After that, 100 MUL of the mixture is injected and after 30s 100 MUL of 3,3',5,5' Tetramethylbenzidine (TMB) is injected and the FIAgram is recorded applying a potential of -0.2V. The linear range obtained is from 0.01 to 1 nM of biotin and the sensitivity is 758 nA/nM. The modification and cleaning of the electrode are performed in an easy way due to the internal magnet of the flow cell. PMID- 25281163 TI - Quantification of acesulfame potassium in processed foods by quantitative 1H NMR. AB - Acesulfame potassium (AceK), a high-intensity and non-caloric artificial sweetener, is used in various processed foods as a food additive. In this study, we established and validated a method for determining the AceK content in various processed foods by solvent extraction and quantitative (1)H NMR, using a certified reference material as the internal standard. In the recovery test, the proposed method gave satisfactory recoveries (88.4-99.6%) and repeatabilities (0.6-5.6%) for various processed foods. The limit of quantification was confirmed as 0.13 g kg(-1), which was sufficiently low for the purposes of monitoring AceK levels. In the analysis of commercially processed foods containing AceK, all AceK contents determined by the proposed method were in good agreement with those obtained by a conventional method based on dialysis and HPLC. Moreover, this method can achieve rapid quantification and yields analytical data with traceability to the International System of Units (SI) without the need for an authentic analyte standard. Therefore, the proposed method is a useful and practical tool for the determination of AceK in processed foods. PMID- 25281164 TI - Fast determination of 40 drugs in water using large volume direct injection liquid chromatography-tandem mass spectrometry. AB - This work describes a rapid analytical method based on direct sample injection of water samples for the simultaneous identification/quantification of 40 emerging compounds, including pharmaceuticals and drugs of abuse. The water samples were analyzed by ultra-high-performance liquid chromatography coupled to hybrid triple quadrupole mass spectrometer (UHPLC-MS/MS QqQ). Taking profit of the increasing sensitivity of nowadays tandem mass spectrometers, direct sample injection of large volumes has been an attractive alternative to pre-concentration steps. In this work, the developed methodology has been validated at three concentration levels (10, 100 and 1000 ng/L) in 10 different water samples of different types (5 effluent wastewater and 5 surface water samples). The majority of compounds could be satisfactory validated at these concentrations, showing good recoveries and precision. With only few exceptions, the limits of quantification (LOQs), estimated from the sample chromatogram at lowest spiked level tested, were below 3 ng/L. The method was applied to the analysis of 10 effluent wastewater and 10 surface water samples. Venlafaxine was the compound most frequently detected (80%) in surface water, followed by acetaminophen (70%). Regarding effluent wastewater, valsartan and 4-acetyl aminoantipyrine were detected in 9 out of 10 samples analyzed. These two compounds together with 4-formyl aminoantipyrine and naproxen showed the highest concentrations (>2000 ng/L). In these cases, a dilution step was required for a correct quantification. As an additional evaluation of the method performance, the same water samples were analyzed in another laboratory by a second analytical methodology, based on on-line solid phase-extraction coupled to LC-MS/MS (QqQ). PMID- 25281166 TI - Determination of secondary and tertiary amines as N-nitrosamine precursors in drinking water system using ultra-fast liquid chromatography-tandem mass spectrometry. AB - N-Nitrosamines are potent mutagenic and carcinogenic emerging water disinfection by-products (DBPs). The most effective strategy to control the formation of these DBPs is minimizing their precursors from source water. Secondary and tertiary amines are dominating precursors of N-nitrosamines formation during drinking water disinfection process. Therefore, the screening and removal of these amines in source water are very essential for preventing the formation of N nitrosamines. A rapid, simple, and sensitive ultrafast liquid chromatography tandem mass spectrometry (UFLC-MS/MS) method has been developed in this study to determine seven amines, including dimethylamine, ethylmethylamine, diethylamine, dipropylamine, trimethylamine, 3-(dimethylaminomethyl)indole, and 4 dimethylaminoantipyrine, as major precursors of N-nitrosamines in drinking water system. No sample preparation process is needed except a simple filtration. Separation and detection can be achieved in 11 min per sample. The method detection limits of selected amines are ranging from 0.02 MUg/L to 1 MUg/L except EMA (5 MUg/L), and good calibration linearity was achieved. The developed method was applied to determine the selected precursors in source water and drinking water samples collected from Midwest area of the United States. In most of water samples, the concentrations of selected precursors of N-nitrosamines were below their method detection limits. Dimethylamine was detected in some of water samples at the concentration up to 25.4 MUg/L. PMID- 25281165 TI - Simultaneous pharmacokinetic and pharmacodynamic analysis of 5alpha-reductase inhibitors and androgens by liquid chromatography tandem mass spectrometry. AB - Benign prostatic hyperplasia and prostate cancer can be treated with the 5alpha reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5alpha-reductases (testosterone, 5alpha dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP((r)) 5500, with a Waters AcquityTM UPLC. Analytes were extracted from serum (500 uL) via solid-phase extraction (Oasis((r)) HLB), with (13)C3 labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 * 3 mm, 2.6 um), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289 -> 97), DHT (m/z 291 -> 255), androstenedione (m/z 287 -> 97), dutasteride (m/z 529 -> 461), finasteride (m/z 373 -> 317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased. PMID- 25281167 TI - Content, participants and outcomes of three diabetes care programmes in three low and middle income countries. AB - AIMS: To improve access and quality of diabetes care for people in low-income countries, it is important to understand which elements of diabetes care are effective. This paper analyses three diabetes care programmes in the DR Congo, Cambodia and the Philippines. METHODS: Three programmes offering diabetes care and self-management were selected. Programme information was collected through document review and interviews. Data about participants' characteristics, health outcomes, care utilisation, expenditures, care perception and self-management were extracted from a study database. Comparative univariate analyses were performed. RESULTS: Kin-reseau (DR Congo) is an urban primary care network with 8000 patients. MoPoTsyo (Cambodia) is a community-based peer educator network, covering 7000 patients. FiLDCare (Philippines) is a programme in which 1000 patients receive care in a health facility and self-management support from a community health worker. Content of care of the programmes is comparable, the focus on self-management largest in MoPoTsyo. On average, Kin-reseau patients have a higher age, longer diabetes history and more overweight. MoPoTsyo includes most female, most illiterate and most lean patients. Health outcomes (HbA1C level, systolic blood pressure, diabetes foot lesions) were most favourable for MoPoTsyo patients. Diabetes-related health care expenditure was highest for FiLDCare patients. CONCLUSIONS: This study shows it possible to maintain a diabetes programme with minimal external resources, offering care and self management support. It also illustrates that health outcomes of persons with diabetes are determined by their bio-psycho-social characteristics and behaviour, which are each subject to the content of care and the approach to chronic illness and self-management of the programme, in turn influenced by the larger context. PMID- 25281168 TI - Psychosomatic and liaison psychiatry in Zaragoza: philosophy, objectives and results in a four decade experience: the 2014 EAPM 'Frits Huyse Award' lecture. PMID- 25281169 TI - Comparison of mailed vs. on-site emergency department patient satisfaction surveys. AB - BACKGROUND: Patient satisfaction is one measure of the quality of emergency department (ED) care. The impact of survey delivery method on patient satisfaction in the ED remains unknown. OBJECTIVE: We hypothesized that self administered surveys in the ED would yield a higher response rate and different satisfaction compared to mailed surveys. METHODS: This observational study was conducted during a 2-month period in an urban, tertiary-care, university-based ED. Eligible patients were randomized to either complete an on-site satisfaction survey in the ED at discharge or to complete an identical survey mailed 1 week after discharge. The primary outcome was the reported overall satisfaction of on site vs. mail-out surveys. Satisfaction was measured using Likert-type scales and dichotomized outcomes were compared using a chi(2) test and logistic regression. RESULTS: Two hundred and forty-two of 457 eligible patients randomized to the on site group and 275 of 1152 patients in the mail-out group completed a survey (53% vs. 24%; p < 0.001). Compared with the mail-out group, on-site subjects reported higher overall satisfaction (79.6% vs. 68.9%; p = 0.006), significantly higher satisfaction with their nurses' (p < 0.001) and doctors' listening skills (p < 0.001), and were more likely to recommend this ED to friends or family (71.4%, vs. 56.6%; p = 0.001). CONCLUSIONS: We found that patients who completed satisfaction surveys in the ED reported higher satisfaction than those who received mailed surveys. In addition, measuring patient satisfaction by self administered on-site surveys at the time of discharge from the ED yields a significantly higher response rate than measuring satisfaction using mailed surveys. PMID- 25281171 TI - The pulmonary embolism severity index: underused despite its clinical merits. PMID- 25281172 TI - Regarding the benefits and harms of blood transfusion in septic patients. PMID- 25281170 TI - Risk factors associated with different types of intimate partner violence (IPV): an emergency department study. AB - BACKGROUND: Domestic intimate partner violence (IPV) is a serious health care concern, which may be mitigated by early detection, screening, and intervention. OBJECTIVES: We examine posited predictors in IPV and non-IPV groups, and in four different IPV profiles. Possible factors include 1) alcohol use, 2) drug use, 3) depression, 4) impulsivity, 5) age, and 6) any childhood experience in observing parental violence. We also introduce a new "Five Steps in Screening for IPV" quick reference tool, which may assist emergency physicians in detection and treatment. METHODS: This was a cross-sectional study using survey data from 412 inner-city emergency department patients. Associations were explored using a chi squared test of independence, independent-samples t-tests, and a one-way analysis of variance. RESULTS: Nearly 16% had experienced IPV. As a group, they were younger, and more depressed and impulsive than the non-IPV group. They were more likely to engage in binge drinking, use drugs, and had more childhood exposure to violence. In the IPV group, 31% were perpetrators, 20% victims, and 49% both victims and perpetrators. The latter group was younger, more impulsive and depressed, used drugs, and was more likely to have observed parental violence as a child. CONCLUSION: Correlates in groups affected by IPV indicate the same general risk factors, which seem to more acutely affect those who are both perpetrators and victims. Alcohol and drug use, depressive symptoms, and childhood exposure to violence may be factors and signs for which emergency physicians should screen in the context of IPV. PMID- 25281173 TI - Postobstructive pulmonary edema in the setting of aspiration and air travel. AB - BACKGROUND: Postobstructive pulmonary edema (POPE)-also referred to as negative pressure pulmonary edema-occurs with deep inspiration against a closed glottis or obstructed airway. The result can be life threatening, however, most cases have a self-limited presentation and resolve with supportive care. OBJECTIVE: Our aim was to critically evaluate a previously unreported mechanism in the exacerbation of POPE. CASE REPORT: This is a report of a 50-year-old woman who experienced an acute episode of hypoxia and altered mental status aboard a transcontinental flight. Her presentation was suggestive of pulmonary embolus. However, a detailed history yielded an episode of preflight choking relieved by the Heimlich maneuver. After 2 days of supportive care she was discharged with a complete return to baseline. CONCLUSIONS: Subclinical cases of POPE can be exacerbated by the low atmospheric pressure experienced on commercial airlines. With early recognition and supportive treatment, the patient returned to baseline before her discharge 2 days later. Making the diagnoses of POPE is not always straightforward for the practitioner and necessitates a broad differential. Initial supportive care focusing on maximizing respiratory support is critical. PMID- 25281174 TI - Improving the success of video laryngoscopic intubation. PMID- 25281175 TI - A novel program to improve patient safety by integrating peer review into the emergency medicine residency curriculum. AB - BACKGROUND: Evaluating the quality of care as part of a quality improvement process is required in many clinical environments by accrediting bodies. It produces metrics used to evaluate department and individual provider performance, provides outcomes-based feedback to clinicians, and identifies ways to reduce error. DISCUSSION: To improve patient safety and train our residents to perform peer review, we expanded our quality assurance program from a narrow, administrative process carried out by a small number of attendings to an educationally focused activity of much greater scope incorporating all residents on a monthly basis. We developed an explicit system by which residents analyze sets of high-risk cases and record their impressions onto structured databases, which are reviewed by faculty. At monthly meetings, results from the month's case reviews are presented, learning points discussed, and corrective actions are proposed. CONCLUSION: By integrating Clinical Quality Review (CQR) as a core, continuous component of the residency curriculum, we increased the number of cases reviewed more than 10-fold and implemented a variety of clinical process improvements. An anonymous survey conducted after 2 years of resident-led CQR indicated that residents value their exposure to the peer review process and feel it benefits them as clinicians, but also that the program requires a significant investment of time that can be burdensome. PMID- 25281176 TI - Inverted Mercedes Benz sign in lumbar spinal subdural hematoma. PMID- 25281177 TI - Prospective evaluation of prehospital trauma ultrasound during aeromedical transport. AB - BACKGROUND: Ultrasound is widely considered the initial diagnostic imaging modality for trauma. Preliminary studies have explored the use of trauma ultrasound in the prehospital setting, but the accuracy and potential utility is not well understood. OBJECTIVE: We sought to determine the accuracy of trauma ultrasound performed by helicopter emergency medical service (HEMS) providers. METHODS: Trauma ultrasound was performed in flight on adult patients during a 7 month period. Accuracy of the abdominal, cardiac, and lung components was determined by comparison to the presence of injury, primarily determined by computed tomography, and to required interventions. RESULTS: HEMS providers performed ultrasound on 293 patients during a 7-month period, completing 211 full extended Focused Assessment with Sonography for Trauma (EFAST) studies. HEMS providers interpreted 11% of studies as indeterminate. Sensitivity and specificity for hemoperitoneum was 46% (95% confidence interval [CI] 27.1%-94.1%) and 94.1% (95% CI 89.2%-97%), and for laparotomy 64.7% (95% CI 38.6%-84.7%) and 94% (95% CI 89.2%-96.8%), respectively. Sensitivity and specificity for pneumothorax were 18.7% (95% CI 8.9%-33.9%) and 99.5% (95% CI 98.2%-99.9%), and for thoracostomy were 50% (95% CI 22.3%-58.7%) and 99.8% (98.6%-100%), respectively. The positive likelihood ratio for laparotomy was 10.7 (95% CI 5.5 21) and for thoracostomy 235 (95% CI 31-1758), and the negative likelihood ratios were 0.4 (95% CI 0.2-0.7) and 0.5 (95% CI 0.3-0.8), respectively. Of 240 cardiac studies, there was one false-positive and three false-negative interpretations (none requiring intervention). CONCLUSIONS: HEMS providers performed EFAST with moderate accuracy. Specificity was high and positive interpretations raised the probability of injury requiring intervention. Negative interpretations were predictive, but sensitivity was not sufficient for ruling out injury. PMID- 25281178 TI - Re: MDMA-associated cerebral edema resembling psychogenic polydipsia? PMID- 25281179 TI - Response to letter to the editor. PMID- 25281180 TI - Ultrasound-guided central venous access using Google Glass. AB - BACKGROUND: The use of ultrasound during invasive bedside procedures is quickly becoming the standard of care. Ultrasound machine placement during procedures often requires the practitioner to turn their head during the procedure to view the screen. Such turning has been implicated in unintentional hand movements in novices. Google Glass is a head-mounted computer with a specialized screen capable of projecting images and video into the view of the wearer. Such technology may help decrease unintentional hand movements. OBJECTIVE: Our aim was to evaluate whether or not medical practitioners at various levels of training could use Google Glass to perform an ultrasound-guided procedure, and to explore potential advantages of this technology. METHODS: Forty participants of varying training levels were randomized into two groups. One group used Google Glass to perform an ultrasound-guided central line. The other group used traditional ultrasound during the procedure. Video recordings of eye and hand movements were analyzed. RESULTS: All participants from both groups were able to complete the procedure without difficulty. Google Glass wearers took longer to perform the procedure at all training levels (medical student year 1 [MS1]: 193 s vs. 77 s, p > 0.5; MS4: 197s vs. 91s, p <= 0.05; postgraduate year 1 [PGY1]: 288s vs. 125 s, p > 0.5; PGY3: 151 s vs. 52 s, p <= 0.05), and required more needle redirections (MS1: 4.4 vs. 2.0, p > 0.5; MS4: 4.8 vs. 2.8, p > 0.5; PGY1: 4.4 vs. 2.8, p > 0.5; PGY3: 2.0 vs. 1.0, p > 0.5). CONCLUSIONS: In this study, it was possible to perform ultrasound-guided procedures with Google Glass. Google Glass wearers, on average, took longer to gain access, and had more needle redirections, but less head movements were noted. PMID- 25281181 TI - Eye on children: acute work-up for pediatric Horner's syndrome. case presentation and review of the literature. AB - BACKGROUND: Ptosis and anisocoria in a child may be subtle indications of occult pathology, and making the observation acutely in the emergency department (ED) is important in guiding patient management and treatment. Emergency physicians must evaluate patients to exclude serious or life-threatening emergencies and ensure correct disposition of patients. Horner syndrome in children may be considered congenital or acquired and may be from benign or malignant causes. When an isolated, acquired Horner syndrome is suspected in a pediatric patient, physical examination of the neck and abdomen for masses, as well as spot urine catecholamines, vanillylmandelic acid and homovanillic acid, and varying degrees of imaging are recommended as part of the initial evaluation. These evaluations may be performed in the ED or may require hospitalization, depending on the suspected anatomical localization and diagnostic considerations. CASE REPORT: A 21-month-old, normally developed girl presented to the University Hospital ED with a 2-h history of right-sided eyelid drooping in the setting of a febrile illness. An eventual diagnosis of Horner syndrome from cervical lymph node compression was made on the basis of history, examination, and imaging findings. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ED evaluations of pediatric patients differ from adults. Evaluation and work-up of Horner syndrome in children can be challenging and can require varying degrees of assessment and evaluation, depending on the diagnostic considerations. This article will address the common pathologies responsible for isolated pediatric Horner syndrome and the recommended ED evaluation. PMID- 25281182 TI - A man with prolonged nasal discharge. PMID- 25281183 TI - RE: The Oregon Physician Orders for Life-Sustaining Treatment Registry. PMID- 25281184 TI - The importance of directed productivity education and training. PMID- 25281185 TI - Mortality in hyperglycemic crisis. PMID- 25281186 TI - Use of serum procalcitonin in evaluation of febrile infants: a meta-analysis of 2317 patients. AB - BACKGROUND: Serum procalcitonin (PCT) concentrations have been studied as a diagnostic test for serious bacterial infections (SBIs) in children. However, the utility of a single measurement in the evaluation of SBIs in febrile infants younger than 91 days is not clear. OBJECTIVE: Use a systematic review and meta analysis to determine: 1) the ability of serum PCT concentrations to identify febrile infants < 91 days of age at high and low risk for SBIs, and 2) to compare its utility with available clinical prediction rules. METHODS: The literature search identified studies of febrile infants segregated into risk groups using serum PCT concentrations. Some authors were contacted to provide subgroups < 91 days of age or to provide data with 0.3 ng/mL PCT cutoff values. Data were combined and validated using standard methodologies. RESULTS: Seven studies encompassing 2317 patients were identified; five of seven studies used a PCT discriminating concentration of 0.3 ng/mL. No heterogeneity or publication bias was identified. The overall relative risk (RR) was 3.97 (95% confidence interval [CI] 3.41-4.62) and was consistent by sensitivity analysis. The RR from a systematic review of clinical prediction rules was 30.6 (95% CI 7.0-68.13) and 8.75 (95% CI 2.29-15.2) for infants untreated and treated with antibiotics, respectively. CONCLUSIONS: Alone, measurement of serum PCT concentrations, though able to identify a group of young infants at risk for SBIs, is inferior to the available clinical prediction rules for identifying young, febrile infants at risk for SBIs. Serum concentrations <= 0.3 ng/mL may be helpful as an add-on test to current rules for identifying low-risk, febrile infants. PMID- 25281187 TI - Neurological prognostication by gender in out-of-hospital cardiac arrest patients receiving hypothermia treatment. AB - OBJECTIVES: This study examined whether the extent to which out-of-hospital cardiac arrest (OHCA) patients recover neurological function after therapeutic hypothermia (TH) is augmented in specific gender, age, and primary ECG group. METHODS: A cross-sectional analysis was conducted using a nationwide database of OHCAs in Korea which was constructed from emergency medical services (EMS) run sheet and hospital medical record review between 2008 and 2012. Patients survived to admission were enrolled. Study endpoint was survival with neurological recovery (cerebral performance category 1 and 2). Main exposure was hypothermia. Gender, age group (<45, 45-65, and >65 years old) and primary ECG rhythm were considered as potential effect modifiers. Potential factors were accounted for adjustment using multivariable logistic regression. RESULTS: Survival with good neurological recovery was 14.6% (9.3% in men and 17.2% in women). TH was performed in 15.5% (n=1140). Strata-specific crude analysis showed enhanced neurological recovery for women of childbearing ages compared to men counterparts (OR=4.38 (1.39, 13.74) vs. OR=1.73 (0.97, 3.10)). After adjusted for effect modifiers and covariates, the strongest effect of TH on neurological recovery was observed in men younger than 45 years of age with shockable rhythm (OR=2.00 (1.26, 3.19)), whereby no statistically significant associations were found in all women. In both genders, the magnitude of association decreased with age and having non-shockable cardiac rhythm. CONCLUSION: TH was the strongest indicator for good neurological recovery in <45-year old men with shockable cardiac rhythm. Across all age groups, women were less likely to benefit from TH than men. PMID- 25281188 TI - Systematic downloading and analysis of data from automated external defibrillators used in out-of-hospital cardiac arrest. AB - BACKGROUND: Valuable information can be retrieved from automated external defibrillators (AEDs) used in victims of out-of-hospital cardiac arrest (OHCA). We describe our experience with systematic downloading of data from deployed AEDs. The primary aim was to compare the proportion of shockable rhythm from AEDs used by laypersons with the corresponding proportion recorded by the Emergency Medical Services (EMS) on arrival. METHODS: In a 20-month study, we collected data on OHCAs in the Capital Region of Denmark where an AED was deployed prior to arrival of EMS. The AEDs were brought to the emergency medical dispatch centre for data downloading and rhythm analysis. Patient data were retrieved from the medical records from the admitting hospital, whereas data on EMS rhythm analyses were obtained from the Danish Cardiac Arrest Register between 2001 and 2010. RESULTS: A total of 121 AEDs were deployed, of which 91 cases were OHCAs with presumed cardiac origin. The prevalence of initial shockable rhythm was 55.0% (95% CI [44.7-64.8%]). This was significantly greater than the proportion recorded by the EMS (27.6%, 95% CI [27.0-28.3%], p<0.0001). Shockable arrests were significantly more likely to be witnessed (92% vs. 34%, p<0.0001) and the bystander CPR rate was higher (98% vs. 85%, p=0.04). More patients with initial shockable rhythm achieved return of spontaneous circulation upon hospital arrival (88% vs. 7%, p<0.0001) and had higher 30-day survival rate (72% vs. 5%, p<0.0001). CONCLUSION: AEDs used by laypersons revealed a higher proportion of shockable rhythms compared to the EMS rhythm analyses. PMID- 25281189 TI - Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). AB - INTRODUCTION: Many patients who suffer cardiac arrest do not respond to standard cardiopulmonary resuscitation. There is growing interest in utilizing veno arterial extracorporeal membrane oxygenation assisted cardiopulmonary resuscitation (E-CPR) in the management of refractory cardiac arrest. We describe our preliminary experiences in establishing an E-CPR program for refractory cardiac arrest in Melbourne, Australia. METHODS: The CHEER trial (mechanical CPR, Hypothermia, ECMO and Early Reperfusion) is a single center, prospective, observational study conducted at The Alfred Hospital. The CHEER protocol was developed for selected patients with refractory in-hospital and out-of-hospital cardiac arrest and involves mechanical CPR, rapid intravenous administration of 30 mL/kg of ice-cold saline to induce intra-arrest therapeutic hypothermia, percutaneous cannulation of the femoral artery and vein by two critical care physicians and commencement of veno-arterial ECMO. Subsequently, patients with suspected coronary artery occlusion are transferred to the cardiac catheterization laboratory for coronary angiography. Therapeutic hypothermia (33 degrees C) is maintained for 24h in the intensive care unit. RESULTS: There were 26 patients eligible for the CHEER protocol (11 with OHCA, 15 with IHCA). The median age was 52 (IQR 38-60) years. ECMO was established in 24 (92%), with a median time from collapse until initiation of ECMO of 56 (IQR 40-85) min. Percutaneous coronary intervention was performed on 11 (42%) and pulmonary embolectomy on 1 patient. Return of spontaneous circulation was achieved in 25 (96%) patients. Median duration of ECMO support was 2 (IQR 1-5) days, with 13/24 (54%) of patients successfully weaned from ECMO support. Survival to hospital discharge with full neurological recovery (CPC score 1) occurred in 14/26 (54%) patients. CONCLUSIONS: A protocol including E-CPR instituted by critical care physicians for refractory cardiac arrest which includes mechanical CPR, peri arrest therapeutic hypothermia and ECMO is feasible and associated with a relatively high survival rate. PMID- 25281190 TI - Turkish doctors face prosecution for treating protesters. PMID- 25281191 TI - Insulin-like growth factor I enhances collagen synthesis in engineered human tendon tissue. AB - OBJECTIVE: Isolated human tendon cells form 3D tendon constructs that demonstrate collagen fibrillogenesis and feature structural similarities to tendon when cultured under tensile load. The exact role of circulating growth factors for collagen formation in tendon is sparsely examined. We investigated the influence of insulin-like growth factor I (IGF-I) on tendon construct formation in 3D cell culture. DESIGN: Tendon constructs were grown in 0.5 or 10% FBS with or without IGF-I (250 mg/ml) supplementation. Collagen content (fluorometric), mRNA levels (PCR) and fibril diameter (transmission electron microscopy) were determined at 7, 10, 14, 21 and 28 days. RESULTS: IGF-I revealed a stimulating effect on fibril diameter (up to day 21), mRNA for collagen (to day 28), tenomodulin (to day 28) and scleraxis (at days 10 and 14), and on overall collagen content. 10% FBS diminished the development of fibril diameter (day 14), collagen content (at days 21 and 28) and mRNA expression for collagen, tenomodulin and scleraxis. CONCLUSION: IGF-I supplementation promotes early onset of tensile load induced collagen formation and tendon structural arrangement, whereas the FBS concentration routinely used in cultures diminishes collagen expression, collagen content and fibril formation. PMID- 25281192 TI - VirS, an OmpR/PhoB subfamily response regulator, is required for activation of vapA gene expression in Rhodococcus equi. AB - BACKGROUND: Rhodococcus equi is an important pulmonary pathogen in foals and in immunocompromised individuals. Virulent R. equi strains carry an 80-90 kb virulence plasmid that expresses the virulence-associated protein A (VapA). VapA expression is regulated by temperature and pH. The LysR-type transcriptional regulator, VirR, is involved in the regulation of the vapA gene. To examine the mechanism underlying transcriptional regulation of vapA, we characterized an R. equi mutant in which another putative transcriptional regulator encoded on the virulence plasmid, VirS, was deleted. RESULTS: Deletion of virS reduced vapA promoter activity to non-inducible levels. Complementary expression of VirS in the virS deletion mutant restored transcription at the PvapA promoter, even under non-inducing conditions (30 degrees C and pH 8.0). In addition, VirS expression increased PvapA promoter activity in the absence of functional VirR. Further, transcription of the icgA operon containing virS was regulated by pH and temperature in the same manner as vapA. CONCLUSIONS: This study suggests that VirS is required for VapA expression and that regulation of PvapA-promoter activity may be achieved by controlling VirS expression levels. PMID- 25281193 TI - The implicit rules of combat. AB - Conspecific violence has been pervasive throughout evolutionary history. The current research tested the hypotheses that individuals implicitly categorize combative contexts (i.e., play fighting, status contests, warfare, and anti exploitative violence) and use the associated contextual information to guide expectations of combative tactics. Using U.S. and non-U.S. samples, Study 1 demonstrated consistent classification of combative contexts from scenarios for which little information was given and predictable shifts in the acceptability of combative tactics across contexts. Whereas severe tactics (e.g., eye-gouging) were acceptable in warfare and anti-exploitative violence, they were unacceptable in status contests and play fights. These results suggest the existence of implicit rules governing the contexts of combat. In Study 2, we explored the reputational consequences of violating these implicit rules. Results suggest that rule violators (e.g., those who use severe tactics in a status contest) are given less respect. These are the first studies to implicate specialized mechanisms for aggression that use contextual cues of violence to guide expectations and behavior. PMID- 25281194 TI - Comparison of two measures of weight criticism in youth: associations with physical activity engagement and attitudes, weight status, and health-related quality of life. AB - The objective of this study was to examine the degree to which 2 measures of weight criticism, the Weight Criticism During Physical Activity (WCA) scale and the Perceptions of Teasing Scale (POTS), represent distinct constructs and in what circumstances each is most appropriately used. A community sample of 307 fourth and fifth graders completed these measures, as well as measures of health related quality of life, physical activity engagement, and attitudes toward physical activity. Body mass index was also calculated. Results of confirmatory factor analysis indicated that the WCA scale and the POTS represented correlated but distinct constructs and related differently to measures of physical activity and weight status. Findings suggested that the WCA scale may be representing criticism regarding athletic competency, not criticism of weight status as described in the literature. The POTS subscales appear to be accurately described and used in the literature. PMID- 25281195 TI - The gap between calculated and actual calcium substitution during citrate anticoagulation in an immobilised patient on renal replacement therapy reflects the extent of bone loss - a case report. AB - BACKGROUND: Demineralisation and bone density loss during immobilisation are known phenomena. However information concerning the extent of calcium loss during immobilisation remains inconsistent within literature. This may explain why treatment of bone loss and prevention of further demineralisation is often initiated only when spontaneous bone fracture occurred.Continuous renal replacement therapy is commonly utilised in critically ill patients with acute kidney injury requiring RRT. Regional anticoagulation with citrate for CRRT is well-established within the intensive care setting. Due to calcium free dialysate, calcium is eliminated directly as well as indirectly via citrate binding necessitating calcium substitution. In anuric patients declining calcium requirements over time reflect bone calcium liberation secondary to immobilisation. The difference between the expected and actual need for calcium infusion corresponds to calcium release from bone which is particularly impressive in patients exposed to long-term immobilisation and CRRT. We report a dialysis period in excess of 250 days with continuous renal replacement therapy and anticoagulation with citrate. CASE PRESENTATION: We present a 30-year old male with prolonged multisystem organ failure after bilateral lung transplantation, in whom during a period of 254 days the cumulative difference between expected and actual need for calcium infusion was 14.25 mol, representing an estimated calcium loss of about 571 g. Comparison of computed tomographic imaging of the lower thoracic vertebrae over this period depicts a radiographically discernible decrease in bone density from 238 to 52 Hounsfield Units. The first spontaneous fracture occurred after 6 months of immobilisation. Despite subsequent treatment with bisphosphonates and androgen therapy resulting in an increase in bone density to 90 HU a further fracture occurred. CONCLUSION: In immobilised patients receiving CRRT and anticoagulation with citrate, decreasing need for calcium substitution reflects the degree of bone demineralisation corresponding with radiographic assessment of declining bone mineral density. Such a declining need for calcium substitution could be useful in clinical practice highlighting relevant bone loss which results in spontaneous fractures in immobilised critically ill patients. PMID- 25281196 TI - Cryopreserved embryo transfer in an artificial cycle: is GnRH agonist down regulation necessary? AB - The use of GnRH agonist downregulation in artificial endometrium priming cycles for cryopreserved embryo transfer was retrospectively investigated to establish whether higher live birth rates resulted. Six hundred and ninety-nine patients underwent 1129 artificial endometrium priming cycles for the transfer of cryopreserved embryos between 1 July 2009 and 1 June 2012. Hormonal supplementation with (group A, n = 280 cycles) or without (group B, n = 849 cycles) GnRH agonist co-treatment was given. Live birth rates were comparable between the two groups per started cycle (14.9% [41/275] in group A versus 15.1% [127/839] in group B) or per embryo transfer (17.5% [41/234] in group A versus 17.6% [127/723] in group B). After logistic regression analysis, the only variables that were significantly associated with live birth rates were day of embryo transfer (OR 0.69; 95% CI 0.48 to 0.98) for day 3 versus day 5 embryos, the number of embryos transferred (OR 2.13; 95% CI 1.58 to 2.86) for two embryos versus one embryo transferred and the endometrial thickness on the day of embryo transfer (OR 1.15; 95% CI 1.05 to 1.25). Live birth rates after cryopreserved embryo transfer in artificial cycles did not increase when a GnRH agonist was administered. PMID- 25281197 TI - Visualization and correction of automated segmentation, tracking and lineaging from 5-D stem cell image sequences. AB - BACKGROUND: Neural stem cells are motile and proliferative cells that undergo mitosis, dividing to produce daughter cells and ultimately generating differentiated neurons and glia. Understanding the mechanisms controlling neural stem cell proliferation and differentiation will play a key role in the emerging fields of regenerative medicine and cancer therapeutics. Stem cell studies in vitro from 2-D image data are well established. Visualizing and analyzing large three dimensional images of intact tissue is a challenging task. It becomes more difficult as the dimensionality of the image data increases to include time and additional fluorescence channels. There is a pressing need for 5-D image analysis and visualization tools to study cellular dynamics in the intact niche and to quantify the role that environmental factors play in determining cell fate. RESULTS: We present an application that integrates visualization and quantitative analysis of 5-D (x,y,z,t,channel) and large montage confocal fluorescence microscopy images. The image sequences show stem cells together with blood vessels, enabling quantification of the dynamic behaviors of stem cells in relation to their vascular niche, with applications in developmental and cancer biology. Our application automatically segments, tracks, and lineages the image sequence data and then allows the user to view and edit the results of automated algorithms in a stereoscopic 3-D window while simultaneously viewing the stem cell lineage tree in a 2-D window. Using the GPU to store and render the image sequence data enables a hybrid computational approach. An inference-based approach utilizing user-provided edits to automatically correct related mistakes executes interactively on the system CPU while the GPU handles 3-D visualization tasks. CONCLUSIONS: By exploiting commodity computer gaming hardware, we have developed an application that can be run in the laboratory to facilitate rapid iteration through biological experiments. We combine unsupervised image analysis algorithms with an interactive visualization of the results. Our validation interface allows for each data set to be corrected to 100% accuracy, ensuring that downstream data analysis is accurate and verifiable. Our tool is the first to combine all of these aspects, leveraging the synergies obtained by utilizing validation information from stereo visualization to improve the low level image processing tasks. PMID- 25281199 TI - Artesunate ameliorates hepatic fibrosis induced by bovine serum albumin in rats through regulating matrix metalloproteinases. AB - The effect of Artesunate on anti-hepatic fibrosis was discovered by our team for the first time. In order to investigate the effect of Artesunate on hepatic fibrosis induced by Bovine serum albumin (BSA) in rats and understand the initiatory mechanism of its effect, several experiments were conducted in this assay. HE staining and Masson's Trichrome staining were employed in observation of morphological changes. The content of hydroxyproline in the hepatic tissue was determined by using an acid hydrolyzation method. In addition, the expression of Matrix metalloproteinase-13 (MMP-13) and type I collagen were tested by western blotting respectively. The expression of Matrix metalloproteinase-2(MMP-2), Matrix metalloproteinase-9 (MMP-9) were determined by Gelatin Zymography Assay. Also, we use immunohistochemical studies to measure the expression of alpha-SMA. The final results indicated that Artesunate could dramatically attenuate the extent of hepatic fibrosis showed by histopathological sections of hepatic tissues, significantly decrease the content of hydroxyproline and efficiently inhibit the protein expression of MMP-2, MMP-9, alpha-SMA and type I collagen. Artesunate could as well promote the expression of MMP-13 at the same time. In conclusion, the results not only suggested that Artesunate could ameliorate hepatic fibrosis, but also suggested the anti-fibrogenic mechanisms of Artesunate might be associated with inhibiting the activation of HSCs, decreasing the expression of MMP-2, MMP-9 and increasing the expression of MMP-13.These results would bring new insights for the treatment for hepatic fibrosis. PMID- 25281198 TI - Allergy and worms: let's bring back old friends? AB - PURPOSE OF REVIEW: In order to survive in their host, parasitic worms (helminths) have evolved cunning strategies to manipulate the host immune system, some of which may lead to protection from immune dysregulatory diseases such as allergy. Thus, loss of exposure to helminths due to a highly hygienic life style might have contributed to the fact that living in an industrialized country is being associated with an increased prevalence of allergic diseases. However, it must be pointed out that certain helminth infections can in fact induce an allergic phenotype. Factors such as different parasite species, timing of infection in relation to allergic sensitization, or duration and intensity of infection may influence the association between helminth infections and the development or clinical course of allergic disease. In the present article, we review studies that have explored the interaction between helminth infections and allergy in epidemiological and experimental studies. Furthermore, the possibility of using helminths or helminth-derived molecules for the treatment of allergic diseases is discussed with a focus on evidence from clinical trials. RECENT FINDINGS: During the past 10 years, many exciting and important studies have found that certain helminth infections protect against the development of allergic diseases. Not surprisingly, several clinical trials investigated the effects of deliberate exposure to parasites like porcine whipworm (Trichuris suis) or hookworm (Necator americanus) to develop "helminth therapies". Although they proved to be a safe option to control aberrant inflammation, the final goal is to identify the parasite-derived immunnomodulatory molecules responsible for protective effects. PMID- 25281200 TI - Cytoprotective effect of melatonin against hypoxia/serum deprivation-induced cell death of bone marrow mesenchymal stem cells in vitro. AB - Bone marrow mesenchymal stem cells (MSCs) have been shown great potential for cardiac regeneration. However the therapeutic efficiency has become a major obstacle due to the poor survival of transplanted MSCs in ischemic cardiac tissue. Previous studies reported that melatonin could protect many different types of cells from apoptosis under various pathological conditions. In the present study, we demonstrated that melatonin, an endogenously secreted indoleamine had cytoprotection from hypoxia/serum deprivation (Hy/SD)-induced cell death in MSCs. We further investigated the possible mechanism and found out that melatonin attenuated (Hy/SD)-induced cell death could be via effectively reducing the generation of intracellular reactive oxygen species, an increase in the ratio of Bax/Bcl-2, loss of mitochondrial membrane potential and then activation of caspase-3 in MSCs in response to Hy/SD exposure. Furthermore, melatonin pretreatment significantly modulated the expression of phospho-P38MAPK and phospho-ERK1/2 in Hy/SD-induced MSCs and the protective effects of melatonin were partially reversed by ERK1/2 inhibitor but not p38 inhibitor, suggesting that melatonin inhibited Hy/SD-induced MSCs cell death through the MAPK signaling pathway in part. Taken together, the findings imply that melatonin could improve the survival of engrafted MSCs under hypoxia and serum deprivation condition. Our findings indicate that combination therapy with melatonin may provide therapeutic benefit for improving myocardial function after infarction. PMID- 25281201 TI - Alpha-lipoic acid attenuates cardiac hypertrophy via downregulation of PARP-2 and subsequent activation of SIRT-1. AB - Alpha-lipoic acid (ALA) has been described as a therapeutic agent for a number of conditions related to cardiovascular disease. However, its role in protecting against cardiac hypertrophy has not been elucidated. In this study, we found that ALA effectively ameliorated cardiac hypertrophy in vivo and in vitro. The mRNA and protein levels of poly (ADP-ribose) polymerase-2 (PARP-2), which were significantly upregulated in heart tissues of abdominal aortic constriction (AAC) rats and cultured cardiomyocytes exposed to angiotensin II(Ang II), were significantly suppressed by ALA treatment. Furthermore, ALA reversed the downregulation of sirtuin 1 (SIRT1) induced by Ang II. However, when cardiomyocytes were co-transfected with PARP-2 plasmid or siRNA for SIRT1, ALA failed to inhibit hypertrophic responses. These observations suggested that ALA attenuated cardiac hypertrophy, at least partially via inhibition of PARP-2 and subsequent activation of SIRT1. These findings may shed new light on the understanding of the cardioprotective effect of ALA. PMID- 25281202 TI - Involvement of GPR40, a long-chain free fatty acid receptor, in the production of central post-stroke pain after global cerebral ischemia. AB - Central post-stroke pain (CPSP), one of the complications of cerebral ischemia and neuropathic pain syndrome, is associated with specific somatosensory abnormalities. Although CPSP is a serious problem, detailed underlying mechanisms and standard treatments for CPSP are not well established. In this study, we assessed the role of GPR40, a long-chain fatty acid receptor, showing anti nociceptive effects, in CPSP. We also examined the role of astrocytes in CPSP due to their effects in mediating the release of polyunsaturated fatty acids, which act as potential GPR40 ligands. The aim of this study was to determine the interactions between CPSP and astrocyte/GPR40 signaling. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical hyperalgesia was measured after BCAO using the von Frey test. Neuronal damage was estimated by histological analysis on day 3 after BCAO. The thresholds for hind paw mechanical hyperalgesia were significantly decreased on days 1-28 after BCAO when compared with those of pre-BCAO assessments. BCAO induced mechanical hyperalgesia was significantly decreased by intracerebroventricular injection of docosahexaenoic acid or GW9508, a GPR40 agonist; furthermore, these effects were reversed by GW1100, a GPR40 antagonist. The expression levels of glial fibrillary acidic protein, an astrocytic marker, and some free fatty acids were significantly decreased 5h after BCAO, although no effects of BCAO were noted on hypothalamic GPR40 protein expression. Our data show that BCAO-induced mechanical hyperalgesia is possible to be regulated by astrocyte activation and stimulation of GPR40 signaling. PMID- 25281203 TI - Strontium ranelate improved tooth anchorage and reduced root resorption in orthodontic treatment of rats. AB - The anchorage mechanisms currently used in orthodontic treatment have various disadvantages. The objective of this study was to determine the applicability of the osteoporosis medication strontium ranelate in pharmacologically induced orthodontic tooth anchorage. In 48 male Wistar rats, a constant orthodontic force of 0.25 N was reciprocally applied to the upper first molar and the incisors by means of a Sentalloy((r)) closed coil spring for two to four weeks. 50% of the animals received strontium ranelate at a daily oral dosage of 900 mg per kilogramme of body weight. Bioavailability was determined by blood analyses. The extent of tooth movement was measured both optometrically and cephalometrically (CBCT). Relative alveolar gene expression of osteoclastic markers and OPG-RANKL was assessed by qRT-PCR and root resorption area and osteoclastic activity were determined in TRAP-stained histologic sections of the alveolar process. Compared to controls, the animals treated with strontium ranelate showed up to 40% less tooth movement after four weeks of orthodontic treatment. Gene expression and histologic analyses showed significantly less osteoclastic activity and a significantly smaller root resorption area. Blood analyses confirmed sufficient bioavailability of strontium ranelate. Because of its pharmacologic effects on bone metabolism, strontium ranelate significantly reduced tooth movement and root resorption in orthodontic treatment of rats. Strontium ranelate may be a viable agent for inducing tooth anchorage and reducing undesired root resorption in orthodontic treatment. Patients under medication of strontium ranelate have to expect prolonged orthodontic treatment times. PMID- 25281205 TI - Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR gamma. AB - Citral, a component of lemongrass oil, has been reported to have many pharmacological activities such as anti-bacterial and anti-inflammatory effects. However, the effects of citral on acute lung injury (ALI) and the molecular mechanisms have not been reported. The aim of this study was to detect the effects of citral on lipopolysaccharide (LPS)-induced acute lung injury and investigate the molecular mechanisms. LPS-induced acute lung injury model was used to detect the anti-inflammatory effect of citral in vivo. The alveolar macrophages were used to investigate the molecular mechanism of citral in vitro. The results showed that pretreatment with citral remarkably attenuated pulmonary edema, histological severities, TNF-alpha, IL-6 and IL-1beta production in LPS induced ALI in vivo. In vitro, citral inhibited LPS-induced TNF-alpha, IL-6 and IL-1beta production in alveolar macrophages. LPS-induced NF-kappaB activation was also inhibited by citral. Furthermore, we found that citral activated PPAR-gamma and the anti-inflammatory effects of citral can be reversed by PPAR-gamma antagonist GW9662. In conclusion, this is the first to demonstrate that citral protects LPS-induced ALI in mice. The anti-inflammatory mechanism of citral is associated with activating PPAR-gamma, thereby inhibiting LPS-induced inflammatory response. PMID- 25281204 TI - NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation. AB - NMDA receptors (NMDAR) are important in the development and maintenance of central sensitization. Our objective was to investigate the role of spinal neurons and NMDAR in the maintenance of chronic visceral pain. Neonatal rats were injected with acidic saline adjusted to pH 4.0 in the gastrocnemius muscle every other day for 12 days. In adult rats, NR1 and NR2B subunits were examined in the lumbo-sacral (LS) spinal cord. A baseline, visceromotor response (VMR) to graded colorectal distension (CRD) was recorded before and after administration of the NMDA antagonist, CGS-19755. Extracellular recordings were performed from CRD sensitive LS spinal neurons and pelvic nerve afferents (PNA) before and after CGS 19755. Rats that received pH 4.0 saline injections demonstrated a significant increase in the expression NR2B subunits and VMR response to CRD>20 mmHg. CGS 19755 (i.v. or i.t.) had no effect in naive rats, but significantly decreased the response to CRD in pH 4.0 saline injected rats. CGS-19755 had no effect on the spontaneous firing of SL-A, but decreased that of SL-S. Similarly, CGS-19755 attenuates the responses of SL-S neurons to CRD, but had no effect on SL-A neurons or on the response characteristics of PNA fibers. Neonatal noxious somatic stimulation results in chronic visceral hyperalgesia and sensitizes a specific subpopulation of CRD-sensitive spinal neurons. The sensitization of these SL-S spinal neurons is attenuated by the NMDAR antagonist. The results of this study suggest that spinal NMDARs play an important role in the development of hyperalgesia early in life. PMID- 25281206 TI - Impacts of human leukocyte antigen DQ genetic polymorphisms and their interactions with hepatitis B virus mutations on the risks of viral persistence, liver cirrhosis, and hepatocellular carcinoma. AB - Human leukocyte antigen (HLA)-DQ genetic polymorphisms have been associated with chronic hepatitis B virus (HBV) outcomes. We aimed to determine impacts of HLA-DQ polymorphisms and their interactions with HBV mutations on the risks of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). rs2856718 (A>G) and rs9275319 (A>G) were genotyped in 1342 healthy controls, 327 HBV surface antigen (HBsAg) seroclearance subjects, 611 asymptomatic HBsAg carriers (ASCs), 1144 chronic hepatitis B (CHB) patients, 734 LC patients, and 1531 HCC patients using quantitative PCR. HBV mutations were detected by direct sequencing. Logistic regression analyses were utilized to assess the factors and/or multiplicative interactions significantly associated with liver diseases. rs9275319 variant genotypes were inversely associated with HBV persistence compared to HBV natural clearance subjects. rs2856718 variant genotypes significantly increased LC risk compared to ASCs plus CHB patients (GG vs. AA: odds ratio [OR], 1.52, 95% confidence interval [CI], 1.17-1.97 and AG+GG vs. AA: OR, 1.27; 95% CI, 1.04 1.54) and decreased HCC risk compared to HCC-free HBV-infected subjects (AG vs. AA: OR, 0.76; 95% CI, 0.65-0.89 and AG+GG vs. AA: OR, 0.78, 95% CI, 0.68-0.90). rs2856718 variant genotypes were significantly associated with an increased frequency of HBV A1726C mutation, a LC-risk, HCC-protective mutation, in genotype C. A rs9275319 variant genotype (GG) was significantly associated with an increased frequency of preS1 start codon mutation, an HCC-risk mutation, in genotype C. The interaction of rs2856718 AG+GG genotype with T1753V, a HCC-risk mutation, significantly reduced LC risk, with an OR of 0.26 (95% CI, 0.09-0.78); whereas the interaction of rs2856718 AG genotype with C1673T, a LC-risk mutation, significantly increased HCC risk, with an OR of 2.80 (95% CI, 1.02-7.66) in genotype C HBV-infected subjects. Conclusively, the HLA-DQ polymorphisms affect the risks of LC and HCC differently in chronic HBV-infected subjects, possibly via interacting with the HBV mutations. PMID- 25281207 TI - Molecular epidemiology of human G2P[4] rotaviruses in Taiwan, 2004-2011. AB - In 2006, two rotavirus vaccines (Rotarix and RotaTeq) became available on the private market in Taiwan. Although vaccine coverage is currently low, molecular surveillance of rotavirus strains can provide pertinent information for evaluation of the potential impact of vaccine introduction and infection control. During January 2008-December 2011, children aged <5 years hospitalized with acute gastroenteritis were enrolled from sentinel surveillance hospitals in three geographic areas of Taiwan. Fecal specimens collected from enrolled patients were tested for rotavirus by enzyme immunoassay and reverse transcriptase-polymerase chain reaction. For genotyping, gene specific primer sets were used to amplify and sequence the genes encoding the neutralization antigens, VP7 and VP4. The resulting sequences were then subjected to phylogenetic analysis. In brief, a total of 4,052 fecal specimens were tested and 742 (18%) samples were positive for rotavirus. The annual range of rotavirus positive specimens varied between 16% and 20.7%. Of all specimens, genotype G1P[8] (63.3%) was the predominant strain, followed by G2P[4] (12.5%), G3P[8] (11.7%), and G9P[8] (5.1%). Uncommon strains were also detected in low percentages. We observed that the rotavirus positivity rate steadily decreased from 21% to 16% during 2008-2010, then slightly increased to 20% in 2011, when an increase in the number of G2P[4] cases was observed. Sequence and phylogenetic analysis was carried out to help understand any potential changes of G2P[4] rotaviruses over time. A number of G2P[4] strains collected between 2004 and 2011 were analyzed in detail and our analyses showed marked genetic and antigenic variability in the VP7 and VP4 genes. The Taiwanese strains could be classified into two major G2 VP7 lineages (IV and V) and two major P[4] VP4 lineages (IV and V) and several minor sublineages within lineage IV. Lineage V within both G2 and P[4] represented newly recognized genetic variants of the respective genotypes. The distribution of individual combinations of the G2 and P[4] (sub)lineages showed some temporal variations. This study provides further evidence for the great genetic diversity among G2P[4] strains and helps understand the epidemiological trends of these strains among children in Taiwan. PMID- 25281208 TI - Genetic variation within and among species of Cloacina (Strongyloidea: Cloacinine) from the swamp wallaby, Wallabia bicolor (Marsupialia: Macropodidae). AB - This study examined genetic variation within and among species of Cloacina found in the swamp wallaby (Wallabia bicolor) collected at different localities along the eastern coast of Australia, and evaluated geographical distance as a potential driver for genetic variation. The first and second internal transcribed spacers (ITS-1 and ITS-2, respectively) of the nuclear ribosomal DNA were used to characterize individuals of 11 morphospecies of Cloacina that parasitize W. bicolor. The results of the molecular analyses revealed multiple genotypes for the nine morphospecies of Cloacina (i.e. Cloacina annulata, Cloacina edwardsi, Cloacina eos, Cloacina gallardi, Cloacina mawsonae, Cloacina papillata, Cloacina papillatissima, Cloacina pollux, and Cloacina wallabiae) for which multiple individuals were available for analysis. However, phylogenetic analyses of the sequence data revealed that for each morphospecies, there was no subdivision of individuals into distinct clades based on geographical region from which they were collected. Additional studies are needed to determine the drivers of genetic variation in cloacinid nematodes, and hence increase our understanding of the diversity of parasitic nematodes in macropodid marsupials. PMID- 25281209 TI - Patient participation in decisions about disease modifying anti-rheumatic drugs: a cross-sectional survey. AB - BACKGROUND: Involvement of patients in decision-making about medication is currently being advocated. This study examined (the concordance between) inflammatory arthritis patients' preferred and perceived involvement in decision making in general, and in four specific decisions about Disease-Modifying Anti Rheumatic Drugs (DMARDs). Furthermore, this study examined how patients' involvement is related to satisfaction about decision-making and which factors are related to preferred roles, perceived roles and concordance. METHODS: Using a cross-sectional survey, 894 patients diagnosed with Rheumatoid Arthritis, Psoriatic Arthritis or Ankylosing Spondylitis were sent a questionnaire which focused on medical decisions in general and on four specific decisions: (a) starting with a traditional DMARD; (b) starting to inject methotrexate; (c) starting a biological DMARD; and (d) decreasing or stopping a DMARD. For each decision preferred and perceived involvement in decision-making was assessed using the Control Preference Scale. Concordance was calculated by subtracting the scores for perceived role from scores for the preferred role. Furthermore, satisfaction with the decision process and socio-demographic, health-related, patient-related and physician-related variables were assessed. RESULTS: The response rate was 58%. For all decisions, most patients (59%-63%) preferred Shared Decision-Making (SDM). SDM was perceived frequently (26%-55%) and patients' preferences were met in 54% of the respondents. Yet, in some specific decisions, 26% to 54% of patients would have liked more participation. Perceiving less participation then preferred was associated with less satisfaction with the decision-process, but perceiving more participation than preferred was not. Our results did not reveal any meaningful models to predict preferred or perceived participation in decision-making in general or with reference to specific decisions about DMARDs. CONCLUSIONS: Most arthritis patients prefer to be involved in decisions about their medication and SDM is perceived frequently. Yet, in some specific decisions patient participation can be further improved. Patients especially prefer more participation in decision-making regarding starting a first traditional DMARD, which occurs most commonly in newly diagnosed patients. Whereas perceiving too little participation was associated with decreased satisfaction, perceiving too much participation was not. Therefore, rheumatologists should urge patients to participate in every medical decision. PMID- 25281210 TI - First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models. AB - JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders. PMID- 25281211 TI - Effect of oxytocin on serum biochemistry, liver enzymes, and metabolic hormones in lactating Nili Ravi buffaloes. AB - Studies reporting the effects of oxytocin on the health of lactating animals are lacking and still no such data is available on Nili Ravi buffalo, the most prominent Asian buffalo breed. The present study was conducted to investigate the effect of oxytocin on physiological and metabolic parameters of lactating Nili Ravi buffaloes. Healthy lactating buffaloes (n = 40) of recent calving were selected from a commercial dairy farm situated in the peri-urban area of district Faisalabad, Pakistan. These buffaloes were randomly allocated to two equal groups viz experimental and control, comprising 20 animals each. Twice-a-day (morning and evening) milking practice was followed. The experimental and control buffaloes were administered subcutaneously with 3 mL of oxytocin (10 IU/mL) and normal saline respectively, prior to each milking. Serum biochemical profile including glucose, total cholesterol (tChol), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total proteins (TP), C-reactive protein (CRP), liver enzymes aspartate transaminase (AST), alanine transaminase (ALT), and metabolic hormones triiodothyronine (T3) and thyroxine (T4) were studied. Results revealed significantly higher (P <= 0.01) levels of glucose, total cholesterol, LDL-C, triglycerides, total proteins, and C-reactive protein in experimental (oxytocin injected) lactating buffaloes compared to control group. Liver enzymes AST and ALT as well as serum T4 concentration was significantly higher (P <= 0.01) in oxytocin-injected lactating buffaloes as compared to control animals. It was concluded that oxytocin had the key role in increasing the metabolic parameters and hormones, resulting in the optimization of production. But, at the same time, it may pose a threat to the animal health. PMID- 25281212 TI - High frequency of porcine norovirus infection in finisher units of Brazilian pig production systems. AB - Norovirus (NoV) is a member of the Caliciviridae family and is considered an emerging human enteric pathogen. NoVs are detected in farm animals such as cattle, sheep and pigs. Porcine NoV (PoNoV) is widespread worldwide, but frequency of infection is often low. This study aimed to investigate the natural PoNoV infection from adult animals of an important Brazilian pig-production region. Faecal samples (n = 112) of asymptomatic pigs aged 9 to 24 weeks old were collected from 16 grower-to-finish herds located in Parana state, Brazilian Southern region, and evaluated for PoNoV presence. A reverse transcription polymerase chain reaction (RT-PCR) assay was performed using specific primers that target a conserved region of the virus capsid gene (VP1). PoNoV was detected in 58 (51.8%) of the 112 faecal samples and in 14 (87.5%) of the 16 herds evaluated. Six of the obtained amplicons were submitted to phylogenetic genotyping analysis. The higher nucleotide (86.5-97.4%) and amino acid (100%) similarities of the sequences in this study were with the representative strains of the porcine NoV genogroup II genotype 11 (PoNoV GII-11). These results reveal that PoNoV infection is endemic in one of the most important pork production areas of Brazil and that the PoNoV GII-11 is prevalent in this region. PMID- 25281213 TI - Hydrocaffeic acid-chitosan nanoparticles with enhanced stability, mucoadhesion and permeation properties. AB - Catechol-containing molecules, such as hydrocaffeic acid (HCA) have been shown to increase the mucoadhesion of several polymers. We report here a simple and bioinspired approach to enhance chitosan (CS) mucoadhesion and stabilize it in nanoparticulate form by preparing HCA-CS conjugates. HCA-CS conjugates containing 6 and 15mol% HCA were synthesized and characterized by FT-IR, (1)H NMR and UV-vis spectrophotometry. HCA-CS nanoparticles prepared by ionic gelation with sodium tripolyphosphate (TPP) ranged in size between 100 and 250nm depending on the polymer and TPP/CS weight ratio. In contrast to CS nanoparticles, which aggregate at pH>6.5, HCA-CS nanoparticles did not show any sign of aggregation or precipitation over the 4-10 pH range and maintain their size. Unexpectedly, HCA CS nanoparticles also maintained their size and polydispersity index at pH 7.4 and NaCl concentrations of up to 500mM. Partial oxidation of HCA resulted in nanoparticle cross-linking and improved stability at pH<4. HCA-CS mucoadhesion to rabbit small intestine was 6 times higher than unmodified CS. CS and HCA-CS nanoparticles were able to induce reversible tight junction opening in Caco-2 cell monolayers. Tight junction opening facilitated the permeability of a model hydrophilic molecule, fluorescein isothiocyanate-labeled dextran (FD4) and was 3 times higher in the cells treated with HCA-CS 15% nanoparticles compared to control groups. HCA-CS conjugates were found to be excellent candidates for stable nanodelivery systems with enhanced oral absorption of hydrophilic molecules. PMID- 25281214 TI - iMSAT: a novel approach to the development of microsatellite loci using barcoded Illumina libraries. AB - BACKGROUND: Illumina sequencing with its high number of reads and low per base pair cost is an attractive technology for development of molecular resources for non-model organisms. While many software packages have been developed to identify short tandem repeats (STRs) from next-generation sequencing data, these methods do not inform the investigator as to whether or not candidate loci are polymorphic in their target populations. RESULTS: We provide a python program iMSAT that uses the polymorphism data obtained from mapping individual Illumina sequence reads onto a reference genome to identify polymorphic STRs. Using this approach, we identified 9,119 candidate polymorphic STRs for use with the parasitoid wasp Trioxys pallidus and 2,378 candidate polymorphic STRs for use with the aphid Chromaphis juglandicola. For both organisms we selected 20 candidate tri-nucleotide STRs for validation. Using fluorescent-labeled oligonucleotide primers, we genotyped 91 female T. pallidus collected in nine localities and 46 female C. juglandicola collected in 4 localities and found 15 of the examined markers to be polymorphic for T. pallidus and 12 of the examined markers to be polymorphic for C. juglandicola. CONCLUSIONS: We present a novel approach that uses standard Illumina barcoding primers and a single Illumina HiSeq run to target polymorphic STR fragments to develop and test STR markers. We validate this approach using the parasitoid wasp T. pallidus and its aphid host C. juglandicola. This approach, which would also be compatible with 454 Sequencing, allowed us to quickly identify markers with known variability. Accordingly, our method constitutes a significant improvement over existing STR identification software packages. PMID- 25281215 TI - Comprehensive diagnosis of whole-body acid-base and fluid-electrolyte disorders using a mathematical model and whole-body base excess. AB - A mathematical model of whole-body acid-base and fluid-electrolyte balance was used to provide information leading to the diagnosis and fluid-therapy treatment in patients with complex acid-base disorders. Given a set of measured laboratory chemistry values for a patient, a model of their unique, whole-body chemistry was created. This model predicted deficits or excesses in the masses of Na(+), K(+), Cl(-) and H2O as well as the plasma concentration of unknown or unmeasured species, such as ketoacids, in diabetes mellitus. The model further characterized the acid-base disorder by determining the patient's whole-body base excess and quantitatively partitioning it into ten components, each contributing to the overall disorder. The results of this study showed the importance of a complete set of laboratory measurements to obtain sufficient accuracy of the quantitative diagnosis; having only a minimal set, just pH and PCO2, led to a large scatter in the predicted results. A computer module was created that would allow a clinician to achieve this diagnosis at the bedside. This new diagnostic approach should prove to be valuable in the treatment of the critically ill. PMID- 25281216 TI - Dual specificity phosphatase 4 gene expression in association with triple negative breast cancer outcome. AB - Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. Dual specificity phosphatase 4 (DUSP4) has recently been suggested as a potential marker of chemotherapy resistance for TNBC. DUSP4 gene expression levels were measured in breast cancer tissue from 469 TNBC patients aged 20-75 years who participated in the Shanghai Breast Cancer Survival Study, and their association with recurrence/breast cancer mortality and total mortality was evaluated. Information on breast cancer diagnosis, treatment, and disease progression was collected via medical chart review and multiple in-person follow up surveys. A Cox regression model was applied in the data analyses. Over a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of transcript variant 1 (NM_001394) and transcript variant 2 (NM_057158) of the DUSP4 gene were studied and were highly correlated (r = 0.76). Low DUSP4 expression levels, particularly of variant 1, were associated with both increased recurrence/breast cancer mortality and increased overall mortality. Hazard ratios with adjustment for age at diagnosis and TNM stage associated with below versus above the median expression level were 1.97 (95 % confidence interval (CI): 1.27-3.05) for recurrence/breast cancer mortality and 2.09 (95 % CI: 1.38-3.17) for overall mortality. Additional adjustment for expression levels of MKI67 and TP53, common treatment types, breast cancer subtype, and grade did not materially alter the observed associations. Low DUSP4 expression levels predict recurrence and mortality in TNBC patients independently from known clinical and molecular predictors. PMID- 25281218 TI - [Atypical MRI image of Tako-Tsubo syndrome: a case report]. AB - Since the 1990s, a new entity cardiomyopathy is described: the Tako-Tsubo syndrome. The Mayo Clinics' criteria have been defined by to help diagnose: LV dysfunction, electrical modifications, and complete recovery. It is a Caucasian woman aged 66 hospitalized for chest pain syndrome occurred during the funeral. In support, we note the presence of STEMI. The patient received the conventional treatment of acute coronary syndrome. Cardiac ultrasound, angiography is in favor of Tako-Tsubo syndrome. MRI shows an unusual location: a delayed enhancement in epicardial associated pericardial effusion mimicking myopericarditis. PMID- 25281217 TI - Short intronic repeat sequences facilitate circular RNA production. AB - Recent deep sequencing studies have revealed thousands of circular noncoding RNAs generated from protein-coding genes. These RNAs are produced when the precursor messenger RNA (pre-mRNA) splicing machinery "backsplices" and covalently joins, for example, the two ends of a single exon. However, the mechanism by which the spliceosome selects only certain exons to circularize is largely unknown. Using extensive mutagenesis of expression plasmids, we show that miniature introns containing the splice sites along with short (~ 30- to 40-nucleotide) inverted repeats, such as Alu elements, are sufficient to allow the intervening exons to circularize in cells. The intronic repeats must base-pair to one another, thereby bringing the splice sites into close proximity to each other. More than simple thermodynamics is clearly at play, however, as not all repeats support circularization, and increasing the stability of the hairpin between the repeats can sometimes inhibit circular RNA biogenesis. The intronic repeats and exonic sequences must collaborate with one another, and a functional 3' end processing signal is required, suggesting that circularization may occur post transcriptionally. These results suggest detailed and generalizable models that explain how the splicing machinery determines whether to produce a circular noncoding RNA or a linear mRNA. PMID- 25281219 TI - [Stress cardiac MRI in management of ischemic heart disease]. AB - Stress magnetic cardiac resonance imaging (MRI) development is in progress. Many cardiac imaging technics already known are completed by this safe radiation free exam with a short time acquisition (30minutes) and a good diagnostic performance in particular for patients with three vessels coronary artery diseases. Best indication concerns symptomatic patients unable to exercise with intermediate or high pretest probability. Pharmacological heart stress can be induced with vasodilatators or dobutamine to identify the presence and extent of myocardial ischemia, with high precision to guide coronary vessels revascularization. MRI gives many other interesting informations like heart anatomy, left ventricular function. Myocardial viability can be assessed with study of late gadolinium enhancement or analysis of contractile reserve with low dose of dobutamine. PMID- 25281220 TI - Vascular biomarkers in migraine. AB - AIM: Migraine has been associated with stroke as well as with several non atherosclerotic vascular conditions leading to discussions about the potential role of endothelium in the etiopathogenesis of migraine and migraine-associated stroke. We present a systematic review of the literature on vascular biomarkers in migraine, including those suggesting endothelial activation and damage. METHODS: We conducted a systematic literature search from 1990 to 2013 using multiple research databases with the keywords "migraine," "headache," "vascular," and "biomarkers." We used selected inclusion and exclusion criteria to create a final pool of studies for this review. RESULTS: The literature search identified a total of 639 citations of which 129 were included in our review. The final pool of clinical- and population-based studies assessed the level of various biomarkers (e.g. inflammatory, prothrombotic, endothelial activation, endothelial repair) in migraineurs of varying ages, gender, and demographic characteristics. Although for each biomarker there is at least one study suggesting an association with migraine, in many cases the quality of evidence is poor and there are conflicting studies showing no relationship. The results were, therefore, in each case inconclusive. CONCLUSION: This systematic review indicated that in migraine populations there are a number of positive vascular biomarker studies, including some involving novel biomarkers such as endothelial microparticles and endothelial precursor cells. These lend insight into possible pathophysiological mechanisms by which migraine may be associated with stroke. More high-quality studies are needed to establish whether a true association between promising vascular biomarkers and migraine exists. PMID- 25281221 TI - Migraine and cerebral blood flow in the general population. AB - INTRODUCTION: Observations that migraine increases risk of cardiovascular disease and ischemic brain changes may suggest sustained vascular differences between migraineurs and controls. In a population-based setting, we compared cerebral blood flow between migraineurs in the attack-free period and controls. METHODS: Between 2006 and 2008, 2642 participants, aged 45-65, from the Rotterdam Study completed a migraine questionnaire and had complete usable MRI data. Participants were classified into controls (N = 2033), probable migraine (N = 153), or migraine (N = 456). Using 2D phase contrast MRI, we performed a cross-sectional analysis of the effect of migraine on total cerebral blood flow (tCBF), parenchymal cerebral blood flow (pCBF), and blood flow in each intracranial arterial using linear regression. Additionally, we performed stratified analysis of subtypes of migraine. RESULTS: Compared with controls, migraineurs had higher pCBF (1.07 ml/min/100 ml, 95% CI 0.08; 2.05). In particular, migraineurs had significantly higher blood flow in the basilar artery (4.70 ml/min, 95% CI 0.77; 8.62). DISCUSSION: Migraineurs in the attack-free period have higher pCBF, particularly basilar artery flow, compared to controls, supporting the notion of sustained vascular differences between these groups outside of migraine attacks. PMID- 25281222 TI - Up-to-dateness of reviews is often neglected in overviews: a systematic review. AB - BACKGROUND AND OBJECTIVE: As systematic reviews may run out of date, it might be necessary to update them. Out-of-date reviews may jeopardize the comparability when used in the context of overviews (review of reviews). METHODS: Seven electronic databases were searched for overviews up to November 2012. We first aimed to analyze whether the authors of overviews additionally searched for primary studies or alternatively explained why they did not. Second, we sought to analyze the actual publication lag (publication date of the overview - publication date of the review) in overviews and to develop recommendations for authors of overviews. RESULTS: We included 147 overviews. The mean publication lag in overviews was more than 5 years. A median of 36% of the reviews were published more than 6 years ago. Only one in four reviews considered up-to dateness. The methods for updating reviews were heterogeneous. We found no overview that systematically investigated whether an update was necessary. CONCLUSION: The issue of up-to-dateness when conducting overviews seems to be neglected by most authors of overviews. Authors should assess the quality of evidence, based on their included reviews first. PMID- 25281223 TI - MDMA: a social drug in a social context. AB - RATIONALE: The drug +/-3,4-methylenedioxymethamphetamine (MDMA, "ecstasy," "molly") is thought to produce prosocial effects and enhance social interaction. However, in most laboratory studies to date, the participants have been tested under nonsocial conditions, which may not simulate the effects the drug produces in more naturalistic social settings. METHODS: Healthy experienced MDMA users participated in three laboratory sessions in which they received MDMA (0.5 or 1.0 mg/kg or placebo, double blind). They were randomly assigned to one of three social conditions, in which they were tested alone (solitary (SOL); N = 10), in the presence of a research assistant (research assistant present (RAP); N = 11) or in the presence of another participant who also received the drug (other participant present (OPP); N = 11). RESULTS: As expected, MDMA increased heart rate and blood pressure and produced positive subjective effects in all the three groups. It also increased ratings of attractiveness of another person and increased social interaction in RAP and OPP. The social context affected certain responses to the drug. The effects of MDMA were greater in the OPP condition, compared to the SOL or RAP conditions, on measures of "feel drug," "dizzy," and on cardiovascular. But responses to the drug on other measures, including social behavior, did not differ across the conditions. CONCLUSIONS: These findings provide some support for the idea that drugs produce greater effects when they are used in the presence of other drug users. However, the influence of the social context was modest, and it remains to be determined whether other variables related to social context would substantially alter the effects of MDMA or other drugs. PMID- 25281225 TI - Discriminative and locomotor effects of five synthetic cathinones in rats and mice. AB - RATIONALE: Synthetic cathinones continue to be sold as "legal" alternatives to methamphetamine or cocaine. As these marginally legal compounds become controlled, suppliers move to other, unregulated compounds. OBJECTIVES: The purpose of these experiments was to determine whether several temporarily controlled cathinone compounds, which are currently abused on the street, stimulate motor activity and have discriminative stimulus effects similar to cocaine and/or methamphetamine. METHODS: Methcathinone, pentedrone, pentylone, 3 fluoromethcathinone (3-FMC), and 4-methylethcathinone (4-MEC) were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, i.p.) or methamphetamine (1 mg/kg, i.p.) from saline. RESULTS: Methcathinone, pentedrone, and pentylone produced locomotor stimulant effects which lasted up to 6 h. In addition, pentylone produced convulsions and lethality at 100 mg/kg. 4-MEC produced locomotor stimulant effects which lasted up to 2 h. Methcathinone, pentedrone, pentylone, 3 FMC, and 4-MEC each produced discriminative stimulus effects similar to those of cocaine and methamphetamine. CONCLUSIONS: All of the tested compounds produce discriminative stimulus effects similar to either those of cocaine, methamphetamine, or both, which suggests that these compounds are likely to have similar abuse liability to cocaine and/or methamphetamine. Pentylone may be more dangerous on the street, as it produced adverse effects at doses that produced maximal stimulant-like effects. PMID- 25281224 TI - Contributions of beta2 subunit-containing nAChRs to chronic nicotine-induced alterations in cognitive flexibility in mice. AB - RATIONALE: Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that beta2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. OBJECTIVES: In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the beta2 subunit-containing nAChR gene (beta2+/- or beta2-/-) performing an operant cognitive flexibility task. RESULTS: Visual discrimination learning was not affected in saline-treated beta2 nAChR mutants as compared to the wild-type (beta2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in beta2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between beta2+/+ and beta2-/- mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in beta2+/- mice. CONCLUSIONS: Collectively, these findings suggest that beta2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies. PMID- 25281226 TI - Pathological spectrums and renal prognosis of severe lupus patients with rapidly progressive glomerulonephritis. AB - The objectives of the study were to investigate the pathological features and renal prognosis of severe lupus patients with rapidly progressive glomerulonephritis. One hundred and one cases of biopsy-proven severe LN with rapidly progressive glomerulonephritis (RPGN) were analyzed in this retrospective study. Another 200 severe LN patients without RPGN were randomly enrolled as a control group. Their clinicopathological data and long-term outcome were compared. There were 76 females and 25 males with an average age of 31.9 +/- 14.2 years followed for a median period of 4 years. Compared with controls, patients with RPGN had shorter LN duration (p = 0.008), higher level of creatinine (p < 0.001), severe anemia (p = 0.037), heavier hematuria (p < 0.001), severe tubular injury parameters [NAG (p < 0.001), RBP (p < 0.001), C3 (p < 0.001)], higher scores of AI (p = 0.001) and CI (p = 0.004), higher proportions of glomerular sclerosis (0.033) and crescents (p < 0.001), severe tubulointerstitial lesions (p < 0.001) and interstitial inflammation (p < 0.001), lower rate of complete remission (33.9 vs 68.2 %) and higher rate of treatment failure (46.8 vs 7.9 %). The 3-, 5- and 10-year cumulative renal survival rates of RPGN and non-RPGN patients were 65.1 versus 53.9 versus 42.9 and 96.9 versus 94.9 versus 91.7 %, respectively. Multivariate analysis revealed that SCr concentration and the proportion of crescents were the most important risk factors for end-stage renal disease (ESRD) in severe LN with RPGN (p < 0.001). In conclusion, RPGN occurred in 3.6 % of LN and is associated with severe renal manifestations, serious sclerotic and crescentic glomeruli lesions, severe tubulointerstitial inflammation, atrophy and fibrosis, prominent leukocyte infiltration and worse treatment response. Multivariate analysis revealed that SCr concentration and the proportion of crescents were the most important risk factors for ESRD. 57.1 % of severe LN patients with RPGN might progress to ESRD within 10 years. PMID- 25281227 TI - Comparison of the acceptability and benefits of two mindfulness-based interventions in women with breast or gynecologic cancer: a pilot study. AB - PURPOSE: The aim of this study was to compare the relative benefits and acceptability of two different group-based mindfulness psychotherapy interventions among women with breast and gynecologic cancer. METHODS: Data from 42 women who completed an 8-week mindfulness-based cognitive therapy (MBCT) program comprising 22 contact hours were compared to data from 24 women who completed a 6-week mindfulness meditation program (MMP) comprising 9 contact hours. Distress, quality of life (QOL), and mindfulness were evaluated pre- (T1) and post-intervention (T2). ANCOVA was used to analyse the relationship between intervention type and T1 score on outcome variable change scores. Participants' perceptions of benefit and acceptability were assessed. RESULTS: The participants did not differ on clinical or demographic variables other than MBCT participants were more likely than MMP participants to have a past history of anxiety or depression (p = .01). Scores on distress, QOL, and mindfulness improved from T1 to T2 with medium to large effect sizes for the MMP (p=.002, d=.7; p=.001, d=.8; p=.005, d=.6, respectively) and MBCT (p<.001,d = .6; p=.008, d = .4; p<.001, d=.9, respectively) interventions. [correted]. ANCOVA showed no main effect for intervention type on outcome change scores and no interaction between intervention type and respective T1 score. Distress and mindfulness scores at T1 had a main effect on respective change scores (p = .02, etap (2) = .87; p = .01, etap (2) = .80, respectively). Both programs were perceived as beneficial and acceptable with no differences between the intervention types. CONCLUSIONS: Within the limits of a small, non-randomized study, these findings provide preliminary support for the utility of a brief mindfulness intervention for improving distress and QOL in a heterogeneous group of women with cancer. Abbreviated interventions are less resource intensive and may be attractive to very unwell patients. PMID- 25281229 TI - The impact of hospice care on survival and cost saving among patients with liver cancer: a national longitudinal population-based study in Taiwan. AB - PURPOSE: The aim of this study was to compare health-care expenditures and survival of these terminally ill patients receiving or not receiving hospice care in their last month of life. METHODS: Using Taiwan's National Health Insurance Claims Database, we analyzed hospitalizations, OPD visits, associated costs, and survival. Logistic regression was used to identify predictors of high cost. RESULTS: We identified 3850 liver cancer patients who died during the 1997-2011 study period, 644 (16.6 %) of whom were hospice care patients. No significant difference was found in mean survival time between the hospice and non-hospice groups (1.77 +/- 2.44 vs. 1.84 +/- 2.37 years, p = 0.217). The mean health-care expenditures per person were US$2370 +/- 3421 and US$2072 +/- 1900 (p = 0.130). A total of 385 patients (10 %) received high-cost care (above US$5422) using 38.6 % of the total health-care expenditures spent on the entire population. The significant predictors of high costs were non-hospice care [odds ratio (OR) = 3.06, 95 % confidence interval (CI) 2.09-4.60], days of admission [risk increase per admission day being (OR = 1.19, 95 % CI 1.17-1.21)], admission into an intensive care unit (OR = 3.17, 95 % CI 1.94 to 5.15), use of ventilator (OR = 3.54, 95 % CI 1.91-6.52), cancer therapy (OR = 1.82, 95 % CI 1.33-2.48), hemodialysis (OR = 2.62, 95 % CI 1.07-6.02), and higher socioeconomic status (OR = 1.65, 95 % CI 1.10-2.45). CONCLUSION: Hospice care did not significantly affect survival, and hospice patients had lower per-patient expenditures and were less likely to require high-cost medical care than their non-hospice counterparts. PMID- 25281228 TI - Association between the duration of palliative care service and survival in terminal cancer patients. AB - PURPOSE: Preliminary studies of early palliative care showed improved quality of life, less medical cost, and better survival time. But, most terminal cancer patients tend to be referred to palliative care late. For the proper care of terminal cancer patients, it is necessary to refer to hospice and palliative care timely. The aim of this study is to analyze the effect of the duration of palliative care services on the survival in terminal cancer patients. METHODS: We reviewed 609 patients who had died from terminal cancer between January 2010 and December 2012. We analyzed correlations of age, first Palliative Performance Scale (PPS) level, duration of palliative care service, and survival time. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. RESULTS: Duration of palliative care services was significantly correlated with survival time. In univariate Cox regression analysis, age, and each group of duration of palliative care service showed significant associations with survival. Final multivariate Cox regression model retained four parameters as independent prognostic factors for survival (age HR = 0.99 (p = 0.002), 1~10 days HR = 2.64 (p < 0.001), 11~30 days HR = 2.43 (p < 0.001), 31~90 days HR = 1.87 (p < 0.001)). CONCLUSIONS: Shorter duration of palliative care services showed poor prognostic factor. Timely referral system from the end of chemotherapy is warranted. PMID- 25281231 TI - Differences in quality of life in obese and normal weight head and neck cancer patients undergoing radiation therapy. AB - PURPOSE: The aim of this study was to evaluate health-related quality of life (HRQOL) in patients with different body mass indices (BMI, <25 vs >=25) undergoing radiation treatment for head and neck cancer. METHODS: HRQOL was examined by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H&N35, in the beginning and in the end of radiation treatment in 60 patients treated at University Hospital in Northern Norway. Information about nutritional status with weight loss, hemoglobin level (Hb), serum albumin, and a study-specific questionnaire also was filled out in the beginning and in the end of treatment. The patients' general condition, skin, and mucous membranes (CTCAE v.3.0) (grades 1 to 5 with unique clinical descriptions) were documented four times during radiation treatment. Changes in HRQOL were calculated and compared by paired sample t test. Multiple regression analyses were used to examine correlations between baseline BMI and changes in HRQOL, CTCAE v.3.0 toxicity, nutritional status, and information that radiotherapists provided to patients. RESULTS: Patients with BMI >= 25 had less mucosal changes after 2 weeks of radiation treatment than patients with BMI < 25 (p = 0.010). Differences regarding feeding tube use (p = 0.037) and intake of nutritional supplements before radiation treatment (p = 0.001) were also seen. Patients with overweight had more dyspnea (p = 0.033) before treatment and more problems with dry mouth (p = 0.042) after treatment. During treatment, patients with BMI >= 25 had more problems with opening mouth (p = 0.034) than patients with BMI < 25 and more changes in sexuality (p = 0.019). Patients with BMI >= 25 received less information about food and drink (p = 0.011) in the radiation treatment period than normal weight patients. CONCLUSIONS: BMI influences HRQOL and toxicity. Additional longitudinal studies should examine whether or not overweight patients persistently experience more problems with dry mouth and opening their mouth. Regardless of BMI, all patients should be informed about nutritional recommendations during treatment. PMID- 25281230 TI - The oncology palliative care clinic at the Princess Margaret Cancer Centre: an early intervention model for patients with advanced cancer. AB - Several recently published randomized controlled trials have demonstrated the benefits of early palliative care involvement for patients with advanced cancer. In the oncology outpatient setting, palliative care clinics are an ideal site for the provision of early, collaborative support, which can be maintained throughout the cancer trajectory. Despite this, access to ambulatory palliative care clinics is limited, even at tertiary cancer centres. Existing programs for outpatient palliative care are variable in scope and are not well described in the literature. We describe the development and expansion of an outpatient palliative care clinic at the Princess Margaret Cancer Centre, Toronto, Canada, demonstrating how the clinic functions at a local and regional level. This clinic served as the intervention for a recent large cluster-randomized trial of early palliative care. The model for this service can be adapted by other palliative care programs that aim to provide early, integrated oncology care. PMID- 25281232 TI - Were Upper Pleistocene human/non-human predator occupations at the Temara caves (El Harhoura 2 and El Mnasra, Morocco) influenced by climate change? AB - The influence of climate change on human settlements in coastal areas is a central question for archaeologists. This paper addresses this issue by focusing on the Temara region in Morocco. The study area was selected for two main reasons. First, it contains numerous caves with Upper Pleistocene deposits, which have yielded remains of anatomically modern humans in association with Aterian and Iberomaurusian artifacts. Second, these caves are currently located on the shore, thus this region is particularly sensitive to major climate change and sea level fluctuations. Diachronic taphonomic study of faunal remains from two sites in the region, El Harhoura 2 and El Mnasra caves, shows alternating human/non human predator occupations. The lower layers of El Mnasra Cave dating to Oxygen Isotope Stage (OIS) 5 have yielded diverse ungulate remains with significant anthropogenic impact marks, together with numerous mollusk shells, Nassarius shell beads, hearths, lithics, some bone tools and used pigments. Faunal remains from the upper layers dating to OIS 4, 3 and 2 of El Harhoura 2 and El Mnasra caves, largely dominated by gazelles, provide evidence of carnivore activities, such as tooth marks, numerous semi-digested bones and coprolites alongside some anthropogenic signatures (cut marks and burnt bones). Non-human predators appear to be the main agents responsible for faunal modifications and accumulations. The 'non-intensive' nature of human occupation is confirmed by analyses of the lithic industry at El Harhoura 2. The 'intensive' human occupations date to OIS 5 and could have taken place during wet periods in connection with high sea levels, which allowed the exploitation of shellfish in this area. 'Non-intensive' human occupations generally correspond to arid periods and lower sea levels, during which the Temara area was further inland and may have been less attractive to humans. PMID- 25281233 TI - Origins of the sympathetic innervation to the nasal-associated lymphoid tissue (NALT): an anatomical substrate for a neuroimmune connection. AB - The participation of sympathetic nerve fibers in the innervation of the nasal associated lymphoid tissues (NALT) was investigated in hamsters. Vesicular monoamine transporter 2 (VMAT2), an established sympathetic marker, is expressed in all neurons of superior cervical ganglia (SCG). In addition, VMAT2 immunoreactive nerve fibers were localized in the NALT as well as in adjacent anatomical structures of the upper respiratory tract. Unilateral surgical ablation of the SCG abolished VMAT2 innervation patterns ipsilaterally while the contra lateral side is unaffected. These results provide the anatomical substrate for a neuroimmune connection in the NALT. PMID- 25281234 TI - CanvasDB: a local database infrastructure for analysis of targeted- and whole genome re-sequencing projects. AB - CanvasDB is an infrastructure for management and analysis of genetic variants from massively parallel sequencing (MPS) projects. The system stores SNP and indel calls in a local database, designed to handle very large datasets, to allow for rapid analysis using simple commands in R. Functional annotations are included in the system, making it suitable for direct identification of disease causing mutations in human exome- (WES) or whole-genome sequencing (WGS) projects. The system has a built-in filtering function implemented to simultaneously take into account variant calls from all individual samples. This enables advanced comparative analysis of variant distribution between groups of samples, including detection of candidate causative mutations within family structures and genome-wide association by sequencing. In most cases, these analyses are executed within just a matter of seconds, even when there are several hundreds of samples and millions of variants in the database. We demonstrate the scalability of canvasDB by importing the individual variant calls from all 1092 individuals present in the 1000 Genomes Project into the system, over 4.4 billion SNPs and indels in total. Our results show that canvasDB makes it possible to perform advanced analyses of large-scale WGS projects on a local server. Database URL: https://github.com/UppsalaGenomeCenter/CanvasDB. PMID- 25281235 TI - The role of visual markers in police victimization among structurally vulnerable persons in Tijuana, Mexico. AB - BACKGROUND: Law enforcement can shape HIV risk behaviours and undermine strategies aimed at curbing HIV infection. Little is known about factors that increase vulnerability to police victimization in Mexico. This study identifies correlates of police or army victimization (i.e., harassment or assault) in the past 6 months among patients seeking care at a free clinic in Tijuana, Mexico. METHODS: From January to May 2013, 601 patients attending a binational student run free clinic completed an interviewer-administered questionnaire. Eligible participants were: (1) >=18 years old; (2) seeking care at the clinic; and (3) spoke Spanish or English. Multivariate logistic regression analyses identified factors associated with police/army victimization in the past 6 months. RESULTS: More than one-third (38%) of participants reported victimization by police/army officials in the past 6 months in Tijuana. In multivariate logistic regression analyses, males (adjusted odds ratio (AOR): 3.68; 95% CI: 2.19-6.19), tattooed persons (AOR: 1.56; 95% CI: 1.04-2.33) and those who injected drugs in the past 6 months (AOR: 2.11; 95% CI: 1.29-3.43) were significantly more likely to report past 6-month police/army victimization. Recent feelings of rejection (AOR: 3.80; 95% CI: 2.47-5.85) and being denied employment (AOR: 2.23; 95% CI: 1.50-3.32) were also independently associated with police/army victimization. CONCLUSION: Structural interventions aimed at reducing stigma against vulnerable populations and increasing social incorporation may aid in reducing victimization events by police/army in Tijuana. Police education and training to reduce abusive policing practices may be warranted. PMID- 25281236 TI - Catechol biosynthesis from glucose in Escherichia coli anthranilate-overproducer strains by heterologous expression of anthranilate 1,2-dioxygenase from Pseudomonas aeruginosa PAO1. AB - BACKGROUND: The aromatic compound catechol is used as a precursor of chemical products having multiple applications. This compound is currently manufactured by chemical synthesis from petroleum-derived raw materials. The capacity to produce catechol is naturally present in several microbial species. This knowledge has been applied to the generation of recombinant Escherichia coli strains that can produce catechol from simple carbon sources. RESULTS: Several strains derived from E. coli W3110 trpD9923, a mutant that overproduces anthranilate, were modified by transforming them with an expression plasmid carrying genes encoding anthranilate 1,2-dioxygenase from Pseudomonas aeruginosa PAO1. The additional expression of genes encoding a feedback inhibition resistant version of 3-deoxy-D arabino-heptulosonate 7-phosphate (DAHP) synthase and transketolase from E. coli, was also evaluated. Generated strains were characterized in complex or minimal medium in shake-flask and fed-batch bioreactor cultures and incubation temperatures ranging from 37 to 28 degrees C. These experiments enabled the identification of culture conditions for the production of 4.47 g/L of catechol with strain W3110 trpD9923, expressing 1,2-dioxygenase, DAHP synthase and transketolase. When considering the amount of glucose consumed, a yield of 16% was calculated, corresponding to 42% of the theoretical maximum as determined by elementary node flux analysis. CONCLUSIONS: This work demonstrates the feasibility of applying metabolic engineering for generating E. coli strains for the production of catechol from glucose via anthranilate. These results are a starting point to further optimize environmentally-compatible production capacity for catechol and derived compounds. PMID- 25281238 TI - Conceptualizations of postpartum depression by public-sector health care providers in Mexico. AB - In this article we describe the knowledge frameworks that 61 physicians, nurses, social workers, and psychologists from five public-sector health care facilities in Mexico used to conceptualize postpartum depression. We also demonstrate how providers applied social and behavioral antecedents in their conceptualizations of postpartum depression. Using grounded theory, we identify two frameworks that providers used to conceptualize postpartum depression: biochemical and adjustment. We highlight an emerging model of the function of social and behavioral antecedents within the frameworks, as well as the representation of postpartum depression by symptoms of distress and the perception among providers that these symptoms affected responsibilities associated with motherhood. The results provide a foundation for future study of how providers' conceptualizations of postpartum depression might affect detection and treatment practices and might be useful in the development of training materials to enhance the quality of care for women who experience any form of distress in the postpartum period. PMID- 25281237 TI - Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs. AB - This study was to compare pharmacokinetics and bile transformation of R enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and three doses of oral administration to rats and beagle dogs. To compare the pharmacokinetics with racemic bambuterol, the same oral doses of racemic bambuterol were also administrated; the blood and bile samples were collected by cannulation. A validated LC-MS/MS method was used to assess the level of bambuterol in plasma and bile. After single intravenous administration, no significant differences were observed between the two drugs in pharmacokinetic data. After oral dosing of R-bambuterol, the AUCs of R-enantiomer presented linear correlation. After same oral dosing of R-enantiomer and its racemate, all the pharmacokinetic parameters were equivalent. However, the clearance and apparent distribution had different results due to species and administration route difference. The bile transformation of these two compounds was similar and implicated that liver transformation accounted for the major metabolism of them. The bioavailability of R-enantiomer and racemate were comparative and relatively high in beagle dogs. Thus, R-enantiomer had a comparative pharmacokinetic profile and bile transformation with racemic bambuterol in rats and beagle dogs. These findings provided references for further clinical study. PMID- 25281239 TI - Cancer care decision making in multidisciplinary meetings. AB - Little research has been undertaken on the actual decision-making processes in cancer care multidisciplinary meetings (MDMs). This article was based on a qualitative observational study of two regional cancer treatment centers in New Zealand. We audiorecorded 10 meetings in which 106 patient cases were discussed. Members of the meetings categorized cases in varying ways, drew on a range of sources of authority, expressed different value positions, and utilized a variety of strategies to justify their actions. An important dimension of authority was encountered authority-the authority a clinician has because of meeting the patient. The MDM chairperson can play an important role in making explicit the sources of authority being drawn on and the value positions of members to provide more clarity to the decision-making process. Attending to issues of process, authority, and values in MDMs has the potential to improve cancer care decision making and ultimately, health outcomes. PMID- 25281240 TI - Older users' perspectives on the benefits of preventive home visits. AB - In this article we explore older people's perspectives on the benefits of preventive home visits (PHVs), after long-term follow-up. PHVs are health services intended to promote older people's health and independence, prevent disease, and postpone functional decline. We applied an explorative and descriptive design and analyzed qualitative research interviews of 10 PHV users who had received multiple visits for at least 6 years. We sought manifest and latent content in our analysis. The participants reported benefits falling within four main categories: to feel safe, to manage everyday life, to live well, and to be somebody. Two latent themes emerged: living with an underlying, realistic concern about an uncertain future, and striving to maintain oneself as a person. The perceived benefits of PHVs differed significantly from the outcome measures commonly used in randomized, controlled trials. PHV interventions should have a longitudinal approach and support each person's current needs and valued goals. PMID- 25281241 TI - Use of social comparisons in interviews about young adults' experiences of chronic illness. AB - In this article I examine how young adults used social comparisons in research interviews about their experiences of chronic illness. The interviews were originally conducted not only to provide data for academic analysis but also to generate experiential accounts for publication online as part of an Internet based health information resource for patients, professionals, and the public wanting to learn about people's real-life experiences of illness in the United Kingdom. Through secondary analysis of these data, I show how the young adults used various social comparisons to represent themselves and their experiences to the target audience. Two new concepts-analogues and foils-are introduced to describe how the young adults likened themselves to, and contrasted themselves with, different reference groups in their accounts. Through these and related strategies, they created positive renditions of their experiences for the audience, helping to inform and support others in the process. PMID- 25281242 TI - Storylines of aging with HIV: shifts toward sense making. AB - Aging with HIV is a new phenomenon. It is expected that by 2015, approximately half of adults living with HIV in the United States will be age 50 and older. We used narrative inquiry to explore how older adults with HIV storied their experience and made sense of aging. Over a 3.5-year period, we interviewed 5 older adults living with HIV for 13 to 24 years. In analyzing the coconstructed stories, we identify six storylines that enhance understanding and guide listening: embodiment of the illness, sense making, death and loss, secrets and stigma, identity, and seeking connection. We theorize that the degree to which one reconciles each storyline influences how well one lives with illness. We share a storied exemplar to illustrate these storylines in one participant's experience of aging with HIV. These findings emphasize how vital is telling one's illness story, because sense making happens in the telling. PMID- 25281243 TI - The relationship between self-harm and teen dating violence among youth in Hawaii. AB - The connection between teen dating violence (TDV) and self-harm is important to consider because of the serious consequences for teens who engage in these behaviors. Self-harm includes nonsuicidal self-injury (NSSI) and suicide behaviors such as suicide attempts or deaths. Although prior research shows that these two public health problems are related, the context in which they occur is missing, including what leads teens to engage in self-harm and the timing of self harming behaviors within the relationship. To fill this gap, we conducted focus groups with 39 high-school-aged teens, all of whom had experienced prior relationship violence. Teens described incidents in which they and their partners engaged in NSSI and suicide attempts. Incidents often were associated with extreme alcohol and drug use and occurred during the break-up stage of the relationship. Prevention and intervention programs are needed that consider the intersections of TDV, substance use, and self-harm. PMID- 25281244 TI - Seeing in different ways: introducing "rich pictures" in the study of expert judgment. AB - In this article we explore the value of using visual data in a study on medical expert judgment to better understand medical experts' conceptualizations of complex, challenging situations. We use examples from a larger study on medical expertise in which rich pictures and interviews were used. The three stories presented in this article belong to experts in the domain of surgery. The stories are used to show the ways in which rich pictures can capture and elucidate potentially hidden aspects of the influence of the context in surgical experts' judgment during challenging operations. We suggest that incorporating visual representations such as rich pictures as research data can aid in understanding previously unarticulated constructions of medical expertise. We conclude that when the researcher strives for capturing complexity, visual methods have the potential to help medical experts deflect from their tendency to simplify descriptions of accounts and to meaningfully engage these individuals in the research process. PMID- 25281245 TI - Acute disseminated encephalomyelitis (ADEM) following a H3N3 parainfluenza virus infection in a pregnant asthmatic woman with respiratory failure. AB - This case report relates to a 31-year-old pregnant woman, asthmatic, admitted to the intensive care unit with respiratory failure, secondary to a viral community acquired pneumonia. A type 3 (H3N3) parainfluenza virus RNA was isolated in her throat swab. The patient developed neurological symptoms (behavioural changes, irritability, agitation and impaired consciousness) while being weaned off sedation and ventilatory support. Cerebrospinal fluid was clear with an opening pressure of 26 cm H2O. Brain MRI showed features compatible with acute disseminated encephalomyelitis. Immune screen and EEG were normal. She was treated with intravenous methylprednisolone followed by oral prednisolone. The patient made an almost full neurological recovery within 4 weeks after starting on steroids. The patient delivered a healthy baby at 38 weeks gestation. This case highlights the importance to keep in mind rare conditions that need early recognition and prompt treatment. Brain MRI is the key to early diagnosis and treatment. PMID- 25281246 TI - Peripheral paraneoplastic sensorimotor polyneuropathy as the presenting symptoms of rectal cancer. PMID- 25281247 TI - beta-blockers in postoperative myocardial diastolic dysfunction: not a panacea. AB - Successful treatment with heart rate lowering medication has been used to treat adults with chronic myocardial dysfunction of various aetiologies for a number of years. There has been recent evidence for the successful use of beta-receptor blocking medication in highly selected group of infants with diastolic myocardial dysfunction. This case series demonstrates that while the use of beta-receptor blockers in infants early following initial treatment of congenital left heart obstructive lesions appears promising and safe adjunct to more conventional management, the medium-term and long-term care of these patients remains as challenging as before. PMID- 25281248 TI - A case of residual inferior sinus venosus defect after ineffective surgical closure. AB - A 38-year-old woman presented with cyanosis and heart failure 34 years after patch closure of an atrial septal defect and partial anomalous pulmonary venous connection. CT and cardiac catheterisation showed a residual defect that caused right-to-left shunting. The patch almost blocked the inferior vena cava from the right atrium, resulting in uncommon drainage of the inferior vena cava into the left atrium. Other anomalies included the coronary-to-pulmonary artery fistula and duplicate inferior vena cava with dilated azygos venous system. A second surgery was performed, and we confirmed an inferior sinus venosus defect, which is rare and can be misdiagnosed. The ineffective patch closure had caused a haemodynamic status that rarely occurs. We describe the diagnostic process and emphasise the importance of correctly understanding the entity. PMID- 25281249 TI - A severe manifestation of primary HIV-1 infection in an adolescent. AB - Primary HIV infection (PHI) is symptomatic in 50-90% of patients with symptoms resembling infectious mononucleosis. The diagnosis, however, is seldom made at first presentation. Clinically severe presentations during primary HIV type 1 infection are considered to occur infrequently. We report a case of a severe manifestation of PHI with meningoencephalitis in the setting of HIV seroconversion in an adolescent girl. PMID- 25281250 TI - A traumatic false aneurysm of the ankle: an unusual bump on the forefoot. PMID- 25281251 TI - Parvovirus and 'weepy red' axillae. PMID- 25281252 TI - Susac's syndrome: the value of fundus fluorescein angiography. AB - A 19-year-old woman presented with a 4-week history of headache, ataxia, vertigo, confusion, intermittent blurred vision in the right eye and intermittent hearing loss. MRI revealed white matter lesions and 'pepper pot' lesions of the corpus callosum. The cerebrospinal fluid had raised protein and lymphocytes. Fundal examination revealed multiple peripheral arterial occlusions in the both eyes confirmed with fundus fluorescein angiography (FFA). A diagnosis of Susac's syndrome was made. The patient was initially treated with steroids, followed by azathioprine and intravenous immunoglobulins (IVIg). Clinical improvement was noted, associated with improvement of the retinal circulation on FFA. PMID- 25281253 TI - Non-metallic foreign body embedded inside tooth. PMID- 25281254 TI - The spray-drying process is sufficient to inactivate infectious porcine epidemic diarrhea virus in plasma. AB - Porcine epidemic diarrhea virus (PEDV) is considered an emergent pathogen associated with high economic losses in many pig rearing areas. Recently it has been suggested that PEDV could be transmitted to naive pig populations through inclusion of spray-dried porcine plasma (SDPP) into the nursery diet which led to a ban of SDPP in several areas in North America and Europe. To determine the effect of spray-drying on PEDV infectivity, 3-week-old pigs were intragastrically inoculated with (1) raw porcine plasma spiked with PEDV (RAW-PEDV-CONTROL), (2) porcine plasma spiked with PEDV and then spray dried (SD-PEDV-CONTROL), (3) raw plasma from PEDV infected pigs (RAW-SICK), (4) spray-dried plasma from PEDV infected pigs (SD-SICK), or (5) spray-dried plasma from PEDV negative pigs (SD NEG-CONTROL). For the spray-drying process, a tabletop spray-dryer with industry like settings for inlet and outlet temperatures was used. In the RAW-PEDV-CONTROL group, PEDV RNA was present in feces at day post infection (dpi) 3 and the pigs seroconverted by dpi 14. In contrast, PEDV RNA in feces was not detected in any of the pigs in the other groups including the SD-PEDV-CONTROL group and none of the pigs had seroconverted by termination of the project at dpi 28. This work provides direct evidence that the experimental spray-drying process used in this study was effective in inactivating infectious PEDV in the plasma. Additionally, plasma collected from PEDV infected pigs at peak disease did not contain infectious PEDV. These findings suggest that the risk for PEDV transmission through commercially produced SDPP is minimal. PMID- 25281255 TI - Agricultural injuries to the hand and upper extremity. AB - Agricultural injuries involving the hand and upper extremity are common, debilitating injuries that reflect the significant occupational hazards associated with the agricultural industry. Farm injuries occur in all age groups and are associated with significant resource utilization and treatment costs. Most of these injuries are associated with machinery, including tractors, power take-off devices, grain augers, hay balers, and combine harvesters. Each piece of machinery produces specific injury patterns and a spectrum of bone and soft tissue injuries that are frequently characterized by the loss of a digit or limb, permanent disability, loss of function, and serious complications such as infection. Management of agricultural injuries includes expedient administration of antibiotic and tetanus prophylaxis, aggressive irrigation, serial debridement, consideration of delayed wound closure, and reconstruction or replantation of amputated digits and limbs, if feasible. PMID- 25281256 TI - Approach to pain management in chronic opioid users undergoing orthopaedic surgery. AB - Opioids are commonly used for the management of pain in patients with musculoskeletal disorders; however, national attention has highlighted the potential adverse effects of the use of opioid analgesia in this and other nonmalignant pain settings. Chronic opioid users undergoing orthopaedic surgery represent a particularly challenging patient population in regard to their perioperative pain control and outcomes. Preoperative evaluation provides an opportunity to estimate a patient's preoperative opioid intake, discuss pain related fears, and identify potential psychiatric comorbidities. Patients using high levels of opioids may also require referral to an addiction specialist. Various regional blockade and pharmaceutical options are available to help control perioperative pain, and a multimodal pain management approach may be of particular benefit in chronic opioid users undergoing orthopaedic surgery. PMID- 25281257 TI - Flatfoot deformity in children and adolescents: surgical indications and management. AB - Most children with flatfeet are asymptomatic and will never require treatment. In general, flatfoot deformity is flexible and will not cause pain or disability; it is a normal variant of foot shape. Thus, it is essential to reassure and educate patients and parents. A flatfoot with a contracture of the Achilles tendon may be painful. In these cases, a stretching program may help relieve pain. Scant convincing evidence exists to support the use of inserts or shoe modifications for effective relief of symptoms, and there is no evidence that those devices change the shape of the foot. The surgeon must be vigilant to identify the rare rigid flatfoot. Indications for flatfoot surgery are strict: failure of prolonged nonsurgical attempts to relieve pain that interferes with normal activities and occurs under the medial midfoot and/or in the sinus tarsi. In nearly all cases, an associated contracture of the heel cord is present. Osteotomies with supplemental soft-tissue procedures are the best proven approach for management of [corrected] flatfoot. PMID- 25281258 TI - Radial head arthroplasty: state of the art. AB - Radial head arthroplasty has joined the armamentarium of options for the treatment of complex radial head fractures, elbow instability, and arthritic conditions. A variety of implants has been introduced in the past decade; these differ in metallic composition, design, and method of fixation. Good short- and intermediate-term outcomes have been reported with the use of loose-fitting prostheses. Press-fit devices restore stability and improve pain and motion but are associated with a greater likelihood of implant loosening, leading to revision surgery. Postoperative elbow stiffness, pain, ulnar nerve palsy, posterior interosseous nerve palsy, and heterotopic ossification have all been reported following radial head surgery, but these complications are likely related to the trauma sustained by the elbow. Adequate knowledge of the surgical indications, types of implants, and surgical technique are essential for a satisfactory outcome when a radial head prosthesis is used for the treatment of nonreconstructable radial head fractures. PMID- 25281259 TI - Diagnosis and management of langerhans cell histiocytosis. AB - Langerhans cell histiocytosis is a rare group of disorders without a well understood etiology. Known formerly as histiocytosis X, the disease has a wide spectrum of clinical presentations, including eosinophilic granuloma (solitary bone lesion), diabetes insipidus, and exophthalmos. It is also known by several eponyms, including Hand-Schuller-Christian disease when it manifests as a triad of cranial bone lesions and Letterer-Siwe disease when it is found in infantile patients with severely disseminated disease. Children aged 5 to 15 years are most commonly affected. Many of these patients initially present to orthopaedic surgeons, and misdiagnosis is frequent. To accurately diagnosis and treat these patients, the orthopaedic surgeon must be familiar with the clinical manifestations and pathophysiology of the disease as well as the treatment guidelines and outcomes for Langerhans cell histiocytosis. PMID- 25281260 TI - Vertebroplasty and kyphoplasty for the treatment of osteoporotic vertebral compression fractures. AB - Vertebroplasty and kyphoplasty have been used to treat osteoporotic compression fractures for many years. In 2009, two randomized controlled trials demonstrated limited effectiveness of vertebroplasty over sham treatment; thus, the American Academy of Orthopaedic Surgeons published evidence-based guidelines recommending "against vertebroplasty for patients who present with an osteoporotic spinal compression fracture." However, several other trials have since been published that contradict these conclusions. A recent meta-analysis cited strong evidence in favor of cement augmentation in the treatment of symptomatic vertebral compression fractures. PMID- 25281261 TI - Controversies in the intramedullary nailing of proximal and distal tibia fractures. AB - Management of tibia fractures by internal fixation, particularly intramedullary nails, has become the standard for diaphyseal fractures. However, for metaphyseal fractures or those at the metaphyseal-diaphyseal junction, choice of fixation device and technique is controversial. For distal tibia fractures, nailing and plating techniques may be used, the primary goal of each being to achieve acceptable alignment with minimal complications. Different techniques for reduction of these fractures are available and can be applied with either fixation device. Overall outcomes appear to be nearly equivalent, with minor differences in complications. Proximal tibia fractures can be fixed using nailing, which is associated with deformity of the proximal short segment. A newer technique-suprapatellar nailing-may minimize these problems, and use of this method has been increasing in trauma centers. However, most of the data are still largely based on case series. PMID- 25281262 TI - Biomaterials for cartilage regeneration. PMID- 25281263 TI - Optimizing BMP-2-induced bone repair with FGF-2. PMID- 25281264 TI - SINE (selective inhibitor of nuclear export)--translational science in a new class of anti-cancer agents. AB - Regulation of protein trafficking between the nucleus and cytoplasm represents a novel control point for antineoplastic intervention. Several proteins involved with cellular growth and survival depend on precise and timely positioning within the cell to fulfill their functions, and the nuclear membrane defines one of the most important compartmental barriers. Chromosome Region Maintenance 1, or exportin-1 (CRM1/XPO1), is involved with the export of more than 200 nuclear proteins, and has intriguingly been shown to have an increased expression in several tumor cell types. Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (SINE) to be developed for clinical use. Preclinical data has demonstrated antineoplastic activity of SINE compounds in many human solid and hematologic malignancies. The clinical development of Selinexor provides an excellent model for translational research. PMID- 25281265 TI - Asthma control in severe asthmatics under treatment with omalizumab: a cross sectional observational study in Italy. AB - Few data are available on the proportion of asthmatics achieving a good asthma control (according GINA guidelines) and on the level of airway inflammation during omalizumab treatment. The aim of this cross-sectional national observational study was to assess the level of control (according to GINA guidelines) achieved in a group of asthmatics on omalizumab treatment, and to characterize the factors that influence the lack of control. We studied 306 asthmatics under omalizumab treatment for a median of 32 months (range 4-120). The level of control according to GINA was good in 25.2%, partial in 47.1% and poor in 24.5% of patients (data were missing for the remaining 3.2%). Comparison between poorly controlled and partially or well controlled asthmatics showed a statistically significant higher prevalence of some comorbidities in the first group, namely obesity, gastro-oesophageal reflux disease (GORD), aspirin intolerance and mental disorders (all p < 0.001). Similarly, asthmatics with at least one exacerbation in the last year showed a significantly higher prevalence of obesity, chronic rhinosinusitis, nasal polyps, GORD, and aspirin intolerance (all p < 0.05) than patients without exacerbations. When we selected patients without relevant comorbidities (upper airways disease, GORD, obesity, aspirin intolerance) and not currently smoking (N = 73), the percentage of well or partially controlled asthmatics was significantly higher than in patients with comorbidities (84.9% vs 71.1%, p = 0.02); the rate of asthmatics without exacerbations in the last year was also higher (73.6% vs 51.1%, p = 0.001). During omalizumab treatment, a high percentage of asthmatics obtain a good or partial control of asthma. Comorbidities are associated with the lack of asthma control and persistence of exacerbations. PMID- 25281267 TI - Immunosuppression withdrawal following liver transplantation. AB - Current immunosuppression regimens in liver transplantation provide excellent short-term survival rates but have many deleterious long-term side effects. They are therefore associated with the higher mortality and morbidity seen in liver transplant recipients compared to the general population and the notion that many liver transplant recipients are over-immunosuppressed is widely accepted. Liver allografts show a greater resistance to alloimmune responses than other solid organ transplants and recent research suggests up to 60% of highly selected recipients could wean off immunosuppression completely. In this review, we look at the evidence from immunosuppression withdrawal trials, the potential benefits of immunosuppression withdrawal and the identification of tolerant transplant recipients. PMID- 25281266 TI - Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain. AB - Bromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ HAT complex and contains a unique combination of domains typically found in chromatin-associated factors, which include plant homeodomain (PHD) fingers, a bromodomain and a proline-tryptophan-tryptophan-proline (PWWP) domain. Bromodomains are conserved structural motifs generally known to recognize acetylated histones, and the BRPF1 bromodomain preferentially selects for H2AK5ac, H4K12ac and H3K14ac. We solved the X-ray crystal structures of the BRPF1 bromodomain in complex with the H2AK5ac and H4K12ac histone peptides. Site-directed mutagenesis on residues in the BRPF1 bromodomain-binding pocket was carried out to investigate the contribution of specific amino acids on ligand binding. Our results provide critical insights into the molecular mechanism of ligand binding by the BRPF1 bromodomain, and reveal that ordered water molecules are an essential component driving ligand recognition. PMID- 25281269 TI - Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists. AB - A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT(2B) and 5-HT(7) receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4',5'-dihydro 3'H-spiro[fluorene-9,2'-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT(2B) (Ki = 5.1 nM) and 5-HT(7) (K(i) = 1.7 nM) receptors with high selectivity over 5-HT(2A), 5-HT(2C), alpha(1), D(2) and M(1) receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R) 17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials. PMID- 25281268 TI - Thymol and eugenol derivatives as potential antileishmanial agents. AB - In Northeastern Brazil visceral leishmaniasis is endemic with lethal cases among humans and dogs. Treatment is toxic and 5-10% of humans die despite treatment. The aim of this work was to survey natural active compounds to find new molecules with high activity and low toxicity against Leishmania infantum chagasi. The compounds thymol and eugenol were chosen to be starting compounds to synthesize acetyl and benzoyl derivatives and to test their antileishmanial activity in vitro and in vivo against L. i. chagasi. A screening assay using luciferase expressing promastigotes was used to measure the growth inhibition of promastigotes, and an ELISA in situ was performed to evaluate the growth inhibition of amastigote. For the in vivo assay, thymol and eugenol derivatives were given IP to BALB/c mice at 100mg/kg/day for 30 days. The thymol derivatives demonstrated the greater activity than the eugenol derivatives, and benzoyl thymol was the best inhibitor (8.67 +/- 0.28 MUg/mL). All compounds demonstrated similar activity against amastigotes, and acetyl-thymol was more active than thymol and the positive control drug amphotericin B. Immunohistochemistry demonstrated the presence of Leishmania amastigote only in the spleen but not the liver of mice treated with acetyl-thymol. Thus, these synthesized derivatives demonstrated anti-leishmanial activity both in vitro and in vivo. These may constitute useful compounds to generate new agents for treatment of leishmaniasis. PMID- 25281270 TI - Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: quinone oxidoreductase 1 for internal radiation therapy. AB - NAD(P)H: quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1 targeted radiolabeled agent to establish a novel internal radiation therapy that amplifies the therapeutic effects when combined with external radiation therapy. We designed three NQO1-targeted radioiodinated compounds including two ether linkage compounds ([(125)I]1 and [(125)I]2) and a sulfide linkage compound ([(125)I]3) based on the selective binding of indolequinone analogs to the active site of NQO1 by the stacking effect. These compounds were successfully prepared using an oxidative iododestannylation reaction with high radiochemical yields and purity. In NQO1-expressing tumor cells, [(125)I]1 and [(125)I]2 were readily metabolized to p-[(125)I]iodophenol or m-[(125)I]iodophenol and [(125)I]I(-), whereas over 85% of the initial radioactivity of [(125)I]3 was observed as an intact form at 1h after incubation. The cellular uptake of [(125)I]3 was significantly higher than those of [(125)I]1 and [(125)I]2. The uptake of [(125)I]3 was specific and was dependent on the expression of NQO1. These data suggest that the novel NQO1-targeted radioiodinated compound [(125)I]3 could be used as a novel internal radiation agent for the treatment of cancer. PMID- 25281271 TI - Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties. AB - Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the MU-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and kappa-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain. PMID- 25281272 TI - Food store owners' and managers' perspectives on the food environment: an exploratory mixed-methods study. AB - BACKGROUND: Neighborhood characteristics such as poverty and racial composition are associated with inequalities in access to food stores and in the risk of obesity, but the pathways between food environments and health are not well understood. This article extends research on consumer food environments by examining the perspectives of food-store owners and managers. METHODS: We conducted semistructured, open-ended interviews with managers and owners of 20 food stores in low-income, predominantly African American neighborhoods in Tallahassee, Florida (USA). The interviews were designed to elicit store managers' and owners' views about healthy foods, the local food environment, and the challenges and opportunities they face in creating access to healthy foods. We elicited perceptions of what constitutes "healthy foods" using two free-list questions. The study was designed and implemented in accord with principles of community-based participatory research. RESULTS: Store owners' and managers' conceptions of "healthy foods" overlapped with public health messages, but (a) agreement about which foods are healthy was not widespread and (b) some retailers perceived processed foods such as snack bars and sugar-sweetened juice drinks as healthy. In semistructured interviews, store owners and managers linked the consumer food environment to factors across multiple levels of analysis, including: business practices such as the priority of making sales and the delocalization of decision-making, macroeconomic factors such as poverty and the cost of healthier foods, individual and family-level factors related to parenting and time constraints, and community-level factors such as crime and decline of social cohesion. CONCLUSIONS: Our results link food stores to multilevel, ecological models of the food environment. Efforts to reshape the consumer food environment require attention to factors across multiple levels of analysis, including local conceptions of "healthy foods", the business priority of making sales, and policies and practices that favor the delocalization of decision making and constrain access to healthful foods. PMID- 25281274 TI - Locust cellular defense against infections: sites of pathogen clearance and hemocyte proliferation. AB - The locust cellular defense is mediated by hemocytes and hematopoietic tissue. In Locusta migratoria, the hemocytes and hematopoietic tissue mutually assist each other in clearing invading pathogens from circulation. A beta-1, 3-glucan infection induces nodule formation and apoptotic, TUNEL positive, cells in the hematopoietic tissue and massive loss of hemocytes in the circulation, calling for instant proliferation of hemocytes and hematopoietic tissue cells to assure continued host cellular defense. As the locust hematopoietic tissue persists at the adult stage, it was originally designated as being the major source for the replenishment process. Revisiting post infection hemocyte proliferation, using immunofluorescence based tests for DNA synthesis and mitosis, evidenced the lack of beta-1, 3-glucan induced cell proliferation in the hematopoietic tissue. Instead these tests identified the circulating hemocytes as the major source for hemocyte replenishment in the circulation. The hematopoietic tissue, however, undergoes a continuous, slow and infection independent regeneration, thereby accumulating potential phagocytes despite infection, and might serve a prophylactic role in containing pathogens in this swarming insect. PMID- 25281276 TI - A review of learner impact on faculty productivity. PMID- 25281273 TI - Role of SIRT1 in autoimmune demyelination and neurodegeneration. AB - Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. SIRT1 is a member of the histone deacetylase class III family of proteins and is an NAD(+) dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and plays an important role as a key regulator of a wide variety of cellular and physiological processes including DNA damage, cell survival, metabolism, aging, and neurodegeneration. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease. SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders. PMID- 25281275 TI - Comparison of the rhythm control treatment strategy versus the rate control strategy in patients with permanent or long-standing persistent atrial fibrillation and heart failure treated with cardiac resynchronization therapy - a pilot study of Cardiac Resynchronization in Atrial Fibrillation Trial (Pilot CRAfT): study protocol for a randomized controlled trial. AB - BACKGROUND: The only subgroups of patients with heart failure and atrial fibrillation in which the efficacy of cardiac resynchronization therapy has been scientifically proven are patients with indications for right ventricular pacing and patients after atrioventricular junction ablation. However it is unlikely that atrioventricular junction ablation would be a standard procedure in the majority of the heart failure patients with cardiac resynchronization therapy and concomitant atrial fibrillation due to the irreversible character of the procedure and a spontaneous sinus rhythm resumption that occurs in about 10% of these patients. METHODS/DESIGN: Pilot-CRAfT is the first randomized controlled trial evaluating the efficacy of a rhythm control strategy in atrial fibrillation patients with cardiac resynchronization therapy devices. The aim of this prospective, single center randomized controlled pilot study is to answer the question whether the patients with cardiac resynchronization therapy and permanent atrial fibrillation would benefit from a strategy to restore and maintain sinus rhythm (that is 'rhythm control' strategy) in comparison to rate control strategy. The study population consists of 60 patients with heart failure and concomitant long-standing persistent or permanent atrial fibrillation who underwent a cardiac resynchronization therapy device implantation at least 3 months before qualification. Study participants are randomly assigned to the rhythm control strategy (including electrical cardioversion and pharmacotherapy) or to the rate control group whose goal is to control ventricular rate. The follow-up time is 12 months. The primary endpoint is the ratio of effectively captured biventricular beats. The secondary endpoints include peak oxygen consumption, six-minute walk test distance, heart failure symptom escalation, reverse remodelling of the heart on echo and quality of life. TRIAL REGISTRATION: NCT01850277 registered on 22 April 2013 (ClinicalTrials.gov). PMID- 25281277 TI - Treatment of low HDL-C subjects with the CETP modulator dalcetrapib increases plasma campesterol only in those without ABCA1 and/or ApoA1 mutations. AB - We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9%) and FCH (+18.4, +12.1%), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (-31.5, +120.9%) and FCH ( 26.6, +111.9%), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0%), but only campesterol was markedly increased in FCH (+25.0%, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans. PMID- 25281278 TI - Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus. AB - In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30 min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors. PMID- 25281281 TI - Persistent spiking fever in a child with acute myeloid leukemia and disseminated infection with enterovirus. AB - We here report a 7 year old acute myeloid leukemia patient with persistent spiking fever likely caused by chronic echovirus 20 infection. After immunoglobulin substitution fevers subsided and the virus was cleared. Enterovirus infection should be considered in immunocompromised patients with unexplained persistent fever. PMID- 25281282 TI - Epigenetic memory in somatic cell nuclear transfer and induced pluripotency: evidence and implications. AB - Six decades ago, seminal work conducted by John Gurdon on genome conservation resulted in major advancements towards nuclear reprogramming technologies such as somatic cell nuclear transfer (SCNT), cell fusion and transcription factor mediated reprogramming. This revolutionized our views regarding cell fate conversion and development. These technologies also shed light on the role of the epigenome in cellular identity, and how the memory of the cell of origin affects the reprogrammed cell. This review will discuss recent work on epigenetic memory retained in pluripotent cells derived by SCNT and transcription factor mediated reprogramming, and the challenges attached to it. PMID- 25281279 TI - Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders. AB - EphA receptors and ephrin-A ligands play important roles in neural development and synaptic plasticity in brain regions where expression persists into adulthood. Recently, EPHA3 and EPHA7 gene mutations were linked with Autism Spectrum Disorders (ASDs) and developmental neurological delays, respectively. Furthermore, deletions of ephrin-A2 or ephrin-A3, which exhibit high binding affinity for EphA3 and EphA7 receptors, are associated with subtle deficits in learning and memory behavior and abnormalities in dendritic spine morphology in the cortex and hippocampus in mice. To better characterize a potential role for these ligands in ASDs, we performed a comprehensive behavioral characterization of anxiety-like, sensorimotor, learning, and social behaviors in ephrin-A2/-A3 double knockout (DKO) mice. The predominant phenotype in DKO mice was repetitive and self-injurious grooming behaviors such as have been associated with corticostriatal circuit abnormalities in other rodent models of neuropsychiatric disorders. Consistent with ASDs specifically, DKO mice exhibited decreased preference for social interaction in the social approach assay, decreased locomotor activity in the open field, increased prepulse inhibition of acoustic startle, and a shift towards self-directed activity (e.g., grooming) in novel environments, such as marble burying. Although there were no gross deficits in cognitive assays, subtle differences in performance on fear conditioning and in the Morris water maze resembled traits observed in other rodent models of ASD. We therefore conclude that ephrin-A2/-A3 DKO mice have utility as a novel ASD model with an emphasis on sensory abnormalities and restricted, repetitive behavioral symptoms. PMID- 25281283 TI - Risk for lung cancer in workers exposed to benzidine and/or beta-naphthylamine: a protocol for systematic review and meta-analysis. AB - BACKGROUND: Risk for lung cancer in workers exposed to benzidine (BZ) and/or beta naphthylamine (BNA), which are well-known bladder carcinogens, has been examined in many epidemiological studies, but individual epidemiological studies generally lack the power to examine the association between BZ/BNA exposure and lung cancer. We conduct a systematic review and meta-analysis to determine the risk for lung cancer among workers exposed to BZ/BNA occupationally. METHODS/DESIGN: Studies will be identified by a MEDLINE, EMBASE, CDSR, and CINAHL search and by the reference lists of articles/relevant reviews. Eligible studies will be cohort and case-control studies that report occupational BZ/BNA exposure and the outcome of interest (lung cancer death/incidence). The method of meta-analysis will be used to combine standardized mortality ratios (SMRs) and/or standardized incidence ratios (SIRs) from retrospective and prospective cohort studies and odds ratios (ORs) from case-control studies. Two reviewers will independently screen articles, extract data, and assess scientific quality using standardized forms and published quality assessment tools tailored for each study design. Overall pooled risk estimates and their corresponding 95% confidence intervals (CIs) will be obtained using random effects model. This systematic review and meta-analysis will be conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines, and results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. DISCUSSION: This review will identify and synthesize studies of the association between occupational BZ/BNA exposure and lung cancer. The findings will help to identify whether BZ/BNA could cause lung cancer and might indicate whether workers with exposure to BZ/BNA have a need for preventive measures against non-urological cancer besides bladder cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010250. PMID- 25281280 TI - An fMRI study of behavioral response inhibition in adolescents with and without histories of heavy prenatal alcohol exposure. AB - Heavy prenatal alcohol exposure results in a range of deficits, including both volumetric and functional changes in brain regions involved in response inhibition such as the prefrontal cortex and striatum. The current study examined blood oxygen level-dependent (BOLD) response during a stop signal task in adolescents (ages 13-16 y) with histories of heavy prenatal alcohol exposure (AE, n=21) and controls (CON, n=21). Task performance was measured using percent correct inhibits during three difficulty conditions: easy, medium, and hard. Group differences in BOLD response relative to baseline motor responding were examined across all inhibition trials and for each difficulty condition separately. The contrast between hard and easy trials was analyzed to determine whether increasing task difficulty affected BOLD response. Groups had similar task performance and demographic characteristics, except for full scale IQ scores (AE50 years were included in this cross-sectional study. Factors related to bone health were categorized into the following groups: (1) behavioral health (smoking, alcohol consumption, and physical activity); (2) measured factors (lean body mass [kg], appendicular skeletal muscle mass [kg], and serum vitamin D level [nmol/L]); and (3) nutritional factors (calcium intake, vitamin/mineral supplementation, and healthy supplementary food). Logistic regression analysis and analysis of covariance was conducted after adjusting for age, education, income, residential area, height, weight, and self-perceived health using a weighted method. RESULTS: Doctors diagnosed 39.5% of patients with osteoporosis, and these patients were compared with the control group. The awareness group, who had been diagnosed with osteoporosis by a doctor, had a lower proportion of smokers and higher serum vitamin D level than the control group, who had never been diagnosed with osteoporosis. No other associations were found for quality of bone health care variables. The awareness group had higher odds ratios of vitamin/mineral replacement and healthy supplementary food but no other differences were observed, indicating the patients' beliefs in bone health care do not follow the recommended clinical guidelines (e.g. higher physical activity, lower alcohol consumption). CONCLUSION: To improve the quality of care for bone health in osteoporotic patients, an initial step should be the development of post-diagnostic procedures such as patient counseling and education through a multi-team care approach. PMID- 25281308 TI - Effects of task-switching on neural representations of ambiguous sound input. AB - The ability to perceive discrete sound streams in the presence of competing sound sources relies on multiple mechanisms that organize the mixture of the auditory input entering the ears. Many studies have focused on mechanisms that contribute to integrating sounds that belong together into one perceptual stream (integration) and segregating those that come from different sound sources (segregation). However, little is known about mechanisms that allow us to perceive individual sound sources within a dynamically changing auditory scene, when the input may be ambiguous, and heard as either integrated or segregated. This study tested the question of whether focusing on one of two possible sound organizations suppressed representation of the alternative organization. We presented listeners with ambiguous input and cued them to switch between tasks that used either the integrated or the segregated percept. Electrophysiological measures indicated which organization was currently maintained in memory. If mutual exclusivity at the neural level was the rule, attention to one of two possible organizations would preclude neural representation of the other. However, significant MMNs were elicited to both the target organization and the unattended, alternative organization, along with the target-related P3b component elicited only to the designated target organization. Results thus indicate that both organizations (integrated and segregated) were simultaneously maintained in memory regardless of which task was performed. Focusing attention to one aspect of the sounds did not abolish the alternative, unattended organization when the stimulus input was ambiguous. In noisy environments, such as walking on a city street, rapid and flexible adaptive processes are needed to help facilitate rapid switching to different sound sources in the environment. Having multiple representations available to the attentive system would allow for such flexibility, needed in everyday situations to maintain stable auditory percepts, and to allow rapid scanning of interesting events in a busy environment. PMID- 25281309 TI - Neuronal substrates of Corsi Block span: Lesion symptom mapping analyses in relation to attentional competition and spatial bias. AB - Spatial working memory problems are frequently reported following brain damage within both left and right hemispheres but with the severity often being grater in individuals with right hemisphere lesions. Clinically, deficits in spatial working memory have also been noted in patients with visuospatial disorders such as unilateral neglect. Here, we examined neural substrates of short-term memory for spatial locations based on the Corsi Block tapping task and the relationship with the visuospatial deficits of neglect and extinction in a group of chronic neuropsychological patients. Principal Component Analysis (PCA) was used to distinguish shared and dissociate functional components. The neural substrates of spatial short-term memory deficits and the components identified by PCA were examined using whole brain voxel-based morphometry and tract-wise lesion deficits analyses. We found that bilateral lesions within occipital cortex (middle occipital gyrus) and right posterior parietal cortex, along with disconnection of the right parieto-temporal segment of arcuate fasciculus, were associated with low spatial memory span. A single component revealed by PCA accounted for over half of the variance and was linked to damage to right posterior brain regions (temporo-parietal junction, the inferior parietal lobule and middle temporal gyrus extending into middle occipital gyrus). We also found link to disconnections within several association pathways including the superior longitudinal fasciculus, arcuate fasciculus, inferior fronto-occipital fasciculus and inferior longitudinal fasciculus. These results indicate that different visuospatial deficits converge into a single component mapped within posterior parietal areas and fronto-parietal white matter pathways. Furthermore, the data presented here fit with the role of posterior parietal cortex/temporo-parietal junction in maintaining a map of salient locations in space, with Corsi Block performance being impaired when the spatial map is damaged. PMID- 25281310 TI - CNV amplitude as a neural correlate for stuttering frequency: A case report of acquired stuttering. AB - A neural hallmark of developmental stuttering is abnormal articulatory programming. One of the neurophysiological substrates of articulatory preparation is the contingent negative variation (CNV). Unfortunately, CNV tasks are rarely performed in persons who stutter and mainly focus on the effect of task variation rather than on interindividual variation in stutter related variables. However, variations in motor programming seem to be related to variation in stuttering frequency. The current study presents a case report of acquired stuttering following stroke and stroke related surgery in the left superior temporal gyrus. A speech related CNV task was administered at four points in time with differences in stuttering severity and frequency. Unexpectedly, CNV amplitudes at electrode sites approximating bilateral motor and left inferior frontal gyrus appeared to be inversely proportional to stuttering frequency. The higher the stuttering frequency, the lower the activity for articulatory preparation. Thus, the amount of disturbance in motor programming seems to determine stuttering frequency. At right frontal electrodes, a relative increase in CNV amplitude was seen at the test session with most severe stuttering. Right frontal overactivation is cautiously suggested to be a compensation strategy. In conclusion, late CNV amplitude elicited by a relatively simple speech task seems to be able to provide an objective, neural correlate of stuttering frequency. The present case report supports the hypothesis that motor preparation has an important role in stuttering. PMID- 25281311 TI - Moving sounds within the peripersonal space modulate the motor system. AB - Interactions between ourselves and the external world are mediated by a multisensory representation of the space surrounding the body, i.e. the peripersonal space (PPS). In particular, a special interplay is observed among tactile stimuli delivered on a body part, e.g. the hand, and visual or auditory external inputs presented close, but not far, from the same body part, e.g. within hand PPS. This coding of multisensory stimuli as a function of their distance from the hand has a role in upper limb actions. However, it remains unclear whether PPS representation affects the motor system only when stimuli occur specifically at the hand location or when they move within a continuous portion of space where the hand can potentially act. Here, in order to study these two alternatively hypotheses, we assessed the critical distance at which moving sounds have a direct effect on hand corticospinal excitability by using Transcranial Magnetic Stimulation (TMS). Specifically, TMS single pulses were delivered when a sound source was perceived at six different positions in space: from very close to subjects' hand (15 cm) to far away (90 cm). Moreover, sound direction was manipulated to test if stimuli approaching and receding from the hand might have the same relevance for the motor system. MEPs amplitude was enhanced when sounds were delivered within a limited distance from the hand (around 60 cm) as compared to when the sounds were beyond this space. This effect captures the spatial boundaries within which PPS representation modulates hand cortico-motor excitability. This spatially-dependent modulation of corticospinal activity was not further affected by the sound direction. Such findings support a strict link between the multisensory representation of the space around the body and the motor representation of potential approaching or defensive acts within that space. PMID- 25281312 TI - CD4 (+)CD 25 (+)Treg cells and IgA nephropathy patients with tonsillectomy: a clinical and pathological study. AB - BACKGROUND: The relationship between tonsillar autoimmune response and the pathogenesis of IgA nephropathy (IgAN) has been previously demonstrated. However, the role of CD4 (+)CD25 (+)Treg cells, which play critical roles in maintaining peripheral tolerance and preventing autoimmunity, has not yet been defined in IgAN. METHODS: Thirty-five patients with IgAN and 35 patients without renal disease were studied. The CD4 (+)CD25 (+)Treg cells were examined by flow cytometry. Clinical and laboratory data, such as serum creatinine and urinary samples, were obtained from each patient. Glomerular injury was assessed by histopathology. Serum IgA, C3, IL-2, IL-4 and IL-6 were analyzed by ELISA. RESULTS: CD4 (+)CD25 (+)Treg cells significantly decreased in IgAN patients compared with the controls before tonsillectomy (p < 0.05). CD4 (+)CD25 (+)Treg cells were negatively correlated with blood urea nitrogen, supernatant IL-4 and proteinuria in IgAN patients, and positively with estimated glomerular filtration rate. CD4 (+)CD25 (+)Treg cells gradually decreased as the severity of renal histology increased. In addition, serum IgA, IL-2, IL-6 and supernatant IL-4 elevated while CD4 (+)CD25 (+)Treg cells decreased in IgAN patients. CD4 (+)CD25 (+)Treg cells were significantly increased when serum IgA, IL-2, IL-6 and supernatant IL-4, urine protein and urine erythrocytes were decreased after tonsillectomy in patients with IgAN, but were still lower than those of the controls (p < 0.05). CONCLUSIONS: CD4 (+)CD25 (+)Treg cells were associated with IgAN, and tonsillectomy may increase CD4 (+)CD25 (+)Treg cells in IgAN patients, leading to clinical improvement. PMID- 25281313 TI - Preparation of PCL/silk fibroin/collagen electrospun fiber for urethral reconstruction. AB - PURPOSE: To prepare polycaprolactone (PCL)/silk fibroin/collagen electrospun nanofiber scaffold and test its effects on growth and proliferation of oral mucosal epithelial cells. METHODS: Regenerated silk fibroin film, water-soluble collagen powder, and PCL, at mass ratios of 1:1:4, 1:1:8, and 1:1:10, were dissolved in hexafluoroisopropanol, and electrostatic spinning method was adopted to prepare PCL/silk fibroin/collagen electrospun nanofiber scaffold. In vitro cultured oral mucosal epithelial cells were inoculated on the material surface, MTT assay and scanning electron microscopy were adopted to study the growth and proliferation of oral mucosal epithelial cells on the material surface, and cell compatibility of PCL/silk fibroin/collagen electrospun nanofiber was evaluated. RESULTS: The result of MTT assay showed that oral mucosal epithelial cells were growing well on the PCL/silk fibroin/collagen electrospun nanofiber scaffold. Scanning electron microscopy showed that the prepared electrospun fiber was uniform in diameter and presented an interconnected porous net structure, and oral mucosal epithelial cells had a good growth form on the surface of the modified material. CONCLUSIONS: PCL/silk fibroin/collagen electrospun nanofiber scaffold has appropriate pore size and porosity, is suitable for the growth of oral mucosal epithelial cells, has good cell compatibility, and is a good scaffold for tissue engineering urethral reconstruction. PMID- 25281314 TI - Vasopressin receptor antagonists for the treatment of heart failure: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND/OBJECTIVES: Elevated vasopressin may increase systemic vascular resistance and pulmonary capillary wedge pressure, subsequently decrease stroke volume and cardiac output. Vasopressin receptor antagonists may counteract these effects and improve outcomes in heart failure. We aimed to assess benefits and harms of vasopressin receptor antagonists (VRAs) versus placebo in addition to standard care in adults with heart failure (HF). METHODS: We conducted a systematic review of randomized controlled trials with searches of CENTRAL and MEDLINE to January 2014 and reference lists without language restriction. Meta analysis using a random-effects model was done for all-cause and cardiovascular mortality, hospitalization for heart failure, changes in clinical assessment of HF, serum sodium concentration (Na), kidney function and treatment-specific side effects. RESULTS: We identified 13 trials and 5,525 participants. In 10 trials, participants received standard therapy for HF. In low-quality evidence, VRAs in patients with HF had no effect on all-cause mortality risk ratios (RR 0.98; CI 0.88-1.08), cardiovascular mortality (RR 1.03; CI 0.91-1.16) or change in creatinine mean difference (MD -0.01; CI -0.10 to 0.09 mg/dL), but reduced body weight by 0.8 kg from baseline (MD -0.83; CI -1.10 to -0.55 kg) and increased Na (MD 2.61; 95 % CI 1.88-3.35 mmol/L). Compared with placebo, VRAs increased the risk of adverse events by 14 % (RR 1.14; CI 1.04-1.26). Studies were generally limited to short-term follow-up with limited data available on patient important outcomes. CONCLUSIONS: Vasopressin receptors antagonists may reduce body weight and increase Na but do not improve all-cause mortality, cardiovascular mortality or kidney function. In addition, acceptability of long-term treatment side effects and hospitalization appears problematic. PMID- 25281315 TI - Nitric oxide synthase inhibition decreases l-DOPA-induced dyskinesia and the expression of striatal molecular markers in Pitx3(-/-) aphakia mice. AB - Nitric oxide (NO), a gaseous messenger molecule synthesized by nitric oxide synthase (NOS), plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). To study the role of the nitrergic system in l-DOPA-induced dyskinesia (LID), we assessed the effect of the pharmacological manipulation of NO levels and NO/cyclic guanosine monophosphate (cGMP) signaling on LID in the Pitx3(-/-) aphakia mouse, a genetic model of PD. To evaluate the effect of decreased NO signaling on the development of LID, Pitx3(-/-) mice were chronically treated with l-DOPA and 7-nitroindazole (7-NI, a neuronal NOS inhibitor). To evaluate its effect on the expression of established LID, 7-NI was administered acutely to dyskinetic mice. The chronic 7-NI treatment attenuated the development of LID in the Pitx3(-/-) mice, and the sub-acute 7-NI treatment attenuated established dyskinesia without affecting the beneficial therapeutic effect of l-DOPA. Moreover, 7-NI significantly reduced FosB and pAcH3 expression in the acutely and chronically l-DOPA-treated mice. We also examined how increasing NO/cGMP signaling affects LID expression by acutely administering molsidomine (an NO donor) or zaprinast (a cGMP phosphodiesterase 5-PDE5 inhibitor) before l-DOPA in mice with established dyskinesia. Paradoxically, the administration of either of these drugs also significantly diminished the expression of established LID; however, the effect occurred at the expense of the antiparkinsonian l-DOPA properties. We demonstrate that targeting the NO/cGMP signaling pathway reduces dyskinetic behaviors and molecular markers, but only the 7-NI treatment preserved the antiparkinsonian effect of l-DOPA, indicating that NOS inhibitors represent a potential therapy to reduce LID. PMID- 25281316 TI - Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome. AB - Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1(+/-) Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans. PMID- 25281319 TI - A new cancer immunology research special feature: perspective from a master of immunology. PMID- 25281318 TI - Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. AB - Current concepts suggest that exposure to THC during adolescence may act as a risk factor for the development of psychiatric disorders later in life. However, the molecular underpinnings of this vulnerability are still poorly understood. To analyze this, we investigated whether and how THC exposure in female rats interferes with different maturational events occurring in the prefrontal cortex during adolescence through biochemical, pharmacological and electrophysiological means. We found that the endocannabinoid system undergoes maturational processes during adolescence and that THC exposure disrupts them, leading to impairment of both endocannabinoid signaling and endocannabinoid-mediated LTD in the adult prefrontal cortex. THC also altered the maturational fluctuations of NMDA subunits, leading to larger amounts of gluN2B at adulthood. Adult animals exposed to THC during adolescence also showed increased AMPA gluA1 with no changes in gluA2 subunits. Finally, adolescent THC exposure altered cognition at adulthood. All these effects seem to be triggered by the disruption of the physiological role played by the endocannabinoid system during adolescence. Indeed, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses. These results suggest that vulnerability of adolescent female rats to long-lasting THC adverse effects might partly reside in disruption of the pivotal role played by the endocannabinoid system in the prefrontal cortex maturation. PMID- 25281320 TI - The path to reactivation of antitumor immunity and checkpoint immunotherapy. AB - Cancer immunology has recently made major therapeutic inroads that represent clinical application of basic insights into mechanisms that govern immunity against tumors. Research into fundamental elements of T-cell and natural killer cell biology, including the basis of antigen recognition, activation, proliferation, and survival, has informed the design of new therapeutic approaches to augment the body's natural anticancer immune response. Here, we describe some of the key steps that have provided the foundation for current strategies of immunotherapy. PMID- 25281317 TI - Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease. AB - Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies. PMID- 25281321 TI - HPV Infection-Associated Cancers: Next-Generation Technology for Diagnosis and Treatment. AB - Disease caused by human papillomavirus (HPV) remains common, despite preventive vaccines and screening strategies. Globally, HPVs cause one third of infection associated cancers. The indolent clinical course of the precursor intraepithelial lesions provides an opportunity to understand immunologic obstacles posed by the microenvironment of incipient disease, and how they might be overcome. Results from recent therapeutic HPV vaccine clinical trials suggest that relevant immune responses may be sequestered at the lesion site and are difficult to detect in the circulation. In this Cancer Immunology at the Crossroads article, we outline the current understanding of the risk, diagnosis, and treatment of HPV infection associated cancers and suggest that quantitative tissue-based endpoints should be included whenever possible in the evaluation of immune-based therapies. PMID- 25281322 TI - Sensitivity and permissivity of Cyprinus carpio to cyprinid herpesvirus 3 during the early stages of its development: importance of the epidermal mucus as an innate immune barrier. AB - Cyprinid herpesvirus 3 (CyHV-3) causes a lethal disease in common and koi carp (Cyprinus carpio). The present study investigated the ability of CyHV-3 to infect common carp during the early stages of its development (from embryos to fingerlings) after inoculation by immersion in water containing the virus. Fish were inoculated at different times after hatching with a pathogenic recombinant CyHV-3 strain expressing luciferase. The sensitivity and permissivity of carp to CyHV-3 were investigated using in vivo bioluminescence imaging. The susceptibility of carp to CyHV-3 disease was investigated by measuring the survival rate. Carp were sensitive and permissive to CyHV-3 infection and susceptible to CyHV-3 disease at all stages of development, but the sensitivity of the two early developmental stages (embryo and larval stages) was limited compared to later stages. The lower sensitivity observed for the early developmental stages was due to stronger inhibition of viral entry into the host by epidermal mucus. In addition, independent of the developmental stage at which inoculation was performed, the localization of light emission suggested that the skin is the portal of CyHV-3 entry. Taken together, the results of the present study demonstrate that carp are sensitive and permissive to CyHV-3 at all stages of development and confirm that the skin is the major portal of entry after inoculation by immersion in infectious water. The results also stress the role of epidermal mucus as an innate immune barrier against pathogens even and especially at the early stages of development. PMID- 25281323 TI - Acculturation and dietary change among Chinese immigrant women in the United States. AB - US Chinese immigrants undergo a transition to increased chronic disease risk commonly attributed to acculturative and dietary changes. Longitudinal data to confirm this are lacking. We examined acculturation and diet over time in 312 Chinese immigrant women in Philadelphia, recruited October 2005 to April 2008 and followed with interviews and dietary recalls until April 2010. Associations were modeled using generalized estimating equations to account for repeated measures over time. Increasing length of US residence was associated with a small (~1%/year) but significant increase in acculturation score (p < 0.0001), which in turn was significantly associated with increased energy density of the diet, percent of energy from fat, and sugar intake, and lower dietary moderation score. These findings provide longitudinal evidence that acculturation increases with length of US residence and is accompanied by dietary changes. However, the changes were small enough that their health impact is unclear. Factors besides acculturation that affect immigrant health and that affect the acculturation trajectory itself warrant investigation. PMID- 25281325 TI - Parental occupational exposure and risk of childhood central nervous system tumors: a pooled analysis of case-control studies from Germany, France, and the UK. AB - PURPOSE: To assess the risk of childhood central nervous system (CNS) tumors associated with parental occupational exposure to polycyclic aromatic hydrocarbons (PAH), diesel motor exhaust (DME), asbestos, crystalline silica, and metals, which are established carcinogens in adults. METHODS: We pooled data from three population-based case-control studies from Germany, France, and the UK. Cases were children aged up to 15 years and diagnosed with CNS tumor, and controls were frequency-matched by age and sex. Socio-demographic data and parental occupation around conception/pregnancy and at diagnosis were collected using standardized interviews, face-to-face or by telephone. A general population job-exposure matrix was used to assign a level of exposure to each job. Logistic regression models were fitted to compute odds ratios and 95 % confidence intervals. RESULTS: Our study included 1,361 cases of CNS tumors and 5,500 controls. Paternal exposure to PAH, asbestos, and metals around conception was associated with an increased moderate risk of CNS tumors, although statistically non-significant. The association with exposure to asbestos around conception and diagnosis was stronger when fathers were exposed to high levels. Paternal exposure to DME and silica, and maternal exposure to PAH, DME, asbestos, silica, and metals, were not associated with an increased risk of CNS tumors. CONCLUSION: Our large pooled study showed weak evidence of a modest association between paternal occupational exposure to PAH and CNS tumor risk. Our findings need further exploration in the future studies. PMID- 25281324 TI - Biphasic modulation of paracellular claudin-5 expression in mouse brain endothelial cells is mediated through the phosphoinositide-3-kinase/AKT pathway. AB - Blood-brain barrier (BBB) integrity is compromised in many central nervous system disorders. Complex astrocyte and vascular endothelial cell interactions that regulate BBB integrity may be disturbed in these disorders. We previously showed that systemic administration of 3-chloropropanediol [(S)-(+)-3-chloro-1,2 propanediol] induces a transitory glial fibrillary acidic protein-astrocyte loss, reversible loss of tight junction complexes, and BBB integrity disruption. However, the intracellular signaling mechanisms that induce BBB integrity marker loss are unclear. We hypothesize that 3-chloropropanediol-induced modulation of tight junction protein expression is mediated through the phosphoinositide-3 kinase (PI3K)/AKT pathway. To test this hypothesis, we used a mouse brain endothelial cell line (bEnd.3) exposed to 3-chloropropanediol for up to 3 days. Results showed early reversible loss of sharp paracellular claudin-5 expression 90, 105, and 120 minutes after 3-chloropropanediol (500 MUM) treatment. Sharp paracellular claudin-5 profiles were later restored, but lost again by 2 and 3 days after 3-chloropropanediol treatment. Western blot and immunofluorescence studies showed increased p85-PI3K expression and transitory increased AKT (Thr308) phosphorylation at 15 and 30 minutes after 3-chloropropanediol administration. PI3K inhibitors LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one hydrochloride; 2.5-25 MUM] and PI-828 [2-(4-morpholinyl)-8-(4 aminopheny)l-4H-1-benzopyran-4-one; 0.1-10 MUM] prevented the 3-chloropropanediol induced AKT (Thr308) phosphorylation and both early and late loss of paracellular claudin-5. However, AKT inhibitors only prevented the early changes in claudin-5 expression. This mechanistic study provides a greater understanding of the intracellular signaling pathways mediating tight junction protein expression and supports a hypothesis that two independent pathways triggered by PI3K mediate early and late loss of paracellular claudin-5 expression. PMID- 25281326 TI - Paternal intake of folate and vitamins B6 and B12 before conception and risk of childhood acute lymphoblastic leukemia. AB - PURPOSE: We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case-control study. METHODS: Data on dietary folate intake during the 6 months before the child's conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed. RESULTS: No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare. CONCLUSIONS: We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents. PMID- 25281327 TI - Risk of death for hematological malignancies for residents close to an Italian petrochemical refinery: a population-based case-control study. AB - PURPOSE: We investigated the risk of death for hematological malignancies (HMs) in the area surrounding an Italian petrochemical refinery, where atmospheric concentrations of benzene (known carcinogen) had not been adequately monitored in the past. METHODS: We performed a population-based case-control study, using conditional logistic regression to estimate odds ratios (ORs) of HM death, with 95 % confidence intervals (CIs), and p trends, in relation to tertiles of time weighted average residential proximity to the refinery. We identified 177 HM deaths and 349 sex- and age-matched controls from municipal files. Confounding factors were investigated from interviews with consenting relatives for 109 HM deaths and 178 matched controls. RESULTS: For males and females combined, risk of HM death was unrelated to residential proximity. For females, ORs of HM death by increasing tertiles of proximity were 1, 2.74 (95 % CI 1.48-5.09, significant) and 1.49 (95 % CI 0.76-2.92) (p trend 0.184). For the subgroup of persons who plausibly spent most of their time at home (long-term retired, homemakers or unemployed, 53 cases, 79 controls), the ORs of leukemia plus non-Hodgkin lymphoma death (38 cases, 56 controls) by increasing tertiles of proximity were 1, 3.44 (95 % CI 1.04-11.37, significant) and 3.25 (95 % CI 0.82-12.87) (p trend 0.083). CONCLUSIONS: No increased risk of HM death for males and females combined living close to the refinery was found. However, the findings for females and a subgroup plausibly spending most of their time at home suggest a relation between increased risk of HM death and residential proximity to the refinery. PMID- 25281328 TI - In Memoriam, Arlette Darfeuille-Michaud, PhD. PMID- 25281329 TI - Thermodynamics of Membrane Insertion and Refolding of the Diphtheria Toxin T Domain. AB - The diphtheria toxin translocation (T) domain inserts into the endosomal membrane in response to the endosomal acidification and enables the delivery of the catalytic domain into the cell. The insertion pathway consists of a series of conformational changes that occur in solution and in the membrane and leads to the conversion of a water-soluble state into a transmembrane state. In this work, we utilize various biophysical techniques to characterize the insertion pathway from the thermodynamic perspective. Thermal and chemical unfolding measured by differential scanning calorimetry, circular dichroism, and tryptophan fluorescence reveal that the free energy of unfolding of the T-domain at neutral and mildly acidic pH differ by 3-5 kcal/mol, depending on the experimental conditions. Fluorescence correlation spectroscopy measurements show that the free energy change from the membrane-competent state to the interfacial state is approximately -8 kcal/mol and is pH-independent, while that from the membrane competent state to the transmembrane state ranges between -9.5 and -12 kcal/mol, depending on the membrane lipid composition and pH. Finally, the thermodynamics of transmembrane insertion of individual helices was tested using an in vitro assay that measures the translocon-assisted integration of test sequences into the microsomal membrane. These experiments suggest that even the most hydrophobic helix TH8 has only a small favorable free energy of insertion. The free energy for the insertion of the consensus insertion unit TH8-TH9 is slightly more favorable, yet less favorable than that measured for the entire protein, suggesting a cooperative effect for the membrane insertion of the helices of the T-domain. PMID- 25281330 TI - Assessment of nutrient remobilization through structural changes of palisade and spongy parenchyma in oilseed rape leaves during senescence. AB - MAIN CONCLUSION: Differential palisade and spongy parenchyma structural changes in oilseed rape leaf were demonstrated. These dismantling processes were linked to early senescence events and associated to remobilization processes. During leaf senescence, an ordered cell dismantling process allows efficient nutrient remobilization. However, in Brassica napus plants, an important amount of nitrogen (N) in fallen leaves is associated with low N remobilization efficiency (NRE). The leaf is a complex organ mainly constituted of palisade and spongy parenchyma characterized by different structures and functions concerning water relations and carbon fixation. The aim of the present study was to demonstrate a specific structural evolution of these parenchyma throughout natural senescence in B. napus, probably linked to differential nutrient remobilization processes. The study was performed on 340 leaves from 32 plants during an 8-week development period under controlled growing conditions. Water distribution and status at the cellular level were investigated by low-field proton nuclear magnetic resonance (NMR), while light and electron microscopy were used to observe cell and plast structure. Physiological parameters were determined on all leaves studied and used as indicators of leaf development and remobilization progress. The results revealed a process of hydration and cell enlargement of leaf tissues associated with senescence. Wide variations were observed in the palisade parenchyma while spongy cells changed only very slightly. The major new functional information revealed was the link between the early senescence events and specific tissue dismantling processes. PMID- 25281331 TI - Comparison of radiographic sagittal spinopelvic alignment between skeletally immature and skeletally mature individuals with Scheuermann's disease. AB - PURPOSE: The aim of this study was to compare radiographic sagittal spinopelvic parameters between skeletally immature and skeletally mature patients with Scheuermann's disease (SD). METHODS: Cross-sectional analysis of standing postero anterior and lateral radiographs of the spine of patients with SD was performed. Sagittal vertical axis (SVA), thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured on the lateral radiographs. Risser's sign was assessed on the postero-anterior radiographs. All of the parameters measured were compared between skeletally immature (Risser's sign 0-3) versus mature patients (Risser's sign 5). PI, PT, and SS in both groups were compared to PI, PT, and SS reported for normal children, adolescents, and adults. RESULTS: Sixty-six patients with SD (33 immature and 33 mature) were retrospectively reviewed and included in the study. There was no significant difference between the two groups of SD patients in: SVA (-16.6 vs. -22.9 mm, p = 0.74), TK (57.8 degrees vs. 56 degrees , p = 0.66), TLK (7.8 degrees vs. 11.7o, p = 0.14), LL (63.2 degrees vs. 62.2 degrees , p = 0.74), PI (36.7 degrees vs. 39.4 degrees , p = 0.20), PT (3.8 degrees vs. 7.3 degrees , p = 0.10), and SS (32.8 degrees vs. 32.1 degrees , p = 0.75). Both, the immature and mature group of SD patients presented significantly lower PI and SS than normal children, adolescents, and adults, and significantly lower PT than normal adults. CONCLUSIONS: There is no significant difference in sagittal spinopelvic parameters between skeletally immature and mature subjects with SD. Pelvic incidence in both groups of SD patients was significantly lower than PI in normal children, adolescents, and adults. This challenges the role of PI in predicting desired LL in patients with SD. PMID- 25281332 TI - Sensitivity and specificity of ultrasound in spinal trauma in 29 consecutive patients. AB - PURPOSE: Indication for surgery in spine trauma patients depends on the extent of destruction of the spine. Computer-assisted tomography scan (CAT scan) is not suitable to diagnose type B-injuries. Aim of the study was to investigate whether ultrasound is able to detect destruction of the posterior ligament complex (PLC). METHODS: Twenty-nine patients were included. The results of ultrasound were compared with magnetic resonance imaging (MRI), CAT scan, X-ray, intraoperative findings. Statistical analysis was carried out by an independent observer. RESULTS: In 27 cases both ultrasound and MRI had the same result. In two cases, ultrasound failed to detect ligamentous injury. The sensitivity of ultrasound was 0.82 (CI 0.48-0.98), its specificity: 1. MRI and Ultrasound findings had a strong positive correlation (phi = 0.85, Cohen's kappa: 0.85, with 95 % confidence interval 0.65-1) and a high significance (Fischer's exact test: p < 0.0001). CONCLUSION: Ultrasound may indicate rupture or integrity of PLC in cases where MRI is missing. PMID- 25281333 TI - Prevalence of low bone mineral density in female dancers. AB - BACKGROUND AND OBJECTIVE: While some authors report that dancers have reduced bone mineral density (BMD) and increased risk of osteoporosis, others have stressed the positive effects of dance training on developing healthy BMD. Given the existing controversy, the aim of this systematic review was to examine the best evidence-based information available in relation to female dancers. METHODS: Four databases (Web of Science, PubMed, EBSCO, Scopus) and two dance science journals (Journal of Dance Medicine and Science and Medical Problems of Performing Artists) were searched for relevant material using the keywords "dance", "ballet", "BMD", "bone density", "osteoporosis" and "female athlete triad syndrome". A total of 257 abstracts were screened using selected inclusion (studies involving bone measurements in dancers) and exclusion (editorials, opinion papers, chapters in books, narrative reviews and non-English language papers) criteria according to PRISMA guidelines. Following the above screening, a total of 108 abstracts were identified as potentially relevant. After the exclusion of conference proceedings, review papers, studies focusing only in male dancers and studies in which dancers' information were combined with other athletes, the eligible papers were subsequently assessed using the GRADE system and grouped according to: (1) prevalence of low BMD and associated factors, (2) incidence of low BMD and risk factors, (3) prevention/treatment of low BMD in dancers, and (4) other studies. RESULTS: Of the 257 abstracts that were initially screened, only 35 studies were finally considered. Only one of these 35 was of high quality, while the remaining 34 were of relatively low quality. Seven studies reported prevalence of low BMD and associated factors, 10 reported associated factors with no prevalence data, while one reported prevalence with no associated factors data. One study cited risk factors, while another one elaborated on the treatment of low BMD in dancers. The remaining 15 studies were classified as "other studies". CONCLUSIONS: It remains unclear whether low BMD is prevalent in female dancers. The present review highlights the need for high quality BMD research in this area. PMID- 25281334 TI - Exercise modalities and endothelial function: a systematic review and dose response meta-analysis of randomized controlled trials. AB - BACKGROUND: Regular exercise is associated with enhanced nitric oxide (NO) bioavailability. Flow-mediated dilation (FMD) is used widely to assess endothelial function (EF) and NO release. OBJECTIVES: The aims of this systematic review and meta-analysis were to (i) investigate the effect of exercise modalities (aerobic, resistance or combined) on FMD; and (ii) determine which exercise and participant characteristics are most effective in improving FMD. METHODS: We searched the MEDLINE, Embase, Cochrane Library, and Scopus databases for studies that met the following criteria: (i) randomized controlled trials of exercise with comparative non-exercise, usual care or sedentary groups; (ii) duration of exercise intervention >=4 weeks; (iii) age >=18 years; and (iv) EF measured by FMD before and after the intervention. Weighted mean differences (WMDs) with 95% confidence interval were entered into a random effect model to estimate the pooled effect of the exercise interventions. RESULTS: All exercise modalities enhanced EF significantly: aerobic (WMD 2.79, 95% CI 2.12-3.45, p = 0.0001), resistance (WMD 2.52, 95% CI 1.11-3.93, p = 0.0001) and combined (WMD 2.07, 95% CI 0.70-3.44, p = 0.003). A dose-response relationship was observed between aerobic exercise intensity and improvement in EF. A 2 metabolic equivalents (MET) increase in absolute exercise intensity or a 10% increase in relative exercise intensity resulted in a 1% unit improvement in FMD. There was a positive relationship between frequency of resistance exercise sessions and improvement in EF (beta 1.14, CI 0.16-2.12, p = 0.027). CONCLUSIONS: All exercise modalities improve EF significantly and there was a significant, positive relationship between aerobic exercise intensity and EF. Greater frequency, rather than intensity, of resistance exercise training enhanced EF. PMID- 25281336 TI - The influence of patient factors on patient-reported outcomes of orthopedic surgery involving implantable devices: a systematic review. AB - OBJECTIVES: Recent evidence suggests that patient factors can influence response to medical and surgical treatment and may play an under-recognized role in predicting treatment outcomes. However, the current state of knowledge concerning potential associations following orthopedic surgery in particular is unclear. The purpose of the present study was to systematically review current literature to investigate the currently known associations between pre-operative patient factors and patient-reported outcomes following orthopedic surgery. METHODS: A systematic review was performed of the PubMed database to identify original studies that investigated the relationships between one or more patient factors and patient-reported outcomes of primary orthopedic surgical procedures involving implantation of a medical device. A total of 10,174 records were identified, with 83 studies included in the final review. RESULTS: The most commonly assessed patient factors included age, sex, and body mass index (BMI), reported in 63%, 55%, and 48% of studies, respectively. The only other patient factors identified were socioeconomic status and race, both of which were assessed in a single study. Considerable heterogeneity was observed in the methods used to stratify subjects by patient factors, patient-reported outcome constructs assessed, and follow-up intervals. Only 10% of studies performed appropriate sample size or power calculations, only 51% used methodologies to control for potentially confounding factors, and 6% assessed responder status. Overall, variable and conflicting findings were seen. While female sex and increasing BMI did appear to be associated with worse absolute outcomes, these differences did not appear to be maintained when differences in baseline status were considered. No clear associations between age and outcomes were identified. CONCLUSIONS: The present understanding of these relationships between patient factors and patient-reported outcomes following orthopedic surgery is limited. There is a need for further studies using high-quality methodology, consistent stratification of participants based on patient factors, accepted patient-reported outcome constructs, and appropriate assessment of responder status. PMID- 25281335 TI - Extracellular recordings reveal absence of magneto sensitive units in the avian optic tectum. AB - There is a consensus that birds detect the earth's magnetic field and use some of its features for orientation and homing purposes. Since the late 1960s, when the first solid behavioral evidence of magnetoreception was obtained, much research has been devoted to describing the ethological aspects of this behavior. The neurophysiological basis of magnetoreception has been much less studied, although a frequently cited 1986 report described a high prevalence (70 %) of magneto sensitive neurons in the pigeon optic tectum with high signal-to-noise ratios (Semm and Demaine, J Comp Physiol A 159:619-625, 1986). Here, we repeated these neurophysiological experiments using anesthetized as well as awake pigeons and new recording techniques. Our data indicate that magneto-sensitive units do not exist in the avian tectum. PMID- 25281337 TI - Phenotypic characterization and risk factors for microtia in East China, a case control study. AB - OBJECTIVE: Although congenital microtia has been reported in various studies, little is known about the etiology of isolated and sporadic cases. The aim was to analyze potential risk factors for isolated and sporadic microtia using case control study in East China. METHODS: The study analyzed data from the hospital based recruitment for deliveries between 2007 and 2013. Nine hundred eleven patients with microtia enrolled in the phenotypic characterization analysis, and then were adjusted by sex, age, region, syndrome and family history to compare with 562 random normal controls for potential risk factors. RESULTS: Microtia is observed more often in males (69.7%), and the cases were typically unilateral (74.0%), right-sided (57.2%), sporadic (92.0%) and isolated (69.5%). Mothers of children with microtia were more likely to have suffered a periconceptional cold like syndrome as well as to have had a history of previous spontaneous abortion. Inflammatory infection (aOR, 3.56; 95% CI, 2.07-6.13) and chemical exposure (aOR, 2.77; 95% CI, 1.78-4.32) was associated with a higher risk of microtia. However, threatened abortion was not the risk factor (aOR, 1.14; 95% CI, 0.78-1.67), using progesterone may increase the risk (aOR, 1.92; 95% CI, 1.03-3.59). CONCLUSION: The results of phenotypic characterization analysis were similar to other studies. By controlling the effects of potential confounders, some risk factors could be teratogens of isolated and sporadic microtia in East China. PMID- 25281338 TI - Genetics of non-syndromic hearing loss in the Middle East. AB - Hearing impairment is the most common sensory disorder, present 1 in every 500 newborns. About 80% of genetic HL is classified as non-syndromic deafness. To date, over 115 non-syndromic loci have been identified of which fifty associated with autosomal recessive non-syndromic hearing loss (ARNSHL). In this review article, we represent the 40 genes function and contribution to genetic deafness in different Middle Eastern populations as well as gene frequencies and mutation spectrum. The wide variety of mutations have so far detected in 19 countries reflects the heterogeneity of the genes involved in HL in this region. The deafness genes can cause dysfunction of cochlear homeostasis, cellular organization, neuronal transmission, cell growth, differentiation, and survival, some coding for tectorial membrane-associated proteins, and the remaining with unknown functions. Non-syndromic deafness is highly heterogeneous and mutations in the GJB2 are responsible for almost 30-50% in northwest to as low as 0-5% in south and southeast of the Middle East, it remain as major gene in ARNSHL in Middle East. The other genes contributing to AR/ADNSHL in some countries have been determined while for many other countries in the Middle East have not been studied or little study has been done. With the advancement of next generation sequencing one could expect in next coming year many of the remaining genes to be determine and to understand their function in the inner ear. PMID- 25281340 TI - Re: Fakhry et al., Fine needle aspiration cytology and frozen section in the diagnosis of malignant parotid tumours. PMID- 25281339 TI - Bacteriology in relation to clinical findings and treatment of acute mastoiditis in children. AB - OBJECTIVE: We assessed clinical, radiological, laboratory and microbiological findings in children with acute mastoiditis in order to improve the diagnostics and treatment of these patients. We also investigated whether different pathogens cause different clinical findings of mastoiditis. METHODS: A retrospective review of the medical records of all children aged 0-16 years treated as in-ward patients for acute mastoiditis at Helsinki University Central Hospital, Department of Otorhinolaryngology, between 2003 and 2012. RESULTS: Fifty-six patients met the inclusion criteria. The incidence of mastoiditis was 1.88/100000/year. The most common pathogens were Streptococcus pneumoniae (38%), Streptococcus pyogenes (11%) and Pseudomonas aeruginosa (11%). Of S. pneumoniae, 48% had reduced susceptibility (intermediate or resistant) for the common antimicrobials; this was clearly overrepresented relative to the background population (p<0.001). Otalgia and retroauricular symptoms were common in the patients with S. pneumoniae. Otorrhoea was less common (p=0.03) in these patients relative to the other pathogens. Patients with S. pneumoniae had more destruction of the mastoid septa (p=0.05) than patients with any of the other pathogens. Mastoidectomy was performed in 34% of all cases, it was most common (60%) in the patients with S. pneumoniae with reduced susceptibility. The patients with S. pyogenes had less otalgia and seemed to have less retroauricular symptoms relative to other pathogens. P. aeruginosa especially affected children with tympanostomy tubes, caused otorrhoea in all patients and caused a milder form of disease with less retroauricular swelling (p=0.04) than the other pathogens, and there was no need for mastoidectomies. The younger children (<2 years) had less otorrhoea and more retroauricular symptoms of infection than the older patients. No significant differences emerged in outcome of the patient groups. CONCLUSIONS: The clinical findings of acute mastoiditis differ according to the causative pathogen. S. pneumoniae, especially strains with reduced susceptibility, causes severe symptoms and leads to mastoidectomy more often than the other pathogens. S. pyogenes causes less otalgia than the other pathogens. P. aeruginosa particularly affects children with tympanostomy tubes and causes a less aggressive form of disease. PMID- 25281341 TI - Estimation of retired mobile phones generation in China: A comparative study on methodology. AB - Due to the rapid development of economy and technology, China has the biggest production and possession of mobile phones around the world. In general, mobile phones have relatively short life time because the majority of users replace their mobile phones frequently. Retired mobile phones represent the most valuable electrical and electronic equipment (EEE) in the main waste stream because of such characteristics as large quantity, high reuse/recovery value and fast replacement frequency. Consequently, the huge amount of retired mobile phones in China calls for a sustainable management system. The generation estimation can provide fundamental information to construct the sustainable management system of retired mobile phones and other waste electrical and electronic equipment (WEEE). However, the reliable estimation result is difficult to get and verify. The priority aim of this paper is to provide proper estimation approach for the generation of retired mobile phones in China, by comparing some relevant methods. The results show that the sales&new method is in the highest priority in estimation of the retired mobile phones. The result of sales&new method shows that there are 47.92 million mobile phones retired in 2002, and it reached to 739.98 million in China in 2012. It presents an increasing tendency with some fluctuations clearly. Furthermore, some discussions on methodology, such as the selection of improper approach and error in the input data, are also conducted in order to improve generation estimation of retired mobile phones and other WEEE. PMID- 25281342 TI - Matthew T. Provencher, M.D., assistant editor-in-chief, plus small joints command large notice, hip dislocation and how to avoid it, hockey player's hip, plus a burst of hip techniques, elbow double-double, and rare level I evidence. PMID- 25281343 TI - Hip arthroscopy dislocation and shoulder arthroscopy positioning. PMID- 25281344 TI - Regarding "capsular laxity of the hip: findings at magnetic resonance arthrography". PMID- 25281345 TI - Author's Reply. PMID- 25281346 TI - Error in the article "early passive motion versus immobilization after arthroscopic rotator cuff repair". PMID- 25281347 TI - Author's reply: To PMID 24813324. PMID- 25281348 TI - Corrections to our article "preoperative diagnosis of pathologic conditions of the ligamentum teres: is MRI a valuable imaging modality?". PMID- 25281349 TI - Distal triceps knotless anatomic footprint repair is superior to transosseous cruciate repair: a biomechanical comparison. AB - PURPOSE: The purpose of this study was to evaluate the biomechanical properties of a method of repair using bone tunnels with multiple high-strength nonabsorbable sutures and one knotless suture anchor compared with the standard transosseous technique for repair of the distal triceps. METHODS: The triceps tendon footprint was measured in 18 cadaveric elbows (9 matched pairs), and a distal tendon rupture was created. Eighteen elbows (9 matched pairs) were randomly assigned to one of 2 repair groups: transosseous cruciate repair group or knotless anatomic footprint repair group. Cyclic loading was performed for a total of 1,500 cycles and displacement was measured. Data for load at yield and peak load were obtained. RESULTS: The average bony footprint of the triceps tendon was 466 mm(2). Cyclic loading of tendons from the 2 repair types showed that the knotless anatomic footprint repair produced less displacement when compared with the transosseous cruciate repair (P < .05). Load at yield and peak load were also greater in the knotless anatomic footprint repair group (P < .05). CONCLUSIONS: Distal triceps knotless anatomic footprint repair in a cadaveric model had a significantly higher load and cycle to failure when compared with the traditional transosseous cruciate repair and produced less repair site motion. CLINICAL RELEVANCE: The increased biomechanical strength and resistance to displacement at the tendon-bone interface may lead to improved clinical outcomes with the knotless anatomic footprint repair technique and warrants further clinical study. PMID- 25281350 TI - Exploring changes in functional status while waiting for transcatheter aortic valve implantation. AB - BACKGROUND: Aortic stenosis (AS) is a structural heart disease primarily associated with ageing. For people with multiple co-morbidities, surgical treatment may not be a safe or feasible option. Transcatheter aortic valve implantation (TAVI) is indicated for patients with symptomatic AS who are at excessive risk for surgical valve replacement and are likely to derive significant benefit. Functional status can deteriorate during the time between referral and procedure because of the rapid disease progression of severe AS and varying wait-times for treatment in Canada. AIMS: The purpose of this study was to examine changes in functional status between time of eligibility assessment and TAVI procedure date. METHODS: An exploratory prospective cohort study was conducted to evaluate changes in functional status including gait speed, frailty scores and cognitive status. RESULTS: Thirty-two patients participated in the study with median age 81 years. Functional status declined between time of eligibility assessment and time of TAVI: gait speed increased by an average of 0.53 s (standard deviation (SD)=1.0, p=0.01) and frailty scores increased by an average of 0.31 (SD=0.64, p=0.01). Patients waiting longer than six weeks for TAVI had a larger decline in gait speed than patients waiting less than six weeks (p=0.02). Patients living alone had a larger increase in frailty scores compared to patients living with another adult (p=0.05). CONCLUSION: Older adults with life-limiting AS are vulnerable to changes in functional status. In the absence of TAVI wait-time benchmarks, findings may be used to facilitate individualized care and management strategies and inform health-care policy. PMID- 25281351 TI - The effect of temperature and body size on metabolic scope of activity in juvenile Atlantic cod Gadus morhua L. AB - Changes in ambient temperature affect the physiology and metabolism and thus the distribution of fish. In this study we used intermittent flow respirometry to determine the effect of temperature (2, 5, 10, 15 and 20 degrees C) and wet body mass (BM) (~30-460g) on standard metabolic rate (SMR, mgO2h(-1)), maximum metabolic rate (MMR, mgO2h(-1)) and metabolic scope (MS, mgO2h(-1)) of juvenile Atlantic cod. SMR increased with BM irrespectively of temperature, resulting in an average scaling exponent of 0.87 (0.82-0.92). Q10 values were 1.8-2.1 at temperatures between 5 and 15 degrees C but higher (2.6-4.3) between 2 and 5 degrees C and lower (1.6-1.4) between 15 and 20 degrees C in 200 and 450g cod. MMR increased with temperature in the smallest cod (50g) but in the larger cod MMR plateaued between 10, 15 and 20 degrees C. This resulted in a negative correlation between the optimal temperature for MS (Topt) and BM, Topt being respectively 14.5, 11.8 and 10.9 degrees C in a 50, 200 and 450g cod. Irrespective of BM cold water temperatures resulted in a reduction (30-35%) of MS whereas the reduction of MS at warm temperatures was only evident for larger fish (200 and 450g), caused by plateauing of MMR at 10 degrees C and above. Warm temperatures thus seem favourable for smaller (50g) juvenile cod, but not for larger conspecifics (200 and 450g). PMID- 25281352 TI - Vitamin D for prevention of type 2 diabetes: a clouded forecast for the sunshine vitamin. PMID- 25281353 TI - Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study. AB - BACKGROUND: Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach. METHODS: Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes. FINDINGS: All four SNPs were associated with 25(OH)D concentrations (p<10(-6)). The mendelian randomisation-derived unconfounded odds ratio for type 2 diabetes was 1.01 (95% CI 0.75-1.36; p=0.94) per 25.0 nmol/L (1 SD) lower 25(OH)D concentration. The corresponding (potentially confounded) relative risk from the meta-analysis of data from observational studies was 1.21 (1.16-1.27; p=7.3 * 10(-19)). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p>0.25). INTERPRETATION: The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes. FUNDING: UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme. PMID- 25281354 TI - Strengthening monitoring and evaluation (M&E) and building sustainable health information systems in resource limited countries: lessons learned from an M&E task-shifting initiative in Botswana. AB - BACKGROUND: The demand for quality data and the interest in health information systems has increased due to the need for country-level progress reporting towards attainment of the United Nations Millennium Development Goals and global health initiatives. To improve monitoring and evaluation (M&E) of health programs in Botswana, 51 recent university graduates with no experience in M&E were recruited and provided with on-the-job training and mentoring to develop a new cadre of health worker: the district M&E officer. Three years after establishment of the cadre, an assessment was conducted to document achievements and lessons learnt. METHODS: This qualitative assessment included in-depth interviews at the national level (n = 12) with officers from government institutions, donor agencies, and technical organizations; and six focus group discussions separately with district M&E officers, district managers, and program officers coordinating different district health programs. RESULTS: Reported achievements of the cadre included improved health worker capacity to monitor and evaluate programs within the districts; improved data quality, management, and reporting; increased use of health data for disease surveillance, operational research, and planning purposes; and increased availability of time for nurses and other health workers to concentrate on core clinical duties. Lessons learnt from the assessment included: the importance of clarifying roles for newly established cadres, aligning resources and equipment to expectations, importance of stakeholder collaboration in implementation of sustainable programs, and ensuring retention of new cadres. CONCLUSION: The development of a dedicated M&E cadre at the district level contributed positively to health information systems in Botswana by helping build M&E capacity and improving data quality, management, and data use. This assessment has shown that such cadres can be developed sustainably if the initiative is country-led, focusing on recruitment and capacity-development of local counterparts, with a clear government retention plan. PMID- 25281356 TI - Subtle bilirubin-induced neurodevelopmental dysfunction (BIND) in the term and late preterm infant: does it exist? AB - Subtle bilirubin-induced neurological dysfunction (BIND) is defined as disturbances in sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone in the absence of the classical findings of kernicterus. This review is restricted to the (sensori)motor signs of BIND associated with unconjugated hyperbilirubinemia in term and late preterm neonates. The diagnosis of BIND at follow-up requires validated, age-specific techniques that are designed to identify these disturbances in infancy and later childhood. The (sensori)motor signs of BIND are compatible with the pathological substrate of unconjugated hyperbilirubinemia and its known effects on the brain. PMID- 25281355 TI - Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. AB - BACKGROUND: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML DNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically. METHODS: We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML DNMT3A/FLT3/NPM1 patients. RESULTS: Patients with AML DNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML DNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation. CONCLUSIONS: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations. PMID- 25281357 TI - Basic obstetric pharmacology. AB - Pregnancy is associated with a variety of physiological changes that can alter the pharmacokinetics and pharmacodynamics of several drugs. However, limited data exists on the pharmacokinetics and pharmacodynamics of the majority of the medications used in pregnancy. In this article, we first describe basic concepts (drug absorption, bioavailability, distribution, metabolism, elimination, and transport) in pharmacokinetics. Then, we discuss several physiological changes that occur during pregnancy that theoretically affect absorption, distribution, metabolism, and elimination. Further, we provide a brief review of the literature on the clinical pharmacokinetic studies performed in pregnant women in recent years. In general, pregnancy increases the clearance of several drugs and correspondingly decreases drug exposure during pregnancy. Based on current drug exposure measurements during pregnancy, alterations in the dose or dosing regimen of certain drugs are essential during pregnancy. More pharmacological studies in pregnant women are needed to optimize drug therapy in pregnancy. PMID- 25281360 TI - Do telephone call interruptions have an impact on radiology resident diagnostic accuracy? AB - RATIONALE AND OBJECTIVES: The purpose of this study was to measure the effect of distractions, in the form of telephone call interruptions, on radiology resident diagnostic accuracy. MATERIALS AND METHODS: Radiology resident discrepancy reports and reading room telephone logs at an academic tertiary care pediatric hospital were collected over a 13-month period. Phone call times and durations were recorded. Major discrepancy shifts (defined as a call shift where at least one major discrepancy was discovered the following morning by the attending radiologist between the resident preliminary and attending final reports), and dictation time stamps for each discrepant preliminary dictation were also recorded. Telephone call volume and preliminary report time stamps were compared between "discrepancy shifts" and "no discrepancy shifts." RESULTS: Each call shift spanned 14 hours, during which one radiology resident was responsible for the generation of preliminary interpretations. Review of the discrepancy log data revealed 51 major discrepancies in 41 shifts, of which 39 discrepancies had documented error details and resident preliminary report time stamps. The average number of telephone calls for the "discrepancy shifts" was slightly greater than the "no discrepancy shifts" (48.59 vs. 44.02) but was not statistically significant (P = .0575). However, there was a statistically significant increase in the average number of phone calls in the 1 hour preceding the generation of a discrepant preliminary report versus the "no discrepancy shifts" (4.23 vs. 3.24 calls, P = .027). One additional phone call during the hour preceding the generation of a discrepant preliminary report resulted in a 12% increased likelihood of a resident error (P = .017). CONCLUSIONS: Distractions in the form of telephone call interruptions may negatively impact on-call radiology resident diagnostic accuracy. Efforts should be made to limit distractions in the reading room. PMID- 25281358 TI - Oseltamivir for influenza in pregnancy. AB - Pregnancy predisposes women to disproportionate morbidity and mortality from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Inactivated yearly influenza vaccines are the best available method of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu((r))) is currently the first-line recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease among exposed individuals, as well as to shorten the duration of illness and lessen the likelihood of complications among those infected. The physiologic adaptations of pregnancy may alter the pharmacokinetics and pharmacodynamics of this important drug. Updated evidence regarding these potential alterations, current knowledge gaps, and future investigative directions is discussed. PMID- 25281359 TI - Contributions of cell subsets to cytokine production during normal and impaired wound healing. AB - The objective of this study was to determine the relative contributions of different cell subsets to the production of cytokines and growth factors during normal and impaired wound healing. Cells were isolated from wounds of non diabetic and diabetic mice and separated by magnetic sorting into neutrophils/T cells/B cells (NTB cell subset), monocytes/macrophages (Mo/Mp subset) and non leukocytic cells including keratinocyte/fibroblast/endothelial cells (KFE subset). On both per cell and total contribution bases, the Mo/Mp subset was the dominant producer of pro-inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 in both non-diabetic and diabetic mice and was a significant producer of vascular endothelial cell growth factor (VEGF)-A, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-beta1. The NTB subset was also a significant producer of TNF-alpha and IL-10 whereas the KFE subset contributed significant amounts of VEGF, IGF-1 and TGF-beta1. Sustained production of pro-inflammatory cytokines and impaired production of healing-associated factors were evident in each subset in diabetic mice. These data will be useful for further experimental and modeling studies on the role of cell subsets in wound healing as well as for designing therapeutic strategies for improving healing. PMID- 25281361 TI - Effect of intracycle motion correction algorithm on image quality and diagnostic performance of computed tomography coronary angiography in patients with suspected coronary artery disease. AB - RATIONALE AND OBJECTIVES: We sought to explore the impact of intracycle motion correction algorithms (MCA) in the interpretability and diagnostic accuracy of computed tomography coronary angiography (CTCA) performed in patients suspected of coronary artery disease (CAD) referred to invasive coronary angiography. MATERIALS AND METHODS: Patients with suspected CAD referred to invasive coronary angiography previously underwent CTCA. Patients under rate-control medications were advised to withhold for the previous 24 hours. The primary end point of the study was to evaluate image interpretability and diagnostic performance of MCA compared to conventional reconstructions in patients referred to invasive angiography because of suspected CAD. RESULTS: Thirty-five patients were prospectively included in the study protocol. The mean age was 61.4 +/- 9.4 years. Twenty-seven (77%) patients were men. A total of 533 coronary segments were evaluated using conventional and MCA reconstructions. MCA reconstructions were associated to higher interpretability rates (525 of 533, 98.5% vs. 515 of 533, 96.6 %; P < .001) and image quality scores (3.88 +/- 0.54 vs. 3.78 +/- 0.76; P < .0001) compared to conventional reconstructions. Although only mild, a significant difference was observed regarding the diagnostic performance between reconstruction modes, with an area under the curve of 0.90 (0.87-0.92) versus 0.89 (0.86-0.92), respectively, for MCA and conventional reconstructions (P = .0447). CONCLUSIONS: In this pilot investigation, MCA reconstructions performed in patients with suspected CAD were associated to higher interpretability rates and image quality scores compared to conventional reconstructions, although only mild differences were observed regarding the diagnostic performance between reconstruction modes. PMID- 25281362 TI - Reply: To PMID 25088867. PMID- 25281363 TI - Does stage of labor at time of cesarean delivery affect risk of subsequent preterm birth? AB - OBJECTIVE: The effect of a cesarean delivery in different stages of labor on spontaneous preterm birth (sPTB) in a subsequent pregnancy has not been studied extensively. The objective of the study was to evaluate the risk of subsequent sPTB after a first-stage or second-stage cesarean delivery compared with a vaginal delivery. STUDY DESIGN: This was a planned secondary analysis of a large retrospective cohort study of women with 2 consecutive deliveries from 2005-2010. Women with a previous sPTB were excluded. First-stage (<10 cm) and second-stage (>=10 cm) cesarean deliveries were compared with vaginal deliveries. Data were obtained through chart abstraction. The primary outcome was sPTB (<37 wk) in a subsequent pregnancy. Categoric variables were compared with the use of chi(2) analyses, and logistic regression was used to calculate odds and control for confounders. RESULTS: Eight hundred eighty-seven women were included (721 vaginal deliveries; 129 first-stage and 37 second-stage cesarean deliveries). The sPTB rate varied between groups (7.8%, 2.3%, and 13.5%, respectively; P = .03). When compared with women with a vaginal delivery, women with a first-stage cesarean delivery had a decreased risk of sPTB, which remained after adjustment for confounders (adjusted odds ratio, 0.30; 95% confidence interval, 0.09-0.99; P = .049). There was a nonsignificant increase in odds of sPTB after a second-stage cesarean delivery compared with a vaginal delivery (adjusted odds ratio, 2.4; 95% confidence interval, 0.77-7.43; P = .13). Women with a second-stage cesarean delivery had a 6-fold higher odds of sPTB compared with women with a first-stage cesarean delivery, which remained after adjustment for confounders (adjusted odds ratio, 5.8; 95% confidence interval, 1.08-30.8; P = .04). CONCLUSION: Women with a full-term second-stage cesarean delivery have a significantly higher than expected rate of subsequent sPTB (13.5%) compared with both the overall national sPTB rate (7-8%) and to a first-stage cesarean delivery (2.3%). As the cesarean delivery rate continues to rise, this potential impact on pregnancy outcomes cannot be ignored. PMID- 25281364 TI - Postpartum care for mothers diagnosed with hepatitis B during pregnancy. AB - OBJECTIVE: We sought to determine rates of maternal postpartum hepatitis B virus (HBV) follow-up with a HBV specialist and identify factors associated with poor follow-up, as prior research has focused on infant outcomes and not maternal care. STUDY DESIGN: We conducted a retrospective review of data from Partners HealthCare system, the largest health care system in Massachusetts, and identified women with chronic HBV who delivered from 2002 through 2012. RESULTS: We identified 291 women (mean age 31.5 years, 51% Asian) with incident HBV during pregnancy. In all, 47% had postpartum follow-up with a HBV specialist, but only 19% also had appropriate laboratory tests (hepatitis B e antigen [HBeAg], hepatitis B e antibody, HBV DNA, and ALT) within 1 year of their HBV diagnosis. Mothers with HBV follow-up were more likely to have a primary care physician (PCP) within the Partners HealthCare system (66% vs 38%, P < .0001), a positive HBeAg (20% vs 8%, P = .004), and elevated AST values (17% vs 8%, P = .02). On multivariable logistic regression analysis, a mother who had a PCP (odds ratio, 2.50; 95% confidence interval, 1.37-4.59) or positive HBeAg (odds ratio, 4.45; 95% confidence interval, 1.64-12.06) had a greater likelihood of having HBV follow-up. CONCLUSION: Only 19% of HBV-infected mothers met care guidelines 1 year after being diagnosed with HBV. Inadequate postpartum HBV care affects women of all races/ethnicities. Women who had a PCP as well as those who were HBeAg positive were more likely to be referred for postpartum follow-up with a HBV specialist, suggesting that providers might be referring patients when they perceive HBV to be more serious or complex. PMID- 25281366 TI - Bioelectric impedance analysis in pregnant women. PMID- 25281365 TI - A systematic evaluation of collagen cross-links in the human cervix. AB - OBJECTIVE: The mechanical strength of the cervix relies on the cross-linking of the tissue's collagen network. Clinically, the internal os is functionally distinct from the external os. We sought to detect specific collagen cross-links in human cervical tissue and determine whether cross-link profiles were similar at the internal and external os. STUDY DESIGN: Transverse slices of cervical tissue were obtained at the internal and external os from 13 nonpregnant, premenopausal women undergoing a benign hysterectomy. To understand how cross links were distributed throughout the entire cervix and at the internal and external os, biopsies were obtained from 3 circumferential zones in 4 quadrants from each slice. Biopsies were pulverized, lyophilized, reduced with sodium borohydride, hydrolyzed with hydrochloric acid, and reconstituted in heptafluorobutyric acid buffer. Hydroxyproline was measured by ultraperformance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI MS/MS), converted to total collagen, and normalized by dry weight. Collagen cross links pyridinoline (PYD), deoxypyridinoline (DPD), dihydroxylysinonorleucine (DHLNL), and the nonenzymatic advanced glycation end product pentosidine (PEN) were measured by UPLC-ESI-MS/MS and reported as cross-link density ratio (cross link/total collagen). Generalized estimated equation analysis was used to compare results between the internal and external os and to compare quadrants and zones within slices from the internal and external os to determine if cross-link profiles were similar. RESULTS: A total of 592 samples from 13 patients were analyzed. Collagen cross-links are detectable in the human cervix by UPLC-ESI MS/MS. When comparing all samples from the internal and external os, similar levels of collagen content, PYD, DHLNL, and DPD were found, but PEN density was higher at the external os (0.005 vs 0.004, P = .001). When comparing all internal os samples, significant heterogeneity was found in collagen content and cross link densities across zones and quadrants. The external os exhibited heterogeneity only across zones. CONCLUSION: Collagen cross-links (PYD, DPD, DHLNL, and PEN) are detectable by UPLC-ESI-MS/MS in the human cervix. The internal os exhibits significant collagen cross-link heterogeneity compared with the external os. Further studies are needed to evaluate how collagen cross-link heterogeneity correlates to the mechanical strength and function of the human cervix. PMID- 25281367 TI - Assessing the environmental sustainability of biofuels. AB - Biofuels vary in their potential to reduce greenhouse gas emissions when displacing fossil fuels. Savings depend primarily on the crop used for biofuel production, and on the effect that expanding its cultivation has on land use. Evidence-based policies should be used to ensure that maximal sustainability benefits result from the development of biofuels. PMID- 25281369 TI - Catastrophic myocardial ischemia resulting from a left coronary artery anomaly with an origin in the right sinus of Valsalva. AB - A congenital left coronary artery anomaly originating from the right aortic sinus is a rare congenital defect associated with the risk of sudden death in young individuals. In most cases, the proximal portion of the anomalous left coronary artery exists between the ascending aorta and pulmonary trunk, and it has an intramural aortic course; this could critically impair the left coronary flow owing to compression of the anomalous left main trunk between the great vessels during exercise. Herein, we report a 14-year-old boy who experienced cardiac collapse due to an acute myocardial infarction after long-distance running. After resuscitation using percutaneous cardiopulmonary support, computed tomography and coronary angiography revealed an anomalous origin of the left main coronary artery in the right sinus of Valsalva and a proximal course between the aorta and pulmonary trunk. The patient was successfully treated using an unroofing procedure of the intramural left coronary artery. PMID- 25281368 TI - Alcohol consumption in relation to plasma sex hormones, prolactin, and sex hormone-binding globulin in premenopausal women. AB - BACKGROUND: Alcohol consumption is a consistent risk factor for breast cancer, and evidence suggests premenopausal plasma hormones are associated with breast cancer. METHODS: Plasma concentrations of estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, prolactin, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were measured in samples collected in 1996-99. Average alcohol intake was calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across alcohol categories and the percentage difference for the highest versus lowest category. RESULTS: Comparing women who consumed >20 g/d with nondrinkers, levels were 25.7% higher for luteal estrone (geometric mean, 106 vs. 84.5 pg/mL; Ptrend = 0.001), 27.2% higher for luteal estradiol (182 vs. 143 pg/mL; Ptrend = 0.006), and 16.8% higher for SHBG (85.6 vs. 73.3 nmol/L; Ptrend = 0.03); concentrations of free testosterone were 17.9% lower (0.16 vs. 0.20 ng/dL; Ptrend = 0.002). Women consuming >10 g/d compared with nondrinkers had 26.5% higher concentrations of follicular estrone sulfate (950 vs. 751 pg/mL; Ptrend = 0.04). We did not observe significant associations between alcohol and the other sex hormones evaluated. Significant positive associations were observed with beer intake, but not other alcohol types, for DHEA (Pinteraction = 0.003) and androstenedione (Pinteraction = 0.006). CONCLUSION: Alcohol consumption was significantly positively associated with plasma luteal estrogen concentrations, but not with androgen levels, nor estrone or estradiol measured in the follicular phase. IMPACT: Differences in premenopausal estrogen levels may contribute to the association between alcohol and breast cancer. PMID- 25281370 TI - Total absence of the pericardium incidentally found during surgery for spontaneous pneumothorax. AB - Congenital absence of the pericardium is a rare malformation which is often found incidentally. We report a case of pericardial absence which was found during surgery for spontaneous pneumothorax. Image analyses suggested that the pericardial absence was bilateral and total. These findings were overlooked on CT, preoperatively. Although rare, the possibility of asymptomatic pericardial absence should be kept in mind when observing the chest images before performing thoracic interventions. PMID- 25281371 TI - Special Issue from IEEE ICCA 2013. PMID- 25281372 TI - A hidden pitfall in the preparation of agar media undermines microorganism cultivability. AB - Microbiologists have been using agar growth medium for over 120 years. It revolutionized microbiology in the 1890s when microbiologists were seeking effective methods to isolate microorganisms, which led to the successful cultivation of microorganisms as single clones. But there has been a disparity between total cell counts and cultivable cell counts on plates, often referred to as the "great plate count anomaly," that has long been a phenomenon that still remains unsolved. Here, we report that a common practice microbiologists have employed to prepare agar medium has a hidden pitfall: when phosphate was autoclaved together with agar to prepare solid growth media (PT medium), total colony counts were remarkably lower than those grown on agar plates in which phosphate and agar were separately autoclaved and mixed right before solidification (PS medium). We used a pure culture of Gemmatimonas aurantiaca T 27(T) and three representative sources of environmental samples, soil, sediment, and water, as inocula and compared colony counts between PT and PS agar plates. There were higher numbers of CFU on PS medium than on PT medium using G. aurantiaca or any of the environmental samples. Chemical analysis of PT agar plates suggested that hydrogen peroxide was contributing to growth inhibition. Comparison of 454 pyrosequences of the environmental samples to the isolates revealed that taxa grown on PS medium were more reflective of the original community structure than those grown on PT medium. Moreover, more hitherto uncultivated microbes grew on PS than on PT medium. PMID- 25281373 TI - Abundance of Vibrio cholerae, V. vulnificus, and V. parahaemolyticus in oysters (Crassostrea virginica) and clams (Mercenaria mercenaria) from Long Island sound. AB - Vibriosis is a leading cause of seafood-associated morbidity and mortality in the United States. Typically associated with consumption of raw or undercooked oysters, vibriosis associated with clam consumption is increasingly being reported. However, little is known about the prevalence of Vibrio spp. in clams. The objective of this study was to compare the levels of Vibrio cholerae, Vibrio vulnificus, and Vibrio parahaemolyticus in oysters and clams harvested concurrently from Long Island Sound (LIS). Most probable number (MPN)-real-time PCR methods were used for enumeration of total V. cholerae, V. vulnificus, V. parahaemolyticus, and pathogenic (tdh(+) and/or trh(+)) V. parahaemolyticus. V. cholerae was detected in 8.8% and 3.3% of oyster (n = 68) and clam (n = 30) samples, with levels up to 1.48 and 0.48 log MPN/g in oysters and clams, respectively. V. vulnificus was detected in 97% and 90% of oyster and clam samples, with median levels of 0.97 and -0.08 log MPN/g, respectively. V. parahaemolyticus was detected in all samples, with median levels of 1.88 and 1.07 log MPN/g for oysters and clams, respectively. The differences between V. vulnificus and total and pathogenic V. parahaemolyticus levels in the two shellfish species were statistically significant (P < 0.001). These data indicate that V. vulnificus and total and pathogenic V. parahaemolyticus are more prevalent and are present at higher levels in oysters than in hard clams. Additionally, the data suggest differences in vibrio populations between shellfish harvested from different growing area waters within LIS. These results can be used to evaluate and refine illness mitigation strategies employed by risk managers and shellfish control authorities. PMID- 25281374 TI - Metabolic engineering of a glycerol-oxidative pathway in Lactobacillus panis PM1 for utilization of bioethanol thin stillage: potential to produce platform chemicals from glycerol. AB - Lactobacillus panis PM1 has the ability to produce 1,3-propanediol (1,3-PDO) from thin stillage (TS), which is the major waste material after bioethanol production, and is therefore of significance. However, the fact that L. panis PM1 cannot use glycerol as a sole carbon source presents a considerable problem in terms of utilization of this strain in a wide range of industrial applications. Accordingly, L. panis PM1 was genetically engineered to directly utilize TS as a fermentable substrate for the production of valuable platform chemicals without the need for exogenous nutrient supplementation (e.g., sugars and nitrogen sources). An artificial glycerol-oxidative pathway, comprised of glycerol facilitator, glycerol kinase, glycerol 3-phosphate dehydrogenase, triosephosphate isomerase, and NADPH-dependent aldehyde reductase genes of Escherichia coli, was introduced into L. panis PM1 in order to directly utilize glycerol for the production of energy for growth and value-added chemicals. A pH 6.5 culture converted glycerol to mainly lactic acid (85.43 mM), whereas a significant amount of 1,3-propanediol (59.96 mM) was formed at pH 7.5. Regardless of the pH, ethanol (82.16 to 83.22 mM) was produced from TS fermentations, confirming that the artificial pathway metabolized glycerol for energy production and converted it into lactic acid or 1,3-PDO and ethanol in a pH-dependent manner. This study demonstrates the cost-effective conversion of TS to value-added chemicals by the engineered PM1 strain cultured under industrial conditions. Thus, application of this strain or these research findings can contribute to reduced costs of bioethanol production. PMID- 25281375 TI - Genetic diversity of picocyanobacteria in tibetan lakes: assessing the endemic and universal distributions. AB - The phylogenetic diversity of picocyanobacteria in seven alkaline lakes on the Tibetan Plateau was analyzed using the molecular marker 16S-23S rRNA internal transcribed spacer sequence. A total of 1,077 environmental sequences retrieved from the seven lakes were grouped into seven picocyanobacterial clusters, with two clusters newly described here. Each of the lakes was dominated by only one or two clusters, while different lakes could have disparate communities, suggesting low alpha diversity but high beta diversity of picocyanobacteria in these high altitude freshwater and saline lakes. Several globally distributed clusters were found in these Tibetan lakes, such as subalpine cluster I and the Cyanobium gracile cluster. Although other clusters likely exhibit geographic restriction to the plateau temporally, reflecting endemicity, they can indeed be distributed widely on the plateau. Lakes with similar salinities may have similar genetic populations despite a large geographic distance. Canonical correspondence analysis identified salinity as the only environmental factor that may in part explain the diversity variations among lakes. Mantel tests suggested that the community similarities among lakes are independent of geographic distance. A portion of the picocyanobacterial clusters appear to be restricted to a narrow salinity range, while others are likely adapted to a broad range. A seasonal survey of Lake Namucuo across 3 years did not show season-related variations in diversity, and depth-related population partitioning was observed along a vertical profile of the lake. Our study emphasizes the high dispersive potential of picocyanobacteria and suggests that the regional distribution may result from adaptation to specified environments. PMID- 25281376 TI - Positive regulation of botulinum neurotoxin gene expression by CodY in Clostridium botulinum ATCC 3502. AB - Botulinum neurotoxin, produced mainly by the spore-forming bacterium Clostridium botulinum, is the most poisonous biological substance known. Here, we show that CodY, a global regulator conserved in low-G+C Gram-positive bacteria, positively regulates the botulinum neurotoxin gene expression. Inactivation of codY resulted in decreased expression of botA, encoding the neurotoxin, as well as in reduced neurotoxin synthesis. Complementation of the codY mutation in trans rescued neurotoxin synthesis, and overexpression of codY in trans caused elevated neurotoxin production. Recombinant CodY was found to bind to a 30-bp region containing the botA transcription start site, suggesting regulation of the neurotoxin gene transcription through direct interaction. GTP enhanced the binding affinity of CodY to the botA promoter, suggesting that CodY-dependent neurotoxin regulation is associated with nutritional status. PMID- 25281377 TI - Detection and quantification of Flavobacterium psychrophilum-specific bacteriophages in vivo in rainbow trout upon oral administration: implications for disease control in aquaculture. AB - The use of bacteriophages in the treatment and prevention of infections by the fish pathogen Flavobacterium psychrophilum has attracted increased attention in recent years. It has been shown recently that phage delivery via the parenteral route resulted in immediate distribution of phages to the circulatory system and the different organs. However, little is known about phage dispersal and survival in vivo in rainbow trout after delivery via the oral route. Here we examined the dispersal and survival of F. psychrophilum phage FpV-9 in vivo in juvenile rainbow trout after administration by three different methods-bath, oral intubation into the stomach, and phage-coated feed-with special emphasis on the oral route of delivery. Phages could be detected in all the organs investigated (intestine, spleen, brain, and kidney) 0.5 h postadministration, reaching concentrations as high as ~10(5) PFU mg intestine(-1) and ~10(3) PFU mg spleen( 1) within the first 24 h following the bath and ~10(7) PFU mg intestine(-1) and ~10(4) PFU mg spleen(-1) within the first 24 h following oral intubation. The phages were most persistent in the organs for the first 24 h and then decreased exponentially; no phages were detected after 83 h in the organs investigated. Phage administration via feed resulted in the detection of phages in the intestine, spleen, and kidney 1 h after feeding. Average concentrations of ~10(4) PFU mg intestine(-1) and ~10(1) PFU mg spleen(-1) were found throughout the experimental period (200 h) following continuous delivery of phages with feed. These experiments clearly demonstrate the ability of the phages to survive passage through the fish stomach and to penetrate the intestinal barrier and enter the circulatory system after oral delivery, although the quantity of phages found in the spleen was 100- to 1,000-fold lower than that in the intestine. It was also shown that phages could tolerate long periods of desiccation on the feed pellets, with 60% survival after storage at -80 degrees C, and 10% survival after storage at 5 degrees C, for ~8 months. Continuous delivery of phages via coated feed pellets constitutes a promising method of treatment and especially prevention of rainbow trout fry syndrome. PMID- 25281378 TI - Microarray-based detection of Salmonella enterica serovar Enteritidis genes involved in chicken reproductive tract colonization. AB - Salmonella enterica serovar Enteritidis has developed the potential to contaminate table eggs internally, by colonization of the chicken reproductive tract and internalization in the forming egg. The serotype Enteritidis has developed mechanisms to colonize the chicken oviduct more successfully than other serotypes. Until now, the strategies exploited by Salmonella Enteritidis to do so have remained largely unknown. For that reason, a microarray-based transposon library screen was used to identify genes that are essential for the persistence of Salmonella Enteritidis inside primary chicken oviduct gland cells in vitro and inside the reproductive tract in vivo. A total of 81 genes with a potential role in persistence in both the oviduct cells and the oviduct tissue were identified. Major groups of importance include the Salmonella pathogenicity islands 1 and 2, genes involved in stress responses, cell wall, and lipopolysaccharide structure, and the region-of-difference genomic islands 9, 21, and 40. PMID- 25281379 TI - Phosphotransferase system-dependent extracellular growth of listeria monocytogenes is regulated by alternative sigma factors sigmaL and sigmaH. AB - Alternative sigma (sigma) factors and phosphotransferase systems (PTSs) play pivotal roles in the environmental adaptation and virulence of Listeria monocytogenes. The growth of the L. monocytogenes parent strain 10403S and 15 isogenic alternative sigma factor mutants was assessed in defined minimal medium (DM) with PTS-dependent or non-PTS-dependent carbon sources at 25 degrees C or 37 degrees C. Overall, our results suggested that the regulatory effect of alternative sigma factors on the growth of L. monocytogenes is dependent on the temperature and the carbon source. One-way analysis of variance (one-way ANOVA) showed that the factor "strain" had a significant effect on the maximum growth rate (MUmax), lag phase duration (lambda), and maximum optical density (ODmax) in PTS-dependent carbon sources (P < 0.05) but not in a non-PTS-dependent carbon source. Also, the ODmax was not affected by strain for any of the three PTS dependent carbon sources at 25 degrees C but was affected by strain at 37 degrees C. Monitoring by quantitative real-time PCR (qRT-PCR) showed that transcript levels for lmo0027, a glucose-glucoside PTS permease (PTS(Glc)-1)-encoding gene, were higher in the absence of sigma(L), and lower in the absence of sigma(H), than in the parent strain. Our data thus indicate that sigma(L) negatively regulates lmo0027 and that the increased MUmax observed for the DeltasigL strain in DM with glucose may be associated with increased expression of PTS(Glc)-1 encoded by lmo0027. Our findings suggest that sigma(H) and sigma(L) mediate the PTS-dependent growth of L. monocytogenes through complex transcriptional regulations and fine-tuning of the expression of specific pts genes, including lmo0027. Our findings also reveal a more important and complex role of alternative sigma factors in the regulation of growth in different sugar sources than previously assumed. PMID- 25281380 TI - Impact of Ralstonia eutropha's poly(3-Hydroxybutyrate) (PHB) Depolymerases and Phasins on PHB storage in recombinant Escherichia coli. AB - The model organism for polyhydroxybutyrate (PHB) biosynthesis, Ralstonia eutropha H16, possesses multiple isoenzymes of granules coating phasins as well as of PHB depolymerases, which degrade accumulated PHB under conditions of carbon limitation. In this study, recombinant Escherichia coli BL21(DE3) strains were used to study the impact of selected PHB depolymerases of R. eutropha H16 on the growth behavior and on the amount of accumulated PHB in the absence or presence of phasins. For this purpose, 20 recombinant E. coli BL21(DE3) strains were constructed, which harbored a plasmid carrying the phaCAB operon from R. eutropha H16 to ensure PHB synthesis and a second plasmid carrying different combinations of the genes encoding a phasin and a PHB depolymerase from R. eutropha H16. It is shown in this study that the growth behavior of the respective recombinant E. coli strains was barely affected by the overexpression of the phasin and PHB depolymerase genes. However, the impact on the PHB contents was significantly greater. The strains expressing the genes of the PHB depolymerases PhaZ1, PhaZ2, PhaZ3, and PhaZ7 showed 35% to 94% lower PHB contents after 30 h of cultivation than the control strain. The strain harboring phaZ7 reached by far the lowest content of accumulated PHB (only 2.0% [wt/wt] PHB of cell dry weight). Furthermore, coexpression of phasins in addition to the PHB depolymerases influenced the amount of PHB stored in cells of the respective strains. It was shown that the phasins PhaP1, PhaP2, and PhaP4 are not substitutable without an impact on the amount of stored PHB. In particular, the phasins PhaP2 and PhaP4 seemed to limit the degradation of PHB by the PHB depolymerases PhaZ2, PhaZ3, and PhaZ7, whereas almost no influence of the different phasins was observed if phaZ1 was coexpressed. This study represents an extensive analysis of the impact of PHB depolymerases and phasins on PHB accumulation and provides a deeper insight into the complex interplay of these enzymes. PMID- 25281381 TI - Coagulase-negative Staphylococci favor conversion of arginine into ornithine despite a widespread genetic potential for nitric oxide synthase activity. AB - Within ecosystems that are poor in carbohydrates, alternative substrates such as arginine may be of importance to coagulase-negative staphylococci (CNS). However, the versatility of arginine conversion in CNS remains largely uncharted. Therefore, a set of 86 strains belonging to 17 CNS species was screened for arginine deiminase (ADI), arginase, and nitric oxide synthase (NOS) activities, in view of their ecological relevance. In fermented meats, for instance, ADI could improve bacterial competitiveness, whereas NOS may serve as an alternative nitrosomyoglobin generator to nitrate and nitrite curing. About 80% of the strains were able to convert arginine, but considerable inter- and intraspecies heterogeneity regarding the extent and mechanism of conversion was found. Overall, ADI was the most commonly employed pathway, resulting in mixtures of ornithine and small amounts of citrulline. Under aerobic conditions, which are more relevant for skin-associated CNS communities, several strains shifted toward arginase activity, leading to the production of ornithine and urea. The obtained data indeed suggest that arginase occurs relatively more in CNS isolates from a dairy environment, whereas ADI seems to be more abundant in strains from a fermented meat background. With some exceptions, a reasonable match between phenotypic ADI and arginase activity and the presence of the encoding genes (arcA and arg) was found. With respect to the NOS pathway, however, only one strain (Staphylococcus haemolyticus G110) displayed phenotypic NOS-like activity under aerobic conditions, despite a wide prevalence of the NOS-encoding gene (nos) among CNS. Hence, the group of CNS displays a strain- and condition-dependent toolbox of arginine-converting mechanisms with potential implications for competitiveness and functionality. PMID- 25281382 TI - Construction of a quadruple auxotrophic mutant of an industrial polyploid saccharomyces cerevisiae strain by using RNA-guided Cas9 nuclease. AB - Industrial polyploid yeast strains harbor numerous beneficial traits but suffer from a lack of available auxotrophic markers for genetic manipulation. Here we demonstrated a quick and efficient strategy to generate auxotrophic markers in industrial polyploid yeast strains with the RNA-guided Cas9 nuclease. We successfully constructed a quadruple auxotrophic mutant of a popular industrial polyploid yeast strain, Saccharomyces cerevisiae ATCC 4124, with ura3, trp1, leu2, and his3 auxotrophies through RNA-guided Cas9 nuclease. Even though multiple alleles of auxotrophic marker genes had to be disrupted simultaneously, we observed knockouts in up to 60% of the positive colonies after targeted gene disruption. In addition, growth-based spotting assays and fermentation experiments showed that the auxotrophic mutants inherited the beneficial traits of the parental strain, such as tolerance of major fermentation inhibitors and high temperature. Moreover, the auxotrophic mutants could be transformed with plasmids containing selection marker genes. These results indicate that precise gene disruptions based on the RNA-guided Cas9 nuclease now enable metabolic engineering of polyploid S. cerevisiae strains that have been widely used in the wine, beer, and fermentation industries. PMID- 25281383 TI - Aerobic biodegradation of 2,4-Dinitroanisole by Nocardioides sp. strain JS1661. AB - 2,4-Dinitroanisole (DNAN) is an insensitive munition ingredient used in explosive formulations as a replacement for 2,4,6-trinitrotoluene (TNT). Little is known about the environmental behavior of DNAN. There are reports of microbial transformation to dead-end products, but no bacteria with complete biodegradation capability have been reported. Nocardioides sp. strain JS1661 was isolated from activated sludge based on its ability to grow on DNAN as the sole source of carbon and energy. Enzyme assays indicated that the first reaction involves hydrolytic release of methanol to form 2,4-dinitrophenol (2,4-DNP). Growth yield and enzyme assays indicated that 2,4-DNP underwent subsequent degradation by a previously established pathway involving formation of a hydride-Meisenheimer complex and release of nitrite. Identification of the genes encoding the key enzymes suggested recent evolution of the pathway by recruitment of a novel hydrolase to extend the well-characterized 2,4-DNP pathway. PMID- 25281384 TI - Molecular epidemiology of Cryptosporidium spp. and Giardia spp. in mussels (Mytilus californianus) and California sea lions (Zalophus californianus) from Central California. AB - Cryptosporidium and Giardia are of public health importance, with recognized transmission through recreational waters. Therefore, both can contaminate marine waters and shellfish, with potential to infect marine mammals in nearshore ecosystems. A 2-year study was conducted to evaluate the presence of Cryptosporidium and Giardia in mussels located at two distinct coastal areas in California, namely, (i) land runoff plume sites and (ii) locations near sea lion haul-out sites, as well as in feces of California sea lions (CSL) (Zalophus californianus) by the use of direct fluorescent antibody (DFA) detection methods and PCR with sequence analysis. In this study, 961 individual mussel hemolymph samples, 54 aliquots of pooled mussel tissue, and 303 CSL fecal samples were screened. Giardia duodenalis assemblages B and D were detected in hemolymph from mussels collected near two land runoff plume sites (Santa Rosa Creek and Carmel River), and assemblages C and D were detected in hemolymph from mussels collected near a sea lion haul-out site (White Rock). These results suggest that mussels are being contaminated by protozoa carried in terrestrial runoff and/or shed in the feces of CSL. Furthermore, low numbers of oocysts and cysts morphologically similar to Cryptosporidium and Giardia, respectively, were detected in CSL fecal samples, suggesting that CSL could be a source and a host of protozoan parasites in coastal environments. The results of this study showed that Cryptosporidium and Giardia spp. from the feces of terrestrial animals and CSL can contaminate mussels and coastal environments. PMID- 25281385 TI - Molecular epidemiology of cases of Mycoplasma californicum infection in Japan. AB - Bovine mastitis due to Mycoplasma californicum is often accompanied by huge economic losses, and the disease spreads very quickly. An appropriate molecular epidemiological analysis is needed to prevent and control infectious disease, but molecular epidemiological analysis methods for M. californicum have not yet been reported. Here we developed a combination of multiple-locus variable-number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE) methods, which are common genotyping methods for various bacteria, for M. californicum. The MLVA is based on four interspersed repeat units that were found in the M. californicum genome data. The MLVA using these repeat units showed sufficient discriminatory power for a molecular epidemiological analysis; i.e., a Hunter-Gaston diversity index (HGDI) of 0.949, against M. californicum strains in Japan and M. californicum strain ATCC 33461. The PFGE for M. californicum also showed sufficient discriminatory power, with an HGDI of 0.985. Strain ATCC 33461 showed MLVA profiles and pulsotypes that differed greatly from those of strains from Japan. These results indicate that MLVA and PFGE are good tools for identifying M. californicum transmission events more accurately. Our combined MLVA and PFGE analysis suggests the persistence of M. californicum infection among herds in a specific area for a long period of time, as well as the movement of cows and heifers accompanying the expansion of M. californicum infection. Failure to identify asymptomatic infected cows is suspected as one of the central causes of the present M. californicum infection scenario in Japan. PMID- 25281386 TI - The RNA-binding protein RBPMS1 represses AP-1 signaling and regulates breast cancer cell proliferation and migration. AB - The activator protein-1 (AP-1) transcription factor complex plays a crucial role in tumor growth and progression. However, how AP-1 transcriptional activity is repressed is not fully understood. Here, we show that RNA-binding protein with multiple splicing 1 (RBPMS1) physically and functionally interacts with AP-1 in vitro and in vivo. The RNA-recognition motif (RRM) and C-terminus of the RBPMS1 isoforms RBPMS1A and RBPMS1C, but not RBPMS1B, interacted with cFos, a member of the AP-1 family that dimerizes with cJun to stimulate AP-1 transcriptional activity. RBPMS1 did not associate with Jun proteins. RBPMS1A and RBPMS1C bound to the basic leucine zipper (bZIP) domain of cFos that mediates dimerization of AP-1 proteins. In addition, RBPMS1A-C interacted with the transcription factor Smad3, which was shown to interact with cJun and increase AP-1 transcriptional activity. RBPMS1 inhibited c-Fos or Smad3-mediated AP-1 transactivation and the expression of AP-1 target genes known to be the key regulators of cancer growth and progression, including vascular endothelial growth factor (VEGF) and cyclin D1. Mechanistically, RBPMS1 blocks the formation of the cFos/cJun or Smad3/cJun complex as well as the recruitment of cFos or Smad3 to the promoters of AP-1 target genes. In cultured cells and a mouse xenograft model, RBPMS1 inhibited the growth and migration of breast cancer cells through c-Fos or Smad3. These data suggest that RBPMS1 is a critical repressor of AP-1 signaling and RBPMS1 activation may be a useful strategy for cancer treatment. PMID- 25281387 TI - Reply to Berardino De Bari, Stefano Arcangeli, and Filippo Alongi's letter to the editor re: Nazareno Suardi, Andrea Gallina, Giuliana Lista, et al. impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur Urol 2014;65:546-51. PMID- 25281388 TI - Re: Nazareno Suardi, Andrea Gallina, Giuliana Lista, et al. Impact of adjuvant radiation therapy on urinary continence recovery after radical prostatectomy. Eur urol 2014;65:546-51. PMID- 25281390 TI - What evidence do we need to support the use of extended pelvic lymph node dissection in prostate cancer? PMID- 25281389 TI - Focal therapy: patients, interventions, and outcomes--a report from a consensus meeting. AB - BACKGROUND: Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field. OBJECTIVE: To gather expert opinion on patient selection, interventions, and meaningful outcome measures for focal therapy in clinical practice and trial design. DESIGN, SETTING, AND PARTICIPANTS: Fifteen experts in focal therapy followed a modified two-stage RAND/University of California, Los Angeles (UCLA) Appropriateness Methodology process. All participants independently scored 246 statements prior to rescoring at a face-to-face meeting. The meeting occurred in June 2013 at the Royal Society of Medicine, London, supported by the Wellcome Trust and the UK Department of Health. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement, disagreement, or uncertainty were calculated as the median panel score. Consensus was derived from the interpercentile range adjusted for symmetry level. RESULTS AND LIMITATIONS: Of 246 statements, 154 (63%) reached consensus. Items of agreement included the following: patients with intermediate risk and patients with unifocal and multifocal PCa are eligible for focal treatment; magnetic resonance imaging-targeted or template-mapping biopsy should be used to plan treatment; planned treatment margins should be 5mm from the known tumor; prostate volume or age should not be a primary determinant of eligibility; foci of indolent cancer can be left untreated when treating the dominant index lesion; histologic outcomes should be defined by targeted biopsy at 1 yr; residual disease in the treated area of <=3 mm of Gleason 3+3 did not need further treatment; and focal retreatment rates of <=20% should be considered clinically acceptable but subsequent whole-gland therapy deemed a failure of focal therapy. All statements are expert opinion and therefore constitute level 5 evidence and may not reflect wider clinical consensus. CONCLUSIONS: The landscape of PCa treatment is rapidly evolving with new treatment technologies. This consensus meeting provides guidance to clinicians on current expert thinking in the field of focal therapy. PATIENT SUMMARY: In this report we present expert opinion on patient selection, interventions, and meaningful outcomes for clinicians working in focal therapy for prostate cancer. PMID- 25281392 TI - Mammalian cell display technology coupling with AID induced SHM in vitro: an ideal approach to the production of therapeutic antibodies. AB - Traditional antibody production technology within non-mammalian cell expression systems has shown many unsatisfactory properties for the development of therapeutic antibodies. Nevertheless, mammalian cell display technology reaps the benefits of producing full-length all human antibodies. Together with the developed cytidine deaminase induced in vitro somatic hypermutation technology, mammalian cell display technology provides the opportunity to produce high affinity antibodies that might be ideal for therapeutic application. This review was concentrated on the development of the mammalian cell display technology as well as the activation-induced cytidine deaminase induced in vitro somatic hypermutation technology and their applications for the production of therapeutic antibodies. PMID- 25281391 TI - Inhibition of human natural killer cell functional activity by human aspartyl beta-hydroxylase. AB - Natural killer (NK) cells are a key component of the innate immune system and play pivotal roles as inflammatory regulators and in tumor surveillance. Human aspartyl beta-hydroxylase (HAAH) is a plasma membrane and endoplasmic reticulum protein with hydroxylation activity, which is over-expressed in many malignant neoplasms and can be detected from the sera of tumor patients. HAAH is involved in regulating tumor cell infiltration and metastasis. Escaping from immune surveillance may help tumor cell infiltration and metastasis. However, the effects of HAAH on tumor immune surveillance have not yet been investigated carefully. The present study investigated the potential use of HAAH as an immune regulator of human NK cells. We assessed the effects of recombinant HAAH (r-HAAH) on primary human NK cell morphology, viability, cytotoxicity, apoptosis, receptors expression and cytokine/cytolytic proteins production. Our results demonstrated that r-HAAH negatively affects NK cell activity in a time and dose dependent manner. It noticeably reduces the viability of the NK cells by increasing apoptosis and necrosis via caspase signaling pathways. Moreover, r HAAH reduces the NK cell cytotoxicity by inhibiting surface expression of NKG2D, NKp44 and IFN-gamma secretion. These findings suggest that one of the ways by which HAAH actively promotes tumor formation and proliferation is by inhibiting NK cell-surveillance activity. PMID- 25281393 TI - Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia. AB - Betulinic acid (BA) is a lupane-type triterpene with a number of biological activities already reported. While potent anti-HIV and antitumoral activities were attributed to BA, it is considered to have a moderate anti-inflammatory activity. Here we evaluated the effects of BA in a mouse model of endotoxic shock. Endotoxemia was induced through intraperitoneally LPS administration, nitric oxide (NO) and cytokines were assessed by Griess method and ELISA, respectively. Treatment of BALB/c mice with BA at 67 mg/kg caused a 100% survival against a lethal dose of lipopolysaccharide (LPS). BA treatment caused a reduction in TNF-alpha production induced by LPS but did not alter IL-6 production. Moreover, BA treatment increased significantly the serum levels of IL 10 compared to vehicle-treated, LPS-challenged mice. To investigate the role of IL-10 in BA-induced protection, wild-type and IL-10(-/-) mice were studied. In contrast to the observations in IL-10(+/+) mice, BA did not protect IL-10(-/-) mice against a lethal LPS challenge. Addition of BA inhibited the production of pro-inflammatory mediators by macrophages stimulated with LPS, while promoting a significant increase in IL-10 production. BA-treated peritoneal exudate macrophages produced lower concentrations of TNF-alpha and NO and higher concentrations of IL-10 upon LPS stimulation. Similarly, macrophages obtained from BA-treated mice produced less pro-inflammatory mediators and increased IL-10 when compared to non-stimulated macrophages obtained from vehicle-treated mice. In conclusion, we have shown that BA has a potent anti-inflammatory activity in vivo, protecting mice against LPS by modulating TNF-alpha production by macrophages in vivo through a mechanism dependent on IL-10. PMID- 25281394 TI - NKG2A expression and impaired function of NK cells in patients with new onset of Graves' disease. AB - BACKGROUND: Graves' disease (GD) is an organ-specific autoimmune disease. A significant decrease of the distribution of NK cells in the peripheral blood in children and adolescents with untreated GD has been observed. However, the role of NK and its subsets in adults with GD remains unclear. METHODS: A total of 28 adult patients with new onset of GD and 23 healthy controls (HC) were recruited. The number of activated inhibitory NK cells in peripheral blood of individual subjects was determined by flow cytometry. RESULTS: The number of CD3(-)CD56(+) and CD3(-)CD16(+)NK cells in peripheral blood was significantly decreased in the GD patients than the HC. Compared to the HCs, decreased number of NKG2D(+), NKG2C(+), NKp30(+) and NKG2A(+) NK cells and increased number of KIR3DL1(+) NK cells were detected in the GD patients. Moreover, the number of inducible CD107a(+) and IFN-gamma-secreting NK cells in GD patients significantly decreased than those in HC. Interestingly, the number of NKG2A(+)NK cells was negatively correlated with the level of serum TRAb in GD patients. CONCLUSION: Our data indicate that decreased number and impaired function of NK cells may contribute to the pathogenesis of GD. PMID- 25281395 TI - Sclerotherapy for rare bleeding stomal varices after ileal conduit urinary diversion: an effective and noninvasive method. AB - INTRODUCTION: Bleeding stomal varices after ileal conduit urinary diversion are rare, but they can develop in patients with portal venous hypertension caused by cirrhosis. CASE PRESENTATION: We report the case of a 68-year-old man who developed stomal haemorrhage two months after radical cystectomy and ileal conduit urinary diversion to treat invasive bladder cancer. Alcoholic cirrhosis and portal venous hypertension were considered to be the causes of varices and bleeding. We chose to control the stomal varices using sclerotherapy. The stomal varices disappeared and no bleeding recurred during one year of follow up. CONCLUSION: We believe that sclerotherapy is a suitable treatment for bleeding stomal varices. PMID- 25281396 TI - Vitamin B12 deficiency causing night sweats. AB - Vitamin B12 deficiency is common. It is known to cause a wide spectrum of neurological syndromes, including autonomic dysfunction. Three cases are discussed here in which drenching night sweats were thought to be caused by vitamin B12 deficiency. All three responded dramatically to vitamin B12 therapy. PMID- 25281397 TI - Gait characteristics in a canine model of X-linked myotubular myopathy. AB - X-linked myotubular myopathy (XLMTM) is a fatal pediatric disease where affected boys display profound weakness of the skeletal muscles. Possible therapies are under development but robust outcome measures in animal models are required for effective translation to human patients. We established a naturally-occurring canine model, where XLMTM dogs display clinical symptoms similar to those observed in humans. The aim of this study was to determine potential endpoints for the assessment of future treatments in this model. Video-based gait analysis was selected, as it is a well-established method of assessing limb function in neuromuscular disease and measures have been correlated to the patient's quality of life. XLMTM dogs (N = 3) and their true littermate wild type controls (N = 3) were assessed at 4-5 time points, beginning at 10 weeks and continuing through 17 weeks. Motion capture and an instrumented carpet were used separately to evaluate spatiotemporal and kinematic changes over time. XLMTM dogs walk more slowly and with shorter stride lengths than wild type dogs, and these differences became greater over time. However, there was no clear difference in angular measures between affected and unaffected dogs. These data demonstrate that spatiotemporal parameters capture functional changes in gait in an XLMTM canine model and support their utility in future therapeutic trials. PMID- 25281398 TI - Hendra virus. AB - Hendra virus infection of horses occurred sporadically between 1994 and 2010 as a result of spill-over from the viral reservoir in Australian mainland flying foxes, and occasional onward transmission to people also followed from exposure to affected horses. An unprecedented number of outbreaks were recorded in 2011 leading to heightened community concern. Release of an inactivated subunit vaccine for horses against Hendra virus represents the first commercially available product that is focused on mitigating the impact of a Biosafety Level 4 pathogen. Through preventing the development of acute Hendra virus disease in horses, vaccine use is also expected to reduce the risk of transmission of infection to people. PMID- 25281399 TI - Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance. AB - OBJECTIVES: Dolutegravir has been recently approved for treatment-naive and experienced HIV-infected subjects, including integrase inhibitor (INI) experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure. METHODS: Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations. RESULTS: Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations. CONCLUSIONS: Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155H raltegravir mutation. PMID- 25281401 TI - Corticotropin (ACTH) regulates alternative RNA splicing in Y1 mouse adrenocortical tumor cells. AB - The stimulatory effect of ACTH on gene expression is well documented and is thought to be a major mechanism by which ACTH maintains the functional and structural integrity of the gland. Previously, we showed that ACTH regulates the accumulation of over 1200 transcripts in Y1 adrenal cells, including a cluster with functions in alternative splicing of RNA. On this basis, we postulated that some of the effects of ACTH on the transcription landscape of Y1 cells are mediated by alternative splicing. In this study, we demonstrate that ACTH regulates the alternative splicing of four transcripts - Gnas, Cd151, Dab2 and Tia1. Inasmuch as alternative splicing potentially affects transcripts from more than two-thirds of the mouse genome, we suggest that these findings are representative of a genome-wide effect of ACTH that impacts on the mRNA and protein composition of the adrenal cortex. PMID- 25281400 TI - Pharmacokinetics and safety of rifabutin in young HIV-infected children receiving rifabutin and lopinavir/ritonavir. AB - OBJECTIVES: Co-treatment of HIV and TB in young children is complicated by limited treatment options and complex drug-drug interactions. Rifabutin is an alternative to rifampicin for adults receiving a ritonavir-boosted PI. We aimed to evaluate the short-term safety and pharmacokinetics of rifabutin when given with lopinavir/ritonavir in children. PATIENTS AND METHODS: We conducted an open label study of rifabutin dosed at 5 mg/kg three times a week in HIV-infected children<=5 years of age receiving lopinavir/ritonavir. Intensive steady-state pharmacokinetic sampling was conducted after six doses. The Division of AIDS 2004, clarification 2009, table for grading severity of adverse events was used to classify drug toxicities. The study was registered with ClinicalTrials.gov, number NCT01259219. RESULTS: Six children completed the study prior to closure by institutional review boards. The median (range) AUC0-48 of rifabutin was 6.91 (3.52-8.67) MUg . h/mL, the median (range) Cmax of rifabutin was 0.39 (0.19-0.46) MUg/mL, the median (range) AUC0-48 of 25-O-desacetyl rifabutin was 5.73 (2.85 9.13) MUg . h/mL and the median (range) Cmax of 25-O-desacetyl rifabutin was 0.17 (0.08-0.32) MUg/mL. The neutrophil count declined in all children; two children experienced grade 4 neutropenia, which resolved rapidly without complications. There was strong correlation between AUC0-48 measures and neutrophil counts. CONCLUSIONS: Rifabutin dosed at 5 mg/kg three times per week resulted in lower AUC0-48, AUC0-24 and Cmax values for rifabutin and 25-O-desacetyl rifabutin compared with adults receiving 150 mg of rifabutin daily, the current recommended dose. We observed high rates of severe transient neutropenia, possibly due to immaturity of CYP3A4 in young children. It remains unclear whether a safe and effective rifabutin dose exists for treatment of TB in children receiving lopinavir/ritonavir. PMID- 25281402 TI - [Finger flexor tenolysis]. AB - Flexor tendon adhesions in zone II are common. The origin of these adhesions is multifactorial. Flexor tenolysis consists of releasing the adhesions to restore the tendon's normal path and the patient's active range of motion. This surgery is complex and extremely delicate. It must be associated with early active mobilization. Any surgical procedure that would hamper this active mobilization must be completed before the flexor tenolysis. The patient should be informed of the risk of flexor digitorum profundus rupture, which is the main complication of this surgery. PMID- 25281403 TI - Glucosylceramide synthase promotes Bcl-2 expression via the ERK signaling pathway in the K562/A02 leukemia drug-resistant cell line. AB - Multidrug resistance (MDR) to chemotherapeutic agents is a major obstacle to curative treatment of cancer. In various types of cancers, overexpression of glucosylceramide synthase (GCS) has been observed to be associated with MDR, thus making GCS a target for reversal of resistance. Our previous work demonstrated that GCS and Bcl-2 are co-overexpressed in the K562/A02 leukemia multidrug resistant cell line compared with its sensitive counterpart, K562. In the present study, we investigated the effects of GCS on apoptosis in K562/A02 and the associated molecular mechanisms. Our results indicate that the inhibition of GCS caused downregulation of Bcl-2 as well as apoptosis enhancement in response to ADM via the ERK pathway, while JNK or p38 MAPK signaling appeared to play less significant roles in the regulation of apoptosis and MDR in K562/A02 cells. Targeting GCS by siRNA also enhanced ceramide accumulation, which is involved in GCS knockdown-induced inhibition of ERK activation and Bcl-2 expression levels. PMID- 25281404 TI - Autologous stem cell transplantation for AL amyloidosis: adjustment of melphalan dose by factors including BNP. AB - High-dose melphalan with autologous stem cell transplantation (HDM/ASCT) is a promising treatment option for eligible patients with systemic immunoglobulin light chain (AL) amyloidosis. We present the results of ASCT following risk adapted melphalan conditioning on the basis of criteria proposed by our group, including B-type natriuretic peptide (BNP). Ten patients with primary systemic AL amyloidosis treated at our institute were evaluated. A full dose of melphalan (200 mg/m(2)) was administered to patients who met all the following: performance status, 0 or 1; number of organs involved, 2 or less; serum creatinine, 1.5 mg/dL or less; EF 50 % or more and BNP 200 pg/mL or less; otherwise 140 mg/m(2). The hematologic complete response was achieved in four and organ response was seen in two patients. The median event-free survival (EFS) of all patients was 21.5 months, and median overall survival (OS) was 47.0 months. EFS and OS were significantly longer for patients who received 200 mg/m(2) of melphalan than for those who received lower dose (EFS: not reached vs. 13.9 months, P = 0.0217; OS: not reached vs. 13.8 months, P = 0.0186). No treatment-related mortality within 100 days from ASCT was observed. Evaluation of cardiac diastolic function may contribute to safer HDM/ASCT and improve outcome of AL amyloidosis. PMID- 25281405 TI - Increased genomic instability may contribute to the development of kinase domain mutations in chronic myeloid leukemia. AB - Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (KDMs). In this single-institution retrospective analysis, patients with KDMs were identified from a cohort of patients treated for CML at our institution. Clinical outcomes were assessed based on the characteristics of the KDMs and results of cytogenetic analysis. In total, we compared 26 patients with KDM to those without; 46 % (n = 12) versus 20 % (n = 57) progressed to advanced phase (P = 0.003). Median overall survival was 22 months, 109 months, and not reached in patients with P-loop, T315I, and non-P loop mutations (P = 0.127). KDM patients had a median progression-free survival (PFS) and overall survival of 75 and 109 months; however, neither was reached in the non-mutation cohort (P = 0.0007, P = 0.235). Median PFS in patients with single versus compound or double mutations was not reached versus 10 months (P = 0.014). We conclude that T315I, P-loop, and compound mutations may worsen prognosis in CML. PMID- 25281407 TI - Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants. AB - Low magnitude high frequency (LMHF) loading has been shown to have an anabolic effect on trabecular bone in vivo. However, the precise mechanical signal imposed on the bone marrow cells by LMHF loading, which induces a cellular response, remains unclear. This study investigates the influence of LMHF loading, applied using a custom designed bioreactor, on bone adaptation in an explanted trabecular bone model, which isolated the bone and marrow. Bone adaptation was investigated by performing micro CT scans pre and post experimental LMHF loading, using image registration techniques. Computational fluids dynamic models were generated using the pre-experiment scans to characterise the mechanical stimuli imposed by the loading regime prior to adaptation. Results here demonstrate a significant increase in bone formation in the LMHF loaded group compared to static controls and media flow groups. The calculated shear stress in the marrow was between 0.575 and 0.7 Pa, which is within the range of stimuli known to induce osteogenesis by bone marrow mesenchymal stem cells in vitro. Interestingly, a correlation was found between the bone formation balance (bone formation/resorption), trabecular number, trabecular spacing, mineral resorption rate, bone resorption rate and mean shear stresses. The results of this study suggest that the magnitude of the shear stresses generated due to LMHF loading in the explanted bone cores has a contributory role in the formation of trabecular bone and improvement in bone architecture parameters. PMID- 25281406 TI - Physalis angulata induces in vitro differentiation of murine bone marrow cells into macrophages. AB - BACKGROUND: The bone marrow is a hematopoietic tissue that, in the presence of cytokines and growth factors, generates all of the circulating blood cells. These cells are important for protecting the organism against pathogens and for establishing an effective immune response. Previous studies have shown immunomodulatory effects of different products isolated from plant extracts. This study aimed to evaluate the immunomodulatory properties of aqueous Physalis angulata (AEPa) extract on the differentiation of bone marrow cells. RESULTS: Increased cellular area, higher spreading ability and several cytoplasmatic projections were observed in the treated cells, using optical microscopy, suggesting cell differentiation. Furthermore, AEPa did not promote the proliferation of lymphocytes and polymorphonuclear leukocytes, however promotes increased the number of macrophages in the culture. The ultrastructural analysis by Transmission Electron Microscopy of treated cells showed spreading ability, high number of cytoplasmatic projections and increase of autophagic vacuoles. Moreover, a high level of LC3b expression by treated cells was detected by flow cytometry, suggesting an autophagic process. Cell surface expression of F4/80 and CD11b also indicated that AEPa may stimulate differentiation of bone marrow cells mainly into macrophages. In addition, AEPa did not differentiate cells into dendritic cells, as assessed by CD11c analysis. Furthermore, no cytotoxic effects were observed in the cells treated with AEPa. CONCLUSION: Results demonstrate that AEPa promotes the differentiation of bone marrow cells, particularly into macrophages and may hold promise as an immunomodulating agent. PMID- 25281408 TI - Extrinsic and intrinsic index finger muscle attachments in an OpenSim upper extremity model. AB - Musculoskeletal models allow estimation of muscle function during complex tasks. We used objective methods to determine possible attachment locations for index finger muscles in an OpenSim upper-extremity model. Data-driven optimization algorithms, Simulated Annealing and Hook-Jeeves, estimated tendon locations crossing the metacarpophalangeal (MCP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints by minimizing the difference between model-estimated and experimentally-measured moment arms. Sensitivity analysis revealed that multiple sets of muscle attachments with similar optimized moment arms are possible, requiring additional assumptions or data to select a single set of values. The most smooth muscle paths were assumed to be biologically reasonable. Estimated tendon attachments resulted in variance accounted for (VAF) between calculated moment arms and measured values of 78% for flex/extension and 81% for ab/adduction at the MCP joint. VAF averaged 67% at the PIP joint and 54% at the DIP joint. VAF values at PIP and DIP joints partially reflected the constant moment arms reported for muscles about these joints. However, all moment arm values found through optimization were non-linear and non-constant. Relationships between moment arms and joint angles were best described with quadratic equations for tendons at the PIP and DIP joints. PMID- 25281409 TI - Computing muscle, ligament, and osseous contributions to the elbow varus moment during baseball pitching. AB - Baseball pitching imposes a dangerous valgus load on the elbow that puts the joint at severe risk for injury. The goal of this study was to develop a musculoskeletal modeling approach to enable evaluation of muscle-tendon contributions to mitigating elbow injury risk in pitching. We implemented a forward dynamic simulation framework that used a scaled biomechanical model to reproduce a pitching motion recorded from a high school pitcher. The medial elbow muscles generated substantial, protective, varus elbow moments in our simulations. For our subject, the triceps generated large varus moments at the time of peak valgus loading; varus moments generated by the flexor digitorum superficialis were larger, but occurred later in the motion. Increasing muscle tendon force output, either by augmenting parameters associated with strength and power or by increasing activation levels, decreased the load on the ulnar collateral ligament. Published methods have not previously quantified the biomechanics of elbow muscles during pitching. This simulation study represents a critical advancement in the study of baseball pitching and highlights the utility of simulation techniques in the study of this difficult problem. PMID- 25281410 TI - Sodium [18F]fluoride PET/CT in myocardial infarction. AB - PURPOSE: Sodium [(18)F]fluoride (Na[(18)F]F) positron emission tomography with integrated computed tomography (PET/CT) has not been used for imaging myocardial infarction (MI). Here, we aimed to investigate the Na[(18)F]F PET/CT features of MI in a rat model. PROCEDURES: MI was induced by coronary artery ligation in 8 week-old male Spraque-Dawley rats (300 +/- 10 g) and confirmed by triphenyl tetrazolium chloride (TTC) staining. Na[(18)F]F PET/CT images were obtained using an animal-dedicated PET/CT scanner (NanoPET/CT, Mediso) in vivo and ex vivo. Uptake of Na[(18)F]F was quantitated using the standardized uptake value (SUV). Myocardial apoptosis was evaluated using histone-1 targeted peptide (ApoPep-1) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, while calcium accumulation was investigated using von Kossa's staining. Na[(18)F]F PET/CT was compared with (99m)Tc-methoxyisobutylisonitrile (MIBI) or (99m)Tc-hydroxymethylenediphosphonate (HMDP) single photon emission computed tomography/computed tomography (SPECT/CT) in rats with day 1 MI. RESULTS: The rats showed strong Na[(18)F]F uptake both in vivo and ex vivo; the maximal uptake occurred 1 day after MI (SUV ratio of infarct to lung = 4.56 +/- 0.74, n = 7, P = 0.0183 vs the control). The Na[(18)F]F uptake area perfectly matched the apoptotic area, determined by ApoPep-1 uptake and TUNEL assay. However, calcification, assessed by von Kossa's staining, was absent in the infarct. Na[(18)F]F PET/CT showed an increased uptake at the perfusion deficit area in [(99m)Tc]MIBI SPECT/CT and an equivalent signal to [(99m)Tc]HMDP SPECT/CT in rats with day 1 MI. CONCLUSIONS: Na[(18)F]F PET/CT is a promising hot-spot imaging modality for MI. PMID- 25281411 TI - Reproducibility and reliability of anti-3-[18F]FACBC uptake measurements in background structures and malignant lesions on follow-up PET-CT in prostate carcinoma: an exploratory analysis. AB - PURPOSE: The aim of this study is to examine the reproducibility of anti-1-amino 3-[(18)F]fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F]FACBC) quantitative measurements in key background structures and untreated malignant lesions. PROCEDURES: Retrospective review of 14 patients who underwent follow-up anti-3 [(18)F]FACBC positron emission tomography-X-ray computed tomography (PET-CT) for prostate carcinoma recurrence. Standard uptake values (SUV) were measured in both original and follow-up scans in key background structures and untreated malignant lesions. Absolute and percent mean difference in SUV between scans and interclass correlation coefficients (ICC) were also computed. RESULTS: Mean (+/-SD, range) scan interval was 17.4 months (+/-7.1, 4-29). %Mean difference in SUVmean was <20 % in background structures with low absolute differences. ICCs were >0.6 except for early-phase blood pool (ICC = 0.4). SUVmax in malignant lesions without interim therapy increased or remained stable over time. CONCLUSIONS: Despite variable time interval between scans, FACBC PET-CT demonstrates acceptable reproducibility in key background structures. Untreated malignant lesions showed stable or increased uptake over time. A formal test-retest study is planned. PMID- 25281413 TI - The effect of exposure duration on visual acuity for letter optotypes and gratings. AB - This study compared the effects of exposure duration on letter and grating targets in a visual acuity (VA) task and determined if the broadband nature of letters accounts for their temporal summation characteristics. Log MAR (minimum angle of resolution) VA of five individuals (ages 25-36) was measured with a set of tumbling E optotypes for durations of 24 ms to 1s. The Es were either unfiltered or low-pass filtered to determine the object frequencies (cycles per letter; cplE) mediating VA. The retinal frequencies mediating VA for the unfiltered E (cycles per degree; cpdE) were derived from the ratio of cplE to MAR. Values of cpdE were compared to threshold retinal frequency obtained with band-limited Es and gratings to further evaluate the effects of stimulus bandwidth. Both log MAR and log cplE for the unfiltered E decreased as duration increased up to approximately 260 ms, and were constant thereafter. VA also improved for gratings and band-pass filtered Es, but over a shorter time course (approximately 150 ms). The effect of duration on VA for the broadband E, Gabor, and band-pass filtered E was similar when the object frequencies mediating VA were included in the definition of VA by converting to cpdE. The results indicate that the pattern of temporal integration for the tumbling E is related to its broadband nature. Band-pass filtered letters can simplify the interpretation of VA because the object frequency information mediating VA is known exactly and is independent of duration and letter size. PMID- 25281412 TI - Probing the functions of contextual modulation by adapting images rather than observers. AB - Countless visual aftereffects have illustrated how visual sensitivity and perception can be biased by adaptation to the recent temporal context. This contextual modulation has been proposed to serve a variety of functions, but the actual benefits of adaptation remain uncertain. We describe an approach we have recently developed for exploring these benefits by adapting images instead of observers, to simulate how images should appear under theoretically optimal states of adaptation. This allows the long-term consequences of adaptation to be evaluated in ways that are difficult to probe by adapting observers, and provides a common framework for understanding how visual coding changes when the environment or the observer changes, or for evaluating how the effects of temporal context depend on different models of visual coding or the adaptation processes. The approach is illustrated for the specific case of adaptation to color, for which the initial neural coding and adaptation processes are relatively well understood, but can in principle be applied to examine the consequences of adaptation for any stimulus dimension. A simple calibration that adjusts each neuron's sensitivity according to the stimulus level it is exposed to is sufficient to normalize visual coding and generate a host of benefits, from increased efficiency to perceptual constancy to enhanced discrimination. This temporal normalization may also provide an important precursor for the effective operation of contextual mechanisms operating across space or feature dimensions. To the extent that the effects of adaptation can be predicted, images from new environments could be "pre-adapted" to match them to the observer, eliminating the need for observers to adapt. PMID- 25281414 TI - Rutin has intestinal antiinflammatory effects in the CD4+ CD62L+ T cell transfer model of colitis. AB - Rutin, one of the most abundant flavonoids in nature, has been shown to exert intestinal antiinflammatory effects in experimental models of colitis. Our aim was to study the antiinflamatory effect of rutin in the CD4+ CD62L+ T cell transfer model of colitis, one of the closest to the human disease. Colitis was induced by transfer of CD4+ CD62L+ T cells to Rag1(-/-) mice. Rutin was administered by gavage as a postreatment. Treatment with rutin improved colitis at the dose of 57mg/kg/day, while no effect was noted with 28.5mg/kg/day. Therapeutic benefit was evidenced by a reduced disease activity index, weight loss and damage score, plus a 36% lower colonic myeloperoxidase and a 54% lower alkaline phosphatase activity. In addition, a decreased secretion of proinflammatory cytokines (IFNgamma and TNFalpha) by mesenteric lymph node cells was observed ex vivo. The colonic expression of proinflammatory genes, including IFNgamma, TNFalpha, CXCL1, S100A8 and IL-1beta, was significantly reduced by more than 80% with rutin as assessed by RT-qPCR. Flavonoid treated mice exhibited decreased activation of splenic CD4+ cells (STAT4 phosphorylation and IFNgamma expression) and reduced plasma cytokine levels. This effect was also apparent in mucosal lymphocytes based on reduced STAT4 phosphorylation. The protective effect was comparable to that of 3mg/kg/day budesonide. Rutin had no effect on splenocytes or murine T cells in vitro, while its aglycone, quercetin, exhibited a concentration dependent inhibition of proinflammatory cytokines, including IFNgamma. Rutin but not quercetin showed vectorial basolateral to apical transport in IEC18 cells, associated with reduced biotransformation. We conclude that rutin exerts intestinal antiinflammatory activity in chronic, T lymphocyte dependent colitis via quercetin release and actions involving mucosal and lymph node T cells. Our results suggest that rutin may be useful in the management of inflammatory bowel disease in appropriate dosage conditions. PMID- 25281415 TI - DPP-4 inhibitor and PPARgamma agonist restore the loss of CA1 dendritic spines in obese insulin-resistant rats. AB - BACKGROUND AND AIMS: Obesity induced by high-fat diet (HFD) impaired brain insulin receptor function, caused cognitive decline as well as reduced dendritic spine density. Previous studies suggested that dipeptidyl peptidase IV (DPP-4) inhibitor and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist exerted the neuroprotective effects in obese insulin-resistant rats. However, the effects of these drugs on dendritic spines in obese insulin resistant rats have not yet been investigated. In the present study, we determined the effects of DPP-4 inhibitor and PPARgamma agonist on dendritic spines density of obese insulin-resistant rats caused by HFD. METHODS: Male Wistar Rats were divided into two groups. Animals in each group were fed with normal diet (ND) or HFD for 12 weeks. After then, rats in each group were subdivided into three subgroups to receive either vehicle or vildagliptin (3 mg/kg/day) or pioglitazone (10 mg/kg/day) for 3-4 weeks. At the end of the experiment, the metabolic parameters and density of dendritic spines in CA1 hippocampus were determined. RESULTS: We found that HFD-fed rats caused peripheral insulin resistance as well as the reduction of the density of dendritic spines in CA1 hippocampus. Treatment with both DPP-4 inhibitor and PPARgamma agonist in HFD-fed rats improved insulin sensitivity as well as increased the number of dendritic spines in CA1 hippocampus. Moreover, both drugs have equally improved this deterioration. CONCLUSION: Our findings indicate that DPP-4 inhibitor and PPARgamma agonist restored the reduction of dendritic spines caused by HFD, suggesting the beneficial roles of DPP-4 inhibitors and PPARgamma agonists in neurodegenerative disorders. PMID- 25281417 TI - Non-selective beta-blockers are associated with improved survival in patients with ascites listed for liver transplantation. AB - OBJECTIVE: Recent data have suggested that non-selective beta-blockers (NSBB) are associated with increased mortality in patients with cirrhosis and refractory ascites. However, other evidence implies that NSBB may be beneficial in this setting by reducing bacterial translocation. Our aim was to determine whether NSBB use was a risk factor for mortality in patients with end-stage chronic liver disease and ascites awaiting liver transplantation. DESIGN: This was a single centre retrospective study of 322 patients with ascites listed January 2007 to July 2011. RESULTS: NSBB patients (n=159) and non-NSBB patients (n=163) were comparable with regards to listing model for end-stage liver disease score (p=0.168), frequency of hepatocellular carcinoma (p=0.193) and refractory ascites (35.2% vs. 37.4%, p=0.681). 82 patients died, 221 patients were transplanted and 19 patients were removed from the list during a median follow-up duration of 72 days; the median time to death was 150 and 54 days in the NSBB and non-NSBB groups, respectively. In a multivariate competing risk Cox model, patients on NSBB had reduced mortality compared with propensity risk score-matched non-NSBB patients (HR 0.55; 95% CI 0.32 to 0.95, p=0.032). Similarly, in the subgroup of patients with refractory ascites (n=117), NSBB remained independently associated with less waitlist death (adjusted HR 0.35; 95% CI 0.14 to 0.86, p=0.022). CONCLUSIONS: NSBB in patients with ascites and refractory ascites listed for liver transplantation are not detrimental, and instead are associated with reduced waitlist death. Our findings argue that NSBB are safe and may confer benefit in patients with ascites complicating end-stage liver disease. PMID- 25281418 TI - miR-10a inhibits dendritic cell activation and Th1/Th17 cell immune responses in IBD. AB - OBJECTIVE: Although both innate and adaptive responses to microbiota have been implicated in the pathogenesis of IBD, it is still largely unknown how they are regulated during intestinal inflammation. In this report, we investigated the role of microRNA (miR)-10a, a small, non-coding RNA, in the regulation of innate and adaptive responses to microbiota in IBD. METHODS: miR-10a expression was analysed in the inflamed mucosa of IBD patients treated with or without antitumour necrosis factor (anti-TNF) monoclonal antibodies (mAb) (infliximab) by qRT-PCR. Human monocyte-derived dendritic cells (DC) and IBD CD4+ T cells were transfected with miR-10a precursor to define their effect on the function of DC and CD4+ T cells. RESULTS: The expression of miR-10a was markedly decreased, while NOD2 and interleukin (IL)-12/IL-23p40 were significantly increased, in the inflamed mucosa of IBD patients compared with those in healthy controls. Commensal bacteria, TNF and interferon-gamma inhibited human DC miR-10a expression in vitro. Anti-TNF mAb treatment significantly promoted miR-10a expression, whereas it markedly inhibited NOD2 and IL-12/IL-23p40 in the inflamed mucosa. We further identified NOD2, in addition to IL-12/IL-23p40, as a target of miR-10a. The ectopic expression of the miR-10a precursor inhibited IL-12/IL-23p40 and NOD2 in DC. Moreover, miR-10a was found to markedly suppress IBD T helper (Th)1 and Th17 cell responses. CONCLUSIONS: Our data indicate that miR-10a is decreased in the inflamed mucosa of IBD and downregulates mucosal inflammatory response through inhibition of IL-12/IL-23p40 and NOD2 expression, and blockade of Th1/Th17 cell immune responses. Thus, miR-10a could play a role in the pathogenesis and progression of IBD. PMID- 25281416 TI - A phase II study of laquinimod in Crohn's disease. AB - OBJECTIVE: Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate-severe CD. DESIGN: Multicentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF). RESULTS: 117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%-96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses. CONCLUSIONS: Laquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD. TRIAL REGISTRATION NUMBER: NCT00737932. PMID- 25281419 TI - TradReg 2013: regulation of herbal and traditional medicinal products--European and global strategies--international symposium. AB - Plants have always been an important source of treatment. The important contribution of phytotherapy became particularly recognised through European Directive 2004/24/EC (Directive 2004/24/EC, 2004), which set up a new Committee dedicated to herbal medicinal products at the European Medicines Agency (EMA). In addition, it created a new status for traditional herbal medicinal products by making possible their simplified "registration" based on plausible level of efficacy. Nearly 10 years after the creation of this new framework, an impressive number of monographs were established. However, implementation remains a challenge. There is also a critical need to encourage innovation and research and to ensure that new pieces of legislation are applied to herbal medicinal products taking due account of their characteristics. This article reflects the concerns and expectations of the European manufacturers of herbal medicines. PMID- 25281420 TI - Modeling cancer-immune responses to therapy. AB - Cancer therapies that harness the actions of the immune response, such as targeted monoclonal antibody treatments and therapeutic vaccines, are relatively new and promising in the landscape of cancer treatment options. Mathematical modeling and simulation of immune-modifying therapies can help to offset the costs of drug discovery and development, and encourage progress toward new immunotherapies. Despite advances in cancer immunology research, questions such as how the immune system interacts with a growing tumor, and which components of the immune system play significant roles in responding to immunotherapy are still not well understood. Mathematical modeling and simulation are powerful tools that provide an analytical framework in which to address such questions. A quantitative understanding of the kinetics of the immune response to treatment is crucial in designing treatment strategies, such as dosing, timing, and predicting the response to a specific treatment. These models can be used both descriptively and predictively. In this chapter, various mathematical models that address different cancer treatments, including cytotoxic chemotherapy, immunotherapy, and combinations of both treatments, are presented. The aim of this chapter is to highlight the importance of mathematical modeling and simulation in the design of immunotherapy protocols for cancer treatment. The results demonstrate the power of these approaches in explaining determinants that are fundamental to cancer immune dynamics, therapeutic success, and the development of efficient therapies. PMID- 25281421 TI - Continuous-time Markov modelling of flexible-dose depression trials. AB - The aim of this paper is to provide a systematic methodology for modelling longitudinal data to be used in contexts of limited or even absent knowledge of the physiological mechanism underlying the disease time course. Adopting a system theoretic paradigm, a population response model is developed where the clinical endpoint is described as a function of the patient's health state. In particular, a continuous-time stochastic approach is proposed where the clinical score and its time-derivative summarize the patient's health state affected by a random term accounting for exogenous unpredictable factors. The proposed approach is validated on experimental data from the placebo and drug arms of a Phase II depression trial. Since some subjects in the trial may undergo changes in their treatment dose due to the flexible dosing scheme, dose escalations are modelled as instantaneous perturbations on the state. In its simplest form--an integrated Wiener process--was able to correctly capture the individual responses in both treatment arms. However, a better description of inter-individual variability was obtained by means of a stable Markovian model. Parameter estimation has been carried out according to the empirical Bayes method. PMID- 25281422 TI - Closed-chest small animal model to study myocardial infarction in an MRI environment in real time. AB - Current models for real time study of the effects of myocardial ischemia/reperfusion have major limitations and confounders. Confounders include the surgical stresses of a thoracotomy and abnormal physiology of an open chest. The need to reposition the animal interferes with the study of the early changes associated with ischemia. Direct comparison of pre-ischemia and post-ischemia images is then difficult. We developed a novel "closed chest" model of ischemia/reperfusion to overcome these issues. Following thoracotomy, we sutured a balloon occluder to the left coronary artery of male Sprague-Dawley rats. We used both visual inspection and ECG to assess for successful occlusion and reperfusion of the coronary artery at the time of operation by brief inflation and deflation of the balloon. The tubing was then placed under the skin and the incision closed. Following a recovery period (5-10 days), the animals underwent MRI. We performed baseline assessment of left ventricle function, and repeated LV measurement during a 15-min coronary occlusion and again during a 60-min reperfusion period following reopening of the coronary artery. The occluder was successfully placed in 40 of 44 animals. Four developed intraoperative complications; two large myocardial infarction, two terminal bleeding. Six died in the week following surgery, [four sudden deaths (presumed arrhythmic), one anterior infarction, one sepsis]. Cine-MRI demonstrated localised hypokinesia in 31 of the remaining 34 animals. LV ejection fraction (EF) was reduced from 63 +/- 7 % at baseline, to 49 +/- 9 % during coronary occlusion. LV EF recovered to 61 +/- 2 %. The area at risk on staining of the heart was 41.9 +/- 15.8 %. This method allows the effects of ischemia/reperfusion to be studied before, during, and after coronary occlusion. Ischemia can be caused while the animal is in the MRI. This new and clinically relevant small animal model is a valuable tool to study the effects of single or repeated coronary occlusion/reperfusion in real time. PMID- 25281423 TI - A prospective two-center study on the associations between microalbuminuria, coronary atherosclerosis and long-term clinical outcome in asymptomatic patients with type 2 diabetes mellitus: evaluation by coronary CT angiography. AB - This study assessed the associations between microalbuminuria in asymptomatic patients with type 2 diabetes and the presence, extent, and severity of coronary atherosclerosis, as measured by coronary computed tomography angiography (CCTA), and the long-term clinical outcomes. In total, the study enrolled 284 consecutive eligible asymptomatic patients with type 2 diabetes and without known coronary artery disease (CAD), who then underwent CCTA and 24 h urine albumin measurements. Microalbuminuria was defined as 30-300 mg/day urinary albumin excretion. Obstructive CAD, as measured by CCTA, was defined as maximum intra luminal stenosis >=50 %. Patients with and without microalbuminuria were compared in terms of obstructive CAD prevalence, and the extent and severity of coronary atherosclerosis. They were evaluated using the following data: coronary artery calcium score (CACS), atheroma burden obstructive score (ABOS), segment involvement score (SIS) and segment stenosis score (SSS). All-cause mortality within a follow-up period of 5 years was also compared. Compared to patients without microalbuminuria, patients with microalbuminuria were more likely to have obstructive CAD (p = 0.004). Microalbuminuria was associated with higher ABOS (p = 0.010), SIS (p = 0.029), and SSS (p = 0.011), except for CACS (p = 0.058). Multivariable analyses adjusted for conventional cardiovascular risk factors revealed that microalbuminuria was an independent predictor of obstructive CAD [odds ratio 2.255, confidence intervals (CI) 1.121-4.538, p = 0.023] and all cause mortality (hazard ratio 3.469, CI 1.319-9.121, p = 0.012). In asymptomatic patients with type 2 diabetes, microalbuminuria was associated with increased risk of CAD and poorer clinical outcomes. PMID- 25281424 TI - Frequency and predictors of thrombus inside the guiding catheter during interventional procedures: an optical coherence tomography study. AB - Optical coherence tomography (OCT) is able to identify thrombus. We detect the frequency of thrombus inside the guiding catheter by OCT and its relationship with clinical and procedural factors. We screened 77 patients who underwent OCT pullbacks. Only patients with visible guiding catheter were finally included (35) and divided into thrombus (21) or no-thrombus group (14). Patients within thrombus group were mostly males (100 vs. 71 %, p = 0.05), with acute coronary syndrome (76 vs. 36 %, p = 0.02) and received more frequently percutaneous coronary intervention (86 vs. 43 %, p = 0.01) as compared to other group. A second dose of heparin was more frequently administered in thrombus than in other group (86 vs. 50 %, p = 0.01). Time between first heparin administration and OCT pullback (41[28-57] vs. 20 min [10-32], p = 0.001), time elapsed from second heparin administration and OCT pullback (29 [19-48] vs. 16 min [12-22], p = 0.002) and total procedural time (47 [36-69] vs. 31 min [26-39], p = 0.005) were longer in thrombus compared to other group. At multivariate analysis, total procedural time and time between first heparin administration and OCT pullback were only predictors of intra-catheter thrombus (HR 0.6 [0.3-0.9], p = 0.03 and HR 1.9 [1.1-3.2], p = 0.02, respectively). Thrombus inside guiding catheter may be a frequent finding in long interventional procedure. Future studies are warranted to determine its clinical impact. PMID- 25281425 TI - CT venography for deep venous thrombosis: can it predict catheter-directed thrombolysis prognosis in patients with iliac vein compression syndrome? AB - To evaluate the prognostic value of CT venography for catheter-directed thrombolysis (CDT) in iliac vein compression syndrome (IVCS) patients with deep venous thrombosis (DVT). The institutional review board approved this retrospective study and waived informed consent. Among the 201 consecutive patients treated in our interventional suite for DVT from January 2001 to June 2013, 48 IVCS patients (12 men, 36 women) who underwent pre-procedural CT venography, CDT with stenting, and follow-up imaging were analyzed. To identify possible determinants of 6-month patency, CT venography was evaluated with Fisher's exact test and logistic regression analyses. Based on the analyses, image-based criteria were established and compared to the current symptom duration-based approach by receiver-operating-characteristic curve analyses and the McNemar test. Recoiling of external iliac vein (EIV) diameter (<120 %) [hazard ratio (HR) 28.652, p = .007] and severe rim enhancement (HR 20.545, p = .016) were significant risk factors for venous occlusion within 6 months of CDT. The dual-parameter image-based criteria were significantly superior to the current symptom duration-based approach in terms of area under the curve value (p = .010) and predictive accuracy (p = .031). With a 2-point cut-off, the proposed criteria demonstrated a 66.7 % sensitivity, 100.0 % specificity, and 92.9 % predictive accuracy for identifying non-responders of CDT. CT venography may be useful in assessing CDT prognoses in IVCS patients, particularly to identify non responders who demonstrate recoiling of EIV diameter and rim enhancement on CT venography. PMID- 25281426 TI - Empirical validation of the diffusion model for recognition memory and a comparison of parameter-estimation methods. AB - The diffusion model introduced by Ratcliff (Psychol Rev 85:59-108, 1978) has been applied to many binary decision tasks including recognition memory. It describes dynamic evidence accumulation unfolding over time and models choice accuracy as well as response-time distributions. Various parameters describe aspects of decision quality and response bias. In three recognition-memory experiments, the validity of the model was tested experimentally and analyzed with three different programs: fast-dm, EZ, and DMAT. Each of three central model parameters was targeted via specific experimental manipulations. All manipulations affected mainly the corresponding parameters, thus supporting the convergent validity of the measures. There were, however, smaller effects on other parameters, showing some limitations in discriminant validity. PMID- 25281427 TI - Priming effects on the perceived grouping of ambiguous dot patterns. AB - For ambiguous stimuli, complex dynamics guide processes of perceptual grouping. Previous studies have suggested two opposing effects on grouping that are produced by the preliminary stimulus state: one that enhances grouping towards the existing structure, and another that opposes this structure. To examine effects of the preliminary state on grouping directly, measurements were made of perceived grouping of dot patterns that followed a visual prime. Three stimuli were presented in sequence: prime, target, and mask. Targets were composed of an evenly spaced dot grid in which grouping was established by similarity in luminance. Subjects indicated the dominant perceived grouping. The prime either corresponded to or opposed the prevailing organization of the target. Contrary to the hypothesis, solid-line primes biased grouping away from the structure of the prime, even when the prevailing organization of dot patterns strongly favored the primes' structure. This effect occurred, although to a lesser extent, when primes did not occupy the same location of targets, but were presented in a marginal area surrounding the grid. Priming effects did not occur for primes constructed of dot patterns. Effects found here may be attributed to a forward masking effect by primes, which more effectively disrupts grouping of patterns matched to the prime. Effects may also be attributed to a type of pattern contrast, in which a grouped pattern dissimilar to primes gains salience. For the pattern contrast model, the partial activation of multiple grouped configurations is compared to the pattern of the solid-line primes. PMID- 25281428 TI - Impaired cAMP generation contributes to defective glucose-stimulated insulin secretion after long-term exposure to palmitate. AB - Chronic palmitate exposure impairs glucose-stimulated insulin secretion and other aspects of beta-cell function, but the underlying mechanisms are not known. Using various live-cell fluorescence imaging approaches, we show here that long-term palmitate treatment influences cAMP signaling in pancreatic beta-cells. Glucose stimulation of mouse and human beta-cells induced oscillations of the subplasma membrane cAMP concentration, but after 48 h exposure to palmitate, most beta cells failed to increase cAMP in response to glucose. In contrast, GLP-1 triggered cAMP formation and glucose- and depolarization-induced increases in cytoplasmic Ca2+ concentration were unaffected by the fatty acid treatment. Insulin secretion from control beta-cells was pulsatile, but the response deteriorated after long-term palmitate exposure. Palmitate-treated mouse islets showed reduced expression of adenylyl cyclase 9, and knockdown of this protein in insulinoma cells reduced the glucose-stimulated cAMP response and insulin secretion. We conclude that impaired glucose-induced generation of cAMP is an important determinant of defective insulin secretion after chronic palmitate exposure. PMID- 25281429 TI - Acute activation of cannabinoid receptors by anandamide reduces gastrointestinal motility and improves postprandial glycemia in mice. AB - The endocannabinoid system (ECS) is associated with an alteration of glucose homeostasis dependent on cannabinoid receptor-1 (CB1R) activation. However, very little information is available concerning the consequences of ECS activation on intestinal glucose absorption. Mice were injected intraperitoneally with anandamide, an endocannabinoid binding both CB1R and CB2R. We measured plasma glucose and xylose appearance after oral loading, gastrointestinal motility, and glucose transepithelial transport using the everted sac method. Anandamide improved hyperglycemia after oral glucose charge whereas glucose clearance and insulin sensitivity were impaired, pointing out some gastrointestinal events. Plasma xylose appearance was delayed in association with a strong decrease in gastrointestinal transit, while anandamide did not alter transporter-mediated glucose absorption. Interestingly, transit was nearly normalized by coinjection of SR141716 and AM630 (CB1R and CB2R antagonist, respectively), and AM630 also reduced the delay of plasma glucose appearance induced by anandamide. When gastric emptying was bypassed by direct glucose administration in the duodenum, anandamide still reduced plasma glucose appearance in wild-type but not in CB1R( /-) mice. In conclusion, our findings demonstrated that acute activation of intestinal ECS reduced postprandial glycemia independently on intestinal glucose transport but rather inhibiting gastric emptying and small intestine motility and strongly suggest the involvement of both CB1R and CB2R. PMID- 25281431 TI - Dose-dependent responses of pigs infected with foot-and-mouth disease virus O/JPN/2010 by the intranasal and intraoral routes. AB - Foot-and-mouth disease virus (FMDV) infection was successfully initiated in pigs by intraoral inoculation of both 10(6) and 10(3) TCID50 of FMDV O/JPN/2010 isolated from the 2010 epidemic in Japan. By intranasal inoculation, infection was established in pigs with 10(6) TCID50 of the isolate, but not with 10(3) TCID50 of the isolate. In the pigs inoculated with 10(6) TCID50 of the isolate, viruses and viral RNAs were obtained earlier from the pigs inoculated by the intraoral route than from the pigs inoculated by the intranasal route. These results support the theory that primary infection of a pig herd is more likely to occur by ingestion than by inhalation and that the oral cavity is likely to be a major entry route for FMDV in naturally exposed pigs. PMID- 25281430 TI - WISP1 is a novel adipokine linked to inflammation in obesity. AB - WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix-associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity. PMID- 25281432 TI - Hearing loss and cognitive decline in older adults: questions and answers. AB - The association between hearing impairment, the diagnosis of dementia, and the role of sensory therapy has been proposed for some time, but further research is needed. Current understanding of this association requires the commitment of those experts who can integrate experience and research from several fields to be able to understand the link from hearing to dementia. A workshop whose panelists included experts from many areas, ranging from ear, nose and throat (ENT) to dementia's specialists, was promoted and organized by the Giovanni Lorenzini Medical Science Foundation (Milan, Italy; Houston, TX, USA) to increase the awareness of the relationship between hearing loss and dementia, and included questions and comments following a presentation from the clinical researcher, Frank Lin, who has been evaluating the relationship between hearing loss and cognitive decline since 2009. PMID- 25281433 TI - Brainstem oligodendroglial tumors in children: two case reports and review of literatures. AB - PURPOSE: There is little information on pediatric oligodendroglial tumor located in the brainstem because of its rarity. METHODS: Here, we present two pediatric cases of pontine oligodendroglial tumors with radiological findings atypical for diffuse intrinsic pontine glioma. RESULTS: The first patient was an 8-year-old boy. Brain magnetic resonance imaging (MRI) demonstrated diffuse high-intensity changes in the pons, left middle cerebellar peduncle, and part of the left cerebellar hemisphere on T2-weighted and fluid-attenuated inversion recovery images, with an enhanced spot lesion in the left cerebellar hemisphere. The pathological diagnosis was anaplastic oligodendroglioma, and we identified a mutation in histone H3.3 in the tumor specimen. He succumbed to massive disseminated relapse 7 months from diagnosis despite local radiation therapy. The second patient, a 2-year-old girl, was diagnosed with oligoastrocytoma. Brain MRI revealed a large mass in her rostral pons extended to the fourth ventricle with obstructive hydrocephalus. The tumor recurred with intracranial dissemination 56 months post-surgery. CONCLUSIONS: Pediatric brainstem oligodendroglial tumors can include histone H3.3-mutated tumors and have a tendency to disseminate throughout the neuroaxis at the time of relapse. PMID- 25281434 TI - Isolated intracranial juvenile xanthogranuloma. A report of two cases and review of the literature. PMID- 25281435 TI - A new C-type lectin (RVsnaclec) purified from venom of Daboia russelii russelii shows anticoagulant activity via inhibition of FXa and concentration-dependent differential response to platelets in a Ca2+-independent manner. AB - This is the first report on the characterization of a snaclec (RVsnaclec) purified from Daboia russelii russelii venom. The RVsnaclec is a heterodimer of two subunits, alpha (15.1 kDa) and beta (9 kDa). These subunits are covalently linked to form multimeric (alphabeta)2 and (alphabeta)4 structures. Peptide mass fingerprinting analysis of RVsnaclec via LC-MS/MS demonstrated its similarity to snaclecs purified from other viperid snake venoms. Two tryptic peptide sequences of RVsnaclec revealed the putative conserved domains of C-type lectin (CTL). RVsnaclec dose-dependently increased the Ca-clotting time and prothrombin time of platelet-poor plasma (PPP); however, it did not affect the partial thromboplastin time (APTT) or thrombin time of PPP. The in vitro and in vivo anticoagulant activity of RVsnaclec is correlated to its binding and subsequent uncompetitive inhibition of FXa (Ki = 0.52 MUmole) in a Ca(2+)-independent manner; however, supplementation with 0.25 mM Ca(2+) enhanced the Xa binding potency of RVsnaclec. Monovalent or polyvalent antivenom failed to neutralize its anticoagulant potency, and RVsnaclec did not inhibit trypsin, chymotrypsin, thrombin or plasmin. RVsnaclec was devoid of hemolytic activity or cytotoxicity against several human cancer cell lines, demonstrated concentration-dependent aggregation and deaggregation of human platelets, and inhibited the ADP-induced aggregation of platelet. RVsnaclec (5.0 mg/kg body weight) was non-lethal to mice and showed no adverse pharmacological effects, suggesting that it has potential as a lead compound for future therapeutic applications in cardiovascular disorders. PMID- 25281436 TI - Accuracy of multidetector computed tomography for detection of coronary artery stenosis in acute coronary syndrome compared with stable coronary disease: a CORE64 multicenter trial substudy. AB - BACKGROUND: Multi-detector computed tomography angiography (MDCTA) is a promising method for risk assessment of patients with acute chest pain. However, its diagnostic performance in higher-risk patients has not been investigated in a large international multicenter trial. Therefore, in the present study we sought to estimate the diagnostic accuracy of MDCTA to detect significant coronary stenosis in patients with acute coronary syndrome (ACS). METHODS: Patients included in the CORE64 study were categorized as suspected-ACS or non-ACS based on clinical data. A 64-row coronary MDCTA was performed before invasive coronary angiography (ICA) and both exams were evaluated by blinded, independent core laboratories. RESULTS: From 371 patients included, 94 were categorized as suspected ACS and 277 as non-ACS. Patient-based analysis showed an area under the receiver-operating-characteristic curve (AUC) for detecting >= 50% coronary stenosis of 0.95 (95% CI: 0.88-0.98) in ACS and 0.92 (95% CI: 0.88-0.95) in non ACS group (P=0.29). The sensitivity, specificity, positive and negative predictive values of MDCTA were 0.90(0.80-0.96), 0.88(0.70-0.98), 0.95(0.87-0.99) and 0.77(0.58-0.90) in suspected ACS patients and 0.87(0.81-0.92), 0.86(0.79 0.92), 0.91(0.85-0.95) and 0.82(0.74-0.89) in non-ACS patients (P NS for all comparisons). The mean calcium scores (CS) were 282 +/- 449 in suspected ACS and 435 +/- 668 in non-ACS group. The accuracy of CS to detect significant coronary stenosis was only moderate and the absence or minimal coronary artery calcification could not exclude the presence of significant coronary stenosis, particularly in ACS patients. CONCLUSIONS: The diagnostic accuracy of MDCTA to detect significant coronary stenosis is high and comparable for both ACS and non ACS patients. PMID- 25281437 TI - Comparison between colloid preload and crystalloid co-load in cesarean section under spinal anesthesia: a randomized controlled trial. AB - BACKGROUND: Hypotension is a common problem during spinal anesthesia for cesarean delivery. Intravenous fluid loading is used to correct preoperative dehydration and reduce the incidence and severity of hypotension. Different fluid regimens have been studied but colloid preload and crystalloid co-load have not been compared. METHODS: In this randomized double-blind study, 210 patients scheduled for elective cesarean section under spinal anesthesia were randomly allocated to receive either 6% hydroxyethyl starch 130/0.4 500 mL before spinal anesthesia (colloid preload) or Ringer's acetate solution 1000 mL administered rapidly starting with intrathecal injection (crystalloid co-load). Maternal hypotension (systolic blood pressure <80% of baseline or <90 mmHg) and severe hypotension (systolic blood pressure <80 mmHg) were treated with 5 and 10mg ephedrine boluses, respectively. The primary outcome was the incidence of hypotension. Secondary outcomes included the incidence of severe hypotension, total ephedrine dose, nausea and vomiting and neonatal outcome assessed by Apgar scores and umbilical artery blood gas analysis. RESULTS: Data analysis was performed on 205 patients; 103 in the colloid preload group and 102 in the crystalloid co-load group. There were no significant differences in the incidence of hypotension (52.4% vs. 42.2%; P=0.18) or severe hypotension (15.5% vs. 9.8%; P=0.31) between colloid preload and crystalloid co-load groups, respectively. The median [range] ephedrine dose was 5 [0-45]mg in the colloid preload group and 0 [0-35]mg in the crystalloid co-load group (P=0.065). There were no significant differences in maternal nausea or vomiting or neonatal outcomes between groups. CONCLUSION: The use of 1000 mL crystalloid co-load has similar effect to 500 mL colloid preload in reducing the incidence of hypotension after spinal anesthesia for elective cesarean delivery. Neither technique can totally prevent hypotension and should be combined with vasopressor use. PMID- 25281438 TI - Bupivacaine-soaked absorbable gelatin sponges in caesarean section wounds: effect on postoperative pain, analgesic requirement and haemodynamic profile. AB - BACKGROUND: Pain is a common distressing adverse effect in the early postoperative period following caesarean section. The aim of this study was to investigate the effect on postoperative pain, analgesic requirement and haemodynamic profile of placing a suprafacial bupivacaine-soaked absorbable gelatin sponge in the caesarean section wound. METHODS: A total of 164 healthy patients scheduled to undergo general anaesthesia for elective caesarean section were randomised to a study group (n=81) or a control group (n=83). In the study group, a bupivacaine-soaked absorbable gelatin sponge was placed subcutaneously in the caesarean section wound. Intramuscular diclofenac 75 mg was given to all patients at 8-h intervals during the first 24h. Postoperatively, visual analogue scale pain scores, requirement for pethidine and diclofenac and changes in blood pressure and heart rate were compared between groups. RESULTS: Pain scores were lower in the study group compared to the control group at all assessments (P<0.001). During the first eight hours after surgery, fewer patients in the study group required rescue pethidine compared with the control group (4 vs. 33, P<0.001). In the study group, total opioid and diclofenac consumption was lower (P<0.001), and blood pressure and heart rate were lower (P<0.001) compared to the control group. CONCLUSION: Suprafascial wound placement of a bupivacaine-soaked absorbable gelatin sponge improved postoperative analgesia and decreased opioid consumption following caesarean section. PMID- 25281439 TI - Health in older women athletes. AB - Physical activity has been identified as a protective factor against a wide spectrum of diseases, but little is known about the link between older women's health and their professional involvement in sport in the past. The aim of this narrative review is to characterize and summarize the available data concerning the influence of physical activity on morbidity and mortality in former female athletes. Concerning bone health, it seems that physical activity in the past can be protective against osteoporosis in postmenopausal women, but these data come from observational studies only. Also the cardiovascular system appears to benefit in older women from regular sport in the past. This refers mainly to better heart efficiency, and improved endothelial function and metabolic profile. The incidence of different types of neoplasms, especially breast cancer, is also decreased in former athletes. Professional sport, on the other hand, acts negatively on the pelvic floor and is a risk factor for urinary incontinence. The overall effect on mortality is difficult to assess, because of many parameters, such as the sport's intensity, variety of the sport and exposure to extreme danger in some disciplines. Also, caution should be kept in interpretation of the data because of the shortage of well-designed studies. PMID- 25281440 TI - Bevacizumab and treatment of cervical cancer. PMID- 25281442 TI - Vets 'must act now' on antimicrobial resistance. PMID- 25281441 TI - Psychological well-being of people living with HIV/AIDS under the new epidemic characteristics in China and the risk factors: a population-based study. AB - OBJECTIVES: The HIV/AIDS epidemic in China is growing and the main transmission mode has changed from contaminated blood products to sexual contact. The aim of this study was to evaluate the levels of anxiety (SAS; Zung Self-Rating Anxiety Scale) and depression (CES-D; Center for Epidemiologic Studies Depression Scale) among people living with HIV/AIDS (PLWHA) under the new epidemic characteristics and to examine associated factors. METHODS: The sample size (N=800) was calculated on the basis of the lowest prevalence of psychological disorders among PLWHA and was enlarged taking into consideration a loss of response. Participants were sampled randomly among all PLWHA registered in Liaoning Province. Questionnaires pertaining to the SAS, CES-D, and related factors were distributed between December 2010 and April 2011; 772 effective responses were received. RESULTS: The prevalence of anxiety (SAS >=40) and depression (CES-D >=16) were 49.0% and 73.1%, respectively. Multivariate logistic regression analysis revealed that SAS was associated with self-rated health, condom use at the last sexual contact, perceived social support, alcohol consumption, and transmission; CES-D was associated with self-rated health, perceived social support, job, and sex. CONCLUSIONS: PLWHA under the new epidemic characteristics in China suffer from serious psychological problems. To improve their psychological well-being, efforts should be focused on improving perceptions of their health condition and increasing perceived social support. PMID- 25281443 TI - Hounds for Heroes founder wins standing ovation. PMID- 25281444 TI - Proposals for new legal controls on TB in non-bovine animals in Scotland. PMID- 25281445 TI - New OV training arrangements: progress so far. PMID- 25281446 TI - AHVLA becomes the APHA. PMID- 25281447 TI - Vets and doctors call for global collaboration to eliminate rabies. PMID- 25281448 TI - Science and politics at the 2014 BEVA congress. PMID- 25281449 TI - Presentation of awards. PMID- 25281450 TI - Veterinary medicines: product update. PMID- 25281451 TI - Honorary doctorate for CVO for Wales. PMID- 25281452 TI - Antimicrobial resistance: challenges ahead. PMID- 25281453 TI - Threat to European cattle from lumpy skin disease. PMID- 25281457 TI - Section IV: non-small cell lung cancer and malignant melanoma. PMID- 25281459 TI - Emotion-based medicine or evidence-based medicine? PMID- 25281458 TI - Specific calpain activity evaluation in Plasmodium parasites. AB - In the intraerythrocytic trophozoite stages of Plasmodium falciparum, the calcium dependent cysteine protease calpain (Pf-calpain) has an important role in the parasite calcium modulation and cell development. We established specific conditions to follow by confocal microscopy and spectrofluorimetry measurements the intracellular activity of Pf-calpain in live cells. The catalytic activity was measured using the fluorogenic Z-Phe-Arg-MCA (where Z is carbobenzoxy and MCA is 4-methylcoumaryl-7-amide). The calmodulin inhibitor calmidazolium and the sarcoplasmic reticulum calcium ATPase inhibitor thapsigargin were used for modifications in the cytosolic calcium concentrations that persisted in the absence of extracellular calcium. The observed calcium-dependent peptidase activity was greatly inhibited by specific cysteine protease inhibitor E-64 and by the selective calpain inhibitor ALLN (N-acetyl-l-leucyl-l-leucyl-l norleucinal). Taken together, we observed that intracellular Pf-calpain can be selectively detected and is the main calcium-dependent protease in the intraerythrocytic stages of the parasite. The method described here can be helpful in cell metabolism studies and antimalarial drug screening. PMID- 25281460 TI - Can we have a better death? PMID- 25281461 TI - Drug interactions between tyrosine-kinase inhibitors and acid suppressive agents: more than meets the eye. PMID- 25281462 TI - Drug interactions between tyrosine-kinase inhibitors and acid suppressive agents: more than meets the eye-Authors' reply. PMID- 25281463 TI - Epidemiological differences in haematological malignancies between Europe and China. PMID- 25281464 TI - Bevacizumab alone or in combination with chemotherapy in glioblastomas? PMID- 25281465 TI - Bevacizumab alone or in combination with chemotherapy in glioblastomas?--authors' reply. PMID- 25281466 TI - Patient priority in the era of patent expiries. PMID- 25281468 TI - Cancer-related inflammation and treatment effectiveness. AB - Inflammation is a recognised hallmark of cancer that substantially contributes to the development and progression of malignancies. In established cancers, there is increasing evidence for the roles that local immune response and systemic inflammation have in progression of tumours and survival of patients with cancer. This knowledge provides an opportunity to target these inflammatory responses to improve patient outcomes. In this Review, we examine the complex interplay between local immune responses and systemic inflammation, and their influence on clinical outcomes, and propose potential anti-inflammatory interventions for patients with cancer. PMID- 25281469 TI - Knowledge, attitudes, and behaviours towards cancer screening in indigenous populations: a systematic review. AB - Cancer mortality among indigenous peoples is increasing, but these populations commonly under use cancer-screening services. This systematic review explores knowledge, attitudes, and behaviours towards cancer screening among indigenous peoples worldwide. Searches of major bibliographic databases identified primary studies published in English up to March, 2014; of 33 eligible studies, three were cohort studies, 27 cross-sectional, and three case-control. Knowledge of and participation in screening was greater for breast cancer than for other cancers. Indigenous peoples tended to have less knowledge, less favourable attitudes, and a higher propensity to refuse screening than non-indigenous populations. The most common factors affecting knowledge, attitudes, and behaviours towards cancer screening included access to screening, knowledge about cancer and screening, educational attainment, perceived necessity of screening, and age. Greater understanding of knowledge, attitudes, and behaviours towards cancer screening in diverse indigenous cultures is needed so that culturally appropriate cancer prevention programmes can be provided. PMID- 25281470 TI - Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. AB - Adult T-cell leukaemia-lymphoma (ATL) is a malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1), and its prognosis is poor. There are an estimated 5 million to 20 million HTLV-1 infected individuals worldwide; their lifetime risk of developing ATL is 3-5%, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Recent advances in the treatment of ATL are the introduction of treatment targeted against CC chemokine receptor 4 (CCR4), which is abundantly expressed on most ATL cells, and allogeneic haemopoietic stem-cell transplantation for aggressive ATL. Promising outcomes are also reported with early intervention for indolent ATL with interferon alpha and zidovudine. Clinical trials should incorporate a validated prognostic index to assess the results, because of the difficulties associated with undertaking large-scale trials and significant diversity of clinical features with ATL, even in the same clinical subtypes (acute, lymphoma, chronic, and smoldering). PMID- 25281467 TI - Prevention and early detection of prostate cancer. AB - Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5alpha-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer. PMID- 25281471 TI - Overexpression of CD163 in vitreous and fibrovascular membranes of patients with proliferative diabetic retinopathy: possible involvement of periostin. AB - AIM: To determine whether CD163, a specific marker for M2 macrophages, is involved in the formation of preretinal fibrovascular membranes (FVMs) present in eyes with proliferative diabetic retinopathy (PDR). METHODS: We measured the levels of soluble (s)CD163, periostin and vascular endothelial growth factor by sandwich ELISA in vitreous samples from 74 eyes of 62 patients with PDR, 20 eyes of 18 patients with proliferative vitreoretinopathy, and 56 eyes of 54 patients with non-diabetic ocular diseases (control group). Immunohistochemical analyses were performed to determine the expressions of CD68, CD163 and periostin in the surgically resected FVMs and idiopathic epiretinal membranes (ERMs). RESULTS: The concentrations of sCD163 and periostin in the vitreous were significantly higher in patients with PDR than in non-diabetic controls (p<0.0001). There was a strong correlation between the vitreous concentrations of sCD163 and periostin. The mean vitreous level of sCD163 was significantly higher in eyes with FVMs than in those without FVMs (epicentre only). The number and percentage of CD163+ macrophages were significantly higher in the FVMs than in the idiopathic ERMs. Immunohistochemical analysis showed co-localisation of CD163 and periostin in FVM cells. CONCLUSIONS: These findings indicate that the overexpression of CD163 by macrophages may be involved in the development of FVMs partly through periostin production. PMID- 25281472 TI - Establishment of a Cre recombinase based mutagenesis protocol for markerless gene deletion in Streptococcus suis. AB - The lack of knowledge about pathogenicity mechanisms of Streptococcus (S.) suis is, at least partially, attributed to limited methods for its genetic manipulation. Here, we established a Cre-lox based recombination system for markerless gene deletions in S. suis serotype 2 with high selective pressure and without undesired side effects. PMID- 25281473 TI - To pre-challenge lactic acid bacteria with simulated gastrointestinal conditions is a suitable approach to studying potential probiotic properties. AB - The potential probiotic properties of lactic acid bacteria (LAB) after treatment with gastrointestinal (GI) conditions were investigated. Some LAB strains that survived simulated GI treatment retained their adhesiveness and antagonism against the pathogen. Therefore pre-challenging LAB with simulated GI conditions is a suitable way for potential probiotic studies. PMID- 25281474 TI - Improving the excess kurtosis (g2) method for localizing epileptic sources in magnetoencephalographic recordings. AB - OBJECTIVE: To suggest ways to apply the excess kurtosis estimator g2, in the detection of epileptic activity with magnetoencephalography, while avoiding its bias towards detecting high-amplitude, infrequent events. METHODS: Synthetic aperture magnetometry (SAM), combined with g2, was applied using window lengths ranging from 0.125 s to 32 s and with sum and maximum metrics on simulated data and recordings of two focal epilepsy patients. RESULTS: Comparing sources with different spike rates (two per second and one per 2s), the sum metric was most efficient when using a window of 0.25s. Simulations showed that the sum metric is insensitive to spike frequency when the window includes more than one spike. SAM(g2) images from long segments with maximum metric resulted in misleading images, showing the strongest activity away from the lesions. CONCLUSIONS: Using a sliding window and the sum metric is beneficial when imaging interictal spikes and status epilepticus. Windows should be short enough not to include more than one interictal event. For continuous events such as electrographic seizures windows should contain baseline data and the epileptic event. SIGNIFICANCE: The sliding window and metric should be set according to the suggested guidelines when using SAM(g2) for presurgical evaluation. PMID- 25281475 TI - Differential effects of facilitatory and inhibitory theta burst stimulation of the primary motor cortex on motor learning. AB - OBJECTIVE: To evaluate the differential effects on motor learning of two types of theta burst stimulation (TBS), the excitatory intermittent TBS (iTBS) and inhibitory continuous TBS (cTBS), if TBS is applied in an early stage of learning process. METHODS: Thirty right handed healthy people were randomly allocated into one of the three groups according to the intervention applied, iTBS, cTBS or placebo. The interventions and measurements targeted the non-dominant side. The reaction time task (RTT) and Purdue pegboard task (PPT) were used. Measurements and motor tasks were carried out at baseline (T0), immediately after the intervention (T1), and 30 min later (T2). RESULTS: Compared to placebo, following cTBS M1 excitability went down and PPT learning was slowed. Following iTBS M1 excitability increased temporarily and PPT learning pattern changed, but learning was not improved. The MEP and PPT changes induced during the T0-T1 time interval correlated significantly. CONCLUSIONS: The early consolidation of the learned material was much more influenced by the TBS induced promotion/suppression of the M1 functional plasticity reserves than by the absolute level of the M1 activation. SIGNIFICANCE: The results may help to better define the use of TBS in promotion of motor learning in neurorehabilitation and cognitive enhancement. PMID- 25281476 TI - Changes to child psychiatric disorders in DSM-5: the good, the bad and everything in between. PMID- 25281477 TI - EMT in cervical cancer: its role in tumour progression and response to therapy. AB - The prognosis of cervical patients significantly decreases as the cancer metastasizes to other parts of the body. The epithelial to mesenchymal transition (EMT) plays an important role in cervical cancer progression and metastasis. Recurrence is the primary cause of the increased number of deaths due to cervical cancer. Oncogenes, such as AEG1, Sam-68, FTS and miR-361-5p, induce EMT in cervical cancer. Tumour suppressors, such as LMX-1, SFRP1, klotho, and miR-155, suppress EMT in cervical cancer. Factors such as hypoxia, the radiation dose, cytokines, proteins, transcription factors, and signalling pathways also play an important role in the induction, progression and maintenance of EMT in cervical cancer. Overall, this review describes a wide range of factors with potential roles in EMT that have been identified to date, and this information could be important for the development of new and more effective therapeutics that ameliorate the negative impact of cervical pathogenesis via EMT. PMID- 25281478 TI - Trans-subscapularis portal versus low-anterior portal for low anchor placement on the inferior glenoid fossa: a cadaveric shoulder study with computed tomographic analysis. AB - PURPOSE: The purpose of this study was to evaluate the accuracy of inserting a glenoid anchor at the 5:30 clockface position using a trans-subscapularis (TSS) portal versus a low anterior (LA) portal. METHODS: Five surgeons (T.D., J.C., C.V., D.J.O-H., J.S.T.) placed a single anchor in 20 fresh-frozen cadaveric shoulders. In each of 2 shoulders, surgeons used an LA portal to insert the anchor, whereas in 2 shoulders a TSS portal was used. Surgeons were directed to place the anchor at the 5:30 position at an angle 45 degrees to the glenoid surface (axial plane) and passing perpendicular to the glenoid rim in the coronal plane. Shoulders were then dissected and computed tomographic (CT) scans obtained. Anchor position relative to the clockface was documented by 2 blinded assessors, as was the angle of insertion in the axial and coronal planes. Statistical significance was calculated with a Student t test for paired samples (confidence interval [CI], 95%; significance, P < .05). RESULTS: The average deviation from the 5:30 position was 48 minutes (standard deviation [SD], 31 minutes) for the LA portal (average position, 4:42 o'clock) versus 28.5 minutes (SD, 19 minutes) for the TSS group (average position, 5:02 o'clock) (P = .15). The average angle of anchor insertion in the axial plane was 67.2 degrees (SD, 19 degrees ) for the LA portal versus 62.8 degrees (SD, 14 degrees ) for the TSS portal (P = .49), whereas the average angle of insertion in the coronal plane was 31.3 degrees (SD, 14 degrees ) of inferior angulation in the LA group and 14.3 degrees (SD, 8 degrees ) of inferior angulation in the TSS group (P = .009). Of the anchors inserted, 9 of 20 (45%) showed evidence of far-cortical perforation. No difference in cortical perforation was seen between the 2 portals, with perforation more likely with anchors inserted greater than 45 degrees in the axial plane (8 of 20) than with those inserted less than 45 degrees (1 of 20) (P = .02). CONCLUSIONS: The use of a TSS portal improves the angle of approach to the inferior glenoid rim in comparison with an LA portal, reducing the acuity of the angle of insertion in the coronal plane. CLINICAL RELEVANCE: The TSS portal is an option for surgeons performing arthroscopic Bankart repair using anchors low on the glenoid rim. PMID- 25281479 TI - [Distribution of human papillomavirus genotypes amongst HIV-negative and HIV positive women diagnosed with ASC-US cytology. Preliminary data of a local retrospective study]. AB - OBJECTIVES: Analysis of the distribution of human papillomavirus (HPV) genotypes amongst HIV-negative and HIV-positive women diagnosed with atypical squamous cells of undetermined significance (ASC-US). PATIENTS AND METHODS: We performed a retrospective study of HPV genotype distribution in 313 ASC-US Pap smears from women who consulted at the University Hospital of Nice between 2008 and 2012. HPV genotyping results, conducted on PapilloCheck((r)) HPV DNA Chip, and information on the status of HIV patients were retrospectively collected. The odds ratio were calculated by logistic regression. RESULTS: In co-infected HIV/HPV women we observed a low prevalence of HPV16, a high prevalence of oncogenic HPV low risk and a high prevalence of HPV 68 compared to non-co-infected women. By grouping HPV HR based on their prevalence in cervical cancer of the uterus and their genetic proximity we observe that HPV 18, 45, 68 (the "alpha-7") are 7.4 times more represented (CI95 [2.48 to 22.35]) than HPV 16, 31, 33, 52, 58 (the "alpha 9") in the population of women co-infected with HIV. DISCUSSION AND CONCLUSION: Given that HPV "alpha-7" are responsible for 46.3% of adenocarcinomas, the high prevalence of these HPV found in ASC-US Pap smears of co-infected women should be put in relation with the highest prevalence of glandular abnormalities found in this population. HPV genotyping could become an essential tool for gynecological care for HIV positive women. PMID- 25281480 TI - [Latest innovation in Gynecologie Obstetrique & Fertilite]. PMID- 25281481 TI - New gene models and alternative splicing in the maize pathogen Colletotrichum graminicola revealed by RNA-Seq analysis. AB - BACKGROUND: An annotated genomic sequence of the corn anthracnose fungus Colletotrichum graminicola has been published previously, but correct identification of gene models by means of automated gene annotation remains a challenge. RNA-Seq offers the potential for substantially improved gene annotations and for the identification of posttranscriptional RNA modifications, such as alternative splicing and RNA editing. RESULTS: Based on the nucleotide sequence information of transcripts, we identified 819 novel transcriptionally active regions (nTARs) and revised 906 incorrectly predicted gene models, including revisions of exon-intron structure, gene orientation and sequencing errors. Among the nTARs, 146 share significant similarity with proteins that have been identified in other species suggesting that they are hitherto unidentified genes in C. graminicola. Moreover, 5'- and 3'-UTR sequences of 4378 genes have been retrieved and alternatively spliced variants of 69 genes have been identified. Comparative analysis of RNA-Seq data and the genome sequence did not provide evidence for RNA editing in C. graminicola. CONCLUSIONS: We successfully employed deep sequencing RNA-Seq data in combination with an elaborate bioinformatics strategy in order to identify novel genes, incorrect gene models and mechanisms of transcript processing in the corn anthracnose fungus C. graminicola. Sequence data of the revised genome annotation including several hundreds of novel transcripts, improved gene models and candidate genes for alternative splicing have been made accessible in a comprehensive database. Our results significantly contribute to both routine laboratory experiments and large scale genomics or transcriptomic studies in C. graminicola. PMID- 25281482 TI - Heart rate reserve predicts cardiovascular death among physically unfit but otherwise healthy middle-aged men: a 35-year follow-up study. AB - BACKGROUND: Heart rate reserve (HRR) has been reported to be inversely associated with cardiovascular (CV) disease and death. The impact of physical fitness (PF) on this relationship has not, however, been described in detail. We investigated how different levels of PF influenced the association between HRR and CV death during a 35-year follow-up. METHODS AND RESULTS: HRR and PF were measured in 2014 apparently healthy, middle-aged men during a symptom-limited bicycle exercise test in 1972-75. The men were divided into tertiles (T1-T3) by age-adjusted HRR. Morbidity and mortality data were registered from hospital charts through 2007 and the Norwegian Cause of Death Registry. Adjusted Cox proportional hazard regression models were used to calculate risks. Incidence of CV death was 528 (26%) during median 30 years of follow-up. Men with the lowest HRR had 41% (HR 1.41 [1.14-1.75]) increased risk of CV death compared with the men with the highest. We found a significant interaction between age-adjusted PF and HRR. After stratifying the men by PF, results were statistically significant only among men with the lowest PF, where the men with lowest HRR had a 70% (HR 1.70 [1.12-2.67]) increased risk of CV death compared with the men with the highest. CONCLUSIONS: Low HRR was independently associated with increased risk of CV death in apparently healthy, middle-aged men. The predictive impact of HRR on CV death risk was, however, confined to unfit men. PMID- 25281483 TI - Estimated daily salt intake in relation to blood pressure and blood lipids: the role of obesity. AB - BACKGROUND: Excessive salt intake causes increased blood pressure which is considered the leading risk for premature death. One major challenge when evaluating associations between daily salt intake and markers of non-communicable diseases is that a high daily salt intake correlates with obesity, which is also a well described risk factor for poor cardiometabolic outcome. The aim of this study was to evaluate the relationship of estimated daily salt intake with blood pressure and blood lipids and to investigate the effect of taking different measures of obesity into account. METHODS: We included 3294 men and women aged 18 69 years from a general population based study in Copenhagen, Denmark. Estimated 24-hour sodium excretion was calculated by measurements of creatinine and sodium concentration in spot urine in combination with information of sex, age, height and weight. The relations of estimated 24-hour sodium excretion with blood pressure and blood lipids were evaluated by linear regression models. RESULTS: The daily mean estimated intake of salt was 10.80 g and 7.52 g among men and women, respectively. Daily salt intake was significantly associated with blood pressure (beta-estimates 1.18 mm Hg/g salt (systolic) and 0.74 mm Hg/g salt (diastolic), p < 0.0001) - however this association was markedly affected by adjustment for obesity (beta-estimates around 0.60 mm Hg/g salt (systolic) and around 0.25 mm Hg/g salt (diastolic), p < 0.05). Also associations between daily salt intake and blood lipids were highly affected by adjustment for obesity. CONCLUSIONS: Associations of estimated daily salt intake with blood pressure and blood lipids were highly affected by adjustment for obesity. PMID- 25281484 TI - NF-kappaB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke. AB - Chronic stroke is the phase of brain recovery and repair generally beginning 3 months after stroke onset. No pharmaceutical approach is currently available to enhance brain repair in chronic stroke. We have previously determined the therapeutic effects of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) alone or in combination (SCF+G-CSF) in an animal model of chronic stroke and demonstrated that only SCF+G-CSF induces long-term functional recovery. However, the mechanism underlying the SCF+G-CSF-induced brain repair in chronic stroke remains largely elusive. In the present study, we determined the role of nuclear factor-kappa B (NF-kappaB) in neurovascular network remodeling and motor function improvement by SCF+G-CSF treatment in chronic stroke. SCF+G CSF was subcutaneously administered for 7 days beginning 17 weeks after induction of experimental stroke. To inhibit NF-kappaB activation, NF-kappaB inhibitor was infused into the brain before SCF+G-CSF treatment. We observed that NF-kappaB inhibitor abolished the SCF+G-CSF-induced axonal sprouting, synaptogenesis and angiogenesis in the ipsilesional somatosensorimotor cortex. In addition, blockage of NF-kappaB activation resulted in elimination of the SCF+G-CSF-induced motor functional restoration in chronic stroke. These data suggest that NF-kappaB is required for the SCF+G-CSF-induced neuron-vascular network remodeling in the ipsilesional somatosensorimotor cortex and motor functional recovery in chronic stroke. PMID- 25281485 TI - Activation of spinal chemokine receptor CXCR3 mediates bone cancer pain through an Akt-ERK crosstalk pathway in rats. AB - Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat's tibia induced a time-dependent phosphorylation of Akt and extracellular signal regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Akt and Raf/MEK/ERK signaling pathways under the BCP condition. PMID- 25281486 TI - A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood. AB - Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60-0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62-0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47-0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53-0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62-0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3'UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. PMID- 25281487 TI - Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the cheliensisin a inhibition of cell transformation. AB - Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the current study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP downregulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A, and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A. PMID- 25281488 TI - Methylation analysis of the FAM19A4 gene in cervical scrapes is highly efficient in detecting cervical carcinomas and advanced CIN2/3 lesions. AB - Primary testing for human papillomavirus (HPV) in cervical screening requires triage to differentiate women with transient infection from those with persistent infection who require more intensive management given their risk for cervical (pre)cancer. In this study, the clinical performance of a novel methylation marker FAM19A4 for the triage of high-risk (hr)HPV-positive women was evaluated. Using a training-validation set approach, we analyzed a FAM19A4 quantitative methylation-specific PCR (qMSP). The training set comprised hrHPV-positive cervical scrapes of 43 women with cervical intraepithelial neoplasia grade 3 or worse (CIN3+) and 135 women with <=CIN1. The validation set comprised hrHPV positive cervical scrapes of 52 women with CIN2+, including 33 CIN3+, 19 CIN2, and 166 women with <=CIN1. The methylation threshold of FAM19A4 qMSP that gave rise to CIN3+ specificity of 70% in the training set was applied in the validation set. This resulted in CIN3+ sensitivity of 75.8% [95% confidence interval (CI), 61.1-90.4] at 67.0% (95% CI, 60.3-73.8) specificity. Next, the validated qMSP was applied to an independent series of hrHPV-positive cervical scrapes of 22 women with cervical cancer, 29 with advanced CIN2/3 [i.e., women with a known preceding hrHPV infection (PHI) lasting >=5 years as proxy of longer duration of lesion existence], and 19 with early CIN2/3 (i.e., PHI <5 years). All carcinomas (22/22) and advanced CIN2/3 lesions (29/29) were FAM19A4 methylation positive, compared with 42.1% (8/19; 95% CI, 19.9-64.3) of early CIN2/3 lesions. In conclusion, FAM19A4 is an attractive triage marker for hrHPV-positive women, with a high reassurance for the detection of cervical carcinoma and advanced CIN2/3 lesions. PMID- 25281489 TI - Root dentin anomaly and a PLG mutation. AB - We report a Thai girl affected with plasminogen deficiency, Type I. Ligneous conjunctivitis was first observed when she was one-month-old. The newly recognized findings include tapered incisor roots as a result of thin root dentin, generalized short tooth roots, and mandibular prognathism. Mutation analysis of PLG demonstrated homozygous c.1193G>A missense mutation. The parents were heterozygous for c.1193G>A mutation. The c.1193G>A mutation is novel and predicted to cause amino acid substitution p.Cys398Tyr. Thin root dentin in the patient who was affected with PLG mutation and immunolocalization of Plg during early root development in mice imply the role of plasminogen in root dentin formation. PMID- 25281490 TI - A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion syndrome, is associated with syndromic intellectual disability. AB - We report a boy with severe syndromic intellectual disability who has a de novo mutation in the ZMYND11 gene. Arguments for pathogenicity of this mutation are found in cases from the literature, especially several with 10p15.3 deletions, harbouring ZMYND11. Additional reports of ZMYND11 mutations in cases with syndromic intellectual disability are needed before the ZMYND11 mutation identified in our case can be considered as definitely pathogenic. PMID- 25281491 TI - Chemotherapy-induced peripheral neuropathy and its impact on health-related quality of life among ovarian cancer survivors: results from the population-based PROFILES registry. AB - OBJECTIVE: This study assessed the prevalence and risk factors of chemotherapy induced peripheral neuropathy, and its impact on health-related quality of life among ovarian cancer survivors, 2-12 years after diagnosis. METHODS: Women (n=348) diagnosed with ovarian cancer between 2000 and 2010, as registered by the Dutch population-based Eindhoven Cancer Registry, were eligible for participation. A questionnaire, including the EORTC QLQ-C30 and EORTC QLQ-OV28 measures, containing 3 items about neuropathy, was returned by 191 women (55%). Recurrence and chemotherapy data were obtained from medical records. RESULTS: Of all 191 women, the 129 women who received chemotherapy more often reported having tingling hands/feet and feeling numbness in fingers/toes, specifically 51% reported "a little" to "very much" of these symptoms vs. about 27% who did not receive chemotherapy. Women reporting more neuropathy symptoms reported lower levels of functioning and overall quality of life. They also reported more symptoms of fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and financial problems. Moreover, women reporting more neuropathy symptoms had experienced the disease and treatment more often as being a burden and were more worried about their health, had more gastrointestinal and hormonal symptoms, hair loss and more other chemotherapy side effects. Linear regression analyses showed that more cycles of chemotherapy, more recurrences and a shorter period since last treatment were associated with a higher neuropathy score. CONCLUSION: Neuropathy symptoms were experienced by 51% of women with ovarian cancer who received chemotherapy even up to 12 years after the end of treatment, and this seriously affected their HRQoL. PMID- 25281492 TI - Impact of secondary cytoreductive surgery on survival in patients with platinum sensitive recurrent ovarian cancer: analysis of the CALYPSO trial. AB - OBJECTIVE: The role of secondary cytoreductive surgery (SCR) in platinum sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis. METHODS: Using data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery. RESULTS: Of the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001). CONCLUSION: SCR was associated with improved OS in platinum sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential. PMID- 25281493 TI - Adoption and impact of concurrent chemoradiation therapy for vaginal cancer: a National Cancer Data Base (NCDB) study. AB - BACKGROUND: Vaginal cancer is an uncommon entity for which concurrent chemoradiation (CCRT) may be used based on small retrospective series and extrapolation from cervical cancer. We explored the adoption rate of CCRT and determined its impact on survival. METHODS: Patients entered into the National Cancer Data Base (NCDB) diagnosed with vaginal cancer from 1998 to 2011 who received definitive radiation therapy were included. Univariate/multivariable exploratory analyses of factors associated with CCRT were performed. Log-rank test and Cox proportional hazards modeling identified the contribution of CCRT on survival. RESULTS: Of the 13,689 patients identified, 8222 (60.1%) received radiation therapy. Of these, 3932 (47.8%) received CCRT and its use increased from 20.8% to 59.1% (1998-2011). Of the 23 patient, disease, facility, and treatment factors, 13 were significantly associated with patient outcomes and were entered into a binary logistic regression model. This evaluation revealed that younger age, larger tumor size, later year of diagnosis, higher facility volume, squamous histology, and higher stage (in order of increasing association) are independently associated with CCRT use. Median overall survival is longer with CCRT compared to radiation alone (56.2 vs. 41.2 months, p<0.0005). On multivariable analysis, younger age, higher facility volume, squamous histology, lower comorbidity score, CCRT, brachytherapy utilization and lower stage (in order of increasing association) are independently prognostic of improved survival. CONCLUSIONS: Use of CCRT for patients with vaginal cancer has increased and is associated with a significant improvement in survival in this large, national cohort. CCRT should be integrated into treatment guidelines for vaginal cancer. PMID- 25281494 TI - Functional variants in CYP1A1 and GSTM1 are associated with clearance of cervical HPV infection. AB - OBJECTIVE: We evaluated time to clearance of high risk (HR) HPV infection in relation to functional variants in three genes (CYP1A1, GSTT1, and GSTM1). METHODS: The study group consisted of 450 HR-HPV infected women from the Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial Lesion Triage Study (ALTS) cohort followed up at the clinical center at Birmingham, Alabama. The Cox proportional hazard model with the Wei-Lin-Weisfeld (WLW) approach was used, controlling for relevant covariates. RESULTS: Women who were polymorphic for CYP1A1 experienced an HR-HPV clearance rate that was 20% (HR=0.80, p=0.04) lower than women without the polymorphism for CYP1A1, adjusting for all other cofactors. The GSTM1 null genotype was associated with higher HR HPV clearance rate (HR=1.39, p=0.006). The polymorphism in GSTT1 was not significantly associated with time to clearance of HR-HPV. CONCLUSIONS: Xenobiotic metabolism genes may influence the natural history of HR-HPV infection and its progression to cervical cancer. PMID- 25281496 TI - Super-sampling SART with ordered subsets. AB - In tomography, the quality of the reconstruction is essential because the complete cascade of the subsequent analysis is based on it. To date, weighted back-projection (WBP) has been the most commonly used technique due to its versatility and performance in sub-tomogram averaging. Here we present super sampling SART that is based on the simultaneous algebraic reconstruction technique. While algebraic reconstruction techniques typically produce better contrast and lately showed a significant improvement in terms of processing speed, sub-tomogram averages derived from those reconstructions were inferior in resolution compared to those derived from WBP data. Super-sampling SART, however, outperforms both in term of contrast and the resolution achieved in sub-tomogram averaging several other tested methods and in particular WBP. The main feature of super-sampling SART, as the name implies, is the super-sampling option - by which parameter-based up-sampling and down-sampling are used to reduce artifacts. In particular, the aliasing that is omnipresent in the reconstruction can be practically eliminated without a significant increase in the computational time. Furthermore, super-sampling SART reaches convergence within a single iteration, making the processing time comparable to WBP, and eliminating the ambiguity of parameter-controlled convergence times. We find that grouping of projections increases the contrast, while when projections are used individually the resolution can be maximized. Using sub-tomogram averaging of ribosomes as a test case, we show that super-sampling SART achieves equal or better sub-tomogram averaging results than WBP, which is of particular importance in cryo-electron tomography. PMID- 25281495 TI - Somatic copy number alterations predict response to platinum therapy in epithelial ovarian cancer. AB - OBJECTIVE: Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. METHODS: SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227). RESULTS: We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7*10(-4); HR=1.82, P=1.9*10( 2) and HR=1.80, P=2.2*10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8*10(-11);R(2)=0.26). CONCLUSIONS: We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy. PMID- 25281497 TI - Changes in tissue directionality reflect differences in myelin content after demyelination in mice spinal cords. AB - Changes in myelin integrity are key manifestations of many neurological diseases including multiple sclerosis but precise measurement of myelin in vivo is challenging. The goal of this study was to evaluate myelin content in histological images obtained from a lysolecithin mouse model of demyelination, using a new quantitative method named structure tensor analysis. Injury was targeted at the dorsal column of mice spinal cords. We obtained 16 histological images stained with luxol fast blue for myelin from 9 mice: 9 images from lesion epicenter and 7 from a distant area 500-MUm away from the epicenter. In each image, we categorized 3 tissue types: healthy, completely demyelinated, and partially demyelinated. Structure tensor analysis was applied to quantify the coherency (anisotropy), energy (trace of dominant directions), and angular entropy (degree of disorder) of each tissue. We found that completely demyelinated lesions had significantly lower coherency and energy but higher angular entropy than partially demyelinated and healthy tissues at both the epicenter and distant areas of the injury. In addition, the coherency of healthy tissue was greater than partially demyelinated tissue at each site. Within tissue category, we did not find differences in any measure between spinal cord locations. Our findings suggest that greater myelin integrity is associated with better tissue anisotropy, independent of injury location. Structure tensor analysis may serve as a new tool for quantitative measurement of myelin content in white matter, and this may help understand disease mechanisms and development in MS and other demyelinating disorders. PMID- 25281498 TI - Long-term outcome comparison of endoscopic resection and surgery in early gastric cancer meeting the absolute indication for endoscopic resection. AB - BACKGROUND: Endoscopic resection (ER) of early gastric cancer (EGC) meeting the absolute indication has excellent long-term outcomes. OBJECTIVE: To compare long term outcomes of ER with those of surgery in patients with EGC who met the absolute indication for ER. DESIGN: Retrospective cohort study. SETTING: A specialized center for the treatment of cancer. PATIENTS AND INTERVENTIONS: We retrospectively reviewed data from patients who underwent gastrectomy or ER for EGC between 2002 and 2007. Gastric cancers were differentiated-type adenocarcinoma without ulceration confined to the mucosal layer and 2 cm or smaller in size. MAIN OUTCOME MEASUREMENTS: The primary outcome was overall survival (OS). Metachronous cancer rates and adverse event rates were compared. Kaplan-Meier plots and Cox proportional hazard regression analyses were applied for comparisons. Differences in baseline characteristics were adjusted by propensity score. RESULTS: Among 375 patients, 261 underwent ER and 114 underwent surgery. The median follow-up duration was 76.4 months. The 5-year OS rates did not significantly differ between the ER and surgery groups (95.7% vs 93.6%, respectively; P = .725 by log-rank test). There were no gastric cancer-related deaths in either group. Metachronous gastric cancer developed more frequently in the ER group (6.1%, 16/261) than in the surgery group (0.9%, 1/114) (P = .024). However, most patients (93.8%, 15/16) in the ER group were curatively treated with repeat ER. Adverse event rates were higher in the surgery group than those in the ER group (7.9% vs 2.7%, P = .028). LIMITATIONS: Retrospective, single center study. CONCLUSIONS: The OS rate after ER for mucosal gastric cancer that met the absolute indication was comparable to that achieved with surgery. Although metachronous cancers were more common after ER, they were usually treatable and did not affect survival. PMID- 25281499 TI - EUS demonstration of nonlifting sign in a dysplastic polyp at the appendiceal orifice. PMID- 25281500 TI - EUS-guided drainage: beware of the pancreatic fluid collection (with videos). PMID- 25281501 TI - Outpatient endoscopic closure of persistent gastrocutaneous fistula with hemoclips in pediatric patients. PMID- 25281502 TI - Endoscopic imaging of the vermiform appendix (with video). AB - BACKGROUND: Chronic appendicitis may be detected in as many as 10% of patients with right lower quadrant pain. Although the appendiceal orifice is easily identified during colonoscopy, its lumen has not been investigated so far. OBJECTIVES: To determine the feasibility of endoscopic appendix imaging to identify features of chronic appendicitis in patients with recurrent right lower quadrant pain. DESIGN: Prospective, proof-of-concept study. SETTING: University based tertiary referral hospital. PATIENTS: Colonoscopy scheduled because of right lower quadrant pain. INTERVENTIONS: First, the appendix orifice was cannulated with a guidewire and a Jagtome. Next fluoroscopic imaging was performed by injection of contrast agent into the appendix orifice, and then a SpyGlass endoscope was inserted for imaging of the appendiceal mucosa and for biopsy. Patients were monitored 3 hours after investigation, with follow-up at 4 weeks. MAIN OUTCOME MEASUREMENTS: Cannulation rate. RESULTS: Thirteen patients were included. Endoscopic imaging of the appendix was successful in 9 of 13 patients (69%). In 10 patients, a guidewire was placed; in 7 patients, biopsy specimens were taken, revealing histological signs of inflammation in 5. In 4 patients, visible fecoliths were removed by flushing. All patients were discharged on the same day. No adverse events occurred. Three patients reported resolution of pain at follow-up. One patient with strictures at appendicoscopy underwent surgical appendectomy. Histology confirmed the findings of chronic appendicitis with fibrosis. LIMITATIONS: Patient number limits power for analysis. CONCLUSION: Endoscopic imaging of the appendix is feasible, safe, and clinically useful in patients with suspected chronic appendicitis. PMID- 25281503 TI - "Made Up from Many Experimentall Notions": The Society of Apothecaries, Medical Humanism, and the Rhetoric of Experience in 1630s London?. AB - This article examines an important new manuscript discovery: a set of lectures delivered at the Society of Apothecaries in 1634 by four members of the Society. No evidence of the intellectual and methodological assumptions of the apothecaries in this period has previously been known; the article contextualizes the lectures, and identifies the authors-a prominent group of apothecaries centered on the controversial John Buggs and the botanist Thomas Johnson. It then proceeds to discuss the contents of the lectures, which consist, to a remarkable extent, of reflections on the nature of physic and pharmacy inspired by the works of sixteenth- and seventeenth-century medical humanists. The apothecaries used the resources of medical humanism to raise the status of pharmacy as a medical discipline, and to argue for the proficiency of the apothecary as a fully fledged physician. Moreover, they emphasized the role of operative arts and used the rhetoric of "experiment" and "experience" in ways that might seem, on first impression, to foreshadow the "new science" that would soon emerge in England. As such, the lectures allow us to make not only some major revisions to existing accounts of the apothecary-physician relationship and the intellectual assumptions behind it, but also to some prominent recent literature in the social history of science and the history of the concept of "experimental philosophy." PMID- 25281504 TI - High-speed circuit training vs hypertrophy training to improve physical function in sarcopenic obese adults: a randomized controlled trial. AB - BACKGROUND: Progressive loss of muscle and strength with age is often coincident with increases in adiposity, leading to a condition called sarcopenic obesity. Studies have shown sarcopenic obese adults to be at higher risk for declines in physical function. Despite this rising public health concern, no intervention studies currently exist in this population. METHODS: A total of 21 sarcopenic obese adults, 60 years or older, were randomized into two groups, strength/hypertrophy (SH, n=9) and high-speed circuit (HSC, n=8) and were trained for 15 weeks. The primary outcome was the SPPB modified as a measure of physical function, assessed by assessors blinded to randomization. Secondary outcomes were lower body and upper body power and strength, instrumental activities of daily living (IADL), ratings of perceived exertion (RPE), body fat % (BF%), skeletal muscle index (SMI), and grip strength (GRP). RESULTS: For the SPPB results favored HSC over SH (1.1, 95% CI (-.1 to 2.4), p=.08) and showed a moderate effect size (Hedge g=0.6, 95% CI (-0.4, 1.6)). For secondary outcomes, lower body power (mean difference=158 W, 95% CI (2, 315); p=.01) and RPE (mean difference= 1.5, 95% CI (-2.9, -0.12); p=.04) also favored HSC. IADL, SMI, BF%, upper and lower body strength and upper body power, showed no statistically significant differences between groups. CONCLUSIONS: Considering the moderate effect size, the large treatment effect shown by the upper limit of the 95% CI, the low perceived exertion, and no adverse effects, HSC training should be further investigated with a larger sample size in sarcopenic obese adults. PMID- 25281505 TI - Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia. AB - Cancer therapeutics is evolving to precision medicine, with the goal of matching targeted compounds with molecular aberrations underlying a patient's cancer. While murine models offer a pre-clinical tool, associated costs and time are not compatible with actionable patient-directed interventions. Using the paradigm of T-cell acute lymphoblastic leukemia, a high-risk disease with defined molecular underpinnings, we developed a zebrafish human cancer xenotransplantation model to inform therapeutic decisions. Using a focused chemical genomic approach, we demonstrate that xenografted cell lines harboring mutations in the NOTCH1 and PI3K/AKT pathways respond concordantly to their targeted therapies, patient derived T-cell acute lymphoblastic leukemia can be successfully engrafted in zebrafish and specific drug responses can be quantitatively determined. Using this approach, we identified a mutation sensitive to gamma-secretase inhibition in a xenograft from a child with T-cell acute lymphoblastic leukemia, confirmed by Sanger sequencing and validated as a gain-of-function NOTCH1 mutation. The zebrafish xenotransplantation platform provides a novel cost-effective means of tailoring leukemia therapy in real time. PMID- 25281506 TI - ETV6 (TEL1) regulates embryonic hematopoiesis in zebrafish. AB - Chromosomal translocations involving fusions of the human ETV6 (TEL1) gene occur frequently in hematologic malignancies. However, a detailed understanding of the normal function of ETV6 remains incomplete. This study has employed zebrafish as a relevant model to investigate the role of ETV6 during embryonic hematopoiesis. Zebrafish possessed a single conserved etv6 ortholog that was expressed from 12 hpf in the lateral plate mesoderm, and later in hematopoietic, vascular and other tissues. Morpholino-mediated gene knockdown of etv6 revealed the complex contribution of this gene toward embryonic hematopoiesis. During primitive hematopoiesis, etv6 knockdown resulted in reduced levels of progenitor cells, erythrocyte and macrophage populations, but increased numbers of incompletely differentiated heterophils. Definitive hematopoiesis was also perturbed, with etv6 knockdown leading to decreased erythrocytes and myeloid cells, but enhanced lymphopoiesis. This study suggests that ETV6 plays a broader and more complex role in early hematopoiesis than previously thought, impacting on the development of multiple lineages. PMID- 25281508 TI - Differentiating maternal fatigue and depressive symptoms at six months and four years post partum: Considerations for assessment, diagnosis and intervention. AB - OBJECTIVE: fatigue and depressive symptoms are common among women in the postpartum period, and it has been proposed that fatigue is a risk factor for later depression. To progress this research, there is a need to clarify the conceptual and measurement issue of whether these two sets of symptoms are distinct constructs. There is also a need to determine whether they are distinct constructs beyond the postnatal period. The aim of the study was to assess the construct and discriminant validity of fatigue and depressive symptoms as measured by the SF-36 Vitality subscale (SF-36) and the Edinburgh Postnatal Depression Scale (EPDS) at six months and at four years post partum. DESIGN, SETTING AND PARTICIPANTS: data from over 1000 women participating in the Maternal Health Study, a longitudinal study of women's physical and psychological health and recovery after childbirth were used. FINDINGS: confirmatory factor analysis revealed a two-factor model of fatigue and depressive symptoms represented as distinct but related constructs was a better fit to the data than a one-factor model of fatigue and depression sharing the same underlying construct at both six months and four years post partum. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: this study provides empirical evidence that maternal fatigue and depression in the first year after having a baby and at four years post partum are best understood as separate psychological constructs or experiences. The findings have important implications for clinical practice, in particular underlining the importance of differentiating tiredness from depression. PMID- 25281509 TI - Open fractures of the foot and ankle. AB - Open fractures of the lower extremity cover a wide gamut of injuries ranging from the mangled, pulseless leg necessitating amputation to the more innocuous pinhole open wounds associated with simple fracture patterns. Prompt diagnosis and appropriate care can make a dramatic difference in decreasing complication rates and improving ultimate outcomes. Principles of management of open fractures have been created with the main goal of decreasing infection rates, while providing for stabilization of the bone and soft tissue injury. PMID- 25281507 TI - The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. AB - T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of natural killer cells are intriguing entities between benign and malignant lymphoproliferation. The molecular pathogenesis has partly been uncovered by the recent discovery of somatic activating STAT3 and STAT5b mutations. Here we show that 43% (75/174) of patients with T-cell large granular lymphocytic leukemia and 18% (7/39) with chronic lymphoproliferative disorder of natural killer cells harbor STAT3 mutations when analyzed by quantitative deep amplicon sequencing. Surprisingly, 17% of the STAT3-mutated patients carried multiple STAT3 mutations, which were located in different lymphocyte clones. The size of the mutated clone correlated well with the degree of clonal expansion of the T-cell repertoire analyzed by T-cell receptor beta chain deep sequencing. The analysis of sequential samples suggested that current immunosuppressive therapy is not able to reduce the level of the mutated clone in most cases, thus warranting the search for novel targeted therapies. Our findings imply that the clonal landscape of large granular lymphocytic leukemia is more complex than considered before, and a substantial number of patients have multiple lymphocyte subclones harboring different STAT3 mutations, thus mimicking the situation in acute leukemia. PMID- 25281510 TI - Diabetic charcot neuroarthropathy of the foot and ankle with osteomyelitis. AB - One of the most devastating foot and/or ankle complications in the diabetic population with peripheral neuropathy is the presence of Charcot neuroarthropathy (CN). In recent years, diabetic limb salvage has been attempted more frequently as opposed to major lower extremity amputation for CN of the foot and ankle with ulceration and/or deep infection. Treatment strategies for osteomyelitis in the diabetic population have evolved. This article reviews some of the most common surgical strategies recommended for the diabetic patient with CN of the foot and/or ankle and concomitant osteomyelitis. PMID- 25281511 TI - Midfoot crush injuries. AB - Treatment of midfoot injuries is surgical or nonsurgical, depending on the injury, the location, and the extent of the injury. Minor injuries usually heal with casting or bracing, whereas more unstable injuries typically need surgery for stability. Whether the injury is in a weight-bearing portion of the foot is also a consideration for surgery. The importance of treating midfoot injuries adequately is shown in how the midfoot is needed for function with weight bearing and its relationship between the front and the back of the foot. It is also important to ensure that the patient is able to ambulate with a reasonably normal gait. PMID- 25281512 TI - Fractures of the talus. AB - The talus is the most proximal bone of the hindfoot that couples the foot to the leg. It is the second most common fracture of the tarsal bones, second in frequency to the calcaneous. However, overall injuries to the talus are relatively rare, and most surgeons have little experience in managing them. This article discusses fractures of the talus, including injuries to the talar neck, body, head, and processes. Although subtalar dislocations and osteochondral injuries are important topics, they are not addressed in this article. PMID- 25281513 TI - Management in high-risk patients. AB - Injuries to the foot and ankle are often missed or underestimated in patients with polytrauma and are a source of long-term limitations. Injures below the knee are among the highest causes for unemployment, longer sick leave, more pain, more follow-up appointments, and decreased overall outcome. As mortalities decrease for patients with polytrauma a greater emphasis on timely diagnosis and treatment of foot and ankle injuries is indicated. Geriatric patients represent nearly one quarter of trauma admissions in the United States. This article discusses perioperative management and complications associated with foot and ankle injuries in polytrauma, and in diabetic and geriatric patients. PMID- 25281514 TI - Surgical treatment of intra-articular calcaneal fractures. AB - Most intra-articular calcaneal fractures are a result of high-energy trauma. The operative management of calcaneal fractures has been based on achieving anatomic reduction and minimizing complications of the compromised soft tissue envelope. The traditional extensile lateral approach offers advantages of achieving adequate fracture reduction with the risk of wound-healing complications and infection. Limited open reduction and internal fixation techniques with or without using external fixation focuses on achieving fracture reduction with less risk of wound complications but higher risk of malunion. This article discusses key points of operative management for various intra-articular calcaneal fracture patterns and clinical presentations. PMID- 25281515 TI - Surgical treatment of tibial plafond fractures. AB - Intra-articular fractures of the tibial plafond are typically the result of rotational or axial loading forces, and both mechanisms of injuries can result in an associated fibula fracture. Rotational distal tibial plafond fractures are typically of lower energy and are associated with less articular injury and chondral impaction, whereas axial load injuries of the distal tibial plafond are associated with a higher incidence of intra-articular and soft tissue injury. The goal of this article is to review the mechanisms of injury, fracture patterns, and potential complications associated with the most common presentations of tibial plafond fractures. PMID- 25281516 TI - The mangled foot and ankle: soft tissue salvage techniques. AB - The mangled foot and ankle can be defined as a severe injury to multiple organ systems of this appendage that can include bone, muscle, tendon, and neurovascular structures. The magnitude and often rate-limiting parameter most likely to affect the decision to attempt foot salvage is the degree of soft tissue destruction. If irreplaceable or if function cannot be restored, amputation should be considered. If reconstruction is attempted, all nonviable tissues regardless of intrinsic function must first be removed by meticulous debridement. PMID- 25281517 TI - Strategies for managing bone defects of the lower extremity. AB - Management of posttraumatic segmental bone loss as a result of severe open injuries of the lower extremity, high-energy closed injuries, and following failed initial treatment of complex fractures that develop pseudarthrosis continues to challenge reconstructive surgeons. There are numerous strategies for dealing with such injuries but the outcome is unpredictable. The procedure is rarely only one stage and complications frequently arise. In most cases the reconstruction process is long and difficult and amputation must be part of the decision-making process. All traditional treatment strategies have advantages and major drawbacks. To overcome some limitations, biologic treatments have been developed based on specific pathways of bone physiology and healing. PMID- 25281518 TI - Rehabilitation after major extremity trauma. AB - Physical therapy is an integral part of rehabilitation after foot and ankle trauma. Workman's compensation may play a role in treatment, prognosis, and added bureaucracy. The foot and ankle surgeon needs to be able to determine when maximum medical improvement has been reached. Patients with foot and ankle trauma must have a coordinated care plan, which may include a case manager, a physician conducting an independent medical examination, and possibly, legal counsel. PMID- 25281519 TI - Supramalleolar osteotomy and ankle arthrodiastasis for juvenile posttraumatic ankle arthritis. AB - Numerous techniques have been described for posttraumatic ankle arthritis with or without an associated lower extremity deformity in the adult population. These surgical procedures may include, but are not limited to, ankle exostectomy with joint resurfacing, ankle arthrodiastasis, ankle arthroplasty, and ankle arthrodesis. Associated deformities may also be addressed with supramalleolar osteotomies, tibia or fibular lengthening, and calcaneal osteotomies. In juvenile patients, surgical treatment options for posttraumatic ankle arthritis can be challenging, especially when an associated deformity is present. This article describes a combined supramalleolar osteotomy and ankle arthrodiastasis for a juvenile patient with posttraumatic ankle arthritis and valgus deformity. PMID- 25281520 TI - Lower extremity trauma and complications. PMID- 25281521 TI - Lower extremity complex trauma and complications. PMID- 25281522 TI - The relationship between prostate cancer and presence of metabolic syndrome and late-onset hypogonadism. AB - OBJECTIVE: To investigate the relationship between prostate cancer (PCa), presence of metabolic syndrome (MetS), and late-onset hypogonadism (LOH). MATERIALS AND METHODS: One hundred seventy patients who underwent transrectal ultrasonography-guided prostate needle biopsy were included in this study. For the diagnosis of MetS, American Heart Association/National Heart, Lung, and Blood Institute criteria were used. For the diagnosis of LOH, Androgen Deficiency in Aging Males questionnaire and serum total and free testosterone levels were used. Patients were divided into 4 groups according to the presence of MetS and LOH: group 1, MetS and LOH; group 2, with MetS but without LOH; group 3, with LOH but without MetS; and group 4, with neither MetS nor LOH. RESULTS: The mean age of the patients was 63.7 +/- 7.2 years. In group 1, 12 patients (37.5%); in group 2, 5 patients (25%); in group 3, 11 patients (26.8%); and in group 4, 14 patients (18.2%) were diagnosed with PCa. Aggressive PCa was determined in 7 patients in group 1 (21.9%), 2 patients in group 2 (10%), 5 patients in group 3 (12.2%), and 5 patients in group 4 (6.5%). There was a statistically significant difference only in between groups 1 and 4 in terms of detection of PCa (37.5% vs 18.2%, P = .031) and aggressive PCa (21.9% vs 6.5%, P = .019). CONCLUSION: These results highlight the fact that coexistence of MetS and LOH increases the risk of PCa and aggressive PCa. PMID- 25281523 TI - Anesthetic exposure in the treatment of symptomatic urinary calculi in pregnant women. AB - OBJECTIVE: To assess the duration and total number of anesthetic exposures required for the treatment of urolithiasis during pregnancy, specifically comparing temporizing measures with active treatment because urolithiasis and its management may pose potential theoretical risks for the mother and fetus. MATERIALS AND METHODS: We retrospectively reviewed patients with a confirmed diagnosis of urolithiasis during pregnancy who underwent surgical intervention from 1997 to 2012 at our institution. The number and duration of anesthetic exposures were assessed. RESULTS: We identified 26 women with urolithiasis during pregnancy, of which 15 (58%) were treated with temporizing stents and 11 (42%) with ureteroscopic stone extraction. In the ureteroscopy group, the median number of anesthetic exposures was 1.18 (interquartile range [IQR], 1-2), and the median total anesthetic time was 80 minutes (IQR, 37-126 minutes). In the stent group, 6 (40%) required multiple stent exchanges for a median of 1.47 (IQR, 1-3) anesthetic events and a median total anesthetic time of 70 minutes (IQR, 29-208 minutes). In the ureteral stent group, 7 women (47%) were induced before spontaneous labor due to inability to tolerate the stent. There was no difference in the number of anesthetic events (P = .208) or anesthesia time (P = .503) between stenting and ureteroscopy. CONCLUSION: Women undergoing ureteroscopic surgical intervention during pregnancy were at no greater risk in the number or cumulative duration of anesthesia exposure than women managed with temporizing ureteral stent placement and subsequent exchanges. PMID- 25281524 TI - Elimination and selection by aspects in health choice experiments: prioritising health service innovations. AB - Priorities for public health innovations are typically not considered equally by all members of the public. When faced with a choice between various innovation options, it is, therefore, possible that some respondents eliminate and/or select innovations based on certain characteristics. This paper proposes a flexible method for exploring and accommodating situations where respondents exhibit such behaviours, whilst addressing preference heterogeneity. We present an empirical case study on the public's preferences for health service innovations. We show that allowing for elimination-by-aspects and/or selection-by-aspects behavioural rules leads to substantial improvements in model fit and, importantly, has implications for willingness to pay estimates and scenario analysis. PMID- 25281525 TI - Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. AB - OBJECTIVE: In endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities. METHODS: 686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray. RESULTS: PR protein level was significantly associated with PGR mRNA expression (P<0.001) and patient survival (P<0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR. CONCLUSION: Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status. PMID- 25281526 TI - Frequency of therapy-relevant staging shifts in colorectal cancer through the introduction of pN1c in the 7th TNM edition. AB - BACKGROUND: pN1c is a novel N-category introduced for colorectal cancer (CRC) in current TNM (Tumour, Node, Metastasis) classification. It represents cancers displaying tumour deposits (TDs) in the fat but no involvement of lymph nodes. pN1c is integrated into the UICC (International Union Against Cancer) staging system and shifts previous stage II cancers (6th edition) to stage III. We investigated the frequency of upstaging and TD prognostic significance. METHODS: 414 CRCs, consecutively collected during a population-based epidemiological study, TNM classified and UICC staged according to the 6th TNM edition were reinvestigated for TD presence. The association with survival was investigated after a median follow-up time of 5years in multivariate analyses among nodal negative and positive cases. RESULTS: TDs were found in 103 (24.9%) cancers and were strongly associated with T-, N- and M-stages (p<0.0001, each). Upstaging of previous stage II cancers by the presence of TDs (pN1c) was found in six of 140 cases (4.3% of stage II, 1.4% of all tumours). For stage III CRC, strongly reduced overall, CRC-specific and recurrence-free survival were observed with the presence of TDs (hazard ratios (HR) 2.29, 95% confidence interval 1.27-4.10, HR 2.51, 1.27-4.98, and HR 2.43, 1.32-4.48, respectively). CONCLUSIONS: Upstaging of CRCs through the introduction of pN1c occurs in less than 5% of previous stage II and less than 2% of all cancers. Given the biologic relevance of TDs, integration into the UICC staging relevant N-category is justified. The high prognostic impact of TDs, however, is not reflected in nodal positive cancers in both the TNM and UICC staging systems. PMID- 25281527 TI - Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I non-small-cell lung cancer in patients at high risk for lobectomy: A propensity score matching analysis. AB - BACKGROUND: The aim of this study was to perform a survival comparison between stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small-cell lung cancer (NSCLC) at high risk for lobectomy. METHODS: All patients who underwent SBRT or SLR because of medical comorbidities for clinical stage I NSCLC were reviewed retrospectively. Propensity score matching (PSM) was performed to reduce selection bias between SLR and SBRT patients based on age, gender, performance status, tumour diameter, forced expiratory volume in 1 second (FEV1) and Charlson comorbidity index (CCI). RESULTS: One hundred and fifteen patients who underwent SBRT and 65 SLR were enrolled. The median potential follow-up periods for SBRT and SLR were 6.7 and 5.3 years, respectively. No treatment-related deaths were observed. Before PSM, the 5-year overall survival (OS) was 40.3% and 60.5% for SBRT and SLR, respectively (P=0.008). PSM identified 53 patients from each treatment group with similar characteristics: a median age of 76 years, a performance status of 0-1, a median tumour diameter of ~20 mm, a median FEV1 of ~1.8L and a median CCI of 1. The difference in OS became insignificant between the matched pairs (40.4% and 55.6% at 5 years with SBRT and SLR; P=0.124). The cumulative incidence of cause specific death was comparable between groups (35.3% and 30.3% at 5 years, P=0.427). CONCLUSION: SBRT can be an alternative treatment option to SLR for patients who cannot tolerate lobectomy because of medical comorbidities. PMID- 25281529 TI - Sales of antibiotics for veterinary use in Portugal between 2006 and 2009. PMID- 25281528 TI - Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation. AB - Albuminuria is not only an important marker of chronic kidney disease but also a crucial contributor to tubulointerstitial inflammation (TIF). In this study, we determined whether activation of the Nlrp3 inflammasome is involved in albuminuria induced-TIF and the underlying mechanisms of inflammasome activation by mitochondrial reactive oxygen species (mROS). We established an albumin overload induced rat nephropathy model characterised by albuminuria, renal infiltration of inflammatory cells, tubular dilation and atrophy. The renal expression levels of the Nlrp3 inflammasome, IL-1beta and IL-18 were significantly increased in this animal model. In vitro, albumin time- and dose dependently increased the expression levels of the Nlrp3 inflammasome, IL-1beta and IL18. Moreover, the silencing of the Nlrp3 gene or the use of the caspase-1 inhibitor Z-VAD-fmk significantly attenuated the albumin-induced increase in IL 1beta and IL-18 expression in HK2 cells. In addition, mROS generation was elevated by albumin stimulation, whereas the ROS scavenger N-acetyl-l-cysteine (NAC) inhibited Nlrp3 expression and the release of IL-1beta and IL-18. In kidney biopsy specimens obtained from patients with IgA nephropathy, Nlrp3 expression was localised to the proximal tubular epithelial cells, and this result is closely correlated with the extent of proteinuria and TIF. In summary, this study demonstrates that albuminuria may serve as an endogenous danger-associated molecular pattern (DAMP) that stimulates TIF via the mROS-mediated activation of the cytoplasmic Nlrp3 inflammasome. PMID- 25281530 TI - Time to treatment in patients of suspected acute coronary syndrome in Pakistan: a clinical audit. AB - OBJECTIVE: Evaluate time to treatment (TT) in suspected acute coronary syndrome (ACS) patients in the Emergency Department (ED) in Pakistan. METHODS: In this clinical audit, medical records of adult patients with suspicion of ACS visiting the ED of a tertiary care facility in Karachi from January to March of 2012 were reviewed and evaluated according to benchmarks from American College of Cardiology/American Heart Association guidelines. RESULTS: Study included 230 patients, of which 62.6% were males (n = 144). Physicians saw most patients (74.1%) in <=10 min (min) of ED triage. ECG was performed in <=10 min in 93 (47.7%) patients. Of the 207 patients being prescribed Aspirin, 41.9% received it in <=10 min. Of 155 patients who were prescribed anti-coagulants (e.g., heparin), 32.9% received them in 10 min. Half of the patients requiring primary coronary intervention underwent the procedure within 90 min. CONCLUSION: Findings warrant exploring interventions to improve TT for ACS care in resource-limited settings. PMID- 25281531 TI - Hypercholesterolemia and its associated risk factors-Kingdom of Saudi Arabia, 2013. AB - PURPOSE: To assess the prevalence of hypercholesterolemia and its associated factors in the Kingdom of Saudi Arabia. METHODS: A national multistage representative sample of Saudis aged 15 years or older was surveyed through face to-face interviews. Data on sociodemographics, risk factors, and health information were collected, and blood sample analysis was performed. Data were analyzed using SAS 9.3 to account for the sample weights and complex survey design. RESULTS: Between April and June 2013, a total of 10,735 participants completed the survey. Overall, 8.5% of Saudis had hypercholesterolemia. Another 19.6% had borderline hypercholesterolemia. Among hypercholesterolemic Saudis, 65.1% were undiagnosed, 2.3% were treated uncontrolled, 28.3% were treated controlled, and 4.3% were untreated. The risk of being hypercholesterolemic increased with age and among individuals who reported consuming margarine, obese individuals, and those who have been previously diagnosed with hypertension or diabetes. CONCLUSIONS: More than a million Saudis have hypercholesterolemia, and 700,000 of them are unaware of their condition which can be controlled through early detection campaigns and lifestyle change and medication. An urgent awareness and screening campaign is needed in Kingdom of Saudi Arabia to prevent and avoid disease progression toward more serious stages. PMID- 25281532 TI - Clinical outcomes after infrainguinal bypass grafting for critical limb ischaemia in patients with dialysis-dependent end-stage renal failure. AB - OBJECTIVE: To assess and risk-stratify the medium-term clinical outcomes after infrainguinal bypass grafting (IBG) to treat critical limb ischaemia (CLI) in patients with end-stage renal disease. METHODS: This was a retrospective single centre study. Between April 2007 and March 2011, 112 limbs from 89 patients were studied. In particular, amputation-free survival (AFS), 30 day mortality, freedom from major adverse limb events (MALE), limb salvage, and overall survival were examined. The aim was to identify outcome predictors. RESULTS: Eight patients (9%) died within 30 days of IBG. The only positive predictor of 30-day mortality was an ejection fraction (EF) < 40% (hazard ratio [HR] 5.57, 95% confidence interval [CI] 1.16-26.83; p = .03). The mean follow-up duration was 14 months. The 1- and 2-year AFS rates were 64% and 43%, respectively, and the rates of freedom from MALE were 81% and 77%, respectively. In addition, the 1- and 2-year limb salvage rates were 89% and 85%, and the survival rates were 68% and 50%, respectively. Non-ambulatory status was negatively associated with AFS (HR 3.04, 95% CI 1.59-5.82; p < .01), freedom from MALE (HR 4.98, 95% CI 1.91-12.96; p < .01), and limb salvage (HR 5.18, 95% CI 1.47-18.30; p = .01). The other negative predictors of overall survival were a serum albumin level <3.0 g/dL (HR 2.26, 95% CI 1.12-4.58; p = .02) and an EF <40% (HR 2.24, 95% CI 1.05-4.79; p = .04). CONCLUSION: Patients with CLI on dialysis enjoyed satisfactory freedom from MALE and limb salvage, but survival and AFS were significantly less than reported for IBG in patients with CLI who did not receive dialysis. In addition, patients with an EF <40%, lower serum albumin (<3.0 g/dL), or non-ambulatory status experienced particularly poor clinical outcomes after IBG. PMID- 25281533 TI - Re. 'Benefits of remote ischemic preconditioning in vascular surgery'. PMID- 25281534 TI - Design of non-aggregating variants of Abeta peptide. AB - Self association of the amyloid-beta (Abeta42) peptide into oligomers, high molecular weight forms, fibrils and ultimately neuritic plaques, has been correlated with progressive cognitive decline in Alzheimer's disease. Thus, insights into the drivers of the aggregation pathway have the capacity to significantly contribute to our understanding of disease mechanism. Functional assays and a three-dimensional crystal structure of the P3 amyloidogenic region 18-41 of Abeta were used to identify residues important in self-association and to design novel non-aggregating variants of the peptide. Biophysical studies (gel filtration, SDS-PAGE, dynamic light scattering, thioflavin T assay, and electron microscopy) demonstrate that in contrast to wild type Abeta these targeted mutations lose the ability to self-associate. Loss of aggregation also correlates with reduced neuronal toxicity. Our results highlight residues and regions of the Abeta peptide important for future targeting agents aimed at the amelioration of Alzheimer's disease. PMID- 25281535 TI - The Arf GTPase-activating protein SMAP1 promotes transferrin receptor endocytosis and interacts with SMAP2. AB - Arf GTPase-activating proteins (Arf GAP) play important roles in the formation of the membrane vesicles that traffic between subcellular membranous organelles. The small Arf GTPase-activating protein (SMAP) subfamily of Arf GAPs has two members, SMAP1 and SMAP2, in mammals. The present study investigated whether these two proteins may have an overlapping function in addition to their previously reported distinct functions. Results showed that the presence of either SMAP1 or SMAP2 was sufficient for endocytosis of the transferrin receptor, and that transferrin incorporation was impaired only by the absence of both SMAP1 and SMAP2. This suggests the involvement of both SMAP1 and SMAP2 in transferrin endocytosis. Results also demonstrated a physical association between SMAP1 and SMAP2, which might serve as a basis for a functional interaction, and identified the intramolecular domains responsible for this association. PMID- 25281536 TI - The human mitotic kinesin KIF18A binds protein phosphatase 1 (PP1) through a highly conserved docking motif. AB - Protein phosphatase 1 (PP1), a serine/threonine protein phosphatase, controls diverse key cellular events. PP1 catalytic subunits form complexes with a variety of interacting proteins that control its ability to dephosphorylate substrates. Here we show that the human mitotic kinesin-8, KIF18A, directly interacts with PP1gamma through a conserved RVxF motif. Our phylogenetic analyses of the kinesins further uncovered the broad conservation of this interaction potential within the otherwise highly diverse motor-protein superfamily. This suggests an ancestral origin of PP1 recruitment to KIF18A and a strategic role in human mitotic cells. PMID- 25281537 TI - Implications of caspase-dependent proteolytic cleavage of cyclin A1 in DNA damage induced cell death. AB - Cyclin A1 is an A-type cyclin that directly binds to CDK2 to regulate cell-cycle progression. In the present study, we found that doxorubicin decreased the expression of cyclin A1 at the protein level in A549 lung cancer cells, while markedly downregulating its mRNA levels. Interestingly, doxorubicin upregulated caspase-1 in a concentration-dependent manner, and z-YAVD-fmk, a specific inhibitor of caspase-1, reversed the doxorubicin-induced decrease in cyclin A1 in A549 lung cancer and MCF7 breast cancer cells. Active caspase-1 effectively cleaved cyclin A1 at D165 into two fragments, which in vitro cleavage assays showed were further cleaved by caspase-3. Finally, we found that overexpression of cyclin A1 significantly reduced the cytotoxicity of doxorubicin, and knockdown of cyclin A1 by RNA interference enhanced the sensitivity of cells to ionizing radiation. Our data suggest a new mechanism for the downregulation of cyclin A1 by DNA-damaging stimuli that could be intimately involved in the cell death induced by DNA damage-inducing stimuli, including doxorubicin and ionizing radiation. PMID- 25281538 TI - A farewell to didanosine: harm reduction and cost savings by eliminating use of didanosine. AB - Didanosine (ddI) is a nucleoside reverse transcriptase inhibitor associated with adverse events and public health concerns which have diminished its place in HIV clinical practice, particularly in resource-rich settings. While international guidelines do not contain ddI-containing regimens in preferred first- or second line antiretroviral therapy (ART), there is no guidance for management of patients currently on ddI. In 2012 at least 20 countries purchased a total of $1 2 million of ddI. Drug purchase data in that year show 3.2-10.3 times higher costs for ddI compared to lamivudine (3TC). Given issues of multiple toxicities, monitoring, drug interactions, inconvenience, and virologic efficacy, as well as cost and formulary concerns, national (including resource-limited setting) ART programmes should consider complete phase-out of ddI. PMID- 25281539 TI - Three different patterns of CD4 recovery in a cohort of Chinese HIV patients following antiretroviral therapy - a five-year observational study. AB - To explore the heterogeneity of CD4 responses following highly active antiretroviral therapy, the patterns of CD4 recovery of HIV-1-infected Chinese patients who have been on their first antiretroviral regimen for >=5 years were analysed. The CD4 trajectories were traced, smoothed and differentiated into three defined profiles. Half (56.3%) were 'satisfactory responders', with CD4 gain of >100 cells/MUL and a peak of >350 cells/MUL, plateauing before the end of Year 5. Thirty-three (24.4%) were 'continuing responders' whose CD4 rise persisted at Year 4-5. The remaining 26 (19.3%) were 'poor responders'. Presentation with AIDS before therapy was common not just among 'poor' but also paradoxically the 'continuing' responders. While a majority had responded well to antiretroviral therapy, older patients and those with AIDS diagnosis before initiation of therapy may never achieve a satisfactory level even with effective treatment. Categorization of HIV patients by their CD4 trajectory may support the prediction of immunological outcome over time, and ultimately inform treatment choices. PMID- 25281540 TI - Glycaemic profile changes by highly active antiretroviral therapy in human immunodeficiency virus-infected patients. AB - To study dysglycaemia in human immunodeficiency virus (HIV)-infected patients we conducted a retrospective cohort study of the glucose profile in HIV-infected patients. The fasting blood glucose was analysed taking into consideration conventional risk factors as well as HIV infection and highly active antiretroviral therapy (HAART). One hundred seventy-three cases were selected for this study. Five risk factors had significant effects (p < 0.05) on glucose levels: age, body mass index (BMI), hepatitis C virus/hepatitis B virus (HCV/HBV) co-infection, viral load (VL), and CD4(+) T-lymphocyte count. Fasting blood glucose levels increased with age (0.59 mg/dL/year), decreased with the VL (-4.1 * 10(-6 )mg/dL/number of viral RNA copies) and the CD4(+) T-lymphocyte count ( 0.016 mg/dL/cell count). Furthermore, obese patients and those co-infected with HCV/HBV were more prone to develop dysglycaemia having, on average, 15.4 mg/dL and 13.8 mg/dL higher levels, respectively, of fasting blood glucose. Despite an increase of 1.0% and 8.4% in the glucose levels noticed among HIV patients treated with non-nucleotide inhibitors of reverse transcriptase and protease inhibitors, respectively, HAART did not prove to be a significant predictor of fasting glucose levels as well as lipodystrophy and male gender. Age, BMI, HCV/HBV co-infection and HIV-related (VL and CD4(+) T-lymphocyte count) factors seem to be the most influential on fasting blood glucose levels in HIV-infected individuals. PMID- 25281541 TI - Cell physiology of the biotechnological relevant bacterium Bacillus pumilus-an omics-based approach. AB - Members of the species Bacillus pumilus get more and more in focus of the biotechnological industry as potential new production strains. Based on exoproteome analysis, B. pumilus strain Jo2, possessing a high secretion capability, was chosen for an omics-based investigation. The proteome and metabolome of B. pumilus cells growing either in minimal or complex medium was analyzed. In total, 1542 proteins were identified in growing B. pumilus cells, among them 1182 cytosolic proteins, 297 membrane and lipoproteins and 63 secreted proteins. This accounts for about 43% of the 3616 proteins encoded in the B. pumilus Jo2 genome sequence. By using GC-MS, IP-LC/MS and H NMR methods numerous metabolites were analyzed and assigned to reconstructed metabolic pathways. In the genome sequence a functional secretion system including the components of the Sec- and Tat-secretion machinery was found. Analysis of the exoproteome revealed secretion of about 70 proteins with predicted secretion signals. In addition, selected production-relevant genome features such as restriction modification systems and NRPS clusters of B. pumilus Jo2 are discussed. PMID- 25281542 TI - The right ventricle following prolonged endurance exercise: are we overlooking the more important side of the heart? A meta-analysis. AB - AIMS: Prolonged endurance exercise is associated with elevated biomarkers associated with myocardial damage and modest evidence of left ventricular (LV) dysfunction. Recent studies have reported more profound effects on right ventricular (RV) function following endurance exercise. We performed a meta analysis of studies reporting RV function pre-endurance and postendurance exercise. METHODS: We performed a search of peer-reviewed studies with the criteria for inclusion in the analysis being (1) healthy adult participants; (2) studies examining RV function following an event of at least 90 min duration; (3) studies reporting RV fractional area change (RVFAC), RV strain (S), RV ejection fraction (RVEF) or tricuspid annular plane systolic excursion (TAPSE) and (4) studies evaluating RV function immediately (<1 h) following exercise. RESULTS: Fourteen studies were included with 329 participants. A random-effects meta analysis revealed significant impairments of RV function when assessed by RVFAC (weighted mean difference (WMD) -5.78%, 95% CI -7.09% to -4.46%), S (WMD 3.71%, 95% CI 2.79% to 4.63%), RVEF (WMD -7.05%, 95% CI -12.3% to -1.8%) and TAPSE (WMD 4.77 mm, 95% CI -8.3 to -1.24 mm). Modest RV dilation was evident in studies reporting RV systolic area postexercise (WMD 1.79 cm(2), 95% CI 0.5 to 3.08 cm(2)). In contrast, no postexercise changes in LV systolic function (expressed as LVFAC or LVEF) were observed in the included studies (standardised mean difference 0.03%, 95% CI -0.13% to 0.18%). CONCLUSIONS: Intense prolonged exercise is associated with a measurable reduction in RV function while LV function is relatively unaffected. Future studies should examine the potential clinical consequences of repeated prolonged endurance exercise on the right ventricle. PMID- 25281543 TI - Solution hybrid selection capture for the recovery of functional full-length eukaryotic cDNAs from complex environmental samples. AB - Eukaryotic microbial communities play key functional roles in soil biology and potentially represent a rich source of natural products including biocatalysts. Culture-independent molecular methods are powerful tools to isolate functional genes from uncultured microorganisms. However, none of the methods used in environmental genomics allow for a rapid isolation of numerous functional genes from eukaryotic microbial communities. We developed an original adaptation of the solution hybrid selection (SHS) for an efficient recovery of functional complementary DNAs (cDNAs) synthesized from soil-extracted polyadenylated mRNAs. This protocol was tested on the Glycoside Hydrolase 11 gene family encoding endo xylanases for which we designed 35 explorative 31-mers capture probes. SHS was implemented on four soil eukaryotic cDNA pools. After two successive rounds of capture, >90% of the resulting cDNAs were GH11 sequences, of which 70% (38 among 53 sequenced genes) were full length. Between 1.5 and 25% of the cloned captured sequences were expressed in Saccharomyces cerevisiae. Sequencing of polymerase chain reaction-amplified GH11 gene fragments from the captured sequences highlighted hundreds of phylogenetically diverse sequences that were not yet described, in public databases. This protocol offers the possibility of performing exhaustive exploration of eukaryotic gene families within microbial communities thriving in any type of environment. PMID- 25281545 TI - The effect on emotions and brain activity by the direct/indirect lighting in the residential environment. AB - This study was performed to explore how direct/indirect lighting affects emotions and brain oscillations compared to the direct lighting when brightness and color temperature are controlled. Twenty-eight subjects (12 females; mean age 22.5) participated. The experimental conditions consisted of two lighting environments: direct/indirect lighting (400 lx downlight, 300 lx uplight) and direct lighting (700 lx downlight). On each trial, a luminance environment was presented for 4 min, followed by participants rated their emotional feelings of the lighting environment. EEG data were recorded during the experiment. Spectral analysis was performed for the range of delta, theta, alpha, beta, and gamma ranges. The participants felt cooler and more pleasant and theta oscillations on the F4, F8, T4, and TP7 electrodes were more enhanced in the direct/indirect lighting environment compared to the direct lighting environment. There was significant correlation between the "cool" rating and the theta power of the F8 electrode. The participants felt more pleasant in the direct/indirect lighting environment, indicating that space with direct/indirect lighting modulated subjective perception. Additionally, our results suggest that theta oscillatory activity can be used as a biological marker that reflects emotional status in different lighting environments. PMID- 25281544 TI - Genomic analysis reveals distinct concentration-dependent evolutionary trajectories for antibiotic resistance in Escherichia coli. AB - Evolution of bacteria under sublethal concentrations of antibiotics represents a trade-off between growth and resistance to the antibiotic. To understand this trade-off, we performed in vitro evolution of laboratory Escherichia coli under sublethal concentrations of the aminoglycoside kanamycin over short time durations. We report that fixation of less costly kanamycin-resistant mutants occurred earlier in populations growing at lower sublethal concentration of the antibiotic, compared with those growing at higher sublethal concentrations; in the latter, resistant mutants with a significant growth defect persisted longer. Using deep sequencing, we identified kanamycin resistance-conferring mutations, which were costly or not in terms of growth in the absence of the antibiotic. Multiple mutations in the C-terminal end of domain IV of the translation elongation factor EF-G provided low-cost resistance to kanamycin. Despite targeting the same or adjacent residues of the protein, these mutants differed from each other in the levels of resistance they provided. Analysis of one of these mutations showed that it has little defect in growth or in synthesis of green fluorescent protein (GFP) from an inducible plasmid in the absence of the antibiotic. A second class of mutations, recovered only during evolution in higher sublethal concentrations of the antibiotic, deleted the C-terminal end of the ATP synthase shaft. This mutation confers basal-level resistance to kanamycin while showing a strong growth defect in the absence of the antibiotic. In conclusion, the early dynamics of the development of resistance to an aminoglycoside antibiotic is dependent on the levels of stress (concentration) imposed by the antibiotic, with the evolution of less costly variants only a matter of time. PMID- 25281546 TI - ID1201, the ethanolic extract of the fruit of Melia toosendan ameliorates impairments in spatial learning and reduces levels of amyloid beta in 5XFAD mice. AB - A previous study has demonstrated the anti-amyloidogenic effects of the ethanolic extract of Meliae Fructus (ID1201) using cell lines with stably expressed human Swedish mutant APP695 and beta-secretase 1, and 5Xfamilial AD (FAD) mice carrying five mutations. Here, we investigated the effects of ID1201 on cognitive impairment in 5XFAD mice. Daily administration of ID1201 was commenced at 3 months of age and continued for 3 months. Mice were serially trained in cued/response and place/spatial training tasks in the Morris water maze. After this training, testing for strategy preference was conducted. Non-transgenic control mice with vehicle treatment, vehicle-treated 5XFAD, and ID1201-treated 5XFAD mice showed equivalent performance in cued/response training. However, as training progressed to the subsequent place/spatial learning, vehicle-treated control and ID1201-treated 5XFAD mice differed significantly from vehicle-treated 5XFAD mice in measures of spatial learning (search error and adaptive spatial learning strategy). In the strategy preference test that followed, control mice preferred a place/spatial strategy relative to vehicle-treated 5XFAD mice, but differences between ID1201-treated 5XFAD mice and vehicle-treated 5XFAD mice were not significant. Additionally, ID1201 treatment reduced hippocampal levels of insoluble Abeta42 and increased cortical levels of soluble amyloid precursor protein alpha. These results indicate that ID1201 may possess potential as a therapeutic agent for Alzheimer's disease by decreasing Abeta deposits. PMID- 25281547 TI - A patient-specific measurement technique to model shoulder joint kinematics. AB - BACKGROUND: Measuring dynamic in vivo shoulder kinematics is crucial to better understanding numerous pathologies. Motion capture systems using skin-mounted markers offer good solutions for non-invasive assessment of shoulder kinematics during dynamic movement. However, none of the current motion capture techniques have been used to study translation values at the joint, which is crucial to assess shoulder instability. The aim of the present study was to develop a dedicated patient-specific measurement technique based on motion capture and magnetic resonance imaging (MRI) to determine shoulder kinematics accurately. HYPOTHESIS: Estimation of both rotations and translations at the shoulder joint using motion capture is feasible thanks to a patient-specific kinematic chain of the shoulder complex reconstructed from MRI data. MATERIALS AND METHODS: We implemented a patient-specific kinematic chain model of the shoulder complex with loose constraints on joint translation. To assess the effectiveness of the technique, six subjects underwent data acquisition simultaneously with fluoroscopy and motion capture during flexion and empty-can abduction. The reference 3D shoulder kinematics was reconstructed from fluoroscopy and compared to that obtained from the new technique using skin markers. RESULTS: Root mean square errors (RMSE) for shoulder orientation were within 4 degrees (mean range: 2.0 degrees -3.4 degrees ) for each anatomical axis and each motion. For glenohumeral translations, maximum RMSE for flexion was 3.7mm and 3.5mm for empty can abduction (mean range: 1.9-3.3mm). Although the translation errors were significant, the computed patterns of humeral translation showed good agreement with published data. DISCUSSION: To our knowledge, this study is the first attempt to calculate both rotations and translations at the shoulder joint based on skin-mounted markers. Results were encouraging and can serve as reference for future developments. The proposed technique could provide valuable kinematic data for the study of shoulder pathologies. LEVEL OF EVIDENCE: Basic Science Study. PMID- 25281548 TI - Advantages and limitations of endoscopic endonasal odontoidectomy. A series of nine cases. AB - INTRODUCTION: Transoral odontoidectomy is the treatment of choice in cases of anterior bulbo-medullary compression. The development of endoscopic procedures has made it possible to perform odontoidectomy via a minimally invasive endoscopic endonasal approach. We discuss the feasibility, advantages, and limitations of this surgical approach. MATERIALS AND METHODS: We report a two center retrospective series of patients who underwent endoscopic endonasal odontoidectomy between September 2011 and February 2013. Preoperative characteristics, intraoperative data, clinical course, and postoperative complications were studied. The patients were followed for a minimum of 6 months. Cervico-occipital posterior fusion was performed during the same hospital stay in cases of preoperative instability. RESULTS: Nine patients underwent decompressive odontoidectomy, for rheumatoid pannus in five cases and basilar impression in four cases. All had progressive neurological symptoms. Seven patients also underwent posterior fusion. In six patients, the C1 anterior arch was preserved. Decompression was achieved satisfactorily in all nine cases. The patients were able to resume oral feeding the day after the intervention. No patient required tracheostomy. We observed no dural fistulae or infectious complications. One patient died 2 months after the intervention of a pulmonary embolism. All patients improved in terms of their preoperative neurological status. CONCLUSION: This short series shows the feasibility of the endoscopic endonasal approach for resection of the dens. This approach allows optimal viewing when using angulated instrumentation and seems to result in low morbidity. In some cases, this approach makes it possible to preserve the C1 anterior arch, thus limiting the risk of cranial settling. LEVEL: IV retrospective study. PMID- 25281549 TI - Does cross-linked polyethylene decrease the revision rate of total hip arthroplasty compared with conventional polyethylene? A meta-analysis. AB - BACKGROUND: Although cross-linked polyethylene is resistant to wear in comparison to conventional polyethylene, it remains unknown whether it can decrease the wear related revision rate of total hip arthroplasty. OBJECTIVES: To determine whether cross-linked polyethylene decreases the wear-related revision rate of total hip arthroplasty compared with conventional polyethylene. DATA SOURCES: Electronic databases, including PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, were queried from inception to July 6, 2013. STUDY SELECTION: Randomized controlled trials (RCTs) comparing cross-linked polyethylene with conventional polyethylene were included. In addition, the standard 28-mm femoral head was used, and follow-up was performed for a minimum of 5 years. The primary outcome assessed was wear-related revision. The secondary outcome measures evaluated were the incidence of osteolysis, the linear wear rate, and the linear head penetration. DATA SYNTHESIS: The Cochrane Collaboration's tool for assessing the risk of bias was used for quality assessment. Data from eligible studies were pooled using a random effects model. RESULTS: Eight studies involving 735 patients were included in this study. Meta-analysis showed there was no significant difference between cross-linked and conventional polyethylene group in terms of osteolysis or wear-related revision. The pooled mean differences were significantly less for the linear wear rate and linear head penetration for cross linked polyethylene than for conventional polyethylene. LIMITATIONS: The studies differed with respect to the cross-linked liner brands, manufacturing processes, and radiological evaluation methods. Moreover, the follow-up periods of the RCTs were not long enough. CONCLUSIONS: The current limited evidence suggests that cross-linked polyethylene significantly reduced the radiological wear compared with conventional polyethylene at midterm follow-up periods. However, there is no evidence that cross-linked polyethylene had an advantage over conventional polyethylene in terms of reducing osteolysis or wear-related revision. Nevertheless, future long-term RCTs on this topic are needed. KEY FINDINGS: Cross linked polyethylene significantly reduced radiological wear but not osteolysis or wear-related revision in comparison to conventional polyethylene at midterm follow-up periods. LEVEL OF EVIDENCE: Level I, systematic review of level I studies. PMID- 25281550 TI - Topical intrawound application of vancomycin powder in addition to intravenous administration of antibiotics: A meta-analysis on the deep infection after spinal surgeries. AB - BACKGROUND: The intrawound application of vancomycin powder in addition to intravenous administration of antibiotics has been reported to be an easy and cost-efficient technique for reducing the deep infection, which is a serious complication of spinal surgeries. The aim of the present meta-analysis was to derive a preliminary estimation on the clinical performance of this technique. HYPOTHESIS: The intrawound application of vancomycin powder in addition to intravenous administration of antibiotics may significantly reduce the risk of deep infection after spinal surgeries. MATERIALS AND METHODS: Studies were identified from PubMed and EMBASE searches. After comprehensive review, data were extracted from eligible studies. A meta-analysis was performed to generate pooled odds ratio (OR) of this technique. RESULTS: Eight studies (4592 patients) were included. The pooled OR (95% CI) was 0.22 (0.07-0.63). I(2) value was 65.2% (P=0.005). The pooled ORs were stable in sensitivity analyses. No analysis of subgroup, meta-regression or publication bias was performed because of inadequate included studies. DISCUSSION: The intrawound application of vancomycin powder in addition to intravenous administration of antibiotics may significantly reduce the risk of deep infection after spinal surgeries. Further studies with large sample size and high quality are needed to provide more evidences. LEVEL OF EVIDENCE: II. PMID- 25281551 TI - Does prior conservative surgery affect survivorship and functional outcome in total hip arthroplasty for congenital dislocation of the hip? A case-control study in 159 hips. AB - INTRODUCTION: The results of total hip arthroplasty (THA) in congenital dislocation of the hip (CDH) are well known, but such is not the case for the impact of prior conservative surgery on THA function and survivorship. The present study compared THA in CDH with prior conservative bone surgery (BS group) versus no prior bone surgery (NBS group), to (1) assess the impact of prior conservative surgery on function and survivorship after THA, and (2) determine whether a particular type of conservative surgery affected function or survivorship. HYPOTHESIS: Prior conservative surgery for CDH does not affect function or survivorship of subsequent THA. PATIENTS AND METHODS: A multicenter retrospective case-control study analyzed 430 THAs in CDH patients (332 patients: 269 female, 63 male; mean age, 56 years [range, 17-80 years]) at a mean 13.2+/ 5.4 years' follow-up (range, 1-29 years). The BS group included 159 hips (37%) (64 pelvic, 81 femoral and 14 combined pelvic and femoral osteotomies), and the NBS group 271 (63%). Groups were comparable for gender, age at surgery, Devane activity score, preoperative Postel Merle d'Aubigne (PMA) functional score and CDH radiographic type following Crowe. RESULTS: At follow-up, PMA scores were comparable: BS, 16.8+/-1.4 (11-18); NBS, 16.9+/-1.5 (7-18). Fifteen-year survivorship censored for implant revision for whatever reason did not significantly differ: BS, 87% (95% CI: 83-91%); NBS, 89% (95% CI: 86-92%). Ten year survivorship on the same criterion did not significantly differ according to type of prior surgery: hip shelf arthroplasty, 97% (95% CI: 95-99%); Chiari osteotomy, 100%; femoral osteotomy, 95% (95% CI: 92-98%); and Milch osteotomy 96% (95% CI: 93-99%). DISCUSSION/CONCLUSION: Conservative surgery for CDH does not impair the functional results or survivorship of subsequent THA. LEVEL OF EVIDENCE: III, case-control study. PMID- 25281552 TI - A new technique to avoid articular cartilage injury in anterior cruciate ligament reconstruction through far antero-medial portal. AB - Far antero-medial (FAM) portal technique is usually used in our department in anterior cruciate ligament (ACL) reconstruction when drilling the femoral tunnel. Although the FAM portal technique carries potential risks, such as cartilage injury of the lateral femoral condyle, peroneal nerve injury and blow out of the lateral femoral condyle's posterior wall, these problems were resolved in a cadaveric study, in which 110 degrees -120 degrees knee flexion was recommended when drilling the femoral tunnel. However, there is a potential risk of injuring the cartilage of the medial femoral condyle especially when drilling the postero lateral bundle. A new method is proposed to ensure that the femoral tunnel drilling does not damage the cartilage of the medial femoral condyle. PMID- 25281553 TI - Serial magnetic resonance imaging study of posterior cruciate ligament reconstruction or augmentation using hamstring tendons. AB - PURPOSE: The purpose of this study was to analyze serial changes in the magnetic resonance imaging (MRI) signals of autograft hamstrings single bundle posterior cruciate ligament (PCL) reconstruction and the effects of remnant preservation (augmentation). MATERIAL AND METHODS: Twenty-two isolated PCL injuries were arthroscopically reconstructed or augmented with hamstring tendons. MRI scans were obtained at 3, 6, and 12 months, and prior to the second-look arthroscopy (average 20.7 months). The patients were divided into 2 groups by remnant preservation: five PCL reconstructions after PCL remnant resection (Group Rec) (23%), and 17 reconstructions preserving the remnant (Group Aug) (77%). The 22 patients were also divided in two groups depending on the location of the PCL tear. There were 9 knees with proximal tear (Type P) (41%) and 13 knees with distal tear (Type D) (59%). The signal intensity and fiber continuity of 4 zones (proximal, middle, distal intra-articular and tibial tunnel zones) were evaluated by the Mariani score. RESULTS: The average MRI evaluation score gradually increased from 6 months through the final MRI. The intra-articular part of the graft exhibited slower maturation (12 months - final scan) as compared with the tibial tunnel (6-12 months). The distal zone underwent better maturation than the proximal or middle zones at all points. In the proximal zone, the score for Group Aug was significantly higher than Group Rec. In the proximal zone, the Type D score with a proximally-preserved remnant was significantly higher than Type P without a proximal remnant. CONCLUSIONS: The hamstring tendons require more than 1 year to achieve low-signal intensity. PCL remnant has a beneficial effect on the maturation of the hamstring graft. LEVEL OF EVIDENCE IV: therapeutic case series. PMID- 25281554 TI - Does partial tear repair of adjacent tendons improve the outcome of supraspinatus tendonfull-thickness tear reinsertion? AB - BACKGROUND: Partial tearing of the infraspinatus and/or subscapularis tendon(s) is frequently associated with supraspinatus full-thickness tears. However, limited data regarding its influence on supraspinatus surgical repair is available. PURPOSE: Our aim was to assess the functional and anatomical outcomes of open repair of supraspinatus full-thickness tears combined with adjacent partial tearing, comparatively to a control. METHODS: We retrospectively identified 22 patients (22 shoulders) with a partial tear, most of them being a delamination tear, of the infraspinatus and/or subscapularis tendons associated with a complete detachment of the supraspinatus tendon. Twenty-seven patients (27 shoulders) treated for an isolated complete detachment of the supraspinatus tendon by open repair served as controls. The mean age was 58 years. A proximalized trans-osseous reinsertion of the supraspinatus tendon was combined with a curettage-closure of the delamination tear. Patients were evaluated with standardized MRI at last follow-up. RESULTS: At a mean of 75-month follow-up, the presence of a partial tear of either infraspinatus or subscapularis, or both, did not influence function and healing rates of supraspinatus tendon repair. Conversely to the control, when a retear occurred, the functional score tended to worsen. Preoperatively, fatty muscular degeneration was more pronounced when a partial tear was present. Fatty degeneration worsened regardless of repair healing. CONCLUSION: Open reinsertion of a supraspinatus full-thickness tear associated with a thorough treatment of partial tear of adjacent tendons led to optimal functional and anatomical mid term outcomes. Our results suggest the presence of a partial tear of adjacent tendons could be associated with poorer function in case of supraspinatus tendon re-rupture. LEVEL OF EVIDENCE: Level III case-control study. PMID- 25281555 TI - Management of neglected open extremity fractures in low-resource settings: Experience of the French Army Medical Service in Chad. AB - INTRODUCTION: The purpose of this study was to report the experience of the French Army Medical Service in the management of neglected open extremity fractures and related-complications in Chad. HYPOTHESIS: Delayed treatment of open extremity fractures is possible in a low-resource setting. METHODS: An observational prospective study was performed in a French Forward Surgical Team deployed in N'Djamena for six months. RESULTS: Twenty-seven patients, 24 men and three women, mean age 30 years old with an open fracture that was managed more than 24 hours after it occurred were included. The mean treatment delay was 83 days. Fractures were located in the tibia in 20 cases. There were 15 non-infected and twelve infected fractures. The number of cases of debridement, flap coverage, and the overall number of procedures were higher in the group with infection, but the difference was not significant. Treatment of infected fractures was complicated by six early recurrent infections, while there were no complications in the group without infection. The mean follow-up was 4.4 months. Infection was controlled in eleven cases, however evaluation of fracture healing was limited because of the short follow-up in the group with infection. Functional outcome of the lower extremities was often complicated by knee stiffness. DISCUSSION: Delayed management of open fractures depends on the available resources. In low resource settings, the goals of surgery should be modest. Treatment of non infected injuries and osteomyelitis is possible. On the other hand, treatment of infected fractures and septic nonunions should be undertaken with caution if all the necessary aspects of treatment, in particular extended antibiotic treatment and sequential procedures are not possible. LEVEL OF EVIDENCE: level IV. PMID- 25281556 TI - Outcomes of bipolar radial head prosthesis to treat complex radial head fractures in 22 patients with a mean follow-up of 50 months. AB - BACKGROUND: Radial head replacement is indicated to treat complex proximal radial fractures that are not amenable to internal fixation. HYPOTHESIS: Implantation of a bipolar radial head prosthesis after radial head excision ensures stability of the elbow and forearm, thereby promoting ligament healing and restoring elbow function. MATERIAL AND METHODS: Twenty-two patients managed with implantation of a bipolar radial head prosthesis (Guepar((r))) were evaluated after a mean follow up of 50 months. The procedure was performed in the acute setting in 16 patients, including 13 with associated injuries; and at the stage of sequelae in 6 patients. RESULTS: Prosthesis removal was required in 4 patients. Of the remaining 18 patients, 14 (77%) had satisfactory Mayo Elbow Performance Score values, 14 (77%) little or no functional impairment, and 11 (61%) little or no pain. Mean motion arcs were 100 degrees in flexion-extension and 143 degrees in pronation-supination. Mean elbow strength in flexion and mean wrist strength were 67% and 86%, respectively, of those on the contralateral normal side. Radio lucent lines were visible around the prosthesis in 5 patients, radial neck osteolysis in 10 patients, and capitellar erosion in 7 patients. Seven patients each experienced a complication. Early revision surgery to treat elbow instability was required in 6 patients. DISCUSSION: Outcomes after Guepar((r)) bipolar radial head prosthesis implantation were disappointing in patients with complex radial head fractures seen in the acute or chronic setting. The associated injuries to bones and ligaments and the measures taken to repair them influence the prognosis. The complication rate is non-negligible and seems to increase over time. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 25281557 TI - Role of cardiac multidetector computed tomography in the exclusion of ischemic etiology in heart failure patients. AB - INTRODUCTION AND AIMS: Differentiation of ischemic from non-ischemic etiology in heart failure (HF) patients has both therapeutic and prognostic implications. One possible approach to this differentiation is direct visualization of the coronary tree. Multidetector computed tomography (MDCT) has emerged as an alternative to invasive coronary angiography (ICA), but its performance and additional clinical value are still not well validated in patients with left ventricular (LV) dysfunction. We aimed to assess the value of coronary MDCT angiography (CTA) in the exclusion of ischemic etiology in HF patients and to determine whether the Agatston calcium score could be used as a gatekeeper for CTA in this context. METHODS: We retrospectively selected symptomatic HF patients with LV ejection fraction (LVEF) <50%, as assessed by echocardiography, referred for CTA between April 2006 and May 2013. Patients with previously known CAD or valvular disease were excluded. The performance of MDCT in the detection of coronary artery disease (CAD) and/or exclusion of an ischemic etiology for HF was studied. Obstructive CAD was defined as the presence of >=50% luminal stenosis in at least one epicardial coronary artery as assessed by CTA and was assumed in patients with an Agatston coronary artery calcium (CAC) score >400. In patients referred for ICA, an ischemic etiology was assumed in the presence of >=75% stenosis in two or more epicardial vessels or >=75% stenosis in the left main or proximal left anterior descending artery. RESULTS: During this period 100 patients (mean age 57.3+/-10.5 years, 64% men) with HF and systolic dysfunction were referred for MDCT to exclude CAD. Median effective radiation dose was 4.8 mSv (interquartile range 5.8 mSv). Mean LVEF was 35+/-7.7% (range 20-48%) and median CAC score was 13 (interquartile range 212). Seven patients were in atrial fibrillation. Almost half of the patients (40%) had no CAC and none of these had significant stenosis on CTA. In an additional group of 33 patients CTA was able to confidently exclude obstructive CAD. Twenty-seven patients were classified as positive for CAD (16 due to CAC >400 and 11 with >=50% stenosis) and were associated with lower LVEF (p=0.004). Of these, 21 patients subsequently underwent ICA: obstructive CAD was confirmed in nine and only six had criteria for ischemic cardiomyopathy. CONCLUSION: In our HF population, MDCT was able to exclude an ischemic etiology in 73% of cases in a single test. According to our results the Agatston calcium score may serve as a gatekeeper for CTA in patients with HF, with a calcium score of zero confidently excluding an ischemic etiology. PMID- 25281558 TI - Homopolymer tract organization in the human malarial parasite Plasmodium falciparum and related Apicomplexan parasites. AB - BACKGROUND: Homopolymeric tracts, particularly poly dA.dT, are enriched within the intergenic sequences of eukaryotic genomes where they appear to act as intrinsic regulators of nucleosome positioning. A previous study of the incomplete genome of the human malarial parasite Plasmodium falciparum reports a higher than expected enrichment of poly dA.dT tracts, far above that anticipated even in this highly AT rich genome. Here we report an analysis of the relative frequency, length and spatial arrangement of homopolymer tracts for the complete P. falciparum genome, extending this analysis to twelve additional genomes of Apicomplexan parasites important to human and animal health. In addition, using nucleosome-positioning data available for P. falciparum, we explore the correlation of poly dA.dT tracts with nucleosome-positioning data over key expression landmarks within intergenic regions. RESULTS: We describe three apparent lineage-specific patterns of homopolymeric tract organization within the intergenic regions of these Apicomplexan parasites. Moreover, a striking pattern of enrichment of overly long poly dA.dT tracts in the intergenic regions of Plasmodium spp. uniquely extends into protein coding sequences. There is a conserved spatial arrangement of poly dA.dT immediately flanking open reading frames and over predicted core promoter sites. These key landmarks are all relatively depleted in nucleosomes in P. falciparum, as would be expected for poly dA.dT acting as nucleosome exclusion sequences. CONCLUSIONS: Previous comparative studies of homopolymer tract organization emphasize evolutionary diversity; this is the first report of such an analysis within a single phylum. Our data provide insights into the evolution of homopolymeric tracts and the selective pressures at play in their maintenance and expansion. PMID- 25281559 TI - Hrr25 phosphorylates the autophagic receptor Atg34 to promote vacuolar transport of alpha-mannosidase under nitrogen starvation conditions. AB - In Saccharomyces cerevisiae, under nitrogen-starvation conditions, the alpha mannosidase Ams1 is recognized by the autophagic receptor Atg34 and transported into the vacuole, where it functions as an active enzyme. In this study, we identified Hrr25 as the kinase that phosphorylates Atg34 under these conditions. Hrr25-mediated phosphorylation does not affect the interaction of Atg34 with Ams1, but instead promotes Atg34 binding to the adaptor protein Atg11, which recruits the autophagy machinery to the Ams1-Atg34 complex, resulting in activation of the vacuolar transport of Ams1. Our findings reveal the regulatory mechanism of a biosynthetic pathway mediated by the autophagy machinery. PMID- 25281560 TI - Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. AB - Mapping protein-protein interactions for chromatin-associated proteins remains challenging. Here we explore the use of BioID, a proximity biotinylation approach in which a mutated biotin ligase (BirA*) is fused to a bait of interest, allowing for the local activation of biotin and subsequent biotinylation of proteins in the bait vicinity. BioID allowed for successful interactome mapping of core histones and members of the mediator complex. We explored the background signal produced by the BioID approach and found that using distinct types of controls increased the stringency of our statistical analysis with SAINTexpress. A direct comparison of BioID with our AP-MS protocol optimized for chromatin-associated protein complexes revealed that the approaches identified few shared interaction partners and enriched for distinct biological processes; yet, both approaches permitted the recovery of biologically meaningful interactions. While no clear bias could be observed for either technique toward protein complexes of particular functions, BioID allowed for the purification of proteins of lower cellular abundance. Finally, we were able to identify a strong association of MED4 with the centrosome by BioID and validated this finding by immunofluorescence. In summary, BioID complements AP-MS for the study of chromatin-associated protein complexes. BIOLOGICAL SIGNIFICANCE: This manuscript describes the application of BioID, a proximity biotinylation approach, to chromatin-associated proteins, namely core histones and members of the mediator complex. We observed that BioID was successful at identifying known interaction partners for the baits tested, but also allowed novel putative interaction partners to be identified. By performing a detailed comparison of BioID versus a standard method for interactome mapping (affinity purification coupled to mass spectrometry, AP-MS), we show that the approaches were complementary, allowing for purification of different interaction partners. These interaction partners were different in the biological processes they are associated with, but also in their abundance. BioID represents a significant technical development in the field of chromatin research by expanding the search space for interactome mapping beyond what is possible with AP-MS. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras. PMID- 25281561 TI - Up-regulation of fatty acid oxidation in the ligament as a contributing factor of ankylosing spondylitis: A comparative proteomic study. AB - OBJECTIVES: The present study first utilized a standardized shotgun proteomic analysis method to determine differences in protein expression of fibroblasts in the ligament between AS patients and healthy controls. METHODS: Proteins extracted from primarily cultured FLLs from 35 AS patients and 10 normal subjects were analyzed by automated 2D-Nano-LC-ESI-MS/MS. Differentially expressed proteins were screened by 2-sample t-test and fold change. Bioinformatics analysis of differentially expressed proteins was based on the IPA. Fatty acid beta-oxidation-related proteins and INSR pathway-related proteins in the ligament were confirmed by real-time PCR and Western blot. RESULTS: A total of 556 differential proteins were screened in AS. Of them, 322 proteins were up regulated and the remaining 234 proteins were down-regulated. GO and pathway analyses showed that six fatty acid beta-oxidation-related proteins (HADHB, ECHS1, ACSL4, ACADM, ACSL1 and HADH) were up-regulated in FLL cells, which was consistent with the results obtained from real-time PCR, Western blot and MS, while INSR pathway-related proteins (INSR, IRS1, PI3K and PKC) was low in the ligament of AS as compared with that in healthy controls. CONCLUSION: The lower body fat level in AS maybe due to up-regulation of fatty acid beta-oxidation related enzymes regulated by INSR/PI3K/PKC pathway. BIOLOGICAL SIGNIFICANCE: Ankylosing spondylitis (AS), a common spondyloarthropathy, is an inflammatory rheumatic disease with a predilection for the axial skeleton. Clinical hallmarks of AS include sacroiliitis, uveitis, enthesitis and persistent spinal inflammation. The pathogenic mechanism of disease causation and perpetuation remains poorly understood. In this study, we primarily cultured fibroblast cells from ligament biopsies, knowing that fibroblast cells are dominant cells in the diseased ligament. One of the characteristic pathologic changes in AS is inflammation of the attachment points, including the muscle, ligament and bone or joint capsule. Inflammation of the tendon attachment point is usually non bacterial and can lead to pain and swelling of the tendon ligament. To obtain more information, we used Shotgun proteomic analysis based on multidimensional liquid chromatography tandem mass spectrometry (LC-MS/MS). we firstly mixed the lysates of FLL cells derived from the ligaments of 35 AS patients and 10 normal subjects, identified proteins by automated 2D-Nano-LC-ESI-MS/MS method, GO and pathway analyses showed that six fatty acid beta-oxidation-related proteins (HADHB, ECHS1, ACSL4, ACADM, ACSL1 and HADH) were up-regulated in the ligament, which was consistent with the results obtained from real-time PCR, Western blot and MS, while INSR pathway-related proteins (INSR, IRS1, PI3K and PKC) was low in the ligament of AS as compared with that in healthy controls. We also find that AS subjects had significantly lower body mass index (BMI) and BMI Z-scores compared with that in healthy controls. The results remind us that up-regulation of fatty acid beta-oxidation-related proteins lower the body fat content, which is a new discovery contributing to the progression of AS. This is the first report on fatty acid oxidation in AS. It was found that the body fat level was low in AS due to high fatty acid oxidation, suggesting that insulin signaling may play an important role in the metabolic switch from predominant to fatty acid metabolism that characterizes the ligament of AS. One mechanism for this transition is increased expression of genes that regulate the rate of fatty acid oxidation. This effect may be mediated by PI3K, a downstream mediator of many receptor tyrosine kinases, including the INSR. This is a newly discovered factor contributing to the progression of AS. PMID- 25281562 TI - Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome. AB - Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss. PMID- 25281563 TI - Characterization of the promoter of Grapevine vein clearing virus. AB - Grapevine vein clearing virus (GVCV) is a recently discovered DNA virus in grapevine that is closely associated with the grapevine vein clearing syndrome observed in vineyards in Missouri and surrounding states. The genome sequence of GVCV indicates that it belongs to the genus Badnavirus in the family Caulimoviridae. To identify the GVCV promoter, we cloned portions of the GVCV large intergenic region in front of a GFP gene present in an Agrobacterium tumefaciens binary vector. GFP expression was assessed by ELISA 3 days after agroinfiltration of Nicotiana benthamiana leaves. We found that the GVCV DNA segment between nts 7332 and 7672 directed expression of GFP and this expression was stronger than expression using the Cauliflower mosaic virus 35S promoter. It was revealed by 5' and 3' RACE that transcription was initiated predominantly at nt 7571 and terminated at nt 7676. PMID- 25281564 TI - Temporal proteomic analysis and label-free quantification of viral proteins of an invertebrate iridovirus. AB - Invertebrate iridescent virus 6 (IIV-6) is a nucleocytoplasmic virus with a ~212 kb linear dsDNA genome that encodes 215 putative ORFs. The IIV-6 virion associated proteins consist of at least 54 virally encoded proteins. One of our previous findings showed that most of these proteins are encoded by genes from the early transcriptional class. This indicated that these structural proteins may not only function in the formation of the virion, but also in the initial stage of viral infection. In the current study, we followed the protein expression profile of IIV-6 over time in Drosophila S2 cells by label-free quantification using a proteomic approach. A total of 95 virally encoded proteins were detected in infected cells, of which 37 were virion proteins. The expressed IIV-6 virion proteins could be categorized into three main clusters based on their expression profiles: proteins with stably low expression levels during infection, proteins with exponentially increasing expression levels during infection and proteins that were initially highly abundant, but showed slightly reduced levels after 48 h post-infection. We thus provided novel information on the kinetics of virion and infected cell-specific protein levels that assists in our understanding of gene regulation in this lesser-known DNA virus model. PMID- 25281565 TI - HTLV-1 bZIP factor suppresses the centromere protein B (CENP-B)-mediated trimethylation of histone H3K9 through the abrogation of DNA-binding ability of CENP-B. AB - Human T-cell leukaemia virus type-1 (HTLV-1) infection causes adult T-cell leukaemia (ATL). The viral protein HTLV-1 bZIP factor (HBZ) is constitutively expressed in ATL cells, suggesting that HBZ plays a major role in the pathogenesis of HTLV-1-associated disease. Here, we identified centromere protein B (CENP-B) as a novel interacting partner of HBZ. HBZ and CENP-B associate with their central regions in cells. Furthermore, overexpression of HBZ abrogated the DNA-binding activity of CENP-B to the alpha-satellite DNA region containing the CENP-B box motif, which in turn inhibited the CENP-B-mediated trimethylation of histone H3K9 in T-cells. PMID- 25281566 TI - Multimodal functional and anatomic imaging identifies preclinical microvascular abnormalities in type 1 diabetes mellitus. AB - Structural and functional changes in the microcirculation in type 1 diabetes mellitus predict future end-organ damage and macrovascular events. We explored the utility of novel signal processing techniques to detect and track changes in ocular hemodynamics in patients with this disease. Twenty-four patients with uncomplicated type 1 diabetes mellitus and eighteen age- and sex-matched control subjects were studied. Doppler ultrasound was used to interrogate the carotid and ophthalmic arteries, and digital photography was used to image the retinal vasculature. Frequency analysis algorithms were applied to quantify velocity waveform structure and retinal photographic data at baseline and after inhalation of 100% O2. Frequency data were compared between groups. No significant differences were found in the resistive index between groups at baseline or after inhaled O2. Frequency analysis of Doppler flow velocity waveforms identified significant differences in bands 3-7 between patients and control subjects in data captured from the ophthalmic artery (P < 0.01 for each band). In response to inhaled O2, changes in frequency band amplitudes were significantly greater in control subjects compared with patients (P < 0.05). Only control subjects demonstrated a positive correlation (R = 0.61) between changes in retinal vessel diameter and frequency band amplitudes derived from ophthalmic artery waveform data. The use of multimodal signal processing techniques applied to Doppler flow velocity waveforms and retinal photographic data identified preclinical changes in the ocular microcirculation in patients with uncomplicated diabetes mellitus. An impaired autoregulatory response of the retinal microvasculature may contribute to the future development of retinopathy in such patients. PMID- 25281567 TI - Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters. AB - The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross sectional area (672 vs. 443 MUm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, beta-myosin heavy chain, c-fos, and c jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea. PMID- 25281568 TI - Thyrotropin-releasing hormone overexpression induces structural changes of the left ventricle in the normal rat heart. AB - Thyrotropin-releasing hormone (TRH) hyperactivity has been observed in the left ventricle of spontaneously hypertensive rats. Its long-term inhibition suppresses the development of hypertrophy, specifically preventing fibrosis. The presence of diverse systemic abnormalities in spontaneously hypertensive rat hearts has raised the question of whether specific TRH overexpression might be capable of inducing structural changes in favor of the hypertrophic phenotype in normal rat hearts. We produced TRH overexpression in normal rats by injecting into their left ventricular wall a plasmid driving expression of the preproTRH gene (PCMV TRH). TRH content and expression of preproTRH, collagen type III, brain natriuretic peptide, beta-myosin heavy chain, Bax-to-Bcl-2 ratio, and caspase-3 were measured. The overexpression maneuver was a success, as we found a significant increase in both tripeptide and preproTRH mRNA levels in the PCMV-TRH group compared with the control group. Immunohistochemical staining against TRH showed markedly positive brown signals only in the PCMV-TRH group. TRH overexpression induced a significant increase in fibrosis, evident in the increase of collagen type III expression accompanied by a significant increase in extracellular matrix expansion. We found a significant increase in brain natriuretic peptide and beta-myosin heavy chain expression (recognized markers of hypertrophy). Moreover, TRH overexpression induced a slight but significant increase in myocyte diameter, indicating the onset of cell hypertrophy. We confirmed the data "in vitro" using primary cardiac cell cultures (fibroblasts and myocytes). In conclusion, these results show that a specific TRH increase in the left ventricle induced structural changes in the normal heart, thus making the cardiac TRH system a promising therapeutic target. PMID- 25281569 TI - Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models. AB - Although most founder mutation carriers of hypertrophic cardiomyopathy (HCM), such as the cardiac myosin-binding protein C gene (MYBPC3), arose from a common ancestor exhibit favorable clinical phenotypes, there still remain small fractions of these carriers associated with increased cardiovascular events. However, few data exist regarding the defining factors that modify phenotypes of these patients, particularly in terms of multiple gene mutations. Therefore, we assessed genotype-phenotype correlations and investigated factors that contribute to phenotypic diversities of mutation carriers from 488 unrelated HCM probands. A prevalent founder mutation (Val762Asp) in MYBPC3 was identified in 33 subjects from 19 families. Among them, 28 carriers harbored an isolated Val762Asp mutation and exhibited a late onset of overt HCM compared with other MYBPC3 mutation carriers (62.8 +/- 3.0 vs 50.1 +/- 2.6 yr, P < 0.05). In contrast, the remaining five carriers had additional sarcomere gene mutations (3 carriers in MYBPC3 and 2 carriers in the cardiac troponin T gene). Of these five carriers, two carriers showed early disease onset and one carrier exhibited end-stage HCM. These phenotypes were recapitulated in zebrafish models; injection of MYBPC3 Val762Asp alone did not alter ventricular size or function, but ventricular dimension was significantly increased when MYBPC3 Val762Asp mRNA was coinjected with MYBPC3 Arg820Gln mRNA. These results demonstrate that MYBPC3 Val762Asp may be associated with unfavorable HCM phenotypes in some cases when combined with another MYBPC3 mutation. PMID- 25281571 TI - In this issue of Occupational Medicine. PMID- 25281570 TI - Resolvin D1 reverses reactivity and Ca2+ sensitivity induced by ET-1, TNF-alpha, and IL-6 in the human pulmonary artery. AB - Pulmonary hypertension (PH) is a rare and progressive disease characterized by an inflammatory status and vessel wall remodeling, resulting in increased pulmonary artery resistance. During the last decade, treatments have been proposed; most of them target the endothelial pathways that stimulate smooth muscle cell relaxation. However, PH remains associated with significant morbidity. We hypothesized that inflammation plays a crucial role in the severity of the abnormal vasoconstriction in PH. The goal of this study was to assess the effects of resolvin D1 (RvD1), a potent anti-inflammatory agent, on the pharmacological reactivity of human pulmonary arteries (HPAs) via an in vitro model of induced hyperreactivity. The effects of RvD1 and monoacylglyceride compounds were measured on contractile activity and Ca(2+) sensitivity developed by HPAs that had been pretreated (or not) under proinflammatory conditions with either 10 ng/ml TNF-alpha or 10 ng/ml IL-6 or under hyperreactive conditions with 5 nM endothelin-1. The results demonstrated that, compared with controls, 24-h pretreatment with TNF-alpha, IL-6, or endothelin-1 increased reactivity and Ca(2+) sensitivity of HPAs as revealed by agonist challenges with 80 mM KCl, 1 MUM serotonin (5-hydroxytryptamine), 30 nM U-46619, and 1 MUM phorbol 12,13 dibutyrate. However, 300 nM RvD1 as well as 1 MUM monoacylglyceride docosapentaenoic acid monoglyceride strongly reversed the overresponsiveness induced by both proinflammatory and hyperreactive treatments. In pretreated pulmonary artery smooth muscle cells, Western blot analyses revealed that RvD1 treatment decreased the phosphorylation level of CPI-17 and expression of transmembrane protein member 16A while increasing the detection of G protein coupled receptor 32. The present data demonstrate that RvD1, a trihydroxylated docosahexaenoic acid derivative, decreases induced overreactivity in HPAs via a reduction in CPI-17 phosphorylation and transmembrane protein member 16A expression. PMID- 25281572 TI - The implications of the Francis report for occupational health in the NHS. PMID- 25281573 TI - Sir Stanley Spencer, Shipbuilding on the Clyde: Burners 1940. PMID- 25281574 TI - Fifty years ago: 'General practice and industrial medicine in the United States'. 1964. PMID- 25281575 TI - Fifty years ago: 'The appointed factory doctor'. 1964. PMID- 25281576 TI - I learned (a bit) about aviation medicine from that. PMID- 25281578 TI - The FAST questionnaire. PMID- 25281579 TI - Identification and characterization of a p38-like gene from amphioxus (Branchiostoma belcheri): an insight into amphioxus innate immunity and evolution. AB - p38 MAP kinases, members of mitogen-activated protein kinases (MAPKs) activated by environmental stresses and cytokines, play important roles in transcription regulation and inflammatory responses. However, the p38 MAP kinase gene has not been identified in amphioxus to date. Here, we identified and characterized a p38 MAP kinase gene from Branchiostoma belcheri (designed as Amphip38). First, we cloned the full length of Amphip38 gene and found that the deduced amino acid sequence of Amphip38 has 80.5-84% similarity and 67.2-72.5% identity to those from other species. Second, we found that Amphip38 contained the conserved TGY motif, ATP binding site (GXGXXG), substrate binding site (ATRW) and ED site in known p38 MAP kinases. The predicted 3D structure of Amphip38 was found to be similar to human p38 MAP kinases. These results indicate that Amphip38 belongs to p38 MAP kinase gene family. Third, we found that the Amphip38 was ubiquitously and differentially expressed in five investigated tissues (intestine, gills, notochord, muscles, and hepatic cecum). Finally, we found that LPS stimulation induced the expression of Amphip38 gene, and lead to increase of phosphorylation p38 MAP kinase. These results indicate that Amphip38 is involved in innate immunity response in amphioxus. In addition, we found that Amphip38 gene might be an ancestor of vertebrate p38 MAP kinase gene via evolutionary analysis. In conclusion, our results provided an insight into the innate immunity response and the evolution of the vertebrate p38 MAP kinase gene family. PMID- 25281580 TI - Adverse and long-term protective effects following oil-adjuvanted vaccination against Aeromonas salmonicida in rainbow trout. AB - Prophylactic measures against Aeromonas salmonicida subsp. salmonicida, the causative agent of furunculosis, have been an active field of research for decades, with studies mainly focused on Atlantic salmon (Salmo salar). In the present study we have examined the protective and adverse effects of mineral oil adjuvanted injection vaccines on rainbow trout (Oncorhynchus mykiss). A commercial vaccine and an experimental auto vaccine, as well as their respective adjuvant formulations alone were used to evaluate their individual effects, both prior to and during an experimental waterborne infection challenge. Macro- and microscopic examination revealed signs of vaccine-induced adverse effects from 10 weeks to 14 months post vaccination. Both vaccines induced statistically significant protection during the experimental challenge (P=0.018 for both vaccines), as well as significantly elevated levels of specific circulating antibodies prior to and during the experimental challenge when compared to an unvaccinated control group. During the early, critical time points of the infection, both vaccines appeared to protect against pathological changes to the liver and spleen, which provides a probable explanation for the reduced mortality seen in the vaccinated groups. A significant correlation was found between the level of A. salmonicida-specific antibodies measured prior to challenge and the endpoint survival of each group after the experimental infection, and furthermore, the levels of these antibodies remained elevated for at least 14 months post vaccination. PMID- 25281581 TI - Quality assurance standards drive improvements in the profile of radiation therapy departments participating in trials of the EORTC Radiation Oncology Group. AB - BACKGROUND AND PURPOSE: The Facility Questionnaire (FQ) of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group (EORTC ROG) evaluates the human, technical and organizational resources at each EORTC member institution. The purpose of this study is to use the FQ database to assess the improvement of radiation therapy (RT) structures and resources within the EORTC compared to the previous surveys performed by our group. MATERIAL AND METHODS: We report the content of the current FQ database, completed online by 156 EORTC candidate member institutions from 22 countries between February 2011 and February 2013. Results are compared to FQ-published data from 1992 and 2007. RESULTS: The average number of patients per year per EORTC institution is 2381 (range 350-12,000) an 18.2% increase compared to the 2007 figures. From 2007 to 2013 the average number of radiation oncologists, physicists and radiation technologists per EORTC institution has increased by 27% (from 8.5 to 10.8), 41% (from 5.2 to 7.4) and 38% (from 26.1 to 36.1) respectively. Consequently the number of patients per year per radiation oncologist has decreased from 258 to 243, for physicists from 426 to 354 and for radiation technologists from 107 to 86. One hundred and forty-six (94%) and 101 (65%) institutions can now deliver IMRT and SBRT, compared to 77 (79%) and 53 (54%) in 2007. CONCLUSIONS: The standards set by the EORTC-ROG are met by a continually improving number of institutions, helping to safeguard use of advanced technologies in EORTC-ROG clinical trials. PMID- 25281582 TI - Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: a systematic review and meta-analysis. AB - PURPOSE: We conducted a systematic review and meta-analysis to quantify the pathological complete response (pCR) rate after preoperative (chemo)radiation with doses of ?60Gy in patients with locally advanced rectal cancer. Complete response is relevant since this could select a proportion of patients for which organ-preserving strategies might be possible. Furthermore, we investigated correlations between EQD2 dose and pCR-rate, toxicity or resectability, and additionally between pCR-rate and chemotherapy, boost-approach or surgical interval. METHODS AND MATERIALS: PubMed, EMBASE and Cochrane libraries were searched with the terms 'radiotherapy', 'boost' and 'rectal cancer' and synonym terms. Studies delivering a preoperative dose of ?60 Gy were eligible for inclusion. Original English full texts that allowed intention-to-treat pCR-rate calculation were included. Study variables, including pCR, acute grade ?3 toxicity and resectability-rate, were extracted by two authors independently. Eligibility for meta-analysis was assessed by critical appraisal. Heterogeneity and pooled estimates were calculated for all three outcomes. Pearson correlation coefficients were calculated between the variables mentioned earlier. RESULTS: The search identified 3377 original articles, of which 18 met our inclusion criteria (1106 patients). Fourteen studies were included for meta-analysis (487 patients treated with ?60 Gy). pCR-rate ranged between 0.0% and 44.4%. Toxicity ranged between 1.3% and 43.8% and resectability-rate between 34.0% and 100%. Pooled pCR-rate was 20.4% (95% CI 16.8-24.5%), with low heterogeneity (I2 0.0%, 95% CI 0.00-84.0%). Pooled acute grade ?3 toxicity was 10.3% (95% CI 5.4-18.6%) and pooled resectability-rate was 89.5% (95% CI 78.2-95.3%). CONCLUSION: Dose escalation above 60 Gy for locally advanced rectal cancer results in high pCR rates and acceptable early toxicity. This observation needs to be further investigated within larger randomized controlled phase 3 trials in the future. PMID- 25281583 TI - Biological conversion of methane to liquid fuels: status and opportunities. AB - Methane is the main component of natural gas and biogas. As an abundant energy source, methane is crucial not only to meet current energy needs but also to achieve a sustainable energy future. Conversion of methane to liquid fuels provides energy-dense products and therefore reduces costs for storage, transportation, and distribution. Compared to thermochemical processes, biological conversion has advantages such as high conversion efficiency and using environmentally friendly processes. This paper is a comprehensive review of studies on three promising groups of microorganisms (methanotrophs, ammonia oxidizing bacteria, and acetogens) that hold potential in converting methane to liquid fuels; their habitats, biochemical conversion mechanisms, performance in liquid fuels production, and genetic modification to enhance the conversion are also discussed. To date, methane-to-methanol conversion efficiencies (moles of methanol produced per mole methane consumed) of up to 80% have been reported. A number of issues that impede scale-up of this technology, such as mass transfer limitations of methane, inhibitory effects of H2S in biogas, usage of expensive chemicals as electron donors, and lack of native strains capable of converting methane to liquid fuels other than methanol, are discussed. Future perspectives and strategies in addressing these challenges are also discussed. PMID- 25281584 TI - Robust fuzzy control subject to state variance and passivity constraints for perturbed nonlinear systems with multiplicative noises. AB - The multi-constrained robust fuzzy control problem is investigated in this paper for perturbed continuous-time nonlinear stochastic systems. The nonlinear system considered in this paper is represented by a Takagi-Sugeno fuzzy model with perturbations and state multiplicative noises. The multiple performance constraints considered in this paper include stability, passivity and individual state variance constraints. The Lyapunov stability theory is employed to derive sufficient conditions to achieve the above performance constraints. By solving these sufficient conditions, the contribution of this paper is to develop a parallel distributed compensation based robust fuzzy control approach to satisfy multiple performance constraints for perturbed nonlinear systems with multiplicative noises. At last, a numerical example for the control of perturbed inverted pendulum system is provided to illustrate the applicability and effectiveness of the proposed multi-constrained robust fuzzy control method. PMID- 25281585 TI - Wilderness image. PMID- 25281586 TI - A lightning multiple casualty incident in Sequoia and Kings Canyon National Parks. AB - Multiple casualty incidents (MCIs) are uncommon in remote wilderness settings. This is a case report of a lightning strike on a Boy Scout troop hiking through Sequoia and Kings Canyon National Parks (SEKI), in which the lightning storm hindered rescue efforts. The purpose of this study was to review the response to a lightning-caused MCI in a wilderness setting, address lightning injury as it relates to field management, and discuss evacuation options in inclement weather incidents occurring in remote locations. An analysis of SEKI search and rescue data and a review of current literature were performed. A lightning strike at 10,600 feet elevation in the Sierra Nevada Mountains affected a party of 5 adults and 7 Boy Scouts (age range 12 to 17 years old). Resources mobilized for the rescue included 5 helicopters, 2 ambulances, 2 hospitals, and 15 field and 14 logistical support personnel. The incident was managed from strike to scene clearance in 4 hours and 20 minutes. There were 2 fatalities, 1 on scene and 1 in the hospital. Storm conditions complicated on-scene communication and evacuation efforts. Exposure to ongoing lightning and a remote wilderness location affected both victims and rescuers in a lightning MCI. Helicopters, the main vehicles of wilderness rescue in SEKI, can be limited by weather, daylight, and terrain. Redundancies in communication systems are vital for episodes of radio failure. Reverse triage should be implemented in lightning injury MCIs. Education of both wilderness travelers and rescuers regarding these issues should be pursued. PMID- 25281587 TI - Characterization of medical care at the 161-km Western States Endurance Run. AB - OBJECTIVE: To examine the medical care at a highly competitive 161-km mountain ultramarathon. METHODS: Encounter forms from the 2010 through 2013 Western States Endurance Run were analyzed for trends in consultation and use of intravenous fluids. RESULTS: A total of 63 consultations (8.2% of starters) were documented in 2012 and 2013, of which 10% involved noncompetitors. Most (77%) of the consultations with competitors occurred on the course rather than at the finish line, and were generally during the middle third of the race. Of the on-course consultations, the runner was able to continue the race 55% of the time, and 75% of those who continued after consultation ultimately finished the race. Relative number of consultations did not differ among competitors within 10-year age groups (P = .7) or between men and women (P = .2). Overall, consultations for medical issues were predominant, and nausea and vomiting accounted for the single highest reason for consultation (24%). Although there was an overall decrease in finish line consultations and intravenous fluid use from 2010 through 2013 (P < .0001 for both) that was independent of maximum ambient temperature (P = .3 and P = .4), the proportion of those being treated with intravenous fluids relative to those receiving consultation at the finish line was directly related to maximum ambient temperature (r = .93, P = .037). Both 2012 and 2013 had a single medical emergency that required emergency evacuation. CONCLUSIONS: This work demonstrates that the medical needs in a 161-km ultramarathon are mostly for minor issues. However, occasional serious issues arise that warrant a well-organized medical system. PMID- 25281588 TI - Effect of head and face insulation on cooling rate during snow burial. AB - OBJECTIVES: Avalanche victims are subjected to a number of physiological stressors during burial. We simulated avalanche burial to monitor physiological data and determine whether wearing head and face insulation slows cooling rate during snow burial. In addition, we sought to compare 3 different types of temperature measurement methods. METHODS: Nine subjects underwent 2 burials each, 1 with head and face insulation and 1 without. Burials consisted of a 60-minute burial phase followed by a 60-minute rewarming phase. Temperature was measured via 3 methods: esophageal probe, ingestible capsule, and rectal probe. RESULTS: Cooling and rewarming rates were not statistically different between the 2 testing conditions when measured by the 3 measurement methods. All temperature measurement methods correlated significantly. CONCLUSIONS: Head and face insulation did not protect the simulated avalanche victim from faster cooling or rewarming. Because the 3 temperature measurement methods correlated, the ingestible capsule may provide an advantageous noninvasive method for snow burial and future hypothermia studies if interruptions in data transmission can be minimized. PMID- 25281589 TI - Utah ski patrol: assessing training types and resources. AB - BACKGROUND: Skiers and snowboarders incur a variety of injuries and medical emergencies each year at ski resorts. The ski patrol is primarily responsible for initial triage, assessment and stabilization of these problems. OBJECTIVE: The purpose of this study was to subjectively evaluate the type of training, resources, and equipment available to local ski patrols within Utah. METHODS: Ski patrol directors at ski resorts in Utah were asked to complete a voluntary computerized survey. RESULTS: Of the 14 ski areas in Utah, ski patrol directors representing 8 resorts responded. The majority of patrols in Utah use Outdoor Emergency Care (OEC) as their primary education and certification source. Most programs also include site-specific training in addition to basic certification. All responding resorts had basic first responder equipment, including splinting devices, basic airway management, and hemorrhage control. Six of 8 responding resorts had affiliated clinics, and all had access to aeromedical transport. All of the responding ski patrol directors believed the current training level was adequate. CONCLUSIONS: Utah area ski patrollers frequently see trauma-related injuries and have the resources to assess and provide initial immobilization techniques. Many resorts have affiliated clinics with advanced providers, and all have access to aeromedical support to rapidly transfer patients to trauma centers. Medical directors may be of use for training as well as developing extended scope of practice protocols for advanced airway use or medication administration. Patrols may benefit from additional resort-specific training that addresses other frequently seen injuries or illnesses. PMID- 25281590 TI - New Zealand land search and rescue operations: an analysis of medical and traumatic conditions. AB - OBJECTIVE: The aim of this study was to describe the range and types of medical and traumatic conditions encountered in land search and rescue operations in New Zealand. METHODS: Twenty months (May 2010 to December 2011) of land search and rescue operations were analyzed. Data on medical and traumatic conditions were extracted from the New Zealand Police search and rescue database. RESULTS: During the period audited, New Zealand Police coordinated 1490 land-based search and rescue operations, from which 611 persons fulfilled the study inclusion criteria. Males accounted for 60.5% of the subjects, and a trauma-related injury was the most commonly encountered condition (37.3% of all). The lower limb was the most commonly injured body site, and most injuries occurred as the result of a slip or fall. Medical conditions were recorded in 11.6% of operations and included a wide spread of conditions, with cardiovascular events being seen most frequently. Hypothermia was diagnosed in 9.3% of all operations, and fatalities made up 5.6% of the sample. Thirty percent of all operations were for persons with cognitive impairment who had wandered away from their usual place of residence. These were almost entirely urban searches and concentrated in districts with large populations. CONCLUSIONS: Search and rescue personnel are exposed to a broad range of medical and traumatic conditions. In New Zealand, they include preexisting cognitive impairment that results in persons lost in urban environments. Notwithstanding this, many subjects will also need to be managed in remote, resource-limited environments for extended periods. First aid training and field equipment should reflect these demands. PMID- 25281591 TI - siRNA nanotherapeutics: a Trojan horse approach against HIV. AB - The concept of RNA interference (RNAi) is gaining popularity for the better management of various diseases, including HIV. Currently, the successful biomedical utilization of siRNA therapeutics is hampered, both in vivo and in vitro, mainly by the inherent inability of naked siRNA to cross the cell membrane. RNAi can potentially improve the weakness of current highly active antiretroviral therapy (HAART) by diminishing the chances of the appearance of antiHIV-resistant strains. Here, we discuss the nanocarrier-mediated delivery of siRNA delivery as well as highlighted the scope of siRNA-mediated gene-silencing technology for improved HIV treatment. PMID- 25281592 TI - The Pistoia Alliance Controlled Substance Compliance Service Project: from start to finish. AB - Pharmaceutical companies and other life science R&D organizations routinely work with controlled substances, and must have adequate controls in place to meet the legislative requirements of the countries in which they operate. Controlled substances include a range of narcotics and psychotropic drugs, which are covered by increasingly complex legislation as legislators attempt to keep up with a rapidly changing environment. This legislation must be interpreted and transformed from legal wording into chemical structures to be used effectively. Over the past year a working party of pharmaceutical and technology companies has come together under the umbrella of the Pistoia Alliance to define a Controlled Substance Compliance Service. We describe the benefits of bringing together this group of experts to solve the pre-competitive issue of controlled substance management. PMID- 25281594 TI - [Privatization or professional leadership]. PMID- 25281593 TI - Stage-specific differential gene expression in Leishmania infantum: from the foregut of Phlebotomus perniciosus to the human phagocyte. AB - BACKGROUND: Leishmania infantum is the etiological agent of zoonotical visceral leishmaniasis in the Mediterranean basin. A recent outbreak in humans has been recently reported in central Spain. Leishmania spp. parasites are transmitted to the mammalian host by the bite of sand flies. The primary vector of L. infantum in Spain is Phlebotomus perniciosus. For decades, research on these parasites has involved the axenic culture model of the promastigote stage including gene expression profiling studies performed in the post-genome era. Unlike the controversial axenic culturing of amastigotes, promastigote cultures are generally accepted and used, although with the precaution of avoiding excessive culture passage.The primary objective of this differentiation study is to compare the gene expression profiles of promastigotes isolated from the foregut of the sand fly and amastigotes. For this purpose, P. perniciosus sand flies were infected with L. infantum and differentiated promastigotes were extracted by dissection of the foreguts. Shotgun DNA microarray hybridization analyses allowed for transcriptome comparison of these promastigotes with amastigotes obtained by infection of the U937 cell line. The results have been compared with those described in published expression analyses using axenic promastigotes. RESULTS: A total of 277 up-regulated genes were found through this hybridization experiment. The comparison of these particular results with published gene expression profile analyses performed using the same experimental procedure to study cultured promastigotes in stationary phase versus amastigotes revealed considerable differences (approximately 95% of the up-regulated genes were different). We found that the up-regulation rate is lower in amastigotes than in sand fly derived promastigotes, which is in agreement with the over-expression of genes involved in gene expression regulation and signaling in those promastigote populations. CONCLUSIONS: The up-regulation rate is lower in intracellular amastigotes than in promastigotes obtained from the sand fly gut. This was also reported by us using the promastigote culture model and is an evidence for the hypothesis of promastigote preadaptation towards life in the intracellular environment. Regarding transcript abundance, the set of differentially regulated genes is notably different when using promastigotes from the sand fly foregut instead of axenic cultures. PMID- 25281595 TI - Flow patterns and preferred sites of atherosclerotic lesions in the human aorta - I. Aortic arch. AB - OBJECTIVES: To elucidate the role of fluid mechanical factors in the localized genesis and development of atherosclerotic lesions in man. METHODS: Flow patterns and preferred sites of atherosclerotic lesions in the human aortic arch were studied in detail using isolated transparent aortic trees prepared from humans postmortem and by means of flow visualization of tracer polystyrene microspheres, using cinemicrographic techniques. RESULTS: Under the condition of steady flow that simulated mid-systole, the flow in the aortic arch consisted of three major components; (i) a straight flow to the brachio-cephalic artery located close to the right dorsal wall of the ascending aorta; (ii) a quasi-parallel undisturbed flow located close to the common median plane of the aortic arch and its side branches, and (iii) a clockwise slow, spiral secondary flow located dominantly near the left ventral wall of the aortic arch. Thus, looking down the aorta from its origin, the flow in the aortic arch appeared as a single helical flow revolving in a clockwise direction. CONCLUSIONS: Atherosclerotic lesions were found mainly in regions of low wall shear stress such as the proximal lip of the orifice of each side branch where a slow recirculation flow formed, and the left ventral wall of the aortic arch where a slow spiral secondary flow formed. PMID- 25281596 TI - The characterization of a non-Newtonian blood analog in natural- and shear-layer induced transitional flow. AB - BACKGROUND: Although a blood analog of aqueous glycerol and xanthan gum was found to replicate the viscoelastic behavior of blood, measurements were restricted to laminar flow. OBJECTIVE: To expand the characterization of a non-Newtonian blood analog of aqueous glycerol and xanthan gum to transitional Reynolds numbers to quantify its behavior as a function of both natural and shear-layer-induced mechanisms. METHODS: A Newtonian analog and a shear-thinning aqueous glycerol, xanthan gum solution were circulated through an in vitro flow loop replicating both a straight and obstructed artery where transition was initiated through natural and shear-layer-induced mechanisms respectively. Steady and pulsatile pressure drop measurements for both fluids were acquired across a range of Reynolds numbers up to 7600 and Womersley numbers of 4 and 6. RESULTS: In steady and pulsatile straight flow, the non-Newtonian analog presented with reduced pressure drops and prolonged laminar flow to Reynolds numbers of 3200 and 3800 respectively. Upon blockage inclusion, non-Newtonian minor losses were comparable to Newtonian in steady flow and greater in pulsatile flow suggesting an elongation of downstream non-Newtonian recirculation. Although non-Newtonian total system pressure drops in both straight and obstructed flows were lower, the ratio of pressure drop difference between the two fluids decreased through shear layer-induced transition. CONCLUSIONS: These findings not only demonstrated the suitability of using a xanthan gum analog to model blood flow in transitional regimes, but also presented the respective differences in analog behavior as a function of transition mechanism. PMID- 25281597 TI - Flow patterns and preferred sites of atherosclerotic lesions in the human aorta - II. Abdominal aorta. AB - OBJECTIVE: As in Part I, to elucidate the role of fluid mechanical factors in the localized genesis and development of atherosclerotic lesions in man, here in the abdominal aorta. METHODS: Flow patterns and preferred sites of atherosclerotic lesions in the aorta were studied in detail using the same isolated transparent aortic trees prepared from humans postmortem and the flow visualization and cinemicrographic techniques as in Part I. RESULTS: Under steady flow simulating mid-systole, the flow was found to be disturbed at the aorto-celiac and aorto superior mesenteric artery junctions by the formation of complex secondary and adverse flows along the lateral and posterior walls of the abdominal aorta. More complex secondary and adverse flows formed at the branching sites of the left and right renal arteries. Furthermore, considerable interactions occurred between the secondary and adverse flows formed at the branching sites of the above four arteries, resulting in the formation of a large and long recirculation zone along the lateral and posterior walls of the abdominal aorta corresponding to these branches. The velocity profile was almost flattened throughout the entire length of the descending aorta. CONCLUSIONS: Atherosclerotic lesions were found mainly at the posterior and lateral walls of the abdominal aorta where slow adverse and recirculation flows formed and where wall shear stress was low. PMID- 25281598 TI - Socio-economic differences in cost of pregnancy-related health services in the peri-urban Accra, Ghana. AB - BACKGROUND: Financial and physical barriers are known to limit access to maternal health services in developing countries. These limitations are often compounded by the low socio-economic status of women. This study examined socio-economic differences in health services cost incurred by pregnant women. METHODS: A cross sectional cost survey of 300 women who had delivered a live birth in the last 12 months was undertaken. RESULTS: Majority of the women were aged between 20 and 39 years. About 63% of the women claimed they were registrants of the National Health Insurance Scheme (NHIS). However, only 64% of them provided valid NHIS identification cards. There were relatively more insured women in the rich quintiles (44%) compared with insured women in the poor quintiles (33%). Generally, women who were in the rich quintile incurred the highest average medical and non-medical costs, spent the highest time prior to service provision and lost the highest average incomes. CONCLUSIONS: Women socio-economic differences play a critical role in access to health services. We recommend that awareness campaigns on the NHIS must be intensified. The Ghana Health Services through its Community-based Health Planning Service should carefully structure its home visits to cover education on pregnancy-related health services. PMID- 25281599 TI - Anticoagulation in adults with congenital heart disease: The who, the when and the how? AB - Adults with congenital heart disease are a growing population. One of the major challenges in the care of these patients is to prevent thromboembolic episodes. Despite relative young age and no typical cardiovascular risk factors, this cohort has a high prevalence of thrombotic events. It is difficult to use treatment algorithms from the general adult population with acquired heart disease in this heterogeneous population due to special conditions such as myocardial scarring after previous surgery, atypical atrial flutter, prothrombotic conditions and the presence of interatrial shunts. Furthermore, there is a lack of scientific evidence regarding how to prevent thromboembolic events with anticoagulation in adults with congenital heart disease. The aim of this paper is to review the current literature pertaining to anticoagulation in adults with congenital heart disease and hence enable recommendations for which patients are likely to benefit from which anticoagulation treatments, when they should be considered and how these would be carried out. PMID- 25281600 TI - Changes in renal function after catheter ablation of atrial fibrillation are associated with CHADS2 and CHA2DS2-VASc scores and arrhythmia recurrences. AB - BACKGROUND: Renal impairment is associated with poor prognosis in the setting of atrial fibrillation (AF). While AF catheter ablation is an effective treatment modality for AF burden reduction and improvement of symptoms, changes in renal function after catheter ablation and their association with rhythm outcome have not been studied in a large contemporary AF ablation cohort. OBJECTIVE: To determine the association between CHADS2 and CHA2DS2-VASc scores and arrhythmia recurrences with changes in renal function following AF catheter ablation. METHODS: Estimated glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation at baseline and during follow-up in 783 patients undergoing de novo AF catheter ablation. Complete rhythm follow-up was achieved in 626 patients (80%) using serial 7-day Holter ECG. RESULTS: The study population (n=783, 61+/-10 years, 64% men, 57% paroxysmal AF) was followed up at median 20 (IQR 12-27) months. Baseline eGFR correlated with CHADS2 (beta=-0.258, p<0.001) and CHA2DS2-VASc scores (beta=-0.434, p<0.001). On multivariable analyses, eGFR changes were associated with AF recurrences (B=-0.136, p=0.014), CHADS2 (B=-0.062, p=0.035) and CHA2DS2-VASc scores (B=-0.057, p=0.003). CONCLUSIONS: In patients after AF catheter ablation, eGFR changes during mid-term follow-up are associated with AF recurrences, CHADS2 and CHA2DS2-VASc scores. PMID- 25281604 TI - Two simple questions may be used as the first screening step for alcohol problems in primary care: systematic review. PMID- 25281602 TI - Subjective memory complaint only relates to verbal episodic memory performance in mild cognitive impairment. AB - BACKGROUND: A cognitive concern from the patient, informant, or clinician is required for the diagnosis of mild cognitive impairment (MCI); however, the cognitive and neuroanatomical correlates of complaint are poorly understood. OBJECTIVE: We assessed how self-complaint relates to cognitive and neuroimaging measures in older adults with MCI. METHOD: MCI participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and dichotomized into two groups based on the presence of self-reported memory complaint (no complaint n = 191, 77 +/- 7 years; complaint n = 206, 73 +/- 8 years). Cognitive outcomes included episodic memory, executive functioning, information processing speed, and language. Imaging outcomes included regional lobar volumes (frontal, parietal, temporal, cingulate) and specific medial temporal lobe structures (hippocampal volume, entorhinal cortex thickness, parahippocampal gyrus thickness). RESULTS: Linear regressions, adjusting for age, gender, race, education, Mini-Mental State Examination score, mood, and apolipoprotein E4 status, found that cognitive complaint related to immediate (beta = -1.07, p < 0.001) and delayed episodic memory performances assessed on a serial list learning task (beta = -1.06, p = 0.001) but no other cognitive measures or neuroimaging markers. CONCLUSIONS: Self reported memory concern was unrelated to structural neuroimaging markers of atrophy and measures of information processing speed, executive functioning, or language. In contrast, subjective memory complaint related to objective verbal episodic learning performance. Future research is warranted to better understand the relation between cognitive complaint and surrogate markers of abnormal brain aging, including Alzheimer's disease, across the cognitive aging spectrum. PMID- 25281603 TI - Influence of the APOE epsilon4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space. AB - The apolipoprotein E (APOE) epsilon4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the epsilon4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in epsilon4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the epsilon4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE epsilon4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration. PMID- 25281605 TI - For newly diagnosed type 2 diabetes, a low-carbohydrate Mediterranean diet may delay need for medication and improve chance of remission compared to a low-fat diet. PMID- 25281606 TI - Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). AB - Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (>=3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care. PMID- 25281608 TI - How I examine my patient: the art of neurological examination for Parkinson's disease. PMID- 25281607 TI - Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms. AB - Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs. PMID- 25281609 TI - Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control. AB - BACKGROUND: Despite the efficacy of highly active antiretroviral treatment (HAART), a large proportion of human immunodeficiency virus (HIV)-infected patients may develop moderate neurocognitive impairment. Antiretroviral drug passage into the central nervous system may be relevant for preventing and treating HIV-associated neurocognitive disorder; nevertheless, clear cerebrospinal fluid (CSF) pharmacodynamic targets are not known. METHODS: HAART treated adults with wild-type HIV were prospectively enrolled. CSF concentrations (measured by mass spectrophotometric methods) and inhibitory quotients (CSF concentrations divided by in vitro 50% and 95% inhibitory concentrations) were compared among different drugs and related to CSF HIV RNA levels. CSF escape was defined as CSF HIV RNA >50 copies/mL despite contemporary plasma HIV RNA below that threshold. RESULTS: One hundred twenty-seven patients (91 male [71.7%], 93 white [73.2%], with a median age of 46 years [interquartile range, 40.5-54.5 years]) provided 174 paired CSF and plasma samples. Twice-daily darunavir, once daily darunavir, and efavirenz had the highest CSF 95% inhibitory quotients (18.5, 8.2, and 6.4, respectively). Higher nadir CD4 cell count (P = .01) and plasma HIV RNA <50 copies/mL (P < .001) were independent predictors of controlled CSF HIV RNA. Optimal drug exposure (CSF detectable drugs and 95% inhibitory quotient >1) was protective for CSF escape (P = .01). CONCLUSIONS: Cerebrospinal fluid 95% inhibitory quotients may be used to compare antiretroviral drug compartmental exposure; they deserve longitudinal studies to assess the adequacy of CSF drug concentrations in treated HIV-infected patients. PMID- 25281611 TI - Editorial commentary: cerebrospinal fluid inhibitory quotients of antiretroviral drugs. PMID- 25281610 TI - The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status. AB - BACKGROUND: Existing data suggest that human immunodeficiency virus (HIV) infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study. METHODS: We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses. RESULTS: Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], 3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001). CONCLUSIONS: Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects. PMID- 25281612 TI - A case of post-traumatic minimally conscious state reversed by midazolam: Clinical aspects and neurophysiological correlates. AB - PURPOSE: We describe the case of a subject in a post-traumatic Minimally Conscious State (MCS) who retrieved full interaction with the environment after midazolam infusion. We studied EEG correlates of the "awakening reaction" in the different domains of frequency, time and cortical topography, along with the intrinsic connectivity within both the task-positive and the linguistic network. METHODS: EEG recorded before and after midazolam administration has been submitted to spectral power analysis, sLORETA analysis and intrinsic connectivity analysis within both functional networks. RESULTS: A critical change in the power spectrum profile was observed after midazolam: a) the power between 1 and 12 Hz decreased, reaching its maximum difference with respect to pre-infusion at about 7 Hz and b) the power between 12 and 30 Hz increased, with a maximum difference at about 15 Hz. At the same time, midazolam induced significant connectivity changes, especially for these two frequency bands, within both functional networks. CONCLUSIONS: We advance some hypotheses about certain aspects of the recovery from the MCS both in terms of anatomo-functional correlations and functional brain systems and we make inferences about the role that some kind of 'catatonic' symptoms might play in determining and/or maintaining this peculiar clinical state. PMID- 25281613 TI - Doctors need to fully investigate cause of blackouts, says NICE. PMID- 25281614 TI - Discharge patterning in rat olfactory bulb mitral cells in vivo. AB - Here we present a detailed statistical analysis of the discharge characteristics of mitral cells of the main olfactory bulb of urethane-anesthetized rats. Neurons were recorded from the mitral cell layer, and antidromically identified by stimuli applied to the lateral olfactory tract. All mitral cells displayed repeated, prolonged bursts of action potentials typically lasting >100 sec and separated by similarly long intervals; about half were completely silent between bursts. No such bursting was observed in nonmitral cells recorded in close proximity to mitral cells. Bursts were asynchronous among even adjacent mitral cells. The intraburst activity of most mitral cells showed strong entrainment to the spontaneous respiratory rhythm; similar entrainment was seen in some, but not all nonmitral cells. All mitral cells displayed a peak of excitability at ~25 msec after spikes, as reflected by a peak in the interspike interval distribution and in the corresponding hazard function. About half also showed a peak at about 6 msec, reflecting the common occurrence of doublet spikes. Nonmitral cells showed no such doublet spikes. Bursts typically increased in intensity over the first 20-30 sec of a burst, during which time doublets were rare or absent. After 20-30 sec (in cells that exhibited doublets), doublets occurred frequently for as long as the burst persisted, in trains of up to 10 doublets. The last doublet was followed by an extended relative refractory period the duration of which was independent of train length. In cells that were excited by application of a particular odor, responsiveness was apparently greater during silent periods between bursts than during bursts. Conversely in cells that were inhibited by a particular odor, responsiveness was only apparent when cells were active. Extensive raw (event timing) data from the cells, together with details of those analyses, are provided as supplementary material, freely available for secondary use by others. PMID- 25281615 TI - Scavenger receptor class B, type I (Scarb1) deficiency promotes osteoblastogenesis but stunts terminal osteocyte differentiation. AB - Scavenger receptor class B type I (SR-BI), the Scarb1 gene product, is a high density lipoprotein (HDL) receptor which was shown to influence bone metabolism. Its absence in mice is associated with alterations of the glucocorticoid/adrenocorticotropic hormone axis, and translated in high bone mass and enhanced bone formation. Since the cellular alterations underlying the enhanced bone formation remain unknown, we investigated Scarb1-deficient marrow stromal cells (MSC) behavior in vitro. No difference in HDL3, cholesteryl ester (CE) or estradiol (E) association/binding was measured between Scarb1-null and wild-type (WT) cells. Scarb1 genic expression was down-regulated twofold following osteogenic treatment. Neither WT nor null cell proliferation was influenced by HDL3 exposure whereas this condition decreased genic expression of osteoblastic marker osterix (Sp7), and osteocyte markers sclerostin (Sost) and dentin matrix protein 1 (Dmp1) independently of genotype. Sost and Dmp1 basal expression in null cells was 40% and 50% that of WT cells; accordingly, osteocyte density was 20% lower in vertebrae from Scarb1-null mice. Genic expression of co receptors for Wnt signaling, namely LDL-related protein (Lrp) 5 and Lrp8, was increased, respectively, by two- and threefold, and of transcription target-genes axis inhibition protein 2 (Axin2) and lymphoid enhancer-binding factor 1 (Lef1) over threefold. Gene expression of Wnt signaling agonist Wnt5a and of the antagonist dickkopfs-related protein 1 (Dkk1) were found to be increased 10- to 20-fold in null MSC. These data suggest alterations of Wnt pathways in Scarb1 deficient MSC potentially explaining their enhanced function, hence contributing to the high bone mass observed in these mice. PMID- 25281616 TI - Exercise-Induced growth hormone during acute sleep deprivation. AB - The effect of acute (24-h) sleep deprivation on exercise-induced growth hormone (GH) and insulin-like growth factor-1 (IGF-1) was examined. Ten men (20.6 +/- 1.4 years) completed two randomized 24-h sessions including a brief, high-intensity exercise bout following either a night of sleep (SLEEP) or (24-h) sleep deprivation (SLD). Anaerobic performance (mean power [MP], peak power [PP], minimum power [MinP], time to peak power [TTPP], fatigue index, [FI]) and total work per sprint [TWPS]) was determined from four maximal 30-sec Wingate sprints on a cycle ergometer. Self-reported sleep 7 days prior to each session was similar between SLEEP and SLD sessions (7.92 +/- 0.33 vs. 7.98 +/- 0.39 h, P = 0.656, respectively) and during the actual SLEEP session in the lab, the total amount of sleep was similar to the 7 days leading up to the lab session (7.72 +/- 0.14 h vs. 7.92 +/- 0.33 h, respectively) (P = 0.166). No differences existed in MP, PP, MinP, TTPP, FI, TWPS, resting GH concentrations, time to reach exercise induced peak GH concentration (TTP), or free IGF-1 between sessions. GH area under the curve (AUC) (825.0 +/- 199.8 vs. 2212.9 +/- 441.9 MUg/L*min, P < 0.01), exercise-induced peak GH concentration (17.8 +/- 3.7 vs. 39.6 +/- 7.1 MUg/L, P < 0.01) and DeltaGH (peak GH - resting GH) (17.2 +/- 3.7 vs. 38.2 +/- 7.3 MUg/L, P < 0.01) were significantly lower during the SLEEP versus SLD session. Our results indicate that the exercise-induced GH response was significantly augmented in sleep-deprived individuals. PMID- 25281619 TI - Exponential growth of tranesesophageal echocardiography in India in the last decade: contribution of Indian Association of Cardiovascular Thoracic Anesthesiologists. PMID- 25281618 TI - Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport. AB - Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase in glycolysis in human tumor cell lines and xenografts. This is indicated by changes in the levels of specific glycolytic metabolites and in changes in glycolytic enzyme kinetics. These drug-induced metabolic changes translate into an inhibition of tumor growth in vivo. Thus, we combined AZD3965 with fractionated radiation to treat small cell lung cancer (SCLC) xenografts and showed that the combination provided a significantly greater therapeutic effect than the use of either modality alone. These results strongly support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors. PMID- 25281620 TI - Predicting mortality after congenital heart surgeries: evaluation of the Aristotle and Risk Adjustement in Congenital Heart Surgery-1 risk prediction scoring systems: a retrospective single center analysis of 1150 patients. AB - AIMS AND OBJECTIVES: To validate Aristotle basic complexity and Aristotle comprehensive complexity (ABC and ACC) and risk adjustment in congenital heart surgery-1 (RACHS-1) prediction models for in hospital mortality after surgery for congenital heart disease in a single surgical unit. MATERIALS AND METHODS: Patients younger than 18 years, who had undergone surgery for congenital heart diseases from July 2007 to July 2013 were enrolled. Scoring for ABC and ACC scoring and assigning to RACHS-1 categories were done retrospectively from retrieved case files. Discriminative power of scoring systems was assessed with area under curve (AUC) of receiver operating curves (ROC). Calibration (test for goodness of fit of the model) was measured with Hosmer-Lemeshow modification of chi2 test. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were applied to assess reclassification. RESULTS: A total of 1150 cases were assessed with an all-cause in-hospital mortality rate of 7.91%. When modeled for multivariate regression analysis, the ABC (chi2 = 8.24, P = 0.08), ACC (chi2 = 4.17 , P = 0.57) and RACHS-1 (chi2 = 2.13 , P = 0.14) scores showed good overall performance. The AUC was 0.677 with 95% confidence interval (CI) of 0.61-0.73 for ABC score, 0.704 (95% CI: 0.64-0.76) for ACC score and for RACHS-1 it was 0.607 (95%CI: 0.55-0.66). ACC had an improved predictability in comparison to RACHS-1 and ABC on analysis with NRI and IDI. CONCLUSIONS: ACC predicted mortality better than ABC and RCAHS-1 models. A national database will help in developing predictive models unique to our populations, till then, ACC scoring model can be used to analyze individual performances and compare with other institutes. PMID- 25281617 TI - Therapeutic silencing of KRAS using systemically delivered siRNAs. AB - Despite being among the most common oncogenes in human cancer, to date, there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed antiproliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nanoliposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were used to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis, and downstream signaling. KRAS siRNA sequences induced >90% knockdown of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, whereas significant increases in caspase-3 activity were only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional "undruggable" targets. PMID- 25281621 TI - Predicting mortality after congenital heart surgeries: evaluation of the Aristotle and Risk Adjustment in Congenital Heart Surgery-1 risk prediction scoring systems: a retrospective single center analysis of 1150 patients. PMID- 25281622 TI - Comparison between continuous non-invasive estimated cardiac output by pulse wave transit time and thermodilution method. AB - AIMS AND OBJECTIVES: Cardiac output (CO) measurement is essential for many therapeutic decisions in anesthesia and critical care. Most available non invasive CO measuring methods have an invasive component. We investigate "pulse wave transit time" (estimated continuous cardiac output [esCCO]) a method of CO measurement that has no invasive component to its use. MATERIALS AND METHODS: After institutional ethical committee approval, 14 adult (21-85 years) patients undergoing surgery and requiring pulmonary artery catheter (PAC) for measuring CO, were included. Postoperatively CO readings were taken simultaneously with thermodilution (TD) via PAC and esCCO, whenever a change in CO was expected due to therapeutic interventions. Both monitoring methods were continued until patients' discharge from the Intensive Care Unit and observer recording values using TD method was blinded to values measured by esCCO system. RESULTS: Three hundred and one readings were obtained simultaneously from both methods. Correlation and concordance between the two methods was derived using Bland Altman analysis. Measured values showed significant correlation between esCCO and TD ( r = 0.6, P < 0.001, 95% confidence limits of 0.51-0.68). Mean and (standard deviation) for bias and precision were 0.13 (2.27) L/min and 6.56 (2.19) L/min, respectively. The 95% confidence interval for bias was - 4.32 to 4.58 L/min and for precision 2.27 to10.85 L/min. CONCLUSIONS: Although, esCCO is the only true non-invasive continuous CO monitor available and even though its values change proportionately to TD method (gold standard) with the present degree of error its utility for clinical/therapeutic decision-making is questionable. PMID- 25281623 TI - Comparison between continuous noninvasive estimated cardiac output by pulse wave transit time and thermodilution method. PMID- 25281624 TI - Echocardiography derived three-dimensional printing of normal and abnormal mitral annuli. AB - AIMS AND OBJECTIVES: The objective of this study was to assess the clinical feasibility of using echocardiographic data to generate three-dimensional models of normal and pathologic mitral valve annuli before and after repair procedures. MATERIALS AND METHODS: High-resolution transesophageal echocardiographic data from five patients was analyzed to delineate and track the mitral annulus (MA) using Tom Tec Image-Arena software. Coordinates representing the annulus were imported into Solidworks software for constructing solid models. These solid models were converted to stereolithographic (STL) file format and three dimensionally printed by a commercially available Maker Bot Replicator 2 three dimensional printer. Total time from image acquisition to printing was approximately 30 min. RESULTS: Models created were highly reflective of known geometry, shape and size of normal and pathologic mitral annuli. Post-repair models also closely resembled shapes of the rings they were implanted with. Compared to echocardiographic images of annuli seen on a computer screen, physical models were able to convey clinical information more comprehensively, making them helpful in appreciating pathology, as well as post-repair changes. CONCLUSIONS: Three-dimensional printing of the MA is possible and clinically feasible using routinely obtained echocardiographic images. Given the short turn around time and the lack of need for additional imaging, a technique we describe here has the potential for rapid integration into clinical practice to assist with surgical education, planning and decision-making. PMID- 25281625 TI - Echocardiography derived three- dimensional printing of normal and abnormal mitral annuli. PMID- 25281626 TI - Therapeutic hypothermia after cardiac arrest. AB - Prognosis following out-of-hospital cardiac arrest is generally poor, which is mostly due to the severity of neuronal damage. Recently, the use of therapeutic hypothermia has gradually occupied an important role in managing neuronal injuries in some cases of cardiac arrests. Some of the clinical trials conducted in comatose post-resuscitation cardiac arrest patients within the last decade have shown induced hypothermia to be effective in facilitating neuronal function recovery. This method has since been adopted in a number of guidelines and protocols as the standard method of treatment in carefully selected patient groups. Patient inclusion criteria ensure that hypothermia-associated complications are kept to a minimum while at the same time maximizing the treatment benefits. In the present work, we have examined different aspects in the use of therapeutic hypothermia as a means of managing comatose patients following cardiac arrest. PMID- 25281627 TI - Successful anesthetic management in a child after traumatic rupture of left main bronchus by a single-lumen cuffed-endotracheal tube. AB - Tracheobronchial injury (TBI) may lead to catastrophe if remains undetected or managed improperly. The incidence of TBI is less in children as compared with adults due to their pliable chest wall. Its clinical manifestations include persistent pneumothorax, cervical subcutaneous emphysema, pneumomediastinum, cyanosis, and respiratory insufficiency. The recommended airway management is to intubate the healthy bronchus with a single-lumen or double-lumen endotracheal tube (ET) and bypassing the injured side. We report successful anesthetic management of traumatic rupture of the left main bronchus in a child by using a single-lumen cuffed-ET. Many factors affect the outcome of such injuries and include the extent of the lesion, the resulting pulmonary status, the adequacy of surgical reconstruction. More severe injury may require lobectomy or pneumonectomy. Early diagnosis and proper management result in good functional outcome. PMID- 25281628 TI - A proposed method to visualize the ductus arteriosus on transesophageal echocardiography. AB - The ductus arteriosus occupies a uniquely privileged position in the management of heart disease; it initiated not only the surgical management of congenital lesions but also the percutaneous management of this subset. During trans thoracic echocardiography (TTE) the ductus is often visualized using 'high' parasternal (or the 'ductal' view) or suprasternal windows. It is generally agreed that imaging ductus during transesophageal echo (TEE) can be sub-optimal. During TEE imaging, visualization of the ductus arteriosus is obscured by the acoustic impedance offered by the left main bronchus; adjunct techniques such as insertion of a saline filled balloon in this airway have been used. We describe a simple maneuver that allows visualization of the patent ductus arteriosus during TEE imaging without the use of any adjuncts. PMID- 25281629 TI - Toe thumb: a musculoskeletal disorder related to transesophageal echocardiography. AB - The musculoskeletal disorders (MSD) are common in healthcare providers and those who are doing sonography are also affected. There are reports of MSD in healthcare providers who do transthoracic echocardiography. Transesophageal echocardiography (TEE) is being regularly used in peri-operative setting. We describe MSD of hand in a cardiovascular and thoracic anesthesiologist who has been performing TEE scanning for 10% of his work-time in operating room and critical care area for the last 8 years. As the role of TEE is increasing and many doctors are doing it on a routine basis, the knowledge of association of MSD with TEE and measures to prevent it is important. PMID- 25281630 TI - Severe tracheobronchial compression in a patient with Turner's syndrome undergoing repair of a complex aorto-subclavian aneurysm: anesthesia perspectives. AB - We present a case of severe tracheobronchial compression from a complex aorto subclavian aneurysm in a patient with Turner's syndrome undergoing open surgical repair. Significant airway compression is a challenging situation and requires careful preoperative preparation, maintenance of spontaneous breathing when possible, and consideration of having an alternative source of oxygenation and circulation established prior to induction of general anesthesia. Cardiopulmonary monitoring is essential for safe general anesthesia and diagnosis of unexpected intraoperative events. PMID- 25281631 TI - Intraoperative transesophageal echocardiography assessment of right atrial myxoma resulting in a change of the surgical plan. AB - Transesophageal echocardiography (TEE) is an important diagnostic tool. It provides structural and functional assessment of cardiac structures which can improve the overall outcome of the patient. We present a case with right atrial myxoma in which TEE helped to find the attachment of the mass so that overall surgical plan was changed. PMID- 25281632 TI - Large Eustachian valve: an incidental finding yet perplexing. AB - Eustachian valve (EV), a remnant of the right valve of sinus venosus in the right atrium can be puzzling. Often it is confused with Chiari network or atrial adhesions and is reported with unusual complications. We report a case of large EV impeding cannulation of inferior vena cava (IVC) during aortic valve replacement. Transesophageal echocardiography diagnosed the presence of large EV and warned of the difficulty with IVC cannulation and helped preparedness for an alternative plan during surgery. PMID- 25281633 TI - Right-sided aortic arch with Kommerell's aneurysm. AB - We present a case report of a 55-year-old lady who presented with progressive dysphagia and was diagnosed with a Kommerell's aneurysm and a right-sided aortic arch. This case report outlines our management strategy and the challenges encountered during the perioperative period in a patient with this rare anomaly. PMID- 25281634 TI - Intraoperative localization and monitoring of migrating foreign body using transesophageal echocardiography. AB - Radiological imaging is often used for the preoperative localization of foreign body following blast injury, but their utility in case of migration during intra operative period is limited. Transesophageal echocardiography (TEE) has been used for intra-operative localization and removal of intra-cardiac foreign body; however, reports for localization of extracardiac migrating foreign body are few. Preoperative radiological imaging, in a victim of factory blast-injury, suggested foreign body in the posterior mediastinum. However, the intra-operative TEE showed it in the left atrium, which later migrated into the left ventricle necessitating a change in surgical approach for its removal. PMID- 25281635 TI - Left atrial band: a rare congenital anomaly. AB - Left atrial fibromuscular band is a rare congenital cardiac anomaly. We present a patient with an incidental finding of left atrial band on an intra-operative transesophageal echocardiogram and characterize its appearance on two-dimensional and three-dimensional echocardiograms. PMID- 25281636 TI - An uncommon presentation of partially ligated left atrial appendage on transesophageal echocardiography. PMID- 25281637 TI - TRPV4: an exciting new target to promote alveolocapillary barrier function. AB - Transient receptor potential (TRP) channels are emerging as important players and drug targets in respiratory disease. Amongst the vanilloid-type TRP channels (which includes the six members of the TRPV family), target diseases include cough, asthma, cancer, and more recently, pulmonary edema associated with acute respiratory distress syndrome. Here, we critically evaluate a recent report that addresses TRPV4 as a candidate target for the management of acute lung injury that develops as a consequence of aspiration of gastric contents, or acute chlorine gas exposure. By use of two new TRPV4 inhibitors (GSK2220691 or GSK2337429A) and a trpv4(-/-) mouse strain, TRPV4 was implicated as a key mediator of pulmonary inflammation after direct chemical insult. Additionally, applied therapeutically, TRPV4 inhibitors exhibited vasculoprotective effects after chlorine gas exposure, inhibiting vascular leakage, and improving blood oxygenation. These observations underscore TRPV4 channels as candidate therapeutic targets in the management of lung injury, with the added need to balance these against the potential drawbacks of TRPV4 inhibition, such as the danger of limiting the immune response in settings of pathogen-provoked injury. PMID- 25281638 TI - Carl Wilhelm Scheele, the discoverer of oxygen, and a very productive chemist. AB - Carl Wilhelm Scheele (1742-1786) has an important place in the history of the discovery of respiratory gases because he was undoubtedly the first person to prepare oxygen and describe some of its properties. Despite this, his contributions have often been overshadowed by those of Joseph Priestley and Antoine Lavoisier, who also played critical roles in preparing the gas and understanding its nature. Sadly, Scheele was slow to publish his discovery and therefore Priestley is rightly recognized as the first person to report the preparation of oxygen. This being said, the thinking of both Scheele and Priestley was dominated by the phlogiston theory, and it was left to Lavoisier to elucidate the true nature of oxygen. In addition to his work on oxygen, Scheele was enormously productive in other areas of chemistry. Arguably he discovered seven new elements and many other compounds. However, he kept a low profile during his life as a pharmacist, and he did not have strong links with contemporary prestigious institutions such as the Royal Society in England or the French Academie des Sciences. He was elected to the Royal Swedish Academy of Science but only attended one meeting. Partly as a result, he remains a somewhat nebulous figure despite the critical contribution he made to the history of respiratory gases and his extensive researches in other areas of chemistry. His death at the age of 43 may have been hastened by his habit of tasting the chemicals that he worked on. PMID- 25281641 TI - Younger diabetes patients receive poorer routine care than older ones, audit finds. PMID- 25281640 TI - Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling. AB - In hypoxic pulmonary arterial (PA) myocytes, challenge with thromboxane mimetic U46619 induces marked actin polymerization and contraction, phenotypic features of persistent pulmonary hypertension of the newborn (PPHN). Rho GTPases regulate the actin cytoskeleton. We previously reported that U46619-induced actin polymerization in hypoxic PA myocytes occurs independently of the RhoA pathway and hypothesized involvement of the Cdc42 pathway. PA myocytes grown in normoxia or hypoxia for 72 h were stimulated with U46619, then analyzed for Rac/Cdc42 activation by affinity precipitation, phosphatidylinositide-3-kinase (PI3K) activity by phospho-Akt, phospho-p21-activated kinase (PAK) by immunoblot, and association of Cdc42 with neuronal Wiskott Aldrich Syndrome protein (N-WASp) by immunoprecipitation. The effect of Rac or PAK inhibition on filamentous actin was quantified by laser-scanning cytometry and by cytoskeletal fractionation; effects of actin-modifying agents were measured by isometric myography. Basal Cdc42 activity increased in hypoxia, whereas Rac activity decreased. U46619 challenge increased Cdc42 and Rac activity in hypoxic cells, independently of PI3K. Hypoxia increased phospho-PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia but increased after U46619 exposure. Hypoxia doubled filamentous-to-globular ratios of alpha- and gamma-actin isoforms. Jasplakinolide stabilized gamma-filaments, increasing force; cytochalasin D depolymerized all actin isoforms, decreasing force. Rac and PAK inhibition decreased filamentous actin in tissues although without decrease in force. Rho inhibition decreased myosin phosphorylation and force. Hypoxia induces actin polymerization in PA myocytes, particularly increasing filamentous alpha- and gamma-actin, contributing to U46619-induced contraction. Hypoxic PA myocytes challenged with a thromboxane mimetic polymerize actin via the Cdc42 pathway, reflecting increased Cdc42 association with N-WASp. Mechanisms regulating thromboxane-mediated actin polymerization are potential targets for future PPHN pharmacotherapy. PMID- 25281639 TI - Animal models of bronchopulmonary dysplasia. The preterm baboon models. AB - Much of the progress in improved neonatal care, particularly management of underdeveloped preterm lungs, has been aided by investigations of multiple animal models, including the neonatal baboon (Papio species). In this article we highlight how the preterm baboon model at both 140 and 125 days gestation (term equivalent 185 days) has advanced our understanding and management of the immature human infant with neonatal lung disease. Not only is the 125-day baboon model extremely relevant to the condition of bronchopulmonary dysplasia but there are also critical neurodevelopmental and other end-organ pathological features associated with this model not fully discussed in this limited forum. We also describe efforts to incorporate perinatal infection into these preterm models, both fetal and neonatal, and particularly associated with Ureaplasma/Mycoplasma organisms. Efforts to rekindle the preterm primate model for future evaluations of therapies such as stem cell replacement, early lung recruitment interventions coupled with noninvasive surfactant and high-frequency nasal ventilation, and surfactant therapy coupled with antioxidant or anti-inflammatory medications, to name a few, should be undertaken. PMID- 25281642 TI - AMPK up-activation reduces motility and regulates other functions of boar spermatozoa. AB - We recently demonstrated that AMPK inhibition in spermatozoa regulates motility, plasma membrane organization, acrosome integrity and mitochondrial membrane potential. As AMPK activity varies in different energy conditions induced by sperm environment, this work investigates the functional effects of AMPK activation in boar spermatozoa. Spermatozoa were incubated under non-stimulating (TBM) or Ca(2+) and [Formula: see text]-stimulating (TCM) media in the presence/absence of AMPK activator, A769662, for different times. AMPK activity, evaluated as Thr(172) phosphorylation by western blot, is effectively increased by A769662 in spermatozoa. AMPK activation significantly reduces the percentage of motile spermatozoa under Ca(2+) and/or [Formula: see text]-stimulating conditions. Moreover, AMPK activation in spermatozoa incubated in TBM or TCM significantly reduces curvilinear VCL, straight-line VSL and average VAP velocities, which subsequently lead to a significant decrease in the percentage of rapid spermatozoa (VAP > 80 MUm/s). The effect of AMPK activation on motility is intensified by the absence of BSA in the incubation medium. AMPK activation for a short time prevents the decline in cell viability and in the sperm population displaying high mitochondrial membrane potential which is induced by Ca(2+) and [Formula: see text]. Sustained (24 h) AMPK activation under TBM or TCM significantly increases both lipid disorganization and phosphatidylserine externalization in the sperm plasma membrane, and diminishes the acrosome membrane integrity. In summary, AMPK activation modifies essential sperm processes such as motility, viability, mitochondrial membrane potential, acrosome membrane integrity, and organization and fluidity of plasma membrane. As these spermatozoa processes are required under different environmental conditions when transiting through the female reproductive tract to achieve fertilization, we conclude that balanced levels of AMPK activity are essential for regulating sperm function. PMID- 25281643 TI - Antibacterial wound dressing from chitosan/polyethylene oxide nanofibers mats embedded with silver nanoparticles. AB - Novel antibacterial nanomaterials have been developed for biomedical applications. The present study involves the preparation and properties of antibacterial nanofibers from chitosan/polyethylene oxide electrospun nanofibers incorporated with silver nanoparticles. Silver nanoparticles were efficiently synthesized in situ after ultra violet (UV) with AgNO3 as precursor and chitosan/polyethylene oxide as reducing agent and protecting agent, respectively. Then the resultant solutions were electrospun into nanofibers. The formation of silver nanoparticles was confirmed with ultraviolet visible (UV-vis) and transmission electron microscopy (TEM), and the electrospun nanofibers were characterized by scanning electron microscopy and energy dispersive X-ray. The resultant fibers exhibited uniform morphology with silver nanoparticles distributed throughout the fiber. Also, the fibers showed certain tensile strength and excellent antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. Sustained release of silver nanoparticles from fibers could last for over 72 h. The silver containing chitosan/polyethylene oxide nanofibers showed excellent cytocompatibility. PMID- 25281644 TI - Combining xanthan and chitosan membranes to multipotent mesenchymal stromal cells as bioactive dressings for dermo-epidermal wounds. AB - The association between tridimensional scaffolds to cells of interest has provided excellent perspectives for obtaining viable complex tissues in vitro, such as skin, resulting in impressive advances in the field of tissue engineering applied to regenerative therapies. The use of multipotent mesenchymal stromal cells in the treatment of dermo-epidermal wounds is particularly promising due to several relevant properties of these cells, such as high capacity of proliferation in culture, potential of differentiation in multiple skin cell types, important paracrine and immunomodulatory effects, among others. Membranes of chitosan complexed with xanthan may be potentially useful as scaffolds for multipotent mesenchymal stromal cells, given that they present suitable physico chemical characteristics and have adequate tridimensional structure for the adhesion, growth, and maintenance of cell function. Therefore, the purpose of this work was to assess the applicability of bioactive dressings associating dense and porous chitosan-xanthan membranes to multipotent mesenchymal stromal cells for the treatment of skin wounds. The membranes showed to be non-mutagenic and allowed efficient adhesion and proliferation of the mesenchymal stromal cells in vitro. In vivo assays performed with mesenchymal stromal cells grown on the surface of the dense membranes showed acceleration of wound healing in Wistar rats, thus indicating that the use of this cell-scaffold association for tissue engineering purposes is feasible and attractive. PMID- 25281645 TI - Coculture with intraocular lens material-activated macrophages induces an inflammatory phenotype in lens epithelial cells. AB - Cataracts are the leading cause of blindness worldwide, requiring surgical implantation of an intraocular lens. Despite evidence of leukocyte ingress into the postoperative lens, few studies have investigated the leukocyte response to intraocular lens materials. A novel coculture model was developed to examine macrophage activation by hydrophilic acrylic (poly(2-hydroxyethyl methacrylate)) and hydrophobic acrylic (polymethylmethacrylate) commercial intraocular lens. The human monocytic cell line THP-1 was differentiated into macrophages and cocultured with human lens epithelial cell line (HLE-B3) with or without an intraocular lens for one, two, four, or six days. Using flow cytometry and confocal microscopy, expression of the macrophage activation marker CD54 (intercellular adhesion molecule-1) and production of reactive oxygen species via the fluorogenic probe 2',7'-dichlorodihydrofluorescein diacetate were examined in macrophages. alpha-Smooth muscle actin, a transdifferentiation marker, was characterized in lens epithelial cells. The poly(2-hydroxyethyl methacrylate) intraocular lens prevented adhesion but induced significant macrophage activation (p < 0.03) versus control (no intraocular lens), while the polymethylmethacrylate intraocular lens enabled adhesion and multinucleated fusion, but induced no significant activation. Coculture with either intraocular lens increased reactive oxygen species production in macrophages after one day (p < 0.03) and increased expression of alpha-smooth muscle actin in HLE B-3 after six days, although only poly(2-hydroxyethyl methacrylate) induced a significant difference versus control (p < 0.01). Our results imply that-contrary to prior uveal biocompatibility understanding-macrophage adherence is not necessary for a strong inflammatory response to an intraocular lens, with hydrophilic surfaces inducing higher activation than hydrophobic surfaces. These findings provide a new method of inquiry into uveal biocompatibility, specifically through the quantification of cell-surface markers of leukocyte activation. PMID- 25281646 TI - Fast in situ generated E-polylysine-poly (ethylene glycol) hydrogels as tissue adhesives and hemostatic materials using an enzyme-catalyzed method. AB - In this study, novel bio-inspired in situ hydrogels as tissue adhesives and hemostatic materials were designed and prepared based on E-polylysine-grafted poly(ethylene glycol) and tyramine via enzymatic cross-linking. The enzymatic cross-linked method enabled fast gelation within seconds, which facilitated its therapeutic applications. By changing the cross-linking conditions, the storage modulus of the hydrogels could be tunable and the mechanical strength influenced the tissue adhesiveness of the hydrogels. Besides, the hydrogels showed fine network structures with appropriate pore sizes, which were thought to be a contributing factor to the strong adhesiveness. Benefiting from the strong mechanical properties and fine network structures, the E-polylysine-grafted poly(ethylene glycol) and tyramine hydrogels exhibited superior wound-healing and hemostatic ability compared to conventional and commercially available medical materials. Moreover, indirect cytotoxicity assessment indicated that the E polylysine-grafted poly(ethylene glycol) and tyramine hydrogels were nontoxic to the L929 cell. These results demonstrated that the enzymatic cross-linked in situ E-polylysine hydrogels hold high potential for tissue sealants and hemostatic materials. PMID- 25281647 TI - The effect of osteotomy dimension on osseointegration to resorbable media-treated implants: a study in the sheep. AB - The drilling technique and the surface characteristics are known to influence the healing times of oral implants. The influence of osteotomy dimension on osseointegration of microroughned implant surfaces treated with resorbable blasting media was tested in an in vivo model. Ninety-six implants (o4.5 mm, 8 mm in length) with resorbable blasting media-treated surfaces were placed in the ileum of six sheep. The final osteotomy diameters were 4.6 mm (reamer), 4.1 mm (loose), 3.7 mm (medium), and 3.2 mm (tight). After three and six weeks of healing, the implants were biomechanically tested and histologically evaluated. Statistical analysis was performed using Page L trend test for ordered and paired sample and linear regression, with significance level at p < 0.05. An overall increase in all dependent variables was observed with the reduction of osteotomy diameter. In addition, all osseointegration scores increased over time. At three weeks, the retention was significantly higher for smaller osteotomies. The histological sections depicted intimate contact of bone with all the implant surfaces and osteoblast lines were visible in all sections. The resorbable blasting media microroughed surfaces achieved successful osseointegration for all the instrumentation procedures tested, with higher osseointegration scores for the high insertion torque group. PMID- 25281648 TI - Initial observations on using magnesium metal in peripheral nerve repair. AB - Biodegradable magnesium metal filaments placed inside biodegradable nerve conduits might provide the physical guidance support needed to improve the rate and extent of regeneration of peripheral nerves across injury gaps. In this study, we examined basic issues of magnesium metal resorption and biocompatibility by repairing sub-critical size gap injuries (6 mm) in one sciatic nerve of 24 adult male Lewis rats. Separated nerve stumps were connected with poly(caprolactone) nerve conduits, with and without magnesium filaments (0.25 mm diameter, 10 mm length), with two different conduit filler substances (saline and keratin hydrogel). At 6 weeks after implantation, magnesium degradation was examined by micro-computed tomography and histological analyses. Magnesium degradation was significantly greater when the conduits were filled with an acidic keratin hydrogel than with saline (p < 0.05). But magnesium filaments in some animals remained intact for 6 weeks. Using histological and immunocytochemical analyses, good biocompatibility of the magnesium implants was observed at 6 weeks, as shown by good development of regenerating nerve mini fascicles and only mild inflammation in tissues even after complete degradation of the magnesium. Nerve regeneration was not interrupted by complete magnesium degradation. An initial functional evaluation, determination of size recovery of the gastrocnemius muscle, showed a slight improvement due to magnesium with the saline but not the keratin filler, compared with respective control conduits without magnesium. These results suggest that magnesium filament implants have the potential to improve repair of injured peripheral nerve defects in this rodent model. PMID- 25281649 TI - In vitro characterization of polyesters of aconitic acid, glycerol, and cinnamic acid for bone tissue engineering. AB - In this study, a novel class of polyesters of glycerol, aconitic acid, and cinnamic acid were synthesized along with their hydroxyapatite (HA) composites, and studied for their potential application in bone defect repair. An osteogenic study was conducted with human adipose derived mesenchymal stem cells (hASCs) to determine the osteoinductive ability of aconitic acid-glycerol (AG) polyesters, AG:HA (80:20), aconitic acid-glycerol-cinnamic acid (AGC) polyesters, and AGC:HA (80:20) to serve as bone scaffolds. The results indicate that AGC scaffolds have the highest mechanical strength in comparison to AG, AG:HA (80:20), and AGC:HA (80:20) scaffolds due to its low porosity. It was determined by cytotoxicity and osteogenesis experiments that hASCs cultured for 21 days on AG:HA (80:20) scaffolds in stromal medium exhibited a greater number of live cells than control PCL:HA composites. Moreover, hASCs cultured on foamed AG:HA (80:20) scaffolds resulted in the highest levels of mineralization, increased alkaline phosphatase (ALP) expression, and the greatest osteocalcin (OCN) expression after 21 days. Overall, AG:HA (100:0 and 80:20) scaffolds had higher mechanical strength and cytocompatibility than the PCL:HA control. In vitro osteogenic study demonstrated that AG:HA (100:0 and 80:20) synthesized using sugarcane industry by-products hold potential as scaffolds for bone tissue engineering applications. PMID- 25281650 TI - Immunohistochemical Expression of Angiogenic Factors by Neoplastic Epithelial Cells Is Associated With Canine Prostatic Carcinogenesis. AB - The dog is the only species, other than humans, in which spontaneous prostatic cancer occurs; therefore, dogs are a valuable model for the study of factors that regulate tumor progression. Angiogenesis is important in the development and spread of a variety of cancers, including prostate cancer. To better define the role of cancer epithelial cells in prostate cancer neovascularization, immunohistochemical staining for angiogenic factors (vascular endothelial growth factor [VEGF], platelet endothelial cell adhesion molecule-1 [PECAM-1], Tie-2, and fibroblast growth factor-2 [FGF-2]) was performed on formalin-fixed, paraffin embedded tissues from 10 normal prostates, 15 hyperplastic prostates, and 11 prostatic carcinomas from dogs. Normal and hyperplastic epithelial cells were negative for PECAM-1, VEGF, and Tie-2, while the same markers were expressed with a variable intensity of cytoplasmic staining by neoplastic cells. Mild to moderate FGF-2 staining was detected in all normal prostates with less than 10% of positive cells, mainly distributed in the basal layer. The percentage of FGF-2 positive hyperplastic cells was variable, with both basal and secretory cells exhibiting a perinuclear to diffuse cytoplasmic staining. The mean number of positive cells and the intensity of staining were higher in prostatic carcinomas than normal and hyperplastic prostates. Moreover, microvessel density analyzed on PECAM-1-stained slides was increased in prostate cancer compared with normal and hyperplastic prostates. Therefore, prostatic neoplastic cells are capable of simultaneous expression of various angiogenic factors and may increase tumor proliferation and angiogenesis in a paracrine and autocrine fashion. PMID- 25281651 TI - Hypervitaminosis D and Metastatic Calcification in a Colony of Inbred Strain 13 Guinea Pigs, Cavia porcellus. AB - A commercial diet fed to a colony of inbred strain 13 guinea pigs for approximately 6 weeks was subsequently recalled for excessive levels of vitamin D. Twenty-one of 62 animals exhibited clinical signs, including anorexia, lethargy, and poor body condition. Nine affected and 4 clinically normal animals were euthanized for further evaluation, including serum chemistry, urinalysis, and gross and/or histopathology. Macroscopic findings included white discoloration in multiple organs in 8 animals, and microscopic evaluation confirmed multiorgan mineralization in tissues from 7 animals. Serum 25 hydroxyvitamin D levels were elevated in 10 animals. Serum inorganic phosphorus and alkaline phosphatase levels were increased in all exposed animals; however, total calcium and ionized calcium levels were not significantly higher in exposed animals than in control strain 13 guinea pigs from a different institution. The data support a diagnosis of hypervitaminosis D with metastatic calcification. Following the diet recall, the remaining guinea pigs increased their food intake and regained body condition. Diagnostic testing of 8 animals euthanized approximately 3 months after returning to a normal diet demonstrated that serum parathyroid hormone remained significantly lower, and ionized calcium and ionized magnesium were significantly higher, in recovered animals compared to controls and exposed animals. These results indicate that diagnostic tests other than serum calcium are necessary for a diagnosis of hypervitaminosis D in guinea pigs. PMID- 25281653 TI - Diagnostic Exercise: Metastatic Calcification in Guinea Pigs. AB - Seven male Hartley guinea pigs, 3 to 18 months old, died or had to be euthanized because of nonspecific clinical signs unresponsive to supportive treatment. Gross necropsy and histopathology findings in all animals included severe soft tissue calcification affecting the myocardium, kidneys, and occasionally the liver. PMID- 25281652 TI - Right Ventricular Epicardial Fibrosis in Mice With Sternal Segment Dislocation. AB - We report coincident sternal segment dislocation and focally extensive right ventricular epicardial fibrosis observed during routine histopathology evaluation of C57BL/6N mice as part of a high throughput phenotyping screen conducted between 4 and 16 weeks of age. This retrospective case series study was conducted to determine whether cardiac fibrosis was a pathological consequence of sternal segment dislocation. We identified sternal segment dislocation in 51 of the total 1103 mice (4.6%) analyzed at 16 weeks of age. Males were more frequently affected. In all cases but 2, the dislocation occurred at the fourth intersternebral joint. In 42 of the 51 cases (82.4%), the dislocation was encased by regenerative cartilaginous callus that protruded internally into the thoracic cavity (intrathoracic callus) and/or externally to the outer aspect of the sternum (extrathoracic callus). Displacement of dislocated ends of the sternum into the thoracic cavity was present in 19 of 51 cases (36.5%). Coincident minimal or mild right ventricular epicardial and subepicardial fibrosis was observed in 22 of the 51 cases (43%) but was not observed in any of the mice in the absence of sternal segment dislocation. Our data suggest that right ventricular fibrosis was likely caused by direct injury of the right ventricle by the dislocated ends of the sternum and/or by intrathoracic callus that develops post dislocation. Potential pathogenesis for the sternal and cardiac lesions and their implication for the interpretation of phenotypes in mouse models of cardiopulmonary and skeletal disease are discussed. PMID- 25281654 TI - Ischemic electrocardiographic abnormalities and prognosis in decompensated heart failure. AB - BACKGROUND: Identification of coronary ischemia may enable targeted diagnostic and therapeutic strategies for acute heart failure. We determined the risk of 30 day mortality associated with ischemic ECG abnormalities in patients with acute heart failure. METHODS AND RESULTS: Among 8772 patients (53.4% women, median 78 years [Q1, Q3: 68,84]) presenting with acute heart failure to 86 hospital emergency departments in Ontario, Canada, Q-waves, T-wave inversion, or ST depression were present in 51.8% of subjects. However, presence of ST-depression was the only finding associated with 30-day mortality with adjusted odds ratio 1.24 (95% confidence interval [CI], 1.02-1.50). Using continuous net reclassification improvement, addition of ST-depression to the Emergency Heart failure Mortality Risk Grade model reclassified 16.9% of patients overall, and 29.3% of those with a history of ischemic heart disease (both P<0.001). By adding ST-depression to the model, the Emergency Heart failure Mortality Risk Grade was extended to predict 30-day death with high discrimination (c-statistic 0.801), with 0.57% mortality rate in the lowest risk decile. Adjusted odds ratios for 30 day mortality were 2.81 (95% CI, 1.48-5.31; P=0.002) in quintile 2, 7.41 (95% CI, 4.13-13.30; P<0.001) in quintile 3, and 14.47 (95% CI, 8.20-25.54; P<0.001) in quintile 4 compared with the lowest risk quintile. When the highest risk quintile was subdivided into 2 equally sized risk strata (deciles 9 and 10), the adjusted odds ratios for 30-day mortality were 27.20 (95% CI, 15.33-48.27; P<0.001) in decile 9 and 58.96 (95% CI, 33.54-103.65; P<0.001) in highest risk decile 10. CONCLUSIONS: Presence of ST-depression on the ECG reclassified risk of 30-day mortality in patients with acute heart failure, identifying both high- and low risk subsets. PMID- 25281656 TI - Impact of hospital volume on long-term survival after resection for oesophageal cancer: a population-based study in Taiwan?. AB - OBJECTIVES: Previous studies have shown that patients who undergo oesophageal cancer surgery in high-volume hospitals have lower postoperative mortality rates. However, the impact of hospital volume on long-term survival is controversial. METHODS: We identified 2151 patients who were diagnosed with oesophageal cancer between 2008 and 2011 from a national population-based cancer registry in Taiwan. High-volume hospitals were defined as those performing more than 86 oesophagectomies during that period (22 cases/year). Patients were stratified by whether they received preoperative chemoradiation. Cox regression analyses were used to determine the survival impact of hospital volume. RESULTS: The 3-year overall survival rates after oesophagectomies were 44.9% in high-volume hospitals, compared with 40.2% in low-volume hospitals (P = 0.002). For patients who received preoperative chemoradiation (n = 850), the 1- and 3-year overall survival rates were 74.7 and 36.8%, respectively, in high-volume hospitals, compared with 73.5 and 42.6%, respectively, in low-volume hospitals (P = 0.333). For patients who did not receive preoperative chemoradiation (n = 1301), the 1- and 3-year overall survival rates were 78.1 and 50.0%, respectively, in high volume hospitals, compared with 67.9 and 38.8%, respectively, in low-volume hospitals (P < 0.001). Multivariate analysis showed that hospital volume, resection margin, cT, pT and pN stages are significant independent prognostic factors. CONCLUSIONS: Overall survival rate of patients who undergo oesophagectomies without preoperative chemoradiation at high-volume hospitals is significantly higher than at low-volume hospitals. However, there was no significant correlation between hospital volume and long-term outcome in patients who received preoperative chemoradiation. PMID- 25281655 TI - Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF. AB - BACKGROUND: Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood. METHODS AND RESULTS: Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76 2.23; P<0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17-2.60; P<0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13-1.52; P=0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06-1.40; P=0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57-2.61; P<0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34-1.86; P<0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22-1.61; P<0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction P=0.874 for death, P=0.908 for death/heart failure hospitalization, P=0.238 death/all-cause hospitalization). CONCLUSIONS: Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. PMID- 25281657 TI - Robotic lobectomy: tips, pitfalls and troubleshooting. AB - The robotic approach in thoracic surgery has rapidly gained popularity in recent years. As with the introduction of any new technology, this warrants not only adaptation of the operative technique itself, but also the evolution of appropriate troubleshooting strategies. A selected number of helpful tips and technical procedural manoeuvres have been compiled to prevent intraoperative problems, as well as to overcome challenging situations that can arise during robotic lobectomies. In robotic surgery, as opposed to open surgery or video assisted thoracic surgery, these tips serve an important purpose for the operating surgeon, as well as the entire surgical team involved in the procedure. All the assembled recommendations have proved their effectiveness and have been successfully used by the authors in many procedures. Furthermore, these manoeuvres have been found to be of great importance in the training and proctoring of thoracic surgeons, fellows and residents (bed-side assistants). This guide of clearly arranged tips and troubleshooting strategies offers surgeons a useful tool to overcome difficult situations in robotic lobectomy and preferably improve the reproducibility and safety of their procedures. PMID- 25281658 TI - Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration. AB - Pathological aggregation and mutation of the 43-kDa TAR DNA-binding protein (TDP 43) are strongly implicated in the pathogenesis amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 neurotoxicity has been extensively modeled in mice, zebrafish, Caenorhabditis elegans and Drosophila, where selective expression of TDP-43 in motoneurons led to paralysis and premature lethality. Through a genetic screen aimed to identify genetic modifiers of TDP 43, we found that the Drosophila dual leucine kinase Wallenda (Wnd) and its downstream kinases JNK and p38 influenced TDP-43 neurotoxicity. Reducing Wnd gene dosage or overexpressing its antagonist highwire partially rescued TDP-43 associated premature lethality. Downstream of Wnd, the JNK and p38 kinases played opposing roles in TDP-43-associated neurodegeneration. LOF alleles of the p38b gene as well as p38 inhibitors diminished TDP-43-associated premature lethality, whereas p38b GOF caused phenotypic worsening. In stark contrast, disruptive alleles of Basket (Bsk), the Drosophila homologue of JNK, exacerbated longevity shortening, whereas overexpression of Bsk extended lifespan. Among possible mechanisms, we found motoneuron-directed expression of TDP-43 elicited oxidative stress and innate immune gene activation that were exacerbated by p38 GOF and Bsk LOF, respectively. A key pathologic role for innate immunity in TDP-43-associated neurodegeneration was further supported by the finding that genetic suppression of the Toll/Dif and Imd/Relish inflammatory pathways dramatically extended lifespan of TDP-43 transgenic flies. We propose that oxidative stress and neuroinflammation are intrinsic components of TDP-43-associated neurodegeneration and that the balance between cytoprotective JNK and cytotoxic p38 signaling dictates phenotypic outcome to TDP-43 expression in Drosophila. PMID- 25281662 TI - DNA replication-dependent induction of gene proximity by androgen. AB - The male hormone androgen, working through the androgen receptor (AR), plays a major role in physiological process and disease development. Previous studies of AR mainly focus on its transcriptional activity. Here, we found that androgen induced TMPRSS2 and ERG gene proximity is mediated by AR control of DNA replication rather than gene transcription. We demonstrate that, in both AR transactivation-positive and -negative prostate cells, androgen regulates DNA replication and androgen-induced gene proximity relies on both DNA replication licensing and actual DNA replication activity. Androgen stimulation advances DNA replication timing of certain genomic regions, which may potentially increase gene proximity through sharing the same replication factory at a similar time. Therefore, we have revealed novel mechanisms of AR biological function, which will stimulate new research directions. PMID- 25281660 TI - Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25. AB - Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.06-1.27; P = 1.2 * 10(-9)]. PMID- 25281663 TI - Effect of total solids content on methane and volatile fatty acid production in anaerobic digestion of food waste. AB - This work investigates the role of the moisture content on anaerobic digestion of food waste, as representative of rapidly biodegradable substrates, analysing the role of volatile fatty acid production on process kinetics. A range of total solids from 4.5% to 19.2% is considered in order to compare methane yields and kinetics of reactors operated under wet to dry conditions. The experimental results show a reduction of the specific final methane yield of 4.3% and 40.8% in semi-dry and dry conditions compared with wet conditions. A decreasing trend of the specific initial methane production rate is observed when increasing the total solids concentration. Because of lack of water, volatile fatty acids accumulation occurs during the first step of the process at semi-dry and dry conditions, which is considered to be responsible for the reduction of process kinetic rates. The total volatile fatty acids concentration and speciation are proposed as indicators of process development at different total solids content. PMID- 25281661 TI - Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population. AB - Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 * 10(-9). Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r(2) = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer. PMID- 25281665 TI - An open-source system for in planta gene stacking by Bxb1 and Cre recombinases. AB - The rapid development of crops with multiple transgenic traits arouses the need for an efficient system for creating stacked cultivars. Most major crops rely on classical breeding to introgress the transgene from a laboratory variety to the numerous cultivars adapted to different growing regions. Even with vegetative propagated crops, genetic crosses are conducted during varietal improvement prior to vegetative cloning. The probability to assort the 'x' number of transgenic loci into a single genome may seem trivial, (1/4) (x) for a diploid species, but given the 'y' number of other nontransgenic traits that breeders also need to assemble into the same genome, the (1/4) (x+y) probability for a 'breeding stack' could quickly make the line conversion process unmanageable. Adding new transgenes onto existing transgenic varieties without creating a new segregating locus would require site-specific integration of new DNA at the existing transgenic locus. Here, we tested a recombinase-mediated gene-stacking scheme in tobacco. Sequential site-specific integration was mediated by the mycobacteriophage Bxb1 integrase-catalyzed recombination between attP and attB sites. Transgenic DNA no longer needed after integration was excised by Cre recombinase-mediated recombination of lox sites. Site-specific integration occurred in ~10% of the integration events, with half of those events usable as substrates for a next round of gene stacking. Among the site-specific integrants, however, a third experienced gene silencing. Overall, precise structure and reproducible expression of the sequentially added triple traits were obtained at an overall rate of ~3% of the transformed clones--a workable frequency for the development of commercial cultivars. Moreover, since neither the Bxb1-att nor the Cre-lox system is under patent, there is freedom to operate. PMID- 25281659 TI - A novel common variant in DCST2 is associated with length in early life and height in adulthood. AB - Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 * 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 * 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 * 10(-4)) and adult height (N = 127 513; P = 1.45 * 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height. PMID- 25281667 TI - Promoting the scholarship of teaching and learning through peer review and public presentation. PMID- 25281666 TI - Suicidal co-degradation of the phytochrome interacting factor 3 and phytochrome B in response to light. PMID- 25281664 TI - Cardiac remodeling in response to 1 year of intensive endurance training. AB - BACKGROUND: It is unclear whether, and to what extent, the striking cardiac morphological manifestations of endurance athletes are a result of exercise training or a genetically determined characteristic of talented athletes. We hypothesized that prolonged and intensive endurance training in previously sedentary healthy young individuals could induce cardiac remodeling similar to that observed cross-sectionally in elite endurance athletes. METHODS AND RESULTS: Twelve previously sedentary subjects (aged 29+/-6 years; 7 men and 5 women) trained progressively and intensively for 12 months such that they could compete in a marathon. Magnetic resonance images for assessment of right and left ventricular mass and volumes were obtained at baseline and after 3, 6, 9, and 12 months of training. Maximum oxygen uptake ( max) and cardiac output at rest and during exercise (C2H2 rebreathing) were measured at the same time periods. Pulmonary artery catheterization was performed before and after 1 year of training, and pressure-volume and Starling curves were constructed during decreases (lower body negative pressure) and increases (saline infusion) in cardiac volume. Mean max rose from 40.3+/-1.6 to 48.7+/-2.5 mL/kg per minute after 1 year (P<0.00001), associated with an increase in both maximal cardiac output and stroke volume. Left and right ventricular mass increased progressively with training duration and intensity and reached levels similar to those observed in elite endurance athletes. In contrast, left ventricular volume did not change significantly until 6 months of training, although right ventricular volume increased progressively from the outset; Starling and pressure-volume curves approached but did not match those of elite athletes. CONCLUSIONS: One year of prolonged and intensive endurance training leads to cardiac morphological adaptations in previously sedentary young subjects similar to those observed in elite endurance athletes; however, it is not sufficient to achieve similar levels of cardiac compliance and performance. Contrary to conventional thinking, the left ventricle responds to exercise with initial concentric but not eccentric remodeling during the first 6 to 9 months after commencement of endurance training depending on the duration and intensity of exercise. Thereafter, the left ventricle dilates and restores the baseline mass-to-volume ratio. In contrast, the right ventricle responds to endurance training with eccentric remodeling at all levels of training. PMID- 25281668 TI - The status of the scholarship of teaching and learning in dental education. AB - The purpose of this study was to determine the current status of the Scholarship of Teaching and Learning (SoTL) within academic dentistry. A twenty-two-item survey was distributed to faculty members of American Dental Education Association (ADEA) member schools asking about their awareness of SoTL practices, perceived barriers to SoTL application, and ways to enhance SoTL activity. Four hundred thirty surveys with equal distribution of assistant, associate, and full professors were received (this may be considered a response rate of 5.4 percent out of roughly 8,000 ADEA faculty members). Almost 70 percent of the respondents indicated that they highly valued SoTL; only 2.1 percent indicated they did not. The extent to which the respondents valued SoTL was positively correlated with their perception of SoTL's value among other faculty members in their program (r(322)=0.374, p<0.001), school (r(299)=0.204, p<0.001), and institution (r(233)=0.296, p<0.002). However, the respondents were generally unsure how SoTL was applied at their institutions. Respondents from private institutions reported making more SoTL presentations at conferences than did those from public institutions (t(303)=-2.761, p=0.006) and stronger promotion of SoTL in their institutional policies (t(330)= -3.004, p=0.003). Barriers to changing the perception and application of SoTL appeared to exist at both organizational and individual levels, and ADEA was perceived to be well positioned to assist with both. PMID- 25281669 TI - Impact of a research requirement in a dental school curriculum. AB - With reported shortages in full-time dental educators across the world, any exposure to teaching and/or research during dental school might increase a graduate's interest in an academic career. Harvard School of Dental Medicine (HSDM) has a mandatory research experience for all students enrolled in the Doctor of Dental Medicine program. Each year, the graduating class is surveyed about characteristics and outcomes of their research experience. The aim of this study was to use the resulting data for five years of graduating classes (2008 to 2012) to assess the impact of the research requirement. The results showed that 54 percent of these students had presented their research projects at a forum outside Harvard. Thirty-six percent had had their research published in peer reviewed journals, 38 percent had manuscripts in preparation or submitted for review, and only 26 percent had no intention to publish their work. Overall, 81.5 percent felt positive about their research experience at HSDM. Only 48 percent said they would definitely have pursued research even if it was not compulsory, and 36 percent were uncertain. However, 83 percent said they would have some involvement in research during their careers, and only 10 percent were uncertain. Implementing a compulsory research experience may lead to increased numbers of graduates pursuing research in their careers and contributing to the scientific development of the dental profession. PMID- 25281670 TI - Current status of patient recall in U.S. predoctoral dental school clinics. AB - The Commission on Dental Accreditation (CODA)'s revised standard 2-23, which went into effect in July 2013, requires U.S. dental graduates to be competent in "evaluation of the outcomes of treatment, recall strategies, and prognosis." To assess the way dental schools are implementing this revised recommendation, a survey was conducted to assess the existence of recall systems in the schools' clinics and factors enhancing or hindering the formation of an effective recall system. Surveys were returned from thirty-five dental schools (54.7 percent response rate). Results showed that most institutions had active recall systems and the respondents believed that program effectiveness can be further improved. Suggested improvements included patient education and tracking patient recall appointments. The results indicate that recall systems exist in predoctoral dental education programs, have high student involvement, and vary among schools. PMID- 25281671 TI - Dental students' perceived level of competence in orofacial pain. AB - Orofacial pain (OFP) is a group of symptoms affecting a significant portion of the population; inadequate diagnosis and management of these symptoms present a potential detrimental effect on the public's health. It has been suggested that dental schools must prepare their graduates to deal with these problems rather than relying on their participation in continuing education courses after graduation. The aim of this study was to determine how third- and fourth-year students at one dental school perceived their level of competence related to OFP. Out of 140 students who were sent the survey, seventy-four (53 percent response rate) completed it in its entirety. The cross-sectional survey included questions regarding the students' familiarity with the categories of OFP. Questions asked how they perceived their knowledge in each of these areas, how comfortable they felt providing diagnosis and treatment, and if more knowledge was needed. The results showed that the fourth-year students were more comfortable than the third year students in diagnosing and managing intraoral pain. Multiple comparisons also showed statistically significant differences between OFP categories for questions related to perceived knowledge, comfort in diagnosing and treating, and perceived need for more information. Overall, the students' perceived knowledge of and confidence in treating OFP varied with respect to certain categories, being lowest for psychogenic pain. PMID- 25281672 TI - Dental student attitudes towards communication skills instruction and clinical application. AB - This study investigated dental students' attitudes towards communication skills instruction and clinical application and explored the impact of a one-semester course and year in school on students' attitudes, measured by the Communication Skills Attitude Scale. Demographic characteristics and self-assessment of communication skills were also analyzed. The study employed a pretest-posttest survey design combined with cross-sectional data. Participants were first- and fourth-year students at a U.S. dental school. Out of a possible 120 students, 106 (fifty-seven D1 and forty-nine D4) participated in the pretest, an 88 percent response rate; out of a possible 121 students, 115 (fifty-seven D1 and fifty eight D4) participated in the posttest, a 95 percent response rate. In the results, D4 students consistently demonstrated less positive attitudes towards communication skills instruction and more negative attitudes regarding the importance of interpersonal skills in clinical encounters than did their D1 counterparts. A single communications course had no discernible effect on attitudes or self-assessments for either cohort. Females reported more positive attitudes towards clinical application of interpersonal skills than did males. Gender significantly interacted with two demographic variables: primary language and parent as health care professional. Female children of health care professionals reported poorer attitudes towards clinical communication skills training and application than did their male counterparts. Generally, parental occupation in health care moderated the decrease in positive attitudes over time towards clinical usefulness of communication skills. The D4 students rated their communication skills higher than did the D1 students. Students who demonstrated more positive attitudes towards communication skills training and application were more likely to say their own skills needed improvement. PMID- 25281673 TI - Dental and dental hygiene students' perceptions of a standardized patient instructor conflict resolution program. AB - The aim of this study was to examine students' perceptions of the value of a standardized patient instructor conflict resolution program designed to strengthen their communication and confidence during difficult patient conversations. Three cohorts of students at one dental school were part of the study: the dental class of 2013, the dental class of 2014, and the dental hygiene class of 2013. The same groups of students completed surveys immediately following the program and one, two, or three years afterwards. Response rates for the survey immediately after the program were 98 percent (n=99) of the dental class of 2013, 97 percent (n=103) of the dental class of 2014, and 100 percent (n=25) of the dental hygiene class of 2013. Response rates for the subsequent survey were 41.5 percent (n=42) of the dental class of 2013, 74.5 percent (n=79) of the dental class of 2014, and 100 percent (n=25) of the dental hygiene class of 2013. In the results, all students reported a high level of satisfaction in their immediate assessment of the program and its ability to prepare them for conflict situations. They also reported a high level of satisfaction in their retrospective self-assessment of conflict resolution skills. However, their assessment of the program's value and applicability appeared to have diminished over time. This study suggests that the program should continue being a part of both dental and dental hygiene curricula, with more training and guided experiences in self-assessment and perhaps supplemental experiences added. PMID- 25281674 TI - Establishing a good dentist-patient relationship: skills defined from the dental faculty perspective. AB - The importance of developing good dentist-patient relationships has been well documented, but previous studies have focused on social techniques, not considering the psychological and behavioral characteristics of patients, and have used definitions and instruments that were not dental-specific. Therefore, the aims of this study were to propose a definition of dentist-patient relationship skills, derived from dental faculty members' criteria and informed by Emotional Intelligence concepts, and to propose a preliminary dental-specific, face-valid, and reliable self-assessment instrument. The study was conducted in three phases. Phases I and II defined dentist-patient relationship competence through literature analysis and semi-structured interviews with expert key informants, establishing the outcome skills. In Phase III, the instrument was constructed and piloted. Communication skills and basic psychological tools resulted in core topics for use in practice. The definition both specifies and broadens social interactions in dentistry by including dental faculty members' criteria and topics such as psychological tools and pre-, intra-, and postoperative topics appropriate for use during consultation, examination, and treatment. The instrument was found suitable, reasonable, and accessible with a Cronbach's alpha level of 0.95. Future studies are needed to confirm the definition, as well as the instrument's validity, reliability, transference, and sensitivity to the dental educational environment. PMID- 25281675 TI - Effectiveness and feasibility of utilizing E4D technology as a teaching tool in a preclinical dental education environment. AB - Recent efforts have been directed towards utilizing CAD/CAM technology in the education of future dentists. The purpose of this pilot study was to investigate the feasibility of implementing CAD/CAM technology in instruction on preparing a tooth for restoration. Students at one dental school were assigned access to CAD/CAM technology vs. traditional preparation methods in a randomized, crossover design. In a convenience sample of a second-year class, seventy-six of the seventy-nine students volunteered to participate, for a response rate of 96 percent. Two analyses were performed on this pilot data: a primary effectiveness analysis comparing students' competency exam scores by intervention group (intention-to-treat analysis) and a secondary efficacy analysis comparing competency exam scores among students who reported using CAD/CAM versus those who did not. The effectiveness analysis showed no difference in outcomes by intervention group assignment. While student survey results indicated interest in utilizing the technology, the actual utilization rate was much less than one might anticipate, yielding a sample size that limited statistical power. The secondary analysis demonstrated higher mean competency exam scores for students reporting use of CAD/CAM compared to those who did not use the technology, but these results did not reach statistical significance (p=0.075). Prior research has investigated the efficacy of CAD/CAM in a controlled educational trial, but this study adds to the literature by investigating student use of CAD/CAM in a real-world, self-study fashion. Further studies should investigate ways in which to increase student utilization of CAD/CAM and whether or not increased utilization, with a larger sample size, would yield significant outcomes. PMID- 25281676 TI - Dental students' opinions of preparation assessment with E4D compare software versus traditional methods. AB - The aim of this study was to evaluate dental students' opinions regarding the utilization of a new grading software program for student self-assessment and a faculty-grading tool in a preclinical course. Using surface mapping technology, this program, called E4D Compare, yields a digital model of a student's preparation that is color-coded to show deficient areas. The program has now been used for two years at the James B. Edwards College of Dental Medicine at the Medical University of South Carolina, and the students previously assessed with E4D Compare have now entered into the dental clinics. For this study, students were asked to complete an anonymous survey for the investigators to evaluate students' attitudes and opinions on the effectiveness of this software in their preclinical courses to determine if this type of feedback helped them develop clinical skills. The survey also sought to collect students' opinions on the traditional objective criteria-based grading system. The survey was distributed to all members of the Classes of 2014 and 2015; it yielded a 59 percent response rate for the two classes, with a total of eighty-one students responding. Overall, the majority of students preferred the E4D Compare grading system over traditional hand-grading methods. The grading system provided instant, objective, and visual feedback that allowed students to easily see where their deficiencies were and encouraged them to work towards an ideal final product. PMID- 25281677 TI - Introducing CAD/CAM into a predoctoral dental curriculum: a case study. AB - This article describes the decision making and implementation process used at Indiana University School of Dentistry to incorporate a CAD/CAM system into the predoctoral curriculum and presents data regarding the opinions of students and faculty members after one year. Using a non-validated survey instrument, D1 students rated their experience fabricating a CAD/CAM-generated crown. Eighty eight of the 105 D1 students (84 percent response rate) responded to the four multiple-choice questions, and a varying number provided written responses. Eighty percent of the responding students rated the overall learning experience as good or excellent, and 43 percent judged that they were prepared to fabricate a crown independently. Students' comments about the experience were generally positive. The twelve supervising faculty members were also surveyed after the first year. When asked to evaluate the initial quality of the crowns at placement, they rated 89 to 98 percent of them good or excellent on the measures of marginal fit, axial contours, proximal contacts, and occlusal contacts. In their judgment, CAD/CAM-generated crowns were as good as or better than those received from commercial labs. After one year, the school's experience has been that the performance of these crowns is consistent with the literature and that they are a viable option. Also, the students are enthusiastic about this addition to the curriculum. PMID- 25281678 TI - Construct validity and expert benchmarking of the haptic virtual reality dental simulator. AB - The aim of this study was to demonstrate construct validation of the haptic virtual reality (VR) dental simulator and to define expert benchmarking criteria for skills assessment. Thirty-four self-selected participants (fourteen novices, fourteen intermediates, and six experts in endodontics) at one dental school performed ten repetitions of three mode tasks of endodontic cavity preparation: easy (mandibular premolar with one canal), medium (maxillary premolar with two canals), and hard (mandibular molar with three canals). The virtual instrument's path length was registered by the simulator. The outcomes were assessed by an expert. The error scores in easy and medium modes accurately distinguished the experts from novices and intermediates at the onset of training, when there was a significant difference between groups (ANOVA, p<0.05). The trend was consistent until trial 5. From trial 6 on, the three groups achieved similar scores. No significant difference was found between groups at the end of training. Error score analysis was not able to distinguish any group at the hard level of training. Instrument path length showed a difference in performance according to groups at the onset of training (ANOVA, p<0.05). This study established construct validity for the haptic VR dental simulator by demonstrating its discriminant capabilities between that of experts and non-experts. The experts' error scores and path length were used to define benchmarking criteria for optimal performance. PMID- 25281679 TI - Development and outcomes of an online-onsite hybrid dental admissions enhancement pilot program. AB - The University of Missouri-Kansas City (UMKC) School of Dentistry has piloted two years of an Admissions Enhancement Program (AEP) with students from underrepresented minority groups and/or economically disadvantaged areas of Missouri interested in applying to dental school. The AEP utilizes an innovative online-onsite hybrid format to elevate students' foundational knowledge in biology, chemistry, organic chemistry, and quantitative reasoning. The online component includes interaction with UMKC instructors using tablet technology and Wimba virtual classroom sessions. The onsite component engages students in academic and professional development, enrichment activities targeting skills training, experience in dental labs and clinics, and mentoring in preparing the dental school application, essay writing, and interviewing. Results to date indicate overall program satisfaction among AEP participants and a dental school acceptance rate of 73.7 percent (14/19 students). Participants reported the mock interviews and essay-writing portions contributed to their becoming competitive candidates for the admission process, and the online material enhanced their preparation for the Dental Admission Test (DAT). Pre- and post-AEP data show participant DAT Academic Average scores increased by two points. The school will continue to monitor program participants in subsequent years. PMID- 25281680 TI - Direct assessment as a measure of institutional effectiveness in a dental hygiene distance education program. AB - This ten-year, longitudinal examination of a dental hygiene distance education (DE) program considered student performance on standard benchmark assessments as direct measures of institutional effectiveness. The aim of the study was to determine if students face-to-face in a classroom with an instructor performed differently from their counterparts in a DE program, taking courses through the alternative delivery system of synchronous interactive television (ITV). This study used students' grade point averages and National Board Dental Hygiene Examination scores to assess the impact of ITV on student learning, filling a crucial gap in current evidence. The study's research population consisted of 189 students who graduated from one dental hygiene program between 1997 and 2006. One hundred percent of the institution's data files for these students were used: 117 students were face-to-face with the instructor, and seventy-two received instruction through the ITV system. The results showed that, from a year-by-year perspective, no statistically significant performance differences were apparent between the two student groups when t-tests were used for data analysis. The DE system examined was considered effective for delivering education if similar performance outcomes were the evaluation criteria used for assessment. PMID- 25281681 TI - Industry sponsorship bias in research findings: a network meta-analysis of LDL cholesterol reduction in randomised trials of statins. AB - OBJECTIVE: To explore the risk of industry sponsorship bias in a systematically identified set of placebo controlled and active comparator trials of statins. DESIGN: Systematic review and network meta-analysis. ELIGIBILITY: Open label and double blind randomised controlled trials comparing one statin with another at any dose or with control (placebo, diet, or usual care) for adults with, or at risk of developing, cardiovascular disease. Only trials that lasted longer than four weeks with more than 50 participants per trial arm were included. Two investigators assessed study eligibility. DATA SOURCES: Bibliographic databases and reference lists of relevant articles published between 1 January 1985 and 10 March 2013. DATA EXTRACTION: One investigator extracted data and another confirmed accuracy. MAIN OUTCOME MEASURE: Mean absolute change from baseline concentration of low density lipoprotein (LDL) cholesterol. DATA SYNTHESIS: Study level outcomes from randomised trials were combined using random effects network meta-analyses. RESULTS: We included 183 randomised controlled trials of statins, 103 of which were two-armed or multi-armed active comparator trials. When all of the existing randomised evidence was synthesised in network meta-analyses, there were clear differences in the LDL cholesterol lowering effects of individual statins at different doses. In general, higher doses resulted in higher reductions in baseline LDL cholesterol levels. Of a total of 146 industry sponsored trials, 64 were placebo controlled (43.8%). The corresponding number for the non-industry sponsored trials was 16 (43.2%). Of the 35 unique comparisons available in 37 non-industry sponsored trials, 31 were also available in industry sponsored trials. There were no systematic differences in magnitude between the LDL cholesterol lowering effects of individual statins observed in industry sponsored versus non-industry sponsored trials. In industry sponsored trials, the mean change from baseline LDL cholesterol level was on average 1.77 mg/dL (95% credible interval -11.12 to 7.66) lower than the change observed in non-industry sponsored trials. There was no detectable inconsistency in the evidence network. CONCLUSIONS: Our analysis shows that the findings obtained from industry sponsored statin trials seem similar in magnitude as those in non industry sources. There are actual differences in the effectiveness of individual statins at various doses that explain previously observed discrepancies between industry and non-industry sponsored trials. PMID- 25281682 TI - Bias related to funding source in statin trials. PMID- 25281683 TI - HIV pandemic originated in Kinshasa around 1920, say scientists. PMID- 25281684 TI - The role of seminal plasma for improved outcomes during in vitro fertilization treatment: review of the literature and meta-analysis. AB - BACKGROUND: There is a growing body of evidence surrounding the role played by seminal plasma in human implantation. Seminal fluid contains several proteins that interact with cervical and uterine epithelial cells inducing active immune tolerance. We sought to answer the study question: Does exposure to seminal plasma improve pregnancy outcomes in women undergoing IVF? METHODS: Randomized controlled trials (RCTs) were searched for via MEDLINE, EMBASE, the Cochrane Library, National Research Register, ISI conference proceedings, ISRCTN register and Meta-register, from 1966 to December 2013. Search terms included: 'seminal plasma', 'seminal fluid', 'sexual intercourse', 'IVF', 'ICSI', 'ART', 'pregnancy rate', 'implantation', 'embryo transfer' and 'live birth'. This analysis included all RCTs comparing the outcome of IVF treatments in patients exposed to seminal plasma near the time of oocyte pickup (OPU) or embryo transfer (ET) with that of placebo controls or controls with no exposure to seminal plasma. The main intervention was exposure to seminal plasma around the time of OPU or embryo transfer during an IVF cycle. The main outcomes were clinical pregnancy and live birth/ongoing pregnancy rates. Data were collected by two independent authors and statistically pooled via meta-analysis following intention to treat and per protocol principles using RevMan (v5.2.10). I(2) statistic, forest plots and chi squared heterogeneity tests were used. RESULTS: In total 2204 patients were included in seven RCTs. Meta-analysis revealed a statistically significant improvement in clinical pregnancy rate (RR 1.23, 95% CI 1.06-1.42, P = 0.006) by intention to treat. Per protocol analysis also revealed a statistically significant improvement in clinical pregnancy rate (RR 1.24, 95% CI 1.07-1.43, P = 0.003). There was no statistically significant improvement seen for the outcome of ongoing pregnancy/live birth rate, but the available data were very limited. The methodology and quality of the studies were variable. CONCLUSIONS: There are significantly improved outcomes when women are exposed to seminal plasma around the time of ovum pick-up or embryo transfer, with statistical significance for clinical pregnancy but not for ongoing pregnancy/live birth rates being achieved. This meta-analysis is limited by the small number of studies of variable methodology. Further research is required to determine the effect on live birth rate; however, this meta-analysis indicates a significantly improved clinical pregnancy rate and a potential method for improving IVF outcomes. PMID- 25281685 TI - Psychological adjustment in adolescents conceived by assisted reproduction techniques: a systematic review. AB - BACKGROUND: Adolescence is a transitional time for identity formation and relationships with parents. While people born through assisted reproduction techniques (ART) appear to be well adjusted in childhood, it is unclear whether these findings carry into adolescence, and whether diverse ART have different psychological outcomes. This review summarizes what is known about the psychological adjustment and family relationships of the growing number of children born through ART who are reaching adolescence. METHODS: The Pubmed, Web of Knowledge, PsycINFO and Scopus databases were searched systematically for peer reviewed papers focusing on adolescent psychological adjustment and parent adolescent relationships in families created by ART. Key search inclusion criteria included all papers published in English relating to adolescents aged between 11 and 18 years. RESULTS: Seventeen publications with varied methodologies were identified by this review. Only papers relating to in vitro fertilization (IVF), egg donation and donor insemination were identified. Results were categorized according to ART that used the parents' own gametes (IVF) and those that involved reproductive donation (egg donation, and donor insemination). Compared with naturally conceived adolescents and standardized normative samples, adolescents born through all ARTs seemed to be equally well adjusted, and to have positive parent-adolescent relationships. Some differences were however identified based on the type of ART used. In particular, the sex of the parent and child, along with age and process of disclosure of the adolescent's conception were identified as key mediators of parent-adolescent relationships in families created by donor insemination. CONCLUSIONS: The studies in this review indicate that children born through ART have positive parent-adolescent relationships and are well adjusted, with some slight differences based on different ART. The generalizability of findings may be limited by the general low level of disclosure to adolescents in some of the publications, the small sample sizes of studies in the field, along with the large age range that encompasses adolescence. Findings should also be interpreted in light of the fact that many publications focus on singleton births. Future studies should also focus on egg donation, surrogacy and embryo donation, as well as the disclosure processes, and adolescents born into non-traditional families (same-sex or single parents) or those born using different types of donor (anonymous, identity-release or known). PMID- 25281686 TI - Chromatin-dependent repression of the Arabidopsis floral integrator genes involves plant specific PHD-containing proteins. AB - The interplay among histone modifications modulates the expression of master regulatory genes in development. Chromatin effector proteins bind histone modifications and translate the epigenetic status into gene expression patterns that control development. Here, we show that two Arabidopsis thaliana paralogs encoding plant-specific proteins with a plant homeodomain (PHD) motif, SHORT LIFE (SHL) and EARLY BOLTING IN SHORT DAYS (EBS), function in the chromatin-mediated repression of floral initiation and play independent roles in the control of genes regulating flowering. Previous results showed that repression of the floral integrator FLOWERING LOCUS T (FT) requires EBS. We establish that SHL is necessary to negatively regulate the expression of SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1), another floral integrator. SHL and EBS recognize di- and trimethylated histone H3 at lysine 4 and bind regulatory regions of SOC1 and FT, respectively. These PHD proteins maintain an inactive chromatin conformation in SOC1 and FT by preventing high levels of H3 acetylation, bind HISTONE DEACETYLASE6, and play a central role in regulating flowering time. SHL and EBS are widely conserved in plants but are absent in other eukaryotes, suggesting that the regulatory module mediated by these proteins could represent a distinct mechanism for gene expression control in plants. PMID- 25281687 TI - Critical function of a Chlamydomonas reinhardtii putative polyphosphate polymerase subunit during nutrient deprivation. AB - Forward genetics was used to isolate Chlamydomonas reinhardtii mutants with altered abilities to acclimate to sulfur (S) deficiency. The ars76 mutant has a deletion that eliminates several genes, including VACUOLAR TRANSPORTER CHAPERONE1 (VTC1), which encodes a component of a polyphosphate polymerase complex. The ars76 mutant cannot accumulate arylsulfatase protein or mRNA and shows marked alterations in levels of many transcripts encoded by genes induced during S deprivation. The mutant also shows little acidocalcisome formation compared with wild-type, S-deprived cells and dies more rapidly than wild-type cells following exposure to S-, phosphorus-, or nitrogen (N)-deficient conditions. Furthermore, the mutant does not accumulate periplasmic L-amino acid oxidase during N deprivation. Introduction of the VTC1 gene specifically complements the ars76 phenotypes, suggesting that normal acidocalcisome formation in cells deprived of S requires VTC1. Our data also indicate that a deficiency in acidocalcisome function impacts trafficking of periplasmic proteins, which can then feed back on the transcription of the genes encoding these proteins. These results and the reported function of vacuoles in degradation processes suggest a major role of the acidocalcisome in reshaping the cell during acclimation to changing environmental conditions. PMID- 25281688 TI - Differentially phased leaf growth and movements in Arabidopsis depend on coordinated circadian and light regulation. AB - In contrast to vastly studied hypocotyl growth, little is known about diel regulation of leaf growth and its coordination with movements such as changes in leaf elevation angle (hyponasty). We developed a 3D live-leaf growth analysis system enabling simultaneous monitoring of growth and movements. Leaf growth is maximal several hours after dawn, requires light, and is regulated by daylength, suggesting coupling between growth and metabolism. We identify both blade and petiole positioning as important components of leaf movements in Arabidopsis thaliana and reveal a temporal delay between growth and movements. In hypocotyls, the combination of circadian expression of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5 and their light-regulated protein stability drives rhythmic hypocotyl elongation with peak growth at dawn. We find that PIF4 and PIF5 are not essential to sustain rhythmic leaf growth but influence their amplitude. Furthermore, EARLY FLOWERING3, a member of the evening complex (EC), is required to maintain the correct phase between growth and movement. Our study shows that the mechanisms underlying rhythmic hypocotyl and leaf growth differ. Moreover, we reveal the temporal relationship between leaf elongation and movements and demonstrate the importance of the EC for the coordination of these phenotypic traits. PMID- 25281689 TI - Arabidopsis ATG8-INTERACTING PROTEIN1 is involved in autophagy-dependent vesicular trafficking of plastid proteins to the vacuole. AB - Selective autophagy has been extensively studied in various organisms, but knowledge regarding its functions in plants, particularly in organelle turnover, is limited. We have recently discovered ATG8-INTERACTING PROTEIN1 (ATI1) from Arabidopsis thaliana and showed that following carbon starvation it is localized on endoplasmic reticulum (ER)-associated bodies that are subsequently transported to the vacuole. Here, we show that following carbon starvation ATI1 is also located on bodies associating with plastids, which are distinct from the ER ATI bodies and are detected mainly in senescing cells that exhibit plastid degradation. Additionally, these plastid-localized bodies contain a stroma protein marker as cargo and were observed budding and detaching from plastids. ATI1 interacts with plastid-localized proteins and was further shown to be required for the turnover of one of them, as a representative. ATI1 on the plastid bodies also interacts with ATG8f, which apparently leads to the targeting of the plastid bodies to the vacuole by a process that requires functional autophagy. Finally, we show that ATI1 is involved in Arabidopsis salt stress tolerance. Taken together, our results implicate ATI1 in autophagic plastid-to vacuole trafficking through its ability to interact with both plastid proteins and ATG8 of the core autophagy machinery. PMID- 25281692 TI - Invited commentary: Interpreting associations between high birth weight and later health problems. AB - High birth weight (>4.0 kg) has been associated with a wide range of health problems later in life. The interpretation of these statistical associations may be difficult, however. These difficulties are closely linked to methodological challenges in this research, such as filtering out confounding from family factors, disentangling associations with prenatal processes from associations with postnatal processes, and uncovering what birth weight actually represents. The well-conducted study by Kristensen et al. (Am J Epidemiol. 2014;180(9):876 884), presented in this issue of the Journal, offers an interesting example of how one can filter out confounding from family factors. In an elegant series of analyses, the authors show how an apparent inverse association between birth weight and later intelligence among those in the highest range of the birth weight scale became a positive association when proper adjustment for family factors was made. Sibling comparisons were important here. PMID- 25281691 TI - Sleep duration and total and cause-specific mortality in a large US cohort: interrelationships with physical activity, sedentary behavior, and body mass index. AB - Both short and long durations of sleep are associated with higher mortality, but little is known about the interrelationship between sleep and other modifiable factors in relation to mortality. In the National Institutes of Health-AARP Diet and Health Study (1995-1996), we examined associations between sleep duration and total, cardiovascular disease (CVD), and cancer mortality among 239,896 US men and women aged 51-72 years who were free of cancer, CVD, and respiratory disease. We evaluated the influence of moderate-to-vigorous physical activity, television viewing, and body mass index (BMI; weight (kg)/height (m)(2)) on the sleep mortality association and assessed their combined association with mortality. During an average of 14 years of follow-up, we identified 44,100 deaths. Compared with 7-8 hours of sleep per day, both shorter and longer sleep durations were associated with higher total and CVD mortality. We found a greater elevation in CVD mortality associated with shorter sleep among overweight and obese people, suggesting a synergistic interaction between sleep and BMI. People in the unhealthy categories of all 4 risk factors (sleep <7 hours/day, moderate-to vigorous physical activity <=1 hour/week, television viewing >=3 hours/day, and BMI >=25) had significantly higher all-cause (relative risk (RR) = 1.42, 95% confidence interval (CI): 1.34, 1.52), CVD (RR = 1.90, 95% CI: 1.67, 2.17), and cancer (RR = 1.21, 95% CI: 1.09, 1.34) mortality. Short sleep duration may predict higher mortality, particularly CVD mortality, among overweight and obese people. PMID- 25281690 TI - CYCLIN-DEPENDENT KINASE8 differentially regulates plant immunity to fungal pathogens through kinase-dependent and -independent functions in Arabidopsis. AB - CYCLIN-DEPENDENT KINASE8 (CDK8) is a widely studied component of eukaryotic Mediator complexes. However, the biological and molecular functions of plant CDK8 are not well understood. Here, we provide evidence for regulatory functions of Arabidopsis thaliana CDK8 in defense and demonstrate its functional and molecular interactions with other Mediator and non-Mediator subunits. The cdk8 mutant exhibits enhanced resistance to Botrytis cinerea but susceptibility to Alternaria brassicicola. The contributions of CDK8 to the transcriptional activation of defensin gene PDF1.2 and its interaction with MEDIATOR COMPLEX SUBUNIT25 (MED25) implicate CDK8 in jasmonate-mediated defense. Moreover, CDK8 associates with the promoter of AGMATINE COUMAROYLTRANSFERASE to promote its transcription and regulate the biosynthesis of the defense-active secondary metabolites hydroxycinnamic acid amides. CDK8 also interacts with the transcription factor WAX INDUCER1, implying its additional role in cuticle development. In addition, overlapping functions of CDK8 with MED12 and MED13 and interactions between CDK8 and C-type cyclins suggest the conserved configuration of the plant Mediator kinase module. In summary, while CDK8's positive transcriptional regulation of target genes and its phosphorylation activities underpin its defense functions, the impaired defense responses in the mutant are masked by its altered cuticle, resulting in specific resistance to B. cinerea. PMID- 25281693 TI - Kristensen et al. respond to "High birth weight and later health". PMID- 25281694 TI - The association of high birth weight with intelligence in young adulthood: a cohort study of male siblings. AB - We aimed to explore why, in population studies, the positive association between normal-range birth weight and intelligence becomes negative at the highest birth weights. The study population comprised 217,746 Norwegian male singletons born at term between 1967 and 1976. All had data on birth weight and intelligence quotient (IQ) score at the time of military conscription; 137,574 had data on sibling birth weights; and 62,906 had data on male sibling birth weights. We estimated associations between birth weight and IQ score by ordinary least squares regression for the total study population and by fixed-effects regression for comparisons of brothers. The crude mean IQ score was 1.2 points (95% confidence interval (CI): 0.3, 2.2) lower for those with birth weights of 5,000 g or more compared with the reference group (with birth weights of 4,000-4,499 g). This difference leveled off to 0.0 (95% CI: -0.8, 0.9) in multivariable ordinary least squares regression and reversed to 2.2 points (95% CI: 0.3, 4.2) higher in fixed-effects regression. Results differed mainly because, at a given birth weight, participants who had a sibling with macrosomia had a lower mean IQ score. Nevertheless, within families with 1 or more macrosomic siblings, as in other families, men with higher birth weights tended to have higher IQ scores. Thus, a family-level confounder introduces a cross-level bias that cannot be detected in individual-level studies. We suggest ways in which future studies might elucidate the nature of this confounder. PMID- 25281695 TI - Ramucirumab: successfully targeting angiogenesis in gastric cancer. AB - Gastric cancer is the fourth most common cancer globally and represents the second most common cause of cancer-related mortality. Early detection, aggressive surgical resection, and postoperative adjuvant therapy have led to survival improvement for early-stage gastric cancer, particularly in Asian countries. Unfortunately, advanced gastric cancer continues to pose a formidable challenge with few gains being reported recently. Trastuzumab was the first targeted agent to be approved for the treatment of advanced gastric cancer in 2010. The failure of the AVAGAST trial was a setback for antiangiogenic therapy for this disease. Ramucirumab is a monoclonal antibody that binds to VEGF-R2 and prevents its activation. The recent REGARD trial was a randomized phase III trial of ramucirumab vs. placebo for patients with advanced, pretreated gastric cancer that met its primary endpoint of increased overall survival. The toxicity of ramucirumab was modest in this setting, with an increased risk of grade 3 or higher hypertension (8% vs. 3%, with ramucirumab and placebo, respectively). The subsequent RAINBOW trial of paclitaxel plus ramucirumab vs. paclitaxel plus placebo for advanced pretreated gastric cancer confirmed the survival advantage of this antiangiogenic agent in gastric cancer. Ramucirumab is the first FDA approved therapy for advanced gastric cancer after prior chemotherapy. PMID- 25281697 TI - Contribution of allied health professionals to NHS care goes unrecorded. PMID- 25281696 TI - NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease. AB - PURPOSE: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy. EXPERIMENTAL DESIGN: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status. RESULTS: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell-related factors (Tel-B associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity. CONCLUSIONS: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control. PMID- 25281698 TI - N-acetylgalactosaminide alpha2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy. AB - BACKGROUND: Galactose-deficient O-glycans in the hinge region (HR) of immunoglobulin A1 (IgA1) play a key role in the pathogenesis of IgA nephropathy (IgAN). O-Glycans of circulatory IgA1 consist of N-acetylgalactosamine (GalNAc) with a beta1,3-linked galactose; both sugars may be sialylated. In patients with IgAN, alpha2,6-sialylated GalNAc is a frequent form of the galactose-deficient O glycans. Prior analyses of IgA1-producing cells had indicated that alpha2,6 sialyltransferase II (ST6GalNAc-II) is likely responsible for sialylation of GalNAc of galactose-deficient IgA1, but direct evidence is missing. METHODS: We produced a secreted variant of recombinant human ST6GalNAc-II and an IgA1 fragment comprised of Calpha1-HR-Calpha2. This IgA1 fragment and a synthetic HR peptide with enzymatically attached GalNAc residues served as acceptors. ST6GalNAc-II activity was assessed in vitro and the attachment of sialic acid to these acceptors was detected by lectin blot and mass spectrometry. RESULTS: ST6GalNAc-II was active with both acceptors. High-resolution mass spectrometry analysis revealed that up to three sialic acid residues were added to the GalNAc residues of the HR glycopeptide. CONCLUSIONS: Our data provide direct evidence that ST6GalNAc-II can sialylate GalNAc of galactose-deficient IgA1. As serum levels of galactose-deficient IgA1 with sialylated glycoforms are increased in IgAN patients, our data explain the corresponding part of the biosynthetic pathway. PMID- 25281699 TI - The multiple roles of pendrin in the kidney. AB - The [Formula: see text] exchanger pendrin (SLC26A4, PDS) is located on the apical membrane of B-intercalated cells in the kidney cortical collecting duct and the connecting tubules and mediates the secretion of bicarbonate and the reabsorption of chloride. Given its dual function of bicarbonate secretion and chloride reabsorption in the distal tubules, it was thought that pendrin plays important roles in systemic acid-base balance and electrolyte and vascular volume homeostasis under basal conditions. Mice with the genetic deletion of pendrin or humans with inactivating mutations in PDS gene, however, do not display excessive salt and fluid wasting or altered blood pressure under baseline conditions. Very recent reports have unmasked the basis of incongruity between the mild phenotype in mutant mice and the role of pendrin as an important player in salt reabsorption in the distal tubule. These studies demonstrate that pendrin and the Na-Cl cotransporter (NCC; SLC12A3) cross compensate for the loss of each other, therefore masking the role that each transporter plays in salt reabsorption under baseline conditions. In addition, pendrin regulates calcium reabsorption in the distal tubules. Furthermore, combined deletion of pendrin and NCC not only causes severe volume depletion but also results in profound calcium wasting and luminal calcification in medullary collecting ducts. Based on studies in pathophysiological states and the examination of genetically engineered mouse models, the evolving picture points to important roles for pendrin (SLC26A4) in kidney physiology and in disease states. This review summarizes recent advances in the characterization of pendrin and the multiple roles it plays in the kidney, with emphasis on its essential roles in several diverse physiological processes, including chloride homeostasis, vascular volume and blood pressure regulation, calcium excretion and kidney stone formation. PMID- 25281701 TI - Leaf hydraulic conductance declines in coordination with photosynthesis, transpiration and leaf water status as soybean leaves age regardless of soil moisture. AB - Photosynthesis requires sufficient water transport through leaves for stomata to remain open as water transpires from the leaf, allowing CO2 to diffuse into the leaf. The leaf water needs of soybean change over time because of large microenvironment changes over their lifespan, as leaves mature in full sun at the top of the canopy and then become progressively shaded by younger leaves developing above. Leaf hydraulic conductance (K(leaf)), a measure of the leaf's water transport capacity, can often be linked to changes in microenvironment and transpiration demand. In this study, we tested the hypothesis that K(leaf) would decline in coordination with transpiration demand as soybean leaves matured and aged. Photosynthesis (A), stomatal conductance (g(s)) and leaf water potential (Psi(leaf)) were also measured at various leaf ages with both field- and chamber grown soybeans to assess transpiration demand. K(leaf) was found to decrease as soybean leaves aged from maturity to shading to senescence, and this decrease was strongly correlated with midday A. Decreases in K(leaf) were further correlated with decreases in g(s), although the relationship was not as strong as that with A. Separate experiments investigating the response of K(leaf) to drought demonstrated no acclimation of K(leaf) to drought conditions to protect against cavitation or loss of g(s) during drought and confirmed the effect of leaf age in K(leaf) observed in the field. These results suggest that the decline of leaf hydraulic conductance as leaves age keeps hydraulic supply in balance with demand without K(leaf)becoming limiting to transpiration water flux. PMID- 25281702 TI - HDL-C vs HDL-P: how changing one letter could make a difference in understanding the role of high-density lipoprotein in disease. PMID- 25281700 TI - Sugar regulation of SUGAR TRANSPORTER PROTEIN 1 (STP1) expression in Arabidopsis thaliana. AB - Sugars regulate the expression of many genes at the transcriptional level. In Arabidopsis thaliana, sugars induce or repress the expression of >1800 genes, including the STP1 (SUGAR TRANSPORTER PROTEIN 1) gene, which encodes an H(+)/monosaccharide cotransporter. STP1 transcript levels decrease more rapidly after the addition of low concentrations of sugars than the levels of other repressed genes, such as DIN6 (DARK-INDUCED 6). We found that this regulation is exerted at the transcriptional level and is initiated by phosphorylatable sugars. Interestingly, the sugar signal that modulates STP1 expression is transmitted through a HEXOKINASE 1-independent signalling pathway. Finally, analysis of the STP1 5' regulatory region allowed us to delimit a region of 309bp that contains the cis elements implicated in the glucose regulation of STP1 expression. Putative cis-acting elements involved in this response were identified. PMID- 25281703 TI - Precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet agent therapy. AB - BACKGROUND: Anticoagulation protocols used during mechanical circulatory support call for titration of antiplatelet agents. We compared the precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet therapy to distinguish their efficacy for titrating antiplatelet therapy. METHODS: We assessed arachidonic acid-induced platelet function by light transmission aggregometry (LTA), Multiplate impedance aggregometry, VerifyNow, and platelet mapping by thromboelastography (TEG PM). We assessed ADP-induced platelet function by the same methods and flow cytometry. Forty healthy volunteers and 10-13 volunteers on daily aspirin and/or clopidogrel therapy were evaluated. We compared tests for intraassay precision, interassay precision (samples from 2 separate blood draws), and reliability coefficient. RESULTS: For arachidonic acid-induced platelet aggregation in healthy volunteers, intra- and interassay CVs were <= 10% for all methods. Intra- and interassay precision among donors on daily aspirin was <= 30% for all methods except LTA (38% interassay CV) and TEG PM (95% intraassay and 104% interassay CV). For ADP induced platelet function, intra- and interassay precision was <= 10% and <= 30% for all methods. Only Multiplate demonstrated moderate or greater (R > 0.40) reliability coefficients for arachidonic acid-induced platelet function among all subjects. All methods of ADP-induced platelet function, except TEG PM, demonstrated substantial or greater (R > 0.60) reliability among all subjects. CONCLUSIONS: TEG PM is least suited to monitor effects of antiplatelet agents. Multiplate impedance aggregometry was the only method to demonstrate an acceptable reliability coefficient among healthy volunteers and donors on both aspirin and clopidogrel therapy. PMID- 25281705 TI - Is endovascular repair of ruptured abdominal aortic aneurysms associated with improved in-hospital mortality compared with surgical repair? AB - A best evidence topic in vascular surgery was constructed according to a structured protocol. The question addressed was whether patients with ruptured abdominal aortic aneurysm (AAA) treated with endovascular aneurysm repair (EVAR) have improved in-hospital outcomes compared with conventional surgical repair. The reported search retrieved 1398 reports, of which 6 papers were thought to represent the best available evidence to answer the study question. Three randomized trials were identified. The first was a pilot trial conducted in a single centre in the UK, which recruited 32 patients and found similar 30-day mortality in the patient groups. The second trial, conducted in Netherlands, recruited 116 patients anatomically suitable for EVAR. This trial found no significant difference in the composite of death and severe complications within 30 days of intervention between patients subjected to EVAR and those undergoing open repair (42 vs 47%; absolute risk reduction 5.4%, 95% confidence interval: 13% to +23%). The IMPROVE trial, based on a pragmatic design, demonstrated similar 30-day mortality in the 613 patients randomized to endovascular strategy or open repair (35.4 vs 37.4%, P = 0.62). The average hospital costs within the first 30 days of randomization were similar between the randomized groups, with an incremental cost-saving for the endovascular strategy vs open repair of L1186. Meta-analysis of all three randomized trials in a Cochrane review found no difference in 30-day or in-hospital mortality between EVAR and open repair (odds ratio: 0.91, 95% confidence interval: 0.67-1.22; P = 0.52). In contrast, a systematic review and meta-analysis, mainly of observational, cohort studies, and another large, nationwide study demonstrated EVAR to be associated with improved in-hospital results compared with open repair, as expressed by mortality, severe complications, length of hospital stay and proportion of patients discharged home. Even though randomized trials demonstrate equivalent in-hospital mortality with EVAR and open repair, large-scale, nationwide, observational studies and meta-analyses have shown EVAR to confer improved in-hospital mortality and morbidity in patients with favourable aneurysm morphology stable enough to undergo imaging. Reconfiguration of acute aortic services and establishment of standardized institutional protocols might be advisable for improvements in the management of ruptured AAA. PMID- 25281704 TI - Preoperative platelet dysfunction predicts blood product transfusion in children undergoing cardiac surgery. AB - OBJECTIVES: Excessive bleeding can be a problem during or after cardiac surgery. While cardiopulmonary bypass-associated platelet dysfunction is an important inducer of coagulopathy, preoperative platelet dysfunction can also contribute to this bleeding. We investigated the relationship between preoperative platelet dysfunction and transfusion of blood products given to children undergoing cardiac surgery. METHODS: The platelet function analyser test measures platelet function in vitro by aspirating blood through a small standard hole (creating high shear) in a collagen membrane infused with a platelet agonist. The time taken to form a platelet plug is known as closure time and prolonged closure time (CT) indicates platelet dysfunction. Three hundred and thirty-eight children who had undergone surgery with cardiopulmonary bypass between 2008 and 2012 were included. The volume of red blood cells and fresh-frozen plasma transfused was recorded. The relationship between closure time and transfusion requirements was analysed using linear and logistic regression. RESULTS: Patients with prolonged closure time had greater odds of getting red blood cells and fresh-frozen plasma transfusions compared with patients with normal closure time (P <0.01). On univariate analysis, age, weight, haematocrit, cardiopulmonary bypass time, Risk Adjustment for Congenital Heart Surgery score and closure time were associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre (P <0.05). However, when logistic multivariable regression analysis was applied, only age, cardiopulmonary bypass time and closure time remained as significant predictive factors for transfusion. CONCLUSIONS: In children who have undergone cardiac surgery, when age and cardiopulmonary bypass time are accounted for, a prolonged preoperative closure time is significantly associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre. This may have implications for planning and utilization of blood products. PMID- 25281706 TI - Is extended arch replacement justified for acute type A aortic dissection? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed is whether patients with acute type A aortic dissection have a better outcome after total arch replacement. Altogether, 138 papers were found using the reported search, of which 8 represented the best evidence to answer the clinical question. The authors, journal, date and country they are from, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All studies are retrospective. Five representative studies reported that total arch replacement could be performed safely without increasing operative mortality and morbidity compared with hemiarch replacement, but with an overall longer time of cardiopulmonary bypass and circulatory arrest. The other three reports documented an apparently higher early mortality rate in the total arch group than in the hemiarch group. In terms of long-term results, freedom from reoperation on the distal aorta is similar for patients treated with total arch replacement and with hemiarch replacement at 5 and 10 years in four papers. As for the false lumen, three reports documented that the rate of complete thrombosis of the false lumen in the proximal descending aorta was significantly higher in the total arch group than in the hemiarch group (P <0.05). Only one study reported similar rates of complete thrombosis formation of the distal aorta in the two groups at different follow-up points (P >0.05). The remaining four reports did not provide information about the false lumen. Evidence for long-term outcomes, albeit limited, has proved that better results of thrombosis of the false lumen can be achieved with a more extensive total arch repair. Although the literature shows no advantage of the total arch over a more limited approach, the more extensive approach may be required to achieve this goal when the entry tear extends to, or is localized in, this segment of the aorta. This suggests that a more extensive surgical strategy can be justified when it is based on circumstances, on the individual patient's clinical condition, and on the anatomical and pathological features of the dissection. PMID- 25281707 TI - Intergenic sequence between Arabidopsis caseinolytic protease B-cytoplasmic/heat shock protein100 and choline kinase genes functions as a heat-inducible bidirectional promoter. AB - In Arabidopsis (Arabidopsis thaliana), the At1g74310 locus encodes for caseinolytic protease B-cytoplasmic (ClpB-C)/heat shock protein100 protein (AtClpB-C), which is critical for the acquisition of thermotolerance, and At1g74320 encodes for choline kinase (AtCK2) that catalyzes the first reaction in the Kennedy pathway for phosphatidylcholine biosynthesis. Previous work has established that the knockout mutants of these genes display heat-sensitive phenotypes. While analyzing the AtClpB-C promoter and upstream genomic regions in this study, we noted that AtClpB-C and AtCK2 genes are head-to-head oriented on chromosome 1 of the Arabidopsis genome. Expression analysis showed that transcripts of these genes are rapidly induced in response to heat stress treatment. In stably transformed Arabidopsis plants harboring this intergenic sequence between head-to-head oriented green fluorescent protein and beta glucuronidase reporter genes, both transcripts and proteins of the two reporters were up-regulated upon heat stress. Four heat shock elements were noted in the intergenic region by in silico analysis. In the homozygous transfer DNA insertion mutant Salk_014505, 4,393-bp transfer DNA is inserted at position -517 upstream of ATG of the AtClpB-C gene. As a result, AtCk2 loses proximity to three of the four heat shock elements in the mutant line. Heat-inducible expression of the AtCK2 transcript was completely lost, whereas the expression of AtClpB-C was not affected in the mutant plants. Our results suggest that the 1,329-bp intergenic fragment functions as a heat-inducible bidirectional promoter and the region governing the heat inducibility is possibly shared between the two genes. We propose a model in which AtClpB-C shares its regulatory region with heat-induced choline kinase, which has a possible role in heat signaling. PMID- 25281708 TI - Arabidopsis PHOSPHOTYROSYL PHOSPHATASE ACTIVATOR is essential for PROTEIN PHOSPHATASE 2A holoenzyme assembly and plays important roles in hormone signaling, salt stress response, and plant development. AB - PROTEIN PHOSPHATASE 2A (PP2A) is a major group of serine/threonine protein phosphatases in eukaryotes. It is composed of three subunits: scaffolding subunit A, regulatory subunit B, and catalytic subunit C. Assembly of the PP2A holoenzyme in Arabidopsis (Arabidopsis thaliana) depends on Arabidopsis PHOSPHOTYROSYL PHOSPHATASE ACTIVATOR (AtPTPA). Reduced expression of AtPTPA leads to severe defects in plant development, altered responses to abscisic acid, ethylene, and sodium chloride, and decreased PP2A activity. In particular, AtPTPA deficiency leads to decreased methylation in PP2A-C subunits (PP2Ac). Complete loss of PP2Ac methylation in the suppressor of brassinosteroid insensitive1 mutant leads to 30% reduction of PP2A activity, suggesting that PP2A with a methylated C subunit is more active than PP2A with an unmethylated C subunit. Like AtPTPA, PP2A-A subunits are also required for PP2Ac methylation. The interaction between AtPTPA and PP2Ac is A subunit dependent. In addition, AtPTPA deficiency leads to reduced interactions of B subunits with C subunits, resulting in reduced functional PP2A holoenzyme formation. Thus, AtPTPA is a critical factor for committing the subunit A/subunit C dimer toward PP2A heterotrimer formation. PMID- 25281709 TI - PINOID AGC kinases are necessary for phytochrome-mediated enhancement of hypocotyl phototropism in Arabidopsis. AB - Several members of the AGCVIII kinase subfamily, which includes PINOID (PID), PID2, and WAVY ROOT GROWTH (WAG) proteins, have previously been shown to phosphorylate PIN-FORMED (PIN) auxin transporters and control the auxin flow in plants. PID has been proposed as a key component of the phototropin signaling pathway that induces phototropic responses, although the responses were not significantly impaired in the pid single and pid wag1 wag2 triple mutants. This raises questions about the functional roles of the PID family in phototropic responses. Here, we investigated hypocotyl phototropism in the pid pid2 wag1 wag2 quadruple mutant in detail to clarify the roles of the PID family in Arabidopsis (Arabidopsis thaliana). The pid quadruple mutants exhibited moderate responses in continuous light-induced phototropism with a decrease in growth rates of hypocotyls and normal responses in pulse-induced phototropism. However, they showed serious defects in enhancements of pulse-induced phototropic curvatures and lateral fluorescent auxin transport by red light pretreatment. Red light pretreatment significantly reduced the expression level of PID, and the constitutive expression of PID prevented pulse-induced phototropism, irrespective of red light pretreatment. This suggests that the PID family plays a significant role in phytochrome-mediated phototropic enhancement but not the phototropin signaling pathway. Red light treatment enhanced the intracellular accumulation of PIN proteins in response to the vesicle-trafficking inhibitor brefeldin A in addition to increasing their expression levels. Taken together, these results suggest that red light preirradiation enhances phototropic curvatures by up regulation of PIN proteins, which are not being phosphorylated by the PID family. PMID- 25281710 TI - Pemetrexed versus gefitinib as a second-line treatment in advanced nonsquamous nonsmall-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial. AB - BACKGROUND: CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m(2)) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data. RESULTS: From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40-0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38-0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49-1.04, P = 0.077). Quality-of life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43-2.08, P = 0.877). CONCLUSIONS: CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients. CLINICALTRIALSGOV IDENTIFIER: NCT00891579. PMID- 25281711 TI - The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer. AB - BACKGROUND: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. PATIENTS AND METHODS: Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. RESULTS: Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). CONCLUSIONS: BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer. PMID- 25281712 TI - Jake MacMillan: A pioneering chemist in plant biology. PMID- 25281714 TI - Pristane-induced granulocyte recruitment promotes phenotypic conversion of macrophages and protects against diffuse pulmonary hemorrhage in Mac-1 deficiency. AB - Diffuse pulmonary hemorrhage (DPH) is an uncommon but critical complication of systemic lupus erythematosus. Peritoneal administration of 2,6,10,14 tetramethylpentadecane (pristane) can recapitulate a lupus-like syndrome in mice, which can develop into DPH within a few weeks, especially in C57BL/6 mice. Mac-1 (CD11b/CD18), a leukocyte adhesion molecule, is known to play a role in inflammation by regulating migration of leukocytes into injured tissue. In this study, we aimed to clarify the role of Mac-1 in pristane-induced DPH, using Mac 1(-/-) and wild-type (WT) mice on a C57BL/6 background. After pristane injection, Mac-1(-/-) mice showed reduced prevalence of DPH and attenuated peritonitis compared with WT mice. Analysis of the peritoneal lavage on days 5 and 10 after pristane treatment revealed increased numbers of eosinophils and alternatively activated macrophages, but decreased numbers of neutrophils and classically activated macrophages in Mac-1(-/-) mice compared with WT. Enhanced production of IL-4 and IL-13, both key mediators of macrophage polarization toward the mannose receptor(+) (MMR(+)) phenotype, was observed in the peritoneal cavity of Mac-1(-/ ) mice. Depletion of neutrophils and eosinophils or adoptive transfer of classically activated macrophages resulted in the exacerbation of pristane mediated DPH in both WT and Mac-1(-/-) mice. Moreover, peritoneal transfer of F4/80(high)MMR(+) alternatively activated macrophages successfully reduced the prevalence of DPH in WT mice. Collectively, Mac-1 promoted acute inflammatory responses in the peritoneal cavity and the lungs by downregulating granulocyte migration and subsequent phenotypic conversion of macrophages in a pristane induced systemic lupus erythematosus model. PMID- 25281715 TI - Fibrocytes are not an essential source of type I collagen during lung fibrosis. AB - Progressive fibrosis involves accumulation of activated collagen-producing mesenchymal cells. Fibrocytes are hematopoietic-derived cells with mesenchymal features that potentially have a unique and critical function during fibrosis. Fibrocytes have been proposed as an important direct contributor of type I collagen deposition during fibrosis based largely on fate-mapping studies. To determine the functional contribution of hematopoietic cell-derived type I collagen to fibrogenesis, we use a double-transgenic system to specifically delete the type I collagen gene across a broad population of hematopoietic cells. These mice develop a robust fibrotic response similar to littermate genotype control mice injured with bleomycin indicating that fibrocytes are not a necessary source of type I collagen. Using collagen-promoter GFP mice, we find that fibrocytes express type I collagen. However, fibrocytes with confirmed deletion of the type I collagen gene have readily detectable intracellular type I collagen indicating that uptake of collagen from neighboring cells account for much of the fibrocyte collagen. Collectively, these results clarify several seemingly conflicting reports regarding the direct contribution of fibrocytes to collagen deposition. PMID- 25281716 TI - Anti-GITR agonist therapy intrinsically enhances CD8 T cell responses to chronic lymphocytic choriomeningitis virus (LCMV), thereby circumventing LCMV-induced downregulation of costimulatory GITR ligand on APC. AB - The costimulatory TNFR family member GITR can provide important survival signals for CD8 T cells. However, little is known about the regulation of this pathway during a chronic infection. In this study, we show that GITR ligand (GITRL) is maximally induced on APCs at day 2 post-lymphocytic choriomeningitis virus (LCMV) clone 13 infection, but is downregulated to below baseline levels by day 8 postinfection (p.i.), and remains so at the chronic stage of infection. At its peak, GITRL expression is highest on macrophages, with lower expression on conventional and plasmacytoid dendritic cells. GITR expression was highest on T regulatory cells but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 p.i. and was maintained at low, but above baseline levels at the chronic stage of LCMV infection. As GITRL was limiting at the chronic stage of infection, we investigated the potential of therapeutic stimulation of GITR at this stage using agonistic anti-GITR Ab. Anti-GITR treatment at day 21 p.i. increased the frequency and number of LCMV-specific CD8 T cells, resulting in increased in vivo CTL activity and a concomitant decrease in viral load, despite the persistence of PD-1 expression. These effects of anti-GITR were CD8 T cell intrinsic, with no detectable effects on Th1 or T regulatory cells. In contrast to other TNFR agonists, such as anti-4-1BB, which can cause immune pathology, a single therapeutic dose of anti-GITR did not induce splenomegaly or increase serum alanine transaminase. These studies identify GITR as a promising therapeutic target for chronic infection. PMID- 25281717 TI - Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms. AB - Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experimental autoimmune encephalomyelitis, disrupts development of the disease. Leukocyte infiltration into the spinal cord is significantly reduced, as well as short-lived and long-lived autoreactive CD138(+) plasma cells in the spleen and bone marrow, respectively. In addition, potentially protective CD1d(hi)CD5(+) regulatory B cells show resistance to depletion, and myelin-specific Foxp3(+) regulatory T cells are expanded. Taken together, these results demonstrate that MEDI551 disrupts experimental autoimmune encephalomyelitis by inhibiting multiple proinflammatory components whereas preserving regulatory populations. PMID- 25281718 TI - Distinct luminal-type mammary carcinomas arise from orthotopic Trp53-null mammary transplantation of juvenile versus adult mice. AB - Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53-null mammary tissue fragments and monitored for one year. Tumors arose sooner from adult hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80% JH vs. 70% AH), but JH tumors were significantly more ER-immunoreactive (P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer. PMID- 25281719 TI - Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma. AB - The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma. PMID- 25281720 TI - Early pregnancy sex steroids and maternal breast cancer: a nested case-control study. AB - Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age >=40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age >=40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association. PMID- 25281721 TI - Globo-H ceramide shed from cancer cells triggers translin-associated factor X dependent angiogenesis. AB - Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca(2+) mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer(+) breast cancer specimens contained higher vessel density than GHCer(-) breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCbeta1 from TRAX to trigger Ca(2+) mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis. PMID- 25281722 TI - Reply to eLetter by Feldtkeller et al. PMID- 25281723 TI - The bad apple theory won't work: response to 'Challenging the systems approach: why adverse event rates are not improving' by Dr Levitt. PMID- 25281724 TI - Challenging the systems approach: why adverse event rates are not improving. PMID- 25281725 TI - Physiological basis of tolerance to complete submergence in rice involves genetic factors in addition to the SUB1 gene. AB - Recurring floods in Asia cause poor crop establishment. Yields decline drastically when plants are completely submerged for a few days. Traditional rice cultivars predominate because they have acquired moderate tolerance to flooding but they carry the penalty of inherently lower grain yields. In contrast, modern high-yielding varieties are highly susceptible to flooding. Cultivars with tolerance to complete submergence were recently developed in the background of popular varieties by transferring the submergence tolerance gene SUBMERGENCE1 (SUB1) from the highly tolerant Indian landrace FR13A. The present study evaluated three pairs of Sub1 near-isogenic lines (NILs) together with FR13A and two of its submergence-tolerant derivatives under field conditions to assess the survival and growth processes occurring during submergence and recovery that are associated with SUB1. Under control conditions, the NILs showed similar growth and biomass accumulation, indicating that SUB1 had no apparent effects. Submergence substantially decreased biomass accumulation but with greater reduction in the genotypes lacking SUB1, particularly when submergence was prolonged for 17 days. When submerged, the lines lacking SUB1 showed greater elongation and lower or negative biomass accumulation. Sub1 lines maintained higher chlorophyll concentrations during submergence and lost less non-structural carbohydrates (NSC) after submergence. This indicates that the introgression of SUB1 resulted in better regulation of NSC during submergence and that high pre submergence NSC is not essential for the submergence tolerance conferred by SUB1. During recovery, chlorophyll degradation was faster in genotypes lacking SUB1 and any surviving plants showed poorer and delayed emergence of tillers and leaves. Sub1 lines restored new leaf and tiller production faster. During submergence, FR13A showed not only slower leaf elongation but also accumulated extra biomass and was able to recover faster than Sub1 lines. This suggests the possibility of further improvements in submergence tolerance by incorporating additional traits present in FR13A or other similar landraces. PMID- 25281726 TI - Gryllotalpicola reticulitermitis sp. nov., isolated from a termite gut. AB - Strain TS-56(T) was isolated from the gut of a wood-feeding termite, Reticulitermes chinensis Snyder. Phylogenetic analyses based on 16S rRNA gene sequences revealed that the strain represented a member of the genus Gryllotalpicola of the family Microbacteriaceae, with sequence similarities to other species of the genus ranging from 96.6 % to 97.8 %. The isolate was Gram stain-positive, non-motile, with light yellow colonies and irregular short rod shaped cells (0.4-0.6 um in diameter, 0.6-1.0 um in length). Growth of TS-56(T) occurred at 20-35 degrees C (optimum, 30 degrees C) and at pH 4.0-8.0 (optimum, pH 5.0). The peptidoglycan of TS-56(T) contained ornithine, glutamic acid, alanine, homoserine and glycine. The acyl type was acetyl. The most abundant cellular fatty acid of TS-56(T) was cyclohexyl-C17 : 0 (88.79 %). The respiratory menaquinone was MK-11. The polar lipid profile contained disphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol and two unknown glycolipids. DNA of the type strain had a G+C content of 67.4 mol%. On the basis of the phylogenetic properties and phenotypic distinctiveness, TS-56(T) represents a novel species of the genus Gryllotalpicola, for which the name Gryllotalpicola reticulitermitis sp. nov. is proposed. The type strain is TS 56(T) ( = CGMCC 1.10363(T) = NBRC 109838(T)). PMID- 25281727 TI - Lactobacillus formosensis sp. nov., a lactic acid bacterium isolated from fermented soybean meal. AB - A Gram-reaction-positive, catalase-negative, facultatively anaerobic, rod-shaped lactic acid bacterium, designated strain S215(T), was isolated from fermented soybean meal. The organism produced d-lactic acid from glucose without gas formation. 16S rRNA gene sequencing results showed that strain S215(T) had 98.74 99.60 % sequence similarity to the type strains of three species of the genus Lactobacillus (Lactobacillus farciminis BCRC 14043(T), Lactobacillus futsaii BCRC 80278(T) and Lactobacillus crustorum JCM 15951(T)). A comparison of two housekeeping genes, rpoA and pheS, revealed that strain S215(T) was well separated from the reference strains of species of the genus Lactobacillus. DNA DNA hybridization results indicated that strain S215(T) had DNA related to the three type strains of species of the genus Lactobacillus (33-66 % relatedness). The DNA G+C content of strain S215(T) was 36.2 mol%. The cell walls contained peptidoglycan of the d-meso-diaminopimelic acid type and the major fatty acids were C18 : 1omega9c, C16 : 0 and C19 : 0 cyclo omega10c/C19 : 1omega6c. Phenotypic and genotypic features demonstrated that the isolate represents a novel species of the genus Lactobacillus, for which the name Lactobacillus formosensis sp. nov. is proposed. The type strain is S215(T) ( = NBRC 109509(T) = BCRC 80582(T)). PMID- 25281728 TI - Serratia myotis sp. nov. and Serratia vespertilionis sp. nov., isolated from bats hibernating in caves. AB - During the study of bacteria associated with bats affected by white-nose syndrome hibernating in caves in the Czech Republic, we isolated two facultatively anaerobic, Gram-stain-negative bacteria, designated strains 12(T) and 52(T). Strains 12(T) and 52(T) were motile, rod-like bacteria (0.5-0.6 um in diameter; 1 1.3 um long), with optimal growth at 20-35 degrees C and pH 6-8. On the basis of the almost complete sequence of their 16S rRNA genes they should be classified within the genus Serratia; the closest relatives to strains 12(T) and 52(T) were Serratia quinivorans DSM 4597(T) (99.5 % similarity in 16S rRNA gene sequences) and Serratia ficaria DSM 4569(T) (99.5% similarity in 16S rRNA gene sequences), respectively. DNA-DNA relatedness between strain 12(T) and S. quinivorans DSM 4597(T) was only 37.1% and between strain 52(T) and S. ficaria DSM 4569(T) was only 56.2%. Both values are far below the 70% threshold value for species delineation. In view of these data, we propose the inclusion of the two isolates in the genus Serratia as representatives of Serratia myotis sp. nov. (type strain 12(T) =CECT 8594(T) =DSM 28726(T)) and Serratia vespertilionis sp. nov. (type strain 52(T) =CECT 8595(T) =DSM 28727(T)). PMID- 25281729 TI - Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract. AB - Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation. NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear. In this study we used whole cell patch clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses. Results show that NMDA receptors contribute up to 70% of the charge transferred across the synapse at high (>5 Hz) firing rates, but have little contribution at lower firing frequencies. Results also show that NMDA receptors critically contribute to the fidelity of transmission across these synapses during high frequency (>5 Hz) afferent discharge rates. This novel role of NMDA receptors may explain in part how primary visceral afferents, including vagal afferents, can maintain fidelity of transmission across a broad range of firing frequencies. Neurons within the nucleus of the solitary tract (NTS) receive vagal afferent innervations that initiate gastrointestinal and cardiovascular reflexes. Glutamate is the fast excitatory neurotransmitter released in the NTS by vagal afferents, which arrive there via the solitary tract (ST). ST stimulation elicits excitatory postsynaptic currents (EPSCs) in NTS neurons mediated by both AMPA- and NMDA-type glutamate receptors (-Rs). Vagal afferents exhibit a high probability of vesicle release and exhibit robust frequency-dependent depression due to presynaptic vesicle depletion. Nonetheless, synaptic throughput is maintained even at high frequencies of afferent activation. Here we test the hypothesis that postsynaptic NMDA-Rs are essential in maintaining throughput across ST-NTS synapses. Using patch clamp electrophysiology in horizontal brainstem slices, we found that NMDA-Rs, including NR2B subtypes, carry up to 70% of the charge transferred across the synapse during high frequency stimulations (>5 Hz). In contrast, their relative contribution to the ST-EPSC is much less during low (<2 Hz) frequency stimulations. Afferent-driven activation of NMDA-Rs produces a sustained depolarization during high, but not low, frequencies of stimulation as a result of relatively slow decay kinetics. Hence, NMDA-Rs are critical for maintaining action potential generation at high firing rates. These results demonstrate a novel role for NMDA-Rs enabling a high probability of release synapse to maintain the fidelity of synaptic transmission during high frequency firing when glutamate release and AMPA-R responses are reduced. They also suggest why NMDA-Rs are critical for responses that may depend on high rates of afferent discharge. PMID- 25281733 TI - Kabuki syndrome: clinical and molecular diagnosis in the first year of life. AB - OBJECTIVE: To review the clinical and molecular genetic characteristics of 16 patients presenting a suspected diagnosis of Kabuki syndrome (KS) in the first year of life, to evaluate the clinical handles leading to a prompt diagnosis of KS in newborns. Clinical diagnosis of KS can be challenging during the first year of life, as many diagnostic features become evident only in subsequent years. METHODS: All patients were clinically investigated by trained clinical geneticists. A literature review was performed using the Pubmed online database and diagnostic criteria suggested by DYSCERNE-Kabuki Syndrome Guidelines (2010) were used (a European Network of Centres of Expertise for Dysmorphology, funded by the European Commission Executive Agency for Health and Consumers (DG Sanco), Project 2006122). Molecular analysis of the known causative genes of KS, KMT2D/MLL2 and KDM6A, was performed through MiSeq-targeted sequencing platform. All mutations identified were validated by Sanger sequencing protocols. RESULTS: Mutations in KMT2D gene were identified in 10/16 (62%) of the patients, whereas none of the patients had KDM6A mutations. Facial dysmorphisms (94%), feeding difficulties (100%) and hypotonia (100%) suggested the clinical diagnosis of KS. No significative differences in terms of facial features were noticed between mutation positive and negative patients of the cohort. Brachydactyly, joint laxity and nail dysplasia were present in about 80% of the patients. Other congenital anomalies were most commonly present in the mutated group of patients, including left-sided cardiac abnormalities, skeletal, renal and anorectal malformations and hypertricosis. CONCLUSIONS: We present an overview of patients with KS diagnosed during the first year of life. Early diagnosis is serviceable in terms of clinical management and for targeted genetic counselling. PMID- 25281731 TI - Skeletal muscle ATP turnover by 31P magnetic resonance spectroscopy during moderate and heavy bilateral knee extension. AB - During constant-power high-intensity exercise, the expected increase in oxygen uptake (VO2) is supplemented by a VO2 slow component (VO2 sc ), reflecting reduced work efficiency, predominantly within the locomotor muscles. The intracellular source of inefficiency is postulated to be an increase in the ATP cost of power production (an increase in P/W). To test this hypothesis, we measured intramuscular ATP turnover with (31)P magnetic resonance spectroscopy (MRS) and whole-body VO2 during moderate (MOD) and heavy (HVY) bilateral knee extension exercise in healthy participants (n = 14). Unlocalized (31)P spectra were collected from the quadriceps throughout using a dual-tuned ((1)H and (31)P) surface coil with a simple pulse-and-acquire sequence. Total ATP turnover rate (ATPtot) was estimated at exercise cessation from direct measurements of the dynamics of phosphocreatine (PCr) and proton handling. Between 3 and 8 min during MOD, there was no discernable VO2 sc (mean +/- SD, 0.06 +/- 0.12 l min(-1)) or change in [PCr] (30 +/- 8 vs. 32 +/- 7 mm) or ATPtot (24 +/- 14 vs. 17 +/- 14 mm min(-1); each P = n.s.). During HVY, the VO2 sc was 0.37 +/- 0.16 l min(-1) (22 +/- 8%), [PCr] decreased (19 +/- 7 vs. 18 +/- 7 mm, or 12 +/- 15%; P < 0.05) and ATPtot increased (38 +/- 16 vs. 44 +/- 14 mm min(-1), or 26 +/- 30%; P < 0.05) between 3 and 8 min. However, the increase in ATPtot (DeltaATPtot) was not correlated with the VO2 sc during HVY (r(2) = 0.06; P = n.s.). This lack of relationship between DeltaATPtot and VO2 sc , together with a steepening of the [PCr]-VO2 relationship in HVY, suggests that reduced work efficiency during heavy exercise arises from both contractile (P/W) and mitochondrial sources (the O2 cost of ATP resynthesis; P/O). PMID- 25281735 TI - Acute medical review by mobile telemedicine for children in hospital-in-the-home: an innovation. PMID- 25281734 TI - Inter-individual variation in midazolam clearance in children. AB - OBJECTIVES: To determine the extent of inter-individual variation in clearance of midazolam in children and establish which factors are responsible for this variation. METHODS: A systematic literature review was performed to identify papers describing the clearance of midazolam in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL and Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. RESULTS: 25 articles were identified. Only 13 studies gave the full range of clearance values for individual patients. The CV was greater in critically ill patients (18%-170%) than non-critically ill patients (13%-54%). Inter-individual variation was a major problem in all age groups of critically ill patients. The CV was 72%-106% in preterm neonates, 18%-73% in term neonates, 31%-130% in infants, 21%-170% in children and 47%-150% in adolescents. The mean clearance was higher in children (1.1-16.7 mL/min/kg) than in neonates (0.78-2.5 mL/min/kg). CONCLUSIONS: Large inter-individual variation was seen in midazolam clearance values in critically ill neonates, infants, children and adolescents. PMID- 25281736 TI - Health policy research: successes and challenges. AB - This review seeks to explore and explain what health policy research is and why it matters, through pooling the evidence and providing case examples. Alongside examining the types of research involved, and their rationale the paper identifies the challenges taking part in this sort of research may create. Finally the paper suggests how to make clinical research more accessible to policy makers. PMID- 25281738 TI - Metabolomic-based strategies for anti-parasite drug discovery. AB - Metabolomics-based studies are proving of great utility in the analysis of modes of action (MOAs) and resistance mechanisms of drugs in parasitic protozoa. They have helped to determine the MOA of eflornithine, half of the gold standard combination therapy in use against human African trypanosomiasis (HAT), as well as the mechanism of resistance to this drug. In Leishmania, metabolomics has also given insight into the MOA of miltefosine, an alkylphospholipid. Several studies on antimony resistance in Leishmania have been conducted, analyzing the metabolic content of resistant lines, offering clues as to the MOA of this class of drugs. A study of chloroquine resistance in Plasmodium falciparum combined metabolomics techniques with other genetic and proteomic techniques to offer new insight into the role of the PfCRT protein. The MOA and mechanism of resistance to a group of halogenated pyrimidines in Trypanosoma brucei have also recently been elucidated. Effective as metabolomics techniques are, care must be taken in the design and implementation of these experiments, to ensure the resulting data are meaningful. This review outlines the steps required to conduct a metabolomics experiment as well as provide an overview of metabolomics-based drug research in protozoa to date. PMID- 25281737 TI - Lead identification to clinical candidate selection: drugs for Chagas disease. AB - Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)-approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing beta-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti-T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series. PMID- 25281739 TI - Novel high-throughput screening method for identification of fungal dimorphism blockers. AB - Invasive mycoses have been increasing worldwide, with Candida spp. being the most prevalent fungal pathogen causing high morbidity and mortality in immunocompromised individuals. Only few antimycotics exist, often with severe side effects. Therefore, new antifungal drugs are urgently needed. Because the identification of antifungal compounds depends on fast and reliable assays, we present a new approach based on high-throughput image analysis to define cell morphology. Candida albicans and other fungi of the Candida clade switch between different growth morphologies, from budding yeast to filamentous hyphae. Yeasts are considered proliferative, whereas hyphae are required for invasion and dissemination. Thus, morphotype switching in many Candida spp. is connected to virulence and pathogenesis. It is, consequently, reasonable to presume that morphotype blockers interfere with the virulence, thereby preventing hazardous colonization. Our method efficiently differentiates yeast from hyphal cells using a combination of automated microscopy and image analysis. We selected the parameters length/width ratio and mean object shape to quantitatively discriminate yeasts and hyphae. Notably, Z' factor calculations for these parameters confirmed the suitability of our method for high-throughput screening. As a second stage, we determined cell viability to discriminate morphotype switching inhibitors from those that are fungicidal. Thus, our method serves as a basis for the identification of candidates for next-generation antimycotics. PMID- 25281740 TI - Plasma membrane cholesterol as a regulator of human and rodent P2X7 receptor activation and sensitization. AB - P2X7 receptors are nonselective cation channels gated by high extracellular ATP, but with sustained activation, receptor sensitization occurs, whereby the intrinsic pore dilates, making the cell permeable to large organic cations, which eventually leads to cell death. P2X7 receptors associate with cholesterol-rich lipid rafts, but it is unclear how this affects the properties of the receptor channel. Here we show that pore-forming properties of human and rodent P2X7 receptors are sensitive to perturbations of cholesterol levels. Acute depletion of cholesterol with 5 mm methyl-beta-cyclodextrin (MCD) caused a substantial increase in the rate of agonist-evoked pore formation, as measured by the uptake of ethidium dye, whereas cholesterol loading inhibited this process. Patch clamp analysis of P2X7 receptor currents carried by Na(+) and N-methyl-D-glucamine (NMDG(+)) showed enhanced activation and current facilitation following cholesterol depletion. This contrasts with the inhibitory effect of methyl-beta cyclodextrin reported for other P2X subtypes. Mutational analysis suggests the involvement of an N-terminal region and a proximal C-terminal region that comprises multiple cholesterol recognition amino acid consensus (CRAC) motifs, in the cholesterol sensitivity of channel gating. These results reveal cholesterol as a negative regulator of P2X7 receptor pore formation, protecting cells from P2X7-mediated cell death. PMID- 25281741 TI - Identification of small molecule inhibitors of pre-mRNA splicing. AB - Eukaryotic pre-mRNA splicing is an essential step in gene expression for all genes that contain introns. In contrast to transcription and translation, few well characterized chemical inhibitors are available with which to dissect the splicing process, particularly in cells. Therefore, the identification of specific small molecules that either inhibit or modify pre-mRNA splicing would be valuable for research and potentially also for therapeutic applications. We have screened a highly curated library of 71,504 drug-like small molecules using a high throughput in vitro splicing assay. This identified 10 new compounds that both inhibit pre-mRNA splicing in vitro and modify splicing of endogenous pre mRNA in cells. One of these splicing modulators, DDD00107587 (termed "madrasin," i.e. 2-((7methoxy-4-methylquinazolin-2-yl)amino)-5,6-dimethylpyrimidin-4(3H)-one RNAsplicing inhibitor), was studied in more detail. Madrasin interferes with the early stages of spliceosome assembly and stalls spliceosome assembly at the A complex. Madrasin is cytotoxic at higher concentrations, although at lower concentrations it induces cell cycle arrest, promotes a specific reorganization of subnuclear protein localization, and modulates splicing of multiple pre-mRNAs in both HeLa and HEK293 cells. PMID- 25281742 TI - The Eph tyrosine kinase receptors EphB2 and EphA2 are novel proteolytic substrates of tissue factor/coagulation factor VIIa. AB - Tissue factor (TF) binds the serine protease factor VIIa (FVIIa) to form a proteolytically active complex that can trigger coagulation or activate cell signaling. Here we addressed the involvement of tyrosine kinase receptors (RTKs) in TF/FVIIa signaling by antibody array analysis and subsequently found that EphB2 and EphA2 of the Eph RTK family were cleaved in their ectodomains by TF/FVIIa. We used N-terminal Edman sequencing and LC-MS/MS analysis to characterize the cleaved Eph isoforms and identified a key arginine residue at the cleavage site, in agreement with the tryptic serine protease activity of FVIIa. Protease-activated receptor 2 (PAR2) signaling and downstream coagulation activity was non-essential in this context, in further support of a direct cleavage by TF/FVIIa. EphB2 was cleaved by FVIIa concentrations in the subnanomolar range in a number of TF expressing cell types, indicating that the active cellular pool of TF was involved. FVIIa caused potentiation of cell repulsion by the EphB2 ligand ephrin-B1, demonstrating a novel proteolytical event to control Eph-mediated cell segregation. These results define Eph RTKs as novel proteolytical targets of TF/FVIIa and provide new insights into how TF/FVIIa regulates cellular functions independently of PAR2. PMID- 25281743 TI - Monoclonal antibodies against Abeta42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. AB - Amyloidogenic proteins generally form intermolecularly hydrogen-bonded beta-sheet aggregates, including parallel, in-register beta-sheets (recognized by antiserum OC) or antiparallel beta-sheets, beta-solenoids, beta-barrels, and beta cylindrins (recognized by antiserum A11). Although these groups share many common properties, some amyloid sequences have been reported to form polymorphic structural variants or strains. We investigated the humoral immune response to Abeta42 fibrils and produced 23 OC-type monoclonal antibodies recognizing distinct epitopes differentially associated with polymorphic structural variants. These mOC antibodies define at least 18 different immunological profiles represented in aggregates of amyloid-beta (Abeta). All of the antibodies strongly prefer amyloid aggregates over monomer, indicating that they recognize conformational epitopes. Most of the antibodies react with N-terminal linear segments of Abeta, although many recognize a discontinuous epitope consisting of an N-terminal domain and a central domain. Several of the antibodies that recognize linear Abeta segments also react with fibrils formed from unrelated amyloid sequences, indicating that reactivity with linear segments of Abeta does not mean the antibody is sequence-specific. The antibodies display strikingly different patterns of immunoreactivity in Alzheimer disease and transgenic mouse brain and identify spatially and temporally unique amyloid deposits. Our results indicate that the immune response to Abeta42 fibrils is diverse and reflects the structural polymorphisms in fibrillar amyloid structures. These polymorphisms may contribute to differences in toxicity and consequent effects on pathological processes. Thus, a single therapeutic monoclonal antibody may not be able to target all of the pathological aggregates necessary to make an impact on the overall disease process. PMID- 25281744 TI - Cyclopamine modulates gamma-secretase-mediated cleavage of amyloid precursor protein by altering its subcellular trafficking and lysosomal degradation. AB - Alzheimer disease (AD) is a progressive neurodegenerative disease leading to memory loss. Numerous lines of evidence suggest that amyloid-beta (Abeta), a neurotoxic peptide, initiates a cascade that results in synaptic dysfunction, neuronal death, and eventually cognitive deficits. Abeta is generated by the proteolytic processing of the amyloid precursor protein (APP), and alterations to this processing can result in Alzheimer disease. Using in vitro and in vivo models, we identified cyclopamine as a novel regulator of gamma-secretase mediated cleavage of APP. We demonstrate that cyclopamine decreases Abeta generation by altering APP retrograde trafficking. Specifically, cyclopamine treatment reduced APP-C-terminal fragment (CTF) delivery to the trans-Golgi network where gamma-secretase cleavage occurs. Instead, cyclopamine redirects APP CTFs to the lysosome. These data demonstrate that cyclopamine treatment decreases gamma-secretase-mediated cleavage of APP. In addition, cyclopamine treatment decreases the rate of APP-CTF degradation. Together, our data demonstrate that cyclopamine alters APP processing and Abeta generation by inducing changes in APP subcellular trafficking and APP-CTF degradation. PMID- 25281745 TI - Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. AB - The multidrug resistance protein 1 (MRP1) encoded by ABCC1 was originally discovered as a cause of multidrug resistance in tumor cells. However, it is now clear that MRP1 serves a broader role than simply mediating the ATP-dependent efflux of drugs from cells. The antioxidant GSH and the pro-inflammatory cysteinyl leukotriene C4 have been identified as key physiological organic anions effluxed by MRP1, and an ever growing body of evidence indicates that additional lipid-derived mediators are also substrates of this transporter. As such, MRP1 is a multitasking transporter that likely influences the etiology and progression of a host of human diseases. PMID- 25281746 TI - Streptococcus pneumoniae phosphoglycerate kinase is a novel complement inhibitor affecting the membrane attack complex formation. AB - The Gram-positive bacterium Streptococcus pneumoniae is a major human pathogen that causes infections ranging from acute otitis media to life-threatening invasive disease. Pneumococci have evolved several strategies to circumvent the host immune response, in particular the complement attack. The pneumococcal glycolytic enzyme phosphoglycerate kinase (PGK) is both secreted and bound to the bacterial surface and simultaneously binds plasminogen and its tissue plasminogen activator tPA. In the present study we demonstrate that PGK has an additional role in modulating the complement attack. PGK interacted with the membrane attack complex (MAC) components C5, C7, and C9, thereby blocking the assembly and membrane insertion of MAC resulting in significant inhibition of the hemolytic activity of human serum. Recombinant PGK interacted in a dose-dependent manner with these terminal pathway proteins, and the interactions were ionic in nature. In addition, PGK inhibited C9 polymerization both in the fluid phase and on the surface of sheep erythrocytes. Interestingly, PGK bound several MAC proteins simultaneously. Although C5 and C7 had partially overlapping binding sites on PGK, C9 did not compete with either one for PGK binding. Moreover, PGK significantly inhibited MAC deposition via both the classical and alternative pathway at the pneumococcal surface. Additionally, upon activation plasmin(ogen) bound to PGK cleaved the central complement protein C3b thereby further modifying the complement attack. In conclusion, our data demonstrate for the first time to our knowledge a novel pneumococcal inhibitor of the terminal complement cascade aiding complement evasion by this important pathogen. PMID- 25281748 TI - 5-Hydroxytryptamine (5-HT) cellular sequestration during chronic exposure delays 5-HT3 receptor resensitization due to its subsequent release. AB - The serotonergic synapse is dynamically regulated by serotonin (5 hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 +/- 45.7 MUM, t1/2 = 28.6 min). This is confirmed for 5-HT3 receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC50 of 2.3 +/- 1.0 MUM, t1/2 = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization. PMID- 25281747 TI - RING finger protein RNF207, a novel regulator of cardiac excitation. AB - Two recent studies (Newton-Cheh, C. et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399-406 and Pfeufer, A. et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407-414) identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in action potential duration prolongation, occasionally a 2:1 atrioventricular block, and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened action potential duration. Using transfections of U-2 OS and HEK293 cells, Western blot analysis and immunocytochemistry data demonstrate that RNF207 and the human ether-a-go-go related gene (HERG) potassium channel interact and colocalize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by ~30-50%, which was dependent on the intact N terminal RING domain of RNF207. Finally, coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone. This effect was dependent on the C terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration, likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner. PMID- 25281751 TI - Reaching rural patients through otolaryngology visiting consultant clinics. AB - Providing otolaryngology care to rural populations is a major challenge. In this study, we focus on rural outreach by the otolaryngology workforce in Iowa, a state with a high proportion of rural residents. Using data from 2013, we find that almost half (46%) of Iowa-based otolaryngologists participate in outreach. Along with colleagues from adjoining states, Iowa otolaryngologists staffed more than 2100 in-person clinic days in 76 mainly rural sites. This system of rural outreach has expanded access from 20 to 85 of the 99 counties in Iowa. These efforts improve access for more than 1 million residents out of a total population of 3 million. However, this improved level of access comes at a cost as visiting otolaryngologists drove an estimated 17,000 miles per month. This established approach to serving rural patients may be negatively impacted by changes under the Affordable Care Act. PMID- 25281750 TI - Cochrane corner: interventions to improve hearing aid use in adult auditory rehabilitation. AB - The "Cochrane Corner" is a section in the journal that highlights systematic reviews relevant to otolaryngology-head and neck surgery, with invited commentary to aid clinical decision making. This installment features the Cochrane review "Interventions to Improve Hearing Aid Use in Adult Auditory Rehabilitation," which identified 32 randomized controlled trials and concluded that there is low quality evidence to support using self-management support and complex interventions (support plus delivery system design) in adult auditory rehabilitation. PMID- 25281752 TI - The in vivo response of naive CD4+ T cells. PMID- 25281749 TI - Computer aided-designed, 3-dimensionally printed porous tissue bioscaffolds for craniofacial soft tissue reconstruction. AB - OBJECTIVE: To determine the potential of an integrated, image-based computer aided design (CAD) and 3-dimensional (3D) printing approach to engineer scaffolds for head and neck cartilaginous reconstruction for auricular and nasal reconstruction. STUDY DESIGN: Proof of concept revealing novel methods for bioscaffold production with in vitro and in vivo animal data. SETTING: Multidisciplinary effort encompassing 2 academic institutions. SUBJECTS AND METHODS: Digital Imaging and Communications in Medicine (DICOM) computed tomography scans were segmented and utilized in image-based CAD to create porous, anatomic structures. Bioresorbable polycaprolactone scaffolds with spherical and random porous architecture were produced using a laser-based 3D printing process. Subcutaneous in vivo implantation of auricular and nasal scaffolds was performed in a porcine model. Auricular scaffolds were seeded with chondrogenic growth factors in a hyaluronic acid/collagen hydrogel and cultured in vitro over 2 months' duration. RESULTS: Auricular and nasal constructs with several types of microporous architecture were rapidly manufactured with high fidelity to human patient anatomy. Subcutaneous in vivo implantation of auricular and nasal scaffolds resulted in an excellent appearance and complete soft tissue ingrowth. Histological analysis of in vitro scaffolds demonstrated native-appearing cartilaginous growth that respected the boundaries of the scaffold. CONCLUSION: Integrated, image-based CAD and 3D printing processes generated patient-specific nasal and auricular scaffolds that supported cartilage regeneration. PMID- 25281753 TI - The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. AB - Programmed death ligand 1 (PD-L1, also known as B7 homolog 1 or CD274) is a major obstacle to antitumor immunity because it tolerizes/anergizes tumor-reactive T cells by binding to its receptor programmed death-1 (CD279), renders tumor cells resistant to CD8(+) T cell- and FasL-mediated lysis, and tolerizes T cells by reverse signaling through T cell-expressed CD80. PD-L1 is abundant in the tumor microenvironment, where it is expressed by many malignant cells, as well as by immune cells and vascular endothelial cells. The critical role of PD-L1 in obstructing antitumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs antitumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment. PMID- 25281755 TI - Efficacy and safety of treatment with an anti-m2e monoclonal antibody in experimental human influenza. AB - BACKGROUND: The efficacy of TCN-032, a human monoclonal antibody targeting a conserved epitope on M2e, was explored in experimental human influenza. METHODS: Healthy volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2) and received a single dose of the study drug, TCN-032, or placebo 24 hours later. Subjects were monitored for symptoms, viral shedding, and safety, including cytokine measurements. Oseltamivir was administered 7 days after inoculation. RESULTS: Although the primary objective of reducing the proportion of subjects developing any grade >=2 influenza symptom or pyrexia, was not achieved, TCN-032 treated subjects showed 35% reduction (P = .047) in median total symptom area under the curve (days 1-7) and 2.2 log reduction in median viral load area under the curve (days 2-7) by quantitative polymerase chain reaction (P = .09) compared with placebo-treated subjects. TCN-032 was safe and well tolerated with no additional safety signals after administration of oseltamivir. Serum cytokine levels (interferon gamma, tumor necrosis factor alpha, and interleukin 8 and 10) were similar in both groups. Genotypic and phenotypic analyses showed no difference between virus derived from subjects after TCN-032 treatment and parental strain. CONCLUSIONS: These data indicate that TCN-032 may provide immediate immunity and therapeutic benefit in influenza A infection, with no apparent emergence of resistant virus. TCN-032 was safe with no evidence of immune exacerbation based on serum cytokine expression. Clinicaltrials.gov registry number. NCT01719874. PMID- 25281756 TI - Advancing treatment options for influenza: challenges with the human influenza challenge. PMID- 25281754 TI - Innate receptors and cellular defense against pulmonary infections. AB - In the United States, lung infections consistently rank in the top 10 leading causes of death, accounting for >50,000 deaths annually. Moreover, >140,000 deaths occur annually as a result of chronic lung diseases, some of which may be complicated by an infectious process. The lung is constantly exposed to the environment and is susceptible to infectious complications caused by bacterial, viral, fungal, and parasitic pathogens. Indeed, we are continually faced with the threat of morbidity and mortality associated with annual influenza virus infections, new respiratory viruses (e.g., SARS-CoV), and lung infections caused by antibiotic-resistant "ESKAPE pathogens" (three of which target the lung). This review highlights innate immune receptors and cell types that function to protect against infectious challenges to the respiratory system yet also may be associated with exacerbations in chronic lung diseases. PMID- 25281758 TI - Phenotype alterations in regulatory T-cell subsets in primary HIV infection and identification of Tr1-like cells as the main interleukin 10-producing CD4+ T cells. AB - BACKGROUND: Conventional regulatory T cells (Tregs) can suppress human immunodeficiency virus type 1 (HIV-1)-specific immune responses but cannot control immune activation in primary HIV infection. Here, we characterized Treg subsets, using recently defined phenotypic delineation, and analyzed the relative contribution of cell subsets to the production of immunosuppressive cytokines in primary HIV infection. METHODS: In a longitudinal prospective study, ex vivo phenotyping of fresh peripheral blood mononuclear cells from patients with primary HIV infection was performed at baseline and month 6 of follow-up to characterize Treg subsets, immune activation, and cytokine production in isolated CD4(+) T cells. RESULTS: The frequency of CD4(+)CD25(+)CD127(low) Tregs and the distribution between the naive, memory, and activated/memory Treg subsets was similar in patients and healthy donors. However, Tregs from patients with primary HIV infection showed peculiar phenotypic profiles, such as elevated FoxP3, ICOS, and CTLA-4 expression, with CTLA-4 expression strikingly increased in all Treg subsets both at baseline and month 6 of follow-up. The great majority of interleukin 10 (IL-10)-producing CD4(+) T cells were FoxP3(neg) (ie, Tr1-like cells). In contrast to conventional Tregs, Tr1-like cells were inversely correlated with immune activation and not associated with lower effector T-cell responses. CONCLUSION: FoxP3(neg) Tr1-like cells-major contributors to IL-10 production-may have a beneficial role by controlling immune activation in early HIV infection. PMID- 25281757 TI - The diaphanous-related formins promote protrusion formation and cell-to-cell spread of Listeria monocytogenes. AB - The Gram-positive bacterium Listeria monocytogenes is a facultative intracellular pathogen whose virulence depends on its ability to spread from cell to cell within an infected host. Although the actin-related protein 2/3 (Arp2/3) complex is necessary and sufficient for Listeria actin tail assembly, previous studies suggest that other actin polymerization factors, such as formins, may participate in protrusion formation. Here, we show that Arp2/3 localized to only a minor portion of the protrusion. Moreover, treatment of L. monocytogenes-infected HeLa cells with a formin FH2-domain inhibitor significantly reduced protrusion length. In addition, the Diaphanous-related formins 1-3 (mDia1-3) localized to protrusions, and knockdown of mDia1, mDia2, and mDia3 substantially decreased cell-to-cell spread of L. monocytogenes. Rho GTPases are known to be involved in formin activation. Our studies also show that knockdown of several Rho family members significantly influenced bacterial cell-to-cell spread. Collectively, these findings identify a Rho GTPase-formin network that is critically involved in the cell-to-cell spread of L. monocytogenes. PMID- 25281759 TI - The importance of first person accounts in education: teacher and student perspectives. PMID- 25281760 TI - Deletion of ELOVL6 blocks the synthesis of oleic acid but does not prevent the development of fatty liver or insulin resistance. AB - Elongation of very long chain fatty acid-like family member 6 (ELOVL6) is a fatty acyl elongase that performs the initial and rate-limiting condensing reaction required for microsomal elongation of long-chain fatty acids. Our previous in vitro studies suggested that ELOVL6 elongated long-chain saturated fatty acids and monounsaturated fatty acids with chain lengths of 12 to 16 carbons. Here, we describe the generation and phenotypic characterization of Elovl6(-/-) mice. As predicted from the in vitro studies, livers from Elovl6(-/-) mice accumulated palmitic (C16:0) and palmitoleic (C16:1, n-7) fatty acids and contained significantly less stearic (C18:0) and oleic (C18:1, n-9) acids, confirming that ELOVL6 is the only enzyme capable of elongating palmitate (C16:0). Unexpectedly, Elovl6(-/-) mice produced vaccenic acid (C18:1, n-7), the elongated product of palmitoleate (C16:1, n-7), suggesting that palmitoleate (C16:1, n-7) to vaccenate (C18:1, n-7) elongation was not specific to ELOVL6. The only detected consequence of deleting Elovl6(-/-) in mice was that their livers accumulated significantly more triglycerides than wild-type mice when fed a fat-free/high-carbohydrate diet. When mice were fed a high-fat diet or ELOVL6 was deleted in ob/ob mice, the absence of ELOVL6 did not alter the development of obesity, fatty liver, hyperglycemia, or hyperinsulinemia. Combined, these results suggest that palmitoleic (C16:1, n-7) and vaccenic (C18:1, n-7) acids can largely replace the roles of oleic acid (C18:1, n-9) in vivo and that the deletion of ELOVL6 does not protect mice from the development of hepatic steatosis or insulin resistance. PMID- 25281761 TI - Cervical ectopy: associations with sexually transmitted infections and HIV. A cross-sectional study of high school students in rural South Africa. AB - OBJECTIVES: It has been hypothesised that ectopy may be associated with increased susceptibility to sexually transmitted infections (STIs). In this cross-sectional study, we wanted to explore the association between STIs (including HIV) and cervical ectopy. METHODS: We included 700 sexually active young women attending randomly selected high schools in a rural district in KwaZulu-Natal, South Africa. The district is endemic of HIV and has a high prevalence of STIs. We did computer-assisted measurements of the ectocervical area covered by columnar epithelium (ectopy) in colposcopic images and STI analyses on cervicovaginal lavage and serum samples. All participating women answered a questionnaire about sexual behaviour and use of contraceptives. RESULTS: The mean age was 19.1 years. Ectopy was found in 27.2%, HIV in 27.8%, chlamydia in 25.3% and gonorrhoea in 15.6%. We found that age, parity, chlamydia and gonorrhoea, years since menarche, years since sexual debut and number of sexual partners were associated with ectopy. In multivariate analysis with chlamydia infection as the dependent variable, women with ectopy had increased odds of having chlamydia infection (adjusted OR 1.78, p=0.033). In women under 19 years of age, we found twofold higher odds of being HIV-positive for those with ectopy (OR 2.19, p=0.014). CONCLUSIONS: In conclusion, cervical ectopy is associated with Chlamydia trachomatis infection and HIV in the youngest women. PMID- 25281762 TI - Transplantation of bone marrow stem cells during cardiac surgery. AB - BACKGROUND: This systematic review with meta-analysis sought to determine the efficacy and safety of intramyocardial transplantation of bone marrow stem cells during coronary artery bypass graft surgery on postoperative cardiac functional parameters such as left ventricular ejection fraction and left ventricular end diastolic volume. METHODS: Medline/PubMed, Embase, Elsevier, Sciences online database, and Google Scholar literature search were searched. The effect sizes measured were risk ratio for categorical variables and weighted mean difference with 95% confidence interval for calculating differences between mean values of baseline and follow-up cardiac functional parameters. A value of p < 0.1 for Q test, or I(2 )> 50%, indicated significant heterogeneity among studies. The literature search retrieved 2900 studies from screened databases, of which 2866 (98.6%) were excluded and 34 (619 patients) were included for scoping review. The final analysis included 9 studies (335 patients). RESULTS: Pooled effects estimates of left ventricular ejection fraction and left ventricular end diastolic volume showed that bone marrow stem cell transplantation had a weighted mean difference of 4.06 (95% confidence interval: 0.41-7.72; p = 0.02) and 7.06 (95% confidence interval: -8.58-22.7; p = 0.3), respectively. CONCLUSIONS: Intramyocardial transplantation of bone marrow stem cells improves cardiac functional parameters, significantly increasing left ventricular ejection fraction with a nonsignificant reduction in left ventricular end-diastolic volume. Also, this therapeutic method has no life-threatening complications and was therefore found to be an effective and safe method. PMID- 25281763 TI - Unusual coexistent rheumatic mitral stenosis and hypertrophic cardiomyopathy. PMID- 25281764 TI - Endotracheal tube as tracheal stent in vascular ring. AB - Management of vascular ring is always a matter of great concern. There is limited literature on management of carbon dioxide retention in mechanically ventilated patients with vascular rings due to double aortic arch, while awaiting corrective cardiac surgery. A 29-day-old girl with complete duplicated double aortic arch, left descending aorta, and a left patent ductus arteriosus, had severe upper respiratory tract obstruction with carbon dioxide retention. She was managed successfully by endotracheal tube manipulation. PMID- 25281765 TI - Early rule-out of acute coronary syndrome using undetectable levels of high sensitivity troponin T. AB - AIMS: To examine whether undetectable high sensitivity troponin T (hsTnT) can be used to safely rule out non-ST-elevation acute coronary syndrome (NSTE-ACS) (using the limit of detection (LOD) as the cut-off) and to compare this strategy to serial hsTnT and the use of combined hsTnT and copeptin. METHODS: In this prospective observational study, 478 patients presenting with chest pain were consecutively included. A combined primary endpoint of ACS, non-elective revascularization and/or death of all causes was used. The follow-up period was 60 days. RESULTS: NSTE-ACS was diagnosed in 107 (22%) patients during hospital stay. Undetectable hsTnT at admission ruled out NSTE-ACS with a negative predictive value of 94% (95% confidence interval (CI): 88-97) giving a sensitivity of 0.90 (95% CI: 0.80-0.95) versus 0.78 (95% CI: 0.66-0.87) for serial hsTnT testing, p=0.008. The combination of hsTnT and copeptin analysed at admission resulted in a sensitivity of 0.83 (95% CI: 0.74-0.89), p=0.07 for comparison with undetectable hsTnT. CONCLUSION: A single hsTnT test at presentation, using the LOD as the cut-off, appears to be a safe and time-saving strategy to rule out NSTE-ACS. Further, undetectable levels of hsTnT were associated with an excellent prognosis and none of the patients with undetectable hsTnT were diagnosed with NSTEMI. Together with ECG and clinical assessment this biomarker strategy might permit outpatient treatment of almost one third of the patients we currently admit for observation. PMID- 25281766 TI - CADM1, MAL and miR124-2 methylation analysis in cervical scrapes to detect cervical and endometrial cancer. AB - AIMS: Gene promoter hypermethylation is recognised as an essential early step in carcinogenesis, indicating important application areas for DNA methylation analysis in early cancer detection. The current study was set out to assess the performance of CADM1, MAL and miR124-2 methylation analysis in cervical scrapes for detection of cervical and endometrial cancer. METHODS: A series of cervical scrapes of women with cervical (n=79) or endometrial (n=21) cancer, cervical intraepithelial neoplasia grade 3 (CIN3) (n=16) or CIN2 (n=32), and women without evidence of CIN2 or worse (n=120) were assessed for methylation of CADM1, MAL and miR124-2. Methylation analysis was done by the PreCursor-M assay, a multiplex quantitative methylation-specific PCR. RESULTS: All samples of women with cervical cancer (79/79, 100%), independent of the histotype, and 76% (16/21; 95% CI 58.0% to 94.4%) of women with endometrial cancer scored positive for DNA methylation for at least one of the three genes. In women without cancer, methylation frequencies increased significantly with severity of disease from 19.2% (23/120; 95% CI 12.1% to 26.2%) in women without CIN2 or worse to 37.5% (12/32; 95% CI 20.7% to 54.3%) and 68.8% (11/16; 95% CI 46.0% to 91.5%) in women with CIN2 and CIN3, respectively. Overall methylation positivity and the number of methylated genes increased proportionally to the lesion severity. CONCLUSIONS: DNA methylation analysis of CADM1, MAL and miR124-2 in cervical scrapes consistently detects cervical cancer and the majority of CIN3 lesions, and has the capacity to broaden its use on cervical scrapes through the detection of a substantial subset of endometrial carcinomas. PMID- 25281767 TI - Immunohistochemical expression of inflammatory markers in sudden infant death; ancillary tests for identification of infection. AB - AIMS: Sudden unexpected death in infancy (SUDI) investigation requires extensive ancillary investigations, the results of which, such as postmortem microbiology, can be difficult to interpret. Markers of an inflammatory response, including interleukin 6 (IL-6), c-reactive protein (CRP) and cellular adhesion molecules are elevated in infections, yet little attention has been paid to their assessment after death. This study investigates the role of inflammatory markers in SUDI autopsies for determining cause of death. METHODS: Cases of SUDI over a 14 year period were identified from an autopsy database and 100 cases were selected for immunohistochemical staining of heart and liver for IL-6, CRP, P selectin, VCAM-1 and ICAM-1 (CD54), with staining patterns compared between five groups, including infectious and unexplained SUDI. RESULTS: There were significant differences between groups. Cases of histological infection demonstrated strongly positive hepatocyte CRP and ICAM-1 expression and increased myocardial staining for CRP. Half of trauma-related deaths demonstrated diffuse hepatic CRP expression but without myocardial CRP staining. Staining of unexplained SUDI cases were predominantly negative, apart from a subgroup in whom Escherichia Coli was identified, who had increased expression of hepatic IL-6. CONCLUSIONS: There were distinct patterns of organ-specific CRP and ICAM-1 expression in SUDI by cause of death. These markers of inflammation were rarely present in unexplained SUDI suggesting either a non-inflammatory cause of death or a failure to mount an effective acute phase response. Immunohistochemical staining offers potential to identify infection-related deaths and provides insight into SUDI mechanisms. PMID- 25281768 TI - Molecular network including eIF1AX, RPS7, and 14-3-3gamma regulates protein translation and cell proliferation in bovine mammary epithelial cells. AB - 14-3-3gamma, an isoform of the 14-3-3 protein family, was proved to be a positive regulator of mTOR pathway. Here, we analyzed the function of 14-3-3gamma in protein synthesis using bovine mammary epithelial cells (BMECs). We found that 14 3-3gamma interacted with eIF1AX and RPS7 by 14-3-3gamma coimmunoprecipitation (CoIP) and matrix-assisted laser desorption/ionization-time-of-flight/time-of flight (MALDI-TOF/TOF) peptide mass fingerprinting analysis. These interactions of 14-3-3gamma with eIF1AX and RPS7 were further confirmed by colocalization and fluorescence resonance energy transfer (FRET) analysis. We also found that methionine could promote protein synthesis and trigger the protein expression levels of 14-3-3gamma, eIF1AX and RPS7. Analysis of overexpression and inhibition of 14-3-3gamma confirmed that it positively affected the protein expression levels of eIF1AX, RPS7, Stat5 and mTOR pathway to promote protein synthesis and cell proliferation in BMECs. We further showed that overexpression of eIF1AX and RPS7 also triggered protein translation and cell proliferation. From these results, we conclude that molecular network including eIF1AX, RPS7, and 14-3 3gamma regulates protein translation and cell proliferation in BMECs. PMID- 25281769 TI - Re: Mumps vaccine effectiveness and risk factors for disease in households during an outbreak in New York City. PMID- 25281770 TI - Microencapsulation of dopamine neurons derived from human induced pluripotent stem cells. AB - BACKGROUND: Dopamine neurons derived from induced pluripotent stem cells have been widely studied for the treatment of Parkinson's disease. However, various difficulties remain to be overcome, such as tumor formation, fragility of dopamine neurons, difficulty in handling large numbers of dopamine neurons, and immune reactions. In this study, human induced pluripotent stem cell-derived precursors of dopamine neurons were encapsulated in agarose microbeads. Dopamine neurons in microbeads could be handled without specific protocols, because the microbeads protected the fragile dopamine neurons from mechanical stress. METHODS: hiPS cells were seeded on a Matrigel-coated dish and cultured to induce differentiation into a dopamine neuronal linage. On day 18 of culture, cells were collected from the culture dishes and seeded into U-bottom 96-well plates to induce cell aggregate formation. After 5 days, cell aggregates were collected from the plates and microencapsulated in agarose microbeads. The microencapsulated aggregates were cultured for an additional 45 days to induce maturation of dopamine neurons. RESULTS: Approximately 60% of all cells differentiated into tyrosine hydroxylase-positive neurons in agarose microbeads. The cells released dopamine for more than 40 days. In addition, microbeads containing cells could be cryopreserved. CONCLUSION: hiPS cells were successfully differentiated into dopamine neurons in agarose microbeads. GENERAL SIGNIFICANCE: Agarose microencapsulation provides a good supporting environment for the preparation and storage of dopamine neurons. PMID- 25281771 TI - Proteomic identification of the heterogeneous nuclear ribonucleoprotein K as irradiation responsive protein related to migration. AB - Irradiation resistance is a major obstacle of head and neck squamous cell carcinoma (HNSCC) therapy, limiting treatment success and patient survival. The aim of our experiments was to identify irradiation-regulated proteins as potential drug targets. Two established HNSCC cell lines (HNSCCUM-01T and HNSCCUM 02T) were treated with a single 8Gy (Gray) fraction of irradiation. Changes in cellular protein expression were studied after 24h by means of 2D-electrophoresis and MALDI-TOF-mass spectrometry. Ninety-four differentially expressed proteins were identified. The expression levels of four proteins were regulated similarly in both cell lines after irradiation treatment, i.e., GRP78, PRDX, ACTC, and the heterogeneous nuclear ribonucleoprotein K (hnRNPK), suggesting a relevant role during irradiation response. hnRNPK as a p53 interacting protein was verified by Western blotting and immunocytochemical staining as well as functionally analyzed. Knock-down by the use of siRNA resulted in only slightly reduced viability, however, migratory activity was strongly reduced. Combined application of siRNA against hnRNPK and irradiation reduced migration almost completely. We conclude that hnRNPK is potentially implicated in the radiogenic response of HNSCC. The inhibition of hnRNPK might reduce the metastasizing potential of HNSCC especially in combination with irradiation and suggest that this molecule should be further evaluated in this context. BIOLOGICAL SIGNIFICANCE: We showed completely impaired migration of irradiated hnRNPK-knock-out HNSCC cells, suggesting this molecule as a potential drug target in combined treatment schedules. PMID- 25281772 TI - A proteomic approach to monitor the dynamic response of the female oviductal epithelial cell surface to male gametes. AB - Sophisticated strategies to analyze cell surface proteins are indispensable to study fundamental biological processes, such as the response of cells to environmental changes or cell-cell communication. Herein, we describe a refined mass spectrometry-based approach for the specific characterization and quantitation of cell surface proteins expressed in the female reproductive tract. The strategy is based on in situ biotinylation of rabbit oviducts, affinity enrichment of surface exposed biotin tagged proteins and dimethyl labeling of the obtained tryptic peptides followed by LC-MS/MS analysis. This approach proved to be sensitive enough to analyze small sample amounts (<1MUg) and allowed further to trace the dynamic composition of the surface proteome of the oviductal epithelium in response to male gametes. The relative protein expression ratios of 175 proteins were quantified. Thirty-one of them were found to be altered over time, namely immediately, 1h and 2h after insemination compared to the time matched control groups. Functional analysis demonstrated that structural reorganization of the oviductal epithelial cell surface was involved in the early response of the female organ to semen. In summary, this study outlines a workflow that is capable to monitor alterations in the female oviduct that are related to key reproductive processes in vivo. BIOLOGICAL SIGNIFICANCE: The proper interaction between the female reproductive tract, in particular, the oviduct and the male gametes, is fundamental to fertilization and embryonic development under physiological conditions. Thereby the oviductal epithelial cell surface proteins play an important role. Besides their direct interaction with male gametes, these molecules participate in signal transduction and, thus, are involved in the mandatory cellular response of the oviductal epithelium. In this study we present a refined LC-MS/MS based workflow that is capable to quantitatively analyze the expression of oviductal epithelial cell surface proteins in response to insemination in vivo. A special focus was on the very early interaction between the female organ and the male gametes. At first, this study clearly revealed an immediate response of the surface proteome to semen, which was modulated over time. The described methodology can be applied for studies of further distinct biological events in the oviduct and therefore contribute to a deeper insight into the formation of new life. PMID- 25281773 TI - Bacterial and algal orthologs of prostaglandin H2synthase: novel insights into the evolution of an integral membrane protein. AB - Prostaglandin H2synthase (PGHS; EC 1.14.99.1), a bi-functional heme enzyme that contains cyclooxygenase and peroxidase activities, plays a central role in the inflammatory response, pain, and blood clotting in higher eukaryotes. In this review, we discuss the progenitors of the mammalian enzyme by using modern bioinformatics and homology modeling to draw comparisons between this well studied system and its orthologs from algae and bacterial sources. A clade of bacterial and algal orthologs is described that have salient structural features distinct from eukaryotic counterparts, including the lack of a dimerization and EGF-like domains, the absence of gene duplicates, and minimal membrane-binding domains. The functional implications of shared and variant features are discussed. PMID- 25281775 TI - In vitro human fecal microbial metabolism of Forsythoside A and biological activities of its metabolites. AB - The present study aimed to investigate the metabolism of Forsythoside A (FTA) by human fecal bacteria to clarify the relationship between its intestinal metabolism and its pharmacological activities. FTA was incubated with human fecal microflora in vitro to investigate its metabolic process, and highly sensitive and specific ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed using MetaboLynx software for metabolite analysis. Caffeic acid (CA) and hydroxytyrosol (HT) were obtained by hydrolysis of FTA, and CA was further hydrogenated to form 3,4 dihydroxybenzenepropionic acid (DCA). The anticomplementary, antimicrobial and antiendotoxin activities of FTA and its metabolites by human fecal microflora were evaluated in vitro with a hemolysis assay, the agar disc-diffusion method, the MIC value and the gel clot LAL assay, respectively. The metabolites showed higher biological activity than FTA, especially HT and DCA. Orally administered FTA may be metabolized to HT and DCA, and the pharmacological effects of FTA may be dependent on intestinal bacterial metabolism. PMID- 25281774 TI - The enduring utility of continuous culturing in experimental evolution. AB - Studying evolution in the laboratory provides a means of understanding the processes, dynamics and outcomes of adaptive evolution in precisely controlled and readily replicated conditions. The advantages of experimental evolution are maximized when the selection is well defined, which enables linking genotype, phenotype and fitness. One means of maintaining a defined selection is continuous culturing: chemostats enable the study of adaptive evolution in constant nutrient limited environments, whereas cells in turbidostats evolve in constant nutrient abundance. Although the experimental effort required for continuous culturing is considerable relative to the experimental simplicity of serial batch culture, the opposite is true of the environments they produce: continuous culturing results in simplified and invariant conditions whereas serially diluted batch cultures are complex and dynamic. The comparative simplicity of the selective environment that is unique to continuous culturing provides an ideal experimental system for addressing key questions in adaptive evolution. PMID- 25281776 TI - (RS)-glucoraphanin purified from Tuscan black kale and bioactivated with myrosinase enzyme protects against cerebral ischemia/reperfusion injury in rats. AB - Ischemic stroke is the result of a transient or permanent reduction in cerebral blood flow caused by the occlusion of a cerebral artery via an embolus or local thrombosis. Restoration of blood supply to ischemic tissues can cause additional damage known as reperfusion injury that can be more damaging than the initial ischemia. This study was aimed to examine the possible neuroprotective role of (RS)-glucoraphanin, bioactivated with myrosinase enzyme (bioactive RS-GRA), in an experimental rat model of brain ischemia/reperfusion injury (I/R). RS-GRA is a thiosaccharidic compound found in Brassicaceae, notably in Tuscan black kale (Brassica oleracea L. var. acephala sabellica). The mechanism underlying the inhibitory effects of bioactive RS-GRA on inflammatory and apoptotic responses, induced by carotid artery occlusion in rats, was carefully examined. Cerebral I/R was induced by the clamping of carotid artery for 1h, followed by 40 min of reperfusion through the release of clamp. Our results have clearly shown that administration of bioactive RS-GRA (10 mg/kg, i.p.) 15 min after ischemia, significantly reduces proinflammatory parameters, such as inducible nitric oxide synthase expression (iNOS), intercellular adhesion molecule 1 (ICAM-1), nuclear factor (NF)-kB traslocation as well as the triggering of the apoptotic pathway (TUNEL and Caspase 3 expression). Taken together our data have shown that bioactive RS-GRA possesses beneficial neuroprotective effects in counteracting the brain damage associated to I/R. Therefore, bioactive RS-GRA, could be a useful treatment in the cerebral ischemic stroke. PMID- 25281777 TI - Challenges to pain medicine management at home: commentary on the Schumacher et al. papers. PMID- 25281778 TI - A randomized, double-blind, solifenacin succinate versus placebo control, phase 4, multicenter study evaluating urinary continence after robotic assisted radical prostatectomy. AB - PURPOSE: Bladder dysfunction influences recovery of urinary continence after radical prostatectomy. We performed a multicenter, randomized, double-blind study evaluating solifenacin vs placebo on return to continence in patients who were still incontinent 7 to 21 days after catheter removal after robot-assisted radical prostatectomy. MATERIALS AND METHODS: A wireless personal digital assistant was given to patients the day of catheter removal. Encrypted answers were transmitted daily to dedicated servers. After a 7 to 21-day treatment-free washout period, patients requiring 2 to 10 pads per day for 7 consecutive days were randomized (1:1) to 5 mg solifenacin daily or placebo. The primary end point was time from first dose to continence defined as 0 pads per day or a dry security pad for 3 consecutive days. Secondary end points included proportion of patients continent at end of study, average change in pads per day number and quality of life assessments. RESULTS: A total of 1,086 screened patients recorded personal digital assistant information. Overall 640 patients were randomized to solifenacin vs placebo and 17 failed to take medication. There was no difference in time to continence (p=0.17). Continence was achieved by study end in 91 of 313 (29%) vs 66 of 309 (21%), respectively (p=0.04). Pads per day change from baseline was -3.2 and -2.9, respectively (p=0.03). Dry mouth was the only common adverse event seen in 6.1% and 0.6%, respectively. Constipation rates were similar. The overall rate of continence in the entire population from screening to end of study was 73%. CONCLUSIONS: There was no effect on primary outcome but some secondary end points benefited the solifenacin arm. The study provides level 1B clinical evidence for continence outcomes after robot-assisted radical prostatectomy. PMID- 25281779 TI - A meta-analysis of the performance of retropubic mid urethral slings versus transobturator mid urethral slings. AB - PURPOSE: We evaluate the efficacy and complications after retropubic and transobturator mid urethral slings in the treatment of female stress urinary incontinence. MATERIALS AND METHODS: A systematic literature review was performed using MEDLINE(r), limited to randomized controlled trials with a minimum followup of 1 year and type 1 grafts. Statistical analyses were performed using StatsDirect Version 2.7.9 (StatsDirect Ltd, Altrincham, UK). RESULTS: Retropubic mid urethral sling procedures showed statistically significant improvements in objective cure (OR 1.35, 95% CI 1.10-1.67, p=0.005) and subjective cure (OR 1.24, 95% CI 1.04-1.49, p=0.02). Bladder perforations (OR 5.72, CI 2.94-11.12, p <0.0001) and bleeding (OR 2.65, CI 1.54-4.59, p=0.0005) were significantly more common with retropubic mid urethral slings, whereas vaginal perforations (OR 0.29, CI 0.15-0.56, p=0.0002) and neurological symptoms (OR 0.35, CI 0.25-0.5, p <0.0001) were more common with transobturator mid urethral slings. Operative time was significantly longer for retropubic mid urethral slings than transobturator mid urethral slings (OR 1.38, p <0.0001). No significant differences were noted in mesh erosions and exposure, urinary retention, infection, lower urinary tract symptoms and length of hospital stay. CONCLUSIONS: Retropubic mid urethral slings showed better objective and subjective cure rates than transobturator mid urethral slings. However, bladder perforation and bleeding were more common with retropubic mid urethral slings. Operative time was longer for retropubic mid urethral slings. Transobturator mid urethral slings were associated with more cases of neurological symptoms and vaginal perforation. PMID- 25281780 TI - Teasing in school locker rooms regarding penile appearance. AB - PURPOSE: Parents of young boys seeking circumcision or circumcision revision commonly cite concern that their sons may be teased in middle or high school due to the appearance of the penis. There are no current data to substantiate or refute the likelihood of such teasing. We explored the validity of this concern by investigating the extent and frequency of teasing regarding penile appearance. MATERIALS AND METHODS: An anonymous questionnaire was administered to undergraduate men at the University of Iowa. Participants answered questions regarding middle and high school demographics, school sports and gym class participation, and any teasing experienced or witnessed due to penile appearance in locker rooms. RESULTS: A total of 290 men completed the questionnaire. Mean subject age was 19.2 years (range 17 to 24). Of the individuals surveyed 98% were required to participate in high school gym class and 96% participated in a school sport. Of the subjects 10% were teased about their penile appearance and 47% reported witnessing someone else being teased. The most common characteristic singled out was penile size. However, having an uncircumcised penis or a "strange" penile appearance accounted for 33% of the witnessed penile teasing. Only 3% of the cohort wished that they had a different penile appearance. CONCLUSIONS: Teasing in the locker room about penile appearance occurs frequently. While our study is limited to 1 Midwestern university population, it appears that parental concerns regarding teasing related to penile appearance are valid, although most causes of teasing may not be alleviated by surgical therapy. PMID- 25281781 TI - Inulin-based polymer coated SPIONs as potential drug delivery systems for targeted cancer therapy. AB - This paper deal with the synthesis and characterization of PEGylated squalene grafted-inulin amphiphile capable of self-assembling and self-organizing into nanocarriers once placed in aqueous media. It was exploited as coating agent for obtaining doxorubicin loaded superparamagnetic iron oxide nanoparticles (SPIONs) endowed with stealth like behavior and excellent physicochemical stability. Inulin was firstly modified in the side chain with primary amine groups, followed in turn by conjugation with squalenoyl derivatives through common amidic coupling agents and PEGylation by imine linkage. Polymer coated SPIONs were so obtained by spontaneous self-assembling of inulin copolymer onto magnetite surface involving hydrophobic-hydrophobic interactions between the metallic core and the squalene moieties. The system was characterized in terms of hydrodynamic radius, zeta potential, shape and drug loading capacity. On the whole, the stealth-like shell stabilized the suspension in aqueous media, though allowing the release of the doxorubicin loaded in therapeutic range. The cytotoxicity profile on cancer (HCT116) cell line and in vitro drug uptake were evaluated both with and without an external magnetic field used as targeting agent and uptake promoter, displaying that magnetic targeting implies advantageous therapeutic effects, that is amplified drug uptake and increased anticancer activity throughout the tumor mass. PMID- 25281782 TI - Identification of high-affinity copper transporters in Aspergillus fumigatus. AB - We investigated the copper metabolism of Aspergillus fumigatus, which has not been characterized well. We cloned the putative copper transporters ctrA2 and ctrC from A. fumigatus and investigated the functions of these transporters in copper metabolism. Four putative copper transporters were identified in the A. fumigatus genome; ctrA2 and ctrC complemented CTR1 functionally and localized to the plasma membrane in Saccharomyces cerevisiae. ctrA2 and ctrC single-deletion mutants and a double-deletion mutant of ctrA2 and ctrC were constructed in A. fumigatus. The ctrA2 and ctrC double-deletion mutant exhibited a growth defect on Aspergillus minimal medium (AMM) supplemented with bathocuproine disulfonic acid (BCS) and was sensitive to H2O2. Furthermore, the deletion of ctrA2 and ctrC reduced superoxide dismutase (SOD) activity, laccase activity, and intracellular copper contents. The activities of the ctrA2 and ctrC genes were up-regulated by BCS treatment. In addition, the deletion of ctrA2 up-regulated ctrC and vice versa. ctrA2 and ctrC were localized to the A. fumigatus plasma membrane. Although ctrA2 and ctrC failed to affect the mouse survival rate, these genes affected conidial killing activity. Taken together, these results indicate that ctrA2 and ctrC may function as membrane transporters and that the involvement of these genes in pathogenicity merits further investigation. PMID- 25281783 TI - Variation in the fumonisin biosynthetic gene cluster in fumonisin-producing and nonproducing black aspergilli. AB - The ability to produce fumonisin mycotoxins varies among members of the black aspergilli. Previously, analyses of selected genes in the fumonisin biosynthetic gene (fum) cluster in black aspergilli from California grapes indicated that fumonisin-nonproducing isolates of Aspergillus welwitschiae lack six fum genes, but nonproducing isolates of Aspergillus niger do not. In the current study, analyses of black aspergilli from grapes from the Mediterranean Basin indicate that the genomic context of the fum cluster is the same in isolates of A. niger and A. welwitschiae regardless of fumonisin-production ability and that full length clusters occur in producing isolates of both species and nonproducing isolates of A. niger. In contrast, the cluster has undergone an eight-gene deletion in fumonisin-nonproducing isolates of A. welwitschiae. Phylogenetic analyses suggest each species consists of a mixed population of fumonisin producing and nonproducing individuals, and that existence of both production phenotypes may provide a selective advantage to these species. Differences in gene content of fum cluster homologues and phylogenetic relationships of fum genes suggest that the mutation(s) responsible for the nonproduction phenotype differs, and therefore arose independently, in the two species. Partial fum cluster homologues were also identified in genome sequences of four other black Aspergillus species. Gene content of these partial clusters and phylogenetic relationships of fum sequences indicate that non-random partial deletion of the cluster has occurred multiple times among the species. This in turn suggests that an intact cluster and fumonisin production were once more widespread among black aspergilli. PMID- 25281784 TI - Validation of a multidisciplinary infrastructure to capture adverse events in a high-volume endoscopy unit. PMID- 25281785 TI - Diabetes augments cognitive dysfunction in chronic cerebral hypoperfusion by increasing neuronal cell death: implication of cilostazol for diabetes mellitus induced dementia. AB - Many patients with diabetes are at increased risk of cognitive dysfunction and dementia. Diabetes mellitus is a vascular risk factor that may increase the risk of dementia through its associations with vascular dementia. We tested whether cognitive impairment could be exacerbated in combined injury using a rat model of chronic cerebral hypoperfusion with diabetes. We also determined whether a potent inhibitor of type III phosphodiesterase could prevent the cognitive decline caused by this combined injury. We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of type II diabetes (T2DM) and Long-Evans Tokushima Otsuka (LETO) rats as a control. Chronic cerebral hypoperfusion was modeled by permanent bilateral common carotid artery occlusion (BCCAO). At 24weeks, the non-diabetic and T2DM rats were randomly assigned into groups for the following experiments: analysis I (1) sham non-diabetic rats (n=8); (2) hypoperfused non-diabetic rats (n=9); (3) sham T2DM rats (n=8); (4) hypoperfused T2DM rats (n=9); analysis II- (1) sham T2DM rats without treatment (n=8); (2) cilostazol-treated T2DM rats (n=8); (3) hypoperfused T2DM rats (n=9); and (4) hypoperfused T2DM rats and cilostazol treatment (n=9). The rats were orally administered cilostazol (50mg/kg) or vehicle once a day for 2weeks after 24weeks. Rats performed Morris water maze tasks, and neuronal cell death and neuroinflammation were investigated via Western blots and histological investigation. Spatial memory impairment was exacerbated synergistically in the hypoperfused T2DM group compared with the hypoperfused non-diabetic group and sham T2DBM group (P<0.05). Compared with the control group, neuronal cell death was increased in the hippocampus of the hypoperfused T2DM group. Cilostazol, a PDE-3 inhibitor, improved the memory impairments through inhibition of neuronal cell death, activation of CREB phosphorylation and BDNF expression in the hypoperfused T2DM group. Our experimental results support the hypothesis that there are deleterious interactions between chronic cerebral hypoperfusion and T2DM. That is, metabolic diseases such as diabetes may exacerbate cognitive impairment in a rat model of vascular dementia. We also suggest that surprisingly, the phosphodiesterase III inhibitor, cilostazol may be useful for the treatment of cognitive impairment in diabetes mellitus-induced dementia. In conclusion, diabetes can aggravate cognitive dysfunction in vascular dementia, and PDE-3 inhibitors, such as cilostazol, may form the basis of a novel therapeutic strategy for diabetes associated cognitive impairment or vascular dementia. PMID- 25281786 TI - Reactive combinatorial synthesis and characterization of a gradient Ag-Ti oxide thin film with antibacterial properties. AB - The growing demand for orthopedic and dental implants has spurred researchers to develop multifunctional coatings, combining tissue integration with antibacterial features. A possible strategy to endow titanium (Ti) with antibacterial properties is by incorporating silver (Ag), but designing a structure with adequate Ag(+) release while maintaining biocompatibility has been shown difficult. To further explore the composition-structure-property relationships between Ag and Ti, and its effects against bacteria, this study utilized a combinatorial approach to manufacture and test a single sample containing a binary Ag-Ti oxide gradient. The sample, sputter-deposited in a reactive (O2) environment using a custom-built combinatorial physical vapor deposition system, was shown to be effective against Staphylococcus aureus with viability reductions ranging from 17 to above 99%, depending on the amount of Ag(+) released from its different parts. The Ag content along the gradient ranged from 35 to 62 wt.%, but it was found that structural properties such as varied porosity and degree of crystallinity, rather than the amount of incorporated Ag, governed the Ag(+) release and resulting antibacterial activity. The coating also demonstrated in vitro apatite-forming abilities, where structural variety along the sample was shown to alter the hydrophilic behavior, with the degree of hydroxyapatite deposition varying accordingly. By means of combinatorial synthesis, a single gradient sample was able to display intricate compositional and structural features affecting its biological response, which would otherwise require a series of coatings. The current findings suggest that future implant coatings incorporating Ag as an antibacterial agent could be structurally enhanced to better suit clinical requirements. PMID- 25281787 TI - Regeneration of high-quality silk fibroin fiber by wet spinning from CaCl2-formic acid solvent. AB - Silks spun by silkworms and spiders feature outstanding mechanical properties despite being spun under benign conditions. The superior physical properties of silk are closely related to its complicated hierarchical structures constructed from nanoscale building blocks, such as nanocrystals and nanofibrils. Here, we report a novel silk dissolution behavior, which preserved nanofibrils in CaCl2 formic acid solution, that enables spinning of high-quality fibers with a hierarchical structure. This process is characterized by simplicity, high efficiency, low cost, environmental compatibility and large-scale industrialization potential, as well as having utility and potential for the recycling of silk waste and the production of silk-based functional materials. PMID- 25281788 TI - Silk microfiber-reinforced silk hydrogel composites for functional cartilage tissue repair. AB - Cartilage tissue lacks an intrinsic capacity for self-regeneration due to slow matrix turnover, a limited supply of mature chondrocytes and insufficient vasculature. Although cartilage tissue engineering has achieved some success using agarose as a scaffolding material, major challenges of agarose-based cartilage repair, including non-degradability, poor tissue-scaffold integration and limited processing capability, have prompted the search for an alternative biomaterial. In this study, silk fiber-hydrogel composites (SF-silk hydrogels) made from silk microfibers and silk hydrogels were investigated for their potential use as a support material for engineered cartilage. We demonstrated the use of 100% silk-based fiber-hydrogel composite scaffolds for the development of cartilage constructs with properties comparable to those made with agarose. Cartilage constructs with an equilibrium modulus in the native tissue range were fabricated by mimicking the collagen fiber and proteoglycan composite architecture of native cartilage using biocompatible, biodegradable silk fibroin from Bombyx mori. Excellent chondrocyte response was observed on SF-silk hydrogels, and fiber reinforcement resulted in the development of more mechanically robust constructs after 42 days in culture compared to silk hydrogels alone. Thus, we demonstrate the versatility of silk fibroin as a composite scaffolding material for use in cartilage tissue repair to create functional cartilage constructs that overcome the limitations of agarose biomaterials, and provide a much-needed alternative to the agarose standard. PMID- 25281789 TI - Differential response of two somatolactin genes to zinc or estrogen in pituitary of Cyprinus carpio. AB - Environmental changes affect gene expression that we addressed in the pituitary, a central regulatory organ at the interface between the central nervous system and the endocrine system. With the aim to reveal effects of changes in the aquatic environment on the expression of hypothalamo-hypophyseal factors, we characterized somatolactin (SL) in Cyprinus carpio. SL, a fish specific pituitary hormone belonging to the prolactin (PRL) superfamily, is involved in background adaptation, osmoregulation, reproduction and fatty acid metabolism. Two sl genes, alpha and beta, were discovered in carp and transcripts of both were detected in pituitaries. Clearly, expression of slalpha and slbeta was modulated significantly in pituitary of male adult carp in response to treatment with ZnCl2 (Zn), but only slbeta responded to 17beta-estrogen (E2), relative to control carp as shown by RT-qPCR analyses. Furthermore, the amount of mRNA of related factors was assessed revealing variable effects on prl, growth hormone (gh), and factors involved in sl regulation: the pituitary transcription factor pit1 and hypothalamic pituitary adenylase cyclase activating peptide (pacap). In parallel, the physiological response of the experimental animals to Zn or E2 was confirmed by showing a significant increase of metallothionein (mt) or vitellogenin (vg) gene expression in liver, classical sentinels for exposure to heavy metal or estrogens. These data suggest that the sl genes seem to be involved in the response to Zn, as well as to estrogen, and could contribute to evaluate biological relevant changes in the aquatic environment. PMID- 25281790 TI - Inhibitory role of the serotonergic system on estrogen receptor alpha expression in the female rat hypothalamus. AB - The role of the serotonergic system in regulating the expression of estrogen receptor (ER) alpha in the hypothalamus was investigated in ovariectomized rats by injecting a serotonin synthesis inhibitor, parachlorophenylalanine (PCPA), or by destroying the dorsal raphe nucleus (DR). The number of ERalpha-immunoreactive (ir) cells was counted in the anteroventral periventricular nucleus in the preoptic area (AVPV), ventrolateral ventromedial hypothalamic nucleus (vlVMN), and arcuate nucleus (ARCN). Seven days after ovariectomy, 100mg/kg PCPA or saline was injected daily for 4 days. Alternatively, radiofrequency lesioning of the DR (DRL) or sham lesions were made on the same time of ovariectomy. One-day after the last injection of PCPA or 7 days after brain surgery, the brain was fixed for immunostaining of ERalpha and the number of ERalpha-ir cell were counted in the nuclei of interest. The mean number of ERalpha-ir cells/mm(3) (density) in the AVPV of the PCPA or DRL groups was statistically higher than that in the saline or sham group. In the vlVMN and ARCN of the PCPA or DRL groups, the mean density of ERalpha-ir cells was comparable to the saline or sham groups. These results suggest that the serotonergic system of the DR plays an inhibitory role on the expression of ERalpha in the AVPV, but not in the vlVMN and ARCN. PMID- 25281791 TI - TIMP1 in conditioned media of human adipose stromal cells protects neurons against oxygen-glucose deprivation injury. AB - Adipose stromal cells (ASC) can protect neurons when administered to brains due to secreted trophic factors. Our previous studies demonstrated that several neurotrophic factors such as brain-derived neurotropic factor (BDNF) and insulin like growth factor-1 (IGF-1) in ASC conditioned media (ASC-CM) can protect brains against hypoxic-ischemic (HI) injury in neonatal rats. In this study, we demonstrated that human ASC-CM potently blockeds caspase-3 mediated cortical neuronal apoptosis under in vitro oxygen-glucose deprivation (OGD). Interestingly, tissue inhibitor of metalloproteinase 1 (TIMP1), a non neurotrophic factor, played a significant role in the ASC-CM-induced neural protection against OGD. Thus, this study establishes the therapeutic potential of TIMP1 together with other neurotrophic factors in ASC-CM for treating cerebral HI disorders. PMID- 25281792 TI - Immunohistochemical detectability of cerebrovascular utrophin depends on the condition of basal lamina. AB - Utrophin is an autosomal homologue of dystrophin. Dystrophin is a member of the dystrophin-glycoprotein complex, which is a cell surface receptor for basal lamina components. In recent opinions utrophin occurs in the cerebrovascular endothelium but not in the perivascular glia. Cerebrovascular laminin immunoreactivity can only be detected in the subpial segments of the vessels, in circumventricular organs lacking blood-brain barrier, in immature vessels and following brain lesions. In our former experience utrophin immunoreactivity showed similar phenomena to that of laminin. The present study investigates the parallel occurrence of vascular utrophin and laminin immunoreactivity in the brain tissue, especially in the circumventricular organs, and during the parallel postnatal regression of both utrophin and laminin immunoreactivity. Their cerebrovascular immunoreactivity observed in frozen sections renders plausible the role of hidden but explorable epitopes, instead of a real absence of laminin and utrophin. The laminin epitopes are supposed to be hidden due to the fusion of the glial (i.e. brain parenchymal) and vascular basal laminae (Krum et al., Exp. Neurol. 111 (1991) 151). In all cases including its post-lesion re-appearance published formerly by us, laminin immunoreactivity may be attributed to the separation of glial and vascular basal laminae. Utrophin is localized, however, intracellularly, therefore a more complex molecular mechanism is to be assumed and it remains to be investigated how structural changes of the basal lamina may indirectly affect the immunoreactivity of utrophin. The results indicate that immunoreactivity may be influenced not only by the presence or absence of macromolecules but also by their functional state. PMID- 25281793 TI - Development of LC-MS methods for quantitation of hepcidin and demonstration of siRNA-mediated hepcidin suppression in serum. AB - INTRODUCTION: A requisite step in developing a therapeutic to modulate the levels of hepcidin is the development of a quantitative method for measuring the concentration of serum hepcidin. METHODS: To this end, an LC-MS method, based on selected reaction monitoring (SRM) with a triple quadrupole MS and an isotopically labeled hepcidin as internal standard, was developed to measure hepcidin in mouse and monkey sera. RESULTS: Initially, 40 normal cynomolgus monkeys and 40 normal mice were studied to determine the normal endogenous levels of hepcidin, and an average of 50ng/mL was found in the monkeys and 46ng/mL in the mice. Next, experiments were conducted where an siRNA, targeting hepcidin, was administered to cynomolgus monkeys, resulting in effective hepcidin reduction (inhibition rate) of 87% after 24h and 74% after 48h, demonstrating to effectively reduce serume level of hepcidin. CONCLUSIONS: For better sensitivity, especially for the low volumes available for mouse sera, a second LC-MS method, based on parallel reaction monitoring (PRM) using a Orbitrap MS was developed and shown to be at least 10 fold lower in detection limits (or consumption of serum volume) than the SRM approach. PMID- 25281794 TI - beta-casomorphin-7 alters MU-opioid receptor and dipeptidyl peptidase IV genes expression in children with atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease with heterogeneous clinical phenotypes reflecting genetic predisposition and exposure to environmental factors. Reactions to food may play a significant role especially in young children. Milk proteins are particularly strong allergens and are additional source of bioactive peptides including beta-casomorphin-7 (BCM7, Tyr Pro-Phe-Pro-Gly-Pro-Ile). BCM7 exerts its influence on nervous, digestive, and immune functions via the MU-opioid receptor (MOR). Proline dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) appears to be the primary degrading enzyme of BCM7. Moreover, DPPIV is known to restrict activity of proinflammatory peptides. BCM7 is considered to modulate an immune response by affecting MOR and DPPIV genes expression. In this study, we determined the MOR and DPPIV genes expression in children diagnosed with a severe form of AD. 40 healthy children and 62 children diagnosed with severe AD (AD score >=60) were included in the study. Peripheral blood mononuclear cells (PBMCs) from the studied subjects were incubated with the peptide extracts of raw and hydrolysed cow milk with defined beta-casein genotypes (A1A1, A2A2 and A1A2) and MOR and DPPIV genes expression was determined with real-time PCR. Incubation PBMCs with peptide extracts from cow milk caused an increase of the MOR gene expression (p<0.05; p<0.001) in AD children with a simultaneous decrease in the DPPIV gene expression (p<0.001). The obtained results supplement the knowledge on the BCM7 participation in AD etiology and provide an important diagnostic tool. PMID- 25281795 TI - Development and evaluation of the Nurotron 26-electrode cochlear implant system. AB - Although the cochlear implant has been widely acknowledged as the most successful neural prosthesis, only a fraction of hearing-impaired people who can potentially benefit from a cochlear implant have actually received one due to its limited awareness, accessibility, and affordability. To help overcome these limitations, a 26-electrode cochlear implant has been developed to receive China's Food and Drug Administration (CFDA) approval in 2011 and Conformite Europeenne (CE) Marking in 2012. The present article describes design philosophy, system specification, and technical verification of the Nurotron device, which includes advanced digital signal processing and 4 current sources with multiple amplitude resolutions that not only are compatible with perceptual capability but also allow interleaved or simultaneous stimulation. The article also presents 3-year longitudinal evaluation data from 60 human subjects who have received the Nurotron device. The objective measures show that electrode impedance decreased within the first month of device use, but was stable until a slight increase at the end of two years. The subjective loudness measures show that electric stimulation threshold was stable while the maximal comfort level increased over the 3 years. Mandarin sentence recognition increased from the pre-surgical 0% correct score to a plateau of about 80% correct with 6-month use of the device. Both indirect and direct comparisons indicate indistinguishable performance differences between the Nurotron system and other commercially available devices. The present 26-electrode cochlear implant has already helped to lower the price of cochlear implantation in China and will likely contribute to increased cochlear implant access and success in the rest of the world. This article is part of a Special Issue entitled . PMID- 25281796 TI - Exploring multiple binding sites of an indoloquinoline in triple-helical DNA: a paradigm for DNA triplex-selective intercalators. AB - Employing NMR spectroscopic methods preferred binding sites of a triplex selective indoloquinoline drug were examined with three DNA triplex targets. To directly derive and evaluate number and type of the different sites of interaction, studies were performed on short triple-helical constructs specifically labeled with 3-(15)N thymidine probes. The detection and assignment of several coexisting species was enabled through the observation of slow exchange on the chemical shift timescale between complexes and free triplex. In general, the 5'-triplex-duplex junction constitutes the most favorable intercalation site, in particular when flanked by a TAT base triad. NMR data also revealed two different orientations for the intercalating indoloquinoline drug. Binding affinity significantly decreases with a C(+)GC triad bordering the junction but junction binding is still preferred over intercalation between TAT base triads within the triplex stem. In addition to the intercalation between two uncharged TAT triplets, intercalation between a TAT and a 3'-terminal C(+)GC triplet was also observed, indicating a non-protonated third strand cytosine at the triplex end position. PMID- 25281797 TI - Menstrual cycle variability of CA 72-4 in healthy women. AB - OBJECTIVES: CA 72-4 is not approved as a tumor marker but has been used as an adjunct marker in gynecological practice. The study aims to evaluate the menstrual cycle variability of CA 72-4 in a population of healthy women. DESIGN AND METHODS: Forty apparently healthy regularly menstruating subjects were included in the cross-sectional study designed in the University Obstetrics and Gynecology outpatient clinic. Venous blood samples from each participant were collected twice: first at the follicular phase (2nd-5th days of the menstrual cycle) for FSH, estradiol, CA 125, CA 72-4 and the other at the luteal phase (21st-24th days of the menstrual cycle) for progesterone, CA 125 and CA 72-4 levels. RESULTS: CA 72-4 values were similar in follicular and luteal phase of the menstrual cycle in apparently healthy regularly menstruating subjects (1.15U/mL (0.2-5.4) vs 1.15 U/mL (0.56-6.3); p=0.326 respectively). Ovulatory or smoking status did not have an effect on CA 72-4 values (p>0.05). CONCLUSION: This first clinical study about the menstrual cycle variability of CA 72-4 revealed that the menstrual cycle does not have a significant impact on CA 72-4 values and that it can be measured at any time during the menstrual period. PMID- 25281798 TI - A family with various symptomatology suggestive of Anderson-Fabry disease and a genetic polymorphism of alpha galactosidase A gene. AB - BACKGROUND: Anderson/Fabry disease expresses a wide range of clinical variability in patients that it is possible to explain referring to a genetic variability with numerous mutations described in the literature (more than 600). METHODS: We report some clinical cases of some members of a Sicilian family to express phenotypical variability of this disease in subjects with the same genetic mutation RESULTS: The first case was a 59-year-old female. Brain MRI revealed right frontal periventricular white matter of likely vascular-degenerative origin. The proband's alpha galactosidase A activity was 3.7nmol/mL/h. Molecular genetics revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C>T. The second case was a 30year-old male affected by acroparesthesias and hypoidrosis since he was an adolescent. Renal impairment was first detected at age 29; it began with high plasma levels of creatinine and microalbuminuria date. The third case was a 41year-old daughter that presented with acroparesthesias, hypoidrosis since she was very young. The patient's alpha galactosidase A activity was 4.1nmol/mL/h, in whole blood, which is compatible with heterozygote subject for Fabry's disease or healthy control. The fourth case was a male grandson of the proband, 9year-old child. He had a classic gastrointestinal involvement. He complained of recurrent abdominal pain, post prandial bloating and pain. This child's enzyme activity was 1.65nmol/mL/h. In cases 2, 3, and 4, molecular genetics revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 CG, IVS6-22C>T polymorphisms occurred in 8.9% and 3.7% of the subjects respectively, and the significance of this haplotype in FD pathology remains unknown but possibly suggestive of Anderson/Fabry disease. PMID- 25281799 TI - Neural mechanisms underlying context-dependent shifts in risk preferences. AB - Studies of risky decision-making have demonstrated that humans typically prefer risky options after incurring a financial loss, while generally preferring safer options after a monetary gain. Here, we examined the neural processes underlying these inconsistent risk preferences by investigating the evaluation of gains and losses, and demonstrating how these responses can impact subsequent preference for either risky or safe choice options. Participants performed a task while undergoing fMRI in which they experienced both gains and losses. Immediately following a gain or loss, participants decided to either play or pass on a "double-or-quits" gamble. The outcome of the gamble could either double or eliminate their initial gain (from the time-estimation task) or redeem or double their initial loss. If they chose not to play this gamble, they retained the initial gain or loss. We demonstrate a shift in risk-taking preferences for identical sets of gambles as a function of previous gains or losses, with participants showing a greater preference towards riskier decisions in the context of a prior loss. An interaction between evaluating gain/loss contexts and subsequent behavioral risk pattern revealed an increased BOLD response in the ventromedial prefrontal cortex (vmPFC), with stronger responses for both gambling in a loss context and safety in a gain context. This suggests that the vmPFC is responsible for integrating these contextual effects, with these processes impacting on subsequent risky choice. PMID- 25281801 TI - Improved poly(3-hydroxybutyrate) production in Escherichia coli by inactivation of cytochrome bd-II oxidase or/and NDH-II dehydrogenase in low efficient respiratory chains. AB - In order to redirect more carbon flux from TCA cycle into poly(3-hydroxybutyrate) (PHB) biosynthesis pathway via increasing respiratory efficiency, appB and ndh genes encoding cytochrome bd-II oxidase and NDH-II dehydrogenase were inactivated in Escherichia coli JM109/pBHR68. All appB or/and ndh knockout strains exhibited significantly increased PHB accumulation accompanying with increased NAD(P)H/NAD(P)(+) ratio and intracellular acetyl-CoA pool. Among them, the Deltandh strain could accumulate up to 6.16g/L PHB from 20g/L glucose and 3.5g/L PHB from 20g/L xylose, respectively, a 1.76-fold and 3.43-fold increase compared to the wild-type control. The PHB production of this strain reached 28.23g/L in a 5-L fermentor study, which was 2.70-fold as much as that of the wild-type control. These results indicated that inactivating the cytochrome bd-II oxidase or/and NDH-II dehydrogenase of the aerobic respiratory chain is a simple and effective strategy to improve PHB biosynthesis in E. coli. To date, this is the first time to improve PHB production by inactivation of cytochrome bd-II oxidase or/and NDH-II dehydrogenase in low efficient respiratory chains. PMID- 25281800 TI - Resting-state networks predict individual differences in common and specific aspects of executive function. AB - The goal of the present study was to examine relationships between individual differences in resting state functional connectivity as ascertained by fMRI (rs fcMRI) and performance on tasks of executive function (EF), broadly defined as the ability to regulate thoughts and actions. Unlike most previous research that focused on the relationship between rs-fcMRI and a single behavioral measure of EF, in the current study we examined the relationship of rs-fcMRI with individual differences in subcomponents of EF. Ninety-one adults completed a resting state fMRI scan and three separate EF tasks outside the magnet: inhibition of prepotent responses, task set shifting, and working memory updating. From these three measures, we derived estimates of common aspects of EF, as well as abilities specific to working memory updating and task shifting. Using Independent Components Analysis (ICA), we identified across the group of participants several networks of regions (Resting State Networks, RSNs) with temporally correlated time courses. We then used dual regression to explore how these RSNs covaried with individual differences in EF. Dual regression revealed that increased higher common EF was associated with connectivity of a) frontal pole with an attentional RSN, and b) Crus I and II of the cerebellum with the right frontoparietal RSN. Moreover, higher shifting-specific abilities were associated with increased connectivity of angular gyrus with a ventral attention RSN. The results of the current study suggest that the organization of the brain at rest may have important implications for individual differences in EF, and that individuals higher in EF may have expanded resting state networks as compared to individuals with lower EF. PMID- 25281802 TI - Efficient enzymatic degradation process for hydrolysis activity of the Carrageenan from red algae in marine biomass. AB - Carrageenan is a generic name for a family of polysaccharides obtained from certain species of red algae. New methods to produce useful cost-efficiently materials from red algae are needed to convert enzymatic processes into fermentable sugars. In this study, we constructed chimeric genes cCgkA and cCglA containing the catalytic domain of kappa-carrageenase CgkA and lambda carrageenase CglA from Pseudoalteromonas carrageenovora fused with a dockerin domain. Recombinant strains expressing the chimeric carrageenase resulted in a halo formation on the carrageenan plate by alcian blue staining. The recombinant cCgkA and cCglA were assembled with scaffoldin miniCbpA via cohesin and dockerin interaction. Carbohydrate binding module (CBM) in scaffoldin was used as a tag for cellulose affinity purification using cellulose as a support. The hydrolysis process was monitored by the amount of reducing sugar released from carrageenan. Interestingly, these results indicated that miniCbpA, cCgkA and cCglA assembled into a complex and that the dockerin-fused enzymes on the scaffoldin had synergistic activity in the degradation of carrageenan. The observed enhancement of activity by carrageenolytic complex was 3.1-fold-higher compared with the corresponding enzymes alone. Thus, the assemblies of advancement of active enzyme complexes will facilitate the commercial production of useful products from red algae biomass which represents inexpensive and sustainable feed-stocks. PMID- 25281803 TI - Stress-induced dendritic internalization and nuclear translocation of the neurokinin-3 (NK3) receptor in vasopressinergic profiles of the rat paraventricular nucleus of the hypothalamus. AB - Central neuronal circuits that relay stress information include vasopressin- (AVP) and oxytocin- (OC) containing neurons of the paraventricular nucleus of the hypothalamus (PVN). These neurons are potentially modulated by neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides. NK3Rs have been localized in PVN neurons and have showed nuclear translocation following an osmotic challenge in rodents. However, their subcellular distribution in AVP or OC neurons of the PVN and plasticity following restraint stress in rats are unknown. In the present study, densities of NK3Rs in PVN AVP- or OC-labeled somatodendritic profiles were measured by quantitative immunoelectron microscopy in control or stressed rats. In resting conditions, NK3Rs were predominantly located in AVP neurons, however sparsely distributed in OC neurons of the PVN. All NK3-labeled somata of the PVN in control rats showed cytoplasmic but no nuclear immunolabeling. An acute restraint stress session of 30 min significantly increased nuclear NK3R density in AVP-labeled somata but not in OC-labeled somata. These changes were accompanied by a respective decrease and increase in plasmalemmal and cytoplamic NK3R densities in AVP-labeled but not in OC-labeled dendrites. The results of this study suggest that in the rat PVN 1) NK3R distribution is conducive to modulation of systemic and/or central AVP release through PVN inputs to the posterior pituitary and/or the amygdala and 2) acute restraint stress activates (internalizes) NK3Rs on surface and evokes nuclear NK3R translocation exclusively in AVP neurons. This trafficking might contribute to neurochemical imbalances observed in neuronal circuits involved in stress related disorders such as anxiety. PMID- 25281804 TI - Galanthamine, an acetylcholine inhibitor, prevents prepulse inhibition deficits induced by adolescent social isolation or MK-801 treatment. AB - Adolescence is a critical period for neurodevelopment. MK-801 treatment and social isolation are important animal models for various neurodevelopmental disorders. Dysfunctions in the central cholinergic system are involved in creating the cognitive deficits observed in neurological diseases. In the present study, we aimed to investigate whether the acetylcholinesterase inhibitor galanthamine could reverse pre-cognitive prepulse inhibition (PPI) deficits and spatial learning deficits of adult rats in the Morris water maze. We induced these effects using either adolescent MK-801 treatment or social isolation from postnatal day (PND) 38-51. Our results showed that both adolescent social isolation and MK-801 treatment impaired PPI in adult rats, but neither had an effect on spatial learning. Furthermore, galanthamine injections over 7 days significantly enhanced PPI of normal rats and improved PPI disruption induced by adolescent pharmacological and rearing interventions. The results suggest that acetylcholinesterase inhibitors, such as galanthamine, might have the potential to improve pre-cognition in neurodevelopmental diseases by improving auditory sensory gating. PMID- 25281805 TI - Circadian feeding entrains anticipatory metabolic activity in piriform cortex and olfactory tubercle, but not in suprachiasmatic nucleus. AB - Animals maintained under conditions of food-availability restricted to a specific period of the day show molecular and physiological circadian rhythms and increase their locomotor activity 2-3h prior to the next scheduled feeding, called food anticipatory activity (FAA). Although the anatomical substrates and underlying mechanisms of the food-entrainable oscillator are not well understood, experimental evidence indicates that it involves multiple structures and systems. Using rabbit pups entrained to circadian nursing as a natural model of food restriction, we hypothesized that the anterior piriform cortex (APCx) and the olfactory tubercle (OTu) are activated during nursing-associated FAA. Two groups of litters were entrained to one of two different nursing times. At postnatal day 7, when litters showed clear FAA, pups from each litter were euthanized at nursing time, or 1, 2, 4, 8, 12, 16 or 20h later. Neural metabolic activities of the APCx, OTu, olfactory bulb (OB) and suprachiasmatic nucleus (SCN) were assessed by cytochrome oxidase histochemistry. Additionally, two fasted groups were nurse-deprived for two cycles before being euthanized at postnatal day 9. In nursed pups, metabolic activity of APCx, OTu and OB increased during FAA and after feeding, independently of the geographical time. Metabolic activity in SCN was not affected by nursing schedule. Given that APCx and OTu are in a key network position to integrate temporal odor signals with body energetic state, brain arousal and reward mechanisms, we suggest that these structures could be an important part of the conditioned oscillatory mechanism that leads to food entrainment. PMID- 25281807 TI - Age dependent nitro-oxidative load and melatonin receptor expression in the spleen and immunity of goat Capra hircus. AB - The decline in the plasma level of melatonin has been associated with increased oxidative stress in the physiological system while aging. The increased levels of oxidants are known to augment the nitro-oxidative stress, which induces the apoptotic factors in lymphoid organs leading to age dependent immunosenescence. There are no reports to date that can suggest how the age dependent nitro oxidative stress can influence the melatonin membrane MT1/MT2R expression and immune status of any small ruminant. In the present study, we noted the expression of melatonin receptors MT1R and MT2R and inducible nitric oxide synthase (iNOS) along with the apoptotic markers (viz. Bcl-2, Bax and Pro-caspase 3) in the spleen of young, middle-aged and old-aged Indian goat Capra hircus. The lymphocyte proliferation was also recorded along with the total nitrite and nitrate ion concentration (NOx) in the spleen and plasma. An age dependent decline in MT1R and MT2R expressions and lymphocyte proliferation with increased level of reactive nitrogen species (RNS) and iNOS expression was noted. An increased Bax/Bcl-2 ratio and a decreased Pro-caspase-3 expression were observed in the spleen of goat with an age dependent decline in the peripheral melatonin level. This decline in melatonin along with reduced melatonin receptor (MT1/MT2) expression and elevated RNS level in the spleen with aging might have an important role in the regulation of immune function of goats. Our observations suggest that the age-associated immunosenescence observed in goats can be a consequence of declining melatonin and its receptor expression and induction of apoptotic factors influenced by the increased RNS level that deteriorates the proper functioning of the spleen. PMID- 25281806 TI - Cellular senescence and the aging brain. AB - Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex 'senescence-associated secretory phenotype' (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest that both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain could therefore constitute novel therapeutic targets for treating age-related neuropathologies. PMID- 25281810 TI - Fungal colonization - an additional risk factor for diseased dogs and cats? AB - The aim of the presented mini-review is to review the literature data referring to opportunistic mycoses in pet dogs and cats suffering from other concurrent diseases, comparable to human medical disorders with high risk of secondary mycoses. This review also presents the preliminary results of a project aimed at understanding the fungal colonization and occurrence of secondary mycoses in pets suffering from metabolic disorders, neoplasms and viral infections. The incidence of opportunistic mycoses is higher in such individuals, mostly because of their impaired immunity. The main risk factors are primary and secondary types of immunodeficiency connected with anti-cancer treatment or neoplastic disease itself. Moreover, literature data and the results of our investigations show that Candida yeasts are prevalent among diabetic animals and indicate that these fungi are the main etiological agents of secondary infections of the oral cavity, GI and urogenital tracts. Other important conditions possibly favoring the development of mycoses are concurrent infections of cats with FeLV and FIV viruses. Thus, in all cases of the mentioned underlying diseases, animals should be carefully monitored by repeated mycological examination, together with inspection of other parameters. Also, the prophylaxis of opportunistic mycoses should be carefully considered alike other factors influencing the prognosis and the outcome of primary diseases. PMID- 25281808 TI - Evolution of high mobility group nucleosome-binding proteins and its implications for vertebrate chromatin specialization. AB - High mobility group (HMG)-N proteins are a family of small nonhistone proteins that bind to nucleosomes (N). Despite the amount of information available on their structure and function, there is an almost complete lack of information on the molecular evolutionary mechanisms leading to their exclusive differentiation. In the present work, we provide evidence suggesting that HMGN lineages constitute independent monophyletic groups derived from a common ancestor prior to the diversification of vertebrates. Based on observations of the functional diversification across vertebrate HMGN proteins and on the extensive silent nucleotide divergence, our results suggest that the long-term evolution of HMGNs occurs under strong purifying selection, resulting from the lineage-specific functional constraints of their different protein domains. Selection analyses on independent lineages suggest that their functional specialization was mediated by bursts of adaptive selection at specific evolutionary times, in a small subset of codons with functional relevance-most notably in HMGN1, and in the rapidly evolving HMGN5. This work provides useful information to our understanding of the specialization imparted on chromatin metabolism by HMGNs, especially on the evolutionary mechanisms underlying their functional differentiation in vertebrates. PMID- 25281811 TI - The application of MALDI-TOF MS for dermatophyte identification. AB - Dermatophytes are keratinolytic fungi responsible for a wide variety of diseases of the skin, nails and hair of mammals. Their identification is often complicated, labor-intensive and time consuming due to the high degree of intra species morphological similarity, and also requires scientific knowledge and practice. The aim of this study was to demonstrate that MALDI-TOF MS technique may be a faster and more sophisticated method useful for the identification of dermatophytes and mycoses in general. PMID- 25281812 TI - Cordyceps fungi as natural killers, new hopes for medicine and biological control factors. AB - The Cordyceps genus includes many species of fungi, most of which are endoparasitoids on arthropods.The distribution of these fungi is cosmopolitan, but many occur in regions such as Asia with a hot, humid climate. These pathogens of insect pests are promising candidates for use as biological control factors. Entomopathogenic fungi including the famous Cordyceps sinensis produce bioactive compounds. Lately Cordyceps sinensis was renamed Ophiocordyceps sinensis. This fungus has a long history as a medicinal fungus. It germinates in a living host, kills and mummifies the larva, and then grows from the body of the host. Is known in Tibet as the "winter worm, summer grass",or "Caterpillar fungus" (Yartsa gunbu). Collecting Ophiocordyceps has become an important source of money for local households in Nepal. Ophiocordyceps sinensis is cultivated as an anamorph for its medicinal and pharmaceutical properties in an artificial medium on an industrial scale. Ophiocordyceps compounds have immunostimulating properties and antitumor activity. PMID- 25281813 TI - Interactions between potentially pathogenic fungi and natural human microbiota. AB - The human body is composed of 1014 cells, of which only 10% of them belong to the human host itself:the remaining 90% are microorganisms. Commensal microorganisms are necessary for the proper functioning of the human body and covers an area that could potentially become sites of adhesion of pathogenic microorganisms, it thus represents a form of competition for potential pathogens. The coexistence of fungi and bacteria in cases of systemic infections is a significant diagnostic and therapeutic problem, and the human immune system reacts differently,depending on the pathogen. Numerous publications exist concerning the relationship between microorganisms belonging to different ecological groups, the majority of which concern the interaction between macro-organisms and potential pathogens, or the synergistic relationship between parasitic species. However, there is still too little information concerning the role of natural microbiota in maintaining homeostasis and the relationships between particular species inhabiting the human organism. PMID- 25281809 TI - Molecular signatures of mouse TRPV1-lineage neurons revealed by RNA-Seq transcriptome analysis. AB - Disorders of pain neural systems are frequently chronic and, when recalcitrant to treatment, can severely degrade the quality of life. The pain pathway begins with sensory neurons in dorsal root or trigeminal ganglia, and the neuronal subpopulations that express the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) ion channel transduce sensations of painful heat and inflammation and play a fundamental role in clinical pain arising from cancer and arthritis. In the present study, we elucidate the complete transcriptomes of neurons from the TRPV1 lineage and a non-TRPV1 neuroglial population in sensory ganglia through the combined application of next-gen deep RNA-Seq, genetic neuronal labeling with fluorescence-activated cell sorting, or neuron-selective chemoablation. RNA-Seq accurately quantitates gene expression, a difficult parameter to determine with most other methods, especially for very low and very high expressed genes. Differentially expressed genes are present at every level of cellular function from the nucleus to the plasma membrane. We identified many ligand receptor pairs in the TRPV1 population, suggesting that autonomous presynaptic regulation may be a major regulatory mechanism in nociceptive neurons. The data define, in a quantitative, cell population-specific fashion, the molecular signature of a distinct and clinically important group of pain sensing neurons and provide an overall framework for understanding the transcriptome of TRPV1 nociceptive neurons. PERSPECTIVE: Next-gen RNA-Seq, combined with molecular genetics, provides a comprehensive and quantitative measurement of transcripts in TRPV1 lineage neurons and a contrasting transcriptome from non-TRPV1 neurons and cells. The transcriptome highlights previously unrecognized protein families, identifies multiple molecular circuits for excitatory or inhibitory autocrine and paracrine signaling, and suggests new combinatorial approaches to pain control. PMID- 25281815 TI - Congenital candidiasis as a subject of research in medicine and human ecology. AB - Congenital candidiasis is a severe complication of candidal vulvovaginitis. It occurs in two forms,congenital mucocutaneous candidiasis and congenital systemic candidiasis. Also newborns are in age group the most vulnerable to invasive candidiasis. Congenital candidiasis should be considered as an interdisciplinary problem including maternal and fetal condition (including antibiotic therapy during pregnancy), birth age and rare genetic predispositions as severe combined immunodeficiency or neutrophil-specific granule deficiency. Environmental factors are no less important to investigate in diagnosing, treatment and prevention. External factors (e.g., food) and microenvironment of human organism (microflora of the mouth, intestine and genitalia) are important for solving clinical problems connected to congenital candidiasis. Physician knowledge about microorganisms in a specific compartments of the microenvironment of human organism and in the course of defined disorders of homeostasis makes it easier to predict the course of the disease and allows the development of procedures that can be extremely helpful in individualized diagnostic and therapeutic process. PMID- 25281814 TI - Insight into tick biocontrol with special regard to fungi. AB - The epidemiological and epizootic importance of ticks has been known for a few decades since of the discovery of their role as vectors of many new diseases, and the better detection of those already known. Given the durability of chemical preparations in the environment and the increasing problem of developing tick resistance, natural strategies for biological control are sought. A promising alternative to chemical pesticides is the use of entomopathogenic organisms for effective integrated pest management of low environmental impact. A number of promising microbes have been identified during the search for effective means of controlling the tick population, but the knowledge about the impact of these pathogens on the environment and other non-target organisms is still insufficient. Previous research has still not provided a definite answer about the safety of their use. It is known, however,that the chemicals which are currently used have a negative impact on the environment and/or cause resistance. No efficient biocompound has yet been devised for commercial use. Potential microorganisms for tick biocontrol (mainly bacteria and fungi) are natural tick pathogens, living in the same environment. With their adhesive properties, and their ability to digest the cuticle, they may constitute an appropriate ingredient of bioacaricides. Until now, fungal insecticides have been used only to control crop pests. PMID- 25281816 TI - Mycological monitoring of selected aquatic ecosystems in the context of epidemiological hazards. Drinking water. AB - Many species of microfungi are reported in aquatic ecosystems with different frequency. Their number constantly fluctuates depending on the concentration of environmental and anthropogenic factors. Drinking water, tap and bottled, is essential for the proper functioning of the human body. It is also the main component of food and hence it should be safe for human health and free of contaminants. The mycological purity of tap water in two large cities in the region (Olsztyn and Ostroleka) and a small village (Gaglawki) as well as bottled, medium-mineralized and curative water stored under different conditions were tested. The laboratory investigations followed a pathway applied in diagnostic mycological laboratories. The conducted tests demonstrated that microfungi were found in tap water originating from the cities and in bottled water. The rural water supply system was free from contaminations. Eighteen species of microfungi were identified in tap water from Olsztyn and 9 species in tap water from Ostroleka. In bottled water, 13 fungal species were detected. Exophiala spinifera and Debaryomyces hansenii were recorded in the water supply systems of both cities, while one common species, i.e. Aspergillus fumigatus, was identified in tap water fromOstroleka and in bottled water. The conducted studies have significant practical implications, for instance in sanitary and epidemiological water evaluation and in medicine in the context of analysing the quality of drinking water in reference to health resorts and nosocomial infections. PMID- 25281817 TI - Yeasts isolated from frequently in-patients and out-patients. AB - The paper is a part of a general mycological monitoring study of nosocomial infections. Differences in the species composition and drug resistance of fungi isolated from in-patients and out-patients prompted an analysis of this topic. The studies were conducted with fungi from the collection of the Department of Mycology, University of Warmia and Mazury in Olsztyn, that were isolated from the oral cavity, sputum, bronchoscopic fluid, anus and skin from 100 in-patients and 100 out-patients. Laboratory analyses, including species categorization of fungi, were performed according to routine mycological diagnostics. Drug sensitivity to fluconazole and nystatin was tested with the disc diffusion method. In the group of in-patients, a wider taxonomic diversity of fungi (12 species) was found in comparison with the out-patients (7 species) and 31 cases of multifocal infections were recorded, while in the second group the number of the latter was only six. In all patients, C. albicans were predominant, constituting the largest proportion in focal infections in all patients and in multifocal infections in the in-patients. In the latter, over a half of the examined individuals were resistant to fluconazole (C. glabrata and C. krusei - 80%, C. tropicalis and S. capsularis - 60%, C.guilliermondii - 50%) and nystatin (T. beigelii - 80%, C. krusei and C. tropicalis - 50%). Substantially lower drug resistance of fungi was recorded in the out-patients. The hospital environment is an abundant reservoir of different fungal species with significantly greater expansiveness and aggressiveness compared to the environment outside a hospital. PMID- 25281818 TI - Signs, symptoms and the prevalence of fungi detected from the oral cavity and pharynx of radiotherapy subjects with head and neck tumors, and their susceptibility to chemotherapeutics. AB - Radio- and chemotherapy for malignant neoplasms, especially in head and neck region, is associated with a greater risk of fungal infections due to secondary alterations in the mucous membranes. The study had three aims: 1.to determine the signs and symptoms which occur among patients undergoing radiotherapy; 2. to determine the fungi prevalence in the mouth and throat of patients before, during and after radiotherapy; 3. to examine the sensitivity of strains to antimycotic drugs. The study comprised 44 patients (11 female, 33 male) with head and neck cancers,examined at the following stages: before radiotherapy (44 patients - batch 1), 3rd week of therapy (30 of the 44 patients- batch 2), last day of therapy (28 of batch 2 - batch 3) and the 6th week after completion of radiotherapy (10 of batch 3 - batch 4). Clinical examination was performed and mycological status was estimated from an oral rinse on a selected medium. The fungal strains were isolated and sensitivity to antifungal drugs was determined. The most common symptoms were pain, dysphagia, and dysgeusia. Physical examination revealed signs of mucositis mainly among patients from batches 2 and 3. The presence of fungi in the mouth and throat was noted in over 2/3 (66.2%) of the patients from batch 1, and in 4/5 (80%) of batch 2. The fungi were detected in over half (57.1%) of patients from batch 3 and also in patients from batch 4. In all cases, fungi of various Candida species were identified: 6 species in batch 1,8 in batch 2, 6 in batch 3 and 5 in batch 4. The most frequently detected species was C. albicans, constituting 40-60%;the other species detected are known to be resistant to antimycotic drugs. The isolated strains were the most sensitive to nystatin and miconazole, and the least to ketoconazole and fluconazole. Conclusions: 1. Patients undergoing radiotherapy complain of pain, dysphagia, and dysgeusia; in most cases mucositis is diagnosed. 2. The high prevalence of fungi in the mouth and throat of patients treated by radiotherapy reinforces the need to perform mycological examinations in this group of patients to detect fungi, identify their species and determine of their sensitivity to drugs in order to prevent complications. 3. The species most frequently isolated from the patients are C. albicans and C.glabrata. The latter is characterized by resistance to the majority of antimycotic medications. 4. Most of the isolated strains are sensitive to nystatin and miconazole (applied locally) and to itraconazole (absorbed from the gastrointestinal tract). PMID- 25281819 TI - Comparison of the effect of the chosen species of saprotrophic fungi on the development of Toxocara canis and Ascaris suum eggs. AB - The study aim was to compare the antagonistic interaction between saprotrophic soil fungi and embryonic development of geohelminths Toxocara canis and Ascaris suum. The experimental cultures were fertilized eggs of T.canis and A. suum incubated together with mycelium of strains: Fusarium culmorum, Metarhizium anisopliae,Paecilomyces fumosoroseus, Trichoderma viride and Trichothecium roseum. In the control cultures the eggs of both nematode species were incubated without fungi. The experiment was conducted at temp. 26 degrees C for 60 days. Compared with the control, all of the tested species of fungi significantly extended the embryonic development of both T. canis and A. suum. Most inhibitory effect on the rate of embryonic development of T. canis and A. suum had three fungal species: P. fumosoreus, M. anisopliae and T. viride. Compared with the control, on the 60th day of incubation in the presence of each of the tested fungal species, a larger percentage (p<0.05) of morphological abnormalities was stated in developing embryos of T. canis (49-69%) than in A. suum (15.1-67.7%). Among the examined fungal species, only incubation with P. fumosoroseus resulted in significantly greater (p<0.05) incidence of embryonic malformations(embryopathies) in T. canis, as compared with A. suum. Also the percentage of dead larvae of T. canis in the control and in cultures with fungi (12% and 100%, respectively) was significantly higher in comparison with A. suum (0.5% and 10.3-36%, respectively). The highest percentage of non-viable larvae of A. suum was found in the presence of P.fumosoroseus, and the lowest in the presence of M. anisopliae. Findings may indicate that T. canis eggs are more sensitive to antagonistic interaction of the examined fungal strains than A. suum eggs. PMID- 25281820 TI - Comparative transcriptome analysis of aboveground and underground tissues of Rhodiola algida, an important ethno-medicinal herb endemic to the Qinghai Tibetan Plateau. AB - Transcriptome sequencing is a powerful tool for the assessment of gene expression and the identification and characterization of molecular markers in non-model organisms. Rhodiola algida L. (Crassulaceae), endemic to the Qinghai-Tibetan Plateau, has long been used in traditional Chinese medicine to prevent altitude sickness and eliminate fatigue. Illumina-based high-throughput transcriptome sequencing of aboveground and underground tissues of R. algida respectively yielded 5.40 million and 5.18 million clean reads. A total of 82,664 unigenes averaging 577 bp in length were generated from the aboveground clean reads, with 86,237 unigenes of 502-bp mean length obtained from the underground tissues. Of 55,028 unigenes compared with sequences in UniProt databases, 20,413 unigenes had significant similarities with existing sequences in NR, NT, Swiss-Prot, GO, KEGG, and COG databases. Single nucleotide polymorphism (SNP) analysis identified 237,294 SNPs from 154,636 contigs of aboveground tissues and 197,540 SNPs from 144,963 underground-derived contigs. The information uncovered in this study should serve as a valuable resource for the characterization of important traits related to secondary metabolite formation and for the identification of associated molecular mechanisms. PMID- 25281821 TI - Maturity onset diabetes of the young (MODY)--history, first case reports and recent advances. AB - The world is seemingly facing a global increase in people suffering from diabetes especially in developing countries. The worldwide occurrence of diabetes for all age groups in year 2000 was estimated to be 2.8% and this number is most certainly expected to rise to 4.4% by 2030. Maturity-onset of diabetes of the young, or MODY, is a form of monogenic diabetes that is caused by mutations occurring in a number of different genes. Mutations in different genes tend to cause a slightly different variant of diabetes. MODY is typically diagnosed during late childhood, adolescence, or early adulthood and is usually observed to develop in adults during their late 50's. One of the main drawbacks in its diagnosis is that many people with MODY are misdiagnosed as having type 1 or type 2 diabetes. However, a molecular and genetic diagnosis can result in a better treatment and could also help in identifying other family members with MODY. This article explores the historical prospect and the genetic background of MODY, a brief summary of the first case reported and the significant factors that differentiate it from type 1 and type 2 diabetes. PMID- 25281822 TI - Identification and characterization of complement factor H in Branchiostoma belcheri. AB - Complement factor H (CFH) is an essential regulator of the complement system and plays very important roles in animal innate immunity. Although the complement system of amphioxus has been extensively studied, the expression in amphioxus and evolution of CFH gene remain unknown. In this study, we identified and characterized an amphioxus (Branchiostoma belcheri) CFH gene (designated as AmphiCFH). Our results showed that the full-length cDNA of AmphiCFH gene consists of 1295 bp nucleotides containing an 855 bp open reading frame (ORF) that was predicted to encode a 284 amino acid protein. The putative AmphiCFH protein possessed the characteristic of the CFH protein family, including typical CCP (complement control protein) domain. Real-time PCR analysis showed that the AmphiCFH was ubiquitously and differentially expressed in five investigated tissues (intestine, gills, notochord, muscles, and hepatic cecum). The expression level of the AmphiCFH gene was induced upon lipopolysaccharide stimulation, indicating that the AmphiCFH gene might be involved in innate immunity. In addition, phylogenetic analysis showed that the AmphiCFH gene was located between that of invertebrates and vertebrates, suggesting that the AmphiCFH gene is a member of the CFH gene family. In conclusion, our findings provided an insight into animal innate immunity and evolution of the CFH gene family. PMID- 25281823 TI - Coaching strategies for enhancing practice transformation. AB - BACKGROUND: Current research on primary care practice redesign suggests that outside facilitation can be an important source of support for achieving substantial change. OBJECTIVES: To analyse the specific sequence of strategies used by a successful practice facilitator during the American Academy of Family Physicians' (AAFP) National Demonstration Project (NDP). METHODS: This secondary analysis describes a sequence of strategies used to produce change in family medicine practices attempting to adopt a new model of care. The authors analysed qualitative data generated by one facilitator and six practices by coding facilitator field notes, site visit reports, qualitative summaries, depth interviews and email strings. RESULTS: The facilitator utilized practice member coaching in addition to consulting, negotiating and connecting approaches. Coaching strategies encouraged: (i) expansive, multi-directional, attentive styles of communication; (ii) solving practical problems together; (iii) modelling facilitative leadership and (iv) encouraging an expanded vision of care. Practice members who received consistent coaching reported internal shifts and new ways of conceptualizing work, not just success at implementing model components. They indicated that their facilitator had helped them think and behave in new ways while helping them achieve benchmarks. CONCLUSIONS: It was once believed that the transition from traditional models of family medicine practice to new models of care meant implementing new technological components, suggesting that outside facilitators should act as technological and care delivery consultants. However, coaches may be especially useful in helpful in practices undertake substantial changes. PMID- 25281824 TI - Neuroprotective action of resveratrol. AB - Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders including macular degeneration, stroke, and cognitive deficits with or without dementia. Resveratrol has been considered as one of the key ingredients responsible for the preventive action of red wine since the stilbene displays a neuroprotective action in various models of toxicity. Besides its well documented free radical scavenging and anti-inflammatory properties, resveratrol has been shown to increase the clearance of beta-amyloid, a key feature of Alzheimer's disease, and to modulate intracellular effectors associated with oxidative stress (e.g. heme oxygenase), neuronal energy homeostasis (e.g. AMP kinase), program cell death (i.e. AIF) and longevity (i.e. sirtuins). This article summarizes the most recent findings on mechanisms of action involved in the protective effects of this multi target polyphenol, and discusses its possible roles in the prevention of various age-related neurological disorders. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. PMID- 25281825 TI - Methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant of the human prion protein. AB - The D178N mutation of the prion protein (PrP) results in the hereditary prion disease fatal familial insomnia (FFI). Little is known regarding the effects of methionine oxidation on the pathogenesis of D178N-associated FFI. In the present study, we found that the D178N variant was more susceptible to oxidation than wild-type PrP, as indicated by reverse-phase high performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) analysis. Circular dichroism (CD), differential scanning calorimetry (DSC), thioflavin T (ThT) binding assay studies demonstrated that methionine oxidation decreased the structural stability of the D178N variant, and the oxidized D178N variant exhibited a greater propensity to form beta-sheet-rich oligomers and aggregates. Moreover, these aggregates of oxidized D178N PrP were more resistant to proteinase K (PK) digestion. Additionally, using fluorescence confocal microscopy, we detected a high degree of aggregation in D178N-transfected Neuro-2a (N2a) cells after treatment with hydrogen peroxide (H2O2). Furthermore, the oxidation and consequent aggregation of the D178N variant induced greater apoptosis of N2a cells, as monitored using flow cytometry. Collectively, these observations suggest that methionine oxidation accelerates the aggregation and enhances the neurotoxicity of the D178N variant, possibly providing direct evidence to link the pathogenesis of D178N-associated FFI with methionine oxidation. PMID- 25281826 TI - Region-specific metabolic alterations in the brain of the APP/PS1 transgenic mice of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, but its etiology is still not completely understood. The identification of underlying pathological mechanisms is becoming increasingly important for the discovery of biomarkers and therapies, for which metabolomics presents a great potential. In this work, we studied metabolic alterations in different brain regions of the APP/PS1 mice by using a high-throughput metabolomic approach based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry. Multivariate statistics showed that metabolomic perturbations are widespread, affecting mainly the hippocampus and the cortex, but are also present in regions not primarily associated with AD such as the striatum, cerebellum and olfactory bulbs. Multiple metabolic pathways could be linked to the development of AD-type disorders in this mouse model, including abnormal purine metabolism, bioenergetic failures, dyshomeostasis of amino acids and disturbances in membrane lipids, among others. Interestingly, region-specific alterations were observed for some of the potential markers identified, associated with abnormal fatty acid composition of phospholipids and sphingomyelins, or differential regulation of neurotransmitter amino acids (e.g. glutamate, glycine, serine, N-acetyl-aspartate), not previously described to our knowledge. Therefore, these findings could provide a new insight into brain pathology in Alzheimer's disease. PMID- 25281827 TI - Long-Term Results of Anderson-Hynes Pyeloplasty in Children: How Long Follow-Up Is Necessary? AB - PURPOSE: After a successful pyeloplasty at 3 to 6 months, the question remains whether children need a long follow-up. METHODS: The medical charts of patients with long-term follow-up (> 5 years), who underwent dismembered pyeloplasty for uretero-pelvic junction obstruction (UPJO) from May 1998 to May 2007, excluding those with bilateral UPJO, solitary kidney, associated vesicoureteral reflux or other abnormalities, and inconclusive renogram due to poor renal function, were retrospectively reviewed. Ultrasonography, differential renal function (DRF, DMSA), and renal drainage on diuretic renography (diethylene-triamine pentaacetate technetium-99 or DTPA-Tc99) were performed at 3 and 6 months every year. RESULTS: Complete data were available for 28 consecutive patients (28 renal unities) with 2 months to 12 years (mean age, 2.4 years) at surgery, of whom 21 (75%) were boys, 17 diagnosed prenatally (61%) and 18 unities (64.3%) were left, with median follow-up of 10.7 years. Images were graded according to the Society for Fetal Urology grading system: Grade III in 11 (49%) and grade IV in 17 (61%). All cases presented > 10% DRF (DMSA) and obstructed DTPA-Tc99. The T1/2 (the half time of drainage) less than 20 minutes at 3 months was found in 21 cases (75%) and less than 25 minutes in 7 cases (25%). Renal function and patency were maintained during follow-up for all units with 8% maximum fluctuation of DRF. One index case (3.6%) of renal function deterioration presented DRF fluctuation > 8% at 3 months (from 23 to 32%) and progressive hydronephrosis and indeterminate DTPA at 6 months. CONCLUSIONS: Satisfactory diuretic renogram at 3 to 6 months after pyeloplasty with maintained renal function and stable hydronephrosis suggests no need for further follow-up and indicates no functional loss with time. More than 8% DRF fluctuation might be a significant cutoff for further intervention aiming nephron preservation. PMID- 25281828 TI - Testicular ascent after laparoscopic percutaneous extraperitoneal closure for inguinal hernias. AB - AIM: Laparoscopic percutaneous extraperitoneal closure (LPEC) has been widely performed for the repair of pediatric inguinal hernias in Japan. This study aimed to evaluate the testicular ascent and orchiopexy after LPEC in males with inguinal hernias. METHODS: The medical records of male patients who underwent LPEC procedures for the repair of an inguinal hernia from January 2010 to December 2013 at our institution were reviewed. The patients who underwent orchiopexy after the LPEC procedure were investigated, the characteristics studied were the birth weight of the patients, the age when they underwent LPEC, the mean time from LPEC to orchiopexy, and the location of the affected testes. The LPEC procedure was performed by extraperitoneal circuit suturing around the internal inguinal ring with a long straight special needle (Lapaherclosure; Hakko Medical Co., Tokyo, Japan). RESULTS: During the 4-year period of this study, 438 LPECs were performed on 367 male patients. Orchiopexy was performed on 14 testes (3.2%) in 10 patients who had previously undergone LPEC. Five of the 10 patients were extremely low-birth-weight infants. The mean time from LPEC to orchiopexy was 13.2 months. In 7 of these 10 patients, both testes were initially identified in the scrotum at 3 months after LPECs, but they later showed ascending or retractile testes. In another three patients, the ipsilateral testes were elevated early after LPECs, and they were thought to be missed congenital undescended testes. At orchiopexy, 10 of the 14 testes were located in the inguinal region, and the other four testes were retractile. During the orchiopexy, the remaining processus vaginalis was found to adhere to the spermatic cord in all of the patients with ascending testes. CONCLUSION: The postoperative testicular ascent should be carefully examined after the LPEC procedure in patients with pediatric inguinal hernias, especially in extremely low-birth-weight infants. PMID- 25281829 TI - ImagePAD, a novel counting application for the Apple iPad, used to quantify axons in the mouse optic nerve. AB - The present article introduces a new and easy to use counting application for the Apple iPad. The application "ImagePAD" takes advantage of the advanced user interface features offered by the Apple iOS platform, simplifying the rather tedious task of quantifying features in anatomical studies. For example, the image under analysis can be easily panned and zoomed using iOS-supported multi touch gestures without losing the spatial context of the counting task, which is extremely important for ensuring count accuracy. This application allows one to quantify up to 5 different types of objects in a single field and output the data in a tab-delimited format for subsequent analysis. We describe two examples of the use of the application: quantifying axons in the optic nerve of the C57BL/6J mouse and determining the percentage of cells labeled with NeuN or ChAT in the retinal ganglion cell layer. For the optic nerve, contiguous images at 60* magnification were taken and transferred onto an Apple iPad. Axons were counted by tapping on the touch-sensitive screen using ImagePAD. Nine optic nerves were sampled and the number of axons in the nerves ranged from 38,872 axons to 50,196 axons with an average of 44,846 axons per nerve (SD = 3980 axons). PMID- 25281831 TI - Digital inequalities of family life information seeking and family well-being among Chinese adults in Hong Kong: a population survey. AB - BACKGROUND: Inequalities in Internet use and health information seeking are well documented, but less is known about information for family life activities. OBJECTIVE: We investigated the social determinants of online family life information seeking behaviors and its associations with family well-being among Chinese adults in Hong Kong. METHODS: A probability-based telephone survey was conducted in 2012 to record family life information seeking behaviors, including frequency of seeking and paying attention to family life information, levels of trust, and perceived usefulness of family life information. Family well-being was assessed using 3 single items on perceived family harmony, happiness, and health, with higher scores indicating greater well-being. Adjusted odds ratios for family life information seeking behaviors by socioeconomic characteristics and lifestyle behaviors, and adjusted beta coefficients for family well-being by family life information seeking behaviors were calculated. RESULTS: Of 1537 respondents, 57.57% (855/1537) had ever and 26.45% (407/1537) sought monthly family life information through the Internet. Lower educational attainment and household income, smoking, and physical inactivity were associated with less frequent seeking and paying attention (all P<.05). Greater perceived family health was associated with more frequent attention (adjusted beta=.32, 95% CI.11-.52), greater levels of trust (adjusted beta=.28, 95% CI .07-.48), and perceived usefulness (adjusted beta=.23, 95% CI .01-.45) of family life information. Frequent attention and higher level of trust were also associated with greater family harmony (adjusted beta=.22, 95% CI .002-.41) and happiness (adjusted beta=.23, 95% CI .003-.42), respectively. CONCLUSIONS: This is the first study investigating family life information seeking behaviors and suggested inequalities of online family life information seeking behaviors. The association between family life information seeking behavior and family well-being needs to be confirmed in prospective studies. PMID- 25281830 TI - Cellular and extracellular matrix modulation of corneal stromal opacity. AB - Stromal transparency is a critical factor contributing to normal function of the visual system. Corneal injury, surgery, disease and infection elicit complex wound healing responses that serve to protect against insults and maintain the integrity of the cornea, and subsequently to restore corneal structure and transparency. However, in some cases these processes result in prolonged loss of corneal transparency and resulting diminished vision. Corneal opacity is mediated by the complex actions of many cytokines, growth factors, and chemokines produced by the epithelial cells, stromal cells, bone marrow-derived cells, lacrimal tissues, and nerves. Myofibroblasts, and the disorganized extracellular matrix produced by these cells, are critical determinants of the level and persistence of stromal opacity after corneal injury. Decreases in corneal crystallins in myofibroblasts and corneal fibroblasts contribute to cellular opacity in the stroma. Regeneration of a fully functional epithelial basement membrane (BM) appears to have a critical role in the maintenance of corneal stromal transparency after mild injuries and recovery of transparency when opacity is generated after severe injuries. The epithelial BM likely has a regulatory function whereby it modulates epithelium-derived growth factors such as transforming growth factor (TGF) beta and platelet-derived growth factor (PDGF) that drive the development and persistence of myofibroblasts from precursor cells. The purpose of this article is to review the factors involved in the maintenance of corneal transparency and to highlight the mechanisms involved in the appearance, persistency and regression of corneal opacity after stromal injury. PMID- 25281833 TI - CoCr wear particles generated from CoCr alloy metal-on-metal hip replacements, and cobalt ions stimulate apoptosis and expression of general toxicology-related genes in monocyte-like U937 cells. AB - Cobalt-chromium (CoCr) particles in the nanometre size range and their concomitant release of Co and Cr ions into the patients' circulation are produced by wear at the articulating surfaces of metal-on-metal (MoM) implants. This process is associated with inflammation, bone loss and implant loosening and led to the withdrawal from the market of the DePuy ASRTM MoM hip replacements in 2010. Ions released from CoCr particles derived from a resurfacing implant in vitro and their subsequent cellular up-take were measured by ICP-MS. Moreover, the ability of such metal debris and Co ions to induce both apoptosis was evaluated with both FACS and immunoblotting. qRT-PCR was used to assess the effects on the expression of lymphotoxin alpha (LTA), BCL2-associated athanogene (BAG1), nitric oxide synthase 2 inducible (NOS2), FBJ murine osteosarcoma viral oncogene homolog (FOS), growth arrest and DNA-damage-inducible alpha (GADD45A). ICP-MS showed that the wear debris released significant (p<0.05) amounts of Co and Cr ions into the culture medium, and significant (p<0.05) cellular uptake of both ions. There was also an increase (p<0.05) in apoptosis after a 48h exposure to wear debris. Analysis of qRT-PCR results found significant up-regulation (p<0.05) particularly of NOS2 and BAG1 in Co pre-treated cells which were subsequently exposed to Co ions+debris. Metal debris was more effective as an inducer of apoptosis and gene expression when cells had been pre-treated with Co ions. This suggests that if a patient receives sequential bilateral CoCr implants, the second implant may be more likely to produce adverse effects than the first one. PMID- 25281832 TI - Molecular epidemiology of measles virus infection in Shanghai in 2000-2012: the first appearance of genotype D8. AB - PURPOSE: The purpose of this study was to identify measles virus in Shanghai in 2012 and study the genotype trend of measles virus epidemic strains during 2000 2012. METHODS: Nose and throat swab specimens were collected from 34 suspected measles cases in Shanghai. Measles virus was isolated using Vero-SLAM cells (African green monkey kidney cells/lymphoid signal activating factor-transfected African green monkey kidney cells). The 450 bp of C terminus of the N gene and the entire hemagglutinin gene sequence was amplified using RT-PCR. Phylogenetic analysis was performed by comparing the seven measles strains in Shanghai with the reference strains for H1a, H1b and D8 genotypes, as well as the Chinese measles virus vaccine strain. RESULTS: Seven measles viruses strains were isolated from the 34 throat swap specimens. Six strains were genotype H1a, which is the predominant strain in China and one strain was genotype D8, which is the first imported strain since 2000. All these seven strains maintained most of the glycosylation sites except subtype H1a, which lost one glycosylation site. CONCLUSION: Since 2000, measles virus strains in Shanghai are consistent with measles virus from other provinces in China with H1a being the predominant genotype. This study is also the first report of genotype D8 strain in Shanghai. All strains maintained their glycosylation sites except H1a that lost one glycosylation site. These strains could still be neutralized by the Chinese measles vaccine. We suggest that Shanghai Center for Disease Control laboratories should strengthen their approaches to monitor measles cases to prevent further spread of imported strains. PMID- 25281834 TI - Elevated levels of plasma uric acid and its relation to hypertension in arsenic endemic human individuals in Bangladesh. AB - Blood uric acid has been recognized as a putative marker for cardiovascular diseases (CVDs). CVDs are the major causes of arsenic-related morbidity and mortality. However, the association of arsenic exposure with plasma uric acid (PUA) levels in relation to CVDs has not yet been explored. This study for the first time demonstrated the associations of arsenic exposure with PUA levels and its relationship with hypertension. A total of 483 subjects, 322 from arsenic endemic and 161 from non-endemic areas in Bangladesh were recruited as study subjects. Arsenic concentrations in the drinking water, hair and nails of the study subjects were measured by inductively coupled plasma mass spectroscopy. PUA levels were measured using a colorimetric method. We found that PUA levels were significantly (p<0.001) higher in males and females living in arsenic-endemic areas than those in non-endemic area. Arsenic exposure (water, hair and nail arsenic) levels showed significant positive correlations with PUA levels. In multiple regression analyses, arsenic exposure levels were found to be the most significant contributors on PUA levels among the other variables that included age, body mass index, blood urea nitrogen, and smoking. There were dose-response relationships between arsenic exposure and PUA levels. Furthermore, diastolic and systolic blood pressure showed significant positive correlations with PUA levels. Finally, the average PUA levels were significantly higher in the hypertensive group than those in the normotensive group in both males and females living in arsenic-endemic areas. These results suggest that arsenic exposure-related elevation of PUA levels may be implicated in arsenic-induced CVDs. PMID- 25281835 TI - Arsenic exposure disrupts epigenetic regulation of SIRT1 in human keratinocytes. AB - Arsenic is an environmental toxin which increases skin cancer risk for exposed populations worldwide; however the underlying biomolecular mechanism for arsenic induced carcinogenesis is complex and poorly defined. Recent investigations show that histone deacetylase and DNA methyltransferase activity is impaired, and epigenetic patterns of gene regulation are consistently altered in cancers associated with arsenic exposure. Expression of the histone deacetylase SIRT1 is altered in solid tumours and haematological malignancies; however its role in arsenic-induced pathology is unknown. In this study we investigated the effect of arsenic on epigenetic regulation of SIRT1 and its targeting microRNA, miR-34a in primary human keratinocytes. Acetylation of histone H4 at lysine 16 (H4K16) increased in keratinocytes exposed to 0.5MUM arsenite [As(III)]; and this was associated with chromatin remodelling at the miR-34a promoter. Moreover, although SIRT1 protein initially increased in these As(III)-exposed cells, after 24days expression was not significantly different from untreated controls. Extended exposure to low-dose As(III) (0.5MUM; >5weeks) compromised the pattern of CpG methylation at SIRT1 and miR-34a gene promoters, and this was associated with altered expression for both genes. We have found that arsenic alters epigenetic regulation of SIRT1 expression via structural reorganisation of chromatin at the miR-34a gene promoter in the initial 24h of exposure; and over time, through shifts in miR-34a and SIRT1 gene methylation. Taken together, this investigation demonstrates that arsenic produces cumulative disruptions to epigenetic regulation of miR-34a expression, and this is associated with impaired coordination of SIRT1 functional activity. PMID- 25281836 TI - Combination therapy with losartan and L-carnitine protects against endothelial dysfunction of streptozotocin-induced diabetic rats. AB - Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications and angiotensin II appears to play a pivotal role in this setting. The present study aimed to investigate whether the combination therapy with losartan and the nutritional supplement, L-carnitine can provide an additional protection against diabetes-associated endothelial dysfunction and elucidate the possible mechanism(s) underlying this effect. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg) in rat. Effects of losartan (20 mg/kg, orally, 3 months) and L-carnitine (200 mg/kg, orally, 3 months) on tumor necrosis factor (TNF)-alpha, oxidative stress parameters, endothelial nitric oxide synthase expression (eNOS), and vascular function were evaluated. Our results showed a marked increase in aortic superoxide anion (O2( )) production and serum malondialdehyde (MDA) level alongside attenuating antioxidant enzyme capacities in diabetic rats. This was associated with a significant increase in anigiotensin II type 1 receptor gene expression and TNF alpha serum level of diabetic rats alongside reducing aortic eNOS gene expression and nitric oxide (NO) bioavailability. The single or combined administration of losartan and L-carnitine significantly inhibited these changes. Additionally, the vascular endothelium-dependent relaxation with acetylcholine (ACh) in aortic diabetic rat was significantly ameliorated by the single and combined administration of losartan or L-carnitine. Noteworthy, the combination therapy exhibited a more profound response over the monotherapy. Collectively, our results demonstrate that the combined therapy of losartan and L-carnitine affords additive beneficial effects against diabetes-associated endothelial dysfunction, possibly via normalizing the dysregulated eNOS and reducing the inflammation and oxidative stress in diabetic rats. PMID- 25281838 TI - Cyclophilin D and myocardial ischemia-reperfusion injury: a fresh perspective. AB - Reperfusion is characterized by a deregulation of ion homeostasis and generation of reactive oxygen species that enhance the ischemia-related tissue damage culminating in cell death. The mitochondrial permeability transition pore (mPTP) has been established as an important mediator of ischemia-reperfusion (IR) induced necrotic cell death. Although a handful of proteins have been proposed to contribute in mPTP induction, cyclophilin D (CypD) remains its only bona fide regulatory component. In this review we summarize existing knowledge on the involvement of CypD in mPTP formation in general and its relevance to cardiac IR injury in specific. Moreover, we provide insights of recent advancements on additional functions of CypD depending on its interaction partners and post translational modifications. Finally we emphasize the therapeutic strategies targeting CypD in myocardial IR injury. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25281837 TI - Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling. AB - (-)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45 min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10 mg/kg) combined with DOX (5 mg/kg). The first dose was given 15 min prior to reperfusion and the second 12 h post-MI. The effects of EPI +/- DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ~46% at 48 h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury. PMID- 25281839 TI - Engineering modular ester fermentative pathways in Escherichia coli. AB - Sensation profiles are observed all around us and are made up of many different molecules, such as esters. These profiles can be mimicked in everyday items for their uses in foods, beverages, cosmetics, perfumes, solvents, and biofuels. Here, we developed a systematic 'natural' way to derive these products via fermentative biosynthesis. Each ester fermentative pathway was designed as an exchangeable ester production module for generating two precursors- alcohols and acyl-CoAs that were condensed by an alcohol acyltransferase to produce a combinatorial library of unique esters. As a proof-of-principle, we coupled these ester modules with an engineered, modular, Escherichia coli chassis in a plug-and play fashion to create microbial cell factories for enhanced anaerobic production of a butyrate ester library. We demonstrated tight coupling between the modular chassis and ester modules for enhanced product biosynthesis, an engineered phenotype useful for directed metabolic pathway evolution. Compared to the wildtype, the engineered cell factories yielded up to 48 fold increase in butyrate ester production from glucose. PMID- 25281840 TI - Laparoscopic radical hysterectomy and pelvic lymphadenectomy can be routinely used for treatment of early-stage cervical cancer: a single-institute experience with 404 patients. AB - STUDY OBJECTIVE: The aim of our study was to determine if laparoscopic radical hysterectomy (LRH) can be routinely used for the treatment of early-stage cervical cancer. DESIGN: From May 2008, LRH was planned for all primarily operable cervical cancer patients after receiving informed consent in our department. The surgical and oncologic outcomes were retrospectively evaluated (Canadian Task Force classification III). SETTING: University teaching hospital. PATIENTS AND INTERVENTIONS: By August 2013, 404 patients with invasive cervical cancer were deemed operable, and all of them were subjected to upfront LRH, except 1 patient who insisted on open surgery. MEASUREMENTS AND MAIN RESULTS: The planned LRH was abandoned in 3 patients because of inoperability. The median operative time was 240 minutes (range, 100-410 minutes). The median blood loss was 300 mL (range, 50-800 mL). The median number of harvested pelvic lymph nodes was 23.5 (range, 11-54). Two patients had positive surgical margins. Intraoperative complications occurred in 7 of the patients, and a conversion to open surgery was mandatory for 2 patients (conversion rate = 0.5%). Postoperative urinary tract fistula developed in 3 patients. Sixty-nine patients underwent adjuvant therapy. The median duration of follow-up was 31 months (range, 7-69 months). Thirty patients developed recurrent disease with a median disease-free interval of 12 months (range, 6-23 months), and 24 died of disease. The estimated 3-year overall survival rate was 94.9% in the women with a tumor <= IB1 and 81.3% in those with a tumor >IB1, and the 3-year progression-free survival rates were 94.1% and 79.6%, respectively. CONCLUSION: LRH is adequate, safe, and feasible for women with cervical cancer, and it can be routinely used for the treatment of early-stage tumors as a primary modality. PMID- 25281841 TI - Constitutive expression of the poplar WRKY transcription factor PtoWRKY60 enhances resistance to Dothiorella gregaria Sacc. in transgenic plants. AB - WRKY proteins are involved in various physiological processes in plants, especially in coping with diverse biotic and abiotic stresses. However, limited information is available on the roles of specific WRKY transcription factors in poplar defense. In this study, we reported the characterization of PtoWRKY60, a Group IIa WRKY member, from Populus tomentosa Carr. The gene expression profile of PtoWRKY60 in various tissues showed that it significantly accumulated in old leaves. Phylogenetic analyses revealed that PtoWRKY60 had a close relationship with AtWRKY18, AtWRKY40 and AtWRKY60. PtoWRKY60 was induced mainly by salicylic acid (SA) and slightly by Dothiorella gregaria Sacc., jasmonic acid, wounding treatment, low temperature and salinity stresses. Overexpression of PtoWRKY60 in poplar resulted in increased resistance to D. gregaria. The defense-associated genes, such as PR5.1, PR5.2, PR5.4, PR5.5 and CPR5, were markedly up-regulated in transgenic plants overexpressing PtoWRKY60. These results indicate that PtoWRKY60 might be partly involved in the signal transduction pathway initiated by SA in Populus. PMID- 25281842 TI - Sodium replacement of potassium in physiological processes of olive trees (var. Barnea) as affected by drought. AB - Potassium (K) is a macro-nutrient understood to play a role in the physiological performance of plants under drought. In some plant species, sodium (Na) can partially substitute K. Although a beneficial role of Na is well established, information regarding its nutritional role in trees is scant and its function under conditions of drought is not fully understood. The objective of the present study was to evaluate the role of K and its possible replacement by Na in olive's (Olea europaea L.) response to drought. Young and bearing olive trees were grown in soilless culture and exposed to gradual drought. In the presence of Na, trees were tolerant of extremely low K concentrations. Depletion of K and Na resulted in ~50% reduction in CO2 assimilation rate when compared with sufficiently fertilized control plants. Sodium was able to replace K and recover the assimilation rate to nearly optimum level. The inhibitory effect of K deficiency on photosynthesis was more pronounced under high stomatal conductance. Potassium was not found to facilitate drought tolerance mechanisms in olives. Moreover, stomatal control machinery was not significantly impaired by K deficiency, regardless of water availability. Under drought, leaf water potential was affected by K and Na. High environmental K and Na increased leaf starch content and affected the soluble carbohydrate profile in a similar manner. These results identify olive as a species capable of partly replacing K by Na. The nutritional effect of K and Na was shown to be independent of plant water status. The beneficial effect of Na on photosynthesis and carbohydrates under insufficient K indicates a positive role of Na in metabolism and photosynthetic reactions. PMID- 25281843 TI - Association between the dynamics of multiple replication origins and the evolution of multireplicon genome architecture in haloarchaea. AB - Haloarchaeal genomes are generally composed of multiple replicons, and each replicon has a single or multiple replication origin(s). The comparative genomic analysis of replication origins from closely related species can be used to reveal the evolutionary mechanisms that account for the development of multiple origin systems. Multiple replication origins have been in silico and experimentally investigated in Haloarcula hispanica, which raise the possibility for comparisons of multiple replication origins in Haloarcula species. Thus, we performed a comparison of H. hispanica replication origins with those from five additional Haloarcula species. We demonstrated that the multiple replication origins in the chromosome were evolved independently multiple times from the oriC1-dependent ancestral chromosome. Particularly, the two origins oriC1 and oriC2 were conserved in location, and both of them were adjacent to an rRNA operon, suggestive of correlations in replication and expression of surrounding genes that may promote the conservation of these two origins. Some chromosomal variable regions were used as hotspots for origin evolution in which replication origins were continually being acquired, lost, and disrupted. Furthermore, we demonstrated that autonomously replicating sequence plasmids with H. hispanica minichromosomal replication origins were extremely unstable. Because both organization and replication origins of minichromosomes were not conserved, we proposed an association between the evolution of extrachromosomal replicons and origin variation. Taken together, we provided insights into the evolutionary history of multiple replication origins in Haloarcula species, and proposed a general model of association between the dynamics of multiple replication origins and the evolution of multireplicon genome architecture in haloarchaea. PMID- 25281845 TI - Parent-to-parent support for parents with children who are deaf or hard of hearing: a conceptual framework. AB - BACKGROUND: Parent-to-parent support for parents with children who are deaf or hard of hearing (D/HH) is identified as an important component of Early Hearing Detection and Intervention (EHDI) programs for children with hearing loss. PURPOSE: The specific aim of this review was to identify the constructs and components of parent-to-parent support for parents of children who are D/HH. RESEARCH DESIGN: An extensive scoping literature review identified 39 peer reviewed articles published from 2000 to 2014. Studies were selected and reviewed based on standardized procedures. RESULTS: Data were identified, extracted, and organized into libraries of thematic and descriptive content. A conceptual framework of parent-to-parent support for parents of children who are D/HH was developed and presented in a comprehensive, bidirectional informational graphic. The constructs and components of the conceptual framework are (a) well-being: parent, family, and child; (b) knowledge: advocacy, system navigation, and education; and (c) empowerment: confidence and competence. CONCLUSION: The findings from this scoping review led to the development of a structured conceptual framework of parent-to-parent support for parents of children who are D/HH. The conceptual framework provides an important opportunity to explore and clearly define the vital contribution of parents in EHDI programs. PMID- 25281844 TI - The mitochondrial genomes of the glaucophytes Gloeochaete wittrockiana and Cyanoptyche gloeocystis: multilocus phylogenetics suggests a monophyletic archaeplastida. AB - A significant limitation when testing the putative single origin of primary plastids and the monophyly of the Archaeplastida supergroup, comprised of the red algae, viridiplants, and glaucophytes, is the scarce nuclear and organellar genome data available from the latter lineage. The Glaucophyta are a key algal group when investigating the origin and early diversification of photosynthetic eukaryotes. However, so far only the plastid and mitochondrial genomes of the glaucophytes Cyanophora paradoxa (strain CCMP 329) and Glaucocystis nostochinearum (strain UTEX 64) have been completely sequenced. Here, we present the complete mitochondrial genomes of Gloeochaete wittrockiana SAG 46.84 (36.05 kb; 33 protein-coding genes, 6 unidentified open reading frames [ORFs], and 28 transfer RNAs [tRNAs]) and Cyanoptyche gloeocystis SAG 4.97 (33.24 kb; 33 protein coding genes, 6 unidentified ORFs, and 26 tRNAs), which represent two genera distantly related to the "well-known" Cyanophora and Glaucocystis. The mitochondrial gene repertoire of the four glaucophyte species is highly conserved, whereas the gene order shows considerable variation. Phylogenetic analyses of 14 mitochondrial genes from representative taxa from the major eukaryotic supergroups, here including novel sequences from the glaucophytes Cyanophora tetracyanea (strain NIES-764) and Cyanophora biloba (strain UTEX LB 2766), recover a clade uniting the three Archaeplastida lineages; this recovery is dependent on our novel glaucophyte data, demonstrating the importance of greater taxon sampling within the glaucophytes. PMID- 25281846 TI - Methods for the quantitative comparison of molecular estimates of clade age and the fossil record. AB - Approaches quantifying the relative congruence, or incongruence, of molecular divergence estimates and the fossil record have been limited. Previously proposed methods are largely node specific, assessing incongruence at particular nodes for which both fossil data and molecular divergence estimates are available. These existing metrics, and other methods that quantify incongruence across topologies including entirely extinct clades, have so far not taken into account uncertainty surrounding both the divergence estimates and the ages of fossils. They have also treated molecular divergence estimates younger than previously assessed fossil minimum estimates of clade age as if they were the same as cases in which they were older. However, these cases are not the same. Recovered divergence dates younger than compared oldest known occurrences require prior hypotheses regarding the phylogenetic position of the compared fossil record and standard assumptions about the relative timing of morphological and molecular change to be incorrect. Older molecular dates, by contrast, are consistent with an incomplete fossil record and do not require prior assessments of the fossil record to be unreliable in some way. Here, we compare previous approaches and introduce two new descriptive metrics. Both metrics explicitly incorporate information on uncertainty by utilizing the 95% confidence intervals on estimated divergence dates and data on stratigraphic uncertainty concerning the age of the compared fossils. Metric scores are maximized when these ranges are overlapping. MDI (minimum divergence incongruence) discriminates between situations where molecular estimates are younger or older than known fossils reporting both absolute fit values and a number score for incompatible nodes. DIG range (divergence implied gap range) allows quantification of the minimum increase in implied missing fossil record induced by enforcing a given set of molecular-based estimates. These metrics are used together to describe the relationship between time trees and a set of fossil data, which we recommend be phylogenetically vetted and referred on the basis of apomorphy. Differences from previously proposed metrics and the utility of MDI and DIG range are illustrated in three empirical case studies from angiosperms, ostracods, and birds. These case studies also illustrate the ways in which MDI and DIG range may be used to assess time trees resultant from analyses varying in calibration regime, divergence dating approach or molecular sequence data analyzed. PMID- 25281847 TI - A Bayesian Supertree Model for Genome-Wide Species Tree Reconstruction. AB - Current phylogenomic data sets highlight the need for species tree methods able to deal with several sources of gene tree/species tree incongruence. At the same time, we need to make most use of all available data. Most species tree methods deal with single processes of phylogenetic discordance, namely, gene duplication and loss, incomplete lineage sorting (ILS) or horizontal gene transfer. In this manuscript, we address the problem of species tree inference from multilocus, genome-wide data sets regardless of the presence of gene duplication and loss and ILS therefore without the need to identify orthologs or to use a single individual per species. We do this by extending the idea of Maximum Likelihood (ML) supertrees to a hierarchical Bayesian model where several sources of gene tree/species tree disagreement can be accounted for in a modular manner. We implemented this model in a computer program called guenomu whose inputs are posterior distributions of unrooted gene tree topologies for multiple gene families, and whose output is the posterior distribution of rooted species tree topologies. We conducted extensive simulations to evaluate the performance of our approach in comparison with other species tree approaches able to deal with more than one leaf from the same species. Our method ranked best under simulated data sets, in spite of ignoring branch lengths, and performed well on empirical data, as well as being fast enough to analyze relatively large data sets. Our Bayesian supertree method was also very successful in obtaining better estimates of gene trees, by reducing the uncertainty in their distributions. In addition, our results show that under complex simulation scenarios, gene tree parsimony is also a competitive approach once we consider its speed, in contrast to more sophisticated models. PMID- 25281848 TI - From gene trees to a dated allopolyploid network: insights from the angiosperm genus Viola (Violaceae). AB - Allopolyploidization accounts for a significant fraction of speciation events in many eukaryotic lineages. However, existing phylogenetic and dating methods require tree-like topologies and are unable to handle the network-like phylogenetic relationships of lineages containing allopolyploids. No explicit framework has so far been established for evaluating competing network topologies, and few attempts have been made to date phylogenetic networks. We used a four-step approach to generate a dated polyploid species network for the cosmopolitan angiosperm genus Viola L. (Violaceae Batch.). The genus contains ca 600 species and both recent (neo-) and more ancient (meso-) polyploid lineages distributed over 16 sections. First, we obtained DNA sequences of three low-copy nuclear genes and one chloroplast region, from 42 species representing all 16 sections. Second, we obtained fossil-calibrated chronograms for each nuclear gene marker. Third, we determined the most parsimonious multilabeled genome tree and its corresponding network, resolved at the section (not the species) level. Reconstructing the "correct" network for a set of polyploids depends on recovering all homoeologs, i.e., all subgenomes, in these polyploids. Assuming the presence of Viola subgenome lineages that were not detected by the nuclear gene phylogenies ("ghost subgenome lineages") significantly reduced the number of inferred polyploidization events. We identified the most parsimonious network topology from a set of five competing scenarios differing in the interpretation of homoeolog extinctions and lineage sorting, based on (i) fewest possible ghost subgenome lineages, (ii) fewest possible polyploidization events, and (iii) least possible deviation from expected ploidy as inferred from available chromosome counts of the involved polyploid taxa. Finally, we estimated the homoploid and polyploid speciation times of the most parsimonious network. Homoploid speciation times were estimated by coalescent analysis of gene tree node ages. Polyploid speciation times were estimated by comparing branch lengths and speciation rates of lineages with and without ploidy shifts. Our analyses recognize Viola as an old genus (crown age 31 Ma) whose evolutionary history has been profoundly affected by allopolyploidy. Between 16 and 21 allopolyploidizations are necessary to explain the diversification of the 16 major lineages (sections) of Viola, suggesting that allopolyploidy has accounted for a high percentage-between 67% and 88%-of the speciation events at this level. The theoretical and methodological approaches presented here for (i) constructing networks and (ii) dating speciation events within a network, have general applicability for phylogenetic studies of groups where allopolyploidization has occurred. They make explicit use of a hitherto underexplored source of ploidy information from chromosome counts to help resolve phylogenetic cases where incomplete sequence data hampers network inference. Importantly, the coalescent-based method used herein circumvents the assumption of tree-like evolution required by most techniques for dating speciation events. PMID- 25281849 TI - Direct distal aortic arch graft cannulation after the elephant trunk procedure: technique for central cannulation during second-stage repair. AB - Arterial cannulation after the elephant trunk (ET) procedure at the time of second-stage distal repair can be achieved through multiple routes. Common strategies for arterial perfusion at the time of second-stage aortic repair include retrograde perfusion (femoral/iliac vessels), transapical or left subclavian artery cannulation. In the event these cannulation options are not practical or advisable, we offer an alternative approach through cannulation of the distal aortic arch Dacron graft through the left thorax. Advantages include forward distal perfusion, minimal proximal ischaemic time, prevention of thromboembolic events from thrombus attached to the ET and avoidance of malperfusion syndromes. PMID- 25281850 TI - Reply to Riquet et al. PMID- 25281851 TI - N2 involvement in lung cancer: the Danaides' barrel. PMID- 25281852 TI - Multiscale quantum chemical approaches to QSAR modeling and drug design. AB - The comparative use of classical, quantum chemical (QC) ligand-based (LB) and structure-based (SB) quantitative structure-activity relationship (QSAR) results in a detailed and mechanistic-causative description, at different scales (multiscale: classical=macroscopic, LB and SB=electronic-atomistic-nanoscale) and resolution levels, of the energetics and thermodynamics of the binding event for a congeneric set of ligands and/or drugs. QC interaction propensity (reactivity) descriptors in LB QSARs provide an implicitly more accurate estimation of the enthalpic contribution to ligand-target interactions compared with classical QSAR. As for QSAR models from ab initio SB fragment molecular orbital calculations, an explicit enthalpic description of the different additive terms in the computed binding energy is obtainable. Moreover, it is possible to estimate the difference in the free energy change of the ligand-target complex formation and evaluate, on a correlative basis, the contribution of each additive free energy term to the total value. PMID- 25281853 TI - Angiotensin receptor blockers: a panacea for Marfan syndrome and related disorders? AB - The study of mouse models for Marfan syndrome, an autosomal dominant connective tissue disorder caused by mutations in fibrillin-1 (FBN1), has shifted our understanding of the pathogenesis of thoracic aortic aneurysm significantly. Multiple lines of evidence support the notion that dysregulation of canonical and noncanonical transforming growth factor (TGF)beta signaling is the responsible pathway in this and related thoracic aortic aneurysm conditions. This exciting knowledge has opened numerous new treatment options, including antagonism of the angiotensin II receptor blocker type 1 (AT1R). In this review, we summarize the current knowledge, the first human losartan Marfan trial results and future therapeutic perspectives for aortic disease in Marfan patients. PMID- 25281854 TI - Recent advances in controlled pulmonary drug delivery. AB - Characterized by large surface area, high vascularization and thin blood-alveolar barrier, drug delivery by the pulmonary route has benefits over other administration routes. However, to date most of the marketed inhalable products are short-acting formulations that require the patient to inhale several times every day, thus reducing patient compliance. Controlled pulmonary drug delivery is a promising system but the formidable airway clearance mechanisms need to be avoided. This review mainly introduces the barriers impeding the development of controlled pulmonary drug delivery and strategies used to overcome them. We believe that large porous particles, swellable microparticles and porous nanoparticle-aggregate-based particles are the most promising carriers to control drug release in the lung. PMID- 25281855 TI - Designing novel building blocks is an overlooked strategy to improve compound quality. AB - One pragmatic way to improve compound quality, while enhancing and accelerating drug discovery projects, is the ability to access a high quality, novel, diverse building block collection. Here, we outline general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects, by discussing design principles for novel reagents and what types of reagents are popular with medicinal chemists in general. We initiated a program in 2009 to address this, which has already delivered three candidate drugs, and the success of that program provides evidence that focussing on building block design is a useful strategy for drug discovery. PMID- 25281856 TI - Development and validation of questionnaires exploring health care professionals' intention to use wiki-based reminders to promote best practices in trauma. AB - BACKGROUND: Little is known about factors influencing professionals' use of wikis. OBJECTIVE: We developed and validated two questionnaires to assess health care professionals' intention to use wiki-based reminders for the management of trauma patients. METHODS: We developed questionnaires for emergency physicians (EPs) and allied health professions (AHPs) based on the Theory of Planned Behavior and adapted them to the salient beliefs of each, identified in an earlier study. Items measured demographics and direct and indirect theoretical constructs. We piloted the questionnaires with 2 focus groups (5 EPs and 5 AHPs) to identify problems of wording and length. Based on feedback, we adjusted the wording and combined certain items. A new convenience sample of 25 EPs and 26 AHPs then performed a test-retest of the questionnaires at a 2-week interval. We assessed internal consistency using Cronbach alpha coefficients and temporal stability of items with an agreement intraclass correlation coefficient (ICC). RESULTS: Five EPs and 5 AHPs (3 nurses, 1 respiratory therapist, and 1 pharmacist) formed 2 focus groups; 25 EPs and 26 AHPs (12 nurses, 7 respiratory therapists, and 7 pharmacists) completed the test and retest. The EP questionnaire test-retest scores for consistency (Cronbach alpha) and stability (ICC) were intention (test: Cronbach alpha=.94; retest: Cronbach alpha=.98; ICC=.89), attitude (.74, .72, .70), subjective norm (.79, .78, .75), perceived behavioral control (.67, .65, .66), attitudinal beliefs (.94, .86, .60), normative beliefs (.83, .87, .79), and control beliefs barriers (.58, .67, .78) and facilitators (.97, .85, .30). The AHP questionnaire scores for consistency and stability were: intention (test Cronbach alpha=.69, retest Cronbach alpha=.81, ICC=.48), attitude (.85, .87, .83), subjective norm (.47, .82, .62), perceived behavioral control (.55, .62, .60), attitudinal beliefs (.92, .91, .82), normative beliefs (.85, .90, .74), and control beliefs barriers (.58, .55, .66) and facilitators (.72, .94, -.05). To improve the psychometric properties of both questionnaires, we reformulated poorly consistent or unstable items. CONCLUSIONS: Our new theory-based questionnaires to measure health care professionals' intention to use wiki-based reminders have adequate validity and reliability for use in large surveys. In the long run, they can be used to develop a theory-based implementation intervention for a wiki promoting best practices in trauma care. PMID- 25281857 TI - Ethnic differences in pre-adipocyte intracellular lipid accumulation and alkaline phosphatase activity. AB - Alkaline phosphatase (ALP) increases lipid accumulation in human pre-adipocytes. This study was performed to assess whether ethnic differences in the prevalence of obesity in African and European females are related to differences in pre adipocyte lipid accretion and ALP activity. Pre-adipocytes were isolated from 13 black and 14 white females. Adipogenesis was quantified using the lipid dye, Oil red O, whilst ALP activity was assayed in cell extracts on day zero and 12days after initiating adipogenesis. Lipid levels (OD units/mg protein) were lower in pre-adipocytes from white than black females on day 0 (0.36+/-0.05 versus 0.44+/ 0.03, respectively; p<0.0005) and day 12 (1.18+/-0.14 versus 1.80+/-0.22, respectively; p<0.0005), as was ALP activity (mU/mg protein) on day zero (36.5+/ 5.8 versus 136.4+/-10.9, respectively; p<0.0005) and day 12 (127+/-16 versus 278+/-27, respectively; p<0.0005). Treatment of pre-adipocytes with histidine, an ALP inhibitor, blocked lipid accumulation. Thus, lipid uptake is higher in pre adipocytes isolated from black compared to white females which parallels the obesity prevalence rates in these population groups. The reason for higher fat accumulation in pre-adipocytes isolated from black females may be related to higher ALP activity. PMID- 25281858 TI - TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice. AB - BACKGROUND & AIMS: Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumour suppressor. To address this dichotomy and to uncover direct regulatory functions of TRIM24 in vivo, we developed a new mouse model that lacks expression of all Trim24 isoforms, as the previous model expressed normal levels of Trim24 lacking only exon 4. METHODS: To produce germline-deleted Trim24(dlE1) mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24(LoxP) mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24(hep)) was achieved by crossing with an albumin-Cre line. Phenotypic analyses were complemented by protein, gene specific and global RNA expression analyses and quantitative chromatin immunoprecipitation. RESULTS: Global loss of Trim24 disrupted hepatic homeostasis in 100% of mice with highly significant, decreased expression of oxidation/reduction, steroid, fatty acid, and lipid metabolism genes, as well as increased expression of genes involved in unfolded protein response, endoplasmic reticulum stress and cell cycle pathways. Trim24(dlE1/dlE1) mice have markedly depleted visceral fat and, like Trim24(hep/hep) mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma. CONCLUSIONS: TRIM24, an epigenetic co-regulator of transcription, directly and indirectly represses hepatic lipid accumulation, inflammation, fibrosis and damage in the murine liver. Complete loss of Trim24 offers a model of human non-alcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity. PMID- 25281859 TI - Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice. AB - BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation. METHODS: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice. RESULTS: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation. CONCLUSIONS: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH. PMID- 25281860 TI - CD4+ CXCR5+ T cells in chronic HCV infection produce less IL-21, yet are efficient at supporting B cell responses. AB - BACKGROUND & AIMS: During chronic HCV infection, T cell dependent virus-specific antibodies are produced. However, the role of B-T cell interaction in chronic HCV is largely unknown. CD4(+)CXCR5(+) T follicular helper (TFH)-cells activate B cells and are important for clearance of various chronic viral infections. We investigated the function of TFH cells and B cells in liver and in peripheral blood of chronic HCV patients. METHODS: T cells from chronic HCV patients and healthy individuals were analysed for expression of CXCR5, PD-1, ICOS, and IL-21 and IFN-gamma production by flow cytometry. CD19(+) B cell subpopulations were identified on the basis of CD27 and IgD expression. In order to assess the frequency and function of T cells and B cells in liver follicles, immunohistochemistry was performed for CD3, CXCR5, Bcl6, IL-21, CD20, IgD, IgM, and IgG. RESULTS: The frequency of IL-21-producing CXCR5(+)CD4(+) T cells in blood was lower in HCV patients compared to healthy individuals (p=0.002), which was reflected by lower serum IL-21 levels (p<0.001). Nonetheless, CXCR5(+)CD4(+) T cells from HCV patients and healthy individuals were equally capable to stimulate CD19(+)CD27(+) memory B cells into IgG and IgM-producing plasmablasts. Importantly, human intrahepatic TFH cells and their related function were identified by immunohistochemistry on liver biopsies for CD3, Bcl6, and CD20 within portal areas and follicles. CONCLUSIONS: The specific localization of TFH cells and IgG and IgD/IgM-producing B cells suggests a functional B-T cell environment in liver follicles during HCV infection. The decreased frequency of IL-21-producing CXCR5(+)CD4(+) T cells and lower serum IL-21 levels in chronic HCV patients did not lead to an altered TFH-B cell interaction. PMID- 25281861 TI - The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis. AB - BACKGROUND & AIMS: Antiviral therapy with interferon and ribavirin (double therapy) is associated with a significant risk of developing bacterial infections in patients with hepatitis C-related cirrhosis. The addition of telaprevir or boceprevir seems to increase this risk but there are no studies yet to compare the infection rate between both treatments. We aimed to assess rate, type and predictive factors of infection in cirrhotic patients undergoing triple or double antiviral therapy. METHODS: This was a retrospective analysis of prospectively collected data. 167 patients with hepatitis C-related cirrhosis undergoing triple therapy (cohort A) and 81 receiving double therapy (cohort B) were enrolled in the study. Only Child-Pugh A patients were included. RESULTS: The infection rate was significantly higher for patients in cohort A as compared to those in cohort B (25% vs. 9%, p=0.001). Interestingly, respiratory tract infections were significantly more frequent in patients in cohort A (12% vs. 1%; p=0.049). The use of triple antiviral therapy was the only predictive factor of infection. Severe infections were also more frequent in patients in cohort A, but the difference did not reach the level of significance (13% vs. 6%, p=0.123). CONCLUSIONS: Triple therapy carries a higher risk of infections in patients with cirrhosis and changes the pattern of infection in this subpopulation. Further studies are needed in order to establish the underlying mechanism of this event. PMID- 25281862 TI - Correction of hyponatraemia in cirrhosis: treating more than a number! PMID- 25281863 TI - Acid sphingomyelinase-ceramide system in steatohepatitis: a novel target regulating multiple pathways. AB - Steatohepatitis (SH) is an intermediate stage of fatty liver disease and is one of the most common causes of chronic liver disease worldwide that may progress to cirrhosis and liver cancer. SH encompasses alcoholic and non-alcoholic steatohepatitis, the latter being of particular concern as it is associated with obesity and insulin resistance and has become a major cause of liver transplantation. The molecular mechanisms governing the transition from steatosis to SH are not fully understood. Here we discuss emerging data indicating that the acid sphingomyelinase (ASMase), a specific mechanism of ceramide generation, is required for the activation of key pathways that regulate steatosis, fibrosis and lipotoxicity, including endoplasmic reticulum stress, autophagy and lysosomal membrane permeabilization. Moreover, ASMase modulates alterations of the methionine cycle and phosphatidylcholine homeostasis, two crucial events involved in SH that regulate methylation reactions, antioxidant defence and membrane integrity. These new findings suggest that targeting ASMase in combination with restoring methionine metabolism and phosphatidylcholine levels may be of utility in the treatment of SH. PMID- 25281864 TI - The reporting of animal welfare details in liver research: a review of studies describing bile duct ligation in mice (2011-2013). PMID- 25281865 TI - Reply: Intravenous thrombolysis for ischaemic strokes: a call for reappraisal. PMID- 25281866 TI - Membrane-shaping disorders: a common pathway in axon degeneration. AB - Neurons with long projections are particularly liable to damage, which is reflected by a large group of hereditary neurodegenerative disorders that primarily affect these neurons. In the group of hereditary spastic paraplegias motor axons of the central nervous system degenerate, while distal pure motor neuropathies, Charcot-Marie-Tooth disorders and the group of hereditary sensory and autonomic neuropathies are characterized by degeneration of peripheral nerve fibres. Because the underlying pathologies share many parallels, the disorders are also referred to as axonopathies. A large number of genes has been associated with axonopathies and one of the emerging subgroups encodes membrane-shaping proteins with a central reticulon homology domain. Association of these proteins with lipid bilayers induces positive membrane curvature and influences the architecture of cellular organelles. Membrane-shaping proteins closely cooperate and directly interact with each other, but their structural features and localization to distinct subdomains of organelles suggests mutually exclusive roles. In some individuals a mutation in a shaping protein can result in upper motor neuron dysfunction, whereas in other patients it can lead to a degeneration of peripheral neurons. This suggests that membrane-shaping disorders might be considered as a continuous disease-spectrum of the axon. PMID- 25281867 TI - Intravenous thrombolysis for ischaemic strokes: a call for reappraisal. PMID- 25281870 TI - Measurement of tear secretion in healthy pigeons by using the phenol red thread test. AB - The objectives of this study were to determine the applicability of the phenol red thread (PRT) test as a new method for the evaluation of tear secretion in healthy male and female pigeons, to establish normal physiologic reference values in these animals, and to compare seasonal variations in these values. Seventy five pigeons of both sexes, with no ocular abnormalities, were included in the study. The phenol red impregnated thread was inserted into the recessus conjunctiva inferior for measuring tear secretion. After 15 seconds, the thread was removed and the wet portion of the thread was measured (in mm). The mean+/-sd PRT values were 23.02+/-2.98 mm/15 seconds and 24.04+/-2.60 mm/15 seconds for the April and June measurements, respectively. There were significant differences in the PRT between the two months, with a significant increase in June. Mean PRT values for males and females were, respectively, 23.30+/-3.35 and 22.79+/-2.65 mm/15 seconds in April, and 24.57+/-2.41 and 23.61+/-2.68 mm/15 seconds in June. There was no significant correlation (r=0.075, P>0.05) between bodyweight and tear production in both eyes of the male and female birds in April and June. The results indicated that seasonal variations have an effect on tear production. The PRT was a viable method for the measurement of tear production in pigeons and these measurements could be accepted as reference values for healthy pigeons. PMID- 25281868 TI - Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia. AB - Progressive external ophthalmoplegia is a common clinical feature in mitochondrial disease caused by nuclear DNA defects and single, large-scale mitochondrial DNA deletions and is less frequently associated with point mutations of mitochondrial DNA. Peripheral neuropathy is also a frequent manifestation of mitochondrial disease, although its prevalence and characteristics varies considerably among the different syndromes and genetic aetiologies. Based on clinical observations, we systematically investigated whether the presence of peripheral neuropathy could predict the underlying genetic defect in patients with progressive external ophthalmoplegia. We analysed detailed demographic, clinical and neurophysiological data from 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia. Seventy-eight patients (67%) had a single mitochondrial DNA deletion, 12 (10%) had a point mutation of mitochondrial DNA and 26 (22%) had mutations in either POLG, C10orf2 or RRM2B, or had multiple mitochondrial DNA deletions in muscle without an identified nuclear gene defect. Seventy-seven patients had neurophysiological studies; of these, 16 patients (21%) had a large fibre peripheral neuropathy. The prevalence of peripheral neuropathy was significantly lower in patients with a single mitochondrial DNA deletion (2%) as compared to those with a point mutation of mitochondrial DNA or with a nuclear DNA defect (44% and 52%, respectively; P<0.001). Univariate analyses revealed significant differences in the distribution of other clinical features between genotypes, including age at disease onset, gender, family history, progressive external ophthalmoplegia at clinical presentation, hearing loss, pigmentary retinopathy and extrapyramidal features. However, binomial logistic regression analysis identified peripheral neuropathy as the only independent predictor associated with a nuclear DNA defect (P=0.002; odds ratio 8.43, 95% confidence interval 2.24-31.76). Multinomial logistic regression analysis identified peripheral neuropathy, family history and hearing loss as significant predictors of the genotype, and the same three variables showed the highest performance in genotype classification in a decision tree analysis. Of these variables, peripheral neuropathy had the highest specificity (91%), negative predictive value (83%) and positive likelihood ratio (5.87) for the diagnosis of a nuclear DNA defect. These results indicate that peripheral neuropathy is a rare finding in patients with single mitochondrial DNA deletions but that it is highly predictive of an underlying nuclear DNA defect. This observation may facilitate the development of diagnostic algorithms. We suggest that nuclear gene testing may enable a more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy. PMID- 25281869 TI - Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model. AB - Cognitive decline in Alzheimer's disease is attributed to loss of functional synapses, most likely caused by synaptotoxic, oligomeric forms of amyloid-beta. Many treatment options aim at reducing amyloid-beta levels in the brain, either by decreasing its production or by increasing its clearance. We quantified the effects of immunotherapy directed against oligomeric amyloid-beta in Tg2576 mice, a mouse model of familial Alzheimer's disease. Treatment of 12-month-old mice with oligomer-specific (A-887755) or conformation-unspecific (6G1) antibodies for 8 weeks did not affect fibrillar plaque density or growth. We also quantified densities of DLG4 (previously known as PSD95) expressing post-synapses and synapsin expressing presynapses immunohistochemically. We found that both pre- and post-synapses were strongly reduced in the vicinity of plaques, whereas distant from plaques, in the cortex and hippocampal CA1 field, only post-synapses were reduced. Immunotherapy alleviated this synapse loss. Synapse loss was completely abolished distant from plaques, whereas it was only attenuated in the vicinity of plaques. These results suggest that fibrillar plaques may act as reservoirs for synaptotoxic, oligomeric amyloid-beta and that sequestering oligomers suffices to counteract synaptic pathology. Therefore, cognitive function may be improved by immunotherapy even when the load of fibrillar amyloid remains unchanged. PMID- 25281871 TI - Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury. AB - Transcranial magnetic stimulation has generated extensive interest within the traumatic brain injury (TBI) rehabilitation community, but little work has been done with repetitive protocols, which can produce prolonged changes in behavior. This is partly because of concerns about the safety of repetitive transcranial magnetic stimulation (rTMS) in subjects with TBI, particularly the risk of seizures. These risks can be minimized by careful selection of the rTMS protocol and exclusion criteria. In this article, we identify guidelines for safe use of rTMS in subjects with TBI based on a review of the literature and illustrate their application with a case study. Our subject is a 48-year-old man who sustained a severe TBI 5 years prior to beginning rTMS for the treatment of post TBI depression. After a 4-week baseline period, we administered daily sessions of low-frequency stimulation to the right dorsolateral prefrontal cortex for 6 weeks. After stimulation, we performed monthly assessments for 3 months. The Hamilton Depression Rating Scale (HAMD) was our primary outcome measure. The stimulation was well tolerated and the patient reported no side effects. After 6 weeks of stimulation, the patient's depression was slightly improved, and these improvements continued through follow-up. At the end of follow-up, the patient's HAMD score was 49% of the average baseline score. PMID- 25281872 TI - Are the barriers for physical activity practice equal for all peripheral artery disease patients? AB - OBJECTIVE: To investigate barriers to physical activity related to the sociodemographic comorbidities and clinical variables of patients with intermittent claudication. DESIGN: Cross-sectional study. SETTING: Ambulatory care. PARTICIPANTS: The medical histories of patients (N=145) aged >=50 years with intermittent claudication were examined. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sociodemographic data (sex, race, level of education, socioeconomic status, marital status), comorbidities (overweight, hypertension, dyslipidemia, diabetes, currently smoking, heart disease), and clinical variables (initial claudication distance, total walking distance, ankle-brachial index). Information on personal and environmental barriers was obtained by questionnaire. RESULTS: Low economic status was most associated with "being afraid of falling" (odd ratios [OR]=2.22; 95% confidence interval [CI], 1.08-4.54). Low education level was most associated with "lack of street pedestrian crossing" (OR=3.34; 95% CI, 1.48-7.52). Diabetes was associated with lack of energy (OR=3.38; 95% CI, 1.68-6.79) and other medical conditions (eg, arthritis, angina) (OR=3.44; 95% CI, 1.65-7.16). Ankle brachial index was associated with "some difficulty in getting to a place where physical activity can be performed" (OR=2.75; 95% CI, 1.22 6.21). Walking capacity was strongly associated with barriers relating to leg pain (OR=7.39; 95% CI, 1.66-32.88). CONCLUSIONS: Older patients, those with a low education level, patients with diabetes, low ankle brachial index, and those with a lower walking capacity are more likely to experience barriers to physical activity. PMID- 25281874 TI - Synthesis of Tat tagged and folate modified N-succinyl-chitosan self-assembly nanoparticles as a novel gene vector. AB - The purpose of this research was to prepare a novel type of Tat tagged and folate modified N-succinyl-chitosan (Tat-Suc-FA) self-assembly nanoparticles, to provide a new vector for tumor gene therapy. In this study, Tat-Suc-FA polymers was synthesized and characterized using (1)H NMR and FT-IR. The copolymer had a mean diameter of 65 +/- 22.6 nm, a zeta potential of 40 +/- 0.2 mV. The cytotoxicity assay showed that Tat-Suc-FA polymers were less toxic than chitosan in the tested concentration range (from 2 to 500 MUg/ml). Tat-Suc-FA/DNA complexes at various weight ratios were formulated and characterized. Particle sizes of Tat-Suc-FA/DNA complexes were between 54 and 106 nm as determined by dynamic light scattering. Accordingly, Transmission electron microscope photo of Tat-Suc-FA/DNA complexes exhibited a spherical and compact morphology. Zeta potentials of these complexes changed as the weight ratio varied (from 3 to 44 mV). Agarose gel electrophoresis assay showed that Tat-Suc-FA could efficiently condense the DNA, when the weight ratio was above 1.5/1. Together, these results suggest that the low toxic Tat-Suc FA cationic polymers could be considered for use as a novel type of gene delivery vectors. PMID- 25281873 TI - Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells. AB - Protein arginine methyltransferase 5 (PRMT5) symmetrically methylates arginine residues of histones and non-histone protein substrates and regulates a variety of cellular processes through epigenetic control of target gene expression or post-translational modification of signaling molecules. Recent evidence suggests that PRMT5 may function as an oncogene and its overexpression contributes to the development and progression of several human cancers. However, the mechanism underlying the regulation of PRMT5 expression in cancer cells remains largely unknown. In the present study, we have mapped the proximal promoter of PRMT5 to the -240bp region and identified nuclear transcription factor Y (NF-Y) as a critical transcription factor that binds to the two inverted CCAAT boxes and regulates PRMT5 expression in multiple cancer cell lines. Further, we present evidence that loss of PRMT5 is responsible for cell growth inhibition induced by knockdown of NF-YA, a subunit of NF-Y that forms a heterotrimeric complex with NF YB and NF-YC for function. Significantly, we have found that activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) in LNCaP prostate cancer cells down-regulates the expression of NF-YA and PRMT5 at the transcription level in a c-Fos-dependent manner. Given that down-regulation of several PKC isozymes is implicated in the development and progression of several human cancers, our findings suggest that the PKC-c-Fos-NF-Y signaling pathway may be responsible for PRMT5 overexpression in a subset of human cancer patients. PMID- 25281875 TI - Biochemical characterization of recombinant mevalonate kinase from Bacopa monniera. AB - Mevalonate kinase (MK; ATP: mevalonate 5-phosphotransferase; EC 2.7.1.36) plays a key role in isoprenoid biosynthetic pathway in plants. MK catalyzes the phosphorylation of mevalonate to form mevalonate-5-phosphate. The recombinant BmMK was cloned and over-expressed in E. coli BL21 (DE3), and purified to homogeneity by affinity chromatography followed by gel filtration. Optimum pH and temperature for forward reaction was found to be 7.0 and 30 degrees C, respectively. The enzyme was most stable at pH 8 at 25 degrees C with deactivation rate constant (Kd*) 1.398 * 10(-4) and half life (t1/2) 49 h. pH activity profile of BmMK indicates the involvement of carboxylate ion, histidine, lysine, arginine or aspartic acid at the active site of enzyme. Activity of recombinant BmMK was confirmed by phosphorylation of RS-mevalonate in the presence of Mg(2+), having Km and Vmax 331.9 MUM and 719.1 pKat MUg(-1), respectively. The values of kcat and kcat/Km for RS-mevalonate were determined to be 143.82 s(-1) and 0.43332 M(-1) s(-1) and kcat and kcat/Km values for ATP were found 150.9 s(-1) and 1.023 M(-1) s(-1). The metal ion studies suggested that BmMK is a metal dependent enzyme and highly active in the presence of MgCl2. PMID- 25281876 TI - Alpha-lipoic acid upregulates SIRT1-dependent PGC-1alpha expression and protects mouse brain against focal ischemia. AB - BACKGROUND AND OBJECT: Silent mating type information regulation 2 homolog 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator activated receptor-gamma co-activator-1alpha (PGC-1alpha) which attenuates oxidative damage. Alpha-lipoic acid (ALA) has been proven to protect the rat brain against cerebral ischemia injury by reducing oxidative stress. However, the underlying mechanisms are poorly understood. In this study, we investigated the potential neuroprotection and the possible role of ALA in SIRT1 pathway. METHODS: Male CD-1 mice were randomly assigned to three groups: Sham, permanent middle cerebral artery occlusion (pMCAO) and ALA group (ALA, 50mg/kg). ALA was administered intraperitoneally 30min prior to ischemia in the ALA group. Neurological deficit, infarct volume, and brain edema were detected at 24h after cerebral ischemia. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of SIRT1 and PGC-1alpha. Activities of superoxide dismutase (SOD) were measured by assay kits. RESULTS: Compared with the pMCAO group, the ALA group significantly ameliorated neurological deficit, lessened infarct volume and brain edema, increased the expression of SIRT1, PGC-1alpha and activities of SOD (P<0.05). CONCLUSIONS: ALA protected the mouse brain against ischemic damage, and this protection may be through up-regulating SIRT1-dependent PGC-1alpha expression. PMID- 25281877 TI - Circadian insights into dopamine mechanisms. AB - Almost every physiological or behavioral process in mammals follows rhythmic patterns, which depend mainly on a master circadian clock located in the hypothalamic suprachiasmatic nucleus (SCN). The dopaminergic (DAergic) system in the brain is principally implicated in motor functions, motivation and drug intake. Interestingly, DA-related parameters and behaviors linked to the motivational and arousal states, show daily rhythms that could be regulated by the SCN or by extra-SCN circadian oscillator(s) modulating DAergic systems. Here we examine what is currently understood about the anatomical and functional central multi-oscillatory circadian system, highlighting how the main SCN clock communicates timing information with other brain clocks to regulate the DAergic system and conversely, how DAergic cues may have feedback effects on the SCN. These studies give new insights into the role of the brain circadian system in DA related neurologic pathologies, such as Parkinson's disease, attention deficit/hyperactive disorder and drug addiction. PMID- 25281878 TI - Metabolic brain activity underlying behavioral performance and spatial strategy choice in sedentary and exercised Wistar rats. AB - We have studied the performance of a spatial reference memory task, the navigation strategy and the changes in the cytochrome c oxidase activity (COx) in different brain regions in exercised (forced exercise, 10 consecutive days, 15min/day) and non-exercised adult Wistar rats. The spatial learning task was carried out in the radial-arm water maze (RAWM) for four days with six daily trials, and on the fifth day, a probe session was run, in which we rotated the position of the distal cues 90 degrees in a clockwise direction. During the four days of training, the exercised group showed shorter latency and distance traveled to find the platform, as well as fewer memory errors and reduced use of non-appropriate navigation strategies according to the protocol of the task (egocentric). Interestingly, the rotation of the cues did not affect the performance of the exercised group, in contrast to the non-exercised group, which spent more time in the center of the maze and traveled longer distance to find the platform. Finally, higher COx activity in the cingulate and the retrosplenial cortices, as well as in the dorsal CA1 and CA3 was found in the exercised group. All in all, it seems that the exercise favored the configuration of an efficient and accurate cognitive map of the environment, which was supported by our finding that the rotation of the cues, without altering their overall configuration, did not affect performance. The brain regions with higher COx activity in the exercised group seem to be involved in this function. PMID- 25281879 TI - What happens to microglial TREM2 in Alzheimer's disease: Immunoregulatory turned into immunopathogenic? AB - Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. Under normal conditions, triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the second category. It pairs with the adaptor protein DNAX-activating protein of 12kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation. Although ligands for TREM2 are largely unknown, the mitochondrial heat shock protein 60, expressed on cell surface of apoptotic neurons, is a specific ligand that activates TREM2-mediated phagocytosis by microglia. TREM2 also phagocytoses amyloid beta peptide in cultured cells. Several TREM2 mutations have been identified recently that increase the risk of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Some of these mutations cause impaired proteolysis of full-length TREM2 at the plasma membrane to different degrees. The defects in the intramembrane cleavage result in dysfunction of phagocytosis signaling. The association of TREM2 mutations with neurodegenerative disease also calls for the understanding of the biology and pathological role of non-mutated TREM2 on human brains and microglia. This review provides a summary of current literature in TREM2 and DAP12 from several aspects, and proposes a theory that loss of TREM2 functions might contribute to the immunopathogenic role of microglia in Alzheimer's disease. PMID- 25281880 TI - Frequency-specific response facilitation of supra and infragranular barrel cortical neurons depends on NMDA receptor activation in rats. AB - Sensory experience has a profound effect on neocortical neurons. Passive stimulation of whiskers or sensory deprivation from whiskers can induce long lasting changes in neuronal responses or modify the receptive field in adult animals. We recorded barrel cortical neurons in urethane-anesthetized rats in layers 2/3 or 5/6 to determine if repetitive stimulation would induce long lasting response facilitation. Air-puff stimulation (20-ms duration, 40 pulses at 0.5-8Hz) was applied to a single whisker. This repetitive stimulation increased tactile responses in layers 2/3 and 5/6 for 60min. Moreover, the functional coupling (coherence) between the sensory stimulus and the neural response also increased after the repetitive stimulation in neurons showing response facilitation. The long-lasting response facilitation was due to activation of N methyl-d-aspartate (NMDA) receptors because it was reduced by APV ((2R)-amino-5 phosphonovaleric acid, (2R)-amino-5-phosphonopentanoate) and MK801 application. Inactivation of layer 2/3 also blocked response facilitation in layer 5/6, suggesting that layer 2/3 may be fundamental in this synaptic plasticity processes. Moreover, i.p. injection of eserine augmented the number of layer 2/3 neurons expressing long-lasting response facilitation; this effect was blocked by atropine, suggesting that muscarinic receptor activation favors the induction of the response facilitation. Our data indicate that physiologically repetitive stimulation of a single whisker at the frequency at which rats move their whiskers during exploration of the environment induces long-lasting response facilitation improving sensory processing. PMID- 25281881 TI - Influence of long-term Sahaja Yoga meditation practice on emotional processing in the brain: An ERP study. AB - Despite growing interest in meditation as a tool for alternative therapy of stress-related and psychosomatic diseases, brain mechanisms of beneficial influences of meditation practice on health and quality of life are still unclear. We propose that the key point is a persistent change in emotional functioning, specifically the modulation of the early appraisal of motivational significance of events. The main aim was to study the effects of long-term meditation practice on event-related brain potentials (ERPs) during affective picture viewing. ERPs were recorded in 20 long-term Sahaja Yoga meditators and 20 control subjects without prior experience in meditation. The meditators' mid latency (140-400ms) ERPs were attenuated for both positive and negative pictures (i.e. there were no arousal-related increases in ERP positivity) and this effect was more prominent over the right hemisphere. However, we found no differences in the long latency (400-800ms) responses to emotional images, associated with meditation practice. In addition we found stronger ERP negativity in the time window 200-300ms for meditators compared to the controls, regardless of picture valence. We assume that long-term meditation practice enhances frontal top-down control over fast automatic salience detection, based on amygdala functions. PMID- 25281882 TI - The cyclic keto-enol insecticide spirotetramat inhibits insect and spider mite acetyl-CoA carboxylases by interfering with the carboxyltransferase partial reaction. AB - Acetyl-CoA carboxylase (ACC) catalyzes the committed and rate-limiting step in fatty acid biosynthesis. The two partial reactions, carboxylation of biotin followed by carboxyl transfer to the acceptor acetyl-CoA, are performed by two separate domains in animal ACCs. The cyclic keto-enol insecticides and acaricides have been proposed to inhibit insect ACCs. In this communication, we show that the enol derivative of the cylic keto-enol insecticide spirotetramat inhibited ACCs partially purified from the insect species Myzus persicae and Spodoptera frugiperda, as well as the spider mite (Tetranychus urticae) ACC which was expressed in insect cells using a recombinant baculovirus. Steady-state kinetic analysis revealed competitive inhibition with respect to the carboxyl acceptor, acetyl-CoA, indicating that spirotetramat-enol bound to the carboxyltransferase domain of ACC. Interestingly, inhibition with respect to the biotin carboxylase substrate ATP was uncompetitive. Amino acid residues in the carboxyltransferase domains of plant ACCs are important for binding of established herbicidal inhibitors. Mutating the spider mite ACC at the homologous positions, for example L1736 to either isoleucine or alanine, and A1739 to either valine or serine, did not affect the inhibition of the spider mite ACC by spirotetramat-enol. These results indicated different binding modes of the keto-enols and the herbicidal chemical families. PMID- 25281883 TI - Effects of action observation on corticospinal excitability: Muscle specificity, direction, and timing of the mirror response. AB - Many human behaviours and pathologies have been attributed to the putative mirror neuron system, a neural system that is active during both the observation and execution of actions. While there are now a very large number of papers on the mirror neuron system, variations in the methods and analyses employed by researchers mean that the basic characteristics of the mirror response are not clear. This review focuses on three important aspects of the mirror response, as measured by modulations in corticospinal excitability: (1) muscle specificity; (2) direction; and (3) timing of modulation. We focus mainly on electromyographic (EMG) data gathered following single-pulse transcranial magnetic stimulation (TMS), because this method provides precise information regarding these three aspects of the response. Data from paired-pulse TMS paradigms and peripheral nerve stimulation (PNS) are also considered when we discuss the possible mechanisms underlying the mirror response. In this systematic review of the literature, we examine the findings of 85 TMS and PNS studies of the human mirror response, and consider the limitations and advantages of the different methodological approaches these have adopted in relation to discrepancies between their findings. We conclude by proposing a testable model of how action observation modulates corticospinal excitability in humans. Specifically, we propose that action observation elicits an early, non-specific facilitation of corticospinal excitability (at around 90ms from action onset), followed by a later modulation of activity specific to the muscles involved in the observed action (from around 200ms). Testing this model will greatly advance our understanding of the mirror mechanism and provide a more stable grounding on which to base inferences about its role in human behaviour. PMID- 25281884 TI - Cognitive correlates of narrative impairment in moderate traumatic brain injury. AB - Traumatic brain injuries (TBIs) are often associated with communicative deficits. The incoherent and impoverished language observed in non-aphasic individuals with severe TBI has been linked to a problem in the global organization of information at the text level. The present study aimed to analyze the features of narrative discourse impairment in a group of adults with moderate TBI (modTBI). 10 non aphasic speakers with modTBI and 20 neurologically intact participants were recruited for the experiment. Their cognitive, linguistic and narrative skills were thoroughly assessed. The persons with modTBI exhibited normal phonological, lexical and grammatical skills. However, their narratives were characterized by lower levels of Lexical Informativeness and more errors of both Local and Global Coherence that, at times, made their narratives vague and ambiguous. Significant correlations were found between these narrative difficulties and the production of both perseverative and non-perseverative errors on the WCST. These disturbances confirm previous findings which suggest a deficit at the interface between cognitive and linguistic processing rather than a specific linguistic disturbance in these patients. PMID- 25281885 TI - Intergroup relationships do not reduce racial bias in empathic neural responses to pain. AB - Perceiving the pain of others activates similar neural structures to those involved in the direct experience of pain, including sensory and affective motivational areas. Empathic responses can be modulated by race, such that stronger neural activation is elicited by the perception of pain in people of the same race compared with another race. In the present study, we aimed to identify when racial bias occurs in the time course of neural empathic responses to pain. We also investigated whether group affiliation could modulate the race effect. Using the minimal group paradigm, we assigned participants to one of two mixed race teams. We examined event-related potentials from participants when viewing members of their own and the other team receiving painful or non-painful touch. We identified a significant racial bias in early ERP components at N1 over frontal electrodes, where Painful stimuli elicited a greater negative shift relative to Non-Painful stimuli in response to own race faces only. A long latency empathic response was also found at P3, where there was significant differentiation between Painful and Non-Painful stimuli regardless of Race or Group. There was no evidence that empathy-related brain activity was modulated by minimal group manipulation. These results support a model of empathy for pain that consists of early, automatic bias towards own-race empathic responses and a later top-down cognitive evaluation that does not differentiate between races and may ultimately lead to unbiased behaviour. PMID- 25281886 TI - Abstract and concrete categories? Evidences from neurodegenerative diseases. AB - We assessed the performance of patients with a diagnosis of Alzheimer's disease (AD) and of the semantic variant of primary progressive aphasia (sv-PPA) in a series of tasks involving both abstract and concrete stimuli, which were controlled for most of the variables that have been shown to affect performance on lexical-semantic tasks. Our aims were to compare the patients' performance on abstract and concrete stimuli and to assess category-effects within the abstract and concrete domains. The results showed: (i) a better performance on abstract than concrete concepts in sv-PPA patients. (ii) Category-related effects in the abstract domain, with emotion concepts being preserved in AD and social relations being selectively impaired in sv-PPA. In addition, a living-non living dissociation may be (infrequently) observed in individual AD patients after controlling for an extensive set of potential confounds. Thus, differences between and within the concrete or abstract domain may be present in patients with semantic memory disorders, mirroring the different brain regions involved by the different pathologies. PMID- 25281887 TI - Role of the precuneus in the detection of incongruency between tactile and visual texture information: A functional MRI study. AB - Visual clues as to the physical substance of manufactured objects can be misleading. For example, a plastic ring can appear to be made of gold. However, we can avoid misidentifying an object's substance by comparing visual and tactile information. As compared to the spatial properties of an object (e.g., orientation), however, little information regarding physical object properties (material properties) is shared between vision and touch. How can such different kinds of information be compared in the brain? One possibility is that the visuo tactile comparison of material information is mediated by associations that are previously learned between the two modalities. Previous studies suggest that a cortical network involving the medial temporal lobe and precuneus plays a critical role in the retrieval of information from long-term memory. Here, we used functional magnetic resonance imaging (fMRI) to test whether these brain regions are involved in the visuo-tactile comparison of material properties. The stimuli consisted of surfaces in which an oriented plastic bar was placed on a background texture. Twenty-two healthy participants determined whether the orientations of visually- and tactually-presented bar stimuli were congruent in the orientation conditions, and whether visually- and tactually-presented background textures were congruent in the texture conditions. The texture conditions revealed greater activation of the fusiform gyrus, medial temporal lobe and lateral prefrontal cortex compared with the orientation conditions. In the texture conditions, the precuneus showed greater response to incongruent stimuli than to congruent stimuli. This incongruency effect was greater for the texture conditions than for the orientation conditions. These results suggest that the precuneus is involved in detecting incongruency between tactile and visual texture information in concert with the medial temporal lobe, which is tightly linked with long-term memory. PMID- 25281888 TI - Processing lexical ambiguity in sentential context: Eye-tracking data from brain damaged and non-brain-damaged individuals. AB - The purpose of the present study was to identify general and syndrome-specific deficits in the lexical processing of individuals with non-fluent and fluent aphasia compared to individuals without cognitive, neurological or language impairments. The time course of lexical access, as well as lexical selection and integration was studied using a visual-world paradigm in three groups of Russian speakers: 36 individuals in the control group, 15 individuals with non-fluent aphasia and eight individuals with fluent aphasia. Participants listened to temporarily ambiguous sentences wherein the context biased the interpretation of an ambiguous word toward one of its two meanings. In half of the experimental sentences, a reanalysis was needed upon encountering the disambiguating phrase. The effect of the length of the intervening material between the ambiguous word and the disambiguation point was additionally monitored. All groups of participants showed intact lexical access under slowed speech rate, but non fluent participants experienced difficulties with timely activation of multiple referents. At later stages of lexical processing, they additionally demonstrated a specific impairment of reanalysis. The deficit in participants with fluent aphasia was not focalized at any specific stage of lexical processing. Rather, the breakdown of lexical processes in fluent aphasia was likely related to difficulties with the inhibition of irrelevant lexical activation, which is further supported by the finding that increased phonological distance between the ambiguous word and ambiguity resolution was influential to the offline performance in this group. PMID- 25281889 TI - Alexithymic features and the labeling of brief emotional facial expressions - An fMRI study. AB - The ability to recognize subtle facial expressions can be valuable in social interaction to infer emotions and intentions of others. Research has shown that the personality trait of alexithymia is linked to difficulties labeling facial expressions especially when these are presented with temporal constraints. The present study investigates the neural mechanisms underlying this deficit. 50 young healthy volunteers had to label briefly presented (<=100ms) emotional (happy, angry, fearful) facial expressions masked by a neutral expression while undergoing functional magnetic resonance imaging (fMRI). A multi-method approach (20-Item Toronto Alexithymia Scale and Toronto Structured Interview for Alexithymia) was administered to assess alexithymic tendencies. Behavioral results point to a global deficit of alexithymic individuals in labeling brief facial expressions. Alexithymia was related to decreased response of the ventral striatum to negative facial expressions. Moreover, alexithymia was associated with lowered activation in frontal, temporal and occipital cortices. Our data suggest that alexithymic individuals have difficulties in creating appropriate representations of the emotional state of other persons under temporal constraints. These deficiencies could lead to problems in labeling other people's facial emotions. PMID- 25281890 TI - Duplex Real-time PCR assay and SYBR green I melting curve analysis for molecular identification of HPV genotypes 16, 18, 31, 35, 51 and 66. AB - Long-term infection with high-risk HPV genotypes is the leading cause of cervical cancer. In the present study a Duplex Real-time PCR assay was developed in order to identify HPV types 16, 18, 31, 35, 51 and 66 in three reactions, through SYBR green I melting curve analysis. The method utilizes type-specific primer sets that allowed the amplification of highly conserved regions of L1 gene. Reconstitution experiments were conducted by using HPV DNA plasmids in order to determine the sensitivity of the assay. The newly designed assay has a limit of detection of 10 copies per reaction. The most prevalent HPV genotype in single and in multiple HPV infections was HPV16 followed by HPV18, HPV51, HPV31, HPV35 and HPV66. The proposed method is a simple, specific, sensitive and cost effective assay that can be easily incorporated in small and medium size laboratories for the rapid identification of the most clinically important HPV genotypes. PMID- 25281891 TI - Pulmonary vein isolation as index procedure for persistent atrial fibrillation: One-year clinical outcome after ablation using the second-generation cryoballoon. AB - BACKGROUND: No data are available about the clinical outcome of pulmonary vein isolation (PVI) as an index procedure for persistent atrial fibrillation (PersAF) ablation using the second-generation cryoballoon (CB-Adv). OBJECTIVE: The purpose of this study was to assess the 1-year efficacy of PVI as an index procedure for PersAF ablation using the novel CB-Adv. METHODS: Sixty-three consecutive patients (45 male [71.4%], mean age 62.7 +/- 9.7 years) with drug-refractory PersAF undergoing PVI using the novel CB-Adv were enrolled. Follow-up was based on outpatient clinic visits including Holter ECGs. Recurrence of atrial tachyarrhythmias (ATas) was defined as a symptomatic or documented episode >30 seconds. RESULTS: A total of 247 PVs were identified and successfully isolated with a mean of 1.7 +/- 0.4 freezes. Mean procedural and fluoroscopy times were 87.1 +/- 38.2 minutes and 14.9 +/- 6.1 minutes, respectively. Among 26 of 63 patients (41.3%) presenting with AF at the beginning of the procedure, 7 of 26 (26.9%) converted to sinus rhythm during ablation. Phrenic nerve palsy occurred in 4 of 63 patients (6.3%). At 1-year follow-up, after a 3-month blanking period (BP), 38 of 63 patients (60.3%) were in sinus rhythm. Because of ATa recurrences, 9 patients underwent a second procedure with radiofrequency ablation showing a pulmonary vein reconnection in 4 right-sided PVs (44.4%) and 3 left-sided PVs (33.3%). Multivariate analysis demonstrated that PersAF duration (P = .01) and relapses during BP (P = .04) were independent predictors of AT recurrences. CONCLUSION: At 1-year follow-up, freedom from ATas following PersAF ablation with the novel CB-Adv is 60%. Phrenic nerve palsy is the most common complication. PersAF duration and relapses during the BP appear to be significant predictors of arrhythmic recurrences. PMID- 25281892 TI - Incidence of sudden cardiac death in high school athletes: Implications for cardiovascular screening. PMID- 25281893 TI - Atrial fibrillation ablation, sinus rhythm, and cardiovascular mortality. PMID- 25281894 TI - Compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD. AB - BACKGROUND: Corticosteroids have been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, whether inhaled corticosteroids (IC) alone have similar effects with systemic corticosteroid (SCS) is still unclear. OBJECTIVES: To compare the efficacy of inhaled budesonide and systemic methylprednisolone on systemic inflammation of AECOPD. METHODS: 30 AECOPD patients were randomly divided into two group. Budesonide group (15 cases) were treated with inhaled budesonide (3 mg Bid); methylprednisolone group (15 cases) were treated with systemic methylprednisolone (methylprednisolone acetate injectable suspension 40 mg Qd for three days and then methylprednisolone tablets 8 mg Bid). Observe symptoms, lung function, blood gas analysis and adverse effects of the patients in two groups. Peripheral blood samples were collected before and after treatment for 1 day, 4 days and 7 days. Interleukin-8 (IL-8) and TNF-alpha levels were determined by an enzyme linked immunosorbent assay (ELISA). Hs-CRP levels were detected by automatic biochemical analyzer. Western blotting was used to determine histone deacetylase 2 (HDAC2) protein expression. MEASUREMENTS AND MAIN RESULTS: Symptoms, pulmonary function and blood gas analysis were significantly improved after treatment in the two groups (P < 0.05) and no significant differences between the two groups (P > 0.05). There were no significant differences of IL-8, TNF-alpha and hs-CRP levels in the two groups (P > 0.05). Besides, the levels of HDAC2 protein expression before treatment were significantly lower comparing to that after treatment for 4 and 7 days. Incidence of adverse events (heart rate, blood pressure, glycemic, sleep condition, gastrointestinal symptoms) in budesonide group was lower than methylprednisolone group (P < 0.05). CONCLUSIONS: Inhaled budesonide and systemic methylprednisolone have the same effects on systemic inflammation of AECOPD. Inhaled corticosteroid alone could instead systemic corticosteroid in AECOPD treatment. PMID- 25281895 TI - Signaling pathway underlying the octopaminergic modulation of myogenic contraction in the cricket lateral oviduct. AB - Octopamine (OA), a biogenic monoamine, is a neurotransmitter and neuromodulator in invertebrates. Here, we report the effect of OA on the spontaneous rhythmic contractions (SRCs) of the lateral oviduct of the cricket Gryllus bimaculatus and the possible signaling pathway involved. Application of OA increased both the frequency and amplitude of SRCs in a dose-dependent manner. The effect of OA was inhibited by subsequent application of the OA receptor antagonist epinastine, indicating that the action of OA is mediated by OA receptor. To investigate the predominant signaling pathway underlying the action of OA, we first examined a possible involvement of the cAMP/cAMP-dependent protein kinase A (PKA) signaling pathway. Application of the membrane-permeable cAMP analog 8-Br-cAMP had little effect on SRCs and the effect of OA was not influenced by subsequent application of the PKA inhibitor H89, indicating that the cAMP/PKA signaling pathway is not the predominant pathway in the action of OA. Next, we examined a possible involvement of the second messenger inositol 1,4,5-trisphosphate in the action of OA. The effect of OA on SRCs was inhibited by subsequent application of the phosphoinositide-specific phospholipase C (PLC) inhibitor U73122, indicating that the PLC pathway is involved in the action of OA. The OA-induced increase in the frequency of SRCs was inhibited by pretreatment of the cell with the ryanodine receptor antagonist tetracaine but was not significantly affected by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB). On the other hand, the OA-induced increase in the amplitude of SRCs was inhibited by pretreatment of the cells with 2-APB but was not significantly affected by tetracaine. Taken together, these results suggest that the OA-induced excitatory effect on SRCs is mediated by the PLC signaling pathway: Ca2+ release from IP3 receptors may contribute to the modulation of the amplitude of SRCs, whereas Ca2+ release from ryanodine receptors may contribute to the modulation of the frequency of SRCs. PMID- 25281896 TI - First steps in exploring prospective exome sequencing of consanguineous couples. AB - Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples. PMID- 25281897 TI - High-level expression of LMW-GS and alpha-gliadin genes promoted by the expressed tag sequence of 5' end in Escherichia coli. AB - Wheat storage protein genes, especially low molecular weight glutenin subunit (LMW-GS) and gliadin genes are difficult to be expressed in Escherichiacoli, mainly due to the presence of highly repetitive sequences. In order to establish a high efficiency expression system for these genes, five different expression plasmids combining with 9 genes, viz. 6 LMW-GS and 3 alpha-gliadin genes isolated from common wheat and related species, were studied for heterologous expression in E. coli. In this study, when an expressed tag sequence encoding signal peptide, His-S or GST-tag was fused to the 5' end of LMW-GS or gliadin gene as the leading sequence, all recombination genes could be stably expressed at a high level. On the contrast, as expected, the inserted genes encoding mature protein failed without an expressed tag sequence. This result indicated that using expressed tag sequences as leading sequences could promote LMW-GS and gliadin genes to be well expressed in E. coli. Further transcriptional analysis by quantitative real-time PCR (qRT-PCR) showed transcription levels of recombination genes (e.g. GST-Glutenin, His-S-Glutenin and SP(*)-His-Glutenin) were 4-fold to 33-fold higher than those of the LMW-GS genes, which suggested these expressed tag sequences might play an important role in stimulating transcription. The possible molecular mechanism under this phenomenon was discussed. PMID- 25281898 TI - 3, 3'-Diindolylmethane alleviates steatosis and the progression of NASH partly through shifting the imbalance of Treg/Th17 cells to Treg dominance. AB - This study was designed to discuss the effects of 3, 3'-diindolylmethane (DIM) on methionine-choline-deficient (MCD)-diet induced mouse nonalcoholic steatohepatitis (NASH) and the potential mechanisms. NASH mice were administrated with or without DIM at different concentrations for 8 weeks. Both the in-vivo and in-vitro effects of DIM on Treg/Th17 imbalance during NASH progression were analyzed. The in-vivo blocking of CD25 or IL-17 was performed to respectively deplete respective function of Treg or Th17 subset. Besides, with the assistance of AhR antagonist CH223191 and anti-TLR4 neutralizing antibody, we designed the in-vitro DIM-incubation experiments to discuss the roles of aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1B1) and toll-like receptor 4 (TLR4) on DIM's effects when shifting Treg/Th17 imbalance. Notably, in NASH mouse models, DIM alleviated hepatic steatosis and inflammation, and shifted the Treg/Th17 imbalance from MCD diet-induced Th17 dominance to Treg dominance. In-vitro, DIM not only significantly up-regulated the mRNAs of Foxp3 (Treg-specific) in purified spleen CD4(+) T cells, but also enhanced the immunosuppressive function of these Treg cells. Besides, DIM significantly up-regulated the proteins of CYP1A1 and CYP1B1 whereas down-regulated those of TLR4 on CD4(+) T cells from MCD-diet mice. Moreover, blocking AhR attenuated while blocking TLR4 enhanced the effects of DIM when regulating Treg/Th17 imbalance. Conclusively, DIM could be used as a potential therapeutic candidate to treat NASH based on its dramatic induction of Treg dominance to alleviate intra-hepatic inflammation, suggesting us a clue that the dietary cruciferous vegetables (containing abundant DIM) might exist as a protective factor for patients with NASH-related liver diseases. PMID- 25281899 TI - alpha7 Nicotinic acetylcholine receptor-specific antibody stimulates interleukin 6 production in human astrocytes through p38-dependent pathway. AB - alpha7 Nicotinic acetylcholine receptors (alpha7 nAChRs) are involved in regulating inflammatory cytokine production in macrophages and astrocytes. In the present paper, it is shown that alpha7-specific agonists PNU282987 (130nM) or choline (1.6mM) attenuated the interleukin-6 (IL-6) production stimulated by bacterial lipopolysaccharide in monocyte-derived U937 and astrocyte-derived U373 cell lines. In contrast, alpha7(179-190)-specific antibody, which bound to and was internalized by U373 cells, stimulated IL-6 production in p38 kinase dependent manner in the absence of lipopolysaccharide. The antibody effect was not due to its Fc-fragment because similar capacity was found for recombinant single-chain (scFv) alpha7(179-190)-specific antibody selected from the gene library of healthy human subject. The data obtained allow suggesting that alpha7 specific antibody can provoke neuroinflammation within the brain by inducing IL-6 production in astrocytes. PMID- 25281900 TI - Cytoskeletal control of nuclear morphology and chromatin organization. AB - The nucleus is sculpted toward various morphologies during cellular differentiation and development. Alterations in nuclear shape often result in changes to chromatin organization and genome function. This is thought to be reflective of its role as a cellular mechanotransducer. Recent evidence has highlighted the importance of cytoskeletal organization in defining how nuclear morphology regulates chromatin dynamics. However, the mechanisms underlying cytoskeletal control of chromatin remodeling are not well understood. We demonstrate here the differential influence of perinuclear actin- and microtubule driven assemblies on nuclear architecture using pharmacological inhibitors and targeted RNA interference knockdown of cytoskeleton components in Drosophila cells. We find evidence that the loss of perinuclear actin assembly results in basolateral enhancement of microtubule organization and this is reflected functionally by enhanced nuclear dynamics. Cytoskeleton reorganization leads to nuclear lamina deformation that influences heterochromatin localization and core histone protein mobility. We also show that modulations in actin-microtubule assembly result in differential gene expression patterns. Taken together, we suggest that perinuclear actin and basolateral microtubule organization exerts mechanical control on nuclear morphology and chromatin dynamics. PMID- 25281901 TI - The temporal expression of estrogen receptor alpha-36 and runx2 in human bone marrow derived stromal cells during osteogenesis. AB - During bone maintenance in vivo, estrogen signals through estrogen receptor (ER) alpha. The objectives of this study were to investigate the temporal expression of ERalpha36 and ascertain its functional relevance during osteogenesis in human bone marrow derived stromal cells (BMSC). This was assessed in relation to runt related transcription factor-2 (runx2), a main modulatory protein involved in bone formation. ERalpha36 and runx2 subcellular localisation was assessed using immunocytochemistry, and their mRNA expression levels by real time PCR throughout the process of osteogenesis. The osteogenically induced BMSCs demonstrated a rise in ERalpha36 mRNA during proliferation followed by a decline in expression at day 10, which represents a change in dynamics within the culture between the proliferative stage and the differentiative stage. The mRNA expression profile of runx2 mirrored that of ERalpha36 and showed a degree subcellular co-localisation with ERalpha36. This study suggests that ERalpha36 is involved in the process of osteogenesis in BMSCs, which has implications in estrogen deficient environments. PMID- 25281902 TI - Suramin inhibits helicase activity of NS3 protein of dengue virus in a fluorescence-based high throughput assay format. AB - Dengue fever is a major health concern worldwide. The virus encoded non structural protein 3 (NS3) is a multifunctional protein endowed with protease, helicase, nucleoside triphosphatase (NTPase) and RNA 5' triphosphatase (RTPase) activities. Helicase activity of NS3 catalyzes the unwinding of double stranded polynucleotides by utilizing the energy released from ATP hydrolysis. As this activity is essential for replication, NS3 helicase represents an attractive drug target for developing a dengue antiviral drug. Here, we report fluorescence based molecular beacon helicase assay using a duplex RNA substrate that contains a fluorophore on the 5' end and a quencher on the 3' end of one of the strands. The assay was optimized with respect to several parameters and adapted to 384-well high-throughput screening format, with an average Z' factor of 0.65. Assay validation with a small diverse set library of 1600 compounds identified, suramin as a significant inhibitor of the helicase activity of NS3. Helicase activity deficient NS3 K199A was used in a counter-screen to identify compounds interfering with the assay. Suramin inhibited DENV (dengue virus) NS3 helicase activity with a Ki of 0.75+/-0.03MUM as a non-competitive inhibitor. The molecular beacon helicase assay together with the counter screen and suramin as a tool compound can be used to identify novel inhibitors of DENV helicase. PMID- 25281903 TI - Pseudogene CYP4Z2P 3'UTR promotes angiogenesis in breast cancer. AB - Pseudogenes have long been marked as "false" genes, which are similar with real genes but have no apparent function. The 3'UTR is well-known to regulate gene expression post-transcriptionally. Our recent evidence, however, indicates novel functional roles of pseudogene CYP4Z2P 3'UTR (Z2P-UTR). We found that ectopic expression of Z2P-UTR in breast cancer cells significantly increased the expression of VEGF-A without affecting cell proliferation in vitro. Meanwhile, conditioned medium (CM) from Z2P-UTR overexpression cells enhanced proliferation, migration and tube formation of HUVEC, and promoted angiogenesis in ex vivo models. Also, CM increased the expression of VEGFR2 in HUVEC. Our data suggest that Z2P-UTR can promote breast cancer angiogenesis partly via paracrine pathway of VEGF-A/VEGFR2. PMID- 25281904 TI - Disease burden of selected gastrointestinal pathogens in Australia, 2010. AB - OBJECTIVE: To estimate and compare disease burden attributable to six gastrointestinal pathogens (norovirus, rotavirus, Campylobacter, non-typhoidal Salmonella, Giardia, and Cryptosporidium) in Australia, 2010. METHODS: We estimated the number of acute gastroenteritis (AGE) cases and deaths, disability adjusted life years (DALYs), and DALY/case for each pathogen. We included AGE cases that did not require medical care. Sequelae were included for Campylobacter (Guillain-Barre syndrome, reactive arthritis (ReA), irritable bowel syndrome (IBS)) and Salmonella (ReA, IBS). RESULTS: We estimated 16626069 AGE cases in Australia in 2010 (population 22 million). Of the pathogens studied, most AGE cases were attributed to norovirus (2180145), Campylobacter (774003), and Giardia (614740). Salmonella caused the fewest AGE cases (71255) but the most AGE deaths (90). The DALY burden was greatest for Campylobacter (18222 DALYs) and Salmonella (3856 DALYs), followed by the viral and protozoal pathogens. The average DALY/case was greatest for Salmonella (54.1 DALY/1000 cases), followed by Campylobacter (23.5 DALY/1000 cases). CONCLUSIONS: The pathogen causing the greatest disease burden varied according to the metric used, however DALYs are considered most useful given the incorporation of morbidity, mortality, and sequelae. These results can be used to prioritize public health interventions toward Salmonella and Campylobacter infections and to measure the impact of these interventions. PMID- 25281905 TI - Better adherence to pre-antiretroviral therapy guidelines after implementing an electronic medical record system in rural Kenyan HIV clinics: a multicenter pre post study. AB - INTRODUCTION: The monitoring of pre-antiretroviral therapy (pre-ART) is a key indicator of HIV quality of care. This study investigated the association of an electronic medical record system (EMR) with adherence to pre-ART guidelines in rural HIV clinics in Kenya. METHODS: A retrospective study was carried out to assess the quality of pre-ART care using three indicators: (1) the performance of a baseline CD4 test, (2) time from enrollment in care to first CD4 test, and (3) time from baseline CD4 to second CD4 test. A comparison of these indicators was made pre and post the introduction of an EMR system in 17 rural HIV clinics. RESULTS: A total of 18523 patients were receiving pre-ART care, of whom 38.8% in the paper group had had at least one CD4 test compared to 53.4% in the EMR group (p<0.001). The adjusted odds of performing a CD4 test in clinics using an EMR was 1.59 (95% confidence interval 1.49-1.69). The median time from enrolment into HIV care to first CD4 test was 1.40 months (interquartile range (IQR) 0.47-4.87) for paper vs. 0.93 months (IQR 0.43-3.37) for EMR. The median time from baseline to first CD4 follow-up was 7.5 months (IQR 5.97-10.73) for paper and 6.53 months (IQR 5.57-7.87) for EMR. CONCLUSION: The use of the EMR system was associated with better compliance to HIV guidelines for pre-ART care. EMRs have a potential positive impact on quality of care for HIV patients in resource-constrained settings. PMID- 25281907 TI - Out-of-hospital cardiac arrest phone detection: those who most need chest compressions are the most difficult to recognize. AB - Dispatcher-assisted cardiopulmonary resuscitation increases the likelihood of survival and thus is highly recommended. However, the detection rate of out-of hospital cardiac arrest (OHCA) is very different from one system to another, and early recognition of cardiac arrest in the dispatch centre remains challenging. The aim of this study was to assess the provision of dispatcher-assisted cardiopulmonary resuscitation in the main French dispatch centre. METHODS: In the Paris Fire Brigade, each patient over 15 years of age who presented an OHCA from 15 to 31 May 2012 was prospectively included. Field data and tape recordings of emergency calls were studied by three experienced physicians, to assess the rate (and delay) of OHCA recognition and chest compression initiation, and identify the causes of unrecognized OHCA. RESULTS: Among 82 consecutive calls for detectable cardiac arrest, the dispatcher recognized 50/82 (61%). The median times from call to OHCA recognition and from call to chest compression initiation were, respectively, 2 min 23s (1 min 51 s to 3 min 7s) and 3 min 37s (2 min 57 s to 5 min). The main causes of non-recognition of OHCA were the absence or incomplete assessment of breathing and the presence of agonal breathing. No cardiac arrest was missed when the dispatcher followed the local dispatch algorithm; this included the gesture of putting the hand on the abdomen and measuring the breathing frequency. Hospital admission with a beating heart was paradoxically 18% for detected cardiac arrest and 47% for undetected cardiac arrest (p=0.007). This paradox could be explained by the relation between agonal breathing and, on the one hand, good prognosis of OHCA and, on the other hand, difficulties in recognizing OHCA. CONCLUSION: The improvement of cardiac arrest recognition in the dispatch centre seemed mandatory, as the cardiac arrests of better immediate prognosis were not well detected. The measurement of OHCA recognition and CPR initiation by phone should be encouraged in dispatch centres as a key to initiating corrective measures. PMID- 25281906 TI - Anaesthetic Postconditioning at the Initiation of CPR Improves Myocardial and Mitochondrial Function in a Pig Model of Prolonged Untreated Ventricular Fibrillation. AB - BACKGROUND: Anaesthetic postconditioning (APoC) attenuates myocardial injury following coronary ischaemia/reperfusion. We hypothesised that APoC at the initiation of cardiopulmonary resuscitation (CPR) will improve post resuscitation myocardial function along with improved mitochondrial function in a pig model of prolonged untreated ventricular fibrillation. METHODS: In 32 pigs isoflurane anaesthesia was discontinued prior to induction of ventricular fibrillation that was left untreated for 15 min. At the initiation of CPR, 15 animals were randomised to controls (CON), and 17 to APoC with 2 vol% sevoflurane during the first 3 min CPR. Pigs were defibrillated after 4 min of CPR. After return of spontaneous circulation (ROSC), isoflurane was restarted at 0.8-1.5 vol% in both groups. Systolic and diastolic blood pressures were measured continuously. Of the animals that achieved ROSC, eight CON and eight APoC animals were randomised to have their left ventricular ejection fraction (LVEF%) assessed by echocardiography at 4h. Seven CON and nine APoC were randomised to euthanasia 15 min after ROSC to isolate mitochondria from the left ventricle for bioenergetic studies. RESULTS: ROSC was achieved in 10/15 CON and 15/17 APoC animals. APoC improved haemodynamics during CPR and post-CPR LVEF%. Mitochondrial ATP synthesis, coupling of oxidative phosphorylation and calcium retention capacity were improved in cardiac mitochondria isolated after APoC. CONCLUSIONS: In a porcine model of prolonged untreated cardiac arrest, APoC with inhaled sevoflurane at the initiation of CPR, is associated with preserved mitochondrial function and improved post resuscitation myocardial dysfunction. Approved by the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation of Hennepin County Medical Center (protocol number 11-05). PMID- 25281909 TI - One precursor, three apolipoproteins: the relationship between two crustacean lipoproteins, the large discoidal lipoprotein and the high density lipoprotein/beta-glucan binding protein. AB - The novel discoidal lipoprotein (dLp) recently detected in the crayfish, differs from other crustacean lipoproteins in its large size, apoprotein composition and high lipid binding capacity, We identified the dLp sequence by transcriptome analyses of the hepatopancreas and mass spectrometry. Further de novo assembly of the NGS data followed by BLAST searches using the sequence of the high density lipoprotein/1-glucan binding protein (HDL-BGBP) of Astacus leptodactylus as query revealed a putative precursor molecule with an open reading frame of 14.7 kb and a deduced primary structure of 4889 amino acids. The presence of an N-terminal lipid bind- ing domain and a DUF 1943 domain suggests the relationship with the large lipid transfer proteins. Two-putative dibasic furin cleavage sites were identified bordering the sequence of the HDL-BGBP. When subjected to mass spectroscopic analyses, tryptic peptides of the large apoprotein of dLp matched the N-terminal part of the precursor, while the peptides obtained for its small apoprotein matched the C-terminal part. Repeating the analysis in the prawn Macrobrachium rosenbergii revealed a similar protein with identical domain architecture suggesting that our findings do not represent an isolated instance. Our results indicate that the above three apolipoproteins (i.e HDL-BGBP and both the large and the small subunit of dLp) are translated as a large precursor. Cleavage at the furin type sites releases two subunits forming a heterodimeric dLP particle, while the remaining part forms an HDL-BGBP whose relationship with other lipoproteins as well as specific functions are yet to be elucidated. PMID- 25281908 TI - What you see depends on what you saw, and what else you saw: the interactions between motion priming and object priming. AB - Both visual object priming and motion priming have been reported independently, but the interactions between the two are still largely unexplored. Here we investigated this question using a novel type of SFM stimuli, 3-D helixes, and found that the motion direction perception of an ambiguous helix can be biased by the motion direction of a preceding SFM stimulus - a classic motion priming effect. However, the effectiveness of motion priming depends on object priming: a neutral object priming produced a weak motion priming, a congruent object priming led to a strong motion priming, and critically, an incongruent object priming abolished and overpowered the motion priming. In contrast, object priming alone (in the absence of motion overlap) had little effects biasing motion perception. Taken together, these results suggest that there exists an integrated neural representation of motion and structure of 3-D SFM stimuli, and motion priming of 3-D SFM stimuli might happen at an intermediate stage between MT/V5 (which is not shape selective) and LO (lateral occipital, which is not motion selective). This novel type of stimuli, 3-D helixes, along with the prime-target paradigm, thus might offer a unique tool to examine neural bases underlying the perception of 3 D SFM stimuli and perceptual priming. PMID- 25281911 TI - Localization of VE-cadherin in plasmalemmal cholesterol rich microdomains and the effects of cholesterol depletion on VE-cadherin mediated cell-cell adhesion. AB - VE-cadherin is the predominant adhesion molecule in vascular endothelial cells being responsible for maintenance of the endothelial barrier function by forming adhesive contacts (adherens junctions) to neighbouring cells. We found by use of single molecule fluorescence microscopy that VE-cadherin is localised in preformed clusters when not inside adherens junctions. These clusters depend on the integrity of the actin cytoskeleton and are localised in cholesterol rich microdomains of mature endothelial cells as found by membrane fractionation. The ability to form and maintain VE-cadherin based junctions was probed using the laser tweezer technique, and we found that cholesterol depletion has dramatical effects on VE-cadherin mediated adhesion. While a 30% reduction of the cholesterol-level results in an increase of adhesion, excessive cholesterol depletion by about 60% leads to an almost complete loss of VE-cadherin function. Nevertheless, the cadherin concentration in the membrane and the single molecule kinetic parameters of the cadherin are not changed. Our results suggest that the actin cytoskeleton, junction-associated proteins and protein-lipid assemblies in cholesterol-rich micro-domains mutually stabilise each other to form functional adhesion contacts. PMID- 25281910 TI - Fluorescence study of domain structure and lipid interaction of human apolipoproteins E3 and E4. AB - Human apolipoprotein E (apoE) isoforms exhibit different conformational stabilities and lipid-binding properties that give rise to altered cholesterol metabolism among the isoforms. Using Trp-substituted mutations and site- directed fluorescence labeling, we made a comprehensive comparison of the conformational organization of the N- and C-terminal domains and lipid interactions between the apoE3 and apoE4 isoforms. Trp fluorescence measurements for selectively Trp substituted variants of apoE isoforms demonstrated that apoE4 adopts less stable conformations in both the N- and C-terminal domains compared to apoE3. Consistent with this, the conformational reorganization of the N-terminal helix bundle occurs at lower guanidine hydrochloride concentration in apoE4 than in apoE3 as monitored by fluorescence resonance energy transfer (FRET) from Trp residues to acrylodan attached at the N-terminal helix. Upon binding of apoE3 and apoE4 variants to egg phosphatidylcholine small unilamellar vesicles, similar changes in Trp fluorescence or FRET efficiency were observed for the isoforms, indi- cating that the opening of the N-terminal helix bundle occurs similarly in apoE3 and apoE4. Introduction of mutations into the C-terminal domain of the apoE isoforms to prevent self-association and maintain the monomeric state resulted in great increase in the rate of binding of the C-terminal helices to a lipid surface. Overall, our results demonstrate that the different conformational organizations of the N- and C-terminal domains have a minor effect on the steady state lipid-binding behavior of apoE3 and apoE4: rather, self-association property is a critical determinant in the kinetics of lipid binding through the C terminal helices of apoE isoforms. PMID- 25281912 TI - Cuscuta chinensis Lam.: A systematic review on ethnopharmacology, phytochemistry and pharmacology of an important traditional herbal medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cuscuta chinensis Lam. has found its use as a traditional medicine in China, Korea, Pakistan, Vietnam, India and Thailand. It is commonly used as an anti-aging agent, anti-inflammatory agent, pain reliever and aphrodisiac. To provide an overview of the ethnopharmacology, phytochemistry, pharmacokinetics, pharmacology and clinical applications of Cuscuta chinensis, as well as being an evidence base for further research works of the plant. MATERIALS AND METHODS: The present review covers the literature available from 1985 to 2014. The information was collected from journals, books, theses and electronic search (Google Scholar, PubMed, ScienceDirect, ESBCO, Springerlink and CNKI). Literature abstracts and full-text articles were analyzed and included in the review. RESULTS: Many phytochemicals have been isolated, identified and published to date, including: at least 18 flavonoids; 13 phenolic acids; 2 steroids; 1 hydroquinone; 10 volatile oils; 22 lignans; 9 polysaccharides; 2 resin glycosides; 16 fatty acids. These phytochemicals and plant extracts exhibit a range of pharmacological activities that include hepatoprotective, renoprotective, antiosteoporotic, antioxidant, anti-aging, antimutagenic, antidepressant, improve sexual function, abortifacient effects, etc. CONCLUSION: This present review offers primary information for further studies of Cuscuta chinensis. The in vitro studies and in vivo models have provided a bioscientific explanation for its various ethnopharmacological uses and pharmacological activities (most notably antioxidant effects) especially in the prevention of hepatic disease and renal failure. It is necessary and important to do more pharmacokinetic and toxicological research works on human subjects in order to inform the possible active compounds in the body and validate its safety in clinical uses. PMID- 25281913 TI - Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis. AB - Among the various respiratory viruses infecting human beings, coronaviruses are important pathogens, which usually infect the upper respiratory tract, where they are mainly associated with common colds. However, in more vulnerable populations, such as newborns, infants, the elderly and immune-compromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, leading to pneumonia, exacerbations of asthma, and various types of respiratory distress syndrome. The respiratory involvement of human coronaviruses has been clearly established since the 1960s. Nevertheless, for almost three decades now, data reported in the scientific literature has also demonstrated that, like it was described for other human viruses, coronaviruses have neuroinvasive capacities since they can spread from the respiratory tract to the central nervous system (CNS). Once there, infection of CNS cells (neurotropism) could lead to human health problems, such as encephalitis and long-term neurological diseases. Neuroinvasive coronaviruses could damage the CNS as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals (virus-induced neuroimmunopathology) and/or viral replication, which directly induces damage to CNS cells (virus-induced neuropathology). Given all these properties, it has been suggested that these opportunistic human respiratory pathogens could be associated with the triggering or the exacerbation of neurologic diseases for which the etiology remains poorly understood. Herein, we present host and viral factors that participate in the regulation of the possible pathogenic processes associated with CNS infection by human coronaviruses and we try to decipher the intricate interplay between virus and host target cells in order to characterize their role in the virus life cycle as well as in the capacity of the cell to respond to viral invasion. PMID- 25281914 TI - Formulation, characterisation and in vitro studies of doxorubicin-loaded silica polydimethylsiloxane granules. AB - The goal was to develop a granule-type formulation, characterised as a long-term, zero-order release delivery system for doxorubicin hydrochloride (DOX) and composed of a sol-gel derived silica-polydimethylsiloxane solid matrix with well defined microstructures. The preparation of the DOX-loaded granule-type formulation was performed using the sol-gel moulding method. A liquid-form of DOX was added to the sol before moulding. Optical microscopy, X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and N2 adsorption/desorption studies were employed to characterise the obtained formulation. The influence of different drug loads of DOX per granule (136, 336 and 555MUg) on the release profiles was assessed on a USP Apparatus 4 dissolution and via UV/Vis end analysis. The in vitro mineralisation of these formulations associated with the nucleation of the apatite layer on their surface was also examined. The semi-ellipse shape and micrometer-size of the DOX-loaded granule type formulation was successfully obtained. These formulations exhibited a mesoporous structure, uniform pore size distribution and good monodispersity. Following an initial burst, the slow drug release from all formulations followed zero order kinetics under infinite sink conditions for over 70days. Besides the formulation's potential properties as a carrier, the material was also surface reactive during in vitro mineralisation. PMID- 25281915 TI - Poly(I:C) as cancer vaccine adjuvant: knocking on the door of medical breakthroughs. AB - Although cancer vaccination has yielded promising results in patients, the objective response rates are low. The right choice of adjuvant might improve the efficacy. Here, we review the biological rationale, as well as the preclinical and clinical results of polyinosinic:polycytidylic acid and its derivative poly ICLC as cancer vaccine adjuvants. These synthetic immunological danger signals enhanced vaccine-induced anti-tumor immune responses and contributed to tumor elimination in animal tumor models and patients. Supported by these results, poly ICLC-containing cancer vaccines are currently extensively studied in the ongoing trials, making it highly plausible that poly-ICLC will be part of the future approved cancer immunotherapies. PMID- 25281916 TI - Tribological and material properties for cartilage of and throughout the bovine stifle: support for the altered joint kinematics hypothesis of osteoarthritis. AB - OBJECTIVE: Prior studies suggest that ligament and meniscus tears cause osteoarthritis (OA) when changes in joint kinematics bring underused and underprepared regions of cartilage into contact. This study aims to test the hypothesis that material and tribological properties vary throughout the joint according to the local mechanical environment. METHOD: The local tribological and material properties of bovine stifle cartilage (N = 10 joints with 20 samples per joint) were characterized under physiologically consistent contact stress and fluid pressure conditions. RESULTS: Overall, cartilage from the bovine stifle had an equilibrium contact modulus of Ec0 = 0.62 +/- 0.10 MPa, a tensile modulus of Et = 4.3 +/- 0.7 MPa, and a permeability of k = 2.8 +/- 0.9 * 10(-3) mm(4)/Ns. During sliding, the cartilage had an effective friction coefficient of MUeff = 0.024 +/- 0.004, an effective contact modulus of Ec = 3.9 +/- 0.7 MPa and a fluid load fraction of F' = 0.81 +/- 0.03. Tibial cartilage exhibited significantly poorer material and tribological properties than femoral cartilage. Statistically significant differences were also detected across the femoral condyle and tibial plateau. The central femoral condyle exhibited the most favorable properties while the uncovered tibial plateau exhibited the least favorable properties. CONCLUSIONS: Our findings support a previous hypothesis that altered loading patterns can cause OA by overloading underprepared regions. They also help explain why damage to the tibial plateau often precedes damage to the mating femoral condyle following joint injury in animal models. Because the variations are driven by fundamental biological processes, we anticipate similar variations in the human knee, which could explain the OA risk associated with ligament and meniscus tears. PMID- 25281917 TI - Combination of microRNA therapeutics with small-molecule anticancer drugs: mechanism of action and co-delivery nanocarriers. AB - MicroRNAs (miRNAs) regulate multiple molecular pathways vital for the hallmarks of cancer with a high degree of biochemical specificity and potency. By restoring tumor suppressive miRNAs or ablating oncomiRs, miRNA-based therapies can sensitize cancer cells to conventional cytotoxins and the molecularly targeted drugs by promoting apoptosis and autophagy, reverting epithelial-to-mesenchymal transition, suppressing tumor angiogenesis, and downregulating efflux transporters. The development of miRNA-based therapeutics in combination with small-molecule anticancer drugs provides an unprecedented opportunity to counteract chemoresistance and improve treatment outcome in a broad range of human cancers. This review summarizes the mechanisms and advantages for the combination therapies involving miRNAs and small-molecule drugs, as well as the recent advances in the co-delivery nanocarriers for these agents. PMID- 25281918 TI - The analysis of mutations and exon deletions at TSC2 gene in angiomyolipomas associated with tuberous sclerosis complex. AB - Angiomyolipomas (AMLs) are relatively rare hamartomatous or benign tumors that occasionally occur as part of tuberous sclerosis complex (TSC). Mutations in either of the two genes, TSC1 and TSC2, have been attributed to the development of TSC. Between 1994 and January 2009, 83 patients were diagnosed with AML at the Samsung Medical Center. In that group of patients, 5 (6%) had AML with TSC (AML TSC). Mutational analysis of the TSC2 gene was performed using 7 samples from the 5 AML-TSC patients and 14 samples from 14 patients with sporadic AML without TSC (AML-non-TSC). From this analysis, mutations in TSC genes were identified in 5 samples from the AML-TSC patients (mutation detection rate=71%) and 3 samples from AML-non-TSC patients (mutation detection rate=21%). In the case of AML-TSC, 6 mutations were found including 3 recurrent mutations and 3 novel mutations, while in the case of AML-non-TSC, 4 mutations were identified once, including 1 novel mutation. Also MLPA analysis of the TSC2 gene showed that TSC2 exon deletion is more frequently observed in AML-TSC patients than in AML-non-TSC patients. This is the first mutation and multiplex ligation-dependent probe amplification (MLPA) analyses of TSC2 in Korean AMLs that focus on TSC. This study provides data that are representative of the distribution of mutations and exon deletions at TSC genes in clinically diagnosed AML-TSC cases of the Korean population. PMID- 25281919 TI - Traumatic brachial plexus root avulsion and cervical spine epidural hematoma in an 18-year-old man. PMID- 25281920 TI - National trends in the surgical treatment for lumbar degenerative disc disease: United States, 2000 to 2009. AB - BACKGROUND CONTEXT: Surgical treatment for lumbar degenerative disc disease (DDD) remains controversial. Options include anterior lumbar interbody fusion, posterior approach fusion procedures such as posterior lumbar interbody fusion (PLIF) and posterolateral lumbar fusion (PLF), anterior and posterior lumbar fusion (APLF), and total disc replacement (TDR). However, the trends during the last decade are uncertain. PURPOSE: To examine the trends in the surgical treatment for lumbar DDD on a national level. STUDY DESIGN: A retrospective analysis of population-based national hospital discharge data collected for the Nationwide Inpatient Sample (NIS). PATIENT SAMPLE: In the NIS from 2000 to 2009, patients aged 18 years or older with primary diagnosis of lumbar/lumbosacral DDD who underwent surgical treatment were included. OUTCOME MEASURES: Trends in the surgical treatment for lumbar DDD. METHODS: Clinical data were derived from the NIS between 2000 and 2009. Patients aged 18 years or older with a primary diagnosis of lumbar/lumbosacral DDD who underwent spinal fusion or TDR were identified. Data regarding patient- and health care system-related characteristics were retrieved and analyzed. RESULTS: A total of 380,305 patients underwent surgical treatment for lumbar DDD between 2000 and 2009. Population adjusted incidence increased 2.4-fold from 2000 to 2009. Among the procedures, APLF increased 3.0-fold and PLIF/PLF increased 2.8-fold. Total disc replacement did not increase significantly. Anterior lumbar interbody fusion was performed in 16.8% of patients, PLIF/PLF in 67.9%, APLF in 13.6%, and TDR in 1.8%. Surgical treatment for lumbar DDD was 1.8 times more common in the Midwest region and 1.7 times more common in the South region than in the Northeast region. Total disc replacement was more common in younger patients and in the Northeast region. Poterior lumbar interbody fusion/PLF was more common in older patients and in the South region. CONCLUSIONS: During the last decade, surgical treatment for lumbar DDD has increased 2.4-fold in the United States. Although all fusion procedures significantly increased, TDR did not increase. Surgical treatment for lumbar DDD was more common in the Midwest and South regions. Trends in the procedures were different depending on the age group and hospital region. PMID- 25281921 TI - Breathing is affected by dopamine D2-like receptors in the basolateral amygdala. AB - The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-) sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses. PMID- 25281922 TI - A phylogeny of the only ground-dwelling radiation of Cyrtodactylus (Squamata, Gekkonidae): diversification of Geckoella across peninsular India and Sri Lanka. AB - The subgenus Geckoella, the only ground-dwelling radiation within Cyrtodactylus, closely overlaps in distribution with brookii group Hemidactylus in peninsular India and Sri Lanka. Both groups have Oligocene origins, the latter with over thrice as many described species. The striking difference in species richness led us to believe that Geckoella diversity is underestimated, and we sampled for Geckoella across peninsular India. A multi-locus phylogeny reveals Geckoella diversity is hugely underestimated, with at least seven undescribed species, doubling previously known richness. Strikingly, the new species correspond to cryptic lineages within described Indian species (complexes); a number of these endemic lineages from the hills of peninsular India outside the Western Ghats, highlighting the undocumented diversity of the Indian dry zone. The Geckoella phylogeny demonstrates deep splits between the Indian species and Sri Lankan G. triedrus, and between Indian dry and wet zone clades, dating back to the late Oligocene. Geckoella and brookii group Hemidactylus show contrasting diversification patterns. Geckoella shows signals of niche conservatism and appears to have retained its ancestral forest habitat. The late Miocene burst in speciation in Geckoella may be linked to the expansion of rain forests during the mid-Miocene climatic optimum and subsequent fragmentation with increasing late Miocene aridification. PMID- 25281923 TI - Is the extremely rare Iberian endemic plant species Castrilanthemum debeauxii (Compositae, Anthemideae) a 'living fossil'? Evidence from a multi-locus species tree reconstruction. AB - The present study provides results of multi-species coalescent species tree analyses of DNA sequences sampled from multiple nuclear and plastid regions to infer the phylogenetic relationships among the members of the subtribe Leucanthemopsidinae (Compositae, Anthemideae), to which besides the annual Castrilanthemum debeauxii (Degen, Hervier & E.Rev.) Vogt & Oberp., one of the rarest flowering plant species of the Iberian Peninsula, two other unispecific genera (Hymenostemma, Prolongoa), and the polyploidy complex of the genus Leucanthemopsis belong. Based on sequence information from two single- to low copy nuclear regions (C16, D35, characterised by Chapman et al. (2007)), the multi-copy region of the nrDNA internal transcribed spacer regions ITS1 and ITS2, and two intergenic spacer regions of the cpDNA gene trees were reconstructed using Bayesian inference methods. For the reconstruction of a multi-locus species tree we applied three different methods: (a) analysis of concatenated sequences using Bayesian inference (MrBayes), (b) a tree reconciliation approach by minimizing the number of deep coalescences (PhyloNet), and (c) a coalescent-based species-tree method in a Bayesian framework ((*)BEAST). All three species tree reconstruction methods unequivocally support the close relationship of the subtribe with the hitherto unclassified genus Phalacrocarpum, the sister-group relationship of Castrilanthemum with the three remaining genera of the subtribe, and the further sister-group relationship of the clade of Hymenostemma+Prolongoa with a monophyletic genus Leucanthemopsis. Dating of the (*)BEAST phylogeny supports the long-lasting (Early Miocene, 15-22Ma) taxonomical independence and the switch from the plesiomorphic perennial to the apomorphic annual life-form assumed for the Castrilanthemum lineage that may have occurred not earlier than in the Pliocene (3Ma) when the establishment of a Mediterranean climate with summer droughts triggered evolution towards annuality. PMID- 25281924 TI - MicroRNA-874 inhibits cell proliferation and induces apoptosis in human breast cancer by targeting CDK9. AB - It has been demonstrated that miR-874 plays important roles in many types of cancers. Nevertheless, its biological function in breast cancer remains largely unknown. In this study, we found that the expression level of miR-874 is down regulated in breast cancer in comparison with the adjacent normal tissues. The overexpression of miR-874 is able to inhibit cell proliferation and induce cell apoptosis and cell cycle arrest in MCF7 and MDA-MB-231 cells. Using a bioinformatics method, we further show that CDK9 is a direct target of miR-874 and that its protein level is negatively regulated by miR-874. Therefore, the data reported in this manuscript demonstrate that miR-874 is an important regulator in breast cancer and imply that the miR-874/CDK9 axis has potential as a therapeutic target for breast cancer. PMID- 25281925 TI - The expression of p21 is upregulated by forkhead box A1/2 in p53-null H1299 cells. AB - The expression of the cell cycle inhibitor p21 is increased in response to various stimuli and stress signals through p53-dependent and independent pathways. We demonstrate in this study that forkhead box A1/2 (FOXA1/2) is a crucial transcription factor in the activation of p21 transcription via direct binding to the p21 promoter in p53-null H1299 lung carcinoma cells. In addition, histone deacetylase inhibitor trichostatin A (TSA)-mediated upregulation of p21 expression was repressed by knockdown of FOXA1/2 in H1299 cells. Consequently, these results suggest that FOXA1/2 is required for p53-independent p21 expression. PMID- 25281927 TI - DISP3 promotes proliferation and delays differentiation of neural progenitor cells. AB - DISP3 (PTCHD2), a sterol-sensing domain-containing protein, is highly expressed in neural tissue but its role in neural differentiation is unknown. In the present study we used a multipotent cerebellar progenitor cell line, C17.2, to investigate the impact of DISP3 on the proliferation and differentiation of neural precursors. We found that ectopically expressed DISP3 promotes cell proliferation and alters expression of genes that are involved in tumorigenesis. Finally, the differentiation profile of DISP3-expressing cells was altered, as evidenced by delayed expression of neural specific markers and a reduced capacity to undergo neural differentiation. PMID- 25281926 TI - Involvement of lysosomal degradation in VEGF-C-induced down-regulation of VEGFR 3. AB - The vascular endothelial growth factor (VEGF)-C-induced down-regulation of VEGF receptor (VEGFR)-3 is important in lymphangiogenesis. Here, we demonstrate that VEGF-C, -D, and -C156S, but not VEGF-A, down-regulate VEGFR-3. VEGF-C stimulates VEGFR-3 tyrosyl phosphorylation and transient phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinases in lymphatic endothelial cells. VEGF-C-induced down-regulation of VEGFR-3 was blocked by a VEGF-C trap, tyrosine kinase inhibitor, and leupeptin, pepstatin, and E64 (LPE), but was unaffected by Notch 1 activator and gamma-secretase inhibitors. Our findings indicate that VEGF-C down-regulates VEGFR-3 in lymphatic endothelial cells through VEGFR-3 kinase activation and, in part, via lysosomal degradation. PMID- 25281929 TI - Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions. AB - Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P?.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments. PMID- 25281930 TI - Lactose intolerance genetic testing: is it useful as routine screening? Results on 1426 south-central Italy patients. AB - Adult-type hypolactasia is a widespread condition throughout the world, causing lactose malabsorption. Several studies suggested that the identification of C/T 13910 and G/A-22018 mutations, located upstream the gene encoding the lactase phlorizin hydrolase (LPH), is a useful tool for the differential diagnosis of hypolactasia. We evaluated the frequencies of C/T-13910 and G/A-22018 variants in a central-south Italian population and the usefulness of lactase deficiency genetic testing in the clinic practice. The genomic DNA of 1426 patients and 1000 healthy controls from central-south Italy was isolated from peripheral whole blood and genotyped for the C/T-13910 and G/A-22018 polymorphisms by high resolution melting analysis (HRMA) and sequencing. The frequencies of genotypes in the 1426 patients analysed were as follows: 1077 CC/GG (75.5%), 287 CT/GA (20.1%), 24 TT/AA (1.7%), 38 CC/GA (2.7%). Only 64 out of 1426 (4.5%) performed also L-BHT test, 29 of which were negative for L-BHT also in presence of different genotypes. Among the 35 individuals with L-BHT positive, 34 were CC/GG and only one CT/GA. Although lactose genetic test is a good predictor of persistence/non-persistence lactase in specific population, its use in the central-south Italy population should be limited given the high prevalence of the CCGG diplotype in normal individuals. PMID- 25281928 TI - TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. AB - Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4 antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia. PMID- 25281931 TI - Clinical application of immunomagnetic reduction for quantitative measurement of insulin-like growth factor binding protein-1 in the prediction of pregnant women with preterm premature rupture of membranes. AB - BACKGROUND: Insulin-like growth factor binding protein-1 (IGFBP-1) constitutes a subgroup of the insulin-like growth factor binding protein systems, and its concentration in amniotic fluid is 100-1000 times higher than the concentration in other body fluids. The aim of this study was to evaluate the clinical application of a novel method immunomagnetic reduction (IMR) for quantitative measurement of IGFBP-1 concentrations in the cervicovaginal secretions to diagnose pregnant women with preterm premature rupture of membranes (PPROM). METHODS: We established a standard calibration curve of IMR intensity against IGFBP-1 concentration based on standard IGFBP-1 samples. We used the IMR assay to detect IGFBP-1 concentrations in the cervicovaginal secretions of pregnant women which were divided into two groups according to the presence or absence of PPROM. RESULTS: The calibration curve extended from 0.1ng/mL to 10000ng/mL with an excellent correlation (R(2)=0.999). Twenty-two pregnant women between 22 and 34weeks of gestation were analyzed in this prospective study, of whom 10 were clinical evidence of PPROM, and 12 were intact membranes. Through the analysis of receiver-operating characteristic curve, the cut-off point for IMR to differentiate intact membranes from PPROM is 1.015%, which resulted in 90.0, 83.3, 81.8, and 90.9% for sensitivity, specificity, positive predictive value, and negative predictive value, respectively. CONCLUSIONS: It is evidenced that IMR assay can quantitatively analyze IGFBP-1 concentrations, and the results show the possibility to diagnose pregnant women with PPROM by IMR assay. PMID- 25281932 TI - Ventral hippocampal nicotinic acetylcholine receptors mediate stress-induced analgesia in mice. AB - Evidence suggests that various stressful procedures induce an analgesic effect in laboratory animals commonly referred to as stress-induced analgesia (SIA). The aim of the present study was to assess the role of ventral hippocampal (VH) nicotinic acetylcholine receptors (nAChRs) in SIA in adult male NMRI mice. The VHs of animals were bilaterally cannulated and nociceptive threshold was measured using infrared source in a tail-flick apparatus. Acute stress was evoked by placing the animals on an elevated platform for 10, 20 and 30 min. The results showed that exposure to 20 and 30 min acute stress produced analgesia, while exposure to 10 min stress had no effect on the pain response. Intra-VH microinjection of nicotine (0.001-0.1 MUg/mouse), 5 min before an ineffective stress (10 min stress), induced analgesia, suggesting the potentiative effect of nicotine on SIA. It is important to note that bilateral intra-VH microinjections of the same doses of nicotine without stress had no effect on the tail-flick test. On the other hand, intra-VH microinjection of mecamylamine (0.5-1 MUg/mouse) 5 min before 20-min stress inhibited SIA. However, bilateral intra-VH microinjections of the same doses of mecamylamine without stress had no effect on the tail-flick response. In addition, the microinjection of mecamylamine into the VH reversed the potentiative effect of nicotine on SIA. Taken together, it can be concluded that exposure to acute stress induces SIA in a time-dependent manner and the ventral hippocampal cholinergic system may be involved in SIA via nAChRs. PMID- 25281933 TI - Tongue images and tongue coating microbiome in patients with colorectal cancer. AB - BACKGROUND: Tongue diagnosis, as a unique method of traditional Chinese medicine (TCM), discriminates physiological functions and pathological conditions by observing the changes of the tongue coating. AIMS: To evaluate the differences of tongue images and tongue coating microbiome between patients with colorectal cancer and healthy people. METHODS: The tongue diagnostic information acquisition system was used to photograph the tongue images and analyze the thickness of the tongue coatings in patients with colorectal cancer and healthy people. The next generation sequencing technology was used to determine the V2-V4 hypervariable region of 16S rDNA to investigate the microbial community structure and diversity on the tongue coating. RESULTS: The tongue coatings in patients with colorectal cancer were obvious thickening compared with tongue images in healthy people. The microbial community structure on the tongue coating was different between patients with colorectal cancer and healthy people. CONCLUSION: Tongue diagnosis may provide important leads towards novel microbiome-related diagnostic tools and tongue coating microbiome may be a novel biomarker for characterizing patient with colorectal cancer. PMID- 25281934 TI - Spatial and molecular cues for cell outgrowth during C. elegans uterine development. AB - The Caenorhabditis elegans uterine seam cell (utse) is an H-shaped syncytium that connects the uterus to the body wall. Comprising nine nuclei that move outward in a bidirectional manner, this synctium undergoes remarkable shape change during development. Using cell ablation experiments, we show that three surrounding cell types affect utse development: the uterine toroids, the anchor cell and the sex myoblasts. The presence of the anchor cell (AC) nucleus within the utse is necessary for proper utse development and AC invasion genes fos-1, cdh-3, him-4, egl-43, zmp-1 and mig-10 promote utse cell outgrowth. Two types of uterine lumen epithelial cells, uterine toroid 1 (ut1) and uterine toroid 2 (ut2), mediate proper utse outgrowth and we show roles in utse development for two genes expressed in the uterine toroids: the RASEF ortholog rsef-1 and Trio/unc-73. The SM expressed gene unc-53/NAV regulates utse cell shape; ablation of sex myoblasts (SMs), which generate uterine and vulval muscles, cause defects in utse morphology. Our results clarify the nature of the interactions that exist between utse and surrounding tissue, identify new roles for genes involved in cell outgrowth, and present the utse as a new model system for understanding cell shape change and, putatively, diseases associated with cell shape change. PMID- 25281935 TI - The conserved barH-like homeobox-2 gene barhl2 acts downstream of orthodentricle 2 and together with iroquois-3 in establishment of the caudal forebrain signaling center induced by Sonic Hedgehog. AB - In this study, we investigated the gene regulatory network that governs formation of the Zona limitans intrathalamica (ZLI), a signaling center that secretes Sonic Hedgehog (Shh) to control the growth and regionalization of the caudal forebrain. Using loss- and gain-of-function, explants and grafting experiments in amphibians, we demonstrate that barhl2 acts downstream of otx2 and together with the iroquois (irx)-3 gene in establishment of the ZLI compartment initiated by Shh influence. We find that the presumptive (pre)-ZLI domain expresses barhl2, otx2 and irx3, whereas the thalamus territory caudally bordering the pre-ZLI expresses barhl2, otx2 and irx1/2 and early on irx3. We demonstrate that Barhl2 activity is required for determination of the ZLI and thalamus fates and that within the p2 alar plate the ratio of Irx3 to Irx1/2 contributes to ZLI specification and size determination. We show that when continuously exposed to Shh, neuroepithelial cells coexpressing barhl2, otx2 and irx3 acquire two characteristics of the ZLI compartment-the competence to express shh and the ability to segregate from anterior neural plate cells. In contrast, neuroepithelial cells expressing barhl2, otx2 and irx1/2, are not competent to express shh. Noteworthy in explants, under Shh influence, ZLI-like cells segregate from thalamic-like cells. Our study establishes that Barhl2 activity plays a key role in p2 alar plate patterning, specifically ZLI formation, and provides new insights on establishment of the signaling center of the caudal forebrain. PMID- 25281936 TI - Green infrastructure as a climate change adaptation policy intervention: muddying the waters or clearing a path to a more secure future? AB - As dangerous climate change looms, decision-makers are increasingly realising that societies will need to adapt to this threat as well as mitigate against it. Green infrastructure (GI) is increasingly seen as an ideal climate change adaptation policy response. However, with this research the authors identify a number of crucial knowledge gaps within GI and, consequently, call for caution and for a concerted effort to understand the concept and what it can really deliver. GI has risen to prominence in a range of policy areas in large part due to its perceived ability to produce multiple benefits simultaneously, termed 'multifunctionality'. This characteristic strengthens the political appeal of the policy in question at a time when environmental issues have slipped down political agendas. Multifunctionality, however, brings its own set of new challenges that should be evaluated fully before the policy is implemented. This research takes important first steps to developing a critical understanding of what is achievable within GI's capacity. It focuses on one of GI's single objectives, namely climate change adaptation, to focus the analysis of how current obstacles in applying GI's multifunctionality could lead to the ineffective delivery of its objective. By drawing on expert opinion from government officials and representatives from the private, non-government organisation (NGO) and academic sectors, this research questions GI's ability to be effectively 'multifunctional' with an inconsistent definition at its core, deficiencies in its understanding and conflicts within its governance. In light of these observations, the authors then reflect on the judiciousness of applying GI to achieve the other objectives it has also been charged with delivering. PMID- 25281937 TI - Point/Counterpoint. Because of the advantages of rotational techniques, conventional IMRT will soon become obsolete. PMID- 25281938 TI - Jacques Ovadia, Ph.D. PMID- 25281939 TI - AAPM and GEC-ESTRO guidelines for image-guided robotic brachytherapy: report of Task Group 192. AB - In the last decade, there have been significant developments into integration of robots and automation tools with brachytherapy delivery systems. These systems aim to improve the current paradigm by executing higher precision and accuracy in seed placement, improving calculation of optimal seed locations, minimizing surgical trauma, and reducing radiation exposure to medical staff. Most of the applications of this technology have been in the implantation of seeds in patients with early-stage prostate cancer. Nevertheless, the techniques apply to any clinical site where interstitial brachytherapy is appropriate. In consideration of the rapid developments in this area, the American Association of Physicists in Medicine (AAPM) commissioned Task Group 192 to review the state-of the-art in the field of robotic interstitial brachytherapy. This is a joint Task Group with the Groupe Europeen de Curietherapie-European Society for Radiotherapy & Oncology (GEC-ESTRO). All developed and reported robotic brachytherapy systems were reviewed. Commissioning and quality assurance procedures for the safe and consistent use of these systems are also provided. Manual seed placement techniques with a rigid template have an estimated in vivo accuracy of 3-6 mm. In addition to the placement accuracy, factors such as tissue deformation, needle deviation, and edema may result in a delivered dose distribution that differs from the preimplant or intraoperative plan. However, real-time needle tracking and seed identification for dynamic updating of dosimetry may improve the quality of seed implantation. The AAPM and GEC-ESTRO recommend that robotic systems should demonstrate a spatial accuracy of seed placement <=1.0 mm in a phantom. This recommendation is based on the current performance of existing robotic brachytherapy systems and propagation of uncertainties. During clinical commissioning, tests should be conducted to ensure that this level of accuracy is achieved. These tests should mimic the real operating procedure as closely as possible. Additional recommendations on robotic brachytherapy systems include display of the operational state; capability of manual override; documented policies for independent check and data verification; intuitive interface displaying the implantation plan and visualization of needle positions and seed locations relative to the target anatomy; needle insertion in a sequential order; robot-clinician and robot-patient interactions robustness, reliability, and safety while delivering the correct dose at the correct site for the correct patient; avoidance of excessive force on radioactive sources; delivery confirmation of the required number or position of seeds; incorporation of a collision avoidance system; system cleaning, decontamination, and sterilization procedures. These recommendations are applicable to end users and manufacturers of robotic brachytherapy systems. PMID- 25281940 TI - Design and experimental testing of air slab caps which convert commercial electron diodes into dual purpose, correction-free diodes for small field dosimetry. AB - PURPOSE: Two diodes which do not require correction factors for small field relative output measurements are designed and validated using experimental methodology. This was achieved by adding an air layer above the active volume of the diode detectors, which canceled out the increase in response of the diodes in small fields relative to standard field sizes. METHODS: Due to the increased density of silicon and other components within a diode, additional electrons are created. In very small fields, a very small air gap acts as an effective filter of electrons with a high angle of incidence. The aim was to design a diode that balanced these perturbations to give a response similar to a water-only geometry. Three thicknesses of air were placed at the proximal end of a PTW 60017 electron diode (PTWe) using an adjustable "air cap". A set of output ratios (ORDet (fclin) ) for square field sizes of side length down to 5 mm was measured using each air thickness and compared to ORDet (fclin) measured using an IBA stereotactic field diode (SFD). kQclin,Qmsr (fclin,fmsr) was transferred from the SFD to the PTWe diode and plotted as a function of air gap thickness for each field size. This enabled the optimal air gap thickness to be obtained by observing which thickness of air was required such that kQclin,Qmsr (fclin,fmsr) was equal to 1.00 at all field sizes. A similar procedure was used to find the optimal air thickness required to make a modified Sun Nuclear EDGE detector (EDGEe) which is "correction-free" in small field relative dosimetry. In addition, the feasibility of experimentally transferring kQclin,Qmsr (fclin,fmsr) values from the SFD to unknown diodes was tested by comparing the experimentally transferred kQclin,Qmsr (fclin,fmsr) values for unmodified PTWe and EDGEe diodes to Monte Carlo simulated values. RESULTS: 1.0 mm of air was required to make the PTWe diode correction free. This modified diode (PTWeair) produced output factors equivalent to those in water at all field sizes (5-50 mm). The optimal air thickness required for the EDGEe diode was found to be 0.6 mm. The modified diode (EDGEeair) produced output factors equivalent to those in water, except at field sizes of 8 and 10 mm where it measured approximately 2% greater than the relative dose to water. The experimentally calculated kQclin,Qmsr (fclin,fmsr) for both the PTWe and the EDGEe diodes (without air) matched Monte Carlo simulated results, thus proving that it is feasible to transfer kQclin,Qmsr (fclin,fmsr) from one commercially available detector to another using experimental methods and the recommended experimental setup. CONCLUSIONS: It is possible to create a diode which does not require corrections for small field output factor measurements. This has been performed and verified experimentally. The ability of a detector to be "correction-free" depends strongly on its design and composition. A nonwater equivalent detector can only be "correction-free" if competing perturbations of the beam cancel out at all field sizes. This should not be confused with true water equivalency of a detector. PMID- 25281941 TI - A system to use electromagnetic tracking for the quality assurance of brachytherapy catheter digitization. AB - PURPOSE: To investigate the use of a system using electromagnetic tracking (EMT), post-processing and an error-detection algorithm for detecting errors and resolving uncertainties in high-dose-rate brachytherapy catheter digitization for treatment planning. METHODS: EMT was used to localize 15 catheters inserted into a phantom using a stepwise acquisition technique. Five distinct acquisition experiments were performed. Noise associated with the acquisition was calculated. The dwell location configuration was extracted from the EMT data. A CT scan of the phantom was performed, and five distinct catheter digitization sessions were performed. No a priori registration of the CT scan coordinate system with the EMT coordinate system was performed. CT-based digitization was automatically extracted from the brachytherapy plan DICOM files (CT), and rigid registration was performed between EMT and CT dwell positions. EMT registration error was characterized in terms of the mean and maximum distance between corresponding EMT and CT dwell positions per catheter. An algorithm for error detection and identification was presented. Three types of errors were systematically simulated: swap of two catheter numbers, partial swap of catheter number identification for parts of the catheters (mix), and catheter-tip shift. Error detection sensitivity (number of simulated scenarios correctly identified as containing an error/number of simulated scenarios containing an error) and specificity (number of scenarios correctly identified as not containing errors/number of correct scenarios) were calculated. Catheter identification sensitivity (number of catheters correctly identified as erroneous across all scenarios/number of erroneous catheters across all scenarios) and specificity (number of catheters correctly identified as correct across all scenarios/number of correct catheters across all scenarios) were calculated. The mean detected and identified shift was calculated. RESULTS: The maximum noise +/-1 standard deviation associated with the EMT acquisitions was 1.0 +/- 0.1 mm, and the mean noise was 0.6 +/- 0.1 mm. Registration of all the EMT and CT dwell positions was associated with a mean catheter error of 0.6 +/- 0.2 mm, a maximum catheter error of 0.9 +/- 0.4 mm, a mean dwell error of 1.0 +/- 0.3 mm, and a maximum dwell error of 1.3 +/- 0.7 mm. Error detection and catheter identification sensitivity and specificity of 100% were observed for swap, mix and shift (>=2.6 mm for error detection; >=2.7 mm for catheter identification) errors. A mean detected shift of 1.8 +/- 0.4 mm and a mean identified shift of 1.9 +/- 0.4 mm were observed. CONCLUSIONS: Registration of the EMT dwell positions to the CT dwell positions was possible with a residual mean error per catheter of 0.6 +/- 0.2 mm and a maximum error for any dwell of 1.3 +/- 0.7 mm. These low residual registration errors show that quality assurance of the general characteristics of the catheters and of possible errors affecting one specific dwell position is possible. The sensitivity and specificity of the catheter digitization verification algorithm was 100% for swap and mix errors and for shifts >=2.6 mm. On average, shifts >=1.8 mm were detected, and shifts >=1.9 mm were detected and identified. PMID- 25281942 TI - Phantomless patient-specific TomoTherapy QA via delivery performance monitoring and a secondary Monte Carlo dose calculation. AB - PURPOSE: To describe the validation and implementation of a novel quality assurance (QA) system for TomoTherapy using a Monte Carlo (MC)-based secondary dose calculation and CT detector-based multileaf collimator (MLC) leaf opening time measurement QA verification. This system is capable of detecting plan transfer and delivery errors and evaluating the dosimetric impact of those errors. METHODS: The authors' QA process, MCLogQA, utilizes an independent pretreatment MC secondary dose calculation and postdelivery TomoTherapy exit detector-based MLC sinogram comparison and log file examination to confirm accurate dose calculation, accurate dose delivery, and to verify machine performance. MC radiation transport simulations are performed to estimate patient dose utilizing prestored treatment machine-specific phase-space information, the patient's planning CT, and MLC sinogram data. Sinogram data are generated from both the treatment planning system (MC_TPS) and from beam delivery log files (MC_Log). TomoTherapy treatment planning dose (DTPS) is compared with DMC_TPS and DMC_Log via dose-volume metrics and mean region of interest dose statistics. For validation, in-phantom ionization chamber dose measurements (DIC) for ten sample patient plans are compared with the computed values. RESULTS: Dose comparisons to in-phantom ion chamber measurements validate the capability of the MCLogQA method to detect delivery errors. DMC_Log agreed with DIC within 1%, while DTPS values varied by 2%-5% compared to DIC. The authors demonstrated that TomoTherapy treatments can be vulnerable to MLC deviations and interfraction output variations during treatment delivery. Interfractional Linac output variations for each patient were approximately 2% and average output was 1%-1.5% below the gold standard. While average MLC leaf opening time error from patient to patient varied from -0.6% to 1.6%, the MLC leaf errors varied little between fractions for the same patient plan, excluding one patient. CONCLUSIONS: MCLogQA is a new TomoTherapy QA process that validates the planned dose before delivery and analyzes the delivered dose using the treatment exit detector and log file data. The MCLogQA procedure is an effective and efficient alternative to traditional phantom-based TomoTherapy plan-specific QA because it allows for comprehensive 3D dose verification, accounts for tissue heterogeneity, uses patient CT density tables, reduces total QA time, and provides for a comprehensive QA methodology for each treatment fraction. PMID- 25281943 TI - Quantifying the effect of seed orientation in postplanning dosimetry of low-dose rate prostate brachytherapy. AB - PURPOSE: Radioactive seed orientations are usually ignored in clinical brachytherapy dosimetry for prostate implants. Associated with the anisotropic dose distribution of seeds, these orientations could cause dose differences between the planning configurations and the clinical postplanning dosimetry. This study will quantify the impact of seed orientation on the dosimetry. METHODS: 3D seed positions and theta and phi polar angles were obtained using five independent fluoroscopic images for 287 patients. Five dose calculation methods are compared: TG43-1D (1), TG43-2D parallel to implant axis (2) and with orientations (3), Monte Carlo (MC) simulations parallel (4), and MC simulations with orientations (5). GEANT4 v4.9.6 MC simulations were made in 1 mm(3) voxelized geometries based on the DICOM-RT information. Materials were assigned using thresholds based on the HU number, as recommended in TG186 reports. Seed voxels are overridden with prostatic materials and the layered mass geometry [Enger et al., Phys. Med. Biol. 57(19), 6269-6277 (2012)] allows subsequent placement of the source geometry. 500 million histories were used per patient. 3D dose and DVHs for each structure were calculated. RESULTS: The various seed orientations do not result in statistically significant differences on the dose metrics for the clinical target volume (CTV) or the urethra, based on the Student t-test p-value. Difference as low as -0.238% and 0.059% has been seen on the CTV D90, respectively, for the MC and the TG43. The difference between parallel and oriented calculations for the organs at risk (OARs) can differ by 2% on average. CONCLUSIONS: Based on the results from this study, seed orientations have no significant impact of CTV and urethra dose metrics but can affect OARs that are external to the CTV. PMID- 25281945 TI - Development of an expanded-field irradiation technique using a gimbaled x-ray head. AB - PURPOSE: The Vero4DRT has a maximum field size of 150.0 * 150.0 mm. The purpose of the present study was to develop expanded-field irradiation techniques using the unique gimbaled x-ray head of the Vero4DRT and to evaluate the dosimetric characteristics thereof. METHODS: Two techniques were developed. One features gimbal swing irradiation and multiple static segments consisting of four separate fields exhibiting 2.39 degrees gimbal rotation around two orthogonal axes. The central beam axis for each piecewise-field is shifted 40 mm from the isocenters of the left-right (LR) and superior-inferior (SI) directions, and, thus, the irradiation field size is expanded to 230.8 * 230.8 mm. Adjacent regions were created at the isocenter (a center-adjacent expandedfield) and 20 mm from the isocenter (an off-adjacent expandedfield). The field gaps or overlaps of combined piecewise-fields were established by adjustment of gimbal rotation and movement of the multileaf collimator (MLC). Another technique features dynamic segment irradiation in which the beam is delivered while rotating the gimbal. The dose profile is controlled by a combination of gimbal swing motion and opening and closing of the MLC. This enabled the authors to expand the irradiation field on the LR axis because the direction of MLC motion is parallel to that axis. A field 220.6 * 150.0 mm in dimensions was configured and examined. To evaluate the dosimetric characteristics of the expandedfields, films inserted into water equivalent phantoms at depths of 50, 100, and 150 mm were irradiated and field sizes, penumbrae, flatness, and symmetry analyzed. In addition, the expanded field irradiation techniques were applied to intensity-modulated radiation therapy (IMRT). A head-and-neck IMRT field, created using a conventional Linac (the Varian Clinac iX), was reproduced employing an expanded-field of the Vero4DRT. The simulated dose distribution for the expanded-IMRT field was compared to the measured dose distribution. RESULTS: The field sizes, penumbrae, flatness, and symmetry of the center- and off-adjacent expanded-fields were 230.2 232.1 mm, 6.8-10.7 mm, 2.3%-5.1%, and -0.5% to -0.4%, respectively, at a depth of 100 mm. Similarly, the field sizes, penumbrae, flatness, and symmetry of dynamic segment irradiation on the LR axis were 219.2 mm, 6.0-6.2 mm, 3.4%, and -0.1%, respectively, at a depth of 100 mm. In the area of expanded-IMRT dose distribution, the passing rate of 5% dose difference was 85.8% between measurements and simulation, and the 3%/3 mm gamma passing rate was 96.4%. CONCLUSIONS: Expanded-field irradiation techniques were developed using a gimbaled x-ray head. The techniques effectively extend target areas, as required when whole-breast irradiation or head-and-neck IMRT is contemplated. PMID- 25281944 TI - Coverage-based treatment planning to accommodate deformable organ variations in prostate cancer treatment. AB - PURPOSE: To compare two coverage-based planning (CP) techniques with standard fixed margin-based planning (FM), considering the dosimetric impact of interfraction deformable organ motion exclusively for high-risk prostate treatments. METHODS: Nineteen prostate cancer patients with 8-13 prostate CT images of each patient were used to model patient-specific interfraction deformable organ changes. The model was based on the principal component analysis (PCA) method and was used to predict the patient geometries for virtual treatment course simulation. For each patient, an IMRT plan using zero margin on target structures, prostate (CTVprostate) and seminal vesicles (CTVSV), were created, then evaluated by simulating 1000 30-fraction virtual treatment courses. Each fraction was prostate centroid aligned. Patients whose D98 failed to achieve 95% coverage probability objective D98,95 >= 78 Gy (CTVprostate) or D98,95 >= 66 Gy (CTVSV) were replanned using planning techniques: (1) FM (PTVprostate = CTVprostate + 5 mm, PTVSV = CTVSV + 8 mm), (2) CPOM which optimized uniform PTV margins for CTVprostate and CTVSV to meet the coverage probability objective, and (3) CPCOP which directly optimized coverage probability objectives for all structures of interest. These plans were intercompared by computing probabilistic metrics, including 5% and 95% percentile DVHs (pDVH) and TCP/NTCP distributions. RESULTS: All patients were replanned using FM and two CP techniques. The selected margins used in FM failed to ensure target coverage for 8/19 patients. Twelve CPOM plans and seven CPCOP plans were favored over the other plans by achieving desirable D98,95 while sparing more normal tissues. CONCLUSIONS: Coverage-based treatment planning techniques can produce better plans than FM, while relative advantages of CPOM and CPCOP are patient-specific. PMID- 25281946 TI - Motion management during IMAT treatment of mobile lung tumors--a comparison of MLC tracking and gated delivery. AB - PURPOSE: To compare real-time dynamic multileaf collimator (MLC) tracking, respiratory amplitude and phase gating, and no compensation for intrafraction motion management during intensity modulated arc therapy (IMAT). METHODS: Motion management with MLC tracking and gating was evaluated for four lung cancer patients. The IMAT plans were delivered to a dosimetric phantom mounted onto a 3D motion phantom performing patient-specific lung tumor motion. The MLC tracking system was guided by an optical system that used stereoscopic infrared (IR) cameras and five spherical reflecting markers attached to the dosimetric phantom. The gated delivery used a duty cycle of 35% and collected position data using an IR camera and two reflecting markers attached to a marker block. RESULTS: The average gamma index failure rate (2% and 2 mm criteria) was <0.01% with amplitude gating for all patients, and <0.1% with phase gating and <3.7% with MLC tracking for three of the four patients. One of the patients had an average failure rate of 15.1% with phase gating and 18.3% with MLC tracking. With no motion compensation, the average gamma index failure rate ranged from 7.1% to 46.9% for the different patients. Evaluation of the dosimetric error contributions showed that the gated delivery mainly had errors in target localization, while MLC tracking also had contributions from MLC leaf fitting and leaf adjustment. The average treatment time was about three times longer with gating compared to delivery with MLC tracking (that did not prolong the treatment time) or no motion compensation. For two of the patients, the different motion compensation techniques allowed for approximately the same margin reduction but for two of the patients, gating enabled a larger reduction of the margins than MLC tracking. CONCLUSIONS: Both gating and MLC tracking reduced the effects of the target movements, although the gated delivery showed a better dosimetric accuracy and enabled a larger reduction of the margins in some cases. MLC tracking did not prolong the treatment time compared to delivery with no motion compensation while gating had a considerably longer delivery time. In a clinical setting, the optical monitoring of the patients breathing would have to be correlated to the internal movements of the tumor. PMID- 25281947 TI - Variation of kQclin,Qmsr (fclin,fmsr) for the small-field dosimetric parameters percentage depth dose, tissue-maximum ratio, and off-axis ratio. AB - PURPOSE: Evaluate the ability of different dosimeters to correctly measure the dosimetric parameters percentage depth dose (PDD), tissue-maximum ratio (TMR), and off-axis ratio (OAR) in water for small fields. METHODS: Monte Carlo (MC) simulations were used to estimate the variation of kQclin,Qmsr (fclin,fmsr) for several types of microdetectors as a function of depth and distance from the central axis for PDD, TMR, and OAR measurements. The variation of kQclin,Qmsr (fclin,fmsr) enables one to evaluate the ability of a detector to reproduce the PDD, TMR, and OAR in water and consequently determine whether it is necessary to apply correction factors. The correctness of the simulations was verified by assessing the ratios between the PDDs and OARs of 5- and 25-mm circular collimators used with a linear accelerator measured with two different types of dosimeters (the PTW 60012 diode and PTW PinPoint 31014 microchamber) and the PDDs and the OARs measured with the Exradin W1 plastic scintillator detector (PSD) and comparing those ratios with the corresponding ratios predicted by the MC simulations. RESULTS: MC simulations reproduced results with acceptable accuracy compared to the experimental results; therefore, MC simulations can be used to successfully predict the behavior of different dosimeters in small fields. The Exradin W1 PSD was the only dosimeter that reproduced the PDDs, TMRs, and OARs in water with high accuracy. With the exception of the EDGE diode, the stereotactic diodes reproduced the PDDs and the TMRs in water with a systematic error of less than 2% at depths of up to 25 cm; however, they produced OAR values that were significantly different from those in water, especially in the tail region (lower than 20% in some cases). The microchambers could be used for PDD measurements for fields greater than those produced using a 10-mm collimator. However, with the detector stem parallel to the beam axis, the microchambers could be used for TMR measurements for all field sizes. The microchambers could not be used for OAR measurements for small fields. CONCLUSIONS: Compared with MC simulation, the Exradin W1 PSD can reproduce the PDDs, TMRs, and OARs in water with a high degree of accuracy; thus, the correction used for converting dose is very close to unity. The stereotactic diode is a viable alternative because it shows an acceptable systematic error in the measurement of PDDs and TMRs and a significant underestimation in only the tail region of the OAR measurements, where the dose is low and differences in dose may not be therapeutically meaningful. PMID- 25281948 TI - Design of an Yb-169 source optimized for gold nanoparticle-aided radiation therapy. AB - PURPOSE: To find an optimum design of a new high-dose rate ytterbium (Yb)-169 brachytherapy source that would maximize the dose enhancement during gold nanoparticle-aided radiation therapy (GNRT), while meeting practical constraints for manufacturing a clinically relevant brachytherapy source. METHODS: Four different Yb-169 source designs were considered in this investigation. The first three source models had a single encapsulation made of one of the following materials: aluminum, titanium, and stainless steel. The last source model adopted a dual encapsulation design with an inner aluminum capsule surrounding the Yb core and an outer titanium capsule. Monte Carlo (MC) simulations using the Monte Carlo N-Particle code version 5 (MCNP5) were conducted initially to investigate the spectral changes caused by these four source designs and the associated variations in macroscopic dose enhancement across the tumor loaded with gold nanoparticles (GNPs) at 0.7% by weight. Subsequent MC simulations were performed using the EGSnrc and norec codes to determine the secondary electron spectra and microscopic dose enhancement as a result of irradiating the GNP-loaded tumor with the mcnp-calculated source spectra. RESULTS: Effects of the source filter design were apparent in the current MC results. The intensity-weighted average energy of the Yb-169 source varied from 108.9 to 122.9 keV, as the source encapsulation material changed from aluminum to stainless steel. Accordingly, the macroscopic dose enhancement calculated at 1 cm away from the source changed from 51.0% to 45.3%. The sources encapsulated by titanium and aluminum/titanium combination showed similar levels of dose enhancement, 49.3% at 1 cm, and average energies of 113.0 and 112.3 keV, respectively. While the secondary electron spectra due to the investigated source designs appeared to look similar in general, some differences were noted especially in the low energy region (<50 keV) of the spectra suggesting the dependence of the photoelectron yield on the atomic number of source filter material, consistent with the macroscopic dose enhancement results. A similar trend was also shown in the so-called microscopic dose enhancement factor, for example, resulting in the maximum values of 138 and 119 for the titanium- and the stainless steel-encapsulated Yb-169 sources, respectively. CONCLUSIONS: The current results consistently show that the dose enhancement achievable from the Yb-169 source is closely related with the atomic number (Z) of source encapsulation material. While the observed range of improvement in the dose enhancement may be considered moderate after factoring all uncertainties in the MC results, the current study provides a reasonable support for the encapsulation of the Yb-core with lower-Z materials than stainless steel, for GNRT applications. Overall, the titanium capsule design can be favored over the aluminum or dual aluminum/titanium capsule designs, due to its superior structural integrity and improved safety during manufacturing and clinical use. PMID- 25281949 TI - A nonrigid registration method for correcting brain deformation induced by tumor resection. AB - PURPOSE: This paper presents a nonrigid registration method to align preoperative MRI with intraoperative MRI to compensate for brain deformation during tumor resection. This method extends traditional point-based nonrigid registration in two aspects: (1) allow the input data to be incomplete and (2) simulate the underlying deformation with a heterogeneous biomechanical model. METHODS: The method formulates the registration as a three-variable (point correspondence, deformation field, and resection region) functional minimization problem, in which point correspondence is represented by a fuzzy assign matrix; Deformation field is represented by a piecewise linear function regularized by the strain energy of a heterogeneous biomechanical model; and resection region is represented by a maximal simply connected tetrahedral mesh. A nested expectation and maximization framework is developed to simultaneously resolve these three variables. RESULTS: To evaluate this method, the authors conducted experiments on both synthetic data and clinical MRI data. The synthetic experiment confirmed their hypothesis that the removal of additional elements from the biomechanical model can improve the accuracy of the registration. The clinical MRI experiments on 25 patients showed that the proposed method outperforms the ITK implementation of a physics-based nonrigid registration method. The proposed method improves the accuracy by 2.88 mm on average when the error is measured by a robust Hausdorff distance metric on Canny edge points, and improves the accuracy by 1.56 mm on average when the error is measured by six anatomical points. CONCLUSIONS: The proposed method can effectively correct brain deformation induced by tumor resection. PMID- 25281950 TI - A nonvoxel-based dose convolution/superposition algorithm optimized for scalable GPU architectures. AB - PURPOSE: Real-time adaptive planning and treatment has been infeasible due in part to its high computational complexity. There have been many recent efforts to utilize graphics processing units (GPUs) to accelerate the computational performance and dose accuracy in radiation therapy. Data structure and memory access patterns are the key GPU factors that determine the computational performance and accuracy. In this paper, the authors present a nonvoxel-based (NVB) approach to maximize computational and memory access efficiency and throughput on the GPU. METHODS: The proposed algorithm employs a ray-tracing mechanism to restructure the 3D data sets computed from the CT anatomy into a nonvoxel-based framework. In a process that takes only a few milliseconds of computing time, the algorithm restructured the data sets by ray-tracing through precalculated CT volumes to realign the coordinate system along the convolution direction, as defined by zenithal and azimuthal angles. During the ray-tracing step, the data were resampled according to radial sampling and parallel ray spacing parameters making the algorithm independent of the original CT resolution. The nonvoxel-based algorithm presented in this paper also demonstrated a trade-off in computational performance and dose accuracy for different coordinate system configurations. In order to find the best balance between the computed speedup and the accuracy, the authors employed an exhaustive parameter search on all sampling parameters that defined the coordinate system configuration: zenithal, azimuthal, and radial sampling of the convolution algorithm, as well as the parallel ray spacing during ray tracing. The angular sampling parameters were varied between 4 and 48 discrete angles, while both radial sampling and parallel ray spacing were varied from 0.5 to 10 mm. The gamma distribution analysis method (gamma) was used to compare the dose distributions using 2% and 2 mm dose difference and distance-to-agreement criteria, respectively. Accuracy was investigated using three distinct phantoms with varied geometries and heterogeneities and on a series of 14 segmented lung CT data sets. Performance gains were calculated using three 256 mm cube homogenous water phantoms, with isotropic voxel dimensions of 1, 2, and 4 mm. RESULTS: The nonvoxel-based GPU algorithm was independent of the data size and provided significant computational gains over the CPU algorithm for large CT data sizes. The parameter search analysis also showed that the ray combination of 8 zenithal and 8 azimuthal angles along with 1 mm radial sampling and 2 mm parallel ray spacing maintained dose accuracy with greater than 99% of voxels passing the gamma test. Combining the acceleration obtained from GPU parallelization with the sampling optimization, the authors achieved a total performance improvement factor of >175 000 when compared to our voxel-based ground truth CPU benchmark and a factor of 20 compared with a voxel-based GPU dose convolution method. CONCLUSIONS: The nonvoxel-based convolution method yielded substantial performance improvements over a generic GPU implementation, while maintaining accuracy as compared to a CPU computed ground truth dose distribution. Such an algorithm can be a key contribution toward developing tools for adaptive radiation therapy systems. PMID- 25281951 TI - A 2D ion chamber array audit of wedged and asymmetric fields in an inhomogeneous lung phantom. AB - PURPOSE: The Australian Clinical Dosimetry Service (ACDS) has implemented a new method of a nonreference condition Level II type dosimetric audit of radiotherapy services to increase measurement accuracy and patient safety within Australia. The aim of this work is to describe the methodology, tolerances, and outcomes from the new audit. METHODS: The ACDS Level II audit measures the dose delivered in 2D planes using an ionization chamber based array positioned at multiple depths. Measurements are made in rectilinear homogeneous and inhomogeneous phantoms composed of slabs of solid water and lung. Computer generated computed tomography data sets of the rectilinear phantoms are supplied to the facility prior to audit for planning of a range of cases including reference fields, asymmetric fields, and wedged fields. The audit assesses 3D planning with 6 MV photons with a static (zero degree) gantry. Scoring is performed using local dose differences between the planned and measured dose within 80% of the field width. The overall audit result is determined by the maximum dose difference over all scoring points, cases, and planes. Pass (Optimal Level) is defined as maximum dose difference <=3.3%, Pass (Action Level) is <=5.0%, and Fail (Out of Tolerance) is >5.0%. RESULTS: At close of 2013, the ACDS had performed 24 Level II audits. 63% of the audits passed, 33% failed, and the remaining audit was not assessable. Of the 15 audits that passed, 3 were at Pass (Action Level). The high fail rate is largely due to a systemic issue with modeling asymmetric 60 degrees wedges which caused a delivered overdose of 5%-8%. CONCLUSIONS: The ACDS has implemented a nonreference condition Level II type audit, based on ion chamber 2D array measurements in an inhomogeneous slab phantom. The powerful diagnostic ability of this audit has allowed the ACDS to rigorously test the treatment planning systems implemented in Australian radiotherapy facilities. Recommendations from audits have led to facilities modifying clinical practice and changing planning protocols. PMID- 25281952 TI - Ghost marker detection and elimination in marker-based optical tracking systems for real-time tracking in stereotactic body radiotherapy. AB - PURPOSE: To propose a simple model to explain the origin of ghost markers in marker-based optical tracking systems (OTS) and to develop retrospective strategies to detect and eliminate ghost markers. METHODS: In marker-based OTS, ghost markers are virtual markers created due to the cross-talk between the two camera sensors, which can lead to system execution failure or inaccuracy in patient tracking. As a result, the users have to limit the number of markers and avoid certain marker configurations to reduce the chances of ghost markers. In this work, the authors propose retrospective strategies to detect and eliminate ghost markers. The two camera sensors were treated as mathematical points in space. The authors identified the coplanar within limit (CWL) condition as the necessary condition for ghost marker occurrence. A simple ghost marker detection method was proposed based on the model. Ghost marker elimination was achieved through pattern matching: a ghost marker-free reference set was matched with the optical marker set observed by the OTS; unmatched optical markers were eliminated as either ghost markers or misplaced markers. The pattern matching problem was formulated as a constraint satisfaction problem (using pairwise distances as constraints) and solved with an iterative backtracking algorithm. Wildcard markers were introduced to address missing or misplaced markers. An experiment was designed to measure the sensor positions and the limit for the CWL condition. The ghost marker detection and elimination algorithms were verified with samples collected from a five-marker jig and a nine-marker anthropomorphic phantom, rotated with the treatment couch from -60 degrees to +60 degrees . The accuracy of the pattern matching algorithm was further validated with marker patterns from 40 patients who underwent stereotactic body radiotherapy (SBRT). For this purpose, a synthetic optical marker pattern was created for each patient by introducing ghost markers, marker position uncertainties, and marker displacement. RESULTS: The sensor positions and the limit for the CWL condition were measured with excellent reproducibility (standard deviation <= 0.39 mm). The ghost marker detection algorithm had perfect detection accuracy for both the jig (1544 samples) and the anthropomorphic phantom (2045 samples). Pattern matching was successful for all samples from both phantoms as well as the 40 patient marker patterns. CONCLUSIONS: The authors proposed a simple model to explain the origin of ghost markers and identified the CWL condition as the necessary condition for ghost marker occurrence. The retrospective ghost marker detection and elimination algorithms guarantee complete ghost marker elimination while providing the users with maximum flexibility in selecting the number of markers and their configuration to meet their clinic needs. PMID- 25281953 TI - Breast tissue decomposition with spectral distortion correction: a postmortem study. AB - PURPOSE: To investigate the feasibility of an accurate measurement of water, lipid, and protein composition of breast tissue using a photon-counting spectral computed tomography (CT) with spectral distortion corrections. METHODS: Thirty eight postmortem breasts were imaged with a cadmium-zinc-telluride-based photon counting spectral CT system at 100 kV. The energy-resolving capability of the photon-counting detector was used to separate photons into low and high energy bins with a splitting energy of 42 keV. The estimated mean glandular dose for each breast ranged from 1.8 to 2.2 mGy. Two spectral distortion correction techniques were implemented, respectively, on the raw images to correct the nonlinear detector response due to pulse pileup and charge-sharing artifacts. Dual energy decomposition was then used to characterize each breast in terms of water, lipid, and protein content. In the meantime, the breasts were chemically decomposed into their respective water, lipid, and protein components to provide a gold standard for comparison with dual energy decomposition results. RESULTS: The accuracy of the tissue compositional measurement with spectral CT was determined by comparing to the reference standard from chemical analysis. The averaged root-mean-square error in percentage composition was reduced from 15.5% to 2.8% after spectral distortion corrections. CONCLUSIONS: The results indicate that spectral CT can be used to quantify the water, lipid, and protein content in breast tissue. The accuracy of the compositional analysis depends on the applied spectral distortion correction technique. PMID- 25281954 TI - Investigation of sagittal image acquisition for 4D-MRI with body area as respiratory surrogate. AB - PURPOSE: The authors have recently developed a novel 4D-MRI technique for imaging organ respiratory motion employing cine acquisition in the axial plane and using body area (BA) as a respiratory surrogate. A potential disadvantage associated with axial image acquisition is the space-dependent phase shift in the superior inferior (SI) direction, i.e., different axial slice positions reach the respiratory peak at different respiratory phases. Since respiratory motion occurs mostly in the SI and anterior-posterior (AP) directions, sagittal image acquisition, which embeds motion information in these two directions, is expected to be more robust and less affected by phase-shift than axial image acquisition. This study aims to develop and evaluate a 4D-MRI technique using sagittal image acquisition. METHODS: The authors evaluated axial BA and sagittal BA using both 4D-CT images (11 cancer patients) and cine MR images (6 healthy volunteers and 1 cancer patient) by comparing their corresponding space-dependent phase-shift in the SI direction (deltaSPS (SI)) and in the lateral direction (deltaSPS (LAT)), respectively. To evaluate sagittal BA 4D-MRI method, a motion phantom study and a digital phantom study were performed. Additionally, six patients who had cancer(s) in the liver were prospectively enrolled in this study. For each patient, multislice sagittal MR images were acquired for 4D-MRI reconstruction. 4D retrospective sorting was performed based on respiratory phases. Single-slice cine MRI was also acquired in the axial, coronal, and sagittal planes across the tumor center from which tumor motion trajectories in the SI, AP, and medial lateral (ML) directions were extracted and used as references from comparison. All MR images were acquired in a 1.5 T scanner using a steady-state precession sequence (frame rate ~ 3 frames/s). RESULTS: 4D-CT scans showed that deltaSPS (SI) was significantly greater than deltaSPS (LAT) (p-value: 0.012); the median phase-shift was 16.9% and 7.7%, respectively. Body surface motion measurement from axial and sagittal MR cines also showed deltaSPS (SI) was significantly greater than deltaSPS (LAT). The median deltaSPS (SI) and deltaSPS (LAT) was 11.0% and 9.2% (p-value = 0.008), respectively. Tumor motion trajectories from 4D MRI matched with those from single-slice cine MRI: the mean (+/-SD) absolute differences in tumor motion amplitude between the two were 1.5 +/- 1.6 mm, 2.1 +/ 1.9 mm, and 1.1 +/- 1.0 mm in the SI, ML, and AP directions from this patient study. CONCLUSIONS: Space-dependent phase shift is less problematic for sagittal acquisition than for axial acquisition. 4D-MRI using sagittal acquisition was successfully carried out in patients with hepatic tumors. PMID- 25281955 TI - ADC texture--an imaging biomarker for high-grade glioma? AB - PURPOSE: Survival for high-grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion-weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers. METHODS: Twenty-three consecutive high-grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1-weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray-level co-occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression. RESULTS: The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001. CONCLUSIONS: By combining PCA and texture analysis, ADC texture characteristics were identified, which seems to hold pretreatment prognostic information, independent of known prognostic factors such as age, stage, and surgical procedure. These findings encourage further studies with a larger patient cohort. PMID- 25281956 TI - High-resolution three-dimensional visualization of the rat spinal cord microvasculature by synchrotron radiation micro-CT. AB - PURPOSE: Understanding the three-dimensional (3D) morphology of the spinal cord microvasculature has been limited by the lack of an effective high-resolution imaging technique. In this study, synchrotron radiation microcomputed tomography (SRuCT), a novel imaging technique based on absorption imaging, was evaluated with regard to the detection of the 3D morphology of the rat spinal cord microvasculature. METHODS: Ten Sprague-Dawley rats were used in this ex vivo study. After contrast agent perfusion, their spinal cords were isolated and scanned using conventional x-rays, conventional micro-CT (CuCT), and SRuCT. RESULTS: Based on contrast agent perfusion, the microvasculature of the rat spinal cord was clearly visualized for the first time ex vivo in 3D by means of SRuCT scanning. Compared to conventional imaging techniques, SRuCT achieved higher resolution 3D vascular imaging, with the smallest vessel that could be distinguished approximately 7.4 MUm in diameter. Additionally, a 3D pseudocolored image of the spinal cord microvasculature was generated in a single session of SRuCT imaging, which was conducive to detailed observation of the vessel morphology. CONCLUSIONS: The results of this study indicated that SRuCT scanning could provide higher resolution images of the vascular network of the spinal cord. This modality also has the potential to serve as a powerful imaging tool for the investigation of morphology changes in the 3D angioarchitecture of the neurovasculature in preclinical research. PMID- 25281957 TI - A simple method to retrospectively estimate patient dose-area product for chest tomosynthesis examinations performed using VolumeRAD. AB - PURPOSE: The purpose of the present work was to develop and validate a method of retrospectively estimating the dose-area product (DAP) of a chest tomosynthesis examination performed using the VolumeRAD system (GE Healthcare, Chalfont St. Giles, UK) from digital imaging and communications in medicine (DICOM) data available in the scout image. METHODS: DICOM data were retrieved for 20 patients undergoing chest tomosynthesis using VolumeRAD. Using information about how the exposure parameters for the tomosynthesis examination are determined by the scout image, a correction factor for the adjustment in field size with projection angle was determined. The correction factor was used to estimate the DAP for 20 additional chest tomosynthesis examinations from DICOM data available in the scout images, which was compared with the actual DAP registered for the projection radiographs acquired during the tomosynthesis examination. RESULTS: A field size correction factor of 0.935 was determined. Applying the developed method using this factor, the average difference between the estimated DAP and the actual DAP was 0.2%, with a standard deviation of 0.8%. However, the difference was not normally distributed and the maximum error was only 1.0%. The validity and reliability of the presented method were thus very high. CONCLUSIONS: A method to estimate the DAP of a chest tomosynthesis examination performed using the VolumeRAD system from DICOM data in the scout image was developed and validated. As the scout image normally is the only image connected to the tomosynthesis examination stored in the picture archiving and communication system (PACS) containing dose data, the method may be of value for retrospectively estimating patient dose in clinical use of chest tomosynthesis. PMID- 25281958 TI - Improving x-ray fluorescence signal for benchtop polychromatic cone-beam x-ray fluorescence computed tomography by incident x-ray spectrum optimization: a Monte Carlo study. AB - PURPOSE: To develop an accurate and comprehensive Monte Carlo (MC) model of an experimental benchtop polychromatic cone-beam x-ray fluorescence computed tomography (XFCT) setup and apply this MC model to optimize incident x-ray spectrum for improving production/detection of x-ray fluorescence photons from gold nanoparticles (GNPs). METHODS: A detailed MC model, based on an experimental XFCT system, was created using the Monte Carlo N-Particle (MCNP) transport code. The model was validated by comparing MC results including x-ray fluorescence (XRF) and scatter photon spectra with measured data obtained under identical conditions using 105 kVp cone-beam x-rays filtered by either 1 mm of lead (Pb) or 0.9 mm of tin (Sn). After validation, the model was used to investigate the effects of additional filtration of the incident beam with Pb and Sn. Supplementary incident x-ray spectra, representing heavier filtration (Pb: 2 and 3 mm; Sn: 1, 2, and 3 mm) were computationally generated and used with the model to obtain XRF/scatter spectra. Quasimonochromatic incident x-ray spectra (81, 85, 90, 95, and 100 keV with 10 keV full width at half maximum) were also investigated to determine the ideal energy for distinguishing gold XRF signal from the scatter background. Fluorescence signal-to-dose ratio (FSDR) and fluorescence-normalized scan time (FNST) were used as metrics to assess results. RESULTS: Calculated XRF/scatter spectra for 1-mm Pb and 0.9-mm Sn filters matched (r >= 0.996) experimental measurements. Calculated spectra representing additional filtration for both filter materials showed that the spectral hardening improved the FSDR at the expense of requiring a much longer FNST. In general, using Sn instead of Pb, at a given filter thickness, allowed an increase of up to 20% in FSDR, more prominent gold XRF peaks, and up to an order of magnitude decrease in FNST. Simulations using quasimonochromatic spectra suggested that increasing source x-ray energy, in the investigated range of 81 100 keV, increased the FSDR up to a factor of 20, compared to 1 mm Pb, and further facilitated separation of gold XRF peaks from the scatter background. CONCLUSIONS: A detailed MC model of an experimental benchtop XFCT system has been developed and validated. In exemplary calculations to illustrate the usefulness of this model, it was shown that potential use of quasimonochromatic spectra or judicious choice of filter material/thickness to tailor the spectrum of a polychromatic x-ray source can significantly improve the performance of benchtop XFCT, while considering trade-offs between FSDR and FNST. As demonstrated, the current MC model is a reliable and powerful computational tool that can greatly expedite the further development of a benchtop XFCT system for routine preclinical molecular imaging with GNPs and other metal probes. PMID- 25281959 TI - Cascaded systems analysis of photon counting detectors. AB - PURPOSE: Photon counting detectors (PCDs) are an emerging technology with applications in spectral and low-dose radiographic and tomographic imaging. This paper develops an analytical model of PCD imaging performance, including the system gain, modulation transfer function (MTF), noise-power spectrum (NPS), and detective quantum efficiency (DQE). METHODS: A cascaded systems analysis model describing the propagation of quanta through the imaging chain was developed. The model was validated in comparison to the physical performance of a silicon-strip PCD implemented on an experimental imaging bench. The signal response, MTF, and NPS were measured and compared to theory as a function of exposure conditions (70 kVp, 1-7 mA), detector threshold, and readout mode (i.e., the option for coincidence detection). The model sheds new light on the dependence of spatial resolution, charge sharing, and additive noise effects on threshold selection and was used to investigate the factors governing PCD performance, including the fundamental advantages and limitations of PCDs in comparison to energy integrating detectors (EIDs) in the linear regime for which pulse pileup can be ignored. RESULTS: The detector exhibited highly linear mean signal response across the system operating range and agreed well with theoretical prediction, as did the system MTF and NPS. The DQE analyzed as a function of kilovolt (peak), exposure, detector threshold, and readout mode revealed important considerations for system optimization. The model also demonstrated the important implications of false counts from both additive electronic noise and charge sharing and highlighted the system design and operational parameters that most affect detector performance in the presence of such factors: for example, increasing the detector threshold from 0 to 100 (arbitrary units of pulse height threshold roughly equivalent to 0.5 and 6 keV energy threshold, respectively), increased the f50 (spatial-frequency at which the MTF falls to a value of 0.50) by ~30% with corresponding improvement in DQE. The range in exposure and additive noise for which PCDs yield intrinsically higher DQE was quantified, showing performance advantages under conditions of very low-dose, high additive noise, and high fidelity rejection of coincident photons. CONCLUSIONS: The model for PCD signal and noise performance agreed with measurements of detector signal, MTF, and NPS and provided a useful basis for understanding complex dependencies in PCD imaging performance and the potential advantages (and disadvantages) in comparison to EIDs as well as an important guide to task-based optimization in developing new PCD imaging systems. PMID- 25281960 TI - A method for avoiding overlap of left and right lungs in shape model guided segmentation of lungs in CT volumes. AB - PURPOSE: The automated correct segmentation of left and right lungs is a nontrivial problem, because the tissue layer between both lungs can be quite thin. In the case of lung segmentation with left and right lung models, overlapping segmentations can occur. In this paper, the authors address this issue and propose a solution for a model-based lung segmentation method. METHODS: The thin tissue layer between left and right lungs is detected by means of a classification approach and utilized to selectively modify the cost function of the lung segmentation method. The approach was evaluated on a diverse set of 212 CT scans of normal and diseased lungs. Performance was assessed by utilizing an independent reference standard and by means of comparison to the standard segmentation method without overlap avoidance. RESULTS: For cases where the standard approach produced overlapping segmentations, the proposed method significantly (p = 1.65 * 10(-9)) reduced the overlap by 97.13% on average (median: 99.96%). In addition, segmentation accuracy assessed with the Dice coefficient showed a statistically significant improvement (p = 7.5 * 10(-5)) and was 0.9845 +/- 0.0111. For cases where the standard approach did not produce an overlap, performance of the proposed method was not found to be significantly different. CONCLUSIONS: The proposed method improves the quality of the lung segmentations, which is important for subsequent quantitative analysis steps. PMID- 25281961 TI - Evaluation of slice sensitivity profiles for helical and axial 4D-CT acquisitions on the Philips Brilliance CT Big Bore. AB - PURPOSE: 4D-CT can be performed using two acquisition modes. One employs a cine axial scan and the other acquires the data using a very low pitch helical acquisition. This study evaluates the longitudinal resolutions of each of these methods by creating slice sensitivity profiles (SSP). METHODS: An SSP phantom was scanned using both axial and helical scanning modes. The phantom was scanned at the center of the field of view (FOV) and at several points offset from the FOV center. For helical scans, the pitch was varied from 0.04 to 0.2. With the axial scans, the phantom position relative to the center of the detector ring was varied. All of these were performed using a 16 * 1.5 mm collimation. RESULTS: The SSP graphs were generated from these scanned datasets. The full width at half maximum (FWHM) of the graphs was used as the surrogate for longitudinal resolution. The results of these experiments demonstrated that axial scans have a slightly better resolution at CT isocenter (1.5 vs 1.8 mm). Helical mode scanning maintained this measurement for varying pitch factors and placement with the scan field. However, the resolution for axial scans degrades as the phantom is moved further from the center of the FOV and is positioned nearer to the edge of the detector rings. CONCLUSIONS: When it is imperative to maintain uniform longitudinal resolution throughout the FOV, it is suggested that helical acquisition be utilized or the axial mode data be reconstructed to account for beam divergence. For axial scans, this will require either limiting the longitudinal extent of each cine axial acquisition and/or using a smaller reconstructed FOV. PMID- 25281962 TI - A new markerless patient-to-image registration method using a portable 3D scanner. AB - PURPOSE: Patient-to-image registration is critical to providing surgeons with reliable guidance information in the application of image-guided neurosurgery systems. The conventional point-matching registration method, which is based on skin markers, requires expensive and time-consuming logistic support. Surface matching registration with facial surface scans is an alternative method, but the registration accuracy is unstable and the error in the more posterior parts of the head is usually large because the scan range is limited. This study proposes a new surface-matching method using a portable 3D scanner to acquire a point cloud of the entire head to perform the patient-to-image registration. METHODS: A new method for transforming the scan points from the device space into the patient space without calibration and tracking was developed. Five positioning targets were attached on a reference star, and their coordinates in the patient space were measured prior. During registration, the authors moved the scanner around the head to scan its entire surface as well as the positioning targets, and the scanner generated a unique point cloud in the device space. The coordinates of the positioning targets in the device space were automatically detected by the scanner, and a spatial transformation from the device space to the patient space could be calculated by registering them to their coordinates in the patient space that had been measured prior. A three-step registration algorithm was then used to register the patient space to the image space. The authors evaluated their method on a rigid head phantom and an elastic head phantom to verify its practicality and to calculate the target registration error (TRE) in different regions of the head phantoms. The authors also conducted an experiment with a real patient's data to test the feasibility of their method in the clinical environment. RESULTS: In the phantom experiments, the mean fiducial registration error between the device space and the patient space, the mean surface registration error, and the mean TRE of 15 targets on the surface of each phantom were 0.34 +/- 0.01 mm and 0.33 +/- 0.02 mm, 1.17 +/- 0.02 mm and 1.34 +/- 0.10 mm, and 1.06 +/- 0.11 mm and 1.48 +/- 0.21 mm, respectively. When grouping the targets according to their positions on the head, high accuracy was achieved in all parts of the head, and the TREs were similar across different regions. The authors compared their method with the current surface registration methods that use only a part of the facial surface on the elastic phantom, and the mean TRE of 15 targets was 1.48 +/- 0.21 mm and 1.98 +/- 0.53 mm, respectively. In a clinical experiment, the mean TRE of seven targets on the patient's head surface was 1.92 +/- 0.18 mm, which was sufficient to meet clinical requirements. CONCLUSIONS: The proposed surface-matching registration method provides sufficient registration accuracy even in the posterior area of the head. The 3D point cloud of the entire head, including the facial surface and the back of the head, can be easily acquired using a portable 3D scanner. The scanner does not need to be calibrated prior or tracked by the optical tracking system during scanning. PMID- 25281963 TI - Fiducial marker and marker-less soft-tissue detection using fast MV fluoroscopy on a new generation EPID: investigating the influence of pulsing artifacts and artifact suppression techniques. AB - PURPOSE: Because frame rates on current clinical available electronic portal imaging devices (EPID's) are limited to 7.5 Hz, a new commercially available PerkinElmer EPID (XRD 1642 AP19) with a maximum frame rate of 30 Hz and a new scintillator (Kyokko PI200) with improved sensitivity (light output) for megavolt (MV) irradiation was evaluated. In this work, the influence of MV pulse artifacts and pulsing artifact suppression techniques on fiducial marker and marker-less detection of a lung lesion was investigated, because target localization is an important component of uncertainty in geometrical verification of real-time tumor tracking. METHODS: VisicoilTM markers with a diameter of 0.05 and 0.075 cm were used for MV marker tracking with a frame rate of, respectively, 7.5, 15, and 30 Hz. A 30 Hz readout of the detector was obtained by a 2 * 2 pixel binning, reducing spatial resolution. Static marker detection was conducted in function of increasing phantom thickness. Additionally, marker-less tracking was conducted and compared with the ground-truth fiducial marker motion. Performance of MV target detection was investigated by comparing the least-square sine wave fit of the detected marker positions with the predefined sine wave motion. For fiducial marker detection, a Laplacian-of-Gaussian enhancement was applied after which normalized cross correlation was used to find the most probable marker position. Marker-less detection was performed by using the scale and orientation adaptive mean shift tracking algorithm. For each MV fluoroscopy, a free running (FR-nF) (ignoring MV pulsing during readout) acquisition mode was compared with two acquisition modes intending to reduce MV pulsing artifacts, i.e., combined wavelet-FFT filtering (FR-wF) and electronic readout synchronized with respect to MV pulses. RESULTS: A 0.05 cm Visicoil marker resulted in an unacceptable root mean square error (RMSE) > 0.2 cm with a maximum frame rate of 30 Hz during FR-nF readout. With a 30 Hz synchronized readout (S-nF) and during 15 Hz readout (independent of readout mode), RMSE was submillimeter for a static 0.05 cm Visicoil. A dynamic 0.05 cm Visicoil was not detectable on the XRD 1642 AP19, despite a fast synchronized readout. For a 0.075 cm Visicoil, deviations of sine wave motion were submillimeter (RMSE < 0.08 cm), independent of the acquisition mode (FR, S). For marker-less tumor detection, FR-nF images resulted in RMSE > 0.3 cm, while for MV fluoroscopy in S-mode RMSE < 0.1 cm for 15 Hz and RMSE < 0.16 cm for 30 Hz. Largest consistency in target localization was experienced during 15 Hz S-nF readout. CONCLUSIONS: In general, marker contrast decreased in function of higher frame rates, which was detrimental for marker detection success. In this work, Visicoils with a thickness of 0.075 cm were showing best results for a 15 Hz frame rate, while non-MV compatible 0.05 cm Visicoil markers were not visible on the new EPID with improved sensitivity compared to EPID models based on a Kodak Lanex Fast scintillator. No noticeable influence of pulsing artifacts on the detection of a 0.075 cm Visicoil was observed, while a synchronized readout provided most reliable detection of a marker-less soft tissue structure. PMID- 25281964 TI - Longitudinal dose distribution and energy absorption in PMMA and water cylinders undergoing CT scans. AB - PURPOSE: The knowledge of longitudinal dose distribution provides the most direct view of the accumulated dose in computed tomography (CT) scanning. The purpose of this work was to perform a comprehensive study of dose distribution width and energy absorption with a wide range of subject sizes and beam irradiated lengths. METHODS: Cumulative dose distribution along the z-axis was calculated based on the previously published CT dose equilibration data by Li, Zhang, and Liu [Med. Phys. 40, 031903 (10pp.) (2013)] and a mechanism for computing dose on axial lines by Li, Zhang, and Liu [Med. Phys. 39, 5347-5352 (2012)]. Full width at half maximum (FWHM), full width at tenth maximum (FWTM), the total energy (E) absorbed in a small cylinder of unit mass per centimeter square about the central or peripheral axis, and the energy (Ein) absorbed inside irradiated length (L) were subsequently extracted from the dose distribution. RESULTS: Extensive results of FWHM, FWTM, and Ein/E were presented on the central and peripheral axes of infinitely long PMMA (diameters 6-50 cm) and water (diameters 6-55 cm) cylinders with L < 100 cm. FWHM was greater than the primary beam width only on the central axes of large phantoms and also with L ranging from a few centimeter to about 33 cm. FWTM generally increased with phantom diameter, and could be up to 32 cm longer than irradiated length, depending on L, phantom diameter and axis, but was insensitive to phantom material (PMMA or water). Ein/E increased with L and asymptotically approached unity for large L. As phantom diameter increased, Ein/E generally decreased, but asymptotically approached constant levels on the peripheral axes of large phantoms. A heuristic explanation of dose distribution width results was presented. CONCLUSIONS: This study enables the reader to gain a comprehensive view of dose distribution width and energy absorption and provides useful data for estimating doses to organs inside or beyond the irradiated region. The dose length product (DLP) presented by CT scanners is equal to neither E nor Ein. Both E and Ein can be evaluated using the equations and results presented in this paper and are robust with both constant and variable tube current scanning techniques. PMID- 25281965 TI - Red emission phosphor for real-time skin dosimeter for fluoroscopy and interventional radiology. AB - PURPOSE: There are no effective real-time direct skin dosimeters for interventional radiology. Such a scintillation dosimeter would be available if there was a suitable red emission phosphor in the medical x-ray range, since the silicon photodiode is a highly efficient device for red light. However, it is unknown whether there is a suitable red emission phosphor. The purpose of this study is to find a suitable red emission phosphor that can be used in x-ray dosimeters. METHODS: Five kinds of phosphors which emit red light when irradiated with electron beams or ultraviolet rays in practical devices were chosen. For the brightness measurement, phosphor was put into transparent plastic cells or coated onto plastic sheets. The phosphors were irradiated with medical range x-rays [60 120 kV(peak), maximum dose rate of 160 mGymin-1], and the emission was measured by a luminance meter. Several characteristics, such as brightness, dose rate dependence, tube voltage dependence, and brightness stability, were investigated. RESULTS: The luminescence of Y V O4:Eu, (Y,Gd,Eu) BO3, and Y2O3:Eu significantly deteriorated by 5%-10% when irradiated with continuous 2 Gy x-rays. The 0.5MgF2?3.5MgO?GeO2:Mn phosphor did not emit enough. Only the Y2O2S:Eu,Sm phosphor had hardly any brightness deterioration, and it had a linear relationship so that the x-ray dose rate could be determined from the brightness with sufficient accuracy. For the tube voltage dependence of the Y2O2S:Eu,Sm phosphor, the brightness per unit dose rate with 120 kV(peak) x-rays was 30% higher than that with 60 kV(peak) x-rays. CONCLUSIONS: Five kinds of phosphors were chosen as an x-ray scintillator for a real-time direct skin dosimeter. The Y V O4:Eu, (Y,Gd,Eu)BO3, and Y2O3:Eu phosphors had brightness deterioration caused by the x-rays. Only the Y2O2S:Eu,Sm phosphor had hardly any brightness deterioration, and it is a candidate for an x-ray scintillator for such a skin dosimeter. PMID- 25281966 TI - Complex dark-field contrast and its retrieval in x-ray phase contrast imaging implemented with Talbot interferometry. AB - PURPOSE: Under the existing theoretical framework of x-ray phase contrast imaging methods implemented with Talbot interferometry, the dark-field contrast refers to the reduction in interference fringe visibility due to small-angle x-ray scattering of the subpixel microstructures of an object to be imaged. This study investigates how an object's subpixel microstructures can also affect the phase of the intensity oscillations. METHODS: Instead of assuming that the object's subpixel microstructures distribute in space randomly, the authors' theoretical derivation starts by assuming that an object's attenuation projection and phase shift vary at a characteristic size that is not smaller than the period of analyzer grating G2 and a characteristic length dc. Based on the paraxial Fresnel Kirchhoff theory, the analytic formulae to characterize the zeroth- and first order Fourier coefficients of the x-ray irradiance recorded at each detector cell are derived. Then the concept of complex dark-field contrast is introduced to quantify the influence of the object's microstructures on both the interference fringe visibility and the phase of intensity oscillations. A method based on the phase-attenuation duality that holds for soft tissues and high x-ray energies is proposed to retrieve the imaginary part of the complex dark-field contrast for imaging. Through computer simulation study with a specially designed numerical phantom, they evaluate and validate the derived analytic formulae and the proposed retrieval method. RESULTS: Both theoretical analysis and computer simulation study show that the effect of an object's subpixel microstructures on x-ray phase contrast imaging method implemented with Talbot interferometry can be fully characterized by a complex dark-field contrast. The imaginary part of complex dark-field contrast quantifies the influence of the object's subpixel microstructures on the phase of intensity oscillations. Furthermore, at relatively high energies, for soft tissues it can be retrieved for imaging with a method based on the phase-attenuation duality. CONCLUSIONS: The analytic formulae derived in this work to characterize the complex dark-field contrast in x-ray phase contrast imaging method implemented with Talbot interferometry are of significance, which may initiate more activities in the research and development of x-ray differential phase contrast imaging for extensive biomedical applications. PMID- 25281967 TI - Measurement of bow tie profiles in CT scanners using a real-time dosimeter. AB - PURPOSE: Several areas of computed tomography (CT) research require knowledge about the intensity profile of the x-ray fan beam that is introduced by a bow tie filter. This information is considered proprietary by CT manufacturers, so noninvasive measurement methods are required. One method using real-time dosimeters has been proposed in the literature. A commercially available dosimeter was used to apply that method, and analysis techniques were developed to extract fan beam profiles from measurements. METHODS: A real-time ion chamber was placed near the periphery of an empty CT gantry and the dose rate versus time waveform was recorded as the x-ray source rotated about the isocenter. In contrast to previously proposed analysis methods that assumed a pointlike detector, the finite-size ion chamber received varying amounts of coverage by the collimated x-ray beam during rotation, precluding a simple relationship between the source intensity as a function of fan beam angle and measured intensity. A two-parameter model for measurement intensity was developed that included both effective collimation width and source-to-detector distance, which then was iteratively solved to minimize the error between duplicate measurements at corresponding fan beam angles, allowing determination of the fan beam profile from measured dose-rate waveforms. Measurements were performed on five different scanner systems while varying parameters such as collimation, kVp, and bow tie filters. On one system, direct measurements of the bow tie profile were collected for comparison with the real-time dosimeter technique. RESULTS: The data analysis method for a finite-size detector was found to produce a fan beam profile estimate with a relative error between duplicate measurement intensities of <5%. It was robust over a wide range of collimation widths (e.g., 1-40 mm), producing fan beam profiles that agreed with a relative error of 1%-5%. Comparison with a direct measurement technique on one system produced agreement with a relative error of 2%-6%. Fan beam profiles were found to differ for different filter types on a given system and between different vendors. CONCLUSIONS: A commercially available real-time dosimeter probe was found to be a convenient and accurate instrument for measuring fan beam profiles. An analysis method was developed that could handle a wide range of collimation widths by explicitly considering the finite width of the ion chamber. Relative errors in the profiles were found to be less than 5%. Measurements of five different clinical scanners demonstrate the variation in bow tie designs, indicating that generic bow tie models will not be adequate for CT system research. PMID- 25281968 TI - Denoised and texture enhanced MVCT to improve soft tissue conspicuity. AB - PURPOSE: MVCT images have been used in TomoTherapy treatment to align patients based on bony anatomies but its usefulness for soft tissue registration, delineation, and adaptive radiation therapy is limited due to insignificant photoelectric interaction components and the presence of noise resulting from low detector quantum efficiency of megavoltage x-rays. Algebraic reconstruction with sparsity regularizers as well as local denoising methods has not significantly improved the soft tissue conspicuity. The authors aim to utilize a nonlocal means denoising method and texture enhancement to recover the soft tissue information in MVCT (DeTECT). METHODS: A block matching 3D (BM3D) algorithm was adapted to reduce the noise while keeping the texture information of the MVCT images. Following imaging denoising, a saliency map was created to further enhance visual conspicuity of low contrast structures. In this study, BM3D and saliency maps were applied to MVCT images of a CT imaging quality phantom, a head and neck, and four prostate patients. Following these steps, the contrast-to-noise ratios (CNRs) were quantified. RESULTS: By applying BM3D denoising and saliency map, postprocessed MVCT images show remarkable improvements in imaging contrast without compromising resolution. For the head and neck patient, the difficult-to see lymph nodes and vein in the carotid space in the original MVCT image became conspicuous in DeTECT. For the prostate patients, the ambiguous boundary between the bladder and the prostate in the original MVCT was clarified. The CNRs of phantom low contrast inserts were improved from 1.48 and 3.8 to 13.67 and 16.17, respectively. The CNRs of two regions-of-interest were improved from 1.5 and 3.17 to 3.14 and 15.76, respectively, for the head and neck patient. DeTECT also increased the CNR of prostate from 0.13 to 1.46 for the four prostate patients. The results are substantially better than a local denoising method using anisotropic diffusion. CONCLUSIONS: The authors showed that it is feasible to extract more soft tissue contrast information from the noisy MVCT images using a nonlocal means 3D block matching method in combination with saliency maps, revealing information that was originally unperceivable to human observers. PMID- 25281969 TI - Task-based optimization of dedicated breast CT via Hotelling observer metrics. AB - PURPOSE: The purpose of this work is to develop and demonstrate a set of practical metrics for CT systems optimization. These metrics, based on the Hotelling observer (HO) figure of merit, are task-based. The authors therefore take the specific example of optimizing a dedicated breast CT system, including the reconstruction algorithm, for two relevant tasks, signal detection and Rayleigh discrimination. METHODS: A dedicated breast CT system is simulated using specifications in the literature from an existing prototype. The authors optimize configuration and image reconstruction algorithm parameters for two tasks: the detection of simulated microcalcifications and the discrimination of two adjacent, high-contrast signals, known as the Rayleigh discrimination task. The effects on task performance of breast diameter, signal location, image grid size, projection view number, and reconstruction filter were all investigated. Two HO metrics were evaluated: the percentage of correct decisions in a two-alternative forced choice experiment (equivalent to area under the ROC curve or AUC), and the HO efficiency, defined as the squared ratio of HO signal-to-noise ratio (SNR) in the reconstructed image to HO SNR in the projection data. RESULTS: The ease and efficiency of the HO metric computation allows a rapid high-resolution survey of many system parameters. Optimization of a range of system parameters using the HO results in images that subjectively appear optimal for the tasks investigated. Further, the results of assessment through the HO reproduce closely many existing results in the literature regarding the impact of parameter selection on image quality. CONCLUSIONS: This study demonstrates the utility of a task-based approach to system design, evaluation, and optimization. The methodology presented is equally applicable to determining the impact of a wide range of factors, including patient parameters, system and acquisition design, and the reconstruction algorithm. The results demonstrate the versatility of the proposed HO formalism by not only generating a set of parameters that are optimal for a given task but also by qualitatively reproducing many existing results from the breast CT literature. Meanwhile, the implementation of the proposed methodology is straightforward and entirely simulation-based. This is an attractive feature for many system optimization problems, where the goal is to analyze the individual system components such as the image reconstruction algorithm. Final assessment of the system as a whole should be based also on real data studies. PMID- 25281970 TI - Evaluation of tumor localization in respiration motion-corrected cone-beam CT: prospective study in lung. AB - PURPOSE: Target localization accuracy of cone-beam CT (CBCT) images used in radiation treatment of respiratory disease sites is affected by motion artifacts (blurring and streaking). The authors have previously reported on a method of respiratory motion correction in thoracic CBCT at end expiration (EE). The previous retrospective study was limited to examination of reducing motion artifacts in a small number of patient cases. They report here on a prospective study in a larger group of lung cancer patients to evaluate respiratory motion corrected (RMC)-CBCT ability to improve lung tumor localization accuracy and reduce motion artifacts in Linac-mounted CBCT images. A second study goal examines whether the motion correction derived from a respiration-correlated CT (RCCT) at simulation yields similar tumor localization accuracy at treatment. METHODS: In an IRB-approved study, 19 lung cancer patients (22 tumors) received a RCCT at simulation, and on one treatment day received a RCCT, a respiratory-gated CBCT at end expiration, and a 1-min CBCT. A respiration monitor of abdominal displacement was used during all scans. In addition to a CBCT reconstruction without motion correction, the motion correction method was applied to the same 1 min scan. Projection images were sorted into ten bins based on abdominal displacement, and each bin was reconstructed to produce ten intermediate CBCT images. Each intermediate CBCT was deformed to the end expiration state using a motion model derived from RCCT. The deformed intermediate CBCT images were then added to produce a final RMC-CBCT. In order to evaluate the second study goal, the CBCT was corrected in two ways, one using a model derived from the RCCT at simulation [RMC-CBCT(sim)], the other from the RCCT at treatment [RMC-CBCT(tx)]. Image evaluation compared uncorrected CBCT, RMC-CBCT(sim), and RMC-CBCT(tx). The gated CBCT at end expiration served as the criterion standard for comparison. Using automatic rigid image registration, each CBCT was registered twice to the gated CBCT, first aligned to spine, second to tumor in lung. Localization discrepancy was defined as the difference between tumor and spine registration. Agreement in tumor localization with the gated CBCT was further evaluated by calculating a normalized cross correlation (NCC) of pixel intensities within a volume-of-interest enclosing the tumor in lung. RESULTS: Tumor localization discrepancy was reduced with RMC-CBCT(tx) in 17 out of 22 cases relative to no correction. If one considers cases in which tumor motion is 5 mm or more in the RCCT, tumor localization discrepancy is reduced with RMC-CBCT(tx) in 14 out of 17 cases (p = 0.04), and with RMC-CBCT(sim) in 13 out of 17 cases (p = 0.05). Differences in localization discrepancy between correction models [RMC-CBCT(sim) vs RMC-CBCT(tx)] were less than 2 mm. In 21 out of 22 cases, improvement in NCC was higher with RMC-CBCT(tx) relative to no correction (p < 0.0001). Differences in NCC between RMC-CBCT(sim) and RMC-CBCT(tx) were small. CONCLUSIONS: Motion corrected CBCT improves lung tumor localization accuracy and reduces motion artifacts in nearly all cases. Motion correction at end expiration using RCCT acquired at simulation yields similar results to that using a RCCT on the treatment day (2-3 weeks after simulation). PMID- 25281971 TI - k-space sampling optimization for ultrashort TE imaging of cortical bone: applications in radiation therapy planning and MR-based PET attenuation correction. AB - PURPOSE: The ultrashort echo-time (UTE) sequence is a promising MR pulse sequence for imaging cortical bone which is otherwise difficult to image using conventional MR sequences and also poses strong attenuation for photons in radiation therapy and PET imaging. The authors report here a systematic characterization of cortical bone signal decay and a scanning time optimization strategy for the UTE sequence through k-space undersampling, which can result in up to a 75% reduction in acquisition time. Using the undersampled UTE imaging sequence, the authors also attempted to quantitatively investigate the MR properties of cortical bone in healthy volunteers, thus demonstrating the feasibility of using such a technique for generating bone-enhanced images which can be used for radiation therapy planning and attenuation correction with PET/MR. METHODS: An angularly undersampled, radially encoded UTE sequence was used for scanning the brains of healthy volunteers. Quantitative MR characterization of tissue properties, including water fraction and R2(*) = 1/T2(*), was performed by analyzing the UTE images acquired at multiple echo times. The impact of different sampling rates was evaluated through systematic comparison of the MR image quality, bone-enhanced image quality, image noise, water fraction, and R2(*) of cortical bone. RESULTS: A reduced angular sampling rate of the UTE trajectory achieves acquisition durations in proportion to the sampling rate and in as short as 25% of the time required for full sampling using a standard Cartesian acquisition, while preserving unique MR contrast within the skull at the cost of a minimal increase in noise level. The R2(*) of human skull was measured as 0.2-0.3 ms(-1) depending on the specific region, which is more than ten times greater than the R2(*) of soft tissue. The water fraction in human skull was measured to be 60%-80%, which is significantly less than the >90% water fraction in brain. High-quality, bone-enhanced images can be generated using a reduced sampled UTE sequence with no visible compromise in image quality and they preserved bone-to-air contrast with as low as a 25% sampling rate. CONCLUSIONS: This UTE strategy with angular undersampling preserves the image quality and contrast of cortical bone, while reducing the total scanning time by as much as 75%. The quantitative results of R2(*) and the water fraction of skull based on Dixon analysis of UTE images acquired at multiple echo times provide guidance for the clinical adoption and further parameter optimization of the UTE sequence when used for radiation therapy and MR-based PET attenuation correction. PMID- 25281973 TI - Characterization of a dielectric phantom for high-field magnetic resonance imaging applications. AB - PURPOSE: In this work, a generic recipe for an inexpensive and nontoxic phantom was developed within a range of biologically relevant dielectric properties from 150 MHz to 4.5 GHz. METHODS: The recipe includes deionized water as the solvent, NaCl to primarily control conductivity, sucrose to primarily control permittivity, agar-agar to gel the solution and reduce heat diffusivity, and benzoic acid to preserve the gel. Two hundred and seventeen samples were prepared to cover the feasible range of NaCl and sucrose concentrations. Their dielectric properties were measured using a commercial dielectric probe and were fitted to a 3D polynomial to generate a recipe describing the properties as a function of NaCl concentration, sucrose concentration, and frequency. RESULTS: Results indicated that the intuitive linear and independent relationships between NaCl and conductivity and between sucrose and permittivity are not valid. A generic polynomial recipe was developed to characterize the complex relationship between the solutes and the resulting dielectric values and has been made publicly available as a web application. In representative mixtures developed to mimic brain and muscle tissue, less than 2% difference was observed between the predicted and measured conductivity and permittivity values. CONCLUSIONS: It is expected that the recipe will be useful for generating dielectric phantoms for general magnetic resonance imaging (MRI) coil development at high magnetic field strength, including coil safety evaluation as well as pulse sequence evaluation (including B1(+) mapping, B1(+) shimming, and selective excitation pulse design), and other non-MRI applications which require biologically equivalent dielectric properties. PMID- 25281974 TI - Denoising of B1+ field maps for noise-robust image reconstruction in electrical properties tomography. AB - PURPOSE: To validate the use of adaptive nonlinear filters in reconstructing conductivity and permittivity images from the noisy B1(+) maps in electrical properties tomography (EPT). METHODS: In EPT, electrical property images are computed by taking Laplacian of the B1(+) maps. To mitigate the noise amplification in computing the Laplacian, the authors applied adaptive nonlinear denoising filters to the measured complex B1(+) maps. After the denoising process, they computed the Laplacian by central differences. They performed EPT experiments on phantoms and a human brain at 3 T along with corresponding EPT simulations on finite-difference time-domain models. They evaluated the EPT images comparing them with the ones obtained by previous EPT reconstruction methods. RESULTS: In both the EPT simulations and experiments, the nonlinear filtering greatly improved the EPT image quality when evaluated in terms of the mean and standard deviation of the electrical property values at the regions of interest. The proposed method also improved the overall similarity between the reconstructed conductivity images and the true shapes of the conductivity distribution. CONCLUSIONS: The nonlinear denoising enabled us to obtain better quality EPT images of the phantoms and the human brain at 3 T. PMID- 25281972 TI - Stereovision to MR image registration for cortical surface displacement mapping to enhance image-guided neurosurgery. AB - PURPOSE: A surface registration method is presented to align intraoperative stereovision (iSV) with preoperative magnetic resonance (pMR) images, which utilizes both geometry and texture information to extract tissue displacements as part of the overall process of compensating for intraoperative brain deformation in order to maintain accurate neuronavigational image guidance during surgery. METHODS: A sum-of-squared-difference rigid image registration was first executed to detect lateral shift of the cortical surface and was followed by a mutual information-based block matching method to detect local nonrigid deformation caused by distention or collapse of the cortical surface. Ten (N = 10) surgical cases were evaluated in which an independent point measurement of a dominant cortical surface feature location was recorded with a tracked stylus in each case and compared to its surface-registered counterpart. The full three-dimensional (3D) displacement field was also extracted to drive a biomechanical brain deformation model, the results of which were reconciled with the reconstructed iSV surface as another form of evaluation. RESULTS: Differences between the tracked stylus coordinates of cortical surface features and their surface registered locations were 1.94 +/- 0.59 mm on average across the ten cases. When the complete displacement map derived from surface registration was utilized, the resulting images generated from mechanical model updates were consistent in terms of both geometry (1-2 mm of model misfit) and texture, and were generated with less than 10 min of computational time. Analysis of the surface-registered 3D displacements indicate that the magnitude of motion ranged from 4.03 to 9.79 mm in the ten patient cases, and the amount of lateral shift was not related statistically to the direction of gravity (p = 0.73 ? 0.05) or the craniotomy size (p = 0.48 ? 0.05) at the beginning of surgery. CONCLUSIONS: The iSV-pMR surface registration method utilizes texture and geometry information to extract both global lateral shift and local nonrigid movement of the cortical surface in 3D. The results suggest small differences exist in surface-registered locations when compared to positions measured independently with a coregistered stylus and when the full iSV surface was aligned with model-updated MR. The effectiveness and efficiency of the registration method is also minimally disruptive to surgical workflow. PMID- 25281975 TI - Fully automated framework for the analysis of myocardial first-pass perfusion MR images. AB - PURPOSE: To develop an automated framework for accurate analysis of myocardial perfusion using first-pass magnetic resonance imaging. METHODS: The proposed framework consists of four processing stages. First, in order to account for heart deformations due to respiratory motion and heart contraction, a two-step registration methodology is proposed, which has the ability to account for the global and local motions of the heart. The methodology involves an affine-based registration followed by a local B-splines alignment to maximize a new similarity function based on the first- and second-order normalized mutual information. Then the myocardium is segmented using a level-set function, its evolution being constrained by three features, namely, a weighted shape prior, a pixelwise mixed object/background image intensity distribution, and an energy of a second-order binary Markov-Gibbs random field spatial model. At the third stage, residual segmentation errors and imperfection of image alignment are reduced by employing a Laplace-based registration refinement step that provides accurate pixel-on pixel matches on all segmented frames to generate accurate parametric perfusion maps. Finally, physiology is characterized by pixel-by-pixel mapping of empirical indexes (peak signal intensity, time-to-peak, initial upslope, and the average signal change of the slowly varying agent delivery phase), based on contrast agent dynamics. RESULTS: The authors tested our framework on 24 perfusion data sets from 8 patients with ischemic damage who are undergoing a novel myoregeneration therapy. The performance of the processing steps of our framework is evaluated using both synthetic and in-vivo data. First, our registration methodology is evaluated using realistic synthetic phantoms and a distance-based error metric, and an improvement of registration is documented using the proposed similarity measure (P-value <=10(-4)). Second, evaluation of our segmentation using the Dice similarity coefficient, documented an average of 0.910 +/- 0.037 compared to two other segmentation methods that achieved average values of 0.862 +/- 0.045 and 0.844 +/- 0.047. Also, the receiver operating characteristic (ROC) analysis of our multifeature segmentation yielded an area under the ROC curve of 0.92, while segmentation based intensity alone showed low performance (an area of 0.69). Moreover, our framework indicated the ability, using empirical perfusion indexes, to reveal regional perfusion improvements with therapy and transmural perfusion differences across the myocardial wall. CONCLUSIONS: By quantitative and visual assessment, our framework documented the ability to characterize regional and transmural perfusion, thereby it augmenting the ability to assess follow-up treatment for patients undergoing myoregeneration therapy. This is afforded by our framework being able to handle both global and local deformations of the heart, segment accurately the myocardial wall, and provide accurate pixel on-pixel matches of registered perfusion images. PMID- 25281976 TI - Detection and severity classification of extracardiac interference in 82Rb PET myocardial perfusion imaging. AB - PURPOSE: Myocardial perfusion imaging (MPI) is used for diagnosis and prognosis of coronary artery disease. When MPI studies are performed with positron emission tomography (PET) and the radioactive tracer rubidium-82 chloride ((82)Rb), a small but non-negligible fraction of studies (~10%) suffer from extracardiac interference: high levels of tracer uptake in structures adjacent to the heart which mask the true cardiac tracer uptake. At present, there are no clinically available options for automated detection or correction of this problem. This work presents an algorithm that detects and classifies the severity of extracardiac interference in (82)Rb PET MPI images and reports the accuracy and failure rate of the method. METHODS: A set of 200 (82)Rb PET MPI images were reviewed by a trained nuclear cardiologist and interference severity reported on a four-class scale, from absent to severe. An automated algorithm was developed that compares uptake at the external border of the myocardium to three thresholds, separating the four interference severity classes. A minimum area of interference was required, and the search region was limited to that facing the stomach wall and spleen. Maximizing concordance (Cohen's Kappa) and minimizing failure rate for the set of 200 clinician-read images were used to find the optimal population-based constants defining search limit and minimum area parameters and the thresholds for the algorithm. Tenfold stratified cross validation was used to find optimal thresholds and report accuracy measures (sensitivity, specificity, and Kappa). RESULTS: The algorithm was capable of detecting interference with a mean [95% confidence interval] sensitivity/specificity/Kappa of 0.97 [0.94, 1.00]/0.82 [0.66, 0.98]/0.79 [0.65, 0.92], and a failure rate of 1.0% +/- 0.2%. The four-class overall Kappa was 0.72 [0.64, 0.81]. Separation of mild versus moderate-or-greater interference was performed with good accuracy (sensitivity/specificity/Kappa = 0.92 [0.86, 0.99]/0.86 [0.71, 1.00]/0.78 [0.64, 0.92]), while separation of moderate versus severe interference severity classes showed reduced sensitivity/Kappa but little change in specificity (sensitivity/specificity/Kappa = 0.83 [0.77, 0.88]/0.82 [0.77, 0.88]/0.65 [0.60, 0.70]). Specificity was greater than sensitivity for all interference classes. Algorithm execution time was <1 min. CONCLUSIONS: The algorithm produced here has a low failure rate and high accuracy for detection of extracardiac interference in (82)Rb PET MPI scans. It provides a fast, reliable, automated method for assessing severity of extracardiac interference. PMID- 25281977 TI - Scattered PET data for attenuation-map reconstruction in PET/MRI. AB - PURPOSE: In hybrid medical imaging devices combining positron emission tomography (PET) with magnetic resonance imaging, PET attenuation correction remains challenging. Known approaches to estimating attenuation (MU-)maps from PET emission data, especially maximum-likelihood reconstruction of activity and attenuation (MLAA), take into account true coincidences only and exhibit two kinds of ambiguities: First, the attenuation sinogram can only be determined up to a constant offset (sinogram ambiguity). Second, the attenuation sinogram is unknown outside of the support of the activity sinogram and does not completely define a MU-map (image-space ambiguity). In this work, the authors aim at using additional information from scattered coincidences to resolve these ambiguities- information that is unavailable using true coincidences. METHODS: The authors propose a two-level scheme for combining measurements of true and scattered coincidences. On the top level, scatter-to-attenuation (S2A) reconstruction recovers the MU-map from a measurement of scattered coincidences and results available from trues-based algorithms. On the lower level, S2A reconstruction is implemented by iterative scatter simulation and a proposed (simplified) S2A back projection. The S2A back-projection is based on determining possible scattering locations in image space from energy measurements (via Compton-scattering angles) and summing contributions from scattered coincidences in image space. S2A back projection is validated with GATE simulations of activity-attenuation configurations with both sinogram and image-space ambiguities. The authors further evaluate the impact of asymmetric source and activity distributions, extended source distributions, and energy uncertainty to demonstrate the limitations of the simplified noniterative S2A back-projection approach. Feasibility of the iterative S2A reconstruction is evaluated in a low-resolution, analytical 2D problem. RESULTS: S2A back-projection of scattered coincidences with scattered-photon energies in the range of 248-478 keV provides image-space information about the attenuation distribution, even in challenging cases of perfect spherical symmetry of attenuation and activity distributions as well as attenuation outside of the activity support. Realistic energy uncertainties (5% and 10% full width at half maximum at 511 keV) deteriorate spatial image resolution in the proposed noniterative method. The iterative S2A reconstruction is able to recover the full MU-map (errors less than 3.7 * 10(-5)/cm) as well as the unknown scaling factor (error smaller than 0.0005%) from scattered coincidences and an activity distribution with unknown scaling. CONCLUSIONS: Scattered coincidences provide information to complement existing PET attenuation correction approaches such as MLAA. The proposed scatter-to-attenuation back projection and reconstruction may constitute a missing piece for resolving ambiguities in the simultaneous reconstruction of activity and attenuation, and improving the quality of MU-maps reconstructed from PET emission data. PMID- 25281978 TI - Validation of simplified dosimetry approaches in 89Zr-PET/CT: the use of manual versus semi-automatic delineation methods to estimate organ absorbed doses. AB - PURPOSE: Increasing interest in immuno-positron emission tomography (PET) studies requires development of dosimetry methods which will provide accurate estimations of organ absorbed doses. The purpose of this study is to develop and validate simplified dosimetry approaches for (89)Zirconium-PET (Zr-PET)/computed tomography (CT) studies. METHODS: Five patients with advanced colorectal cancer received 37.1 +/- 0.9 MBq (89)Zr-cetuximab within 2 h after administration of a therapeutic dose of 500 mg m(-2) cetuximab. PET/CT scans were obtained 1, 24, 48, 94, and 144 h post injection. Volumes of interest (VOIs) were manually delineated in lungs, liver, spleen, and kidneys for all scans, providing a reference VOI set. Simplified manual VOIs were drawn independently on CT scans using larger voxel sizes. The transformation of VOIs based on rigid and/or nonrigid registrations of the first CT scan (CT1) onto all successive CT scans was also investigated. The transformation matrix obtained from each registration was applied to the manual VOIs of CT1 to obtain VOIs for the successive scans. Dice similarity coefficient (DSC) and Hausdorff distance were used to assess the performance of the registrations. Organ total activity, organ absorbed dose, and effective dose were calculated for all methods. RESULTS: Semi-automatic delineation based on nonrigid registration showed excellent agreement for lungs and liver (DSC: 0.90 +/- 0.04; 0.81 +/- 0.06) and good agreement for spleen and kidneys (DSC: 0.71 +/- 0.07; 0.66 +/- 0.08). Hausdorff distance ranged from 13 to 16 mm depending on the organ. Simplified manual delineation methods, in liver and lungs, performed similarly to semi-automatic delineation methods. For kidneys and spleen, however, poorer accuracy in total activity and absorbed dose was observed, as the voxel size increased. Organ absorbed dose and total activity based on nonrigid registration were within 10%. The effective dose was within +/ 3% for all VOI delineation methods. CONCLUSIONS: A fast, semi-automatic, and accurate delineation method based on nonrigid registration was developed for determination of organ absorbed and effective dose in (89)Zr-PET/CT studies which may also be applied to other long-lived radionuclide PET/CT studies. PMID- 25281980 TI - Integration of optical imaging with a small animal irradiator. AB - PURPOSE: The authors describe the integration of optical imaging with a targeted small animal irradiator device, focusing on design, instrumentation, 2D to 3D image registration, 2D targeting, and the accuracy of recovering and mapping the optical signal to a 3D surface generated from the cone-beam computed tomography (CBCT) imaging. The integration of optical imaging will improve targeting of the radiation treatment and offer longitudinal tracking of tumor response of small animal models treated using the system. METHODS: The existing image-guided small animal irradiator consists of a variable kilovolt (peak) x-ray tube mounted opposite an aSi flat panel detector, both mounted on a c-arm gantry. The tube is used for both CBCT imaging and targeted irradiation. The optical component employs a CCD camera perpendicular to the x-ray treatment/imaging axis with a computer controlled filter for spectral decomposition. Multiple optical images can be acquired at any angle as the gantry rotates. The optical to CBCT registration, which uses a standard pinhole camera model, was modeled and tested using phantoms with markers visible in both optical and CBCT images. Optically guided 2D targeting in the anterior/posterior direction was tested on an anthropomorphic mouse phantom with embedded light sources. The accuracy of the mapping of optical signal to the CBCT surface was tested using the same mouse phantom. A surface mesh of the phantom was generated based on the CBCT image and optical intensities projected onto the surface. The measured surface intensity was compared to calculated surface for a point source at the actual source position. The point-source position was also optimized to provide the closest match between measured and calculated intensities, and the distance between the optimized and actual source positions was then calculated. This process was repeated for multiple wavelengths and sources. RESULTS: The optical to CBCT registration error was 0.8 mm. Two-dimensional targeting of a light source in the mouse phantom based on optical imaging along the anterior/posterior direction was accurate to 0.55 mm. The mean square residual error in the normalized measured projected surface intensities versus the calculated normalized intensities ranged between 0.0016 and 0.006. Optimizing the position reduced this error from 0.00016 to 0.0004 with distances ranging between 0.7 and 1 mm between the actual and calculated position source positions. CONCLUSIONS: The integration of optical imaging on an existing small animal irradiation platform has been accomplished. A targeting accuracy of 1 mm can be achieved in rigid, homogeneous phantoms. The combination of optical imaging with a CBCT image-guided small animal irradiator offers the potential to deliver functionally targeted dose distributions, as well as monitor spatial and temporal functional changes that occur with radiation therapy. PMID- 25281979 TI - 4D numerical observer for lesion detection in respiratory-gated PET. AB - PURPOSE: Respiratory-gated positron emission tomography (PET)/computed tomography protocols reduce lesion smearing and improve lesion detection through a synchronized acquisition of emission data. However, an objective assessment of image quality of the improvement gained from respiratory-gated PET is mainly limited to a three-dimensional (3D) approach. This work proposes a 4D numerical observer that incorporates both spatial and temporal informations for detection tasks in pulmonary oncology. METHODS: The authors propose a 4D numerical observer constructed with a 3D channelized Hotelling observer for the spatial domain followed by a Hotelling observer for the temporal domain. Realistic (18)F fluorodeoxyglucose activity distributions were simulated using a 4D extended cardiac torso anthropomorphic phantom including 12 spherical lesions at different anatomical locations (lower, upper, anterior, and posterior) within the lungs. Simulated data based on Monte Carlo simulation were obtained using geant4 application for tomographic emission (GATE). Fifty noise realizations of six respiratory-gated PET frames were simulated by GATE using a model of the Siemens Biograph mMR scanner geometry. PET sinograms of the thorax background and pulmonary lesions that were simulated separately were merged to generate different conditions of the lesions to the background (e.g., lesion contrast and motion). A conventional ordered subset expectation maximization (OSEM) reconstruction (5 iterations and 6 subsets) was used to obtain: (1) gated, (2) nongated, and (3) motion-corrected image volumes (a total of 3200 subimage volumes: 2400 gated, 400 nongated, and 400 motion-corrected). Lesion-detection signal-to-noise ratios (SNRs) were measured in different lesion-to-background contrast levels (3.5, 8.0, 9.0, and 20.0), lesion diameters (10.0, 13.0, and 16.0 mm), and respiratory motion displacements (17.6-31.3 mm). The proposed 4D numerical observer applied on multiple-gated images was compared to the conventional 3D approach applied on the nongated and motion-corrected images. RESULTS: On average, the proposed 4D numerical observer improved the detection SNR by 48.6% (p < 0.005), whereas the 3D methods on motion-corrected images improved by 31.0% (p < 0.005) as compared to the nongated method. For all different conditions of the lesions, the relative SNR measurement (Gain = SNRObserved/SNRNongated) of the 4D method was significantly higher than one from the motion-corrected 3D method by 13.8% (p < 0.02), where Gain4D was 1.49 +/- 0.21 and Gain3D was 1.31 +/- 0.15. For the lesion with the highest amplitude of motion, the 4D numerical observer yielded the highest observer-performance improvement (176%). For the lesion undergoing the smallest motion amplitude, the 4D method provided superior lesion detectability compared with the 3D method, which provided a detection SNR close to the nongated method. The investigation on a structure of the 4D numerical observer showed that a Laguerre-Gaussian channel matrix with a volumetric 3D function yielded higher lesion-detection performance than one with a 2D-stack-channelized function, whereas a different kind of channels that have the ability to mimic the human visual system, i.e., difference of-Gaussian, showed similar performance in detecting uniform and spherical lesions. The investigation of the detection performance when increasing noise levels yielded decreasing detection SNR by 27.6% and 41.5% for the nongated and gated methods, respectively. The investigation of lesion contrast and diameter showed that the proposed 4D observer preserved the linearity property of an optimal-linear observer while the motion was present. Furthermore, the investigation of the iteration and subset numbers of the OSEM algorithm demonstrated that these parameters had impact on the lesion detectability and the selection of the optimal parameters could provide the maximum lesion-detection performance. The proposed 4D numerical observer outperformed the other observers for the lesion-detection task in various lesion conditions and motions. CONCLUSIONS: The 4D numerical observer shows substantial improvement in lesion detectability over the 3D observer method. The proposed 4D approach could potentially provide a more reliable objective assessment of the impact of respiratory-gated PET improvement for lesion-detection tasks. On the other hand, the 4D approach may be used as an upper bound to investigate the performance of the motion correction method. In future work, the authors will validate the proposed 4D approach on clinical data for detection tasks in pulmonary oncology. PMID- 25281981 TI - Phase synchronization analysis of prefrontal tissue oxyhemoglobin oscillations in elderly subjects with cerebral infarction. AB - PURPOSE: This study aims to assess the phase relationship of prefrontal tissue oxyhemoglobin oscillations using wavelet phase coherence analysis of cerebral Delta [HbO2] signals in cerebral infarction (CI) patients during the resting state. METHODS: Continuous recordings of near-infrared spectroscopy signals were obtained from the left and right prefrontal lobes in 21 subjects with CI (Group CI, age: 76.6 +/- 8.5 yr) and 21 healthy elderly subjects (Group Healthy, age: 69.0 +/- 7.4 yr) during the resting state. The Group CI was further divide into two groups: CI with hypertension and CI without hypertension. The phase synchronization between left and right prefrontal Delta [HbO2] oscillations in four frequency intervals (I, 0.6-2 Hz; II, 0.145-0.6 Hz; III, 0.052-0.145 Hz; and IV, 0.021-0.052 Hz) was analyzed using wavelet phase coherence method. RESULTS: The phase coherences in intervals III and IV were significantly lower in CI with hypertension than in healthy elderly subjects (F = 12.974, p = 0.001 for III and F = 10.073, p = 0.004 for interval IV). The phase coherence of CI without hypertension in interval III was significantly lower than in healthy elderly subjects (F = 9.909, p = 0.004). Also, the phase coherence in interval IV was significantly lower in CI with hypertension than in CI without hypertension (F = 5.665, p = 0.028). Also, the phase agreement in interval IV showed evident difference between Group CI with hypertension and without hypertension. CONCLUSIONS: The difference in phase characteristics of prefrontal tissue oxyhemoglobin oscillations between the CI patients and healthy elderly indicates altered phase synchronization. Moreover, the CI combined with hypertension would aggravate this process. This study provides new insight into the phase dynamics of cerebral oxygenation and may be useful in assessing the risk for stroke. PMID- 25281982 TI - Vaporization dynamics of volatile perfluorocarbon droplets: a theoretical model and in vitro validation. AB - PURPOSE: Perfluorocarbon (PFC) microdroplets, called phase-change contrast agents (PCCAs), are a promising tool in ultrasound imaging and therapy. Interest in PCCAs is motivated by the fact that they can be triggered to transition from the liquid state to the gas state by an externally applied acoustic pulse. This property opens up new approaches to applications in ultrasound medicine. Insight into the physics of vaporization of PFC droplets is vital for effective use of PCCAs and for anticipating bioeffects. PCCAs composed of volatile PFCs (with low boiling point) exhibit complex dynamic behavior: after vaporization by a short acoustic pulse, a PFC droplet turns into a vapor bubble which undergoes overexpansion and damped radial oscillation until settling to a final diameter. This behavior has not been well described theoretically so far. The purpose of our study is to develop an improved theoretical model that describes the vaporization dynamics of volatile PFC droplets and to validate this model by comparison with in vitro experimental data. METHODS: The derivation of the model is based on applying the mathematical methods of fluid dynamics and thermodynamics to the process of the acoustic vaporization of PFC droplets. The used approach corrects shortcomings of the existing models. The validation of the model is carried out by comparing simulated results with in vitro experimental data acquired by ultrahigh speed video microscopy for octafluoropropane (OFP) and decafluorobutane (DFB) microdroplets of different sizes. RESULTS: The developed theory allows one to simulate the growth of a vapor bubble inside a PFC droplet until the liquid PFC is completely converted into vapor, and the subsequent overexpansion and damped oscillations of the vapor bubble, including the influence of an externally applied acoustic pulse. To evaluate quantitatively the difference between simulated and experimental results, the L2-norm errors were calculated for all cases where the simulated and experimental results are compared. These errors were found to be in the ranges of 0.043-0.067 and 0.037 0.088 for OFP and DFB droplets, respectively. These values allow one to consider agreement between the simulated and experimental results as good. This agreement is attained by varying only 2 of 16 model parameters which describe the material properties of gaseous and liquid PFCs and the liquid surrounding the PFC droplet. The fitting parameters are the viscosity and the surface tension of the surrounding liquid. All other model parameters are kept invariable. CONCLUSIONS: The good agreement between the theoretical and experimental results suggests that the developed model is able to correctly describe the key physical processes underlying the vaporization dynamics of volatile PFC droplets. The necessity of varying the parameters of the surrounding liquid for fitting the experimental curves can be explained by the fact that the parts of the initial phospholipid shell of PFC droplets remain on the surface of vapor bubbles at the oscillatory stage and their presence affects the bubble dynamics. PMID- 25281983 TI - Automatic slice selection and diagnosis of breast strain elastography. AB - PURPOSE: Generally speaking, breast imaging experts and physicians select a representative slice from the strain elastographic image sequences to diagnose the tumor. Given the strain image qualities, it is difficult to make a successful diagnosis using human eyes only. The main purpose of this study is to develop an automatic and reliable method to select the representative slice from the elastography cine loops and/or video and then diagnose the tumor by means of the elastographic features generated from the selected slice. METHODS: In this study, the authors collected 80 biopsy-proven breast tumors, comprising of 45 benign and 35 malignant lesions, to estimate the performance of the automatic slice selection method. Images chosen using several slice selection criteria (e.g., whole-image analysis or tumor region analysis) were compared to the physician selected images to determine the best selection criterion. The level set tumor segmentation method was applied to the corresponding B-mode part of the representative elastographic slice to overlap tumor boundaries on strain images and to calculate elastographic features for diagnosis. RESULTS: The experiment showed that the diagnostic performance, in terms of accuracy, sensitivity, and specificity, evaluated by the leave-one-out method, based on the elastographic features for the representative slice selected by the proposed slice selection method, was 71.3%, 91.4%, and 55.6%, respectively, while the performance values for the physician-selected slice were 65.0%, 77.1%, and 55.6%, respectively. CONCLUSIONS: Both the sensitivity and accuracy of the proposed slice selection method were better than those of the physician-selected slice, and the specificity of these two different schemes is similar. According to the statistical analysis of experimental results, the performance of the proposed slice selection method was similar to that of the physician's selection. The authors concluded that the proposed slice selection method could assist the physician in selecting the appropriate representative slice and in decreasing the time of selection. PMID- 25281984 TI - A multiscale adaptive mask method for rigid intraoperative ultrasound and preoperative CT image registration. AB - PURPOSE: Rigid registration of intraoperative ultrasound (US) and preoperative CT image is important for providing real-time guidance during operations. However, due to the low spatial and temporal resolutions and the dissimilarity between US and CT, accurate registration of CT and US images is still a challenging problem. METHODS: The authors propose an adaptive-mask-based CT and US registration method. The registration is initialized by matching the image regions of CT and US with intensity distinctiveness. The registration is a multistage iterative process in which the US region mask is adaptively updated. Each stage is an interleaving process of optimizing a global similarity energy and updating the mask of US by selecting high saliency and local statistical dependency regions. RESULTS: Performances of their proposed method and mutual information (MI) based method are validated with simulated, in vitro phantom and real patient datasets. Results show that their method has larger capture range in all datasets. The estimated transformation parameters in their method are more accurate than the mutual information based method. CONCLUSIONS: By using an adaptively updated mask of the US image, regions with salient intensity information and high intensity correlation with CT are included in the registration. Regions which have low correlation with CT such as artifacts are excluded in the registration so that the robustness and accuracy of the intensity-based registration method are improved. PMID- 25281985 TI - Breast cancer detection using interferometric MUSIC: experimental and numerical assessment. AB - PURPOSE: In microwave breast cancer detection, it is often beneficial to arrange sensors in close proximity to the breast. The resultant coupling generally changes the antenna response. As an a priori characterization of the radio frequency system becomes difficult, this can lead to severe degradation of the detection efficacy. The purpose of this paper is to demonstrate the advantages of adopting an interferometric multiple signal classification (I-MUSIC) approach due to its limited dependence from a priori information on the antenna. The performance of I-MUSIC detection was measured in terms of signal-to-clutter ratio (SCR), signal-to-mean ratio (SMR), and spatial displacement (SD) and compared to other common linear noncoherent imaging methods, such as migration and the standard wideband MUSIC (WB-MUSIC) which also works when the antenna is not accounted for. METHODS: The data were acquired by scanning a synthetic oil-in gelatin phantom that mimics the dielectric properties of breast tissues across the spectrum 1-3 GHz using a proprietary breast microwave multi-monostatic radar system. The phantom is a multilayer structure that includes skin, adipose, fibroconnective, fibroglandular, and tumor tissue with an adipose component accounting for 60% of the whole structure. The detected tumor has a diameter of 5 mm and is inserted inside a fibroglandular region with a permittivity contrast epsilonr-tumor/epsilonr-fibroglandular < 1.5 over the operating band. Three datasets were recorded corresponding to three antennas with different coupling mechanisms. This was done to assess the independence of the I-MUSIC method from antenna characterizations. The datasets were processed by using I-MUSIC, noncoherent migration, and wideband MUSIC under equivalent conditions (i.e., operative bandwidth, frequency samples, and scanning positions). SCR, SMR, and SD figures were measured from all reconstructed images. In order to benchmark experimental results, numerical simulations of equivalent scenarios were carried out by using CST Microwave Studio. The three numerical datasets were then processed following the same procedure that was designed for the experimental case. RESULTS: Detection results are presented for both experimental and numerical phantoms, and higher performance of the I-MUSIC method in comparison with the WB-MUSIC and noncoherent migration is achieved. This finding is confirmed for the three different antennas in this study. Although a delocalization effect occurs, experimental datasets show that the signal-to clutter ratio and the signal-to-mean performance with the I-MUSIC are at least 5 and 2.3 times better than the other methods, respectively. The numerical datasets calculated on an equivalent phantom for cross-testing confirm the improved performance of the I-MUSIC in terms of SCR and SMR. In numerical simulations, the delocalization effect is dramatically reduced up to an SD value of 1.61 achieved with the I-MUSIC in combination with the antipodal Vivaldi antenna. This shows that mechanical uncertainties are the main reason for the delocalization effect in the measurements. CONCLUSIONS: Experimental results show that the I-MUSIC generates images with signal-to-clutter levels higher than 5.46 dB across all working conditions and it reaches 7.84 dB in combination with the antipodal Vivaldi antenna. Numerical simulations confirm this trend and due to ideal mechanical conditions return a signal-to-clutter level higher than 7.61 dB. The I MUSIC largely outperforms the methods under comparison and is able to detect a 5 mm tumor with a permittivity contrast of 1.5. PMID- 25281986 TI - Comment on "A method for multichannel dosimetry with EBT3 radiochromic films" [Med. Phys. 41, 062101 (10pp.) (2014)]. PMID- 25281987 TI - Response to "Comment on 'A method for multichannel dosimetry with EBT3 radiochromic films' " [Med. Phys. 41, 062101 (10pp.) (2014)]. PMID- 25281989 TI - Regulation of assisted reproduction in the USA--a just target or a target of unfair criticism? PMID- 25281990 TI - Mental health of single fathers living in an urban community in South Korea. AB - OBJECTIVE: The aims of this study were to understand the mental health of single fathers relative to married fathers as the population of single fathers continues to increase and to use the resultant data for the establishment of public health policies. METHODS: We evaluated the mental health of 58 single fathers and 256 married fathers living in an urban community in South Korea. Self-reported questionnaires including the Global Assessment of Recent Stress, Center for Epidemiologic Studies-Depression, Scale for Suicidal Ideation, the Korean version of the Alcohol Use Disorder Identification Test, and the World Health Organization Quality of Life Assessment Instrument were used for evaluation. The mental health scale scores and the prevalence of mental health problems were compared between the single and the married fathers. We also assessed the factors associated with poor QOL, depressive symptoms, and severe stress among single fathers. RESULTS: The single fathers had poorer quality of life (OR 7.30, 95% CI 2.82-18.74), more depressive symptoms (OR 3.85, 95% CI 1.29-11.45), and more stress (OR 3.36, 95% CI 1.25-8.98) than did the married fathers even after controlling for socio-demographic factors. Among the single fathers, poor socioeconomic conditions, such as no house ownership, manual occupations, having two or more children, and having a youngest child in elementary school or middle school, were significantly associated with poorer mental health. CONCLUSIONS: This study demonstrated that single fathers have poorer mental health than do married fathers. Single parenthood was significantly associated with their mental health. Therefore, we should attempt to provide practical support to reduce the social burden and offer earlier psychological interventions to reduce distress in single fathers. PMID- 25281991 TI - Predictors of life disability in trichotillomania. AB - BACKGROUND: Limited research has investigated disability and functional impairment in trichotillomania (TTM) subjects. This study examined the relationships between hair pulling (HP) style and severity and disability while controlling for mood severity. Disability was measured in individual life areas (work, social, and family/home life) instead of as a total disability score as in previous studies. METHODS: One hundred fifty three adult hair pullers completed several structured interviews and self-report instruments. HP style and severity, as well as depression, anxiety, and stress were correlated with work, social, and family/home life impairment on the Sheehan Disability Scale (SDS). Multiple regression analyses were performed to determine significant predictors of life impairment. RESULTS: Depressive severity was a significant predictor for all SDS life areas. In addition, interference/avoidance associated with HP was a predictor for work and social life disability. Distress from HP was a significant predictor of social and family/home life disability. Focused HP score and anxiety were significant predictors of family/home life disability. CONCLUSIONS: As expected, depression in hair pullers predicted disability across life domains. Avoiding work and social situations can seriously impair functioning in those life domains. Severity of distress and worry about HP may be most elevated in social situations with friends and family and thus predict impairment in those areas. Finally, since HP often occurs at home, time spent in focused hair pulling would have a greater negative impact on family and home responsibilities than social and work life. PMID- 25281992 TI - Effects of aripiprazole once-monthly on domains of personal and social performance: results from 2 multicenter, randomized, double-blind studies. AB - OBJECTIVE: To assess the effects of maintenance therapy with aripiprazole once monthly 400mg on personal and social functioning. METHODS: Data were analyzed from 2 randomized, double-blind trials of patients with schizophrenia requiring chronic antipsychotic treatment. One study was a 52-week trial of aripiprazole once-monthly 400mg versus placebo; the other was a 38-week trial of aripiprazole once-monthly 400mg, oral aripiprazole (10-30 mg daily), and aripiprazole once monthly 50mg (subtherapeutic dose to test assay sensitivity). Functioning was assessed using the Personal and Social Performance (PSP) scale, comprising 4 domain subscales. RESULTS: In the 52-week study, 403 patients stabilized on aripiprazole once-monthly 400mg were randomized to receive aripiprazole once monthly 400mg (n=269) or placebo (n=134). In the 38-week study, 662 patients stabilized on oral aripiprazole were randomized to receive aripiprazole once monthly 400mg (n=265), oral aripiprazole (n=266), or aripiprazole once-monthly 50mg (subtherapeutic dose; n=131). In the 52-week study, mean changes from baseline were significantly worsened with placebo compared with aripiprazole once monthly 400mg for PSP total score (P<0.001) and domain scores for Personal and Social Relationships (P<0.001), Self-Care (P<0.01), and Disturbing and Aggressive Behavior (P<0.0001). In the 38-week study, mean changes from baseline were significantly worsened with aripiprazole once-monthly 50mg compared with aripiprazole once-monthly 400mg for PSP total score (P<0.05) and the Personal and Social Relationships domain score (P<0.05). CONCLUSION: Patient functioning, assessed using the PSP scale, was maintained in stabilized patients treated with aripiprazole once-monthly in 2 pivotal relapse studies. PMID- 25281993 TI - FemoSeal Evaluation Registry (FER). Prospective study of femoral arterial closure with a mechanical system on 100 patients who underwent angioplasty procedures. AB - BACKGROUND: The objective of this study is to evaluate the effectiveness and the safety of the FemoSeal mechanical closure system in order to obtain hemostasis of the puncture site following angioplasty procedures performed through femoral arterial approach. METHOD: A single-centre prospective registry was conducted from November 2010 to April 2011, comparing the results of manual compression (n=111 patients), hemostatic bandages compression (n=43 patients) and FemoSeal mechanical closure (n=100 patients). The end points evaluated were the following: successful hemostasis, major and minor complications right after the procedures and major and minor complications at 1 month follow-up. The patients' feedback about their comfort was also collected right after the procedure and after one month. RESULTS: Successful hemostasis with FemoSeal was obtained in 93% of the patients (n=93). Seven patients required additional slight manual compressions or compression bandages. The use of FemoSeal was not associated with any major complications, significantly reducing (P<0.05) the number of complications compared to other compression techniques over the studied period. Only one minor complication was observed with FemoSeal (a 1.5-cm-hematoma, which reabsorbed spontaneously without any issue). CONCLUSION: In our experience, the use of FemoSeal is effective in achieving hemostasis performed through femoral arterial approach up to 7F and is associated with a very low rate of complications. PMID- 25281995 TI - [Sudden cardiac death in the youth. Is the new subcutaneous implantable cardioverter defibrillator S-ICD an alternative solution?]. AB - Implantable cardioverter defibrillator (ICD) is well-recognized therapy to prevent sudden cardiac death. Classic ICD need the use of permanent endocavitary leads, which may cause serious troubles (lead dislodgement, ventricular perforation, lead infections, etc.). The subcutaneous implantable cardioverter defibrillator (S-ICD) is a new device provided by only a subcutaneous lead. It has been developed for the last five years and it is becoming at present a real alternative to classic ICD. We report a clinical case of a 34 y.o. woman who presented a sudden cardiac death and who benefited the implantation of this new technology. This paper deals with the potential indications, usefulness benefits, and problems of the S-ICD. PMID- 25281994 TI - [Long term results of implantable loop recorder in patients with syncope: results of a French survey]. AB - BACKGROUND AND OBJECTIVE: A first publication of our group demonstrated that implantation of a loop recorder in 30 patients experiencing an unexplained syncope (Medtronic Reveal DX or XT) definitively determined that an arrhythmia was the cause of symptoms in 10 patients (32%). However, we lack the results of a survey evaluating the results of long term follow-up after a loop recorder implantation and the results in case of wider indications of implantation of loop recorders. METHODS AND RESULTS: A device (Medtronic Reveal DX or XT) was implanted in 97 patients between january 2009 and june 2014. During a mean follow up of 21+/-19 months, loop recording determined that an arrhythmia was the cause of symptoms in 34 patients (35%). For the management of these arrhythmias, treatments received by patients were a pacemaker implantation in 18 patients (53%), an implantable cardioverter-defibrillator in four patients (12%) and a supraventricular tachycardia ablation (cryo or radiofrequency ablation) in three patients (9%). For nine patients (26%), the arrhythmic events were asymptomatic and didn't justify a specific treatment. The final positive rate of loop monitoring implantation was of 25/97 (26%). The study demonstrated that the positivity of the follow-up was demonstrated after two years of follow-up in 26% of the cases. CONCLUSION: Long-term follow-up of 97 patients implanted by a loop monitor leaded to an interventional rythmology procedure in 26% of the cases. In 26% of patients, loop-monitoring follow-up was positive after a duration of more than two years. PMID- 25281996 TI - [Nephrotic syndrome revealed by pulmonary embolism: about four cases]. AB - Nephrotic syndrom is an association of proteinuria>3g/d or 50mg/kg/d, an hypoalbuminemia<30g/L and a hypoproteinemia<60g/L. Primary etiologies are minimal glomerular injury, focal segmental glomerulosclerosis and non membranous glomerulonephritis. Secondary etiologies are diabetes, high blood pressure and amyloidosis. We present four cases about nephrotic syndrome after thromboembolic disease. In every case, patients show a pulmonary embolism symptomatic of a nephrotic syndrom, whose diagnostic could be delayed up to six months after first pulmonary symptoms. This raised the problem of renal biopsy in these patients who need anticoagulation. In minimal change nephrosis, without hematuria, high blood pressure or renal dysfonction, a corticosteroid therapy test could be done assuming that is corticosensitive minimal glomerular injury. In every case, anticoagulation course must be completed and maintained in case of patent nephrotic syndrom with an albuminemia under 20g/L. In case of pulmonary embolism or deep vein thrombosis, idiopathic-looking, a nephrotic syndrome must be sought after. The two diagnosis ways are the proteinuria on the urine dipstick and the hypoproteinemia on usual biology. The main mechanism is the coagulation factor leak, side effect of the nephrotic syndrom, notably because of the antithrombin III. PMID- 25281997 TI - [Interest of emergency coronary computed tomography for exclusion of coronary artery disease in patients with acute chest pain and low to intermediate risk]. AB - PURPOSE: To demonstrate the usefulness of the multislice computer tomography coronary angiography (CCTA) in patients with suspected acute chest pain without electrical changes or enzyme rise, and with low cardiovascular risk. PATIENTS AND METHODS: Fifty-three patients at low or intermediate risk for coronary artery disease, who were admitted in the emergency department for an acute chest pain, and who underwent a CCTA, were included in the study. Results of the CCTA were classified as normal, non-obstructive stenosis (<= 50% stenosis in diameter), obstructive stenosis (> 50% stenosis in diameter). The mortality was assessed during a 4-years follow-up period. RESULTS: Mean age was 61 years (36-86), 43% of patients were women. The CCTA was normal in 35 patients (66%), seven patients (13%) had non-obstructive stenosis and 11 (21%) had obstructive stenosis. In the group of normal CCTA, 8.5% of patients were admitted in cardiac intensive care unit, 57.1% in the non-obstructive stenosis and 90.9% in the group of obstructive stenosis. No deaths occurred during the 4-year follow up in the group of patients with normal CCTA. CONCLUSION: This study confirms the negative predictive value of CCTA for the diagnosis of coronary artery disease and for further clinical events in patients at low or intermediate risk referred to emergency department for an acute chest pain. PMID- 25281998 TI - Use of the structure-function relationship in detecting glaucoma progression in early glaucoma. AB - BACKGROUND: To evaluate the use of optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and visual field (VF) measurements in detecting disease progression in patients with early glaucoma. METHODS: Over a 3 year period, this study examined 60 eyes of 39 glaucoma patients whose total deviation in the superior or inferior hemifield was more than -6 dB. All eyes underwent at least four serial RNFL measurements performed by Cirrus OCT, with the first and last measurements separated by at least three years. On the same day as the RNFL imaging, VF testing was also performed by using the Swedish Interactive Threshold Algorithm Standard 30-2 program of the Humphrey Field Analyzer. Serial RNFL thicknesses and VF progression were assessed using the Guided Progression Analysis (GPA) software program. RNFL thickness progression and VF progression were evaluated by the event analysis. RESULTS: The mean observation period was 57.6 +/- 10.0 months, and during this time, a total of 366 OCT and 366 VF measurements were performed. Using only OCT, progression was found in 2 eyes, while progression was found in 1 eye when only using VF GPA. When combined measurement findings were used, the analysis found progression in 8 eyes. CONCLUSIONS: When mild VF defect is present, OCT RNFL thickness measurements can be helpful in discerning glaucoma progression. PMID- 25281999 TI - N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia. AB - BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia. PMID- 25282000 TI - Ocular rehabilitation following socket reconstruction with amniotic membrane transplantation with failed primary hydroxyapatite implant post enucleation. AB - There are several clinical situations that require enucleation in children, with retinoblastoma being the most common. Intra-orbital implants are routinely placed in children at the time of initial surgery to provide motility and cosmesis in addition to adequate orbital volume. Current practice employs intra-orbital implants made of nonporous silicone, hydroxyapatite, or porous polyethylene. Complications are usually minimal with these implants but they do occur. The purpose of this clinical report is to describe the rehabilitation of a pediatric patient with failed primary intra-orbital coralline hydroxyapatite implant post enucleation, who was successfully fitted with custom ocular prosthesis following secondary socket reconstruction with amniotic membrane transplantation after removal of infected implant. PMID- 25282001 TI - Lymphatic filariasis morbidity mapping: a comprehensive examination of lymphoedema burden in Chikwawa district, Malawi. AB - BACKGROUND: Managing lymphatic filariasis (LF) morbidity and reducing disability is one of the two primary goals of the Global Programme to Eliminate Lymphatic Filariasis. However, in order to achieve this, the geographical distribution of LF morbidity needs to be better estimated. METHODS: All cases of lymphoedema within a single health centre catchment area (pop. 42 000) in the southern region of Malawi were examined. Maps of lymphoedema burden were produced and trends in patient demographics, severity of lymphoedema (Dreyer staging) and health-seeking behaviour were explored. The number of lymphoedema cases was compared with records maintained by the Ministry of Health, Malawi. RESULTS: A total of 69 lymphoedema cases were identified (32 per 10 000 population), of which 48 (70%) were female and 21 (30%) male. The majority of cases (51/69) had Dreyer stage 2 3, and almost all (65/69) had experienced acute attacks as a result of their lymphoedema. This burden was much greater than that estimated by Ministry of Health (33 cases). CONCLUSIONS: Current case detection methods underestimate the burden of lymphoedema in Malawi. There is a continued need to develop new LF morbidity identification and surveillance approaches to ensure that future morbidity management strategies are effectively targeted. PMID- 25282002 TI - Severe weight gain and generalized insulin edema after the starting of an insulin pump. AB - The possibility of the occurrence of a generalized edema after initiation or intensification of insulin treatment in patients with diabetes, although considered a rare event, has long been described in the literature. In this case, a state of clinically significant edema, with a concurrent severe weight gain, occurred in a patient with type 1 diabetes in whom the implantation of an insulin pump resulted in a dramatic and abrupt improvement in glycemic control. PMID- 25282003 TI - Intentional hypoglycemia to control bingeing in a patient with type 1 diabetes and bulimia nervosa. AB - Most cases of eating disorders associated with type 1 diabetes mellitus are categorized as diabulimia, a disorder of withholding insulin treatment to lose weight through sustained hyperglycemia. In this paper, we report a unique case of a patient with both type 1 diabetes and bulimia nervosa who has an atypical way of controlling her bingeing by keeping her blood sugars low. This pattern of intentionally sustained hypoglycemia has not been previously described in the literature to the best of our knowledge. Knowing various presentations of eating disorders in patients with type 1 diabetes can provide healthcare workers with enhanced ability in recognizing and educating at-risk patients, in the hope of preventing serious hypoglycemia or complications. Furthermore, a patient's awareness of complications associated with suboptimal control of diabetes, whether by overdosing or underdosing their insulin regimen, might lead to avoidance of disordered eating behaviours. PMID- 25282004 TI - Angiographic evidence of peripheral ischemia in diabetic retinopathy and the risk of impending neovascularisation. AB - The appearance of biomicroscopic evidence of neovascularisation is the main indication for scatter laser treatment in patients with known diabetic eye disease. We describe a patient with an unusually aggressive variant of proliferative disease and a distinct angiographic signature. In an interventional case report with angiographic findings, we found that angiographic evidence of extensive capillary dropout in patients with known diabetic retinopathy should translate into a low threshold for panretinal photocoagulation treatment based on a high risk for progression to sight-threatening proliferative disease. Angiography may be a useful adjunct in stratifying patients with diabetic eye disease according to risk. Those with extensive ischemia, even without neovascularisation, should be considered for early panretinal photocoagulation. PMID- 25282005 TI - Association between PGC-1alpha gene polymorphisms and type 2 diabetes risk: a case-control study of an Iranian population. AB - OBJECTIVE: The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene could play a role in the onset of type 2 diabetes mellitus. The aim of this study was to explore the possible associations among polymorphisms Gly482Ser, Thr394Thr and Thr528Thr of the PGC-1alpha gene and the risk of type 2 diabetes in Kurdish-Iranians. METHODS: DNA specimens from all 173 type 2 diabetes subjects and 173 normoglycemic subjects were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Genotypic and allelic frequencies were analyzed in each group. Serum lipids, fasting glucose, fasting serum insulin, homeostasis model assessment of insulin resistance and glycated hemoglobin levels were determined using the conventional methods. The data were analyzed using SPSS software. RESULTS: The GA genotype of Gly482Ser was associated with a significant susceptibility for type 2 diabetes (odds ratio 5.23, p<0.000). Furthermore, the GA genotype of Thr528Thr had a higher risk for type 2 diabetes (odds ratio 2.37, p<0.002). Normoglycemic persons carrying the GA+AA genotypes of Gly482Ser variation had significantly lower high density lipoprotein cholesterol in comparison with persons having GG genotype. In comparison with GG genotype carriers, normoglycemic subjects carrying the GA+AA genotypes of Thr394Thr variation had significantly higher fasting blood sugar, fasting serum insulin and homeostasis model assessment of insulin resistance. Normoglycemic subjects with the GA+AA genotypes of Thr528Thr variation had significantly higher levels of low-density lipoprotein cholesterol compared with subjects having the GG genotype. Type 2 diabetes subjects carrying the GA+AA genotypes of this polymorphism had significantly higher waist-hip ratio in comparison with the GG genotype carriers. We also found that haplotype 394-GG/482 GA/528-GG of PGC-1alpha was significantly associated with higher risk of type 2 diabetes. CONCLUSIONS: Our findings revealed significant associations between PGC 1alpha Gly482Ser and Thr528Thr polymorphisms and type 2 diabetes in Kurdish Iranians. PMID- 25282006 TI - Understanding the associations between modifying factors, individual health beliefs, and hemodialysis patients' adherence to a low-phosphorus diet. AB - OBJECTIVE: Hyperphosphatemia in end-stage renal disease is associated with significant morbidity and mortality. Because phosphorus is not effectively dialyzed, dietary adherence remains a significant problem. Previous studies have examined the health belief model, but none have looked at stages of change and dietary adherence in patients undergoing hemodialysis (HD). DESIGN: Cross sectional survey. SETTING: Three dialysis centers in Columbus, Ohio, between August 2012 and March 2013. SUBJECTS: English-speaking patients age 18 or older on HD without dementia or developmental delay. INTERVENTION: None. MAIN OUTCOME MEASURE: Associations between dietary adherence based on the Precaution Adoption Process Model (stages of change) and serum phosphorus levels via a conceptual model incorporating modifying factors and individual health beliefs. RESULTS: Ninety-five patients completed the survey; 59 (62%) endorsed adherence to a low phosphorus diet and 32 (34%) had phosphorus values <=5.5 mg/dL. Modifying factors associated with diet adherence included nonminority status odds ratio (OR), 95%CI 8.99 (1.08-74.60), greater level of education OR 18.23 (1.62-205.00), better quality of life OR 9.28 (1.35-63.71), and time on dialysis OR 1.04 (1.01-1.07). Individual health beliefs associated with diet adherence included perceived benefits OR 3.18 (1.47-6.88) and self-efficacy OR 1.22 (1.09-1.38). Modifying factors associated with phosphorus control included: age OR 0.94 (0.90-0.99), minority status OR 0.11 (0.02-0.68), greater level of education OR 6.60 (1.41 31.04), knowledge about chronic kidney disease OR 1.48 (1.03-2.13), and time on dialysis OR 0.98 (0.96-0.99). Individual health beliefs associated with phosphorus control included self-efficacy OR 1.08 (1.01-1.16). CONCLUSION: HD clinicians and educators may obtain better results with dietary adherence and phosphorus control if they focus not only toward disease and dietary education but also on understanding modifying factors and individual health beliefs. Assessing where the patient is with regard to stages of change may assist health care providers in better matching interventions that build patients' self efficacy. PMID- 25282007 TI - Insulin therapy in type 2 diabetes: a reflection on the state of the art today and the potential journeys yet to come. PMID- 25282008 TI - Challenges associated with insulin therapy in type 2 diabetes mellitus. AB - Despite advances in treatment for type 2 diabetes in recent decades, many patients are failing to achieve adequate glycemic control. Poor glycemic control has been shown to have a detrimental effect on patients' health and well-being, and to have significant negative financial implications for both patients and healthcare systems. Insulin therapy has been proven to significantly reduce glycated hemoglobin levels; however, both patients and physicians can be reluctant to initiate insulin therapy. Research shows that both patient and provider factors contribute to a delay in initiation of insulin therapy. This review discusses the most common barriers contributing to this delay with potential solutions to overcome them. PMID- 25282009 TI - Hypoglycemia. AB - Hypoglycemia is a common, potentially avoidable consequence of diabetes treatment and is a major barrier to initiating or intensifying antihyperglycemic therapy in efforts to achieve better glycemic control. Therapy regimen and a history of hypoglycemia are the most important predictors of future events. Other risk factors include renal insufficiency, older age, and history of hypoglycemia associated autonomic failure. Reported rates of hypoglycemia vary considerably among studies because of differences in study design, definitions used, and population included, among other factors. Although occurring more frequently in type 1 diabetes, hypoglycemia also is clinically important in type 2 diabetes. Symptoms experienced by patients vary among individuals, and many events remain undiagnosed. The incidence of severe events is unevenly distributed, with only a small proportion (~ 5%) of individuals accounting for >50% of events. Consequently, clinicians must be conscientious in obtaining thorough patient histories, because an accurate picture of the frequency and severity of hypoglycemic events is essential for optimal diabetes management. Severe hypoglycemia in particular is associated with an increased risk of mortality, impairments in cognitive function, and adverse effects on patients' quality of life. Economically, hypoglycemia burdens the healthcare system and adversely affects workplace productivity, particularly after a nocturnal event. Ongoing healthcare reform efforts will result in even more emphasis on reducing this side effect of diabetes treatment. Therefore, improving patients' self-management skills and selecting or modifying therapy to reduce the risk of hypoglycemia will increase in importance for clinicians and patients alike. PMID- 25282010 TI - Evolution of insulin: from human to analog. AB - The development of insulin analogs has made improved treatment of type 2 diabetes possible. In this article, structural alterations, pharmacokinetics and pharmacodynamics, clinical end points, and safety issues are reviewed for the currently available basal insulins, rapid-acting insulins, and premixes. The flatter activity profiles of insulin glargine and insulin detemir translate into good clinical efficacy with a lower risk of hypoglycemia relative to neutral protamine Hagedorn insulin. Weight gain is consistently lower with insulin detemir than with neutral protamine Hagedorn insulin. Insulin degludec, licensed in Europe and Japan but not yet in the United States, has a mean half-life of 25.4 hours, a duration of action of >42 hours, and low variability. In trials in type 2 diabetes, rates of nocturnal hypoglycemia were lower with insulin degludec than with insulin glargine, and more flexible; once-daily dose timing was shown to be possible. Insulin lispro, insulin aspart, and insulin glulisine are rapidly absorbed after injection and thus provide better coverage of the post-prandial glucose surge compared with human insulin. Trials and meta-analyses show that reductions in glycated hemoglobin are similar and control of postprandial glucose is better with the rapid-acting analogs versus human insulin. Convenience is greater for patients because the analogs can be injected just before a meal. In premix or biphasic insulins, a proportion of the rapid-acting analog is protaminated, providing both rapid-acting and intermediate-acting components in one formulation, thus reducing the number of injections required. Alterations to human insulin have resulted in improvements in safety, efficacy, tolerability, and convenience for patients. PMID- 25282011 TI - Individualizing insulin therapy in the management of type 2 diabetes. AB - It is recognized that reducing hyperglycemia early on in disease progression has long-term benefits for patients with diabetes. Insulin therapy has greater potential to reduce hyperglycemia than other therapies; however, there is often a significant delay in insulin initiation and intensification. Insulin replacement therapy in type 2 diabetes should no longer be viewed as the treatment of last resort. With the development of modern insulin analogs, the field has evolved. Large clinical trials have improved our understanding of the potential benefits and risks associated with intensive glycemic control in different patient populations and highlighted the need for individualization of glycemic targets and treatment strategies. Current treatment guidelines recognize the important role of insulin therapy both early on and throughout the progression of type 2 diabetes. PMID- 25282012 TI - New developments in insulin therapy for type 2 diabetes. AB - Insulin has classically been considered a treatment of last resort for individuals with type 2 diabetes, delayed until all other efforts by the patient and healthcare provider have failed. Recent treatment guidelines recommend the use of insulin, in particular basal insulin, as part of a treatment regimen earlier in the disease process. Many patients are reticent about initiating insulin, so therapies that allow insulin treatment to be more tailored to individual needs are likely to result in greater acceptance and patient adherence with therapy. To meet this need, a range of insulin products are in development that aim to increase absorption rate or prolong the duration of action, reduce peak variability and weight gain associated with insulin treatment, and offer alternative delivery methods. This review describes insulin products in clinical development, new combination therapies, and new devices for insulin delivery. PMID- 25282013 TI - Low temperature storage affects the ascorbic acid metabolism of cherry tomato fruits. AB - Tomato fruits are an important source of l-Ascorbic acid, which is an essential compound of human diet. The effect of the widespread practice of cold storing (5 10 degrees C) tomato fruits was monitored to determine its impact on the concentration and redox status of l-Ascorbic acid. Total l-Ascorbic acid levels were well maintained in both attached fruits and cold treated fruits, while in other treatments its levels were considerably reduced. However, low temperature storage conditions enhanced the expression of most genes coding for enzymes involved in l-Ascorbic acid biosynthesis and redox reactions. The findings suggest that the transcriptional up-regulation under chilling stress conditions of most genes coding for l-Ascorbic acid biosynthetic genes galactono-1,4-lactone dehydrogenase, GDP-d-mannose 3,5-epimerase but also for the isoenzymes of ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase enzyme, glutathione reductase that are strongly correlated to the l-Ascorbic redox status. Moreover, fruits stored at 10 degrees C exhibited higher levels of transcript accumulation of MDHAR2, DHAR1, DHAR2, GR1 and GR2 genes, pointing to a better ability to manage chilling stress in comparison to fruits stored at 5 degrees C. PMID- 25282014 TI - Apples: content of phenolic compounds vs. variety, part of apple and cultivation model, extraction of phenolic compounds, biological properties. AB - Apples are among the most popular fruits in the world. They are rich in phenolic compounds, pectin, sugar, macro- and microelements. Applying different extraction techniques it is possible to isolate a particular group of compounds or individual chemicals and then test their biological properties. Many reports point to the antioxidant, antimicrobial, anticancer and many other beneficial effects of apple components that may have potential applications in food, pharmaceutical and cosmetic industries. This paper summarizes and compiles information about apple phenolic compounds, their biological properties with particular emphasis on health-related aspects. The data are reviewed with regard to different apple varieties, part of apple, cultivation model and methods of extraction. PMID- 25282015 TI - Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is manifested by adult onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity. Previously reported prevalence rates have been widely variable based on the population studied, method of diagnosis, and definition of aspirin sensitivity. OBJECTIVE: We sought to determine the prevalence of AERD among asthmatic adults. METHODS: A systematic review of databases was performed to identify all clinical trials published on or before June 16, 2013, that evaluated the prevalence of AERD. The studies were clustered into 7 different groups based on underlying disease (asthma, nasal polyps or chronic rhinosinusitis, or both), as well as on the methodology of prevalence determination. RESULTS: A total of 1770 articles were identified, with 27 considered appropriate for inclusion. Prevalence rates of AERD ranged from 5.5% to 12.4% based on study type. Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%). The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%]). Among patients with nasal polyps and chronic rhinosinusitis, the prevalence was 9.69% (95% CI, 2.16% to 17.22%) and 8.7% (95% CI, -1.02% to 18.34%), respectively. CONCLUSION: AERD is a distinct and important subtype of asthma and polypoid sinus disease. The prevalence of AERD is 7% in typical adult asthmatic patients and twice that number in patients with severe asthma, which underscores the importance of recognizing this disorder. Early identification of this syndrome is critical in view of the increased morbidity and costs associated with asthma exacerbations and the option to treat patients with AERD with long-term aspirin treatment after desensitization. PMID- 25282016 TI - CD45RA depletion in HLA-mismatched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study. AB - BACKGROUND: Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD). OBJECTIVE: In view of the growing evidence that alloreactivity is mainly derived from human naive T cells, the selective depletion of naive T cells from allografts might constitute a way of reducing alloreactivity while maintaining memory T-cell responsiveness to pathogens. METHODS: Five consecutive patients with CIDs and chronic viral infections underwent an allogeneic, HLA-mismatched HSCT. Given the patients' infection status and the potential risk of severe GVHD in the mismatched setting, the CD34(-) fraction of the allograft was depleted of naive T cells by using magnetic CD45RA beads. RESULTS: Engraftment occurred in 4 of the 5 patients. No severe GVHD occurred. In the 4 engrafted patients viral infections were cleared within 2 months of the HSCT, and both cellular and humoral immunity were re established within a year of the HSCT. An early T-cell response against viral pathogens was documented in 2 patients. CONCLUSION: The present pilot study shows that clinical-grade depletion of naive T cells from an allograft through the use of magnetic CD45RA beads seems to be a feasible and efficacious option for the treatment of patients with CIDs at high risk of GVHD, infection, or both in an HLA-mismatched setting. PMID- 25282017 TI - Immunologic characterization of 3 murine regimens of allergen-specific immunotherapy. AB - BACKGROUND: Allergen-specific immunotherapy (ASIT) is used to treat the symptoms of immediate type I hypersensitivity. The mechanisms driving establishment of allergen tolerance are not yet fully understood. OBJECTIVE: The goal of this study was to develop and immunologically characterize 3 murine models of ASIT to simulate protocols currently used to treat patients with type I hypersensitivities. METHODS: Ovalbumin (OVA)-sensitized mice were desensitized to OVA by means of repeated injections of OVA with a rapid, intermediate, or gradual protocol. After desensitization, mice were assessed for clinical sensitivity to OVA, and immunologic parameters were assessed. RESULTS: Mice in all treatment protocols displayed decreased vascular permeability in response to OVA challenge after desensitization. Circulating OVA-specific IgE levels, as well as basophil activation in response to OVA stimulation and IgE cross-linking, were significantly decreased in all treatment groups. Intermediate and gradual protocols, but not rapid desensitization, suppressed splenocyte proliferation and production of IL-4, IL-5, and IFN-gamma in response to OVA and polyclonal activation. Similarly, significant increases in IL-10 production, numbers of CD4(+)CD25(+) forkhead box protein 3-positive regulatory T cells, and OVA specific IgG1 antibody levels were only observed in mice undergoing prolonged ASIT regimens. CONCLUSION: Suppression of IgE-mediated activation is a common feature of all desensitization schedules. Induction of immunoregulatory networks requires prolonged desensitization schedules. PMID- 25282018 TI - Allergy to furry animals: New insights, diagnostic approaches, and challenges. AB - The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components. PMID- 25282019 TI - Fecal sterols, seasonal variability, and probable sources along the ring of cenotes, Yucatan, Mexico. AB - Rapid development in Yucatan has had a dramatic impact on the environment, especially the water supply. Groundwater is the only source of water in Yucatan, since surface water is virtually absent due to the karstic nature of the soil. The ring of cenotes (RC) is a geological feature which functions as a source of water and as nodes in the underground river system that canalizes water towards the coast. Numerous productive and domestic activities take place around the RC in the absence of wastewater treatment or sewage systems. Consequently, a number of researchers have hypothesized that pollutants could migrate from the land surface to the underlying aquifer and, eventually, to the coast. Therefore, the present study investigates the relationship among sources of fecal sterols and their levels in cenotes, using the expected levels of fecal sterols obtained by a spatial analysis of the sources and a Pollution Source Index. Accordingly, expected levels are compared with the detected levels of fecal sterols in 5 areas around the RC. Regarding levels, observed during a sampling campaign carried out along the RC during September 2011 (rainy season) and May 2012 (dry season), varied from low to high concentrations of sterols (0.5-2396.42 MUg g(-1)) and fecal sterols (0.3-1690.18 MUg g(-1)). These concentrations showed no relationship between neighboring cenotes, where similar fecal sterol concentrations or gradients were expected. When comparing expected fecal sterols levels with the detected ones, only two of the five analyzed areas concur, suggesting that no clear relationship exists among sources and fecal sterols levels at the regional scale. Multivariate analysis showed that fecal sterols were associated with sterols and fine grain particulates during the rainy season, which suggests co-transport. During the dry season, fecal sterols associated with fine grain particulate and organic matter, which indicates a change to a deposition phenomenon. These findings indicate that defining a relationship among sources and fecal sterols levels is highly difficult and this could be the result of the absorption or migration through an intricate conduit, crack, or fracture karst system. Nevertheless, the "source-levels approach", used in this study, was consistent for the northeast edge and the middle western part of the RC. New and more extensive research should be done to assess the environmental fate of fecal sterols, especially considering the intricate karstic system and its compound retention capacity. PMID- 25282020 TI - TDDFT study of twisted intramolecular charge transfer and intermolecular double proton transfer in the excited state of 4'-dimethylaminoflavonol in ethanol solvent. AB - Time-dependent density functional theory method at the def-TZVP/B3LYP level was employed to investigate the intramolecular and intermolecular hydrogen bonding dynamics in the first excited (S1) state of 4'-dimethylaminoflavonol (DMAF) monomer and in ethanol solution. In the DMAF monomer, we demonstrated that the intramolecular charge transfer (ICT) takes place in the S1 state. This excited state ICT process was followed by intramolecular proton transfer. Our calculated results are in good agreement with the mechanism proposed in experimental work. For the hydrogen-bonded DMAF-EtOH complex, it was demonstrated that the intermolecular hydrogen bonds can induce the formation of the twisted intramolecular charge transfer (TICT) state and the conformational twisting is along the C3-C4 bond. Moreover, the intermolecular hydrogen bonds can also facilitate the intermolecular double proton transfer in the TICT state. A stepwise intermolecular double proton transfer process was revealed. Therefore, the intermolecular hydrogen bonds can alter the mechanism of intramolecular charge transfer and proton transfer in the excited state for the DMAF molecule. PMID- 25282021 TI - Synthesis, spectral and theoretical studies of Ni(II), Pd(II) and Pt(II) complexes of 5-mercapto-1,2,4-triazole-3-imine-2'-hydroxynaphthaline. AB - Ni(II), Pd(II) and Pt(II) complexes of 5-mercapto-1,2,4-triazole-3-imine-2' hydroxynaphthaline have been isolated and characterized by elemental analysis, IR, (1)H NMR, EI-mass, UV-vis, molar conductance, magnetic moment measurements and thermogravimetric analysis. The molar conductance values indicated that the complexes are non-electrolytes. The magnetic moment values of the complexes displayed diamagnetic behavior for Pd(II) and Pt(II) complexes and tetrahedral geometrical structure for Ni(II) complex. From the bioinorganic applications point of view, the interaction of the ligand and its metal complexes with CT-DNA was investigated using absorption and viscosity titration techniques. The Schiff base ligand and its metal complexes have also been screened for their antimicrobial and antitumor activities. Also, theoretical investigation of molecular and electronic structures of the studied ligand and its metal complexes has been carried out. Molecular orbital calculations were performed using DFT (density functional theory) at B3LYP level with standard 6-31G(d,p) and LANL2DZ basis sets to access reliable results to the experimental values. The calculations were performed to obtain the optimized molecular geometry, charge density distribution, extent of distortion from regular geometry, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), Mulliken atomic charges, reactivity index (DeltaE), dipole moment (D), global hardness (eta), softness (sigma), electrophilicity index (omega), chemical potential and Mulliken electronegativity (chi). PMID- 25282022 TI - A vibrational spectroscopic study of the anhydrous phosphate mineral sidorenkite Na3Mn(PO4)(CO3). AB - Sidorenkite is a very rare low-temperature hydrothermal mineral, formed very late in the crystallization of hyperagpaitic pegmatites in a differentiated alkalic massif (Mt. Alluaiv, Kola Peninsula, Russia). Sidorenkite Na3Mn(PO4)(CO3) is a phosphate-carbonate of sodium and manganese. Such a formula with two oxyanions lends itself to vibrational spectroscopy. The sharp Raman band at 959 cm(-1) and 1012 cm(-1) are assigned to the PO4(3-) stretching modes, whilst the Raman bands at 1044 cm(-1) and 1074 cm(-1) are attributed to the CO3(2-) stretching modes. It is noted that no Raman bands at around 800 cm(-1) for sidorenkite were observed. The infrared spectrum of sidorenkite shows a quite intense band at 868 cm(-1) with other resolved component bands at 850 and 862 cm(-1). These bands are ascribed to the CO3(2-) out-of-plane bend (nu2) bending mode. The series of Raman bands at 622, 635, 645 and 704 cm(-1) are assigned to the nu4 phosphate bending modes. The observation of multiple bands supports the concept of a reduction in symmetry of the carbonate anion from D3h or even C2v. PMID- 25282023 TI - The spectroscopic characterization, photochromism of cadmium(II)-iodo complexes of 1-alkyl-2-(arylazo)imidazoles and DFT computation of representative complexes. AB - [Cd(Raai-C(n)H(2n+1))(MU-I)I]2 and [Cd(Raai-C(n)H(2n+1))2I2] are synthesized by the reaction of CdI2 with 1-alkyl-2-(arylazo)imidazole (Raai-C(n)H(2n+1), n=4, 6, 8) in MeOH in 1:1 and 1:2 M ratio of salt and ligands, respectively. The complexes have been characterized by spectral data (UV-Vis, IR, (1)H NMR, Mass). The coordinated Raai-C(n)H(2n+1) shows photochromism, E(trans)-to-Z(cis) isomerisation, upon UV light irradiation. The reverse process, Z-to-E, is very slow in visible light irradiation process while the reaction is sensitive to change of reaction temperature. The quantum yields (phiE->Z) for E-to-Z and the activation energy (Ea) of Z-to-E isomerisation are calculated and found that the complexes show subordinate results compared to free ligand. DFT computations of two representative complexes were carried out to explain the spectral and photochromic phenomena. PMID- 25282024 TI - Experimental and theoretical study on free 5-nitroquinoline, 5-nitroisoquinoline, and their zinc(II) halide complexes. AB - In this study where the interpretations of the experimental IR and Raman spectra recorded at room temperature for the ligands 5-nitroquinoline (5NQ) and 5 nitroisoquinoline (5NIQ) and also for their Zn(II) halide (halogen: chlorine, bromine, iodine) complexes were first reported, the assignments of the observed fundamental bands were achieved in the light of the vibrational spectral data and total energy distribution (TED) values calculated at B3LYP/6-311++G(d,p) and B3LYP/LANL2DZ levels of theory. The equilibrium geometrical parameters, Natural Bond Orbital (NBO) charges and frontier orbital (HOMO, LUMO) energies of these molecular structures were also calculated at the same level of theory. Comparisons over the corresponding experimental and theoretical data obtained for the title ligands and their complexes revealed that in complex form both ligands bond to Zn(II) ion through their ring nitrogen atoms and NO2 groups at the same time. PMID- 25282025 TI - Novel anthracene-based fluorescent sensor for selective recognition of acetate anions in protic media. AB - Novel 9-substituted anthracene derivatives were synthesized and characterized by IR, HRMS, (1)H and (13)C NMR. The fluorescence titration experiments were explored to study the interaction between the compounds and some anions, such as H2PO4(-), P2O7(4-), F(-), Cl(-), Br(-), I(-), AcO(-) in H2O (0.01 M HEPES, pH=7.4) under imitated physiological conditions. One of these compounds, bearing a phenylalaninol unit, showed specific fluorescence enhancement with acetate anion. The sensor L1 was found to present good selective fluorescence sensing ability to acetate anion through photoinduced electron-transfer mechanism in protic media. PMID- 25282026 TI - First principles and DFT supported investigations on vibrational spectra and electronic structure of 2-((phenylamino)methyl)isoindoline-1,3-dione--an antioxidant active Mannich base. AB - The 2-((phenylamino)methyl)isoindoline-1,3-dione (PID) is a synthesized Mannich base which has significant antioxidant activity and biological importance. Quantum mechanical calculations on energy, geometry and vibrational wavenumber of PID were computed using ab initio HF and density functional theory (DFT/B3LYP) methods with 6-31+G/6-311++G(d,p) basis sets. Optimized geometrical parameters obtained by HF and DFT calculations were indicatively agreement with experimental crystal geometry. The experimental FT-Raman and FT-IR spectra of PID has been recorded and analyzed by comparing with simulated spectra. The (1)H and (13)C NMR spectra of title molecule records the chemical shift resulted from shielding and deshielding effects. Natural bond orbital (NBO) analysis has been carried out to calculate various intramolecular interactions that are accountable for the stabilization of this Mannich base. The predicted HOMO-LUMO gap offers interesting information on intramolecular charge transfer and reactivity of the molecular system. Molecular electrostatic potential (MEP) imprint visualize the reactive sites in PID, which is also supported by Mulliken, ESP, Hirshfeld and NBO charges. Thermodynamic properties of PID at various temperatures have been calculated at B3LYP/6-311++G(d,p) in gas phase and the correlations between standard entropies (S), internal energy (E or U) and standard heat capacity (C) with different temperatures. PMID- 25282027 TI - Polyether precursors of molecular recognition systems based on the 9,10 anthraquinone moiety. AB - A series of novel polyether derivatives of 9,10-anthraquinone (AQ) was synthesized and characterized by means of UV-Vis spectroscopy, acid-base titration and complexometric titration. The results were compared with 1-NEt2AQ and 1-NHEtAQ--model compounds of alkylaminoanthraquinones. Acetonitrile and methanol were used as solvents for determination of spectroscopic and acid-base properties. Complexometric titrations were carried out exclusively in acetonitrile. Spectral characteristic of these compounds strongly depends on pH. Addition of acid causes the decrease of absorption intensity and in some cases also a shift of the visible range band. The weakest base is the compound (2), and the strongest--compound (1), both in methanol and acetonitrile solution. The introduction of an additional substituent in the position 8 of the anthraquinone compound increases its basicity. The presence of metal ions causes changes in intensity of absorption (decrease for compounds (2) and (3) and increase with bathochromic shift for (1) and (4)). For the determination of the coordination properties aluminum (III) ions were chosen. The highest complex stability constant with Al (III) ions is observed for compound (1), and the weakest for compound (3). The elongation of the polyether chain decreases the stability of the complex formed. PMID- 25282028 TI - A new direction for albuminuria: an enigmatic multibiomarker. PMID- 25282029 TI - Insights into defibrillator shocks: what OPTION teaches us. PMID- 25282030 TI - Time to energize coenzyme Q10 for patients with heart failure? PMID- 25282031 TI - The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. AB - OBJECTIVES: This randomized controlled multicenter trial evaluated coenzyme Q10 (CoQ10) as adjunctive treatment in chronic heart failure (HF). BACKGROUND: CoQ10 is an essential cofactor for energy production and is also a powerful antioxidant. A low level of myocardial CoQ10 is related to the severity of HF. Previous randomized controlled trials of CoQ10 in HF were underpowered to address major clinical endpoints. METHODS: Patients with moderate to severe HF were randomly assigned in a 2-year prospective trial to either CoQ10 100 mg 3 times daily or placebo, in addition to standard therapy. The primary short-term endpoints at 16 weeks were changes in New York Heart Association (NYHA) functional classification, 6-min walk test, and levels of N-terminal pro-B type natriuretic peptide. The primary long-term endpoint at 2 years was composite major adverse cardiovascular events as determined by a time to first event analysis. RESULTS: A total of 420 patients were enrolled. There were no significant changes in short-term endpoints. The primary long-term endpoint was reached by 15% of the patients in the CoQ10 group versus 26% in the placebo group (hazard ratio: 0.50; 95% confidence interval: 0.32 to 0.80; p = 0.003) by intention-to-treat analysis. The following secondary endpoints were significantly lower in the CoQ10 group compared with the placebo group: cardiovascular mortality (9% vs. 16%, p = 0.026), all-cause mortality (10% vs. 18%, p = 0.018), and incidence of hospital stays for HF (p = 0.033). In addition, a significant improvement of NYHA class was found in the CoQ10 group after 2 years (p = 0.028). CONCLUSIONS: Long-term CoQ10 treatment of patients with chronic HF is safe, improves symptoms, and reduces major adverse cardiovascular events. (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]; ISRCTN94506234). PMID- 25282033 TI - Reduced risk for inappropriate implantable cardioverter-defibrillator shocks with dual-chamber therapy compared with single-chamber therapy: results of the randomized OPTION study. AB - OBJECTIVES: The OPTION (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator Patients Without Pacing Indications) trial sought to compare long-term rates of inappropriate shocks, mortality, and morbidity between dual-chamber and single-chamber settings in implantable cardioverter defibrillators (ICDs) patients. BACKGROUND: The use of dual-chamber ICDs potentially allows better discrimination of supraventricular arrhythmias and thereby reduces inappropriate shocks. However, it may lead to detrimental ventricular pacing. METHODS: This prospective multicenter, single-blinded trial enrolled 462 patients with de novo primary or secondary prevention indications for ICD placement and with left ventricular ejection fractions <=40% despite optimal tolerated pharmacotherapy. All patients received atrial leads and dual chamber defibrillators that were randomized to be programmed either with dual chamber or single-chamber settings. In the dual-chamber setting arm, the PARAD+ algorithm, which differentiates supraventricular from ventricular arrhythmias, and SafeR mode, to minimize ventricular pacing, were activated. In the single chamber setting arm, the acceleration, stability, and long cycle search discrimination criteria were activated, and pacing was set to VVI 40 beats/min. Ventricular tachycardia detection was required at rates between 170 and 200 beats/min, and ventricular fibrillation detection was activated above 200 beats/min. RESULTS: During a follow-up period of 27 months, the time to the first inappropriate shock was significantly longer in the dual-chamber setting arm (p = 0.012, log-rank test), and 4.3% of patients in the dual-chamber setting group compared with 10.3% in the single-chamber setting group experienced inappropriate shocks (p = 0.015). Rates of all-cause death or cardiovascular hospitalization were 20% for the dual-chamber setting group and 22.4% for the single-chamber setting group and satisfied the pre-defined margin for equivalence (p < 0.001). CONCLUSIONS: Therapy with dual-chamber settings for ICD discrimination combined with algorithms for minimizing ventricular pacing was associated with reduced risk for inappropriate shock compared with single-chamber settings, without increases in mortality and morbidity. (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator [ICD] Patients Without Pacing Indications [OPTION]; NCT00729703). PMID- 25282034 TI - Microbial diversity supporting dark fermentation of waste. AB - Microbial diversity is essential for human well-being and ecosystem services. Use of microorganisms in biomolecule production is common, but involves single-strain cultures. Microbial consortia provide advantages in the process of degrading organic waste to yield biomolecules of biotechnological interest. Microbial diversity in consortia can be an asset in the context of bioenergy and chemical production, which are key concerns for global energy demands. Improving knowledge of microbial consortia will therefore be important for biotechnology. PMID- 25282032 TI - Albuminuria is independently associated with cardiac remodeling, abnormal right and left ventricular function, and worse outcomes in heart failure with preserved ejection fraction. AB - OBJECTIVES: The purpose of this study was to determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied. METHODS: We measured urinary albumin-to creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes. RESULTS: The mean age was 66 +/- 11 years, 62% were female, and 42% were African American. Higher UACR was associated with greater left ventricular mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher [95% confidence interval: 0.05 to 0.14 mm; p = 0.001, adjusted p = 0.01]) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower [95% confidence interval: 0.14 to 0.98%; p = 0.01, adjusted p = 0.03]. The association between UACR and RV parameters persisted after the exclusion of patients with macroalbuminuria (UACR >300 mg/g). Increased UACR was also independently associated with worse outcomes. CONCLUSIONS: In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and left ventricular remodeling and longitudinal systolic dysfunction. (Classification of Heart Failure With Preserved Ejection Fraction; NCT01030991). PMID- 25282036 TI - A 9-protein biomarker molecular signature for predicting histologic type in endometrial carcinoma by immunohistochemistry. AB - Histologic typing may be difficult in a subset of endometrial carcinoma (EC) cases. In these cases, interobserver agreement improves when immunohistochemistry (IHC) is used. A series of endometrioid type (EEC) grades 1, 2, and 3 and serous type (SC) were immunostained for p53, p16, estrogen receptor, PTEN, IMP2, IMP3, HER2, cyclin B2 and E1, HMGA2, FolR1, MSLN, Claudins 3 and 4, and NRF2. Nine biomarkers showed significant differences with thresholds in IHC value scale between both types (p53 >= 20, IMP2 >= 115, IMP3 >= 2, cyclin E1 >= 220, HMGA2 >= 30, FolR1 >= 50, p16 >= 170, nuclear PTEN >= 2 and estrogen receptor <= 50; P < .005). This combination led to increased discrimination when considering cases satisfying 0 to 5 conditions predicted as EEC and those satisfying 6 to 9 conditions predicted as SC. This signature correctly predicted all 48 EEC grade 1 2 cases and 18 SC cases, but 3 SC cases were wrongly predicted as EEC. Sensitivity was 86% (95% confidence interval [CI], 64%-97%), and specificity was 100% (95% CI, 89%-100%). The classifier correctly predicted all 28 EEC grade 3 cases but only identified the EEC and SC components in 4 of 9 mixed EEC-SC. An independent validation series (29 EEC grades 1-2, 28 EEC grade 3, and 31 SC) showed 100% sensitivity (95% CI, 84%-100%) and 83% specificity (95% CI, 64%-94%). We propose an internally and externally validated 9-protein biomarker signature to predict the histologic type of EC (EEC or SC) by IHC. The results also suggest that mixed EEC-SC is molecularly ambiguous. PMID- 25282035 TI - Methods to study the tumor microenvironment under controlled oxygen conditions. AB - The tumor microenvironment (TME) is a complex heterogeneous assembly composed of a variety of cell types and physical features. One such feature, hypoxia, is associated with metabolic reprogramming, the epithelial-mesenchymal transition, and therapeutic resistance. Many questions remain regarding the effects of hypoxia on these outcomes; however, only a few experimental methods enable both precise control over oxygen concentration and real-time imaging of cell behavior. Recent efforts with microfluidic platforms offer a promising solution to these limitations. In this review, we discuss conventional methods and tools used to control oxygen concentration for cell studies, and then highlight recent advances in microfluidic-based approaches for controlling oxygen in engineered platforms. PMID- 25282037 TI - Autoimmune myelofibrosis: an update on morphologic features in 29 cases and review of the literature. AB - Autoimmune myelofibrosis (AIMF) is a distinct clinicopathological entity associated with diffuse bone marrow fibrosis and a benign clinical course. Distinction from neoplastic etiologies of marrow fibrosis, particularly primary myelofibrosis, is imperative, but few studies have documented histopathologic features in a large series. We describe 29 patients with AIMF, defined as marrow reticulin fibrosis and lymphocytic infiltration in the context of an established autoimmune disorder (secondary AIMF) or autoantibodies without a defined disorder (primary AIMF). Excluded were cases with atypical megakaryocytes, dysplasia, basophilia, osteosclerosis, unexplained splenomegaly, or neoplasms associated with myelofibrosis (MF). All cases were stained for reticulin, CD3, and CD20, with a subset additionally stained for CD138, kappa, lambda, immunoglobulin G (IgG), and IgG4. Lymphoid aggregates, where present, were classified into T-cell and B-cell patterns of distribution. Most patients (93%) presented with cytopenias. Sixty-nine percent (n = 20) were considered secondary AIMF and the remainder primary AIMF (n = 9). Peripheral blood showed absent-to-rare blasts and teardrop erythrocytes and absence of eosinophilia or basophilia. Characteristic bone marrow findings included hypercellularity with erythroid and megakaryocytic hyperplasias, mild reticulin fibrosis, intrasinusoidal hematopoiesis, T-cell pattern in lymphoid aggregates, mild polytypic plasmacytosis, and absence of IgG4 positive plasma cells. Primary and secondary AIMF were pathologically indistinguishable, except for an increased incidence of granulocytic hyperplasia in primary AIMF. This series confirms and expands the utility of the original diagnostic criteria for AIMF. Recognizing the characteristic morphology of AIMF and its associated clinical and laboratory features distinguishes autoimmune from neoplastic causes of MF and guides further evaluation and management. PMID- 25282038 TI - Historical development of active middle ear implants. AB - Active middle ear implants (AMEIs) are sophisticated technologies designed to overcome many of the shortcomings of conventional hearing aids, including feedback, distortion, and occlusion effect. Three AMEIs are currently approved by the US Food and Drug Administration for implantation in patients with sensorineural hearing loss. In this article, the history of AMEI technologies is reviewed, individual component development is outlined, past and current implant systems are described, and design and implementation successes and dead ends are highlighted. Past and ongoing challenges facing AMEI development are reviewed. PMID- 25282039 TI - Vibrant Soundbridge rehabilitation of conductive and mixed hearing loss. AB - The Vibrant Soundbridge is the world's most often implanted active middle ear implant or hearing aid. During the last few years, the device indications have expanded from sensorineural hearing loss to conductive and mixed hearing loss. Titanium couplers have led to improved contact of the floating mass transducer with the middle ear structures. The resulting hearing gain is satisfying for most patients, but so far, there is no clear audiologic advantage over conventional hearing aids. Currently, the indications are mainly related to intolerance of conventional hearing aids (eg, chronic otitis externa), severe mixed hearing loss with a destructed middle ear and certain medical diagnosis (eg, congenital atresia). PMID- 25282040 TI - Green tea extract impairs meat emulsion properties by disturbing protein disulfide cross-linking. AB - The dose-dependent effects of green tea extract (100, 500, or 1500ppm) on the textural and oxidative stability of meat emulsions were investigated, and compared to a control meat emulsion without extract. All levels of green tea extract inhibited formation of TBARS as a measure for lipid oxidation. Overall protein thiol oxidation and myosin heavy chain (MHC) cross-linking were inhibited by 100ppm green tea extract without jeopardizing the textural stability, while increasing concentrations of extract resulted in reduced thiol concentration and elevated levels of non-reducible protein modifications. Addition of 1500ppm green tea extract was found to modify MHC as evaluated by SDS-PAGE combining both protein staining and specific thiol staining, indicating that protein modifications generated through reactions of green tea phenolic compounds with protein thiols, disrupted the meat emulsion properties leading to reduced water holding capacity and textural stability. Hence, a low dose of green tea extract preserves both the textural and the oxidative stability of the meat proteins. PMID- 25282041 TI - Meat quality, fatty acid composition of tissue and gastrointestinal content, and antioxidant status of lamb fed seed of a halophyte (Suaeda glauca). AB - Twenty-four Merino lambs were randomly assigned to four treatments: control diet (CT) consisting of 300g concentrates with ad libitum Leymus chinensis hay; C with 150g (T150), 300g (T300) and 450g (T450) Suaeda glauca seed, respectively. Meat quality, fatty acid composition of meat and lipid tissue and antioxidant status of lamb were evaluated. Inclusion of S. glauca seeds significantly increased selenium (Se) concentrations of muscle. The proportions of C18:1 trans-11 in muscle, C18:2 n-6, PUFA, n-6 series fatty acids, and the ratios of P:S in rumen contents, as well as the ratios of n-6:n-3 in adipose tissue, rumen and duodenum content have been significantly (P<0.05) improved with supplementation of S. glauca seeds to lamb diets. No significant effect was found on antioxidant status. The results suggest that S. glauca seed supplementation in lamb diets may change fatty acid composition in tissues and content of digestive tract. PMID- 25282042 TI - In vivo tracking and immunological properties of pulsed porcine monocyte-derived dendritic cells. AB - Cellular therapies using immune cells and in particular dendritic cells (DCs) are being increasingly applied in clinical trials and vaccines. Their success partially depends on accurate delivery of cells to target organs or migration to lymph nodes. Delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. Thus, the design of an optimal DC therapy would be improved by optimizing technologies for monitoring DC trafficking. Magnetic resonance imaging (MRI) represents a powerful tool for non-invasive imaging of DC migration in vivo. Domestic pigs share similarities with humans and represent an excellent animal model for immunological studies. The aim of this study was to investigate the possibility using pigs as models for DC tracking in vivo. Porcine monocyte derived DC (MoDC) culture with superparamagnetic iron oxide (SPIO) particles was standardized on the basis of SPIO concentration and culture viability. Phenotype, cytokine production and mixed lymphocyte reaction assay confirmed that porcine SPIO-MoDC culture were similar to mock MoDCs and fully functional in vivo. Alike, similar patterns were obtained in human MoDCs. After subcutaneous inoculation in pigs, porcine SPIO MoDC migration to regional lymph nodes was detected by MRI and confirmed by Perls staining of draining lymph nodes. Moreover, after one dose of virus-like particles-pulsed MoDCs specific local and systemic responses were confirmed using ELISPOT IFN-gamma in pigs. In summary, the results in this work showed that after one single subcutaneous dose of pulsed MoDCs, pigs were able to elicit specific local and systemic immune responses. Additionally, the dynamic imaging of MRI based DC tracking was shown using SPIO particles. This proof-of-principle study shows the potential of using pigs as a suitable animal model to test DC trafficking with the aim of improving cellular therapies. PMID- 25282043 TI - Increased serum IgA in Fcalpha/MUR-deficient mice on the (129 x C57BL/6) F1 genetic background. AB - Fcalpha/MUR (CD351) is an Fc receptor for both IgA and IgM, which is abundantly expressed in the small intestine. However, the role of Fcalpha/MUR in the intestinal tissue is largely unknown. Here, we found that Fcalpha/MUR is highly expressed on follicular dendritic cells (FDCs) in Peyer's patches (PP) in the small intestine. Fcalpha/MUR-deficient mice on the (129 x C57BL/6) F1 background showed increased serum, but not fecal, IgA level in response to gut-oriented antigens. IgA(+) B cells were increased in PP, but not in the lamina propria, of Fcalpha/MUR-deficient mice, which was attenuated after reduction of commensal microbiota by oral treatment with antibiotics. Analyses of bone marrow chimeric mice, in which either FDCs or blood cells or both lack the expression of Fcalpha/MUR, suggested that FDCs, but not blood cells, were responsible for the increased serum IgA concentration in Fcalpha/MUR-deficient mice. Moreover, Fcalpha/MUR-deficient mice showed enhanced germinal center formation against commensal microbiota in PP. Thus, serum IgA production against gut-oriented antigens is negatively regulated by Fcalpha/MUR on FDCs in the F1 mice. PMID- 25282045 TI - Continuous-wave biexciton lasing at room temperature using solution-processed quantum wells. AB - Solution-processed inorganic and organic materials have been pursued for more than a decade as low-threshold, high-gain lasing media, motivated in large part by their tunable optoelectronic properties and ease of synthesis and processing. Although both have demonstrated stimulated emission and lasing, they have not yet approached the continuous-wave pumping regime. Two-dimensional CdSe colloidal nanosheets combine the advantage of solution synthesis with the optoelectronic properties of epitaxial two-dimensional quantum wells. Here, we show that these colloidal quantum wells possess large exciton and biexciton binding energies of 132 meV and 30 meV, respectively, giving rise to stimulated emission from biexcitons at room temperature. Under femtosecond pulsed excitation, close-packed thin films yield an ultralow stimulated emission threshold of 6 MUJ cm(-2), sufficient to achieve continuous-wave pumped stimulated emission, and lasing when these layers are embedded in surface-emitting microcavities. PMID- 25282044 TI - Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. AB - When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti HIV effects, neuroprotective effects and DNA-protective effects. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin. PMID- 25282046 TI - Electrostatic control of thermoelectricity in molecular junctions. AB - Molecular junctions hold significant promise for efficient and high-power-output thermoelectric energy conversion. Recent experiments have probed the thermoelectric properties of molecular junctions. However, electrostatic control of thermoelectric properties via a gate electrode has not been possible due to technical challenges in creating temperature differentials in three-terminal devices. Here, we show that extremely large temperature gradients (exceeding 1 * 10(9) K m(-1)) can be established in nanoscale gaps bridged by molecules, while simultaneously controlling their electronic structure via a gate electrode. Using this platform, we study prototypical Au-biphenyl-4,4'-dithiol-Au and Au-fullerene Au junctions to demonstrate that the Seebeck coefficient and the electrical conductance of molecular junctions can be simultaneously increased by electrostatic control. Moreover, from our studies of fullerene junctions, we show that thermoelectric properties can be significantly enhanced when the dominant transport orbital is located close to the chemical potential (Fermi level) of the electrodes. These results illustrate the intimate relationship between the thermoelectric properties and charge transmission characteristics of molecular junctions and should enable systematic exploration of the recent computational predictions that promise extremely efficient thermoelectric energy conversion in molecular junctions. PMID- 25282047 TI - An algorithm of discovering signatures from DNA databases on a computer cluster. AB - BACKGROUND: Signatures are short sequences that are unique and not similar to any other sequence in a database that can be used as the basis to identify different species. Even though several signature discovery algorithms have been proposed in the past, these algorithms require the entirety of databases to be loaded in the memory, thus restricting the amount of data that they can process. It makes those algorithms unable to process databases with large amounts of data. Also, those algorithms use sequential models and have slower discovery speeds, meaning that the efficiency can be improved. RESULTS: In this research, we are debuting the utilization of a divide-and-conquer strategy in signature discovery and have proposed a parallel signature discovery algorithm on a computer cluster. The algorithm applies the divide-and-conquer strategy to solve the problem posed to the existing algorithms where they are unable to process large databases and uses a parallel computing mechanism to effectively improve the efficiency of signature discovery. Even when run with just the memory of regular personal computers, the algorithm can still process large databases such as the human whole-genome EST database which were previously unable to be processed by the existing algorithms. CONCLUSIONS: The algorithm proposed in this research is not limited by the amount of usable memory and can rapidly find signatures in large databases, making it useful in applications such as Next Generation Sequencing and other large database analysis and processing. The implementation of the proposed algorithm is available at http://www.cs.pu.edu.tw/~fang/DDCSDPrograms/DDCSD.htm. PMID- 25282048 TI - Supplementation of moist and dehydrated citrus pulp in the diets of sheep artificially and naturally infected with gastrointestinal nematodes on the parasitological parameters and performance. AB - The inclusion of industrial byproducts such as citrus pulp in the composition of animal diets has been widely recommended due to sustainability aspects and their high level of carbohydrates. Limonene is found in citrus pulp and has been described elsewhere as a major compound of citrus essential oils with excellent anthelmintic activity. The objective of this study was to evaluate the parasitological parameters of lambs artificially infected (Experiment 1) with Haemonchus contortus and naturally infected (Experiment 2) by gastrointestinal nematodes, fed diets with dehydrated citrus pulp or silage of moist orange pulp. Both experiments had three treatments (C: control, DP: diet+dehydrated citrus pulp, and MP: diet+silage of moist orange pulp). The diets were isoproteic (11% crude protein) and the concentrate was corrected every 14 days according to animal weight. Parasitological parameters were evaluated for both experiments each 14 days (body weight, body condition; fecal egg counts-FEC, egg hatch assay EHA, coproculture, and packed cell volume-PCV). Analysis of variance (GLM of the SAS software) was performed with repeated measures in time, and the means were compared by the Tukey test. Gas chromatography with mass spectrometry was used to detect constituents of dry or moist citrus pulp. Dehydrated citrus pulp had 0.02% essential oil (major compounds were 85.9% limonene and 7.6% valencene). Moist orange pulp contained 1.5% essential oil (major compounds were 65.5% limonene and 31.2% alpha- and gamma-terpineol). In both experiments, the weight gain among the treatments was similar (p>0.05) demonstrating that both moist and dehydrated orange pulp can be used to replace corn kernels to feed infected lambs. The supplementation with orange pulp did not decrease natural or artificial infections of gastrointestinal nematodes according to the FEC results (p>0.05). However, PCV increased from animals fed dehydrated and moist pulp in natural infection (Experiment 2, p<0.05) in comparison with the control group. In addition, the consumption of the dehydrated citrus pulp from animals infected with H. contortus (Experiment 1) caused lower hatching rates after 42 days of consumption (p<0.05), suggesting a tendency to shed fewer eggs to the environment. PMID- 25282049 TI - Tissue-specific distribution of serine/threonine protein phosphatase 1 of Toxocara canis. AB - Serine/threonine protein phosphatase 1 (PP1) is expressed in developing and reproductively active male Toxocara canis. To investigate the tissue-specific expression of PP1 in T. canis, the PP1 protein was expressed in Escherichia coli, and the recombinant protein was used to generate a rabbit polyclonal antiserum. Indirect fluorescence immunohistochemical analysis of adult male T. canis showed that PP1 was expressed in the germ line tissues, primarily in the testis, seminal vesicle, vas deferens, and sperm cells, indicating the potential roles of PP1 in spermatogenesis. What's more, structural predictions of PP1 in T. canis were performed. The predictions of the structure indicated that PP1 may be a potential target for antihelmintic drugs. This is the first report of the tissue distributions and structural prediction of PP1 in T. canis, which might lead to the development of novel, innovative strategies for controlling T. canis infestations. PMID- 25282050 TI - Botulinum Toxin-A dose dependent perceptual loss on the hand after its cosmetic use on the face. PMID- 25282051 TI - Cross-modal repetition effects in the mu rhythm indicate tactile mirroring during action observation. AB - Similar cortical activations during the experience and observation of touch suggest the presence of a tactile mirroring system. However, the specificity of observation-related activity - i.e., whether observation excites the same representations as experience of that specific tactile stimulation - is still to be established. Furthermore, central mu rhythms are attenuated during the experience and observation of touch, and also during action observation and execution, making it unclear whether they index processing of predominantly tactile or motor features of observed actions. The present study used an electroencephalography (EEG) cross-modal repetition paradigm to assess the relative tactile and motor specificity of mu attenuation during action observation. Two experiments were carried out during which participants executed and observed actions in alternation, and the repetition of either tactile or motor features of the actions were manipulated. The mu signal over central electrodes varied as a function of tactile repetition, consistent with the claim of a tactile mirroring system and its reflection in the mu signal. Of note was the fact that mu attenuation was sensitive only to manipulation of tactile - not motor - properties of actions, suggesting that caution should be employed when interpreting mu effects during action observation as reflective of motor mirroring. PMID- 25282052 TI - tDCS to temporoparietal cortex during familiarisation enhances the subsequent phonological coherence of nonwords in immediate serial recall. AB - Research has shown that direct current stimulation (tDCS) over left temporoparietal cortex - a region implicated in phonological processing - aids new word learning. The locus of this effect remains unclear since (i) experiments have not empirically separated the acquisition of phonological forms from lexical semantic links and (ii) outcome measures have focused on learnt associations with a referent rather than phonological stability. We tested the hypothesis that left temporoparietal tDCS would strengthen the acquisition of phonological forms, even in the absence of the opportunity to acquire lexical-semantic associations. Participants were familiarised with nonwords paired with (i) photographs of concrete referents or (ii) blurred images where no clear features were visible. Nonword familiarisation proceeded under conditions of anodal tDCS and sham stimulation in different sessions. We examined the impact of these manipulations on the stability of the phonological trace in an immediate serial recall (ISR) task the following day, ensuring that any effects were due to the influence of tDCS on long-term learning and not a direct consequence of short-term changes in neural excitability. We found that only a few exposures to the phonological forms of nonwords were sufficient to enhance nonword ISR overall compared to entirely novel items. Anodal tDCS during familiarisation further enhanced the acquisition of phonological forms, producing a specific reduction in the frequency of phoneme migrations when sequences of nonwords were maintained in verbal short-term memory. More of the phonemes that were recalled were bound together as a whole correct nonword following tDCS. These data show that tDCS to left temporoparietal cortex can facilitate word learning by strengthening the acquisition of long-term phonological forms, irrespective of the availability of a concrete referent, and that the consequences of this learning can be seen beyond the learning task as strengthened phonological coherence in verbal short-term memory. PMID- 25282053 TI - Transcranial direct current stimulation over the left prefrontal cortex increases randomness of choice in instrumental learning. AB - INTRODUCTION: There is growing evidence from neuro-computational studies that instrumental learning involves the dynamic interaction of a computationally rigid, low-level striatal and a more flexible, high-level prefrontal component. METHODS: To evaluate the role of the prefrontal cortex in instrumental learning, we applied anodal transcranial direct current stimulation (tDCS) optimized for the left dorsolateral prefrontal cortex, by using realistic MR-derived finite element model-based electric field simulations. In a study with a double-blind, sham-controlled, repeated-measures design, sixteen male participants performed a probabilistic learning task while receiving anodal and sham tDCS in a counterbalanced order. RESULTS: Compared to sham tDCS, anodal tDCS significantly increased the amount of maladaptive shifting behavior after optimal outcomes during learning when reward probabilities were highly dissociable. Derived parameters of the Q-learning computational model further revealed a significantly increased model parameter that was sensitive to random action selection in the anodal compared to the sham tDCS session, whereas the learning rate parameter was not influenced significantly by tDCS. CONCLUSION: These results congruently indicate that prefrontal tDCS during instrumental learning increased randomness of choice, possibly reflecting the influence of the cognitive prefrontal component. PMID- 25282054 TI - Organising white matter in a brain without corpus callosum fibres. AB - Isolated corpus callosum dysgenesis (CCD) is a congenital malformation which occurs during early development of the brain. In this study, we aimed to identify and describe its consequences beyond the lack of callosal fibres, on the morphology, microstructure and asymmetries of the main white matter bundles with diffusion imaging and fibre tractography. Seven children aged between 9 and 13 years old and seven age- and gender-matched control children were studied. First, we focused on bundles within the mesial region of the cerebral hemispheres: the corpus callosum, Probst bundles and cingulum which were selected using a conventional region-based approach. We demonstrated that the Probst bundles have a wider connectivity than the previously described rostrocaudal direction, and a microstructure rather distinct from the cingulum but relatively close to callosal remnant fibres. A sigmoid bundle was found in two partial ageneses. Second, the corticospinal tract, thalamic radiations and association bundles were extracted automatically via an atlas of adult white matter bundles to overcome bias resulting from a priori knowledge of the bundles' anatomical morphology and trajectory. Despite the lack of callosal fibres and the colpocephaly observed in CCD, all major white matter bundles were identified with a relatively normal morphology, and preserved microstructure (i.e. fractional anisotropy, mean diffusivity) and asymmetries. Consequently the bundles' organisation seems well conserved in brains with CCD. These results await further investigations with functional imaging before apprehending the cognition variability in children with isolated dysgenesis. PMID- 25282055 TI - Sensory contribution to vocal emotion deficit in Parkinson's disease after subthalamic stimulation. AB - Subthalamic nucleus (STN) deep brain stimulation in Parkinson's disease induces modifications in the recognition of emotion from voices (or emotional prosody). Nevertheless, the underlying mechanisms are still only poorly understood, and the role of acoustic features in these deficits has yet to be elucidated. Our aim was to identify the influence of acoustic features on changes in emotional prosody recognition following STN stimulation in Parkinson's disease. To this end, we analysed the performances of patients on vocal emotion recognition in pre-versus post-operative groups, as well as of matched controls, entering the acoustic features of the stimuli into our statistical models. Analyses revealed that the post-operative biased ratings on the Fear scale when patients listened to happy stimuli were correlated with loudness, while the biased ratings on the Sadness scale when they listened to happiness were correlated with fundamental frequency (F0). Furthermore, disturbed ratings on the Happiness scale when the post operative patients listened to sadness were found to be correlated with F0. These results suggest that inadequate use of acoustic features following subthalamic stimulation has a significant impact on emotional prosody recognition in patients with Parkinson's disease, affecting the extraction and integration of acoustic cues during emotion perception. PMID- 25282057 TI - Sound symbolism scaffolds language development in preverbal infants. AB - A fundamental question in language development is how infants start to assign meaning to words. Here, using three Electroencephalogram (EEG)-based measures of brain activity, we establish that preverbal 11-month-old infants are sensitive to the non-arbitrary correspondences between language sounds and concepts, that is, to sound symbolism. In each trial, infant participants were presented with a visual stimulus (e.g., a round shape) followed by a novel spoken word that either sound-symbolically matched ("moma") or mismatched ("kipi") the shape. Amplitude increase in the gamma band showed perceptual integration of visual and auditory stimuli in the match condition within 300 msec of word onset. Furthermore, phase synchronization between electrodes at around 400 msec revealed intensified large scale, left-hemispheric communication between brain regions in the mismatch condition as compared to the match condition, indicating heightened processing effort when integration was more demanding. Finally, event-related brain potentials showed an increased adult-like N400 response - an index of semantic integration difficulty - in the mismatch as compared to the match condition. Together, these findings suggest that 11-month-old infants spontaneously map auditory language onto visual experience by recruiting a cross-modal perceptual processing system and a nascent semantic network within the first year of life. PMID- 25282056 TI - A dissociation between stopping and switching actions following a lesion of the pre-supplementary motor area. AB - INTRODUCTION: Although the pre-supplementary motor area (pre-SMA) is one of the most frequently reported areas of activation in functional imaging studies, the role of this brain region in cognition is still a matter of intense debate. Here we present a patient with a focal lesion of caudal pre-SMA who displays a selective deficit in updating a response plan to switch actions, but shows no impairment when required to withhold a response - stopping. MATERIALS & METHODS: The patient and a control group underwent three tasks designed to measure different aspects of cognitive control and executive function. RESULTS: The pre SMA patient displayed no impairment when responding in the face of distracting stimuli (Eriksen flanker paradigm), or when required to halt an on-going response (STOP task). However, a specific deficit was observed when she was required to rapidly switch between response plans (CHANGE task). CONCLUSIONS: These findings suggest that the caudal pre-SMA may have a particularly important role in a network of brain regions required for rapidly updating and implementing response plans. The lack of any significant impairment on other measures of cognitive control suggests that this is not likely due to a global deficit in cognitive control. We discuss the implications of these results in the context of current theories of pre-SMA function. PMID- 25282058 TI - Impaired threat prioritisation after selective bilateral amygdala lesions. AB - The amygdala is proposed to process threat-related information in non-human animals. In humans, empirical evidence from lesion studies has provided the strongest evidence for a role in emotional face recognition and social judgement. Here we use a face-in-the-crowd (FITC) task which in healthy control individuals reveals prioritised threat processing, evident in faster serial search for angry compared to happy target faces. We investigate AM and BG, two individuals with bilateral amygdala lesions due to Urbach-Wiethe syndrome, and 16 control individuals. In lesion patients we show a reversal of a threat detection advantage indicating a profound impairment in prioritising threat information. This is the first direct demonstration that human amygdala lesions impair prioritisation of threatening faces, providing evidence that this structure has a causal role in responding to imminent danger. PMID- 25282059 TI - Mechanical problem-solving and imitation of meaningless postures in left brain damaged patients: two sides of the same coin? PMID- 25282060 TI - Brain vessels mummification in an individual of ancient Egypt. PMID- 25282061 TI - Behavioral and electrophysiological evidence of opposing lateral visuospatial asymmetries in the upper and lower visual fields. AB - Neurologically healthy individuals typically exhibit a subtle bias towards the left visual field during spatial judgments, known as "pseudoneglect". However, it has yet to be reliably established if the direction and magnitude of this lateral bias varies along the vertical plane. Here, participants were required to distribute their attention equally across a checkerboard array spanning the entire visual field in order to detect transient targets that appeared at unpredictable locations. Reaction times (RTs) were faster to left hemifield targets in the lower visual field but the opposite trend was observed for targets in the upper field. Electroencephalogram (EEG) analyses focused on the interval prior to target onset in order to identify endogenous neural correlates of these behavioral asymmetries. The relative hemispheric distribution of pre-target oscillatory alpha power was predictive of RT bias to targets in the lower visual field but not the upper field, indicating separate attentional mechanisms for the upper and lower visual fields. Analysis of multifocal visual-evoked potentials (MVEP) in the pre-target interval also indicated that the opposing upper and lower field asymmetries may impact on the magnitude of primary visual cortical responses. These results provide new evidence of a functional segregation of upper and lower field visuospatial processing. PMID- 25282062 TI - Efficacy and safety of high-dose propranolol for the management of infant supraventricular tachyarrhythmias. AB - OBJECTIVE: To report our experience with high-dose propranolol monotherapy for prophylaxis and treatment of infant supraventricular arrhythmias (SAs). STUDY DESIGN: Patients <1 year of age initiated on enteral propranolol as inpatients for management of SA were identified during a 10-year time period from the Texas Children's Hospital pharmacy database. Patients were included if they received propranolol monotherapy for SA. Propranolol therapy was considered successful when patients were initiated and discharged on monotherapy, without documented recurrence of arrhythmia or requiring additional antiarrhythmic medication. Patients discharged on propranolol were followed as outpatients until therapy was discontinued or a year from initiation, whichever came first. RESULTS: A total of 287 patients met study criteria (59.2% male). Propranolol therapy was initiated at a median of 17 days of age (IQR 6-33 days) at a total daily dose of 3.6 +/- 1.0 mg/kg/day. Propranolol was successful in controlling SA throughout the inpatient stay in 67.3% of patients. Only one patient experienced a clinically significant adverse event that required propranolol discontinuation. A multivariable logistic regression analysis identified the presence of congenital heart disease (OR 0.42, 95% CI 0.19-0.94, P = .04) and Wolff-Parkinson-White (OR 0.42, 95% CI 0.21-0.87, P = .01) as factors for nonsuccessful inpatient propranolol monotherapy. Of 190 patients discharged on propranolol monotherapy, 87.7% were recurrence free during follow-up. CONCLUSIONS: High-dose propranolol is safe and reasonably successful in the treatment of infant SA. Inpatient control may be a predictor of continued outpatient efficacy. PMID- 25282063 TI - Do correlates of preterm infants' attention problems have clinical utility? PMID- 25282064 TI - Multicentric Castleman disease presenting with fever. AB - Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder that usually manifests with nonspecific symptoms, including fever and lymphadenopathy. Treatment of pediatric MCD varies greatly. A 21-month-old child was diagnosed with MCD after presenting with fever. He had incomplete response to initial therapy directed at interleukin-6, but improved with subsequent chemotherapy. PMID- 25282065 TI - Early life growth and the development of preschool wheeze, independent from overweight: the LucKi Birth Cohort Study. AB - OBJECTIVE: To investigate whether birth weight and postnatal growth rates are independently related to the development of overweight and wheeze up to age 3 years. STUDY DESIGN: Children from the LucKi Birth Cohort Study with complete follow-up for repeated questionnaires (at age 0, 7, and 14 months and 3 years) and informed consent to use height and weight data (measured by trained personnel at age 0, 7, and 14 months and 2 and 3 years) were included (n = 566). Wheeze (parental-reported) and overweight (body mass index [BMI] >85th percentile) were regressed with generalized estimating equations on birth weight and relative growth rates (difference SDS for weight, height, and BMI). RESULTS: Higher birth weight and higher weight and BMI growth rates were associated with increased risk of overweight, but not of wheeze, up to age 3 years. Higher height growth rate was associated with lower risk of wheeze up to 3 years, independent of overweight (aOR, 0.65; 95% CI, 0.53-0.79). In time-lag models, wheeze was associated with subsequently reduced height growth up to age 14 months, but not vice versa. CONCLUSION: Only height growth rate, and not weight and BMI growth rate, is associated with preschool wheeze, independent of overweight. Children who wheeze demonstrate a subsequent reduction in height growth up to age 14 months, but not vice versa. Because height growth rate is not associated with overweight, preschool wheeze and overweight are not associated throughout early life growth. PMID- 25282066 TI - Serum 25-hydroxyvitamin D levels in relation to lung function and exhaled nitric oxide in children. AB - OBJECTIVE: To investigate the relationship of vitamin D status with lung function and fraction of exhaled nitric oxide (FeNO) in a population sample of children. STUDY DESIGN: A total of 1315 children aged 5-18 years were evaluated using serum 25-hydroxyvitamin D [25(OH)D] levels, spirometry, a single-breath online FeNO measurement, and questionnaires. RESULTS: After adjusting for confounders, the mean forced vital capacity was 53.4 mL (SE, 26.5 mL; P = .045), and the mean forced expiratory volume in 1 second was 48.2 mL (SE, 23.6 mL; P = .042) lower for children with insufficient serum 25(OH)D levels (20-29.9 ng/mL) compared with those with sufficient 25(OH)D levels (>=30 ng/mL). The mean difference between children with deficient (<20 ng/mL) and sufficient levels of serum 25(OH)D was 81.9 mL (SE, 26.7 mL; P = .002) for forced vital capacity and 55.2 mL (SE, 23.7 mL; P = .020) for forced expiratory volume in 1 second. There was no significant association between serum 25(OH)D levels and FeNO after adjusting for confounders. CONCLUSIONS: Our results demonstrate a significant relationship between insufficient serum vitamin D levels and worse lung function in children in the community with a suggested dose-response effect. Our findings also suggest that vitamin D status is not a significant determinant of FeNO in children in the general population. PMID- 25282068 TI - Birth asphyxia: 100 years of progress. PMID- 25282067 TI - Neurodevelopment and behavior after transcatheter versus surgical closure of secundum type atrial septal defect. AB - OBJECTIVE: To assess the neuropsychological and behavioral profiles of school aged children treated for atrial septal defect, secundum type (ASD-II) with open heart surgery or catheterization. STUDY DESIGN: Patients (n = 48; mean age, 9 years, 3 months) and a matched healthy group (mean age, 9 years, 2 months) were evaluated with a shortened intelligence scale (Wechsler Intelligence Scale for Children, third edition, Dutch version) and a developmental neuropsychological test battery (Developmental Neuropsychological Assessment, second edition, Dutch version). Parents completed behavioral checklists (Achenbach Child Behavior Checklist for Children aged 6-18). Hospitalization variables were retrieved from medical files for studying associations with long-term neurodevelopment. RESULTS: Compared with the healthy matched controls, patients treated for ASD-II had significantly lower scores on subtasks underlying such Developmental Neuropsychological Assessment, second edition, Dutch version domains as Attention and Executive Functioning, Language, Working Memory, Sensorimotor Functioning, Social Cognition, and Visuospatial Information Processing. Only subtle differences, mainly in Visuospatial Information Processing, were found between the surgical repair and transcatheter repair groups. Socioeconomic status, longer hospital stay, and larger defect size were associated with neurocognitive outcome measures. Parents of patients reported more thought problems, posttraumatic stress problems, and lower school performance compared with parents of healthy peers. CONCLUSION: After treatment for ASD-II, children display a range of neuropsychologic difficulties that may increase their risk for learning problems and academic underachievement. Differences related to treatment were not found. Our results suggest that neurodevelopmental and behavioral follow-up at school age is warranted in this group. PMID- 25282069 TI - Obesity in total joint arthroplasty: an issue with gravity. PMID- 25282070 TI - Patient-centered clinical data and the National Surgical Quality Improvement Program: how best to advance care in total hip arthroplasty. In reply. PMID- 25282071 TI - The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. AB - Efforts continue to improve pain after total knee arthroplasty (TKA) in order to allow for accelerated rehabilitation. The purpose of this study was to evaluate pain control after TKA. A randomized prospective study of 80 consecutive patients was performed comparing Exparel versus femoral nerve block (FNB). Inpatient pain control was the primary outcome. Secondary outcome measures included ROM (extension and flexion), nausea and vomiting, narcotic consumption, ambulation distance, and length of stay (LOS). There were no statistically significant differences between the groups with regard to pain, nausea and vomiting, and narcotic consumption. The FNB group had greater flexion but the Exparel group had improved early ambulation and decreased LOS. Exparel provided similar pain relief to a FNB after TKA without compromising early rehabilitation. PMID- 25282072 TI - Long term follow-up of successfully treated superficial wound infections following TKA. AB - The relevance of wound complications in association with acute prosthetic joint infection (PJI) is well known. However, whether a successfully treated superficial infection can result in a chronic deep infection remains unclear. The aim of this study was to determine the prevalence, treatment and late complications of superficial wound infections following TKA. In a 3000 TKA prospective cohort, 45 superficial infections were diagnosed and treated successfully with antibiotic therapy along with or without surgical debridement. None of the cases developed deep chronic PJI at 70 months of follow-up. Three cases were in need of a TKA exchange due to aseptic loosening. A successfully treated superficial wound infection does not result in a chronic deep TKA infection. PMID- 25282073 TI - The potential influence of regionalization strategies on delivery of care for elective total joint arthroplasty. AB - Regionalization of total joint arthroplasty (TJA) to high volume hospitals (HVHs) may affect access to care and complication risk. Using administrative data, 2,560,314 patients who underwent primary total hip or knee arthroplasty from 1991 to 2006 were categorized by whether an HVH (>200 annual TJAs) was available locally. Associations among patient characteristics, hospital utilization, and in hospital complications were estimated using regression modeling. The complication risk was higher (Odds Ratio 1.18 [95% CI: 1.16, 1.20]) if patients went to a local low volume hospital. Black and Medicaid patients were more likely to utilize the local low volume hospital than a local HVH. Utilizing a local HVH is associated with lower complication risks. However, patients from vulnerable groups were less likely to utilize these patterns. PMID- 25282074 TI - Assessing morbidity and mortality following total hip arthroplasty. PMID- 25282075 TI - A comparison of static and dynamic optimization muscle force predictions during wheelchair propulsion. AB - The primary purpose of this study was to compare static and dynamic optimization muscle force and work predictions during the push phase of wheelchair propulsion. A secondary purpose was to compare the differences in predicted shoulder and elbow kinetics and kinematics and handrim forces. The forward dynamics simulation minimized differences between simulated and experimental data (obtained from 10 manual wheelchair users) and muscle co-contraction. For direct comparison between models, the shoulder and elbow muscle moment arms and net joint moments from the dynamic optimization were used as inputs into the static optimization routine. RMS errors between model predictions were calculated to quantify model agreement. There was a wide range of individual muscle force agreement that spanned from poor (26.4% Fmax error in the middle deltoid) to good (6.4% Fmax error in the anterior deltoid) in the prime movers of the shoulder. The predicted muscle forces from the static optimization were sufficient to create the appropriate motion and joint moments at the shoulder for the push phase of wheelchair propulsion, but showed deviations in the elbow moment, pronation-supination motion and hand rim forces. These results suggest the static approach does not produce results similar enough to be a replacement for forward dynamics simulations, and care should be taken in choosing the appropriate method for a specific task and set of constraints. Dynamic optimization modeling approaches may be required for motions that are greatly influenced by muscle activation dynamics or that require significant co-contraction. PMID- 25282076 TI - A finite element analysis of the retinal hemorrhages accompanied by shaken baby syndrome/abusive head trauma. AB - We aimed to elucidate the mechanism of the retinal hemorrhage (RH) accompanied by shaken baby syndrome or abusive head trauma (SBS/AHT) by analyses using a computational model. We focused on a hypothesis that the vitreoretinal traction due to acceleration and deceleration caused by abusive shaking leads to retinal hemorrhage. A finite element (FE) mechanical model with simple spherical geometry was constructed. When the FE mechanical model was virtually shaken, the intensity of the stress applied to the retinal plane agreed well with the results from an analysis using a physical model made of agar gel. Impacts due to falling events induced more intensive tensile stresses, but with shorter duration, than the shake did. By applying a mathematical theory on tackiness, we propose a hypothesis that the time integration of the stress, in the unit of Pa.s, would be a good predictor of the RH accompanied by SBS/AHT. A single cycle of abusive shake amounted to 101Pa.s of time integration of inflicted stress, while a single impact event amounted to 36Pa.s. This would explain the paradoxical observation that shaking induces RH while RH due to impact events is only seen in a major event such as a fatal motor vehicle accident. PMID- 25282077 TI - A novel electrochemical method to detect theophylline utilizing silver ions captured within abasic site-incorporated duplex DNA. AB - We herein describe a novel and label-free electrochemical system to detect theophylline. The system was constructed by immobilizing duplex DNA containing an abasic site opposite cytosine on the gold electrode surface. In the absence of theophylline in a sample, silver ions freely bind to the empty abasic site in the duplex DNA leading to the highly elevated electrochemical signal by the redox reaction of silver ions. On the other hand, when theophylline is present, it binds to the abasic site by pseudo base pairing with the opposite cytosine nucleobase, which consequently prevents silver ions from binding to the abasic site. As a result, redox reaction of silver ions would be greatly reduced resulting in the accordingly decreased electrochemical signal. By employing this electrochemical strategy, theophylline was reliably detected at a concentration as low as 3.2 MUM with the high selectivity over structurally similar substances such as caffeine and theobromine. Finally, the diagnostic capability of this method was also successfully verified by reliably detecting theophylline present in a real human serum sample with an excellent recovery ratio within 100+/-6%. PMID- 25282078 TI - A paper strip based non-invasive glucose biosensor for salivary analysis. AB - In our present study, we developed an optical biosensor for direct determination of salivary glucose by using immobilized glucose oxidase enzyme on filter paper strip (specific activity 1.4 U/strip) and then reacting it with synthetic glucose samples in presence of co-immobilized color pH indicator. The filter paper changed color based on concentration of glucose in reaction media and hence, by scanning this color change (using RGB profiling) through an office scanner and open source image processing software (GIMP) the concentration of glucose in the reaction medium could be deduced. Once the biosensor was standardized, the synthetic glucose sample was replaced with human saliva from donors. The individual's blood glucose level at the time of obtaining saliva was also measured using an Accuchek(TM) active glucometer (Roche Inc.). In this preliminary study, a correlation of nearly 0.64 was found between glucose levels in saliva and blood of healthy individuals and in diabetic patients it was nearly in the order of 0.95, thereby validating the importance of salivary analysis. The RGB profiling method obtained a detection range of 9-1350 mg/dL glucose at a response time of 45 s and LOD of 22.2 mg/dL. PMID- 25282080 TI - Healthy lifestyle guidelines--are they good enough? PMID- 25282079 TI - Chromatin structure is distinct between coding and non-coding single nucleotide polymorphisms. AB - BACKGROUND: Previous studies suggested that nucleosomes are enriched with single nucleotide polymorphisms (SNPs) in humans and that the occurrence of mutations is closely associated with CpG dinucleotides. We aimed to determine if the chromatin organization is genomic locus specific around SNPs, and if newly occurring mutations are associated with SNPs. RESULTS: Here, we classified SNPs according their loci and investigated chromatin organization in both CD4+ T cell and lymphoblastoid cell in humans. We calculated the SNP frequency around somatic mutations. The results indicated that nucleosome occupancy is different around SNPs sites in different genomic loci. Coding SNPs are mainly enriched at nucleosomes and associated with repressed histone modifications (HMs) and DNA methylation. Contrastingly, intron SNPs occur in nucleosome-depleted regions and lack HMs. Interestingly, risk-associated non-coding SNPs are also enriched at nucleosomes with HMs but associated with low GC-content and low DNA methylation level. The base-transversion allele frequency is significantly low in coding synonymous SNPs (P < 10-11). Another finding is that at the -1 and +1 positions relative to the somatic mutation sites, the SNP frequency was significantly higher (P < 3.2 * 10-5). CONCLUSIONS: The results suggested chromatin structure is different around coding SNPs and non-coding SNPs. New mutations tend to occur at the -1 and +1 position immediately near the SNPs. PMID- 25282081 TI - The Look AHEAD study: a missed opportunity. PMID- 25282082 TI - Diabetic kidneys do deserve a lifestyle change. PMID- 25282083 TI - The Look AHEAD study: a missed opportunity--authors' reply. PMID- 25282085 TI - Hypothyroidism in India: more to be done. AB - The incidence of thyroid disorders in India is high, with hypothyroidism a particular problem that is not adequately controlled in the country at present. Sanjeet Bagcchi reports on this important public health issue. PMID- 25282086 TI - Tumoral calcinosis in chronic renal failure. PMID- 25282088 TI - Life cycle assessments of urban water systems: a comparative analysis of selected peer-reviewed literature. AB - Water is a growing concern in cities, and its sustainable management is very complex. Life cycle assessment (LCA) has been increasingly used to assess the environmental impacts of water technologies during the last 20 years. This review aims at compiling all LCA papers related to water technologies, out of which 18 LCA studies deals with whole urban water systems (UWS). A focus is carried out on these 18 case studies which are analyzed according to criteria derived from the four phases of LCA international standards. The results show that whereas the case studies share a common goal, i.e., providing quantitative information to policy makers on the environmental impacts of urban water systems and their forecasting scenarios, they are based on different scopes, resulting in the selection of different functional units and system boundaries. A quantitative comparison of life cycle inventory and life cycle impact assessment data is provided, and the results are discussed. It shows the superiority of information offered by multi-criteria approaches for decision making compared to that derived from mono-criterion. From this review, recommendations on the way to conduct the environmental assessment of urban water systems are given, e.g., the need to provide consistent mass balances in terms of emissions and water flows. Remaining challenges for urban water system LCAs are identified, such as a better consideration of water users and resources and the inclusion of recent LCA developments (territorial approaches and water-related impacts). PMID- 25282089 TI - Performance of an AnMBR pilot plant treating high-strength lipid wastewater: biological and filtration processes. AB - The performance of an anaerobic membrane bioreactor (AnMBR) treating wastewater with high levels of oil and grease content from a snacks factory is studied and its effectiveness is demonstrated. The relation between the reversible and the irreversible fouling rate and the fouling propensity of the fatty matter were evaluated under a subcritical flux of 7.9 and 8.3 L/m(2) h. Low Oil and Grease (O&G) concentrations of 500 mg/L produced an irreversible fouling rate of only 0.09 mbar/d, while the fouling rate was between 0.96 and 3.95 mbar/d for an average O&G concentration of 6 g/L. In spite of the significant increase in filtration resistance from 0.31 to 6.08 * 10(12) m(-1) after 40 days of continuous operation, the critical flux level hardly decreased from 11.1 to 9.7 L/(m(2) h). With regard to the biological process, after a start-up period with an organic loading rate (OLR) of below 2 kg COD/(m(3) d), the system was able to treat wastewater between 4.6 and 36 g O&G/L and the system remained stable for OLR at around 17 kg COD/(m(3) d) for 2.8 d, without inhibitory signals. Acclimated sludge quickly reached maximum methane production and digested substrate with high oil and grease content, observing an increase in palmitic acid the first days and constant levels of propionic acid while fatty acids were in the medium. PMID- 25282090 TI - Laccase immobilized manganese ferrite nanoparticle: synthesis and LSSVM intelligent modeling of decolorization. AB - Laccase was immobilized onto manganese ferrite nanoparticle (MFN) and dye decolorization from single and binary systems was studied. The characteristics of laccase immobilized manganese ferrite nanoparticle (LIMFN) were investigated using Fourier transform infrared (FTIR) and scanning electron microscopy (SEM). Direct red 31 (DR31), Acid blue 92 (AB92) and Direct green 6 (DG6) were used. A least square support vector machine (LSSVM) was developed to predict the decolorization efficiency of various single and binary systems based on the obtained laboratory data under different experimental conditions. Statistical and graphical quality measures were also employed to evaluate the performance and accuracy of the developed intelligent models. It is shown that the predictions of the designed LSSVM models are in close agreement with the experimental data. The effects of LIMFN dosage, pH and dye concentration on dye decolorization from single and binary systems were evaluated. Decolorization kinetics followed Michaelis-Menten Model. PMID- 25282087 TI - Immune surveillance of the central nervous system in multiple sclerosis- relevance for therapy and experimental models. AB - Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events. PMID- 25282091 TI - Impact of organic nutrient load on biomass accumulation, feed channel pressure drop increase and permeate flux decline in membrane systems. AB - The influence of organic nutrient load on biomass accumulation (biofouling) and pressure drop development in membrane filtration systems was investigated. Nutrient load is the product of nutrient concentration and linear flow velocity. Biofouling - excessive growth of microbial biomass in membrane systems - hampers membrane performance. The influence of biodegradable organic nutrient load on biofouling was investigated at varying (i) crossflow velocity, (ii) nutrient concentration, (iii) shear, and (iv) feed spacer thickness. Experimental studies were performed with membrane fouling simulators (MFSs) containing a reverse osmosis (RO) membrane and a 31 mil thick feed spacer, commonly applied in practice in RO and nanofiltration (NF) spiral-wound membrane modules. Numerical modeling studies were done with identical feed spacer geometry differing in thickness (28, 31 and 34 mil). Additionally, experiments were done applying a forward osmosis (FO) membrane with varying spacer thickness (28, 31 and 34 mil), addressing the permeate flux decline and biofilm development. Assessed were the development of feed channel pressure drop (MFS studies), permeate flux (FO studies) and accumulated biomass amount measured by adenosine triphosphate (ATP) and total organic carbon (TOC). Our studies showed that the organic nutrient load determined the accumulated amount of biomass. The same amount of accumulated biomass was found at constant nutrient load irrespective of linear flow velocity, shear, and/or feed spacer thickness. The impact of the same amount of accumulated biomass on feed channel pressure drop and permeate flux was influenced by membrane process design and operational conditions. Reducing the nutrient load by pretreatment slowed-down the biofilm formation. The impact of accumulated biomass on membrane performance was reduced by applying a lower crossflow velocity and/or a thicker and/or a modified geometry feed spacer. The results indicate that cleanings can be delayed but are unavoidable. PMID- 25282092 TI - In-situ biofilm characterization in membrane systems using Optical Coherence Tomography: formation, structure, detachment and impact of flux change. AB - Biofouling causes performance loss in spiral wound nanofiltration (NF) and reverse osmosis (RO) membrane operation for process and drinking water production. The development of biofilm formation, structure and detachment was studied in-situ, non-destructively with Optical Coherence Tomography (OCT) in direct relation with the hydraulic biofilm resistance and membrane performance parameters: transmembrane pressure drop (TMP) and feed-channel pressure drop (FCP). The objective was to evaluate the suitability of OCT for biofouling studies, applying a membrane biofouling test cell operated at constant crossflow velocity (0.1 m s(-1)) and permeate flux (20 L m(-2)h(-1)). In time, the biofilm thickness on the membrane increased continuously causing a decline in membrane performance. Local biofilm detachment was observed at the biofilm-membrane interface. A mature biofilm was subjected to permeate flux variation (20 to 60 to 20 L m(-2)h(-1)). An increase in permeate flux caused a decrease in biofilm thickness and an increase in biofilm resistance, indicating biofilm compaction. Restoring the original permeate flux did not completely restore the original biofilm parameters: After elevated flux operation the biofilm thickness was reduced to 75% and the hydraulic resistance increased to 116% of the original values. Therefore, after a temporarily permeate flux increase the impact of the biofilm on membrane performance was stronger. OCT imaging of the biofilm with increased permeate flux revealed that the biofilm became compacted, lost internal voids, and became more dense. Therefore, membrane performance losses were not only related to biofilm thickness but also to the internal biofilm structure, e.g. caused by changes in pressure. Optical Coherence Tomography proved to be a suitable tool for quantitative in-situ biofilm thickness and morphology studies which can be carried out non-destructively and in real-time in transparent membrane biofouling monitors. PMID- 25282094 TI - Switching robust control for ozone generators using the attractive ellipsoid method. AB - This paper deals with a switching robust tracking feedback design for a corona effect ozone generator. The generator is considered as a switched systems in the presence of bounded model uncertainties as well as external perturbations. Three nonlinear dynamic models under arbitrary switching mechanisms are considered assuming that a sample-switching times are known. The stabilization issue is achieved in the sense of a practical stability. We apply the newly elaborated (extended) version of the conventional attractive ellipsoid method (AEM) for this purpose. The same analysis was efficient to obtain the minimal size of region where the tracking error between the trajectories of the ozone generator and reference states converges. The numerically implementable sufficient conditions for the practical stability of systems are derived based on bilinear matrix inequalities (BMIs). PMID- 25282093 TI - Electrochemical transformation of trichloroethylene in aqueous solution by electrode polarity reversal. AB - Electrode polarity reversal is evaluated for electrochemical transformation of trichloroethylene (TCE) in aqueous solution using flow-through reactors with mixed metal oxide electrodes and Pd catalyst. The study tests the hypothesis that optimizing electrode polarity reversal will generate H2O2 in Pd presence in the system. The effect of polarity reversal frequency, duration of the polarity reversal intervals, current intensity and TCE concentration on TCE removal rate and removal mechanism were evaluated. TCE removal efficiencies under 6 cycles h( 1) were similar in the presence of Pd catalyst (50.3%) and without Pd catalyst (49.8%), indicating that Pd has limited impact on TCE degradation under these conditions. The overall removal efficacies after 60 min treatment under polarity reversal frequencies of 6, 10, 15, 30 and 90 cycles h(-1) were 50.3%, 56.3%, 69.3%, 34.7% and 23.4%, respectively. Increasing the frequency of polarity reversal increases TCE removal as long as sufficient charge is produced during each cycle for the reaction at the electrode. Electrode polarity reversal shifts oxidation/reduction and reduction/oxidation sequences in the system. The optimized polarity reversal frequency (15 cycles h(-1) at 60 mA) enables two reaction zones formation where reduction/oxidation occurs at each electrode surface. PMID- 25282095 TI - Application of higher order spectral features and support vector machines for bearing faults classification. AB - Condition monitoring and fault diagnosis of rolling element bearings timely and accurately are very important to ensure the reliability of rotating machinery. This paper presents a novel pattern classification approach for bearings diagnostics, which combines the higher order spectra analysis features and support vector machine classifier. The use of non-linear features motivated by the higher order spectra has been reported to be a promising approach to analyze the non-linear and non-Gaussian characteristics of the mechanical vibration signals. The vibration bi-spectrum (third order spectrum) patterns are extracted as the feature vectors presenting different bearing faults. The extracted bi spectrum features are subjected to principal component analysis for dimensionality reduction. These principal components were fed to support vector machine to distinguish four kinds of bearing faults covering different levels of severity for each fault type, which were measured in the experimental test bench running under different working conditions. In order to find the optimal parameters for the multi-class support vector machine model, a grid-search method in combination with 10-fold cross-validation has been used. Based on the correct classification of bearing patterns in the test set, in each fold the performance measures are computed. The average of these performance measures is computed to report the overall performance of the support vector machine classifier. In addition, in fault detection problems, the performance of a detection algorithm usually depends on the trade-off between robustness and sensitivity. The sensitivity and robustness of the proposed method are explored by running a series of experiments. A receiver operating characteristic (ROC) curve made the results more convincing. The results indicated that the proposed method can reliably identify different fault patterns of rolling element bearings based on vibration signals. PMID- 25282096 TI - [Hyperechogenic fetal bowel: Which fetal and neonatal outcome? A French study of 149 cases]. AB - OBJECTIVES: In case of hyperechogenic fetal bowel (HFB), invasive procedures such as amniocentesis are often proposed to detect an underlying cause. Our goal is to study etiologies and prognosis of HFB according to antenatal sonographic findings in order to evaluate the relevance of antenatal assessment. MATERIALS AND METHODS: It is a retrospective monocentric study lead from 2008 to 2012, including all patients with a suspicion of HFB on routine sonography. We analysed the antenatal and neonatal results, distinguishing four situations: isolated HFB, HFB+other digestive anomalies, HFB+vascular pathology, HFB+other associated anomalies. RESULTS: For 149 patients, HBF was confirmed. Sixty-nine were isolated HFB, 24 associated with other digestive anomalies, 16 with vascular pathology and 40 with other anomalies. Pregnancy outcomes were different with 92.8, 41.7, 0 and 45.0% of healthy newborns. In the case of isolated HBF, we noted 2.9% cystic fibrosis and 2.9% congenital infection. CONCLUSION: Isolated HBF seems to have a better prognosis than associated forms. However, prenatal investigations to eliminate cystic fibrosis or congenital infection should be offered and may be initially non-invasive, if a larger series confirmed the absence of dyschromosomy in this population. PMID- 25282097 TI - [Sensory blockade and efficiency of the "pec block 2" for postoperative analgesia after breast cancer surgery]. PMID- 25282098 TI - In-vitro biomechanical evaluation of stress shielding and initial stability of a low-modulus hip stem made of beta type Ti-33.6Nb-4Sn alloy. AB - Stress shielding-related proximal femoral bone loss after total hip arthroplasty occurs because of the different stiffness of metallic alloy stems and host bone. To overcome this, we fabricated a low-modulus cementless hip stem from beta-type Ti-33.6Nb-4Sn alloy (TNS). Then we evaluated its stiffness, stress shielding, and initial stability compared with a similar Ti-6Al-4V alloy stem. Stiffness was determined by axial compression and cantilever-bending tests. Thirteen triaxial strain gages measured cortical strain. Stress shielding was defined as the percentage of intact strain after stem insertion. To evaluate initial stability, displacement transducers measured axial relative displacement and rotation. Intact and implanted femurs underwent single-leg-stance loading. Axial stiffness was 56% lower in the TNS stem than in the Ti-6Al-4V stem, and bending stiffness of the TNS stem decreased gradually from the proximal region to the distal region, being <= 53% that of the Ti-6Al-4V stem, indicating gradation of Young's modulus. The TNS stem decreased stress shielding in the proximal calcar region (A1: 83%, B1: 85% relative to intact cortical strain) without affecting the proximal lateral region (B3: 53%). The initial stabilities of the stems were comparable. These findings indicate that the TNS stem with gradation of Young's modulus minimizes proximal femoral bone loss and biological fixation, improving long-term stability. PMID- 25282099 TI - Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. AB - BACKGROUND: The primary treatment of soft tissue sarcomas (STS) is a radical resection of the tumor with adjuvant radiotherapy. Conventional fractionation of preoperative radiotherapy is 50 Gy in fraction of 2 Gy a day. The purpose of the conducted study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in STS patients. METHODS: 272 patients participated in this prospective study conducted from 2006 till 2011. Tumors were localized on the extremities or trunk wall. Median tumor size was 8.5 cm, 42% of the patients had tumor larger than 10 cm, whereas 170 patients (64.6%) had high grade (G3) tumors. 167 patients (61.4%) had primary tumors. Patients were treated with preoperative radiotherapy for five consecutive days in 5 Gy per fraction, with an immediate surgery. Median follow up is 35 months. RESULTS: 79 patients died at the time of the analysis, the 3-year overall survival was 72%. Local recurrences were observed in 19.1 % of the patients. Factors that had a significant adverse impact on local recurrence were tumor size of 10 cm or more and G3 grade. 114 patients (42%) had any kind of treatment toxicity, vast majority with tumors located on lower limbs. 7% (21) of the patients required surgery for treatment of the complications. CONCLUSION: In this non-selected group of locally advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (81%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrant further evaluation. PMID- 25282100 TI - Nano graphene oxide: a novel carrier for oral delivery of flavonoids. AB - The interesting physical and chemical properties of graphene oxide (GO) have led to much excitement among biomedical scientists in recent years. It is known that many potent, often aromatic medicines are water insoluble, and this has hindered their administration to treat diseases. Nano GO was synthesized and investigated for its biological application as a carrier for quercetin, a focused bioactive flavonoid widely used as a health supplement and a drug candidate. Different techniques were used to fully evaluate the synthesis, cytotoxicity, and quercetin loading capacity of nano GO. AFM and TEM results confirmed the preparation of planar nanoparticles without aggregation which was verified by reported size results (30 nm) obtained with a particle size analyzer. FTIR and DSC results proved the drug-carrier interaction. In vitro cytotoxicity assays showed that nano GO had no cytotoxicity on A549 cells in different amounts after incubation for 72 h, confirming its suitability as a drug carrier. Our results showed that nano GO can be proposed as a new carrier due to its small size, large specific surface area, low cost, and useful non-covalent interactions with aromatic low soluble flavonoids such as quercetin. Moreover, it may find widespread applications in biomedicine. PMID- 25282101 TI - Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. AB - The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-beta signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm. PMID- 25282102 TI - Recombination drives genome evolution in outbreak-related Legionella pneumophila isolates. AB - Legionella pneumophila is a strictly environmental pathogen and the etiological agent of legionellosis. It is known that non-vertical processes have a major role in the short-term evolution of pathogens, but little is known about the relevance of these and other processes in environmental bacteria. We report the whole genome sequencing of 69 L. pneumophila strains linked to recurrent outbreaks in a single location (Alcoy, Spain) over 11 years. We found some examples where the genome sequences of isolates of the same sequence type and outbreak did not cluster together and were more closely related to sequences from different outbreaks. Our analyses identify 16 recombination events responsible for almost 98% of the SNPs detected in the core genome and an apparent acceleration in the evolutionary rate. These results have profound implications for the understanding of microbial populations and for public health interventions in Legionella outbreak investigations. PMID- 25282104 TI - Ictal and postictal semiology in patients with bilateral temporal lobe epilepsy. AB - Bilateral temporal lobe epilepsy is characterized by evidence of seizure onset independently in both temporal lobes. The main aim of the present study was to determine whether patients with evidence of independent bilateral temporal lobe epilepsy (biTLE) can be identified noninvasively on the basis of seizure semiology analysis. Thirteen patients with biTLE, as defined by invasive EEG, were matched with 13 patients with unilateral temporal lobe epilepsy (uniTLE). In all 26 patients, the frequency of predefined clusters of ictal and periictal signs were evaluated: ictal motor signs (IMSs), periictal motor signs (PIMSs), periictal vegetative signs (PIVSs), the frequency of early oroalimentary automatisms (EOAs), and the duration of postictal unresponsiveness (PU). Some other noninvasive and clinical data were also evaluated. A lower frequency of IMSs was noted in the group with biTLE (patients = 46.2%, seizures = 20.7%) than in the group with uniTLE (patients = 92.3%, seizures = 61.0%) (p = 0.030; p < 0.001, respectively). The individual IMS average per seizure was significantly lower in the group with biTLE (0.14; range = 0-1.0) than in the group with uniTLE (0.80; range = 0-2.6) (p = 0.003). Postictal unresponsiveness was longer than 5 min in more patients (75.0%) and seizures (42.9%) in the group with biTLE than in the group with uniTLE (patients = 30.8%, seizures = 18.6%) (p = 0.047; p = 0.002). The frequency of EOAs, PIMSs, PIVSs, and other clinical data did not differ significantly. There is a lower frequency of ictal motor signs and longer duration of postictal unresponsiveness in patients with biTLE. PMID- 25282105 TI - Clobazam is efficacious for patients across the spectrum of disease severity of Lennox-Gastaut syndrome: post hoc analyses of clinical trial results by baseline seizure-frequency quartiles and VNS experience. AB - Lennox-Gastaut syndrome (LGS) severity varies considerably, so the potential impact of differences in baseline severity on patient outcome following treatment is clinically informative. Here, two surrogate indicators of LGS severity (baseline seizure frequency and vagus nerve stimulation [VNS] use) were used in post hoc analyses of both short- and long-term clobazam trials (Phase III OV-1012 [CONTAIN] and open-label extension [OLE] OV-1004). In CONTAIN, 217 patients comprised the modified, intention-to-treat population. Each baseline seizure frequency quartile had ~40 patients, and baseline weekly drop-seizure frequency ranges were as follows: <10 (Quartile 1), 10-30 (Quartile 2), 32-86 (Quartile 3), and 86-1077 (Quartile 4). Mean percentage decreases in average weekly drop and total seizures were similar for all quartiles. More than 50% of patients in all 4 quartiles demonstrated >= 50% decreases in weekly drop- and total-seizure frequency. The percentage of patients achieving 100% reduction in drop seizures was 33% for clobazam-treated patients (vs. 7% for placebo) in Quartile 1. Five percent of clobazam-treated patients in Quartile 4 (most severe LGS) vs. 0% for placebo achieved 100% reduction in drop seizures. A total of 267 of 306 possible patients entered the OLE (61/68 from a Phase II study and 206/238 from Phase III CONTAIN). Each quartile had ~66 patients, and baseline weekly drop-seizure ranges were as follows: <10 (Quartile 1), 10-31 (Quartile 2), 32-110 (Quartile 3), and 111-1147 (Quartile 4). Median percentage decreases in average weekly drop and total seizures were similar between quartiles. Through 5 years of therapy, >50% of patients in all 4 quartiles demonstrated >= 50% decreases in weekly frequency for drop seizures. More than 12% of patients in Quartile 4 achieved 100% reduction in drop seizures from Month 3 through Year 5. For the VNS analyses in CONTAIN, the least-squares mean decreases in average weekly rate of drop seizures (mITT population) were 52% for VNS patients receiving clobazam vs. -22% for placebo (p < 0.01). For non-VNS patients, these percentages were 53% for clobazam and 26% for placebo (p < 0.01). Moreover, 50% and 54% of clobazam-treated patients in the VNS and non-VNS groups demonstrated >= 50% decreases in average weekly drop- and total-seizure frequencies, and 11% and 14% in the two groups achieved drop-seizure freedom, respectively. Analyses using baseline seizure frequency and VNS use as surrogates for disease severity showed that clobazam treatment of patients with less severe or severe LGS was equally efficacious. PMID- 25282106 TI - [Acute mesenteric ischemia: do biomarkers contribute to diagnosis?]. AB - Acute mesenteric ischemia is an emergency condition that requires immediate therapy. Despite advances in the fields of surgery and intensive therapy, the mortality of this condition remains high. This is due to the broad variability of clinical presentations and non-specific laboratory findings, which delay the diagnosis allowing the ischemia to progress and further worsening the patients' chances of survival. Thus, there is a significant need for reliable and enhanced serological markers of intestinal ischemia. The authors review the traditionally used and novel experimental serological markers for early diagnosis of mesenteric ischemia. PMID- 25282107 TI - [Assessment of left atrial size and function -- from M-mode to 3D speckle tracking echocardiography]. AB - Left atrium is not a passive heart chamber, because it has a dynamic motion respecting heart cycle and, in accordance with its stretching, it releases atrial natriuretic peptides. Since in the course of certain invasive procedures the size of left atrium may change substantially, its exact measurement and functional characterization are essential. The aim of the present review is to summarize echocardiographic methods for the assessment of left atrial size and functional parameters. PMID- 25282108 TI - [The role of virological tests in the diagnosis of cytomegalovirus infection in pregnant women]. AB - INTRODUCTION: The most harmful and most frequent foetal agent is cytomegalovirus. The progress in diagnostic tools and therapeutic opportunities opened new perspectives in the diagnosis and management of foetal cytomegalovirus infection. AIM: Evaluation of cytomegalovirus virological test results performed during pregnancy between 2007 and 2012. METHOD: Clinical and virology data were retrospectively analysed. RESULTS: 64.5% of the 956 tested women were serologically protected and 33.3% were susceptible to cytomegalovirus. Recent infection was confirmed in 10 pregnant women, while the infection could not be confirmed or excluded in 3 pregnant women. Six pregnant women were asymptomatic, 5 had typical disease, and 2 had abnormal fetal ultrasound. One fetus aborted, congenital infection was confirmed in 2, and was excluded in one of the four newborns tested. CONCLUSIONS: The immunity of women to cytomegalovirus reflects high socioeconomic circumstances. Confimatory tests must be done both in women who have cytomegalovirus disease and those who have IgM positive result detected by enzyme (linked) immunoassay. Screening must be done prior to pregnancy. Strict collaboration between professionals of different medical specialties is necessary. PMID- 25282109 TI - [Epidemiology of idiopathic inflammatory myopathy in Hungary]. AB - INTRODUCTION: Idiopathic inflammatory myopathy (called also myositis) is a systemic autoimmune disease mainly characterised with proximal muscle weakness. The most frequent subsets are polymyositis and dermatomyositis. The epidemiology of these diseases is not entirely explored. There is a need to build national and international registries which may help to obtain more data. The Myositis Team at the Department of Clinical Immunology, University of Debrecen, has been established in 1975. AIM: The aim of the authors was to obtain epidemiological data on this disease. METHOD: The authors analysed the database of the National Health Insurance Fund Administration of Hungary which included 1119 patients with myositis, of which 289 patients were followed up by the authors. RESULTS: The average incidence of the disease was found to be 0.95/100.000/year. The male/female ratio was 1/2. Dermatomyositis occurred both in children and adult, but polymyositis was found mainly in adults. These epidemiological data partly correlate with those published in the international literature. CONCLUSIONS: The authors propose to establish a National Myositis Registry in the frame of multicentric collaboration in order to have more information about the disease. PMID- 25282110 TI - [Endoscopic ultrasound-guided ethanol ablation: an alternative option for the treatment of pancreatic insulinoma]. AB - Endoscopic ultrasound is the most accurate imaging modality for the diagnosis of pancreatic cancer, and endoscopic ultrasound-guided fine needle injection has already been used for palliative interventions. Surgical resection is currently the standard treatment for pancreatic insulinoma. Medical treatment may be necessary for symptomatic patients with unresectable disease. Case reports have been published about the success of endoscopic ultrasound-guided alcoholic ablation, but it has not been reported previously in Hungarian literature. The authors present the history of an 83-year-old woman who was evaluated because of repeated hypoglycemic coma occurring during the night. Endosonographic image and laboratory findings (elevated serum insulin and chromogranin A) revealed pancreatic insulinoma. Because of severe comorbidities and high risk of surgical resection, the decision was made to ablate the insulinoma by endoscopic ultrasound-guided alcohol injection. A total of 3 mL 95% ethanol was injected into the tumor. Despite the discontinuation of the diazoxide therapy the hypoglycemic episodes disappeared. This case history confirms that endoscopic ultrasound-guided alcoholic ablation is a novel, minimal invasive alternative treatment for patients with pancreatic neuroendocrine tumors in whom surgery is not feasible. PMID- 25282112 TI - The effect of exercise and metformin treatment on circulating free DNA in pregnancy. AB - INTRODUCTION: Some pregnancy complications are characterized by increased levels of cell-free fetal (cffDNA) and maternal DNA (cfmDNA), the latter may also be elevated during physical strain. This study aims at assessing the impact of exercise and metformin intervention in pregnancy, and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis. METHODS: Consecutive women from two previous randomized controlled trials in pregnancy were included. Women came from a trial with organized exercise vs. standard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women. Levels of cffDNA, cfmDNA and cell-free total DNA (cftDNA) were measured by qPCR. RESULTS: Training in pregnancy did not affect the levels of cffDNA, cfmDNA or cftDNA. PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 (mean +/- SD: 301 +/- 162 versus 570 +/- 337, p = 0.012, 345 +/- 173 versus 635 +/- 370, p = 0.019); otherwise the levels were comparable to PCOS controls. Metformin-treated PCOS-women had higher cffDNA at inclusion, in the 1st trimester; later on in pregnancy the levels in the metformin and placebo groups were equal. A comparison of pregnant women in the exercise study (TRIP) to placebo-treated pregnant PCOS-women, showed the levels of cffDNA, cfmDNA or cftDNA during mid-pregnancy (weeks 18-36) to be equal. DISCUSSION: Training during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA, but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women. PMID- 25282113 TI - Trinucleotide expansion in disease: why is there a length threshold? AB - Trinucleotide repeats (TNRs) expansion disorders are severe neurodegenerative and neuromuscular disorders that arise from inheriting a long tract (30-50 copies) of a trinucleotide unit within or near an expressed gene (Figure 1a). The mutation is referred to as 'trinucleotide expansion' since the number of triplet units in a mutated gene is greater than the number found in the normal gene. Expansion becomes obvious once the number of repeating units passes a critical threshold length, but what happens at the threshold to render the repeating tract unstable? Here we discuss DNA-dependent and RNA-dependent models by which a particular DNA length permits a rapid transition to an unstable state. PMID- 25282115 TI - Sexual history taking in the emergency department - more specificity required. AB - BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are the most reported diseases in the United States, and emergency departments (ED) serve a population presenting with increased infection risk. However, identifying patients for whom sexually transmitted infection (STI) screening is appropriate requires accurate sexual history reporting. STUDY OBJECTIVES: To examine the consistency with which ED patients answer general and specific sexual activity questions, and how responses relate to perceived STI risk. METHODS: Urban ED patients aged 15-34 years completed a sexual history survey containing sexual activity and perceived infection risk questions and provided urine and pharyngeal specimens for CT/GC analysis. RESULTS: Participants included 192 males and 301 females with a mean age of 25.2 years and were 65.7% white and 33.3% black. Thirty-eight (7.7%) were infected with CT or GC. In patients denying sexual activity in the past year (general question), 40.7% of such males and 45.0% of females also reported some form of specific sexual activity (activity misclassification). Among self-identified heterosexuals, 7.2% males and 7.5% females reported some form of homosexual activity (orientation misclassification; OM). OM individuals were more likely to perceive themselves at risk of infection both orally (odds ratio 2.92, confidence interval 1.12-7.63) and genitally (odds ratio 3.36, confidence interval 1.55-7.30). CONCLUSIONS: Given that reported sexual activity and age are the only criteria for routine female screening, and that homosexual activity is one of the few screening criteria for males, our results show that a substantial proportion of ED patients eligible for screening may not be identified by reliance upon general sexual history questions. PMID- 25282114 TI - Somatic mutations, genome mosaicism, cancer and aging. AB - Genomes are inherently unstable due to the need for DNA sequence variation in the germ line to fuel evolution through natural selection. In somatic tissues mutations accumulate during development and aging, generating genome mosaics. There is little information about the possible causal role of increased somatic mutation loads in late-life disease and aging, with the exception of cancer. Characterizing somatic mutations and their functional consequences in normal tissues remains a formidable challenge due to their low, individual abundance. Here, I will briefly review our current knowledge of somatic mutations in animals and humans in relation to aging, how they arise and lead to genome mosaicism, the technology to study somatic mutations and how they possibly could cause non clonal disease. PMID- 25282116 TI - Mechanical falls: are patients willing to discuss their risk with a health care provider? AB - BACKGROUND: Falls in the elderly cause serious injury. OBJECTIVE: We aimed to determine subjects' comfort in discussing fall risk and home safety evaluations. METHODS: This prospective study surveyed a convenience sample of subjects (>=50 years old) in an emergency department (ED), health fair (HF), and family practice (FP). The survey included the Falls Efficacy Scale and Vulnerable Elders Survey validated surveys measuring fall concern and functional decline. Other data environmental living conditions, participant behaviors, fall frequency-were collected. The associations between perceived fall risk and participant characteristics were assessed using descriptive statistics and random-effects logistic regression. RESULTS: Participants (n = 416, 38% males, 62% females) had a mean age of 67.6 years; 35% were high fall risk. Previous year falls (p = 0.002), use of assistive device (p < 0.001), having at least one alcoholic drink/week (p = 0.043), and poor or fair perceived health status (p < 0.001) were associated with perceived fall risk. HF respondents were more willing than FP respondents to discuss falls (84.9% vs. 73.1%, p = 0.025). The difference was not significant between the HF and ED respondents (84.9% vs. 76.9, p = 0.11). HF subjects were more willing than FP to have a home safety inspection (68.9% vs. 45.9%, p < 0.001). The difference was not significant between the HF and ED respondents (68.9% vs 58.5, p = 0.09). CONCLUSIONS: Perceived and actual fall risks are highly associated. Most participants are willing to discuss their fall risk and a home safety evaluation. HF subjects were most willing to have these discussions; ED subjects were less willing than HF, but not significantly different from health fair participants. FP participants were significantly less willing to have these discussions than HF participants. This may suggest a meaningful opportunity for fall risk prevention in outpatient settings such as health fairs and the ED. PMID- 25282117 TI - Osmoregulatory mechanisms differentiate MDMA-associated hyponatremia from psychogenic polydipsia. PMID- 25282118 TI - Corneal clouding complicating a corneal transplant. PMID- 25282119 TI - Septic arthritis in intravenous drug abusers: a historical comparison of habits and pathogens. AB - BACKGROUND: Intravenous drug abuse (IVDA) is a common problem; there were more than 16 million users worldwide in 2008. Numerous reports highlight the infectious skeletal complication associated with IVDA. OBJECTIVE: To determine septic arthritis pathogens in IVDA in a U.S. hospital and compare the current causative organisms to a cohort from the 1980s at the same institution. METHODS: An institutional review board-approved retrospective cohort study compared a consecutive series of IVDA septic arthritis patients over a 10-year period, 1999 2008 (Group B), with an IVDA septic arthritis database that was collected in the 1980s (Group A). Endpoints were: bacterial species and staph species antibiotic susceptibility. RESULTS: Group B included 58 patients (35 men, 23 women) with a median age of 46.5 years. Group A included 38 patients (30 men, 8 women), with a median age of 32.5 years. The sets were significantly different in pathogens (p = 0.0443). The most common organisms were Staphylococcus (staph) species (B 74.51%, A 52.63%), followed by Streptococcus (strep) species (B 7.84%, A 31.58%), Pseudomonas (B 13.73%, A 13.16%), and Serratia (B 3.92%, A 2.63%). Of the total number of septic joints, methicillin-resistant Staphylococcus aureus (MRSA) made up 39% of Group B and 34% of Group A. However, within the staph species, MRSA made up 53% of Group B and 65% of Group A. Strep species made up 7.84% (Group B) vs. 31.58% (Group A), and Pseudomonas (13%) and Serratia (3-4%) were similar. In the Group B cohort, methicillin-susceptible Staphylococcus aureus (MSSA) had a predilection to infect the knee (94.4%), whereas MRSA was found more often in the hip (57.1%). CONCLUSIONS: In IVDAs, MRSA is the most common pathogen causing septic arthritis. The ratio of staph species in septic joints is increasing, and the ratio of MRSA to MSSA remains high (>50%). Strep species are much less common. PMID- 25282120 TI - Acute cyanide intoxication due to apricot seeds: is "evidence" countable? PMID- 25282121 TI - United States emergency department visits coded for intimate partner violence. AB - BACKGROUND: Limited information exists about medical treatment for victims of intimate partner violence (IPV). OBJECTIVE: Our aim was to estimate the number of emergency department (ED) visits and subsequent hospitalizations that were assigned a code specific to IPV and to describe the clinical and sociodemographic features of this population. METHODS: Data from the Nationwide Emergency Department Sample from 2006-2009 were analyzed. Cases with an external cause of injury code of E967.3 (battering by spouse or partner) were abstracted. RESULTS: From 2006-2009, there were 112,664 visits made to United States EDs with an e code for battering by a partner or spouse. Most patients were female (93%) with a mean age of 35 years. Patients were significantly more likely to reside in communities with the lowest median income quartile and in the Southern United States. Approximately 5% of visits resulted in hospital admission. The mean charge for treat-and-release visits was $1904.69 and $27,068.00 for hospitalizations. Common diagnoses included superficial injuries and contusions, skull/face fractures, and complications of pregnancy. Females were more likely to experience superficial injuries and contusions, and males were more likely to have open wounds of the head, neck, trunk, and extremities. CONCLUSIONS: From 2006 to 2009, there were approximately 28,000 ED visits per year with an e-code specific to IPV. Although a minority, 7% of these visits were made by males, which has not been reported previously. Future prospective research should confirm the unique demographic and geographic features of these visits to guide development of targeted screening and intervention strategies to mitigate IPV and further characterize male IPV visits. PMID- 25282122 TI - It all unraveled from there: case report of a central venous catheter guidewire unraveling. AB - BACKGROUND: Inferior vena cava (IVC) filters can present challenges to emergency physicians in the process of central venous catheter (CVC) placement. CASE REPORT: A 68-year-old woman presented to the emergency department with severe shortness of breath and was intubated. A central line was placed after the intubation to facilitate peripheral access. A CVC guidewire unraveled during placement after getting caught on an IVC filter. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of the complications that IVC filters can cause in the placement of CVCs. Imaging and identification of IVC filters beforehand will allow for proper planning of how to manage the case in which a filter catches on the guidewire. Simple anecdotal techniques, such as advancing the guidewire and spinning the guidewire between the fingers, can facilitate the removal of the guide wire from the IVC filter. PMID- 25282123 TI - Death before disco: the effectiveness of a musical metronome in layperson cardiopulmonary resuscitation training. AB - BACKGROUND: A novel musical memory aid has been proposed for aiding laypersons in complying with the American Heart Association (AHA) cardiopulmonary resuscitation (CPR) guidelines of 100 compressions per minute (cpm). OBJECTIVE: This study tested usefulness of such a memory aid to improve layperson long-term compliance with CPR compression rate guidelines. METHODS: A prospective randomized controlled trial was conducted using CPR-untrained laypersons. Subjects received either a standard CPR educational experience (AHA Heartsaver(r) CPR class) or an experimental CPR educational experience (AHA Heartsaver(r) CPR class augmented with a musical metronome). Experimental group subjects were taught to perform compressions to the cadence of a pop music song (The Bee Gees "Stayin' Alive"; Saturday Night Fever, The Original Movie Soundtrack; Polygram International Music, 1977) with a tempo of 100 beats/min. Compression rates, depth of compressions, and correct compressions were measured initially and upon retesting >=6 weeks post-training. RESULTS: Control subjects had a higher mean compression rate both immediately (121 [standard deviation {SD} = 21] vs. 109 [SD = 15] cpm; 95% confidence interval [CI] of mean difference 4-19; p = 0.002) and at follow-up (120 [SD = 20] vs. 111 [SD = 13] cpm; 95% CI of mean difference 2-16; p = 0.014). Compression rates stratified to 100-120 cpm demonstrated no difference between groups initially (39% vs. 48%; p = 0.382), but more experimental subjects maintained these rates at follow-up (43% vs. 74%; p = 0.003). CONCLUSIONS: Subjects trained to use a musical metronome more often maintained a compression rate of 100-120 cpm at >=6-week follow-up, suggesting the memory aid may improve long-term guideline adherence. PMID- 25282125 TI - Co-creating health's lively, moving frontiers: brief observations on the facets and possibilities of non-representational theory. AB - This paper follows up a recent debate on the potential of non-representational theory in health geography (see Andrews et al 2014; Kearns 2014; Hanlon 2014; Andrews 2014c) by outlining, more broadly, some of its key facets and investigative possibilities. The intention is to provide a helpful introduction, and entry point, to this particular way of understanding the world and of going about research that might help scholars reverberate the 'taking place' of health and health care. PMID- 25282124 TI - Does poor health predict moving, move quality, and desire to move?: A study examining neighborhood selection in US adolescents and adults. AB - To date, research has rarely considered the role of health in shaping characteristics of the neighborhood, including mobility patterns. We explored whether individual health status shapes and constrains where individuals live. Using the National Longitudinal Study of Adolescent Health data, we examined whether 16 health indicators predicted moving, move quality, and desire to move. 3.8% of adolescents (n=490) reported a move in the past year. In the unadjusted models, 10 health indicators were associated with moving; the magnitude of association for these health indicators was similar to socio-demographic characteristics. 7 of these health-moving associations persisted after adjusting for covariates. Health was also associated with moving quality, with a greater number of past year health problems in the child being associated with moving to a lower income neighborhood and parent disability or poor health being associated with moving to a higher income neighborhood. Almost every poor health status indicator was associated with a greater desire to move. Findings suggest that health status influences moving, and a reciprocal framework is more appropriate for examining health-neighborhood linkages. PMID- 25282126 TI - Evaluating potential non-point source loading of PAHs from contaminated soils: a fugacity-based modeling approach. AB - Soils contaminated by Polycyclic Aromatic Hydrocarbons (PAHs) are subject to significant non-point source (NPS) pollution during rainfall events. Recent studies revealed that the classic enrichment ratio (ER) approach may not be applicable to PAHs. This study developed a model to estimate the ER of PAHs which innovatively applies the fugacity concept. The ER model has been validated with experimental data, which suggested that the transport of PAHs not only depends on their physicochemical properties, but on the sediment composition and how the composition evolves during the event. The modeling uncertainty was systematically examined, and found to be highly compound-dependent. Based on the ER model, a strategy was proposed to practically evaluate the potential NPS loading of PAHs in watersheds with heterogeneous soils. The study results have important implications to modeling and managing the NPS pollution of PAHs (or other chemicals alike) at a watershed scale. PMID- 25282127 TI - What does impacted look like? High diversity and abundance of epibiota in modified estuaries. AB - Ecosystems modified by human activities are generally predicted to be biologically impoverished. However, much pollution impact theory stems from laboratory or small-scale field studies, and few studies replicate at the level of estuary. Furthermore, assessments are often based on sediment contamination and infauna, and impacts to epibiota (sessile invertebrates and algae) are seldom considered. We surveyed epibiota in six estuaries in south-east Australia. Half the estuaries were relatively pristine, and half were subject to internationally high levels of contamination, urbanisation, and industrialisation. Contrary to predictions, epibiota in modified estuaries had greater coverage and were similarly diverse as those in unmodified estuaries. Change in epibiota community structure was linearly correlated with sediment-bound copper, and the tubeworm Hydroides elegans showed a strong positive correlation with sediment metals. Stressors such as metal contamination can reduce biodiversity and productivity, but others such as nutrient enrichment and resource provision may obscure signals of impact. PMID- 25282128 TI - Curcumin attenuates adhesion molecules and matrix metalloproteinase expression in hypercholesterolemic rabbits. AB - Curcumin, the yellow substance found in turmeric, possesses antioxidant, anti inflammation, anticancer, and lipid-lowering properties. Because we hypothesized that curcumin could ameliorate the development of atherosclerosis, the present study focused on the effects and potential mechanisms of curcumin consumption on high-cholesterol diet-induced atherosclerosis in rabbits. During our study, New Zealand white rabbits were fed 1 of 3 experimental diets: a normal diet, a normal diet enriched with 1% cholesterol (HCD), or an HCD supplemented with 0.2% curcumin. At the end of 8 weeks, blood samples were collected to determine the levels of serum lipids, cytokines, and soluble adhesion molecule levels. Gene expression of adhesion molecules and matrix metalloproteinases (MMPs) in aortas were measured by quantitative real-time polymerase chain reaction and Western blot. Compared with the HCD group, rabbits fed an HCD supplemented with 0.2% curcumin had significantly less aortic lesion areas and neointima thickening. Curcumin reduced the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and oxidized low-density lipoprotein cholesterol in serum by 30.7%, 41.3%, 30.4%, and 66.9% (all P < .05), respectively, but did not affect high-density lipoprotein cholesterol levels. In addition, curcumin attenuated HCD-induced CD36 expression, circulating inflammatory cytokines, and soluble adhesive molecule levels. Curcumin reduced the mRNA and protein expression of intracellular adhesion molecule-1, vascular cell adhesion molecule 1, P-selectin, and monocyte chemotactic protein-1, and it inhibited HCD-induced up-regulation of MMP-1, MMP-2, and MMP-9. Our results demonstrate that curcumin exerts an antiatherosclerotic effect, which is mediated by multiple mechanisms that include lowering serum lipids and oxidized low-density lipoprotein, thus modulating the proinflammatory cytokine levels and altering adhesion molecules and MMP gene expression. PMID- 25282129 TI - Global mortality from conditions with skin manifestations. AB - BACKGROUND: Global Burden of Disease Study is a research database containing systematically compiled information from vital statistics and epidemiologic literature to inform research, public policy, and resource allocation. OBJECTIVE: We sought to compare mortality among conditions with skin manifestations in 50 developed and 137 developing countries from 1990 to 2010. METHODS: This was a cross-sectional study to calculate mean age-standardized mortality (per 100,000 persons) across countries for 10 disease categories with skin manifestations. We compared differences in mortality from these disorders by time period (year 1990 vs year 2010) and by developing versus developed country status. RESULTS: Melanoma death rates were 5.6 and 4.7 times greater in developed compared with developing countries in 1990 and 2010, respectively. Measles death rates in 1990 and 2010 were 345 and 197 times greater in developing countries, and corresponding syphilis death rates were 33 and 45 times greater. LIMITATIONS: Inability to adjust for patient-, provider-, and geographic-level confounders may limit the accuracy and generalizability of these results. CONCLUSION: The mortality burden from skin-related conditions differs between developing and developed countries, with the greatest differences observed for melanoma, measles, and syphilis. These results may help prioritize and optimize efforts to prevent and treat these disorders. PMID- 25282130 TI - Reaction profiling by ultra high-pressure liquid chromatography/time-of-flight mass spectrometry in support of the synthesis of DNA-encoded libraries. AB - An ultra high-pressure liquid chromatography/mass spectrometry (UHPLC/MS) separation and analysis method has been devised for open access analysis of synthetic reactions used in the production of DNA-encoded chemical libraries. The aqueous mobile phase is 100mM hexafluoroisopropanol and 8.6mM triethylamine; the organic mobile phase is methanol. The UHPLC separation uses a C18 OST column (50mm*2.1mm*1.7MUm) at 60 degrees C, with a flow rate of 0.6mL/min. Gradient concentration is from 10 to 40% B in 1.0min, increasing to 95% B at 1.2min. Cycle time was about 5min. This method provides a detection limit of a 20-mer oligonucleotide by mass spectrometry of better than 1pmol on-column. Linear UV response for 20-mer extends from 2 to 200pmol/MUL in concentration, same-day relative average deviations are less than 5% and bias (observed minus expected) is less than 10%. Deconvoluted mass spectra are generated for components in the predicted mass range using a maximum entropy algorithm. Mass accuracy of deconvoluted spectra is typically 20ppm or better for isotopomers of oligonucleotides up to 7000Da. PMID- 25282131 TI - Scientific hypotheses can be tested by comparing the effects of one treatment over many diseases in a systematic review. AB - OBJECTIVES: To describe the use of systematic reviews or overviews (systematic reviews of systematic reviews) to synthesize quantitative evidence of intervention effects across multiple indications (multiple-indication reviews) and to highlight issues pertaining to such reviews. STUDY DESIGN AND SETTING: MEDLINE was searched from 2003 to January 2014. We selected multiple-indication reviews of interventions of allopathic medicine that included evidence from randomized controlled trials. We categorized the subject areas evaluated by these reviews and examined their methodology. Utilities and caveats of multiple indication reviews are illustrated with examples drawn from published literature. RESULTS: We retrieved 52 multiple-indication reviews covering a wide range of interventions. The method has been used to detect unintended effects, improve precision by pooling results across indications, and examine scientific hypotheses across disease classes. CONCLUSION: Systematic reviews of interventions are typically used to evaluate the effects of treatments, one indication at a time. Here, we argue that, with due attention to methodological caveats, much can be learned by comparing the effects of a given treatment across many related indications. PMID- 25282132 TI - [Interpretation of basic urinalysis in athletes]. AB - Basic urinalysis is a quick and easy method to obtain diagnostic information on diseases that primarily affect the urinary system. However, performing intense physical exercise by healthy individuals can cause changes in various organs, particularly in the urinary tract. Hematuria and proteinuria are abnormalities commonly found after sports activity, This phenomenon can occur in non-contact sports as well as in contact sports. It is important to differentiate between benign alterations in sports practice and true pathological conditions, excluding misdiagnosis of kidney or lower urinary tract disease. PMID- 25282134 TI - Challenges facing physician scientist trainees: a survey of trainees in Canada's largest undergraduate and postgraduate programs in a single centre. AB - PURPOSE: A number of indicators suggest that the physician scientist career track is threatened. As such, it is an opportune time to evaluate current training models. Perspectives on physician scientist education and career path were surveyed in trainees at the University of Toronto, home to Canada's longest standing physician scientist training programs. METHODS: Trainees from the Clinician Investigator Program (CIP) and MD/PhD Program at the University of Toronto were surveyed. Liekert-style closed-ended questions were used to assess future career goals, present and future perspectives and concerns about and beliefs on training. Demographic information was collected regarding year of study, graduate degree program and focus of clinical and health research. Statistical analysis included non-parametric tests for sub-group comparisons. RESULTS: Both groups of trainees were motivated to pursue a career as a physician scientist. While confident in their decision to begin and complete physician scientist training, they expressed concerns about the level of integration between clinical and research training in the current programs. They also expressed concerns about career outlook, including the ability to find stable and sustainable careers in academic medicine. Trainees highlighted a number of factors, including career mentorship, as essential for career success. CONCLUSION: These findings indicate that while trainees at different stages consistently express career motivation, they identified concerns that are program and training stage-specific. These concerns mirror those highlighted in the medical education literature regarding threats to the physician scientist career path. Understanding these different and changing perspectives and exploring those differences could form an important basis for trainee program improvements both nationally and internationally. PMID- 25282133 TI - [Consensus document for the detection and management of chronic kidney disease]. AB - Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations. PMID- 25282135 TI - A prescription that addresses the decline of basic science education in medical school. AB - Over 30 years ago a cry rang out through the proverbial halls of academia; "The clinician scientist is an endangered species." These prophetic words have been reverberated in the ears of every specialty and every general medical organization in deafening tones. Why is the role of the clinician scientist or clinician investigator so important that this phrase has been repeated subsequently in medical and educational journals? Simply put, the clinician scientist bridges the ravine between the ever-growing mountain of scientific knowledge and the demanding patient centered clinical care. Here, we describe the current educational model established by the University of Calgary, Leaders in Medicine Program. Our program seeks to train future physicians and clinician scientists by incorporating training in basic science, translational and clinical research with clinical and medical education in a longitudinal program to students of traditional MD/PhD, MD/MSc or MD/MBA stream as well as interested Doctor of Medicine students. PMID- 25282137 TI - 'INSPIRED' COPD Outreach ProgramTM: doing the right things right. AB - The well-documented gaps between needed and provided care for patients and families living with chronic obstructive pulmonary disease (COPD) mandate changes to clinical practice. The multifaceted evidence-based INSPIRED COPD Outreach ProgramTM was first implemented in Halifax, Nova Scotia, Canada in 2010 (INSPIRED = Implementing a Novel and Supportive Program of Individualized care for patients and families living with REspiratory Disease) and undergoes ongoing evaluation. By enhancing patient confidence to manage their illness more effectively in their homes and communities, there has been a sustained and substantial reduction in facility-based care in comparison with patient care experience pre-INSPIRED. Sustaining and spreading a program recently designated a leading practice by Accreditation Canada, and especially modifying the program as new evidence emerges, requires integrating and modeling at the 'bedside' both evidence-based medicine ('doing the right things') and quality improvement ('doing them right'). In Canada, where COPD care gaps are common, a new pan-Canadian INSPIRED-based quality improvement program is supporting multidisciplinary healthcare teams to bridge the chasm between evidence and practice by working together to 'do the right things right' in COPD care. PMID- 25282138 TI - Evaluation of E-cadherin, beta-catenin and vimentin protein expression using quantitative immunohistochemistry in nasopharyngeal carcinoma patients. AB - PURPOSE: Aberrant expression of proteins involved in epithelial-to-mesenchymal transition have been described in various cancers. In this retrospective study, we sought to evaluate E-cadherin, beta-catenin and vimentin protein expression in non-metastatic nasopharyngeal (NPC) patients treated with curative intent, examine their relationship with each other, and with clinical outcome measures. METHODS: Pre-treatment formalin-fixed paraffin-embedded biopsies of 140 patients treated between January 2000 and December 2007 were assembled into a tissue microarray (TMA). Automated quantitative immunohistochemistry (AQUA(r)) was performed on sequential TMA sections stained with fluorescent-labeled antibodies against E-cadherin, beta-catenin and vimentin. Cox proportional hazards regression was used to estimate the effect of cytoplasmic vimentin, cytoplasmic E cadherin, beta-catenin nuclear/cytoplasmic ratio expression on overall survival and disease-free survival. RESULTS: The average age of the patients was 51.7 years (SD=12.1; range 18-85), 66% were male, 71% had a KPS >= 90% at the start of treatment and 65% had stage III/IV disease. After adjusting for performance status, WHO and stage, high E-cadherin levels over the 75th percentile were found to produce a significantly increased risk for both a worse overall survival (HR = 2.53, 95% CI 1.21, 5.27) and disease free survival (DFS; HR = 2.14, 95%CI 1.28, 3.59). Vimentin levels over the first quartile produced an increased risk for a worse DFS (HR = 2.21, 95% CI 1.11, 4.38). No association was seen between beta catenin and survival. CONCLUSION: In this cohort of NPC patients, higher levels of E-cadherin and higher levels of vimentin were associated with worse outcomes. Further work is needed to understand the role of these epithelial mesenchymal transition proteins in NPC. PMID- 25282139 TI - Characterization of the withdrawal phase in a swine controlled intestinal donation after circulatory death model. AB - PURPOSE: Transplantation of donation after cardiac death (DCD) intestine has higher rates of organ failure and complications. Fortunately, this is less grievous in a subclass of DCD called controlled (CDCD), those with irreversible but incomplete brain injury. The aim of the paper is to establish a CDCD porcine model which is closely mimicking human CDCD scenario, and investigate the physiologic changes from withdrawal of ventilatory support to circulatory arrest. METHOD: Ten domestic crossbred pigs were anesthetized and ventilated with room air. Once all baseline data was taken, atracurium besilate (0.9 mg/kg, 3*ED95) was administered and the ventilator was discontinued while the animal was under deep anesthesia to establish the porcine CDCD model. Meanwhile, heparin (150~200 U/kg) was administered after discontinuation of the ventilator. The time to death and the changes of arterial blood gases and hemodynamic parameters were monitored every 5 minutes until circulatory arrest. In addition, histopathology, ultrastructures (via electron microscope) and expression of tight junction proteins of intestinal mucosa were observed at the baseline and the time of death. RESULT: The mean time to death was approximately (21.8+/-3.12 min. Within 5 minutes of removal of the ventilator, there was a hyperdynamic period. Systolic blood pressure and heart rate quickly increased to 118.5+/-10.4 mmHg and 108.2+/ 4.94 bpm, respectively. Blood pressure and heart rate then reduced rapidly until circulatory arrest. Moreover, the PaO2 quickly dropped to 17.4+/-3.13 mmHg, the blood gases throughout the apneic time showed a rapid hypercapnia and acidosis. In addition, warm ischemia damaged intestinal mucosa and reduced TJ proteins expression. CONCLUSION: A new swine CDCD model, simulating three stages of "withdrawal of ventilation, systemic anticoagulation and determination of death", which closely mimics the human DCD scenario and can thus be used in studies related to organ transplantation, was successfully established. PMID- 25282140 TI - Adropin: a new marker for predicting late saphenous vein graft disease after coronary artery bypass grafting. AB - PURPOSE: Saphenous vein graft disease (SVGD), defined as an occlusion of 50% or more of the SVG excluding distal anastomotic occlusion, is an important predictor of morbidity after coronary artery bypass grafting (CABG). Late graft occlusion is a serious complication that often limits the use of the saphenous vein as a coronary bypass graft. Late graft occlusion is particularly common in old, degenerated venous grafts with advanced atherosclerotic plaques. Adropin has been implicated in the homeostatic control of metabolism. The purpose of this study was to investigate whether serum adropin levels are associated with late SVGD following CABG. METHODS: Thirty-eight patients with SVGD involving at least one graft (occluded group; 14 females, 24 males) and 42 patients with a patent saphenous vein graft (patent group; 15 females, 27 males) were enrolled in this study. Venous blood samples were taken from all of the participants to measure plasma adropin levels using an enzyme-linked immunsorbent assay kit. RESULTS: The mean adropin level was significantly lower in the occluded group than in the patent group (3.2 +/- 0.71 vs. 4.9 +/- 1.51 ng/mL, p < 0.001). Multivariate regression analysis showed that the adropin level was the independent predictor of late saphenous vein graft occlusion. CONCLUSIONS: Adropin levels are lower in patients with late saphenous vein graft occlusion and these reduced adropin levels, together with other factors, may lead to saphenous vein graft occlusion. Larger and prospective studies are needed to determine if adropin plays a role in the pathogenesis of SVGD. PMID- 25282141 TI - Serum total bilirubin and long-term outcome in patients undergoing percutaneous coronary intervention. AB - PURPOSE: The purpose of this study was to investigate the associated between serum total bilirubin (STB) levels and long-term outcomes in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: A total of 1,273 consecutive patients were enrolled. Patients were grouped according to their baseline STB levels: Group 1 (STB < 3.4 MUmol/L), Group 2 (3.4 MUmol/L <= STB <= 10.3 MUmol/L), Group 3 (10.3 MUmol/L < STB <= 17.1 MUmol/L), and Group 4 (STB < 17.1 MUmol/L) and the rate of major adverse cardiovascular events (MACE) was determined RESULTS: A total of 1,152 patients were successfully followed up (90.5%) for a mean period of 30 +/- 5 months, including 187 patients experiencing a major adverse cardiovascular event (MACE: death from any cause, myocardial infarction, repeat revascularization or readmission). The MACE rate in Groups 3 and 4 was lower than in Groups 1 and 2 (P < 0.01). After adjusted the confounding factors with Cox regression analysis, the MACE rates in Groups 2-4 were still lower than in Group 1 (Group 2, RR=0.293, 95% CI 0.167-0.517, P < 0.01; Group 3, RR=0.142, 95% CI 0.065-0.312, P < 0.01; Group 4, RR=0.134, 95% CI 0.071-0.252, P < 0.01). The cumulative survival rates of Groups 3 and 4 were higher than that of Groups 1and 2 (P < 0.01). CONCLUSIONS: High STB concentration is associated with lower MACE in patients with ACS after PCI. PMID- 25282103 TI - Defining the role of common variation in the genomic and biological architecture of adult human height. AB - Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants. PMID- 25282142 TI - Non-specific physiological background effects of acupuncture revealed by proteomic analysis in normal rats. AB - BACKGROUND: The total effects of adequate real acupuncture treatment consist of pathologic-specific and non-specific physiological effects. The latter may be the fundamental component of the therapeutic effects of acupuncture. This study investigated the physiological background effects of acupuncture in normal rats treated with acupuncture. METHODS: Manual acupuncture was performed on normal rats at experienced acupoints, GV14 (Dazhui), BL12 (Fengmen) and BL13 (Feishu), once every other day for two weeks. The proteomic profile of rat lung tissue was examined using 2-DE/MS-based proteomic techniques. Gene Ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were analyzed for differentially expressed proteins using the WebGestalt toolkit. RESULTS: In total, 25 differentially expressed protein spots were detected in the 2-DE gels. Among these spots, 24 corresponded to 20 unique proteins that were successfully identified using mass spectrometry. Subsequent GO and KEGG pathway analyses demonstrated that these altered proteins were mainly involved in biological processes, such as 'protein stabilization', 'glycolysis/gluconeogenesis' and 'response to stimulus'. CONCLUSIONS: Our study indicated the non-specific background effects of acupuncture at acupoints GV14, BL12 and BL13 likely maintained internal homeostasis via regulation of the local stimulus response, energy metabolism, and biomolecule function balance, which may be important contributors to the therapeutic effects of acupuncture. PMID- 25282144 TI - The relationship between internalizing psychopathology and suicidality, treatment seeking, and disability in the Australian population. AB - BACKGROUND: Recent evidence has emerged suggesting that multiple mood and anxiety disorders may be better assessed using a single dimension representing internalizing liability. The current study seeks to demonstrate the validity and utility of internalizing liability when accounting for suicidality, treatment seeking, and disability over and above any disorder specific relationship. METHODS: Data were from the 2007 Australian National Survey of Mental Health and Wellbeing. A model containing a single factor was fit to the data as a means of explaining the shared relationship across seven DSM-IV mood and anxiety disorders. The shared and specific relationships between lifetime and past 12 months internalizing and mental health consultations, suicidality, and disability were examined using Multiple Indicators, Multiple Causes models. RESULTS: General levels of latent internalizing were significantly related to all covariates of interest across both lifetime and past 12 months diagnoses. Models that included the specific relationship between various internalizing disorders and the clinical correlates failed to significantly improve model fit over and above a model that already included the general relationship between latent internalizing and the covariates. LIMITATIONS: Limitations include the use of cross-sectional data and diagnostic assessments based on self-report lay-administered interviews. CONCLUSIONS: The overall internalizing latent variable sufficiently explains the majority of the relationship between multiple mood and anxiety disorders and suicidality, treatment seeking, and disability. Researchers should focus on investigating the shared or common components across all mood and anxiety disorders particularly with respect to individuals presenting with higher rates of suicidality, treatment seeking behavior, and disability. PMID- 25282143 TI - Identification of the neural correlates of cyclothymic temperament using a working memory task in fMRI. AB - BACKGROUND: Recently, we reported a significantly negative association of cyclothymic temperament scores with activations of the left lingual gyrus during esthetic judgments of paintings, suggesting that cyclothymic temperament may be associated with the left lingual gyrus. In view of potential associations of cyclothymic temperament, bipolar disorder and dementia, this study examined the relationship of temperament to lingual gyrus activity using a working memory task as a new context. METHODS: N-back tasks (0-, 1-, 2- and 3-back tasks) were performed on 34 healthy subjects using functional MRI. Multiple regression analyses were applied to measure the association between cyclothymic temperament scores and each of 4 beta images corresponding to 0-, 1-, 2- and 3-back tasks with gender, age and the other temperament scores (depressive, hyperthymic, irritable and anxious) as covariates. RESULTS: The whole brain analysis corrected for multiple comparisons revealed a significant activation of the left lingual gyrus associated with cyclothymic temperament scores in a new context-working memory for both 2- and 3-back tasks. LIMITATIONS: The number of subjects was relatively small. The subjects were almost medical staff or students and the results should be interpreted with caution. CONCLUSIONS: The present findings reconfirm that cyclothymic temperament may be associated with the left lingual gyrus. PMID- 25282146 TI - Self-objectification and depression: an integrative systematic review. AB - BACKGROUND: Objectification Theory positions self-objectification as a cause of depression. In particular, the authors offer Objectification Theory as a partial explanation for the higher prevalence of depression among women than men. To investigate the validity of this theory, we undertook a systematic review of quantitative studies that have investigated self-objectification as a predictor of depression. METHODS: Studies were identified by searching the PsycINFO, Medline, EMBASE and Cochrane Library databases. Search terms were 'objectif*' OR 'body conscious*' AND 'depressi*' OR 'dysthymi*' OR 'mood disorder'. To be eligible, studies were required to be in the English-language, to include a measure of depression and a measure of self-objectification. Studies were excluded if they did not explicitly examine the association between these variables. RESULTS: Among women most studies found a mediated effect for self objectification on depression. All studies including adolescents found a direct effect. Each of the two prospective longitudinal studies found that an increase in self-objectification over time was associated with a concomitant increase in depression, suggesting a causal relationship. Among men the results were mixed. LIMITATIONS: The review did not include a quantitative synthesis due to the heterogeneity of the included observational studies. The majority of the studies were cross-sectional precluding conclusions concerning causality. Generalisations to culturally and linguistically diverse populations must be made with caution given the limited cultural diversity within the studies CONCLUSIONS: Self objectification may be a useful predictor of depression, particularly among women and adolescents, and may have clinical relevance among these populations. PMID- 25282147 TI - [Urinary tract infection due to Aerococcus urinae]. PMID- 25282145 TI - A randomized head to head trial of MoodSwings.net.au: an Internet based self-help program for bipolar disorder. AB - BACKGROUND: Adjunctive psychosocial interventions are efficacious in bipolar disorder, but their incorporation into routine management plans are often confounded by cost and access constraints. We report here a comparative evaluation of two online programs hosted on a single website (www.moodswings.net.au). A basic version, called MoodSwings (MS), contains psychoeducation material and asynchronous discussion boards; and a more interactive program, MoodSwings Plus (MS-Plus), combined the basic psychoeducation material and discussion boards with elements of Cognitive Behavioral Therapy. These programs were evaluated in a head-to-head study design. METHOD: Participants with Bipolar I or II disorder (n=156) were randomized to receive either MoodSwings or MoodSwings-Plus. Outcomes included mood symptoms, the occurrence of relapse, functionality, Locus of Control, social support, quality of life and medication adherence. RESULTS: Participants in both groups showed baseline to endpoint reductions in mood symptoms and improvements in functionality, quality of life and medication adherence. The MoodSwings-Plus group showed a greater number of within-group changes on symptoms and functioning in depression and mania, quality of life and social support, across both poles of the illness. MoodSwings-Plus was superior to MoodSwings in improvement on symptoms of mania scores at 12 months (p=0.02) but not on the incidence of recurrence. LIMITATIONS: The study did not have an attention control group and therefore could not demonstrate efficacy of the two active arms. There was notable (81%) attrition by 12 months from baseline. CONCLUSION: This study suggests that both CBT and psychoeducation delivered online may have utility in the management of bipolar disorder. They are feasible, readily accepted, and associated with improvement. PMID- 25282148 TI - Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor. AB - Mutations in BRCA2 increase susceptibility to breast, ovarian and prostate cancers. The product of human BRCA2, BRCA2 protein, has a key role in the repair of DNA double-strand breaks and interstrand cross-links by RAD51-mediated homologous recombination. Here, we present a biochemical and structural characterization of full-length (3,418 amino acid) BRCA2, alone and in complex with RAD51. We show that BRCA2 facilitates nucleation of RAD51 filaments at multiple sites on single-stranded DNA. Three-dimensional EM reconstructions revealed that BRCA2 exists as a dimer and that two oppositely oriented sets of RAD51 molecules bind the dimer. Single-stranded DNA binds along the long axis of BRCA2, such that only one set of RAD51 monomers can form a productive complex with DNA and establish filament formation. Our data define the molecular mechanism by which this tumor suppressor facilitates RAD51-mediated homologous recombinational repair. PMID- 25282149 TI - A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters. AB - Neurotransmitter/sodium symporters (NSSs) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters. Key conformational states have been reported for the bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, an NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-tryptophan, providing insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. We propose a mechanism, based on our structural and functional findings, in which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state. PMID- 25282150 TI - A genome-wide map of adeno-associated virus-mediated human gene targeting. AB - To determine which genomic features promote homologous recombination, we created a genome-wide map of gene targeting sites. We used an adeno-associated virus vector to target identical loci introduced as transcriptionally active retroviral vectors. A comparison of ~2,000 targeted and untargeted sites showed that targeting occurred throughout the human genome and was not influenced by the presence of nearby CpG islands, sequence repeats or DNase I-hypersensitive sites. Targeted sites were preferentially located within transcription units, especially when the target loci were transcribed in the opposite orientation to their surrounding chromosomal genes. We determined the impact of DNA replication by mapping replication forks, which revealed a preference for recombination at target loci transcribed toward an incoming fork. Our results constitute the first genome-wide screen of gene targeting in mammalian cells and demonstrate a strong recombinogenic effect of colliding polymerases. PMID- 25282152 TI - CLAP: a web-server for automatic classification of proteins with special reference to multi-domain proteins. AB - BACKGROUND: The function of a protein can be deciphered with higher accuracy from its structure than from its amino acid sequence. Due to the huge gap in the available protein sequence and structural space, tools that can generate functionally homogeneous clusters using only the sequence information, hold great importance. For this, traditional alignment-based tools work well in most cases and clustering is performed on the basis of sequence similarity. But, in the case of multi-domain proteins, the alignment quality might be poor due to varied lengths of the proteins, domain shuffling or circular permutations. Multi-domain proteins are ubiquitous in nature, hence alignment-free tools, which overcome the shortcomings of alignment-based protein comparison methods, are required. Further, existing tools classify proteins using only domain-level information and hence miss out on the information encoded in the tethered regions or accessory domains. Our method, on the other hand, takes into account the full-length sequence of a protein, consolidating the complete sequence information to understand a given protein better. RESULTS: Our web-server, CLAP (Classification of Proteins), is one such alignment-free software for automatic classification of protein sequences. It utilizes a pattern-matching algorithm that assigns local matching scores (LMS) to residues that are a part of the matched patterns between two sequences being compared. CLAP works on full-length sequences and does not require prior domain definitions.Pilot studies undertaken previously on protein kinases and immunoglobulins have shown that CLAP yields clusters, which have high functional and domain architectural similarity. Moreover, parsing at a statistically determined cut-off resulted in clusters that corroborated with the sub-family level classification of that particular domain family. CONCLUSIONS: CLAP is a useful protein-clustering tool, independent of domain assignment, domain order, sequence length and domain diversity. Our method can be used for any set of protein sequences, yielding functionally relevant clusters with high domain architectural homogeneity. The CLAP web server is freely available for academic use at http://nslab.mbu.iisc.ernet.in/clap/. PMID- 25282151 TI - Crystal structures of free and antagonist-bound states of human alpha9 nicotinic receptor extracellular domain. AB - We determined the X-ray crystal structures of the extracellular domain (ECD) of the monomeric state of human neuronal alpha9 nicotinic acetylcholine receptor (nAChR) and of its complexes with the antagonists methyllycaconitine and alpha bungarotoxin at resolutions of 1.8 A, 1.7 A and 2.7 A, respectively. The structure of the monomeric alpha9 ECD superimposed well with the structures of homologous proteins in pentameric assemblies, denoting native folding, despite the absence of a complementary subunit and transmembrane domain. The interaction motifs of both antagonists were similar to those in the complexes with homologous pentameric proteins, thus highlighting the major contribution of the principal side of alpha9 ECD to their binding. The structures revealed a functionally important beta7-beta10 strand interaction in alpha9-containing nAChRs, involving their unique Thr147, a hydration pocket similar to that of mouse alpha1 ECD and a membrane-facing network coordinated by the invariant Arg210. PMID- 25282153 TI - Risk of using logistic regression to illustrate exposure-response relationship of infectious diseases. AB - BACKGROUND: In most biological experiments, especially infectious disease, the exposure-response relationship is interrelated by a multitude of factors rather than many independent factors. Little is known about the suitability of ordinary, categorical exposures, and logarithmic transformation which have been presented in logistic regression models to assess the likelihood of an infectious disease as a function of a risk or exposure. This study aims to examine and compare the current approaches. METHODS: A simulated human immunodeficiency virus (HIV) population, dynamic infection data for 100,000 individuals with 1% initial prevalence and 2% infectivity, was created. Using the Monte Carlo method (computational algorithm) to repeat random sampling to obtain numerical results, linearity between log odds and exposure, and suitability in practice were examined in the three model approaches. RESULTS: Despite diverse population prevalence, the linearity was not satisfied between log odds and raw exposures. Logarithmic transformation of exposures improved the linearity to a certain extent, and categorical exposures satisfied the linear assumption (which was important for modelling). When the population prevalence was low (assumed < 10%), performances of the three models were significantly different. Comparing to ordinary logistic regression, the logarithmic transformation approach demonstrated better accuracy of estimation except that at the two inflection points: likelihood of infection increased from slowly to sharply, then slowly again. The approach using categorical exposures had better estimations around the real values, but the measurement was coarse due to categorization. CONCLUSIONS: It is not suitable to directly use ordinary logistic regression to explore the exposure-response relationship of HIV as an infectious disease. This study provides some recommendations for practical implementations including: 1) utilize categorical exposure if a large sample size and low population prevalence are provided; 2) utilize a logarithmic transformed exposure if the sample size is insufficient or the population prevalence is too high (such as 30%). PMID- 25282154 TI - Neovascular glaucoma after central retinal vein occlusion in pre-existing glaucoma. AB - BACKGROUND: To determine the outcome of central retinal vein occlusion (CRVO) in pre-existing glaucoma and the predisposing factors of developing neovascular glaucoma (NVG). METHODS: We retrospectively assessed a pre-existing glaucoma CRVO group and a non-glaucoma CRVO group to elucidate the demographics, clinical course and ocular parameters of these two cohorts. Among the pre-existing glaucoma cases, the predisposing factors for the development of NVG were monitored, including the retinal capillary non-perfusion status, intraocular pressure (IOP) and best-corrected visual acuity (BCVA) at presentation. RESULTS: Of 642 CRVO patients reviewed in this 10-year cohort study, 60 (9.3%) had pre existing glaucoma at a mean follow-up of 30.8 months, including 28 (4.4%) primary open angle glaucoma (POAG), 27 (4.2%) primary angle closure glaucoma (PACG), and 5 (0.8%) normal tension glaucoma (NTG) cases. Although the presence of glaucoma in the CRVO eyes was not significantly associated with the risk of developing NVG, the incidence of developing NVG in pre-existing glaucoma eyes was significantly higher in the group with IOP greater than 20 mmHg at CRVO presentation (P = 0.02, Chi-square test) as well as in the ischemic CRVO group compared to the non-ischemic patients (P = 0.005, Fisher's exact test). Overall, 20% of pre-existing glaucoma patients needed glaucoma surgery after a CRVO event, including 11.7% of patients who developed iris neovascularisation (INV) and 8.3% of patients who developed a high IOP without INV. CONCLUSIONS: Both the retinal non-perfusion status and uncontrolled IOP contribute to NVG in patients with pre existing glaucoma after CRVO. Following CRVO, glaucoma surgery is necessary for pre-existing glaucoma cases with intractable elevated IOP with or without INV. PMID- 25282155 TI - Independent factors for prediction of poor outcomes in patients with febrile neutropenia. AB - BACKGROUND: Febrile neutropenia (FN) is a life-threatening condition that requires urgent management in the emergency department (ED). Recent progress in the treatment of neutropenic fever has underscored the importance of risk stratification. In this study, we aimed to determine independent factors for prediction of poor outcomes in patients with FN. MATERIAL AND METHODS: We retrospectively evaluated 200 chemotherapy-induced febrile neutropenic patients who visited the ED. Upon arrival at the ED, clinical data, including sex, age, vital signs, underlying systemic diseases, laboratory test results, estimated GFR, blood cultures, CRP, radiologic examinations, and Multinational Association of Supportive Care in Cancer (MASCC) score of all febrile neutropenic patients were obtained. Outcomes were categorized as "poor" if serious complications during hospitalization, including death, occurred. RESULTS: The platelet count <50 000 cells/mm3 (OR 3.90, 95% CI 1.62-9.43), pulmonary infiltration (OR 3.45, 95% CI 1.48-8.07), hypoproteinemia <6 g/dl (OR 3.30, 95% CI 1.27-8.56), respiratory rate >24/min (OR 8.75, 95% CI 2.18-35.13), and MASCC score <21 (OR 9.20, 95% CI 3.98-21.26) were determined as independent risk factors for the prediction of death. The platelet count <50 000 cells/mm3 (OR 3.93, 95% CI 1.42 10.92), serum CRP >50 mg/dl (OR 3.80, 95% CI 1.68-8.61), hypoproteinemia (OR 7.81, 95% CI 3.43-17.78), eGFR <=90 ML/min/1.73 m2 (OR 3.06, 95% CI 1.13-8.26), and MASCC score <21 (OR 3.45, 95% CI 1.53-7.79) were determined as independent risk factors for the prediction of poor clinical outcomes of FN patients. Platelet count, protein level, respiratory rate, pulmonary infiltration, CRP, MASCC score, and eGFR were shown to have a significant association with outcome. CONCLUSIONS: The results of our study may help emergency medicine physicians to prevent serious complications with proper use of simple independent risk factors besides MASCC score. PMID- 25282156 TI - [Abstracts of the 58th National Congress of Spanish Society of Hospital Pharmacy, September 30-October 3, 2014, Valladolid, Spain]. PMID- 25282158 TI - Is the Kidney Donor Risk Index a step forward in the assessment of deceased donor kidney quality? AB - The allocation of deceased donor kidneys has become more complex because of the increasing spectrum of donors and recipients age and comorbidities. Several scoring systems have been proposed to evaluate the donor quality of deceased donor kidneys, based on clinical, pathological or combined parameters to predict the risk of renal allograft failure. Nonetheless, besides the dichotomous extended criteria donor (ECD) score, none of the others have been used in clinical practice because of numerous reasons, ranging from lack of robust validation to the technical challenges associated with the evaluation of donor biopsies. Recently, the Kidney Donor Risk Index (KDRI) and Profile Index (KDPI) were introduced in the USA as a refined version of the ECD score. This scoring system is based on 10 donor factors, therefore providing a finely granulated evaluation of donor quality without the need of a kidney biopsy.Here, we review the advantages and drawbacks of the main scoring systems, and we describe the components of the KDRI and KDPI. It is an easily accessible online tool, based solely on donor factors readily available at the moment of the donor offer. Importantly, the KDPI has also been made part of the 'longevity matching' allocation in the USA, where the best kidneys are allocated to the recipients with the longest predicted post-transplant survival. The KDRI should provide us with a robust qualitative evaluation of deceased donor quality, and therefore will probably play a role in deceased donor kidney allocation policies across Europe in the near future. Hopefully, the KDRI and the KDPI should help transplant programmes to better allocate the scarce resource of deceased donor kidneys. PMID- 25282157 TI - Protein and microRNA biomarkers from lavage, urine, and serum in military personnel evaluated for dyspnea. AB - BACKGROUND: We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan. METHODS: Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbon monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid. RESULTS: Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency. CONCLUSIONS: Candidate proteins and miRNAs associated with the general diagnosis of dyspnea have been identified in subjects with differing medical diagnoses. Since these markers can be measured in readily obtained clinical samples, further studies are possible that test the value of these findings in more formal classification or case-control studies in much larger cohorts of subjects with specific lung diseases such as asthma, emphysema, or some other well-defined lung disease. PMID- 25282159 TI - The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells. AB - TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses. PMID- 25282161 TI - Achieving cost-neutrality with long-acting reversible contraceptive methods. AB - OBJECTIVES: This analysis aimed to estimate the average annual cost of available reversible contraceptive methods in the United States. In line with literature suggesting long-acting reversible contraceptive (LARC) methods become increasingly cost-saving with extended duration of use, it aimed to also quantify minimum duration of use required for LARC methods to achieve cost-neutrality relative to other reversible contraceptive methods while taking into consideration discontinuation. STUDY DESIGN: A three-state economic model was developed to estimate relative costs of no method (chance), four short-acting reversible (SARC) methods (oral contraceptive, ring, patch and injection) and three LARC methods [implant, copper intrauterine device (IUD) and levonorgestrel intrauterine system (LNG-IUS) 20 mcg/24 h (total content 52 mg)]. The analysis was conducted over a 5-year time horizon in 1000 women aged 20-29 years. Method specific failure and discontinuation rates were based on published literature. Costs associated with drug acquisition, administration and failure (defined as an unintended pregnancy) were considered. Key model outputs were annual average cost per method and minimum duration of LARC method usage to achieve cost-savings compared to SARC methods. RESULTS: The two least expensive methods were copper IUD ($304 per women, per year) and LNG-IUS 20 mcg/24 h ($308). Cost of SARC methods ranged between $432 (injection) and $730 (patch), per women, per year. A minimum of 2.1 years of LARC usage would result in cost-savings compared to SARC usage. CONCLUSIONS: This analysis finds that even if LARC methods are not used for their full durations of efficacy, they become cost-saving relative to SARC methods within 3 years of use. IMPLICATIONS: Previous economic arguments in support of using LARC methods have been criticized for not considering that LARC methods are not always used for their full duration of efficacy. This study calculated that cost-savings from LARC methods relative to SARC methods, with discontinuation rates considered, can be realized within 3 years. PMID- 25282162 TI - Hypothesis: amenorrhea-inducing contraception may reduce HIV acquisition risk. PMID- 25282160 TI - Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. AB - Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell promoting factors IL-6, ICOS, c-Rel, IRF4, IkappaBNS and IkappaBzeta. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation. PMID- 25282163 TI - Root replacement surgery versus more conservative management during type A acute aortic dissection repair. AB - BACKGROUND: Aortic root management in type A acute aortic dissection is controversial. This study compared outcomes of root replacement (RR) interventions versus more conservative root (CR) management. METHODS: Of 1,995 type A acute aortic dissection patients enrolled in the International Registry of Acute Aortic Dissection, 699 (35%) underwent RR interventions and 1,296 (65%) underwent CR management. Independent predictors of hospital and 3-year survival were identified using multivariable logistic and Cox regression models. RESULTS: Compared with CR patients, RR patients were younger (56.9 versus 62.3 years; p = 0.023) and more likely to present with larger root diameter (4.7 cm versus 4.0 cm; p < 0.001), Marfan syndrome (8.7% versus 2.5%; p < 0.001), aortic insufficiency (64.0% versus 50.3%; p < 0.001), and hypotension, shock, or tamponade (33.0% versus 26.5%; p = 0.003). Root replacement management did not increase hospital mortality (propensity score-adjusted odds ratio, 1.14; p = 0.674). On Kaplan-Meier analysis, 3-year survival (RR, 92.5% +/- 1.7% versus CR, 91.6% +/- 1.3%; log-rank p = 0.623) and freedom from aortic root reintervention (RR, 99.2% +/- 0.1% versus CR, 99.3% +/- 0.1%; log-rank p = 0.770) were similar. Only 2 patients (1 per group) underwent follow-up root reintervention. Propensity score-adjusted Cox regression excluded a relationship between root treatment and follow-up survival (hazard ratio, 1.5; 95% confidence interval, 0.502 to 5.010; p = 0.432). CONCLUSIONS: In type A acute aortic dissection patients more-extensive RR interventions are not associated with increased hospital mortality. This supports such an approach in young patients and patients with connective tissue diseases and bicuspid aortic valves. Excellent midterm survival and freedom from root reintervention in both groups suggest stable behavior of the nonreplaced aortic sinuses at 3 years. Thus, pending studies with longer follow-up, the use of aggressive RR techniques can be determined by patient-specific and dissection related factors. PMID- 25282164 TI - Pneumonectomy: the burden of death after discharge and predictors of surgical mortality. AB - BACKGROUND: Pneumonectomy has the highest mortality rate among resections for lung cancer, with limited literature differentiating predictors of postpneumonectomy in-hospital mortality (IHM) from early postdischarge mortality (PDM). This study aims to examine the burden of death over time and to identify potential predictive factors, including patient comorbidities and hospital and surgeon volumes. METHODS: Data were abstracted from an Ontario population-based linked database from 2005 to 2011. Proportional mortality and cumulative survival attributable to IHM and 90-day PDM is reported. Logistic and Cox regression analyses examined the role of potential factors related to death. Odds ratios (ORs) and hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. RESULTS: Of 505 patients who underwent pneumonectomy, the median length of stay was 6 days (1-30 days). IHM was 4.4% (2.9%-6.5%), and 90-day PDM was an additional 6.4% (4.6%-9.0%). Logistic regression showed that congestive heart failure (CHF) (OR, 23.5; range, 4.0-136.0), cerebrovascular disease (OR, 12.5; range, 1.2-128.0), renal disease (OR, 8.8; range, 1.3-60.5), and previous myocardial infarction (MI) (OR, 5.4; range, 1.5-20.0) were predictive of IHM, whereas age (HR, 1.4; range, 1.1-1.7) per year and CHF (HR, 18.0; range, 4.0 79.0) were predictive of PDM. All other factors were not significant. CONCLUSIONS: PDM represents a distinct and underrecognized burden of postoperative death. More than half of postpneumonectomy mortality occurred after discharge, and the rate remained unchanged over the study period. Patient factors play a major role in both IHM and PDM, whereas institutional and physician volume do not influence outcome, suggesting the importance of patient selection and the need for continued evaluation of mortality. PMID- 25282165 TI - Multicenter evaluation of high-risk mitral valve operations: implications for novel transcatheter valve therapies. AB - BACKGROUND: The MitraClip REALISM (Abbott Vascular, Menlo Park, CA) trial included several inclusion criteria to identify patients at high risk for conventional mitral valve (MV) surgery. This study evaluated contemporary surgical outcomes for high-risk surgical patients who met these defined criteria to serve as a benchmark to evaluate appropriateness in treatment allocation between surgical and percutaneous MV repair. METHODS: A statewide Society for Thoracic Surgeons (STS) database was queried for patients undergoing isolated mitral valve surgery over a 12-year study period from 17 different hospitals. Patients were stratified into high-risk (HR) versus non-high-risk (non-HR) cohorts based upon clinical criteria similar to those utilized in the REALISM trial. Mixed effects multivariable regression modeling was used to evaluate study endpoints including mortality, morbidity, and resource utilization. RESULTS: Of 2,440 isolated mitral operations, 29% (n = 698) were HR per REALISM criteria. Median STS Predicted Risk of Mortality (PROM) for HR patients was 6.6% compared with 1.6% for non-HR patients (p < 0.001). The HR patients more commonly underwent MV replacement as well as urgent (30% vs 19%, p < 0.001) operations. High-risk patients incurred higher morbidity and mortality (7% vs 1.6%) with longer intensive care unit (48 vs 41 hours) and hospital stays (7 vs 6 days, all p < 0.001). Among REALISM criteria, STS PROM 12% or greater and high-risk STS criteria were the only criteria associated with mortality. CONCLUSIONS: Select REALISM criteria, including reoperation with patent grafts and functional MR with ejection fraction less than 0.40, may not identify patients truly at high risk of death with surgery. In addition to conventional STS criteria, risk assessment by surgeons is essential to direct appropriate treatment allocation for high-risk mitral disease. PMID- 25282166 TI - The David procedure for salvage of a failing autograft after the Ross operation. AB - BACKGROUND: Dilatation of the pulmonary autograft is a major fear after the Ross procedure. We analyzed the results after reoperation for autograft dysfunction using a valve-sparing reimplantation technique (David procedure). METHODS: From 1995 to 2012, 645 Ross operations were performed, with 630 (98%) of these as freestanding root replacements (mean follow-up, 8.3 +/- 4.6 years). Forty-nine autograft reoperations occurred in 46 patients (0.89%/patient-year). Between 2005 and 2013, reoperation using a David procedure was performed in 18 of 35 patients (52%) with autograft dilatation at a mean interval of 11 +/- 3.2 years after the Ross operation. RESULTS: The mean age of 18 patients receiving a David procedure as reoperation was 49.8 +/- 13.9 years; 83% were male. The 30-day reoperative mortality was zero. The mean vascular graft size used for reimplantation was 29.5 +/- 1.7 mm. At a mean follow-up time of 3.2 +/- 2.3 years (100% complete), all patients (18 of 18) were alive and in New York Heart Association functional class I. One patient (5%) needed valve replacement for recurrent aortic regurgitation 2.6 years after the David procedure. In the remaining patients (95%), freedom from aortic regurgitation of grade 2 or greater was 100% at 3 years (regurgitation grade <1, 14 of 17; 82%). Aortic valve gradients were clinically insignificant at 5.8 +/- 2.1 mm Hg. CONCLUSIONS: Performing a David procedure was successful in the vast majority of patients with dilatation of the pulmonary autograft after a Ross operation and revealed good function of the preserved autograft at midterm follow-up. Reoperations could be performed with low perioperative morbidity and mortality. PMID- 25282167 TI - Predictors of imaging surveillance for surgically treated early-stage lung cancer. AB - BACKGROUND: Current guidelines recommend routine imaging surveillance for patients with non-small cell lung cancer (NSCLC) after treatment. Little is known about surveillance patterns for patients with surgically resected early-stage lung cancer in the community at large. We sought to characterize surveillance patterns in a national cohort. METHODS: We conducted a retrospective study using the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database (1995 2010). Patients with stage I/II NSCLC treated with surgical resection were included. Our primary outcome was receipt of imaging between 4 and 8 months after the surgical procedure. Covariates included demographics and comorbidities. RESULTS: Chest radiography (CXR) was the most frequent initial modality (60%), followed by chest computed tomography (CT) (25%). Positron emission tomography (PET) was least frequent as an initial imaging modality (3%). A total of 13% of patients received no imaging within the initial surveillance period. Adherence to National Comprehensive Cancer Network (NCCN) guidelines for imaging by overall prevalence was 47% for receipt of CT; however, rates of CT increased over time from 28% to 61% (p < 0.01). Reduced rates of CT were associated with stage I disease and surgical resection as the sole treatment modality. CONCLUSIONS: Imaging after definitive surgical treatment for NSCLC predominantly used CXR rather than CT. Most of this imaging is likely for surveillance, and in that context CXR has inferior detection rates for recurrence and new cancers. Adherence to guideline-recommended CT surveillance after surgical treatment is poor, but the reasons are multifactorial. Efforts to improve adherence to imaging surveillance must be coupled with greater evidence demonstrating improved long term outcomes. PMID- 25282168 TI - Thoracic endovascular aortic repair for chronic DeBakey IIIb aortic dissection. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) for chronic DeBakey IIIb dissection with associated descending aneurysm remains controversial. This study examines long-term results of TEVAR for this disorder including examination of anatomic features associated with TEVAR outcomes. METHODS: Between July 2005 and January 2013, 32 patients underwent TEVAR for chronic (>30 days) DeBakey IIIb dissection involving the descending thoracic aorta at a single institution and constituted the study cohort. RESULTS: The mean interval from dissection to TEVAR was 32 +/- 44 months (range, 1 to 146 months). There were no 30-day or in hospital deaths, strokes, or paraplegia. During a 54-month median follow-up, there were no aortic-related deaths. Significant thoracic aneurysm sac regression (>1 cm) in the intervened segment was observed in 89%. Thoracic remodeling was not correlated with the number of visceral vessels arising from the true lumen or the number or size of residual distal fenestrations; failure of thoracic remodeling was associated with fenestrations distal to the endograft(s) in the descending thoracic aorta, most often stent graft-induced new entry tears. Complete resolution of the thoracic and abdominal false lumen after TEVAR was observed in 15.6% (n = 5). All patients in this group had all visceral vessels arising from the true lumen and fewer than three residual distal fenestrations. CONCLUSIONS: Thoracic endovascular aortic repair is effective for chronic DeBakey IIIb dissection with associated descending aneurysm, with excellent 30-day and long-term outcomes and significant aortic remodeling in the vast majority of patients. Thoracic remodeling does not appear dependent on distal anatomic characteristics of the true and false lumens, although care should be taken to cover all thoracic fenestrations and avoid creation of stent graft-induced new entry tears to ensure clinical success. Complete aortic remodeling was observed only in the setting of all visceral vessels off the true lumen with fewer than three residual distal fenestrations, and this would appear the ideal anatomy for TEVAR in this scenario. PMID- 25282169 TI - Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. AB - Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2-4 MUg/mL). This multicentre, retrospective, case-control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs >= 2 MUg/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3-15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3-7.5 days) vs. 8 days (IQR, 5.8-19.5 days); P=0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P=0.06) and 6% vs. 38% (P=0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections. PMID- 25282170 TI - Genetic data, reproduction season and reproductive strategy data support the existence of biological species in Ophioderma longicauda. AB - Cryptic species are numerous in the marine environment. The brittle star Ophioderma longicauda is composed of six mitochondrial lineages, encompassing brooders, which form a monophyletic group, and broadcasters, from which the brooders are derived. To clarify the species limits within O. longicauda, we compared the reproductive status of the sympatric lineages L1 and L3 (defined after sequencing a portion of the mitochondrial gene COI) during the month of May in Greece. In addition, we genotyped a nuclear marker, intron i51. Each L3 female was brooding, whereas all L1 specimens displayed full gonads, suggesting temporal pre-zygotic isolation between brooders and broadcasters. Statistical differences were found among lineages in morphology and bathymetric distribution. Finally, the intron i51 was polymorphic in L1 (60 individuals), but monomorphic in L3 (109 individuals), confirming the absence of gene flow between brooders and broadcasters. In conclusion, the broadcasting lineage L1 and the brooding lineage L3 are different biological species. PMID- 25282171 TI - Haloperidol treatment at pre-exposure phase reduces the disturbance of latent inhibition in rats with neonatal ventral hippocampus lesions. AB - Animals with neonatal ventral hippocampal lesions develop during or after adolescence abnormal behaviors related to schizophrenia such as anxiety and latent inhibition disruption. The aim of this study was to test whether haloperidol injection prior to pre-exposure session in the latent inhibition test would facilitate latent inhibition. Lesioned animals showed a significant decrease in the number and duration of social interactions, a decrease in the marbles buried, a significant increase in locomotor activity, and a disruption of latent inhibition. In the conditioned taste aversion test, injection of haloperidol produced the recovery of latent inhibition. These findings demonstrate that neonatal lidocaine lesion of the ventral hippocampus can induce behavioral changes related to schizophrenia, and injection of haloperidol, when restricted only to a three-day pre-exposure, is sufficient to facilitate latent inhibition. PMID- 25282172 TI - Hypericin biosynthesis in Hypericum hookerianum Wight and Arn: investigation on biochemical pathways using metabolite inhibitors and suppression subtractive hybridization. AB - The biochemical pathway to hypericin biosynthesis is presumed to be polyketide synthase (PKS) mediated, but it has not been experimentally validated, and no alternate route (chorismate/o-succinylbenzoate pathway) has been analyzed. We report here our earlier developed auxin inducible culture systems of Hypericum hookerianum as a model, to study the metabolic pathway to hypericin synthesis. Inhibitors of the alternate pathway at varying concentrations showed steady synthesis of total hypericins with means of 2.80+/-0.22, 18.75+/-0.01; 16.39+/ 3.75, 29.60+/-1.90 (mevinolin) 2.53+/-0.10, 18.12+/-0.56; 0.14+/-0.01, 14.28+/ 1.11 (fosmidomycin) and 2.7+/-0.35, 18.75+/-0.61; 0.14+/-0.01, 12.80+/-1.09 mg g( 1) DW (glyphosate) in the control and auxin-induced shoot and shoot-forming callus cultures, respectively. SSH analysis classified the differentially expressed sequences into protein synthesis (38%), modification (20%), electron transport (9%) and remaining as unclassified (11%) and unknown proteins (22%). Functional annotation of sequences indicates the presence of additional protein components besides PKS activity. Our results demonstrate direct biochemical and molecular evidence of PKS hypothesis of hypericin biosynthesis for the first time. PMID- 25282173 TI - Potential lactoferrin activity against pathogenic viruses. AB - Lactoferrin (LF) is an 80-kDa globular glycoprotein with high affinity for metal ions, particularly for iron. This protein possesses many biological functions, including the binding and release of iron and serves as one of the important components of the innate immune system, where it acts as a potent inhibitor of several pathogens. LF has efficacious antibacterial and antiviral activities against a wide range of Gram-positive and Gram-negative bacteria and against both naked and enveloped DNA and RNA viruses. In its antiviral pursuit, LF acts predominantly at the acute phase of the viral infection or even at the intracellular stage, as in hepatitis C virus infection. LF inhibits the entry of viral particles into host cells, either by direct attachment to the viral particles or by blocking their cellular receptors. This wide range of activities may be attributed to the capacity of LF to bind iron and its ability to interfere with the cellular receptors of both hosts and pathogenic microbes. PMID- 25282174 TI - The genus Hormiops Fage, 1933 (Hormuridae, Scorpiones), a palaeoendemic of the South China Sea: systematics and biogeography. AB - The monotypic genus Hormiops Fage, 1933 is so far only known from two groups of granitic islands off the coasts of Peninsular Malaysia and Vietnam. Examination of newly collected material from both archipelagos and of the type series of Hormiops davidovi Fage, 1933 reveals previously disregarded morphological differences sufficient to assign the Malaysian specimens to a distinct species, described here as Hormiops infulcra sp. nov. An updated diagnosis of the genus, as well as a dichotomic key enabling the determination of Hormiops from its close relatives, Hormurus Thorell, 1876 and Liocheles Sundevall, 1833 are also provided. The phylogenetic position, distribution pattern, and ecology of these insular scorpions suggest that they are palaeoendemics, remnants of a previously more widely distributed lineage. A biogeographical model is proposed for the genus based on these observations and on a synthesis of palaeogeographical and palaeoenvironmental data currently available for Sundaland. PMID- 25282175 TI - Composition, removal, redox, and metal complexation properties of dissolved organic nitrogen in composting leachates. AB - This study investigated the composition, removal, redox, and metal complexation characteristics of dissolved organic nitrogen (DON) in composting leachates. Results showed that the leachate-derived DON comprised proteinaceous compounds and amines, and most of them were integrated into the fulvic- and humic-like substances. Neutral, basic, acidic, hydroxylic, aromatic, and sulfuric amino acids all were detected in the influent leachates. However, most of them were removed by the biological and physical processes, and only neutral amino acids were detected in the effluent. The DON was not the main contributor to the redox capability of the leachate dissolved organic matter (DOM). However, it exhibited a strong capability for metal complexation. The amines formed strong complexes with the metals Mo, Co, Cr, and Ni, while the proteinaceous matter interacted with the metals Cr and Ni. PMID- 25282176 TI - Porous geopolymeric spheres for removal of Cu(II) from aqueous solution: synthesis and evaluation. AB - Porous geopolymeric spheres were synthetized by a suspension and solidification method, which were used as adsorbents for the removal of Cu(II) from aqueous solution. The influences of pH, geopolymeric spheres dosage, contact time, and initial Cu(II) concentration on adsorption capacity were investigated in detail. The adsorption kinetics and adsorption isotherms were fitted well by a pseudo second-order model and a Langmuir isotherm model, respectively. The maximum adsorption capacity of Cu(II) by the spheres calculated from Langmuir isotherm model was 52.63 mg/g. The porous geopolymeric spheres showed higher adsorption capacity than the commercial spherical 4A molecular sieve and some other reported spherical materials. The continuous removal of Cu(II) from an effluent was also conducted in column mode. The results confirmed that porous geopolymeric spheres could be used for the cleanup of heavy metal ions from wastewater in a continuous column process. PMID- 25282177 TI - Elemental mercury oxidation and adsorption on magnesite powder modified by Mn at low temperature. AB - Mn modified the commercial magnesite powder prepared by wet impregnation method has been shown to be effective for gas-phase elemental mercury (Hg(0)) removal at low temperatures. The prepared samples are characterized in detail across multiform techniques: XRF, BET, SEM-EDX, XRD, H2-TPR, and XPS, and all the results show that the amorphous MnO2 impregnated on magnesite powder improves the removal efficiency of Hg(0). Through further analysis by TG and in situ FTIR, the reasonable removal mechanism is also speculated. The results indicate that chemisorbed oxygen is an important reactant in the heterogeneous reaction, and gas-phase Hg(0) is adsorbed and then oxidized to solid MnHgO3 on the surface of the adsorbent. PMID- 25282178 TI - In vivo genotoxic effects of four different nano-sizes forms of silica nanoparticles in Drosophila melanogaster. AB - Although the use of synthetic amorphous silica (SAS) is steady increasing, scarce information exists on its potential health risk. In particular few and conflictive data exist on its genotoxicity. To fill in this gap we have used Drosophila melanogaster as in vivo model test organism to detect the genotoxic activity of different SAS with different primary sizes (6, 15, 30 and 55 nm). The wing-spot assay and the comet assay in larvae haemocytes were used, and the obtained results were compared with those obtained with the microparticulated form (silicon dioxide). All compounds were administered to third instar larvae at concentrations ranging from 0.1 to 10mM. No significant increases in the frequencies of mutant spots were observed in the wing-spot assay with any of the tested compounds. On the other hand, significant dose-dependent increases in the levels of primary DNA damage, measured by the comet assay, were observed for all the SAS evaluated but mainly when high doses (5 and 10mM) were used. These in vivo results contribute to increase the database dealing with the potential genotoxic risk associated to SAS nanoparticles exposure. PMID- 25282180 TI - Kinetic speciation and bioavailability of copper and nickel in mangrove sediments. AB - An attempt was made to establish a mechanistic linkage between chemical speciation of copper and nickel, and their bioavailability in mangrove ecosystem. Kinetic speciation study was performed to determine the concentrations of labile metal-complexes and their dissociation rate constants in mangrove sediments. Concentrations of copper and nickel in the mangrove roots were used as indicators of their bioavailability. It was found that the bioaccumulation of both the metals gradually increased with the increasing concentrations of the labile metal complexes and their dissociation rate constants in the mangrove sediments. This study shows that concentration of labile metal (copper and nickel) complexes and their dissociation rate constants in mangrove sediment can be a good indicator of their bioavailability. PMID- 25282179 TI - Ethylene vinyl acetate polymer as a tool for passive sampling monitoring of hydrophobic chemicals in the salmon farm industry. AB - Current monitoring programs are focused on hydrophobic chemicals detection in aquatic systems, which require the collection of high volumes of water samples at a given time. The present study documents the preliminary use of the polymer ethylene vinyl acetate (EVA) as a passive sampler for the detection of a hydrophobic chemical used by salmon industries such as cypermethrin. Initially, an experimental calibration in laboratory was performed to determine the cypermethrin equilibrium between sampler and aquatic medium, which was reached after seven days of exposure. A logarithm of partitioning coefficient EVA-water (logKEVA-W) of 5.6 was reported. Field deployment of EVA samplers demonstrated average concentrations of cypermethrin in water to be 2.07 +/- 0.7 ng L(-)(1) close to salmon cages, while near-shore was 4.39 +/- 0.8 ng L(-)(1). This was a first approach for assessing EVA samplers design as a tool of monitoring in water for areas with salmon farming activity. PMID- 25282181 TI - Monitoring toxic Ostreopsis cf. ovata in recreational waters using a qPCR based assay. AB - Ostreopsis sp. is a toxic marine benthic dinoflagellate that causes high biomass blooms, posing a threat to human health, marine biota and aquaculture activities, and negatively impacting coastal seawater quality. Species-specific identification and enumeration is fundamental because it can allow the implementation of all the necessary preventive measures to properly manage Ostreopsis spp. bloom events in recreational waters and aquaculture farms. The aim of this study was to apply a rapid and sensitive qPCR method to quantify Ostreopsis cf. ovata abundance in environmental samples collected from Mediterranean coastal sites and to develop site-specific environmental standard curves. Similar PCR efficiencies of plasmid and environmental standard curves allowed us to estimate the LSU rDNA copy number per cell. Moreover, we assessed the effectiveness of mitochondrial COI and cob genes as alternative molecular markers to ribosomal genes in qPCR assays for Ostreopsis spp. quantification. PMID- 25282182 TI - Evaluation of a simulation training program for uncomplicated fishhook removal. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of a fishhook removal simulation workshop using investigator-developed diagrams, practice models, and a teaching video. METHODS: This was a descriptive, prospective educational study with Institutional Review Board approval. The primary outcomes were the learner's perception of ease of learning, performance ability, and amount of tissue damage for each technique. A 23/4-minute educational video, instructional visual diagrams, and a simulated model were created to teach 4 techniques: simple retrograde, string pull, advance and cut, and needle cover. Learners performed each technique on a model to assess whether they could remove the hook on the first attempt for each technique. They then rank ordered their technique preferences for ease of learning, performance, perceived tissue damage, and overall choice. RESULTS: Of a total of 34 participants who completed the study, 71% of learners were emergency medicine residents or faculty, 65% were male, 42% were recreational fishers, and 68% had previous fishhook removal experience. On first attempt, more than 88% of participants demonstrated successful fishhook removal using all techniques except needle cover (47%). Simple retrograde was rated easiest to learn (74%) and perform (59%), was perceived to cause the least tissue damage (44%), and was the overall preferred technique. Needle cover was ranked hardest to learn (88%) and perform (82%), was perceived to cause the worst tissue damage (41%), and was the overall least preferred technique. CONCLUSIONS: This study is the first to describe a simulation training program for uncomplicated fishhook removal, and to experimentally evaluate physician learning and preferences for fishhook removal techniques. After a brief educational session, physicians could effectively use all techniques except needle cover. Simple retrograde was the overall preferred technique. PMID- 25282183 TI - Effects of edaravone, a free radical scavenger, on circulating levels of MMP-9 and hemorrhagic transformation in patients with intravenous thrombolysis using low-dose alteplase. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) plays a key role for the blood brain barrier disruption and intravenous tissue plasminogen activator (iv-tPA) therapy increases MMP-9. Edaravone, a free radical scavenger, reduces MMP-9 related blood-brain barrier disruption. We aimed to investigate whether edaravone would suppress the MMP-9 increase after iv-tPA using low-dose alteplase (0.6 mg/kg). SUBJECTS: Patients hospitalized within 12 hours after ischemic stroke onset between April 2008 and June 2013 were retrospectively examined. Patients with slight deficits (National Institutes of Health Stroke Scale score <= 4), stroke caused by arterial dissection, severe inflammatory disease or autoimmune disease, or regular use of steroid were excluded. Serum concentrations of high sensitivity C-reactive protein, interleukin-6, MMP-2, and MMP-9 were serially measured at admission, after 24 hours, day 7, and day 14. General linear models were used to compare changes in concentrations of these biomarkers over time. RESULTS: A total of 63 patients (38 men, aged 74.48 +/- 13.8 years) were studied. Patients were divided into 2 groups according to the iv-tPA therapy, that is, tPA group (n = 32) and non-tPA group (n = 31). Edaravone was administered routinely except for contraindication (90.6% in the tPA group and 87.1% in the non-tPA group). Significant interaction of group * time factor was observed only in MMP-9 concentrations by repeated-measure analysis of variance (P = .004). Association between iv-tPA therapy and subsequent hemorrhagic transformation was highly significant, but MMP-9 concentrations at any point did not predictive of subsequent hemorrhagic transformation (area under the receiver operating characteristic curve, .681). CONCLUSIONS: Low-dose iv-tPA increases MMP-9 concentration even in combination with Edaravone. The effect of higher dosage of Edaravone on circulating MMP-9 concentration and subsequent hemorrhagic transformation should be investigated. PMID- 25282184 TI - Prothrombin complex concentrate (Beriplex P/N)-related renal and cerebral infarctions in a patient with warfarin-associated intracerebral hemorrhage. AB - A 45-year-old man receiving warfarin treatment suffered from an intracerebral hemorrhage. Four-factor prothrombin complex concentrate (PCC) was administered to correct coagulopathy. However, bilateral renal infarcts and a cerebral infarct developed on day 5 and 7, respectively after PCC administration. Although the occurrence of PCC-related thromboembolism is low, health care practitioners should closely follow-up the symptoms and signs of thrombosis after PCC administration. PMID- 25282185 TI - Two soluble isoforms of receptors for advanced glycation end products (RAGE) in carotid atherosclerosis: the difference of soluble and endogenous secretory RAGE. AB - BACKGROUND: Advanced glycation end products (AGEs) promote atherosclerosis through binding to their receptor, RAGE. Since soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) may suppress AGEs-RAGE signaling, we examined the usefulness of sRAGE and esRAGE as biomarkers of early-stage atherosclerosis. METHODS: Serum sRAGE and esRAGE levels were measured in 284 subjects with no history of atherothrombotic diseases. The subjects were divided into high-sRAGE and low-sRAGE groups and high-esRAGE and low-esRAGE groups based on respective median values. We investigated the relationships between these parameters and the following factors: number of metabolic components, maximum intima-media thickness of the common carotid artery (IMT Cmax), carotid plaque calcification, and asymptomatic cerebral white matter lesions. RESULTS: The low-sRAGE and low-esRAGE groups exhibited significantly more components of metabolic syndrome than the high-sRAGE and high-esRAGE groups, respectively. IMT Cmax was significantly higher in the low-sRAGE and low-esRAGE groups. Low-sRAGE levels were significantly associated with carotid plaque calcification. Multiple linear regression analysis identified body mass index (BMI), age, and high-sensitivity C reactive protein as determinants of sRAGE, whereas only BMI was identified as a determinant of esRAGE. CONCLUSIONS: We demonstrated that sRAGE and esRAGE are associated with atherosclerotic risk factors in early-stage atherosclerosis, suggesting that their levels evolve in correlation with those of metabolic components and inflammation. Interestingly, low-sRAGE and esRAGE levels are associated with high IMT Cmax, but only low-sRAGE levels were associated with carotid plaque calcification. Thus, sRAGE and esRAGE may reflect different aspects of atherosclerosis in its early stage. PMID- 25282186 TI - Hypomanic episode improved spontaneously after isolated acute cerebellar infarct: a case report. AB - Cerebellum provides functions to be maintained at a basal level by regulating mental performance by means of functional and anatomic links critical for cognition structures. The status emerging with the determination of cognitive and affective disorders after the posterior lobe injury of the cerebellum was termed as a "Cerebellar Cognitive Affective Syndrome" by Schmahmann and Sherman in 1998. The present report presents the clinical course in a patient with a diagnosis of hypomanic episode after cerebellar infarct. PMID- 25282187 TI - The great imitator--still today! A case of meningovascular syphilis affecting the posterior circulation. AB - Cerebral ischemia due to meningovascular syphilis is rare and more frequently affects the anterior circulation than the posterior circulation. We describe clinical features and imaging studies of a 50-year-old patient with Parinaud syndrome and a syphilitic dorsal midbrain infarction. Brain magnetic resonance imaging indicated vasculitis of the posterior circulation. The diagnosis of meningovascular syphilis was established by serum and cerebrospinal fluid examinations. Although rare, because of the high impact on treatment, clinicians should always be aware of meningovascular syphilis in the differential diagnosis of stroke, particularly in young and male patients with cryptogenic stroke. PMID- 25282189 TI - Ankle-brachial index and neurologic deterioration in acute ischemic stroke. AB - BACKGROUND: Few studies have examined the relationship between abnormal ankle brachial index (ABI) and short-term outcome in patients with acute ischemic stroke (AIS). METHODS: We included 209 consecutive patients with AIS admitted to our hospital and divided them into abnormal ABI (<=.9) and normal ABI (>.9) groups. We defined neurologic deterioration (ND) as an increase of 1 or more points in the National Institutes of Health Stroke Scale score within 7 days of stroke onset. Clinical characteristics were compared between the 2 groups. Then, we performed a multiple logistic regression analysis to identify independent predictors of ND. In the multivariate analysis, the ABI values were used separately as binary variables in different cutoff thresholds (.9, 1.0, and 1.1). RESULTS: Of the 209 patients, 24 (11.5%) had an abnormal ABI. The patients in abnormal and normal ABI groups showed significant differences in carotid arterial stenosis (37.5% versus 18.9%; P = .040), intracranial artery stenosis (54.2% versus 18.9%; P < .001), and previous use of antiplatelet drugs (58.3% versus 29.2%; P = .004). According to the multivariate analysis, ABIs of .9 or less and 1.0 or less were positively associated with ND (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.03-2.89; P = .034 and OR, 1.63; 95% CI, 1.05-2.54; P = .027, respectively), whereas an ABI value of 1.1 or less was not an independent predictor of ND (OR, 1.17; 95% CI, 0.79-1.74; P = .43). CONCLUSIONS: Not only an ABI of .9 or less but also an ABI of 1.0 or less can be a predictor of ND in patients with AIS. PMID- 25282190 TI - Neuroprotective effect of punicalagin against cerebral ischemia reperfusion induced oxidative brain injury in rats. AB - BACKGROUND: Punicalagin (PG) is a hydrolyzable polyphenol in Punica granatum. It has been previously reported that it has a protective effect against hypoxia induced ischemia brain injury. It is a potent antioxidant. The present study is aimed to evaluate the antioxidant potential of PG against focal cerebral ischemia reperfusion injury in rats subjected to middle cerebral artery occlusion (MCAO). METHODS: Rats were randomly divided into sham, MCAO, PG-treated groups. PG (15 and 30 mg/kg) vehicle was administered orally for 7 days before MCAO. Rats were anesthetized with ketamine (100 mg/kg), xylazine (10 mg/kg), and subjected to 2 hours occlusion, and 22 hours reperfusion. Neurologic deficit, brain water content (BWC), histopathology changes, and oxidative stress markers were evaluated after 22 hours of reperfusion. In comparison with MCAO model group, treatment with PG significantly reduced the neurologic deficit scores and BWC. RESULTS: PG-attenuated neuronal damage occurred by downregulating the levels of malondialdehyde, sodium-potassium adenosine triphosphatase activity, nitric oxide, protein carbonyl content, and mitochondria-generated reactive oxygen species and upregulating the superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, glutathione reductase activities. CONCLUSIONS: Taken together, these results suggested that supplementation of PG treatment effectively ameliorates the cerebral ischemia/reperfusion induced oxidative damage by virtue of its antioxidant potential. PMID- 25282188 TI - Relationship between QT interval dispersion in acute stroke and stroke prognosis: a systematic review. AB - BACKGROUND: QT dispersion (QTd) has been proposed as an indirect electrocardiography (ECG) measure of heterogeneity of ventricular repolarization. The predictive value of QTd in acute stroke remains controversial. We aimed to clarify the relationship between QTd and acute stroke and stroke prognosis. METHODS: A systematic review of the literature was performed using prespecified medical subjects heading terms, Boolean logic, and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies included ischemic or hemorrhagic stroke and provided QTd measurements. RESULTS: Two independent reviewers identified 553 publications. Sixteen articles were included in the final analysis. There were a total of 888 stroke patients: 59% ischemic and 41% hemorrhagic. There was considerable heterogeneity in study design, stroke subtypes, ECG assessment time, control groups, and comparison groups. Nine studies reported a significant association between acute stroke and baseline QTd. Two studies reported that QTd increases are specifically related to hemorrhagic strokes, involvement of the insular cortex, right-side lesions, larger strokes, and increases in 3,4-dihydroxyphenylethylene glycol in hemorrhagic stroke. Three studies reported QTd to be an independent predictor of stroke mortality. One study each reported increases in QTd in stroke patients who developed ventricular arrhythmias and cardiorespiratory compromise. CONCLUSIONS: There are few well designed studies and considerable variability in study design in addressing the significance of QTd in acute stroke. Available data suggest that stroke is likely to be associated with increased QTd. Although some evidence suggests a possible prognostic role of QTd in stroke, larger and well-designed studies need to confirm these findings. PMID- 25282191 TI - Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective and frequently used surgical treatment for severe obesity. Postoperative weight loss varies markedly, but biomarkers to predict weight loss outcomes remain elusive. Levels of the satiety gut hormones glucagon like peptide-1 (GLP-1) and peptide YY (PYY) are attenuated in obese patients but elevated after RYGB surgery. We aimed to evaluate the preoperative responses of GLP-1 and PYY to a standard meal as a predictor of weight loss after RYGB surgery. We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. METHODS: Preoperatively 43 patients (F = 25/M = 18) had GLP-1 and PYY measured in the fasting state and at 30-minute intervals over 180 minutes after a standard 400 kcal mixed meal. Weight loss was assessed at weight stability after surgery (mean 16.2 mo [CI 15.516.9]). RESULTS: Body mass index decreased from 44.0 kg/m(2) (CI 42.2-45.7) before surgery to 30.3 kg/m(2) (CI 28.4-32.2) after surgery (P<.001). Preoperative GLP-1 and PYY responses to food intake; as delta value between fasting and maximum as well as total responses during 180 minutes did not correlate to total weight loss (GLP-1; rho = .060 and rho = -.089, PYY; rho = -.03 and rho = -.022, respectively) or to excess weight loss % (GLP-1; rho = .051 and rho = -.064, PYY; rho = -.1 and rho = -.088, respectively). CONCLUSION: Preoperative responses of GLP-1 and PYY to a 400 kcal mixed meal do not correlate to postoperative weight loss after RYGB surgery for morbid obesity. PMID- 25282192 TI - The influence of the percentage of the common limb in weight loss and nutritional alterations after laparoscopic gastric bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is considered the gold standard for the treatment of morbid obesity. There is no consensus over ideal limb length when the bypass is created and published studies do not take into account the influence of the common limb (CL) on weight loss. The objective was to study the influence of the common limb after RYGB. The setting was the Virgen de la Arrixaca University Clinical Hospital in Murcia, Spain. MATERIAL AND METHODS: This prospective study includes 151 patients undergoing laparoscopic RYGB surgery for morbid obesity. The patients were divided into 2 groups according to their body mass index. The small intestine (SI) was measured using micro forceps so that the percentage of common limb (%CL) could then be compared against the total SI in each patient. The percentage of excess weight loss (%EWL) in relation to the %CL was calculated at 3, 12, and 24 months. A series of tests was conducted simultaneously to analyze nutritional deficiencies and their relation to the %CL. RESULTS: The total jejunoileal segment and the %CL in the groups of both obese and super-obese patients had no influence on the %EWL in either group for any of the periods studied. The patients with a %CL<50% had greater nutritional deficiencies in the follow-up period and required supplements and more frequent laboratory tests. CONCLUSIONS: The %CL has no effect on weight loss in RYGB patients. A lower %CL is related to greater nutritional deficiencies. PMID- 25282193 TI - Can bariatric surgery improve cardiovascular risk factors in the metabolically healthy but morbidly obese patient? AB - BACKGROUND: Bariatric surgery has been shown to be effective in resolving co morbid conditions even in patients with a body mass index (BMI)<35 kg/m(2). A question arises regarding the metabolic benefits of bariatric surgery in metabolically healthy but morbidly obese (MHMO) patients, characterized by a low cardiometabolic risk. The objective of this study was to assess the effects of bariatric surgery on cardiometabolic risk factors among MHMO and metabolically unhealthy morbidly obese (MUMO) adults. METHODS: A nonrandomized, prospective cohort study was conducted on 222 severely obese patients (BMI>40 kg/m(2)) undergoing either laparoscopic roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy. Patients were classified as MHMO if only 1 or no cardiometabolic factors were present: high blood pressure, triglycerides, blood glucose (or use of medication for any of these conditions), decreased high-density lipoprotein cholesterol (HDL-C) levels, and insulin resistance defined as homeostasis model assessment for insulin-resistance (HOMA-IR)> 3.29. RESULTS: Forty-two (18.9%) patients fulfilled the criteria for MHMO. They were younger and more frequently female than MUMO patients. No differences between groups were observed for weight, BMI, waist and hip circumference, total and LDL-C. MHMO patients showed a significant decrease in blood pressure, plasma glucose, HOMA-IR, total cholesterol, LDL-C and triglycerides and an increase in HDL-C 1 year after bariatric surgery. Weight loss 1 year after bariatric surgery was similar in both groups. CONCLUSION: Eighteen percent of patients with morbid obesity fulfilled the criteria for MHMO. Although cardiovascular risk factors in these patients were within normal range, an improvement in all these factors was observed 1 year after bariatric surgery. Thus, from a metabolic point of view, MHMO patients benefited from bariatric surgery. PMID- 25282194 TI - Gastroesophageal reflux disease in the bariatric population: when is a laparoscopic sleeve gastrectomy the right choice? PMID- 25282195 TI - Bariatric surgery improves the circulating numbers and biological activity of late outgrowth endothelial progenitor cells. AB - BACKGROUND: Although the salutary effects of bariatric surgery as a treatment for excess weight and type 2 diabetes are established, there is scant evidence for effects on other contributors to cardiovascular diseases such as repair of endothelial dysfunction. This study evaluates outcomes of bariatric surgery on late outgrowth endothelial progenitor cells (LOEPCs), a cell phenotype essential for endothelial repair. METHODS: Patients with a body mass index >35 kg/m(2) and type 2 diabetes were enrolled into either medical or bariatric surgical arms. Primary outcomes included analysis of isolated LOEPCs from peripheral blood for growth, function, and mitochondrial respiration. Plasma was used for metabolic profiling. RESULTS: Medical arm patients showed no improvement in any of the parameters tested. Bariatric surgical arm patients showed a 24% reduction in body mass index as early as 3 months postintervention and resolution of type 2 diabetes at 24 months postintervention (HbA1c 31% reduction; fasting glucose 29% reduction). Bariatric surgery increased the numbers of LOEPCs 8-fold and increased LOEPC network formation 3-fold at 24 months postintervention. The increased numbers and activity of LOEPCs in the bariatric surgical arm correlated with improvements in body mass index, insulin, and triglyceride levels only at 24 month postintervention. LOEPC mitochondrial respiration displayed a trend toward improvement compared with baseline as evidenced by an increase (36%) at 24 months in the bariatric arm. CONCLUSION: Bariatric surgery increases LOEPC levels and activity, which correlates with weight loss and improved metabolic profile at 24 months postintervention. PMID- 25282196 TI - Predicting 90-day mortality after bariatric surgery: an independent, external validation of the OS-MRS prognostic risk score. AB - BACKGROUND: The Obesity Surgery Mortality Risk Score (OS-MRS) was developed using data from 1995 to 2004; it has yet to be validated for more recent patients in integrated delivery system settings. The objective of this study was to validate the OS-MRS using data from electronic health records in a distributed data network. METHODS: We conducted a retrospective cohort study of 3,817 adults who underwent an open (21.4%) or laparoscopic (78.6%) gastric bypass surgery between 2005 and 2007 in the Scalable Partnering Network. Our main outcome was all-cause mortality during the 90 days after surgery. We scored patients' risk of mortality by adding characteristics according to the OS-MRS (i.e., 1 point for each predictor). RESULTS: Sixteen of 3,817 (0.42/100; 95% CI, .24-.68) patients died within 90 days. The OS-MRS discriminated low-risk and high-risk patients effectively: low-risk (2 of 1,654 patients; .12 deaths/100 patients), intermediate-risk (10 of 2,008 patients; .50 deaths/100 patients), and high-risk (4 of 155 patients; 2.58 deaths/100 patients). High-risk patients were 21.3 times more likely to die in the first 90 days after surgery than low-risk patients (risk ratio = 21.3; 95% CI, 3.9-115.6). CONCLUSION: In these 10 U.S. healthcare delivery systems, the OS-MRS appears valid-albeit with the caveat that we observed a small number of deaths. The OS-MRS appears useful for identifying the small fraction of patients at high risk for 90-day mortality after open and laparoscopic RYGB. PMID- 25282198 TI - Same, same-but different: on the use of Navon derived measures of global/local processing in studies of face processing. AB - Some studies have reported a significant correlation between face discrimination/recognition ability and indexes of global/local processing derived from the Navon paradigm. Other studies, however, have failed to find such a relationship. In this paper we examine three aspects related to the Navon paradigm that may have contributed to this discrepancy but which have been largely neglected: (i) the use of different types of compound stimuli across studies, (ii) differences between studies in the type of index derived from the Navon paradigm, and (iii) the reliability of these indexes. In a Navon experiment comparing performance with compound letters and compound shapes in normal participants, we find little consistency both within and across participants in how they perform with these stimulus types, despite the fact that both stimulus types give rise to the typical effects. In addition we find that many of the Navon derived indexes of global/local effects used in studies examining face processing have low reliability and do not measure the same aspects of global/local processing. Echoing the results from the normal participants, we also find little consistency in how a congenital prosopagnosic performs in the Navon paradigm. With compound letters, she responds much faster to local than to global aspects of the stimuli; a pattern not seen in a single of the normal participants. With compound shapes, however, she exhibits no such abnormality. These findings question the validity of the conclusions in studies relating Navon derived indexes of global/local processing to face processing. PMID- 25282199 TI - Co-speech iconic gestures and visuo-spatial working memory. AB - Three experiments tested the role of verbal versus visuo-spatial working memory in the comprehension of co-speech iconic gestures. In Experiment 1, participants viewed congruent discourse primes in which the speaker's gestures matched the information conveyed by his speech, and incongruent ones in which the semantic content of the speaker's gestures diverged from that in his speech. Discourse primes were followed by picture probes that participants judged as being either related or unrelated to the preceding clip. Performance on this picture probe classification task was faster and more accurate after congruent than incongruent discourse primes. The effect of discourse congruency on response times was linearly related to measures of visuo-spatial, but not verbal, working memory capacity, as participants with greater visuo-spatial WM capacity benefited more from congruent gestures. In Experiments 2 and 3, participants performed the same picture probe classification task under conditions of high and low loads on concurrent visuo-spatial (Experiment 2) and verbal (Experiment 3) memory tasks. Effects of discourse congruency and verbal WM load were additive, while effects of discourse congruency and visuo-spatial WM load were interactive. Results suggest that congruent co-speech gestures facilitate multi-modal language comprehension, and indicate an important role for visuo-spatial WM in these speech-gesture integration processes. PMID- 25282200 TI - Use of text messaging services to promote health behaviors in children. AB - OBJECTIVE: To examine adherence to, satisfaction with, and preliminary efficacy of mobile phone short message service (SMS) to promote health behaviors in school aged children. METHODS: A total of 49 children (aged 8-10 years) were randomized by school classes into a monitoring vs no-monitoring group. All children participated in 2 educational group sessions that focused on health behaviors: the advantages of increasing fruit and vegetable consumption and physical activity, and decreasing screen time. The monitoring group also reported daily behavior using SMS and received supportive feedback for 8 weeks. RESULTS: Children submitted 61% of the required SMS, which indicated good adherence to the intervention. A number of children (95%) reported being satisfied with the program. Analyses of covariance indicated increase in fruit and vegetable consumption (chi2 [2] = 7.27; P < .05) and a decrease in screen time (chi2 [2] = 6.79; P < .05). CONCLUSIONS AND IMPLICATIONS: The current SMS intervention was a useful tool to monitor and promote health behaviors in children. PMID- 25282201 TI - Invited commentary. PMID- 25282202 TI - Invited commentary. PMID- 25282203 TI - Invited commentary. PMID- 25282204 TI - Invited commentary. PMID- 25282206 TI - Invited commentary. PMID- 25282205 TI - Modified TandemHeart ventricular assist device for infant and pediatric circulatory support. AB - PURPOSE: The development of pediatric ventricular assist device (VAD) circuits with lower flow ranges for infants and small children is ongoing. We present our results with modifying a readily available adult VAD to support the pediatric population. DESCRIPTION: The TandemHeart VAD (CardiacAssist, Pittsburgh, PA) circuit was modified to include a variable restrictive recirculation shunt to permit lower flow ranges in small pediatric patients. EVALUATION: Initial benchtop flow rates and pressures were studied. Hemolysis trials were performed using whole bovine blood to compare plasma-free hemoglobin levels between modified and unmodified VAD circuits. The modified VAD was surgically implanted in 7 piglets (6 to 14 kg) and which supported them for 4 hours. Levels of hemolysis did not increase and full hemodynamic support was achieved. The modified TandemHeart VAD with a recirculation shunt was subsequently implanted in 2 pediatric patients who were bridged to transplant successfully. CONCLUSIONS: Because of its simplicity, availability, low prime volume, greater patient flow range, and lower cost, the modified TandemHeart VAD with a recirculation shunt should be considered as an alternative to extracorporeal membrane oxygenation and other pulsatile VADs in children. PMID- 25282207 TI - Transcatheter aortic valve replacement for patients with aortic valve stenosis complicated with moyamoya disease. AB - Moyamoya disease (MMD) is a rare disease characterized by occlusive intracranial arteriopathy with formation of abnormal cerebrovascular collateral networks. Conventional cardiovascular surgical procedures using cardiopulmonary bypass for patients with MMD is challenging because low cerebral perfusion pressure and nonpulsatile (continuous) flow during cardiopulmonary bypass can cause severe cerebral ischemia. We successfully performed transcatheter aortic valve replacement in 3 women with severe aortic valve stenosis complicated with MMD. Transcatheter aortic valve replacement may be useful for patients with severe aortic valve stenosis complicated with severe cerebral ischemia, including MMD. PMID- 25282208 TI - Primary modified bentall's procedure in a case of Laubry-Pezzi syndrome. AB - Modified Bentall's procedure done as part of the primary repair in Laubry-Pezzi syndrome is very rarely described in the literature. We present a case of a 33 year-old man with a subpulmonic venticular septal defect, aneurysmal dilatation of the aortic root and ascending aorta, with an associated patent ductus arteriosus, corrected by the incorporation of Yacoub's techique for ventricular septal defect closure with a modified Bentall's procedure and transpulmonary patent ductus arteriosus ligation. The postoperative course was unremarkable. Early follow-up reports show good biventricular function without residual ventricular septal defect or iatrogenic ventricular outflow tract obstructions. PMID- 25282209 TI - Isolated tricuspid valve repair after metastatic tumor resection. AB - Isolated tricuspid valve repairs are performed in adults most commonly as a result of infective endocarditis, traumatic injury, rheumatic involvement, and ischemia. The use of neochordae made from polytetrafluoroethylene, being widespread in mitral valve operations, is gaining ground in tricuspid valve repair. We report a very rare case that describes isolated tricuspid valve repair using neochordae after resection of a right ventricular tumor involving the tricuspid valve. The tumor isolated was metastatic teratoma in a patient with growing teratoma syndrome. We further describe our technique of tricuspid neochord implantation and the rationale behind the repair. PMID- 25282210 TI - An unusual complication of three-patch repair of supravalvar aortic stenosis. AB - Three-patch repair of supravalvar aortic stenosis is a widely accepted surgical approach for this congenital heart lesion. We describe an unusual complication of this approach, which resulted in ischemia in the left anterior coronary artery distribution. Subtle oversizing of the left sinus of Valsalva patch led to kinking of the origin of the left anterior descending artery; the circumflex artery was not affected. Sinus of Valsalva reconstruction and reimplantation of the left coronary button restored normal coronary perfusion. PMID- 25282211 TI - Successful treatment of a patient with purulent pericarditis by daily intrapericardial washouts. AB - Purulent pericarditis in adults is rare, but once it develops, it carries a high mortality rate. Adequate pericardial drainage and proper antibiotic treatment are essential in the successful management of purulent effusions, for which percutaneous catheter drainage is the most commonly performed technique. We herein report the case of a 75-year-old woman with purulent pericarditis attributable to methicillin-resistant Staphylococcus aureus. Although percutaneous pericardial drainage by catheter was used, the drainage was insufficient because of hyperviscous effusion. We performed surgical subxiphoid pericardial drainage, and a piece of a purulent stone was found in the pericardial cavity with purulent effusion. Additionally, daily intrapericardial washouts with physiologic saline alone were used as adjunct therapy. Five weeks later, the patient had a decreasing inflammatory reaction and symptom relief. She was discharged with no complications such as constrictive pericarditis. PMID- 25282212 TI - Off-pump revascularization in a 2-year-old girl after neonatal arterial switch. AB - One drawback of the arterial switch operation for treating transposition of the great arteries is the occurrence of coronary lesions, found during follow-up in about 5% of (a)symptomatic children. The established corrective procedures include coronary artery proximal patch arterioplasty or coronary artery bypass grafting (CABG). To avoid aortic manipulations and extracorporeal circulation, off-pump coronary artery bypass (OPCAB) has become increasingly used in the adult population. We report a case of OPCAB revascularization in a symptomatic 2-year old child. PMID- 25282213 TI - Spindle cell sarcoma of the mitral valve: an unusual cause of acute coronary syndrome in a child. AB - We present an unusual case of acute myocardial infarction by embolic obstruction of both the left anterior descending and right coronary arteries in a 14-year-old girl. Echocardiography showed mobile lesions on the mitral valve and into the left ventricular outflow tract with poor left ventricular function, eventually suggesting endocarditis. Successful surgery comprised mitral valve plasty after complete resection of the tumoral lesion, in association with coronary artery embolectomy. Histologic examination revealed a malignant spindle cell sarcoma treated with adjuvant chemotherapy. We emphasize here the differential diagnosis of acute coronary syndrome in children by a rare cardiac tumor. PMID- 25282214 TI - Intrathoracic rosai-dorfman disease: hemorrhage with routine diagnostic procedure. AB - We present a case of a 33-year-old female with a slow growing, right peribronchial vascular mass and associated symptoms of progressive cough, dyspnea on exertion, and hemoptysis. On routine diagnostic flexible bronchoscopy with needle biopsy, the lesion hemorrhaged extensively requiring emergent thoracotomy, right lower and middle bilobectomy. The histopathology of the specimen was consistent with the rare and unusually located entity Rosai-Dorfman disease. PMID- 25282215 TI - Four cases of contralateral pneumothorax after pneumonectomy. AB - Contralateral pneumothorax after pneumonectomy (CPAP) is a rare but potentially fatal condition. Therefore, when treating CPAP prevention of recurrence is very important. Despite a number of case reports about CPAP, its management is still controversial. We describe 4 cases of CPAP that were treated successfully by bullectomy and coverage with absorbable polyglactin mesh. PMID- 25282216 TI - Spontaneous bilateral pneumothorax resulting from iatrogenic buffalo chest after the nuss procedure. AB - We describe a case of iatrogenic buffalo chest resulting in spontaneous bilateral pneumothorax in a 14-year-old boy with pectus excavatum in the late postoperative period after the Nuss procedure. The patient presented with a sudden onset of dyspnea 2 months after the Nuss procedure, and a chest roentgenogram showed a bilateral pneumothorax. We performed an emergency operation and found a communication between the chest cavities and a ruptured bulla in the left lung. This case highlights the potential development of simultaneous bilateral pneumothorax caused by a communication between the chest cavities after the Nuss procedure. PMID- 25282217 TI - Benign imitation of malignancy: avoiding resection in immunoglobulin g4-related lung disease. AB - We report the case of a 32-year-old woman who presented with cough, pleuritic pain, and a solitary lung mass. Computed tomography demonstrated a 3.7-cm spiculated right lower lobe mass, and 18-fluoro-deoxy-glucose positron emission tomography/computed tomography demonstrated significant hypermetabolism, both most suggestive of invasive adenocarcinoma. The results of fine needle aspirate biopsy favored a benign inflammatory process. Video-assisted thoracoscopic surgery right lower lobectomy was performed, and histopathologic examination of the mass was consistent with immunoglobulin G4-related disease (IgG4-RD). A definitive diagnosis of IgG4-RD often requires correlating several nonspecific findings with surgical lung biopsy. We discuss important diagnostic and treatment considerations for pulmonary IgG4-RD. PMID- 25282218 TI - Multiple lung adenocarcinomas associated with von hippel-lindau disease. AB - Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas. PMID- 25282219 TI - Isolated nodular thymic amyloidosis associated with diplopia. AB - An 85-year-old man presented with diplopia and anterior mediastinal tumor that had enlarged during the preceding 4-year period. Computed tomographic chest imaging showed an irregularly shaped mass comprising two nodules (diameter, 4 cm) with calcification. Suspecting thymoma, we performed video-assisted thoracoscopic thymectomy. The resected specimen showed deposition of homogeneous eosinophilic and hyalinized material around the vessel wall in thymic tissue, and it stained positively for anti-lambda antibody, indicating localized AL amyloidosis. There was no other organ dysfunction or symptoms and no evidence of systemic amyloidosis. Diplopia resolved immediately after thymectomy; however, the connection of diplopia with amyloidoma and thymic tissue remains uncertain. PMID- 25282220 TI - Bulky mediastinal aspergillosis mimicking cancer in an immunocompetent patient. AB - We describe the case of a previously healthy 42-year-old woman who presented with a chronic cough and occasional night sweats. Radiologic exploration showed a bulky mediastinal mass surrounding the aortic arch, associated with a left subclavicular lymph node and a cerebral round lesion, mimicking a disseminated lung cancer. Surgical left subclavicular and computed tomography-guided mediastinal biopsy specimens showed granulomatous patterns. Mycologic culture of both samples grew Aspergillus flavus. Resolution was obtained after 9 months of oral voriconazole therapy. PMID- 25282221 TI - Successful repair of benign left atriogastric fistula after transhiatal esophagectomy. AB - Benign gastrocardiac fistula is a rare complication following esophagectomy that can occur when the gastric tube is placed in the retrosternal space. We describe a benign fistula between the left atrium and the gastric conduit following transhiatal esophagectomy. The surgical technique that was used for successfully repair is also discussed. PMID- 25282222 TI - Left atrial appendage thrombus after successful surgical exclusion on anticoagulation: a need for closer postintervention monitoring. PMID- 25282223 TI - Computed tomography angiography and bicaval dual-lumen catheter positioning. PMID- 25282224 TI - Giant left ventricular pseudoaneurysm as a complication after mitral valve replacement surgery. PMID- 25282225 TI - Esophageal foreign body: hooked fishing lure. PMID- 25282226 TI - Transapical arterial cannulation for salvage cardiopulmonary bypass in transcatheter aortic valve replacement. AB - Hemodynamic instability during transcatheter aortic valve replacement procedures may require transient cardiopulmonary bypass for support. In patients with severe atherosclerosis, peripheral cannulation may not be possible. This method of direct left ventricle cannulation during transapical TAVR is a facile means to provide arterial inflow. PMID- 25282228 TI - The "sport model": extracorporeal membrane oxygenation using the subclavian artery. AB - Venoarterial extracorporeal membrane oxygenation is used for patients with refractory cardiopulmonary failure. Arterial cannulation by means of femoral arteries is fraught with potential complications. We present a technique for subclavian artery cannulation to provide a safe and durable means of venoarterial extracorporeal membrane oxygenation support. PMID- 25282227 TI - The Cor-Knot device may serve as an ideal radiopaque marker of the annular plane for future valve-in-valve implantation. AB - A 55-year-old man underwent aortic root and ascending aortic replacement with a 27-mm Freestyle porcine neoroot with reimplantation of the coronary ostia as well as ascending aortic replacement with a 28-mm straight Dacron graft. A knot-tying device consisting of radiopaque Titan clips (Cor-Knot device, LSI Solutions, Inc, Victor, NY) for anchoring the porcine neoroot was used. PMID- 25282229 TI - Transcervical repair of tracheal diverticulum. AB - Tracheal diverticula are rare congenital or acquired abnormalities of the posterior tracheal wall. They are usually asymptomatic, and therefore treatment has not been widely reported. We describe the entity and surgical management of a symptomatic tracheal diverticulum. PMID- 25282231 TI - Repair of complete longitudinal esophageal rupture with preservation of esophageal motility. AB - There is no consensus on the ideal treatment for esophageal perforation and on the maximal extent of esophageal disruption amenable to primary repair. The effect of extensive esophageal injury on postoperative esophageal motility is also unknown. We report the case of a longitudinal iatrogenic esophageal laceration extending from the hypopharynx to the cardia in a morbidly obese patient treated with primary repair. The patient exhibited no postoperative esophageal leak or stricture and maintained a preserved esophageal peristalsis on manometry at 3 months. An extensively lacerated esophagus can be repaired primarily while maintaining a normal postoperative function. PMID- 25282230 TI - Exposure of difficult left hilum in bilateral sequential lung transplantation. AB - Left hilar exposure can be challenging during bilateral sequential lung transplantation, particularly in patients with idiopathic pulmonary fibrosis due to the overlying heart and limited space. We describe a cost-effective technique that has been used in off-pump cardiopulmonary bypass to retract the heart away from the left hilum, without causing hemodynamic instability, thereby allowing implantation of the left lung without the use of cardiopulmonary bypass. PMID- 25282232 TI - George Jerome Magovern, MD, November 17, 1923-November 4, 2013. AB - George Jerome Magovern, the 20th president of The Society of Thoracic Surgeons (1984-1985) and emeritus member of the American Board of Thoracic Surgery (1984 1991), died surrounded by his family on November 4, 2013. He leaves behind him a lasting commitment to the advancement of patient care, education, and research. PMID- 25282233 TI - Can timely ECMO initiation mitigate pre-ECMO risk factors for acute kidney injury? PMID- 25282234 TI - Reply: To PMID 24681030. PMID- 25282235 TI - On breast implants, belly button piercings, transumbilical thoracic sympathectomy, and the big picture. PMID- 25282236 TI - Choice of right ventricle-pulmonary artery conduit in infants. PMID- 25282237 TI - Is the thoracic revised cardiac risk index really a useful scoring system? PMID- 25282238 TI - Reply: To PMID 24565405. PMID- 25282239 TI - Reply: To PMID 24820385. PMID- 25282240 TI - Oligometastatic non-small cell lung cancer: the pivotal role of nodal status. PMID- 25282241 TI - Prognostic stratification of node-negative NSCLC patients: is it worthwhile? PMID- 25282242 TI - Reply: To PMID 24266949. PMID- 25282243 TI - Partial aortic valve replacement: a new and simple approach for endocarditis. AB - We describe the replacement of a single cusp in two patients with severe aortic regurgitation due to endocarditis with a one third stentless bioprosthesis, with excellent results in both. PMID- 25282244 TI - Endocardial tuberculosis. AB - We report a 30-year-old male patient with persistent fever, history of stroke, and a left atrial mass. He was diagnosed as miliary pulmonary tuberculosis radiologically and had fever despite 2 months of antitubercular treatment. The mass was excised and fever resolved. Acid fast bacilli (AFB) were demonstrable on Ziehl Neelsen stain and routine histopathology. To the best of our knowledge, the visualization of AFB from an intracardiac lesion on ZN staining has not been reported earlier and tuberculosis must be considered in the differential diagnosis of left atrial masses. PMID- 25282245 TI - Successful repair of a bicuspid aortic valve with anomalous chordal attachment to the aortic wall. AB - The congenitally bicuspid aortic valve with anomalous chordal attachment of the fused cusp to the aortic wall is a rare and unappreciated cause of aortic insufficiency. We report the case of a 43-year-old male patient who presented with severe aortic insufficiency caused by this anomaly and in whom surgical aortic valve repair was successfully performed. To our knowledge, this is the first report to describe the successful surgical repair of this rare variant of bicuspid aortic valve. PMID- 25282246 TI - Giant aneurysm of right coronary artery fistula into left ventricle coexisting with noncompaction of left ventricular myocardium. AB - Coronary artery fistula (CAF) and noncompaction of the ventricular myocardium (NCVM) result from obliteration or compact failure of the intramyocardial trabecular sinusoids to form a ventricular cavity wall. The draining site of a right coronary artery (RCA) fistula may usually be the right ventricle, right atrium, or pulmonary artery. An RCA aneurysm with a fistula to the left ventricle is rare. We report a patient with an RCA aneurysm with a fistula to the left ventricle coexisting with NCVM. The patient's condition was diagnosed by echocardiography and contrast-enhanced multidetector computed tomography. PMID- 25282247 TI - Awake cardiopulmonary bypass to prevent hemodynamic collapse and loss of airway in a severely symptomatic patient with a mediastinal mass. AB - Management of a large mediastinal mass causing respiratory and hemodynamic compromise represents a major challenge during induction of anesthesia and surgical resection. The hemodynamic changes associated with anesthetic induction and initiation of positive-pressure ventilation can lead to acute hemodynamic collapse or inability to ventilate, or both. Initiation of cardiopulmonary bypass before anesthetic induction represents a safe alternative. We present a 37-year old woman who underwent successful resection of a large anterior mediastinal mass through sternotomy. Cardiopulmonary bypass was instituted using the right femoral vessels under local analgesia to allow safe anesthetic induction. Her postoperative course was uneventful. This represents an example of a team approach to the management of a complex patient to achieve a successful outcome. PMID- 25282248 TI - Thoracoscopic transclavicular approach for a large thoracic inlet tumor. AB - Large lesions of the thoracic inlet represent a significant challenge to surgeons due to their close relationship with important adjacent neurovascular structures. We report a case of neurofibromatosis type 1 presented with a large neurofibroma located in the right thoracic inlet, and a malignant peripheral nerve sheath tumor in the right clavicle and treated with a hybrid thoracoscopic anterior transclavicular approach to remove the tumors. Combination of thoracoscopic and minimal chest wall resection may serve as a feasible option for resection of the large and benign thoracic inlet tumor in a way of minimal invasiveness and safety. PMID- 25282249 TI - Thoracoscopic pneumonectomy in management of histoplasmosis and fibrosing mediastinitis. AB - Pulmonary histoplasmosis is generally a self-limited respiratory illness in endemic areas. Fibrosing mediastinitis is a severe chronic complication of pulmonary histoplasmosis in which pulmonary vessels and airways can be compressed with the potential for life-threatening implications. We present a 50-year-old male patient who presented with a total occlusion of the left pulmonary artery due to fibrosing mediastinitis. PMID- 25282250 TI - Arterial switch operation for double-outlet left ventricle. AB - Conventional repair of the double-outlet left ventricle involves a complex intraventricular tunnel, extracardiac conduit, or the pulmonary artery translocation operation. We report an arterial switch operation and closure of ventricular septal defect for anatomic correction of this anomaly. PMID- 25282252 TI - Retinal imaging in the twenty-first century: state of the art and future directions. AB - Assessment of chorioretinal disease is dependent on the ability to visualize pathologic changes occurring in the posterior segment of the eye using optical instruments, termed ophthalmoscopy. Ophthalmoscopy, in turn, has been enhanced greatly by the development of techniques that allow recording of these changes, termed retinal imaging. As well as documenting pathologic features, retinal and fundal imaging facilitates the identification of morphologic features not visible to the clinician on biomicroscopy. As such, advances in retinal imaging have proven fundamental to many paradigm shifts in our understanding and treatment of ocular disease. In the 1950s, with the advent of electronic flashes and 35-mm cameras, the field of modern fundus photography was born. Similarly, in the 1960s and 1970s, the introduction of fluorescein and indocyanine green angiography revolutionized our ability to assess the integrity of the chorioretinal vasculature. More recently, in the 1990s, the introduction of a wholly new form of noninvasive cross-sectional imaging, optical coherence tomography, has greatly facilitated use of emerging pharmacotherapies in diagnosing and monitoring chorioretinal disease. In this translational science review, we provide an overview of current, state-of-the-art retinal imaging technologies, as well as highlight many emerging imaging technologies that we believe are likely to transform the provision of eye care in the 21st century. PMID- 25282251 TI - Prosthetic replacement of the ocular surface ecosystem as treatment for ocular surface disease in patients with a history of Stevens-Johnson syndrome/toxic epidermal necrolysis. AB - PURPOSE: To report the visual outcomes of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in patients with ocular surface disease related to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). DESIGN: Retrospective cohort study. SUBJECTS: We included 86 patients (167 eyes) with history of SJS/TEN who underwent PROSE treatment from January 1, 2006, to January 1, 2011. METHODS: Etiology, previous interventions, change in visual acuity, change in visual function, and duration of follow-up are reported. Paired t test and Friedman test with Dunn's post hoc test for multiple comparisons were used for statistical analysis. MAIN OUTCOME MEASURES: Visual acuity at last follow-up and visual function based on the National Eye Institute 25-item Visual Functioning Questionnaire (NEI VFQ-25) at 6 months. RESULTS: We treated 35 males and 51 females with a history of SJS/TENS; median age was 36 years. The most common reported etiologies for SJS/TENS were antibiotics (n = 25), ibuprofen (n = 15), and lamotrigine (n = 11). The median visual acuity at the initial visit was 20/60 (range, 20/400-20/25; 0.48 logarithm of the minimum angle of resolution [logMAR]), and the visual acuity at completion of customization was 20/25 (range, 20/200-20/20; 0.096 logMAR; P < 0.001), with no decline in median acuity at the end of follow-up. Median duration of follow-up was 16 months. There was a significant improvement in the visual function of the patients based on the NEI VFQ-25 questionnaire (mean of 48 points at baseline vs. mean of 72 points at 6 months; P < 0.001). In addition, there was also an improvement in the self reported general health of the patients (mean of 57 points at baseline vs. mean of 65 points at 6 months; P < 0.01). CONCLUSIONS: In a large cohort of patients with chronic ocular surface disease related to SJS/TEN, PROSE treatment offers sustained and significant large improvement in visual function and acuity. PMID- 25282253 TI - The symbolic value of prostheses in maxillofacial rehabilitation. PMID- 25282254 TI - Response to: 'Pre-medications for cetuximab induced infusion reactions - commentary'. PMID- 25282255 TI - Personal safety issues related to the use of pesticides in agricultural production in the Al-Batinah region of Northern Oman. AB - The level of uptake and use of personal protective equipment (PPE) by farm workers in Oman is low; the conditions under which pesticides are stored are frequently below acceptable international standards. Research was undertaken to explore the drivers working against safe storage of agrochemicals and effective personal protection usage by pesticide application personnel. Results from a survey of over 200 respondents, representing workers in, and owners of, farms either within or outside a local farmer's association (FA), suggest that FA membership raises standards of behaviour both in terms of safe pesticide storage and use of PPE. Age of respondents had no apparent effect on the likelihood of PPE (gloves and masks) use. PPE use was, however, highest among respondents with more advanced educational backgrounds. Positive responses for glove and mask use, when applying pesticides, were higher for owners and workers in FA farms compared to non-FA farms. Lowest reported use of PPE was among workers in non-FA farms. Analysis of responses appears to indicate that behaviour patterns of workers in FA farms mirror that of the farm owners. This was not the case in non-FA farms. The results suggest that conformity to social norms, in this case acceptable work environment behaviour, is a powerful driver behind raised usage levels of PPE in farms in Oman. PMID- 25282256 TI - [Prenatal diagnosis of abdominal mass: review of the foetus in foetu]. PMID- 25282257 TI - [Medication errors in paediatrics: in search of a new vaccine]. PMID- 25282258 TI - Three-level rating of turns while walking. AB - Research concerning the assessment of turns during walking in healthy older adults is scarce. This study compared three independent assessments of entry and exit points of turns during walking; participant, clinical rater, and a computer algorithm. Nineteen non-demented and nondisabled older adults (mean age 75.40 +/- 5.52 years) participated in the current study. Results revealed that overall the three assessment methods were consistent (68-100% agreement). However, participants determined their turn exit point before the algorithm, (-304.53 +/- 326.67 ms), t(18) = -4.06, p = .001, 95% CI [-461.98, -147.08], and clinical rater, (-225.79 +/- 303.79 ms), t(18) = -3.24, p = .005, 95% CI [-372.21, 79.37]. The differences in turn determination between the algorithm and rater were significant at turn entry points (131.24 +/- 127.25 ms), t(18) = 4.50, p < .001, 95% CI [69.91, 192.58] but not at turn exit points (-78.74 +/- 259.66 ms), t(18) = -1.32, p < .20, 95% CI [-203.89, -46.41]. Greater time discrepancies in assessing turn exit points between the participants and both the algorithm and clinical rater were associated with worse visuospatial performance. Despite the relatively small difference among the three assessments of turns, they were consistent and can be utilized interchangeably. Further studies are necessary to determine whether differences in the ability to accurately determine turns entry and exit points are related to fall risk in normal and disease populations. PMID- 25282259 TI - Reproducibility of spatio-temporal and dynamic parameters in various, daily occurring, turning conditions. AB - OBJECTIVE: This study aims to assess the test-retest reproducibility of specific spatio-temporal (foot placement, foot contact time) and dynamic (resultant horizontal and vertical ground reaction force) gait parameters of three different, everyday occurring, turning conditions. The subjects were tested at two subsequent days. Out of this setting the purpose of this study is to clarify, if turning locomotion is stable when performed at different test occurrences. METHODS: Eight subjects completed three different daily occurring turning conditions along turns with a given walking velocity of 5 km/h (+/- 10%). Subjects had to complete the turns three times clockwise and counter clockwise. The measurements were recorded with a 3D motion analysis system (Vicon((r))) and two force sensitive platforms (AMTI((r))), connected to the motion analysis system. RESULTS: The analysis yields for most of the parameters and turning conditions ICCs from good (r = 0.72; p = .06) to high (r = 0.96; p < .01) magnitude for the measured spatio-temporal and dynamic parameters. CONCLUSIONS: Based on our findings it can be assumed that locomotion strategies, related to the measured gait parameters of common daily turning tasks, are stable and reproducible. PMID- 25282260 TI - Diastereoselective synthesis of potent antimalarial cis-beta-lactam agents through a [2 + 2] cycloaddition of chiral imines with a chiral ketene. AB - The effect of double asymmetric induction for the synthesis of new cis-beta lactams by [2 + 2] cycloaddition reactions of chiral imines with a chiral ketene was investigated. The cycloaddition reaction was found to be totally diastereoselective leading exclusively to the formation of the cis-beta-lactam derivatives. The newly synthesized cycloadducts were evaluated for their antimalarial activities against Plasmodium falciparum K14 resistant strain with moderate to excellent IC50 values varying from 8 to 50 MUM. Of the fifteen beta lactams tested, four showed IC50 <= 11 MUM. PMID- 25282261 TI - Novel phenyl and pyridyl substituted derivatives of isoindolines: Synthesis, antitumor activity and DNA binding features. AB - Novel phenyl-substituted (3a-3d, 4a, 5, 8a, 8b and 9a) and pyridyl-substituted (3e-3i, 4b, 8c-8e, 9b and 9c) isoindolines were prepared in the reaction of o phthalaldehyde and corresponding substituted aromatic and heteroaromatic amines by modification of reaction conditions from low to high temperature and from neutral to acidic environment. The antiproliferative activity of chosen substituted isoindolines was assessed on a panel of tumour cell lines and normal human fibroblasts. The majority of tested compounds was active at the highest tested concentrations phenyl-substituted isoindolines 3a and 3b and pyridyl substituted isoindoline 3g showed a selective effect at micromolar concentrations on HepG2 cell line in comparison with other tested tumour cell lines and normal human fibroblasts. The strongest yet non-selective effect was observed for the pyridyl-substituted isoindoline 8c. These isoindoline derivatives showed diverse mechanism of action on tumour cell death induction as compounds 3a and 8c probably induced mitotic catastrophe while compound 3b induced apoptosis. Indeed, DNA binding properties evidenced that compounds 8a, 8c and 8d bind to DNA as highly potent DNA intercalators. By contrast, compounds 3b, 3e, 3i, 4a and 5 did not target the DNA. At last, the phenyl-substituted compound 8b proved to be a strong DNA binding compound with sequence selective binding and without DNA intercalation profile. PMID- 25282262 TI - Fluorinated analogues of marsanidine, a highly alpha2-AR/imidazoline I1 binding site-selective hypotensive agent. Synthesis and biological activities. AB - The aim of these studies was to establish the influence of fluorination of the indazole ring on the pharmacological properties of two selective alpha2 adrenoceptor (alpha2-AR) agonists: 1-[(imidazolidin-2-yl)imino]-1H-indazole (marsanidine, A) and its methylene analogue 1-[(4,5-dihydro-1H-imidazol-2 yl)methyl]-1H-indazole (B). Introduction of fluorine into the indazole ring of A and B reduced both binding affinity and alpha2-AR/I1 imidazoline binding site selectivity. The most alpha2-AR-selective ligands were 6-fluoro-1-[(imidazolidin 2-yl)imino]-1H-indazole (6c) and 7-fluoro-1-[(imidazolidin-2-yl)imino]-1H indazole (6d). The in vivo cardiovascular properties of fluorinated derivatives of A and B revealed that in both cases the C-7 fluorination leads to compounds with the highest hypotensive and bradycardic activities. The alpha2-AR partial agonist 6c was prepared as a potential lead compound for development of a radiotracer for PET imaging of brain alpha2-ARs. PMID- 25282263 TI - Multidrug resistance (MDR) reversers: High activity and efficacy in a series of asymmetrical N,N-bis(alkanol)amine aryl esters. AB - As a continuation of our research on potent and efficacious P-gp-dependent multidrug resistance (MDR) reversers, several new N,N-bis(alkanol)amine aryl esters were designed and synthesized, varying the aromatic moieties or the length of the methylenic chain. The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay, where most of the new compounds were shown to be active. In particular the asymmetrical compounds, characterized by two linkers of different length, generally showed fairly high activities as MDR reversers. Some selected compounds (isomers 15-17) were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) on the K562/DOX cell line. The results of both pharmacological assays indicate that compounds 16 (GDE6) and 17 (GDE19) could be interesting leads for the development of new P-gp dependent MDR modulators. PMID- 25282264 TI - Bioreducible cross-linked polymers based on G1 peptide dendrimer as potential gene delivery vectors. AB - A series of cationic polymers based on low generation (G1) peptide dendrimer were synthesized with disulfide-containing linkages. The DNA binding abilities of the target polymers were studied by gel electrophoresis and fluorescence quenching assay. The bioreducible property of the disulfide-containing polymers P2 and P3 was also investigated in the presence of dithiothreitol (DTT). Results from dynamic light scattering (DLS) and transmission electron microscopy (TEM) assays reveal that these materials may condense DNA into nanoparticles with proper sizes and zeta-potentials. In vitro cell experiments show that compared to branched 25 KDa PEI, P2 and P3 may exhibit much higher gene transfection efficiency and lower cytotoxicity in both HEK293 and U-2OS cells. Additionally, polymer prepared from Michael addition gives better gene transfection ability, while polymer prepared from ring-opening reaction has better serum tolerance. Results indicate that these polymers might be promising non-viral gene vectors for their easy preparation, very low cytotoxicity, and good transfection efficiency. PMID- 25282265 TI - Synthesis and antiproliferative activity of 6-phenylaminopurines. AB - A series of novel 6-phenylaminopurines have been efficiently synthesized in 3 steps exploring different groups at positions 2, 8 and 9 of the purine ring and at the exocyclic nitrogen atom at position 6. Among the newly described purines, five compounds showed antiproliferative activity with IC50 values below 10 MUM, the tetrahydroquinoline derivative at position 6 of phenylaminopurine being the most active of the series in the six cell lines tested. Moreover, the compounds induced G2/M phase arrest in human cervical carcinoma HeLa cells as reported for tubulin depolymerizing agents. PMID- 25282266 TI - Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer's disease. AB - A series of indanone derivatives were designed, synthesized, and tested using a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations assessed the activities of the agents for the inhibition of cholinesterases (AChE and BuChE), the inhibition of amyloid beta (Abeta) self-assembly, and the catalysis of the disassembly of preformed Abeta oligomers and measured their antioxidant activities. Our results demonstrate that most of the synthesized compounds demonstrated good inhibitory activity against AChE with IC50 values in the nanomolar range. In particular, compounds 9 (IC50 = 14.8 nM) and 14 (IC50 = 18.6 nM) exhibited markedly higher inhibitory activities than tacrine and similar activities to donepezil. In addition, 9 and 14 significantly inhibited Abeta aggregation (inhibition rates of 85.5% and 83.8%, respectively), catalysed the disaggregation of Abeta fibrils generated by self induced Abeta aggregation, and exhibited antioxidant activity. Furthermore, these two compounds can cross the blood-brain barrier (BBB) in vitro. These properties highlight the potential of these new compounds to be developed as multi functional drugs for the treatment of Alzheimer's disease. PMID- 25282268 TI - Extraction of SAR information from activity cliff clusters via matching molecular series. AB - The vast majority of activity cliffs that occur is sets of bioactive compounds are formed in a coordinated manner. This means that multiple and overlapping cliffs are formed by groups of structural analogs with varying activity. In network representations, coordinated activity cliffs emerge as clusters of varying size and topology. Activity cliff clusters are typically rich in structure-activity relationship (SAR) information but often difficult to analyze from a medicinal chemistry viewpoint. A key question is how to best access SAR information contained in activity cliff clusters without the need to evaluate many different clusters individually. Herein, we introduce a methodology for the systematic extraction of SAR information from activity cliff clusters that utilizes the concept of matching molecular series (MMS). Sequences of activity cliff-forming compounds are isolated from clusters that follow a activity gradient and series spanning large activity differences are preferentially selected. In addition to its systematic nature, an attractive feature of the approach is that SAR information associated with extracted series is readily interpretable. We show that MMS are abundant in activity cliff clusters from the current spectrum of bioactive compounds and that many MMS share compounds. The resulting pairs of connected MMS contain compounds with closely related structural cores and alternative substitution sites that reveal SAR determinants and preferred substituents. PMID- 25282267 TI - New series of monoamidoxime derivatives displaying versatile antiparasitic activity. AB - Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 MUM), whereas a polysubstituted group (36 37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 MUM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore. PMID- 25282269 TI - All trans 1-(3-arylacryloyl)-3,5-bis(pyridin-4-ylmethylene)piperidin-4-ones as curcumin-inspired antineoplastics. AB - A series of eleven N-acryloyl/N-cinnamoyl 3,5-bis(pyridin-4-yl)methylene-4 piperidones were synthesized as curcumin-based candidate antineoplastic agents. The cytostatic potency of these compounds was evaluated against three representative cell lines and all compounds were found to exhibit significant anti-cancer cell activity in vitro. QSAR studies using several physicochemical parameters and 50% inhibitory concentration (IC50) values resulted in certain important correlations which will aid design of more potent analogs. Representative test compounds were investigated in the NCI 60-cell line panel where they were found to display a profound cytotoxicity. These compounds were also potent anti-oxidants and inhibitors of human topoisomerase IIalpha. Representative compounds were well-tolerated by human fibroblasts and by mice during the survival/toxicity studies. PMID- 25282270 TI - Selenium analogues of raloxifene as promising antiproliferative agents in treatment of breast cancer. AB - Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF 7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth. PMID- 25282271 TI - A new series of diarylamides possessing quinoline nucleus: Synthesis, in vitro anticancer activities, and kinase inhibitory effect. AB - Synthesis of a new series of diarylamides possessing 6,7 dimethoxy(dihydroxy)quinoline scaffold is described. Their in vitro antiproliferative activities against NCI-58 human cancer cell lines of nine different cancer types were tested. Compounds 1a and 1d-g showed the highest mean %inhibition values over the 58 cell line panel at 10 MUM, and they were further tested in 5-dose testing mode to determine their IC50 values. The five compounds were more potent than Imatinib against all the cell lines of nine different cancer types. Compound 1g showed the highest potencies. It showed inhibitory effect against C-RAF kinase (76.65% at 10 MUM concentration). PMID- 25282272 TI - Epigallocatechin gallate potentially attenuates Fluoride induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. AB - The present study was undertaken to evaluate the cardioprotective role of (-) epigallocatechin-gallate (EGCG) against Fluoride (F) induced oxidative stress mediated cardiotoxicity in rats. The animals exposed to F as sodium Fluoride (NaF) (25mg/kg BW) for 4 weeks exhibited a significant increase in the levels of cardiac troponins T and I (cTnT & I), cardiac serum markers, lipid peroxidative markers and plasma total cholesterol (TC), triglycerides (TG), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol, very low density lipoprotein cholesterol as well as cardiac lipids profile (TC, TG and FFA) with the significant decrease of high density lipoprotein cholesterol and cardiac phospholipids. F intoxication also decreased the levels of mitochondrial enzymes such as ICDH, SDH, MDH, alpha-KGDH and NADH in the cardiac tissue of rats. The mitochondrial Ca(2+) ion level was also significantly reduced along with the significant decrease in the levels of enzymatic and non enzymatic antioxidants. Furthermore, F treatment significantly increased the DNA fragmentation, up regulate cardiac pro-apoptotic markers, inflammatory markers and down-regulate the anti-apoptotic markers in the cardiac tissue. Pre administration of EGCG (40mg/kg/bw) in F intoxicated rats remarkably recovered all these altered parameters to near normalcy through its antioxidant nature. Thus, results of the present study clearly demonstrated that treatment with EGCG prior to F intoxication has a significant role in protecting F-induced cardiotoxicity and dyslipidemia in rats. PMID- 25282273 TI - Enamel thickness variation of deciduous first and second upper molars in modern humans and Neanderthals. AB - Enamel thickness and dental tissue proportions have been recognized as effective taxonomic discriminators between Neanderthal and modern humans teeth. However, most of the research on this topic focused on permanent teeth, and little information is available for the deciduous dentition. Moreover, although worn teeth are more frequently found than unworn teeth, published data for worn teeth are scarce and methods for the assessment of their enamel thickness need to be developed. Here, we addressed this issue by studying the 2D average enamel thickness (AET) and 2D relative enamel thickness (RET) of Neanderthal and modern humans unworn to moderately worn upper first deciduous molars (dm(1)s) and upper second deciduous molars (dm(2)s). In particular, we used 3D MUCT data to investigate the mesial section for dm(1)s and both mesial and buccal sections for dm(2)s. Our results confirmed previous findings of an Neanderthal derived condition of thin enamel, and thinner enamel in dm(1)s than dm(2)s in both Neanderthal and modern humans. We demonstrated that the Neanderthal 2D RET indices are significantly lower than those of modern humans at similar wear stages in both dm(1)s and dm(2)s (p < 0.05). The discriminant analysis showed that using 2D RET from dm(1) and dm(2) sections at different wear stages up to 93% of the individuals are correctly classified. Moreover, we showed that the dm(2) buccal sections, although non-conventionally used, might have an advantage on mesial sections since they distinguish as well as mesial sections but tend to be less worn. Therefore, the 2D analysis of enamel thickness is suggested as a means for taxonomic discrimination between modern humans and Neanderthal unworn to moderately worn upper deciduous molars. PMID- 25282274 TI - Dental microwear profilometry of African non-cercopithecoid catarrhines of the Early Miocene. AB - The Early Miocene of Kenya has yielded the remains of many important stem catarrhine species that provide a glimpse of the East African primate radiation at a time of major faunal turnover. These taxa have been subject to innumerable studies, yet there is still no consensus on their dietary niches. Here we report results of an analysis of dental microwear textures of non-cercopithecoid catarrhines from the Early Miocene of Kenya. Scanning confocal profilometry of all available molar specimens with undamaged occlusal surfaces revealed 82 individuals with unobscured antemortem microwear, representing Dendropithecus, Micropithecus, Limnopithecus, Proconsul, and Rangwapithecus. Scale-sensitive fractal analysis was used to generate microwear texture attributes for each individual, and the fossil taxa were compared with each other using conservative non-parametric statistical tests. This study revealed no discernible variation in microwear texture among the fossil taxa, which is consistent with results from a previous feature-based microwear study using smaller samples. Our results suggest that, despite their morphological differences, these taxa likely often consumed foods with similar abrasive and fracture properties. However, statistical analyses of microwear texture data indicate differences between the Miocene fossil sample and several extant anthropoid primate genera. This suggests that the African non-cercopithecoid catarrhines included in our study, despite variations in tooth form, had generalist diets that were not yet specialized to the degree of many modern taxa. PMID- 25282275 TI - Assessment of perfluoroalkyl substances in food items at global scale. AB - This study assessed the levels of 21 perfluoroalkyl substances (PFASs) in 283 food items (38 from Brazil, 35 from Saudi Arabia, 174 from Spain and 36 from Serbia) among the most widely consumed foodstuffs in these geographical areas. These countries were chosen as representatives of the diet in South America, Western Asia, Mediterranean countries and South-Eastern Europe. The analysis of foodstuffs was carried out by turbulent flow chromatography (TFC) combined with liquid chromatography with triple quadrupole mass spectrometry (LC-QqQ-MS) using electrospray ionization (ESI) in negative mode. The analytical method was validated for the analysis of different foodstuff classes (cereals, fish, fruit, milk, ready-to-eat foods, oil and meat). The analytical parameters of the method fulfill the requirements specified in the Commission Recommendation 2010/161/EU. Recovery rates were in the range between 70% and 120%. For all the selected matrices, the method limits of detection (MLOD) and the method limits of quantification (MLOQ) were in the range of 5 to 650 pg/g and 17 to 2000 pg/g, respectively. In general trends, the concentrations of PFASs were in the pg/g or pg/mL levels. The more frequently detected compounds were perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorobutanoic acid (PFBA). The prevalence of the eight-carbon chain compounds in biota indicates the high stability and bioaccumulation potential of these compounds. But, at the same time, the high frequency of the shorter chain compounds is also an indication of the use of replacement compounds in the new fluorinated materials. When comparing the compounds profile and their relative abundances in the samples from diverse origin, differences were identified. However, in absolute amounts of total PFASs no large differences were found between the studied countries. Fish and seafood were identified as the major PFASs contributors to the diet in all the countries. The total sum of PFASs in fresh fish and seafood was in the range from the MLOQ to 28ng/g ww. According to the FAO-WHO diets composition, the daily intake (DI) of PFASs was calculated for various age and gender groups in the different diets. The total PFASs food intake was estimated to be between 2300 and 3800 ng /person per day for the different diets. Finally, the risk intake (RI) was calculated for selected relevant compounds. The results have indicated that by far in no case the tolerable daily intake (TDI) (150, 1500, 50,000, 1,000,000, 150, 1500 ng/kg body weight, for perfluorohexanesulfonate (PFHxS), fluorotelomer alcohol (FTOH), perfluorobutanesulfonic acid (PFBS), perfluorobutanoic acid (PFBA), PFOS and PFOA, respectively) was exceeded. PMID- 25282276 TI - Sources of halogenated brominated retardants in house dust in an industrial city in southern China and associated human exposure. AB - Halogenated flame retardants (HFRs) are a class of ubiquitous pollutants in the environment and attract increasing attention. In the present study, HFR concentrations were measured in indoor and outdoor dust in an important industrial city (Dongguan) in southern China, in which their presence and associated human exposure are unknown. The HFRs were dominated by polybrominated diphenyl ethers (PBDEs) and decabromodiphenyl ethane (DBDPE), with mean concentrations of 2365 and 2441 ng/g in the indoor dust, respectively, which were 2-3 order of magnitude higher the concentrations of other HFRs. However elevated tri- to hepta-BDE concentrations (869 ng/g) were found in Houjie Town, a furniture manufacturing center. The mean indoor/outdoor (I/O) ratios of HFR concentrations in the dust were all larger than one (1.55-16.4), suggesting the importance of indoors sources for HFRs in indoor dust in this industrial city. Principal component analysis (PCA) showed that the correlations among the HFRs in the indoor dust probably revealed differences in their commercial applications, while most HFRs in the outdoor dust have similar sources except for phased-out BDE47 and 99. The compositions of lower brominated PBDEs varied among the towns, probably due to their different sources or influence of photo-degradation. Nevertheless, the similar composition of highly brominated congeners indicated little photo-degradation encountered in the ambient environment. The non-cancer risk associated with indoor dust ingestion is low for the general population in Dongguan, but some children in the furniture manufacturing center have significantly high risk of exposure to banned PBDEs. PMID- 25282277 TI - Acute toxic and genotoxic activities of widely used cytostatic drugs in higher plants: Possible impact on the environment. AB - Cytostatic drugs are highly toxic pharmaceuticals and it was repeatedly postulated that they may cause adverse effects in ecosystems. The acute toxic and genotoxic properties of these drugs have not been adequately investigated in higher plants so far; therefore, we studied the most widely used drugs (5 flurouracil, 5FU; etoposide, Et; cisplatin, CisPt; carboplatin, CaPt; vincristine sulfate, VinS and cyclophosphamide monohydrate, CP) in micronucleus (MN) assays with meiotic pollen tetrad cells of Tradescantia and with root cells from Allium cepa. MNi are formed as a consequence of chromosome breaks and aneuploidy. We monitored also the acute toxic properties of the drugs, i.e. inhibition of cell division (mitotic indices and retardation of root growth) in the latter species. All compounds caused in both indicator plants genotoxic effects. The order of genotoxic potencies expressed as NOELs in uM was CisPt (0.1)>= Et (0.5)>CP (1.0)>CaPt (10)>5FU (30)>VinS (100) in Tradescantia. A similar order was seen in Allium MN but Et was less active (5.0uM). Four compounds caused alterations of the mitotic indices under the present conditions namely CisPt (0.5), Et (10.0), 5FU (10.0) and VinS (100). Inhibition of root growth decreased in the order CisPt (0.5)>Et (1.0)>=VinS (1.0)>5FU (5.0)>CaPt (33.0)>CP (>1000). Comparisons of the NOELs with the predicted environmental concentrations (PEC) show that the latter values are at least 5 orders of magnitude lower and indicate that it is unlikely that their release in the environment may cause adverse effects in higher plants. However, it is notable that the levels of both platinum compounds and of 5FU in hospital effluents may reach levels which may induce damage of the genetic material. PMID- 25282278 TI - A national satellite-based land-use regression model for air pollution exposure assessment in Australia. AB - Land-use regression (LUR) is a technique that can improve the accuracy of air pollution exposure assessment in epidemiological studies. Most LUR models are developed for single cities, which places limitations on their applicability to other locations. We sought to develop a model to predict nitrogen dioxide (NO2) concentrations with national coverage of Australia by using satellite observations of tropospheric NO2 columns combined with other predictor variables. We used a generalised estimating equation (GEE) model to predict annual and monthly average ambient NO2 concentrations measured by a national monitoring network from 2006 through 2011. The best annual model explained 81% of spatial variation in NO2 (absolute RMS error=1.4 ppb), while the best monthly model explained 76% (absolute RMS error=1.9 ppb). We applied our models to predict NO2 concentrations at the ~350,000 census mesh blocks across the country (a mesh block is the smallest spatial unit in the Australian census). National population weighted average concentrations ranged from 7.3 ppb (2006) to 6.3 ppb (2011). We found that a simple approach using tropospheric NO2 column data yielded models with slightly better predictive ability than those produced using a more involved approach that required simulation of surface-to-column ratios. The models were capable of capturing within-urban variability in NO2, and offer the ability to estimate ambient NO2 concentrations at monthly and annual time scales across Australia from 2006-2011. We are making our model predictions freely available for research. PMID- 25282279 TI - Association between annual river flood pulse and paediatric hospital admissions in the Mekong Delta area. AB - The Mekong Delta is the most vulnerable region to extreme climate and hydrological conditions however the association between these conditions and children's health has been little studied. We examine the association between annual river flood pulse and paediatric hospital admissions in a Vietnam Mekong Delta city. Daily paediatric hospital admissions (PHA) were collected from the City Paediatric Hospital, and daily river water level (RWL) and meteorological data were retrieved from the Southern Regional Hydro-Meteorological Centre from 2008 to 2011. We evaluated the association between annual river flood pulse (>=90th percentile of RWL) and PHA using the Poisson distributed lag model, controlling for temperature, relative humidity, day of week, seasonal and long term trends. The seasonal pattern of PHA was examined using harmonic and polynomial regression models. The cumulative risk ratios estimated for a 15-day period following an extreme RWL was 1.26 (95%CI, 1.2-1.38) for all age groups, 1.27 (95%CI, 1.23-1.30) for under five-years and 1.15 (95%CI, 1.07-1.20) for school-aged children, 1.24 (95%CI, 1.21-1.27) for all-causes, 1.18 (95%CI, 1.12 1.21) for communicable infection, 1.66 (95%CI, 1.57-1.74) for respiratory infection and 1.06 (95%CI, 1.01-1.1) for other diseases. The peak PHA risk is in the September-October period corresponding to the highest RWL, and the PHA-RWL association was modified by temperature. An increase in PHA is significantly associated with annual river flood, and the pattern of PHA is seasonally correspondent to the RWL. These findings combined with projected changes in climate conditions suggest important implications of climate change for human health in the Mekong Delta region. PMID- 25282281 TI - Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia. AB - We have recently identified up- or down-regulation of the olfactory (OR) and taste (TASR) chemoreceptors in the human cortex in several neurodegenerative diseases, raising the possibility of a general deregulation of these genes in neuropsychiatric disorders. In this study, we explore the possible deregulation of OR and TASR gene expression in the dorsolateral prefrontal cortex in schizophrenia. We used quantitative polymerase chain reaction on extracts from postmortem dorsolateral prefrontal cortex of subjects with chronic schizophrenia (n = 15) compared to control individuals (n = 14). Negative symptoms were evaluated premortem by the Positive and Negative Syndrome and the Clinical Global Impression Schizophrenia Scales. We report that ORs and TASRs are deregulated in the dorsolateral prefrontal cortex in schizophrenia. Seven out of eleven ORs and four out of six TASRs were down-regulated in schizophrenia, the most prominent changes of which were found in genes from the 11p15.4 locus. The expression did not associate with negative symptom clinical scores or the duration of the illness. However, most ORs and all TASRs inversely associated with the daily chlorpromazine dose. This study identifies for the first time a decrease in brain ORs and TASRs in schizophrenia, a neuropsychiatric disease not linked to abnormal protein aggregates, suggesting that the deregulation of these receptors is associated with altered cognition of these disorders. In addition, the influence of antipsychotics on the expression of ORs and TASRs in schizophrenia suggests that these receptors could be involved in the mechanism of action or side effects of antipsychotics. PMID- 25282282 TI - Decreased cortical thickness in drug naive first episode schizophrenia: in relation to serum levels of BDNF. AB - This study was to examine cortical thickness in drug naive, first episode schizophrenia patients, and to explore its relationship with serum levels of brain-derived neurotrophic factor (BDNF). Forty-five drug naive schizophrenia patients and 28 healthy controls were enrolled in the study. Freesurfer was used to parcellate cortical regions, and vertex-wise group analysis was used for whole brain cortical thickness. The clusters for the brain regions that demonstrated group differences were extracted, and the mean values of thickness were calculated. Serum levels of BDNF were measured using enzyme-linked immunosorbent assay (ELISA). After controlling for age and gender, significantly thinner cortical thickness was found in left insula and superior temporal gyrus in the patient group compared with the healthy control group (HC group) (p's < 0.001). Lower serum levels of BDNF were also found in the patient group compared with the HC group (p = 0.001). Correlation analysis showed a significant positive relationship between thickness of left insula and serum levels of BDNF within the HC group (r = 0.396, p = 0.037) but there was no such relationship within the patient group (r = 0.035, p = 0.819). Cortical thinning is present in drug naive, first episode schizophrenia patients, indicating neurodevelopmental abnormalities at the onset of schizophrenia. Left insula might be an imaging biomarker in detecting the impaired protective role of neurotrophic factor for the brain development in schizophrenia. PMID- 25282280 TI - Exposure to airborne polycyclic aromatic hydrocarbons during pregnancy and risk of preterm birth. AB - BACKGROUND: Preterm birth is an important marker of health and has a prevalence of 12-13% in the U.S. Polycyclic aromatic hydrocarbons (PAHs) are a group of organic contaminants that form during the incomplete combustion of hydrocarbons, such as coal, diesel and gasoline. Studies suggest that exposure to PAHs during pregnancy is related to adverse birth outcomes. The aim of this study is to evaluate the association between exposure to PAHs during the pregnancy and preterm birth. METHODS: The study population included births from years 2001 to 2006 of women whose maternal residence was within 20km of the primary monitoring site in Fresno, California. Data in the Fresno area were used to form a spatio temporal model to assign daily exposure to PAHs with 4, 5, or 6 rings at the maternal residence throughout pregnancy of all of the births in the study area. Gestational age at birth and relevant covariates were extracted from the birth certificate. RESULTS: We found an association between PAHs during the last 6 weeks of pregnancy and birth at 20-27 weeks (OR=2.74; 95% CI: 2.24-3.34) comparing the highest quartile to the lower three. The association was consistent when each quartile was compared to the lowest (OR2nd=1.49, 95% CI: 1.08-2.06; OR3rd=2.63, 95% CI:1.93-3.59; OR4th=3.94, 95% CI:3.03-5.12). Inverse associations were also observed for exposure to PAHs during the entire pregnancy and the first trimester and birth at 28-31 weeks and 20-27 weeks. CONCLUSION: An association between PAH exposure during the 6 weeks before delivery and early preterm birth was observed. However, the inverse association with early preterm birth offers an unclear, and potentially complex, inference of these associations. PMID- 25282283 TI - A Christmas shopping complication: traumatic epidural hematoma leading to cerebral sinus thrombosis. PMID- 25282284 TI - Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. AB - BACKGROUND: Low-dose CT screening is recommended for individuals at high risk of developing lung cancer. However, CT screening does not detect all lung cancers: some might be missed at screening, and others can develop in the interval between screens. The NELSON trial is a randomised trial to assess the effect of screening with increasing screening intervals on lung cancer mortality. In this prespecified analysis, we aimed to assess screening test performance, and the epidemiological, radiological, and clinical characteristics of interval cancers in NELSON trial participants assigned to the screening group. METHODS: Eligible participants in the NELSON trial were those aged 50-75 years, who had smoked 15 or more cigarettes per day for more than 25 years or ten or more cigarettes for more than 30 years, and were still smoking or had quit less than 10 years ago. We included all participants assigned to the screening group who had attended at least one round of screening. Screening test results were based on volumetry using a two-step approach. Initially, screening test results were classified as negative, indeterminate, or positive based on nodule presence and volume. Subsequently, participants with an initial indeterminate result underwent follow up screening to classify their final screening test result as negative or positive, based on nodule volume doubling time. We obtained information about all lung cancer diagnoses made during the first three rounds of screening, plus an additional 2 years of follow-up from the national cancer registry. We determined epidemiological, radiological, participant, and tumour characteristics by reassessing medical files, screening CTs, and clinical CTs. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. FINDINGS: 15,822 participants were enrolled in the NELSON trial, of whom 7915 were assigned to low dose CT screening with increasing interval between screens, and 7907 to no screening. We included 7155 participants in our study, with median follow-up of 8.16 years (IQR 7.56-8.56). 187 (3%) of 7155 screened participants were diagnosed with 196 screen-detected lung cancers, and another 34 (<1%; 19 [56%] in the first year after screening, and 15 [44%] in the second year after screening) were diagnosed with 35 interval cancers. For the three screening rounds combined, with a 2-year follow-up, sensitivity was 84.6% (95% CI 79.6-89.2), specificity was 98.6% (95% CI 98.5-98.8), positive predictive value was 40.4% (95% CI 35.9-44.7), and negative predictive value was 99.8% (95% CI 99.8-99.9). Retrospective assessment of the last screening CT and clinical CT in 34 patients with interval cancer showed that interval cancers were not visible in 12 (35%) cases. In the remaining cases, cancers were visible when retrospectively assessed, but were not diagnosed because of radiological detection and interpretation errors (17 [50%]), misclassification by the protocol (two [6%]), participant non-compliance (two [6%]), and non-adherence to protocol (one [3%]). Compared with screen-detected cancers, interval cancers were diagnosed at more advanced stages (29 [83%] of 35 interval cancers vs 44 [22%] of 196 screen-detected cancers diagnosed in stage III or IV; p<0.0001), were more often small-cell carcinomas (seven [20%] vs eight [4%]; p=0.003) and less often adenocarcinomas (nine [26%] vs 102 [52%]; p=0.005). INTERPRETATION: Lung cancer screening in the NELSON trial yielded high specificity and sensitivity, with only a small number of interval cancers. The results of this study could be used to improve screening algorithms, and reduce the number of missed cancers. FUNDING: Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds. PMID- 25282286 TI - Lung cancer screening: achieving more by intervening less. PMID- 25282285 TI - Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. AB - BACKGROUND: The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Management protocols use thresholds for nodule size and growth rate to determine which nodules require additional diagnostic procedures, but these should be based on individuals' probabilities of developing lung cancer. In this prespecified analysis, using data from the NELSON CT screening trial, we aimed to quantify how nodule diameter, volume, and volume doubling time affect the probability of developing lung cancer within 2 years of a CT scan, and to propose and evaluate thresholds for management protocols. METHODS: Eligible participants in the NELSON trial were those aged 50-75 years, who have smoked 15 cigarettes or more per day for more than 25 years, or ten cigarettes or more for more than 30 years and were still smoking, or had stopped smoking less than 10 years ago. Participants were randomly assigned to low-dose CT screening at increasing intervals, or no screening. We included all participants assigned to the screening group who had attended at least one round of screening, and whose results were available from the national cancer registry database. We calculated lung cancer probabilities, stratified by nodule diameter, volume, and volume doubling time and did logistic regression analysis using diameter, volume, volume doubling time, and multinodularity as potential predictor variables. We assessed management strategies based on nodule threshold characteristics for specificity and sensitivity, and compared them to the American College of Chest Physicians (ACCP) guidelines. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. FINDINGS: Volume, volume doubling time, and volumetry-based diameter of 9681 non-calcified nodules detected by CT screening in 7155 participants in the screening group of NELSON were used to quantify lung cancer probability. Lung cancer probability was low in participants with a nodule volume of 100 mm(3) or smaller (0.6% [95% CI 0.4-0.8]) or maximum transverse diameter smaller than 5 mm (0.4% [0.2-0.7]), and not significantly different from participants without nodules (0.4% [0.3-0.6], p=0.17 and p=1.00, respectively). Lung cancer probability was intermediate (requiring follow-up CT) if nodules had a volume of 100-300 mm(3) (2.4% [95% CI 1.7-3.5]) or a diameter 5-10 mm (1.3% [1.0-1.8]). Volume doubling time further stratified the probabilities: 0.8% (95% CI 0.4-1.7) for volume doubling times 600 days or more, 4.0% (1.8-8.3) for volume doubling times 400-600 days, and 9.9% (6.9-14.1) for volume doubling times of 400 days or fewer. Lung cancer probability was high for participants with nodule volumes 300 mm(3) or bigger (16.9% [95% CI 14.1-20.0]) or diameters 10 mm or bigger (15.2% [12.7-18.1]). The simulated ACCP management protocol yielded a sensitivity and specificity of 90.9% (95% CI 81.2-96.1), and 87.2% (86.4-87.9), respectively. A diameter-based protocol with volumetry-based nodule diameter yielded a higher sensitivity (92.4% [95% CI 83.1-97.1]), and a higher specificity (90.0% [89.3-90.7). A volume-based protocol (with thresholds based on lung cancer probability) yielded the same sensitivity as the ACCP protocol (90.9% [95% CI 81.2-96.1]), and a higher specificity (94.9% [94.4-95.4]). INTERPRETATION: Small nodules (those with a volume <100 mm(3) or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (>=300 mm(3) or >=10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100-300 mm(3) or diameter of 5-10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol. FUNDING: Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds. PMID- 25282287 TI - Clinical implications of the obese-asthma phenotypes. AB - The concomitant increase in obesity and asthma in recent years has led to the classification of two obese-asthma phenotypes, characterized by the age of asthma onset and atopy. Asthma tends to be more severe, harder to control, and more resistant to standard medications among members of these two groups. Because of the limited effectiveness of inhaled corticosteroids, dietary changes and weight loss measures must be considered in the management of these patients. Furthermore, comorbidities such as depression and obstructive sleep apnea must be addressed to provide optimal care for this group of difficult-to-control asthmatics. PMID- 25282288 TI - Childhood obesity and risk of allergy or asthma. AB - The simultaneous increment in the prevalence of obesity and allergic diseases suggests a possible link between them. This review focuses on the consequences of obesity on allergic diseases, especially asthma in children and adolescents, and evaluates the available evidence on the possible mechanisms. Obesity is related more strongly to nonatopic than atopic asthma, suggesting non-eosinophilic inflammation and Th1 polarization. Among other allergic diseases, the association is more consistent with eczema compared to allergic rhinitis/rhinoconjunctivitis. The mechanisms of asthma in obese individuals could involve mechanical effects of obesity on lung function, adipokines-mediated inflammation, shared factors (diet, genetics, sedentary lifestyle) and comorbidities. PMID- 25282289 TI - Arginine metabolism in asthma. AB - Nitric oxide (NO) is important in the regulation of airway tone and airway responsiveness. Alterations in the L-arginine metabolism resulting in reduced availability of the substrate L-arginine for NO synthases, as well as the presence of NO synthase inhibitors such as asymmetric dimethylarginine, contribute to the reduced NO formation and airway dysfunction in asthma. Therapeutic interventions aiming to modulate the impaired L-arginine metabolism may help correct the enhanced airway tone and responsiveness in asthma. PMID- 25282290 TI - Metabolic asthma: is there a link between obesity, diabetes, and asthma? AB - Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. However, the relationship between asthma, obesity, and abnormal metabolism is not well understood nor has it been adequately explored in children. This article discusses the concept of metabolic asthma and the recent hypothesis that early derangement in lipid and glucose metabolism is independently associated with increased risk for asthma. PMID- 25282292 TI - Role of weight management in asthma symptoms and control. AB - Obesity and asthma have increasingly been linked with an increased risk of developing asthma associated with increasing body mass index. Overweight/obese patients with asthma have more symptoms, poor asthma control, and decreased response to conventional asthma therapies. Weight loss may be associated with improvements in asthma control, response to medications, and overall asthma related quality of life. This article discusses the effect of weight loss via dietary modifications and surgical interventions on asthma symptoms and control. Weight loss should be encouraged as a means of improving asthma control but there are insufficient data to recommend surgical interventions solely for this purpose. PMID- 25282291 TI - Obesity, metabolic syndrome, and airway disease: a bioenergetic problem? AB - Multiple studies have determined that obesity increases asthma risk or severity. Metabolic changes of obesity, such as diabetes or insulin resistance, are associated with asthma and poorer lung function. Insulin resistance is also found to increase asthma risk independent of body mass. Conversely, asthma is associated with abnormal glucose and lipid metabolism, insulin resistance, and obesity. Here we review our current understanding of how dietary and lifestyle factors lead to changes in mitochondrial metabolism and cellular bioenergetics, inducing various components of the cardiometabolic syndrome and airway disease. PMID- 25282294 TI - Nutritional influences on epigenetic programming: asthma, allergy, and obesity. AB - Observational studies show consistent links between early-life nutritional exposures as important risk factors for the development of asthma, allergy, and obesity. Reliance on increasing use of dietary supplementation and fortification (eg, with folate) to compensate for increased consumption of processed foods is also influencing immune and metabolic outcomes. Epigenetics is providing substantial advances in understanding how early-life nutritional exposures can effect disease development. This article summarizes current evidence linking the influence of early-life nutritional exposures on epigenetic regulation with a focus on the disease outcomes of asthma, allergy, and obesity. PMID- 25282295 TI - Obesity and asthma: the role of environmental pollutants. AB - Air pollution is a well-known risk for lung diseases, including asthma. Growing evidences suggesting air pollution as a novel risk factor for the development of obesity. Several Epidemiological studies have ascertained an association between various ambient and indoor air pollutants and obesity by medium of endocrine disruptive chemicals that can disrupt the normal development and homeostatic controls over adipogenesis and energy balance and induce obesity. Several obesity induced mechanisms have been proposed that increases this vulnerability of obese individuals to harmful effects of air pollution rendering them more susceptible to developing air-pollution driven incident asthma or worsening of already existing asthma. PMID- 25282296 TI - Obesity and asthma--is there a causal association? PMID- 25282293 TI - Novel therapeutic strategies for adult obese asthmatics. AB - Asthma is a complex syndrome that affects an estimated 26 million people in the United States but gaps exist in the recognition and management of asthmatic subgroups. This article proposes alternative approaches for future treatments of adult obese asthmatics who do not respond to standard controller therapies, drawing parallels between seemingly disparate therapeutics through their common signaling pathways. How metformin and statins can potentially improve airway inflammation is described and supplements are suggested. A move toward more targeted therapies for asthma subgroups is needed. These therapies address asthma and the comorbidities that accompany obesity and metabolic syndrome to provide the greatest therapeutic potential. PMID- 25282297 TI - Urban, obese, allergic, and breathless: the shape of things to come? PMID- 25282298 TI - Ulnar styloid process nonunion and outcome in patients with a distal radius fracture: a meta-analysis of comparative clinical trials. AB - PURPOSE: There is no consensus on the relation between ulnar styloid process nonunion and outcome in patients with distal radius fractures. The aim of this study was to analyze whether patient-reported outcome is influenced by the nonunion of the accompanying ulnar styloid fracture in distal radius fracture patients. METHODS: A meta-analysis of published studies comparing outcomes after distal radius fractures with a united versus a non-united ulnar styloid process was performed. In addition, if provided by the authors, the raw data of these studies were pooled and analysed as one study. The outcome measures of the analyses included patient-reported outcome, functional outcome, grip-strength, pain, and distal radioulnar joint (DRUJ) instability. RESULTS: Data from six comparative studies were included, concerning 365 patients with a distal radius fracture. One hundred and thirty-five patients with an ulnar styloid union were compared with 230 patients with a nonunion of the ulnar styloid. No significant differences were found between groups regarding any outcome measure. CONCLUSION: Based on this meta-analysis, there is no relation between the nonunion of the ulnar styloid process and function in patients with a distal radius fracture. PMID- 25282299 TI - Trauma registry methodology: a survey of trauma registry custodians to determine current approaches. AB - INTRODUCTION: The global burden of injury is enormous, especially in developing countries. Trauma systems in highincome countries have reduced mortality and disability. An important component of trauma quality improvement programmes is the trauma registry which monitors the epidemiology, processes and outcomes of trauma care. There is a severe deficit of trauma registries in developing countries and there are few resources to support the development of trauma registries. Specifically, publicly available information of trauma registry methodology in developed trauma registries is sparse. The aim of this study was to describe and compare trauma registries globally. METHODS: A survey of trauma registry custodians was conducted. Purposive sampling was used to select trauma registries following a structured review of the literature. Registries for which there were at least two included abstracts over the five-year period were defined as active and selected. Following piloting and revision, a detailed survey covering physical and human resources, administration and methodology was distributed. The survey responses were analysed; single hospital and multi hospital registries were compared. RESULTS: Eighty-four registries were emailed the survey. Sixty-five trauma registries participated, giving a response rate of 77%. Of the 65 participating registries, 40 were single hospital registries and 25 were multi-hospital registries. Fifteen countries were represented; more than half of the participating registries were based in the USA. There was considerable variation in resourcing and methodology between registries. A trauma registry most commonly had at least three staff, reported to both the hospital and government, included more than 1000 cases annually, listed admission, death and transfer amongst inclusion criteria, mandated collection of more than 100 data elements, used AIS Version 2005 (2008 update) and used age, the Glasgow Coma Scale and the Injury Severity Score for injury severity adjustment. CONCLUSION: Whilst some characteristics were common across many trauma registries, the resourcing and methodology varied markedly. The common features identified may serve as a guide to those looking to establish a trauma registry. However much remains to be done for trauma registries to determine the best standardised approach. PMID- 25282300 TI - Perforator-based propeller flap with venous axial supercharging for reconstruction of a leg defect. PMID- 25282301 TI - Contextual information influences the feeling of knowing in episodic memory. AB - The feeling of knowing (FOK) predicts the likelihood of eventually recognizing currently unrecalled items. Koriat (1993, 1995) showed that retrieval of partial target information influences FOK ratings. Building on Koriat's view, the noncriterial-recollection hypothesis contends that contextual information influences FOKs (Brewer, Marsh, Clark-Foos, & Meeks, 2010). Our study assessed the validity of the noncriterial-recollection hypothesis by controlling the amount of potentially-retrievable contextual information presented to participants. We varied the amount of contextual information accompanying the name and image of imaginary animals. There were three information conditions: minimum (name and image), medium (name, image, and country), and maximum (name, image, country, diet and weight). Information condition did not affect recall accuracy. The minimum condition resulted in greater response output (recall and commission errors together). FOKs for unrecalled items were lower in the minimum condition than the other conditions. Consistent with the noncriterial recollection hypothesis, FOKs were positively correlated with the retrieval of contextual information. PMID- 25282302 TI - I think, therefore I am? Examining conceptions of the self, soul, and mind. AB - In order to delineate among conceptions of the self, soul, and mind, participants reported where they believe these entities are located in the body and provided definitions of each entity. Results indicated that most people consider the self, soul, and mind localized in specific regions in the body. In contrast to previous research, however, some participants reported that the self is not centralized in one location. Participants tended to locate the self and mind in the head and the soul in the chest. The self and mind were commonly defined in mental terms and the soul as one's essence. These results suggest that people tend to distinguish the soul from the mind, both in how they define each entity and where they locate them in the body. Although some people locate the soul in the same region as the self, most people more closely align the mind with the self. PMID- 25282303 TI - Current treatment of nasal vestibular stenosis with CO2-laser surgery: prolonged vestibular stenting versus intraoperative mitomycin application. A case series of 3 patients. AB - These case studies describe three cases of unilateral nasal vestibular stenoses caused by chemical cauterization. Each case was treated with CO2-laser surgery together with intraoperative topic application of mitomycin or prolonged vestibular stenting for prevention of restenosis. Two patients received intraoperative mitomycin application and one patient received prolonged vestibular stenting. Results were documented using high-resolution photographs. The follow up period ranged from 1 year and 3 months to 4 years and 9 months. All patients improved after CO2-laser surgery. No complications were reported. We consider CO2-laser surgery for relief of nasal vestibular stenosis as a feasible surgical technique for relieve of nasal vestibular stenosis. Prolonged vestibular stenting seems to be an important factor for the prevention of restenosis in which the value of intraoperative mitomycin application without prolonged vestibular stenting remains uncertain. PMID- 25282304 TI - Polysomnographic results of prone versus supine positioning in micrognathia. AB - BACKGROUND: Children with micrognathia commonly present with upper airway symptoms and are at risk for developing obstructive sleep apnea (OSA). Prone positioning is widely used as first-line management for micrognathic children with obstructive symptoms. The aim of the present study was to document the effect of positioning on oxygenation and upper airway obstruction as measured by polysomnography (PSG). METHODS: Three children with micrognathia from two institutions underwent PSG in both the prone and supine position. RESULTS: Patient ages were 1 week, 3 months, and 7 months. Supine obstructive apnea hypopnea indices (oAHI) were severe for all 3 children, with a mean of 21.9 events/hour (range 16.8 to 26.3). In the prone position, the oAHI significantly improved in 2 of 3 children, with a mean of 5.1 events/hour (range 0.3 to 10.3). The frequency of central apnea events increased in 1 child following supine positioning. Nadir oxygen saturation improved in 2 of 3 children and remained within normal limits in the third. CONCLUSIONS: This is the first report of the effect of positioning on changes in PSG indices of micrognathic children. Improvement in obstructive PSG indices occurred with prone positioning, though OSA persisted in 2 of 3 children. The effect of positioning on central apnea was unclear. In light of these findings, we recommend that routine PSG be considered in micrognathic children undergoing prone positioning for definitive therapy of upper airway obstruction. PMID- 25282305 TI - Computational models to predict endocrine-disrupting chemical binding with androgen or oestrogen receptors. AB - Rapidly and correctly identifying endocrine-disrupting chemicals (EDCs) is an important issue in environmental risk assessment. Major EDCs are associated with the androgen receptor (AR) and oestrogen receptors (ERs). Because of the high cost and time-consuming nature of experimental tests, in silico methods are valuable alternative tools for the identification of EDCs. In this study, a large dataset related to EDCs was constructed. Each molecule was represented with seven fingerprints, and computational models were subsequently developed to predict AR and ER binders via machine learning methods including k-nearest neighbour (kNN), C4.5 decision tree (C4.5 DT), naive Bayes (NB), and support vector machine (SVM) algorithms. The best model for predicting AR binders was PubChem Fingerprint-SVM, which exhibited an accuracy of 0.84. For ER binders, the best method was Extended Fingerprint-SVM with an accuracy of 0.79. Moreover, several representative substructure alerts for characterizing EDCs, such as phenol, trifluoromethyl, and annelated rings, were identified using the combination of information gain and substructure frequency analysis. Our study involved a systematic computational assessment of EDCs related to AR and ERs, and provides significant information on the structural characteristics of these chemicals, which are a great help in identifying EDCs. PMID- 25282306 TI - Driving under the influence among frequent ecstasy consumers in Australia: trends over time and the role of risk perceptions. AB - BACKGROUND: Driving under the influence (DUI) of alcohol and illicit drugs is a serious road safety concern. This research aimed to examine trends in DUI across time and changes in attitudes towards the risks (crash and legal) associated with DUI among regular ecstasy users (REU) interviewed in Australia. METHODS: Participants were regular (at least monthly) ecstasy users surveyed in 2007 (n=573) or 2011 (n=429) who had driven a car in the last six months. Face to face interviews comprised questions about recent engagement of DUI and roadside breath (alcohol) and saliva (drug) testing. Participants also reported the risk of crash and of being apprehended by police if DUI of alcohol, cannabis, ecstasy, and methamphetamine. RESULTS: There were significant reductions in DUI of psychostimulants (ecstasy, methamphetamine, cocaine, LSD) but not alcohol or cannabis between 2007 and 2011. This was accompanied by increased experience of roadside saliva testing and increases in crash and legal risk perceptions for ecstasy and methamphetamine, but not alcohol or cannabis. When the relationship between DUI and risk variables was examined, low crash risk perceptions were associated with DUI of all substances and low legal risk perceptions were associated with DUI of ecstasy. CONCLUSIONS: The observed reduction in DUI of psychostimulants among frequent ecstasy consumers may be related to increased risk awareness stemming from educational campaigns and the introduction of saliva testing on Australian roads. Such countermeasures may be less effective in relation to deterring or changing attitudes towards DUI of cannabis and alcohol among this group. PMID- 25282307 TI - Dynamics in the costs of criminality among opioid dependent individuals. AB - BACKGROUND: Research into the avoided crime-related costs associated with methadone maintenance treatment (MMT) is sparse. Our objective was to characterize the dynamics in crime-related costs associated with MMT effectiveness among opioid dependent individuals in Vancouver, Canada. METHODS: We considered individuals enrolled in a prospective study between December, 2011 and May, 2013. Monthly crime-related costs (2013 CAD) were derived from self reported criminal activity. On the basis of MMT receipt and illicit opioid use, individuals were classified in mutually exclusive health states: (i) MMT high effectiveness; (ii) MMT low effectiveness; (iii) opioid abstinence; or (iv) relapse. We classified individuals as daily, non-daily or non-stimulant users and controlled for demographic and socio-economic characteristics. A two-part multiple regression model was constructed; the first part modeled non-zero cost probability, the second estimated the level of costs. Avoided costs were estimated for each health state and stratified by stimulant use intensity. RESULTS: Our study included 982 individuals (median age 47, 38% female) for 2232 observations. Individuals on MMT with high effectiveness incurred lower monthly costs of criminality (avoided costs of $6298; 95% C.I. ($1578, $11,017)), as did opioid abstinent individuals ($6563 ($1564, $11,561)). Avoided costs for daily stimulant users were greater than for non-daily users, both for individuals on MMT with high effectiveness ($12,975 vs. $4125) and opioid abstinent ($12,640 vs. $4814). CONCLUSION: Using longitudinal data on individuals with a history of MMT, we found substantially lower costs of criminality associated with high effect to MMT. Avoided costs were highest among daily stimulant users that were on MMT with high effectiveness or those opioid abstinent. PMID- 25282309 TI - Opioid attentional bias and cue-elicited craving predict future risk of prescription opioid misuse among chronic pain patients. AB - BACKGROUND: Some chronic pain patients receiving long-term opioid analgesic pharmacotherapy are at risk for misusing opioids. Like other addictive behaviors, risk of opioid misuse may be signaled by an attentional bias (AB) towards drug related cues. The purpose of this study was to examine opioid AB as a potential predictor of opioid misuse among chronic pain patients following behavioral treatment. METHODS: Chronic pain patients taking long-term opioid analgesics (n=47) completed a dot probe task designed to assess opioid AB, as well as self report measures of opioid misuse and pain severity, and then participated in behavioral treatment. Regression analyses examined opioid AB and cue-elicited craving as predictors of opioid misuse at 3-month posttreatment follow-up. RESULTS: Patients who scored high on a measure of opioid misuse risk following treatment exhibited significantly greater opioid AB scores than patients at low risk for opioid misuse. Opioid AB for 200 ms cues and cue-elicited craving significantly predicted opioid misuse risk 20 weeks later, even after controlling for pre-treatment opioid dependence diagnosis, opioid misuse, and pain severity (Model R(2)=.50). CONCLUSION: Biased initial attentional orienting to prescription opioid cues and cue-elicited craving may reliably signal future opioid misuse risk following treatment. These measures may therefore provide potential prognostic indicators of treatment outcome. PMID- 25282310 TI - Branched polymers characterized by comprehensive two-dimensional separations with fully orthogonal mechanisms: molecular-topology fractionation*size-exclusion chromatography. AB - Polymer separations under non-conventional conditions have been explored to obtain a separation of long-chain branched polymers from linear polymers with identical hydrodynamic size. In separation media with flow-through channels of the same order as the size of the analyte molecules in solution, the separation and the elution order of polymers are strongly affected by the flow rate. At low flow rates, the largest polymers are eluted last. At high flow rates, they are eluted first. By tuning the channel size and flow rate, conditions can be found where separation becomes independent of molar mass or size of linear polymers. Long-chain branched polymers did experience lower migration rates under these conditions and can be separated from linear polymers. This type of separation is referred to as molecular-topology fractionation (MTF) at critical conditions. Separation by comprehensive two-dimensional molecular-topology fractionation and size-exclusion chromatography (MTF*SEC) was used to study the retention characteristics of MTF. Branching selectivity was demonstrated for three- and four-arm "star" polystyrenes of 3-5*10(6)g/mol molar mass. Baseline separation could be obtained between linear polymer, Y-shaped molecules, and X-shaped molecules in a single experiment at constant flow rate. For randomly branched polymers, the branching selectivity inevitably results in an envelope of peaks, because it is not possible to fully resolve the huge numbers of different branched and linear polymers of varying molar mass. It was concluded that MTF involves partial deformation of polymer coils in solution. The increased coil density and resistance to deformation can explain the different retention behavior of branched molecules. PMID- 25282308 TI - Factors associated with initiating someone into illicit drug injection. AB - AIMS: Most people who inject drugs (PWID) were first initiated into injection by a current PWID. Few studies have examined PWID who assist others into drug injection. Our goal is to describe the prevalence of and risk factors for initiating someone into injection in the last 12 months. METHODS: We recruited a cross-sectional sample of PWID (N=605) in California from 2011 to 2013. We examined bivariate and multivariate risk factors for initiating someone into injection with a focus on behaviors that might encourage injection initiation such as injecting in front of non-PWID, describing how to inject to non-PWID, and willingness to initiate someone into drug injection. RESULTS: Having initiated someone into injection was reported by 34% of PWID overall and 7% in the last 12 months. Forty-four PWID had assisted 431 people into injection in the past year. Factors independently associated with initiating someone into injection in the last 12 months were self-reported likelihood of initiating someone in the future (Adjusted Odds Ratio [AOR]=7.09; 95% Confidence Interval [CI]=3.40, 14.79), having injected another PWID in past month (AOR=4.05; 95% confidence interval [CI]=1.94, 8.47), having described how to inject to non-injectors (2.61; 95% CI=1.19, 5.71), and non-injection powder cocaine use in past month (AOR=4.97; 95% CI=2.08, 11.84) while controlling for study site. CONCLUSION: Active PWID are important in facilitating the process of drug injection uptake. Interventions to reduce initiation should include efforts to change behaviors and intentions among PWID that are associated with injection uptake among others. PMID- 25282311 TI - Application of one- and two-dimensional high-performance liquid chromatography methodologies for the analysis of C-glycosylflavones from fenugreek seeds. AB - The composition of C-glycosylflavones in fenugreek seeds is complicated and comprises of flavone mono- and di-C-glycosides, derivatives of both apigenin and luteolin as well as their ester forms. In this paper the application of one- and two-dimensional HPLC techniques: off-line heart-cutting and on-line comprehensive for the analysis of flavone C-glycosides in fenugreek seeds is presented. For the identification of flavone C-glycosides two types of detectors: diode array detector and mass detector, coupled to HPLC were used. 18 flavones were separated and identified in the methanol extract from fenugreek seeds. The best separation was achieved in off-line heart-cutting mode. The presence of two new compounds in fenugreek seeds was shown, namely: vicenin-3 and isoschaftoside. Furthermore, five unknown C-glycosides, possibly derivatives of apigenin were revealed. PMID- 25282312 TI - Liquid chromatography-mass spectrometry structural characterization of neo glycoproteins aiding the rational design and synthesis of a novel glycovaccine for protection against tuberculosis. AB - Hereby we describe a pilot study for the rational design and synthesis of a glycoconjugate vaccine against Tuberculosis (TB) by site-specific coupling of well-defined glycans to non-antigenic amino acids in a selected protein carrier. A combination of ESI-MS and LC-MS analytical methods was applied for the systematic characterization of the reactivity of the surface amino acids in the glycosylation reaction with monosaccharides towards 2-iminomethoxyethyl or homobifunctional (4-nitrophenyl ester) linkers, both on the model protein, ribonuclease A (RNase A) and on TB10.4, the simplest antigenic protein isolated from Mycobacterium tuberculosis (MTB). Intact protein analysis was carried out to quantify the glycosylation degree and profile the glycoform composition of all the prepared neo glycoconjugates, while pronase and chymotriptic digests were analyzed to map and rank the reactivity of protein residues. Neo glycopeptides were purified by on-line porous graphitized carbon solid-phase extraction, separated by hydrophilic interaction liquid chromatography and analyzed by electrospray mass spectrometry (ESI-MS(n)). Significantly, different site specificity and glycosylation efficiency were demonstrated for the two linkers, resulting in structurally diverse glycoconjugates. A computational analysis of the amino acids involved in the epitope formation in TB10.4 addressed the choice to 2-iminomethoxyethyl-saccharide activation, that resulted in a more targeted and selective conjugation preserving the protein antigenicity. Additionally, a rational design of experiments lead to the identification of suitable experimental conditions for the preparation of highly pure and homogeneous neo glycoconjugates. PMID- 25282313 TI - Determination of organophosphorus flame retardants in fish by pressurized liquid extraction using aqueous solutions and solid-phase microextraction coupled with gas chromatography-flame photometric detector. AB - A novel method was developed for the determination of organophosphorus flame retardants (PFRs) in fish. The method consists of a combination of pressurized liquid extraction (PLE) using aqueous solutions and solid-phase microextraction (SPME), followed by gas chromatography-flame photometric detector (GC-FPD). The experimental parameters that influenced extraction efficiency were systematically evaluated. The optimal responses were observed by extracting 1g of fish meat with the solution of water:acetonitrile (90:10, v/v) at 150 degrees C for 5min and acid-washed silica gel used as lipid sorbent. The obtained extract was then analyzed by SPME coupled with GC-FPD without any additional clean-up steps. Under the optimal conditions, the proposed procedure showed a wide linear range (0.90 5000ngg(-1)) obtained by analyzing the spiked fish samples with increasing concentrations of PFRs and correlation coefficient (R) ranged from 0.9900 to 0.9992. The detection limits (S/N=3) were in the range of 0.010-0.208ngg(-1) with standard deviations (RSDs) ranging from 2.0% to 9.0%. The intra-day and inter-day variations were less than 9.0% and 7.8%, respectively. The proposed method was successfully applied to the determination of PFRs in real fish samples with recoveries varying from 79.8% to 107.3%. The results demonstrate that the proposed method is highly effective for analyzing PFRs in fish samples. PMID- 25282314 TI - Editorial overview: Molecular and genetic bases of disease: the double life of DNA. AB - This issue of Current Opinions focuses on the dual role of DNA in life and death. In ancient Roman religion and myth, Janus is the god who looks both to the past and to the future. He guides the beginnings of life, its progression from one condition to another, and he foresees distant events. The analogy to DNA could not be stronger. Closely interacting with the environment, our basic genetics provides the origin of life, guides the quality of health with age, predicts disease, and ultimately foresees our end. A shared and deep interest with the origin of life has long prompted our desire to define aging, and, ultimately, to understand whether it can be reversed. In this special issue, the authors collectively review concepts of normative aging, DNA instability, DNA repair, the genetic contribution of age and diet to disease, and how the basic molecular transactions of DNA guide both the transitions to life as well as the transitions to death. PMID- 25282315 TI - Relation between coronary arterial dominance and left ventricular ejection fraction after ST-segment elevation acute myocardial infarction in patients having percutaneous coronary intervention. AB - The presence of a left dominant coronary artery system is associated with worse outcome after ST-segment elevation myocardial infarction (STEMI) compared with right dominance or a balanced coronary artery system. However, the association between coronary arterial dominance and left ventricular (LV) function at follow up after STEMI is unclear. The present study aimed at evaluating the relation between coronary arterial dominance and LV ejection fraction (LVEF) shortly after STEMI and at 12-month follow-up. A total of 741 patients with STEMI (mean age 60 +/- 11 years and 77% men) were evaluated with 2-dimentional echocardiography within 48 hours of admission (baseline) and at 12-month follow-up after STEMI. Coronary arterial dominance was assessed on the angiographic images obtained during primary percutaneous coronary intervention. A right, left, and balanced dominant coronary artery system was noted in 640 (86%), 58 (8%), and 43 (6%) patients, respectively. At baseline, significant difference in LV function was observed, with slightly lower LVEF in patients with a left dominant coronary artery system (LVEF 45 +/- 8% vs 48 +/- 9% and 50 +/- 9%, for left dominant, right dominant, and balanced coronary artery system respectively, p = 0.03). However, at 12-month follow-up no differences in LV function or volumes were observed among the different coronary arterial dominance groups. In conclusion, patients with a left dominant coronary artery system had lower LVEF early after STEMI. At 12-month follow-up, differences in LVEF were no longer present among the different coronary arterial dominance groups. PMID- 25282317 TI - Impact of baseline lipoprotein and C-reactive protein levels on coronary atheroma regression following high-intensity statin therapy. AB - Guidelines now recommend high-intensity statin therapy in all patients with proven atherosclerotic disease. Yet the impact of baseline lipoprotein and C reactive protein (CRP) levels on measures of disease regression to this therapy are unknown. The aim of this study was to test the hypothesis that high-intensity statin therapy causes equivalent degrees of coronary atheroma regression irrespective of baseline lipoprotein and CRP levels. In 8 prospective randomized trials using serial coronary intravascular ultrasound, 1,881 patients who maintained or switched to 18- to 24 months of high-intensity statin therapy (rosuvastatin 40 mg or atorvastatin 80 mg) were stratified according to baseline lipoprotein and CRP levels. Changes in coronary percentage atheroma volume (PAV) and total atheroma volume (TAV) were evaluated. High-intensity statin therapy produced significant reductions from baseline in low-density lipoprotein cholesterol by 38.4%, non-high-density lipoprotein (HDL) cholesterol by 33.6%, triglycerides by 13.1%, and CRP by 33.3%, while increasing HDL cholesterol by 11.7% (p <0.001 for all). This was associated with regression of PAV by 0.7% and of TAV by 8.2 mm(3) (p <0.001 for both). No significant differences of changes in PAV and TAV were observed across baseline quintiles of low-density lipoprotein cholesterol, HDL cholesterol, non-HDL cholesterol, triglycerides, or CRP. Moreover, across all measured lipoproteins and CRP, most patients demonstrated plaque regression (defined as any change from baseline in PAV or TAV <0). In conclusion, high-intensity statin therapy attenuated the natural progression of coronary atherosclerosis in all strata of patients with coronary artery disease irrespective of baseline lipoprotein or CRP levels. These findings provide support for the latest United States guideline recommendations for the broad use of high-intensity statin therapy in all patients with atherosclerosis, regardless of baseline lipid status. PMID- 25282318 TI - Next-generation transcatheter aortic valves. An opportunity to expand therapeutic indications? PMID- 25282316 TI - Coronary artery calcium and risk of atrial fibrillation (from the multi-ethnic study of atherosclerosis). AB - Calcified coronary arteries are associated with the development of cardiovascular disease and stroke. It is currently unknown whether coronary artery calcium (CAC) is associated with an increased risk for atrial fibrillation (AF). The aim of this study was to address this question in 6,641 participants (mean age 62 +/- 10 years, 53% women, 62% nonwhites) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of baseline clinical cardiovascular disease and AF. CAC measurements were assessed by cardiac computed tomography at study baseline. AF was ascertained by review of hospital discharge records and from Medicare claims data until December 31, 2010. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between CAC and AF. During a median follow-up period of 8.5 years, 308 participants (4.6%) developed AF. In a model adjusted for sociodemographics, cardiovascular risk factors, and potential confounders, higher CAC scores were associated with increased risk for AF (CAC = 0: HR 1.0, referent; CAC = 1 to 100: HR 1.4, 95% CI 1.01 to 2.0; CAC = 101 to 300: HR 1.6, 95% CI 1.1 to 2.4; CAC >300: HR 2.1, 95% CI 1.4 to 2.9). The addition of CAC to the Framingham Heart Study and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AF risk scores yielded integrated discrimination improvement of 0.0033 (95% CI 0.0015 to 0.0066) and 0.0028 (95% CI 0.0012 to 0.0057), with relative integrated discrimination improvement of 0.10 (95% CI 0.061 to 0.15) and 0.077 (95% CI 0.040 to 0.11), respectively. In conclusion, CAC is independently associated with increased risk for AF. PMID- 25282319 TI - Utilization of predefined stimulation groups by essential tremor patients treated with VIM-DBS. AB - OBJECTIVE: To identify the utilization and general acceptance of switching between predefined stimulation groups in essential tremor (ET) patients treated with deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus. METHODS: Thirty-eight patients treated with VIM-DBS completed a telephone survey. This was designed to identify the general utilization of patient controllers and the specific usage of stimulation groups. RESULTS: Thirty eight patients were interviewed via phone. More than half (21 of 38 patients, 55%) of all contacted ET patients were aware of the possibility of switching between pre-defined stimulation programs themselves. Again, more than half of these patients (13 of the 21 patients) switch between the different programs on a regular basis (8 monthly, 2 weekly, and 3 daily), mainly due to occurring side effects. Age did not differ between the group of patients switching between stimulation groups, and those who did not (65.38 years (+/-11.36) vs. 69.15 years (+/-9.92), p = 0.297). CONCLUSION: Some patients frequently use different stimulation settings, mainly to be able to control side effects when necessary. All patients - independent of their age - and especially patients with stimulation induced side effects, should therefore be informed about the possibility to switch between predefined stimulation groups. We propose a training for patients by specialized nurses, to give them confidence in handling the patient controllers. PMID- 25282320 TI - Managing Salmonella in equine populations. AB - Infection control is achieved through all efforts used to prevent the introduction and limit the spread of contagious pathogens within a facility or population, with the goal of eliminating sources of potentially pathogenic microorganisms and to disrupt infectious disease transmission. Congregating animals from multiple sources, as occurs at veterinary hospitals, racetracks, equestrian events, and boarding and training facilities, increases the risk for transmission of infectious diseases such as salmonella. There is a recognizable standard of practice for infection control and due effort must be given to control and prevention of infectious disease transmission within animal populations and facilities. PMID- 25282321 TI - Equine influenza virus. AB - For decades the horse has been viewed as an isolated or "dead-end" host for influenza A viruses, with equine influenza virus being considered as relatively stable genetically. Although equine influenza viruses are genetically more stable than those of human lineage, they are by no means in evolutionary stasis. Moreover, recent transmission of equine-lineage influenza viruses to dogs also challenges the horse's status as a dead-end host. This article reviews recent developments in the epidemiology and evolution of equine influenza virus. In addition, the clinical presentation of equine influenza infection, diagnostic techniques, and vaccine recommendations are briefly summarized. PMID- 25282322 TI - Rhodococcus equi foal pneumonia. AB - Pneumonia caused by Rhodococcus equi is an important cause of disease and death in foals. This article reviews current knowledge of the epidemiology, clinical signs, diagnosis, treatment, prevention, and control of R equi pneumonia in foals. PMID- 25282323 TI - Trends in the Mexican infant mortality paradox over the past two decades. AB - PURPOSE: Mexicans in the United States have lower rates of several important population health metrics than non-Hispanic whites, including infant mortality. This mortality advantage is particularly pronounced among infants born to foreign born Mexican mothers. However, the literature to date has been relegated to point in-time studies that preclude a dynamic understanding of ethnic and nativity differences in infant mortality among Mexicans and non-Hispanic whites. METHODS: We assessed secular trends in the relation between Mexican ethnicity, maternal nativity, and infant mortality between 1989 and 2006 using a linked birth-death data set from one US state. RESULTS: Congruent to previous research, we found a significant mortality advantage among infants of Mexican relative to non-Hispanic white mothers between 1989 and 1991 after adjustment for baseline demographic differences (relative risk = 0.78, 95% confidence interval, 0.62-0.98). However, because of an upward trend in infant mortality among infants of Mexican mothers, the risk of infant mortality was not significantly different from non-Hispanic white mothers in later periods. CONCLUSIONS: Our findings suggest that the "Mexican paradox" with respect to infant mortality is resolving. Changing sociocultural norms among Mexican mothers and changes in immigrant selection and immigration processes may explain these observations, suggesting directions for future research. PMID- 25282324 TI - Variability in date of prostate cancer diagnosis: a comparison of cancer registry, pathology report, and electronic health data sources. AB - PURPOSE: The date of cancer diagnosis is a critical data element for clinical care and research. Because this date can be abstracted from various data sources, its comparability from source to source is unclear. This study compared the date of diagnosis from multiple sources within the same population of prostate cancer patients. METHODS: We linked cancer registry, pathology report, and electronic health data sources from the Kaiser Permanente Southern California health data systems for a cohort of 22,666 members diagnosed with prostate cancer between 2000 and 2010. The magnitude and direction of the differences in date of diagnosis were assessed for each date pairwise comparison. We reviewed 454 medical records to determine reasons for date discrepancies. RESULTS: Among the date pairwise comparisons, differences in date of diagnosis spanned from 9.6 years earlier to 10 years later than each other. However, the overall median difference ranged from 1 to 16 days, thus suggesting that the vast majority of the date differences were small. Chart review results identified major categories of date discrepancies. CONCLUSIONS: These data demonstrate variability in date of diagnosis across these data sources. This variability may have implications for epidemiologic estimates or patient identification in research studies using different data sources. PMID- 25282325 TI - Statement on surgical pre-residency preparatory courses. PMID- 25282326 TI - Breast cancer screening programmes: challenging the coexistence with opportunistic mammography. AB - OBJECTIVE: This study investigated predictive factors of women's participation in organized mammography screening (OrgMS) and/or opportunistic mammography screening (OppMS) when the two screening modes coexist. METHODS: Questionnaires were sent to 6,000 women aged 51-74 years old invited to attend an OrgMS session between 2010 and 2011 in France. Data collected concerned the women's healthcare behaviour and their socioeconomic characteristics. Women without a personal or family history of breast cancer that could explain their participation in OppMS were retained in the generalized logits analysis. RESULTS: The data of 1,202 women were analysed. Of these, 555 (46.2%) had attended OrgMS only, 105 (8.7%) OppMS only and 542 (45.1%) had performed both OrgMS and OppMS. Multivariable analyses showed that women who had regular gynaecological check-ups were more likely to perform OppMS only or both OrgMS and OppMS, OR 95% CI were 2.1 [1.1 3.9], 1.9 [1.4-2.6], respectively. Being employed also increased participation in OppMS only [OR: 2.1 (1.2-3.7)] or both OrgMS and OppMS [OR: 1.5 (1.1-2.05)]. CONCLUSION AND PRACTICE IMPLICATIONS: In countries where OrgMS and OppMS coexist, strategies involving gynaecologists, referring doctors or company doctors and the organization of healthcare services to promote adequate screening round may help to reduce the overuse of mammography. PMID- 25282328 TI - Prolonged training does not result in a greater extent of interlimb transfer following visuomotor adaptation. AB - Learning a visumotor adaptation task with one arm typically facilitates subsequent performance with the other. The extent of transfer across the arms, however, is generally much smaller than that across different conditions within the same arm. This may be attributed to a possibility that intralimb transfer involves both algorithmic and instance-reliant learning, whereas interlimb transfer only involves algorithmic learning. Here, we investigated whether prolonged training with one arm could facilitate subsequent performance with the other arm to a greater extent, by examining the effect of varying lengths of practice trials on the extent of interlimb transfer. We had 18 subjects adapt to a 30 degrees visuomotor rotation with the left arm first (training), then with the right arm (transfer). During the training session, the subjects reached toward multiple targets for 160, 320 or 400 trials; during the transfer session, all subjects performed the same task for 160 trials. Our results revealed substantial initial transfer from the left to the right arm in all three conditions. However, neither the amount of initial transfer nor the rate of adaptation during the transfer session was significantly different across the conditions, indicating that the extent of transfer was similar regardless of the length of initial training. Our findings suggest that interlimb transfer of visuomotor adaptation may only occur through algorithmic learning, which is effector independent, and that prolonged training may only have beneficial effects when instance-reliant learning, which is effector dependent, is also involved in the learning process. PMID- 25282327 TI - Family involvement is helpful and harmful to patients' self-care and glycemic control. AB - OBJECTIVE: We assessed the relationships between supportive and obstructive family behaviors and patients' diabetes self-care activities and HbA1C, and potential interaction effects and differences by demographic characteristics. METHODS: In a cross-sectional study, 192 adults with type 2 diabetes completed the Diabetes Family Behavior Checklist-II, the Summary of Diabetes Self-Care Activities, and a glycemic control (HbA1C) test. RESULTS: Participants reported similar rates of supportive and obstructive behaviors that were positively correlated (rho=0.61, p<0.001). In adjusted analyses, supportive family behaviors were associated with adherence to different self-care behaviors (beta=0.20 to 0.50, p<0.05), whereas obstructive family behaviors were associated with less adherence to self-care behaviors (beta=-0.28 to -0.39, p<0.01) and worse HbA1C (beta=0.18, p<0.05). Supportive behaviors protected against the detrimental effect of obstructive behaviors on HbA1C (interaction beta=-0.22, p<0.001). Non Whites reported more supportive and obstructive behaviors than Whites, but race did not affect the relationships between family behaviors and self-care or HbA1C. CONCLUSION: Involving family members in patients' diabetes management may impede patients' self-care and compromise their glycemic control unless family members are taught to avoid obstructive behaviors. PRACTICE IMPLICATIONS: Our findings endorse interventions that help family members develop actionable plans to support patients' self-care and train them to communicate productively about diabetes management. PMID- 25282329 TI - The correlation between emotional intelligence and gray matter volume in university students. AB - A number of recent studies have investigated the neurological substrates of emotional intelligence (EI), but none of them have considered the neural correlates of EI that are measured using the Schutte Self-Report Emotional Intelligence Scale (SSREIS). This scale was developed based on the EI model of Salovey and Mayer (1990). In the present study, SSREIS was adopted to estimate EI. Meanwhile, magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to evaluate the gray matter volume (GMV) of 328 university students. Results found positive correlations between Monitor of Emotions and VBM measurements in the insula and orbitofrontal cortex. In addition, Utilization of Emotions was positively correlated with the GMV in the parahippocampal gyrus, but was negatively correlated with the VBM measurements in the fusiform gyrus and middle temporal gyrus. Furthermore, Social Ability had volume correlates in the vermis. These findings indicate that the neural correlates of the EI model, which primarily focuses on the abilities of individuals to appraise and express emotions, can also regulate and utilize emotions to solve problems. PMID- 25282330 TI - Percutaneous valvulation of failing Fontan: rationale, acute effects and follow up. AB - BACKGROUND: Fontan circulation is fragile and unfavourable evolution is frequent. Fontan physiology largely depends on respiration and gravity. The hypothesis for valvulation is that valvulation of the circuit reduces the effects of respiration and the proclive position, and increases anterograde flow towards the systemic circulation, with increasing exercise capacity and benefits for enteropathy. Because it originates from the bovine jugular vein, the Melody((r)) valve (Medtronic, Minneapolis, MN, USA) is naturally designed to work in a low-pressure environment. AIMS: To report our experience of percutaneous valvulation of refractory failing Fontan circulation. METHODS: We reviewed all patients who received a Melody valve in Fontan circulation in our unit. RESULTS: Four patients were included: two had severe and refractory protein-losing enteropathy; one had severe oedema and ascites; and one had very severe lower limb venous insufficiency. The Melody valve was successfully implanted in all patients. Central venous pressure and inferior vena cava pressure did not change after valvulation. There were no early complications. At follow-up, no acute or mid term thrombosis was noted. Two patients had intracardiac echocardiography 6 and 24 months after valvulation: the Melody valve was found not to be functioning in both cases. One patient died 3 months after valvulation; the cause was unrelated to the procedure. CONCLUSION: Percutaneous valvulation of Fontan circulation is technically feasible. More clinical studies are needed before considering this treatment as an option. PMID- 25282331 TI - Transcatheter tricuspid valve implantation: a multicentre French study. AB - BACKGROUND: Transcatheter valve-in-valve (VIV) implantation in failing bioprosthesis is an emerging field in cardiology. AIM: To report on a French multicentre experience and a literature review of tricuspid VIV implantation. METHODS: We approached different institutions and collected 10 unpublished cases; a literature review identified 71 patients, including our 10 cases. Clinical aspects and haemodynamic data are discussed. RESULTS: Among our 10 unpublished cases, the reason for implantation was significant tricuspid stenosis (n = 4), significant tricuspid regurgitation (n = 1) or mixed lesion (n = 5). Implantation was performed under general anaesthesia at mean age 28 +/- 17 years. The 22 mm Melody valve was implanted in seven patients; the Edwards SAPIEN valve was implanted in three patients. The procedure succeeded in all cases, despite two embolizations in the right cardiac chambers; in both cases, the valve was stabilized close to the tricuspid annulus using a self-expandable stent, before implantation of a second Edwards SAPIEN valve. Functional class improved in all but one case. Mean diastolic gradient decreased from 9 +/- 2.45 mmHg to 3.65 +/- 0.7 mmHg (p = 0.007); no more than trivial regurgitation was noticed. Among the published cases, the Melody valve was implanted in 41 patients, the Edwards SAPIEN valve in 29 patients and the Braile valve in one patient. Short-term results were similar for our 10 cases, but mid-term results are not yet available. CONCLUSIONS: Tricuspid VIV implantation using the Melody or Edwards SAPIEN valves is a feasible and effective procedure for selected patients with failing bioprosthesis. PMID- 25282332 TI - Cardiac biomarkers in patients suspected of acute myocardial infarction: where do we stand and where do we go? PMID- 25282333 TI - Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4. AB - Acute leukemias caused by translocations of the MLL gene at chromosome 11 band q23 (11q23) are characterized by a unique gene expression profile. More recently, data from several laboratories indicate that the most commonly encountered MLL fusion proteins, MLLT1, MLLT3, and AFF1 are found within a molecular complex that facilitates the elongation phase of mRNA transcription. Mutational analyses suggest that interaction between the MLLT1/3 proteins and AFF family proteins are required for experimental transformation of hematopoietic progenitor cells (HPCs). Here, we define a specific pairing of two amino acids that creates a salt bridge between MLLT1/3 and AFF proteins that is critically important for MLL mediated transformation of HPCs. Our findings, coupled with the newly defined structure of MLLT3 in complex with AFF1, should facilitate the development of small molecules that block this amino acid interaction and interfere with the activity of the most common MLL oncoproteins. PMID- 25282335 TI - Neutralizing IL-17 protects the optic nerve from autoimmune pathology and prevents retinal nerve fiber layer atrophy during experimental autoimmune encephalomyelitis. AB - Optic neuritis is a common inflammatory manifestation of multiple sclerosis (MS). In experimental autoimmune encephalomyelitis (EAE), the optic nerve is affected as well. Here, we investigated whether autoimmune inflammation in the optic nerve is distinct from inflammation in other parts of the central nervous system (CNS). In our study, inflammatory infiltrates in the optic nerve and the brain were characterized by a high fraction of Ly6G(+) granulocytes whereas in the spinal cord, macrophage infiltrates were predominant. At the peak of disease, IL-17 mRNA abundance was highest in the optic nerve as compared with other parts of the CNS. The ratio of IL-17 vs IFN-gamma producing CD4(+) T cells was higher in the optic nerve and brain than in the spinal cord and more effector CD4(+) T cells were committed to the Th17 transcriptional program in the optic nerve than in the spinal cord. IL-17 producing gammadelta T cells but rather not Ly6G(+) granulocytes themselves contributed to IL-17 production. Optical coherence tomography (OCT) studies on murine eyes revealed a decline in thickness of the retinal nerve fiber layer (RNFL) and the common layer of ganglion cells and inner plexiform layer (GCL+) after the recovery from motor symptoms indicating that autoimmune inflammation induced a significant atrophy of optic nerve fibers during EAE. Neutralization of IL-17 by treatment with anti-IL-17 antibodies reduced but did not abrogate motor symptoms of EAE. However, RNFL and GCL+ atrophy were completely prevented by blocking IL-17. Thus, the optic nerve compartment is particularly prone to support IL-17 mediated inflammatory responses during CNS autoimmunity and structural integrity of the retina can be preserved by neutralizing IL-17. PMID- 25282334 TI - Multiple mechanisms contribute to the synergistic anti-myeloma activity of the pan-histone deacetylase inhibitor LBH589 and the rapalog RAD001. AB - We examined the pre-clinical activity of pan-histone deacetylase inhibitor LBH589 in combination with mTORC1 inhibitor RAD001 and observed that the drug combination strongly synergized in inducing cytotoxicity in multiple myeloma (MM) cells. LBH589 caused an increase in acetylated histones and RAD001 inhibited mTORC1 activity. RAD001 caused potent G0/G1 arrest while LBH589 induced pronounced apoptosis, both of which were enhanced when the drugs were used in combination. LBH589/RAD001 combination led to down regulation of pStat3, cyclins, CDKs and XIAP and up regulation of pro-apoptotic Bcl-2 family proteins. A clinical trial is underway using LBH589/RAD001 combination in relapsed MM patients. PMID- 25282336 TI - Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer's disease. AB - Hippocampus-related topographic amnesia is the most common symptom of memory disorders in Alzheimer's disease (AD) patients. Recent studies have revealed that experience-mediated DNA methylation, which is regulated by enzymes with DNA methyltransferase (DNMT) activity, is required for the formation of recent memory as well as the maintenance of remote memory. Notably, overexpression of DNMT3a in the hippocampus can reverse spatial memory deficits in aged mice. However, a decline in global DNA methylation was found in the autopsied hippocampi of patients with AD. Exactly, what endogenous factors that affect DNA methylation still remain to be elucidated. Here, we report a marked increase in endogenous formaldehyde levels is associated with a decline in global DNA methylation in the autopsied hippocampus from AD patients. In vitro and in vivo results show that formaldehyde in excess of normal physiological levels reduced global DNA methylation by interfering DNMTs. Interestingly, intrahippocampal injection of excess formaldehyde before spatial learning in healthy adult rats can mimic the learning difficulty of early stage of AD. Moreover, injection of excess formaldehyde after spatial learning can mimic the loss of remote spatial memory observed in late stage of AD. These findings suggest that aging-associated formaldehyde contributes to topographic amnesia in AD patients. PMID- 25282338 TI - Factors associated with cognitive achievement in late childhood and adolescence: the Young Lives cohort study of children in Ethiopia, India, Peru, and Vietnam. AB - BACKGROUND: There is a well-established link between various measures of socioeconomic status and the schooling achievement and cognition of children. However, less is known about how cognitive development is impacted by childhood improvements in growth, a common indicator of child nutritional status. This study examines the relationship between socioeconomic status and child growth and changes in cognitive achievement scores in adolescents from resource-poor settings. METHODS: Using an observational cohort of more than 3000 children from four low- and middle-income countries, this study examines the association between cognitive achievement scores and household economic, educational, and nutritional resources to give a more accurate assessment of the influence of families on cognitive development. A composite measure of cognition when children were approximately 8, 12, and 15 years of age was constructed. Household factors included maternal schooling, wealth, and children's growth. RESULTS: A positive and statistically significant relationship between household factors and child cognition was found for each country. If parents have more schooling, household wealth increases, or child growth improves, then children's cognitive scores improve over time. Results for control variables are less consistent. CONCLUSION: Our findings suggest there is a consistent and strong association between parental schooling, wealth, and child growth with child cognitive achievement. Further, these findings demonstrate that a household's ability to provide adequate nutrition is as important as economic and education resources even into late childhood and adolescence. Hence, efforts to improve household resources, both early in a child's life and into adolescence, and to continue to promote child growth beyond the first few years of life have the potential to help children over the life course by improving cognition. PMID- 25282337 TI - Deficits in audiovisual speech perception in normal aging emerge at the level of whole-word recognition. AB - Over the next 2 decades, a dramatic shift in the demographics of society will take place, with a rapid growth in the population of older adults. One of the most common complaints with healthy aging is a decreased ability to successfully perceive speech, particularly in noisy environments. In such noisy environments, the presence of visual speech cues (i.e., lip movements) provide striking benefits for speech perception and comprehension, but previous research suggests that older adults gain less from such audiovisual integration than their younger peers. To determine at what processing level these behavioral differences arise in healthy-aging populations, we administered a speech-in-noise task to younger and older adults. We compared the perceptual benefits of having speech information available in both the auditory and visual modalities and examined both phoneme and whole-word recognition across varying levels of signal-to-noise ratio. For whole-word recognition, older adults relative to younger adults showed greater multisensory gains at intermediate SNRs but reduced benefit at low SNRs. By contrast, at the phoneme level both younger and older adults showed approximately equivalent increases in multisensory gain as signal-to-noise ratio decreased. Collectively, the results provide important insights into both the similarities and differences in how older and younger adults integrate auditory and visual speech cues in noisy environments and help explain some of the conflicting findings in previous studies of multisensory speech perception in healthy aging. These novel findings suggest that audiovisual processing is intact at more elementary levels of speech perception in healthy-aging populations and that deficits begin to emerge only at the more complex word-recognition level of speech signals. PMID- 25282339 TI - Inflammasome activation in response to dead cells and their metabolites. AB - Cell death cannot go unnoticed. It demands that the surrounding cells clear away the corpses in a manner appropriate to the type of cell death. Dying cells represent a threat to the body that should be eliminated by the host immune response. Inflammasome activation followed by IL-1alpha release and IL-1beta maturation is crucial for tackling pathological conditions, including infections, whereas inflammasome activation precedes inflammatory pyroptotic cell death. On the other hand, recent studies have shown that the inflammasome plays an important role in the pathogenesis of metabolic diseases, including obesity, diabetes, and atherosclerosis. Here, we review current knowledge of the association between cell death, excess metabolites, and inflammasome activation as it relates to chronic inflammatory diseases. PMID- 25282341 TI - The kinetics of cystatin C removal by hemodialysis. PMID- 25282340 TI - Risk factors for reported obstetric complications and near misses in rural northwest Bangladesh: analysis from a prospective cohort study. AB - BACKGROUND: In rural Bangladesh, more than 75% of all births occur at home in the absence of skilled birth attendants. Population-based data are lacking on the burden and risk factors for obstetric complications in settings with low rates of institutional delivery. We sought to describe the prevalence of reported complications and to analyze risk factors for obstetric complications and near misses, using data from a representative, rural setting of Bangladesh. METHODS: This study utilized existing data on 42,214 pregnant women enrolled in a micronutrient supplementation cohort trial between 2007 and 2011 in rural northwest Bangladesh. Based on self-report of complications, women were categorized as having obstetric complications, near misses, or non-complicated pregnancies using definitions modified from the World Health Organization. Multivariable multinomial regression was used to analyze the association of biological, socioeconomic, and psychosocial variables with obstetric complications or near misses. RESULTS: Of enrolled women, 25% (n = 10,380) were classified as having at least one obstetric complication, 2% (n = 1,004) with reported near misses, and 73% (n = 30,830) with non-complicated pregnancies. Twelve percent (n = 5,232) reported hemorrhage and 8% (n = 3,259) reported sepsis. Of the 27,241 women with live births or stillbirths, 11% (n = 2,950) reported obstructed labor and 1% (n = 328) reported eclampsia. Biological risk factors including women's age less than 18 years (Relative Risk Ratio [RRR] 1.26 95%CI:1.14-1.39) and greater than 35 years (RRR 1.23 95%CI:1.09-1.38), history of stillbirth or miscarriage (RRR 1.15 95%CI:1.07-1.22), and nulliparity (RRR 1.16 95%CI:1.02-1.29) significantly increased the risk of obstetric complications. Neither partner wanting the pregnancy increased the risk of obstetric complications (RRR 1.33 95%CI:1.20-1.46). Mid-upper arm circumference <21.5 cm increased the risk of hemorrhage and sepsis. CONCLUSIONS: These analyses indicate a high burden of obstetric morbidity. Maternal age, nulliparity, a history of miscarriage or stillbirth, and lack of pregnancy wantedness were associated with increased risk of obstetric complications. Policies to address early marriage, unmet need for contraception, and maternal undernutrition may help mitigate this morbidity burden in rural Bangladesh. PMID- 25282342 TI - The relationship between emotional intelligence, previous caring experience and mindfulness in student nurses and midwives: a cross sectional analysis. AB - BACKGROUND: Emotional Intelligence (EI), previous caring experience and mindfulness training may have a positive impact on nurse education. More evidence is needed to support the use of these variables in nurse recruitment and retention. OBJECTIVE: To explore the relationship between EI, gender, age, programme of study, previous caring experience and mindfulness training. DESIGN: Cross sectional element of longitudinal study. SETTING AND PARTICIPANTS: 938year one nursing, midwifery and computing students at two Scottish Higher Education Institutes (HEIs) who entered their programme in September 2013. DATA: Participants completed a measure of 'trait' EI: Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF); and 'ability' EI: Schutte's et al. (1998) Emotional Intelligence Scale (SEIS). Demographics, previous caring experience and previous training in mindfulness were recorded. METHODS: Relationships between variables were tested using non-parametric tests. RESULTS: Emotional intelligence increased with age on both measures of EI [TEIQ-SF H(5)=15.157 p=0.001; SEIS H(5)=11.388, p=0.044]. Females (n=786) scored higher than males (n=149) on both measures [TEIQ-SF, U=44,931, z=-4.509, p<.001; SEIS, U=44,744, z=-5.563, p<.001]. Nursing students scored higher that computing students [TEIQ-SF H(5)=46,496, p<.001; SEIS H(5)=33.309, p<0.001. There were no statistically significant differences in TEIQ-SF scores between those who had previous mindfulness training (n=50) and those who had not (n=857) [U=22,980, z=0.864, p = 0.388]. However, median SEIS was statistically significantly different according to mindfulness training [U=25,115.5, z=2.05, p=.039]. Neither measure demonstrated statistically significantly differences between those with (n=492) and without (n=479) previous caring experience, [TEIQ-SF, U=112, 102, z=0.938, p=.348; SEIS, U=115,194.5, z=1.863, p=0.063]. CONCLUSIONS: Previous caring experience was not associated with higher emotional intelligence. Mindfulness training was associated with higher 'ability' emotional intelligence. Implications for recruitment, retention and further research are explored. PMID- 25282343 TI - Novel intein-containing DNA specific primers for rapid identification of Candida glabrata using Real-Time PCR assays. AB - Candida glabrata is an opportunistic human pathogen known to cause systemic and vaginal candidiasis. Rapid detection of Candida glabrata is indispensable for appropriate selection of antifungal drugs for chemotherapy. The study describes a unique intein-containing DNA fragment for specific detection of C. glabrata. The designed oligonucleotides detected C. glabrata (Ct mean: 24.75 +/- 1.1 and Tm: 70.08 +/- 0.23 degrees C) in Real-Time PCR assays. The fluorescent signals were negative when the primers were tested for cross-species and cross-genera amplifications. In conclusion, our study recommends a novel primer set for developing a quick identification system which does not require laborious and time-consuming experimentations. PMID- 25282344 TI - Functional genomics of acclimation and adaptation in response to thermal stress in Daphnia. AB - BACKGROUND: Gene expression regulation is one of the fundamental mechanisms of phenotypic plasticity and is expected to respond to selection in conditions favoring phenotypic response. The observation that many organisms increase their stress tolerance after acclimation to moderate levels of stress is an example of plasticity which has been long hypothesized to be based on adaptive changes in gene expression. We report genome-wide patterns of gene expression in two heat tolerant and two heat-sensitive parthenogenetic clones of the zooplankton crustacean Daphnia pulex exposed for three generations to either optimal (18 degrees C) or substressful (28 degrees C) temperature. RESULTS: A large number of genes responded to temperature and many demonstrated a significant genotype-by environment (GxE) interaction. Among genes with a significant GxE there were approximately equally frequent instances of canalization, i.e. stronger plasticity in heat-sensitive than in heat-tolerant clones, and of enhancement of plasticity along the evolutionary vector toward heat tolerance. The strongest response observed is the across-the-board down-regulation of a variety of genes occurring in heat-tolerant, but not in heat-sensitive clones. This response is particularly obvious among genes involved in core metabolic pathways and those responsible for transcription, translation and DNA repair. CONCLUSIONS: The observed down-regulation of metabolism, consistent with previous findings in yeast and Drosophila, may reflect a general compensatory stress response. The associated down-regulation of DNA repair pathways potentially creates a trade-off between short-term benefits of survival at high temperature and long-term costs of accelerated mutation accumulation. PMID- 25282346 TI - ["Reversing" the teaching of medicine, yesterday and today]. AB - Recently the radical critique has been revived of medicine teaching developed some fifty years ago by G.A. Maccacaro with special focus on Italy. He maintained that a dominating biological perspective obscured all social dimensions of health and disease, educating doctors poorly equipped to grasp the practical relevance of social determinants of diseases and to correctly perceive their own role in society. In fifty years, many aspects of the practice of medicine have however changed: how such changes relate to the current teaching of medicine? Three key developments have taken place. First, separate specialties and subspecialties have multiplied at fast pace, and teaching has usually favoured this increasing fragmentation. Second, in actual practice doctors need to overcome disciplinary segmentation and collaborate, often to a substantial extent: little trace of how best to implement this is present in academic teaching. Third evidence-based medicine and guidelines for preventive, diagnostic and therapeutic interventions have become common currency in medicine: teaching of these topics is, notably in Italy, in general weak, leaving future doctors unprepared to a critical understanding and use of evidence-based medicine and guidelines in the daily practice. Substantial changes in medical teaching appear needed today no less than fifty years ago, but they can only start from a recognition of medicine as it stands today rather than fifty years ago. PMID- 25282345 TI - Early intervention program reduces stress in parents of preterms during childhood, a randomized controlled trial. AB - BACKGROUND: It is well documented that heightened levels of parenting stress have a negative influence on children's socio-emotional and behavioral development. Parenting stress may therefore be regarded as an outcome variable in its own right. This study investigated whether a sensitizing intervention influences stress reported by parents of prematurely born children until the children were age nine. METHODS: Preterm infants (N = 146, birth weight <2,000 g) were randomized to intervention (N = 72) with the Mother-Infant Transaction Program (MITP) or a preterm control group (N = 74) that received standard hospital care. A term reference group comprised 75 healthy, full-term neonates. Parents reported on the Parenting Stress Index (PSI) when the children were 6 months, 1, 2, 3, 5, 7 years old and on the PSI-Short Form (PSI-SF) at age 9. Main outcomes were the mother's and father's reports of total, child and parent-related stress. Cross sectional and longitudinal analyses were performed using linear mixed models (LMM), taking dependency in the data caused by twin pairs and repeated measures into account. Response rates were high across all follow-ups, and still reached 85% from mothers and 72% from fathers at 9 years. RESULTS: Mothers in the intervention group reported better longitudinal development of child-related stress than mothers of preterm controls, as they perceived their children as being more adaptable and less moody throughout childhood until the age of seven. Less stress in the intervention group was revealed by cross-sectional analysis of maternal reports at all ages, while fathers reported similar differences at ages three and five. Parents in the intervention group reported stronger agreement on several stress scores on several occasions. Fathers with high interventional participation (mean 54%) reported significantly less stress at age nine than those who participated less. Both parents in the intervention group reported levels of stress similar to those experienced by the term reference group at all follow-ups, while differences between the preterm control and term reference groups increased. CONCLUSIONS: This early intervention reduces stress among parents of prematurely born children to a level reported by parents of term-born children and enhances agreement between parents. TRIAL REGISTRATION: Clinical Trials Gov identifier NCT00222456, 05.09.2005. PMID- 25282347 TI - [Donatori di Musica: when oncology meets music]. AB - Donatori di Musica is a network of musicians - both physicians and volunteers - that was initially founded in 2009 with the aim to set up and coordinate classical music concerts in hospitals. This activity was initially started and led by the Oncology Departments at Carrara and Bolzano Hospitals, where high profile professional musicians make themselves available for concerts in support of Oncological in/out-patients of that specific Hospital. A live classical music performance is a deeply touching experience - particularly for those who live a critical condition like cancer. Main characteristics of Donatori di Musica concerts are: continuity (concerts are part of a regular and non-stopping music season); quality (concerts are held by well-established professional musicians); philanthropic attitude (musicians do not wear a suit and usually chat with patients; they also select an easy-to-listen program; a convivial event is usually organized after the performance with the aim of overcoming distinctions and barriers between physician and patient); no profit: musicians perform for free - travel expenses and/or overnight staying only can be claimed; concerts have free access for patients, their families and hospital staff.Patients and musicians therefore do get in close contact and music is able to merge each other experiences - with patients being treated by the beauty of music and musicians being treated theirselves by patients daily-life feedback. The Donatori di Musica experience is therefore able to help Medicine to retrieve its very first significance - the medical act regain that human and cultural dimension that seems to be abandoned in the last decades in favour of a mere technicism. This is the spirit and the deep significance of Donatori di Musica - "[...] the hope that Music can become a key support to medical treatments in every Oncology department" (by Gian Andrea Lodovici). PMID- 25282348 TI - [Evidence-based medicine: a new paradigm for medicine and a brand for the megastore of medicinal literature]. AB - The current debate about the state of evidence based medicine (EBM) led to hypothesize a "crisis", claiming the need for a "renaissance" of the EBM movement. During the last two decades, EBM contributed to make medical practice more scientific, as clinical epidemiology became a science basic for clinical medicine. The traditional hierarchical structure of medicine was thwarted, and endorsing clinical decisions with the best available evidence became a moral obligation. However, although the benefits from the widespread diffusion of EBM are well known and sometimes overemphasized, the negative consequences of a mechanistic and dogmatic application of EBM cannot be ignored. For example, the need of combining scientific evidence with clinical expertise was claimed, but what's expertise not defined. Diagnostic studies are underdeveloped as compared with intervention trials. Furthermore, outcomes are mainly confined to simple accuracy measurements, and hypotheses generation, the first crucial phase of the diagnostic pathway frequently omitted. These limitations may have reduced the potential of EBM, contributing to its criticisms. PMID- 25282349 TI - [Diabetes, psychosocial distress and quality of care]. AB - Diabetes is on the rise world wide; according to the latest report from the International Diabetes Federation, the number of people affected by the disease will increase by 55% from 382 in 2013 to almost 600 million in 2033. Individuals living with type 1 or type 2 diabetes are at increased risk for depression and anxiety. Diabetes impacts on physical, emotional, social and financial aspects of life across cultures and countries, yet gaps in care exist around psychosocial and self-management education and support. The DAWN2 study provides a first multinational, multidisciplinary systematic framework for the comparison of unmet needs of people with diabetes and those who care for them in four continents. it is necessary to develop a system of patient-centered care, in which the empowerment of the person is the main instrument, and at the same time target on which to focus. Transforming study results into actions at the national level will represent one of the main activities of the DAWN2 initiative. In Italy, to do so, it is not enough write new documents but new resources are required. PMID- 25282351 TI - [QT Variability Index as a tool for risk stratification of sudden cardiac death]. AB - Sudden cardiac death is the leading cause of mortality in patients with chronic heart failure (CHF) and history of myocardial infarction. Selection of patients at risk of sudden cardiac death is dramatically important to choose the correct therapeutic approach. The QT Variability Index (QTVI) is a non-invasive measure of repolarization lability that has been applied to a wide variety of subjects with cardiovascular disease. It is a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of the autonomic nervous system tone. As opposed to T wave alternans, QTVI assesses variance in repolarization at all frequencies. Recent studies suggest that QTVI may help clinicians choosing the appropriate implantable cardiovester defibrillator timing implantation, in patients with dilated or hypertrophic cardiomyopathy or CHF because of its efficacy in patient evaluation and follow up. PMID- 25282352 TI - [Coping with the clinical complexity of adolescents with cancer: an ad hoc Italian scientific society is born (SIAMO)]. AB - Adolescents with cancer are a unique group, with special characteristics. Patients in this age group seem to inhabit a "no man's land", neither belonging to the pediatric nor to the adult worlds of oncology. Their optimal management (e.g. coping with their complex psychological and social needs, providing age appropriate facilities, their access to referral cancer centers and the inclusion in clinical trials) remains a challenge that requires broad-based processes. In 2014 SIAMO, an Italian national comprehensive project dedicated to adolescents with cancer, has been founded, with the main aim of bridging the gap of the inadequate access to optimal cancer services and the lack of improvement in survival rates observed for patients in this age group. PMID- 25282350 TI - [Surveillance of severe cutaneous drug reactions: experience REACT-Lombardia]. AB - Adverse drug reactions affecting the skin have particular relevance as they may cause significant mortality and a possible modification of the benefit/risk profile of the concerned drug. The following entities are of special importance: Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and drug rash with eosinophilia and systemic symptoms (DRESS). On the above mentioned reactions we focused our surveillance programme in the Lombardy region, the REACT-Lombardia project. The REACT registry involved 22 hospital-based dermatological centres, collecting, from April 2009 up to March 2014, a total of 72 cases of SJS-TEN, 17 cases of AGEP and 9 cases of DRESS. Allopurinol was the drug associated with the largest number of cases of SJS/TEN (21 cases) followed by paracetamol (8 cases), levofloxacine (6 cases) and carbamazepine (4 cases). The risk for specific drug exposures was estimated by employing drug utilization data expressed as Defined Daily Doses (DDD). Mortality rate from SJS-TEN was 21%. Together with the registry, a "hub and spoke" clinical network for the management of severe cutaneous reactions was established with the Burn Unit of Niguarda Ca' Granda Hospital as the reference center for the most critical patients. PMID- 25282353 TI - [Cinema and medicine]. PMID- 25282354 TI - [Medicine and literature: an anthology]. PMID- 25282356 TI - Validity of an algorithm for determining sleep/wake states using a new actigraph. AB - BACKGROUND: This study aimed to develop an algorithm for determining sleep/wake states by using chronological data on the amount of physical activity (activity intensity) measured with the FS-750 actigraph, a device that can be worn at the waist, allows for its data to be downloaded at home, and is suitable for use in both sleep research and remote sleep medicine. METHODS: Participants were 34 healthy young adults randomly assigned to two groups, A (n =17) and B (n =17), who underwent an 8-hour polysomnography (PSG) in the laboratory environment. Simultaneous activity data were obtained using the FS-750 attached at the front waist. Sleep/wake state and activity intensity were calculated every 2 minutes (1 epoch). To determine the central epoch of the sleep/wake states (x), a five variable linear model was developed using the activity intensity of Group A for five epochs (x-2, x-1, x, x+1, x+2; 10 minutes). The optimal coefficients were calculated using discriminant analysis. The agreement rate of the developed algorithm was then retested with Group B, and its validity was examined. RESULTS: The overall agreement rates for group A and group B calculated using the sleep/wake score algorithm developed were 84.7% and 85.4%, respectively. Mean sensitivity (agreement rate for sleep state) was 88.3% and 90.0% and mean specificity (agreement rate for wakeful state) was 66.0% and 64.9%, respectively. These results confirmed comparable agreement rates between the two groups. Furthermore, when applying an estimation rule developed for the sleep parameters measured by the FS-750, no differences were found in the average values between the calculated scores and PSG results, and we also observed a correlation between the two sets of results. Thus, the validity of these evaluation indices based on measurements from the FS-750 is confirmed. CONCLUSIONS: The developed algorithm could determine sleep/wake states from activity intensity data obtained with the FS-750 with sensitivity and specificity equivalent to that determined with conventional actigraphs. The FS-750, which is smaller, less expensive, and able to take measurements over longer periods than conventional devices, is a promising tool for advancing sleep studies at home and in remote sleep medicine. PMID- 25282355 TI - Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials. AB - Antibiotics target conserved bacterial cellular pathways or growth functions and therefore cannot selectively kill specific members of a complex microbial population. Here, we develop programmable, sequence-specific antimicrobials using the RNA-guided nuclease Cas9 (refs.1,2) delivered by a bacteriophage. We show that Cas9, reprogrammed to target virulence genes, kills virulent, but not avirulent, Staphylococcus aureus. Reprogramming the nuclease to target antibiotic resistance genes destroys staphylococcal plasmids that harbor antibiotic resistance genes and immunizes avirulent staphylococci to prevent the spread of plasmid-borne resistance genes. We also show that CRISPR-Cas9 antimicrobials function in vivo to kill S. aureus in a mouse skin colonization model. This technology creates opportunities to manipulate complex bacterial populations in a sequence-specific manner. PMID- 25282357 TI - Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. AB - Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D. PMID- 25282360 TI - Severe thrombocytopenia after laparoscopic distal pancreatectomy with splenic preservation and resection of splenic vessels. PMID- 25282359 TI - De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. AB - Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases. PMID- 25282361 TI - Giant hepatic hydatidosis. PMID- 25282358 TI - PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. AB - Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation. PMID- 25282362 TI - Insight and satisfaction with life among adolescents with mental disorders: assessing associations with self-stigma and parental insight. AB - OBJECTIVE: The purpose of the current study was to assess the associations of illness perception-related variables with satisfaction with life (SwL) among adolescents with mental disorders. METHODS: Insight into mental disorder (SAI-E), Internalized stigma of mental illness (ISMI) and Multidimensional Students' Life Satisfaction Scale (MSLSS) were administrated to 30 adolescent patients. Adapted version for parents of the SAI-E was also administrated to 37 of their parents. RESULTS: Significant positive correlations were found between insight into the illness, self-stigma and parental insight. Insight and self-stigma were significantly negatively related to the total score of SwL and few of its dimensions while parental insight was significantly associated only with the SwL dimensions of school and self. Regression models revealed main negative effects of insight and self-stigma on SwL and no interaction effect. CONCLUSIONS: The possible independent contribution of insight and self-stigma to SwL should be addressed in interventions designed for family and adolescents coping with mental illness. Special attention should be given to the possible negative implications that insight possesses. In lack of support of the moderation role of self-stigma, reported in studies among adults with mental illness, future studies should trace other variables in order to further understand the insight paradox among adolescents. PMID- 25282363 TI - Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: an open trial. AB - The aim of this open trial was to assess the antidepressant/anxiolytic effects of oxytocin used as an adjunct to antidepressant in treatment-resistant depression. Fourteen patients, who have not responded to 40mg of escitalopram, received intranasal synthetic oxytocin during 4 weeks, in association with antidepressant. This is the first open trial study suggesting OT in association with escitalopram significantly reduced scores on Hamilton Depression Rating Scale. PMID- 25282364 TI - Re: Firas Abdollah, Giorgio Gandaglia, Nazareno Suardi, et al. More Extensive Pelvic Lymph Node Dissection Improves Survival in Patients with Node-positive Prostate Cancer. Eur Urol 2015;67:212-9: Extended Lymph Node Dissection and the Will Rogers Phenomenon. PMID- 25282365 TI - Understanding long-term urinary adverse events after treatment of localized prostate cancer: a key tool in informed decision-making. PMID- 25282366 TI - Melatonin, sleep, and prostate cancer in elderly men: study, hypothesis development, and icelandic options. PMID- 25282367 TI - Nephron-sparing techniques independently decrease the risk of cardiovascular events relative to radical nephrectomy in patients with a T1a-T1b renal mass and normal preoperative renal function. AB - BACKGROUND: Some reports have suggested that nephron-sparing surgery (NSS) may protect against cardiovascular events (CVe) when compared with radical nephrectomy (RN). However, previous studies did not adjust the results for potential selection bias secondary to baseline cardiovascular risk. OBJECTIVE: To test the effect of treatment type (NSS vs RN) on the risk of developing CVe after accounting for individual cardiovascular risk. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional collaboration including 1331 patients with a clinical T1a T1b N0 M0 renal mass and normal renal function before surgery (defined as an estimated glomerular filtration rate>=60 ml/min/1.73 m2). INTERVENTION: RN (n=462, 34.7%) or NSS (n=869, 65.3%) between 1987 and 2013. OUTCOME MEASUREMENT AND STATISTICAL ANALYSES: CVe was defined as onset during the follow-up period of coronary artery disease, cardiomyopathy, hypertension, vasculopathy, heart failure, dysrhythmias, or cerebrovascular disease not known before surgery. Cox regression analyses were performed. To adjust for inherent baseline differences among patients, we performed multivariate analyses adjusting for all available characteristics depicting the overall and cardiovascular-specific profile of the patients. RESULTS AND LIMITATIONS: When stratifying for treatment type, the proportion of patients who experienced CVe at 1, 5, and 10 yr was 5.5%, 9.9%, and 20.2% for NSS patients compared to 8.7%, 15.6%, and 25.9%, respectively, for RN patients (p=0.001). In multivariate analyses, patients who underwent NSS showed a significantly lower risk of developing CVe compared with their RN counterparts (hazard ratio 0.57, 95% confidence interval 0.34-0.96; p=0.03) after accounting for clinical characteristics and cardiovascular profile. Limitations include the retrospective design of the study because other potential confounders may exist. CONCLUSIONS: The risk of CVe after renal surgery is not negligible. Patients treated with NSS have roughly half the risk of developing CVe relative to their RN counterparts. After accounting for clinical characteristics, comorbidities, and cardiovascular risk at diagnosis, NSS independently decreases the risk of CVe relative to RN. PATIENT SUMMARY: The risk of having a cardiovascular event after renal surgery decreases if a portion of the affected kidney is spared. PMID- 25282368 TI - Recurrent angioedema after naproxen use in a patient stabilized with losartan. PMID- 25282369 TI - Cytokine responses to egg protein in previously allergic children who developed tolerance naturally. PMID- 25282370 TI - Obstacles to the uptake of breast, cervical, and colorectal cancer screenings: what remains to be achieved by French national programmes? AB - BACKGROUND: In France, equality in access to screening has been one of the main thrusts of public policies implemented between 2009 and 2013 (the national cancer plan). Our aim in this study was to analyse the obstacles to and levers for breast, cervical, and colorectal cancer screening uptake and their trends over time. METHODS: Based on representative data from the French Health Care and Health Insurance Survey (three independent, cross-sectional surveys: 2006, 2008, and 2010), multivariate logistic regressions were used to model the association between the nonuse of screening for the three cancers and various independent variables. Then, interactions with survey year dummies allowed the changes in the determinants of these cancer screenings over time to be estimated. RESULTS: Whereas the incentives for screening were strengthened during the period considered, cervical and breast cancer screenings decreased, and colorectal cancer screenings increased sharply (from 18.2% (95% CI = [17.0-19.4]) in 2006 to 38.9% (95% CI = [37.4-40.5] in 2010. Under-users of the three cancer screenings were primarily unskilled workers (ORcervix = 1.64 [1.38-1.95]), individuals without complementary health insurance (ORbreast = 2.05 [1.68-2.51]), or individuals with free complementary health insurance who more rarely use outpatient care. Moreover, individuals reporting either risky behaviours, namely heavy smokers (ORcolorectal = 1.70) and high-risk drinkers (ORcervix = 1.42) or very safe behaviours, namely neither smoking nor drinking, underused screenings. Despite the implementation of national programmes for breast and colorectal cancer screenings, the disparities and inequalities in screening uptake did not decrease over the study period. CONCLUSIONS: These results demonstrate the need for additional primary prevention efforts targeting the identified under-users by focusing on, for instance, individuals with a very healthy lifestyle. Health authorities could also intensify their efforts to promote increased access to screening for the most disadvantaged individuals. PMID- 25282371 TI - Comparative evaluation of calcium hypochlorite and sodium hypochlorite associated with passive ultrasonic irrigation on antimicrobial activity of a root canal system infected with Enterococcus faecalis: an in vitro study. AB - INTRODUCTION: The purpose of this study was to compare in vitro the effectiveness of calcium hypochlorite (Ca[OCl]2) and sodium hypochlorite (NaOCl) associated with passive ultrasonic irrigation in root canals of bovine teeth infected with Enterococcus faecalis. METHODS: The root canals of 60 single-rooted bovine extracted teeth were enlarged up to a file 45, autoclaved, inoculated with Enterococcus faecalis, and incubated for 30 days. The samples were divided into 6 groups (n = 10) according to the protocol for decontamination: G1: no treatment; G2: distilled water; G3: 2.5% NaOCl; G4: 2.5% Ca(OCl)2; G5: 2.5% NaOCl with ultrasonic activation; and G6: 2.5% Ca(OCl)2 with ultrasonic activation (US). Microbiological testing (colony-forming unit [CFU] counting) was performed to evaluate and show, respectively, the effectiveness of the proposed treatments. Data were subjected to 1-way analysis of variance followed by the post hoc Tukey test (alpha = 0.05). RESULTS: Groups 1 and 2 showed the highest mean contamination (3.26 log10 CFU/mL and 2.69 log10 CFU/mL, respectively), which was statistically different from all other groups (P < .05). Group 6 (Ca[OCl]2 + US) showed the lowest mean contamination (1.00 log10 CFU/mL), with no statistically significant difference found in groups 3 (NaOCl), 4 (Ca[OCl]2), and 5 (NaOCl + US) (P < .05). CONCLUSIONS: Ca(OCl)2 as well as passive ultrasonic irrigation can aid in chemomechanical preparation, contributing in a significant way to the reduction of microbial content during root canal treatment. PMID- 25282372 TI - Effects of mineral trioxide aggregate mixed with hydration accelerators on osteoblastic differentiation. AB - INTRODUCTION: Despite good physical and biological properties, mineral trioxide aggregate (MTA) has a long setting time. A hydration accelerator could decrease the setting time of MTA. This study assessed the biocompatibility of MTA mixed with hydration accelerators (calcium chloride and low-dose citric acid) and investigated the effect of these materials on osteoblast differentiation. METHODS: Cell viability was evaluated by the EZ-Cytox assay kit (Daeil Lab Service, Seoul, Korea). The gene expressions of osteocalcin and bone sialoprotein were detected by reverse-transcription polymerase chain reaction and real-time polymerase chain reaction. The mineralization behavior was evaluated with alizarin red staining. RESULTS: There was no statistically significant difference in cell viability between experimental groups. The messenger RNA level of osteogenic genes significantly increased in MTA mixed with hydration accelerators compared with the control and MTA mixed with water. MTA mixed with the hydration accelerators resulted in similar mineralization compared with MTA mixed with water. CONCLUSIONS: Hydration accelerators increase the osteogenic effect and show a similar effect on the mineralization of MTA, which may have clinical applications. PMID- 25282373 TI - Influence of chlorhexidine application time on the bond strength between fiber posts and dentin. AB - INTRODUCTION: The aim of this study was to investigate the effects of chlorhexidine (CHX) application time on the bond strength and durability of the adhesion of fiber posts relined with resin composite to the root dentin. METHODS: Eighty bovine incisor roots were divided into 4 groups after root preparation: control group (irrigation with physiological solution) and experimental groups, CHX for 30 seconds, CHX for 60 seconds, and CHX for 120 seconds. Fiber posts relined with resin composite were cemented with RelyX ARC. The Scotchbond Multi Purpose total-etching adhesive system was used in half of the samples of each group, and the Clearfil SE Bond self-etching adhesive system was used in the other half. The samples were randomly divided into 2 subgroups, 24 hours of storage and 12 months of storage. All roots were sectioned transversely, and push out tests were performed. Bond strength means were analyzed by analysis of variance and Tukey test (alpha = 0.05). Failure mode was determined by examining specimen's surfaces under scanning electron microscope, and its distribution was evaluated by using chi(2) test (alpha = 0.05). RESULTS: CHX pretreatment resulted in homogeneous bond strength values at 24 hours and 12 months of storage, irrespective of the CHX application time and adhesive system (P < .05). A significant bond strength decrease was noticed after 12 months of storage when irrigation was performed with physiological solution in the control groups (P > .05). Significant differences were observed for fracture patterns (P < .001). CONCLUSIONS: The use of CHX pretreatment could preserve the bond strength of the fiber post relined with resin composite to root dentin for 12 months, irrespective of the CHX application time and adhesive system used. PMID- 25282374 TI - Periapical microsurgery: the effect of root dentinal defects on short- and long term outcome. AB - INTRODUCTION: The purpose of this prospective clinical study was to evaluate the clinical outcome of endodontic microsurgery on roots exhibiting the presence or absence of dentinal defects at 1-year and 3-year follow-up period. METHODS: One hundred fifty-five teeth were treated with periapical microsurgery using a modern microsurgical protocol in a private practice setting. The root apices were resected and inspected for dentinal defects with a surgical operating microscope and a 0.8-mm head diameter light-emitting diode microscope diagnostic probe light. After inspection, root-end preparations were performed using ultrasonic tips, and root-end fillings were placed. Follow-up visits occurred at 1 year and 3 years postoperatively. The primary outcome measure used was the change in the radiographic apical bone density, and the secondary outcome measure used was the absence of clinical symptoms. RESULTS: Of the 155 treated teeth, a total of 134 teeth were assessed at the 1-year follow-up and 127 teeth at the 3-year evaluation. In the "intact" group, 94.8% healed at 1 year, and 97.3% healed at 3 years. In the "dentinal defect" group, 29.8% healed at 1 year, and 31.5% healed at 3 years. The baseline root condition of either "dentinal defect" or "intact" showed a statistical difference in the healing outcome at both 1 and 3 years. CONCLUSIONS: This prospective periapical microsurgery study showed a significant superior clinical outcome for intact roots when compared with roots with dentinal defects at both 1 year and at 3 years postoperatively. PMID- 25282375 TI - Tricalcium silicate cements with resins and alternative radiopacifiers. AB - OBJECTIVE: The objectives of this study were the investigation of the setting mechanisms and characterization of radiopacified tricalcium silicate-based materials mixed with different liquid vehicles. METHODS: Tricalcium silicate cement replaced with 20% of either zirconium oxide or barium zirconate radiopacifier was investigated. The cements were mixed with water, an epoxy resin, or a light-cured Bis-GMA-based resin. The setting mechanism and characterization of set materials after immersion in Hank's balanced salt solution (HBSS) for 28 days were investigated by scanning electron microscopy of polished specimens and x-ray diffraction analysis. The bioactivity and surface microstructure of cements immersed in HBSS or water were also assessed by similar techniques together with leaching in solution investigated by inductively coupled plasma emission spectroscopy. RESULTS: The formation of calcium hydroxide as a by product of cement reaction was affected by the type of radiopacifier and also by the resin vehicle used. Barium zirconate enhanced the formation of calcium hydroxide as indicated by both scanning electron microscopy and x-ray diffraction analysis. The use of resins as vehicles reduced the formation of calcium hydroxide, with the Bis-GMA-based resin being mostly affected. Calcium hydroxide was deposited on the material surface regardless of the type of vehicle used. Formation of beta calcium phosphate was observed on materials containing barium zirconate radiopacifier immersed in HBSS. Inductively coupled plasma emission spectroscopy analysis showed high levels of calcium leached from materials by using water and light-curable resin as mixing vehicles. Barium was leached in solution, with the highest amount from the water-based mixtures. Zirconium leaching was negligible in materials containing zirconium oxide as radiopacifier, but leaching of zirconium was measurable in materials by using barium zirconate with tricalcium silicate. CONCLUSIONS: The resin type and composition of the radiopacifier affect the calcium releasing ability and bioactivity of tricalcium silicate cements. Barium was leached in solution with barium zirconate radiopacified variants. Light-cured Bis-GMA-based resins did not exhibit cement hydration; however, they encouraged leaching of calcium ions in solution and promoted surface deposition of calcium phosphate. PMID- 25282376 TI - Assessment of oxygen saturation in dental pulp of permanent teeth with periodontal disease. AB - INTRODUCTION: In individuals with periodontal disease, dental pulp status should be determined before a treatment plan is made. Pulse oximeters are promising diagnostic tools to evaluate pulp vascularization. This study used pulse oximetry to determine the level of oxygen saturation in dental pulp of intact permanent teeth with periodontal attachment loss (PAL) and gingival recession (GR) and to evaluate the correlation between periodontal disease and level of oxygen saturation in the pulp. METHODS: This study included 67 anterior teeth of 35 patients; all teeth showed intact crowns, PAL, a periodontal pocket (PP), and GR. The teeth underwent periodontal examination, cold and electric pulp testing, and pulse oximetry measurements. The Pearson correlation coefficient and a linear regression coefficient were calculated to evaluate the degree of correlation between periodontal disease markers (PAL, PP, and GR) and the level of oxygen saturation in dental pulp. These tests also evaluated possible associations between oxygen saturation and cold and electric pulp testing. RESULTS: PAL, PP, and GR had negative correlations with oxygen saturation in dental pulp. Conversely, no statistically significant association was found between oxygen saturation in dental pulp and the response to electric sensibility testing. CONCLUSIONS: Oxygen saturation was lower in the pulp of permanent teeth with PAL, PP, and GR, indicating that periodontal disease correlates with the level of oxygen saturation in the pulp. PMID- 25282377 TI - Energy consumption of ProTaper Next X1 after glide path with PathFiles and ProGlider. AB - INTRODUCTION: Instrument failure caused by excessive torsional stress can be controlled by creating a manual or mechanical glide path. The ProGlider single file system (Dentsply Maillefer, Ballaigues, Switzerland) was recently introduced to perform a mechanical glide path. This study was designed to compare the effect of a glide path performed with PathFiles (Dentsply Maillefer) and ProGlider on torque, time, and pecking motion required for ProTaper Next X1 (Dentsply Maillefer) to reach the full working length in simulated root canals. METHODS: Forty Endo Training Blocks (Dentsply Maillefer) were used. Twenty were prepared with a mechanical glide path using PathFiles 1 and 2 (the PathFile group), and 20 were prepared with a mechanical glide path using a ProGlider single file (the ProGlider group). All samples were shaped with ProTaper Next X1 driven by an endodontic motor connected to a digital wattmeter. The required torque for root canal instrumentation was analyzed by evaluating the electrical power consumption of the endodontic engine. Electric power consumption (mW/h), elapsed time (seconds), and number of pecking motions required to reach the full working length with ProTaper Next X1 were calculated. Differences among groups were analyzed with the parametric Student t test for independent data (P < .05). RESULTS: Elapsed time and electric power consumption were significantly different between groups (P = .0001 for both). ProGlider appears to perform more efficiently than PathFiles in decreasing electric power consumption of ProTaper Next X1 to reach the full working length. CONCLUSIONS: This study confirmed the ability of ProGlider to reduce stress in ProTaper Next X1 during shaping through a glide path and preliminary middle and coronal preflaring. PMID- 25282378 TI - Initial transient accumulation of M2 macrophage-associated molecule-expressing cells after pulpotomy with mineral trioxide aggregate in rat molars. AB - INTRODUCTION: M2 (alternatively activated) macrophages are known to participate in wound healing and tissue repair. This study aimed to analyze the temporospatial changes in the distribution and density of M2 macrophage associated molecule-expressing cells after pulpotomy with mineral trioxide aggregate (MTA) in rat molars to ascertain the role played by M2 macrophages in the healing of MTA-capped pulp tissue. METHODS: The maxillary first molars of 8 week-old Wistar rats were pulpotomized and capped with MTA. After 1-14 days, the teeth were examined after hematoxylin-eosin staining or immunoperoxidase staining of CD68 (a general macrophage marker) and M2 macrophage markers (CD163 and CD204). The density of positively stained cells was enumerated in the surface and inner regions (0-100 MUm and 300-400 MUm, respectively, from the wound surface). RESULTS: MTA capping initially caused mild inflammatory changes and the formation of a degenerative layer followed by progressive new matrix formation and calcified bridging. At 1-2 days, CD68-, CD163-, and CD204-positive cells started to accumulate beneath the degenerative layer, and the density of these cells was significantly higher in the surface region than in the inner region (P < .05). From 7 days onward, the 3 types of cells displayed an almost normal distribution beneath the newly formed dentinlike matrix. CONCLUSIONS: After the pulpotomy of rat molars with MTA, M2 macrophage-associated molecule-expressing cells transiently accumulated beneath the degenerative layer under the MTA. This suggests that M2 macrophages participate in the initial phases of the healing of MTA-capped pulp tissue. PMID- 25282379 TI - Extraradicular infection as the cause of persistent symptoms: a case series. AB - INTRODUCTION: This article describes 3 cases that presented persistent symptoms after appropriate endodontic treatment. Histopathologic and histobacteriologic investigation were conducted for determination of the cause. METHODS: Three cases are reported that presented with persistent symptoms after endodontic retreatment (cases 1 and 2) or treatment (case 3). Periapical surgery was indicated and performed in these cases. The biopsy specimens, consisting of root apices and the apical periodontitis lesions, were subjected to histopathologic and histobacteriologic analyses. RESULTS: Case 1 was an apical cyst with necrotic debris, heavily colonized by ramifying bacteria, in the lumen. No bacteria were found in the apical root canal system. Case 2 was a granuloma displaying numerous bacterial aggregations through the inflammatory tissue. Infection was also present in the dentinal tubules at the apical root canal. Case 3 was a cyst with bacterial colonies floating in its lumen; bacterial biofilms were also seen on the external apical root surface, filling a large lateral canal and other apical ramifications, and between layers of cementum detached from the root surface. No bacteria were detected in the main root canal. CONCLUSIONS: Different forms of extraradicular infection were associated with symptoms in these cases, leading to short-term endodontic failure only solved by periapical surgery. PMID- 25282380 TI - The effect of medicaments used in endodontic regeneration technique on the dislocation resistance of mineral trioxide aggregate to root canal dentin. AB - INTRODUCTION: The aim of this study was to evaluate the effect of calcium hydroxide (CH) and antibiotic pastes, including a mixture of metronidazole and ciprofloxacin, with and without minocycline or cefaclor, on the dislocation resistance of mineral trioxide aggregate (MTA) to root dentin. METHODS: Eighty single-rooted human mandibular premolars were selected. The teeth were prepared by using the ProTaper system. The prepared teeth were then instrumented to a #6 Peeso reamer to obtain a standard internal diameter of 1.5 mm. The reamers were passed 1 mm beyond apex to simulate immature teeth. The specimens were then randomly divided into a control group (no intracanal medicament was used) and 4 experimental groups that were treated with an intracanal medicament: CH, double antibiotic paste (DAP) with metronidazole and ciprofloxacin, triple antibiotic paste (TAP) with minocycline, or TAP with cefaclor (n = 16). After 3 weeks, the medicaments were removed, and approximately 3 mm of MTA was placed in the coronal third of the canals. A push-out test was used to measure the dislocation resistance between the root dentin and MTA. Data were analyzed by using one-way analysis of variance and Tukey post hoc tests. RESULTS: The dislocation resistance values of the CH, TAP with minocycline, and TAP with cefaclor groups were similar to those of the control group (P > .05), whereas the DAP group had the lowest dislocation resistance when compared with the other groups (P < .05). Overall, there was a predominance of cohesive failures between root dentin and MTA. CONCLUSIONS: The results of this study indicate that the application of DAP as an intracanal medicament reduced the dislocation resistance of MTA to root dentin. PMID- 25282382 TI - SNARE-ing the structures of Sec1/Munc18 proteins. AB - Membrane fusion is essential for cellular transport in eukaryotes. Abnormalities contribute to a wide range of diseases including diabetes and neurological disorders. A key regulator of SNARE-mediated membrane fusion is the Sec1/Munc18 (SM) protein family. Universal structural features of SM proteins have been identified that affect the way these interact with their partner Syntaxin SNARE proteins. Whilst the molecular basis for SM-regulated SNARE complex formation has been extensively studied, it remains poorly understood. Recent crystal structures of SM proteins alone or in complex have provided new insight. Here we examine the available structural information on SM proteins for clues to how these enigmatic proteins might regulate SNARE complex assembly and membrane fusion. PMID- 25282383 TI - Early-life predictors of leisure-time physical inactivity in midadulthood: findings from a prospective British birth cohort. AB - Much adult physical inactivity research ignores early-life factors from which later influences may originate. In the 1958 British birth cohort (followed from 1958 to 2008), leisure-time inactivity, defined as activity frequency of less than once a week, was assessed at ages 33, 42, and 50 years (n = 12,776). Early life factors (at ages 0-16 years) were categorized into 3 domains (i.e., physical, social, and behavioral). We assessed associations of adult inactivity 1) with factors within domains, 2) with the 3 domains combined, and 3) allowing for adult factors. At each age, approximately 32% of subjects were inactive. When domains were combined, factors associated with inactivity (e.g., at age 50 years) were prepubertal stature (5% lower odds per 1-standard deviation higher height), hand control/coordination problems (14% higher odds per 1-point increase on a 4 point scale), cognition (10% lower odds per 1-standard deviation greater ability), parental divorce (21% higher odds), institutional care (29% higher odds), parental social class at child's birth (9% higher odds per 1-point reduction on a 4-point scale), minimal parental education (13% higher odds), household amenities (2% higher odds per increase (representing poorer amenities) on a 19-point scale), inactivity (8% higher odds per 1-point reduction in activity on a 4-point scale), low sports aptitude (13% higher odds), and externalizing behaviors (i.e., conduct problems) (5% higher odds per 1-standard deviation higher score). Adjustment for adult covariates weakened associations slightly. Factors from early life were associated with adult leisure-time inactivity, allowing for early identification of groups vulnerable to inactivity. PMID- 25282384 TI - Nurses' report of in-hospital pediatric pain assessment: examining challenges and perspectives. AB - Pain is a symptom pediatric nurses commonly encounter in the hospital setting. Untreated pain can lead to adverse physiologic and psychological effects. This study examines in-hospital pain assessment methods nurses report using and assesses challenges, difficulties, and barriers nurses report to assessing pain in hospitalized children. Cross-sectional study of 82 pediatric nurses from all pediatric departments of a tertiary hospital in Israel. A self-report questionnaire was developed to examine how nurses assess children's in-hospital pain and barriers to in-hospital pain assessment. Nearly all nurses (90%) reported having enough knowledge to assess children's pain in the hospital, relying on child's self-report (86%) and being familiar with commonly used validated pain scales (90%). However, a majority (75%) reported not using pain scales recently and only half (58%) reported using an alternative method involving the child. Most nurses (86%) reported relying on their own overall impression of the child's pain and only a third (34%) reported involving the parents in their pain assessments. Nurses included comments stressing the importance of pain assessments and their frustration with the current validated measures available. This study adds to a growing body of literature demonstrating a gap between recommended pediatric pain assessment guidelines and reported practice, with nurses showing a resistance to relying on single-item or unidimensional measures to assess and evaluate the rich and complex pain experience. A multidimensional approach involving child self-report, parent report, and nurses' own overall impression based on clinical assessment skills of pain is discussed. PMID- 25282381 TI - Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research. AB - The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross validation across cohorts and laboratories. PMID- 25282385 TI - Australian Football League clinics promoting health, hygiene and trachoma elimination: the Northern Territory experience. AB - Australia is the only developed country to suffer trachoma and it is only found in remote Indigenous communities. In 2009, trachoma prevalence was 14%, but through screening, treatment and health promotion, rates had fallen to 4% in 2012. More work needs to be done to sustain these declining rates. In 2012, 25% of screened communities still had endemic trachoma and 8% had hyperendemic trachoma. In addition, only 58% of communities had reached clean face targets in children aged 5-9 years. Australian Football League (AFL) players are highly influential role models and the community love of football provides a platform to engage and strengthen community participation in health promotion. The University of Melbourne has partnered with Melbourne Football Club since 2010 to run trachoma football hygiene clinics in the Northern Territory (NT) to raise awareness of the importance of clean faces in order to reduce the spread of trachoma. This activity supports Federal and state government trachoma screening and treatment programs. Between 2010 and 2013, 12 football clinics were held in major towns and remote communities in the NT. Almost 2000 children and adults attended football clinics run by 16 partner organisations. Awareness of the football clinics has grown and has become a media feature in the NT trachoma elimination campaign. The hygiene station featured within the football clinic could be adapted for other events hosted in remote NT community events to add value to the experience and reinforce good holistic health and hygiene messages, as well as encourage interagency collaboration. PMID- 25282386 TI - Perceptions of physiotherapists about their role in health promotion at an acute hospital: a qualitative study. AB - OBJECTIVE: To investigate the perceptions of physiotherapists about their role in health promotion in an acute inpatient setting. DESIGN: Qualitative design using focus groups within a constructivist framework. Focus groups were recorded, transcribed verbatim and analysed using a constant comparative method. SETTING: An acute National Health Service (NHS) hospital trust. PARTICIPANTS: Three focus groups were conducted with a total of 22 physiotherapists who were recruited purposively from the medical and surgical unit of the study hospital. FINDINGS: Participants generally perceived health promotion to be within their scope of practice, particularly in relation to the promotion of physical activity and smoking cessation. Whilst some facilitators to engaging in health promotion were discussed, a large number of barriers to routine engagement in health promotion were identified. These included time constraints, the focus of acute settings on discharge, and scepticism of effectiveness. CONCLUSION: Pre- and postregistration physiotherapy education as well as mandatory training in NHS trusts should be reviewed to equip the workforce to engage in this crucial area of health care. PMID- 25282387 TI - Clinical incidents involving students on placement: an analysis of incident reports to identify potential risk factors. AB - BACKGROUND: Students are sometimes involved in incidents during clinical training. To the authors' knowledge, no quantitative studies of incidents specifically involving physiotherapy students on clinical placement are available in the literature. METHODS: A retrospective audit (2008 to 2011) of incident reports involving physiotherapy students was conducted to identify the nature and features of incidents. The study aimed to determine if injuries to a student or patient were more or less likely when the supervisor was in close proximity, and whether students with lower academic performance in their preclinical semester were more likely to be involved in an incident. RESULTS: There were 19 care delivery-related and three equipment-related incidents. There were no incidents of violent, aggressive or demeaning behaviour towards students. The incident rate was 9.0/100,000 student-hours for third-year students and 6.8/100,000 student hours for fourth-year students. The majority of incidents (55%) occurred from 11 am to 12-noon and from 3 pm to 3.30 pm. Incidents more often resulted in patient or student injury when the supervisor was not in close proximity (approximately 50% vs approximately 20%), although the difference was not significant (P=0.336). The academic results of students involved in incidents were equivalent to the whole cohort in their preclinical semester {mean 75 [standard deviation (SD) 6] vs 76 (SD 7); P=0.488}. CONCLUSIONS: The unexpected temporal clustering of incidents warrants further investigation. Student fatigue may warrant attention as a potential contributor; however, contextual factors, such as staff workload, along with organisational systems, structures and procedures may be more relevant. The potential relationship between supervisor proximity and injury also warrants further exploration. The findings of the present study should be integrated into clinical education curricula and communicated to clinical educators. PMID- 25282388 TI - Body position influences the maximum inspiratory and expiratory mouth pressures of young healthy subjects. AB - OBJECTIVE: The purpose of this study was to determine the effects of body position on respiratory muscle strength of young healthy subjects. PARTICIPANTS: Sixty-three (50 female, mean age 19.7+/-1.5 years) healthy subjects participated in the study. DESIGN: Participants were measured in the sitting position, semi upright sitting position, and in the supine position. The order of the three conditions was randomly determined. OUTCOME MEASURES: Maximal inspiratory and expiratory mouth pressures (PImax, PEmax) and lung function. RESULTS: A significant effect of body position was observed on PEmax values, controlling for gender. PImax in the sitting position (92.8+/-20.05 cm H2O) was significantly higher than in the supine (84.1+/-15.1 cm H2O; mean difference: 8.70, 95% CI [5.95, 12.45], p<0.001) and semi-upright sitting positions (84.4+/-17.5 cm H2O; mean difference: 8.43, 95% CI [5.78, 11.07], p<0.001). PEmax was also significantly higher in the sitting position (125.4+/-34.2 cm H2O) than in the supine (115.8+/-29.0 cm H2O; mean difference: 9.59, 95% CI [4.86, 14.32], p<0.001) and semi-upright sitting positions (120.2+/-33.9 cm H2O; mean difference: 5.21, 95% CI [0.87, 9.54], p=0.013). CONCLUSIONS: Body position influences respiratory muscle strength of young healthy subjects. PImax and PEmax are higher in the sitting position than in the supine or semi-upright sitting positions. PMID- 25282389 TI - Relative utility of a visual analogue scale vs. a six-point Likert scale in the measurement of global subject outcome in patients with low back pain receiving physiotherapy. AB - BACKGROUND: Patients' subjective impression of change is an important construct to measure following physiotherapy, but little evidence exists about the best type of measure to use. OBJECTIVE: To compare the construct validity and utility of two forms of a global subjective outcome scale (GSOS) in patients with back pain: Likert and visual analogue scale (VAS) GSOS. DESIGN: Two samples of patients attending physiotherapy for back pain completed a questionnaire battery at discharge from physiotherapy including either a Likert or VAS GSOS. PARTICIPANTS: One hundred and eighty-seven {79 males, mean age 52.1 [standard deviation (SD) 15.5] years} patients completed the Likert GSOS and a separate sample of 144 patients [62 males, mean age 55.7 (SD 15.9) years] completed the VAS GSOS upon discharge from physiotherapy. MAIN COMPARISONS: The two versions of the GSOS were compared using pre- and post-treatment changes in scores using a VAS (pain), Roland-Morris Disability Questionnaire (18-item version) and catastrophising subscale of the Coping Strategies Questionnaire 24. RESULTS: Both versions of the GSOS showed significant (P<0.01) moderate correlations (r between 0.30 and 0.46) with changes in pain and disability. The correlations between the two types of GSOS and changes in catastrophising were trivial and not significant (Likert GSOS: r=0.07, P=0.372; VAS GSOS: r=0.10, P=0.267). There were fewer missing values in the Likert GSOS (1%) compared with the VAS GSOS (8%). CONCLUSIONS: The two versions of the GSOS showed similar validity; however, use of the Likert GSOS is recommended because of its greater utility. PMID- 25282390 TI - Reprint of: The Great Beauty of the osteoclast. AB - Much has been written recently on osteoclast biology, but this cell type still astonishes scientists with its multifaceted functions and unique properties. The last three decades have seen a change in thinking about the osteoclast, from a cell with a single function, which just destroys the tissue it belongs to, to an "orchestrator" implicated in the concerted regulation of bone turnover. Osteoclasts have unique morphological features, organelle distribution and plasma membrane domain organization. They require polarization to cause extracellular bone breakdown and release of the digested bone matrix products into the circulation. Osteoclasts contribute to the control of skeletal growth and renewal. Alongside other organs, including kidney, gut, thyroid and parathyroid glands, they also affect calcemia and phosphatemia. Osteoclasts are very sensitive to pro-inflammatory stimuli, and studies in the '00s ascertained their tight link with the immune system, bringing about the question why bone needs a cell regulated by the immune system to remove the extracellular matrix components. Recently, osteoclasts have been demonstrated to contribute to the hematopoietic stem cell niche, controlling local calcium concentration and regulating the turnover of factors essential for hematopoietic stem cell mobilization. Finally, osteoclasts are important regulators of osteoblast activity and angiogenesis, both by releasing factors stored in the bone matrix, and secreting "clastokines" that regulate the activity of neighboring cells. All these facets will be discussed in this review article, with the aim of underscoring The Great Beauty of the osteoclast. PMID- 25282391 TI - Stowaways in the history of science: the case of simian virus 40 and clinical research on federal prisoners at the US National Institutes of Health, 1960. AB - In 1960, J. Anthony Morris, a molecular biologist at the US National Institutes of Health conducted one of the only non-therapeutic clinical studies of the cancer virus SV40. Morris and his research team aimed to determine whether SV40 was a serious harm to human health, since many scientists at the time suspected that SV40 caused cancer in humans based on evidence from in vivo animal studies and experiments with human tissue. Morris found that SV40 had no significant effect but his claim has remained controversial among scientists and policymakers through the present day--both on scientific and ethical grounds. Why did Morris only conduct one clinical study on the cancer-causing potential of SV40 in healthy humans? We use the case to explain how empirical evidence and ethical imperatives are, paradoxically, often dependent on each other and mutually exclusive in clinical research, which leaves answers to scientific and ethical questions unsettled. This paper serves two goals: first, it documents a unique- and uniquely important--study of clinical research on SV40. Second, it introduces the concept of "the stowaway," which is a special type of contaminant that changes the past in the present moment. In the history of science, stowaways are misfortunes that nonetheless afford research that otherwise would have been impossible specifically by creating new pasts. This case (Morris' study) and concept (the stowaway) bring together history of science and philosophy of history for productive dialog. PMID- 25282392 TI - Trends in yield of a code stroke program for enhancing thrombolysis. AB - As the benefit of thrombolytic therapy in acute ischemic stroke is time dependent, a code stroke program needs to be implemented, maintained, and improved with continuous efforts to expedite thrombolytic therapy. We analyzed the long-term yield and efficiency of our code stroke program. Using a prospective single-center registry, we assessed the rates of stroke diagnosis and thrombolysis, door-to-CT scan and door-to-needle times, and annual trends in patients with code stroke activation between May 2007 and December 2011. Of the 791 patients with code stroke activation during the 4.7 year study period, 626 (79.1%) had a stroke, with 461 (58.3%) ischemic strokes and 165 (20.9%) hemorrhagic strokes. Along with an increase of code stroke activation (from 105/year to 236/year) and thrombolytic therapy volumes (from 24/year to 77/year), the rate of thrombolytic therapy among ischemic stroke patients increased from 33.3% to 59.2% (p for trend=0.0001). However, code activations for a non-stroke case also significantly increased (p for trend=0.0001). Door-to-CT scan time (p for trend=0.0011) and proportion of CT scan initiation ? 25 minutes after arrival improved (p for trend=0.0022), and were 18.4 minutes and 76.7%, respectively, in 2011. However, the door-to-needle time and proportion of door-to-needle time ? 60 minutes did not significantly improve, they were (43.3 minutes and 83.1%, respectively, in 2011). Our code stroke program yielded a high rate of detecting thrombolysis candidates and a continuous increase in rates of administration of thrombolytic therapy. These findings support the stroke team members' collaborative effort to treat more patients and to treat patients faster. PMID- 25282393 TI - Pediatric awake craniotomy and intra-operative stimulation mapping. AB - The indications for operating on lesions in or near areas of cortical eloquence balance the benefit of resection with the risk of permanent neurological deficit. In adults, awake craniotomy has become a versatile tool in tumor, epilepsy and functional neurosurgery, permitting intra-operative stimulation mapping particularly for language, sensory and motor cortical pathways. This allows for maximal tumor resection with considerable reduction in the risk of post-operative speech and motor deficits. We report our experience of awake craniotomy and cortical stimulation for epilepsy and supratentorial tumors located in and around eloquent areas in a pediatric population (n=10, five females). The presenting symptom was mainly seizures and all children had normal neurological examinations. Neuroimaging showed lesions in the left opercular (n=4) and precentral or peri-sylvian regions (n=6). Three right-sided and seven left-sided awake craniotomies were performed. Two patients had a history of prior craniotomy. All patients had intra-operative mapping for either speech or motor or both using cortical stimulation. The surgical goal for tumor patients was gross total resection, while for all epilepsy procedures, focal cortical resections were completed without any difficulty. None of the patients had permanent post-operative neurologic deficits. The patient with an epileptic focus over the speech area in the left frontal lobe had a mild word finding difficulty post-operatively but this improved progressively. Follow-up ranged from 6 to 27 months. Pediatric awake craniotomy with intra-operative mapping is a precise, safe and reliable method allowing for resection of lesions in eloquent areas. Further validations on larger number of patients will be needed to verify the utility of this technique in the pediatric population. PMID- 25282394 TI - Bedside saccadometry as an objective and quantitative measure of hemisphere specific neurological function in patients undergoing cranial surgery. AB - Cranial surgery continues to carry a significant risk of neurological complications. New bedside tools that can objectively and quantitatively evaluate cerebral function may allow for earlier detection of such complications, more rapid initiation of therapy, and improved patient outcomes. We assessed the potential of saccadic eye movements as a measure of cerebral function in patients undergoing cranial surgery peri-operatively. Visually evoked saccades were measured in 20 patients before (-12 hours) and after (+2 and +5 days) undergoing cranial surgery. Hemisphere specific saccadic latencies were measured using a simple step-task and saccadic latency distributions were compared using the Kolmogorov-Smirnov test. Saccadic latency values were incorporated into an empirically validated mathematical model (Linear Approach to Threshold with Ergodic Rate [LATER] model) for further analysis (using Wilcoxon signed rank test). Thirteen males and seven females took part in our study (mean age 55 +/- 4.9 years). Following cranial surgery, saccades initiated by the cerebral hemisphere on the operated side demonstrated significant deteriorations in function after 2 days (p < 0.01) that normalised after 5 days. Analysis using the LATER model confirmed these findings, highlighting decreased cerebral information processing as a potential mechanism for noted changes (p < 0.05). No patients suffered clinical complications after surgery. To conclude, bedside saccadometry can demonstrate hemisphere-specific changes after surgery in the absence of clinical symptoms. The LATER model confirms these findings and offers a mechanistic explanation for this change. Further work will be necessary to assess the practical validity of these changes in relation to clinical complications after surgery. PMID- 25282395 TI - Low-dose pulse cyclophosphamide in interstitial lung disease associated with systemic sclerosis (SSc-ILD): efficacy of maintenance immunosuppression in responders and non-responders. AB - OBJECTIVE: To investigate the long-term disease course of patients with recently deteriorated systemic sclerosis (SSC)-interstitial lung disease (ILD) undergoing continuous immunosuppressive treatment with cyclophosphamide (CYC) as induction therapy. METHODS: A total of 45 consecutive SSc patients were treated with weekly pulses of 500mg of CYC up to 10-g cumulative dose followed by azathioprine (AZA) in those experiencing improvement (>10% increase) or stabilization of both forced vital capacity and diffusion lung capacity for carbon dioxide and by micophenolic acid (MMF) in those experiencing deterioration (>10% decrease of either parameter). The follow-up ranged from 6 to 62 months post-CYC regimen (median = 36 months). RESULTS: Overall, 39 patients completed the CYC regimen. Of them, 24 (61.5%) experienced improvement or stabilization of lung function parameters and received AZA; the remaining 15 received MMF. During follow-up, lung function parameters improved in 3 (12.5%), remained stable in 18 (75%), and worsened in 3 (12.5%) AZA-treated patients, whereas they worsened in 8 (67%) and remained stable in 4 (33%) MMF-treated patients. The incidence of improvement or stabilization was significantly higher in AZA-treated than in MMF-treated patients (p = 0.001). The time to the decline of lung function was significantly shorter in CYC non-responders, and CYC unresponsiveness was predictive of lung function worsening over time in a multivariate analysis (HR = 9.14; 95% CI: 2.28 36.64; p = 0.0018). CONCLUSION: Our study supports the use of low-dose pulse CYC as induction therapy of recently deteriorated SSc-ILD. Moreover, it suggests that AZA should be administered to CYC-responsive patients but does not show any definite effect of MMF in unresponsive patients. PMID- 25282396 TI - Multiplexed electrochemical coding of DNA-protein bindings. AB - A simple, sensitive and multiplexed electrochemical sensor for the detection of DNA-protein binding based on the exonuclease protection strategy is described. Two electroactive species, methylene blue (MB)- and ferrocene (Fc)-labeled dsDNA probes are self-assembled on a gold electrode to prepare the sensor surface. The target proteins, vascular endothelial growth factor (VEGF) and estrogen receptor (ERalpha), bind to the dsDNA probes and protect the probes from digesting by exonuclease III due to the steric hindrance of the bound proteins. These protein protected, MB/Fc-labeled sequences remaining on the sensor surface display two distinct voltammetric peaks, whose peak potentials (MB: -0.27 V; Fc: +0.27 V) and intensities reflect the identities and amounts of the corresponding target proteins, for simultaneous and multiplexed detection of DNA-protein bindings. The proposed sensor is also selective to the target proteins against other interference molecules. By using labels with distinct voltammetric peaks, the developed method can be easily expanded for simultaneous detection of multiple DNA-protein bindings. PMID- 25282397 TI - Recyclable three-dimensional Ag nanoparticle-decorated TiO2 nanorod arrays for surface-enhanced Raman scattering. AB - Multifunctional Ag nanoparticle-decorated TiO2 nanorod arrays were prepared by two simple processes. TiO2 nanorod arrays were first fabricated by the hydrothermal route and then Ag nanoparticles were decorated on the nanorods by the chemical reduction impregnation method. Three-dimensional Ag/TiO2 arrays were used as an active substrate for surface-enhanced Raman scattering (SERS). The results show that the detection limit for rhodamine 6G (R6G) was as low as 10( 7)M and the Raman enhancement factor was as large as 10(5). After calibrating the Raman peak intensities of R6G, it could be quantitatively detected. More importantly, the photocatalytic activity of TiO2 provides a self-cleaning capability to the SERS substrate, which can be recycled and used to degrade many Ag surface adsorbates such as R6G, methyl orange, Congo red, and methylene blue after exposure to visible light. The absorbed small molecules can all be rapidly and completely removed from the SERS substrate, which has been successfully reused four times without a decrease in accuracy or sensitivity. Our results reveal that the unique recyclable property not only paves a new way to solve the single-use problem of traditional SERS substrates but also provides more SERS platforms for multiple detections of other organic molecular species. PMID- 25282398 TI - Highly sensitive photoelectrochemical assay for DNA methyltransferase activity and inhibitor screening by exciton energy transfer coupled with enzyme cleavage biosensing strategy. AB - Highly sensitive DNA methyltransferase (MTase) activity and inhibitor screening photoelectrochemical (PEC) assay was developed based on the exciton energy transfer (EET) effect coupled with site-specific cleavage of restriction endonuclease (HpaII). The assay was designed by integrating the Au nanoparticles (NPs) labeled probe DNA (pDNA-Au) with CdSe quantum dots (QDs). The strong EET effect between Au NPs and CdSe QDs resulted in the dramatic decrease of photocurrent signal. The pDNA carried a sensing region for specifically recognizing target DNA (tDNA) and hybridizing with it to form a DNA duplex. With the site-specific cleavage of HpaII, the DNA duplex could be cleaved and Au NPs would be released, which broke the EET and resulted in the restoration of photocurrent signal. However, when the DNA duplex was methylated by M.SssI MTase, this cleavage of HpaII was blocked, and therefore the unbroken EET effect kept the lower photocurrent signal. That was, the restored photocurrent was inversely proportional to the MTase activity. Based on this strategy, the PEC assay could determine as low as ~0.0042 U/mL of M.SssI MTase with a linear range from 0.01 to 150 U/mL. In addition, the assay could be used for the screening of the inhibitors of MTase. This PEC assay provides a promising platform for monitoring the activity and inhibition of DNA MTase, and thus shows a great potential in cancer diagnostics and anti-cancer drugs discovery. PMID- 25282399 TI - The unusual lipid binding proteins of parasitic helminths and their potential roles in parasitism and as therapeutic targets. AB - In this review paper we aim at presenting the current knowledge on structural aspects of soluble lipid binding proteins (LBPs) found in parasitic helminths and to discuss their potential role as novel drug targets. Helminth parasites produce and secrete a great variety of LBPs that may participate in the acquisition of nutrients from their host, such as fatty acids and cholesterol. It is also postulated that LBPs might interfere in the regulation of the host's immune response by sequestering lipidic intermediates or delivering bioactive lipids. A detailed comprehension of the structure of these proteins, as well as their interactions with ligands and membranes, is important to understand host-parasite relationships that they may mediate. This information could also contribute to determining the role that these proteins may play in the biology of parasitic helminths and how they modulate the immune systems of their hosts, and also towards the development of new therapeutics and prevention of the diseases caused by these highly pathogenic parasites. PMID- 25282400 TI - Breath metabolite response to major upper gastrointestinal surgery. AB - BACKGROUND: Esophagectomy and gastrectomy are associated with profound metabolic changes and significant postoperative morbidity. The aim of this prospective clinical study was to determine whether breath analysis can offer novel insight into the surgical metabolic response and identify biomarkers of postoperative complications, including lung injury. METHODS: Breath samples were collected preoperatively and at 24, 48, 72, 96 and 168 h after esophagectomy (n = 25) and gastrectomy (n = 15). Targeted analysis of four prominent breath metabolites was performed by selected ion flow-tube mass spectrometry. Patients with nonsurgical lung injury (community-acquired pneumonia) were recruited as positive controls. RESULTS: Perioperative starvation and subsequent reintroduction of nutritional input were associated with significant changes in breath acetone levels. Breath acetone levels fell after esophagectomy (P = 0.008) and were significantly lower than in gastrectomy patients at postoperative time points 48 (P < 0.001) and 72 h (P < 0.001). In contrast, concentrations of isoprene increased significantly after esophagectomy (P = 0.014). Pneumonia was the most frequently observed postoperative complication (esophagectomy 36% and gastrectomy 7%). The concentration of hydrogen cyanide was significantly lower in the breath of patients who developed pneumonia, 72 h after surgery (P = 0.008). Exhaled hydrogen cyanide (P = 0.001) and isoprene (P = 0.014) were also reduced in patients with community-acquired pneumonia compared with healthy controls. CONCLUSIONS: Selected ion flow-tube mass spectrometry can be used as a totally noninvasive resource to monitor multiple aspects of metabolic alterations in the postoperative period. Exhaled concentrations of several prominent metabolites are significantly altered after major upper gastrointestinal surgery and in response to pneumonia. PMID- 25282401 TI - Editorial overview: Gastrointestinal: gastrointestinal research-mucosal injury, protection, and repair at organ, cellular, and molecular levels. PMID- 25282402 TI - Potential risk of port-site adhesions in patients after laparoscopic myomectomy using radially expanding trocars. AB - OBJECTIVE: To investigate the incidence of port-site adhesions following use of radially expanding trocars (RETs) at laparoscopic myomectomy by observation via second-look laparoscopy (SLL). METHODS: In a retrospective study, data from patients who underwent SLL after laparoscopic myomectomy between January 2007 and June 2012 at Juntendo University Hospital, Tokyo, were assessed for the incidence of port-site adhesions forming below RET incisional scars when fascial and peritoneal defects had not been closed. RESULTS: During the study period, 554 patients underwent SLL, and 2176 incisional scars were examined. Adhesions were detected in 15 patients (2.8%); thus, the incidence of port-site adhesions under scars was 0.7% (15/2176). Among these 15 patients, the wounds with adhesions were located as follows: 6 (1.1%) under the umbilical scar, 5 (0.9%) under the right lower abdominal scar, 2 (0.4%) under the left upper abdominal scar, and 2 (0.4%) under the left lower abdominal scar. According to multiple regression analysis, the duration of laparoscopic myomectomy was positively associated with port-site adhesions (odds ratio, 1.79; 95% confidence interval, 1.09-2.94; P=0.02). CONCLUSION: The present data suggest that the incidence of port-site hernias and adhesions under RET incisional scars is low despite the non-closure of fascial and peritoneal defects. PMID- 25282403 TI - Visual long-term memory and change blindness: Different effects of pre- and post change information on one-shot change detection using meaningless geometric objects. AB - To clarify the relationship between visual long-term memory (VLTM) and online visual processing, we investigated whether and how VLTM involuntarily affects the performance of a one-shot change detection task using images consisting of six meaningless geometric objects. In the study phase, participants observed pre change (Experiment 1), post-change (Experiment 2), or both pre- and post-change (Experiment 3) images appearing in the subsequent change detection phase. In the change detection phase, one object always changed between pre- and post-change images and participants reported which object was changed. Results showed that VLTM of pre-change images enhanced the performance of change detection, while that of post-change images decreased accuracy. Prior exposure to both pre- and post-change images did not influence performance. These results indicate that pre change information plays an important role in change detection, and that information in VLTM related to the current task does not always have a positive effect on performance. PMID- 25282404 TI - Autophagy in Huntington disease and huntingtin in autophagy. AB - Autophagy is an important biological process that is essential for the removal of damaged organelles and toxic or aggregated proteins by delivering them to the lysosome for degradation. Consequently, autophagy has become a primary target for the treatment of neurodegenerative diseases that involve aggregating proteins. In Huntington disease (HD), an expansion of the polyglutamine (polyQ) tract in the N terminus of the huntingtin (HTT) protein leads to protein aggregation. However, HD is unique among the neurodegenerative proteinopathies in that autophagy is not only dysfunctional but wild type (wt) HTT also appears to play several roles in regulating the dynamics of autophagy. Herein, we attempt to integrate the recently described novel roles of wtHTT and altered autophagy in HD. PMID- 25282405 TI - 2,6-Bis(2,6-diethylphenyliminomethyl)pyridine coordination compounds with cobalt(II), nickel(II), copper(II), and zinc(II): synthesis, spectroscopic characterization, X-ray study and in vitro cytotoxicity. AB - Coordination compounds with cobalt(II), nickel(II), copper(II) and zinc(II) and the ligand 2,6-bis(2,6-diethylphenyliminomethyl)pyridine (L) were synthesized and fully characterized by IR and UV-Vis-NIR spectroscopy, elemental analysis, magnetic susceptibility and X-ray diffraction for two representative cases. These novel compounds were designed to study their activity as anti-proliferative drugs against different human cancer cell lines. The tridentate ligand forms heptacoordinated compounds from nitrate metallic salts, where the nitrate acts in a chelating form to complete the seven coordination positions. In vitro cell growth inhibition was measured for Co(II), Cu(II) and Zn(II) complexes, as well as for the free ligand. Upon coordination, the IC50 value of the transition-metal compounds is improved compared to the free ligand. The copper(II) and zinc(II) compounds are the most promising candidates for further in vitro and in vivo studies. The activity against colon and prostate cell lines merits further research, in views of the limited therapeutic options for such cancer types. PMID- 25282406 TI - 'Organised' cervical screening 45 years on: How consistent are organised screening practices? AB - Organised screening programmes have been remarkably successful in reducing incidence and mortality from cervical cancer, while opportunistic screening varies in its effectiveness. Experts recommend that cervical screening or HPV testing be carried out only in the context of an organised programme. We sought to answer the following study questions: What does it mean for a cervical screening programme to be organised? Is there a place for opportunistic screening (in an organised programme)? We reviewed 154 peer-reviewed papers on organised and opportunistic approaches to cervical screening published between 1970 and 2014 to understand how the term 'organised' is used, formally and in practice. We found that despite broad recognition of a prescriptive definition of organisation, in practice the meaning of organisation is much less clear. Our review revealed descriptions of organised programmes that differ significantly from prescribed norms and from each other, and a variety of ways that opportunistic and organised programmes intersect. We describe the breadth of the variation in cervical cancer screening programmes and examine the relationships and overlaps between organised and opportunistic screening. Implications emerging from the review include the need to better understand the breadth of organisation in practice, the drivers and impacts of opportunistic screening and the impact of opportunistic screening on population programme outcomes. Appreciation of the complexity of cervical screening programmes will benefit both screeners and women as programmes are changed to reflect a partially vaccinated population, new evidence and new technologies. PMID- 25282407 TI - Fertility traits of purebred Holsteins and 2- and 3-breed crossbred heifers and cows obtained from Swedish Red, Montbeliarde, and Brown Swiss sires. AB - The objective of this study was to compare fertility traits of heifers and primiparous cows from Swedish Red * Holstein (SR * HO; n=634 and 581, respectively), Montbeliarde * Holstein (MO * HO; n=126 and 114, respectively), Brown Swiss * Holstein (BS * HO; n=59 and 50, respectively), and MO * (SR * HO) (n=241 and 139, respectively) crossbreds, versus those of Holstein heifers and cows (HO; n=3,483 and 2,549, respectively). Animals were born between 2007 and 2011, and belonged to 4 herds located in northern Italy. Heifers were compared for age at first service (AFS), age at first conception (AFC), interval between first service and conception (IFC), nonreturn rate at 56 d after first service (NR56), conception rate at first service (CR), and number of inseminations required for conception (INS). The same traits were evaluated in primiparous cows, except that AFS and AFC were replaced with days at first service (DFS) and days open (DO). The AFS, AFC, IFC, DFS, and DO traits were continuous variables and were thus analyzed under a proportional hazards Cox model that properly accounted for censoring among cows that were culled or failed to conceive. The NR56, CR, and INS traits were analyzed as binary traits using logistic regression. Our results indicated that, among heifers, SR * HO crossbreds had a better chance of having an earlier first service and conceiving earlier than HO, with hazard ratios (HR) of 1.31 for AFS and 1.34 for AFC. Similarly, MO * (SR * HO) crossbreds differed from HO heifers in this regard (HR=1.18 and 1.24, respectively). For the primiparous cows, all crossbreds showed significant differences for DFS, DO, and IFC relative to purebred HO, with the exception of the BS * HO crossbreds. The MO * HO, SR * HO, and MO * (SR * HO) crossbred cows showed increased chances of having fewer DFS (HR=1.40, 1.30, and 1.27, respectively), fewer DO (HR=1.59, 1.43, and 1.58, respectively), and fewer IFC (HR=1.52, 1.26, and 1.39, respectively) than HO cows. All crossbred genotypes, including BS * HO cows, showed higher probabilities for higher NR56, higher CR, and lower INS than purebred HO cows. Together, these findings indicate that the studied crossbred cows have higher reproductive potential than Holsteins. PMID- 25282408 TI - Implementing electronic identification for performance recording in sheep: I. Manual versus semiautomatic and automatic recording systems in dairy and meat farms. AB - With the aim of assessing the secondary benefits of using electronic identification (e-ID) in sheep farms, we compared the use of manual (M), semiautomatic (SA), and automatic (AU) data-collection systems for performance recording (i.e., milk, lambing, and weight) in 3 experiments. Ewes were identified with visual ear tags and electronic rumen boluses. The M system consisted of visual ear tags, on-paper data recording, and manual data uploading to a computer; the use of a personal digital assistant (PDA) for data recording and data uploading was also done in M. The SA system used a handheld reader (HHR) for e-ID, data recording, and uploading. Both PDA and HHR used Bluetooth for uploading. The AU system was only used for body weight recording and consisted of e-ID, data recording in an electronic scale, and data uploading. In experiment 1, M and SA milk-recording systems were compared in a flock of 48 dairy ewes. Ewes were milked once- (*1, n=24) or twice- (*2, n=24) daily in a 2 * 12 milking parlor and processed in groups of 24. Milk yield (1.21 +/- 0.04 L/d, on average) was 36% lower in *1 than *2 ewes and milk recording time correlated positively with milk yield (R(2)=0.71). Data transfer was markedly faster for PDA and HHR than for M. As a result, overall milk recording time was faster in SA (*1=12.1 +/ 0.6 min/24 ewes; *2=22.1 +/- 0.9 min/24 ewes) than M (*1=14.9 +/- 0.6 min/24 ewes; *2=27.9 +/- 1.0 min/24 ewes). No differences between PDA and HHR were detected. Time savings, with regard to M, were greater for *2 than for *1 (5.6 +/ 0.2 vs. 2.8 +/- 0.1 min per 24 ewes, respectively), but similar for PDA and HHR. Data transfer errors averaged 3.6% in M, whereas no errors were found in either SA system. In experiment 2, 73 dairy and 80 meat ewes were monitored at lambing using M and SA. Overall time for lambing recording was greater in M than SA in dairy (1.67 +/- 0.06 vs. 0.87 +/- 0.04 min/ewe) and meat (1.30 +/- 0.03 vs. 0.73 +/- 0.03 min/ewe) ewes. Recording errors were greater in dairy (9.6%) than in meat (1.9%) ewes. Data uploading errors only occurred in M (4.9%). In experiment 3, 120 dairy and 120 meat ewes were weighed using M and AU systems. In both flocks, mean BW recording and data uploading times, as well as overall BW recording time (0.63 +/- 0.02 and 0.25 +/- 0.01 min/ewe, respectively) were greater in M than in AU, and uploading errors only occurred in M (8.8%). In conclusion, HHR and PDA systems were time-effective for performance recording, both saving time and improving data accuracy. Working load and time for ewe identification were faster in HHR but it did not affect the performance recording time. The PDA was the fastest device for data download. Further research will evaluate the costs of implementing e-ID for performance recording and other uses in sheep farms. PMID- 25282409 TI - Potassium sorbate reduces production of ethanol and 2 esters in corn silage. AB - The objective of this work was to evaluate the effects of biological and chemical silage additives on the production of volatile organic compounds (VOC; methanol, ethanol, 1-propanol, methyl acetate, and ethyl acetate) within corn silage. Recent work has shown that silage VOC can contribute to poor air quality and reduce feed intake. Silage additives may reduce VOC production in silage by inhibiting the activity of bacteria or yeasts that produce them. We produced corn silage in 18.9-L bucket silos using the following treatments: (1) control (distilled water); (2) Lactobacillus buchneri 40788, with 400,000 cfu/g of wet forage; (3) Lactobacillus plantarum MTD1, with 100,000 cfu/g; (4) a commercial buffered propionic acid-based preservative (68% propionic acid, containing ammonium and sodium propionate and acetic, benzoic, and sorbic acids) at a concentration of 1 g/kg of wet forage (0.1%); (5) a low dose of potassium sorbate at a concentration of 91 mg/kg of wet forage (0.0091%); (6) a high dose of potassium sorbate at a concentration of 1g/kg of wet forage (0.1%); and (7) a mixture of L. plantarum MTD1 (100,000 cfu/g) and a low dose of potassium sorbate (91 mg/kg). Volatile organic compound concentrations within silage were measured after ensiling and sample storage using a headspace gas chromatography method. The high dose of potassium sorbate was the only treatment that inhibited the production of multiple VOC. Compared with the control response, it reduced ethanol by 58%, ethyl acetate by 46%, and methyl acetate by 24%, but did not clearly affect production of methanol or 1-propanol. The effect of this additive on ethanol production was consistent with results from a small number of earlier studies. A low dose of this additive does not appear to be effective. Although it did reduce methanol production by 24%, it increased ethanol production by more than 2-fold and did not reduce the ethyl acetate concentration. All other treatments increased ethanol production at least 2-fold relative to the control, and L. buchneri addition also increased the 1-propanol concentration to approximately 1% of dry matter. No effects of any treatments on fiber fractions or protein were observed. However, L. buchneri addition resulted in slightly more ammonia compared with the control. If these results hold under different conditions, a high dose of potassium sorbate will be an effective treatment for reducing VOC production in and emission from silage. Regulations aimed at reducing VOC emission could be ineffective or even increase emission if they promote silage additives without recognition of different types of additives. PMID- 25282410 TI - Volatile compounds and sensory properties of Montasio cheese made from the milk of Simmental cows grazing on alpine pastures. AB - The aim of this study was to analyze the volatile compounds, physicochemical characteristics, and sensory properties of Montasio, a semicooked pressed cheese, produced from the milk of the dual-purpose Italian Simmental cows grazing on alpine pastures. A total of 72 cows grazing on 2 pastures, which differed in botanical composition (nutrient-rich pasture vs. nutrient-poor pasture), received 2 different levels of supplementation (3.0 vs 1.5 kg/head per day). The experimental cheeses were produced from whole, raw milk and ripened for 60 d. Sixty-one volatile compounds, including alcohols (11), aldehydes (6), ketones (10), lactones (2), esters (6), hydrocarbons (3), carboxylic acids (6), phenolic compounds (4), monoterpenes (7), sesquiterpenes (1), sulfur compounds (4), and amines (1), were detected. The main families in terms of relative weight appeared to be carboxylic acids, esters, and alcohols. A panel of trained assessors described the experimental cheeses as having an intense color; small and evenly distributed eyes; an intense odor and flavor of milk-sour, milk, and cow; and a tender and creamy texture. The pasture type affected the volatile fraction, particularly ketones, phenolic compounds, and terpenes, which are overall higher in nutrient-poor pastures. A slight effect on the sensory analyses, in particular the effect of the cow attribute on odor and flavor, was perceived by the panelists. The cheeses produced on nutrient-rich pasture had higher b* (yellowness) index. These results were consistent with the color evaluation of the sensory panel. In addition, the pasture affected some textural attributes (adhesivity, creaminess, and granules) as perceived by the panelists. Concentrate supplementation, which is required to meet the feeding requirements of grazing cows, had no clear effect on either the volatile compounds or the sensory properties of the cheeses. Thus, at least within levels of integration adopted, it is expected not to alter the organoleptic characteristics of this product. PMID- 25282411 TI - Short communication: Factors affecting hair cortisol concentrations in lactating dairy cows. AB - Cortisol has long been used as a marker of the stress response in animals. Cortisol can be analyzed from different media, most notably from the blood, saliva, and feces; however, the collection of cortisol from some of these media requires invasive procedures or excessive handling of the animals. Furthermore, it is not possible to capture long-term increases in circulating concentrations of cortisol from the blood, saliva, or feces. Hair cortisol has been found to be a reliable alternative for measuring chronic stress. With this emerging measure, appropriate sampling methodology must be developed and validated. The aim of this study was to determine the effects of hair color, sampling location, and processing method on cortisol concentrations in hair from lactating black and white Holstein cows (n=18). Furthermore, we aimed to measure the hair growth rates at different body locations (n=12) and test hair cortisol levels when resampled over short intervals (n=37). Both black- and white-colored hair was collected from the shoulder, top line, hip, and tail switch of Holsteins; due to breed characteristics only white hair was harvested from the tail switch. All samples were cleaned with water and isopropanol, and then ground in a ball mill or finely cut with scissors once dry. Cortisol was extracted with methanol before being measured using a commercially available ELISA kit. Concentrations of cortisol were greater in white than in black hair (7.8 +/- 1.1 vs. 3.8 +/- 1.1 pg/mg). When only white samples were analyzed, hair from the tail switch had more cortisol than hair from the shoulder (11.0 +/- 1.2 vs. 6.2 +/- 1.2 pg/mg), whereas no difference was found when compared with the hip and top line. Samples ground with a ball mill had greater concentrations of cortisol extracted than those minced with scissors (10.4 +/- 1.2 vs. 4.7 +/- 1.2 pg/mg). The growth rate of hair was significantly greater at the tail switch compared with the hip and shoulder (0.51 +/- 0.05 vs. 0.04 +/- 0.05 vs. 0.03 +/- 0.05 mm/d). When hair was collected every 3 wk after calving, a tendency was detected for multiparous cows to have greater concentrations of hair cortisol and significantly greater concentrations of cortisol on d 0 and 21 after calving compared with d 42, 84, and 126. In Holsteins, the hair on the tail switch is always white, grows more rapidly than other sites, and is sensitive enough to capture changes in cortisol over intervals as short as 3 wk, making it the ideal location for measuring hair cortisol. PMID- 25282412 TI - Influence of corn silage hybrid type on lactation performance by Holstein dairy cows. AB - The primary objective of this study was to determine lactation performance by dairy cows fed nutridense (ND), dual-purpose (DP), or brown midrib (BM) corn silage hybrids at the same concentration in the diets. A secondary objective was to determine lactation performance by dairy cows fed NutriDense corn silage at a higher concentration in the diet. One hundred twenty-eight Holstein and Holstein * Jersey cows (105 +/- 38 d in milk) were stratified by breed and parity and randomly assigned to 16 pens of 8 cows each. Pens were then randomly assigned to 1 of 4 treatments. Three treatment total mixed rations (TMR; DP40, BM40, and ND40) contained 40% of dry matter (DM) from the respective corn silage hybrid and 20% of DM from alfalfa silage. The fourth treatment TMR had ND corn silage as the sole forage at 65% of DM (ND65). A 2-wk covariate adjustment period preceded the treatment period, with all pens receiving a TMR with equal proportions of DP40, BM40, and ND40. Following the covariate period, cows were fed their assigned treatment diets for 11 wk. nutridense corn silage had greater starch and lower neutral detergent fiber (NDF) content than DP or BM, resulting in ND40 having greater energy content (73.2% of total digestible nutrients, TDN) than DP40 or BM40 (71.9 and 71.4% TDN, respectively). Cows fed BM40 had greater milk yield than DP40, whereas ND40 tended to have greater milk yield and had greater protein and lactose yields compared with DP40. No differences in intake, component corrected milk yields, or feed efficiency were detected between DP40, BM40, and ND40. Milk yield differences may be due to increased starch intake for ND40 and increased digestible NDF intake for BM40 compared with DP40. Intake and milk yield and composition were similar for ND40 compared with BM40, possibly due to counteracting effects of higher starch intake for ND40 and higher digestible NDF intake for BM40. Feeding ND65 reduced intake, and thus milk and component yields, compared with ND40 due to either increased ruminal starch digestibility or increased rumen fill for ND65. Nutridense corn silage was a viable alternative to both DP and BM at 40% of diet DM; however, lactation performance was reduced when nutridense corn silage was fed at 65% of DM. PMID- 25282413 TI - Pregnancy outcomes after change in dose delivery of prostaglandin F2alpha and time of gonadotropin-releasing hormone injection in a 5-day timed artificial insemination program in lactating dairy cows. AB - We demonstrated that 50mg of PGF2alpha on d 6 successfully induced luteolysis in lactating dairy cows enrolled in a traditional 5-d Ovsynch-72 program [GnRH injection 5 d before (d 0; GnRH-1) and 56 (p.m. on d 7; GnRH-2) or 72 h (d 8; GnRH-2) after a 25-mg injection of PGF2alpha (d 5 and 6 after GnRH injection); timed artificial insemination (AI) on d 8]. Our current objective was to determine pregnancy outcomes in lactating dairy cows after a 50-mg injection of PGF2alpha on d 6 or a 25-mg injection of PGF2alpha on d 5 and 6 in a 5-d Ovsynch program. Cows in herd 1 diagnosed not pregnant between 30 and 36 d since last AI were enrolled to receive either a 50-mg injection of PGF2alpha on d 6 (1 * 50; n=134) or a 25-mg injection of PGF2alpha on d 5 and 6 (2 * 25; n=139) after GnRH 1 (d 0), with GnRH-2 at 72 h after PGF2alpha injection (d 5), concurrent with timed AI (d 8). Cows in herd 2 diagnosed not pregnant between 34 and 40 d were treated similarly: even-tagged cows received the 2 * 25 (n=422) treatment, and odd-tagged cows received the 1 * 50 (n=450) treatment, except that GnRH-2 was administered at 56 h. Blood collected from cows in herd 1 at d 0, 5, 6, and 8 was assayed for progesterone. Luteolysis was defined to occur when progesterone concentration was >=1 ng/mL on d 5, and 72 h later (d 8) was either <0.5 ng/mL or <1 ng/mL. Progesterone concentrations did not differ between treatments on pretreatment d 0 and 5, but were greater in 1 * 50 than 2 * 25 cows on d 6 (4.7 +/- 0.2 vs. 1.1 +/- 0.2 ng/mL) and d 8 (0.43 +/- 0.04 vs. 0.19 +/- 0.04 ng/mL), respectively. Luteolysis was greater in the 2 * 25 versus 1 * 50 treatment when the cut point was 0.5 ng/mL, whereas no difference was detected when the cut point was <1 ng/mL on d 8. Lack of complete luteolysis was greater in cows classified as early cycle on d 0 or having a new corpus luteum after d 0 because progesterone concentration was greater on d 5 and 6 than for cows classified as late cycle on d 0 or cows having low progesterone on d 0 and 5. Pregnancy per AI at 30 to 40 d did not differ between 2 * 25 and 1 * 50 cows having luteolysis by d 8 or in all cows (37.2 vs. 33.3%) in herd 1, respectively, but differed in herd 2 (24.7 vs. 19.5%; no treatment by herd interaction). We conclude that incomplete luteolysis by d 8 was greater in 1 * 50 cows using a cut point of <0.5 ng/mL at AI. The difference in pregnancy outcome in herd 2 may have resulted from insufficient time for complete luteolysis before GnRH-2 at 56 h compared with GnRH-2 at 72 h (at AI) in herd 1. PMID- 25282414 TI - Evaluation of 2 electronic handheld devices for diagnosis of ketonemia and glycemia in dairy goats. AB - The objective of this study was to evaluate the suitability of the electronic handheld devices FreeStyle Precision (FSP; Abbott Germany, Wiesbaden, Germany) and GlucoMen LX Plus (GML; A. Menarini GmbH, Vienna, Austria) for the measurement of beta-hydroxybutyrate (BHBA) in whole blood in dairy goats. Additionally, glucose concentration was analyzed with the FSP device. For method comparison, the samples were also analyzed in the laboratory by standard methods, which served as the gold standard in our study. A further objective was to evaluate the agreement between samples obtained by minimal invasive venipuncture of an ear vein and measurements of whole blood samples from the jugular vein (vena jugularis). In total, 173 blood sample pairs collected from 28 goats were obtained from an ear vein and from the jugular vein. The Spearman correlation coefficients (rsp) for BHBA concentrations determined with the FSP or GML and the gold standard were 0.95 and 0.85 for the ear vein and 0.98 and 0.88 for the jugular vein, respectively. Bland-Altman plots of differences showed a positive bias of 0.12 (ear vein) and 0.21 (jugular vein) when determination was performed with the FSP and a negative bias of 0.21 (ear vein) and 0.24 (jugular vein) when using the GML. For the FSP, applying the adjusted thresholds determined by ROC analysis of 0.9 (ear vein) and 1.0 mmol/L (jugular vein) allowed to distinguish between healthy goats and animals with hyperketonemia with sensitivities (Se) and specificities (Sp) for samples from the ear vein of 0.98 and 0.85, and from the jugular vein of 0.99 and 0.94, respectively. For the GML, adjusted thresholds were 0.5 mmol/L for the ear vein (Se=0.94, Sp=0.75) and 0.6 mmol/L for the jugular vein (Se=0.88, Sp=0.91). Repeated analyses of defined whole blood samples showed average inter- and intraassay coefficients of variation of 6.6 and 7.3% for FSP, and of 35.6 and 35.4% for GML, respectively. Test characteristics for determining glucose concentration with the FSP compared with the gold standard were poor (ear vein: rsp=0.41; jugular vein: rsp=0.51), with low validity to distinguish between hypo- and normoglycemia (Se=0.71, Sp=0.66). The present study showed good test characteristics for the FSP and moderate for the GML device for determining BHBA concentrations in whole blood. Additionally the results demonstrate the suitability of testing BHBA concentration in a blood drop obtained from an ear vein. Based on the results of this study, the FSP device is not suitable to differentiate normo- from hypoglycemia in goats. PMID- 25282415 TI - Milk-derived ribonuclease 5 preparations induce myogenic differentiation in vitro and muscle growth in vivo. AB - Ribonuclease 5, also known as angiogenin, is a stable and abundant ribonuclease in milk whey protein, which is able to regulate several cellular functions, including capillary formation, neuron survival, and epithelial cell growth. Ribonuclease 5 is important for protein synthesis directly stimulating rRNA synthesis in the nucleolus. Here, we show that biologically active RNase5 can be purified from bovine milk. Furthermore, we show that milk-derived RNase5 directly stimulates muscle cell differentiation in vitro, inducing C2C12 cell differentiation and myogenesis. When supplemented into the diet of healthy adult mice, milk-derived RNase5 preparations promoted muscle weight gain and grip strength. Collectively, these data indicate that milk-derived RNase5 preparations exhibit a novel role in skeletal muscle cell function. PMID- 25282416 TI - Smartamine M and MetaSmart supplementation during the peripartal period alter hepatic expression of gene networks in 1-carbon metabolism, inflammation, oxidative stress, and the growth hormone-insulin-like growth factor 1 axis pathways. AB - Peripartal cows likely require greater amounts of Met not only at the tissue and cell level for methylation reactions but also for milk protein synthesis after calving. Thirty-nine Holstein cows were fed throughout the peripartal period (-21 d to 30 d in milk) a basal control (CON) diet (n=14) with no Met supplementation, CON plus MetaSmart (MS; Adisseo Inc., Antony, France; n=12), or CON plus Smartamine M (SM; Adisseo Inc.; n=13). The Met supplements were adjusted daily and top-dressed over the total mixed ration at a rate of 0.19 or 0.07% (dry matter) of feed for MS or SM. Liver tissue was collected on -10, 7, and 21 d for transcriptome profiling of genes associated with Met and glutathione metabolism as well as components of the inflammation, oxidative stress, growth hormone/insulin-like growth factor-1 axis, and DNA methylation pathways. Data were analyzed using PROC MIXED of SAS (SAS Institute Inc., Cary, NC) with the preplanned contrasts CON versus SM + MS and SM versus MS. The S adenosylhomocysteine hydrolase (SAHH) gene was the most abundant among all genes evaluated, with overall greater expression in Met-supplemented cows than CON, and in SM than MS. Expression of Met adenosyltransferase 1A (MAT1A) was greater in Met-supplemented cows than CON by 21 d postpartum. A greater overall expression of 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) occurred in Met supplemented cows than CON. In contrast, the expression of glutathione synthase (GSS); glutamate-cysteine ligase, catalytic subunit (GCLC); and superoxide dismutase 1, cytosolic (SOD1) was lower in Met-supplemented cows than CON. A greater overall expression of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and greater upregulation of haptoglobin (HP) on d 7 occurred in Met-supplemented cows than CON. Expression of DNA cytosine-5 methyltransferase 3 alpha (DNMT3A) was greater but expression of DNMT1 was lower in Met-supplemented cows than CON. The response observed in SAHH reflects its importance to Met supplementation during the peripartum period. Despite greater HP expression after calving, the lower expression of glutathione (GSS and GCLC) metabolism genes and SOD1 due to Met reflect a lower oxidative stress and mild inflammatory status. The extent to which changes in expression of DNMT3A and DNMT1 result in epigenetic effects partly responsible for the previously observed enhanced performance in Met-supplemented cows remains to be examined. Increasing the supply of Met as SM or MS can affect expression of genes in the Met cycle to various extents and, hence, the supply of methyl donors such as S adenosylmethionine and antioxidants such as glutathione. These compounds likely are in high demand during the peripartum period. PMID- 25282417 TI - Prevalence and characterization of foodborne pathogens from Australian dairy farm environments. AB - The ability of foodborne pathogens to gain entry into food supply systems remains an ongoing concern. In dairy products, raw milk acts as a major vehicle for this transfer; however, the sources of pathogenic bacteria that contaminate raw milk are often not clear, and environmental sources of contamination or the animals themselves may contribute to the transfer. This survey examined the occurrence of 9 foodborne pathogens in raw milk and environments of 7 dairy farms (3 bovine, 3 caprine, and 1 ovine farm) in summer and autumn, in Victoria, Australia. A total of 120 samples were taken from sampling points common to dairy farms, including pasture, soil, feed, water sources, animal feces, raw milk, and milk filters. The prevalence of the Bacillus cereus group, Campylobacter, Clostridium perfringens, Cronobacter, Shiga-toxigenic Escherichia coli, Listeria, Salmonella, coagulase positive staphylococci (CPS), and Yersinia enterocolitica across the farms was investigated. The 2 most prevalent bacteria, which were detected on all farms, were the B. cereus group, isolated from 41% of samples, followed by Cl. perfringens, which was isolated from 38% of samples. The highest occurrence of any pathogen was the B. cereus group in soil, present in 93% of samples tested. Fecal samples showed the highest diversity of pathogens, containing 7 of the 9 pathogens tested. Salmonella was isolated from 1 bovine farm, although it was found in multiple samples on both visits. Out of the 14 occurrences where any pathogen was detected in milk filters, only 5 (36%) of the corresponding raw milk samples collected at the same time were positive for the same pathogen. All of the CPS were Staphylococcus aureus, and were found in raw milk or milk filter samples from 6 of the 7 farms, but not in other sample types. Pathogenic Listeria species were detected on 3 of the 7 farms, and included 4 L. ivanovii-positive samples, and 1 L. monocytogenes-positive water sample. Shiga-toxigenic Escherichia coli were identified in fecal samples from 3 of the 7 farms and in a single raw milk sample. Cronobacter species were identified on 4 of the 7 farms, predominantly in feed samples. No Y. enterocolitica was detected. Results of this study demonstrate high standards of pathogen safety across the 7 farms, with a low incidence of pathogens detected in raw milk samples. Monitoring feed contamination levels may help control the spread of bacterial species such as Cl. perfringens and B. cereus through the farm environment, which is a natural reservoir for these organisms. PMID- 25282418 TI - Implementing electronic identification for performance recording in sheep: II. Cost-benefit analysis in meat and dairy farms. AB - Costs and secondary benefits of implementing electronic identification (e-ID) for performance recording (i.e., lambing, body weight, inventory, and milk yield) in dairy and meat ewes were assessed by using the results from a previous study in which manual (M), semiautomatic (SA), and automatic (AU) data collection systems were compared. Ewes were identified with visual ear tags and electronic rumen boluses. The M system used visual identification, on-paper data recording, and manual data uploading to a computer. The SA system used e-ID with a handheld reader in which performances were typed and automatic uploaded to a computer. The use of a personal digital assistant (PDA) for recording and automatic data uploading, which transformed M in a SA system, was also considered. The AU system was only used for BW recording and consisted of e-ID, automatic data recording in an electronic scale, and uploading to a computer. The cost-benefit study was applied to 2 reference sheep farms of 700 meat ewes, under extensive or intensive production systems, and of 400 dairy ewes, practicing once- or twice-a-day machine milkings. Sensitivity analyses under voluntary and mandatory e-ID scenarios were also included. Benefits of using e-ID for SA or AU performance recording mainly depended on sheep farm purpose, number of test days per year, handheld reader and PDA prices, and flock size. Implementing e-ID for SA and AU performance recording saved approximately 50% of the time required by the M system, and increased the reliability of the data collected. Use of e-ID increased the cost of performance recording in a voluntary e-ID scenario, paying only partially the investment made (15 to 70%). For the mandatory e-ID scenario, in which the cost of e-ID devices was not included, savings paid 100% of the extra costs needed for using e-ID in all farm types and conditions. In both scenarios, the reader price was the most important extra cost (40 to 90%) for implementing e-ID in sheep farms. Calculated extra costs of using the PDA covered more than 100% of the implementation costs in all type of sheep farms, indicating that this device was cost-effective for sheep-performance recording. PMID- 25282419 TI - Biomarkers of inflammation, metabolism, and oxidative stress in blood, liver, and milk reveal a better immunometabolic status in peripartal cows supplemented with Smartamine M or MetaSmart. AB - The peripartal dairy cow experiences a state of reduced liver function coupled with increased inflammation and oxidative stress. This study evaluated the effect of supplementing basal diets with rumen-protected Met in the form of MetaSmart (MS) or Smartamine M (SM) (both from Adisseo Inc., Antony, France) during the peripartal period on blood and hepatic biomarkers of liver function, inflammation, and oxidative stress. Thirty-seven multiparous Holstein cows were fed the same basal diet from -50 to -21 d relative to expected calving [1.24 Mcal/kg of dry matter (DM); no Met supplementation]. From -21 d to calving, the cows received diets (1.54 Mcal/kg of DM) with no added Met (control, CON; n=13), CON plus MS (n=11), or CON plus SM (n=13). From calving through 30 d in milk (DIM), the cows received the same postpartal diet (1.75 Mcal/kg of DM; CON), or CON plus MS or CON plus SM. Liver and blood samples were harvested at various time points from -21 to 21 d relative to calving. Preplanned contrasts of CON versus SM + MS during prepartum (-21 and -10 d before calving) and postpartum (7, 14, and 21 d after calving) responses were evaluated. Cows fed MS or SM compared with CON had lower overall concentrations of plasma ceruloplasmin and serum amyloid A (SAA). Compared with CON, Met-supplemented cows had greater overall plasma oxygen radical absorbance capacity. Liver concentrations of glutathione and carnitine also were greater overall with Met supplementation. Milk choline and liver phosphatidylcholine were lower overall in cows fed Met compared with controls. Liver tissue choline concentrations did not differ. Data indicate that supplemental Met enhanced de novo glutathione and carnitine synthesis in liver and, thus, increased antioxidant and beta-oxidation capacity. The greater decrease of IL-6 after calving coupled with lower ceruloplasmin and SAA in Met supplemented cows indicated a reduction in proinflammatory signaling within liver. The lower hepatic phosphatidylcholine in Met-supplemented cows might have been associated with greater assembly or export of very low density lipoproteins. Overall, biomarker analyses in blood and tissue indicate that the beneficial effect of feeding SM and MS on postpartal cow performance is due in part to a better immunometabolic status. PMID- 25282420 TI - Antioxidant and antibacterial activities of exopolysaccharides from Bifidobacterium bifidum WBIN03 and Lactobacillus plantarum R315. AB - The objective of this study was to investigate the antioxidant and antibacterial activities of exopolysaccharide (EPS) from Bifidobacterium bifidum WBIN03 (B-EPS) and Lactobacillus plantarum R315 (L-EPS). The 1,1-diphenyl-2-picrylhydrazyl (DPPH)-radical scavenging, hydroxyl radical-scavenging, and superoxide radical scavenging abilities were measured to evaluate antioxidant activity. Inhibition of erythrocyte hemolysis and lipid peroxidation was also measured. Both B-EPS and L-EPS had strong scavenging ability against DPPH and superoxide radicals at high concentration. The inhibitory effect of B-EPS on erythrocyte hemolysis was stronger than that of L-EPS in a concentration range from 0.30 to 1.00 mg/mL, whereas the hydroxyl scavenging ability of L-EPS (39.15 +/- 0.58%) was significantly higher than that of 0.15 mg/mL ascorbic acid (24.33 +/- 1.17%) and B-EPS (17.89 +/- 3.30%) at 0.10 mg/mL. The inhibition of lipid peroxidation of 0.50 mg/mL B-EPS and L-EPS was 13.48 +/- 1.74% and 12.43 +/- 0.51%, respectively, values lower than that of ascorbic acid at the same concentration (23.20 +/- 1.41%). Furthermore, all these abilities were enhanced in a concentration dependent manner. Agar diffusion assay showed that both EPS exhibited antibacterial activities against tested pathogens such as Cronobacter sakazakii, Escherichia coli, Listeria monocytogenes, Staphyloccocus aureus, Candida albicans, Bacillus cereus, Salmonella typhimurium, and Shigella sonnei at 300 MUg/mL. In conclusion, both EPS have antimicrobial and antioxidant activities and could have applications in the food industry. PMID- 25282421 TI - Comparison of single-trait to multi-trait national evaluations for yield, health, and fertility. AB - Flexible software was designed to replace the current animal model programs used for national genetic evaluations. Model improvements included (1) multi-trait processing, (2) multiple fixed class and regression variables, (3) differing models for different traits, (4) random regressions, and (5) foreign data included using pseudo-records. Computational improvements included (6) parallel processing, (7) renumbering class variables to equation numbers within the program so that estimated effects are output with original identification numbers, and (8) reliability computed within the same program. When applied to 3 fertility traits of 27,971,895 cows and heifers, the new model used daughter pregnancy rate as a correlated trait to improve heifer and cow conception rate evaluations for older animals and in herd-years where records are missing, and also added information from crossbreds. When applied to 7 traits and 76,846,327 lactation records of 30,064,300 cows, gains in accuracy were small for yield and somatic cell score, moderate for daughter pregnancy rate, and larger for productive life for recent bulls compared with single-trait evaluations. For very old bulls, multi-trait gains were also large for protein because lactation records were available only for milk and fat. Multi-trait productive life was computed with exact rather than approximate methods; however, correlated information from conformation was excluded, reducing advantages of the new model over the previous software. Estimates of breed differences, inbreeding depression, and heterosis were similar to previous estimates; new estimates were obtained for conception rates. Predictions were compared by truncating 4 yr of data, and genetic trend validation was applied to all breed-trait combinations. The estimates of trend account for increases in inbreeding across time. Incorporation of foreign data gave correlations above 0.98 for new with previous evaluations of foreign Holstein bulls, but lower for other breeds. The 7-trait model required 35 GB of memory and 3 d to converge using 7 processors. The new software was implemented for fertility traits in 2013 and is scheduled for implementation with yield, somatic cell score, and productive life in 2014. Further revision of the models and software may be needed in the near future to account for genomic preselection. PMID- 25282422 TI - Optimizing the design of small-sized nucleus breeding programs for dairy cattle with minimal performance recording. AB - Dairy cattle breeding programs in developing countries are constrained by minimal and erratic pedigree and performance recording on cows on commercial farms. Small sized nucleus breeding programs offer a viable alternative. Deterministic simulations using selection index theory were performed to determine the optimum design for small-sized nucleus schemes for dairy cattle. The nucleus was made up of 197 bulls and 243 cows distributed in 8 non-overlapping age classes. Each year 10 sires and 100 dams were selected to produce the next generation of male and female selection candidates. Conception rates and sex ratio were fixed at 0.90 and 0.50, respectively, translating to 45 male and 45 female candidates joining the nucleus per year. Commercial recorded dams provided information for genetic evaluation of selection candidates (bulls) in the nucleus. Five strategies were defined: nucleus records only [within-nucleus dam performance (DP)], progeny records in addition to nucleus records [progeny testing (PT)], genomic information only [genomic selection (GS)], dam performance records in addition to genomic information (GS+DP), and progeny records in addition to genomic information (GS+PT). Alternative PT, GS, GS+DP, and GS+PT schemes differed in the number of progeny per sire and size of reference population. The maximum number of progeny records per sire was 30, and the maximum size of the reference population was 5,000. Results show that GS schemes had higher responses and lower accuracies compared with other strategies, with the higher response being due to shorter generation intervals. Compared with similar sized progeny-testing schemes, genomic-selection schemes would have lower accuracies but these are offset by higher responses per year, which might provide additional incentive for farmers to participate in recording. PMID- 25282423 TI - Lameness detection challenges in automated milking systems addressed with partial least squares discriminant analysis. AB - Lameness causes decreased animal welfare and leads to higher production costs. This study explored data from an automatic milking system (AMS) to model on-farm gait scoring from a commercial farm. A total of 88 cows were gait scored once per week, for 2 5-wk periods. Eighty variables retrieved from AMS were summarized week-wise and used to predict 2 defined classes: nonlame and clinically lame cows. Variables were represented with 2 transformations of the week summarized variables, using 2-wk data blocks before gait scoring, totaling 320 variables (2 * 2 * 80). The reference gait scoring error was estimated in the first week of the study and was, on average, 15%. Two partial least squares discriminant analysis models were fitted to parity 1 and parity 2 groups, respectively, to assign the lameness class according to the predicted probability of being lame (score 3 or 4/4) or not lame (score 1/4). Both models achieved sensitivity and specificity values around 80%, both in calibration and cross-validation. At the optimum values in the receiver operating characteristic curve, the false-positive rate was 28% in the parity 1 model, whereas in the parity 2 model it was about half (16%), which makes it more suitable for practical application; the model error rates were, 23 and 19%, respectively. Based on data registered automatically from one AMS farm, we were able to discriminate nonlame and lame cows, where partial least squares discriminant analysis achieved similar performance to the reference method. PMID- 25282424 TI - Premilking teat disinfection: is it worthwhile in pasture-grazed dairy herds? AB - A controlled trial was conducted in 5 pasture-grazed commercial dairy herds in Australia in 2012 to determine whether premilking teat disinfection and drying of teats reduces clinical mastitis incidence during early lactation by at least 50%. A 50% reduction was estimated to be the minimum required to justify additional costs of labor, disinfectants, and other resources if premilking teat disinfection was implemented in a 500-cow herd averaging 8 clinical cases per 100 cow-months. A secondary aim was to determine whether this premilking teat disinfection routine reduces incidence of new udder infections. Treatment was applied in each herd for approximately 60 d (range of 59.5 to 61 d), commencing in each herd soon after the start of the herd's main or only calving period. Within each herd, cows were allocated to either the treatment (premilking disinfection) or the control (no premilking disinfection) group based on their herd identity number. During the trial period, any cow having a new case of clinical mastitis or an individual cow cell count greater than 250,000 cells/mL of milk (when preceded by individual cow cell counts of 250,000 cells/mL of milk or below) was deemed to have had a new infection. Overall, neither clinical mastitis incidence nor new infection rate differed significantly between treatment and control groups. Over the whole study period, 98 of the 1,029 cows in the premilking disinfection group and 97 of the 1,025 cows in the control group had clinical mastitis. Total cow-days at risk of clinical mastitis were similar in each group. However, clinical incidence rates were markedly lower in treatment cows in one herd (herd 3; incidence rate ratio=0.34) and there was some evidence that new infection incidence rates were lower in treated cows in this herd (incidence rate ratio=0.42). Rainfall during the study period was below long term district average in all 5 study herds. Cows' teats were less dirty than in previous, wetter years for the 4 herds where no significant clinical mastitis response was detected but some teat soiling was observed in herd 3 during the study period. Routine application of premilking teat disinfection in pasture grazed herds is unlikely to produce a worthwhile (economic) reduction in the number of clinical mastitis cases when teats are relatively clean and dry and the clinical mastitis incidence is low. However, premilking disinfection might be worthwhile during periods when teats are heavily soiled and the incidence of clinical mastitis due to environmental pathogens is high. PMID- 25282425 TI - Stage of lactation and corresponding diets affect in situ protein degradation by dairy cows. AB - The influence of stage of lactation and corresponding diets on rates of protein degradation (kd) is largely unstudied. Study objectives were to measure and compare in situ ruminal kd of crude protein (CP) and estimate rumen CP escape (rumen-undegradable protein; RUP) of selected feeds by cows at 3 stages of lactation fed corresponding diets, and to determine the incubation times needed in an enzymatic in vitro procedure, using 0.2 units of Streptomyces griseus protease per percent of true CP, that predicted in situ RUP. Residue CP was measured after in situ fermentation for 4, 8, 12, 24, 36, 48, and 72 h of 5 protein sources and 3 total mixed rations, which were fed to the in situ cows. Two nonlactating (dry) cows and 2 cows each at 190 (mid) and 90 (peak) days of lactation were used. Each pair of cows was offered free-choice diets that differed in composition to meet their corresponding nutrient requirements. Diets had decreasing proportions of forages and contained (dry matter basis) 11.9, 15.1 and 16.4% CP and 54.3, 40.3 and 35.3% neutral detergent fiber, for dry, mid, and peak TMR (TMR1, TMR2, and TMR3), respectively. Intakes were 10.3, 21.4, and 23.8kg of dry matter/d, respectively. Kinetic CP fractions (extractable, potentially degradable, undegradable, or slowly degradable) were unaffected by treatment. Lag time and kd varied among feeds. The kd was faster for all feeds (0.136/h) when incubated in dry-TMR1 cows compared with mid-TMR2 (0.097/h) or peak-TMR3 (0.098/h) cows, and no differences in lag time were detected. Calculated RUP, using estimated passage rates for each cow based on intake, differed between dry-TMR1 (0.382) and mid-TMR2 (0.559) or peak-TMR3 (0.626) cows, with a tendency for mid-TMR2 to be different from peak-TMR3. Using the average kd and lag time obtained from dry-TMR1 to calculate RUP for mid-TMR2 and peak-TMR3 cows using their passage rates reduced RUP values by 6.3 and 9.5 percentage units, respectively. Except for that of herring meal, in vitro residue CP at 6, 12, and 48h of enzymatic hydrolysis was correlated (r=0.90) with in situ RUP of peak-TMR3, mid-TMR2, and dry-TMR1, respectively. Although confounded within treatments, stage of lactation, diet, and intake appeared to affect CP degradation parameters and RUP. Using kd from nonlactating cows, or the RUP calculated from them, may bias diet evaluation or ration formulation for lactating cows. In addition, enzymatic in vitro predictions of RUP should be measured using incubation times that are appropriate for lactating cows. PMID- 25282426 TI - Active dry Saccharomyces cerevisiae can alleviate the effect of subacute ruminal acidosis in lactating dairy cows. AB - The objective of the study was to determine the effect of active dry Saccharomyces cerevisiae (ADSC) supplementation on dry matter intake, milk yield, milk components, ruminal pH, and microbial community during a dietary regimen that leads to subacute ruminal acidosis (SARA). Sixteen multiparous, rumen cannulated lactating Holstein cows were randomly assigned to 1 of 2 dietary treatments that included ADSC (Biomate; AB Vista, Marlborough, UK; 8 * 10(10) cfu/head per day) or control. During wk 1 to 6, all cows received a high-forage (HF) diet (77:23, forage:concentrate). Cows were then abruptly switched during wk 7 to a high-grain (HG) diet (49:51, forage:concentrate) and remained on the HG until the end of wk 10. Feed intake and milk yields were recorded daily. Ruminal pH was recorded continuously using an indwelling system for 1 to 2 d per week during the pre-experimental phase, and wk 6, 7, and 10. Ruminal digesta samples were collected at the end of the experiment and analyzed for relative change in microbial communities using real-time quantitative PCR. Cows were considered to have SARA if the duration below pH 5.6 was >=300 min/d. Ruminal pH during wk 6 (HF plateau) was not different across treatments (15 +/- 46 min/d at pH <5.6). The dietary regimen successfully induced SARA during wk 7 (transition from HF to HG diet), and ruminal pH (551 +/- 46 min/d at pH <5.6) was not different across treatments. However, cows receiving ADSC had an improved ruminal pH (122 +/- 57 vs. 321 +/- 53 min/d at pH <5.6) during wk 10 (HG plateau) compared with control. Additionally, cows receiving ADSC had a better dry matter intake (23.3 +/- 0.66 vs. 21.6 +/- 0.61 kg/d) and 4% fat-corrected milk yield (29.6 +/- 1.2 vs. 26.5 +/ 1.2 kg/d) than control cows during the HG phase (wk 8 to 10). During HG feeding, cows receiving ADSC had greater total volatile fatty acid and propionate concentrations (175 +/- 7.5 vs. 154 +/- 7.5 and 117 +/- 6.1 vs. 94 +/- 5.7 mM for ADSC and control, respectively) and lower acetate:propionate ratio (0.26 +/- 0.5 vs. 0.36 +/- 0.05 for ADSC and control, respectively). Microbial analyses conducted on samples collected during wk 10 showed that cows supplemented with S. cerevisiae had a 9-fold, 2-fold, 6-fold, 1.3-fold, and 8-fold increase in S. cerevisiae, Fibrobacter succinogenes, Anaerovibrio lipolytica, Ruminococcus albus, and anaerobic fungi, respectively, which suggested an increase in cellulolytic microbes within the rumen. Cows supplemented with ADSC had 2.2-fold reduction in Prevotella albensis, which is a gram-negative bacterium predominant during SARA. Prevotella spp. are suggested to be an important source of lipopolysaccharide responsible for inflammation within the rumen. Cows supplemented with ADSC had a 2.3-fold increase in Streptococcus bovis and a 12 fold reduction in Megasphaera elsdenii. The reduction in M. elsdenii may reflect lower concentration of lactic acid within the rumen for ADSC cows. In conclusion, ADSC supplementation to dairy cows was demonstrated to alleviate the condition of SARA caused by abrupt dietary changes from HF to HG, and can potentially improve rumen function, as indicated by greater numbers of cellulolytic microorganisms within the rumen. PMID- 25282427 TI - [Assessment of individual clinical outcomes: regarding an electroconvulsive therapy case]. AB - Evaluation of therapeutic results and of the efficacy and effectiveness of treatments is an area of interest both for clinicians and researchers. In general, randomized controlled trial designs have been used as the methodology of choice in which intergroup comparisons are made having a minimum of participants in each arm of treatment. However, these procedures are seldom used in daily clinical practice. Despite this fact, the evaluation of treatment results for a specific patient is important for the clinician in order to address if therapeutic goals have been accomplished both in terms of statistical significance and clinical meaningfulness. The methodology based on the reliable change index (Jacobson y Truax)1 provides an estimate of these two criteria. The goal of this article is to propose a procedure to apply the methodology with a single case study of a woman diagnosed with major depression and treated with electroconvulsive therapy. PMID- 25282428 TI - Helping smokers quit in the "real world". PMID- 25282429 TI - Prospective cohort study of the effectiveness of smoking cessation treatments used in the "real world". AB - OBJECTIVE: To estimate the "real-world" effectiveness of commonly used aids to smoking cessation in England by using longitudinal data. PATIENTS AND METHODS: We conducted a prospective cohort study in 1560 adult smokers who participated in an English national household survey in the period from November 2006 to March 2012, responded to a 6-month follow-up survey, and made at least 1 quit attempt between the 2 measurements. The quitting method was classified as follows: (1) prescription medication (nicotine replacement therapy [NRT], bupropion, or varenicline) in combination with specialist behavioral support delivered by a National Health Service Stop Smoking Service; (2) prescription medication with brief advice; (3) NRT bought over the counter; (4) none of these. The primary outcome measure was self-reported abstinence up to the time of the 6-month follow up survey, adjusted for key potential confounders including cigarette dependence. RESULTS: Compared with smokers using none of the cessation aids, the adjusted odds of remaining abstinent up to the time of the 6-month follow-up survey were 2.58 (95% CI, 1.48-4.52) times higher in users of prescription medication in combination with specialist behavioral support and 1.55 (95% CI, 1.11-2.16) times higher in users of prescription medication with brief advice. The use of NRT bought over the counter was associated with a lower odds of abstinence (odds ratio, 0.68; 95% CI, 0.49-0.94). CONCLUSION: Prescription medication offered with specialist behavioral support and that offered with minimal behavioral support are successful methods of stopping cigarette smoking in England. PMID- 25282430 TI - Pertussis outbreak, southeastern Minnesota, 2012. AB - OBJECTIVE: To describe clinical and laboratory findings from the 2012 southeastern Minnesota pertussis outbreak. PATIENTS AND METHODS: Patients were selected for 2 parts of the study. In the first part, nasopharyngeal swabs from a convenience sample of 265 unique patients were used for both the clinician requested polymerase chain reaction (PCR) test and culture. B pertussis isolates were tested for macrolide susceptibility and typed using whole genome sequencing and pulsed-field gel electrophoresis. Pertactin gene sequences were analyzed to identify pertactin-deficient B pertussis. In the second part, all patients seen at Mayo Clinic in Rochester, Minnesota, who had PCR results positive for Bordetella pertussis or Bordetella parapertussis between January 1, 2012, and December 31, 2012, were analyzed for patient demographic features and vaccination records. RESULTS: One hundred sixty patients had results positive for B pertussis, and 21 patients had results positive for B parapertussis. Among the 265 swabs cultured, B pertussis was detected by both culture and PCR in 11. One swab was positive for B pertussis by culture alone, and 13 were positive by PCR alone. Polymerase chain reaction detected B pertussis more frequently than did culture (P=.001). No macrolide resistance was detected. All 12 isolates tested had an altered pertactin gene, including 9 with a signal sequence deletion, 2 with insertion sequence disruptions, and 1 with a premature stop codon. Nine and 3 isolates were pertactin types prn1 and prn2, respectively. Whole genome sequencing and pulsed-field gel electrophoresis detected the presence of multiple B pertussis strains. The mean age of patients with pertussis was younger than that of those without pertussis (15.6 and 25.5 years, respectively; P=.002). Compared with those whose test results were negative for B pertussis, fewer patients with positive results had received whole-cell pertussis vaccine (P=.02). In the subgroup who had received acellular vaccine exclusively, the time since the most recent pertussis vaccination in those with results positive for B pertussis was longer than that in those with negative results (1363 vs 1010 days; P=.004). CONCLUSION: The 2012 pertussis outbreak in southeastern Minnesota included multiple strains of B pertussis, all putatively lacking pertactin. Our findings may indicate decreased efficacy of (and waning immunity from) acellular vaccines as contributors to the outbreak. PMID- 25282432 TI - 79-year-old man with chronic bilateral calf pain. PMID- 25282431 TI - Mild cognitive impairment and mild dementia: a clinical perspective. AB - Mild cognitive impairment and mild dementia are common problems in the elderly. Primary care physicians are the first point of contact for most patients with these disorders and should be familiar with their diagnosis, prognosis, and management. Both mild cognitive impairment and mild dementia are characterized by objective evidence of cognitive impairment. The main distinctions between mild cognitive impairment and mild dementia are that in the latter, more than one cognitive domain is invariably involved and substantial interference with daily life is evident. The diagnosis of mild cognitive impairment and mild dementia is based mainly on the history and cognitive examination. The prognosis for mild cognitive impairment and mild dementia is an important motivation for diagnosis because in both, there is a heightened risk for further cognitive decline. The etiology of mild cognitive impairment and mild dementia can often be established through the clinical examination, although imaging and other laboratory tests may also contribute. Although Alzheimer disease is the most common cause of both, cerebrovascular disease and Lewy body disease make important contributions. Pharmacological treatments are of modest value in mild dementia due to Alzheimer disease, and there are no approved pharmacological treatments for mild cognitive impairment of any etiology. Nonetheless, new-onset cognitive impairment is a worrisome symptom to patients and families that demands answers and advice. If a patient is having difficulties managing medications, finances, or transportation independently, diagnosis and intervention are necessary to ensure the health and safety of the patient. PMID- 25282433 TI - Resistance training and cancer survival. PMID- 25282434 TI - In reply-Resistance Training and Cancer Survival. PMID- 25282435 TI - Bruce Beutler: innate immunity and Toll-like receptors. PMID- 25282437 TI - 23-year-old woman with syncope. PMID- 25282438 TI - Scalp necrosis in giant cell arteritis. PMID- 25282439 TI - Prevalence and risk factors of diastasis recti abdominis from late pregnancy to 6 months postpartum, and relationship with lumbo-pelvic pain. AB - Diastasis recti abdominis (DRA) is an impairment characterized by a midline separation of the rectus abdominis muscles along the linea alba. It has its onset during pregnancy and the first weeks following childbirth. There is scant knowledge on both prevalence and risk factors for development of the condition. The aim of this study was to investigate the prevalence of DRA at gestational week 35 and three timepoints postpartum, possible risk factors, and the relationship between DRA and lumbo-pelvic pain. Ultrasound images of inter rectus distance (IRD) were recorded in 84 healthy primiparous women, at three locations on the linea alba. The IRD was measured at: gestational week 35 and 6-8, 12-14, and 24-26 weeks postpartum. Diagnosis of DRA was defined as 16 mm at 2 cm below the umbilicus. Independent sample t-test and binary logistic regression was used to assess differences and risk factors in women with and without DRA and women with and without lumbo-pelvic pain. P < 0.05 was considered statistically significant. The prevalence of DRA decreased from 100% at gestational week 35-39% at 6 months postpartum. No statistically significant differences were found in prepregnancy body mass index (BMI), weight gain, baby's birth weight or abdominal circumference between women with and without DRA at 6 months postpartum. Women with DRA at 6 months postpartum were not more likely to report lumbo-pelvic pain than women without DRA. DRA is prevalent at 6 months postpartum, but is not linked with lumbo-pelvic pain. PMID- 25282440 TI - Analgesic effects of manual therapy in patients with musculoskeletal pain: a systematic review. AB - BACKGROUND: Current evidence shows that manual therapy elicits analgesic effect in different populations (healthy, pain inflicted and patients with musculoskeletal pain) when carried out at the spinal column, although the clinical significance of these effects remains unclear. Also the analgesic effects of manual therapy on peripheral joints have not been systematically reviewed. METHODS: A systematic review was carried out following the PRISMA guidelines. Manual therapy was defined as any manual induced articular motion with the aim of inducing analgesic effects. Outcome measure was pain threshold. RESULTS: A total of 13 randomized trials were included in the review. In 10 studies a significant effect was found. Pressure pain thresholds increased following spinal or peripheral manual techniques. In three studies both a local and widespread analgesic effect was found. No significant effect was found on thermal pain threshold. DISCUSSION: Moderate evidence indicated that manual therapy increased local pressure pain thresholds in musculoskeletal pain, immediately following the intervention. No consistent result was found on remote pressure pain threshold. No significant changes occured on thermal pain threshold values. The clinical relevance of these effects remains contradictory and therefore unclear. PMID- 25282441 TI - Sensitization of a stray-field NMR to vibrations: a potential for MR elastometry with a portable NMR sensor. AB - An NMR signal from a sample in a constant stray field of a portable NMR sensor is sensitized to vibrations. The CPMG sequence is synchronized to vibrations so that the constant gradient becomes an "effective" square-wave gradient, leading to the vibration-induced phase accumulation. The integrating nature of the spot measurement, combined with the phase distribution due to a non-uniform gradient and/or a wave field, leads to a destructive interference, the drop in the signal intensity and changes in the echo train shape. Vibrations with amplitudes as small as 140 nm were reliably detected with the permanent gradient of 12.4 T/m. The signal intensity depends on the phase offset between the vibrations and the pulse sequence. This approach opens the way for performing elastometry and micro rheology measurements with portable NMR devices beyond the walls of a laboratory. Even without synchronization, if a vibration frequency is comparable to 1/2TE of the CPMG sequence, the signal can be severely affected, making it important for potential industrial applications of stray-field NMR. PMID- 25282442 TI - Slow motions in microcrystalline proteins as observed by MAS-dependent 15N rotating-frame NMR relaxation. AB - (15)N NMR relaxation rate R1rho measurements reveal that a substantial fraction of residues in the microcrystalline chicken alpha-spectrin SH3 domain protein undergoes dynamics in the MUs-ms timescale range. On the basis of a comparison of 2D site-resolved with 1D integrated (15)N spectral intensities, we demonstrate that the significant fraction of broad signals in the 2D spectrum exhibits the most pronounced slow mobility. We show that (15)N R1rho's in proton-diluted protein samples are practically free from the coherent spin-spin contribution even at low MAS rates, and thus can be analysed quantitatively. Moderate MAS rates (10-30 kHz) can be more advantageous in comparison with the rates >50-60 kHz when slow dynamics are to be identified and quantified by means of R1rho experiments. PMID- 25282443 TI - [Intravenous lidocaine: an increasing but unauthorized prescription]. PMID- 25282444 TI - [Interest of ultrasound-guided lateral pectoral nerve block associated with paravertebral block for complete mastectomy pain management]. PMID- 25282445 TI - [Hemorrhagic stroke and new oral anticoagulants]. AB - The recent release of new oral anticoagulants (NOAC) raises the question of the management of intracranial hemorrhage occurring during treatment with these molecules. Dabigatran, rivaroxaban and apixaban have different pharmacological characteristics that physicians need to know to adjust their prescription to each patient. Studies of efficacy and safety prior to the marketing of these molecules showed a decreased risk of intracranial hemorrhage compared with vitamin K antagonists. However, no reliable data are available regarding the prognosis of these hemorrhages occurring during NOAC treatment. In addition, there is no specific antidote and reversal protocol validated in humans. So, physicians are in a difficult situation when critical bleeding occurs. The timing of recovering normal hemostatic capacity is then a determinant factor of prognosis. Studies in animals or healthy volunteers showed a correction of the biological parameters using prothrombin complex concentrates activated or not, without reducing the volume of hematoma. On this basis, proposals have been issued by the french group of interest for perioperative hemostasis (GIHP) for the management of bleeding under NOAC treatment, which include management of intracranial hemorrhage. PMID- 25282446 TI - [Observational study on outpatient sleeve gastrectomy]. AB - The development of outpatient surgery is one of the major goals of the public health policy in 2010. The purpose of this observational study is to evaluate the feasibility of the laparoscopic sleeve gastrectomy (LSG) in ambulatory. METHODS: This prospective observational study was conducted from May 2011 to June 2013. The procedure was proposed for patients undergoing LSG who were predetermined inclusion criteria. Following preoxygenation, anaesthesia was induced with propofol and sufentanil. Tracheal intubation was facilitated with rocuronium. Anaesthesia was maintained with desflurane and remifentanil target-controlled infusion. Antiemetic prophylaxis was supplied with intravenous (IV) droperidol and dexamethasone; postoperative pain prophylaxis was IV paracetamol, nefopam, tramadol, and ropivacaine infiltration. The patients were extubated in the operating room and kept in the postoperative care unit. A water-soluble contrast examination was performed in the output of the postoperative care unit. Oral feeding was resumed immediately in the absence of fistula on this leak test in an ambulatory surgical unit. When the patient has satisfied the modified Post Anaesthesia Discharge Scoring System (PADSS) criteria, he or she can then be discharged and sent home. RESULTS: Among 280 patients operated on for obesity by laparoscopic sleeve gastrectomy during the study period, 68 (24.2 %) underwent ambulatory procedure. Of the 68 obese patients, 94.1 % were female. Mean age was 34.4 years (22-55). Mean preoperative BMI was 42.6kg/m(2). Thirteen patients (19.1 %) had HTN; 7 (10.2 %) had dyslipidemia and 6 (8.8 %) had diabetes not requiring treatment. The mean operating time was 60minutes (range, 45-95) and there were no conversions to open surgery. No intra-operative anesthetic or surgical complications occurred. Mean time in the recovery room was 86.5minutes (35-240). The overall satisfaction rate was 92.6 % (n=63). No patients were admitted because of nausea or inadequate pain control. There were no re admissions or hospitalizations were reported. We recorded five surgical complications including two case of gastric fistula, one case of gastric stenosis, one case of scar dehiscence and one case of splenic upper pole ischemia. Its complications have arisen from the fourth postoperative day. This does not undermine the ambulatory procedure. CONCLUSION: The laparoscopic sleeve gastrectomy in ambulatory is feasible with a dedicated anesthesiological concept in an expert surgical team. Appropriate patient selection is important in order to secure safety and quality of care within outpatient program. The risk versus benefit must be adequately evaluated on an individual basis. PMID- 25282447 TI - Current trends in U.S. cardiology practice. AB - Over the last six years, the practice of cardiology in the U.S. has experienced a substantial transition from independent practice to practices integrated within hospital systems. This change has been driven by major economic factors that have largely been determined by the federal government. Meanwhile, cardiologists' salaries and the demand for new cardiologists have remained stable. Best practices have embraced this new partnership with hospital systems to improve quality, cost, and access to cardiovascular care. PMID- 25282448 TI - Warfarin pharmacogenetics. AB - The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID- 25282449 TI - Bursin-like peptide (BLP) enhances H9N2 influenza vaccine induced humoral and cell mediated immune responses. AB - Vaccination with H9N2 avian influenza whole-inactivated virus (WIV) has been shown to be ineffective at eliciting sufficient humoral and cellular immunity against H9N2 avian influenza virus. This study assessed the effects of a synthetic Bursin-like epitope peptide (BLP) as adjuvant for H9N2 WIV in mice. Titers HI and avian influenza virus neutralizing antibodies, subtypes of HA antibodies, T helper (Th) cytokine levels, cytotoxic T-lymphocyte activities and changes in spleen T-cell subsets and natural killer cells were determined. We found that BLP induced a balance between IgG1 and IgG2a secretion levels. WIV antigen alone induced mainly Th1 cytokines secretion, whereas BLP showed increased secretion of Th1 and Th2 cytokines, including interleukin (IL)-2, interferon-gamma (IFN-gamma) and IL-4, but not IL-10, and may be resembles a Th0 like response. BLP significantly promoted growth and expansion of natural killer cells and of CD4(+) and CD8(+) T-cell subsets in the spleen. Meanwhile, BLP induced a better cytotoxic T-lymphocyte response to H9N2 virus. Furthermore, virus challenge experiments confirmed that BLP contributed to inhibition replication of the virus from mouse lungs. Taken together, these findings suggest that BLP may be an effective adjuvant for H9N2 avian influenza vaccine. PMID- 25282450 TI - [Two pediatric cases of anti-NMDA receptor antibody encephalitis]. AB - Although less frequent than viral encephalitis, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a frequent form of acute pediatric encephalitis. After a prodromal phase of flu-like symptoms, psychiatric symptoms predominate - agitation, anxiety, hallucinations - and can make correct diagnosis more difficult. Also noted are abnormal dyskinesia and dystonia-like movements, partial seizures, difficulties talking or memorizing, and autonomic manifestations. The presentation of two cases of anti-NMDAR encephalitis illustrates the symptoms of this disease. Although the CSF abnormalities are not highly specific of this disease, and MRI most often normal, EEG shows more specific signs. These observations enable us to discuss different treatment options and understand the progression of this disease. PMID- 25282451 TI - Chickenpox complicated by pneumococcal meningitis: a rare coinfection. AB - Bacterial complications, particularly skin superinfections, are common during chickenpox. However, reports of acute bacterial meningitis associated with chickenpox are unusual and amount to only a very few observations. For the most part, they are caused by Neisseria meningitidis or Streptococcus pyogenes. We report an infrequent occurrence of pneumococcal meningitis 2 days after the onset of a chickenpox rash in a 7-year-old previously healthy boy. Based on data from the literature, we attempt to understand the possible mechanisms resulting in bacterial complications, particularly meningitis, during chickenpox and to determine the means to prevent it. PMID- 25282452 TI - [Shoulder pain in a 13-year-old boy]. PMID- 25282453 TI - [A rare cause of recurrent meningitis in children: cochleovestibular dysplasia]. AB - Recurrent bacterial meningitis is an uncommon disease of childhood. It occurs most often in children who have an underlying predisposing disorder that can result from anatomic fistula or immunodeficiency. Cochleovestibular dysplasia is a rare malformation of the inner ear that is often associated with translabyrinthine cerebrospinal fistula and then can cause recurrent bacterial meningitis. We report an unusual case of recurrent meningitis revealing cochleovestibular dysplasia in a 9-year-old child. The malformation was confirmed by imaging and the child had surgery. The outcome was favourable with no recurrence of meningitis during the 3 years after the operation. PMID- 25282454 TI - [Acute epiglottitis due to group A beta-hemolytic streptococcus in a child]. AB - Acute epiglottitis has become an exceptional observation in pediatrics. The introduction of Haemophilus influenzae type B vaccine changed the morbidity, mortality, and microbiology of this disease. We report the case of an 11-month old infant with acute epiglottitis due to group A beta-hemolytic streptococcus. PMID- 25282455 TI - [Tocilizumab: experience in a French rheumatological pediatric center]. AB - Tocilizumab (TCZ) is an anti-interleukin-6-receptor antibody. The blockade of IL 6 is used as a strategy for the treatment of systemic juvenile idiopathic arthritis (S-JIA) and multicentric Castleman disease (MCD). In this study, we describe the tolerability profile of tocilizumab in eight children followed in a pediatric rheumatology department. Six patients were treated for S-JIA and two for a MCD. They received doses of TCZ between 8 and 12mg/kg of body weight depending on their disease. Infusions were received every 2-4 weeks. The mean duration of treatment was 32.9 months (14 months to 4.5 years). Clinical adverse events were all mild or moderate. No cases of macrophage activation syndrome and no anaphylactic reactions were reported. TCZ was never stopped for a clinical adverse event. Neutropenia was the most common biological adverse event, sometimes requiring dose adjustments. Thrombopenia, lymphopenia, and increased liver enzymes were reported as well, but treatment was not modified. All these biological adverse events were not complicated by any clinical manifestation. In conclusion, TCZ had a good tolerability profile in these eight patients with partial or total efficacy. Despite this advantageous profile, TCZ should be closely monitored because of the potential severity of adverse events. Moreover, long-term safety has still not been assessed. PMID- 25282456 TI - [Comparison of two protocols of prophylactic antibiotic therapy in childhood appendectomy]. AB - OBJECTIVE: Antibiotic administration during acute appendicitis in children continues to be debated. The purpose of this study was to compare efficacy of two prophylactic antibiotic treatment guidelines in acute appendicitis and peritonitis in children. MATERIEL AND METHODS: The infectious complication rate after appendicectomy was compared during two distinct periods (before/after study). During the first period, the guidelines for antibiotic administration were based on ticarcillin-clavulanic acid. During the second period, the guidelines were based on amoxicillin-clavulanic acid for non-perforated appendicitis or appendicitis with localized peritonitis, and clavulanic acid was reserved for general peritonitis. All children younger than 16 years of age who underwent appendicectomy during the periods studied were included. Data were retrospectively collected from surgical and anesthetics charts. RESULTS: Ninety five children during the first period and 238 during the second were included. In the children with non-perforated appendicitis, no postoperative infectious complication occurred in 74 children during the first period versus two out of 153 (1%) during the second period. In cases of perforated appendicitis, postoperative infectious complications occurred two cases (10%) during the first period versus nine (11%) during the second. There were no significant differences between the two periods. CONCLUSION: In this population, antibiotic administration guidelines based on amoxicillin-clavulanic acid for stages I-III of appendicitis maintained a low rate of postoperative infectious complications and were not associated with a higher postoperative infectious complication rate than guidelines based on ticarcillin-clavulanic acid. PMID- 25282457 TI - [Relevance of electroencephalography in infants presenting to an emergency department who have had an apparent life-threatening event]. AB - OBJECTIVES: Neurological causes are common diagnoses for apparent life threatening events in infants. The objective of this study was to evaluate the relevancy of electroencephalography performed after an apparent life-threatening event. MATERIAL AND METHODS: A retrospective study was conducted in a children's hospital over a 1-year period. The charts of infants under 2 years of age who were admitted following an apparent life-threatening event were reviewed. Clinical and biological data were collected and electroencephalograms - divided into normal and abnormal - were reviewed. To evaluate the follow-up state of the patients, parents were invited to complete an evaluation form an average 13 months after the event. The yield for electroencephalography was established according to the ratio of positive results contributing to the diagnosis of the cause of the apparent life-threatening event. RESULTS: A total of 47 patients met the inclusion criteria. Fifteen had had an EEG, 32 had not. The rate of abnormal neurological signs described by parents during the apparent life-threatening event was higher in the EEG group compared to the group without EEG (53% vs. 22%, P=0.05). In the follow-up, 35% of the children presented a second event, which was described as being similar or less impressive and occurred in the 1st month after the event (91%). Of the eight abnormal electroencephalograms, six had no specific abnormalities and two contributed to the diagnosis of epileptic seizure. Therefore, the diagnostic yield of electroencephalography in this study was 13% (2/8). CONCLUSIONS: The yield of electroencephalography performed after an apparent life-threatening event is low. Neurological history and repeated physical examinations still remain the major diagnostic tools before resorting to electroencephalography. PMID- 25282458 TI - Unusual sites of cystic lymphangioma in children. PMID- 25282459 TI - [Severe hypernatremia due to sea water ingestion in a child]. AB - Drowning in sea water is an unusual cause of severe hypernatremia. We report the case of a 3.5-year-old boy who died 11h after drowning in sea water, with a serum sodium level of 178 mmoL/L. In this case, hypernatremia was aggravated by diarrhea and hyperglycemia with glycosuria. Usually, correction of acute hypernatremia must be quick and early, aiming at a reduction of serum sodium concentration of up to 1-2 mmoL per liter per hour. PMID- 25282460 TI - [Congenital portosystemic shunts: experience of the western region of France over 5 years]. AB - INTRODUCTION: Congenital portosystemic shunts (CPS) are rare vascular malformations that lead to liver metabolic modifications. The aim of this study was to describe the management and outcome of CPS in children who were followed in the western region of France and to compare our experience to a literature review. PATIENTS AND METHODS: This retrospective study reports nine children with CPS who were followed in the western region of France between 2008 and 2013. RESULTS: Among these nine children, six were detected by prenatal ultrasonography, one had cholestatic jaundice during the postoperative period, one had cholestatic jaundice during the first days of life, and one had dyspnea and fatigue. Two children had liver tumors. The CPS was intrahepatic for four children and extrahepatic for two children. Three others had a patent ductus venosus. Among the intrahepatic shunts that were discovered before the age of 2 years, three closed spontaneously. The five other shunts were closed surgically or by interventional radiology techniques, after angiography for four children. After closure of eight shunts, the outcome was favorable for six children. Two children presented complications after surgery: portal hypertension and portal thrombus. CONCLUSION: When CPS is suspected, the diagnosis should be confirmed and complications should be investigated. Shunt closure restores portal flow and prevents complications. PMID- 25282461 TI - [Septic arthritis in children with normal initial C-reactive protein: clinical and biological features]. AB - Septic arthritis has to be suspected in children with joint effusion and fever so as to perform joint aspiration, which will confirm the diagnosis by bacteriological methods, and to perform surgical treatment by joint lavage. Since development of current molecular methods, such as real-time PCR, Kingella kingae has become the first microbial agent of osteoarticular infections in young children, whereas Staphylococcus aureus is second. C-reactive protein (CRP) is an aid used to diagnose septic arthritis, but its elevation could be moderate. In a previous study, conducted at our hospital, 10% of children hospitalized for S. aureus or K. kingae septic arthritis had a CRP level<10 mg/L. To determine if diagnosis of septic arthritis could be made by other parameters, we analyzed the clinical and biologic features of these patients and compared them to those of children hospitalized for septic arthritis with initial CRP >=10 mg/L. Among the 89 children with septic arthritis, 10% (n=9) had initial CRP<10 mg/L (K. kingae, n=5/63 ; S. aureus, n=4/26). Initial temperature and fibrinogen were significantly lower in the CRP<10 mg/L group than in the other (37.3 degrees C vs. 37.9 degrees C, P=0.039 and 4.19 vs. 5.72 g/L, P=0.003, respectively). Age, symptom duration before diagnosis, as well as leukocyte and platelet counts were similar in both groups. Two children (2/89=2.2%) with S. aureus septic arthritis had no fever, CRP elevation, or fibrinogen elevation. In the CRP-negative group, three of four children with S. aureus arthritis and one of five with K. kingae arthritis had a high CRP level (34, 40, 61, and 13 mg/L, respectively) 3 days after surgery and antibiotic treatment. One child with K. kingae septic arthritis and initial CRP<10 mg/L needed a second surgical drainage because of relapse of arthritis. In the S. aureus arthritis group, none of the children with initial CRP<10 mg/L experienced complications, while six of those with initial CRP>=10 mg/L needed a second surgical act or hospitalization in an intensive care unit. While CRP is most often>10 mg/L during septic arthritis in children, it could be negative in up to 20% of patients in different studies. However, a mild inflammatory syndrome or even a CRP<10 mg/L cannot exclude diagnosis of septic arthritis. Therefore, a first episode of monoarthritis in children has to be considered as septic arthritis and treatment should not be delayed. PMID- 25282462 TI - [Familial Wolfram syndrome]. AB - Wolfram syndrome (WS) is a rare autosomal recessive progressive neurodegenerative disorder, and it is mainly characterized by the presence of diabetes mellitus and optic atrophy. Other symptoms such as diabetes insipidus, deafness, and psychiatric disorders are less frequent. The WFS1 gene, responsible for the disease and encoding for a transmembrane protein called wolframin, was localized in 1998 on chromosome 4p16. In this report, we present a familial observation of Wolfram syndrome (parents and three children). The propositus was a 6-year-old girl with diabetes mellitus and progressive visual loss. Her family history showed a brother with diabetes mellitus, optic atrophy, and deafness since childhood and a sister with diabetes mellitus, optic atrophy, and bilateral hydronephrosis. Thus, association of these familial and personal symptoms is highly suggestive of Wolfram syndrome. The diagnosis was confirmed by molecular analysis (biology), which showed the presence of WFS1 homozygous mutations c.1113G>A (p.Trp371*) in the three siblings and a heterozygote mutation in the parents. Our observation has demonstrated that pediatricians should be aware of the possibility of Wolfram syndrome when diagnosing optic atrophy in diabetic children. PMID- 25282463 TI - [Mitochondrial neurogastrointestinal encephalopathy disease]. AB - Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) is a rare autosomal-recessive syndrome, resulting from mutations in the TYMP gene, located at 22q13. The mutation induces a thymidine phosphorylase (TP) deficit, which leads to a nucleotide pool imbalance and to instability of the mitochondrial DNA. The clinical picture regroups gastrointestinal dysmotility, cachexia, ptosis, ophthalmoplegia, peripheral neuropathy, and asymptomatic leukoencephalopathy. The prognosis is unfavorable. We present the case of a 14-year-old Caucasian female whose symptoms started in early childhood. The diagnosis was suspected after magnetic resonance imaging (MRI), performed given the atypical features of mental anorexia, which revealed white matter abnormalities. She presented chronic vomiting, postprandial abdominal pain, and problems gaining weight accompanied by cachexia. This diagnosis led to establishing proper care, in particular an enteral and parenteral nutrition program. There is no known specific effective treatment, but numerous studies are in progress. In this article, after reviewing the existing studies, we discuss the main diagnostic and therapeutic aspects of the disease. We argue for the necessity of performing a cerebral MRI given the atypical features of a patient with suspected mental anorexia (or when the clinical pattern of a patient with mental anorexia seems atypical), so that MNGIE can be ruled out. PMID- 25282464 TI - [Pulmonary zygomycosis in a diabetic child complicated with thrombus of the left atrial auricle]. AB - Mucormycosis is a rare but fatal, opportunistic fungal infection caused by fungi of the order of mucorales in the class of Zygomycetes. Isolated pulmonary mucormycosis is rare and occurs principally in particular conditions, especially in patients with uncontrolled diabetes. The fungi invades the blood vessels and causes distal ischemic necrosis. We report a case in a 13-year-old girl with diabetes mellitus who developed pulmonary zygomycosis complicated with thrombus of the left atrial auricle. The diagnosis of mucormycosis was confirmed by histologic examination of endobronchial biopsies. Combined treatment with systemic amphotericin B and surgery resulted in a favorable outcome. This difficult diagnosis must be raised in diabetic patients with unresponsive lung infections in order to apply early aggressive therapy. Successful management continues to be early diagnosis, followed by systemic antifungal therapy and surgical resection combined with control of the underlying disease. PMID- 25282465 TI - [Proposals to adapt the protection of children to the realities of today]. AB - The report titled "40 propositions pour adapter la protection de l'enfance et l'adoption aux realites d'aujourd'hui" ("Forty proposals to adapt protection of children to the realities of today") was presented in February 2014 by the "Protection de l'enfance et adoption" working group to the Minister for Family Affairs within the framework of the preparation of the French family law. The medical field is an important link in the chain of child protection. Of the 40 proposals, particular attention was paid to the identification of children at risk and to improving the protection of newborns (shaken baby syndrome, unexpected infant death) and to adoption issues. PMID- 25282466 TI - [DRESS syndrome]. AB - DRESS syndrome (drug reaction eosinophilia and systemic symptoms) is a rare and serious drug toxidermia with potentially multiple organ dysfunctions. This report relates the case of a 9-year-old girl who presented a right cervical and mediastinal adenopathy with a mediastinal lump, fever, and deterioration of the general condition. The hospital assessment concluded in an abscess due to Staphylococcus aureus secreting a Panton-Valentine toxin with nonsevere pleuritis and pericarditis. The outcome was favorable with antibiotic treatment consisting of amoxicillin-acid clavulanic, amikacin, and clindamycin followed by oxacillin, rifampicin, and colchicine. On the 25th day of treatment, she presented recurrence of fever with a generalized rash, moderate hepatic cytolysis, hypereosinophilia, with the presence of activated lymphocytes that were further suggestive of visceral DRESS syndrome. A skin biopsy was performed that confirmed the diagnosis. The outcome was favorable after stopping all ongoing treatments even though none of the administered treatments were classically responsible for the syndrome. Symptomatic treatments (antihistaminic and topical steroids) were also administered. Patch tests, performed secondarily, were positive to penicillins; amoxicillin-clavulanic acid or oxacillin were then suspected of being responsible for the DRESS syndrome. Potentially serious, the DRESS syndrome should be considered together with atoxic epidermal necrolysis or Stevens-Johnson syndromes in the case of any rash appearing after drug administration, especially in the presence of face and eyelid edema. PMID- 25282467 TI - Effect of surface treatment and liner material on the adhesion between veneering ceramic and zirconia. AB - Fully sintered zirconia blocks, each with one polished surface, were treated with one of the followings: 1) no treatment, 2) airborne-particle abrasion with 50MUm alumina, and 3) airborne-particle abrasion with 125MUm alumina. Before veneering with glass ceramic, either liner Alpha or liner B were applied on the treated surfaces. All veneered blocks were subjected to shear force in a universal testing machine. For the groups with liner A, irrespective of the particle size, air abrasion on Y-TZP surfaces provided greater bond strength than polishing. Application of liner B on an abraded zirconia surface yielded no significant influence on the adhesion. In addition, specimens with liner A showed higher bond strength than those with liner B, if applied on roughened surfaces. Fractured surfaces were observed as mixed patterns in all groups. For the liner A, surface treatment was helpful in bonding with veneering ceramic, while it was ineffective for the liner B. PMID- 25282468 TI - Technical note: The two step procedure (TSP) for the determination of age at death of adult human remains in forensic cases. AB - This paper presents the principles and results of TSP (the two step procedure), a comprehensive (combined) method of age estimation in mature human skeletal remains. The first step consists of the examination of the pubic symphysis using the Suchey-Brooks system for a "pre-choice". Then for SBS phases I, II, III, (young adults up to about 40) the age estimate is given using the chronological interval corresponding to each phase. For SBS phase is IV, V or VI (mature adults, about 40 to 60), then (second step) the dental method of Lamendin (using single rooted tooth) will be applied alone. Both methods are fast, easy to learn and to use (requiring no preparation except cleaning soft tissues from the pubic bone) and are not expensive, making TSP usable by all pathologists or anthropologists in any Forensic unit. It is also of great practical use in mass disaster and mass grave situation. After 15 years of use, a literature review and four evaluation studies we confirm that TSP is more accurate than any single method for aging adults and at least as good as more complicated combined methods. Despite its advantages TSP is, like all other aging methods, not efficient in adults over 65 years of age. PMID- 25282470 TI - Heparin for assisted reproduction: summary of a Cochrane review. AB - It is suggested that heparin given in the peri-implantation period may improve clinical outcomes in women undergoing assisted reproduction techniques (ART). This systematic review evaluates the use of heparin in subfertile women undergoing ART. PMID- 25282469 TI - Transcriptional profiling of peripheral CD8+T cell responses to SIVDeltanef and SIVmac251 challenge reveals a link between protective immunity and induction of systemic immunoregulatory mechanisms. AB - Immunization of macaques with attenuated simian immunodeficiency virus (SIV) with deletions in nef (SIVDeltanef) is shown to elicit protective immunity to infection by pathogenic SIV, yet the mechanisms that orchestrate protection and prevent pathogenesis remains unknown. We utilized whole-genome transcriptional profiling to reveal molecular signatures of protective immunity in circulating CD8+ T cells of rhesus macaques vaccinated with SIVmac239Deltanef and challenged with pathogenic SIVmac251. Our findings suggest that protective immunity to pathogenic SIV infection induced by SIVmac239?nef is associated with balanced induction of T cell activation and immunoregulatory mechanisms and dampened activation of interferon-induced signaling pathways and cytolytic enzyme production as compared with pathogenic SIVmac251 infection of unvaccinated controls. We provide evidence that protective immunity to SIVmac251 correlates with induction of biomarkers of T cell activation, differentiation, signaling, and adhesion that were down regulated in unvaccinated controls. The study highlights potential immunomodulatory networks associated with protective immunity against the virus. PMID- 25282471 TI - Ultrashort flare gonadotropin-releasing hormone (GnRH) agonist/GnRH antagonist protocol: a valuable tool in the armamentarium of ovulation induction for in vitro fertilization. PMID- 25282472 TI - Intraductal neoplasms of the pancreas. AB - There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs); the rare, usually solid intraductal tubulopapillary neoplasms (ITPNs); and the rare intraductal tubular pyloric gland-type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors, and undifferentiated carcinomas may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors; into low- and high-grade dysplasia groups; and into tumors with intestinal, pancreatobiliary, oncocytic, or gastric cellular differentiation. The intestinal-, pancreatobiliary-, and oncocytic-type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric-type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process, and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head, and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS, and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild-type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations also holds promise for the future development of novel gene-based diagnostic tests in intraductal neoplasms of the pancreas that might even be used in preoperative conditions. PMID- 25282473 TI - Transcutaneous bilirubinometry. AB - Although the modern era of transcutaneous bilirubin monitoring (TcB) began only about 35 years ago, this screening tool is now widely used in newborn nurseries and outpatient clinics, offices, and emergency departments to obtain a rapid and non-invasive estimate of the degree of hyperbilirubinemia. TcB devices have become more sophisticated, and major breakthroughs include the following: (a) ability to report a bilirubin value rather than an index value, (b) enhanced correction for chromophores other than bilirubin, and (c) technologic improvements including interface with electronic medical records. Good agreement with laboratory bilirubin measurement has been demonstrated, and the ability of TcB screening to predict and decrease the incidence of subsequent hyperbilirubinemia has been well-documented. To date, it has not been shown that this screening results in improved long-term outcomes. PMID- 25282475 TI - BCG coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study. AB - BACKGROUND: BCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination ("restricted vial-opening policy"). BCG coverage is usually reported as 12-month coverage, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau. METHODS: Bandim Health Project (BHP) runs a health and demographic surveillance system covering women and their children in 182 randomly selected village clusters in rural Guinea-Bissau. BCG coverage was assessed for children born in 2010, when the restricted vial-opening policy was universally implemented, and in 2012-2013, where BHP provided BCG to all children at monthly visits in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log binomial regression models providing prevalence ratios. RESULTS: Among 3951 children born in 2010, vaccination status was assessed for 84%. BCG coverage by 1 week of age was 11%, 38% by 1 month, and 92% by 12 months. If BCG had been given at first contact with the health system, 1-week coverage would have been 35% and 1-month coverage 54%. When monthly visits were introduced in intervention regions, 1-month coverage was higher in intervention regions (88%) than in control regions (51%), the prevalence ratio being 1.74 (1.53-2.00). Several factors, including socioeconomic factors, were associated with delayed BCG vaccination in the 2010-birth cohort. When BCG was available at monthly visits these factors were no longer associated with delayed BCG vaccination, only region of residence was associated with delayed BCG vaccination. CONCLUSION: BCG coverage during the first months of life is low in Guinea-Bissau. Providing BCG at monthly vaccination visits removes the risk factors associated with delayed BCG vaccination. PMID- 25282474 TI - Is personalized medicine achievable in obstetrics? AB - Personalized medicine seeks to identify the right dose of the right drug for the right patient at the right time. Typically, individualization of therapy is based on the pharmacogenomic makeup of the individual and environmental factors that alter drug disposition and response. In addition to these factors, during pregnancy, a woman's body undergoes many changes that can impact the therapeutic efficacy of medications. Yet, there is minimal research regarding personalized medicine in obstetrics. Adoption of pharmacogenetic testing into the obstetrical care is dependent on evidence of analytical validity, clinical validity, and clinical utility. Here, we briefly present information regarding the potential utility of personalized medicine for treating the obstetric patient for pain with narcotics, hypertension, and preterm labor, and discuss the impediments of bringing personalized medicine to the obstetrical clinic. PMID- 25282477 TI - Relationships among psychosocial factors, biomarkers, preeclampsia, and preterm birth in African American women: a pilot. AB - AIM: To explore the relationships among psychosocial factors (optimism, uncertainty, social support, coping, psychological distress), biomarkers (cortisol, cytokines), preeclampsia, and preterm birth in African American women. METHODS: Forty-nine pregnant African American women completed psychosocial questionnaires and had blood collected for biomarkers between 26 and 36 weeks of gestation. Birth outcomes were obtained from birth records. RESULTS: Women reporting higher levels of social support had lower levels of pro-inflammatory cytokines (IL-2, IL-5, and IL-6). Surprisingly, compared with low-risk pregnant women, women diagnosed with preeclampsia reported more optimism and less avoidance, and had lower levels of cortisol and IFN-gamma. Similarly, compared to women with full-term birth, women with preterm birth reported higher levels of optimism and lower levels of avoidance, and had lower levels of IL-10. CONCLUSION: Psychosocial factors influence inflammation and pregnancy outcomes. Close assessment and monitoring of psychosocial factors may contribute to improved pregnancy outcomes. PMID- 25282476 TI - Mina: a Th2 response regulator meets TGFbeta. AB - The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFbeta may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context. PMID- 25282478 TI - Relation between self-image score of SRS-22 with deformity measures in female adolescent idiopathic scoliosis patients. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a pathology which affects the individual's functioning in the widely understood physical, psychic, and social aspects. More attention should be paid to patients' perception of self image when evaluating the spine deformity. The present retrospective study evaluated the associations between the deformity measures and self-image score as determined by the SRS-22 questionnaire in Chinese female AIS patients. HYPOTHESIS: The self-image score correlates significantly with deformity measures. The location of main curve apex and the number of curve could affect the self-image score. MATERIALS AND METHODS: We retrospectively reviewed the records of 202 female patients, collected data on patient's age, body mass index, radiographic and physical measures and self-image score of SRS-22 questionnaire. According to the location of main curve apex and the number of curve, the patients were divided to different subgroups. Correlations between deformity measures and self-image score of different groups were evaluated by the Spearman correlation test. RESULTS: The self-image score correlated negatively with the main Cobb angle, apical vertebral translation (AVT), and razor hump height. There is no significant difference of self-image score between thoracic curve (TC) and thoracolumbar curve (TL/LC) subgroups. And the self-image scores of one-curve, two-curve and three-curve subgroups are similar. DISCUSSION: For Chinese female AIS patients in our study, self-image was found to correlate negatively with the main Cobb angle, AVT and razor hump height. And the location of scoliosis apex and the number of curve are not influencing factors of self-image perception. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25282479 TI - "We talk it over"--mixed-method study of interdisciplinary collaborations in private practice among urologists and oncologists in Germany. AB - BACKGROUND: Utilisation of multidisciplinary teams is considered the best approach to care and treatment for cancer patients. However, the multidisciplinary approach has mainly focused on inpatient care rather than routine outpatient care. The situation in private practice care and outpatient care is gradually changing. We aimed to 1), investigate interdisciplinary cooperations in the care of tumor patients among urologists and oncologists in the community setting, 2), establish an estimate of the prevalence of cooperation among oncologists and organ-specific providers in community settings in Germany and 3), characterise existing cooperations among oncologists and urologists. METHODS: We conducted simultaneously a cross-sectional survey with private practice urologists (n=1,925) and a qualitative study consisting of semi structured interviews with urologists and oncologists (n=42), primarily with private practices, who had indicated cooperation the care of urological tumor patients. RESULTS: Most of the participants (66%) treated their own tumor patients. When physicians referred patients, they did so for co- and subsequent treatments (43%). Most cooperating urologists were satisfied with the partnership and appreciated the competency of their partners. Qualitative interviews revealed two types of collaboration in the community setting: formal and informal. Collaborations were usually ongoing with many physicians and depended equally on both patient preference and diagnosis. CONCLUSION: Joint patient treatment requires clear delineation of roles and responsibilities and simple means of communication. Formal frameworks should allow for incorporation of patients' critical role in collaboration decisions in treatment and care. PMID- 25282480 TI - Pathways to health and well-being. PMID- 25282481 TI - Normal liver stiffness in healthy adults assessed by real-time shear wave elastography and factors that influence this method. AB - Real-time shear wave elastography (SWE) is a novel two-dimensional elastographic method that is used to estimate the severity of liver fibrosis. However, the normal range of liver stiffness (LS) and the possible factors that influence SWE are not well understood. The aims of the current study are to define the normal range of LS in healthy subjects and to explore the factors that may affect SWE. A total of 509 healthy subjects underwent SWE to determine the stiffness of their livers, and the effects of gender, age and body mass index (BMI) on LS were analyzed. The effects of different factors on SWE, including the testing position, measurement depth and size of the region of interest (ROI), were analyzed in 137 subjects. SWE imaging was successfully performed in 502 healthy subjects (98.6%, 502/509). The mean value of the SWE measurements in 502 individuals was 5.10 +/- 1.02 kPa, and the 95% confidence interval was 5.02-5.19 kPa (range: 2.4-8.7 kPa). We found that the detective position within the liver had a significant impact on the liver stiffness measurement (LSM), and the lowest coefficient of variation (CV = 8%) was obtained for LSMs made at segment V. LS was greater at a depth >5 cm (5.78 +/- 1.66 kPa) compared with depths <=5 cm (4.66 +/- 0.77 kPa, p < 0.001); LS was also greater in men than in women (5.45 +/ 1.02 kPa vs. 4.89 +/- 0.96 kPa, p < 0.001). However, there were no significant differences in the LS values regarding the size of the ROI, age or BMI (all p > 0.05). The mean LS value in all 502 healthy subjects was 5.10 +/- 1.02 kPa. The mean LS value obtained by SWE was not influenced by the size of the ROI, age or BMI, but the mean value was significantly influenced by the different segments of the liver, the detection depth and gender. PMID- 25282482 TI - Volume flow in arteriovenous fistulas using vector velocity ultrasound. AB - Volume flow in arteriovenous fistulas for hemodialysis was measured using the angle-independent ultrasound technique Vector Flow Imaging and compared with flow measurements using the ultrasound dilution technique during dialysis. Using an UltraView 800 ultrasound scanner (BK Medical, Herlev, Denmark) with a linear transducer, 20 arteriovenous fistulas were scanned directly on the most superficial part of the fistula just before dialysis. Vector Flow Imaging volume flow was estimated with two different approaches, using the maximum and the average flow velocities detected in the fistula. Flow was estimated to be 242 mL/min and 404 mL/min lower than the ultrasound dilution technique estimate, depending on the approach. The standard deviations of the two Vector Flow Imaging approaches were 175.9 mL/min and 164.8 mL/min compared with a standard deviation of 136.9 mL/min using the ultrasound dilution technique. The study supports that Vector Flow Imaging is applicable for volume flow measurements. PMID- 25282483 TI - Imaging ultrasonic dispersive guided wave energy in long bones using linear radon transform. AB - Multichannel analysis of dispersive ultrasonic energy requires a reliable mapping of the data from the time-distance (t-x) domain to the frequency-wavenumber (f-k) or frequency-phase velocity (f-c) domain. The mapping is usually performed with the classic 2-D Fourier transform (FT) with a subsequent substitution and interpolation via c = 2pif/k. The extracted dispersion trajectories of the guided modes lack the resolution in the transformed plane to discriminate wave modes. The resolving power associated with the FT is closely linked to the aperture of the recorded data. Here, we present a linear Radon transform (RT) to image the dispersive energies of the recorded ultrasound wave fields. The RT is posed as an inverse problem, which allows implementation of the regularization strategy to enhance the focusing power. We choose a Cauchy regularization for the high resolution RT. Three forms of Radon transform: adjoint, damped least-squares, and high-resolution are described, and are compared with respect to robustness using simulated and cervine bone data. The RT also depends on the data aperture, but not as severely as does the FT. With the RT, the resolution of the dispersion panel could be improved up to around 300% over that of the FT. Among the Radon solutions, the high-resolution RT delineated the guided wave energy with much better imaging resolution (at least 110%) than the other two forms. The Radon operator can also accommodate unevenly spaced records. The results of the study suggest that the high-resolution RT is a valuable imaging tool to extract dispersive guided wave energies under limited aperture. PMID- 25282484 TI - Assessment of sedated pediatric brain with 3D-FLAIR sequence at 3T MRI. AB - BACKGROUND AND PURPOSE: In sedated pediatric brains, 2D-FLAIR causes increased signal intensity of the cerebrospinal fluid (CSF) leading to false-positive diagnoses. Our aim is to determine whether increased CSF signal intensity is observed on 3D-FLAIR images. METHODS: In this institutional review board-approved study, a 2-year retrospective analysis of our MRI database was conducted which revealed 48 sedated pediatric patients with normal cranial MRI findings and 3D FLAIR sequence. One adult volunteer was imaged before and after O2 inhalation with 2D and 3D-FLAIR sequences. The hyperintensity in the subarachnoid spaces and basal cisterns were quantified as follows: 0: artifact free; 1: homogeneous minimal CSF signal; 2: abnormal CSF signal. Inter-observer agreement was assessed with kappa agreement analysis. RESULTS: Grade 0 and grade 1 signals were observed at inferior to Liliequist membrane (LLQ) in 48/48 and 0/48 cases; prepontine cistern 47/48 and 1/48; superior to LLQ 26/48 and 22/48; 4th ventricle 16/48 and 32/48; 3rd ventricle 34/48 and 14/48; lateral ventricle 3/48 and 45/48; subarachnoid space 36/48 and 12/48, respectively. No patients showed grade 2 signal. Inter-observer agreement was 0.81-1. In the volunteer, after O2 inhalation, grade 2 signal intensity was evident on 2D-FLAIR however; 3D-FLAIR did not show any signal increase. CONCLUSIONS: In sedated pediatric brains, 3D FLAIR suppresses CSF signal, and enables reliable assessment free from CSF artifacts. PMID- 25282485 TI - Dopa-Responsive Dystonia and gait analysis: A case study of levodopa therapeutic effects. AB - INTRODUCTION: Patients suffering Dopa-Responsive Dystonia present dystonia, abnormal postural balance and gait impairment. Treatment with levodopa typically improves these three symptoms. The present study provides an extensive analysis of gait and posture in a patient with Dopa-Responsive Dystonia, prior to and during levodopa therapy. METHOD: The patient was assessed with the Unified Dystonia Rating Scale, underwent motion analysis with an optoelectronic system and postural analysis with force plates. RESULTS: This study provides a detailed quantification of gait parameters in a Dopa-Responsive Dystonia patient. Prior to treatment, mean walking speed was severely reduced, gait cadence and step length were decreased and stride width was increased. Right lower limb and pelvis showed kinematic defects, trunk and Centre of Mass were backwards. During levodopa therapy, the walking speed was doubled, gait cadence and step length were increased and stride width was reduced. Nearly all kinematic parameters of lower limbs were significantly improved. The patient's Centre of Mass during gait and Centre of pressure in static position both shifted forward. CONCLUSION: Levodopa dramatically decreased dystonia and improved spatio-temporal, kinematic and posture parameters. Our main pathophysiological hypothesis is that trunk tilt and its consequences on the Centre of Mass position have a pivotal influence on gait and balance, explaining both the initial impairments and the therapeutic effects. Gait analysis proves to be an effective tool to understand the pathophysiology of this patient, the therapeutic effects and mild residual gait defects in order to plan further rehabilitation strategy for this DRD patient. We propose that it will also prove to be useful for the exploration of other dystonic patients. PMID- 25282486 TI - [Iron deficiency and digestive disorders]. AB - Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption. PMID- 25282487 TI - [Responsibility for prescribing and monitoring an act transfusion and safety blood transfusion]. AB - The act to transfuse is a prescription following basic rules similar to drug prescriptions. If harm happens, potentially linked with this prescription, the harm's responsibility is borne by the physician, the paramedics, the care organization but by the supplier laboratory too. The setting of good practice rules consistent with science data at the time when the act is performed, the respect of the patient's rights and the quality of supplied products will be assessed during the expertise. Under restorative responsibility, it is necessary to previously establish a direct and certain causation between the litigious act and the harm to enforce the vicarious liability. Nowadays, legal precedents grant a larger protection to more and more numerous victims, enhancing the field of the fault with the appeal to assumption of fault. At the same time, the lawmaker himself promulgated objective conditions of compensation for many categories of victims of medical risk from which transfused people are part. The law of March the 4th of 2002 went one step closer devoting a new foundation of compensation: national solidarity. PMID- 25282488 TI - [Current management of thalassemia intermedia]. AB - Thalassemia intermedia is a clinical entity where anemia is mild or moderate, requiring no or occasional transfusion. Non-transfusion-dependent thalassemia encompasses 3 main clinical forms: beta-thalassemia intermedia, hemoglobin E/beta thalassemia and alpha-thalassemia intermedia (HbH disease). Clinical severity of thalassemia intermedia increases with age, with more severe anemia and more frequent complications such as extramedullary hematopoiesis and iron overload mainly related to increased intestinal absorption. Numerous adverse events including pulmonary hypertension and hypercoagulability have been associated with splenectomy, often performed in thalassemia intermedia patients. The potential preventive benefit of transfusion and chelation therapies on the occurrence of numerous complications supports the strategy of an earlier therapeutic intervention. Increasing knowledge about pathophysiological mechanisms involved in thalassemia erythropoiesis and related iron overload is currently translating in novel therapeutic approaches. PMID- 25282489 TI - [Platelet transfusion and immunization anti-Rh1: implication for immunoprophylaxis]. AB - Rhesus (Rh) antigens are not expressed on platelets but residual red cells carry the risk of anti-D iso-immunization in transfusion recipients of platelet concentrates (PC). The main theoretical risk associated with this reaction relates to female subjects due to potential obstetrical situations of maternal foetal Rh incompatibility. Isogroup PC transfusion in this system is therefore advised. However, logistical constraints impose frequent Rh-incompatible transfusions that require the recommendation of anti-Rh immunoglobulin in a girl of childbearing age in this situation. This recommendation, already restricted to a group of patients deserves to be questioned over a decade after being issued. Data from published reports are difficult to interpret because of the heterogeneity of the few series (CP type, immune status, timing of biological tests) but the current techniques for preparing products and most common use of CP apheresis limited the risk of immunization. Moreover, platelet transfusions are particularly relevant to immunocompromised populations which, to what extent (heavy chemotherapy and/or hematopoietic stem cells recipients) seems to be protected from this risk. It is noteworthy that the clinical consequences that may be expected from such immunization are not reported. Although some authors emphasize significant isoimmunization rates (maximum 19%), the heterogeneous conditions and the lack of evidence of clinical consequence suggest evaluating the recommendations or revising them towards more targeted indications of seroprophylaxis. PMID- 25282490 TI - [Sickle cell pathophysiology]. AB - Sickle cell disease is associated with the inversion of one base pair (A = T -> A = T). The sixth codon of the beta globin chain [GAA] becomes [GTA]. Accordingly, the sixth amino acid (glutamic acid, negatively charged) is replaced by valine, hydrophobic. A hydrophobic site is present on the outside of the HbS beta chain. This incurs a hydrophobic bond with the phenylalanine in position 85 and leucine in position 88, in which outsource deoxy haemoglobin. Therefore, it creates a HbS polymer that deforms the red blood cell and causes vaso-occlusive crisis in the capillary venous pole. In this conventional design, the roles are added to the nitrogen monoxide and vascular tone, the increase in adhesion of red blood cells to the endothelium damage caused by red blood cells HbS: dehydration, senescence, formation of microvesicles. If these advances in our understanding of the pathophysiology have not yet had a clinical application, they will happen one day. It is therefore particularly important to pursue in France the network structure of sickle cell disease with a view to set up multicenter trials when the day comes. PMID- 25282491 TI - [Postdonation information: the French fourth hemovigilance sub-process]. AB - Postdonation information is the knowledge of information about the donor or his donation, occurring after it, which challenges quality or safety of the blood products stemming from this or other donations. Classical hemovigilance sub processes concerning donors or recipients adverse events do not cover this topic. France is just about to make it official as a fourth sub-process. Less formal management of postdonation information is already set up for more than ten years. French data of the year 2013 are presented, including the regional notification level and the national reporting one. A significant level of heterogeneity is observed as for other hemovigilance sub-processes. It is mainly due to subjective rather than objective differences in risk appreciation. A real consensual work is expected about it in the future. PMID- 25282492 TI - Genetic and epigenetic regulation of gene expression in fetal and adult human livers. AB - BACKGROUND: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. RESULTS: By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue specificity for the identified associations between CpG methylation and gene expression. CONCLUSIONS: Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases. PMID- 25282493 TI - Effects of cryopreservation on motility characteristics and enzyme activity of sperm in a Chinese fish Nibea albiflora. AB - BACKGROUND: Growing evidence suggests that among the causes which deteriorate qualitative and functional characteristics of sperm after freezing and thawing, there are those linked to decrease of sperm motility and release of various enzymes in the cells and seminal plasma. OBJECTIVE: In the present study, the motility, fertilization and enzyme activity of sperm were analyzed after cryopreservation. MATERIALS AND METHODS: Computer-assisted sperm motility analysis (CASA) was used to evaluate the effect of cryopreservation on sperm motility of Nibea albiflora. RESULTS: The activities of total adenosine triphosphatase (ATPase), creatine kinase (CK), succinate dehydrogenase (SDH), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) in fresh and frozen seminal plasma and spermatozoa were measured respectively. Cryopreservation led to a decline in the percentage of motile sperm, moreover, other parameters of sperm motion, curvilinear and straight line velocities, linearity were changed observably (p < 0.05), the fertilizing capacity of post thaw sperm was lower than that of the fresh sperm significantly. After cryopreservation, the activities of total ATPase, CK, SDH, LDH, SOD, CAT and GSH Px increased in seminal plasma and decreased in spermatozoa respectively, but GR activity varied contrarily, GR activity dropped in seminal plasma and increased in spermatozoa. CONCLUSION: Cryopreservation had significant effects on the motility characteristics, fertilization ability and enzyme activity of the sperm of Nibea albiflora. PMID- 25282494 TI - Effect of different disaccharides on the integrity and fertilising ability of freeze-dried boar spermatozoa: a preliminary study. AB - Freeze-drying spermatozoa is a developing technique that facilitates semen storage and transport. However, freeze-dried sperm exhibits impaired DNA integrity, which is associated with reduced fertilizing ability. Boar spermatozoa were freeze-dried in three different freeze-drying EDTA buffers with trehalose (75mM) and lactose (75mM) (EDTA-TL), (2) with sucrose (75mM) and lactose (75mM) (EDTA-SL) or just lactose (150mM) (EDTA-LL) using two freeze-drying protocols. In experiment 1 a one-step protocol was used and in experiment 2 a two-steps protocol was used. Spermatozoa were stored in1.5 mL cryo-tubes and 1.5 mL glass ampules at both 16 degree C and 25 degree C for 1 month. Successfully freeze dried spermatozoa were stained with acridine-orange to assess chromatin stability. Freeze-drying was most successful when the 2-step protocol was used (experiment 2). Chromatin stability was greater in samples stored in glass ampules compared to cryo tubes. Chromatin stability was also greater in samples freeze-dried in EDTA-LL compared to EDTA-SL or EDTA-TL buffers. Spermatozoa freeze-dried in EDTA-LL and stored for 14 and 28 days at either 16 degree C or 25 degree C were utilized for ICSI. Two pronuclear formation wasgreatest using spermatozoa stored at 25 degree C (69.23%) and for 28 days (50%). Although 16 degree C spermatozoa samples had better stable chromatin, 25 degree C spermatozoa samples offered better two pronuclear formation results. In conclusion, boar spermatozoa freeze-dried using media containing disaccharides exhibit high chromatin stability and are able to fertilise oocytes following ICSI. Disaccharides may therefore advance the development of freeze-drying techniques for spermatozoa enabling ease of sperm storage and transportation. PMID- 25282495 TI - Generation of live offspring from vitrified embryos with synthetic polymers SuperCool X-1000 and SuperCool Z-1000. AB - BACKGROUND: Ice growth and recrystallisation are considered important factors in determining vitrification outcomes. Synthetic polymers inhibit ice formation during cooling or warming of the vitrification process. OBJECTIVE: The aim of this study was to assess the effect of adding commercially available synthetic polymers SuperCool X-1000 and SuperCool Z-1000 to vitrification media on in vivo development competence of rabbit embryos. METHODS: Four hundred and thirty morphologically normal embryos recovered at 72 h of gestation were used. The vitrification media contained 20% dimethyl sulphoxide and 20% ethylene glycol, either alone or in combination with 1% of SuperCool X-1000 and 1% SuperCool. RESULT: Our results show that embryos can be successfully vitrified using SuperCool X-1000 and SuperCool Z-1000 and when embryos are transferred, live offspring can be successfully produced. CONCLUSIONS: In conclusion, our results demonstrated that we succeeded for the first time in obtaining live offspring after vitrification of embryos using SuperCool X-1000 and SuperCool Z-1000 polymers. PMID- 25282496 TI - Cryoprotectant-free freezing of the goat epididymal sperm. AB - BACKGROUND: Cryoprotectant free approach successfully removed the impact of physical and chemical damages in preserving human sperm in a vitrification protocol. There is no any report on this technology in farm animal sperm freezing. OBJECTIVE: The aim of the present study was to find the efficacy of cholesterol-loaded cyclodextrin (CLC; 1 mg per 60 million) and sucrose (0.1 and 0.2 M) on freezing of the goat epididymal sperm. METHODS: Caudal epididymides (n=5 pairs) were dissected, incised and incubated in the Tris-BSA solution for 15 min, followed by swim-up at room temperature. Sperm was loaded in 0.25 mL French straws and cooled on nitrogen vapor for 3 min then immersed in liquid nitrogen and remained for 48 h. Then the straws thawed by immersing in 37 degree C waterbath for 30 sec and analyzed. RESULT: The results showed the impact of freezing on the goat epididymal sperm motility, viability and DNA fragmentation that were improved by incorporation of CLC and sucrose (0.2 M). CONCLUSIONS: In conclusion, the goat epididymal sperm was frozen in a cryoprotectant-free freezing model. CLC and 0.4 M sucrose protected the goat epididymal sperm against freezing-induced damages. PMID- 25282497 TI - Effects of some cryopreservation procedures on recalcitrant zygotic embryos of Ammocharis coranica. AB - BACKGROUND: Cryopreservation, the most promising method for the long-term conservation of recalcitrant (desiccation-sensitive) seed germplasm, is often associated with high viability losses. Cryo-procedures involve a sequence of steps which must be optimised to reduce the impact of the stresses. OBJECTIVE: This study reports on the effects of some of the steps of cryopreservation on the recalcitrant zygotic embryos of the amaryllid, Ammocharis coranica. MATERIALS AND METHODS: Embryos were subjected to cryoprotection with glycerol and/or DMSO, rapid (flash) drying, and rapid (>100 degree C s(-1)) or slow (1 degree C s(-1)) cooling. RESULTS: Rapid dehydration (from c. 2.7 to 0.9 g g(-1) over 60 min) and cooling had a detrimental effect on the viability of the embryos, which was exacerbated when these steps were applied sequentially. After cooling, seedling production (30%) was obtained only from embryos that had been cryoprotected with glycerol prior to drying and rapid cooling, while 30% of non-treated embryos and 70% of those that had undergone cathodic protection during flash drying produced callus. CONCLUSION: Noting that no post-cryo survival of A. coranica embryos had previously been obtained, this study identified cryoprotection with glycerol and the incorporation of cathodic protection during flash drying as promising intervention points for future studies. PMID- 25282498 TI - Effect of glutathione and Y27632 on the viability of cryopreserved porcine adipose-derived stem cells. AB - BACKGROUND: Recently it has been reported that reduced glutathione (GSH) and/or Rho-associated kinase (ROCK) inhibitor supplemented in cryopreservation solution could improve the viability of cells. OBJECTIVE: To identify the cryopreservation efficiency of GSH and ROCK inhibitor on porcine ADSCs. MATERIALS AND METHODS: Porcine ADSCs were separated and cultured. Cells at the 4th passage were suspended in cryopreservation solution supplemented with Y-27632 and GSH or both, and then frozen and thawed. The viability of cryopreserved ADSCs was compared using a MTT assay. RESULTS: The addition of GSH and Y-27632 to cryopreservation solution (dimethyl sulfoxide) and post-thaw culture medium significantly improves the post-thaw viability of ADSCs. CONCLUSION: GSH and Y-27632 are able to increase the survival of ADSCs, and they have an additive effect, as compared to GSH or Y27632 alone. PMID- 25282499 TI - Wide-scale pollen banking of ornamental plants through cryopreservation. AB - BACKGROUND: Cryopreservation has been proved to be an efficient method for the long-term storage of pollen, based on our previous studies establishing cryo pollen banks for Camellia, Paeonia, and Prunus mume. OBJECTIVE: In the present study, we aimed to extend and verify the applicability of the cryopreservation protocol for ornamental plants. MATERIALS AND METHODS: 71 species or cultivars from 19 families were cryopreserved using the established protocol. RESULTS: Pollen from 60 species or cultivars (85% of those experimented on) retained viability after 1 year's cryopreservation; of these, 36 (51% of the total investigated) retained a sufficiently high germination capability compared with fresh pollen to enable longer term cryopreservation. CONCLUSION: This study confirms that wide-scale pollen banking of ornamental plants is feasible. PMID- 25282501 TI - Effect of cryopreservation on in vitro seed germination and protocorm growth of Mediterranean orchids. AB - BACKGROUND: Cryopreservation is an effective method for the long-term conservation of plant germplasm. OBJECTIVE: In the present study the effect of liquid nitrogen on seed structure, germination and protocorm development of eight Mediterranean orchid species was evaluated. MATERIALS AND METHODS: A scanning electron microscopy analysis was conducted to investigate the effect of the immersion in liquid nitrogen on seed integuments. Germination and protocorms growth were obtained applying in vitro cultures techniques. RESULTS: No micro morphological differences emerged between cryopreserved and untreated seeds. The effect of the treatment on the seed germination varied on the basis of the species. For Ophrys sphegodes ssp. passionis and Orchis mascula, freezing resulted in a significant increase of germination percentages. Protocorms of all species showed a positive growth trend although some significant differences of size occurred among the protocorms derived from treated and untreated seeds. CONCLUSION: Cryogenic techniques seem to have great potential in orchid germplasm conservation. PMID- 25282500 TI - Use of cyclodextrins to increase cytoplasmic cholesterol in rabbit embryos and their impact on live kits derived from vitrified embryos. AB - BACKGROUND: Low cryotolerance in oocytes and embryos is frequently associated with lipid accumulation in the cytoplasm. OBJECTIVE: This study aimed to evaluate the effect of cyclodextrin used as a cholesterol loader to change cytoplasmic cholesterol content of embryos and raise their tolerance to cryopreservation. METHODS: In the first experiment compact morulae-early blastocysts were exposed to CLC (0.11 mM and 0.23 mM cholesterol) for 1 hour. In the second experiment, embryos were exposed to CLC (0.11 mM and 0.23 mM cholesterol) and then vitrified. RESULT: Using both concentrations, cytoplasmic cholesterol content was increased. Vitrified groups demonstrated a lower capacity for embryonic development (in vitro and in vivo) compared to the control groups. Nevertheless, live young were obtained in all groups. CONCLUSIONS: In conclusion, we have demonstrated the feasibility of using cyclodextrin as a carrier for cholesterol into rabbit embryo cytoplasm, although further studies are required to clarify the usefulness of CLC use in embryo cryopreservation. PMID- 25282502 TI - Chelation of trace elements in preservation medium influences the quality of boar spermatozoa during liquid preservation at 5 degrees C for 4 weeks. AB - BACKGROUND: The addition of a metal chelator, ethylenediaminetetraacetic acid (EDTA), to semen extender has the purpose of capturing trace element ions. OBJECTIVE: This study was conducted to evaluate the effects of EDTA on the quality and in vitro fertilisability of liquid-preserved boar spermatozoa. METHODS: In Experiment 1, semen samples were preserved in the semen extender supplemented with 0, 3, 6, or 12 mM of Na-EDTA at 5 degree C for 4 weeks. In Experiment 2, semen samples were preserved in the extender supplemented with 3 mM of Na-EDTA, Ca-EDTA, or Zn-EDTA and without chelator EDTA. RESULTS: When Na-EDTA was used as a chelating substance in the extender, 3 mM was a most suitable concentration for sperm motility and viability after cold preservation. The supplementation of 3 mM Ca-EDTA had advantages regarding sperm motility, viability and plasma membrane integrity. CONCLUSION: Our findings indicate that 3 mM Ca-EDTA is the most suitable metal-chelating substance for the liquid preservation of boar semen. PMID- 25282503 TI - Liquidus tracking: controlled rate vitrification for the cryopreservation of larger volumes and tissues. AB - BACKGROUND: Vitrification of cells or tissue at controlled cooling rates suitable for larger volumes, and with reduced cryoprotectant toxicity. OBJECTIVE: To set out the current understanding of the LiquidusTracking (LT) vitrification technique, and to discuss the challenges and benefits of translating the method into laboratory protocols more generally applicable to meet requirements of large volume and 3-D cryo-banking in the era of regenerative medicine. METHODS: By adding small amounts of cryoprotectants at each step and subsequently cooling the sample just above its freezing point before further increasing CPA concentration, cryoprotectant toxicity is minimized. RESULT: CPA toxicity can be reduced by lowering the temperature. Different manual approaches to LT were evaluated and further improved. CONCLUSIONS: Manual liquidus tracking is complicated and exhibits potential high variability. Nevertheless, this approach offers the possibility of testing several conditions simultaneously and could be used to pre test conditions prior to automatic LT development. PMID- 25282506 TI - Triplet excitons: Bringing dark states to light. PMID- 25282504 TI - A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy. AB - Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer-like T (NKT) cell agonist alpha galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts. PMID- 25282505 TI - A semisynthetic carbohydrate-lipid vaccine that protects against S. pneumoniae in mice. AB - Severe forms of pneumococcal meningitis, bacteraemia and pneumonia result in more than 1 million deaths each year despite the widespread introduction of carbohydrate-protein conjugate vaccines against Streptococcus pneumoniae. Here we describe a new and highly efficient antipneumococcal vaccine design based on synthetic conjugation of S. pneumoniae capsule polysaccharides to the potent lipid antigen alpha-galactosylceramide, which stimulates invariant natural killer T (iNKT) cells when presented by the nonpolymorphic antigen-presenting molecule CD1d. Mice injected with the new lipid-carbohydrate conjugate vaccine produced high-affinity IgG antibodies specific for pneumococcal polysaccharides. Vaccination stimulated germinal center formation; accumulation of iNKT cells with a T follicular helper cell phenotype; and increased frequency of carbohydrate specific, long-lived memory B cells and plasmablasts. This new lipid-carbohydrate vaccination strategy induced potent antipolysaccharide immunity that protected against pneumococcal disease in mice and may also prove effective for the design of carbohydrate-based vaccines against other major bacterial pathogens. PMID- 25282507 TI - Energy harvesting of non-emissive triplet excitons in tetracene by emissive PbS nanocrystals. AB - Triplet excitons are ubiquitous in organic optoelectronics, but they are often an undesirable energy sink because they are spin-forbidden from emitting light and their high binding energy hinders the generation of free electron-hole pairs. Harvesting their energy is consequently an important technological challenge. Here, we demonstrate direct excitonic energy transfer from 'dark' triplets in the organic semiconductor tetracene to colloidal PbS nanocrystals, thereby successfully harnessing molecular triplet excitons in the near infrared. Steady state excitation spectra, supported by transient photoluminescence studies, demonstrate that the transfer efficiency is at least (90 +/- 13)%. The mechanism is a Dexter hopping process consisting of the simultaneous exchange of two electrons. Triplet exciton transfer to nanocrystals is expected to be broadly applicable in solar and near-infrared light-emitting applications, where effective molecular phosphors are lacking at present. In particular, this route to 'brighten' low-energy molecular triplet excitons may permit singlet exciton fission sensitization of conventional silicon solar cells. PMID- 25282508 TI - Oligopeptide complex for targeted non-viral gene delivery to adipocytes. AB - Commercial anti-obesity drugs acting in the gastrointestinal tract or the central nervous system have been shown to have limited efficacy and severe side effects. Anti-obesity drug development is thus focusing on targeting adipocytes that store excess fat. Here, we show that an adipocyte-targeting fusion-oligopeptide gene carrier consisting of an adipocyte-targeting sequence and 9-arginine (ATS-9R) selectively transfects mature adipocytes by binding to prohibitin. Injection of ATS-9R into obese mice confirmed specific binding of ATS-9R to fat vasculature, internalization and gene expression in adipocytes. We also constructed a short hairpin RNA (shRNA) for silencing fatty-acid-binding protein 4 (shFABP4), a key lipid chaperone in fatty-acid uptake and lipid storage in adipocytes. Treatment of obese mice with ATS-9R/shFABP4 led to metabolic recovery and body-weight reduction (>20%). The ATS-9R/shFABP4 oligopeptide complex could prove to be a safe therapeutic approach to regress and treat obesity as well as obesity-induced metabolic syndromes. PMID- 25282509 TI - Resonant energy transfer of triplet excitons from pentacene to PbSe nanocrystals. AB - The efficient transfer of energy between organic and inorganic semiconductors is a widely sought after property, but has so far been limited to the transfer of spin-singlet excitons. Here we report efficient resonant-energy transfer of molecular spin-triplet excitons from organic semiconductors to inorganic semiconductors. We use ultrafast optical absorption spectroscopy to track the dynamics of triplets, generated in pentacene through singlet exciton fission, at the interface with lead selenide (PbSe) nanocrystals. We show that triplets transfer to PbSe rapidly (<1 ps) and efficiently, with 1.9 triplets transferred for every photon absorbed in pentacene, but only when the bandgap of the nanocrystals is close to resonance (+/-0.2 eV) with the triplet energy. Following triplet transfer, the excitation can undergo either charge separation, allowing photovoltaic operation, or radiative recombination in the nanocrystal, enabling luminescent harvesting of triplet exciton energy in light-emitting structures. PMID- 25282510 TI - Sickle cell nephropathy. PMID- 25282511 TI - Increased association over time between regional frontal lobe BOLD change magnitude and cardiac vagal control with sertraline treatment for major depression. AB - Regions of the medial visceromotor network (MVN) participate in concurrently regulating shifts in both affective state and cardiac vagal control in the attentional background, and this regulatory ability may be impaired in depression. We examined whether the relationship between changes in BOLD within MVN regions and changes in cardiac vagal control (VC) during affective state shifting changed with depression treatment. Ten depressed and ten control subjects performed an emotional counting Stroop task designed to trigger affective change in the attentional background while undergoing functional magnetic resonance imaging and concurrent electrocardiography (ECG) on four occasions: week 0 (pre-treatment) and weeks 2, 6 and 12 of treatment on sertraline. We measured the absolute value of change between adjacent emotional and neutral conditions in both VC and the BOLD signal in specific regions of the MVN. Over time consistent increases were observed in BOLD-VC magnitude correlations in depressed subjects in subgenual ACC and left DLPFC, which strongly correlated with depressive symptom improvement. Symptom improvement over time was also associated with decreases in the magnitude of both BOLD shifts and VC shifts within-subjects. This suggests that as depressive symptoms improve on sertraline, subgenual ACC and DLPFC may more efficiently regulate visceral states during affective state shifting. PMID- 25282512 TI - Effects of laser energy and wavelength on the analysis of LiFePO4 using laser assisted atom probe tomography. AB - The effects of laser wavelength (355 nm and 532 nm) and laser pulse energy on the quantitative analysis of LiFePO4 by atom probe tomography are considered. A systematic investigation of ultraviolet (UV, 355 nm) and green (532 nm) laser assisted field evaporation has revealed distinctly different behaviors. With the use of a UV laser, the major issue was identified as the preferential loss of oxygen (up to 10 at%) while other elements (Li, Fe and P) were observed to be close to nominal ratios. Lowering the laser energy per pulse to 1 pJ/pulse from 50 pJ/pulse increased the observed oxygen concentration to nearer its correct stoichiometry, which was also well correlated with systematically higher concentrations of (16)O2(+) ions. Green laser assisted field evaporation led to the selective loss of Li (~33% deficiency) and a relatively minor O deficiency. The loss of Li is likely a result of selective dc evaporation of Li between or after laser pulses. Comparison of the UV and green laser data suggests that the green wavelength energy was absorbed less efficiently than the UV wavelength because of differences in absorption at 355 and 532 nm for LiFePO4. Plotting of multihit events on Saxey plots also revealed a strong neutral O2 loss from molecular dissociation, but quantification of this loss was insufficient to account for the observed oxygen deficiency. PMID- 25282513 TI - Long-term trends of PBDEs, triclosan, and triclocarban in biosolids from a wastewater treatment plant in the Mid-Atlantic region of the US. AB - In the US, land application of biosolids has been utilized in government regulated programs to recycle valuable nutrients and organic carbon that would otherwise be incinerated or buried in landfills. While many benefits have been reported, there are concerns that these practices represent a source of organic micropollutants to the environment. In this study, biosolids samples from a wastewater treatment plant in the Mid-Atlantic region of the US were collected approximately every 2 months over a 7-year period and analyzed for brominated diphenyl ethers (BDE-47, BDE-99, and BDE-209), triclosan, and triclocarban. During the collection period of 2005-2011, concentrations of the brominated diphenyl ethers BDE-47+BDE-99 decreased by 42%, triclocarban decreased by 47%, but BDE-209 and triclosan remained fairly constant. Observed reductions in contaminant concentrations could not be explained by different seasons or by volumetric changes of wastewaters arriving at the treatment plant and instead may be the result of the recent phaseout of BDE-47 and BDE-99 as well as potential reductions in the use of triclocarban. PMID- 25282514 TI - Immaturity of smooth muscle cells in the neointima is associated with acute coronary syndrome. AB - BACKGROUND: Acute coronary syndrome (ACS) is mostly caused by ruptured plaques. The characteristics of rupture-prone vulnerable plaques include thin fibrous cap, large lipid core, and lower number of smooth muscle cells. Smooth muscle cells appearing in neointimal plaques are currently thought to have a uniformly synthetic phenotype, and their sub-classification has not been performed by h caldesmon, which is supposed to be expressed in vascular smooth muscle cells that are beyond intermediately differentiated. METHODS: Stenotic coronary arteries were obtained from autopsy material of 51 adults. Cases were divided into three groups: those who died from ACS, those with a past history of ACS but died from other causes, and those without ACS history. Histological data including fibrous cap and lipid core were measured in each specimen. Immunohistochemistry for alpha smooth muscle actin (alpha-SMA), h-caldesmon, and smoothelin was performed. The ratio of h-caldesmon(+) cells to alpha-SMA(+) cells was counted in the neointima. RESULTS: The positivity ratio of neointimal h-caldesmon decreased in a step-wise manner from cases without history of ACS through cases with past history of ACS to cases with ACS with statistical significance (P<.001). The correlation between h-caldesmon expression and progression of ACS among the different groups was more prominent than the differences in the extent of fibrous cap and lipid core. Smoothelin(+) cells were rarely observed in the neointima. CONCLUSIONS: Decreased positivity of h-caldesmon in neointimal smooth muscle cells is indicative of a more immature phenotype, thus may be associated with plaque vulnerability that will promote ACS. PMID- 25282515 TI - [Treatment of child hydrocephalus by endoscopic third ventriculostomy in Senegal]. AB - INTRODUCTION: Since its advent, endoscopic third ventriculostomy (ETV) has been an effective alternative to shunt placement for the treatment of hydrocephalus. The aim of this study was to report the results of our experience with this technique in children in Senegal. MATERIALS AND METHODS: This was a retrospective study of 70 cases of children aged between 5 months to 15 years who were treated by ETV in the Neurosurgery Department of Fann Hospital in Dakar, between January 2010 to December 2012. The results were evaluated based on the clinical criteria of Drake and the Canadian Pediatric Neurosurgery Study Group. The mean follow-up duration was 24 months (9-32 months). RESULTS: The mean age at diagnosis was 29 months. A male predominance (sex-ratio 1/3) was observed. We also noted a macrocephaly in 64.4 % of cases, psychomotor retardation in 40 % and decreased vision in 31.4 %. Headache and vomiting were found in 42.8 % and 61.4 % respectively. The main etiology was a stenosis of the mesencephalon aqueduct (30 %), followed by a Dandy-Walker malformation (25.7 %). Significant intraoperative bleeding was found in 2.8 % of patients. The most common postoperative complication was CSF leakage (18.6 %), followed by infections (14.2 %). The success rate according to the clinical criteria of Drake was 71.4 %. This success rate was influenced by the age of patients and the hydrocephalus etiology. No deaths occurred. CONCLUSION: The endoscopic third ventriculostomy is a simple, safe and effective technique. Its advantages in terms of quality of life and morbidity compared with bypass valves makes it the technique of choice, particularly in developing countries. PMID- 25282516 TI - A nested real-time PCR assay for the quantification of Plasmodium falciparum DNA extracted from dried blood spots. AB - BACKGROUND: As public health efforts seek to eradicate malaria, there has been an emphasis on eliminating low-density parasite reservoirs in asymptomatic carriers. As such, diagnosing submicroscopic Plasmodium infections using PCR-based techniques has become important not only in clinical trials of malaria vaccines and therapeutics, but also in active malaria surveillance campaigns. However, PCR based quantitative assays that rely on nucleic acid extracted from dried blood spots (DBS) have demonstrated lower sensitivity than assays that use cryopreserved whole blood as source material. METHODS: The density of Plasmodium falciparum asexual parasites was quantified using genomic DNA extracted from dried blood spots (DBS) and the sensitivity of two approaches was compared: quantitative real-time PCR (qPCR) targeting the P. falciparum 18S ribosomal RNA gene, either with an initial conventional PCR amplification prior to qPCR (nested qPCR), or without an initial amplification (qPCR only). Parasite densities determined by nested qPCR, qPCR only, and light microscopy were compared. RESULTS: Nested qPCR results in 10-fold higher sensitivity (0.5 parasites/MUl) when compared to qPCR only (five parasites/ul). Among microscopy-positive samples, parasite densities calculated by nested qPCR correlated strongly with microscopy for both asymptomatic (Pearson's r=0.58, P<0.001) and symptomatic (Pearson's r=0.70, P<0.0001) P. falciparum infections. CONCLUSION: Nested qPCR improves the sensitivity for the detection of P. falciparum blood-stage infection from clinical DBS samples. This approach may be useful for active malaria surveillance in areas where submicroscopic asymptomatic infections are prevalent. PMID- 25282517 TI - Familial hypercholesterolaemia: PCSK9 inhibitors are coming. PMID- 25282518 TI - Causes of child deaths: looking to the future. PMID- 25282521 TI - Perceptions of advantages and barriers to radial-access percutaneous coronary intervention in VA cardiac catheterization laboratories. AB - BACKGROUND/PURPOSE: Compared with trans-femoral percutaneous coronary intervention (TFI), trans-radial PCI (TRI) has a lower risk of bleeding, access site complications and hospital costs, and is preferred by patients. However, TRI accounts for a minority of PCIs in the US, and there is currently little research that explores why. METHODS/MATERIAL: We conducted a national survey in February 2013 to assess perceptions of TRI vs. TFI, and barriers to TRI adoption and implementation among interventional cardiologists employed by the US Veterans Health Administration (VHA), and linked these data to site-level TRI annual rates for 2013. RESULTS: We received 78 completed surveys (32% response rate). Respondents at sites that perform few or no TRIs identified increased radiation exposure as the greatest barrier while at sites that perform a high percentage of TRIs respondents identified the steep learning curve as the greatest barrier. Majorities of survey respondents at all sites rated TRI as superior on 5 of 7 criteria, including patient comfort and bleeding complications, but rated TFI as superior on procedure time and procedure success. CONCLUSIONS: Even interventional cardiologists at sites that perform few or any TRIs recognized the superiority of TRI for patient comfort and safety, but rated it inferior to TFI on procedure time and technical results. Interventional cardiologists at high-TRI labs rated TRI as equivalent on procedure time and technical results. Efforts to increase TRI adoption and implementation may be more successful if they emphasize that procedure times and technical results depend on achieving proficiency. PMID- 25282522 TI - Characterization of multi-scale porous structure of fly ash/phosphate geopolymer hollow sphere structures: from submillimeter to nano-scale. AB - In the present work, the porous structure of fly ash/phosphate geopolymer hollow sphere structures (FPGHSS), prepared by pre-bonding and curing technology, has been characterized by multi-resolution methods from sub-millimeter to nano-scale. Micro-CT and confocal microscopy could provide the macroscopic distribution of porous structure on sub-millimeter scale, and hollow fly ashes with sphere shape and several sub-millimeter open cells with irregular shape were identified. SEM is more suitable to illustrate the distribution of micro-sized open and closed cells, and it was found that the open cells of FPGHSS were mainly formed in the interstitial porosity between fly ashes. Mercury porosimeter measurement showed that the micro-sized open cell of FPGHSS demonstrated a normal/bimodal distribution, and the peaks of pore size distribution were mainly around 100 and 10 MUm. TEM observation revealed that the phosphate geopolymer was mainly composed of the porous area with nano-pores and dense areas, which were amorphous Al-O-P phase and alpha-Al2O3 respectively. The pore size of nano-pores demonstrated a quasi-normal distribution from about 10 to 100 nm. Therefore, detailed information of the porous structure of FPGHSS could be revealed using multiple methods. PMID- 25282520 TI - Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Homozygous familial hypercholesterolaemia is a rare, serious disorder caused by very low or absent plasma clearance of LDL, substantially raised LDL cholesterol, and accelerated development of cardiovascular disease. Conventional lipid-lowering treatments are modestly effective. Evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced LDL cholesterol by 16% in a pilot study. We now report results with evolocumab in a randomised, double-blind, placebo-controlled phase 3 trial. METHODS: This randomised, double-blind, placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America, Europe, the Middle East, and South Africa. 50 eligible patients (aged >=12 years) with homozygous familial hypercholesterolaemia, on stable lipid-regulating therapy for at least 4 weeks, and not receiving lipoprotein apheresis, were randomly allocated by a computer generated randomisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Randomisation was stratified by LDL cholesterol at screening (<11 mmol/L or >=11 mmol/L) and implemented by a computerised interactive voice-response system. Patients, study personnel, and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit. The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01588496. FINDINGS: Of the 50 eligible patients randomly assigned to the two treatment groups, 49 actually received the study drug and completed the study (16 in the placebo group and 33 in the evolocumab group). Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30.9% (95% CI -43.9% to 18.0%; p<0.0001). Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development was detected during the study. INTERPRETATION: In patients with homozygous familial hypercholesterolaemia receiving stable background lipid lowering treatment and not on apheresis, evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo. FUNDING: Amgen Inc. PMID- 25282519 TI - PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo controlled trial. AB - BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2.6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4.1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59.2% reduction [95% CI 53.4-65.1], monthly dose: 61.3% reduction [53.6-69.0]; both p<0.0001) and at the mean of weeks 10 and 12 (60.2% reduction [95% CI 54.5-65.8] and 65.6% reduction [59.8-71.3]; both p<0.0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc. PMID- 25282523 TI - Synthetic relaxins. AB - The relaxin subfamily of peptides within the human insulin superfamily consists of seven members including relaxin-2 and relaxin-3. The former is a pleiotropic hormone that is a vasodilator and cardiac stimulant in the cardiovascular system and an antifibrotic agent whereas the latter is primarily a neuropeptide involved in stress and metabolic control. Both possess the unique three-disulfide heterodimeric peptide structure of insulin. Consequently, the synthesis, both chemical and biological, of relaxin-2 and relaxin-3 has long represented a special challenge to further understanding their structural and functional relationships. This review highlights past and recent developments in the use of chemical and recombinant DNA methods of synthesis of these peptides and current resulting knowledge of their biology. PMID- 25282525 TI - Role of medial prefrontal cortex in representing one's own subjective emotional responses: a preliminary study. AB - The medial prefrontal cortex (mPFC) has been implicated in attending to one's own emotional states, but the role of emotional valence in this context is not understood. We examined valence-specific BOLD activity in a previously validated functional magnetic resonance imaging (fMRI) paradigm. Ten healthy subjects viewed emotional pictures and categorized their experience as pleasant, unpleasant or neutral. All three categories activated a common region within mPFC. Subtraction of neutral from pleasant or unpleasant conditions instead revealed ventromedial PFC (vmPFC), suggesting that this region represents emotional valence. During exteroceptive attention, greater mPFC responses were observed in response to emotional relative to neutral stimuli, consistent with studies implicating mPFC in the top-down modulation of emotion-biased attention. These findings may help to integrate the two proposed roles of mPFC in emotional representation and top-down modulation of subcortical structures. PMID- 25282524 TI - Mirror image proteins. AB - Proteins composed entirely of unnatural d-amino acids and the achiral amino acid glycine are mirror image forms of their native l-protein counterparts. Recent advances in chemical protein synthesis afford unique and facile synthetic access to domain-sized mirror image d-proteins, enabling protein research to be conducted through 'the looking glass' and in a way previously unattainable. d Proteins can facilitate structure determination of their native l-forms that are difficult to crystallize (racemic X-ray crystallography); d-proteins can serve as the bait for library screening to ultimately yield pharmacologically superior d peptide/d-protein therapeutics (mirror-image phage display); d-proteins can also be used as a powerful mechanistic tool for probing molecular events in biology. This review examines recent progress in the application of mirror image proteins to structural biology, drug discovery, and immunology. PMID- 25282526 TI - Cannabis, cannabidiol, and epilepsy--from receptors to clinical response. AB - Recreational cannabis use in adults with epilepsy is widespread. The use of cannabis for medicinal purposes is also becoming more prevalent. For this purpose, various preparations of cannabis of varying strengths and content are being used. The recent changes in the legal environment have improved the availability of products with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) concentrations. There is some anecdotal evidence of their potential efficacy, but the mechanisms of such action are not entirely clear. Some suspect an existence of synergy or "entourage effect" between CBD and THC. There is strong evidence that THC acts via the cannabinoid receptor CB1. The mechanism of action of CBD is less clear but is likely polypharmacological. The scientific data support the role of the endocannabinoid system in seizure generation, maintenance, and control in animal models of epilepsy. There are clear data for the negative effects of cannabis on the developing and mature brain though these effects appear to be relatively mild in most cases. Further data from well designed studies are needed regarding short- and long-term efficacy and side effects of CBD or high-CBD/low-THC products for the treatment of seizures and epilepsy in children and adults. PMID- 25282527 TI - Statement on surgical preresidency preparatory courses. PMID- 25282528 TI - Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases? AB - BACKGROUND: Meticulous selection of patients who can undergo the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure safely will be paramount to minimize the associated morbidity and mortality. METHODS: We collected data prospectively on 14 consecutive patients who underwent the ALPPS procedure for planned resection of colorectal liver metastases at London Health Sciences Centre, Canada, between April 2012 and November 2013. RESULTS: The median relative increase of the standardized future liver remnant after the ALPPS procedure was 93 +/- 28%. The standardized future liver remnant rate of volume increase was 35 +/- 13 mL/day. Biopsies of the FLR were taken during stage 1 and 2. These biopsies showed a mean preregeneration Ki 67 index of 0% and a postregeneration index of 14 +/- 3%. All 14 ALPPS patients completed the 2-stage hepatectomy. No complications occurred after ALPPS stage 1. After ALPPS stage 2, 5 patients had complications (36%), with 2 patients (14%) having a severe complication (Clavien-Dindo >= IIIB). Median follow-up was 9 months. Overall survival at the time of follow-up was 100%. Recurrence developed in 2 patients. One patient had recurrence in the liver and lungs 5 months after stage 2 and was offered more chemotherapy. The other patient developed recurrence in the liver remnant 9 months after stage 2 and underwent additional chemotherapy with a possible future resection of the recurrence. CONCLUSION: Low morbidity and negligible mortality can be achieved with the ALPPS procedure, and the high rates published in previous reports can be improved with refinements in technique and patient selection. The ALPPS approach may be a valid option to enable resection in selected patients with colorectal liver metastases considered unresectable previously by standard techniques. PMID- 25282529 TI - Laparoscopic versus open liver resection for metastatic colorectal cancer: a metaanalysis of 610 patients. AB - BACKGROUND: Laparoscopic liver resection (LLR) for metastatic colorectal cancer (mCRC) remains controversial. The objective of this manuscript was to perform a metaanalysis comparing outcomes of LLR with open liver resection (OLR) in patients with hepatic mCRC, and to identify which patients were suitable candidates for LLR. STUDY DESIGN: A PubMed search identified 2,122 articles. When filtered for case-matched articles comparing LLR with OLR for mCRC, 8 articles were identified consisting of 610 patients (242 LLR, 368 OLR). A random effects metaanalysis was performed. RESULTS: The 2 groups were well-matched for age, sex, American Society of Anesthesiologists score, tumor size, number of metastases, extent of major hepatectomy, and use of neoadjuvant/adjuvant chemotherapy. The mean number of metastases in the LLR and OLR groups were 1.4 and 1.5, respectively (P = .14). Estimated blood loss was less in LLR group (262 vs 385 mL; P = .049). Transfusion rate was significantly less in LLR group (9.9 vs 19.8%; P = .004). There was no difference in operative time (248.7 vs 262.8 min; P = .85). Length of stay (LOS) was less in the LLR group (6.5 vs 8.8 days; P = .007). The overall complication rate was less in LLR group (20.3% vs 33.2%; P = .03). Importantly, there was no difference in the 1-, 3-, and 5-year disease-free survival (DFS) or overall survival (OS) rates. CONCLUSION: In carefully selected patients with limited mCRC (1 or 2 tumors), LLR provides marked perioperative benefits without compromising oncologic outcomes or long-term survival. Specifically, LLR offers decreased blood loss, LOS, and overall complication rates with comparable 5-year OS and DFS. PMID- 25282530 TI - HHV-7 in adults with drug-resistant epilepsy: a pathological role in hippocampal sclerosis? AB - BACKGROUND: Human herpesvirus-7 (HHV-7) is a beta-herpesvirus associated with febrile seizures. No association between HHV-7 and epilepsy has been confirmed. OBJECTIVES: The aim of this study was to investigate the presence of HHV-7 protein (KR4) in brain tissue from patients with drug-resistant epilepsy and to determine whether inflammatory molecules are activated in the presence of HHV-7 infection. STUDY DESIGN: We used immunohistochemistry (IHC) to detect HHV-7 protein KR4 in samples from 305 patients with drug-resistant epilepsy. Liquid nitrogen-preserved hippocampal sclerosis (HS) samples from 63 of these patients were available, and we used nested polymerase chain reaction (PCR) to detect HHV 7 DNA. Inflammatory molecules including tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-1 (IL-1) and interleukin 6 (IL-6) were identified by real-time PCR (rt-PCR) and IHC. RESULTS AND CONCLUSIONS: The study sample included 201 male subjects. The mean age was 23.9, SD 6.2 years (range 15-45). HS was the pathology in 69 samples (23%). The HHV-7 protein was detected in 27 (9%) of the 305 samples and in none of the 42 controls. The factors associated with HHV-7 infection were HS (11/69), glial scar (8/58), arachnoid cyst (2/21), focal cortical dysplasia (2/31) and vascular malformation (4/52). HHV-7 antigen was distributed mainly in the cytoplasm of astrocyte and oligodendrocyte in HS samples. HHV-7 DNA was detected in 20 of the 63 nitrogen preserved HS samples. The expression of TGF-beta was up-regulated in samples that were positive for the HHV-7 protein and was mainly detected in neurons. This finding suggests a possible association between HHV-7 positivity, activation of TGF-beta and drug-resistant epilepsy, especially HS, but these data need to be replicated. PMID- 25282531 TI - Alcohol and the paradox of self-control. PMID- 25282532 TI - Ghrelin in addictive behaviors: plenus venter non studet libenter. PMID- 25282533 TI - Deep repetitive transcranial magnetic stimulation for smoking cessation: is going deeper better? PMID- 25282534 TI - Outcomes after delirium in a Japanese intensive care unit. AB - OBJECTIVE: Delirium in the intensive care unit (ICU) is recognized as a major public health problem. Few Japanese outcome studies have been reported. The purpose of the study was to investigate the hospital outcomes of ICU delirium in a Japanese general hospital. METHODS: Patients were drawn from consecutive admissions to an ICU at a tertiary care university hospital. Delirium assessments were conducted using the Intensive Care Delirium Screening Checklist (ICDSC). The following information was recorded: age, sex, the reason for ICU admission, the ICDSC scores, the COmplexity PRediction Instrument (COMPRI) scores, the length of stay (LOS) in the ICU, the total hospital LOS, hospital outcomes and social worker's consultation. RESULTS: Of the 126 patients who were evaluated, 35 (27.8%) developed delirium during the ICU stay. Older age and biopsychosocial vulnerability assessed by the COMPRI were risk factors of ICU delirium. ICU delirium was a predictor of increased mortality and associated with prolonged ICU and hospital LOS. ICU delirium was an independent risk factor for having social worker's consultation after ICU discharge. CONCLUSIONS: ICU delirium is associated with worse outcomes including mortality and LOS in Japan. ICU delirium is independently associated with further social worker's consultations, suggesting that early proactive social worker's intervention may be beneficial for the patients with ICU delirium. PMID- 25282535 TI - Rejection sensitivity and adolescents' perceptions of romantic interactions. AB - Rejection sensitivity - the tendency to expect, perceive, and overreact to rejection by others - is linked with individuals' expectations that their romantic partners' behaviors have negative intent, even if, perhaps, such behaviors could be considered neutral when observed by another. The aim of the present study was to test this proposition, derived from rejection sensitivity theory, using a Video-Recall Procedure with adolescent couples in the US (N = 386 adolescents, 50% girls). We examined whether adolescents who were more sensitive to rejection perceived their romantic partners' behaviors as more conflictual than when viewed by trained, third-party observers. Findings suggest that, at the micro-analytic level, higher rejection sensitivity is associated with adolescents' heightened perception of their romantic partners as conflictual when compared to observers, who more often coded the same behaviors as neutral rather than conflictual. Implications for adolescent mental health and well-being are discussed. PMID- 25282536 TI - Detecting temporal protein complexes from dynamic protein-protein interaction networks. AB - BACKGROUND: Proteins dynamically interact with each other to perform their biological functions. The dynamic operations of protein interaction networks (PPI) are also reflected in the dynamic formations of protein complexes. Existing protein complex detection algorithms usually overlook the inherent temporal nature of protein interactions within PPI networks. Systematically analyzing the temporal protein complexes can not only improve the accuracy of protein complex detection, but also strengthen our biological knowledge on the dynamic protein assembly processes for cellular organization. RESULTS: In this study, we propose a novel computational method to predict temporal protein complexes. Particularly, we first construct a series of dynamic PPI networks by joint analysis of time course gene expression data and protein interaction data. Then a Time Smooth Overlapping Complex Detection model (TS-OCD) has been proposed to detect temporal protein complexes from these dynamic PPI networks. TS-OCD can naturally capture the smoothness of networks between consecutive time points and detect overlapping protein complexes at each time point. Finally, a nonnegative matrix factorization based algorithm is introduced to merge those very similar temporal complexes across different time points. CONCLUSIONS: Extensive experimental results demonstrate the proposed method is very effective in detecting temporal protein complexes than the state-of-the-art complex detection techniques. PMID- 25282537 TI - Botulinum neurotoxins: new questions arising from structural biology. AB - Botulinum neurotoxins (BoNTs) are the most toxic substances known and cause botulism in vertebrates. They have also emerged as effective and powerful reagents for cosmetic and medical applications. One important prerequisite for understanding BoNT function in disease, and the further development of the toxins for cosmetic and medical applications, is a detailed knowledge of BoNT interactions with non-toxic neurotoxin-associated proteins and cell surface receptors. Based on the substantial recent progress in obtaining high-resolution crystal structures of key BoNT complexes, we summarize the major advances in understanding BoNT interactions and discuss the resulting potential implications, in particular those relating to BoNT serotype A. PMID- 25282538 TI - Advances in colposcopy: new technologies to challenge current practice. AB - Colposcopy has a poor sensitivity to detect precancerous abnormalities of the cervix. These abnormalities will become less common after HPV vaccinated girls enter the screened population. However HPV-based screening is likely to result in more colposcopic referrals. Both these changes to cervical screening programs will reduce the incidence of high grade CIN and cervical cancer as well as the prevalence of high grade CIN presenting to the colposcopist. As a consequence the diagnostic performance of conventional colposcopy will be further challenged. This review aims to discuss leading technologies which are currently available as an alternative or in addition to colposcopy and may serve to improve the current colposcopic assessment of precancerous cervical abnormalities. PMID- 25282539 TI - The impact of donor insemination on the risk of preeclampsia: a systematic review and meta-analysis. AB - A systematic review and meta-analysis were performed to evaluate whether women who conceive with donor sperm have an increased risk of preeclampsia compared with those who use their partner's sperm. Studies that compared women who were impregnated by donor and partner sperm were included. The main outcomes assessed were preeclampsia and gestational hypertension rates. Altogether, 10,898 women (2342 pregnancies by donor sperm versus 8556 by the partner's sperm) were included from seven observational studies. Conception using donor sperm was associated with an increased risk of preeclampsia (odds ratio [OR] 1.63, 95% CI 1.36-1.95) compared with using a partner's sperm. No difference was observed in the risk of gestational hypertension (OR 0.94, 95% CI 0.43-2.03). In conclusion, pregnancies achieved by donor sperm significantly increase the risk of preeclampsia, although the underlying mechanisms remain unclear. Additional studies are required to confirm these findings. PMID- 25282540 TI - Measurement of procoagulant activity of microparticles in plasma: feasibility of new functional assays. PMID- 25282541 TI - Patent foramen ovale increases the risk of acute ischemic stroke in patients with acute pulmonary embolism leading to right ventricular dysfunction. AB - BACKGROUND: Patent foramen ovale (PFO) is an established risk factor for ischemic stroke. Since acute right ventricular dysfunction (RVD) observed in patients with PE can lead to right-to-left inter-atrial shunt via PFO, we hypothesized that PFO is a risk factor for ischemic stroke in PE with significant right ventricular dysfunction. METHODS: 55 patients (31 F, 24M), median age 49 years (range 19-83 years) with confirmed PE underwent echocardiography for RVD and PFO assessment. High risk acute PE was diagnosed in 3 (5.5%) patients, while 16 (29%) hemodynamically stable with RVD patients formed a group with intermediate-risk PE. PFO was diagnosed in 19 patients (34.5%). Diffusion-weighted MRI of the brain for acute ischemic stroke (AIS) was performed in all patients 4.91 +/- 4.1 days after admission. RESULTS: AIS was detected by MRI in 4 patients (7.3%). Only one stroke was clinically overt and resulted in hemiplegia. All 4 AIS occurred in the PFO positive group (4 of 19 patients), and none in subjects without PFO (21.0% vs 0%, p=0.02). Moreover, all AIS occurred in patients with RVD and PFO, and none in patients with PFO without RVD (50% vs 0%, p=0.038). CONCLUSION: Our data suggest that acute pulmonary embolism resulting in right ventricular dysfunction may lead to acute ischemic stroke in patients with patent foramen ovale. However, the clinical significance of such lesions remains to be determined. PMID- 25282542 TI - Challenges in the quantification and interpretation of spike-LFP relationships. AB - Brain signals often show fluctuations in particular frequency bands, which are highly conserved across species and are associated with specific behavioural states. Such rhythmic patterns can be captured in the local field potential (LFP), which is obtained by low-pass filtering the extracellular signal recorded from microelectrodes. However, LFP also captures other neural processes that are associated with spikes, such as synaptic events preceding a spike, low-frequency component of the action potential ("spike bleed-through") and spike afterhyperpolarization, which pose difficulties in the estimation of the amplitude and phase of the rhythm with respect to spikes. Here we discuss these issues and different techniques that have been used to dissociate the rhythm from other neural events in the LFP. PMID- 25282543 TI - Impact of anxiety and depression on respiratory symptoms. AB - Psychological factors such as anxiety and depression are prevalent in patients with asthma. The purpose of this study was to investigate the relationship between respiratory symptoms and psychological status and to estimate the importance of psychological status in comparison with other factors that are known to be associated with respiratory symptoms. This study included 2270 subjects aged 20-44 (52% female) from Sweden, Iceland, and Norway. Each participant underwent a clinical interview including questions on respiratory symptoms. Spirometry and methacholine challenge were performed. Symptoms of depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS). Eighty-two percent of the subjects reported no anxiety or depression whatsoever, 11% reported anxiety, 2.5% depression and 4% reported both anxiety and depression. All respiratory symptoms, such as wheezing, breathlessness and nightly symptoms, were more common, at a statistically significant level, in participants who had depression and anxiety, even after adjusting for confounders (ORs 1.33-1.94). The HADS score was the most important determinant for nightly symptoms and attacks of breathlessness when at rest whereas bronchial responsiveness was the most important determinant for wheezing, and breathlessness when wheezing. The probability of respiratory symptoms related to HADS score increased with increasing HADS score for all respiratory symptoms. In conclusion, there is a strong association between respiratory symptoms and psychological status. There is therefore a need for interventional studies designed to improve depression and anxiety in patients with respiratory symptoms. PMID- 25282544 TI - Stenogyria - not only in Chiari II malformation. AB - Stenogyria, meaning multiple small compacted gyri separated by shallow sulci, is reported in the literature in association with Chiari II malformation (CM II) which in turn is reported in association with myelomeningocele (MMC). The authors present five cases of stenogyria (and other abnormalities found in CM II, like callosal hypoplasia/dysplasia, agenesis of the anterior commissure, hypoplasia of the falx cerebri) in children without the history of MMC or any other form of open spinal dysraphism. In these cases stenogyria was associated with Chiari I malformation, rhombencephalosynapsis and spina bifida. Stenogyria, which is not a true neuronal migration disorder, should not be mistaken for polymicrogyria which is also present in CM II. It is histologically different from polymicrogyria because the cortex is normally organized. Also on MRI, the general sulcal pattern is preserved in stenogyria, while it is completely distorted in polymicrogyria. The authors conclude that features traditionally attributed to CM II, like stenogyria, occur not only in the population of patients with MMC as opposed to the widely accepted theory. PMID- 25282545 TI - Cannabidiol and endogenous opioid peptide-mediated mechanisms modulate antinociception induced by transcutaneous electrostimulation of the peripheral nervous system. AB - Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological therapy for the treatment of pain. The present work investigated the effect of cannabidiol, naloxone and diazepam in combination with 10 Hz and 150 Hz TENS. Male Wistar rats were submitted to the tail-flick test (baseline), and each rodent received an acute administration (intraperitoneal) of naloxone (3.0mg/kg), diazepam (1.5mg/kg) or cannabidiol (0.75 mg/kg, 1.5mg/kg, 3.0mg/kg, 4.5mg/kg, 6.0mg/kg and 12.0mg/kg); 10 min after the acute administration, 10 Hz or 150 Hz TENS or a sham procedure was performed for 30 min. Subsequently, tail-flick measures were recorded over a 90-min period, at 5-min intervals. 10 Hz TENS increased the nociceptive threshold during the 90-min period. This antinociceptive effect was reversed by naloxone pre-treatment, was not altered by diazepam pre-treatment and was abolished by cannabidiol pre-treatment (1.5mg/kg). Moreover, 150 Hz TENS increased tail-flick latencies by 35 min post-treatment, which was partially inhibited by naloxone pre-treatment and totally inhibited by cannabidiol (1.5mg/kg). These data suggest the involvement of the endogenous opioid system and the cannabinoid-mediated neuromodulation of the antinociception induced by transcutaneous electrostimulation at 10 Hz and 150 Hz TENS. PMID- 25282546 TI - Ex vivo intra-arterial methylene blue injection in the operation theater may improve the detection of lymph node metastases in colorectal cancer. AB - INTRODUCTION: Lymph node (LN) assessment after colorectal cancer resection is fundamentally important for therapeutic and prognostic reasons. LN positivity is an indication for adjuvant treatment. This study aimed to investigate whether immediate postoperative intra-arterial methylene blue (MB) injection (MBI) into colorectal cancer specimens by a surgeon in the operating room could improve the rate of total LN and metastatic LN recovery for pathological examination. MATERIALS AND METHODS: Seventy-three consecutive patients prospectively enrolled between January 2011 and December 2013 were assigned to the methylene blue (MB) stained group and compared with 107 controls in the unstained group. RESULTS: The median number and range values of metastatic LNs, the number of LNs <0.5 cm, the total number of LNs harvested, and the number of cases with LN metastasis were significantly different between the MB-stained and MB-unstained groups (p = 0.016, p = 0.010, p = 0.025, and p = 0.006 respectively). CONCLUSIONS: Immediate MBI (fresh, unfixed samples) by a surgeon in the operating room may result in a significant increase in the number of metastatic LNs diagnosed and the number of cases with positive LNs. Shifting of the injection from the pathology laboratory to the operation theater would be a good alternative whenever the operation theater is not the area located as the pathology department. PMID- 25282547 TI - Computational model of visual hallucination in dementia with Lewy bodies. AB - Patients with dementia with Lewy bodies (DLB) frequently experience visual hallucination (VH), which has been aptly described as people seeing things that are not there. The distinctive character of VH in DLB necessitates a new theory of visual cognition. We have conducted a series of studies with the aim to understand the mechanism of this dysfunction of the cognitive system. We have proposed that if we view the disease from the internal mechanism of neurocognitive processes, and if also take into consideration recent experimental data on conduction abnormality, at least some of the symptoms can be understood within the framework of network (or disconnection) syndromes. This paper describes the problem from a computational aspect and tries to determine whether conduction disturbances in a computational model can in fact produce a "computational" hallucination under appropriate assumptions. PMID- 25282548 TI - Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation. AB - The inhibitor of apoptosis (IAP) family members, notably cIAP1, cIAP2, and XIAP, are critical and universal regulators of tumor necrosis factor (TNF) mediated survival, inflammatory, and death signaling pathways. Furthermore, IAPs mediate the signaling of nucleotide-binding oligomerization domain (NOD)1/NOD2 and other intracellular NOD-like receptors in response to bacterial pathogens. These pathways are important to the pathogenesis and treatment of inflammatory bowel disease (IBD). Inactivating mutations in the X-chromosome-linked IAP (XIAP) gene causes an immunodeficiency syndrome, X-linked lymphoproliferative disease type 2 (XLP2), in which 20% of patients develop severe intestinal inflammation. In addition, 4% of males with early-onset IBD also have inactivating mutations in XIAP. Therefore, the IAPs play a greater role in gut homeostasis, immunity and IBD development than previously suspected, and may have therapeutic potential. PMID- 25282549 TI - Evaluation of occipitocervical neutral position using lateral radiographs. AB - BACKGROUND: Intraoperative assessment of neutral occipitocervical balance during a fusion procedure is challenging. We designed this study to introduce a more comprehensive method of evaluating the occipitocervical neutral position using lateral radiographs. METHODS: One hundred neutral lateral cervical spine radiographs interpreted as normal were studied. Cervical spine radiographs were performed using a standard technique. The occipitocervical angle, the occipitocervical distance, and the mandible cervical distance were measured by different observers. RESULTS: A difference analysis was performed between males and females. The mean mandible cervical distances were 11.0 and 11.2 mm in males and females, respectively. The mean occipitocervical distances were 22.0 mm (male) and 19.6 mm (female), and the occipitocervical angles were 47.2 degrees (male) and 45.5 degrees (female). The occipitocervical distance revealed significant differences between males and females (p <0.01). However, there were no significant differences between sexes for the occipitocervical angle or the mandible cervical distance (p >0.01). CONCLUSIONS: This study offers reference values for the occipitocervical angle and occipitocervical distance for the estimation of the occipitocervical neutral position. The introduction of the mandible cervical distance may make the evaluation more direct and more comprehensive during surgery because of its sensitivity to changes in head position. PMID- 25282550 TI - Do children overestimate the extent of smoking among their peers? A feasibility study of the social norms approach to prevent smoking. AB - Social norms approaches (SNA) are based on the premise that we frequently overestimate risk behaviours among our peers. By conducting campaigns to reduce these misperceptions, SNAs aim to reduce risk behaviours. This study examines the extent to which 12 to 13year old pupils overestimate smoking among their peers and explores the appropriateness of using SNA in secondary schools to prevent smoking uptake. METHODS: The extent of overestimation of smoking among peers was assessed through an on-line SNA questionnaire in five schools (n=595). Based on questionnaire results, pupils developed SNA campaigns in each school. Qualitative methods of focus groups (7), interviews (7) and observation were used to explore in-depth, from the perspective of staff and pupils, the appropriateness and feasibility of the SNA to prevent smoking uptake in secondary schools. RESULTS: A quarter of pupils, 25.9% (95% CI 25.6% to 26.1%) believed that most of their peers smoked, however, only 3% (95% CI 2.8% to 3.3%) reported that they actually did; a difference of 22.9% (95% CI 19.1% to 26.6%). Self-reported smoking was not significantly different between schools (X(2)=8.7 p=0.064), however, perceptions of year group smoking was significantly different across schools (X(2)=63.9 p<0.001). Qualitative analysis identified full school engagement, minimal teacher time requirements, pupils' belief in questionnaire results and understanding wider context, as key in optimising implementation. CONCLUSION: This study shows significant misperception between self-reported and perceived smoking among peers in secondary schools, thus supporting a key premise of social norms theory. Implementing SNAs and studying effects is feasible within secondary schools. PMID- 25282551 TI - Structure-activity relationships of non-opioid [des-Arg(7)]-dynorphin A analogues for bradykinin receptors. AB - In our earlier studies, bradykinin receptors (BRs) were identified as a potential target for the neuroexcitatory effects of dynorphin A (Dyn A) in the central nervous system (CNS), and [des-Arg(7)]-Dyn A-(4-11) (6) was discovered as a lead ligand to modulate Dyn A-(2-13) induced neuroexcitatory effects in the CNS as an antagonist. In an effort to gain insights into key structural features of the Dyn A for the BRs, we pursued further structure-activity relationships (SAR) study on the [des-Arg(7)]-Dyn A analogs and confirmed that all of the [des-Arg(7)]-Dyn A analogues showed good binding affinities at the BRs. PMID- 25282552 TI - Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives as novel c-Met kinase inhibitors. AB - We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine substituents. PMID- 25282553 TI - Analysis of the serum concentrations of kisspeptin and neurokinin B in the geese during reproductive cycle and their localisation in the ovary. AB - Kisspeptin and neurokinin B (NKB) have various functions. Their expression has been demonstrated in rat and human ovary, and estrogen affects their activity, suggesting a role for these molecules in the control of ovary function. However, whether these signaling systems are present in geese ovary, and the associated with serum estrogen remains largely unexplored. In this study we investigated the expression of kisspeptin and NKB in the ovary, and analysed their changes in the serum during the reproductive cycle and their association with serum estradiol in the geese. The results showed both kisspeptin and NKB immunoreactivity was found in the ovary, with marked expression in the granular layer and theca of the follicle, where intense coexpression of kisspeptin and NKB was also detected. The serum concentrations of kisspeptin and NKB in geese were significantly higher (P<0.05) in broody period than in laying period and laying cessation stage. However, the level of estradiol was markedly higher (P<0.05) in laying period than in broody and laying cessation stage. Serum kisspeptin was positively correlated with NKB (r=0.866, P<0.001), serum estradiol was negatively correlated with kisspeptin (r=-0.977, P<0.05) and NKB (r=-0.887, P<0.05). Overall, the existence of kisspeptin and NKB in geese ovary, and the difference of their serum concentrations during reproductive cycle and the inverse correlation with serum estradiol are highly suggestive of a role for kisspeptin and NKB in the regulation of geese reproductive function. PMID- 25282554 TI - Predicting ejaculate quality and libido in male ostriches: effect of season and age. AB - The success of artificial breeding program depends largely on the reproductive performance of males. Male performance can vary with season and age impacting on quality and quantity of semen collected for artificial insemination purposes and therefore fertility of inseminated females. We examined variation in semen output and male libido of seven male ostriches (aged 2-5 years) over a period of 24 months. We collected ejaculates using a dummy female and measured semen characteristics (ejaculate volume, sperm concentration, number of spermatozoa per ejaculate, sperm motility and morphology) and male libido (willingness to mount the dummy). A total of 1006 ejaculates were collected. Across months, the volume of semen (mean +/- SEM) ranged from 1.03 +/- 0.12 mL to 1.85 +/- 0.07 mL, the sperm concentration from 3.21 +/- 0.12 * 10(9)/mL to 4.16 +/- 0.74 * 10(9)/mL, and the number of spermatozoa from 3.42 +/- 0.28 * 10(9) to 7.66 +/- 0.47 * 10(9). The largest volume of ejaculates and the highest number of sperm were collected in spring. Ejaculates with higher number of normal sperm were also collected in spring-early summer, whereas ejaculates with higher numbers of live abnormal and dead sperm were collected in winter. Sperm motility was relatively constant over months, despite a reduction in summer (January-February), while male libido peaked in winter (June-July) and spring (October-November). Furthermore, we observed high individual variation between males for all variables tested, except for motility. These results indicate that collections conducted in spring yield higher number of spermatozoa, when the libido of males is also at a maximum. Therefore in this species seasonal variation in semen quality should be considered in breeding programmes by artificial insemination to maximise fertility. PMID- 25282555 TI - The availability of prior ECGs improves paramedic accuracy in recognizing ST segment elevation myocardial infarction. AB - INTRODUCTION: Early and accurate identification of ST-elevation myocardial infarction (STEMI) by prehospital providers has been shown to significantly improve door to balloon times and improve patient outcomes. Previous studies have shown that paramedic accuracy in reading 12 lead ECGs can range from 86% to 94%. However, recent studies have demonstrated that accuracy diminishes for the more uncommon STEMI presentations (e.g. lateral). Unlike hospital physicians, paramedics rarely have the ability to review previous ECGs for comparison. Whether or not a prior ECG can improve paramedic accuracy is not known. STUDY HYPOTHESIS: The availability of prior ECGs improves paramedic accuracy in ECG interpretation. METHODS: 130 paramedics were given a single clinical scenario. Then they were randomly assigned 12 computerized prehospital ECGs, 6 with and 6 without an accompanying prior ECG. All ECGs were obtained from a local STEMI registry. For each ECG paramedics were asked to determine whether or not there was a STEMI and to rate their confidence in their interpretation. To determine if the old ECGs improved accuracy we used a mixed effects logistic regression model to calculate p-values between the control and intervention. RESULTS: The addition of a previous ECG improved the accuracy of identifying STEMIs from 75.5% to 80.5% (p=0.015). A previous ECG also increased paramedic confidence in their interpretation (p=0.011). CONCLUSIONS: The availability of previous ECGs improves paramedic accuracy and enhances their confidence in interpreting STEMIs. Further studies are needed to evaluate this impact in a clinical setting. PMID- 25282556 TI - The evaluation of the OMOM capsule endoscopy with similar pictures elimination mode. AB - BACKGROUND AND OBJECTIVE: The reading of capsule endoscopy (CE) is time consuming. Thus, several time-saving features have been added to the CE software by different CE companies. However, the similar pictures elimination mode in the OMOM capsule endoscopy software has not been evaluated yet. Our aim is to evaluate the sensitivity and specificity of the similar pictures elimination mode. METHODS: We retrospectively studied 200 consecutive capsule endoscopy procedures in Nanfang Hospital between April 2012 and July 2012, among which 52 cases were excluded for poor bowel preparation, failure to reach the colon or data missing. All images of the small-bowel were re-evaluated with four different reading modes (conventional mode and three levels of similar pictures elimination mode) by four experienced endoscopists. Then, the reading time, the number of detected lesions, kappa value, sensitivity and specificity were compared between 4 methods. RESULTS: The mean reading time with levels I to III, respectively, was significantly shorter than with conventional mode (P<0.001, conventional mode 33.25min, level I 24.90min, level II 20.54min, level III 14.96min). The sensitivity between conventional mode and level I were similar (93.8% vs. 87.7%, P=0.073), while the sensitivity of levels II and III was significantly lower than conventional mode (77.8% vs. 93.8%, 70% vs. 93.8%, respectively). The specificity between all 4 modes were similar (100% for conventional mode, 98.5% for levels I to III). CONCLUSIONS: Level I reading mode was as efficient as the conventional mode and less time-consuming. Its sensitivity and specificity were similar compared with the conventional mode. PMID- 25282557 TI - The soybean mycorrhiza-inducible phosphate transporter gene, GmPT7, also shows localized expression at the tips of vein endings of senescent leaves. AB - GmPT7 was originally identified as an arbuscular mycorrhiza-inducible gene of soybean that encodes a member of subfamily I in the PHOSPHATE TRANSPORTER 1 family. In the present study, we established conditions under which a number of dwarf soybean plants complete their life cycles in a growth chamber. Using this system, we grew transgenic soybean with a GmPT7 promoter-beta-glucuronidase fusion gene and evaluated GmPT7 expression in detail. GmPT7 was highly expressed in mature, but not in collapsed, arbuscule-containing cortical cells, suggesting its importance in the absorption of fungus-derived phosphate and/or arbuscule development. GmPT7 was also expressed in the columella cells of root caps and in the lateral root primordia of non-mycorrhizal roots. The expression of GmPT7 occurred only in the late stage of phosphorus translocation from leaves to seeds, after water evaporation from the leaves ceased, and later than the expression of GmUPS1-2, GmNRT1.7a and GmNRT1.7b, which are possibly involved in nitrogen export. GmPT7 expression was localized in a pair of tracheid elements at the tips of vein endings of senescent leaves. Transmission electron microscopy revealed that the tip tracheid elements in yellow leaves were still viable and had intact plasma membranes. Thus, we think that GmPT7 on the plasma membranes transports phosphate from the apoplast into the tip elements. GmPT7 knockdown resulted in no significant effects, the function of GmPT7 remaining to be clarified. We propose a working model in which phosphate incorporated in vein endings moves to seeds via xylem to phloem transfer. PMID- 25282558 TI - Cell-by-cell developmental transition from embryo to post-germination phase revealed by heterochronic gene expression and ER-body formation in Arabidopsis leafy cotyledon mutants. AB - LEC1, LEC2, FUS3 and ABI3 (collectively abbreviated LEC/ABI3 here) are required for embryo maturation and have apparent roles in repressing post-germinative development. lec mutant embryos exhibit some heterochronic characteristics, as exemplified by the development of true leaf-like cotyledons during embryogenesis. Although the roles of LEC/ABI3 as positive regulators of embryo maturation have been extensively studied, their roles in the negative regulation of post germinative development have not been explored in detail. Based on microarray analyses, we chose PYK10, which encodes an endoplasmic reticulum (ER)-body localized protein, as a molecular marker of post-germinative development. lec/abi3 embryos exhibited PYK10 misexpression and the formation of 'constitutive' ER-bodies, which develop specifically during the seedling stage, confirming the heterochronic nature of these mutants at both the gene expression and cellular levels. The PYK10 reporter expression in lec1 embryos started as early as the globular-heart transition stage. The onset of PYK10 promoter enhanced green fluorescent protein (EGFP) reporter expression occurred in a stochastic, cell-by-cell manner in both developing lec/abi3 embryos and germinating wild-type seedlings. Additionally, clustered EGFP-positive cells were frequently found along cell files, probably representing the transmission of the expression state via cell division. These observations, together with the results of the experiments using PYK10-EGFP/PYK10-CFP double reporter transgenic lines and the analyses of H3K27me3 levels in the PYK10 chromatin, suggested the involvement of epigenetic mechanisms in repressing post-germinative genes during embryogenesis and derepressing these genes upon the transition to post germinative development. PMID- 25282560 TI - The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials. AB - The lack of core outcome sets for atopic eczema (AE) is a major obstacle for advancing evidence-based treatment. The global Harmonising Outcome Measures for Eczema (HOME) initiative has already defined clinical signs, symptoms, quality of life, and long-term control of flares as core outcome domains for AE trials. This article deals with the standardization of measurement instruments to assess clinical signs of AE. To resolve the current lack of standardization of the assessment of clinical signs of AE, we followed a structured process of systematic reviews and international consensus sessions to identify 1 core outcome measurement instrument for assessment of clinical signs in all future AE trials. Systematic reviews indicated that from 16 different instruments identified to assess clinical signs of AE, only the Eczema Area and Severity Index (EASI) and the objective Scoring Atopic Dermatitis (SCORAD) index were identified as extensively validated. The EASI has adequate validity, responsiveness, internal consistency, and intraobserver reliability. The objective SCORAD index has adequate validity, responsiveness, and interobserver reliability but unclear intraobserver reliability to measure clinical signs of AE. In an international consensus study, patients, physicians, nurses, methodologists, and pharmaceutical industry representatives agreed that the EASI is the preferred core instrument to measure clinical signs in all future AE trials. All stakeholders involved in designing, reporting, and using clinical trials on AE are asked to comply with this consensus to enable better evidence based decision making, clearer scientific communication, and improved patient care. PMID- 25282561 TI - Peeling off the genetics of atopic dermatitis-like congenital disorders. AB - The epidermis forms during the course of a complex differentiation process known as cornification, which culminates with the formation of the epidermal barrier. The epidermal barrier serves as a vital line of defense against the environment and mainly consists of 3 elements: intracellular keratin filaments, intercellular lipids, and the cornified cell envelope. Adequate epidermal barrier function is also critically dependent on normal shedding of terminally differentiated keratinocytes, a process termed desquamation, which requires the dissolution of cell-cell junctions in the upper granular layers. Although much has been learned about epidermal differentiation through the deciphering of the molecular basis of various cornification disorders, less is currently known about the mechanisms regulating epidermal desquamation and disorders resulting from disruption of this process. Netherton syndrome, peeling skin syndrome type B, and skin dermatitis- multiple severe allergies--metabolic wasting syndrome are 3 autosomal recessive conditions resulting from aberrant regulation of epidermal desquamation. The deciphering of their pathogenesis has not only broadened our understanding of this process but has also shed new light on clinical and mechanistic links between allergic reactions and abnormal desquamation, substantiating the notion that allergic manifestations might, under some circumstances, be the sole consequence of a primary epidermal defect. PMID- 25282559 TI - Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. AB - Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It often precedes the development of food allergy and asthma. Recent insights into AD reveal abnormalities in terminal differentiation of the epidermal epithelium leading to a defective stratum corneum, which allows enhanced allergen penetration and systemic IgE sensitization. Atopic skin is also predisposed to colonization or infection by pathogenic microbes, most notably Staphylococcus aureus and herpes simplex virus. Causes of this abnormal skin barrier are complex and driven by a combination of genetic, environmental, and immunologic factors. These factors likely account for the heterogeneity of AD onset and the severity and natural history of this skin disease. Recent studies suggest prevention of AD can be achieved through early interventions to protect the skin barrier. Onset of lesional AD requires effective control of local and systemic immune activation for optimal management. Early intervention might improve long-term outcomes for AD and reduce the systemic allergen sensitization that leads to associated allergic diseases in the gastrointestinal and respiratory tract. PMID- 25282563 TI - Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. AB - BACKGROUND: Atopic dermatitis (atopic eczema) is a chronic inflammatory skin disease that has reached epidemic proportions in children worldwide and is increasing in prevalence. Because of the significant socioeconomic effect of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on disease prevention, with limited success. Recent advances in cutaneous biology suggest skin barrier defects might be key initiators of atopic dermatitis and possibly allergic sensitization. OBJECTIVE: Our objective was to test whether skin barrier enhancement from birth represents a feasible strategy for reducing the incidence of atopic dermatitis in high-risk neonates. METHODS: We performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for atopic dermatitis. Parents in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. RESULTS: Forty-two percent of eligible families agreed to be randomized into the trial. All participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of atopic dermatitis with a relative risk reduction of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). There were no emollient related adverse events and no differences in adverse events between groups. CONCLUSION: The results of this trial demonstrate that emollient therapy from birth represents a feasible, safe, and effective approach for atopic dermatitis prevention. If confirmed in larger trials, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases. PMID- 25282565 TI - Randomized trial of vitamin D supplementation for winter-related atopic dermatitis in children. AB - BACKGROUND: Epidemiologic and preclinical data, and a small randomized trial in Boston, suggest that vitamin D supplementation may improve winter-related atopic dermatitis (AD). OBJECTIVE: To determine the effect of vitamin D supplementation on winter-related AD. METHODS: We performed a randomized, double-blind, placebo controlled trial of Mongolian children with winter-related AD (clinicaltrials.gov identifier: NCT00879424). Baseline eligibility included age 2 to 17 years, AD score 10 to 72 using the Eczema Area and Severity Index (EASI), and winter related AD (eg, history of AD worsening during the fall-to-winter transition). Subjects were enrolled in Ulaanbaatar during winter and randomly assigned to oral cholecalciferol (1000 IU/day) versus placebo for 1 month. All children and parents received emollient and patient education about AD and basic skin care. The main outcomes were changes in EASI score and in Investigator's Global Assessment. RESULTS: The 107 enrolled children had a mean age of 9 years (SD 5), and 59% were male. Their median age of AD onset was 3 months (interquartile range 2 months to 1 year) and mean EASI score at baseline 21 (SD 9). One-month follow up data were available for 104 (97%) children. Compared with placebo, vitamin D supplementation for 1 month produced a clinically and statistically significant improvement in EASI score (adjusted mean change: -6.5 vs -3.3, respectively; P = .04). Moreover, change in Investigator's Global Assessment favored vitamin D over placebo (P = .03). There were no adverse effects in either group. CONCLUSION: Vitamin D supplementation improved winter-related AD among Mongolian children, a population likely to have vitamin D deficiency in winter. PMID- 25282564 TI - Application of moisturizer to neonates prevents development of atopic dermatitis. AB - BACKGROUND: Recent studies have suggested that epidermal barrier dysfunction contributes to the development of atopic dermatitis (AD) and other allergic diseases. OBJECTIVE: We performed a prospective, randomized controlled trial to investigate whether protecting the skin barrier with a moisturizer during the neonatal period prevents development of AD and allergic sensitization. METHODS: An emulsion-type moisturizer was applied daily during the first 32 weeks of life to 59 of 118 neonates at high risk for AD (based on having a parent or sibling with AD) who were enrolled in this study. The onset of AD (eczematous symptoms lasting >4 weeks) and eczema (lasting >2 weeks) was assessed by a dermatology specialist on the basis of the modified Hanifin and Rajka criteria. The primary outcome was the cumulative incidence of AD plus eczema (AD/eczema) at week 32 of life. A secondary outcome, allergic sensitization, was evaluated based on serum levels of allergen-specific IgE determined by using a high-sensitivity allergen microarray of diamond-like carbon-coated chips. RESULTS: Approximately 32% fewer neonates who received the moisturizer had AD/eczema by week 32 than control subjects (P = .012, log-rank test). We did not show a statistically significant effect of emollient on allergic sensitization based on the level of IgE antibody against egg white at 0.34 kUA/L CAP-FEIA equivalents. However, the sensitization rate was significantly higher in infants who had AD/eczema than in those who did not (odds ratio, 2.86; 95% CI, 1.22-6.73). CONCLUSION: Daily application of moisturizer during the first 32 weeks of life reduces the risk of AD/eczema in infants. Allergic sensitization during this time period is associated with the presence of eczematous skin but not with moisturizer use. PMID- 25282566 TI - Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. AB - BACKGROUND: The stratum corneum and tight junctions (TJs) form physical barriers in the epidermis. Dendrites of activated Langerhans cells (LCs) extend beyond the TJs to capture external antigens in mice. LCs and inflammatory dendritic epidermal cells (IDECs) are observed in the skin of patients with atopic dermatitis (AD). OBJECTIVE: We sought to investigate the characteristics of LCs and IDECs and the distribution of their antigen capture receptors in relation to TJs in normal and AD skin. METHODS: We characterized the interactions of LCs and IDECs with TJs and the expression patterns of langerin and FcepsilonRI by using whole-mount epidermal sheets from healthy subjects and patients with AD, ichthyosis vulgaris, and psoriasis vulgaris. RESULTS: As in mouse skin, activated LCs penetrate TJs in human skin. The number of LCs with TJ penetration increased approximately 5-fold in erythematous lesional skin of patients with AD but not in nonlesional skin of patients with AD or lesions of patients with ichthyosis vulgaris or psoriasis. In contrast, IDECs localized in the lower part of the epidermis, and their dendrites extended horizontally without penetration through TJs. Although langerin accumulated on the tips of dendrites of activated LCs, FcepsilonRI was expressed diffusely on the cell surfaces on LCs and IDECs in lesional skin from patients with AD. CONCLUSIONS: These findings highlight interesting differences between LCs and IDECs in epidermis of patients with AD, where LCs, but not IDECs, extend dendrites through the TJs, likely to capture antigens from outside the TJ barrier with a polarized distribution of langerin but not FcepsilonRI. These behavioral differences between skin dendritic cells might reflect an important pathophysiology of AD. PMID- 25282567 TI - Eczematous sensitization, a novel pathway for allergic sensitization, can occur in an early stage of eczema. PMID- 25282569 TI - Proteome analysis of stratum corneum from atopic dermatitis patients by hybrid quadrupole-orbitrap mass spectrometer. PMID- 25282568 TI - Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations. AB - BACKGROUND: Filaggrin (FLG) loss-of-function mutations lead to an impaired skin barrier associated with peanut allergy. Household peanut consumption is associated with peanut allergy, and peanut allergen in household dust correlates with household peanut consumption. OBJECTIVE: We sought to determine whether environmental peanut exposure increases the odds of peanut allergy and whether FLG mutations modulate these odds. METHODS: Exposure to peanut antigen in dust within the first year of life was measured in a population-based birth cohort. Peanut sensitization and peanut allergy (defined by using oral food challenges or component-resolved diagnostics [CRD]) were assessed at 8 and 11 years. Genotyping was performed for 6 FLG mutations. RESULTS: After adjustment for infantile atopic dermatitis and preceding egg skin prick test (SPT) sensitization, we found a strong and significant interaction between natural log (ln [loge]) peanut dust levels and FLG mutations on peanut sensitization and peanut allergy. Among children with FLG mutations, for each ln unit increase in the house dust peanut protein level, there was a more than 6-fold increased odds of peanut SPT sensitization, CRD sensitization, or both in children at ages 8 years, 11 years, or both and a greater than 3-fold increased odds of peanut allergy compared with odds seen in children with wild-type FLG. There was no significant effect of exposure in children without FLG mutations. In children carrying an FLG mutation, the threshold level for peanut SPT sensitization was 0.92 MUg of peanut protein per gram (95% CI, 0.70-1.22 MUg/g), that for CRD sensitization was 1.03 MUg/g (95% CI, 0.90-1.82 MUg/g), and that for peanut allergy was 1.17 MUg/g (95% CI, 0.01-163.83 MUg/g). CONCLUSION: Early-life environmental peanut exposure is associated with an increased risk of peanut sensitization and allergy in children who carry an FLG mutation. These data support the hypothesis that peanut allergy develops through transcutaneous sensitization in children with an impaired skin barrier. PMID- 25282570 TI - Comparing safety of abrasion and tape-stripping as skin preparation in allergen specific epicutaneous immunotherapy. PMID- 25282571 TI - [Comparative analysis of patients admitted to Spanish Intensive Care Units due to medical and surgical disease]. AB - OBJECTIVE: To describe the characteristics of the patients case-mix admitted to ICUs due to medical and surgical disease, and to compare both groups. DESIGN: Analysis of data covering the period 2006-2011 in the ENVIN-HELICS registry. An observational, prospective, multicenter and voluntary participation study. SETTING: A total of 188 Spanish ICUs. PATIENTS: All patients admitted for more than 24 hours. MAIN VARIABLES: Demographic data, cause of admission, severity scores, length of stay, mortality. RESULTS: A total of 138,999 patients were analyzed. Of these, 65,467 (47.1%) were admitted due to a non-coronary medical cause, 27,785 (20,0%) due to coronary-related illness, 28,044 (20,2%) after elective surgery and 17,613 (12.7%) after urgent surgery. Use of devices, nosocomial infections and isolation of multirresistant organisms were more prevalent in urgent surgery patients. Longer length of stay (median 5 days; interquartile range 2-11) as well as higher severity scale values (APACHE II and SAPS II) corresponded to this same group of patients. Mortality was higher in non coronay medical patients. On categorizing the patients according to the APACHE II score, mortality was seen to be higher in urgent surgery cases than in elective surgery patients in all groups. The largest difference was observed in the APACHE II score 6-10 group (3% vs. 0.9%) (OR: 2.14, 95% CI 1.825-2.513; p<0.001). CONCLUSIONS: The mortality rate is higher in non-coronary medical patients, though resource use per patient is greater in the urgent surgery cases. The APACHE II scale underestimates mortality in emergency surgery patients. PMID- 25282572 TI - [Tuberculosis prevention]. AB - Tuberculosis prevention is classically based on early detection of potential contagious cases and their effective treatment. But due to new parameters such as migration flows around the world, the emergence of Mycobacterium tuberculosis resistant strains and the increase of the population at risk, screening should be more active and target those who are more vulnerable to developing the disease. Traditional screening methods such as chest X-ray and tuberculin skin test, due to their high sensitivity and low cost, remain valid especially in populations with a high prevalence of the disease. The interferon-gamma release assays (IGRAs) seem to be very useful in immunodeficient patients with prior BCG vaccination. The treatment of subjects at high risk of developing active tuberculosis with a daily isoniazid self-administrated dosage for a period of 9 months is a prevention measure not only at the individual level but also at the collective one. All prevention interventions should be part of a national program concordant with the guidelines of the WHO Stop TB program that recommend a universal access to quality diagnosis and treatment focused on the patient. OUTLOOK: New methods of detection based on gene amplification would better suit to detect tuberculosis in immunodeficient patients and identify treatment resistant strains. The development of the third part of the Stop TB project would reduce the morbidity and mortality of this disease by 2025. CONCLUSION: The prevention of tuberculosis has been a major epidemiological challenge around the world and is continuously improving to adapt to the evolving disease. PMID- 25282573 TI - Electromyographic analysis of rectus femoris activity during seated to standing position and walking in water and on dry land in healthy children and children with cerebral palsy. AB - PURPOSE: To analyze rectus femoris activity during seated to standing position and walking in water and on dry land comparing a group of children with the spastic diparesis type of cerebral palsy (CP) and a group of children without neurological disorders. METHODS: This study included a group of nine children with CP and a control group of 11 children. The study compared the electromyographic activity of the rectus femoris during seated to standing position and walking, in water and on land. RESULTS: A greater activation of the rectus femoris was observed in the group of children with CP compared with the control group when moving from a seated position to a standing position in water (p=0.0039) and while walking on land (p=0.0014) or in the pool (p=0.007). CONCLUSION: This study demonstrated the activation of the rectus femoris while walking or standing up from a seated position in water was greater in the group of children with CP. Further studies should be performed to better understand the extent of muscular activation during body immersion in individuals with neurological disorders. PMID- 25282574 TI - An isokinetic method for inducing a localised fatigue effect in the plantarflexors and dorsiflexors of the ankle. AB - To examine the effects of dysfunction of specific musculature of the shank a reliable and valid protocol can be used to induce a localised fatigue effect. A localised dynamometry based protocol was developed to illicit a fatigue effect in either plantar flexors or dorsiflexors. An isokinetic protocol allowing for movement through the full range of motion, set at an angular velocity of 45 degrees s(-1), was used to allow fatigue to be developed. Fatigue was established when three consecutive torque measures dropped below 50% of the average three peak contractions. Bouts of activity were based on a ratio of 40 contractions interspaced with a 30s rest. Results suggest that the protocol elicited a fatigue effect in the prime movers of either plantar flexion or dorsiflexion, supported through the analysis of power spectral density and amplitude shift of surface electromyography measures. The protocol demonstrated sound reliability with Interclass Correlation scores for all measures ranging from 0.441-0.962. The protocol is a valid and repeatable process for establishing muscular weakness in the working muscles of either plantar or dorsi flexion, as observed in the fatigued state. This can allow further examination of the effects of a localised muscular weakness on daily living tasks. PMID- 25282575 TI - Prolonged cycling alters stride time variability and kinematics of a post-cycle transition run in triathletes. AB - Previous studies have employed relatively short cycling protocols to investigate the effect of cycling on muscle activation and kinematics in running. The aim of this study was to investigate the effect of 3h of cycling on stride time variability (STV), stride length, tibialis anterior (TA) activation, and lower limb range of motion (ROM) in a transition run. Eight triathletes completed a run cycle-run protocol. Data were collected from a pre-cycle run and a transition run after 3h of cycling. STV, stride length and ROM were assessed using three dimensional motion analysis, and TA activation was recorded using surface electromyography. Results showed that compared with the pre-cycle run triathletes exhibited increased STV (Cohen's d=0.95) and shorter strides (d=0.15) in the transition run (p<0.05). TA activation and ROM did not change. After 10min of transition running, ankle and hip ROM significantly increased (d=0.40 and 0.41 respectively) compared to the beginning of the transition run (p<0.05) but no other changes were observed. The results suggest that locomotor control and kinematics in a transition run are affected by prolonged cycling and stride time variability is potentially a novel method of evaluating the immediate effect of prolonged cycling on the locomotor control of running. PMID- 25282576 TI - Comparison of isometric exercises for activating latissimus dorsi against the upper body weight. AB - Because there is little agreement as to which exercise is the most effective for activating the latissimus dorsi, and its intramuscular components are rarely compared, we investigated the intramuscular components of the latissimus dorsi during both trunk and shoulder exercises. Sixteen male subjects performed four isometric exercises: inverted row, body lifting, trunk extension, and trunk lateral bending. Surface electromyography (sEMG) was used to collect data from the medial and lateral components of the latissimus dorsi, lower trapezius, and the erector spinae at the 12th thoracic level during the isometric exercises. Two way repeated analysis of variance with two within-subject factors (muscles and exercise conditions) was used to determine the significance of differences between the muscles and differences between exercise variations. The inverted row showed the highest values for the medial latissimus dorsi, which were significantly higher than those of the body lifting or trunk extension exercises. For the lateral latissimus dorsi, lateral bending showed significantly higher muscle activity than the inverted row or trunk extension. During body lifting, the % maximum voluntary isometric contraction (MVIC) of the erector spinae showed the lowest value, significantly lower than those of the other isometric exercises. The inverted row exercise was effective for activating the medial latissimus dorsi versus the shoulder depression and trunk exertion exercises. The lateral bending and body lifting exercises were favorable for activating the lateral component of the latissimus dorsi. Evaluating trunk lateral bending is essential for examining the function of the latissimus dorsi. PMID- 25282577 TI - Selective internal radiotherapy of the liver: at the crossroads of interventional oncology research and national health service commissioning. PMID- 25282578 TI - A randomized trial of computerized vs. in-person brief intervention for illicit drug use in primary care: outcomes through 12 months. AB - This study examined outcomes through 12 months from a randomized trial comparing computerized brief intervention (CBI) vs. in-person brief intervention (IBI) delivered by behavioral health counselors for adult community health center patients with moderate-level drug misuse (N=360). Data were collected at baseline, 3-, 6-, and 12-month follow-up, and included the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) and laboratory analysis of hair samples. Repeated measures analyses examined differential change over time. There were no significant differences in drug-positive hair tests over time or by condition. Global ASSIST scores decreased in both conditions (p<.001), but there were no significant differences between conditions in overall change across 12 months of follow-up (p=.13). CBI produced greater overall reductions in alcohol (p=.04) and cocaine (p=.02) ASSIST scores than IBI, with initial differences dissipating over time. Computerized brief interventions present a viable alternative to traditional in-person brief interventions. PMID- 25282579 TI - Clinical outcomes and incremental costs from a medication adherence pilot intervention targeting low-income patients with diabetes at risk of cost-related medication nonadherence. AB - PURPOSE: The extent to which reducing cost-related barriers affects diabetes outcomes and medication adherence among uninsured patients is not known. The purpose of these analyses was to understand the clinical impact and cost considerations of a prescription assistance program targeting low-income, minority patients with diabetes and at high risk for cost-related medication nonadherence. METHODS: Patients received diabetes medications without copayments for 12 months. Change in diabetes control was calculated by using glycosylated hemoglobin (HbA1c) level at follow-up compared with baseline. Clinical data were collected from the electronic health record. Medication adherence for diabetes medications was estimated by using proportion of days covered (PDC). Incremental acquisition and per-patient costs, based on actual hospital medication costs, were calculated for different baseline HbA1c levels. FINDINGS: Patients with baseline HbA1c levels >=7%, >=8%, and >=9% experienced mean HbA1c reductions of 0.82% (P = 0.008), 1.02% (P = 0.010), and 1.47% (P = 0.010), respectively, during the 12-month period. The average PDC was 70.55%; 45.24% had a PDC >=80%, indicating an adequate level of medication adherence. Medication adherence >=80% was associated with ethnicity (P = 0.015), whereas mean PDC was associated with number of diabetes medication classes used (P = 0.031). Acquisition cost for 1242 prescriptions filled by 103 patients was $13,365.82, representing per-patient costs of $132.39; however, as baseline targets increased, acquisition costs decreased and per-patient costs increased from $10,682.59 and $169.56 to $6509.91 and $192.27, respectively. IMPLICATIONS: Clinically significant reductions in HbA1c levels were achieved for all patients, although greater reductions were achieved with modest per-patient cost increases when considering patients with uncontrolled diabetes. Incorporating a multifactorial intervention to address cost-related medication nonadherence with a behavior change component may yield greater reductions in HbA1c with improved diabetes outcomes and meaningful hospital-based cost savings. PMID- 25282580 TI - Cleaning the paracolic gutter: transcutaneous endoscopic necrosectomy through a fully covered metal esophageal stent. PMID- 25282581 TI - The neutrophil protein S100A12 is associated with a comprehensive ultrasonographic synovitis score in a longitudinal study of patients with rheumatoid arthritis treated with adalimumab. AB - BACKGROUND: The calcium-binding protein S100A12 correlates with measures of disease activity in patients with rheumatoid arthritis (RA). The protein reflects neutrophil activation and the present objective was to explore in a pilot study the associations between S100A12 and other inflammatory markers, clinical assessments as well as degree of synovitis detected by a comprehensive ultrasonography (US) examination in RA patients during biologic treatment. METHODS: Twenty patients with RA were examined clinically and by use of US as well as laboratory markers S100A12, calprotectin, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) before starting adalimumab, with follow-up after 1, 3, 6 and 12 months. Ultrasonographic B-mode (BM) and power Doppler (PD) assessments of 78 joints, 36 tendons/tendon groups and 2 bursas were performed, and sum US scores calculated. Wilcoxon signed rank test assessed treatment response and Spearman rank correlation test was used to calculate correlations. RESULTS: The concentrations of S100A12 decreased after 3 months (p < 0.01) and significant correlations were found between S100A12 and the other laboratory markers during follow-up (0.50-0.62, p < 0.05). Of the clinical assessments, S100A12 had highest correlations with the assessor's global VAS (0.46-0.85, p < 0.05). Compared with CRP and ESR, S100A12 showed higher correlations with the sum US scores (both BM and PD), with median (range) correlation coefficients of 0.55 (0.35-0.78 (NS-p < 0.001)) for sum BM scores and 0.45 (0.27-0.75 (NS-p < 0.001)) for sum PD scores. CONCLUSIONS: The S100A12 protein was significantly associated with other inflammatory markers, clinical assessments as well as sum US scores, indicating that S100A12 is a potential marker of inflammation in RA patients. PMID- 25282582 TI - Post-stroke hemiplegia rehabilitation: evolution of the concepts. AB - Stroke rehabilitation has undergone a revolution over the last three decades. Cohort studies have consistently reinforced the importance of post-stroke rehabilitation to stimulate recovery, but the concepts of empirical methods originally proposed by therapists to rehabilitate these patients have not withstood clinical analysis. Functional neuroimaging and animal models have unveiled the mechanisms underlying functional recovery and helped teams understand its limitations and improvement modalities. These neuroscience discoveries constitute the grounds needed to understand the emergence of new technologies: robotics and virtual reality. The objective of this review of the literature was to select key works in this field to better understand current therapeutic possibilities. PMID- 25282583 TI - Stem cells and motor recovery after stroke. AB - In stroke patients with severe persistent neurological deficits, alternative therapeutic modalities are limited. Stem cell therapy might be an opportunity when the safety profile of this approach will be achieved. This review will give possible mechanisms of restoration of function in animals and a statement of clinical trials in humans. The sources of neural stem cells for therapeutic use will be detailed. Potentials mechanisms of transplanted cell-mediated recovery are described with a particular emphasis on ipsilesional post-stroke plasticity. The optimal conditions for cell transplant therapy after stroke are evoked but not yet clearly defined. Finally, since multimodality imaging will be crucial in the post-transplantation patient assessment, the final part describes recent advances in the in vivo monitoring of repair progress. PMID- 25282584 TI - Time course of contrast enhancement by micro-CT with dedicated contrast agents in normal mice and mice with hepatocellular carcinoma: comparison of one iodinated and two nanoparticle-based agents. AB - RATIONALE AND OBJECTIVES: The aim of the present study was to characterize the kinetics of two nanoparticle-based contrast agents for preclinical imaging, Exitron nano 6000 and Exitron nano 12000, and the iodinated agent eXIA 160 in both healthy mice and in a mouse model of hepatocellular carcinoma (HCC). Semiautomatic segmentation of liver lesions for estimation of total tumor load of the liver was evaluated in HCC mice. MATERIALS AND METHODS: The normal time course of contrast enhancement was assessed in 15 healthy C57BL/6 mice. Imaging of tumor spread in the liver was evaluated in 15 mice harboring a transgenic HCC model (ASV-B mice). Automatic segmentation of liver lesions for determination of total tumor burden of the liver was tested in three additional ASV-B mice before and after an experimental therapy. RESULTS: In healthy mice, clearance of the contrast agent from blood was completed within 3-4 hours for eXIA 160 and Exitron nano 6000, whereas complete blood clearance of Exitron nano 12000 required about 24 hours. eXIA 160 provided maximum liver contrast at 1 hour post injection (p.i.) followed by a continuous decline. Enhancement of liver contrast with Exitron nano 6000 and Exitron nano 12000 reached a plateau at about 4 hours p.i., which lasted until the end of the measurements at 96 hours p.i. Maximum contrast enhancement of the liver was not statistically different between Exitron nano 6000 and Exitron nano 12000, but was about three times lower for eXIA 160 (P < .05). Visually Exitron nano 12000 provided the best liver-to-tumor contrast. Semiautomatic liver and tumor segmentation was feasible after the administration of Exitron nano 12000 but did not work properly for the other two contrast agents. CONCLUSIONS: Both nanoparticle-based contrast agents provided stronger and longer lasting contrast enhancement of healthy liver parenchyma. Exitron nano 12000 allowed automatic segmentation of tumor lesions for estimation of the total tumor load in the liver. PMID- 25282585 TI - The brassinosteroid chemical toolbox. AB - Chemical biology approaches have been instrumental in understanding the mode of action of brassinosteroids, a group of plant steroid hormones essential for plant development and growth. The small molecules used for such approaches include inhibitors of biosynthetic enzymes and signaling components. Additionally, recent structural data on the brassinosteroid receptor complex together with its ligand brassinolide, the most active brassinosteroid, and knowledge on its different analogs have given us a better view on the recognition of the hormone and signaling initiation. Moreover, a fluorescently labeled brassinosteroid enabled the visualization of the receptor-ligand pair in the cell. Given the insights obtained, small molecules will continue to provide new opportunities for probing brassinosteroid biosynthesis and for unraveling the dynamic and highly interconnected signaling. PMID- 25282587 TI - pH in the plant endomembrane system-an import and export business. AB - pH homeostasis is an essential process in all plant cells and the maintenance of correct luminal pH in the compartments of the endomembrane system is important not only for secondary active transport but also for a variety of cellular functions including protein modification, sorting, and trafficking. Due to their electrogenicity primary H(+)-pumps cannot establish and control the often large proton-gradients single-handedly but require the co-action of other ion transporters that serve as either shunt conductances or proton-leaks. Here, I will thus focus on recent results that highlight the interplay of proton-pumps and proton-coupled transporters in controlling pH in the compartments of the plant endomembrane system. PMID- 25282586 TI - The wiring diagram for plant G signaling. AB - Like electronic circuits, the modular arrangement of cell-signaling networks decides how inputs produce outputs. Animal heterotrimeric guanine nucleotide binding proteins (G-proteins) operate as switches in the circuits that signal between extracellular agonists and intracellular effectors. There still is no biochemical evidence for a receptor or its agonist in the plant G-protein pathways. Plant G-proteins deviate in many important ways from the animal paradigm. This review covers important discoveries from the last two years that enlighten these differences and ends describing alternative wiring diagrams for the plant signaling circuits regulated by G-proteins. We propose that plant G proteins are integrated in the signaling circuits as variable resistor rather than switches, controlling the flux of information in response to the cell's metabolic state. PMID- 25282588 TI - mRNA-based protein targeting to the endoplasmic reticulum and chloroplasts in plant cells. AB - The targeting of proteins to subcellular organelles is specified by the presence of signal/leader peptide sequences normally located on the N-terminus. In the past two decades, messenger RNA (mRNA) localization, a pathway driven by cis acting localization elements within the RNA sequence, has emerged as an alternative mechanism for protein targeting to specific locations in the cytoplasm, on the endoplasmic reticulum or to mitochondria and chloroplasts. In this review, we will summarize studies on mRNA-based protein targeting to the endoplasmic reticulum and chloroplast within plant cells. PMID- 25282589 TI - Endosomal trafficking and signaling in plant defense responses. AB - Plant defense responses are initiated by ligand-receptor recognition. The receptor may contain a motif for endocytosis and endocytosis is important for defense signaling in some cases. Recently, endosomal trafficking during defense has begun to be elucidated. In some cases, defense receptors are internalized into early endosomes, recycled back to the plasma membrane (PM) on recycling endosomes, and targeted for degradation via the late endosome pathway in an ESCRT dependent manner. Endosomal signaling has been proposed for several receptors. Defense receptors have been shown to reside on endosomes during the signaling time window. Increasing the endosomal presence of a receptor can cause a concomitant increase in signaling, while abolishing the formation of endosomes after the receptor has already been internalized can cause signaling attenuation. PMID- 25282591 TI - Effects of maxillomandibular advancement on systemic blood pressure in patients with obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is associated with resistant hypertension. We investigated to what extent maxillomandibular advancement affected a patient's blood pressure postoperatively. We retrospectively analysed consecutive patients who had Bimaxillary advancement for OSA at our hospital following referral from the local sleep clinic. We collected relevant data on clinical characteristics and explored the changes in systolic and diastolic blood pressures, as well as mean arterial pressure (MAP) preoperatively, with those taken 6 months following surgery. We identified 51 patients with a mean (SD) age of 44 (8) years and a mean (SD) body mass index of 29 (3.4). Preoperative and postoperative data on blood pressure were available for analysis in 45. The mean (SD) systolic blood pressure was significantly reduced in our sample following surgery (from 131(12.6) to 127 (12.5)mmHg, p<0.001). The mean (SD) reduction in postoperative MAP values in the overall group, approached statistical significance (recorded MAP 96.6(10) to 93.1(8)mmHg, p=0.06). In a subgroup of 10 patients who had established hypertension the reduction in values postoperatively (mean reduction: systolic blood pressure 6 mmHg, diastolic blood pressure 10 mmHg, mean arterial pressure 9 mmHg) was greater than that observed in the overall group. Our results have shown an improvement in systemic blood pressure after maxillomandibular advancement for OSA, particularly in those with established hypertension. The data suggest that in addition to being a highly effective treatment for OSA, this surgery may more effectively lower systemic blood pressure than other treatment modalities. PMID- 25282590 TI - Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer. AB - BACKGROUND: We investigated the role of the HIPK2-p53 signaling pathway in tumorigenesis and resistance to the drug Verbascoside (VB) in colorectal cancer (CRC), using in vivo and in vitro experiments. METHODS: Primary human CRC samples and normal intestinal tissues from patients were analyzed for HIPK2 expression by immunohistochemistry (IHC) and its expression was correlated against patients' clinicopathological characteristics. Human CRC HCT-116 cells were implanted in BALB/c nude mice; mice with xenografted tumors were randomly administrated vehicle (control), 20, 40, or 80 mg/mL VB, or 1 mg/mL fluorouracil (5-FU). HIPK2, p53, Bax, and Bcl-2 expression in these tumors were determined by IHC. In vitro effects of VB on CRC cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry; HIPK2, p53, p-p53, Bax, and Bcl-2 were measured by western blot. RESULTS: IHC analysis for 100 human CRC tumor samples and 20 normal intestinal tissues, showed HIPK2 expression to inversely correlate with Dukes stage and depth of invasion in CRC (P<0.05). In vivo, the inhibition rates of 20, 40, and 80 mg/mL VB on CRC xenograft tumor weight were 42.79%, 53.90%, and 60.99%, respectively, and were accompanied by increased expression of HIPK2, p53, and Bax, and decreased Bcl-2 expression in treated tumors. In vitro, VB significantly inhibited proliferation of CRC cell lines HCT-116, HT-29, LoVo, and SW620, in a time- and dose-dependent manner. The apoptosis rates of 25, 50, and 100 MUM VB on HCT-116 cells were 10.83+/-1.28, 11.25+/-1.54, and 20.19+/-2.87%, and on HT-29 cells were 18.92+/-6.12, 21.57+/-4.05, and 25.14+/-6.73%, respectively. In summary, VB treatment significantly enhanced the protein expression of pro-apoptotic HIPK2, p53, p-p53, Bax, and decreased anti-apoptotic Bcl-2 expression in CRC cells. CONCLUSIONS: HIPK2 protein modulates the phosphorylation status of p53, and levels of Bax and Bcl-2 in CRC. We also found that VB effectively activated the HIPK2-p53 signaling pathway, resulting in increased CRC cell apoptosis. PMID- 25282592 TI - Simple novel technique to accurately control the depth of drill holes during transbuccal osteosynthesis of mandibular fractures. PMID- 25282593 TI - Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed. AB - Recent data suggest that the traditional definition of bisphosphonate-associated osteonecrosis of the jaw (ONJ) may exclude patients who present with the non exposed variant of the condition. To test the hypothesis that a proportion of patients with ONJ remain undiagnosed because their symptoms do not conform to the traditional case definition, we did a secondary analysis of data from MISSION (Multicentre study on phenotype, definition and classification of osteonecrosis of the jaws associated with bisphosphonates), a cross-sectional study of a large population of patients with bisphosphonate-associated ONJ who were recruited in 13 European centres. Patients with exposed and non-exposed ONJ were included. The main aim was to quantify the proportion of those who, according to the traditional case definition, would not be diagnosed with ONJ because they had no exposed necrotic bone. Data analysis included descriptive statistics, median regression, and Fisher's exact test. A total of 886 consecutive patients were recruited and 799 were studied after data cleaning (removal or correction of inaccurate data). Of these, 607 (76%) were diagnosed according to the traditional definition. Diagnosis in the remaining 192 (24%) could not be adjudicated, as they had several abnormal features relating to the jaws but no visible necrotic bone. The groups were similar for most of the phenotypic variables tested. To our knowledge this is the first study in a large population that shows that use of the traditional definition may result in one quarter of patients remaining undiagnosed. Those not considered to have ONJ had the non-exposed variant. These findings show the importance of adding this description to the traditional case definition. PMID- 25282594 TI - Novel technique to narrow the wide midface in Asians. AB - PURPOSE: To develop a novel technique for narrowing the wide midface in Asians using virtual surgical planning (VSP) and 2-bent plate fixation. MATERIALS AND METHODS: A total of 19 patients with a wide midface underwent midface narrowing by VSP and 2-bent plate fixation from 2009 to 2013. In each case, a 3-dimensional spiral computed tomography (CT) scan of the skull was obtained before surgery. The CT data were imported into the SurgiCase software, and VSP was performed. VSP was used to direct the amount of adduction and advancement during the midface narrowing surgery. During the actual surgery, we combined zygomatic arch osteotomy and I-shaped osteotomy of the zygomatic body and moved the zygomatic complex upward and inward in accordance with the preoperative data. We then reset the free zygomatic complex to a target position and fixed it with 2 bent plates. The correction effectiveness was then evaluated using 3-dimensional CT and pre- and postoperative standard facial photographs. RESULTS: Most patients were satisfied with the results and experienced no severe complications. No cases of nonunion or permanent facial nerve injury were reported. CONCLUSIONS: VSP can provide precise data to guide modified reduction of a zygomatic arch protrusion. The bent-plate fixation method can provide sufficient support and ideal midfacial contours. Our technique is recommended for narrowing the wide midface caused by a lateral prominent zygomatic arch. PMID- 25282595 TI - Response to 'Re: Fakhry et al., Fine needle aspiration cytology and frozen section in the diagnosis of malignant parotid tumours'. PMID- 25282596 TI - Low-level laser therapy improves peri-implant bone formation: resonance frequency, electron microscopy, and stereology findings in a rabbit model. AB - Previous studies have reported positive effects of low-level laser therapy (LLLT) on bone healing. This study evaluated the effects of LLLT on peri-implant healing in vivo. Thirty-two rabbits had their mandibular left incisors removed, followed by immediate insertion of a dental implant into the fresh socket. Animals were assigned randomly to four groups: control (non-irradiated) or LLLT at three different doses per session: 5J/cm(2), 10J/cm(2), and 20J/cm(2). A GaAlAs laser (830nm, 50mW) was applied every 48h for 13 days, starting immediately after surgery. The implant stability quotient (ISQ) was measured using resonance frequency analysis upon implant insertion and immediately after death, 30 days after the last application. Tissues were prepared for scanning electron microscopy (SEM) and stereology. Variables measured were bone-implant contact (BIC) and bone neoformation within implant threads at three different sites. The results showed better ISQ for the 20J/cm(2) group (P=0.003). BIC values were significantly higher (P<0.05) in the 20J/cm(2) group, on both SEM and stereology. Bone area values were better in the 10J/cm(2) (P=0.036) and 20J/cm(2) (P=0.016) groups compared to the control group. Under these conditions, LLLT enhanced peri implant bone repair, improving stability, BIC, and bone neoformation. The findings support and suggest parameters for the design of clinical trials using LLLT after implant placement. PMID- 25282597 TI - Differences in functional connectivity between alcohol dependence and internet gaming disorder. AB - INTRODUCTION: Internet gaming disorder (IGD) and alcohol dependence (AD) have been reported to share clinical characteristics including craving and over engagement despite negative consequences. However, there are also clinical factors that differ between individuals with IGD and those with AD in terms of chemical intoxication, prevalence age, and visual and auditory stimulation. METHODS: We assessed brain functional connectivity within the prefrontal, striatum, and temporal lobe in 15 patients with IGD and in 16 patients with AD. Symptoms of depression, anxiety, and the attention deficit hyperactivity disorder were assessed in patients with IGD and in patients with AD. RESULTS: Both AD and IGD subjects have positive functional connectivity between the dorsolateral prefrontal cortex (DLPFC), cingulate, and cerebellum. In addition, both groups have negative functional connectivity between the DLPFC and the orbitofrontal cortex. However, the AD subjects have positive functional connectivity between the DLPFC, temporal lobe and striatal areas while IGD subjects have negative functional connectivity between the DLPFC, temporal lobe and striatal areas. CONCLUSIONS: AD and IGD subjects may share deficits in executive function, including problems with self-control and adaptive responding. However, the negative connectivity between the DLPFC and the striatal areas in IGD subjects, different from the connectivity observed in AD subjects, may be due to the earlier prevalence age, different comorbid diseases as well as visual and auditory stimulation. PMID- 25282599 TI - Simultaneous determination of five naphthoylindole-based synthetic cannabinoids and metabolites and their deposition in human and rat hair. AB - The continuing appearance of new synthetic cannabinoids has been a major issue in the field of forensic and clinical toxicology. In response to that, analytical methods for synthetic cannabinoids have been increasingly established in a variety of biological matrices. Since most of synthetic cannabinoids with structure similarity share some enzymatic metabolites, making the interpretation of analytical results and the discovery of the parent drug actually ingested very complicated, the investigation on metabolites of the first generation of synthetic cannabinoids with their relatively short side chains in chemical structure could be more important. Therefore, in the present study, we developed the analytical method for AM-2201, JWH-122 and MAM-2201 with JWH-018 as a precursor and their monohydroxylated metabolites in hair matrix. Also, using a rat model, AM-2201 and its monohydroxylated metabolites were identified and then the ratios of metabolite-to-parent drug were estimated to be used as criteria on external contamination. All analytes were extracted with methanol from washed and cut hair samples and the extracts were injected into LC-MS/MS with electrospray ion source in the positive ionization mode. Matrix effect and recovery were evaluated in hair matrices and no significant variations were observed. The validation results for precision and accuracy were satisfactory in both human and rat hair. The LOD and LOQ were 0.5 pg/10mg and 1.0 pg/10mg in human hair and 0.5 pg/20mg and 1.0 pg/20mg in pigmented and non-pigmented rat hair, respectively. Additionally, as a result of the animal study, there were not significant differences in the effect of pigmentation on the distribution of AM-2201 and its monohydroxylated metabolites in hair. Wide variations were observed for the concentrations of the naphthoylindole-based synthetic cannabinoids and metabolites in authentic hair samples from nine cases; those were 0.4-59.2 pg/mg for JWH-018, 0.1-0.8 pg/mg for JWH-073, 1.7-739.0 pg/mg for AM-2201, 0.1-402.0 pg/mg for JWH-122, 0.2-276.0 pg/mg for MAM-2201, 0.2-1.1 pg/mg for JWH-018 N COOH, 0.3-37.2 pg/mg for JWH-018 N-5-OH, 0.3 pg/mg for JWH-073 N-COOH, 0.4 pg/mg for AM-2201 N-4-OH, 0.2-3.1 pg/mg for AM-2201 N-6-OHindole and 0.1-3.5 pg/mg for JWH-122 N-5-OH. This quantitative LC-MS/MS analytical method for five naphthoylindole-based synthetic cannabinoids and their metabolites was very useful to be applied to authentic hair samples, of which their analytical results suggested the incorporation of synthetic cannabinoids in the hair matrix and provided the information on ingested parent drugs. PMID- 25282600 TI - The development and validation of a rapid method for the determination of antimicrobial agent residues in milk and meat using ultra performance liquid chromatography coupled to quadrupole--Orbitrap mass spectrometry. AB - A new multi-class method has been developed for the identification and quantification of the residues of 26 antibiotics from different classes (sulfonamides, macrolides, tetracyclines, penicillins, and quinolones) in milk and meat by ultra performance liquid chromatography coupled to hybrid quadrupole high resolution Orbitrap mass spectrometry (UPLC-qOrbitrap). The sample preparation included extraction of two analytical portions with acetonitrile and 5% trichloroacetic acid, respectively, followed by centrifugation and filtration. The method was validated over three days at 50% of MRL (maximum residue limit) set in the European Union. Experiments on spiked meat and milk samples showed that the average recovery of the antibiotics ranged from 83% to 112%, and the coefficients of variation were between 8.9% and 39%. PMID- 25282598 TI - Opioid withdrawal, craving, and use during and after outpatient buprenorphine stabilization and taper: a discrete survival and growth mixture model. AB - INTRODUCTION: Most patients relapse to opioids within one month of opioid agonist detoxification, making the antecedents and parallel processes of first use critical for investigation. Craving and withdrawal are often studied in relationship to opioid outcomes, and a novel analytic strategy applied to these two phenomena may indicate targeted intervention strategies. METHODS: Specifically, this secondary data analysis of the Prescription Opioid Addiction Treatment Study used a discrete-time mixture analysis with time-to-first opioid use (survival) simultaneously predicted by craving and withdrawal growth trajectories. This analysis characterized heterogeneity among prescription opioid dependent individuals (N=653) into latent classes (i.e., latent class analysis [LCA]) during and after buprenorphine/naloxone stabilization and taper. RESULTS: A 4-latent class solution was selected for overall model fit and clinical parsimony. In order of shortest to longest time-to-first use, the 4 classes were characterized as 1) high craving and withdrawal, 2) intermediate craving and withdrawal, 3) high initial craving with low craving and withdrawal trajectories and 4) a low initial craving with low craving and withdrawal trajectories. Odds ratio calculations showed statistically significant differences in time-to-first use across classes. CONCLUSIONS: Generally, participants with lower baseline levels and greater decreases in craving and withdrawal during stabilization combined with slower craving and withdrawal rebound during buprenorphine taper remained opioid-free longer. This exploratory work expanded on the importance of monitoring craving and withdrawal during buprenorphine induction, stabilization, and taper. Future research may allow individually tailored and timely interventions to be developed to extend time-to-first opioid use. PMID- 25282601 TI - Comparative study of lanostane-type triterpene acids in different parts of Poria cocos (Schw.) Wolf by UHPLC-Fourier transform MS and UHPLC-triple quadruple MS. AB - Poria cocos (Schw.) Wolf is widely used as a traditional Chinese medicine, and approximately 10% of traditional Chinese medicinal preparations contain this material, according to the Chinese Pharmacopoeia (2010 edition). Although the epidermis (fulingpi in Chinese, or FLP) and the inner parts (baifuling in Chinese, or BFL) of P. cocos had different therapeutic applications in history, studies pertaining to a comparative analysis of their chemical constituents have been scarce. UHPLC-DAD-FT/MS(n) has been used in the current study to identify the triterpene acids present in fungus based on a detailed analysis of the fragmentation behavior of 13 standard compounds. This analysis allowed for the identification of 27 triterpene acids, including five groups of isomers and four potential new compounds. Furthermore, a UHPLC-MS/MS method has been developed for quantifying the amounts of nine bioactive triterpene acids in samples of the FLP and BFL, including three 3,4-seco-lanostane-type triterpene acids. These results revealed significant differences in the amounts of these compounds in the FLP and BFL samples. Principal component analysis and partial least squares discriminant analysis of the results for the FLP and BFL samples clearly demonstrated that dehydrotumulosic acid, trametenolic acid, dehydrotrametenolic acid and poricoic acid A were the main compounds contributing to the clusters in FLP and BFL. The observed differences in the chemical compositions of FLP and BFL could provide some explanation of the differences in their clinic applications. This study represents the first reported comprehensive analysis of lanostane-type triterpene acids in FLP and BFL parts of P. cocos. PMID- 25282603 TI - A SNaPshot of next generation sequencing for forensic SNP analysis. AB - Forensic phenotyping can provide useful intelligence regarding the biogeographical ancestry (BGA) and externally visible characteristics (EVCs) of the donor of an evidentiary sample. Currently, single nucleotide polymorphism (SNP) based inference of BGA and EVCs is performed most commonly using SNaPshot((r)), a single base extension (SBE) assay. However, a single SNaPshot multiplex PCR is limited to 30-40 SNPs. Next generation sequencing (NGS) offers the potential to genotype hundreds to thousands of SNPs from multiple samples in a single experimental run. The PCR multiplexes from five SNaPshot assays (SNPforID 52plex, SNPforID 34plex, Eurasiaplex, IrisPlex and an unpublished BGA assay) were applied to three different DNA template amounts (0.1, 0.2 and 0.3 ng) in three samples (9947A and 007 control DNAs and a male donor). The pooled PCR amplicons containing 136 unique SNPs were sequenced using Life Technologies' Ion TorrentTM PGM system. Approximately 72 Mb of sequence was generated from two 10 Mb Ion 314TM v1 chips. Accurate genotypes were readily obtained from all three template amounts. Of a total of 408 genotypes, 395 (97%) were fully concordant with SNaPshot across all three template amounts. Of those genotypes discordant with SNaPshot, six Ion Torrent sequences (1.5%) were fully concordant with Sanger sequencing across the three template amounts. Seven SNPs (1.7%) were either discordant between template amounts or discordant with Sanger sequencing. Sequence coverage observed in the negative control, and, allele coverage variation for heterozygous genotypes highlights the need to establish a threshold for background levels of sequence output and heterozygous balance. This preliminary study of the Ion Torrent PGM system has demonstrated considerable potential for use in forensic DNA analyses as a low to medium throughput NGS platform using established SNaPshot assays. PMID- 25282602 TI - Development of the default mode and central executive networks across early adolescence: a longitudinal study. AB - The mature brain is organized into distinct neural networks defined by regions demonstrating correlated activity during task performance as well as rest. While research has begun to examine differences in these networks between children and adults, little is known about developmental changes during early adolescence. Using functional magnetic resonance imaging (fMRI), we examined the Default Mode Network (DMN) and the Central Executive Network (CEN) at ages 10 and 13 in a longitudinal sample of 45 participants. In the DMN, participants showed increasing integration (i.e., stronger within-network correlations) between the posterior cingulate cortex (PCC) and the medial prefrontal cortex. During this time frame participants also showed increased segregation (i.e., weaker between network correlations) between the PCC and the CEN. Similarly, from age 10 to 13, participants showed increased connectivity between the dorsolateral prefrontal cortex and other CEN nodes, as well as increasing DMN segregation. IQ was significantly positively related to CEN integration at age 10, and between network segregation at both ages. These findings highlight early adolescence as a period of significant maturation for the brain's functional architecture and demonstrate the utility of longitudinal designs to investigate neural network development. PMID- 25282604 TI - Enhanced low-template DNA analysis conditions and investigation of allele dropout patterns. AB - Forensic DNA analysis applying PCR enables profiling of minute biological samples. Enhanced analysis conditions can be applied to further push the limit of detection, coming with the risk of visualising artefacts and allele imbalances. We have evaluated the consecutive increase of PCR cycles from 30 to 35 to investigate the limitations of low-template (LT) DNA analysis, applying the short tandem repeat (STR) analysis kit PowerPlex ESX 16. Mock crime scene DNA extracts of four different quantities (from around 8-84 pg) were tested. All PCR products were analysed using 5, 10 and 20 capillary electrophoresis (CE) injection seconds. Bayesian models describing allele dropout patterns, allele peak heights and heterozygote balance were developed to assess the overall improvements in EPG quality with altered PCR/CE settings. The models were also used to evaluate the impact of amplicon length, STR marker and fluorescent label on the risk for allele dropout. The allele dropout probability decreased for each PCR cycle increment from 30 to 33 PCR cycles. Irrespective of DNA amount, the dropout probability was not affected by further increasing the number of PCR cycles. For the 42 and 84 pg samples, mainly complete DNA profiles were generated applying 32 PCR cycles. For the 8 and 17 pg samples, the allele dropouts decreased from 100% using 30 cycles to about 75% and 20%, respectively. The results for 33, 34 and 35 PCR cycles indicated that heterozygote balance and stutter ratio were mainly affected by DNA amount, and not directly by PCR cycle number and CE injection settings. We found 32 and 33 PCR cycles with 10 CE injection seconds to be optimal, as 34 and 35 PCR cycles did not improve allele detection and also included CE saturation problems. We find allele dropout probability differences between several STR markers. Markers labelled with the fluorescent dyes CXR-ET (red in electropherogram) and TMR-ET (shown as black) generally have higher dropout risks compared with those labelled with JOE (green) and fluorescein (blue). Overall, the marker D10S1248 has the lowest allele dropout probability and D8S1179 the highest. The marker effect is mainly pronounced for 30-32 PCR cycles. Such effects would not be expected if the amplification efficiencies were identical for all markers. Understanding allele dropout risks and the variability in peak heights and balances is important for correct interpretation of forensic DNA profiles. PMID- 25282605 TI - Screening for dysglycaemia during pregnancy: Proposals conciliating International Association of Diabetes and Pregnancy Study Group (IADPSG) and US National Institutes of Health (NIH) panels. AB - The International Association of Diabetes and Pregnancy Study Group (IADPSG) has proposed that blood glucose levels for the diagnosis of gestational diabetes mellitus (GDM) be the values associated with a 1.75-fold increase in the risk of neonatal complications in the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study. However, this recommendation was not adopted by the US National Institutes of Health (NIH) panel as it would have been responsible for a huge increase in the prevalence of GDM with no clear evidence of a reduction of events at such blood glucose values. Considering this aspect, we now propose the use of a blood glucose threshold combination associated with an odds-ratio of 2.0 for neonatal disorders [fasting plasma glucose (FPG)>= 95 mg/dL, or a 1-h glucose value after a 75-g oral glucose tolerance test (OGTT)>= 191 mg/dL or a 2-h glucose value >= 162 mg/dL] for GDM diagnosis. This would lead to a lower prevalence of GDM and concentrate medical resources on those with the highest risk of complications. This would also allow the use of a similar FPG value for both the diagnosis and therapeutic target of GDM. The IADPSG also proposed screening for dysglycaemia during early pregnancy, using FPG measurement with a similar threshold after 24 weeks of gestation. We propose the same strategy considering an FPG value >= 95 mg/dL as abnormal, but only after confirmatory measurements. We also believe that an OGTT should not be used before 24 weeks of gestation as normal values during that time are as yet unknown. PMID- 25282606 TI - Causes and consequences of anti-infective drug stock-outs. AB - Anti-infective drugs stock-outs are increasingly frequent, and this is unlikely to change. There are numerous causes for this, mostly related to parameters difficult to control: i) 60 to 80% of raw material or components are produced outside of Europe (compared to 20% 30 years ago), with subsequent loss of independence for their procurement; ii) the economic crisis drives the pharmaceutical companies to stop producing drugs of limited profitability (even among important drugs); iii) the enforcement of regulatory requirements and quality control procedures result in an increasing number of drugs being blocked during production. The therapeutic class most affected by drug stock-outs is that of anti-infective drugs, especially injectable ones, and many therapeutic dead ends have recently occurred. We provide an update on this issue, and suggest 2 major actions for improvement: i) to implement a group dedicated to anticipating drug stock-outs within the anti-infective committee in each health care center, with the objectives of organizing and coordinating the response whenever a drug stock-out is deemed at risk (i.e., contingency plans, substitution, communication to prescribers); ii) a national reflection lead by scientific societies, in collaboration with government agencies, upstream of the most problematic drug stock-outs, to elaborate and disseminate consensus guidelines for the management of these stock-outs. PMID- 25282607 TI - [Fluticasone-ritonavir: a drug-drug interaction causing iatrogenic Cushing's syndrome and adrenal insufficiency]. PMID- 25282608 TI - Head Position Change Is Not Associated with Acute Changes in Bilateral Cerebral Oxygenation in Stable Preterm Infants during the First 3 Days of Life. AB - OBJECTIVE: Several recent intraventricular hemorrhage prevention bundles include midline head positioning to prevent potential disturbances in cerebral hemodynamics. We aimed to study the impact of head position change on regional cerebral saturations (SctO2) in preterm infants (< 30 weeks gestational age) during the first 3 days of life. STUDY DESIGN: Bilateral SctO2 was measured by near-infrared spectroscopy. The infant's head was turned sequentially to each side from midline (baseline) in 30-minute intervals while keeping the body supine. Bilateral SctO2 before and after each position change were compared using paired t-test. RESULTS: In relatively stable preterm infants (gestational age 26.5 +/- 1.7 weeks, birth weight 930 +/- 220 g; n = 20), bilateral SctO2 remained within normal range (71.1-75.3%) when the head was turned from midline position to either side. CONCLUSION: Stable preterm infants tolerated brief changes in head position from midline without significant alternation in bilateral SctO2; the impact on critically ill infants needs further evaluation. PMID- 25282609 TI - Monoculture parameters successfully predict coculture growth kinetics of Bacteroides thetaiotaomicron and two Bifidobacterium strains. AB - Microorganisms rarely live in isolation but are most often found in a consortium. This provides the potential for cross-feeding and nutrient competition among the microbial species, which make it challenging to predict the growth kinetics in coculture. In this paper we developed a mathematical model to describe substrate consumption and subsequent microbial growth and metabolite production for bacteria grown in monoculture. The model characterized substrate utilization kinetics of 18 Bifidobacterium strains. Some bifidobacterial strains demonstrated preferential degradation of oligofructose in that sugars with low degree of polymerization (DP) (DP<=3 or 4) were metabolized before sugars of higher DP, or vice versa. Thus, we expanded the model to describe the preferential degradation of oligofructose. In addition, we adapted the model to describe the competition between human colonic bacteria Bacteroides thetaiotaomicron LMG 11262 and Bifidobacterium longum LMG 11047 or Bifidobacterium breve Yakult for inulin as well as cross-feeding of breakdown products from the extracellular hydrolysis of inulin by B. thetaiotaomicron LMG 11262. We found that the coculture growth kinetics could be predicted based on the respective monoculture growth kinetics. Using growth kinetics from monoculture experiments to predict coculture dynamics will reduce the number of in vitro experiments required to parameterize multi culture models. PMID- 25282611 TI - Time-resolved crystallography using the Hadamard transform. AB - We describe a method for performing time-resolved X-ray crystallographic experiments based on the Hadamard transform, in which time resolution is defined by the underlying periodicity of the probe pulse sequence, and signal/noise is greatly improved over that for the fastest pump-probe experiments depending on a single pulse. This approach should be applicable on standard synchrotron beamlines and will enable high-resolution measurements of protein and small molecule structural dynamics. It is also applicable to other time-resolved measurements where a probe can be encoded, such as pump-probe spectroscopy. PMID- 25282610 TI - A general design strategy for protein-responsive riboswitches in mammalian cells. AB - RNAs are ideal for the design of gene switches that can monitor and program cellular behavior because of their high modularity and predictable structure function relationship. We have assembled an expression platform with an embedded modular ribozyme scaffold that correlates self-cleavage activity of designer ribozymes with transgene translation in bacteria and mammalian cells. A design approach devised to screen ribozyme libraries in bacteria and validate variants with functional tertiary stem-loop structures in mammalian cells resulted in a designer ribozyme with a protein-binding nutR-boxB stem II and a selected matching stem I. In a mammalian expression context, this designer ribozyme exhibited dose-dependent translation control by the N-peptide, had rapid induction kinetics and could be combined with classic small molecule-responsive transcription control modalities to construct complex, programmable genetic circuits. PMID- 25282612 TI - Macular and optic disc edema and retinal vascular leakage in familial amyloid polyneuropathy with a transthyretin Val30Met mutation: a case report. AB - INTRODUCTION: Familial amyloid polyneuropathy is a group of autosomal dominant disorders characterized by extracellular amyloid deposition in several target organs. This paper aims to report an unusual manifestation of retinal vascular leakage including optic disc and macular edema in a patient with familial amyloid polyneuropathy. CASE PRESENTATION: A 37-year-old Portuguese Caucasian man with Val30Met transthyretin-related familial amyloid polyneuropathy presented with rapidly progressing visual loss in his left eye. He had undergone liver transplantation at the age of 30 with neurologic stabilization. Fundoscopy and fluorescein angiogram revealed optic disc and macular edema as well as vessel wall staining with leakage in the posterior pole and mid-periphery, without vitreous opacities. A diagnostic work-up for infectious, autoimmune and neoplasic conditions was negative. Systemic immunosuppression was increased but without improvement. Sustained resolution of macular edema was observed after intravitreal injection of dexamethasone implant and laser panretinal photocoagulation. CONCLUSIONS: To the best of our knowledge, this is the first report of a rare ocular manifestation of familial amyloid polyneuropathy which represents a new therapeutic challenge. Intravitreal injection of sustained release dexamethasone implant and panretinal photocoagulation may be an effective eye-saving therapeutic approach. PMID- 25282613 TI - Evolution of multipartite mitochondrial genomes in the booklice of the genus Liposcelis (Psocoptera). AB - BACKGROUND: The genus Liposcelis (Psocoptera: Troctomorpha) has more than 120 species with a worldwide distribution and they pose a risk for global food security. The organization of mitochondrial (mt) genomes varies between the two species of booklice investigated in the genus Liposcelis. Liposcelis decolor has its mt genes on a single chromosome, like most other insects; L. bostrychophila, however, has a multipartite mt genome with genes on two chromosomes. RESULTS: To understand how multipartite mt genome organization evolved in the genus Liposcelis, we sequenced the mt genomes of L. entomophila and L. paeta in this study. We found that these two species of booklice also have multipartite mt genomes, like L. bostrychophila, with the mt genes we identified on two chromosomes. Numerous pseudo mt genes and non-coding regions were found in the mt genomes of these two booklice, and account for 30% and 10% respectively of the entire length we sequenced. In L. bostrychophila, the mt genes are distributed approximately equally between the two chromosomes. In L. entomophila and L. paeta, however, one mt chromosome has most of the genes we identified whereas the other chromosome has largely pseudogenes and non-coding regions. L. entomophila and L. paeta differ substantially from each other and from L. bostrychophila in gene content and gene arrangement in their mt chromosomes. CONCLUSIONS: Our results indicate unusually fast evolution in mt genome organization in the booklice of the genus Liposcelis, and reveal different patterns of mt genome fragmentation among L. bostrychophila, L. entomophila and L. paeta. PMID- 25282614 TI - Representation of aversive prediction errors in the human periaqueductal gray. AB - Pain is a primary driver of learning and motivated action. It is also a target of learning, as nociceptive brain responses are shaped by learning processes. We combined an instrumental pain avoidance task with an axiomatic approach to assessing fMRI signals related to prediction errors (PEs), which drive reinforcement-based learning. We found that pain PEs were encoded in the periaqueductal gray (PAG), a structure important for pain control and learning in animal models. Axiomatic tests combined with dynamic causal modeling suggested that ventromedial prefrontal cortex, supported by putamen, provides an expected value-related input to the PAG, which then conveys PE signals to prefrontal regions important for behavioral regulation, including orbitofrontal, anterior mid-cingulate and dorsomedial prefrontal cortices. Thus, pain-related learning involves distinct neural circuitry, with implications for behavior and pain dynamics. PMID- 25282615 TI - Cortical neurogenesis in the absence of centrioles. AB - Neuronal production in the mammalian cortex depends on extensive mitoses of radial glial progenitors (RGPs) residing in the ventricular zone (VZ). We examined the function of centrioles in RGPs during cortical neurogenesis in mice by conditional removal of SAS-4, a protein that is required for centriole biogenesis. SAS-4 deletion led to a progressive loss of centrioles, accompanied by RGP detachment from the VZ. Delocalized RGPs did not become outer subventricular zone RGPs (oRGs). Although they remained proliferative, ectopic RGPs, as well as those in the VZ, with a centrosomal deficit exhibited prolonged mitosis, p53 upregulation and apoptosis, resulting in neuronal loss and microcephaly. Simultaneous removal of p53 fully rescued RGP death and microcephaly, but not RGP delocalization and randomized mitotic spindle orientation. Our findings define the functions of centrioles in anchoring RGPs in the VZ and ensuring their efficient mitoses, and reveal the robust adaptability of RGPs in the developing cortex. PMID- 25282617 TI - Osteochondromas of the spine. AB - Osteochondromas are common developmental benign bone lesions, which rarely involve the spine. In a narrow space, such as the spinal canal, they may potentially lead to serious complications. Moreover, because this condition is fairly rare in the spine, it may be confused with other entities. The objective of this review is to describe the typical imaging findings of this rare, but occasionally significant condition of the spine. PMID- 25282618 TI - Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol. AB - (13)C, (15)N and (2)H solid-state NMR spectroscopy have been used to rationalize arrangement and dynamics of solvent molecules in a set of isostructural solvates of droperidol. The solvent molecules are determined to be dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. (2)H NMR spectra of deuterium-labelled samples allowed the characterization of the solvent molecule dynamics in the alcohol solvates and the non-stoichiometric hydrate. The likely motion of the alcohol molecules is rapid libration within a site, plus occasional exchange into an equivalent site related by the inversion symmetry, while the water molecules are more strongly disordered. DFT calculations strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent molecule. PMID- 25282619 TI - [Malignant teratoid medulloepithelioma of the ciliary body presenting with spontaneous hyphema]. PMID- 25282616 TI - Anchoring the neural compass: coding of local spatial reference frames in human medial parietal lobe. AB - The neural systems that code for location and facing direction during spatial navigation have been investigated extensively; however, the mechanisms by which these quantities are referenced to external features of the world are not well understood. To address this issue, we examined behavioral priming and functional magnetic resonance imaging activity patterns while human subjects recalled spatial views from a recently learned virtual environment. Behavioral results indicated that imagined location and facing direction were represented during this task, and multivoxel pattern analyses indicated that the retrosplenial complex (RSC) was the anatomical locus of these spatial codes. Critically, in both cases, location and direction were defined on the basis of fixed elements of the local environment and generalized across geometrically similar local environments. These results suggest that RSC anchors internal spatial representations to local topographical features, thus allowing us to stay oriented while we navigate and retrieve from memory the experience of being in a particular place. PMID- 25282621 TI - Establishing a gingival fibroblast phenotype in a perfused degradable polyurethane scaffold: mediation by TGF-beta1, FGF-2, beta1-integrin, and focal adhesion kinase. AB - Medium perfusion has been shown to enhance cell proliferation and matrix protein production. In more recent work, under perfusion, a degradable/polar/hydrophobic/ionic polyurethane (D-PHI) scaffold was shown to enhance growth and production of collagen by human gingival fibroblasts (HGFs). However, the nature of the HGFs cultured in the perfused D-PHI scaffolds, and the mechanisms by which medium perfusion activates these cells to facilitate proliferation and collagen production are not defined. The current study sought to investigate HGF interaction within the D-PHI scaffolds under perfusion by examining the production and the spatial distribution of alpha-smooth muscle actin (alpha-SMA) and type I collagen (Col I), the secretion of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (FGF-2) in the conditioned medium, with a goal of defining the mechanistic pathways affecting the production of these markers in the dynamic culture. It was found that the perfused D-PHI scaffold shifted the HGF phenotype from myofibroblast-like (upregulation of alpha-SMA) to fibroblast-like (downregulation of alpha-SMA) over the course of 28 days. Both TGF-beta1 and FGF-2 were significantly greater in the dynamic vs. static culture at day 1. Although TGF-beta1 has been often reported to increase alpha-SMA and collagen expression, the D-PHI material and significant high level of FGF-2 at day 1 of dynamic culture appear to play a role in regulating alpha-SMA production while allowing HGFs to increase Col I production. beta1-integrin production was increased and focal adhesion kinase (FAK) were activated 2 h after HGFs were exposed to medium perfusion, which may have in part promoted cell growth, alpha-SMA and Col I production in the early dynamic culture. Consequently, the D-PHI material and medium perfusion has modulated fibroblast phenotype, and enhanced cell growth and Col I production through the coordinated actions of TGF-beta1, FGF-2, beta1-integrin and FAK. PMID- 25282620 TI - Evaluation of an eyelid warming device (Blephasteam) for the management of ocular surface diseases in France: the ESPOIR study. AB - INTRODUCTION: Eyelid hygiene, including massage and warm compresses, is an important part of the treatment and prevention of Meibomian gland dysfunction (MGD). Although effective, it requires active participation of the patient and lacks standardisation. Blephasteam is a medical device designed to warm and humidify the eyelid with heating glasses, in order to liquify meibum, thus relieving symptoms and preventing relapse. MATERIALS AND METHODS: The ESPOIR study (Evaluation of the Satisfaction of Patients with Management of Ocular Surface Diseases) presented herein was designed to evaluate the safety and efficacy of this medical device in patients with MGD. A total of 28 French centers participated in the study. One hundred and two patients presenting with symptomatic dysfunction or Meibomian-related dry eye underwent two sessions per day with the eyelid warming device and recorded diary entries on a number of parameters every 2 days for the first week and then weekly for the remaining 2 weeks. Patients were assessed on days 0 and 21. RESULTS: Symptomatology, as recorded on a visual analogue scale (VAS) by the investigator (the primary efficacy variable) was significantly (P<0.001) improved at the end of the study (59.97, 95% CI 55.64-64.30 vs. 39.71, 95% CI 34.78-44.65 on Days 0 and 21 respectively), as was the mean symptoms score (mean decrease of 19.93 +/- 22.15 VAS units; P<0.001), hyperemia score (-1.57 +/- 1.96 and -1.45 +/- 1.85; P<0.001, in the worse and contralateral eye respectively), and quality of meibum (mean 4.03 +/- 3.08; P<0.001 and -3.32 +/- 3.20; P<0.01, in the worse and contralateral eye respectively). More than twice as many reported their symptoms had improved or disappeared compared with those whose symptoms had not changed or had worsened. Global symptomatology, as assessed by the patients, declined throughout the study, and a large majority of patients were satisfied or very satisfied with the treatment. Clear vision and blinking were not impaired during use of the eyelid warming device, which insures proper spreading of the tear film, and patients were able to continue daily activities such as reading and watching television. No adverse events were reported, and there were no changes in intraocular pressure or visual acuity. Safety was rated as satisfactory or very satisfactory by more than 95% of the investigators. CONCLUSION: The study suggests that the eyelid warming device is safe and effective in reducing ocular discomfort and symptoms in MGD. PMID- 25282622 TI - Acquisition of epithelial-mesenchymal transition and cancer stem-like phenotypes within chitosan-hyaluronan membrane-derived 3D tumor spheroids. AB - Cancer drug development has to go through rigorous testing and evaluation processes during pre-clinical in vitro studies. However, the conventional two dimensional (2D) in vitro culture is often discounted by the insufficiency to present a more typical tumor microenvironment. The multicellular tumor spheroids have been a valuable model to provide more comprehensive assessment of tumor in response to therapeutic strategies. Here, we applied chitosan-hyaluronan (HA) membranes as a platform to promote three-dimensional (3D) tumor spheroid formation. The biological features of tumor spheroids of human non-small cell lung cancer (NSCLC) cells on chitosan-HA membranes were compared to those of 2D cultured cells in vitro. The cells in tumor spheroids cultured on chitosan-HA membranes showed higher levels of stem-like properties and epithelial-mesenchymal transition (EMT) markers, such as NANOG, SOX2, CD44, CD133, N-cadherin, and vimentin, than 2D cultured cells. Moreover, they exhibited enhanced invasive activities and multidrug resistance by the upregulation of MMP2, MMP9, BCRC5, BCL2, MDR1, and ABCG2 as compared with 2D cultured cells. The grafting densities of HA affected the tumor sphere size and mRNA levels of genes on the substrates. These evidences suggest that chitosan-HA membranes may offer a simple and valuable biomaterial platform for rapid generation of tumor spheroids in vitro as well as for further applications in cancer stem cell research and cancer drug screening. PMID- 25282623 TI - E-cadherin and CD10 expression in atypical hyperplastic and malignant endometrial lesions. AB - BACKGROUND: Loss of E-cadherin is a critical step for development and progression of malignant tumors. CD10; a marker of non-neoplastic and neoplastic endometrial stroma, is associated with aggressiveness of many epithelial malignancies. AIMS: To evaluate expression and correlation of E-cadherin and CD10 in endometrial lesions and their possible role in differentiating atypical endometrial hyperplasia from endometrial carcinoma. The association of E-cadherin and CD10 expression with clinico-pathological parameters of endometrial carcinoma was also investigated. MATERIALS AND METHODS: Fifty four cases including 28 endometrial carcinomas; 19 endometrial hyperplasia and 7 cases of normal endometrial changes were enrolled for this study. The expression of E-cadherin and CD10 was evaluated by immunohistochemistry using the streptavidin-biotin technique. RESULTS: There was a strong association between malignant change of endometrial glands and membrano-cytoplasmic localization of E-cadherin (p<0.001). Expression of E cadherin but not CD10 was significantly higher in endometrial carcinomas compared to atypical endometrial hyperplasia (p<0.01). Expression of E-cadherin was not associated with CD10 expression in different endometrial lesions. High grade tumors expressed low levels of both E-cadherin (p<0.01) and CD10 (p<0.05) and serous endometrial carcinoma had low E-cadherin and CD10 expression compared to endometrioid carcinoma (p<0.01 and <0.05, respectively). Expression of both molecules showed no association with depth of tumor invasion or FIGO stage. Tumors with lower E-cadherin or CD10 expression had higher rates of vascular tumor emboli (p<0.01 and <0.07, respectively). CONCLUSIONS: Although expression of E-cadherin and CD10 in endometrial lesions was not correlated, reduced expression of both molecules could be critical for progression of endometrial carcinoma. PMID- 25282625 TI - A review of the quality of care following prolonged seizures in 1-18 year olds with epilepsies. AB - PURPOSE: To review the quality of care of children and young people with epilepsies who, following a prolonged seizure, received high-dependency or intensive care. To identify and learn from clinical, organisational, management or personal issues that contributed to these admissions, in order to inform practice and improve clinical services for children across the UK. METHOD: Notifications were collected from consultant paediatricians in England, Wales, Scotland and Northern Ireland over a 10-month period. For all eligible cases a clinical questionnaire was sent to the notifying clinician. A sample of these cases were selected for a detailed case note review. Case notes were reviewed by paediatrician-nurse pairs using a purpose-built assessment tool derived from national guidelines. RESULTS: Data were collected from 135 clinical questionnaires, and 36 sets of case notes were reviewed. Findings were compared to national standards of care and emerging themes identified. There was evidence of good epilepsy management in many cases. In some cases there was evidence of a lack of clear emergency care plans, of delays in administration of emergency medication, and of deviation from established national guidelines. CONCLUSION: The findings of this review suggest there have been improvements in the care of children and young people with epilepsies presenting with prolonged seizures compared to previous studies. Nevertheless, further improvements are needed, particularly in communication with families and prompt administration of emergency medication. PMID- 25282624 TI - Meta-analysis of nonsteroidal anti-inflammatory drug intake and prostate cancer risk. AB - BACKGROUND: Epidemiological studies of the association between nonsteroidal anti inflammatory drug (NSAID) intake and the risk of prostate cancer still remain controversial. Therefore, we conducted a meta-analysis to evaluate the potential association between NSAID intake and prostate cancer risk. METHODS: Eligible studies were retrieved by both computerized searches and reviews of references. Subgroup analyses on country and design of study were also performed. Random or fixed-effect models were used to pool estimates of odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We observed that the intake of aspirin was associated with a marginally decreased risk of prostate cancer (OR = 0.95, 95% CI = 0.93 to 0.98). A similar result was found between nonaspirin NSAIDs and prostate cancer risk (OR = 0.94, 95% CI =0.90 to 0.98). However, a positive relation between all-NSAID intake and prostate cancer risk was observed (OR = 1.18, 95% CI = 1.15 to 1.22). CONCLUSIONS: We observed a marginally inverse correlation between the intake of aspirin and prostate cancer risk. On the contrary, a positive relationship between all-NSAID intake and prostate cancer was detected. Further research needs to be conducted to better clarify potential biological mechanisms. PMID- 25282626 TI - Therapist effects and IAPT Psychological Wellbeing Practitioners (PWPs): a multilevel modelling and mixed methods analysis. AB - The aim of this research was (a) to determine the extent of therapist effects in Psychological Wellbeing Practitioners (PWPs) delivering guided self-help in IAPT services and (b) to identify factors that defined effective PWP clinical practice. Using patient (N = 1122) anxiety and depression outcomes (PHQ-9 and GAD 7), the effectiveness of N = 21 PWPs across 6 service sites was examined using multi-level modelling. PWPs and their clinical supervisors were also interviewed and completed measures of ego strength, intuition and resilience. Therapist effects accounted for around 9 per cent of the variance in patient outcomes. One PWP had significantly better than average outcomes on both PHQ-9 and GAD-7 while 3 PWPs were significantly below average on the PHQ-9 and 2 were below average on the GAD-7. Computed PWP ranks identified quartile clusters of the most (N = 5) and least (N = 5) effective PWPs. More effective PWPs generated higher rates of reliable and clinically significant change and displayed greater resilience, organisational abilities, knowledge and confidence. Study weaknesses are identified and methodological considerations for future studies examining therapist effects in low intensity cognitive behaviour therapy are provided. PMID- 25282627 TI - Interpreting the synergistic effect in combined ultrasonication-ozonation sewage sludge pre-treatment. AB - The sequential combination of ultrasonication and ozonation as sewage sludge treatment prior to anaerobic digestion was investigated. Synergistic volatile suspended solids (VSS) solubilization was observed when low energy ultrasonication (?12kJg(-1) TS) was followed by ozonation. 0.048gO3g(-1) TS ozonation induced the maximum VSS solubilization of 41.3% when the sludge was pre ultrasonicated at 9kJg(-1) TS; while, the same ozone dosage applied without prior ultrasonication only induced 21.1% VSS solubilization. High molecular weight (MW) components (MW>500kDa) were found to be the main solubilization products when sludge was only ozonated. However, solubilization products by ozone were mainly in the form of low MW components (MW<27kDa) when sludge was pre-ultrasonicated. The high MW products generated by ultrasound were effectively degraded in the subsequent ozonation. Anaerobic biodegradability increased by 34.7% when ultrasonication (9kJg(-1) TS) and ozonation (0.036gO3g(-1) TS) were combined sequentially. The maximum methane production rate increased from 3.53 to 4.32, 4.21 and 4.54mL CH4d(-1) after ultrasonication, ozonation and ultrasonication ozonation pre-treatments, respectively. PMID- 25282628 TI - Comments concerning "A possible simplification of the Goss-modified Abraham solvation equation". PMID- 25282629 TI - Anticholinergic drug use and negative outcomes among the frail elderly population living in a nursing home. AB - AIM: Increasing evidence from experimental studies and clinical observations suggests that drugs with anticholinergic properties can cause physical and mental impairment. The aim of the present study was to evaluate the relationship between the use of drugs with anticholinergic activity and negative outcomes in older nursing home residents. METHODS: We used data from the database of the U.L.I.S.S.E project (Un Link Informatico sui Servizi Sanitari Esistenti per l'Anziani), a prospective multicenter observational study. Patients from 31 facilities in Italy were assessed at baseline and at 6 and 12 months by trained personnel, using the Minimum Data Set for Nursing Home (MDS-NH). The only exclusion criterion was age younger than 65 years. The Anticholinergic Risk Scale (ARS), a list of commonly prescribed drugs with potential anticholinergic effects, was used to calculate the anticholinergic load. RESULTS: A total population of 1490 patients was analyzed; almost half of the sample (48%) was using drugs with anticholinergic properties. The population of patients with ARS 1 or higher had a higher comorbidity index (P < .003) and greater cognitive impairment (CPS 5-6) (P < .007). They were more likely to suffer from heart failure, Parkinson disease, depression, anxiety, and schizophrenia. In multivariate analysis, a higher score in the ARS scale was associated with a greater likelihood of functional decline (described as the loss of >=1 ADL point) (odds ratio [OR] 1.13; confidence interval [CI] 1.03-1.23), to a higher rate of falls (OR 1.26; CI 1.13-1.41), and to a higher incidence of delirium (OR 1.16; CI 1.02-1.32) during a 1-year follow-up. CONCLUSIONS: The use of medications with anticholinergic properties is common among older nursing home residents. Our results suggest that among older nursing home residents the use of anticholinergic drugs is associated with important negative outcomes, such as functional decline, falls, and delirium. PMID- 25282630 TI - Do internal medicine residents know enough about skilled nursing facilities to orchestrate a good care transition? AB - BACKGROUND: Although many older adults require skilled nursing facility (SNF) care after acute hospitalization, it is unclear whether internal medicine residents have sufficient knowledge of the care that can be provided at this site. METHODS: We developed a 10-item multiple choice pre-test that assessed knowledge of the definition of a SNF, SNF staffing requirements, and SNF services provided on-site. The test was administered to trainees on the first day of a mandatory SNF rotation that occurred during their first, second or third year of training. RESULTS: Sixty-seven internal medicine residents [41 postgraduate year (PGY)-1, 11 PGY-2, and 15 PGY-3] were assessed with the test. The mean number of questions answered correctly was 4.9, with a standard deviation of 1.6. Regardless of their level of training, residents had a poor baseline knowledge of SNF care (mean scores 4.2 for PGY-1, 5.3 for PGY-2, and 6.3 for PGY-3) (P < .0001). Performance on some questions improved with increased level of training but others did not. CONCLUSIONS: Medical residents have insufficient knowledge about the type of care that can be provided at a SNF and efforts to improve this knowledge are needed to assure proper triage of patients and safe transitions to the SNF. PMID- 25282631 TI - Effects of a whole body vibration (WBV) exercise intervention for institutionalized older people: a randomized, multicentre, parallel, clinical trial. AB - OBJECTIVES: To assess the efficacy of an exercise program on a whole-body vibration platform (WBV) in improving body balance and muscle performance and preventing falls in institutionalized elderly people. DESIGN/SETTING/PARTICIPANTS: A multicentre randomized parallel assessor-blinded clinical trial was conducted in elderly persons living in nursing homes. INTERVENTIONS: Participants were randomized to an exercise program performed either on a whole body vibratory platform (WBV plus exercise group) or on a stationary surface (exercise group). The exercise program for both groups consisted of static and dynamic exercises (balance and strength training over a 6 week training period of 3 sessions per week). The frequency applied on the vibratory platform was 30 to 35 Hz and amplitude was 2 to 4 mm. MEASUREMENTS: The primary outcome measurement was static/dynamic body balance. Secondary outcomes were muscle strength and number of falls. Efficacy was analyzed on an intention to-treat basis and per protocol. The effects of the intervention were evaluated using the t test, Mann-Whitney test, or chi-square test, depending on the type of outcome. Follow-up measurements were collected 6 weeks and 6 months after randomization. RESULTS: A total of 159 participants from 10 centers were included: 81 in the WBV plus exercise group and 78 in the control group. Mean age was 82 years, and 67.29% were women. The Tinetti test score showed a significant overall improvement in both groups (P < .001). No significant differences were found between groups at week 6 (P = .890) or month 6 (P = .718). The Timed Up and Go test did not improve (P = .599) in either group over time, and no significant differences were found between groups at week 6 (P = .757) or month 6 (P = .959). Muscle performance results from the 5 Sit-To-Stand tests improved significantly across time (P = .001), but no statistically significant differences were found between groups at week 6 (P = .709) or month 6 (P = .841). A total of 57 falls (35.8%) were recorded during the follow-up period, with no differences between groups (P = .406). CONCLUSION: Exercise program on a vibratory platform provides benefits similar to those with exercise program on a stationary surface in relation to body balance, gait, functional mobility, and muscle strength in institutionalized elderly people. Longer studies in larger samples are needed to assess falls. PMID- 25282632 TI - Diagnostic utility of Montreal Cognitive Assessment in the Fifth Edition of Diagnostic and Statistical Manual of Mental Disorders: major and mild neurocognitive disorders. AB - OBJECTIVES: The Montreal Cognitive Assessment (MOCA) is a screening tool for mild cognitive impairment (MCI) and dementia. The new criteria for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) mild neurocognitive disorder (NCD) define participants with cognitive decline but no dementia, and major NCD (dementia). We explored the usefulness of MOCA to detect major and mild NCD. DESIGN: Cross-sectional test research. SETTING: Tertiary hospital memory clinic and community-based Singapore Longitudinal Aging Study (SLAS). PARTICIPANTS: Participants with questionable dementia (clinical dementia rating, CDR = 0.5) and early dementia (CDR <=1) over a period of 1 year were identified from the memory clinic registry. The patient records were reviewed and the diagnostic labels of major and mild NCD were applied accordingly. Healthy controls (HC) (CDR = 0, Mini-Mental State Examination >26) were recruited from the on-going SLAS. MEASUREMENTS: Major and mild NCD were diagnosed based on medical history, clinical examination, basic and instrumental activities of daily living, locally validated bedside cognitive tests (Mini-Mental State Examination, Frontal Assessment Battery, and Clock Drawing Test), relevant laboratory investigations and standardized neuropsychological assessment. RESULTS: Two hundred fifty-one participants were included (41 mild NCD, 64 major NCD, 146 HC). On receiver operating characteristic curve analysis, the diagnostic performance by area under the curve (AUC) for MOCA was 0.99 [95% confidence interval (CI) 0.98-1.0] for major NCD and 0.77 (95% CI 0.67-0.86) for mild NCD. For diagnosis of mild NCD, MOCA performed better in those with lower education (primary and below) (AUC 0.90) compared with those with secondary education and beyond (AUC 0.66). CONCLUSION: MOCA has high diagnostic utility for major NCD but its usefulness in detecting mild NCD is more modest. Possible reasons include greater heterogeneity in participants with mild NCD and how "quantified clinical assessment" in the DSM-5 mild NCD criteria is interpreted and operationalized. PMID- 25282633 TI - Adipogenic differentiation of adipose-derived stem cells in 3-dimensional spheroid cultures (microtissue): implications for the reconstructive surgeon. AB - BACKGROUND: Adipose-derived stem cells (ADSC) can be readily extracted from adipose tissue, expanded in vitro, and have the capacity to differentiate into multiple cell lineages. This makes this cell type of great interest to the field of regenerative medicine. This study focuses on the isolation and characterisation of ADSC and their differentiation into adipocytes in a 3D microtissue model. METHODS: Human ADSC were isolated from abdominal adipose tissue and characterised using multiparameter flow cytometry. ADSC were then expanded in culture and used to produce 3D scaffold-free micro-tissue. Adipogenic differentiation potential of micro-tissue constructs were subsequently characterised using Oil Red O staining. RESULTS: Flow cytometric analysis showed ADSC were uniformly positive for CD34, CD73, CD90, and CD105, and negative for CD19, CD14, and CD45. The cells were functionally induced into adipocytes in the presence of appropriate conditioned media. CONCLUSION: We have demonstrated that adipose-derived stem cells have the ability to form of microtissue and survive in vitro. We postulate that in the future this will result in an ADSC population which is injectable and can extend the delivery options of current stem cell based therapies. PMID- 25282634 TI - Re: Toxic epidermal necrolysis (TEN): The Chelsea and Westminster hospital wound management algorithm. PMID- 25282635 TI - Production of squalene by squalene synthases and their truncated mutants in Escherichia coli. AB - Squalene is a precursor of thousands of bioactive triterpenoids and also has industrial value as a lubricant, health-promoting agent, and/or drop-in biofuel. To establish an efficient Escherichia coli-based system for squalene production, we tested two different squalene synthases and their mutants in combination with precursor pathways. By co-expressing a chimeric mevalonate pathway with human or Thermosynechococcus squalene synthase, E. coli accumulated squalene up to 230 mg/L or 55 mg/g-DCW in flask culture. We also determined that a significant truncation of squalene synthase at the C-terminus retains partial cellular activity. The squalene-producing strain described herein represents a convenient platform for gene discovery and the construction of the pathway toward natural and non-natural hopanoids/steroids. PMID- 25282636 TI - New enzymatic methods for selective assay of L-lysine using an L-lysine specific decarboxylase/oxidase from Burkholderia sp. AIU 395. AB - We developed new enzymatic methods for the selective assay of L-lysine by utilizing an oxidase reaction and a decarboxylation reaction by the L-lysine specific decarboxylase/oxidase (L-Lys-DC/OD) from Burkholderia sp. AIU 395. The method utilizing the oxidase reaction of this enzyme was useful for determination of high concentrations of L-lysine. The method utilizing the decarboxylase reaction, which proceeded via the combination of the L-Lys-DC/OD and putrescine oxidase (PUO) from Micrococcus rubens, was effective for determination of low concentrations of L-lysine. Both methods showed good linearity, and neither was affected by other amino acids or amines. In addition, the within-assay and between-assay precisions of both methods were within the allowable range. The coupling of L-Lys-DC/OD with PUO was also useful for the differential assay of L lysine and cadaverine. These newly developed methods were applied to the assay of L-lysine in biological samples and found to be effective. PMID- 25282637 TI - Cordyceptin induces apoptosis through repressing hTERT expression and inducing extranuclear export of hTERT. AB - Cordycepin is an adenosine analog originally extracted from Cordyceps militaris that possesses many pharmacological effects including immune activation and antioxidant and antitumor effects. However, the underlying relationship between apoptosis and telomerase activity in response to cordycepin exposure has not been investigated. In this study, we found that cordycepin-induced apoptosis of human leukemia cells (H937 and THP-1 cells) was associated with inactivation of telomerase and downregulation of human telomerase reverse transcriptase (hTERT) as well as the transcription factors c-Myc and Sp1, which are required for basal transcription from the hTERT gene promoter. Cordycepin also attenuated the activation of phosphoinositide-3-kinase (PI3K)/Akt signaling, thereby reducing phosphorylation and nuclear translocation of hTERT. We further showed that the PI3K inhibitor LY29004 significantly decreased telomerase activity in cordycepin treated cells and increased cordycepin-induced cell death. These findings demonstrate that cordycepin is cytotoxic to human leukemia cells and suppresses telomerase activity through transcriptional and post-translational suppression of hTERT by inactivating the PI3K/Akt signaling pathway. PMID- 25282638 TI - Synergistic interaction between wavelength of light and concentration of H2O2 in bactericidal activity of photolysis of H2O2. AB - The present study aimed to evaluate the interaction between wavelength of light in the range of ultra violet A-visible and concentration of H2O2 in the reaction of photolysis of H2O2 from the point of view of hydroxyl radical (.OH) generation and the bactericidal activity. Light emitting diodes (LEDs) emitting the light at wavelengths of 365, 385, 400 and 465 nm were used at an irradiance of 1000 mW/cm(2). H2O2 was used at the final concentrations of 0, 250, 500, and 1000 mM. Quantitative analysis of .OH generated by the LED irradiation of H2O2 were performed using an electron spin resonance-spin trapping technique. In a bactericidal assay, a bacterial suspension of Staphylococcus aureus prepared in sterile physiological saline was irradiated with the LEDs. The bactericidal activity of each test condition was evaluated by viable counts. When H2O2 was irradiated with the LEDs, .OH was generated and bacteria were killed dependently on the concentration of H2O2 and the wavelength of LED. The two-way analysis of variance revealed that the wavelength, the H2O2 concentration and their interaction significantly affected the yield of .OH and the bactericidal activity of the photolysis of H2O2. Therefore, it is suggested that bactericidal activity of photolysis of H2O2 could be enhanced by controlling the wavelength and the concentration of H2O2, which may contributes to shortening the treatment time and/or to reducing the concentration of H2O2. PMID- 25282639 TI - Improved ethanol production from xylose in the presence of acetic acid by the overexpression of the HAA1 gene in Saccharomyces cerevisiae. AB - The hydrolysis of lignocellulosic biomass liberates sugars, primarily glucose and xylose, which are subsequently converted to ethanol by microbial fermentation. The rapid and efficient fermentation of xylose by recombinant Saccharomyces cerevisiae strains is limited by weak acids generated during biomass pretreatment processes. In particular, acetic acid negatively affects cell growth, xylose fermentation rate, and ethanol production. The ability of S. cerevisiae to efficiently utilize xylose in the presence of acetic acid is an essential requirement for the cost-effective production of ethanol from lignocellulosic hydrolysates. Here, an acetic acid-responsive transcriptional activator, HAA1, was overexpressed in a recombinant xylose-fermenting S. cerevisiae strain to yield BY4741X/HAA1. This strain exhibited improved cell growth and ethanol production from xylose under aerobic and oxygen limited conditions, respectively, in the presence of acetic acid. The HAA1p regulon enhanced transcript levels in BY4741X/HAA1. The disruption of PHO13, a p-nitrophenylphosphatase gene, in BY4741X/HAA1 led to further improvement in both yeast growth and the ability to ferment xylose, indicating that HAA1 overexpression and PHO13 deletion act by different mechanisms to enhance ethanol production. PMID- 25282640 TI - Systematic exploration of guide-tree topology effects for small protein alignments. AB - BACKGROUND: Guide-trees are used as part of an essential heuristic to enable the calculation of multiple sequence alignments. They have been the focus of much method development but there has been little effort at determining systematically, which guide-trees, if any, give the best alignments. Some guide tree construction schemes are based on pair-wise distances amongst unaligned sequences. Others try to emulate an underlying evolutionary tree and involve various iteration methods. RESULTS: We explore all possible guide-trees for a set of protein alignments of up to eight sequences. We find that pairwise distance based default guide-trees sometimes outperform evolutionary guide-trees, as measured by structure derived reference alignments. However, default guide-trees fall way short of the optimum attainable scores. On average chained guide-trees perform better than balanced ones but are not better than default guide-trees for small alignments. CONCLUSIONS: Alignment methods that use Consistency or hidden Markov models to make alignments are less susceptible to sub-optimal guide-trees than simpler methods, that basically use conventional sequence alignment between profiles. The latter appear to be affected positively by evolutionary based guide trees for difficult alignments and negatively for easy alignments. One phylogeny aware alignment program can strongly discriminate between good and bad guide trees. The results for randomly chained guide-trees improve with the number of sequences. PMID- 25282641 TI - CompMap: a reference-based compression program to speed up read mapping to related reference sequences. AB - SUMMARY: Exhaustive mapping of next-generation sequencing data to a set of relevant reference sequences becomes an important task in pathogen discovery and metagenomic classification. However, the runtime and memory usage increase as the number of reference sequences and the repeat content among these sequences increase. In many applications, read mapping time dominates the entire application. We developed CompMap, a reference-based compression program, to speed up this process. CompMap enables the generation of a non-redundant representative sequence for the input sequences. We have demonstrated that reads can be mapped to this representative sequence with a much reduced time and memory usage, and the mapping to the original reference sequences can be recovered with high accuracy. AVAILABILITY AND IMPLEMENTATION: CompMap is implemented in C and freely available at http://csse.szu.edu.cn/staff/zhuzx/CompMap/. CONTACT: xiaoyang@broadinstitute.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25282642 TI - LocalAli: an evolutionary-based local alignment approach to identify functionally conserved modules in multiple networks. AB - MOTIVATION: Sequences and protein interaction data are of significance to understand the underlying molecular mechanism of organisms. Local network alignment is one of key systematic ways for predicting protein functions, identifying functional modules and understanding the phylogeny from these data. Most of currently existing tools, however, encounter their limitations, which are mainly concerned with scoring scheme, speed and scalability. Therefore, there are growing demands for sophisticated network evolution models and efficient local alignment algorithms. RESULTS: We developed a fast and scalable local network alignment tool called LocalAli for the identification of functionally conserved modules in multiple networks. In this algorithm, we firstly proposed a new framework to reconstruct the evolution history of conserved modules based on a maximum-parsimony evolutionary model. By relying on this model, LocalAli facilitates interpretation of resulting local alignments in terms of conserved modules, which have been evolved from a common ancestral module through a series of evolutionary events. A meta-heuristic method simulated annealing was used to search for the optimal or near-optimal inner nodes (i.e. ancestral modules) of the evolutionary tree. To evaluate the performance and the statistical significance, LocalAli were tested on 26 real datasets and 1040 randomly generated datasets. The results suggest that LocalAli outperforms all existing algorithms in terms of coverage, consistency and scalability, meanwhile retains a high precision in the identification of functionally coherent subnetworks. AVAILABILITY: The source code and test datasets are freely available for download under the GNU GPL v3 license at https://code.google.com/p/localali/. CONTACT: jialu.hu@fu-berlin.de or knut.reinert@fu-berlin.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25282643 TI - Using the plurality of codon positions to identify deleterious variants in human exomes. AB - MOTIVATION: A codon position could perform different or multiple roles in alternative transcripts of a gene. For instance, a non-synonymous position in one transcript could be a synonymous site in another. Alternatively, a position could remain as non-synonymous in multiple transcripts. Here we examined the impact of codon position plurality on the frequency of deleterious single-nucleotide variations (SNVs) using data from 6500 human exomes. RESULTS: Our results showed that the proportion of deleterious SNVs was more than 2-fold higher in positions that remain non-synonymous in multiple transcripts compared with that observed in positions that are non-synonymous in one or some transcript(s) and synonymous or intronic in other(s). Furthermore, we observed a positive relationship between the fraction of deleterious non-synonymous SNVs and the number of proteins (alternative splice variants) affected. These results demonstrate that the plurality of codon positions is an important attribute, which could be useful in identifying mutations associated with diseases. CONTACT: s.subramanian@griffith.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25282644 TI - SIST: stress-induced structural transitions in superhelical DNA. AB - SUMMARY: Supercoiling imposes stress on a DNA molecule that can drive susceptible sequences into alternative non-B form structures. This phenomenon occurs frequently in vivo and has been implicated in biological processes, such as replication, transcription, recombination and translocation. SIST is a software package that analyzes sequence-dependent structural transitions in kilobase length superhelical DNA molecules. The numerical algorithms in SIST are based on a statistical mechanical model that calculates the equilibrium probability of transition for each base pair in the domain. They are extensions of the original stress-induced duplex destabilization (SIDD) method, which analyzes stress-driven DNA strand separation. SIST also includes algorithms to analyze B-Z transitions and cruciform extrusion. The SIST pipeline has an option to use the DZCBtrans algorithm, which analyzes the competition among these three transitions within a superhelical domain. AVAILABILITY AND IMPLEMENTATION: The package and additional documentation are freely available at https://bitbucket.org/benhamlab/sist_codes. CONTACT: dzhabinskaya@ucdavis.edu. PMID- 25282645 TI - An alternative approach to multiple testing for methylation QTL mapping reduces the proportion of falsely identified CpGs. AB - INTRODUCTION: An increasing number of studies investigates the influence of local genetic variation on DNA methylation levels, so-called in cis methylation quantitative trait loci (meQTLs). A common multiple testing approach in genome wide cis meQTL studies limits the false discovery rate (FDR) among all CpG-SNP pairs to 0.05 and reports on CpGs from the significant CpG-SNP pairs. However, a statistical test for each CpG is not performed, potentially increasing the proportion of CpGs falsely reported on. Here, we presented an alternative approach that properly control for multiple testing at the CpG level. RESULTS: We performed cis meQTL mapping for varying window sizes using publicly available single-nucleotide polymorphism (SNP) and 450 kb data, extracting the CpGs from the significant CpG-SNP pairs ([Formula: see text]). Using a new bait-and-switch simulation approach, we show that up to 50% of the CpGs found in the simulated data may be false-positive results. We present an alternative two-step multiple testing approach using the Simes and Benjamini-Hochberg procedures that does control the FDR among the CpGs, as confirmed by the bait-and-switch simulation. This approach indicates the use of window sizes in cis meQTL mapping studies that are significantly smaller than commonly adopted. DISCUSSION: Our approach to cis meQTL mapping properly controls the FDR at the CpG level, is computationally fast and can also be applied to cis eQTL studies. AVAILABILITY AND IMPLEMENTATION: An examplary R script for performing the Simes procedure is available as supplementary material. CONTACT: e.w.van_zwet@lumc.nl or b.t.heijmans@lumc.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25282646 TI - VCF2Networks: applying genotype networks to single-nucleotide variants data. AB - SUMMARY: A wealth of large-scale genome sequencing projects opens the doors to new approaches to study the relationship between genotype and phenotype. One such opportunity is the possibility to apply genotype networks analysis to population genetics data. Genotype networks are a representation of the set of genotypes associated with a single phenotype, and they allow one to estimate properties such as the robustness of the phenotype to mutations, and the ability of its associated genotypes to evolve new adaptations. So far, though, genotype networks analysis has rarely been applied to population genetics data. To help fill this gap, here we present VCF2Networks, a tool to determine and study genotype network structure from single-nucleotide variant data. AVAILABILITY AND IMPLEMENTATION: VCF2Networks is available at https://bitbucket.org/dalloliogm/vcf2networks. CONTACT: giovanni.dallolio@kcl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25282648 TI - Structure-activity relationship study of arbidol derivatives as inhibitors of chikungunya virus replication. AB - Chikungunya virus (CHIKV), a mosquito-borne arthrogenic Alphavirus, causes an acute febrile illness in humans, that is, accompanied by severe joint pains. In many cases, the infection leads to persistent arthralgia, which may last for weeks to several years. The re-emergence of this infection in the early 2000s was exemplified by numerous outbreaks in the eastern hemisphere. Since then, the virus is rapidly spreading. Currently, no drugs have been approved or are in development for the treatment of CHIKV, which makes this viral infection particularly interesting for academic medicinal chemistry efforts. Several molecules have already been identified that inhibit CHIKV replication in phenotypic virus-cell-based assays. One of these is arbidol, a molecule that already has been licensed for the treatment of influenza A and B virus infections. For structural optimization, a dedicated libraries of 43 indole-based derivatives were evaluated leading to more potent analogues (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities higher than those of the other derivatives, including the lead compound, and with a selective index of inhibition 13.2 and 14.6, respectively, higher than that of ARB (4.6). PMID- 25282647 TI - Expanding the results of a high throughput screen against an isochorismate pyruvate lyase to enzymes of a similar scaffold or mechanism. AB - Antibiotic resistance is a growing health concern, and new avenues of antimicrobial drug design are being actively sought. One suggested pathway to be targeted for inhibitor design is that of iron scavenging through siderophores. Here we present a high throughput screen to the isochorismate-pyruvate lyase of Pseudomonas aeruginosa, an enzyme required for the production of the siderophore pyochelin. Compounds identified in the screen are high nanomolar to low micromolar inhibitors of the enzyme and produce growth inhibition in PAO1 P. aeruginosa in the millimolar range under iron-limiting conditions. The identified compounds were also tested for enzymatic inhibition of Escherichia coli chorismate mutase, a protein of similar fold and similar chemistry, and of Yersinia enterocolitica salicylate synthase, a protein of differing fold but catalyzing the same lyase reaction. In both cases, subsets of the inhibitors from the screen were found to be inhibitory to enzymatic activity (mutase or synthase) in the micromolar range and capable of growth inhibition in their respective organisms (E. coli or Y. enterocolitica). PMID- 25282649 TI - Discovery and structure-activity relationship studies of irreversible benzisothiazolinone-based inhibitors against Staphylococcus aureus sortase A transpeptidase. AB - Gram-positive bacteria, in general, and staphylococci, in particular, are the widespread cause of nosocomial and community-acquired infections. The rapid evolvement of strains resistant to antibiotics currently in use is a serious challenge. Novel antimicrobial compounds have to be developed to fight these resistant bacteria, and sortase A, a bacterial cell wall enzyme, is a promising target for novel therapies. As a transpeptidase that covalently attaches various virulence factors to the cell surface, this enzyme plays a crucial role in the ability of bacteria to invade the host's tissues and to escape the immune response. In this study we have screened a small molecule library against recombinant Staphylococcus aureus sortase A using an in vitro FRET-based assay. The selected hits were validated by NMR methods in order to exclude false positives and to analyze the reversibility of inhibition. Further structural and functional analysis of the best hit allowed the identification of a novel class of benzisothiazolinone-based compounds as potent and promising sortase inhibitors. PMID- 25282650 TI - Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA. AB - A series of twenty seven substituted 2-(2-oxobenzo[d]oxazol-3(2H)-yl)acetamide derivatives were designed based on our earlier reported Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein reductase (InhA) lead. Compounds were evaluated for MTB InhA inhibition study, in vitro activity against drug sensitive and -resistant MTB strains, and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)-N-(5 nitrothiazol-2-yl)acetamide (30) was found to be the most promising compound with IC50 of 5.12 +/- 0.44 MUM against MTB InhA, inhibited drug sensitive MTB with MIC 17.11 MUM and was non-cytotoxic at 100 MUM. The interaction with protein and enhancement of protein stability in complex with compound 30 was further confirmed biophysically by differential scanning fluorimetry. PMID- 25282651 TI - SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position. AB - A series of C4-N-substituted podophyllum derivatives were synthesized and tested for cytotoxicity in HeLa, BGC-823, A549, Huh7 and MCF-7 cells by MTT assay. Pharmacologically, most derivatives displayed potent cytotoxicity against at least one of the tested tumor cell lines. Structure activity relationship (SAR) analysis suggests that compounds with imidogen exposed on the pyridine, rather than pyrimidine, exhibited significantly elevated potency. Moreover, the presence of a chlorine atom in the heterocyclic ring enhanced cytotoxicity, with the order 3-position>4-position>5-position>6-position. Specifically, two compounds, 3g and 3h, with 2-amino-3-chloropyridine substituted into the podophyllotoxin (PPT) and 4'-O-demethylepipodophyllotoxin (DMEP) scaffolds were shown to have the most potent HeLa cells cytotoxicity compared to other synthesized derivatives or reference compounds PPT, DMEP and etoposide (VP-16). The compound 3g was shown to inhibit microtubule polymerization and compound 3h affected topoisomerase II catalytic activity. Both compounds resulted in G2/M phase arrest and apoptosis, purportedly by increasing the expression of P53, followed by Bax up-regulation, Bcl-2 down-regulation, and caspase-3 activation. As a result of this work, we conclude that compounds 3g and 3h are more potent anticancer agents than VP-16, and that they work by different antitumor mechanisms. PMID- 25282652 TI - Synthesis of 3',4'-difluoro-3'-deoxyribonucleosides and its evaluation of the biological activities: discovery of a novel type of anti-HCV agent 3',4' difluorocordycepin. AB - Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF(2)/BF3 . OEt(2), the respective novel 3',4'-difluoro-3' deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3',4'-unsaturated adenosine provided the beta-face adducts as sole stereoisomers whereas alpha-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3' deoxy-3',4'-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3',4'-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4'-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity. PMID- 25282655 TI - Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). AB - The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid pKa of 8-10, while diverse leaving groups are tolerated for FAAH inhibitors. PMID- 25282654 TI - Design, synthesis and evaluation of novel tacrine-(beta-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. AB - A series of tacrine-(beta-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced beta-amyloid (Abeta) aggregation, Cu(2+)-induced Abeta (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Abeta aggregation (65.8% at 20 MUM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment. PMID- 25282656 TI - Protein carbonylation associated to high-fat, high-sucrose diet and its metabolic effects. AB - The present research draws a map of the characteristic carbonylation of proteins in rats fed high-caloric diets with the aim of providing a new insight of the pathogenesis of metabolic diseases derived from the high consumption of fat and refined carbohydrates. Protein carbonylation was analyzed in plasma, liver and skeletal muscle of Sprague-Dawley rats fed a high-fat, high-sucrose (HFHS) diet by a proteomics approach based on carbonyl-specific fluorescence-labeling, gel electrophoresis and mass spectrometry. Oxidized proteins along with specific sites of oxidative damage were identified and discussed to illustrate the consequences of protein oxidation. The results indicated that long-term HFHS consumption increased protein oxidation in plasma and liver; meanwhile, protein carbonyls from skeletal muscle did not change. The increment of carbonylation by HFHS diet was singularly selective on specific target proteins: albumin from plasma and liver, and hepatic proteins such as mitochondrial carbamoyl-phosphate synthase (ammonia), mitochondrial aldehyde dehydrogenase, argininosuccinate synthetase, regucalcin, mitochondrial adenosine triphosphate synthase subunit beta, actin cytoplasmic 1 and mitochondrial glutamate dehydrogenase 1. The possible consequences that these specific protein carbonylations have on the excessive weight gain, insulin resistance and nonalcoholic fatty liver disease resulting from HFHS diet consumption are discussed. PMID- 25282653 TI - Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA. AB - Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI(50) in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety of in vitro and cell based assays all of the hybrids tested were shown to target topoisomerase II. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles matching both etoposide and the N-mustard compounds from which they were derived. These results supported the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA. PMID- 25282657 TI - Novel technique for delayed sternal closure: soft tissue approximation with substernal bridge. PMID- 25282658 TI - Discussion. PMID- 25282660 TI - Prophylactic peritoneal dialysis after the Norwood procedure: worth the risk? PMID- 25282662 TI - The role of cognitive dissonance in the management of functional tricuspid regurgitation at the time of degenerative mitral valve repair. PMID- 25282661 TI - Biventricular assist device implantation as bridge to transplantation after Mustard procedure. PMID- 25282659 TI - Validation of association of the apolipoprotein E epsilon2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. AB - OBJECTIVE: Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE epsilon2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association. METHODS: The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores. RESULTS: Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE epsilon2 allele was associated with a lower PDI score (P = .038). Patients with the epsilon2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the epsilon2 allele was present in only 11% of the patients. There was a marginal effect of the epsilon2 allele on MDI scores (P = .058). CONCLUSIONS: These data validate the association of the APOE epsilon2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD. PMID- 25282663 TI - Lipid composition is an important determinant of antimicrobial activity of alpha melanocyte stimulating hormone. AB - We have reported strong antimicrobial activity of cationic neuropeptide alpha-MSH against Staphylococcus aureus. Clinical S. aureus isolates non-susceptible to the peptide had higher amount of cationic phospholipid. To elucidate the molecular basis of lipid selectivity and antimicrobial activity of alpha-MSH, studies were carried out on SUVs having different combinations of neutral DMPC and anionic lipids DMPG to mimic mammalian and bacterial membrane. The peptide interacted with the DMPG containing vesicles only, as evident from the changes in Trp fluorescence. CD spectroscopy revealed that despite interaction, the peptide retained its native random coil structure. The perturbation of the vesicles caused by peptide interaction is strongly dependent on peptide concentration as seen both by DLS and Tb(3+)/DPA based fluorescence leakage assay. Our data clearly demonstrate the preference of alpha-MSH to interact with anionic DMPG containing vesicles leading to significant permeabilization which is the molecular basis behind the selectivity of alpha-MSH for bacterial systems. PMID- 25282665 TI - Ebola in west Africa: from disease outbreak to humanitarian crisis. PMID- 25282664 TI - Standard and advanced echocardiography in takotsubo (stress) cardiomyopathy: clinical and prognostic implications. AB - Echocardiography is frequently the initial noninvasive imaging modality used to assess patients with takotsubo cardiomyopathy (TTC). Standard transthoracic echocardiography can provide, even in the acute care setting, useful information about left ventricular (LV) morphology as well as regional and global systolic or diastolic function. It allows the differentiation of different LV morphologic patterns according to the localization of wall motion abnormalities. A "circumferential pattern" of LV myocardial dysfunction characterized by symmetric wall motion abnormalities involving the midventricular segments of the anterior, inferior, and lateral walls should be considered suggestive of TTC and included in the differential diagnosis of acute coronary syndromes. Moreover, advanced echocardiographic techniques, including speckle-tracking, myocardial contrast, and coronary flow studies, are providing mechanistic and pathophysiologic insights into this unique syndrome. Early identification of any potential complications (i.e., LV outflow tract obstruction, reversible moderate to severe mitral regurgitation, right ventricular involvement, thrombus formation, and cardiac rupture) are crucial for the management, risk stratification, and follow up of patients with TTC. Because of the dynamic evolution of the syndrome, comprehensive serial echocardiographic examinations should be systematically performed. This review focuses on these aspects of imaging and the increasing understanding of the clinical and prognostic utility of echocardiography in TTC. PMID- 25282666 TI - Ebola and compliance with infection prevention measures in Nigeria. PMID- 25282668 TI - Effect of pulsed electric field treatments at various stages during conditioning on quality attributes of beef longissimus thoracis et lumborum muscle. AB - Beef longissimus thoracis et lumborum (LTL) muscle was used to evaluate the effect of PEF treatments (1.4 kV/cm, 10 Hz, 20 MUs, 300 and 600 pulses) on meat quality attributes (weight loss, colour, cook loss and texture) and its evolution at various stages during ageing (2, 10, 18 and 26 days post-mortem). The length of meat ageing before and after PEF application exerted no influence on weight loss, colour and cook loss. Results also demonstrated that PEF treatments applied at different times post-mortem (2, 10, 18 and 26 days) showed a tendency towards reducing toughness of beef samples but that the application of PEF did not affect the tenderization process provided by ageing itself. 60% of the sensory panellists scored PEF treated samples as tender (>=6.0 points out of 9.0) whereas only 27.5% did so for untreated samples. PMID- 25282667 TI - Factors related to incomplete treatment of breast cancer in Kumasi, Ghana. AB - PURPOSE: The burden of cancer in Africa is an enlarging public health challenge. Breast cancer in Ghana is the second most common cancer among Ghanaian women and the proportion of diagnosed patients who complete prescribed treatment is estimated to be very limited, thereby potentially adding to lower survival and poor quality of life after diagnosis. The objective of this study was to identify the patient and system factors related to incomplete treatment of breast cancer among patients. METHODS: This study was conducted at the Komfo Anokye Teaching Hospital in Kumasi, Ghana. We interviewed 117 breast cancer patients and next of kin of breast cancer patients diagnosed from 2008 to 2010. RESULTS: Islamic religion, seeking treatment with traditional healers, and lack of awareness about national health insurance coverage of breast cancer treatment were predictors of incomplete treatment. CONCLUSIONS: The results of this study support that Ghanaian women with diagnosed breast cancer have multiple addressable and modifiable patient factors that may deter them from completing the prescribed treatment. The results highlight the need for developing and testing specific interventions about the importance of completing treatment with a special focus on addressing religious, cultural, and system navigation barriers in developing countries. PMID- 25282669 TI - Pre-slaughter conditions influence skatole and androstenone in adipose tissue of boars. AB - Boar taint in carcasses may vary between farms and abattoirs, although the underlying mechanisms are not yet fully understood. In the present study, 169 boars from three farms were split into two groups and slaughtered at two abattoirs. Duration of transport and the time between arrival at the abattoir and unloading (pre-unloading time) were recorded. During slaughter, blood, feces, and urine were collected to measure testosterone and cortisol levels. Carcasses were classified according to the number of skin lesions, and fat samples were taken to determine skatole, indole and androstenone levels. Androstenone in fat and testosterone in blood, feces, and urine were mainly influenced by the duration of transport. Skatole and indole concentrations were increased by both pre-unloading time and duration of transport, but were also related to skin lesions. Thus it is concluded that androstenone and skatole concentrations in fat are significantly modified by pre-slaughter conditions. PMID- 25282670 TI - Meat morals: relationship between meat consumption consumer attitudes towards human and animal welfare and moral behavior. AB - The aim of this work is to explore the relation between morality and diet choice by investigating how animal and human welfare attitudes and donation behaviors can predict a meat eating versus flexitarian versus vegetarian diet. The results of a survey study (N=299) show that animal health concerns (measured by the Animal Attitude Scale) can predict diet choice. Vegetarians are most concerned, while full-time meat eaters are least concerned, and the contrast between flexitarians and vegetarians is greater than the contrast between flexitarians and full-time meat eaters. With regards to human welfare (measured by the Moral Foundations Questionnaire), results show that attitudes towards human suffering set flexitarians apart from vegetarians and attitudes towards authority and respect distinguish between flexitarians and meat eaters. To conclude, results show that vegetarians donate more often to animal oriented charities than flexitarians and meat eaters, while no differences between the three diet groups occur for donations to human oriented charities. PMID- 25282671 TI - Biological evaluation of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivatives targeting the YycG histidine kinase. AB - With an intention to potent inhibitors of YycG histidine kinase, a series of halogenated thiazolo[3,2-a]pyrimidin-3-one carboxylic acid derivatives were synthesized and evaluated for their antibacterial, antibiofilm and hemolytic activities. The majority of the compounds showed good activity against Staphylococcus epidermidis and Staphylococcus aureus, with MIC values of 1.56 6.25 MUM, simultaneously presented promising antiobifilm activity against S. epidermidis ATCC35984 at 50 MUM. The test of inhibitory activity on YycG kinase suggested the antibacterial activities of these derivatives are based on inhibiting the enzyme activity of the YycG HK domain. The hemolytic activity test suggested these compounds exhibited in vitro antibacterial activity at non hemolytic concentrations. PMID- 25282672 TI - Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors. AB - A series of 4-(2-fluorophenoxy)quinoline derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five cancer cell lines (A549, H460, HT-29, MKN-45, and U87MG). Most compounds showed weak to excellent antiproliferative activity. The most promising analog, 40 (c-Met IC50 = 1.86 nM), displayed 1.3-, 6.8-, 1.5-, 3.5-fold increase against HT-29, H460, A549 and U87MG cell lines, respectively, compared with Foretinib. An analysis of structure-activity relationships revealed that an acylhydrazone scaffold with an unsubstituted sp(2) hybridized carbon adjacent to the 4-CF3 phenyl ring is favorable for antitumor activity. PMID- 25282673 TI - Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with (188)Re. AB - Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine containing C-terminal peptide-based chelators on the biodistribution and renal retention of (188)Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all (188)Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The (188)Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of (188)Re-ZHER2:V2 (3.1 +/- 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental (188)Re-ZHER2:2395 (172 +/- 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of (188)Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs. PMID- 25282674 TI - Severe hypoplasia of the posterior mitral leaflet: a rare cause of congenital mitral regurgitation assessed by three-dimensional transesophageal echocardiography. PMID- 25282675 TI - A free-choice premium in the basal ganglia. AB - Apparently, the act of free choice confers value: when selecting between an item that you had previously chosen and an identical item that you had been forced to take, the former is often preferred. What could be the neural underpinnings of this free-choice bias in decision making? An elegant study recently published in Neuron suggests that enhanced reward learning in the basal ganglia may be the culprit. PMID- 25282676 TI - Pharmacomechanical thrombolysis of symptomatic acute and subacute deep vein thrombosis with a rotational thrombectomy device. AB - PURPOSE: To retrospectively evaluate the efficacy and safety of pharmacomechanical thrombolysis (PMT) with the use of a rotational thrombectomy device for symptomatic deep vein thrombosis (DVT). MATERIALS AND METHODS: Between July 2012 and August 2013, 41 patients with acute or subacute DVT underwent PMT. The Cleaner thrombectomy device was used in a single-session technique for patients with lower-extremity DVT. Based on contrast venography, the extent of lysis was graded from I (< 50%) to III (complete). RESULTS: Sixteen patients (39.0%) had a femoropopliteal thrombosis and 25 (61.0%) had an iliofemoral venous thrombosis. The mean duration of symptoms was 11.0 days (range, 3-25 d). The mean quantity of tissue plasminogen activator was 20.7 mg (range, 10-50), and the mean duration of the procedure was 74.3 minutes (range, 30-240 min). At the end of the PMT procedure, 29 patients (70.7%) had complete (grade III) thrombus resolution. Grade I and II lysis were noted in one (2.4%) and 11 (26.8%) patients, respectively. Thirty-eight of the 41 patients were treated with PMT in a single session, and three (7.3%) required an additional lytic infusion as a result of residual thrombi. The overall grade III, II, and I thrombus resolution rates, including the supplemental thrombolysis, were 73.2% (n = 30), 22.0% (n = 9), and 4.9% (n = 2), respectively. There was no mortality. CONCLUSIONS: Use of the Cleaner thrombectomy device is a promising alternative to current treatment modalities for the management of DVT in a single session of PMT. PMID- 25282677 TI - Transcatheter arterial embolization with N-butyl cyanoacrylate for nonvariceal upper gastrointestinal bleeding in hemodynamically unstable patients: results and predictors of clinical outcomes. AB - PURPOSE: To assess the safety, efficacy, clinical outcomes, and prognostic factors associated with transcatheter arterial embolization (TAE) with N-butyl cyanoacrylate (NBCA) for nonvariceal upper gastrointestinal (GI) hemorrhage in hemodynamically unstable patients. MATERIALS AND METHODS: Between January 2008 and December 2012, 49 hemodynamically unstable patients (systolic blood pressure < 90 mm Hg and ongoing transfusion requirement) underwent emergency TAE with NBCA for nonvariceal upper GI bleeding and were included in the study. The technical (cessation of extravasation) and clinical (no residual bleeding within 7 d) success rates, incidence of ischemic complications, and clinical and technical predictors of recurrent bleeding within 30 days were analyzed. RESULTS: The technical and clinical success rates were 98% and 71%, respectively. There were no ischemic bowel complications; one patient experienced hepatic infarction with elevated liver enzymes. The incidence of major complications was 2%. The incidence of rebleeding within 30 days was 39%. Hematologic malignancies (P = .017), coagulopathy (P = .003), steroid pulse therapy (P = .025), and the absence of NBCA in the target lesions (P = .003) were associated with recurrent bleeding. CONCLUSIONS: NBCA embolization can be safely performed in hemodynamically unstable patients with active nonvariceal upper GI bleeding. The clinical factors associated with rebleeding might influence the clinical outcome. PMID- 25282678 TI - Pain, disability, and diagnostic accuracy of clinical instability and endurance tests in subjects with lumbar spondylolisthesis. AB - OBJECTIVE: The aims of this study were (1) to investigate the relationship between the main clinical tests to detect spinal instability, the perceived pain and disability, and symptomatic spondylolisthesis (SPL) characteristics, (2) to investigate the relationship between endurance and instability tests, and (3) to measure the diagnostic accuracy of these tests in unstable SPL diagnosed against dynamic radiographs. METHODS: Four instability tests were evaluated on 119 subjects: aberrant movements, active straight leg raising (ASLR), prone instability test, and passive lumbar extension test (PLE); and 2 endurance tests, prone bridge test and supine bridge test (SBT). The results were compared with the numeric rating scale for pain and the Oswestry Disability Index for disability. These tests were used as index tests and compared with dynamic radiographs as reference standard on 64 subjects. RESULTS: A significant relationship between disability and all the clinical tests but ASLR was observed. The relation between tests and pain was weaker, not significant for prone instability test and aberrant movement and critical for ASLR (P = .05). There was a low relationship between endurance tests and instability tests. Only PLE showed a significant association with dynamic radiographs (P = .017). CONCLUSION: Endurance and instability tests appear to be weakly related to the amount of pain but significantly related to the disability in symptomatic SPL. Of the tests evaluated, PLE exhibited the best ability to predict positive dynamic radiographs. PMID- 25282679 TI - Immediate effects of active versus passive scapular correction on pain and pressure pain threshold in patients with chronic neck pain. AB - OBJECTIVE: The purpose of this study was to investigate the effect of active vs passive scapular correction on pain and pressure pain threshold at the most symptomatic cervical segment in patients with chronic neck pain. METHODS: Twenty three volunteers with chronic, idiopathic neck pain were recruited (age, 38.9 +/- 14.4 years; sex [man/woman], 3/20; Neck Disability Index, 28.1% +/- 9.9%). Subjects were randomly allocated to 2 groups: active scapular correction or passive scapular correction. Pressure pain threshold and pain intensity rated on a numerical rating scale during a posteroanterior glide over the most symptomatic cervical segment were measured before and immediately after the active or passive scapular intervention. RESULTS: Only the active scapular correction produced a reduction in pain (pre, 6.3 +/- 1.2; post, 3.7 +/- 2.4; P < .05) and increase in pressure pain threshold (pre, 8.7 +/- 4.2 kg/cm(2); post, 10.1 +/- 3.8 kg/cm(2); P < .05) at the most painful cervical segment. CONCLUSIONS: An active scapular correction exercise resulted in an immediate reduction of pain and pressure pain sensitivity in patients with chronic neck pain and scapular dysfunction. PMID- 25282680 TI - Assessment of scoliotic deformity using spinous processes: comparison of different analysis methods of an ultrasonographic system. AB - OBJECTIVE: The purpose of this study was to evaluate the performance of 5 analysis methods in quantifying scoliotic deformity, using the spatial positions of SP tips acquired by a custom-developed ultrasound-based system, with different curve fitting methods and angle metrics in terms of their correlation with Cobb angle, test-retest reliability, vulnerability to digitization errors, and accuracy of identifying end vertebrae and convexity direction. METHODS: Three spinal column dry bone specimens were randomly configured to 30 different scoliotic deformities. Raw spatial data of the SP tips were processed by the following 3 methods: (1) fifth-order polynomial fitting, (2) locally weighted polynomial regression (LOESS) with smoothing parameter (alpha) = .25, and (3) LOESS with alpha = .4. Angle between the 2 tangents along the spinal curve with the most positive and negative slopes (ie, posterior deformity angle) and summation of the angles formed by every 2 lines joining 3 neighboring SPs between the end vertebrae (ie, accumulating angle) were computed to quantify scoliotic deformity. Their performances were compared in terms of their correlation with Cobb angle, test-retest reliability, vulnerability to digitization errors, and accuracy of identifying end vertebrae. RESULTS: Posterior deformity angle calculated from the spinal curve constructed by LOESS with alpha = .4 excelled in every aspect of the comparison (ie, Cobb angle, test-retest reliability, vulnerability to digitization errors, and accuracy of identifying end vertebrae and convexity direction), making it the method of choice of those tested for processing the spatial data of the SP tips in this ultrasonography study using dry bone specimens. CONCLUSIONS: The ultrasound-based system and the LOESS (0.4) posterior deformity angle method developed for this study offer a viable technology for quantifying scoliotic deformity in a reliable and radiation-free manner. However, further validation using scoliosis subjects is needed before they can be used to quantify spinal deformity in the clinical setting. PMID- 25282681 TI - beta-Cell Ca(2+) dynamics and function are compromised in aging. AB - Defects in pancreatic beta-cell function and survival are key components in type 2 diabetes (T2D). An age-dependent deterioration in beta-cell function has also been observed, but little is known about the molecular mechanisms behind this phenomenon. Our previous studies indicate that the regulation of cytoplasmic free Ca(2+) concentration ([Ca(2+)]i) may be critical and that this is dependent on the proper function of the mitochondria. The [Ca(2+)]i dynamics of the pancreatic beta-cell are driven by an interplay between glucose-induced influx of extracellular Ca(2+) via voltage-dependent Ca(2+) channels and the inositol 1,4,5 trisphosphate (Ins(1,4,5)P3)-mediated liberation of Ca(2+) from intracellular stores. Our previous work has indicated a direct relationship between disruption of Ins(1,4,5)P3-mediated Ca(2+) regulation and loss of beta-cell function, including disturbed [Ca(2+)]i dynamics and compromised insulin secretion. To investigate these processes in aging we used three mouse models, a premature aging mitochondrial mutator mouse, a mature aging phenotype (C57BL/6) and an aging-resistant phenotype (129). Our data suggest that age-dependent impairment in mitochondrial function leads to modest changes in [Ca(2+)]i dynamics in mouse beta-cells, particularly in the pattern of [Ca(2+)]i oscillations. These changes are driven by modifications in both PLC/Ins(1,4,5)P3-mediated Ca(2+) mobilization from intracellular stores and decreased beta-cell Ca(2+) influx over the plasma membrane. Our findings underscore an important concept, namely that even relatively small, time-dependent changes in beta-cell signal-transduction result in compromised insulin release and in a diabetic phenotype. PMID- 25282682 TI - Changes in the connective tissue sheath of Wistar rat nerve with aging. AB - The alterations due to aging in the peripheral nerves can affect the physiology of these structures. Thus, the purpose of the present study was to describe the activity of the MMP-2 and MMP-9, as well as the structure and composition of the extracellular matrix of the rat sciatic nerve during maturation and aging. Our results have shown that the extracellular matrix of the sciatic nerve of 30-, 180 and 730-day-old Wistar rats present ultrastructural, morphometrical and biochemical changes during aging. The perineurium was the structure most affected by age, as evidenced by a decrease in thickness and in collagen fibril content. Cytochemical analysis detected proteoglycans in the basal membrane of Schwann cells and around perineural cells, as well as on the collagen fibrils of the perineurium and endoneurium at all ages. Biochemical analyses showed that the quantity of non-collagenous proteins was higher in 730-day-old animals compared to other ages, while the uronic acid content was higher in 30-day-old animals. Morphometrical analysis detected greater numbers of myelinated fibers and increased myelin thickness in 180-day-old animals. Zymography analysis detected greater amounts and activity of MMP-2 and MMP-9 in 180- and 730-day-old animals compared to younger rats. In conclusion, our results showed changes in the structural organization and composition of extracellular matrix of the sciatic nerve during aging, such as increase in the non-collagenous protein content and higher MMP-2 and MMP-9 activity, decrease in uronic acid concentration and in collagen fibril content in the perineurium, as well as degeneration of nerve fibers. PMID- 25282683 TI - Statement on surgical preresidency preparatory courses. AB - The leadership of the surgical community is actively engaged in improving the preparation of incoming residents to assume responsibility and accountability for key elements of care and stewardship. To better prepare for this transition, it is essential that all matriculants to surgery residency successfully complete a preparatory course of blended learning that specifically addresses the essential components of quality care and patient safety before the start of their training. A national multidimensional curriculum, along with objective assessment tools, has been developed to accelerate readiness, responsibility, and accountability during the transition from medical school to surgery residency. We strongly endorse this effort and encourage medical schools to adopt this or a similar program. We stand ready to assist medical schools and medical students in the implementation of this important initiative. PMID- 25282684 TI - Variability of palmprint ridge density in a North Indian population and its use in inference of sex in forensic examinations. AB - Fingerprints and palmprints are unique to an individual, and these biometric characters are used in the identification of individuals. In the recent past, ridge density (ridge count in a defined area) has been explored for its applicability in inference of sex from the fingerprints and palmprints recovered at the crime scene. The present research aims to study the variability of palmprint ridge density in a North Indian population, and its significance in inference of sex in forensic examinations. The sample consisted of 157 healthy young adults (110 females and 47 males) from Shimla city in North India. Bilateral palmprints were taken from all the participants following standard methods. The palmprints were manually analyzed in four defined areas of each palmprint that included the central prominent part of the thenar eminence (P1), the mount distal to the axial triradius on the hypothenar region (P2), the mount proximal to the triradius of the second digit (P3) and the mount proximal to the triradius of the fifth digit (P4). The ridge density was calculated diagonally using a square measuring 5 mm * 5 mm. The sex differences in palmprint ridge densities were statistically analyzed for each of the designated areas using statistical considerations. Receiver operating characteristic (ROC) curve analysis was done to test the overall ability of the palmprint ridge densities obtained from each area in inference of sex. The mean palmprint ridge density was found to be significantly greater in females than in males in all the four defined areas of the palmprint. Ridge densities in P3 and P4 areas of the palmprint showed statistically significant bilateral differences in both males and females. The study observed variations in the ridge density between the four designated areas of the palmprint. Based on the area under the ROC curve (AUC), maximum sexing potential for the palmprint ridge density was observed in the P4 area, followed by P3 area on both right and left sides. ROC analysis of the total palmprint ridge density indicated that the sexing accuracy from the right and left palmprint ridge densities was 70.2% and 71.8% respectively. The study shows variability of palmprint ridge density among sexes and in different regions of the palm on both sides. In view of the considerable overlapping in male and female values and lower levels of accuracy obtained in ROC analysis, the present research concludes that the palmprint ridge density cannot be used as an effective tool in inference of sex. However, in absence of other more reliable means/evidence, it still can be considered as a supportive trait in sex inference. PMID- 25282685 TI - Serum concentrations of galectin-3 in patients with cardiac syndrome X. AB - OBJECTIVE: Microvascular dysfunction has been reported in cardiac syndrome X (CSX), even though the underlying mechanisms still remain uncertain. Galectin-3 has been recently recognized as a biomarker of cardiovascular fibrosis and inflammation. We sought to investigate the role of galectin-3 in the CSX. METHODS: We studied 115 consecutive CSX patients (mean age 55.43 +/- 8.71 years, 36 men) and 74 healthy controls (mean age 54.53 +/- 10.07 years, 31 men). Serum concentrations of galectin-3 and high-sensitive C-reactive protein (hs-CRP) were measured on the blood samples. RESULTS: Galectin-3 concentrations were significantly higher in patients with CSX compared to controls (0.90 ng/ml; IQR, 0.40-1.70 ng/ml vs 0.40 ng/ml; IQR, 0.36-0.44 ng/ml, p < 0.0001). Although, the prevalence of diabetes mellitus, hypertension and family history of coronary artery disease (CAD) were significantly higher among patients with CSX, following adjustment for diabetes mellitus, hypertension, and family history of CAD, serum galectin-3 concentrations were still found significantly increased in patients with CSX. Galectin-3 concentrations correlated positively with hs-CRP (r = 0.16, p = 0.03). In addition, concentrations of galectin-3, hs-CRP, fasting glucose, uric acid and family history of CAD were determined as independent predictors of the CSX. CONCLUSION: It was found that galectin-3 serum concentrations are higher in patients with CSX compared to healthy controls. Further studies on larger population are needed to confirm the relation between the fibrosis and the CSX, as well as to explore the potential role of galectin-3 in the CSX. PMID- 25282686 TI - Double jeopardy: multi-modality imaging of monozygotic "twin cap" atherosclerosis. AB - The investigation of asymptomatic but potentially vulnerable atherosclerosis is not yet a major focus for clinical Cardiologists. We have illustrated the contemporary investigation and treatment of such disease using a clinical case that involved monozygotic twins. One twin (T1) had unfortunately suffered a cardiac arrest whilst jogging and survived only due to bystander CPR and prompt defibrillation. His identical twin brother (T2), on subsequent investigation, harbours a compositionally identical lesion in a proximal coronary vessel that has not yet ruptured or provoked a clinical event. Following the presentation of both non-invasive and invasive images, we discuss the need for active suspicion and intensive treatment for those people with a 'genetic' risk of future myocardial infarction. PMID- 25282687 TI - Lack of association between serum gamma-glutamyltransferase and carotid atherosclerosis: the Namwon Study. AB - OBJECTIVES: There is little evidence for an association between gamma glutamyltransferase (GGT) and carotid atherosclerosis, an independent predictor of cardiovascular disease. We examined the association between serum GGT and carotid atherosclerotic parameters, including carotid intima-media thickness (IMT) and plaques, in a large general population. METHODS: The study population consisted of community-dwelling adults who participated in the baseline survey of the Namwon Study. A total of 9120 subjects aged 45-74 years were included in the analyses. High-resolution B-mode ultrasound was used to measure carotid IMT and to evaluate the presence of carotid plaques. A mean carotid IMT of >=1.0 mm was classified as 'high carotid IMT'. RESULTS: Serum GGT levels were classified into quartiles. In a fully adjusted model, we found no linear trend between GGT quartile and mean carotid IMT (P for trend = 0.167). Compared with the first quartile (the reference category), the odds ratios (ORs) and 95% confidence intervals (CIs) for high carotid IMT were 0.89 (0.68-1.16), 1.10 (0.84-1.43), and 0.97 (0.71-1.33) for the second, third, and fourth quartiles (P for trend = 0.754), respectively. The ORs (95% CIs) for carotid plaques were 0.89 (0.77 1.02), 0.95 (0.82-1.10), and 0.94 (0.79-1.11) for the second, third, and fourth quartiles, respectively, in the fully adjusted model (P for trend = 0.644). CONCLUSIONS: No significant association of GGT concentration with carotid IMT or plaques was found in this large cross-sectional study. Further longitudinal studies are needed to confirm our findings. PMID- 25282689 TI - Single-descriptor based quantum-chemical QSPRs for physico-chemical properties of polychlorinated-dibenzo-p-dioxins and -dibenzo-furans (PCDD/Fs): exploring the role of electron-correlation. AB - In this work, we propose and analyze single-descriptor based quantitative structure-property relationships (QSPRs) developed using quantum-chemical descriptors and their electron-correlation contribution, for various physico chemical properties, namely, aqueous solubility, subcooled liquid vapour pressure, n-octanol/water and n-octanol/air partition coefficients of polychlorinated-dibenzo-p-dioxins (PCDDs) and -dibenzo-furans (PCDFs). The predictivity of the developed QSPRs is examined through external validation procedures employing an external prediction set of chemicals not used in the QSPR model development. From the comparison of different models, it is observed that the total energy and the mean polarizability of a molecule are highly significant in determining the predictivity of a QSPR, whereas dipole moment is found to be a poor descriptor in the models developed for all the properties analyzed. Besides these, the electron density based descriptors, namely, absolute electronegativity and electrophilicity index, were also observed to be highly influential in determining the external prediction for partition coefficients. PMID- 25282688 TI - Sender-receiver systems and applying information theory for quantitative synthetic biology. AB - Sender-receiver (S-R) systems abound in biology, with communication systems sending information in various forms. Information theory provides a quantitative basis for analysing these processes and is being applied to study natural genetic, enzymatic and neural networks. Recent advances in synthetic biology are providing us with a wealth of artificial S-R systems, giving us quantitative control over networks with a finite number of well-characterised components. Combining the two approaches can help to predict how to maximise signalling robustness, and will allow us to make increasingly complex biological computers. Ultimately, pushing the boundaries of synthetic biology will require moving beyond engineering the flow of information and towards building more sophisticated circuits that interpret biological meaning. PMID- 25282690 TI - Cerebral venous thrombosis-a primer for the haematologist. AB - Cerebral venous thrombosis (CVT) is a condition that can affect all age groups and can often be difficult to diagnose and treat. The difficulties in diagnosis are mainly due to the non-specific presenting features of CVT, which can range from isolated headache and visual or auditory problems, to serious symptoms such as hemiparesis and coma. Therefore, it can present to various specialists including general physicians, obstetricians and neurologists. In recent years, more widespread use of cerebral imaging has led to the diagnosis being made more often. Since thrombosis is the key component, haematologists are consulted in the management of these patients including for identification of a causative factor for CVT. In this regard, the pivotal International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) has shed more light on its epidemiology and management options. This review aims to provide guidance to haematologists when faced with a patient with CVT, based on the currently available evidence. PMID- 25282692 TI - Adjunctive technique for the use of ProGlide vascular closure device to improve hemostasis. AB - The Perclose ProGlide (Abbott Vascular, Santa Clara, Calif) is indicated for the closure of 5F to 21 F femoral artery access sites. We describe an adjunctive technique for the use of the ProGlide vascular closure device to improve hemostasis. After routine use of the device, a hollow tube (cut from the injection port of an introducer sheath) is placed over the free tails of suture. These tubes are secured in place by a hemostat that grasps the free suture tails, creating a Rummel-style tourniquet that compresses the arteriotomy, improving hemostasis. The tubes doubly serve as a conduit for the administration of prothrombotic agents directly in the event that hemostasis is not adequately achieved. PMID- 25282691 TI - Popliteal artery aneurysms differ from abdominal aortic aneurysms in cellular topography and inflammatory markers. AB - OBJECTIVE: Popliteal artery aneurysms (PAAs) and abdominal aortic aneurysms (AAAs) frequently coincide; however, symptoms differ. We systematically assessed aneurysm cellular wall composition and inflammatory markers to compare both anatomic locations. METHODS: Aneurysmal walls of 38 PAAs and 198 AAAs were harvested from patients undergoing elective open surgical repair. Elastin, collagen, smooth muscle cells, iron, and inflammatory cells were quantified by immunohistochemistry. In addition, protease and cytokine levels were measured. RESULTS: Aneurysmal degradation resulted in similarly degraded media. The location of inflammation differed: the focus for T and B lymphocytes and plasma cells was the intima in PAAs (all P < .001) and the adventitia for AAAs (all P < .001). Iron was more often observed in PAAs than in AAAs (68% vs 1%; P < .001), indicating more previous intramural hemorrhages. Matrix metalloproteinase 2 activity was higher in PAAs than in AAAs (median [interquartile range], 0.363 [0.174-0.556] vs 0.187 [0.100-0.391]; P = .008), whereas matrix metalloproteinase 9 showed no difference. Walls of AAAs were richer in tested cytokine levels than were walls of PAAs. CONCLUSIONS: PAAs showed more signs of previous intramural hemorrhages compared with AAAs. In addition, inflammation in PAAs is mainly located in the intima, whereas its focus in AAAs is the adventitia. These results suggest important differences in the pathophysiologic mechanism of aneurysm formation between these locations and might explain the differences in presentation on diagnosis. PMID- 25282693 TI - Of strategies and chances. PMID- 25282694 TI - Discussion. PMID- 25282695 TI - An early validation of the Society for Vascular Surgery lower extremity threatened limb classification system. AB - OBJECTIVE: The Society for Vascular Surgery (SVS) recently established the Lower Extremity Threatened Limb Classification System, a staging system using Wound characteristic, Ischemia, and foot Infection (WIfI) to stratify the risk for limb amputation at 1 year. Although intuitive in nature, this new system has not been validated. The purpose of the following study was to determine whether the WIfI system is predictive of limb amputation and wound healing. METHODS: Between 2007 and 2010, we prospectively obtained data related to wound characteristics, extent of infection, and degree of postrevascularization ischemia in 139 patients with foot wounds who presented for lower extremity revascularization (158 revascularization procedures). After adapting those data to the WIfI classifications, we analyzed the influence of wound characteristics, extent of infection, and degree of ischemia on time to wound healing; empirical Kaplan Meier survival curves were compared with theoretical outcomes predicted by WIfI expert consensus opinion. RESULTS: Of the 158 foot wounds, 125 (79%) healed. The median time to wound healing was 2.7 months (range, 1-18 months). Factors associated with wound healing included presence of diabetes mellitus (P = .013), wound location (P = .049), wound size (P = .007), wound depth (P = .004), and degree of ischemia (P < .001). The WIfI clinical stage was predictive of 1-year limb amputation (stage 1, 3%; stage 2, 10%; stage 3, 23%; stage 4, 40%) and wound nonhealing (stage 1, 8%; stage 2, 10%; stage 3, 23%; stage 4, 40%) and correlated with the theoretical outcome estimated by the SVS expert panel. CONCLUSIONS: The theoretical framework for risk stratification among patients with critical limb ischemia provided by the SVS expert panel appears valid. Further validation of the WIfI classification system with multicenter data is justified. PMID- 25282696 TI - Smoking cessation is associated with decreased mortality and improved amputation free survival among patients with symptomatic peripheral artery disease. AB - OBJECTIVE: Although smoking cessation is recommended for all patients with peripheral artery disease, there are little data regarding the prevalence of smoking among patients at the time of angiography or the effect of smoking cessation on clinical outcomes. METHODS: Consecutive patients with claudication or critical limb ischemia who underwent peripheral angiography from 2006 to 2013 were included in an observational cohort analysis. Smoking status was assessed at the time of angiography and during follow-up clinic visits. Kaplan-Meier analysis was used to assess the relationship between smoking cessation, mortality, and amputation-free survival. RESULTS: Among 739 patients (423 men and 316 women; mean age, 60 +/- 12 years), 204 (28%) remained active smokers at the time of lower extremity angiography. At the time of angiography, the mean number of cigarettes smoked per day was 16 +/- 10, and the mean pack-years was 40 +/- 25. During the course of the subsequent year, 61 patients (30%) successfully quit smoking and maintained continued abstinence. Baseline medication use between groups did not differ significantly. The mean ankle-brachial index was also similar for quitters vs nonquitters (0.53 +/- 24 vs 0.49 +/- 0.22; P = .3). During follow-up to 5 years, patients who quit smoking had significantly lower all-cause mortality (14% vs 31%; hazard ratio, 0.40; 95% confidence interval, 0.18-0.90) and improved amputation-free survival (81% vs 60%; hazard ratio, 0.43, 95% confidence interval, 0.22-0.86) compared with patients who continued smoking, with most of the difference driven by reduced mortality among patients who quit smoking. The findings remained significant on multivariable analysis. CONCLUSIONS: Approximately one-third of active smokers with peripheral artery disease successfully quit smoking <= 1 year after lower extremity angiography. Patients who quit smoking have lower mortality and improved amputation-free survival compared with patients who continue smoking. PMID- 25282697 TI - Ruptured splenic artery aneurysms are exceedingly rare in pregnant women. AB - OBJECTIVE: Pregnancy is cited as the most important risk factor for splenic artery aneurysm (SAA) rupture, but the true rupture rate of SAAs during pregnancy is unknown. Our objective was to evaluate the prevalence of SAAs, based on diagnostic and procedural codes, in an urban population treated in a county hospital with the highest number of births in the United States. We hypothesized that SAA rupture in pregnant women is very low and that SAAs are more likely to be diagnosed in older patients. METHODS: Patients diagnosed with a SAA during a recent 5-year period were identified using International Classification of Diseases-Ninth Edition, Clinical Modification, and Current Procedural Terminology (American Medical Association, Chicago, Ill) codes. Demographics, imaging, and risk factors for rupture were reviewed. RESULTS: We identified 35 patients with SAA. Patients were a median age of 63 years (interquartile range [IQR], 54-74 years), and 28 (80%) were women who were a median age of 62 years (IQR, 54-74 years). The SAAs in the 35 patients were a median size of 1.3 cm (IQR, 1-1.9 cm), and eight (23%) were >2 cm. Despite the very large number of deliveries recorded during the study period (67,616 births), no women who were pregnant or aged <45 years were identified. However, 89% of women with an SAA had previous pregnancies. Two women and one man (8.6%) experienced rupture, resulting in one death (2.9%). More than one imaging study was available for 19 patients (60%) without intervention for a median of 32 months (IQR, 7-76 months), with no significant change noted. Three patients underwent elective repair due to size criteria. Six patients (17%) had concurrent aneurysms, including three renal artery aneurysms, one aortic aneurysm, and three intracranial aneurysms. No risk factor for enlargement or rupture was particularly prevalent. CONCLUSIONS: Ruptured SAAs are exceedingly rare in young women, and no ruptured SAA were identified during pregnancy in this study. SAA are frequently diagnosed as an incidental finding in middle-aged adults and tend to remain stable over time in this population. PMID- 25282698 TI - Clinical application and early outcomes of the aortouni-iliac configuration for endovascular aneurysm repair. AB - OBJECTIVE: The objective of this study was to review the current anatomic indications for and early results of aortouni-iliac (AUI) devices for endovascular aneurysm repair. METHODS: A total of 128 patients receiving an Endurant (Medtronic Inc, Minneapolis, Minn) AUI device in the U.S. Investigational Device Exemption trial (44 patients) or the Endurant Stent Graft Natural Selection Global Postmarket Registry (84 patients) were reviewed. Preoperative computed tomography imaging of patients in the Investigational Device Exemption trial and case report forms of Registry patients were used to determine anatomic indications. Baseline characteristics and early results were compared with those of 1305 patients receiving a bifurcated (BIF) device in sister studies. RESULTS: The indication for the AUI device was unclear from case report forms in two Registry cases. The remaining 126 patients had a unilateral iliac occlusion in 30 (23%), a severely narrowed aortic segment in 58 (45%), severe iliac occlusive disease in 28 (22%), severe iliac tortuosity in 29 (23%), or complex iliac aneurysms in 19 (15%). Two patients had a previous aortobifemoral graft; 38 patients (30%) had multiple indications. The AUI cohort included more women than the BIF group did (19% vs 10%; P < .01) and had more severe comorbidities. Successful deployment was achieved in all AUI cases. The 30 day mortality was 2% (BIF cohort, 1%; P = .21). More AUI patients underwent repair under general anesthesia (81% vs 64%; P < .01), and procedures were longer (110.9 +/- 54.9 minutes vs 99.2 +/- 44.3 minutes; P = .02). Except for longer intensive care unit stays (19.6 +/- 80.0 hours vs 9.0 +/- 34.8 hours; P = .01) and higher myocardial infarction rates (4% vs 1%; P < .01), outcomes of the AUI cohort were similar to those of the BIF cohort. There were no migrations, ruptures, fractures, or open conversions at up to 1-year follow-up. CONCLUSIONS: The AUI configuration extends endovascular aneurysm repair feasibility to several hostile anatomic conditions. Despite increased comorbidities in the recipient patient population and associated higher rates of postoperative myocardial infarction and respiratory complications, early outcomes with the new generation of AUI devices are acceptable and comparable to those after treatment with BIF configurations. PMID- 25282699 TI - Outcomes of reoperative open or endovascular interventions to treat patients with failing open mesenteric reconstructions for mesenteric ischemia. AB - OBJECTIVE: Outcomes of reinterventions for failing mesenteric open reconstructions (ORs) have not been described. Mesenteric reoperative ORs (R-ORs) are challenging because of excessive scar and more advanced mesenteric disease. The purpose of this study was to evaluate outcomes of R-ORs and endovascular revascularization (ER) in patients with stenosis or occlusion of mesenteric grafts. METHODS: We reviewed 701 patients treated for chronic mesenteric ischemia (CMI) in two academic centers from 1991 to 2013. Clinical data and outcomes of patients treated for failing ORs with R-ORs or ERs were included in the analysis. A 1:2 case-control matching was used to analyze outcomes of R-ORs compared with patients who underwent their first-time ORs for CMI. End points were early and late mortality, morbidity, patency rates, and freedom from symptom recurrence and reintervention. RESULTS: There were 47 patients (five men, 42 women; mean age, 58 +/- 13 years) with failing ORs who were treated by R-ORs. Clinical presentation was CMI in 38 patients (81%) or acute mesenteric ischemia (AMI) in nine (19%). Reinterventions included R-ORs in 28 patients (19 CMI and nine AMI) and ERs in 19, all for CMI. Early mortality was 22% in patients treated by R-ORs for AMI. There were no early deaths among patients treated for CMI with R-OR or ER. Early morbidity was 78% for R-ORs in patients treated for AMI. Morbidity was significantly higher for R-ORs than for ERs in patients with CMI (63% vs 16%; P < .05). Mean follow-up was 50 +/- 60 months. Patient survival at 5 years was 60% +/ 8% for the entire cohort. Primary and secondary patency at 1 year were 61% +/- 10% and 92% +/- 8% for R-ORs (P = .34) and 77% +/- 10% and 100% for ERs (P = .41). Freedom from symptom recurrence and reinterventions at 1 year was 88% +/- 6% and 87% +/- 7% for R-ORs and 83% +/- 8% and 71% +/- 10% for ERs. Case case control (1:2) matching showed R-OR was associated with similar early mortality and morbidity and also similar freedom from recurrence and reintervention but with lower primary patency rates at 1 year compared with first time ORs (66% +/- 11% and 94% +/- 5%; P < .05). CONCLUSIONS: R-OR or ER interventions for failing mesenteric ORs carry similar mortality, recurrence, and reintervention rates. Early morbidity is lower with ER compared with R-OR. R-ORs are associated with similar morbidity and mortality and lower primary patency compared with first time OR for CMI. PMID- 25282700 TI - Use of three-dimensional contrast-enhanced duplex ultrasound imaging during endovascular aneurysm repair. AB - BACKGROUND: Iodinated contrast during endovascular aneurysm repair (EVAR) is used with caution in patients with chronic kidney disease. Contrast-enhanced ultrasound (CEUS) imaging using nonnephrotoxic sulphur hexafluoride microbubble contrast is a novel imaging modality that accurately identifies and characterizes endoleaks during EVAR follow-up. We report our initial experience of using three dimensional (3D) CEUS imaging intraoperatively as completion imaging after endograft deployment. Our aim was to compare intraoperative 3D CEUS against uniplanar angiography in the detection of endoleak, stent deformity, and renal artery perfusion during EVAR. METHODS: The study enrolled 20 patients undergoing elective conventional infrarenal EVAR, after which a completion angiogram was performed and the presence of endoleak, renal artery perfusion, or device deformity were recorded. With the patient still under anesthetic, a vascular scientist blinded to angiographic findings performed 3D CEUS and reported on the same parameters. RESULTS: Three endoleaks, one type I and two type II, were detected on uniplanar angiography and 13 endoleaks, 11 type II and two type I, were found using 3D CEUS imaging. Of note, one of these type I endoleaks was not seen on angiography, and this patient underwent balloon moulding of the neck with resolution of the endoleak on repeat imaging. Of the 11 type II endoleaks seen with 3D CEUS imaging, the inflow vessel was identified in nine cases. No graft deformity or limb kinking was seen in any patient. Both renal arteries could be visualized in 10 patients, whereas the target renal artery was seen in 11 patients. In the remaining patients, the renal arteries could not be visualized, mainly due to intra-abdominal gas or patient body habitus. CONCLUSIONS: 3D CEUS imaging detected endoleaks not seen on uniplanar digital subtraction angiography, including a clinically important type I endoleak, and was also more sensitive than 2D CEUS imaging for the detection of the source of endoleak. This technology has the potential to supplement or replace digital subtraction angiography for completion imaging to reduce the use of x-ray contrast. Intraoperative 3D CEUS has been applied to allow safe EVAR with ultralow or no iodinated contrast usage in selected cases, without compromising completion imaging. PMID- 25282702 TI - Qualitative improvement of low meat beef burger using Aloe vera. AB - Low meat beef burgers have found their niche in the food markets in developing countries because of their lower price. However, these burgers still lack an acceptable quality. This study investigates the effects of different concentrations of Aloe vera on the quality of this food product. For this purpose, beef burgers were produced with 0%, 1%, 3%, and 5% Aloe vera and the changes in their cooking parameters, lipid oxidation, texture, and appeal to consumers over 7days of refrigerated storage were evaluated. Results indicate that Aloe vera contributed to some extent to decreased cooking loss and diameter reduction in the burgers. Increased concentrations of Aloe vera led to improvements in the water absorption and texture of the burgers as well as their lipid stability. However, a concentration level of 3% led to the most acceptability of the product to the panelists. Finally, it was found that Aloe vera acts as a hydrocolloid and improves the quality of burgers. PMID- 25282701 TI - Preoperative prediction of spinal cord ischemia after thoracic endovascular aortic repair. AB - OBJECTIVE: Spinal cord ischemia (SCI) is a devastating but potentially preventable complication of thoracic endovascular aortic repair (TEVAR). The purpose of this analysis was to determine what factors predict SCI after TEVAR. METHODS: All TEVAR procedures at a single institution were reviewed for patient characteristics, prior aortic repair history, aortic centerline of flow analysis, and procedural characteristics. SCI was defined as any lower extremity neurologic deficit that was not attributable to an intracranial process or peripheral neuropathy. Forty-three patient and procedural variables were evaluated individually for association with SCI. Those with the strongest relationships to SCI (P < .1) were included in a multivariable logistic regression model, and a stepwise variable elimination algorithm was bootstrapped to derive a best subset of predictors from this model. RESULTS: From 2002 to 2013, 741 patients underwent TEVAR for various indications, and 68 (9.2%) developed SCI (permanent: n = 38; 5.1%). Because of the lack of adequate imaging for centerline analysis, 586 patients (any SCI, n = 43; 7.4%) were subsequently analyzed. Patients experiencing SCI after TEVAR were older (SCI, 72 +/- 11 years; no SCI, 65 +/- 15 years; P < .0001) and had significantly higher rates of multiple cardiovascular risk factors. The stepwise selection procedure identified five variables as the most important predictors of SCI: age (odds ratio [OR] multiplies by 1.3 per 10 years; 95% confidence interval [CI], 0.9-1.8, P = .06), aortic coverage length (OR multiplies by 1.3 per 5 cm; CI, 1.1-1.6; P = .002), chronic obstructive pulmonary disease (OR, 1.9; CI, 0.9-4.1; P = .1), chronic renal insufficiency (creatinine concentration >= 1.6 mg/dL; OR, 1.9; CI, 0.8-4.2; P = .1), and hypertension (defined as chart history or medication; OR, 6.4; CI, 2.6-18; P < .0001). A logistic regression model with just these five covariates had excellent discrimination (area under the receiver operating characteristic curve = .83) and calibration (chi(2) = 9.8; P = .28). CONCLUSIONS: This analysis generated a simple model that reliably predicts SCI after TEVAR. This clinical tool can assist decision-making about when to proceed with TEVAR, guide discussions about intervention risk, and help determine when maneuvers to mitigate SCI risk should be implemented. PMID- 25282703 TI - Classification of fresh and frozen-thawed pork muscles using visible and near infrared hyperspectral imaging and textural analysis. AB - The potential of visible and near infrared hyperspectral imaging was investigated as a rapid and nondestructive technique for classifying fresh and frozen-thawed meats by integrating critical spectral and image features extracted from hyperspectral images in the region of 400-1000 nm. Six feature wavelengths (400, 446, 477, 516, 592 and 686 nm) were identified using uninformative variable elimination and successive projections algorithm. Image textural features of the principal component images from hyperspectral images were obtained using histogram statistics (HS), gray level co-occurrence matrix (GLCM) and gray level gradient co-occurrence matrix (GLGCM). By these spectral and textural features, probabilistic neural network (PNN) models for classification of fresh and frozen thawed pork meats were established. Compared with the models using the optimum wavelengths only, optimum wavelengths with HS image features, and optimum wavelengths with GLCM image features, the model integrating optimum wavelengths with GLGCM gave the highest classification rate of 93.14% and 90.91% for calibration and validation sets, respectively. Results indicated that the classification accuracy can be improved by combining spectral features with textural features and the fusion of critical spectral and textural features had better potential than single spectral extraction in classifying fresh and frozen thawed pork meat. PMID- 25282704 TI - Long-term follow-up of TaG1 non-muscle-invasive bladder cancer. AB - OBJECTIVES: To retrospectively assess the long-term outcome of patients initially diagnosed with TaG1 non-muscle-invasive bladder cancer (NMIBC) with no immediate postoperative instillation of intravesical chemotherapy and evaluate the reproducibility of the European Organization for Research and Treatment of Cancer (EORTC) scoring system for predicting bladder cancer outcome. METHODS AND MATERIALS: A retrospective analysis of 481 consecutive cases of initially diagnosed TaG1 NMIBC according to the 1973 World Health Organization classification between 1995 and 2008 in a single institution was performed. Time to first recurrence, time to progression to T1 or G3 bladder cancer, and time to progression to muscle-invasive bladder cancer were studied. Time to event distributions was estimated by means of cumulative incidence functions to accurately take into account the patients who died (competing risk) before recurrence or progression. The Harrell c statistic calculation was used for our study's data results as well the original data from EORTC to compare the predictive power of a survival model. RESULTS: The median follow-up was 88 months (interquartile range: 51-135 mo). The 10-year recurrence-free, T1 or G3 NMIBC progression-free, and muscle-invasive bladder cancer progression-free survival rates were 64.2%, 96.6%, and 97%, respectively. In multivariate analysis, tumor size and number of lesions were prognostic variables of the risk of recurrence. In our study and EORTC data sets, the Harrell c values obtained were c = 0.85 (95% CI: [0.75, 0.93]) and c = 0.85 (95% CI: [0.75, 0.93]), respectively. CONCLUSION: Our study reports a detailed and extensive outcome of TaG1 NMIBC treated by TURB with no immediate postoperative intravesical instillation of chemotherapy. Our results suggest that the EORTC is a useful external validation scoring system for predicting bladder cancer outcome. PMID- 25282705 TI - A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in a Chinese patient with non-familial nocturnal frontal lobe epilepsy. AB - So far, only two mutations in the CHRNA4 gene (in three studies) and one mutation in the CHRNB2 gene had been identified in the patients with sporadic nocturnal frontal lobe epilepsy (NFLE). The absence of mutations in the candidate genes in the majority of sporadic NFLE patients suggest that they are rare loci for the disease, but the necessity of performing genetic testing for sporadic cases should not be neglected. We designed mutation screening of exon 5 of CHRNA4, exon 5 of CHRNB2, and exon 6 of CHRNA2 in a group of 56 Chinese sporadic NFLE cases. A de novo missense mutation in the transmembrane domain M2 segment of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor, c.823A>T, was found in a 15 year-old right-handed male, but was not observed in his parents and 400 control chromosomes. The mutation decreased the surrounding hydrophobicity and slightly altered secondary structure of the protein. No mutations were found in CHRNB2 and CHRNA2. PMID- 25282706 TI - Validation of a multigenic model to predict seizure control in newly treated epilepsy. AB - A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly diagnosed epilepsy cohort using a k-nearest neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n=281; SANAD, n=491). A "leave-one-out" cross-validation was also employed, with training sets derived internally from the UK datasets. The multigenic classifier using the Australian cohort as the training set was unable to predict treatment response in either UK cohort. In the "leave-one-out" analysis, the five SNPs collectively predicted treatment response in both Glasgow and SANAD patients prescribed either carbamazepine or valproate (Glasgow OR=3.1, 95% CI=1.4-6.6, p=0.018; SANAD OR=2.8, 95% CI=1.3-6.1, p=0.048), but not those receiving lamotrigine (Glasgow OR=1.3, 95% CI=0.6-2.8, p=1.0; SANAD OR=2.2, 95% CI=0.9-5.4, p=0.36) or other AEDs (Glasgow OR=0.6, 95% CI=0.2-2.0, p=1.0; SANAD OR=1.9, 95% CI=0.9-4.2, p=0.36). The Australian-based multigenic kNN model is not predictive of initial treatment response in UK cohorts of newly-diagnosed epilepsy. However, the five SNPs identified in the original Australian study appear to collectively have a predictive influence in UK patients prescribed either carbamazepine or valproate. PMID- 25282707 TI - Recurring patterns of atrial fibrillation in surface ECG predict restoration of sinus rhythm by catheter ablation. AB - BACKGROUND: Non-invasive tools to help identify patients likely to benefit from catheter ablation (CA) of atrial fibrillation (AF) would facilitate personalised treatment planning. AIM: To investigate atrial waveform organisation through recurrence plot indices (RPI) and their ability to predict CA outcome. METHODS: One minute 12-lead ECG was recorded before CA from 62 patients with AF (32 paroxysmal AF; 45 men; age 57+/-10 years). Organisation of atrial waveforms from i) TQ intervals in V1 and ii) QRST suppressed continuous AF waveforms (CAFW), were quantified using RPI: percentage recurrence (PR), percentage determinism (PD), entropy of recurrence (ER). Ability to predict acute (terminating vs. non terminating AF), 3-month and 6-month postoperative outcome (AF vs. AF free) were assessed. RESULTS: RPI either by TQ or CAFW analysis did not change significantly with acute outcome. Patients arrhythmia-free at 6-month follow-up had higher organisation in TQ intervals by PD (p<0.05) and ER (p<0.005) and both were significant predictors of 6-month outcome (PD (AUC=0.67, p<0.05) and ER (AUC=0.72, p<0.005)). For paroxysmal AF cases, all RPI predicted 3-month (AUC(ER)=0.78, p<0.05; AUC(PD)=0.79, p<0.05; AUC(PR)=0.80, p<0.01) and 6-month (AUC(ER)=0.81, p<0.005; AUC(PD)=0.75, p<0.05; AUC(PR)=0.71, p<0.05) outcome. CAFW derived RPIs did not predict acute or postoperative outcomes. Higher values of any RPI from TQ (values greater than 25th percentile of preoperative distribution) were associated with decreased risk of AF relapse at follow-up (hazard ratio <=0.52, all p<0.05). CONCLUSIONS: Recurring patterns from preprocedural 1-minute recordings of ECG TQ intervals were significant predictors of CA 6-month outcome. PMID- 25282708 TI - Gene expression microarray classification using PCA-BEL. AB - In this paper, a novel hybrid method is proposed based on Principal Component Analysis (PCA) and Brain Emotional Learning (BEL) network for the classification tasks of gene-expression microarray data. BEL network is a computational neural model of the emotional brain which simulates its neuropsychological features. The distinctive feature of BEL is its low computational complexity which makes it suitable for high dimensional feature vector classification. Thus BEL can be adopted in pattern recognition in order to overcome the curse of dimensionality problem. In the experimental studies, the proposed model is utilized for the classification problems of the small round blue cell tumors (SRBCTs), high grade gliomas (HGG), lung, colon and breast cancer datasets. According to the results based on 5-fold cross validation, the PCA-BEL provides an average accuracy of 100%, 96%, 98.32%, 87.40% and 88% in these datasets respectively. Therefore, they can be effectively used in gene-expression microarray classification tasks. PMID- 25282709 TI - Simultaneous whole-body 18F-FDG PET-MRI in primary staging of breast cancer: a pilot study. AB - PURPOSE: Accurate initial staging in breast carcinoma is important for treatment planning and for establishing the likely prognosis. The purpose of this study was to assess the utility of whole body simultaneous (18)F-FDG PET-MRI in initial staging of breast carcinoma. METHODS: 36 patients with histologically confirmed invasive ductal carcinoma underwent simultaneous whole body (18)F-FDG PET-MRI on integrated 3T PET-MR scanner (Siemens Biograph mMR) for primary staging. Primary lesion, nodes and metastases were evaluated on PET, MRI and PET-MRI for lesion count and diagnostic confidence (DC). Kappa co relation analysis was done to assess agreement between the satellite, nodal and metastatic lesions detected by PET and MRI. Histopathology, clinical/imaging follow-up served as the reference standard. RESULTS: 36 patients with 37 histopathologically proven index breast cancer were retrospectively studied. Of 36 patients, 25 patients underwent surgery and 11 patients received systemic therapy. All index cancers were seen on PET and MR. Fused PET-MRI showed highest diagnostic confidence score of 5 as compared to PET (median 4; range 3-5) and MRI (median 4; range 4-5) alone. 2/36 (5.5%) patients were detected to have unsuspected contralateral synchronous cancer. 47 satellite lesions were detected on DCE MRI of which 23 were FDG avid with multifocality and multicentricity in 21 (58%) patients. Kappa co relation analysis revealed fair agreement for satellite lesion detection by the two modalities (kappa=0.303; P=0.003). The study showed a sensitivity of 60% and 93.3% on PET and MRI respectively for detection of axillary lymph nodes with a specificity of 91% for both and a false negative rate of 6.7% on MRI and 40% on PET. Kappa co relation analysis between PET and MRI for all the lymph nodes detected revealed fair agreement by the two modalities (kappa=0.337; P=0.000). Combined PET-MRI increased diagnostic confidence for nodal involvement (median DC 5, range 4-5; P<0.05). Distant metastases were found in 8/36 (22%) patients at the time of diagnosis with a total of 91 metastatic lesions on PET (DC>=4) and 105 on MRI (DC>=4), the difference being statistically significant (P=0.001) while Kappa co relation analysis showed significant agreement between the two modalities (kappa=0.667; P=0.000). Overall PET-MRI led to a change in management in 12 (33.3%) patients. CONCLUSION: In this pilot study, simultaneous (18)F-FDG PET-MR, has been found to be useful in whole-body initial staging of breast cancer patients. PMID- 25282710 TI - Chronic obstructive pulmonary disease exacerbation by corynebacterium propinquum. PMID- 25282711 TI - Intraparenchymal pulmonary lipoma clinically mimicking malignant neoplasm. PMID- 25282712 TI - Obstructive sleep apnea refractory to treatment due to floppy epiglottis. PMID- 25282713 TI - Morbidity and mortality in octogenarians with lung cancer undergoing pneumonectomy. AB - OBJECTIVE: Evaluate the restrictiveness of selection criteria for lung resection in lung cancer patients over 80 years of age compared to those applied in younger patients. Compare and analyze 30-day mortality and postoperative complications in both groups of patients. METHODS: Case-controlled retrospective analysis. STUDY POPULATION: Consecutive patients undergoing elective anatomical lung resection. Population was divided into octogenarians (cases) and younger patients (controls). Variables determining surgical risk (BMI, FEV1%, postoperative FEV1%, FEV1/FVC, DLCO and pneumonectomy rate) were compared using either Wilcoxon or Chi squared tests. Thirty-day mortality and morbidity odds ratio were calculated. A logistic regression model with bootstrap resampling was constructed, including postoperative complications as dependent variable and age and post-operative FEV1% as independent variables. Data were retrieved from a prospective database. RESULTS: No statistically significant differences were found in BMI (P=.40), FEV1% (P=.41), postoperative FEV1% (P=.23), FEV1/FVC (P=.23), DLCO (P=.76) and pneumonectomy rate (P=.90). Case mortality was 1.85% and control mortality was 1.26% (OR: 1.48). Cardiorespiratory complications occurred in 12.80% of younger subjects and in 13.21% of patients aged 80 years or older. (OR: 1.03). In the logistic regression, only FEV1% was related to postoperative complications (P<.005). CONCLUSION: Selection criteria for octogenarians are similar to those applied in the rest of the population. Advanced age is not a factor for increased 30-day mortality or postoperative morbidity. PMID- 25282714 TI - Theoretical investigation on remote-control photocycloreversion of dithienylethene driven by azobenzene chromophores. AB - When adding two azobenzene chromophores on a dithienylethene molecule, the irradiation at 450 nm can effectively arouse the cycloreversion reaction of the ring-closed dithienylethene. We investigated the frontier molecular orbitals and absorption properties of such series of molecules and inferred the mechanism of the ring-opening reaction. The 450 nm light sensed by the side azobenzene groups can excite the whole molecule to a high excited state, and through electronic transition and energy transfer the active electron may centre on the dithienylethene ring part, then the ring-opening happens. While for the ring-open form, the energy of the 450 nm light is not high enough to promote the electron to the exact molecular orbital occupying the central dithienylethene ring, so it cannot cause the ring-closing reaction. PMID- 25282715 TI - Effects of ultra violet radiation on the soluble proteins of human hair. AB - Exposure of hair fibers from healthy volunteers to Ultra Violet Radiation (UVR) under laboratory conditions enhanced protein elution from the hair tresses into a buffer solution (pH 10.5). At the same time the UVR decreased the intensity of tryptophan fluorescence in the eluted proteins. After mechanical homogenization of these hair samples, the increase of soluble protein was registered for UVR treated hair as well as the rise in sulfhydryl group content of these proteins. Analysis of soluble proteins from hair samples homogenized before and after protein elution has shown that mainly proteins rich in sulfhydryl groups were eluted and as a result sulfhydryl content of proteins in hair shaft decreased. The hypothesis concerning the effects of environmental factors on the properties of hair shaft proteins was examined, the proximal and distal parts of normal hair (0-5 cm and 15-20 cm from hair root) were compared. In the distal parts there was a higher quantity of soluble proteins registered after homogenization, with decreased sulfhydryl group content and tryptophan fluorescence. It could be supposed that this difference results from the steady rupture of cystine in sulfur bridges and tryptophan under exposure to environmental factors (mainly, UVR), followed by elution of the resulting peptides. PMID- 25282716 TI - Facing the challenges of ventricular hypertrophy: the eyes don't lie. AB - We describe the case of a 47-year-old man with new-onset heart failure who was found to have severe biventricular wall thickening. We present comprehensive data from invasive and non-invasive multimodality imaging, genetic and histologic tests, and briefly describe their importance in the final diagnosis. To our knowledge, this is the first case of the Portuguese variant of familial amyloid polyneuropathy presenting with heart failure in the fifth decade of life. This is an unusual case report, but also an illustration of how to approach any patient with suspected infiltrative cardiomyopathy. PMID- 25282717 TI - Trapeziometacarpal dislocation without fracture. PMID- 25282718 TI - Flexor tendon-to-volar plate repair: an experimental study and 3 case reports. AB - PURPOSE: To investigate the histology and tensile strength of flexor tendon-to volar plate repair in a sheep model and to evaluate outcomes in 3 clinical cases. METHODS: The flexor digitorum profundus (FDP) tendon of the hind limb of the sheep was cut at the ankle. The proximal end of the FDP tendon was then repaired to a distally based flap of the underlying volar plate after 2 cm of the distal FDP tendon were excised such that the distal FDP tendon was not directly in contact with the repair site. The repair was studied histologically and tested biomechanically at 8 intervals (0, 1, 2, 3, 4, 5, 6, 8, and 12 wk) following repair. Three clinical cases with flexor tendon-to-volar plate repair are presented. In all cases, the circumstances of the injury precluded the usual tendon-to-tendon repair. The first patient had a laceration of FDP in zone 1A and the other 2 patients had delayed 2-stage flexor tendon reconstruction. RESULTS: The mean breaking strength of the tendon-to-volar plate repair was 26 N at 0 week, 62 N at 1 week, 52 N at 2 weeks, and then progressively increased to reach 312 N at 12 weeks. Histologically, thin randomly arranged collagen fibers were seen at the repair site at 3 weeks; and healing with thick parallel collagen bundles were seen at 6 weeks. Clinically, the flexor tendon-to-volar plate repairs healed without rupture. All patients obtained full active range of motion at the metacarpophalangeal and proximal interphalangeal joints. The active range of motion at the distal interphalangeal joint was 0 degrees to 50 degrees in 2 patients and 0 degrees to 40 degrees in the third patient. CONCLUSIONS: The flexor tendon can heal to the volar plate in the sheep model. CLINICAL RELEVANCE: Suture of tendon to volar plate is an option in distal zone 1 FDP repair and FDP tendon reconstruction. PMID- 25282719 TI - Release of the A4 pulley to facilitate zone II flexor tendon repair. AB - During primary or delayed primary repair of the flexor digitorum profundus tendon, surgeons often face difficulty in passing the retracted tendon or repaired tendon under the dense, fibrous A4 pulley. The A4 pulley is the narrowest part of the flexor sheath, proximal to the terminal tendon. Disrupted tendon ends (or surgically repaired tendons) are usually swelling, making passage of the tendons under this pulley difficult or even impossible. During tendon repair in the A4 pulley area, when the trauma is in the middle part of the middle phalanx and the A3 pulley is intact, the A4 pulley can be vented entirely to accommodate surgical repair and facilitate gliding of the repaired tendon after surgery. Venting the pulley does not disturb tendon function when the other major pulleys are intact and when the venting of the A4 pulley and adjacent sheath is limited to the middle half of the middle phalanx. Such venting is easily achieved through a palmar midline or lateral incision of the A4 pulley and its adjacent distal or/and proximal sheath, which helps ensure a more predictable recovery of digital flexion and extension. PMID- 25282720 TI - Coronal shift of distal radius fractures: influence of the distal interosseous membrane on distal radioulnar joint instability. PMID- 25282721 TI - Persistent fracture line after scaphoid fracture fixation. PMID- 25282722 TI - Author's reply: To PMID 24434412. PMID- 25282723 TI - Authors reply. PMID- 25282724 TI - Organ donation and transplantation in the Kingdom of Saudi Arabia 2013. PMID- 25282725 TI - [What is the role of the nutrition care with regard to malnutrition in the elderly?-editorial]. PMID- 25282726 TI - [Celiac disease in patients with type 1 diabetes mellitus- editorial]. PMID- 25282727 TI - [Diagnosis written in cuneiform script - editorial]. PMID- 25282728 TI - [Diabetes mellitus in women -editorial]. PMID- 25282729 TI - [Manual instruments for ledge polishing by tooth preparation for crown]. PMID- 25282730 TI - [Anesthesia and sedation by admixture of xenon-oxygen in dentistry. Part II]. PMID- 25282731 TI - [On the history of Evdokimov Moscow State Medical and Dental University]. PMID- 25282732 TI - [Hepatocellular carcinoma associated with continuous and discontinuous application of nucleoside analogues in the treatment of chronic hepatitis B]. PMID- 25282733 TI - [Viral relapse and genetic resistance after a nearly 8-year cessation of lamivudine therapy in a patient with chronic hepatitis B: a case report]. PMID- 25282734 TI - [Diffuse hepatic scrotiform cavernous hemangioma with Kasabach-Merritt syndrome: a case report]. PMID- 25282735 TI - [Report of the Fifth Symposium on the Hotspots and Challenges in Research of Antiviral Therapy for Chronic Hepatitis B and Chronic Hepatitis C]. PMID- 25282736 TI - [Advances in therapeutic regulation of long non-coding RNA for treating hepatocellular carcinoma]. PMID- 25282737 TI - [Roles of microRNAs in non-alcoholic fatty liver disease]. PMID- 25282738 TI - [Recent advances in the research of IgG4-associated autoimmune hepatitis]. PMID- 25282739 TI - [Recent progress in understanding the role of the inflammasome in the pathogenesis of liver disease]. PMID- 25282740 TI - [Risk of infection by Foot and Ankle Surgery - increased healing risk for diabetics?]. PMID- 25282741 TI - [Pelvic ring fractures - subcutaneous internal anterior fixation vs. external fixation?]. PMID- 25282742 TI - [Lumbar Spinal Stenosis - decompression with vs. without instrumented fusion]. PMID- 25282743 TI - [Helmet therapy - a conservative therapy option in discussion]. PMID- 25282744 TI - [A question of competence]. PMID- 25282745 TI - [Phytopharmacy-- traditional empiricism or pharmacological evidence? Part 1: Generalized anxiety and anxiolytics]. PMID- 25282746 TI - [Marburg and Ebola hemorrhagic fevers--pathogens, epidemiology and therapy]. AB - Marburg and Ebola hemorrhagic fevers are severe, systemic viral diseases affecting humans and non-human primates. They are characterized by multiple symptoms such as hemorrhages, fever, headache, muscle and abdominal pain, chills, sore throat, nausea, vomiting and diarrhea. Elevated liver-associated enzyme levels and coagulopathy are also associated with these diseases. Marburg and Ebola hemorrhagic fevers are caused by (Lake victoria) Marburg virus and different species of Ebola viruses, respectively. They are enveloped, single stranded RNA viruses and belong to the family of filoviridae. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, ranging from 25 to 90% or more. Outbreaks of Marburg and Ebola hemorrhagic fever occur in certain regions of equatorial Africa at irregular intervals. Since 2000, the number of outbreaks has increased. In 2014, the biggest outbreak of a filovirus-induced hemorrhagic fever that has been documented so far occurred from March to July 2014 in Guinea, Sierra Leone, Liberia and Nigeria. The outbreak was caused by a new variant of Zaire Ebola Virus, affected more than 2600 people (stated 20 August) and was associated with case-fatality rates of up to 67% (Guinea). Treatment of Marburg and Ebola hemorrhagic fevers is symptomatic and supportive, licensed antiviral agents are currently not available. Recently, BCX4430, a promising synthetic adenosine analogue with high in vitro and in vivo activity against filoviruses and other RNA viruses, has been described. BCX4430 inhibits viral RNA polymerase activity and protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. Nucleic acid-based products, recombinant vaccines and antibodies appear to be less suitable for the treatment of Marburg and Ebola hemorrhagic fevers. PMID- 25282747 TI - [The information flood--a multicomponent mixture. Analytical methods for the extraction of valid information]. AB - Over the centuries some individual scientists have challenged their knowledge, believes and behaviour. The common knowledge developed very fast, but the challenge still remains to ask the question "what do we really know"? And "what is the basis of our decisions and recommendations?" The scattered individual efforts finally advanced to a consolidated methodology--known as "evidence based medicine". This is the first article of a series to get German speaking pharmacists familiar with the basic concepts of evidence based methodology. The series gives some examples how the concept of evidence based medicine can be implemented in pharmaceutical practice. PMID- 25282748 TI - [Which triptan is most effective in acute migraine attack?]. PMID- 25282749 TI - [Healthy eating reduces risk of preterm birth]. PMID- 25282750 TI - [Drug therapy supports reduction of alcohol consumption]. PMID- 25282751 TI - [Pain relief and functional improvement through physical therapy?]. PMID- 25282752 TI - [Fixed-dose combination of proven active ingredients in new inhaler]. PMID- 25282753 TI - [Immunotherapy seems to help in the fight against cancer]. PMID- 25282754 TI - [Can perioperative aspirin prevent heart attacks?]. PMID- 25282755 TI - [Research for a healthier future]. PMID- 25282756 TI - [What vaccinations do seniors require?]. PMID- 25282758 TI - [Multiple and extensive antibiotic resistance in Europe]. PMID- 25282757 TI - [Endogenous bacterial flora - better decolonize?]. PMID- 25282759 TI - [Recommendation for antibiotics according to hierarchical principle]. PMID- 25282760 TI - [Rocky road to new therapeutic options]. PMID- 25282761 TI - [Differences between men and women]. PMID- 25282762 TI - [What is the optimal therapy?]. PMID- 25282763 TI - The need to reinvent. PMID- 25282764 TI - The politics of the plow. PMID- 25282765 TI - Culture clubs. PMID- 25282766 TI - A new direction. PMID- 25282767 TI - Regional relevance. PMID- 25282768 TI - One version of the trilogy. PMID- 25282769 TI - Sticking together. PMID- 25282770 TI - A shift in focus. PMID- 25282771 TI - This is your brain on sports. Measuring concussions in high school athletes in the Twin Cities metropolitan area. AB - Concussions can have a negative impact on students' ability to perform in the classroom as well as on their health and well-being. Therefore, timely treatment is especially important. To better understand the scope of the problem in Minnesota, the Minnesota Department of Health piloted an online sports-related concussion reporting system in 36 public high schools in the Twin Cities metropolitan area. In the 2013-2014 academic year, 730 concussions were reported to our system from certified athletic trainers working with those schools, with one out of every 100 athletes sustaining concussions. From this, we estimated that 2,974 sports-related concussions occurred among high school athletes statewide. This information is useful for evaluating and guiding prevention efforts and for informing clinicians on how to treat concussions. PMID- 25282772 TI - Inspiring innovation in medical education. AB - Traditionally, changes to medical education come from the top down, an approach that potentially misses important contributions from medical students, residents, faculty and staff. In order to provide an avenue for them to bring forward their ideas for educational improvements, the University of Minnesota Medical School sponsored the "What's the Bright Idea?" contest. Through the contest, we sought to foster a culture of innovation and collaboration among faculty, staff and students. The contest included five phases: launch, idea submission, online voting, follow-up and implementation. Seventy-six ideas were submitted, and 902 people participated in the online voting. When asked in a follow-up survey whether the submitter would have developed their idea without the contest, 27% of respondents answered "no" and 18% answered "maybe." Three-fourths stated the contest stimulated networking and collaboration. Four of the recommendations are now being implemented. PMID- 25282773 TI - Cost savings using minimal draping for routine hand procedures. PMID- 25282774 TI - CMV esophagitis as a cause of failure to thrive. PMID- 25282775 TI - Incidence of burning mouth syndrome: a population-based study of Olmsted County, Minnesota. PMID- 25282776 TI - Seventy years of the Vojnosanitetskipregled. PMID- 25282777 TI - Quantitative and qualitative gait assessments in Parkinson's disease patients. AB - BACKGROUND/AIM: Postural impairments and gait disorders in Parkinson's disease (PD) affect limits of stability, impaire postural adjustment, and evoke poor responses to perturbation. In the later stage of the disease, some patients can suffer from episodic features such as freezing of gait (FOG). Objective gait assessment and monitoring progress of the disease can give clinicians and therapist important information about changes in gait pattern and potential gait deviations, in order to prevent concomitant falls. The aim of this study was to propose a method for identification of freezing episodes and gait disturbances in patients with PD. A wireless inertial sensor system can be used to provide follow up of the treatment effects or progress of the disease. METHODS: The system is simple for mounting a subject, comfortable, simple for installing and recording, reliable and provides high-quality sensor data. A total of 12 patients were recorded and tested. Software calculates various gait parameters that could be estimated. User friendly visual tool provides information about changes in gait characteristics, either in a form of spectrogram or by observing spatiotemporal parameters. Based on these parameters, the algorithm performs classification of strides and identification of FOG types. RESULTS: The described stride classification was merged with an algorithm for stride reconstruction resulting in a useful graphical tool that allows clinicians to inspect and analyze subject's movements. CONCLUSION: The described gait assessment system can be used for detection and categorization of gait disturbances by applying rule-based classification based on stride length, stride time, and frequency of the shank segment movements. The method provides an valuable graphical interface which is easy to interpret and provides clinicians and therapists with valuable information regarding the temporal changes in gait. PMID- 25282778 TI - Glycaemic control and prevalence of hypoglycaemic events in children and adolescents with type 1 diabetes mellitus treated with insulin analogues. AB - BACKGROUND/AIM: An ideal insulin regimen for children and adolescents with type 1 diabetes mellitus (T1DM) should be physiological, flexibile and predictable, protecting against hypoglycaemia. The aim of this study was to evaluate the influence of insulin analogues on glycaemic control and the occurance of hypoglycaemic episodes in children and adolescents with T1DM. METHODS: The study group consisted of 151 children and adolescents (90 boys, 61 girls) treated with human insulins for at least 12 months before introducing insulin analogues. All the patients were divided into two groups: the group I consisted of 72 (47.7%) patients treated with three injections of regular human insulin before meals and long-acting analogue (RHI/LA), and the group II of 79 (52.30%) patients treated with a combination of rapid-acting and long-acting analogue (RA/LA). The levels of glycated hemoglobin (HbA1c) and the number of hypoglycaemic episodes were assessed at the beginning of therapy with insulin analogues, and after 6 and 12 months. RESULTS: The mean HbA1c was significantly lower in the group I (RHI/LA) after 6 months (9.15% vs 8.20%, p < 0.001) and after 12 months (9.15% vs 8.13%, p < 0.001) as well as in the group II (RA/LA) after 6 months (9.40% vs 8.240%, p < 0.001) and after 12 months of insulin analogues treatment (9.40% vs 8.38%, p < 0.001). The frequency of severe hypoglycaemia was significantly lower in both groups after 6 months (in the group I from 61.1% to 4.2% and in the group II from 54.4% to 1.3%, p < 0.001), and after 12 months (in the group I from 61.1% to 1.4% and in the group II from 54.4% to 1.3%, p < 0.001). CONCLUSION: Significantly better HbA1c values and lower risk of severe hypoglycaemia were established in children and adolescents with T1DM treated with insulin analogues. PMID- 25282779 TI - Limb apraxia in multiple sclerosis. AB - BACKGROUND/AIM: There are almost no studies on apraxia in people with multiple sclerosis. Although the white matter is damaged in MS, it is not the only location in which the pathological changes are present. Demyelinated lesions in the cortex have recently been recognized as important components of multiple sclerosis pathology. The aim of this study was to determine whether apraxia is present among people with MS, and the importance of demographic characteristics and impairment of functional systems at conceptualization and execution of movements. METHODS: The experimental group consisted of 30 patients, mean age 51.34 +/- 7.70 years. The patients in the experimental group were diagnosed with MS according to the McDonald criteria. The control group consisted of 30 healthy subjects, mean age 50.30 +/- 10.47 years. For research purposes, we used the following instruments: Questionnaire for Collecting Demographic Data, Kurtzke Functional Systems Scores, Waterloo-Sunnybrook Apraxia Battery (WatAB). Execution of motion tasks that are a part of the WatAB were incorporated in the System for the Observation and Analysis of Motor Behavior. RESULTS: Our study showed that limb apraxia was common in people with MS. Apraxia was present during pantomime in 26.70% of the patients, and during the imitation of movements in 44.80% of the patients. Gender, age, education level, duration of disease and a form of MS did not determine the quality of conceptualization and execution of movements. The time elapsed from the last exacerbation was a determinant of quality of executed movements. Impairments of functional systems predicted impairments of movement execution. The expanded disability scale score correlated with the severity of apraxia. CONCLUSION: Our study confirm the presence of apraxia in MS. It is necessary to carry out further studies using functional magnetic resonance imaging, as well as the conduct longitudinal studies to determine the precise structure of motor behavior in people with MS. PMID- 25282780 TI - Histological characteristics and markers of proliferation and differentiation in rat brain with experimental glioma. AB - BACKGROUND/AIM: The cell line C6 is a continuous cell line of rat glioma and, as a transplantable line, is frequently used for induction into in vivo model of primary brain tumor. It is believed that, pursuant to its histological traits and biological behavior, this experimental tumor corresponds to human anaplastic astrocytoma of grade II/III, which is characterized by proliferative and invasive potency, and marked cell differentiation. The aim of this study was to determine macroscopic analysis of rat brain with implanted tumor during tumorigenesis, histological features of tumor cells of induced brain tumor and markers of proliferation (proliferation cell nuclear antigen - PCNA, cytokeratin - CK 19) and differentiation (glial fibrillary acidic protein -GFAP) in rat brain with implanted tumor. METHODS: To determine histological structure of the brain with implanted C6 cells, we used brain sections stained for hematoxylin-eosin or kresyl violet, whereas other sections were immunohistochemically stained for GFAP, CK 19 and PCNA. RESULTS: A statistically significant difference in weights of the left and right brain hemispheres with implanted tumors during tumorigenesis in as soon as 7 days from the day of inducing tumors was revealed. The tumor was of cellular type, with distinct pleomorphism of cells and frequent hyperchromasia of the nucleus. Immunohistochemical staining for PCNA revealed a significant number of positive cells on the days 7, 14 and 21 day following the implantation of C6 cells. CK 19 positive cells were present in both brain hemispheres, and numerous GFAP positive astrocytes were found around the puncture lesion. CONCLUSIONS: Within the experimental conditions of the present research, C6 glioma did not demonstrate any relevant deviations concerning development, clinical symptomatology and macroscopic anatomy relative to those already described in the literature. PMID- 25282781 TI - Correlation of clinical and neurophysiological findings with health-related quality of life in patients with diabetic polyneuropathy. AB - BACKGROUND/AIM: Diabetic polyneuropathy is defined as the presence of clinical or subclinical symptoms and/or signs of peripheral nerve damage in patients with diabetes mellitus in the absence of the other causes of peripheral neuropathy. The aim of this study was to assess health-related quality of life (HRQoL) in patients with diabetic polyneuropathy and its correlation with clinical and neurophysiological findings. METHODS: This study comprised 60 patients with distal, symmetric, sensorimotor diabetic polyneuropathy and type 2 diabetes mellitus. For evaluation of clinical findings the following scales were used: Medical Research Council strenth score (MRC sum score), Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (arm disability and leg disability scales), INCAT sensory sum score, Hamilton depression and anxiety rating scales. Nerve conduction study (NCS) was performed on the motor part of the median and peroneal nerves, the sensory part of the median nerve and sural nerve. All the patients completed the Serbian version of the SF-36 questionnaire as a measure of HRQoL. RESULTS: Our results showed mild to moderate QoL impairment in the patients with diabetic polyneuropathy with no difference in physical and mental composite scores (p > 0.05). The age of the patients, mean MRC sum score, arm disability scale score, leg disability scale score and mean INCAT sensory sum score correlated with scores in the SF-36 questionnaire (p < 0.01). The patients with higher scores of anxiety and depression had significantly worse health perception for all QoL domains, for both composite scores and for the total SF-36 score (p < 0.01). Both motor and sensory NCS parameters of the median nerve showed significant correlations with QoL scores (p < 0.05). CONCLUSION: Our results showed mild to moderate QoL impairment in the patients with diabetic polyneuropathy. HRQoL significantly correlated with the age of the patients, muscle strength, disability, sensory complaints, depressiveness and anxiety of the patients. Electrophysiological examination of median nerve significantly correlated with QoL in the patients with diabetic polyneuropathy. PMID- 25282782 TI - The prevalence of pseudoexfoliation syndrome and possible systemic associations in patients scheduled for cataract surgery at the Military Medical Academy in Belgrade. AB - BACKGROUND/AIM: Pseudoexfoliation syndrome (PEX) is an age-related systemic degenerative disorder characterized by the production and progressive accumulation of extracellular fibrillar eosinophilic material in the anterior segment of the eye. The aim of the study was to evaluate several clinical aspects of PEX, such as frequency of PEX and pseudoexfoliation glaucoma (PEXG), intraocular pressure (IOP), the type of lens opacity, and the possible relationship of PEX and systemic diseases. METHODS: All 674 cataract patients had a comprehensive eye examination, including slitlamp biomicroscopy before and after mydriasis, IOP measurement, and fundus examination. The patients were classified into two groups: the PEX and the non-PEX group. RESULTS: The overall prevalence of PEX syndrome was found to be 17.5% (118 patients). The mean age of PEX patients (79.7 +/- 6.1 years) was significantly higher when compared with those without PEX (73.5 +/- 9.1 years) (p = 0.000). The prevalence of PEX syndrome was found to increase with age, from 7.3% in the 7th decade of life to 27% in patients older than 80 years (p < 0.001). The most common cataract type in the PEX patients was mature cataract observed in 40.7% of patients. The rest of the patients had mixed (30.5%), nuclear (25.4%), cortical (1.7%) and hypermature cataract (1.7%). Among the PEX patients 44 (37.2%) had glaucoma. Intraocular pressure was significantly higher in eyes with pseudoexfoliations than in eyes without it (17.8 +/- 3.2 mmHg and 15.8 +/- 2.8 mmHg, respectively; p = 0.001). Moreover, the prevalence of coronary heart disease was found to be higher in PEX patients. CONCLUSION: PEX syndrome is a common problem among Serbian patients scheduled for cataract surgery. It represents one of the major glaucoma risk factors and probably associated with ischemic heart disease, intraoperative and postoperative problems in cataract surgery. PMID- 25282783 TI - Factors associated with positive outcome of avulsion injuries in children. AB - INTRODUCTION/AIM: Avulsions are severe dental injuries with high impact on patients' quality of life due to prolonged treatment and possible severe complications. The aim of the study was to analyze the epidemiological factors related to the occurrence, treatment and outcome of avulsions in Serbian children. METHODS: This research included 2,194 patients aged 1-18 years with traumatic dental injuries. The history, demographic, clinical and radiographic data of the patients were observed from dental medical records. RESULTS: A total of 266 avulsions were observed in 207 patients. The frequency of avulsions was 12% in primary dentition and 5% in permanent dentition. A statistically significant relationship between place, cause of avulsion and outcome was observed. Replantation of permanent teeth was performed in 46.7% with a mean time 6.9 h. Almost a half of permanently avulsed teeth (48.7%) were not retrieved from the accident site and 11.3% of replanted teeth were transported in adequate media. The observed incidence of complications was 31.9%. CONCLUSION: Replantation was not performed in more than a half of all eligible teeth due to either loss or inadequate/delayed transport, which emphasizes the need for preventive strategies and health education in population. PMID- 25282784 TI - Scoring system development for prediction of extravesical bladder cancer. AB - BACKGROUND/AIM: Staging of bladder cancer is crucial for optimal management of the disease. However, clinical staging is not perfectly accurate. The aim of this study was to derive a simple scoring system in prediction of pathological advanced muscle-invasive bladder cancer (MIBC). METHODS: Logistic regression and bootstrap methods were used to create an integer score for estimating the risk in prediction of pathological advanced MIBC using precystectomy clinicopathological data: demographic, initial transurethral resection (TUR) [grade, stage, multiplicity of tumors, lymphovascular invasion (LVI)], hydronephrosis, abdominal and pelvic CT radiography (size of the tumor, tumor base width), and pathological stage after radical cystectomy (RC). Advanced MIBC in surgical specimen was defined as pT3-4 tumor. Receiving operating characteristic (ROC) curve quantified the area under curve (AUC) as predictive accuracy. Clinical usefulness was assessed by using decision curve analysis. RESULTS: This single-center retrospective study included 233 adult patients with BC undergoing RC at the Military Medical Academy, Belgrade. Organ confined disease was observed in 101 (43.3%) patients, and 132 (56.7%) had advanced MIBC. In multivariable analysis, 3 risk factors most strongly associated with advanced MIBC: grade of initial TUR [odds ratio (OR) = 4.7], LVI (OR = 2), and hydronephrosis (OR = 3.9). The resultant total possible score ranged from 0 to 15, with the cut-off value of > 8 points, the AUC was 0.795, showing good discriminatory ability. The model showed excellent calibration. Decision curve analysis showed a net benefit across all threshold probabilities and clinical usefulness of the model. CONCLUSION: We developed a unique scoring system which could assist in predicting advanced MIBC in patients before RC. The scoring system showed good performance characteristics and introducing of such a tool into daily clinical decision-making may lead to more appropriate integration of perioperative chemotherapy. Clinical value of this model needs to be further assessed in external validation cohorts. PMID- 25282785 TI - Stress hyperglycemia in acute myocardial infarction. PMID- 25282786 TI - Is there enough evidence for routine use of drug-eluting stents in acute myocardial infarction with ST segment elevation? PMID- 25282788 TI - Visceral hybrid reconstruction of thoracoabdominal aortic aneurysm after open repair of type A aortic dissection by the Bentall procedure with the elephant trunk technique--a case report. AB - INTRODUCTION: Reconstruction of chronic type B dissection and thoracoabdominal aortic aneurysm (TAAA) remaining after the emergency reconstruction of the ascending thoracic aorta and aortic arch for acute type A dissection represents one of the major surgical challenges. Complications of chronic type B dissection are aneurysmal formation and rupture of an aortic aneurysm with a high mortality rate. We presented a case of visceral hybrid reconstruction of TAAA secondary to chronic dissection type B after the Bentall procedure with the 'elephant trunk' technique due to acute type A aortic dissection in a high-risk patient. CASE REPORT: A 62 year-old woman was admitted to our institution for reconstruction of Crawford type I TAAA secondary to chronic dissection. The patient had had an acute type A aortic dissection 3 years before and undergone reconstruction by the Bentall procedure with the 'elephant trunk' technique with valve replacement. On admission the patient had coronary artery disease (myocardial infarction, two times in the past 3 years), congestive heart disease with ejection fraction of 25% and chronic obstructive pulmonary disease. On computed tomography (CT) of the aorta TAAA was revealed with a maximum diameter of 93 mm in the descending thoracic aorta secondary to chronic dissection. All the visceral arteries originated from the true lumen with exception of the celiac artery (CA), and the end of chronic dissection was below the origin of the superior mesenteric artery (SMA). The patient was operated on using surgical visceral reconstruction of the SMA, CA and the right renal artery (RRA) as the first procedure. Postoperative course was without complications. Endovascular TAAA reconstruction was performed as the second procedure one month later, when the 'elephant trunk' was used as the proximal landing zone for the endograft, and distal landing zone was the level of origin of the RRA. Postoperatively, the patient had no neurological deficit and renal, liver function and functions of the other abdominal organs were normal. Control CT after 6 months showed full exclusion of the aneurysm from the systemic circulation without endoleak and good flow through visceral anastomosis. CONCLUSION: In patients with comorbidities, like in the presented case, visceral hybrid reconstruction of chronic dissection type B with TAAA could be the treatment of choice. PMID- 25282787 TI - Paraganglioma of the thyroid gland: a case report. AB - INTRODUCTION: Thyroid paraganglioma is a very rare malignant neuroendocrine tumor. Immunohistochemical features of thyroid paraganglioma are helpful for the diagnosis. CASE REPORT: A 69-year-old female came to hospital with the presence of a growing thyroid nodule of the left lobe. Ultrasonic neck examination showed 5 cm hypoechoic nodule in the left thyroid lobe. Thyroid scintigraphy showed a big cold nodule in the left lobe. Computed tomography (CT) scan showed left lobe thyroid tumor with tracheal deviation on the right site. Extended total thyroidectomy was done. Intraoperative consultation with the pathologist confirmed thyroid cancer. The pathologist diagnosed thyroid paraganglioma on the base of immuohistochemical investigation. This thyroid paraganglioma was positive for neuron-specific enolase, chomogranin A, synaptophysin, and S-100 protein highlighted the sustentacular cells. Tumor cells were negative for thyroglobulin, epithelial membrane antigen, cytokeratin, calcitonin, and carcinoembryonic. After the surgery the patient was treated with chemotherapy, peptide receptor radionuclide therapy, and permanent TSH suppressive therapy. The patient was followed with measurements of thyroid hormone and serum neuron-specific enolase, chromogranin A level, every 6 months. Gastroscopy, colonoscopy, chest and abdomen CT scan as well as further tests (chest xray, ultrasound of the neck, and whole body octreotide scintigraphy) were done. No primary neuroendocrine tumor in digestive sistem or in the chest was found. After more than 3 years the patient has no evidence of the recurrent disease. CONCLUSION: Radical resection of thyroid paraganglioma, followed by chemotherapy and peptide receptor radionuclide therapy, should be considered the treatment of choice in patients with thyroid gland paraganglioma. PMID- 25282789 TI - Identification of Clostridium septicum in a tubo-ovarian abscess: a rare case and review of the literature. AB - INTRODUCTION: Tubo-ovarian abscess (TOA) is a conglomerated mass of pelvic organs including the tube, the ovary, and the bowel. The most commonly isolated organisms from TOAs are Escherichia coli (E. coli) and Bacteroides species. CASE REPORT: We reported a case of Clostridium septicum (C. septicum) infection from a ruptured TOA with atypical clinical features. Culture of intra-abdominal free fluid obtained during surgery yielded C. septicum. VITEK II (bioMerieux, France) automated system was used for advanced identification of the bacteria. Parenteral clindamycin in combination with an aminoglycoside was used. The patient was discharged 19 days after the surgery and was clinically asymptomatic 6 months after the surgery. CONCLUSION: The differential diagnosis of TOA caused by C. septicum can be difficult, due to the lack of the symptoms. Tissues infected with C. septicum can become necrotic. A combination of early, adequate antibiotic therapy and surgery is the key point of the treatment. PMID- 25282790 TI - The contribution of Serbian doctors to the development of physical exercise in the Kingdom of Serbia. PMID- 25282797 TI - [Topical aspects of contemporary forms of occupational bronchial asthma]. AB - Occupational bronchial asthma is a variable, heterogenious disease. Occupational factors are triggers and inductors of the pathologic process, cause formation of various clinical phenotypes of asthma, on background of genetic predisposition, changed metabolic adaptation, energetic systems, neuro-humoral regulation, immune state. PMID- 25282798 TI - [Occupational lung diseases caused by exposure to chrysotile asbestos dust and the preventive measures]. AB - To reveal major principles in system of occupational lung diseases prevention among workers engaged into extraction and usage of chrysotile asbestos, the authors specified main criteria for diagnosis of asbestos-related pulmonary diseases and signs of exposure to chrysotile dust, with identification of risk groups for occupational diseases development. The authors formulated main principles of prevention and rehabilitation for workers with asbestos-related pulmonary diseases. Special attention was paid to harmonization of all medical and technical measures aimed at prevention and liquidation of occupational asbestos-related diseases. PMID- 25282799 TI - [Clinical and pathogenetic features of occupational bronchitis]. AB - With multidimentional correlation analysis, the authors studied clinical and pathogenetic features of occupational bronchitis development. Analysis covered relationships of symptoms and syndromes of the disease, main spirometric signs of bronchial obstruction, presence and character of exogenic risk factors and the patients age. The authors revealed regularities of interrelations of clinical, instrumental and environmental characteristics of dust diseases, their role in unfavorable course and outcomes of occupational bronchitis. PMID- 25282800 TI - [Effect of vibration, noise, physical exertion and unfavorable microclimate on carbohydrate metabolism in workers engaged into mining industry and machine building]. AB - The authors studied influence of vibration, noise, physical overexertion and microclimate on carbohydrates metabolism and insulin resistance in metal mining industry workers. Findings are that vibration disease appeared to have maximal effect on insulin resistance test results and insulin level. The authors suggested biomarkers for early diagnosis of insulin resistance disorders in metal mining industry workers. PMID- 25282801 TI - [Influence of occupational factors on the bone and joint functional state in the upper extremities and cervical spine in female workers of clothing manufacture]. AB - The studies using multiple X-ray methods covered influence of complex containing working process and occupational environment factors on locomotory apparatus of upper limbs and cervical spine in female seamers engaged into various productions. Comparative analysis involved results of regular (standard X-ray) and special X-ray methods (stereoroentgenography, high definition roentgenography, roentgen densitometry, roentgenogrammetry) in 370 examinees with early and moderate clinical symptoms of occupationally mediated diseases of the stated areas. X-ray studies of locomotory apparatus of upper limbs and cervical spine in clothing manufacture workers, with special diagnostic methods, enabled to determine incidence and severity of functional and structural changes more reliably than via standard examination. The changes revealed were assigned mostly in "early" and "moderate" categories and matched with occupational peculiarities of the workers examined. PMID- 25282802 TI - [Evaluation of active equipment protecting distal parts of hands and feet against cold]. AB - Experimental studies covered thermoregulatory reactions of feet and hands, when using equipment protecting distal parts of hands and feet and using "active" heating (electric heating and thermochemical heater). Findings are that "active" heaters with output range 4-8 watt, as electrically heated inserts in gauntlets and welts, at air temperatures of -5 to -10 degrees C maintained average skin temperature of hand at 17-20 degrees C; using "active" heaters with output of 12 watt increased heat insulation of gauntlets and shoes up to 0.609-0.609 degrees C x m2/watt--that enables to conduct averagely hard work at cold climate up to 2 hours in all climate regions--IA (special), IB (climate zone IV), II (climate zone III) and III (climate zone II). Using 2 thermochemical heaters in gauntlets prevented local cooling, and heat insulation of the gauntlets therefore increased 1.6 times--that enables to widen temperature range of safe usage of equipment protecting hands against cold up to climate region II (climate zone III) during continuous physical work of average hardiness in cold climate up to 2 hours. PMID- 25282803 TI - [Occupational hearing loss--problem of health and safety]. AB - On the basis of the literature review the critical analysis of the recommendations (the letter of Ministry of Health of Russia from 6/11/2012 N 14 1/10/2-3508) on occupation noise-induced hearing loss (HL) assessment is presented. Need of more strict criteria of HL assessment for workers, than for the general population according to ICF (WHO, 2001), in order to avoid growth of accidents and injury rate is proved. The illegitimacy of a deduction of statistical presbiacusia values from individual audiograms as human rights violation is stressed. Some terminological defects are noted. It is necessary to cancel recommendations and to develop the sanitary norms or state standard with the program of hearing conservation at work. PMID- 25282804 TI - [Biologic monitoring as a stage in medical and prophylactic measures system managing chemical risks for public health in Sverdlovsk region]. AB - Biomonitoring is one among key elements of medical prophylactic measures within public health risk management system created in Sverdlovsk region, for residents of territories with chemically polluted environment. Biologic monitoring enables to determine levels of chemical load, to form risk groups among children and pregnant women for rehabilitation and health-imporving measures, and to evaluate efficiency of these measures. PMID- 25282805 TI - [Hygienic evaluation of environment, morbidity among pregnant women and newborns within social hygienic monitoring system]. AB - Hygienic evaluation covered health state of pregnant women and newborns, subjected to chemical pollution of environment by aluminium industrial enterprises. The data obtained helped to suggest methodic approach to selection of priority territories, environmental and health state parameters within social hygienic monitoring system, to form recommendations on creation of system supporting management decisions to lower negative influence of chemical environmental factors on health of pregnant women and newborns. PMID- 25282806 TI - [Evaluation of carcinogenic risk assessment of metallurgic copper production based on mortality studies and predictive risk values]. AB - Comparative evaluation covered carcinogenic jeopardy at metallurgic copper production through studies of the workers' mortality with malignancies and calculation of individual carcinogenic risks. Findings are that the individual carcinogenic risks calucations correspond to the data obtained in epidemiologic study of the mortality with malignancies and could be used for evaluation of carcinogenic jeopardy. PMID- 25282807 TI - [Evaluation of aerogenic occupational health risk for workers engaged into periclase-carbon refractories production]. AB - The work is aimed to evaluate aerogenic occupational health risk for workers engaged into preparation and formation of technologic mass in periclase-carbon refractories production, using organic binding agent according to criteria R 2.2.2006-05 and R 2.2.1716-03. Occupational dust is a complicated chemical mixture containing manganum oxide, phenol, formaldehyde, aerosols containing silicon, benzpyrene (if "Carbores" binding agent used). Hygienic evaluation revealed occupational health risk due to occupational dust at workplaces of runners operator, press operator, batching feeder, crane operator. Aerogenic occupational risk at workplace of grinder operator is assessed as negligibly small (tolerable). Experimental and epidemiologic studies prove probable (proof category 1B) occupational risk of respiratory disease at the studied production. PMID- 25282808 TI - [Occupational hygiene topics in ferroalloys production]. AB - Hygienic evaluation covered work conditions of main occupations in ferroalloys production on a plant in Ural regions. The occupations are: ferroalloy furnace operator, ferroalloy furnace worker and crane operator. The findings proved that the workers are exposed to a complex of occupational hazards among which dust and unfavorable microclimate play major role. At the enterprise, occupational dust disease cases (silicosis from exposure to silicon-containing dust) are registered, with average development duration of 28.7 +/- 6.2 years. PMID- 25282809 TI - [Occupational health risk assessment for workers in pipe rolling production]. AB - Certification of workplaces, monitoring of work conditions, information on number and occupational morbidity in 42 occupations at 10 occupational areas in pipe rolling workshop helped to evaluate occupational risk for the workers' health. Prior estimate based on integral evaluation of work conditions revealed 5 risk categories--from minor to extremely high. Unbearable occupational risk was determined mostly by the workers' exposure to occupational noise. The occupations of extremely high risk were characterized by prevalent exposure to one of the factors corresponding to class 4, and by combined exposure to several factors with high hazard degree with working conditions classes 3.4-4. Posterior estimate demonstrated occupations with proven risk of neurosensory deafness and registered medium occupational risk of dust diseases. In the course of occupational risk evaluation, the authors revealed the occupations necessitating complex programs and specific measures to lower occupational risk. PMID- 25282810 TI - [Risk factors and development of metabolic disorders in workers of "Uralasbest" enterprise]. AB - The authors evaluated possible increase in metabolic disorders risk in workers exposed to natural asbestos and to mixed asbestos stock dust, on the background of improper nutrition. Findings are excessive intake of food with high content of free sugar, saturated fatty acids and common salt (2.3-11.0 times) with lack of chicken meat, cereals, fish, vegetables, fruits and cultured milk foods in diet. Excessive body weight was seen in 81.0% of the workers, every third worker was obese. Chances ratio proved that the workers with excessive body weight are more probable in developing high serum levels of glucose, cholesterol, triglycerids, low density lipoproteins, higher atherogenicity index (2.4-3.1 times), and probability of arterial hypertension is higher by 78%. PMID- 25282811 TI - [Experimental evaluation of efficiency of bioprophylactic complex aimed at reduction of toxic effects caused by copper oxide nanoparticles]. AB - In subchronic intoxication via repeated intraperitoneal injection of copper oxide nanoparticles (diameter 20 nm, 19 times in dose of 10 mg/kg of rats, 3 times per week), findings are that oral intake of bioprotectors complex (pectine, polyvitamin and polymineral preparation, sodium glutaminate, glycine, acetylcysteine and fish oil preparation with high content of unsaturated fatty acids of omega-3 group) decreases copper accumulation in viscera (including statistically significantly in spleen) and slows development of pathologic changes in liver, brain and kidneys. With that, genotoxic effect of nanocopper also decreases--according to lower fragmentation of genome DNA in liver and spleen cells. PMID- 25282812 TI - [Experimental evaluation of combined effects caused by stress and metals (cadmium and aluminium) in reproductivity of male rats]. AB - To investigate combined effects of stress and metal (aluminium, cadmium) on reproductivity, male rats twice per week received intraperitoneal injections of aluminium (3.8 mg Al3+ per kg of body weight) or cadmium (0.3 mg Cd2+ per kg of body weight) and were subjected to stress via short-term immobilization during spermatogenic cycle (54 +/- 3 days). Findings are cumulation of both cadmium and aluminium in genitals and brain, increasing under stress. When acting separately to the laboratory animals, the three factors (aluminium/cadmium/stress) increase serum corticosterone level, change testosterone level, increase number of aberrant mitoses of spermatogenic epithelium cells, increased sperm count with fragmented DNA, lower percentage of the impregnated females. If the exposure combined with stress, spermatogenesis disorders are more marked, and preimplantation death rate of intact females' offspirngs becomes statistically significant. PMID- 25282813 TI - [Certain toxicodynamic and toxicokinetic features of combined subchronic intoxication with hexavalent chromium and nickel]. AB - Repeated intraperitoneal injections of nickel and chromium (VI) into rats appeared to demonstrate that the combined subchronic toxicity can be additive or vary (mostly to subadditivity) in accordance with effect on which they are evaluated. With moderate general toxic effects, the studied combination has marked genotoxicity with additive effect. The studies demonstrated reciprocal influence of nickel and chromium on accumulation of the second metal in some organs (especially, in spleen), but not on its renal excretion. PMID- 25282814 TI - [Problem connected with specification of hygienic norms for aerosols containing nanoparticles]. AB - With rapid development of nanotechnologies, with wide industrialization and using new nanomaterials, necessity is to approve norms for workplace air with consideration of nanoparticles presence. Major goal for norms creation is unified and technologic methods for selection, separation and identification of nanoparticles in environment. Besides that, review and specification of integrated mechanisms to define and set concentrations of chemical hazards at international level. PMID- 25282817 TI - [Neuronal and glial antigen distribution in the columns of somatosensory cortex of rat brain (an immunohistochemical study)]. AB - The aim of the study was to detect the neocortical columns in the S1 field on frontal sections of brain of albino rats using the method of immunohistochemistry and the antibodies against neuronal (synaptophysin, neurofilament) and gliocyte (glial fibrillary acidic protein--GFAP, myelin basic protein) proteins. The examination of the expression of the major neurospecific antigens revealed that on thin sections (4 micromin) a column could be identified due to accumulations of the astrocytes and neuronal processes--axons and dendrites. GFAP expression study also showed that cortical layer I usually contained multiple large astrocytes with branching processes, as well as numerous smaller processes with high intensity of expression. Synaptophysin content was high in all the layers of the cortex, but the most intense reaction was detected in the molecular layer, similarly with the intensity of GFAP reaction. The expression of myelin basic protein was detected in accordance with the radially extending myelinated processes of the neurons in the cortex. PMID- 25282818 TI - [Development of Meynert cells in cat visual cortex under the conditions of flickering light stimulation]. AB - To examine the effect of rhythmical light stimulation on postnatal development of the visual system, the formation of Meynert cells was studied in area 17 and posteromedial suprasylvian area (PMLS) of kittens reared under the conditions of flickering light stimulation (15 Hz frequency). Profile area of neuronal cell bodies and cytochrome oxidase (CO) activity level were measured in frontal sections of the visual cortex in control (n = 6) and stimulated (n = 6) kittens. Meynert cells located in area 17 and PMLS demonstrated an approximately 37% increase in CO activity in the stimulated animals. At the same time, the profile area of Meynert cell bodies in PMLS was decreased by 20% as compared to that in normal animals. The presence of functional disturbances of Y-conducting visual channel and the possibility of binocular vision suppression in the stimulated animals are discussed. PMID- 25282819 TI - [Effect of hypoxic postconditioning on the expression of antiapoptotic protein Bcl-2 and neurotrophin BDNF in CA1 hippocampal field of rats surviving severe hypoxia]. AB - Using the method of quantitative immunohistochemistry, the expression of antiapoptotic protein Bcl-2 and neurotrophin BDNF was studied in CA1 hippocampal field of rats that survived severe hypoxia (SH), the damaging effects of which were compensated by subsequent three postconditioning (PC) sessions of mild hypobaric hypoxia (360 mm Hg, 2 hours, three times with 24 hour intervals). It was shown that the expression of the proteins studied was decreased in rat hippocampus after SH. Hypoxic postconditioning which improved the structural and functional rehabilitation after SH, was shown to up-regulate the expression of Bcl-2 and BDNF in hippocampal CA1 neurons in rats that survived SH. These results suggest the involvement of Bcl-2 and BDNF in processes of adaptation to SH and compensation of its damaging effects. PMID- 25282820 TI - [Morphological changes of lymphoid apparatus of the larynx after experimental exposure to various balneal factors]. AB - The aim of this investigation was to detect the structural changes of lymphoid components of rat pharynx in an experiment after a course of exposure to various balneal procedures. The studies were performed on 90 outbred mature 3 month-old male rats (20 animals in each experimental group and 10 animals in each control groups). The animals were exposed to a course of weakly mineralized organic bituminous, thermal iodobromine and strong (concentrated) sulfide baths present on the territory of Azerbaijan. The experiments performed have shown a significant sensitivity of the lymphoid structures of the rat pharynx to the balneal procedures. After exposure to iodobromine and bituminous baths, the signs of lymphocytopoiesis activation were noted. The exposure to strong sulfide baths resulted in a morphological regression of lymphoid apparatus of rat larynx, which raises the question on the expediency of the use of these procedures in practical balneology. PMID- 25282821 TI - [Interrelations of pineal gland morpho-functional indices and immune system organs in rats exposed to natural illumination regime and continuous illumination]. AB - The objective of this investigation was to determine the complex response of the pineal gland (PG) and of the organs of the immune system in Wistar rats in response to a violation of the illumination regime in the experiment. Animals were kept under natural light regime and continuous illumination for 14 days. After that rats were sacrificed and the mass of the body, PG, gonads, thymus and spleen was measured. Thymus and spleen cell subpopulations were determined by flow cytometry. The lipofuscin content in PG was determined by measuring an autofluorescence intensity in frozen tissue sections in the wavelength range of 505-545 nm using a confocal laser scanning microscope LSM 510 META (Carl Zeiss). The correlation analysis showed an increase in the amount and the change of sign and direction of relations between the indices of the state of PG and the immune system. This indicates the up-regulation of the intensity of inter-system relationships and the change of migration and differentiation vector of immunocompetent cells. PMID- 25282822 TI - [Esophageal wall structure in people of elderly and senile age]. AB - Using histological methods, the esophageal wall structure and the cytoarchitectonics of mucous membrane were studied in the individuals of elderly (n = 5) and senile (n = 10) age. The control group included the individuals of I (n = 3) and II (n = 3) periods of mature age. It was demonstrated that with advancing age in most cases the destructive processes took place in the epithelium (delamination of the layer, separation of large fragments, formation of microerosions etc.) in most of the studied cases. Lymphocytes, neutrophils and eosinophils were found between the epithelial cells; the numbers of infiltrating cells was increased 2-3 times during aging. Mucosal lamina propria and the submucosa, in particular, were characterized by the thickening of the bundles of collagen fibers. A two-fold increase in the number of the cells of the fibroblast lineage was found. The number of leukocytes in the lamina propria was increased by the eldery age in the upper and lower parts of the esophagus (3.5 and 1.75 times respectively). The changes in lamina muscularis were manifested by its thinning, delamination and myocyte dissociation. Remodeling of the muscular tunic was less pronounced. The degree of changes increased distally and varied widely depending on the individual peculiarities. PMID- 25282823 TI - [Comparative study of morphometric parameters of the descending sigmoid sphincter according to the data of optical and virtual colonoscopy]. AB - Morphometric parameters of a descending sigmoid sphincter (DSS) were defined in 32 patients of both sexes aged 20-71 years (average age: 48.0 +/- 2.2 years) with various forms of colon lumen at the site of sphincter. Densitometric indices of DSS and surrounding soft tissues were estimated. Vital morphological peculiarities of descending-sigmoid junction of the colon were demonstrated, and the diameter of the colon at the level of a sphincter was defined. The data obtained confirm the anatomical character of the colon sphincters and may be used as a basis for the interpretation of optical and virtual endoscopic images and DSS description for the application in differential diagnostics and precision surgery of various colon diseases. PMID- 25282824 TI - [Characteristics of the spermatogenic epithelium in the testis of newborn rats- the offspring of female rats with chronic liver injury of various genesis]. AB - The effect of chronic injury of hepatobiliary system of various genesis in females rats on the formation of spermatogenic epithelium in the testis of their newborn offspring was studied. The models of toxic (CCl4) and medicinal (tetracycline, paracetamol) liver injury were used. The state of the seminiferous epithelium was assessed on the serial histological sections of the testis with the use of the morphometric device. In experimental animals, a reduction of the diameter and the area of the seminiferous tubules (ST) was detected, associated with the decline of the total number of spermatogenic cells, spermatogonia of various generations, total number of spermatocytes and Sertoli cells. At the same time, in the newborn rats of all the experimental groups, the number of ST with the desquamated epithelium, and that one of the multinucleated spermatogenic cells with fragmented and pyknotic nuclei were increased. PMID- 25282825 TI - [Placenta of normal women and of patients with bronchial asthma of various degrees of severity (immunohistochemical and histological study)]. AB - The aim of the study was to examine the immunomorphological features and expression of immunohistochemical markers that indicate the presence of immune inflammation in the placenta in normal pregnancy and in pregnancy complicated by bronchial asthma (BA) of varying degrees of severity. The of 80 samples of placenta from patients with BA were studied immunohistochemically and histologically to demonstrate the fixation of C3 fraction of complement, fibrinogen, IL-4, IL-6, IgA, IgM, IgG, and the expression of CD31, CD35, CD57 and CD83 molecules. The largest number of immune deposits fixed in the placenta and damaging the structures of the placental barrier (vascular endothelium and syncytiotrophoblast membranes) was found in women with moderate to severe BA. Their precipitation lead to the development of immunopathological process in the placenta and could result in placental insufficiency, adversely affecting the course of pregnancy and childbirth. The presence of pathogenic immune complexes in the placenta and the detection of antigen-presenting cells in areas of immunological inflammation in the placenta of women with BA are associated with the unfavorable course of pregnancy, parturition and could be a predictor of the possible development of allergic diseases in children. PMID- 25282826 TI - [Morphological changes in the fatty tissue after a single exposure to the ultrasound]. AB - The morphological changes in the fatty tissue of the posterior surface of knee joint were studied in rats (n = 96) using the method of light microscopy 1, 2, 3, 4 and 5 days after a single ultrasonic exposure of various duration (5, 10, 20 min)) in a diagnostic mode. This exposure resulted in hyperemia, lymphostasis and increase of vascular permeability. The degree of changes was found to increase in proportion to the duration of exposure. All the changes detected were reversible, and the majority of them disappeared within 1-2 days. During the practical application, it is necessary to take into account the possibility the induction of cell and tissue damage during the ultrasonographic examinations. Development and application of the measures directed to decrease the edema and to stabilize the vascular wall both during the ultrasonography and immediately after it are expedient. Ultrasonography should be performed only when there are significant medical indications, and to receive the required diagnostic information, the lowest power of the device should be used. PMID- 25282827 TI - [The peculiarities of petrotympanic fissure topography in Costen syndrome and possible causes of its development]. AB - A complex study of morphometric characteristics of the articular surfaces of the temporomandibular joint and the examination of the peculiarities of the petrotympanic fissure topography were performed on 138 samples of skulls of adult individuals with intact occlusion, complete anodontia and different forms of cranial skull (dolicho-, meso- and brachicranial). No distinct differences in studied parameters were found between the studied groups. However, in the hypsicranial group the petrotympanic fissure was found to pass more often through the medial third of the mandibular fossa, which may be a predisposing anatomical factor for Costen syndrome. Due to the fact that in anodontia the parameters characterizing the articular surfaces of the temporomandibular joint, are significantly changed, the immediate cause of the Costen syndrome are the changes of the articular surfaces of the temporomandibular joint, primarily the reduction in the size of mandibular condyle, which is accompanied by its pathological displacement and compression of the chorda tympani. PMID- 25282828 TI - [Morphometric assessment of gender differences in human constitution]. AB - In 154 girls and 58 young men aged 17-21 years, a new body mass index (BMI2 = M/H3), body form index (BFI=S/M2/3), body build index IBBI = (M/H3)1/2], and body fatness index (BFI = M/HC2) were determined; in which C, H, M, S correspond to the wrist circumference, body height, body mass and body area. It was shown that all the indices mentioned demonstrated highly significant gender differences if calculation of each of them was based, not on the body mass, but on a conventional body volume obtained by division of the factual body mass by the average statistical body density corresponding to 1.064 kg/dm3 in men and 1.034 kg/dm3 in women. PMID- 25282829 TI - [Subependymal microgliocytes of the third ventricle of the brain]. AB - The goal of the study was to identify the subependymal microglial cells of the III ventricle of the rat brain and to determine their structural characteristics. The sections of the brain of intact Wistar (n = 3) and Sprague-Dawley (n = 3) male rats were studied using the methods of immunocytochemistry and confocal laser microscopy. Subependymal microglia of the III ventricle was found to be a constantly present cell population. Two types of subependymal microgliocytes were identified--spindle-like and basket cells. Their processes penetrate the ependymal layer and reach its surface, thus contacting the cerebrospinal fluid (CSF), which suggests a possible participation of these cells in the structure of CSF-brain barrier. PMID- 25282830 TI - [Method for simultaneous visualization of mast cells and nerve terminals in the rodent thymus]. AB - The purpose of this study was to develop the method for the simultaneous visualization of mast cells (MCs) and nerve terminals, based on generally accepted techniques of histochemical identification of MCs with alcian blue and immunohistochemical detection of synaptophysin. The protocol presented allows simultaneous identification of mast cells and nerve terminals in the sections of paraffin-embedded thymus of laboratory mammals with high selectivity and good reproducibility. The method can be used for both visualization of spatial relationship between MCs and nerve terminals and independent research of the innervation of mammalian internal organs. Zinc-ethanol-formaldehyde is recommended as an optimal fixative. PMID- 25282831 TI - [The concept of tissues: the history and the present]. AB - The concept of tissues is one of the main categories in histology. This paper describes the evolution of the tissue concept during the last century. The review of different definitions of tissues found in Russian and foreign educational and scientific literature published in XX-XXI centuries, is presented. Special attention is given to the changes of the concept of tissues that due to the appearance of the new approaches and concepts in tissue biology (doctrine of stem cells, differon principle of tissue organization, histione conception). A brief characteristic of different definitions of tissues based on various approaches that were suggested by Russian and foreign histologists, is given. The data are discussed that support the idea that the "tissue" concept belongs to a number of undefinable basic concepts of tissue biology. PMID- 25282832 TI - [The effects of alcohol on the developing brain]. AB - In the review the literature data on the effect of alcohol on the developing brain of human and animals are summarized. The information is presented on the neuroimaging, histological, cellular and molecular-genetic disturbances in the brain in fetal alcohol syndrome and following exposure to alcohol during the early postnatal period. The structural developmental abnormalities of the different parts of the brain, disorders of neurogenesis and neuronal apoptosis, changes in metabolism, receptors and secondary signals system of neurons are described. Prenatal alcohol exposure causes significant, various long-term disturbances of the brain structures at the organ, tissue, cellular and subcellular level, which may lay in the basis of the observed neurological, behavioral and metal disorders. PMID- 25282833 TI - [Eminent Russian anatomist Josias Weitbrecht-- a founder of syndesmology]. PMID- 25282834 TI - [Diagnosis of intrauterine brain hypoxia bt thermal imaging video monitoring of the fetus]. PMID- 25282835 TI - [Blood level sensor based on digital video analyzer for autotransfusion devices]. PMID- 25282836 TI - [Multichannel network analyzer of biopotentials for remote control of rehabilitation in patients with postural deficits]. PMID- 25282837 TI - [A device for albumin and cytosol detoxication]. PMID- 25282838 TI - [The technique for experimental evaluation of dynamic visual activity using high speed video of eye movement]. PMID- 25282839 TI - [Automatic detection of pathological resorption zones in the cross-section cuts of human jaw bones from computer tomography data]. PMID- 25282840 TI - [Diagnosis of cardiovascular activity based on comparative assessment of parameters of the electrocardiogram]. PMID- 25282841 TI - [Biotechnical system of an intravascular robotic complex]. PMID- 25282842 TI - [Static elastography research by mathematical modelling]. PMID- 25282843 TI - [Problems of certification and quality monitoring of magnetic resonance imaging rooms]. PMID- 25282844 TI - [Pore geometry optimization for an implantable artificial kidney]. PMID- 25282845 TI - [Structure of arterial pulse signal transducers]. PMID- 25282846 TI - [Analysis of modern techniques for breast cancer diagnosis]. PMID- 25282847 TI - [The device for correction of urodynamics disorders of upper urinary tract in children with chronic pyelonephritis]. PMID- 25282848 TI - [A system for monitoring and correction of angular deviations of dental instruments]. PMID- 25282849 TI - [Retrofit device for evaluation of metabolic activity in herpes virus infected cell cultures]. PMID- 25282850 TI - [The effect of elasticity of tubes of hydraulic pressure simulator on the results of calibration of noninvasive sphygmomanometers]. PMID- 25282851 TI - [Determination of dermatoglyphic predictors of sex organ development pathology in women]. PMID- 25282853 TI - [Metrological support of stabilometric studies]. PMID- 25282852 TI - [A method and a device for metrological testing of laser Doppler flowmetry monito]. PMID- 25282854 TI - [Automatic recognition of cysts in the cross-section cuts of maxillofacial area obtained by computed tomography]. PMID- 25282855 TI - [Assessment of changes in right ventricle function in patients with left ventricle auxiliary circulation system]. PMID- 25282856 TI - [Pulse wave contour analysis in automated mode]. PMID- 25282857 TI - [A diagnostic system for screening of neurologic diseases in children]. PMID- 25282858 TI - [A device for noninvasive determination of human body composition under spaceflight conditions]. PMID- 25282859 TI - [Technology of research into sound absorption properties of materials based on tone audiometry]. PMID- 25282861 TI - Here come the physician assistants. PMID- 25282860 TI - Sovaldi dilemma likely to get worse. PMID- 25282862 TI - Do we overspend on health care, underspend on social needs? PMID- 25282863 TI - Medication adherence study looks at types of interventions. PMID- 25282864 TI - Will we ever achieve the 'holographic organization'? PMID- 25282865 TI - Population care coordinators: a key to improved care at lower cost? PMID- 25282866 TI - As mentally ill fall through net, insurers asked to take up slack. PMID- 25282867 TI - Costs of biologics for inflammatory conditions vary. PMID- 25282868 TI - Highmark leads on procedure but other plans slow to follow. PMID- 25282869 TI - One-shot staph treatment offers many advantages. PMID- 25282870 TI - COPD costs to approach $50B per year in 2020. PMID- 25282871 TI - A home-based weight lifting program for patients with arm lymphedema following breast cancer treatment: a pilot and feasibility study. AB - It is well documented that resistance exercise can be performed by patients with breast cancer-related arm lymphedema. The aim of this pilot study was to evaluate the feasibility and safety of a 12-week self-administered weight lifting program for arm and shoulder, and its influence on arm lymphedema status, upper extremity muscle strength, and disability. Twenty-three patients with breast cancer-related arm lymphedema performed the program 3 times/week. The weight resistance levels were individually adjusted for shoulder flexion and adduction, and elbow extension and flexion corresponding to a repetition range of 8-12 repetition maximum. A log book was used to evaluate adherence to the program, wearing of compression sleeve and perceived exertion. Measurements were performed before a 2 week control period without intervention, and before and after intervention, and with arm volume measurements every fortnight to check for adverse events. Results revealed no significant changes during the control period. Adherence to the intervention program was excellent, and two adverse events were registered during the first weeks. After intervention, an increase of shoulder and arm strength (measured by an isometric muscle strength device) was found in all exercises (p = 0.001-0.003). A reduction of excess volume was shown, in ml (p = 0.03) and percentage (p = 0.005), measured by water displacement method. A tendency towards reduction (p = 0.07) of fat tissue in the upper arm (n = 10) in both arms was found measured by MRI. In this pilot study, we concluded that a home-based weight lifting program performed by patients with breast cancer-related arm lymphedema is feasible and safe providing that the program includes regular follow-up for safety. PMID- 25282872 TI - Evaluation of the Og34C filter paper technique in lymphatic filariasis prevalence studies. AB - Currently there are several tests which can be used for monitoring and evaluating lymphatic filariasis prevalence in mass drug administration (MDA) programs with the ICT as most commonly accepted field test. However, other techniques to determine circulating antigen are available that also could be suitable in these programs. Our aim was to determine the suitability of the Og4C3 filter paper technique to determine antigen prevalence for lymphatic filariasis. We compared multiple antigen methods during the course of baseline clinical prevalence studies in Papua, New Guinea in over 800 subjects. We found that the ICT and Og4C3 filter paper techniques and using blood from the ICT card in the Og4C3 ELISA were equivalent in performance and that the serum Og4C3 ELISA test detected significantly more antigenic individuals. In addition, we found that modification of the Og4C3 assay by removing the boiling step did not affect its performance. Our results indicate that the Og4C3 filter paper technique is suitable for use in elimination of transmission of lymphatic filariasis monitoring and evaluation programs, quality control of ICT testing could be accomplished by using blood from the ICT test card, and with appropriate logistics in place, venous sampling and testing by the serum Og4C3 ELISA is achievable in monitoring and evaluation and would better identify areas with low level antigenaemia prevalence and possible ongoing transmission. PMID- 25282874 TI - Physiotherapy in upper limb lymphedema after breast cancer treatment: a randomized study. AB - Our aim was to compare the responses of physical treatment with or without manual lymphatic drainage (MLD) in lymphedema after breast cancer treatment in a Brazilian population. This was a controlled clinical trial with lymphedema secondary to breast cancer treatment patients that were randomized into either: Group 1 consisting of MLD, skin care, bandaging and remedial exercises; or Group 2 using skin care, bandaging and remedial exercises. Sixty-six patients were randomized and 9 were excluded during the first phase, resulting in a total of 57 patients eligible for analyzes with 28 in Group 1 and 29 in Group 2. The first phase of treatment had an average duration of 24 days (+/- 12.38) and final volume excess average (VE) between limbs was 494.51 ml, corresponding to 29.18% of the initial volume. Volume reduction was highly significant, independent of the intervention (p < 0.001), and both treatments led to an average of percentage volume excess reduction (PVER) of 15.02%. Patients with incomplete range of motion and lymphatic-related fibrotic tissues showed a statistically significant reduction in the percentage of volume excess (p = 0.010; p = 0.009). The presence of arm paresthesia was associated with the lowest therapeutic response (p = 0.024). Both treatment groups demonstrated absolute and relative reductions of excess limb volume, and the addition of MLD did not significantly increase the therapeutic response in women with lymphedema after breast cancer. PMID- 25282873 TI - Novel characterization of bEnd.3 cells that express lymphatic vessel endothelial hyaluronan receptor-1. AB - Murine bEnd.3 endothelioma cell line has been widely used in vascular research and here we report the novel finding that bEnd.3 cells express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR-3). Moreover, these cells express progenitor cell markers of Sca-1 and CD133. Upon stimulation with tumor necrosis factor-alpha (TNF-alpha), the bEnd.3 cells demonstrate enhanced formation of capillary-type tubes, which express LYVE-1. As the bEnd.3 cell line is derived from murine endothelioma, we further examined human tissues of endothelioma and identified lymphatic vessels in the tumor samples which express both LYVE-1 and podoplanin. Moreover, a significantly higher number of lymphatic vessels were detected in the endothelioma samples compared with normal control. Taken together, this study not only redefines bEnd.3 cells for vascular research, but also indicates a broader category of human diseases that are associated with lymphatics, such as endothelioma. PMID- 25282875 TI - Short time effects of radiotherapy on lymphatic vessels and restorative lymphatic pathways: experimental approaches ina mouse model. AB - Radiotherapy (RT) is an important component in the therapeutic approach to oncologic conditions. This study presents the investigative results on the impact of RT on lymphatic vessels and on the regenerative response of the lymphatic system in a mouse model. We first irradiated 3 groups of ten mice using brachytherapy in a single treatment of 20 Gy. We then performed morphological examination of the irradiated lymphatic vessels using an in vivo microscopic transillumination technique at 2, 4, and 6 weeks. Next we evaluated lymphatic flow using lymphoscintigraphy and in vivo microscopy at 6 to 11 weeks in: 10 additional mice following irradiation as above (IR), in 10 mice following incision of a lymphatic vessel (I), and in a non-treated control group of 10 mice (N). Intact lymphatic vessels were observed in all mice at 2, 4, and 8 weeks following the single dose of radiotherapy in the first group of mice and normal lymphatic flow was fully restored in the irradiated (IR) and incised (I) mice indicating that the reparative substitution lymphatic pathways are functioning normally. We found that following irradiation with one dose of 20 Gy, lymphatic vessels were not visibly damaged and also that lymphatic flow was consistently restored and substitutive lymphatic pathways formed. PMID- 25282876 TI - [Applications of mathematical statistics methods on compatibility researches of traditional Chinese medicines formulae]. AB - The compatibility of traditional Chinese medicines (TCMs) formulae containing enormous information, is a complex component system. Applications of mathematical statistics methods on the compatibility researches of traditional Chinese medicines formulae have great significance for promoting the modernization of traditional Chinese medicines and improving clinical efficacies and optimizations of formulae. As a tool for quantitative analysis, data inference and exploring inherent rules of substances, the mathematical statistics method can be used to reveal the working mechanisms of the compatibility of traditional Chinese medicines formulae in qualitatively and quantitatively. By reviewing studies based on the applications of mathematical statistics methods, this paper were summarized from perspective of dosages optimization, efficacies and changes of chemical components as well as the rules of incompatibility and contraindication of formulae, will provide the references for further studying and revealing the working mechanisms and the connotations of traditional Chinese medicines. PMID- 25282877 TI - [Advance in studies on TRPV1 and analgesic effect of traditional Chinese medicines]. AB - Transient receptor potential vanilloid 1 (TRPV1) is a non-selective positive ion channel that is mainly expressed in sensory neurons and a member of transient receptor potential (TRP) family. The receptor could be activated by mechanical irritation, chemical irritation or endogenous ligand to mediate pains and cause injury to body functions. Traditional Chinese medicine believes that the mechanism of pain is that "stagnation leads to pain". Specifically, both of the contracture and tautness caused by cold and the blood stasis could result in blood impassability and pain. Most of traditional Chinese medicines for clearing heat and removing toxicity have the anti-inflammatory effect, while those for warming interior, and promoting blood circulation to remove blood stasis have the effect in smoothening blood vessels. Therefore, either with the anti-inflammatory effect or the effect in smoothening blood vessels, traditional Chinese medicines for clearing heat and removing toxicity, warming interior, and promoting blood circulation have the analgesic effect In this paper, the authors summarize the analgesic effect of the above three traditional Chinese medicines, with TRPV1 as the target. PMID- 25282878 TI - [Effect of environmental factors on photosynthetic physiology and flavonoid constituent of Scutellaria baicalensis]. AB - To discuss the effect of environmental factors and photosynthesis on the growing of plant and the content of active components in Scutellaria baicalensis, the photosynthetic physiology index and diurnal changes of flavonoid constituent of S. Baicalensis were observed and tested in flowering and fruiting stages, and in the meantime environmental parameters were recorded. The obtained data were analyzed data by using path analysis and gray correlation analysis. The results showed that PAR and SWC were important environmental factors impacting on photosynthesis of S. baicalensis. SWC, RH and Ca were important environmental factors impacting on baicalin content. PAR, Po and Ta were important environmental factors impacting on baicalein content. PMID- 25282879 TI - [Cloning and expression analysis of cinnamate 4-hydroxylase (C4H) reductase gene from Aquilaria sinensis]. AB - The study aimed to clone the open reading frame of cinnamate 4-hydroxylase (C4H) from Aquilaria sinensis and analyze the bioinformatics and expression of the gene. One unique sequence containing C4H domain was discovered in our previous reported wound transcriptome dataset of A. sinensis. The open reading frame of C4H was cloned by RT-PCR strategy with the template of mixed RNA extracted from A. sinensis stem which treated by different wound time. The bioinformatic analysis of this gene and its corresponding protein was performed. C4H expression profiles in responds to MeJA (methyl jasmonate) application were analyzed by real time PCR. The length of C4H open reading frame (ORF) was 1 515 bp, encoding 514 amino acids. The GenBank accession number is KF134783. Inducible-experiments showed that the genes were induced by mechanical wound as well as MeJA induction, and reached the highest expression level at 8 h and 20 h, respectively. The full length cDNA of C4H and its expression patterns will provide a foundation for further research on its function in the molecular mechanisms of aromatic compounds and flavonoids biosynthesis. PMID- 25282880 TI - [Effects of different K fertilizer and water level on growth and physiological characteristics of Isatis indigotica]. AB - The experiment included three potassium levels (K0 0 g x kg(-1), K1 0.33 g x kg( 1), K2 0.67 g x kg(-1)) and two water gradients (well watered and drought stress), then measured growth indicators, SOD, POD, CAT activities and concents of osmotic regulation substances. To explore the effects of K fertilizer and water on growth and physiological characteristics of Isatis indigotica, providing reference for improving drought resistance of I. indigotica. The result showed drought stress inhibited the growth and decreased the biomass of I. indigotica but K fertilizer can alleviate the drought stress. Compared with K0 treatment, K1, K2 treatment increased the biomass of overground part of by 89. 13% ,60. 87% under drought stress. The corresponding increase in soluble sugar content was 16.67%, 5.00%, and in proline content was 42.41%, 65.62%, respectively. SOD,POD and CAT activities was significantly improved in K1, K2 treatment in comparison with K0 treatment under drought stress, but soluble protein content significantly reduced. The conclusion is that appropriate amount of K fertilizer can increase the activities of antioxidase and the content of osmoregulation substance under drought stress, and improve drought resistance of I. indigotica. PMID- 25282882 TI - [Colonization characteristics of endophytic bacteria NJ13 in Panax ginseng and its biocontrol efficiency against Alternaria leaf spot of ginseng]. AB - To reveal the colonization characteristics in host of endophytic biocontrol bacteria NJ13 isolated from Panax ginseng, this study obtained the marked strain NJ13-R which was double antibiotic resistant to rifampicin and streptomycin through enhancing the method of inducing antibiotic. The colonization characteristics in ginseng and its biocontrol efficiency against Alternaria spot of ginseng in the field were studied. The results showed that the strain could colonize in root, stem and leaf of ginseng and the colonization amount was positive correlated with inoculation concentration. Meanwhile, the strain could infect and then transfer in different tissues of ginseng The colonization amount of strain in roots and leaves of ginseng increased first and then decreased. However, the tendency of colonization amount of strain in stems was ascend at first and then descend slowly, and was more than that in roots and leaves along with time, which had a preference to specific tissue of its host. In field experiment, the endophytic bacteria NJ13 was proved to be effective in controlling Alternaria leaf spot of ginseng. The biocontrol efficiency of fermentation broth at the concentration of 0.76 x 10(8) cfu x mL(-1) reached 75.62%, which was close to the controlling level (73.06%) of 0.67 mg x L(-1) 50% cyprodinil WG. PMID- 25282881 TI - [Evaluation of high-resolution images application for wild medicinal plants macro monitoring: a case of Apocynum]. AB - To investigate the resources of medicinal plant, such as wild Apocynum, supervised classification based on Principal Component Analysis (PCA) and texture feature were used to monitor wild medicinal plants from image captured by ZY-3 and World-view-2 and compare which satellite Image are more appropriate to monitor the wild medicinal plants. The research results shows that: for more complex growth conditions wild medicinal plants Apocynum, high-resolution images Worldview-2 is more suitable for its remote identification, the low-resolution satellite ZY-3 can only recognizes the wild medicinal plants which distributed intensively. If the study target distribution is more intensive and larger scale, and cultivated type medicinal plants, the use of satellite ZY-3 in low resolution remote sensing data to identify the target can be a good choice, it is not necessary to buy high-resolution data, in order to avoid waste of expenditure, for the scattered distribution, the high-resolution satellite imagery data may be indispensable to identify targets. PMID- 25282883 TI - [Effect of ABA on transcriptionally active Ty1-copia retrotransposons in Dendrobium officinale]. AB - Using universal primer Tyl-copia retrotransposon RT, the conserved reverse transcriptase domain of about 260 bp was amplified by RT-PCR from the Dendrobium officinale which induced by 100 micromol x L(-1) abscisic acid (ABA), indicating these retrotransposons activated by 100 micromol x L(-1) ABA. The amplicons were recovered and cloned,then sequenced and analyzed by related bioinformatics software. Forty-two Ty1-copia like retrotransposon RT transcriptionally activated were obtained with high heterogeneity. The length of these sequences varied from 247 to 266 bp, and was rich in AT and homology ranged from 46.3% to 98.9%. The same to Ty1-copia like retrotransposon RT of genome, different c/s-acting regulatory elements induced by stress conditions and the starting transcription signals, corresponding to CAAT box, TATA box conserved sequences and some other regulatory elements. The c/s-acting regulatory elements induced by stress conditions of reverse transcriptase transcriptionally activated of Tyl-copia retrotransposons were significantly increased than that of Ty1-copia like retrotransposon RT of genome. When being translated into amino acids, fifteen sequences presented stop codon mutation, nineteen sequences presented frameshift mutation, and all sequences presented conserved sequence "SLYGKQ" mutation. Five categories were identified through phylogenic analysis after alignment analyses of their amino acid sequences, and with Ty1-copia like retrotransposon RT of genome having low homology, which indicated that reverse transcriptase transcriptionally activated of Ty1-copia retrotransposons which induced by ABA had Significantly differences with Ty1-copia like retrotransposon RT of genome. PMID- 25282884 TI - [Pollination biology of Fritillaria delavayi]. AB - In this study, the processes of pollination ecology of Fritillaria delavayi were investigated to document its reproductive characteristics. Some individuals of F. delavayi could produce seeds under bagging without emasculation (11%), but the rate was significantly lower than that of the natural control (87%). It is suggesting that pollination of F. delavayi largely depends on pollen vectors. Bombus sushikini was the only effective pollinator of F. delavayi and the visitation frequency was 0.003 time xXflower(-1) x min(-1). Flowering of F. delavayi in whole population lasted for 35 d and single flower for 11 d. Pollen viability and stigma receptivity lasted for 9 d and were relatively long compared with other Fritillaria genus plants. Consequently, bumblebee pollination and long floral longevity seem to be important for reproductive assurance of F. delavayi in harsh alpine environments. PMID- 25282885 TI - [Preparation and characterization of cucurbitacin B sodium deoxycholate/phospholipid-mixed oral fast dissolving film and antitumor activity study]. AB - A novel drug delivery system combining oral fast dissolving film with sodium deoxycholate/phospholipid mixed micelles was prepared to increase the absorption of cucurbitacin B that is a poor aqueous solubility substance. Encapsulation efficiency, particle size, zeta potential, polydispersity coefficient, investigated the morphology, disintegration time of oral fast dissolving film and the pharmacodynamic properties of cucurbitacin B sodium deoxycholate/phospholipid mixed micelles before and after solidified in mice were evaluated and compared. The oral fast dissolving film prepared in this study showed a homogeneous pale yellow and could completely disintegrated in the 30 s. It could meet the requirements of rapidly disintegrating fully. The encapsulation efficiency, particle size, zeta potential, polydispersity coefficient of cucurbitacin B sodium deoxycholate/phospholipid-mixed micelles loaded in oral fast dissolving film were (43.36 +/- 2.12)%, (108.82 +/- 5.2) nm, (-34.18 +/- 1.07) mV, 0.088 +/- 0.012, respectively. The encapsulation efficiency, particle size, zeta potential, polydispersity coefficient of cucurbitacin B sodium deoxycholate/phospholipid mixed micelles in solution were (41.26 +/- 2.22)%, (181.82 +/- 4.48) nm, (-30.67 +/- 0.81) mV, 0.092 +/- 0.012, respectively. The difference of pharmacodynamics among film of cucurbitacin B-loaded micelles, cucurbitacin B-loaded micelles and free cucurbitacin B in vivo was compared. Solubility of cucurbitacin B loaded in sodium deoxycholate/phospholipid-mixed micelles has also been greatly improved. The tumor inhibition rate of cucurbitacin B loaded in sodium deoxycholate/phospholipid-mixed micelles was significantly improved and did not change significantly before and after solidified. These showed that the sodium deoxycholate/phospholipid-mixed micelles could enhance the antitumor activities of cucurbitacin B and the stability of cucurbitacin B sodium deoxycholate/phospholipid-mixed micelles was improved significantly after solidified by oral fast dissolving film technology without pharmacodynamic properties changed significantly. PMID- 25282886 TI - [Preparation technology and dissolution research of Blumea volatile oil suppository]. AB - OBJECTIVE: To research the preparation technology and dissolution of Blumea volatile oil suppository. METHOD: In order to establish the content determination and methodology inspection method of Blumea volatile oil plug, the extraction process of Blumea volatile oil was optimized by using orthogonal test. Optimization on the investigation to the suppository matrix by melting time, appearance and dissolution was carried on. The best prescription craft was determined by determining the best molding temperature, dosage of the matrix and complementary makings. The determination method of dissolution was established by investigating different dissolution method and its impact on the preparation of dissolution. RESULT: The best conditions of steam distillation extracted Blumea volatile oil was as followed, the ratio of gardenia to liquor 1:6, 2.5% drug amount of sodium, 8 hours of extracting time. The optimum temperature for mold was 60-65 degrees C. Preparation technique of Blumea volatile oil suppository was stable, which after 45 minutes and 3 h in pH 4.5 PBS released at least 70% and 90%. CONCLUSION: Blumea volatile oil suppository with rational prescription, simple preparation and good stability. PMID- 25282887 TI - [Application of quantitative fingerprint to amino acids composition analysis of Xingnao Tongluo injection]. AB - OBJECTIVE: To control the quality of the product, quantitative fingerprint was used to evaluate the composition of the amino acids in the Xingnao Tongluo injection. METHOD: The method of the quantitative fingerprint to the amino acids composition was established through AccQ Tag precolumn derivatization. The quality was evaluated by the quantitative test of the amino acids and the similarity in ten batches. RESULT: The Xingnao Tongluo injection contained 12 amino acids and the contents of these amino acids were stable. All the ten batches of the samples had similarity of more than 0.90. CONCLUSION: The method was accurate, feasible and could be a simple and effective way to evaluate the quality of the traditional Chinese medicine. PMID- 25282888 TI - [Quality assessment of Liuwei Wuling tablet by HPLC fingerprint and quantitative analysis]. AB - Reversed phase high performance liquid chromatography with diode array detector was employed for simultaneous determination of six components and specific chromatograms analysis in Liuwei Wuling tablets with gradient elution of acetonitrile and water containing 0.1% phosphoric acid as mobile phase. The results showed that six components containing specnuezhenide, phillyrin, schisandrin, schisantherin A, schizandrin A and schizandrin B were separated well under the analytical condition. The average recoveries ranged from 98.96% to 100.5% with RSD less than 2. 0%. Twenty-five common peaks were selected as the specific chromatograms of Liuwei Wuling tablets with schisantherin A as the reference peak. Similarities calculated by cosine of angle, correlation coefficient and peak area ratio similarity (PAR) were all above 0. 95, indicating a good similarity between the reference and twenty batches of samples. Grubbs test and cluster analysis indicated that the established HPLC fingerprints and HPLC quantitative analysis can be used efficiently in the quality control of Liuwei Wuling tablets. PMID- 25282889 TI - [Determination of twelve active compounds in Qili Qiangxin capsules by UPLC-MS]. AB - In order to establish an UPLC-MS method for determination of twelve active compounds in Qili Qiangxin capsules including astragaloside, calycosin-7-0 glucoside, ginsenoside Rb1, ginsenoside Re, ginsenoside Rd, ginsenoside Rg1, ginsenoside Rf, periplocin, periplocoside H1, hesperidin, narirutin, isoquercitrin, the chromatographic separations were performedon a Phenomenex UPLC Kinetex C18 column (2.1 mm x 100 mm, 2.6 microm) with gradient elution of acetonitrile and 0.1% aqueous formic acidat a flow rate of 0.4 mL x min(-1). The temperature was set as 40 degrees C and injection volume was 5 microL. The monitoring of all analytes was achieved under the negative ionization mode with TOF-MS and TOF-MS/MS method. The twelve analytes showed good linearity (R2 > 0.9990) within the test ranges, the average recoveries were 98.0%-102%, respectively, and the RSD were less than 3.9%, respectively. The established method is simple, rapid, and sensitive, and can be used for quality control of Qili Qiangxin capsules. PMID- 25282890 TI - [Feasibility study of QAMS for quantitative analysis of multiple structural types of ingredients in Zhizi Jinhua pill]. AB - OBJECTIVE: To study the technical feasibility of QAMS to determine different structural types of ingredients in Zhizi Jinhua pill, a Chinese patent medicine. METHOD: Emodin was chosen as the internal reference substance. The relative correction factors (RCF) of berberine, baicalin, wogonoside, baicalein, aloe emodin, wogonin, rhein, chrysophanol and physcion to emodin were calculated with the peak areas determined at 254 nm. The ruggedness of these RCFs was validated. The contents of emodin in the samples of Zhizi Jinhua pill were determined by using the external standard method, and the contents of the other nine ingredients were calculated by their RCFs. The contents of these ten ingredients in all samples were also determined by the external standard method. RESULT: No significant differences were observed between the quantitative results of the two methods. The obtained RCFs were credible. CONCLUSION: The established QAMS method can be used for quantitative determination of different structural types of multi compounds in Zhizi Jinhua pill. It can provide reference for the quality control of Chinese patent medicine. PMID- 25282891 TI - [A new lanostane-type triterpenoid from Cymbopogon citratus]. AB - To study the chemical constituents of Cymbopogon citratus, isolation and purification of constituents were carried out on silica gel, Sephadex LH-20 and prepatative HPLC. The structures of the compounds were identified by physicchemical properties and spectral data analysis. Eight compounds were isolated and identified as 3beta-methoxy lanosta-9(11)-en-27-ol (1), 3beta hydroxylanosta-9 (11)-en (2), (24S) -3beta-methoxylanosta-9(11), 25-dien-24-ol (3), 8-hydroxyl-neo-menthol (4), (2E)-3,7-dimethyl-2,7-octadiene-1, 6-diol (5), (+)-citronellol (6), 7-hydroxymenthol (7) and ethyl nonadecanoate(8). Compounds 1 is a new one. Compounds 2-3 are obtained from C. citratus for the first time. PMID- 25282892 TI - [Chemical constituents from Bidens bipinnata]. AB - To investigate the chemical constituents of the whole plants of Bidens bipinnata, the separation and purification of constituents were performed by chromatography on macroporous resin, silica gel, MCI and Sephadex LH-20. Their structures were elucidated by spectroscopic data as quercetin (1), quercetin-3-0-alpha-L rhamnoside (2), keampferol-3-O-beta-D-glucopyranoside (3), keampferol-3-O-alpha-L rhamnoside (4), 3', 5-dyhydroxy-3, 6, 4'-trimethoxyl -7-O-beta-D-glucopyranoside flavonoid (5), 7, 8, 3', 4'-tetraflavanone(6), (2S)- and (2R)-isookanin-7-O-beta D- glucopyranoside (7a/7b), (2S)- and (2R)-3'-methoxy-isookanin-8-O-beta-D glucopyranoside (8a/8b), 6, 7, 3', 4'-tetrahydroxyaurone(9), maritimetin (10), esculetin (11), 3-O-caffeoyl-2-methyl-d-erythrono-1, 4-lactone (12), (7S, 8R) balanophonin-4-O-beta-D-glucopyranoside (13), eugenyl-O-beta-apiofuranosyl-( 1" 6') -O-beta-glucopyranoside (14), and (+)-syringaresinol-4'-O-beta-D glucopyranoside (15). Compounds 8, 13, 14, and 15 were isolated from this genus for the first time. Compounds 1 and 6 were potent inhibitors against HSC-T6 cells in vitro and compounds 1, 2, 6, and 7 were capable of decreasing the inflammatory cytokine production of macrophage cells in vitro. PMID- 25282893 TI - [Chemical constituents from ethyl acetate extract of flower of Albizia julibrissin]. AB - The ethyl acetate extract of the flower of Albizia julibrissin was isolated and purified by silica gel, Sephadex LH-20 and MCI GEL CHP-20P column chromatography to yield 29 compounds. Their structures were elucidated as 8-hydroxy-2, 6 dimethyl-2E, 6Z-octadienoic acid (1), 8-O-formyl-2, 6-dimethyl-2E, 6Z-octadienoic acid (la), 8-hydroxy-2, 6-dimethyl-2E, 6E-octadienoic acid (2), 8-O-formyl-2, 6 dimethyl-2E, 6E-octadienoic acid (2a), (2E, 6S)-2, 6-dimethyl-6-O-beta-D xylpyranosyloxy-2, 7-menthia-folic acid (3), clovan-2beta, 9alpha-diol (4), 2beta O-formyl-clovan-9alpha-ol (4a), 2beta, 9alpha-O-diformyl-clovan (4b), vomifoliol (5), (6S, 9R)-roseoside (6), vanillin (7), 4-O-ethylgallic acid (8), 3-ethoxy4 hydroxy-benzoic acid (9), p-hydroxybenzaldehyde (10), gallic acid (11), protocatechoic acid (12), stearic acid (13), palmitic acid (14), 2, 3 dihydroxypropyl hexadecanoate (15), linoleic acid (16), scopoletin (17), indole-3 carboxaldehyde (18), 2-furoic acid (19), 5-(hydroxymethyl)-2-furaldehyde (20), (22E, 24R)-5alpha, 8alpha-epidioxy-ergosta-6, 22-dien-3beta-ol (21), (22E, 24R) 5alpha, 8alpha-epidioxy-ergosta-6, 9, 22-trien-3beta-ol (22), (+)-lariciresinol 9'-stearate (23), formononetin (24) and uridine (25). Compounds 1a, 2a, 4a and 4b were new artifacts from the separation process, and others were obtained from A. julibrissin for the first time. PMID- 25282894 TI - [Phenolic constituents from Oplopanax horridus]. AB - The chemical constituents were isolated and purified by various chromatographic techniques indluding silica gel, reverse phase silica gel, sephadex LH-20 and pre HPLC and identified by their physicochemical properties and spectral data. Sixteen phenolic compounds had been isolated and n-butanol extracts which were fractionated from the ethanol extract of Oplopanax horridus roots bark. Their structures were identified as below, including 7 phenylpropanoid compounds, ferulic acid (1), 3-acetylcaffeic acid (2), caffeic acid (3), homovanillyl alcohol 4-O-beta-D-glucopyranoside (4), 3-hydroxyphenethyl alcohol 4-O-beta-D glucopyranoside (5), 3, 5-dimethoxycinnamyl alcohol 4-O-beta-D-glucopyranoside (6), and 3-dimethoxycinnamyl alcohol 4-O-beta-D-glucopyranoside (7). Three coumarins, scopoletin (8), esculetin (9) and 3'-angeloyl-4'-acetyl-cis knellactone (10). And 6 lignan compounds, (+)-isolaricires-inol-9'-O-beta-D glucopyranoside (11), 3, 3'-dimethoxy-4, 9, 9'-trihydroxy-4', 7-epoxy-5', 8 lignan-4, 9-bis-O-beta-D-glucopyranoside (12), (+)-5, 5'-dimethoxylariciresinol 4'-O-beta-D-glucopyranoside (13), (-)-5,5'-dimethoxylariciresinol 4'-O-beta-D glucopyranoside (14), (-)-pinoresinol 4'-O-beta-D-glucopyranoside (15), and (+) 5, 5'-dimethoxylariciresinol 9'-O-beta-D-glucopyranoside (16). All compounds were isolated and identified for the first time from this plant All the constituents except compounds 4, 6, 12 and 13 were obtained for the first time from the genus Oplopanax. PMID- 25282895 TI - [Chemical constituents from barks of Nothopanax delavayi]. AB - Eleven compounds were isolated and purified from the barks extract of Nothopanax delavayi and their structures were identified as serratagenic acid-3-O-alpha-L arabinopyranosyl-28-O-beta-D-glucopyranosyl ester (1), serratagenic acid-3-0 alpha-L-arabi-nopyranosyl-28-O-[alpha-L-rhamnopyranosyl-(1-->4)-beta-D glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester (2), serratagenic acid (3), serratagenic acid-3-O-alpha-L-arabinopyranoside (4), serratagenic acid-beta-O beta-(2', 4'-O-diacetyl) -D-xylopyranosyl-28-O-[alpha-L-rhamnopy-ranosyl-(1-->4) beta-D-glucopyranosyl-(1-->46)-beta-D-glucopyranosyl] ester (5), serratagenic acid-3-O-alpha-(4'-O-acetyl)-L-arabino pyrano-syl-28-0- [-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester(6), serratagenic acid-3-O-alpha-(2'-O-acetyl)-L-arabinopyranosyl-28-O-[-alpha-L rhamnopyranosyl- (1-->4) -beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester(7), serratagenic acid-3-0-beta-D-xylopyranosyl-28-O-[-alpha-L rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester (8), protocatechuic acid (9), ethyl caffeate (10) and caffeic anhydride (11) by physicochemical properties and spectroscopic data analysis. Among them, compounds 3-4 and 9-11 were firstly isolated from the genus Nothopanax, and compounds 5-8 were isolated from this plant for the first time. PMID- 25282896 TI - [Qualitative and quantitative research on sulfur fumigation of Angelicae Dahuricae Radix (Baizhi) by near-infrared spectroscopy]. AB - The contents of coumarins in the sulfur fumigated Angelicae Dahuricae Radix (Baizhi, ADR) were reduced significantly. To achieve the quality control of ADR, the qualitative identification of sulfur fumigated ADR and quantitative model of imperatorin content should be established. The near-infrared (NIR) spectrograms of non-sulfur and sulfur fumigated ADR were collected by NIR diffuse reflectance spectroscopy technology and pretreated by the method of first derivative derivation and vector normalization. The Ward's Algorithm method was used for the cluster analysis. The non-sulfur and sulfur fumigated ADR can be quickly identified in the range of 8,806. 0-3 811.0 cm(-1) based on the cluster analysis. The NIR quantitative model of imperatorin was established by the contents of imperatorin determined by HPLC in combination with partial least squares regression analysis. According to the calibration model established in this study, correlation coefficients (R2), the root-mean-square error of cross validation (RMSECV), and the root-mean-square error of prediction (RMSEP) for imperatorin were 0.982 8, 0.006 8, 0.011 8, respectively. The quantitative model of imperatorin can be applied to determine the content of imperatorin in ADR accurately. PMID- 25282897 TI - [Effect of Buzhong Yiqi decoction on PI3K and AKT in spleen, stomach and lung of nude mice with lung adenocarcinoma transplantation tumor]. AB - OBJECTIVE: To explore the effect of Buzhong Yiqi decoction on PI3K/AKT signaling pathway in spleen, stomach and lung of nude mice with lung adenocarcinoma transplantation tumor. METHOD: Totally 60 nude mice were randomly divided into the blank control group, the tumor-bearing control group, the cisplatin group, the low-dose Buzhong Yiqi decoction group, the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group. After the corresponding interventions, efforts were made to measure the transplanted tumor volume and calculate the tumor inhibiting rate. The immunohistochemical method and real time PCR were used to detect the expression of PI3K and AKT level in nude mice spleen, stomach and lung. RESULT: Buzhong Yiqi decoction of different concentrations combined with cisplatin could inhibit the growth of the transplanted tumor, with the strongest inhibitory effect in the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group. All of the expressions of PI3K and AKT protein and gene in the spleen, stomach and lung increased, with the most significant increase in the tumor-bearing group. Along with the increase of the concentration of cisplatin and Buzhong Yiqi decoction, the expressions of PI3K and AKT gradually reduced. Compared with the tumor-bearing control group, there were statistical differences in spleen and stomach tissues (P < 0.05). Compared with the cisplatin group, the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group showed statistical differences (P < 0.05), but without statistical difference compared with the blank control group. CONCLUSION: Among nude mice with lung adenocarcinoma transplantation tumor, the PI3K and AKT protein and gene expressions in spleen, stomach and lung tissues increased, which might indicated the effect of cisplatin and Buzhong Yiqi decoction in reducing PI3K and AKT expressions and the relations between the reduction degree and the concentrations of Buzhong Yiqi decoction. Cisplatin combined with Buzhong Yiqi decoction could decrease the PI3K and AKT protein and gene expression in spleen, stomach and lung, and make the pathway closer to normal, so as to protect the functions of spleen, stomach and lung, there may be target spots of Buzhong Yiqi decoction in PI3K/AKT signal pathway. PMID- 25282898 TI - [Study on differentially expressed proteins of effect of kudiezi injection on cerebral cortexin rats with cerebral ischemic stroke and heat toxin syndrome]. AB - This study is to investigate the modulation of Kudiezi (KDZ) injection on differential protein expression in cerebral cortex of rats with cerebral ischemic stroke and heat toxin syndrome established by intraperitoneal injection of carrageenan and middle cerebral artery occlusion (MCAO) methods. According to random number table rats were divided into three groups: drug group, model group and sham group. The tripheye tetrazolium chloride (TTC) staining and HE staining were used to observe brain tissue injury of rats. After therapeutic intervention with above drug for seventy-two hours, the level of differential protein expression was analyzed by two-dimensional gel electrophoresis (2-DE). The results show that there are differential protein expressions between cerebral ischemic stroke and heat toxin syndrome rats and sham rats. Furthermore, as a Chinese medicine injection with effect of clearing heat, resolving toxin and dredging collaterals, KDZ injection can decrease alleviate morphological changes of cerebral ischemia, regulate the levels of some differential proteins expression. PMID- 25282899 TI - [Study of screening nephroprotective bioactive substances based on triple-color fluorescence probes in Carthami flos]. AB - In this study, an approach based on triple-color fluorescence probes was developed for screening potential nephro-protective bioactive substances. Three fluorescent probes (i. e. FDA, MTR and Hoechst 33342) were used to label HK-2 cells injured by doxorubicin hydrochloride, and cellular fluorescence images were subsequently acquired and analyzed by a cellular-fluorescence image microscopy platform. The established method was applied to screening 53 components of Carthami Flos, and three components C17, C18 and C19 were found to exhibit nephroprotective effects against doxorubicin hydrochloride induced injury on HK-2 cells. Eight compounds (i. e. hydroxysafflor yellow A, 6-hydroxykaempferol-3-O rutinoside-6-O-glucoside, 6-hydroxykaempferol-3,6-di-O-gluco-side or 6 hydroxykaempferol-6, 7-di-O-glucoside, 6-hydroxykaempferol-3-O-rutinoside, 6 hydroxykaempferol-3-O-glucoside or 6-hydroxykaempferol-7-O-glucoside, rutin, isoquercetin, and kaempferol-3-O-rutinoside) in components C17, C18 and C19 were preliminarily identified by liquid chromatography-mass spectrometry (LC-MS). Isoquercetin, rutin, kaempferol-3-O-rutinoside, and hydroxysafflor yellow A were confirmed by comparing with reference substances, Further study indicated that these four compounds had moderate nephroprotective effects, while isoquercetin showed a significant nephroprotective effect in a dose-dependent manner. These results suggest that isoquercetin, rutin, kaempferol-3-O-rutinoside and hydroxysafflor yellow A might be the nephroprotective bioactive substances in Carthami Flos. PMID- 25282900 TI - [Study on effect of Polygonatum sibiricum on Yin deficiency model rats induced by long-term overload swimming]. AB - OBJECTIVE: To observe the effect of Polygonatum sibiricum on Yin deficiency model rats induced by long-term overload swimming. METHOD: Except for the normal group, all of the remaining rats performed the long-term overload swimming for eight weeks, with five days every week and once every day, to establish the Yin deficiency model. The daily swimming time increased from 10 min to 180 min at the end of the 7th week, with the water depth of 60 cm and the water temperature at 30 degrees C. After the success of the modeling, the rats were orally administered with different doses of aqueous extracts from P. sibiricum (2.5, 10 g x kg(-1)) for eight weeks. After the final administration, their blood were collected from orbits to measure immunoglobulin A, G and M (IgA, IgG, IgM), interleukin 2 and 6 (IL-2, IL-6) and cAMP, cGMP contents in plasma General behavioral indicators (weight, facial temperature, pain threshold and holding power) of rats were observed during the drug administration. RESULT: Compared with the model control group, aqueous extracts from P. sibiricum was given for eight weeks to significantly increase the rat weight and holding power of Yin deficiency model rats, decrease the facial temperature and the sensitivity of pain threshold, and increase IgA, IgG, IgM and IL-6 content and IgG content in serum, but without statistical difference. Aqueous extracts from P. sibiricum (10 g x kg(-1)) could also increase IL-2 content in serum, and decrease cAMP content and cAMP/cGMP ratio. CONCLUSION: P. sibiricum could improve the general behavioral indicators (weight, holding power, pain threshold and facial temperature), immunologic functions (IgA, IgG, IgM) and cyclic nucleotide (cAMP, cAMP/cGMP), so as to ameliorate such Yin deficiency symptoms as dysphoria in chestpalms-soles, weight loss, soreness and weakness of waist and knees, immunologic dysfunction and cyclic nucleotide system disorders. PMID- 25282901 TI - [Distinct effect of Wansheng Huafeng Dan containing ardisia crenata on renal transporters, mercury accumulation and Kim-1 expression from mercuric chloride]. AB - To study the effect of Wansheng Huafeng Dan (WSHFD) and mercuric chloride on renal mercury (Hg) extraction transporters (Oat1, Oct2), renal mercury excretion transporters (Mrp4, Mate2K), renal mercury accumulation and kidney injury molecule-1 (Kim-1). The ancient prescription of WSHFD containing 10-fold Hg caused much lower renal mercury accumulation and renal toxicity than HgCl2 in rats, with less effect on renal transporters than HgCl2. The above indicators had no significant difference in WSHFDO, WSHFD2 and WSHFD3 groups, indicating no effect of WSHFD with reduced or no cinnabar. PMID- 25282902 TI - [Protective effect of rosmarinic acid on hypoxia/reoxygenation injury in cardiomyocytes]. AB - OBJECTIVE: To study the protective effect of rosmarinic acid (Ros A) on the primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. METHOD: Primary cardiomyocytes of rats were cultured in vitro to establish the H/R injury of cardiomyocytes and observe the changes in the cell viability and LDH leakage. The changes in ATP content and ROS in cardiomyocytes were measured by using chemiluminescence and fluorescent probe technique. The effects of rosmarinic acid on the apoptosis of cardiomyocytes, cleaved-caspase 3, Akt and p-Akt protein expression were further detected by flow cytometry and western blot analysis. RESULT: According to the experimental results, Ros A at doses of 25, 50, 100 mg x L(-1) could inhibit the decrease in H/R-induced cell viability, LDH leakage and excessive ROS generation, and maintain the ATP level in cells. Ros A at doses of 50, 100 mg x L(-1) could remarkably inhibit the H/R-induced cardiomyocyte apoptosis and down-regulate the expression of cleaved caspase-3. Moreover, Ros A at doses of 100 mg x L(-1) could significantly up-regulate the expression of p Akt. CONCLUSION: Ros A has the significant effect in resisting the cardiomyocyte H/R injury, improve cardiomyocyte energy metabolism and reduce cell apoptosis, which is related to the activation of Akt pathway. PMID- 25282903 TI - [Inhibitory effect of taurine in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation and signal transduction mechanism]. AB - OBJECTIVE: To discuss the effect of taurine (Tau) on the proliferation of hypoxia induced pulmonary artery smooth muscle cells (PASMCs), and study whether the extracellular signal-regulated kinase 1/2 (ERK1/2) signal pathway participated in the Tau-inhibited PASMC proliferation process and the possible molecular mechanism. METHOD: The primary culture was performed for PASMCs in rats. The second to fifth generations were adopted for the experiment. The Tau concentration was 80 mmol x L(-1). The concentration of ERK1/2 blocker (PD98059) was 50 micromol x L(-1). The drug administration time was 24 h. The effect of Tau on the PASMC proliferation was detected by MTT assay, immunofluorescence staining method and western blot under different conditions. The PASMCs were growing were divided into four groups: the normoxia group, the normoxia + Tau group, the hypoxia group and the hypoxia + Tau group. The Western blot was adopted to detect whether the ERK1/2 signal pathway participated in the Tau-inhibited PASMC proliferation process. Subsequently, the PASMCs were divided into five groups: the normoxia group, the hypoxia group, the hypoxia + Tau group, the hypoxia + Tau + PD98059 group and the hypoxia + PD98059 group. RESULT: Hypoxia could induce the PASMC proliferation. Under the conditions of normoxia, Tau had no effect on the PASMC proliferation. Under the conditions of normoxia and hypoxia, Tau had no effect on the expression of the tumor necrosis factor-alpha (TNF-alpha) among PASMCs. Tau could reverse the expression up-regulation of hypoxia-induced proliferative cell nuclear antigen (PCNA) (P < 0.01) and Cyclin A (Cyclin A) (P < 0. 05). Under the conditions of normoxia, Tau had no effect on the expression of phosphoryl extracellular signal-regulated kinase 1/2 (p-ERK1/2). Hypoxia could up regulate the p-ERK1/2 expression (P < 0.01). Tau could reverse the up-regulation of the hypoxia-induced p-ERK1/2 expression(P < 0.01). Both PD98059 and Tau could inhibit the up-regulated expressions of PCNA, Cyclin A and p-ERK1/2. According to the comparison between the single addition of Tau and PD98059 under conditions of hypoxia, the hypoxia + Tau + PD98059 group showed more significant down regulation in the expressions of PCNA, Cyclin A and p-ERK1/2. CONCLUSION: Tau could inhibit the hypoxia-induced PASMC proliferation, and may regulate it through ERK1/2 pathway. PMID- 25282904 TI - [Effect of Tongluo Xingnao effervescent tablets on learning and memory dysfunction in rats with chronic cerebral ischemia]. AB - OBJECTIVE: To study the effect of Tongluo Xingnao effervescent tablets on learning and memory capacity and expression of Na(+)-K(+)-ATPase in hippocampus of rats with chronic cerebral ischemia-induced learning and memory dysfunction model. METHOD: The 2-VO method was used to establish sd rat model learning and memory dysfunction induced by chronic cerebral ischemia. The 50 rats in the successfully established model were randomly divided into the model control group, the Dihydroergotoxine Mesylate tablets group (0.7 mg x kg(-1), Tongluo Xingnao effervescent tablets high dose (7.56 g x kg(-1)), middle dose (3.78 g x kg(-1)) and low dose (1.59 g x kg(-1)) groups and the sham operation group (n = 10) as the control group. The groups were orally given 10 ml x kg(-1) x d(-1) drugs for consecutively 90 days. On the 86th day, Morris water maze was adopted for them. On the 90th day, a leaning and memory capacity test was held. The brain tissues were fixed with 10% formaldehyde and observed for pathomorphism after routine slide preparation and staining. The expression of hippocampal Na(+)-K(+) ATPase was detected with immunohistochemistry and image quantitative analysis. RESULT: Compared with the model group, all of Tongluo Xingnao effervescent tablets groups showed significant decrease in the escape latency at the 5th day in the Morris water maze, and notable increase in the frequency of the first quadrant dwell, the frequency passing the escape platform and the frequency entering effective area (p < 0.05). According to the pathomorphological detection, the control group showed a significantly higher pathological score than the sham operation group (p < 0.01), the middle dose group showed a significantly lower pathological score than the model group (p < 0.05). According to the immunohistochemistical detection, the model control group showed a remarkably lower mean OD value of Na(+)-K(+)-ATPase than the sham operation group (p < 0.05), high and middle dose groups showed a significantly higher mean od value than the model control group (p < 0.01). CONCLUSION: Tongluo Xingnao effervescent tablets can improve the learning and memory capacity, reduce pathological changes of hippocampal tissues of rats with chronic cerebral ischemia-induced learning and memory dysfunction model, and promote the expression of Na(+)-K(+)-ATPase in hippocampus. PMID- 25282905 TI - [Effect of total flavones of Epimedium leptorrhizum on osteoporosis in ovariectomized rats]. AB - OBJECTIVE: To observe the effect of total flavones of Epimedium leptorrhizum (YYH C) on osteoporosis in ovariectomized rats. METHOD: Ovariectomized female rats were randomly divided into the model group, YYH-C lower, middle and high dose (0.7, 1.4, 2.8 g x kg(-1)) groups, the positive drug Bujiale (0.15 mg x kg(-1)) group, and the sham group. The rats were orally ad-ministrated with drugs for three months. Parathyroid hormone (PTH), procollagen I N-terminal peptide (PINP), alkaline phosphatase (ALP), calcium (Ca) and phosphrous (P) in serum were detected. Femur bones and vertebrae bones of left side were collected to determined bone metrological indexes, including bone mineral density (BMD), bone Ca, and bone ash weight/dry weight percentage. Femur bones of right side were collected to for a morphological observation of bone. RESULT: Compared with the sham group, the model group showed significantly higher PTH and ALP content but obviously lower PINP and Ca content. The three YYH-C 3 groups could resist the decrease of PINP. Specifically, low and middle dose groups could remarkably inhibit the increase of PTH, and the high dose group could increase the Ca content in serum, but without significant effect on the rise in ALP. There was no significant difference in P content in serum in each group. BMD, ash weight/dry weight percentage, Ca and P content of the model group were significantly lower than those in the sham group. The high dose YYH-C group could significantly increase BMD. All of the three YYH-C groups could notably increase ash weight/dry weight percentage and Ca, P content in femur bones and vertebrae bones. YYH-C could significantly increase average thickness, area, area percentage of bony trabeculae, cortical bone area percentage of femoral shaft and the number of osteoblasts on the surface of bony trabeculae, and decrease the number of osteoclasts. CONCLUSION: YYH-C can effectively control the bone mass loss of rats with ovariectomy-induced osteoporosis, prevent the changes in bone microstructure, and inhibit bone absorption, so as to resist high turn-over osteoporosis after ovariectomy. [Key words] total flavones of Epimedium leptorrhizum; ovariectomized rat; osteoporosis PMID- 25282906 TI - [Influence of Kudou Shencha decotion on INF-gamma, ICAM-1, MCP-1 levels of prostate tissue homogenate in immunity prostatitis model rats]. AB - OBJECTIVE: To investigate the influence of Kudou Shencha decotion on INF-y, ICAM 1, MCP-1 levels of prostate tissue homogenate in immunity prostatitis model rats. METHOD: Forty Wistar male rats were divided into 5 groups randomly: Kudou Shencha decotion group with high dosage and low dosage, Qianleitai group, the model control group and normal group. The rat model of chronic nonbacterial prostatitis was established by multiple hypodermical injection of the suspension of prostatic protein purification with Freund's completed adjuvant. The level of intercellular adhesion molecule (ICAM-1), interferon gamma (INF-gamma) and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay (ELISA). RESULT: The content of ICAM-1 and MCP-1 in the model group was higher than that of the normal group (P < 0.05), the content of ICAM-1 was obviously decreased in Kudou Shencha decotion group with high dosage (P <0.05), the contents of MCP-1 were all obviously decreased in Kudou Shencha decotion groups and Qianlietai group. Compared with the model group, the contents of INF-gamma in all treatment groups were decreased insignificantly. CONCLUSION: Kudou Shencha decotion has the action of lowering the level of ICAM-1 and MCP-1, which may be one of the mechanisms of Kudou Shencha decotion in the therapy of chronic prostatitis. PMID- 25282907 TI - [Comparative pharmacokinetics of syringin, eleutheroside E and isofraxidin in rat plasma after intravenous administration of each monomer and Ciwujia injection]. AB - To compare the pharmacokinetics of syringin, eleutheroside E and isofraxidin after intravenous administration of each monomer and Ciwujia injection. Twenty four Sprague-Dawley rats were randomly divided into four groups and intravenously administrated with syringin, eleutheroside E, isofraxidin, and Ciwujia injection, respectively. The concentrations of the three components in rat plasma were determined by LC-MS/MS. DAS 2.0 software was applied to calculate the pharmacokinetic parameters while the SPSS 17.0 software was used for statistical analysis. Significant difference (P < 0.05) was found between each monomer and the injection on the main pharmacokinetic parameters such as AUC, CL and t1,/2. Compared with the injection, the group treated with the syringin has obvious decrease in AUC, and increase in CL while the group treated with eleutheroside E has obvious increase in AUC, and decrease in CL The t1/2 of isofraxidin was prolonged in Ciwujia injection. Pharmacokinetic characters of the ingredients in the injection varied greatly from the monomer. Other constituents in the injection may have an impact on the pharmacokinetic profiles of these three components. PMID- 25282908 TI - [Determination of plasma concentration of five phenolic acid by LC-MS/MS and study of pharmacokinetics in rats after Mailuoning injection]. AB - To establish a LC-MS/MS method for quantification of chlorogenic acid, caffeic acid, 3,4-DCQA, ferulic acid and cinnamic acid in rats plasma and study its pharmacokinetics after administration of Mailuoning injection at a single dose to rats. Plasma samples were acidified with hydrochloric acid and extracted with ethyl acetate. The analytes were determined by LC-MS-MS using a ZOBAX SB C18 column with a mobile phase of methanol-water (containing 2 mmol x L(-1) ammonium acetic) (60:40)at a flow rate of 0.5 mL x min(-1) and detected using ESI with negative ionization mode. Ions monitored in the multiple reaction monitoring (MRM) mode were m/z 353.1/191.0 [M-H]- for chlorogenic acid, m/z 178.9/134.9 [M H]- for caffeic acid, m/z 515.2/353.0 [M-H]-for 3,4-DCQA, m/z 193.0/133.9 [M-H] for ferulic acid, m/z 146.9/102.9 [M-H]- for cinnamic acid and m/z 246.0/125.8 [M H]- for tinidazole (IS). After administration of Mailuoning injection at a single dose to eight Sprague-Dawley rats, the concentrations of chlorogenic acid, caffeic acid, 3,4-DCQA, ferulic acid and cinnamic acid in plasma were determined by LC-MS/MS method. The main pharmacokinetics parameters of measured data were caluculated by using DASver 1.0 software. The linear concentration ranges of the calibration curves for chlorogenic acid, caffeic acid, 3,4-DCQA and cinnamic acid were 2.006-1,027 microg x L(-1) (r = 0.999 6), 1.953-1,000 microg x L(-1) (r = 0.999 7), 28.51-1.459 x 10(4) microg x L(-1) (r = 0.998 9), 1.836-940.0, g x L( 1) (r = 0.997 7) and 4.780-2,447 microg x L(-1) (r = 0.998 6) respectively. The inner and inter-days relative standard deviations were both less than 5.0%, indicating legitimate precise and accuracy to the requirement of biological sample analysis. For chlorogenic acid, the pharmacokinetic parameter t1/2, AUC0 t, and CL were (49.78 +/- 12.81) min, (123.55 +/- 14.82) mg x min x L(-1) and (0.004 3 +/- 0.000 5) L x min(-1), respectively. For caffeic acid, the pharmacokinetic parameter t1/2, AUC0-t, and CL were (36.65 +/- 10.59) min, (91.67 +/- 11.77) mg x min L(-1) and (0.005 7 +/- 0.000 7) L x min(-1), respectively. For 3,4-DCQA, the pharmacokinetic parameter t1/2, AUC0-t, and CL were (50.08 +/- 13.78) min, (278.34 +/- 31.82) mg x min x L-1 and (0.001 6 +/- 0.000 2) L x min( 1), respectively. For ferulic acid, the pharmacokinetic parameter t1/2, AUC0-t, and CL were (51.39 +/- 15.52) min, (34.72 +/- 4.67) mg x min x L(-1) and (0.000 4 +/- 0.0001) L x min(-1), respectively. For cinnamic acid, the pharmacokinetic parameter t1/2, AUCo-t, and CL were (74.42 +/- 18.32) min, (34.63 +/- 4.82) mg x min x L(-1) and (0.007 7 +/- 0.001 1) L x min-', respectively. The assay method is proved to be sensitive, accurate and convenient. It can be applied to the pharmacokinetic study of chlorogenic acid, caffeic acid, 3,4-DCQA, ferulic acid and cinnamic acid. PMID- 25282909 TI - [Pharmacokinetic comparison of baicalin absorption medicine Qinbai Qingfei concentrated pellets drug compatibility]. AB - The Qinbai Qingfei concentrated pellets by traditional Chinese medicine theoryand party and group, the rats were given the drugs group, comparison of pharmacokinetics parameters changes of baicalin , discusses the rationality of Qinbai prescription. The rats were gavaged monarch drug group (Huang Qincu extract, mainly forbaicalin), and official medicine group, adjuvant group, medicine group and Qinbai group (Quan Fangzu) the content of baicalin equal as the monarch drug group, in the 28 h collection in rat plasma at different time point, application of HPLC determination of baicalin glycosides in rat plasmaconcentration time curve, with 3P97 practical pharmacokinetics program to process the data Based on the data analysis, baicalin in rat plasma of Qinbai group Cmax is 4 times as big as monarch druggroup, AUC is 6 times as big as monarch drug group; the content of baicalin in plasma of rats the highest is Qinbai group, the minister drug group, adjuvant group, medicine group of baicalin in rat plasma content of less than the Qinbai group, but was significantly higher than that of monarch drug group; the medicine group is slightly higher than that adjuvant the content of baicalin in plasma of rats. The pharmacokinetic results show that the measured plasma concentration in rats that Qinbai can significantly increase Cmax and AUC of baicalin, other components of qinbai can promoted the baicalin absorption in vivo. It showed that the reasonable of Qinbai compound compatibility. The minister drug can promote the absorption of baicalin in vivo. PMID- 25282910 TI - [Clinical study of area of Jiangsu province of polycystic ovarian syndrome correlation distribution of traditional Chinese medicine syndrome type and improper diet]. AB - Polycystic ovary syndrome (PCOS) is one of the most popular diseases in obstetrics and gynecology research at internal and abroad at present, traditional Chinese medicine(TCM)in the clinical treatment of the disease have the advantage. Clinical epidemiological study of descriptive research method this research adopts investigation, observation of TCM syndromes and improper diet through 401 cases in Jiangsu Province confirmed PCOS patients, to explore the relationship between TCM syndrome type distribution and improper diet factors, and to provide the clinical basis for further etiology of this disease research. TCM syndrome type distribution of the disease is kidney deficiency, phlegm stagnation syndrome, qi stagnation and blood stasis syndrome, syndrome of dampness heat of liver channel and is composed of 4 basic syndromes and formed complex syndrome, and the composite and syndrome type (60.85%); combined with the analysis of traditional Chinese medicine dialectical, Pure empirical syndrome this disease (46.88%), followed by the actual card (45.39%), pure deficiency is rare. Improper diet factors associated with the disease, in which improper diet with different TCM syndrome type distribution significantly related. Stagnation of phlegm dampness syndrome is the main syndrome of the disease type, improper diet factors and every syndrome PCOS type distribution is as follows: the partial eclipse fatness greasy with basic syndromes of phlegm dampness stagnation of kidney deficiency syndrome, the nephrasthenia syndrome is less; eating spicy stimulation by basic syndromes of stagnation of Qi and blood stasis; eating cold people the basic certificate type of qi stagnation and blood stasis; The diet of patients are more prone to stagnation of phlegm dampness syndrome. PMID- 25282911 TI - [Effects of Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats]. AB - OBJECTIVE: To observe the effects of Mongolian pharmaceutical Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats. METHOD: Sixty male Wistar rats were randomly divided into six groups according to the sugar consumption test (10 rats in each group), normal control group,model group,fluoxetine group (3.3 mg x kg( 1)) and low dose, medium dose and high dose group (0.25, 0.5, 1 g x kg(-1)) of Betel shisanwei ingredients pill. Except the normal control,the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely raising for 28 days. 10 mL x kg(-1) of drugs were given to each rat once daily,continuously for 28 days. The AC activity of the hippocampus and prefrontal cortex were determined by radiation immunity analysis (RIA), while cAMP and PKA quantity were determinated by Enzyme-linked immunosorbent (ELISA). RESULT: The AC activity, cAMP and PKA quantity of hippocampus and prefrontal of mouse model of Chronic stress depression decreased significantly than those of control group (P < 0.05 or P < 0.01). However, the AC activity, cAMP and PKA quantity of rat hippocampus and prefrontal cortex in the fluoxetine group and the Mongolian pharmaceutical Betel shisanwei ingredients pill group indecreased significantly than those of model group (P < 0.01 or P < 0.05). Especially for the high dose group of Mongolian pharmaceutical Betel shisanwei ingredients pill. CONCLUSION: The AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depression model of rats is down-regulated, whereas Mongolian pharmaceutical Betel shisanwei ingredients pill could up-regulated it to resist depression. PMID- 25282912 TI - [Systolic heart failure. New drug improves prognosis significantly]. PMID- 25282913 TI - [SIGNIFY study is a disappointment. Ivabradine cannot stop of the progression of coronary heart disease]. PMID- 25282914 TI - [Curvature of toenails. Could a foot fungus be responsible?]. PMID- 25282915 TI - [Life style change. The family practitioner as fitness coach]. PMID- 25282916 TI - [Additional fees 2015 - but only for practices that can invest]. PMID- 25282917 TI - [Don't forget the rare GOA numbers!]. PMID- 25282918 TI - [Settling geriatric and dementia test fees correctly]. PMID- 25282919 TI - [A new age range for HPV vaccination is preferred]. PMID- 25282920 TI - [Billing in accordance with GOA. Detailed certificates are not an unprofitable art]. PMID- 25282921 TI - [EMB hassle. Added fee for service 03040 also in a substitute case]. PMID- 25282922 TI - [MFA general practice magazine "info general practice team". An ever increasing number of patients abstain from meat]. PMID- 25282923 TI - [Private colleges. An expensive medical education of questionable quality]. PMID- 25282924 TI - [What needs to be considered in the assessment of dyspnea. Why does my have such breathing difficulty?]. PMID- 25282925 TI - [Platelet inhibitor and oral anticoagulants. Discontinue antithrombotic drugs before colonoscopy?]. PMID- 25282926 TI - [Naturopathy consultation. Devil's claw and gymnastics for knee and shoulder]. PMID- 25282927 TI - [Infection related emergencies require rapid management. Winning the race with time]. PMID- 25282928 TI - [Red spots, then joint pain. From the skin to the lung for a diagnosis]. PMID- 25282929 TI - [Tympanostomy tubes and otorrhea - how to manage?]. PMID- 25282930 TI - [Fecal microbiome transfer helps in clostridium infections]. PMID- 25282931 TI - [What will not be publicized]. PMID- 25282932 TI - [Eye diseases--an endemic health care problem]. PMID- 25282933 TI - [Benefits and risks of laser treatment for the correction of ametropias]. PMID- 25282934 TI - [Glaucoma: informations for the general practitioner]. PMID- 25282935 TI - [Emergency checklist: Anaphylaxis]. PMID- 25282936 TI - [Ability to work and mental disorders]]. PMID- 25282937 TI - [Prescription of benzodiazepines in GP practices; adverse drug reaction and the risk of low-dose-dependency]. PMID- 25282938 TI - [Penile melanocytic nevi]. PMID- 25282939 TI - [Diabetes prevention--what's new?]. PMID- 25282940 TI - [Usual back pain?]. PMID- 25282941 TI - [In this issue of Ginecologia y Obstetricia de Mexico]. PMID- 25282942 TI - [Laparoscopic cholecystectomy in pregnant patient: experience in hospital General de Mexico in a period of 5 years (2008-2012)]. AB - BACKGROUND: Cholecystitis is the second cause of abdominal pain during pregnancy. 1-8 of 10,000 requiring surgery, being performed in the first and second quarter laparoscopically. 100% of patients with cholecystitis, about 12% are associated with pancreatitis with high rates of maternal and fetal morbidity and mortality. OBJECTIVE: To evaluate advantages--disadvantages of maternal-fetal pregnancy laparoscopic cholecystectomy and its preventive character avoiding cases of pancreatitis. We analyze the results obtained in Perinatology Service in General Hospital of Mexico (2008 to 2012) comparing them with the current literature. MATERIAL AND METHODS: A retrospective, cross sectional, descriptive. Analyzing the following variables: maternal age, gestational age, number of gestations, surgical technique, and postoperative complications trans, maternal and perinatal morbidity, gallbladder colic episodes prior, liver ultrasound report--bile ducts, tocolytic management. RESULTS: 20 laparoscopic cholecystectomies were performed in pregnant patients. Maternal age 21-38 years, mostly multigesta. 5 patients was performed at weeks 9, 14, 20 and 25 between the SDG and 1 at 27.5 SDG.Vesicular colicky eight previous USG mostly with gallstones.Two cases of mild acute pancreatitis satisfactorily resolved. No trans or postoperative complications. Open technique for performing pneumoperitoneum (Hasson). Tocolytic management indomethacin in 100% of cases. CONCLUSIONS: The results obtained are consistent with the current literature, confirming that laparoscopic cholecystectomy is the best treatment option with minimal fetal maternal morbidity, reducing the incidence of pancreatitis and maternal- fetal consequences. PMID- 25282943 TI - [Cervical cryosurgery: thousand cases report]. AB - BACKGROUND: Treatments for cervical lesions through the years have been varied, from cauterization with chemicals, to the use of electrosurgery with diathermic loop, however the method to be chosen should be one that offers greater benefits and lower risks. OBJECTIVE: Present a well structured study protocol in patients presenting with cervical disease and offer treatment cryotherapy as ablative method of choice in this group of patients and returning this widely known process, but nevertheless had been relegated. MATERIAL AND METHOD: By an analytical and descriptive retrospective study and treatment of one thousand patients with cervical pathology in the course of 20 years, in which in addition to the drug treatment of individual patients, treatment was performed as ablative cryosurgery cervical is reported, having obtained very good results. RESULTS: With ablative treatment indicated the problem of all' patients resolved, having had a very satisfactory in the short, medium and long term, have had no significant morbidity, thus fulfilling the stated objective. CONCLUSION: Research carried out shows that the surgical procedure performed in carefully selected patients with cervical pathology coursing was appropriate because the results thus demonstrated. PMID- 25282944 TI - [Ultrasonography as a method to determine the correct implantation of intratubaric devices]. AB - BACKGROUND: Essure procedure consists in the placement of two coils in the intramural segment of Fallopian tubes by hysteroscopic causing a fibrosis reaction that unleashes a physiological obstruction. Hysterosalpingography, until today, is the gold standard checking the success of this method of sterilization. OBJECTIVE: Determining if a scan at three months postimplantation is sufficient to confirm the correct positioning of the device. MATERIAL AND METHODS: Descriptive study with 61 patients undergoing definitive hysteroscopic sterilization to validate transvaginal ultrasound as a technique to determine the effectiveness of the method. RESULTS: There were placed 120 devices, of which 117 (97'5%) were visible by ultrasound. Comparing ultrasound findings with gold standard, we obtain that in cases of proper bilateral implantation by hysterosalpingography, with ultrasound we diagnosed the 81 '13%; in cases of correct unilateral implantation we detected 75% with ultrasound, except one patient who was considered proper placement of the coil by ultrasound but hysterosalpingography reported that it was misplaced and the Fallopian tube was permeable. DISCUSSION: Transvaginal ultrasound is an appropriate method to confirm the correct position of intratubaric Essure devices, its safety, low cost and reproducibility. However, our study cannot replace the hysterosalpingography as gold standard. PMID- 25282945 TI - [Cesarean scar defect]. AB - BACKGROUND: Caesarean section has immediate complications and traditional, well known later, but of equal or greater importance are the risks for the next pregnancy, due to the possibility of uterine rupture, placenta accreta, placenta previa, pregnancy or cervical scar hysterorrhaphy, and other complications not well disseminated or known defects associated with scar hysterorrhaphy (dehiscence). OBJECTIVE: Show off frequency and caracteristics of the cesarean scar defects. MATERIAL AND METHOD: Retrospective and observational study, by reviewing videos of patients subjected to exploration of the endocervical canal and uterine cavity whith hysteroscope in a 5 year period, in patients with a history of previous cesarean section, evaluating the integrity of the scar. The defects were classified into three categories according to the depth of the defect. RESULTS: Patients with previous c-section, 62.5% had a defect of the closure of the scar. The total dehiscence of the muscular layer was found in patients with 1, 2 and 3 or more c-section, and only 3 cases (12%) of the defects were found at the level of the isthmus. CONCLUSION: Cesarean scar defects are more frequent than we assumed. Since they favour obstetric and gynecological obstetric pathology, with the increase in the number of patients who undergo caesarean section, this has become a health problem, and we must know and promote its relationship with abnormal uterine bleeding and secondary sterility. PMID- 25282946 TI - [Posterior tibial nerve stimulation for pelvic floor dysfunction. Review]. AB - Pelvic floor dysfunction is a highly prevalent functional pathology that affects women and can present with different clinical symptoms that include urinary urgency with or without incontinence, diurnal and nocturnal frequency, urinary retention, fecal incontinence, obstructive defecation, sexual dysfunction and pelvic pain. Lately, concern arised as to offer patients an advanced therapy within an integral approach. This interest was first focused in sacral nerve root modulation, a key element for pelvic function. Neuromodulation is considered a normal characteristic of the nervous system that regulates or modifies the electric impulses that come from different nervous body tissues. Neuromodulation is carried out through sacral neurostimulation (SNS), posterior tibial nerve stimulation (PNTS), which are reversible non destructive therapies used for peripheric stimulation of nerves, ganglia, spinal medula and brain. Even though there is evidence of efficacy for sacral nerve stimulation at short, medium and long-term, there are two main concerns within this approach: invasivity and high cost. It seems posterior nerve tibial stimulation has the same neuromodulatory effect as the one obtained by sacral nerve stimulation through a less invasive route and lower cost. PMID- 25282948 TI - [Placenta accreta with placenta previa. Case report]. AB - The placenta praevia and acretism placental were concurrently and are conditions of abnormal placenta, in which the villus sampling invade the myometrium at the site of implantation and is associated with the partial or complete absence of the decidua. Clinical case: Patient's 32 years of age, with 34 weeks pregnancy. Obstetric history of previous cesarean section, transvaginal bleeding several times; the diagnosis by ultrasound showed placenta praevia occlusive. Surgical treatment was abdominal total hysterectomy. PMID- 25282947 TI - [Contraception and breastfeeding. Spacing of pregnancies. Present concepts]. AB - The risk of pregnancy in breastfeeding should be a concern of women. Family planning programs in the post natal period contraceptive choices offer high efficiency. Breastfeeding is a natural contraception method (LAM) as a contraceptive shield has 98% efficiency. Women should consider using an alternate contraceptive method when feeding requirements for this method to be effective are not met. Some of contraceptive alternatives in lactation include hormonal methods. According to the Medical Eligibility Criteria for Contraceptive Use WHO combined hormonal methods are contraindicated during breastfeeding, hormonal progestogen only methodo are considered only in Group 3 and Group 1 immediate postpartum after 6 weeks postpartum. There are modifications to these criteria by the CDC and the UK for the use of these hormones in early in lactation. PMID- 25282949 TI - [Vulvar carcinoma in situ in 19 year old woman: a case report and literature report]. AB - The vulvar cancer is a rare disease. It's incidence is about 2.2 cases per 100, 000 women. The presentation of invasive vulvar cancer and in situ vulvar cancer has arrise in it's presentation with an increse of 2.4% per year. The National Cancer Institute has reported that vulvar cancer has been one of the twelve maliganant tumors that have increased thei incidence. The following is a case report of a 19 years old woman with diagnose of in situ vulvar cancer found incidentally on the perineal skin during the performing of a uterine curettage, with the diagnosis of abortion. The treatment consisted in a wide resecction of the perineal skin and residual condilomas and evaporation of vaginal condilomas with laser argon, following vulvar reconstruction. After the surgical treatment 5% imiquimod cream was used in the site of the surgery three times a week for an eight weeks period. Complete remision was achived and there was not early recurrences. PMID- 25282950 TI - [Management of ovarian metastasis from a lobular breast carcinoma]. AB - Ovarian metastatic breast cancer is infrequent and usually is originating from lobular carcinomas. It was found that the risk of developing an ovarian neoplasm is approximately doubled in women with a history of breast cancer. The finding of an adnexal mass in these patients involves a particular concern and requires a study. We report a case of a 67-year-old female diagnosed of an infiltrating lobular breast carcinoma. It is done lumpectomy and an axillary dissection of lymph nodes resulting 2 of 13 lymph nodes positives. She was treated with chemotherapy and hormone treatment staying the disease in remission for years. After she was admitted with malignant pleural effusion and pathological costal fracture. The ultrasound shows an increase of size of annexes and a CA125 and CA15.3 increased in the analysis. Bilateral oophorectomy was performed. The pathology was consistent with lobular breast carcinoma. Subsequently another income was required because of disease progression. Currently after almost two years since the adnexectomy, is in close monitoring by medical oncologists. Although the diagnosis of an adnexal mass in a woman who has had breast cancer is usually a benign finding, the risk in these women to develop a malignant ovarian pathology is increased compared to the general population. Therefore, although the patient remains asymptomatic, it is important an abdominopelvic exploration from time to time. If the ultrasound image of the adnexal mass is suspect, the CA125 is increased, or estrogen receptors are negatives in the original breast tumor, should be performed surgical evaluation. PMID- 25282951 TI - [Updating the surgical treatment of cervical cancer. 1958]. PMID- 25282952 TI - Contamination status and possibility of toxic effects of co-planar polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and dichlorodiphenyltrichloroethane in large japanese field mouse (Apodemus speciosus) collected from Hokkaido and Aomori. AB - Contamination levels of coplanar polychlorinated biphenyls (Co-PCBs), polycyclic aromatic hydrocarbons (PAHs), and dichlorodiphenyltrichloroethane (DDTs) were measured in the entire body of the large Japanese field mouse (Apodemus speciosus) collected from Hokkaido (Ishikari and Rankoshi) and Aomori prefecture (Takko) in Japan. Higher concentrations of PCBs including Co-PCBs, were observed in the mice collected from Ishikari than those from Rankoshi. The concentration of PAHs in the soil from Ishikari was also higher than that in the other sampling sites. The findings suggest that Ishikari is the most polluted area, probably because of human activities, depending on the population distribution. However, the observed contaminant levels were extremely lower compared to those in previous studies. The ratio of testis weight to body weight (TW/BW) was the lowest in the mice collected from Ishikari, which is the area contaminated with PAHs and p,p'-dichlorodiphenyldichloroethylene (DDE). However, the serum testosterone levels of mice from the Ishikari area were higher than those from the non-contaminated other areas although no significant differences. Previous studies have shown that a low-level exposure to dioxin related compounds (DRCs) disturbances in sexual function, resulting in the production of testosterone. This study showed that POPs exposure is one of the possibility of the high testosterone concentration in the mice of the Ishikari area in addition to a cause of biological and environmental factors such as habitat density, age, temperatures and/or food riches. PMID- 25282953 TI - Organ-specific changes in norepinephrine turnover against various stress conditions in thermoneutral mice. AB - The effects of three stressors of different categories, namely cold exposure, immobilization, and lipopolysaccharide (LPS) treatment, on sympathetic nerve activity were examined by assessing its biochemical index norepinephrine (NE) turnover in peripheral organs of C57BL/6 mice. NE turnover was assessed by measuring the decrease in the organ NE concentration 3 h after inhibition of catecholamine biosynthesis with alpha-methyl-p-tyrosine. NE turnover in brown adipose tissue (BAT) in the room temperature (23 degrees C) control group was as high as that in the cold exposure (4 degrees C) group. Similarly, the mRNA level of the thermogenic marker uncoupling protein 1 (UCP1) in the room temperature control group was as high as that in the cold exposure group. As sympathetic stimulation upregulates the UCP1 mRNA level, we thought that sympathetic nerve tonus in BAT was already accelerated at room temperature. To exclude factors affecting basal sympathetic nerve activity, mice housed at thermoneutral temperature (30 degrees C) were used as controls for the subsequent experiments. In this condition, cold exposure accelerated NE turnover in the BAT, as well as heart and pancreas. The corticosterone level showed a higher trend in the cold exposure group in comparison to the control group. Immobilization accelerated NE turnover in the spleen, pancreas, and white adipose tissue and elevated the corticosterone level. LPS (3 mg/kg, i.p.) did not affect NE turnover in all peripheral organs but elevated the corticosterone level. In summary, the sympathetic nervous and adrenocortical responses to three stressors differed greatly. In particular, sympathetic responses showed clear organ-specific acceleration patterns. This important feature may improve our understanding of the multiplicity of biological responses. PMID- 25282954 TI - Salmonella serovars and antimicrobial resistance in strains isolated from wild animals in captivity in Sinaloa, Mexico. AB - The aim of the present study was to evaluate the frequency of antibiotic resistance in Salmonella spp. strains from wild animals in captivity at the Culiacan Zoo and the Mazatlan Aquarium in Sinaloa, Mexico. We identified 17 different Salmonella enterica serovars at a prevalence of 19.90% (Culiacan Zoo) and 6.25% (Mazatlan Aquarium). Antibiotic sensitivity tests revealed that, of the 83 strains studied, 100% were multidrug resistant (MDR). The drugs against which the greatest resistance was observed were: penicillin, erythromycin, dicloxacillin, ampicillin, cephalothin, and chloramphenicol. We therefore conclude that MDR is common among Salmonella isolates originating from wild animals in captivity in Sinaloa. PMID- 25282955 TI - Effects of in vitro-growth culture duration on fertilizability of bovine growing oocytes and proliferation of cells surrounding oocytes. AB - The effects of in vitro-growth (IVG) culture duration (12 and 14 days) on the fertilizability and the developmental ability of IVG oocytes matured with pre maturational culture, and on the proliferation of cells surrounding oocytes during IVG culture were examined. The fertilization and cleavage rates of 12- and 14-day IVG oocytes were similar; however, 14-day IVG oocytes showed lower blastocyst development rate than 12-day IVG oocytes. In addition, the number of cells surrounding oocytes increased until 12 days of IVG, but decreased at 14 days. The results indicated that the extension of IVG period beyond 12 days impaired the proliferation of cells surrounding oocytes, leading to the decrease of developmental ability but not fertilizability of 14-day IVG oocytes. PMID- 25282956 TI - Contamination status and accumulation characteristics of metals and a metalloid in birds on Teuri Island, Hokkaido, Japan. AB - Teuri Island, Hokkaido in Japan is an important place for seabirds breeding. We measured the concentrations of heavy metals (Hg, Cd, Cr, Co, Ni, Cu, Zn, and Pb) and a metalloid (As) in rhinoceros auklet (Cerorhinca monocerata) (n = 7), thick billed murre (Uria lomvia) (n = 2), spectacled guillemot (Cepphus carbo) (n = 6), slaty-backed gull (Larus schistisagus) (n = 15), jungle crow (Corvus macrorhynchos) (n = 3), Japanese anchovy (Engraulis japonica) (n = 6) and Atka mackerel (Pleurogrammus azonus) (n = 2). Spectacled guillemot had high As concentrations, with its source being their feeding habitat. Concentration of Hg in kidney of jungle crow was higher than other seabird species at Teuri. PMID- 25282957 TI - Changing views on medical education and training. PMID- 25282958 TI - Medical students' views on selection tools for medical school--a mixed methods study. AB - It is important to ensure that the tools used in Medical School selection are acceptable to students and applicants. A questionnaire was administered to year 1 medical students in 2010 to determine the suitability of a variety of selection tools and the acceptability of HPAT-Ireland in particular. There were 291 respondents a 77% response rate representing approximately one third of all school leaver entrants that year. While the majority 285 (98%) were in favour of using school leaving examinations there was also support for the use of interviews 215 (74%) and other tools. Three quarters of Irish respondents 159 (76%) agreed that HPAT-Ireland is a fair test overall however section 3 (non verbal reasoning) appeared less acceptable and relevant than other sections. A little over half had taken a preparatory HPAT-Ireland course 112 (54%). Medical school applicants appear to accept the use of non-traditional tools in the selection process. PMID- 25282959 TI - A national survey of implementation of guidelines for gestational diabetes mellitus. AB - In 2010, national guidelines for the management of gestational diabetes mellitus (GDM) were published by the Health Service Executive (HSE). In 2012, a questionnaire was distributed to all maternity units to survey implementation of the guidelines. All units screened women for GDM, but used different screening tests with fifteen units (79%) using the recommended 75g OGTT, three units (16%) using a 100g OGTT and one unit (5%) using a 50g glucose challenge test. Optimal outcomes are best achieved through multidisciplinary diabetes-obstetric care and this was available in nine of the units (47%). The prevalence of GDM varied from 2.2 - 7.4%. Insulin usage varied from 15-56%. Six centres (31%) had not implemented the national guidelines in full because of lack of resources. Despite national endorsement of the guideline, significant variations remain in implementation. This may lead to differences in clinical outcomes depending on where a woman attends for obstetric care. PMID- 25282960 TI - Primary care in nursing homes revisited: survey of the experiences of primary care physicians. AB - The Irish Health Information and Quality Authority (HIQA) published National Quality Standards for Residential Care Settings for Older People in 2009. We reported on experiences of general practitioners (GPs) in Dublin caring for nursing home patients (NHPs) in 2006. We revisit these experiences following publication of HIQA's standards. 400 GPs received an anonymous postal survey. Of 204 respondents, 145 (71%) felt NHPs required more contact time and 124 (61%) reported more complex consultations compared to other patients. Only 131 (64%) felt adequately trained in gerontology. 143 (70%) reported access to specialist advice, but only 6 (3%) reported a change in this following HIOA standards. 65 (32%) had witnessed substandard care in a NH, of which 16 (25%) made no report, similar figures to 2006. There remains similar levels of concern regarding patient complexity, substandard care, access to specialist support and training in the care of NHPs. Many GPs expressed uncertainty regarding their role in implementing HIQA standards. PMID- 25282961 TI - Staff attitudes to an ultrasound-guided peripheral nerve block room for orthopaedic patients. AB - Ultrasound-guided peripheral nerve blocks have well recognised benefits in orthopaedic patients. Some hospitals, to maximise these benefits, establish dedicated "block rooms" to deliver this service. Orthopaedic surgery makes up a large proportion of our hospitals work load, and many of these patients would benefit from ultrasound-guided peripheral nerve blocks. We analysed the attitudes of key staff in our hospital towards the establishment of a block room. Sixty questionnaires were distributed and 47 (78%) were completed. Orthopaedic surgeons (n = 6) were concerned ultrasound-guided peripheral nerve blocks would delay theatre lists (83%), and cause patients pain (67%) and increased anxiety (67%). Anaesthetists (n = 10) and Nurses (n = 30) were concerned there was insufficient experience in their departments to deliver this service (80% and 77%, respectively). However, 91% of all staff believed funding should be available for a block room. Our survey has identified areas of concern, and deficiencies that we must address before proceeding with the development of such a service. PMID- 25282962 TI - Clinical pregnancy following pre-implantation genetic diagnosis for cystic fibrosis. AB - Pre-implantation genetic diagnosis (PGD) is an established alternative to prenatal testing for couples at risk of transmitting genetic disorders such as cystic fibrosis (CF).PGD screens pre-implantation embryos, allowing the safe transfer of those identified as unaffected. Awareness of CF carrier status in Ireland is increasing following the introduction of neonatal screening in 2011. PGD is the most acceptable reproductive strategy for many at risk Irish couples but until now the treatment necessitated travelling abroad. In 2012, the Irish Medicines Board licenced two Irish fertility clinics to carry out embryo biopsy for PGD. This is the first reported clinical pregnancy following PGD carried out in Ireland. PMID- 25282963 TI - A 76 year old female diagnosed with cystic fibrosis. AB - The diagnosis of Cystic Fibrosis (CF) requires a high clinical suspicion in patients presenting at all ages. Early recognition permits referral to a specialist centre and may reduce the morbidity and mortality associated with CF. We report the case of the oldest patient in Ireland diagnosed with CF at 76 years of age and highlight the clinical features of her presentation. PMID- 25282964 TI - Terminal ileum and total colonic duplication associated with a rectovestibular fistula in a child. AB - The presence of terminal ileum and complete colonic duplication associated with a rectovestibular fistula, caecal diverticulum and multiple appendixes in a child presents an extremely rare diagnostic and management conundrum. We report our surgical approach to successfully correcting this anomaly. PMID- 25282965 TI - Lemierre's syndrome, the forgotten disease. AB - Lemierre's syndrome is a rare and potentially fatal entity affecting otherwise healthy and young adults. The infection originates in the throat and spreads via a septic trombophlebitis of the internal jugular vein, with development of distant septic emboli. This clinical picture is characteristic but many clinicians are unaware of the condition and diagnosis is often delayed with potentially fatal consequences. PMID- 25282966 TI - Oesophageal candidiasis in an immunocompetent child. AB - We are reporting a rare case of oesophageal candidiasis in an immunocompetent child secondary to prolonged use of inhaled steroids. PMID- 25282967 TI - Imaging of gunshot injuries in a west Dublin teaching hospital--a ten year review. AB - There has been an increase in gun-related crime in Ireland over the last decade to gangland violence, especially in west Dublin. This places a burden on hospital services not previously encountered. The aim of this study was to examine the demographics of gunshot: injuries presenting to a Dublin teaching hospital, and the impact on radiology over a ten year period. A total of 65 gunshot injuries were seen. Mortality for high velocity wounds was much higher (10/23, 43%) than for low-velocity shotgun injuries (2/34, 6%). PMID- 25282968 TI - A novel semi-automated method of tracking fetal movements. AB - We have designed software that can "look" at recorded ultrasound sequences. We analyzed fifteen video sequences representing recorded ultrasound scans of nine fetuses. Our method requires a small amount of user labelled pixels for processing the first frame. These initialize GrowCut, a background removal algorithm, which was used for separating the fetus from its surrounding environment (segmentation). For each subsequent frame, user input is no longer necessary as some of the pixels will inherit labels from the previously processed frame. This results in our software's ability to track movement. Two sonographers rated the results of our computer's 'vision' on a scale from 1 (poor fit) to 10 (excellent fit). They assessed tracking accuracy for the entire video as well as segmentation accuracy (the ability to identify fetus from non-fetus) for every 100th processed frame. There was no appreciable deterioration in the software's ability to track the fetus over time. PMID- 25282969 TI - Tolerance of colonoscopy and questioning its utility in the elderly population. AB - This study was carried out from Jan '12-Dec '12 to assess current practice in Kerry General Hospital against the age related indicators for colonoscopies. A total of 1474 colonoscopies were performed, 1177 (79.9%) were diagnostic and 297 (20.10%) were therapeutic, patients were divided into 4 age groups under 75, 75 80, 81-85, 86+. The trend analysis revealed an increase in diagnostic colonoscopies and decrease in therapeutic colonoscopies with age. 664 (45.04%) of colonoscopies were reported normal which made up the majority of the total diagnoses, 1330 (90.2%) of colonoscopies occurred without any complications. Main complications were patient discomfort being the highest, present in 112 (7.6%) of patients, and lowest being urticaria around the IV site present in 1 (0.1%) of the cases. Patient discomfort was higher in younger patients as evidenced by 98 cases aged < 75, followed by 11 cases aged 75-80, 2 cases aged 81-85 and 1 case aged > 86. Highest percentage of poor tolerance was found in 14 (1.1%) of total patients < 75, 1 (0.8%) of total patients aged 75-80, 1(1.7%) of total patients in age group 81-85 and none (0%) in age group > 86. We have established the safety of colonoscopy, low rate of complications and a better tolerance in the elderly from this study, however, its utility, especially in presence of other comorbidities in elderly is questionable. PMID- 25282970 TI - Trisomy 21--incidence and outcomes in the first year, in Ireland today. AB - Incidence of Trisomy 21 in Ireland, 1:546 live births, is the highest in Europe. This project aimed to define the incidence of T21 amongst liveborn infants at Cork University Maternity Hospital (CUMH), and to describe neonatal outcomes and progress in their first year. Infants were identified from Social Work department records. A retrospective review of the neonatal inpatient database, outpatient letters and medical charts was performed. Forty three infants with T21 were born in CUMH in 2010 and 2011. Incidence of T21 was 1:411. Antenatal diagnosis was uncommon at 14% (6). 34 (79%) were admitted to the neonatal unit. Co-morbidities included congenital heart disease 22 (51%) and duodenal atresia 2 (5%). Thirty four were followed-up in CUMH outpatient department. Of these, 34 (100%) had thyroid function testing, 29 (85%) ophthalmology and audiology referral, and 7 (21%) were referred for hip review. Mortality rate was 9% (4). Readmission to hospital in the first year of life was 42% (18). PMID- 25282971 TI - Placental pathology associated with small for gestational age infants. AB - Infants with intrauterine growth restriction (IUGR) are at an increased risk of perinatal disease, including death. Many, but not all small for gestational age infants (SGA) have IUGR. Placental disease is an important cause of IUGR, and gross and microscopic examination is critical in explaining such cases. Reports of placentas from infants with a birth weight < 2SD from the mean (approx 3rd centile) born between Jan 2004-Dec 2011 were evaluated. The principal pathology was determined in each case. Where two or more pathologic findings were present, they were ranked as principal and co-existing in terms of severity. There were 69,493 deliveries over the study period. 461 SGA cases were identified. No placenta was available in 44 cases, and 21 cases of known anomalies were excluded, leaving a study group of 396 cases. Pathology potentially causing or contributing to SGA and/or IUGR was identified in 84.1% of cases. Significant co existing pathology was seen in 88 cases (22%). Placental examination provides key information in understanding abnormal fetal growth. PMID- 25282972 TI - Neonatal telephone consultations in the National Maternity Hospital. AB - Details of telephone consultations concerning infants were recorded prospectively over a two month period in the National Maternity Hospital (NMH). There were one hundred and forty-six calls recorded. One hundred and sixteen (79.5%) calls were from mothers. The average age of the infants was twenty-eight days. Eighty (54.8%) calls were answered by Nursing Staff while the remainder were taken by Doctors. There were thirty-nine (26.7%) calls relating to the gastrointestinal system. There were twenty-seven (18.5%) calls regarding infants with respiratory concerns. The next most common problem was irritability followed by calls concerning jaundice, rashes and umbilical issues. Fifty-five (37.7%) callers were given home care advice or reassurance. Thirty-six (24.7%) were advised to attend a Paediatric Emergency Department (ED). GP visits and Baby Clinic appointments were advised for twenty-four (16.4%) and twenty-three (15.8%) infants respectively while six (4.1%) of the callers were directed to attend NMH immediately. PMID- 25282973 TI - Incidence of central line related/associated bloodstream infections in an acute hospital. AB - Bloodstream infection related to a central venous catheter in the intensive care unit is a substantial clinical and economic problem. The aim of the study was to examine the incidence of central line related bloodstream infections and central line associated bloodstream infections in Our Lady of Lourdes Hospital, Drogheda, during a six month period, using an active patient based prospective surveillance method. CLRBSI rate in ICU/HDU was 0.93/1000 central line days. There was no CLABSI identified in the studied time period. However, further interventions are needed, particularly with CVC care bundle. Also, the implementation of 2% chlorhexidin in 70% isopropylalcohol use for skin asepsis, which is recommended by the Irish national guidelines, would be beneficial. PMID- 25282974 TI - A patient reported outcome measure (PROM) assessing quality of care in the urology hospital outpatient setting. AB - A prospective blind PROM (patient reported outcome measure) study performed in our urology department examined the outpatient-clinic experience. 104 questionnaires were completed. 23 patients (22%) felt the waiting times for appointments was excessive. 13 patients (13%) experienced difficulty in contacting administrative staff. 98 patients (94%) considered the waiting areas good but 31 patients (31%) considered lack of privacy an issue. Consultants saw 65 patients (63%). 62 patients (60%) expected to be seen by a consultant. 32 patients (31%) felt consultation with a different doctor on return visits was unsatisfactory. 76 patients (73%) "fully trusted" their doctors. 78 patients (75%) rated their visit excellent, 10 patients (10%) added comments. Despite frustration with waiting times, the experience of patients reflects a positive rapport and trust between patient and doctor. PMID- 25282976 TI - Response to "Desperate for a hot shower". PMID- 25282975 TI - Using lateral radiographs to determine umbilical venous catheter tip position in neonates. AB - We aimed to assess the difference in measurement of the distance of the UVC tip from the diaphragm between (Anteroposterior) AP and lateral radiographs and to determine the reliability of the measurement of UVC tip distance from the diaphragm between the two views. A retrospective review of paired AP and lateral radiographs taken to assess UVC tip position was carried out in 25 infants was conducted and reliability analysis was carried out. There was a significant difference in the mean (SD) distance of the UVC catheter above the diaphragm between the AP and lateral radiographs: 8.7 (7.8) mm versus 11.6 (7.3) mm (p = 0.003) respectively. Measurements using lateral radiographs were more reliable (Intraclass correlation coefficient: 0.99 vs. 0.93). Inter-observer reliability analysis yielded similar results. Lateral radiographs are more reliable in measurement of UVC tip position and should be performed in conjunction with AP films to aid in determining UVC position. PMID- 25282977 TI - Intra-hepatic haemorrhage and shock during post-natal period, in two brothers with haemophilia. PMID- 25282978 TI - Body fat distribution in Turner syndrome and the influence of puberty. PMID- 25282979 TI - Sun protection awareness and practice among an adult general practice population. PMID- 25282980 TI - Congenital diaphragmatic hernia surveillance. PMID- 25282981 TI - Significant potential for lower costs. AB - Switching to LED lighting has, specialist supplier of such technology, Exled maintains, 'proven to be one of the most significant cost-saving activities hospitals can undertake'. Alongside the financial gains, other benefits include higher levels of patient satisfaction with lighting 'quality' and ambience, and improved environmental credentials. Here Exled MD, Michael Renecle, discusses LED lighting in healthcare in some detail, offers useful pointers on specification, examines some of the 'significant savings and environmental improvements' available to those 'making the switch', and considers the positive experiences of a number of NHS Trusts who have done so. PMID- 25282982 TI - Absence of practical skills addressed. AB - George McDonagh, validation test engineer and University teacher for Decontamination Sciences at the University of Glasgow Dental Hospital and School, and Professor Andrew J Smith, Professor of Clinical Bacteriology, honorary consultant microbiologist, and lead microbiology consultant for Decontamination, NHS Greater Glasgow and Clyde, at the same establishment, describe the instrument decontamination teaching being provided to dental students on the Bachelor of Dental Surgery module at the Dental Hospital and School. The module's objective is to give the students sufficient knowledge and skills to allow them to manage a local decontamination unit (LDU) within their own dental practice. PMID- 25282983 TI - Navigating through 'a labyrinth' of guidance. AB - Devising a strategy to deliver safe water to thousands of outlets spread across numerous buildings is always going to be a challenge, so how do you navigate your way through a bewildering labyrinth of sometimes contradictory guidance documents? Is there, in fact, simply too much guidance? Posing this question at a recent one-day conference on waterborne infections in healthcare facilities, Paul Nolan, authorised water engineer (AE), and operations manager for PFI provider, Lend Lease, took delegates through a review of the latest guidance and regulations, as Susan Pearson reports. PMID- 25282984 TI - Oil-free compressor benefits explained. AB - Oil-free technology for the production of medical air is used in many medical gas systems around the world, and is a requirement of the standards in many places. Under the Department of Health's Health Technical Memorandum, HTM O2-O1, this is not the case, although 'oil-free' is an option. Mark Allen, vice-president of Medical Marketing at Atlas Copco/BeaconMedaes, who is involved with the National Fire Protection Association (NFPA) in the US, the Canadian Standards Association (CSA) in Canada, and the ISO SC-6 (a technical committee on indoor air), discusses how harnessing such technology impacts on production of medical air under the pharmacopeia, and the potential opportunities to reduce maintenance and system problems. PMID- 25282985 TI - Annual verifications--a tick-box exercise? AB - With the onus on healthcare providers and their staff to protect patients against all elements of 'avoidable harm' perhaps never greater, Gwen Walker, a highly experienced infection prevention control nurse specialist, and David Williams, MD of Approved Air, who has 30 years' experience in validation and verification of ventilation and ultraclean ventilation systems, examine changing requirements for, and trends in, operating theatre ventilation. Validation and verification reporting on such vital HVAC equipment should not, they argue, merely be viewed as a 'tick-box exercise'; it should instead 'comprehensively inform key stakeholders, and ultimately form part of clinical governance, thus protecting those ultimately named responsible for organisation-wide safety at Trust board level'. PMID- 25282986 TI - TR/19 update--key concerns addressed. AB - With trade association for the heating, ventilating, air-conditioning, and refrigeration sectors, the Building and Engineering Services Association (B&ES), having recently updated its 'TR/19' guidance document--dealing with the internal cleanliness of ventilation systems--Health Estate Journal (HEJ) asks Richard Norman (RN), chairman of the Association's Ventilation Hygiene Group Branch, and MD of specialist ventilation cleaning services provider, Indepth Hygiene, about the changes, and why the revisions were needed. PMID- 25282987 TI - New training building heralds new chapter. AB - Established in 1969 by the Department of Health as the National Centre for Hospital Engineering, Eastwood Park is today acknowledged as one of the UK's leading providers of specialist technical, engineering, estates, and facilities management training to the healthcare sector. Having celebrated 40 years in business in 2009, and with the breadth of its portfolio growing year-on-year, the training provider has recently entered a particularly exciting new chapter, as plans for a new 3,000 m2 training centre, due to open late next year, and equipped with facilities which Eastwood Park's management say will be 'unrivalled anywhere else in the world', come to fruition. HEJ editor, Jonathan Baillie reports. PMID- 25282988 TI - Benefits of copper recognised worldwide. AB - In an article that first appeared in the June 2014 issue of Health Estate Journal's sister publication, The Clinical Services Journal, the Copper Development Association highlights the growing recognition, both in the UK, and among healthcare research and provider bodies overseas, of the significant part that antimicrobial copper can play in preventing and controlling infection in healthcare settings. Over the past few months, the Association explains, antimicrobial copper's infection-beating properties have been acknowledged by a variety of 'research and horizon-scanning' bodies, among them one in Canada, as well as by a leading UK consultancy and research provider to the NHS. The material is also increasingly being specified by hospitals worldwide following trials which have demonstrated clearly its efficacy in 'beating the bugs'. PMID- 25282989 TI - Creating the right light for older people. AB - In last month's HEJ first we ran the first of a two-part focus, by Carl Gardner, former editor of the Institution of Lighting Professionals' Lighting Journal, on the issues surrounding lighting and the ageing population, which focused particularly on effective task lighting. In the second part of the article, the author considers the important psychological, physiological, and biological effects of lighting on older people--and how improved lighting design can benefit this group in a number of ways. PMID- 25282990 TI - A new approach to radiopharmacy waste. AB - Christine Lawlor, the deputy radiopharmacy manager and a senior clinical technologist in nuclear medicine at Lincoln County Hospital, who has worked at the healthcare facility for over 10 years, reports on a scheme initiated last December which is seeing all recyclable waste removed from the radiopharmacy's 'offensive waste' stream, in the process reducing costs, benefiting the environment, and contributing towards the sustainability goals of the NHS Carbon Reduction Strategy for England. PMID- 25282991 TI - Uninterrupted service on the hospital menu. AB - Lee Vines, sales and marketing director at PKL Group, a leading supplier of temporary and permanent catering infrastructure, considers the challenges facing hospital caterers and estates managers in ensuring that catering equipment is kept up-to-date and fit-for-purpose. He also discusses the options available to make sure kitchen services are able to run without interruption during planned or unplanned periods of kitchen 'downtime'. PMID- 25282992 TI - Smart specification for sustainability. AB - This article details a study reviewing the potential for 'smart specification' of air filtration for air-handling units (AHUs) to offer NHS Trusts sustainability savings, including 'hard cost' reductions. The study, involving three separate NHS Trusts--Calderdale and Huddersfield NHS Foundation Trust, York Teaching Hospital NHS Foundation Trust, and Harrogate and District NHS Foundation Trust- proves that sustainability savings can be realised without significant financial investment. The key investment is manpower, and the study suggests that the use of a third-party supplier would offer the Trusts involved net productivity gains. PMID- 25282993 TI - Buildings rise from natural contours. AB - This October will see the completion of a pound 42 million, two-phase construction project by main contractor, Medicinq Osborne, to deliver a new 86 bed adult acute inpatient mental health unit for Hertfordshire Partnership University NHS Foundation Trust (HPFT) at Kingsley Green near Radlett. Recently named Kingfisher Court--after 150 staff, service-users, and members of the public made their suggestions, and a majority felt 'particularly engaged' with a bird theme--the new facility is a key element of a pound100 m, five-year 'Transformation Programme' through which the Trust is aiming to significantly improve the efficiency and quality of its services across Hertfordshire, North Essex, and Norfolk. As HEJ editor, Jonathan Baillie reports, HPFT's goal is to incorporate into Kingfisher Court 'world-class, state-of-the-art facilities' that will help it achieve its 'vision' of becoming England's best provider of mental healthcare and specialist learning disability services. PMID- 25282994 TI - Energy challenges a central theme. AB - HEJ looks forward to some of the highlights at next month's Healthcare Estates 2014 conference and exhibition in Manchester, set to be the year's largest gathering of personnel from the UK healthcare engineering and estates management sector under one roof. PMID- 25282995 TI - Global climate change: the quantifiable sustainability challenge. AB - Population growth and the pressures spawned by increasing demands for energy and resource-intensive goods, foods, and services are driving unsustainable growth in greenhouse gas (GHG) emissions. Recent GHG emission trends are consistent with worst-case scenarios of the previous decade. Dramatic and near-term emission reductions likely will be needed to ameliorate the potential deleterious impacts of climate change. To achieve such reductions, fundamental changes are required in the way that energy is generated and used. New technologies must be developed and deployed at a rapid rate. Advances in carbon capture and storage, renewable, nuclear and transportation technologies are particularly important; however, global research and development efforts related to these technologies currently appear to fall short relative to needs. Even with a proactive and international mitigation effort, humanity will need to adapt to climate change, but the adaptation needs and damages will be far greater if mitigation activities are not pursued in earnest. In this review, research is highlighted that indicates increasing global and regional temperatures and ties climate changes to increasing GHG emissions. GHG mitigation targets necessary for limiting future global temperature increases are discussed, including how factors such as population growth and the growing energy intensity of the developing world will make these reduction targets more challenging. Potential technological pathways for meeting emission reduction targets are examined, barriers are discussed, and global and US. modeling results are presented that suggest that the necessary pathways will require radically transformed electric and mobile sectors. While geoengineering options have been proposed to allow more time for serious emission reductions, these measures are at the conceptual stage with many unanswered cost, environmental, and political issues. Implications: This paper lays out the case that mitigating the potential for catastrophic climate change will be a monumental challenge, requiring the global community to transform its energy system in an aggressive, coordinated, and timely manner. If this challenge is to be met, new technologies will have to be developed and deployed at a rapid rate. Advances in carbon capture and storage, renewable, nuclear, and transportation technologies are particularly important. Even with an aggressive international mitigation effort, humanity will still need to adapt to significant climate change. PMID- 25282996 TI - Modeled and observed fine particulate matter reductions from state attainment demonstrations. AB - States rely upon photochemical models to predict the impacts of air quality attainment strategies, but the performance of those predictions is rarely evaluated retrospectively. State implementation plans (SIPs) developed to attain the 1997 U.S. standard for fine particulate matter (PM2.5; denoting particles smaller than 2.5 microns in diameter) by 2009 provide the first opportunity to assess modeled predictions of PM2.5 reductions at the state level. The SIPs were the first to rely upon a speciated modeled attainment test methodology recommended by the U.S. Environmental Protection Agency to predict PM2.5 concentrations and attainment status. Of the 23 eastern U.S. regions considered here, all but one achieved the 15 microg/m3 standard by 2009, and the other achieved it the following year with downward trends sustained in subsequent years. The attainment tests predicted 2009 PM2.5 design values at individual monitors with a mean bias of 0.38 microg/m3 and mean error of 0.68 microg/m3, and were 95% accurate in predicting whether a monitor would achieve the standard. All of the errors were false alarms, in which the monitor observed attainment after a modeled prediction of an exceedance; in these cases, the states used weight-of evidence determinations to argue that attainment was likely. Overall, PM2.5 concentrations at monitors in the SIP regions declined by 2.6 microg/m3 from 2000 2004 to 2007-2009, compared with 1.6 microg/m3 in eastern U.S. regions originally designated as attainment. Air quality improvements tended to be largest at monitors that were initially the most polluted. Implications: As states prepare to develop plans for attaining a more stringent standard for fine particulate matter, this retrospective analysis documents substantial and sustained air quality improvements achieved under the previous standard. Significantly larger air quality improvements in regions initially designated nonattainment of the 1997 standard indicate that this status prompted heightened control efforts: The speciated modeled attainment test is found to be accurate and slightly conservative in predicting particulate concentrations for the cases considered here, providing confidence for its use in upcoming attainment plans. PMID- 25282997 TI - Changes in air quality at near-roadway schools after a major freeway expansion in Las Vegas, Nevada. AB - Near-roadway ambient black carbon (BC) and carbon monoxide (CO) concentrations were measured at two schools adjacent to a freeway and at an urban background school 2 km from the freeway to determine the change in concentrations attributable to vehicle emissions after the three-lane expansion of U.S. Highway 95 (US 95) in Las Vegas, Nevada. Between summer 2007 and summer 2008, average weekday small-vehicle volume increased by 40% +/- 2% (standard error). Average weekday large-vehicle volume decreased by 17% +/- 5%, due to a downturn in the economy and an associated decline in goods movement. Average vehicle speed increased from 58 to 69 mph, a 16% +/- 1% increase. The authors compared BC and CO concentrations in summer 2007 with those in summer 2008 to understand what effect the expansion of the freeway may have had on ambient concentrations: BC and CO were measured 17 m north of the freeway sound wall, CO was measured 20 m south of the sound wall, and BC was measured at an urban background site 2 km south of the freeway. Between summer 2007 and summer 2008, median BC decreased at the near-road site by 40% +/- 2% and also decreased at the urban background site by 24% +/- 4%, suggesting that much of the change was due to decreases in emissions throughout Las Vegas, rather than only on US 95. CO concentrations decreased by 14% +/- 2% and 10% +/- 3% at the two near-road sites. The decrease in BC concentrations after the expansion is likely due to the decrease in medium- and heavy-duty-vehicle traffic resulting from the economic recession. The decrease in CO concentrations may be a result of improved traffic flow, despite the increase in light-duty-vehicle traffic. Implications: Monitoring of BC and CO at near-road locations in Las Vegas demonstrated the impacts of changes in traffic volume and vehicle speed on near-road concentrations. However, urban scale declines in concentrations were larger than near-road changes due to the impacts of the economic recession that occurred contemporaneously with the freeway expansion. PMID- 25282998 TI - Effects of remediation train sequence on decontamination of heavy metal contaminated soil containing mercury. AB - When a contaminated site contains pollutants including both nonvolatile metals and Hg, one single remediation technology may not satisfactorily remove all contaminants. Therefore, in this study, chemical extraction and thermal treatment were combined as a remediation train to remove heavy metals, including Hg, from contaminated soil. A 0.2 M solution of ethylenediamine tetraacetic acid (EDTA) was shown to be the most effective reagent for extraction of considerable amounts of Cu, Pb, and Zn (> 50%). Hg removal was ineffective using 0.2 M EDTA, but thermogravimetric analysis suggested that heating to 550 degrees C with a heating rate of 5 degrees C/min for a duration of 1 hr appeared to be an effective approach for Hg removal. With the employment of thermal treatment, up to 99% of Hg could be removed. However executing thermal treatment prior to chemical extraction reduced the effectiveness of the subsequent EDTA extraction because nonvolatile heavy metals were immobilized in soil aggregates after the 550 degrees C treatment. The remediation train of chemical extraction followed by thermal treatment appears to remediate soils that have been contaminated by many nonvolatile heavy metals and Hg. Implications: A remediation train conjoining two or more techniques has been initialized to remove multiple metals. Better understandings of the impacts of treatment sequences, namely, which technique should be employed first on the soil properties and the decontamination efficiency, are in high demand. This study provides a strategy to remove multiple heavy metals including Hg from a contaminated soil. The interactions between thermal treatment and chemical extraction on repartitioning of heavy metals was revealed. The obtained results could offer an integrating strategy to remediate the soil contaminated with both heavy metals and volatile contaminants. PMID- 25282999 TI - Decomposition of organochlorine compounds in flue gas from municipal solid waste incinerators using natural and activated acid clays. AB - High-temperature particle control (HTPC) using a ceramic filter is a dust collection method without inefficient cooling and reheating of flue gas treatment; thus, its use is expected to improve the energy recovery efficiency of municipal solid waste incinerators (MSWIs). However there are concerns regarding de novo synthesis and a decrease in the adsorptive removal efficiency of dioxins (DXNs) at approximately 300 degrees C. In this study, the effect of natural and activated acid clays on the decomposition of monochlorobenzene (MCB), one of the organochlorine compounds in MSW flue gas, was investigated. From the results of MCB removal tests at 30-300 degrees C, the clays were classified as adsorption, decomposition, and low removal types. More than half of the clays (four kinds of natural acid clays and two kinds of activated acid clays) were of the decomposition type. In addition, the presence of Cl atoms detached from MCB was confirmed by washing the clay used in the MCB removal test at 300 degrees C. Activated acid clay was expected to have high dechlorination performance because of its proton-rich-composition, but only two clays were classed as decomposition type. Conversely, all the natural acid clays used in this work were of the decomposition type, which contained relatively higher di- and trivalent metal oxides such as Al2O3, Fe2O3, MgO, and CaO. These metal oxides might contribute to the catalytic dechlorination of MCB at 300 degrees C. Therefore, natural and activated acid clays can be used as alternatives for activated carbon at 300 degrees C to remove organochloride compounds such as DXNs. Their utilization is expected to mitigate the latent risks related to the adoption of HTPC, and also to contribute to the improvement of energy recovery efficiency of MSWI. Implications: The effect of natural and activated acid clays on MCB decomposition was investigated to evaluate their suitability as materials for the removal of organochlorine compounds, such as DXNs, from MSWI flue gas at approximately 300 degrees C. More than half of the clays used in this study showed the decomposition characteristics of MCB. The presence of Cl atoms in the clay used in the MCB removal test at 300 degrees C proved the occurrence of MCB decomposition. The results of this study suggest a novel flue gas treatment method to establish high-energy efficient MSWI systems. PMID- 25283000 TI - Evaluating the capabilities of aerosol-to-liquid particle extraction system (ALPXS)/ICP-MS for monitoring trace metals in indoor air. AB - This study investigates the application of the Aerosol-to-Liquid Particle Extraction System (ALPXS), which uses wet electrostatic precipitation to collect airborne particles, for multi-element indoor stationary monitoring. Optimum conditions are determined for capturing airborne particles for metal determination by inductively coupled plasma-mass spectrometry (ICP-MS), for measuring field blanks, and for calculating limits of detection (LOD) and quantification (LOQ). Due to the relatively high flow rate (300 L min(-1)), a sampling duration of 1 hr to 2 hr was adequate to capture airborne particle-bound metals under the investigated experimental conditions. The performance of the ALPXS during a building renovation demonstrated signal-to-noise ratios appropriate for sampling airborne particles in environments with elevated metal concentrations, such as workplace settings. The ALPXS shows promise as a research tool for providing useful information on short-term variations (transient signals) and for trapping particles into aqueous solutions where needed for subsequent characterization. As the ALPXS does not provide size-specific samples, and its efficiency at different flow rates has yet to be quantified, the ALPXS would not replace standard filter-based protocols accepted for regulatory applications (e.g., exposure measurements), but rather would provide additional information if used in conjunction with filter based methods. Implications: This study investigates the capability of the Aerosol-to-Liquid Particle Extraction System (ALPXS) for stationary sampling of airborne metals in indoor workplace environments, with subsequent analysis by ICP-MS. The high flow rate (300 L/min) permits a short sampling duration (< 2 hr). Results indicated that the ALPXS was capable of monitoring short-term changes in metal emissions during a renovation activity. This portable instrument may prove to be advantageous in occupational settings as a qualitative indicator of elevated concentrations of airborne metals at short time scales. PMID- 25283001 TI - Simultaneous removal of sulfur dioxide and polycyclic aromatic hydrocarbons from incineration flue gas using activated carbon fibers. AB - Incineration flue gas contains polycyclic aromatic hydrocarbons (PAHs) and sulfur dioxide (SO2). The effects of SO2 concentration (0, 350, 750, and 1000 ppm), reaction temperature (160, 200, and 280 degrees C), and the type of activated carbon fibers (ACFs) on the removal of SO2 and PAHs by ACFs were examined in this study. A fluidized bed incinerator was used to simulate practical incineration flue gas. It was found that the presence of SO2 in the incineration flue gas could drastically decrease removal of PAHs because of competitive adsorption. The effect of rise in the reaction temperature from 160 to 280 degrees C on removal of PAHs was greater than that on SO2 removal at an SO2 concentration of 750 ppm. Among the three ACFs studied, ACF-B, with the highest microporous volume, highest O content, and the tightest structure, was the best adsorbent for removing SO2 and PAHs when these gases coexisted in the incineration flue gas. Implications: Simultaneous adsorption of sulfur dioxide (SO2) and polycyclic aromatic hydrocarbons (PAHs) emitted from incineration flue gas onto activated carbon fibers (ACFs) meant to devise a new technique showed that the presence of SO2 in the incineration flue gas leads to a drastic decrease in removal of PAHs because of competitive adsorption. Reaction temperature had a greater influence on PAHs removal than on SO2 removal. ACF-B, with the highest microporous volume, highest O content, and tightest structure among the three studied ACFs, was found to be the best adsorbent for removing SO2 and PAHs. PMID- 25283002 TI - Difference in concentration trends of airborne particulate matter during rush hour on weekdays and Sundays in Tokyo, Japan. AB - Suspended particulate matter (SPM) and fine particulate matter (less than or equal to 2.5 microm: PM2.5) have generally been decreasing for the last decade in Tokyo, Japan. To elucidate the major cause of this decrease, the authors investigated the different trends of airborne particulates (both SPM and PM2.5 concentrations) by evaluating comparisons based on the location of the monitoring stations (roadside vs. ambient), days of the week (weekdays vs. Sundays), and daily fluctuation patterns (2002 vs. 2010). Hourly mean SPM and PM2.5 concentrations were obtained at four monitoring stations (two roadside stations, two ambient stations) in Tokyo, Japan. Annual mean concentrations of each day of the week and of each hour of the day from 2002 to 2010 were calculated. The results showed that (1) the daily differences in annual mean concentration decreased only at the two roadside monitoring stations; (2) the high hourly mean concentrations observed on weekdays during the daily rush hour at the two roadside monitoring stations observed in 2002 diminished in 2010; (3) the SPM concentration that decreased the most since 2002 was the PM2.5 concentration; and (4) the fluctuation of hourly concentrations during weekdays at the two roadside monitoring stations decreased. A decreasing trend of airborne particulates during the daily rush hour in Tokyo, Japan, was observed at the roadside monitoring stations on weekdays since 2002. The decreasing PM2.5 concentration resulted in this decreasing trend of airborne particulate concentrations during the daily rush hours on weekdays, which indicates fewer emissions were produced by diesel vehicles. Implications: The authors compared the trends of SPM and PM2.5 in Tokyo by location (roadside vs. ambient), days of the week (weekdays vs. Sundays), and daily fluctuation patterns (2002 vs. 2010). The high hourly mean concentrations observed at the roadside location during rush hour on weekdays in 2002 diminished in 2010. The SPM concentration that decreased during rush hour the most was the PM2.5 concentration. This significant decrease in the PM2.5 concentration resulted in the general decreasing trend of SPM concentrations during the rush hours on weekdays, which indicates fewer emissions were produced from diesel vehicles. PMID- 25283003 TI - Installation of platform screen doors and their impact on indoor air quality: Seoul subway trains. AB - In this study, variations of particulate matter (PM) concentrations in subway trains following installation of platform screen doors (PSDs) in the Seoul subway system were investigated. PM samples were collected in the trains on subway lines 1-8 before and after installation of PSDs. It was found that the mean PM10 concentration in the trains after PSDs installation increased significantly by 29.9% compared to that before installation. In particular, the increase of PM10 in line 6 was the highest at 103%. When the relationship between PM10 and PM2.5 was compared, coefficients of determination (r2) before and after PSDs installations were 0.696 and 0.169, respectively. This suggests that air mixing between the platform and the tunnel after PSDs installation was extremely restricted. In addition, the indoor/outdoor PM10 ratio following PSDs installation increased from 1.32 to 2.97 relative to the period with no installed PSDs. Furthermore, this study revealed that PM levels in subway trains increased significantly after all underground PSDs were put in use. Several potential factors were examined that could result in this PM increase, such as train ventilation systems, operational conditions, passenger volume, subway depth, and the length of underground segments. Implications: PM10 concentrations inside the subway trains increased after PSDs installation. This indicates that air quality in trains was very seriously impacted by PSDs. PM10 levels were also influenced by the tunnel depth and length of the underground segments. To prevent the adverse effect on human health by PM10 emitted from the tunnel, an applicable ventilation system to reduce PM10 is required inside trains and tunnels. PMID- 25283004 TI - Measurement of atmospheric pollutants associated with oil and natural gas exploration and production activity in Pennsylvania's Allegheny National Forest. AB - Oil and natural gas exploration and production (E&P) activities generate emissions from diesel engines, compressor stations, condensate tanks, leaks and venting of natural gas, construction of well pads, and well access roads that can negatively impact air quality on both local and regional scales. A mobile, autonomous air quality monitoring laboratory was constructed to collect measurements of ambient concentrations of pollutants associated with oil and natural gas E&P activities. This air-monitoring laboratory was deployed to the Allegheny National Forest (ANF) in northwestern Pennsylvania for a campaign that resulted in the collection of approximately 7 months of data split between three monitoring locations between July 2010 and June 2011. The three monitoring locations were the Kane Experimental Forest (KEF) area in Elk County, which is downwind of the Sackett oilfield; the Bradford Ranger Station (BRS) in McKean County, which is downwind of a large area of historic oil and gas productivity; and the U.S. Forest Service Hearts Content campground (HC) in Warren County, which is in an area relatively unimpacted by oil and gas development and which therefore yielded background pollutant concentrations in the ANF. Concentrations of criteria pollutants ozone and NO2 did not vary significantly from site to site; averages were below National Ambient Air Quality Standards. Concentrations of volatile organic compounds (VOCs) associated with oil and natural gas (ethane, propane, butane, pentane) were highly correlated. Applying the conditional probability function (CPF) to the ethane data yielded most probable directions of the sources that were coincident with known location of existing wells and activity. Differences between the two impacted and one background site were difficult to discern, suggesting the that the monitoring laboratory was a great enough distance downwind of active areas to allow for sufficient dispersion with background air such that the localized plumes were not detected. Implications: Monitoring of pollutants associated with oil and natural gas exploration and production activity at three sites within the Allegheny National Forest (ANF) showed only slight site-to-site differences even with one site far removed from these activities. However, the impact was evident not in detection of localized plumes but in regional elevated ethane concentrations, as ethane can be considered a tracer species for oil and natural gas activity. The data presented serve as baseline conditions for evaluation of impacts from future development of Marcellus or Utica shale gas reserves. PMID- 25283005 TI - A comparative examination of MBR and SBR performance for the treatment of high strength landfill leachate. AB - The management of landfill leachate is challenging, with relatively limited work targeting high-strength leachate. In this study, the performance of the membrane bioreactor (MBR) and sequencing batch reactor (SBR) technologies are compared in treating high-strength landfill leachate. The MBR exhibited a superior performance with removal efficiencies exceeding 95% for BOD5, TN, and NH3 and an improvement on SBR efficiencies ranging between 21 and 34%. The coupled experimental results contribute in filling a gap toward improving the management of high-strength landfill leachate and providing comparative guidelines or selection criteria and limitations for MBR and SBR applications. Implications: While the sequencing batch reactor (SBR) technology offers some flexibility in terms of cycle time and sequence, its performance is constrained when considering landfill leachate associated with significant variations in quality and quantity. Combining membrane separation and biodegradation processes or the membrane bioreactor (MBR) technology improved removal efficiencies significantly. In the context of leachate management using the MBR technology, more efforts have targeted low-strength leachate with limited attempts at moderate to high strength leachate. In this study, the SBR and MBR technologies were tested under different operating conditions to compare and evaluate their feasibility for the management of high-strength leachate from a full-scale operating landfill. Such a comparison has not been reported for high-strength leachate. PMID- 25283006 TI - Encapsulation of nonmetallic fractions recovered from printed circuit boards waste with thermoplastic. AB - The present work includes a process for encapsulation by combining substantially simultaneously dry nonmetallic printed circuit boards (PCBs) powder and recycled high-density polyethylene (rHDPE) in an extruder to form a homogenous matrix. The extruded materials were then molded into standard tensile, flexural, and impact properties testing specimens. Nonmetallic PCB mainly consists of large amount of glass fiber-reinforced epoxy resin materials. Incorporation of 50 wt% nonmetallic PCB in rHDPE matrix had increased the flexural strength and modulus by 35% and 130%, respectively. Tensile strength reported to be constant without much improvement. However, the Young's modulus has increased by 180%, with incorporation of 50 wt% nonmetallic PCB. The addition of 6 phr (parts per hundred) maleated polyethylene (MAPE) resulted in 2-fold increase in tensile and flexural strength. Regarding the leaching properties, Cu was identified as the metal that leached at the highest level from the raw nonmetallic PCB, at 59.09 mg/L. However, after the nonmetallic PCB was filled in rHDPE/PCB composites, the concentration of Cu was reduced far below the regulatory limit, to only 3 mg/L. Thermal properties of composites were studied, and it was found out that incorporation of nonmetallic PCB fillers in rHDPE resulted in low thermal conductivity, whereas mechanical strength of the composites showed maximum improvements at 220 degrees C. Overall, the encapsulation technique using nonmetallic PCB waste has formed a monolithic waste form that provides a barrier to the dispersion of wastes into the environment. Implications: Nonmetallic materials reclaimed from waste PCBs were used to analyze the chemical composition, and it was found that nonmetalllic PCBs mainly consist of glass fiber-reinforced epoxy resin materials. With such millions of glass fibers in nonmetallic PCBs, there are mass-excellent supporting bodies that enhance the mechanical properties of composites. In fact, utilization of nonmetallic PCB waste as filler in composites can dramatically restrain the solubility of heavy metals in leachate solution, thus making it safe to be used in practical products. PMID- 25283007 TI - [Alcohol drinking as a risk factor for cancer]. PMID- 25283008 TI - Successful resection of a giant mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose accumulation after neoadjuvant chemotherapy: report of a case. AB - A 32-year-old man presented with a mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose (FDG) accumulation (maximum standardized uptake value = 22.21) and extremely elevated blood alpha-fetoprotein (AFP) level (9203.0 ng/ml). The patient underwent 4 cycles of neoadjuvant chemotherapy (cisplatin, bleomycin, and etoposide), which normalized the AFP level and reduced the tumor size, allowing complete resection without a support of extracorporeal circulation. Despite preoperative positron emission tomography revealing increased FDG uptake in the residual tumor (maximum standardized uptake value = 3.59), the pathologic evaluation revealed that no viable germ cell tumor cells remained. We believe FDG uptake should not be used as a criterion for surgical resection after neoadjuvant chemotherapy. It is appropriate to resect the residual tumor regardless of FDG uptake after induction chemotherapy if a tumor is resectable and the AFP level normalizes. PMID- 25283009 TI - [Clinical characteristics of pulmonary Mycobacterium avium complex infection complicated with lung cancer]. AB - OBJECTIVES: The coexistence of lung cancer and pulmonary Mycobacterium avium complex (MAC) infection has not been well reported. This study illustrated the clinical characteristics of pulmonary MAC infections complicated with lung cancer. PATIENTS AND METHODS: We conducted a retrospective analysis of the clinical characteristics of patients with pulmonary MAC infections complicated with newly diagnosed lung cancer between 2006 and 2012. RESULTS: Of 530 patients with pulmonary MAC infections, 13 (2.4%) were complicated with lung cancer. Six men and 7 women with a mean age of 73 years were also diagnosed with cancer, and 5 had a smoking history. Six patients were diagnosed concurrently, and 7 patients were diagnosed with pulmonary MAC infections prior to being diagnosed with cancer. Histological examination revealed adenocarcinoma, small cell carcinoma, and other cancer types in 9, 2, and 2 patients, respectively. Eleven of 13 patients had cancers of stages I-IIIA, and 10 underwent cancer resection. Analysis of the anatomical relationship between lung cancer and MAC revealed that both diseases were present in the same lobe in 10 patients. The disease extent was within one-third of a single lung field in 9 patients. Anti-MAC treatment was initiated in 7 patients, but was discontinued in 2 patients owing to side effects. Six patients did not receive anti-MAC treatment. CONCLUSION: In this study, lung cancer was frequent among patients with pulmonary MAC infections, and both diseases tended to be in the early stages. Physicians should consider coexisting lung cancer when managing MAC infections. PMID- 25283010 TI - [New criteria enable shorter hospitalization of patients with continuously smear positive pulmonary tuberculosis]. AB - BACKGROUND: Sputum conversion defined as 3 consecutive smear-negative sputum samples collected on different days is one of standard requirements for discontinuation of isolation for patients with smear-positive pulmonary tuberculosis (SPpTB). Sputum smear conversion is usually seen prior to culture conversion. However, in some patients, sputum smear tests are continuously positive for a long time. To discontinue isolation of the patients, culture conversion is required instead of smear conversion. Culture testing requires a long incubation period, which results in longer patient stay and isolation. OBJECTIVES: To identify a more efficient definition of culture conversion, which will enable treating physicians to take the decision to discontinue isolation. METHODS: The charts of patients with SPpTB admitted from September 2007 to March 2011 were reviewed. The recent definition of culture conversion is 3 subsequent culture-negative sputum specimens incubated for 6 weeks (3 CNs for 6 weeks) in liquid media. Treatment days and admission days were calculated based on the application of the new 3 definitions (3 CNs for 4 weeks, 2 CNs for 6 weeks, 2 CNs for 4 weeks). RESULTS: Of 301 patients, 224 were discharged after smear conversion; 77 were continuously smear-positive and were discharged after culture conversion. The median hospital stay was 56 days in patients discharged due to smear conversion and 107 days in patients discharged due to culture conversion, based on the recent definition. The numbers of treatment days needed for culture conversion were identical in most patients, regardless of definitions. At the time of reporting, all patients conformed to the new definitions and all the patients' sputum specimens were 3 CNs for 6 weeks except for one patient happened to be with 2 consecutive smear-negative specimens at an early phase of chemotherapy. The most efficient definition of culture conversion in this study was 2 CNs for 4 weeks. This enabled to shorten each patient's stay by 31 days and to lessen each patient's cost of hospitalization by about 4,900 dollars. CONCLUSION: Two subsequent CNs for 4 weeks of smear-positive sputum samples is enough to enable discontinuation of patient isolation and may thus shorten hospital stay. PMID- 25283011 TI - [Genetic analysis reveals misidentification of Mycobacterium lentiflavum as Mycobacterium intracellulare by the COBAS TaqMan MAI test]. AB - OBJECTIVE: To evaluate COBAS TaqMan MAI test misidentification of Mycobacterium lentiflavum as Mycobacterium intracellulare. MATERIALS AND METHODS: Preliminary comparative analysis identified 13 clinical isolates used in this study as COBAS Amplicor MAV and MIN-negative but COBAS TaqMan MAI-positive. The COBAS TaqMan MAI test limit of detection and reproducibility were evaluated by tenfold dilution series from 3 x 10(8) CFU/mL. Isolate 16S rDNA nucleotide sequences were compared with Mycobacterium avium and M. intracellulare. RESULTS: Discrepancies were observed between isolates identified as M. lentiflavum by 16S rDNA sequencing and as M. intracellulare by the COBAS TaqMan MAI test. The false-positive results were verified by sequence comparison of a randomly sampled clinical isolate and the M. intracellulare reference strain. Sequence analysis of M. lentiflavum and M. intracellulare 16S rDNA amplification products showed at least 3 mismatches between species. The high identity in the sequence was found for M. intracellulare by COBAS TaqMan MAI. CONCLUSION: In Japan, commercially available nucleic acid probe- and amplification-based tests cannot identify M. lentiflavum. Correct identification, though challenging, is possible using standard cultivation procedures for colony growth. Misleading results using the COBAS TaqMan MAI kit may lead to erroneous diagnoses. PMID- 25283013 TI - A personal perspective. PMID- 25283012 TI - [A case of esophageal and intestinal tuberculosis that occurred during treatment of rheumatoid arthritis with etanercept]. AB - An 88-year-old woman with rheumatoid arthritis who had started etanercept treatment in July 2011 was referred to our hospital in February 2012 for right sided pleural effusion. Chest computed tomography showed right pleural effusion, partial swelling of a calcified mediastinal lymph node, and mid-esophageal thickening of the mucosal wall. Gastroendoscopy showed mid-esophageal ulceration. Histological examination of biopsy specimens from this ulceration revealed noncaseating granulomas with Langhans giant cells. Ziehl-Neelsen staining of this section was positive for acid-fast bacilli. Polymerase chain reaction analysis of gastric juice was positive for Mycobacterium tuberculosis; we therefore diagnosed the patient with esophageal tuberculosis. However, since abdominal computed tomography showed swelling of mesenteric lymph nodes, we also suspected intestinal tuberculosis. Colonoscopy showed multiple ileal erosions; histological analyses of biopsied specimens revealed granulomas with Langhans giant cells, similar to the esophageal findings. We finally diagnosed the patient with both esophageal and intestinal tuberculosis. After anti-tuberculosis treatment, the right pleural effusion disappeared and the abdominal lesions improved. Although mycobacterial involvement of both the esophagus and intestine is rare in immunocompromised and immunocompetent hosts, differential diagnosis of these diseases is likely to become more important. PMID- 25283014 TI - The mobile implant practitioner. PMID- 25283015 TI - Scheduling Institute. Transforming thousands of dental practices each year...it all starts with new patients! PMID- 25283017 TI - A cold case solved? Thank (perhaps) the teeth. PMID- 25283016 TI - Focus on: aesthetics versus cosmetics. PMID- 25283018 TI - Attention, little leaguers: "play with grit. Strive to hit. But never spit!". PMID- 25283019 TI - Cancer-preventing gum? PMID- 25283020 TI - Technology hailed as major breakthrough in oral care. PMID- 25283021 TI - Rapid HIV testing in a dental setting. PMID- 25283022 TI - Brush like this. No, brush like this! No! PMID- 25283023 TI - Lifelong tooth damage ocurs within the first 30 seconds of contact with high acidity liquids. PMID- 25283024 TI - Goldstein, Garber, and Salama: a legacy lives. PMID- 25283025 TI - MAC and ZAC: clinical protocols for predictable implant aesthetics. PMID- 25283026 TI - Success with screw-retained zirconia bridges, part one. PMID- 25283027 TI - Three breakthrough implant procedures. PMID- 25283028 TI - Injection overmolding for aesthetics and strength, Part 2. Treating black triangles in post-ortho cases. PMID- 25283029 TI - Ten myths about endodontics: "fact versus pulp fiction". PMID- 25283030 TI - Are you prescribing bruxism appliances? PMID- 25283031 TI - An implant-assisted removable partial denture. A 36-month follow-up case report. PMID- 25283032 TI - Treating obstructive sleep apnea. A manifest destiny for 21st century dentists. PMID- 25283033 TI - Learning from biofilms. An overview, history, and the lessons they provide for the dental team. PMID- 25283034 TI - Perry L. Parke, Microcopy. PMID- 25283035 TI - A minimally invasive revolution? PMID- 25283036 TI - Dentist to physician patient advocacy for health's sake. PMID- 25283037 TI - Early detection of cancer is seriously important for dentists. PMID- 25283038 TI - Focus on: aesthetic dentistry. PMID- 25283039 TI - Genetic signature reveals new way to classify periodontal disease. PMID- 25283040 TI - Breakthrough salivary test to aid in the fight against oral cancer. PMID- 25283041 TI - Dental trends: knowing these can optimize your practice! PMID- 25283042 TI - Understanding light curing, Part I. Delivering predictable and successful restorations. PMID- 25283043 TI - Are full-coverage crowns overutilized? Supragingival partial-coverage designs as a first option. PMID- 25283044 TI - Importance of lip classification. PMID- 25283045 TI - Stop giving gold back to your patients... you're not doing them any favors. PMID- 25283046 TI - The modern aesthetic mixed restorative case. PMID- 25283047 TI - Solutions to debridement dilemmas. PMID- 25283048 TI - Minimally invasive treatment of brown spot fluorosis. PMID- 25283049 TI - Applying foundational principles to digital technologies. Ensuring success in aesthetic dentistry. PMID- 25283050 TI - Dental digital photography update. A report from the 2014 Chicago midwinter meeting. PMID- 25283051 TI - An effective external bleaching technique. PMID- 25283052 TI - The medical history update: compromised or complete? Obtaining--and maintaining- patient health history information. PMID- 25283053 TI - Integrative transcriptomic and metabonomic molecular profiling of colonic mucosal biopsies indicates a unique molecular phenotype for ulcerative colitis. AB - Ulcerative colitis is the most prevailing entity of several disorders under the umbrella term inflammatory bowel disease, with potentially serious symptoms and devastating consequences for affected patients. The exact molecular etiology of ulcerative colitis is not yet revealed. In this study, we characterized the molecular phenotype of ulcerative colitis through transcriptomic and metabonomic profiling of colonic mucosal biopsies from patients and controls. We have characterized the extent to which metabonomic and transcriptomic molecular phenotypes are associated with ulcerative colitis versus controls and other disease-related phenotypes such as steroid dependency and age at diagnosis, to determine if there is evidence of enrichment of differential expression in candidate genes from genome-wide association studies and if there are particular pathways influenced by disease-associated genes. Both transcriptomic and metabonomic data have previously been shown to predict the clinical course of ulcerative colitis and related clinical phenotypes, indicating that molecular phenotypes reveal molecular changes associated with the disease. Our analyses indicate that variables of both transcriptomics and metabonomics are associated with disease case and control status, that a large proportion of transcripts are associated with at least one metabolite in mucosal colonic biopsies, and that multiple pathways are connected to disease-related metabolites and transcripts. PMID- 25283054 TI - Extremity trauma: field management of sports injuries. AB - Traumatic injuries to the extremities are common in athletic competitions. The practitioner providing coverage of sporting events must be prepared to diagnose and provide initial treatment of these injuries. A thorough history and physical examination should result in a provisional diagnosis. Many injuries will require subsequent radiographs or orthopedic consultation. Limb threatening emergencies are rare but must be promptly recognized and referred to a hospital. Early treatment can protect athletes from further injury and may hasten their return to competition. Some athletes with extremity trauma can return to the contest, but this decision must be made on an individual basis. PMID- 25283055 TI - Slow carboxylation of Rubisco constrains the rate of carbon fixation during Antarctic phytoplankton blooms. AB - High-latitude oceans are areas of high primary production despite temperatures that are often well below the thermal optima of enzymes, including the key Calvin Cycle enzyme, Ribulose 1,5 bisphosphate carboxylase oxygenase (Rubisco). We measured carbon fixation rates, protein content and Rubisco abundance and catalytic rates during an intense diatom bloom in the Western Antarctic Peninsula (WAP) and in laboratory cultures of a psychrophilic diatom (Fragilariopsis cylindrus). At -1 degrees C, the Rubisco turnover rate, kcat (c) , was 0.4 C s( 1) per site and the half saturation constant for CO2 was 15 MUM (vs c. 3 C s(-1) per site and 50 MUM at 20 degrees C). To achieve high carboxylation rates, psychrophilic diatoms increased Rubisco abundance to c. 8% of biomass (vs c. 0.6% at 20 degrees C), along with their total protein content, resulting in a low carbon : nitrogen ratio of c. 5. In psychrophilic diatoms, Rubisco must be almost fully active and near CO2 saturation to achieve carbon fixation rates observed in the WAP. Correspondingly, total protein concentrations were close to the highest ever measured in phytoplankton and likely near the maximum possible. We hypothesize that this high protein concentration, like that of Rubisco, is necessitated by slow enzyme rates, and that carbon fixation rates in the WAP are near a theoretical maximum. PMID- 25283057 TI - Implementation strategies of Systems Medicine in clinical research and home care for cardiovascular disease patients. AB - Insights from the "-omics" science have recently emphasized the need to implement an overall strategy in medical research. Here, the development of Systems Medicine has been indicated as a potential tool for clinical translation of basic research discoveries. Systems Medicine also gives the opportunity of improving different steps in medical practice, from diagnosis to healthcare management, including clinical research. The development of Systems Medicine is still hampered however by several challenges, the main one being the development of computational tools adequate to record, analyze and share a large amount of disparate data. In addition, available informatics tools appear not yet fully suitable for the challenge because they are not standardized, not universally available, or with ethical/legal concerns. Cardiovascular diseases (CVD) are a very promising area for translating Systems Medicine into clinical practice. By developing clinically applied technologies, the collection and analysis of data may improve CV risk stratification and prediction. Standardized models for data recording and analysis can also greatly broaden data exchange, thus promoting a uniform management of CVD patients also useful for clinical research. This advance however requires a great organizational effort by both physicians and health institutions, as well as the overcoming of ethical problems. This narrative review aims at providing an update on the state-of-art knowledge in the area of Systems Medicine as applied to CVD, focusing on current critical issues, providing a road map for its practical implementation. PMID- 25283056 TI - Griscelli syndrome type 3-like phenotype with MYO-5A exon-F deletion. PMID- 25283058 TI - Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity. AB - The pathogenic relevance of sphingolipid metabolism is increasingly being recognised. Here we elaborate on a new player within the sphingolipid field: the degs1 enzyme, a recently discovered enzyme that catalyses the final step in the de novo biosynthesis of ceramides controlling the step from dihydroceramides to ceramides. Here, we describe its function and dysregulation by factors such as oxidative stress, hypoxia and inflammation and provide evidence indicating that dihydroceramides constitute a biologically active molecule from the sphingolipid family with certain differential characteristics with respect to its delta-4 unsaturated counterparts, the ceramides. Finally we present pathophysiological scenarios characterised by specific increases in dihydroceramide that challenge the concept that "all ceramides species are the same". This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. PMID- 25283059 TI - Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4 associated bull's-eye maculopathy. AB - PURPOSE: Quantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease. DESIGN: Prospective cross-sectional study at an academic referral center. SUBJECTS: Thirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy. METHODS: Autofluorescence (AF) images (30 degrees , 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7 degrees to 9 degrees in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next generation sequencing, or both. MAIN OUTCOME MEASURES: Quantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants. RESULTS: ABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9+/-8.3 years) than patients without ABCA4 mutations (mean age, 42.1+/ 14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range. CONCLUSIONS: The qAF method can differentiate between ABCA4 associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing. PMID- 25283060 TI - Vision-threatening lesions developing with longer-term follow-up after treatment of neovascular age-related macular degeneration. AB - PURPOSE: To assess the development of vision-threatening lesions at least 3.5 years after initiating anti-vascular endothelial growth factor (VEGF) for choroidal neovascularization (CNV) in eyes with age-related macular degeneration (AMD). DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 75 patients (81 eyes) with CNV secondary to AMD who received intravitreous anti-VEGF treatment and were followed for at least 3.5 years after initiating treatment. METHODS: Retrospective record review of patients initiating anti-VEGF treatment between November 2005 and June 2008 at a university-based institution for whom at least 3.5 years of follow-up was available at the same institution. MAIN OUTCOME MEASURES: Predominantly hemorrhagic lesions or geographic atrophy (GA). RESULTS: Among 75 patients (81 eyes; 59% were women; median age, 78 years), mean follow-up was 4.9 years and at least 6 years for 40%. Median visual acuity (VA) was 20/80 (interquartile range [IQR], 20/50-20/100) initially, 20/63 (IQR, 20/40-20/160) at 2 years, 20/80 (IQR, 20/40-20/200) at 3.5 years, and 20/63 (IQR 20/32-20/200) at 6 years. Six eyes (7%) had predominantly hemorrhagic lesions initially, whereas this developed in an additional 3 eyes (4%, 95% confidence interval [CI], 1% to 10%) in 3.5 years and in 1 additional eye (1%, 95% CI, 0.03% to 7%) at more than 3.5 years of follow-up. Initially, GA within or overlapping the boundary of the entire CNV was present in 4 eyes (5%) and outside this boundary in 8 eyes (10%). Geographic atrophy enlarged in each eye over time. The only eyes that developed GA outside the CNV boundary were those that had GA outside the lesion at baseline. Additional atrophy within the boundary of CNV defined at baseline, termed "atrophic disciform scars," developed in 5 eyes (6%), all within 4 years of treatment initiation. CONCLUSIONS: Longer-term follow-up of neovascular AMD managed with anti-VEGF therapy suggests that predominantly hemorrhagic lesions may develop within 3.5 years of initiating therapy and more than 3.5 years after initiating therapy. In contrast, new areas of GA beyond the boundaries of the CNV lesion as defined at initiation of anti-VEGF therapy seem unlikely to develop if there is no GA outside of the CNV lesion initially. PMID- 25283061 TI - Diabetes, fasting glucose, and the risk of glaucoma: a meta-analysis. AB - TOPIC: We performed a systematic review to summarize the association of diabetes and blood glucose levels with glaucoma, intraocular pressure (IOP), and ocular hypertension in the general population. CLINICAL RELEVANCE: Diabetes has been proposed as a risk factor for glaucoma, but epidemiologic studies have been inconsistent, and the association is still controversial. Furthermore, no systematic reviews evaluated other metabolic abnormalities, such as the metabolic syndrome, with the risk of glaucoma. METHODS: We identified the studies by searching the PubMed and EMBASE databases. We used inverse-variance weighted random-effects models to summarize relative risks across studies. RESULTS: We identified 47 studies including 2 981 342 individuals from 16 countries. The quality of evidence generally was higher in the cohort compared with case-control or cross-sectional studies. The pooled relative risk for glaucoma comparing patients with diabetes with those without diabetes was 1.48 (95% confidence interval [CI], 1.29-1.71), with significant heterogeneity across studies (I(2) = 82.3%; P < 0.001). The risk of glaucoma increased by 5% (95% CI, 1%-9%) for each year since diabetes diagnosis. The pooled average difference in IOP comparing patients with diabetes with those without diabetes was 0.18 mmHg (95% CI, 0.09 0.27; I(2) = 73.2%), whereas the pooled average increase in IOP associated with an increase in 10 mg/dl in fasting glucose was 0.09 mmHg (95% CI, 0.05-0.12; I(2) = 34.8%). CONCLUSIONS: Diabetes, diabetes duration, and fasting glucose levels were associated with a significantly increased risk of glaucoma, and diabetes and fasting glucose levels were associated with slightly higher IOP. PMID- 25283062 TI - Does internal podalic version of the non-vertex second twin still have a place in obstetrics? A Danish national retrospective cohort study. AB - OBJECTIVE: Investigate the rate of internal podalic version followed by breech extraction for a second non-vertex twin with the first delivered vaginally, and compare neonatal outcome with emergency cesarean section. DESIGN: Cohort study. SETTING: National Danish Registers. POPULATION: Twin pregnancies (1997-2012) with gestational age >=34 weeks; first twin delivered vaginally, second by internal podalic version and breech extraction or cesarean section. METHODS: Data were collected from the Danish National Patient Register and the Danish National Birth Register. MAIN OUTCOME MEASURES: Rates of delivery mode, 5-min Apgar score, asphyxia, umbilical cord pH, admission to neonatal intensive care unit, treatment by mechanical ventilation, and experience level of obstetricians performing internal podalic version. RESULTS: 457 births were available for analysis: 39 cases of internal podalic version and breech extraction and 418 cesarean section cases for second twin. Compared with the cesarean section group, the internal podalic version group had lower rates of asphyxia. Apgar scores and umbilical cord pH levels were not significantly different, although with a tendency to be higher in the internal version than the cesarean section group, however, fewer cases needed mechanical ventilation. Thirty internal versions and breech extractions were performed by obstetricians with >5 years clinical experience and three by trainees. CONCLUSION: Cesarean sections for a second twin seem to have been frequent during the last 15 years while internal podalic version is a vanishing procedure. A slight tendency for better neonatal outcome was found in the internal podalic version and extraction group than cesarean section. PMID- 25283063 TI - A call to action for evidence-based safer conception interventions for HIV affected couples desiring children in Sub-Saharan Africa. PMID- 25283064 TI - Improvement of spinal contusion model by cotransplanting bone marrow stromal cells and induced BMSCs into oligodendrocytes-like cells. AB - BACKGROUND: Demyelination is a common lesion in spinal cord injury, cell therapy is one of the approaches for replacing the lost oligodendrocytes. In this study, bone marrow stromal cells (BMSCs) have been transdifferentiated into oligodendrocyte-like cells (OLCs) and used in cytotherapy of contused spinal cords in rats. METHODS: The BMSCs were collected from the rat long bones, and cultured and characterized by different markers, then they were preinduced with dimethyl sulfoxide followed by retinoic acid, and then the preinduced cells were induced with combination of basic fibroblast growth factor, platelet-derived growth factor and heregulin, followed by triiodothyronine. The OLCs were transplanted in the contused spinal cords of the rats, combined with undifferentiated BMSCs. Specific markers were used in order to characterize the cells by immunohistochemistry and real-time polymerase chain reaction. The BMSCs showed typical immnuoreactivity to the markers, and the OLCs were immunostained with specific markers. RESULTS: There was an improvement in the Basso, Beattie and Bresnahan score with reduction in the cavitation in the contused rats treated with OLCs combined with BMSCs. The transplanted cells were detected in the contused spinal cord. CONCLUSIONS: The combination of the transdifferentiated BMSCs into OLCs with the undifferentiated BMSCs improved the contused spinal cord. PMID- 25283065 TI - Essential role of RVL medullary neuronal activity in the long term maintenance of hypertension in conscious SHR. AB - BACKGROUND: It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions whose role on neurogenic hypertension remains unknown. OBJECTIVE: To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neuron activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). METHODS: In SHR, a lentiviral vector LVV hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP) and heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex functions were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. RESULTS: LVV hKir2.1 expression in RVLM, but not in MCPA, produced a significant time dependent decrease in systolic, diastolic, mean-BP and LF of systolic BP at 60 days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. CONCLUSION: Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP-LF band. Our data are amongst the firsts to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy. PMID- 25283066 TI - Infection of the Invisible: Impressions of a Tuberculosis Intervention Program for Migrants in Istanbul. AB - This paper reviews the experience of the Istanbul Tuberculosis Aid Program, which targeted tuberculosis (TB) disease in the growing irregular migrant populations of Istanbul. This experience illustrated the importance of community-based public health interventions when dealing with an infectious disease like TB among vulnerable groups. Our data is derived primarily from a qualitative study carried out with program stakeholders. We summarize lessons for success of ITAP as: (1) Strengthening impact and outreach of TB intervention among irregular migrant communities through involvement of multiple stakeholders (2) Increasing TB awareness through a community targeted approach (3) Increasing TB contact tracing and treatment success among infected irregular migrants, and, (4) Improving overall health seeking behavior of irregular migrants through empowerment and trust. Given these particularities we list our policy suggestions for revision of regulations regarding TB control and healthcare needs of irregular migrant populations. PMID- 25283067 TI - Subgingival microbiome in smokers and non-smokers in Korean chronic periodontitis patients. AB - Smoking is a major environmental factor associated with periodontal diseases. However, we still have a very limited understanding of the relationship between smoking and subgingival microflora in the global population. Here, we investigated the composition of subgingival bacterial communities from the pooled plaque samples of smokers and non-smokers, 134 samples in each group, in Korean patients with moderate chronic periodontitis using 16S rRNA gene-based pyrosequencing. A total of 17,927 reads were analyzed and classified into 12 phyla, 126 genera, and 394 species. Differences in bacterial communities between smokers and non-smokers were examined at all phylogenetic levels. The genera Fusobacterium, Fretibacterium, Streptococcus, Veillonella, Corynebacterium, TM7, and Filifactor were abundant in smokers. On the other hand, Prevotella, Campylobacter, Aggregatibacter, Veillonellaceae GQ422718, Haemophilus, and Prevotellaceae were less abundant in smokers. Among species-level taxa occupying > 1% of whole subgingival microbiome of smokers, higher abundance (>= 2.0-fold compared to non-smokers) of seven species or operational taxonomic units (OTUs) was found: Fusobacterium nucleatum, Neisseria sicca, Neisseria oralis, Corynebacterium matruchotii, Veillonella dispar, Filifactor alocis, and Fretibacterium AY349371. On the other hand, lower abundance of 11 species or OTUs was found in smokers: Neisseria elongata, six Prevotella species or OTUs, Fusobacterium canifelinum, Aggregatibacter AM420165, Selenomonas OTU, and Veillonellaceae GU470897. Species richness and evenness were similar between the groups whereas diversity was greater in smokers than non-smokers. Collectively, the results of the present study indicate that differences exist in the subgingival bacterial community between smoker and non-smoker patients with chronic moderate periodontitis in Korea, suggesting that cigarette smoking considerably affects subgingival bacterial ecology. PMID- 25283068 TI - Reading polymers: sequencing of natural and synthetic macromolecules. AB - The sequencing of biopolymers such as proteins and DNA is among the most significant scientific achievements of the 20th century. Indeed, modern chemical methods for sequence analysis allow reading and understanding the codes of life. Thus, sequencing methods currently play a major role in applications as diverse as genomics, gene therapy, biotechnology, and data storage. However, in terms of fundamental science, sequencing is not really a question of molecular biology but rather a more general topic in macromolecular chemistry. Broadly speaking, it can be defined as the analysis of comonomer sequences in copolymers. However, relatively different approaches have been used in the past to study monomer sequences in biological and manmade polymers. Yet, these "cultural" differences are slowly fading away with the recent development of synthetic sequence controlled polymers. In this context, the aim of this Minireview is to present an overview of the tools that are currently available for sequence analysis in macromolecular science. PMID- 25283069 TI - Impulse control disorder and rapid eye movement sleep behavior disorder in Parkinson's disease. AB - INTRODUCTION: The relationship between ICD and RBD is still not yet understood and the results from the current literature are contradictory in PD. We aimed to explore the association between rapid eye movement (REM) sleep behavior disorder (RBD) and impulse control disorder in Parkinson's disease. METHODS: Ninety-eight non-demented patients with Parkinson's disease underwent one night of video polysomnography recording. The diagnosis of RBD was established according to clinical and polysomnographic criteria. Impulse control disorders were determined by a gold standard, semi-structured diagnostic interview. RESULTS: Half of the patients (n = 49) reported clinical history of RBD while polysomnographic diagnosis of RBD was confirmed in 31.6% of the patients (n = 31). At least one impulse control disorder was identified in 21.4% of patients, 22.6% with RBD and 20.9% without. Logistic regression controlling for potential confounders indicated that both clinical RBD (OR = 0.34, 95% CI = 0.07-1.48, P = 0.15) and polysomnographic confirmed RBD diagnoses (OR = 0.1.28, 95% CI = 0.31-5.33, P = 0.34) were not associated with impulse control disorder. CONCLUSION: In Parkinson's disease, REM Sleep Behavior Disorder is not associated with impulse control disorder. The results of our study do not support the notion that PSG confirmed RBD and ICD share a common pathophysiology. PMID- 25283070 TI - Effects of augmented visual feedback during balance training in Parkinson's disease: a pilot randomized clinical trial. AB - BACKGROUND: Balance training has been demonstrated to improve postural control in patients with Parkinson's disease (PD). The objective of this pilot randomized clinical trial was to investigate whether a balance training program using augmented visual feedback is feasible, safe, and more effective than conventional balance training in improving postural control in patients with PD. METHODS: Thirty-three patients with idiopathic PD participated in a five-week training program consisting of ten group treatment sessions of 60 min. Participants were randomly allocated to (1) an experimental group who trained on workstations consisting of interactive balance games with explicit augmented visual feedback (VFT), or (2) a control group receiving conventional training. Standing balance, gait, and health status were assessed at entry, at six weeks, and at twelve weeks follow-up. RESULTS: Sixteen patients were allocated to the control group and seventeen to the experimental group. The program was feasible to apply and took place without adverse events. Change scores for all balance measures favored VFT, but the change in the primary outcome measure, i.e. the Functional Reach test, did not differ between groups (t(28) = -0.116, p = .908). No other differences between groups were statistically significant. CONCLUSIONS: VFT proved to be a feasible and safe approach to balance therapy for patients with PD. In this proof of-concept study VFT was not superior over conventional balance training although observed trends mostly favored VFT. These trends approached clinical relevance only in few cases: increasing the training load and further optimization of VFT may strengthen this effect. TRIAL REGISTRATION: Controlled Trials, ISRCTN47046299. PMID- 25283072 TI - Vehicle refuelling, use of domestic wood heaters and the risk of childhood brain tumours: Results from an Australian case-control study. AB - BACKGROUND: The aetiology of childhood brain tumours (CBT) is largely unknown. Damage to germ cells after parental exposure to airborne carcinogens, such as volatile organic compounds and polycyclic aromatic hydrocarbons is one plausible pathway. This analysis aimed to investigate whether parental refuelling of vehicles or the use of domestic wood heaters in key time periods relating to the child's birth was associated with an increased risk of CBT. PROCEDURE: Cases <15 years of age were recruited through 10 paediatric oncology centres around Australia; controls were recruited through nationwide random-digit dialling, frequency matched to cases on age, sex and State of residence. Exposure to refuelling and wood heaters was ascertained through questionnaires from both parents. Odds ratios (ORs) and confidence intervals (CIs) were estimated using unconditional logistic regression, adjusting for relevant covariates. RESULTS: Data were available for 306 case and 950 control families. Paternal refuelling >=4 times/month was associated with an increased risk of CBT (OR 1.59, 95% CI: 1.11, 2.29), and a dose-dependent trend was observed (P = 0.004). No association was seen for maternal refuelling. Use of closed, but not open, wood heaters before (OR 1.51, 95% CI: 1.05, 2.15) and after (OR 1.44, 95% CI: 1.03, 2.01) the child's birth was associated with increased risk of CBT, but dose-response relationships were weak or absent. CONCLUSIONS: Paternal refuelling of vehicles >=4 times/month and the use of closed wood heaters before the child's birth may increase the risk of CBT. Replication in larger studies is needed. Pediatr Blood Cancer 2015;62:229-234. (c) 2014 Wiley Periodicals, Inc. PMID- 25283071 TI - Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells. AB - Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N(tau)-alkylation of histidine residues already bearing a N(pi)- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD binding peptides and peptide mimetics. PMID- 25283073 TI - Non-suicidal self-injury in trans people: associations with psychological symptoms, victimization, interpersonal functioning, and perceived social support. AB - INTRODUCTION: There is a paucity of systematic research in the area of non suicidal self-injury (NSSI) in trans people. AIM: The aim of this study was to investigate the prevalence of NSSI in trans people and the associations with intra- and interpersonal problems. METHODS: Participants were 155 untreated individuals with a diagnosis of transsexualism (according to International Classification of Disease-10 criteria) attending a national gender identity clinic. MAIN OUTCOME MEASURES: All participants completed the Self-Injury Questionnaire, the Symptom Checklist-90-Revised, the Rosenberg Self-Esteem Scale, the Hamburg Body Drawing Scale, the Experiences of Transphobia Scale, the Inventory of Interpersonal Problems-32, and the Multidimensional Scale of Perceived Social Support. RESULTS: The sample consisted of 66.5% trans women and 33.5% trans men and 36.8% of them had a history of engaging in NSSI. The prevalence of NSSI was significantly higher in trans men (57.7%) compared with trans women (26.2%). Trans individuals with NSSI reported more psychological and interpersonal problems and perceived less social support compared with trans individuals without NSSI. Moreover, the probability of having experienced physical harassment related to being trans was highest in trans women with NSSI (compared with those without NSSI). The study found that with respect to psychological symptoms, trans women reported significantly more intrapersonal and interpersonal symptoms compared with trans men. Finally, the results of the regression analysis showed that the probability of engaging in NSSI by trans individuals was significantly positively related to a younger age, being trans male, and reporting more psychological symptoms. CONCLUSIONS: The high levels of NSSI behavior and its association with interpersonal and interpersonal difficulties and lack of social support need to be taken into consideration when assessing trans individuals. The effect of cross-sex hormones and sex reassignment surgery on psychological functioning, including NSSI behavior, as part of the transitional journey of trans individuals should be explored in future studies. PMID- 25283074 TI - Genetic testing for hereditary colorectal cancer syndromes: a significant change in technology and its clinical implications. PMID- 25283076 TI - Ca(2+) /calmodulin dependent kinase II: a critical mediator in determining reperfusion outcomes in the heart? AB - Ischaemic heart disease is a major cause of death and disability in the Western world, and a substantial health burden. Cardiomyocyte Ca(2+) overload is known to significantly contribute to contractile dysfunction and myocyte death in ischaemia and reperfusion, and significant advancements have been made in identifying the downstream mediators and cellular origins of this Ca(2+) mismanagement. Ca(2+) /calmodulin-dependent kinase II (CaMKII) is recognized as an important mediator linking pathological changes in subcellular environments to modifications in cardiomyocyte Ca(2+) handling. Activated in response to fluctuations in cellular Ca(2+) and to various post-translational modifications, CaMKII targets numerous Ca(2+) channels/transporters involved in Ca(2+) handling and contractile function regulation. CaMKII is activated early in reperfusion, where it exacerbates Ca(2+) leak from the sarcoplasmic reticulum and promotes the onset of ventricular arrhythmias. Inhibiting CaMKII can increase functional recovery in reperfusion and reduce apoptotic/necrotic death, at least partly through indirect and direct influences on mitochondrial Ca(2+) levels and function. Yet, CaMKII can also have beneficial actions in ischaemia and reperfusion, in part by providing inotropic support for the stunned myocardium and contributing as an intermediate to cardioprotective preconditioning signalling cascades. There is considerable potential in targeting CaMKII as a part of a surgical reperfusion strategy, though further mechanistic understanding of the relationship between CaMKII activation status and the extent of ischaemia/reperfusion injury are required to fully establish an optimal pharmacological approach. PMID- 25283075 TI - Invasive lobular breast cancer: the prognostic impact of histopathological grade, E-cadherin and molecular subtypes. AB - AIMS: The aim of this study was to compare breast cancer specific survival (BCSS) for invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) and, further, to evaluate critically the prognostic value of histopathological grading of ILC and examine E-cadherin as a prognostic marker in ILC. METHODS AND RESULTS: The study comprised 116 lobular and 611 ductal breast carcinomas occurring between 1961 and 2008. All cases had been classified previously according to histopathological type and grade, stained for oestrogen receptor (ER), progesterone receptor (PR), antigen Ki67 (Ki67), epithelial growth factor receptor (EGFR), cytokeratin 5 (CK5) and human epidermal growth factor receptor 2 (HER2) and classified into molecular subtypes. For the present study, immunohistochemical staining for E-cadherin was performed. The Kaplan-Meier method and Cox proportional hazards models were used in the analyses. Grade 2 tumours comprised 85.3% of the lobular tumours and 51.9% of the ductal tumours. BCSS in ILC grade 2 was comparable to that of IDC grade 3. E-cadherin-negative ILC had a poorer prognosis compared to E-cadherin positive ILC and to IDC regardless of E-cadherin status. CONCLUSIONS: The implication of histopathological grading may differ in ILC compared to IDC. E-cadherin may be useful in prognostication in ILC and thereby influence the determination of treatment strategies for this group of women. PMID- 25283077 TI - Microfluidic control of axonal guidance. AB - The precision of axonal pathfinding and the accurate formation of functional neural circuitry are crucial for an organism during development as well as during adult central and peripheral nerve regeneration. While chemical cues are believed to be primarily responsible for axonal pathfinding, we hypothesize that forces due to localized fluid flow may directly affect neuronal guidance during early organ development. Here, we report direct evidence of fluid flow influencing axonal migration, producing turning angles of up to 90 degrees . Microfluidic flow simulations indicate that an axon may experience significant bending force due to cross-flow, which may contribute to the observed axonal turning. This method of flow-based guidance was successfully used to fasciculate one advancing axon onto another, showcasing the potential of this technique to be used for the formation of in vitro neuronal circuits. PMID- 25283078 TI - C-type natriuretic peptide ameliorates ischemia/reperfusion-induced acute kidney injury by inhibiting apoptosis and oxidative stress in rats. AB - AIMS: Although atrial natriuretic peptide has been shown to attenuate ischemia reperfusion (IR)-induced kidney injury, the effect of natriuretic peptide receptor (NPR)-B activation on IR-induced acute kidney injury is not well documented. The purpose of the present study was to identify the effect of C-type natriuretic peptide (CNP), a selective activator of NPR-B, on the IR-induced acute kidney injury and its mechanisms involved. MAIN METHODS: Unilaterally nephrectomized rats were insulted by IR in their remnant kidney, and they were randomly divided into three groups: sham, vehicle+IR, and CNP+IR groups. CNP (0.2MUg/kg/min) was administered intravenously at the start of a 45-min renal ischemia for 2h. Rats were then killed 24h after I/R, and the blood and tissue samples were collected to assess renal function, histology, TUNEL assay, and Western blot analysis of kidney Bax and Bcl-2 expressions. KEY FINDINGS: The levels of blood urea nitrogen and serum creatinine were significantly increased in rats after IR compared with vehicle-treated rats. IR elevated apoptosis, Bcl 2/Bax ratio, TUNEL positivity, oxidative stress parameters, malondialdehyde concentration, and superoxide dismutase activity. IR also induced epithelial desquamation of the proximal tubules and glomerular shrinkage. CNP significantly attenuated the IR-induced increase in BUN and serum creatinine. Furthermore, CNP restored the suppressed renal cyclic guanosine 3' 5'-monophosphate levels caused by IR insult. SIGNIFICANCE: Study findings suggest that CNP could ameliorate IR induced acute kidney injury through inhibition of apoptotic and oxidative stress pathways, possibly through NPR-B-cGMP signaling. PMID- 25283079 TI - Immunohistochemical evaluation of midkine and nuclear factor-kappa B as diagnostic biomarkers for papillary thyroid cancer and synchronous metastasis. AB - AIMS: Midkine (MK) is a multifunctional cytokine identified to be a promising cancer biomarker. Nuclear factor-kappa B (NF-kappaB) is an important transcription factor that plays a pivotal role in tumorigenesis. We aimed to investigate values of MK and NF-kappaB as markers for diagnosis and synchronous metastasis prediction in papillary thyroid cancer (PTC). MAIN METHODS: 76 cases of PTC and 70 cases of multi-nodular goiter (MNG) were retrieved. The PTC group was further divided into subgroup 1 (16 cases with synchronous metastases) and subgroup 2 (60 cases without metastases). A retrospective review of demographic and clinical information was performed. Immunohistochemistry of MK, NF-kappaB p65 and Ki-67 was performed on paraffin-embedded specimens and results were quantified. Diagnostic values of the parameters were conducted by receiver operating characteristic (ROC) curves. Protein levels of MK and NF-kappaB p65 were then confirmed by Western blot. KEY FINDINGS: Immunoreactivities of MK, NF kappaB p65 and Ki-67 were significantly higher in the PTC group than in the MNG group with good differential diagnostic capabilities. Moreover, immunoreactivities of all three parameters were significantly higher in subgroup 1 than in subgroup 2 with good synchronous metastasis predictive efficacies. Western blot showed that MK and NF-kappaB p65 protein levels in lesions from subgroup 1 were significantly higher than those from subgroup 2, both of which were significantly higher than in MNG lesions. SIGNIFICANCE: We discovered that MK and NF-kappaB immunohistochemistries can potentially be used for differential diagnosis between PTC and MNG, and for prediction of synchronous metastases. PMID- 25283080 TI - Proposing interactions between maternal phospholipids and the one carbon cycle: A novel mechanism influencing the risk for cardiovascular diseases in the offspring in later life. AB - Studies have adequately demonstrated the importance of maternal nutrition, particularly, micronutrients (folic acid, vitamin B12) and long chain polyunsaturated fatty acids (LCPUFAs) in determining pregnancy outcome. Reports indicate that children born preterm or to mothers with preeclampsia are at increased risk of developing cardiovascular diseases (CVD) in later life although mechanisms are unclear. Our earlier studies have established that micronutrients (folic acid, vitamin B12) and LCPUFAs are interlinked in the one carbon cycle and influence methylation reactions. Here, we propose a novel hypothesis that altered phospholipid metabolism and dysregulation in the one carbon cycle will result in altered epigenetic programming of placental genes leading to an adverse pregnancy outcome with increased risk of adult diseases in the offspring. Folic acid and vitamin B12 are involved in S-adenosylmethionine (SAM) synthesis, the major methyl donor for most methyl acceptors. Inadequacy of LCPUFA containing phospholipids, one of the major methyl group acceptors in the one carbon metabolic pathway, may cause diversion of methyl groups toward deoxyribonucleic acid (DNA) eventually resulting in aberrant DNA methylation patterns. These modified DNA methylation patterns lead to alterations in the expression of vital genes e.g. angiogenic factor genes thereby contributing to the dysregulation of angiogenesis/vasculogenesis further affecting placental development. This consequently would adversely "program" the fetus for increased risk of CVD in later life. PMID- 25283081 TI - The effect of TSPP-mediated photodynamic therapy and Parecoxib in experimental tumours. AB - AIMS: The study investigated the effects of the combined treatment Parecoxib (Pcox) and 5,10,15,20-tetra-sulphonato-phenyl-porphyrin(TSPP)-mediated photodynamic therapy on Walker 256 carcinosarcoma. MAIN METHODS: Five groups of male Wistar rats were used: the control group, treated with TSPP, group 2, irradiated 24 h thereafter, group 3, treated with Pcox and irradiated 24 h thereafter, groups 4 and 5 treated with combined therapies, TSPP and Pcox before irradiation, and Pcox 24 h after TSPP and irradiation respectively. Tumour inflammation, growth and non-growth factors, apoptosis/necrosis rate and oxidative/nitrosative stress markers were investigated. KEY FINDINGS: Malondialdehyde levels and cyclooxygenase (COX)-2 expression increased significantly in the group treated with Pcox after TSPP-PDT when compared with TSPP + IR group (p < 0.05, p < 0.001 respectively), in correlation with a decrease in glutathione levels (p < 0.05). The quantification of apoptosis, based on the TUNEL-assay, and necrosis rate revealed an increase of apoptotic/necrotic index in the same group (p < 0.05). On the other hand, Pcox administered before irradiation showed a significant increase in both vascular endothelial growth factor (VEGF) and COX-2 levels (p < 0.05) and in nitric oxide production (p < 0.01), when compared with the control group. SIGNIFICANCE: The administration of Pcox after TSPP-mediated PDT showed promising antitumoural effects, leading to an increase in oxidative and nitrosative stress as well as apoptosis/necrosis rate in tumour tissue. These results show that combined regimens that involve selective COX-2 inhibitors administration after irradiation may improve the therapeutic effectiveness of PDT. PMID- 25283082 TI - Swimming training promotes cardiac remodeling and alters the expression of mRNA and protein levels involved in calcium handling in hypertensive rats. AB - AIM: The aim of this study was to identify the effects of swimming training on the mRNA expression and protein levels of the calcium handling proteins in the hearts of renovascular hypertensive rats submitted to swimming protocol during 6 weeks. MAIN METHODS: Fischer rats with renovascular hypertension 2-kidney 1-clip (2K1C) and SHAM groups were divided among sedentary and exercised groups. The exercise protocol lasted for 6 weeks (1 h/day, 5*/week), and the mean arterial pressure, cardiomyocytes hypertrophy parameters, mRNA expression and protein levels of some calcium handling proteins in the left ventricle were evaluated. KEY FINDINGS: Swimming training was able to reduce the levels of mean arterial pressure in the hypertensive group compared to 2K1C SED, and to promote cardiac hypertrophy in SHAM EX and 2K1C EX groups in comparison to the respective control groups. The mRNA levels of B-type natriuretic peptide were reduced in the 2K1C EX when compared to 2K1C SED. The mRNA and protein levels of the sarcoplasmic reticulum Ca2 +-ATPase increased after the swimming training in SHAM and 2K1C groups. The mRNA and protein levels of phospholamban, displayed an increase in their levels in the exercised SHAM and in hypertensive rats in comparison to their respective controls; while mRNA levels of Na+/Ca2 + exchanger was reduced in the left ventricle comparing to the sedentary hypertensive rats. SIGNIFICANCE: Taken altogether, we provide evidence that the aerobic training may lead to cardiac remodeling, and modulate the calcium handling proteins expression in the heart of hypertensive rats. PMID- 25283083 TI - Bimagnetic h-Co/h-CoO nanotetrapods: preparation, nanoscale characterization, three-dimensional architecture and their magnetic properties. AB - Well-defined bimagnetic h-Co decorated wurtzite h-CoO nanotetrapods with uniform size have been successfully fabricated by a one-pot thermal decomposition method for the first time, and their three-dimensional architecture, crystal structure, chemical phase and exchange bias effect are characterized at the nanoscale. It is found that individual bimagnetic h-Co/h-CoO nanotetrapods are made of a h-CoO nanotetrapod skeleton to which multiple nanocrystals of ferromagnetic metallic h Co are directly attached. The chemical analysis shows that the mass ratio of h CoO and h-Co is 65 : 35. The detailed investigations of the crystal structure reveal that both the h-CoO nanotetrapod skeleton and h-Co nanoparticles have hexagonal structure. The four pods of individual nanotetrapods are single crystals with the same [001] orientation along with their pod axes and grow together by twinning with (110) the twin interface and the 120 degrees spatial boundary angle. The magnetic measurements reveal that the h-Co/h-CoO nanotetrapods have a surprisingly strong room temperature ferromagnetism and there exists a weak exchange coupling between the h-CoO nanotetrapod skeleton and the decorated h-Co tiny nanoparticles. It is believed that our new structural form of the bimagnetic h-Co/h-CoO nanotetrapods provides not only a smart functional 3D nanoarchitecture as building block in nanoelectronics and nanosensors, but also an ideal specimen for a further understanding of weak antiferromagnetic-ferromagnetic interaction. PMID- 25283084 TI - Sparse Multi-Task Regression and Feature Selection to Identify Brain Imaging Predictors for Memory Performance. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive impairment of memory and other cognitive functions, which makes regression analysis a suitable model to study whether neuroimaging measures can help predict memory performance and track the progression of AD. Existing memory performance prediction methods via regression, however, do not take into account either the interconnected structures within imaging data or those among memory scores, which inevitably restricts their predictive capabilities. To bridge this gap, we propose a novel Sparse Multi-tAsk Regression and feaTure selection (SMART) method to jointly analyze all the imaging and clinical data under a single regression framework and with shared underlying sparse representations. Two convex regularizations are combined and used in the model to enable sparsity as well as facilitate multi-task learning. The effectiveness of the proposed method is demonstrated by both clearly improved prediction performances in all empirical test cases and a compact set of selected RAVLT-relevant MRI predictors that accord with prior studies. PMID- 25283085 TI - Update on skin allergy. AB - Skin diseases with an allergic background such as atopic dermatitis, allergic contact dermatitis, and urticaria are very common. Moreover, diseases arising from a dysfunction of immune cells and/or their products often manifest with skin symptoms. This review aims to summarize recently published articles in order to highlight novel research findings, clinical trial results, and current guidelines on disease management. In recent years, an immense progress has been made in understanding the link between skin barrier dysfunction and allergic sensitization initiating the atopic march. In consequence, new strategies for treatment and prevention have been developed. Novel pathogenic insights, for example, into urticaria, angioedema, mastocytosis, led to the development of new therapeutic approaches and their implementation in daily patient care. By understanding distinct pathomechanisms, for example, the role of IL-1, novel entities such as autoinflammatory diseases have been described. Considerable effort has been made to improve and harmonize patient management as documented in several guidelines and position papers. PMID- 25283086 TI - Roles of obese-insulin resistance and anti-diabetic drugs on the heart with ischemia-reperfusion injury. AB - The incidence of obesity with insulin resistance is increasing worldwide. This condition is also known as a risk factor of coronary artery disease and associated with increased arrhythmias, impaired left ventricular function, and increased infarct size during cardiac ischemia-reperfusion (I/R) injury. The proposed mechanisms are due to impaired glucose utilization and pro-survival signaling molecules, and increased inflammatory cytokines, which have been demonstrated in the I/R hearts in various models of obese-insulin resistance. However, the cardiac effects of diets in the I/R heart are still unsettled since several studies reported that high-caloric diet consumption might protect the heart from I/R injury. Although several therapeutic strategies such as anti diabetic drugs, natural compounds as well as treadmill exercise have been proposed to exert cardioprotection in the I/R heart in obese-insulin resistant animals, some interventions including ischemic post-conditioning failed to protect the heart from I/R injury. In this comprehensive review, reports from both genetic deletion and dietary-induced obese-insulin resistant animal models regarding the effects of obese-insulin resistance on metabolic parameters, cardiac function, infarct size, and molecular mechanisms under I/R injury are summarized. Moreover, the effects of anti-diabetic drugs and other pharmacological interventions on these parameters in an obese-insulin resistant model under I/R injury are also comprehensively summarized and discussed. PMID- 25283087 TI - Atorvastatin inhibits CD68 expression in aortic root through a GRP78-involved pathway. AB - PURPOSE: Glucose-regulated protein 78 (GRP78) is a chaperone protein in the endoplasmic reticulum (ER). Previous studies have suggested that statins favorably affect ER stress by upregulating GRP78. This study was designed to investigate whether the anti-atherosclerotic effect of atorvastatin is modulated by a GRP78-involved pathway. METHODS: Hamsters were made diabetic and randomly divided into a diabetic control group (DMC), a diabetic group with low-dose atorvastatin (DML, 2.5 mg/kg/day), and a diabetic group with high-dose atorvastatin (DMH, 5 mg/kg/day). Pathological examinations of the aortic root were performed, and the level of GRP78 and CD68 expression in the aortic root was detected by immunohistochemistry and RT-PCR analysis. In vitro THP-1 macrophages were treated with glucose and atorvastatin, and their GRP78 and CD68 protein expression levels were measured by Western blot. Next, with and without co incubation with the GRP78 inhibitor, deoxynivalenol (DON), CD68 protein expression was again analyzed. RESULTS: We found that in vivo atorvastatin prominently limited the area of macrophage infiltration in the subendothelial spaces of the aortic root in the DML and DMH groups, and significantly inhibited CD68 expression (DML or DMH vs. DMC, all p < 0.001) and increased GRP78 expression (DML or DMH vs. DMC, p < 0.05 ~ 0.001). In vitro Western blot results showed that atorvastatin decreased CD68 and increased GRP78 protein expression in glucose-treated THP-1 macrophages, and the suppressing effect of atorvastatin on CD68 expression was almost abolished by co-incubation with the GRP78 inhibitor. CONCLUSIONS: Our results clearly showed that atorvastatin inhibited CD68 expression through GRP78 regulation, and that GRP78 could exert a protective effect in the early stages of atherosclerosis beyond being a chaperone protein, providing a new perspective into the anti-atherosclerosis mechanism of atorvastatin. PMID- 25283088 TI - Are acute infarcts the cause of leukoaraiosis? Brain mapping for 16 consecutive weeks. AB - Neuroimaging of older adults commonly reveals abnormality (leukoaraiosis) in the cerebral white matter. Studies have established that extensive leukoaraiosis predicts dementia and disability, but the pathogenesis of leukoaraiosis remains unclear. We recruited 5 patients with leukoaraiosis and performed magnetic resonance mapping of the brain for 16 consecutive weeks. We observed tiny lesions arising de novo in the cerebral white matter. These lesions were clinically silent. They had the signature features of acute ischemic stroke. With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis. Together, these findings suggest that tiny silent acute infarcts are a cause of leukoaraiosis. PMID- 25283090 TI - Characterization of the intestinal absorption of inorganic mercury in Caco-2 cells. AB - The main form of mercury exposure in the general population is through food. Intestinal absorption is therefore a key step in the penetration of mercury into the systemic circulation, and should be considered when evaluating exposure risk. Many studies have investigated the transport of mercury species in different cell lines, though the mechanisms underlying their intestinal absorption are not clear. This study evaluates the accumulation and transport of Hg(II), one of the mercury species ingested in food, using Caco-2 cells as intestinal epithelium model with the purpose of clarifying the mechanisms involved in its absorption. Hg(II) shows moderate absorption, and its transport fundamentally takes place via a carrier-mediated transcellular mechanism. The experiments indicate the participation of an energy-dependent transport mechanism. In addition, H(+)- and Na(+)-dependent transport is also observed. These data, together with those obtained from inhibition studies using specific substrates or inhibitors of different transporter families, suggest the participation of divalent cation and amino acid transporters, and even some organic anion transporters, in Hg(II) intestinal transport. An important cellular accumulation of up to 51% is observed - a situation which in view of the toxic nature of this species could affect intestinal mucosal function. This study contributes new information on the mechanisms of transport of Hg(II) at intestinal level, and which may be responsible for penetration of this mercurial form into the systemic circulation. PMID- 25283089 TI - Validation of murine and human placental explant cultures for use in sex steroid and phase II conjugation toxicology studies. AB - Human primary placental explant culture is well established for cytokine signaling and toxicity, but has not been validated for steroidogenic or metabolic toxicology. The technique has never been investigated in the mouse. We characterized human and mouse placental explants for up to 96 h in culture. Explant viability (Lactate dehydrogenase) and sex steroid levels were measured in media using spectrophotometry and ELISA, respectively. Expression and activities of the steroidogenic (3beta-hydroxysteroid dehydrogenase, Cytochrome P45017A1, Cytochrome P45019), conjugation (UDP-glucuronosyltransferase, sulfotransferase (SULT)), and regeneration (beta-glucuronidase, arylsulfatase C (ASC)) enzymes were determined biochemically in tissues with fluorimetric and spectrophotometric assays, and western blot. Explants were viable up to 96 h, but progesterone, estrone, and 17beta-estradiol secretion decreased. Steroidogenic enzyme expression and activities were stable in mouse explants and similar to levels in freshly isolated tissues, but were lower in human explants than in fresh tissue (P<0.01). Human and mouse explants exhibited significantly less conjugation after 96 h, SULT was not detected in the mouse, and neither explants had active ASC, although proteins were expressed. Mouse explants may be useful for steroid biochemistry and endocrine disruption studies, but not metabolic conjugation. In contrast, human explants may be useful for studying conjugation for <48 h, but not for steroid/endocrine studies. PMID- 25283091 TI - Non-specific interaction of carbon nanotubes with the resazurin assay reagent: impact on in vitro assessment of nanoparticle cytotoxicity. AB - In vitro cytotoxicity assays are essential tools in the screening of engineered nanomaterials (NM) for cellular toxicity. The resazurin live cell assay is widely used because it is non-destructive and is well suited for high-throughput platforms. However, NMs, in particular carbon nanotubes (CNT) can interfere in assays through quenching of transmitted light or fluorescence. We show that using the resazurin assay with time-point reading of clarified supernatants resolves this problem. Human lung epithelial (A549) and murine macrophage (J774A.1) cell lines were exposed to NMs in 96-well plates in 200 MUL of media/well. After 24 h incubation, 100 MUL of supernatant was removed, replaced with resazurin reagent in culture media and aliquots at 10 min and 120 min were transferred to black wall 96-well plates. The plates were quick-spun to sediment the residual CNTs and fluorescence was top-read (lambdaEx=540 nm, lambdaEm=600 nm). The procedure was validated for CNTs as well as silica nanoparticles (SiNP). There was no indication of reduction of resazurin by the CNTs. Stability of resorufin, the fluorescent product of the resazurin reduction was then assessed. We found that polar CNTs could decrease the fluorescence signal for resorufin, possibly through oxidation to resazurin or hyper-reduction to hydroxyresorufin. This effect can be easily quantified for elimination of the bias. We recommend that careful consideration must be given to fluorimetric/colorimetric in vitro toxicological assessments of optically/chemically active NMs in order to relieve any potential artifacts due to the NMs themselves. PMID- 25283092 TI - Impact of "Grain to Green" Programme on echinococcosis infection in Ningxia Hui Autonomous Region of China. AB - Cystic echinococcosis (CE) is endemic among the human population of Xiji County, Ningxia Hui Autonomous Region, China, where the prevalence is estimated to be between 2.2% and 3.6%. Government-run sheep abattoirs in Xiji County have closed in recent years and, as a consequence, slaughter is carried out mostly at rural market places. The market place in Xinglong Township, Xiji County, is home to an increasing number of stray dogs and the lack of government control over slaughter practices potentially favours Echinococcus granulosus transmission. A survey of sheep, goats and cattle reared in Xiji County was conducted in Xinglong Market and Xinglong Township to determine prevalence and transmission dynamics of E. granulosus infection. The liver and lungs of all livestock aged one year and older were examined macroscopically post mortem; visual examination and palpation of organs determined overall prevalence of E. granulosus. Cysts consistent in appearance with E. granulosus were observed in 2/184 sheep (prevalence 1.0%) and 1/55 of the cattle examined (prevalence 1.8%); 0/13 goats were found to be infected. However, microscopic examination of these suspected cysts failed to confirm these samples as E. granulosus, giving a prevalence of confirmed infection of zero percent in all three species. The prevalence of liver fluke was 61.3% in sheep and 12.7% in cattle with a significant difference between males and females (p <= 0.001). Considering the high prevalence of echinococcosis in the local human population, the absence of CE observed among commercially slaughtered livestock was surprising. Several explanations for this discrepancy and their implications are proposed. PMID- 25283093 TI - Comparative biochemical changes in young Zebu cattle experimentally infected with Trypanosoma vivax from tsetse infested and non-tsetse infested areas of northwest Ethiopia. AB - Trypanosomosis is a vector-borne protozoan disease of animals and humans in sub Saharan Africa. In Ethiopia, particularly the northwest region is affected by both tsetse and non-tsetse transmitted trypanosomosis. The aim of the present study was to determine the effects and compare differences in virulence of Trypanosoma vivax infection between tsetse and non-tsetse infested areas of northwest Ethiopia on the basis of serum biochemical values in Zebu cattle. Eighteen cattles purchased from trypanosome free area and aged between 9 and 12 months were assigned into three groups of six animals (Group TT=infected with T. vivax from tsetse infested area, Group NT=infected with T. vivax from non-tsetse infested area and Group C=non-infected control). For each experimental animal 3 ml of blood from naturally infected cattle was inoculated intravenously at 10(6) trypanosomes/ml except the control. Blood sample was collected once a week for 8 consecutive weeks for analyzing serum biochemical values (glucose, total cholesterol, total protein, albumin, and enzymes including GOT, GPT and ALP) using a Humastar 80 clinical chemistry analyzer. Both T. vivax parasites caused an acute infection with parasites appearing in circulation on 6 and 12 days post infection for NT and TT cattle, respectively. A significant reduction (P<0.001) in glucose levels was observed in infected groups compared with the control with mean values of 33.8 +/- 3.6 mg/dl for TT, 34.3 +/- 3.6 mg/dl for NT and 70.9 +/- 3.0 mg/dl for control groups. A similar reduction was also seen in total cholesterol values (P=0.001) with 70.4 +/- 10.6 mg/dl for TT and 78.0 +/- 10.6 mg/dl for NT groups compared to 139.5 +/- 8.7 mg/dl for the control group. No difference was observed for total serum protein between the three groups (P=0.260) whereas the mean albumin level was significantly (P<0.001) decreased (3.5 +/- 0.1g/dl and 2.9 +/- 0.1g/dl in TT and NT groups respectively) compared to that for control cattle (4.5 +/- 0.1g/dl). On the other hand, infected groups had higher ALP values compared to the control (P=0.007), with a mean value of 538. 4 +/- 64.4 IU/L, 564.9 +/- 64.4 IU/L and 273.2 +/- 52.6 IU/L for TT, NT and control cattle, respectively. In conclusion, the two T. vivax parasites caused significant biochemical changes indicative of pathological responses. However, there was no significant variation between the two parasites in initiating these changes despite the difference in the onset of parasitaemia. PMID- 25283095 TI - Nematodes from galls on Myrtaceae. VIII. Fergusobia from small galls on shoot buds, with descriptions of four new species. AB - Small shoot bud galls induced by the Fergusobia (Nematoda: Neotylenchidae)/Fergusonina (Diptera: Fergusoninidae) mutualism occur on various Eucalyptus spp. Four new species of Fergusobia, collected from small shoot bud galls on Eucalyptus camaldulensis, E. gomphocephala and E. leucoxylon, are described. Fergusobia gomphocephalae Davies n. sp. is morphologically characterized by a combination of a small C-shaped parthenogenetic female with a variable, conoid tail, a small C-shaped infective female with a hemispherical tail tip, and an arcuate or J-shaped male with a broad tail, angular spicule and short peloderan bursa. Fergusobia leucoxylonae Davies n. sp. has a C-shaped parthenogenetic female with a conoid tail with a narrowly rounded tip, an arcuate infective female with a broadly rounded tail tip, and an almost straight to barely J-shaped male with angular (not heavily sclerotised) spicule and short bursa. Fergusobia schmidti Davies & Bartholomaeus n. sp. has an arcuate to open C shaped parthenogenetic female with a relatively large body diameter, relatively long stylet and small tail with a broadly rounded tail tip, an open C-shaped infective female with a broadly rounded to hemispherical tail tip, and an arcuate to barely J-shaped male with spicules angular at about 33% of their length and peloderan bursa arising at about half body length. Fergusobia sporangae Davies n. sp. has an arcuate to open C-shaped parthenogenetic female with a relatively long stylet and a broadly rounded tail tip, an arcuate infective female with a short tail with a broadly rounded to hemispherical tip, and an arcuate to barely J shaped male with angular (not heavily sclerotised) spicule and short peloderan bursa. Various forms of small shoot bud galls are described. From phylogenetic analyses based on sequences of the D2/D3 expansion segment of the large subunit rRNA gene, the four new species belong to two sister clades of Fergusobia. The larval shield morphology of their associated fly species and possible genetic relationships are discussed. PMID- 25283094 TI - Low frequency of anti-D alloimmunization following D+ platelet transfusion: the Anti-D Alloimmunization after D-incompatible Platelet Transfusions (ADAPT) study. AB - The reported frequency of D alloimmunization in D- recipients after transfusion of D+ platelets varies. This study was designed to determine the frequency of D alloimmunization, previously reported to be an average of 5 +/- 2%. A primary anti-D immune response was defined as the detection of anti-D >= 28 d following the first D+ platelet transfusion. Data were collected on 485 D- recipients of D+ platelets in 11 centres between 2010 and 2012. Their median age was 60 (range 2 100) years. Diagnoses included: haematological (203/485, 42%), oncological (64/485, 13%) and other diseases (218/485, 45%). Only 7/485 (1.44%; 95% CI 0.58 2.97%) recipients had a primary anti-D response after a median serological follow up of 77 d (range: 28-2111). There were no statistically significant differences between the primary anti-D formers and the other patients, in terms of gender, age, receipt of immunosuppressive therapy, proportion of patients with haematological/oncological diseases, transfusion of whole blood-derived or apheresis platelets or both, and total number of transfused platelet products. This is the largest study with the longest follow-up of D alloimmunization following D+ platelet transfusion. The low frequency of D alloimmunization should be considered when deciding whether to administer Rh Immune Globulin to D- males and D- females without childbearing potential after transfusion of D+ platelets. PMID- 25283096 TI - Taxonomic revision of the cleptoparasitic bee genus Epiclopus Spinola, 1851 (Hymenoptera: Apidae: Ericrocidini). AB - A taxonomic revision of the cleptoparasitic bee genus Epiclopus Spinola is presented. The following species are recognized: Epiclopus gayi Spinola, E. lendlianus (Friese), E. wagenknechti (Ruiz) and E. ecphorus new species from northern Chile. Floral associations, hosts, distribution records and diagnoses of both sexes based on type specimens, are given. An identification key, illustrations and an updated catalogue of the species are provided. In addition, a neotype for Mesonychium wagenknechti and lectotypes for Melissa (Epiclopus) gayi albescens Friese and M. lendliana are also designated. PMID- 25283097 TI - The sparid fishes of Pakistan, with new distribution records. AB - The family sparidae is represented in Pakistan by 14 species belonging to eight genera: the genus Acanthopagrus with four species, A. berda, A. arabicus, A. sheim, and A. catenula; Rhabdosargus, Sparidentex and Diplodus are each represented by two species, R. sarba and R. haffara, Sparidentex hasta and S. jamalensis, and Diplodus capensis and D. omanensis, and the remaining four genera are represented by single species, Crenidens indicus, Argyrops spinifer, Pagellus affinis, and Cheimerius nufar. Five species, Acanthopagrus arabicus, A. sheim, A. catenula, Diplodus capensis and Rhabdosargus haffara are reported for the first time from Pakistani coastal waters. The Arabian Yellowfin Seabream Acanthopagrus arabicus and Spotted Yellowfin Seabream Acanthopagrus sheim have only recently been described from Pakistani waters, while Diplodus omanensis and Pagellus affinis are newly identified from Pakistan. Acanthopagrus catenula has long been incorrectly identified as A. bifasciatus, a species which has not been recorded from Pakistan. All species are briefly described and a key is provided for them. PMID- 25283098 TI - A new species of Axymyiidae (Diptera) from western North America and a key to the Nearctic species. AB - Adult, pupal and larval stages of the western Nearctic axymyiid, Protaxymyia thuja Fitzgerald and Wood n. sp., are described. The generic placement of this taxon is discussed in the context of the world axymyiid fauna and a key to differentiate all known life stages of Nearctic axymyiids is provided. PMID- 25283099 TI - Two new species of Conognatha Eschscholtz, 1829 (Coleoptera, Buprestidae, Stigmoderini) from Southeast and South Brazilian regions with distributional notes. AB - Conognatha (Pithiscus) coffeatus sp. nov. and Conognatha (Pithiscus) puris sp. nov., both from the Atlantic Rainforest (type locality: Itatiaia, Rio de Janeiro State, Brazil), are described and illustrated. They differ from each other mainly by the elytral colour pattern, presence of a short longitudinal groove between the vertex and the frons in C. (P.) puris sp. nov., and differences in frons shape, antennae sensory fields, pronotum and aedeagus. The distribution of C. (P.) gounellei is extended to the State of Minas Gerais, Brazil. A modified key to include the new species, as well as illustrations, are presented. PMID- 25283100 TI - Discovery of the most ancient member of family Tanyderidae (Diptera) from the Lower Jurassic (Sinemurian) of England. AB - Nannotanyderus oliviae sp. nov. from the Lower Jurassic (Sinemurian) of England, the oldest representative of family Tanyderidae, is described and illustrated. PMID- 25283101 TI - A new species of Arnobia (Orthoptera: Phaneropteridae: Phaneropterinae) from Sakaerat, Thailand. AB - From Sakaerat Environmental Research Station, Nakhon Ratchasima, Thailand, one new species of Arnobia (Orthoptera: Phaneropterinae) is described: Arnobia tinae sp. n. PMID- 25283102 TI - Description of the males of Euprosthenops australis Simon, 1898 and Euprosthenopsis pulchella (Pocock, 1902) (Araneae: Pisauridae). PMID- 25283103 TI - The identity of the invasive fouling bryozoan Watersipora subtorquata (d'Orbigny) and some other congeneric species. AB - Watersipora subtorquata (d'Orbigny, 1852) has been widely reported as a fouling species from tropical to temperate waters. The continued confusion over the correct name for this species led us to provide a redescription of d'Orbigny's type of Cellepora subtorquata, and to make comparisons with other species of Watersipora. We show that the majority of specimens assigned to W. subovoidea (d'Orbigny, 1852) are morphologically distinct from the recently erected neotype of W. subovoidea; these specimens are here reidentified as Watersipora subtorquata. Other specimens previously assigned to W. subtorquata belong to W. subatra (Ortmann, 1890), described originally from Japan. Owing these inconsistences, we suggest setting aside the neotype of Watersipora subovoidea, which is based on Busk's Lepralia cucullata and is not from the same locality as d'Orbigny's type. Watersipora cucullata is redescribed and figured using Busk's specimens; the species is known from the Mediterranean, including the Adriatic. Three other species--Watersipora atrofusca (Busk, 1856), Watersipora aterrima (Ortmann, 1890) and Watersipora nigra (Canu & Bassler, 1930)--are also refigured. Watersipora edmondsoni Soule & Soule, 1975 is synonymised with W. subtorquata (d'Orbigny). Two new species are described, Watersipora mawatarii n. sp. from Japan and Watersipora souleorum n. sp. from the Azores, Cape Verde, Naples and Indian Ocean. A key is given to the Recent species of Watersipora. PMID- 25283104 TI - Two new species and new records of Microprosthema Stimpson, 1860 (Crustacea: Decapoda: Stenopodidea: Spongicolidae) from the Indo-West Pacific. AB - Two new species of the spongicolid shrimp genus Microprosthema Stimpson, 1860 are described and illustrated on the basis of material collected recently in Australia and Japan. Type specimens of Microprosthema ningaloo sp. nov. were collected on Ningaloo Reef, Western Australia, whereas type specimens of Microprosthema pallidum sp. nov. were collected on a coral reef off Ishigaki Island, Ryukyu Archipelago, southern Japan. Microprosthema ningaloo sp. nov. and M. pallidum sp. nov. differ from all other species of the genus by a combination of morphological characters, including the gill-exopod formulae, and by their diagnostic colour patterns. This study increases the total number of species described in the genus Microprosthema to 16, nine of them in the Indo-West Pacific. In addition, new records are provided for M. lubricum Saito & Okuno, 2011 (Guam), M. plumicorne (Richters, 1880) (Red Sea, Mariana and Marshall Islands, French Polynesia), M. scabricaudatum (Richters, 1880) (Red Sea, Glorieuses and Tuamotu Islands), and M. validum Stimpson, 1860 (Red Sea, Madagascar, Singapore, French Polynesia), significantly extending their previously known distribution ranges. PMID- 25283105 TI - Taxonomic value of morphological and morphometrical characters in the immature stages of four species of Kampimodromus Nesbitt (Acari: Phytoseiidae) from Italy and Croatia. AB - The immature stages of four species of Kampimodromus Nesbitt (Acari: Phytoseiidae) from Italy and Croatia have been studied and identified both at stage and species level. Larval stages of Kampimodromus corylosus Kolodochka and all immature stages of Kampimodromus ericinus Ragusa di Chiara & Tsolakis and Kampimodromus langei Wainstein & Arutunjan are described for the first time. The relative length of the posterior dorsal setae Z4 make the larvae of Kampimodromus aberrans (Oudemans) easy to separate from those of the other three species. Nymphs of each species had similar diagnostics to the adults of the respective species. Ontogeny of the idiosomal and leg setation of the Kampimodromus immatures studied in comparison to the available data from immatures of other phytoseiid species is discussed. The length of seta Z4 in the K. aberrans larva, and the number of setae on leg IV of the deutonymphs of the four Kampimodromus species, are proposed as additional taxonomic traits for Phytoseiidae. PMID- 25283106 TI - Seven new South American species of Regalana DeLong & Freytag (Cicadellidae: Iassinae: Gyponini). AB - Seven new species of the previously monotypic genus Regalana DeLong & Freytag, 1975, described from Panama, are described and illustrated. The new species are described from lowland and montane Amazonian/Andeanrain forests and Cerrado savanna of Brazil, Ecuador, French Guiana, and Peru. They can be distinguished from each other, as well as from the type-species, R. corona DeLong & Freytag, 1975, mainly by features of the aedeagus. A key to the now eight known species of Regalana is provided. PMID- 25283107 TI - Nine new species of Phoridae (Insecta: Diptera) from Spain. AB - One new species of Triphleba Rondani and eight new species of Megaselia Rondani are described from Montseny Natural Park (mainland Spain). The new species are Megaselia arbuciensis Garcia-Romera sp.nov., Megaselia barrientosi Garcia-Romera sp. nov., Megaselia callunae Garcia-Romera sp. nov., Megaselia carminis Garcia Romera sp. nov., Megaselia ivanis Garcia-Romera sp. nov., Megaselia longianalis Garcia-Romera sp. nov., Megaselia montseniensis Garcia-Romera sp. nov., Megaselia sarae Garcia-Romera sp. nov., Triphleba beatricis Garcia-Romera sp. nov. PMID- 25283108 TI - Onciderini Thomson, 1860 (Coleoptera: Cerambycidae: Lamiinae) types of The Natural History Museum (BMNH). AB - The primary types of Onciderini Thomson, 1860 deposited at The Natural History Museum (BMNH), London, United Kingdom, are catalogued and illustrated. Data on the original combination, current name, and type locality are verified and presented. There are 39 primary types of Onciderini including 11 in Oncideres Lacordaire, 1830; and three each in Hesycha Fairmaire & Germain, 1859; Hypselomus Perty, 1832; Lamia Fabricius, 1775; and Tybalmia Thomson, 1868. Of the 39 primary types, 17 were described by H. W. Bates and seven by F. P. Pascoe. Five lectotypes are designated. Notes on additional Onciderini types once believed to be deposited at the BMNH are presented. PMID- 25283109 TI - Two new species of Geodiscelis Michener & Rozen (Hymenoptera: Apoidea: Colletidae) with a phylogenetic analysis and subgeneric classification of the genus. AB - Two new species of the genus Geodiscelis are described: Geodiscelis nazcalinea Packer & Dumesh, sp. nov. from Peru (the first record of the genus from that country) and G. phisquiri Packer & Dumesh, sp. nov. from northern Chile. The new species are most closely related to G. longiceps, but differ primarily in having somewhat less elongate heads and in details of the male terminalia. A key to the five known species of the genus is provided as are the results of a phylogenetic analysis based upon 68 characters, and the genus is formally divided into three subgenera: Geodiscelis s. str. Michener and Rozen, Geodiscelis (Nazcoediscelis) Packer and Dumesh, subgenus nov. and Geodiscelis (Thaumoediscelis) Packer and Dumesh, subgenus nov. The two new species described herein belong to subgenus Geodiscelis (Nazcoediscelis). Figures of the most important characters are provided. Tiquilia sp. (Boraginaceae) is the probable floral host of both new species and it is suggested that all species are ground-nesters. Sexual dimorphism in an unusual character is recorded for G. thaumaskelos Packer. PMID- 25283110 TI - New species and records of Macrodactylus Dejean (Coleoptera: Scarabaeidae: Melolonthinae: Macrodactylini) from Bolivia. AB - Two new species of Macrodactylus Dejean (Coleoptera: Scarabaeidae: Melolonthinae) from Bolivia are described and illustrated: M. megaphyllus new species (from Comarapa, Santa Cruz and Sehuenca, Cochabamba) and M. yunganus new species (from Mairana and Comarapa, Santa Cruz). In addition, the species Macrodactylus bolivianus Moser, M. gracilis Moser, and M. nobilis Frey are redescribed and illustrated to help facilitate identification of these species. A key to the 10 species of Macrodactylus presently known from Bolivia is provided. PMID- 25283111 TI - New species of Cheiracanthium (Araneae: Eutichuridae) from Madagascar and the Comoros Islands. AB - The Afrotropical representatives of the spider genus Cheiracanthium C.L. Koch, 1839 from Madagascar and the Comoros Islands are revised, and new species are described. Five described species are recognized: C. africanum Lessert, 1921, C. furculatum Karsch, 1879, C. insulare (Vinson, 1863), C. leucophaeum Simon, 1896, and C. ludovici Lessert, 1921. The internal genitalia of the female of C. insulare, and the female of C. ludovici, are described for the first time. Thirteen new species, C. ambrense sp. nov. (??), C. ampijoroa sp. nov. (?), C. andranomay sp. nov. (?), C. anjozorobe sp. nov. (??), C. ashleyi sp. nov. (??), C. fisheri sp. nov. (??), C. foulpointense sp. nov. (??), C. griswoldi sp. nov. (??), C. jocquei sp. nov. (??), C. madagascarense sp. nov. (??), C. mahajanga sp. nov. (?), C. ransoni sp. nov. (??) and C. rothi sp. nov. (??), are described. In most of the endemic Madagascan species the female genital depression is divided by a central septum and the male cymbial apophysis is bent distally. PMID- 25283112 TI - Taxonomic remarks, phylogeny and evolutionary notes on the leaf beetle species belonging to the Cryptocephalus sericeus complex (Coleoptera: Chrysomelidae: Cryptocephalinae). AB - A cladistic analysis was carried out for a complex of 33 species of the genus Cryptocephalus that has been recognized for some time as monophyletic. 55 morphological adult characters have been used, with 119 character states. Analyses were performed using parsimony procedures as well as Bayesian inference. Further information about phylogenetic scenarios were obtained by combining the morphological dataset with a sequence of 507 bp of the central portion of the 18S ribosomal RNA. Illustrations are provided for most morphological characters used in the analyses. Besides, the following taxonomic changes are proposed here: subg. Cerodens has to be considered a new synonym of subg. Cryptocephalus; C. zambanellus is raised again to species level; C. sericeus intrusus has to be considered a new synonym of C. zambanellus; C. telueticus has to be considered a new synonym of C. azurescens; all the populations of C. violaceus ranging from Iberian Peninsula to central Alps are attributed to the subspecies scaffaiolus Burlini, formerly described from the Northern Apennines. Biogeographic remarks are given and some evolutionary hypotheses about the radiation of the monophylum are proposed on the basis of the acquired knowledge. An identification key for the species is also provided. PMID- 25283113 TI - Studies in Guatemalan Caelifera: New grasshoppers and monkey grasshoppers (Orthoptera: Caelifera: Acridoidea & Eumastacoidea) and an updated checklist. AB - We describe six species of Acridomorpha, Orthoptera from Guatemala: Paralethus rowelli n. sp., Paralethus cerezoi n. sp., Episactus schusteri n. sp. (Episactidae: Episactinae), Pararhicnoderma eniocanoi n. sp. (Romaleidae: Bactrophorinae), Tela neumanni n. sp. and Leioscapheus faustinoi n. sp. (Acrididae: Proctolabinae). four genera and five species are recorded for Guatemala and, at the same time a checklist is provided for Caelifera species found so far in the country. PMID- 25283114 TI - World catalogue of the family Tanypezidae (diptera: Schizophora). AB - Family, genus and species group names in the family Tanypezidae (Diptera: Schizophora) are catalogued, providing references to occurrence in the literature and nomenclature. Full synonymies are provided, including generic combinations for species, type localities, and repositories and sex for name-bearing types. Species distributions by country are provided, noting biogeographic region(s). The Tanypezidae are known from 28 species in two genera (Tanypeza Fallen and Neotanypeza Hendel). PMID- 25283115 TI - Review of the Oriental genus Neoclarkinella Rema and Narendran, 1996 (Hymenoptera: Braconidae, Microgastrinae) with the description of two new species from India. AB - The rarely collected Oriental genus Neoclarkinella Rema and Narendran, 1996 is reviewed. Four species, all from India, are recognized of which two are described as new, namely Neoclarkinella janakikkadensis sp. nov., and N.narendrani sp. nov. from Kerala, India. A key to the oriental species of the genus is provided along with a character state matrix. PMID- 25283116 TI - Macropharyngodon pakoko, a new species of wrasse (Teleostei: Labridae) endemic to the Marquesas Islands, French Polynesia. AB - A new species of wrasse, Macropharyngodon pakoko, is described from the Marquesas Islands, bringing the total number of species of the genus Macropharyngodon to 12. Macropharyngodon pakoko was found at depths from 0-42 m and is endemic to the Marquesas Islands. Macropharyngodon pakoko is similar to M. meleagris, which is widely distributed from the central and western Pacific to Cocos-Keeling in the Indian Ocean, but differs genetically and in several coloration characters: males with irregularly curved black humeral blotch with incomplete iridescent blue border; inverted irregular "U"- shaped band on the cheek; a small black spot at the upper base of the pectoral fin; and background color of the body greenish with faint bluish black spots on each scale. Females lack black pigment on the chest posterior to the ventral attachment of the gill membranes; reddish black blotches on the body are widely spaced, particularly on the head where they are more reddish and half the size of those on body; caudal fin with small, bright yellow spots arranged in narrow vertical bands with pale interspaces; pelvic fins pale with three reddish yellow cross-bands; a small black spot at the upper base of the pectoral fin; and small reddish spots along the base of the anal fin. Juveniles have irregular black blotches on the body, a small black spot instead of an ocellus posteriorly on the dorsal fin and lack large black spots and ocellus on the anal fin. PMID- 25283117 TI - Description of two new species of Portanus Ball, 1932 (Hemiptera: Cicadellidae: Portanini) from Northeastern Brazil. AB - Two new species of Portanus Ball, 1932 are described and illustrated from Brazil. P. hastatus sp. nov. from Ceara State, can be recognized by its acute pygofer apex and aedeagus with pair of apical processes directed dorsally. Portanus phoenicius sp. nov. from Piaui State, can be recognized by its rounded pygofer lobe with dorsal tooth turned inwardly, aedeagus apex with pair of elongate processes and pair of rounded flanges directed ventrally. Portanus boliviensis is newly recorded from Brazil. These findings double the number of species of Portanini recorded from Northeastern Brazil. PMID- 25283118 TI - A review of the subfamily Harpypalpinae Fain, 1972 (Acariformes: Harpirhynchidae) -parasites of passerine birds. AB - The subfamily Harpypalpinae Fain, 1972 (Acariformes: Cheyletoidea: Harpirhynchidae) is revised. Diagnoses of the subfamily and its two constituent genera, Harpypalpus Dubinin, 1957 and Harpypalpoides Lombert and Moss, 1979, and keys to females of all known species are provided. Data on harpypalpine hosts and distribution are summarized, and nine new species are described: Harpypalpus lonchura sp. nov. from Lonchura castaneothorax (Gould) (Estrildidae) in Australia, Harpypalpus pyrrhula sp. nov. from Pyrrhula pyrrhula (Linnaeus) (Fringillidae) in the Netherlands, Harpypalpus sturnus sp. nov. from Sturnus vulgaris Linnaeus (Sturnidae) in the Netherlands, Harpypalpus taeniopygia sp. nov. from Taeniopygia guttata (Vieillot) (Estrildidae) in Australia, Harpypalpoides hirundinoides sp. nov. from Hirundo rustica Linnaeus (Hirundinidae) in the Netherlands, Harpypalpoides johnstoni sp. nov. from Fringilla coelebs Linnaeus (Fringillidae) (type host) in the Netherlands and Fringilla montifringilla Linnaeus in Kazakhstan, Harpypalpoides regulus sp. nov. from Regulus regulus (Linnaeus) (Regulidae) in the Netherlands, Harpypalpoides sitta sp. nov. from Sitta pygmaea Vigors (Sittidae) in the USA (Arizona, California), and Harpypalpoides sylvia sp. nov. from Sylvia atricapilla (Linnaeus) (Sylviidae) in the Netherlands. PMID- 25283119 TI - Three new gnathiid species with larvae ectoparasitic on coastal sharks from southwestern Japan (Crustacea: Isopoda). AB - Gnathiid larvae were collected from the gill chambers of coastal sharks in southwestern Japan. Some were reared in a laboratory aquarium and successfully metamorphosed into adults. Morphological observations of the adult males identified three undescribed species, which are designated Gnathia albipalpebrata n. sp., G. parvirostrata n. sp., and G. dejimagi n. sp. on the basis of their larval morphologies and pigmentation patterns. PMID- 25283120 TI - Phylogenetic re-evaluation of fossil and extant micro-echinoids with revision of Tridium, Cyamidia, and Lenicyamidia (Echinoidea: Clypeasteroida). AB - Tridium kieri Tandon & Srivastava, 1980, a clypeasteroid micro-echinoid from the Middle Eocene of Kachchh, India, has an apical system with just 3 gonopores. This condition is otherwise almost unknown among clypeasteroids, yet the morphology of Tridium is very similar to that of extant Fibularia, including members of another relatively poorly known genus from the Indian subcontinent and Western Australia, Cyamidia Lambert & Thiery, 1914. Re-examination of the type and additional material of T. kieri and Cyamidia paucipora Brunnschweiler, 1962, along with specimens identified as C. nummulitica nummulitica (Duncan & Sladen, 1884), allows for redescription of these forms. For the first time, maps of coronal plate architecture of Tridium and Cyamidia are developed, and SEM images of test surface details of the former are provided. Such new sources of data aid determination of their phylogenetic position among a subset of laganiform clypeasteroid taxa. During these analyses, new data were uncovered for two additional enigmatic, fibulariid taxa, Leniechinus herricki Kier, 1968 (Middle Eocene, North America), and Lenicyamidia compta Brunnschweiler, 1962 (Eocene, Western Australia). Both species were added to the overall analysis. These observations lead to the conclusion that Tridium falls within the genus Fibularia Lamarck, 1816, prompting reassignment of T. kieri to Fibularia along with refinement of the diagnosis of the Fibulariidae Gray, 1855. The Western Australian representative of Cyamidia, C. paucipora, was found to represent juveniles of Lenicyamidia compta; it is here synonymized with the latter. The genus Cyamidia thus appears to be restricted to the Indian Subcontinent. PMID- 25283121 TI - Taxonomic revision of wasp-like richardiids, Neoidiotypa Osten-Sacken (Diptera, Tephritoidea, Richardiidae). AB - Previously Neoidiotypa was a monotypic genus represented by a peculiar wasp-like richardiid from Cuba - N. appendiculata (Loew). In this work, five new species are described in this genus: N. mexicana sp. nov. from Mexico; N. alamagna sp. nov., N. flaviatra sp. nov., N. nigra sp. nov. and N. sticta sp. nov. from Costa Rica. New diagnostic characters for the genus are included. An identification key and illustrations for all species are provided. PMID- 25283122 TI - Revision of the Apocephalus analis group of ant-decapitating flies (Diptera: Phoridae). AB - The species of the mostly Neotropical Region Apocephalus analis group are revised, and found to comprise 21 species, 19 of which are new to science: A. bilineatus, A. euryacanthus, A. holdenae, A. mexacanthus, A. paracanthus, and A. rectisetus in the newly recognized A. comatus series, and the following unclassified species: A. amacayacuensis, A. amati, A. amenti, A. amorimi, A. camarae, A. criniventris, A. gonzalezae, A. marinhoi, A. papei, A. pittadearaujoi, A. riccardae, A. strazhnikae, and A. xavierfilhoi. Little is known of the natural history of this group, other than that the two previously known species, A. analis Borgmeier and A. comatus Borgmeier, were collected with the army ant Labidus coecus (Latreille). PMID- 25283123 TI - A review of quill mites (Acari: Syringophilidae) parasitising Kenyan birds. AB - Two new species of quill mites (Acari: Prostigmata: Syringophilidae) collected from passeriform and coraciiform birds from Kenya are described : Neoaulonastus apalis sp. nov. from Apalis porphyrolaema Reichenow and Neumann (Passeriformes: Cisticolidae) and Peristerophila upupi sp. nov. from Upupa epops Linnaeus (Coraciiformes: Upupidae). Additionally, 3 new host species: Cisticola hunteri Shelley, 1889; Acrocephalus baeticatus (Vieillot, 1817) and Ploceus xanthops (Hartlaub, 1862) from Kenya and two new localities are recorded for genera: Aulobia Kethley, 1970; Neoaulonastus Skoracki, 2004 and Syringophiloidus Kethley, 1970. The previous and the latest knowledge about syringophilid mites from Kenya is summarized in tabular form. PMID- 25283124 TI - Redescription of Parapercis okamurai Kamohara, 1960 (Perciformes: Pinguipedidae), based on specimens newly collected from Taiwan and Japan. AB - A rare species of sandperch, Parapercis okamurai, is redescribed based on 2 types and 15 specimens newly collected from Taiwan and Japan. The species is unique in having cycloid scales on the parietal, opercle and subopercle, except for few large ctenoid scale that covers the base of the opercular spine; body color yellowish dorsally, with 10 or 11 faint yellow bands on lateral body and pale ventrally; and black spots on inner side of upper pectoral fin base. It can also be distinguished from congeners by having a combination of the following characters: dorsal-fin rays V, 23; anal-fin rays I, 19; pectoral-fin rays 18; pored lateral-line scales 59-64; medial predorsal scales 9-10; transverse scale rows 4.5-5.5/14-15; circumpeduncular scales 20-21; gill raker4-5+9-10=13-16; -4 pairs of canine teeth at front of lower jaw; 2-4 rows of teeth on vomer; 2 rows of teeth on palatines; scales on cheek moderately large, each half embedded; and body color yellowish dorsally and a prominent ocellus at upper caudal-fin base. PMID- 25283125 TI - New species of Dorcopsinema and Paralabiostrongylus (Nematoda: Chabertiidae: Cloacininae) from Indonesia, with a key to species of Dorcopsinema. AB - Two new species of nematodes (Chabertiidae: Labiostrongylinea) from Dorcopsis muelleri in Raja Ampat Island, Papua, were described and figured. Dorcopsinema longispicularis sp.nov.is most similar to D. simile, but can be distinguished from it in being a smaller worm with longer spicules and a relatively longer oesophagus, as well as in the form of the posterior lip of the genital cone, the form of the spicule tips and the spiked tip of the female tail. Paralabiostrongylus rajampatensis sp. nov. differs from its congener, P. bicollaris, in having the deirids and excretory pore at about the same level, and in the form of the dorsal ray, with lateral branches proximal to the bifurcation of the dorsal trunk, the relatively longer spicule with ala extending to the tip and the form of the posterior lip of the genital cone. PMID- 25283126 TI - Serranus magnificus Macleay 1882, a junior synonym of Epinephelus lanceolatus (Bloch 1790) (Teleostei: Serranidae). PMID- 25283127 TI - Painful multiple mononeuropathy as a first symptom of cardiac myxoma: an unusual clinical presentation. AB - BACKGROUND: Atrial myxoma (AM) is responsible for multiple serious complications, such as ischemic stroke, and requires cardiac surgery. However, diagnosis and, thus, treatment may be delayed by an initial misleading clinical presentation including nonspecific extracardiac symptoms. Involvement of the peripheral nervous system as a first symptom of AM has been reported only once before and never in the form of multiple mononeuropathy. CASE: We report the case of a 51 year-old woman who had suffered from pharmacoresistant neurological pain sequentially in several peripheral nerve territories for more than a year before the appearance of purpuric macules on the palms and soles and emergence of a biological inflammatory syndrome. Cardioembolic disease was suspected after radiological examination detected multiple asymptomatic renal and splenic infarctions and a small right frontal cortical ischemic stroke. Transoesophageal echocardiography revealed an atrial mass which was removed by surgery. AM was confirmed after histopathological analysis. The neurological pain resolved along with embolic and systemic signs of AM, and the patient has since been free of pain. CONCLUSION: Multiple mononeuropathy is a possible symptom of AM and may precede onset of other embolic or systemic signs by several months. PMID- 25283128 TI - IgG4-related disease of the aortic valve: a report of two cases and review of the literature. AB - IgG4-related disease (IgG4-RD) is a relatively recently described disorder that can affect multiple organ systems, including the cardiovascular system. While most reported cases of cardiovascular involvement are of the aorta, usually the abdominal aorta, rare isolated reports of involvement of the heart proper have been described. Herein, we describe two cases of IgG4-RD involving the aortic valve. Each case was found to be associated with increased levels of IgG4 in the tissue and one case resulted in the subsequent discovery of IgG4-related pancreatitis. PMID- 25283129 TI - Tissue proteomics using chemical immobilization and mass spectrometry. AB - Proteomics analysis is important for characterizing tissues to gain biological and pathological insights, which could lead to the identification of disease associated proteins for disease diagnostics or targeted therapy. However, tissues are commonly embedded in optimal cutting temperature medium (OCT) or are formalin fixed and paraffin-embedded (FFPE) in order to maintain tissue morphology for histology evaluation. Although several tissue proteomic analyses have been performed on FFPE tissues using advanced mass spectrometry (MS) technologies, high-throughput proteomic analysis of OCT-embedded tissues has been difficult due to the interference of OCT in the MS analysis. In addition, molecules other than proteins present in tissues further complicate tissue proteomic analysis. Here, we report the development of a method using chemical immobilization of proteins for peptide extraction (CIPPE). In this method, proteins are chemically immobilized onto a solid support; interferences from tissues and OCT embedding are removed by extensive washing of proteins conjugated on the solid support. Peptides are then released from the solid phase by proteolysis, enabling MS analysis. This method was first validated by eliminating OCT interference from a standard protein, human serum albumin, where all of the unique peaks contributed by OCT contamination were eradicated. Finally, this method was applied for the proteomic analysis of frozen and OCT-embedded tissues using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and two-dimensional liquid chromatography tandem mass spectrometry. The data showed reproducible extraction and quantitation of 10,284 proteins from 3996 protein groups and a minimal impact of OCT embedding on the analysis of the global proteome of the stored tissue samples. PMID- 25283131 TI - A direct hybridization between isocharged nanosheets of layered metal oxide and graphene through a surface-modification assembly process. AB - An efficient and universal method to directly hybridize isocharged nanosheets of layered metal oxide and reduced graphene oxide (rGO) is developed on the basis of the surface modification and an electrostatically driven assembly process. On the basis of this synthetic method, the CoO2 -rGO nanocomposite can be synthesized with exfoliated CoO2 and rGO nanosheets, and transformed into CoO-CoO2 -rGO nanocomposites with excellent electrode performance for lithium-ion batteries. Also, this surface-modification assembly route is successfully applied for the synthesis of another mesoporous TiO2 -rGO nanocomposite. This result provides clear evidence for the usefulness of the present method as a universal way of hybridizing isocharged anionic nanosheets of inorganic solids and graphene. PMID- 25283130 TI - A high-performance liquid chromatography-based assay of glutathione transferase omega 1 supported by glutathione or non-physiological reductants. AB - The unusual glutathione S-transferase GSTO1 reduces, rather than conjugates, endo and xenobiotics, and its role in diverse cellular processes has been proposed. GSTO1 has been assayed spectrophotometrically by measuring the disappearance of its substrate, S-(4-nitrophenacyl)glutathione (4-NPG), in the presence of 2 mercaptoethanol that regenerates GSTO1 from its mixed disulfide. To assay GSTO1 in rat liver cytosol, we have developed a high-performance liquid chromatography (HPLC)-based procedure with two main advantages: (i) it measures the formation of the 4-NPG reduction product 4-nitroacetophenone, thereby offering improved sensitivity and accuracy, and (ii) it can use glutathione, the physiological reductant of GSTO1, which is impossible to do with the spectrophotometric procedure. Using the new assay, we show that (i) the GSTO1-catalyzed reduction of 4-NPG in rat liver cytosol also yields 1-(4-nitrophenyl)ethanol, whose formation from 4-nitroacetophenone requires NAD(P)H; (ii) the two assays measure comparable activities with 2-mercaptoethanol or tris(2-carboxyethyl)phosphine used as reductant; (iii) the cytosolic reduction of 4-NPG is inhibited by GSTO1 inhibitors (KT53, 5-chloromethylfluorescein diacetate, and zinc), although the inhibitory effect is strikingly influenced by the type of reductant in the assay and by the sequence of reductant and inhibitor addition. Characterization of GSTO1 inhibitors with the improved assay provides better understanding of interaction of these chemicals with the enzyme. PMID- 25283132 TI - Morphology-driven absorption and emission colour changes in liquid-crystalline, cyclometallated platinum(II) complexes. AB - Platinum(II) complexes of 1,3-bis(2-pyridyl)benzene containing two alkyl chains are unexpectedly mesomorphic and capable of changing absorption and emission colour depending on the phase obtained after thermal treatment. PMID- 25283133 TI - Obstructive sleep apnea in women: Prevalence, risk factors and relation to menopausal status. PMID- 25283134 TI - Pancreatic congestion in liver cirrhosis correlates with impaired insulin secretion. AB - BACKGROUND: Although impaired glucose tolerance is common in cirrhosis, this condition's pathogenesis remains undefined. This study aimed to clarify pathogenesis related to the pancreas in cirrhotic patients, and to evaluate associations between insulin secretion and pancreatic congestion due to portal hypertension. METHODS: Pancreatic perfusion parameters were analyzed by dynamic contrast-enhanced ultrasound (CE-US) in 41 patients (20 cirrhotic, 21 non cirrhotic; age, 67.9 +/- 13.3; female, 19), and prospectively compared to delta C peptide immunoreactivity (DeltaCPR). In a separate study, a retrospective chart review with human autopsy specimens was conducted, and vessels and islets of the pancreas were analyzed in 43 patients (20 cirrhotic, 23 controls; age, 71.5 +/- 11.6; female, 15). RESULTS: In the CE-US study, the clinical characteristics indicative of portal hypertension (e.g., ascites and varices) had significantly higher incidences in the cirrhotic group than in the control group. Pancreatic drainage times were greater in the cirrhotic group (p < 0.0001), and had a significant negative correlation with DeltaCPR (R = 0.42, p = 0.0069). In the histopathological study, the islets were enlarged in the cirrhotic group (p < 0.0001). However, the percentage of insulin-positive area per islet was decreased in the cirrhotic group (p < 0.0001), and had a significant negative correlation with the wall thickness of the pancreatic vein (R = 0.63, p < 0.0001). CONCLUSIONS: Pancreatic congestion was present in cirrhotic patients. Moreover, pancreatic congestion and insulin secretion were significantly correlated. This pathogenesis could be a key factor underlying the development of hepatogenous diabetes in cirrhotic patients. PMID- 25283136 TI - Development of a solid-phase microextraction fiber by the chemical binding of graphene oxide on a silver-coated stainless-steel wire with an ionic liquid as the crosslinking agent. AB - Graphene oxide was bonded onto a silver-coated stainless-steel wire using an ionic liquid as the crosslinking agent by a layer-by-layer strategy. The novel solid-phase microextraction fiber was characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy and Raman microscopy. A multilayer graphene oxide layer was closely coated onto the supporting substrate. The thickness of the coating was about 4 MUm. Coupled with gas chromatography, the fiber was evaluated using five polycyclic aromatic hydrocarbons (fluorene, anthracene, fluoranthene, 1,2-benzophenanthrene, and benzo(a)pyrene) as model analytes in direct-immersion mode. The main conditions (extraction time, extraction temperature, ionic strength, and desorption time) were optimized by a factor-by-factor optimization. The as-established method exhibited a wide linearity range (0.5-200 MUg/L) and low limits of determination (0.05-0.10 MUg/L). It was applied to analyze environmental water samples of rain and river water. Three kinds of the model analytes were quantified and the recoveries of samples spiked at 10 MUg/L were in the range of 92.3-120 and 93.8-115%, respectively. The obtained results indicated the fiber was efficient for solid phase microextraction analysis. PMID- 25283135 TI - The Wide Range Achievement Test-4 Reading subtest "holds" in HIV-infected individuals. AB - BACKGROUND: In order to detect HIV-associated neurocognitive decline, it is important to accurately estimate individuals' premorbid levels of cognitive functioning. Although previous studies have operated under the assumption that word reading tests are valid and stable indicators of premorbid abilities in HIV infection, studies of other populations have found that this is not always the case. Therefore, it is important to empirically examine the validity of word reading tests as estimates of premorbid functioning specifically within the HIV population. METHOD: The Wide Range Achievement Test-4 Reading subtest (WRAT-4 Reading) was administered along with comprehensive neurocognitive assessments to 150 HIV seropositive (HIV+) and 76 HIV seronegative (HIV-) age-, education-, and sex-matched participants; a subset of 48 HIV+ individuals completed a second study visit (M = 14.4 months), in which the alternate version of the WRAT-4 was administered. RESULTS: Although HIV+ individuals evidenced worse current neurocognitive functioning than HIV- participants, WRAT-4 Reading performance was comparable between groups. Longitudinally, HIV+ participants evidenced improved disease and neuropsychological functioning, yet WRAT-4 Reading demonstrated strong test-retest reliability and no practice effect, and did not differ between the initial and follow-up assessments. Test-retest differences in reading performance were minor and were not associated with changes in neurocognitive performance or changes in HIV disease. CONCLUSIONS: We found no evidence of WRAT 4 Reading performance decline in HIV infection, despite HIV+/HIV- group differences in neurocognitive functioning. Additionally, reading performances among HIV+ individuals demonstrated consistency across study visits. These results begin to support the validity of the WRAT-4 Reading subtest as an indicator of premorbid cognitive functioning in HIV+ individuals. PMID- 25283137 TI - Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans. AB - BACKGROUND: Chloral hydrate (CH), a sedative and metabolite of the environmental contaminant trichloroethylene, is metabolized to trichloroacetic acid, trichloroethanol, and possibly dichloroacetate (DCA). DCA is further metabolized by glutathione transferase zeta 1 (GSTZ1), which is identical to maleylacetoacetate isomerase (MAAI), the penultimate enzyme in tyrosine catabolism. DCA inhibits its own metabolism through depletion/inactivation of GSTZ1/MAAI with repeated exposure, resulting in lower plasma clearance of the drug and the accumulation of the urinary biomarker maleylacetone (MA), a metabolite of tyrosine. It is unknown if GSTZ1/MAAI may participate in the metabolism of CH or any of its metabolites and, therefore, affect tyrosine catabolism. Stable isotopes were utilized to determine the biotransformation of CH, the kinetics of its major metabolites, and the influence, if any, of GSTZ1/MAAI. METHODS: Eight healthy volunteers (ages 21-40 years) received a dose of 1 g of CH (clinical dose) or 1.5 MUg/kg (environmental) for five consecutive days. Plasma and urinary samples were analyzed by gas chromatography-mass spectrometry. RESULTS: Plasma DCA (1.2-2.4 MUg/mL), metabolized from CH, was measured on the fifth day of the 1 g/day CH dosage but was undetectable in plasma at environmentally relevant doses. Pharmacokinetic measurements from CH metabolites did not differ between slow and fast GSTZ1 haplotypes. Urinary MA levels increased from undetectable to 0.2-0.7 MUg/g creatinine with repeated CH clinical dose exposure. Kinetic modeling of a clinical dose of 25 mg/kg DCA administered after 5 days of 1 g/day CH closely resembled DCA kinetics obtained in previously naive individuals. CONCLUSIONS: These data indicate that the amount of DCA produced from clinically relevant doses of CH, although insufficient to alter DCA kinetics, is sufficient to inhibit MAAI and tyrosine catabolism, as evidenced by the accumulation of urinary MA. PMID- 25283138 TI - Salivary morning androstenedione and 17alpha-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia. AB - BACKGROUND: Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17alpha hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione during monitoring. METHODS: We evaluated A-dione and 17OHP levels in nearly 2000 salivary samples collected during long-term treatment of 84 paediatric patients with classic 21 hydroxylase deficiency. RESULTS: A-dione and 17OHP levels and its ratio 17OHP/A dione remained constant from 4 to 11 years with no sex-related differences. During puberty, A-dione and 17OHP levels both increased, starting at earlier age in girls than in boys. The ratio 17OHP/A-dione declined. Normalised A-dione concomitant with elevated 17OHP [1.43 nmol/L (0.46-4.41) during prepuberty; 2.36 nmol/L (0.63-8.89) for boys and 1.99 nmol/L (0.32-6.98) for girls during puberty] could be obtained with overall median glucocorticoid doses of 11-15 mg/m2/day. A dione levels above the upper reference limit (URL), suggesting undertreatment, coincided with 17OHP levels >=10 times URL. The percentage of A-dione levels above URL was 16% at ages 4-8 years, but increased to 31% for girls at 16 years and 46% for boys at 17 years. CONCLUSIONS: Normalised A-dione consistent with 17OHP three times URL during prepuberty and normalised A-dione consistent with 4 6 times URL during puberty could be obtained by moderate glucocorticoid dosages. A constant 17OHP/A-dione ratio during prepuberty suggested absence of adrenarche. During puberty, a higher percentage of samples met the criteria for undertreatment, especially of boys. PMID- 25283139 TI - One year B-vitamins increases serum and whole blood folate forms and lowers plasma homocysteine in older Germans. AB - BACKGROUND: We aimed to study the effect of long-term supplementation of B vitamins on folate forms in serum and whole blood (WB) in elderly German subjects. METHODS: 59 participants (mean age 67 years) were randomized to daily receive either vitamin D3 (1200 IU), folic acid (500 MUg), vitamin B12 (500 MUg), vitamin B6 (50 mg), and calcium carbonate (456 mg) or vitamin D3 plus calcium carbonate. Serum and WB folate forms were measured before and after 6 and 12 months. RESULTS: B-vitamins supplementation for 6 months led to higher concentrations of 5-methyltetrahydrofolate (5-methylTHF) in serum (mean 49.1 vs. 19.6 nmol/L) and WB (1332 vs. 616 nmol/L). Also non-methyl-folate concentrations in serum and WB were higher after 6 months with B-vitamins supplementation. Unmetabolized folic acid (UFA) increased after supplementation. tHcy concentration was lowered after 1 year of B-vitamin supplementation (mean 13.1 vs. 9.6 MUmol/L). A stronger reduction of tHcy after 1 year was found in participants who had baseline level >12.5 MUmol/L (mean 17.0 vs. 11.9 MUmol/L) compared to those with baseline tHcy lower than this limit (mean 9.1 vs. 7.4 MUmol/L). In contrast, the increases in serum and WB 5-methylTHF were comparable between the two groups. CONCLUSIONS: One year B-vitamins supplementation increased the levels of 5-methylTHF and non-methyl-folate in serum and WB, normalized tHcy, but caused an increase in the number of cases with detectable UFA in serum. Lowering of tHcy was predicted by baseline tHcy, but not by baseline serum or WB 5-methylTHF. PMID- 25283140 TI - An approach to establish the uncertainty budget of catalytic activity concentration measurements in a reference laboratory. AB - BACKGROUND: Reference laboratories providing reference services recognized by the Joint Committee for Traceability in Laboratory Medicine (JCTLM) must be accredited as calibration laboratories according to ISO 17025 and ISO 15195. These standards require laboratories to establish an uncertainty budget, in which the uncertainty contributions of the relevant uncertainty components are specified. We present a model to estimate the measurement uncertainty of creatine kinase catalytic activity concentration results obtained by IFCC primary reference measurement procedure. METHODS: The measurement uncertainty has been estimated by following the next steps: 1) specification of the measurand; 2) identification of the most relevant uncertainty sources; 3) estimation of standard uncertainties by either type A or type B evaluation; 4) estimation of combined uncertainty while taking into account sensitivity coefficients, as well as existence of correlated uncertainty sources; and 5) estimation of expanded uncertainty with a defined coverage probability. RESULTS: The estimated expanded uncertainty was 2.2% (k=2). Uncertainty sources with a significant contribution to the measurement uncertainty were the following: pH adjustment (0.68%), absorbance accuracy (0.48%), wavelength adjustment (0.20%), reaction temperature (0.19%), volume fraction of sample (0.15%) and absorbance linearity (0.06%). CONCLUSIONS: The present model is an approach to establish the uncertainty budget of primary reference procedures for the measurement of the catalytic activity concentration of enzymes, and aims at being an example to be followed by other reference laboratories, as well as by laboratories that carry out primary reference measurement procedures. PMID- 25283141 TI - High-sensitivity cardiac troponin I in the general population--defining reference populations for the determination of the 99th percentile in the Gutenberg Health Study. AB - BACKGROUND: The 99th percentile of cardiac troponin levels, determined in a reference population, is accepted as threshold for diagnosis of acute myocardial infarction (AMI). However, there is no common consensus of how to define the reference population. The aim of the present study was to determine 99th percentile reference values, determined by a high-sensitivity assay (hsTnI), according to different health status and cardiovascular risk factor prevalence in a large population-based sample. METHODS: Troponin I was determined using the Abbott ARCHITECT STAT highly sensitive troponin I immunoassay in 4138 participants of the Gutenberg Health Study. RESULTS: hsTnI was detectable in 81.6% of all individuals. The 99th percentile of the overall population was 27 ng/L. Age and gender had a prominent influence on these values. Exclusion of individuals with elevated natriuretic peptide levels or cardiac abnormalities resulted in lower 99th percentile values, whereas exclusion of individuals with an impaired estimated glomerular filtration rate (eGFR) or with prevalent coronary artery disease/myocardial infarction (CAD/MI) did not result in a meaningful change. CONCLUSIONS: Troponin I, measured by a high-sensitivity assay, can be reliably detected in the vast majority of the general population. hsTnI values were dependent on age, gender as well as structural and functional cardiac abnormalities. PMID- 25283142 TI - Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. AB - The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune-mediated and adaptation represents immune tolerance. In this study we found that AQ treatment of Cbl-b(-/-) and PD-1(-/-) mice, which have impaired immune tolerance, resulted in a slightly greater injury. Cotreatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in T regulatory (Treg) cells and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the alanine aminotransferase (ALT) activity in these mice returned to normal despite continued treatment. Cotreatment of PD-1(-/-) mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200-300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis. The lymphocyte infiltration included T and B cells, and the CD8(+) T cells produced perforin and granzyme. In addition, the ALT activity in PD-1(-/-) mice cotreated with anti-CTLA4 antibody and AQ did not return to normal, as it had in other mice. CONCLUSION: We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance. PMID- 25283143 TI - Transient increase in urine protein excretion during treatment with terlipressin and albumin for type-1 hepatorenal syndrome. PMID- 25283147 TI - o-Benzyne fragmentation and isomerization pathways: a CASPT2 study. AB - The mechanisms of the fragmentation and isomerization pathways of o-benzyne were studied at the multi-configurational second-order perturbative level [CAS(12,12) PT2]. The direct fragmentation of o-benzyne to C2H2 + C4H2 follows two mechanisms: a concerted mechanism and a stepwise mechanism. Although the concerted mechanism is characterized by a single closed-shell transition structure, the stepwise pathway is more complex and structures with a strong diradical character are seen. A third diradicaloid fragmentation pathway of o benzyne yields C6H2 as the final product. As an alternative to fragmentation, o benzyne can also undergo rearrangement to its meta and para isomers and to the open chain cis and trans isomers of hexa-3-en-1,6-diyne (HED). These easily fragment to C2H2 + C4H2 or C6H2. Kinetic modelling at several different temperatures between 800 and 3000 K predicted that the thermal decomposition of o benzyne should yield C2H2, C4H2 and C6H2 as the main products. Small amounts of the HED isomers accumulated at temperatures <1200 K, but they rapidly decompose at higher temperatures. Between 1000 and 1400 K, C2H2 + C4H2 are formed exclusively from the decomposition of trans-HED. At temperatures >1400 K, C2H2 + C4H2 also form from the direct fragmentation of o-benzyne. The formation of C2H2 + C4H2 prevails up to 1600 K but above this temperature the formation of C6H2 prevails. At temperatures >2400 K, the direct fragmentation of o-benzyne again leads to the formation of C2H2 + C4H2. The formation of hydrogen atoms is also explained by our proposed mechanisms. PMID- 25283145 TI - The FHIT gene product: tumor suppressor and genome "caretaker". AB - The FHIT gene at FRA3B is one of the earliest and most frequently altered genes in the majority of human cancers. It was recently discovered that the FHIT gene is not the most fragile locus in epithelial cells, the cell of origin for most Fhit-negative cancers, eroding support for past claims that deletions at this locus are simply passenger events that are carried along in expanding cancer clones, due to extreme vulnerability to DNA damage rather than to loss of FHIT function. Indeed, recent reports have reconfirmed FHIT as a tumor suppressor gene with roles in apoptosis and prevention of the epithelial-mesenchymal transition. Other recent works have identified a novel role for the FHIT gene product, Fhit, as a genome "caretaker." Loss of this caretaker function leads to nucleotide imbalance, spontaneous replication stress, and DNA breaks. Because Fhit loss induced DNA damage is "checkpoint blind," cells accumulate further DNA damage during subsequent cell cycles, accruing global genome instability that could facilitate oncogenic mutation acquisition and expedite clonal expansion. Loss of Fhit activity therefore induces a mutator phenotype. Evidence for FHIT as a mutator gene is discussed in light of these recent investigations of Fhit loss and subsequent genome instability. PMID- 25283146 TI - Dynamic droplets: the role of cytoplasmic inclusions in stress, function, and disease. AB - Neurodegenerative diseases and other proteinopathies constitute a class of several dozen illnesses etiologically linked to pathological protein misfolding and aggregation. Because of this strong association with disease pathology, cell death, and aging, accumulation of proteins in aggregates or aggregation associated structures (inclusions) has come to be regarded by many as a deleterious process, to be avoided if possible. Recent work has led us to see inclusion structures and disordered aggregate-like protein mixtures (which we call dynamic droplets) in a new light: not necessarily as a result of a pathological breakdown of cellular order, but as an elaborate cellular architecture regulating function and stress response. In this review, we discuss what is currently known about the role of inclusion structures in cellular homeostasis, stress response, toxicity, and disease. We will focus on possible mechanisms of aggregate toxicity, in contrast to the homeostatic function of several inclusion structures. PMID- 25283148 TI - ABRO1 suppresses tumourigenesis and regulates the DNA damage response by stabilizing p53. AB - Abraxas brother 1 (ABRO1) has been reported to be a component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin. However, current knowledge of the functions of ABRO1 is limited. Here we report that ABRO1 is frequently downregulated in human liver, kidney, breast and thyroid gland tumour tissues. Depletion of ABRO1 in cancer cells reduces p53 levels and enhances clone formation and cellular transformation. Conversely, overexpression of ABRO1 suppresses cell proliferation and tumour formation in a p53-dependent manner. We further show that ABRO1 stabilizes p53 by facilitating the interaction of p53 with USP7. DNA-damage induced accumulation of endogenous ABRO1 as well as translocation of ABRO1 to the nucleus, and the induction of p53 by DNA damage is almost completely attenuated by ABRO1 depletion. Our study shows that ABRO1 is a novel p53 regulator that plays an important role in tumour suppression and the DNA damage response. PMID- 25283149 TI - Anticholinergics/antimuscarinic drugs in asthma. AB - Anticholinergic alkaloids have been used for thousands of years for the relief of bronchoconstriction and other respiratory symptoms, and their use in the treatment of chronic obstructive pulmonary disease is well established. Acetylcholine, acting through muscarinic receptor (M) receptor, modulates multiple physiologic functions pertinent to asthma including airway muscle tone, mucus gland secretion, and various parameters of inflammation and remodeling. In addition, activation of M receptors may inhibit beta2 adrenoreceptor. These observations offer the rationale for the use of M receptors antagonists in the treatment of asthma. Short-acting antimuscarinic agents may be effective alone or in combination with short-acting beta agonists for the relief of acute symptoms. Long-acting antimuscarinic agents have emerged as potentially useful in the long term treatment of difficult-to-control asthma. This review will analyze the mechanisms of action and therapeutic role of antimuscarinic agents on asthma including current guidelines regarding antimuscarinic drugs, recent studies in asthma, special populations to consider, and possible predictors of response. PMID- 25283150 TI - The use of non-invasive ventilation in very old patients with hypercapnic acute respiratory failure because of COPD exacerbation. AB - AIMS: We prospectively enrolled 207 patients (121 were 75 or older and 86 younger than 75) who were admitted to three Respiratory Monitoring Units. The primary outcomes were intubation and mortality rates; the secondary outcomes were changes in arterial blood gases analysis, non-invasive ventilation (NIV) duration and length of hospital stay. RESULTS: Hospital mortality was similar in the two groups, as were intubation rates. The proportion who died in the very old patient group was 19.8% (24/121) vs. 10.4% (9/86) in the younger group. Intubation rate was 10.7% (13/121) in the very old patient group and 11.6% (10/86) in the younger group. The presence of comorbidities, the severity of illness (SAPS II), the level of consciousness, NIV failure (intubation), absolute value of pH prior to NIV, as well as the changes in pH and paCO2 and PaO2 /FiO2 after 2 h of NIV, were the variables associated with higher mortality. Very old patients had significantly higher NIV duration than younger patients (69.0 +/- 47.0 vs. 57.0 +/- 27.0 h) (p <= 0.03) and hospital stays (11.6 +/- 3.8 vs. 8.4 +/- 1.4) (p <= 0.02). CONCLUSIONS: The use of NIV in very old patients was effective in many cases. Endotracheal intubation after NIV failure was not efficacious in either group. PMID- 25283151 TI - Participation of older people in preauthorization trials of recently approved medicines. AB - OBJECTIVES: To investigate the inclusion of older people in clinical trials of recently authorized medicines, evaluating adherence to the 20-year-old International Conference of Harmonisation (ICH) guideline on geriatrics (E7). DESIGN: Observational. SETTING: European public assessment reports, published clinical trials, World Health Organization International Clinical Trials Registry Platform. PARTICIPANTS: Individuals aged 65 and older and 75 and older. MEASUREMENTS: Number and proportion of randomized participants and all exclusion criteria of studies involving diseases characteristically associated with aging (venous thromboembolism, osteoporosis, atrial fibrillation) and diseases not unique to older adults (type 2 diabetes mellitus, depression, bipolar disorder, epilepsy). RESULTS: In 114 Phase II and III trials of 12 medicines, 43.1% of participants were aged 65 and older, and 16.1% were aged 75 and older. In trials involving diseases characteristically associated with ageing, 57% were aged 65 and older; 22% were aged 75 and older. In trials involving diseases not unique to old age, 9% were aged 65 and older, and 1% were aged 75 and older. Upper age limits were applied in 30.7% of the trials; the frequency did not differ between larger (sample size >= 500) and smaller trials (P = .36), although it was significantly lower in trials involving diseases characteristically associated with aging (18.0%) than in trials of diseases not unique to old age (45.3%; P = .002). Age-sensitive exclusion criteria, based on comorbidity (75.4%), concomitant medication (71.9%), and other criteria correlated with age (60.5%) were applied more frequently in larger trials (P < .02). CONCLUSION: Studies of diseases not uniquely associated with old age included an unacceptably low proportion of older people, contrary to the recommendations of the ICH E7 guideline. Although the proportion of older participants in trials of diseases characteristically associated with aging was appropriate for certain medicines, the use of age-sensitive exclusion criteria limits the representativeness of the trial population for daily practice. PMID- 25283152 TI - Catalytic enantioselective quick route to aldol-tethered 1,6- and 1,7-enynes from omega-unsaturated aldehydes. AB - An effective asymmetric route to functionalized 1,6- and 1,7-enynes has been developed based on a direct cross-aldol reaction between omega-unsaturated aldehydes and propargylic aldehydes (alpha,beta-ynals) promoted by combined alpha,alpha-dialkylprolinol ether/Bronsted acid catalysis. This synergistic activation strategy is key to accessing the corresponding aldol adducts with high stereoselectivity, both enantio- and diastereoselectivity. The aldol reaction also proceeds well with propargylic ketones (alpha,beta-ynones) thus enabling a stereocontrolled access to the corresponding tertiary alcohols. The utility of these adducts, which are difficult to prepare through standard methodology, is demonstrated by their transformation into trisubstituted bicyclic enones using standard Pauson-Khand conditions. PMID- 25283153 TI - Identification of the growth hormone-releasing hormone analogue [Pro1, Val14] hGHRH with an incomplete C-term amidation in a confiscated product. AB - In this work, a modified version of the 44 amino acid human growth hormone releasing hormone (hGHRH(1-44)) containing an N-terminal proline extension, a valine residue in position 14, and a C-terminus amidation (sequence: PYADAIFTNSYRKVVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2 ) has been identified in a confiscated product by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Investigation of the product suggests also an incomplete C-term amidation. Similarly to other hGHRH analogues, available in black markets, this peptide can potentially be used as performance-enhancing drug due to its growth hormone releasing activity and therefore it should be considered as a prohibited substance in sport. Additionally, the presence of partially amidated molecule reveals the poor pharmaceutical quality of the preparation, an aspect which represents a big concern for public health as well. PMID- 25283156 TI - Iridium(I)-catalyzed regioselective C-H activation and hydrogen-isotope exchange of non-aromatic unsaturated functionality. AB - Isotopic labelling is a key technology of increasing importance for the investigation of new C?H activation and functionalization techniques, as well as in the construction of labelled molecules for use within both organic synthesis and drug discovery. Herein, we report for the first time selective iridium catalyzed C?H activation and hydrogen-isotope exchange at the beta-position of unsaturated organic compounds. The use of our highly active [Ir(cod)(IMes)(PPh3 )][PF6 ] (cod=1,5-cyclooctadiene) catalyst, under mild reaction conditions, allows the regioselective beta-activation and labelling of a range of alpha,beta unsaturated compounds with differing steric and electronic properties. This new process delivers high levels of isotope incorporation over short reaction times by using low levels of catalyst loading. PMID- 25283154 TI - Non-invasive imaging of allogeneic transplanted skin graft by 131I-anti-TLR5 mAb. AB - Although (18)F-fluorodeoxyglucose ((18)F-FDG) uptake can be used for the non invasive detection and monitoring of allograft rejection by activated leucocytes, this non-specific accumulation is easily impaired by immunosuppressants. Our aim was to evaluate a (131)I-radiolabelled anti-Toll-like receptor 5 (TLR5) mAb for non-invasive in vivo graft visualization and quantification in allogeneic transplantation mice model, compared with the non-specific radiotracer (18)F-FDG under using of immunosuppressant. Labelling, binding, and stability studies were performed. BALB/c mice transplanted with C57BL/6 skin grafts, with or without rapamycin treatment (named as allo-treated group or allo-rejection group), were injected with (131)I-anti-TLR5 mAb, (18)F-FDG, or mouse isotype (131)I-IgG, respectively. Whole-body phosphor-autoradiography and ex vivo biodistribution studies were obtained. Whole-body phosphor-autoradiography showed (131)I-anti TLR5 mAb uptake into organs that were well perfused with blood at 1 hr and showed clear graft images from 12 hrs onwards. The (131)I-anti-TLR5 mAb had significantly higher graft uptake and target-to-non-target ratio in the allo treated group, as determined by semi-quantification of phosphor-autoradiography images; these results were consistent with ex vivo biodistribution studies. However, high (18)F-FDG uptake was not observed in the allo-treated group. The highest allograft-skin-to-native-skin ratio (A:N) of (131)I-anti-TLR5 mAb uptake was significantly higher than the ratio for (18)F-FDG (7.68 versus 1.16, respectively). (131)I-anti-TLR5 mAb uptake in the grafts significantly correlated with TLR5 expression in the allograft area. The accumulation of (131)I-IgG was comparable in both groups. We conclude that radiolabelled anti-TLR5 mAb is capable of detecting allograft with high target specificity after treatment with the immunosuppressive drug rapamycin. PMID- 25283155 TI - Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes. AB - BACKGROUND: Metformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India. METHODS: Type 2 diabetes patients from two secondary care diabetic centres (Europeans - UK and Indians - India) were studied. Serum vitamin B12, folate and biochemical parameters were measured. RESULTS: The prevalence rates of vitamin B12 deficiency (<191 ng/L) were 27% and 12% in Europeans and Indians, respectively and higher in metformin treated type 2 diabetes patients. In linear regression analysis, after adjusting for all likely confounding factors, vitamin B12 independently associated with triglycerides in both the populations and cholesterol/HDL ratio in Indians. Logistic regression showed type 2 diabetes patients with vitamin B12 deficiency were at significantly higher odds of having coexisting coronary artery disease (CAD) in Europeans with similar but non significant trend in Indians, after adjusting for all likely confounding factors. CONCLUSIONS: The prevalence of vitamin B12 deficiency is common in type 2 diabetes patients and is associated with adverse lipid parameters. Type 2 diabetes management guidelines should include the recommendation for regular testing for B12 levels, especially for those on metformin. PMID- 25283157 TI - Linking secondary school physical education with community sport and recreation for girls: a process evaluation. AB - BACKGROUND: The purpose of this study was to undertake a process evaluation to examine the reach, adoption and implementation of a school-community linked physical activity (PA) program for girls aged 12 - 15 years (School Years 7 - 9) using the RE-AIM framework. METHODS: Various approaches were used to assess 'reach', 'adoption' and implementation: (a) a school environment survey of intervention schools (n = 6); (b) teacher feedback regarding the professional development component (91.1% response rate) and lesson implementation (60.8% response rate); and (c) post-intervention focus group interviews with physical education (PE) teachers (n = 29), students (n = 125), coaches (n = 13) and instructors (n = 8) regarding program experiences. RESULTS: Reach and Adoption: Seven schools (n = 1491 Year 7-9 female student enrolment; 70% adoption rate), five tennis clubs, eight football clubs and five leisure centres participated in the program during 2011. IMPLEMENTATION: Program design and professional development opportunities (training, resource manual and opportunities to work with coaches and instructors during PE classes) supported implementation and student engagement in PA. However, there was a lack of individual and organisational readiness to adopt program principles. For some deliverers there were deeply embedded ideologies that were not aligned with the Game Sense teaching approach upon which the program was based. Further, cognitive components of the program such as self-management were not widely adopted as other components of the program tended to be prioritised. CONCLUSION: The program design and resources supported the success of the program, however, some aspects were not implemented as intended, which may have affected the likelihood of achieving further positive outcomes. Barriers to program implementation were identified and should be considered when designing school-community linked interventions. In particular, future programs should seek to assess and adjust for organizational readiness within the study design. For example, shared commitment and abilities of program deliverers to implement the program needs to be determined to support program implementation. TRIAL REGISTRATION: ACTRN12614000446662. April 30th 2014. PMID- 25283158 TI - Highly specific electrochemical analysis of cancer cells using multi-nanoparticle labeling. AB - Circulating tumor cells (CTCs) can be collected noninvasively and provide a wealth of information about tumor phenotype. For this reason, their specific and sensitive detection is of intense interest. Herein, we report a new, chip-based strategy for the automated analysis of cancer cells. The nanoparticle-based, multi-marker approach exploits the direct electrochemical oxidation of metal nanoparticles (MNPs) to report on the presence of specific surface markers. The electrochemical assay allows simultaneous detection of multiple different biomarkers on the surfaces of cancer cells, enabling discrimination between cancer cells and normal blood cells. Through multiplexing, it further enables differentiation among distinct cancer cell types. We showcase the technology by demonstrating the detection of cancer cells spiked into blood samples. PMID- 25283159 TI - IAA production by Bacillus sp. JH 2-2 promotes Indian mustard growth in the presence of hexavalent chromium. AB - Bacillus sp. strain JH 2-2, isolated from the rhizosphere of plants at a multi metal contaminated mine site, has the potential to reduce Cr(VI) to Cr(III) and promote plant growth by reducing Cr toxicity and producing IAA. The minimum inhibitory concentration of Cr(VI) to Bacillus sp. JH 2-2 was 1000 mg L(-1) and the strain reduced 99% of 10 mg Cr(VI) L(-1) to Cr(IV) within 24 h. Lower Cr(VI) stress (10 mg L(-1) ) stimulated IAA production, but much less IAA was produced at 30 or 50 mg Cr(VI) L(-1) . Inoculation with Bacillus sp. JH 2-2 increased the length of Brassica juncea L. roots by 364% and stems by 735% in the presence of 10 mg Cr(VI) L(-1) from those of uninoculated control plants. These findings suggest potential use of Bacillus sp. JH 2-2 to promote phytoremediation of soil contaminated with Cr(VI). PMID- 25283160 TI - Solid state and solution fine tuning of the linear and nonlinear optical properties of (2-pyrene-1-yl-vinyl)pyridine by protonation-deprotonation reactions. AB - The unexpected and acido-triggered reversible luminescence and nonlinear optical properties of (2-pyrene-1-yl-vinyl)pyridine, a simple and highly transparent chromophore, are studied both in solution and in the solid state. Remarkably, for the first time the acidomodulation of the NLO response of a poled thin film is reported. PMID- 25283161 TI - Cancer registration in Pakistan: a dilemma that needs to be resolved. PMID- 25283162 TI - Atomic domain magnetic nanoalloys: interplay between molecular structure and temperature dependent magnetic and dielectric properties in manganese doped tin clusters. AB - We present extensive temperature dependent (16-70 K) magnetic and electric molecular beam deflection measurements on neutral manganese doped tin clusters Mn/SnN (N = 9-18). Cluster geometries are identified by comparison of electric deflection profiles and quantum chemical data obtained from DFT calculations. Most clusters adopt endohedral cage structures and all clusters exhibit non vanishing magnetic dipole moments. In the high temperature regime all species show exclusively high field seeking magnetic response and the magnetic dipole moments are extracted from the shift of the molecular beam. At low nozzle temperatures, some of the clusters show considerably broadened beam profiles due to non-uniform deflection in the magnetic field. The results reflect the influence of the chemical environment on the magnetic properties of the transition metal in atomic domain magnetic nanoalloys. Different ground state spin multiplicities and coupling of rotational and vibrational degrees of freedom with the spin angular momentum of isolated clusters of different size apparently cause these variations of spin orientation. This is discussed by taking electronic and molecular structure data into account. PMID- 25283163 TI - Clotting of mammalian fibrinogens by papain: a re-examination. AB - Papain has long been known to cause the gelation of mammalian fibrinogens. It has also been reported that papain-fibrin is insoluble in dispersing solvents like strong urea or sodium bromide solutions, similar to what is observed with thrombin-generated clots in the presence of factor XIIIa and calcium. In those old studies, both the gelation and subsequent clot stabilization were attributed to papain, although the possibility that the second step might be due to contaminating factor XIII in fibrinogen preparations was considered. I have revisited this problem in light of knowledge acquired over the past half-century about thiol proteases like papain, which mostly cleave peptide bonds, and transglutaminases like factor XIIIa that catalyze the formation of epsilon-lysyl gamma-glutamyl cross-links. Recombinant fibrinogen, inherently free of factor XIII and other plasma proteins, formed a stable gel when treated with papain alone. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the intermolecular cross-linking in papain-fibrin leads to gamma-chain dimers, trimers, and tetramers, just as is the case with thrombin-factor XIIIa-stabilized fibrin. Mass spectrometry of bands excised from gels showed that the cross-linked material is quite different from what occurs with factor XIIIa, however. With papain, the cross-linking occurs between gamma chains in neighboring protofibrils becoming covalently linked in a "head-to-tail" fashion by a transpeptidation reaction involving the alpha-amino group of gamma-Tyr1 and a papain cleavage site at gamma-Gly403 near the carboxy terminus, rather than by the (reciprocal) "tail to-tail" manner that occurs with factor XIIIa and that depends on cross-links between gamma-Lys406 and gamma-Gln398. PMID- 25283164 TI - Incidence of palatal fistula formation after primary palatoplasty in northern Finland. AB - OBJECTIVE: The purpose of this retrospective study was to determine the incidence of palatal fistulas after primary cleft palate repair. STUDY DESIGN: The study included 136 patients who were treated at the Oulu University Hospital cleft lip and palate center between 1998 and 2011. All patients were treated by the same surgeons with 1-stage palatoplasty closing the hard and soft palate concurrently. RESULTS: The overall frequency of postoperative fistula was 9.6% of patients. Patients with cleft lip and palate (20.0%) were more likely to develop postoperative palatal fistulas than patients with cleft palate (6.6%). Surgical technique and cleft severity were not significant factors for the development of palatal fistulas. CONCLUSIONS: The majority of patients undergoing primary palatal repair do not develop palatal fistulas. PMID- 25283166 TI - Density-dependent habitat selection of spawning Chinook salmon: broad-scale evidence and implications. AB - An extensive body of theory suggests that density-dependent habitat selection drives many fundamental ecological processes. The ideal free distribution and the ideal despotic distribution make contrasting predictions about the effect of total population size on relative abundances among habitats. Empirical assessment of these habitat selection models is uncommon because data must be collected over large temporal and spatial scales. I ask whether fluctuation in Chinook salmon (Oncorhynchus tshawytscha) spawner population size through time leads to different relative densities over space. Twenty-six years of monitoring data on spawning Chinook salmon across the entire coast of Oregon, USA, were used to evaluate models that make contrasting statements about the interactions of a latent population abundance parameter with physical habitat characteristics. There is strong information-theoretic support for models that include terms that allow the spatial variation in density to change as population size changes through time. Analysis of the best model reveals nonlinear isodars, which suggests a 'despotic' or 'preemptive' distribution of individuals across habitats, indicating that dominant or early-arriving individuals exclude others from breeding sites. This finding has implications for genetic dynamics, population dynamics and conservation metrics of these highly valued fish. The novel application of modelling techniques used here to assess mechanisms of habitat selection from observational data can be used in the emerging field of eco-evolutionary dynamics. PMID- 25283167 TI - Non-transplant surgical therapy options of heart failure. AB - Congestive heart failure (CHF) results from damage to the myocardium and has a broad etiology ranging from ischemic to non--ischemic etiology. It is one of the leading causes of cardiovascular morbidity and mortality and carries a 5--year mortality of 50%, estimated by WHO to represent 30% of deaths in the United States. Costs related to the care of patients with CHF have increased substantially over the past 2 decades partly owing to increased frequency of hospitalization, implantation of costly novel devices and, as the disease progresses, consideration for heart transplantation, mechanical circulatory support, and end--of--life care. CHF progression is accompanied by changes within the myocardium, collectively referred to as left ventricular remodeling, which can be categorized into changes in the cardiomyocytes and changes that occur in the volume and composition of the extracellular matrix. Since remodeling in heart failure is progressive and detrimental, the majority of treatment strategies are aimed at stopping or possibly reversing this process. Some successful methods include medical management, long--term or destination mechanical circulatory support, cardiac resychronization therapy, and biventricular pacemakers. During the last few decades, the management of heart failure has evolved tremendously with the introduction of new therapies and assist devices. Advances in mechanical support, left ventricular assist devices (LVADs), and total artificial heart have significantly reduced mortality in patients awaiting transplantation. This manuscript is an overview of non--transplant surgical options in the management of CHF. PMID- 25283165 TI - Reduced sensitivity to both positive and negative reinforcement in mice over expressing the 5-hydroxytryptamine transporter. AB - The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5 HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits. PMID- 25283168 TI - Effects of beta-blockers for congestive heart failure in pediatric and congenital heart disease patients: a meta-analysis of published studies. AB - AIM: The effects of beta-blockers in pediatric and congenital heart disease (CHD) patients suffering from heart failure are controversial. We performed a meta analysis to determine whether beta-blockers are effective for heart failure in pediatric and CHD patients. METHODS: We searched for clinical trials focusing on clinical on clinical and ventricular functional/dimensional changes after beta blocker therapy in PubMed (from its inception to August 2013) and bibliographies of identified studies. Studies investigating any of three beta blockers (carvedilol, bisoprolol, and extended release metoprolol succinate) which are known to be effective in adult patients with heart failure were included. RESULTS: Of the 158 screened, 17 (N.=476) fulfilled the study criteria and were analyzed. Beta-blockers were associated with significant improvements in left ventricular (LV) ejection fraction (EF) (12.47%; 95% CI, 10.36 to 14.61), fraction shortening (5.75%; 95% CI, 4.42 to 7.08), LV end-diastolic dimension ( 2.91 mm; 95% CI, -5.46 to -0.36), and LV systolic dimension (-4.03 mm; 95% CI, 6.81 to -1.25). No significant change in the pooled mean difference of the right ventricular (RV) EF (3.50%; P=0.08) was observed. However, the RV EF in the untreated group showed a deteriorating trend (-3%), which was different from the trend in the treatment group. There was a significant reduction in the incidence of clinical worsening (odds ratio, 2.15; 95% CI, 1.27 to 3.66). CONCLUSION: Beta blocker therapy was associated with a significant improvement of echocardiographic parameters in patients with systemic LV failure. However, the use of beta-blockers did not provide significant benefits in terms of improving the EF in patients with RV failure. Nonetheless, beta-blockers may be effective to prevent the clinical deterioration of pediatric and CHD patients with heart failure. PMID- 25283170 TI - Drugs for dengue: a patent review (2010-2014). AB - INTRODUCTION: Almost half the global population is estimated to be at risk of contracting dengue infection. Of the 400 million infections estimated to occur annually, 4 million can be potentially life-threatening leading to vascular leakage and shock. The only treatment available to severe dengue patients is fluid replacement therapy and supportive care. A drug for treating dengue is an urgent need. AREAS COVERED: This article endeavors to provide an overview of the experimental dengue drugs being developed around the world as reflected in the recent patent literature spanning the last few years (2010-2014). EXPERT OPINION: Dengue drug development is essentially in its infancy and currently hobbled by multiple factors including a poor understanding of the molecular mechanism of severe disease and lack of reliable small animal model for preclinical drug evaluation. More intense R&D coupled to setting up product development partnerships to facilitate the efficient movement of a drug molecule from the laboratory to the clinic is needed to make antiviral therapy for dengue a reality in the coming future. PMID- 25283169 TI - Out of Sight and Out of Mind? Evaluating the Impact of Point-of-Sale Tobacco Display Bans on Smoking-Related Beliefs and Behaviors in a Sample of Australian Adolescents and Young Adults. AB - INTRODUCTION: The Australian states of New South Wales (NSW) and Queensland implemented bans on tobacco pack displays at point-of-sale (PoS) in July 2010 and November 2011, respectively. This study evaluated the medium-term impact of the bans on youth. METHODS: Data were drawn from the Tobacco Promotion Impact Study, a repeated cross-sectional survey of youth (12-24 years) in NSW and Queensland conducted yearly 2010-2012 (n = 6,014). Regression analyses examined differences in youth's recall of PoS tobacco displays, smoking-related beliefs, and smoking behaviors in relation to the timing of the PoS display bans. RESULTS: Recall of PoS tobacco displays was significantly less likely for youth interviewed after the bans versus before (OR = 0.45, 95% CI = 0.39, 0.52, p < .01). They were also less likely to report tobacco brand awareness (OR = 0.76, 95% CI = 0.62, 0.92, p < .01), to over-estimate peer smoking (OR = 0.84, 95% CI = 0.74, 0.96, p < .01), or be current smokers (OR = 0.73, 95% CI = 0.55, 0.96, p < .05). Stratified analyses showed that these differences were primarily apparent in the group of youth most likely to be affected by tobacco PoS displays: those who visit tobacco retailers most frequently. After the bans, smokers were less likely to report that they think about smoking as a result of seeing PoS tobacco displays (OR = 0.60, 95% CI = 0.37, 0.97, p < .039). CONCLUSIONS: Our findings suggest an immediate impact of display bans on youth's exposure to tobacco pack displays, and likely impacts on smoking-related outcomes. These results suggest that removing tobacco displays from retail environments can positively contribute to the denormalization of smoking among youth. PMID- 25283171 TI - Revision of the New World species of Houghia Coquillett (Diptera, Tachinidae) reared from caterpillars in Area de Conservacion Guanacaste, Costa Rica. AB - Thirty-five species of the genus Houghia Coquillett (Tachinidae, Exoristinae, Goniini) are described, 34 new and one previously described, all reared from various species of caterpillars collected in Area de Conservacion Guanacaste (ACG), northwestern Costa Rica. A matrix of character states and a key for the identification of the species are also provided. By coupling morphology, life history and molecular data, with photographic documentation, a clear and concise description of each species is provided. The following 34 new species of Houghia are described, all authored by Fleming and Wood: H. aerata sp. nov., H. aurifera sp. nov., H. biseriata sp. nov., H. bivittata sp. nov., H. blancoi sp. nov., H. brevipilosa sp. nov., H. chavarriae sp. nov., H. confinis sp. nov., H. delospilota sp. nov., H. destituta sp. nov., H. fimbriata sp. nov., H. gracilis sp. nov., H. graciloides sp. nov., H. griseifrons sp. nov., H. inflatipalpis sp. nov., H. latigena sp. nov., H. latilobus sp. nov., H. longicercus sp. nov., H. longipilosa sp. nov., H. luteiventris sp. nov., H. macilenta sp. nov., H. marini sp. nov., H. matarritai sp. nov., H. nigrofemur sp. nov., H. ochrofemur sp. nov., H. omissa sp. nov., H. pallida sp. nov., H. parmata sp. nov., H. pilosifrons sp. nov., H. romeroae sp. nov., H. sexmaculata sp. nov., H. spathulata sp. nov., H. triangularis sp. nov., and H. velutina sp. nov. The following are proposed by Wood as new synonyms of Houghia: Actinoprosopa Townsend syn. nov., Agrarialia Curran syn. nov., Anhangabahuia Townsend syn. nov., Aridalia Curran syn. nov., Bolohoughia Townsend syn. nov., Carceliocephala Townsend syn. nov., Chrysohoughia Townsend syn. nov., Eumacrohoughia Townsend syn. nov., Macrohoughia Townsend syn. nov., Orohoughia Townsend syn. nov., Pammaerus Aldrich syn. nov., Pararrhinactia Townsend syn. nov., Petrargyrops Townsend syn. nov., Sisyrohoughia Townsend syn. nov., Tapajohoughia Townsend syn. nov., and Verrugomyia Townsend syn. nov. New combinations are proposed by Wood as a result of the new synonymies, as follows: H. analis (Townsend) comb. nov., H. approximata (van der Wulp) comb. nov., H. aurata (Townsend) comb. nov., H. aurometallica (Townsend) comb. nov., H. bistrigata (van der Wulp) comb. nov., H. calcarata (van der Wulp) comb. nov., H. chlorescens (Townsend) comb. nov., H. crypta (Townsend) comb. nov., H. facialis (Townsend) comb. nov., H. impedita (van der Wulp) comb. nov., H. lateralis (Curran) comb. nov., H. leptotrichopa (Brauer & Bergenstamm) comb. nov., H. maris (Townsend) comb. nov., H. marmorata (Townsend) comb. nov., H. minor (Thompson) comb. nov., H. nuda (Townsend) comb. nov., H. orbitalis (Townsend) comb. nov., H. orbitalis (Curran) comb. nov., H. parva (Townsend) comb. nov., H. plagioides (van der Wulp) comb. nov., H. punctiger (Townsend) comb. nov., H. quadra (Wiedemann) comb. nov., H. sexualis (Curran) comb. nov., H. similis (Townsend) comb. nov., H. simillima (Thompson) comb. nov., H. sordida (van der Wulp) comb. nov., H. tenuiseta (Macquart) comb. nov., and H. tropica (Townsend) comb. nov. Houghia orbitalis (Curran, 1934a, described in Sturmia), junior homonym of H. orbitalis (Townsend, 1927, described in Verrugomyia) is synonymized by Wood with Houghia leptotrichopa (Brauer & Bergenstamm, 1891), and need not be renamed while in synonymy. Lectotypes are designated by Wood for the following ten valid species of Houghia: Anisia approximata van der Wulp, 1890, Actinoprosopa facialis Townsend, 1927, Masicera impedita van der Wulp, 1890, Macrohoughia marmorata Townsend, 1927, Eumacrohoughia minor Thompson, 1963, Prospherysa plagioides van der Wulp, 1890, Petrargyrops punctiger Townsend, 1927, Carceliocephala simillima Thompson, 1963, Masicera sordida van der Wulp, 1890, and Masicera tenuiseta Macquart, 1846: 292. PMID- 25283172 TI - Bivalves from the latest Jurassic-earliest Cretaceous hydrocarbon seep carbonates from central Spitsbergen, Svalbard. AB - The bivalve fauna from the latest Jurassic-earliest Cretaceous hydrocarbon seep deposits from central Spitsbergen, Svalbard comprises at least 17 species, four of which belong to chemosymbiotic taxa often found at seeps. These are the solemyid Solemya (Petrasma) cf. woodwardiana; Nucinella svalbardensis sp. nov., which belongs to a group of large Nucinella species known from seeps and deep water environments; the lucinid bivalve, Tehamatea rasmusseni sp. nov., included in a genus widely distributed in other Jurassic-Cretaceous seeps; and Cretaxinus hurumi gen. et sp. nov., which is the oldest known thyasirid and is discussed in relation to other large seep-restricted genera in this family. The remaining species in the fauna belong to 'background' genera known from coeval normal marine sediments, mostly from the Boreal area. These include the nuculid Dacromya chetaensis, two new malletiids (Mesosaccella rogovi sp. nov. and M. toddi sp. nov.), the oxytomiid Oxytoma octavia, at least three Buchia species, at least two pectinids, including Camptonectes (Costicamptonectes) aff. milnelandensis and Camptonectes (Camptochlamys) clatrathus, the limid Pseudolimea arctica, the arcticid Pseudotrapezium aff. groenlandicum, and the pholadomyid Goniomya literata. The large number of 'background' species in the bivalve fauna is probably a reflection of the shallow-water setting of the Svalbard seeps. This might also explain the lack of the seep-restricted modiomorphid bivalve Caspiconcha from the fauna. With solemyids, Nucinella, lucinids and thyasirids, the latest Jurassic-earliest Cretaceous bivalve seep fauna of Svalbard contains typical representatives of the Mesozoic bivalve seep faunas, both long established and young evolutionary colonists. PMID- 25283173 TI - Quantification of plasma HIV RNA using chemically engineered peptide nucleic acids. AB - The remarkable stability of peptide nucleic acids (PNAs) towards enzymatic degradation makes this class of molecules ideal to develop as part of a diagnostic device. Here we report the development of chemically engineered PNAs for the quantitative detection of HIV RNA at clinically relevant levels that are competitive with current PCR-based assays. Using a sandwich hybridization approach, chemical groups were systematically introduced into a surface PNA probe and a reporter PNA probe to achieve quantitative detection for HIV RNA as low as 20 copies per millilitre of plasma. For the surface PNA probe, four cyclopentane groups were incorporated to promote stronger binding to the target HIV RNA compared with PNA without the cyclopentanes. For the reporter PNA probe, 25 biotin groups were attached to promote strong signal amplification after binding to the target HIV RNA. These general approaches to engineer PNA probes may be used to detect other RNA target sequences. PMID- 25283174 TI - Mesoporous hexagonal Co3O4 for high performance lithium ion batteries. AB - Mesoporous Co3O4 nanoplates were successfully prepared by the conversion of hexagonal beta-Co(OH)2 nanoplates. TEM, HRTEM and N2 sorption analysis confirmed the facet crystal structure and inner mesoporous architecture. When applied as anode materials for lithium storage in lithium ion batteries, mesoporous Co3O4 nanocrystals delivered a high specific capacity. At 10 C current rate, as prepared mesoporous Co3O4 nanoplates delivered a specific capacity of 1203 mAh/g at first cycle and after 200 cycles it can still maintain a satisfied value (330 mAh/g). From ex-situ TEM, SAED and FESEM observation, it was found that mesoporous Co3O4 nanoplates were reduced to Li2O and Co during the discharge process and re-oxidised without losing the mesoporous structure during charge process. Even after 100 cycles, mesoporous Co3O4 crystals still preserved their pristine hexagonal shape and mesoporous nanostructure. PMID- 25283175 TI - Developing antifouling biointerfaces based on bioinspired zwitterionic dopamine through pH-modulated assembly. AB - The use of synthetic biomaterials as implantable devices typically is accompanied by considerable nonspecific adsorption of proteins, cells, and bacteria. These may eventually induce adverse pathogenic problems in clinical practice, such as thrombosis and biomaterial-associated infection. Thus, an effective surface coating for medical devices has been pursued to repel nonspecific adsorption from surfaces. In this study, we employ an adhesive dopamine molecule conjugated with zwitterionic sulfobetaine moiety (SB-DA), developed based on natural mussels, as a surface ligand for the modification of TiO2. The electrochemical study shows that the SB-DA exhibits fully reversible reduction-oxidation behavior at pH 3, but it is irreversible at pH 8. A contact angle goniometer and X-ray photoelectron spectroscopy were utilized to explore the surface hydration, chemical states, and bonding mechanism of SB-DA. The results indicate that the binding between hydroxyl groups of SB-DA and TiO2 converts from hydrogen bonds to bidentate binding upon the pH transition from pH 3 to 8. In order to examine the antifouling properties of SB-DA thin films, the modified substrates were brought into contact with bovine serum albumin and bacteria solutions. The fouling levels were monitored using a quartz crystal microbalance with dissipation sensor and fluorescence optical microscope. Tests showed that the sample prepared via the pH transition approach provides the best resistance to nonspecific adsorption due to the high coverage and stability of the SB-DA films. These findings support the mechanism of the pH-modulated assembly of SB-DA molecules, and for the first time we demonstrate the antifouling properties of the SB-DA to be comparable with traditional thiol-based zwitterionic self-assemblies. The success of modification with SB-DA opens an avenue for developing a biologically inspired surface chemistry and can have applications over a wide spectrum of bioapplications. The strategy of the pH transition can also be applied to other functional dopamine derivatives. PMID- 25283176 TI - A call for a moratorium on the .health generic top-level domain: preventing the commercialization and exclusive control of online health information. AB - In just a few weeks, the Internet could be expanded to include a new .health generic top-level domain name run by a for-profit company with virtually no public health credentials - unless the international community intervenes immediately. This matters to the future of global public health as the "Health Internet" has begun to emerge as the predominant source of health information for consumers and patients. Despite this increasing use and reliance on online health information that may have inadequate quality or reliability, the Internet Corporation for Assigned Names and Numbers (ICANN) recently announced it intends to move forward with an auction to award the exclusive, 10 year rights to the .health generic top-level domain name. This decision is being made over the protests of the World Medical Association, World Health Organization, and other stakeholders, who have called for a suspension or delay until key questions can be resolved. However, rather than engage in constructive dialogue with the public health community over its concerns, ICANN chose the International Chamber of Commerce-a business lobbying group for industries to adjudicate the .health concerns. This has resulted in a rejection of challenges filed by ICANN's own independent watchdog and others, such that ICANN's Board decided in June 2014 that there are "no noted objections to move forward" in auctioning the .health generic top-level domain name to the highest bidder before the end of the year. This follows ICANN's award of several other health-related generic top-level domain names that have been unsuccessfully contested. In response, we call for an immediate moratorium/suspension of the ICANN award/auction process in order to provide the international public health community time to ensure the proper management and governance of health information online. PMID- 25283177 TI - REGULARIZED IMAGE RECONSTRUCTION FOR PS MODEL-BASED CARDIOVASCULAR MRI. AB - Real-time cardiovascular MRI is a useful and challenging dynamic imaging application. The partial separability (PS) model enables reconstruction of dynamic cardiac images from highly undersampled (k, t)-space data. However, the underlying PS model-based reconstruction problem is ill-conditioned, so regularization is often necessary to stabilize its solution. It has been shown that l1 regularization is useful for finding sparse solutions, and l2 regularization is widely used to incorporate anatomical constraints. An important practical question is which regularization scheme to use for PS model-based cardiovascular imaging. We address this problem by implementing both schemes and evaluating their performances in terms of reconstruction error, image artifacts, image noise, computation time, and performance characterizability. The l1 regularized results exhibit lower reconstruction error, artifact energy, and noise variance, while l2 regularization is much faster and produces predictable reconstruction results. This study indicates that the l1 scheme is preferable when image quality is the main concern. PMID- 25283178 TI - High temperature electrolysis in alkaline cells, solid proton conducting cells, and solid oxide cells. PMID- 25283179 TI - Immunomodulatory effects of Stachytarpheta cayennensis leaf extract and its synergistic effect with artesunate. AB - BACKGROUND: The leaves of Stachytarpheta cayennensis C. Rich. (Verbenaceae) have been reported to possess potent anti-inflammatory and anti-malarial activities. Due to close association between inflammatory and immune responses, we evaluated the immunomodulatory activity of leaves extract of S. cayennensis. The combined effects of the leaves extract and artesunate, a standard antimalarial agent with immunomodulatory effects, were also evaluated. METHODS: The immunomodulatory activity of the methanol extract of the leaves of S. cayennensis (MESC) was evaluated in mice using the Delayed-Type hypersensitivity response (DTHR), primary and secondary humoral immune responses and the in vivo leucocyte mobilization tests. The immunomodulatory effect of artesunate and the combined effects of MESC and artesunate were evaluated using the phagocytic activity of polymorphonuclear neutrophils. Acute toxicity and lethality test in addition to the preliminary phytochemical studies of MESC were also performed. RESULTS: The MESC exhibited 64.21% inhibition of DTHR at 500 mg/kg dose and evoked 139.64% of phagocytic stimulation at 100 MUg/ml dose. Also MESC significantly (p < 0.05) showed dose related stimulation of humoral immunity and a highest percentage leucocyte mobilization of 10.15% at 250 mg/kg dose. Artesunate offered a non significant (p > 0.05) percentage phagocytic stimulation (PPS) while the combined effect of artesunate and MESC exhibited a significant (p < 0.05) dose dependent PPS with highest PPS of 393.77% at 100 MUg/ml. The LD50 of the MESC was estimated to be greater than 5000 mg/kg since there were no lethality and signs of acute intoxication after 48 h observation. Preliminary phytochemical analysis revealed the presence of carbohydrates, glycosides, flavonoids, saponins, alkaloids, terpenoids and steroids. CONCLUSIONS: The results of this study indicated that MESC possesses immunostimulatory action with significant synergistic effects with artesunate, and can therefore, offer immune boosting activities in disorders of immune suppression. PMID- 25283180 TI - Understanding and modulating motor learning with cerebellar stimulation. AB - Non-invasive brain stimulation techniques are a powerful approach to investigate the physiology and function of the central nervous system. Recent years have seen numerous investigations delivering transcranial magnetic stimulation (TMS) and or transcranial direct current stimulation (tDCS) to the cerebellum to determine its role in motor, cognitive and emotional behaviours. Early studies have shown that it is possible to assess cerebellar-motor cortex (CB-M1) connectivity using a paired-pulse TMS paradigm called cerebellar inhibition (CBI), and indirectly infer the state of cerebellar excitability. Thus, it has been shown that CBI changes proportionally to the magnitude of locomotor learning and in association with reaching adaption tasks. In addition, CBI has been used to demonstrate at a physiological level the effects of applying TMS or tDCS to modulate, up or down, the excitability of cerebellar-M1 connectivity. These studies became the fundamental substrate to newer investigations showing that we can affect motor, cognitive and emotional behaviour when targeting the cerebellum with TMS or tDCS in the context of performance. Furthermore, newer investigations are starting to report the effects of cerebellar non-invasive stimulation to treat symptoms associated with neurological conditions such as stroke and dystonia. Altogether, given the scarcity of current effective therapeutic options, non-invasive cerebellar stimulation can potentially become a game changer for the management of conditions that affect the cerebellum. This brief manuscript presents some of the current evidence demonstrating the effects of cerebellar stimulation to modulate motor behaviour and its use to assess physiological processes underlying motor learning. PMID- 25283181 TI - Is motor inhibition mediated by cerebello-cortical interactions? AB - Motor inhibition is an essential skill for fully adapted behavior requiring motor control and higher-order functions of motor cognition. A wide set of cortical and subcortical areas, including the right inferior frontal gyrus, the pre supplementary motor area, and the subthalamic nucleus in the basal ganglia, contribute to convey the inhibitory command to the motor cortex. In the present review, we discuss how recent evidence supports the idea that the cerebellum may also have a relevant contribution in certain aspects of motor inhibition. This evidence were provided by behavioral data collected in patients with cerebellar lesions, functional magnetic resonance (fMRI) investigations conducted in clinical samples and in healthy participants, and by transcranial magnetic stimulation (TMS) techniques used to non-invasively test cerebello-motor functional connectivity. The application of these methods, combined with the execution of inhibitory tasks, could provide new evidence for a causal role of the effective cerebello-cortical connectivity in motor inhibition. Understanding the neurophysiological mechanisms that mediate motor inhibition through the cerebellum could be essential to design new rehabilitative protocols for treating several neurological and psychiatric disorders characterized by disinhibited behavior such as addiction, schizophrenia, attention deficit hyperactivity disorder (ADHD) and Parkinson's disease. PMID- 25283183 TI - Development of a medical humanities and ethics certificate program in Texas. AB - Education in the medical humanities and ethics is an integral part of the formation of future physicians. This article reports on an innovative approach to incorporating the medical humanities and ethics into the four-year curriculum in a Certificate Program spanning all four years of the medical school experience. The faculty of the McGovern Center for Humanities and Ethics at the University of Texas Medical School at Houston conceived and implemented this program to teach medical students a range of scholarly topics in the medical humanities and to engage the full human experience into the process of becoming a physician. This study follows six years of experience, and we report student experiences and learning in their own words. PMID- 25283182 TI - Reproducibility of Tract-based and Region-of-Interest DTI Analysis of Long Association Tracts. AB - PURPOSE: Reproducibility of two different methods for quantifying fiber tracts by using a diffusion tensor imaging (DTI) sequence suitable for clinical magnetic resonance imaging (MRI) protocols was evaluated. METHODS: DTI of 15 subjects was used to analyze intra-rater and inter-rater reproducibility. Another 10 subjects underwent MRI twice for assessment of between-scan reliability. Ten long association tracts were defined by fiber tracking using inclusion and exclusion regions of interest (ROIs). Whole-tract analysis and tractography-based core analysis were performed, and the effect of fractional anisotropy (FA 0.15/0.30) and turning angle threshold (27 degrees /60 degrees ) on reproducibility was evaluated. Additionally, ROI measurements were performed in the core of the tracts. RESULTS: For the tract-based methods, intra-rater and inter-rater reliabilities of FA and mean diffusivity (MD) measurements were excellent. Between-scan reproducibility was good or excellent in 127 of 130 of the measurements. There was no systematic difference in the reproducibility of the FA, MD, and volume measurements depending on the FA or turning angle threshold. For the cross-sectional ROI measurements, reliability showed large variation from poor to excellent depending on the tract. CONCLUSIONS: Compared with the commonly used cross-sectional core ROI method, the tract-based analyses seem to be a more robust way to identify and measure white matter tracts of interest, and provide a novel reproducible tool to perform core analysis. PMID- 25283184 TI - Role of oral pre-exposure prophylaxis (PrEP) in current and future HIV prevention strategies. AB - Treatment as prevention is expected to have a major role in reducing HIV incidence, but other prevention interventions will also be required to bring the epidemic under control, particularly among key populations. One or more forms of pre-exposure prophylaxis (PrEP) will likely play a critical role. Oral PrEP with emtricitabine-tenofovir (Truvada(r)) is currently available in the US and some other countries, but uptake has been slow. We review the concerns that have contributed to this slow uptake and discuss current and future research in this critical area of HIV prevention research. PMID- 25283185 TI - Contraception for women with heart disease. AB - There is a lack of studies dealing specifically with contraceptive use in women with heart disease. This may generate doubts in professionals counseling on the patient's risk of pregnancy as a function of her cardiomyopathy. Moreover, uncertainties may arise with respect to the optimal contraceptive choice for each individual case. In view of the increasing number of women of reproductive age with cardiac disease, this review aims at providing practical guidance for clinicians, including cardiologists, obstetricians, general practitioners and family planning specialists, with regards to safe contraceptive choices and counseling on the risk of pregnancy in women with heart disease. PMID- 25283186 TI - Effect of methylprednisolone on mammalian neuronal networks in vitro. AB - Glucocorticosteroids (GCS) are widely used for the treatment of neurological diseases, e.g. multiple sclerosis. High levels of GCS are toxic to the central nervous system and can produce adverse effects. The effect of methylprednisolone (MP) on mammalian neuronal networks was studied in vitro. We demonstrate a dose dependent excitatory effect of MP on cultured neuronal networks, followed by a shut-down of electrical activity using the microelectrode array technique. PMID- 25283187 TI - Neurotropin((r)) ameliorates chronic pain via induction of brain-derived neurotrophic factor. AB - Neurotropin (NTP)((r)), a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, is used clinically for the treatment of neuropathic pain. Moreover, NTP may activate the descending pain inhibitory system. Depression-like behavior is often complicated by chronic pain. However, little is known about NTP-mediated prevention of mood disorders in chronic pain and its molecular mechanisms. We aimed to investigate the effects of NTP on brain derived neurotrophic factor (BDNF)-mediated signaling and gene expression in chronic pain. In addition, these effects of NTP were compared with pregabalin which is an anticonvulsant, anxiolytic analgesic used to treat neuropathic pain and fibromyalgia. A chronic constriction injury model was established in Sprague Dawley rats. The pain response was assessed using a paw withdrawal latency (PWL) test and depression was assessed by the immobility time in a forced swim test (FST). NTP was orally administered in two doses of 50 NU (Neurotropin Unit) and 100 NU/kg for 7 days from day 7 after injury. To measure the analgesic and anti depressant effects of NTP, either K252a (a tyrosine kinase inhibitor), or 5,7 dihydroxy tryptamine (5,7-DHT, a selective toxin for 5-HTergic neurons) was administered by intracerebroventricular injection. Changes in pERK1/2 and pCREB (immunohistochemistry), 5-HT, and BDNF protein level (ELISA) and BDNF mRNA (RT PCR) were measured in the anterior cingulate cortex (ACC) and in the rostral ventromedial medulla (RVM) 14 days after injury. After injury, the rats showed a decrease in PWL associated with the increase in time of immobility in FST. In this injury model, NTP blocked both the decrease in PWL and the increase in the FST, while pregabalin (10 mg/kg, po.) did not affect the increase in the FST. These effects of NTP were reversed by K252a, and 5,7-DHT. The analgesic effects of pregabalin were not reversed by K252a. NTP normalized the injury-induced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA in the ACC and in the RVM, and these changes were reversed by 5,7-DHT. In contrast, pregabalin did not affect either pCREB or BDNF levels in the chronic pain model. NTP ameliorated chronic pain and pain-related depression by normalizing the induction of BDNF associated with the 5-HTergic system. Pregabalin showed the analgesic effects but had no effects on either depression or the BDNF pathway. These results suggest that NTP may represent an additional drug strategy for chronic pain associated with depression. PMID- 25283188 TI - Generic Synopsis of the Formicidae of Vietnam (Insecta: Hymenoptera), Part II- Cerapachyinae, Aenictinae, Dorylinae, Leptanillinae, Amblyoponinae, Ponerinae, Ectatomminae and Proceratiinae. AB - Of the subfamilies and genera known from Vietnam, the following taxa are treated in this second part of the series entitled "Generic Synopsis of the Formicidae of Vietnam": Cerapachyinae: Cerapachys, Simopone; Aenictinae: Aenictus; Dorylinae: Dorylus; Leptanillinae: Leptanilla, Protanilla; Amblyoponinae: Myopopone, Mystrium, Opamyrma, Prionopelta, Stigmatomma; Ponerinae: Anochetus, Brachyponera, Buniapone, Centromyrmex, Cryptopone, Diacamma, Ectomomyrmex, Euponera, Harpegnathos, Hypoponera, Leptogenys, Mesoponera, Odontomachus, Odontoponera, Parvaponera, Platythyrea, Ponera, Pseudoneoponera; Ectatomminae: Gnamptogenys; Proceratiinae: Discothyrea, Probolomyrmex, Proceratium. For each of these subfamilies we provide keys to genera (when there is more than one genus) known from Vietnam. For each genus we provide a synopsis and a list of Vietnamese species. PMID- 25283189 TI - Key to the species of Eotrechinae (Hemiptera: Heteroptera: Gerridae) of Thailand and review of the fauna of the Phetchabun Mountain Range. AB - Water striders of the subfamily Eotrechinae from the Phetchabun Mountain Range can be found at the margins of rock pools and puddles, and in hygropetric habitats including waterfalls. Twenty-two species in three genera are known from Thailand. In the Phetchabun Mountain Range, 12 species representing all three genera were recorded from over a decade of collections (2002-2012). This paper provides taxonomic, biological, and ecological information for taxa of the Phetchabun Mountain Range in Thailand and a taxonomic key to all known species from Thailand. PMID- 25283190 TI - Morphological variation and taxonomy of Atractus latifrons (Gunther, 1868) (Serpentes: Dipsadidae). AB - As currently understood Atractus latifrons is widely distributed in South America, occurring from Suriname to the east of the Andes in Bolivia. Throughout this widespread distribution, at least three distinct color patterns were previously reported in the literature. Here, we test whether quantitative variation and qualitative distribution of morphological characters are correlated with any color pattern displayed by the species along its range. We recognize three aposematic color patterns (bicolor in monads, tricolor in dyads, and tricolor in tetrads) for A. latifrons. We found no obvious correspondence between these patterns and any character systems analyzed herein. Additionally, we redescribe the holotype of A. latifrons and report on morphological variability (meristics, morphometrics, color patterns, and hemipenis) and geographical distribution (extending its distribution to the state Roraima, Brazil) of the species. PMID- 25283191 TI - A new sericomyiine flower fly from China (Diptera: Syrphidae). AB - A new species of flower flies is described from China (Sichuan & Yunnan: Hengduan Mountains), Sericomyia khamensis Thompson & Xie). A key is provided to the species of the subtribe Sericomyiina found in China along with nomenclatural and taxonomical notes on them. PMID- 25283192 TI - Archaeoditomotarsus crassitylus, gen. and sp. nov. (Hemiptera: Heteroptera: Acanthosomatidae) from Chile. AB - Archaeoditomotarsus crassitylus, gen. and sp. nov. of Acanthosomatidae (Ditomotarsinae: Ditomotarsini), is described and illustrated. The biogeography of the new taxon is discussed and a key to the Chilean genera of Ditomotarsinae is included. PMID- 25283193 TI - Neoribates alius Fujikawa, 2007, a junior synonym of Neoribates pallidus Aoki, 1988 (Acari, Oribatida, Parakalummidae). AB - The morphology of adult instars of two oribatid mites of the genus Neoribates, N. pallidus Aoki, 1988 and N. alius Fujikawa, 2007, is analyzed. Comparisons were based on holotype and paratypes (for N. alius) and specimens identified by the original author (for N. pallidus). Both species were described from Japan. Neoribates alius is recognized as a junior subjective synonym of N. pallidus. PMID- 25283194 TI - Stenonartonia tekoraava sp. nov. (Hymenoptera: Vespidae: Eumeninae), a new member of a typical Amazonian mimicry ring. AB - Stenonartonia tekoraava sp. nov., a new species of potter wasp is described from central Amazonia. By size and color pattern, this species falls into the typically Amazonian mimicry ring of the social wasp Polybia liliacea (Fabricius) [Vespidae: Polistinae]. Comments are made on the Mullerian mimicry rings as a common phenomenon in Hymenoptera and particularly in the family Vespidae. PMID- 25283195 TI - An illustrated key to and diagnoses of the species of Staphylinidae (Coleoptera) associated with decaying carcasses in Argentina. AB - A key to 24 Staphylinidae species associated with decaying carcasses in Argentina is presented, including diagnoses, illustrations, distributional and bionomical data for these species. This article provides a table of all species associated with carcasses, detailing the substrate from which they were collected and geographical distribution by province. All 24 Staphylinidae species recorded are grouped into three subfamilies: Aleocharinae (three species of Aleochara Gravenhorst and one species of Atheta Thomson), Oxytelinae (one species of Anotylus Thomson) and Staphylininae (18 species, two belonging to the tribe Xantholinini and 16 species belonging to the tribe Staphylinini). A discussion is presented on the potential forensic importance of some species collected on human and pig carcasses. PMID- 25283196 TI - Fungus-feeding phlaeothripine Thysanoptera in the genus Holothrips from Australia and New Caledonia, with a structurally similar new genus, Holoengythrips. AB - Ten species of Holothrips, including seven new species, are recognized from Australia, with one further new species from New Caledonia. A new genus, Holoengythrips, is described from Australia, with nine new species that look similar to Holothrips species in having elongate maxillary stylets that are close together medially for the full length of the head. In contrast to species of Holothrips, the species of Holoengythrips are strongly sexually dimorphic, with antennal segment VIII separated from VII and the maxillary stylets more slender, and the males have a pore plate on the eighth sternite. Holoengythrips is therefore considered to be more closely related to Hoplandrothrips. PMID- 25283197 TI - A revised generic arrangement for the eagle ray family Myliobatidae, with definitions for the valid genera. AB - The generic arrangement of the eagle rays (Family Myliobatidae) is revised and the genus Pteromylaeus Garman, 1913 is placed into the synonymy of Aetomylaeus Garman, 1908. Definitions are provided for the three valid genera, Aetobatus, Aetomylaeus and Myliobatis, and nomenclatural issues are discussed. Aetobatus differs from the latter two genera in having: a deeply notched nasal curtain, both jaws with a single row of chevron-shaped teeth, broadly rounded pectoral-fin free rear tips, pectoral fins separate from rostral lobe and joining head at level of eye. Aetomylaeus differs from the other two genera in having: pectoral fins separate from rostral lobe and joining head below level of eye, and stinging spine absent or present (usually not well developed when present). Myliobatis differs from the other two genera in having the pectoral fins joined to the rostral lobe by a subocular ridge. A list of valid species is provided, including a list of junior synonyms. Myliobatis australis Macleay, 1881 from southern Australia is placed into the synonymy of the previously considered endemic New Zealand species, M. tenuicaudatus Hector, 1877. PMID- 25283198 TI - Riegeriana, a new genus for Physopelta apicalis, and checklist of the genus Iphita (Hemiptera: Heteroptera: Largidae) with description of one new species. AB - Riegeriana gen. nov. is described to accommodate Physopelta apicalis Walker, 1873. A lectotype of Ph. apicalis is de-signated. Iphita fasciata Stehlik & Jindra, 2008, syn. nov., is recognized as a new junior subjective synonym of Riegeriana apicalis. In addition, Iphita lata sp. nov. is described from southern India and a check-list of the species of the genus Iphita Stal, 1873 is provided. The etymology of Iphita nigris Ahmad & Abbas, 1992 and the lectotype designation of Dindymellus coimbatorensis Distant, 1919 are discussed. The following new or confirmed country records are provided: Iphita coimbatorensis (Distant, 1919) from India (Karnataka, Orissa); I. dubia (Breddin, 1901) from Indonesia (Papua); I. limbata Stal, 1870 from Cambodia, China (Hainan), India (Arunachal Pradesh), Indonesia (Sumatra, Kalimantan), Malaysia (Pahang: Tioman Island), and Vietnam; I. lycoides (Walker, 1873) from the Philippines (Panay Island). PMID- 25283199 TI - The minute, fungus-feeding species of Sophiothrips (Thysanoptera, Phlaeothripinae) from Australia and New Zealand. AB - Five new species of Sophiothrips are described from mainland Australia, of which one is widespread in the eastern part of the continent, with a second widespread across the northern tropical zone. These species appear to be members of the breviceps species-group from the Old World tropics. One of these five is particularly unusual within the genus in that the maxillary stylets are retracted into the head anterior to the postoccipital ridge. A sixth new species is described from Australia that is known only from Norfolk Island, but this is closely related to two species that are endemic to New Zealand. A key is provided to the nine species recognised. PMID- 25283200 TI - Neurellipes rhoko sp. n. from the Cross River Loop, Eastern Nigeria (Lepidoptera: Lycaenidae: Polyommatinae). AB - A new species belonging to the recently revised Neurellipes mahota-group has been found in the Cross River Loop, Eastern Nigeria. It resembles the recently described Liberian N. georgiadisi Larsen, 2009, but differs from it by the wing shape and the extent and shape of orange patches on the hindwing, also on the forewing, especially in the discoidal cell. The species is described as N. rhoko sp. n.; a detailed comparison with the other species in the N. mahota-group is given, as well as notes on the biogeography of N. rhoko and its Liberian sub region vicariant N. georgiadisi. PMID- 25283201 TI - More species of the Agononida incerta complex revealed by molecules and morphology (Crustacea: Decapoda: Anomura: Munididae). AB - Squat lobsters from Madagascar, Vanuatu, Papua New Guinea, Fiji, eastern Australia and French Polynesia belonging to the Agononida incerta (Henderson, 1888) species complex are described as four new species: A. madagascerta, A. polycerta, A. tasmancerta and A. vanuacerta. This brings to ten the number of species in this complex. All species are morphologically distinguishable only on the basis of the shape of the anterolateral margin of the telson and setation of the dactyli of pereopods 2-4. The morphological delineation of nine of the species and their taxonomic status are robustly supported by phylogenetic analysis of the partial 16S rDNA gene and the partial mitochondrial cytochrome oxidase subunit 1 genes, and in some cases by colour. A phylogenetic analysis of the nine species for which molecular data are available grouped the species in two clades, one of four species with facial spines on the upper surface of pereopod 4 and the other of five species lacking facial spines. PMID- 25283202 TI - A new species of Eucosma Hubner and two new species of Cydia Hubner (Lepidoptera: Tortricidae) from the United States. AB - Three new species of Olethreutinae (Lepidoptera: Tortricidae) from the United States are described and illustrated. Eucosma paregoria Brown, n. sp., is associated with prairies and glades, primarily in midwestern U.S. Cydia marita Brown, n. sp., is common in southeastern U.S., ranging from Texas to Florida and north along the eastern seaboard to Virginia. Cydia timara Brown, n. sp., occurs in the southwestern U.S. (Arizona and New Mexico). Both species of Cydia are associated with habitats that support Pinus species, the probable larval hosts. PMID- 25283203 TI - Some remarks on rare and new Palaearctic species of the genus Zodion Latreille (Diptera: Conopidae). AB - Zodion hispanicum spec. nov. is described from Spain (Murcia, Sierra Espuna) and Zodion hauseri spec. nov. is described from Kazakhstan (Almaty Province, Charyn Valley). A diagnosis is given for Zodion andersoni Krober, 1936 and Zodion vsevolodi Zimina, 1974. Zodion asiaticum Becker, 1922 is placed as a junior synonym of Zodion cinereum (Fabricius, 1794) (syn. nov.). New faunistic records are presented for Z. andersoni and Z. vsevolodi. PMID- 25283204 TI - Schistura andrewi, a new species of loach (Teleostei: Nemacheilidae) from Mizoram, northeastern India. AB - Schistura andrewi, a new species of loach, is described from a tributary of Kaladan River in Mizoram, northeastern India. It is distinguished from its congeners in having the following combination of characters: long axillary pelvic lobe; complete lateral line with 82-95 pores; 2 unbranched dorsal and anal fin rays; 6-7 broad, wider than interspace, black bars on the body; 2 rows of black spots horizontally across the dorsal fin; a deeply emarginate caudal fin, with 2 vertical rows of black spots across the fin, and 9 + 8 branched caudal fin rays. PMID- 25283205 TI - CLSM anatomy of internal genitalia of Mackiella reclinata n. sp. and systematic remarks on eriophyoid mites from the tribe Mackiellini Keifer, 1946 (Eriophyoidea: Phytoptidae). AB - A new mackielline mite, Mackiella reclinata n. sp., from a South African indigenous palm-tree, Phoenix reclinata, is described in detail using different microscopy techniques. A CSLM study of M. reclinata n. sp. internal genitalia shows that mites of this genus possess teardrop shaped spermathecae, sausage-like spermathecal tubes directed anteriad and a subtrapezoidal anterior genital apodeme with a peculiar apical plate, orthogonal to the anterior-posterior body axis. Pairwise angles between the spermatheca, spermathecal tube and the longitudinal bridge of M. reclinata n. sp. females were measured. The angle between the spermathecal tube and longitudinal bridge is a quite stable morphometric character and thus is considered to be appropriate for comparison of different eriophyoid taxa. LTSEM and CLSM study shows that M. reclinata n. sp. possesses a unique, broadened frontal lobe of the prodorsal shield comprised of apical and basal parts entirely covering the dorsal palpcoxae. The incompletely described mite species Mackiella borasis Mohanasundaram, 1981 does not conform to the diagnosis of Mackiella and herein is transferred to the subfamily Phytoptinae incertae sedis. PMID- 25283206 TI - Review of the idiocerine leafhoppers of Pakistan (Hemiptera, Cicadellidae) with a description of a new species. AB - The Idiocerinae of Pakistan are reviewed and a new species, Tasnimocerus sindhensis sp. nov. (Pakistan: Tandojam), is described and illustrated from Pakistan. Two new junior synonyms of Idioscopus nitidulus (Walker) are recognized: Idioscopus karachiensis Ahmed, Naheed & Ahmed syn. nov. and I. freytagi Ahmed, Naheed & Ahmed syn. nov. Idioscopus nagpurensis (Pruthi) is newly recorded from Pakistan. A checklist of Idiocerinae from Pakistan is also provided together with a key to genera and species. PMID- 25283207 TI - Moczariella, a bizarre new genus of Mesitiinae (Hymenoptera, Bethylidae) from Arab Peninsula. AB - Mesitiinae include 203 species classified in 22 genera and four tribes. In this work we proposed a new genus. Moczariella centenaria Barbosa & Azevedo gen. et sp. nov. are described from United Arab Emirates. The main diagnostic characteristics is body wholly unfoveolate, clypeus without lateral lobes, post occipital depression present, propodeum with discal carinae incomplete, and without posterior one, propodeal spiracle placed laterally, claws single, and genital basal ring with dorsal half distinctly longer than ventral one. PMID- 25283208 TI - Description of the tadpole of Proceratophrys carranca Godinho, Moura, Lacerda and Feio, 2013, (Anura, Odontophrynidae). PMID- 25283209 TI - New Harpirhynchinae Dubinin (Acariformes: Harpirhynchidae)--intracutaneous and feather-base parasites of birds. AB - Seven new species of intracutaneous parasites of the subfamily Harpirhynchinae Dubinin (Acariformes: Cheyletoidea: Harpirhynchidae) are described: Anharpyrhynchus elizae sp. nov. from Cyanocitta cristata (type host), Cyanocitta stelleri (Passeriformes: Corvidae), and Colaptes auratus (Piciformes: Picidae) from the USA; Anharpyrhynchus apodus sp. nov. from Lichmera indistincta (type host) and Phylidonyris novaehollandiae (Passeriformes: Meliphagidae) from Australia; Anharpyrhynchus lukoschusi sp. nov. from Manorina flavigula (type host) and Certhionyx pectoralis (Passeriformes: Meliphagidae) from Australia; Fainharpirhynchus legatus sp. nov. from Legatus leucophaius (Passeriformes: Tyrannidae) from Trinidad and Tobago; Fainharpirhynchus mossi sp. nov. from Myiarchus crinitus (Passeriformes: Tyrannidae) from an unknown locality in North America; Perharpyrhynchus caprimulgus sp. nov. from Caprimulgus fossii (Caprimulgidae: Caprimulgiformes) from Mozambique; Perharpyrhynchus elseyornis sp. nov. from Elseyornis melanops (Charadriiformes: Charadriidae) from Australia. Keys to females of the genera Anharpyrhynchus, Fainharpirhynchus, and Perharpyrhynchus are provided and data on hosts and distributions of all known intracutaneous harpirhynchines are summarized. In addition, a new non subcutaneous harpirhynchine is described: Trichorhynchiella myiarchus sp. nov. from feather bases of Myiarchus crinitus (Passeriformes: Tyrannidae) from an unknown locality in North America. PMID- 25283210 TI - Contribution to the knowledge of cotylean flatworms (Turbellaria, Polycladida) from Iranian coasts: Introducing a new species, with remarks on new records. AB - Very little information is available regarding marine free-living flatworms not only from Iran, but throughout the countries surrounding the Persian Gulf and the Gulf of Oman. The present study first introduces a new euryleptid species, and then reports four pseudocerotid polyclads which inhabit Iranian shallow rocky shores of the Persian Gulf and the Gulf of Oman. Maritigrella makranica sp. nov. is characterized dorsally by a medial cream or white reticulated appearance containing pale orange spots in a honeycomb pattern, a distinct orange submarginal band around the entire body margin and between the marginal tentacles, black spots scattered around mid-dorsal surface, becoming more sparse on raised median region and towards body margin, surrounded by a dark-grey halo around the body midline and orange-black halo towards margin. Three of the four pseudocerotids species belonging to the genera Pseudobiceros Faubel, 1984; Pseudoceros Lang, 1884; and Thysanozoon Grube, 1840, are new records for the studied areas, while the other has been reported in the Persian Gulf previously. Comments on Iranian species are provided and associations of flatworms with ascidians and sponges were observed. PMID- 25283211 TI - A new species of Onuphis (Polychaeta: Onuphidae) from Southern Portugal, with comments on the validity of O. pancerii Claparede, 1868. AB - Onuphis farensis sp. nov. (Annelida, Polychaeta) is described, based on a population inhabiting intertidal sandbanks in the mesotidal coastal lagoon of Ria Formosa (Southern Portugal). It can be distinguished from all other known species within the genus by having bi- and tridentate pseudocompound hooks on the first 4 chaetigers, single filament branchiae from chaetiger 5, and subacicular hooks from chaetiger 9. The species was previously collected in the Bay of Cadiz and Isla Cristina (SW Spain), in a similar habitat to Ria Formosa, but referred to O. geophiliformis Moore, 1903. The taxonomic status of other Onuphis species recorded in the European waters is also discussed. On the whole, O. pancerii Claparede, 1868, described from the Gulf of Naples, has been treated as a junior synonym of O. eremita Audouin & Milne-Edwards, 1833, but taking the more restrictive definition of this species accepted today, should be considered as a valid Mediterranean species. Finally, O. opalina (Verrill, 1873) and O. rullieriana (Amoureux, 1977) may be synonymous, as both species are similar morphologically, occur at similar depths, and have partially overlapping geographical distributions. The different diagnostic characters utilised for the new species are analysed, with the number of chaetigers with postchaetal lobes determined to be a poor taxonomic character for the genus Onuphis, proving to be size-related. A synoptic table with all worldwide species of the genus Onuphis is provided, together with a dichotomic key for the species hitherto recorded in the European and nearby waters. PMID- 25283212 TI - Validation of the taxon Ixodes aragaoi Fonseca (Acari: Ixodidae) based on morphological and molecular data. AB - The species Ixodes aragaoi Fonseca was described as Ixodes ricinus aragaoi, and later placed in synonymy with Ixodes affinis. However, this synonymy was rejected and the subspecies was elevated to species, and named as I. aragaoi. Some researchers did not consider the validity of I. aragaoi and maintained the synonymy proposed until 1998 when I. aragaoi was revalidated, and it was suggested that Ixodes pararicinus could be a synonym. The aim of this study was to confirm the taxonomic validity of I. aragaoi by means of redescription of adults and molecular analysis. Morphological studies were performed by optical and scanning electron microscopy; types of I. aragaoi were compared with those of I. pararicinus from Argentina, and also with material of I. pararicinus from Uruguay and I. affinis from the United States. Mitochondrial 16S rDNA sequences were obtained for determining phylogenetic relationships based on maximum parsimony. Morphological and molecular differences between I. aragaoi, I. pararicinus from Argentina, and I. affinis confirm the validity of the first each of these species. The morphological similarities of I. pararicinus from Uruguay with I. aragaoi, and the small distance of nucleotide sequences between them, confirm that the Uruguayan ticks are in fact I. aragaoi and expand the geographical distribution of this species. Based on the specimens of Ixodes examined in the present study, from the same locality of the types of I. ricinus rochensis in Uruguay, we agree with the synonymy of this subspecies with I. aragaoi as previously reported. Finally, our analyses indicate that both I. aragaoi and Ixodes fuscipes, another South American tick species, belong to the I. ricinus complex, currently composed of 19 species. PMID- 25283213 TI - Revision of Megascogaster (Hymenoptera, Braconidae, Cheloninae), with a new species from Sulawesi, Indonesia. AB - Megascogaster wallacei sp. n. is described from Sulawesi, Indonesia. This is the first representative south of the Philippines and is only the second species of this rare genus described since the type species, M. elongata Baker, 1926. The presence of Megascogaster in Sulawesi, a part of Wallacea, points to a broader distribution of the genus in Southeast Asia. A redescription of M. elongata and a description of the new species M. wallacei are presented along with a key to separate them. PMID- 25283214 TI - Molecular phylogeny and biogeography of the genus Acanthodactylus Fitzinger, 1834 (Reptilia: Lacertidae) in Iran, inferred from mtDNA Sequences. AB - Phylogenetic relationships of Iranian Acanthodactylus species were investigated using 1407 bp of mitochondrial DNA including 606 bp of cytochrome b and 801 bp of NADH dehydrogenase subunit 4 (ND4). Analyses done with maximum parsimony, maximum likelihood, and Bayesian inference included 67 specimens from 27 geographically distinct localities in Iran. Our molecular results proposed three clear and geographically isolated clades by their phylogenetic positions and genetic differences. These three major clades are: (1) A. micropholis+ A. grandis+ A. khamirensis; (2) A. blanfordi+ A. schmidti+ Acanthodactylus sp1; (3) A. nilsoni+ A. boskianus + Acanthodactylus sp2. The phylogenetic analyses of the genus did not group A. grandis with the remaining species of the A. boskianus group and clustered it along with A. khamirensis within the A. micropholis group. In addition, phylogenetic results revealed a monophyletic status for A. schmidti and A. micropholis groups. Molecular clock approach indicated that the most recent divergence event splits A. micropholis from A. khamirensis about 2 MYA and results of dispersal-vicariance analyses showed that this diversification occurred by dispersal event rather than vicariance. Results of Reconstruct Ancestral State in Phylogenies (RASP) showed that Most Recent Common Ancestor (MRCA) of A. micropholis, A. blanfordi and A. sp1 originated in eastern Iran. The first diversification of the genus in Iran most likely occurred between 8.5-9 MYA corresponding with the hypothesis that the genus has entered Iran long after the complete uplifting of the Zagros Mts. (10-12 MYA) which limited its dispersal only to the Persian Gulf shores and western slopes of the Zagros Mts. PMID- 25283215 TI - Expanding the geographic cytogenetic studies in the bush crickets Eneoptera surinamensis (De Geer, 1773) (Orthoptera, Gryllidae, Eneopterinae) from Brazilian Atlantic and Amazon Forest. PMID- 25283216 TI - Compartmentalized gene expression of toll-like receptors 2, 4 and 9 in the brain and peripheral lymphoid organs during canine visceral leishmaniasis. AB - Visceral leishmaniasis is an important parasitic disease that affects humans and animals. The response against the protozoan involves the interaction of both innate and adaptive branches of the immune system, and an important immune sensor is represented by the toll-like receptor (TLR) family. Here, we investigated the pattern of TLR-2, TLR-4 and TLR-9 gene expression in different compartments (brain, choroid plexus, spleen and lymph node) of dogs naturally infected with Leishmania infantum. Gene expression of the TLRs varied according to the compartment evaluated. In the brain, there was only an upregulation of TLR-2, whereas in the choroid plexus, TLR-2 and TLR-9 were both upregulated. Further, the peripheral lymphoid organs (spleen and lymph nodes) showed increased TLR-2 and TLR-4 expression. This study provides the first insight about TLR expression in the central nervous system of infected dogs, and gives additional evidence of the compartmentalization of the immune response during visceral leishmaniasis. PMID- 25283217 TI - Influence of cell-associated tissue factor concentration on the anticoagulant activity of dabigatran. A possible explanation for the reduced incidence of intracranial bleeding. PMID- 25283218 TI - Drivers of parasite sharing among Neotropical freshwater fishes. AB - Because host-parasite interactions are so ubiquitous, it is of primary interest for ecologists to understand the factors that generate, maintain and constrain these associations. Phylogenetic comparative studies have found abundant evidence for host-switching to relatively unrelated hosts, sometimes related to diversification events, in a variety of host-parasite systems. For Monogenoidea (Platyhelminthes) parasites, it has been suggested that the co-speciation model alone cannot explain host occurrences, hence host-switching and/or non-vicariant modes of speciation should be associated with the origins and diversification of several monogenoid taxa. The factors that shape broad patterns of parasite sharing were investigated using path analysis as a way to generate hypotheses about the origins of host-parasite interactions between monogenoid gill parasites and Neotropical freshwater fishes. Parasite sharing was assessed from an interaction matrix, and explanatory variables included phylogenetic relationships, environmental preferences, biological traits and geographic distribution for each host species. Although geographic distribution of hosts and host ecology are important factors to understand host-parasite interactions, especially within host lineages that share a relatively recent evolutionary history, phylogeny had the strongest overall direct effect on parasite sharing. Phylogenetic contiguity of host communities may allow a 'stepping-stone' mode of host-switching, which increases parasite sharing. Our results reinforce the importance of including evolutionary history in the study of ecological associations, including emerging infectious diseases risk assessment. PMID- 25283219 TI - Negative predictive value of drug provocation tests in children. AB - BACKGROUND: The negative predictive value of the drug provocation test is important for both the patient and the physician. However, in children, this predictive value is unresolved. METHODS: The study included patients who had drug provocation test with a suspected drug and was diagnosed as 'not allergic to the drug'. Three months after allergy workup, the patients were contacted and asked for reexposure to the tested drug. Patients who have reported reactions during reexposure were reevaluated with skin tests and drug provocation. RESULTS: During the study period, 217 provocations were performed to 203 patients. Of these, 163 patients (80.3%) with 175 negative drug provocation tests could be contacted. Ninety-one (52%) of the 175 cases reported to use the tested drug again, and 11 (12%) of these cases declared that they had a new reaction. Two of the eleven cases refused reevaluation. Nine cases were evaluated by drug allergy workup. Two of the nine cases were classified as allergic after retests. Collectively, the negative predictive value was 95.6% (87 of 91 cases) for all drug challenges. CONCLUSIONS: The negative predictive value of the drug provocation test is abundant in children; however, negative drug provocation tests do not necessarily predict tolerance for the drug. PMID- 25283221 TI - [Esophageal sensation and hypersensitivity: its mechanism and clinical implication]. PMID- 25283222 TI - [Pathophysiology of gastroesophageal reflux disease from the viewpoint of esophageal motility]. PMID- 25283223 TI - [Esophageal motility disorders (except GERD)]. PMID- 25283220 TI - Recent advances in the epidemiology, clinical and diagnostic features, and control of canine cardio-pulmonary angiostrongylosis. AB - The aim of this review is to provide a comprehensive update on the biology, epidemiology, clinical features, diagnosis, treatment, and prevention of canine cardio-pulmonary angiostrongylosis. This cardiopulmonary disease is caused by infection by the metastrongyloid nematode Angiostrongylus vasorum. The parasite has an indirect life cycle that involves at least two different hosts, gastropod molluscs (intermediate host) and canids (definitive host). A. vasorum represents a common and serious problem for dogs in areas of endemicity, and because of the expansion of its geographical boundaries to many areas where it was absent or uncommon; its global burden is escalating. A. vasorum infection in dogs can result in serious disorders with potentially fatal consequences. Diagnosis in the live patient depends on faecal analysis, PCR or blood testing for parasite antigens or anti-parasite antibodies. Identification of parasites in fluids and tissues is rarely possible except post mortem, while diagnostic imaging and clinical examinations do not lead to a definitive diagnosis. Treatment normally requires the administration of anthelmintic drugs, and sometimes supportive therapy for complications resulting from infection. PMID- 25283224 TI - [Treatment for GERD and esophageal motility disorders]. PMID- 25283225 TI - [Case of computed tomography (CT) gastrography for the detection of multiple gastric submucosal tumors: a case report]. AB - A 66-year-old female underwent esophagogastroduodenoscopy, which revealed a 17-mm gastric submucosal tumor (SMT) located in the posterior wall of the upper area of the stomach. She was referred to our hospital for further investigation because of accumulation of radioactive substance in the gastric wall by PET-CT. CT gastrography (CTG) revealed three gastric SMTs in total. Partial gastrectomy was performed; histopathologically, they were diagnosed as gastrointestinal stromal tumor (GIST), benign schwannoma, and necrotic tissue. Gastric schwannoma is very rare, and we could find no cases with both GIST and schwannoma. Additionally, the three gastric SMTs were only detected clearly via CTG. We report on the details of this case and the usefulness of CTG for the detection of gastric SMT. PMID- 25283226 TI - [A case report of endosonography used for the diagnosis of early gastric cancer and gastrointestinal stromal tumor]. AB - A 79-year-old man was referred to our hospital complaining of weight loss. Esophagogastroduodenoscopy revealed a flat, elevated lesion of 30-mm diameter located on the posterior wall of the upper gastric body. The lesion was histologically diagnosed as a well-differentiated adenocarcinoma. Endosonography showed a submucosal tumor under the carcinoma, which was highly suspicious of a gastrointestinal tumor derived from the muscle layer. Adenocarcinoma was diagnosed as an intramucosal lesion, but laparoscopic fundectomy was performed because of the submucosal tumor. Pathological diagnosis was U, less, pType 0-IIa, 18*30 mm, pT1b (SM1), tub2, int, INFa, ly0, v0, pN0, H0, P0, CYX, M0, pStage IA, gastrointestinal stromal tumors, prognostic group 1. PMID- 25283227 TI - [Disappearance of a gastric lesion following modified FOLFOX6 chemotherapy in a patient with metastatic colorectal cancer: a case report and literature review]. AB - A 48-year-old man with colorectal cancer and right inguinal lymph node metastasis had previously undergone radiotherapy and chemotherapy (uracil/tegafur/leucovorin) after a colostomy in another hospital before being referred to us. Esophagogastroduodenoscopy (EGD) revealed the presence of a gastric metastatic lesion. After three courses of treatment with a modified regimen of leucovorin plus 5-fluorouracil plus oxaliplatin-6 (mFOLFOX6), EGD revealed that the gastric lesion had disappeared; computed tomography revealed that the size of the primary tumor and inguinal lymph node metastasis were markedly reduced. Subsequently, he underwent rectal resection of the primary tumor and continued treatment with mFOLFOX6 in combination with bevacizumab. We reviewed 29 similar cases from the literature, and determined that surgical resection of the tumor and appropriate chemotherapy can lead to long-term survival for patients with gastric metastases from colorectal cancer. Furthermore, positive CK20 and CDX2 expression and negative CK7 expression were useful adjuncts in the immunohistochemical diagnosis of gastric metastases from colorectal adenocarcinoma. PMID- 25283228 TI - [A case of long-term survival without recurrence from an unknown primary carcinoma after resection of lymph node metastases]. AB - A 76-year-old woman was diagnosed with intraabdominal tumors at a regular medical check-up. The tumors were resected and were identified as number 8a and 3 lymph nodes with adenocarcinoma. No primary was identified despite various studies; the final diagnosis was of adenocarcinoma of unknown primary. No recurrence developed; the patient has survived for 5 years without postoperative chemotherapy. The patient was disease-free 5 years after diagnosis. To the best of our knowledge, this is the first report of long-term survival of number 8a and 3 lymph node metastasis from an unknown primary carcinoma. PMID- 25283229 TI - [A case of chronic hepatitis C with pancreas divisum and acute pancreatitis during combination treatment with telaprevir/peginterferon/ribavirin]. AB - A 47-year-old man developed acute pancreatitis during combination treatment with telaprevir/peginterferon/ribavirin for chronic hepatitis C. Cessation of telaprevir, fasting, and gabexate mesilate improved the pancreatitis. Although peginterferon and ribavirin treatment was continued, there was no recurrence of the pancreatitis. Endoscopic retrograde cholangiopancreatography incidentally showed a pancreas divisum. We definitively diagnosed drug-induced acute pancreatitis due to telaprevir. PMID- 25283230 TI - [Diagnostic benefits of adrenocortical scintigraphy in hepatic adrenal rest tumor]. AB - An 81-year-old female was referred to our hospital for the examination of an S7 liver tumor. The tumor was suspected to be a hepatic adrenal rest tumor (HART) based on ultrasonography, dynamic CT, Gd-EOB-DTPA-enhanced MRI, and CT during abdominal angiography. After various hormonal tests, the tumor was confirmed as hormonally non-functional. The diagnosis of HART was confirmed based on (131)I adosterol accumulation in the tumor by adrenocortical scintigraphy. The resected tumor was histologically compatible with HART, and it may have been able to produce cortisol based on the immunohistochemical findings of various adrenocortical hormone metabolic enzymes. Adrenocortical scintigraphy may thus be useful in diagnosing HART. PMID- 25283231 TI - [Bacillus cereus septicemia and necrotizing fasciitis in a patient with liver cirrhosis: a case report]. AB - A 54-year-old woman with hematemesis was referred to our hospital. She had a history of liver cirrhosis and diabetes mellitus. After inserting a Sengstaken Blakemore tube, we performed endoscopic variceal ligation for ruptured esophageal varices. On the third day of admission, she developed septicemia and necrotizing fasciitis caused by Bacillus cereus. She was successfully treated with early debridement of both lower extremities and intravenous treatment with vancomycin, ciprofloxacin, and clindamycin. Although B. cereus is an attenuate bacterium, it can occasionally cause fatal infection in immuno-compromised individuals, such as those with liver cirrhosis. PMID- 25283232 TI - [A case of gastric anisakiasis with hemorrhagic gastric ulcer and ulcerative scarring]. PMID- 25283233 TI - Anti-proliferative of physcion 8-O-beta-glucopyranoside isolated from Rumex japonicus Houtt. on A549 cell lines via inducing apoptosis and cell cycle arrest. AB - BACKGROUND: Lung cancers are leading causes of cancer death, and Rumex japonicus has been traditionally used in folk medicine as anti-microorganic, anti inflammatory and anti-tumor agents. This study was designed to investigate the anti-proliferative activity of physcion 8-O-beta-glucopyranoside (PG) isolated from Rumex japonicus Houtt. on A549 cell lines. METHODS: In our present study, PG was isolated and identified from the ethanol extracts of R. japonicus. MTT method was used to evaluate the anti-proliferative activity of PG on A549 cell lines, and cell cycle distribution assay, apoptosis assay, and western blot analysis in vitro were used to explore the possible mechanisms. RESULTS: From the results of our present study, cell viability was obviously inhibited by PG, in a dose- and time-dependent manner. Our results also suggested that the anti-proliferative effect of PG was related to cell cycle arrest at the G2/M phase through repression of cdc2 and Cyclin B1 protein expression. In addition, the results of apoptosis assay and western blot analysis indicated that the anti-proliferative activity could be related to apoptosis via up-regulating the expressions of Bax, caspase-3 and caspase-7, and down-regulating the expressions of Bcl-2. CONCLUSIONS: In conclusion, the PG has significant anti-proliferative activity on A549 cell lines, and the possible mechanism was related to cell cycle arrest at the G2/M phase, and apoptosis via the regulations of Bax, Bcl-2, and caspase-3 and caspase-7. PMID- 25283234 TI - Hydrogen adsorption on bimetallic PdAu(111) surface alloys: minimum adsorption ensemble, ligand and ensemble effects, and ensemble confinement. AB - The adsorption of hydrogen on structurally well defined PdAu-Pd(111) monolayer surface alloys was investigated in a combined experimental and theoretical study, aiming at a quantitative understanding of the adsorption and desorption properties of individual PdAu nanostructures. Combining the structural information obtained by high resolution scanning tunneling microscopy (STM), in particular on the abundance of specific adsorption ensembles at different Pd surface concentrations, with information on the adsorption properties derived from temperature programmed desorption (TPD) spectroscopy and high resolution electron energy loss spectroscopy (HREELS) provides conclusions on the minimum ensemble size for dissociative adsorption of hydrogen and on the adsorption energies on different sites active for adsorption. Density functional theory (DFT) based calculations give detailed insight into the physical effects underlying the observed adsorption behavior. Consequences of these findings for the understanding of hydrogen adsorption on bimetallic surfaces in general are discussed. PMID- 25283235 TI - Folic acid supplementation and methylenetetrahydrofolate reductase (MTHFR) gene variations in relation to in vitro fertilization pregnancy outcome. AB - OBJECTIVE: To study folic acid intake, folate status and pregnancy outcome after infertility treatment in women with different infertility diagnoses in relation to methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C and 1793G>A polymorphisms. Also the use of folic acid supplements, folate status and the frequency of different gene variations were studied in women undergoing infertility treatment and fertile women. DESIGN: Observational study. SETTING: University hospital. POPULATION: Women undergoing infertility treatment and healthy, fertile, non-pregnant women. METHODS: A questionnaire was used to assess general background data and use of dietary supplements. Blood samples were taken to determine plasma folate and homocysteine levels, and for genomic DNA extraction. A comparison of four studies was performed to assess pregnancy outcome in relation to MTHFR 677 TT vs. CC, and 1298 CC vs. AA polymorphisms. MAIN OUTCOME MEASURES: Folic acid supplement intake, and plasma folate, homocysteine and genomic assays. RESULTS: Women in the infertility group used significantly more folic acid supplements and had better folate status than fertile women, but pregnancy outcome after fertility treatment was not dependent on folic acid intake, folate status or MTHFR gene variations. CONCLUSION: High folic acid intakes and MTHFR gene variations seem not to be associated with helping women to achieve pregnancy during or after fertility treatment. PMID- 25283236 TI - Complete mesocolic excision in colorectal cancer: a systematic review. AB - AIM: Several studies have suggested an increased lymph node yield, reduced locoregional recurrence and increased disease-free survival after complete mesocolic excision (CME) for colorectal cancer. This review was undertaken to assess the use of CME for colon cancer by evaluating the technique and its clinical outcome. METHOD: A literature search of publications was performed using PubMed and Medline. Only studies published in English were included. Studies assessed for quality and data were extracted by two independent reviewers. End points included number of lymph nodes per patient, quality of the plane of mesocolic excision, postoperative mortality and morbidity, 5-year locoregional recurrence and 5-year cancer-specific survival. RESULTS: There were 34 articles comprising 12 retrospective studies, nine prospective studies and 13 original articles including case series, observational studies and editorials. Of the prospective studies, four reported an increased lymph node harvest and a survival benefit. The others reported an improvement in the quality of the specimen as assessed by histopathological examination. Laparoscopic CME has the same oncological outcome as open surgery but completeness of excision during laparoscopy may be compromised for tumours in the transverse colon. CONCLUSION: Studies demonstrate that CME removes significantly more tissue around the tumour including maximal lymph node clearance. There is little information on serious adverse events after CME and a long-term survival benefit has not been proved. PMID- 25283238 TI - 201Tl+-labelled Prussian blue nanoparticles as contrast agents for SPECT scintigraphy. AB - Prussian blue (PB) and its analogues on the nanometric scale are exciting nano objects that combine the advantages of molecular-based materials and nanochemistry. Herein, we demonstrate that ultra-small PB nanoparticles of 2-3 nm can be easily labelled with radioactive (201)Tl(+) to obtain new nanoprobes as radiotracers for 201-thallium-based imaging. PMID- 25283239 TI - From sphere to polyhedron: a hypothesis on the formation of high-index surfaces in nanocrystals. AB - The morphology of tetrahexahedral nanocrystals could be understood on the basis of a hypothesis that the atoms or molecules on or near spherical surfaces can migrate till reaching their equilibrium positions. Such migration of atoms/molecules is shown to be closely related to the formation of high-index surfaces in nanopolyhedrons. On account of this hypothesis, a theoretical calculation about the indices of the surfaces in tetrahexahedrons is found in good agreement with the empirical results. A group of high-index surfaces for nanocrystals that can be formed under certain environments are thus predicted. This study may provide a novel idea for preparing the catalysts at nanoscale. PMID- 25283237 TI - Hypoxia during sleep and the risk of falls and fractures in older men: the Osteoporotic Fractures in Men Sleep Study. AB - OBJECTIVES: To test the hypothesis that low arterial oxygen saturation during sleep is associated with a greater risk of falls and fractures. DESIGN: Prospective cohort study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Men aged 67 and older (N = 2,911). MEASUREMENTS: The primary exposure measure was percentage of sleep time with arterial oxygen saturation less than 90% measured using polysomnography. The main outcome measures were incident falls within 1 year and incident nonspine fractures over an average follow-up of 6.8 years. RESULTS: Men with 10% or more of sleep time at an arterial oxygen saturation of less than 90% were older, reported more comorbidities, had poorer physical function, and were more likely to have sleep disordered breathing than men with less than 10% sleep time at an arterial oxygen saturation of less than 90%. After multivariate adjustment, men with 10% or more of sleep time with arterial oxygen saturation of less than 90% had a greater risk of having one or more falls (relative risk (RR) = 1.25, 95% confidence interval (CI) = 1.04-1.51) and two or more falls (RR = 1.43, 95% CI = 1.06-1.92) than those with less than 10% of sleep time with less than 90% arterial oxygen saturation. Men with greater percentage of sleep time with arterial oxygen saturation less than 90% had a 30% to 40% greater risk of nonspine fracture than those with normal nocturnal oxygen saturation in models adjusting for sleep disordered breathing. CONCLUSION: Hypoxia during sleep may be a risk factor for falls and fractures in older men. Interventions aimed at decreasing nocturnal hypoxia may decrease falls and fractures. PMID- 25283240 TI - The importance of lipid modified proteins in plants. AB - Membranes have long been known to act as more than physical barriers within and between plant cells. Trafficking of membrane proteins, signalling from and across membranes, organisation of membranes and transport through membranes are all essential processes for plant cellular function. These processes rely on a myriad array of proteins regulated in a variety of manners and are frequently required to be directly associated with membranes. For integral membrane proteins, the mode of membrane association is readily apparent, but many peripherally associated membrane proteins are outwardly soluble proteins. In these cases the proteins are frequently modified by the addition of lipids allowing direct interaction with the hydrophobic core of membranes. These modifications include N myristoylation, S-acylation (palmitoylation), prenylation and GPI anchors but until recently little was truly known about their function in plants. New data suggest that these modifications are able to act as more than just membrane anchors, and dynamic S-acylation in particular is emerging as a means of regulating protein function in a similar manner to phosphorylation. This review discusses how these modifications occur, their impact on protein function, how they are regulated, recent advances in the field and technical approaches for studying these modifications. PMID- 25283242 TI - Polypoid stromal lesions of the intestines. AB - Interpretation of intestinal mesenchymal lesions is simplified merely by knowing in which anatomic layer they are usually found. For example, Kaposi sarcoma is detected on mucosal biopsies, whereas inflammatory fibroid polyp is almost always in the submucosa. Gastrointestinal stromal tumours (GIST) are centred generally in the muscularis propria. Schwannomas are essentially always in the muscularis propria. Knowledge of the favoured layer is also most important in interpreting colon biopsies, as many mesenchymal polyps are encountered in the colon. Herein we discuss several mesenchymal lesions and point out some diagnostic pitfalls. PMID- 25283243 TI - Mechanism of DNA adsorption and desorption on graphene oxide. AB - Graphene oxide (GO) adsorbing a fluorophore-labeled single-stranded (ss) DNA serves as a sensor system because subsequent desorption of the adsorbed probe DNA from GO in the presence of complementary target DNA enhances the fluorescence. In this study, we investigated the interaction of single- and double-stranded (ds) DNAs with GO by using a fluorescently labeled DNA probe. Although GO is known to preferentially interact with ssDNA, we found that dsDNA can also be adsorbed on GO, albeit with lower affinity. Furthermore, the status of ssDNA or dsDNA previously adsorbed on the GO surface was investigated by adding complementary or noncomplementary DNA (cDNA or non-cDNA) to the adsorption complex. We observed that hybridization occurred between the cDNA and the probe DNA on the GO surface. On the basis of the kinetics driven by the incoming additional DNA, we propose a mechanism for the desorption of the preadsorbed probe DNA from the GO surface: the desorption of the GO-adsorbed DNA was facilitated following its hybridization with cDNA on the GO surface; when the GO surface was almost saturated with the adsorbed DNA, nonspecific desorption dominated the process through a simple displacement of the GO-adsorbed DNA molecules by the incoming DNA molecules because of the law of mass action. Our results can be applied to design appropriate DNA probes and to choose proper GO concentrations for experimental setups to improve specific signaling in many biosensor systems based on the GO platform. PMID- 25283241 TI - Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. Cell-replacement therapies have emerged as a promising strategy to slow down or replace neuronal loss. Compared to other stem cell types, endometrium-derived stem cells (EDSCs) are an attractive source of stem cells for cellular therapies because of their ease of collection and vast differentiation potential. Here we demonstrate that endometrium-derived stem cells may be transplanted into an MPTP exposed monkey model of PD. After injection into the striatum, endometrium-derived stem cells engrafted, exhibited neuron-like morphology, expressed tyrosine hydroxylase (TH) and increased the numbers of TH positive cells on the transplanted side and dopamine metabolite concentrations in vivo. Our results suggest that endometrium derived stem cells may provide a therapeutic benefit in the primate model of PD and may be used in stem cell based therapies. PMID- 25283244 TI - Emerging applications of liquid metals featuring surface oxides. AB - Gallium and several of its alloys are liquid metals at or near room temperature. Gallium has low toxicity, essentially no vapor pressure, and a low viscosity. Despite these desirable properties, applications calling for liquid metal often use toxic mercury because gallium forms a thin oxide layer on its surface. The oxide interferes with electrochemical measurements, alters the physicochemical properties of the surface, and changes the fluid dynamic behavior of the metal in a way that has, until recently, been considered a nuisance. Here, we show that this solid oxide "skin" enables many new applications for liquid metals including soft electrodes and sensors, functional microcomponents for microfluidic devices, self-healing circuits, shape-reconfigurable conductors, and stretchable antennas, wires, and interconnects. PMID- 25283245 TI - Differential involvement of glutathione S-transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids. AB - On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S-transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1-transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1-wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R-VCR, CAL1R VDS, CAL1R-VRB, respectively. All resistant lines displayed more than 10-fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1-mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R-VCR and CAL1R-VDS, and a distinct one for CAL1R-VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB. PMID- 25283246 TI - Inflammatory cytokine tumor necrosis factor alpha suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor 2alpha. AB - Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFalpha in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFalpha suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration dependent manner. TNFalpha inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2alpha rather than HIF 1alpha. The effects of TNFalpha in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2alpha, which is regulated by the nuclear factor (NF)-kappaB signaling pathway. TNFalpha treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFalpha signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. PMID- 25283248 TI - Sodium borohydride stabilizes very active gold nanoparticle catalysts. AB - Long-term stable 3 nm gold nanoparticles are prepared by a simple reaction between HAuCl4 and sodium borohydride in water under ambient conditions which very efficiently catalyze 4-nitrophenol reduction to 4-nitroaniline. PMID- 25283250 TI - The use of robotics in surgery: a review. AB - IMPORTANCE: There is an ever-increasing drive to improve surgical patient outcomes. Given the benefits which robotics has bestowed upon a wide range of industries, from vehicle manufacturing to space exploration, robots have been highlighted by many as essential for continued improvements in surgery. OBJECTIVE: The goal of this review is to outline the history of robotic surgery, and detail the key studies which have investigated its effects on surgical outcomes. Issues of cost-effectiveness and patient acceptability will also be discussed. RESULTS AND CONCLUSION: Robotic surgery has been shown to shorten hospital stays, decrease complication rates and allow surgeons to perform finer tasks, when compared to the traditional laparoscopic and open approaches. These benefits, however, must be balanced against increased intraoperative times, vast financial costs and the increased training burden associated with robotic techniques. The outcome of such a cost-benefit analysis appears to vary depending on the procedure being conducted; indeed the strongest evidence in favour of its use comes from the fields of urology and gynaecology. It is hoped that with the large-scale, randomised, prospective clinical trials underway, and an ever expanding research base, many of the outstanding questions surrounding robotic surgery will be answered in the near future. PMID- 25283249 TI - Long-distance endosome trafficking drives fungal effector production during plant infection. AB - To cause plant disease, pathogenic fungi can secrete effector proteins into plant cells to suppress plant immunity and facilitate fungal infection. Most fungal pathogens infect plants using very long strand-like cells, called hyphae, that secrete effectors from their tips into host tissue. How fungi undergo long distance cell signalling to regulate effector production during infection is not known. Here we show that long-distance retrograde motility of early endosomes (EEs) is necessary to trigger transcription of effector-encoding genes during plant infection by the pathogenic fungus Ustilago maydis. We demonstrate that motor-dependent retrograde EE motility is necessary for regulation of effector production and secretion during host cell invasion. We further show that retrograde signalling involves the mitogen-activated kinase Crk1 that travels on EEs and participates in control of effector production. Fungal pathogens therefore undergo long-range signalling to orchestrate host invasion. PMID- 25283251 TI - Referred pain location depends on the affected section of the sacroiliac joint. AB - PURPOSE: Pain referred from the sacroiliac joint (SIJ) may originate in the joint's posterior ligamentous region. The site of referred pain may depend on which SIJ section is affected. This study aimed to determine the exact origin of pain referred from four SIJ sections. METHODS: The study included 50 patients with SIJ dysfunction, confirmed by more than 70 % pain relief after periarticular injection of local anesthetic into the SIJ. The posterior SIJ was divided into four sections-upper, middle, lower, and other (cranial portion of the ilium outside the SIJ)-designated sections 1, 2, 3, and 0, respectively. We then inserted a needle into the periarticular SIJ under fluoroscopy. After the patient identified the area(s) in which the needle insertion produced referred pain, we injected a mixture of 2 % lidocaine and contrast medium into the corresponding SIJ section. RESULTS: Referred pain from SIJ section 0 was mainly located in the upper buttock along the iliac crest; pain from section 1, around the posterosuperior iliac spine; pain from section 2, in the middle buttock area; pain from section 3, in the lower buttock. In all, 22 (44.0 %) patients complained of groin pain, which was slightly relieved by lidocaine injection into SIJ sections 1 and 0. CONCLUSIONS: Dysfunctional upper sections of the SIJ are associated with pain in the upper buttock and lower sections with pain in the lower buttock. Groin pain might be referred from the upper SIJ sections. PMID- 25283252 TI - Effect of high advanced-collagen tripeptide on wound healing and skin recovery after fractional photothermolysis treatment. AB - BACKGROUND: Collagens have long been used in pharmaceuticals and food supplements for the improvement of skin. AIM: We evaluated the efficacy of high advanced collagen tripeptide (HACP) on wound healing and skin recovery. METHODS: Using an in vitro model, we performed HaCaT cell migration assays and collagen gel contraction assays using HACP concentrations of 1, 10 and 100 MUg/mL. In this pilot study, eight healthy volunteers were randomly divided into two groups. Both the control and experimental groups received fractional photothermolysis treatment, but in the experimental group, four subjects received 3 g/day of oral collagen peptide (CP) for 4 weeks. To assess transepidermal water loss in each patient before and after the treatment, we used a Corneometer and a Cutometer, and we also assessed the patient's Erythema Index. RESULTS: The cell migration assay showed that HACP enhanced wound closure, but not in a dose-dependent manner. The collagen gel contraction assay showed increased contractility when patients were treated with 100 MUg/mL HACP, but the results were not significantly different from those of controls. We found that post-laser erythema resolved faster in the experimental group than in the control group (P < 0.05). In addition, the recovery of skin hydration after fractional laser treatment was greater in the experimental group than in the control group by day 3 (P < 0.05), and the experimental group showed significantly improved post-treatment skin elasticity compared with the controls by day 14 (P < 0.05). CONCLUSIONS: Collagen tripeptide treatment appears to be an effective and conservative therapy for cutaneous wound healing and skin recovery after fractional photothermolysis treatment. PMID- 25283253 TI - Expanding access to naloxone in the United States. PMID- 25283254 TI - An 11-year review of levetiracetam ingestions in children less than 6 years of age. AB - BACKGROUND: Levetiracetam is a new anticonvulsant, which works to block high voltage-activated Ca(++) channels in children, for partial-onset seizures. Reports of clinical experience with pediatric ingestions are minimal. The purpose of this study was to characterize the toxicity of accidental levetiracetam exposures in children less than 6 years of age. METHODS: This was an 11-year retrospective observational case series of pediatric (< 6 years old) levetiracetam ingestions reported to a Poison Control System from 2002 to 2013. Case narratives were individually reviewed to collect desired information on exposure and clinical course. Inclusion criteria were levetiracetam as a single ingested medication, age less than 6 years, treatment in a health care facility, and followed to a known outcome. RESULTS: Eighty-two cases met inclusion criteria with 55% female patients and overall median age of 2.0 years (range: 1-60 months). The levetiracetam dose ingested was reported in 69 (84.1%) cases, with exact dose (median dose, 45.0 mg/kg; range, 10.5-1429 mg/kg) reported in 33 cases (40.2%). Of these, twenty-nine cases (88%) involved the oral solution formulation and 28 cases (85%) had unintentional therapeutic error as the cause of the exposure. No dose-response relationship was demonstrated; however, the odds of a levetiracetam-naive patient, (median dose, 26.9 mg/kg; N = 15) with an unintentional exposure, developing drowsiness or ataxia was 6 times that of a patient who was not naive to levetiracetam (median dose, 70.1 mg/kg; N = 20) (Odds ratio [OR], 6.0; 95% confidence interval [CI], 1.03-35.91).Of the 82 cases, 17 (20.7%) developed untoward clinical effects of drowsiness and/or ataxia. Eighty patients (97.6%) were treated and discharged from the emergency department, and two patients (2.4%) were admitted. The two patients admitted included a two-month old who was accidentally given a dose 10 times that of her usual dose and a 3-year old who was lethargic on arrival to the hospital after ingestion of an unknown dose. Of all patients, 66 patients (80.5%) had no effect from the drug exposure. The medical outcome was considered to be minor in 15 cases (18.3%), and moderate in 1 case (1.2%). There were no cases with major outcomes and no deaths. CONCLUSIONS: Pediatric levetiracetam exposures were associated with few transient clinical effects. Poison Control Centers may wish to consider acuity of ingestion when developing send-in protocols. PMID- 25283256 TI - Therapeutic strategies in extrinsic atopic dermatitis: focus on inhibition of IL 4 as a new pharmacological approach. AB - INTRODUCTION: Recent data about atopic dermatitis (AD) pathogenesis postulate that T cells and their related cytokines and chemokines are primarily responsible for the inflammatory responses. AREAS COVERED: AD, the primary complex disease associated with filaggrin deficiency, is characterized by cutaneous inflammation driven by type 2 helper T (TH2) cells. TH2-related molecules, such as IL-4, IL 13, dominate the immune infiltrate. Experimental evidences suggest that these cytokines may be considered attractive therapeutic targets in AD, particularly in extrinsic AD with IgE overproduction. Recently, a fully human monoclonal antibody directed against the IL-4 receptor alpha subunit blocking IL-4 and IL-13 signaling has been evaluated in Phase I and Phase II clinical trials in patients with moderate-to-severe AD with significant improvement in disease severity. Phase III trials are ongoing. EXPERT OPINION: Treatment of AD represents a therapeutic challenge. TH2 cytokine-targeted therapies represent promising treatment options that could improve the therapeutic armamentarium for AD. These therapies are likely to become future therapeutic options in AD, particularly in the extrinsic AD. PMID- 25283257 TI - Spatial and temporal variation in superfoetation and related life history traits of two viviparous fishes: Poeciliopsis gracilis and P. infans. AB - Superfoetation is the ability of females to simultaneously bear multiple broods of embryos at different developmental stages. Most studies on the phylogenetic distribution of superfoetation and on the factors that potentially promote superfoetation ignore variation within species. Here, we studied 11 populations of two species of viviparous fishes of the family Poeciliidae (Poeciliopsis gracilis and Poeciliopsis infans) and document wide variation in superfoetation and in three related life history traits: brood size, individual embryo mass and total reproductive allotment. We found significant differences in the average number of simultaneous broods among populations of P. gracilis but not among populations of P. infans. In addition, we found even greater variation between months within populations for both species, although no specific pattern of temporal variation was evident. Instead of the expected consistency of seasonal differences in superfoetation across populations, we found that large variation among months within seasons and the amount and direction of this monthly variation differed widely between populations. Our results emphasize the importance of including intraspecific variation in superfoetation and other life history traits in studies that aimed at finding general explanations of life history trait evolution. PMID- 25283258 TI - Pelvic endometriosis in women under 25: a specific management? AB - AIM: The aim of this study was to describe the characteristics of women under 25 years with pelvic endometriosis and assess their potential for recurrence and fertility after surgery. METHODS: In a comparative retrospective study, 108 patients aged less than 25 years who underwent surgery for pelvic endometriosis were included: 49 in the DIE group (deep infiltrating endometriosis) and 59 in the SE group (superficial endometriosis). The main outcome measures were complications, recurrence and fertility. This study received the favorable opinion of the CEROG No 2012-GYN-04-02. RESULTS: The diagnosis was made at 21.6 +/- 2.8 years, mainly considering clinical signs (78.4%), and on average 4.3 +/- 3.7 years after the onset of symptoms; 16.1% of patients had to be reoperated (N.=5/31) due to a recurrence of their endometriosis. There were more recurrent pain (50% vs. 21.7%, P=0.005) and endometriosis (35.7 vs. 19.6%, P=0.08) in the DIE group. 75% (N.=33/44) patients desired pregnancy after surgery and 50% of them became pregnant, with one third thanks to assisted reproductive technology. CONCLUSION: In young women, endometriosis is often more severe. The early treatment does not improve the rate of recurrence and fertility, but can reduce pain and thus improve the quality of life. PMID- 25283259 TI - Extracorporeal respiratory support: on the road to an artificial lung. AB - Extracorporeal membrane oxygenation (ECMO) technology has undergone significant advancement in the last several years. These changes have led to more compact circuits that are increasingly efficient at gas exchange while decreasing the complication rates often associated with its use. The ability to remove carbon dioxide at relatively low flows has broadened the application of ECMO in the management of respiratory failure. As this technology continues to evolve, there is great promise of a portable lung replacement therapy, an artificial lung, which would have far-reaching implications in the approach to both acute and chronic respiratory failure. PMID- 25283260 TI - The SAPIEN 3 valve: lights and shadows. AB - Transcatheter aortic valve implantation (TAVI) has become an accepted alternative treatment option for high-risk or inoperable patients with symptomatic severe aortic stenosis. The future challenge for TAVI devices is to ensure results in terms of safety and efficacy that may justify an eligibility extension for this procedure to patients at intermediate and low risk for surgery. The ideal aortic valve prosthesis should be durable, with optimal hemodynamic performance and able to reduce the current major complications of TAVI procedure, in particular vascular complications (not infrequent with the transfemoral access route), paravalvular leaks, stroke and atrioventricular block requiring a permanent pacemaker. The SAPIEN 3TM (S3) (Edwards Lifesciences, Irvine, CA, USA) is the last Edwards family's transcatheter heart valves and incorporates a number of new and enhanced features intended to reduce the risk of vascular injury and paravalvular regurgitation, and to facilitate rapid and accurate positioning and implantation. The first data on S3 (SAPIEN3 trial) were presented at the EuroPCR 2014 and confirmed the advantage of the S3 compared with the previous Edwards valves (SAPIEN and SAPIEN XT) in terms of prevention of vascular complications and of moderate-severe paravalvular leaks, but showed an increase in the need of a permanent pacemaker post-TAVR. The S3 is certainly a promising evolution of transcatheter valves which may effectively reduce the risk of vascular complications and paravalvular leak. However, the S3 seems to be related to an increased risk of atrioventricular block, even if this complication could be due to the need to implant the valve in a higher position compared to previous models. PMID- 25283255 TI - Treatment for calcium channel blocker poisoning: a systematic review. AB - CONTEXT: Calcium channel blocker poisoning is a common and sometimes life threatening ingestion. OBJECTIVE: To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. METHODS: Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types. RESULTS: The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4 aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue. CONCLUSIONS: The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality. PMID- 25283261 TI - Reliability of SleepStrip as a screening test in obstructive sleep apnea patients: methodological issues to avoid misinterpretation. PMID- 25283262 TI - Speech and language development after cochlear implantation in children with bony labyrinth malformations: long-term results. AB - The aim of this study was to investigate speech and language development after long-term cochlear implantation in children with bony labyrinth malformations (BLMs) and to present the surgical findings in this group of patients. The auditory and linguistic skills of 21 children who had BLM were assessed in this study. They were implanted between 1998 and 2009. Twenty-two sex-matched and age matched implantees without BLM were evaluated as the control group. To compare speech perception and speech intelligibility between the groups, the categories of auditory performance (CAP) test and speech intelligibility rating (SIR) test, respectively, were administered. The Turkish version of the Test of Early Language Development (TELD-3-T) was administered to evaluate and compare the linguistic skills of the groups. Surgical findings and complications were also analyzed. Implanted anomalies were common cavity in five patients, incomplete partition type 1 in 5 patients, and incomplete partition type 2 in 11 patients. The CAP and SIR scores were significantly higher in the control group (p < 0.05), but the TELD-3-T test scores were comparable among the groups (p > 0.05). Based on the specific type of malformation, the CAP and SIR scores were comparable between the subgroups (p > 0.05). No perioperative complications occurred in the control group. However, various perioperative complications (gusher, etc.) and surgical difficulty occurred in the anomaly group. The malformation group had unsatisfactory results with regard to speech perception skills; however, this group and the non-anomalous group exhibited comparable long-term results on linguistic development. PMID- 25283263 TI - Dipeptidyl-peptidase-4 Inhibitors and Heart Failure: Class Effect, Substance Specific Effect, or Chance Effect? AB - OPINION STATEMENT: The increased risk of heart failure hospitalizations related to treatment with the DPP-4 inhibitor saxagliptin observed in the SAVOR TIMI 53 trial, is likely not to be a chance effect, but rather a previously unrecognized side effect of this drug, as this risk was very consistently apparent across all subgroups of this large multicenter, prospective, randomized trial. Whether this side effect might represent a class effect of all DPP-4 inhibitors remains to be seen. Results of randomized prospective multicenter trials with the DPP-4 inhibitors alogliptin and vildagliptin have in fact generated new uncertainties and clearly not totally excluded the possibility of a class side effect. A meta analysis of 59 randomized controlled trials with various DPP-4 inhibitors evaluating data from 36,620 patients with diabetes and a minimal observation period of 24 weeks, confirmed a 21 % increase of heart failure events compared to placebo treatment, however, not in comparison to treatment with other blood glucose lowering drugs. German registry data also did not show an increased risk for heart failure for the latter comparison. Potential interactions of DPP-4 inhibitors with other drugs, e.g. ACE inhibitors, have been discussed in relation to the increased heart failure risk, as well as interactions with peptides regulating cardiovascular functions that are also split by DPP-4 enzymes such as BNP, substance P, and NPY. Results from ongoing large multicenter trials with the DPP-4 inhibitors sitagliptin and linagliptin are expected to clarify the potential heart failure issue related to treatment with DPP-4 inhibitors. PMID- 25283264 TI - Design, synthesis and pharmacological evaluation of novel NO-releasing benzimidazole hybrids as potential antihypertensive candidate. AB - Two series of novel NO-releasing benzimidazole derivatives (8a-e, 9a-g) were designed and synthesized by coupling nitro ester and furoxan NO-donor moieties with benzimidazole biphenyl skeleton. The NO-releasing assay indicated that all the target compounds had different level of NO-releasing ability. Furthermore, the isolated organ assay (rat aortic strips) was used to evaluate the antagonism of Ang II-induced vasoconstriction ability. It was observed that the pA2 values of compounds 8e and 9e were better than that of lead compound 6. Moreover, the pharmacological investigation showed that the antagonism of Ang II-induced pressure response by oral administration of compound 8e was obviously superior to that of lead compound 6, and comparable to that of the positive control losartan. These results suggested that NO-releasing hybrids may provide a promising approach for the discovery of novel antihypertensive agents. PMID- 25283265 TI - Prevalence of gallstone disease in patients with type 2 diabetes and the risk factors in North Indian population: a case control study. AB - BACKGROUND: Age, female sex, and obesity are considered to be risk factors for gallstone disease. The role of type 2 diabetes (T2D) in gallstone formation is still uncertain, and data in Indians is limited. OBJECTIVES: This is a case control study to determine the prevalence of gallstones (GS) in patients with T2D, risk factors, and the relative risk compared with subjects without diabetes, selected from the general population. METHODS: Among 450 cases with T2D of a >=2 year duration, 377 (88.8 %) participated. Diagnosis of GS was made at ultrasonography and history of cholecystectomy for GS. Controls were selected from the general population and diabetes excluded by oral glucose tolerance test. Cases and controls were matched for age, gender, and body mass index (BMI). RESULTS: Gallstones were seen in 67 (17.7 %) cases compared to 40 (5.8 %) in controls (p = 0.001). Prevalence increased with increasing age with peak in the sixth decade (23.4 % in cases and 4.4 % in controls (p = 0.001) and was higher in women (27.9 %) in cases and (7.8 %) in controls, (p = 0.001). In univariate analysis, risk factors for GS included age, female sex, BMI, multiparity, family history of GS, and high triglycerides and cholesterol with low high-density lipoprotein cholesterol. In multivariate analysis, age, (relative risk [RR] 1.54, confidence interval [CI] 1.1-2.1), female sex (RR 1.6, CI 1.0-1.9), and BMI (RR 1.5, CI 1.3-2.5) were the independent risk factors in gallstone formation. CONCLUSION: Patients with T2D had higher probability of having GS compared to the general population. Increasing age, female sex, and higher BMI were independently associated with gallstone disease. PMID- 25283267 TI - The effects of different molecular weight chondroitin-4-sulfates in chondrocyte pellet culture. AB - For this study, we cultured chondrocyte pellets in Dulbecco's modified Eagle's medium plus a 2 % fetal bovine serum medium, and treated them with 2- to 8-mer oligosaccharides of chondroitin sulfate A to examine the effects of these oligosaccharides on the differentiation and protection of chondrocytes. We found low-molecular-weight CSAs to increase the ratio of the gene expression levels of collagen II/collagen I of chondrocytes from the first day up to 14 days after culture compared with those under a CSA-free medium. Moreover, low-molecular weight CSAs inhibited the expression of matrix metalloproteinases and peptidases, and stimulated an endogenous tissue inhibitor of metalloproteinases. The dp-8 (8 mer) CSA yielded the most effective response among promoting collagen type II protein secretions compared with other groups. PMID- 25283266 TI - Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokine-refractory metastatic renal cell carcinoma. AB - In an open-label, multicenter phase II study of Japanese patients with cytokine refractory metastatic renal cell carcinoma, axitinib showed substantial antitumor activity with an acceptable safety profile. Here, we report overall survival and updated efficacy and safety results. Sixty-four Japanese patients with metastatic renal cell carcinoma following prior therapy with cytokines were treated with axitinib at a starting dose of 5 mg b.i.d. Following median treatment duration of 14.2 months, median overall survival was 37.3 months (95% CI, 28.6-49.9). The objective response rate, the primary endpoint of the study, was 51.6% (95% CI, 38.7-64.2); the median duration of response, 11.1 months (95% CI, 8.2-13.7); and the median progression-free survival was 11.0 months (95% CI, 9.2-12.0), assessed by the independent review committee. Common treatment-related all-grade adverse events were hypertension (88%), hand-foot syndrome (75%), diarrhea (66%), proteinuria (63%), fatigue (55%) and dysphonia (53%). In an exploratory analysis, median overall survival was found to be significantly longer in patients who had greater decreases in plasma levels of soluble vascular endothelial growth factor receptor-2 during the first cycle of treatment. In conclusion, the present study showed axitinib to be effective, and toxicities with long-term treatment were generally controllable with axitinib dose modification and/or standard medications in these Japanese patients. Some frequently reported adverse events warrant close monitoring and management. Changes in the plasma levels of soluble vascular endothelial growth factor receptor-2 may be used as a prognostic factor for overall survival in metastatic renal cell carcinoma following axitinib treatment. This study is registered at ClinicalTrial.gov (identifier NCT00569946). PMID- 25283268 TI - Clinical endpoint sensitivity in rheumatoid arthritis: modeling and simulation. AB - The commonly used efficacy endpoints in Rheumatoid Arthritis (RA) clinical trials are American College of Rheumatology 20 % improvement criteria (ACR20), ACR50, and ACR70 response rates, and the 28-joint disease activity score (DAS28). Longitudinal models to quantitate the exposure-response relationships for ACRs and DAS28 score were developed for four biologics used for the management of RA. The models were then used to simulate the clinical outcome at various time points following different treatment regimens. Discriminative sensitivity of these endpoints was assessed using a power analysis. The trial simulation and subsequent power analysis showed that both ACR20 and DAS28 exhibit much lower power in distinguishing between two doses investigated compared with distinguishing treatment effect over placebo/Methotrexate (MTX) control. ACR20 response rate is generally more powerful in detecting treatment effect over placebo/MTX control as compared to DAS28. The findings of current study provide useful information which will help future clinical trial design for the treatment of patients with RA. PMID- 25283269 TI - Reversible formation of a poly[3]rotaxane based on photo dimerization of an anthracene-capped [3]rotaxane. AB - We prepared a poly[3]rotaxane consisting of a ''topologically linked polymer backbone'' in one pot from readily available, modular building blocks via a dynamic polymerization strategy based on reversible anthracene dimerization. PMID- 25283270 TI - The role of surface States in the oxygen evolution reaction on hematite. AB - Hematite (alpha-Fe2 O3 ) is an extensively investigated semiconductor for photoelectrochemical (PEC) water splitting. The nature and role of surface states on the oxygen evolution reaction (OER) remain however elusive. First-principles calculations were used to investigate surface states on hematite under photoelectrochemical conditions. The density of states for two relevant hematite terminations was calculated, and in both cases the presence and the role of surface states was rationalized. Calculations also predicted a Nerstian dependence on the OER onset potential on pH, which was to a very good extent confirmed by PEC measurements on hematite model photoanodes. Impedance spectroscopy characterization confirmed that the OER takes place via the same surface states irrespective of pH. These results provide a framework for a deeper understanding of the OER when it takes place via surface states. PMID- 25283271 TI - Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder. AB - Germline mutations in CBL have been identified in patients with Noonan syndrome like phenotypes, while juvenile myelomonocytic leukemia (JMML) harbors duplication of a germline CBL, resulting in acquired isodisomy. The association between moyamoya disease and Noonan syndrome carrying a PTPN11 mutation has recently been reported. We present a patient with JMML who developed moyamoya disease and neovascular glaucoma. Our patient exhibited a Noonan syndrome-like phenotype. Genetic analysis revealed acquired isodisomy and a germline heterozygous mutation in CBL. This is a rare case of CBL mutation associated with moyamoya disease. Prolonged RAS pathway signaling may cause disruption of cerebrovascular development. PMID- 25283272 TI - Seasonal variation of relapse rate in multiple sclerosis is latitude dependent. AB - OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10 degrees of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere. PMID- 25283273 TI - Psd1 binding affinity toward fungal membrane components as assessed by SPR: The role of glucosylceramide in fungal recognition and entry. AB - Psd1 is a plant defensin that has antifungal activity against several pathogenic and nonpathogenic fungi. Previous analysis of Psd1 chemical shift perturbations by nuclear magnetic resonance (NMR) spectroscopy demonstrated that this defensin interacts with phospholipids and the sphingolipid glucosylceramide isolated from Fusarium solani (GlcCer(Fusarium solani)). In this study, these interactions were evaluated by real-time surface plasmon resonance (SPR) analysis. The data obtained demonstrated that Psd1 could bind more strongly to small unilamellar vesicles (SUV)-containing GlcCer(Fusarium solani) than to SUV that was composed of phosphatidylcholine (PC) alone or was enriched with GlcCer that had been isolated from soybeans. An increase in the SPR response after cholesterol or ergosterol incorporation in PC-SUV was detected; however, SUV composed of PC:Erg (7:3; molar:molar) became unstable in the presence of Psd1, suggesting membrane destabilization. We also observed a lack of Psd1 internalization in Candida albicans strains that were deficient in the glucosyl ceramide synthase gene. Together, these data indicate that GlcCer is essential for Psd1 anchoring in the fungal plasma membrane as well as internalization. PMID- 25283274 TI - Preparation of two flavonoid glycosides with unique structures from barley seedlings by membrane separation technology and preparative high-performance liquid chromatography. AB - Barley seedlings are rich in flavones that can have positive effects on people with antihypoxia and antifatigue. Lutonarin and saponarin are two major flavonoid glycosides that have unique structures in barley seedlings. This study presents a new approach for the preparation of lutonarin and saponarin from barely seedlings by membrane separation technology and preparative high-performance liquid chromatography. Preparative conditions of these two flavonoid glycosides by membrane separation technology were studied using response surface methodology. Under the optimized conditions, the total contents of these two flavonoid glycosides amounts to 17.0%. PMID- 25283275 TI - Generation of a Tlx1(CreER-Venus) knock-in mouse strain for the study of spleen development. AB - The spleen is a lymphoid organ that serves as a unique niche for immune reactions, extramedullary hematopoiesis, and the removal of aged erythrocytes from the circulation. While much is known about the immunological functions of the spleen, the mechanisms governing the development and organization of its stromal microenvironment remain poorly understood. Here we report the generation and analysis of a Tlx1(Cre) (ER) (-Venus) knock-in mouse strain engineered to simultaneously express tamoxifen-inducible CreER(T2) and Venus fluorescent protein under the control of regulatory elements of the Tlx1 gene, which encodes a transcription factor essential for spleen development. We demonstrated that Venus as well as CreER expression recapitulates endogenous Tlx1 transcription within the spleen microenvironment. When Tlx1(Cre) (ER) (-Venus) mice were crossed with the Cre-inducible reporter strain, Tlx1-expressing cells as well as their descendants were specifically labeled following tamoxifen administration. We also showed by cell lineage tracing that asplenia caused by Tlx1 deficiency is attributable to altered contribution of mesenchymal cells in the spleen anlage to the pancreatic mesenchyme. Thus, Tlx1(Cre) (ER) (-Venus) mice represent a new tool for lineage tracing and conditional gene manipulation of spleen mesenchymal cells, essential approaches for understanding the molecular mechanisms of spleen development. PMID- 25283276 TI - Hepatic congestion leads to fibrosis: findings in a newly developed murine model. PMID- 25283278 TI - Comparison of LUMIPULSE((r)) G1200 With Kryptor and Modular E170 for the Measurement of Seven Tumor Markers. AB - BACKGROUND: Tumor marker measurements are becoming essential for prognosis and follow-up of patients in oncology. In this context, we aimed to compare a new analyzer, Lumipulse((r)) G1200 (Fujirebio group, distributed in Europe by the Innogenetics group) with Kryptor((r)) (Thermo Fisher Scientific B.R.A.H.M.S, Asnieres, France) and Modular((r)) Elecsys E170 (Roche Diagnostics, Meylan, France) for the measurement of seven tumor markers: PSA, AFP, CEA, CA 15-3, CA 125, CA 19-9, and Cyfra 21-1. METHODS: A total of 471 serum samples from patients with elevated tumor markers and 100 serum from healthy patients were analyzed with Lumipulse((r)) G1200 and either Kryptor((r)) (for AFP) or Modular((r)) (for the six other markers). RESULTS: The good precision of Lumipulse((r)) G1200 assays was confirmed with CVs < 2.5% and < 5.0%, obtained, respectively, for within-run imprecision and intermediate imprecision (except for Cyfra 21-1: CV < 13%). For all markers, Lumipulse results were well correlated with Modular or Kryptor results (r >= 0.94). Concordance of results interpretation was > 95% and tumor marker kinetics were all similar. CONCLUSION: We confirmed the analytical performances of Lumipulse((r)) tumor marker assays except for the CYFRA 21-1 assay for which performances were poor in this study. We noticed a few discrepancies for the CEA assay. Besides, values obtained for CA 19-9 were higher with Lumipulse leading to a bias (slope = 1.5). But for the four other tumor markers assays (PSA, AFP, CA 125, CA 15-3), the results were directly transferable between Lumipulse and Kryptor or Modular, thus facilitating an eventual substitution of one system by another. PMID- 25283277 TI - Kinesin family member 6 (kif6) is necessary for spine development in zebrafish. AB - BACKGROUND: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model. RESULTS: We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6(gw326) ) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6(gw326) mutants. CONCLUSIONS: Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis. PMID- 25283279 TI - New species and taxonomic notes on Anteros Hubner, [1819] and Ourocnemis Bethune Baker, 1887 (Lepidoptera: Riodinidae). AB - Three new species of Anteros Hubner, [1819] from south and southeastern Brazil are described: A. aliceae Dias & Siewert, sp. nov., A. zikani Siewert, Dias & Dolibaina, sp. nov. and A. ethani Dias, Dolibaina & Mielke, sp. nov. Habitus and genitalia of male and female specimens of the new species are illustrated, along with illustrations of the habitus and male genitalia of the most similar species for proper distinction. The following taxonomic changes are proposed: A. micon Druce, 1875, stat. rest., A. roratus Godman & Salvin, 1886, stat. rest., and A. theleia Stichel, 1910, stat. nov. Anteros formosus stramentarius Stichel, 1909, syn. nov. is sunk as a junior subjective synonym of A. formosus. Additionally, Ourocnemis axiochus (Hewitson, 1867), stat. rest., is recognized as a species distinct from O. archytas (Stoll, 1787); illustrations of the male genitalia and of the differential characters of the wing pattern of both species are provided. A male of the rare Ourocnemis boulleti Le Cerf, 1911, is reported from southeastern Peru. Distributional data and a map are provided for all species studied. PMID- 25283280 TI - Revision of Lissoporcellana streptochiroides (Johnson, 1970) (Crustacea: Decapoda: Anomura: Porcellanidae), with description of a new species of Lissoporcellana Haig, 1978 from Beibu Bay, South China Sea. AB - A new porcellanid crab, Lissoporcellana demani n. sp. is described based on material from the Beibu Bay in the northern South China Sea. The new species can be distinguished from other congeners by the shape of rostrum, form of fixed finger of smaller cheliped and armature of lateral margins of carapace. The poorly known species L. streptochiroides (Johnson, 1970), which resembles L. demani n. sp. in carapace shape, is redescribed on the basis of examination of the syntypes from Singapore and transferred to Pisidia Leach, 1820. PMID- 25283281 TI - A revision of the genus Nyctimenius Gressitt, 1951 (Coleoptera: Cerambycidae: Lamiinae), with description of a new species. AB - A taxonomic revision of the genus Nyctimenius Gressitt is presented. A new species, N. chiangi sp. nov., is described from China. Two new combinations, N. mamutensis (Hayashi, 1975) comb. nov. and N. sabahensis (Hayashi, 1975) comb. nov., are proposed. A new status, N. palawanicus (Aurivillius, 1922) stat. n., is proposed, and a lectotype is designated for N. palawanicus. The male terminalia and aedeagus of N. ochraceovittatus are described for the first time. Nyctimenius is redescribed, and a key to Nyctimenius species is presented. PMID- 25283282 TI - Extension of historical range of Betylobraconinae (Hymenoptera: Braconidae) into Palaearctic Region based on a Baltic amber fossil, and description of a new species of Mesocentrus Szepligeti from Papua New Guinea. AB - Two new species of the parasitic wasp genus Mesocentrus Szepligeti (Betylobraconinae) are described. One based on a new species from Papua New Guinea, the other the first Palaearctic member of the subfamily based on a 30+ mya, species from Baltic amber. The second species is illustrated using synchrotron X-ray microtomography. Whereas the extant Betylobraconinae are restricted to Australia, New Guinea and New Caledonia, their ancestral distribution is now known to have extended considerably further. A key to the four species of Mesocentrus known from Papua New Guinea is provided. Both species possess some putatively plesiomorphic characters absent in other extant Mesocentrus spp. The new extant species differs in having a considerably larger number of antennal segments and a less laterally depressed frons, while the extinct one has the clypeus separated from the face dorsally and strongly developed hypoclypeal depression. Availability of sequence data for this species enabled further analysis of the relationships of the subfamily, which we present in a phylogenetic analysis additionally including the release of a number of new sequences of related taxa. PMID- 25283283 TI - Solenoxyphus Reuter, 1875 (Hemiptera: Heteroptera: Miridae: Phylinae): revised diagnosis, a new species and new generic synonym. AB - Solenoxyphus kazakhstanicus sp. n. is described from the vicinity of Dzhezkazgan, Western Kazakhstan. The generic name Voruchia Reuter, 1879 is synonymized with Solenoxyphus Reuter, 1875. Illustrations of the male and female genitalia, photographs of the dorsal habitus, host, and distributional records are given for the new species and S. vittiger comb. nov., the type species of Voruchia. Female genitalia of Solenoxyphus and Boopidocoris spp. are studied for the first time and an updated generic diagnosis of the former genus is provided. The placement of both genera within the tribe Nasocorini sensu Schuh & Menard (2013) is briefly discussed. PMID- 25283284 TI - The Iranian Dendrothripinae (Thysanoptera: Thripidae) with description of a new genus and species. AB - Iranodendrothrips kamalii gen. et sp. n. is described from northeast of Iran and the morphological relationships among the closely related genera, Dendrothrips and Filicopsothrips, are discussed. Pseudodendrothrips bhattii is reported for the first time from Iran. Illustrated keys are provided to the genera and species of Dendrothripinae from Iran. PMID- 25283285 TI - Review of species of the genus Nicotikis Marseul, 1883 (Coleoptera: Histeridae) from Southeast Asia. AB - A study of specimens of family Histeridae from Southeast Asia yielded two species of the genus Nicotikis, which are here described: Nicotikis kabakovi sp. n. (Thailand and Vietnam) and N. korshunovi sp. n. (Thailand). Both species are illustrated and a key to species of Nicotikis from Southeast Asia is provided. PMID- 25283286 TI - A new Ochterus (Hemiptera: Heteroptera: Ochteridae) from northeastern Brazil, with a key to the species recorded from the country. AB - Ochterus santosi sp. nov., from the state of Piaui, northeastern Brazil, is described, illustrated, and compared with other species of the genus from the Americas. An identification key to the species recorded from the country is also presented. PMID- 25283287 TI - A new species of the genus Toxoides Hampson, 1893 (Lepidoptera: Thyatiridae) from China. AB - A new species of the genus Toxoides, T. sichuanensis sp. n. is described based on specimens collected in Sichuan, China. Illustrations of male adult and male genitalia are provided, together with a distribution map of the genus Toxoides. PMID- 25283288 TI - Revision of Caloapenesia (Hymenoptera, Bethylidae), with description of sixteen new species. AB - Caloapenesia Terayama is characterized by having the costal cell very long, the stigma of forewing absent, and the paramere deeply divided into two arms. Three species of this genus were known from Oriental Region. Sixteen new species from Indonesia, Thailand and Vietnam: C. ana sp. nov., C. arbeni sp. nov., C. diba sp. nov., C. edas sp. nov., C. heira sp. nov., C. inyara sp. nov., C. jailuna sp. nov., C. lani sp. nov., C. launeci sp. nov., C. leptata sp. nov., C. mugra sp. nov., C. nadaili sp. nov., C. paruwa sp. nov., C. rikawa sp. nov., C. sabeli sp. nov. and C. supra sp. nov. are described and illustrated. A character list for delimiting species and comments about generic male characters as a key to males are given. PMID- 25283289 TI - Additions to the reported Elimaea species (Orthoptera: Phaneropteridae: Phaneropterinae) from India. AB - The genus Elimaea (Tettigoniidae: Phaneropterinae) has reportedly been represented in India by eight species. Four species in addition to the existing checklist are described, which were earlier reported from the Malay Peninsula, based on the teeth on stridulatory file (on the underside of male left tegmen) and modifications of the gonangulum of the ovipositor. The morphometric variations in the reported species have been given, which include E. securigera, E. subcarinata, E. thaii, E. chloris, E. nautica and E. subcarinata sp. nov. (that differs from E. subcarinata). PMID- 25283290 TI - A new microhylid frog, genus Rhombophryne, from northeastern Madagascar, and a re description of R. serratopalpebrosa using micro-computed tomography. AB - The rainforests of the Marojejy massif in northern Madagascar are a well-known hotspot of amphibian species diversity and endemism. In the present paper, we re describe Rhombophryne serratopalpebrosa (Guibe 1975), a cophyline microhylid frog from high altitude on this massif, based on a re-examination of its holotype, and describe Rhombophryne vaventy sp. nov. using characters of external morphology and osteology, illustrated by pdf-embedded comparative 3D models of their skeletons. Rhombophryne serratopalpebrosa differs from R. vaventy sp. nov. by smaller size (28 mm snout-vent length vs. 52.9 mm), skin texture (granular vs. rough and tubercular skin respectively), supratympanic fold shape (strong, long and straight reaching the eye vs. curved and not extending anteriorly beyond the tympanum), relative tympanum diameter (78% vs. 41% of eye diameter), shape of the postchoanal prevomerine palate, shape of the footplate of the columella, length of prepollex, and by other subtle osteological features. Morphological comparisons suggest that a specimen from Ambolokopatrika assigned to R. serratopalpebrosa in previous genetic studies might belong to yet another undescribed species, closely related to R. vaventy sp. nov., whereas DNA sequences of the topotypic R. serratopalpebrosa remain unknown. We therefore emphasise the need for collecting additional material from high altitudes of the Marojejy massif to understand the systematics, as well as the natural history, of this poorly known species. For the new species described herein, we propose a Red List threat status of Vulnerable, in line with other Marojejy endemics from a similar altitude. PMID- 25283291 TI - Moina hemanti sp. nov., a new species of the genus Moina s.l. (Branchiopoda: Anomopoda) from Pune, India. AB - We describe and figure Moina hemanti sp. nov. from ephemeral pools on the campus of Pune University, India. Although the pools flood during the monsoon, the moinid only appears irregularly and for a short period of time. In morphology, it is extremely close to Moina dumonti from Mexico and Cuba. This geographic gap remains unexplained for the time being, although more similar cases among cladocerans are on record. Molecular analysis has suggested that M. hemanti is relatively close to Moinodaphnia, and might form a genus in its own right, presumably together with M. dumonti. The latter, however, remains to be analyzed. Further candidates for this clade are Moina oryzae and M. rostrata, if the presence of an ocellus and/or a rostrum can be shown to be apomorphies. PMID- 25283292 TI - Colombiathelphusa, a new genus of freshwater crab from Colombia, and the first location record of Eidocamptophallus chacei (Pretzmann, 1967) (Crustacea: Decapoda: Pseudothelphusidae). AB - A new genus of pseudothelphusid crab, Colombiathelphusa gen. nov., is established to include Colombiathelphusa culmarcuata n. sp., from the Choco Department, western Colombia. The new genus is characterized by the morphology of the male first gonopod, which has a prominent lateral process, a cephalic surface with two spine-like cephalic processes subdistally, and the outline of the apex strongly recurved, resembling a bow's arch. The new species is described and illustrated. The first location record of Eidocamptophallus chacei (Pretzmann, 1967), is made and its male first gonopod is redescribed and illustrated. Possible affinities of both taxa are discussed. PMID- 25283293 TI - First record of the hermit crab genus Cestopagurus Bouvier, 1897 (Crustacea: Decapoda: Anomura: Paguridae) from the South Pacific Ocean and description of a new species. AB - A fifth species of the pagurid genus Cestopagurus Bouvier, 1897, is described and illustrated on the basis of a single male specimen collected at a depth of 499 m from Hinepuia submarine volcano in the Kermadec Arc, New Zealand. The new species, C. hinepuia, appears similar to C. puniceus Komai & Takeda, 2005 known from waters off Japan, but the different armature of chelipeds distinguishes the new species. It is the first representative of the genus recorded from the South Pacific Ocean. A key for identification of species of the genus is presented. PMID- 25283294 TI - Veraphis yoshitomii sp. n. (Coleoptera, Staphylinidae, Scydmaeninae) from Japan. AB - A new species of Eutheiini, Veraphis yoshitomii sp. n. is described from Shikoku, Japan. Diagnostic characters are discussed and key structures, including the aedeagus, are illustrated. The new species belongs to the Veraphis japonicus species group, which includes five species distributed in mountains of Japan and five possibly closely related ones in the sub-Himalayan China. The distribution of Japanese Veraphis is summarized and discussed. PMID- 25283295 TI - The type of the land crab Cardisoma hirtipes Dana, 1851 (Crustacea: Brachyura: Gecarcinidae). PMID- 25283297 TI - Control of regioselectivity over gold nanocrystals of different surfaces for the synthesis of 1,4-disubstituted triazole through the click reaction. AB - Gold nanocubes, octahedra, and rhombic dodecahedra were examined for facet dependent catalytic activity in the formation of triazoles. Rhombic dodecahedra gave 100% regioselective 1,4-triazoles. The product yield was increased by decreasing the particle size. However, a mixture of 1,4- and 1,5-triazoles was obtained in lower yields when cubes and octahedra of similar sizes were used. The lowest Au-atom density on the {110} surface and largest unsaturated coordination number of surface Au atoms may explain their best catalytic efficiency and product regioselectivity. Various spectroscopic techniques were employed to verify the formation of the Au-acetylide intermediate and establish the reaction mechanism, in which phenylacetylene binds to the Au {110} surface through the terminal-binding mode to result in the exclusive formation of 1,4-triazoles. The smallest rhombic dodecahedra can give diverse 1,4-disubstituted triazoles in good yields by coupling a wide variety of alkynes and organic halides. PMID- 25283299 TI - Liquid-free lithium-oxygen batteries. AB - Non-aqueous lithium-oxygen batteries are considered as most advanced power sources, albeit they are facing numerous challenges concerning almost each cell component. Herein, we diverge from the conventional and traditional liquid-based non-aqueous Li-O2 batteries to a Li-O2 system based on a solid polymer electrolyte (SPE-) and operated at a temperature higher than the melting point of the polymer electrolyte, where useful and most applicable conductivity values are easily achieved. The proposed SPE-based Li-O2 cell is compared to Li-O2 cells based on ethylene glycol dimethyl ether (glyme) through potentiodynamic and galvanostatic studies, showing a higher cell discharge voltage by 80 mV and most significantly, a charge voltage lower by 400 mV. The solid-state battery demonstrated a comparable discharge-specific capacity to glyme-based Li-O2 cells when discharged at the same current density. The results shown here demonstrate that the safer PEO-based Li-O2 battery is highly advantageous and can potentially replace the contingent of liquid-based cells upon further investigation. PMID- 25283300 TI - Chemical modification and energetically favorable atomic disorder of a layered thermoelectric material TmCuTe2 leading to high performance. AB - Thermoelectric (TE) materials have continuously attracted interest worldwide owing to their capability of converting heat into electricity. However, discovery and design of new TE material system remains one of the greatest difficulties. A TE material, TmCuTe2 , has been designed by a substructure approach and successfully synthesized. The structure mainly features CuTe4 -based layers stacking along the c axis that are separated by Tm(3+) cations. Such an intrinsic Cu site vacancy structure undergoes a first-order phase transition at around 606 K driven by the energetically favorable uniform Cu atom re-distribution on the covalent CuTe4 -based layer substructure, as shown by crystal structure simulations and variable-temperature XRD data. Featured with very low thermal conductivity (ca. 0.6 W m(-1) K(-1) ), large Seebeck coefficient (+185 MUV K(-1) ), and moderate electrical conductivity (220 S cm(-1) ), TmCuTe2 has a maximum ZT of 0.81 at 745 K, which is nine times higher than the value of 0.09 for binary Cu2 Te, thus making it a promising candidate for mid-temperature TE applications. Theoretical studies uncover the electronic structure modifications from the metallic Cu2 Te to the narrow gap semiconductor TmCuTe2 that lead to such a remarkable performance enhancement. PMID- 25283301 TI - Post-encystment/established immunity in cystic echinococcosis: is it really that simple? AB - In 1982, Rickard & Williams stated that immunity to larval taeniid cestodes could be divided into two different phases: the establishment phase, operating against oncospheres, and the established phase, operating against established metacestodes in the tissues. These concepts were largely based on experimental and veterinary data. As a result of subsequent research combined with clinical data, we can consider that, for metacestodes of Echinococcus spp, a single established phase is probably too simple a concept. These parasites show developmental changes in different hosts over time, the most significant being growth, fertility and degeneration. Recent clinical cyst classifications (WHO/IWGE) have highlighted that all hydatid cysts are morphologically not the same. This is important for treatment but fails to completely address variation in the host/parasite response and the understanding of parasite survival. This review attempts to relate the immunological and developmental data obtained from experimental, veterinary and medical studies to update our understanding of established immunity against E. granulosus. It proposes that a single 'Established' phase for E. granulosus could be subdivided into four additional phases: maturing; stable; unstable and degenerative. Combining this type of information with existing cyst classification systems could significantly benefit our understanding of the parasites immunobiology. PMID- 25283302 TI - A high and increasing HPV prevalence in tonsillar cancers in Eastern Denmark, 2000-2010: the largest registry-based study to date. AB - The aim was to explore whether the incidence of tonsillar squamous cell carcinomas (TSCCs) increased in Eastern Denmark, 2000-2010, and whether human papillomavirus (HPV) could explain the increase, and to assess the association of HPV prevalence with gender, age, and origin (i.e., the certainty of tonsillar tumor origin). We applied HPV DNA PCR and p16 immunohistochemistry to all TSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and in the Danish Pathology Data Bank (n = 632). Pathologists reviewed and subdivided the tumors into two groups: specified and nonspecified TSCCs. Approximately 10% of HPV positive tumors was genotyped by amplicon next-generation sequencing. The overall crude incidence of TSCCs increased significantly (2.7% per year) and was explained by an increasing incidence of HPV-positive TSCCs (4.9% per year). The overall HPV prevalence was 58%, with HPV16 being the predominant HPV type. In multivariate analysis, the HPV prevalence was associated with age (<55 vs. >60 years) (OR, 1.72; 95% CI 1.13-2.63) and origin (nonspecified vs. specified TSCCs) (OR, 0.15; 95% CI 0.11-0.22). The association of HPV prevalence with origin increased over time in specified TSCCs (OR per year, 1.10; 95% CI 1.01-1.19), whereas no change over time was observed among nonspecified TSCCs (OR per year, 0.99; 95% CI 0.90-1.08). In conclusion, the observed increase in the number of HPV-positive TSCCs can explain the increasing number of TSCCs in Eastern Denmark, 2000-2010. HPV prevalence was associated with younger age (<55 years) and a high certainty of tonsillar tumor origin. PMID- 25283303 TI - RNAIII suppresses the expression of LtaS via acting as an antisense RNA in Staphylococcus aureus. AB - RNAIII is known as the key effector of staphylococcal accessory gene regulator (agr) quorum-sensing system, which plays a central role in the pathogenesis of Staphylococcus aureus. As a regulatory RNA, RNAIII regulates multiple targets, including exoproteins and cell-wall-associated proteins. Lipoteichoic acid synthase (LtaS) is involved in the synthesis of lipoteichoic acid (LTA) that is one of the major components of cell wall. The chemical compound targeting to LtaS decreases S. aureus growth via blocking LTA production. Until now, the regulatory mechanism of LtaS expression is still not clear. The level of ltaS mRNA in S. aureus is analyzed by semi-quantitative RT-PCR analysis and qRT-PCR. The protein level of LtaS is determined by Western blotting. The putative interaction sites between RNAIII and LtaS mRNA are predicted. And LtaS-5oUTR-lacZ and LtaS-5oUTR mutant-lacZ reporter vectors are constructed according to the putative interaction sites. Our data show that the expression of ltaS is regulated by RNAIII in S. aureus. The level of LtaS is significantly higher in the RNAIII deficient strain compared to its parent strain. In the further investigation, 5oUTR of ltaS was predicted to be the putative interaction site of RNAIII. The results of detection of beta-galactosidase activities suggest that RNAIII can inhibit the expression level of LtaS through acting on the 5oUTR region of LtaS mRNA. Our finding presents that LtaS is another target of RNAIII and RNAIII suppresses the expression of LtaS via acting as an antisense RNA in S. aureus. PMID- 25283304 TI - Natural history of allergic sensitization in infants with early-onset atopic dermatitis: results from ORCA Study. AB - BACKGROUND: Early-onset atopic dermatitis (AD) is a particular phenotype that may convey a risk of developing multiple sensitizations to allergens but little is known about the pathway of sensitization. The aims of this study were to describe the natural history of sensitization to allergens for this phenotype and to identify the most predictive marker associated with the risk of developing sensitization to inhaled allergens in a well-selected cohort of infants with AD. METHODS: Infants with active AD were enrolled and prospectively explored for biological markers of atopy every year until the age of 6 yr. Allergic sensitization was defined as the presence of positive specific IgEs to allergens and multiple sensitizations as being sensitized to >=2 allergens. Elevated blood eosinophilia was defined as an eosinophil blood count >=470 eosinophils/mm(3) and elevated total IgE as a serum IgE level >=45 kU/l. RESULTS: Two hundred and twenty-nine infants were included. Elevated blood eosinophilia was observed at baseline in 60 children (26.2%) and elevated total IgE in 85 (37.1%). When elevated at baseline, eosinophilia and IgE levels remained significantly higher during the follow-up period. Sensitization to food allergens decreased from 58% to 34%, whereas sensitization to inhaled allergens increased over time from 17% to 67%. Initial multiple sensitizations to food allergens were the most predictive factor for the risk of developing sensitization to inhaled allergens at 6 yr (OR 3.72 [1.68-8.30] p < 0.001). CONCLUSIONS: In the early-onset AD phenotype, multiple sensitization to food allergens conveys a higher risk of sensitization to inhaled allergens than single sensitization. PMID- 25283305 TI - Season-specific and guild-specific effects of anthropogenic landscape modification on metacommunity structure of tropical bats. AB - Fragmentation per se due to human land conversion is a landscape-scale phenomenon. Accordingly, assessment of distributional patterns across a suite of potentially connected communities (i.e. metacommunity structure) is an appropriate approach for understanding the effects of landscape modification and complements the plethora of fragmentation studies that have focused on local community structure. To date, metacommunity structure within human-modified landscapes has been assessed with regard to nestedness along species richness gradients. This is problematic because there is little support that species richness gradients are associated with the factors moulding species distributions. More importantly, many alternative patterns are possible, and different patterns may manifest during different seasons and for different guilds because of variation in resource availability and resource requirements of taxa. We determined the best-fit metacommunity structure of a phyllostomid bat assemblage, frugivore ensemble, and gleaning animalivore ensemble within a human modified landscape in the Caribbean lowlands of Costa Rica during the dry and wet seasons to elucidate important structuring mechanisms. Furthermore, we identified the landscape characteristics associated with the latent gradient underlying metacommunity structure. We discriminated among multiple metacommunity structures by assessing coherence, range turnover, and boundary clumping of an ordinated site-by-species matrix. We identified the landscape characteristics associated with the latent gradient underlying metacommunity structure via hierarchical partitioning. Metacommunity structure was never nested nor structured along a richness gradient. The phyllostomid assemblage and frugivore ensemble exhibited Gleasonian structure (range turnover along a common gradient) during the dry season and Clementsian structure (range turnover and shared boundaries along a common gradient) during the wet season. Distance between forest patches and forest edge density structured the phyllostomid metacommunity during the dry and wet seasons, respectively. Proportion of pasture and forest patch density structured the frugivore metacommunity during the dry season. Gleaning animalivores exhibited chequerboard structure (mutually exclusive species pairs) during the dry season and random structure during the wet season. Metacommunity structure was likely mediated by differential resource use or interspecific relationships. Furthermore, the interaction between landscape characteristics and seasonal variation in resources resulted in season-specific and guild-specific distributional patterns. PMID- 25283306 TI - IUTA: a tool for effectively detecting differential isoform usage from RNA-Seq data. AB - BACKGROUND: Most genes in mammals generate several transcript isoforms that differ in stability and translational efficiency through alternative splicing. Such alternative splicing can be tissue- and developmental stage-specific, and such specificity is sometimes associated with disease. Thus, detecting differential isoform usage for a gene between tissues or cell lines/types (differences in the fraction of total expression of a gene represented by the expression of each of its isoforms) is potentially important for cell and developmental biology. RESULTS: We present a new method IUTA that is designed to test each gene in the genome for differential isoform usage between two groups of samples. IUTA also estimates isoform usage for each gene in each sample as well as averaged across samples within each group. IUTA is the first method to formulate the testing problem as testing for equal means of two probability distributions under the Aitchison geometry, which is widely recognized as the most appropriate geometry for compositional data (vectors that contain the relative amount of each component comprising the whole). Evaluation using simulated data showed that IUTA was able to provide test results for many more genes than was Cuffdiff2 (version 2.2.0, released in Mar. 2014), and IUTA performed better than Cuffdiff2 for the limited number of genes that Cuffdiff2 did analyze. When applied to actual mouse RNA-Seq datasets from six tissues, IUTA identified 2,073 significant genes with clear patterns of differential isoform usage between a pair of tissues. IUTA is implemented as an R package and is available at http://www.niehs.nih.gov/research/resources/software/biostatistics/iuta/index.cfm CONCLUSIONS: Both simulation and real-data results suggest that IUTA accurately detects differential isoform usage. We believe that our analysis of RNA-seq data from six mouse tissues represents the first comprehensive characterization of isoform usage in these tissues. IUTA will be a valuable resource for those who study the roles of alternative transcripts in cell development and disease. PMID- 25283307 TI - Amide hydrogen exchange in HIV-1 subtype B and C proteases--insights into reduced drug susceptibility and dimer stability. AB - Since its identification, HIV has continued to have a detrimental impact on the lives of millions of people throughout the world. The protease of HIV is a major target in antiviral treatment. The South African HIV-1 subtype C (C-SA) protease displays weaker binding affinity for some clinically approved protease inhibitors in comparison with the HIV-1 subtype B protease. The heavy HIV burden in sub Saharan Africa, where subtype C HIV-1 predominates, makes this disparity a topic of great interest. In light of this, the enzyme activity and affinity of protease inhibitors for the subtype B and C-SA proteases were determined. The relative vitality, indicating the selective advantage of polymorphisms, of the C-SA protease relative to the subtype B protease in the presence of ritonavir and darunavir was four- and tenfold greater, respectively. Dynamic differences that contribute to the reduced drug susceptibility of the C-SA protease were investigated by performing hydrogen-deuterium exchange/mass spectrometry (HDX/MS) on unbound subtype B and C-SA proteases. The reduced propensity to form the E35 R57 salt bridge, and alterations in the hydrophobic core of the C-SA protease, are proposed to affect the anchoring of the flexible flaps, resulting in an increased proportion of the fully open flap conformation. HDX/MS data suggested that the N-terminus of both proteases is less stable than the C-terminus of the proteases, thus explaining the increased efficacy of dimerization inhibitors targeted toward the C-terminus of HIV proteases. As far as we are aware, this is the first report on assessment of HIV protease dynamics using HDX/MS. PMID- 25283308 TI - Evaluation of acute toxicity and gastroprotective activity of curcuma purpurascens BI. rhizome against ethanol-induced gastric mucosal injury in rats. AB - BACKGROUND: Curcuma purpurascens BI. is a medicinal plant from the Zingiberaceae family, which is widely used as a spice and as folk medicine. The aim of the present study is to investigate the gastroprotective activity of C. purpurascens rhizome hexane extract (CPRHE) against ethanol- induced gastric ulcers in rats. METHODS: Acute toxicity test was carried out on 36 rats (18 males and 18 females) with low dose of CPRHE (1 g/kg), high dose of CPRHE (2 g/kg) and vehicle (5% Tween 20). To determine the gastroprotective effect of CPRHE, gastric juice acidity, gross and histological gastric lesions, mucus content and ulcer index were evaluated in ethanol-induced ulcer in rats. In addition, superoxide dismutase activity, nitric oxide level and immunohistochemical evaluation of Bax and HSP70 proteins were examined. RESULTS: The CPRHE acute toxicity test on rats did not reveal any signs of mortality and toxicity up to 2 g/kg. The oral administration of CPRHE at doses of 200 mg/kg and 400 mg/kg and omeprazole (positive control) at a dose of 20 mg/kg to rats remarkably attenuated gastric lesions induced by ethanol. Pre-treatment of rats with CPRHE significantly replenished the depletion of mucus content caused by ethanol administration and decreased the acidity of gastric walls. Further examination of gastric mucosal homogenate revealed significant elevation of superoxide dismutase and nitric oxide activities and reduction in malondialdehyde level in CPRHE-treated group, compared to the lesion control group. Histological assessment of gastric walls obtained from rats pre-treated with CPRHE demonstrated a noteworthy decrease in hemorrhagic mucosal lesions. Immunohistochemical staining showed down-regulation of Bax protein and up-regulation of Hsp70 protein. CONCLUSION: Taken together, these findings confirmed the gastroprotective effect of Curcuma purpurascens rhizome against gastric damage. PMID- 25283309 TI - Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. AB - OBJECTIVE: Treatment of bipolar depression is complicated by variable response and risk of switch to mania. Guidance is informed by the strength of evidence rather than by comparative data. METHOD: We performed a multiple-treatments meta analysis of randomised, double-blind, controlled comparisons of 4-16 weeks in adults in bipolar depression. The primary efficacy outcome was effect size. The primary acceptability outcome was 'switch to mania'. Secondary outcomes were likelihood of response and withdrawals from trials. RESULTS: Twenty-nine studies were included (8331 participants). Olanzapine + fluoxetine and olanzapine performed best on primary outcome measure being ranked highest for effect size. Switch to mania was least likely with ziprasidone and then quetiapine. Olanzapine + fluoxetine was also ranked the highest for response with lurasidone second, but olanzapine + fluoxetine and olanzapine had the optimal effect on response and withdrawal from treatment when the two parameters were considered together. Several treatments [monoamine oxidase inhibitors (MAOIs), ziprasidone, aripiprazole and risperidone] have limited or no therapeutic activity in bipolar depression. CONCLUSION: Olanzapine + fluoxetine should be first-line treatment. Olanzapine, quetiapine, lurasidone, valproate and selective serotonin re-uptake inhibitors are also recommended. Tricyclic antidepressants and lithium are worthy of consideration but lamotrigine (high risk of switching, less robust efficacy) and MAOIs, ziprasidone, aripiprazole and risperidone (no evidence of efficacy) should not be used. PMID- 25283310 TI - Longitudinal analyses of childhood growth: evidence from Project Koshu. AB - Recently, it has been suggested that fetal and infant environments are associated with childhood and adulthood health status, specifically regarding presence of obesity and chronic diseases. This concept is known as the "Developmental Origins of Health and Disease (DOHaD) hypothesis." Thus, it is necessary to collect information about the fetal and infancy periods in order to examine the association between fetal and infancy exposures and later growth. Based on the DOHaD hypothesis, childhood growth trajectories, which were described by multilevel analysis, might be important in examining the effects of early-life environment on later-life health. The author and colleagues examined the association between maternal smoking during pregnancy and fetal/childhood growth, specifically risk of childhood obesity, by using the dataset from an ongoing prospective cohort study called "Project Koshu," which enrolled pregnant women and their children from a rural area of Japan. Children born to smoking mothers were likely to have lower birth weights and, thereafter, to show an increase in body mass index compared to children of non-smoking mothers. Differences in pubertal growth patterns by gender and childhood weight status were then examined. Growth rate and height gain trajectories were similar between genders, although pubertal growth spurts were observed earlier in girls than in boys. The overweight/obese children grew faster than did the non-overweight children in the early pubertal stages, and the non-overweight children caught up and showed greater height gains at older ages. Because Project Koshu is ongoing, further studies examining new research questions will be conducted with larger sample sizes. PMID- 25283311 TI - Descriptive epidemiology of prion disease in Japan: 1999-2012. AB - BACKGROUND: Epidemiologic features of prion diseases in Japan, in particular morbidity and mortality, have not been clarified. METHODS: Since 1999, the Research Committee has been conducting surveillance of prion diseases, and the surveillance data were used to assess incident cases of prion diseases. For the observation of fatal cases, vital statistics were used. RESULTS: Both incidence and mortality rates of prion diseases increased during the 2000s in Japan. However, this increase was observed only in relatively old age groups. CONCLUSIONS: The increased number of patients among old age groups might be due to increased recognition of the diseases. If so, the number of cases should plateau in the near future. PMID- 25283313 TI - Improving timely detection and recording of colorectal peritoneal metastases. PMID- 25283312 TI - Serum HBV surface antigen positivity is associated with low prevalence of metabolic syndrome in Korean adult men. AB - BACKGROUND: Metabolic syndrome has clinical implications for chronic liver disease, but the relationship between chronic hepatitis B and metabolic syndrome remains unclear. The aim of this study was to determine whether hepatitis B surface antigen (HBsAg) positivity is associated with metabolic syndrome. METHODS: Data were obtained from the Third Korean National Health and Nutrition Examination Survey (KNHANES). Participant sera were tested for HBsAg. Metabolic syndrome was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III guidelines for Koreans. RESULTS: Of the 5108 participants, 209 (4.1%) tested positive for HBsAg, and 1364 (26.7%) were diagnosed with metabolic syndrome. The prevalence of metabolic syndrome was 23.4% in HBsAg-positive men, 31.5% in HBsAg-negative men, 18.6% in HBsAg-positive women, and 23.7% in HBsAg-negative women. After adjusting for multiple factors, male participants who tested positive for serum HBsAg had an odds ratio of 0.612 (95% confidence interval [CI] 0.375-0.998) for metabolic syndrome and an odds ratio of 0.631 (95% CI 0.404-0.986) for elevated triglycerides. Women who tested positive for serum HBsAg had an odds ratio of 0.343 (95% CI 0.170-0.693) for elevated triglycerides. CONCLUSIONS: Positive results for serum HBsAg are inversely associated with metabolic syndrome in men and with elevated triglycerides in men and women. This suggests that elevated triglycerides may contribute to the inverse association between HBsAg and metabolic syndrome. PMID- 25283315 TI - Criticality of surface topology for charge-carrier transport characteristics in two-dimensional borocarbonitrides: design principles for an efficient electronic material. AB - We have studied the effect of the spatial distribution of B, N and C domains in 2 dimensional borocarbonitrides and its influence on carrier mobility, based on density functional theory coupled with the Boltzmann transport equation. Two extreme features of C-domains in BN-rich B2.5CN2.5, namely, BCN-I (random) and BCN-II (localized), have been found to exhibit an electron (hole) mobility of ~10(6) cm(2) V(-1) s(-1) (~10(4) cm(2) V(-1) s(-1)) and ~10(3) cm(2) V(-1) s(-1) (~10(6) cm(2) V(-1) s(-1)), respectively. We have ascertained the underlying microscopic mechanisms behind such an extraordinarily large carrier mobility and the reversal of conduction polarity. Finally, we have derived the principle underlying the maximization of mobility and for obtaining a particular (electron/hole) conduction polarity of this nanohybrid in any stoichiometric proportion. PMID- 25283316 TI - Human Papillomavirus (HPV) - structure, epidemiology and pathogenesis. AB - The number of cancers is constantly increasing. An important role in the etiology of many of them is played by the viral factor, by oncogenic viruses, such as the Human Papillomavirus. The article shows current epidemiological situation and describes the structure of the virus and modes of transmission. It also explains the role of HPV infection in cancer with particular emphasis on oropharynx and head and neck cancer. Summarizing, HPV infection plays an important role in carcinogenesis of the oropharynx tumors. The presence of viral genetic material in the tumor may influence prognosis and treatment method choices. PMID- 25283317 TI - Comparison of voice quality in patients with GERD-related dysphonia or chronic cough. AB - OBJECTIVE: The aim was to compare a voice quality in patients with GERD-related dysphonia or chronic cough and to determine whether there is a relationship between the main symptom reported and voice quality. MATERIAL AND METHODS: 249 consecutive patients diagnosed with GERD-related chronic cough or dysphonia were involved in this retrospective study and were divided into two main groups of men and women, and furthermore into groups of chronic cough and dysphonia. Laryngeal lesions were evaluated with videolaryngostroboscopy using Reflux Finding Score. Voice quality was assessed using GRBAS scale, sonograms, and multidimensional voice program (MDVP). RESULTS: All subjects were found to have vocal abnormalities both in subjective and objective voice analysis. Perceptual assessment of voice (GRBAS) did not reveal any differences between analyzed groups depending on the reported symptom. In MDVP analysis, the group of women with cough as the main symptom demonstrated significantly less abnormalities in VTI value. In men with cough as their main complaint, significantly less MDVP abnormalities were found in Jita, Jitt, RAP, PPQ, and sPPQ parameters. CONCLUSIONS: The comparison of voice perceptual assessment in patients with GERD related dysphonia or chronic cough revealed no differences between analyzed groups. In objective voice analysis, the latter group presented lower degree of hoarseness in Yanagihara's scale. In objective MDVP analysis, the chronic cough group presented lower degree of abnormalities only in one of the noise related parameters in females and five frequency perturbation parameters in males. PMID- 25283318 TI - Sensitivity evaluation in air and water caloric stimulation of the vestibular organs using videonystagmography. AB - INTRODUCTION: The aim of the study was to compare air and water caloric stimulation of the vestibular organs using videonystagmography (VNG). MATERIAL AND METHODS: The study covered 18 women aged 21-63 and 11 men aged 21-74 years hospitalized at the ENT, without complaints for vertigo and/or balance disorders. The alternate binaural bithermal caloric test with cool 30 degrees C and warm 44 degrees C air or water irrigations (after 2h interval for the recordings) with the use of VNG was done. RESULTS: All parameters of air and water vestibular caloric stimulations, assessed in the VNG, differed significantly but were within the normal range. The research showed a statistically significant difference between canal paresis but only for the left ear at 30 degrees C and 44 degrees C. Absolute directional preponderance, relative directional preponderance, vestibular excitability, slow component velocity, frequency were different statistically for both ears at both temperatures. CONCLUSIONS: Our study showed that both air and water caloric stimulations were able to distinguish physiological and impaired vestibular function. The obtained results showed statistically higher response for water than air stimulation. PMID- 25283319 TI - [Operation treatment results of laryngeal cancer in different types of partial laryngectomy based on own material]. AB - THE AIM: of the study was to evaluate the oncological results of laryngeal cancer treatment performed in the Laryngology University Ward in Zabrze in the years 1990-2000, depending on the type of partial surgery applied. MATERIALS AND METHODS: Retrospective clinical material includes 209 patients in whom surgery was a primary treatment method. No distant metastases (M1) or another malignant cancer were found. In all 209 patients the squamous cell carcinoma of various degree of malignancy (G1-G3) was found. The most common operation in the analyzed group was a chordectomy - 83 surgeries (40%), next, vertical partial laryngectomies - 38 (18%), horizontal glottis surgeries - 28 (13%). In 79 patients (38%) partial laryngectomy was complemented with a nodal operation. The median of the observation period was 9 years. Local recurrence, nodal recurrence and distant metastasis are rated as treatment failure. Treatment effectiveness was evaluated with relation to overall survival, disease-free survival, cause specific survival and local control. All the above-mentioned parameters were analyzed with the updated percentages method. The level of statistical significance was assumed to be p<=0.05. RESULTS: The best oncological results were observed after vertical operations. In the vertical operations group the most favourable oncological results were noted after chordectomy. 83% overall survivals, 82% disease-free survivals, 93% cause specific survivals and 96% local controls in the 5-year observation. On the other hand, the least favourable treatment results were observed after 3/4 subtotal partial operation, after horizontal supraglottic operation and after reconstruction operation with CHP. Statistically significant differences in treatment results between the groups of patients after various types of partial operations were found in relation to local controls and disease-free survivals. PMID- 25283320 TI - [Odontogenic inflammations of head and neck area treated in the Department of Otolaryngology in St. Lukasz Regional Hospital - five years observation]. AB - INTRODUCTION: In the ethology of inflammations within the head and neck area, odontogenic ethology still plays an important role. Early recognition, diagnosis and management of odontogenic infections are requisites for avoiding or minimizing the development of potential complications. THE AIM OF THE STUDY: The aim of this study was to retrospectively analyze the clinical presentation, surgical management and cost implications of patients treated for odontogenic inflammations of head and neck area at the Department of Otolaryngology in the Regional Hospital in Tarnow in last 5 years. MATERIALS AND METHODS: The study was based on medical documentations of 65 patients, 34 males and 31 females between the age of 16-83 years. RESULTS: Despite common accessibility of wholesome education and dental prevention, a lot of patients disregard their disorders. That's why treatment of odontogenic inflammations is often difficult and prolonged. The authors reveal a cost burden in a public health care as a result of odontogenic inflammations. PMID- 25283321 TI - [The healing process of tympanic membrane perforations in rats]. AB - INTRODUCTION: Tympanic membrane (TM) perforations are commonly seen in clinical practice as a result of trauma or in the course of otitis media. The TM is a unique structure suspended in air which makes its healing processes different than in the skin wounds. The aim of the study was otoscopical and histological evaluation of the rat's TM healing process. MATERIAL AND METHODS: 56 male Wistar rats were used for the study. Fifty of them had TMs perforated bilaterally using CO2 laser, additional 6 served as a controls. The animals were sacrificed on either day 1, 2, 3, 6 and 10 post injury. Process of healing was assessed otoscopicaly, subsequently TM were dissected and processed for histological evaluation. RESULTS: At day 6 after perforation half and on day 10 all of TM were healed. On the first day, in histological evaluation, focal thickening of the epithelial layer was observed at some distance from the edge of perforation, on the side of annulus. On the following day proliferation of epithelium covering outer surface of TM on the side of the malleus handle and annulus was clearly visible. An eosinophilic mass containing macrophages and granulocytes was seen in front of the migrating epithelium. On day 3-6 migrating epithelium reached the edge of perforation. Proliferation of the connective tissue layer followed the epithelium. CONCLUSIONS: The present results indicate that the squamous epithelium covering the outer surface of TM constitutes the first layer which restores continuity of TM. The proliferation of the connective tissue occurs in the direct vicinity of the proliferating and migrating epithelium. PMID- 25283322 TI - [Inverted papilloma of the nose and paranasal sinuses in own material]. AB - INTRODUCTION: The aim of this work was to analyze the occurrence of inverted papilloma within the nose and paranasal sinuses, the extent of lesions and the clinical course in the patients who underwent endoscopic surgery. MATERIALS AND METHODS: Between the years of 2006-2012, at the Department of Otolaryngology and Laryngological Oncology, 2295 patients were subjected to surgery due to paranasal sinus diseases. The material was based on their past medical histories. The analysis includes the age and gender of the patients, the type of surgery, and results of histopathological examinations. A surgical procedure covered the paranasal sinuses with lesions diagnosed in CT. The qualified patients had inverted papilloma in histopathological results. RESULTS: Among 2295 patients who were operated because of chronic inflammatory changes, inverted papilloma was histopathologically diagnosed in 49 cases. In 16 patients with inverted papilloma, inflammatory changes were present on one side only, while in 33 cases inverted papilloma was confirmed histopathologically on one side. The analysis of age and gender of the study group showed that the highest occurrence of inverted papilloma was in patients over 50 years of age. In the majority of the studied cases, inverted papilloma spread in the middle nasal concha and the maxillary or ethmoid sinus. CONCLUSIONS: In surgery, the endoscopic technique allows for an effective removal of inverted papilloma from the nose and paranasal sinuses. According to the authors, endoscopy is the most valuable method for post operative monitoring of recurrent inverted papilloma. PMID- 25283323 TI - [Estimation of quality of voice after removal of neoplasms T1 and T2 of glottis with simultaneous reconstruction of vocal fold with pedunculated sterno-thyroid muscle flap]. AB - INTRODUCTION: In recent years there has been an increasing number of cases of cancer, including cancer of the larynx. The choice of treatment should be primarily dictated by the complete elimination of cancer, but from the point of view of the patient, an important factor to keep in mind, is the quality of the voice that will be created at the end of the therapeutic process. AIM: The aim of this study was to evaluate the voice quality of patients after partial surgery of the larynx with vocal fold reconstruction pedunculated sterno-thyroid muscle flap. MATERIALS AND METHODS: The study included 30 men aged 53-72 years who were treated at the Clinic of Otorhinolaryngology Department of Medical-Dental Medical University of Warsaw on account of cancer of the larynx, qualified according to the TNM classification T1 or T2. The radical removal of cancer was associated with resection of one vocal fold, laryngeal pouches and ventricular fold. In 15 patients, included to the group I at the end of phase oncology surgery, a reconstruction of "vocal fold" pedunculated sterno-thyroid muscle flap were performed simultaneously. The group II consisted of 15 patients who underwent surgery that removed only the cancerous lesions. Impact assessments arising after surgery of voice disorders on quality of life were made using the self-test failure of the voice (Voice Handicap Index in the Pruszewicz modification). The nature of the created voice was studied using GRBAS scale. All patients performed the laryngostroboscope examination. With "IRIS" program, prepared by a team at Wroclaw University of Technology, the voice was recorded, and then was subjected to acoustic analysis. In addition, noise level and the maximum phonation time was measured. RESULTS: The results indicate that the patients of group I gained a better voice confirming the values of objective acoustic analysis. The assessment made by the scale GRBAS patients who supplemented the resulting loss after tumour removal, with much less hoarseness of voice, did not have the hyperkinesis and there was no puff character. They had the better flow of voice and phonation time of vowels "a" was much longer. The assessment of quality of life of patients in group I made in a test of the VHI was higher than in group II. The laryngostroboscope examination confirmed a good phonatory occlusion and a nearly regular, healthy vocal fold vibration in patients who had received flap of muscle. CONCLUSIONS: Evaluation of the quality of voice after removing the tumor multiplicity in the glottis with simultaneous reconstruction "vocal fold" has confirmed that this is a very good surgical technique, which allows radically curing cancer for the simultaneous preservation of a good voice. The operation has limited indications for radiotherapy because of the desire to preserve the phonatory function of the larynx, and thus avoids the negative effects of radiation. PMID- 25283324 TI - Radiological quiz. Sudden sensorineural hearing loss due to multiple sclerosis. AB - OBJECTIVE: A case with sudden sensorineural hearing loss (SSNHL) owing to multiple sclerosis (MS) who had clinical and dramatic radiological improvement just after medical therapy was reported in this article. METHOD: Case report and review of related literature. RESULTS: A 22-year-old female patient with MS related SSNHL was presented in this article. Magnetic resonance imaging (MRI) revealed an MS plaque localized at pons extending from right cochlear nucleus to proximal part of the right cochlear nerve. Most dramatic recovery was present in the 5th day control MRI, where the plaque located on pons disappeared completely. On the 10th day control audiogram hearing recovery was observed and pure tone audiogram levels were almost normal. CONCLUSION: Sudden sensorineural hearing loss owing to MS is seen more common than expected. It has good prognosis. Magnetic resonance imaging is also thought to have an important role in diagnosis and treatment efficacy of SSNHL owing to MS. PMID- 25283325 TI - Basaloid squamous cell carcinoma of the oropharynx: comparison of two cases and review of the literature. AB - We describe a rare case of BSCC in the retromolar trigone with only 3 other cases in the literature and also compare the differences between 2 cases of BSCC in terms of presentation and progression. The first patient had a markedly slower progression with painful retromolar trigone swelling over 4 months without nodal metastases. In contrast, the second patient gave a 2-week history of neck swelling with nodal involvement, indicating extremely rapid progression. Our management was tailored accordingly with the first patient undergoing intraoral excision of tumour and adjuvant radiotherapy while the other had bilateral neck dissection with postoperative chemoradiotherapy. Both patients achieved good outcome and are free from disease. PMID- 25283326 TI - Contrasting radiological presentation of cervical sympathetic chain schwannoma: case series of two cases. AB - Splaying of carotid bifurcation on imaging, known as Lyre sign, is seen characteristically in carotid body tumors. Is positive Lyre sign always confirmatory of carotid body tumor? Here we discuss two cases of cervical sympathetic chain schwannoma. The first case presented radiologically as an enhancing lesion with splaying of external carotid artery and internal carotid artery (positive Lyre sign) and misled us to the diagnosis of carotid body tumor. The second case presented as an enhancing lesion causing anterior displacement of external carotid artery and internal carotid artery (negative Lyre sign). Both lesions were confirmed as cervical sympathetic schwannoma. Post-operatively both patients developed Horner's syndrome. Lyre sign is not always confirmatory of carotid body tumor. PMID- 25283327 TI - Postauricular advancement fascio-cutaneo-periosteal flap for closure of mastoid cutaneous fistula. AB - BACKGROUND: Postauricular cutaneous mastoid fistula (PCMF) is a rare complication of chronic suppurative otitis media, may also complicate ear surgery and, very rarely, has been reported to complicate congenital cholesteatoma. Few authors have given descriptions of techniques of closure, with majority agreeing on the difficulty in managing such fistula due to the necrotic nature of the margin. SETTING: A tertiary care urban referral hospital in a developing economy. METHODOLOGY: A new technique of closure of PCMF is described. This technique utilizes the postauricular fascio-cutaneo-periosteal advancement flap with Burow's triangles following excision of the fistula margin. Details of this technique are described. RESULTS: Two women with cholesteatoma, aged 33 and 41 years, were successfully managed using this technique. The first case was diagnosed with right ear cholesteatoma with automastoidectomy and persistent discharging cutaneous mastoid fistula and had completion of canal wall-down mastoidectomy with postoperative cleaning of the mastoid cavity. The mastoid cutaneous fistula persisted postoperative despite conservative treatment and was treated using this technique 14 months postsurgery with successful outcome. The second case with left attic cholesteatoma extending to the mastoid antrum had canal wall-up mastoidectomy with limited atticotomy, but developed persistent mastoid cutaneous fistula 4 months postoperative and was treated with this technique. She had delayed wound healing but the fistula eventually closed. Both cases have been followed up for 24 and 18 months respectively with no recurrence. CONCLUSION: Postauricular advancement flap is effective for closure of persistent cutaneous mastoid fistula. PMID- 25283329 TI - Involvement of de novo ceramide synthesis in pro-inflammatory adipokine secretion and adipocyte-macrophage interaction. AB - Interaction between adipocytes and macrophages has been suggested to play a central role in the pathogenesis of obesity. Ceramide, a sphingolipid de novo synthesized from palmitate, is known to stimulate pro-inflammatory cytokine secretion from multiple types of cells. To clarify whether de novo synthesized ceramide contributes to cytokine dysregulation in adipocytes and macrophages, we observed cytokine secretion in mature 3T3-L1 adipocytes (L1) and RAW264.7 macrophages (RAW) cultured alone or co-cultured under the suppression of de novo ceramide synthesis. Palmitate enhanced ceramide accumulation and stimulated the expression and secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in L1. The suppression of serine-palmitoyl transferase, a rate limiting enzyme of de novo ceramide synthesis, by myriocin or siRNA attenuated those palmitate-induced alterations, and a ceramide synthase inhibitor fumonisin B1 showed similar results. In contrast, the inhibitor of sphingosine kinase or a membrane-permeable ceramide analogue augmented the cytokine secretion. Myriocin effects on the palmitate-induced changes were not abrogated by toll-like receptor 4 blockade. Although palmitate stimulated RAW to secrete tumor necrosis factor alpha (TNF-alpha), it did not significantly increase ceramide content, and neither myriocin nor fumonisin B1 attenuated the TNF-alpha hypersecretion. The co culture of L1 with RAW markedly augmented IL-6 and MCP-1 levels in media. Myriocin or fumonisin B1 significantly lowered these cytokine levels and suppressed the gene expression of TNF-alpha and MCP-1 in RAW and of IL-6 and MCP 1 in L1. In conclusion, de novo synthesized ceramide partially mediates the palmitate effects on pro-inflammatory adipokines and is possibly involved in the interaction with macrophages. PMID- 25283328 TI - Reduced signaling of PI3K-Akt and RAS-MAPK pathways is the key target for weight loss-induced cancer prevention by dietary calorie restriction and/or physical activity. AB - Weight control through either dietary calorie restriction (DCR) or exercise has been associated with cancer prevention in animal models. However, the underlying mechanisms are not fully defined. Bioinformatics using genomics, proteomics and lipidomics was employed to elucidate the molecular targets of weight control in a mouse skin cancer model. SENCAR mice were randomly assigned into four groups for 10 weeks: ad-libitum-fed sedentary control, ad-libitum-fed exercise (AE), exercise but pair-fed isocaloric amount of control (PE) and 20% DCR. Two hours after topical TPA treatment, skin epidermis was analyzed by Affymetrix for gene expression, DIGE for proteomics and lipidomics for phospholipids. Body weights were significantly reduced in both DCR and PE but not AE mice versus the control. Among 39,000 transcripts, 411, 67 and 110 genes were significantly changed in DCR, PE and AE, respectively. The expression of genes relevant to PI3K-Akt and Ras-MAPK signaling was effectively reduced by DCR and PE but not AE as measured through GenMAPP software. Proteomics analysis identified ~120 proteins, with 27 proteins significantly changed by DCR, including up-regulated apolipoprotein A-1, a key antioxidant protein that decreases Ras-MAPK activity. Of the total 338 phospholipids analyzed by lipidomics, 57 decreased by PE including 5 phophatidylinositol species that serve as PI3K substrates. Although a full impact has not been determined yet, it appears that the reduction of both Ras-MAPK and PI3K-Akt signaling pathways is a cancer preventive target that has been consistently demonstrated by three bioinformatics approaches. PMID- 25283331 TI - Mitochondrial swinger replication: DNA replication systematically exchanging nucleotides and short 16S ribosomal DNA swinger inserts. AB - Assuming systematic exchanges between nucleotides (swinger RNAs) resolves genomic 'parenthood' of some orphan mitochondrial transcripts. Twenty-three different systematic nucleotide exchanges (bijective transformations) exist. Similarities between transcription and replication suggest occurrence of swinger DNA. GenBank searches for swinger DNA matching the 23 swinger versions of human and mouse mitogenomes detect only vertebrate mitochondrial swinger DNA for swinger type AT+CG (from five different studies, 149 sequences) matching three human and mouse mitochondrial genes: 12S and 16S ribosomal RNAs, and cytochrome oxidase subunit I. Exchange A<->T+C<->G conserves self-hybridization properties, putatively explaining swinger biases for rDNA, against protein coding genes. Twenty percent of the regular human mitochondrial 16S rDNA consists of short swinger repeats (from 13 exchanges). Swinger repeats could originate from recombinations between regular and swinger DNA: duplicated mitochondrial genes of the parthenogenetic gecko Heteronotia binoei include fewer short A<->T+C<->G swinger repeats than non duplicated mitochondrial genomes of that species. Presumably, rare recombinations between female and male mitochondrial genes (and in parthenogenetic situations between duplicated genes), favors reverse-mutations of swinger repeat insertions, probably because most inserts affect negatively ribosomal function. Results show that swinger DNA exists, and indicate that swinger polymerization contributes to the genesis of genetic material and polymorphism. PMID- 25283330 TI - Phloretin promotes adipocyte differentiation in vitro and improves glucose homeostasis in vivo. AB - Adipocyte dysfunction is associated with many metabolic diseases such as obesity, insulin resistance and diabetes. Previous studies found that phloretin promotes 3T3-L1 cells differentiation, but the underlying mechanisms for phloretin's effects on adipogenesis remain unclear. In this study, we demonstrated that phloretin enhanced the lipid accumulation in porcine primary adipocytes in a time dependent manner. Furthermore, phloretin increased the utilization of glucose and nonesterified fatty acid, while it decreased the lactate output. Microarray analysis revealed that genes associated with peroxisome proliferator-activated receptor-gamma (PPARgamma), mitogen-activated protein kinase and insulin signaling pathways were altered in response to phloretin. We further confirmed that phloretin enhanced expression of PPARgamma, CAAT enhancer binding protein alpha (C/EBPalpha) and adipose-related genes, such as fatty acids translocase and fatty acid synthase. In addition, phloretin activated the Akt (Thr308) and extracellular signal-regulated kinase, and therefore, inactivated Akt targets protein. Wortmannin effectively blocked the effect of phloretin on Akt activity and the protein levels of PPARgamma, C/EBPalpha and fatty acid binding protein-4 (FABP4/aP2). Oral administration of 5 or 10 mg/kg phloretin to C57BL BKS-DB mice significantly decreased the serum glucose level and improved glucose tolerance. In conclusion, phloretin promotes the adipogenesis of porcine primary preadipocytes through Akt-associated signaling pathway. These findings suggested that phloretin might be able to increase insulin sensitivity and alleviate the metabolic diseases. PMID- 25283332 TI - Sequence-specific formation of d-amino acids in a monoclonal antibody during light exposure. AB - The photoirradiation of a monoclonal antibody 1 (mAb1) at lambda = 254 nm and lambdamax = 305 nm resulted in the sequence-specific generation of d-Val, d-Tyr, and potentially d-Ala and d-Arg, in the heavy chain sequence [95-101] YCARVVY. d Amino acid formation is most likely the product of reversible intermediary carbon centered radical formation at the (alpha)C-positions of the respective amino acids ((alpha)C(*) radicals) through the action of Cys thiyl radicals (CysS(*)). The latter can be generated photochemically either through direct homolysis of cystine or through photoinduced electron transfer from Trp and/or Tyr residues. The potential of mAb1 sequences to undergo epimerization was first evaluated through covalent H/D exchange during photoirradiation in D2O, and proteolytic peptides exhibiting deuterium incorporation were monitored by HPLC-MS/MS analysis. Subsequently, mAb1 was photoirradiated in H2O, and peptides, for which deuterium incorporation in D2O had been documented, were purified by HPLC and subjected to hydrolysis and amino acid analysis. Importantly, not all peptide sequences which incorporated deuterium during photoirradiation in D2O also exhibited photoinduced d-amino acid formation. For example, the heavy chain sequence [12-18] VQPGGSL showed significant deuterium incorporation during photoirradiation in D2O, but no photoinduced formation of d-amino acids was detected. Instead this sequence contained ca. 22% d-Val in both a photoirradiated and a control sample. This observation could indicate that d-Val may have been generated either during production and/or storage or during sample preparation. While sample preparation did not lead to the formation of d-Val or other d-amino acids in the control sample for the heavy chain sequence [95-101] YCARVVY, we may have to consider that during hydrolysis N-terminal residues (such as in VQPGGSL) may be more prone to epimerization. We conclude that the photoinduced, radical dependent formation of d-amino acids requires not only the intermediary formation of a (alpha)C(*) radical but also sufficient flexibility of the protein domain to allow both pro-chiral faces of the (alpha)C(*) radical to accept a hydrogen atom. PMID- 25283333 TI - Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus recover genotype cross-reactive neutralising antibodies to HCV during antiretroviral therapy. AB - When severely immunodeficient HIV/HCV co-infected patients are treated with antiretroviral therapy, it is important to know whether HCV-specific antibody responses recover and whether antibody profiles predict the occurrence of HCV associated immune restoration disease (IRD). In 50 HIV/HCV co-infected patients, we found that antibody reactivity and titres of neutralising antibodies (nAb) to JFH-1 (HCV genotype 2a virus) increased over 48 weeks of therapy. Development of HCV IRD was associated with elevated reactivity to JFH-1 before and during the first 12 weeks of therapy. Individual analyses of HCV IRD and non-HCV IRD patients revealed a lack of an association between nAb responses and HCV viral loads. These results showed that increased HCV-specific antibody levels during therapy were associated with CD4(+) T-cell recovery. Whilst genotype cross reactive antibody responses may identify co-infected patients at risk of developing HCV IRD, neutralising antibodies to JFH-1 were not involved in suppression of HCV replication during therapy. PMID- 25283334 TI - Evidence of type-II band alignment in III-nitride semiconductors: experimental and theoretical investigation for In 0.17 Al 0.83 N/GaN heterostructures. AB - Type-II band alignment structure is coveted in the design of photovoltaic devices and detectors, since it is beneficial for the transport of photogenerated carriers. Regrettably, for group-III-nitride wide bandgap semiconductors, all existing devices are limited to type-I heterostructures, owing to the unavailable of type-II ones. This seriously restricts the designing flexibility for optoelectronic devices and consequently the relevant performance of this material system. Here we show a brandnew type-II band alignment of the lattice-matched In 0.17 Al 0.83 N/GaN heterostructure from the perspective of both experimental observations and first-principle theoretical calculations. The band discontinuity is dominated by the conduction band offset DeltaEC, with a small contribution from the valence band offset DeltaEV which equals 0.1 eV (with E(AlInN(VBM) being above E(GaN)(VBM)). Our work may open up new prospects to realize high performance III-Nitrides optoelectronic devices based on type-II energy band engineering. PMID- 25283335 TI - Synthesis, characterization, and X-ray attenuation properties of ultrasmall BiOI nanoparticles: toward renal clearable particulate CT contrast agents. AB - A unique decelerated hydrolytic procedure is developed and reported here for the preparation of ultrasmall nanoparticles (NPs) of PVP-coated BiOI with a narrow size distribution, i.e., 2.8 +/- 0.5 nm. The crystal structure of this compound is determined by X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, and potential use of the PVP-coated ultrasmall BiOI NPs as a CT contrast agent are investigated. Because of the combined X-ray attenuation effect of bismuth and iodine, such NPs exhibit a CT value that is among the best of those of the inorganic nanoparticle-based CT contrast agents reported in the literature. PMID- 25283336 TI - ARTD1 (PARP1) activation and NAD(+) in DNA repair and cell death. AB - Nicotinamide adenine dinucleotide, NAD(+), is a small metabolite coenzyme that is essential for the progress of crucial cellular pathways including glycolysis, the tricarboxylic acid cycle (TCA) and mitochondrial respiration. These processes consume and produce both oxidative and reduced forms of NAD (NAD(+) and NADH). NAD(+) is also important for ADP(ribosyl)ation reactions mediated by the ADP ribosyltransferase enzymes (ARTDs) or deacetylation reactions catalyzed by the sirtuins (SIRTs) which use NAD(+) as a substrate. In this review, we highlight the significance of NAD(+) catabolism in DNA repair and cell death through its utilization by ARTDs and SIRTs. We summarize the current findings on the involvement of ARTD1 activity in DNA repair and most specifically its involvement in the trigger of cell death mediated by ARTD1 activation and energy depletion. By sharing the same substrate, the activities of ARTDs and SIRTs are tightly linked, are dependent on each other and are thereby involved in the same cellular processes that play an important role in cancer biology, inflammatory diseases and ischaemia/reperfusion. PMID- 25283338 TI - Synechococcus: 3 billion years of global dominance. AB - Cyanobacteria are among the most important primary producers on the Earth. However, the evolutionary forces driving cyanobacterial species diversity remain largely enigmatic due to both their distinction from macro-organisms and an undersampling of sequenced genomes. Thus, we present a new genome of a Synechococcus-like cyanobacterium from a novel evolutionary lineage. Further, we analyse all existing 16S rRNA sequences and genomes of Synechococcus-like cyanobacteria. Chronograms showed extremely polyphyletic relationships in Synechococcus, which has not been observed in any other cyanobacteria. Moreover, most Synechococcus lineages bifurcated after the Great Oxidation Event, including the most abundant marine picoplankton lineage. Quantification of horizontal gene transfer among 70 cyanobacterial genomes revealed significant differences among studied genomes. Horizontal gene transfer levels were not correlated with ecology, genome size or phenotype, but were correlated with the age of divergence. All findings were synthetized into a novel model of cyanobacterial evolution, characterized by serial convergence of the features, that is multicellularity and ecology. PMID- 25283337 TI - Cumulative associations between midlife health behaviors and physical functioning in early old age: a 17-year prospective cohort study. AB - OBJECTIVES: To examine cumulative associations between midlife health behaviors and walking speed and upper-limb strength in early old age. DESIGN: Prospective cohort study. SETTING: Whitehall II Study. PARTICIPANTS: Individuals (mean age 49.1 +/- 5.9 in 1991-93) with health behavior data for at least two of the three assessments (1991-93, 1997-99, 2002-04) and physical functioning measures in 2007 09 (mean age 65.9 +/- 5.9) (N = 5,671). MEASUREMENTS: A trained nurse assessed walking speed and upper-limb strength. Unhealthy behaviors were defined as current or recent smoking, nonmoderate alcohol consumption (abstinence or heavy drinking), fruit and vegetable consumption less than twice per day, and physical inactivity (<1 h/wk of moderate and <1 h/wk of vigorous physical activity). For each unhealthy behavior, a cumulative score was calculated as the number of times a person reported the behavior over the three assessments divided by 3. The score ranged between 0 (never) and 1 (all three times). RESULTS: In linear regression models adjusted for age, sex, education, marital status, and height, all unhealthy behaviors in 1991-93 were associated with slower walking speed in 2007 09, with differences ranging from 0.10 (nonmoderate alcohol consumption) to 0.25 (physical inactivity) of a standard deviation between participants with and without the unhealthy behavior (Pt-test <.001). For walking speed, the accumulation-of-risk model provided the best fit for unhealthy diet (beta for a 1 point increment in the low fruit and vegetable consumption score = -0.29, 95% confidence interval (CI) = -0.36 to -0.22) and physical inactivity (beta = -0.37, 95% CI = -0.45 to -0.29). For smoking and nonmoderate alcohol consumption, a cumulative effect was also observed, but partial F-tests did not suggest that it provided a better fit than models with behaviors in 1991-93, 1997-99, or 2002-04. All behavioral scores except smoking were associated with grip strength, but F tests supported the accumulation-of-risk hypothesis only for physical inactivity. CONCLUSION: These findings highlight the importance of duration of unhealthy behaviors, particularly for diet and physical activity, when examining associations with physical functioning. PMID- 25283339 TI - Presence of pharmaceuticals in benthic fauna living in a small stream affected by effluent from a municipal sewage treatment plant. AB - Aquatic organisms can be affected not only via polluted water but also via their food. In the present study, we examined bioaccumulation of seventy pharmaceuticals in two benthic organisms, Hydropsyche sp. and Erpobdella octoculata in a small stream affected by the effluent from a sewage treatment plant (STP) in Prachatice (South Bohemia region, Czech Republic). Furthermore, water samples from similar locations were analyzed for all seventy pharmaceuticals. In water samples from a control locality situated upstream of the STP, ten of the seventy pharmaceuticals were found with average total concentrations of 200 ng L(-1). In water samples collected at STP-affected sites (downstream the STP's effluent), twenty-nine, twenty-seven and twenty-nine pharmaceuticals were determined at average total concentrations of 2000, 2100 and 1700 ng L(-1), respectively. Six of the seventy pharmaceuticals (azithromycin, citalopram, clarithromycin, clotrimazole, sertraline, and verapamil) were found in Hydropsyche. Four pharmaceuticals (clotrimazole, diclofenac, sertraline, and valsartan) were detected in Erpobdella. Using evaluation criterion bioconcentration factor (BCF) is higher than 2000 we can assign azithromycin and sertraline as bioaccumulative pharmaceuticals. Even pharmaceuticals present at low levels in water were found in benthic organisms at relatively high concentrations (up to 85 ng g(-1) w.w. for azithromycin). Consequently, the uptake of pharmaceuticals via the food web could be an important exposure pathway for the wild fish population. PMID- 25283340 TI - Protein kinase Cdelta promotes proliferation and induces malignant transformation in skeletal muscle. AB - In this paper, we investigated the isoform-specific roles of certain protein kinase C (PKC) isoforms in the regulation of skeletal muscle growth. Here, we provide the first intriguing functional evidence that nPKCdelta (originally described as an inhibitor of proliferation in various cells types) is a key player in promoting both in vitro and in vivo skeletal muscle growth. Recombinant overexpression of a constitutively active nPKCdelta in C2C12 myoblast increased proliferation and inhibited differentiation. Conversely, overexpression of kinase negative mutant of nPKCdelta (DN-nPKCdelta) markedly inhibited cell growth. Moreover, overexpression of nPKCdelta also stimulated in vivo tumour growth and induced malignant transformation in immunodeficient (SCID) mice whereas that of DN-nPKCdelta suppressed tumour formation. The role of nPKCdelta in the formation of rhabdomyosarcoma was also investigated where recombinant overexpression of nPKCdelta in human rhabdomyosarcoma RD cells also increased cell proliferation and enhanced tumour formation in mouse xenografts. The other isoforms investigated (PKCalpha, beta, epsilon) exerted only minor (mostly growth inhibitory) effects in skeletal muscle cells. Collectively, our data introduce nPKCdelta as a novel growth-promoting molecule in skeletal muscles and invite further trials to exploit its therapeutic potential in the treatment of skeletal muscle malignancies. PMID- 25283341 TI - Dopaminergic activity and behaviour in SOCS2 transgenic mice: Revealing a potential drug target for schizophrenia. AB - Alterations in immune function have been implicated in the aetiopathogenesis of schizophrenia. Specifically, the induction of inflammatory cytokines, which are important immunological factors in infection or inflammation, may be critical factors altering the normal course of brain development and increasing schizophrenia risk. Suppressor of cytokine signalling 2 (SOCS2) can negatively regulate the signalling of cytokines. The present study aimed to determine the behavioural phenotype of transgenic mice over-expressing SOCS2 (SOCS2 Tg) in paradigms of relevance to schizophrenia. Both male and female SOCS2 Tg mice displayed reduced locomotor hyperactivity after the administration of the dopamine releaser, amphetamine, compared to wildtype controls (WT). However, only male SOCS2 Tg mice showed enhanced prepulse inhibition compared to WT. Dopamine D2 receptors mRNA expression was reduced and dopamine transporter mRNA expression was increased in the nucleus accumbens of female, but not male, SOCS2 Tg mice, compared to WT. The role of hyperdopaminergia has long been implicated in the aetiology of schizophrenia. This study shows that over-expression of SOCS2 reduces the psychostimulant effects of amphetamine, enhances PPI, and alters mesolimbic dopaminergic activity. SOCS2 may provide a novel target in the development of treatments for schizophrenia. PMID- 25283343 TI - Advanced glycation end products-induced chondrocyte apoptosis through mitochondrial dysfunction in cultured rabbit chondrocyte. AB - Advanced glycation end products (AGEs) are an important mediator in osteoarthritis (OA) and cause apoptosis in articular chondrocytes. Mitochondrial function is involved in modulating apoptosis of articular chondrocytes. This study was performed to investigate the mechanism of AGEs-induced chondrocyte apoptosis. The ratio of apoptotic cell and cell viability was surveyed by TUNEL, MTT,LDH release assay. The reactive oxygen species was determined by the fluorescent probe 2', 7'-dichlorofluorescein diacetate. The expression of caspase 3 and cytochrome c was detected by Western blot. The mitochondrial membrane potential (?Psim) was evaluated by rhodamine-123 fluorescence. We found that AGEs induced apoptosis in primary rabbit chondrocytes, upregulation of ROS production, cytochrome c, and caspase-3 levels. Simultaneously, AGEs decreases the levels of ?Psim and ATP production; however, the antibody of AGEs (sRAGE) and antioxidant-N acetylcys-teine (NAC) significantly reversed AGEs-induced the above damage thus to protect the cells from apoptosis. These observations suggested that the mechanism of AGEs-induced chondrocyte apoptosis was primarily via ROS production and mitochondria-mediated caspase-3 activation. PMID- 25283342 TI - Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder. AB - BACKGROUND: Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms. METHODS: Twenty-four subjects (ages 13 17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms. RESULTS: At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms. DISCUSSION: Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder. PMID- 25283345 TI - An update on anal neoplasia. AB - Although anal cancer remains a relatively uncommon tumour its frequency is rising, especially in high-risk groups. It is now well recognized that anal squamous cell carcinoma, the largely predominant tumour type, shares many similarities with cancer of the uterine cervix, with a major role for oncogenic human papilloma viruses in both tumours. Anal squamous precancerous lesions have now to be classified with the same criteria and terminology as their cervical counterparts, by using the Lower Anogenital Squamous Terminology (LAST) proposal. Only p16 protein is a useful marker in this setting at the present time. As most cases of anal cancer are treated by non-surgical procedures, pathology has a limited role in the staging of the disease, except for early lesions treated by local excision, and when the sentinel lymph node procedure is undertaken that is still under evaluation. A variety of other tumour types can occur more rarely, with difficult diagnostic issues, solved in most cases by immunohistochemistry. PMID- 25283344 TI - Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity squamous carcinoma: a preliminary study. AB - OBJECTIVES: Tumor infiltrating lymphocytes (TILs) in the microenvironment reflect may tumor biology and predict outcome. We previously demonstrated that infiltrates of CD4, CD8, and FoxP3 positive lymphocytes were associated with HPV status and survival in oropharyngeal cancers. To determine if TILs were of prognostic importance in oral cancer, TIL levels were evaluated retrospectively in 52 oral cancer patients treated with surgery and correlations with outcome determined. METHODS: Complete TIL and clinical data were available for 39 patients. Levels of CD4, CD8, FoxP3 (Treg), CD68 and NK cells were assessed by immunohistochemistry in tumor cores on a tissue microarray. Associations with clinical variables, tobacco and alcohol use and histologic features were assessed using Spearman correlation coefficient and the non-parametric Kruskal-Wallis testing. Time-to-event outcomes were determined using univariate and multivariate Cox models. Median follow up was 60 months. RESULTS: The ratio of CD4/CD8 (p=.01) and CD8 infiltrates (p=.05) were associated with tumor recurrence but not overall survival. Lower CD4 infiltrates were associated with alcohol use (p=.005) and poor tumor differentiation (p=.02). Interestingly, higher levels of CD68+ macrophages were found associated with positive nodes (p=.06) and poorer overall survival (p=.07). Overall and DSS survival were significantly shorter for patients with positive nodes, extracapsular spread, or perineural invasion. CONCLUSION: Infiltrating immune cell levels in oral cavity cancer appear influenced by health behaviors and tumor characteristics. In contrast to oropharynx cancer, infiltrates of CD68 positive tumor associated macrophages may contribute to metastatic behavior and outcome in advanced oral cavity carcinoma. PMID- 25283346 TI - The transgenerational effects of heat stress in the nematode Caenorhabditis remanei are negative and rapidly eliminated under direct selection for increased stress resistance in larvae. AB - Parents encountering stress environments can influence the phenotype of their offspring in a form of transgenerational phenotypic plasticity that has the potential to be adaptive if offspring are thereby better able to deal with future stressors. Here, we test for the existence of anticipatory parental effects in the heat stress response in the highly polymorphic nematode Caenorhabditis remanei. Rather providing an anticipatory response, parents subject to a prior heat stress actually produce offspring that are less able to survive a severe heat shock. Selection on heat shock resistance within the larvae via experimental evolution leads to a loss of sensitivity (robustness) to environmental variation during both the parental and larval periods. Whole genome transcriptional analysis of both ancestor and selected lines shows that there is weak correspondence between genetic pathways induced via temperature shifts during parental and larval periods. Parental effects can evolve very rapidly via selection acting directly on offspring. PMID- 25283347 TI - Segmentation and quantification of blood vessels for OCT-based micro-angiograms using hybrid shape/intensity compounding. AB - Optical coherence tomography (OCT) based microangiography is capable of visualizing 3D functional blood vessel networks within microcirculatory tissue beds in vivo. To provide the quantitative information of vasculature from the microangiograms such as vessel diameter and morphology, it is necessary to develop efficient vessel segmentation algorithms. In this paper, we propose to develop a hybrid Hessian/intensity based method to segment and quantify shape and diameter of the blood vessels innervating capillary beds that are imaged by functional OCT in vivo. The proposed method utilizes multi-scale Hessian filters to segment tubular structures such as blood vessels, but compounded by the intensity-based segmentation method to mitigate the limitations of Hessian filters' sensitivity to the selection of scale parameters. Such compounding segmentation scheme takes advantage of the morphological nature of Hessian filters while correcting for the scale parameter selection by intensity-based segmentation. The proposed algorithm is tested on a wound healing model and its performance of segmentation vessels is quantified by a publicly available manual segmentation dataset. We believe that this method will play an important role in the quantification of micro-angiograms for microcirculation research in ophthalmology and diagnosing retinal eye diseases involved with microcirculation. PMID- 25283349 TI - Inspection of feasible calibration conditions for UV radiometer detectors with the KI/KIO3 actinometer. AB - UV radiometers are widely employed for irradiance measurements, but their periodical calibrations not only induce an extra cost but also are time consuming. In this study, the KI/KIO3 actinometer was applied to calibrate UV radiometer detectors at 254 nm with a quasi-collimated beam apparatus equipped with a low-pressure UV lamp, and feasible calibration conditions were identified. Results indicate that a washer constraining the UV light was indispensable, while the size (10 or 50 mL) of a beaker containing the actinometer solution had little influence when a proper washer was used. The absorption or reflection of UV light by the internal beaker wall led to an underestimation or overestimation of the irradiance determined by the KI/KIO3 actinometer, respectively. The proper range of the washer internal diameter could be obtained via mathematical analysis. A radiometer with a longer service time showed a greater calibration factor. To minimize the interference from the inner wall reflection of the collimating tube, calibrations should be conducted at positions far enough away from the tube bottom. This study demonstrates that after the feasible calibration conditions are identified, the KI/KIO3 actinometer can be applied readily to calibrate UV radiometer detectors at 254 nm. PMID- 25283348 TI - Hyperglycemia and redox status regulate RUNX2 DNA-binding and an angiogenic phenotype in endothelial cells. AB - Angiogenesis is regulated by hyperglycemic conditions, which can induce cellular stress responses, reactive oxygen species (ROS), and anti-oxidant defenses that modulate intracellular signaling to prevent oxidative damage. The RUNX2 DNA binding transcription factor is activated by a glucose-mediated intracellular pathway, plays an important role in endothelial cell (EC) function and angiogenesis, and is a target of oxidative stress. RUNX2 DNA-binding and EC differentiation in response to glucose were conserved in ECs from different tissues and inhibited by hyperglycemia, which stimulated ROS production through the aldose reductase glucose-utilization pathway. Furthermore, the redox status of cysteine and methionine residues regulated RUNX2 DNA-binding and reversal of oxidative inhibition was consistent with an endogenous Methionine sulfoxide reductase-A (MsrA) activity. Low molecular weight MsrA substrates and sulfoxide scavengers were potent inhibitors of RUNX2 DNA binding in the absence of oxidative stress, but acted as antioxidants to increase DNA binding in the presence of oxidants. MsrA was associated with RUNX2:DNA complexes, as measured by a sensitive, quantitative DNA-binding ELISA. The related RUNX2 protein family member, RUNX1, which contains an identical DNA-binding domain, was a catalytic substrate of recombinant MsrA. These findings define novel redox pathways involving aldose reductase and MsrA that regulate RUNX2 transcription factor activity and biological function in ECs. Targeting of these pathways could result in more effective strategies to alleviate the vascular dysfunction associated with diabetes or cancer. PMID- 25283351 TI - Knee extensor and flexor muscle power explains stair ascension time in patients with unilateral late-stage knee osteoarthritis: a cross-sectional study. AB - OBJECTIVES: To determine the extent of asymmetrical deficits in knee extensor and flexor muscles, and to examine whether asymmetrical muscle deficits are associated with mobility limitations in persons with late-stage knee osteoarthritis (OA). DESIGN: Cross-sectional. SETTING: Research laboratory. PARTICIPANTS: A clinical sample (N=56; age range, 50-75y) of eligible persons with late-stage knee OA awaiting knee replacement. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Knee extensor and flexor power and torque assessed isokinetically; thigh muscle cross-sectional area (CSA) assessed by computed tomography; mobility limitation assessed by walking speed and stair ascension time; and pain assessed with the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire. RESULTS: The asymmetrical deficits in knee extensor and flexor power and torque were between 18% and 29% (P<.001). Regarding the thigh muscle CSA, the asymmetrical deficit was 4% (P<.001). Larger asymmetrical knee extensor power deficits and weaker knee extensor and flexor power on the contralateral side were associated with slower stair ascension times. Moreover, weaker knee extensor and flexor power on the ipsilateral side were associated with slower stair ascension times. Greater knee pain in the OA joint was independently associated with slower stair ascending time in both models. CONCLUSIONS: The knee extensor and flexor muscle power of both the ipsilateral and contralateral sides and the pain in the OA knee were independently associated with stair ascension times. These results highlight the importance of assessing muscle power on both sides and knee pain in the prevention of mobility limitations in patients with knee OA. PMID- 25283350 TI - Safety of primed repetitive transcranial magnetic stimulation and modified constraint-induced movement therapy in a randomized controlled trial in pediatric hemiparesis. AB - OBJECTIVE: To investigate the safety of combining a 6-Hz primed low-frequency repetitive transcranial magnetic stimulation (rTMS) intervention in the contralesional hemisphere with a modified constraint-induced movement therapy (mCIMT) program in children with congenital hemiparesis. DESIGN: Phase 1 randomized, double-blinded, placebo-controlled pretest/posttest trial. SETTING: University academic facility and pediatric specialty hospital. PARTICIPANTS: Subjects (N = 19; age range, 8-17 y) with congenital hemiparesis caused by ischemic stroke or periventricular leukomalacia. No subject withdrew because of adverse events. All subjects included completed the study. INTERVENTIONS: Subjects were randomized to 1 of 2 groups: either real rTMS plus mCIMT (n = 10) or sham rTMS plus mCIMT (n = 9). MAIN OUTCOME MEASURES: Adverse events, physician assessment, ipsilateral hand function, stereognosis, cognitive function, subject report of symptoms assessment, and subject questionnaire. RESULTS: No major adverse events occurred. Minor adverse events were found in both groups. The most common events were headaches (real: 50%, sham: 89%; P = .14) and cast irritation (real: 30%, sham: 44%; P = .65). No differences between groups in secondary cognitive and unaffected hand motor measures were found. CONCLUSIONS: Primed rTMS can be used safely with mCIMT in congenital hemiparesis. We provide new information on the use of rTMS in combination with mCIMT in children. These findings could be useful in research and future clinical applications in advancing function in congenital hemiparesis. PMID- 25283352 TI - Novel interventions for HIV self-management in African American women: a systematic review of mHealth interventions. AB - The purpose of this systematic review was to assess the quality of interventions using mobile health (mHealth) technology being developed for and trialed with HIV infected African American (AA) women. We aimed to assess rigor and to ascertain if these interventions have been expanded to include the broad domain of self management. After an extensive search using the PRISMA approach and reviewing 450 records (411 published studies and 39 ongoing trials at clinicaltrials.gov), we found little completed research that tested mHealth HIV self-management interventions for AA women. At clinicaltrials.gov, we found several mHealth HIV intervention studies designed for women in general, forecasting a promising future. However, most studies were exploratory in nature and focused on a single narrow outcome, such as medication adherence. Given that cultural adaptation is the key to successfully implementing any effective self-management intervention, culturally relevant, gender-specific mHealth interventions focusing on HIV infected AA women are warranted for the future. PMID- 25283353 TI - Understanding HIV testing behaviors of minority adolescents: a health behavior model analysis. AB - Adolescents and young adults are the fastest-growing age group of people living with HIV infection in the United States. Yet many adolescents and young adults with high-risk behaviors for HIV are unaware of their HIV status and have never had an HIV test. The purpose of our work was to understand minority adolescents' beliefs, attitudes, and behaviors related to HIV testing. We conducted focus group sessions with 41 minority adolescents to assess their perceptions about HIV testing. We triangulated the findings from our focus group data with data from a 125-question survey. Analysis of focus group data demonstrated that Perceived Susceptibility, Perceived Severity, Perceived Benefits, Perceived Barriers, and Cues to Action influenced adolescents' decisions to get tested for HIV. Findings support the need to design interventions that address adolescents' perceived barriers to HIV testing and increase access to and knowledge about HIV testing. PMID- 25283354 TI - Practical management of sunitinib toxicities in the treatment of pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (pNETs) are infrequent malignancies which manifest in both functional (hormone-secreting) and more commonly non-functional (non-secreting) forms. The oral multitargeted tyrosine kinase inhibitor sunitinib and mammalian target of rapamycin (mTOR) inhibitor everolimus are approved as targeted therapies for patients with well-differentiated, non-resectable disease and evidence of disease progression. The recent approval of sunitinib for the management of advanced pNET is based on a continuous daily dosing (CDD) schedule that differs from the intermittent 4weeks on/2weeks off (4/2) schedule approved for sunitinib in advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Therefore, although clinicians may be familiar with therapy management approaches for sunitinib in advanced RCC and GIST, there is less available experience for the management of patients with a CDD schedule. Here, we discuss the similarities and differences in the treatment of pNET with sunitinib compared with advanced RCC and GIST. In particular, we focus on the occurrence and management of sunitinib-related toxicity in patients with pNET by drawing on experience in these other malignancies. We aim to provide a relevant and useful guide for clinicians treating patients with pNET covering the management of events such as fatigue, mucositis, hand-foot syndrome, and hypertension. PMID- 25283355 TI - An acute injection of corticosterone increases thyrotrophin-releasing hormone expression in the paraventricular nucleus of the hypothalamus but interferes with the rapid hypothalamus pituitary thyroid axis response to cold in male rats. AB - The activity of the hypothalamic-pituitary-thyroid (HPT) axis is rapidly adjusted by energy balance alterations. Glucocorticoids can interfere with this activity, although the timing of this interaction is unknown. In vitro studies indicate that, albeit incubation with either glucocorticoid receptor (GR) agonists or protein kinase A (PKA) activators enhances pro-thyrotrophin-releasing hormone (pro-TRH) transcription, co-incubation with both stimuli reduces this enhancement. In the present study, we used primary cultures of hypothalamic cells to test whether the order of these stimuli alters the cross-talk. We observed that a simultaneous or 1-h prior (but not later) activation of GR is necessary to inhibit the stimulatory effect of PKA activation on pro-TRH expression. We tested these in vitro results in the context of a physiological stimulus on the HPT axis in adult male rats. Cold exposure for 1 h enhanced pro-TRH mRNA expression in neurones of the hypophysiotrophic and rostral subdivisions of the paraventricular nucleus (PVN) of the hypothalamus, thyrotrophin (TSH) serum levels and deiodinase 2 (D2) activity in brown adipose tissue (BAT). An i.p. injection of corticosterone stimulated pro-TRH expression in the PVN of rats kept at ambient temperature, more pronouncedly in hypophysiotrophic neurones that no longer responded to cold exposure. In corticosterone-pretreated rats, the cold-induced increase in pro-TRH expression was detected only in the rostral PVN. Corticosterone blunted the increase in serum TSH levels and D2 activity in BAT produced by cold in vehicle-injected animals. Thus, increased serum corticosterone levels rapidly restrain cold stress-induced activation of TRH hypophysiotrophic neurones, which may contribute to changing energy expenditure. Interestingly, TRH neurones of the rostral PVN responded to both corticosterone and cold exposure with an amplified expression of pro-TRH mRNA, suggesting that these neurones integrate stress and temperature distinctly from the hypophysiotrophic neurones. PMID- 25283356 TI - Nanostructured donor-acceptor self assembly with improved photoconductivity. AB - Nanostructured supramolecular donor-acceptor assemblies were formed when an unsymmetrical N-substituted pyridine functionalized perylenebisimide (UPBI-Py) was complexed with oligo(p-phenylenevinylene) (OPVM-OH) complementarily functionalized with hydroxyl unit and polymerizable methacrylamide unit at the two termini. The resulting supramolecular complex [UPBI-Py (OPVM-OH)]1.0 upon polymerization by irradiation in the presence of photoinitiator formed well defined supramolecular polymeric nanostructures. Self-assembly studies using fluorescence emission from thin film samples showed that subtle structural changes occurred on the OPV donor moiety following polymerization. The 1:1 supramolecular complex showed red-shifted aggregate emission from both OPV (~500 nm) and PBI (~640 nm) units, whereas the OPV aggregate emission was replaced by intense monomeric emission (~430 nm) upon polymerizing the methacrylamide units on the OPVM-OH. The bulk structure was studied using wide-angle X-ray diffraction (WXRD). Complex formation resulted in distinct changes in the cell parameters of OPVM-OH. In contrast, a physical mixture of 1 mol each of OPVM-OH and UPBI-Py prepared by mixing the powdered solid samples together showed only a combination of reflections from both parent molecules. Thin film morphology of the 1:1 molecular complex as well as the supramolecular polymer complex showed uniform lamellar structures in the domain range <10 nm. The donor-acceptor supramolecular complex [UPBI-Py (OPVM-OH)]1.0 exhibited space charge limited current (SCLC) with a bulk mobility estimate of an order of magnitude higher accompanied by a higher photoconductivity yield compared to the pristine UPBI-Py. This is a very versatile method to obtain spatially defined organization of n and p-type semiconductor materials based on suitably functionalized donor and acceptor molecules resulting in improved photocurrent response using self-assembly. PMID- 25283359 TI - A ratiometric fluorescent probe for sensing HOCl based on a coumarin-rhodamine dyad. AB - We developed a ratiometric fluorescent probe for sensing HOCl based on coumarin and rhodamine acid that is directly used as a detection moiety. The probe shows high selectivity and sensitivity toward HOCl under best working conditions of myeloperoxidase by which HOCl can be generated from hydrogen peroxide and chloride. PMID- 25283357 TI - Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation. AB - Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascular (BV) disorder characterized by CM and fast flow BV lesions. Inactivating mutations of the RASA1 gene are the cause of CM-AVM in most cases. RASA1 is a GTPase-activating protein that acts as a negative regulator of the Ras small GTP-binding protein. In addition, RASA1 performs Ras-independent functions in intracellular signal transduction. Whether CM-AVM results from loss of an ability of RASA1 to regulate Ras or loss of a Ras-independent function of RASA1 is unknown. To address this, we generated Rasa1 knockin mice with an R780Q point mutation that abrogates RASA1 catalytic activity specifically. Homozygous Rasa1(R780Q/R780Q) mice showed the same severe BV abnormalities as Rasa1-null mice and died midgestation. This finding indicates that BV abnormalities in CM AVM develop as a result of loss of an ability of RASA1 to control Ras activation and not loss of a Ras-independent function of this molecule. More important, findings indicate that inhibition of Ras signaling is likely to represent an effective means of therapy for this disease. PMID- 25283360 TI - A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes. AB - The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis. PMID- 25283361 TI - An unusual cutaneous souvenir. PMID- 25283362 TI - Stand-alone anchored cage versus cage with plating for single-level anterior cervical discectomy and fusion: a prospective, randomized, controlled study with a 2-year follow-up. AB - To avoid complications associated with plating in anterior cervical discectomy and fusion (ACDF), stand-alone anchored PEEK cage was developed and favourable outcomes with a low rate of dysphasia have been described. The objective of this study was to compare the clinical and radiological outcomes of ACDF using a standalone anchored PEEK cage (PREVAIL; Medtronic Sofamor Danek, Memphis, TN) with those of a PEEK cage with plating in a prospective randomized manner. Fifty patients with single-level cervical radiculopathy were randomly assigned to a PREVAIL or a PEEK cage with plating. Following 3, 6, 12, and 24 months, clinical and radiological outcomes were assessed. The mean surgical time for the patients with a PREVAIL was significantly shorter than that for those with a PEEK cage with plating. The clinical outcomes evaluated by visual analogue scale for pain and the Odom's criteria were comparable between both the groups. Both the groups demonstrated the high fusion rate (92% in PREVAIL; 96% in PEEK cage with plating). The subsidence rate and the improvement of cervical alignment were comparable between both the groups. The incidence of adjacent-level ossification was significantly lower for patients with a PREVAIL than that for those with a PEEK cage with plating. The rate of dysphasia graded by the method of Bazaz and measurement of prevertebral soft tissue swelling indicated no significant differences between both the groups. Our prospective randomized study confirmed that stand-alone anchored PEEK cage is a valid alternative to plating in ACDF with a low rate of adjacent-level ossification. However, the potential to reduce the incidence of dysphasia was not confirmed. PMID- 25283363 TI - Association of Superoxide dismutases (SOD1 and SOD2) and Glutathione peroxidase 1 (GPx1) gene polymorphisms with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a metabolic disorder resulting from oxidative stress (OS), the root cause of insulin resistance, beta-cell dysfunction, and impaired glucose tolerance. Antioxidant enzymes play key roles in cellular defense and can be used as important biomarkers for T2DM. The present study was undertaken to evaluate three genetic polymorphisms viz. SOD1 + 35A/C, SOD2 + 47C/T, and GPx + 599C/T in 207 T2DM cases and 210 healthy controls from North India. DNA was extracted from blood samples and genotyping was done by PCR-RFLP. Genotypic/allelic frequencies and haplotype/gene-gene interaction analysis were performed using SPSS (version 15.0) and SHEsis (v. online). Except age, all other biochemical parameters showed highly significant association in T2DM cases (P < 0.001). In North Indian population, SOD1 + 35A/C variant was monomorphic. Genotype/allele frequencies of SOD2 + 47C/T polymorphism and carriage rate of 'C' allele showed significant association (p < 0.05, < 0.001; OR 2.434). Genotype/allele frequencies of GPx1 + 599C/T and carriage rate showed no association although the odds ratio of GPx1 'C' allele indicated a 1.362 times higher risk of T2DM. SOD2 'CT' and GPx1 'CC' genotypes showed maximum association with biochemical parameters. Haplotype/gene-gene interaction analysis in controls and cases showed that SOD2 + 47C/T and GPx1 + 599C/T were in linkage disequilibrium (D: 0.168; r(2): 0.10) and individuals with this combination had a 1.273 times higher risk [OR; CI (95%)] of developing T2DM. Thus, we conclude that it is essential to assess the combinatorial association of gene variants with T2DM in order to identify risk haplotypes in a population. PMID- 25283364 TI - Evaluation of intensity of artefacts in CBCT by radio-opacity of composite simulation models of implants in vitro. AB - OBJECTIVES: The aim was to compare the intensity of artefacts in CBCT images caused by different percentages of radio-opacifying material in composite simulation models of implants. Titanium and zirconia models of implants were used as a reference for the evaluation of the intensity of artefacts. METHODS: Seven different percentages of radio-opacifying BaAlSiO2 fillers were added to composite resin to fabricate seven step wedges and simulation models of implants. Titanium and zirconia simulation models of implants were also fabricated. Aluminium step wedge was used as a reference for the measurement of grey values in intraoral radiographs. Step wedges were exposed with a Planmeca Intra X-ray machine (Planmeca Oy, Helsinki, Finland). All composite, titanium and zirconia simulation models of implants were exposed with a SCANORA((r)) 3D dental X-ray machine (Soredex, Tuusula, Finland). Images and grey values were analysed with ImageJ software (National Institutes of Health, Bethesda, MD). To demonstrate possible artefacts between all the simulation models of implants, the images were also visually compared with each other using ImageJ software. RESULTS: Artefacts were clearly present in CBCT images caused by titanium and zirconia and when the composite material consisted at least 20% BaAlSiO2. The intensity of artefacts increased when the radio-opacity of the composite material increased. CONCLUSIONS: Materials containing less radio-opacity produce less pronounced artefacts. The cut-off point for artefacts is at 20% radio-opaque filling material in composite material. PMID- 25283365 TI - Relative value of the Ankle-Brachial Index of intermittent claudication. AB - INTRODUCTION: The Ankle-Brachial Index (ABI) makes it possible to identify patients with peripheral artery disease (PAD). Intermittent claudication (IC) is the first major symptom of PAD, although many patients with an ABI <= 0.9 do not exhibit IC, and the range of ABI among those who do have IC is very variable. This study evaluates the correlation between ABI and the perception (symptomatology) of claudicant patients. MATERIAL AND METHODS: An observational, cross-sectional and multicentre, study of 920 patients with IC. Clinical history, ABI, Walking Impairment Questionnaire (WIQ) and European Quality of Life Questionnaire (EQ-5D) were recorded. Associations were analysed using Spearman's correlation coefficient. RESULTS: The mean ABI of the series was 0.63 (SD = 0.19). The mean WIQ-distance was 34.07 (SD = 26.77), values being smaller for lower ABI values (r = 0.343, p < 0.001). The mean EQ-5D score of the series was 0.58 (SD = 0.21), also showing lower values as the ABI decreased (r = 0.278, p < 0.001). The correlations of WIQ and EQ-5D with ABI were statistically significant in both cases, but always less than 0.400 (between 0.278 and 0.343). CONCLUSIONS: The correlations of ABI with the questionnaires of walking capacity and quality of life are weak. For this reason, although in clinical practice the ABI of CI patients is commonly measured, decisions should not be taken during the development of IC exclusively on the basis of the ABI. PMID- 25283367 TI - Effects of the bioaccumulative polybrominated diphenyl ether flame retardant congener BDE-47 on growth, development, and reproductive success in zebra finches. AB - This study investigated the effects of the polybrominated diphenyl ether congener, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on the growth and development, and subsequent breeding success of exposed zebra finches (Taeniopygia guttata). Using oral dosing procedures and treatments adjusted by weight, we treated newly hatched chicks daily for the first 20-days-post-hatch (dph) with varying treatments of BDE-47 (0, 5, 50, and 500 ng/g bw/day). Weight and tarsal measurements were monitored from hatch to 90 dph, but no differences were observed between treatment groups at any age. Treated females that reached sexual maturity were mated with untreated males; however, again no treatment effects were observed on breeding success. Analysis of tissue samples at 21 dph did indicate that debromination of BDE-47 had occurred resulting in BDE-28 and BDE-17 metabolites. PMID- 25283366 TI - Biodegradation and interaction of quinoline and glucose in dual substrates system. AB - An indigenous mixed culture of microorganisms, isolated from a full-scale coal gasification wastewater treatment plant, was used in degrading quinoline in presence of glucose as an alternative carbon source. The results showed that biodegradation kinetics of both quinoline and glucose could be described by first order reaction kinetics model. It was also found that the biodegradation rate of quinoline was accelerated by the presence of glucose, while glucose degradation was inhibited by the presence of quinoline. Both the biomass yield coefficient and specific growth rate were increased with the increasing of the glucose concentrations in the dual substrates system. A sum kinetics model was used to describe the relative effects of the two substrates on their individual uptakes. The interaction parameter values indicated that quinoline exhibits stronger inhibition on glucose degradation. But for glucose, its effect on quinoline utilization was stimulative. Furthermore, the stimulation was positively correlated with the concentration of glucose in the system. PMID- 25283368 TI - Comparison of the toxicity of two chelated copper algaecides and copper sulfate to non-target fish. AB - New pesticide products are reviewed by the United States Environmental Protection Agency for possible effects to non-target aquatic organisms. The required toxicity data are for the active ingredient only, and fail to include toxicity of the mixture of other ingredients found in these pesticides. These ingredients may increase the toxicity of the active ingredient to non-target organisms. Our study compares the toxicity of two formulations of chelated copper algaecides with each other, and to a copper sulfate algaecide. We were particularly interested in the effects of a surfactant that is present in one of the formulations. We found that copper becomes less toxic to fish (e.g. fathead minnow 48-h LC50 = 0.90 mg/L) when it is chelated, providing an additional margin of safety to non-target fish compared to copper sulfate. However, inclusion of a surfactant to the formulation resulted in increased toxicity (e.g. fathead minnow 48-h LC50 = 0.30 mg/L). PMID- 25283370 TI - Collaboration spotting for dental science. AB - AIM: The goal of the Collaboration Spotting project is to create an automatic system to collect information about publications and patents related to a given technology, to identify the key players involved, and to highlight collaborations and related technologies. The collected information can be visualized in a web browser as interactive graphical maps showing in an intuitive way the players and their collaborations (Sociogram) and the relations among the technologies (Technogram). We propose to use the system to study technologies related to Dental Science. METHODS: In order to create a Sociogram, we create a logical filter based on a set of keywords related to the technology under study. This filter is used to extract a list of publications from the Web of ScienceTM database. The list is validated by an expert in the technology and sent to CERN where it is inserted in the Collaboration Spotting database. Here, an automatic software system uses the data to generate the final maps. RESULTS: We studied a set of recent technologies related to bone regeneration procedures of oro- maxillo--facial critical size defects, namely the use of Porous HydroxyApatite (HA) as a bone substitute alone (bone graft) or as a tridimensional support (scaffold) for insemination and differentiation ex--vivo of Mesenchymal Stem Cells. We produced the Sociograms for these technologies and the resulting maps are now accessible on--line. CONCLUSION: The Collaboration Spotting system allows the automatic creation of interactive maps to show the current and historical state of research on a specific technology. These maps are an ideal tool both for researchers who want to assess the state--of--the--art in a given technology, and for research organizations who want to evaluate their contribution to the technological development in a given field. We demonstrated that the system can be used for Dental Science and produced the maps for an initial set of technologies in this field. We now plan to enlarge the set of mapped technologies in order to make the Collaboration Spotting system a useful reference tool for Dental Science research. PMID- 25283369 TI - Toxic effects of oil and dispersant on marine microalgae. AB - To better understand the potential impacts of the deepwater horizon oil spill on lower trophic level food sources, a series of toxicological laboratory experiments were conducted with two microalgae species. The acute toxicity of oil (tar mat and MC252 crude oil), dispersant (Corexit 9500A), and dispersed oil on growth inhibition (IC50) and motility of Isochrysis galbana and Chaetoceros sp. were determined. There was no impact on cell division (growth) for microalgae exposed to both oil types and mean motility of I. galbana never dropped below 79 %. However, the addition of dispersant inhibited cell division and motility within 24 h, with Chaetoceros sp. being more susceptible to sublethal effects than I. galbana. These results highlight microalgae sensitivity to the use of dispersants in bioremediation processes, which may be a concern for long-term impacts on fisheries recruitment. PMID- 25283371 TI - Staff perceptions of primary healthcare service change: influences on staff satisfaction. AB - Strong primary healthcare (PHC) services are efficient, cost-effective and associated with better population health outcomes. However, little is known about the role and perspectives of PHC staff in creating a sustainable service. Staff from a single-point-of-entry primary health care service in Elmore, a small rural community in north-west Victoria, were surveyed. Qualitative methods were used to collect data to show how the key factors associated with the evolution of a once struggling medical service into a successful and sustainable PHC service have influenced staff satisfaction. The success of the service was linked to visionary leadership, teamwork and community involvement while service sustainability was described in terms of inter-professional linkages and the role of the service in contributing to the broader community. These factors were reported to have a positive impact on staff satisfaction. The contribution of service delivery change and ongoing service sustainability to staff satisfaction in this rural setting has implications for planning service change in other primary health care settings. WHAT IS KNOWN ABOUT THIS TOPIC?: Integrated PHC services have an important role to play in achieving equitable population health outcomes. Many rural communities struggle to maintain viable PHC services. Innovative PHC models are needed to ensure equitable access to care and reduce the health differential between rural and metropolitan people. WHAT DOES THIS PAPER ADD?: Multidisciplinary teams, visionary leadership, strong community engagement combined with service partnerships are important factors in the building of a rural PHC service that substantially contributes to enhanced staff satisfaction and service sustainability. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS?: Understanding and engaging local community members is a key driver in the success of service delivery changes in rural PHC services. PMID- 25283372 TI - Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei. AB - Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents. PMID- 25283373 TI - Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment. AB - RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies. PMID- 25283374 TI - DCLK1 is detectable in plasma of patients with Barrett's esophagus and esophageal adenocarcinoma. AB - BACKGROUND: Doublecortin-like kinase 1 (DCLK1), a putative tumor stem cell marker has been shown to be highly expressed in the stromal and epithelial compartments in colon and pancreatic cancer as well as Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). AIM: To prospectively investigate whether the immunohistochemical expression of DCLK1 was associated with detectable DCLK1 plasma expression in patients with existing BE and EAC. METHODS: Immunohistochemistry was performed on paraffin-embedded sections using DCLK1 antibody and scored based on staining intensity and tissue involvement. Purified human plasma samples were subjected to Western blot and ELISA analysis. RESULTS: Forty (40) patients were enrolled: 10 controls (normal endoscopy) and 30 with BE/EAC (13 nondysplastic BE [NDBE], 9 dysplastic BE [DBE] and 8 EAC). Mean epithelial DCLK1 staining was as follows: controls = 0.11, NDBE = 3.83, DBE = 6.0, EAC = 7.17. Mean stromal DCLK1 staining was as follows: NDBE = 5.83, DBE = 5.375, EAC = 10.83. DCLK1 was detected by plasma Western blot in 1 control and in all patients with BE/EAC p < 0.0005. Plasma DCLK1 was elevated by ELISA in EAC compared to other groups, p < 0.05. CONCLUSIONS: Increased expression of DCLK1 was observed in the epithelium, stroma and plasma of patients with BE/EAC. Furthermore, the presence of detectable DCLK1 in plasma of BE/EAC patients may provide a less invasive, detection tool in those patients as well as represent a novel molecular marker distinguishing between normal esophageal mucosa and BE or EAC. PMID- 25283376 TI - Low SVR rates in clinical practice for treating genotype 1 chronic hepatitis C with protease inhibitors boceprevir and telaprevir. PMID- 25283375 TI - Protective effects of garlic extract, PMK-S005, against nonsteroidal anti inflammatory drugs-induced acute gastric damage in rats. AB - BACKGROUND: PMK-S005 is synthetic s-allyl-L-cysteine (SAC), a sulfur-containing amino acid, which was initially isolated from garlic. The antioxidant and anti inflammation activities of SAC have been demonstrated in diverse experimental animal models. AIMS: The purpose of this study was to investigate the gastroprotective effects of PMK-S005 against NSAIDs-induced acute gastric damage in rats. METHODS: Eight-week SD rats were pretreated with PMK-S005 (1, 5, or 10 mg/kg) or rebamipide (50 mg/kg) 1 h before administration of NSAIDs including aspirin (200 mg/kg), diclofenac (80 mg/kg), and indomethacin (40 mg/kg). After 4 h, the gross ulcer index, histological index, and gastric mucus level were determined. Myeloperoxidase (MPO), TNF-alpha, IL-1beta, PGE2, and LTB4 levels were estimated in the gastric mucosal tissue by ELISA. Protein expressions of cPLA2, COX-1, and COX-2 were assessed by Western blot analysis. RESULTS: Pretreatment with PMK-S005 significantly attenuated the NSAIDs-induced gastric damage and increased the gastric mucus level. In addition, PMK-S005 attenuated increases in MPO, TNF-alpha, and IL-1beta production. The expressions of cPLA2 and COX-2 induced by NSAIDs were decreased by PMK-S005 pretreatment. PMK-S005 did not cause suppression of PGE2 synthesis induced by NSAIDs, but LTB4 production was significantly suppressed by PMK-S005. The effects of PMK-S005 were consistently maximized at a concentration of 5 mg/kg, which were frequently superior to those of rebamipide. CONCLUSIONS: These results strongly suggest that PMK-S005 can be a useful gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, down-regulating cPLA2, COX-2 and LTB4 expression, and increasing the synthesis of mucus. PMID- 25283377 TI - The resolution of visual noise in word recognition. AB - This study examined lexical processing in English by native speakers of Korean and Chinese, compared to that of native speakers of English, using normal, alternated, and inverse fonts. Sixty four adult students participated in a lexical decision task. The findings demonstrated similarities and differences in accuracy and latency among the three L1 groups. The participants, regardless of L1, had a greater advantage in nonwords than words for the normal fonts because they were able to efficiently detect the illegal letter strings. However, word advantages were observed in the visually distorted stimuli (i.e., alternated and inverse fonts). These results were explained from the perspectives of the theory of psycholinguistic grain size, L1-L2 distance, and the mechanism of familiarity discrimination. The native speakers of Chinese were more sensitive to visual distortions than the Korean counterpart, suggesting that the linguistic template established in L1 might play a role in word processing in English. PMID- 25283378 TI - The Separability of Morphological Processes from Semantic Meaning and Syntactic Class in Production of Single Words: Evidence from the Hebrew Root Morpheme. AB - In the present study we investigated to what extent the morphological facilitation effect induced by the derivational root morpheme in Hebrew is independent of semantic meaning and grammatical information of the part of speech involved. Using the picture-word interference paradigm with auditorily presented distractors, Experiment 1 compared the facilitation effect induced by semantically transparent versus semantically opaque morphologically related distractor words (i.e., a shared root) on the production latency of bare nouns. The results revealed almost the same amount of facilitation for both relatedness conditions. These findings accord with the results of the few studies that have addressed this issue in production in Indo-European languages, as well as previous studies in written word perception in Hebrew. Experiment 2 compared the root's facilitation effect, induced by morphologically related nominal versus verbal distractors, on the production latency of bare nouns. The results revealed a facilitation effect of similar size induced by the shared root, regardless of the distractor's part of speech. It is suggested that the principle that governs lexical organization at the level of morphology, at least for Hebrew roots, is form-driven and independent of semantic meaning. This principle of organization crosses the linguistic domains of production and written word perception, as well as grammatical organization according to part of speech. PMID- 25283379 TI - The Effect of Non-sentential Context Prosody on Homographs' Lexical Activation in Persian. AB - This study examines the effect of non-sentential context prosody pattern on lexical activation in Persian. For this purpose a questionnaire including target and non-target words is used. The target words are homographs with two possible stress patterns belonging to different syntactic categories. Participants are asked to read out the words aloud and note the first word that comes to their mind. The results show that by reading the target words, both meanings of the target words are activated in mind and the prosodic pattern of the non-sentential preceding context does not affect the activation of the other stress pattern meaning. This result suggests that the metrical prosodic pattern of non sentential context is not a strong constraint to determine which meaning of the target word must be activated. The experiment also illustrates that the stress pattern used to read the target words does not necessarily matches the stress pattern of the target word which relates to the written word. These findings confirm Swinney (Verb Learn Verb Behav 18:645-665, 1979) and Elston-Guttler and Friederici's (J Mem Lang 52(2):256-283, 2005) finding that both meanings of an ambiguous word are accessed at the first stage. This study shows that in lack of semantic context, Persian natives behave homographs as ambiguous words and there is no bias towards preferring one meaning over another. PMID- 25283380 TI - Visualization of nitroxyl (HNO) in vivo via a lysosome-targetable near-infrared fluorescent probe. AB - We have presented a near-infrared fluorescent probe Lyso-JN for the detection of nitroxyl (HNO) in cells and in vivo. Lyso-JN is comprised of three moieties: an Aza-BODIPY fluorophore, a HNO-response modulator, diphenylphosphino-benzoyl, and a lysosomal locator, alkylmorpholine. The detection mechanism is based on aza ylide intramolecular ester aminolysis reaction with HNO. The probe holds the ability to capture lysosomal HNO in RAW 264.7 cells, and it is also successfully employed to visualize HNO in mice. PMID- 25283381 TI - Laryngeal adductor function in experimental models of recurrent laryngeal nerve injury. AB - OBJECTIVES/HYPOTHESIS: Most patients with unilateral vocal fold paralysis experience some degree of spontaneous reinnervation, which depends upon the type and severity of recurrent laryngeal nerve (RLN) injury. After partial recovery, the paretic vocal fold may or may not adduct adequately to allow glottic closure, which in turn affects phonatory and swallowing outcomes. This process was studied in a series of canine laryngeal nerve injury models. STUDY DESIGN: Animal (canine) experiments. METHODS: Maximum stimulable laryngeal adductor pressure (LAP) was measured pretreatment (baseline) and at 6 months following experimental RLN injuries (total n = 59). The nine study groups were designed to simulate a range of severities of RLN injury. RESULTS: The greatest LAP recovery, at 108% of original baseline, was seen in a 50% transection model; the least recovery was seen when the RLN underwent complete transection with repair, at 56% with precise alignment and 50% with alignment reversed. Intermediate models (partial RLN injuries) gave intermediate results. Crush models recovered 105% of LAP, whereas a half-transection, half-crush injury recovered 72%, and cautery injuries recovered 61%. Controls (complete transection without repair) had no measurable recovery. CONCLUSIONS: The injured RLN has a strong tendency to recover. Restoration of adductor strength, as determined by the LAP, was predictably related to the severity of RLN injury. The model RLN injuries studied provide a range of expected outcomes that can be used for future experiments exploring interventions that may improve postinjury adductor function. LEVEL OF EVIDENCE: NA. PMID- 25283382 TI - Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. AB - Gliomas are the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve therapies, their prognosis remains very poor. Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered frequently in glioma patients and are strongly correlated with improved survival. However, the effect of IDH1 mutations on the chemosensitivity of gliomas remains unclear. In this study, we generated clonal U87 and U251 glioma cell lines overexpressing the R132H mutant protein (IDH1-R132H). Compared with control cells and cells overexpressing IDH wild type (IDH1-WT), both types of IDH1-R132H cells were more sensitive to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP) in a time and dose-dependent manner. The IDH1-R132H-induced higher chemosensitivity was associated with nicotine adenine disphosphonucleotide (NADPH), glutathione (GSH) depletion, and reactive oxygen species (ROS) generation. Accordingly, this IDH1 R132H-induced growth inhibition was effectively abrogated by GSH in vitro and in vivo. Our study provides direct evidence that the improved survival in patients with IDH1-R132H tumors may partly result from the effects of the IDH1-R132H protein on chemosensitivity. The primary cellular events associated with improved survival are the GSH depletion and increased ROS generation. PMID- 25283383 TI - Sports-induced blood sugar utilization prevents development of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor of extremely high lethality in humans. Pancreatic intraepithelial neoplasia (PanIN) is the predominant precancerous lesion for PDAC and is frequently detected in the normal and inflamed pancreas. However, only a few of PanIN eventually progress into PDAC. Thus, understanding of the regulation of PanIN-to-PDAC conversion appears to be critical for prevention of the occurrence of PDAC. Here, we evaluated the effect of sports on the progression of PanIN into PDAC in an established mouse PDAC model (Ptf1a-Cre; K-ras fx/fx). We found that swimming (3 min twice per day) since 12 weeks of age significantly decreased the incidence of the development of PDAC in these PanIN-baring mice at 24 weeks of age. Moreover, swimming significantly decreased fasting blood sugar and improved glucose response in these mice, compared to the control. Furthermore, implantation of insulin pellets into the mice not only reduced fasting blood sugar and improved glucose response, but also significantly reduced the incidence of development of PDAC, which mimicked the effect of swimming. Taken together, our study suggests that sports induced blood sugar utilization may prevent development of PDAC. PMID- 25283384 TI - Enantioselective iron-catalyzed intramolecular cyclopropanation reactions. AB - An iron-catalyzed asymmetric intramolecular cyclopropanation was realized in high yields and excellent enantioselectivity (up to 97% ee) by using the iron complexes of chiral spiro-bisoxazoline ligands as catalysts. The superiority of iron catalysts exhibited in this reaction demonstrated the potential abilities of this sustainable metal in asymmetric carbenoid transformation reactions. PMID- 25283385 TI - Double-stranded DNA stereoselectively promotes aggregation of amyloid-like fibrils and generates peptide/DNA matrices. AB - An amyloidogenic LAM-L peptide (AASIKVAVSADR, all-L configuration) derived from laminin promoted cell adhesion, neurite outgrowth, and angiogenesis. Here, we prepared novel matrices using double-stranded DNA and the LAM-L peptide. Double stranded DNA promoted aggregation of amyloid-like fibrils and generated a LAM L/DNA matrix through electrostatic interactions between the phosphate groups of DNA and the amino groups of LAM-L. This formation of peptide/DNA matrix depends on the Ile-Lys-Val-Ala-Val (IKVAV) sequence in the peptide, since LAM-RM peptide (AASVVIAKSADR), which is scrambled peptide of LAM-L, did not form a matrix with DNA. Further, LAM-D (all-D configuration of LAM-L), which forms amyloid-like fibrils and promotes similar biological activities as LAM-L, did not form amyloid like fibrils with DNA, suggesting that DNA selectively interacts with the L configured peptide. Moreover, the LAM-L/DNA matrices showed stronger cell attachment activity compared with LAM-L alone, suggesting the LAM-L/DNA matrices have potential for use as a novel biomaterial in tissue engineering. PMID- 25283386 TI - Quaternary climate change and social behavior shaped the genetic differentiation of an endangered montane primate from the southern edge of the Tibetan Plateau. AB - Multiple factors, including climate change, dispersal barriers, and social behavior influence the genetic structure of natural populations. While the effects of extrinsic factors such as historical climatic change and habitat topography have been well studied, mostly in temperate habitats, the simultaneous effects of intrinsic factors such as social behavior on genetic structure have rarely been explored. Such simultaneous effect, however, may particularly be common in social mammals such as many primates. Consequently, we studied the population structure of a rare and endangered social primate, the Arunachal macaque Macaca munzala, endemic to the northeastern Indian state of Arunachal Pradesh, located on the subtropical southern edge of the Tibetan Plateau and forming part of the Eastern Himalayan biodiversity hotspot. We studied a 534 bp long mitochondrial DNA sequence and 22 autosomal microsatellite loci in individuals from three populations, Tawang, Upper Subansiri, and West Siang. The mtDNA data revealed three major divergence events: that between the Arunachal and bonnet macaques (ca. 1.61 mya), the founding of the West Siang population and the ancestral population of the present-day bonnet macaques (ca. 1.32 mya), and the divergence between the Tawang and Upper Subansiri populations (ca. 0.80 mya) that coincided with the major glacial events in the region. Comparing mitochondrial DNA with autosomal microsatellites, we also found evidence for female philopatry and male-driven long-distance gene flow. Arunachal macaques thus appear to be characterized by groups of philopatric females separated by geographical barriers and harsh climate but with dispersing males exerting a homogenizing effect on the nuclear gene pool. Given that severe population differentiation is of major concern in species conservation, we suggest that our study populations represent significant conservation units of this rare, endangered primate but, more importantly, emphasize the complex interplay of extrinsic and intrinsic factors in shaping the population structure of a social mammalian species. PMID- 25283387 TI - RARbeta2 expression is induced by the down-regulation of microRNA 133a during caudal spinal cord regeneration in the adult newt. AB - BACKGROUND: Adult urodele amphibians represent unique model organisms to study spinal cord regeneration. Trauma to the spinal cord induces an ependymal response, activating multipotent neural stem cells that contribute to the redifferentiation of both glia and neurons in the regenerate. The molecular events underlying this ependymal response are not completely understood, but likely involve coordinated global changes in gene expression. MicroRNAs and retinoid signaling are postulated to orchestrate these patterns of gene expression in response to trauma. Our objectives were to determine the roles played by some miRNAs as potential regulators of retinoid signaling in this process. RESULTS: We found that the expression levels of miRNAs 133a, 203, and 124a are dysregulated during the first 21 days post amputation (dpa). Interestingly, these miRNAs are expressed primarily within the ependymoglia. We have shown in vitro that a miR-133a mimic targets the 3' UTR of the newt RARbeta2 transcript. Importantly, upregulation of this mimic in vivo led to a significant decline in RARbeta2 protein at 14 dpa and inhibited regeneration. CONCLUSIONS: These data are the first to link miRNAs and retinoid signaling during spinal cord regeneration and provide support for miR-133a as an upstream regulator of RARbeta2 expression in this process. PMID- 25283389 TI - "difficile est tenere quae acceperis nisi exerceas". PMID- 25283388 TI - Binding of scandium ions to metalloporphyrin-flavin complexes for long-lived charge separation. AB - A porphyrin-flavin-linked dyad and its zinc and palladium complexes (MPor-Fl: 2 M, M=2 H, Zn, and Pd) were newly synthesized and the X-ray crystal structure of 2 Pd was determined. The photodynamics of 2-M were examined by femto- and nanosecond laser flash photolysis measurements. Photoinduced electron transfer (ET) in 2-H2 occurred from the singlet excited state of the porphyrin moiety (H2 Por) to the flavin (Fl) moiety to produce the singlet charge-separated (CS) state (1) (H2 Por(.+) -Fl(.-) ), which decayed through back ET (BET) to form (3) [H2 Por]*-Fl with rate constants of 1.2*10(10) and 1.2*10(9) s(-1) , respectively. Similarly, photoinduced ET in 2-Pd afforded the singlet CS state, which decayed through BET to form (3) [PdPor]*?Fl with rate constants of 2.1*10(11) and 6.0*10(10) s(-1) , respectively. The rate constant of photoinduced ET and BET of 2-M were related to the ET and BET driving forces by using the Marcus theory of ET. One and two Sc(3+) ions bind to the flavin moiety to form the Fl-Sc(3+) and Fl-(Sc(3+) )2 complexes with binding constants of K1 =2.2*10(5) M(-1) and K2 =1.8*10(3) M(-1) , respectively. Other metal ions, such as Y(3+) , Zn(2+) , and Mg(2+) , form only 1:1 complexes with flavin. In contrast to 2-M and the 1:1 complexes with metal ions, which afforded the short-lived singlet CS state, photoinduced ET in 2-Pd???Sc(3+) complexes afforded the triplet CS state ((3) [PdPor(.+) -Fl(.-) ?(Sc(3+) )2 ]), which exhibited a remarkably long lifetime of tau=110 ms (kBET =9.1 s(-1) ). PMID- 25283390 TI - Revision of Charaea (Coleoptera: Chrysomelidae: Galerucinae) from Taiwan. AB - Eleven species of the genus Charaea Baly, 1878 are recorded for Taiwan. These are illustrated and a key to the species is provided. Three species, Ch. houjayi sp. nov., Ch. maxbarclayi sp. nov. and Ch. haruoi sp. nov., are described and compared with similar species. Charaea kelloggi (Gressitt & Kimoto, 1963) is reported from Taiwan for the first time. Colour photos of habitus and drawings of both male and female genitalia are presented. PMID- 25283391 TI - Review of Mediterranean members of the Aphaenogaster cecconii group (Hymenoptera: Formicidae), with description of four new species. AB - A group of six Mediterranean species related to Aphaenogaster cecconii Emery is reviewed. Four new species are described: A. equestris (SW Turkey), A. jolantae (Greece, Rhodes), A. lykiaensis (SW Turkey) and A. olympica (Greece, Karpathos). Aphaenogaster cecconii Emery and A. phillipsi Wheeler & Mann are redescribed. Detailed measurements and some observations on the location of nests and activity of workers are given. PMID- 25283392 TI - Griveaudus gen. nov. (Hemiptera: Fulgoromorpha: Flatidae) from Tsaratanana Massif supports the biodiversity of montane flatids in Madagascar. AB - The paper describes a new flatid genus, Griveaudus gen. nov., comprising two species G. issidiformis sp. nov. and G. tsarantananae sp. nov. from Madagascar. Additionally, the illustrations of the female internal genital structures are provided. PMID- 25283393 TI - Eriophyoid mites (Acari: Trombidiformes: Eriophyoidea) of Rosales trees in Iran: two new species and three new records. AB - This paper describes two new species of Eriophyoidea associated with trees belonging to the order Rosales in the south-western portion of East Azerbaijan province, Iran, collected during a survey in 2011: Aceria lobolinguae n. sp. on Elaeagnus angustifolia L. (Elaeagnaceae) and Rhinophytoptus nemalobos n. sp. on Prunus domestica L. (Rosaceae). Additionally, Phyllocoptes abaenus Keifer on Prunus armeniaca L. (Rosaceae), Aculus fockeui (Nalepa & Trouessart) on Prunus amygdalus Stokes and Malus domestica Borkh. (Rosaceae), and Aceria mori (Keifer) on Morus alba L. (Moraceae) were collected and are new records for the mite fauna of Iran. New locality records and host plant data are provided for Eriophyes similis (Nalepa), Eriophyes pyri (Pagenstecher) and Calepitrimerus baileyi (Keifer) which are eriophyoid species previously known from Iran. PMID- 25283394 TI - A new species of Naxia Latreille, 1825 (Brachyura: Majidae) from deep water off Brazil. AB - A new species of spider crab, Naxia atlantica n. sp., is described and illustrated from deep waters off Sao Paulo (southeastern Brazil). The new species can be separated from its congeners by a suite of characters including shapes of the propodi of the walking legs, rostrum and basal antennal article. This is the first record of the genus outside southern Australia and New Zealand. PMID- 25283395 TI - Psoralis mirnae sp. nov., the first species of the skipper genus from Central America (Lepidoptera: Hesperiidae). PMID- 25283396 TI - Scapanoclypeus hardap (Coleoptera: Scarabaeidae: Melolonthinae: Tanyproctini), a new species from Hardap province, Namibia. AB - Scapanoclypeus hardap Sehnal, new species (Coleoptera: Scarabaeidae: Melolonthinae: Tanyproctini), from Hardap province, Namibia, is described and an updated key to species of Scapanoclypeus Evans, 1987 is presented. PMID- 25283397 TI - Taxonomic revision of Neodiogmites Carrera, 1949 (Diptera, Asilidae) and description of two new species. AB - Neodiogmites Carrera, 1949, a rare Neotropical genus of Asilidae, is revised and divided into three species groups: (1) the melanogaster group, including N. carrerai Artigas & Papavero, N. melanogaster (Wiedemann, 1821), N. tenebrosus Carrera and N. carolindae sp. nov.; (2) the alexanderi group, including N. atriapex (Carrera & Papavero), N. alexanderi (Carrera), N. mixtus (Carrera), N. modestus (Carrera) reval., N. niger (Carrera) and N. papaveroi sp. nov.; and (3) the lanei group including N. lanei (Carrera) and N. tauauna Artigas & Papavero. A key to the 12 species is included, species distributions are summarized, and two new species are described and illustrated. PMID- 25283398 TI - A new and a rare species of Chydorus Leach, 1816 (Branchiopoda: Cladocera: Anomopoda) from Cat Tien National Park, Vietnam. AB - The present study of cladocera of the genus Chydorus from South Vietnam revealed a new species, C. idrisi sp. nov. and a rare species, C. breviceps (Stingelin, 1905). C. idrisi sp. nov. belongs to the C. eurynotus Sars, 1901 group, characterized by small labral plate with rounded tip and by absence of honeycomb sculpture on the valves. C. idrisi sp. nov. differs from other species of the group by the sculpture of valves, morphology of rostrum, postabdominal claw, inner distal lobe of first thoracic limb and male postabdomen. Morphology of C. breviceps was studied for the first time. C. breviceps has only one major head pore, and differs from the majority of Chydorus species by numerous other characters. Taxonomic position of studied species is discussed. PMID- 25283399 TI - Hidden diversity within the polychaete Onuphis eremita sensu lato (Annelida: Onuphidae)--redescription of O. eremita Audouin & Milne-Edwards, 1833 and reinstatement of Onuphis pancerii Claparede, 1868 . AB - Onuphis eremita, type species of the genus, and Onuphis pancerii, originally from La Rochelle (France) and Gulf of Naples (Italy) respectively, are two of the earliest described species of the family Onuphidae. Yet, the definition of the former was extremely confused, the latter was considered its synonym for nearly a century, and types do not exist. We have examined a large amount of material, old museum collections and newly collected specimens from the European Atlantic and Mediterranean and conclude that both, O. eremita and O. pancerii, are valid species. The most obvious differences are that O. eremita is a slender species with only tridentate pseudocompound hooks while O. pancerii is much more robust and has pseudocompound hooks with bi- and tridentate (or even multidentate) tips. Neotypes have been designated for both species and the two taxa are redescribed and illustrated. We regard O. eremita sensu stricto, as redefined on the neotype here, to be restricted to the European Atlantic and western and central Mediterranean; other records need to be re-evaluated. Some specimens of both species were collected with eggs (~ 200 um diameter) protruding through openings in the body wall, and some O. eremita had ect-aquasperm, suggesting that reproduction is by broadcast spawning and indirect development. PMID- 25283400 TI - The Pselaphinae (Coleoptera: Staphylinidae) of Madagascar. III. Additional description of Andasibe sahondrae Hlavac & Banar, 2012 based on males. AB - An additional description of Andasibe sahondrae Hlavac & Banar, 2012 is given due to the discovery of male, male terminalia and sexual dimorphism are described. Distribution of the species is illustrated. PMID- 25283401 TI - A new genus and species of Delphacini (Hemiptera: Fulgoroidea: Delphacidae) from Argentina. AB - A new genus of Delphacini is described from Argentina, Pyrophagus Remes Lenicov gen. n., with one new species, P. tigrinus Remes Lenicov & Varela sp. n. The new species, distributing over a wide cultivated area of Northwestern and Central Argentina and recently confirmed as a vector of MRCV (Rio Cuarto maize virus) in experimental conditions, is one of the most frequently found delphacid species on wheat, oat, maize, triticale, rye, barley and wild Gramineae. The main diagnostic features of the new genus and species are described and illustrated, and information on the host plants, geographical distribution and vector capacity of the new species is provided. PMID- 25283402 TI - Two new Anoplocheylus species (Acari: Trombidiformes: Pseudocheylidae) from Kurdistan province of Iran. AB - Two new species of the genus Anoplocheylus Berlese, 1910 are described: Anoplocheylus marivaniensis sp. nov. collected from soil and rotten leaves under oak trees and Anoplocheylus qorvehiensis sp. nov. from soil under Astragalus sp. bushes in Kurdistan province, Iran. A key to females of all known species of Anoplocheylus is provided, based on original descriptions and other literature. PMID- 25283403 TI - New taxa of the subfamily Picobiinae (Cheyletoidea: Syringophilidae) parasitizing antbirds and gnateaters (Passeriformes: Thamnophilidae, Conopophagidae) in Guyana. AB - A new genus and three new species of the picobiin quill mites (Cheyletoidea: Syringophilidae) are described from passeriform birds in Guyana, Phipicobia pygiptilae gen. nov. and sp. nov. parasitizing Pygiptila stellaris (Spix) (Thamnophilidae), Rafapicobia thamnophili sp. nov. from Thamnophilus insignis Salvin et Godman (type host), Myrmoborus leucophrys (Tschudi), Myrmeciza ferruginea (St. Muller), Myrmotherula longipennis Pelzeln, and Hypocnemis cantator (Boddaert) (Thamnophilidae), and Rafapicobia milenskyi sp. nov. from Conopophaga aurita (Gmelin) (Conopophagidae). PMID- 25283404 TI - Two new species of Anagyrus (Hymenoptera: Encyrtidae) from Argentina, parasitoids of Hypogeococcus spp. (Hemiptera: Pseudococcidae), with taxonomic notes on some congeneric taxa. AB - Two new species of Anagyrus Howard (Hymenoptera: Encyrtidae) are described from Argentina, A. cachamai Triapitsyn, Logarzo & Aguirre sp. n. (Catamarca, Cordoba, Salta and Tucuman Provinces) and A. quilmes Triapitsyn, Logarzo & Aguirre sp. n. (Catamarca, Salta and Tucuman). Both new species are parasitoids of Hypogeococcus spp. (Hemiptera: Pseudococcidae). Anagyrus cachamai is a parasitoid of H. pungens Granara de Willink on Alternanthera paronychioides, A. pungens and Gomphrena sp. (Amaranthaceae), and also of a Hypogeococcus sp. on Cleistocactus baumannii and Hypogeococcus sp. on C. smaragdiflorus (Cactaceae). Anagyrus quilmes is a parasitoid of H. pungens on A. paronychioides, A. pungens and Gomphrena sp. Other biological traits of the new species are also reported. These parasitoids may be of importance as potential candidate biological control agents against a Hypogeococcus sp., commonly called the Harrisia cactus mealybug and identified as H. pungens, but possibly not belonging to that species. This mealybug threatens the native cacti in some Caribbean islands and Florida, USA, and is devastating the native columnar cacti in Puerto Rico. Illustrations and taxonomic notes on the type specimens of some other, little known described species of Anagyrus from Argentina and Chile are provided, and a key to females of the 14 species of Anagyrus known from Argentina is given. Anagyrus nigriceps (De Santis) syn. n. is synonymized under A. bellator (De Santis). Lectotypes are designated for Paranusia bifasciata Brethes, Philoponectroma pectinatum Brethes, and Protanagyrus aciculatus Blanchard. PMID- 25283405 TI - Two new species of Clito from South America and a revision of the Clito littera group (Lepidoptera: Hesperiidae: Pyrginae). AB - Two new species of Clito from the C. littera group are described: C. palotschka, sp. nov. from the Choco region in Ecuador is the most distinctive in the group, and C. litteroides, sp. nov. from Venezuela is superficially more similar to C. littera differing mostly in the shape of male genitalic valvae. Comparative analyses of male genitalia and wing patterns suggest that C. anda Evans, 1953, new status; and C. nebulosa (Draudt, 1924), reinstated status are species-level taxa. A lectotype for Telemiades littera Mabille, 1877 is designated to ensure nomenclatural stability. Primary type specimens of all seven species in the C. littera group are illustrated with photographs, and an identification key to males is given. PMID- 25283406 TI - A new species of Pseudopaludicola Miranda-Ribeiro, 1926 (Anura: Leptodactylidae: Leiuperinae) from northwestern state of Sao Paulo, Brazil. AB - A new species of Pseudopaludicola is described from human-altered areas originally covered by Semideciduous Forest in northwestern state of Sao Paulo, southeastern Brazil. Morphologically, the new species differs from four species belonging to the P. pusilla group by the absence of either T-shaped terminal phalanges or toe tips expanded, and from all other congeners except P. canga and P. facureae by possessing an areolate vocal sac, with dark reticulation. The higher duration (300-700 ms) of each single, pulsed note (9-36 nonconcatenated pulses) that compose the call in the new species distinguishes it from all other 14 species of Pseudopaludicola with calls already described (10-290 ms). Absence of harmonics also differ the advertisement call of the new species from the call of its sister species P. facureae, even though these two species presented unexpected low genetic distances. Although we could not identify any single morphological character distinguishing the new species from P. facureae, a PCA and DFA performed using 12 morphometric variables evidenced significant size differences between these two species. PMID- 25283407 TI - Two squat lobster species (Crustacea: Decapoda: Anomura) from the Persian Gulf, with description of a new species of Raymunida Macpherson & Machordom, 2000. AB - Galathea ternatensis De Man, 1902 and Raymunida iranica n. sp., are reported from the Iranian coast as the first records of squat lobster species from the Persian Gulf. The new species morphologically resembles R. cagnetei Macpherson & Machordom, 2000, but is unique in the genus in having a small spine near the base of each supraocular spine and a spine ventral to the second branchial marginal spine of the carapace. PMID- 25283408 TI - Reconsideration of Xysticus species described by Ehrenfried Schenkel from Mongolia and China in 1963 (Araneae: Thomisidae). AB - The types of nine Xysticus species described by Schenkel (1963) from China and Mongolia are revised. Comments on all 16 species described by Schenkel in 1963 are provided. Three species are synonymised with Xysticus davidi Schenkel, 1963: X. excavatus Schenkel, 1963, syn. n., X. hotingchiehi Schenkel, 1963, syn. n., X. pentagonius Seyfulina & Mikhailov, 2004, syn. n. Xysticus fagei Schenkel 1963, syn. n. is a junior synonym of X. ephippiatus Simon, 1880. Xysticus lesserti Schenkel, 1963 is revalidated and removed from synonymy with X. kurilensis Strand, 1907. A male specimen from Gansu identified by Schenkel as Xysticus sibiricus Kulczynski, 1908 is described as a new species X. courti sp. n. PMID- 25283409 TI - A new species of Loxosomatidae (Entoprocta, Solitaria) from the White Sea: Loxosomella unicornis sp. nov. AB - A new solitary entoproct, Loxosomella unicornis sp. nov., is described. The species was found on the gymnolaemate bryozoans Cribrilina sp. and Electra sp. in Kandalaksha Bay, White Sea. Loxosomella unicornis sp. nov. is a medium-sized species with a total length up to 650 um, eight tentacles and a conspicuous horn shaped appendage on the top part of calyx. PMID- 25283410 TI - First report of Ricania speculum (Walker, 1851) in Europe (Hemiptera: Fulgoromorpha: Ricaniidae). AB - Ricania speculum (Walker, 1851) (Hemiptera: Fulgoromorpha: Ricaniidae) is reported for the first time in Europe. Both nymphs and adults were observed from 2009 in several municipalities of Liguria (Italy). Since the species is extremely polyphagous and is a real pest for several crops in tropical and subtropical areas, the presence of this alien insect is noteworthy, representing a new possible threat for native species and human activities. PMID- 25283411 TI - Revision on genus Xizicus Gorochov (Orthoptera, Tettigoniidae, Meconematinae, Meconematini) with description of three new species form China. AB - This work presents a revision of genus Xizicus, two new subgenera are described: Xizicus (Zangxizicus) subgen. nov. and Xizicus (Haploxizicus) subgen. nov. Three new species are described, namely Xizicus (Paraxizicus) fallax sp. nov., Xizicus (Zangxizicus) tibeticus sp. nov. and Xizicus (Zangxizicus) quadrifascipes sp. nov.. Keys to subgenera and species are provided. PMID- 25283412 TI - Morphological and molecular evidence for the occurrence of three Hippocampus species (Teleostei: Syngnathidae) in Brazil. AB - For many decades only two species of seahorses were recognized from Brazil: Hippocampus reidi Ginsburg, 1933, the long snout seahorse, and H. erectus Perry, 1810, the lined seahorse. The presence of a possible third species, recognized in 2002, brought about the need for a broad revision of the genus in Brazilian waters. A total of 335 specimens of seahorses, obtained from Brazilian and other collections, representing the three putative species from Brazil were analyzed: H. reidi, the species of greatest abundance and occurs in estuaries and the sea; H. erectus, which occurs only in the sea, and Hippocampus patagonicus was also determined to be present based on multiple specimens. Our morphometric / numerical and molecular analysis showed that the species currently identified as H. erectus in Brazil is actually H. patagonicus Piacentino & Luzatto, 2004. The existence of a possible third species, was instead based on the true H. erectus, as confirmed in the present study by the study of classical systematic and mitochondrial analysis. Thus, we recognize three species of seahorses in Brazil: H. erectus, H. reidi and H. patagonicus. PMID- 25283413 TI - Three new polar species of Sternaspis Otto, 1821 (Polychaeta: Sternaspidae). AB - Two sternaspid species, Sternaspis fossor Stimpson, 1853 and S. scutata (Ranzani, 1817), have been recorded from many localities including polar or subpolar environments. The study of the collections of five major institutions cannot confirm their presence in high latitudes. On the contrary, the specimens are regarded as different, undescribed species, and are herein described as one from Arctic environments, S. buzhinskajae n. sp., and two others from Antarctic localities: S. monroi n. sp., and S. sendalli n. sp. A key to identify all Sternaspis species is included. PMID- 25283414 TI - Acutihumerus patagoniensis (Sieg, 1986) (Tanaidacea: Kalliapseudidae): supplementary description and remarks on its taxonomic status. AB - Acutihumerus patagoniensis (Sieg, 1986) was originally described based on a single specimen from Golfo Nuevo, northern Patagonia, Argentina. Over 3000 specimens referable to this species from just a few miles of its type locality are now available. Based on these specimens, the description of A. patagoniensis is completed and the ontogenetic changes of the male cheliped are described and illustrated. Acutihumerus patagoniensis has recently been considered a junior synonym of A. cavooreni (Bacescu & Absalao, 1985) from southern Brazil. However, these species can be distinguished mainly by the male chela: A. patagoniensis has a much wider notch palm than A. cavooreni. Furthermore, most of the males herein reported from off the Rio de la Plata have a chela with a narrow notch, a fact that suggests that this area might be a zone of hybridization or contact between A. patagoniensis and A. cavooreni. Hence, we claim that the recently proposed synonymy has not been proven, and the resolution of this taxonomic problem must await additional specimens of A. cavooreni from its type locality (Rio Grande do Sul, Brazil). PMID- 25283415 TI - New records and a new species of the cavernicolous genus Guiodytes Tian, 2013 from Guangxi, China (Coleoptera: Carabidae: Scaritinae). AB - A new species of the genus Guiodytes Tian, 2013 is described from a limestone cave called Shuiku Dong in Huanjiang County of northernmost Guangxi, southern China. G. deharvengi n. sp. is the first depigmented species of Guiodytes. It is close to G. cavicola Tian, 2013, but easily recognized by its broader and yellowish brown body. In addition, new records for G. cavicola Tian, 2013 are provided from two caves in Du'an County of northern Guangxi, with description of the male genitalia. A key to all three known species and a distributional map of Guiodytes are also given. PMID- 25283416 TI - The identity of Australia's northern-most giant pill-millipedes (Diplopoda, Sphaerotheriida). AB - The redescription of the lectotype of Zephronia larvalis Butler, 1878, from the Torres Strait islands between Australia and Papua-New Guinea, shows that it does not represent a member of the SE Asian Zephroniidae, but is a species of the Australian genus Cyliosoma of the Cyliosomatidae, C. larvalis new combination. The syntypes of Cyliosoma albertisii (Silvestri, 1895; Cyliosomatidae), Australia's northern-most Sphaerotheriida species described from Somerset (close to the Torres Strait islands), were restudied, and a lectotype was selected. C. albertisii is discovered to be a junior synonym of C. larvalis (Butler, 1878). C. larvalis, originally described as Zephronia larvalis, clearly belongs to the genus Cyliosoma, but displays some characters, such as a high number (25-30) of apical cones on the antennae, and the reduction of the spine-like projection of the stigmatic plates, that are unique in the genus and family. This synonymy confirms the Torres Strait giant pill-millipede fauna to be an Australian element, and not the first representative of a still undiscovered Papua-New Guinean fauna. PMID- 25283417 TI - New Tortricidae (Lepidoptera) from East Africa with an account of the tortricid fauna of acacia in the Kenyan Rift Valley. AB - Species of Tortricidae whose larvae feed on acacia are listed, including five new species: Hystrichophora bussei Agassiz, Endotera cyaneana Agassiz, Paraeccopsis variegana Agassiz & Aarvik, Coniostola flavitinctana Agassiz & Aarvik, and C. rufitinctana Agassiz & Aarvik. Six additional species related to the aforementioned, whose life histories are not known, also are described: Paraeccopsis tanzanica Aarvik, P. addis Aarvik, P. turi Aarvik, P. botswanae Aarvik, P. pseudoinsellata Aarvik, and Coniostola laikipiana Agassiz & Aarvik. Endotera nodi Agassiz is synonymised with Endotera cyphospila (Meyrick), comb. n.; and Coniostola omistus Diakonoff is synonymised with Coniostola stereoma (Meyrick). Paraeccopsis inflicta (Meyrick) and Paraeccopsis atricapsis (Meyrick) are removed from the synonymy of Paraeccopsis insellata (Meyrick). Eucosma pharangodes Meyrick is transferred to Eucosmocydia Diakonoff. Age onychistica Diakonoff is recorded from Africa for the first time. PMID- 25283418 TI - One new species of the genus Kuzicus (Orthoptera: Tettigoniidae: Meconematinae) from Yunnan, China. AB - One new species is described, i.e. Kuzicus (Kuzicus) compressus Han & Shi sp. nov. The type species is preserved in the Museum of Hebei University. PMID- 25283419 TI - Mollusks from late Mesozoic seep deposits, chiefly in California. AB - Twenty-nine mollusk species from Late Jurassic to Eocene hydrocarbon seep deposits from California (USA), Japan, New Zealand, and Barbados are described and illustrated. Twenty species belong to Gastropoda and nine to Bivalvia. Seven new species, three new genera, and one new family are introduced. The gastropod Hikidea gen. nov. includes smooth-shelled Cantrainea-like colloniins from Cretaceous hydrocarbon seeps and plesiosaur falls. Hikidea osoensis sp. nov. is the oldest species of this genus. Chilodonta? reticulata sp. nov. is a distinctive vetigastropod though its supraspecific position is unclear. Phanerolepida onoensis sp. nov. is the first species of this colloniin genus from a seep deposit. We describe two new genera of Hokkaidoconchidae: Abyssomelania gen. nov. and Ascheria gen. nov.; this family includes now four genera (including Hokkaidoconcha and Humptulipsia) and ranges from the Late Jurassic to the Eocene. Abyssomelania is characterized by a large, high-spired shell and unusual widely spaced prosocline riblets (here called abyssomelaniid riblets). Abyssomelania is represented by two new species: A. cramptoni sp. nov. from the Late Cretaceous of New Zealand and A. campbellae sp. nov. from the Early Cretaceous of California. Ascheria gen. nov. is characterized by a large high-spired cerithiform shell, a subsutural constriction, and mostly reticulate ornament. Two nominate species are included: Ascheria gigantea (Kiel et al., 2008) and A. eucosmeta (Ascher, 1906), both of Early Cretaceous age. Two further species potentially belonging to Ascheria from the Eocene of Barbados are reported in open nomenclature and are re illustrated and re-described for comparison. Humtulipsia nobuharai sp. nov. is described based on specimens from the Campanian-Maastrichtian Sada Limestone seep deposit in Japan. The new family Paskentanidae fam. nov. is introduced for the genera Paskentana and Atresius. The species of this family are characterized by thin-shelled, broad to high-spired littoriniform adult shells and juvenile teleoconchs with a subsutural ramp. Paskentana hamiltonensis sp. nov. is described from the Early Cretaceous of California. Ataphrus is considered to represent a nomen dubium because its type species is poorly preserved and there are uncertainties regarding its type locality and age. The bivalves reported herein belong to known species, but our new material revealed additional characters, and/or their supraspecific position is revised and new combinations are proposed: Solemya stantoni Vokes, 1955 is transferred to Acharax, Nucula gabbi Stanton, 1895 is transferred to Leionucula, Pecten complexicostata Gabb, 1869 is transferred to Lyriochlamys, Astarte californica Stanton, 1895 is transferred to Neocrassina, Astarte trapezoidalis Stanton, 1895 is transferred to Oxyeurax, and Corbula? persulcata Stanton, 1895 is transferred to Cuspidaria? PMID- 25283420 TI - Nomenclatural status of the 'pocketknife fly': Stomoxoides Schaeffer, 1766 (Diptera: Conopidae). AB - The nomenclatural status of the genus Stomoxoides Schaeffer, 1766 is discussed and a timeline of usage is given. The name is shown to be available and date from Schaeffer's 1766 work, and by invoking Article 70.3 of the ICZN Code, the type species of Stomoxoides is fixed as Conops ferrugineus Linnaeus, 1761, misidentified as Conops testacea Linnaeus, 1767 in the fixation by subsequent monotypy as proposed by Linnaeus in 1767. Stomoxoides is thereby synonymous with Sicus Scopoli, 1763 as originally proposed by Yeats in 1773. PMID- 25283421 TI - Two new species of Simulium (Gomphostilbia) (Diptera: Simuliidae) from Peninsular India with keys to Peninsular Indian members of the genus Simulium. AB - Two new species of black flies, Simulium (Gomphostilbia) peteri sp. nov. and S. (G.) takaokai sp. nov., are described on the basis of reared adult, pupal and larval specimens collected from Peninsular India. These two new species are placed in the batoense species group within the subgenus Gomphostilbia. S. (G.) peteri sp. nov. is distinguished in the female by having a medium-sized round opening of the sensory vesicle and a large basal tooth on the claw, in the male by 12 vertical columns in the upper eye large facets, in the pupa by a ventral pair of 2 gill filaments somewhat thicker than the other filaments and in the larva by 5 hypostomal bristles per side lying parallel to the lateral margin. S. (G.) takaokai sp. nov. is characterized in the pupa by having the eight gill filaments with a medium-long common basal stalk and in the larva by the labral fan with 38 main rays and 4 hypostomal bristles on each side. Keys to 13 black fly species reported from Peninsular India are provided for females, males and pupae. PMID- 25283422 TI - Description of immatures of Mesomphalia gibbosa (Fabricius, 1781) and Mesomphalia turrita (Illiger, 1801) (Coleoptera: Chrysomelidae: Cassidinae: Mesomphaliini). AB - Immatures of Mesomphalia gibbosa (Fabricius, 1781) and Mesomphalia turrita (Illiger, 1801) (Coleoptera, Chrysomelidae, Cassidinae, Mesomphaliini) are described based on specimen collections from Rio de Janeiro state, Brazil. The last-instar larva and pupal exuviae of M. gibbosa (Fabricius, 1781) and the eggs, first-instar larva, and pupa of M. turrita (Illiger, 1801) are described, photographed and illustrated, with emphasis on chaetotaxy. Additional notes on their biology are presented. PMID- 25283423 TI - Taxonomic notes on Mahanarva (Ipiranga) (Hemiptera, Cercopidae) with description of a new species. AB - Mahanarva (Ipiranga) takiyae sp. nov. (Cercopidae) is described and illustrated from Brazil. This new species can be distinguished from other known species in the genus by the tegmen with three rounded yellow spots and the shape of the paramere. Mahanarva (Mahanarva) rubripennis is transferred to the subgenus Mahanarva (Ipiranga). PMID- 25283424 TI - The histo structure of galls induced by aphids as a useful taxonomic character: the case of Rectinasus (Hemiptera, Aphididae, Eriosomatinae). AB - Morphological differentiation of gall tissues induced on plants may play a role to characterize the real taxonomic position of the gall inducer. We verified this hypothesis with galls induced by Rectinasus buxtoni on Pistacia palaestina. There is controversy about the taxonomic localization of genus Rectinasus: in one classification it is situated with the genera Forda and Paracletus while in another it is linked to the genera Geoica and Baizongia. Histological examination of the walls of the galls reveals the presence of two opposed vascular bundles and an inner surface of the gall with cavities. These features place Rectinasus in the same group as Geoica and Baizongia, and not with Paracletus and Forda, whose galls have a different histological structure, as generally admitted. PMID- 25283425 TI - Camptotarsopoda annulitarsis Stein: redescription, description of terminalia and new record to South Africa (Diptera: Muscidae). AB - Camptotarsopoda Strand (Diptera, Muscidae) comprises five species restricted to the Afrotropical region. The genus belongs to the subfamily Coenosiinae and tribe Limnophorini. The type-species, C. annulitarsis (Stein), is redescribed and the male and female terminalia are described and illustrated for the first time. The species is newly recorded from South Africa. The systematic placement of the genus is confirmed among the basal Limnophorini. PMID- 25283426 TI - Dendroblatta iani (Rocha e Silva-Albuquerque, 1964) n. comb. (Ectobiidae, Blattellinae). PMID- 25283427 TI - Two new species of Gaeolaelaps (Acari: Mesostigmata: Laelapidae) from Iran, with a revised generic concept and notes on significant morphological characters in the genus. AB - Two new species of laelapid mites of the genus Gaeolaelaps Evans & Till are described based on adult females collected from soil and litter in Kerman Province, southeastern Iran, and Mazandaran Province, northern Iran. Gaeolaelaps jondishapouri Nemati & Kavianpour is redescribed based on the holotype and additional specimens collected in southeastern Iran. The concept of the genus is revised to incorporate some atypical characters of recently described species. Finally, some morphological attributes with potential to define natural species groupings as well as hypoaspidine genera are discussed, particularly idiosomal gland pores and poroids. PMID- 25283428 TI - A new species and new records of the genus Eustigmaeus (Acari: Prostigmata: Stigmaeidae) from Western Siberia. AB - A new species of the genus Eustigmaeus Berlese, 1910 (Acari: Stigmaeidae), E. tjumeniensis sp. nov. is described from mosses of fens in Western Siberia, Russia. Eutigmaeus collarti (Cooreman, 1955), E. ioanninensis Kapaxidi and Papadoulis, 1999, E. jiangxiensis Hu, Chen and Huang, 1996 are recorded from Russia for the first time. Eustigmaeus parvisetus (Chaudhri, 1965) is recorded from Eurasia for the first time. Eustigmaeus collarti and E. parvisetus are redescribed based on material from Western Siberia. A key to Eustigmaeus species of Russia is provided. PMID- 25283429 TI - Records of chimaeroid fishes (Holocephali: Chimaeriformes) from the Pacific coast of Costa Rica, with the description of a new species of Chimera (Chimaeridae) from the eastern Pacific Ocean. AB - A new species of Chimaera Linnaeus 1758 is described from three specimens collected from off the Pacific coasts of Costa Rica and Peru. Chimaera orientalis n. sp., the first species of the genus described from the eastern Pacific Ocean, is distinguished from its other congeners by a combination of coloration and morphology. Additionally, new records of occurrence for another four species of chimaeroid fishes (Harriotta raleighana (Goode & Bean 1895), Rhinochimaera africana Compagno, Stehmann & Ebert 1990, Hydrolagus colliei Lay & Bennett 1839, and H. macrophthalmus de Buen 1959) previously unknown for the continental shelf of the Pacific coast of Costa Rica and Central America are reported. A key to the eastern Pacific species of the order Chimaeriformes is also presented. PMID- 25283430 TI - Miyazakia, a new aphid genus from Japan (Hemiptera: Aphididae: Macrosiphini). AB - Miyazakia gen. nov. with type species Miyazakia ranunculi (Miyazaki, 1971) comb. nov. is described. The species is illustrated and biometric data are provided for all morphs, except the fundatrix. This aphid genus is closely related to Sappaphis Matsumura, 1919. M. ranunculi is a heteroecious species; its primary host is probably Photinia villosa (Thunb.) DC and its secondary host is Ranunculus. PMID- 25283431 TI - First record of the velvet ants (Hymenoptera: Mutillidae) reared from puparia of the ber fruit fly Carpomya vesuviana Costa (Diptera: Tephritidae) in Iran. AB - Two species of mutillids, Smicromyrme (Astomyrme) nikolskajae Lelej, 1985 and S. (Eremotilla) tekensis Skorikov, 1935, reared from puparia of ber fruit fly, Carpomya vesuviana Costa, in South Khorasan, Iran are recorded. Both mutillids are newly recorded from Iran. An overview of eight species of mutillids associated with six species of flies is given in the appendix. PMID- 25283432 TI - Two new endemic species of Lygaeinae from Baja California, Mexico (Hemiptera: Heteroptera: Lygaeidae) . AB - Two new species of Lygaeinae endemic to the Peninsula of Baja California, Mexico, are described. Dalmochrimnus insularis sp. nov. endemic to San Ildefonso Island in the Gulf of California and Melacoryphus lagunensis sp. nov. endemic to the Reserve area of Sierra La Laguna in the South of the Peninsula. A discussion about their relationships within their genera and their endemic status is also provided. PMID- 25283433 TI - Discovery of Setihercostomus Zhang et Yang in the Afrotropical Region (Diptera: Dolichopodidae). PMID- 25283434 TI - Bone morphogenetic proteins: a powerful osteoinductive compound with non negligible side effects and limitations. AB - Healing and regeneration of large bone defects leading to non-unions is a great concern in orthopedic surgery. Since auto- and allografts have limitations, bone tissue engineering and regenerative medicine (TERM) has attempted to solve this issue. In TERM, healing promotive factors are necessary to regulate the several important events during healing. An ideal treatment strategy should provide osteoconduction, osteoinduction, osteogenesis, and osteointegration of the graft or biomaterials within the healing bone. Since many materials have osteoconductive properties, only a few biomaterials have osteoinductive properties which are important for osteogenesis and osteointegration. Bone morphogenetic proteins (BMPs) are potent inductors of the osteogenic and angiogenic activities during bone repair. The BMPs can regulate the production and activity of some growth factors which are necessary for the osteogenesis. Since the introduction of BMP, it has added a valuable tool to the surgeon's possibilities and is most commonly used in bone defects. Despite significant evidences suggesting their potential benefit on bone healing, there are some evidences showing their side effects such as ectopic bone formation, osteolysis and problems related to cost effectiveness. Bone tissue engineering may create a local environment, using the delivery systems, which enables BMPs to carry out their activities and to lower cost and complication rate associated with BMPs. This review represented the most important concepts and evidences regarding the role of BMPs on bone healing and regeneration from basic to clinical application. The major advantages and disadvantages of such biologic compounds together with the BMPs substitutes are also discussed. PMID- 25283435 TI - High-performance liquid-catalyst fuel cell for direct biomass-into-electricity conversion. AB - Herein, we report high-performance fuel cells that are catalyzed solely by polyoxometalate (POM) solution without any solid metal or metal oxide. The novel design of the liquid-catalyst fuel cells (LCFC) changes the traditional gas-solid surface heterogeneous reactions to liquid-catalysis reactions. With this design, raw biomasses, such as cellulose, starch, and even grass or wood powders can be directly converted into electricity. The power densities of the fuel cell with switchgrass (dry powder) and bush allamanda (freshly collected) are 44 mW cm(-2) and 51 mW cm(-2) respectively. For the cellulose-based biomass fuel cell, the power density is almost 3000 times higher than that of cellulose-based microbial fuel cells. Unlike noble-metal catalysts, POMs are tolerant to most organic and inorganic contaminants. Therefore, almost any raw biomass can be used directly to produce electricity without prior purification. PMID- 25283436 TI - Cobalt phenanthroline-indole macrocycles as highly active electrocatalysts for oxygen reduction. AB - The replacement of scarce and expensive platinum species poses a challenge in fuel-cell development. The design and synthesis of a novel type of Co(II) -N4 macrocyclic complex, [CoN4 ], based on the phenanthroline-indole macrocyclic ligand (PIM) is reported. This unique ligand allows the formation of mono- and dinuclear complexes with defined active sites that facilitate the direct four electron reduction of oxygen. Electrochemical measurements revealed that the [CoN4 ]/C (20 wt %) catalysts have a high activity and long-term stability for the oxygen-reduction reaction (ORR) under alkaline conditions, similar to the Pt/C catalyst. These structurally well-defined complexes represent a nonprecious alternative to platinum species for future fuel-cell applications. PMID- 25283438 TI - Augmentation of virulence related traits of pqs mutants by Pseudomonas quinolone signal through membrane vesicles. AB - Pathogenicity of opportunistic Pseudomonas aeruginosa is mediated through expression of different virulence determinants, most of which are under the control of quorum sensing. Besides acylhomoserine lactones, P. aeruginosa produces Pseudomonas quinolone signal (PQS) molecules which co-regulate expression of overlapping subset of genes. In the present study, effect of mutations in the pqs genes on the production of virulence factors, biofilm, and membrane vesicles (MVs) was studied using standard strain and isogenic pqs mutants of P. aeruginosa. Mutations in pqs genes severely reduced elastase, pyocyanin, siderophores, biofilm formation, and production of MVs. Further, effect of synthetic PQS on virulence of P. aeruginosa and its correlation with MVs was investigated. Supplementation of PQS resulted in enhancement of phenotypic expression of virulence factors and biofilm forming capacity of these strains. Restoration of virulent phenotype of mutants in presence of PQS indicated that PQS system play an important role in the virulence of P. aeruginosa. In addition, PQS also induced substantial release of MVs in all strains. When vesicles containing natural PQS were added to the mutants, significant increase in production of virulence factors was observed. This augmentation of the virulence traits may be associated with the efficient delivery of PQS among bacterial cells, which could be one possible mechanism of pqs system contributing to the overall virulence of P. aeruginosa. PMID- 25283437 TI - Amyloid precursor protein (APP) affects global protein synthesis in dividing human cells. AB - Hypoxic non-small cell lung cancer (NSCLC) is dependent on Notch-1 signaling for survival. Targeting Notch-1 by means of gamma-secretase inhibitors (GSI) proved effective in killing hypoxic NSCLC. Post-mortem analysis of GSI-treated, NSCLC burdened mice suggested enhanced phosphorylation of 4E-BP1 at threonines 37/46 in hypoxic tumor tissues. In vitro dissection of this phenomenon revealed that Amyloid Precursor Protein (APP) inhibition was responsible for a non-canonical 4E BP1 phosphorylation pattern rearrangement-a process, in part, mediated by APP regulation of the pseudophosphatase Styx. Upon APP depletion we observed modifications of eIF-4F composition indicating increased recruitment of eIF-4A to the mRNA cap. This phenomenon was supported by the observation that cells with depleted APP were partially resistant to silvestrol, an antibiotic that interferes with eIF-4A assembly into eIF-4F complexes. APP downregulation in dividing human cells increased the rate of global protein synthesis, both cap- and IRES-dependent. Such an increase seemed independent of mTOR inhibition. After administration of Torin-1, APP downregulation and Mechanistic Target of Rapamycin Complex 1 (mTORC-1) inhibition affected 4E-BP1 phosphorylation and global protein synthesis in opposite fashions. Additional investigations indicated that APP operates independently of mTORC-1. Key phenomena described in this study were reversed by overexpression of the APP C-terminal domain. The presented data suggest that APP may be a novel regulator of protein synthesis in dividing human cells, both cancerous and primary. Furthermore, APP appears to affect translation initiation using mechanisms seemingly dissimilar to mTORC-1 regulation of cap dependent protein synthesis. PMID- 25283439 TI - Examining change in cortisol patterns during the 10-week transition to a new child-care setting. AB - The transition to out-of-home child care brings a number of challenges for children, including complex peer interactions and extended separations from parents. Children often show a midmorning to afternoon rise in cortisol on child care days, compared to the typical diurnal decline seen at home. Changes in cortisol were examined in a wide age range of children (N = 168; 1.2 months to 8 years, M = 3.27 years) during the 10-week transition to a new child-care setting. Structural equation modeling using latent change scores showed that children experienced an increase in the cortisol rise at child care across the 10-week transition. Furthermore, child age moderated the difference between home- and child-care cortisol patterns. Findings are placed in a developmental context, and potential implications and future directions are discussed. PMID- 25283440 TI - The role of casein-specific IgA and TGF-beta in children with food protein induced enterocolitis syndrome to milk. AB - BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a gastrointestinal hypersensitivity disorder with a poorly understood pathophysiology and no biomarkers to aid in diagnosis. OBJECTIVE: To investigate humoral and cellular responses to casein in children with milk-FPIES, including the role of casein-specific (cs) IgA and T-cell mediated TGF-beta responses. PATIENTS AND METHODS: Thirty-one children previously diagnosed with milk-FPIES were challenged with milk. Twelve age-matched children with FPIES to other foods and 6 milk-tolerant children without a history of FPIES were used as controls. Casein-specific IgE, IgG, IgG4, and IgA were measured in serum and TGF-beta levels in supernatants of casein-stimulated PBMCs. RESULT: Twenty-six children with milk-FPIES reacted (active milk-FPIES) and five tolerated milk (milk-FPIES resolved) during food challenge. All of them had significantly lower levels of csIgG, csIgG4, and csIgA than control children (p-value<0.001). There were no TGF beta responses in supernatants of active milk-FPIES children. CONCLUSION: Children with milk-FPIES have low levels of csIgG, csIgG4, and csIgA. In particular, children with active FPIES to cow's milk have deficient T-cell mediated TGF-beta responses to casein, rendering TGF-beta a promising biomarker in identifying children who are likely to experience FPIES reactions to this allergen. Prospective studies are needed to validate these findings, elucidate their role in FPIES pathophysiology, and establish the diagnostic utility of TGF beta in milk-induced FPIES. PMID- 25283441 TI - Assembly patterns of mixed-species avian flocks in the Andes. AB - The relative contribution of deterministic and stochastic processes in the assembly of biotic communities is a central issue of controversy in community ecology. However, several studies have shown patterns of species segregation that are consistent with the hypothesis that deterministic factors such as competition and niche-partitioning structure species assemblages in animal communities. Community assembly provides a theoretical framework for understanding these processes, but it has been seldom applied to social aggregations within communities. In this research, we assessed patterns of non-randomness in Andean mixed-species flocks using three assembly models: (i) co-occurrence patterns; (ii) guild proportionality; and (iii) constant body-size ratios using data from 221 species of resident and Neotropical migrant birds participating in 311 mixed species flocks at 13 regions distributed in Venezuela, Colombia, Ecuador and Peru. Significant assembly patterns for mixed-species flocks based on co occurrence models and guild proportionality models suggest that competitive interactions play an important role in structuring this social system in the Andes. Distribution of species among foraging guilds (i.e. insectivore, frugivore, omnivore, nectivore) was generally similar among flocks, though with some regional variation. In contrast, we found little evidence that structuring of mixed-species flocks in the Andes was mediated by body size. Rather, we found greater than expected variance of body-size ratios within flocks, indicating that birds did not segregate morphologically. Overall, our findings suggest that deterministic factors associated to competitive interactions are important contributors to mixed-species flock assemblages across the Andes. PMID- 25283443 TI - Stereospecific mechanism of DJ-1 glyoxalases inferred from their hemithioacetal containing crystal structures. AB - DJ-1 family proteins have recently been characterized as novel glyoxalases, although their cofactor-free catalytic mechanisms are not fully understood. Here, we obtained crystals of Arabidopsis thaliana DJ-1d (atDJ-1d) and Homo sapiens DJ 1 (hDJ-1) covalently bound to glyoxylate, an analog of methylglyoxal, forming a hemithioacetal that presumably mimics an intermediate structure in catalysis of methylglyoxal to lactate. The deuteration level of lactate supported the proton transfer mechanism in the enzyme reaction. Differences in the enantiomeric specificity of d/l-lactacte formation observed for the DJ-1 superfamily proteins are explained by the presence of a His residue in the active site with essential Cys and Glu residues. The model for the stereospecificity was further evaluated by a molecular modeling simulation with methylglyoxal hemithioacetal superimposed on the glyoxylate hemithioacetal. The mechanism of DJ-1 glyoxalase provides a basis for understanding the His residue-based stereospecificity. DATABASE: Structural data have been submitted to the Protein Data Bank under accession numbers 4OFW (structure of atDJ-1d), 4OGF (structure of hDJ-1 with glyoxylate) and 4OGG (structure of atDJ-1d with glyoxylate). PMID- 25283444 TI - Disclosing unavoidable causes of adverse events improves patients' feelings towards doctors. AB - The process of medical mediation involves the reconstruction of doctor-patient relationships through sharing mutual truthful information and encouraging dialogue between doctors and their patients. This study was designed to examine the effects of disclosing the avoidable as well as unavoidable causes of doctors' behavior following malpractice or perceived inconsiderate behavior on patients' feelings in medical mediation. An avoidable cause was defined as doctor's behavior that was incautious or showed insufficient empathy. An unavoidable one, however, was defined as any cause other than doctors' behavior. A questionnaire was administered to 385 Japanese hospital outpatients, in which participants were presented a range of scenarios with the above two causes for doctor's behavior or an adverse event. Participants' feelings toward the doctor in each scenario were measured on a seven-point scale following disclosure of each cause. The five scenarios provoking negative feelings toward doctors involved "(the patient) being ignored," "refusal of a request," "dominating behavior," "a minor incident," and "an adverse event." The valid response rate was 62.9% (242/385). Negative feelings were evoked in all five scenarios. After disclosure of avoidable causes, scores for negative feelings significantly increased between 3% and 33%. In contrast, after disclosure of unavoidable causes, scores for negative feelings significantly decreased between 11% and 43%. These findings imply that disclosure of causal information in medical mediation will provide the opportunity to reevaluate unexpected doctors' behavior and change patients' negative feelings. Therefore, disclosures should be made in the case of not only unavoidable causes but also avoidable ones. PMID- 25283442 TI - Non-typeable pneumococci circulating in Portugal are of cps type NCC2 and have genomic features typical of encapsulated isolates. AB - BACKGROUND: Pneumococcus is a major human pathogen and the polysaccharide capsule is considered its main virulence factor. Nevertheless, strains lacking a capsule, named non-typeable pneumococcus (NT), are maintained in nature and frequently colonise the human nasopharynx. Interest in these strains, not targeted by any of the currently available pneumococcal vaccines, has been rising as they seem to play an important role in the evolution of the species. Currently, there is a paucity of data regarding this group of pneumococci. Also, questions have been raised on whether they are true pneumococci. We aimed to obtain insights in the genetic content of NT and the mechanisms leading to non-typeability and to genetic diversity. RESULTS: A collection of 52 NT isolates representative of the lineages circulating in Portugal between 1997 and 2007, as determined by pulsed field gel electrophoresis and multilocus sequence typing, was analysed. The capsular region was sequenced and comparative genomic hybridisation (CGH) using a microarray covering the genome of 10 pneumococcal strains was carried out. The presence of mobile elements was investigated as source of intraclonal variation. NT circulating in Portugal were found to have similar capsular regions, of cps type NCC2, i.e., having aliB-like ORF1 and aliB-like ORF2 genes. The core genome of NT was essentially similar to that of encapsulated strains. Also, competence genes and most virulence genes were present. The few virulence genes absent in all NT were the capsular genes, type-I and type-II pili, choline-binding protein A (cbpA/pspC), and pneumococcal surface protein A (pspA). Intraclonal variation could not be entirely explained by the presence of prophages and other mobile elements. CONCLUSIONS: NT circulating in Portugal are a homogeneous group belonging to cps type NCC2. Our observations support the theory that they are bona-fide pneumococcal isolates that do not express the capsule but are otherwise essentially similar to encapsulated pneumococci. Thus we propose that NT should be routinely identified and reported in surveillance studies. PMID- 25283445 TI - Geriatric medicine and counterinsurgency: what can we learn about combating frailty? PMID- 25283446 TI - Enhanced formation of aromatic amino acids increases fragrance without affecting flower longevity or pigmentation in Petunia * hybrida. AB - Purple Petunia * hybrida V26 plants accumulate fragrant benzenoid-phenylpropanoid molecules and anthocyanin pigments in their petals. These specialized metabolites are synthesized mainly from the aromatic amino acids phenylalanine. Here, we studied the profile of secondary metabolites of petunia plants, expressing a feedback-insensitive bacterial form of 3-deoxy-di-arabino-heptulosonate 7 phosphate synthase enzyme (AroG*) of the shikimate pathway, as a tool to stimulate the conversion of primary to secondary metabolism via the aromatic amino acids. We focused on specialized metabolites contributing to flower showy traits. The presence of AroG* protein led to increased aromatic amino acid levels in the leaves and high phenylalanine levels in the petals. In addition, the AroG* petals accumulated significantly higher levels of fragrant benzenoid phenylpropanoid volatiles, without affecting the flowers' lifetime. In contrast, AroG* abundance had no effect on flavonoids and anthocyanins levels. The metabolic profile of all five AroG* lines was comparable, even though two lines produced the transgene in the leaves, but not in the petals. This implies that phenylalanine produced in leaves can be transported through the stem to the flowers and serve as a precursor for formation of fragrant metabolites. Dipping cut petunia stems in labelled phenylalanine solution resulted in production of labelled fragrant volatiles in the flowers. This study emphasizes further the potential of this metabolic engineering approach to stimulate the production of specialized metabolites and enhance the quality of various plant organs. Furthermore, transformation of vegetative tissues with AroG* is sufficient for induced production of specialized metabolites in organs such as the flowers. PMID- 25283447 TI - Promoting siRNA delivery via enhanced cellular uptake using an arginine-decorated amphiphilic dendrimer. AB - RNA interference (RNAi) with small interfering RNA (siRNA) is expected to offer an attractive means to specifically and efficiently silence disease-associated genes for treating various diseases provided that safe and efficient delivery systems are available. In this study, we have established an arginine-decorated amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic PAMAM dendron bearing arginine terminals as nonviral vector for siRNA delivery. Indeed, this dendrimer proved to be very effective at delivering siRNAs in human prostate cancer PC-3 cells and in human hematopoietic CD34+ stem cells, leading to improved gene silencing compared to the corresponding nonarginine decorated dendrimer. Further investigation confirmed that this dendrimer was granted with the capacity to form stable nanoparticles with siRNA and significantly enhance cellular uptake of siRNA. In addition, this dendrimer revealed no discernible cytotoxicity. All these findings demonstrate that decoration of the dendrimer surface with arginine residues is indeed a useful strategy to improve the delivery ability of dendrimers. PMID- 25283448 TI - Evaluation of direct versus multi-layer passivation and capture chemistries for nanoparticle-based biosensor applications. AB - Nanoparticles used in biosensor applications often fail when deployed directly in complex biological fluids. This is due to surface fouling and interference from the large concentration of non-specific binders (proteins, lipids, nucleic acids and saccharides) in the matrix. We systematically investigate four orthogonal approaches for decorating nanoparticle surfaces with affinity probes and evaluate their performance in buffer and serum. Carbodiimide coupling, cooper-mediated 'click' coupling, copper-free click coupling and thiol-maleimide coupling were quantitatively controlled during the fabrication process. Analyte mediated aggregation of fluorescent reporters and paramagnetic nanoparticle in a sandwich immunoassay was then used to probe assay sensitivity and specificity using an early biomarker of dengue fever, NS-1, as an exemplar and clinically relevant analyte. The type of surface functionalization played a vital role in assay performance in buffer versus serum at the assay sensitivity limit (3 ng/mL in serum) and over the linearity of response of the assay's dynamic range. There was a 10 fold increase on the dynamic range of the detection of NS1 comparing copper free click coupling to carbodiimide coupling, one of the most common approaches for nanoparticle functionalization. By tuning their size, we could carefully monitor the evolution of nanoparticle populations by flow cytometer and discriminate between unbound and fluorescent nanoparticles. This subtle control on each assay component resulted in more than a 10-fold reduction in fluorescence background and improved the sensitivity of almost two orders of magnitude compared to endpoint measurements. PMID- 25283450 TI - Erratum. PMID- 25283449 TI - Droplet-based immunoassay on a 'sticky' nanofibrous surface for multiplexed and dual detection of bacteria using smartphones. AB - We have developed a rapid, sensitive, and specific droplet-based immunoassay for the detection of Escherichia coli and Salmonella within a single-pipetted sample. Polycaprolactone (PCL) electrospun fibers on indium-tin-oxide (ITO) glass provide a sufficient surface to render a non-slip droplet condition, and while the PCL fibers lend a local hydrophilicity (contact angle theta=74 degrees ) for sufficient sub-micron particle adhesion, air pockets within the fibers lend an apparent hydrophobicity. Overall, the contact angle of water on this electrospun surface is 119 degrees , and the air pockets cause the droplet to be completely immobile and resistant to movement, protecting it from external vibration. By using both anti-E. coli conjugated, 510 nm diameter green fluorescent particles (480 nm excitation and 520 nm emission) and anti-Salmonella conjugated, 400 nm diameter red fluorescent particles (640 nm excitation and 690 nm emission), we can detect multiple targets in a single droplet. Using appropriate light sources guided by fiber optics, we determined a detection limit of 10(2) CFU mL(-1). Immunoagglutination can be observed under a fluorescence microscope. Fluorescence detection (at the emission wavelength) of immunoagglutination was maximum at 90 degrees from the incident light, while light scattering (at the excitation wavelength) was still present and behaved similarly, indicating the ability of double detection, greatly improving credibility and reproducibility of the assay. A power function (light intensity) simulation of elastic Mie scatter confirmed that both fluorescence and light scattering were present. Due to the size of the fluorescent particles relative to their incident excitation wavelengths, Mie scatter conditions were observed, and fluorescence signals show a similar trend to light scattering signals. Smartphone detection was included for true portable detection, in which the high contact angle pinning of the droplet makes this format re-usable and re-configurable. PMID- 25283451 TI - Preoperative evaluation of the body contouring patient: the cornerstone of patient safety. AB - The obesity pandemic has resulted in increasing cases of bariatric surgery and subsequent issues related to excess skin and laxity for patients. This patient population requires unique insight and consideration as part of the preoperative evaluation. Nutritional derangements are common, psychosocial issues are prevalent, and the sequelae of past and present medical conditions can all affect surgical planning and outcomes. This article familiarizes the plastic surgeon with the issues of the body contouring candidate and provides tools that may assist in surgical planning. PMID- 25283452 TI - Assessing outcomes in body contouring. AB - Patient-reported outcome (PRO) instruments are questionnaires designed to measure outcomes of importance to patients from their perspective. This article describes the methods used to develop a new PRO instrument for obese patients and patients having bariatric and cosmetic body contouring surgery. The BODY-Q is composed of 19 newly designed scales that measure: (1) appearance; (2) health-related quality of life; and (3) process of care. Recommended guidelines for PRO instrument development were followed to ensure that the BODY-Q meets requirements of regulatory bodies. The BODY-Q is currently being field-tested in an international study. PMID- 25283453 TI - Abdominoplasty: classic principles and technique. AB - Examination of abdominal contour surgery candidates permits categorization of patients (the abdominolipoplasty system of classification and treatment) according to their treatable soft tissue layers of skin, fat, and muscle into the appropriate treatment level. Typically, postpartum abdominal wall changes are most thoroughly addressed by abdominoplasty. The indications and goals for abdominoplasty with liposuction (lipoadminoplasty) or without liposuction are presented. Surgical markings, technique, pain management, and postoperative care are described. PMID- 25283454 TI - The Fleur-De-Lis abdominoplasty. AB - Vertical abdominoplasty is a safe and effective procedure to correct abdominal contour abnormalities in individuals with excessive soft tissue in both the vertical and transverse orientation. The literature, although limited, supports the effectiveness of this procedure in addressing this clinical scenario. Further, the complication rates are comparable to a standard transverse abdominoplasty. PMID- 25283455 TI - Two position comprehensive approach to abdominoplasty. AB - Modern abdominoplasty is a powerful and safe body sculpturing tool. In combination with other body contouring procedures, it can lead to a comprehensive body transformation: anatomic, physiologic, and psychological. With vigilant patient screening, preoperative planning, and aggressive postoperative management, modern abdominoplasty can be safely and effectively performed in combination with other procedures. PMID- 25283456 TI - The extended abdominoplasty. AB - This article illustrates the author's approach of directly excising adipose tissue excess in the lateral and posterior hip region by extending the lateral extent of the horizontal incision in a full abdominoplasty toward the posterior axillary line to produce a superior contour in this region. It is most applicable in patients with a significant adipose tissue excess in the lateral hip area that produces an outward convexity seen in the frontal, posterior, or oblique view. Such an excess represents a soft tissue "dog ear" composed of skin, and adipose tissue both deep and superficial to the superficial fascial system. PMID- 25283457 TI - The bra-line back lift: a simple approach to correcting severe back rolls. AB - Anatomic sequelae of the upper back that occur with age or weight loss have been somewhat underserved in the plastic surgery literature. Zones of adherence in the upper posterior trunk create overhanging folds of skin and subcutaneous tissue, which are disturbing to the patient both functionally and cosmetically. These adherence points prove challenging in that they prevent contouring of the upper back with procedures such as traditional abdominoplasty or lower body lift. The bra line back lift provides a reliable and consistent method of addressing these issues by eliminating excess redundant skin and adiposity from the region. PMID- 25283458 TI - The vertical medial thigh lift. AB - This article discusses management of the post-weight loss thigh deformity. Beginning with an explanation of the soft tissue variables contributing to the thigh and medial thigh deformity in the postbariatric individual, the article describes the important elements of selecting and screening candidates for surgery and the ideal sequence of procedures that should be followed to optimize results in this patient population. A detailed step-by-step description of the author's technique for medial thigh lift is provided along with multiple examples of outcomes. Aftercare is reviewed along with potential complications and their management. PMID- 25283459 TI - Brachioplasty. AB - This article contrasts the ideal appearance of the female upper arm, axilla, and upper midlateral chest with the sagging and/or oversized deformity. The constellation of postbrachioplasty aesthetic deformity is introduced. These aesthetic shortcomings are best avoided, because they are difficult to correct. The L brachioplasty with liposuction is described in a recent case and applied to a variety of deformities to show the range of applicability and quality of results. The role of liposuction in arm reshaping is examined. The aesthetic advantages and low complication rate of the L brachioplasty are contrasted with other currently popular brachioplasties. PMID- 25283460 TI - Brachioplasty with limited scar. AB - There is a growing interest in upper arm aesthetic surgery but many patients do not accept the visible inner arm scar. Minimal incision brachioplasty using a shorter scar, concealed in the axilla, produces results equal to that of the traditional approach in comparable cases. Patients with massive weight loss may not meet the criteria for surgery. Patient selection and careful preoperative markings are critical to the success of the procedure. The author describes the technique he has been using for more than 30 years along with refinements. Minimal incision brachioplasty is an alternative to the traditional long scar approach in selected patients. It is a less involved procedure, with a low complication rate and high patient satisfaction. PMID- 25283461 TI - Circumferential truncal contouring: the belt lipectomy. AB - The primary goal of belt lipectomy surgery is to improve the contour of the inferior truncal circumferential unit and to place the resultant scar in natural junctions. Excessive intra-abdominal content is a contraindication for belt lipectomy. The higher the presenting patient's body mass index (BMI), the higher the risk of postoperative complications and the less impressive the results. The converse is also true: the lower the BMI, the lower the risk of complications and the better the results. The most common complications are small wound separations and seromas. PMID- 25283462 TI - Circumferential body contouring: the lower body lift. AB - A 2-position circumferential approach for body contouring of the lower trunk is presented. Mostly indicated in patients after massive weight loss, this approach allows the simultaneous skin resection and reshaping in the abdominal, flank, lateral thigh, back, and gluteal region in the same operation, with only one position change during surgery. Reconstruction of the abdominal wall and gluteal restoration allow volume and shape enhancement with autologous tissue transpositioning. This article explains the required preconditions, assessment of gluteal deformities, and perioperative management of this procedure, and presents common complications. PMID- 25283463 TI - Noninvasive and minimally invasive techniques in body contouring. AB - Major surgical body contouring procedures have several inherent drawbacks, including hospitalization, anesthetic use, pain, swelling, and prolonged recovery. It is for these reasons that body contouring through noninvasive and minimally invasive methods has become one of the most alluring areas in aesthetic surgery. Patient expectations and demands have driven the field toward safer, less-invasive procedures with less discomfort, fewer complications, and a shorter recovery. In this article, the current minimally invasive and noninvasive modalities for body contouring are reviewed. PMID- 25283465 TI - Body contouring. PMID- 25283464 TI - Prevention and management of complications in body contouring surgery. AB - This patient safety article discusses strategies to prevent, diagnose, and manage complications from body contouring surgery. Preoperative, intraoperative, and postoperative approaches to avoiding, identifying, and treating complications are addressed. Individual complications, such as hematoma, seroma, infection, dehiscence, suture extrusion, deep venous thrombosis, and pulmonary embolism are discussed and a review of complication rates in the body contouring literature is provided. The article addresses procedure-specific complications and pearls to avoiding complications in these cases. Difficult problems such as skin relaxation and management of the disappointed patient are also discussed. PMID- 25283466 TI - Beyond the great wall: recent advances in molecular pharmaceutics research in China. PMID- 25283467 TI - Diversity in ATP concentrations in a single bacterial cell population revealed by quantitative single-cell imaging. AB - Recent advances in quantitative single-cell analysis revealed large diversity in gene expression levels between individual cells, which could affect the physiology and/or fate of each cell. In contrast, for most metabolites, the concentrations were only measureable as ensemble averages of many cells. In living cells, adenosine triphosphate (ATP) is a critically important metabolite that powers many intracellular reactions. Quantitative measurement of the absolute ATP concentration in individual cells has not been achieved because of the lack of reliable methods. In this study, we developed a new genetically encoded ratiometric fluorescent ATP indicator "QUEEN", which is composed of a single circularly-permuted fluorescent protein and a bacterial ATP binding protein. Unlike previous FRET-based indicators, QUEEN was apparently insensitive to bacteria growth rate changes. Importantly, intracellular ATP concentrations of numbers of bacterial cells calculated from QUEEN fluorescence were almost equal to those from firefly luciferase assay. Thus, QUEEN is suitable for quantifying the absolute ATP concentration inside bacteria cells. Finally, we found that, even for a genetically-identical Escherichia coli cell population, absolute concentrations of intracellular ATP were significantly diverse between individual cells from the same culture, by imaging QUEEN signals from single cells. PMID- 25283468 TI - Microdamage assessment of bone-cement interfaces under monotonic and cyclic compression. AB - Bone-cement interface has been investigated under selected loading conditions, utilising experimental techniques such as in situ mechanical testing and digital image correlation (DIC). However, the role of bone type in the overall load transfer and mechanical behaviour of the bone-cement construct is yet to be fully quantified. Moreover, microdamage accumulation at the interface and in the cement mantle has only been assessed on the exterior surfaces of the samples, where no volumetric information could be obtained. In this study, some typical bone-cement interfaces, representative of different fixation scenarios for both hip and knee replacements, were constructed using mainly trabecular bone, a mixture of trabecular and cortical bone and mainly cortical bone, and tested under static and cyclic compression. Axial displacement and strain fields were obtained by means of digital volume correlation (DVC) and microdamage due to static compression was assessed using DVC and finite element (FE) analysis, where yielded volumes and strains (epsilonzz) were evaluated. A significantly higher load was transferred into the cement region when mainly cortical bone was used to interdigitate with the cement, compared with the other two cases. In the former, progressive damage accumulation under cyclic loading was observed within both the bone-cement interdigitated and the cement regions, as evidenced by the initiation of microcracks associated with high residual strains (epsilonzz_res). PMID- 25283469 TI - Using multiple daily pain ratings to improve reliability and assay sensitivity: how many is enough? AB - The Initiative for Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has reported diminished assay sensitivity in pain treatment trials and recommended investigation of the causes. Specific recommendations included examination of outcome measure reliability and lengthening the baseline measurement period to allow more measurements to be collected. This secondary data analysis evaluated the minimum number of daily pain intensity ratings required to obtain a reliability of at least .90 and whether a composite of this smaller number of ratings was interchangeable with the composite of all ratings. Veterans Affairs medical center patients made 14 daily calls to an automated telephone system to report their average daily pain intensity rating. A single daily rating produced less than adequate reliability (intraclass correlation coefficient = .65), but a composite of the average of 5 ratings resulted in reliability above .90. A Bland-Altman analysis revealed that the differences between a 5-day composite and the composite of all ratings were small (mean .09 points, standard deviation = .45; 95% confidence interval = -.05 to .23) and below the threshold for a clinically meaningful difference, indicating that the 2 measurements are interchangeable. Our results support the IMMPACT recommendations for improving assay sensitivity by collecting a multiple-day baseline of pain intensity ratings. PERSPECTIVE: This study examined the minimum number of pain ratings required to achieve reliability of .90 and examined whether this smaller subset of ratings could be used interchangeably with a composite of all available ratings. Attention to measure reliability could enhance the assay sensitivity, power, and statistical precision of pain treatment trials. PMID- 25283470 TI - Segregating the cerebral mechanisms of antidepressants and placebo in fibromyalgia. AB - Antidepressant drugs are commonly used to treat fibromyalgia, but there is little knowledge about their mechanisms of action. The aim of this study was to compare the cerebral and behavioral response to positive treatment effects of antidepressants or placebo. Ninety-two fibromyalgia patients participated in a 12 week, double-blind, placebo-controlled clinical trial with milnacipran, a serotonin-norepinephrine reuptake inhibitor. Before and after treatment, measures of cerebral pain processing were obtained using functional magnetic resonance imaging. Also, there were stimulus response assessments of pressure pain, measures of weekly pain, and fibromyalgia impact. Following treatment, milnacipran responders exhibited significantly higher activity in the posterior cingulum compared with placebo responders. The mere exposure to milnacipran did not explain our findings because milnacipran responders exhibited increased activity also in comparison to milnacipran nonresponders. Stimulus response assessments revealed specific antihyperalgesic effects in milnacipran responders, which was also correlated with reduced clinical pain and with increased activation of the posterior cingulum. A short history of pain predicted positive treatment response to milnacipran. We report segregated neural mechanisms for positive responses to treatment with milnacipran and placebo, reflected in the posterior cingulum. The increase of pain-evoked activation in the posterior cingulum may reflect a normalization of altered default mode network processing, an alteration implicated in fibromyalgia pathophysiology. PERSPECTIVE: This study presents neural and psychophysical correlates to positive treatment responses in patients with fibromyalgia, treated with either milnacipran or placebo. The comparison between placebo responders and milnacipran responders may shed light on the specific mechanisms involved in antidepressant treatment of chronic pain. PMID- 25283471 TI - Lenalidomide for complex regional pain syndrome type 1: lack of efficacy in a phase II randomized study. AB - Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as >=30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials. PERSPECTIVE: This article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials. PMID- 25283472 TI - The formation of highly oxidized multifunctional products in the ozonolysis of cyclohexene. AB - The prompt formation of highly oxidized organic compounds in the ozonolysis of cyclohexene (C6H10) was investigated by means of laboratory experiments together with quantum chemical calculations. The experiments were performed in borosilicate glass flow tube reactors coupled to a chemical ionization atmospheric pressure interface time-of-flight mass spectrometer with a nitrate ion (NO3(-))-based ionization scheme. Quantum chemical calculations were performed at the CCSD(T)-F12a/VDZ-F12//omegaB97XD/aug-cc-pVTZ level, with kinetic modeling using multiconformer transition state theory, including Eckart tunneling corrections. The complementary investigation methods gave a consistent picture of a formation mechanism advancing by peroxy radical (RO2) isomerization through intramolecular hydrogen shift reactions, followed by sequential O2 addition steps, that is, RO2 autoxidation, on a time scale of seconds. Dimerization of the peroxy radicals by recombination and cross-combination reactions is in competition with the formation of highly oxidized monomer species and is observed to lead to peroxides, potentially diacyl peroxides. The molar yield of these highly oxidized products (having O/C > 1 in monomers and O/C > 0.55 in dimers) from cyclohexene ozonolysis was determined as (4.5 +/- 3.8)%. Fully deuterated cyclohexene and cis-6-nonenal ozonolysis, as well as the influence of water addition to the system (either H2O or D2O), were also investigated in order to strengthen the arguments on the proposed mechanism. Deuterated cyclohexene ozonolysis resulted in a less oxidized product distribution with a lower yield of highly oxygenated products and cis-6-nonenal ozonolysis generated the same monomer product distribution, consistent with the proposed mechanism and in agreement with quantum chemical modeling. PMID- 25283474 TI - Signals of heterogeneous selection at an MHC locus in geographically proximate ecotypes of sockeye salmon. AB - The genes of the major histocompatibility complex (MHC) are an important component of the vertebrate immune system and can provide insights into the role of pathogen-mediated selection in wild populations. Here, we examined variation at the MHC class II peptide-binding region in 27 populations of sockeye salmon (Oncorhynchus nerka), distributed among three distinct spawning ecotypes, from a complex of interconnected rivers and lakes in south-western Alaska. We also obtained genotypes from 90 putatively neutral single nucleotide polymorphisms for each population to compare the relative roles of demography and selection in shaping the observed MHC variation. We found that MHC divergence was generally partitioned by spawning ecotype (lake beaches, rivers and streams) and was 30 times greater than variation at neutral markers. Additionally, we observed substantial differences in modes of selection and diversity among ecotypes, with beach populations displaying higher levels of directional selection and lower MHC diversity than the other two ecotypes. Finally, the level of MHC differentiation in our study system was comparable to that observed over much larger geographic ranges, suggesting that MHC variation does not necessarily increase with increasing spatial scale and may instead be driven by fine-scale differences in pathogen communities or pathogen virulence. The low levels of neutral structure and spatial proximity of populations in our study system indicate that MHC differentiation can be maintained through strong selective pressure even when ample opportunities for gene flow exist. PMID- 25283473 TI - High prevalence of falls, fear of falling, and impaired balance in older adults with pain in the United States: findings from the 2011 National Health and Aging Trends Study. AB - OBJECTIVES: To determine the prevalence of clinically relevant falls-related outcomes according to pain status in older adults in the United States. DESIGN: Cross-sectional analysis of the 2011 National Health and Aging Trends Study, a sample of Medicare enrollees aged 65 and older (response rate 71.0%). SETTING: In person assessments were conducted in the home or residential care facility of the sampled study participant. PARTICIPANTS: Individuals aged 65 and older (n = 7,601, representing 35.3 million Medicare beneficiaries). MEASUREMENTS: Participants were asked whether they had been "bothered by pain" and the location of pain, as well as questions about balance and coordination, fear of falling, and falls. RESULTS: Fifty-three percent of the participants reported bothersome pain. The prevalence of recurrent falls in the past year (>= 2 falls) was 19.5% in participants with pain and 7.4% in those without (age- and sex-adjusted prevalence ratio (PR) = 2.63, 95% confidence interval (CI) = 2.28-3.05). The prevalence of fear of falling that limits activity was 18.0% in those with pain and 4.4% in those without (adjusted PR = 3.98, 95% CI = 3.24-4.87). Prevalence of balance and falls outcomes increased with number of pain sites. For example, prevalence of problems with balance and coordination that limited activity was 6.6% in participants with no pain, 11.6% in those with one site of pain, 17.7% in those with two sites, 25.0% in those with three sites, and 41.4% in those with four or more sites (P < .001 for trend). Associations were robust to adjustment for several potential confounders, including cognitive and physical performance. CONCLUSION: Falls-related outcomes were substantially more common in older adults with pain than in those without. Accordingly, pain management strategies should be developed and evaluated for falls prevention. PMID- 25283475 TI - Prognostic relevance of estrogen receptor-alpha Ser167 phosphorylation in stage II-III colon cancer patients. AB - Preclinical and clinical data suggest a protective role for estrogens on colon cancer (CRC) risk. estrogen receptor (ER) beta is the prevalent ER in normal colonic mucosa, whereas its expression is significantly reduced in CRC. An increased ERalpha/beta ratio has been documented in colon carcinomas and is associated with increased proliferation and decreased apoptosis. The aim of our study was to evaluate the expression of activated ERalpha and its prognostic implications in patients with stage II-III CRC. Phospho-ERalpha(Ser167) (pERalpha(Ser167)) expression was assessed by immunohistochemistry in 218 CRC paraffin-embedded tumor samples. A high pERalpha(Ser167) expression was more commonly observed in women, older patients, and patients with high baseline glucose levels. This higher pERalpha(Ser167) expression was associated with decreased 5-year disease-free interval (DFI; 66% versus 78%, P = .07) and overall survival (65% versus 73%, P = .46). The negative impact of high pERalpha(Ser167) expression on DFI was particularly significant (P < .05) in women (85% versus 60%), young (82% versus 61%), nondiabetic (85% versus 66%), and stage II patients (86% versus 72% and low versus high pERalpha(Ser167), respectively). Multivariate analysis confirmed that pERalpha(Ser167) score was a significant prognostic factor for both DFI and overall survival, independent of sex, age, glucose levels, tumor stage, bowel obstruction/perforation, or adjuvant chemotherapy. These findings illustrate the relevance of estrogen pathways in colon cancer biology and may provide novel therapeutic avenues to be explored in this context. PMID- 25283476 TI - Telocytes are reduced during fibrotic remodelling of the colonic wall in ulcerative colitis. AB - Ulcerative colitis (UC) is characterized by chronic relapsing intestinal inflammation finally leading to extensive tissue fibrosis and resulting in a stiff colon unable to carry out peristalsis or to resorb fluids. Telocytes, a peculiar type of stromal cells, have been recently identified in the human gastrointestinal tract. Several roles have been proposed for telocytes, including mechanical support, intercellular signalling and modulation of intestinal motility. The aim of the present work was to investigate the presence and distribution of telocytes in colonic specimens from UC patients compared with controls. Archival paraffin-embedded samples of the left colon from UC patients who underwent elective bowel resection and controls were collected. Tissue sections were stained with Masson's trichrome to detect fibrosis. Telocytes were identified by CD34 immunohistochemistry. In early fibrotic UC cases, fibrosis affected the muscularis mucosae and submucosa, while the muscularis propria was spared. In advanced fibrotic UC cases, fibrosis extended to affect the muscle layers and the myenteric plexus. Few telocytes were found in the muscularis mucosae and submucosa of both early and advanced fibrotic UC colonic wall. In the muscle layers and myenteric plexus of early fibrotic UC, telocytes were preserved in their distribution. In the muscularis propria of advanced fibrotic UC, the network of telocytes was reduced or even completely absent around smooth muscle bundles and myenteric plexus ganglia, paralleling the loss of the network of interstitial cells of Cajal. In UC, a loss of telocytes accompanies the fibrotic remodelling of the colonic wall and might contribute to colonic dysmotility. PMID- 25283477 TI - Divergent nod-containing Bradyrhizobium sp. DOA9 with a megaplasmid and its host range. AB - Bradyrhizobium sp. DOA9, a non-photosynthetic bacterial strain originally isolated from the root nodules of the legume Aeschynomene americana, is a divergent nod-containing strain. It exhibits a broad host range, being able to colonize and efficiently nodulate the roots of most plants from the Dalbergioid, Millettioid, and Robinioid tribes (7 species of Papilionoideae). In all cases, nodulation was determinate. The morphology and size of DOA9 bacteroids isolated from the nodules of various species of Papilionoideae were indistinguishable from the free-living form. However, they were spherical in Arachis hypogaea nodules. GusA-tagged DOA9 also colonized rice roots as endophytes. Since broad-host-range legume symbionts often carry multiple replicons in their genome, we analyzed the replicons for symbiosis genes by electrophoresis. DOA9 carried two replicons, a chromosome (cDOA9) and single megaplasmid (pDOA9) larger than 352 kb. The genes for nodulation (nodA, B, C) and nitrogen fixation (nifH) were localized on the megaplasmid. Southern blot hybridization revealed two copies of nodA on the megaplasmid, single copies of nodB and C on the megaplasmid, and one copy each of nifH on the chromosome and megaplasmid. These results suggested that Bradyrhizobium sp. DOA9 may have the unusual combination of a broad host range, bacteroid differentiation, and symbiosis-mediating replicons. PMID- 25283478 TI - Intestinal colonization by a Lachnospiraceae bacterium contributes to the development of diabetes in obese mice. AB - The aim of the present study was to identify bacteria that may contribute to the onset of metabolic dysfunctions. We isolated and identified a candidate bacterium belonging to Lachnospiraceae (strain AJ110941) in the feces of hyperglycemic obese mice. The colonization of germ-free ob/ob mice by AJ110941 induced significant increases in fasting blood glucose levels as well as liver and mesenteric adipose tissue weights, and decreases in plasma insulin levels and HOMA-beta values. These results indicated that the specific gut commensal bacterium AJ110941 influenced the development of obesity and diabetes in ob/ob mice with genetic susceptibility for obesity. PMID- 25283479 TI - Periodontally compromised vs. periodontally healthy patients and dental implants: a systematic review and meta-analysis. AB - OBJECTIVES: To test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for the insertion of dental implants in periodontally compromised patients (PCPs) compared to the insertion in periodontally healthy patients (PHPs), against the alternative hypothesis of a difference. METHODS: An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomized or not. RESULTS: 2768 studies were identified in the search strategy and 22 studies were included. The estimates of relative effect were expressed in risk ratio (RR) and mean difference (MD) in millimetres. All studies were judged to be at high risk of bias, none were randomized. A total of 10,927 dental implants were inserted in PCPs (587 failures; 5.37%), and 5881 implants in PHPs (226 failures; 3.84%). The difference between the patients significantly affected the implant failure rates (RR 1.78, 95% CI 1.50-2.11; P<0.00001), also observed when only the controlled clinical trials were pooled (RR 1.97, 95% CI 1.38-2.80; P=0.0002). There were significant effects of dental implants inserted in PCPs on the occurrence of postoperative infections (RR 3.24, 95% CI 1.69-6.21; P=0.0004) and in marginal bone loss (MD 0.60, 95% CI 0.33-0.87; P<0.0001) when compared to PHPs. CONCLUSIONS: The present study suggests that an increased susceptibility for periodontitis may also translate to an increased susceptibility for implant loss, loss of supporting bone, and postoperative infection. The results should be interpreted with caution due to the presence of uncontrolled confounding factors in the included studies, none of them randomized. CLINICAL SIGNIFICANCE: There is some evidence that patients treated for periodontitis may experience more implant loss and complications around implants including higher bone loss and peri-implantitis than non-periodontitis patients. As the philosophies of treatment may alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures. This would form a basis for optimum treatment. PMID- 25283480 TI - Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomised controlled trial. AB - AIM: To determine whether vitamin D supplementation reduces primary care visits for acute respiratory infection (ARI). METHODS: A randomised, double-blind, placebo-controlled trial was conducted in New Zealand and powered to determine the vitamin D dose needed to achieve normal vitamin D status during infancy. Healthy pregnant women, from 27 weeks' gestation to birth, and their infants, from birth to age 6 months, were assigned to placebo or one of the two dosages of daily oral vitamin D3 . Woman/infant pairs were randomised to placebo/placebo, 1000 IU/400 IU or 2000 IU/800 IU. For this ad hoc analysis, the primary care records of enrolled children were audited to age 18 months. RESULTS: Two hundred and sixty pregnant women were randomised to placebo (n = 87), lower-dose (n = 87) or higher-dose (n = 86) vitamin D3 . In comparison with the placebo group (99%), the proportion of children making any ARI visits was smaller in the higher-dose (87%, p = 0.004), but not the lower-dose vitamin D3 group (95%, p = 0.17). The median number of ARI visits/child was less in the higher-dose vitamin D3 group from age 6-18 months (placebo 4, lower dose 3, higher dose 2.5; p = 0.048 for higher-dose vitamin D3 vs. placebo). CONCLUSION: Vitamin D3 supplementation during pregnancy and infancy reduces primary care visits for ARI during early childhood. PMID- 25283481 TI - Histological study of the external, middle and inner ear of horses. AB - Clinical, anatomical and histological aspects of the equine acoustic organ have been poorly investigated and illustrated in literature so far. It is understood that an intact acoustic organ and hearing function are of vital importance for the well-being of flight animals like horses. The knowledge of the acoustic organ is usually transferred analogously from other mammals to horses. The purpose of this study was to provide a detailed and complete histological description of the healthy equine auditory organ, and to determine its congruity to other mammalians. Anatomical dissections and histological preparations were carried out on ten cadaver heads. Specimens of various parts of the equine acoustic organ were taken and evaluated histologically. The histological composition of external, middle and inner ear structures are predominantly congruent to those of other mammals, especially to human beings. Unique inwardly directed rete pegs within the osseous ear canal and the prominent tensor tympani muscle are described for the first time. Results obtained in this study can be employed as references for further research on the equine acoustic organ and improve the understanding of the clinical development of hearing loss, otitis externa/media/interna or tympanosclerosis. PMID- 25283482 TI - Commentary on "Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis". PMID- 25283483 TI - Low dose pramipexole causes D3 receptor-independent reduction of locomotion and responding for a conditioned reinforcer. AB - Pramipexole is a clinically important dopamine receptor agonist with reported selectivity for dopamine D3 receptors over other dopaminergic and non dopaminergic sites. Many of its behavioural effects are therefore attributed to D3 receptor activity. Here we relate pramipexole's ex vivo D2 and D3 receptor binding (measured using [(3)H]-(+)-PHNO binding experiments) to its effects on locomotion and operant responding for primary and conditioned reinforcers. We show that pramipexole has inhibitory behavioural effects on all three behaviours at doses that occupy D3 but not D2 receptor. However, these effects are 1) not inhibited by a D3 selective dose of the antagonist SB-277011-A, and 2) present in D3 receptor knockout mice. These results suggest that a pharmacological mechanism other than D3 receptor activity must be responsible for these behavioural effects. Finally, our receptor binding results also suggest that these behavioural effects are independent of D2 receptor activity. However, firmer conclusions regarding D2 involvement would be aided by further pharmacological or receptor knock-out experiments. The implications of our findings for the understanding of pramipexole's behavioural and clinical effects are discussed. PMID- 25283484 TI - Photostability of cosmetic UV filters on mammalian skin under UV exposure. AB - Previous studies showed that the common UV filter substances benzophenone-3 (BP 3), butyl methoxydibenzoylmethane (BM-DBM), octocrylene (OCR), ethylhexyl methoxycinnamate (EHMC), ethylhexyl salicylate (EHS) and ethylhexyl triazone (EHT) were able to react with amino side chains of different proteins in vitro. To transfer the results to mammalian skin conditions, sunscreen products were applied on both prepared fresh porcine skin and glass plates, followed by UV irradiation and the determination of depletion of the respective UV filters. Significantly lower recoveries of the UV filters extracted from skin samples than from glass plates indicated the additional reaction of the UV filters with skin constituents, when proteins will be the most important reactants. Among the products tested, BP-3 showed the greatest differences in recoveries between glass and skin samples of about 13% and 24% after 2 and 4 h of irradiation, respectively, followed by EHS > BM-DBM > OCR > EHMC > EHT. The obtained results raise the question, whether the common in vitro evaluations of sunscreens, using inert substrate materials like roughened quartz or polymethyl methacrylate (PMMA) plates are really suitable to fully replace in vivo methods, as they cannot include skin-typical reactions. PMID- 25283485 TI - Triple combination of insulin glargine, sitagliptin and metformin in type 2 diabetes: the EASIE post-hoc analysis and extension trial. AB - AIM: We examined the effects of adding glargine to metformin-sitagliptin (MS+G) or sitagliptin to metformin-glargine (MG+S) therapy in type 2 diabetic persons uncontrolled after 24-week MS or MG dual therapy. METHODS: Subjects with A1c>=7% on MS or MG treatment were respectively given glargine (0.2U/kg starting dose) or sitagliptin (100mg daily) for 12weeks. The primary endpoint was number of subjects attaining A1c goal defined as <7%. RESULTS: After receiving 24-week MS or MG dual therapy in the original EASIE Study, 42% (104/248) on MS and 68% (152/224) on MG attained A1c<7% (p<0.0001). The reduction in A1c was negatively associated with baseline fasting blood glucose (FBG) only in the MG group. Reduction in A1c was not related to baseline postprandial blood glucose (PPBG) in either the MG or MS group. Amongst 194 eligible patients, 57.7% (n=111) entered the 12-week extension trial [MS+G:74/131, 57.3%; MG+S:37/63, 58.7%) with 55 (51.9%) subjects attaining goal [MS+G:59.2%; MG+S:37.1%] at week 12. The final insulin dosage was similar in both groups [MS+G: 0.46U/kg; MG+S: 0.45U/kg] with a higher rate of hypoglycemia in the MG+S (6.5 events/patient-year) than the MS+G group (3.2 events/patient-year), although neither group had severe hypoglycemia. CONCLUSION: In metformin-treated type 2 diabetes patients, high fasting BG predicted greater A1c reductions with the addition of glargine, but not with sitagliptin. In subjects uncontrolled with 6-month dual therapy of MS or MG, 50% attained A1c<7% with triple therapy of MS+G or MG+S in 12weeks. The increased rate of hypoglycemia with MG+S (but not with MS+G) underlines the need to take measures to avoid the hypoglycemia. PMID- 25283486 TI - Is depression a risk factor for diabetic foot ulcers? 11-years follow-up of the Nord-Trondelag Health Study (HUNT). AB - AIM: To prospectively examine whether depressive symptoms increase the risk of diabetes and a diabetic foot ulcer. METHODS: The Nord-Trondelag Health Study (HUNT) is a community-based longitudinal study. The Hospital Anxiety and Depression Scale (HADS-D subscale) assessed depressive symptoms. We followed individuals with complete HADS-D data from HUNT2 (1995-97) and assessed whether they reported diabetes with or without a history of diabetic foot ulcer (DFU) in HUNT3 (2006-08) (n=36,031). Logistic regression was used to investigate the effect of depressive symptoms on subsequent development of diabetes and of DFU. RESULTS: Unadjusted odds for reporting diabetes at follow-up was higher among individuals who reported a HADS-D score>=8 at baseline (OR 1.30 95% CI, 1.07 1.57) than among those reporting a lower score. After adjusting for age, gender and BMI, this association was no longer significant. The odds of developing a DFU was almost two-fold (OR=1.95 95% CI, 1.02-3.74) for those reporting a HADS-D score of 8-10, and 3-fold (OR=3.06 95% CI, 1.24-7.54) for HADS-D scores>=11, compared to HADS-D scores<8, after adjusting for age, gender and serum glucose. CONCLUSIONS: Symptoms of depression at baseline are associated with an increased risk of a diabetic foot ulcer in a dose response manner during this 11-year follow-up. PMID- 25283487 TI - Pro-angiogenic efficacy of transplanting endothelial progenitor cells for treating hindlimb ischemia in hyperglycemic rabbits. AB - AIMS: To evaluate the effectiveness of endothelial progenitor cells (EPCs) therapy in ischemia with or without hyperglycemia. METHODS: Japanese White Rabbits were randomly assigned to three groups, group SH, hyperglycemia with sham therapy (n=10); group NE, normoglycemia with autologous EPCs transplantation therapy (n=12); and group HE, hyperglycemia with autologous EPCs transplantation therapy (n=12). Hyperglycemia was induced by injecting alloxan and sustained for 12weeks. Hindlimb ischemia was induced by complete excision of the femoral artery. Ex vivo-expanded EPCs were derived from autologous bone marrow and transplanted intermuscularily in the ischemic hindlimb. Fourteen days after transplantation, the indicators were determined. RESULTS: There is no difference of the functions of ex vivo-expanded EPCs from autologous bone marrow between normoglycemic and hyperglycemic groups. We found significant improvement in both EPCs transplantation therapy groups compared to sham, in terms of the angiogenesis index (8.62+/-1.36, 11.12+/-2.23, 12.35+/-2.97), capillary density (7.06+/-0.91, 13.51+/-1.16, 13.90+/-2.78), capillary to muscle fiber ratio (0.68+/-0.09, 0.96+/-0.11,0.89+/-0.10), muscle VEGF expression (0.22+/-0.07, 0.41+/-0.08, 0.38+/-0.07ng/g). We found no significant differences between hyperglycemic and normoglycemic EPCs therapy groups except for 5 pro-angiogenic genes that were upregulated in HE as compared to NE. CONCLUSION: Ex vivo expanded EPCs from autologous bone marrow transplantation is an effective therapeutic method for hindlimb ischemia in rabbits regardless of glycemic state. PMID- 25283488 TI - Real-time optical studies of respiratory Complex I turnover. AB - Reduction of Complex l (NADH:ubiquinone oxidoreductase l) from Escherichia coli by NADH was investigated optically by means of an ultrafast stopped-flow approach. A locally designed microfluidic stopped-flow apparatus with a low volume (0.21Jl) but a long optical path (10 mm) cuvette allowed measurements in the time range from 270 ).IS to seconds. The data acquisition system collected spectra in the visible range every 50 )JS. Analysis of the obtained time-resolved spectral changes upon the reaction of Complex I with NADH revealed three kinetic components with characteristic times of <270 ).IS, 0.45-0.9 ms and 3-6 ms, reflecting reduction of different FeS clusters and FMN. The rate of the major ( T = 0.45-0.9 ms) component was slower than predicted by electron transfer theory for the reduction of all FeS clusters in the intraprotein redox chain. This delay of the reaction was explained by retention of NAD+ in the catalytic site. The fast optical changes in the time range of 0.27- 1.5 ms were not altered significantly in the presence of 1 0-fold excess of NAD+ over NADH. The data obtained on the NuoF E95Q variant of Complex I shows that the single amino acid replacement in the catalytic site caused a strong decrease of NADH binding and/or the hydride transfer from bound NADH to FMN. PMID- 25283489 TI - Effect of anxiety and catastrophic pain ideation on early recovery after surgery for distal radius fractures. AB - PURPOSE: To evaluate the effects of preoperative anxiety and catastrophic pain ideation on perceived disability and objective measures after distal radius fracture surgery. METHODS: A total of 121 patients with distal radius fractures treated with volar plate fixation were enrolled. The wrist range of motion (ROM), grip strength, and perceived disability as measured by the Michigan Hand Questionnaire (MHQ) score were assessed 4, 12, and 24 weeks after surgery. To evaluate psychological factors related to pain, catastrophic pain ideation was measured using the Pain Catastrophizing Scale (PCS) and pain anxiety was measured using the Pain Anxiety Symptom Scale (PASS). Then relative contributions of pain anxiety and catastrophic pain ideation and other clinical parameters to functional recovery in terms of grip strength, ROM, and MHQ score were assessed. RESULTS: An increase in the PCS score was associated with the wrist ROM and grip strength only at week 4, whereas an increase in the PASS score was associated with the wrist ROM at week 4 and grip strength at weeks 4 and 12. According to a multivariate regression analysis, an increase in the PCS score was associated with a decrease in grip strength, ROM, and MHQ score at week 4; and an increase in the PASS score was associated with a decrease in grip strength, ROM, and MHQ score at week 4 and grip strength and MHQ score at week 12. At week 24, only age and fracture severity were associated with the MHQ score. In addition, age was associated with grip strength and fracture type was associated with ROM. CONCLUSIONS: Preoperative PCS and PASS were significantly associated with delayed recovery as evidenced by scores on both objective and subjective measures of function. Given these relationships, it becomes important to assess preoperative PCS and PASS and address issues for patients at risk with brief psychosocial intervention early in the recovery process. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25283490 TI - Wide-awake extensor indicis proprius to extensor pollicis longus tendon transfer. AB - This article provides video and narration to describe the technical details of how to inject local anesthesia and perform the extensor indicis proprius to extensor pollicis longus tendon transfer in patients with wide-awake local anesthesia and no tourniquet. Lidocaine for anesthesia and epinephrine for hemostasis are the only 2 medications given to the patient. Sedation and the tourniquet are not required. Wide-awake patients are comfortable, cooperative, and educable, and are able to help the surgeon set the correct tension for the transfer. They flex and extend the thumb before the skin is closed to make sure the transfer is not too tight or too loose. It helps that they remember seeing the thumb move nicely during the surgery when they are in postoperative hand therapy. PMID- 25283493 TI - Length-dependent plasmon resonance in single-walled carbon nanotubes. AB - The optical response of single-walled carbon nanotubes (SWCNTs) to far-infrared (FIR) radiation was systematically studied using various SWCNTs with different tube-length distributions. The observed peak position in the FIR spectra linearly scaled with the inverse of tube length irrespective of diameter, which is consistent with the dispersion relation predicted by the one-dimensional plasmon resonance model. The effects of chemical doping on the FIR spectra of the separated metallic and semiconducting SWCNTs clearly indicate that the motion of plasmons in the electronic band structures is primarily responsible for the optical response in these spectral regions. The observed absorption peaks are naturally sensitive to the presence of defects on the tube wall and correlated with the electric resistance, suggesting that the plasmons resonate with the current path length of the SWCNTs. PMID- 25283492 TI - Direct regulation of gonadotrophin-releasing hormone (GnRH) transcription by RF amide-related peptide-3 and kisspeptin in a novel GnRH-secreting cell line, mHypoA-GnRH/GFP. AB - RF-amide-related peptide-3 [RFRP-3; also often referred to as the mammalian orthologue of the avian gonadotrophin-inhibitory hormone (GnIH)] and kisspeptin have emerged as potent modulators of neuroendocrine function via direct regulation of the reproductive axis in the hypothalamus and pituitary. There are few studies focusing on the direct regulatory effects of RFRP-3 and kisspeptin on gonadotrophin-releasing hormones (GnRH) neurones. We report their effect on GnRH mRNA expression and release in a novel GnRH neuronal cell model, mHypoA-GnRH/GFP, generated from adult-derived GnRH-GFP neurones. The neurones express receptors for both RFRP-3 and kisspeptin, Gpr147 and Gpr54, respectively. Incubation with 100 nm RFRP-3 results in attenuation of GnRH mRNA expression by approximately 60%. Conversely, incubation with 10 nm of Kiss-10 induced GnRH mRNA expression, whereas the combined effect was an overall repression of GnRH mRNA levels. With transcription inhibitors, the repression of GnRH mRNA levels was linked to a transcriptional mechanism but not mRNA stability. No significant changes in GnRH secretion were observed upon RFRP-3 exposure in these neurones. Our findings suggest that the suppressive signalling of RFRP-3 on GnRH transcription may dominate over kisspeptin induction in the mHypoA-GnRH/GFP GnRH neuronal cell model. PMID- 25283491 TI - Trigger finger: assessment of surgeon and patient preferences and priorities for decision making. AB - PURPOSE: To test the null hypothesis that there are no differences in the priorities and preferences of patients with idiopathic trigger finger (TF) and hand surgeons. METHODS: One hundred five hand surgeons of the Science of Variation Group and 84 patients with TF completed a survey about their priorities and preferences in decision making regarding the management of TF. The questionnaire was structured according the Ottawa Decision Support Framework for the development of a decision aid. RESULTS: Patients desired orthotics more and surgery less than physicians. Patients and physicians disagreed on the main advantage of several treatment options for TFs and on disadvantages of the treatment options. Patients preferred to decide for themselves after receiving advice, whereas physicians preferred a shared decision. Patients preferred booklets, and physicians opted for Internet and video decision aids. CONCLUSIONS: Comparing patients and hand surgeons, there were some differences in treatment preferences and perceived advantages and disadvantages regarding idiopathic TF differences that might be addressed by a decision aid. CLINICAL RELEVANCE: Information that helps inform patients of their options based on current best evidence might help them understand their own preferences and values, reduce decisional conflict, limit surgeon-to-surgeon variations, and improve health. PMID- 25283495 TI - Middle-Eastern plant communities tolerate 9 years of drought in a multi-site climate manipulation experiment. AB - For evaluating climate change impacts on biodiversity, extensive experiments are urgently needed to complement popular non-mechanistic models which map future ecosystem properties onto their current climatic niche. Here, we experimentally test the main prediction of these models by means of a novel multi-site approach. We implement rainfall manipulations--irrigation and drought--to dryland plant communities situated along a steep climatic gradient in a global biodiversity hotspot containing many wild progenitors of crops. Despite the large extent of our study, spanning nine plant generations and many species, very few differences between treatments were observed in the vegetation response variables: biomass, species composition, species richness and density. The lack of a clear drought effect challenges studies classifying dryland ecosystems as most vulnerable to global change. We attribute this resistance to the tremendous temporal and spatial heterogeneity under which the plants have evolved, concluding that this should be accounted for when predicting future biodiversity change. PMID- 25283496 TI - A high rotational barrier for physisorbed hydrogen in an fcu-metal-organic framework. AB - A combined inelastic neutron scattering (INS) and theoretical study of H2 sorption in Y-FTZB, a recently reported metal-organic framework (MOF) with fcu topology, reveals that the strongest binding site in the MOF causes a high barrier to rotation on the sorbed H2. This rotational barrier for H2 is the highest yet of reported MOF materials based on physisorption. PMID- 25283497 TI - The combination of tumour necrosis factor-alpha -308A and interleukin-10 -1082G gene polymorphisms and increased serum levels of related cytokines: susceptibility to vitiligo. AB - BACKGROUND: The aetiopathogenesis of vitiligo is still under investigation. AIM: To assess the role of single nucleotide polymorphisms (SNPs) of the genes for tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10, as well as the serum levels of these three cytokines in the pathogenesis of vitiligo. METHODS: The study enrolled 105 patients with vitiligo, and 211 age- and sex-matched controls. TNF-alpha (-308), IL-6 (-174) and IL-10 (-1082) promoter polymorphisms were investigated by LightSNiP assay and analysed by chi(2) test. Subsequently, the serum cytokine levels were assessed by ELISA and evaluated by Mann-Whitney U test and Kruskal-Wallis test. RESULTS: The frequency of the GG genotype of the IL 10 -1082 polymorphism was significantly higher in the vitiligo group compared with the healthy control group (P = 0.02). Further investigations using combinations of these variant alleles detected a significant risk for vitiligo for individuals carrying both the IL-10 -1082G and TNF-alpha -308A alleles (OR = 12.57, 95% CI 1.44-110.0, P < 0.01). Serum IL-10 and TNF-alpha levels were higher in the vitiligo group (P = 0.001). In addition, TNF-alpha levels in patients with active disease were significantly higher than in patients with stable disease (P < 0.02). CONCLUSIONS: The concomitant presence of IL-10 -1082G and TNF-alpha 308A alleles significantly raises the risk for vitiligo. Furthermore, in accordance with these findings, serum IL-10 and TNF-alpha were also increased in this study, confirming the role of these cytokines in the pathogenesis of vitiligo. PMID- 25283498 TI - In vitro streptozotocin model for modeling Alzheimer-like changes: effect on amyloid precursor protein secretases and glycogen synthase kinase-3. AB - There is accumulating evidence for a pathogenetic link between sporadic Alzheimer's disease (AD) and diabetes mellitus (DM). At subdiabetogenic doses, the cerebral administration of the diabetogenic substance streptozotocin (STZ) induces an insulin-resistant brain state (IRBS). The aim of the present pilot study was to investigate the effect of STZ on Alzheimer-like characteristics such as amyloid precursor protein (APP) cleavage secretases, betaA4 fragment, and glycogen synthase kinase (GSK) in vitro. Different STZ concentrations (0-5 mM) and incubation intervals (0-48 h) were tested to find appropriate cell culture conditions for further biochemical analyses in human neuroblastoma cells (SK-N MC). Lactate dehydrogenase (LDH) was measured spectrophotometrically. Intracellular ATP was determined using bioluminescent luciferase assay. Secretase activity (alpha, beta, and gamma) was measured by employing commercial fluorometric secretase activity assay kits, betaA4 fragment by immunoprecipitation. Glycogen synthase kinase-3alpha/beta (total and phospho-GSK) content was assayed by ELISA technique. In vitro STZ administration (1 mM) induced a significant reduction in intracellular ATP concentration without pronounced cell death after 24 and 48 h as measured by LDH. Under these experimental conditions, a significant increase in beta-secretase and a significant drop in alpha-secretase were obtained, whereas gamma-secretase was not changed significantly. Simultaneously, the betaA4 concentration was increased by about threefold. Furthermore, STZ significantly increased total GSK and markedly decreased phospho-GSK. A direct link between STZ, intracellular ATP deficit, and Alzheimer-related enzymes was shown in this in vitro pilot study. Thus, these results support the hypothesis that sporadic AD is being recognized as an IRBS, which can be modulated by in vitro STZ model. Continuing investigations relating pathogenetic mechanisms and AD-like hallmarks are necessary to modulate different cascades of the IRBS using in vitro models. PMID- 25283499 TI - Significant renoprotective effect of telbivudine during preemptive antiviral therapy in advanced liver cancer patients receiving cisplatin-based chemotherapy: a case-control study. AB - OBJECTIVE: Cisplatin is a known nephrotoxic agent requiring vigorous hydration before use. However, aggressive hydration could be life-threatening. Therefore, in cirrhotic patients with advanced hepatocellular carcinoma (HCC) under cisplatin-based chemotherapy, the risk of nephrotoxicity increased. Because previous studies showed that long-term telbivudine treatment improved renal function in chronic hepatitis B virus (HBV) infected patients, we conducted a case-control study to evaluate the clinical outcome of telbivudine preemptive therapy in HBV-related advanced HCC patients treated by combination chemotherapy comprising 5-fluorouracil, mitoxantrone and cisplatin (FMP). MATERIAL AND METHODS: From June 2007 to March 2012, 60 patients with HBV-related advanced HCC, all receiving the same FMP chemotherapy protocol, were enrolled. Of them, 20 did not receive any antiviral therapy, whereas the remaining 40 patients (sex and age matched) received telbivudine preemptive therapy. RESULTS: Progressive decrease of aminotransferase levels (p < 0.05) and progressive increase of viral clearance rates (p < 0.001) were found in telbivudine-treated group. No drug resistance developed during the course of treatment. When compared with non-antiviral treated patients, a significantly higher post-therapeutic estimated glomerular filtration rate (eGFR) was found in the telbivudine-treated group (p < 0.001). In patients with initial eGFR >100 ml/min (n = 34), the median overall survival was significantly longer in the telbivudine-treated group (12.1 vs. 4.9 months; p = 0.042). CONCLUSION: Preemptive use of telbivudine significantly prevented eGFR deterioration caused by cisplatin-based chemotherapy in HBV-related advanced HCC. In patients with initially sufficient eGFR level, telbivudine treatment was associated with a longer overall survival. PMID- 25283500 TI - Development of UK guidance on the management of erectile dysfunction resulting from radical radiotherapy and androgen deprivation therapy for prostate cancer. AB - AIM: To develop a management strategy (rehabilitation programme) for erectile dysfunction (ED) after radiotherapy (RT) or androgen deprivation therapy (ADT) for prostate cancer that is suitable for use in a UK NHS healthcare context. METHODS: PubMed literature searches of ED management in this patient group together with a survey of 28 experts in the management of treatment-induced ED from across the UK were conducted. RESULTS: Data from 19 articles and completed questionnaires were collated. The findings discussed in this article confirm that RT/ADT for prostate cancer can significantly impair erectile function. While many men achieve erections through PDE5-I use, others need combined management incorporating exercise and lifestyle modifications, psychosexual counselling and other erectile aids. This article offers a comprehensive treatment algorithm to manage patients with ED associated with RT/ADT. CONCLUSION: Based on published research literature and survey analysis, recommendations are proposed for the standardisation of management strategies employed for ED after RT/ADT. In addition to implementing the algorithm, understanding the rationale for the type and timing of ED management strategies is crucial for clinicians, men and their partners. PMID- 25283501 TI - Morphologic evaluation of remnant anterior cruciate ligament bundles after injury with three-dimensional computed tomography. AB - PURPOSE: This study aimed to investigate the morphological patterns of remnant anterior cruciate ligament bundles after injury (ACL remnant) on three dimensional computed tomography (3DCT) and compare them with those on arthroscopy. METHODS: Sixty-three patients (33 males and 30 females; mean age 25.2 +/- 10.1 years) who had undergone primary ACL reconstruction between March 2011 and December 2012 were included in this study. The average durations between traumas and 3DCT and between 3DCT and surgery were 101.7 +/- 87.2 and 38.2 +/- 38.7 days, respectively. ACL remnants were classified into four morphological patterns on 3DCT. 3DCT findings were compared with arthroscopic findings with and without probing. RESULTS: The morphological patterns of the ACL remnants on 3DCT were well matched with those on arthroscopy without probing (the concordance rate was 77.8%). However, the concordance rate was reduced to 49.2% when arthroscopic probing was used to confirm the femoral attachment of ACL remnants (p <= 0.05). CONCLUSIONS: This study demonstrates that the morphological patterns of ACL remnants on 3DCT were well matched with those on arthroscopy without probing. Therefore, the technique can be useful for preoperative planning of the ACL reconstruction or informed consent to the patients. However, for definitive diagnosis, arthroscopic probing is required. LEVEL OF EVIDENCE: IV. PMID- 25283502 TI - No clinical benefit of titanium nitride coating in cementless mobile-bearing total knee arthroplasty. AB - PURPOSE: Titanium nitride (TiN) coating of cobalt-chromium-molybdenum (CoCrMo) implants has shown to improve the biomechanical properties of the implant surface and to reduce adhesive wear in vitro. It is yet unknown whether TiN coating of total knee prosthesis (TKP) affects the postoperative clinical outcome of total knee arthroplasty (TKA). METHODS: In a double-blind randomized controlled clinical trial, 101 patients received an uncemented mobile-bearing CoCrMo TKP, either TiN coated or uncoated. Primary outcome measure visual analogue scale (VAS) score for pain, and secondary outcome measures Knee Society Score (KSS), revision rate and adverse events, range of motion of the knee as well as knee circumference and knee skin temperature were assessed 6 weeks, 6 months, 1 year and 5 years postoperative. Repeated measures analysis was used to evaluate the postoperative outcome measures over time. RESULTS: There was no difference between the two groups in VAS score, KSS, revision rate, range of motion of the knee, knee circumference and knee skin temperature. There were no adverse events that could be related to the TiN coating. CONCLUSIONS: TiN-coated TKP does not influence the postoperative outcome of uncemented mobile-bearing TKA regarding postoperative pain, revision rate, range of motion, swelling and temperature of the knee. Therefore, TiN coating of CoCrMo TKP has no clinical benefit on the outcome of cementless mobile-bearing TKA. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 25283503 TI - The role of the orphan nuclear receptor COUP-TFII in tumorigenesis. AB - The chicken ovalbumin upstream promoter transcription factors (COUP-TFs), members of the nuclear receptor superfamily, consist of two highly homologous subtypes, COUP-TFI (EAR-3, NR2F1) and COUP-TFII (ARP-1, NR2F2). They are referred to as orphan receptors because the COUP-TF ligands have yet to be identified. Since the discovery of COUP-TFs in 1986, extensive studies have demonstrated their crucial functions in a variety of developmental processes, such as organogenesis, angiogenesis, and metabolic homeostasis. Recently, emerging evidence has highlighted that COUP-TFs, specifically COUP-TFII, play important roles in tumorigenesis. In this review, we will discuss the critical functions of COUP TFII in the development of the tumor microenvironment, the progression of various cancers, and its underlying mechanisms. PMID- 25283504 TI - Pharmacodynamic analysis of intravenous recombinant urate oxidase using an indirect pharmacological response model in healthy subjects. AB - AIM: Pharmacodynamic analysis of intravenous recombinant urate oxidase produced by Escherichia coli was performed in healthy subjects using a pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: A randomized, single blind, placebo-controlled study was performed in 40 healthy Chinese subjects (4 groups of 10 subjects each, placebo 4:1 ratio) who received infusions of uricase (single doses of 0.1, 0.2, and 0.3 mg/kg; multiple doses of 0.2 mg.kg(-1).d(-1) for 7 d). PK profiles were determined through plasma uricase activity, and PD profiles were established using uric acid levels in plasma and urine. The plasma PD parameter was estimated as changes in plasma uric acid levels as the effect in the indirect response model. Adverse events were also monitored. RESULTS: A two compartment PK model with constant iv input and first-order output was used to describe the kinetic process of plasma uricase. The low value (2.8 U/L) of drug concentration that achieved 50% of maximum effect (EC50) indicated that low plasma uricase concentrations were sufficient to produce pharmacological effects. A strong relationship (r(2)=0.9991) between the mean uric acid concentration in blood and the mean uric acid excretion rate in urine in the range of 11 to 30 h after single dosing was found. Infusions of uricase were well tolerated in all subjects. CONCLUSION: The PK/PD model predicted the effective dose to be 0.1 mg/kg in healthy subjects. The excretion rate of uric acid in urine may be used as a new index for pharmacological effects in further clinical trials. PMID- 25283505 TI - Pyrroloquinoline quinone protects mouse brain endothelial cells from high glucose induced damage in vitro. AB - AIM: To investigate the effects of pyrroloquinoline quinone (PQQ), an oxidoreductase cofactor, on high glucose-induced mouse endothelial cell damage in vitro. METHODS: Mouse brain microvascular endothelial bEND.3 cells were exposed to different glucose concentrations (5.56, 25 and 40 mmol/L) for 24 or 48 h. The cell viability was examined using MTT assay. Flow cytometry was used to analyze the apoptosis and ROS levels in the cells. MitoTracker Green staining was used to examine the mitochondria numbers in the cells. Western blot analysis was used to analyze the expression of HIF-1alpha and the proteins in JNK pathway. RESULTS: Treatment of bEND.3 cells with high glucose significantly decreased the cell viability, while addition of PQQ (1 and 10 MUmol/L) reversed the high glucose induced cell damage in a concentration-dependent manner. Furthermore, PQQ (100 MUmol/L) significantly suppressed the high glucose-induced apoptosis and ROS production in the cells. PQQ significantly reversed the high glucose-induced reduction in both the mitochondrial membrane potential and mitochondria number in the cells. The high glucose treatment significantly increased the expression of HIF-1alpha and JNK phosphorylation in the cells, and addition of PQQ led to a further increase of HIF-1alpha level and a decrease of JNK phosphorylation. Addition of JNK inhibitor SP600125 (10 MUmol/L) also significantly suppressed high glucose-induced apoptosis and JNK phosphorylation in bEND.3 cells. CONCLUSION: PQQ protects mouse brain endothelial cells from high glucose damage in vitro by suppressing intracellular ROS and apoptosis via inhibiting JNK signaling pathway. PMID- 25283506 TI - Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy. AB - AIM: TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1 (GLP-1) secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betulinic acid. METHODS: A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. RESULTS: Biological data revealed that the 3-alpha-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-beta-OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-alpha betulinic derivatives and enhanced the activity differences between 3-alpha and 3-beta derivatives. The 3-alpha-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. CONCLUSION: This study demonstrates that highly lipophilic 3-epi betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists. PMID- 25283507 TI - Selective alpha1B- and alpha1D-adrenoceptor antagonists suppress noradrenaline induced activation, proliferation and ECM secretion of rat hepatic stellate cells in vitro. AB - AIM: To explore the effects of noradrenaline (NA) on hepatic stellate cells (HSCs) in vitro and to determine the adrenoceptor (AR) subtypes and underlying mechanisms. METHODS: The distribution and expressions of alpha1A-, alpha1B-, and alpha1D-ARs in HSC-T6 cells were analyzed using immunocytochemistry and RT-PCR. Cell proliferation was evaluated with MTT assay. The expression of HSC activation factors [transforming factor-beta1 (TGF-beta1) and alpha-smooth muscle actin (alpha-SMA)], extracellular matrix (ECM) secretion factors [tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen-Iota (ColIota)] and PKC-PI3K-AKT signaling components (PKC, PI3K, and AKT) in the cells were detected by Western blotting and RT-PCR. RESULTS: Both alpha1B- and alpha1D-AR were expressed in the membrane of HSC-T6 cells, whereas alpha1A-AR was not detected. Treatment of the cells with NA concentration-dependently increased cell proliferation (EC50=277 nmol/L), which was suppressed by the alpha1B-AR antagonist CEC or by the alpha1D AR antagonist BMY7378. Furthermore, NA (0.001, 0.1, and 10 MUmol/L) concentration dependently increased the expression of TGF-beta1, alpha-SMA, TIMP-1 and ColIota, PKC and PI3K, and phosphorylation of AKT in HSC-T6 cells, which were suppressed by CEC or BMY7378, or by pertussis toxin (PT), RO-32-0432 (PKC antagonist), LY294002 (PI3K antagonist) or GSK690693 (AKT antagonist). CONCLUSION: NA promotes HSC-T6 cell activation, proliferation and secretion of ECM in vitro via activation of Galpha-coupled alpha1B-AR and alpha1D-AR and the PKC-PI3K-AKT signaling pathway. PMID- 25283509 TI - Educational and health impact of the Baume Report: 'A Cutting Edge: Australia's Surgical Workforce'. AB - OBJECTIVES: The Baume Report (1994) on Australia's surgical workforce had the potential to impact upon the health and educational sectors. This paper analyses the recommendations of this report and their impact at the time and 15 years later (2009). METHODS: A questionnaire-based study was performed with the 18 senior Fellows and the Royal Australasian College of Surgeons (RACS) solicitor who had been instrumental in facilitating responses to the review. RESULTS: The 19 respondents were asked to evaluate 22 areas from the Baume Report. The most highly ranked areas identified as being reasonable in 1994 were: additional funding being made available for more training positions, identifying workforce deficits, moving towards compulsory continuing professional development and having evidence of competence before introducing new technology. In 2009, the most highly ranked areas were: funding for more training positions; compulsory continuing professional development, involving the profession in improvements and broadening the training environment beyond public hospitals. Areas considered to be substantially addressed were: the selection process and encouragement of diversity, workforce numbers and deficits, confirming the educational merit of the training program and the role of professional colleges. CONCLUSIONS: The Baume Report highlighted many issues including workforce planning, the role of professional organisations in society and the complex interface between health and education. Issues of ongoing standards through a surgical career, access for patients to surgical services, funding for more training posts to provide the appropriate workforce level and distribution, and the assessment and introduction of technology remain priorities. Time has not diminished the relevance of these issues. WHAT IS KNOWN ABOUT THIS TOPIC?: The impact of key government reviews can always be substantial. The Baume Report was directed to postgraduate specialist medical training, particularly surgical training. There have been substantial changes in the health and educational sectors since the report, with significantly more regulation and transparency. WHAT DOES THIS PAPER ADD?: Analysis of the Baume Report after 15 years by the senior office bearers of the RACS who were actively involved in handling and implementing many of the recommendations provides an insight into the dynamics of specialist training. It outlines the significant changes that have occurred and the things that still need to be done. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS?: Professional bodies have an influential presence across society. They are particularly focused on the standards required to become a practitioner of that profession and the ongoing maintenance of these standards. However, this comes with responsibility for and accountability to society and the community. External reviews, particularly with a political imperative, change both the dynamics and key relationships, issues that the professional bodies must commit to addressing in a positive manner. PMID- 25283508 TI - Serum uric acid levels are associated with polymorphisms in the SLC2A9, SF1, and GCKR genes in a Chinese population. AB - AIM: Genome-wide association studies have identified several novel loci associated with serum uric acid concentrations in individuals of European descent. In the current study, we aimed to evaluate the associations between these loci and serum uric acid concentrations in a Chinese population. METHODS: Fourteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped in 2329 Chinese subjects in Shanghai. Serum biochemical parameters including uric acid concentrations were determined. All the variants were analyzed for gender differences since uric acid metabolism differed between genders. RESULTS: In males after adjustments for age and BMI, GCKR rs780094, SLC2A9 rs11722228 and SF1 rs606458 were associated with the uric acid concentrations, which were statistically significant (P=0.016, 0.001 and 0.03, respectively), whereas SLC2A9 rs3775948 was marginally associated with the uric acid concentrations (P=0.071). In females, SLC22A12 rs506338 was also marginally associated with the uric acid concentrations (P=0.057). The meta-analysis for combined data from both males and females revealed that rs3775948 and rs606458 were associated with the uric acid concentrations (P=0.036 and 0.043, respectively). Furthermore, the gender significantly affected the association of rs11722228 with serum uric acid levels (P=0.012). CONCLUSION: The SLC2A9 rs11722228, SF1 rs606458 and GCKR rs780094 variants modulate uric acid concentrations in Chinese males, while SF1 rs606458 and SLC2A9 rs3775948 are associated with the uric acid concentrations in both Chinese males and females. PMID- 25283511 TI - Four endoplasmic reticulum resident selenoproteins may be related to the protection of selenium against cadmium toxicity in chicken lymphocytes. AB - Cadmium could induce the damage of endoplasmic reticulum. In the present study, we investigated the effect of Cadmium on messenger RNA expressions of endoplasmic reticulum resident selenoproteins, selenoprotein K, selenoprotein N, selenoprotein S, and selenoprotein T, in cultured chicken lymphocytes and the antagonistic effect of Selenium. Chicken splenic lymphocytes were treated with 10(-7) mol/L Selenium, 10(-6) mol/L Cadmium, and the mixture of 10(-6) mol/L Selenium and 10(-7) mol/L Cadmium in the culture medium for 12, 24, 36, and 48 h, respectively. Then, we detected the messenger RNA expressions of selenoprotein K, selenoprotein N, selenoprotein S, and selenoprotein T by using real-time polymerase chain reaction method. The results indicated that Selenium significantly increased the expressions of selenoprotein K, selenoprotein N, selenoprotein S, and selenoprotein T, which were reduced by Cadmium in chicken splenic lymphocytes. It indicated that endoplasmic reticulum was one target of Cadmium toxication, and Cadmium toxicity might be related to the reduced expressions of selenoprotein K, selenoprotein N, selenoprotein S, and selenoprotein T in chicken lymphocytes. Selenium reserved the protective role by increasing the expressions of selenoprotein K, selenoprotein N, selenoprotein S, and selenoprotein T. The present study provided a useful clue to investigate the possible pathogenesis of Cadmium toxicity. PMID- 25283510 TI - Varenicline for smoking cessation in people with schizophrenia: systematic review and meta-analysis. AB - We performed an updated meta-analysis of randomized double-blind placebo controlled trials (RCTs) on the effects of varenicline adjuvant therapy for smoking cessation in people with schizophrenia, on the basis of a previous meta analysis (Tsoi in Cochrane Database Syst Rev 2:CD007253, 2013). We searched PubMed, the Cochrane Library databases, and PsycINFO up to August 1, 2014. RCTs comparing varenicline adjuvant therapy with placebo in schizophrenia were included. The risk ratio (RR), number needed to harm (NNH), and standardized mean differences with its 95% confidence interval (CI) were used. Seven studies (total n = 439), including 6 with only schizophrenia (total n = 352), 1 with both schizophrenia (n = 77) and bipolar disorder (n = 10), were included. Varenicline was not superior to placebo in smoking cessation (RR = 0.79, 95% CI 0.58-1.08, p = 0.14, 5 RCTs, n = 322). Varenicline failed to show its superiority to placebo for overall, positive, negative, and depressive symptoms. Moreover, there was no significant difference in the discontinuation rate due to all causes, clinical deterioration, or side effects between varenicline and placebo. Although varenicline caused less abnormal dreams/nightmares than placebo (RR = 0.47, 95% CI 0.22-0.99, p = 0.05, NNH = not significant, 4 RCTs, n = 288), it caused more nausea (RR = 1.79, 95% CI 1.20-2.67, p = 0.004, NNH = 6, p = 0.004, 6 RCTs, n = 417). We detected no significant difference in suicidal ideation and depression between varenicline and placebo. Our results suggest that although varenicline adjuvant therapy is well tolerated, varenicline is not superior to placebo for smoking cessation in people with schizophrenia. Because of the limited sample sizes of the available studies, future studies will require larger samples to ensure that these findings are generalizable. PMID- 25283512 TI - Environmental concentrations of metals in the catalan stretch of the ebro river, Spain: assessment of temporal trends. AB - The aim of this study was to investigate the environmental impact and the human health risks associated with exposure to a number of metals before and after initiating the decontamination process in Flix dam (Catalonia, Spain). The concentrations of As, Cd, Cr, Cu, Mn, Hg, Ni, and Pb were determined in samples of drinking water, river water, and soils collected in the Catalan stretch of the Ebro River, Spain. The results were compared with those of previous surveys performed in the same zones. Human exposure to metals, as well as the associated carcinogenic and non-carcinogenic risks, was also estimated. In river and drinking waters, most analyzed metals showed increases, being significant that of Cr. The movements of polluted sludge in Flix dam could be the reason for the Cr levels found in the current survey. However, Hg was not detected in both drinking and river waters. Important differences on Mn levels were found, being higher those in river water than in drinking water. In turn, although soil concentrations of all analyzed metals showed a decreasing temporal trend, the reductions were only significant for Ni. The hazard quotient (HQ) of all elements was below the unity, considered the safe threshold. For carcinogenic risks, all values were found to be lower than 10(-5), which has been defined as the maximum recommended excess of cancer risk according to the Spanish Legislation. The only exception was the As exposure through soil and drinking water, which slightly exceeded this threshold. The current results indicate the need to perform a continuous assessment of metal levels not only in river waters, but also in drinking water in order to assure the harmlessness of the decontamination process for the health of the population living downriver (Ebro) the Flix dam. PMID- 25283513 TI - Inhibition of transforming growth factor beta/SMAD signal by MiR-155 is involved in arsenic trioxide-induced anti-angiogenesis in prostate cancer. AB - Prostate cancer is the most common cause of cancer-related deaths in men. Current practices for treatment of prostate cancer are less than satisfactory because of metastasis and recurrence, which are primarily attributed to angiogenesis. Hence, anti-angiogenesis treatment is becoming a promising new approach for prostate cancer therapy. In addition to treating acute promyelocytic leukemia, arsenic trioxide (As2 O3 ) suppresses other solid tumors, including prostate cancer. However, the effects of As2 O3 on angiogenesis in prostate cancer cells, and the underlying molecular mechanisms remain unclear. In the present study, As2 O3 attenuated angiogenic ability through microRNA-155 (miR-155)-mediated inhibition of transforming growth factor beta (TGF-beta)/SMAD signal pathway in human prostate cancer PC-3 and LNCaP cells in vitro and in vivo. Briefly, As2 O3 inhibited the activations/expressions of both TGFbeta-induced and endogenous SMAD2/3. Furthermore, As2 O3 improved the expression of miR-155 via DNA demethylation. MiR-155, which targeted the SMAD2-3'UTR, decreased the expression and function of SMAD2. Knockdown of miR-155 abolished the As2 O3 -induced inhibitions of the TGF-beta/SMAD2 signaling, the vascular endothelial growth factor secretion and angiogenesis. Through understanding a novel mechanism whereby As2 O3 inhibits angiogenic potential of prostate cancer cells, our study would help in the development of As2 O3 as a potential chemopreventive agent when used alone or in combination with other current anticancer drugs. PMID- 25283514 TI - Long-term outcomes of risk-reducing surgery in unaffected women at increased familial risk of breast and/or ovarian cancer. AB - This study prospectively investigated long-term psychosocial outcomes for women who opted for risk-reducing mastectomy (RRM) and/or risk-reducing salpingo oophorectomy (RRSO). Unaffected women from high-risk breast cancer families who had completed baseline questionnaires for an existing study and subsequently underwent RRM and/or RRSO, completed measures of perceived breast and ovarian cancer risk, anxiety, depression, cancer-related anxiety, body image, sexual functioning, menopausal symptoms, use of hormone replacement therapy and decision regret 3 years post-surgery. Outcomes were compared to age- and risk-matched controls. Participants (N = 233) were 17 women who had RRM (39 controls), 38 women who had RRSO (94 controls) and 15 women who had RRM + RRSO (30 controls). Women who underwent RRM and those who underwent RRM + RRSO reported reductions in perceived breast cancer risk and perceived breast and ovarian cancer risk respectively, compared to their respective controls. RRM women reported greater reductions in cancer-related anxiety compared with both controls and RRSO women. RRSO women reported more sexual discomfort than controls and more urogenital menopausal symptoms than controls and RRM only women. No differences in general anxiety, depression or body image were observed. Regret was associated with greater reductions in body image since surgery and more sexual discomfort, although overall regret levels were low. Women who undergo RRM experience psychological benefits associated with reduced breast cancer risk. Although women who undergo RRSO experience some deterioration in sexual and menopausal symptoms, they do not regret their surgery decision. It is vital that women considering these procedures receive detailed information about potential psychosocial consequences. PMID- 25283515 TI - Modulation of LXR-alpha and the effector genes by Ascorbic acid and Statins in psoriatic keratinocytes. AB - Recent studies have revealed critical roles that nuclear receptors like LXR-alpha (Liver X Receptor- alpha) plays as a class of post-transcriptional gene regulator in skin development and diseases. Keeping in view the fact that LXR-alpha plays crucial role in keratinocyte proliferation and differentiation, it becomes imperative to dissect the pathways and role of LXR-alpha genomics in the pathogenesis of psoriasis with ultimate aim to explore novel preventive/therapeutic strategies as treatment options. To explore the effects of agonists and activators of LXR-alpha on its own gene expression and the putative targets in psoriatic keratinocytes. Identification of promoter sequences for (vitamin D receptor) VDR and Catalase were done using in silico analysis followed by beta-galactosidase (beta-gal) reporter plasmid assay in keratinocytes from clinically heathy subjects. Determination of relative levels of LXR-alpha,VDR and catalase in control versus treated cells upon activation of LXR-alpha with Atorvastatin + 22R hydroxycholestrol and Ascorbic acid + 22R hydroxycholestrol was done by PCR and Cell Proliferation Assay. The cells transfected with the reporter plasmid element for VDR and catalase showed more than 5 and 4 fold increase respectively in the beta-gal activity compared to the control. An increase of 55% in LXR-alpha gene expression at RNA level was observed in Atorvastatin + 22-R hydroxycholestrol compared to 24% in Ascorbic acid + 22-ROH cholesterol. The expression of the VDR and Catalase was significantly increased in both treated keratinocytes compared to its normal counterpart. PMID- 25283516 TI - Enantioseparations 2014. PMID- 25283521 TI - Tissue distribution and ontogeny of multidrug resistance protein 2, a phosphatidylcholine translocator, in rats. AB - Multidrug resistance protein 2 (Mdr2), encoded by ATP-binding cassette b4 (Abcb4), serves as a phospholipid flippase that is indispensable for phosphatidylcholine translocation. However, little was known about the regulation of Mdr2 in Sprague-Dawley rats, although they are commonly used for pre-clinical investigation as well as mechanistic study. Present study aims at determining the tissue distribution, gender difference and ontogeny of Mdr2 in rats on both gene and protein levels. Results showed that Mdr2 was highly expressed in liver, modestly enriched in brain and testis, and less distributed in gastrointestinal tracts. Gender-divergent and male-dominated distribution was observed in the Mdr2 mRNA expression of liver and generative organs. Developmental pattern of rat Mdr2 on protein level was not exactly consistent with that on mRNA level. In conclusion, there was a considerable distribution of rat Mdr2 in the brain, testis and intestine besides liver, and the ontogeny of Mdr2 performed in an age dependent pattern with the post-transcriptional regulation. PMID- 25283522 TI - Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration. AB - The intravenous (iv) formulation of levetiracetam has been available in clinical practice worldwide for several years, but not in Japan. Two open-label studies were conducted: Study A evaluated the bioequivalence of iv and oral tablet formulations in healthy Japanese volunteers; and Study B subsequently compared the pharmacokinetics of iv levetiracetam in healthy Japanese and Caucasian volunteers. Study A had a randomised, two-way crossover design; a single 1,500 mg levetiracetam dose was administered as a 15-min iv infusion and as 3 * 500 mg oral tablets to Japanese volunteers. In Study B, 1,500 mg levetiracetam was administered as single and repeated 15-min iv infusions to Japanese and Caucasian volunteers. Overall, 26/27 volunteers completed Study A and 32/32 (16 Japanese; 16 Caucasian) completed Study B. In Study A, the point estimate and 90 % confidence interval (CI) for the geometric least squares mean (LSM) ratio (iv vs oral) were fully included within the acceptance range for bioequivalence (0.85 1.25) for the area under plasma concentration-time curve from 0 to last quantifiable observation (AUClast 0.97 [0.95, 0.99]), but not for the maximum plasma concentration (C max 1.64 [1.47, 1.83]). In Study B, after a single iv infusion, the point estimates (90 % CI) for the geometric LSM ratio (Japanese vs Caucasian) for body weight-normalised C max and AUClast were 1.21 (1.07, 1.36) and 0.97 (0.90, 1.04), respectively. Corresponding values after repeated iv infusions were C max,ss 1.01 (0.91, 1.12) and AUCtau,ss 0.89 (0.83, 0.96). Levetiracetam was well tolerated in both studies. Study A did not demonstrate the bioequivalence of single doses of levetiracetam 1,500 mg administered as an iv infusion and as oral tablets in healthy Japanese adults. Study B, however, showed that pharmacokinetic profiles were generally similar between Japanese and Caucasian adults after single and repeated iv infusions of levetiracetam 1,500 mg. PMID- 25283523 TI - In vivo monitoring of rat macrophages labeled with poly(l-lysine)-iron oxide nanoparticles. AB - Coprecipitation of FeCl2 and FeCl3 with aqueous ammonia was used to prepare iron oxide nanoparticles dispersible in aqueous medium. Oxidation of the particles with sodium hypochlorite then yielded maghemite (gamma-Fe2 O3 ) nanoparticles which were coated with two types of coating -d-mannose or poly(l-lysine) (PLL) as confirmed by FTIR analysis. The particles were <10 nm according to transmission electron microscopy. Their hydrodynamic particle size was ~180 nm (by dynamic light scattering). The d-mannose-, PLL-coated, and neat gamma-Fe2 O3 particles as well as commercial Resovist(r) were used to label rat macrophages. The viability and contrast properties of labeled macrophages were compared. PLL-coated gamma Fe2 O3 nanoparticles were found optimal. The labeled macrophages were injected to rats monitored in vivo by magnetic resonance imaging up to 48 h. Transport of macrophages labeled with PLL-gamma-Fe2 O3 nanoparticles in rats was confirmed. Tracking of macrophages using the developed particles can be used for monitoring of inflammations and cell migration in cell therapy. PMID- 25283524 TI - Interfacing synthetic DNA logic operations with protein outputs. AB - DNA logic gates are devices composed entirely of DNA that perform Boolean logic operations on one or more oligonucleotide inputs. Typical outputs of DNA logic gates are oligonucleotides or fluorescent signals. Direct activation of protein function has not been engineered as an output of a DNA-based computational circuit. Explicit control of protein activation enables the immediate triggering of enzyme function and could yield DNA computation outputs that are otherwise difficult to generate. By using zinc-finger proteins, AND, OR, and NOR logic gates were created that respond to short oligonucleotide inputs and lead to the activation or deactivation of a split-luciferase enzyme. The gate designs are simple and modular, thus enabling integration with larger multigate circuits, and the modular structure gives flexibility in the choice of protein output. The gates were also modified with translator circuits to provide protein activation in response to microRNA inputs as potential cellular cancer markers. PMID- 25283525 TI - NCI launches program for community-based clinical research: NCORP replaces 2 previous programs. PMID- 25283526 TI - American Society of Clinical Oncology Annual Meeting highlights. PMID- 25283527 TI - Comparative network analysis via differential graphlet communities. AB - While current protein interaction data provides a rich resource for molecular biology, it mostly lacks condition-specific details. Abundance of mRNA data for most diseases provides potential to model condition-specific transcriptional changes. Transcriptional data enables modeling disease mechanisms, and in turn provide potential treatments. While approaches to compare networks constructed from healthy and disease samples have been developed, they do not provide the complete comparison, evaluations are performed on very small networks, or no systematic network analyses are performed on differential network structures. We propose a novel method for efficiently exploiting network structure information in the comparison between any graphs, and validate results in non-small cell lung cancer. We introduce the notion of differential graphlet community to detect deregulated subgraphs between any graphs such that the network structure information is exploited. The differential graphlet community approach systematically captures network structure differences between any graphs. Instead of using connectivity of each protein or each edge, we used shortest path distributions on differential graphlet communities in order to exploit network structure information on identified deregulated subgraphs. We validated the method by analyzing three non-small cell lung cancer datasets and validated results on four independent datasets. We observed that the shortest path lengths are significantly longer for normal graphs than for tumor graphs between genes that are in differential graphlet communities, suggesting that tumor cells create "shortcuts" between biological processes that may not be present in normal conditions. PMID- 25283528 TI - Prognostic role of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma undergoing liver transplantation. AB - Vascular endothelial growth factor (VEGF) is pivotal in the development of hepatocellular carcinoma (HCC). Studies have demonstrated the prognostic value of circulating VEGF levels in patients undergoing liver resection or locoregional therapy (LRT) for HCC. We investigated the significance of preoperative plasma VEGF levels in patients with HCC undergoing liver transplantation (LT) at a Western transplant center. Pre-LT plasma VEGF levels were measured with an enzyme linked immunoassay for 164 patients with HCC undergoing LT. The preoperative plasma VEGF level was correlated with clinicopathological variables and overall and recurrence-free post-LT survival. A higher pre-LT plasma VEGF level was significantly associated with pre-LT LRT (P = 0.01), multiple tumors (P = 0.02), a total tumor diameter >= 5 cm (P = 0.01), bilobar tumor distribution (P = 0.03), tumor vascular invasion (VI; P < 0.001), and HCC beyond the Milan criteria (P < 0.001). Patients with a plasma VEGF level > 44 pg/mL had significantly worse overall and disease-free survival than those with VEGF levels <= 44 pg/mL (P = 0.04 and P = 0.02, respectively). In a multivariate analysis, a plasma VEGF level > 44 pg/mL was independently associated with tumor VI (P < 0.001) and recurrence free survival (hazard ratio = 2.12, 95% confidence interval = 1.08-4.14, P = 0.03). In conclusion, in patients with chronic end-stage liver disease and HCC, a pre-LT plasma VEGF level > 44 pg/mL may be a predictor of tumor VI and recurrence free post-LT survival. PMID- 25283529 TI - Novel capsaicin analogues as potential anticancer agents: synthesis, biological evaluation, and in silico approach. AB - A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (uM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents. PMID- 25283530 TI - 'Venturing Towards the Dark Side': The Use of Imagery Interventions by Recently Qualified Cognitive-Behavioural Therapists. AB - Despite the growing recognition of the value of mental imagery within the field of cognitive-behavioural therapy (CBT), there is minimal research relating to clinicians' experiences of using imagery. This paper explores recently qualified CBT therapists' clinical experiences of using imagery and their perception of the role of imagery within their practice. Twelve therapists, qualified within the past 4 years, were interviewed using a semi-structured format, and the resulting transcriptions were analysed using Interpretative Phenomenological Analysis (IPA). The analysis identified six super-ordinate themes: (1) broad and fluid conception of imagery; (2) the importance given to imagery and the varied rationale for its inclusion; (3) varied application; (4) clinician avoidance and apprehension; (5) personal experience of imagery and impact on use; and (6) limited core training and the potential for future use. The themes, as a whole, described a complex and often dichotomous reaction to imagery amongst the therapists. Although a section of participants reported a natural affinity with imagery, other therapists felt that using, and experiencing, imagery was anxiety provoking and problematic. There was, however, unity in the value placed on imagery, the strong rationale for usage and the importance given to imagery specific training. Avoidance and apprehension regarding imagery were evident in the majority of participants, and the reasons for such responses included personal, clinical and cultural factors. The overall findings highlight the importance of clinician factors in the way in which imagery is utilized and understood, which has positive implications for training, personal development and future research. KEY PRACTITIONER MESSAGE: There is a universal recognition of the value of imagery for experiential learning and emotional connection. Therapists apply a variety of rationales for using imagery. Avoidance of using imagery in CBT practice is widely reported and occurs for a variety of personal and clinical reasons. Clinicians' own experience of imagery has a significant influence on the way in which imagery is understood, utilized and experienced in therapy. Future training and research in imagery should more explicitly address the clinician factors that can inhibit or facilitate the use of evidence-based imagery interventions. PMID- 25283531 TI - Dimers of nineteen-electron sandwich compounds: crystal and electronic structures, and comparison of reducing strengths. AB - The dimers of some Group 8 metal cyclopentadienyl/arene complexes and Group 9 metallocenes can be handled in air, yet are strongly reducing, making them useful n-dopants in organic electronics. In this work, the X-ray molecular structures are shown to resemble those of Group 8 metal cyclopentadienyl/pentadienyl or Group 9 metal cyclopentadienyl/diene model compounds. Compared to those of the model compounds, the DFT HOMOs of the dimers are significantly destabilized by interactions between the metal and the central C?C sigma-bonding orbital, accounting for the facile oxidation of the dimers. The lengths of these C?C bonds (X-ray or DFT) do not correlate with DFT dissociation energies, the latter depending strongly on the monomer stabilities. Ru and Ir monomers are more reducing than their Fe and Rh analogues, but the corresponding dimers also exhibit much higher dissociation energies, so the estimated monomer cation/neutral dimer potentials are, with the exception of that of [RhCp2 ]2 , rather similar (-1.97 to -2.15 V vs. FeCp2 (+/0) in THF). The consequences of the variations in bond strength and redox potentials for the reactivity of the dimers are discussed. PMID- 25283532 TI - How the physical properties of food influence its selection by infant Japanese macaques inhabiting a snow-covered area. AB - Dietary differences exist between infant and adult female non-human primates. These differences are considered to be related to the low ability of infants to bite, handle, and obtain food items. This study aimed to provide a comprehensive examination of how the physical properties of food items (fracture toughness, size, processing, and height) influence food selection by infant primates. In this study, four mother-infant Japanese macaque (Macaca fuscata) pairs were investigated in a snow-covered area during winter. The feeding behavior of both mothers and infants was recorded. The size, need for processing, and height of food items were recorded by direct observation, while the fracture toughness of food items (evaluating the required bite force by incisors) was measured using a rheometer. On average, infants spent 14% less time feeding than their mothers, and there were dietary differences between mothers and infants. Compared to their mothers, infants fed relatively more frequently on food items that were small, at a low position, or that could be consumed without processing. In addition, infants spent less time feeding on food items that were tougher than 2,000 J/m(2) . Thus, infants fed relatively more frequently on food items that are easy to obtain. This food selection by infants reduced the costs of feeding and allowed them to avoid falling from high trees. PMID- 25283533 TI - Anatomy of sex: Revision of the new anatomical terms used for the clitoris and the female orgasm by sexologists. AB - Sexual medicine experts and sexologists must spread certainties on the biological basis of the female orgasm to all women, not hypotheses or personal opinions. Therefore, they must use scientific anatomical terminology. The anatomy of the clitoris and the female orgasm are described in textbooks, but some researchers have proposed a new anatomical terminology for the sexual response in women. The internal/inner clitoris does not exist: the entire clitoris is an external organ. The clitoris is not composed of two arcs but of the glans, body, and crura or roots. "Clitoral bulbs" is an incorrect term from an embryological and anatomical viewpoint: the correct term is "vestibular bulbs." The bulbocavernosus muscles are implicated in inferior vaginismus, while the pubovaginal muscle is responsible for superior vaginismus. The clitoral or clitoris-urethro-vaginal complex has no embryological, anatomical and physiological support: the vagina has no anatomical relationship with the clitoris, and the clitoris is a perineal organ while the supposed G-spot is in the pelvic urethra. G-spot/vaginal/clitoral orgasm, vaginally activated orgasm, and clitorally activated orgasm, are incorrect terms: like "male orgasm," "female orgasm" is the correct term. The "vaginal" orgasm that some women report is always caused by the surrounding erectile organs (triggers of female orgasm). The male penis cannot come in contact with the venous plexus of Kobelt or with the clitoris during vaginal intercourse. Also, female ejaculation, premature ejaculation, persistent genital arousal disorder (PGAD), periurethral glans, vaginal-cervical genitosensory component of the vagus nerve, and G-spot amplification, are terms without scientific basis. Female sexual satisfaction is based on orgasm and resolution: in all women, orgasm is always possible if the female erectile organs, i.e. the female penis, are effectively stimulated during masturbation, cunnilingus, partner masturbation, or during vaginal/anal intercourse if the clitoris is simply stimulated with a finger. Clin. Anat. 28:293-304, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25283534 TI - A revision of the Mexican Anolis (Reptilia, Squamata, Dactyloidae) from the Pacific versant west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla, with the description of six new species . AB - We revise the species of anoles occurring along the Pacific versant of Mexico west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla. Based on our analyses of morphological and molecular genetic data, we recognize 21 species, six of which we describe as new (i.e., Anolis carlliebi sp. nov., A. immaculogularis sp. nov., A. nietoi sp. nov., A. sacamecatensis sp. nov., A. stevepoei sp. nov., and A. zapotecorum sp. nov.). Furthermore, we synonymize Anolis forbesi Smith & Van Gelder 1955 with Anolis microlepidotus Davis 1954. Of the recognized species, six have smooth ventral scales (i.e., Anolis dunni, A. gadovii, A. liogaster, A. omiltemanus, A. peucephilus, and A. taylori) and 14 have keeled ventral scales (i.e., A. boulengerianus, A. carlliebi, A. immaculogularis, A. megapholidotus, A. microlepidotus, A. nebuloides, A. nebulosus, A. nietoi, A. quercorum, A. sacamecatensis, A. stevepoei, A. subocularis, A. unilobatus, and A. zapotecorum). In one species, A. macrinii, the ventral scales vary from smooth to weakly keeled. For each species we provide color descriptions in life, color photographs in life, descriptions and illustration of hemipenis morphology (if available), description of external morphology, distribution maps based on the specimensexamined, comments on the conservation status, and natural history notes. Finally, we provide a dichotomous key for the identification of the 21 species of anoles occurring along the Pacific versant of Mexico west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla. PMID- 25283535 TI - Diversity, natural history, and geographic distribution of snakes in the Caatinga, Northeastern Brazil. AB - The present study is a synthesis on snake diversity and distribution in the Caatinga region of northeastern Brazil, providing an updated species list and data on natural history and geographic distribution. Our study is based on the careful revision of 7,102 voucher specimens, housed in 17 herpetological collections, complemented by data on taxonomic literature. We recorded a total of 112 snake species in the Caatinga, belonging to nine families: Anomalepididae, Leptotyphlopidae, Typhlopidae, Aniliidae, Boidae, Viperidae, Elapidae, Colubridae, and Dipsadidae. Our list includes at least 13 never recorded species for this region, as well as distribution records for all species known from the Caatinga (including expansion and new records of distribution). The snake assemblage of the Caatinga is complex, sharing species with other continental open areas (38.4%), forested areas (27.7%), and both open and forested areas (32.1%). The richest areas were isolated plateaus, followed by contact areas, semi-arid caatinga, and sandy dunes of the Sao Franscisco River. We identified 22 Caatinga endemic species with the sandy dunes of Sao Franscico River showing the highest endemism level (12 species, with six endemic species restricted to the area) followed by semi-arid caatinga, and isolated plateaus (eight endemic species each, and six and three endemic species with restricted distribution to each area, respectively). Most species show relatively restricted ranges in parts of the Caatinga. The snake assemblage in Caatinga includes mainly terrestrial species (38.4%), followed by fossorial/cryptozoic (26.8%), arboreal/semi-arboreal (26.8%), and aquatic/semi-aquatic (7.1%) species. Vertebrates are the most important dietary item (80.4%), with 56.6% of species being generalist consumers of this kind of prey; 24.4% are frog-eaters, 7.8% prey on caecilians/amphisbaenians, 6.7% lizard-eaters, 3.3% mammal-eaters, and 1.1% are fish-eaters. Only 18.7% of the snakes eat invertebrate prey, as arthropods, annelids, and mollusks. In relation to time of activity, 35.7% of snakes are both diurnal and nocturnal, 33.0% are strictly nocturnal, and 30.4% are diurnal. The data provided herein increase the list of Caatinga snake species from 50 to 112, and includes detailed maps and information on geographic distribution. The Caatinga snake assemblage shows high richness and endemism levels, and our results highlight the usefulness of basic natural history data and revision of voucher specimens as baseline information for biogeographic studies and conservation strategies. PMID- 25283536 TI - Faunistic review of the cuckoo wasps of Fennoscandia, Denmark and the Baltic countries (Hymenoptera: Chrysididae). AB - A critical and annotated review of published records of the Chrysididae of the Nordic and Baltic countries and the Russian part of Fennoscandia is presented with some taxonomic and faunistic notes. A total of 73 species are listed from the region. Additionally, 17 species are deleted. Three species are recorded for the first time from Denmark, six species from Estonia, one from Finland, eleven from Latvia, four from Norway, one from Sweden and 15 from Russian Fennoscandia. Elampus foveatus and Chrysis pulcherrima are reported for the first time from the Nordic and Baltic countries. Lectotypes are designated for Hedychrum cupreum Dahlbom, 1845, Chrysis zetterstedti Dahlbom, 1845, Chrysis succincta var. chrysoprasina Trautmann, 1927, Chrysis succincta var. virideocincta Trautmann, 1927 and Chrysis succincta var. nordstromi Trautmann, 1927. Information and images of the holotypes of Hedychrum metallicum Dahlbom, 1854, Chrysis var. westerlundi Trautmann, 1927 are given. Chrysis integra Dahlbom, 1829 is found to be a new synonym of Hedychridium ardens (Coquebert, 1801) and Chrysis scintillans Valkeila, 1971 a new synonym of Chrysis solida Haupt, 1957. Chrysis terminata Dahlbom, 1854 is reported for the first time as the valid name for C. ignita Form A sensu Linsenmaier, 1959. PMID- 25283537 TI - Phytoseiid mites (Acari: Phytoseiidae) from Egypt, with new records, descriptions of new species, and a key to species. AB - The present paper refers to the identification of phytoseiid specimens newly collected by the first author of this paper and her collaborators, as well as to the examination of type specimens of species previously described from Egypt. The taxonomy of phytoseiid mites has been studied in Egypt since 1967. Until now, 78 nominal species have been recorded, of which 60 are valid. One of those species, Phytoseius plumifer (Canestrini & Fanzago), appears to be based on an incorrect record. An additional species (Typhlodromus hellei Hassan, Afifi & Nawar), described from Egypt, is not sufficiently characterised to allow its correct generic classification and the determination of its validity. Eight new records are reported in this paper, including two new species, Proprioseiopsis ismailiaensis n. sp. and Typhlodromus (Anthoseius) fayoumensis n. sp., which are described. Complementary descriptions of 11 known species are given. An updated survey of all species reported from Egypt and a taxonomic key to separate them are also presented. Six new synonymies are proposed. PMID- 25283538 TI - An amphipathic polypeptide derived from poly-gamma-glutamic acid for the stabilization of membrane proteins. AB - Difficulties in the extraction of membrane proteins from cell membrane and their solubilization in native conformations have hindered their structural and biochemical analysis. To overcome these difficulties, an amphipathic polypeptide was synthesized by the conjugation of octyl and glucosyl groups to the carboxyl groups of poly-gamma-glutamic acid (PGA). This polymer, called amphipathic PGA (APG), self-assembles as mono-disperse oligomers consisted of 4-5 monomers. APG shows significantly low value of critical micelle concentration and stabilization activity toward membrane proteins. Most of the sodium dodecyl sulfate (SDS) solubilized membrane proteins from Escherichia coli remain soluble state in the presence of APG even after the removal of SDS. In addition, APG stabilizes purified 7 transmembrane proteins such as bacteriorhodopsin and human endothelin receptor Type A (ETA ) in their active conformations. Furthermore, ETA in complex with APG is readily inserted into liposomes without disrupting the integrity of liposomes. These properties of APG can be applied to overcome the difficulties in the stabilization and reconstitution of membrane proteins. PMID- 25283539 TI - Emerging concept in DNA methylation: role of transcription factors in shaping DNA methylation patterns. AB - DNA methylation in mammals is a key epigenetic modification essential to normal genome regulation and development. DNA methylation patterns are established during early embryonic development, and subsequently maintained during cell divisions. Yet, discrete site-specific de novo DNA methylation or DNA demethylation events play a fundamental role in a number of physiological and pathological contexts, leading to critical changes in the transcriptional status of genes such as differentiation, tumor suppressor or imprinted genes. How the DNA methylation machinery targets specific regions of the genome during early embryogenesis and in adult tissues remains poorly understood. Here, we report advances being made in the field with a particular emphasis on the implication of transcription factors in establishing and in editing DNA methylation profiles. PMID- 25283540 TI - Thermally triggered frame-guided assembly. AB - We report a thermally triggered frame-guided assembly (FGA) strategy for the preparation of vesicles. We employ thermally responsive poly(propylene oxide) (PPO) to make the leading hydrophobic groups (LHGs) thermally responsive, so that they are hydrophilic below the low critical solution temperature (LCST) and the frame forms in a homogeneous environment. When the temperature is increased above the LCST, the LHGs become hydrophobic and the assembly process is triggered, which drives DNA-b-PPO to assemble around the LHGs, forming vesicles. This work verified that FGA is a general strategy and can be applied to polymeric systems. The thermally triggered assembly not only provides more controllability over the FGA process but also promotes an in-depth understanding of the FGA strategy and in a broad view, the formation mechanism and functions of cell membrane. PMID- 25283541 TI - Cone beam computed tomography and periapical lesions: a systematic review analysing studies on diagnostic efficacy by a hierarchical model. AB - AIM: To evaluate using a systematic review approach the diagnostic efficacy of CBCT for periapical lesions, focusing on the evidence level of the included studies using a six-tiered hierarchical model. METHODOLOGY: The MEDLINE bibliographic database was searched from 2000 to July 2013 for studies evaluating the potential of CBCT imaging in the diagnosis and planning of treatment for periapical lesions. The search strategy was limited to English language publications using the following combined terms in the search strategy: apical pathology or endodontic pathology or periapical or lesion or healing and CBCT or cone beam CT. The diagnostic efficacy level of the studies was assessed independently by four reviewers. RESULTS: The search identified 25 publications that qualitatively or quantitatively assessed the use of CBCT for the diagnosis of periapical lesions, in which the methodology/results comprised at least one of the following parameters: the methods, the imaging protocols or qualitative/quantitative information on how CBCT influenced the diagnosis and/or treatment plan. CONCLUSION: From the assessed studies, it can be concluded that although there is a tendency for a higher accuracy for periapical lesion detection using CBCT compared to two-dimensional imaging methods, no studies have been conducted that justify the standard use of CBCT in diagnosing periapical lesions. In addition, it should be considered that, at the present time, the efficacy of CBCT as the diagnostic imaging method for periapical lesions has been assessed merely at low diagnostic efficacy levels. PMID- 25283542 TI - Functionalized membranes for photocatalytic hydrogen production. AB - Functionalized vesicles for photocatalytic hydrogen production in water have been prepared by co-embedding of amphiphilic photosensitizers and a hydrogen-evolving catalyst in phospholipid membranes. The self-assembly allows a simple two dimensional arrangement of the multicomponent system with close spatial proximity, which gave turnover numbers up to 165 for the incorporated amphiphilic cobaloxime water reduction catalyst 3 b under optimized conditions in purely aqueous solution. Superior photocatalytic activity in fluid membranes indicates that mobility and dynamic reorganization of catalytic subunits in the membrane promote the visible-light-driven hydrogen production. The functionalized membranes represent nanostructured assemblies for hydrogen production in aqueous solution mimicking natural photosynthesis. PMID- 25283543 TI - Influence of highly-active antiretroviral therapy on the subgingival biofilm in HIV-infected patients. AB - AIM: Highly-active antiretroviral therapy (HAART) has been associated with alterations in subgingival biofilm and periodontal disease. The purpose of the present study was to investigate the association between different HAART regimens and the prevalence of periodontal pathogens in HIV-infected patients with chronic periodontitis. METHODS: Subgingival periodontal pathogens were determined by a DNA chip microarray in a case series in 14 HIV-infected patients receiving HAART with different drug combinations: protease inhibitor (PI)-based HAART versus non nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. A statistical analysis was conducted to determine whether specific HAART regimens were associated with 10 periodontal pathogens using odds ratios (OR). RESULTS: At baseline and after treatment, the patients did not show significant clinical and immunological differences. In general, the highest OR for the prevalence of periodontal pathogens were found in the PI HAART group for Actinomyces viscosus (A. viscosus) (OR: 303), Campylobacter rectus (OR: 90), and Treponema denticola (OR: 25). In the NNRTI HAART group, higher OR were documented for Fusobacterium nucleatum (OR: 56) and Eikenella corrodens (OR: 25). The association between A. viscosus and PI HAART was statistically significant (P = 0.03). CONCLUSIONS: The results demonstrated statistical associations between subgingival bacteria and antiretroviral drug therapies. Further investigation on the clinical significance and underlying mechanisms are needed to support these findings. PMID- 25283544 TI - AHL-type quorum sensing and its regulation on symplasmata formation in Pantoea agglomerans YS19. AB - Pantoea agglomerans YS19, an endophytic diazotrophic bacterium isolated from rice, is characterized by the formation of multicellular aggregate structure called symplasmata, which not only bestow the strong stress-resistance of the bacterium, but also contribute to the specific adaptation in the endophyte-host association. Acyl-homoserine lactones (AHLs), as the important signal molecule in the quorum sensing (QS) system of gram-negative bacteria, were demonstrated to regulate motility, cell-aggregation, and other bacterial behaviors. Here, the production of AHL by P. agglomerans YS19 and its regulation on the symplasmata formation were studied. It was revealed that the production of AHL by YS19 was initiated at the exponential growth stage and from then on, reached the peak values at the stationary growth stage in LB medium. The AHL was identified as N-3 oxooctanoyl-L-homoserine lactone (OOHL) by MALDI-TOF-MS analysis. The AHL synthesis gene pagI and receptor gene pagR in YS19 were cloned and phylogenetic analysis showed that they were high conservative among strains in species of P. agglomerans. It was revealed that AHL promoted the bacterial growth and symplasmata formation of YS19. Meanwhile, the colonization ability and growth promoting effect of YS19 on the host plant were also enhanced by AHL. These results strongly suggest the pleiotropic effects of the AHL-type QS system in endophytic life of the strain. PMID- 25283545 TI - Complementary and dynamic type II cadherin expression associated with development of the primate visual system. AB - The middle temporal visual area (MT, also known as V5) is a visual association area that is particularly evolved in the primate brain. The MT receives input from the primary visual area (V1), constitutes part of the dorsal visual pathway, and plays an essential role in processing motion. Connections between the MT and V1 in the primate brain are formed after birth, and are related to the maturation of visual system. However, it remains to be determined what molecular mechanisms control the formation and maturation of the visual system. Cadherins are transmembrane proteins, originally isolated as cell adhesion molecules, which have multiple roles in synapse formation and function. To investigate potential involvement of cadherins in development of the primate visual system, we examined type II cadherin expression (cadherin-6, -8, -12) in cortical and thalamic visual areas of pre- and postnatal brains of the common marmoset (Callithrix jacchus). In the prenatal brain, cadherin-6 was dominantly expressed in the pulvino-MT pathway whereas cadherin-8 was dominant in the lateral geniculate nucleus (LGN) V1 pathway. During postnatal development, there was a downregulation of cadherin 6 and upregulation of cadherin-8 expression in the MT. The timing of this cadherin exchange preceded the development of V1-MT connections. Our results suggest the possibility that changes in cadherin expression are involved in the development of the primate visual system, and that a switch in cadherin expression may be a general mechanism to control neural plasticity of highly cognitive abilities. PMID- 25283546 TI - Moving on with foraging theory: incorporating movement decisions into the functional response of a gregarious shorebird. AB - Models relating intake rate to food abundance and competitor density (generalized functional response models) can predict forager distributions and movements between patches, but we lack understanding of how distributions and small-scale movements by the foragers themselves affect intake rates. Using a state-of-the art approach based on continuous-time Markov chain dynamics, we add realism to classic functional response models by acknowledging that the chances to encounter food and competitors are influenced by movement decisions, and, vice versa, that movement decisions are influenced by these encounters. We used a multi-state modelling framework to construct a stochastic functional response model in which foragers alternate between three behavioural states: searching, handling and moving. Using behavioural observations on a molluscivore migrant shorebird (red knot, Calidris canutus canutus), at its main wintering area (Banc d'Arguin, Mauritania), we estimated transition rates between foraging states as a function of conspecific densities and densities of the two main bivalve prey. Intake rate decreased with conspecific density. This interference effect was not due to decreased searching efficiency, but resulted from time lost to avoidance movements. Red knots showed a strong functional response to one prey (Dosinia isocardia), but a weak response to the other prey (Loripes lucinalis). This corroborates predictions from a recently developed optimal diet model that accounts for the mildly toxic effects due to consuming Loripes. Using model averaging across the most plausible multi-state models, the fully parameterized functional response model was then used to predict intake rate for an independent data set on habitat choice by red knot. Comparison of the sites selected by red knots with random sampling sites showed that the birds fed at sites with higher than average Loripes and Dosinia densities, that is sites for which we predicted higher than average intake rates. We discuss the limitations of Holling's classic functional response model which ignores movement and the limitations of contemporary movement ecological theory that ignores consumer-resource interactions. With the rapid advancement of technologies to track movements of individual foragers at fine spatial scales, the time is ripe to integrate descriptive tracking studies with stochastic movement-based functional response models. PMID- 25283547 TI - Detection of viable antibiotic-resistant/sensitive Acinetobacter baumannii in indoor air by propidium monoazide quantitative polymerase chain reaction. AB - Acinetobacter baumannii represents a significant cause of nosocomial infections. Therefore, we combined real-time quantitative polymerase chain reaction (PCR) with the propidium monoazide (PMA-qPCR) to assess the feasibility of detecting viable, airborne A. baumannii. The biological collection efficiencies of three samplers for collecting airborne A. baumannii were evaluated by PMA-qPCR in a chamber study. After sampling, the effects of storage in collection fluid on A. baumannii were evaluated. The results showed that the culturable ratio of A. baumannii measured using the culture method was significantly correlated with the viable ratio measured using PMA-qPCR, but was not significantly correlated with the qPCR results. It was indicated that the AGI-30 impinger and the BioSampler were much more effective than the Nuclepore filter sampler for collecting airborne A. baumannii. The storage temperature was critical for aerosol samples, as the loss of viable A. baumannii was minimized when the PMA-bound DNA was stored at -20 degrees C or if the collected cells were stored at 4 degrees C and subsequently processed by PMA-qPCR within 1 month. The PMA-qPCR method was also to distinguish between colistin-sensitive and colistin-resistant A. baumannii, and no colistin-sensitive A. baumannii was detected by PMA-qPCR upon treatment of the BioSampler collection medium with 2 MUg/ml colistin for 5 min. PMID- 25283548 TI - High-throughput multiplex HLA genotyping by next-generation sequencing using multi-locus individual tagging. AB - BACKGROUND: Unambiguous human leukocyte antigen (HLA) typing is important in transplant matching and disease association studies. High-resolution HLA typing that is not restricted to the peptide-binding region can decrease HLA allele ambiguities. Cost and technology constraints have hampered high-throughput and efficient high resolution unambiguous HLA typing. We have developed a method for HLA genotyping that preserves the very high-resolution that can be obtained by next-generation sequencing (NGS) but also achieves substantially increased efficiency. Unambiguous HLA-A, B, C and DRB1 genotypes can be determined for 96 individuals in a single run of the Illumina MiSeq. RESULTS: Long-range amplification of full-length HLA genes from four loci was performed in separate polymerase chain reactions (PCR) using primers and PCR conditions that were optimized to reduce co-amplification of other HLA loci. Amplicons from the four HLA loci of each individual were then pooled and subjected to enzymatic library generation. All four loci of an individual were then tagged with one unique index combination. This multi-locus individual tagging (MIT) method combined with NGS enabled the four loci of 96 individuals to be analyzed in a single 500 cycle sequencing paired-end run of the Illumina-MiSeq. The MIT-NGS method generated sequence reads from the four loci were then discriminated using commercially available NGS HLA typing software. Comparison of the MIT-NGS with Sanger sequence based HLA typing methods showed that all the ambiguities and discordances between the two methods were due to the accuracy of the MIT-NGS method. CONCLUSIONS: The MIT-NGS method enabled accurate, robust and cost effective simultaneous analyses of four HLA loci per sample and produced 6 or 8-digit high-resolution unambiguous phased HLA typing data from 96 individuals in a single NGS run. PMID- 25283549 TI - NLS copy-number variation governs efficiency of nuclear import--case study on dUTPases. AB - Nucleocytoplasmic trafficking of large macromolecules requires an active transport machinery. In many cases, this is initiated by binding of the nuclear localization signal (NLS) peptide of cargo proteins to importin-alpha molecules. Fine orchestration of nucleocytoplasmic trafficking is of particularly high importance for proteins involved in maintenance of genome integrity, such as dUTPases, which are responsible for prevention of uracil incorporation into the genome. In most eukaryotes, dUTPases have two homotrimeric isoforms: one of these contains three NLSs and is present in the cell nucleus, while the other is located in the cytoplasm or the mitochondria. Here we focus on the unusual occurrence of a pseudo-heterotrimeric dUTPase in Drosophila virilis that contains one NLS, and investigate its localization pattern compared to the homotrimeric dUTPase isoforms of Drosophila melanogaster. Although the interaction of individual NLSs with importin-alpha has been well characterized, the question of how multiple NLSs of oligomeric cargo proteins affect their trafficking has been less frequently addressed in adequate detail. Using the D. virilis dUTPase as a fully relevant physiologically occurring model protein, we show that NLS copy number influences the efficiency of nuclear import in both insect and mammalian cell lines, as well as in D. melanogaster and D. virilis tissues. Biophysical data indicate that NLS copy number determines the stoichiometry of complexation between importin-alpha and dUTPases. The main conclusion of our study is that, in D. virilis, a single dUTPase isoform efficiently reproduces the cellular dUTPase distribution pattern that requires two isoforms in D. melanogaster. PMID- 25283551 TI - Site-specific proteolytic degradation of IgG monoclonal antibodies expressed in tobacco plants. AB - Plants are promising hosts for the production of monoclonal antibodies (mAbs). However, proteolytic degradation of antibodies produced both in stable transgenic plants and using transient expression systems is still a major issue for efficient high-yield recombinant protein accumulation. In this work, we have performed a detailed study of the degradation profiles of two human IgG1 mAbs produced in plants: an anti-HIV mAb 2G12 and a tumour-targeting mAb H10. Even though they use different light chains (kappa and lambda, respectively), the fragmentation pattern of both antibodies was similar. The majority of Ig fragments result from proteolytic degradation, but there are only a limited number of plant proteolytic cleavage events in the immunoglobulin light and heavy chains. All of the cleavage sites identified were in the proximity of interdomain regions and occurred at each interdomain site, with the exception of the VL /CL interface in mAb H10 lambda light chain. Cleavage site sequences were analysed, and residue patterns characteristic of proteolytic enzymes substrates were identified. The results of this work help to define common degradation events in plant-produced mAbs and raise the possibility of predicting antibody degradation patterns 'a priori' and designing novel stabilization strategies by site-specific mutagenesis. PMID- 25283550 TI - microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity. AB - BACKGROUND: The AKT/mammalian target of rapamycin (mTOR) signaling pathway is regulated by 17alpha-estradiol (E2) signaling and mediates E2-induced proliferation and progesterone receptor (PgR) expression in breast cancer. METHODS AND RESULTS: Here we use deep sequencing analysis of previously published data from The Cancer Genome Atlas to demonstrate that expression of a key component of mTOR signaling, rapamycin-insensitive companion of mTOR (Rictor), positively correlated with an estrogen receptor-alpha positive (ERalpha+) breast tumor signature. Through increased microRNA-155 (miR-155) expression in the ERalpha+ breast cancer cells we demonstrate repression of Rictor enhanced activation of mTOR complex 1 (mTORC1) signaling with both qPCR and western blot. miR-155-mediated mTOR signaling resulted in deregulated ERalpha signaling both in cultured cells in vitro and in xenografts in vivo in addition to repressed PgR expression and activity. Furthermore we observed that miR-155 enhanced mTORC1 signaling (observed through western blot for increased phosphorylation on mTOR S2448) and induced inhibition of mTORC2 signaling (evident through repressed Rictor and tuberous sclerosis 1 (TSC1) gene expression). mTORC1 induced deregulation of E2 signaling was confirmed using qPCR and the mTORC1-specific inhibitor RAD001. Co-treatment of MCF7 breast cancer cells stably overexpressing miR-155 with RAD001 and E2 restored E2-induced PgR gene expression. RAD001 treatment of SCID/CB17 mice inhibited E2-induced tumorigenesis of the MCF7 miR 155 overexpressing cell line. Finally we demonstrated a strong positive correlation between Rictor and PgR expression and a negative correlation with Raptor expression in Luminal B breast cancer samples, a breast cancer histological subtype known for having an altered ERalpha-signaling pathway. CONCLUSIONS: miRNA mediated alterations in mTOR and ERalpha signaling establishes a new mechanism for altered estrogen responses independent of growth factor stimulation. PMID- 25283552 TI - Do gerontology nurse specialists make a difference in hospitalization of long term care residents? Results of a randomized comparison trial. AB - Residents of long-term care facilities have highly complex care needs and quality of care is of international concern. Maintaining resident wellness through proactive assessment and early intervention is key to decreasing the need for acute hospitalization. The Residential Aged Care Integration Program (RACIP) is a quality improvement intervention to support residential aged care staff and includes on-site support, education, clinical coaching, and care coordination provided by gerontology nurse specialists (GNSs) employed by a large district health board. The effect of the outreach program was evaluated through a randomized comparison of hospitalization 1 year before and after program implementation. The sample included 29 intervention facilities (1,425 residents) and 25 comparison facilities (1,128 residents) receiving usual care. Acute hospitalization rate unexpectedly increased for both groups after program implementation, although the rate of increase was significantly less for the intervention facilities. The hospitalization rate after the intervention increased 59% for the comparison group and 16% for the intervention group (rate ratio (RR) = 0.73, 95% confidence interval (CI) = 0.61-0.86, P < .001). Subgroup analysis showed a significantly lower rate change for those admitted for medical reasons for the intervention group (13% increase) than the comparison group (69% increase) (RR = 0.67, 95% CI = 0.56-0.82, P < .001). Conversely, there was no significant difference in the RR for surgical admissions between the intervention and comparison groups (RR = 1.0, 95% CI = 0.68-1.46, P = .99). The integration of GNS expertise through the RACIP intervention may be one approach to support staff to provide optimal care and potentially improve resident health. PMID- 25283554 TI - Design, synthesis, and structure-activity relationship of novel opioid kappa receptor selective agonists: alpha-iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton. AB - The alpha-iminoamide derivative, 4b was designed and synthesized as a novel agonist selective for the opioid kappa receptor. The amide was constrained to an orientation horizontal to the F-ring of the azabicyclo[2.2.2]octane skeleton, which remarkably improved its affinity, selectivity, and agonistic activity for the kappa receptor. This finding was newly established by chemical modification of the nitrogen atom at the 8-position in the azabicyclo[2.2.2]octane skeleton. This modification would never have been found with KNT-63, a derivation of oxabicyclo[2.2.2]octane. These results may provide valuable information for the future development of novel kappa selective agonists. PMID- 25283555 TI - New antibacterial xanthone from the marine sponge-derived Micrococcus sp. EG45. AB - Microluside A [4 (19-para-hydroxy benzoyloxy-O-beta-D-cellobiosyl), 5 (30-para hydroxy benzoyloxy-O-beta-D-glucopyranosyl) xanthone (1)] is a unique O glycosylated disubstituted xanthone isolated from the broth culture of Micrococcus sp. EG45 cultivated from the Red Sea sponge Spheciospongia vagabunda. The structure of microluside A was determined by 1D- and 2D-NMR techniques as well as high resolution tandem mass spectrometry. The antimicrobial activity evaluation showed that 1 exhibited antibacterial potential against Enterococcus faecalis JH212 and Staphylococcus aureus NCTC 8325 with MIC values of 10 and 13 MUM, respectively. PMID- 25283553 TI - Inhibition of the ANT(2")-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic alpha-hydroxytropolones. AB - Aminoglycoside-2"-O-nucleotidyltransferase ANT(2")-Ia is an aminoglycoside resistance enzyme prevalent among Gram-negative bacteria, and is one of the most common determinants of enzyme-dependant aminoglycoside-resistance. The following report outlines the use of our recently described oxidopyrylium cycloaddition/ring-opening strategy in the synthesis and profiling of a library of synthetic alpha-hydroxytropolones against ANT(2")-Ia. In addition, we show that two of these synthetic constructs are capable of rescuing gentamicin activity against ANT-(2")-Ia-expressing bacteria. PMID- 25283556 TI - Templated DNA ligation with thiol chemistry. AB - We describe two DNA-templated ligation strategies: native chemical ligation (NCL), and thiol-disulfide exchange. Both systems result in successful ligation in the presence of a DNA template. The stability of the product from the NCL reaction relies on exogenous thiol, while the thiol-disulfide reaction proceeds in a catalyst-free manner. PMID- 25283558 TI - Fertility: progress and uncertainty. PMID- 25283557 TI - Rethinking volitional control over task choice in multitask environments: use of a stimulus set selection strategy in voluntary task switching. AB - Under conditions of volitional control in multitask environments, subjects may engage in a variety of strategies to guide task selection. The current research examines whether subjects may sometimes use a top-down control strategy of selecting a task-irrelevant stimulus dimension, such as location, to guide task selection. We term this approach a stimulus set selection strategy. Using a voluntary task switching procedure, subjects voluntarily switched between categorizing letter and number stimuli that appeared in two, four, or eight possible target locations. Effects of stimulus availability, manipulated by varying the stimulus onset asynchrony between the two target stimuli, and location repetition were analysed to assess the use of a stimulus set selection strategy. Considered across position condition, Experiment 1 showed effects of both stimulus availability and location repetition on task choice suggesting that only in the 2-position condition, where selection based on location always results in a target at the selected location, subjects may have been using a stimulus set selection strategy on some trials. Experiment 2 replicated and extended these findings in a visually more cluttered environment. These results indicate that, contrary to current models of task selection in voluntary task switching, the top-down control of task selection may occur in the absence of the formation of an intention to perform a particular task. PMID- 25283559 TI - Tuberculosis rates still high in the UK. PMID- 25283560 TI - Concerns about UK emergency surgery death rates. PMID- 25283561 TI - The Institut Pasteur network: a crucial partner against Ebola. PMID- 25283562 TI - Fertility preservation: challenges and opportunities. PMID- 25283564 TI - Glenda Gray: leading South Africa's future in medical research. PMID- 25283565 TI - Neuraminidase inhibitors for influenza complications. PMID- 25283566 TI - Neuraminidase inhibitors for influenza complications--Authors' reply. PMID- 25283567 TI - Ireland's health system at a crossroads. PMID- 25283568 TI - Misunderstanding "Comrades in Health". PMID- 25283569 TI - Misrepresentation of statin safety evidence. PMID- 25283570 TI - Fertility preservation in men with cancer. AB - During the past decade, advances in cancer treatment have increased survival rates of both boys and men. However, cancer treatment itself can compromise fertility, especially exposure to alkylating agents and whole body irradiation, which cause substantial germ cell loss. Children and adolescents with testicular cancer, leukaemia, and Ewing sarcomas are at the highest risk of developing permanent sterility from cancer treatment. Consequently, various strategies to preserve fertility are necessary. Sperm cryopreservation is an effective but underused method to safeguard spermatozoa. In the past few years, large advances have been made in prepubertal germ cell storage aimed at subsequent transplantation of testicular tissue and associated stem cells. Although still experimental, these approaches offer hope to many men in whom germ cell loss is associated with sterility. The derivation of male gametes from stem cells also holds much promise; however, data are only available in animals, and the use of this method in human beings is probably many years away. PMID- 25283572 TI - Fertility preservation for age-related fertility decline. AB - Cryopreservation of eggs or ovarian tissue to preserve fertility for patients with cancer has been studied since 1994 with R G Gosden's paper describing restoration of fertility in oophorectomised sheep, and for decades previously by others in smaller mammals. Clinically this approach has shown great success. Many healthy children have been born from eggs cryopreserved with the Kuwayama egg vitrification technique for non-medical (social) indications, but until now very few patients with cancer have achieved pregnancy with cryopreserved eggs. Often, oncologists do not wish to delay cancer treatment while the patient goes through multiple ovarian stimulation cycles to retrieve eggs, and the patient can only start using the oocytes after full recovery from cancer. Ovarian stimulation and egg retrieval is not a barrier for patients without cancer who wish to delay childbearing, which makes oocyte cryopreservation increasingly popular to overcome an age-related decline in fertility. Cryopreservation of ovarian tissue is an option if egg cryopreservation is ruled out. More than 35 babies have been born so far with cryopreserved ovarian tissue in patients with cancer who have had a complete return of hormonal function, and fertility to baseline. Both egg and ovarian tissue cryopreservation might be ready for application to the preservation of fertility not only in patients with cancer but also in countering the increasing incidence of age-related decline in female fertility. PMID- 25283573 TI - No cure of HIV infection in a child despite early treatment and apparent viral clearance. PMID- 25283571 TI - Fertility preservation in women with cancer. AB - Enhanced long-term survival rates of young women with cancer and advances in reproductive medicine and cryobiology have culminated in an increased interest in fertility preservation methods in girls and young women with cancer. Present data suggest that young patients with cancer should be referred for fertility preservation counselling quickly to help with their coping process. Although the clinical application of novel developments, including oocyte vitrification and oocyte maturation in vitro, has resulted in reasonable success rates in assisted reproduction programmes, experience with these techniques in the setting of fertility preservation is in its infancy. It is hoped that these and other approaches, some of which are still regarded as experimental (eg, ovarian tissue cryopreservation, pharmacological protection against gonadotoxic agents, in-vitro follicle growth, and follicle transplantation) will be optimised and become established within the next decade. Unravelling the complex mechanisms of activation and suppression of follicle growth will not only expand the care of thousands of women diagnosed with cancer, but also inform the care of millions of women confronted with reduced reproductive fitness because of ageing. PMID- 25283574 TI - [Reperfusion in ST elevation myocardial infarction. From the guidelines to practice]. AB - BACKGROUND: International guidelines have recommendations for selecting the type of reperfusion (fibrinolysis or angioplasty) in the setting of ST-segment elevation myocardial infarction (STEMI), and suggest that emergency-care networks adapt these recommendations according to the local environment. AIM: To assess the proportions of STEMI patients treated with fibrinolysis or angioplasty in accordance with regional guidelines. METHOD: Observational study based on a permanent registry of patients with STEMI of <12h duration in an emergency network in the French North Alps (Isere, Savoie, Haute-Savoie) from January 2009 to December 2012. RESULTS: The registry included 2620 patients. Reperfusion was given in 2425/2620 (93%) of patients. Reperfusion type was in accordance with recommendations in 1567/2620 (60%) patients. Guideline-recommended fibrinolysis and angioplasty were performed in 47% (656/1385) and 79% (911/1149) respectively, of patients. In multivariable analysis, variables independently associated with guideline-recommended reperfusion were: an age < 65 years (OR 1.60; 95%CI 1.33 1.90), being managed in Haute-Savoie versus Isere or Savoie (OR 1.38; 95%CI 1.12 1.71), an arterial tension < 100mmHg (OR 1.73; 95%CI 1.27-2.35), a cardiogenic shock (OR 0.50; 95%CI 0.30-0.84), a pacemaker or left bundle branch block (OR 0.49; 95%CI 0.28-0.88), and an initial management outside the network (followed by treatment in an interventional centre in the network) (OR 0.62; 95%CI 0.40 0.94). Patients initially treated by mobile intensive care units were more often reperfused in accordance with recommendations when admitted < 3 (versus >= 3) h following symptom onset (adjusted OR 2.05; 95% CI 1.61-2.59), while those initially treated by in-hospital emergency units were less often reperfused in accordance with recommendation when treated < 3h following symptom onset (adjusted OR 0.67; 95% CI 0.46-0.97). In-hospital major adverse cardiac events (9.1% vs. 8.5%) and in-hospital mortality (6.4% vs. 5.1%) were not significantly different between patients reperfused in accordance with (versus not) recommendations. CONCLUSIONS: Forty percent of patients with STEMI were not reperfused with fibrinolysis or angioplasty in accordance with regional guidelines. Characterization of this population should allow us to improve guideline adherence. PMID- 25283575 TI - [Clinical research in cardiology in French non-academic hospitals]. PMID- 25283576 TI - Modeling of the total antioxidant capacity of rooibos (Aspalathus linearis) tea infusions from chromatographic fingerprints and identification of potential antioxidant markers. AB - Models to predict the total antioxidant capacity (TAC) of rooibos tea infusions from their chromatographic fingerprints and peak table data (content of individual phenolic compounds), obtained using HPLC with diode array detection, were developed in order to identify potential antioxidant markers. Peak table data included the content of 12 compounds, namely phenylpyruvic acid-2-O glucoside, aspalathin, nothofagin, isoorientin, orientin, ferulic acid, quercetin 3-O-robinobioside, vitexin, hyperoside, rutin, isovitexin and isoquercitrin. The TAC values, measured using the oxygen radical absorbance capacity (ORAC) and DPPH radical scavenging assays, could be predicted from the peak table data or the chromatographic fingerprints (prediction errors 9-12%) using partial least squares (PLS) regression. Prediction models created from samples of only two production years could additionally be used to predict the TAC of samples from another production year (prediction errors<13%) indicating the robustness of the models in a quality control environment. Furthermore, the uninformative variable elimination (UVE)-PLS method was used to identify potential antioxidant markers for rooibos infusions. All individual phenolic compounds that were quantified were selected as informative variables, except vitexin, while UVE-PLS models developed from chromatographic fingerprints indicated additional antioxidant markers, namely (S)-eriodictyol-6-C-glucoside, (R)-eriodictyol-6-C-glucoside, aspalalinin and two unidentified compounds. The potential antioxidant markers should be validated prior to use in quality control of rooibos tea. PMID- 25283577 TI - Use of chelating agents to improve the resolution and consistency of cation exchange chromatography of monoclonal antibodies. AB - Analytical cation-exchange chromatography (CEX) is widely used to profile the charge heterogeneity of therapeutic monoclonal antibodies (mAbs). However, the consistency of CEX profiles of a mAb can be significantly reduced by metal ion impurities from sample, mobile phase or leachates from the stainless steel components of the pumping system. In this work, we have developed a new CEX method that dynamically removes metal ions during sample analysis by incorporating the use of chelating agents (1-5mM) in HPLC mobile phases. Among four different chelating agents that were evaluated, EDTA and oxalic acid showed excellent capability of removing metal ions and provided consistent CEX chromatograms for mAb1. Furthermore, the use of oxalic acid in mobile phases not only improved the reproducibility of CEX chromatograms, but also increased the resolution of charge isoforms. Oxalic acid appears capable of binding to mAbs and reducing the positive surface charge density, resulting in a modulation of chromatographic separation. Due to this modulation effect, the CEX resolution was dependent on the concentration of the chelating agent. Optimal resolution for mAb1 was obtained with 2mM of oxalic acid. The oxalic acid modulated CEX method was shown to be capable of monitoring the degradation of mAb1. We further qualified this method according to International Committee on Harmonization (ICH) guidelines and demonstrated that the oxalic acid modulated CEX method is precise and robust at different chromatographic conditions and is suitable for use in a development and/or GMP setting. PMID- 25283578 TI - Association of TPH2 and dopamine receptor gene polymorphisms with obsessive compulsive symptoms and perfectionism in healthy subjects. PMID- 25283579 TI - Lanthanoid "bottlebrush" clusters: remarkably elongated metal-oxo core structures with controllable lengths. AB - Large metal-oxo clusters consistently assume spherical or regular polyhedral morphologies rather than high-aspect-ratio structures. Access to elongated core structures has now been achieved by the reaction of lanthanoid salts with a tetrazole-functionalized calixarene in the presence of a simple carboxylate co ligand. The resulting Ln19 and Ln12 clusters are constructed from apex-fused Ln5O6 trigonal bipyramids and are formed consistently under a range of reaction conditions and reagent ratios. Altering the carboxylate co-ligand structure reliably controls the cluster length, giving access to a new class of rod-like clusters of variable length. PMID- 25283580 TI - Antidepressants for functional esophageal disorders: evidence- or eminence-based medicine? PMID- 25283581 TI - Spirochetes as an almost forgotten cause of hepatitis. PMID- 25283582 TI - Effects of antiviral therapy for patients with inflammatory bowel disease and a positive intestinal biopsy for cytomegalovirus. AB - BACKGROUND & AIMS: Cytomegalovirus (CMV) is an opportunistic pathogen; documented tissue involvement of patients with inflammatory bowel disease (IBD) is associated with adverse outcomes. We quantified the density of CMV inclusions in biopsy specimens from patients with IBD and assessed their response to antiviral therapy. METHODS: In a case-control study, we identified all small bowel and colon biopsy specimens collected from 1111 patients with IBD that had been submitted to the Department of Laboratory Medicine and Pathology, Mayo Clinic, to evaluate for CMV in intestinal tissue from 2005 through 2011. All positive cases were reviewed to confirm the diagnosis of CMV in tissue. We determined the number of viral inclusions in each processed biopsy sample. Biopsy specimens with 5 or more inclusions were considered to have high-grade CMV density. We collected data on response to antiviral therapy and history of surgical resection within 1 year after diagnosis of CMV in tissue. CMV-negative samples (controls) were selected from the same IBD population. Primary outcomes included clinical improvement, hospital admission, time to admission, need for surgical procedures, time to surgery, escalation of therapy, and relapse of CMV infection. RESULTS: In our analysis of the biopsy samples, 68 (6%) were found to contain CMV. Follow-up data and treatment outcomes were available from 50 cases, including 16 patients with high-grade CMV density (all treated) and 34 with low-grade CMV density (20 treated). There was no overall difference in survival, free of surgery, between patients with or without CMV 1 year after diagnosis in tissue. Antiviral treatment improved surgery-free survival outcomes of patients with CMV infection particularly of patients with high-grade CMV density. CONCLUSIONS: Patients with IBD and a high density of CMV inclusions in intestinal biopsy specimens benefit from antiviral therapy. Patients with fewer viral inclusions in biopsy specimens also might benefit, but the severity of the IBD should be the prime consideration in determining treatment strategies. PMID- 25283583 TI - Low-temperature excess heat capacity in fresnoite glass and crystal. AB - The effect of thermal annealing on low-temperature excess heat capacity was investigated in fresnoite (Ba2TiSi2O8) glass. The amplitudes of the excess heat capacity decreased, and their positions shifted to a higher temperature by relaxation or crystallization. In particular, we revealed that the change in the excess heat capacity during transition from the glassy state to the crystalline state is relatively small compared with that of other oxides. Therefore, it is suggested that distribution of the excess vibrational density of states of the glass is similar to that of the corresponding crystal. PMID- 25283584 TI - Vitamin D levels and cognition in elderly adults in China. AB - OBJECTIVES: To evaluate the association between vitamin D level and cognitive impairment in individuals aged 60 and older. DESIGN: Cross-sectional cohort study. SETTING: Chinese Longitudinal Healthy Longevity Survey, a community-based cohort study in areas in China where the density of centenarians is exceptionally high. PARTICIPANTS: Individuals with mean age of 84.9 +/- 12.7 (N = 2,004). MEASUREMENTS: Participants' cognitive state was evaluated using the Mini-Mental State Examination (MMSE). Vitamin D was measured in plasma using an enzyme-linked immunoassay. RESULTS: The cross-sectional association between quartiles of plasma vitamin D level and cognitive impairment (MMSE score <18) was modeled using logistic regressions. Plasma vitamin D levels were lower in individuals with cognitive impairment (31.9 +/- 15.3 nmol/L) than in those without (45.6 +/- 19.6 nmol/L). There was a reverse association between plasma vitamin D and cognitive impairment. After adjusting for age, sex, chronic conditions, smoking and drinking habits, outdoor activities, depression, and activity of daily living limitations, the association remained significant. The multivariable-adjusted odds ratio for lowest versus highest vitamin D levels was 2.15 (95% confidence interval (CI) = 1.05-4.41) for cognitive impairment, and the multivariable odds ratio associated with a 1-standard deviation decrement in plasma vitamin D was 1.32 (95% CI = 1.00-1.74) for cognitive impairment. CONCLUSION: Low plasma vitamin D levels were associated with greater odds of cognitive impairment. Further prospective studies in Asian populations are needed to examine the causal direction of this association. PMID- 25283585 TI - The lowest VE/VCO2 ratio best identifies chronic thromboembolic pulmonary hypertension. AB - INTRODUCTION: The natural history of acute pulmonary embolism (PE) under treatment is about a gradual resolution of the thrombi, and uncommonly, the development of chronic thromboembolic pulmonary hypertension (CTEPH). We hypothesized that ventilatory efficiency parameters during cardiopulmonary exercise testing (CPET) may be able to monitor the process and predict CTEPH. METHODS: 15 patients rehabilitated from acute PE (total resolution of thrombi), 44 patients with chronic PE (with residual thrombi), 66 patients with CTEPH, and 36 sedentary healthy controls performed incremental CPET. RESULTS: The lowest VE/VCO2 was higher in CTEPH patients than that in chronic PE and rehabilitated patients (43.4 L/min vs 29.9 L/min vs 27.1 L/min, p<0.005). The VE/VCO2 slope (48.4 L/min/L/min vs 29.9 L/min/L/min vs 28.0 L/min/L/min, p<0.005) and oxygen uptake efficiency plateau (OUEP) (37.1 L/min vs 27.0 L/min vs 25.2L/min, p<0.005) had the similar changes. In logistic regression analysis, the lowest VE/VCO2 >= 34.35 L/min was the best predictor of CTEPH (OR 159.0, 95% CI 36.0-702.3, p<0.001). The lowest VE/VCO2 was higher in chronic PE patients compared with the controls (29.9 L/min vs 26.5 L/min, p<0.05), but there was no difference between the rehabilitated patients and the controls. In multiple linear regression analysis, the percentage of vascular obstruction by ventilation-perfusion lung scanning (PVO) was the most significant independent predictor for indices of ventilatory efficiency in chronic PE and rehabilitated patients. CONCLUSIONS: CTEPH is associated with weakened ventilatory efficiency. The lowest VE/VCO2 ratio has the best capability to predict CTEPH. Ventilatory inefficiency improves along with recovery of acute PE. PMID- 25283586 TI - Comparison of the hemostatic effects of a levonorgestrel-releasing intrauterine system and leuprolide acetate in women with endometriosis: a randomized clinical trial. AB - INTRODUCTION: The hemostatic and inflammatory systems may activate each other. Endometriosis is a chronic inflammatory disease affecting 10% of women. The objective of this study was to compare the hemostatic effects of two treatments widely prescribed to women with endometriosis: the levonorgestrel intrauterine system (LNG-IUS) and the gonadotropin-releasing hormone analog (GnRHa) leuprolide acetate. MATERIALS AND METHODS: In this randomized open-label controlled trial, 44 women with endometriosis were randomly allocated to one of two groups: 22 women were assigned to use LNG-IUS and 22 to use GnRHa. The assessed variables were D-dimers, fibrinogen, prothrombin time, activated partial thromboplastin time, coagulation factors (F) II, V, VII, VIII, IX, X, and XI, antithrombin (AT), protein C, free protein S, tissue plasminogen activator (t-PA), alpha2 antiplasmin, thrombin-antithrombin complex, and prothrombin fragment 1+2. All variables were assessed before treatment and six months after treatment onset. RESULTS: In the LNG-IUS group, FVIII decreased 10% after six months of use. In the GnRHa group, there was a 6% increase in AT, 29% reduction in D-dimers, and 19% increase in t-PA. The LNG-IUS users exhibited a significantly greater reduction of FVIII than the GnRHa users (LNG-IUS: -6.4 +/- 14.3% vs. GnRHa: 4.2 +/- 12.3%, p=0.02). The women in the GnRHa group exhibited a greater increase of AT than the LNG-IUS users (LNG-IUS: -0.7 +/- 9.5% vs. GnRHa: 6.5 +/- 10.1%, p=0.02). CONCLUSION: Both hormonal treatments for endometriosis exhibited no association with a procoagulant profile. PMID- 25283587 TI - Multilocus evidence for globally distributed cryptic species and distinct populations across ocean gyres in a mesopelagic copepod. AB - Zooplanktonic taxa have a greater number of distinct populations and species than might be predicted based on their large population sizes and open-ocean habitat, which lacks obvious physical barriers to dispersal and gene flow. To gain insight into the evolutionary mechanisms driving genetic diversification in zooplankton, we developed eight microsatellite markers to examine the population structure of an abundant, globally distributed mesopelagic copepod, Haloptilus longicornis, at 18 sample sites across the Atlantic and Pacific Oceans (n = 761). When comparing our microsatellite results with those of a prior study that used a mtDNA marker (mtCOII, n = 1059, 43 sample sites), we unexpectedly found evidence for the presence of a cryptic species pair. These species were globally distributed and apparently sympatric, and were separated by relatively weak genetic divergence (reciprocally monophyletic mtCOII lineages 1.6% divergent; microsatellite FST ranging from 0.28 to 0.88 across loci, P < 0.00001). Using both mtDNA and microsatellite data for the most common of the two species (n = 669 for microsatellites, n = 572 for mtDNA), we also found evidence for allopatric barriers to gene flow within species, with distinct populations separated by continental landmasses and equatorial waters in both the Atlantic and Pacific Ocean basins. Our study shows that oceanic barriers to gene flow can act as a mechanism promoting allopatric diversification in holoplanktonic taxa, despite the high potential dispersal abilities and pelagic habitat for these species. PMID- 25283588 TI - The association between traumatic dental injuries and atypical external root resorption in maxillary primary incisors. AB - Atypical root resorption (ARR), which is observed on radiographs of primary incisors, has been reported in the dental literature to result from digit sucking; thus ignoring any association between ARR and traumatic dental injuries (TDI). The purpose of this study was to evaluate and compare the contributions of sucking habits and TDI to external ARR in primary incisors. A history of dental trauma was assessed based on clinical and radiographic findings. Periapical radiographs of the premaxilla were evaluated for the presence of ARR. The presence or history of sucking habits was based on parents' report. Data were collected from files of 727 patients with a mean age of 52 months. Sixty-four children (8.8%) presented ARR in one or both central incisors. All 64 had experienced some type of TDI. Five hundred and forty-nine (76%) of the children had sucking habits; of them, 501 were pacifier-suckers and 48 digit suckers. Digit sucking was found in only 4 (6%) of the 64 children presenting ARR. These findings support the association of traumatic dental injury, and not of digit sucking, with ARR in primary incisors. PMID- 25283589 TI - The correlation between body mass index and breast cancer risk or estrogen receptor status in Okinawan women. AB - Dietary changes resulting from the post-World War II occupation of Okinawa by the US military have been largely deleterious, resulting in a marked increase of obesity among Okinawan residents. In this study, we examined the association between BMI and the risk of developing breast cancer according to the menstruation status and age, and the correlation between BMI and expression of estrogen receptor (ER). Breast cancer cases were 3,431 females without any personal or family history of breast cancer. Control subjects were 5,575 women drawn from the clinical files of Nahanishi Clinic. We found that women, who were overweight or obese, regardless of menopausal stage, had a higher risk of breast cancer compared to women with normal weight and this difference was statistically significant (p < 0.001, respectively). This risk was especially apparent in older (> 40 years) overweight or obese women. The women who were overweight or obese during postmenopausal ages were at higher risk of ER-positive breast cancer compared to women with normal weight. Results of our present study clearly indicate that increased BMI was associated with increased risk of developing breast cancer in Okinawan women, regardless of menopausal status. In addition, there was statistically significant correlation between BMI and ER expression in the postmenopausal period. Given the obesity epidemic associated with the extreme sociological and dietary changes brought about by the post-war occupation of Okinawa, the present study provides essential guidelines on the management, treatment and future breast cancer risk in Okinawa. PMID- 25283590 TI - Physiological weight loss chart helps to identify high-risk infants who need breastfeeding support. AB - AIM: Healthy, full-term, exclusively breastfed infants are expected to lose weight in the first days after birth, but experts disagree about what constitutes a physiological neonatal weight loss and there is a lack of evidence-based data. Our study aimed to construct a centile chart of neonatal weight loss in a healthy population of exclusively breastfed term neonates. METHODS: We retrospectively studied all infants born at an Italian centre that focused on natural childbirth from April 2007 to December 2012 and who complied with World Health Organization guidance on infant feeding. The infants' weight loss was recorded after 12, 24, 36, 48, 60 and 72 h of life. RESULTS: We included 1760 healthy, full-term, singleton babies born by vaginal delivery. Their mean weight loss was 5.95 +/- 1.73%, 72.2% had maximal weight loss before discharge, only 3.9% lost more than 9% of their birthweight, and no infant lost more than 10%. We measured the percentage weight change from birth and each time the infant was examined, summarising how their weight varied in the first 72 h of life. CONCLUSION: Our normative chart of physiological weight loss provided an important instrument for identifying high-risk infants who required breastfeeding support. PMID- 25283591 TI - Cancer Core Europe: a first step towards a virtual cancer institute in Europe? PMID- 25283592 TI - [Adverse effects and hemodynamic effects of nifedipine as a tocolytic]. AB - OBJECTIVES: To describe maternal and fetal adverse effects, in particular cardiorespiratory, of nifedipine as tocolytic, as well as effects on hemodynamic parameters. MATERIALS AND METHODS: A retrospective evaluative study describing the use of nifedipine as tocolytic at CHU Sainte-Justine in Montreal. Demographic data as well as maternal blood pressure and adverse effects, and maternal and fetal heart rate were collected from medical records of women treated with nifedipine following our tocolysis protocol between January 1st 2004 and March 1st 2007. RESULTS: The medical records of 213 pregnant women were included in the study. Cardiorespiratory adverse effects were noted in 69 (32.4%); of these, 19 (8.9%) had serious cardiorespiratory adverse events, including 6 acute pulmonary edema or overload. Mean maternal systolic and diastolic blood pressures were significantly decreased and mean maternal and fetal heart rates were significantly increased after the bolus dose. Other adverse effects were reported for 100 (46.9%) women. CONCLUSION: Nifedipine may cause cardiorespiratory adverse effects warranting a close monitoring. PMID- 25283593 TI - Poor cognitive flexibility, and the experience thereof, in a subclinical sample of female students with obsessive-compulsive symptoms. AB - Research indicates that people with obsessive-compulsive disorder (OCD) have poor cognitive flexibility. However, studies have largely focused on actual abilities and while individuals' emotional responses may be just as important, little is known about how those with OCD experience a situation that requires cognitive flexibility. It is furthermore largely unknown whether cognitive flexibility may also be important for people with OCD symptoms, rather than only to those with full blown disorders. This study investigates the relationship between cognitive flexibility, and the experience thereof in female students with and without OCD symptoms. It was expected that poor cognitive flexibility would be positively associated to OCD symptoms, and that those with OCD symptoms would display poor cognitive flexibility, and experience situations requiring cognitive flexibility as more difficult, than those without OCD symptoms. Participants completed a measure for OCD symptoms, a neuropsychological task to measure cognitive flexibility, and a self-report measure assessing emotional experience of situations requiring cognitive flexibility. Positive associations between OCD symptoms and both poor cognitive flexibility and negative experience of situations requiring cognitive flexibility were found. Furthermore, those with OCD symptoms performed poorer on the cognitive flexibility task than those without OCD symptoms, and reported higher scores on the cognitive inflexibility questionnaire. Results confirm a relation between OCD symptoms and poor cognitive flexibility in a subclinical sample and identify a relation between OCD symptoms and a negative experience of situations that require cognitive flexibility. Overall findings suggest that poor cognitive flexibility may be an important part of OCD symptomatology. PMID- 25283595 TI - Putrescine controls the formation of Escherichia coli persister cells tolerant to aminoglycoside netilmicin. AB - Persisters are suggested to be the products of a phenotypic variability that are quasi-dormant forms of regular bacterial cells highly tolerant to antibiotics. Our previous investigations revealed that a decrease in antibiotic tolerance of Escherichia coli cells could be reached through the inhibition of key enzymes of polyamine synthesis (putrescine, spermidine). We therefore assumed that polyamines could be involved in persister cell formation. Data obtained in our experiments with the polyamine-deficient E. coli strain demonstrate that the formation of persisters tolerant to netilmicin is highly upregulated by putrescine in a concentration-dependent manner when cells enter the stationary phase. This period is also accompanied by dissociation of initially homogenous subpopulation of persister cells to some fractions differing in their levels of tolerance to netilmicin. With three independent experimental approaches, we demonstrate that putrescine-dependent upregulation of persister cell formation is mediated by stimulation of rpoS expression. Complementary activity of putrescine and RpoS results in ~ 1000-fold positive effect on persister cell formation. PMID- 25283596 TI - Bim regulation miRrors microRNA 17~92 cluster expression in endothelial cells in vivo. PMID- 25283597 TI - The influence of NaYF4:Yb,Er size/phase on the multimodality of co-encapsulated magnetic photon-upconverting polymeric nanoparticles. AB - We report the synthesis, characterisation and evaluation of the in vitro biocompatibility of polymeric nanoparticles with both magnetic and upconverting fluorescent properties. The particles consist of superparamagnetic iron oxide nanoparticles and upconverting NaYF4:Yb,Er nanoparticles co-encapsulated within a poly(glycidyl methacrylate) sphere. Two different upconverting nanoparticles (10 nm alpha-NaYF4:Yb,Er and 50 nm beta-NaYF4:Yb,Er) were synthesised and the optical and magnetic properties of the composite polymeric nanoparticle systems assessed by near infra-red laser spectroscopy, SQUID magnetometry and proton relaxometry. A live-dead assay was used to assess the viability of PC-12 neural cells incubated with varying concentrations of the nanoparticles. The composite nanoparticles produced no observed impact on cellular viability even at concentrations as high as 1000 MUg mL(-1). Confocal microscopy revealed uptake of nanoparticles by PC-12 cells and peri-nuclear cytoplasmic localisation. Both particle systems show favourable magnetic properties. However, only the nanospheres containing 50 nm beta-NaYF4:Yb,Er were suitable for optical tracking because the presence of iron oxide within the composites imparts a significant quenching of the upconversion emission. This study demonstrates the size and phase of the upconverting nanoparticles are important parameters that have to be taken into account in the design of multimodal nanoparticles using co encapsulation strategies. PMID- 25283598 TI - Aqueous gating of van der Waals materials on bilayer nanopaper. AB - In this work, we report transistors made of van der Waals materials on a mesoporous paper with a smooth nanoscale surface. The aqueous transistor has a novel planar structure with source, drain, and gate electrodes on the same surface of the paper, while the mesoporous paper is used as an electrolyte reservoir. These transistors are enabled by an all-cellulose paper with nanofibrillated cellulose (NFC) on the top surface that leads to an excellent surface smoothness, while the rest of the microsized cellulose fibers can absorb electrolyte effectively. Based on two-dimensional van der Waals materials, including MoS2 and graphene, we demonstrate high-performance transistors with a large on-off ratio and low subthreshold swing. Such planar transistors with absorbed electrolyte gating can be used as sensors integrated with other components to form paper microfluidic systems. This study is significant for future paper-based electronics and biosensors. PMID- 25283601 TI - Non-heme iron hydroperoxo species in superoxide reductase as a catalyst for oxidation reactions. AB - The non-heme high-spin ferric iron hydroperoxo species formed in superoxide reductase catalyzes oxidative aldehyde deformylation through its nucleophilic character. This species also acts as an electrophile to catalyze oxygen atom transfer in sulfoxidation reactions, highlighting the oxidation potential of non heme iron hydroperoxo species. PMID- 25283599 TI - SDF-1alpha is a novel autocrine activator of platelets operating through its receptor CXCR4. AB - Platelets store and secrete the chemokine stromal cell-derived factor (SDF) 1alpha upon platelet activation, but the ability of platelet-derived SDF-1alpha to signal in an autocrine/paracrine manner mediating functional platelet responses relevant to thrombosis and haemostasis is unknown. We sought to explore the role of platelet-derived SDF-1alpha and its receptors, CXCR4 and CXCR7 in facilitating platelet activation and determine the mechanism facilitating SDF 1alpha-mediated regulation of platelet function. Using human washed platelets, CXCR4 inhibition, but not CXCR7 blockade significantly abrogated collagen mediated platelet aggregation, dense granule secretion and thromboxane (Tx) A2 production. Time-dependent release of SDF-1alpha from collagen-activated platelets supports a functional role for SDF-1alpha in this regard. Using an in vitro whole blood perfusion assay, collagen-induced thrombus formation was substantially reduced with CXCR4 inhibition. In washed platelets, recombinant SDF 1alpha in the range of 20-100 ng/mL(-1) could significantly enhance platelet aggregation responses to a threshold concentration of collagen. These enhancements were completely dependent on CXCR4, but not CXCR7, which triggered TxA2 production and dense granule secretion. Rises in cAMP were significantly blunted by SDF-1alpha, which could also enhance collagen-mediated Ca2+ mobilisation, both of which were mediated by CXCR4. This potentiating effect of SDF-1alpha primarily required TxA2 signalling acting upstream of dense granule secretion, whereas blockade of ADP signalling could only partially attenuate SDF 1alpha-induced platelet activation. Therefore, this study supports a potentially novel autocrine/paracrine role for platelet-derived SDF-1alpha during thrombosis and haemostasis, through a predominantly TxA2-dependent and ADP-independent pathway. PMID- 25283600 TI - Symmetric dimethylarginine alters endothelial nitric oxide activity in glomerular endothelial cells. AB - Circulating symmetric dimethylarginine (SDMA) is increased in patients with chronic kidney disease. SDMA is considered an inert metabolite, but because it can transported into cells, we studied the effect of SDMA on glomerular endothelial cells. SDMA suppressed VEGF-induced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide production, but not VEGFR2 activation and signaling leading to eNOS activation. SDMA caused eNOS uncoupling and increased superoxide anion production in response to VEGF. All these effects were blocked by preventing cellular uptake of SDMA with a molar excess of arginine. These data show that SDMA interferes with nitric oxide production by uncoupling eNOS and leads to oxidative stress in glomerular endothelial cells. In conclusion, our data show that SDMA is not an inert metabolite and that it could contribute to oxidative stress in the renal endothelium. PMID- 25283602 TI - Anti-carbonic anhydrase antibodies in iron deficiency anemia. AB - OBJECTIVES: Studies on experimental animals have shown that elevated oxidative stress in erythrocytes leads to the formation of autoantibodies against carbonic anhydrase (CA) and anemia. This study investigated the presence of CA I and II autoantibodies in patients with iron deficiency anemia (IDA). METHODS: Forty patients with IDA and 40 healthy controls were included in the study. Serum CA I and II autoantibody levels were analyzed using enzyme-linked immunosorbent assay. Serum malondialdehyde (MDA) levels were also measured in order to evaluate oxidative stress. RESULTS: CA I and II antibody titers in patients with IDA were higher than those in the controls (P = 0.005 and 0.010, respectively). A weak negative correlation was determined between anti-CA I antibody titers and ferritin, iron and mean cell volume (MCV) levels (P = 0.013, 0.042, and 0.021, respectively). Serum MDA levels were also significantly higher in the IDA group (P < 0.001). At an anti-CA I cut-off point of 0.155 absorbance unit (ABSU), sensitivity was 70% and specificity 65%. At an anti-CA II cut-off point of 0.088 ABSU, sensitivity was 60% and specificity 75%. DISCUSSION AND CONCLUSION: In conclusion, an immune response against CA I and II develops in IDA. CA I autoantibodies are correlated with hematological parameters used in the diagnosis of IDA and have the potential to be used in treatment. PMID- 25283603 TI - Preheated autologous serum skin test in localized heat urticaria. AB - Localized heat urticaria (LHU) is a rare type of physical urticaria, characterized by itching and erythema and well-demarcated weals, appearing within minutes at heat-exposed body sites. Its pathogenesis has not yet been clarified. We report the case of a 46-year-old woman with a generalized form of LHU, which was induced by exposure to warm baths, and consumption of warm food and drinks. Weal reaction was obtained 10 min after application of a metal cylinder heated to 43 degrees C. Interestingly, only serum previously heated to 56 degrees C and injected intradermally for autologous serum skin test induced a weal and flare reaction, whereas serum preheated to 45 degrees C did not induce any reaction. Our patient did not respond to high-dose antihistamines, and refused a heat desensitization programme. Treatment with colchicine 1 mg/day or ciclosporin A 3.5 mg/kg/day for 1 month yielded no improvement. Mild improvement was obtained with intramuscular injection of triamcinolone acetonide 40 mg every 2 weeks for 2 months. PMID- 25283605 TI - Visual abilities are important for auditory-only speech recognition: evidence from autism spectrum disorder. AB - In auditory-only conditions, for example when we listen to someone on the phone, it is essential to fast and accurately recognize what is said (speech recognition). Previous studies have shown that speech recognition performance in auditory-only conditions is better if the speaker is known not only by voice, but also by face. Here, we tested the hypothesis that such an improvement in auditory only speech recognition depends on the ability to lip-read. To test this we recruited a group of adults with autism spectrum disorder (ASD), a condition associated with difficulties in lip-reading, and typically developed controls. All participants were trained to identify six speakers by name and voice. Three speakers were learned by a video showing their face and three others were learned in a matched control condition without face. After training, participants performed an auditory-only speech recognition test that consisted of sentences spoken by the trained speakers. As a control condition, the test also included speaker identity recognition on the same auditory material. The results showed that, in the control group, performance in speech recognition was improved for speakers known by face in comparison to speakers learned in the matched control condition without face. The ASD group lacked such a performance benefit. For the ASD group auditory-only speech recognition was even worse for speakers known by face compared to speakers not known by face. In speaker identity recognition, the ASD group performed worse than the control group independent of whether the speakers were learned with or without face. Two additional visual experiments showed that the ASD group performed worse in lip-reading whereas face identity recognition was within the normal range. The findings support the view that auditory-only communication involves specific visual mechanisms. Further, they indicate that in ASD, speaker-specific dynamic visual information is not available to optimize auditory-only speech recognition. PMID- 25283606 TI - Prognostication following cardiac arrest: making sense of the data. PMID- 25283604 TI - Pain management in internal medicine and effects of a standardised educational intervention: the FADOI-DOMINO study. AB - PURPOSE: Few real-world data are available on the frequency and management of pain in Internal Medicine (IM). Aims of our study were to assess the prevalence of pain in IM, and to evaluate the effects on pain management of a standardised educational programme. MATERIALS AND METHODS: The study was performed in 26 IM Units in Italy, with two cross-sectional surveys (PRE phase and POST phase) interspersed with an educational programme. In PRE phase each Centre reviewed the hospital charts of the last 100 consecutive patients hospitalised for any cause. An educational programme was conducted in each Centre by means of the 'outreach visit', a face-to-face meeting between health personnel and a trained external expert. Six months after, each Centre repeated the data collection (POST phase), specular to the PRE. RESULTS: A total of 5200 medical charts were analysed. Pain was documented in 37.5% of the patients. After the educational intervention, the intensity of pain was appropriately assessed in a higher percentage of patients (77.4% vs. 47.8%, p = 0.0001), and it was more frequently monitored during hospitalisation. Qualitative definition of pain (pathogenesis, duration, etc.) increased in POST phase (75.4% vs. 62.7%, p = 0.0001). A 73.3% increase in the use of strong opioids was detected following educational programme. CONCLUSIONS: Pain affects 4 out of 10 patients hospitalised in IM. According to our large real world study, to implement a standardised one-shot educational programme may persistently improve the attitude of health personnel towards the characterisation and management of pain. PMID- 25283607 TI - Central V1b receptor antagonism in lactating rats: impairment of maternal care but not of maternal aggression. AB - Maternal behaviour in rodents is mediated by the central oxytocin and vasopressin systems, amongst others. The role of vasopressin, acting via the V1a receptor (V1aR), on maternal care and maternal aggression has recently been described. However, a potential involvement of the V1b receptor (V1bR) in maternal behaviour has only been demonstrated in knockout mice. The present study aimed to examine the effects of central pharmacological manipulation of the V1bR on maternal behaviour in lactating Wistar rats. On pregnancy day 18, female rats were implanted with a guide cannula targeting the lateral ventricle. After parturition, dams received an acute central infusion of a specific V1bR agonist (d[Leu4,Lys8]VP) or V1bR antagonist (SSR149415) once daily, followed by observations of maternal care [lactation day (LD) 1], maternal motivation in the pup retrieval test (LD 2), anxiety-related behaviour on the elevated plus-maze (LD 3) and maternal aggression in the maternal defence test followed by maternal care monitoring (LD 4). Our data demonstrate that, under nonstress conditions, the V1bR antagonist decreased the occurrence of both nursing and mother-pup interaction, whereas the V1bR agonist did not affect either parameter. Under stress conditions (i.e. after the maternal defence test), mother-pup interaction was decreased by infusion of the V1bR antagonist. During the maternal defence test, neither treatment affected aggressive or non-aggressive behaviour. Finally, neither treatment altered maternal motivation or anxiety. In conclusion, central V1bR antagonism modulates aspects of maternal care but not of maternal aggression or maternal motivation in lactating rats. These findings further extend our knowledge on the vasopressin system as a vital mediator of maternal behaviour. PMID- 25283608 TI - Phylogenomic analyses uncover origin and spread of the Wolbachia pandemic. AB - Of all obligate intracellular bacteria, Wolbachia is probably the most common. In general, Wolbachia are either widespread, opportunistic reproductive parasites of arthropods or essential mutualists in a single group of filarial nematodes, including many species of medical significance. To date, a robust phylogenetic backbone of Wolbachia is lacking and consequently, many Wolbachia-related phenomena cannot be discussed in a broader evolutionary context. Here we present the first comprehensive phylogenomic analysis of Wolbachia supergroup relationships based on new whole-genome-shotgun data. Our results suggest that Wolbachia has switched between its two major host groups at least twice. The ability of some arthropod-infecting Wolbachia to universally infect and to adapt to a broad range of hosts quickly is restricted to a single monophyletic lineage (containing supergroups A and B). Thus, the currently observable pandemic has likely a single evolutionary origin and is unique within the radiation of Wolbachia strains. PMID- 25283609 TI - High rate of detection of G8P[6] rotavirus in children with acute gastroenteritis in Sao Tome and Principe. AB - The burden of rotavirus infections greatly affects the low-income African countries. In the absence of epidemiological data on pediatric diarrhea in Sao Tome and Principe (STP), a study was conducted from August to December 2011. Rotavirus antigen was detected in 36.7 % of the collected fecal samples (87/237). G8P[6] was identified as the predominant genotype (71.1 % detection rate), while G1P[8] represented only 8.4 %. Phylogenetic analysis of VP7 G8 strains showed clustering within lineage G8d, while VP4 P[6] strains clustered within lineage 1a. Our results represent the first report on rotavirus from STP and show one of the highest detection rates of G8 rotaviruses worldwide. PMID- 25283610 TI - Phylogenetic relationships and the occurrence of interspecific recombination between beet chlorosis virus (BChV) and Beet mild yellowing virus (BMYV). AB - Samples containing two viruses belonging to the genus Polerovirus, beet chlorosis virus (BChV) and beet mild yellowing virus (BMYV), were collected from French and Polish sugar beet fields. The molecular properties of 24 isolates of BChV and BMYV were investigated, and their genetic diversity was examined in the coat protein (CP)- and P0-encoding genes. For the first time, we have demonstrated that beet polerovirus populations include recombinants between BChV and BMYV containing breakpoints within the CP gene. Moreover, a partial correlation between geographic origin and phylogenetic clustering was observed for BMYV isolates. PMID- 25283611 TI - Serological and virological survey of hepatitis E virus in wild boar populations in northwestern Italy: detection of HEV subtypes 3e and 3f. AB - Although rare in developed countries, most acquired human cases of hepatitis E virus (HEV) infection are associated with travel to developing countries where HEV is endemic. Increasingly, however, sporadic, non-travel-related HEV cases have been reported in developed countries. In Italy, only two studies to date have investigated the presence of HEV in wild boars. Here, we report a serological and virological survey of HEV in wild boar populations in northwestern Italy. During the hunting season, 594 serum and 320 liver samples were collected and screened for antibodies to HEV and HEV RNA. Overall, the seroprevalence was 4.9 %, and HEV RNA was detected in 12 liver samples (p = 3.7 %). No serum samples tested positive for HEV RNA. Phylogenetic analysis of the ORF2 region revealed that the isolates clustered within genotype 3, subtypes 3e and 3f, and were closely related to HEV strains previously detected in domestic pigs farmed in the same geographic area. Although the routes of viral transmission are still poorly understood, our data show that HEV genotypes 3e and 3f circulate in wild boars in northwestern Italy. Also, they provide evidence that autochthonous HEV infections in Italy could also be linked to wild boar populations, suggesting an increased risk for domestically acquired HEV infection in humans through wild animals. The HEV sequences determined in this study may be useful for comparing present and future human isolates to identify transmission events between wild boar, humans, and farmed pigs. Similarly to other more commonly known zoonotic agents, HEV should be included in national or regional disease surveillance programs for wild animals. PMID- 25283612 TI - Effectiveness of cataract phacoemulsification with toric intraocular lenses in addressing astigmatism after keratoplasty. AB - PURPOSE: To assess the effectiveness of toric intraocular lenses (IOLs) in the management of post-keratoplasty astigmatism. SETTING: Public university hospital, Auckland, New Zealand. DESIGN: Retrospective case series. METHODS: The study analyzed post-keratoplasty eyes after cataract surgery and toric IOL (Acrysof SN60AT or T-flex 623T/573T) implantation. RESULTS: Twenty-six eyes were included. The mean age at cataract surgery was 57.1 years +/- 11.2 (SD). Previous keratoplasty was penetrating (84.6%) or deep anterior lamellar (15.4%). Keratoconus (73.1%) was the major indication for keratoplasty. The mean IOL cylinder power was 6.85 +/- 3.02 diopters (D). No IOL required postoperative realignment. The mean follow-up was 14 +/- 11 months. The mean refractive spherical equivalent decreased significantly, from -3.67 +/- 5.76 D to -0.58 +/- 1.71 D (P=.01). The mean refractive astigmatism also decreased significantly, from -5.49 +/- 3.72 D to -2.61 +/- 2.10 D (P<.01). There was a significant improvement in the mean uncorrected distance visual acuity (UDVA) (from 1.12 +/- 0.67 logMAR to 0.45 +/- 0.39 logMAR) and in the mean corrected distance visual acuity (CDVA) (from 0.70 +/- 0.66 logMAR to 0.15 +/- 0.16 logMAR) from preoperatively to the last follow-up (both P<.01). Postoperatively, the UDVA and CDVA were 20/40 or better in 61.5% of eyes and 92.3% of eyes, respectively. CONCLUSION: Cataract surgery with toric IOL implantation was safe and effective in significantly reducing corneal astigmatism and improving visual acuity in a large cohort of post-keratoplasty eyes. PMID- 25283613 TI - Numerical modeling of bi-polar (AC) pulse electroporation of single cell in microchannel to create nanopores on its membrane. AB - AC electroporation of a single cell in a microchannel was numerically studied. A 15 MUm diameter cell was considered in a microchannel 25 MUm in height and the influences of AC electric pulse on its membrane were numerically investigated. The cell was assumed to be suspended between two electroporative electrodes embedded on the walls of a microchannel. An amplitude and a time span of applied electric pulse were chosen to be 80 kV/m and 10 MUs, respectively. For different frequency values (50, 100, 200, and 500 kHz), simulations were performed to show how the cell membrane was electroporated and the creation of nanopores. Obtained numerical results show that the most and the largest nanopores are created around poles of cell (nearest points of cell membrane to the electrodes). The numerical simulations also demonstrate that increased frequency will slightly decrease electroporated area of the cell membrane; additionally, growth of the created nanopores will be stabilized. It has also been proven that size and number of the created nanopores will be decreased by moving from the poles to the equator of the cell. There is almost no nanopore created in the vicinity of the equator. Frequency affects the rate of generation of nanopores. In case of AC electroporation, creation of nanopores has two phases that periodically repeat over time. In each period, the pore density sharply increases and then becomes constant. Enhancement of the frequency will result in decrease in time span of the periods. In each period, size of the created nanopores sharply increases and then slightly decreases. However, until the AC electric pulse is present, overall trends of creation and development of nanopores will be ascending. Variation of the size and number of created nanopores can be explained by considering time variation of transmembrane potential (difference of electric potential on two sides of cell membrane) which is clear in the results presented in this study. PMID- 25283614 TI - Correlating FAAH and anandamide cellular uptake inhibition using N-alkylcarbamate inhibitors: from ultrapotent to hyperpotent. AB - Besides the suggested role of a putative endocannabinoid membrane transporter mediating the cellular uptake of the endocannabinoid anandamide (AEA), this process is intrinsically coupled to AEA degradation by the fatty acid amide hydrolase (FAAH). Differential blockage of each mechanism is possible using specific small-molecule inhibitors. Starting from the natural product-derived 2E,4E-dodecadiene scaffold previously shown to interact with the endocannabinoid system (ECS), a series of diverse N-alkylcarbamates were prepared with the aim of generating novel ECS modulators. While being inactive at cannabinoid receptors and monoacylglycerol lipase, these N-alkylcarbamates showed potent to ultrapotent picomolar FAAH inhibition in U937 cells. Overall, a highly significant correlation (Spearman's rho=0.91) was found between the inhibition of FAAH and AEA cellular uptake among 54 compounds. Accordingly, in HMC-1 cells lacking FAAH expression the effect on AEA cellular uptake was dramatically reduced. Unexpectedly, 3-(4,5-dihydrothiazol-2-yl)phenyl carbamates and the 3-(1,2,3 thiadiazol-4-yl)phenyl carbamates WOBE490, WOBE491 and WOBE492 showed a potentiation of cellular AEA uptake inhibition in U937 cells, resulting in unprecedented femtomolar (hyperpotent) IC50 values. Potential methodological issues and the role of cellular accumulation of selected probes were investigated. It is shown that albumin impacts the potency of specific N alkylcarbamates and, more importantly, that accumulation of FAAH inhibitors can significantly increase their effect on cellular AEA uptake. Taken together, this series of N-alkylcarbamates shows a FAAH-dependent inhibition of cellular AEA uptake, which can be strongly potentiated using specific head group modifications. These findings provide a rational basis for the development of hyperpotent AEA uptake inhibitors mediated by ultrapotent FAAH inhibition. PMID- 25283615 TI - High rate of complications following volar plating of distal radius fractures. AB - INTRODUCTION: Fracture of the distal radius (DRF) is one of the most common fractures treated by orthopaedic surgeons. The most common operative treatments of these fractures are open reduction and internal fixation. The incidents and types of complications associated with the use of these operations have not been studied in detail. MATERIAL AND METHODS: We performed a retrospective study documenting types of complications and their occurrence in a group of patients who received open reduction and internal fixation. Our definition of a complication was a case in which the patient had one or more complications which required an operation, or suffered from complex regional pain syndrome, or skin healing problems lasting more than four weeks from the operation. RESULTS: A total of 165 patients were included. In all, 39 complications in 30 wrists were registered: i.e. 18% had a minimum of one complication. CONCLUSION: Our finding that 18% suffer from a serious complication when treated using a volar locking plate must be taken into consideration when surgeons choose between conservative or operative treatment for DRF treatment. A few other studies have looked at the incidents of complications and have reported similar results. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25283616 TI - Treatment and clinical outcome in patients with idiopathic normal pressure hydrocephalus--a systematic review. AB - INTRODUCTION: Treatment of idiopathic normal pressure hydrocephalus (iNPH) is challenging. It is well known that patients with iNPH experience short-term symptom relief after shunt implantation, but the long-term effect of shunting has yielded diverging results. The objective of the present study was to review the literature and to investigate the diagnostics, treatment and outcome of patients with iNPH after shunt treatment. METHODS: A PubMed search was performed and 430 articles were identified. The search was further limited to humans, language (English and Norwegian) and publication dates after 1990. A total of 343 articles were retrieved, and 43 of these articles were found to be applicable to the research question and were therefore screened. A total of ten articles were discarded after reviewing their abstracts as the articles were not relevant to the question of interest. Another ten articles were identified from the reference lists of the initial articles which yielded a total of 43 relevant articles. The main reason for exclusion of articles was a lack of match between the articles' search criteria and the research question herein. RESULTS: Approximately 40% of the studies were prospective. The overall success rate from surgical treatment varied from 30% to 90%. Direct comparison was hampered by the lack of a common protocol regarding symptoms and outcome. Factors suggestive of a good outcome were early diagnosis, gait disturbance as the predominant preoperative complaint, and a positive response to cerebrospinal fluid dynamic tests. CONCLUSION: Shunting remains the preferred treatment, but endoscopic third ventriculostomy is reported as a possible alternative in some studies. PMID- 25283617 TI - Dependency and transfer incomes in idiopathic Parkinson's disease. AB - INTRODUCTION: Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder affecting approximately 1% of the population above 65 years of age. The aim of this study was to define the estimated Danish IPD population and to elucidate source of income and labour market affiliation for working-age IPD patients. MATERIAL AND METHODS: IPD cases were included through the Danish Register of Medicinal Product Statistics. The participants had to be alive by the end of 2010 and at least twice have cashed in prescriptions on IPD medication in the 2009-2010 period. Information on employment status and transfer income was retrieved through the DREAM database under the Danish Ministry of Employment. RESULTS: A total of 7,033 estimated IPD patients were identified. The mean age at time of registration (2010, week 50) was 72 years. Overall, 7% of the IPD patients were employed and 5% were self-supportive. In the working age range (18-64 years), 25% were employed and 10% enrolled in supported employment. Compared with the age-adjusted general population, twice as many IPD patients were outside the ordinary labour market and, furthermore, the proportion receiving anticipatory pension was increased threefold. The majority (89%) of the patients were living at home with a spouse (59%). 11% were nursing home residents. CONCLUSION: The working age IPD population was more prone to be outside employment and to receive public transfer income than an age-adjusted population sample. FUNDING: The study was funded by the Danish Parkinson Association. TRIAL REGISTRATION: not relevant. PMID- 25283618 TI - Non-attendance and drop-out in cardiac rehabilitation among patients with ischaemic heart disease. AB - INTRODUCTION: Previous studies have shown drop-out from cardiac rehabilitation (CR) to have prognostic influence on morbidity and mortality among patients with ischaemic heart disease (IHD). We aimed to identify and clarify patients' reasons for non-attendance and drop-out from CR. MATERIAL AND METHODS: A total of 872 consecutive patients with acute myocardial infarction and/or after percutaneous coronary intervention or coronary artery bypass surgery were asked by conventional mail to fill in a self-completion questionnaire on their choice of post-hospital CR and their reasons for drop-out or for non-attendance. RESULTS: Age, employment and marital status had a statistically significant influence on the overall course of CR. Younger age, affiliation with the labour market and living alone were related to a higher drop-out from CR in univariate analysis. We found no evidence of a gender difference among the patients who withdrew. Lack of time was stated as the prevailing reason for non-attendance and withdrawal from CR programmes among employed patients and in people aged 65 years or younger. Patients above 75 years of age asked for additional differentiation of exercise levels; currently two levels are offered. Or they found CR meaningless given their physical condition or their overall life situation. CONCLUSION: In patients with IHD, age, marital status and employment status play a role in the patient's attendance or drop out from CR. Different physical conditions, lack of time, too great a distance from residence to hospital, transport problems and lack of understanding of the benefits of CR explain why patients refuse to participate in or drop-out from CR. FUNDING: supported by grant from The Danish Ministry of Health. TRIAL REGISTRATION: not relevant. PMID- 25283619 TI - Massive open online courses are relevant for postgraduate medical training. AB - INTRODUCTION: The CanMEDS framework describes seven roles in postgraduate training, but training and courses relevant to these roles can be limited. Massive open online courses (MOOCs) - free online courses in which anyone can participate, anywhere - may improve course participation. This study investigates the relevance of MOOCs for postgraduate medical training within the CanMEDS framework. MATERIAL AND METHODS: We extracted a list of all courses posted by the two largest MOOC providers, Coursera and EdX, and reviewed all course descriptions and categorised each course into one of three categories- "relevant," "possibly relevant" or "not relevant"--reflecting the degree of relevance to each of the seven CanMEDS roles. We also noted course workload, duration and the name of the educational institution. RESULTS: We agreed the most on the role of health advocate (Cronbach's alpha = 0.85) and the least on the role of collaborator (Cronbach's alpha = 0.46). After a consensus-building process, 165 courses were found to be relevant or possibly relevant, mostly to the roles as scholar (n = 75) and medical expert (n = 57). The courses had a median duration of seven weeks and a median weekly workload of 4.5 hours, and were predominantly from North American universities. CONCLUSION: A large number of MOOCs are relevant for postgraduate medical training. A weekly workload of 4.5 hours may enable course participation even for busy clinicians. Physicians should consider these free and universally available courses as relevant and potentially effective means of education. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25283620 TI - Non-survivors after admission to trauma centre. AB - INTRODUCTION: Knowledge of trauma patients is often based on US studies. However, these may not be representative of the Scandinavian population. Knowing which trauma patients are at risk of dying might help us target and optimise their treatment. The purpose of this study was to examine the epidemiological characteristics and the mortality among patients who did not survive after being admitted to a Danish trauma centre. MATERIAL AND METHODS: This was a historical cohort study. The study population comprised trauma patients admitted to Aarhus University Hospital from January 2000 to July 2011. Those admitted alive and who subsequently died while still at the hospital were analysed as dead. All injuries were scored according to the abbreviated injury scale, and the mechanisms of trauma were categorised by the NOMESCO classification system. The annual odds ratios (OR) for death were calculated adjusting for potential confounders using logistic regression analysis. RESULTS: During the study period, a total of 6,299 trauma patients were admitted of whom 280 (4.4%) died. The OR for death was significantly lower in 2004 than in the remaining years, but there was no difference in mortality during the rest of the study period. Most patients died within the first 24 hours (67%), and 87% died within the first week. The primary cause of death was damage to the central nervous system (56%) and exsanguination (13%). CONCLUSION: Survival has not been improved in the period from January 2000 to July 2011. Initiatives that could potentially improve survival include the introduction of an increased focus on older patients, treatment within the first 24 hours and treatment of cerebral and vascular injuries. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25283621 TI - Treatment of varicose veins in Denmark. AB - INTRODUCTION: The aim of this study is to report the treatment of varicose veins in Denmark in the five-year period from 2007 to 2011, primarily based on reports to the nationwide Clinical Vein Database (KVD). MATERIAL AND METHODS: The KVD collects clinical patient data before, during and after invasive treatment of varicose veins in public hospitals, private outpatient clinics and private hospitals. RESULTS: A slight decrease was observed in the total number of treated legs from about 15,000 annually to nearly 14,000 during the period. Public hospitals and private outpatient clinics treat an almost equal number of patients, whereas private hospitals perform 3% of the treatments. The coverage rate of KVD in public hospitals has been almost complete (94%), but it has been approx. 40% in private outpatient clinics and private hospitals. In 84% of the legs, there were only subjective complaints. The remaining 16% had developed complications, i.e. eczema, varicophlebitis, ulcers or bleeding. Operations still make up the vast majority of the procedures, and although the number of endovenous procedures has increased during the period, these procedures account for only 15% of the procedures performed in 2011. Of all legs, 36% had previously been treated for varicose veins. CONCLUSION: The literature and our results show that there has been no significant change in the number of varicose vein treatments in Denmark for the past 20 years. Endovenous procedures still account for a small number of the procedures. Despite the increased focus on the treatment of varicose veins, just as many patients are treated for recurrence as in the 1990s. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25283622 TI - High rate of benign histology in radiologically suspect renal lesions. AB - INTRODUCTION: The objective of this study was to determine the incidence of benign renal lesions for clinically localised renal masses and the need for new diagnostic procedures to assess these lesions. MATERIAL AND METHODS: This retrospective study included patients who underwent partial or radical nephrectomy between November 2010 and July 2013. All patients underwent a multiphase helical computed tomography (CT), which revealed suspected renal malignancy. The exclusion criteria were cystic tumours, biopsy before surgery, and disseminated and locally advanced disease. Lesions were defined as follows: small <= 4 cm, intermediate > 4 and <= 7 cm, and large > 7 cm. RESULTS: A total of 226 patients underwent radical or partial nephrectomy; of these 75 patients were excluded. In all, 151 had masses suspected of being malignant tumours on CT. The mean age was 62.9 years. The male: female ratio was 3:1. The distribution of small, intermediate and large lesions were 75 (49.7%), 47 (31.1%) and 29 (19.2%), respectively. Among the three types of lesions, 15 (20%), 5 (10.6%) and 3 (10.3%) were benign, respectively (p = 0.27). Partial nephrectomy was performed in 69.3% of patients with small tumours versus 23.4% of patients with intermediate tumours, p < 0.001. CONCLUSION: Benign lesions were observed in 20% of small renal masses <= 4 cm even though CT revealed a suspect renal lesion. The need for new diagnostic approaches for clinically localised renal lesions is evident. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25283623 TI - Adolescent girls in Denmark use oral contraceptives at an increasingly young age, and with more pauses and shifts. AB - INTRODUCTION: Use of hormonal contraceptives for birth control is commonplace in the Western World. In Europe, there is considerable variety in the frequency of use of hormonal contraceptives and in the age at which these contraceptives are initiated. The purpose of the present study was to describe the use of hormonal contraceptives among the Danish adolescent female population, focusing on age, period and cohort effects and including types of hormonal contraceptives. MATERIAL AND METHODS: All women aged 14-50 years during the 1995-2012 period were identified through the Central Person Register. Furthermore, the National Registry of Medicinal Products Statistics provided information on redeemed prescriptions for hormonal contraceptives characterised by Anatomical-Therapeutic Chemical (ATC) classification codes. RESULTS: At the age of 17 years, more than 50% of the Danish adolescent population had redeemed a prescription for hormonal contraceptives. At the age of 20 years, 85% had ever used hormonal contraceptives. This amounts to a significant decrease in age at which hormonal contraceptives were initiated in the younger birth cohorts compared to the older cohorts. Additionally, adolescent girls have more pauses and shifts between types of hormonal contraceptives. Since 2010 there has been a shift toward use of second generation oral contraceptives away from third and fourth generation contraceptives. CONCLUSION: Adolescent girls tend to initiate their use of oral contraceptives at a younger age than the older cohorts do. Furthermore, they have more pauses and shift between products more frequently than older cohorts. The type of oral contraceptive used has shifted since 2010 towards older products with second generation progestins. FUNDING: The study was funded by salaries from North Zealand Hospital. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (J. No. 2010-41-4778). PMID- 25283624 TI - Prostate stent is an option for selected patients who are unsuitable for transurethral resection of the prostate. AB - INTRODUCTION: Transurethral resection of the prostate (TUR-P) is the gold standard for treatment of severe lower urinary tract symptoms (LUTS) or urine retention. Some patients are unfit for surgery due to much co-morbidity and need alternative treatment. Intraprostatic stents are one example of minimally invasive treatment for LUTS. We present our results for 27 consecutive intraprostatic stents. MATERIAL AND METHODS: A retrospective chart review of all patients who had received an intraprostatic stent between January 2012 and December 2013 by the same surgeon at the Department of Urology, Roskilde Hospital, Denmark. RESULTS: A total of 27 consecutive intraprostatic stents placed in 25 patients were reported. In all, 14 stents were still functioning at the end of follow-up after a mean 432.5 days. Four patients had died of reasons unrelated to the stent with a functioning stent in situ after an average of 102 days. A total of nine stents (33%) were removed in seven patients after a mean 165 days due to migration in two cases, infection in two cases, incontinence in two cases and retention in three cases. Residual urine was significantly reduced after placement of the stents. 72% of the patients avoided surgery or an indwelling catheter. CONCLUSION: An intraprostatic stent can be an important option in highly selected patients with considerable co-morbidity who are unsuitable for TUR-P. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25283625 TI - Mortality and readmissions in patients with acute exacerbation of chronic obstructive pulmonary disease treated at a specialised pulmonary ward and general wards. AB - INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the most common cause of admission to medical wards. In Denmark, patients are often referred to general medical wards, e.g. departments of internal medicine (IM), and only a minority are admitted to highly specialised units such as departments of pulmonary diseases (DPD). MATERIAL AND METHODS: This retrospective study investigated the risk of readmission 12 months after primary admission in 136 patients admitted to either IM or DPD due to AECOPD. Furthermore, mortality 18 months after primary admission was investigated. A subanalysis was made for patients receiving non-invasive ventilation and for patients with telehealthcare. Data were obtained from patients' case records. RESULTS: There was no difference in readmission in patients' primary admission at DPD versus IM. The median number of readmissions for patients participating in telehealthcare was four compared with two in patients who did not (p = 0.026). In hospital mortality during primary admission was significantly higher at DPD than at IM (relative risk (RR) = 3.54; p = 0.047). Telehealthcare participation was associated with a trend towards a lower mortality. Mortality was significantly higher in patients receiving non-invasive ventilation than in patients at DPD who did not receive non-invasive ventilation at their primary admission (RR = 5.02; p = 0.011). CONCLUSION: There was no difference in the risk of readmission in patients admitted to DPD and IM, respectively. Patients assigned to telehealthcare did not have a higher readmission rate, but those who were readmitted were readmitted more times (p = 0.026). FUNDING: not relevant. TRIAL REGISTRATION: This trial was registered with the Danish Data Protection Agency (J. no. 2008-58-0028). PMID- 25283626 TI - Alcoholic hepatitis. AB - Alcoholic hepatitis (AH) is an acute inflammatory syndrome causing significant morbidity and mortality. The prognosis is strongly dependent on disease severity, as assessed by clinical scoring systems. Reliable epidemiological data as well as knowledge of the clinical course of AH are essential for planning and resource allocation within the health care system. Likewise, individual evaluation of risk is desirable in the clinical handling of patients with AH as it can guide treatment, improve patient information, and serve as strata in clinical trials. The present PhD thesis is based on three studies using a cohort of nearly 2000 patients diagnosed with AH in Denmark from 1999 to 2008 as a cohort, in a population-based study design. The aims of this thesis were as follows. (1) To describe the incidence and short- and long-term mortality, of AH in Denmark (Study I). (2) To validate and compare the ability of the currently available prognostic scores to predict mortality in AH (Study II). (3) To investigate the short- and long-term causes of death of patients with AH (Study III). During the study decade, the annual incidence rate in the Danish population rose from 37 to 46 per 106 for men and from 24 to 34 per 106 for women. Both short- and long-term mortality rose for men and women, and the increase in short-term mortality was attributable to increasing patient age and prevalence of cirrhosis. Our evaluation of the most commonly used prognostic scores for predicting the mortality of patients with AH showed that all scores performed similarly, with Area under the Receiver Operator Characteristics curves giving values between 0.74 and 0.78 for 28-day mortality assessed on admission. Our study on causes of death showed that in the short-term (< 84 days after diagnosis), patients with AH were likely to die from liver-related events and infections. In the long-term (>= 84 days after diagnosis), those who developed cirrhosis mainly died from liver related causes, and those who did not develop cirrhosis mainly died from causes related to alcohol abuse. In conclusion, the present thesis provides novel warranted epidemiological information about AH that shows increasing incidence and mortality rates. Consequently, it reiterates the fact that AH is a life threatening disease and suggests that AH is an increasing public health concern. The most widely used prognostic models may be helpful adjuvants in the routine management of patients with AH, provided that clinicians are aware of the models' limitations. The causes of death in AH are primarily due to liver-related complications, suggesting that patients with AH could benefit from continued follow-up by a hepatologist after the acute episode. PMID- 25283627 TI - Mechanisms underlying social inequality in post-menopausal breast cancer. AB - This thesis is based on studies conducted in the period 2010-2014 at Department of Public Health, University of Copenhagen and at Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York. The results are presented in three scientific papers and a synopsis. The main objective of the thesis was to determine mechanisms underlying social inequality (defined by educational level) in postmenopausal breast cancer (BC) by addressing mediating effects through hormone therapy (HT) use, BMI, lifestyle and reproductive factors. The results of previous studies suggest that the higher risk of postmenopausal BC among women of high socioeconomic position (SEP) may be explained by reproductive factors and health behaviors. Women of higher SEP generally have fewer children and give birth at older ages than women of low SEP, and these factors have been found to affect the risk of BC - probably through altered hormone levels. Adverse effects on BC risk have also been documented for modifiable health behaviors that may affect hormone levels, such as alcohol consumption, high BMI, physical inactivity, and HT use. Alcohol consumption and HT use are likewise more common among women of higher SEP. The analyses were based on the Social Inequality in Cancer (SIC) cohort and a subsample of the Women's Health Initiative Observational Study (WHI-OS). The SIC cohort was derived by pooling 6 individual studies from the Copenhagen area including 33,562 women (1,733 BC cases) aged 50-70 years at baseline. The subsample of WHI-OS consisted of two case-cohort studies with measurements of endogenous estradiol (N = 1,601) and insulin (N = 791). Assessment of mediation often relies on comparing multiplicative models with and without the potential mediator. Such approaches provide potentially biased results, because they do not account for mediator outcome confounding, exposure-dependent mediator-outcome confounding, exposure mediator interaction and interactions between mediators. In addition, these simple methods do not allow for a decomposition of the total effect into direct and indirect pathways. The counterfactual-based methods for quantifying mediating effects in this thesis were developed specifically for this project taking into account some of the shortcomings of previous methods. The results of this thesis showed that a high versus low educational level was associated with a higher risk of postmenopausal BC and that this effect was partly mediated through HT use, fertility patterns and alcohol consumption in the SIC data. Overall BMI did not mediate the education-BC relation. The results from the WHI-OS for the effect of alcohol consumption on BC risk did not - as hypothesized - seem to be mediated by endogenous estradiol levels; however, the observed higher risk of BC with higher levels of alcohol was restricted to estrogen-receptor positive cases, which indicates a role of estrogens in this relation. In the WHI-OS subsample of non-HT users, a higher risk of BC was found with higher levels of BMI; both estradiol and insulin mediated the effect of BMI on BC. The effect of HT use on BC interacted synergistically with alcohol consumption and this combination appeared to be associated with very high serum levels of estradiol in the SIC data. For BMI combined with HT use, a modest positive association was observed for non-HT users whereas markedly higher risks were observed across all BMI groups in current HT-users with a tendency towards a U-shaped relation. In conclusion, the social inequality in postmenopausal BC seems to be largely mediated by HT use, alcohol consumption and reproductive factors. Various sources of bias - especially misclassification of mediators, but also exposure-dependent confounding - raise some concern about the observed relations. Future studies should focus on life-course perspectives to identify certain windows of susceptibility and collect data on repeated measurements of mediators to enable health behavior trajectories over time. In addition, there is a need for further development of the methodology for the quantification of mediating effects to handle current shortcomings such as exposure-dependent confounding and the potential interactions between mediators. PMID- 25283628 TI - Systematic reviews of randomised clinical trials examining the effects of psychotherapeutic interventions versus "no intervention" for acute major depressive disorder and a randomised trial examining the effects of "third wave" cognitive therapy versus mentalization-based treatment for acute major depressive disorder. AB - Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Cognitive therapy and psychodynamic therapy may be effective treatment options for major depressive disorder, but the effects have only had limited assessment in systematic reviews. The two modern forms of psychotherapy, "third wave" cognitive therapy and mentalization-based treatment, have both gained some ground as treatments of psychiatric disorders. No randomised trial has compared the effects of these two interventions for major depressive disorder. We performed two systematic reviews with meta-analyses and trial sequential analyses using The Cochrane Collaboration methodology examining the effects of cognitive therapy and psycho-dynamic therapy for major depressive disorder. We developed a thorough treatment protocol for a randomised trial with low risks of bias (systematic error) and low risks of random errors ("play of chance") examining the effects of third wave' cognitive therapy versus mentalization-based treatment for major depressive disorder. We conducted a randomised trial according to good clinical practice examining the effects of "third wave" cognitive therapy versus mentalisation-based treatment for major depressive disorder. The first systematic review included five randomised trials examining the effects of psychodynamic therapy versus "no intervention' for major depressive disorder. Altogether the five trials randomised 365 participants who in each trial received similar antidepressants as co-interventions. All trials had high risk of bias. Four trials assessed "interpersonal psychotherapy" and one trial "short psychodynamic supportive psychotherapy". Both of these interventions are different forms of psychodynamic therapy. Meta-analysis showed that psychodynamic therapy significantly reduced depressive symptoms on the Hamilton Depression Rating Scale (HDRS) compared with "no intervention" (mean difference 3.01 (95% confidence interval -3.98 to -2.03; p = 0.00001), no significant heterogeneity between trials). Trial sequential analysis confirmed this result. The second systematic review included 12 randomised trials examining the effects of cognitive therapy versus "no intervention" for major depressive disorder. Altogether a total of 669 participants were randomised. All trials had high risk of bias. Meta-analysis showed that cognitive therapy significantly reduced depressive symptoms on the HDRS compared with "no intervention" (four trials; mean difference -3.05 (95% confidence interval, -5.23 to -0.87; p = 0.006)). Trial sequential analysis could not confirm this result. The trial protocol showed that it seemed feasible to conduct a randomised trial with low risks of bias and low risks of random errors examining the effects of "third wave" cognitive therapy versus mentalization-based therapy in a setting in the Danish healthcare system. It turned out to be much more difficult to recruit participants in the randomised trial than expected. We only included about half of the planned participants. The results from the randomised trial showed that participants randomised to "third wave" therapy compared with participants randomised to mentalization-based treatment had borderline significantly lower HDRS scores at 18 weeks in an unadjusted analysis (mean difference -4.14 score; 95% CI -8.30 to 0.03; p = 0.051). In the adjusted analysis, the difference was significant (p = 0.039). Five (22.7%) of the participants randomised to "third wave" cognitive therapy had remission at 18 weeks versus none of the participants randomised to mentalization-based treatment (p = 0.049). Sequential analysis showed that these findings could be due to random errors. No significant differences between the two groups was found regarding Beck's Depression Inventory (BDI II), Symptom Checklist 90 Revised (SCL 90-R), and The World Health Organization-Five Well-being Index 1999 (WHO 5). We concluded that cognitive therapy and psychodynamic therapy might be effective interventions for depression measured on HDRS and BDI, but the review results might be erroneous due to risks of bias and random errors. Furthermore, the effects seem relatively small. The trial protocol showed that it was possible to develop a protocol for a randomised trial examining the effects of "third wave" cognitive therapy versus mentalization-based treatment with low risks of bias and low risks of random errors. Our trial results showed that "third wave" cognitive therapy might be a more effective intervention for depressive symptoms measured on the HDRS compared with mentalization-based treatment. The two interventions did not seem to differ significantly regarding BDI II, SCL 90-R, and WHO 5. More randomised trials with low risks of bias and low risks of random errors are needed to assess the effects of cognitive therapy, psychodynamic therapy, "third wave" cognitive therapy, and mentalization-based treatment. PMID- 25283629 TI - The prognostic value of clinical factors and cancer stem cell-related markers in gliomas. AB - Gliomas are the most frequent brain tumours among adults, and it is estimated that gliomas constitute half of the about 1500 new brain tumours diagnosed in Denmark every year. Existing treatment strategies include neurosurgery, radiation, and chemotherapy. Therapy selection is based on experiences from clinical trials, with the risk that the results obtained are restricted to highly selected patients only. Moreover, these studies provided only little knowledge of the clinical behaviour of the tumours. For some time, it has been believed that somatic stem cells are responsible for self-renewal, proliferation, and differentiation during development of different (normal) tissues. The same characteristics were identified in cancer cells, and recently a major part of the glioma research has focused on the cancer stem cell (CSC) hypothesis, suggesting that only CSCs posses the ability of initiating new tumours. Moreover, CSCs have been suggested as the cause of resistance towards radiotherapy and chemotherapy. In gliomas, CSCs were originally identified by means of the expression of CD133, but other proteins have subsequently been suggested as CSC related. To improve patients' survival, further knowledge about the biological but also about the clinical presentation of gliomas and of glioma patients in an entire population was needed. Identification of patients who would benefit from standard treatment as well as identification of patients who need more aggressive treatment at the time of diagnosis is essential. Equally important is the identification of patients who will not benefit from current standard treatment. Moreover, as common exclusion criteria in clinical trials are age, performance status, and a histologically verified diagnosis, knowledge regarding clinical characteristics in the total population was highly needed. In manuscripts 1 and 2, sampling from national registries was performed and clinical data were collected in order to indentify a clinical prognostic profile for patients with WHO grade I-II tumours (LGG) and WHO grade III-IV tumours (HGG). By using a population-based setup, we identified 433 patients who were diagnosed with a primary glioma in the period 1 January 2005 to 31 December 2009, and of these 76 patients were clinically diagnosed and 357 had a histologically verified diagnosis. We found that younger age, a non-astrocytic histology, having performance status (PS) 0-1, and the absence of neurological deficits were associated with a better prognosis in patients with LGGs. In patients with HGGs younger age, having PS 0-1, absence of neurological deficits, having a tumour that does not cross the midline, and receiving curatively intended post-surgical treatment were associated with a superior prognosis. Older patients also benefitted from curatively intended treatment, although their survival was inferior as compared to younger patients receiving similar treatment. In addition, the prognostic value of having somatic mutation affecting the protein isocitrate dehydrogenase 1 (IDH1) was evaluated. Presence of a mutated IDH1 was associated with a better prognosis in patients with WHO grade II and III tumours, whereas no prognostic potential was identified in the group of GBMs. In manuscript 3, the independent prognostic value of the RNA-binding protein Musashi-1 was evaluated using fluorescence-based automated quantitative image acquisition. The prognostic significance was subsequently investigated in relation to the observed clinical prognostic variables. We found that Musashi-1 was not prognostic in WHO grade II tumours, but in WHO grade III high levels of Musashi-1 were associated with poor survival, although the conclusion is based on very few patients. The opposite effect was identified in a sub-group of postsurgical treated GBM patients expressing high levels of Musashi 1 and a superior prognosis. It may be speculated that Musashi-1 status has a predictive value to the effect of chemo radiotherapy in GBM patients, but the study was not designed to explore a potential predictive potential, and this should be investigated in further material. In manuscript 4, a double staining of CD133 and nestin was performed. The use of fluorescence made it possible to identify expression of CD133 and nestin in the same cell, which has never been done before. However, neither co-localisation nor expression of CD133 or nestin was associated with survival. IN CONCLUSION: Clinical variables associated with better survival were identified for patients with both LGGs and HGGs. All variables are already used in clinical decision making, and they can be used in prognostic counselling of the patients and to guide clinicians regarding the potential benefit from standard treatment in specific patients. Musashi-1 was a predictor of poor survival in WHO grade III tumours, but in patients with GBMs, high levels of Musashi-1 were associated with improved survival. No prognostic value was identified regarding CD133, nestin, or co-localisation of these markers in multivariate analysis adjusted for clinical variables. None of the investigated CSC markers can be used in a clinical setting at the present time. Quantitative automated image acquisition and processing was demonstrated to be a feasible, robust, and reproducible method that will be used in future projects investigating other potential prognostic factors. PMID- 25283630 TI - Fertility treatment: long-term growth and mental development of the children. AB - Fertility treatment has been associated with obstetrical and perinatal complications. It is, however, uncertain whether fertility treatment or parental subfertility is associated with long-term development of the children. We aimed to assess the growth and mental health of children and adolescents conceived after fertility treatment compared to spontaneously conceived controls. First, we evaluated all previous studies comparing neurodevelopmental outcomes between children conceived after fertility treatment and spontaneous conceived controls. The systematic review clarified methodological limitations in the existing literature on the long-term development of children conceived after medical assisted reproduction. Although several studies had been published, large, well controlled studies with long-term follow-up and thorough statistical adjustments were still few. Second, we evaluated the children's mental health by assessing the risk of mental disorders. We studied a population of 555,828 children conceived after spontaneous conception and 33,139 children conceived after fertility treatment with follow-up in 2012 when the children were 8-17 years old. The absolute risk and hazard ratio of overall and specific mental disorders were estimated while adjusting for potential confounding variables. Further, we estimated the association between subtypes of procedures, hormonal treatment, gamete types and cause of infertility on the one hand and the risk of mental disorders on the other. Children conceived after ovulation induction had a low, but significantly increased risks of autism spectrum disorders, hyperkinetic disorders, conduct, emotional, or social disorders, and tic disorders. Children conceived after IVF or ICSI showed no increased risk, except for a small risk of tic disorders. There was no risk systematically related to any specific type of hormone drug treatment. Thus, the increased risks may rely on residual confounding such as unknown parental factors associated with infertility in the ovulation induction group. Third, we assessed the intelligence, attention and executive functions in 1782 5-year-old singletons. Compared with children conceived after spontaneous conception, there were no differences in test scores in children conceived by subfertile parents waiting more than 12 months before conceiving naturally or children born by parents conceiving after fertility treatment. Finally, we evaluated the growth of children born after fertility treatment or to subfertile parents. Compared to children conceived spontaneously, children born after fertility treatment or by subfertile parents had a significantly lower birth weight - an important predictor of mental development. In contrast, no differences on height, weight, or head circumference were found at the age of 5 years. In conclusion, we found no differences on long-term growth and neurodevelopment of children conceived after fertility treatment or by subfertile parents compared with spontaneously conceived children. Children born after ovulation induction had a low, but increased risk of mental disorders in childhood or adolescence, although this risk may rely on unknown parental factors associated with infertility. PMID- 25283631 TI - Bevacizumab for choroidal neovascularization secondary to age-related macular degeneration and pathological myopia. AB - INTRODUCTION: Many retinal specialists have utilized intravitreal bevacizumab as an anti-VEGF to treat choroidal neovascularization (CNV), secondary to age related macular degeneration (AMD) and pathological myopia, with favorable results. Bevacizumab is currently approved only for the systemic treatment of colon carcinoma, whereas it is widely used off-label for treating ocular neovascular diseases. AREAS COVERED: In this review, after thorough search, 33 relevant studies conducted in the last 4 years were found. These articles comprised 14 studies about use of bevacizumab alone or in combination with other therapeutic agents to treat exudative AMD, and 19 studies on the use of myopic CNV. EXPERT OPINION: Although bevacizumab is widely used as an anti-VEGF agent for the treatment of exudative AMD, data on its systemic side effects are limited because of studies' short follow-up periods, absence of appropriate controls, limitation in reporting outcomes, and lack of controlled clinical trials in Phase III. Some safety studies demonstrated no difference between bevacizumab and ranibizumab in occurrence of heart attacks or stroke. Conducting proper randomized clinical trials with long-term follow-up is crucial to make sure about efficacy and safety of bevacizumab. PMID- 25283633 TI - The survey on implementation of evidence-based nursing in preventing ventilator associated pneumonia and the effect observation. AB - The objective is to survey the effect of evidence-based nursing (EBN) in preventing ventilator-associated pneumonia and to observe the effect, providing a reference for clinical nursing intervention. 146 patients with mechanical ventilator were included and randomly divided into control group (n = 73) and observation group (n = 73). Patients in control group received conventional nursing method, and patients in observation group received EBN according to the nursing principles. The questions were raised and the literatures were retrieved to formulate the optimum nursing strategy according to clinical experience and patient need. After nursing, morbidity of VAP in observation group was significantly lower than control group, and length of stay, length of stay in ICU, and the duration of mechanical ventilation were also significantly lower than control group; the differences were statistically significant (P < 0.05). After nursing, the physiological function, physical role, somatic pain, and mental health scores in observation group were significantly higher than control group (P < 0.05). Oral hygiene status in observation group was significantly better than control group; the difference was statistically significant (P < 0.05). After nursing, IL-1, IL-6, and TNF-alpha in two groups were both decreased (P < 0.05); IL-1, IL-6 and TNF-alpha in observation group were significantly lower than control group (P < 0.05). When patients were discharged, satisfaction degree in observation group was significantly higher than control group; the difference was statistically significant (P < 0.05). The implementation of EBN can effectively prevent the occurrence of ventilator-associated pneumonia and improve the clinical nursing quality, which is worthy of clinical application. PMID- 25283636 TI - Unhealthy dietary behavior in refractory functional dyspepsia: a multicenter prospective investigation in China. AB - OBJECTIVE: To determine the association of dietary behavior with refractory functional dyspepsia (RFD) and its subtypes in Chinese patients. METHODS: The medical records of patients admitted to the Outpatient Department of Gastroenterology of four hospitals in Mainland China for upper gastrointestinal (GI) symptoms from June to September 2012 were reviewed and their characteristics were collected. Functional dyspepsia (FD) was diagnosed based on the Rome III criteria. RFD was defined as FD with continuous symptoms for at least 6 months that was unresponsive to at least two kinds of medications. Another 100 healthy volunteers were included as controls. The participants' dietary behaviors were investigated using a questionnaire survey. RESULTS: Overall, 1341 FD patients were enrolled in the study, including 327 RFD and 1014 non-RFD (NRFD). Unhealthy dietary behaviors were more prevalent in both RFD and NRFD than in the healthy controls. Skipping meals, eating extra meals and a preference to sweet food and gas-producing food were more common in the RFD patients. Compared with NRFD, RFD epigastric pain syndrome (EPS) patients preferred spicy food, whereas those with postprandial distress syndrome (PDS) preferred sweet food and gas-producing food, and those with both EPS and PDS were found to skip meals and take extra meals more often. Logistic regression analysis showed that skipping meals, eating extra meals and a preference to sweet food and gas-producing food were risk factors for RFD. CONCLUSION: Unhealthy dietary behaviors, especially skipping meals, eating extra meals and a preference to sweet food and gas-producing food, were correlated with RFD and its subtypes. PMID- 25283635 TI - Suprabasin as a novel tumor endothelial cell marker. AB - Recent studies have reported that stromal cells contribute to tumor progression. We previously demonstrated that tumor endothelial cells (TEC) characteristics were different from those of normal endothelial cells (NEC). Furthermore, we performed gene profile analysis in TEC and NEC, revealing that suprabasin (SBSN) was upregulated in TEC compared with NEC. However, its role in TEC is still unknown. Here we showed that SBSN expression was higher in isolated human and mouse TEC than in NEC. SBSN knockdown inhibited the migration and tube formation ability of TEC. We also showed that the AKT pathway was a downstream factor of SBSN. These findings suggest that SBSN is involved in the angiogenic potential of TEC and may be a novel TEC marker. PMID- 25283638 TI - Isolation of an imino-N-heterocyclic carbene/germanium(0) adduct: a mesoionic germylene equivalent. AB - An autoionization of germanium dichloride/dioxane complex with an imino-N heterocyclic carbene ligand (L) afforded a novel germyliumylidene ion, [(L)GeCl](+)[GeCl3](-), which was fully characterized. Reduction of the germyliumylidene ion with potassium graphite produced a cyclic species [(L)Ge], which can be viewed as both a Ge(0) species and a mesoionic germylene. X-ray diffraction analysis and computational studies revealed one of the lone pairs on the Ge atom is involved in the pi system on the GeC2N2 five-membered ring. It was also confirmed that the nucleophilic behavior of [(L)Ge] as a two lone-pair donor. PMID- 25283637 TI - 9-O-acetylated sialic acids differentiating normal haematopoietic precursors from leukemic stem cells with high aldehyde dehydrogenase activity in children with acute lymphoblastic leukaemia. AB - Childhood acute lymphoblastic leukaemia (ALL) originates from mutations in haematopoietic progenitor cells (HPCs). For high-risk patients, treated with intensified post-remission chemotherapy, haematopoietic stem cell (HSC) transplantation is considered. Autologous HSC transplantation needs improvisation till date. Previous studies established enhanced disease-associated expression of 9-O-acetylated sialoglycoproteins (Neu5,9Ac2-GPs) on lymphoblasts of these patients at diagnosis, followed by its decrease with clinical remission and reappearance with relapse. Based on this differential expression of Neu5,9Ac2 GPs, identification of a normal HPC population was targeted from patients at diagnosis. This study identifies two distinct haematopoietic progenitor populations from bone marrow of diagnostic ALL patients, exploring the differential expression of Neu5,9Ac2-GPs with stem cell (CD34, CD90, CD117, CD133), haematopoietic (CD45), lineage-commitment (CD38) antigens and cytosolic aldehyde dehydrogenase (ALDH). Normal haematopoietic progenitor cells (ALDH(+)SSC(lo)CD45(hi)Neu5,9Ac2 -GPs(lo)CD34(+)CD38(-)CD90(+)CD117(+)CD133(+)) differentiated into morphologically different, lineage-specific colonies, being crucial for autologous HSC transplantation while leukemic stem cells (ALDH(+)SSC(lo)CD45(lo)Neu5,9Ac2 -GPs(hi)CD34(+)CD38(+)CD90(-)CD117(-)CD133(-)) lacking this ability can be potential targets for minimal residual disease detection and drug-targeted immunotherapy. PMID- 25283634 TI - Do lamin A and lamin C have unique roles? AB - The A-type lamins, lamin A and lamin C, generated from a single gene, LMNA, are major structural components of the nuclear lamina. The two alternative splice products have mostly been studied together because they have been considered to be interchangeable. However, several lines of evidence indicate that in spite of being generated from the same gene and having high similarities in their primary sequences, the two isoforms are not equivalent in different biological aspects in both health and disease. The key question is whether they have both overlapping and unique functions and whether they are distinctly regulated. Based on the so far available experimental evidence, lamin A appears to be the most regulated A type isoform during development, aging, and disease which indicates that lamin A is implicated in many different biological aspects and may have a greater repertoire of specialized functions than lamin C. The aim of this review is to point out differences between the two major LMNA splice variants and the consequences of these differences on their functions. This may guide further research and be of prime importance for the understanding of the pathogenesis of LMNA mutations. PMID- 25283639 TI - In vitro culture may be the major contributing factor for transgenic versus nontransgenic proteomic plant differences. AB - Identification of differences between genetically modified plants and their original counterparts plays a central role in risk assessment strategy. Our main goal was to better understand the relevance of transgene presence, genetic, and epigenetic changes induced by transgene insertion, and in vitro culture in putative unintended differences between a transgenic and its comparator. Thus, we have used multiplex fluorescence 2DE coupled with MS to characterize the proteome of three different rice lines (Oryza sativa L. ssp. japonica cv. Nipponbare): a control conventional line (C), an Agrobacterium-transformed transgenic line (Ta) and a negative segregant (NSb). We observed that Ta and NSb appeared identical (with only one spot differentially abundant--fold difference >= 1.5), contrasting with the control (49 spots with fold difference >= 1.5, in both Ta and NSb vs. control). Given that in vitro culture was the only event in common between Ta and NSb, we hypothesize that in vitro culture stress was the most relevant condition contributing for the observed proteomic differences. MS protein identification support our hypothesis, indicating that Ta and NSb lines adjusted their metabolic pathways and altered the abundance of several stress related proteins in order to cope with in vitro culture. PMID- 25283640 TI - Association between anesthesiologist experience and mortality after orthotopic liver transplantation. AB - The anesthesiologist has been recognized as an integral member of the liver transplant team, and previous studies have demonstrated that inter anesthesiologist variability can be a driver of outcomes for high-risk patients. We hypothesized that anesthesiologist experience, defined as the number of previous liver transplants performed at our institution, the Icahn School of Medicine at Mount Sinai, would be independently associated with outcomes for liver transplant patients. Eight hundred forty-nine liver transplants performed between January 2003 and January 2013 with a total of 22 anesthesiologists were analyzed. Each transplant was assigned an incremental case number that corresponded to the number of transplants that the attending anesthesiologist had already performed at our institution. Several perioperative covariates were controlled for in the context of a generalized linear mixed effects model to detail the influence of threshold levels of the incremental case number on the primary outcome, 30-day mortality, and a secondary outcome, 30-day graft failure. Sensitivity analyses were conducted to confirm the robustness of these findings. An incremental case number <= 5 was associated with a significantly greater risk of 30-day mortality (odds ratio = 2.24, 95% confidence interval = 1.11-4.54, P = 0.025), and there was evidence suggestive of a greater risk of 30-day graft failure (odds ratio = 1.93, 95% confidence interval = 0.95-3.93, P = 0.071). Sensitivity analyses ruled out threats to the validity of these findings, including dropout effects and time trends in the overall performance of the transplantation unit. In conclusion, this study shows that an anesthesiologist's level of experience has a significant effect on outcomes for liver transplant recipients, with increased mortality and possibly graft failure during a provider's first 5 cases. These findings may indicate the need for increased training and supervision for anesthesiologists joining the liver transplant team. PMID- 25283641 TI - The 1,25D3 -MARRS receptor/PDIA3/ERp57 and lifespan. AB - Using MRI on mice bearing a targeted knockout (KO) of the 1,25D3 -MARRS receptor/PDIA3/ERp57 we found that they had decreased body fat relative to their littermate (LM) controls, a condition associated with increased lifespan. Others have found that lower body fat is correlated with decreased lipid droplets in intestinal cells that may be mediated by a factor secreted by germ cells (possibly estradiol). In a reducing environment estradiol competed for binding to the 1,25D3-MARRS receptor/PDIA3/ERp57. A consequence of this was that estradiol stimulated calcium uptake in enterocytes isolated from LM mice. In time course studies, lipid droplets increased in response to 1 nM estradiol from 1-5 D of culture, relative to corresponding controls, while at 6 and 7 D this steroid decreased lipid droplets. Enterocytes from LM or KOs incubated with estradiol for 1-4 D showed the hormone increased lipid droplets. Using the 4 D culture period, 1 and 10 nM estradiol significantly increased the number of lipid droplets in cells from LM mice by 40-60%, compared to equivalent conditions in KO mice. In assessing signal transduction pathways, the hormone increased phospho-Akt levels, but no differences were observed in phospho-mTORC1, or phospho-S6K (although cells from chicks did exhibit a hormone-mediated difference). Finally, the remaining mice (which had stopped reproducing) were allowed to die naturally and lifespan recorded. LM mice lived 687 +/- 77 D (without an outlying value) while KO mice lived 740 D +/- 80 D. These data suggest the 25D3 -MARRS receptor/PDIA3/ERp57 may contribute to the length of lifespan in mammals. PMID- 25283642 TI - Prevalence and prognostic value of human papillomavirus genotypes in tonsillar squamous cell carcinoma: a Korean multicenter study. AB - BACKGROUND: This study was aimed at investigating the change in the prevalence of human papillomavirus (HPV) genotypes in tonsillar squamous cell carcinoma (TSCC) and the association of the HPV genotype with the prognosis. METHODS: This multicenter study included 175 patients with TSCC from 3 general hospitals between 1991 and 2009. HPV DNA was detected in paraffin-embedded tissues with genotyping chips. A survival analysis that considered clinicopathological factors, the HPV genotype, and the expression of p53, retinoblastoma protein, p16, and epidermal growth factor receptor (assessed with immunohistochemistry) was performed with Cox regression analysis. RESULTS: High-risk HPV types were found in 23.4% of the cases. The prevalence of HPV-18 (10.3%) was as high as that of HPV-16 (10.3%). The proportion of high-risk HPV-positive tumors increased from 5.9% in 1991 to 31.6% in 2009. HPV-16 positivity was associated with an advanced stage and lymph node metastasis, whereas HPV-18 positivity was associated with old age and an advanced T stage. The survival analysis showed that old age and T classification were poor prognostic factors, whereas the expressions of various biomarkers were not associated with prognosis. HPV-18-positive cases had a poorer prognosis than HPV-16-positive cases and non-HPV-related TSCC cases. A multivariate analysis revealed that HPV-18 positivity, old age, and an advanced T stage were independent prognostic factors for predicting poor outcomes for patients with TSCC. CONCLUSIONS: The proportion of HPV-positive tonsillar cancer cases has increased during the last 20 years in the Republic of Korea. The presence of HPV-18 may serve as a biomarker for a poor prognosis. PMID- 25283643 TI - One-pot glovebox-free synthesis, characterization, and self-assembly of novel amphiphilic poly(sarcosine-b-caprolactone) diblock copolymers. AB - Novel amphiphilic polypeptoid-polyester diblock copolymers based on poly(sarcosine) (PSar) and poly(epsilon-caprolactone) (PCL) are synthesized by a one-pot glovebox-free approach. In this method, sarcosine N-carboxy anhydride (Sar-NCA) is firstly polymerized in the presence of benzylamine under N(2) flow, then the resulting poly(sarcosine) is used in situ as the macro-initiator for the ring-opening polymerization (ROP) of epsilon-caprolactone using tin(II) octanoate as a catalyst. The degree of poly-merization of each block is controlled by various feed ratios of monomer/initiator. The diblock copolymers with controlled molecular weight and narrow molecular weight distributions (D(M) < 1.2) are characterized by (1)H NMR, (13)C NMR, and size-exclusion chromatography. The self assembly behavior of PSar-b-PCL in water is investigated by dynamic light scattering (DLS) and transmission electron microscopy. DLS results reveal that the diblock copolymers associate into nanoparticles with average hydrodynamic diameters (D(H)) around 100 nm in water, which may be used as drug delivery carriers. PMID- 25283644 TI - Sequential MR imaging demonstrates evolution of a fibular intraneural ganglion cyst after knee dislocation. PMID- 25283645 TI - Zadbimyia, a new genus of asynaptine Porricondylinae (Diptera: Cecidomyiidae) with twenty-two new species from the cloud forest of Costa Rica. AB - Twenty-two new species of Zadbimyia, a new genus of the tribe Asynaptini, are described from Costa Rica, the first new descriptions of Neotropical Porricondylinae (Cecidomyiidae) in modern times. The new species are: Zadbimyia aberrans, Z. anniae, Z. artborkenti, Z. browni, Z. carolinae, Z. costaricensis, Z. dubia, Z. elenae, Z. elviae, Z. holdenae, Z. inornata, Z. lasalturas, Z. marcoi, Z. membranacea, Z. minima, Z. spinapiscis, Z. talamanca, Z. tapanti, Z. viquezi, Z. wendyae, Z. zumbadoi, and Z. zurqui. All species were found during the Zurqui All-Diptera Biodiversity Inventory, in mid-elevation (1600 m) cloud forest in the central highlands of Costa Rica. A maximum of 19 species occurred at a single site. Pseudocamptomyia Parnell, a genus known from one species in northeastern United States and possibly two species in Somalia, was identified as the closest relative of Zadbimyia. Ultraviolet light traps proved to be the most effective device to collect adults of Zadbimyia. As a peculiarity in Porricondylinae, the circumfila of Zadbimyia males are multi-looped and not substantively different from the circumfila known from male Cecidomyiidi (subfamily Cecidomyiinae). PMID- 25283646 TI - Review of the millipede genus Sibiriulus Gulicka, 1972, with descriptions of three new species from Altai, Siberia, Russia (Diplopoda, Julida, Julidae). AB - The genus Sibiriulus Gulicka, 1963, which has hitherto been known to comprise only four species, is rediagnosed and shown to include seven species from Siberia, Russia. Three species are described here as new to science: S. latisupremus sp. nov., S. baigazanensis sp. nov., S. aktashensis sp. nov. The species Sibiriulus profugus (Stuxberg, 1876) is recorded in the fauna of the Altai Province and the Republic of Altai for the first time. All currently known species of Sibiriulus are keyed and mapped, including the new species. PMID- 25283647 TI - Two new Salamanders of the genus Onychodactylus from Eastern Honshu, Japan (Amphibia, Caudata, Hynobiidae). AB - We describe two new species of hynobiid salamanders in the genus Onychodactylus from eastern Honshu, Japan, based on the morphological and genetic evidence. Onychodactylus intermedius sp. nov. is distributed in southern part of Tohoku District and northern Ibaraki and Niigata Prefectures, and was previously reported as S-Tohoku group. Onychodactylus intermedius belongs to the O. japonicus species complex, and differs from the other congeners in having relatively long tail, narrow head, short snout, 18 presacral vertebrae, and distinctly curved vomerine tooth series without gap. Onychodactylus fuscus sp. nov. is known from only four localities in Fukushima and Niigata Prefectures of Tohoku and Hokuriku Districts. It also belongs to the O. japonicus complex, but lacks the dorsal stripe, which is a diagnostic character of the species complex. In other characteristics, O. fuscus differs from the other congeners in having comparatively long tail, wide head and internarial space, shallowly curved vomerine tooth series with gap, and relatively few vomerine teeth. Both species described here breed in winter. Phylogenetically, the two new species are closely related to each other, forming a well-supported clade with O. tsukubaensis as their sister species. Onychodactylus intermedius sp. nov. is known to be parapatric with O. japonicus and O. nipponoborealis without hybridization, whereas O. fuscus sp. nov. is sympatric with O. japonicus at least in a single known locality, and analysis of microsatellite loci indicates they are reproductively isolated. PMID- 25283648 TI - On the taxonomy of the tribe Pisachini (Hemiptera: Fulgoromorpha: Nogodinidae) with the description of new taxa from China and Vietnam. AB - Goniopsarites gen. nov. is described from China in the tribe Pisachini with G. fronticonvexus sp. nov. as the type species. The genus Pisacha is revised, four new species P. yinggensis sp. nov., P. baculiformis sp. nov., P. falcata sp. nov., P. balteiformis sp. nov. are described, and P. encaustica (Jacobi, 1916) comb. nov. & stat. rev. is reestablished which has been treated as P. naga according to specimens from Taiwan. Identification keys to three genera of the tribe Pisachini and to all species of Pisacha are presented. PMID- 25283649 TI - Earthworms of the 'acaecate' Pheretima group in Vietnam (Oligochaeta: Megascolecidae), with description of a new species from the Mekong delta. AB - The 'acaecate' Pheretima group from Vietnam is revised, with description of a new species, Polypheretima mekongmontis sp. nov. A total of 18 species of three genera, Metapheretima Michaelsen, 1928, Planapheretima Michaelsen, 1934, and Polypheretima Michaelsen, 1934 has been recorded from Vietnam. Caecate species of Planapheretima are included here as well. Planapheretima arboricola (Rosa, 1890), Pl. lacertina (Chen, 1946), Pl. tenebrica (Chen, 1946), Polypheretima elongata (Perrier, 1872), and Po. taprobanae (Beddard, 1892) are originally recorded from other countries; all remaining species are native to Vietnam. The species Polypheretima tani (Thai, 1996) and Po. tiencanhensis (Pham, 1995) are transferred to the genus Metapheretima. A key to species and distribution maps are also presented. PMID- 25283650 TI - A new concept of Absoloniella (=Ruffodytes syn. n.) for five blind Mediterranean species (Coleoptera: Brachyceridae: Erirhininae). AB - A hundred year-long taxonomic ambiguity surrounding two mysterious species originally described as Caulomorphus reitteri Muller, 1912 and Absoloniella cylindrica Formanek, 1913, both known from single specimens believed to be lost, is resolved. This is achieved by designation of their neotypes based on the same specimen collected together, and considered conspecific, with the holotype of Ruffodytes hellenicus Osella, 1973, the latter the type of the genus Ruffodytes Osella, 1973. This action triggers the following nomenclatorial and taxonomic changes: (1) the generic name Ruffodytes Osella, 1973 syn. n. is a junior subjective synonym of Absoloniella Formanek, 1913; (2) the names cylindrica syn. n. and hellenica syn. n. are junior objective and subjective synonyms, respectively, of the name reitteri for the species Absoloniella reitteri (Muller, 1912); (3) the genus Absoloniella currently comprises five species: A. reitteri (Muller, 1912), A. italica (Osella, 1976) comb. n., A. pacei (Osella, 1976) comb. n., A. servadeii (Osella, 1982) and A. nitidipennis (Osella, 1989) comb. n. Puzzling distribution of blind and wingless Mediterranean Absoloniella is briefly discussed. PMID- 25283651 TI - Discovery of new populations and DNA barcoding of the Arapahoe snowfly Arsapnia arapahoe (Plecoptera: Capniidae). AB - The Arapahoe Snowfly, Arsapnia arapahoe (Nelson & Kondratieff)was recently discovered in six different first-order streams outside of the Cache la Poudre River Basin where it was previously considered endemic. Specimens of A. arapahoe were always collected in much lower relative abundance, 1.09% (+/-2.3SD), than other sympatric adult capniids. The first mitochondrial deoxyribonucleic acid (DNA) barcodes for A. arapahoe and A. coyote (Nelson & Baumann) are presented and compared with those of A. decepta. DNA barcoding was not able to differentiate between A. arapahoe and A. decepta Banks but it was able to indicate that A. coyote is specifically distinct. PMID- 25283652 TI - Notoatherix antiqua gen. et sp. nov., first fossil water snipe fly from the Late Jurassic of Australia (Diptera: Athericidae). AB - The first water snipe fly (Diptera: Tabanomorpha) fossil discovered in the Late Jurassic Talbragar Fish Bed in Australia is described and illustrated. Notoatherix antiqua gen. et sp. nov., described from a single wing specimen, is assigned to the family Athericidae based on the diagnostic feature of this family: the vein R2+3 ending very near to R1 (marginal cell closed). It is the first record of Athericidae from Australia and the oldest adult record of this family worldwide. PMID- 25283653 TI - Drepanosticta machadoi spec. nov. from New Guinea (Odonata: Platystictidae). AB - Drepanosticta machadoi sp. nov. (Holotype ?: Dablin Creek, Hindenburg Range) from Papua New Guinea is described. The new species is a predominantly black damselfly, the male with four pale/bright pattern elements on each side of the synthorax, dorsum of segments 9 and 10 largely bright blue, and a uniquely shaped posterior lobe of the pronotum which is a wide-angled fork with rather straight, narrow finger-like prongs. It is referred to the Drepanosticta conica group of species and a key to the males of the D. conica group is provided. PMID- 25283654 TI - Studies of Madagascan Ptiliidae (Coleoptera) 3: The genus Acrotrichis including twenty seven new species . AB - This is the third report detailing Ptiliidae collected from forest leaf litter by the Moravian Museum (Brno, Czech Republic) expeditions to Madagascar 2010-2013. After completion of the first draft, which identified 16 new species, more Madagsacan Acrotrichis, collected at earlier dates, were found in the Natural History Museum in London (BMNH). These included 17 unpublished new species determined by Colin Johnson in 1969, 7 of which proved to be the same as those in the Czech material. The decision was taken, therefore, to broaden the scope of the report to include all the mounted Madagascan material in the Museum and to use Johnson's ms names to avoid potential future confusion. 27 new species are described and figured: Acrotrichis absona sp. n.; A. barclayi sp. n.; A. bibula sp. n.; A. boothi sp. n.; A. clareae sp. n.; A. colini sp. n.; A. cuspida sp. n.; A. difficilis sp. n.; A. exigua sp. n.; A. hammondi sp. n.; A. heissi sp. n.; A. hova sp. n.; A. impressa sp. n.; A. lacrimosa sp. n.; A. lauta sp. n.; A. loganovi sp. n.; A. magnifica sp. n.; A. malitiosa sp. n.; A. obscura sp. n.; A. perexigua sp. n.; A. perfida sp. n.; A. strenua sp. n.; A. subafricana sp. n.; A. tampoketsae sp. n.; A. terminalis sp. n.; A. truncata sp. n. and A. tuberosa sp. n., and new data recorded for six others: a. africana Johnson, A. africanoides Johnson, A. cursitans (Nietner), A. discoloroides Johnson, A. minuscula Johnson, and A. superbioides Johnson. New criteria for assessing speciation in Acrotrichis are suggested, the definition of subgenera discussed and a key to all the known species from the island provided. PMID- 25283655 TI - A reanalysis of the morphological phylogeny of the spider genus Physocyclus Simon (Araneae: Pholcidae) with the description of a new species and description of the female of Physocyclus paredesi Valdez-Mondragon from Mexico. AB - A new species of spider from Michoacan, Physocyclus peribanensis sp. nov. is described. This description is based on a male holotype and one female paratype. Also, the first description of the female of Physocyclus paredesi Valdez Mondragon from Oaxaca, Mexico is provided, as well as the redescription of the male. This paper provides a cladistic reanalysis of the spider genus Physocyclus Simon, corroborating the monophyly of the genus with morphological data. The phylogenetic reanalysis was done with 54 morphological characters (44 binary and 10 multistate) using equal and implied weighting approach. The equal weighting analysis found two most parsimonious trees, whereas the analysis with implied weighting found just one most parsimonious trees with the concavity values (K= 5 10). The genus Physocyclus is composed by two clades or species groups: the globosus and the dugesi groups. Physocyclus peribanensis sp. nov. belongs to the dugesi group composed of 21 species, and P. paredesi to the globosus group composed of 11 species. With the new species described here, the number of known species of the genus Physocyclus increases to 32 species. The globosus group has a biogeographical distribution pattern in the Mesoamerican and Mexican Mountain biotic components, whereas the dugesi group has a biogeographical distribution in the Mesoamerican and Continental Nearctic biotic components. PMID- 25283656 TI - Checklist of earthworms (Oligochaeta: Lumbricidae) from Germany. AB - A checklist of the German earthworm fauna (Oligochaeta: Lumbricidae) is presented, including published data, data from reports, diploma- and PhD- theses as well as unpublished data from museum collections, research institutions and private persons. Overall, 16,000 datasets were analyzed to produce the first German checklist of Lumbricidae. The checklist comprises 46 earthworm species from 15 genera and provides ecological information, zoogeographical distribution type and information on the species distribution in Germany. Only one species, Lumbricus badensis Michaelsen, 1907, is endemic to Germany, whereas 41% are peregrine. As there are 14 species occurring exclusively in the southern or eastern part of Germany, the species numbers in German regions increase from north to south. PMID- 25283657 TI - A new species of Riama Gray, 1858 (Squamata: Gymnophthalmidae) from the Tropical Andes. AB - A new species of Riama lizard from the western slopes of the Andes in northern Ecuador is described herein. Morphologically, Riama yumborum sp. nov. can be distinguished from all other congenerics by having an incomplete nasoloreal suture and a cylindrical hemipenial body with diagonally orientated flounces on its lateral aspect. Phylogenetic analyses of mitochondrial and nuclear DNA support the monophyly of the new species and its sister taxon relationship with R. labionis, which occurs allopatrically. PMID- 25283658 TI - Two new deep-sea stalked barnacles, Arcoscalpellum epeeum sp. nov. and Gymnoscalpellum indopacificum sp. nov., from the Coral Sea, with descriptions of the penis in Gymnoscalpellum dwarf males. AB - The present study describes a new species of Arcoscalpellum Hoek, 1907, and a new species of Gymnoscalpellum Newman & Ross, 1971, collected by deep-sea expeditions led by the Museum national d'Histoire naturelle (Paris) in the Coral Sea off New Caledonia, Papua New Guinea (PNG), the Solomon Islands and Vanuatu. Arcoscalpellum epeeum sp. nov. differs from all described species of Arcoscalpellum by the presence of a long, sharp, sword-shaped carina, which extends beyond the apices of the terga by 1/3 to 1/4 of their length. The species is dioecious, with large females and dwarf males that are sac-like, lack shell plates and are housed in paired receptacles at the inner edges of the scutal plates. Arcoscalpellum epeeum sp. nov. was collected in the waters of New Caledonia and Vanuatu. Gymnoscalpellum indopacificum sp. nov. differs from the six currently described species of Gymnoscalpellum by having a very small inframedian latus and a branched upper latus. The species is dioecious, with large females and dwarf males, the latter composed of 4 shell plates and housed in paired receptacles at the inner edges of the scutal plates. The penis of the dwarf males of G. indopacificum sp. nov. is about 0.8 of the total length of the male and has five side branches extending out along its length. Gymnoscalpellum indopacificum sp. nov. is distributed in the waters of Papua New Guinea, the Solomon Islands and Vanuatu, and represents the first record of this genus in the Indo-Pacific region. PMID- 25283659 TI - Pratylenchus quasitereoides n. sp. from cereals in Western Australia. AB - Pratylenchus quasitereoides n. sp. is described from Western Australia. It is characterized by 2 external incisures in the head cuticle, 4 lateral incisures at mid body, stylet length 17 um to 19 um, V greater than 75%, PUS less than 2 body diameters long and crenate tail terminus. Molecular data confirm the separation of the new species from morphologically similar and sympatric congeners. The host range also differs from P. teres as well as the sympatric P. neglectus, P. thornei and P. penetrans. Reproduction rates on oat and lupin differed between the new species and P. neglectus. The species was originally described as P. teres, but the species concept of P. teres now encompasses a considerable range of different attributes spread over two described subspecies and three variant populations. The new species differs from all these subspecies and populations in at least two characters. It differs from all populations of P. teres teres most notably in having four rather than 6 lateral lines and a more posterior vulva. It differs from P. teres vandebergae in having a longer stylet and longer overlap of the intestine by the oesophageal glands. Characters which can be used under low magnification to separate the new species from the closest sympatric congeners (P. thornei and P. crenatus) are discussed. PMID- 25283660 TI - Scydmepitoxis gen. n., a new genus of Cyrtoscydmini (Coleoptera: Staphylinidae: Scydmaeninae) from Australia. AB - A new Australian genus of Cyrtoscydmini, Scydmepitoxis gen. n. with a single species S. paradoxa sp. n. is described from New South Wales. A remarkable character of the new genus is a deep sub-basal constriction of the pronotum. The morphology of Scydmepitoxis is described and illustrated in detail, and its diagnostic characters are discussed. Possible affinities with Sciacharis and Sciacharoides are suggested. PMID- 25283661 TI - A new species of genus Schizopelex McLachlan (Trichoptera, Sericostomatidae), from the southern Iberian Peninsula. AB - The West Palearctic genus Schizopelex McLachlan 1876 is represented by eleven recognized species. The center of its distribution area is in Turkey, where seven species have been reported (Malicky 2004; Sipahiler 2005, 2012; Olah 2010; Sipahiler & Pauls 2012). These 7 species are S. anatolica Schmid 1964, S. rhamnes Malicky 1976, S. sinopica Sipahiler 2012, S. yenicensis Sipahiler & Pauls 2012, S. boluensis Sipahiler 2012 (in Sipahiler & Pauls 2012), S. cachetica Martynov 1913a, S. pontica Martynov 1913b. Schizopelex cachetica and S. pontica have also been reported from the Caucasus and the Transcaucasia, respectively (Martynov 1913a, 1913b; Ivanov 2011). In addition, two species (S. huettingeri Malicky 1974 and S. persica Schmid 1964) are known from the Balkans and Iran, respectively. The two remaining species are distributed in the southwestern West Palearctic region (southwestern Europe): Schizopelex furcifera McLachlan 1880 has been reported from the northeastern Iberian Peninsula and the Pyrenees (Gonzalez et al. 1992; Martinez-Menendez & Gonzalez 2010); Schizopelex festiva (Rambur 1842) is distributed throughout most of the Iberian Peninsula and the Maghreb (Gonzalez et al. 1992; Gonzalez & Martinez 2011). In this paper is described and illustrated for the first time a new species of Schizopelex from the southern Iberian Peninsula. PMID- 25283662 TI - New records of Pauropoda (Myriapoda) with descriptions of new taxa. AB - Nine species new to science are described, five species in Pauropodidae: Allopauropus circulus n. sp. from France, Decapauropus extremus n. sp. from Mexico, D. pyriformis n. sp. from Italy, Stylopauropus laminatus n. sp. from Thailand, S. longus n. sp. from Siberia; one in Brachypauropodidae: Mojingapauropus biappendiculatus n. gen., n. sp. from Panama; one species in Eurypauropodidae Trachypauropus lusitanicus n. sp. from Portugal; and two species in Sphaeropauropodidae: Sphaeropauropus exilis n. sp. from Papua New Guinea and S. rotatilis n. sp. from China. Pauropoda are reported for the first time from New Guinea. New collecting sites are given for 69 species. PMID- 25283663 TI - A new species of Andinobates (Amphibia: Anura: Dendrobatidae) from west central Panama. AB - Dendrobatid frogs are among the best known anurans in the world, mainly due to their toxicity and associated bright colors. A recently described dendrobatid genus, Andinobates, comprises frogs distributed among the Colombian Andes and Panama. During field work in the Distrito de Donoso, Colon province, Panama, we found a poison frog that we here describe as a new species. The new species belongs to the A. minutus species group and is described herein as Andinobates geminisae sp. nov. This new species differs from all other members of the group by having uniformly orange smooth skin over the entire body and a distinctive male advertisement call. The new species is smaller than other colorful dendrobatids present in the area, such as Oophaga pumilio and O. vicentei. We also provide molecular phylogenetic analyses of mitochondrial DNA sequences of dendrobatids and summarize genetic distances among Andinobates species. Andinobates geminisae occurs in Caribbean versant rainforest on the westernmost edge of the known distribution of A. minutus, and represents the fourth species within this genus in Panama. This is vulnerable to habitat loss and excessive harvesting and requires immediate conservation plans to preserve this species with a restricted geographic range. PMID- 25283664 TI - Reconsidering the taxonomy of the Black-Faced Uacaris, Cacajao melanocephalus group (Mammalia: Pitheciidae), from the northern Amazon Basin. AB - The black-faced uacaris are a poorly known group of platyrrhine monkeys from the Rio Negro basin in northwestern Amazonia. Originally described as two distinct species-Cacajao melanocephalus (Humboldt 1812) and Cacajao ouakary (Spix 1823) from opposite banks of the Negro, they were treated as a single species until the end of the twentieth century, when molecular studies reconfirmed their status as true species. One of these studies not only nominated a third (northern) species, Cacajao ayresi Boubli et al. 2008, but also identified C. ouakary as a junior synonym of C. melanocephalus, resulting in the introduction of a new nomen, Cacajao hosomi Boubli et al. 2008. In the present study, additional evidence on morphological and zoogeographic variables is analyzed, which indicates that C. ouakary should be reinstated, and supports the nomination of a neotype of C. melanocephalus. The molecular and zoogeographic data on the species status of the ayresi form are also re-assessed, leading to the conclusion that, on the basis of the evidence available at the present time, this form should be considered a subspecies of C. melanocephalus. A new taxonomic arrangement is proposed, which recognizes two species, C. ouakary and C. melanocephalus, the latter with two subspecies, C. m. melanocephalus and C. m. ayresi. PMID- 25283665 TI - New synonymies and new records of Afrotropical and Madagascan Pentatominae (Hemiptera: Heteroptera: Pentatomidae). AB - The following new synonymies within the family Pentatomidae, subfamily Pentatominae, are established: Aesula Stal, 1876 = Pseudacrosternum Day, 1965, syn. nov. (Nezarini), Aesula viridissima (Signoret, 1861) = Aesula signoretiana Kirkaldy, 1909, syn. nov. = Pseudacrosternum cachani Day, 1965, syn. nov. = Pseudacrosternum cachani var. scutellatum Day, 1965, syn. nov., and Andocides vittaticeps (Stal, 1858) = Andocides vittaticeps var. viridescens Schumacher, 1913, syn. nov. Afrania brachyptera (Schaum, 1853), stat. restit., is restored as the oldest available name for that species, with Afrania wahlbergi Stal, 1854, syn. restit., being its junior synonym. Lectotype of Pentatoma viridissima Signoret, 1861 is designated, and lectotype designation of Pseudolerida incerta (Schouteden, 1909) is commented. The following new or confirmed state records are provided: Cappaeini: Leridella kenyensis Jeannel, 1913 (Cameroon), Paralerida bolivari (Schouteden, 1904) (Republic of the Congo, Uganda), P. niokana Linnavuori, 1982 (Uganda), Tripanda (Tripanda) dispar Schouteden, 1964 (Cameroon, Ghana, Liberia), T. (T.) horacekorum Kment & Jindra, 2009 (Cameroon, Guinea), T. (T.) jurickorum Kment & Jindra, 2009 (Gabon, Ivory Coast), T. (T.) longiceps (Villiers, 1967) (Democratic Republic of the Congo, Gabon), T. (T.) signitenens (Distant, 1898) (Democratic Republic of the Congo, Mozambique), T. (Tenerva) decorata (Jensen-Haarup, 1937) (Kenya, Oman, Tanzania); Carpocorini: Andocides vittaticeps (Angola); Diploxyini: Acoloba lanceolata (Fabricius, 1803) (Angola, Central African Republic, Zambia, Zimbabwe); Eysarcorini: Pseudolerida bitalensis Schouteden, 1958 (Cameroon), Pseudolerida incerta (Equatorial Guinea: Bioko Island, Tanzania, Uganda); Myrocheini: Humria bimaculicollis Linnavuori, 1975 (Botswana, Democratic Republic of the Congo, Guinea, Kenya, Mozambique, Namibia, South Africa, Zambia, Zimbabwe); Strachiini: Afrania brachyptera (Schaum, 1853) (Botswana, Democratic Republic of the Congo; Tanzania: Tanganyika, Zanzibar; Uganda). Variability of Tripanda jurickorum, Pseudolerida incerta and Humria bimaculicollis is discussed. PMID- 25283666 TI - New taxa and data for Neotropical Phalangopsidae (Orthoptera, Grylloidea). AB - New data are presented for Neotropical Phalangopsidae (Orthoptera, Grylloidea). Four new species are described, Luzara brevipennis Desutter-Grandcolas, n. sp., Miogryllodes hebardi Desutter-Grandcolas, n. sp., Aclella brevipennis Desutter Grandcolas, n. sp. and Aclella nova Desutter-Grandcolas, n. sp. Nine new recombinations are proposed: Lerneca digrediens (Otte, 2006) n. comb. (Amphiacusta), Lernecella erinys (Otte & Perez-Gelabert, 2009) n. comb. (Uvaroviella), Lernecella minor (Otte, 2006) n. comb. (Paraclodes), Lernecella mirabilis (Otte & Perez-Gelabert, 2009) n. comb. (Uvaroviella), Lernecella simlense (Otte & Perez-Gelabert, 2009) n. comb. (Uvaroviella), Miogryllodes diaphoros (Otte, 2006) n. comb. (Amphiacusta), Niquirana phyxelis (Otte, 2006) n. comb. (Luzara), Aclella troxalis (Otte, 2006) n. comb. (Selvacla), and Neoacla clandestina (Nischk and Otte, 2000) n. comb. (Hattersleya). The synonymy of Acla Hebard, 1928 with Aclodes Hebard, 1928 is confirmed and discussed, and Hattersleya Nischk & Otte, 2000 is newly synonymized with Neoacla Desutter, 1988. The diagnosis and/or description of several genera and species are completed. PMID- 25283667 TI - Species of Blepharicera Macquart from China with descriptions of two new species (Diptera: Blephariceridae). AB - Blepharicera asiatica (Brodsky, 1930) is newly recorded from China. Two species, Blepharicera hainana sp. nov. and B. hebeiensis sp. nov., are described as new to science. A key to the known species of the genus Blepharicera from China is presented. PMID- 25283668 TI - Two new species of Pleciobates (Hemiptera: Gerromorpha: Gerridae) from India, with a key to the species of Pleciobates. AB - Two new species of water striders in the genus Pleciobates are described from India and compared with allied species. Pleciobates bengalensis Jehamalar, Basu & Zettel sp. nov. is described from the Jalpaiguri District, West Bengal and Pleciobates expositus Jehamalar, Chandra & Zettel sp. nov. (Hemiptera: Gerridae) is described from the Dhubri District, Assam. A key to the species of Pleciobates and a distribution map of the species of Pleciobates from India are provided. For the first time the genitalia of Pleciobates females are described in detail. PMID- 25283669 TI - New World Stephanocampta (Hymenoptera: Mymaridae)--descriptions of a new species from Argentina and of the male of S. masoni . PMID- 25283670 TI - Carabus of Subgenus Cathoplius C.G. Thomson, 1875, with description of their life way, life-cycle and pre-imaginal morphology (Coleoptera: Carabidae) . AB - According to current taxonomy, Subgenus Cathoplius C.G. Thomson, 1875, within the Genus Carabus Linnaeus, 1758 (in the broad sense), includes two species: C. (Cathoplius) asperatus (Dejean, 1826), monotypic with a northern distribution, and the southern polytypic substitutive species C. (Cathoplius) stenocephalus Lucas, 1866. The authors describe the life-way, life-cycle and pre-imaginal characters of the taxa currently ascribed to Subgenus Cathoplius, with details never provided before. Cathoplius are ground beetles adapted to live in arid environments and extreme habitats such as sub-desert areas. All of them are strictly helicophagous, both during the pre-imaginal stages and as adults, and are localized in a narrow fringe along the Atlantic coast of northwestern Africa. Several data and observations on the eco-ethology of the different taxa, obtained both in field and in laboratory, are reported. The life-cycle of Cathoplius belongs to the winter breeding type, with an extremely high fecundity rate concentrated in a very short period of time, that has no similarity to any other Carabus species. Eggs, larvae and pupae of the different species and subspecies of Cathoplius are described and illustrated. Larval characters clearly place Subgenus Cathoplius into the lineage of Neocarabi, confirming it as a monophyletic and homogeneous assemblage. Hybridization trials between some taxa led to a reduced survival rate of the progeny, thus confirming their specific or subspecific differentiation as proposed by classical taxonomy. Furthermore, hybridization results suggest that C. (Cathoplius) stenocephalus aliai could be considered as a distinct species. Notes about the origin, biogeography and phylogeny of Cathoplius are also provided. PMID- 25283671 TI - New olenelloid trilobites from the Northwest Territories, Canada. AB - The Olenelloidea are a superfamily of early Cambrian trilobites, which have been the subject of several phylogenetic analyses and also used to address macroevolutionary questions regarding the nature and timing of the Cambrian radiation. The Sekwi Formation of the Mackenzie Mountains, Northwest Territories, Canada, has yielded numerous species from this clade, and here we present new information that expands on the diversity known from this biogeographically and biostratigraphically important region. In particular, we describe seven new species, (Olenellus baileyi, Mesonacis wileyi, Elliptocephala jaredi, Holmiella taurus, H. domackae, Mummaspis delgadoae, and Bristolia colberti). Also recovered are specimens of Elliptocephala logani, specimens that shared affinities with Olenellus clarki, O. getzi, O. fowleri, and Frizolenellus hanseni, and one partial specimen, which appears to be a new species of Bolbolenellus. PMID- 25283672 TI - The scale insects (Hemiptera: Coccoidea) of the Maltese Archipelago. AB - Past works on scale insects (Hemiptera: Coccoidea) from the Maltese Archipelago are reviewed. Based on the literature and contemporary collections, a total of 93 species of scale insects belonging to 12 scale insect families are here reported (Aclerdidae 1 species; Asterolecaniidae 4; Coccidae 17; Diaspididae 46; Eriococcidae 5; Kermesidae 1; Margarodidae 1; Micrococcidae 1; Monophlebidae 2; Pseudoccocidae 11; Putoidae 2 and Rhizoecidae 2). Of these, 17 species represent new distribution records. Ten species are excluded from the scale insect fauna of the Maltese Islands. Of the 93 species present, only 29 (31.18%) are probably indigenous and the rest (68.82%) represent established introductions from elsewhere. More than 65% of the indigenous species are typical Mediterranean in distribution, with a few species having a mainly European chorotype. A quarter of the established aliens originate from Eurasia, followed by an East Asian/ Oriental component (20.31%); European (14.06%); Neotropical (14.06%); cryptogenic (14.06%); African (7.81%) and Australasian (4.70%). Movement of live fruit trees and ornamental plants into the Maltese Archipelago from nearby countries is probably the main route for entry of alien scale insects into the country. Some possible future introductions are discussed. PMID- 25283673 TI - New Patagonian species of Liolaemus (Iguania: Liolaemidae) and novelty in the lepidosis of the southernmost lizard of the world: Liolaemus magellanicus. AB - We describe a new species within the genus Liolaemus from southeast Argentine Patagonia. This new taxon, Liolaemus yatel sp. nov., presents anatomical traits shared with the Liolaemus lineomaculatus section within the Liolaemus lineomaculatus group, especially the absence of precloacal pores in both sexes. However, Liolaemus yatel sp. nov. does not exhibit trifid dorsal scales, which is a diagnostic character of the L. lineomaculatus group. Moreover, this new species differs from other taxa of the L. lineomaculatus group in that dorsal and nuchal scales either completely lack keels or are slightly keeled. We also report, for the first time, the presence of trifid scales in Liolaemus magellanicus, another species included in the L. lineomaculatus section but constituting an independent lineage regarding the L. lineomaculatus group. The phenotypic traits of L. yatel sp. nov. and the presence of trifid scales in L. magellanicus provide additional information for the study of evolutionary relationships among the species of the L. lineomaculatus section, especially the establishment of their diagnostic character states. PMID- 25283674 TI - A new species of Catocala Schrank, 1802 (Lepidoptera: Noctuidae (sensu lato): Erebinae) from Kazakhstan. PMID- 25283675 TI - Three new species of Simulium (Nevermannia) (Diptera: Simuliidae) from Vietnam. AB - Three new species of black flies, Simulium (Nevermannia) langbiangense, S. (N.) phami, and S. (N.) bachmaense, are described on the basis of females, males, pupae and larvae collected in Vietnam. All three species are assigned to the Simulium feuerborni species-group of Simulium (Nevermannia). Simulium (N.) langbiangense sp. nov. is characterized by the female sensory vesicle with a large opening, and a short common basal stalk of the six pupal gill filaments, S. (N.) phami sp. nov. is most striking in having the pupal gill with five filaments, a character not reported in species of the S. feuerborni species group, and S. (N.) bachmaense sp. nov. is characterized by the female genital fork with a triangular lobe-like projection pointed posteromedially on each arm, and the small larval postgenal cleft. This represents the first record of the S. feuerborni species-group from Vietnam. PMID- 25283676 TI - A new species of Sybistroma Meigen (Diptera: Dolichopodidae) from the Middle East with a key to West-Palaearctic species of the genus. AB - A new species, Sybistroma occidasiatica sp. nov., from the Middle East is described. It is close to S. inornata (Loew, 1857), but is distinguished by its long arista-like antennal stylus (longer than postpedicel) and short apicoventral epandrial lobe of the hypopygium (much shorter than cercus). The new species is peculiar in comprising two phenotypes, which can be distinguished by the length ratio of 1st and 2nd articles of the antennal stylus. The following recombination is also proposed: Sybistroma caudata (Loew, 1859), comb. nov. (transferred from Gymnopternus Loew, 1857). A checklist of the 26 West Palaearctic species of the genus is compiled, as well as a key based mainly on male secondary sexual characters. The known distribution of Sybistroma Meigen, 1824, is discussed. PMID- 25283677 TI - Stalk-eyed wasps--review of a largely unnoticed group of morphologically bizarre chalcidoid wasps (Hymenoptera: Eurytomidae: Axima) . AB - Axima Walker is a small genus of Eurytomidae (Hymenoptera: Chalcidoidea) exclusive to the Western Hemisphere. Some species are distinctive in having stalked eyes and Axima sidi, sp. n. is described as the third stalk-eyed species based on a single female from Colombia. A key to facilitate species identification of stalk-eyed Axima is included. The only species of Axima for which host biology is known is a primary parasitoid of dwarf carpenter bees of the genus Ceratina Latreille (Apidae: Xylocopinae). A hypothesis about the possible function of stalked eyes in Axima as devices to assist the escape of adult wasps from hosts enclosed in the soft pith of plant stems is proposed. PMID- 25283678 TI - Two new species of Apobaetis Day, 1955 (Ephemeroptera: Baetidae) from Brazil. AB - Apobaetis Day, 1955 species are known for their small size and preference for sandy stream substrate. Species which possess such habitat preference commonly possess long and slender legs and claws, but, in Apobaetis, the length of the tarsal claw rarely is so long that it exceeds the length of tarsus, occurring only in two species: A. lakota McCafferty, 2000 from USA and A. hamadae Cruz, Boldrini & Salles, 2011 from Brazil. In the present study, two new species with tarsal claws that exceed the length of the tarsi are described: Apobaetis pucupi sp. nov. from southeast Brazil and Apobaetis kethepiali sp. nov. from northernmost Brazil. Additionally, a new key for nymphs of Apobaetis is proposed. PMID- 25283680 TI - Interpersonal problems, dependency, and self-criticism in major depressive disorder. AB - OBJECTIVES: The goal of the present research was the examination of overlap between 2 research traditions on interpersonal personality traits in major depression. We hypothesized that Blatt's (2004) dimensions of depressive experiences around the dimensions of relatedness (i.e., dependency) and self definition (i.e., self-criticism) are associated with specific interpersonal problems according to the interpersonal circumplex model (Leary, 1957). In addition, we examined correlations of interpersonal characteristics with depression severity. METHOD: Analyses were conducted on 283 patients with major depressive disorder combined from 2 samples. Of the patients, 151 participated in a randomized controlled trial in the United States, and 132 patients were recruited in an inpatient unit in Germany. Patients completed measures of symptomatic distress, interpersonal problems, and depressive experiences. RESULTS: Dependency was associated with more interpersonal problems related to low dominance and high affiliation, while self-criticism was associated with more interpersonal problems related to low affiliation. These associations were independent of depression severity. Self-criticism showed high overlap with cognitive symptoms of depression. CONCLUSION: The findings support the interpersonal nature of Blatt's dimensions of depressive experiences. Self criticism is associated with being too distant or cold toward others as well as greater depression severity, but is not related to the dimension of dominance. PMID- 25283681 TI - A review of the effects of formaldehyde release from endodontic materials. AB - Formaldehyde is present in most living cells and the environment. In dentistry, patients may be exposed to formaldehyde through the use of several endodontic materials (e.g. AH 26) and during formocresol pulpotomies. This review outlines how the human body reacts to formaldehyde exposure, how recent data has relooked at the issue of carcinogenicity and leukaemia associated with formaldehyde, and whether it is possible to quantify the amount of formaldehyde produced by endodontic cements. The review analyses the way formaldehyde is produced from epoxy resins and addresses the question of whether the amount of formaldehyde from endodontic cements is large enough to override the body's ability to deal with its own endogenous levels of formaldehyde and should the amount of formaldehyde produced be a concern. PMID- 25283683 TI - Breaking the odd-even effect in the self-assembly of linear bis(benzamides). AB - The twisting of supramolecular aggregates formed from simple linear bis(benzamides) has been investigated. The antiparallel arrangement of the amide functional groups controls the generation of twisted supramolecular structures. The results presented herein could contribute to elaborate predictive tools applicable in the generation of chiral supramolecular structures. PMID- 25283682 TI - Tumoral load quantification of positive sentinel lymph nodes in breast cancer to predict more than two involved nodes. AB - AIM: One-Step Nucleic Acid Amplification (OSNA) can detect isolated tumour loads in axillary lymph nodes of breast cancer patients. We investigated the predictability of the non-sentinel lymph node (SLN) metastatic involvement (MI) based on the OSNA SLN assessment in surgical invasive breast cancer. METHODS: We studied surgical breast invasive carcinoma patients, not taking neoadjuvant chemotherapy, having SLN positive by OSNA and having received axillary lymphadenectomy. Age, basic histopathological, immunohistochemical, SLN biopsy and lymphadenectomy data were compared between patients with or without MI of more than 2 non-SLN in both univariate and multivariate analyses. The discriminating capacity of the multivariate model was characterized by the ROC AUC. RESULTS: 726 patients from 23 centers in Spain aged 55.3 +/- 12.2 years were analysed. The univariate analysis comparing patients with or without MI of more than 2 non-SLN detected statistically significant differences in primary tumour size, multifocality, presence of lymphovascular infiltration, positive proliferation index with ki67, immunophenotype and logTTL (Tumour Total Load). The multivariate logistic analyses (OR (95% CI)) confirmed multifocality (2.16 (1.13-4.13), p = 0.019), lymphovascular infiltration (4.36 (2.43-7.82), p < 0.001) and logTTL (1.22 (1.10-1.35), p < 0.001) as independent predictors, and exhibit an AUC (95% CI) of 0.78 (0.72-0.83) with an overall fit (Hosmer-Lemeshow test) of 0.359. A change in the slope of both sensitivity and specificity is observed at about 10,000 copies/MUL, without relevant changes in the Negative Predictive Values. CONCLUSIONS: Using OSNA technique, the MI of more than 2 non SLN can be reliably predicted. PMID- 25283684 TI - Palladium-catalyzed cross-coupling of styrenes with aryl methyl ketones in ionic liquids: direct access to cyclopropanes. AB - The combined use of Pd(OAc)2 , Cu(OAc)2 , and dioxygen in molten tetrabutylammonium acetate (TBAA) promotes an unusual cyclopropanation reaction between aryl methyl ketones and styrenes. The process is a dehydrogenative cyclizing coupling that involves a twofold C?H activation at the alpha-position of the ketone. The substrate scope highlights the flexibility of the catalyst; a reaction mechanism is also proposed. PMID- 25283685 TI - Asperger syndrome in males over two decades: stability and predictors of diagnosis. AB - OBJECTIVE: To examine the diagnostic stability of a childhood diagnosis of Asperger Syndrome (AS) into adulthood in a prospective longitudinal study, and identify the predictors of stability. METHODS: One hundred males with AS diagnosed in childhood (T0) according to Gillberg's AS criteria, were followed up prospectively into adulthood over an average of 19 years (range 13-26 years). Fifty males (mean age 30 years) participated in this second follow-up (T2) of the cohort. Seventy-six had participated in a previous follow-up (T1) at mean age 22 years (47 participated in both follow-ups). Diagnosis at T2 was assessed using three sets of diagnostic criteria (Gillberg's AS criteria, DSM-IV Pervasive Developmental Disorder (PDD) and DSM-5 Autism Spectrum Disorder (ASD) criteria) and compared to previous assessments. Background predictors of diagnostic stability were analyzed. General functioning at T2 was assessed and compared to T1. RESULTS: There was a decline in the stability of AS diagnosis over time, the rate dropping from 82% at T1 to 44% at T2, when using the Gillberg criteria. There was also a significant decrease in the rate of cases fulfilling any PDD diagnosis according to the DSM-IV, from 91% at T1 to 76% at T2 in the 47 cases followed up twice. Severity of autism spectrum symptoms at T1 was the main predictor of diagnostic stability at T2. Twenty percent of those meeting criteria for a PDD diagnosis according to DSM-IV, did not meet DSM-5 ASD criteria although they had marked difficulties in everyday life. CONCLUSION: Asperger Syndrome, when considered as an ASD/PDD diagnosis, was fairly stable into adulthood, but there was a significant increase over time in cases no longer meeting criteria for an ASD diagnosis according to the DSM-IV, or AS according to the Gillberg criteria. Cases with a stable diagnosis showed significantly more core ASD symptoms in adolescence/young adulthood. PMID- 25283686 TI - Pacing and sensing interference by air bubble surrounding the non-extended helix of intact active fixation lead. AB - BACKGROUND: Active fixation pacing leads with silicon cylinder tips have been used for their safety and flexibility. Measurement of baseline sensing/pacing characteristics before fixation of helix helps to identify the optimal pacing site, but we encountered difficulties in making these measurements despite multiple attempts with the model LPA 1200M lead. To identify the cause and overcome this complication, we compared 4 different retractable active fixation lead models, which enabled baseline sensing/pacing measurements before extension of helix. METHODS AND RESULTS: We immersed 4 different lead tips and rings in a 0.18% saline solution, and measured the lead impedance before and after flushing of air bubble visible inside the lead tip. Before evacuation of the air bubble, the impedance of the model LPA 1200M lead was >4,000 Omega in 8 out of 10 measurements, although that of the other leads was within the measurable range. After evacuation of the air bubble, the lead impedance returned to within the measurable range. There was no prominent change in the impedance of the metal cylinder tip lead. CONCLUSIONS: Air bubbles may interfere with the measurement of baseline sensing/pacing characteristics before active fixation of pacing leads with cylindrical silicon tips. In the case of high impedance beyond the measurable range before extension of helix, the measurement should be repeated after fixation into the myocardium before suspecting lead dysfunction. PMID- 25283687 TI - Three-dimensional echocardiography-derived vena contracta area at rest and its increase during exercise predicts clinical outcome in mild-moderate functional mitral regurgitation. AB - BACKGROUND: This study assessed the independent significance of color Doppler 3-D vena contracta area (VCA) at rest and during exercise as a predictor of clinical outcome in mild-moderate functional mitral regurgitation (FMR). METHODS AND RESULTS: The subjects consisted of 62 patients (age, 68+/-11 years; 76% male) with chronic systolic heart failure and mild-moderate FMR (<2+/4) at rest. All patients underwent VCA assessment at rest and during semi-supine bicycle exercise. During median follow-up of 17 months (IQR, 13-20 months), 15 patients (24%) had composite endpoint of all-cause death (n=3), heart failure admission (n=11), and heart transplantation (n=1). At baseline, patients with vs. without endpoint had significantly larger VCA at rest (17+/-6 mm(2)vs. 13+/-7 mm(2), P=0.002) and at peak exercise (35+/-16 mm(2)vs. 21+/-12 mm(2), P<0.001). On Cox regression analysis, large (>=15-mm(2)) resting VCA (HR, 7.6; 95% CI: 1.93-13.02; P=0.004) and large (>=20-mm(2)) exercise-induced increase of VCA (HR, 5.1; 95% CI: 1.39-15.21; P=0.014) were independently associated with composite endpoint. Concomitant presence of large VCA at rest and its large increase during exercise occurred in 53% of patients with, vs. in only 8% without, endpoint (negative predictive value, 86%). CONCLUSIONS: The presence of relatively large VCA at rest and its significant increase during exercise is independently associated with adverse clinical outcome in patients with mild-moderate FMR at rest. PMID- 25283688 TI - Nkx2.5 is involved in myeloid cell differentiation at anterior ventral blood islands in the Xenopus embryo. AB - We have shown previously that two populations of myeloid cells emerge in the anterior and posterior ventral blood islands (aVBI and pVBI) at the different stages in Xenopus laevis embryo. In order to elucidate the regulatory mechanism of myeloid cell differentiation in the aVBI, we examined the role of Nkx2.5, an essential transcription factor for heart differentiation, in regulation of the myeloid cell differentiation in this region. Knockdown of endogenous Nkx2.5 by introducing MO into the dorsal marginal zone (DMZ) suppressed the expression of MHCalpha as well as that of mpo and spib in the resultant embryos and in DMZ explants made from the injected embryos. Expression of c/ebpalpha was less affected in the embryos injected with Nkx2.5 MO. The effect of Nkx2.5 MO in myeloid cell differentiation was recovered by coinjection of nkx2.5 or c/ebpalpha mRNA, indicating that Nkx2.5 functions at the same or the upper level of C/EBPalpha for the specification of myeloid cells. An attempt to identify transcription factors for myeloid cell differentiation in ventral marginal zone (VMZ) explants demonstrated that coinjection of two transcription factors out of three factors, namely C/EBPalpha, Nkx2.5 and GATA4, was sufficient to induce a certain amount of mpo expression. We suggest that C/EBPalpha is an unequivocal factor for myeloid cell differentiation in the aVBI and that Nkx2.5 and GATA4 cooperate with C/EBPalpha for promotion of myeloid cell differentiation. PMID- 25283690 TI - The impact of cellulose nanocrystals on the aggregation and initial adhesion of Pseudomonas fluorescens bacteria. AB - Deposition on silica surfaces of two Pseudomonas fluorescens strains (CHA0 and CHA19-WS) having different extracellular polymeric substance (EPS) producing capacities was studied in the absence and presence of cellulose nanocrystals (CNCs). Batch (batch soaking) and continuous flow (quartz crystal microbalance with dissipation) methods were used to evaluate the impact of CNCs on bacterial initial adhesion. This study demonstrated that bacterial initial adhesion to solid surfaces can be significantly hindered by CNCs using both methods. In the presence of CNCs, it was observed that bacteria with more EPS aggregated more significantly compared to bacteria with less EPS, and that bacterial deposition under this condition decreased to a greater extent. The classic DLVO theory failed to predict bacterial adhesion behavior in this study. A detailed discussion is provided regarding potential antibacterial adhesion mechanisms of CNCs. PMID- 25283689 TI - Residual ridge dimensions at edentulous maxillary first molar sites and periodontal bone loss among two ethnic cohorts seeking tooth replacement. AB - OBJECTIVES: To study residual ridge dimensions at edentulous first molar sites in relation to periodontal bone loss among cohorts of partially edentulous Asian Indian and Hong Kong Chinese subjects seeking tooth replacement. MATERIALS AND METHODS: A total of 628 edentulous maxillary first molar sites were analyzed on Cone Beam Computed Tomography scans of 225 Asian Indian (I) and 232 Hong Kong Chinese (C) partially edentulous adults seeking tooth replacement. Age, ethnicity, gender, total tooth loss, the presence or absence of adjacent teeth, categories of periodontal status defined according to radiographic alveolar bone loss (P0: periodontal health, P1: incipient to moderate disease, P2: severe periodontal disease) and sinus membrane abnormalities were noted. Alveolar ridge height (RH), widths at 1 and 3 mm from crest (RW1; RW3), and relative position of the bone crest (RR) were measured. RESULTS: Prevalence of P2 status was most frequent in both cohorts(C: 50.4% I: 49.2%). P2 had lowest ridge heights; 13.1% C P2 and 14%I P2 had RH < 2 mm. Sites with both RH <8 mm and RW1 < 6 mm occurred at 59%C P2 and 68%I P2. Sinus membrane abnormalities were most frequent in P2. Periodontal status and sinus membrane abnormality increased the odds of RH <5 mm and RH <8 mm more than 2-fold; additionally, gender and ethnicity significantly impacted RH <8 mm. Gender and adjacent tooth status significantly affected RW1. CONCLUSION: Incident advanced periodontal disease was common among Asian Indian and Hong Kong Chinese subjects seeking tooth replacement and associated with lower available bone heights. Ethnicity, gender, sinus membrane thickening affected available bone height in the subsinus region, while the presence of adjacent teeth- and age-affected residual ridge width. PMID- 25283691 TI - Changes in cellular and molecular components of peripheral blood in patients with generalized aggressive periodontitis. AB - AIM: The association between periodontitis and systemic health is evident; however, until recently, there has been a lack of scientific evidence to define the relationship between aggressive periodontitis and systemic conditions. The aim of the present study was to evaluate the changes in the white blood cell count and levels of serum proteins in patients with generalized aggressive periodontitis (GAP) and to compare it with periodontally-healthy controls. METHODS: Patients with GAP (n = 60) and periodontally-healthy controls (n = 60) were recruited. Clinical parameters, including probing depth and clinical attachment level, were examined. Blood cell variables, including leukocyte, neutrophil, and lymphocyte counts, and serum protein parameters, including total protein, albumin (ALB), globulin (GLB), ALB/GLB (A/G) ratio, and C-reactive protein levels, were analyzed. RESULTS: The results showed a statistically significant increase in neutrophil numbers and serum GLB and C-reactive protein levels in patients with GAP compared to the controls (P < 0.001), whereas the ALB level and A/G ratio were significantly lower compared to the control group. CONCLUSION: The results showed possible changes in the cellular and molecular components of peripheral blood in patients with GAP compared to periodontally healthy controls. These changes might represent the contribution of periodontal infections to systemic inflammation in relatively young individuals. PMID- 25283692 TI - Children adopted from Poland display a high risk of foetal alcohol spectrum disorders and some may go undiagnosed. AB - AIM: Children adopted from Central and Eastern Europe have often had negative early experiences, including prenatal exposure to alcohol. We examined a group of Polish children, adopted by Dutch parents, to see how many were diagnosed with foetal alcohol spectrum disorders (FASD) and to what extent features of FASD were present. METHODS: The 121 children, aged between 6 and 17 years, were adopted from Poland at a mean age of 3 years (standard deviation 1.6 years). Their parents answered a questionnaire regarding FASD diagnosis, growth, educational attainment and the Behaviour Rating Inventory of Executive Function. RESULTS: Three groups were identified: children with an FASD diagnosis (31%), children whose adoptive parents suspected FASD (21%) and children whose adoptive parents did not suspect FASD (49%). Growth deficiency, enrolment in special education and difficulties with executive functioning were most frequently observed in children diagnosed with FASD. However, features of FASD were also observed in the other two groups. CONCLUSION: Children adopted from Poland showed a high risk of FASD and some children may go undiagnosed. Adoptive parents and professionals need to be aware of the potential consequences of prenatal exposure to alcohol. PMID- 25283694 TI - Selective catalytic behavior of a phosphine-tagged metal-organic framework organocatalyst. AB - Steric hindrance by a metal-organic framework (MOF) is shown to influence the outcome of a catalytic reaction by controlling the orientation of its intermediates. This is demonstrated using an organocatalyst, phosphine MOF LSK-3, which is evaluated with the aid of molecular modeling and NMR spectroscopy techniques. This report is the first application of phosphine MOFs in organocatalysis and explores the potential of a framework steric hindrance to impose selectivity on a catalytic reaction. These findings expand the opportunities for control and design of the active site in the pocket of heterogeneous catalysts. PMID- 25283693 TI - Topical axitinib suppresses angiogenesis pathways induced by pulsed dye laser. AB - BACKGROUND: The recurrence of port-wine stain (PWS) blood vessels by pulsed dye laser (PDL)-induced angiogenesis is a critical barrier that must be overcome to achieve a better therapeutic outcome. OBJECTIVES: To determine whether PDL induced angiogenesis can be suppressed by topical axitinib. METHODS: The mRNA expression profiles of 86 angiogenic genes and phosphorylation levels of extracellular signal regulated kinases (ERKs), phosphorylated protein kinase B (AKT) and ribosomal protein S6 kinase (p70S6K) in rodent skin were examined with or without topical axitinib administration after PDL exposure. RESULTS: The PDL induced increased transcriptional levels of angiogenic genes peaked at days 3-7 post-PDL exposure. Topical application of 0.5% axitinib effectively suppressed the PDL-induced increase in mRNA levels of the examined angiogenic genes and activation of AKT, P70S6K and ERK from days 1 to 7 post-PDL exposure. After topical administration, axitinib penetrated into rodent skin to an approximate depth of 929.5 MUm. CONCLUSIONS: Topical application of 0.5% axitinib can systematically suppress the PDL-induced early stages of angiogenesis via inhibition of the AKT/mammalian target of rapamycin/p70S6K and Src homology 2 domain containing transforming protein-1/mitogen-activated protein kinase kinase/ERK pathway cascades. PMID- 25283695 TI - Teaching geriatrics using an innovative, individual-centered educational game: students and educators win. A proof-of-concept study. AB - Given the increasingly aging population, nearly every doctor will encounter elderly adults who present with multiple complex comorbidities that can challenge even experienced physicians. This may explain why many medical students do not have a positive attitude toward elderly adults and find the complexity of their problems overwhelming. It was hypothesized that a recently developed medical school geriatrics course, based on the game GeriatriX and designed specifically to address the complexities associated with decision-making in geriatrics, can have a positive effect on attitudes toward geriatrics and on perceived knowledge of geriatrics. The effects of this game-based course were evaluated as a proof of concept. The assessment was based on the Aging Semantic Differential (ASD) and a validated self-perceived knowledge scale of geriatric topics. The usability of (and satisfaction with) GeriatriX was also assessed using a 5-point Likert scale. After completion of the course, the ASD changed significantly in the geriatrics course group (n = 29; P = .02) but not in a control group that took a neuroscience course (n = 24; P = .30). Moreover, the geriatrics course group had a significant increase in self-perceived knowledge for 12 of the 18 topics (P = .002), whereas in the control group self-perceived knowledge increased significantly for one topic only (sensory impairment) (P = .04). Finally, the geriatrics students reported enjoying GeriatriX. This proof-of-concept study clearly supports the hypothesis that a 4-week course using a modern educational approach such as GeriatriX can improve students' self-perceived knowledge of geriatrics and their attitudes toward elderly adults. PMID- 25283696 TI - Postoperative atrial fibrillation prophylaxis after lung surgery: systematic review and meta-analysis. AB - BACKGROUND: Atrial fibrillation after thoracic surgery is frequent and increases morbidity and mortality. A number of trials have investigated medical prophylaxis for the prevention of atrial fibrillation after surgery for lung cancer. However, the literature is diverse and hence difficult to review. The aim of this study was to evaluate the safety and efficacy of reducing the risk of postoperative atrial fibrillation by the use of medical prophylaxis in patients undergoing surgery for lung cancer. METHODS: A systematic review and meta-analysis of randomized, controlled trials investigating prophylactic medical interventions to reduce the risk of postoperative atrial fibrillation was performed. RESULTS: A total number of 10 trials were identified. A significant reduction in the risk of postoperative atrial fibrillation was found with a relative risk of 0.53 (95% confidence interval, 0.42 to 0.67) and a number needed-to-treat of 8.5 (95% confidence interval, 6.4 to 13.3). Amiodarone was found to be the most effective prophylactic agent with a relative risk of 0.32 (95% confidence interval, 0.19 to 0.50) and a number needed-to-treat of 4.8 (95% confidence interval, 3.7 to 7.6) and regarded as safe, with no severe adverse events registered. The risk of atrial fibrillation was overall reduced from 25.1% to 13.4% (p < 0.001) and for amiodarone as a single therapy from 30.4% to 9.6% (p < 0.001). CONCLUSIONS: Medical prophylaxis with calcium-channel blockers, magnesium sulfate, or amiodarone significantly reduces the risk of developing atrial fibrillation after lung reduction surgery. However, amiodarone and magnesium sulfate were the most effective and safest drugs causing no increased risk of adverse events. PMID- 25283697 TI - Do withdrawal-like symptoms mediate increased marijuana smoking in individuals treated with venlafaxine-XR? AB - BACKGROUND AND AIMS: Cannabis-dependent participants with depressive disorder are less likely to achieve abstinence with venlafaxine-XR (VEN-XR) treatment. Individuals on VEN-XR reported more severe withdrawal, despite not reducing their smoking behavior. We hypothesized that withdrawal-like symptoms, likely medication side effects, led to continued marijuana smoking in this group. METHODS: We conducted a secondary analysis using Marijuana Withdrawal Checklist (MWC) scores and urine THC to test whether severity of withdrawal-like symptoms mediates the relationship between VEN-XR treatment and continued marijuana smoking. We included 103 participants (VEN-XR=51, Placebo=52). Marijuana use was dichotomized into smoking (THC>100 ng/ml) and non-smoking (THC <= 100 ng/ml) weeks. MWC scores were obtained weekly. We used three models in a regression based mediation analysis. RESULTS: The estimated risk of smoking marijuana was greater for individuals on VEN-XR in weeks 7-9, even when controlling for MWC scores (week 7 Risk Difference (RD)=0.11, p=0.034; week 8 RD=0.20, p=0.014), and higher scores mediated this effect. In weeks 10 and 11, the estimated effect was stronger (week 10 RD=0.03, p=0.380; week 11 RD=0.07, p=0.504), and worse withdrawal-like symptoms more fully accounted for continued marijuana smoking in the VEN-XR group, according to the models. CONCLUSIONS: Individuals treated with VEN-XR had more severe withdrawal-like symptoms, which mediated their continued marijuana smoking. Noradrenergic agents, such as VEN-XR, may negatively impact treatment outcomes in cannabis-dependent patients attempting to reduce or stop their use. PMID- 25283698 TI - Gastro-floating bilayer tablets for the sustained release of metformin and immediate release of pioglitazone: preparation and in vitro/in vivo evaluation. AB - Owing to the complementary mechanisms of action of metformin hydrochloride (MH) and pioglitazone hydrochloride (PG), combination therapy for type 2 diabetes mellitus using the two drugs is highly desired; on the other hand, MH is not well absorbed in lower gastrointestinal tract and has a short half-life, therefore compromising the therapeutic effects. Herein, the present study was to develop gastro-floating bilayer matrix tablets in which the two drugs were incorporated into two separate layers, aiming at sustaining MH release with enhanced absorption and achieving immediate release of PG. The tablets of the optimized formulation floated on the test medium for more than 24 h with 5 min of floating lag time, and sustained MH release for 12 h via a diffusion-dependent manner; and complete release of PG within 5 min were achieved. Moreover, a steady plasma concentration of MH with a 1.5-fold increase in bioavailability, decreased C(max) and reduced T(max) was obtained, and the in vivo behavior of PG was similar to the marked product. Summarily, sustained MH release with improved absorption and immediate release of PG were obtained simultaneously using the gastro-floating bilayer tablet, allowing strengthened combination therapy for diabetes mellitus. PMID- 25283699 TI - Injectable chitosan thermogels for sustained and localized delivery of pingyangmycin in vascular malformations. AB - Pingyangmycin (PYM) is an effective drug to treat vascular malformations (VM), but can easily diffuse from the injection site, which will reduce its therapeutic effect and increase side effect. Our study was to evaluate PYM-loaded chitosan thermogels for sustained and localized embolization therapy. It was shown that in vitro release of PYM thermogels could be delayed up to 12 days. The results measured by MTT assay showed that PYM thermogels could inhibit proliferation and induce apoptosis of EA.hy926 cells in a concentration and time dependent manner. In vivo pharmacokinetics study demonstrated that compared with PYM injections, PYM thermogels had a better sustained delivery of PYM. Macroscopic observation and histological examination of rabbit ear veins displayed that after administration with PYM thermogels for 18 days, obvious venous embolization and inflammatory response could be found. These results indicate that PYM thermogels is likely to achieve excellent prospects for VM treatment. PMID- 25283700 TI - The cell size distribution of tomato fruit can be changed by overexpression of CDKA1. AB - Tomato is one of the most cultivated vegetables in the world and an important ingredient of the human diet. Tomato breeders and growers face a continuous challenge of combining high quantity (production volume) with high quality (appearance, taste and perception for the consumers, processing quality for the processing industry). To improve the quality of tomato, it is important to understand the regulation of fruit development and of fruit cellular structure, which is in part determined by the sizes and numbers of cells within a tissue. The role of the cell cycle therein is poorly understood. Plant cyclin-dependent kinases (CDKs) are homologues of yeast cdc2, an important cell cycle regulator conserved throughout all eukaryotes. CDKA1 is constitutively expressed during the cell cycle and has dual functions in S- and M-phase progression. We have produced transgenic tomato plants with increased expression of CDKA1 under the control of the fruit-specific TPRP promoter, which despite a reduced number of seeds and diminished amount of jelly, developed fruits with weight and shape comparable to that of wild-type fruits. However, the phenotypic changes with regard to the pericarp thickness and placenta area were remarkable. Fruits of tomato plants with the highest expression of CDKA1 had larger septa and columella (placenta), compared with wild-type fruits. Our data demonstrate the possibility of manipulating the ratio between cell division and expansion by changing the expression of a key cell cycle regulator and probably its activity with substantial effects on structural traits of the harvested fruit. PMID- 25283701 TI - Editorial comment. PMID- 25283702 TI - Active surveillance of prostate cancer in African American men. AB - Active surveillance (AS) is a treatment strategy for prostate cancer (PCa) whereby patients diagnosed with PCa undergo ongoing characterization of their disease with the intent of avoiding radical treatment. Previously, AS has been demonstrated to be a reasonable option for men with low-risk PCa, but existing cohorts largely consist of Caucasian Americans. Because African Americans have a greater incidence, more aggressive, and potentially more lethal PCa than Caucasian Americans, it is unclear if AS is appropriate for African Americans. We performed a review of the available literature on AS with a focus on African Americans. PMID- 25283703 TI - Lingual mucosal graft in treatment of Peyronie disease. AB - OBJECTIVE: To evaluate the use of lingual mucosal graft (LMG) as a substitute for tunica albuginea in the treatment of Peyronie disease (PD). PATIENTS AND METHODS: Seventeen patients, reporting normal erectile function, with PD interfering with sexual function were operated on by plaque excision and grafting with LMG. Preoperative assessment included: the International Index of Erectile Function-5 score, penile duplex, and penile curvature angle measurement. Postoperative erectile function and penile deformity were assessed every 3 months for 9-18 months. RESULTS: Mean age of the patients was 52 (+/- 4.7) years and mean angle of deformity was 60 degrees (+/- 5.1). Donor site complications occurred in the form of mild transient swelling, numbness, and pain. Postoperative assessment showed complete penile straightening in 15 patients with mild curvature recurrence (<20 degrees ) in 2 patients at the third month. De novo mild erectile dysfunction was reported by 1 patient who responded to low-dose phosphodiesterase type 5 inhibitor. Patients' and partners' satisfaction was reported in 16 (94%) patients. These results remained stable until the end of the follow-up period. CONCLUSION: LMG seems to be a valuable substitute for tunica albuginea in cases of PD. It is readily available and shows early graft take. It also proved safety, reliability, feasibility, and a satisfactory short-term outcome for the treatment of PD. PMID- 25283704 TI - Reply: To PMID 25283701. PMID- 25283705 TI - Flexible ureterorenoscopy is safe and efficient for the treatment of kidney stones in patients with chronic kidney disease. AB - OBJECTIVE: To evaluate the outcomes of kidney stone treatment using flexible ureterorenoscopy (f-URS) among patients with chronic kidney disease (CKD). PATIENTS AND METHODS: Data of patients who underwent f-URS between January 2009 and December 2012 were collected. Patients were staged according to estimated glomerular filtration rate. Patients with stage >= 3 were accepted as having CKD (study group). These patients were matched with a group of patients without CKD (control group). Operative characteristics, complication rates, and third-month success rates were compared. RESULTS: Overall, 339 patients underwent f-URS and 62 (18.28%) had CKD. Control group constituted of 87 patients. Having a solitary kidney (17.4% vs 3.5%; P = .003) and history of stone intervention (51.6% vs 23%; P = .001) were more common in the CKD group. Similarly, access sheath was more commonly used among patients with CKD (87.1% vs 70.22%; P = .015). Both perioperative (19.35% vs 19.54; P = .372) and postoperative (22.6% vs 16.1%; P = .214) complication rates were similar in patients with and without CKD. Hospitalization time was 25.70 +/- 25.62 and 24.5 +/- 25 hours (P = .871) for patients with and without CKD, respectively. Although mean third postoperative estimated glomerular filtration rate of patients with CKD did not change significantly (48.16 +/- 8.72 vs 49.08 +/- 9.26; P = .431), CKD stage of 13 patients shifted from 3 to 2. At the third postoperative month, stone free rate in patients with and without CKD was 87.1% vs 86.2% (P = .875). CONCLUSION: f-URS is a safe and effective procedure in patients with CKD and it is associated with improved overall kidney function. PMID- 25283706 TI - Susceptibility to Klebsiella pneumonaie infection in collaborative cross mice is a complex trait controlled by at least three loci acting at different time points. AB - BACKGROUND: Klebsiella pneumoniae (Kp) is a bacterium causing severe pneumonia in immunocompromised hosts and is often associated with sepsis. With the rise of antibiotic resistant bacteria, there is a need for new effective and affordable control methods; understanding the genetic architecture of susceptibility to Kp will help in their development. We performed the first quantitative trait locus (QTL) mapping study of host susceptibility to Kp infection in immunocompetent Collaborative Cross mice (CC). We challenged 328 mice from 73 CC lines intraperitoneally with 104 colony forming units of Kp strain K2. Survival and body weight were monitored for 15 days post challenge. 48 of the CC lines were genotyped with 170,000 SNPs, with which we mapped QTLs. RESULTS: CC lines differed significantly (P < 0.05) in mean survival time, between 1 to 15 days post infection, and broad sense heritability was 0.45. Distinct QTL were mapped at specific time points during the challenge. A QTL on chromosome 4 was found only on day 2 post infection, and QTL on chromosomes 8 and 18, only on day 8. By using the sequence variations of the eight inbred strain founders of the CC to refine QTL localization we identify several candidate genes. CONCLUSION: Host susceptibility to Kp is a complex trait, controlled by multiple genetic factors that act sequentially during the course of infection. PMID- 25283707 TI - Autologous in vitro cultured vaginal tissue for vaginoplasty in women with Mayer Rokitansky-Kuster-Hauser syndrome: anatomic and functional results. AB - STUDY OBJECTIVE: To present the procedure and the results of a technique in which in vitro autologous cell cultures were used for the canal lining in patients with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) subjected to vaginoplasty with a modified Abbe-McIndoe technique. MRKHS is a rare anomaly characterized by vaginal agenesis with variable mullerian duct abnormalities. The Abbe-McIndoe procedure is 1 of the most frequent surgical treatments adopted in these women. In the last decades, several modifications have been introduced by different authors, mostly changing the lining material, but no consensus has been reached on what material should be used for the neovagina canal wall lining. DESIGN: A pilot study (Canadian Task Force classification II-1). SETTING: Policlinico Umberto I, "Sapienza" University of Rome. PATIENTS: A consecutive series of 23 women with MRKHS underwent neovaginoplasty with autologous vaginal tissue as the graft material between 2006 and 2013. INTERVENTIONS: Each patient with MRKHS was subjected to a full-thickness mucosal biopsy from the vaginal vestibule. After enzymatic dissociation, cells were inoculated onto collagen IV-coated plates and cultured for 2 to 3 weeks. The patients were subjected to vaginoplasty with a modified Abbe-McIndoe technique with autologous in vitro cultured vaginal tissue. Patients underwent clinical follow-up visits at 1, 3, 6, and 12 months after surgery and every year thereafter. Anatomic, functional, and sexual results were assessed. MEASUREMENTS AND MAIN RESULTS: In all cases, the vagina appeared normal in length and depth. A vaginal cytology and a vaginal biopsy obtained at the 3 month follow-up visit revealed physiological vaginal tissue. All 23 patients completed the Female Sexual Function Index questionnaire at 12 months after surgery. The results showed a total score of 27.2. These results indicate a satisfactory quality of sexual life. CONCLUSION: The modified Abbe-McIndoe technique with autologous vaginal tissue appears to be safe and feasible. This technique allows normal and satisfying sexual intercourse. Larger series with longer follow-ups will be necessary to confirm if this technique represents the ideal procedure for vaginal agenesis. PMID- 25283709 TI - Reversible photoswitching specifically responds to mercury(II) ions: the gated photochromism of bis(dithiazole)ethene. AB - Photoswitching of bis(dithiazole)ethene can be regulated by Hg(II) ions and EDTA in a "lock-and-unlock" manner. The molecular photoswitch provides an enzyme-like binding pocket that selectively binds specifically to mercury ions, thus modulating the degree of photoswitching in its presence. PMID- 25283708 TI - Intrauterine devices that do not fit well cause side effects, become embedded, or are expelled and can even perforate the uterine wall. PMID- 25283710 TI - Cycloadditions of cyclohexynes and cyclopentyne. AB - We report the strategic use of cyclohexyne and the more elusive intermediate, cyclopentyne, as a tool for the synthesis of new heterocyclic compounds. Experimental and computational studies of a 3-substituted cyclohexyne are also described. The observed regioselectivities are explained by the distortion/interaction model. PMID- 25283711 TI - Physiology of functional and effective networks in epilepsy. AB - Epilepsy is a network phenomenon characterized by atypical activity during seizure both at the level of single neurons and neural populations. The etiology of epilepsy is not completely understood but a common theme among proposed mechanisms is abnormal synchronization between neuronal populations. Recent advances in novel imaging and recording technologies have enabled the inference of comprehensive maps of both the anatomical and physiological inter relationships between brain regions. Clinical protocols established for diagnosis and treatment of epilepsy utilize both advanced neuroimaging techniques and neurophysiological data. These growing clinical datasets can be further exploited to better understand the complex connectivity patterns in the epileptic brain. In this article, we review results and insights gained from the growing body of research focused on epilepsy from a network perspective. In particular, we put an emphasis on two different notions of network connectivity: functional and effective; and studies investigating these notions in epilepsy are highlighted. We also discuss limitations and opportunities in data collection and analyses that will further our understanding of epileptic networks and the mechanisms of seizures. PMID- 25283713 TI - Biochemical characterization of the water-soluble squalene synthase from Methylococcus capsulatus and the functional analyses of its two DXXD(E)D motifs and the highly conserved aromatic amino acid residues. AB - Information regarding squalene synthases (SQSs) from prokaryotes is scarce. We aimed to characterize the SQS from Methylococcus capsulatus. We studied its reaction mechanism by kinetic analysis and evaluated the structure of the substrate/inhibitor-binding sites via homology modeling. The cloned M. capsulatus SQS was expressed in Escherichia coli and purified by nickel-nitrilotriacetic acid column chromatography. Interestingly, M. capsulatus SQS was water-soluble and did not require any detergent for its higher activity, unlike other SQSs studied previously; supplementation of any type of detergent inhibited enzyme activity. The specific activity and the kinetic values (Km and kcat ) for the substrate farnesyl diphosphate and NADPH are reported. The substrate analog farnesyl methylenediphosphonate showed potent inhibition toward the enzyme. We prepared the site-specific mutants directed at potential active-site residues (58) DXX(61) E(62) D (S1 site) and (213) DXX(216) D(217) D (S2 site), which were assumed to be involved in the binding of the substrate farnesyl diphosphate through the Mg(2+) ion. We first demonstrated that the S1 site and the two basic residues (R55 and K212) were responsible for the binding of farnesyl diphosphate. Furthermore, we examined the catalytic roles of the highly conserved aromatic residues and demonstrated that the Y164 residue abstracts the proton of cation 5, which is produced during the first half-reaction (Scheme 1), to afford presqualene diphosphate, and that the W224 residue stabilizes the intermediary cation 5 via the cation-pi interaction. Furthermore, we confirm for the first time that the F32 and the Y51 residues also stabilize the carbocation intermediate(s) generated during the second half-reaction. PMID- 25283712 TI - Timing of motor cortical stimulation during planar robotic training differentially impacts neuroplasticity in older adults. AB - OBJECTIVE: The objective was to determine how stimulation timing applied during reaching influenced neuroplasticity related to practice. Older adult participants were studied to increase relevance for stroke rehabilitation and aging. METHODS: Sixteen participants completed 3 sessions of a reaching intervention with 480 planar robotic movement trials. Sub-threshold, single-pulse transcranial magnetic stimulations (TMS) were delivered during the late reaction time (LRT) period, when muscle activity exceeded a threshold (EMG-triggered), or randomly. Assessments included motor evoked potentials (MEP), amplitude, and direction of supra-threshold TMS-evoked movements and were calculated as change scores from baseline. RESULTS: The direction of TMS-evoked movements significantly changed after reaching practice (p<0.05), but was not significantly different between conditions. Movement amplitude changes were significantly different between conditions (p<0.05), with significant increases following the LRT and random conditions. MEP for elbow extensors and flexors, and the shoulder muscle that opposed the practice movement were significantly different between conditions with positive changes following LRT, negative changes following EMG-triggered, and no changes following the random condition. Motor performance including movement time and peak velocity significantly improved following the training but did not differ between conditions. CONCLUSIONS: The responsiveness of the motor cortex to stimulation was affected positively by stimulation during the late motor response period and negatively during the early movement period, when stimulation was combined with robotic reach practice. SIGNIFICANCE: The sensitivity of the activated motor cortex to additional stimulation is highly dynamic. PMID- 25283714 TI - The ultraviolet A-activated photosensitizer 2-(4-aminophenyl)-7 methoxybenzothiazole suppresses proliferation and induces apoptosis of keloid fibroblasts: a potential adjunctive therapy for keloids. AB - BACKGROUND: Photodynamic therapy (PDT), a therapeutic approach employing a photosensitizer and a specific wavelength of light, is an emerging option for treating neoplastic and nonneoplastic diseases. Keloids are fibroproliferative dermal lesions characterized by the proliferation of fibroblasts. Recently, PDT has been demonstrated as a potential treatment for keloids. AIM: To investigate the effects of our newly synthesized photosensitizer 2-(4-aminophenyl)-7 methoxybenzothiazole (6d) plus ultraviolet (UV)A irradiation (6d-UVA) on proliferation and apoptosis in keloid fibroblasts (KFs). METHODS: Fibroblasts cultured from normal skin and keloids were treated with 6d-UVA. Relevant assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-bromo-2'-deoxyuridine incorporation assay, immunofluorescence assay and flow cytometry analysis were performed. RESULTS: The combination of 6d (2.0 or 5.0 MUmol/L) and UVA 0.5 J/cm(2) significantly decreased the viability and proliferation of KFs but not normal fibroblasts (NFs). Cell cycle analyses showed significant G0/G1 arrest and increased sub-G1 distribution in NFs induced by UVA activated 6d at 5.0 MUmol/L (hereafter referred to as 6d-UVA). This treatment also significantly induced generation of intracellular reactive oxygen species (ROS), loss of mitochondrial membrane potential (DeltaPsim), and increased expression of active caspase-3. Pretreatment with N-acetyl-L-cysteine (aROS scavenger) reversed the increased active caspase-3 expression induced by 6d-UVA, indicating the involvement of ROS in 6d-UVA-induced apoptosis. CONCLUSIONS: This study indicates that 6d-UVA treatment exerts antiproliferative and pro-apoptotic effects in KFs. We propose that 6d-UVA could be a potentially usefull ancillary method for keloid treatment. PMID- 25283716 TI - In Memory of Charles Anthony Walton, Ph.D., FCCP 1926-2014. PMID- 25283715 TI - Determinants of clinical improvement after surgical replacement or transcatheter aortic valve implantation for isolated aortic stenosis. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement (SAVR) in patients with aortic stenosis (AS) and high surgical risk. Hemodynamic performance after TAVI is superior, but the impact of reverse remodeling on clinical improvement is controversial. We aim to address the differences in hemodynamic changes between SAVR and TAVI, and its correlation with LV remodeling and clinical improvement at 6 months follow-up. METHODS: Forty-two patients treated by TAVI were compared with 45 SAVR patients with a stented bioprosthesis. Clinical, 2D and 3D echocardiographic data were prospectively obtained before and six months after intervention. RESULTS: Patients had similar distribution for sex, body surface area and AS severity. TAVI patients were older, more symptomatic and had more comorbidities. They also had higher LV filling pressures, larger 3D indexed left atrium volume, but similar 3D indexed LV mass. At 6 months, TAVI patients had greater clinical improvement and higher effective orifice area index (EAOI), but only SAVR patients already had a significant decrease in 3D indexed LV mass and diastolic volume. In univariate analysis older age, NYHA class >= III, increase in EAOI and TAVI were related with functional class improvement. After multivariate analysis only NYHA class >= III (OR 8.81, CI:2.13-36.52; p=0.003) and an increase in EAOI >= 105% (OR 3.87, CI:1.02-14.70; p=0.04) were predictors of clinical improvement. CONCLUSIONS: At 6 months, functional class improvement was greater after TAVI. Higher initial NYHA class and an increase in EAOI >= 105% were independently associated with functional enhancement. It is debatable if left ventricular remodeling is determinant for functional class improvement. PMID- 25283718 TI - Functional characterization of a cadmium resistance operon in Staphylococcus aureus ATCC12600: CadC does not function as a repressor. AB - Sequencing of a cadmium resistance operon from a Staphylococcus aureus ATCC12600 plasmid revealed that it is identical to a cadCA operon found in MRSA strains. Compared to plasmid-cured and cadC-mutant strains, cadC-positive ATCC12600 cells had increased resistance to cadmium (1 mg ml(-1) cadmium sulfate) and zinc (4 mg ml(-1) zinc sulfate), but not to other metal ions. After growth in media containing 20 ug ml(-1) cadmium sulfate, cadC-mutant cells contained more intracellular cadmium than cadC-positive ATCC12600 cells, suggesting that cadC absence results in impaired cadmium efflux. Electrophoretic mobility shift assays were performed with CadC proteins encoded by the S. aureus ATCC12600 plasmid and by the cadC gene of pI258, which is known to act as a transcriptional repressor and shares only 47% protein sequence identity with ATCC12600 CadC. Mobility shifts occurred when pI258 CadC protein was incubated with the promoter DNA regions from the pI258 and S. aureus ATCC12600 cadCA operons, but did not occur with S. aureus ATCC12600 CadC protein, indicating that the ATCC12600 CadC protein does not interact with promoter region DNA. This cadCA operon, found in MRSA strains and previously functionally uncharacterized, increases resistance to cadmium and zinc by an efflux mechanism, and CadC does not function as a transcriptional repressor. PMID- 25283719 TI - Autoantibodies to neurofascin-186 and gliomedin in multifocal motor neuropathy. AB - We tested autoantibodies to neurofascin-186 (NF186) and gliomedin in sera from patients with multifocal motor neuropathy (MMN, n=53) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=95) by ELISA. IgG antibodies to NF186 or gliomedin were found in 62% of MMN and 1% of CIDP sera, and IgM antibodies to the same antigens in 12% of MMN and 1% of CIDP sera. These autoantibodies activated complement. Ten percent of the MMN sera without IgM anti-GM1 reactivity had anti NF186 antibodies. Because NF186 and gliomedin play a crucial role for salutatory conduction, the autoantibodies may contribute to produce motor nerve conduction block and muscle weakness in MMN. PMID- 25283720 TI - Synthesis and characterization of highly crystalline graphene aerogels. AB - Aerogels are used in a broad range of scientific and industrial applications due to their large surface areas, ultrafine pore sizes, and extremely low densities. Recently, a large number of reports have described graphene aerogels based on the reduction of graphene oxide (GO). Though these GO-based aerogels represent a considerable advance relative to traditional carbon aerogels, they remain significantly inferior to individual graphene sheets due to their poor crystallinity. Here, we report a straightforward method to synthesize highly crystalline GO-based graphene aerogels via high-temperature processing common in commercial graphite production. The crystallization of the graphene aerogels versus annealing temperature is characterized using Raman and X-ray absorption spectroscopy, X-ray diffraction, and electron microscopy. Nitrogen porosimetry shows that the highly crystalline graphene macrostructure maintains a high surface area and ultrafine pore size. Because of their enhanced crystallinity, these graphene aerogels exhibit a ~ 200 degrees C improvement in oxidation temperature and an order of magnitude increase in electrical conductivity. PMID- 25283721 TI - Subgingival bacterial recolonization after scaling and root planing in smokers with chronic periodontitis. AB - BACKGROUND: The aim of this study was to compare subgingival bacterial recolonization patterns after scaling and root planing in current smokers and non smokers. METHODS: 15 smokers and 15 non-smokers with chronic periodontitis received scaling and root planing in six visits lasting one hour each, over a period of 21 days. Clinical monitoring was performed at baseline and 180 days, and microbiological monitoring was performed at baseline, immediately after scaling and root planing (Day 0) and at 42, 63 and 180 days post-therapy. Subgingival plaque samples were analysed by checkerboard DNA-DNA hybridization. RESULTS: An improvement in clinical condition was observed for smokers and non smokers; however, non-smokers showed a greater reduction in mean clinical attachment level in intermediate sites in comparison with smokers (p < 0.05). At Day 0, there was a significant reduction in the mean counts of the three pathogens from the red complex, Eubacterium nodatum and Parvimonas micra only in non-smokers (p < 0.05). There was a significant increase in the proportion of host-compatible species in non-smokers and smokers from baseline to 180 days post therapy (p < 0.05). However, a significant decrease in the pathogenic species was observed only in non-smokers. CONCLUSIONS: Smokers were more susceptible to the re-establishment of a pathogenic subgingival biofilm than non-smokers. PMID- 25283722 TI - Traumatic carotid-cavernous fistula in a multiple facial fractures patient: case report and literature review. AB - Carotid-cavernous fistula (CCF) is a pathologic communication between internal carotid artery (ICA) and cavernous sinus (CS). CCF occurs most commonly in association with craniofacial trauma. Traumatic CCFs are very rare, occurring in 0.17-0.27% of craniomaxillofacial trauma cases. We present a case of the patient treated for multiple facial fractures, who developed symptoms of CCF with several days latency and was successfully treated by endovascular occlusion of ICA. Anatomy of CS, pathophysiology of CCFs and treatment options are concisely reviewed. PMID- 25283723 TI - How to train your Bayesian: a problem-representation transfer rather than a format-representation shift explains training effects. AB - People improve their Bayesian reasoning most when they are trained to represent single-event probabilities as natural frequencies; nevertheless, the underlying mechanism of this representational training remains unclear. Several authors suggested that people learn to shift the initial format to natural frequencies, and improve their reasoning because natural frequencies align with an evolutionary designed frequency-coding mechanism--the format-representation shift hypothesis. Alternatively, people may acquire a generic problem representation in terms of nested sets that is then transferred to similar problems--the problem representation transfer hypothesis. To disentangle the effect of the format shift from problem representation transfer, we devised two types of training with problems featuring a nonfrequency format and a concealed nested-sets structure. Participants learnt the adequate problem representation in both training manipulations, but in only one did they learn, in addition, to shift the format to frequencies. Substantial evidence (BF01 = 5, where BF = Bayes factor) indicates that both types of training improved reasoning in an immediate and a one-week follow-up posttest to the same extent. Such findings support the problem representation transfer hypothesis because learning an adequate nested-sets problem representation accounts for the performance improvement, whereas the frequency format per se confers no additional benefit. We discuss the implications of these findings for two dominant accounts of statistical reasoning. PMID- 25283724 TI - Aeromonas hydrophila produces conductive nanowires. AB - Aeromonas hydrophila is a facultative anaerobe which, under conditions of oxygen depletion, uses Fe(III) as electron acceptor. A. hydrophila produces pili during growth with Fe(III). The study was focused on the characterization of the morphology, the electrical properties and the nature of the bacterial pili. Scanning electron microscopy and conductive-probe atomic force microscopy revealed the presence of filaments between cells and substrate and their conductive nature. Our results indicate that pili of A. hydrophila strain A might serve as biological nanowires, transferring electrons from the cell surface to the surface of Fe(III) oxides and, in addition, the possibility of playing a role in inter/intra species signaling. Quorum sensing (QS) is recognized as one of the main regulatory ways for extracellular polymeric substances (EPS) production and biofilm formation. We present evidence that nanowire formation can be regulated by addition of synthetic acyl-homoserine lactones (AHL). These conductive pili may be involved in various interactions, and their protein components might be usable in the future for biotechnological approaches in materials science. PMID- 25283725 TI - A C-terminal truncated mutation of licC attenuates the virulence of Streptococcus pneumoniae. AB - LicC has been identified as a virulence factor of Streptococcus pneumoniae. However, its role in virulence is still not fully understood because deletion of licC is lethal for the bacterium. In this study, a mutant with 78-bp truncation at the C-terminus of licC was obtained from a signature-tagged mutagenesis (STM) library. The mutant was viable with a large reduction in enzymatic activity as CTP:phosphocholine cytidylyltransferase detected in vitro using a firefly luciferase assay. The mutation attenuated the adhesion and invasion of S. pneumoniae ST556 (serotype 19F) to epithelial cells by 72% and 80%, respectively, and increased the phagocytosis by macrophages for 16.5%, compared to the parental strain. When the mutation was introduced into the encapsulated D39 strain (serotype 2), it led to attenuated virulence in mouse models either by intranasal colonization or by intraperitoneal infection. In addition, the phosphocholine (PCho) on cell surface was decreased, and the choline binding proteins (CBPs) were impaired, which may explain the attenuated virulence of the mutant. These observations indicate that C-terminus of licC is accounted for the main activity of LicC in PCho metabolism and is essential for the virulence of S. pneumoniae, which provides a novel target for drug design against pneumococcal infection. PMID- 25283726 TI - Antibiotic resistance differentiates Echinacea purpurea endophytic bacterial communities with respect to plant organs. AB - Recent findings have shown that antibiotic resistance is widespread in multiple environments and multicellular organisms, as plants, harboring rich and complex bacterial communities, could be hot spot for emergence of antibiotic resistances as a response to bioactive molecules production by members of the same community. Here, we investigated a panel of 137 bacterial isolates present in different organs of the medicinal plant Echinacea purpurea, aiming to evaluate if different plant organs harbor strains with different antibiotic resistance profiles, implying then the presence of different biological interactions in the communities inhabiting different plant organs. Data obtained showed a large antibiotic resistance variability among strains, which was strongly related to the different plant organs (26% of total variance, P < 0.0001). Interestingly this uneven antibiotic resistance pattern was present also when a single genus (Pseudomonas), ubiquitous in all organs, was analyzed and no correlation of antibiotic resistance pattern with genomic relatedness among strains was found. In conclusion, we speculate that antibiotic resistance patterns are tightly linked to the type of plant organ under investigation, suggesting the presence of differential forms of biological interaction in stem/leaves, roots and rhizosphere. PMID- 25283727 TI - Characterization and complete genome sequence of a novel N4-like bacteriophage, pSb-1 infecting Shigella boydii. AB - Shigellosis is one of major foodborne pathogens in both developed and developing countries. Although antibiotic therapy is considered an effective treatment for shigellosis, the imprudent use of antibiotics has led to the increase of multiple antibiotic-resistant Shigella species globally. In this study, we isolated a virulent Podoviridae bacteriophage (phage), pSb-1, that infects Shigella boydii. One-step growth analysis revealed that this phage has a short latent period (15 min) and a large burst size (152.63 PFU/cell), indicating that pSb-1 has good host infectivity and effective lytic activity. The double-stranded DNA genome of pSb-1 is composed of 71,629 bp with a G + C content of 42.74%. The genome encodes 103 putative ORFs, 9 putative promoters, 21 transcriptional terminators, and one tRNA region. Genome sequence analysis of pSb-1 and comparative analysis with the homologous phage EC1-UPM, N4-like phage revealed that there is a high degree of similarity (94%, nucleotide sequence identity) between pSb-1 and EC1-UPM in 73 of the 103 ORFs of pSb-1. The results of this investigation indicate that pSb-1 is a novel virulent N4-like phage infecting S. boydii and that this phage might have potential uses against shigellosis. PMID- 25283729 TI - Retraction: The Predictors of the Job Stress among Female Married Hospital Nurses. AB - This article has been retracted by the Editorial Board of INDUSTRIAL HEALTH due to violation of our publishing policies and procedures as of September 26, 2014. PMID- 25283730 TI - Endothelin-1 expression and alterations of cerebral microcirculation after experimental subarachnoid hemorrhage. AB - INTRODUCTION: Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) often leads to poor outcomes in SAH patients. Overexpression of endothelin-1 (ET-1) could contribute to the development of CVS. The purpose of this study was to investigate cerebral microcirculation by whole-brain perfusion CT scan and ET-1 expression following SAH. METHODS: SAH was induced in rabbits. Cerebral blood flow (CBF), cerebral blood volume (CBV), time to peak (TTP), and mean transit time (MTT) were measured with CT perfusion techniques at days 1, 4, 7, and 14 following SAH. Expression of ET-1 was determined by ELISA accordingly. Histological sections of the brain tissue were also examined. RESULTS: Whole brain perfusion showed that CBV and TTP increased at day 4 and maintained elevated rate until day 14. MTT increased at day 4, peaked at day 7, and then decreased at day 14. CBV of the occipital lobe was greater than that in the frontal and parietal lobes at day 4. CBF of the occipital lobe increased significantly compared to that of other lobes at day 7. ET-1 expression in the SAH group was significantly greater than that in the control at various time points. Moreover, ET-1 levels were positively correlated with MTT value. CONCLUSION: CTP detects changes in cerebral microcirculation following SAH. Microcirculation of each lobe was different and could be quantified to identify high-risk areas of cerebral ischemia. ET-1 expression was significantly increased and was correlated with MTT as well, suggesting that ET-1 influences cerebral microcirculation following SAH. PMID- 25283728 TI - Clostridium perfringens type A-E toxin plasmids. AB - Clostridium perfringens relies upon plasmid-encoded toxin genes to cause intestinal infections. These toxin genes are associated with insertion sequences that may facilitate their mobilization and transfer, giving rise to new toxin plasmids with common backbones. Most toxin plasmids carry a transfer of clostridial plasmids locus mediating conjugation, which likely explains the presence of similar toxin plasmids in otherwise unrelated C. perfringens strains. The association of many toxin genes with insertion sequences and conjugative plasmids provides virulence flexibility when causing intestinal infections. However, incompatibility issues apparently limit the number of toxin plasmids maintained by a single cell. PMID- 25283731 TI - Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass. AB - BACKGROUND: Reliable methods that allow appropriate triage of women with an adnexal mass to a gynecologic oncologist are needed. We evaluated the clinical performance of OVA1 and ROMA for the prediction of malignancy in women with an adnexal mass. METHODS: One hundred forty-six prospectively collected serum samples were collected from women with an adnexal mass, 31 of whom had surgically confirmed malignancies. OVA1 and ROMA tests were performed on all samples. Receiver operating characteristic curve analysis was used to determine interpretive cutoffs for ROMA. Performance characteristics of both tests were determined and compared. RESULTS: The sensitivity of OVA1 and ROMA was 97% and 87%, respectively (p=0.25). ROMA was more specific than OVA1 (83% vs. 55%, respectively; p<0.0001). The negative predictive values of both tests were similar (98.4% and 96.0%, respectively). ROMA performed on all patients identified as high risk by OVA1 (a sequential strategy) produced a positive predictive value of 69%. CONCLUSIONS: OVA1 and ROMA have similar performance characteristics, with OVA1 having non-significant greater diagnostic sensitivity and ROMA having greater diagnostic specificity. The use of these tests to appropriately triage women with an adnexal mass should be gauged within the context of their respective limitations. A sequential testing strategy may improve overall performance. PMID- 25283733 TI - Achievements in uranium alkyl chemistry: celebrating sixty years of synthetic pursuits. AB - Organouranium complexes containing uranium-carbon sigma-bonds have been highly sought after since the initial exploration of these complexes during the 1950s. Since this time, a variety of uranium starting materials have been developed and alkylating reagents used in order to generate such species. Trivalent uranium alkyl compounds have recently moved past using the bis(trimethylsilyl)methyl ligand with the use of larger ancillary hydrotris(pyrazolyl)borate ligands. The uranium(iv) congeners are dominated by cyclopentadienyl ligands, but recent developments have shown that amides, alkoxides, and phosphines are also suitable ligand frameworks for supporting such species. A family of uranium(iv) alkyls formed via cyclometallation and neutral homoleptics have also been described. Highly reactive uranium(v) and (vi) alkyl complexes have recently been synthesized at low temperatures. The representative studies highlighted herein have helped to pioneer the field of organouranium alkyl chemistry. PMID- 25283732 TI - Angiographic coronary artery disease and high-sensitivity troponin-T in a native Pakistani cohort presenting with chronic chest pain. AB - OBJECTIVE: To determine the relationship between troponin-T levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease (CVD) risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and troponin-T levels. Coronary atheroma burden was quantified by Gensini score. RESULTS: Clinically significant elevated troponin-T levels (> 30 pmol/l) were found in 40 patients (10%) with equal numbers in groups selected with or without angiographic disease. Troponin-T elevation (> 13 pmol/l) was present in 59 vs. 47 patients (30% vs. 24%; p = 0.04). Troponin-T levels did not correlate with any measured demographical, environmental, drug therapy or biochemical risk factor. No difference was found in concentrations of lipids, apolipoproteins, insulin resistance, C-reactive protein or sialic acid in cohorts stratified by troponin-T concentrations. In univariate analysis comparing patients with high (> 30 pmol/l) and low troponin-T levels (< 13 pmol/l) higher plasma total protein (91 g/l vs. 85 g/l; p = 0.01), increased immunoglobulin levels (41 g/l vs. 36 g/l; p = 0.02) and prevalence of hyperparathyroidism (40% vs. 21%; p = 0.04) were associated with higher troponin-T concentrations. CONCLUSIONS: This study shows that measurement of troponin-T is not an alternative to imaging in an Indian asian population, but that it does identify a separate potentially high-risk population that would not be identified by the use of imaging alone which is potentially at higher risk of CVD events. PMID- 25283734 TI - Multiple invasion mechanisms and different intracellular Behaviors: a new vision of Salmonella-host cell interaction. AB - Salmonella is a facultative intracellular bacterium found within a variety of phagocytic and nonphagocytic cells in vitro and in vivo For decades, it has been accepted that Salmonella can enter cells only through a Trigger mechanism mediated by a type three secretion system, called T3SS-1. However, recent researches have shown that this bacterium can use other invasion pathways mediating either Trigger or Zipper entry processes. Following eukaryotic cell invasion, Salmonella has to ensure its survival and proliferation within host cells. To do so, this bacterium resides either within a membrane-bound vacuole or freely within host cell cytosol. It is not clear why Salmonella has developed these alternate mechanisms for cell invasion and proliferation, but this provides a new insight into the mechanisms leading to Salmonella-induced diseases. Thus, the aim of this review is to show the evolution of Salmonella-host cell interaction paradigms by summarizing the different strategies used by Salmonella serotypes to invade and proliferate into eukaryotic cells. PMID- 25283735 TI - Message from editor-in-chief. PMID- 25283737 TI - Recommended surgery of Kaposi's sarcoma nodules. AB - BACKGROUND: Classic Kaposi's sarcoma [KS] is a chronic, multifocal, vascular proliferation, which commonly presents purplish nodules on the distal extremities of elderly men. Excisional surgery is one of the traditional therapies, but is generally time consuming and costly. OBJECTIVE: To evaluate the safety and efficacy of curettage for the treatment of KS nodules. METHODS: A single arm, prospective study in patients with at least one KS nodule removed by curettage. Hemostasis was obtained using 130-volume hydrogen peroxide [H2O2] and the wound was left to heal by secondary intention. Follow-up was done after 15 days, 1, 3, 6 and 12 months. RESULTS: Ninety patients [88 male, 2 female] with mean age of 75.8 years were enrolled. Eighty-two of the curetted nodules were localized on the lower limbs, five on the face, and three on the upper limbs. No postoperative complications were encountered, and cosmetic outcome was rated excellent by 87 patients and good by the remaining 3 patients. After 3 months, we noticed only minimal hypo-/hyperpigmentation in 59 cases, while in the remaining 31 patients the scar appeared imperceptible. Recurrence after 12 months was null. CONCLUSION: Curettage followed by the application of H2O2 is a safe, effective and simple technique for the treatment of KS nodules in elderly patients. PMID- 25283738 TI - Synthesis and mesomorphic properties of novel dibenz[a,c]anthracenedicarboximides. AB - The synthesis and characterization of a novel series of dibenz[a,c]anthracenedicarboximides is reported. Incorporating electron withdrawing imides bearing flexible alkyl chains allowed for the production of materials that self-assemble into hexagonal columnar mesophases featuring broad temperature ranges. Furthermore, longer N-alkyl chains or branched N-alkyl chains broaden the mesophase temperature range by lowering the melting transition without greatly influencing the clearing point. PMID- 25283736 TI - Large-scale introduction of the Indo-Pacific damselfish Abudefduf vaigiensis into Hawai'i promotes genetic swamping of the endemic congener A. abdominalis. AB - Hybridization in the ocean was once considered rare, a process prohibited by the rapid evolution of intrinsic reproductive barriers in a high-dispersal medium. However, recent genetic surveys have prompted a reappraisal of marine hybridization as an important demographic and evolutionary process. The Hawaiian Archipelago offers an unusual case history in this arena, due to the recent arrival of the widely distributed Indo-Pacific sergeant (Abudefduf vaigiensis), which is hybridizing with the endemic congener, A. abdominalis. Surveys of mtDNA and three nuclear loci across Hawai'i (N = 396, Abudefduf abdominalis and N = 314, A. vaigiensis) reveal that hybridization is significantly higher in the human-perturbed southeast archipelago (19.8%), tapering off to 5.9% in the pristine northwest archipelago. While densities of the two species varied throughout Hawai'i, hybridization was highest in regions with similar species densities, contradicting the generalization that the rarity of one species promotes interspecific mating. Our finding of later generation hybrids throughout the archipelago invokes the possibility of genetic swamping of the endemic species. Exaptation, an adaptation with unintended consequences, may explain these findings: the endemic species has transient yellow coloration during reproduction, whereas the introduced species has yellow coloration continuously as adults, in effect a permanent signal of reproductive receptivity. Haplotype diversity is higher in Hawaiian A. vaigiensis than in our samples from the native range, indicating large-scale colonization almost certainly facilitated by the historically recent surge of marine debris. In this chain of events, marine debris promotes colonization, exaptation promotes hybridization, and introgression invokes the possible collapse of an endemic species. PMID- 25283739 TI - Surface 12 lead electrocardiogram recordings using smart phone technology. AB - IMPORTANCE: AliveCor ECG is an FDA approved ambulatory cardiac rhythm monitor that records a single channel (lead I) ECG rhythm strip using an iPhone. In the past few years, the use of smartphones and tablets with health related applications has significantly proliferated. OBJECTIVE: In this initial feasibility trial, we attempted to reproduce the 12 lead ECG using the bipolar arrangement of the AliveCor monitor coupled to smart phone technology. METHODS: We used the AliveCor heart monitor coupled with an iPhone cellular phone and the AliveECG application (APP) in 5 individuals. RESULTS: In our 5 individuals, recordings from both a standard 12 lead ECG and the AliveCor generated 12 lead ECG had the same interpretation. CONCLUSIONS: This study demonstrates the feasibility of creating a 12 lead ECG with a smart phone. The validity of the recordings would seem to suggest that this technology could become an important useful tool for clinical use. This new hand held smart phone 12 lead ECG recorder needs further development and validation. PMID- 25283740 TI - The "call for help": intraoperative consultation and the surgeon-patient relationship. PMID- 25283741 TI - Book-binding technique for Billroth I anastomosis during totally laparoscopic distal gastrectomy. PMID- 25283742 TI - Use of endoscopic ultrasound in the preoperative staging of gastric cancer: a multi-institutional study of the US gastric cancer collaborative. AB - BACKGROUND: Endoscopic ultrasound (EUS) can be used to guide the therapeutic plan for patients with gastric adenocarcinoma (GAC), but data on its use and accuracy remain poorly defined. We sought to define the use of EUS, as well as characterize the diagnostic accuracy of EUS among patients with GAC. STUDY DESIGN: We identified 960 patients who underwent resection of GAC between 2000 and 2012 from 7 major academic institutions participating in the US Gastric Cancer Collaborative. Clinicopathologic and EUS data were collected and analyzed using chi and kappa statistics. RESULTS: Of 960 patients, 223 (23.2%) underwent evaluation with preoperative EUS. Among patients who underwent EUS, 74 (33.2%) received neoadjuvant chemotherapy; 149 (66.8%) proceeded directly to resection. Among patients who did not receive neoadjuvant therapy and received curative intent gastric resection, the EUS T classifications were T1 (33.3%), T2 (35.6%), T3 (18.9%), T4 (12.1%) and the N classifications were N0 (68.1%) and N >= 1 (31.9%). In contrast, when tumor stage was based on the final surgical specimen, there was a higher proportion of cases with more advanced T stage (T1, 36.4%; T2, 14.4%; T3, 23.5%; T4, 25.7%) and N stage (N0, 51.3%; N >= 1, 48.7%). The agreement of preoperative EUS compared with surgical staging for T (kappa = 0.28, p < 0.001) and N (kappa = 0.33, p < 0.001) classification was only fair. CONCLUSIONS: Less than one-quarter of patients with GAC underwent preoperative EUS staging. In patients who did not receive preoperative chemotherapy, tumor stage on EUS often did not correlate with T stage and N stage on final pathologic analysis. Endoscopic ultrasound should be combined with other staging modalities to optimize staging of patients with GAC. PMID- 25283743 TI - Laparoscopic repair of median arcuate ligament syndrome: a new approach. PMID- 25283744 TI - Mechanically modulated dewetting by atomic force microscope for micro- and nano- droplet array fabrication. AB - Organizing a material into well-defined patterns during the dewetting process provides an attractive micro-/nano-fabrication method without using a conventional lithographic process, and hence, offers potential applications in organic electronics, optics systems, and memory devices. We report here how the mechanical modification of polymer surface by an Atomic Force Microscope (AFM) can be used to guide thin film dewetting evolution and break the intrinsic spatial correlation of spontaneous instability. An AFM is used to implement the mechanical modification of progressively narrow grids to investigate the influence of pattern size on the modulation of ultrathin polystyrene films dewetting evolution. For films with different initial thicknesses, when grid size is close to or below the characteristic wavelength of instability, the spinodal dewetting is suppressed, and film rupture is restricted to the cutting trench. We will show in this paper it is possible to generate only one droplet per gridded area on a thin film subsequent to nucleation dominated dewetting on a non patterned substrate. Furthermore, when the grid periodicity exceeds the spinodal length, the number of droplets in predefined areas gradually approaches that associated with unconfined dewetting. PMID- 25283746 TI - Editorial commentary: "What does immunology have to do with brain development and neuropsychiatric disorders?". PMID- 25283747 TI - Goal orientation by geometric and feature cues: spatial learning in the terrestrial toad Rhinella arenarum. AB - Although of crucial importance in vertebrate evolution, amphibians are rarely considered in studies of comparative cognition. Using water as reward, we studied whether the terrestrial toad, Rhinella arenarum, is also capable of encoding geometric and feature information to navigate to a goal location. Experimental toads, partially dehydrated, were trained in either a white rectangular box (Geometry-only, Experiment 1) or in the same box with a removable colored panel (Geometry-Feature, Experiment 2) covering one wall. Four water containers were used, but only one (Geometry-Feature), or two in geometrically equivalent corners (Geometry-only), had water accessible to the trained animals. After learning to successfully locate the water reward, probe trials were carried out by changing the shape of the arena or the location of the feature cue. Probe tests revealed that, under the experimental conditions used, toads can use both geometry and feature to locate a goal location, but geometry is more potent as a navigational cue. The results generally agree with findings from other vertebrates and support the idea that at the behavioral-level geometric orientation is a conserved feature shared by all vertebrates. PMID- 25283745 TI - Alternative splicing of EKLF/KLF1 in murine primary erythroid tissues. AB - Alternative splicing has emerged as a vital way to expand the functional repertoire of a set number of mammalian genes. For example, such changes can dramatically alter the function and cellular localization of transcription factors. With this in mind, we addressed whether EKLF/KLF1 mRNA, coding for a transcription factor that plays a critical role in erythropoietic gene regulation, is alternatively spliced. We find that EKLF mRNA undergoes exon skipping only in primary tissues and that this splice variant (SV) remains at a very low level in both embryonic and adult erythroid cells, as well as during terminal differentiation. The resultant protein is truncated and partially encodes a non-erythroid Kruppel-like factor amino acid sequence. Its overexpression can alter full-length erythroid Kruppel-like factor function at selected promoters. We discuss these results in the context of stress and with respect to recent global studies on the role of alternative splicing during terminal erythroid differentiation. PMID- 25283748 TI - Oestrogen-induced activation of preoptic kisspeptin neurones may be involved in the luteinising hormone surge in male and female Japanese monkeys. AB - The oestrogen-induced luteinising hormone (LH) surge is evident in male primates, including humans, whereas male rodents never show the LH surge, even when treated with a preovulatory level of oestrogen. This suggests that the central mechanism governing reproductive hormones in primates is different from that in rodents. The present study aimed to investigate whether male Japanese monkeys conserve a brain mechanism mediating the oestrogen-induced LH surge via activation of kisspeptin neurones. Adult male and female Japanese monkeys were gonadectomised and then were treated with oestradiol-17beta for 2 weeks followed by a bolus injection of oestradiol benzoate. Both male and female monkeys showed an oestrogen-induced LH surge. In gonadectomised monkeys sacrificed just before the anticipated time of the LH surge, oestrogen treatment significantly increased the number of KISS1-expressing cells in the preoptic area (POA) and enhanced the expression of c-fos in POA KISS1-positive cells of males and females. The oestrogen treatment failed to induce c-fos expression in the arcuate nucleus (ARC) kisspeptin neurones in both sexes just prior to LH surge onset. Thus, kisspeptin neurones in the POA but not in the ARC might be involved in the positive-feedback action of oestrogen that induces LH surge in male Japanese monkeys, as well as female monkeys. The present results indicate that oestrogen induced activation of POA kisspeptin neurones may contribute to the LH surge generation in both sexes. The conservation of the LH surge generating system found in adult male primates, unlike rodents, could be a result of the capability of oestrogen to induce POA kisspeptin expression and activation. PMID- 25283749 TI - Epigenetic approaches to regeneration of bone and cartilage from stem cells. AB - INTRODUCTION: Embryonic stem cells (ESCs) or adult stem cells, especially mesenchymal stem cells (MSCs), have been intensively studied for skeletal tissue regeneration including bone and cartilage. Epigenetic mechanisms play essential roles in stem cell maintenance and differentiation. However, little is known about the epigenetic regulation of osteogenesis and chondrogenesis of stem cells. AREAS COVERED: In this review, features of ESCs and adult stem cells, epigenetics and chromatin structure, as well as epigenetic mechanisms, such as chromatin remodeling, DNA methylation and histone modifications, polycomb group (PcG) proteins and microRNAs are described. Epigenetic researches of stem cell are introduced. EXPERT OPINION: Epigenetic alterations of stem cell during the in vitro differentiation can be controlled for clinical applications. MSCs are effective resources for skeletal tissue regeneration in both undifferentiated and differentiated states. Understanding epigenetic signatures of MSC is crucial to maintain the stemness. In addition, investigation of epigenetic changes in the differentiation of MSCs is very important to develop methods or chemicals to promote efficient differentiation of MSCs. Inhibition of PcG protein enhancer of zeste (Ezh2) a chromatin modifier, could be a promising candidate to improve MSC differentiation by decreasing Ezh2-mediated H3K27me3. PMID- 25283750 TI - Prevention of epileptogenesis--a new goal for epilepsy therapy. PMID- 25283751 TI - Cognitive impairment associated with low ferritin responsive to iron supplementation. AB - BACKGROUND: Iron deficiency is the most common nutritional deficiency in children. It affects 9% of children ages 1-3 years. Iron is essential for effective mitochondrial electron transport and neurotransmitter synthesis. Iron deficiency has been correlated with impaired psychomotor development, pica, attention deficit disorder, periodic limb movements of sleep, and breath-holding spells. Ferritin is the storage form of iron. PATIENT SERIES: We assessed three children referred for developmental concerns. Extensive testing and neuroimaging were all unremarkable except for low iron stores. Dietary histories revealed excessive milk consumption in two of the children. After dietary adjustments and iron supplementation, iron stores normalized. CONCLUSIONS: This cohort demonstrated a dramatic improvement in cognition once iron stores were repleted, suggesting iron studies should be considered as part of initial investigations of patients with cognitive concerns. PMID- 25283753 TI - Use of the 2010 McDonald criteria can facilitate early diagnosis of pediatric multiple sclerosis in a predominantly black cohort. AB - BACKGROUND: Pediatric-onset multiple sclerosis represents around 3-5% of all patients with multiple sclerosis. Both the 2005 and 2010 McDonald criteria for multiple sclerosis have been suggested for the possible use in pediatric-onset multiple sclerosis. Modifications incorporated into the 2010 criteria enabled the fulfillment of dissemination in time to be met with the initial magnetic resonance imaging. The present study was designed to compare the diagnostic sensitivity of these criteria at initial presentation, the time to fulfilling them, and secondary effects of ethnicity in pediatric-onset multiple sclerosis. METHODS: Twenty-five children with clinically definite multiple sclerosis (mean age, 14.6 +/- 3.1 years; 15 girls) from a single center between 2005 and 2012 were analyzed using both the 2005 and 2010 McDonald criteria based on initial clinical presentation and neuroimaging findings comparing diagnostic sensitivity, time interval to meet diagnosis, and ethnicity. RESULTS: Initial multiple sclerosis diagnosis rates applying the 2005 McDonald criteria were 32% compared with 92% for the 2010 criteria (P = 0.0003). The mean time after initial signs until the 2005 and 2010 McDonald criteria for multiple sclerosis were met was 5.0 vs 0.7 months, respectively (P = 0.001). Time to diagnosis using the 2010 criteria was shorter in black children than the European white (P = 0.005). CONCLUSIONS: The 2010 McDonald criteria are an appropriate tool for the timely diagnosis of pediatric multiple sclerosis, especially in black children, potentially allowing an earlier initiation of disease-modifying therapy. PMID- 25283754 TI - Aligned Fe2TiO5-containing nanotube arrays with low onset potential for visible light water oxidation. AB - There remains a pressing challenge in the efficient utilization of visible light in the photoelectrochemical applications of water splitting. Here, we design and fabricate pseudobrookite Fe2TiO5 ultrathin layers grown on vertically aligned TiO2 nanotube arrays that can enhance the conduction and utilization of photogenerated charge carriers. Our photoanodes are characterized by low onset potentials of ~0.2 V, high photon-to-current efficiencies of 40-50% under 400-600 nm irradiation and total energy conversion efficiencies of ~2.7%. The high performance of Fe2TiO5 nanotube arrays can be attributed to the anisotropic charge carrier transportation and elongated charge carrier diffusion length (compared with those of conventional TiO2 or Fe2O3 photoanodes) based on electrochemical impedance analysis and first-principles calculations. The Fe2TiO5 nanotube arrays may open up more opportunities in the design of efficient and low cost photoanodes working in visible light for photoelectrochemical applications. PMID- 25283755 TI - Decision-making dilemma in drug-induced acute pancreatitis. PMID- 25283752 TI - Pubertal development in Rett syndrome deviates from typical females. AB - BACKGROUND: Rett syndrome is a unique neurodevelopmental disorder, affecting approximately one in 10,000 live female births, most experiencing reduced growth. We characterized pubertal trajectories in females with Rett syndrome. We hypothesized that pubertal trajectory deviates from the general female population with early pubertal onset and delayed menarche. METHODS: Participants were individuals enrolled in the Rett Syndrome Natural History Study with clinical diagnosis of Rett syndrome or mutations in MECP2. Intervals to thelarche, adrenarche, and menarche were assessed by survival analysis; body mass index, mutation type, clinical severity, and pubertal milestone relationships were assessed by log-likelihood test; pathway synchrony (relationship between thelarche, adrenarche, and menarche) was assessed by chi-squared analysis. RESULTS: Compared with the general female population, more than 25% initiated puberty early, yet entered menarche later (median age 13.0 years). A total of 19% experienced delayed menarche. Median length of puberty, from thelarche to menarche, was 3.9 years. Higher body mass index correlated with earlier thelarche and adrenarche but not menarche; milder mutations correlated with earlier menarche; and milder clinical presentation correlated with earlier thelarche and menarche. Fifty-two percent entered puberty in synchrony, but different from the general population, 15% led with thelarche and 32% with adrenarche. CONCLUSIONS: Pubertal trajectories in Rett syndrome differ from general population, entering puberty early and reaching menarche later. Body mass index affects pubertal timing, but the relationship between specific mutations, clinical presentation, and underlying neuroendocrine pathology is less clear. PMID- 25283756 TI - Modern education, modern media: patient empowerment in today's medicine. PMID- 25283757 TI - Educating orally anticoagulated patients in drug safety: a cluster-randomized study in general practice. AB - BACKGROUND: Orally anticoagulated patients with insufficient knowledge about their treatment have a higher risk of complications. Standardized patient education could raise their level of knowledge and improve time spent within target INR range. METHODS: This cluster randomized trial included 319 anticoagulated patients drawn from 22 general medical practices. 185 patients received patient education, conducted by practice nurses, consisting of a video, a brochure, and a questionnaire; 134 control patients received only the brochure. The primary endpoint was knowledge about treatment six months after the patient education session. The secondary endpoints were time in the INR (international normalized ratio) target range and complications of anticoagulation. RESULTS: Patients in the intervention and control groups were of comparable mean age (73 vs. 72 years). They answered a comparable number of questions correctly before the intervention (6.8 +/- 0.2 vs. 6.7 +/- 0.2) but differed significantly on this measure at six months (9.9 +/- 0.2 vs. 7.6 +/- 0.2, mean difference 2.3 questions, 95% confidence interval [CI] 1.5-3.1, p< 0.001). In the six months prior to the intervention, the INR was in the target range 65 +/- 2% vs. 66 +/- 3% of the time; in the six months afterward, 71 +/- 1% vs. 64 +/- 3% of the time (mean difference 7 percentage points, 95% CI -2 to -16 percentage points, p = 0.11). The complication rates were comparable in the two groups (12% vs. 16%, p = 0.30). Patients in the intervention group approved of patient education sessions to a greater extent than control patients (87% vs. 56%). CONCLUSION: Patient education was found to be practical, to improve knowledge relating to patient safety in a durable manner, and to meet with the approval of the patients who received it. There was a statistically non-significant trend toward an improvement of the time spent in the INR target range. In view of the major knowledge deficits of orally anticoagulated patients, standardized patient education ought to be made a part of their routine care. PMID- 25283758 TI - Different study methods. PMID- 25283759 TI - Large numbers do not make for great science. PMID- 25283760 TI - In reply. PMID- 25283761 TI - Urinalysis in children and adolescents. AB - BACKGROUND: Urinalysis is the most commonly performed biochemical test in infancy and early childhood. The urine sample should be correctly obtained, age-specific aspects should be considered, and age-dependent reference values should be used. METHOD: This review is based on a selective literature search in electronic databases, textbooks, and guidelines from Germany and abroad on the acquisition of urine samples and the performance of urinalysis in infancy and early childhood. RESULTS: The timing and mode of acquisition of the urine sample affect the assessment of hematuria, proteinuria, leukocyturia, nitrituria, and the uropathogenic bacterial colony count in the urine culture. Dipstick tests can be used for targeted screening for these features. The test results should be interpreted together with the findings of urine microscopy, the medical history, and the physical examination. Proteinuria should be quantified and differentiated; both of these things can be done either from collected urine or (especially in infants and young children) from a spontaneously voided urine sample, by determination of the protein/creatinine quotient. Orthostatic proteinuria in an adolescent requires no further evaluation or treatment. Hematuria should be characterized as either glomerular or non-glomerular erythrocyturia. Asymptomatic, isolated microhematuria in childhood is not uncommon and often transient; in the absence of a family history, it usually does not require an extensive work-up. Proteinuria combined with hematuria should arouse the suspicion of glomerulonephritis. CONCLUSION: Urinalysis in infancy and early childhood is a simple and informative diagnostic test as long as the urine sample has been obtained properly and the results are interpreted appropriately for this age group. PMID- 25283763 TI - Tissue-engineered cartilage: the crossroads of biomaterials, cells and stimulating factors. AB - Damage to cartilage represents one of the most challenging tasks of musculoskeletal therapeutics due to its limited propensity for healing and regenerative capabilities. Lack of current treatments to restore cartilage tissue function has prompted research in this rapidly emerging field of tissue regeneration of functional cartilage tissue substitutes. The development of cartilaginous tissue largely depends on the combination of appropriate biomaterials, cell source, and stimulating factors. Over the years, various biomaterials have been utilized for cartilage repair, but outcomes are far from achieving native cartilage architecture and function. This highlights the need for exploration of suitable biomaterials and stimulating factors for cartilage regeneration. With these perspectives, we aim to present an overview of cartilage tissue engineering with recent progress, development, and major steps taken toward the generation of functional cartilage tissue. In this review, we have discussed the advances and problems in tissue engineering of cartilage with strong emphasis on the utilization of natural polymeric biomaterials, various cell sources, and stimulating factors such as biophysical stimuli, mechanical stimuli, dynamic culture, and growth factors used so far in cartilage regeneration. Finally, we have focused on clinical trials, recent innovations, and future prospects related to cartilage engineering. PMID- 25283762 TI - Investigation of human embryonic stem cell-derived keratinocytes as an in vitro research model for mechanical stress dynamic response. AB - The epidermis is mainly composed of keratinocytes forming a protective barrier. It is perpetually subjected to mechanical stress and strain during development, homeostasis and disease. Perturbation of the normal strain with alteration of its biological response may lead to severe diseases such as psoriasis and epidermolysis bullosa. To date, most of the studies about skin response to mechanical stress used immortalized cell lines (i.e. HaCaT) or primary cells from donors, which suffer issues of limited physiological relevance and inter-donor variability. It is therefore necessary to develop a new human model for the study of normal skin physiology and response to mechanical stress. In this study, we investigated the use of keratinocytes derived from human embryonic stem cells (hESCs) as a reliable alternative model to HaCaT for study of the effects of mechanical tension. With comparison to HaCaT, hESC-derived keratinocytes (hESC Kert) were exposed to up to 3 days of cyclic mechanical stress, and gene expression changes were analyzed. Dynamic expression of several key mechanical stress related-genes was studied at mRNA level using qPCR. The expression of matrix-metallopeptidase9 was studied at protein level using ELISA. The two cell types displayed similar gene expression kinetics for most of the genes including E-cadherin, cateninbeta1, connexin43, desmoglein1, endothelin1, integrinalpha6, interleukinalpha1, keratin1, 6, and 10, keratinocyte growth-factor-receptor and lamininalpha5. Unlike HaCaT, hESC-Kert displayed early gene and protein expression of matrix metallopeptidase 9 following mechanical stimulation, suggesting that these cells have remodeling capacity that resembles that of normal human skin. Our study confirmed the use of hESC-Kert as a good model for study of skin response to mechanical stress. PMID- 25283764 TI - Preschoolers with Down syndrome do not yet show the learning and memory impairments seen in adults with Down syndrome. AB - Individuals with Down syndrome (DS) exhibit a behavioral phenotype of specific strengths and weaknesses, in addition to a generalized cognitive delay. In particular, adults with DS exhibit specific deficits in learning and memory processes that depend on the hippocampus, and there is some suggestion of impairments on executive function tasks that depend on the prefrontal cortex. While these functions have been investigated in adults with DS, it is largely unclear how these processes develop in young children with DS. Here we tested preschoolers with DS and typically developing children, age-matched on either receptive language or non-verbal scores as a proxy for mental age (MA), on a battery of eye-tracking and behavioral measures that have been shown to depend on the hippocampus or the prefrontal cortex. Preschoolers with DS performed equivalently to MA-matched controls, suggesting that the disability-specific memory deficits documented in adults with DS, in addition to a cognitive delay, are not yet evident in preschoolers with DS, and likely emerge progressively with age. Our results reinforce the idea that early childhood may be a critical time frame for targeted early intervention. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=r6GUA6my22Q&list=UU3FIcom6UpITHZOIEa8Onnw. PMID- 25283765 TI - Decision-making in post-acquittal hospital release: how do forensic evaluators make their decisions? AB - A large number of individuals are acquitted of criminal charges after being found "not guilty by reason of insanity." Most of these individuals are hospitalized and later seek hospital discharge under a court-ordered provision called conditional release ("CR"). Courts rely on opinions from forensic evaluators to determine acquittees' readiness for CR. However, how evaluators make these decisions are unknown. Eighty-nine CR readiness evaluators from nine states were surveyed to understand which factors evaluators prioritize and to understand evaluators' assessment methodologies and their beliefs about the CR process itself. Little uniformity was found among evaluators on any aspect of the decision-making process. Evaluators utilized a wide variety of methodologies when making their decisions on readiness for CR. Moreover, evaluators' conceptualizations of the CR process itself varied widely. The results highlight the difficulty and confusion evaluators face when conducting CR readiness evaluations, and demonstrate the need for enhanced training, statutory guidance, and standardized evaluation protocols for these evaluations. PMID- 25283766 TI - Pediatric hospitalist comanagement of surgical patients: structural, quality, and financial considerations. AB - Comanagement of surgical patients is occurring more commonly among adult and pediatric patients. These systems of care can vary according to institution type, comanagement structure, and type of patient. Comanagement can impact quality, safety, and costs of care. We review these implications for pediatric surgical patients. PMID- 25283768 TI - An efficient analysis of covariance model for crossover thorough QT studies with period-specific pre-dose baselines. AB - Baseline adjustment is an important consideration in thorough QT studies for non antiarrhythmic drugs. For crossover studies with period-specific pre-dose baselines, we propose a by-time-point analysis of covariance model with change from pre-dose baseline as response, treatment as a fixed effect, pre-dose baseline for current treatment and pre-dose baseline averaged across treatments as covariates, and subject as a random effect. Additional factors such as period and sex should be included in the model as appropriate. Multiple pre-dose measurements can be averaged to obtain a pre-dose-averaged baseline and used in the model. We provide conditions under which the proposed model is more efficient than other models. We demonstrate the efficiency and robustness of the proposed model both analytically and through simulation studies. The advantage of the proposed model is also illustrated using the data from a real clinical trial. PMID- 25283767 TI - Hypertension: an unstudied potential risk factor for adverse outcomes during continuous flow ventricular assist device support. AB - In end-stage heart failure, left ventricular assist devices (LVADs) represent an exciting new frontier in which post-device implantation survival approaches that of heart transplant. However, expansion of this technology is still limited by complications that impact morbidity and mortality. Thus, it is essential to identify and optimize modifiable predictors of poor outcomes. One such predictor may be hypertension (HTN). Not only may chronic HTN as a traditional cardiovascular risk factor be present during long-term LVAD support, but HTN may also contribute to device malfunction or device-associated complications. Although current guidelines identify blood pressure (BP) control as important to outpatient continuous flow (CF) LVAD management, there is no evidence base to support these guidelines. Indeed, our comprehensive literature search did not identify any studies that evaluated post-device implantation HTN as a potential predictor of adverse CF-LVAD outcomes. HTN among CF-LVAD patients is likely a relatively unstudied factor because of difficulties using standard noninvasive techniques to measure BP in the setting of reduced pulsatile flow. Fortunately, recent research has elucidated the meaning of Doppler BP measurements and validated a slow-cuff deflation system for BP measurements in the setting of CF LVAD support. Therefore, CF-LVAD researchers and clinicians may (1) consider potential mechanisms relating HTN to poor outcomes, (2) realize that HTN management is a stated goal despite scarce evidence, and (3) utilize the new reliable and valid methods for outpatient BP measurement that make research and management possible. It is critical and now feasible that research on HTN in the CF-LVAD patient population move forward. PMID- 25283769 TI - Limb-shaking TIA during balloon test occlusion of the internal carotid artery. PMID- 25283770 TI - Cerebellar and brainstem variant of posterior reversible encephalopathy syndrome. PMID- 25283771 TI - Graefe's archive for clinical and experimental ophthalmology-instant glue for retinal detachment surgery? PMID- 25283772 TI - Macroscopic chirality of supramolecular gels formed from achiral tris(ethyl cinnamate) benzene-1,3,5-tricarboxamides. AB - A C3 -symmetric benzene-1,3,5-tricarboxamide substituted with ethyl cinnamate was found to self-assemble into supramolecular gels with macroscopic chirality in a DMF/H2 O mixture. The achiral compound simultaneously formed left- and right handed twists in an unequal number, thus resulting in the macroscopic chirality of the gels without any chiral additives. Furthermore, ester-amide exchange reactions with chiral amines enabled the control of both the handedness of the twists and the macroscopic chirality of the gels, depending on the structures of the chiral amines. These results provide new prospects for understanding and regulating symmetry breaking in assemblies of supramolecular gels formed from achiral molecular building blocks. PMID- 25283773 TI - Electronic circular dichroism of chiral alkenes: B3LYP and CAM-B3LYP calculations. AB - Time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) are widely used to determine absolute configurations (ACs) of chiral molecules. Two very popular DFT exchange-correlation functionals, one hybrid (B3LYP) and one long-range corrected (CAM-B3LYP), along with a hierarchical sequence of basis sets were investigated, and the ECD spectra predicted for eight alkenes and compared to gas-phase experimental spectra. Little variation in predicted ECD spectra was found with the basis set size enlargement, but the sensitivity to the functional is greater. Good agreement was obtained only with the CAM-B3LYP functional, leading to the conclusion that TDDFT calculations of ECD spectra can routinely provide reliable ACs if and only if an appropriate functional is used. For camphene, twistene, syn-(E)-bisfenchylidene, and phyllocladene, solvent effects were estimated. PMID- 25283774 TI - Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: results of a multicenter prospective phase 2 trial. AB - BACKGROUND: The optimal intensity of myeloablation delivered as part of a reduced intensity/toxicity conditioning (RIC/RTC) regimen to decrease the recurrence rate, without increasing nonrecurrence mortality (NRM), remains to be established. METHODS: The current phase 2, prospective, multicenter trial aimed to assess the efficacy and safety of an RIC/RTC regimen based on busulfan at a dose of 130 mg/m(2) /day intravenously for 3 days, fludarabine at a dose of 30 mg/m(2) /day for 5 days, and antithymocyte globulins at a dose of 2.5 mg/kg/day for 2 days. A total of 80 patients (median age, 53 years; range, 25-64 years) with hematological malignancies were included. RESULTS: With a median follow-up of 21 months (range, 12-36.5 months), the Kaplan-Meier estimates of overall and disease-free survival at 2 years were 62% (95% confidence interval [95% CI], 51% 73%) and 50% (95% CI, 33%-57%), respectively. The cumulative incidences of grade 2 to 4 acute graft-versus-host disease (GVHD) and chronic GVHD (all grades) were 29% (95% CI, 19%-39%) and 35% (95% CI, 24%-46%), respectively. At 2 years, the cumulative incidence of recurrence/disease progression and NRM were 44% (95% CI, 31%-56%) and 11% (95% CI, 6%-19%), respectively. Patient age, diagnosis, donor type, sex, presence of comorbidities, and the Hematopoietic cell transplantation specific comorbidities index did not appear to have any statistically significant impact on NRM, recurrence/disease progression, disease-free survival, or overall survival. CONCLUSIONS: The RIC/RTC regimen used in the current study appeared to be safe, with a low NRM rate at 2 years noted among high-risk patients, and efficient disease control, warranting prospective phase 3 trials. PMID- 25283776 TI - Rapid evolution of the cerebellum in humans and other great apes. AB - Humans' unique cognitive abilities are usually attributed to a greatly expanded neocortex, which has been described as "the crowning achievement of evolution and the biological substrate of human mental prowess". The human cerebellum, however, contains four times more neurons than the neocortex and is attracting increasing attention for its wide range of cognitive functions. Using a method for detecting evolutionary rate changes along the branches of phylogenetic trees, we show that the cerebellum underwent rapid size increase throughout the evolution of apes, including humans, expanding significantly faster than predicted by the change in neocortex size. As a result, humans and other apes deviated significantly from the general evolutionary trend for neocortex and cerebellum to change in tandem, having significantly larger cerebella relative to neocortex size than other anthropoid primates. These results suggest that cerebellar specialization was a far more important component of human brain evolution than hitherto recognized and that technical intelligence was likely to have been at least as important as social intelligence in human cognitive evolution. Given the role of the cerebellum in sensory-motor control and in learning complex action sequences, cerebellar specialization is likely to have underpinned the evolution of humans' advanced technological capacities, which in turn may have been a preadaptation for language. PMID- 25283777 TI - Doublecortin recognizes the longitudinal curvature of the microtubule end and lattice. AB - BACKGROUND: Microtubule ends have distinct biochemical and structural features from those of the lattice. Several proteins that control microtubule behavior can distinguish the end of a microtubule from the lattice. The end-binding protein EB1, for example, recognizes the nucleotide state of microtubule ends, which are enriched in GTP-tubulin. EB1 shares its binding site with Doublecortin (DCX), a protein expressed in developing neurons. We showed recently that DCX binds with highest affinity to microtubule ends. RESULTS: Here we show that DCX recognizes microtubule ends by a novel mechanism based on lattice curvature. Using single molecule microscopy, we show that DCX "comets" do not elongate at faster microtubule growth rates and DCX does not recognize two out of three GTP analogs. We demonstrate that DCX binds with higher affinity to curved microtubule lattices than to straight ones. We find that curvature recognition is a property of single DCX molecules. Straightening of protofilaments (pfs) at microtubule ends with paclitaxel significantly attenuates end-recognition by DCX, but not EB1. Mutations in DCX found in patients with double cortex syndrome disrupted curvature recognition. CONCLUSIONS: We propose a model in which DCX recognizes microtubule ends through specific interactions with their structure. We conclude that microtubule ends have two distinct features that proteins can recognize independently, namely a structural feature related to curvature and nucleotide state. PMID- 25283775 TI - Moniliform deformation of retinal ganglion cells by formaldehyde-based fixatives. AB - Protocols for characterizing cellular phenotypes commonly use chemical fixatives to preserve anatomical features, mechanically stabilize tissue, and stop physiological responses. Formaldehyde, diluted in either phosphate-buffered saline or phosphate buffer, has been widely used in studies of neurons, especially in conjunction with dyes and antibodies. However, previous studies have found that these fixatives induce the formation of bead-like varicosities in the dendrites and axons of brain and spinal cord neurons. We report here that these formaldehyde formulations can induce bead formation in the dendrites and axons of adult rat and rabbit retinal ganglion cells, and that retinal ganglion cells differ from hippocampal, cortical, cerebellar, and spinal cord neurons in that bead formation is not blocked by glutamate receptor antagonists, a voltage gated Na(+) channel toxin, extracellular Ca(2+) ion exclusion, or temperature shifts. Moreover, we describe a modification of formaldehyde-based fixatives that prevents bead formation in retinal ganglion cells visualized by green fluorescent protein expression and by immunohistochemistry. PMID- 25283778 TI - Dopamine reward prediction error responses reflect marginal utility. AB - BACKGROUND: Optimal choices require an accurate neuronal representation of economic value. In economics, utility functions are mathematical representations of subjective value that can be constructed from choices under risk. Utility usually exhibits a nonlinear relationship to physical reward value that corresponds to risk attitudes and reflects the increasing or decreasing marginal utility obtained with each additional unit of reward. Accordingly, neuronal reward responses coding utility should robustly reflect this nonlinearity. RESULTS: In two monkeys, we measured utility as a function of physical reward value from meaningful choices under risk (that adhered to first- and second-order stochastic dominance). The resulting nonlinear utility functions predicted the certainty equivalents for new gambles, indicating that the functions' shapes were meaningful. The monkeys were risk seeking (convex utility function) for low reward and risk avoiding (concave utility function) with higher amounts. Critically, the dopamine prediction error responses at the time of reward itself reflected the nonlinear utility functions measured at the time of choices. In particular, the reward response magnitude depended on the first derivative of the utility function and thus reflected the marginal utility. Furthermore, dopamine responses recorded outside of the task reflected the marginal utility of unpredicted reward. Accordingly, these responses were sufficient to train reinforcement learning models to predict the behaviorally defined expected utility of gambles. CONCLUSIONS: These data suggest a neuronal manifestation of marginal utility in dopamine neurons and indicate a common neuronal basis for fundamental explanatory constructs in animal learning theory (prediction error) and economic decision theory (marginal utility). PMID- 25283779 TI - Specialized myrmecophily at the ecological dawn of modern ants. AB - Myrmecophiles--species that depend on ant societies--include some of the most morphologically and behaviorally specialized animals known. Remarkable adaptive characters enable these creatures to bypass fortress-like security, integrate into colony life, and exploit abundant resources and protection inside ant nests. Such innovations must result from intimate coevolution with hosts, but a scarcity of definitive fossil myrmecophiles obscures when and how this lifestyle arose. Here, we report the earliest known morphologically specialized and apparently obligate myrmecophile, in Early Eocene (~ 52 million years old) Cambay amber from India. Protoclaviger trichodens gen. et sp. nov. is a stem-group member of Clavigeritae, a speciose supertribe of pselaphine rove beetles (Coleoptera: Staphylinidae) heavily modified for myrmecophily via reduced mouthparts for trophallaxis with worker ants, brush-like trichomes that exude appeasement compounds, and fusions of many body and antennal segments. Protoclaviger captures a transitional stage in the evolutionary development of this novel body plan, most evident in its still-distinct abdominal tergites. The Cambay paleobiota marks one of the first occurrences in the fossil record of a significant presence of modern ants. Protoclaviger reveals that sophisticated social parasites were nest intruders throughout, and probably before, the ascent of ants to ecological dominance, with ancient groups such as Clavigeritae primed to radiate as their hosts became increasingly ubiquitous. PMID- 25283780 TI - Training transfers the limits on perception from parietal to ventral cortex. AB - Visually guided behavior depends on (1) extracting and (2) discriminating signals from complex retinal inputs, and these perceptual skills improve with practice. For instance, training on aerial reconnaissance facilitated World War II Allied military operations; analysts pored over stereoscopic photographs, becoming expert at (1) segmenting pictures into meaningful items to break camouflage from (noisy) backgrounds, and (2) discriminating fine details to distinguish V-weapons from innocuous pylons. Training is understood to optimize neural circuits that process scene features (e.g., orientation) for particular purposes (e.g., judging position). Yet learning is most beneficial when it generalizes to other settings and is critical in recovery after adversity, challenging understanding of the circuitry involved. Here we used repetitive transcranial magnetic stimulation (rTMS) to infer the functional organization supporting learning generalization in the human brain. First, we show dissociable contributions of the posterior parietal cortex (PPC) versus lateral occipital (LO) circuits: extracting targets from noise is disrupted by PPC stimulation, in contrast to judging feature differences, which is affected by LO rTMS. Then, we demonstrate that training causes striking changes in this circuit: after feature training, identifying a target in noise is not disrupted by PPC stimulation but instead by LO stimulation. This indicates that training shifts the limits on perception from parietal to ventral brain regions and identifies a critical neural circuit for visual learning. We suggest that generalization is implemented by supplanting dynamic processing conducted in the PPC with specific feature templates stored in the ventral cortex. PMID- 25283781 TI - Serial dependence in the perception of faces. AB - From moment to moment, we perceive objects in the world as continuous despite fluctuations in their image properties due to factors like occlusion, visual noise, and eye movements. The mechanism by which the visual system accomplishes this object continuity remains elusive. Recent results have demonstrated that the perception of low-level stimulus features such as orientation and numerosity is systematically biased (i.e., pulled) toward visual input from the recent past. The spatial region over which current orientations are pulled by previous orientations is known as the continuity field, which is temporally tuned for the past 10-15 s. This perceptual pull could contribute to the visual stability of low-level features over short time periods, but it does not address how visual stability occurs at the level of object identity. Here, we tested whether the visual system facilitates stable perception by biasing current perception of a face, a complex and behaviorally relevant object, toward recently seen faces. We found that perception of face identity is systematically biased toward identities seen up to several seconds prior, even across changes in viewpoint. This effect did not depend on subjects' prior responses or on the method used to measure identity perception. Although this bias in perceived identity manifests as a misperception, it is adaptive: visual processing echoes the stability of objects in the world to create perceptual continuity. The serial dependence of identity perception promotes object identity invariance over time and provides the clearest evidence for the existence of an object-selective perceptual continuity field. PMID- 25283783 TI - Explosive adaptive radiation and extreme phenotypic diversity within ant-nest beetles. AB - Ant-nest beetles (Paussus) are the quintessential Trojan horses of the insect world. They hack the complex communication system of ants, allowing them to blend into the ant society and be treated as royalty, all the while preying upon the ants and the ants' brood and duping the ants into rearing their young. Here we present results of the first molecular-based phylogeny of ant-nest beetles, which reveals that this symbiosis has produced one of the most stunning examples of rapid adaptive radiation documented to date. The most recent ancestor of a Paussus clade endemic to Madagascar is only 2.6 million years old. This species gave rise to a remarkably phenotypically diverse clade of 86 extant species with a net diversification interval of 0.38-0.81 million years, a rate of radiation faster than classic textbook examples of large, recent, rapid radiations such as Anolis lizards on Caribbean islands, cichlids of the East African Great Lakes, finches on the Galapagos Islands, and Drosophila and tetragnathid spiders on the Hawaiian Islands. In order for Paussus to adapt to a new host ant species, the beetle's ability to perceive, deceive, and communicate with the new host must evolve quickly and in synchrony in both the larval and adult life stages, resulting in unusually strong selective pressure levied by their host ants. Data on host associations suggest that the history of host shifts may help explain both the striking phenotypic diversity within the Malagasy radiation and the evolution of phenotypically similar yet distantly related species in Madagascar and Africa. PMID- 25283784 TI - A generic review of the lysianassoid family Uristidae and descriptions of new taxa from Australian waters (Crustacea, Amphipoda, Uristidae). AB - In this paper we review the genera of the family Uristidae and report for the first time from Australian waters: the new genus and species Des griffini; the genus Euonyx with two new species; Koroga megalops; the genus Parschisturella with three new species; and Stephonyx arabiensis plus one new species. We provide keys to species in the genera Abyssorchomene, Euonyx, and Parschisturella. Ten genera and 24 species of uristid lysianassoids are now known from Australian waters. PMID- 25283782 TI - Neurons in the monkey amygdala detect eye contact during naturalistic social interactions. AB - Primates explore the visual world through eye-movement sequences. Saccades bring details of interest into the fovea, while fixations stabilize the image. During natural vision, social primates direct their gaze at the eyes of others to communicate their own emotions and intentions and to gather information about the mental states of others. Direct gaze is an integral part of facial expressions that signals cooperation or conflict over resources and social status. Despite the great importance of making and breaking eye contact in the behavioral repertoire of primates, little is known about the neural substrates that support these behaviors. Here we show that the monkey amygdala contains neurons that respond selectively to fixations on the eyes of others and to eye contact. These "eye cells" share several features with the canonical, visually responsive neurons in the monkey amygdala; however, they respond to the eyes only when they fall within the fovea of the viewer, either as a result of a deliberate saccade or as eyes move into the fovea of the viewer during a fixation intended to explore a different feature. The presence of eyes in peripheral vision fails to activate the eye cells. These findings link the primate amygdala to eye movements involved in the exploration and selection of details in visual scenes that contain socially and emotionally salient features. PMID- 25283785 TI - Taxonomic review of the family Colatooeciidae Winston, 2005 (Bryozoa, heilostomata), with description of seven new species. AB - Colatooeciidae includes the genera Colatooecia, Cigclisula and Trematooecia. While Colatooecia is considered a well-defined genus, the differences between Cigclisula and Trematooecia are poorly defined. This taxonomic review was undertaken to understand the morphological differences between Cigclisula and Trematooecia. The type species of Cigclisula is redescribed and the type species of Trematooecia is designated and redescribed. Diagnostic characters of both genera are redefined. Six new species of Cigclisula and one of Trematooecia are described: Cigclisula australis n. sp., Cigclisula buski n. sp., Cigclisula fistulosa n. sp., Cigclisula osburni n. sp., Cigclisula perforata n. sp., Cigclisula winstonae n. sp. and Trematooecia rotunda n. sp. Four species previously assigned to Cigclisula are transferred to Trematooecia: Trematooecia arborescens (Canu & Bassler, 1928) n. comb., Trematooecia gemmea (Winston & Woollacott, 2009) n. comb., Trematooecia hexagonalis (Canu & Bassler, 1930), and Trematooecia verticalis (Maplestone, 1910) n. comb. Two species previously assigned to Trematooecia are transferred to Cigclisula: Cigclisula turrita (Smitt, 1873) and Cigclisula psammophila(Winston & Hakansson, 1986) n. comb. PMID- 25283786 TI - CBCT-based volume of simulated root resorption - influence of FOV and voxel size. AB - AIM: To examine the influence of the field of view (FOV) and voxel size on the measurement of the volume of simulated internal root resorption (IRR) lesions through cone-beam computed tomography (CBCT). METHODOLOGY: Eleven single-rooted teeth with IRR simulated by acid demineralization were studied. CBCT images were acquired using large FOV (voxel sizes of 0.200, 0.250 and 0.300 mm) and limited FOV (voxel sizes of 0.076, 0.100 and 0.200 mm). The IRR volumes were calculated using the Dolphin((r)) software. Volumetric measurements were validated using IRR silicone putty casts. The analysis of variance (anova) for randomized block design complemented with the Tukey's test was employed. RESULTS: IRR volumes obtained using voxel sizes of 0.200 and 0.250 mm were similar (P > 0.05). However, both these values were significantly different from that obtained using the 0.300-mm voxel (P < 0.05). There was no significant difference between IRR volumes measured through voxel sizes of 0.076 and 0.100 mm (P > 0.05), but both differed significantly from that obtained through the 0.200-mm voxel (P < 0.05). There was no significant difference between the volumetric measurements of the 0.200-mm voxel images of the restricted and large FOV protocols. The mean volumes of the silicone casts were smaller than those calculated using a 0.200-mm voxel, but were similar to those obtained using voxel sizes of 0.076 and 0.300 mm. CONCLUSIONS: Despite the FOV protocol, voxel size can influence measurement of simulated IRR volumes. The importance of standardization of CBCT image acquisition protocols is emphasized, especially during follow-up of an IRR lesion, to prevent misinterpretation of its extent, which can create a bias in clinical decisions. PMID- 25283787 TI - Thermodynamic study of dihydrogen phosphate dimerisation and complexation with novel urea- and thiourea-based receptors. AB - Complexation of dihydrogen phosphate by novel thiourea and urea receptors in acetonitrile and dimethyl sulfoxide was studied in detail by an integrated approach by using several methods (isothermal titration calorimetry, ESI-MS, and (1)H NMR and UV spectroscopy). Thermodynamic investigations into H2PO4(-) dimerisation, which is a process that has been frequently recognised, but rarely quantitatively described, were carried out as well. The corresponding equilibrium was taken into account in the anion-binding studies, which enabled reliable determination of the complexation thermodynamic quantities. In both solvents the thiourea derivatives exhibited considerably higher binding affinities with respect to those containing the urea moiety. In acetonitrile, 1:1 and 2:1 (anion/receptor) complexes formed, whereas in dimethyl sulfoxide only the significantly less stable complexes of 1:1 stoichiometry were detected. The solvent effects on the thermodynamic parameters of dihydrogen phosphate dimerisation and complexation reactions are discussed. PMID- 25283788 TI - Recent strategies to develop polysaccharide-based nanomaterials for biomedical applications. AB - Polysaccharides are abundant in nature, renewable, nontoxic, and intrinsically biodegradable. They possess a high level of functional groups including hydroxyl, amino, and carboxylic acid groups. These functional groups can be utilized for further modification of polysaccharides with small molecules, polymers, and crosslinkers; the modified polysaccharides have been used as effective building blocks in fabricating novel biomaterials for various biomedical applications such as drug delivery carriers, cell-encapsulating biomaterials, and tissue engineering scaffolds. This review describes recent strategies to modify polysaccharides for the development of polysaccharide-based biomaterials; typically self-assembled micelles, crosslinked microgels/nanogels, three dimensional hydrogels, and fibrous meshes. In addition, the outlook is briefly discussed on the important aspects for the current and future development of polysaccharide-based biomaterials, particularly tumor-targeting intracellular drug delivery nanocarriers. PMID- 25283789 TI - Composite aromatic boxes for enzymatic transformations of quaternary ammonium substrates. AB - Cation-pi interactions to cognate ligands in enzymes have key roles in ligand binding and enzymatic catalysis. We have deciphered the key functional role of both charged and aromatic residues within the choline binding subsite of CTP:phosphocholine cytidylyltransferase and choline kinase from Plasmodium falciparum. Comparison of quaternary ammonium binding site structures revealed a general composite aromatic box pattern of enzyme recognition sites, well distinguished from the aromatic box recognition site of receptors. PMID- 25283791 TI - Diagnostic accuracy of Global Registry of Acute Coronary Events (GRACE) risk score in ST-elevation myocardial infarction for in-hospital and 360-day mortality in Japanese patients. AB - BACKGROUND: The purpose of the present study was to confirm the diagnostic accuracy of Global Registry of Acute Coronary Events (GRACE) risk score 1.0 (GRACE 1.0) and updated GRACE 1.0 (GRACE 2.0) for in-hospital and 360-day mortality in ST-elevation myocardial infarction (STEMI) in Japanese patients. GRACE 1.0 and GRACE 2.0 are the established predictive models in acute coronary syndrome, but their application to Japanese patients has not been fully verified. METHODS AND RESULTS: The present study retrospectively analyzed 412 consecutive STEMI patients who had undergone primary percutaneous coronary intervention from January 2006 to September 2011. All causes of death during hospitalization were examined to confirm the diagnostic accuracy of GRACE 1.0 on receiver operating characteristic (ROC) analysis. Similarly, all causes of death during the 360 days after hospitalization were analyzed to confirm the diagnostic accuracy of GRACE 2.0. The average GRACE 1.0 score was 175.8+/-50.9. In-hospital and 360-day mortality were 13.1% and 15.5%, respectively. Area under the ROC curve, which describes the diagnostic accuracy of the GRACE 1.0 predicted in-hospital mortality and the GRACE 2.0 predicted 360-day mortality, was as high as 0.95 and 0.92, respectively. CONCLUSIONS: Both GRACE 1.0 and GRACE 2.0 had a high diagnostic accuracy for prediction of in-hospital and 360-day mortality in Japanese STEMI patients. PMID- 25283790 TI - Sex differences in ADHD symptom severity. AB - BACKGROUND: Males show higher rates of attention deficit hyperactivity disorder (ADHD) than do females. Potential explanations include genuine etiological differences or artifact. METHODS: 2,332 twin and sibling youth participated in behavioral and cognitive testing. Partially competing models of symptom severity distribution differences, the mean difference, and variance difference models, were tested within a randomly selected subsample. The Delta method was used to test for mediation of sex differences in ADHD symptom severity by processing speed, inhibition and working memory. RESULTS: The combined mean difference and variance difference models fully explained the sex difference in ADHD symptom severity. Cognitive endophenotypes mediated 14% of the sex difference effect. CONCLUSIONS: The sex difference in ADHD symptom severity is valid and may be due to differing genetic and cognitive liabilities between the sexes. PMID- 25283792 TI - Vessel response after first- and second-generation drug-eluting stent detected by optical coherence tomography. PMID- 25283793 TI - Left ventricular hypertrophy as a target of treatment in patients with hypertension. PMID- 25283796 TI - Regulation of later neurogenic stages of adult-derived neural stem/progenitor cells by L-type Ca2+ channels. AB - In the adult hippocampus, new neurons are continuously generated and incorporated into the local circuitry in a manner dependent on the network activity. Depolarization evoked by neurotransmitters has been assumed to activate L-type Ca2+ channels (LTCC) which regulate the intracellular Ca2+ -dependent signaling cascades. The process of neurogenesis contains several stages such as proliferation, fate determination, selective death/survival and maturation. Here, we investigated which stage of neurogenesis is under the regulation of LTCC using a clonal line of neural stem/progenitor cells, PZ5, which was derived from adult rat hippocampus. Although undifferentiated PZ5 cells were type 1-like cells expressing both nestin and glial fibrillary acidic protein, they generated neuronal, astrocytic and oligodendrocytic populations in differentiation medium containing retinoic acid. Proliferation of undifferentiated PZ5 cells was dependent on neither the LTCC antagonist, nimodipine (Nimo) nor the LTCC agonists, Bay K 8644 (BayK) or FPL 64176 (FPL), whereas the fraction of neuronal population that expressed both betaIII-tubulin and MAP2 was reduced by Nimo but increased by BayK or FPL. At an earlier period of differentiation (e.g., day 4), the fraction of PZ5 cells expressing HuC/D, pan-neuronal marker, was not affected either by the LTCC activation or inhibition. At a later period of differentiation (e.g., day 9), the fraction of dying neurons was decreased by LTCC activation and increased by LTCC inhibition. It is suggested that the LTCC activation facilitates the survival and maturation of immature neurons, and that its inhibition facilitates the neuronal death. PMID- 25283797 TI - Ultrasound-induced controllable morphology and growth dimension in a dihydrazide based self-assembly system. AB - We have demonstrated ultrasound-induced organogels based on twin-tapered dihydrazide derivatives, oxalyl acid N,N-di(3,4,5-trialkoxybenzoyl)hydrazide (FH Tn). Ultrasound irradiation has been proved to influence gel properties at micro levels. Different self-assembled structures from entangled fibers to tube-like structures and nanoparticles can be easily manipulated by tuning irradiation time and water bath temperature. FT-IR spectra exhibit weakened hydrogen bonding interactions, and XRD studies showed different packing modes before and after sonication. In addition, ultrasound can have effects on gel properties at macro levels. Gels obtained from ultrasound treatment possess different wetting properties, relatively worse rheological properties and thermo-stability. Kinetic studies based on dynamic fluorescence spectra, rheological studies and theoretical calculations suggest that molecular aggregation mode differed from one-dimension to two-dimension for the gel after sonication. PMID- 25283798 TI - Ligand-controlled regiodivergent pathways of rhodium(III)-catalyzed dihydroisoquinolone synthesis: experimental and computational studies of different cyclopentadienyl ligands. AB - Rh(III) -catalyzed directed C-H functionalizations of arylhydroxamates have become a valuable synthetic tool. To date, the regioselectivity of the insertion of the unsaturated acceptor into the common cyclometalated intermediate was dependent solely on intrinsic substrate control. Herein, we report two different catalytic systems that allow the selective formation of regioisomeric 3-aryl dihydroisoquinolones and previously inaccessible 4-aryl dihydroisoquinolones under full catalyst control. The differences in the catalysts are computationally examined using density functional theory and transition state theory of different possible pathways to elucidate key contributing factors leading to the regioisomeric products. The stabilities of the initially formed rhodium complex styrene adducts, as well as activation barrier differences for the migratory insertion, were identified as key contributing factors for the regiodivergent pathways. PMID- 25283794 TI - Unilateral whisker clipping exacerbates ethanol-induced social and somatosensory behavioral deficits in a sex- and age-dependent manner. AB - Prenatal exposure to ethanol results in sensory deficits and altered social interactions in animal and clinical populations. Sensory stimuli serve as important cues and shape sensory development; developmental exposure to ethanol or sensory impoverishment can impair somatosensory development, but their combined effects on behavioral outcomes are unknown. We hypothesized 1) that chronic prenatal ethanol exposure would disrupt social interaction and somatosensory performance during adolescence, 2) that a mild sensory impoverishment (neonatal unilateral whisker clipping; WC) would have a mildly impairing to sub-threshold effect on these behavioral outcomes, and 3) that the effect of ethanol would be exacerbated by WC. Long-Evans dams were fed a liquid diet containing ethanol or pair-fed with a non-ethanol diet on gestational days (G) 6-G21. Chow-fed control animals were also included. One male and female pup per litter underwent WC on postnatal day (P)1, P3, and P5. Controls were unclipped. Offspring underwent social interaction on P28 or P42, and gap-crossing (GC) on P31 or P42. Ethanol-exposed pups played less and crossed shorter gaps than control pups regardless of age or sex. WC further exacerbated ethanol induced play fighting and GC deficits in all males but only in 28-day-old females. WC alone reduced sniffing in all males and in younger females. Thus, prenatal ethanol exposure induced deficits in social interaction and somatosensory performance during adolescence. Sensory impoverishment exacerbates ethanol's effect in 28-day-old male and female animals and in 42-day-old males, suggesting sex- and age-dependent changes in outcomes in ethanol-exposed offspring. PMID- 25283799 TI - Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. AB - AIM: This study measured autoantibodies against tissue transglutaminase (anti tTG) to detect untreated coeliac disease in children with type 1 diabetes and their siblings. METHODS: Anti-tTG was measured in prospectively collected sera from 169 children at the onset of diabetes, 88 of their siblings and 96 matched control children. Coeliac disease was confirmed with a small intestinal biopsy. RESULTS: Coeliac disease was diagnosed in five children before diabetes onset. A further 12 children were diagnosed after diabetes onset, without any gastrointestinal symptoms, and 11 of these had anti-tTG at the onset of diabetes, with the remaining child showing seroconversion within 6 months. Hence, all the children with both diseases had anti-tTG at or before diabetes diagnosis, and the prevalence of coeliac disease was 10.1%. Moreover, 6.8% of the siblings and 3.1% of the control children had elevated levels of anti-tTG. None of the siblings reported any coeliac-related symptoms, despite being positive for anti-tTG, and coeliac disease has so far been biopsy confirmed in 4.5%. CONCLUSION: Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. All diabetes children and their siblings should be tested and followed for the presence of anti-tTG and coeliac disease. PMID- 25283800 TI - Impact of human maxillary sinus volume on grafts dimensional changes used in maxillary sinus augmentation: a multislice tomographic study. AB - PURPOSE: To assess the influence of complete maxillary sinus volume on the dimensional changes of different grafts used in maxillary sinus lift. MATERIALS AND METHODS: Analysis of 50 surgical procedures of maxillary sinus lift performed on 43 subjects using different grafting materials: fresh frozen allogenic particulated bone (11), hydroxyapatite (Endobon((r))) (17), 60% hydroxyapatite + 40% beta-tricalcium phosphate (Bone Ceramic((r))) (12) and Bone Ceramic((r)) + Emdogain((r)) (10). One hundred and fifty multislice tomographic images of the maxillary sinus were obtained using the software Syngo CT 2011 A VOLUME, measuring complete maxillary sinus volume (T0) and dimensional changes of different graft materials during periods of 15 days (T1) and 180 days (T2). The factor studied was the influence of maxillary sinus volume on the dimensional changes of different graft materials used in maxillary sinus lift in patients with posterior edentulism. Data obtained were assessed using the Student's t-test and Pearson's correlation coefficient. RESULTS: No correlation (r 0.112) between the total maxillary sinus volume and the dimensional changes of the different graft materials used in this study was observed (P > 0.05). CONCLUSION: This study demonstrated that there is no sufficient evidence to support the thesis that the volume of the maxillary sinus influences the contraction of the grafts, at least on sample or the biomaterials evaluated in this cohort study. PMID- 25283801 TI - Comparison of in-person and telephone administration of the Mini-Mental State Examination in the University of Alabama at Birmingham Study of Aging. AB - OBJECTIVES: To validate the Mini-Mental State Examination (MMSE) Telephone (MMSET) against the MMSE. DESIGN: Cross-sectional. SETTING: Homes of community dwelling older adults. PARTICIPANTS: African-American and non-Hispanic white adults aged 75 and older participating in the University of Alabama at Birmingham Study of Aging II, a longitudinal epidemiological study across the state of Alabama (N = 419). MEASUREMENTS: Cognition, measured using the MMSE, MMSET, and Six-Item Screener (SIS), and function, based on self-reported difficulty performing instrumental activities of daily living (IADLs). Correlation and agreement coefficients were used to examine concordance of the MMSE and MMSET; linear and logistic regressions were used to test associations with clinical outcomes of IADL difficulty and verified diagnoses of dementia. RESULTS: The MMSET showed good internal consistency (Cronbach alpha = 0.845), similar to the full MMSE, and strong correlation with the latter (Spearman rho = 0.694, P < .001). The MMSET explained a similar proportion of IADL difficulty as the full MMSE (coefficient of variation = 0.201 and 0.189, respectively). The MMSET was also associated with verified dementia diagnoses (area under the receiver operating characteristic curve = 0.73), which was similar to the full MMSE. CONCLUSION: The MMSET is a brief, valid measure of cognition in older adults with psychometric properties similar to that of the full MMSE. Because it can be administered over the telephone, further use in epidemiological studies is promising. PMID- 25283802 TI - Composition of Anopheles coluzzii and Anopheles gambiae microbiota from larval to adult stages. AB - During their immature life stages, malaria mosquitoes are exposed to a wide array of microbes and contaminants from the aquatic habitats. Although prior studies have suggested that environmental exposure shapes the microbial community structure in the adult mosquito, most reports have focused on laboratory-based experiments and on a single mosquito epithelium, the gut. In this study, we investigated the influence of the breeding site on the development of the Anopheles coluzzii and Anopheles gambiae microbiota in natural conditions. We characterized bacterial communities from aquatic habitats, at surface microlayer and subsurface water levels, to freshly emerge adult mosquitoes using multiplexed 16S rRNA gene pyrosequencing and we separately analyzed the microbiota associated with the different epithelia of adult individual, midguts, ovaries and salivary glands. We found that the distribution of bacterial communities in the aquatic habitats differed according to the depth of water collections. Inter-individual variation of bacterial composition was large in larvae guts but adult mosquitoes from a same breeding site shared quite similar microbiota. Although some differences in bacterial abundances were highlighted between the different epithelia of freshly emerged An. coluzzii and An. gambiae, an intriguing feature from our study is the particular similarity of the overall bacterial communities. Our results call for further investigations on the bacterial population dynamics in the different tissues to determine the distinctive characteristics of each microbiota during the mosquito lifespan and to identify specific interactions between certain key phyla or species and the insect life history traits. PMID- 25283803 TI - Molecular evolution of human respiratory syncytial virus attachment glycoprotein (G) gene of new genotype ON1 and ancestor NA1. AB - We conducted a comprehensive genetic analysis of the C-terminal 3rd hypervariable region of the attachment glycoprotein (G) gene in human respiratory syncytial virus subgroup A (HRSV-A) genotype ON1 (93 strains) and ancestor NA1 (125 strains). Genotype ON1 contains a unique mutation of a 72 nucleotide tandem repeat insertion (corresponding to 24 amino acids) in the hypervariable region. The Bayesian Markov chain Monte Carlo (MCMC) method was used to conduct phylogenetic analysis and a time scale for evolution. We also calculated pairwise distances (p-distances) and estimated the selective pressure. Phylogenetic analysis showed that the analyzed ON1 and NA1 strains formed 4 lineages. A strain belonging to lineage 4 of ON1 showed wide genetic divergence (p-distance, 0.072), which suggests that it might be a candidate new genotype, namely ON2. The emergence of genotype NA1 was estimated to have occurred in 2000 (95% of highest probability density, HPD; 1997-2002) and that of genotype ON1 in 2005 (95% HPD; 2000-2010) based on the time-scaled phylogenetic tree. The evolutionary rate of genotype ON1 was higher than that of ancestral genotype NA1 (6.03*10(-3) vs. 4.61*10(-3) substitutions/site/year, p<0.05). Some positive and many negative selection sites were found in both ON1 and NA1 strains. The results suggested that the new genotype ON1 is rapidly evolving with antigenic changes, leading to epidemics of HRSV infection in various countries. PMID- 25283804 TI - Overexpression of a NF-YC transcription factor from bermudagrass confers tolerance to drought and salinity in transgenic rice. AB - Nuclear factor Y (NF-Y) is a ubiquitous transcription factor formed by three distinct subunits, namely NF-YA, NF-YB and NF-YC. A stress-responsive cDNA of NF YC (Cdt-NF-YC1) was isolated from triploid bermudagrass (Cynodon dactylon * Cynodon transvaalensis), and its role in abiotic stress tolerance was investigated in this study. Cdt-NF-YC1 transcript was detected in all vegetative tissues with higher levels being observed in roots. Transcription of Cdt-NF-YC1 in leaves was induced by dehydration, salinity, and treatments with abscisic acid (ABA), hydrogen peroxide (H2 O2 ) or nitric oxide (NO), but not altered by cold. The dehydration- or salt-induced transcription of Cdt-NF-YC1 was blocked by inhibitor of ABA synthesis and scavenger of H2 O2 or NO, indicating that ABA, H2 O2 and NO were involved in the dehydration- and salt-induced transcription of Cdt NF-YC1. Overexpression of Cdt-NF-YC1 resulted in elevated tolerance to drought and salt stress and increased sensitivity to ABA in transgenic rice. Transcript levels of stress/ABA responsive genes (OsLEA3, OsRAB16A, OsLIP9 and OsP5CS1), ABA synthesis and signalling genes (OsNCED3 and OsABI2), and ABA-independent genes (OsDREB1A, OsDREB1B and OsDREB2A) were substantially higher in transgenic rice than in wild-type plants. The results suggested that that Cdt-NF-YC1 is a good candidate gene to increase drought and salinity tolerance in transgenic rice through modulating gene regulation in both ABA-dependent and ABA-independent pathways. PMID- 25283806 TI - Copper on responsive polymer microgels: a recyclable catalyst exhibiting tunable catalytic activity. AB - Copper has been immobilized on a chitosan-based responsive polymer microgel by simply stirring the microgel dispersion with copper sulfate. The ensuing catalyst is highly active for a model azide-alkyne [3+2]-cycloaddition reaction, and can be recycled at least 5 times; the catalytic activity can be tuned via swelling deswelling transitions of the polymer gels. PMID- 25283807 TI - Enhanced cellular content and lactate fraction of the poly(lactate-co-3 hydroxybutyrate) polyester produced in recombinant Escherichia coli by the deletion of sigma factor RpoN. AB - A new approach at the transcriptional level was applied to lactate-based polyester production. Four sigma factor disruptants, DeltarpoN, DeltarpoS, DeltafliA and DeltafecI, of Escherichia coli were used as hosts for poly(lactate co-3-hydroxybutyrate) production from glucose. Among them, DeltarpoN caused dual positive effects of polymer production, enhanced cellular content and lactate fraction. PMID- 25283805 TI - An RNA-Seq based gene expression atlas of the common bean. AB - BACKGROUND: Common bean (Phaseolus vulgaris) is grown throughout the world and comprises roughly 50% of the grain legumes consumed worldwide. Despite this, genetic resources for common beans have been lacking. Next generation sequencing, has facilitated our investigation of the gene expression profiles associated with biologically important traits in common bean. An increased understanding of gene expression in common bean will improve our understanding of gene expression patterns in other legume species. RESULTS: Combining recently developed genomic resources for Phaseolus vulgaris, including predicted gene calls, with RNA-Seq technology, we measured the gene expression patterns from 24 samples collected from seven tissues at developmentally important stages and from three nitrogen treatments. Gene expression patterns throughout the plant were analyzed to better understand changes due to nodulation, seed development, and nitrogen utilization. We have identified 11,010 genes differentially expressed with a fold change >= 2 and a P-value < 0.05 between different tissues at the same time point, 15,752 genes differentially expressed within a tissue due to changes in development, and 2,315 genes expressed only in a single tissue. These analyses identified 2,970 genes with expression patterns that appear to be directly dependent on the source of available nitrogen. Finally, we have assembled this data in a publicly available database, The Phaseolus vulgaris Gene Expression Atlas (Pv GEA), http://plantgrn.noble.org/PvGEA/ . Using the website, researchers can query gene expression profiles of their gene of interest, search for genes expressed in different tissues, or download the dataset in a tabular form. CONCLUSIONS: These data provide the basis for a gene expression atlas, which will facilitate functional genomic studies in common bean. Analysis of this dataset has identified genes important in regulating seed composition and has increased our understanding of nodulation and impact of the nitrogen source on assimilation and distribution throughout the plant. PMID- 25283808 TI - A new aldehyde oxidase catalyzing the conversion of glycolaldehyde to glycolate from Burkholderia sp. AIU 129. AB - We found a new aldehyde oxidase (ALOD), which catalyzes the conversion of glycolaldehyde to glycolate, from Burkholderia sp. AIU 129. The enzyme further oxidized aliphatic aldehydes, an aromatic aldehyde, and glyoxal, but not glycolate or alcohols. The molecular mass of this enzyme was 130 kDa, and it was composed of three different subunits (alphabetagamma structure), in which the alpha, beta, and gamma subunits were 76 kDa, 36 kDa, and 14 kDa, respectively. The N-terminal amino acid sequences of each subunit showed high similarity to those of putative subunits of xanthine dehydrogenase. Metals (copper, iron and molybdenum) and chelating reagents (alpha,alpha'-dipyridyl and 8 hydroxyquinoline) inhibited the ALOD activity. The ALOD showed highest activity at pH 6.0 and 50 degrees C. Twenty mM glycolaldehyde was completely converted to glycolate by incubation at 30 degrees C for 3 h, suggesting that the ALOD found in this study would be useful for enzymatic production of glycolate. PMID- 25283810 TI - Postoperative atrial fibrillation: role of inflammatory biomarkers and use of colchicine for its prevention. AB - Postoperative atrial fibrillation (POAF) is the most common complication following cardiac surgery, occurring in up to 65% of cardiac surgical patients. It is a condition associated with increased morbidity, increased length of hospital stay, and increased health care costs. One of the many potential causes of POAF is postsurgical inflammation, as demonstrated by increased levels of inflammatory biomarkers such as C-reactive protein and interleukin-6. Although still a subject of debate, the role of these inflammatory markers in the pathogenesis of POAF remains under vigorous investigation. Several antiinflammatory drugs have demonstrated promising results in prevention of POAF, including nonsteroidal antiinflammatory drugs, glucocorticoids, and statins. Colchicine is one of the oldest medications used in modern medicine, typically for the treatment and prevention of gout. New evidence has recently surfaced that colchicine may also be useful in the prevention of POAF. In recent studies, colchicine has demonstrated both safety and efficacy in the prevention of POAF. Several new studies are currently being initiated that may further elucidate colchicine's role in the prevention of POAF. PMID- 25283811 TI - Two novel missense mutations of ATP2A2 in two Chinese patients with sporadic Darier disease. AB - Darier disease (DD) is a rare autosomal dominant skin disorder with characteristic abnormal keratinization and acantholysis. The causative gene, ATP2A2, is located on chromosome 12, and encodes a sarco/endoplasmic reticulum calcium pump ATPase (SERCA2). Two Chinese patients with sporadic DD participated in this study. Genomic sequence analysis identified two novel missense mutations (c.742C>A and c.2098A>G) in the ATP2A2 gene. Our findings provide an additional ATP2A2 mutation causative for DD development, and new lines of evidences for the understanding of genotype-phenotype correlations. PMID- 25283809 TI - Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity. AB - YES-associated protein 2 (YAP2) transcriptional regulator drives a multitude of cellular processes, including the newly discovered Hippo tumor suppressor pathway, by virtue of the ability of its WW domains to bind and recruit PPXY containing ligands to specific subcellular compartments. Herein, we employ an array of biophysical tools to investigate allosteric communication between the WW tandem domains of YAP2. Our data show that the WW tandem domains of YAP2 negatively cooperate when binding to their cognate ligands. Moreover, the molecular origin of such negative cooperativity lies in an unfavorable entropic contribution to the overall free energy relative to ligand binding to isolated WW domains. Consistent with this notion, the WW tandem domains adopt a fixed spatial orientation such that the WW1 domain curves outwards and stacks onto the binding groove of the WW2 domain, thereby sterically hindering ligand binding to both itself and its tandem partner. Although ligand binding to both WW domains disrupts such interdomain stacking interaction, they reorient themselves and adopt an alternative fixed spatial orientation in the liganded state by virtue of their ability to engage laterally so as to allow their binding grooves to point outwards and away from each other. In short, while the ability of WW tandem domains to aid ligand binding is well documented, our demonstration that they may also be subject to negative binding cooperativity represents a paradigm shift in our understanding of the molecular action of this ubiquitous family of protein modules. PMID- 25283812 TI - Pd-catalyzed chemoselective carbonylation of aminophenols with iodoarenes: alkoxycarbonylation vs aminocarbonylation. AB - Palladium-catalyzed chemoselective carbonylation of aminophenols with iodoarenes was realized by changing ligand and base. 3- or 4-Aminophenols afforded esters in high yields and selectivities using 1,3-bis(diphenylphosphino)propane as the ligand and K2CO3 as the base, and gave amides in high yields and selectivities using 1,3-bis(diisobutylphosphino)propane as the ligand and DBU as the base. 2 Aminophenol only gave amides in high yields under both conditions. PMID- 25283813 TI - Assessment of new public management in health care: the French case. AB - The French health care system embraced New Public Management (NPM) selectively, and crafted their own version of NPM using Diagnostic-Related-Group accounting to re-centralize the health care system. Other organizational changes include the adoption of quasi-markets, public private partnerships, and pay-for-performance schemes for General Practitioners. There is little evidence that these improved the performance of the system. Misrepresentation has remained high. With the 2009 Hospital, Patients, Health and Territories Act physician participation in hospital governance receded. Decision-making powers and health units were re concentrated to instill greater national coherence into the health system. PMID- 25283814 TI - Salvage focal prostate cryoablation for locally recurrent prostate cancer after radiotherapy: initial results from the cryo on-line data registry. AB - BACKGROUND: Several investigators have tried to apply salvage focal prostate cryoablation to small numbers of patients with biopsy-proven unilateral recurrent prostate cancer (PCa) after radiotherapy with the aim of decreasing complications of salvage cryoablation. We report contemporary outcomes of salvage focal cryoablation for locally recurrent PCa after radiotherapy within the Cryo On-Line Data (COLD) Registry. METHODS: We queried the COLD Registry to identify patients diagnosed as locally recurrent PCa after radiotherapy and treated with salvage focal cryoablation. Patients with hormone ablation after cryotherapy were excluded. The biochemical disease-free survival and morbidities were analyzed. Biochemical failure was defined using the Phoenix definition. RESULTS: From 2002 to 2012, 91 patients with biopsy-proven radio-recurrent PCa underwent salvage focal cryoablation with curative intent. The biochemical disease-free survival rates were 95.3%, 72.4%, and 46.5% at 1, 3, and 5 years, respectively. Positive biopsies after salvage focal cryoablation were observed in four of 14 patients who underwent biopsy (28.6%). Rectourethral fistula was observed in three cases (3.3%). Urinary retention was observed in six cases (6.6%). Incontinence (requiring pad use) was reported in five cases (5.5%). Intercourse was reported in 10 of 20 patients (50%) who reported potency before salvage focal cryoablation. CONCLUSIONS: The outcomes from this observational study indicate that salvage focal cryoablation can be an effective treatment with encouraging potency preservation for patients with locally recurrent PCa after radiotherapy. However, other morbidity including rectourethral fistula and incontinence are not clearly lower than for patients treated with salvage whole gland cryoablation. Studies with longer follow-up, more patients, and direct comparison to salvage whole gland cryoablation are needed before recommending salvage focal cryoablation as a standard treatment option for these patients. PMID- 25283816 TI - Nanoporous hollow transition metal chalcogenide nanosheets synthesized via the anion-exchange reaction of metal hydroxides with chalcogenide ions. AB - Nanoporous hollow transition metal chalcogenides are of special interest for a variety of promising applications. Although some advanced synthetic methods have been reported, the development of a facile and general strategy to fabricate porous hollow nanostructures of transition metal chalcogenides, especially with enhanced electrocatalytic performance, still remains highly challenged. Herein, we report a facile chemical transformation strategy to prepare nanoporous hollow Co3S4 nanosheets via the anion exchange reaction of Co(OH)2 with sulfide ions. The chemical transformation mechanism involves the as-formed layer of nanoporous cobalt sulfide on Co(OH)2 driven by the anion-exchange-reaction and lattice mismatch induced quick strain release, a following diffusion-effect-dominated core-shell hollow intermediate with hollow interiors, and subsequent Ostwald ripening growth of hollow nanosheets at elevated temperatures. This anion exchange strategy of transition metal hydroxides with chalcogenide ions is also suitable for fabricating nanoporous hollow nanosheets of other metal chalcogenides (e.g., CoSe2, CoTe2, CdS, and NiS). The as-prepared nanoporous hollow Co3S4 nanosheets are found to be highly active and stable for electrocatalytic oxygen evolution reaction. PMID- 25283815 TI - Pulmonary vein stenosis due to invasion of metastatic clear cell sarcoma. PMID- 25283817 TI - Evaluation and prevention of enamel surface damage during dental restorative procedures. AB - BACKGROUND: This study examined the effect of operator experience, dominance, tooth position and access, on frequency and extent of iatrogenic damage to approximal tooth surfaces during conventional Class II cavity preparations. The effectiveness of protective devices in minimizing damage was also explored. METHODS: 10 students and 10 experienced dentists each prepared 24 Class II cavity preparations in typodont teeth without protection; 10 utilizing stainless steel matrix bands and 10 utilizing protective wedges. The frequency and extent of damage were analysed with respect to the above variables. Subsequently, 20 natural and 20 typodont teeth were utilized to establish the relationship in depth of damage caused by a high-speed diamond bur on typodont versus natural teeth. RESULTS: Dentists caused iatrogenic damage on 74% of approximal surfaces without protection, which fell to 50% and 46% respectively when matrix bands and wedges were used as guards. The corresponding rates of damage for students were 94%, 80% and 44%. There was no difference in depth of damage caused on the two types of teeth when bur was in contact with teeth for a very short time. CONCLUSIONS: Greater operator experience and the use of guards reduces iatrogenic damage to proximal surfaces during preparation with high-speed rotary instruments. PMID- 25283818 TI - Normative reference ranges for binocular summation as a function of age for low contrast letter charts. AB - PURPOSE: Binocular summation (BiS), defined as the superiority of binocular over monocular viewing on visual threshold tasks, is most often studied in laboratory settings. Few studies have evaluated BiS with readily available clinical tools. Low contrast acuity (LCA) charts are increasingly popular in clinical research, yet their utility in detecting BiS has not been evaluated. METHODS: 129 normal subjects aged 3 to 85 years were prospectively enrolled and underwent monocular and binocular testing using 2.5% and 1.25% Sloan LCA charts and Pelli-Robson (PR) contrast sensitivity (CS) charts at an academic institution. Subjects also underwent similar testing with Early Treatment Diabetic Retinopathy Study (ETDRS) VA charts. BiS was calculated as the difference between the better eye and binocular scores. RESULTS: Monocular and binocular scores decreased with increasing age for all metrics. The mean (+/-SD) BiS scores for 2.5% and 1.25% Sloan LCA were 6+/-4.5 and 3+/-5 letters, respectively. BiS score was 4.5+/-7 letters for PR charts and 2+/-3 letters for ETDRS VA. There was a significant effect of age on BiS for the low contrast metrics (P<=0.001 for all), but not for high-contrast ETDRS VA. Linear regression revealed significant associations between increased interocular difference (IOD) in acuity and decreased BiS for all tests, and associations between increasing age and decreased BiS for the LCA tests. CONCLUSION: Of the clinical tests evaluated, 2.5% and 1.25% Sloan LCA charts most readily demonstrated BiS in young normal subjects. BiS declined with increasing age and increased IOD. Median values presented in this study may be useful for future clinical studies utilizing LCA. PMID- 25283819 TI - Mitochondrial apoptosis-inducing factor is involved in doxorubicin-induced toxicity on H9c2 cardiomyoblasts. AB - The cardiotoxicity induced by the anti-cancer doxorubicin involves increased oxidative stress, disruption of calcium homeostasis and activation of cardiomyocyte death. Nevertheless, antioxidants and caspase inhibitors often show little efficacy in preventing cell death. We hypothesize that a caspase independent cell death mechanism with the release of the apoptosis-inducing factor from mitochondria is involved in doxorubicin toxicity. To test the hypothesis, H9c2 cardiomyoblasts were used as model for cardiac cells. Our results demonstrate that z-VAD-fmk, a pan-caspase inhibitor, does not prevent doxorubicin toxicity in this cell line. Doxorubicin treatment results in AIF translocation to the nuclei, as confirmed by Western Blotting of cell fractions and confocal microscopy. Also, doxorubicin treatment of H9c2 cardiomyoblasts resulted in the appearance of 50kbp DNA fragments, a hallmark of apoptosis inducing factor nuclear effects. Apoptosis-inducing factor knockdown using a small-interfering RNA approach in H9c2 cells resulted in a reduction of doxorubicin toxicity, including decreased p53 activation and poly-ADP-ribose polymerase cleavage. Among the proteases that could be responsible for apoptosis inducing factor cleavage, doxorubicin decreased calpain activity but increased cathepsin B activation, with inhibition of the latter partly decreasing doxorubicin toxicity. Altogether, the results support that apoptosis-inducing factor release is involved in doxorubicin-induced H9c2 cell death, which explains the limited ability of caspase inhibitors to prevent toxicity. PMID- 25283820 TI - H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis. AB - H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90days (presymptomatic), 110days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions. PMID- 25283822 TI - Suitable design of mouthguard for sports-active person with spaced dentition. AB - AIM: Custom-made mouthguard (MG) is popularly used by sports-active persons or athletes having either normo-occlussion or malocclusion to prevent dental injury. For sports-active person with malocclusion, specially designed mouthguard is often required. The purpose of this study was to make a suitable design custom made mouthguard for sports-active person with spaced dentition by the shock absorption capability. MATERIALS AND METHODS: Two different types of double layered mouthguards were made from a model of a sports-active person having spaced dentition with polyolefin sheets. One type was made by filling the interproximal spaces of the spaced dentition and the other type, which was devoid of interproximal space covering, without mouthguard materials (keeping space). The impact tests were carried out by a free-falling object via testing machine and a vertical rod. The strains of the dentition with mouthguard were measured by means of strain gage system to compare between two different designs of mouthguard. Unpaired t-test was carried out as statistical analysis. RESULT: The strains of the dentition with mouthguard by filling the interproximal spaces were significantly low compared with the mouthguard by keeping spaces (P < 0.05). CONCLUSION: For sports-active person with spaced dentition, it is important for reducing injury risks that the mouthguard covered the teeth and filled or embedded interproximal space certainly. PMID- 25283821 TI - Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na(+)-ATPase in chronically undernourished rats. AB - This study has investigated the participation of altered signaling linked to angiotensin II (Ang II) that could be associated with increased Na(+) reabsorption in renal proximal tubules during chronic undernutrition. A multideficient chow for rats (basic regional diet, BRD) was used, which mimics several human diets widely taken in developing countries. The Vmax of the ouabain resistant Na(+)-ATPase resident in the basolateral membranes increased >3-fold (P<0.001) accompanied by an increase in Na(+) affinity from 4.0 to 0.2mM (P<0.001). BRD rats had a >3-fold acceleration of the formation of phosphorylated intermediates in the early stage of the catalytic cycle (in the E1 conformation) (P<0.001). Immunostaining showed a huge increase in Ang II-positive cells in the cortical tubulointerstitium neighboring the basolateral membranes (>6-fold, P<0.001). PKC isoforms (alpha, epsilon, lambda, zeta), Ang II type 1 receptors and PP2A were upregulated in BRD rats (in %): 55 (P<0.001); 35 (P<0.01); 125, 55, 11 and 30 (P<0.001). PKA was downregulated by 55% (P<0.001). With NetPhosK 1.0 and NetPhos 2.0, we detected 4 high-score (>0.70) regulatory phosphorylation sites for PKC and 1 for PKA in the primary sequence of the Na(+)-ATPase alpha subunit, which are located in domains that are key for Na(+) binding and catalysis. Therefore, chronic undernutrition stimulates tubulointerstitial activity of Ang II and impairs PKC- and PKA-mediated regulatory phosphorylation, which culminates in an exaggerated Na(+) reabsorption across the proximal tubular epithelium. PMID- 25283823 TI - [A case of myasthenia gravis with invasive thymoma associated with diffuse panbronchiolitis, alopecia, dysgeusia, cholangitis and myositis]. AB - A 43-year-old man was admitted to our hospital because of diplopia, ptosis, and dysphagia that had begun three years previously. He was diagnosed with myasthenia gravis (MG) and invasive thymoma and treated with corticosteroid, thymectomy, and radiation therapy. Ten years after the thymectomy, computed tomography (CT) showed metastasis of the thymoma in the left lower lobe of the lung. Two years after this recurrence, when the patient was 55, respiratory symptoms such as wheezing, persistent cough, and dyspnea appeared. Chronic sinusitis, diffuse centrilobular opacities on CT, and positivity for HLA-B54 led to a diagnosis of diffuse panbronchiolitis (DPB). Despite treatment with clarithromycin, the respiratory symptoms worsened. The patient developed alopecia and body hair loss at the age of 56 followed by dysgeusia, cholangitis, and myositis with positivity for anti-Kv1.4 antibodies. Although treatment with an increased dose of corticosteroid improved hair loss, dysgeusia, cholangitis, and myositis, he died of progression of DPB and serious respiratory infection at the age of 58. In this case, various autoimmune disorders occurred together with MG as complications of thymoma. Although alopecia, dysgeusia, and myositis are already known as complications of MG associated with thymoma, cholangitis is not well-recognized since there have been few reports suggesting a causal relationship between cholangitis and thymoma. Furthermore, DPB caused by immunodeficiency and respiratory tract hypersensitivity associated with thymoma and HLA-B54, respectively, is the distinctive feature of our case. Neurologists should be aware that various organs can be damaged directly and indirectly by abnormal T cells from thymoma in patients with MG. PMID- 25283824 TI - [Lymphocytic primary angiitis of the central nervous system with fan-shaped linear enhancement converging to the lateral ventricles: a case report]. AB - We report a case of lymphocytic primary angiitis of the central nervous system (PACNS) with a characteristic gadolinium-enhancement pattern on magnetic resonance imaging (MRI). A 48-year-old, right-handed man presented with a 3-month history of tremor and progressing dementia. Neurologic examination revealed cognitive decline with anterograde amnesia and postural tremor of the fingers. Except for the positive result of serum antinuclear antibody, intense investigations for infectious, rheumatic and neoplastic diseases were negative. Analysis of cerebrospinal fluid showed mild pleocytosis (14 cells/MUl). Brain MRI revealed diffuse hyperintense areas in the deep cerebral white matter on T2 weighted images. Gadolinium-enhanced T1-weighted images demonstrated fan-shaped multiple linear enhancements converging to the body of the lateral ventricles. Brain biopsy showed intense infiltration of small lymphocytes without atypia or granuloma mainly within the vessel walls and perivascular spaces. The diagnosis of lymphocytic PACNS was made. Administration of corticosteroid markedly improved the tremor and cognitive dysfunction. MRI after the treatment showed resolution of the abnormal fan-shaped linear enhancement. He returned to his previous occupation. PACNS should be included in the differential diagnosis for fan-shaped linear enhancement converging to the lateral ventricles on MRI in patients with unexplained progressing dementia. PMID- 25283825 TI - [Acute encephalitis with refractory partial status epilepticus treated with early immunotherapies including plasma exchange: a case report]. AB - We describe a patient of acute encephalitis with refractory partial status epilepticus who was successfully treated with early immunotherapy. A 35-year-old male presented with generalized seizures a week after febrile upper respiratory illness. He developed refractory multifocal and generalized seizures despite multiple antiepileptic drug therapies, thereby requiring intubation on the 8(th) day after admission. No significant improvement was observed after steroid pulse and intravenous immunoglobulin (IVIG) therapies. On the 18(th) day, he received plasma exchange (PE) therapy in combination with intravenous thiamylal and lidocaine to achieve burst-suppression coma. This multidisciplinary treatment led to remission of refractory status epilepticus and subsequent withdrawal from general anesthesia. Although anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid were negative, other neural surface antibodies may responsible for the development of status epilepticus in this case. Clinical features in this case, including previous good health, an antecedent febrile illness, and prolonged treatment-resistant status epilepticus, were similar to those of the acute phase of new-onset refractory status epilepticus (NORSE) syndrome. Consecutive use of glucocorticoids, IVIG, and PE in the early phase was speculated to ameliorate seizures by suppressing abnormal activation of humoral immunity. This indicates that early aggressive immunotherapy may prevent complications resulting from immune-mediated treatment-resistant status epilepticus. PMID- 25283826 TI - [HIV encephalopathy due to drug resistance despite 2-year suppression of HIV viremia by cART]. AB - A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy. PMID- 25283827 TI - [Pure word deafness due to a localization-related seizure: a case study]. AB - We describe a 31-year-old, right-handed man who exhibited pure word deafness (PWD) due to a localization-related seizure. The patient was suddenly unable to comprehend spoken words, whereas he had no difficulty in speaking, comprehending written language, or discriminating non-verbal sounds. Diffusion-weighted imaging and fluid-attenuated inversion recovery on brain magnetic resonance imaging revealed hyperintense lesions in the left superior temporal gyrus (STG) and left superior marginal gyrus (SMG). Furthermore, brain single-photon emission computed tomography showed that these lesions were hyperperfused. An electroencephalogram (EEG) showed multiple spike-and-slow-wave complexes spreading to the left temporal regions. Immediately after administering midazolam intravenously, the patient was able to comprehend spoken words, and the epileptiform discharges in the left temporal regions disappeared. These findings indicate that he suffered from PWD resulting from a dysfunction of the left hemisphere alone. Furthermore, they suggest that the left STG and left SMG play an important role in the recognition of spoken words. PMID- 25283828 TI - [Pathognomonic magnetic resonance imaging (MRI) finding of fluid-fluid level in pyogenic ventriculitis: two case reports]. AB - Pyogenic ventriculitis is an uncommon and potentially fatal central nervous system infection. Delayed treatment due to non specific clinical symptoms may lead to an unfavorable outcome. Brain magnetic resonance imaging (MRI) plays an important role in the diagnosis of pyogenic ventriculitis. We describe two patients with pyogenic ventriculitis presenting with a pathognomonic MRI finding. The first patient, a 77-year-old female, developed high fever and consciousness disturbance. MR images revealed hyperintense lesions with a fluid-fluid level in the bilateral lateral ventricles on diffusion-weighted images (DWIs) and hypointense lesions on T2-weighted images (T2WIs). MR images also revealed findings of left otitis media. The second patient, a 63-year-old male, who had a past history of multiple myeloma and had received chemotherapy, developed high fever and left hemiparesis. MR images revealed a hyperintense lesion with a fluid fluid level in the right lateral ventricle on DWIs and a hypointense lesion on T2WIs, multiple ring-enhancing lesions on gadolinium enhanced T1-weighted images, and pontine infarction on DWIs. Chest computed tomography revealed an infiltrative shadow in the lower lobe of the left lung. On the basis of MRI findings, both patients were diagnosed as having pyogenic ventriculitis and were administered high-dose meropenem intravenously. The second patient was also administered sulfamethoxazole-trimethoprim orally. Intraventricular abnormalities disappeared and the patients achieved complete remission after the antibacterial treatment. Intraventricular hyperintense lesions on DWIs and hypointense ones on T2WIs with a fluid-fluid level is a pathognomonic finding of pyogenic ventriculitis and has not been previously reported in other diseases. Recognition of the characteristic MRI features and initiation of high-dose and appropriate antibiotics in an early stage may lead to a favorable outcome of the disease. PMID- 25283829 TI - [A case of cerebral syphilitic gumma mimicking a brain tumor]. AB - We report a case of young immunocompetent woman who was presented with a left parieto-temporal mass as the first and single manifestation of syphilis. A 23 year-old woman with no significant past medical history was reffered to our hospital due to 3 month history of headache. She had a single unprotected sexual intercourse with a promiscuous man 6 month before the time of admission. Physical and neurological examinations revealed no obvious abnormalities. A brain tumor was firstly suggested according to the findings of brain magnetic resonance imaging (MRI). However, the serologic and cerebrospinal fluid test of syphilis proved to be positive, syphilitic gumma was most likely suspected. She responded dramatically to benzylpenicillin potassium. Cerebral syphilitic gumma is a rare manifestations of the neurosyphilis. Treponemal invasion of the cerebrospinal fluid occurs in approximately 25 to 60% of patients after the infection, but most cases spend asymptomatic. Cerebral gumma should be considered in differential diagnosis of any intracranial mass lesions, even in the early syphilitic stages. PMID- 25283830 TI - [A 53-year-old man with herpes encephalitis showing acceleration of improvement in higher brain function after general anesthesia with sevoflurane: a case report]. AB - We experienced a right-handed 53-year-old man who presented with disturbance of consciousness and fever. Herpes simplex encephalitis (HSE) was diagnosed based on the detection of herpes simplex virus DNA in the cerebrospinal fluid. The administration of acyclovir for 42 days improved his consciousness level. Drowsiness, fever and seizures reappeared 20 days after stopping acyclovir treatment (day 67) and he responded well to vidarabine and methylprednisolone pulse therapy. An assessment of aphasia on day 98 revealed transcortical sensory aphasia. Brain MRI showed lesion in the left temporal lobe, bilateral insular cortexes and bilateral frontal lobe. His higher brain dysfunction continued. On day 156, he underwent hip replacement arthroplasty under general anesthesia sevoflurane. His higher brain dysfunction rapidly improved thereafter. We concluded that the accelerated improvement in our patient's higher brain function was related to the protective effect of sevoflurane. Some reports also show the protective effects of sevoflurane in experimental allergic encephalomyelitis by inhibition of T cell activation. These protective and anti-inflammatory effects may explain the accelerated improvement in higher brain function after general anesthesia. PMID- 25283831 TI - [A case of adult-onset type II citrullinemia (CTLN2) triggered by an overseas travel]. AB - A 43-year-old male presented with abnormal behavior and consciousness disturbance on the day after traveling abroad and was admitted to our hospital. Laboratory tests showed hyperammonemia and hypercitrullinemia. The electro-encephalogram showed frontal dominant bilateral slow delta burst. He had a peculiar taste for nuts. But he didn't take nuts during the overseas travel for 3 days. The family history revealed that his younger brother died of a status epilepticus of unknown cause at the age of 29. These findings were compatible with hepatic encephalopathy due to adult-onset type II citrullinemia (CTLN2). Gene analysis provided a definite diagnosis of CTLN2. Diet and drug therapy have improved his condition. He is due to have liver transplantation which is the only established radical treatment for CTLN2 if his condition becomes worse. The present case shows that cessation of the habitual intake of nuts only for 3 days could lead to onset of CTLN2. PMID- 25283832 TI - [Skeletal muscle magnetic resonance imaging study in a patient with diabetic lumbosacral radiculoplexus neuropathy]. AB - A 63-year-old man with type 2 diabetes mellitus developed deep aching and numbness in the right hip and lower extremity with rapid body weight loss. Neurological examination revealed weakness of the right hamstrings, tibialis anterior, and peroneus longus muscles with diminished ankle tendon reflex. We diagnosed him with diabetic lumbosacral radicuoloplexus neuropathy (DLRPN) based on neurological, radiological, and neurophysiological findings. Magnetic resonance imaging (MRI) of skeletal muscles showed high intensity signals on T2 weighted images in bilateral hamstrings, adductor magnus and right tensor fasciae latae, and lower leg extensor muscles. The MRI findings suggested muscle edema caused by acute denervation. DLRPN, or diabetic amyotrophy, is known to be caused by ischemic axonal degeneration. Our patient showed good functional recovery, and abnormal MRI signals in the involved muscles mostly disappeared in parallel to the clinical course. Distribution of the denervated muscles suggested that our patient had either patchy lesions in the lumbosacaral plexus or mononeuropathy multiplex in the nerve branches. The current study highlights the potential of skeletal muscle MRI for clinical evaluation of DLRPN. PMID- 25283833 TI - [The proceedings of the 206th Kyushyu Regional Meeting of the Japanese Society of Neurology]. PMID- 25283836 TI - Recovery of rare earth elements from the sulfothermophilic red alga Galdieria sulphuraria using aqueous acid. AB - The demand for rare earth elements has increased dramatically in recent years because of their numerous industrial applications, and considerable research efforts have consequently been directed toward recycling these materials. The accumulation of metals in microorganisms is a low-cost and environmentally friendly method for the recovery of metals present in the environment at low levels. Numerous metals, including rare earth elements, can be readily dissolved in aqueous acid, but the efficiency of metal biosorption is usually decreased under the acidic conditions. In this report, we have investigated the use of the sulfothermophilic red alga Galdieria sulphuraria for the recovery of metals, with particular emphasis on the recovery of rare earth metals. Of the five different growth conditions investigated where G. sulphuraria could undergo an adaptation process, Nd(III), Dy(III), and Cu(II) were efficiently recovered from a solution containing a mixture of different metals under semi-anaerobic heterotrophic condition at a pH of 2.5. G. sulphuraria also recovered Nd(III), Dy(III), La(III), and Cu(II) with greater than 90% efficiency at a concentration of 0.5 ppm. The efficiency remained unchanged at pH values in the range of 1.5-2.5. Furthermore, at pH values in the range of 1.0-1.5, the lanthanoid ions were collected much more efficiently into the cell fractions than Cu(II) and therefore successfully separated from the Cu(II) dissolved in the aqueous acid. Microscope observation of the cells using alizarin red suggested that the metals were accumulating inside of the cells. Experiments using dead cells suggested that this phenomenon was a biological process involving specific activities within the cells. PMID- 25283837 TI - Multi-isotope ((15)N, (18)O and (13)C) indicators of sources and fate of nitrate in the upper stream of Chaobai River, Beijing, China. AB - Dual isotopes of nitrate ((15)N and (18)O) and carbon isotopes of dissolved inorganic carbon ((13)C) together with water chemistry were used to identify the sources and fate of nitrate in the upper stream of Chaobai River, north China. The results show that NO3(-) concentrations ranges from 0.03 mmol L(-1) to 0.80 mmol L(-1). Sampling sites from watershed with dominant forest land had higher NO3(-) concentrations and lower delta(15)N-NO3(-) (<100/00) in the wet season than in the dry season, while those from watershed with more anthropogenic activities had lower NO3(-) concentrations and higher delta(15)N-NO3(-) (>100/00) in the wet season. Compositions of isotopes and chemistry indicated that NO3(-) originated mainly from soil N, sewage and livestock wastes and atmospheric nitrogen. Furthermore, the mixing model suggested that soil N was the major NO3( ) source in the wet season, while the sewage and livestock wastes contributed the most in the dry season. Compared to rivers, the Miyun Reservoir had a higher contribution of atmospheric N and the N input from the upper rivers exerted significant influence over the reservoir. Mineralization and nitrification played an important role in N biogeochemistry based on the isotopes ((15)N and (18)O and (13)C) and chemical data. There appeared to be no significant denitrification in the watershed according to the three isotopes and chemical ions. The combined use of (15)N, (18)O and (13)C proved to be useful for further identification of the sources and fate of nitrate in watersheds with dominant forest land in the wet season. PMID- 25283838 TI - Bacillus thuringiensis membrane-damaging toxins acting on mammalian cells. AB - Bacillus thuringiensis is widely used as a biopesticide in forestry and agriculture, being able to produce potent species-specific insecticidal toxins and considered nonpathogenic to other animals. More recently, however, repeated observations are documenting the association of this microorganism with various infectious diseases in humans, such as food-poisoning-associated diarrheas, periodontitis, bacteremia, as well as ocular, burn, and wound infections. Similar to B. cereus, B. thuringiensis produces an array of virulence factors acting against mammalian cells, such as phosphatidylcholine- and phosphatidylinositol specific phospholipase C (PC-PLC and PI-PLC), hemolysins, in particular hemolysin BL (HBL), and various enterotoxins. The contribution of some of these toxins to B. thuringiensis pathogenicity has been studied in animal models of infection, following intravitreous, intranasal, or intratracheal inoculation. These studies lead to the speculation that the activities of PC-PLC, PI-PLC, and HBL are responsible for most of the pathogenic properties of B. thuringiensis in nongastrointestinal infections in mammals. This review summarizes data regarding the biological activity, the genetic basis, and the structural features of these membrane-damaging toxins. PMID- 25283839 TI - Interleukin-2 receptor antagonists for pediatric liver transplant recipients: a systematic review and meta-analysis of controlled studies. AB - IL-2RA are frequently used as induction therapy in liver transplant recipients to decrease the risk of AR while allowing the reduction of concomitant immunosuppression. The exact association with the use of IL-2RA, however, is uncertain. We performed a systematic literature search for relevant studies. Random effects models were used to assess the incidence of AR, steroid-resistant rejection, graft loss, patient death, and adverse drug reaction, with or without IL-2RA. Six studies (two randomized and four non-randomized) met the eligibility criteria. Acute rejection at six months or later favored the use of IL-2RA significantly (RR 0.38; 95% CI 0.22-0.66, p = 0.0005). Although not statistically significant, IL-2RA showed a substantial reduction of the risk of steroid resistant rejection (RR 0.32; CI 0.19-1.03, p = 0.0594). Graft loss and patient death showed a reductive tendency through the use of IL-2RA. The use of IL-2RA is safe and is associated with a statistically significantly lower incidence of AR after transplantation and substantial reduction of steroid-resistant rejection, graft loss, and patient death. PMID- 25283840 TI - The Kruppel-like factor 2 transcription factor gene is recurrently mutated in splenic marginal zone lymphoma. PMID- 25283841 TI - A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. AB - AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs, for example, Vorinostat), which interrupt the DNA damage response, to kill p53-wild type (wt) or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knockdown significantly sensitized cells to HDACIs. Although AZD1775 induced Chk1 activation, reflected by markedly increased Chk1 S296/S317/S345 phosphorylation leading to inhibitory T14 phosphorylation of cdc2/Cdk1, these compensatory responses were sharply abrogated by HDACIs. This was accompanied by premature mitotic entry, multiple mitotic abnormalities and accumulation of early S-phase cells displaying increased newly replicated DNA, culminating in robust DNA damage and apoptosis. The regimen was active against patient-derived acute myelogenous leukemia (AML) cells harboring either wt or mutant p53 and various next-generation sequencing-defined mutations. Primitive CD34(+)/CD123(+)/CD38(-) populations enriched for leukemia-initiating progenitors, but not normal CD34(+) hematopoietic cells, were highly susceptible to this regimen. Finally, combining AZD1775 with Vorinostat in AML murine xenografts significantly reduced tumor burden and prolonged animal survival. A strategy combining Wee1 with HDACI inhibition warrants further investigation in AML with poor prognostic genetic aberrations. PMID- 25283842 TI - The role of TLR8 signaling in acute myeloid leukemia differentiation. AB - Acute myeloid leukemia (AML) is an aggressive disease with a poor 5-year survival of 21% that is characterized by the differentiation arrest of immature myeloid cells. For a rare subtype of AML (acute promyeloctyic leukemia, 5-10% of cases), all-trans retinoic acid therapy removes the differentiation block, yielding over a 90% cure rate. However, this treatment is not effective for the other 90-95% of AML patients, suggesting that new differentiation strategies are needed. Interestingly, differentiation is induced in normal hematopoietic cells through Toll-like receptor (TLR) stimulation and TLRs are expressed on AML cells. We present evidence that the TLR8 activation promotes AML differentiation and growth inhibition in a TLR8/MyD88/p38-dependent manner. We also show that that TLR7/TLR8 agonist, R848, considerably impairs the growth of human AML cells in immunodeficient mice. Our data suggests TLR8 activation has direct anti-leukemic effects independent of its immunomodulating properties that are currently under investigation for cancer therapy. Taken together, our results suggest that treatment with TLR8 agonists may be a promising new therapeutic strategy for AML. PMID- 25283843 TI - Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2 transgenic mice. AB - Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T cell acute leukemias, in particular poor prognosis early T-cell precursor-like (ETP-) acute lymphoblastic leukemia (ALL). The primary effect of Lmo2 is to cause self-renewal of developing CD4(-)CD8(-) (double negative, DN) T cells in the thymus, leading to serially transplantable thymocytes that eventually give rise to leukemia. These self-renewing thymocytes are intrinsically radioresistant implying that they may be a source of leukemia relapse after therapy. The homeobox transcription factor, Hhex, is highly upregulated in Lmo2-transgenic thymocytes and can phenocopy Lmo2 in inducing thymocyte self-renewal, implying that Hhex may be a key component of the Lmo2-induced self-renewal program. To test this, we conditionally deleted Hhex in the thymi of Lmo2-transgenic mice. Surprisingly, this did not prevent accumulation of DN thymocytes, nor alter the rate of overt leukemia development. However, deletion of Hhex abolished the transplantation capacity of Lmo2-transgenic thymocytes and overcame their radioresistance. We found that Hhex regulates Kit expression in Lmo2-transgenic thymocytes and that abrogation of Kit signaling phenocopied loss of Hhex in abolishing the transplantation capacity and radioresistance of these cells. Thus, targeting the Kit signaling pathway may facilitate the eradication of leukemia initiating cells in immature T-cell leukemias in which it is expressed. PMID- 25283844 TI - The interleukin (IL)-31/IL-31R axis contributes to tumor growth in human follicular lymphoma. AB - Interleukin (IL)-31A binds to an heterodimer composed of IL-31 receptor A (IL 31RA) and Oncostatin M Receptor (OSMR). The IL-31/IL-31R complex is involved in the pathogenesis of various skin diseases, including cutaneous T-cell lymphoma. No information is available on the relations between the IL-31/IL-31R complex and B-cell lymphoma. Here we have addressed this issue in follicular lymphoma (FL), a prototypic germinal center(GC)-derived B-cell malignancy. IL-31 enhanced primary FL cell proliferation through IL-31R-driven signal transducer and activator of transcription factor 1/3 (STAT1/3), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation. In contrast, GC B cells did not signal to IL-31 in spite of IL-31R expression. GC B cells expressed predominantly the inhibitory short IL-31RA isoform, whereas FL cells expressed predominantly the long signaling isoform. Moreover, GC B cells lacked expression of other IL-31RA isoforms potentially involved in the signaling pathway. IL-31 protein expression was significantly higher in surface membrane than in cytosol of both FL and GC B cells. IL-31 was detected in plasma membrane microvesicles from both cell types but not released in soluble form in culture supernatants. IL-31 and IL-31RA expression was higher in lymph nodes from FL patients with grade IIIa compared with grade I/II, suggesting a paracrine and/or autocrine role of IL-31/IL-31RA complex in tumor progression through microvesicle shedding. PMID- 25283846 TI - Infants at risk of cerebral palsy: a systematic review of outcomes used in Cochrane studies of pregnancy, childbirth and neonatology. AB - OBJECTIVE: To systematically review meta-analyses (MAs) and randomised controlled trials (RCTs) of interventions for infants at risk of cerebral palsy (CP), to determine if consensus exists in study end-points. METHODS: MAs within the "Neonatal" and "Pregnancy and Childbirth" Review Groups in Cochrane Database of Systematic Reviews (to June 2011) were included if they contained risk factors for CP as a study end-point, and were either published in 2010 or 2011 or cited >20 times in Sciverse Scopus. Up to 20 RCTs from each MA were included. Outcome measures, definitions and cut-points for ordinal groupings were extracted from MAs and RCTs and frequencies calculated. RESULTS: Twenty-two MAs and 165 RCTs were appraised. High consistency existed in types of outcome domains listed as important in MAs. For 10/16 most frequently cited outcome domains, <50% of RCTs contributed data for meta-analyses. Low consistency in outcome definitions, measures, cut-points in RCTs and long-term follow-up prohibited data aggregation. CONCLUSIONS: Variation in outcome measurement and long-term follow up has hampered the ability of RCTs to contribute data on important outcomes for CP, resulting in lost opportunities to measure the impact of maternal and neonatal interventions. There is an urgent need for and long-term follow up of these interventions and an agreed set of standardised and clinically relevant common data elements for study end-points. PMID- 25283845 TI - Transcriptomic profiling of human choriodecidua during term labor: inflammation as a key driver of labor. AB - PROBLEM: Inflammation is a driver of labor in myometrium and cervix; however, the involvement of decidua is poorly defined. We have reported decidual leukocyte infiltration prior to and during labor; the regulators of these inflammatory processes are unknown. METHOD OF STUDY: Choriodecidua RNA obtained after term labor or elective cesarean delivery was applied to Affymetrix GeneChips. Pathway analysis and gene validation were performed. RESULTS: Extensive inflammatory activation was identified in choriodecidua following labor, predominantly upregulation of genes regulating leukocyte trafficking and cytokine signalling. Genes governing cell fate, tissue remodelling, and translation were also altered. Upregulation of candidate genes (ICAM1, CXCR4, CD44, TLR4, SOCS3, BCL2A, and IDO) was confirmed. NFkappaB, STAT1&3, HMGB1, and miRNA-21, miRNA-46, miRNA-141, and miRNA-200 were predicted upstream regulators. CONCLUSION: This study confirms inflammatory processes are major players in labor events in choriodecidua, as in other gestational tissues. Suppressing uterine inflammation is likely to be critical for arresting premature labor. PMID- 25283847 TI - Asynclitism: a literature review of an often forgotten clinical condition. AB - Asynclitism is defined as the "oblique malpresentation of the fetal head in labor". Asynclitism is a clinical diagnosis that may be difficult to make; it may be found during vaginal examination. It is significant because it may cause failure of progress operative or cesarean delivery. We reviewed all literature for asynclitism by performing an extensive electronic search of studies from 1959 to 2013. All studies were first reviewed by a single author and discussed with co authors. The following studies were identified: 8 book chapters, 14 studies on asynclitism alone and 10 papers on both fetal occiput posterior position and asynclitism. The fetal head in a laboring patient may be associated with some degree of asynclitism; this is seen as usual way of the fetal head to adjust to maternal pelvic diameters. However, marked asynclitism is often detected in presence of a co-existing fetal head malposition, especially the transverse and occipital posterior positions. Digital diagnosis of asynclitism is enhanced by intrapartum ultrasound with transabdominal or transperineal approach. The accurate diagnosis of asynclitism, in an objective way, may provide a better assessment of the fetal head position that will help in the correct application of vacuum and forceps, allowing the prevention of unnecessary cesarean deliveries. PMID- 25283848 TI - Skin conductance activity in post-term pregnancies. AB - OBJECTIVE: The pain threshold in humans rises during late pregnancy, and the woman becomes less sensitive to stress. The aim of this study was to investigate whether monitoring the sympathetic nervous system response to stimuli by skin conductance activity might be a useful predictor of spontaneous onset of labour in post-term pregnancies. STUDY DESIGN: A prospective observational study. Fifty two healthy pregnant women were consecutively asked for inclusion in the study at their post-term pregnancy examination. Initially, a Ctg (cardiotocography) registration was performed, followed by 5 min of skin conductance measurement including a "cold pressor test". Finally, a vaginal examination with a cervical assessment were performed according to clinical guidelines. RESULTS: A statistically significant lower pain reaction during the period of provocation was seen in deliveries close to spontaneous onset of labour compared with induced deliveries with an non-spontaneous onset of labour before 294 days (p = 0.02). Sixty-three per cent (19/30) of the women with spontaneous onset had a negative value at provocation compared with 30% (6/20) in the induced group. CONCLUSIONS: Decreased response to pain stimuli, as an indication of decreased activity in the sympathetic nervous system, has a correlation to spontaneous onset of labour in post-term pregnancies. PMID- 25283849 TI - Relationship of neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin levels with the presence and severity of the preeclampsia. AB - OBJECTIVE: The aim of the present study was to evaluate changes in maternal serum neutrophil gelatinase-associated lipocalin (NGAL) and procalcitonin (PCT) concentrations in preeclampsia. MATERIAL AND METHOD: This case-control study consisted of 40 preeclamptic and 40 healthy singleton pregnancies matched for age and body mass index. Serum NGAL and PCT levels were compared between the groups. Diagnostic performance and clinical association of these markers were evaluated. RESULTS: NGAL and PCT concentrations were significantly higher in preeclamptic group (p < 0.0001 and p = 0.001, respectively) and their levels were correlated with the severity of the preeclampsia. There were significant positive correlation between these markers and mean arterial pressure (MAP) and spot urine protein excretion. There was negative correlation between NGAL and apgar scores and fetal birth weight. Pregnancies with higher NGAL (OR: 4.89; 95% CI: 1.81 13.21) and higher PCT (OR: 6.67; 95% CI: 2.44-18.21) concentrations had higher risk for preeclampsia. CONCLUSION: NGAL and PCT may be potential biomarkers for preeclampsia. Their levels increase significantly in preeclampsia and they are related to the severity of the disease. These results are in agreement with the generalized endothelial damage and persistant inflammatory status in preeclampsia. NGAL may also be an indicator for adverse neonatal outcomes with decreased placental hypoperfusion. PMID- 25283850 TI - A late-preterm, early-term stratified analysis of neonatal outcomes by gestational age in placenta previa: defining the optimal timing for delivery. AB - OBJECTIVE: Though no official guidelines address the issue of the optimal timing of delivery in placenta previa, common practice is to conduct delivery between 36 and 37 weeks gestation. Given the rising concerns regarding unnecessary premature deliveries, the objective of this study was to compare neonatal outcomes among pregnancies complicated by placenta previa delivered at the late-preterm period (35, 36 weeks) relative to the early-term period (37 and 38 weeks). METHODS: We conducted a retrospective, population-based, cohort study using the CDC's Linked Birth-Infant Death data files from the U.S. for the year 2004. We stratified the cohort according to gestational age and placenta previa status. Using 38 weeks gestation as reference controls, the effect of delivery in a pregnancy with placenta previa at 35, 36 and 37 weeks gestation on the risk of several neonatal outcomes was estimated using logistic regression analysis, adjusting for relevant confounders. RESULTS: We analyzed a total of 4 118 956 births, of which 5675 (0.1%) met inclusion criteria. Late-preterm delivery was associated with lower birthweight and increased adequacy of care. Relative to neonates born at 38 weeks, birth at 35, 36 and 37 weeks was associated with no greater odds of meconium passage, fetal distress, fetal anemia, neonatal seizures, increased ventilator needs, or infant death at 1 year. However, odds of 5-min APGAR scores <7 were greater at 35 and 36 weeks (aOR [95% CI]): 3.33 [1.71-6.47] and 2.17 [1.11-4.22], respectively; as were odds of NICU admission rates: 2.25 [2.01-2.50] and 1.57 [1.38-1.76], respectively. Conclusions: Barring maternal indications, early-term delivery in placenta previa is associated with fewer complications and no greater risk than late-preterm delivery. This information may be helpful in the development of future guidelines, which are currently needed to guide the management of these pregnancies. PMID- 25283851 TI - "The Original Sound": a new non-pharmacological approach to the postnatal stress management of preterm infants. AB - OBJECTIVE: To evaluate the effect of the exposure to "The Original Sound" (TOS), an original track composed of different sounds such as fetal heartbeat, breathing, blood flow, and ambience sounds, specifically created for this study, on physiological stability of preterm infants during a 10-d hospitalization. METHODS: Thirty-four preterm infants (32-37 weeks of gestation) were randomized to receive either TOS or environmental noise. TOS was provided for a 20-min period, three times a day, using two speakers and a MP3 player placed in the cradle. Cardiorespiratory and behavioral parameters were recorded. RESULTS: Heart rate in the treated group was positively correlated with TOS exposure, showing a significant reduction on day 2 and lower values during the first day. A decrease in RR is also recorded on day two in the TOS group, although not significant. CONCLUSION: This study provides preliminary evidence for short-term improvements in the physiological stability of preterm infants using TOS. Future studies are needed to investigate the potential of this non-pharmacological approach and its clinical relevance to postnatal stress management in neonatal intensive care units. PMID- 25283852 TI - Comparison of changes in etiologic microorganisms causing early-onset neonatal sepsis between preterm labor and preterm premature rupture of membranes. AB - OBJECTIVE: To investigate changes in the etiologic microorganisms causing early onset neonatal sepsis (EONS) in preterm labor (PTL) or preterm premature rupture of membranes (pPROM) cases over the past 16 years and to analyze the associated factors. METHODS: We included consecutive singleton pregnancies delivered before 34 weeks due to PTL or pPROM. The etiologic microorganisms causing EONS in PTL and pPROM cases were compared between period 1 (1996-2004) and period 2 (2005 2012). RESULTS: There was no difference in the incidence of Gram-positive bacteria causing EONS between period 1 and 2, either in PTL (2.0% versus 2.1%, p = 1.0) or in pPROM (1.5% versus 1.6%, p = 1.0). However, the incidence of EONS caused by Gram-negative bacteria was significantly increased in pPROM (0.6% versus 2.7%, p = 0.040) during period 2, compared to period 1; but not in PTL (0.3% versus 1.2%, p = 0.211). Multivariable analysis revealed that a prolonged ROM-to-delivery interval (>7 d) was significantly associated with EONS caused by Gram-negative bacteria in pPROM (odds ratio: 6.6, 95% confidence interval: 1.4 31.8, p = 0.018). CONCLUSIONS: The etiologic microorganisms causing EONS have changed over the past 16 years in pPROM cases but not in PTL cases. PMID- 25283853 TI - Perinatal outcomes in pregnancies with oligohydramnios after preterm premature rupture of membranes. AB - OBJECTIVE: Our purpose was to determine whether singleton pregnancies complicated by preterm premature rupture of membranes (PPROM) and oligohydramnios are at an increased risk of having maternal and neonatal morbidity. METHODS: We performed a retrospective analysis of 389 women with PPROM between 24 and 34 weeks of gestation in a single tertiary center during 2008-2014. Patients were divided into two groups on the basis of amniotic fluid index (AFI) < 5 cm (n = 188) or AFI >= 5 cm (n = 201). Perinatal outcomes were compared according to amniotic fluid volume. The Student's t-test and Mann-Whitney U test were used to compare variables with normal and abnormal distribution, respectively. Categorical variables were examined by the chi-square test. RESULTS: Patients with an AFI < 5 cm demonstrated a significantly shorter latency to delivery (p < 0.001), a higher rate of clinical chorioamnionitis (p = 0.029) and emergency cesarean delivery (p = 0.043) and a lower neonatal Apgar score at first minute (p = 0.004). CONCLUSION: Initial oligohydramnios after PPROM is associated with shorter latency to delivery, higher rate of clinical chorioamnionitis, higher rate of emergency cesarean delivery, and lower 1-min Apgar score. PMID- 25283854 TI - Human parvovirus B19: a review. AB - Parvovirus B19 (B19V) is a small non-enveloped single-stranded DNA (ssDNA) virus of the family Parvoviridae, the subfamily Parvovirinae, the genus Erythrovirus and Human parvovirus B19 type species. It is a common community-acquired respiratory pathogen without ethnic, socioeconomic, gender, age or geographic boundaries. Moreover, the epidemiological and ecological relationships between human parvovirus B19, man and environment have aroused increasing interest in this virus. B19V infection is associated with a wide spectrum of clinical manifestations, some of which were well established and some are still controversial, however, it is also underestimated from a clinical perspective. B19V targets the erythroid progenitors in the bone marrow by binding to the glycosphingolipid globoside (Gb4), leading to large receptor-induced structural changes triggering cell death either by lysis or by apoptosis mediated by the nonstructural (NS)1 protein. The pattern of genetic evolution, its peculiar properties and functional profile, the characteristics of its narrow tropism and restricted replication, its complex relationship with the host and its ample pathogenetic potential are all topics that are far from a comprehensive understanding. The lack of efficient adaptation to in vitro cellular cultures and the absence of animal models have limited classical virological studies and made studies on B19V dependent on molecular biology. The present review looks at the nature of this virus with the view to provide more information about its biology, which may be useful to the present and future researchers. KEYWORDS: human parvovirus B19; respiratory pathogen; biology; genome; fifth disease; transient aplastic crisis; anemia. PMID- 25283855 TI - Molecular characterization of barley yellow dwarf virus in Tunisia. AB - Barley yellow dwarf disease is a worldwide ubiquitous virus disease of cereal crops. In order to characterize the B/CYDV isolates occurring in Tunisia, 240 barley leaves were randomly sampled from 6 fields following a North-South trend and analyzed by serological and molecular tests. DAS-ELISA results showed 40 positive samples with a prevalence of barley yellow dwarf virus (BYDV)-PAV (77.5%), followed by cereal yellow dwarf virus (CYDV)-RPV (25%) and BYDV-MAV (15%). Studies of the geographic distribution showed a high incidence of B/CYDV in the Tunisian Southern provinces. RT-PCR assays were performed to amplify the viral coat protein gene (CP) and sequence analyses revealed six BYDV-PAV haplotypes named PAV-TN1 to PAV-TN6. Phylogenetic analysis showed that the six Tunisian haplotypes were close to BYDV-PAV-II subspecies and had a strong similarity with Moroccan, Czech, French and German haplotypes. Although PAV-TN2 and PAV-TN5 showed up to 10% divergence from BYDV-PAV-II at the amino acid level, it seems to belong to the same subspecies but in a separated cluster. Our results will be important in developing appropriate control measures against BYDV disease in Tunisia. PMID- 25283856 TI - Different outcomes of infection of chickens and ducks with a duck-origin H9N2 influenza A virus. AB - As the major aquatic and terrestrial hosts for avian influenza viruses (AIVs), ducks and chickens play a critical role in the evolution and spread of the H9N2 virus. However, the outcomes of infection of ducks and chickens with the H9N2 virus are not sufficiently documented. In this study, we compared the outcomes of infection of chickens and Peking ducks with a duck-origin H9N2 virus. The results showed that this virus caused more pronounced clinical signs and histological lesions in chickens. As for the virus shedding, chickens shed more virus in the trachea and less virus in the cloaca in levels of interferon (IFN) gamma were found in the trachea of ducks compared with chickens, while comparison with ducks. As for cytokines, namely IFNs and interleukins (IL), higher higher levels of IFN-beta, IFN-gamma, IL-1beta, and IL-6 were observed in the ileum of chickens compared with ducks. Eventually, serum hemagglutination-inhibition (HI) antibody titers were higher in chickens than in ducks. Taken together, ducks and chickens use different strategies in response to the H9N2 virus infection in tissues representing main replication sites of low-pathogenic AIVs. Given the different outcomes of the H9N2 virus infection in ducks and chickens, different measures should be taken in vaccination and treatment. PMID- 25283857 TI - Pretreatment and on-treatment indicators of virologic breakthrough of lamivudine therapy in chronic hepatitis B patients: an Egyptian study. AB - The primary objectives of hepatitis B treatment include improved clinical and histological progression as well as virus eradication. For many years, lamivudine was a first-line therapy for treating hepatitis B virus (HBV) infection. However, its long-term use is associated with high resistance rates (up to 70% after 5 years) due to mutations in the viral YMDD motif. The purpose of this study was to outline factors responsible for the development of viral resistance during long term lamivudine therapy. Initially, 230 patients receiving lamivudine therapy for chronic hepatitis B (CHB) infection were enrolled in the study. All subjects received follow-ups in the first year to assess viral and biochemical responses. Only 136 and 104 patients received follow-up assessments during the second and third years of treatment, respectively. Viral breakthrough (VBT) occurred in 49 of 230 patients (21.3%). Hepatitis B "e" antigen (HBeAg) status before treatment was significantly associated with VBT in the first 2 years of treatment; however, this effect was not significant in the third year. Pre-treatment HBV DNA levels were predictive of VBT in the HBeAg-positive subgroup after all years of treatment (P = 0.001, P = 0.002, and P = 0.002, respectively). These levels were also predictive in the HBeAg-negative subgroup after 1 year of treatment (P = 0.001). In resource-poor communities, financial concerns drive the selection of antiviral therapy to treat CHB. Lamivudine monotherapy is a relatively cheap and effective treatment to manage CHB. However, consistent follow-ups and treatment modifications appear essential to prevent long-term treatment failure. PMID- 25283858 TI - Hepatitis C virus infection in vitro triggers endoplasmic reticulum stress and downregulates insulin receptor substrates 1 and 2 through upregulation of cytokine signaling suppressor 3. AB - Hepatitis C virus (HCV) infection is highly prevalent worldwide and most of HCV infections enter into chronic phase subsequently leading to insulin resistance (IR) and clinical complications. Although the clinics of chronic HCV infection is well described, there is need to better understand the molecular mechanisms of HCV-induced IR. Therefore this study was aimed to unveil the role of host genes involved in the development of HCV-induced IR. For this purpose the expression of selected genes in HCV-infected and non-infected Huh-7 cells at various time post infection (p.i.) was assayed by real-time PCR. HCV infection was found to trigger endoplasmic reticulum (ER) stress response as demonstrated by an increase in the expression of calreticulin (Cal) gene but no change in the expression of Gadd153 gene. The infection also enhanced the expression of suppressor of cytokine signaling 3 (SOCS-3), responsible for the degradation of insulin receptor substrates (IRS). Moreover, it led to a decreased expression of key signaling molecules IRS-1 and IRS-2, unchanged expression of SOCS-7 and increased expression of downstream signaling molecule Akt. Altogether these findings indicate that the HCV infection induces ER stress and IR in Huh-7 cells in vitro. PMID- 25283859 TI - Prevalence and genetic diversity of fig mosaic virus isolates infecting fig tree in Iran. AB - Commercial and outdoor fig orchards in four Iranian provinces were surveyed for the incidence of fig mosaic virus (FMV), fig leaf mottle associated virus 2 (FLMaV-2) and fig mild mottle associated virus (FMMaV) from March 2011 to October 2012. A total of 350 asymptomatic and symptomatic fig samples were collected and tested by dot-immunobinding assay (DIBA) for the fig mosaic disease (FMD) using a polyclonal antiserum. According to DIBA results, FMD was present in 73% of the collected symptomatic samples from all visited regions. Samples with positive reactions in DIBA were then analyzed by RT-PCR using with specific primers. PCR results showed that about 14.8% of the FMD-positive samples from three inspected provinces are infected with at least one virus. FMV was the most widely spread virus (14%) followed by FLMaV-2 (1.5%), whereas FMMaV was not found. Phylogenetic analysis of the glycoprotein nucleotide and amino acid sequences of known FMV isolates showed two independent groups with high bootstrap values, with all Iranian isolates distinctly clustered in group I, subgroup IA beside those reported in Turkey. Nucleotide diversity was high within but low between different selected geographic regions and except for Europe, nucleotide distance within geographic regions was low. Statistical analyses indicated a correlation between the genetic structure of the FMV isolates and the geographical origin of isolation. Our analyses suggested that the FMV population is in a state of increase following a bottleneck or founder event in Iran. PMID- 25283860 TI - Enhanced oxidative damage to DNA, lipids, and proteins and levels of some antioxidant enzymes, cytokines, and heat shock proteins in patients infected with influenza H1N1 virus. AB - Overweight and obesity is becoming widespread enough to generate an acceptable and misleading social status. By 2030, in the USA up to 86 % of adults will be overweight or obese. Some selected statistical data based on the body mass index (BMI) indicated that overweight was not associated with increased mortality, this provoked a conceivable interest. Added to this is the observation that while the prevalence of obesity is dramatically increasing, the cardiovascular mortality and life expectancy in the European Union and USA has improved. When more sensitive indicators of body adiposity and its distribution than the BMI, like the waist-thigh ratio in both sexes and the waist-hip ratio in women are projected on mortality, it becomes obvious that even overweight is associated with an increased health risk. Gaining excessive body fat is a continuous, frequently progressive process. Present obesity epidemic in childhood will manifest with deleterious consequences only in future years when adolescents reach adulthood. Prevention is thus essential even before the overweight sets in. Improved life expectancy observed in large populations despite obesity epidemic, is a favourable medical success in the management of hypertension, of serum lipid disorders and diabetes. While encouraging, when it is observed in large population, it does not take away the potential health risk of a metabolic disorder in an individual who is overweight (Fig. 7, Ref. 25). PMID- 25283861 TI - Resistance of non-transgenic papaya plants to papaya ringspot virus (PRSV) mediated by intron-containing hairpin dsRNAs expressed in bacteria. AB - RNA-mediated virus resistance based on natural antiviral RNA silencing has been exploited as a powerful tool for engineering virus resistance in plants. In this study, a conserved 3'-region (positions 9839-10117, 279 nt) of the capsid protein (CP) gene of papaya ringspot virus (PRSV), designated CP279, was used to generate an intron-containing hairpin RNA (ihpRNA) construct by one-step, zero-background ligation-independent cloning (OZ-LIC). The RNaseIII-deficient Escherichia coli strain M-JM109lacY was identified as the best choice for producing large quantities of specific ihpRNA-CP279. Resistance analyses and ELISA data verified that most papaya plants mechanically co-inoculated with TRIzol-extracted ihpRNA CP279 and PRSV were resistant to PRSV, and resistance was maintained throughout the test period (>2 months post-inoculation). In contrast, a 1-2 day interval between sequential inoculation of PRSV and ihpRNA-CP279 did not result in complete protection against PRSV infection, but delayed the appearance of viral symptoms by 3 to 4 days. These findings indicate that direct mechanical inoculation of papaya plants with bacterially-expressed ihpRNA-CP279 targeting the PRSV CP gene can interfere with virus infection. This work lays a foundation for developing a non-transgenic approach to control PRSV by directly spraying plants with ihpRNA or crude bacterial extract preparations. PMID- 25283862 TI - Identification of an immunodominant epitope in glycoproteins B and G of herpes simplex viruses (HSVs) using synthetic peptides as antigens in assay of antibodies to HSV in herpes simplex encephalitis patients. AB - Herpes simplex encephalitis (HSE) is a severe viral infection of the central nervous system (CNS). Assay of antibody response is widely used in diagnostics of HSE. The aim of this study was to identify an immunodominant epitope determining the antibody response to herpes simplex viruses (HSVs) in cerebrospinal fluid (CSF) of HSE patients. The synthetic peptides that resembled type-common as well as type-specific domains of glycoproteins B (gB) and G (gG) of these viruses were evaluated for binding with IgM and IgG antibodies in CSF samples from HSE and non HSE patients in ELISA. The QLHDLRF peptide, derived from gB of HSV was found to be an immunodominant epitope in the IgM and IgG antibody response. The patients with confirmed and suspected HSE showed in ELISA against this peptide 26% and 23% positivities for IgM, 43% and 37% positivities for IgG and 17% and 15% for both IgM and IgG antibodies, respectively. The total positivities of 86% and 75% for both IgM and IgG antibodies were obtained in the patients with confirmed and suspected HSE, respectively. These results demonstrate that a synthetic peptide based diagnostics of HSE can be an efficient and easily accessible alternative. This is the first report describing the use of synthetic peptides derived from HSVs in diagnostics of HSE using patients' CSF samples. PMID- 25283863 TI - Transient expression of the influenza A virus PB1-F2 protein using a plum pox virus-based vector in Nicotiana benthamiana. AB - PB1-F2 protein of influenza A virus (IAV) was cloned in a plum pox virus (PPV) genome-based vector and attempts to express it in biolistically transfected Nicotiana benthamiana plants were performed. The vector-insert construct replicated in infected plants properly and was stable during repeated passage by mechanical inoculation, as demonstrated by disease symptoms and immunoblot detection of PPV capsid protein, while PB1-F2-specific band was more faint. We showed that it was due its low solubility. Modification of sample preparation (denaturation/solubilization preceding the centrifugation of cell debris) led to substantial signal enhancement. Maximal level of PB1-F2 expression in plants was observed 12 days post inoculation (dpi). Only 1% SDS properly solubilized the protein, other detergents were much less efficient. Solubilization with 8M urea released approximately 50% of PB1-F2 from the plant tissues, thus the treatment with this removable chaotropic agent may be a good starting point for the purification of the protein for eventual functional studies in the future. PMID- 25283864 TI - Significance of mutations in hepatitis B virus X gene for the pathogenesis of HB associated glomerulonephritis. AB - In this study, the significance of hepatitis virus (HBV) X gene mutations for the pathogenesis of HBV-associated glomerulonephritis (HBV-GN) was investigated. DNA was extracted from 50 HBV-GN patients and 60 asymptomatic HBV carriers and subjected to PCR amplification and sequencing of HBV X gene. In HBV-GN patients, missense nucleotide mutations of C1653T, A1726C, A1727T, C1730G, T1753C, A1762T, and G1764A were detected in 84% of subjects, all located in the trans-acting regulatory region of the X gene. In control patients, missense nucleotide mutations of A1632C and A1635C were detected in 8% of subjects, both located in the non-functional region of the X gene. We conclude that, in most HBV-GN patients, X gene missense mutations occurred at some key sites playing an important role in the pathogenesis of HBV-GN. PMID- 25283865 TI - Acetylation changes at lysine 5 of histone H4 associated with lytic gene promoters during reactivation of Kaposi's sarcoma-associated herpesvirus. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a pathogenic agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease in humans. Similarly to other gammaherpesviruses such as Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), KSHV displays two alternative life cycles, latent and lytic one. The transactivation from latency to the lytic phase is the result of transcriptional changes in the KSHV genome caused by the replication and transcriptional activator (RTA). During KSHV reactivation, epigenetic modifications of histone protein on the viral genome occur, which regulate the transcriptional activation of a number of lytic genes. The reactivation of EBV from latency to lytic cycle, induced by an immediate-early Zta protein, was shown to be accompanied by acetylation of specific lysines in histone H4. Accordingly, we hypothesized that the RTA-induced transactivation of KSHV could also be accompanied by histone acetylation. To validate this hypothesis, we assayed alterations of acetyl-histone H4-lysine 5 (acH4K5) during the RTA-mediated KSHV reactivation. While the modified histone protein in a total cell lysate was not distinguished between control and RTA-expressed cells, upregulated acH4K5 was detected on several lytic gene promoter regions during KSHV reactivation. Our results clearly indicate that this epigenetic change is related to transcription of genes expressed in the lytic cycle of KSHV. PMID- 25283866 TI - Wild and attenuated vaccine RS-12 strains of mumps virus exhibit differences in amino acid sequences of their proteins. AB - Attenuated mumps virus (MuV) RS-12 strain-based vaccine is one of several effective vaccines available in the prevention of mumps. Since previous studies have unveiled only about one-third of the attenuated vaccine RS-12 strain genome sequence, the rest of sequence and molecular basis for attenuation remained unsolved. Therefore, in this study, the full-length genome sequences of wild and attenuated RS-12 strains were determined and compared. The comparison revealed nucleotide substitutions at 9 positions leading to amino acid substitutions at 6 positions in P, V, I, M, and L proteins, while the remaining substitutions were silent. This result indicates that the observed mutations in P, V, I, M, and L proteins of MuV might be responsible for the attenuation of the RS-12 vaccine strain. PMID- 25283867 TI - Autophagy in cultured murine neurons infected with equid herpesvirus 1. AB - In this study we investigated the relationship of equid herpesvirus 1 (EHV-1) infection to autophagy in primary culture of murine neurons. Infection with both Jan-E and Rac-H strains of EHV-1 resulted in the formation of autophagosomes in the cytoplasm during early stages of infection, while in late stages of infection autophagosomes were mainly concentrated around the nucleus what suggests the induction of nuclear envelope-derived autophagy (NEDA). No significant effect of an authophagy inhibitor-chloroquine on final virus titers demonstrated that autophagy is not essential for EHV-1 replication. PMID- 25283868 TI - L2 segment-based phylogenetic relationships among duck reoviruses from China. AB - KEYWORDS: duck reovirus; L2 segment sequence; phylogenetic analysis. PMID- 25283869 TI - First report of cucumber green mottle mosaic virus association with the leaf green mosaic disease of a vegetable crop, Luffa acutangula L. PMID- 25283871 TI - Photochromic molecular implementations of universal computation. AB - Unconventional computing is an area of research in which novel materials and paradigms are utilised to implement computation. Previously we have demonstrated how registers, logic gates and logic circuits can be implemented, unconventionally, with a biocompatible molecular switch, NitroBIPS, embedded in a polymer matrix. NitroBIPS and related molecules have been shown elsewhere to be capable of modifying many biological processes in a manner that is dependent on its molecular form. Thus, one possible application of this type of unconventional computing is to embed computational processes into biological systems. Here we expand on our earlier proof-of-principle work and demonstrate that universal computation can be implemented using NitroBIPS. We have previously shown that spatially localised computational elements, including registers and logic gates, can be produced. We explain how parallel registers can be implemented, then demonstrate an application of parallel registers in the form of Turing machine tapes, and demonstrate both parallel registers and logic circuits in the form of elementary cellular automata. The Turing machines and elementary cellular automata utilise the same samples and same hardware to implement their registers, logic gates and logic circuits; and both represent examples of universal computing paradigms. This shows that homogenous photochromic computational devices can be dynamically repurposed without invasive reconfiguration. The result represents an important, necessary step towards demonstrating the general feasibility of interfacial computation embedded in biological systems or other unconventional materials and environments. PMID- 25283870 TI - A combined method to quantify the retinal metabolic rate of oxygen using photoacoustic ophthalmoscopy and optical coherence tomography. AB - Quantitatively determining physiological parameters at a microscopic level in the retina furthers the understanding of the molecular pathways of blinding diseases, such as diabetic retinopathy and glaucoma. An essential parameter, which has yet to be quantified noninvasively, is the retinal oxygen metabolic rate (rMRO2). Quantifying rMRO2 is challenging because two parameters, the blood flow rate and hemoglobin oxygen saturation (sO2), must be measured together. We combined photoacoustic ophthalmoscopy (PAOM) with spectral domain-optical coherence tomography (SD-OCT) to tackle this challenge, in which PAOM measured the sO2 and SD-OCT mapped the blood flow rate. We tested the integrated system on normal wild type rats, in which the measured rMRO2 was 297.86 +/- 70.23 nl/minute. This quantitative method may shed new light on both fundamental research and clinical care in ophthalmology in the future. PMID- 25283872 TI - Performance characteristics of the Beckman Coulter total betahCG (5th IS) assay. AB - BACKGROUND: Beckman Coulter recently released the first commercially available hCG reagent calibrated against the 5th International Standard (IS) for hCG (total betahCG (5th IS)). We performed a comprehensive analytical validation of this reagent. METHODS: Precision experiments were completed using 3 concentrations of commercial quality control material. Linearity, sample stability, and analytical sensitivity were evaluated using pools of human serum. Reportable range was assessed by comparing manual dilutions to those performed by the instrument. Male and female reference intervals were established using residual serum specimens submitted for routine testing. Inter-lot variability of hCG assay reagent was assessed by analyzing serum specimens with detectable hCG using 2 different reagent lots. Inter-assay variability was established using 203 serum specimens analyzed for hCG on 6 different reagent platforms. RESULTS: Inter-day precision showed a CV of <6.0% for all concentrations of QC material. LOB, LOD, and LOQ were determined to be 0.3, 0.4, and 0.6 U/l, respectively. The Access (5th IS) reagent has an average positive bias of approximately 20% when compared to most platforms and the previous generation Beckman hCG assay. Results were consistent between lots. Female reference intervals varied by age: <1.0 U/l (<41 y), <6.0 U/l (41-50 y), and <8.0 U/l (>50 y). Male reference intervals were <2.0 U/l. CONCLUSIONS: The analytical performance of the total betahCG (5th IS) was established. Care should be taken to re-baseline patients needing serial monitoring and/or notify physicians when transitioning to the total betahCG (5th IS) reagent. PMID- 25283873 TI - COMT and STH polymorphisms interaction on cognition in schizophrenia. AB - Catechol-O-methyltransferase (COMT) gene, a key regulator of prefrontal cortex (PFC) dopamine (DA) availability, has been extensively studied in relation to cognitive domains, mainly executive functions, that are impaired in schizophrenia, but results are still controversial. Since recent studies in patients affected by neurodegenerative and psychiatric disorders suggested a role of saitohin (STH) gene as a concurring factor in hypofrontality, we hypothesize that STH and COMT polymorphisms could have an additive effect on cognition in schizophrenia. Three forty three clinically stabilized patients with schizophrenia were assessed with a broad neuropsychological battery including the Brief Assessment of Cognition in Schizophrenia, the Wisconsin Card Sorting Test and the Continuous Performance Test and were genotyped for COMT Val108/158Met and STH Q7R polymorphisms. We observed the effects of COMT on speed of processing and executive functions, as well as a significant effect of STH on executive functions performances. Moreover, a significant interaction between COMT and STH polymorphisms was found on executive functions, with COMT Val/Val and STH R carriers performing worse. Our results showed a significant interaction effect of COMT and STH polymorphisms on cognitive performances, strengthening the involvement of STH in cognitive impairments, especially in the domains commonly impaired in schizophrenia. PMID- 25283874 TI - The Vat locus encodes for a CC-NBS-LRR protein that confers resistance to Aphis gossypii infestation and A. gossypii-mediated virus resistance. AB - Aphis gossypii is a polyphagous sucking aphid and a vector for many viruses. In Cucumis melo, a dominant locus, Vat, confers a high level of resistance to Aphis gossypii infestation and to viruses transmitted by this vector. To investigate the mechanism underlying this double resistance, we first genetically dissected the Vat locus. We delimited the double resistance to a single gene that encodes for a coiled-coil-nucleotide-binding-site-leucine-rich repeat (CC-NBS-LRR) protein type. To validate the genetic data, transgenic lines expressing the Vat gene were generated and assessed for the double resistance. In this analysis, Vat transgenic plants were resistant to A. gossypii infestation as well as A. gossypii-mediated virus transmission. When the plants were infected mechanically, virus infection occurred on both transgenic and non-transgenic control plants. These results confirmed that the cloned CC-NBS-LRR gene mediates both resistance to aphid infestation and virus infection using A. gossypii as a vector. This resistance also invokes a separate recognition and response phases in which the recognition phase involves the interaction of an elicitor molecule from the aphid and Vat from the plant. The response phase is not specific and blocks both aphid infestation and virus infection. Sequence analysis of Vat alleles suggests a major role of an unusual conserved LRR repeat in the recognition of A. gossypii. PMID- 25283875 TI - Neoplasia following use of BMPs: is there an increased risk? AB - INTRODUCTION: Bone morphogenetic proteins are multi-functional growth factors, which play an important role in embryonic development and cellular functions. Among several molecules in this family, BMP-2 and BMP-7 are currently being used in the clinical setting. Main clinical targets include the treatment of non union, open fractures and spinal fusion. Their use has not been without complications, one of which might be a carcinogenic effect. AREAS COVERED: The authors offer a comprehensive review of the existing literature on the clinical studies analysing the role of bone morphogenetic proteins (BMPs) on carcinogenesis. The authors analyse the available literature and describe potential signalling pathways that can be affected as per available experimental in vitro and in vivo models. EXPERT OPINION: The available experimental data and clinical evidence are rather inadequate to allow any safe scientific conclusions. Clinical studies provide incomplete evidence to support the hypothesis that BMPs are carcinogenic. The available literature has several limitations including incomplete documentation, unreported data and inhered bias as a large number of trials have been funded by the industry. The need of well-structured studies is essential to address these safety concerns. PMID- 25283876 TI - Single-molecule diffusion and conformational dynamics by spatial integration of temporal fluctuations. AB - Single-molecule localization and tracking has been used to translate spatiotemporal information of individual molecules to map their diffusion behaviours. However, accurate analysis of diffusion behaviours and including other parameters, such as the conformation and size of molecules, remain as limitations to the method. Here, we report a method that addresses the limitations of existing single-molecular localization methods. The method is based on temporal tracking of the cumulative area occupied by molecules. These temporal fluctuations are tied to molecular size, rates of diffusion and conformational changes. By analysing fluorescent nanospheres and double-stranded DNA molecules of different lengths and topological forms, we demonstrate that our cumulative-area method surpasses the conventional single-molecule localization method in terms of the accuracy of determined diffusion coefficients. Furthermore, the cumulative-area method provides conformational relaxation times of structurally flexible chains along with diffusion coefficients, which together are relevant to work in a wide spectrum of scientific fields. PMID- 25283877 TI - Effect of a common genetic variant microRNA-146a rs2910164 on colorectal cancer: a meta-analysis. AB - OBJECTIVE: There is emerging evidence that the microRNA-146a (miR-146a) rs2910164 polymorphism might be associated with the susceptibility to colorectal cancer (CRC). However, previous published studies have failed to achieve a definitive conclusion. We aimed to address this issue in an updated meta-analysis. METHODS: A comprehensive literature search was conducted in PubMed, Embase, China BioMedicine, the Cochrane Library and Google Scholar to identify eligible studies. Case-control studies written in English that evaluated the association between miR-146a polymorphism and CRC were included. Odds ratio and 95% confidence interval were calculated in the quantitative synthesis. RESULTS: Overall seven case-control studies including a total of 2978 cases and 3576 cancer-free or healthy controls were enrolled in the meta-analysis. The results indicated that there was no association between miR-146a G/C rs2910164 polymorphism and CRC risk either in the overall analysis or among Asians, when stratified on the basis of ethnicity. CONCLUSION: miR-146a G/C genetic polymorphism was not related to the susceptibility to CRC. PMID- 25283879 TI - Antibiotic resistance in acute postoperative endophthalmitis. AB - Acute postoperative endophthalmitis (APE) is a serious, although infrequent, complication of eye surgery that can result in significant morbidity and costs. This review addresses APE risk factors, associated bacterial pathogens, antibiotic resistance, and prevention. PMID- 25283880 TI - Measuring teacher implementation in delivery of a bullying prevention program: the impact of instructional and procedural adherence and competence on student responsiveness. AB - Although there is evidence that school-based prevention programs can produce positive effects on students' academic and behavioral functioning, the ability of teachers to sustain high-quality implementation remains an open and vexing question. Because teachers are often the intervention agents in school-based prevention programs, assessing both their adherence to program procedures and their competence in program delivery is critical for ensuring student responsiveness to prevention programs, which in turn may impact their efficacy. The current study assessed treatment fidelity of implementation of the Olweus' Bullying Prevention Program (OBPP) in two urban middle schools. Trained observers completed 280 observations of teachers' delivery of the class meeting component of the OBPP and rated teachers' instructional and procedural adherence and competence of delivery and students' responsiveness. Analyses using multilevel modeling indicated that competence of delivery was significantly related to student responsiveness above and beyond teacher instructional behavior adherence, such that class meetings conducted with higher instructional adherence and procedural competence resulted in higher student responsiveness to the program after controlling for the clustered nature of teachers, and several observation level and teacher-level covariates. This study highlights the need for strategies to increase teacher use of effective instructional practices and competence with program procedures to enhance the efficacy of prevention programming in schools. PMID- 25283881 TI - The development of adaptive conformity in young children: effects of uncertainty and consensus. AB - Human culture relies on extensive use of social transmission, which must be integrated with independently acquired (i.e. asocial) information for effective decision-making. Formal evolutionary theory predicts that natural selection should favor adaptive learning strategies, including a bias to copy when uncertain, and a bias to disproportionately copy the majority (known as 'conformist transmission'). Although the function and causation of these evolved strategies has been comparatively well studied, little is known of their development. We experimentally investigated the development of the bias to copy when-uncertain and conformist transmission in children from the ages of 3 to 7, testing predictions derived from theoretical models. Children first attempted to solve a binary-choice quantity discrimination task themselves using asocial information, but were then given the decisions of informants, and an opportunity to revise their answer. We investigated whether children's revised judgments were adaptively contingent on (i) the difficulty of the trial and (ii) the degree of consensus amongst informants. As predicted, older but not younger children copied others more on more difficult trials than on easier trials, even though older children also showed a tendency to stick with their initial, asocial decision. We also found that older children, like adults, were disproportionately receptive to non-total majorities (i.e. were conformist) whereas younger children were receptive only to total (i.e. unanimous) majorities. We conclude that, whilst the mechanism for incorporating social information into decision-making is initially very blunt, across the course of early childhood it converges on the adaptive learning mechanisms observed in adults and predicted by cultural evolutionary theory. A video abstract of this article can be viewed at http://youtu.be/Qb6JINGYqVk. PMID- 25283882 TI - Adsorption of fibronectin on salt-etched polyelectrolyte multilayers and its roles in mediating the adhesion and migration of vascular smooth muscle cells. AB - Protein adsorption on biomaterials strongly mediates the subsequent cell responses. Here adsorption of fibronectin (Fn) on salt-treated PEI(PSS/PDDA)7 multilayers was characterized. The amounts of adsorbed Fn increased linearly along with the increase of thickness of multilayers pretreated with 1 M and 5 M NaCl solutions (Multilayer-1M and 5M), but was independent on the thickness of Multilayer-3M. The normalized relative RGD activity of Fn were significantly higher on the Multilayer-3M than on others. By comparison of cellular behaviors of VSMCs being cultured in the normal and Fn-depleted serum-containing medium, the significant role of Fn on modulating the behaviors of VSMCs was verified. The Fn adsorption model and its role on linking the biomaterials surface to the VSMCs behaviors are proposed. PMID- 25283883 TI - Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a Chinese population. AB - Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterized by ptosis, dysphagia, and proximal muscle weakness. The genetic basis has been identified as an abnormal (GCN) expansion encoding the polyalanine tract in exon 1 of the polyadenylate binding protein nuclear 1 gene (PABPN1). OPMD is worldwide distributed, but has rarely been reported in East Asians. In this study, we summarized the clinical and genetic characteristics of 34 individuals from 13 unrelated families in Chinese population. In our cohort, the mean age at onset was 47.2 years. Dysphagia, rather than ptosis, was the most common initial symptom. Genetically, we identified seven genotypes in our patients, including one compound heterozygote of (GCN)11/(GCN)12. The genetic heterogeneity implies that there is no single founder effect in Chinese population, and our data also support that the (GCN)11 polymorphism may have a disease-modifying effect. Additionally, the clinical features showed homogeneity within families, which suggests that other genetic factors apart from the already known genotype also play a role in modifying the phenotype. PMID- 25283885 TI - Metabolic profiling of synovial fluid in a unilateral ovine model of anterior cruciate ligament reconstruction of the knee suggests biomarkers for early osteoarthritis. AB - Joint injuries and subsequent osteoarthritis (OA) are the leading causes of chronic joint disease. In this work, we explore the possibility of applying magnetic resonance spectroscopy-based metabolomics to detect host responses to an anterior cruciate ligament (ACL) reconstruction injury in synovial fluid in an ovine model. Using multivariate statistical analysis, we were able to distinguish post-injury joint samples (ACL and sham surgery) from the uninjured control samples, and as well the ACL surgical samples from sham surgery. In all samples there were 65 metabolites quantified, of which six could be suggested as biomarkers for early post-injury degenerative changes in the knee joints: isobutyrate, glucose, hydroxyproline, asparagine, serine, and uridine. Our results raise a cautionary note indicating that surgical interventions into the knee can result in metabolic alterations that need to be distinguished from those caused by the early onset of OA. Our findings illustrate the potential application of metabolomics as a diagnostic and prognostic tool for detection of injuries to the knee joint. The ability to detect a unique pattern of metabolic changes in the synovial fluid of sheep offers the possibility of extending the approach to precision medicine protocols in patient populations in the future. PMID- 25283886 TI - Lapatinib ameliorates experimental arthritis in rats. AB - Epidermal growth factor receptor (EGFR) and its ligands are commonly expressed by synovial cells. The aim of the present study was to detect the potential effect of lapatinib an inhibitor of EGFR tyrosine kinases on collagen-induced arthritis. Thirty Wistar albino female rats were randomized into three groups. Arthritis was induced by intradermal injection of chicken type II collagen with incomplete Freund's adjuvant. Serum TNF-alpha, IL-17, and malondialdehyde (MDA) levels were analyzed. Tissue superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activities, and nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxgenase-1 (HO-1) expressions were determined. TNF-alpha, IL-17 and MDA levels, and Nrf2 and HO-1 expressions were lower in lapatinib-treated (30 mg/kg/day) group compared to sham group, while SOD, catalase, and GPx activities were higher (p < 0.05). Moreover, lapatinib ameliorated perisynovial inflammation and cartilage-bone destruction (p < 0.001). In conclusion, EGFR may have prominent pathogenic role and lapatinib may be an effective therapeutic option for arthritis. PMID- 25283887 TI - Efficacy of sorafenib and impact on cardiac function in patients with thyroid cancer: a retrospective analysis. AB - PURPOSE: Sorafenib has recently been recognized as an important standard option for the management of patients with differentiated thyroid cancer. Although data concerning cardiac safety are available in pan-tumor studies, no data are available on its use in everyday clinical practice in patients with thyroid cancer. METHODS: In the off-label program of our institution, we enrolled 14 patients with different histological types of thyroid cancer suitable for treatment with sorafenib. Our aims were to evaluate cardiac safety factors-LVEF (left ventricular ejection fraction), heart rate and blood pressure-the cardiac markers NT-proBNP and troponin I, radiological response evaluated by CT and (18)FDG-PET (according to RECIST 1.1 criteria) and biomarker reduction (Eastern Cooperative Oncology Group Performance Status: ECOG PS) 0-2. RESULTS: Patients with ECOG PS 2 accounted for 36%. After starting sorafenib, many patients displayed reduced or stabilized metabolic activity in target lesions (clinical benefit = 44%), radiologic reduction or stabilization (74%) and decreased cancer markers (90%). Lung metastases displayed the largest reductions in size. Median overall survival (OS) was 7 months and median progression-free survival (PFS) was 3 months. No sign of cardiotoxicity was observed in almost all patients. LVEF was altered in two patients and proved symptomatic in one. CONCLUSIONS: Sorafenib seems to be effective in reducing disease progression in the early stages of treatment (3-6 months). Responses varied considerably according to the criteria investigated. Cardiac toxicities did not raise concerns and were in line with data reported in other malignancies. However, cardiac monitoring is recommended. PMID- 25283888 TI - Effects of different types of bedding materials on behavioral development in laboratory CD1 mice (Mus musculus). AB - Male and female mice were housed in cages, containing different types of bedding materials (wood flakes or pulp chips), from 4 weeks of age in the F0 generation to 11 weeks of age in the F1 generation; selected reproductive and neurobehavioral parameters were measured in the F1 generation. There were no adverse effects of bedding materials on litter size, litter weight, or sex ratios at the time of birth. With regard to behavioral development parameters, bedding materials did not influence any variables (p > 0.05) in both sexes. Regarding exploratory behavior in the F1 generation, number of defecations significantly varied (p = 0.0203) with bedding materials in males at 3 weeks of age. The number of horizontal activities also significantly varied (p = 0.0342) with bedding materials in males at 8 weeks of age. Multiple-T water maze performance data indicated that the time required was significantly shortened across trials in pulp chips group than wood flakes group in males (p = 0.0211). Moreover, all spontaneous behavior variables in males significantly varied with bedding materials, particularly the average time of movement was significantly different (p = 0.0037) in distance between parallel lines of types of bedding materials in the F1 generation. The present study shows that bedding materials influence the neurobehavioral development in mice. PMID- 25283890 TI - Synthesis of novel camphor-derived bifunctional thiourea organocatalysts. AB - Synthesis and catalyst performance of 2,3- (types and ) and 2,8-disubstituted (type ) thiourea bifunctional organocatalysts was attempted. The synthesis of catalyst of type has, so far, not been realized, while catalysts of type , i.e., the 2,3-exo- and the 2-endo-3-exo-thiourea catalysts, were prepared in six steps starting from (+)-camphor. The catalysts of type were prepared from (+)-camphor in eight steps. All the potential catalysts as well as most of the intermediate products were carefully structurally characterized. The thiourea bifunctional organocatalysts were tested in a model reaction of Michael addition of dimethyl malonate to trans-beta-nitrostyrene. PMID- 25283889 TI - Buffering effects of job resources on the association of overtime work hours with psychological distress in Japanese white-collar workers. AB - PURPOSE: The purpose of the present study was to investigate the buffering effects of job resources, utilizing the job demands-control (or demand-control support) and effort-reward imbalance models (i.e., job control, workplace social support, and extrinsic reward), on the association of overtime work hours with psychological distress in Japanese employees. METHODS: A total of 1,198 participants (valid response rate = 93.7 %) from five branches of a manufacturing company in Japan completed a self-administered questionnaire comprising the scales assessing job resources, psychological distress, and demographic characteristics. We obtained the information on working hours in the most recent month from the personnel records of the surveyed company. Multiple logistic regression analyses were conducted. In a series of analyses, interaction term of overtime work hours with each job resource was included in the model. RESULTS: Significant interaction effect of overtime work hours with job control was observed. Among the low job control group, the long overtime (80 h or more) subgroup had a significantly higher prevalence odds ratio of psychological distress compared to the short overtime (44 h or less) subgroup. No significant association of overtime work hours with psychological distress was found among the high job control group. On the other hand, there was no significant interaction effect of overtime work hours with workplace social support or extrinsic reward. CONCLUSIONS: The present findings suggest that high job control has an effect on reducing psychological distress in relation to overtime work hours in Japanese employees. PMID- 25283891 TI - B(C6F5)3-catalyzed hydrogenation of oxime ethers without cleavage of the N-O bond. AB - The hydrogenation of oximes and oxime ethers is usually hampered by N-O bond cleavage, hence affording amines rather than hydroxylamines. The boron Lewis acid B(C6F5)3 is found to catalyze the chemoselective hydrogenation of oxime ethers at elevated or even room temperature under 100 bar dihydrogen pressure. The use of the triisopropylsilyl group as a protecting group allows for facile liberation of the free hydroxylamines. PMID- 25283892 TI - Epigenetics reloaded: the single-cell revolution. AB - Mechanistically, how epigenetic states are inherited through cellular divisions remains an important open question in the chromatin field and beyond. Defining the heritability of epigenetic states and the underlying chromatin-based mechanisms within a population of cells is complicated due to cell heterogeneity combined with varying levels of stability of these states; thus, efforts must be focused toward single-cell analyses. The approaches presented here constitute the forefront of epigenetics research at the single-cell level using classic and innovative methods to dissect epigenetics mechanisms from the limited material available in a single cell. This review further outlines exciting future avenues of research to address the significance of epigenetic heterogeneity and the contributions of microfluidics technologies to single-cell isolation and analysis. PMID- 25283893 TI - Smoking history predicts for increased risk of second primary lung cancer: a comprehensive analysis. AB - BACKGROUND: Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). METHODS: All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. RESULTS: A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P = .031]), corresponding to an 8% increased risk per 10 pack-year exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P = .069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. CONCLUSIONS: SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival. PMID- 25283894 TI - Two new skinks (Scincidae: Glaphyromorphus) from rainforest habitats in north eastern Australia. AB - Tropical rainforest is largely restricted in Australia to the fairly continuous Wet Tropics region and disconnected patches to the north on Cape York. The Wet Tropics is relatively well explored and studied, whereas the rainforests of Cape York have received less attention due to their remoteness. Here we describe two new species of Glaphyromorphus skinks from rainforest areas on Cape York. The two new species are most similar to each other and to G. fuscicaudis and G. nigricaudis, but both are readily diagnosed on numerous traits. Glaphyromorphus othelarrni sp. nov. is diagnosed from all similar species by its supralabial count (typically 8 vs 7), high number of subdigital lamellae beneath the 4th finger (14-15 vs < 14), and its relatively longer limbs. Glaphyromorphus nyanchupinta sp. nov. is diagnosed from all similar species by its small body size (max SVL = ~ 54 mm vs > 85 mm) and slender body shape, low number of subdigital lamellae beneath the 4th toe (17-20 vs generally 20 or more), and head and body pattern. Both species also differ from each other and similar congeners in other aspects of body shape, scalation and colour pattern. Glaphyromorphus othelarrni sp. nov. is restricted to boulder-strewn rainforest of the Melville Range, whilst Glaphyromorphus nyanchupinta sp. nov. is known only from upland rainforest in the McIlwraith Range. We discuss patterns of rainforest vertebrate endemism on Cape York, and the importance of lithorefugia in generating these. PMID- 25283895 TI - Description of Amplimerlinius uramanatiensis sp. n. (Nematoda: Merliniidae) and observations on three other species of the genus from Iran. AB - A new species of the genus Amplimerlinius is described and illustrated from the rhizosphere of Vitis sp. from Kurdistan province in western Iran. A. uramanatiensis sp. n. is characterized by having seven to eight head annuli up to the end of the outer extension of the cephalic framework, 29-31 um long stylet and cylindrical-clavate tail with a thin hyaline region (9-11 um) and smooth terminus. Furthermore, A. paraglobigerus and A. macrurus were identified and intra-specific variability of A. globigerus was studied in detail, based on 21 populations collected from different regions of Iran. A key and diagnostic compendium to the species of the genus is provided. PMID- 25283896 TI - New Palaeogene horntail wasps (Hymenoptera, Siricidae) and a discussion of their fossil record. AB - The phylogenetic placement of siricid hymenopterans and especially the relationships among Siricidae are not resolved, and are in need of further investigation. The fossil record helps to illuminate the evolutionary history of this group. In this paper, Xoanon? eocenicus sp. nov. is newly described from the Eocene Fossillagerstatte Grube Messel (Germany). Although several characters of the wing venation of this fossil are similar to the extant genus Xoanon, there remain some doubts concerning the generic placement. A newly found fossil is attributed to Urocerus ligniticus (Piton, 1940) from the Paloecene Fossillagerstatte Menat (France) and provides more morphological information on this species. An overview of the fossil record of Siricidae in the strict sense is given and the state of knowledge on the different fossils is reviewed. PMID- 25283897 TI - A new species of Opecarcinus Kropp & Manning, 1987 (Crustacea: Brachyura: Cryptochiridae) associated with the stony corals Pavona clavus (Dana, 1846) and P. bipartita Nemenzo, 1980 (Scleractinia: Agariciidae). AB - A new species of Opecarcinus Kropp & Manning, 1987, is described from Indonesia and Malaysia. Opecarcinus cathyae sp. nov. is associated with the scleractinian corals Pavona clavus (Dana, 1846) and P. bipartita Nemenzo, 1980, inhabiting crescent-shaped cavities or tunnels on the coral surface. The new species is the ninth assigned to the genus. It can be separated from congeners by the anterolateral orientation of the cornea, the carapace with shallow transverse depressions, lacking longitudinal depressions, and the smooth dorsal margin of the fifth female pereiopod carpus. The distinctive colour pattern can be used as a diagnostic character in live specimens. PMID- 25283898 TI - Sirindhornia Pinkaew and Muadsub (Lepidoptera: Tortricidae), a new enarmoniine genus from Thailand. AB - A new enarmoniine genus, Sirindhornia, n. gen., is described based on the type species, Sirindhornia pulchella, n. sp., and three additional new species: Sirindhornia chaipattana, n. sp., Sirindhornia curvicosta, n. sp., and Sirindhornia bifida, n. sp., all from Thailand. A fifth species represented only by a single female is morphologically characterized but not formally described. Sirindhornia is most closely related to Anthozela Meyrick and Irianassa Meyrick but is easily distinguished by unique appendages of the tegumen and a conspicuous henion in the male genitalia. PMID- 25283899 TI - Cyrtodactylus saiyok sp. nov., a new dry evergreen forest-dwelling Bent-toed Gecko (Squamata: Gekkonidae) from Kanchanaburi Province, western Thailand. AB - We describe Cyrtodactylus saiyok sp. nov. from a dry evergreen forest on a limestone hill in Khao Krajae, Sai Yok District, Kanchanaburi Province, western Thailand. It is characterized by a maximal known SVL of 61.0 mm; 18-19 longitudinal rows of dorsal tubercles; 23 or 24 ventral scale rows between ventrolateral skin folds; a continuous series of enlarged femoro-precloacal scales, including 5 pore-bearing precloacal scales (males); no precloacal groove or depression; transversely enlarged subcaudal scales; a complete black nuchal loop; a W-shaped band above shoulders and 3-5 irregular, medially interrupted or not, black dorsal bands between limb insertions. Cyrtodactylus saiyok sp. nov. is the sixth reptile species that is possibly endemic to Sai Yok District. PMID- 25283900 TI - The larva of Athripsodes genei (Rambur 1842) (Trichoptera, Leptoceridae). AB - This paper describes the previously unknown larva of Athripsodes genei (Rambur 1842). Information on the morphology of the 5th larval instar is given and the most important diagnostic features are illustrated. In the context of existing identification keys the larva of A. genei keys together with A. albifrons (Linnaeus 1758), A. commutatus (Rostock 1874), A. leucophaeus (Rambur 1842) and Athripsodes tavaresi (Navas 1916). These species differ in the number of ventral edge setae at the 1st tibia and in the shape and colour of the submentum. With respect to zoogeography, Athripsodes genei is a (micro-)endemic of the collin and planar regions of Sardinia and Corsica (Graf et al. 2008). According to mandible morphology, A. genei is a collector-gatherer, shredder and, to a minor extent, also a predator. PMID- 25283901 TI - On the identity of Trichogramma demoraesi Nagaraja (Hymenoptera: Trichogrammatidae), with a checklist and a key to Trichogramma species associated with Erinnyis ello (L.) (Lepidoptera, Sphingidae) in Brazil. AB - Specimens collected from eggs of the cassava hornworm Erinnyis ello, originally identified as T. demoraesi, were compared with the paratype of this species. Based on morphological analysis, the specimens from E. ello actually belong to Trichogramma marandobai Brun, Moraes and Soares, 1986. Therefore, T. demoraesi is not a parasitoid of the eggs of E. ello, a major pest of cassava. The main features separating the two species, and a checklist and key to the species of Trichogramma associated with E. ello are presented. PMID- 25283902 TI - Reinstatement of Distantasca Dworakowska (Hemiptera: Cicadellidae: Typhlocybinae: Empoascini) as a valid genus with new species and new combinations. AB - Distantasca Dworakowska originally established as a genus but more recently has been treated as a subgenus of Empoasca Walsh. Here we reinstate Distantasca as a valid genus and provide a revised diagnosis. New combinations created are Distantasca atika (Dworakowska), n. comb., Distantasca barawa (Dworakowska), n. comb., Distantasca bulbosa (Dworakowska), n. comb., Distantasca latava (Dworakowska), n. comb., Distantasca latibasis (Zhang & Liu), n. comb., Distantasca paraterminalis (Qin & Zhang), n. comb., Distantasca riora (Dworakowska), n. comb., Distantasca rokasa (Dworakowska), n. comb., Distantasca serratipenis (Qin & Zhang), n. comb., Distantasca tiaca (Dworakowska), n. comb., Distantasca tna (Dworakowska), n. comb., Distantasca tuberculata (Zhang & Liu), n. comb., all from Empoasca (Distantasca). Distantasca terminalis (Distant) and D. faciata Dworakowska are reinstated from Empoasca (Distantasca). Two new species, Distantasca longihamatilis Zhang & Liu and Distantasca ricina Zhang & Liu spp. nov. are described and illustrated. Empoasca (Empoasca) smithi Fletcher & Donaldson, 1992 is transferred into the genus as Distantasca smithi (Fletcher & Donaldson). PMID- 25283903 TI - Type species fixation of the genus Abloxurina Johnson, 1992 (Lepidoptera: Lycaenidae: Theclinae). AB - The goal of this paper is to clarify the status and identity of the type species of the lycaenid genus Abloxurina Johnson, 1992 so that the name can be used correctly in future taxonomic work. Abloxurina was originally typified with Thecla amatista Dognin, 1895. However, the specimen examined and illustrated by Johnson (1992) to diagnose the genus was an individual of Penaincisalia ismaeli Busby & Hall, 2005, an undescribed species at that time. Consequently, Johnson's original typification was based on a misidentification. In order to make Abloxurina available, its type species is fixed under Article 70.3.2 of the International Code of Zoological Nomenclature (1999) as P. ismaeli. PMID- 25283904 TI - Checklist of Gastrotricha of the Polish Baltic Sea with the first reports of Heterolepidoderma joermungandri Kanneby, 2011, and Turbanella hyalina Schultze, 1853. AB - Gastrotricha is a cosmopolitan phylum of aquatic and semi-terrestrial invertebrates comprising more than 800 described species. Up to now, only five taxonomic and faunistic papers have been published on the gastrotrichs of the Polish Baltic Sea and 27 taxa have been found (including three freshwater, which were found in estuaries). This article presents a complete list of brackish and estuarine Gastrotricha from the Polish Baltic Sea accompanied by localities and the first observations of gastrotrich species inhabiting the underwater macrophytes. Although the group has been studied for more than 150 years, the gastrotrich community of marine macrophytes has not been studied in any great detail. Here we provide data on gastrotrich communities living on macrophytes and also in sandy sediments. In total, nine species were found (seven from sandy sediments, two species from macrophytes). Seven of the species belong to Chaetonotida: Halichaetonotus balticus Kisielewski, 1975, H. lamellatus Kisielewski, 1975, H. schromi Kisielewski, 1975, Heterolepidoderma joermungandri Kanneby, 2011, Lepidodermella squamata (Dujardin, 1841), Xenotrichula intermedia Remane, 1934, and X. velox Remane, 1927(c). Two of species belong to Macrodasyida: Turbanella cornuta Remane, 1925, and T. hyalina Schultze, 1853. H. joermungandri and T. hyalina are new for Polish fauna. Both species correspond with the original descriptions but differ by some morphometric characters. Taxonomic, morphometric, and biogeographic remarks are provided for the new records together with differential interference contrast (DIC) microphotographs. PMID- 25283905 TI - Larval morphology of Hydryphantes clypeatus Thor, 1899, H. dispar Schaub, 1888 and H. planus Thon, 1899 (Acari, Hydrachnidia: Hydryphantidae). AB - Larvae of the water mite species Hydryphantes clypeatus Thor, 1899 are described for the first time, and redescriptions of the larvae H. dispar (Schaub, 1888) and H. planus Thon, 1899 are presented. The present data suggest that H. clypeatus and H. hellichi Thor, 1899, two species recently considered as a junior synonyms of H. planus resp. H. ruber (Geer, 1787) should be recognized as separate species. Separate keys to all named species based on larvae and adults are given. PMID- 25283906 TI - Japanese species of the genus Proutia Tutt, 1899 (Lepidoptera: Psychidae). AB - Two new species of the genus Proutia are described from Japan based on both sexes. Proutia maculatella sp. nov. is distinctive in having maculated forewing upperside. Proutia nigra, sp. nov. has unicolorous blackish brown forewing upperside and similar to the European species, P. betulina, but differs from the latter in the longer processes of the male valvae and shorter female antennae. PMID- 25283907 TI - Redescription of Iberoiulus cavernicola Ceuca, 1967, and the relationships of the genus Iberoiulus Mauries, 1985 (Diplopoda, Julida, Blaniulidae). AB - The Iberian blaniulid millipede Iberoiulus cavernicola Ceuca, 1967, is redescribed based on abundant new material collected in a cave in Villaluenga del Rosario, Cadiz, Spain. The relationships of the genus Iberoiulus Mauries, 1985, to other blaniulid genera are discussed. PMID- 25283908 TI - A new genus and two new species, one extant and one fossil, in the family Troctopsocidae (Psocodea: 'Psocoptera': Troctomorpha: Amphientometae: Electrentomoidea). AB - We describe a new genus, Troctopsocoides, in the family Troctopsocidae with two new species, T. erwini n. sp. (Madre de Dios, Peru) and T. gracilis n. sp., a fossil in amber from the Dominican Republic. We include a diagnosis of the family Troctopsocidae following a recent important change in its status and a key to the known genera of the family. PMID- 25283909 TI - Haruchlora maesi, a new emerald moth genus and species from Mesoamerica (Lepidoptera, Geometridae, Geometrinae). AB - A new genus and species of Neotropical emerald geometrid moths, Haruchlora Viidalepp & Lindt, gen. nov., and Haruchlora maesi Viidalepp & Lindt, sp. nov. are described. The new genus differs from all other New World Geometrinae genera in having a bifid uncus, in characters of the pregenital segments of the male abdomen, and in the male genitalia. PMID- 25283910 TI - A new Corononcodes Speiser from the Palaearctic Region, with a key to species (Diptera: Acroceridae). AB - Corononcodes ziegleri spec. nov. is described and illustrated based on material from Iran. The species represents the second Palaearctic representative of this panopine genus. In addition, C. siculus Bezzi is recorded from Fuerteventura (Canary Islands, Spain) for the first time. An identification key to the Palaearctic species of Corononcodes is presented. Additional faunistic records for the Iranian fauna comprise Acrocera orbiculus (Fabricius) and an apparently undescribed species of Ogcodes Latreille. DNA-barcodes for all Iranian taxa are provided. PMID- 25283911 TI - Description of a new genus and species, Pseudobasidissus barclayi (Coleoptera: Anthribidae), from east Madagascar. AB - A new genus and species, Pseudobasidissus barclayi Tryzna & Banar gen. nov. et sp. nov. (Anthribidae: Anthribinae: Platyrhinini), from Madagascar is described. Male and female genitalia are studied and illustrated. Colour photographs of the holotype and genitalia of both sexes are provided. Comparison is made with the similar genus Basidissus Fairmaire. PMID- 25283912 TI - A new genus and two new species of Alysiinae (Hymenoptera: Braconidae) from Papua New Guinea. AB - Two new species of the genus Leptotrema van Achterberg, 1988 and one new genus of the Alysiinae from Mt Wilhelm, Madang Province, Papua New Guinea are described and illustrated. The distribution of the genus Leptotrema is extended to the Australasian region. Three new combinations are established Idiasta fulmeki (Fischer, 2010) comb. n. (=Microcrasis fulmeki Fischer, 2010), Apiasta postfurcata (Papp, 1966) comb. n. (= Microcrasis postfurcata (Papp, 1966)), and Leptotrema. bovefemora (Bhat, 1979) comb. nov. (=Aspilota bovefemora Bhat, 1979). The status of the genus Apiasta Wharton, 2002 (stat. n.) is reviewed. Keys are provided to enable their identification. PMID- 25283913 TI - On the identity of Thespis disparilis Westwood, 1889 (Mantodea: Mantidae: Mantinae). PMID- 25283914 TI - A new toothed pterosaur (Pterodactyloidea: Anhangueridae) from the Early Cretaceous Romualdo Formation, NE Brazil. AB - A new species of pterosaur, Maaradactylus kellneri gen. nov., sp. nov. (Archosauria: Pterosauria) from the Romualdo Formation (Aptian/Albian), is herein described. The specimen (MPSC R 2357) was found at Sitio Sao Goncalo, Santana do Cariri city (State of Ceara, northeast Brazil) and consists of the skull, atlas and axis, and represents one of the largest skulls of the Anhangueridae from the Araripe Basin described. The autapomorphies of the new pterosaur include the following characters: a premaxillary sagittal crest that is relatively long and high, beginning at the anterior part of the skull (rostrum) and extending to the 22nd pair of alveoli, not covering the nasoantorbital fenestra or the choanaes, and also the presence of 35 pairs of alveoli; smooth palatal ridge, which starts on the 5th pair of alveoli and ends on the 13th pair; palate is convex shaped in the anterior region; choanae not extending laterally; small and convex palatal elevation; the 5th, 6th and 7th alveoli smaller than the 4th and 8th; the alveoli decreasing in size from the 9th to the 12th and increasing from the 13th to 18th, and from the 18th to the 35th they are arranged in triplets. Furthermore, the lateral surface of the premaxillary crest shows grooves and tridimensional structures that may have housed blood vessels. PMID- 25283915 TI - A new skink (Scincidae: Carlia) from the rainforest uplands of Cape Melville, north-east Australia. AB - Carlia skinks are widespread in New Guinea, Wallacea, and northern and eastern Australia. Most Australian species occur in dry woodlands and savannas or marginal rainforest habitats associated with these. There are two rainforest species, parapatrically distributed in coastal mid-eastern Queensland (C. rhomboidalis) and the Wet Tropics of north-eastern Queensland (C. rubrigularis). These two sister species share a diagnostic morphological trait in having the interparietal scale fused to the frontoparietal. Here I describe a third species in this group, Carlia wundalthini sp. nov., from rainforest uplands of the Melville Range, a rainforest isolate 170 km north of the Wet Tropics. This species is diagnosable on male breeding colouration, morphometrics and scalation. The description of C. wundalthini sp. nov. brings the number of vertebrate species known to be endemic to the rainforest and boulder-fields of Cape Melville to seven. Carlia wundalthini sp. nov. is distinct among these endemics in being the only one that does not appear to be directly associated with rock, being found in rainforest leaf-litter. PMID- 25283916 TI - Review of amphipods of the Melita group (Amphipoda: Melitidae) from the coastal waters of Sakhalin Island (Far East of Russia). II. Genera Quasimelita Jarrett & Bousfield, 1996 and Melitoides Gurjanova, 1934. AB - Based on new material, three new species of the genus Quasimelita are described: Q. tolyza sp. nov., Q. jarettii sp. nov. and Q. serraticoxae sp. nov. from northern shelf of Sakhalin Island and contiguous area. The new species of the genus Melitoides, M. kawaii sp. nov. is described from north-east shelf of Sakhalin Island. Keys to the world species of genera Quasimelita and Melitoides are provided. Cladistic analysis of morphological relationships within genera Quasimelita and Melitoides are implemented. PMID- 25283917 TI - Xynocoris, new genus of Ochlerini from Central and South America (Hemiptera: Pentatomidae: Discocephalinae). AB - Xynocoris Garbelotto & Campos gen. nov. is proposed for a monophyletic group recovered in the previous cladistic analysis of the Herrichella clade. The genus is proposed based in two synapomorphies: the presence of long, projected, and acute anteocular processes, and apices of posterolateral angles of pygophore tumid. Nine new species are described (X. crinitus Garbelotto & Campos sp. nov., X. recavus Garbelotto & Campos sp. nov., X. tuberculatus Garbelotto & Campos sp. nov., X. insularis Garbelotto & Campos sp. nov., X. egeri Garbelotto & Campos sp. nov., X. calosus Garbelotto & Campos sp. nov., X. meridionalis Garbelotto & Campos sp. nov., X. lucidus Garbelotto & Campos sp. nov. and X. cupreus Garbelotto & Campos sp. nov.) and one new combination is proposed for Alitocoris parvus (Distant). PMID- 25283918 TI - Parachiloglanis bhutanensis, a new species of torrent catfish (Siluriformes:Sisoridae) from Bhutan. AB - Parachiloglanis bhutanensis is a newly discovered species of torrent catfish from eastern Bhutan. With its discovery, the genus Parachiloglanis is no longer monotypic. The species differs from Parachiloglanis hodgarti in meristic, mensural, and coloration characters. Parachiloglanis bhutanensis is confirmed as a member of the genus by the absence of a post-labial grove on the lower lip, which is present in other genera of the subfamily Glyptosterninae (as either complete or incomplete). It is diagnosed within the genus by the presence (versus absence) of a series of 35-40 large white pores along the lateral line, a tall adipose fin (roughly two times the height of the adipose fin in P. hodgarti), a less dorsoventrally flattened body than P. hodgarti, a deeper head, wider mouth, longer inner- and outer-mandibular barbels, a truncate (versus indented to lunate) caudal fin, and the absence (versus presence) of black and white pigmentation on the caudal fin. PMID- 25283919 TI - New species and records of Apseudomorpha (Crustacea: Tanaidacea) from Taiwan. AB - The present study reports the first record of Apseudomorpha from Taiwan and includes descriptions of three new species and one new species record. Paradoxapseudes pangcahi sp. nov. differs from the most similar congener, Paradoxapseudes littoralis, by having one segment less in the antennal flagellum and fewer segments in the uropod endopod. Pseudoapseudomorpha tagopilosus sp. nov. is distinguished from its most similar congener, Pseudoapseudomorpha ornata, by having one long lateral seta on pleonite 4, a four-segmented antennular outer flagellum, and a male with smaller and thinner 'small' cheliped than that of the female and with vestigial pleopods on pleonite 3. Indoapseudes multituberculata sp. nov. stands out from its congeners by having pleopods only on the last two pleonites in females, many small tubercles terminally on the pleotelson, and mandibular palp article 1 with noticeable distal teeth. The Synapseudes species recorded in the present study morphologically agrees with Synapseudes hansmuelleri that was originally described from the Tioman Archipelago, Malaysia, South China Sea. Morphological comparisons between each of the three newly described species and its congeners are tabulated. PMID- 25283920 TI - Calicnemia fortis sp. nov. from Pakistan (Odonata: Zygoptera: Platycnemididae) . AB - Calicnemia fortis sp. nov. is described from Azad Jammu and Kashmir in Pakistan and compared with other group 2 species of Calicnemia. PMID- 25283921 TI - Correcting the "correct" name for the Asian Brown Flycatcher (Aves: Passeriformes, Muscicapidae, Muscicapa). PMID- 25283922 TI - The case for using the infraorder Coccomorpha above the superfamily Coccoidea for the scale insects (Hemiptera: Sternorrhyncha). PMID- 25283923 TI - Sea snakes in Australian waters (Serpentes: subfamilies Hydrophiinae and Laticaudinae)--a review with an updated identification key. AB - Sea snakes (Elapidae, subfamilies Hydrophiinae and Laticaudinae) reach high species richness in the South China Sea and in the Australian region; however, most countries in the two regions still lack up-to-date checklists and identification tools for these snakes. We present an updated reviewed checklist and a new complete identification key to sea snakes in Australian waters. The identification key includes 29 species documented and 4 possibly occurring taxa and is based mostly on easy-to-use external characters. We find no evidence for breeding populations of Laticauda in Australian waters, but include the genus on the list of possibly occurring taxa. PMID- 25283924 TI - A new genus and species of ibis fly in the Lowermost Eocene amber of Oise (France) (Diptera: Athericidae). AB - A new athericid genus and species, Eoatrichops jeanbernardi, gen. n., sp. n., is described, based on four specimens from the Lowermost Eocene of Oise (France). Its external morphology is analyzed and compared with of all genera of Athericidae. Eoatrichops is very similar to the modern genus Atrichops Verrall, differences concern the wing venation and tibial spur formula. PMID- 25283925 TI - Saltbush-associated Asphondylia species (Diptera: Cecidomyiidae) in the Mediterranean Basin and their chalcidoid parasitoids (Hymenoptera: Chalcidoidea). AB - Numerous species of gall midges (Diptera: Cecidomyiidae) have been recorded from saltbush (Chenopodiaceae: Atriplex) around the world but only 11 of them belong to the large cecidomyiid genus Asphondylia. Of these, two species were described in the late 19th century from complex bud galls on Atriplex halimus in the Mediterranean Basin. In the present study Asphondylia punica is redescribed, A. conglomerata is synonymized with it, and Asphondylia scopuli is described from Atriplex lanfrancoi, an endemic plant to the Maltese Islands. Descriptions are accompanied by information about the galls and life history of the gall midges, and a review of the parasitic Hymenoptera associated with A. scopuli is provided. Four species of parasitoids were found and attributed to the families Eurytomidae, Pteromalidae, Eupelmidae and Eulophidae, of which the pteromalid Mesopolobus melitensis is described as new. PMID- 25283926 TI - A tiny new species of leaf insect (Phasmatodea, Phylliidae) from New Guinea. AB - The female and egg of the new Papuan leaf insect Phyllium (Phyllium) riedeli n. sp. are described and illustrated. The species belongs in the siccifolium species group of the subgenus Phyllium and, with a body length of 56.3 mm, represents the smallest leaf insect so far described for the genus. The type-specimens are stored in the State Museum of Natural History Karlsruhe, Germany (SMNK). A checklist and key is provided for the New Guinean representatives of Phyllium (Phyllium) Illiger, 1798. PMID- 25283927 TI - Apistogramma ortegai (Teleostei: Cichlidae), a new species of cichlid fish from the Ampyiacu River in the Peruvian Amazon basin. AB - Apistogramma ortegai, new species, is described from small streams tributaries of the Ampiyacu River near Pebas, in eastern Peru. It belongs to the Apistogramma regani species group and is distinguished from all other species of Apistogramma by the combination of contiguous caudal spot to bar 7, presence of abdominal stripes, short dorsal-fin lappets in both sexes, absence of vertical stripes on the caudal fin, and reduced number of predorsal and prepelvic scales. PMID- 25283928 TI - A review of the glyptosternine catfish genus Exostoma Blyth 1860 from Thailand, with descriptions of two new species (Teleostei: Siluriformes). AB - We review members of the sisorid catfish genus Exostoma known from Thailand. Three species are recognized, of which two from the headwaters of the Chao Phraya River drainage in northwestern Thailand, are described here as new: E. effrenum and E. peregrinator. In addition to the two new species, E. berdmorei (which is here redescribed) is also known from the Salween River drainage in western Thailand. The three species can be distinguished from each other and other congeners by the morphologies of the adipose and caudal fins, as well as morphometric data for the eye diameter, head width, dorsal-to-adipose distance, body depth at anus, caudal-peduncle length, caudal-peduncle depth, and numbers of branched pectoral-fin rays and preanal vertebrae. PMID- 25283929 TI - Revalidation of the Brazilian Atlantic Forest dung beetle species Coprophanaeus (Metallophanaeus) machadoi (Pereira & d'Andretta, 1955) (Coleoptera: Scarabaeidae: Scarabaeinae: Phanaeini) based on morphological and distributional evidence. AB - Coprophanaeus machadoi, species described based on a single male from Minas Gerais, was recently synonymized with C. saphirinus (Sturm, 1826). In this work, based on examination of more than 500 specimens from Brazilian Atlantic Forest, we introduce new evidence supporting the validity of C. machadoi, including differences in male pronotal ornamentation, in the form of the parameres, and in distribution. We also describe for the first time the female of C. machadoi and discuss the intraspecific color variation of C. saphirinus. PMID- 25283930 TI - Ascetoaxinus quatsinoensis sp. et gen. nov. (Bivalvia: Thyasiroidea) from Vancouver Island, with notes on Conchocele Gabb, 1866, and Channelaxinus Valentich-Scott & Coan, 2012. AB - Ascetoaxinus quatsinoensis sp. et gen. nov. is described from deep waters off the coast of Vancouver Island, British Columbia, Canada. The shell of this species is quite unusual in that the margin of the lunule is distinctly scalloped, a feature not reported previously for the Thyasiroidea. Further investigation led to the discovery of another similarly scalloped shell, represented by the unique type specimen of Cryptodon ovoideus Dall, 1890, herein re-classified as Ascetoaxinus ovoidea (Dall, 1890). Results obtained from scanning electron microscopy reveal additional anatomical differences, including distinct gill structure, that distinguish A. quatsinoensis from other thyasirids examined. Morphological comparisons of this new species to closely related taxa has resulted in a re evaluation of the genera Conchocele Gabb, 1866, and Channelaxinus Valentich-Scott and Coan, 2012. PMID- 25283931 TI - Three new species of Thrasychiroides Soares & Soares, 1947 from Brazilian Mountains (Opiliones, Eupnoi, Neopilionidae). AB - Three new species of the genus Thrasychiroides are described from the Brazilian Atlantic Rain Forest mountains: Thrasychiroides moporanga sp. nov. (type locality: Reserva Biologica de Alto da Serra de Paranapiacaba, State of Sao Paulo), T. toryba sp. nov. (type locality: Sao Francisco de Paula, State of Rio Grande do Sul) and T. ybytyra sp. nov. (type locality: Parque Nacional do Itatiaia, State of Minas Gerais). The male genital of Thrasychiroides brasilicus Soares & Soares, 1947 is illustrated for the first time. A remarkable structure on the penis of Thrasychiroides species is described and defined as pair of "arms", also considered a putative synapomorphy of the genus. PMID- 25283932 TI - Three new species of the genus Otacilia Thorell (Araneae: Phrurolithidae) from China. AB - Three new species of the spider genus Otacilia are diagnosed, described and illustrated from China: Otacilia fujiana sp. nov. (male, female), O. pseudostella sp. nov. (male, female) and O. zhangi sp. nov. (male). PMID- 25283933 TI - A new Neotropical genus of Ommatolampidinae (Orthoptera: Acridoidea: crididae) from Brazilian Atlantic Forest, with chromosome complement. AB - A new Neotropical genus of Ommatolampidinae belonging to the genus group Ommatolampae Brunner von Wattenwyl, 1893 from Brazilian Atlantic Forest was described, diagnosed, and illustrated. The description was based on the external morphology, as well as genitalia and chromosomal characterization. Muriciacris n. gen. was proposed to include Muriciacris triflavovittata n. sp. (type species) described from northeastern of Brazil, state of Alagoas. PMID- 25283934 TI - Taxonomic notes on some species of Euselasia Hubner, [1819] from the "Uriiformes" group, with the description of the immature stages of Euselasia satyroides Lathy, 1926, stat. rev. (Lepidoptera: Riodinidae: Euselasiinae). AB - The specific status of Euselasia satyroides Lathy, 1926, stat. rev., currently recognized as a synonym of Eurygona modesta Hewitson, 1856, is reinstated, and its immature stages, reared on Pouteria salicifolia (Sapotaceae), are thoroughly described and illustrated. The identity of some species of the genus Euselasia Hubner, [1819] belonging to the "Uriiformes" species group is clarified: lectotypes are designated to Eurygona eugeon Hewitson, 1856, Eurygona modesta Bates, 1868, Euselasia geon Seitz, 1913, and Euselasia satyroides Lathy, 1926, stat. rev.; Euselasia geon Seitz, 1913, syn. rev. is considered a synonym of Eurygona eugeon Hewitson, 1856. Additionally, a taxonomic dichotomous key for the species belonging to the "Uriiformes" group is provided. PMID- 25283936 TI - Two new species of Atanatolica Mosely 1936 (Trichoptera: Leptoceridae) from Peru and Northeastern Brazil. AB - We describe and illustrate two new species of Atanatolica from Brazil and Peru, representing the first record of the genus from Peru and the first record of the genus from Ceara state, Brazil. Atanatolica nordestina sp. nov. is recognized by short inferior appendages, with their basal portions subquadrangular, in ventral view; and by tergum X without the typical digitate apical processes, but with a pair of short rounded projections. Atanatolica quechua sp. nov. is recognized by preanal appendages long and slender, by the inferior appendages with the apicodorsal portion broader distally, and by the apicolateral processes of tergum X slightly capitate. PMID- 25283935 TI - A taxonomic revision of the soil-feeding termite genus Anhangatermes (Isoptera: Termitidae: Nasutitermitinae). AB - The taxonomy of Anhangatermes Constantino 1990 is revised. Four new species are described: Anhangatermes anhanguera, sp. n., Anhangatermes eurycephalus, sp. n., Anhangatermes juruena, sp. n., and Anhangatermes pilosus, sp. n. The imago of Anhangatermes is described for the first time (A. pilosus). A key to the species of the genus based on soldiers and workers is provided. The diagnosis of the genus is updated to accommodate the new species. The geographic range of the genus is expanded to the Cerrado region of Central Brazil. The gizzard armature of the worker of Anhangatermes is described in detail for the first time. PMID- 25283937 TI - Notes on a collection of the tribe Meconematini (Orthoptera: Tettigoniidae) from Hainan, China. AB - This paper deals with 7 genera and 12 species of the tribe Meconematini from Hainan, China, three of which are new species, i.e. Xizicus (Axizicus) bispinus sp. nov., Xizicus (Eoxizicus) furcutus sp. nov. and Xizicus (Eoxizicus) streptocercus sp. nov., and the first record of Xizicus (Axizicus) szechwanensis (Tinkham, 1944), Xiphidiopsis (Xiphidiopsis) autumnalis Gorochov, 1998 and the female of Teratura (Teratura) flexispatha Qiu & Shi, 2010. The specimens examined are deposited in the Museum of Hebei University. PMID- 25283938 TI - Description of Epistylis riograndensis n.sp. (Ciliophora: Peritrichia) found in an artificial lake in Southern Brazil. AB - Epistylis riograndensis n. sp., a freshwater peritrich hosting symbiotic algae in its cytoplasm, was collected from an artificial lake, in a Botanical garden in Southern Brazil. Its detailed morphology was investigated using live and silver stained specimens. The colonial sessile E. riograndensis has elongate zooids measuring, on average, 162 MUm in length and 45 MUm in width. A single contractile vacuole located near the infundibulum and a C-shaped macronucleus located transversely in the adoral half of the cell were also observed. The oral infraciliature revealed in silver-stained specimens was typical of peritrich ciliates. Three infundibular polykineties consisting of 3 rows of kinetosomes were observed. Molecular analyses of 18s rDNA placed E. riograndensis among other Epistylis species in the Order Vorticellida. PMID- 25283939 TI - Description of a new montane freshwater crab (Crustacea: Potamidae: Geothelphusa) from northern Taiwan. AB - A new freshwater crab is described from a montane area in northern Taiwan based on morphological characters and molecular evidence. Geothelphusa cilan sp. nov., from the Cilan Forest, situated on the boundary of Hsinchu and Yilan (= Ilan) counties, is close to G. monticola Shy, Ng & Yu, 1994, and G. takuan Shy, Ng & Yu, 1994, but can be distinguished by its male first gonopod (G1) and the ratio of thoracic sternites. Molecular evidence from mitochondrial cytochrome oxidase subunit I (COI) also supports the identity of the new species. PMID- 25283941 TI - A new species of Tomarus Erichson, 1847 (Coleoptera: Scarabaeidae: Dynastinae: Pentodontini), with a key to the species in Colombia. AB - A new Tomarus Erichson, 1847 (Coleoptera: Scarabaeidae: Dynastinae: Pentodontini) species is described from western Colombia. The new species is compared with Tomarus laevicollis (Bates, 1888) from Central America. An identification key is also provided to the species occurring in the country. PMID- 25283940 TI - A new species of Nilothauma Kieffer from China, with a key to known species of the genus (Diptera: Chironomidae). AB - A new species of the genus Nilothauma Kieffer, N. pandum sp. n., is described, and its morphological descriptions and illustrations are also given. A key to the males of Nilothauma is given. The adult male of N. pandum sp. n. can be distinguished from known species of the genus by the following combination of characters: anal point very broadly lanceolate with microtrichia in median ridge and apical margin, rounded at apex; superior volsella pad-like, expanded distally; median volsella curved, rounded at apex, with 2 long basal setae and 1 long median seta. PMID- 25283942 TI - A taxonomic revision of two local endemic Radix spp. (Gastropoda: Lymnaeidae) from Khodutka geothermal area, Kamchatka, Russian Far East. PMID- 25283943 TI - A new name for Myrmecodesmus potosinus (Shear) 1973, a homonym of Myrmecodesmus potosinus (Chamberlin) 1943 (Diplopoda, Polydesmida, Pyrgodesmidae). PMID- 25283944 TI - First record of Otibazo (Coleoptera: Curculionidae: Molytinae) outside of Japan, with description of a new species from Vietnam. AB - A new species of wingless leaf litter weevil, Otibazo polyphemus sp. n., is described from Tam Dao, northern Vietnam. This is the fourth named species in the genus, with its three other species known only from Japan. Habitus and genitalia of the male holotype are illustrated and DNA barcoding data are provided. PMID- 25283945 TI - Sequence differences in the internal transcribed spacer 1 and 5.8S ribosomal RNA among three Moniezia species isolated from ruminants in Japan. AB - This study was designed to clarify the differences in the internal transcribed spacer (ITS) 1 and 5.8S nucleotide sequences of Moniezia expansa, M. benedeni and M. monardi isolated from ruminants in Japan and to determine their phylogenetic relationships. A 98% similarity in the 5.8S sequences was observed among the 3 Moniezia species, whereas many nucleotide indels and substitutions were observed in the ITS1 sequences among the three Moniezia species. These results suggest that the ITS1 region could serve as a potential marker for discriminating the 3 Moniezia species. In the phylogenetic tree based on the ITS1 sequences, M. monardi and M. benedeni showed genetically closer relationship to each other than to M. expansa. PMID- 25283946 TI - A rare case of hepatic T-cell rich B-cell lymphoma (TCRBCL) in a juvenile dog. AB - A 7-month-old castrated male French Bull dog was presented with vomiting, lethargy, anorexia and weight loss of 2 weeks duration. The patient's history and clinical manifestations of suspected hepatopathy were subjected to ultrasonography, radiography, biochemical investigations and cytology of hepatic lesion. The cytologic impression was hepatic lymphoma, which was later confirmed by histopathology. The neoplastic cells were strongly diffusely immunoreactive for PAX5, but not immunoreactive for CD3, and B lymphocyte specific clonal proliferation was detected using by assay of antigen receptor rearrangement. Large numbers of immunoreactive mature non-neoplastic lymphocytes were admixed with the neoplastic cell population. Therefore, the immunohistochemical results were definitively consistent with a T-cell rich B-cell lymphoma (TCRBCL). This is the first description of a hepatic TCRBCL in a juvenile dog showing a poor response to aggressive chemotherapy. PMID- 25283948 TI - Manipulating nanowire assembly for flexible transparent electrodes. AB - Manipulating nanowire assembly could help the design of hierarchical structures with unique functionalities. Herein, we first report a facile solution-based process under ambient conditions for co-assembling two kinds of nanowires which have suitable composition and functionalities, such as Ag and Te nanowires, for the fabrication of flexible transparent electrodes. Then Te nanowires can be etched away easily, leaving Ag nanowire networks with controllable pitch. By manipulating the assembly of Ag and Te nanowires, we can precisely tailor and balance the optical transmittance and the conductivity of the resulting flexible transparent electrodes. The network of Ag nanowires which have tunable pitch forms a flexible transparent conducting electrode with an averaged transmission of up to 97.3 % and sheet resistances as low as 2.7 Omega/sq under optimized conditions. The work provides a new way for tailoring the properties of nanowire based devices. PMID- 25283949 TI - Developing together. PMID- 25283947 TI - Amphotericin B induces glial cell line-derived neurotrophic factor in the rat brain. AB - Amphotericin B (AmB) is a polyene antifungal drug and is reported to be one of a few reagents having therapeutic effects on prion diseases, that is, a delay in the appearance of clinical signs and prolongation of the survival time in an animal model. In prion diseases, glial cells have been suggested to play important roles; however, the therapeutic mechanism of AmB on prion diseases remains elusive. We have previously reported that AmB changed the expression of neurotrophic factors in microglia and astrocytes (Motoyoshi et al., 2008, Neurochem. Int. 52, 1290-1296; Motoyoshi-Yamashiro et al., 2013, ibid. 63, 93 100). These results suggested that neurotrophic factors derived from glial cells might be involved in the therapeutic mechanism of AmB. In the present study, we examined immunohistochemically the effects of AmB on the expression of neurotrophic factors in the rat brain. We found that direct injection of AmB into the striatum significantly enhanced the expression of glial cell line-derived neurotrophic factor protein. Amphotericin B also increased the expressions of CD11b and glial fibrillary acidic protein, markers of microglia and astrocytes, respectively. Moreover, expressions of the two neurotrophic factors by AmB were co-localized with the expression of CD11b or glial fibrillary acidic protein. These results suggest that AmB in vivo might also activate glial cells and induce the production of neurotrophic factors protecting neurons in prion diseases. PMID- 25283950 TI - Reproducing superhydrophobic leaves as coatings by micromolding surface-initiated polymerization. AB - Micromolding surface-initiated polymerization enables the fabrication of polymer coatings that reproduce the microscale surface topography of superhydrophobic leaves onto solid supports. Here, the surfaces of superhydrophobic leaves from Trifolium repens and Aristolochia esperanzae are molded and reproduced as the topography of a partially fluorinated polymer coating through the surface initiated ring-opening metathesis polymerization of 5-(perfluorooctyl)norbornene (NBF8). The polymer coatings have thicknesses exceeding 100 MUm, which can be tailored by the amount of monomer added to the mold. These coatings are robustly bound to the substrate, contain compositions not found in nature, and achieve superhydrophobicity that is comparable to the actual leaf. PMID- 25283952 TI - Influence of polyelectrolyte shape on its sedimentation behavior: effect of relaxation electric field. AB - The sedimentation of an isolated, charged polyelectrolyte (PE) subjected to an applied field is modeled theoretically, taking into account the variation of its shape. In particular, the effects of double-layer relaxation, effective charge density, and strength of the induced relaxation electric field are examined. We show that the interaction of these effects yields complex and interesting sedimentation behaviors. For example, the behavior of the electric force acting on a loosely structured PE can be different from that on a compactly structured one; the former is dominated mainly by the convective fluid flow. For thick double layers, electric force has a local maximum as the Reynolds number varies, but tends to increase monotonically with increasing Reynolds number if the layer is thin. The drag factor is found to behave differently from literature results. The shape of a PE significantly influences its sedimentation behavior by affecting the amount of counterions attracted to its interior and the associated local electric field. Interestingly, a more stretched PE has a higher effective charge density but experiences a weaker electric force. PMID- 25283951 TI - Absorption of ethanol, acetone, benzene and 1,2-dichloroethane through human skin in vitro: a test of diffusion model predictions. AB - The overall goal of this research was to further develop and improve an existing skin diffusion model by experimentally confirming the predicted absorption rates of topically-applied volatile organic compounds (VOCs) based on their physicochemical properties, the skin surface temperature, and the wind velocity. In vitro human skin permeation of two hydrophilic solvents (acetone and ethanol) and two lipophilic solvents (benzene and 1,2-dichloroethane) was studied in Franz cells placed in a fume hood. Four doses of each (14)C-radiolabed compound were tested - 5, 10, 20, and 40MULcm(-2), corresponding to specific doses ranging in mass from 5.0 to 63mgcm(-2). The maximum percentage of radiolabel absorbed into the receptor solutions for all test conditions was 0.3%. Although the absolute absorption of each solvent increased with dose, percentage absorption decreased. This decrease was consistent with the concept of a stratum corneum deposition region, which traps small amounts of solvent in the upper skin layers, decreasing the evaporation rate. The diffusion model satisfactorily described the cumulative absorption of ethanol; however, values for the other VOCs were underpredicted in a manner related to their ability to disrupt or solubilize skin lipids. In order to more closely describe the permeation data, significant increases in the stratum corneum/water partition coefficients, Ksc, and modest changes to the diffusion coefficients, Dsc, were required. The analysis provided strong evidence for both skin swelling and barrier disruption by VOCs, even by the minute amounts absorbed under these in vitro test conditions. PMID- 25283953 TI - Cognitive-communication disorders in children with traumatic brain injury. AB - Children with moderate to severe traumatic brain injury (TBI) are at risk of developing cognitive-communication disorders that have devastating effects on their school life, family life, and social life. These problems can be difficult for families to describe and may be overlooked by community-based providers who are unfamiliar with TBI sequelae. To support the identification and management of cognitive-communication disorders, we review the common signs and symptoms of these disorders in children with TBI and discuss principles of assessment and intervention. PMID- 25283954 TI - Ruthenium(II)-catalyzed oxidative C-H alkenylations of sulfonic acids, sulfonyl chlorides and sulfonamides. AB - Twofold C-H functionalization of aromatic sulfonic acids was achieved with an in situ generated ruthenium(II) catalyst. The optimized cross-dehydrogenative alkenylation protocol proved applicable to differently substituted arenes and a variety of alkenes, including vinyl arenes, sulfones, nitriles and ketones. The robustness of the ruthenium(II) catalyst was demonstrated by the chemoselective oxidative olefination of sulfonamides as well as sulfonyl chlorides. Mechanistic studies provided support for a reversible, acetate-assisted C-H ruthenation, along with a subsequent olefin insertion. PMID- 25283955 TI - Sleep disturbance in osteoarthritis: linkages with pain, disability, and depressive symptoms. AB - OBJECTIVE: It is known that osteoarthritis (OA) increases the risk of sleep disturbance, and that both pain and sleep problems may trigger functional disability and depression. However, studies examining all 4 variables simultaneously are rare. The aim of this study was to examine cross-sectional and longitudinal associations of self-reported sleep disturbance with OA-related pain and disability and depressive symptoms. METHODS: At baseline, 367 persons with physician-diagnosed knee OA reported sleep disturbances, pain, functional limitations, and depressive symptoms. At 1-year followup, all measures were repeated in 288 of the subjects. Baseline analyses examined the independent and interactive associations of sleep disturbance with pain, disability, and depression, net of demographics and general health. Longitudinal analyses used baseline sleep disturbance to predict the 1-year change in pain, disability, and depression. RESULTS: At baseline, sleep was independently associated with pain and depression but not disability. The sleep-pain relationship was mediated by depressive symptoms; sleep interacted with pain to exacerbate depression among persons with high levels of pain. Baseline sleep disturbance predicted increased depression and disability, but not pain, at followup. CONCLUSION: These data confirm known cross-sectional relationships between sleep disturbance and pain and depression and provide new insights regarding longitudinal associations among those variables. Depression appears to play a strong role in the sleep-pain linkage, particularly when pain is severe. The unique predictive role of sleep in the progression of disability requires further study but may be an important point of intervention to prevent OA-related functional decline among persons whose sleep is disrupted by OA-related pain. PMID- 25283956 TI - Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation. AB - Recombinant human erythropoietin (rHuEPO) is an effective treatment for anaemia but concerns that it causes disease progression in cancer patients by activation of EPO receptors (EPOR) in tumour tissue have been controversial and have restricted its clinical use. Initial clinical studies were flawed because they used polyclonal antibodies, later shown to lack specificity for EPOR. Moreover, multiple isoforms of EPOR caused by differential splicing have been reported in cancer cell lines at the mRNA level but investigations of these variants and their potential impact on tumour progression, have been hampered by lack of suitable antibodies. The EpoCan consortium seeks to promote improved pathological testing of EPOR, leading to safer clinical use of rHuEPO, by producing well characterized EPOR antibodies. Using novel genetic and traditional peptide immunization protocols, we have produced mouse and rat monoclonal antibodies, and show that several of these specifically recognize EPOR by Western blot, immunoprecipitation, immunofluorescence, flow cytometry and immunohistochemistry in cell lines and clinical material. Widespread availability of these antibodies should enable the research community to gain a better understanding of the role of EPOR in cancer, and eventually to distinguish patients who can be treated safely by rHuEPO from those at increased risk from treatment. PMID- 25283957 TI - Esophageal carcinoid tumor treated by endoscopic resection. AB - The present report describes a rare case of esophageal carcinoid tumor that was treated by endoscopic resection. A 43-year-old woman underwent esophagogastroduodenoscopy at her family clinic for screening of the upper digestive tract and a small lesion resembling a submucosal tumor was detected in the lower esophagus. A biopsy sample from the lesion was diagnosed as esophageal carcinoid tumor and the patient visited our hospital for detailed examination. The tumor was approximately 3 mm in diameter and its surface appeared to be covered with normal squamous epithelium. The tumor had a shiny reddish surface without ulceration or erosion. Magnifying endoscopy with narrow-band imaging showed structures resembling reticular vessels under the epithelium. Endoscopic ultrasonography depicted the tumor as a low-echoic mass within the lamina propria. Computed tomography did not detect the tumor and no metastatic lesions were evident in other organs. With the patient's informed consent, the tumor was resected using endoscopic submucosal dissection, with a sufficient free margin in both the vertical and horizontal directions. Magnifying endoscopic examination showed the resected tumor to have abundant reticular vessels. Finally, the tumor was diagnosed immunopathologically as an esophageal carcinoid tumor (neuroendocrine cell tumor, grade 1), without lymphatic or vascular invasion. PMID- 25283958 TI - Regarding initial ring opening of propylene oxide in its copolymerization with CO2 catalyzed by a cobalt(III) porphyrin complex. AB - Cobalt(III) tetraphenylporphyrin chloride (TPPCoCl) was experimentally proved to be an active catalyst for poly(propylene carbonate) production. It was chosen as a model catalyst in the present work to investigate the initiation step of propylene oxide (PO)/CO2 copolymerization, which is supposed to be the ring opening of the epoxide. Ring-opening intermediates (1-7) were detected by using (1) H NMR spectroscopy. A first-order reaction in TPPCoCl was determined. A combination of monometallic and bimetallic ring-opening pathways is proposed according to kinetics experiments. Addition of onium salts (e.g., bis(triphenylphosphine)iminium chloride, PPNCl) efficiently promoted the PO ring opening rate. The existence of axial ligand exchange in the cobalt porphyrin complex in the presence of onium salts was suggested by analyzing collected (1) H NMR spectra. PMID- 25283959 TI - Screening for frailty in older adults using a postal questionnaire: rationale, methods, and instruments validation of the INTER-FRAIL study. AB - OBJECTIVES: To develop and test a postal screening questionnaire to intercept frailty in older community-dwelling individuals. DESIGN: A questionnaire was developed on the basis of expert consensus and preliminarily tested against the occurrence of incident disability, in secondary analyses of previous epidemiological studies. The questionnaire was then mailed and its concurrent validity, defined from the association between its individual items and summary score and the presence of the Fried frailty phenotype (FFP), was subsequently evaluated cross-sectionally with in-person examination of initial participants. SETTING: Community-based. PARTICIPANTS: Individuals aged 70 and older living in two communities near Florence, Italy. MEASUREMENTS: A home comprehensive geriatric assessment including the FFP was conducted in participants who screened positive for frailty and in a limited sample of negative responders. RESULTS: A 10-item questionnaire, developed based on expert consensus, was preliminarily tested on preexisting epidemiological data and showed an area under the receiver operating characteristic curve (AUC) of 0.716 versus incident disability. The questionnaire was then mailed to 15,774 subjects, whose response rate was 53.6%. Of the first 1,037 participants included in the concurrent validation study, 833 (80.3%) screened positive, and 380 (36.6%) were frail on assessment. The ability of the questionnaire summary score to predict frailty was adequate, with an AUC of 0.695, a sensitivity of 71%, and a specificity of 58%. CONCLUSION: A simple questionnaire delivered by mail was able to identify FFP in the community. This would facilitate large-scale screening for frailty in older persons. PMID- 25283960 TI - Identification of putative virulence-associated genes among Haemophilus parasuis strains and the virulence difference of different serovars. AB - This study was aimed at determining virulence-associated genes among Haemophilus parasuis (H. parasuis) strains, and supplying for the Kielstein-Rapp-Gabrielson serotyping scheme. The subtractive fragments, obtained through suppression subtractive hybridization and reverse Southern blot hybridization, were found to encode genes representative of 7 different functions. PCR was used to investigate the distribution of these fragments in H. parasuis strains isolated from different infection sites in pigs. Mice challenge was then used to analyze the correlationship between subtractive fragments, infection sites and bacterial virulence. Eight weeks old female BALB/c mice (10 mice/group) were inoculated intraperitoneally with 3.0 * 10(9) CFU suspension (0.5 ml/mouse) of H. parasuis strains in PBS. Results indicated that H. parasuis possessed varied virulence even among the same serovar strains. Transcription units hsdR, hsdS, gpT and ompP2, identified from the subtractive fragments, were uniformly expressed in highly virulent strains, while absent in weakly virulent strains, and demonstrated variable degrees of expression in moderately virulent strains. Moreover, H. parasuis strains, isolated from pericardium and heart blood, were all highly virulent strains, while from nasal cavity and joint were moderately or weakly virulent strains. This study indicated that fragments hsdR, hsdS, gpT and ompP2 were associated with the virulence of H. parasuis. The virulence of H. parasuis strains isolated from different infection sites was different. The current research provides a new reference for determining bacterial virulence in different H. parasuis strains. PMID- 25283961 TI - Desmoplastic melanoma in a fingertip: a rare entity. PMID- 25283962 TI - Variation in genes encoding for interferon lambda-3 and lambda-4 in the prediction of HCV-1 treatment-induced viral clearance. AB - BACKGROUND & AIMS: In patients with chronic HCV-1 infection, recent evidences indicate that determination of a dinucleotide polymorphism (ss469415590, DeltaG/TT) of a new gene, designated IFN lambda-4, might be more accurate than the 12979860CC type of the IL28B locus in predicting sustained virological response (SVR) following peg-interferon and ribavirin. In addition, combined genotyping of different SNPs of the IL28B locus was shown to help dissect patients most prone to SVR among those with rs12979860CT. We examined whether single or combined genotyping of two IL28B SNPs, rs12979860 and rs8099917, and ss469415590 variation might improve the prediction of SVR. RESULTS: In the study cohort of 539 patients, 38% had SVR. The SNPs 12979860CC, rs8099917TT, and rs469415590TT/TT correlated significantly with SVR (68%, 50%, and 67%). Carriers of either the triplotype rs12979860CC_ss469415590TT/TT_rs8099917TT or the diplotype rs12979860CC_ss469415590TT/TT had the highest SVR rate (72%). In carriers of the rs12979860 T allele, neither the rs8099917 nor the ss469415590 improved the response prediction. After pooling this finding with data from previous studies, in rs12979860 T heterozygous individuals the co-presence of the rs8099917TT SNP was associated with improved response prediction. CONCLUSION: In HCV-1 patients, the rs12979860 polymorphism appeared as the hit SNP better predicting response following peg-interferon and ribavirin treatment. Additional ss469415590 or rs8099917 genotyping had no added benefit for response prediction. In the subset of carriers of the rs12979860 T allele, genotyping of the rs8099917 SNP was unhelpful in the present investigation, but may inform clinical prediction of treatment response when our data were pooled with previous investigations. PMID- 25283964 TI - Chiral metal phosphate catalysis: highly asymmetric hetero-Diels-Alder reactions. AB - We report a highly enantioselective hetero-Diels-Alder reaction of alpha-keto esters and isatins catalyzed by chiral calcium BINOL-derived phosphates. The structure of the catalyst is detailed by X-ray crystal structure analysis. PMID- 25283963 TI - Accuracy of the Berger-Exner test for detecting third-order selection bias in randomised controlled trials: a simulation-based investigation. AB - BACKGROUND: Randomised controlled trials (RCT) are highly influential upon medical decisions. Thus RCTs must not distort the truth. One threat to internal trial validity is the correct prediction of future allocations (selection bias). The Berger-Exner test detects such bias but has not been widely utilized in practice. One reason for this non-utilisation may be a lack of information regarding its test accuracy. The objective of this study is to assess the accuracy of the Berger-Exner test on the basis of relevant simulations for RCTs with dichotomous outcomes. METHODS: Simulated RCTs with various parameter settings were generated, using R software, and subjected to bias-free and selection bias scenarios. The effect size inflation due to bias was quantified. The test was applied in both scenarios and the pooled sensitivity and specificity, with 95% confidence intervals for alpha levels of 1%, 5%, and 20%, were computed. Summary ROC curves were generated and the relationships of parameters with test accuracy were explored. RESULTS: An effect size inflation of 71% - 99% was established. Test sensitivity was 1.00 (95% CI: 0.99 - 1.00) for alpha level 1%, 5%, and 20%; test specificity was 0.94 (95% CI: 0.93 - 0.96); 0.82 (95% CI: 0.80 - 0.84), and 0.56 (95% CI: 0.54 - 0.58) for alpha 1%, 5%, and 20%, respectively. Test accuracy was best with the maximal procedure used with a maximum tolerated imbalance (MTI) = 2 as the randomisation method at alpha 1%. CONCLUSIONS: The results of this simulation study suggest that the Berger-Exner test is generally accurate for identifying third-order selection bias. PMID- 25283965 TI - Structural basis for the binding of the membrane-proximal C-terminal region of chemokine receptor CCR2 with the cytosolic regulator FROUNT. AB - The membrane-proximal C-terminal region (Pro-C) is important for the regulation of G-protein-coupled receptors (GPCRs), but the binding of the Pro-C region to a cytosolic regulator has not been structurally analyzed. The chemokine receptor CCR2 is a member of the GPCR superfamily, and the Pro-C region of CCR2 binds to the cytosolic regulator FROUNT. Studying the interaction between CCR2 Pro-C and FROUNT at an atomic level provides a basis for understanding the signal transduction mechanism via GPCRs. NOE-based NMR experiments showed that, when bound to FROUNT, CCR2 Pro-C adopted a helical conformation, as well as when embedded in dodecylphosphocholine micelles. A comparison of two types of cross saturation-based NMR experiments, applied to a three-component mixture of Pro-C, FROUNT and micelles or a two-component mixture of Pro-C and micelles, revealed that the hydrophobic binding surface on Pro-C for FROUNT mostly overlapped with the binding site for micelles, suggesting competitive binding of Pro-C between FROUNT and micelles. Leu316 was important for both FROUNT and micelle binding. Phe319 was newly identified to be crucial for FROUNT binding, by NMR and mutational analyses. The association and dissociation rates of CCR2 Pro-C for lipid bilayer biomembranes were faster than those for FROUNT. We previously reported that FROUNT binding to CCR2 is detectable even in unstimulated cells and increases in response to chemokine stimulation. Taken together, these results support a model of CCR2 equilibrium: chemokine binding changes the conformational equilibrium of CCR2 toward the active state, and Pro-C switches its binding partner from the membrane to FROUNT. PMID- 25283966 TI - The measurement of protein synthesis for assessing proteostasis in studies of slowed aging. AB - Slowing the aging process can reduce the risk for multiple chronic diseases simultaneously. It is increasingly recognized that maintaining protein homeostasis (or proteostasis) is important for slowing the aging process. Since proteostasis is a dynamic process, monitoring it is not a simple task and requires use of appropriate methods. This review will introduce methods to assess protein and DNA synthesis using deuterium oxide (D2O), and how protein and DNA synthesis outcomes provide insight into proteostatic mechanisms. Finally, we provide a discussion on how these assessments of protein and DNA synthesis are "mechanistic" investigations and provide an appropriate framework for the further development of slowed aging treatments. PMID- 25283968 TI - Increase in skin perfusion pressure after maggot debridement therapy for critical limb ischaemia. AB - Skin perfusion pressure (SPP) is the perfusion pressure at the skin level, and it can serve as an index of peripheral circulation in the skin and subcutaneous tissue. We report a 78-year-old man with critical limb ischaemia who, despite having undergone several catheter interventions, still had severe ulcers with exposed bone on his right foot. We performed transmetatarsal amputation. The tissue around the surgical site became necrotic several days later, and did not respond to conservative therapy. Therefore, we opted for maggot debridement therapy (MDT), given that maggots favour necrotic tissue. After the therapy, SPP around the ulcer increased from 12 to 54 mmHg on the dorsal aspect, and from 17 to 44 mmHg on the plantar aspect. Wound healing was successfully activated by MDT, leading to complete healing within 2.5 months after MDT. We believe that MDT probably contributed to increase the blood supply to the ischaemic wound. PMID- 25283967 TI - gammadelta T cell surveillance via CD1 molecules. AB - gammadelta T cells are a prominent epithelial-resident lymphocyte population, possessing multi-functional capacities in the repair of host tissue, pathogen clearance, and tumor surveillance. Although three decades have now passed since their discovery, the nature of gammadelta T cell receptor (TCR)-mediated ligand recognition remains poorly defined. Recent studies have provided structural insight into this recognition, demonstrating that gammadelta T cells survey both CD1 and the presented lipid, and in some cases are exquisitely lipid specific. We review these findings here, examining the molecular basis for and the functional relevance of this interaction. We discuss potential implications on the notion that non-classical major histocompatibility complex (MHC) molecules may function as important restricting elements of gammadelta TCR specificity, and on our understanding of gammadelta T cell activation and function. PMID- 25283969 TI - Impact of an antimicrobial stewardship program on the use of carbapenems in a tertiary women's and children's hospital, Singapore. AB - OBJECTIVES: Antimicrobial stewardship programs (ASPs) promote the judicious use of antimicrobials by limiting inappropriate use. This article evaluates the impact of a prospective-audit-and-feedback ASP implementation on the appropriate utilization of carbapenems in a tertiary pediatrics and obstetrics/gynecology hospital in Singapore (KKH) after the establishment of an ASP in July 2011. METHODS: This was a prospective, single-center, pre-post intervention study designed to analyze the appropriate prescribing of carbapenems pre-ASP (October 2009 to June 2011) and post-ASP (July 2011 to December 2013). Utilization of carbapenems was evaluated by daily defined doses (DDDs), days of therapy (DOTs), prescriptions, as well as cost per 100 patient-days pre-ASP and post-ASP using a segmented regression of interrupted time series analysis. RESULTS: Of 404 prescriptions for carbapenems reviewed post-ASP, 70.3% were appropriate compared with those prescribed pre-ASP (55.9%; p=0.027). Reasons for inappropriate prescribing included inappropriate choice (36.1%) and duration (31.3%). A total of 61.2% of the interventions (213 of 348) were accepted. For pediatrics, there was a significant decrease in DDDs per 100 patient-days by 55.6% from a baseline of 0.9-0.4 (p=0.013) post-ASP and a reduction in DOTs per 100 patient-days by 46.7% from a baseline of 1.5-0.8 (p=0.06) post-ASP without significant changes in prescription rates. Pediatrics utilization cost increased from a pre-ASP mean of $175 per 100 patient-days to a peak of $238 (p<0.001) and decreased significantly post-ASP to a mean of $149 (p=0.01). For obstetrics/gynecology, there were no significant changes in DDDs (0.3 vs 0.3, p=0.99), DOTs (0.2 vs 0.3, p=0.36), prescriptions (0.03 vs 0.04, p=0.38), or cost ($45 vs $52, p=0.63) per 100 patient-days pre- versus post-ASP. CONCLUSIONS: ASPs improved the appropriateness of carbapenems prescribing overall and reduced utilization in pediatrics. Identification of areas of inappropriate prescribing will be valuable in guiding future ASP efforts. PMID- 25283970 TI - Preclinical evaluation of investigational radiopharmaceutical RISAD-P intended for use as a diagnostic and molecular radiotherapy agent for prostate cancer. AB - BACKGROUND: The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2' deoxyuridin-5'-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated. METHODS: Effects of nonradioactive ISAD-P and RISAD-P labeled with (123) I, (124) I, and (125) I were evaluated in male mice. Expanded acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice. RESULTS: RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for (18) F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after (125) IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1,240 Gy * MBq(-1) * g(-1) for (125) I-, (123) I-, and (124) I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed. CONCLUSIONS: Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer. PMID- 25283972 TI - Hybrid nanotrimers for dual T1 and T2-weighted magnetic resonance imaging. AB - Development of multifunctional nanoparticle-based probes for dual T1- and T2 weighted magnetic resonance imaging (MRI) could allow us to image and diagnose the tumors or other abnormalities in an exceptionally accurate and reliable manner. In this study, by fusing distinct nanocrystals via solid-state interfaces, we built hybrid heteronanostructures to combine both T1 and T2- weighted contrast agents together for MRI with high accuracy and reliability. The resultant hybrid heterotrimers showed high stability in physiological conditions and could induce both simultaneous positive and negative contrast enhancements in MR images. Small animal positron emission tomography imaging study revealed that the hybrid heterostructures displayed favorable biodistribution and were suitable for in vivo imaging. Their potential as dual contrast agents for T1 and T2 weighted MRI was further demonstrated by in vitro and in vivo imaging and relaxivity measurements. PMID- 25283973 TI - Development of an Activity Card Sort for Australian adults aged 18-64 years. AB - BACKGROUND/AIM: The Activity Card Sort (ACS) is an interview-based, client centred tool that measures the activity engagement of older adults aged 65 years and above. The tool consists of photos which clients are asked to sort into categories to reflect their previous and current level of engagement. The activities that older adults engage in may differ to that of younger adults and there is a need to explore the development of an ACS Australia for adults aged 18 64 years. METHODS: The Delphi survey method as applied by previous ACS development was used in this study. Purposeful and snowball sampling were employed to recruit participants between the ages of 18 and 64 years who were Australian citizens or residents. Demographic information was obtained via a questionnaire. There were two stages in the study. The first Delphi survey generated, selected and finalised activities and the second Delphi survey generated, selected and finalised categories. RESULTS: Australian citizens and residents were involved in the development of the activities (n = 61) and categories (n = 65). The final tool includes 85 activities sorted into three broad categories representing personal care, daily life and home maintenance; rest and relaxation; and high and low impact activities. CONCLUSIONS: This study has resulted in the development of a preliminary version of an ACS for adults aged 18-64 years. Further work is required to determine the psychometric properties of the tool. PMID- 25283974 TI - Concomitant metastatic lung tumor and hamartoma. AB - A 65-year-old woman who had undergone surgery for rectal cancer was referred to our hospital with an abnormal shadow on chest X-ray. Chest computed tomography (CT) revealed a 3-cm-diameter mass with ill-defined margins in the left lower lobe and a well-defined, 1-cm-diameter, round nodule in the right upper lobe. Transbronchial lung biopsy (TBLB) of the left lung tumor revealed metastatic adenocarcinoma originating from the rectal cancer. The patient underwent synchronous partial resection of the right upper lobe and left lower lobectomy under video-assisted thoracoscopic surgery (VATS). The pathological diagnosis of the right lung tumor was chondromatous hamartoma, and the left lung tumor was metastasis originating from the rectal cancer. The patient's postoperative course was uneventful, and she was well and free of disease 4 years after pulmonary metastasectomy. PMID- 25283971 TI - Emerging microengineered tools for functional analysis and phenotyping of blood cells. AB - The available techniques for assessing blood cell functions are limited considering the various types of blood cell and their diverse functions. In the past decade, rapid advances in microengineering have enabled an array of blood cell functional measurements that are difficult or impossible to achieve using conventional bulk platforms. Such miniaturized blood cell assay platforms also provide the attractive capabilities of reducing chemical consumption, cost, and assay time, as well as exciting opportunities for device integration, automation, and assay standardization. This review summarizes these contemporary microengineered tools and discusses their promising potential for constructing accurate in vitro models and rapid clinical diagnosis using minimal amounts of whole-blood samples. PMID- 25283975 TI - Evacuation effect on excess mortality among institutionalized elderly after the fukushima daiichi nuclear power plant accident. AB - The Great East Japan Earthquake hit Fukushima Prefecture on March 11, 2011, just over 3 years ago and it continues to affect our lives. In Fukushima, many people are confirmed dead or still missing due to the earthquake and/or tsunami. Additional "disaster-related deaths" have been attributed to the Fukushima Daiichi Nuclear Power Plant (NPP) accident. Mortality among the institutionalized elderly rates after the NPP accident were exceptionally high during the first 3 months, and persisted at a lower level for 9 months, in comparison with similar periods before the accident. This study demonstrates the great impact of evacuation on mortality of institutionalized elderly, excluding inpatients. We need to pay special attention to evacuation of the elderly, regardless of whether voluntary or forced. PMID- 25283976 TI - Four-year follow-up of pregnancy-associated osteoporosis: a case report. AB - A 22-year-old woman presented with complaints of severe pain in a wide region of the thoracolumbar spine. She developed severe pain in the thoracolumbar spine region 2 months after her first delivery and was referred 1 month later. A lateral thoracic X-ray showed depressed degenerative vertebrae (T7, T9). One month after the initial examination, thoracic sagittal magnetic resonance imaging showed low intensity areas on T1-weighted imaging and iso-high intensity areas on T2-weighted imaging at T5, 7, 8, 9 and 11. Bone mineral density measured by ultrasound was low (%YAM 76%). The bone metabolic markers were high, suggesting accelerated osteoclast activity. These findings prompted a diagnosis of pregnancy associated osteoporosis. She was asked to stop breastfeeding and to wear a lumbar brace, and treatment with nutritional calcium, activated vitamin D3, and risedronate sodium was started. Her low back pain almost disappeared after treatment. Bone metabolic markers showed normalization 8 months after the initial examination. Risedronate sodium was stopped 2 years and 2 months after the initial examination. Teriparatide treatment was started because her bone mineral density remained low; however, the osteoblast marker P1NP was not increased 5 months after the start of teriparatide treatment. PMID- 25283977 TI - Remnant left lobe torsion causing hepatic venous outflow obstruction after hepatic right lobectomy for giant hepatocellular carcinoma: report of a case. AB - We report the case of a 67-year-old man with remnant left liver torsion causing acute hepatic venous outflow obstruction after right hepatectomy for giant hepatocellular carcinoma, which was successfully treated with surgery. After the primary surgery, he developed significant liver dysfunction and renal failure. Doppler ultrasonography disclosed gradual reduction of hepatic perfusion. Abdominal computed tomography revealed that the swollen remnant liver was dislocated in the right subphrenic space. After surgical repositioning of the left lobe into its anatomical position, the hepatic congestion immediately disappeared, and the hemodynamic parameters improved. The falciform and round ligaments were fixed to the anterior abdominal wall to keep the remnant liver in the anatomical position. His postoperative course was uneventful. Doppler ultrasonography was useful to assess hepatic perfusion for screening of acute hepatic venous outflow obstruction and abdominal computed tomography is definitive for diagnosis. Fixation of remnant liver may be effective for preventing hepatic venous outflow obstruction after right hepatectomy, particularly for giant tumor. PMID- 25283978 TI - Correlations among heavy metals in blood and urine and their relations to depressive symptoms in Parkinson's disease patients. AB - OBJECTIVES: From our previous results, manganese (Mn) and iron (Fe) in the blood of Parkinson's disease (PD) patients without depression were higher than those of both the PD patients with depression and controls, the hypothesis that "two types of PD exist-PD without depression and affected by Mn and Fe, and PD with depression and unaffected by Mn or Fe" was induced. To investigate the hypothesis, correlations among blood and urine metals were compared in the subjects. METHODS: Subjects comprised PD patients with depression, PD patients without depression and controls recruited from an outpatient clinic in China. Morning blood and urine samples were used to measure concentrations of metals. RESULTS: In the controls, Mn, Fe and zinc (Zn) levels in blood strongly correlated with each other. The correlation coefficient between Mn and Zn in blood was significant in the PD patients with depression and the controls, but not in the PD patients without depression. Correlations of Fe between blood and urine in the PD patients without depression were significant, but not in the PD patients with depression and the controls. CONCLUSIONS: A common route of simultaneous intake of Mn, Fe and Zn could exist in our subjects, however in PD patients without depression, a large intake of Mn may have been from another route. Some results of the PD patients without depression were different from those of the PD patients with depression and the controls. Thus, two types of PD may exist. PMID- 25283979 TI - Tactile sensor is useful for estimating liver hardness and liver fibrosis compared with ultrasonography and computed tomography. AB - BACKGROUND/AIMS: We examined whether conventional ultrasonography (US) and computed tomography (CT) were useful to evaluate liver hardness and hepatic fibrosis by comparing the results with those obtained by a tactile sensor using rats with liver fibrosis. METHODOLOGY: We used 44 Wistar rats in which liver fibrosis was induced by intraperitoneal administration of thioacetamide. The CT and US values of each liver were measured before laparotomy. After laparotomy, a tactile sensor was used to measure liver hardness. We prepared Azan stained sections of each excised liver specimen and calculated the degree of liver fibrosis (HFI: hepatic fibrosis index) by computed color image analysis. RESULTS: The stiffness values and HFI showed a positive correlation (r=0.690, p<0.001), as did the tactile values and HFI (r=0.709, p<0.001).In addition, the stiffness and tactile values correlated positively with each other (r=0.814, p<0.001). There was no correlation between the CT values and HFI, as well as no correlation between the US values and HFI. CONCLUSION: We confirmed that it was difficult to evaluate liver hardness and HFI by CT or US examination, and considered that, at present, a tactile sensor is useful method for evaluating HFI. PMID- 25283980 TI - Effectiveness of cognitive behavioral therapy based on the pain sustainment/exacerbation model in patients with tension-type headache: a pilot study. AB - The purpose of this study was to carry out a program of Cognitive Behavioral Therapy (CBT) based on the pain sustainment/exacerbation model for tension-type headache (TTH) patients and to examine the effectiveness as a pilot study. The participants were 4 TTH patients who consulted the outpatient clinic of a university hospital. It consisted of 4 individualized sessions as CBT program (including psychological education, self-monitoring, relaxation technique, cognitive restricting and exposure), and a follow-up examination was carried out 1 month after its completion. The sessions, each of which was 60 minutes long, were executed at weekly intervals. As a result, the score of the Pain Catastrophizing Scale (PCS) decreased after program compared with before program in all patients. The score of escape/avoidance was also reduced at the post program and follow-up (1 month later) compared with the score of pre-program in patients except Case 2, in whom the score was 0 throughout the study. The degree of the Headache Impact Test (HIT-6) improved by program and changed to "mild" or "none" in all participants. These findings show that in patients with TTH this short CBT program has effect on pain catastrophizing, escape/avoidance and daily disability. PMID- 25283981 TI - Ultrasonographic assessment of the flexor pronator muscles as a dynamic stabilizer of the elbow against valgus force. AB - Flexor pronator muscles (FPMs) play a key role in stabilizing the elbow joint against valgus forces. However, no studies have investigated the in vivo kinematics of FPMs against these forces on the elbow. This study aimed to clarify the in vivo contribution of each FPM as a dynamic stabilizer in a clinical situation.Twelve healthy volunteers participated in this study. Verbal informed consent was obtained from all subjects. The elbow was flexed to 90 degrees, and the forearm was placed in the neutral position. Manual valgus stress was applied to the elbow joint until maximal shoulder external rotation was achieved. The width of the ulnohumeral joint space and the ulnar shift of the sublime tubercle were measured before and after isometric contraction of FPMs using ultrasonography.The horizontal distances were decreased 1.1+/-0.6 mm after forearm pronation, 0.6+/-0.5 mm after wrist palmar flexion, 0.1+/-0.4 mm after wrist ulnar flexion, and 0.2+/-0.5 mm after finger flexion. Significant changes were observed during forearm pronation, wrist palmar flexion, and finger flexion but not during wrist ulnar flexion (p<0.05). The sublime tubercle was significantly shifted 0.5+/-0.1 mm medially after forearm pronation, 0.2+/-0.1 mm medially after wrist palmar flexion, and 0.1+/-0.1 mm laterally after wrist ulnar flexion and finger flexion (p<0.05). The FPMs, especially the pronator teres and the flexor carpi radialis, function as dynamic stabilizers against elbow valgus stress. The results of this study may be useful in developing injury prevention and rehabilitation strategies for throwing injuries of the elbow. PMID- 25283982 TI - The acetabular fossa hot spot on 18F-FDG PET/CT: epidemiology, natural history, and proposed etiology. AB - OBJECTIVE: To describe a benign focus of increased activity in the acetabular fossa (the acetabular fossa hot spot, AFHS) on (18) F-FDG PET/CT that can mimic a neoplasm. MATERIALS AND METHODS: (18)F-FDG PET/CT images from four patient populations were examined. Group 1 (n = 13) was collected from a search of radiology reports and used to define the AFHS and for hypothesis generation. Group 2 (n = 1,150) was used for prevalence of AFHS. Group 3 (n = 1,213) had PET/CT and MRI pelvis within a week of each other and was used to correlate metabolic and anatomic findings. Group 4 (n = 100) was used to generate the control group. Data were collected on demographics, common comorbidities, underlying cancer diagnosis and status, and hip symptoms. RESULTS: Prevalence of AFHS was 0.36 % (95 % CI 0.10-0.91 %). None progressed to malignancy or was associated with cancer status. The majority (71 %) were on the left, and 6 % were bilateral. Mean SUVmax of the AFHS was 4.8 (range, 2.7-7.8). Male patients were more likely to have the AFHS (OR = 8.69, 95 % CI 1.88-40.13). There was no difference with respect to other collected data, including hip symptoms. Average minimum duration of AFHS was 346 days (range, 50-1,010 days). Readers did not detect corresponding hip abnormalities on MRIs. CONCLUSIONS: AFHS is a benign finding that may be caused by subclinical ligamentum teres injury, focal synovitis, or degeneration of acetabular fossa fat. Despite uncertainty regarding its etiology, recognition of AFHS as a benign finding can prevent morbidity associated with unnecessary biopsy or initiation of therapy. PMID- 25283983 TI - Incarceration of the intermeniscal ligament in tibial eminence injury: a block to closed reduction identified using MRI. AB - Tibial eminence fractures are a relatively uncommon injury, but most frequently occur in children and adolescents with open physes. Entrapment of the intermeniscal ligament or the meniscus itself can occur in the setting of a tibial eminence fracture and when present, poses a significant obstacle to successful closed or surgical reduction. Identification of these entrapped structures on preoperative imaging may be helpful to the physicians caring for these patients and assist with preoperative planning. We present a case of a 13 year-old male who sustained a tibial eminence fracture while playing football. Review by the orthopedic surgeon identified entrapment of the intermeniscal ligament. Subsequently, a closed reduction attempt under anesthesia prior to surgery was unsuccessful and arthroscopy was needed to remove the entrapped intermeniscal ligament and reduce the tibial eminence fracture. Pre-operative knowledge of entrapped soft tissue structures under the fracture plane, particularly the meniscus and intermeniscal ligament, provides the surgeon with valuable insight as to how to best counsel patients on the success of treatment options, how to best prepare for operative treatment, and can guide the surgeon during open reduction to maximize treatment success. PMID- 25283984 TI - AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo. AB - Parkinson's disease (PD) is a neurodegenerative disorder with prominent neuronal cell death in the substantia nigra (SN) and other parts of the brain. Previous studies in models of traumatic and neurodegenerative CNS disease showed that pharmacological inhibition of Rho-associated kinase (ROCK), a molecule involved in inhibitory signaling in the CNS, by small-molecule inhibitors improves neuronal survival and increases regeneration. Most small-molecule inhibitors, however, offer only limited target specificity and also inhibit other kinases, including both ROCK isoforms. To establish the role of the predominantly brain expressed ROCK2 isoform in models of regeneration and PD, we used adeno associated viral vectors (AAV) to specifically knockdown ROCK2 in neurons. Rat primary midbrain neurons (PMN) were transduced with AAV expressing short-hairpin RNA (shRNA) against ROCK2 and LIM-domain kinase 1 (LIMK1), one of the downstream targets of ROCK2. While knock-down of ROCK2 and LIMK1 both enhanced neurite regeneration in a traumatic scratch lesion model, only ROCK2-shRNA protected PMN against 1-methyl-4-phenylpyridinium (MPP+) toxicity. Moreover, AAV.ROCK2-shRNA increased levels of the pro-survival markers Bcl-2 and phospho-Erk1. In vivo, AAV.ROCK2-shRNA vectors were injected into the ipsilateral SN and a unilateral 6 OHDA striatal lesion was performed. After four weeks, behavioral, immunohistochemical and biochemical alterations were investigated. Downregulation of ROCK2 protected dopaminergic neurons in the SN from 6-OHDA-induced degeneration and resulted in significantly increased TH-positive neuron numbers. This effect, however, was confined to nigral neuronal somata as striatal terminal density, dopamine and metabolite levels were not significantly preserved. Interestingly, motor behavior was improved in the ROCK2-shRNA treated animals compared to control after four weeks. Our studies thus confirm ROCK2 as a promising therapeutic target in models of PD and demonstrate that neuron-specific inhibition of ROCK2 promotes survival of lesioned dopaminergic neurons. PMID- 25283985 TI - Interactive actions of Bdnf methylation and cell metabolism for building neural resilience under the influence of diet. AB - Quality nutrition during the period of brain formation is a predictor of brain functional capacity and plasticity during adulthood; however it is not clear how this conferred plasticity imparts long-term neural resilience. Here we report that early exposure to dietary omega-3 fatty acids orchestrates key interactions between metabolic signals and Bdnf methylation creating a reservoir of neuroplasticity that can protect the brain against the deleterious effects of switching to a Western diet (WD). We observed that the switch to a WD increased Bdnf methylation specific to exon IV, in proportion to anxiety-like behavior, in Sprague Dawley rats reared in low omega-3 fatty acid diet, and these effects were abolished by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. Blocking methylation also counteracted the reducing action of WD on the transcription regulator CTCF binding to Bdnf promoter IV. In vitro studies confirmed that CTCF binding to Bdnf promoter IV is essential for the action of DHA on BDNF regulation. Diet is also intrinsically associated to cell metabolism, and here we show that the switch to WD downregulated cell metabolism (NAD/NADH ratio and SIRT1). The fact that DNA methyltransferase inhibitor did not alter these parameters suggests they occur upstream to methylation. In turn, the methylation inhibitor counteracted the action of WD on PGC-1alpha, a mitochondrial transcription co-activator and BDNF regulator, suggesting that PGC-1alpha is an effector of Bdnf methylation. Results support a model in which diet can build an "epigenetic memory" during brain formation that confers resilience to metabolic perturbations occurring in adulthood. PMID- 25283987 TI - In situ normothermic regional perfusion for controlled donation after circulatory death--the United Kingdom experience. AB - Organs recovered from donors after circulatory death (DCD) suffer warm ischemia before cold storage which may prejudice graft survival and result in a greater risk of complications after transplant. A period of normothermic regional perfusion (NRP) in the donor may reverse these effects and improve organ function. Twenty-one NRP retrievals from Maastricht category III DCD donors were performed at three UK centers. NRP was established postasystole via aortic and caval cannulation and maintained for 2 h. Blood gases and biochemistry were monitored to assess organ function. Sixty-three organs were recovered. Forty-nine patients were transplanted. The median time from asystole to NRP was 16 min (range 10-23 min). Thirty-two patients received a kidney transplant. The median cold ischemia time was 12 h 30 min (range 5 h 25 min-18 h 22 min). The median creatinine at 3 and 12 months was 107 umol/L (range 72-222) and 121 umol/L (range 63-157), respectively. Thirteen (40%) recipients had delayed graft function and four lost the grafts. Eleven patients received a liver transplant. The first week median peak ALT was 389 IU/L (range 58-3043). One patient had primary nonfunction. Two combined pancreas-kidney transplants, one islet transplant and three double lung transplants were performed with primary function. NRP in DCD donation facilitates organ recovery and may improve short-term outcomes. PMID- 25283986 TI - Strains of the Morphospecies Ploeotia costata (Euglenozoa) Isolated from the Western North Pacific (Taiwan) Reveal Substantial Genetic Differences. AB - Two phagotrophic euglenid strains (Strains Pac and Tam) were isolated from coastal locations in Taiwan. Ultrastructural characteristics of the strains included five pellicle strips joined at the posterior end. The strips were formed by major grooves with bifurcated edges. At the cell anterior, the feeding structure formed a lip. Underneath the lip was a comb composed of layers of microtubules. Farther back, two supporting rods tapered toward the posterior end, and a number of vanes with attached microtubules were present between the rods. The morphological characteristics agree with Ploeotia costata Strain CCAP 1265/1. However, the 18S rDNA sequences of Strains Pac/Tam lacked a group I intron and possessed three extra insertions of 116, 67, and 53 bp. Phylogenetic analysis indicated low sequence similarity between Strains Pac/Tam and CCAP 1265/1 (92%). The morphospecies P. costata apparently includes a substantial level of DNA sequence divergence, and likely represents multiple molecular species units. PMID- 25283989 TI - Exploring coherent transport through pi-stacked systems for molecular electronic devices. AB - Understanding electron transport across pi-stacked systems can help to elucidate the role of intermolecular tunneling in molecular junctions and potentially with the design of high-efficiency molecular devices. Here we show how conjugation length and substituent groups influence the electron transport and thermoelectric response in the pi-stacked structures by investigating five representative stacked molecular junctions. We found that a pi-stacked system of two substituted anthracenes exhibits good thermopower and a high power factor, suggesting that increased conjugation can enhance the thermoelectric response. The fully eclipsed structure of quinhydrone exhibits a high power factor at the minimum energy structure and could thus be a better candidate in a thermoelectric device compared with the other pi-stacked systems considered. PMID- 25283988 TI - Gene redundancy of two-component (chloro)phenol hydroxylases in Rhodococcus opacus 1CP. AB - Among other factors, a distinct gene redundancy is discussed to facilitate high metabolic versatility of rhodococci. Rhodococcus opacus 1CP is a typical member in that respect and degrades a multitude of (chlorinated) aromatic compounds. In contrast to the central pathways of aromatic degradation in strain 1CP, little is known about the degree of gene redundancy and to what extent this is reflected on protein level within the steps of peripheral degradation. By means of degenerated primers deduced from tryptic peptides of a purified phenol hydroxylase component and using the amplified fragment as a labelled probe against genomic 1CP-DNA, three gene sets encoding three different two-component phenol hydroxylases pheA1/pheA2(1-3) could be identified. One of them was found to be located on the megaplasmid p1CP, which confirms the role of these elements for metabolic versatility. Protein chromatography of phenol- and 4-chlorophenol-grown 1CP biomass gave first evidences on a functional expression of these oxygenases, which could be initially characterised in respect of their substrate specificity. PMID- 25283990 TI - Prediction of gestational diabetes mellitus in the first trimester: comparison of C-reactive protein, fasting plasma glucose, insulin and insulin sensitivity indices. AB - OBJECTIVE: To develop a predictive index based on high sensitivity C-reactive protein (hs-CRP), fasting plasma glucose (FPG) and fasting plasma insulin (FPI) measurements for early diagnosis of gestational diabetes mellitus (GDM). METHODS: Healthy pregnant women who were screened for GDM during their first antenatal visit were included in this retrospective cohort study. FPG, FPI and serum hs-CRP concentrations were measured between weeks 11 and 14. A two-step glucose challenge test was carried out between gestational weeks 24 and 28. Fasting glucose/insulin ratio (FIGR), Homeostatic Model Assessment Insulin Resistance (HOMA-IR), HOMA-beta indices and Quantitative Insulin Sensitivity Check Index (QUICKI) were used to estimate insulin sensitivity and beta-cell function. RESULTS: Of the 450 women who were eligible for the study, 49 (11.2%) were diagnosed with GDM at weeks 24-28. The median FPG and hs-CRP levels were higher in the GDM diagnosed women compared to the others. Comparison of accuracy measures resulted in the highest specificity (87.2%; 95% CI 83.5-90.1) and diagnostic odds ratio (3.9; 95% CI 2.1-7.6) for hs-CRP. CONCLUSION: FPG and hs CRP in the first trimester are correlated with later development of GDM in the pregnancy. In our study, FPG provided a better sensitivity while hs-CRP exhibited a better specificity for prediction of GDM. PMID- 25283991 TI - Association between insulin-like growth factor-1 and cognitive functions in alcohol-dependent patients. AB - Studies in alcohol-dependent patients show that cognitive function can be influenced by chronic use of alcohol. Alcohol is a known neurotoxin that induces neurodegeneration in the brain. Although there are various causes of cognitive deficiency in alcohol-dependent patients, in this study we focus on the role of corticosteroids. The hypothalamus-pituitary-adrenal system (i.e., the HPA axis) plays a part in the control of corticosteroids. Recent studies show that insulin like growth factor-1 (IGF-1) reflects the status of growth hormones under the action of the HPA axis. Therefore, IGF-1 is a potential indicator that reflects activity of the HPA axis, and a biomarker that may reflect the decline of cognitive function associated with alcohol-induced hypercortisolism. The purposes of this study are to identify an association between cognitive function and IGF 1, and to investigate IGF as the biological marker of cognitive decline in alcohol-dependent patients. Forty alcohol-dependent patients were selected as the subjects of this study. IGF-1 was measured through an enzyme-linked immunosorbent assay (ELISA). Clinical features were examined using the Korean version of the alcohol dependence scale (ADS-K). Cognitive functions were measured using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Comparative analysis was utilized to identify an association between CERAD measurement items and IGF-1. Alcohol-dependent patients demonstrated stable performance of most of the CERAD measures. Among the measures of the CERAD, only trail making test A showed a correlation to IGF-1. Compared to trail making test B, trail making test A is assumed to reflect basic cognitive functions including psychomotor speed, visual search and sequencing in alcohol-dependent patients, regardless of demographic characteristics such as the level of education of patients. Therefore, IGF-1 seems to play an important role in detecting the decline of basic cognitive functions in alcohol-dependent patients. PMID- 25283992 TI - Protective effect of delta opioid agonist [D-Ala2, D-Leu5] enkephalin on spinal cord ischemia reperfusion injury by regional perfusion into abdominal aorta in rabbits. AB - [D-Ala(2), D-Leu(5)] enkephalin (DADLE) has been reported to exhibit protective effects against hypoxic or ischemic induced brain insult. However its efficacy on the spinal cord ischemia-reperfusion injury remains unclear. Here we investigate whether DADLE could attenuate ischemia and reperfusion induced neural injury in the rabbit spinal cord. New Zealand white rabbits were subjected to spinal cord ischemia by infrarenal aortic occlusion for 30 min. In the period of spinal cord ischemia, DADLE 0.5 mg/kg or NS were infused continuously into the distal clamped abdominal aorta. The heart rate, blood pressure, and core temperature were monitored continuously during the whole experimental procedure. Then the neurological behavioral function was assessed with Tarlov scale system at 1h, 6h, 24h, 48 h after reperfusion, and neuronal injury evaluation in the ventral horn of gray matter was measured by counting the normal motor neurons at 48 h after reperfusion. Comparing with the control group, the Tarlov scores were significantly higher and the incidences of paraplegia were significantly lower in the DADLE group at four time-point recorded. In addition, the normal neurons numbers in the DADLE group were significant more than those in the control group at 48 h after reperfusion. These results suggested that DADLE infused into the abdominal aorta during ischemia period could attenuate behavioral retardation and the loss of normal motor neuron induced by ischemia-reperfusion in rabbits. PMID- 25283993 TI - Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells. AB - The vasculature is a prominent component of the subventricular zone neural stem cell niche. Although quiescent neural stem cells physically contact blood vessels at specialized endfeet, the significance of this interaction is not understood. In contrast, it is well established that vasculature-secreted soluble factors promote lineage progression of committed progenitors. Here we specifically investigated the role of cell-cell contact-dependent signalling in the vascular niche. Unexpectedly, we find that direct cell-cell interactions with endothelial cells enforce quiescence and promote stem cell identity. Mechanistically, endothelial ephrinB2 and Jagged1 mediate these effects by suppressing cell-cycle entry downstream of mitogens and inducing stemness genes to jointly inhibit differentiation. In vivo, endothelial-specific ablation of either of the genes which encode these proteins, Efnb2 and Jag1 respectively, aberrantly activates quiescent stem cells, resulting in depletion. Thus, we identify the vasculature as a critical niche compartment for stem cell maintenance, furthering our understanding of how anchorage to the niche maintains stem cells within a pro differentiative microenvironment. PMID- 25283995 TI - Qualitative exploration of rural focus group members' participation in the Chronic Disease Self-Management Program, USA. AB - INTRODUCTION: Nearly half of rural residents in the USA have at least one chronic condition, and meeting the complex needs of these individuals has become a challenge for the current healthcare system. A self-management approach enables individuals with chronic illnesses to gain skills needed to improve the management of their conditions. Rural areas have a higher proportion of individuals who are likely to be affected by chronic conditions. Based on these factors, it is necessary to provide programs to help rural residents self-manage their health. The purpose of this qualitative, exploratory study is to explore the benefits perceived by rural residents due to their participation in six weekly group sessions, which are referred to as the Chronic Disease Self Management Program (CDSMP). METHODS: Individuals who completed the CDSMP were recruited to participate in a focus group regarding their experience with the program. Thirty-four of the 45 respondents (75%) who completed the CDSMP participated in six focus groups. When the respondents returned for the scheduled focus groups, they were asked to share their experience with the CDSMP. Each focus group was located at the same site that housed the program in their community. Phenomenological and consensual qualitative approaches were used in the data analysis for the present study. FINDINGS: The majority (91%) of the participants were female. Of those, 97% were non-Hispanic whites. The mean number of chronic conditions was two, with a range between one and eight chronic conditions per participant. Two prominent themes emerged from the six focus groups: respondent interaction in behavior change and prioritizing health behavior change. CONCLUSIONS: The study findings support that chronic disease self-management programs can initiate positive behavioral changes, and those lifestyle changes can influence and improve the health of rural populations. Similar programs can yield beneficial results on important behavior change for the rural communities, an underserved population with chronic conditions. PMID- 25283994 TI - Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization. AB - We have previously demonstrated that Stat3 regulates lysosomal-mediated programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride. Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness. Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo. We propose that Stat3 regulates LM-PCD in mouse mammary gland by switching cellular function from secretion to uptake of MFGs. Thereafter, perturbation of lysosomal vesicle membranes by high levels of free fatty acids results in controlled leakage of cathepsins culminating in cell death. PMID- 25283996 TI - Differences in EQ-5D-3L health state valuations among patients with musculoskeletal diseases, health care professionals and healthy volunteers. AB - BACKGROUND: Results from existing studies indicate that different respondent groups' health state valuations in cost-utility analyses are not equivalent. OBJECTIVES: The objectives in our study were to analyse differences in health state valuations among three respondent groups in the context of medical rehabilitation in Germany. METHODS: Using the time trade-off (TTO) technique, valuations of EQ-5D-3L health states were obtained from patients with musculoskeletal diseases, healthy volunteers and health care professionals. We used linear mixed models to predict TTO utilities and specified and tested interaction effects. RESULTS: We identified statistically significant (p < 0.05) differences among the three groups in six out of 42 health states. On average, patients' TTO values were somewhat higher compared with other respondent groups. Most of these differences occurred in severe health states. Mean differences and mean absolute differences were 0.02 and 0.14 for patients vs healthy volunteers and 0.06 and 0.14 for patients vs health care professionals. Furthermore, significant effects among respondents were observed for seven of the 22 possible interactions describing differences between respondent groups. Coefficients associated with significant interaction effects ranged from 0.08 to 0.18 (absolute values). CONCLUSION: The results of our study suggest that TTO valuations of health states differ depending on the specific respondent group from which valuations are obtained. On average, these differences were small. However, researchers and decision makers should remain aware of these differences when interpreting incremental cost-utility assessments. PMID- 25283997 TI - A longitudinal retrospective analysis of left ventricular mass in a cohort of pediatric kidney transplant recipients. AB - Childhood end-stage kidney disease is associated with increased risk for early adulthood cardiovascular (CV) morbidity and mortality. Increased LVM is an early indicator of CV disease. Previous studies have suggested that LVM decreases after kidney transplantation; however, trends have been inconsistent. A single center retrospective longitudinal cohort analysis of LVM, documented annually, starting before kidney transplantation for up to 10 yr after transplantation was performed. BP documented by annual 24-h ambulatory monitoring studies, and BMI values were also reviewed. Twenty-seven children followed for a mean period of 5.3 yr were included. Depending on definition of LVH, its prevalence pretransplant and in the first years post-transplant was up to 33% dropping to 0 25% thereafter. Individual longitudinal LVM z-score trends were highly variable but generally trended toward the mean immediately after transplant and toward negative values in the following years. BP was stable during the follow-up period while mean annual BMI increased in the first-year post-transplant but declined thereafter. In a cohort of pediatric renal transplant recipients, prevalence of LVH decreased after transplant; however, individual longitudinal LVM trends were highly variable among patients. Prospective studies are needed to correlate individual LVM trends with outcomes. PMID- 25283998 TI - Fractal multi-level organisation of human groups in a virtual world. AB - Humans are fundamentally social. They form societies which consist of hierarchically layered nested groups of various quality, size, and structure. The anthropologic literature has classified these groups as support cliques, sympathy groups, bands, cognitive groups, tribes, linguistic groups, and so on. Anthropologic data show that, on average, each group consists of approximately three subgroups. However, a general understanding of the structural dependence of groups at different layers is largely missing. We extend these early findings to a very large high-precision large-scale internet-based social network data. We analyse the organisational structure of a complete, multi-relational, large social multiplex network of a human society consisting of about 400,000 odd players of an open-ended massive multiplayer online game for which we know all about their various group memberships at different layers. Remarkably, the online players' society exhibits the same type of structured hierarchical layers as found in hunter-gatherer societies. Our findings suggest that the hierarchical organisation of human society is deeply nested in human psychology. PMID- 25283999 TI - Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis. AB - The INO80 chromatin-remodelling complex has been implicated in DNA replication during stress in yeast. However, its role in normal DNA replication and its underlying mechanisms remain unclear. Here, we show that INO80 binds to replication forks and promotes fork progression in human cells under unperturbed, normal conditions. We find that Ino80, which encodes the catalytic ATPase of INO80, is essential for mouse embryonic DNA replication and development. Ino80 is recruited to replication forks through interaction with ubiquitinated H2A--aided by BRCA1-associated protein-1 (BAP1), a tumour suppressor and nuclear de ubiquitinating enzyme that also functions to stabilize Ino80. Importantly, Ino80 is downregulated in BAP1-defective cancer cells due to the lack of an Ino80 stabilization mechanism via BAP1. Our results establish a role for INO80 in normal DNA replication and uncover a mechanism by which this remodeler is targeted to replication forks, suggesting a molecular basis for the tumour suppressing function of BAP1. PMID- 25284000 TI - Zolpidem use as a predictor of Parkinson's disease. PMID- 25284001 TI - Probing formation of cargo/importin-alpha transport complexes in plant cells using a pathogen effector. AB - Importin-alphas are essential adapter proteins that recruit cytoplasmic proteins destined for active nuclear import to the nuclear transport machinery. Cargo proteins interact with the importin-alpha armadillo repeat domain via nuclear localization sequences (NLSs), short amino acids motifs enriched in Lys and Arg residues. Plant genomes typically encode several importin-alpha paralogs that can have both specific and partially redundant functions. Although some cargos are preferentially imported by a distinct importin-alpha it remains unknown how this specificity is generated and to what extent cargos compete for binding to nuclear transport receptors. Here we report that the effector protein HaRxL106 from the oomycete pathogen Hyaloperonospora arabidopsidis co-opts the host cell's nuclear import machinery. We use HaRxL106 as a probe to determine redundant and specific functions of importin-alpha paralogs from Arabidopsis thaliana. A crystal structure of the importin-alpha3/MOS6 armadillo repeat domain suggests that five of the six Arabidopsis importin-alphas expressed in rosette leaves have an almost identical NLS-binding site. Comparison of the importin-alpha binding affinities of HaRxL106 and other cargos in vitro and in plant cells suggests that relatively small affinity differences in vitro affect the rate of transport complex formation in vivo. Our results suggest that cargo affinity for importin-alpha, sequence variation at the importin-alpha NLS-binding sites and tissue-specific expression levels of importin-alphas determine formation of cargo/importin-alpha transport complexes in plant cells. PMID- 25284002 TI - Usefulness of plasma neutrophil gelatinase-associated lipocalin as an early marker of acute kidney injury after cardiopulmonary bypass in Korean cardiac patients: a prospective observational study. AB - OBJECTIVES: Development of acute kidney injury (AKI) after cardiopulmonary bypass (CPB) is relatively common and associated with increased mortality. Recently, plasma neutrophil gelatinase-associated lipocalin (NGAL) was used for the prediction of AKI. We evaluated the clinical usefulness of plasma NGAL. DESIGN AND METHODS: One hundred twelve adult patients undergoing cardiovascular surgery with CPB were included. Blood samples were obtained at baseline, at intensive care unit (ICU) admission, and 24h after ICU admission. The development of AKI, which is defined as an increase in serum creatinine by more than 50% within 3 postoperative days, was monitored. NGAL levels were analyzed by a Biosite Triage meter (Alere Medical, USA). Diagnostic performance of NGAL was analyzed using the area under the receiver operating characteristic curve. RESULTS: In AKI patients (n=13), plasma NGAL levels at ICU admission were significantly higher than those at baseline [177 (122-402) vs. 121 (74-158) ng/mL, median (interquartile range), p=0.028], whereas serum creatinine showed no significant change. The predictive value of NGAL at ICU admission was 0.812 [95% confidence interval (CI), 0.68 to 0.95] with a cut-off value of 168.5ng/mL (sensitivity, 61.5%; specificity, 88.9%). After the exclusion of 35 patients with preoperative decreased renal function, the predictive value was increased to 0.911 (95% CI, 0.82 to 1.00). CONCLUSIONS: This study showed that plasma NGAL may serve as a useful biomarker for the early detection of AKI in adult patients following CPB. PMID- 25284003 TI - Annexin A2 in renal cell carcinoma: expression, function, and prognostic significance. AB - OBJECTIVE: Renal cell carcinoma (RCC) is the most lethal genitourinary cancer and intrinsically resistant to chemotherapy, radiotherapy, and hormone therapy. Annexin A2 (Anxa2) is a calcium-dependent phospholipid-binding protein found on various cell types that plays multiple roles in regulating cellular functions. In RCC, Anxa2 expression was correlated with tumor differentiation, clinical outcomes, and the metastatic potential; however, the underlying mechanisms remain obscure. This study investigated the role of Anxa2 in regulating tumorigenesis of RCC. MATERIALS AND METHODS: Commercial RCC tissue microarray arrays and a kidney cancer quantitative polymerase chain reaction array were used to examine Anxa2 by immunohistochemistry and real-time polymerase chain reaction analysis. Short hairpin (sh)RNA-based lentiviral system technology was used to evaluate the effects of manipulating Anxa2 expression on multiple malignant features of 2 RCC cell lines, A498 and 786-O, and its mechanisms. RESULTS: (1) The Anxa2 expression level was generally elevated to varying degrees in RCC tissues. In adjacent noncancerous tissues, Anxa2 was mainly expressed in glomeruli and slightly expressed in the cytoplasm of proximal tubules. (2) An increased Anxa2 expression level was found in tissues of clear cell RCC, papillary RCC, and chromophobe RCC, and it was prominently expressed in cancer cell membranes. In addition, the Anxa2 expression level was correlated with poor prognosis. (3) Silencing Anxa2 expression suppressed the abilities of cell migration and invasion, but cell proliferation was less affected. (4) Diminished Anxa2 expression caused alterations in the cell polarity, disrupted the formation of actin filaments, and reduced CXCR4 expression. (5) Inhibition of the Rho/Rock axis restored silencing of Anxa2-mediated suppression of cell motility. CONCLUSIONS: Overall, our study points out the regulatory function of Anxa2 in RCC cell motility and provides a molecular-based mechanism of Anxa2 positivity in the progression of RCC. PMID- 25284004 TI - Dovitinib: rationale, preclinical and early clinical data in urothelial carcinoma of the bladder. AB - INTRODUCTION: Bladder cancer (BC) is the third and fifth cancer in men in terms of incidence and mortality in the US. Overexpression and mutations of fibroblast growth factor receptor 3 (FGFR3) are frequently found in BC and can represent a very interesting therapeutic target. Different FGFR3-targeted strategies have been investigated through in vitro and in vivo settings, including FGFR3 tyrosine kinase inhibitors such as dovitinib . AREAS COVERED: The authors review the data that provide a scientific rationale for FGFR3-targeted therapy in BC. They also provide an evaluation of the currently available in vitro and in vivo data on the use of dovitinib in BC patients. EXPERT OPINION: The development and progression of BC rely on a very complex signaling network that involves many different receptors aside from FGFR3 and VEGFR2. The involved signaling network can also be very different from one BC to the other, and can also evolve through time in the same patient. Inhibiting only one single target may thus not be sufficient to achieve a complete downstream oncogenic signaling blockage. Additionally, in vitro data on the use of neutralizing monoclonal antibodies targeting FGFR3 show that it can be a more efficient strategy to reach the same goal, with the potential advantage of less toxicity. PMID- 25284007 TI - Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins. AB - Molecular diversity of surface receptors has been hypothesized to provide a mechanism for selective synaptic connectivity. Neurexins are highly diversified receptors that drive the morphological and functional differentiation of synapses. Using a single cDNA sequencing approach, we detected 1,364 unique neurexin-alpha and 37 neurexin-beta mRNAs produced by alternative splicing of neurexin pre-mRNAs. This molecular diversity results from near-exhaustive combinatorial use of alternative splice insertions in Nrxn1alpha and Nrxn2alpha. By contrast, Nrxn3alpha exhibits several highly stereotyped exon selections that incorporate novel elements for posttranscriptional regulation of a subset of transcripts. Complexity of Nrxn1alpha repertoires correlates with the cellular complexity of neuronal tissues, and a specific subset of isoforms is enriched in a purified cell type. Our analysis defines the molecular diversity of a critical synaptic receptor and provides evidence that neurexin diversity is linked to cellular diversity in the nervous system. PMID- 25284006 TI - States of curiosity modulate hippocampus-dependent learning via the dopaminergic circuit. AB - People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day-delayed memory tests, participants showed improved memory for information that they were curious about and for incidental material learned during states of high curiosity. Functional magnetic resonance imaging results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity to create more effective learning experiences. PMID- 25284008 TI - Pedagogical cues encourage toddlers' transmission of recently demonstrated functions to unfamiliar adults. AB - Young children use pedagogical cues as a signal that others' actions are social or cultural conventions. Here we show that children selectively transmit (enact in a new social situation) causal functions demonstrated pedagogically, even when they have learned and can produce alternative functions as well. Two-year-olds saw two novel toys, each with two functions. One experimenter demonstrated one function using pedagogical cues (eye contact and child-directed speech) and a second experimenter demonstrated the alternative function using intentional actions towards the object, but without pedagogical cues. Children imitated both functions at equal rates initially, indicating equal causal learning from both types of demonstration. However, they were significantly more likely to enact the pedagogical function for a new adult not present during the initial demonstrations. These results indicate that pedagogical cues influence children's transmission of information, perhaps playing a role in the dissemination of cultural conventions from a young age. PMID- 25284005 TI - Refinement of the retinogeniculate synapse by bouton clustering. AB - Mammalian sensory circuits become refined over development in an activity dependent manner. Retinal ganglion cell (RGC) axons from each eye first map to their target in the geniculate and then segregate into eye-specific layers by the removal and addition of axon branches. Once segregation is complete, robust functional remodeling continues as the number of afferent inputs to each geniculate neuron decreases from many to a few. It is widely assumed that large scale axon retraction underlies this later phase of circuit refinement. On the contrary, RGC axons remain stable during functional pruning. Instead, presynaptic boutons grow in size and cluster during this process. Moreover, they exhibit dynamic spatial reorganization in response to sensory experience. Surprisingly, axon complexity decreases only after the completion of the thalamic critical period. Therefore, dynamic bouton redistribution along a broad axon backbone represents an unappreciated form of plasticity underlying developmental wiring and rewiring in the CNS. PMID- 25284009 TI - Structural evolution of small gold clusters doped by one and two boron atoms. AB - The potential energy surfaces (PES) of a series of gold-boron clusters with formula Aun B (n = 1-8) and Aum B2 (m = 1-7) have been explored using a modified stochastic search algorithm. Despite the complexity of the PES of these clusters, there are well-defined growth patterns. The bonding of these clusters is analyzed using the adaptive natural density partitioning and the natural bonding orbital analyses. Reactivity is studied in terms of the molecular electrostatic potential. PMID- 25284010 TI - The expression of proteins involved in digestion and detoxification are regulated in Helicoverpa armigera to cope up with chlorpyrifos insecticide. AB - Helicoverpa armigera is a key pest in many vital crops, which is mainly controlled by chemical strategies. To manage this pest is becoming challenging due to its ability and evolution of resistance against insecticides. Further, its subsequent spread on nonhost plant is remarkable in recent times. Hence, decoding resistance mechanism against phytochemicals and synthetic insecticides is a major challenge. The present work describes that the digestion, defense and immunity related enzymes are associated with chlorpyrifos resistance in H. armigera. Proteomic analysis of H. armigera gut tissue upon feeding on chlorpyrifos containing diet (CH) and artificial diet (AD) using nano-liquid chromatography mass spectrometry identified upregulated 23-proteins in CH fed larvae. Database searches combined with gene ontology analysis revealed that the identified gut proteins engrossed in digestion, proteins crucial for immunity, adaptive responses to stress, and detoxification. Biochemical and quantitative real-time polymerase chain reaction analysis of candidate proteins indicated that insects were struggling to get nutrients and energy in presence of CH, while at the same time endeavoring to metabolize chlorpyrifos. Moreover, we proposed a potential processing pathway of chlorpyrifos in H. armigera gut by examining the metabolites using gas chromatography-mass spectrometry. H. armigera exhibit a range of intriguing behavioral, morphological adaptations and resistance to insecticides by regulating expression of proteins involved in digestion and detoxification mechanisms to cope up with chlorpyrifos. In these contexts, as gut is a rich repository of biological information; profound analysis of gut tissues can give clues of detoxification and resistance mechanism in insects. PMID- 25284012 TI - In vitro and in vivo characterization of several functionalized ultrasmall particles of iron oxide, vectorized against amyloid plaques and potentially able to cross the blood-brain barrier: toward earlier diagnosis of Alzheimer's disease by molecular imaging. AB - Alzheimer's disease (AD) is a neurodegenerative disorder most often diagnosed 10 years after its onset and development. It is characterized by the accumulation of amyloid-beta peptide (ABP) into amyloid plaques between nerve cells, which produces a massive local neurodegeneration. Molecular magnetic resonance imaging allows diagnosis of AD by showing ABP accumulation in the brain. The ultrasmall particles of iron oxide (USPIO) derivatives proposed in the present work were functionalized with peptides that present an affinity for ABP, independently of its state of aggregation. Their nanomolar Kd * confirms the high affinity of our vectorized contrast agents (VCA) for ABP and therefore their high labeling potential, specificity and sensitivity. Their lack of toxicity has been demonstrated, both by in vitro studies using the MTT method on several cell types, and by in vivo investigations with assessment of renal and hepatic biomarkers and by histopathology evaluation. The results of biodistribution studies corroborated by MRI demonstrate that USPIO-PHO (USPIO coupled to peptide C-IPLPFYN-C) are able to cross the blood-brain barrier without any facilitating strategy, and accumulates in the brain 90 min after its injection in NMRI mice. None of the USPIO derivatives were found in any organs one week after administration. To conclude, USPIO-PHO seems to have a genuine potential for labeling amyloid plaques in the brain; it has a nanomolar binding affinity, no toxic effects, and its elimination half-life is about 3 h. Further tests will be made on transgenic mice, aimed at confirming the potential of early AD diagnosis using our VCA. PMID- 25284011 TI - A digital atlas of ion channel expression patterns in the two-week-old rat brain. AB - The approximately 350 ion channels encoded by the mammalian genome are a main pillar of the nervous system. We have determined the expression pattern of 320 channels in the two-week-old (P14) rat brain by means of non-radioactive robotic in situ hybridization. Optimized methods were developed and implemented to generate stringently coronal brain sections. The use of standardized methods permits a direct comparison of expression patterns across the entire ion channel expression pattern data set and facilitates recognizing ion channel co expression. All expression data are made publically available at the Genepaint.org database. Inwardly rectifying potassium channels (Kir, encoded by the Kcnj genes) regulate a broad spectrum of physiological processes. Kcnj channel expression patterns generated in the present study were fitted with a deformable subdivision mesh atlas produced for the P14 rat brain. This co registration, when combined with numerical quantification of expression strengths, allowed for semi-quantitative automated annotation of expression patterns as well as comparisons among and between Kcnj subfamilies. The expression patterns of Kcnj channel were also cross validated against previously published expression patterns of Kcnj channel genes. PMID- 25284013 TI - Gait deviations and compensations in pediatric patients with increased femoral torsion. AB - Coxa antetorta describes an abnormal torsion of the femur. It is commonly considered a cosmetic problem and is treated surgically only in severe cases and the presence of physical complaints. The purpose of this study was to identify deviations in gait kinematics and kinetics in pediatric patients caused by coxa antetorta and to categorize these deviations into primary and secondary deviations. We conducted a retrospective, cross-sectional three-dimensional (3D) gait analysis study to detect gait deviations in adolescents (n = 18; age range 10.5-17.5 years) with coxa antetorta compared to age-matched healthy control subjects (n = 17). Principal component (PC) analysis was used for data reduction. Linear mixed models applied to PC-scores were used to estimate the main effects within retained PCs followed by a post-hoc subgroup analysis. Patients walked with smaller external foot progression angle, greater knee adduction, more internally rotated and flexed hips and greater anterior pelvic tilt. Subgroup analysis revealed that-depending on knee alignment-patients had higher knee and hip adduction moments. These deviations in joint kinematics and kinetics may be associated with physical complaints and accelerated development of osteoarthritis. Assessment of gait deviations related to coxa antetorta using 3D gait analysis may be an additional tool in individual clinical decision-making. PMID- 25284014 TI - The orphan nuclear receptor NR4A1 specifies a distinct subpopulation of quiescent myeloid-biased long-term HSCs. AB - Hematopoiesis is maintained throughout life by self-renewing hematopoietic stem cells (HSCs) that differentiate to produce both myeloid and lymphoid cells. The NR4A family of orphan nuclear receptors, which regulates cell fate in many tissues, appears to play a key role in HSC proliferation and differentiation. Using a NR4A1(GFP) BAC transgenic reporter mouse we have investigated NR4A1 expression and its regulation in early hematopoiesis. We show that NR4A1 is most highly expressed in a subset of Lin(-) Sca-1(+) c-Kit(+) CD48(-) CD150(+) long term (LT) HSCs, and its expression is tightly associated with HSC quiescence. We also show that NR4A1 expression in HSCs is induced by PGE2, a known enhancer of stem cell engraftment potential. Finally, we find that both NR4A1(GFP+) and NR4A1(GFP-) HSCs successfully engraft primary and secondary irradiated hosts; however, NR4A1(GFP+) HSCs are distinctly myeloid-biased. These results show that NR4A1 expression identifies a highly quiescent and distinct population of myeloid biased LT-HSCs. PMID- 25284015 TI - Confocal scanning laser tomography of the optic nerve head on the patients with Alzheimer's disease compared to glaucoma and control. AB - The purpose of this study was to evaluate optic nerve head (ONH) differences of the patients with Alzheimer's disease (AD) measured by confocal scanning laser tomography [Heidelberg Retina Tomograph (HRT) III] and compare with glaucoma and control subjects. Eighty-four patients were enrolled into the study: 44 eyes of 24 patients with mild to moderate AD (Group 1), 68 eyes of 35 patients with glaucoma (Group 2), and 49 eyes of 25 heathy volunteers as a control (Group 3). A complete ophthalmologic examination as well as a confocal scanning laser ophthalmoscopic assessment with HRT III were performed on all patients. Mean values of the ONH topographic parameters such as rim area (RA), rim volume (RV), height variation contour, linear cup/disc ratio, cup shape measure, and retinal nerve fiber layer (RNFL) were recorded. Mean values of RNFL thickness was 0.23 +/ 0.07 in AD, 0.22 +/- 0.09 in glaucoma and 0.24 +/- 0.07 in the control group (p = 0.323). RA and RV were significantly lower, and linear C/D ratio was significantly higher in the glaucoma group when compared to AD and control (p < 0.05). There was no statistically significant difference between AD and control for the optic disc parameters tested (p > 0.05). We observed a negative correlation of the age with RNFL in all of the groups (p < 0.005). Age was the most important parameter affecting RNFL. Our results suggest that HRT does not demonstrate ONH differences between AD and control group, while it successfully differentiates glaucoma from AD and control cases of older age. PMID- 25284016 TI - Not all mind wandering is created equal: dissociating deliberate from spontaneous mind wandering. AB - In two large samples we show a dissociation between trait-level tendencies to mind-wander spontaneously (unintentionally) and deliberately (intentionally). Participants completed online versions of the Mind Wandering Spontaneous (MW-S) and the Mind Wandering Deliberate (MW-D) self-report scales and the Five Facet Mindfulness Questionnaire (FFMQ). The results revealed that deliberate and spontaneous mind wandering were uniquely associated with some factors of the FFMQ. Notably, while the MW-D and the MW-S were positively associated with each other, the MW-D was uniquely positively associated with the 'Non-Reactivity to Inner Experience' factor of the FFMQ, whereas the MW-S was uniquely negatively associated with this factor. We also showed that conflating deliberate and spontaneous mind wandering can result in a misunderstanding of how mind wandering is related to other traits. We recommend that studies assessing individual differences in mind wandering should distinguish between deliberate and spontaneous subtypes of mind wandering to avoid possibly erroneous conclusions. PMID- 25284017 TI - Aurora kinase A mediates c-Myc's oncogenic effects in hepatocellular carcinoma. AB - Dysregulation of c-Myc (Myc) has been shown to contribute to progression of hepatocellular carcinoma, however, the detailed molecular mechanism remains poorly understood. Here, we report that Myc binds to the Aurora kinase A (Aurka) promoter and induces expression of Aurka in HCC cells. Increased expression of Aurka correlates with that of Myc in HCC. Nuclear accumulation of Aurka was confirmed by subcellular protein fractionation and immunoblot experiments in HCC cells. Myc inhibition decreases the nuclear accumulation of Aurka in HCC cells. Also Aurka accumulating in the nucleus up-regulates Myc transcription by binding the Myc promoter containing the highly conserved CCCTCCCCA in the NHE region of the CpG islands. Inhibition of Myc or Aurka diminishes the malignant phenotypes of HCC cells by down-regulating some common target genes. Also Aurka and Myc mediates the effects of each other, at least partially, on proliferation, anchorage-independent soft agar growth, and ATP production. Blocking Aurka in an orthotopic model significantly impairs tumor growth in mice. These results identify a Myc-Aurka feedback loop in which Myc and Aurka regulate expression of each other at the transcriptional level and both play an important role in hepatocarcinogenesis. PMID- 25284018 TI - Self-assembly of a 3d-5f trinuclear single-molecule magnet from a pentavalent uranyl complex. AB - Mixed-metal uranium compounds are very attractive candidates in the design of single-molecule magnets (SMMs), but only one 3d-5f hetero-polymetallic SMM containing a uranium center is known. Herein, we report two trimeric heterodimetallic 3d-5f complexes self-assembled by cation-cation interactions between a uranyl(V) complex and a TPA-capped M(II) complex (M=Mn (1), Cd (2); TPA=tris(2-pyridylmethyl)amine). The metal centers were strategically chosen to promote the formation of discrete molecules rather than extended chains. Compound 1, which contains an almost linear {Mn?O?U?O?Mn} core, exhibits SMM behavior with a relaxation barrier of 81+/-0.5 K-the highest reported for a mono-uranium system arising from intramolecular Mn-U exchange interactions combined with the high Ising anisotropy of the uranyl(V) moiety. Compound 1 also exhibits an open magnetic hysteresis loop at temperatures less than 3 K, with a significant coercive field of 1.9 T at 1.8 K. PMID- 25284019 TI - A phase II study to determine the efficacy and safety of oral treosulfan in patients with advanced pre-treated Ewing sarcoma ISRCTN11631773. AB - We report a prospective Phase II study of efficacy and toxicity for oral treosulfan in advanced Ewing sarcoma. Twenty patients, median age 19 years (range 7-39) from five UK sites, were treated with oral treosulfan 1 g/m(2) daily for 7 days in 28. Primary endpoint was objective response rate. Best response was stable disease in one patient. All patients died of progressive disease, after median 6.41 months. Median progression free survival was 1.8 months. Toxicity was minimal. No activity was demonstrated for treosulfan at this dose. Progression free survival data should be able to be used for comparison when planning future clinical trials. PMID- 25284020 TI - Heparin-conjugated poly(lactic-co-glycolic acid) nanospheres enhance large-wound healing by delivering growth factors in platelet-rich plasma. AB - Platelet-rich plasma (PRP) contains many growth factors that are involved in tissue regeneration processes. For successful tissue regeneration, protein growth factors require a delivery vehicle for long-term and sustained release to a defect site in order to maintain their bioactivity. Previously, we showed that heparin-conjugated poly(lactic-co-glycolic acid) nanospheres (HCPNs) can provide long-term delivery of growth factors with affinity for heparin. In this study, we hypothesize that treatment of a skin wound with a mixture of PRP and HCPNs would provide long-term delivery of several growth factors contained in PRP to promote the skin wound healing process with preservation of bioactivity. The release of platelet-derived growth factor-BB (PDGF-BB), contained in PRP, from HCPN with fibrin gel (FG) showed a prolonged release period versus a PRP mixture with FG alone (FG-PRP). Also, growth factors released from PRP with HCPN and FG showed sustained human dermal fibroblast growth for 12 days. Full-thickness skin wound treatment in mice with FG-HCPN-PRP resulted in much faster wound closure as well as dermal and epidermal regeneration at day 9 compared with treatment with FG HCPN or FG-PRP. The enhanced wound healing using FG-HCPN-PRP may be due to the prolonged release not only of PDGF-BB but also of other growth factors in the PRP. The delivered growth factors accelerated angiogenesis at the wound site. PMID- 25284022 TI - The goblin spider genus Xyphinus (Araneae; Oonopidae). AB - The goblin spider genus Xyphinus Simon 1893 presents several peculiar characters, such as spines and spikes on carapace and abdomen in different sizes and shapes, strongly modified male palps with distinct apophyses and female epigastric modifications with sclerotized scapi, which can be short or long or even contorted. The genus is restricted to the Old World tropics, except for one species collected also in Australia; as revised here, the group currently comprises 20 species, 10 are newly described: X. holgeri sp. nov., X. deelemanae sp. nov., X. acutus sp. nov., X. sabal sp. nov., X. krabi sp. nov., X. infaustus sp. nov., X. rogerfedereri sp. nov., X. pachara sp. nov., X. baehrae sp. nov., and X. distortus sp. nov. Pseudotriaeris Brignoli 1974 is placed as junior synonym of Xyphinus. PMID- 25284021 TI - 'Green mice' display limitations in enhanced green fluorescent protein expression in retina and optic nerve cells. AB - Characterization of retinal cells, cell transplants and gene therapies may be helped by pre-labeled retinal cells, such as those transfected with vectors for green fluorescent protein expression. The aim of this study was to analyze retinal cells and optic nerve components from transgenic green mice (GM) with the 'enhanced' green fluorescent protein (EGFP) gene under the control of the CAG promoter (a chicken beta-actin promoter and a cytomegalovirus enhancer). The structural analysis and electroretinography recordings showed a normal, healthy retina. Surprisingly, EGFP expression was not ubiquitously located in the retina and optic nerve. Epithelial cells, photoreceptors and bipolar cells presented high green fluorescence levels. In contrast, horizontal cells, specific amacrine cells and ganglion cells exhibited a null EGFP expression level. The synaptic terminals of rod bipolar cells displayed a high green fluorescence level when animals were kept in the dark. Immature retinas exhibited different EGFP expression patterns to those noted in adults. Axons and glial cells in the optic nerve revealed a specific regional EGFP expression pattern, which correlated with the presence of myelin. These results suggest that EGFP expression might be related to the activity of both the CAG promoter and beta-actin in mature retinal neurons and oligodendrocytes. Moreover, EGFP expression might be regulated by light in both immature and adult animals. Since GM are used in numerous retina bioassays, it is essential to know the differential EGFP expression in order to select cells of interest for each study. PMID- 25284023 TI - Western Hemisphere Lasiochilinae (Hemiptera: Heteroptera: Anthocoridae) with comments on some extralimital species and some considerations on suprageneric relationships . AB - Seven Western Hemisphere genera (six known and one new), and 39 species (27 known and 12 new) of Lasiochilinae are redefined based on known and new characters. These new characters are briefly discussed. Plochiocorini, a new tribe, is erected in the basis of two genera: Plochiocoris Champion and Dolichiella Reuter. Anaelia, a new genus of Lasiochilini, is also erected based on the species Lasiochilus mirificus Drake & Harris. Ten new species are described as follows: Dilasia carvalhoi, D. cuscoensis, D. crassicornis, D. gracilicornis, D. neotropicalis, D. similis, Eusolenophora divisoides, E. testaceoides, Lasiochilus colpoides, L. duckei, Lasiocolpus vivianai and L. maesi. Taxonomic position of most of the Old World species is discussed. A table with measurements and ratios is included, and distributional maps are provided. In addition, a key to the tribes and genera of world Lasiochilinae is given, and relationships between cimicoid families is briefly revised. PMID- 25284025 TI - Effects of metal ions and hydrogen peroxide on the phenotype of yeast hom6Delta mutant. AB - HOM6 is a major gene in the aspartate pathway which leads to biosynthesis of threonine and methionine. The phenotypes of the gene deletion mutant (hom6?) in a variety of cultural conditions have previously provided meaningful insights into the biological roles of HOM6 and its upstream intermediate metabolites. Here, we conducted a survey on a spectrum of metal ions for their effect on the aspartate pathway and broader sulphur metabolism. We show that manganese (Mn(2+) ) promoted the growth of hom6? under both anaerobic and aerobic conditions. Unexpectedly, 4 mmol l(-1) hydrogen peroxide (H2 O2 ), a dose normally causing temporary cell growth arrest, enhanced the growth of hom6? under the anaerobic condition only, while it had no effect on the wild type strain BY4743. We propose that Mn(2+) and H2 O2 promote the growth of hom6? by reducing the accumulation of the toxic intermediate metabolite-aspartate beta-semialdehyde, via directing the aspartate pathway to the central sugar metabolism-tricarboxylic acid cycle. SIGNIFICANCE AND IMPACT OF THE STUDY: This study focuses on the yeast strain which lacks homoserine dehydrogenase encoded by HOM6 gene in aspartate metabolism. The HOM6 deletion mutant (hom6Delta) was analysed in the context of varying environmental parameters such as metal ions and oxidants, under anaerobic and aerobic conditions. We demonstrated that both manganese and hydrogen peroxide can promote the growth of hom6Delta, with the latter exerting such effect only under anaerobic condition. The findings are relevant to the research areas of ageing and anti-fungal drug development. It highlights the importance of interactions between gene expression and environmental factors as well as culture conditions. PMID- 25284026 TI - Evaluation of commercial kits for dual extraction of DNA and RNA from human body fluids. AB - STR typing of DNA evidence can identify the donor with a high power of discrimination but cannot identify the tissue origin of a body-fluid stain. Using RNA to attribute a crime scene stain to a particular tissue may aid in reconstruction efforts. With blood from 10 donors, four DNA and RNA coextraction kits were evaluated by measuring yields and STR and mRNA profiles. T tests indicated some significant differences in kit performance. The Zymo Research ZR Duet(TM) kit performed best based on average DNA (41.4 ng) and mRNA (4.07 ng) yields and was the only kit to provide complete DNA/RNA profiles for all samples. The consistency of this kit was challenged by data from additional blood and saliva donors. Further testing is advised before a superior kit is unequivocally chosen. Stand-alone DNA or RNA purification generally offers higher yield, but coextraction may still allow successful STR profiling and tissue source identification. PMID- 25284027 TI - Post-polymerization of urease-induced calcified, polymer hydrogels. AB - Urease-induced calcification is an innovative method to artificially produce highly filled CaCO3-based composite materials by intrinsic mineralization of hydrogels. The mechanical properties of these hybrid materials based on poly(2 hydroxyethylacrylate) cross-linked by triethylene glycol dimethacrylate are poor. Increasing the degree of calcification to up to 94 wt% improves the Young's moduli (YM) of the materials from some 40 MPa to more than 300 MPa. The introduction of calcium carbonate affine groups to the hydrogel matrix by copolymerizing acrylic acid and [2-(methacryloyloxy) ethyl]trimethylammonium chloride, respectively, does not increase the stiffness of the composites. A Young's modulus of more than 1 GPa is achieved by post-polymerization (PP) of the calcified hydrogels, which proves that the size of the contact area between the matrix and calcium carbonate crystals is the most crucial parameter for controlling the stiffness of hybrid materials. Switching from low Tg to high Tg hydrogel matrices (based on poly(N,N-dimethyl acrylamide)) results in a YM of up to 3.5 GPa after PP. PMID- 25284028 TI - Direct mass spectrometry analysis of biofluid samples using slug-flow microextraction nano-electrospray ionization. AB - Direct mass spectrometry (MS) analysis of biofluids with simple procedures represents a key step in the translation of MS techniques to clinical and point of-care applications. The current study reports the development of a single-step method using slug-flow microextraction and nano-electrospray ionization for MS analysis of organic compounds in blood and urine. High sensitivity and quantitation precision have been achieved in the analysis of therapeutic and illicit drugs in 5 MUL samples. Real-time chemical derivatization has been incorporated for analyzing anabolic steroids. The monitoring of enzymatic functions has also been demonstrated with cholinesterase in wet blood. The reported study encourages the future development of disposable cartridges, which function with simple operation to replace the traditional complex laboratory procedures for MS analysis of biological samples. PMID- 25284029 TI - Reprogramming cellular phenotype by soft collagen gels. AB - A variety of cell types exhibit phenotype changes in response to the mechanical stiffness of the substrate. Many cells excluding neurons display an increase in the spread area, actin stress fiber formation and larger focal adhesion complexes as substrate stiffness increases in a sparsely populated culture. Cell proliferation is also known to directly correlate with these phenotype changes/changes in substrate stiffness. Augmented spreading and proliferation on stiffer substrates require nuclear transcriptional regulator YAP (Yes associated protein) localization in the cell nucleus and is tightly coupled to larger traction force generation. In this study, we show that different types of fibroblasts can exhibit spread morphology, well defined actin stress fibers, and larger focal adhesions even on very soft collagen gels (modulus in hundreds of Pascals) as if they are on hard glass substrates (modulus in GPa, several orders of magnitude higher). Strikingly, we show, for the first time, that augmented spreading and other hard substrate cytoskeleton architectures on soft collagen gels are not correlated with the cell proliferation pattern and do not require YAP localization in the cell nucleus. Finally, we examine the response of human colon carcinoma (HCT-8) cells on soft collagen gels. Recent studies show that human colon carcinoma (HCT-8) cells form multicellular clusters by 2-3 days when cultured on soft polyacrylamide (PA) gels with a wide range of stiffness (0.5-50 kPa) and coated with an extracellular matrix, ECM (collagen monomer/fibronectin). These clusters show limited spreading/wetting on PA gels, form 3D structures at the edges, and eventually display a remarkable, dissociative metastasis like phenotype (MLP), i.e., epithelial to rounded morphological transition after a week of culture on PA gels only, but not on collagen monomer coated stiff polystyrene/glass where they exhibit enhanced wetting and form confluent monolayers. Here, we show that HCT-8 cell clusters also show augmented spreading/wetting on soft collagen gels and eventually form confluent monolayers as on rigid glass substrates and MLP is completely inhibited on soft collagen gels. Overall, these results suggest that cell-material interactions (soft collagen gels in this case) can induce cellular phenotype and cytoskeleton organization in a remarkably distinct manner compared to a classical synthetic polyacrylamide (PA) hydrogel cell culture model and may contribute in designing new functional biomaterials. PMID- 25284030 TI - Endoscopic ultrasonography-guided gallbladder drainage for acute cholecystitis: from evidence to practice. AB - With the evolution of the linear echoendoscope and the improved ability to direct a needle within the field of interest, the therapeutic potential of endoscopic ultrasonography (EUS) has greatly expanded. Endoscopic ultrasonography-guided transmural gallbladder drainage (EUS-GBD) may be the next frontier for therapeutic EUS. Since EUS-GBD was first described in 2007, recent reports have suggested it as an alternative to external gallbladder drainage for acute cholecystitis. EUS-GBD includes EUS-guided transmural nasogallbladder drainage, EUS-guided gallbladder aspiration, and EUS-guided transmural gallbladder stenting. Indications for the EUS-GBD technique as currently practiced, including equipment, technical details, complications, and efficacy are herein reviewed. PMID- 25284031 TI - Introduction: Recommendations regarding management of patients with Lennox Gastaut syndrome. PMID- 25284032 TI - Lennox-Gastaut syndrome: a consensus approach to differential diagnosis. AB - Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that shares many features and characteristics of other treatment-resistant childhood epilepsies. Accurate and early diagnosis is essential to both prognosis and overall patient management. However, accurate diagnosis of LGS can be clinically challenging. This article summarizes key characteristics of LGS and areas of overlap with other childhood epilepsies. Drawing upon input from a committee of established LGS experts convened in June 2012 in Chicago, Illinois, the authors highlight key diagnostic tests for making the differential diagnosis and propose a diagnostic scheme for people with suspected LGS. PMID- 25284033 TI - The efficacy and tolerability of pharmacologic treatment options for Lennox Gastaut syndrome. AB - Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that appears in childhood. LGS is characterized by a slow spike-wave pattern on electroencephalogram (EEG), cognitive impairment, and multiple seizure types. This mixture of seizure types, along with the need to use more than one type of medication, makes LGS one of the most complicated epilepsies to treat successfully. Recent developments in approved therapies for the treatment of LGS offer physicians more options, but also make developing a treatment strategy that minimizes adverse events more challenging. There are currently 5 treatment options for LGS: felbamate, lamotrigine, topiramate, rufinamide, and clobazam, and several others that are used off-label, each of which has benefits and limitations. There are several factors that must be considered when determining which medication to use when treating patients with LGS, including efficacy, which is assessed by seizure frequency, tolerability, and the anticipated duration of treatment. In this article, data supporting current treatment options are discussed, and important considerations about the treatment of LGS are reviewed. PMID- 25284034 TI - Surgical options for patients with Lennox-Gastaut syndrome. AB - Despite ongoing investigation into pharmacologic treatments for Lennox-Gastaut syndrome (LGS), outcomes for chronic administration of medications remain disappointing. In many instances LGS is treatment refractory, resulting in poor prognoses that include intellectual disability, persisting seizures, and psychiatric conditions. For patients with treatment resistance to other modalities for LGS, a further option is surgical intervention. Evaluation for surgery should involve interictal electroencephalogram (EEG), magnetic resonance imaging (MRI) analysis, and age-appropriate neuropsychological/developmental assessment. Resective surgery, where seizure foci are removed, successfully controls seizures in many cases, particularly where lesionectomy or lobar resections are appropriate. Recent studies of resective surgery on individuals with LGS show promising results, with a high percentage of patients having improved seizure control. Corpus callosotomy is a palliative surgical approach that aims at controlling potentially injurious seizures, for example, atonic or drop seizures, by preventing the bilateral spread of epileptic activity. Once associated with a high risk for morbidity and mortality, microsurgical techniques and surgery limited to the anterior region of the callosum have greatly diminished complications of corpus callosotomy surgery. Vagus nerve stimulation, another palliative procedure, offers rates of seizure improvement similar to those of corpus callosotomy, with the exception of atonic seizure for which corpus callosotomy may lead to a greater reduction. Recent advances in surgical techniques offer encouraging options for treatment of LGS. PMID- 25284035 TI - Nonpharmacologic care for patients with Lennox-Gastaut syndrome: ketogenic diets and vagus nerve stimulation. AB - Individuals with Lennox-Gastaut syndrome (LGS) often do not respond to or become resistant to pharmacologic treatments. Ketogenic diets (KDs) and vagus nerve stimulation (VNS) are nonpharmacologic treatment options for these intractable patients. The classic KD, a high-fat, low-carbohydrate diet with 90% of calories derived from fat, has been used in the treatment of seizures for >90 years. About half of patients with LGS respond to the KD with a >50% reduction in seizures and some patients may achieve a >90% reduction. Vagus nerve stimulation therapy involves a surgically implanted generator that delivers intermittent electrical stimuli to the brain via an electrode wrapped around the left vagus nerve. It is utilized as adjunctive therapy for patients with drug-resistant epilepsy (including patients with LGS) who are not suitable candidates for resective surgery. Similar to the KD, about half of LGS patients respond to VNS therapy, with a >50% reduction in seizures, and the response may improve over time. Both the KD and VNS are options for patients with LGS. PMID- 25284036 TI - Wrong blood in tube - potential for serious outcomes: can it be prevented? AB - 'Wrong blood in tube' (WBIT) errors, where the blood in the tube is not that of the patient identified on the label, may lead to catastrophic outcomes, such as death from ABO-incompatible red cell transfusion. Transfusion is a multistep, multidisciplinary process in which the human error rate has remained unchanged despite multiple interventions (education, training, competency testing and guidelines). The most effective interventions are probably the introduction of end-to-end electronic systems and a group-check sample for patients about to receive their first transfusion, but neither of these eradicates all errors. Further longer term studies are required with assessment before and after introduction of the intervention. Although most focus has been on WBIT in relation to blood transfusion, all pathology samples should be identified and linked to the correct patient with the same degree of care. Human factors education and training could help to increase awareness of human vulnerability to error, particularly in the medical setting where there are many risk factors. PMID- 25284037 TI - Self-sampling experiences among non-attendees to cervical screening. AB - OBJECTIVE: High coverage and attendance is essential to positive cervical cancer screening results. Offering self-sampling for HPV-testing to the non-attendees of the program may improve attendance rates. Information on women's perceptions and experiences with self-sampling (acceptability) is needed to further optimize attendance by this method. METHODS: A questionnaire study focusing on women's experiences on the screening method was embedded in a trial investigating the effects and feasibility of self-sampling among non-attendees of cervical screening in 31 Finnish municipalities in 2011-2012 (n=4688). Reasons for non attendance in routine screening were also surveyed. RESULTS: Response rate to the questionnaire was 98.8% (909/920) among women who performed self-sampling. Self sampling participants reported mainly good experiences. Negative experiences (difficulties in sample taking, pain, fear, anxiety, insecurity) were reported rarely, but more commonly among women with a mother tongue other than Finnish or Swedish (immigrants). Most common reason for non-attendance in routine screening was a recent Pap-smear elsewhere (opportunistic screening). Practical reasons (pregnancy, scheduling difficulties) were reported by 42%, emotional or attitudinal reasons by 17%, and 16% forgot to take part. Response yield to questionnaire was unsatisfactory among those women who declined the self-sampling option. CONCLUSIONS: Optimizing the practical aspects of screening and offering a self-sampling option to non-attendees can help to overcome a large variety of both practical and emotional barriers to traditional screening. More research is needed among the non-attendees to routine screening who decline also the self sampling option. PMID- 25284038 TI - Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer. AB - OBJECTIVE: Ovarian cancer is the most deadly gynecologic malignancy worldwide. Since the pathogenesis of ovarian cancer is incompletely understood, and there are no available screening techniques for early detection, most patients are diagnosed with advanced, incurable disease. In an effort to develop innovative and effective therapies for ovarian cancer, we tested the effectiveness of Galecti-3C in vitro. This is a truncated, dominant negative form of Galectin-3, which is thought to act by blocking endogenous Galectin-3. METHODS: We produced a truncated, dominant-negative form of Galectin-3, namely Galetic-3C. Ovarian cancer cell lines and primary cells from ovarian cancer patients were treated with Galectin-3C, and growth, drug sensitivity, and angiogenesis were tested. RESULT: We show, for the first time, that Galectin-3C significantly reduces the growth, motility, invasion, and angiogenic potential of cultured OC cell lines and primary cells established from OC patients. CONCLUSIONS: Our findings indicate that Galectin-3C is a promising new compound for the treatment of ovarian cancer. PMID- 25284039 TI - Value of endocervical margin and high-risk human papillomavirus status after conization for high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, and microinvasive carcinoma of the uterine cervix. AB - OBJECTIVE: The aim of this study was to analyze clinico-pathologic factors and the optimal cut-off value of high-risk human papillomavirus (HR-HPV) viral load for predicting high-grade residual/recurrent disease after the conization in cervical intraepithelial neoplasia (CIN 2-3), adenocarcinoma in situ (AIS), and microinvasive carcinoma of the uterine cervix (MICA). METHODS: We retrospectively reviewed data from 701 patients with CIN 2-3, AIS, and MICA who underwent conization between September 2003 and June 2012. Receiver-operating characteristic curve analysis was used to find out the cut-off value of HR-HPV viral load for predicting residual/recurrent disease. Clinico-pathologic variables, including resection margin and HR-HPV status, were evaluated as possible predictors of residual/recurrent disease. RESULTS: At a cut-off value of 1.16 RLU/CO for post-cone HR-HPV viral load, the sensitivity was 88.2% and the specificity was 98.3%. Multivariate analysis demonstrated that post-cone cytology (p=0.001, OR=83.808, 95% CI=6.688-1050.232), endocervical margin status (p<0.001, OR=80.478, 95% CI=7.421-872.732), and post-cone HR-HPV status (p<0.001, OR=79.660, 95% CI=8.539-743.129) were significantly associated with residual/recurrent disease. The post-cone HR-HPV positivity was observed more in the patients who showed positive endocervical margin than in the patients with positive ectocervical margin (32.6% vs. 5.3%, p=0.002). CONCLUSIONS: Follow-up using liquid based cytology in combination with HR-HPV test at 12 months after the conization, and not the early HR-HPV test, might be acceptable. Post-cone endocervical margin status combined with post-cone HR-HPV test is critical for predicting residual/recurrent disease and clinical management. PMID- 25284040 TI - Statin use and pain in older people with cancer: a cross-sectional study. AB - OBJECTIVES: To investigate statin use and pain in people with cancer aged 70 to 79 and 80 and older. DESIGN: Cross-sectional. SETTING: Medical oncology outpatient clinic at the Royal Adelaide Hospital. PARTICIPANTS: Individuals aged 70 and older who presented consecutively between January 2009 and June 2010 (n = 385), of whom 106 were aged 80 and older. MEASUREMENTS: Participants completed a structured data collection instrument, documenting medication use, comorbidities and a general pain assessment (10-point visual analogue scale (VAS)). Unadjusted and adjusted logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with statin use. RESULTS: The prevalence of statin use was 35% (n = 97) in people aged 70 to 79 and 39% (n = 41) in those aged 80 and older. After adjusting for age, sex, Charlson Comorbidity Index, and analgesic use, statin use was associated with self reported pain (VAS >= 5) (OR = 4.09, 95% CI = 1.32-12.68) in people aged 80 and older but not in those aged 70 to 79. Half of participants using statins (51% n = 70) had a palliative treatment approach. Of the 41 statin users aged 80 and older, 20 (49%) were using statins for primary prevention. CONCLUSION: The prevalence of statin use was similar in people aged 70 to 79 years and those aged 80 and older, with statin use associated with self-reported pain in people aged 80 and older. This highlights a potential benefit of "deprescribing" statins in older people with cancer, especially those aged 80 and older. PMID- 25284041 TI - Late pancreas retransplantation. AB - Pancreas retransplantation, excluding immediate retransplantation for graft thrombosis, is a technically treacherous operation with the added challenges of adhesions from the prior transplant and difficulties identifying usable recipient vessels. The goal of this study was to review our single-center experience with late pancreas retransplantation. Charts for all pancreas transplant recipients between 01/2003 and 04/2013 were reviewed for demographics, graft and patient survival, length of stay (LOS), readmissions, and technical complications. Of 473 pancreas transplants, there were 20 late pancreas retransplants compared to 441 first transplants. There were no significant differences in donor or recipient demographics. There was no significant difference in graft or patient survival. The mean and median lengths of stay were 22 and nine d, respectively (range 5-175 d), and 11 recipients required readmission within the first three months post transplant. Five patients were reexplored in the early postoperative period for an enteric leak at the site of the primary allograft (n = 1), complications of percutaneous gastrostomy tube placement (n = 1), hemorrhage (n = 1), and negative laparotomy for hyperglycemia (n = 2). Pancreas retransplantation is technically challenging but can be safely performed with graft and recipient survival comparable to primary transplants. PMID- 25284042 TI - Correlation between age and the parameters of medial epiphysis and metaphysis of the clavicle using CT volume rendering images. AB - OBJECTIVES: The aim of this study was to evaluate the correlation between age and the parameters of medial epiphysis of clavicle based on CT volume rendering (VR) images. MATERIALS AND METHODS: The CT images of the medial clavicle from 795 teenagers (387 male and 408 female) between 15 and 25 years were collected in East and South China. VR images were recombined from 0.60 mm thickness slice CT images. The ratio of epiphyseal diameter/metaphyseal diameter and the ratio of epiphyseal area/metaphyseal area of two sides of medial clavicle were measured and calculated by three different examiners, the quantitative data consistency was checked by intraclass correlation coefficients (ICC). The diameter ratio of left and right side are depicted as X1 and X3, and the area ratio of left and right side as X2 and X4. Descriptive statistic analysis of the data was performed and several mathematical models were established using least square. CT images from additional 60 teenagers (30 male and 30 female) were used to verify the accuracy of the established mathematical models. RESULTS: ICC indicated that the measurement of epiphyseal diameter, metaphyseal diameter, the ratio of epiphyseal diameter/metaphyseal diameter, epiphyseal area, metaphyseal area and the ratio of epiphyseal area/metaphyseal area of medial clavicle in the left and right side of the three examiners was approaching 1. The 95% reference range for the mean of every examination of both genders gradually increased with age. Females' data indicated by medial epiphysis of the clavicle development were earlier than male's, especially from 15 to 21 years. The difference of medial epiphysis of the clavicle development in gender becomes smaller after 21 years. The highest accuracy of the mathematical models made clear that male's accuracy was 73.5% (+/ 1.0 year) and 85.3% (+/-1.5 year), and female's was 68.6% (+/-1.0 year) and 82.2% (+/-1.5 year) respectively. CONCLUSION: The methods of data collection and analysis were reliable and feasible. Combined the high accuracy of these established mathematical models, it is applicable to use the ratio of epiphyseal diameter/metaphyseal diameter and the ratio of epiphyseal area/metaphyseal area of left and right side of medial clavicle to estimate the teenager's age. Bearing this in mind, further studies are needed to evaluate slice thickness as the most critical parameter. PMID- 25284043 TI - Care coordination between convenient care clinics and healthcare homes. AB - PURPOSE: Patient care coordination is foundational to high-quality health care and is a national priority. Since its inception, convenient health care has been criticized for its potential to decrease patient care coordination. The purpose of this study is to investigate care coordination between convenient care clinics and healthcare homes. DATA SOURCES: The care coordination practices of Minute Clinic, which represents over 40% of the convenient care industry, were studied. Patient identification of healthcare homes and consent to transmit visit records were abstracted from the health records of 1,014,249 patients dated July 1 to December 31, 2012. The completeness of record content and timeliness of record transmission were assessed by means of interviewing Minute Clinic's Director of Quality and reviewing patient electronic health records. CONCLUSIONS: Minute Clinic attempts to coordinate care with healthcare homes, but opportunities for improved care coordination exist. IMPLICATIONS FOR PRACTICE: Increased vigilance on the part of providers, patients, and healthcare systems is needed to mitigate barriers to care coordination. Future research is needed to examine care coordination from multiple convenient care operators and explore how to increase care coordination with healthcare homes. PMID- 25284045 TI - For a long time we thought all was lost.... PMID- 25284044 TI - Exploring the potential of fulvalene dimetals as platforms for molecular solar thermal energy storage: computations, syntheses, structures, kinetics, and catalysis. AB - A study of the scope and limitations of varying the ligand framework around the dinuclear core of FvRu2 in its function as a molecular solar thermal energy storage framework is presented. It includes DFT calculations probing the effect of substituents, other metals, and CO exchange for other ligands on DeltaHstorage . Experimentally, the system is shown to be robust in as much as it tolerates a number of variations, except for the identity of the metal and certain substitution patterns. Failures include 1,1',3,3'-tetra-tert-butyl (4), 1,2,2',3' tetraphenyl (9), diiron (28), diosmium (24), mixed iron-ruthenium (27), dimolybdenum (29), and ditungsten (30) derivatives. An extensive screen of potential catalysts for the thermal reversal identified AgNO3 -SiO2 as a good candidate, although catalyst decomposition remains a challenge. PMID- 25284046 TI - A new strategy to synthesize bottlebrushes with a helical polyglutamate backbone via N-carboxyanhydride polymerization and RAFT. AB - Polyglutamate bottlebrushes with poly(oligo(ethylene glycol)acrylate) as side chains were successfully prepared for the first time by combination of N carboxyanhydride polymerization and reversible addition-fragmentation chain transfer (RAFT) polymerization. This work has provided a metal-free polymerization strategy and can be applicable to synthesize well-defined polypeptide bottlebrushes for bio-application purposes. PMID- 25284047 TI - Acute mesenteric ischemia caused by venous thrombosis in a patient with Leiden V factor mutation. PMID- 25284048 TI - A motivational intervention for patients with COPD in primary care: qualitative evaluation of a new practitioner role. AB - BACKGROUND: Long-term conditions such as chronic obstructive pulmonary disease (COPD) are growing challenges for health services. Psychosocial co-morbidity is associated with poorer quality of life and greater use of health care in these patients but is often un-diagnosed or inadequately treated in primary care, where most care for these patients is provided. We developed a brief intervention, delivered by 'liaison health workers' (LHWs), to address psychosocial needs in the context of an integrated approach to physical and mental health. We report a qualitative study in which we characterize the intervention through the experience of the patients receiving it and examine how it was incorporated into primary care. METHODS: Qualitative study using patient and practice staff informants. We audio-recorded interviews with 29 patients offered the intervention (three had declined it or withdrawn) and 13 practice staff (GPs, nurses and administrators). Analysis used a constant comparative approach. RESULTS: Most patients were enthusiastic about the LHWs, describing the intervention as mobilizing their motivation for self-management. By contrast with other practitioners, patients experienced the LHWs as addressing their needs holistically, being guided by patient needs rather than professional agendas, forming individual relationships with patients and investing in patients and their capacity to change. Practices accommodated and accepted the LHWs, but positioned them as peripheral to and separate from the priority of physical care. CONCLUSIONS: Despite being a short-term intervention, patients described it as having enduring motivational benefits. The elements of the intervention that patients described map onto the key features of motivating interventions described by Self-Determination Theory. We suggest that the LHWs motivated patients to self-management by: (i) respecting patients' competence to decide on needs and priorities; (ii) forming relationships with patients as individuals; and (iii) fostering patients' sense of autonomy. While truly integrated primary care for patients with long-term conditions such as COPD remains elusive, existing practice staff might adopt elements of the LHWs' approach to enhance motivational change in patients with long-term conditions such as COPD. PMID- 25284049 TI - Heparan sulfate in the regulation of neural differentiation and glioma development. AB - Heparan sulfate proteoglycans (HSPGs) are the main components of the extracellular matrix, where they interact with a large number of physiologically important macromolecules. The sulfation pattern of heparan sulfate (HS) chains determines the interaction potential of the proteoglycans. Enzymes of the biosynthetic and degradation pathways for HS chains are thus important regulators in processes ranging from embryonic development to tissue homeostasis, but also for tumor development. Formation of the nervous system is also critically dependent on intact HSPGs, and several studies have outlined the role of HS in neural induction from embryonic stem cells. High-grade glioma is the most common malignant primary brain tumor among adults, and the outcome is poor. Neural stem cells and glioma stem cells have several common traits, such as sustained proliferation and a highly efficient migratory capacity in the brain. There are also similarities between the neurogenic niche where adult neural stem cells reside, and the tumorigenic niche. These include interactions with the extracellular matrix, and many of the matrix components are deregulated in glioma, e.g. HSPGs and enzymes implementing the biosynthesis and modification of HS. In this article, we will present how HS-regulated pathways are involved in neural differentiation, and discuss their impact on brain development. We will also review and critically discuss the important role of structural modifications of HS in glioma growth and invasion. We propose that targeting invasive mechanisms of glioma cells through modulation of HS structure and HS-mediated pathways may be an attractive alternative to other therapeutic attempts, which so far have only marginally increased survival for glioma patients. PMID- 25284050 TI - Comparative proteomic and physiological analyses reveal the protective effect of exogenous calcium on the germinating soybean response to salt stress. AB - Calcium enhances salt stress tolerance of soybeans. Nevertheless, the molecular mechanism of calcium's involvement in resistance to salt stress is unclear. A comparative proteomic approach was used to investigate protein profiles in germinating soybeans under NaCl-CaCl2 and NaCl-LaCl3 treatments. A total of 80 proteins affected by calcium in 4-day-old germinating soybean cotyledons and 71 in embryos were confidently identified. The clustering analysis showed proteins were subdivided into 5 and 6 clusters in cotyledon and embryo, respectively. Among them, proteins involved in signal transduction and energy pathways, in transportation, and in protein biosynthesis were largely enriched while those involved in proteolysis were decreased. Abundance of nucleoside diphosphate kinase and three antioxidant enzymes were visibly increased by calcium. Accumulation of gamma-aminobutyric acid and polyamines was also detected after application of exogenous calcium. This was consistent with proteomic results, which showed that proteins involved in the glutamate and methionine metabolism were mediated by calcium. Calcium could increase the salt stress tolerance of germinating soybeans via enriching signal transduction, energy pathway and transportation, promoting protein biosynthesis, inhibiting proteolysis, redistributing storage proteins, regulating protein processing in endoplasmic reticulum, enriching antioxidant enzymes and activating their activities, accumulating secondary metabolites and osmolytes, and other adaptive responses. Biological significance Soybean (Glycine max L.), as a traditional edible legume, is being targeted for designing functional foods. During soybean germination under stressful conditions especially salt stress, newly discovered functional components such as gamma-aminobutyric acid (GABA) are rapidly accumulated. However, soybean plants are relatively salt-sensitive and the growth, development and biomass of germinating soybeans are significantly suppressed under salt stress condition. According to previous studies, exogenous calcium counters the harmful effect of salt stress and increases the biomass and GABA content of germinating soybeans. Nevertheless, the precise molecular mechanism underlying the role of calcium in resistance to salt stress is still unknown. This paper is the first study employing comparative proteomic and physiological analyses to reveal the protective effect of exogenous calcium in the germinating soybean response to salt stress. Our study links the biological events with proteomic information and provides detailed peptide information on all identified proteins. The functions of those significantly changed proteins are also analyzed. The physiological and comparative proteomic analyses revealed the putative molecular mechanism of exogenous calcium treatment induced salt stress responses. The findings from this paper are beneficial to high GABA-rich germinating soybean biomass. Additionally, these findings also might be applicable to the genetic engineering of soybean plants to improve stress tolerance. PMID- 25284052 TI - Quantitative proteomics and bioinformatic analysis provide new insight into protein function during avian eggshell biomineralization. AB - Gallus gallus eggshell is a bioceramic composed of 95% calcium carbonate in calcitic form and 3.5% extracellular organic matrix. The calcification process occurs in the uterine fluid where biomineralization follows a temporal sequence corresponding to the initiation, growth and termination stages of crystal growth. Eggshell texture and its ultrastructure are regulated by organic matrix proteins, which control mineralization process and influence the eggshell biomechanical properties. We performed proteomic qualitative analyses and identified 308 uterine fluid proteins. Quantitative analysis showed differential abundances at the three stages of shell biomineralization for 64 of them. Cluster analysis revealed a first group of proteins related to mineralization and mainly present at the onset of calcification including OVOT, OVAL, OC-17, and two novel calcium binding proteins (EDIL3, MFGE8). A second group of proteins mainly present at the initiation and termination of shell formation was potentially involved in the regulation of the activity of the uterine fluid proteins (e.g. molecular chaperones, folding proteins, proteases and protease inhibitors). OCX21, a protein highly concentrated in the fluid and the shell, belongs to this group. A third group equally represented at all stages of shell mineralization corresponded to antibacterial proteins that could protect the forming egg against microbial invasion. BIOLOGICAL SIGNIFICANCE: The calcitic avian eggshell protects the developing embryo and, moreover, ensures that the nutritious table egg remains free of pathogens. The eggshell is formed by nucleation upon a fibrous scaffold (the eggshell membranes) followed by an interaction between the growing mineral crystals and the shell organic matrix. This interaction leads to a highly ordered shell microstructure and texture which contribute to its exceptional mechanical properties. Shell mineralization occurs in three distinct phases of calcification (initiation, growth and termination), which are associated with distinct populations of matrix proteins that are secreted into the acellular uterine fluid as modulators of the process. The recent development of high throughput methods has led to the identification of many proteins in the shell, but little is known concerning their role in shell formation. In order to determine precisely the importance of particular proteins relative to eggshell mineralization, this project used qualitative and quantitative proteomics of the uterine fluid constituents, coupled with bioinformatic analysis, to predict the functional role of proteins secreted at each of the three main stages of shell calcification. Besides its relevance to food production and to hen reproduction, eggshell calcification is furthermore a relevant model for studying calcium carbonate biomineralization on a two-dimensional membrane support. Better understanding of this process will provide insight into the fabrication of ceramics at ambient pressure and temperature. PMID- 25284051 TI - Proteomic profile of Bithynia siamensis goniomphalos snails upon infection with the carcinogenic liver fluke Opisthorchis viverrini. AB - The snail Bithynia siamensis goniomphalos acts as the first intermediate host for the human liver fluke Opisthorchis viverrini, the major cause of cholangiocarcinoma (CCA) in Northeast Thailand. The undisputed link between CCA and O. viverrini infection has precipitated efforts to understand the molecular basis of host-parasite interactions with a view to ultimately developing new control strategies to combat this carcinogenic infection. To date most effort has focused on the interactions between the parasite and its human host, and little is known about the molecular relationships between the liver fluke and its snail intermediate host. In the present study we analyse the protein expression changes in different tissues of B. siamensis goniomphalos induced by infection with larval O. viverrini using iTRAQ labelling technology. We show that O. viverrini infection downregulates the expression of oxidoreductases and catalytic enzymes, while stress-related and motor proteins are upregulated. The present work could serve as a basis for future studies on the proteins implicated in the susceptibility/resistance of B. siamensis goniomphalos to O. viverrini, as well as studies on other pulmonate snail intermediate hosts of various parasitic flukes that infect humans. BIOLOGICAL SIGNIFICANCE: Despite the importance and high prevalence of opisthorchiasis in some regions of Southeast Asia and the direct relationship between infection by Opisthorchis viverrini and the incidence of cholangiocarcinoma, little is known of the modifications induced by this parasite in its snail intermediate hosts. This time-course study provides the first in-depth quantitative proteomic analysis of experimentally infected Bithynia siamensis goniomphalos. We show how motor and stress-related proteins are upregulated in infected snails, while O. viverrini infection downregulates the expression of oxidoreductases and catalytic enzymes. This work serves as a basis for the development of new strategies, focused on the invertebrate intermediate hosts, to control parasite transmission. PMID- 25284054 TI - About some behavioral and psychosocial aspects related to epilepsy. PMID- 25284055 TI - The human face of epilepsy: a tribute to Epilepsy & behavior. PMID- 25284053 TI - Urine, peritoneal fluid and omental fat proteomes of reproductive age women: Endometriosis-related changes and associations with endocrine disrupting chemicals. AB - Endometriosis, ectopic growth of the uterine lining (endometrium), which affects 6-11% of reproductive age women, is associated with pelvic pain and infertility. We investigated the peritoneal fluid (PF), urine and omental fat (OF) proteomes of women with endometriosis vs. individuals with no surgically visualized endometriosis. All participants were enrolled in the NICHD-funded ENDO Study. A two-step proteomic study was performed. The first, a broad survey, employed a semi-quantitative gel LC-mass spectrometry (MS) workflow: SDS PAGE fractionation, trypsin digestion and LC-MS/MS. The results showed sample integrity but failed to detect any differences between women with and without endometriosis. The second step was a quantitative analysis of OF samples. We employed another sample set (n=30) from women +/- disease and isobaric mass-tag (iTRAQ) chemistry to label peptides and 2D LC-MS/MS for protein identification and quantification. Three proteins-matrix metalloproteinase-9, neutrophil elastase, and FAM49B-were significantly lower in abundance in samples from women with endometriosis. Interestingly, neutrophil elastase and FAM49B levels were associated with higher levels of a subset of endocrine disrupting chemicals (EDCs) that were previously measured in the same samples. The results of these experiments showed the feasibility of associating endometriosis with changes in the OF protein repertoire and EDC levels. BIOLOGICAL SIGNIFICANCE: Endometriosis, pathological growth of the uterine lining, is associated with significant morbidities, including pain and infertility. However, the causes of this common condition are poorly understood. This study determined whether endometriosis was associated with changes in the protein composition of peritoneal fluid, urine and/or omental fat. A protein of unknown function (FAM49B) and two proteinases (metalloproteinase-9, neutrophil elastase) were down regulated in OF samples from women with versus without endometriosis. These findings suggested proteinase imbalances at sites that were distant from the endometriotic lesions. Additionally, FAM49B and neutrophil elastase levels were associated with higher levels of a subset of environmental chemicals that were quantified in the same samples, suggesting other possible associations. Thus, this work generated hypotheses that will be tested in further studies. PMID- 25284056 TI - Recent changes in practice guidelines for atrial fibrillation management. PMID- 25284057 TI - Temporary radiation-induced alopecia after embolization of a cerebral arteriovenous malformation. PMID- 25284059 TI - Key changes in wine aroma active compounds during bottle storage of Spanish red wines under different oxygen levels. AB - Samples from 16 Spanish red wines have been stored for 6 months at 25 degrees C under different levels of oxygen (0-56 mg/L). Amino acids, metals, and phenolic compounds were analyzed and related to the production or depletion of key oxidation- and reduction-related aroma compounds. Oxidation brings about sensory relevant increases in Strecker aldehydes, 1-octen-3-one, and vanillin. Formation of Strecker aldehydes correlates to the wine content on the corresponding amino acid precursor, Zn, and caffeic acid ethyl ester and negatively to some flavonols and anthocyanin derivatives. Formation of most carbonyls correlates to wine combined SO2, suggesting that part of the increments are the result of the release of aldehydes forming bisulfite combinations once SO2 is oxidized. Methanethiol (MeSH) and dimethylsulfide (DMS), but not H2S levels, increase during storage. MeSH increments correlate to methionine levels and proanthocyanidins and negatively to resveratrol and aluminum. H2S, MeSH, and DMS levels all decreased with oxidation, and for the latter two, there are important effects of Mn and pH, respectively. PMID- 25284058 TI - Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis. AB - BACKGROUND: Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms by inducing fibrosis. We previously used a well-characterized mouse model of bacterial-induced prostate inflammation to demonstrate that chronic prostatic inflammation induces collagen deposition. Here, we examined stability of the newly synthesized collagen in bacterial induced prostatic inflammation and the reversibility of fibrosis after resolution of infection and inflammation. METHODS: Uropathogenic Escherichia coli 1677 was instilled transurethrally into adult C3H/HeOuJ male mice to induce chronic prostatic inflammation. Collagen was labeled by (3) H-proline administration for 28 days post-inoculation and (3) H-hydroxyproline incorporation measured to determine stability of the newly synthesized collagen. Inflammation score was graded using a previously established system and total collagen content was measured by picrosirius red staining quantitation and hydroxyproline content. Resolution of inflammation and reversal of collagen deposition was assessed after treatment with antibiotic enrofloxacin for 2 weeks on day 28 post-inoculation followed by an 8-week recovery period. RESULTS: Decay analysis of incorporated (3) H-hydroxyproline revealed the half-life of newly synthesized collagen to be significantly shorter in infected/inflamed prostates than in controls. Treatment with antibiotic enrofloxacin completely eradicated bacterial infection and allowed resolution of inflammation. This was followed by marked attenuation of collagen content and correlation analysis verified a positive association between the resolution of inflammation and the reversal of collagen deposition. CONCLUSIONS: These data demonstrate, for the first time, that inflammation induced prostatic fibrosis is a reversible process. PMID- 25284061 TI - Weighing up the commitment: a grounded theory of the transition from occupational therapy clinician to academic. AB - BACKGROUND/AIM: Growth in the number of occupational therapy programmes in Australia has resulted in a critical shortage of academics. When experienced clinicians are recruited into academia, they may find the transition process difficult. The study aimed to explore clinicians' perspectives of what happens when they transition into academia. METHOD: A constructivist grounded theory approach was used in this qualitative research project. Recruitment was conducted using purposive and theoretical sampling from occupational therapy programmes in Australia. Interview transcripts were analysed using constant comparative method through a process of open, axial, selective and theoretical coding. RESULTS: Sixteen participants engaged in semi-structured in-depth interviews. The theory of transition into academia included a process of 'weighing up the commitment' to academia and the core category of 'a good fit for me'. The transition was characterised by the taxing nature of the work, the need to learn multiple aspects of a new role, the different values and beliefs in an academic environment and the amount of time it took to achieve success. Participants underwent a shift in identity to adjust to the academic environment and eventually reached a point where they were able to judge if academia suited them. CONCLUSION: Australian universities have long-standing cultural practices which differ considerably from clinical settings. Transitioning from a clinical to an academic occupational therapy role requires complex adjustments to values, beliefs and identity. The process involved consideration by the new academics of their 'fit' for academia, and how committed they were to stay. PMID- 25284060 TI - Perspectives on human-human sensorimotor interactions for the design of rehabilitation robots. AB - Physical interactions between patients and therapists during rehabilitation have served as motivation for the design of rehabilitation robots, yet we lack a fundamental understanding of the principles governing such human-human interactions (HHI). Here we review the literature and pose important open questions regarding sensorimotor interaction during HHI that could facilitate the design of human-robot interactions (HRI) and haptic interfaces for rehabilitation. Based on the goals of physical rehabilitation, three subcategories of sensorimotor interaction are identified: sensorimotor collaboration, sensorimotor assistance, and sensorimotor education. Prior research has focused primarily on sensorimotor collaboration and is generally limited to relatively constrained visuomotor tasks. Moreover, the mechanisms by which performance improvements are achieved during sensorimotor cooperation with haptic interaction remains unknown. We propose that the effects of role assignment, motor redundancy, and skill level in sensorimotor cooperation should be explicitly studied. Additionally, the importance of haptic interactions may be better revealed in tasks that do not require visual feedback. Finally, cooperative motor tasks that allow for motor improvement during solo performance to be examined may be particularly relevant for rehabilitation robotics. Identifying principles that guide human-human sensorimotor interactions may lead to the development of robots that can physically interact with humans in more intuitive and biologically inspired ways, thereby enhancing rehabilitation outcomes. PMID- 25284062 TI - An assessment of the magnitude of intra-fraction movement of head-and-neck IMRT cases and its implication on the action-level of the imaging protocol. AB - BACKGROUND AND PURPOSE: A planning margin ?3 mm is employed in some head-and-neck IMRT cases due to the proximity of critical structures. This study aims to explore the need to redefine the action-level in the head-and-neck imaging protocol in consideration of the intra-fraction movement. MATERIAL AND METHODS: This is a local study of 18 patients treated using the same immobilisation system and setup protocol. Post-treatment orthogonal pair of kilovoltage X-ray images was acquired on the first three days of treatment. 106 sets of pre- and post treatment kV X-ray images acquired over 53 fractions were analysed against the treatment planning DRR for calculation of intra-fraction movement. RESULTS: Individual mean intra-fraction movement in all directions ranged from -1.8 to 1.1 mm. Population mean (median) intra-fraction movement in the x-, y-, and z-planes were -0.1 mm (0 mm), -0.3 mm (-0.3 mm) and -0.2 mm (-0.2 mm) respectively. Intra fraction movement in all three dimensions, x-, y- and z-planes were considered statistically significant (p<0.05). 7 out of 53 fractions (13.2%) were highlighted as the combined magnitude of the intra-fraction motion with the uncorrected pre-treatment setup errors had exceeded the boundaries of given margins. CONCLUSIONS: 3 mm-AL was not adequate to account for intra-fraction movement when the CTV-PTV margin was ?3 mm and should be excluded from the routine imaging protocol and daily image-guided radiotherapy should be employed. Adjusting the action-level to 2 mm would allow a more confident approach in delivery of the prescribed dose in head-and-neck IMRT cases. PMID- 25284064 TI - Time-lapse analysis of tangential migration in Sema6A and PlexinA2 knockouts. AB - In the developing cerebellum, granule cells migrate tangentially in the external granule cell layer and then radially and inward, across the molecular layer and Purkinje cell layer. We showed previously that the transmembrane semaphorin Sema6A and its receptor PlexinA2 control the ability of migrating granule cells to switch from one mode of migration to the other. In both Sema6A and PlexinA2 knockouts, a large number of granule cells remain in the molecular layer, a defect that is most likely due to abnormal nuclear translocation. We show here that the lack of Sema6A or PlexinA2 preferentially much more severely perturbs the migration of later-born granule cells than early-born ones. We also use a cerebellum slice model system and electroporation to perform time-lapse analysis of granule cell migration in wild-type mice, Sema6A and PlexinA2 knockouts. This study reveals that defects of tangential migration can be detected in bipolar granule cells before the initiation of radial migration. Our results also directly confirm that the absence of Sema6A does not perturb radial migration. PMID- 25284063 TI - Determinates of tumor response to radiation: tumor cells, tumor stroma and permanent local control. AB - BACKGROUND AND PURPOSE: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. MATERIAL AND METHODS: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs(-/-)) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD50 assay. Vascular effects were evaluated by functional vascular density assays. RESULTS: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. CONCLUSION: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose. PMID- 25284065 TI - Recent clinical trials for the etiological treatment of chronic chagas disease: advances, challenges and perspectives. AB - Chagas disease, a chronic systemic parasitosis caused by the Kinetoplastid protozoon Trypanosoma cruzi, is the first cause of cardiac morbidity and mortality in poor rural and suburban areas of Latin America and the largest parasitic disease burden in the continent, now spreading worldwide due to international migrations. A recent change in the scientific paradigm on the pathogenesis of chronic Chagas disease has led to a consensus that all T. cruzi seropositive patients should receive etiological treatment. This important scientific advance has spurred the rigorous evaluation of the safety and efficacy of currently available drugs (benznidazole and nifurtimox) as well as novel anti T. cruzi drug candidates in chronic patients, who were previously excluded from such treatment. The first results indicate that benznidazole is effective in inducing a marked and sustained reduction in the circulating parasites' level in the majority of these patients, but adverse effects can lead to treatment discontinuation in 10-20% of cases. Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, are better tolerated but their efficacy at the doses and treatment duration used in the initial studies was significantly lower; such results are probably related to suboptimal exposure and/or treatment duration. Combination therapies are a promising perspective but the lack of validated biomarkers of response to etiological treatment and eventual parasitological cures in chronic patients remains a serious challenge. PMID- 25284066 TI - Biodistribution of X-ray iodinated contrast agent in nano-emulsions is controlled by the chemical nature of the oily core. AB - In this study, we investigated the role of the chemical nature of the oil droplet core of nano-emulsions used as contrast agents for X-ray imaging on their pharmacokinetics and biodistribution. To this end, we formulated PEGylated nano emulsions with two iodinated oils (i.e., iodinated monoglyceride and iodinated castor oil) and compared them with another iodinated nano-emulsion based on iodinated vitamin E. By using dynamic light scattering and transmission electron microscopy, the three iodinated nano-emulsions were found to exhibit comparable morphologies, size, and surface composition. Furthermore, they were shown to be endowed with very high iodine concentration, which leads to stronger X-ray attenuation properties as compared to the commercial iodinated nano-emulsion Fenestra VC. The three nano-emulsions were i.v. administered in mice and monitored by microcomputed tomography (micro-CT). They showed high contrast enhancement in blood with similar half-life around 6 h but very different accumulation sites. While iodinated monoglycerides exhibited low accumulation in liver and spleen, high accumulation in spleen was observed for iodinated castor oil and in liver for vitamin E. These data clearly highlighted the important role of the oil composition of the nano-emulsion core to obtain strong X-ray contrast enhancement in specific targets such as liver, spleen, or only blood. These differences in biodistribution were partly attributed to differences in the uptake of the nanodroplets by the macrophages in vitro. Another key feature of these nano-emulsions is their long half-elimination time (several weeks), which offers sufficient retention for micro-CT imaging. This work paves the way for the design of nanoparticulate contrast agents for X-ray imaging of selected organs. PMID- 25284068 TI - A computational study of potential molecular switches that exploit Baird's rule on excited-state aromaticity and antiaromaticity. AB - A series of tentative single-molecule conductance switches which could be triggered by light were examined by computational means using density functional theory (DFT) with non-equilibrium Green's functions (NEGF). The switches exploit the reversal in electron counting rules for aromaticity and antiaromaticity upon excitation from the electronic ground state (S0) to the lowest pipi* excited singlet and triplet states (S1 or T1), as described by Huckel's and Baird's rules, respectively. Four different switches and one antifuse were designed which rely on various photoreactions that either lead from the OFF to the ON states (switches 1, 2 and 4, and antifuse 5) or from the ON to the OFF state (switch 3). The highest and lowest ideal calculated switching ratios are 1175 and 5, respectively, observed for switches 1 and 4. Increased thermal stability of the 1 ON isomer is achieved by benzannulation (switch 1B-OFF/ON). The effects of constrained electrode-electrode distances on activation energies for thermal hydrogen back-transfer from 1-ON to 1-OFF and the relative energies of 1-ON and 1 OFF at constrained geometries were also studied. The switching ratio is strongly distance-dependent as revealed for 1B-ON/OFF where it equals 711 and 148 when the ON and OFF isomers are calculated in electrode gaps with distances confined to either that of the OFF isomer or to that of the ON isomer, respectively. PMID- 25284069 TI - Assessment of professional competency and need of smoking cessation counseling for dental students. AB - PURPOSE: The aim of this study was to analyze the smoking prevalence among dental students and to assess the need for promoting tobacco education and intervention by exploring their knowledge about smoking related risk factors. The study also examined the attitudes and practices of the students toward tobacco consumption, and their responsibilities toward the community. METHODS: In total, 53 male students participated in the study (21 juniors and 32 seniors). The training program was divided into three modules, and the questionnaire was administered before and after the counseling sessions, which provided the comparative data on the students' views about smoking cessation. RESULTS: The most commonly practiced mode of tobacco consumption was found to be cigarette smoking (90.6 %), while a few consumed Gutkha (9.4%). All the junior students (100%) reported to have been benefitted by the counseling program, while 68.8% of the students from the senior group reported the same. Bivariate statistical analysis was conducted using the Pearson's chi-square test for testing the difference across the age groups. P values less than 0.05 were considered statistically significant. CONCLUSION: Curbing tobacco influence on dental students in their initial days can ensure a smoke-free life for them, as well as prevents them from feeling embarrassed or experiencing a lack of confidence while seeing their patients. Thus, tobacco education and intervention programs can motivate the students and increase their potential to be credible advisors regarding smoking cessation. PMID- 25284070 TI - Classification of neuropathic pain in cancer patients: A Delphi expert survey report and EAPC/IASP proposal of an algorithm for diagnostic criteria. AB - Neuropathic pain (NP) in cancer patients lacks standards for diagnosis. This study is aimed at reaching consensus on the application of the International Association for the Study of Pain (IASP) special interest group for neuropathic pain (NeuPSIG) criteria to the diagnosis of NP in cancer patients and on the relevance of patient-reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified 2-round Internet-based Delphi survey. Relevant topics investigated were: peculiarities of NP in patients with cancer, IASP NeuPSIG diagnostic criteria adaptation and assessment, and standardized PRO assessment for NP screening. Median consensus scores (MED) and interquartile ranges (IQR) were calculated to measure expert consensus after both rounds. Twenty-nine experts answered, and good agreement was found on the statement "the pathophysiology of NP due to cancer can be different from non cancer NP" (MED=9, IQR=2). Satisfactory consensus was reached for the first 3 NeuPSIG criteria (pain distribution, history, and sensory findings; MEDs?8, IQRs?3), but not for the fourth one (diagnostic test/imaging; MED=6, IQR=3). Agreement was also reached on clinical examination by soft brush or pin stimulation (MEDs?7 and IQRs?3) and on the use of PRO descriptors for NP screening (MED=8, IQR=3). Based on the study results, a clinical algorithm for NP diagnostic criteria in cancer patients with pain was proposed. Clinical research on PRO in the screening phase and on the application of the algorithm will be needed to examine their effectiveness in classifying NP in cancer patients. PMID- 25284071 TI - Early evoked pain or dysesthesia is a predictor of central poststroke pain. AB - Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a cerebrovascular lesion affecting the central somatosensory nervous system. Once developed, CPSP is difficult to treat, so there is an interest in identifying stroke patients at risk for the development of CPSP. This study examined if sensory abnormalities, including evoked dysesthesia, allodynia, or hyperalgesia to static and dynamic touch, cold, and pinprick, at stroke onset are a predictor for the development of CPSP. Consecutive stroke patients were recruited from a large prospective study of poststroke pain in Aarhus, Denmark, between 2007 and 2008. Patients underwent a structured pain interview and a standardized sensory examination within 4 days of admission, and a structured telephone interview was conducted after 3 and 6months. Patients who developed poststroke pain in the affected side without any other plausible cause were classified as having possible CPSP. A total of 275 stroke patients completed the study, and 29 patients (10.5%) were classified as having possible CPSP. The diagnosis was confirmed by a clinical examination in 15 of 17 patients, corresponding to a prevalence of 8.3%. The presence of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset increased the odds for CPSP at 6months by 4.6 (odds ratio; 95% confidence interval 1.5-13.9). The combination of reduced or absent sensation to pinprick or cold and early evoked pain or dysesthesia at onset increased odds by 8.0 (odds ratio; 95% confidence interval 2.6-24.8). In conclusion, early evoked pain or dysesthesia is a predictor for CPSP. PMID- 25284072 TI - Reporting of intention-to-treat analyses in recent analgesic clinical trials: ACTTION systematic review and recommendations. AB - The intention-to-treat (ITT) principle states that all subjects in a randomized clinical trial (RCT) should be analyzed in the group to which they were assigned, regardless of compliance with assigned treatment. Analyses performed according to the ITT principle preserve the benefits of randomization and are recommended by regulators and statisticians for analyses of RCTs. The objective of this study was to determine the frequency with which publications of analgesic RCTs in 3 major pain journals report an ITT analysis and the percentage of the author declared ITT analyses that include all randomized subjects and thereby fulfill the most common interpretation of the ITT principle. RCTs investigating noninvasive, pharmacologic and interventional (eg, nerve blocks, implantable pumps, spinal cord stimulators, surgery) treatments for pain, published between January 2006 and June 2013 (n=173), were included. None of the trials using experimental pain models reported an ITT analysis; 47% of trials investigating clinical pain conditions reported an ITT analysis, and 5% reported a modified ITT analysis. Of the analyses reported as ITT, 67% reported reasons for excluding subjects from the analysis, and 18% of those listing reasons for exclusion did not do so in the Methods section. Such mislabeling can make it difficult to identify traditional ITT analyses for inclusion in meta-analyses. We hope that deficiencies in reporting identified in this study will encourage authors, reviewers, and editors to promote more consistent use of the term "intention to treat" for more accurate reporting of RCT-based evidence for pain treatments. PMID- 25284073 TI - Carbon-centered radical addition to O=C of amides or esters as a route to C-O bond formations. AB - Among various types of radical reactions, the addition of carbon radicals to unsaturated bonds is a powerful tool for constructing new chemical bonds, in which the typical applied unsaturated substrates include alkenes, alkynes and imines. Carbonyl is perhaps the most common unsaturated group in nature. This work demonstrates a novel C-O bond formation through carbon-centered radical addition to the carbonyl oxygen of amide or ester, in which amide and ester groups are easily activated through the radical process. EPR spectroscopy and radical clock experiments support the radical process for this transformation, and density functional theory (DFT) calculations support the possibility of carbon-centered radical addition to the carbonyl oxygen of amides or esters. PMID- 25284074 TI - Continuous wireless pressure monitoring and mapping with ultra-small passive sensors for health monitoring and critical care. AB - Continuous monitoring of internal physiological parameters is essential for critical care patients, but currently can only be practically achieved via tethered solutions. Here we report a wireless, real-time pressure monitoring system with passive, flexible, millimetre-scale sensors, scaled down to unprecedented dimensions of 1 * 1 * 0.1 cubic millimeters. This level of dimensional scaling is enabled by novel sensor design and detection schemes, which overcome the operating frequency limits of traditional strategies and exhibit insensitivity to lossy tissue environments. We demonstrate the use of this system to capture human pulse waveforms wirelessly in real time as well as to monitor in vivo intracranial pressure continuously in proof-of-concept mice studies using sensors down to 2.5 * 2.5 * 0.1 cubic millimeters. We further introduce printable wireless sensor arrays and show their use in real-time spatial pressure mapping. Looking forward, this technology has broader applications in continuous wireless monitoring of multiple physiological parameters for biomedical research and patient care. PMID- 25284076 TI - A struggle to survive: the experience of awaiting pediatric heart transplantation. AB - Despite the establishment of heart transplantation as a life-saving therapy for children and adolescents, little research has focused on the biopsychosocial impact of the transplant process. Few studies have captured the subjective experiences of young heart transplant recipients. This study examined the experiences and perspectives of children and adolescents during the pretransplant phase of waiting for a donor organ. Grounded theory methods guided data collection and analysis. A total of 27 adolescents participated in semistructured qualitative interviews. Findings illuminate the waiting period for pediatric heart transplantation to be a pervasive experience, with consequent impact on physical, psychological, and social well-being. Participants described various biopsychosocial processes and experiences that occurred during this time, with data analysis yielding themes reflecting notions of "struggling to survive," including physical limitations, lethargy, social isolation, discomfort with physical appearance, and academic issues. This research identifies the pretransplant experience as a period framed within a text of debilitation and negative self-perceptions related to health and well-being. Supporting children and their families as they navigate this complex and uncertain journey is merited, and results invite further interventional development and research. PMID- 25284077 TI - A young adult male with peripheral artery disease. AB - A 19-year-old man was admitted with severe symptoms suggestive for bilateral occlusive disease of his lower extremities. Clinical, laboratory, and radiological evaluation established the diagnosis of Buerger's disease. Buerger's disease often poses a diagnostic challenge and requires a high degree of suspicion. Although rare for this patient's young age, it is important that a correct diagnosis is being made, because the disease process can be stopped if the patient stops smoking. PMID- 25284075 TI - Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERK pathway. AB - miR-3127-5p is a primate-specific miRNA which is down-regulated in recurrent NSCLC tissue vs. matched primary tumor tissue (N = 15) and in tumor tissue vs. normal lung tissue (N = 177). Reduced miR-3127-5p expression is associated with a higher Ki-67 proliferation index and unfavorable prognosis in NSCLC. Overexpression of miR-3127-5p significantly reduced NSCLC cells proliferation, migration, and motility in vitro and in vivo. The oncogene ABL1 was a direct miR 3127-5p target, and miR-3127-5p regulated the activation of the Abl/Ras/ERK pathway and transactivated downstream proliferation/metastasis-associated molecules. Overexpression of miR-3127-5p in A549 or H292 cells resulted in enhanced resistance to dasatinib, an Abl/src tyrosine kinase inhibitor. miR-3127 5p expression levels were correlated with dasatinib sensitivity in NSCLC cell lines without K-Ras G12 mutation. In conclusion, miR-3127-5p acts as a tumor suppressor gene and is a potential biomarker for dasatinib sensitivity in the non mutated Ras subset of NSCLC. PMID- 25284078 TI - Association between CLPTM1L-TERT rs401681 polymorphism and risk of pancreatic cancer: a meta-analysis. AB - Telomere biology plays a critical and complex role in the initiation and progression of cancer. Several recent studies have provided evidence that rs401681 polymorphisms in intronic region of cleft lip and palate trans-membrane 1-like (CLPTM1L) gene sequence are associated with pancreatic cancer (PC) development, but a comprehensive synopsis is not available. We performed a meta analysis of 6 case-control studies that included 8,253 pancreatic cancer cases and 37,646 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95 % confidence intervals (CIs). Overall, this meta analysis showed that rs401681 allele T was associated with a significantly increased PC risk (OR = 1.17, 95 % CI = 1.12-1.22, P heterpgeneity = 0.596 and I (2) = 0). Similarly, in the subgroup analysis by ethnicity, a significantly increased risk was found among Asians (OR = 1.15, 95 % CI = 1.07-1.24, P heterpgeneity = 0.297 and I (2) = 8.0 %) and among Caucasian (OR = 1.13, 95 % CI = 1.02-1.26, P heterpgeneity = 0.385 and I (2) = 0). No publication bias was found in the present study. This meta-analysis suggests that T allele of CLPTM1L telomerase reverse transcriptase rs401681 polymorphism is associated with an increased PC risk, especially among Chinese. Further large and well-designed studies are needed to confirm this association. PMID- 25284079 TI - Arabidopsis acyl-CoA-binding protein ACBP3 participates in plant response to hypoxia by modulating very-long-chain fatty acid metabolism. AB - In Arabidopsis thaliana, acyl-CoA-binding proteins (ACBPs) are encoded by a family of six genes (ACBP1 to ACBP6), and are essential for diverse cellular activities. Recent investigations suggest that the membrane-anchored ACBPs are involved in oxygen sensing by sequestration of group VII ethylene-responsive factors under normoxia. Here, we demonstrate the involvement of Arabidopsis ACBP3 in hypoxic tolerance. ACBP3 transcription was remarkably induced following submergence under both dark (DS) and light (LS) conditions. ACBP3-overexpressors (ACBP3-OEs) showed hypersensitivity to DS, LS and ethanolic stresses, with reduced transcription of hypoxia-responsive genes as well as accumulation of hydrogen peroxide in the rosettes. In contrast, suppression of ACBP3 in ACBP3-KOs enhanced plant tolerance to DS, LS and ethanol treatments. By analyses of double combinations of OE-1 with npr1-5, coi1-2, ein3-1 as well as ctr1-1 mutants, we observed that the attenuated hypoxic tolerance in ACBP3-OEs was dependent on NPR1 and CTR1-mediated signaling pathways. Lipid profiling revealed that both the total amounts and very-long-chain species of phosphatidylserine (C42:2- and C42:3 PS) and glucosylinositolphosphorylceramides (C22:0-, C22:1-, C24:0-, C24:1-, and C26:1-GIPC) were significantly lower in ACBP3-OEs but increased in ACBP3-KOs upon LS exposure. By microscale thermophoresis analysis, the recombinant ACBP3 protein bound VLC acyl-CoA esters with high affinities in vitro. Further, a knockout mutant of MYB30, a master regulator of very-long-chain fatty acid (VLCFA) biosynthesis, exhibited enhanced sensitivities to LS and ethanolic stresses, phenotypes that were ameliorated by ACBP3-RNAi. Taken together, these findings suggest that Arabidopsis ACBP3 participates in plant response to hypoxia by modulating VLCFA metabolism. PMID- 25284080 TI - Semi-quantitative data on ethanol consumption in 354 ET cases and 370 controls. AB - The notion that there is an association between essential tremor (ET) and higher ethanol consumption has crept into the literature; however, the data are limited and conflicted. A total of 354 ET cases and 370 matched controls were enrolled in a clinical-epidemiological study. Average current daily ethanol consumption was estimated using the Willett Semi-quantitative Food Frequency Questionnaire. The proportion of cases and controls who drank any ethanol was similar: 66.7% vs. 64.1%, p=0.46, as was the proportion who reported heavy ethanol consumption: 4.0% vs. 3.5%, p=0.74. The average daily ethanol intake was numerically higher in cases than controls (7.99 +/- 12.39 [median=3.03] vs. 6.55 +/- 10.62 [median=1.80] g), but this difference did not reach significance (p=0.15). Among cases, there was no correlation between average daily ethanol intake and tremor severity (r=0.008, p=0.88). These data, on more than 700 enrollees, do not support any sizable differences between ET cases and controls in terms of average daily ethanol consumption or ethanol overuse. The absence of a correlation in cases between ethanol consumption and tremor severity goes against the hypothesis that ET patients are self-medicating to a significant degree. PMID- 25284081 TI - C9orf72 hexanucleotide repeat expansion analysis in Chinese spastic paraplegia patients. AB - BACKGROUND: Recently, a hexanucleotide repeat expansion in the C9orf72 gene has been identified to cause frontotemporal dementia, amyotrophic lateral sclerosis families and many other neurodegenerative diseases. Owing to the overlapping phenotypes among HSP, frontotemporal dementia and amyotrophic lateral sclerosis we hypothesized that C9orf72 expansions might be a genetic risk factor or modifier of HSP. OBJECTIVES: The aim of this study was to find out whether C9orf72 expansions also confer risk to spastic paraplegia (SPG). METHODS: We recruited 112 genetically unidentified SPG patients, 68 SPG4 patients and 313 controls in mainland China to determine if hexanucleotide repeat of C9orf72 plays a role in spastic paraplegia. RESULTS: No large expansion was detected in all subjects. C9orf72 repeat expansions were not associated with onset of HSP. CONCLUSION: Our results support the notion that repeat expansions in C9orf72 may not be associated with HSP in China. PMID- 25284082 TI - Primary progressive aphasia with occipital impairment. PMID- 25284083 TI - Acute recanalization and hyperperfusion in MCA territory due to sole t-PA bolus. A case report. PMID- 25284084 TI - A case of Andersen-Tawil syndrome presenting periodic paralysis exacerbated by acetazolamide. PMID- 25284085 TI - Unravelling the mechanism of non-ribosomal peptide synthesis by cyclodipeptide synthases. AB - Cyclodipeptide synthases form cyclodipeptides from two aminoacyl transfer RNAs. They use a ping-pong mechanism that begins with transfer of the aminoacyl moiety of the first aminoacyl tRNA onto a conserved serine, yielding an aminoacyl enzyme. Combining X-ray crystallography, site-directed mutagenesis and affinity labelling of the cyclodipeptide synthase AlbC, we demonstrate that the covalent intermediate reacts with the aminoacyl moiety of the second aminoacyl tRNA, forming a dipeptidyl enzyme, and identify the aminoacyl-binding sites of the aminoacyl tRNAs. PMID- 25284086 TI - Update on the efficacy of pharmacotherapy for social anxiety disorder: a meta analysis. AB - INTRODUCTION: Social anxiety disorder (SAD) is a common mental health problem that tends to be chronic in nature; fortunately, effective pharmacotherapy options exist. The current study provides an updated meta-analytic review of their efficacy and potential guidelines for their application in SAD. METHODS: A comprehensive search of the current literature yielded 39 randomized, pill placebo-controlled trials of pharmacotherapy for adults diagnosed with SAD. Data on potential moderators of treatment outcome were collected, as well as data necessary to calculate effect sizes using Hedges's g. RESULTS: The overall effect size of pharmacotherapy for SAD is small to medium (Hedges's g = 0.39). The most effective pharmacotherapy type was phenelzine (Hedges's g = 1.14), followed by paroxetine (Hedges's g = 0.49), venlafaxine ER (Hedges's g = 0.45) and moclobemide (Hedges's g = 0.23). CONCLUSION: Effect sizes were not moderated by age, sex, length of treatment, diagnostic subtype initial severity, maximum potential dose, or publication year. It is concluded that pharmacotherapy is effective for treating SAD, but there is considerable variation and room for further improvement. Future directions may include pharmacological enhancement of psychological processes, such as d-cycloserine augmentation of exposure procedures. PMID- 25284087 TI - The development of route learning in Down syndrome, Williams syndrome and typical development: investigations with virtual environments. AB - The ability to navigate new environments has a significant impact on the daily life and independence of people with learning difficulties. The aims of this study were to investigate the development of route learning in Down syndrome (N = 50), Williams syndrome (N = 19), and typically developing children between 5 and 11 years old (N = 108); to investigate use of landmarks; and to relate cognitive functions to route-learning ability in these groups. Overall, measures of attention and long-term memory were strongly associated with route learning, even once non-verbal ability was controlled for. All of the groups, including 5- to 6 year-old TD children, demonstrated the ability to make use of all landmark types to aid route learning; those near junctions, those further from junctions, and also distant landmarks (e.g. church spire, radio mast). Individuals with WS performed better than a matched subset of TD children on more difficult routes; we suggest that this is supported by relatively strong visual feature recognition in the disorder. Participants with DS who had relatively high levels of non verbal ability performed at a similar level to TD participants. PMID- 25284089 TI - Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial. AB - OBJECTIVE: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS: Patients with Morquio A syndrome aged >=5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. RESULTS: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. CONCLUSIONS: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population. PMID- 25284090 TI - TTV DNA plasma load and its association with age, gender, and HCMV IgG serostatus in healthy adults. AB - Understanding immunosenescence and changes in antimicrobial immune response with age is of high importance. The association of immunosenescence with gender and persistent infection with human cytomegalovirus (HCMV) is a matter of intensive research. We determined whether replication of another persistent and highly prevalent virus, Torque teno virus (TTV), is related to age, gender, and HCMV IgG serostatus of the host. TTV DNA load in plasma was assessed by real-time PCR in 313 healthy persons: 20-30 years old (young, n = 104), 50-60 years old (middle aged, n = 101), or >80 years old (elderly, n = 108). TTV DNA loads were further associated with age-groups, gender, and HCMV IgG serostatus. TTV load was significantly higher in the elderly compared to the young group (p < 0.001; Tukey's honest significant difference (HSD)), and the higher TTV DNA levels over age were found to be gender-specific (p = 0.002; ANOVA), with young women showing the lowest TTV load compared to young men (p = 0.009, t test) and compared to the other female age-groups (middle-aged p = 0.005; elderly p < 0.001; Tukey's HSD). TTV load of HCMV IgG-seropositive persons was significantly higher than that of the HCMV IgG seronegative in the young (p = 0.005; t test) and middle-aged (p = 0.016; t test) groups. These results indicate that the host's immune control of TTV replication decreases with age and is gender-specific. Persistent HCMV infection is significantly related to higher TTV DNA loads, especially at a younger age. Therefore, the influence of gender and HCMV on immunosenescence earlier in life should be further explored. PMID- 25284091 TI - Transcriptional regulators in the Hippo signaling pathway control organ growth in Xenopus tadpole tail regeneration. AB - The size and shape of tissues are tightly controlled by synchronized processes among cells and tissues to produce an integrated organ. The Hippo signaling pathway controls both cell proliferation and apoptosis by dual signal transduction states regulated through a repressive kinase cascade. Yap1 and Tead, transcriptional regulators that act downstream of the Hippo signaling kinase cascade, have essential roles in regulating cell proliferation. In amphibian limb or tail regeneration, the local tissue outgrowth terminates when the correct size is reached, suggesting that organ size is strictly controlled during epimorphic organ-level regeneration. We recently demonstrated that Yap1 is required for the regeneration of Xenopus tadpole limb buds (Hayashi et al., 2014, Dev. Biol. 388, 57-67), but the molecular link between the Hippo pathway and organ size control in vertebrate epimorphic regeneration is not fully understood. To examine the requirement of Hippo pathway transcriptional regulators in epimorphic regeneration, including organ size control, we inhibited these regulators during Xenopus tadpole tail regeneration by overexpressing a dominant-negative form of Yap (dnYap) or Tead4 (dnTead4) under a heat-shock promoter in transgenic animal lines. Each inhibition resulted in regeneration defects accompanied by reduced cell mitosis and increased apoptosis. Single-cell gene manipulation experiments indicated that Tead4 cell-autonomously regulates the survival of neural progenitor cells in the regenerating tail. In amphibians, amputation at the proximal level of the tail (deep amputation) results in faster regeneration than that at the distal level (shallow amputation), to restore the original-sized tail with similar timing. However, dnTead4 overexpression abolished the position dependent differential growth rate of tail regeneration. These results suggest that the transcriptional regulators in the Hippo pathway, Tead4 and Yap1, are required for general vertebrate epimorphic regeneration as well as for organ size control in appendage regeneration. In regenerative medicine, these findings should contribute to the development of three-dimensional organs with the correct size for a patient's body. PMID- 25284092 TI - Nurses' roles in direct nursing care delivery in China. AB - AIM: To study the nurses' roles in direct nursing care delivery in the neurology ward in China. BACKGROUND: As patients' demands for healthcare have increased, the quality of the nursing service has become a focus of attention. Nurses play an important role in the delivery of care and can affect the quality of patient care. METHODS: This was a non-participation, observational, time-task/activity study. All nursing care providers were observed during two shifts (16 hours) as constituents of the workload to explain the nurses' roles. RESULTS: An astonishingly low percentage (25.6%) of the total patient care workload was conducted by registered nurses. The rest of the care was provided by nursing students (10.5%), health care assistants (21%), and a substantial portion by the patients' relatives (43.7%). CONCLUSIONS: Nurses' roles in direct nursing care delivery are inadequate in China. Nurse staffing and allocation must meet the increasing demand from clients to secure the highest quality and safety of healthcare. PMID- 25284093 TI - Chronic eye disease and the WHO Universal Eye Health Global Action Plan 2014 2019. PMID- 25284095 TI - Relative importance of the components of the Canadian Residency Matching Service application. AB - OBJECTIVE: The primary goal of this project was to investigate Canadian ophthalmology residency program directors' and department heads' perceptions about the relative importance of the various components of the Canadian Residency Matching Service (CaRMS) application package. Secondary goals were: (i) to investigate the perceptions of all program directors and department heads at Queen's University's residency programs; and (ii) to compare faculty's perceptions with the perceptions of medical students at Queen's University. DESIGN: Survey. PARTICIPANTS: Queen's University medical students, Queen's University faculty, and Canadian Ophthalmology faculty participated in this survey. METHODS: A validated survey was administered to faculty and students. The study targeted program directors and department heads of 15 Canadian ophthalmology residency programs, 18 residency programs at Queen's University, as well as 404 medical students at Queen's University. Qualitative questions were included in the faculty survey. Quantitative data were analyzed with nonparametric tests. Qualitative data were organized according to primary themes. RESULTS: Response rates ranged from 64% to 87%. On a scale of 1 to 4 in order of increasing importance, faculty and students respectively assigned the highest scores to the following components: interview performance (3.73, 3.89), electives (3.64, 3.83), reference letters (3.53, 3.74), and personal letter (3.27, 3.58). For all 4 components, student scores were significantly higher than faculty scores. First- and fourth-year medical students' scores differed significantly in eight areas including research experience and volunteer experience. In both of these components, there were statistical differences between fourth-year student scores and faculty scores, whereas the first-year class had scores that were comparable with faculty scores. Queen's University faculty and Ophthalmology faculty did not differ significantly. Faculty scores also did not differ significantly based on age or sex. CONCLUSIONS: Faculty and students agreed on the most important components of the application, but significant differences were found in their perceptions of the relative importance of other components. PMID- 25284096 TI - Outcome of viscodilation and tensioning of Schlemm's canal for uveitic glaucoma. AB - OBJECTIVE: To evaluate the safety and efficacy of circumferential viscodilation and tensioning of Schlemm's canal (canaloplasty) in the treatment of uveitic glaucoma (UG). DESIGN: Pilot, retrospective, noncomparative case series. PARTICIPANTS: Nineteen uveitic eyes of 15 patients with UG. METHODS: The main outcome measure was surgical success. Secondary outcome measures included intraocular pressure, usage of ocular hypotensive medication, visual acuity, and sight-threatening complications. Patients were included when UG could not be controlled despite maximum tolerated medical therapy. Exclusion criteria were peripheral anterior synechiae and previous glaucoma surgery. RESULTS: Mean follow up time from canaloplasty was 2.6 +/- 1.1 years. Mean intraocular pressure decreased from 30.4 +/- 8.4 mm Hg preoperatively to 13.8 +/- 5.0 mm Hg at last follow-up (p < 0.001). The mean number of ocular hypotensive medications decreased from 3.7 +/- 0.8 preoperatively to 0.4 +/- 1.0 at last follow-up (p < 0.001). At last follow-up, the complete success, qualified success, and failure rates were 73.7%, 10.5%, and 15.8%, respectively. No canaloplasty-related permanent sight-reducing complications occurred. Preoperative best corrected visual acuity decreased more than 1 Snellen line in 1 eye due to exacerbation of uveitis 18 months postoperatively. CONCLUSIONS: Canaloplasty appears to be a relatively safe and effective initial surgical intervention in UG. PMID- 25284097 TI - Symptoms reported by patients with varying stages of glaucoma: review of 401 cases. AB - OBJECTIVE: To elucidate the symptoms that patients with glaucoma voluntarily report and to determine the correlation between the symptoms and the stage of glaucoma. DESIGN: Retrospective case series. PARTICIPANTS: A total of 401 patients who presented to the Glaucoma Service from January 2012 through November 2013. METHODS: The Wills Eye Hospital Glaucoma Research Center retrospectively reviewed the medical records of patients who visited the Glaucoma Service from January 2012 through November 2013. We recorded any symptom written in the charts at the last eligible visit of each patient. The patients were classified by different stages according to the mean deviation of the Octopus visual field. RESULTS: We analyzed 401 patients, who were graded with mild (n = 170), moderate (n = 106), or severe (n = 125) visual-field loss. The majority of patients did not report any symptoms (56.0%); 24.2% reported ocular surface disease (OSD) symptoms; and 25.8% reported visual complaints. The presence of symptoms positively correlated with the severity of glaucoma (p = 0.01) and the number of surgeries (p = 0.02). Burning/smarting/stinging and blurry vision showed a positive correlation with the severity of glaucoma (p < 0.05). Older patients (> 69 years) showed a significant increase in OSD symptoms (p = 0.001). CONCLUSIONS: About one-fourth of the patients with glaucoma reported visual complaints, and another fourth reported OSD symptoms, both of which correlated with glaucoma severity. The high prevalence of OSD symptoms suggests that patients should be specifically questioned about these symptoms and treated as indicated. This information is of value particularly in the new era of nonpreserved glaucoma medications. PMID- 25284098 TI - Antioxidant properties of amniotic membrane: novel observations from a pilot study. AB - OBJECTIVE: Amniotic membrane (AM) is used to manage various debilitated ocular surface conditions. The impact of oxidative stress and free radicals on the ocular surface is increasingly being recognized. Hyaluronic acid (HA) has anti inflammatory properties and is abundantly present in AM. In this in vitro pilot study, we investigated the potential of AM for intrinsic free radical scavenging properties. METHODS: Strips of AM were incubated in sealed tubes with hydrogen peroxide (H2O2). After being sonicated, uptake of reactive oxygen species (ROS) was measured by the Amplex Red Hydrogen Peroxide/Peroxidase assay. For comparison, 1630 kDA HA was used. RESULTS: There was uptake of ROS by all AM samples, which decreased with increasing concentrations of H2O2. Mean ROS uptake for 5 different AMs at 1 hour was significantly greater for 50 MUM (83%; SD 11.7, SEM 5.23) compared with 100 MUM (67%; SD 20.48, SEM 9.16; p = 0.028; 95% CI 2.8 29.2). The HA comparison group showed similar uptake and trend. CONCLUSION: This pilot study demonstrates that AM is able to remove ROS from its environment. Demonstrating total antioxidant capacity in AM provides evidence for use as a free radical scavenger. The antioxidant properties of AM and the contribution from HA require more research. PMID- 25284099 TI - Switch to a single dose of aflibercept in bevacizumab nonresponders with AMD. AB - OBJECTIVE: This study aimed to report on the efficacy of 1 dose of aflibercept in bevacizumab nonresponders. DESIGN: This was a retrospective, single-centre, interventional, noncomparative study. PARTICIPANTS: This study retrospectively analyzed 23 patients with persistent intraretinal or subretinal fluid treated with 6 or more monthly bevacizumab injections. METHODS: Patients were switched to 1 dose of aflibercept and afterward continued their therapy with bevacizumab for at least another 6 months. We performed spectral domain optical coherence tomography monthly and evaluated visual acuity, central retinal thickness, and photoreceptor defects. The main outcome measures were visual and anatomic outcome 1 and 6 months after administering aflibercept. RESULTS: Visual acuity significantly improved (p = 0.01) after the switch to aflibercept (from 0.39 to 0.49 Snellen). This improvement was stable for the remaining 6 months of the study (final visual acuity, 0.46 Snellen); 47% of patients experienced an improvement of at least 5 letters from baseline on a chart of the ETDRS type (Early Treatment Diabetic Retinopathy Study). Central retinal thickness decreased from 521 um to 446 um (p = 0.01) and remained stable for the next 6 months (452 um). Complete resolution of intraretinal and subretinal fluid was observed in 30% of eyes. CONCLUSIONS: In bevacizumab nonresponders, switching to a single dose of aflibercept before continuing the therapy with bevacizumab improves visual outcome and anatomic results. PMID- 25284100 TI - Outer retinal morphological changes and visual function after removal of epiretinal membrane. AB - OBJECTIVE: To determine the relation between the recovery of the cone outer segment tips (COST) line and the best-corrected visual acuity (BCVA) after epiretinal membrane (ERM) surgery. DESIGN: Retrospective, consecutive, interventional case series. PARTICIPANTS: Sixty-one eyes of 56 patients with an idiopathic ERM were studied. All participants underwent a complete ophthalmic examination including spectral-domain optical coherence tomography before and after ERM removal surgery. METHODS: The integrities of the photoreceptor layer including the external limiting membrane line, photoreceptor inner segment/outer segment (IS/OS) line, and COST line in the spectral-domain optical coherence tomography images at the fovea were determined. The associations of these morphological parameters to the BCVA were determined. RESULTS: Better BCVAs were found more frequently in eyes with an intact COST line than in eyes with a disrupted or absent COST line at 1 (p < 0.001), 6 (p = 0.003), and 12 months (p < 0.001). Among the external limiting membrane, IS/OS, and COST line parameters, the IS/OS line had higher correlations with the BCVA by multivariate analysis. No significant difference was observed in central retinal thickness between eyes with intact and nonintact COST lines. Eight (30.8%) of 26 eyes with BCVA >= 20/20 had nonintact COST lines at 12 months after the ERM surgery. CONCLUSIONS: Eyes with an intact COST line had better BCVA after ERM surgery. However, even at 12 months after ERM surgery, COST lines remained disrupted in many eyes with good BCVA. PMID- 25284101 TI - Rapamycin inhibits oxidative and angiogenic mediators in diabetic retinopathy. AB - OBJECTIVE: To evaluate the role of rapamycin in the prevention of diabetic oxidative stress and the regulation of angiogenic factors. DESIGN: Experimental animal study. METHODS: Diabetes was induced in 20 adult male Wistar rats by a single intraperitoneal administration of streptozotocin (60 mg/kg). Rats were randomly assigned into diabetic and rapamycin groups (n = 10). Ten healthy normal adult male rats of same age formed the control group. All groups were followed for 3 months. Rapamycin group received 1 mg/kg rapamycin via orogastric gavage during the last 4 weeks. At the end of 12 weeks, rats were sacrificed and biochemical oxidative stress markers (malondialdehyde and nitrotyrosine), together with vascular endothelial growth factor, hypoxia-inducible factor 1alpha, and pigment epithelium-derived factor, were measured in the retina. Blood biochemical analyses were also done. RESULTS: In the diabetic group, retinal malondialdehyde and nitrotyrosine levels were increased in comparison with control and rapamycin groups (p < 0.05). Rapamycin suppressed oxidative stress and showed a beneficial effect. It also decreased all angiomodulator cytokines compared with the diabetic group (p < 0.05). Correspondingly, rapamycin also decreased plasma malondialdehyde levels compared with the diabetic group (p = 0.037). CONCLUSIONS: Rapamycin may have a protective role against diabetes induced oxidative retinal injury and may decrease angiomodulator cytokines. PMID- 25284102 TI - Intravitreal bevacizumab for retinal capillary hemangioblastoma: A case series and literature review. AB - OBJECTIVE: To evaluate the long-term outcomes of intravitreal bevacizumab for peripheral and juxtapapillary retinal capillary hemangioblastoma (RCH). DESIGN: We conducted a retrospective noncomparative interventional case series. PARTICIPANTS: There were 4 patients (5 eyes) presenting with RCH. METHODS: Five eyes with RCH presented with exudative changes and visual loss. Three eyes of 2 patients with peripheral RCH were treated with cryotherapy and 2 intravitreal injections of bevacizumab (0.5 mg). Two eyes with juxtapapillary RCH were treated with 3 intravitreal injections of bevacizumab. The main outcome measures were changes in best-corrected visual acuity (BCVA), lesion size, exudation, and retinal thickness. RESULTS: In peripheral RCH, improvement of BCVA from counting fingers to 20/400 was obtained in 1 eye. One patient with bilateral RCH maintained a vision of 20/20 in 1 eye with complete anatomic regression of the 3 small peripheral RCH lesions. The fellow eye with fibrotic bands from the RCH to the optic nerve head developed a tractional retinal detachment after the first injection and was treated with pars plana vitrectomy. In patients with juxtapapillary RCH, bevacizumab injections resulted in an improvement of BCVA from 20/80 to 20/20 in 1 eye, whereas the second eye did not show an improvement of BCVA despite a regression of the tumour. CONCLUSIONS: Intravitreal anti vascular endothelial growth factor agents, alone or in combination with other treatment modalities, may improve visual acuity. Further trials evaluating the dose, the number of injections, and the route of administration will be important in advancing antiangiogenic therapies for RCH. PMID- 25284103 TI - Treatment of ocular metastasis with anti-VEGF: a literature review and case report. AB - PURPOSE: This is the first case report where 1.25mg intravitreal bevacizumab (IVB) correlated with choroidal mass resolution from metastatic breast cancer given concurrently with chemotherapy demonstrating, at best, disease stability in other organs. STUDY DESIGN: Case report. METHODS: Upon confirmation of choroidal, liver and bone metastasis from breast carcinoma, a 72-year-old female received four intravitreal bevacizumab 1.25mg injections based on the presence of subretinal and intraretinal fluid. Visual outcomes were analyzed by ophthalmologic evaluation, B-scan, fluorescein angiography, and optical coherence tomography. RESULTS: After 3 treatments of 1.25mg intravitreal bevacizumab, visual acuity improved from 20/125 OD to 20/30 OD. These results were maintained for 5 months, after which a 4th IVB injection was given to try to further improve visual outcomes. Following this, complete resolution of the mass was observed with remaining pigmentary changes and vision improved to 20/25 one month following this. IVB was administered concurrently to systemic chemotherapy that demonstrated at best disease stability in metastases in other organs. CONCLUSION: In this case 1.25mg intravitreal bevacizumab proved to be a safe, effective and relatively easy treatment for choroidal metastasis from breast cancer. An important benefit of intravitreal bevacizumab therapy for choroidal metastasis is the ease of administration and minimal time commitment required as compared to other therapies. Further studies should be conducted to confirm the appropriate dosing and long-term outcomes of intravitreal bevacizumab to treat choroidal metastasis. PMID- 25284104 TI - Primary transpupillary thermotherapy for choroidal indeterminate melanocytic lesions. AB - OBJECTIVE: This study aimed to assess the ocular and metastatic outcomes of patients with choroidal indeterminate melanocytic lesions treated by primary transpupillary thermotherapy (TTT). DESIGN: Retrospective case series. PARTICIPANTS: Eight patients presenting choroidal indeterminate melanocytic lesions treated by primary TTT. METHODS: A retrospective chart review was conducted for patients with a newly diagnosed choroidal indeterminate melanocytic lesion treated by at least 3 TTT sessions from 2002 to 2011. Best-corrected visual acuity and lesion dimensions were measured at baseline and during follow up. Complications were recorded including lesion growth, metastasis, melanoma related mortality, and treatment-related complications. RESULTS: Mean initial thickness was 2.0 +/- 0.8 mm. Patients had an average of 3.0 +/- 0.9 risk factors for lesion growing. Three patients (38%) had lesion growth. Two patients (25%) had severe visual loss (>1.0 logMAR) directly related to TTT treatment. There were no fatalities due to metastasis. CONCLUSIONS: Despite careful patient selection and systematic treatment with at least 3 TTT sessions, the use of primary TTT to treat patients with choroidal indeterminate melanocytic lesions with >= 1 risk factor for lesion growth yielded poor local lesion control and the possibility for severe ocular complications. PMID- 25284105 TI - Periocular mass lesions secondary to dermatologic fillers: report of 3 cases. AB - OBJECTIVE: To describe findings in patients who received dermal fillers and later developed peri-ocular mass lesions. DESIGN: Retrospective case series. PARTICIPANTS: Patients who presented with peri-ocular masses secondary to dermal filler use. METHODS: Retrospective chart review. RESULTS: Three patients with remote filler injection (hyaluronic acid and polyalkylimide), not volunteered on initial history, presented with peri-orbital swelling and/or inflammation that was suspicious in each case for more serious pathology. CONCLUSIONS: It is important for the injecting physician, the ophthalmologist, and the patient to recognize this complication to permit appropriate investigation and management. PMID- 25284106 TI - Neuro-ophthalmic presentations and treatment of Cryptococcal meningitis-related increased intracranial pressure. AB - OBJECTIVE: To illustrate three different ophthalmic presentations of cryptococcal meningitis (CM). INTRODUCTION: CM is the most common manifestation of extra pulmonary cryptococcosis. Intracranial hypertension occurs in up to 75% of patients with CM and is associated with increased mortality. CM can present to the ophthalmologist as vision loss, papilledema, abducens palsy, and/or other cranial neuropathies. PARTICIPANTS AND METHODS: We report three cases, two C. neoformans and one C. gattii, highlighting the various CM presentations. The first was a woman immunosuppressed following kidney transplantation in whom idiopathic intracranial hypertension (IIH) was initially suspected. The second was a man immunocompromised by previously undiagnosed HIV/AIDS who presented with signs and symptoms of increased intracranial pressure. The third case is an immunocompetent man with bilateral disc edema and an incomplete macular star diagnosed with presumed neuroretinitis. Further evaluation revealed positive CSF cryptococcal antigen with culture positive for C. gattii. CONCLUSIONS: Ophthalmologists should be aware that cryptococcosis can mimic more benign etiologies including IIH and neuroretinitis. Additionally, C. gattii, an emerging organism, can infect immunocompetent patients. In contrast to the typical treatment of increased ICP, serial lumbar punctures are recommended while acetazolamide and surgical CSF shunting may be harmful. PMID- 25284107 TI - Re: Intravitreal triamcinolone acetonide as an adjuvant in the management of acute retinal necrosis. PMID- 25284108 TI - Consecutive cyclic esotropia after surgery for intermittent exotropia. PMID- 25284109 TI - Solitary fibrous tumour of the lacrimal sac presenting with recurrent dacryocystitis. PMID- 25284110 TI - Traumatic complete evulsion of the globe and optic nerve. PMID- 25284111 TI - Unilateral primary cutaneous amyloidosis of the eyelid masquerading as a chalazion. PMID- 25284112 TI - Case of rapid bilateral cataract development in teenager using selective serotonin reuptake inhibitors. PMID- 25284113 TI - Temporal changes in a giant macular hole formed secondary to toxoplasmic retinochoroiditis. PMID- 25284114 TI - Delayed lymph node metastasis of excised caruncular sebaceous carcinoma in an atypical demographic. PMID- 25284115 TI - Transient homonymous hemianopia caused by cerebral venous sinus thrombosis: case report. PMID- 25284116 TI - Proton beam radiotherapy of progressive pediatric choroidal osteoma: first experience. PMID- 25284117 TI - Peripheral retinal ischemia after intravenous tissue plasminogen activator for central retinal artery occlusion. PMID- 25284118 TI - Bilateral retinal detachment in Seckel syndrome. PMID- 25284119 TI - Selective remanent ambipolar charge transport in polymeric field-effect transistors for high-performance logic circuits fabricated in ambient. AB - Ambipolar polymeric field-effect transistors can be programmed into a p- or n type mode by using the remanent polarization of a ferroelectric gate insulator. Due to the remanent polarity, the device architecture is suited as a building block in complementary logic circuits and in CMOS-compatible memory cells for non destructive read-out operations. PMID- 25284120 TI - Differentiation of canine bone marrow stromal cells into voltage- and glutamate responsive neuron-like cells by basic fibroblast growth factor. AB - We investigated the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into voltage- and glutamate-responsive neuron-like cells. BMSCs were obtained from the bone marrow of healthy beagle dogs. Canine BMSCs were incubated with the basal medium for neurons containing recombinant human basic fibroblast growth factor (bFGF; 100 ng/ml). The viability of the bFGF-treated cells was assessed by a trypan blue exclusion assay, and the morphology was monitored. Real time RT-PCR was performed to evaluate mRNA expression of neuronal, neural stem cell and glial markers. Western blotting and immunocytochemical analysis for the neuronal markers were performed to evaluate the protein expression and localization. The Ca(2+) mobilization of the cells was evaluated using the Ca(2+) indicator Fluo3 to monitor Ca(2+) influx. To investigate the mechanism of bFGF induced neuronal differentiation, the fibroblast growth factor receptor inhibitor, the phosphoinositide 3-kinase inhibitor or the Akt inhibitor was tested. The bFGF treatment resulted in the maintenance of the viability of canine BMSCs for 10 days, in the expression of neuronal marker mRNAs and proteins and in the manifestation of neuron-like morphology. Furthermore, in the bFGF-treated BMSCs, a high concentration of KCl and L-glutamate induced an increase in intracellular Ca(2+) levels. Each inhibitor significantly attenuated the bFGF induced increase in neuronal marker mRNA expression. These results suggest that bFGF contributes to the differentiation of canine BMSCs into voltage- and glutamate-responsive neuron-like cells and may lead to the development of new cell-based treatments for neuronal diseases. PMID- 25284121 TI - Parathyroid carcinoma in the setting of tertiaryhyperparathyroidism after renal transplant. PMID- 25284123 TI - Fertility preservation in the female cancer patient. AB - Hundreds of thousands of young women are diagnosed with cancer each year, but due to advances in screening, diagnosis, and treatment, survival rates have improved dramatically. With improved survival, long-term effects of cancer treatment including infertility need to be addressed and should be discussed as soon as possible. Oncologists should be familiar with their patients' risks of infertility and available options for fertility preservation and future reproduction. PMID- 25284122 TI - Case report: adrenal oncocytoma associated with markedly increased FDG uptake and immunohistochemically positive for GLUT1. AB - Usually, benign tumors are not associated with an increased F-18 fluorodeoxyglucose (F-18 FDG) uptake on positron emission tomography (PET), although some exceptions have been reported in adrenal neoplasms. We present a rare case of adrenocortical oncocytoma associated with markedly increased FDG uptake, demonstrating a maximum standardized uptake value of 46.8. Histological examination demonstrated diffuse proliferation of tumor cells with eosinophilic and granular cytoplasm that were diffusely immunopositive for mitochondria and glucose transport protein 1, with focal and weak immunopositivity for 3beta hydroxysteroid dehydrogenase. Ultrastructural examination also revealed abundant mitochondria in the tumor cells. The tumor was diagnosed as adrenocortical oncocytoma and was considered benign according to Lin-Weiss-Bisceglia criteria. Diagnosis of adrenocortical oncocytoma can pose difficulties during both preoperative radiological and postoperative histopathological investigations. PMID- 25284124 TI - Forming buried junctions to enhance the photovoltage generated by cuprous oxide in aqueous solutions. AB - Whereas wide-bandgap metal oxides have been extensively studied for the photooxidation of water, their utilization for photoreduction is relatively limited. An important reason is the inability to achieve meaningful photovoltages with these materials. Using Cu2 O as a prototypical photocathode material, it is now shown that the photovoltage barrier can be readily broken by replacing the semiconductor/water interface with a semiconductor/semiconductor one. A thin ZnS layer (ca. 5 nm) was found to form high-quality interfaces with Cu2 O to increase the achievable photovoltage from 0.60 V to 0.72 V. Measurements under no net exchange current conditions confirmed that the change was induced by a thermodynamic shift of the flatband potentials rather than by kinetic factors. The strategy is compatible with efforts aimed at stabilizing the cathode that otherwise easily decomposes and with surface catalyst decorations for faster hydrogen evolution reactions. A combination of NiMo and CoMo dual-layer alloy catalysts was found to be effective in promoting hydrogen production under simulated solar radiation. PMID- 25284125 TI - Alpha thalassemia allelic frequency in Lebanon. AB - BACKGROUND: Hemoglobinopathies are the most common reported monogenic disorders worldwide. It is well established that Mediterranean and Arab countries are high risk areas for thalassemia in general, and for alpha thalassemia in particular. Reports of alpha thalassemia gene mutations from the Lebanese population are limited. PROCEDURE: We investigated the spectrum of alpha thalassemia mutations in a sample of 70 unrelated Lebanese families. Six different mutations of alpha thalassemia gene were identified. RESULTS: The most prevalent mutations were the single gene deletion -alpha(3.7) (43%) and the non-gene deletion alpha2 IVS1 [ 5nt] (37%). The double deletional determinant -(MED) was detected only in 14% of thalassemic chromosomes. CONCLUSION: We determined the mutational spectrum of alpha thalassemia which might be used in the future for molecular investigations of the disease in susceptible patients in our population. PMID- 25284126 TI - Nogo-A deletion increases the plasticity of the optokinetic response and changes retinal projection organization in the adult mouse visual system. AB - The inhibitory action of Nogo-A on axonal growth has been well described. However, much less is known about the effects that Nogo-A could exert on the plasticity of neuronal circuits under physiological conditions. We investigated the effects of Nogo-A knock-out (KO) on visual function of adult mice using the optokinetic response (OKR) and the monocular deprivation (MD)-induced OKR plasticity and analyzed the anatomical organization of the eye-specific retinal projections. The spatial frequency sensitivity was higher in intact Nogo-A KO than in wild-type (WT) mice. After MD, Nogo-A KO mice reached a significantly higher spatial frequency and contrast sensitivity. Bilateral ablation of the visual cortex did not affect the OKR sensitivity before MD but reduced the MD induced enhancement of OKR by approximately 50% in Nogo-A KO and WT mice. These results suggest that cortical and subcortical brain structures contribute to the OKR plasticity. The tracing of retinal projections to the dorsal lateral geniculate nucleus (dLGN) revealed that the segregation of eye-specific terminals was decreased in the adult Nogo-A KO dLGN compared with WT mice. Strikingly, MD of the right eye led to additional desegregation of retinal projections in the left dLGN of Nogo-A KO but not in WT mice. In particular, MD promoted ectopic varicosity formation in Nogo-A KO dLGN axons. The present data show that Nogo-A restricts visual experience-driven plasticity of the OKR and plays a role in the segregation and maintenance of retinal projections to the brain. PMID- 25284127 TI - Endoscopic transsphenoidal surgery of Rathke's cleft cyst. AB - Rathke's cleft cysts (RCC) are benign lesions that originate from remnants of Rathke's pouch. They can compress adjacent structures causing visual loss and endocrine dysfunction. The endoscopic endonasal transsphenoidal approach (EETA) has gained popularity in the surgical management of pituitary and parasellar tumors. However, postoperative cyst recurrence and endocrine dysfunction are still major concerns. A retrospective chart review was performed on 11 patients who underwent a purely EETA. Subtotal resection of the cyst wall with drainage of the intracystic contents followed by obliteration of the cyst with a fat graft was performed in all patients. Two patients underwent repeated surgeries for symptomatic cyst recurrence. One patient ultimately underwent extracapsular removal of the entire cyst wall because of multiple recurrences after simple drainage. There were no incidences of new permanent hypopituitarism, visual deficits, or postoperative cerebrospinal fluid leaks. All patients reported an improvement of initial preoperative symptoms. A non-aggressive strategy of partial cyst wall removal and simple drainage of cyst contents via EETA is a viable approach for surgical treatment of RCC with a low rate of postoperative endocrine and visual complications. A more aggressive strategy of extracapsular removal of the cyst wall may be indicated in patients with repeated recurrence. PMID- 25284128 TI - One-pot transformation of simple furans into 4-hydroxy-2-cyclopentenones in water. AB - A highly efficient one-pot transformation of readily accessible furans into 4 hydroxy-2-cyclopentenones in H2O, using singlet oxygen as oxidant, has been developed. PMID- 25284130 TI - NMDA receptors interact with the retrieval memory enhancing effect of pioglitazone in mice. AB - PURPOSE: The present study has been undertaken to investigate the possible involvement of the glutamatergic pathway in the beneficial effects of pioglitazone on consolidation and retrieval phases of memory. MATERIALS AND METHODS: The Y-maze task was used to assess short-term spatial recognition memory in animals. Scopolamine (1mg/kg, i.p.) or MK-801 (dizocilpine) (0.03, 0.1 and 0.3mg/kg, i.p.) were administered immediately after the training session to impair memory consolidation or 30min before the retention trial to impair memory retrieval. Pioglitazone (10, 20, 40 and 80mg/kg, p.o.) was administered 2h before the retention session in memory retrieval experiments or immediately after the training session in consolidation experiments. And finally NMDA (N-methyl-d aspartate) (75mg/kg, i.p) was administered 15min before the administration of pioglitazone. RESULTS: 1) MK-801 (0.3mg/kg) impaired the retrieval of spatial recognition memory. 2) Pioglitazone failed to improve MK-801 induced impairment of retrieval of spatial recognition memory. 3) The 20mg/kg dose of pioglitazone significantly improved memory in mice with scopolamine induced impairment of memory retrieval. 4) Sub-effective dose of MK-801 (0.1mg/kg) was capable of reversing the beneficial effect of pioglitazone on retrieval of memory in scopolamine-treated mice, 5) Administration of NMDA (75mg/kg) and a sub-effective dose of pioglitazone (10mg/kg) reversed the effect of scopolamine and promoted memory retrieval. 6) MK-801 did not affect the consolidation phase of spatial recognition memory. 7) Pioglitazone did not affect scopolamine-induced impairment of memory consolidation. CONCLUSIONS: Sub-effective dose of MK-801 is capable of reversing the protective action of pioglitazone on scopolamine-induced impairment of memory retrieval. Additionally, co-administration of 75mg/kg NMDA and a sub effective dose of pioglitazone potentiated the effect of pioglitazone on memory retrieval impaired by scopolamine. These results support the idea that pioglitazone plays its memory retrieval enhancement role through the glutamatergic pathway. PMID- 25284129 TI - 3,4-Methylenedioxypyrovalerone (MDPV)-induced conditioned taste avoidance in the F344/N and LEW rat strains. AB - The inbred Fischer (F344) and Lewis (LEW) rats, while originally developed as animal models for cancer and tissue transplantation research, have since been used to study genetic differences in a variety of physiological and behavioral endpoints. In this context, LEW rats show greater sensitivity to the aversive effects of cocaine as compared to F344 rats in a conditioned taste avoidance procedure. Like cocaine, 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") acts as a dopamine transport blocker and possesses aversive properties, making it a good candidate for assessing whether the aforementioned strain differences with cocaine would generalize to drugs with similar biochemical action. Accordingly, male F344 and LEW rats were exposed to a novel saccharin solution followed by injections of one of four doses of MDPV in a taste avoidance procedure. Over the four saccharin/MDPV pairings during conditioning, core body temperatures were also assessed. Similar to previous research, MDPV induced robust dose-dependent taste avoidance, although no effect of strain was observed. MDPV also produced hyperthermia that was independent of strain and unrelated to the conditioned taste avoidance. These findings argue for a complex influence of multiple (and likely interacting) monoaminergic systems mediating MDPV-induced taste avoidance in the two strains and suggest different mechanisms of avoidance learning for cocaine and MDPV. PMID- 25284131 TI - Microinjection of the mGluR5 antagonist MTEP into the nucleus accumbens attenuates the acquisition but not expression of morphine-induced conditioned place preference in rats. AB - Previous studies suggest that metabotropic glutamate receptor type 5 (mGluR5) plays an important role in modulation of the rewarding properties of morphine. Little is known about the role of mGluR5 in the nucleus accumbens (NAc), as one of the important regions of the reward circuitry. In the present study, we investigated the effects of intra-accumbal injection of mGluR5 antagonist, 3-[(2 methyl-4-thiazolyl) ethynyl] pyridine, MTEP, on the acquisition and expression of morphine induced Conditioned Place Preference (CPP) in the rats. Eighty four adult male Wistar rats (220-260g) were bilaterally implanted with cannulae into the NAc. Subjects were tested in a CPP paradigm. Different doses of MTEP (0.3, 1 and 3MUg/0.5MUl per side) were delivered bilaterally into NAc during 3 conditioning days (Acquisition) or post-conditioning day (Expression). Results showed that bilateral intra accumbal administration of MTEP (1 and 3MUg) significantly attenuated the acquisition but not expression of morphine-induced CPP in a dose-dependent manner. Our findings indicated that blockade of mGluR5 reduces rewarding properties of morphine. Further studies are needed to know the involved mechanisms. PMID- 25284132 TI - Serotonin antagonists induce anxiolytic and anxiogenic-like behavior in zebrafish in a receptor-subtype dependent manner. AB - Motor function and anxiety-like responses are easily quantifiable in zebrafish, a novel model organism for behavioral pharmacology. Activation of serotonin receptors through the use of selective agonists has been shown to alter anxiety like behaviors in zebrafish. However, few studies have examined the effect of blockade of specific serotonin receptors. In the current study, we examine the effect of 4 serotonin receptor antagonists selective for 5-HT1A, 5-HT1B/D, 5-HT2, and 5-HT3 receptors on zebrafish motor and anxiety-like responses. Exposure to the receptor antagonists did not change baseline motor responses. However, when placed in a novel environment, zebrafish previously exposed to GR 55562 (5-HT1B/D antagonist) exhibited reduced anxiety-like behavior, whereas zebrafish previously exposed to p-MPPF (5-HT1A antagonist), Ketanserin (5-HT2 antagonist), or Ondasetron (5-HT3 antagonist) exhibited increased anxiety-like behaviors. These results show that drugs developed for mammalian serotonin receptors are efficacious in the zebrafish too, a finding that demonstrates evolutionary conservation of the serotoninergic system. The results also imply that zebrafish may be an appropriate animal model for examining the serotonergic neurotransmitter system in vertebrates. PMID- 25284133 TI - Hemophagocytic lymphohistiocytosis in a patient with Goodpasture's syndrome: a rare clinical association. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome. HLH can occur in the setting of an autoimmune disease, chronic immunosuppression, malignancy, and infection. We discuss a rare case of a young woman who was diagnosed with Goodpasture's syndrome that was most likely complicated by HLH. To the best of our knowledge, this is the first report of HLH in the setting of this rare autoimmune disease. CASE REPORT: A 31-year-old woman who was diagnosed with Goodpasture's syndrome 7 years prior presented with febrile neutropenia. She was initially receiving treatment with azathioprine and prednisone, which was subsequently switched to hydroxychloroquine. Over time, she had developed polyarthritis and was later diagnosed with MPO-ANCA-positive vasculitides. On this admission, her clinical status deteriorated from persistent pancytopenia. This was initially attributed to the immunosuppressive effect of hydroxychloroquine. A bone marrow biopsy was performed and revealed hypercellular bone marrow without any cytogenetic abnormalities. Due to a prolonged pancytopenia thought to be of autoimmune etiology, treatment with high-dose steroids was initiated. With the persistent febrile episodes, hepatosplenomegaly on examination, and laboratory workup that revealed hyperferritinemia and pancytopenia, HLH syndrome was suspected. A repeat bone marrow biopsy confirmed this diagnosis with the presence of hemophagocytosis, demonstrated by the presence of histiocytes engulfing erythroid cells. She also met 5 of 8 diagnostic criteria, which confirmed the diagnosis of HLH. The patient eventually died despite aggressive treatment with high-dose steroid therapy for her autoimmune disorder, as well intravenous antibiotics and supportive care for her underlying infections. CONCLUSIONS: HLH is a syndrome marked by a hyper-inflammatory state aggravated by specific triggers. To make the diagnosis of HLH, at least 5 of the 8 criteria must be met. Treatment involves suppression of the overwhelming inflammatory response by the use of immunomodulators. The mortality rate can range from 50-90% due to delayed recognition and onset of treatment. Here, we present a rare case of Goodpasture's syndrome with overlap and pauci-immune vasculitis, which may have triggered the HLH. This correlation has not been described before in the literature. PMID- 25284135 TI - An environment-adaptive management algorithm for hearing-support devices incorporating listening situation and noise type classifiers. AB - In order to provide more consistent sound intelligibility for the hearing impaired person, regardless of environment, it is necessary to adjust the setting of the hearing-support (HS) device to accommodate various environmental circumstances. In this study, a fully automatic HS device management algorithm that can adapt to various environmental situations is proposed; it is composed of a listening-situation classifier, a noise-type classifier, an adaptive noise reduction algorithm, and a management algorithm that can selectively turn on/off one or more of the three basic algorithms-beamforming, noise-reduction, and feedback cancellation-and can also adjust internal gains and parameters of the wide-dynamic-range compression (WDRC) and noise-reduction (NR) algorithms in accordance with variations in environmental situations. Experimental results demonstrated that the implemented algorithms can classify both listening situation and ambient noise type situations with high accuracies (92.8-96.4% and 90.9-99.4%, respectively), and the gains and parameters of the WDRC and NR algorithms were successfully adjusted according to variations in environmental situation. The average values of signal-to-noise ratio (SNR), frequency-weighted segmental SNR, Perceptual Evaluation of Speech Quality, and mean opinion test scores of 10 normal-hearing volunteers of the adaptive multiband spectral subtraction (MBSS) algorithm were improved by 1.74 dB, 2.11 dB, 0.49, and 0.68, respectively, compared to the conventional fixed-parameter MBSS algorithm. These results indicate that the proposed environment-adaptive management algorithm can be applied to HS devices to improve sound intelligibility for hearing-impaired individuals in various acoustic environments. PMID- 25284136 TI - Columnar-thin-film-assisted visualization of depleted sebaceous fingermarks on nonporous metals and hard plastics. AB - A fingermark on a nonporous substrate can be developed by depositing a columnar thin film (CTF) on it, but the CTF technique's sensitivity for low-quality fingermarks is unknown. The optimized CTF and traditional development of several depletion series of sebaceous-loaded fingermarks were compared using a split print methodology as well as subjective and objective grading schemes, in a limited laboratory trial. CTF development was superior to development with selected traditional techniques on brass, anodized aluminum, black acrylonitrile butadiene styrene (ABS), and white nylon. On white ABS and black nylon, the CTF technique performed poorly but still as well as the best-performing traditional development technique. The CTF technique was more sensitive on brass and anodized aluminum than, and as sensitive on the four hard plastics and stainless steel as, the best-performing traditional technique. Thus, the CTF technique is useful to develop friction-ridge detail from limited fingermark residue on some smooth substrates. PMID- 25284134 TI - Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients. AB - BACKGROUND: Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors. AIM: To investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse. METHODS: This was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use >=3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively. RESULTS: 237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4-8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035). Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007). CONCLUSION: Thiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis. PMID- 25284137 TI - Comparison of three transgenic Bt rice lines for insecticidal protein expression and resistance against a target pest, Chilo suppressalis (Lepidoptera: Crambidae). AB - Two transgenic rice lines (T2A-1 and T1C-19b) expressing cry2A and cry1C genes, respectively, were developed in China, targeting lepidopteran pests including Chilo suppressalis (Walker) (Lepidoptera: Crambidae). The seasonal expression of Cry proteins in different tissues of the rice lines and their resistance to C. suppressalis were assessed in comparison to a Bt rice line expressing a cry1Ab/Ac fusion gene, Huahui 1, which has been granted a biosafety certificate. In general, levels of Cry proteins were T2A-1 > Huahui 1 > T1C-19b among rice lines, and leaf > stem > root among rice tissues. The expression patterns of Cry protein in the rice line plants were similar: higher level at early stages than at later stages with an exception that high Cry1C level in T1C-19b stems at the maturing stage. The bioassay results revealed that the three transgenic rice lines exhibited significantly high resistance against C. suppressalis larvae throughout the rice growing season. According to Cry protein levels in rice tissues, the raw and corrected mortalities of C. suppressalis caused by each Bt rice line were the highest in the seedling and declined through the jointing stage with an exception for T1C-19b providing an excellent performance at the maturing stage. By comparison, T1C-19b exhibited more stable and greater resistance to C. suppressalis larvae than T2A-1, being close to Huahui 1. The results suggest cry1C is an ideal Bt gene for plant transformation for lepidopteran pest control, and T1C-19b is a promising Bt rice line for commercial use for tolerating lepidopteran rice pests. PMID- 25284138 TI - Impact of induction immunosuppression on survival in heart transplant recipients: a contemporary analysis of agents. AB - INTRODUCTION: The impact of induction immunosuppression on long-term survival in heart transplant recipients is unclear. Over the past three decades, practices have varied as induction agents have changed and experiences grew. We sought to evaluate the effect of contemporary induction immunosuppression agents in heart transplant recipients with the primary endpoint of survival, utilizing national registry data. METHODS: We queried the United Network for Organ Sharing (UNOS) data registry for all heart transplants from 1987 to 2012. We restricted our analysis to adult (>=18 yr) recipients performed from 2001-2011 (to allow for the potential for a minimum of 12 months post-transplant follow-up) who received either: no antibody based induction (NONE) or the contemporary agents (INDUCED) of either: basiliximab/daclizumab (IL-2Rab), alemtuzumab, or ATG/ALG/thymoglobulin. Kaplan-Meier estimates of the survival function as well as Cox proportional hazards models were utilized. RESULTS: Of the 17 857 heart transplants that met the inclusion criteria, there were 4635 (26%) reported deaths during the follow-up period. There were 8216 (46%) patients who were INDUCED. Of the INDUCED agents, 55% were IL-2Rab, 4% alemtuzumab, and 40% ALG/ATG/thymoglobulin. Donor and recipient characteristics were evaluated. Overall, being INDUCED did not significantly affect survival in univariable (p = 0.522) and multivariable (p = 0.130) Cox models as well as a propensity score adjusted model (p = 0.733). Among those induced, ATG/ALG/thymoglobulin appeared to have superior survival as compared with IL-2Rab (log-rank p = 0.007, univariable hazard ratio [HR] = 0.886; 95% CI: 0.811-0.968; p = 0.522). However, in a multivariable Cox model that adjusted for recipient age, VAD, BMI, steroid use, CMV match, and ischemic time, the hazard ratio for ALG/ATG/thymoglobulin vs. IL-2Rab was no longer statistically significant (HR = 0.948; 95% CI: 0.850-1.058; p = 0.341). CONCLUSION: In a contemporary analysis of heart transplant recipients, an overall analysis of induction agents does not appear to impact survival, as compared to no induction immunosuppression. While ALG/ATG/thymoglobulin appeared to have a beneficial effect on survival compared to IL-2Rab in the univariable model, this difference was no longer statistically significant once we adjusted for clinically relevant covariates. PMID- 25284139 TI - Organized assemblies of colloids formed at the poles of micrometer-sized droplets of liquid crystal. AB - We report on the formation of organized assemblies of 1 MUm-in-diameter colloids (polystyrene (PS)) at the poles of water-dispersed droplets (diameters 7-20 MUm) of nematic liquid crystal (LC). For 4-cyano-4'-pentylbiphenyl droplets decorated with two to five PS colloids, we found 32 distinct arrangements of the colloids to form at the boojums of bipolar droplet configurations. Significantly, all but one of these configurations (a ring comprised of five PS colloids) could be mapped onto a local (non-close packed) hexagonal lattice. To provide insight into the origin of the hexagonal lattice, we investigated planar aqueous-LC interfaces, and found that organized assemblies of PS colloids did not form at these interfaces. Experiments involving the addition of salts revealed that a repulsive interaction of electrostatic origin prevented formation of assemblies at planar interfaces, and that regions of high splay near the poles of the LC droplets generated cohesive interactions between colloids that could overcome the repulsion. Support for this interpretation was obtained from a model that included (i) a long-range attraction between adsorbed colloids and the boojum due to the increasing rate of strain (splay) of LC near the boojum (splay attraction), (ii) an attractive inter-colloid interaction that reflects the quadrupolar symmetry of the strain in the LC around the colloids, and (iii) electrostatic repulsion between colloids. The model predicts that electrostatic repulsion between colloids can lead to a ~1000kBT energy barrier at planar interfaces of LC films, and that the repulsive interaction can be overcome by splay attraction of the colloids to the boojums of the LC droplets. Overall, the results reported in this paper advance our understanding of the directed assembly of colloids at interfaces of LC droplets. PMID- 25284140 TI - Tissue engineered bone using select growth factors: A comprehensive review of animal studies and clinical translation studies in man. AB - There is a growing socio-economic need for effective strategies to repair damaged bone resulting from disease, trauma and surgical intervention. Bone tissue engineering has received substantial investment over the last few decades as a result. A multitude of studies have sought to examine the efficacy of multiple growth factors, delivery systems and biomaterials within in vivo animal models for the repair of critical-sized bone defects. Defect repair requires recapitulation of in vivo signalling cascades, including osteogenesis, chondrogenesis and angiogenesis, in an orchestrated spatiotemporal manner. Strategies to drive parallel, synergistic and consecutive signalling of factors including BMP-2, BMP-7/OP-1, FGF, PDGF, PTH, PTHrP, TGF-beta3, VEGF and Wnts have demonstrated improved bone healing within animal models. Enhanced bone repair has also been demonstrated in the clinic following European Medicines Agency and Food and Drug Administration approval of BMP-2, BMP-7/OP-1, PDGF, PTH and PTHrP. The current review assesses the in vivo and clinical data surrounding the application of growth factors for bone regeneration. This review has examined data published between 1965 and 2013. All bone tissue engineering studies investigating in vivo response of the growth factors listed above, or combinations thereof, utilising animal models or human trials were included. All studies were compiled from PubMed-NCBI using search terms including 'growth factor name', 'in vivo', 'model/animal', 'human', and 'bone tissue engineering'. Focus is drawn to the in vivo success of osteoinductive growth factors incorporated within material implants both in animals and humans, and identifies the unmet challenges within the skeletal regenerative area. PMID- 25284141 TI - Defective bone repair in mast cell deficient mice with c-Kit loss of function. AB - KitW-sh mice carry an inactivating mutation in the gene encoding the receptor for stem cell factor, which is expressed at high levels on the surface of haematopoietic precursor cells. The mutation results in mast cell deficiency, a variety of defects in innate immunity and poorly defined abnormalities in bone. The present study was designed to characterise healing of a cortical window defect in skeletally mature KitW-sh mice using high-resolution micro computed tomographic imaging and histological analyses. The cortical bone defect healed completely in all wild type mice but failed to heal in about half of the KitW-sh mice by 12 weeks post-operative. Defective healing was associated with premature and excessive expression of TRAP positive cells embedded in fibrous marrow but with little change in ALP activity. Immuno-histochemical analyses revealed reduced CD34 positive vascular endothelial cells and F4/80 positive macrophages at 1 and 2 weeks post-operative. Impaired bone healing in the KitW-sh mice was therefore attributed to altered catabolic activity, impaired re-vascularisation and compromised replacement of woven with compact bone. PMID- 25284143 TI - Improving documentation of quality measures in the electronic health record. AB - PURPOSE: Oncology quality measures provide an important tool to evaluate care received by cancer patients. These measures are frequently addressed by oncology nurse practitioners (NPs). NP documentation of quality oncology practice initiative (QOPI) measures in the electronic health record (EHR) is evaluated in this study. DATA SOURCES: NP documentation of specific QOPI measures before and after an educational intervention (EI) was evaluated. EHR shortcuts, called "SmartPhrases," were used to increase efficiency in documentation of these measures. CONCLUSIONS: Preintervention chart audits found compliance <80% in the multiple measurement areas. Following the EI, NPs surveyed identified greater understanding of QOPI measures and an interest in using "SmartPhrases" to aid in measure documentation. The postintervention audit demonstrated improvement in all areas addressed during the EI noting the use of "SmartPhrases" based on descriptive findings. IMPLICATIONS FOR PRACTICE: NPs play a significant role in providing quality care for oncology patients. By increasing knowledge related to the documentation of quality measures and providing tools to increase the efficiency associated with their documentation, a positive impact can be made in efforts to promote quality patient care. PMID- 25284142 TI - Efficacy of transoral fundoplication for treatment of chronic gastroesophageal reflux disease incompletely controlled with high-dose proton-pump inhibitors therapy: a randomized, multicenter, open label, crossover study. AB - BACKGROUND: The aim of this randomized, crossover study was to determine if transoral fundoplication (TF) could further improve clinical outcomes in partial responders to high-dose (HD) proton-pump inhibitor (PPI) therapy and to evaluate durability of TF. METHODS: In seven United States centers, patients with hiatal hernia <= 2 cm and abnormal esophageal acid exposure (EAE) were randomized to TF (n = 40) or HD PPIs (n = 23) group. At 6-month follow-up, PPI patients underwent crossover. We assessed clinical outcomes 6-month post TF in crossover patients (COP), as compared to 6-month of HD PPI therapy, and 12-month outcomes in patients initially randomized to TF. The primary outcome was symptom control evaluated by Reflux Disease Questionnaire and Reflux Symptom Index. Secondary outcomes included healing of esophagitis, normalization of EAE and PPI use after TF. We analyzed 21 COP and 39 TF patients. McNemar's test or Fisher exact test was used to compare proportions. RESULTS: Of 63 randomized patients, 3 were lost to follow-up, leaving 39 TF and 21 COP for analyses. In the COP, TF further improved control of regurgitation and of atypical symptoms achieved after six months of HD PPIs. Of 20 patients with GERD symptoms after six months of high dose PPI therapy, 65% (13/20) reported global elimination of troublesome regurgitation and atypical symptoms post TF off PPIs; 67% (6/9) reported no troublesome regurgitation. Esophagitis further healed in 75% (6/8) of patients. Seventy-one percent of COP patients were off PPIs six months following TF. Normalization of EAE decreased from 52% after HD PPIs (on PPIs) to 33% after TF (off PPIs), p =0.388. In the original TF group, 12-month post TF, 77% of patients achieved complete symptom control, 82% ceased PPI therapy, 100% healed esophagitis and 45% normalized EAE. CONCLUSIONS: The results of this study indicate that in patients with incomplete symptom control on high-dose PPI therapy TF may provide further elimination of symptoms and esophagitis healing. In the original TF group, the clinical outcomes of TF remained stable between 6- and 12-month follow-up. PMID- 25284144 TI - Multiple anticholinergic medication use and risk of hospital admission for confusion or dementia. AB - OBJECTIVES: To identify the association between use of multiple anticholinergic medications and risk of hospitalization for confusion or dementia. DESIGN: Retrospective cohort study conducted over 2 years between July 2010 and June 2012, using administrative claims data from the Australian Department of Veterans' Affairs. SETTING: Australia. PARTICIPANTS: Australian veterans dispensed at least one moderately or highly anticholinergic medication in the year before study start. MEASUREMENTS: Cumulative anticholinergic use on each day of the study period was determined. The association between hospitalization for confusion or dementia and number of anticholinergic medications used at the time of admission was compared against times during which participants were not taking anticholinergic medications. Sensitivity analyses were undertaken limiting the outcome to admissions for acute confusion and excluding individuals taking antipsychotics. RESULTS: Adjusted results showed a significantly greater risk of hospitalization for confusion or dementia when individuals were taking two or more anticholinergic medications. The adjusted incident rate ratios (IRRs) were 2.58 (95% confidence interval (CI) = 1.91-3.48) for those taking two anticholinergics and 3.87 (95% CI = 1.83-8.21) for those taking three or more. Sensitivity analyses in which participants taking antipsychotic medications were excluded and the outcome was limited to acute confusion also found similar risks for those taking two (IRR 1.82, 95% CI = 1.18-2.80) and three or more (IRR = 3.98 95% CI = 1.50-10.58) anticholinergic medications. CONCLUSION: Taking more anticholinergic medications is associated with greater risk of hospitalization for confusion or dementia. Strategies to reduce anticholinergic medication burden are likely to translate into significant health benefits. PMID- 25284145 TI - The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long term clinical outcome in chronic hepatitis B patients. AB - BACKGROUND & AIMS: We aimed to assess the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) I148M polymorphism, liver histology and long-term outcome in chronic hepatitis B (CHB) patients. METHODS: We enrolled 531 consecutive treatment naive CHB patients diagnosed from 1985 to 2012 with an available liver biopsy for reassessment, and sample for genetic testing. Data on all-cause mortality and hepatocellular carcinoma (HCC) at long-term follow-up were obtained from national database registries. RESULTS: The prevalence of steatohepatitis increased with PNPLA3 CC (14%), CG (20%) and GG (43%) (P < 0.001). The association was altered by both gender (P = 0.010) and overweight (P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronounced among non overweight females (adjusted OR 13.4, 95%CI: 3.7-51.6, P < 0.001), and non overweight males (adjusted OR 2.4, 95%CI: 1.4-4.3, P = 0.002). Furthermore, PNPLA3 GG genotype was associated with iron depositions (OR 2.8, 95%CI: 1.2-6.4, P = 0.014) and lobular inflammation (OR 2.2, 95%CI: 1.1-4.5, P = 0.032), but not with advanced fibrosis (OR 1.1, 95%CI: 0.7-1.8, P = 0.566). The median follow-up was 10.1 years (interquartile range 5.6 - 15.8), during which 13 patients developed HCC and 28 died. Steatohepatitis was associated with all-cause mortality [Hazard ratio (HR) 3.1, 95%CI: 1.3-7.3, P = 0.006] and HCC (HR 2.8, 95%CI: 0.9-9.2, P = 0.078), but no significant association was observed for PNPLA3. CONCLUSIONS: In this cohort of biopsied CHB patients, PNPLA3 was independently associated with steatosis, steatohepatitis, lobular inflammation and iron depositions, but not with advanced fibrosis, HCC development or all cause mortality. The effect of PNPLA3 on steatohepatitis was particularly pronounced among female patients without severe overweight. PMID- 25284146 TI - The role for surgery when primary (radio)chemotherapy treatment of gastro intestinal tumors results in clinical complete response. PMID- 25284147 TI - Comparison between double-guidewire technique and transpancreatic sphincterotomy technique for difficult biliary cannulation. AB - BACKGROUND AND AIM: The aim of the present study was to compare the effectiveness and complications of the double-guidewire technique (DWT) with the transpancreatic sphincterotomy (TPS) technique. METHODS: From January 2013 to December 2014, 366 consecutive endoscopic retrograde cholangiopancreatography (ERCP) procedures were carried out. Of 366 procedures, 354 procedures were carried out in patients with native major papilla biliary cannulation. A total of 279 consecutive therapeutic ERCP were included in the study and data of included patients were collected retrospectively. One hundred and thirty-seven procedures (49.1%) were done with DWT and 142 procedures (50.9%) were done with TPS for patients with difficult cannulation. The results and complications of ERCP were compared. RESULTS: Success rate of first-attempt cannulation was 62.0% in the DWT group and 81.0% in the TPS group (P = 0.00). Final rate of successful cannulation of the two biliary cannulation techniques was 86.9% and 90.8%, respectively (P = 0.09). Cannulation time in the DWT group was 7.8 +/- 1.7 min compared with 3.7 +/ 2.3 min in the TPS group (P = 0.00). Overall incidence of post-ERCP pancreatitis (PEP), hemorrhage, perforation and cholangitis was 1.8%, 1.1%, 0.4% and 1.1%, respectively. Adverse event rate was 2.19% in the DWT group and 7.04% in the TPS group (P = 0.04). CONCLUSIONS: DWT and TPS procedures were safe and effective. Overall cannulation rate was similar between the groups. Although DWT had a longer cannulation time, it could be considered the preferred technique in patients with failed standard cannulation for lower adverse event rate. PMID- 25284148 TI - Efficient end-capping synthesis of neutral donor-acceptor [2]rotaxanes under additive-free and mild conditions. AB - Efficient end-capping synthesis of neutral donor-acceptor (D-A) [2]rotaxanes without loading any catalysts or activating agents was achieved by utilizing high reactivity of a pentacoordinated hydrosilane toward salicylic acid derivatives. As components of [2]rotaxanes, an electron-deficient naphthalenediimide containing axle with a salicylic acid terminus and several electron-rich bis(naphthocrown) ether macrocycles were employed. End-capping reactions with the pentacoordinated hydrosilane underwent smoothly even at low temperature to afford the corresponding [2]rotaxanes in good yields. A [2]rotaxane containing bis-1,5 (dinaphtho)-38-crown-10 ether as a wheel molecule was synthesized and isolated in 84% yield by the end-capping at -10 degrees C, presenting the highest yield ever reported for the end-capping synthesis of a neutral D-A [2]rotaxane. It was found that the yields of the [2]rotaxanes in the end-capping reactions were almost parallel to the formation ratios of the corresponding pseudo[2]rotaxanes estimated by utilizing model systems. These results indicate that the end-capping reaction using the pentacoordinated hydrosilane proceeded without perturbing the threading process, and most of the pseudo[2]rotaxanes underwent efficient end capping reaction even at low temperature. PMID- 25284149 TI - Polyfluorene polyelectrolyte nanoparticles: synthesis of innovative stabilizers for heterophase polymerization. AB - Polyfluorene-bearing bromohexyl side chains are quaternized by 1-vinylimidazole in order to attach dialkylimidazolium bromide ionic liquid (IL) species along the conjugated backbone. Subsequently, polyfluorene polyelectrolyte nanoparticles (NPs) of 40 nm in average size are created via radical cross-linking of the pendant vinylimidazolium groups. Anion exchange from Br(-) to BF(4)(-), PF(6)(-), and bis(trifluoromethylsulfonyl)imide anion (TFSI(-) renders NPs adjustable dispersability in various organic solvents. The hydrophobic-conjugated backbone and the hydrophilic dialkylimidazolium bromide IL moieties depict an amphiphilic profile, which allows the NPs to be deployed as conductive stabilizer in the emulsion polymerization of styrene. The resultant latexes are fluorescent, tunable in size and can be transferred to organic solvents without forfeiting their colloidal stability. PMID- 25284150 TI - CO2 as a smart gelator for Pluronic aqueous solutions. AB - It was found that CO2 could induce the gelation of Pluronic aqueous solutions, during which the microstructure of the solution transforms from randomly dispersed spherical micelles to cubic close packed micelles. The gelation switched by compressed CO2 has many advantages and can be applied in the synthesis of porous materials. PMID- 25284151 TI - Bacteria from diverse habitats colonize and compete in the mouse gut. AB - To study how microbes establish themselves in a mammalian gut environment, we colonized germ-free mice with microbial communities from human, zebrafish, and termite guts, human skin and tongue, soil, and estuarine microbial mats. Bacteria from these foreign environments colonized and persisted in the mouse gut; their capacity to metabolize dietary and host carbohydrates and bile acids correlated with colonization success. Cohousing mice harboring these xenomicrobiota or a mouse cecal microbiota, along with germ-free "bystanders," revealed the success of particular bacterial taxa in invading guts with established communities and empty gut habitats. Unanticipated patterns of ecological succession were observed; for example, a soil-derived bacterium dominated even in the presence of bacteria from other gut communities (zebrafish and termite), and human-derived bacteria colonized germ-free bystander mice before mouse-derived organisms. This approach can be generalized to address a variety of mechanistic questions about succession, including succession in the context of microbiota-directed therapeutics. PMID- 25284153 TI - Target tissue ectoenzyme CD39/CD73-expressing Foxp3+ regulatory T cells in patients with psoriasis. AB - BACKGROUND: Psoriasis is a chronic, relapsing, inflammatory skin disease, in which regulatory T cells (Tregs) play an important role. Recently, human Treg ectoenzymes (CD39/CD73) have been reported to mediate the suppressive activity of Tregs. AIM: To investigate the proportions of CD39/CD73 expressing Foxp3(+) regulatory T cells in different types of psoriatic lesions. METHODS: Immunohistochemical staining was used to analyse expression of Foxp3, CD39 and CD73 in biopsy tissue from healthy controls and from patients with different types of psoriasis. RESULTS: In normal control biopsies, CD39(+) cells were scattered throughout the epidermis and dermis, while CD73(+) cells were localized predominantly in the dermis. The proportion of cells that were both CD39(+) and Foxp3(+) was significantly lower in pustular psoriasis (PP) and erythrodermic psoriasis (EP) than in psoriasis vulgaris (PV) (25.0 +/- 2.6%, 26.5 +/- 2.0% and 45.1 +/- 3.5%, respectively; P < 0.001). Likewise, CD73(+) Foxp3(+) cells were lower in PP and EP than in PV (6.2 +/- 1.9%, 11.6 +/- 2.8% and 17.7 +/- 2.3% respectively, P < 0.001). There were no significant differences in the population size of double-staining cells in EP compared with PP. CONCLUSION: The relative reduced expressions of CD39 and CD73 within Foxp3(+) Tregs may imply a different immunopathogenesis for different psoriatic lesions. PMID- 25284152 TI - Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. AB - In the thymus, high-affinity, self-reactive thymocytes are eliminated from the pool of developing T cells, generating central tolerance. Here, we investigate how developing T cells measure self-antigen affinity. We show that very few CD4 or CD8 coreceptor molecules are coupled with the signal-initiating kinase, Lck. To initiate signaling, an antigen-engaged T cell receptor (TCR) scans multiple coreceptor molecules to find one that is coupled to Lck; this is the first and rate-limiting step in a kinetic proofreading chain of events that eventually leads to TCR triggering and negative selection. MHCII-restricted TCRs require a shorter antigen dwell time (0.2 s) to initiate negative selection compared to MHCI-restricted TCRs (0.9 s) because more CD4 coreceptors are Lck-loaded compared to CD8. We generated a model (Lck come&stay/signal duration) that accurately predicts the observed differences in antigen dwell-time thresholds used by MHCI- and MHCII-restricted thymocytes to initiate negative selection and generate self tolerance. PMID- 25284155 TI - Tumor volume in insignificant prostate cancer: increasing threshold gains increasing risk. AB - BACKGROUND: An increased tumor volume threshold (<2.5 ml) is suggested to define insignificant prostate cancer (iPCa). We hypothesize that an increasing tumor volume within iPCa patients increases the risk of biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: We relied on RP patients treated between 1992 and 2008. Multivariable Cox regression analyses predicting BCR within patients harboring favorable pathological characteristics (<=pT2, pN0/Nx, Gleason 3 + 3). Kaplan-Meier analysis was performed for BCR-free survival within iPCa patients (<=pT2, pN0/Nx, Gleason 3 + 3, tumor volume: <0.5 vs. 0.5-2.49 ml). RESULTS: From 1,829 patients, 141 (7.7%) and 310 (16.9%) harbored iPCa (tumor volume: <0.5 vs. 0.5-2.49 ml), respectively. Of those, 21 (14.9%) versus 31 (10.0%) had PSA >10 ng/ml. Tumor volume achieved independent predictor status for BCR. Specifically, iPCa patients with increasing tumor volume (0.5-2.49 ml) were at higher risk of BCR after RP than those with tumor volume <0.5 ml (HR: 8.8, 95% CI: 1.2-65.9, P = 0.04). Kaplan-Meier analysis recorded superior BCR-free survival in iPCa patients with lower tumor volume (<0.5 ml) (log-rank P = 0.009). The 10-year cancer-specific death rate was 0 versus 0.5%. CONCLUSIONS: Contemporary iPCa definition incorporates intermediate and high-risk patients (PSA: 10-20 and >20 ng/ml). Despite most favorable pathological characteristics, iPCa patients are not devoid of BCR after RP. Moreover, iPCa patients were at higher risk of BCR, when increasing tumor volume up to 2.49 ml was at play. Taken together the contemporary concept of iPCa is suboptimal. Especially, an increased tumor volume threshold for defining iPCa cannot be recommended according to our data. Clinicians might take these considerations into account during decision making process. PMID- 25284154 TI - Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia. AB - Natural killer (NK) large granular lymphocyte (LGL) leukaemia features a clonal proliferation of CD3(-) NK cells that can be classified into either aggressive or chronic categories. The NKL cell line, derived from an aggressive Asian NK cell leukaemia, and patient samples from chronic NK-LGL leukaemia were used in our study to probe for synergistic efficacy of the epigenetic drugs vorinostat (SAHA) and cladribine in this disease. We demonstrate that histone deacetylases (HDACs) are over-expressed in both aggressive and chronic NK leukaemia. Administration of the HDAC inhibitor SAHA reduces class I and II HDAC expression and enhances histone acetylation in leukaemic NK cells. In vitro combination treatment with SAHA and cladribine dose-dependently exerts synergistic cytotoxic and apoptotic effects on leukaemic NK cells. Expression profiling of apoptotic regulatory genes suggests that both compounds led to caspase-dependent apoptosis through activation of intrinsic mitochondrial and extrinsic death receptor pathways. Collectively, these data show that combined epigenetic therapy, using HDAC and DNA methyltransferase inhibitors, may be a promising therapeutic approach for NK LGL leukaemia. PMID- 25284156 TI - Predicting the stiffness and strength of human femurs with real metastatic tumors. AB - BACKGROUND: Predicting patient specific risk of fracture in femurs with metastatic tumors and the need for surgical intervention are of major clinical importance. Recent patient-specific high-order finite element methods (p-FEMs) based on CT-scans demonstrated accurate results for healthy femurs, so that their application to metastatic affected femurs is considered herein. METHODS: Radiographs of fresh frozen proximal femur specimens from donors that died of cancer were examined, and seven pairs with metastatic tumor were identified. These were CT-scanned, instrumented by strain-gauges and loaded in stance position at three inclination angles. Finally the femurs were loaded until fracture that usually occurred at the neck. Histopathology was performed to determine whether metastatic tumors are present at fractured surfaces. Following each experiment p-FE models were created based on the CT-scans mimicking the mechanical experiments. The predicted displacements, strains and yield loads were compared to experimental observations. RESULTS: The predicted strains and displacements showed an excellent agreement with the experimental observations with a linear regression slope of 0.95 and a coefficient of regression R(2)=0.967. A good correlation was obtained between the predicted yield load and the experimental observed yield, with a linear regression slope of 0.80 and a coefficient of regression R(2)=0.78. DISCUSSION: CT-based patient-specific p-FE models of femurs with real metastatic tumors were demonstrated to predict the mechanical response very well. A simplified yield criterion based on the computation of principal strains was also demonstrated to predict the yield force in most of the cases, especially for femurs that failed at small loads. In view of the limited capabilities to predict risk of fracture in femurs with metastatic tumors used nowadays, the p-FE methodology validated herein may be very valuable in making clinical decisions. PMID- 25284157 TI - High prevalence of vitamin D deficiency among middle-aged and elderly individuals in northwestern China: its relationship to osteoporosis and lifestyle factors. AB - PURPOSE: Vitamin D deficiency has reached epidemic proportions; this deficiency has been associated with osteoporosis and certain lifestyle factors in adults. This relationship is not well documented among the Lanzhou population in northwest China. This study sought to determine the prevalence of vitamin D deficiency and its risk factors in addition to its relationship with osteoporosis in a Chinese population living in Lanzhou. METHODS: This cross-sectional study involved 2942 men and 7158 women aged 40-75years who were randomly selected from 3 communities in the Lanzhou urban district and examined medically. Levels of 25 hydroxy-vitamin D [25(OH)D] and other parameters were measured according to detailed inclusion criteria. Vitamin D deficiency was defined as serum 25(OH)D levels below 20ng/mL. Calcaneus bone mineral density (BMD) was measured by quantitative ultrasound (QUS). RESULTS: The prevalence of vitamin D deficiency (25(OH)D levels <20ng/mL) was present in 75.2% of the entire study population. Vitamin D deficiency was more prevalent in women (79.7%) than in men (64%; P<0.001). Multiple logistic regression analysis revealed that the significant predictors of vitamin D deficiency included coronary heart disease (CHD), obesity, dyslipidemia, older age, female sex, and smoking (all P<0.05), whereas tea intake, moderate physical activity, milk intake, vitamin D supplementation and sun exposure were protective (all P<0.05). No significant difference in calcaneus BMD measured by QUS was noted between subjects with <20ng/mL and >=20ng/mL vitamin D levels (0.53+/-0.13 vs. 0.54+/-0.13; P=0.089). The risk of having osteoporosis did not increase when vitamin D levels decreased from >=20ng/mL to <20ng/mL after multiple adjustments (OR=1.00; 95% CI 0.85-1.16; P=0.357). CONCLUSIONS: Vitamin D deficiency is prevalent in the middle-aged and elderly northwestern Chinese population and is largely attributed to CHD, obesity, dyslipidemia, older age, female sex, and smoking. Reduced 25(OH)D levels are not associated with an increased osteoporosis risk. PMID- 25284158 TI - Refinement of collagen-mineral interaction: a possible role for osteocalcin in apatite crystal nucleation, growth and development. AB - Mineralization of vertebrate tissues such as bone, dentin, cementum, and calcifying tendon involves type I collagen, which has been proposed as a template for calcium and phosphate ion binding and subsequent nucleation of apatite crystals. Type I collagen thereby has been suggested to be responsible for the deposition of apatite mineral without the need for non-collagenous proteins or other extracellular matrix molecules. Based on studies in vitro, non-collagenous proteins, including osteocalcin and bone sialoprotein, are thought to mediate vertebrate mineralization associated with type I collagen. These proteins, as possibly related to mineral deposition, have not been definitively localized in vivo. The present study has reexamined their localization in the leg tendons of avian turkeys, a representative model of vertebrate mineralization. Immunocytochemistry of osteocalcin demonstrates its presence at the surface of, outside and within type I collagen while that of bone sialoprotein appears to be localized at the surface of or outside type I collagen. The association between osteocalcin and type I collagen structure is revealed optimally when calcium ions are added to the antibody solution in the methodology. In this manner, osteocalcin is found specifically located along the a4-1, b1, c2 and d bands defining in part the hole and overlap zones within type I collagen. From these data, while type I collagen itself may be considered a stereochemical guide for intrafibrillar mineral nucleation and subsequent deposition, osteocalcin bound to type I collagen may also possibly mediate nucleation, growth and development of platelet-shaped apatite crystals. Bone sialoprotein and osteocalcin as well, each immunolocalized at the surface of or outside type I collagen, may affect mineral deposition in these portions of the avian tendon. PMID- 25284159 TI - Editorial introduction. Stem cells and bone. PMID- 25284160 TI - HILIC-MS for metabolomics: An attractive and complementary approach to RPLC-MS. AB - Hydrophilic interaction chromatography (HILIC) is an emerging separation mode of liquid chromatography (LC). Using highly hydrophilic stationary phases capable of retaining polar/ionic metabolites, and accompany with high organic content mobile phase that offer readily compatibility with mass spectrometry (MS) has made HILIC an attractive complementary tool to the widely used reverse-phase (RP) chromatographic separations in metabolomic studies. The combination of HILIC and RPLC coupled with an MS detector expands the number of detected analytes and provides more comprehensive metabolite coverage than use of only RP chromatography. This review describes the recent applications of HILIC-MS/MS in metabolomic studies, ranging from amino acids, lipids, nucleotides, organic acids, pharmaceuticals, and metabolites of specific nature. The biological systems investigated include microbials, cultured cell line, plants, herbal medicine, urine, and serum as well as tissues from animals and humans. Owing to its unique capability to measure more-polar biomolecules, the HILIC separation technique would no doubt enhance the comprehensiveness of metabolite detection, and add significant value for metabolomic investigations. (c) 2014 Wiley Periodicals, Inc. Mass Spec Rev 35:574-600, 2016. PMID- 25284162 TI - A multi-site randomised controlled trial of evidence-based supported employment for adults with severe and persistent mental illness. AB - BACKGROUND/AIM: The Individual Placement and Support (IPS) approach is an evidence-based form of supported employment for people with severe and persistent mental illness. This approach is not yet widely available in Australia even though there is mounting evidence of its generalisability outside the USA. One previous Australian randomised controlled trial found that IPS is effective for young people with first episode psychosis. The aim of the current trial was to assess the effectiveness of evidence-based supported employment when implemented for Australian adult consumers of public mental health services by utilising existing service systems. METHODS: A four-site randomised control trial design (n = 208) was conducted in Brisbane (two sites), Townsville and Cairns. The intervention consisted of an IPS supported employment service hosted by a community mental health team. The control condition was delivered at each site by mental health teams referring consumers to other disability employment services in the local area. RESULTS: At 12 months, those in the IPS condition had 2.4 times greater odds of commencing employment than those in the control condition (42.5% vs. 23.5%). The conditions did not differ on secondary employment outcomes including job duration, hours worked, or job diversity. Attrition was higher than expected in both conditions with 28.4% completing the baseline interview but taking no further part in the study. CONCLUSION: The results support previous international findings that IPS-supported employment is more effective than non integrated supported employment. IPS can be successfully implemented this way in Australia, but with a loss of effect strength compared to previous USA trials. PMID- 25284161 TI - (-)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic delta-sarcoglycan null mouse striated muscle. AB - Muscular dystrophies (MDs) are a group of heterogeneous genetic disorders characterized by progressive striated muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism of disease pathogenesis remains unclear. The presence of oxidative stress (OS) is known to contribute to the pathophysiology and severity of the MD. Mitochondrial dysfunction is observed in MD, and probably represents an important determinant of increased OS. Experimental antioxidant therapies have been implemented with the aim of protecting against disease progression, but results from clinical trials have been disappointing. In this study, we explored the capacity of the cacao flavonoid (-)-epicatechin (Epi) to mitigate OS by acting as a positive regulator of mitochondrial structure/function endpoints and redox balance control systems in skeletal and cardiac muscles of dystrophic, delta sarcoglycan (delta-SG) null mice. Wild-type or delta-SG null 2.5-month-old male mice were treated via oral gavage with either water (controls) or Epi (1 mg.kg( 1) , twice daily) for 2 weeks. The results showed significant normalization of total protein carbonylation, recovery of the glutathione/oxidized glutathione ratio and enhanced superoxide dismutase 2, catalase and citrate synthase activities with Epi treatment. These effects were accompanied by increases in the protein levels of thioredoxin, glutathione peroxidase, superoxide dismutase 2, catalase, and mitochondrial endpoints. Furthermore, we found decreases in heart and skeletal muscle fibrosis, accompanied by an improvement in skeletal muscle function, with treatment. These results warrant further investigation of Epi as a potential therapeutic agent to mitigate MD-associated muscle degeneration. PMID- 25284163 TI - Relationship between sucrose metabolism and anthocyanin biosynthesis during ripening in Chinese bayberry fruit. AB - Two cultivars of Chinese bayberry fruit cvs 'Dongkui' and 'Biqi' with five different ripening stages were used to investigate the relationship between anthocyanin biosynthesis and sugar metabolism during fruit development. The results showed that anthocynin accumulated with the increased ripening stage in both of the two cultivars of bayberries. As compared to 'Biqi' fruit, a higher level of anthocyanin content was observed in 'Dongkui' fruit due to the increased expression of anthocyanin biosynthetic and regulatory genes especially MrCHI, MrDFR1, MrANS, and MrMYB1. Meanwhile, 'Dongkui' fruit also experienced higher levels of soluble sugars including sucrose, glucose, and fructose and expression of genes such as MrSPS1, MrSPS2, MrSPS3, MrINV1, MrINV2, and MrINV3 involved in sugar metabolism. Correlation analysis showed anthocyanin content had a significant relationship with all the three soluble sugars in bayberry fruit. Therefore, our results suggested that the higher anthocyanin content in 'Dongkui' fruit might be associated with its increased levels of soluble sugars. PMID- 25284164 TI - Health care worker influenza vaccination in Oregon nursing homes: correlates of facility characteristics. PMID- 25284165 TI - Potentially inappropriate drug prescribing and associated factors in nursing homes. AB - IMPORTANCE: Polymedication is frequent in nursing home (NH) residents. This increases the risk of potentially inappropriate drug prescribing (PIDP), which can lead to adverse drug events, such as falls and hospitalization. OBJECTIVE: To identify PIDP in NH residents and to investigate subject-related and NH structural and organizational factors associated with PIDP. DESIGN: Cross sectional study. SETTING: A total of 175 NHs in Midi-Pyrenees region, South Western France. PARTICIPANTS: A total of 974 subjects randomly selected from the 6275 NH residents participating in the IQUARE study. EXPOSURE: Patients with PIDP. MAIN OUTCOMES AND MEASURES: PIDP was the main outcome measure. It was defined using a specific indicator, based on the Summary of Product Characteristics, on the Laroche list, and on residents' clinical data. PIDP was defined as the presence of at least 1 of the following criteria: (1) drug with an unfavorable benefit-to-risk ratio; (2) drug with questionable efficacy according to the Laroche list; (3) absolute contraindication; (4) significant drug-drug interaction. Associated factors were identified by using multivariable logistic regression models. RESULTS: Among the 974 residents included, 71% had PIDP. PIDP was more frequent in patients without dementia, with several comorbidities and taking multiple medications. In the multivariable analysis, age (odds ratio [OR] 1.02; 95% confidence interval [CI] 1.01-1.03) and Charlson Comorbidity Index (CCI; P = .003, CCI = 1 versus 0: OR1/0 1.22; 95% CI 0.85-1.74, CCI >= 2 versus 0: OR2/0 1.72; 95% CI 1.23-2.41) were associated with an increased likelihood of PIDP. By contrast, dementia was associated with a lower likelihood of PIDP (OR 0.70; 95% CI 0.53-0.94). Among NH structural and organizational characteristics, the access to psychiatric advice and/or to hospitalization in a psychiatric unit (OR 1.36; 95% CI 1.02-1.82) and the presence of a reevaluation of drug prescriptions (OR 1.45; 95% CI 1.07-1.96) were associated with an increased likelihood of PIDP. CONCLUSIONS AND RELEVANCE: Our work suggests that some NH characteristics are associated with an increased likelihood of PIDP. Gaining a better understanding of the factors influencing PIDP, especially structural and organizational NH factors, can help to determine the interventions that should be implemented. PMID- 25284166 TI - Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia. AB - Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO's licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto's odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84-0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90-1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed. PMID- 25284167 TI - Expanded graphite loaded with lanthanum oxide used as a novel adsorbent for phosphate removal from water: performance and mechanism study. AB - A novel adsorbent of expanded graphite (EG) loaded with lanthanum oxide (EG-LaO) was prepared for phosphate removal from water and characterized by scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR) spectroscopy. The effects of impregnation time, La3+ concentration, activation time, and activation temperature on the phosphate removal performance of the adsorbent were studied for optimization of preparation conditions. Isothermal adsorption studies suggested that the Langmuir model fits the experimental data well. Adsorption kinetics investigation showed that the pseudo-second-order model fits the experimental data quite well, indicating that the adsorption process is mainly a process of chemical adsorption, and chloride ions compete to react with the active sites of the adsorbent but do not prevent phosphate from adsorbing onto EG LaO. The adsorption mechanism studies were performed by a pH dependence study of the adsorption amount. The results demonstrated that the probable mechanisms of phosphate adsorption on EG-LaO were electrostatic and Lewis acid-base interactions in addition to ion exchange. PMID- 25284168 TI - Tacrolimus therapeutic drug monitoring and pediatric renal transplant graft outcomes. AB - Predose monitoring of tacrolimus levels is standard practice in the care of pediatric renal transplant patients. This is despite a paucity of data investigating the ideal target range in children, and controversy as to whether tacrolimus levels correlate with renal transplant outcomes. We performed a retrospective cohort analysis of 48 renal transplant patients at a single Canadian pediatric transplant center following the initiation of a tacrolimus mycophenolate-prednisone-based IS protocol. We analyzed the relationship of graft function, as defined by GFR up to five yr post-transplant, to the preceding mean tacrolimus level. There was no significant correlation between absolute GFR and mean tacrolimus levels (r = 0.206, p = 0.38). However, a higher mean tacrolimus level, particularly >=10 ng/mL in the first three months after transplantation, was associated with a slower rate of decline in GFR with time (r = 0.608, p = 0.004) and with a less likelihood of developing CKD five yr after transplant. We suggest that the optimal target range for tacrolimus levels may be at the upper end of what is currently practiced and that further research to validate these findings would be useful. PMID- 25284169 TI - Rapid synthesis of hollow Ag-Au nanodendrites in 15 seconds by combining galvanic replacement and precursor reduction reactions. AB - Metallic nanomaterials displaying hollow interiors as well as sharp tips/branches at their surface (such as hollow nanodendrites) are attractive, because these features enable higher surface-to-volume ratios than their solid and/or rounded counterparts. This paper describes a simple strategy for the synthesis of Ag-Au nanodendrites in 15 s using Ag nanospheres prepared in a previous synthetic step as seeds. Our approach was based on the utilization of Ag nanospheres as seeds for Au deposition by a combination of galvanic replacement reaction between Ag and AuCl4(-)(aq) and AuCl4(-)(aq) reduction using hydroquinone in the presence of polyvinylpyrrolidone (PVP) as a stabilizer and water as the solvent. The produced Ag-Au nanodendrites presented monodisperse sizes, and their surface morphologies could be tuned as a function of growth time. Owing to their hollow interiors and sharp tips, the Ag-Au nanodendrites performed as effective substrates for surface enhanced Raman scattering (SERS) detection of 4-MPy (4-mercaptopyridine) and R6G (rhodamine 6G) as probe molecules. We believe that the approach described herein can serve as a protocol for the fast and one-step synthesis of Ag-Au hollow nanondendrites with a wide range of sizes, compositions, and surface morphologies for applications in SERS and catalysis. PMID- 25284170 TI - Neonatomics and childomics: the right route to the future. PMID- 25284171 TI - Urinary metabolomics of pregnant women at term: a combined GC/MS and NMR approach. AB - BACKGROUND: Physiological changes leading to parturition are not completely understood while clinical diagnosis of labour is still retrospective. Gas chromatography mass spectrometry (GC/MS) and nuclear magnetic resonance spectroscopy (NMR) represent two of the main analytical platforms used in clinical metabolomics. Metabolomics might help us to improve our knowledge about the biochemical mechanisms underlying labour. METHODS: Urine samples (n = 59), collected from pregnant women at term of gestation before and/or after the onset of labour, were analysed by GC/MS and NMR techniques in order to identify the metabolic profile. Both GC/MS and NMR data matrices containing the identified metabolites were analysed by multivariate statistical techniques in order to characterise the discriminant variables between labour (L) and not labour (NL) status. RESULTS: 18 potential metabolites (11 with (1)H-NMR, eight with GC-MS: glycine was relevant in both) were found discriminant in urine of women during labour. Taken together, the identified metabolites produced a composite biomarker pattern, a sort of barcode, capable of differentiating between labour and not labour conditions. Major discriminant metabolites for NMR and GC/MS analysis were: alanine, glycine, acetone, 3-hydroxybutiyric acid, 2,3,4-trihydroxybutyric acid and succinic acid, giving a urine metabolite signature on the late phase of labour. CONCLUSIONS: The metabolomics analysis evidenced clusters of metabolites involved in labour condition able to discriminate between urine samples collected before the onset and during labour, potentially offering the promise of a robust screening test. PMID- 25284172 TI - Investigation of the 1H-NMR based urine metabolomic profiles of IUGR, LGA and AGA newborns on the first day of life. AB - (1)H-NMR spectroscopy coupled with multivariate statistical analysis was used for the first time to compare the urinary NMR metabolic profiles of neonates with intrauterine growth retardation (IUGR) and large for gestational age (LGA). For the sake of comparison, infants who were adequate for gestational age (AGA) were also analyzed. Pattern recognition methods, including Principal Component Analyses (PCA), Partial Least Squares Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA), were used to analyze NMR data. Clear differences among the metabolic profiles of AGA, IUGR and LGA were observed. The main metabolites responsible for these differentiations were identified as myo-inositol, creatinine, creatine, citrate, urea and glycine. In particular, among these, myo-inositol may be a potential biomarker of an altered glucose metabolism during fetal development both in IUGR and LGA. This study highlights the applicability of NMR-based metabolomics for improving the understanding of the relations among nutrition, integrated metabolism and health in neonatology. PMID- 25284174 TI - A metabolomic study of preterm and term human and formula milk by proton MRS analysis: preliminary results. AB - OBJECTIVE: To investigate changes in global metabolic profile between: 1 - breast milk and formula milk, 2 - breast milk from mothers delivering at different gestational age (GA) collected within one week from delivery, and then week by week until term equivalent age. METHODS: Proton magnetic resonance spectroscopy (MRS) was used to analyze the water-soluble and lipid fractions extracted from 50 milk samples, 46 human milk at different GA, from 23 weeks of gestation until term equivalent age and four different formula milks. RESULTS: The formula milk for premature infants was the most similar to breast milk of preterm babies. Breast milk showed higher lactose concentrations than formula milk, that conversely presented higher galactose 1-phosphate and maltose concentrations. Mother's milk of very preterm babies (23-25 wks of GA) showed a different metabolic profile from preterm infants >=29 wks of GA with a subsequent trend to similarity around the 30th week of post-natal age. Breast milk from preterm infants of 29-34 wks, collected up to 40 wks of post-natal age showed a temporal change over the first three weeks of lactation, approaching to zero with the achievement of term age. CONCLUSIONS: Metabolome is a promising tool to study human and artificial milk global metabolic profile. PMID- 25284173 TI - Urinary metabolomics (GC-MS) reveals that low and high birth weight infants share elevated inositol concentrations at birth. AB - OBJECTIVE: Metabolomics is a new "omics" platform aimed at high-throughput identification, quantification and characterization of small-molecule metabolites. The metabolomics approach has been successfully applied to the classification different physiological states and identification of perturbed biochemical pathways. The purpose of the current investigation is the application of metabolomics to explore biological mechanisms which may lead to the onset of metabolic syndrome in adulthood. METHODS: We evaluated differences in metabolites in the urine collected within 12 h from 23 infants with IUGR (IntraUterine Growth Restriction), or LGA (Large for Gestational Age), compared to control infants (10 patients defined AGA: Appropriate for Gestational Age). Urinary metabolites were quantified by GC-MS and used to highlight similarities between the two metabolic diseases and identify metabolic markers for their predisposition. Quantified metabolites were analyzed using a multivariate statistics coupled with receiver operator characteristic curve (ROC) analysis of identified biomarkers. RESULTS: Urinary myo-inositol was the most important discriminant between LGA + IUGR and control infants, and displayed an area under the ROC curve = 1. CONCLUSION: We postulate that the increase in plasma and consequently urinary inositol may constitute a marker of altered glucose metabolism during fetal development in both IUGR and LGA newborns. PMID- 25284175 TI - Monitoring neonatal fungal infection with metabolomics. AB - The objective of our study was to evaluate the capability of the metabolomics approach to identify the variations of urine metabolites over time related to the neonatal fungal septic condition. The study population included a clinical case of a preterm neonate with invasive fungal infection and 13 healthy preterm controls. This study showed a unique urine metabolic profile of the patient affected by fungal sepsis compared to urine of controls and it was also possible to evaluate the efficacy of therapy in improving patient health. PMID- 25284176 TI - Urinary metabolomics of bronchopulmonary dysplasia (BPD): preliminary data at birth suggest it is a congenital disease. AB - OBJECTIVE: Bronchopulmonary dysplasia (BPD) or chronic lung disease is one of the principal causes of mortality and morbidity in preterm infants. Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. The trigger cause of the disease comprehends the impairment of the alveolar development and the increased angiogenesis. Nevertheless, the molecular pathways characterizing the disease are still unclear. Therefore, the use of the metabolomics technique, due to the capability of identifying instantaneous metabolic perturbation, might help to recognize metabolic patterns associated with the condition. METHODS: The purpose of this study is to compare urinary metabolomics at birth in 36 newborns with a gestational age below 29 weeks and birth weight <1500 g (very low birth weight - VLBW), admitted in Neonatal Intensive Care Unit (NICU) divided into two groups: the first group (18 cases) consisting of newborns who have not yet developed the disease, but who will subsequently develop it and the second group (18 controls) consisting of newborns not affected by BPD. Urine samples were collected within 24-36 h of life and immediately frozen at -80 degrees C. RESULTS: The (1)H-NMR spectra were analyzed using a partial least squares discriminant analysis (PLS-DA) model coupled with orthogonal Signal Correction. Using this approach it was possible with urine at birth to discriminate newborns that will be later have a diagnosis of BPD with a high statistics power. In particular, we found five important discriminant metabolites in urine in BPD newborns: lactate, taurine, TMAO, myoinositol (which increased) and gluconate (which decreased). CONCLUSION: These preliminary results seem to be promising for the identification of predictor's biomarkers characterizing the BPD condition. These data may suggest that BPD is probably the result of an abnormal development (respiratory bud, vascular tree, hypodysplasia of pneumocytes) and could be considered a congenital disease (genetics plus intrauterine epigenetics). Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. PMID- 25284177 TI - The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings. AB - OBJECTIVE: A supervised multivariate model to classify the metabolome alterations between autistic spectrum disorders (ASD) patients and controls, siblings of autistic patients, has been realized and used to realize a network model of the ASD patients' metabolome. METHODS: In our experiment we propose a quantification of urinary metabolites with the Mass Spectroscopy technique couple to Gas Chromatography. A multivariate model has been used to extrapolate the variables of importance for a network model of interaction between metabolites. In this way we are able to propose a network-based approach to ASD description. RESULTS: Children with autistic disease composing our studied population showed elevated concentration of several organic acids and sugars. Interactions among diet, intestinal flora and genes may explain such findings. Among them, the 3-(3 hydroxyphenyl)-3-hydroxypropanoic acid has been previously described as altered in autistic subjects. Other metabolites increased are 3,4-dihydroxybutyric acid, glycolic acid and glycine, cis-aconitic acid; phenylalanine, tyrosine, p hydroxyphenylacetic acid, and homovanillic acid are all involved in the tyrosine pathway leading to neurotransmitter cathecolamine. CONCLUSION: GC-MS-based metabolomic analysis of the urinary metabolome suggests to have the required sensitivity and specificity to gain insight into ASD phenotypes and aid a personalized network-based medicine approach. PMID- 25284178 TI - Metabolomics technology and their application to the study of the viral infection. AB - OBJECTIVE: In the present review article we have summarized the use of the metabolomics approach to study the metabolic modifications occurring in several bio-fluids due to viral infections. The aim is to highlight the ability of metabolomics to find early fingerprints, which are related to the infections. METHODS: The (1)H-NMR, UHPLC/MS/MS(2), UPLC/ESI-SYNAPT-HDMS, UPLC-Q-TOF-HDMS analyses were used for the determination of several metabolites representative of the viral infections. The data were analyzed by Principal Component Analysis (PCA), Partial Least Square Discriminant Analysis (PLS-DA) and by regression techniques. RESULTS: The major changes were related to nucleotide, carbohydrates, lipids and amino acid metabolisms. CONCLUSIONS: The metabolomics approach could be considered a viable option for characterization of the viral infection and for detecting on going differences in the bio-fluids composition. PMID- 25284179 TI - The triple-I (interactive, intersectorial, interdisciplinary) approach to validate "omics" investigations on body fluids and tissues in perinatal medicine. AB - Proteomics and metabolomics are emerging in recent years as one of the most challenging topics in neonatology. They are characterized by a large amount of data that reflect the complexity of all biological systems more accurately than traditional methods utilized in clinical chemistry. In this review paper we present the modifications of the salivary proteome, which represents an easy and non-invasive method that offers the opportunity to investigate changes in the metabolism of preterm infants and in pediatric patients. Moreover, we present the metabolomics-histologic correlations in newborn piglets at baseline and following normocapnic hypoxia and reoxygenation. A new method of data analysis, here summarized as the "triple-I" approach will be finally discussed: interdisciplinary, intersectorial, interactive. PMID- 25284180 TI - The identification of the first molluscan Akirin2 with immune defense function in the Hong Kong oyster Crassostrea hongkongensis. AB - The Akirin protein is a nuclear factor in the innate immune system that is highly conserved from insects to mammals and plays key roles in diverse biological processes, including immunity, myogenesis, development and the cellular stress response. However, the function of Akirins in mollusk, the second most diverse group of animals, is still poorly understood. In this study, we report the discovery of an Akirin2 gene homolog (ChAkirin2) and its biological functions in the Hong Kong oyster Crassostrea hongkongensis. ChAkirin2 is 189 amino acids in length and shares significant homology with invertebrate homologs. Phylogenetic analysis results revealed that ChAkirin2 is clustered with invertebrate Akirin2s. A sequence analysis of the 5' flanking regions of ChAkirin2 indicated that it harbors several potential PAMP-activated transcription factor binding sites (TFB), including sites for NF-kappaB, C/EBPalpha, AP-1, SRF, Oct-1 and GATA-1. An RT-PCR analysis showed that ChAkirin2 mRNA was ubiquitously expressed in various tissues and at different embryonic and larval stages. Additionally, upon infection by pathogens (Vibrio alginolyticus, Staphylococcus haemolyticus and Saccharomyces cerevisiae) and pathogen-associated molecular patterns (PAMPs: LPS, PGN and polyI:C), the expression of ChAkirin2 was significantly up-regulated. Moreover, fluorescence microscopy observations show that ChAkirin2 is located in the nuclei of HeLa cells, and the overexpression of ChAkirin2 activated the transcriptional activities of the NF-kappaB reporter gene in HEK293T cells. Altogether, this report provided the first experimental demonstration that mollusks possess a functional Akirin2 that is involved in the innate defense and embryogenesis processes of the oyster. PMID- 25284182 TI - Closer to home? PMID- 25284183 TI - Maximising influenza vaccination uptake among older people. AB - Older adults aged 65 years and over are particularly vulnerable to seasonal influenza as their immune system is weaker than that of younger adults. The influenza vaccination helps to reduce influenza severity and the incidence of complications, but a range of factors can affect uptake among older people. These factors can be categorised as follows: the system of vaccination; influenza vaccination mistrust and fear of side-effects; health beliefs and behaviours; and other factors. Various interventions to maximise influenza vaccination uptake among older people in the community have been identified, including: interventions to increase community demand, enhance access and improve influenza vaccination among community nurses, as well as provider or system-based interventions and societal interventions. Community nurses have been found to have a positive influence on influenza vaccination uptake and should continue to promote the benefits of influenza vaccination to their patients who are 'persistent decliners'. PMID- 25284181 TI - Lanthanide nano-drums: a new class of molecular nanoparticles for potential biomedical applications. AB - We are developing a new class of lanthanide-based self-assembling molecular nanoparticles as potential reporter molecules for imaging, and as multi functional nanoprobes or nanosensors in diagnostic systems. These lanthanide "nano-drums" are homogeneous 4d-4f clusters approximately 25 to 30 A in diameter that can emit from the visible to near-infrared (NIR) wavelengths. Here, we present syntheses, crystal structures, photophysical properties, and comparative cytotoxicity data for six nano-drums containing either Eu, Tb, Lu, Er, Yb or Ho. Imaging capabilities of these nano-drums are demonstrated using epifluorescence, total internal reflection fluorescence (TIRF), and two-photon microscopy. We discuss how these molecular nanoparticles can to be adapted for a range of assays, particularly by taking advantage of functionalization strategies with chemical moieties to enable conjugation to protein or nucleic acids. PMID- 25284184 TI - Common skin problems in the community and primary care. AB - Skin problems can be hard to diagnose, leaving clinicians frustrated and patients incorrectly treated, but rashes and lesions can be markers of systemic disease and infections. However, by using simple history-taking and mnemonics, safety and correct diagnoses can be achieved. This article will consider some common problems encountered in primary and community care, issues that need to be excluded, resources that will help with diagnosis and some management guidelines. This is not an exhaustive guide, and advice should be sought from learned colleagues in specific cases. Pressure area care and the use of compression bandaging will not be discussed unless it is of relevance to the subject of rashes and lesions. PMID- 25284185 TI - Advance care planning for people living with dementia. AB - The prevalence of dementia is increasing, however it is only recently that dementia has been recognised as a terminal disease where end-of-life care needs to be discussed and planned with the patient and their family. Early diagnosis of dementia enables the person with dementia and their family to discuss the future, including plans for end-of-life care such as Advance Care Planning (ACP). However, discussions regarding end-of-life care are not routine practice for people with dementia and their families. This article reviews the literature regarding barriers that impact on healthcare professionals' engagement with ACP for people with dementia and their families. PMID- 25284186 TI - Supporting the use of evidence in community nursing: a national strategic approach. AB - While there is an acceptance across all stakeholders that nursing practice should be informed by evidence, there is a substantial literature on the challenges this creates for nurses in the delivery of services. These challenges are accentuated for nurses in community settings, where accessible, up-to-date research evidence is more problematic because of the decentralised organisation and delivery of these services. Recognising this gap, and the consequent needs of its members, the Institute of Community Health Nursing (ICHN) in Ireland has commenced a national strategic development in this area. The purpose of the strategy is to actively support and facilitate public health and community nurses to provide services to individuals, families and communities that are based on the best available research evidence. This article provides a brief overview of the development and key components of the ICHN strategy. PMID- 25284187 TI - Enhancing person-centred care through the development of a therapeutic relationship. AB - More than ever, district nurses require highly developed communication and interpersonal skills to enable and nurture a therapeutic relationship. The 'shift left'-whereby patients are being assessed and cared for in the community at a much earlier stage of their illness or recovery-has significant implications. The complexity of patient care and the need for collaborative working and shared decision making necessitates a focus on fostering person-centred care and improving the patient experience in practice. District nurses are adept communicators with a specialist body of knowledge and skills. In Northern Ireland, the single assessment tool (NISAT) is used by health professionals and follows a person-centred framework. This case study reflects on the assessment process used by a district nursing student in clinical practice and demonstrates how a therapeutic relationship is developed, thereby supporting person centredness. PMID- 25284188 TI - Principled decision making in district nurse practice. AB - This article outlines a case study in which Sister Mary Newsome is in conflict with her district nurse colleague over the care of Margaret, 67, who they visit to monitor blood glucose levels and calculate the insulin dose to manage her diabetes. Recently, Margaret has been refusing to answer the door to the district nurses and has been eating sugary foods that have resulted in five admissions for diabetic ketoacidosis. While Sister Newsome believes continued care at home is best for Margaret, her colleague believes that only residential care will ensure Margaret maintains an appropriate diet and receives her insulin. Sister Newsome considers how best to resolve the conflict over the care of Margaret. PMID- 25284189 TI - Clostridium difficile in the community: time to clean up? PMID- 25284190 TI - COPD in the community: working beyond boundaries. PMID- 25284191 TI - Avoiding burnout syndrome in palliative care. PMID- 25284192 TI - Moral challenges. PMID- 25284193 TI - Precision genome editing in plants via gene targeting and piggyBac-mediated marker excision. AB - Precise genome engineering via homologous recombination (HR)-mediated gene targeting (GT) has become an essential tool in molecular breeding as well as in basic plant science. As HR-mediated GT is an extremely rare event, positive negative selection has been used extensively in flowering plants to isolate cells in which GT has occurred. In order to utilize GT as a methodology for precision mutagenesis, the positive selectable marker gene should be completely eliminated from the GT locus. Here, we introduce targeted point mutations conferring resistance to herbicide into the rice acetolactate synthase (ALS) gene via GT with subsequent marker excision by piggyBac transposition. Almost all regenerated plants expressing piggyBac transposase contained exclusively targeted point mutations without concomitant re-integration of the transposon, resulting in these progeny showing a herbicide bispyribac sodium (BS)-tolerant phenotype. This approach was also applied successfully to the editing of a microRNA targeting site in the rice cleistogamy 1 gene. Therefore, our approach provides a general strategy for the targeted modification of endogenous genes in plants. PMID- 25284194 TI - Selenium Treatment and Chagasic Cardiopathy (STCC): study protocol for a double blind randomized controlled trial. AB - BACKGROUND: Heart disease progression occurs in 30% of patients with chronic Trypanosoma cruzi infection. Supplementation with selenium (Se) in animal model of T. cruzi infection produced promising results. There is evidence that patients with Chagas heart disease have lower Se levels than healthy individuals and patients with T. cruzi infection without of cardiac disease. The aim of this investigation is to estimate the effect of Se treatment on prevention of heart disease progression in patients with chagasic cardiopathy. METHODS: The Selenium Treatment and Chagasic Cardiopathy trial is a superiority, double-blind, placebo controlled, randomized clinical trial. The eligibility criteria are as follows: (1) a Chagas disease diagnosis confirmed by serology; (2) segmental, mild or moderate global left ventricular systolic dysfunction; and (3) age between 18 and 65 years. The exclusion criteria are as follows: (1) pregnancy, (2) diabetes mellitus, (3) tobacco use, (4) alcohol abuse, (5) evidence of nonchagasic heart disease, (6) depression, (7) dysphagia with evidence of food residues in the esophagus, (8) dysphagia with weight loss higher than 15% of usual weight in the last four months and/or (9) conditions that may result in low protocol adherence. The intervention will be 100 MUg of sodium selenite once daily for 365 consecutive days compared to placebo. The following are the primary outcomes to be measured: (1) the trajectories of the left ventricular ejection fraction in the follow-up period; (2) reduction of heart disease progression rates, with progression defined as a 10% decrease in left ventricular ejection fraction; and (3) rate of hospital admissions attributable to dysrhythmia, heart failure or stroke due to Chagas disease. One hundred thirty patients will be randomly allocated into either the intervention or placebo group at a ratio of 1:1. The sequence allocation concealment and blinding were planned to be conducted with the strategy of numbered boxes. Both patients and health-care providers will remain blinded to the intervention groups during the 5 years of follow-up. DISCUSSION: If Se treatment reduces the progression of Chagas cardiopathy, the inclusion of this micronutrient in the daily diet can improve the therapeutic regimen for this neglected tropical disease at low cost. TRIAL REGISTRATION: Clinical Trials.gov ID: NCT00875173 (registered 20 October 20 2008). PMID- 25284195 TI - Health effects of chronic arsenic exposure. AB - Arsenic is a unique element with distinct physical characteristics and toxicity whose importance in public health is well recognized. The toxicity of arsenic varies across its different forms. While the carcinogenicity of arsenic has been confirmed, the mechanisms behind the diseases occurring after acute or chronic exposure to arsenic are not well understood. Inorganic arsenic has been confirmed as a human carcinogen that can induce skin, lung, and bladder cancer. There are also reports of its significant association to liver, prostate, and bladder cancer. Recent studies have also suggested a relationship with diabetes, neurological effects, cardiac disorders, and reproductive organs, but further studies are required to confirm these associations. The majority of research to date has examined cancer incidence after a high exposure to high concentrations of arsenic. However, numerous studies have reported various health effects caused by chronic exposure to low concentrations of arsenic. An assessment of the health effects to arsenic exposure has never been performed in the South Korean population; thus, objective estimates of exposure levels are needed. Data should be collected on the biological exposure level for the total arsenic concentration, and individual arsenic concentration by species. In South Korea, we believe that biological exposure assessment should be the first step, followed by regular health effect assessments. PMID- 25284196 TI - Environmental source of arsenic exposure. AB - Arsenic is a ubiquitous, naturally occurring metalloid that may be a significant risk factor for cancer after exposure to contaminated drinking water, cigarettes, foods, industry, occupational environment, and air. Among the various routes of arsenic exposure, drinking water is the largest source of arsenic poisoning worldwide. Arsenic exposure from ingested foods usually comes from food crops grown in arsenic-contaminated soil and/or irrigated with arsenic-contaminated water. According to a recent World Health Organization report, arsenic from contaminated water can be quickly and easily absorbed and depending on its metabolic form, may adversely affect human health. Recently, the US Food and Drug Administration regulations for metals found in cosmetics to protect consumers against contaminations deemed deleterious to health; some cosmetics were found to contain a variety of chemicals including heavy metals, which are sometimes used as preservatives. Moreover, developing countries tend to have a growing number of industrial factories that unfortunately, harm the environment, especially in cities where industrial and vehicle emissions, as well as household activities, cause serious air pollution. Air is also an important source of arsenic exposure in areas with industrial activity. The presence of arsenic in airborne particulate matter is considered a risk for certain diseases. Taken together, various potential pathways of arsenic exposure seem to affect humans adversely, and future efforts to reduce arsenic exposure caused by environmental factors should be made. PMID- 25284197 TI - Influence of the nursing practice environment on job satisfaction and turnover intention. AB - OBJECTIVES: To examine whether the nursing practice environment at the hospital level affects the job satisfaction and turnover intention of hospital nurses. METHODS: Among the 11 731 nurses who participated in the Korea Health and Medical Workers' Union's educational program, 5654 responded to our survey. Data from 3096 nurses working in 185 general inpatient wards at 60 hospitals were analyzed using multilevel logistic regression modeling. RESULTS: Having a standardized nursing process (odds ratio [OR], 4.21; p<0.001), adequate nurse staffing (OR, 4.21; p<0.01), and good doctor-nurse relationship (OR, 4.15; p<0.01), which are hospital-level variables based on the Korean General Inpatients Unit Nursing Work Index (KGU-NWI), were significantly related to nurses' job satisfaction. However, no hospital-level variable from the KGU-NWI was significantly related to nurses' turnover intention. CONCLUSIONS: Favorable nursing practice environments are associated with job satisfaction among nurses. In particular, having a standardized nursing process, adequate nurse staffing, and good doctor-nurse relationship were found to positively influence nurses' job satisfaction. However, the nursing practice environment was not related to nurses' turnover intention. PMID- 25284198 TI - Age at smoking initiation and subsequent smoking among Korean adolescent smokers. AB - OBJECTIVES: The aim of this study was to investigate the relationship between age at cigarette smoking initiation and smoking level among adolescent current smokers. METHODS: In 2007, students from one or two classes of the 10th or 11th grade were randomly selected using the probability proportional to size sampling method. In total, 743 current smokers were included. Multiple logistic regression was used to determine the association between age at smoking initiation and smoking level as either frequent, daily, or heavy smokers. RESULTS: The adjusted odds ratios for each smoking level were significantly higher for younger ages of smoking initiation than those for older ages of initiation were (p for trend <0.001). Compared with the students who started smoking in grades 10 to 11, the adjusted odds ratios for frequent, daily, and heavy smokers increased from 2.24 (95% confidence interval [CI], 1.30 to 3.87) to 3.90 (95% CI, 2.02 to 7.56), from 1.56 (95% CI, 0.92 to 2.62) to 3.17 (95% CI, 1.70 to 5.92), and from 2.56 (95% CI, 1.21 to 5.42) to 5.67 (95% CI, 2.61 to 12.30) with younger ages of smoking initiation. CONCLUSIONS: Smoking frequency and amount were closely associated with age at smoking initiation. Therefore, smoking prevention programs should be initiated from the young adolescent period. PMID- 25284199 TI - Nurse-perceived patient adverse events and nursing practice environment. AB - OBJECTIVES: To evaluate the occurrence of patient adverse events in Korean hospitals as perceived by nurses and examine the correlation between patient adverse events with the nurse practice environment at nurse and hospital level. METHODS: In total, 3096 nurses working in 60 general inpatient hospital units were included. A two-level logistic regression analysis was performed. RESULTS: At the hospital level, patient adverse events included patient falls (60.5%), nosocomial infections (51.7%), pressure sores (42.6%) and medication errors (33.3%). Among the hospital-level explanatory variables associated with the nursing practice environment, 'physician- nurse relationship' correlated with medication errors while 'education for improving quality of care' affected patient falls. CONCLUSIONS: The doctor-nurse relationship and access to education that can improve the quality of care at the hospital level may help decrease the occurrence of patient adverse events. PMID- 25284200 TI - Differences in the levels of gastric cancer risk factors between Nanjing and Minqing counties, China. AB - OBJECTIVES: In Fujian Province, China, gastric cancer is one of the leading causes of mortality among all malignant tumors. Nanjing county and Minqing county are located in inland Fujian and have similar general demographics. However, the adjusted mortality rate of gastric cancer in Minqing was found to be much higher than that in Nanjing. We sought to explore factors associated with this increased risk of gastric cancer between the two counties. METHODS: We recruited 231 and 224 residents from Nanjing and Minqing, respectively, and analyzed differences between their dietary habits, Helicobacter pylori infection rates, and concentrations of serum pepsinogen I, pepsinogen II, gastrin-17, and ratio of pepsinogen I:II. RESULTS: Subjects in Minqing had more first-degree relatives who had been diagnosed with upper gastrointestinal tumor, more unhealthy dietary habits, a higher Helicobacter pylori positive rate, and greater proportion of abnormal serum gastrin-17 than those in Nanjing did. CONCLUSIONS: The factors that differed between these two counties might indicate that residents in Minqing have a higher risk for developing gastric cancer than those in Nanjing do. PMID- 25284202 TI - Genomic characterization of phiRS603, a filamentous bacteriophage that is infectious to the phytopathogen Ralstonia solanacearum. AB - A filamentous bacteriophage (phi), phiRS603, which is infectious to the phytopathogen Ralstonia solanacearum was isolated. phiRS603 was found to have a circular single-stranded DNA genome composed of 7679 nucleotides and to contain 13 putative open reading frames (ORFs). The phiRS603 genome showed strong similarity with those of Ralstonia phages phiRSM1 and phiRSM3, as reported by Askora et al. The phiRS603 genome had no ORFs corresponding to ORFs 2, 3, 13 and 14 (integrase) of phiRSM3. phiRS603 had an ORF that was homologous to other Ralstonia phages phiRSS0 and phiRSS1; however, phiRSM1 and phiRSM3 did not. PMID- 25284203 TI - Determination of absolute quantum efficiency of X-ray nano phosphors by thin film photovoltaic cells. AB - The absolute optical power at 611 nm emitting from Eu doped Gd2O3 nano phosphors upon X-ray excitation from a microfocus X-ray source operated at 100 kV was measured with thin film photovoltaic cells (TFPCs), whose optical response was calibrated using an He-Ne laser at 632 nm. The same TFPCs were also used to determine the absorbed X-ray power by the nano phosphors. These measurements provided a convenient and inexpensive way to determine the absolute quantum efficiency of nano phosphors, normally a difficult task. The measured absolute X ray-to-optical fluorescence efficiency of the nano phosphors annealed at 1100 degrees C was 3.2%. This is the first time such efficiency for Eu/Gd2O3 nano phosphors is determined, and the measured efficiency is a fraction of the theoretically predicted maximum efficiency of 10% reported in the literature. PMID- 25284201 TI - Assembly dynamics and the roles of FliI ATPase of the bacterial flagellar export apparatus. AB - For construction of the bacterial flagellum, FliI ATPase forms the FliH2-FliI complex in the cytoplasm and localizes to the flagellar basal body (FBB) through the interaction of FliH with a C ring protein, FliN. FliI also assembles into a homo-hexamer to promote initial entry of export substrates into the export gate. The interaction of FliH with an export gate protein, FlhA, is required for stable anchoring of the FliI6 ring to the gate. Here we report the stoichiometry and assembly dynamics of FliI-YFP by fluorescence microscopy with single molecule precision. More than six FliI-YFP molecules were associated with the FBB through interactions of FliH with FliN and FlhA. Single FliI-YFP molecule exchanges between the FBB-localized and free-diffusing ones were observed several times per minute. Neither the number of FliI-YFP associated with the FBB nor FliI-YFP turnover rate were affected by catalytic mutations in FliI, indicating that ATP hydrolysis by FliI does not drive the assembly-disassembly cycle of FliI during flagellar assembly. We propose that the FliH2FliI complex and FliI6 ring function as a dynamic substrate carrier and a static substrate loader, respectively. PMID- 25284204 TI - Advances in mass spectrometry driven O-glycoproteomics. AB - BACKGROUND: Global analyses of proteins and their modifications by mass spectrometry are essential tools in cell biology and biomedical research. Analyses of glycoproteins represent particular challenges and we are only at the beginnings of the glycoproteomic era. Some of the challenges have been overcome with N-glycoproteins and proteome-wide analysis of N-glycosylation sites is accomplishable today but only by sacrificing information of structures at individual glycosites. More recently advances in analysis of O-glycoproteins have been made and proteome-wide analysis of O-glycosylation sites is becoming available as well. SCOPE OF REVIEW: Here we discuss the challenges of analysis of O-glycans and new O-glycoproteomics strategies focusing on O-GalNAc and O-Man glycoproteomes. MAJOR CONCLUSIONS: A variety of strategies are now available for proteome-wide analysis of O-glycosylation sites enabling functional studies. However, further developments are still needed for complete analysis of glycan structures at individual sites for both N- and O-glycoproteomics strategies. GENERAL SIGNIFICANCE: The advances in O-glycoproteomics have led to identification of new biological functions of O-glycosylation and a new understanding of the importance of where O-glycans are positioned on proteins. PMID- 25284205 TI - Morphological Study of the Encystment and Excystment of Vermamoeba vermiformis Revealed Original Traits. AB - Free-living amoebae are ubiquitous protozoa commonly found in water. Among them, Acanthamoeba and Vermamoeba (formerly Hartmannella) are the most represented genera. In case of stress, such as nutrient deprivation or osmotic stress, these amoebae initiate a differentiation process, named encystment. It leads to the cyst form, which is a resistant form enabling amoebae to survive in harsh conditions and resist disinfection treatments. Encystment has been thoroughly described in Acanthamoeba but poorly in Vermamoeba. Our study was aimed to follow the encystment/excystment processes by microscopic observations. We show that encystment is quite rapid, as mature cysts were obtained in 9 h, and that cyst wall is composed of two layers. A video shows that a locomotive form is likely involved in clustering cysts together during encystment. As for Acanthamoeba, autophagy is likely active during this process. Specific vesicles, possibly involved in ribophagy, were observed within the cytoplasm. Remarkably, mitochondria rearranged around the nucleus within the cyst, suggesting high needs in energy. Unlike Acanthamoeba and Naegleria, no ostioles were observed in the cyst wall suggesting that excystment is original. During excystment, large vesicles, likely filled with hydrolases, were found in close proximity to cyst wall and digest it. Trophozoite moves inside its cyst wall before exiting during excystment. In conclusion, Vermamoeba encystment/excystment displays original trends as compare to Acanthamoeba. PMID- 25284206 TI - Gigahertz single-trap electron pumps in silicon. AB - Manipulation of single electrons is the key to developing ultimate electronics such as single-electron-based information processors and electrical standards in metrology. Especially, high-frequency and high-accuracy single-electron pumps are essential to realize practical current standards. While electrically defined quantum dots are widely used to build single-electron pumps, a localized state in semiconductors is also a potential candidate for accurate pumps because it can have a large activation energy for the captured electron. However, the transfer mechanism of such localized-state-mediated single-electron pumps for high accuracy operation at a high frequency has not been well examined. Here we demonstrate a single-electron pump using a single-trap level with an activation energy of a few ten millielectron volts in Si nanotransistors. By means of gate control of capture and emission rates, the pump operates at a frequency of 3 GHz with an accuracy of better than 10(-3) at 17 K, indicating that an electric field at the trap level lowers the capture and emission time to less than 25 ps. PMID- 25284207 TI - Neonatal double switch for congenitally corrected transposition with Ebstein anomaly and bilateral superior venae cavae. PMID- 25284208 TI - Coronary artery bypass grafting: learning to do common things uncommonly well. PMID- 25284209 TI - Zazen meditation and no-task resting EEG compared with LORETA intracortical source localization. AB - Meditation is a self-induced and willfully initiated practice that alters the state of consciousness. The meditation practice of Zazen, like many other meditation practices, aims at disregarding intrusive thoughts while controlling body posture. It is an open monitoring meditation characterized by detached moment-to-moment awareness and reduced conceptual thinking and self-reference. Which brain areas differ in electric activity during Zazen compared to task-free resting? Since scalp electroencephalography (EEG) waveforms are reference dependent, conclusions about the localization of active brain areas are ambiguous. Computing intracerebral source models from the scalp EEG data solves this problem. In the present study, we applied source modeling using low resolution brain electromagnetic tomography (LORETA) to 58-channel scalp EEG data recorded from 15 experienced Zen meditators during Zazen and no-task resting. Zazen compared to no-task resting showed increased alpha-1 and alpha-2 frequency activity in an exclusively right-lateralized cluster extending from prefrontal areas including the insula to parts of the somatosensory and motor cortices and temporal areas. Zazen also showed decreased alpha and beta-2 activity in the left angular gyrus and decreased beta-1 and beta-2 activity in a large bilateral posterior cluster comprising the visual cortex, the posterior cingulate cortex and the parietal cortex. The results include parts of the default mode network and suggest enhanced automatic memory and emotion processing, reduced conceptual thinking and self-reference on a less judgmental, i.e., more detached moment-to moment basis during Zazen compared to no-task resting. PMID- 25284211 TI - Individuation training with other-race faces reduces preschoolers' implicit racial bias: a link between perceptual and social representation of faces in children. AB - The present study examined whether perceptual individuation training with other race faces could reduce preschool children's implicit racial bias. We used an 'angry = outgroup' paradigm to measure Chinese children's implicit racial bias against African individuals before and after training. In Experiment 1, children between 4 and 6 years were presented with angry or happy racially ambiguous faces that were morphed between Chinese and African faces. Initially, Chinese children demonstrated implicit racial bias: they categorized happy racially ambiguous faces as own-race (Chinese) and angry racially ambiguous faces as other-race (African). Then, the children participated in a training session where they learned to individuate African faces. Children's implicit racial bias was significantly reduced after training relative to that before training. Experiment 2 used the same procedure as Experiment 1, except that Chinese children were trained with own-race Chinese faces. These children did not display a significant reduction in implicit racial bias. Our results demonstrate that early implicit racial bias can be reduced by presenting children with other-race face individuation training, and support a linkage between perceptual and social representations of face information in children. PMID- 25284213 TI - Kinetic resolution of racemic mandelic acid esters by N,N'-dioxide-scandium complex-catalyzed enantiomer-selective acylation. AB - A simple and efficient acylative kinetic resolution of racemic mandelic acid esters was accomplished with a chiral N,N'-dioxide-scandium(III) complex under mild and base-free reaction conditions. A variety of mandelic acid esters performed well in the reaction, obtaining both acylated products (up to 49% yield, 97% ee) and recovered substrates (up to 49% yield, 95% ee) in high enantioselectivities with perfect selectivity factors (up to 247). The enantioselective recognition and catalytic models were also proposed for the catalytic KR reaction. PMID- 25284214 TI - Combinatorial crystal synthesis: structural landscape of phloroglucinol:1,2-bis(4 pyridyl)ethylene and phloroglucinol:phenazine. AB - A large number of crystal forms, polymorphs and pseudopolymorphs, have been isolated in the phloroglucinol-dipyridylethylene (PGL:DPE) and phloroglucinol phenazine (PGL:PHE) systems. An understanding of the intermolecular interactions and synthon preferences in these binary systems enables one to design a ternary molecular solid that consists of PGL, PHE, and DPE, and also others where DPE is replaced by other heterocycles. Clean isolation of these ternary cocrystals demonstrates synthon amplification during crystallization. These results point to the lesser likelihood of polymorphism in multicomponent crystals compared to single-component crystals. The appearance of several crystal forms during crystallization of a multicomponent system can be viewed as combinatorial crystal synthesis with synthon selection from a solution library. The resulting polymorphs and pseudopolymorphs that are obtained constitute a crystal structure landscape. PMID- 25284210 TI - NK1.1+ CD8+ T cells escape TGF-beta control and contribute to early microbial pathogen response. AB - Following microbial pathogen invasion, one of the main challenges for the host is to rapidly control pathogen spreading to avoid vital tissue damage. Here we report that an effector CD8(+) T-cell population that expresses the marker NK1.1 undergoes delayed contraction and sustains early anti-microbial protection. NK1.1(+) CD8(+) T cells are derived from CD8(+) T cells during priming, and their differentiation is inhibited by transforming growth factor-beta signalling. After their own contraction phase, they form a distinct pool of KLRG1 CD127 double positive memory T cells and rapidly produce both interferon-gamma and granzyme B, providing significant pathogen protection in an antigen-independent manner within only a few hours. Thus, by prolonging the CD8(+) T-cell response at the effector stage and by expressing exacerbated innate-like features at the memory stage, NK1.1(+) cells represent a distinct subset of CD8(+) T cell that contributes to the early control of microbial pathogen re-infections. PMID- 25284212 TI - Embryologists' health: a nationwide online questionnaire. AB - PURPOSE: The present study evaluates health status and its relation with occupational characteristics and with burnout syndrome among embryologists. METHODS: A cross-sectional design was used to conduct an online self-assessment survey, sent to all members of the Spanish Association of Clinical Embryologists. The questionnaire contained occupational questions and two standard instruments: 'Short Form-12 Health Survey' as a measure of physical (PCS-12) and mental (MCS 12) health and the Maslach Burnout Inventory-General Survey (MBI-GS) to evaluate the degree of burnout. RESULTS: The PCS-12 obtained for the Spanish embryologists was higher than that for the reference population. However, the total MCS-12 was significantly lower than that observed in non-institutionalised males and females representative of the general Spanish population aged 35-44 years. In the linear regression model, the dependent variable PCS-12 was related indirectly with the variables number of hours worked per week, BMI, back pain, leg pain and visual discomfort. In the linear regression model, the dependent variable MCS-12 was indirectly related to the gender (male reference; female coefficient regression: 3.23), exhaustion and cynicism dimensions of the MBI-GS. A total of 87 (36.3%) embryologists presented a high score on at least one of the MBI-GS dimensions. CONCLUSION: In this sample of Spanish embryologists, a norm measure (SF-12) showed their physical health to be better than the average for the general population, but that their mental health was poorer. A significant indirect relation was observed between mental health and burnout syndrome. Strategies to reduce occupational stress and problems should form part of the training provided for clinical embryologists. PMID- 25284215 TI - Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: possible implication of serotonergic system. AB - Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes. Experimentally, Swiss albino mice were rendered diabetic by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg). After 8 weeks, diabetic mice received a single dose of vehicle/ondansetron (0.5 and 1 mg/kg, p.o.)/fluoxetine (the positive control, 10 mg/kg p.o.) for 28 days. Thereafter, behavioral studies were conducted to test depression-like behavior using forced swim test (FST) and anxiety-like deficits using hole-board and light dark tests, followed by biochemical estimation of serotonin content in discrete brain regions. The results demonstrated that, STZ-induced diabetic mice exhibited increased duration of immobility and decreased swimming behavior in FST, reduced exploratory behavior during hole-board test and increased aversion to brightly illuminated light area in light-dark test as compared to non-diabetic mice, while ondansetron (similar to fluoxetine) treatment significantly reversed the same. Biochemical assay revealed that ondansetron administration attenuated diabetes induced neurochemical impairment of serotonin function, indicated by elevated serotonin levels in discrete brain regions of diabetic mice. Collectively, the data indicate that ondansetron may reverse depression and anxiety-like behavioral deficits associated with diabetes in mice and modulation of serotonergic activity may be a key mechanism of the compound. PMID- 25284216 TI - Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine. AB - INTRODUCTION: Although clozapine (CLZ) is considered the best evidence-based therapeutic option for treatment of resistant schizophrenia patients, a significant proportion of CLZ-treated patients show a partial or inadequate response to treatment, leading to increased healthcare cost and poor quality of life for affected individuals. AREAS COVERED: This paper comprises a review of main research in CLZ augmentation strategies for treatment-refractory schizophrenia, with a focus on research conducted between 1990 and 2014. Databases that were searched include: PubMed, CINAHL, EMBASE PsychINFO, AgeLine and Cochrane Database of Systematic Reviews. Primary search terms were 'clozapine augmentation', 'clozapine and add-on' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. We reviewed the available evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents. EXPERT OPINION: Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. More research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and more well designed trials are required to establish true efficacy and safety of CLZ augmentation strategies. PMID- 25284217 TI - Long-term characterization of persistent atrial fibrillation: wave morphology, frequency, and irregularity analysis. AB - Short-term properties of atrial fibrillation (AF) frequency, f-wave morphology, and irregularity parameters have been thoroughly studied, but not long-term properties. In the present work, f-wave morphology is characterized by principal component analysis, introducing a novel temporal parameter defined by the cumulative normalized variance of the three largest principal components (r3). Based on 7-day recordings from nine patients with stable chronic heart failure and persistent AF, long-term properties were studied in terms of r3 AF frequency, and sample entropy (SampEn). The main result of the present study is that detection of circadian rhythms depends on the parameter considered: rhythms were found in six (r3, SampEn) and five (AF frequency) patients, but not always in the same patient. Another important result is that circadian rhythms detected in 7 day recordings could not always be detected in 24-h periods, thus shedding new light on the results in previous studies which all were based on 24-h recordings. Infradian rhythms were found in four (r3, SampEn) and one (AF frequency) patients. PMID- 25284218 TI - Feature selection and classification of leukocytes using random forest. AB - In automatic segmentation of leukocytes from the complex morphological background of tissue section images, a vast number of artifacts/noise are also extracted causing large amount of multivariate data generation. This multivariate data degrades the performance of a classifier to discriminate between leukocytes and artifacts/noise. However, the selection of prominent features plays an important role in reducing the computational complexity and increasing the performance of the classifier as compared to a high-dimensional features space. Therefore, this paper introduces a novel Gini importance-based binary random forest feature selection method. Moreover, the random forest classifier is used to classify the extracted objects into artifacts, mononuclear cells, and polymorphonuclear cells. The experimental results establish that the proposed method effectively eliminates the irrelevant features, maintaining the high classification accuracy as compared to other feature reduction methods. PMID- 25284219 TI - A review of ultrasound common carotid artery image and video segmentation techniques. AB - The determination of the wall thickness [intima-media thickness (IMT)], the delineation of the atherosclerotic carotid plaque, the measurement of the diameter in the common carotid artery (CCA), as well as the grading of its stenosis are important for the evaluation of the atherosclerosis disease. All these measurements are also considered to be significant markers for the clinical evaluation of the risk of stroke. A number of CCA segmentation techniques have been proposed in the last few years either for the segmentation of the intima media complex (IMC), the lumen of the CCA, or for the atherosclerotic carotid plaque from ultrasound images or videos of the CCA. The present review study proposes and discusses the methods and systems introduced so far in the literature for performing automated or semi-automated segmentation in ultrasound images or videos of the CCA. These are based on edge detection, active contours, level sets, dynamic programming, local statistics, Hough transform, statistical modeling, neural networks, and an integration of the above methods. Furthermore, the performance of these systems is evaluated and discussed based on various evaluation metrics. We finally propose the best performing method that can be used for the segmentation of the IMC and the atherosclerotic carotid plaque in ultrasound images and videos. We end the present review study with a discussion of the different image and video CCA segmentation techniques, future perspectives, and further extension of these techniques to ultrasound video segmentation and wall tracking of the CCA. Future work on the segmentation of the CCA will be focused on the development of integrated segmentation systems for the complete segmentation of the CCA as well as the segmentation and motion analysis of the plaque and or the IMC from ultrasound video sequences of the CCA. These systems will improve the evaluation, follow up, and treatment of patients affected by advanced atherosclerosis disease conditions. PMID- 25284220 TI - Continuous flow left ventricular pump support and its effect on regional left ventricular wall stress: finite element analysis study. AB - Left ventricular assist device (LVAD) support unloads left ventricular (LV) pressure and volume and decreases wall stress. This study investigated the effect of systematic LVAD unloading on the 3-dimensional myocardial wall stress by employing finite element models containing layered fiber structure, active contractility, and passive stiffness. The HeartMate II((r)) (Thoratec, Inc., Pleasanton, CA) was used for LV unloading. The model geometries and hemodynamic conditions for baseline (BL) and LVAD support (LVsupport) were acquired from the Penn State mock circulatory cardiac simulator. Myocardial wall stress of BL was compared with that of LVsupport at 8,000, 9,000, 10,000 RPM, providing mean pump flow (Q(mean)) of 2.6, 3.2, and 3.7 l/min, respectively. LVAD support was more effective at unloading during diastole as compared to systole. Approximately 40, 50, and 60% of end-diastolic wall stress reduction were achieved at Q(mean) of 2.6, 3.2, and 3.7 l/min, respectively, as compared to only a 10% reduction of end systolic wall stress at Q(mean) of 3.7 l/min. In addition, there was a stress concentration during systole at the apex due to the cannulation and reduced boundary motion. This modeling study can be used to further understand optimal unloading, pump control, patient management, and cannula design. PMID- 25284221 TI - Magnetically responsive yeast cells: methods of preparation and applications. AB - Magnetically modified yeast cells represent an interesting type of biocomposite material, applicable in various areas of bioanalysis, biotechnology and environmental technology. In this review, typical examples of magnetic modifications of yeast cells of the genera Saccharomyces, Kluyveromyces, Rhodotorula and Yarrowia are presented, as well as their possible applications as biocatalysts, active part of biosensors and biosorbents for the separation of organic xenobiotics, heavy metal ions and radionuclides. PMID- 25284222 TI - Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. AB - Phosphorylation is often used to promote protein ubiquitylation, yet we rarely understand quantitatively how ligase activation and ubiquitin (UB) chain assembly are integrated with phosphoregulation. Here we employ quantitative proteomics and live-cell imaging to dissect individual steps in the PINK1 kinase-PARKIN UB ligase mitochondrial control pathway disrupted in Parkinson's disease. PINK1 plays a dual role by phosphorylating PARKIN on its UB-like domain and poly-UB chains on mitochondria. PARKIN activation by PINK1 produces canonical and noncanonical UB chains on mitochondria, and PARKIN-dependent chain assembly is required for accumulation of poly-phospho-UB (poly-p-UB) on mitochondria. In vitro, PINK1 directly activates PARKIN's ability to assemble canonical and noncanonical UB chains and promotes association of PARKIN with both p-UB and poly p-UB. Our data reveal a feedforward mechanism that explains how PINK1 phosphorylation of both PARKIN and poly-UB chains synthesized by PARKIN drives a program of PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage. PMID- 25284225 TI - The outstanding achievements of the TraumaRegister. PMID- 25284224 TI - Electrophysiologic features of fetal ventricular aneurysms and diverticula. AB - OBJECTIVE: Congenital ventricular wall defects are very rare and include congenital ventricular aneurysms (CVAs) and diverticula (CVDs). METHOD: We report a series of five fetuses: three with CVAs and two with CVDs referred due to fetal arrhythmia. In addition to routine fetal echocardiography, fetal magnetocardiography (fMCG) was used. The literature in CVA and CVD is reviewed. RESULTS: Incessant premature ventricular contractions (PVC), mainly bigeminy and trigeminy were found in three fetuses with CVAs and in one with CVD, who also had ventricular couplets. The other fetus with CVD, referred because of PVCs, had only sinus tachycardia. ST elevation was noted in two. Fetal movement had a variable impact on PVCs. Postnatal evaluation demonstrated two persistent left ventricular aneurysms and one persistent right CVD; one CVD resolved at 35-week gestation. Two neonates had incessant PVCs. Both arrhythmias resolved spontaneously while being treated with propranolol. CONCLUSION: FMCG is complementary to echocardiographic imaging. In fetuses with left ventricular wall defects, additional electrophysiological diagnosis can be made by fMCG, including the complexity of ventricular ectopy, arrhythmic response to fetal movement, presence of ST-T wave abnormalities, and atrial amplitude increases. Prenatal risk factor assessment using fMCG can additionally support post-natal treatment and follow-up. PMID- 25284223 TI - Oxidative stress diverts tRNA synthetase to nucleus for protection against DNA damage. AB - Tyrosyl-tRNA synthetase (TyrRS) is known for its essential aminoacylation function in protein synthesis. Here we report a function for TyrRS in DNA damage protection. We found that oxidative stress, which often downregulates protein synthesis, induces TyrRS to rapidly translocate from the cytosol to the nucleus. We also found that angiogenin mediates or potentiates this stress-induced translocalization. The nuclear-localized TyrRS activates transcription factor E2F1 to upregulate the expression of DNA damage repair genes such as BRCA1 and RAD51. The activation is achieved through direct interaction of TyrRS with TRIM28 to sequester this vertebrate-specific epigenetic repressor and its associated HDAC1 from deacetylating and suppressing E2F1. Remarkably, overexpression of TyrRS strongly protects against UV-induced DNA double-strand breaks in zebrafish, whereas restricting TyrRS nuclear entry completely abolishes the protection. Therefore, oxidative stress triggers an essential cytoplasmic enzyme used for protein synthesis to translocate to the nucleus to protect against DNA damage. PMID- 25284226 TI - Quality of life two years after severe trauma: a single-centre evaluation. AB - INTRODUCTION: Trauma related injuries are a main cause for long-lasting morbidity and disability especially in younger patients with their productive years ahead. On a routine basis, we assessed health related quality of life two years after trauma of severely injured patients at our level-I trauma centre via posted survey. PATIENTS AND METHODS: The posted survey included (1) POLO-Chart questionnaire with European Quality of Life (EuroQoL), Short Form Health Survey 36 (SF 36) and the recently developed and validated Trauma Outcome Profile (TOP) combined with (2) single centre data according to TraumaRegister DGU((r)) data sets including trauma mechanism, injuries and initial treatment. Inclusion criteria were severely injured patients >= 18 years, treated between 2008 and 2010. Exclusion criteria were death, cognitive impairment, lack of German language and denial of participation. RESULTS: 129 datasets were eligible for analysis reflecting a typical trauma collective with mean age 44 years, predominantly male (67%), mean ISS 22 and 98% blunt trauma. Two years after trauma, 62% of the patients reported of relevant remaining pain and 64% of severe functional deficit in at least one body region. Sixty-four percent of the patients suffered from decreased overall quality of life (EuroQoL<=0.8). Additionally, all domains of SF-36 were impaired compared to an age and gender adjusted cohort of healthy individuals, especially domains of pain and activity of daily living. These impairments were associated with decreased 'social functioning' and 'emotional role functioning'. TOP results confirmed these findings: Quality of life was decreased in almost every dimension. TOP additionally identified sequels especially in domains of "Mental Functioning" and impairments in psychological recovery including post-traumatic stress disorder, depression and anxiety. Socioeconomic impairments were frequent including further hospitalisations (62%), duration of inability to work >= 6 month (54%), financial disadvantages (45%) and work loss (26%). CONCLUSION: Our results demonstrate that multiple trauma patients two years after injury suffer from impairments including persisting pain, functional deficits, mental and socioeconomic deficits. The 'Trauma Outcome Profile' instrument seems a proper tool to discover impairments in trauma patients early on and guide proper rehabilitation resources to the best of the patient. PMID- 25284227 TI - 20 years of trauma documentation in Germany--actual trends and developments. AB - INTRODUCTION: The TraumaRegister DGU((r)) has been founded 20 years ago. Although initially supported by larger hospitals and universities, it has recently become a representative registry for the care of severely injured patients in Germany. Based on the registry data some important trends and developments of the recent decades are presented. PATIENTS AND METHODS: German trauma patients with an Injury Severity Score (ISS)>= 16 were eligible if primary admitted from the scene. All cases documented between 1993 and 2012 (20 years) were eligible. For selected variables, an average change per years was calculated using linear regression analysis. RESULTS: A total of 49,801 patients was analysed. The mean age was 46.3 years, and 72% were males. The following relevant trends could be observed: The average age increased dramatically from 38 to 50 years. Pre hospital intubation rate was halfed in patients with Glasgow Coma Scale (GCS)>8 but remained constant in unconscious patients (GCS <= 8; 90% intubation rate). Pre-hospital volume administration decreased as well, which led to less blood transfusions (from 45% to 16%). The use of helicopters for transportation into a trauma centre decreased as well but today still 27% of all cases are transported by air. Whole-body CT was performed in about 80% of patients; this value is stable in the last four years. Hospital mortality could be reduced and was 2-3% lower than expected in recent years. The Revised Injury Severity Classification (RISC) score used as a reference here was based on TR-DGU data from the 1990s. CONCLUSION: Standardised prospective registration of severely injured patients over 20years allows to empirically monitor trends and developments in acute trauma care. PMID- 25284228 TI - An improvement in risk adjusted outcomes over time and increasing engagement. PMID- 25284229 TI - Female sex protects from organ failure and sepsis after major trauma haemorrhage. AB - INTRODUCTION: Biological sex is considered a risk factor for adverse outcome after major trauma. We hypothesized that female sex is protective against organ failure, sepsis and mortality in patients with traumatic haemorrhage. PATIENTS AND METHODS: We selected patients from TraumaRegister DGU((r)) (TR-DGU) with primary admission for blunt trauma with an injury severity score >= 16 and an ICU stay >= 3 days that presented with relevant bleeding in the years 2007-2012. Relevant bleeding was defined as Abbreviated Injury Scale (AIS) >= 3 with an estimated blood loss exceeding 20%, any femoral shaft fracture, any pelvic clamp as surrogate for unstable pelvic fracture or the presence of at least one criteria of haemorrhagic shock: shock index of 0.8-1.4; base excess of -2.0 to 10.0 mmol/L; body temperature <= 34 degrees C; transfusion of >= 4 units of packed red blood cells; application of recombinant activated factor VII; any embolization during trauma room phase and pre-hospital resuscitation volume >= 3000 ml or any catecholamine use during pre-hospital care in the absence of cardiopulmonary resuscitation. A total of 7560 males and 2774 females were selected and analyzed for sex differences. RESULTS: Higher rates of multiple organ failure (24.4 vs. 21.3%, Odds ratio [OR] 1.19 (95% confidence interval [95%CI] 1.07-1.33), p=0.001*) and sepsis (16.5 vs. 11.3%, OR 1.55 (95%CI 1.35 1.77), p<0.001*) were observed in males. Organ function of lung, cardio circulatory system, liver and kidney were better in females, however, there was no difference in mortality. Stratification by age group revealed that in particular age-group 16-44 years was related to improved organ function which may indicate effects of sex hormones in females at reproductive age. Increased rates of sepsis in males were observed throughout virtually all age groups starting at 16 years of age, except in age group 54-64 years. This may suggest suppressive effect of testosterone on immune function. CONCLUSIONS: Our study supports the hypothesis that female sex is associated with improved organ function following traumatic injury and haemorrhagic shock, in particular in age groups that are at reproductive age. However, further studies are warranted before sex steroids can be deployed as therapeutic intervention in critically ill trauma patients. PMID- 25284230 TI - Risk stratification in trauma and haemorrhagic shock: scoring systems derived from the TraumaRegister DGU((r)). AB - Scoring systems commonly attempt to reduce complex clinical situations into one dimensional values by objectively valuing and combining a variety of clinical aspects. The aim is to allow for a comparison of selected patients or cohorts. To appreciate the true value of scoring systems in patients with multiple injuries it is necessary to understand the different purposes of quantifying the severity of specific injuries and overall trauma load, being: (1) clinical decision making; (2) triage; (3) planning of trauma systems and resources; (4) epidemiological and clinical research; (5) evaluation of outcome and trauma systems, including quality assessment; and (6) estimation of costs and allocation of resources. For the first two, easy-to estimate scores with immediate availability are necessary, mainly based on initial physiology. More sophisticated scores considering age, gender, injury pattern/severity and more are usually used for research and outcome evaluation, once the diagnostic and therapeutic process has been completed. For score development large numbers of data are necessary and thus, it appears as a logical consequence that large registries as the TraumaRegister DGU((r)) of the German Trauma Society (TR-DGU) are used to derive and validate clinical scoring systems. A variety of scoring systems have been derived from this registry, the majority of them with focus on hospital mortality. The most important among these systems is probably the RISC score, which is currently used for quality assessment and outcome adjustment in the annual audit reports. This report summarizes the various scoring systems derived from the TraumaRegister DGU((r)) over the recent years. PMID- 25284231 TI - The ATLS((r)) classification of hypovolaemic shock: a well established teaching tool on the edge? AB - Uncontrolled bleeding is the leading cause of shock in trauma patients and delays in recognition and treatment have been linked to adverse outcomes. For prompt detection and management of hypovolaemic shock, ATLS((r)) suggests four shock classes based upon vital signs and an estimated blood loss in percent. Although this classification has been widely implemented over the past decades, there is still no clear prospective evidence to fully support this classification. In contrast, it has recently been shown that this classification may be associated with substantial deficits. A retrospective analysis of data derived from the TraumaRegister DGU((r)) indicated that only 9.3% of all trauma patients could be allocated into one of the ATLS((r)) shock classes when a combination of the three vital signs heart rate, systolic blood pressure and Glasgow Coma Scale was assessed. Consequently, more than 90% of all trauma patients could not be classified according to the ATLS((r)) classification of hypovolaemic shock. Further analyses including also data from the UK-based TARN registry suggested that ATLS((r)) may overestimate the degree of tachycardia associated with hypotension and underestimate mental disability in the presence of hypovolaemic shock. This finding was independent from pre-hospital treatment as well as from the presence or absence of a severe traumatic brain injury. Interestingly, even the underlying trauma mechanism (blunt or penetrating) had no influence on the number of patients who could be allocated adequately. Considering these potential deficits associated with the ATLS((r)) classification of hypovolaemic shock, an online survey among 383 European ATLS((r)) course instructors and directors was performed to assess the actual appreciation and confidence in this tool during daily clinical trauma care. Interestingly, less than half (48%) of all respondents declared that they would assess a potential circulatory depletion within the primary survey according to the ATLS((r)) classification of hypovolaemic shock. Based on these observations, a critical reappraisal of the current ATLS((r)) classification of hypovolaemic seems warranted. PMID- 25284232 TI - Pre-hospital and early in-hospital management of severe injuries: changes and trends. AB - The pre-hospital and early in-hospital management of most severely injured patients has dramatically changed over the last 20 years. In this context, the factor time has gained more and more attention, particularly in German-speaking countries. While the management in the early 1990s aimed at comprehensive and complete therapy at the accident site, the premise today is to stabilise trauma patients at the accident site and transfer them into the hospital rapidly. In addition, the introduction of training and education programmes such as Pre hospital Trauma Life Support (PHTLS((r))), Advanced Trauma Life Support (ATLS((r))) concept or the TEAM((r)) concept has increased the quality of treatment of most severely injured trauma patients both in the preclinical field and in the emergency trauma room. Today, all emergency surgical procedures in severely injured patients are generally performed in accordance with the Damage Control Orthopaedics (DCO) principle. The advancements described in this article provide examples for the improved quality of the management of severely injured patients in the preclinical field and during the initial in-hospital treatment phase. The implementation of trauma networks, the release of the S3 polytrauma guidelines, and the DGU "Weibetabuch" have contributed to a more structured management of most severely injured patients. PMID- 25284233 TI - Preface. German Trauma Registry. PMID- 25284234 TI - Pre-hospital rescue times and actions in severe trauma. A comparison between two trauma systems: Germany and the Netherlands. AB - INTRODUCTION: The aim of this study was to compare the effect of national pre hospital rescue strategies on the status of severely injured patients at the time of admission to a Trauma Center (TC) in Germany or the Netherlands. PATIENTS AND METHODS: This retrospective database analysis based on the TraumaRegister DGU((r)) (TR-DGU) of the German Trauma Society compares the pre-hospital trauma system of Germany with three Trauma Centers (TCs) from the Netherlands. It comprises trauma patients from 2009 to 2012 admitted to a Level I TC, all patients aged 16-80 years primarily admitted with an ISS >= 16 and data available for mode of transport, pre-hospital measures and total pre-hospital time. Additionally three subgroups were formed by mode of transportation and involved personnel: Ambulance/Physician, Helicopter/Physician, Ambulance/EMT. Primary endpoint is the patient's status at the time of admission to the trauma room. Secondary endpoint is hospital mortality. RESULTS: A total of 12,168 patients met the inclusion criteria. Major differences in the injury patterns, pre-hospital rescue time, transport strategy and actions are documented. The mean ISS in the German overall group was 28.6 +/- 12.2 compared to 27.4 +/- 12.8 in the Dutch overall group. In the subgroups the highest injury severity with 29.8 +/- 12.7 for German patients and 31.0 +/- 14.6 for Dutch patients was found in the Helicopter/Physician subgroups and the lowest in patients transported by ambulance under emergency medical technician (EMT) care i.e. 24.2 +/- 8.9 for German patients and 23.6 +/- 10.3 for Dutch patients. The mean total pre-hospital time for patients admitted to Dutch TCs of 53.8 +/- 28.7 min was 15.1 min shorter than for patients transported to German TCs 68.7 +/- 28.6 min. The overall mean pre-hospital volume replacement of 1103 +/- 821 ml for German patients was about twice as high as for Dutch patients (541 +/- 700 ml). In physician led subgroups in the Netherlands higher rates of intubation, catecholamine administration and chest tubes are recorded. The basic vital signs from on-scene to hospital admission did not show relevant changes. Additional parameters available in the trauma room revealed a lower mean Base Excess (BE) for Dutch patients and a diminished mean prothrombin ratio for German patients. No reliable evidence was found that differences in the mortality analysis resulted from different national pre-hospital strategy. CONCLUSIONS: Many differences in the national pre-hospital strategy were demonstrated but the effect on patient's status at the time of admission to trauma room remains unclear. A follow-up study, which mitigates the now known injury patterns has to be initiated to further substantiate the findings of this study. PMID- 25284235 TI - Ten years of helicopter emergency medical services in Germany: do we still need the helicopter rescue in multiple traumatised patients? AB - BACKGROUND: Helicopter emergency medical service (HEMS) has been established in the preclinical treatment of multiple traumatised patients despite an ongoing controversy towards the potential benefit. Celebrating the 20th anniversary of TraumaRegister DGU((r)) of the German Trauma Society (DGU) the presented study intended to provide an overview of HEMS rescue in Germany over the last 10 years analysing the potential beneficial impact of a nationwide helicopter rescue in multiple traumatised patients. PATIENTS AND METHODS: We analysed TraumaRegister DGU((r)) including multiple traumatised patients (ISS >= 16) between 2002 and 2012. In-hospital mortality was defined as main outcome. An adjusted, multivariate regression with 13 confounders was performed to evaluate the potential survival benefit. RESULTS: 42,788 patients were included in the present study. 14,275 (33.4%) patients were rescued by HEMS and 28,513 (66.6%) by GEMS. Overall, 66.8% (n=28,569) patients were transported to a level I trauma centre and 28.2% (n=12,052) to a level II trauma centre. Patients rescued by HEMS sustained a higher injury severity compared to GEMS (ISS HEMS: 29.5 +/- 12.6 vs. ISS GEMS: 27.5 +/- 11.8). Helicopter rescue teams performed more on-scene interventions, and mission times were increased in HEMS rescue (HEMS: 77.2 +/- 28.7 min. vs. GEMS: 60.9 +/- 26.9 min.). Linear regression analysis revealed that the frequency of HEMS rescue has decreased significantly between 2002 and 2012. In case of transportation to level I trauma centres a decrease of 1.7% per year was noted (p<0.001) while a decline of 1.6% per year (p<0.001) was measured for level II trauma centre admissions. According to multivariate logistic regression HEMS was proven a positive independent survival predictor between 2002 and 2012 (OR 0.863; 95%-CI 0.800-0.930; Nagelkerkes-R(2) 0.539) with only little differences between each year. CONCLUSIONS: This study was able to prove an independent survival benefit of HEMS in multiple traumatised patients during the last 10 years. Despite this fact, a constant decline of HEMS rescue missions was found in multiple trauma patients due to unknown reasons. We concluded that HEMS should be used more often in case of trauma in order to guarantee the proven benefit for multiple traumatised patients. PMID- 25284236 TI - Limited volume resuscitation in hypotensive elderly multiple trauma is safe and prevents early clinical dilutive coagulopathy -- a matched-pair analysis from TraumaRegister DGU((r)). AB - BACKGROUND: The use of permissive hypotension includes a restrained volume preclinical therapy. However, in the elderly patients, this approach has raised concerns because of the increased cardiovascular risk profile and a higher incidence of hypertension under normal conditions. The aim of the study was to examine whether preclinical administration of restrictive volume therapy in the elderly patient can be safe. PATIENTS AND METHODS: A retrospective matched-pair analysis with the data set of the TraumaRegister DGU((r)) (TR-DGU) was performed based on data of 176 pairs of totally 67,000 patients. To address elderly potentially bleeding patients without major brain injury the following inclusion criteria were chosen: patients >= 60 years, ISS >= 16, AIS head<4, preclinical blood pressure between 60 and 100 mmHg and recorded preclinical volume administration. Patients that met the inclusion criteria (908) were divided into two groups: pre-clinical volume resuscitation <= 1000 ml (=low volume) and >1000 ml (high volume). Patients with high- and low-volume fluid replacement were matched according to the following criteria: age group, gender, date of the accident +/- 5 years, ISS, GCS, preclinical intubation, ground-/air-transport, pre-clinical blood pressure. RESULTS: Preclinical volume resuscitation showed a difference of about 1000 ml between the "low volume" and "high volume" group. The "low volume" group showed a significantly elongated prothrombin time. The amount of blood products given in the emergency department was not significantly different. The ventilation was 2 days shorter in the "low volume", although the number of patients with severe thoracic trauma was greater in this group. The length of stay in the ICU differed by 3 days in favour of the "low volume" group. The overall mortality was almost the same in both groups. CONCLUSIONS: Based on these data it can be assumed that the lower preclinical volume administration has a positive effect on the initial coagulation status in elderly patients. In spite of some limitations such as low number of matched pairs, we draw the cautious conclusion that a restrictive preclinical volume therapy is safe and also indicated in elderly patients. PMID- 25284237 TI - 20 years TraumaRegister DGU((r)): development, aims and structure. AB - The TraumaRegister DGU((r)) organisational and technical development has undergone an evolution process, which started 20 years ago. Currently, the management of the registry is under the management of the "AUC - Academy for Trauma Surgery" (infrastructure) and the "Sektion NIS" (scientific responsibility). The aim of the registry was to establish an inter-hospital quality assessment tool with the option to use the increasing database for scientific evaluations of acute care. Year after year and most recently with the obligatory participation of certified hospitals the number of participating hospitals has grown as well as the registered cases per annum. Recently, even hospitals from other countries joined the registry too. Starting with six German hospitals and 260 cases in 1993, 20 years later more than 600 hospitals from eleven countries deliver over 30,000 trauma cases per year resulting in over 150,000 reported cases until 2013. In this article a historical perspective is presented of the evolution and current status of the TraumaRegister DGU((r)). PMID- 25284238 TI - How to define severely injured patients? -- an Injury Severity Score (ISS) based approach alone is not sufficient. AB - INTRODUCTION: Multiple injured patients, polytrauma or severely injured patients are terms used as synonyms in international literature describing injured patients with a high risk of mortality and cost consuming therapeutic demands. In order to advance the definition of these terms, we analysed a large trauma registry. In detail, we compared critically ill trauma patients first specified on a pure anatomical base according to the ISS or NISS, second in the original "polytrauma definition" with two body regions affected and finally all of them combined with a physiological component. PATIENTS AND METHODS: Records that were collected in the TraumaRegister DGU((r)) of the German Trauma Society (Deutsche Gesellschaft fur Unfallchirurgie, DGU) between 1993 and 2011 (92,479 patients) were considered for this study. All patients with primary admission from scene with a minimum hospital stay of 48 h and an Injury Severity Score (ISS)>= 16 were included. Pre-hospital and early admission data were used to determine physiological risk factors and calculate individual risk of death using the Revised Injury Severity Classification (RISC). RESULTS: 45,350 patients met inclusion criteria. The overall hospital mortality rate was 20.4%. The predicted mortality according to the RISC-Score was 21.6%. 36,897 patients (81.4%) had injuries in several body regions. The prevalence of the five physiological risk factors varied between 17% (high age) and 34% (unconsciousness). There were 17,617 patients (38.8%) without any risk factor present on admission, while 30.6% (n=13,890) of the patients had one and 30.5% (n=13,843) had two or more factors present. Patients with ISS >= 16 but no physiological risk factor present had a very low mortality rate of 3.1% (542 of 17,617). With an increasing number of physiological factors there was an almost linear increase in mortality up to an 86% rate in patients with all five factors present. The 'polytrauma' definition of Butcher and colleagues with AIS >= 3 in at least two different body regions would apply to only 56.2% of patients in the present group with ISS >= 16. The mortality in this subgroup is only marginally higher (21.8%; 5559 of 25,494) than in the group of patients with only one severely affected body region (18.5%; 3675 of 19,875). CONCLUSIONS: In our opinion the principle of sharpening an anatomically based definition by a defined physiological problem will help to specify the really critically ill trauma patients. PMID- 25284239 TI - Pelvic fracture in multiple trauma: are we still up-to-date with massive fluid resuscitation? AB - Until today the mortality of complex pelvic trauma remains unacceptably high. On the one hand this could be attributed to a biological limit of the survivable trauma load, on the other hand side an ongoing inadequate treatment might be conceivable too. For the management of multiple trauma patients with life threatening pelvic fractures, there is ongoing international debate on the adequate therapeutic strategy, e.g. arterial embolization or pelvic packing, as well as aggressive or restrained volume therapy. Whereas traditional pelvis specific trauma algorithms still recommend massive fluid resuscitation, there is upcoming evidence that a restrained volume therapy in the preclinical setting may improve trauma outcomes. Less intravenous fluid administration may also reduce haemodilution and concomitant trauma-associated coagulopathy. After linking the data of the TraumaRegister DGU((r)) and the German Pelvic Injury Register, for the first time, the initial fluid management for complex pelvic traumas as well as for different Tile/OTA types of pelvic ring fractures could be addressed. Unfortunately, the results could not answer the question of the adequate fluid resuscitation but confirmed the actuality of massive fluid resuscitation in the prehospital and emergency room setting. Low-volume resuscitation seems not yet accepted in practice in managing multiple trauma patients with pelvic fractures at least in Germany. Nevertheless, prevention of exsanguination and of complications like multiple organ dysfunction syndrome still poses a major challenge in the management of complex pelvic ring injuries. Even nowadays, fluid management for trauma, not only for pelvic fractures, remains a controversial area and further research is mandatory. PMID- 25284240 TI - Effect of the localisation of the CT scanner during trauma resuscitation on survival -- a retrospective, multicentre study. AB - INTRODUCTION: Whole-body computed tomography (WBCT) is increasingly becoming the standard diagnostic technique during the resuscitation of severely injured patients. However, little is known about the ideal localisation of the CT scanner within the emergency setting. We intended to analyse the potential effect of the localisation of the CT scanner on outcome. PATIENTS AND METHODS: In a retrospective multicentre cohort study involving 8004 adult blunt major trauma patients out of 312 hospitals, we analysed the effect of the distance of the trauma room to the CT scanner on the outcome. Three groups were built: 1. CT in the trauma room 2. CT equal or less than 50 m away and 3. CT more than 50 m away. Using data derived from the 2007-2011 version of TraumaRegister DGU((r)) and the structure data bank of the TraumaNetzwerk DGU((r)) (trauma network, TNW; German Trauma Society, DGU) we determined the observed and predicted mortality and calculated the standardised mortality ratio (SMR) as well as logistic regressions. RESULTS: n=8004 patients fulfilled the inclusion criteria: their mean age was 46.4 +/- 21.0 years. 72.8% of them were male and the mean injury severity score (ISS) was 28.6 +/- 11.8. The overall mortality rate was 16.0%. The mean time from hospital admission to whole-body CT was 17.1 +/- 12.3 min for group 1, 22.7 +/- 15.5 min for group 2 and 27.7 +/- 17.1 min for group 3, p<0.001. Risk adjusted SMR was 0.74 (CI 95% 0.67-0.81) in group 1, 0.81 (CI 95% 0.76-0.87) in group 2, and 0.88 (CI 95% 0.79-0.98) in group 3. SMR group 1 vs. SMR group 2: p=0.130. SMR group 2 vs. SMR group 3: p=0.170. SMR group 1 vs. SMR group 3: p=0.016. SMR groups 1+2 vs. SMR group 3: p=0.046. Comparable data were found for the subgroup analysis of Level-I trauma centres only. Logistic regression confirmed the positive effect of a close localisation of the CT to the trauma room. The odds ratio (OR) was lowest for the localisation of the CT in the trauma room (OR 0.68, CI 95% 0.54-0.86, p<0.001). CONCLUSIONS: It was proven for the first time that a close distance of the CT scanner to the trauma room has a significant positive effect on the probability of survival of severely injured patients. The closer the CT is located to the trauma room, the better the probability of survival. Distances of more than 50 m had a significant negative effect on the outcome. If new emergency departments are planned or rebuilt, the CT scanner should be placed less than 50 m away from or preferably in the trauma room. PMID- 25284241 TI - Strategies for comparative analyses of registry data. AB - The present paper is a description and summary of methods used in non-randomised cohort data where the comparability of the study groups usually is not granted. Such study groups are formed by a diagnostic or therapeutic intervention, or by other characteristics of the patient or the treatment environment. This is a typical situation in the analysis of registry data. The methods are presented together with an illustrative example of whole-body computed tomography in the early phase of treatment of severe trauma cases. The following approaches are considered: (i) unadjusted direct comparisons; (ii) parallelisation; (iii) subgroup analysis; (iv) matched-pairs analysis; (v) outcome adjustment; and (vi) propensity score analysis. All these approaches have in common that they try to separate, or limit, the influence of confounding variables, which are unevenly distributed among the study groups, but also influence the outcome of interest. They differ in the number of confounders being considered, as well as the number of patients regarded. The more sophisticated the approach, the more effectively such confounding factors could be reduced. However, any method used for the reduction of bias depends on the quality and completeness of recorded confounders. Factors which are difficult or even impossible to be measured could thus not be adjusted for. This is a general limitation of retrospective analyses of cohort data. PMID- 25284242 TI - TraumaNetzwerk DGU((r)): optimizing patient flow and management. AB - PURPOSE: Caring for severely injured trauma patients is challenging for all medical professionals involved both in the preclinical and in the clinical course of treatment. While the overall quality of care in Germany is high there still are significant regional differences remaining. Reasons are geographical and infrastructural differences as well as variations in personnel and equipment of the hospitals. METHODS: To improve state-wide trauma care the German Trauma Society (DGU) initiated the TraumaNetzwerk DGU((r)) (TNW) project. The TNW is based on five major components: (a) Whitebook for the treatment of severely injured patients; (b) evidence-based guidelines for the medical care of severe injury; (c) local auditing of participating hospitals; (d) contract of interhospital cooperation; (d) TraumaRegister DGU((r)) documentation. RESULTS: By the end of 2013, 644 German Trauma Centres (TC) had successfully passed the audit. To that date 44 regional TNWs with a mean of 13.5 TCs had been established and certified. The TNWs cover approximately 90% of the country's surface. Of those hospitals, 2.3 were acknowledged as Supraregional TC, 5.4 as Regional TC and 6.7 as Lokal TC. Moreover, cross border TNW in cooperation with hospitals in The Netherlands, Luxembourg, Switzerland and Austria have been established. Preparing for the audit 66% of the hospitals implemented organizational changes (e.g. TraumaRegister DGU((r)) documentation and interdisciplinary guidelines), while 60% introduced personnel and 21% structural (e.g. X-ray in the ER) changes. CONCLUSIONS: The TraumaNetzwerk DGU((r)) project combines the control of common defined standards of care for all participating hospitals (top down) and the possibility of integrating regional cooperation by forming a regional TNW (bottom up). Based on the joint approach of healthcare professionals, it is possible to structure and influence the care of severely injured patients within a nationwide trauma system. PMID- 25284243 TI - External factors and the incidence of severe trauma: time, date, season and moon. AB - BACKGROUND: To detect whether external factors (time of day, day of week, month and season, lunar phases) influence incidence and outcome of severely injured trauma patients. PATIENTS AND METHODS: A retrospective cohort analysis of the TraumaRegister DGU((r)) (TR-DGU) was carried out over a period of 10 years (January 2002-December 2011). Data of 35,432 primary admitted patients from Germany with a severe trauma (Injury Severity Score (ISS) >15) were analysed in this study. For the outcome evaluation transferred patients were excluded as well as those who did not have a valid Revised Injury Severity Classification (RISC) prognostic score. The outcome analysis could be performed in 31,596 (89.2%) patients. Incidence, demographics and injury pattern were analysed. For outcome analysis the observed hospital mortality was compared with the expected prognosis. RESULTS: Time of day was the factor that showed the highest variation in trauma incidence due to rush hours. Saturday was the day with the highest accident rate. Most accidents in the night happened on weekends. June and July were the months with the highest trauma rate with a large portion of two-wheel drivers. The days of year with the lowest trauma incidence rate were those between Christmas and New Year, and the highest rate was observed on May 1st. The outcome of the trauma patients was close to the prognosis in all investigated subgroups. CONCLUSION: There are clear differences in incidence but not in outcome of the patients due to external factors. PMID- 25284244 TI - The melanocortin 1 receptor (Mc1r) variants do not account for the co-occurrence of Parkinson's disease and malignant melanoma. AB - Parkinson's disease (PD) is characterized by loss of melanin-positive dopaminergic neurons in the substantia nigra. Malignant melanoma (MM), a melanocyte-derived neoplasm, occurs with higher than expected frequency among PD patients. Red-haired individuals exhibit a threefold risk for developing MM than dark-haired people; PD risk also increases with lighter hair color. One plausible explanation for the associations between MM, hair color, and PD is the melanocortin-1 receptor (MC1R) gene that plays a key role in hair and skin pigmentation as well as in MM predisposition. We hypothesized that specific MC1R variants may predispose to both MM and PD. Genotyping of the MC1R gene was performed for 16 PD patients with MM (PD+ MM+) and for three sets of age, sex, and ethnically matched controls, including 36 patients with PD (PD+ MM-), 37 with MM (PD- MM+) and 37 with neither diagnosis (PD- MM-). No association was found between MC1R variants and the co-occurrence of PD and MM. The risk for MM was higher in carriers of two MC1R variants versus with no MC1R variant (odds ratio (OR)=5.0, 95% confidence interval (CI) 1.7-14.4, p=0.003). The risk for PD in carriers of two MC1R variants was markedly lower (OR=0.213, 95% CI 0.063-0.725) compared with individuals with no MC1R variant (p=0.013). In this study, MC1R variants were not associated with both MM and PD. Further studies in larger cohorts are necessary to confirm these preliminary results. PMID- 25284245 TI - MiRNA profile in the substantia nigra of Parkinson's disease and healthy subjects. AB - The deregulation of several microRNAs (miRNAs) has been associated with neurodegenerative processes, including Parkinson's disease (PD). Our aim was to characterize the level of miRNAs in the substantia nigra (SN) of PD patients and healthy donors. This is an important issue to characterize new putative markers and therapeutic targets for PD. RNA was extracted from the SN of postmortem PD (n=8) and healthy (n=4) subjects, and the level of 733 human miRNAs was assayed with TaqMan low-density arrays (TLDAs). Overall, there was a miRNA downregulation in the SN of patients. The mean level of 11 miRNAs was significantly different (p<0.05) between patients and controls, with 10 downregulated among the patients. MiR-198, -135b, -485-5p, and -548d were the best candidates and were quantified with individual TaqMan assays in the 12 samples. MiR-135b showed the most significant difference between patients and healthy donors. The bioinformatic analysis suggested that this miRNA could bind to genes implicated in several neurodegenerative pathways. PMID- 25284246 TI - Urinary calcium to creatinine ratio: a potential marker of secondary hyperparathyroidism in patients with vitamin D-dependent rickets type 1A. AB - Patients with vitamin D-dependent rickets type 1A (VDDR1A) are usually treated with alfacalcidol, an analog of vitamin D. Around puberty, an increased dose of alfacalcidol is recommended for these patients to avoid hypocalcemia and secondary hyperparathyroidism. However, no indicators of secondary hyperparathyroidism except for PTH are presently known. The aim of this study is to evaluate whether urinary calcium to creatinine ratio (U-Ca/Cr) is useful as a biomarker of secondary hyperparathyroidism in VDDR1A patients in order to determine the proper dose of alfacalcidol. Two brothers with VDDR1A were recruited who had null mutations of CYP27B1 which encodes 1-alpha-hydroxylase of vitamin D. We investigated the relationship between U-Ca/Cr and intact-PTH around puberty when the brothers showed hypocalcemia with secondary hyperparathyroidism. The results were compared to those of five patients with vitamin D deficiency (VDD). As a result, high intact-PTH levels were observed when U-Ca/Cr decreased to less than 0.1 (mg/mg) in both VDDR1A brothers. This relationship was also observed in the VDD patients. However, it is necessary to take into account body calcium status, either in depletion or in excess, to accurately evaluate the relationship between U-Ca/Cr and secondary hyperparathyroidism. First, low U Ca/Cr was detected in situations with calcium depletion without hyperparathyroidism in the VDDR1A patients. Second, high U-Ca/Cr with hyperparathyroidism could be detected theoretically in a condition of excess calcium supply. In conclusion, a U-Ca/Cr ratio of less than 0.1 (mg/mg) in VDDR1A patients is useful to accurately evaluate calcium depletion and secondary hyperparathyroidism. PMID- 25284247 TI - The prevalence of acromegaly in hospitalized patients with type 2 diabetes. AB - The prevalence of acromegaly is estimated to be 8-24/100,000, but several recent studies suggest it is underestimated. In particular, acromegaly is considered more prevalent in patients with type 2 diabetes mellitus (T2DM) than in the normal population. This study aimed to evaluate the prevalence of acromegaly in hospitalized patients with T2DM. A total of 327 hospitalized patients with T2DM were recruited as subjects. If serum insulin-like growth factor 1 (IGF-1) levels were found to be elevated, random GH level was measured or oral glucose tolerance test (OGTT) was performed. Five patients with elevated serum IGF-1 levels and random GH level or inadequate suppression of GH in the OGTT underwent pituitary magnetic resonance imaging. Of those patients, pituitary adenoma was detected in 2 patients. These 2 patients were diagnosed with acromegaly, as they also exhibited mild acromegalic features. Intriguingly, both these patients exhibited severe macroangiopathy and an absence of microangiopathy. The prevalence of acromegaly in the hospitalized patients with T2DM in this study was therefore 0.6%, suggesting a higher prevalence than that predicted. Although a large-scale prospective study is required to clarify the precise prevalence of acromegaly in hospitalized patients with T2DM, the present study shows that it is useful to screen hospitalized patients with T2DM for acromegaly by measuring their serum IGF-1 level. PMID- 25284248 TI - beta-Functionalization of carboxylic anhydrides with beta-alkyl substituents through carbene organocatalysis. AB - The first NHC-catalyzed functionalization of carboxylic anhydrides is described. In this reaction, the beta carbon behaves as a nucleophilic carbon and undergoes asymmetric reactions with electrophiles. Anhydrides with challenging beta-alkyl substituents work effectively. PMID- 25284249 TI - Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase. AB - Enoyl-acyl carrier protein reductase (ENR), a critical enzyme in type II fatty acid biosynthesis, is a promising target for drug discovery against hepatocyte stage Plasmodium falciparum. In order to identify PfENR-specific inhibitors, we docked 70 FDA-approved, bioactive, and/or natural product small molecules known to inhibit the growth of whole-cell blood-stage P. falciparum into several PfENR crystallographic structures. Subsequent in vitro activity assays identified a noncompetitive low-micromolar PfENR inhibitor, celastrol, from this set of compounds. PMID- 25284251 TI - Tritium-labelled isovaleryl-RYYRIK-NH2 as potential antagonist probe for ORL1 nociceptin receptor. AB - IsoVa-RYYRIK-NH2 is a highly specific antagonist ligand of the opioid receptor like 1 (ORL1) receptor, an endogenous ligand of which is 17-mer peptide nociceptin. ORL1 antagonists have potential for clinical use as analgesic and antineuropathic drugs, and thus information on the receptor-binding characteristics of antagonists is very important for rational drug design. In the present study, we prepared tritium-labelled isova-RYYRIK-NH2 from its precursor with the 3-methylcrotonyl (CH3)2CCHCO group by a catalytic reduction using tritium gas. The resulting [(3)H]isoVa-RYYRIK-NH2 was evaluated in a saturation binding assay using the COS-7 cell membrane preparations of transiently expressed ORL1. It exhibited more than 90% specific binding with a dissociation constant of 1.21+/-0.03nM. From the mutual heterologous binding assays using [(3)H]isoVa RYYRIK-NH2 and [(3)H]nociceptin, isoVa-RYYRIK-NH2 and nociceptin were found to share the receptor-binding site, but each also had a separate specific binding site of its own. They differentiated the two different binding states or conformations of ORL1, which might represent the agonist-active and antagonist inactive conformations of ORL1. [(3)H]isoVa-RYYRIK-NH2 is thus a key tracer to uncover the amino acid residues important for receptor inactivation. PMID- 25284250 TI - Tryptophan-based fluorophores for studying protein conformational changes. AB - With the continuing interest in deciphering the interplay between protein function and conformational changes, small fluorescence probes will be especially useful for tracking changes in the crowded protein interior space. Presently, we describe the potential utility of six unnatural amino acid fluorescence donors structurally related to tryptophan and show how they can be efficiently incorporated into a protein as fluorescence probes. We also examine the various photophysical properties of the new Trp analogues, which are significantly redshifted in their fluorescence spectra relative to tryptophan. In general, the Trp analogues were well tolerated when inserted into Escherichia coli DHFR, and did not perturb enzyme activity, although substitution for Trp22 did result in a diminution in DHFR activity. Further, it was demonstrated that D and E at position 37 formed efficient FRET pairs with acridon-2-ylalanine (Acd) at position 17. The same was also true for a DHFR construct containing E at position 79 and Acd at position 17. Together, these findings demonstrate that these tryptophan analogues can be introduced into DHFR with minimal disruption of function, and that they can be employed for the selective study of targeted conformational changes in proteins, even in the presence of unmodified tryptophans. PMID- 25284252 TI - Synthesis of chiral chloroquine and its analogues as antimalarial agents. AB - In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelii in vivo. Compounds S-13 b, S 13c, S-13 d and S-13 i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively, in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13 d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization. PMID- 25284253 TI - Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs. AB - Non-secosteroidal vitamin D receptor (VDR) ligands are promising candidates for many clinical applications. We recently developed novel non-secosteroidal VDR agonists based on p-carborane (an icosahedral carbon-containing boron cluster) as a hydrophobic core structure. Here, we report the design, synthesis and biological evaluation of carborane-based vitamin D analogs bearing various substituents at the diol moiety. Among the synthesized compounds, methylene derivative 31 exhibited the most potent vitamin D activity, which was comparable to that of the natural hormone, 1alpha,25(OH)2D3. This compound is one of the most potent non-secosteroidal VDR agonists reported to date, and is a promising lead for development of novel drug candidates. PMID- 25284255 TI - The oxidation of thiols by flavoprotein oxidases: a biocatalytic route to reactive thiocarbonyls. AB - Flavoprotein oxidases are a diverse class of biocatalysts, most of which catalyze the oxidation of C-O, C-N, or C-C bonds. Flavoprotein oxidases that are known to catalyze the oxidation of C-S bonds are rare, being limited to enzymes that catalyze the oxidative cleavage of thioethers. Herein, we report that various flavoprotein oxidases, previously thought to solely act on alcohols, also catalyze the oxidation of thiols to thiocarbonyls. These results highlight the versatility of enzymatic catalysis and provide a potential biocatalytic route to reactive thiocarbonyl compounds, which have a variety of applications in synthetic organic chemistry. PMID- 25284254 TI - Design, synthesis, and immunologic evaluation of vaccine adjuvant conjugates based on QS-21 and tucaresol. AB - Immunoadjuvants are used to potentiate the activity of modern subunit vaccines that are based on molecular antigens. An emerging approach involves the combination of multiple adjuvants in a single formulation to achieve optimal vaccine efficacy. Herein, to investigate such potential synergies, we synthesized novel adjuvant conjugates based on the saponin natural product QS-21 and the aldehyde tucaresol via chemoselective acylation of an amine at the terminus of the acyl chain domain in QS saponin variants. In a preclinical mouse vaccination model, these QS saponin-tucaresol conjugates induced antibody responses similar to or slightly higher than those generated with related QS saponin variants lacking the tucaresol motif. The conjugates retained potent adjuvant activity, low toxicity, and improved activity-toxicity profiles relative to QS-21 itself and induced IgG subclass profiles similar to those of QS-21, indicative of both Th1 cellular and Th2 humoral immune responses. This study opens the door to installation of other substituents at the terminus of the acyl chain domain to develop additional QS saponin conjugates with desirable immunologic properties. PMID- 25284256 TI - Haemogregarina spp. in a wild population from Podocnemis unifilis Troschel, 1848 in the Brazilian Amazonia. AB - The study objectives were to characterize the morphology of the parasitic forms and describe the prevalence and intensity of Haemogregarina spp. in a population of the turtle Podocnemis unifilis as well as to examine the relationships between parasitism and turtle variables such as gender, size, and weight. Samples were taken in the Tapajos and Jamanxim rivers, Itaituba, Para state, Brazil. Blood was collected from the tail vein of 72 P. unifilis specimens, including 35 males, 36 females, and one unsexed juvenile. The prevalence of Haemogregarina spp. was 98% (n = 71). The mean parasite intensity of Haemogregarina spp. was 118 (1-582) parasites/2000 blood cells (6%). There was no significant difference in the mean parasite intensity between male (137.68 +/- 121.8, n = 35) and female turtles (101.42 +/- 123.59, n = 35). There was no relationship between parasite intensity and carapace length. Although the relationship between parasite intensity and host body weight was significant, the relationship was weak. This is the first study on Haemogregarina parasitism with a relatively high number of turtles in Brazil. PMID- 25284257 TI - Variation in adult longevity of Culex pipiens f. pipiens, vector of the West Nile Virus. AB - The common house mosquito, Culex pipiens (Diptera: Culicidae), which is considered the primary bridge vector of West Nile Virus (WNV) to humans, is a wide spread insect pest with medical importance and consists of two distinct bioforms, Cx. pipiens f. pipiens and Cx. pipiens f. molestus. Here, we consider the adult lifespan of male and female Cx. pipiens f. pipiens under controlled conditions at five constant temperature regimes (15, 20, 25, 27.5, and 30 degrees C). Our results show that adult longevity was affected by temperature, as it significantly decreased with increase in temperature. At the highest tested temperature, mean adult longevity did not exceed 12 days for both sexes and thus makes impossible the risk of WNV transmission. On the other hand at the lowest temperature, longevity was extremely high with some individuals surviving up to 129 and 132 days, males and females, respectively, and thus enable them to function as potential vectors of WNV for a prolonged period of time. As far as sex is concerned, adult females displayed a 1.2-1.4-fold longer longevity compared to the male ones. However, this difference was significant only at the lowest and highest tested temperature regime. This information is useful in determining the critical temperatures which may affect the distribution of Cx. pipiens and consequently the risk of WNV transmission. Moreover, the effect of environmental temperature should be considered when evaluating the abundance of these species. PMID- 25284258 TI - Routine screening of hospital patients for secondhand tobacco smoke exposure: a feasibility study. AB - OBJECTIVE: Secondhand tobacco smoke (SHS) exposure causes over 40,000 deaths per year, but healthcare systems rarely address this risk factor. In September 2012, Massachusetts General Hospital initiated routine inpatient screening for SHS exposure by adding a question to the nurses' computerized admission assessment form ("Is smoking allowed in your home or car?"). We measured the implementation of this screening question over 1year. METHODS: Multivariable analysis of hospital records of adult and pediatric admissions (N=35,701) from September 1, 2012 to August 31, 2013, to assess screening question completion and identify characteristics of nonsmokers who may be exposed to SHS. RESULTS: Nurses entered "Yes" or "No" to the screening question for 91% of 34,295 adult admissions and 86% of 1406 pediatric admissions. Among nonsmokers, smoking in the home or car was allowed for 3% of adult admissions and 4% of pediatric admissions. Adults admitted for psychiatric diagnoses, children admitted for asthma, and patients with Medicaid insurance had higher odds of exposure to SHS in their home or car. CONCLUSION: Routine screening of SHS among hospitalized patients by nurses is feasible. Doing so offers hospitals an opportunity to intervene and to promote smoke-free policies in patients' homes and cars. PMID- 25284259 TI - Coastal proximity and physical activity: Is the coast an under-appreciated public health resource? AB - BACKGROUND: Recent findings suggest that individuals living near the coast are healthier than those living inland. Here we investigated whether this may be related to higher levels of physical activity among coastal dwellers in England, arising in part as a result of more visits to outdoor coastal settings. METHOD: Participants (n=183,755) were drawn from Natural England's Monitor of Engagement with the Natural Environment Survey (2009-2012). Analyses were based on self reported physical activity for leisure and transport. RESULTS: A small, but significant coastal proximity gradient was seen for the likelihood of achieving recommended guidelines of physical activity a week after adjusting for relevant area and individual level controls. This effect was statistically mediated by the likelihood of having visited the coast in the last seven days. Stratification by region, however, suggested that while the main effect was relatively strong for west coast regions, it was not significant for those in the east. CONCLUSIONS: In general, our findings replicate and extend work from Australia and New Zealand. Further work is needed to explain the marked regional differences in the relationship between coastal proximity and physical activity in England to better understand the coast's potential role as a public health resource. PMID- 25284260 TI - Differences in anthropometric measures in immigrants and Swedish-born individuals: results from two community-based cohort studies. AB - AIM: To study differences in body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), waist-hip-height ratio (WHHR) and percent body fat in immigrants and Swedish-born men and women in two large population-based samples. METHODS: A cross-sectional analysis of 60-year old individuals, n=4 232. To replicate the results, we also assessed another large independent cohort cross-sectionally, the Malmo Diet and Cancer Study (MDC, n=26 777). The data from both cohorts were collected in the 1990s in Sweden. RESULTS: Significant differences between Finnish-born, Middle Eastern and women from the rest of the world were seen for all anthropometric measures, using Swedish-born women as referent. However, WHHR was the only anthropometric measure that identified all these three groups of immigrant women as different from Swedish-born women with high statistical certainty (p<0.001). Apart from WHHR that identified differences in anthropometry in all immigrant groups of men using Swedish-born men as referent, few significant differences were seen in anthropometry among groups of immigrant men. These finding were observed in both cohorts, and remained after adjustments for smoking, physical activity and educational level. CONCLUSION: The present study confirms previous findings of more obesity among immigrants and is the first to report that WHHR measurements may detect anthropometric differences between different ethnic groups better than other anthropometrical measures. PMID- 25284262 TI - Obesity prevention lessons from Latin America. AB - This is an invited commentary for the Active Living Research (ALR) special issue. The commentary focuses on the lessons that can be learned from Latin America regarding obesity prevention. Examples from Brazil, Mexico, and Colombia that may inform US policy are described. PMID- 25284261 TI - Effects of breastfeeding on postpartum weight loss among U.S. women. AB - OBJECTIVE: The aim of this study is to evaluate the effects of breastfeeding on maternal weight loss in the 12months postpartum among U.S. women. METHODS: Using data from a national cohort of U.S. women conducted in 2005-2007 (N=2102), we employed propensity scores to match women who breastfed exclusively and non exclusive for at least three months to comparison women who had not breastfed or breastfed for less than three months. Outcomes included postpartum weight loss at 3, 6, 9, and 12months postpartum; and the probability of returning to pre pregnancy body mass index (BMI) category and the probability of returning to pre pregnancy weight. RESULTS: Compared to women who did not breastfeed or breastfed non-exclusively, exclusive breastfeeding for at least 3months resulted in 3.2 pound (95% CI: 1.4,4.7) greater weight loss at 12months postpartum, a 6.0 percentage-point increase (95% CI: 2.3,9.7) in the probability of returning to the same or lower BMI category postpartum; and a 6.1-percentage-point increase (95% CI: 1.0,11.3) in the probability of returning to pre-pregnancy weight or lower postpartum. Non-exclusive breastfeeding did not significantly affect any outcomes. CONCLUSION: Our study provides evidence that exclusive breastfeeding for at least three months has a small effect on postpartum weight loss among U.S. women. PMID- 25284263 TI - Minimally invasive surgery of neuroblastic tumors in children: Indications depend on anatomical location and image-defined risk factors. AB - BACKGROUND: Minimally invasive surgery (MIS) is still not a well-accepted surgical approach to remove neuroblastic tumors. We aimed to assess the indications and limits of MIS in this childhood tumor according to tumor location and image-defined risk factors (IDRFs). PROCEDURE: Between 2006 and 2012, 39 patients underwent MIS for neuroblastic tumors, using thoracoscopic (n = 20), retroperitoneoscopic (n = 1) or laparoscopic approaches (n = 18). The tumor locations were paravertebral (n = 18; thoracic n = 15, lumbar n = 3), perivascular (n = 5; abdominal n = 2; thoracic n = 3), adrenal (n = 13), pleural (n = 2) and pelvic (n = 1). Two patients were treated for relapses. According to the INRG staging system, IDRFs were absent in 20 patients and present in 19 patients. Ten patients received chemotherapy preoperatively. Mean largest diameter was 35 mm for thoracic tumors (range: 7-85 mm) and 34 mm for abdominal tumors (range: 10-75 mm). Mean follow-up was 25 months (range: 5-116 months). RESULTS: Resection was macroscopically incomplete (R2) for six thoracic tumors and one adrenal tumor. Conversion was necessary for three thoracic L2 tumors. Postoperative complications consisted of chylothorax in three patients with L2 paravertebral thoracic tumors, Horner's syndrome in a patient with a cervicothoracic tumor, and renal atrophy in a patient with a L2 abdominal tumor. No perioperative or postoperative complications occurred in patients with adrenal and abdominal paravertebral tumors. The overall survival rate was 98%. CONCLUSION: In carefully selected cases, MIS permits safe and efficient resection of neuroblastic tumors in children. Open surgical approach should be considered if organ or vascular control or quality of resection is jeopardized. Pediatr Blood Cancer 2015;62:257-261. (c) 2014 Wiley Periodicals, Inc. PMID- 25284264 TI - Differential in vivo expression of mycobacterial antigens in Mycobacterium tuberculosis infected lungs and lymph node tissues. AB - BACKGROUND: The clinical course of tuberculosis (TB) infection, bacterial load and the morphology of lesions vary between pulmonary and extrapulmonary TB. Antigens expressed in abundance during infection could represent relevant antigens in the development of diagnostic tools, but little is known about the in vivo expression of various M. tuberculosis antigens in different clinical manifestations. The aim of this study was to study the differences in the presence of major secreted as well as somatic mycobacterial antigens in host tissues during advanced rapidly progressing and fatal pulmonary disease with mainly pneumonic infiltrates and high bacterial load, and to compare this to the presence of the same antigens in TB lymphadenitis cases, which is mainly chronic and self-limiting disease with organised granulomas and lower bacterial load. METHODS: Human pulmonary (n = 3) and lymph node (n = 17) TB biopsies, and non-TB controls (n = 12) were studied. Ziehl-Neelsen stain, nested PCR 1S6110 and immunohistochemistry were performed. Major secreted (MPT32, MPT44, MPT46, MPT51, MPT53, MPT59, MPT63, and MPT64) and somatic mycobacterial antigens (Mce1A, Hsp65, and MPT57) were detected by using rabbit polyclonal antibodies. RESULTS: Plenty of bacilli were detectable with Ziehl-Neelsen stain in the lung biopsies while no bacilli were detected in the lymph node biopsies. All the cases were shown to be positive by PCR. Both secretory and somatic antigens were expressed in abundance in pulmonary infiltrates, while primarily somatic antigens were detected in the lymphadenitis cases. Of the secreted antigens, only MPT64 was consistently detected in both cases, indicating a preferential accumulation of this antigen within the inflammatory cells, even if the cells of the granuloma can efficiently restrict bacterial growth and clear away the secreted antigens. CONCLUSIONS: This study shows that major secreted mycobacterial antigens were found in high amounts in advanced pulmonary lesions without proper granuloma formation, while their level of staining was very low, or absent, in the lymph node TB lesions with organised granulomas and very low bacillary load, with one exception of MPT64, suggesting its role in the persistence of chronic infection. These findings have implication for development of new diagnostic tools. PMID- 25284265 TI - Effects of multispectral excitation on the sensitivity of molecular optoacoustic imaging. AB - Molecular optoacoustic (photoacoustic) imaging typically relies on the spectral identification of absorption signatures from molecules of interest. To achieve this, two or more excitation wavelengths are employed to sequentially illuminate tissue. Due to depth-related spectral dependencies and detection related effects, the multispectral optoacoustic tomography (MSOT) spectral unmixing problem presents a complex non-linear inversion operation. So far, different studies have showcased the spectral capacity of optoacoustic imaging, without however relating the performance achieved to the number of wavelengths employed. Overall, the dependence of the sensitivity and accuracy of optoacoustic imaging as a function of the number of illumination wavelengths has not been so far comprehensively studied. In this paper we study the impact of the number of excitation wavelengths employed on the sensitivity and accuracy achieved by molecular optoacoustic tomography. We present a quantitative analysis, based on synthetic MSOT datasets and observe a trend of sensitivity increase for up to 20 wavelengths. Importantly we quantify this relation and demonstrate an up to an order of magnitude sensitivity increase of multi-wavelength illumination vs. single or dual wavelength optoacoustic imaging. Examples from experimental animal studies are finally utilized to support the findings. In vivo MSOT imaging of a mouse brain bearing a tumor that is expressing a near-infrared fluorescent protein. (a) Monochromatic optoacoustic imaging at the peak excitation wavelength of the fluorescent protein. (b) Overlay of the detected bio-distribution of the protein (red pseudocolor) on the monochromatic optoacoustic image. (c) Ex vivo validation by means of cryoslicing fluorescence imaging. PMID- 25284266 TI - Influence of spinal and general anesthesia on the metabolic, hormonal, and hemodynamic response in elective surgical patients. AB - BACKGROUND: The aim of the study was to determine the significance of spinal anesthesia in the suppression of the metabolic, hormonal, and hemodynamic response to surgical stress in elective surgical patients compared to general anesthesia. MATERIAL AND METHODS: The study was clinical, prospective, and controlled and it involved 2 groups of patients (the spinal and the general anesthesia group) who underwent the same surgery. We monitored the metabolic and hormonal response to perioperative stress based on serum cortisol level and glycemia. We also examined how the different techniques of anesthesia affect these hemodynamic parameters: systolic arterial pressure (AP), diastolic AP, heart rate (HR), and arterial oxygen saturation (SpO2). These parameters were measured before induction on anesthesia (T1), 30 min after the surgical incisions (T2), 1 h postoperatively (T3) and 24 h after surgery (T4). RESULTS: Serum cortisol levels were significantly higher in the general anesthesia group compared to the spinal anesthesia group (p<0.01). Glycemia was significantly higher in the general anesthesia group (p<0.05). There was a statistically significant, positive correlation between serum cortisol levels and glycemia at all times observed (p<0.01). Systolic and diastolic AP did not differ significantly between the groups (p=0.191, p=0.101). The HR was significantly higher in the general anesthesia group (p<0.01). SpO2 values did not differ significantly between the groups (p=0.081). CONCLUSIONS: Based on metabolic, hormonal, and hemodynamic responses, spinal anesthesia proved more effective than general anesthesia in suppressing stress response in elective surgical patients. PMID- 25284267 TI - Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation. AB - Cardiac allograft vasculopathy remains one of the major causes of death post heart transplantation. Its etiology is multifactorial and prevention is challenging. The aim of this study was to prospectively determine factors related to cardiac allograft vasculopathy after heart transplantation. This research was planned on 179 patients submitted to heart transplant. Performance of an early coronary angiography with endothelial function evaluation was scheduled at three month post-transplant. Patients underwent a second coronary angiography after five-yr follow-up. At the 5- +/- 2-yr follow-up, 43% of the patients had developed cardiac allograft vasculopathy (severe in 26% of them). Three independent predictors of cardiac allograft vasculopathy were identified: cardiogenic shock at the time of the transplant operation (OR: 6.49; 95% CI: 1.86 22.7, p = 0.003); early coronary endothelial dysfunction (OR: 3.9; 95% CI: 1.49 10.2, p = 0.006), and older donor age (OR: 1.05; 95% CI: 1.00-1.10, p = 0.044). Besides early endothelial coronary dysfunction and older donor age, a new predictor for development of cardiac allograft vasculopathy was identified: cardiogenic shock at the time of transplantation. In these high-risk patient subgroups, preventive measures (treatment of cardiovascular risk factors, use of novel immunosuppressive agents such as mTOR inhibitors) should be earlier and much more aggressive. PMID- 25284268 TI - Increased arterial stiffness in young normotensive patients with Turner syndrome: associations with vascular biomarkers. AB - OBJECTIVES: Factors contributing to arteriopathy in patients with Turner syndrome (TS) remain unclear. We assessed arterial stiffness in young, normotensive patients with TS and correlated arterial stiffness with vascular biomarkers, GH treatment and oestrogen exposure. Sixty-one patients with TS (mean age, 12.6 years; range 6.6-21.3 years) were matched for age and sex with 61 healthy peers. Associations between arterial stiffness and high-sensitivity C-reactive protein (hsCRP), B-type natriuretic peptide (BNP), atrial NP (ANP), plasma aldosterone/plasma renin activity (PRA), IGF1 and IGFBP3 were examined after adjusting for well-established confounders of vascular disease. RESULTS: Carotid intima media thickness standard deviation score (SDS), arterial stiffness index SDS and incremental modulus of elasticity SDS were higher, and distensibility coefficient SDS was lower in patients with TS. The duration of GH treatment and oestrogen exposure was not associated with indices of arterial stiffness. TS patients had higher hsCRP, BNP and ANP. Plasma aldosterone/PRA, IGF1 and IGFBP3 were similar in patients and controls. Multivariable regression analyses (R(2) = 0.200-0.668, P < 0.01) showed that BNP was associated with all indices of arterial stiffness. We found that hsCRP was associated with distensibility coefficient SDS (beta = -0.16, P < 0.01). TS was independently associated with increased arterial stiffness (beta = 0.420-3.424, P < 0.001 for all, R(2) = 0.06 0.31). CONCLUSIONS: Young, normotensive TS patients had increased arterial stiffness than that of healthy peers. BNP, and possibly hsCRP, was independently associated with arterial stiffness in TS. Further research will determine any causal inference of these relationships. PMID- 25284269 TI - Impact of the 2008 U.S. Preventative Services Task Force recommendation on frequency of prostate-specific antigen screening in older men. AB - OBJECTIVES: To evaluate the effect of the 2008 U.S. Preventative Services Task Force recommendation against prostate-specific antigen (PSA) screening in men aged 75 and older on frequency of PSA screening in elderly men. DESIGN: Retrospective, cross-sectional analysis. SETTING: Fifteen community primary care practices in western Massachusetts. PARTICIPANTS: Men aged 65 and older with one or more annual physicals between January 1, 2006, and December 31, 2010. MEASUREMENTS: PSA testing was determined from the electronic health record. Mixed effects logistic regression was used to model the rate of PSA testing over time for two age groups: 65 to 74, and 75 and older. RESULTS: Of the 7,833 men in this study, 60% were younger than 75. PSA screening rates were consistently lower in men aged 75 and older. Annual rates, adjusted for number of clinic visits, ranged from 12% to 28% in men aged 75 and older, and 37% to 49% in men aged 65 to 74. In the 2 years before the guideline was released, there was already a slow decline in screening rate in men aged 75 and older, whereas the screening rate in men aged 65 to 74 was rising. Compared to 2008, there was a 36% relative reduction in screening rate in 2009 and a 51% relative reduction in 2010 for men aged 75 and older, and a 12% relative reduction in screening rate in 2009 and a 24% relative reduction in 2010 for men aged 65 to 74. CONCLUSION: The 2008 recommendation appeared to reduce PSA screening rates in older men in 2009 and 2010; there was a substantial reduction in men aged 75 and older and a more modest reduction in men aged 65 to 74. PMID- 25284270 TI - Pulmonary rehabilitation for interstitial lung disease. AB - BACKGROUND: Interstitial lung disease (ILD) is characterised by reduced functional capacity, dyspnoea and exercise-induced hypoxia. Pulmonary rehabilitation, an intervention that includes exercise training, is beneficial for people with other chronic lung conditions; however its effects in ILD have not been well characterised. OBJECTIVES: * To determine whether pulmonary rehabilitation in patients with ILD has beneficial effects on exercise capacity, symptoms, quality of life and survival compared with no pulmonary rehabilitation in patients with ILD.* To assess the safety of pulmonary rehabilitation in patients with ILD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6), MEDLINE (Ovid), EMBASE (Ovid), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO) and the Physiotherapy Evidence Database (PEDro) (all searched from inception to June 2014). We also searched the reference lists of relevant studies, international clinical trial registries and respiratory conference abstracts to look for qualifying studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials in which pulmonary rehabilitation was compared with no pulmonary rehabilitation or with other therapy in people with ILD of any origin were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias. Study authors were contacted to provide missing data and information regarding adverse effects. A priori subgroup analyses were specified for participants with idiopathic pulmonary fibrosis (IPF) and participants with severe lung disease (low diffusing capacity or desaturation during exercise). We planned to subgroup according to training modality applied, but there were insufficient data. MAIN RESULTS: Nine studies were included, six of which were published as abstracts. Five studies were included in the meta-analysis (86 participants who undertook pulmonary rehabilitation and 82 control participants). One study used a blinded assessor and intention-to-treat analysis. No adverse effects of pulmonary rehabilitation were reported. Pulmonary rehabilitation improved the six-minute walk distance with weighted mean difference (WMD) of 44.34 metres (95% confidence interval (CI) 26.04 to 62.64 metres) and improved oxygen consumption (VO2) peak with WMD of 1.24 mL/kg/min(-1) (95% CI 0.46 to 2.03 mL/kg/min(-1)). Improvements in six-minute walk distance and VO2 peak were also seen in the subgroup of participants with idiopathic pulmonary fibrosis (IPF) (WMD 35.63 metres, 95% CI 16.02 to 55.23 metres; WMD 1.46 mL/kg/min(-1), 95% CI 0.54 to 2.39 mL/kg/min(-1), respectively). Reduced dyspnoea (standardised mean difference (SMD) -0.66, 95% CI -1.05 to -0.28) following pulmonary rehabilitation was also seen in the IPF subgroup (SMD -0.68, 95% CI -1.12 to -0.25). Quality of life improved following pulmonary rehabilitation for all participants on a variety of measures (SMD 0.59, 95% CI 0.20 to 0.98) and for the subgroup of people with IPF (SMD 0.59, 95% CI 0.14 to 1.03). Two studies reported longer-term outcomes, with no significant effects of pulmonary rehabilitation on clinical variables or survival at three or six months. Available data were insufficient to allow examination of the impact of disease severity or exercise training modality. AUTHORS' CONCLUSIONS: Pulmonary rehabilitation seems to be safe for people with ILD. Improvements in functional exercise capacity, dyspnoea and quality of life are seen immediately following pulmonary rehabilitation, with benefits also evident in IPF. Because of inadequate reporting of methods and small numbers of included participants, the quality of evidence was low to moderate. Little evidence was available regarding longer-term effects of pulmonary rehabilitation. PMID- 25284271 TI - Encapsulation of anticancer drug by hydrogen-bonded multilayers of tannic acid. AB - Tannic acid (TA)-based multilayer assemblies have attracted increasing interest for biomedical applications. Here we explore properties of TA-poly(N vinylpyrrolidone) (TA-PVPON) hydrogen-bonded multilayers for drug encapsulation and long-term storage. We demonstrate that the small molecular weight anticancer drug, doxorubicin (DOX), can be successfully loaded into (TA-PVPON) capsules with high encapsulation efficiency. We have also found that the encapsulated DOX can be efficiently stored inside the capsules for the pH range from pH = 7.4 to pH = 5. We show that the chemical and functional stability of TA at neutral and basic pH values is achieved through complexation with PVPON. The UV-vis spectrophotometry and in situ ellipsometry analyses of the hydrogen bonding interactions between TA and PVPON at different pH values reveal pH-dependent behavior of TA-PVPON capsules for the pH range from pH = 7.4 to pH = 5. Increasing deposition pH value from pH = 5 to pH = 7.4 leads to a 2-fold decrease in capsule thickness. However, this trend is reversed when salt concentration of the deposition solutions is increased from 0.01 M to 0.1 M NaCl. We have also demonstrated that the permeability of (TA-PVPON) capsules prepared using low salt deposition conditions and pH = 7.4 can be increased 2-fold by exposure of the capsules to 0.1 M NaCl salt solutions at the same pH. Our work opens new perspectives for design of novel polymer carriers for controlled drug delivery in cancer therapy. PMID- 25284272 TI - Effects of incentives, age, and behavior on brain activation during inhibitory control: a longitudinal fMRI study. AB - We investigated changes in brain function supporting inhibitory control under age controlled incentivized conditions, separating age- and performance-related activation in an accelerated longitudinal design including 10- to 22-year-olds. Better inhibitory control correlated with striatal activation during neutral trials, while Age X Behavior interactions in the striatum indicated that in the absence of extrinsic incentives, younger subjects with greater reward circuitry activation successfully engage in greater inhibitory control. Age was negatively correlated with ventral amygdala activation during Loss trials, suggesting that amygdala function more strongly mediates bottom-up processing earlier in development when controlling the negative aspects of incentives to support inhibitory control. Together, these results indicate that with development, reward-modulated cognitive control may be supported by incentive processing transitions in the amygdala, and from facilitative to obstructive striatal function during inhibitory control. PMID- 25284274 TI - Hepatitis B knowledge and preventive practices of Chinese American immigrants in Southern California. AB - PURPOSE: Chinese American immigrants have higher rates of chronic hepatitis B virus (HBV) infections and consequently higher rates of liver cancer compared to the general U.S. POPULATION: The need to assess this vulnerable population's knowledge and health practices is important to prevent HBV infections and improve outcomes. The purpose of this study was to describe HBV knowledge and preventive practices among Chinese American immigrants in Southern California. DATA SOURCES: Convenience sample of 179 Chinese American immigrants age >=18 years from Los Angeles County (CA) participated in the study by completing a modified version of the B Free CEED's Hepatitis B Needs Assessment survey. CONCLUSIONS: Most participants were knowledgeable of HBV (91.6%) or HBV vaccination (70.5%), yet screening and vaccination for the virus were low (36.9% and 26.3%, respectively). Low knowledge was also found regarding modes of disease transmission. Barriers to engage preventive practices included: "feeling well/no health problems" and "not suggested by a doctor." These findings suggest the need for further education. IMPLICATIONS FOR PRACTICE: Nurse practitioners can play a significant role in assessing risk and implementing programs that are community focused, culturally sensitive, and evidence based to improve knowledge, screening, and preventive behaviors on HBV infections for this vulnerable population. PMID- 25284273 TI - Age-related increases in long-range connectivity in fetal functional neural connectivity networks in utero. AB - Formation of operational neural networks is one of the most significant accomplishments of human fetal brain growth. Recent advances in functional magnetic resonance imaging (fMRI) have made it possible to obtain information about brain function during fetal development. Specifically, resting-state fMRI and novel signal covariation approaches have opened up a new avenue for non invasive assessment of neural functional connectivity (FC) before birth. Early studies in this area have unearthed new insights about principles of prenatal brain function. However, very little is known about the emergence and maturation of neural networks during fetal life. Here, we obtained cross-sectional rs-fMRI data from 39 fetuses between 24 and 38 weeks postconceptual age to examine patterns of connectivity across ten neural FC networks. We identified primitive forms of motor, visual, default mode, thalamic, and temporal networks in the human fetal brain. We discovered the first evidence of increased long-range, cerebral-cerebellar, cortical-subcortical, and intra-hemispheric FC with advancing fetal age. Continued aggregation of data about fundamental neural connectivity systems in utero is essential to establishing principles of connectomics at the beginning of human life. Normative data provides a vital context against which to compare instances of abnormal neurobiological development. PMID- 25284275 TI - Adalimumab retreatment successfully restores clinical response and health-related quality of life in patients with moderate to severe psoriasis who undergo therapy interruption. AB - BACKGROUND: Published evaluations of skin disease signs and health-related quality of life (HRQoL) upon therapy withdrawal and retreatment in psoriatic patients are limited to results of drug withdrawal after short-term treatment. Analyses are lacking that evaluate patients' response to retreatment for patients treated successfully long-term. OBJECTIVE: To study the efficacy and safety of adalimumab in patients with long-term clinical responses to adalimumab who then discontinue therapy and are retreated with the same dosing regimen as the initial course. Skin disease signs and patients' HRQoL are evaluated. METHODS: This post hoc analysis of an open-label study (NCT00195676) included patients who had responded favourably to adalimumab during initial treatment (>=75% improvement in Psoriasis Area and Severity Index [PASI 75 response]) and had maintained good clinical response for an extended period (up to 252 weeks); patients had Physician's Global Assessment (PGA) 0 or 1 before treatment interruption. Following drug withdrawal (up to 40 weeks), all patients were retreated with adalimumab 80 mg initial dose, followed by 40 mg every-other-week for 16 weeks. PASI response and HRQoL were evaluated. RESULTS: Of the 133 patients in this analysis, 24 (18%) relapsed during therapy withdrawal. After 16 weeks of retreatment, 75% who relapsed and 89.9% who did not relapse, had a PASI 75 response; 89.5% achieved European Consensus Programme treatment goals after 16 weeks of retreatment. During drug withdrawal, HRQoL disproportionally worsened compared to skin disease signs; HROoL also considerably worsened for patients who did not relapse. Patients regained HRQoL upon retreatment with adalimumab. No new safety signals were identified in this study. CONCLUSION: Retreatment with adalimumab was successful in improving psoriasis skin signs and HRQoL in this subgroup with initial and extended responses to therapy followed by relapse after treatment withdrawal. Patient's HRQoL should be considered, as it may substantially worsen during therapy interruption. PMID- 25284276 TI - Dithienobenzothiadiazole-based conjugated polymer: processing solvent-relied interchain aggregation and device performances in field-effect transistors and polymer solar cells. AB - DTfBT-Th(3), a new conjugated polymer based on dithienobenzothiadiazole and terthiophene, possesses a bandgap of ~1.86 eV and a HOMO level of -5.27 eV. Due to strong interchain aggregation, DTfBT-Th(3) can not be well dissolved in chloro benzene (CB) and o-dichlorobenzene (DCB) at room temperature (RT), but the polymer can be processed from hot CB and DCB solutions of ~100 degrees C. In CB, with a lower solvation ability, a certain polymer chain aggregation can be preserved, even in hot solution. DTfBT-Th(3) displays a field-effect hole mobility of 0.55 cm(2) V(-1) s(-1) when fabricated from hot CB solution, which is higher than that of the device processed from hot DCB (0.16 cm(2) V(-1) s(-1) In DTfBT-Th(3) -based polymer solar cells, a good power conversion efficiency from 5.37% to 6.67% can be achieved with 150-300 nm thick active layers casted from hot CB solution, while the highest efficiency for hot DCB-processed solar cells is only 5.07%. The results demonstrate that using a solvent with a lower solvation ability, as a "wet control" process, is beneficial to preserve strong interchain aggregation of a conjugated polymer during solution processing, showing great potential to improve its performances in optoelectronic devices. PMID- 25284277 TI - Controlled release of fragrant molecules with visible light. AB - Controlled release of odorous molecules is the key to digital scent technology which will add another dimension to electronics. Photorelease is a cold mechanism that promises better temporal and spatial control than thermal release. Herein we report a novel material composed of an acid-sensitive polymer carrying a fragrant aldehyde and a reversible metastable-state photoacid. It releases the fragrant molecule under visible light, and stops releasing it after the light is turned off. A metastable-state photoacid with a fast reverse-reaction rate was developed to quickly stop the release after irradiation. Both the carrier polymer and the photoacid can be reused after all the fragrant molecules have been released. The material combines the advantages of visible-light activity, fast on/off rate, easy preparation, and recyclability, and thus is promising for digital scent technology. PMID- 25284278 TI - Rational design of signal-on biosensors by using photoinduced electron transfer between Ag nanoclusters and split G-quadruplex halves-hemin complexes. AB - Photoinduced electron transfer (PET) between DNA-Ag nanoclusters (AgNCs) and G quadruplex halves-hemin has been used for building a new sensing platform for the signal-on detection of adenosine and RNA. PMID- 25284279 TI - Psychometric properties of a Chinese version of the Stigma Scale: examining the complex experience of stigma and its relationship with self-esteem and depression among people living with mental illness in Hong Kong. AB - BACKGROUND: Stigma of mental illness is a global public health concern, but there lacks a standardized and cross-culturally validated instrument for assessing the complex experience of stigma among people living with mental illness (PLMI) in the Chinese context. AIM: This study examines the psychometric properties of a Chinese version of the Stigma Scale (CSS), and explores the relationships between stigma, self-esteem and depression. METHODS: A cross-sectional survey was conducted with a community sample of 114 Chinese PLMI in Hong Kong. Participants completed the CSS, the Chinese Self-Stigma of Mental Illness Scale, the Chinese Rosenberg Self-Esteem Scale, and the Chinese Patient Health Questionnaire-9. An exploratory factor analysis was conducted to identify the underlying factors of the CSS; concurrent validity assessment was performed via correlation analysis. RESULTS: The original 28-item three-factor structure of the Stigma Scale was found to be a poor fit to the data, whereas a revised 14-item three-factor model provided a good fit with all 14 items loaded significantly onto the original factors: discrimination, disclosure and positive aspects of mental illness. The revised model also displayed moderate to good internal consistency and good construct validity. Further findings revealed that the total stigma scale score and all three of its subscale scores correlated negatively with self-esteem; but only total stigma, discrimination and disclosure correlated positively with depression. CONCLUSION: The CSS is a short and user-friendly self-administrated questionnaire that proves valuable for understanding the multifaceted stigma experiences among PLMI as well as their impact on psychiatric recovery and community integration in Chinese communities. PMID- 25284280 TI - Relationship of clinical course of illness variables to medical comorbidities in 900 adult outpatients with bipolar disorder. AB - BACKGROUND: Medical illnesses are highly comorbid with bipolar disorder, but their relationship to illness characteristics has not been previously delineated. METHODS: The incidence of 34 medical conditions and 6 poor prognosis factors (PPFs) was derived from answers to a questionnaire in over 900 outpatients with bipolar disorder who gave informed consent. The relationship of PPFs to the number of medical comorbidities was examined by Mann-Whitney U, Pearson r, and logistic regression. RESULTS: When examined individually, each of the 6 PPFs associated with an adverse course of bipolar disorder was significantly related to the number of medical comorbidities patients had. When age, gender, and independence of their relationships to each other were controlled for via regression, 3 of the PPFs remained significant (anxiety disorder, childhood abuse, and age of onset), and having 20 or more prior episodes was a strong trend. The number of PPFs was correlated with the number of comorbidities, although the above 3 PPFs show a similar magnitude of relationship. CONCLUSION: A history of childhood adversity, early age of onset of bipolar disorder, and an anxiety comorbidity were independently related to the number of medical comorbidities that patients experienced as adults. While the nature and mechanisms of this linkage remain to be further explored, the findings indicate the need for greater attention to and treatment of these 3 PPFs in hopes of ameliorating both the adverse course of bipolar illness and the burden of medical comorbidities with which they are associated. PMID- 25284281 TI - Comparison of the pregnancy rates and costs per calf born after fixed-time artificial insemination or artificial insemination after estrus detection in Bos indicus heifers. AB - This study compared pregnancy rates (PRs) and costs per calf born after fixed time artificial insemination (FTAI) or AI after estrus detection (i.e., estrus detection and AI, EDAI), before and after a single PGF2alpha treatment in Bos indicus (Brahman-cross) heifers. On Day 0, the body weight, body condition score, and presence of a CL (46% of heifers) were determined. The heifers were then alternately allocated to one of two FTAI groups (FTAI-1, n = 139) and (FTAI-2, n = 141) and an EDAI group (n = 273). Heifers in the FTAI groups received an intravaginal progesterone-releasing device (IPRD; 0.78 g of progesterone) and 1 mg of estradiol benzoate intramuscularly (im) on Day 0. Eight days later, the IPRD was removed and heifers received 500 MUg of PGF2alpha and 300 IU of eCG im; 24 hours later, they received 1 mg estradiol benzoate im and were submitted to FTAI 30 to 34 hours later (54 and 58 hours after IPRD removal). Heifers in the FTAI-2 group started treatment 8 days after those in the FTAI-1 group. Heifers in the EDAI group were inseminated approximately 12 hours after the detection of estrus between Days 4 and 9 at which time the heifers that had not been detected in estrus received 500 MUg of PGF2alpha im and EDAI continued until Day 13. Heifers in the FTAI groups had a higher overall PR (proportion pregnant as per the entire group) than the EDAI group (34.6% vs. 23.2%; P = 0.003), however, conception rate (PR of heifers submitted for AI) tended to favor the estrus detection group (34.6% vs. 44.1%; P = 0.059). The cost per AI calf born was estimated to be $267.67 and $291.37 for the FTAI and EDAI groups, respectively. It was concluded that in Brahman heifers typical of those annually mated in northern Australia FTAI compared with EDAI increases the number of heifers pregnant and reduces the cost per calf born. PMID- 25284282 TI - Thyroid hormone inhibits the proliferation of piglet Sertoli cell via PI3K signaling pathway. AB - Accumulating researches show that thyroid hormone (TH) inhibits Sertoli cells (SCs) proliferation and stimulates their functional maturation in prepubertal rat testis, confirming that TH plays a key role in testicular development. However, the mechanism under the T3 regulation of piglet SC proliferation remains unclear. In the present study, in order to investigate the possible mechanism of T3 on the suppression of SC proliferation, the expression pattern of TRalpha1 and cell cycle-related molecules, effect of T3 on SC proliferation, and the role of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway on the T3-mediated SC proliferation in piglet testis were explored. Our results demonstrated that TRalpha1 was expressed in all tested stages of SCs and decreased along with the ages. T3 inhibited the proliferation of SCs in a time- and dose-dependent manner, and T3 treatment downregulated the expressions of cell cycling molecules, such as cyclinA2, cyclinD1, cyclinE1, PCNA, and Skp2, but upregulated the p27 expression in SCs. Most importantly, the suppressive effects of T3 on SC proliferation seemed dependent on the inhibition of PI3K/Akt signaling pathway, and pre stimulation of PI3K could enhance such suppressive effects. Together, our findings demonstrate that TH inhibits the proliferation of piglet SCs via the suppression of PI3K/Akt signaling pathway. PMID- 25284283 TI - Free factor XIII activation peptide affects factor XIII function. PMID- 25284285 TI - Subacute cutaneous lupus erythematosus: a paraneoplastic phenomenon in oropharyngeal squamous cell carcinoma. PMID- 25284284 TI - Selenoprotein and antioxidant genes and the risk of high-grade prostate cancer and prostate cancer recurrence. AB - BACKGROUND: Observational studies suggest an inverse association between selenium and risk of prostate cancer. However, randomized controlled trials of selenium supplementation have reported conflicting results. Thus, we examined plasma selenium and selenium-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with non metastatic disease. METHODS: We measured plasma selenium and genotyped 73 single nucleotide polymorphisms in TXNRD1, TXNRD2, GPX1, GPX3, GPX4, SEP15, SEPP1, SELENBP1, OGG1, and CAT among 568 men with non-metastatic prostate cancer who underwent radical prostatectomy. We examined associations between plasma selenium, genotypes, and risk of high-grade prostate cancer (Gleason grade >=8 or 7 with primary score >=4; n = 111) using logistic regression, and risk of prostate cancer recurrence (61 events; 3.8 y median follow-up) using Cox proportional hazards regression. RESULTS: Plasma selenium was not associated with risk of high-grade prostate cancer or prostate cancer recurrence. Less common alleles of rs11913319 in TXNRD2 and rs125701 in OGG1 were associated with an increased risk of high-grade prostate cancer. We observed associations between the risk of prostate cancer recurrence and multiple SNPs in TXNRD1, TXNRD2, GPX3, and SEP15. These associations were no longer statistically significant after adjustment for multiple comparisons. CONCLUSIONS: Among men with non-metastatic prostate cancer, there is suggestive evidence that genetic variation in selenoproteins and related antioxidant enzymes may be associated with risk of high-grade disease at diagnosis and prostate cancer recurrence. PMID- 25284286 TI - Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis. AB - The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons. PMID- 25284287 TI - Inhibition of bladder cancer invasion by Sp1-mediated BTG2 expression via inhibition of DNA methyltransferase 1. AB - Significantly lower endogenous expression of B-cell translocation gene 2 (BTG2) was observed in human muscle-invasive bladder cancers (MIBC) than matched normal tissues and non-muscle invasive bladder cancers (NMIBC). BTG2 expression was inversely correlated with increased expression of the DNA methyltransferases DNMT1 and DNMT3a in MIBC, but not NMIBC, suggesting a potential role for BTG2 expression in muscle invasion of bladder cancer. Over 90% of tumor tissues revealed strong methylation at CpG islands of the BTG2 gene, compared with no methylation in the normal tissues, implying epigenetic regulation of BTG2 expression in bladder carcinogenesis. By using EJ bladder cancer cells and the demethylating agent decitabine, transcription of BTG2 was shown to be up regulated by inhibiting DNMT1 expression via modification at CpG islands. DNMT1 binding to the BTG2 gene further regulated BTG2 expression by chromatin remodeling, such as H3K9 dimethylation and H3K4 trimethylation, and Sp1 activation. Induced BTG2 expression significantly reduced EJ cell tumorigenesis and invasiveness together with induction of G2 /M arrest. These results demonstrate an important role for the BTG2(/TIS21/PC3) gene in the progression of bladder cancers, and suggest that BTG2(/TIS21/PC3) is a promising epigenetic target for prevention of muscle invasion in human bladder cancers. PMID- 25284289 TI - Development and validation of the activity significance personal evaluation (ASPEn) scale. AB - BACKGROUND/AIM: Engagement in desired occupations can promote health and wellbeing in older adults. Assessments of engagement often measure frequency, amount or importance of specific activities. This study aimed to develop a scale to measure older adults' evaluation of the extent to which their everyday activities are contributing to their health and wellness. METHODS: Eighteen items, each scored with a seven-point rating scale, were initially developed by content experts, covering perceptions of how daily activities contribute to physical and mental health, as well as satisfaction and activity participation in the last six months. Rasch analysis methods were used to refine the scale using the pencil and paper responses of 460 community-living older adults. RESULTS: Initial Rasch analysis indicated three unlabelled rating scale categories were seldom used, reducing measurement precision. Five items were conceptually different by misfit statistics and principal component analysis. Subsequently, those items were removed and the number of rating scale steps reduced to 4. The remaining 13-item, 4-step scale, termed the Activity Significance Personal Evaluation (ASPEn), formed a unidimensional hierarchy with good fit statistics and targeting. Person separation reliability (2.7) and internal consistency (.91) indicated the tool is appropriate for individual person measurement. Relative validity indicated equivalence between Rasch measures and total raw scores. CONCLUSIONS: ASPEn is a brief, easily administered assessment of older adults' perception of the contribution of everyday activities to personal health and wellness. ASPEn may facilitate occupational therapy practice by enabling clinicians to assess change in meaning of an older adult's activity over time. PMID- 25284288 TI - Higher-order genetic interactions and their contribution to complex traits. AB - The contribution of genetic interactions involving three or more loci to complex traits is poorly understood. These higher-order genetic interactions (HGIs) are difficult to detect in genetic mapping studies, therefore, few examples of them have been described. However, the lack of data on HGIs should not be misconstrued as proof that this class of genetic effect is unimportant. To the contrary, evidence from model organisms suggests that HGIs frequently influence genetic studies and contribute to many complex traits. Here, we review the growing literature on HGIs and discuss the future of research on this topic. PMID- 25284290 TI - GCMS investigation of volatile compounds in green coffee affected by potato taste defect and the Antestia bug. AB - Potato taste defect (PTD) is a flavor defect in East African coffee associated with Antestiopsis orbitalis feeding and 3-isopropyl-2-methoxypyrazine (IPMP) in the coffee. To elucidate the manifestation of PTD, surface and interior volatile compounds of PTD and non-PTD green coffees were sampled by headspace solid phase microextraction and analyzed by gas chromatography mass spectrometry. Principal component analysis of the chromatographic data revealed a profile of surface volatiles distinguishing PTD from non-PTD coffees dominated by tridecane, dodecane, and tetradecane. While not detected in surface volatiles, IPMP was found in interior volatiles of PTD coffee. Desiccated antestia bugs were analyzed by GCMS, revealing that the three most prevalent volatiles were tridecane, dodecane, and tetradecane, as was found in the surface profile PTD coffee. Coffee having visible insect damage exhibited both a PTD surface volatile profile and IPMP in interior volatiles, supporting the hypothesis linking antestia bug feeding activity with PTD profile compounds on the surface and IPMP in the interior of the beans. PMID- 25284292 TI - Optimization and interpretation of O3 and O3/H2O2 oxidation processes to pretreat hydrocortisone pharmaceutical wastewater. AB - Chemical synthetic pharmaceutical wastewater must be pretreated before traditional biological treatment to improve the biodegradability of pollutants due to their high concentration and complex composition. This study investigated O3 and O3/H2O2 systems to pretreat hydrocortisone wastewater. The optimum treatment efficiency of the O3 system was achieved under pH value of 5.76, dosage of O3 of 217.5 mg/L, and reaction time of 90 min. The removal efficiency of chemical oxygen demand (COD) and total organic carbon (TOC) was 94% and 92%, respectively. The ratio of biochemical oxygen demand (BOD) and COD (B/C) increased from 0.066 to 0.310. Moreover, the optimum H2O2/O3 molar ratio was 0.3 with the optimum pH of 3, and reaction time was reduced to 15 min to reach COD removal efficiency of 67.3% in the O3/H2O2 oxidation system. Interestingly, isobutanol was assumed to be a good hydroxyl radical trapping agent due to the great decrease of Fenton reagent reaction rate constant. By comparing two different kinetic models, oxidation mechanism could be interpreted by the pseudo first-order kinetic model with the high correlation coefficient R2 above 0.9787. It can be concluded that ozonation system was controlled by both direct oxidation and free radical oxidation, and particularly the later one played a dominant role. PMID- 25284294 TI - My welcome to the world of wound care. PMID- 25284291 TI - Biological roles of fungal carotenoids. AB - Carotenoids are terpenoid pigments widespread in nature, produced by bacteria, fungi, algae and plants. They are also found in animals, which usually obtain them through the diet. Carotenoids in plants provide striking yellow, orange or red colors to fruits and flowers, and play important metabolic and physiological functions, especially relevant in photosynthesis. Their functions are less clear in non-photosynthetic microorganisms. Different fungi produce diverse carotenoids, but the mutants unable to produce them do not exhibit phenotypic alterations in the laboratory, apart of lack of pigmentation. This review summarizes the current knowledge on the functional basis for carotenoid production in fungi. Different lines of evidence support a protective role of carotenoids against oxidative stress and exposure to visible light or UV irradiation. In addition, the carotenoids are intermediary products in the biosynthesis of physiologically active apocarotenoids or derived compounds. This is the case of retinal, obtained from the symmetrical oxidative cleavage of beta carotene. Retinal is the light-absorbing prosthetic group of the rhodopsins, membrane-bound photoreceptors present also in many fungal species. In Mucorales, beta-carotene is an intermediary in the synthesis of trisporoids, apocarotenoid derivatives that include the sexual hormones the trisporic acids, and they are also presumably used in the synthesis of sporopollenin polymers. In conclusion, fungi have adapted their ability to produce carotenoids for different non essential functions, related with stress tolerance or with the synthesis of physiologically active by-products. PMID- 25284295 TI - Probing the wound healing potential of biogenic silver nanoparticles. AB - OBJECTIVE: Silver nanoparticles (AgNPs) are known for their antimicrobial profile and wound healing activities. However, cytotoxicity and cosmetic abnormalities associated with silver pose a major challenge in their translation for therapeutic applications. Our objective was to develop biogenic AgNPs, using a single-step green synthesis, and to investigate their in vitro and in vivo behaviour as wound-healing agents. METHOD: AgNPs were prepared using the green synthesis approach with aqueous Bryonia laciniosa leaves extract. The AgNPs were then evaluated for physicochemical properties, stability, and antimicrobial and in vivo wound healing activities. RESULTS: Stable AgNPs with characteristic absorption at 408nm and 15+/-3nm particle size were generated via the active involvement of Bryonia laciniosa. No loss of stability was detected after 6 months at room temperature. Antibacterial activity was observed against both Gram negative and Gram-positive bacteria with no cytotoxicity observed in vitro at a concentration of 200 MUg/mL and effective cytokine modulation. In vivo wound healing experiments showed improved wound contracting ability in rats where, after 14 days, wound alleviation was 47.1+/-2.2% in the control groups, compared with 78.1+/-1.4% and 92.6+/-6.7% for a silver-based marketed cream and the AgNPs, respectively. CONCLUSION: The developed AgNPs proved to be superior wound healing agents owing to scarless healing with insignificant inflammation and toxicity. DECLARATION OF INTEREST: There were no external sources of funding for this study. The authors have no conflicts of interest to declare. PMID- 25284296 TI - Impact of compression therapy using Unna's boot on the self-esteem of patients with venous leg ulcers. AB - OBJECTIVE: To assess self-esteem in patients with venous leg ulcers treated with Unna's boot. * METHOD: A descriptive, analytic, clinical study was conducted from June 2010 to May 2011 in an outpatient wound care clinic in Sao Paulo, Brazil. Patients of both sexes, aged >=18 years, who had had a venous leg ulcer for more than one year and a Doppler ankle brachial index ranging from 0.8-1.0 were consecutively selected for inclusion. Patients were treated with wound dressings and Unna's boot. Self-esteem was assessed using the Brazilian version of the Rosenberg Self-Esteem Scale (RSE) at inclusion (baseline) and after 4, 8, and 12 months of compression therapy using Unna's boot. The scale is reverse-scored; thus lower scores indicate higher levels of self-esteem. * RESULTS: The patients showed a slight but significant improvement in self-esteem after 4 months of treatment (mean RSE score=17.12) compared with baseline (mean RSE score=24.90). However, a marked and significant improvement in self-esteem was observed after 8 months (mean RSE score=7.40) and 12 months (mean RSE score=2.10) of compression therapy using Unna's boot. * CONCLUSION: Patients with venous leg ulcers treated with Unna's boot for 12 months showed a significant improvement in self-esteem * DECLARATION OF INTEREST: All authors declare that no competing financial interests exist. There was no external funding for this study. PMID- 25284293 TI - Role of flippases, scramblases and transfer proteins in phosphatidylserine subcellular distribution. AB - It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then distributed to different cellular locations in order to create the distinct membrane compositions observed in eukaryotes. However, the mechanisms by which specific lipid species are trafficked to and maintained in specific areas of the cell are poorly understood and constitute an active area of research. Of particular interest is the distribution of phosphatidylserine (PS), an anionic lipid that is enriched in the cytosolic leaflet of the plasma membrane. PS transport occurs by both vesicular and non-vesicular routes, with members of the oxysterol-binding protein family (Osh6 and Osh7) recently implicated in the latter route. In addition, the flippase activity of P4-ATPases helps build PS membrane asymmetry by preferentially translocating PS to the cytosolic leaflet. This asymmetric PS distribution can be used as a signaling device by the regulated activation of scramblases, which rapidly expose PS on the extracellular leaflet and play important roles in blood clotting and apoptosis. This review will discuss recent advances made in the study of phospholipid flippases, scramblases and PS-specific lipid transfer proteins, as well as how these proteins contribute to subcellular PS distribution. PMID- 25284297 TI - Extended applications of gauze-based negative pressure wound therapy in hand surgery: a review of five cases. AB - Negative pressure wound therapy (NPWT) is an established treatment for a wide variety of acute and chronic wounds. Although the exact mechanism of action is still undefined, the proposed benefits of NPWT have been well described in the literature and include improved wound perfusion, granulation and reduction of oedema and bacteria. Here we describe a series of five challenging cases where NPWT dressings were applied for both elective and traumatic wounds of the upper limb. We describe the application of the dressing and the benefits seen in our patients. We believe the patients would have had inferior outcomes if managed by the best alternative conventional dressings. DECLARATION OF INTEREST: All named authors hereby declare that they have no conflicts of interest to disclose. PMID- 25284298 TI - Modified NPWT using round channel drain for pacemaker pocket non-healing complex wound: a case report. AB - Infection of cardiovascular implantable electronic devices poses a serious medical problem. Management of infected pocket wounds may be challenging for the physician and cause prolonged morbidity for the patient. The mainstay of treatment for infected cardiovascular implantable electronic devices is complete removal of the infected device and appropriate antibiotic therapy. In contrast, removal is not required for superficial or incisional infection at the pocket site if there is no involvement of the device. Here, we describe a modified negative pressure wound therapy (NPWT) technique using a round channel drain for pacemaker pocket non-healing complex wound, which started as a superficial incisional wound infection. PMID- 25284299 TI - A comparison of 2-octyl cyanoacrylate with nylon for wound closure of knee arthroscopy portals. AB - OBJECTIVE: To compare the cosmetic results, complications and patient satisfaction of 2-octyl cyanoacrylate (Dermabond, Ethicon Inc. Somerville, NJ, USA), a liquid bonding agent, with 3-0 nylon sutures (Ethilon, Ethicon Inc) skin closure in two groups of patients undergoing elective knee arthroscopy at 6 weeks. METHOD: The retrospective clinical audit recruited patients undergoing knee surgery for the first time between October 2010 and August 2011. The patients were either treated with the liquid bonding agent or nylon sutures. The patients in the bonding agent group were allowed to shower as normal on postoperative day one, while patients in the suture group kept their wounds dry for 2 weeks. RESULTS: Between the two groups (40 patients per group) there was no difference in the cosmetic outcome (p=0.285), patient satisfaction (p=0.29), pain scores (p=0.44) or wound complication rate (p<0.05). Patient satisfaction was high in both groups. Furthermore, 83.75% of all patients indicated they would prefer the liquid bonding closure over nylon sutures if undergoing the same procedure in the future as they could shower the next day and avoid suture removal. CONCLUSION: 2-octyl cyanoacrylate is safe to use in the short term in knee arthroscopy providing comparable results to nylon suture closure. Allowing patients to shower the next day appears to cause no adverse effects. DECLARATION OF INTEREST: The authors would like to state that they do not have any economic or social interest in any of the products used or mentioned. No grant or finance was received for this study, nor any input from other sources. PMID- 25284300 TI - Phosphinothiolates as ligands for polyhydrido copper nanoclusters. AB - The reaction of [CuI(HSC6 H4 PPh2 )]2 with NaBH4 in CH2 Cl2 /EtOH led to air- and moisture-stable copper hydride nanoparticles (CuNPs) containing phosphinothiolates as new ligands, one of which was isolated by crystallization. The X-ray crystal structure of [Cu18 H7 L10 I] (L=(-) S(C6 H4 )PPh2 ) shows unprecedented features in its 28-atom framework (18 Cu and 10 S atoms). Seven hydrogen atoms, in hydride form, are needed for charge balance and were located by density functional theory methods. H2 was released from the copper hydride nanoparticles by thermolysis and visible light irradiation. PMID- 25284302 TI - Recursive approach of EEG-segment-based principal component analysis substantially reduces cryogenic pump artifacts in simultaneous EEG-fMRI data. AB - Electroencephalography (EEG) data simultaneously acquired with functional magnetic resonance imaging (fMRI) data are preprocessed to remove gradient artifacts (GAs) and ballistocardiographic artifacts (BCAs). Nonetheless, these data, especially in the gamma frequency range, can be contaminated by residual artifacts produced by mechanical vibrations in the MRI system, in particular the cryogenic pump that compresses and transports the helium that chills the magnet (the helium-pump). However, few options are available for the removal of helium pump artifacts. In this study, we propose a recursive approach of EEG-segment based principal component analysis (rsPCA) that enables the removal of these helium-pump artifacts. Using the rsPCA method, feature vectors representing helium-pump artifacts were successfully extracted as eigenvectors, and the reconstructed signals of the feature vectors were subsequently removed. A test using simultaneous EEG-fMRI data acquired from left-hand (LH) and right-hand (RH) clenching tasks performed by volunteers found that the proposed rsPCA method substantially reduced helium-pump artifacts in the EEG data and significantly enhanced task-related gamma band activity levels (p=0.0038 and 0.0363 for LH and RH tasks, respectively) in EEG data that have had GAs and BCAs removed. The spatial patterns of the fMRI data were estimated using a hemodynamic response function (HRF) modeled from the estimated gamma band activity in a general linear model (GLM) framework. Active voxel clusters were identified in the post-/pre central gyri of motor area, only from the rsPCA method (uncorrected p<0.001 for both LH/RH tasks). In addition, the superior temporal pole areas were consistently observed (uncorrected p<0.001 for the LH task and uncorrected p<0.05 for the RH task) in the spatial patterns of the HRF model for gamma band activity when the task paradigm and movement were also included in the GLM. PMID- 25284301 TI - Identifying Sparse Connectivity Patterns in the brain using resting-state fMRI. AB - The human brain processes information via multiple distributed networks. An accurate model of the brain's functional connectome is critical for understanding both normal brain function as well as the dysfunction present in neuropsychiatric illnesses. Current methodologies that attempt to discover the organization of the functional connectome typically assume spatial or temporal separation of the underlying networks. This assumption deviates from an intuitive understanding of brain function, which is that of multiple, inter-dependent spatially overlapping brain networks that efficiently integrate information pertinent to diverse brain functions. It is now increasingly evident that neural systems use parsimonious formations and functional representations to efficiently process information while minimizing redundancy. Hence we exploit recent advances in the mathematics of sparse modeling to develop a methodological framework aiming to understand complex resting-state fMRI connectivity data. By favoring networks that explain the data via a relatively small number of participating brain regions, we obtain a parsimonious representation of brain function in terms of multiple "Sparse Connectivity Patterns" (SCPs), such that differential presence of these SCPs explains inter-subject variability. In this manner the sparsity-based framework can effectively capture the heterogeneity of functional activity patterns across individuals while potentially highlighting multiple sub-populations within the data that display similar patterns. Our results from simulated as well as real resting state fMRI data show that SCPs are accurate and reproducible between sub samples as well as across datasets. These findings substantiate existing knowledge of intrinsic functional connectivity and provide novel insights into the functional organization of the human brain. PMID- 25284303 TI - Amygdala habituation: a reliable fMRI phenotype. AB - Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test-retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies. PMID- 25284305 TI - Functional brain networks contributing to the Parieto-Frontal Integration Theory of Intelligence. AB - The refinement of localization of intelligence in the human brain is converging onto a distributed network that broadly conforms to the Parieto-Frontal Integration Theory (P-FIT). While this theory has received support in the neuroimaging literature, no functional magnetic resonance imaging study to date has conducted a whole-brain network-wise examination of the changes during engagement in tasks that are reliable measures of general intelligence (e.g., Raven's Progressive Matrices Test; RPM). Seventy-nine healthy subjects were scanned while solving RPM problems and during rest. Functional networks were extracted from the RPM and resting state data using Independent Component Analysis. Twenty-nine networks were identified, 26 of which were detected in both conditions. Fourteen networks were significantly correlated with the RPM task. The networks' spatial maps and functional connectivity measures at 3 frequency levels (low, medium, & high) were compared between the RPM and rest conditions. The regions involved in the networks that were found to be task related were consistent with the P-FIT, localizing to the bilateral medial frontal and parietal regions, right superior frontal lobule, and the right cingulate gyrus. Functional connectivity in multiple component pairs was differentially affected across all frequency levels during the RPM task. Our findings demonstrate that functional brain networks are more stable than previously thought, and maintain their general features across resting state and engagement in a complex cognitive task. The described spatial and functional connectivity alterations that such components undergo during fluid reasoning provide a network-wise framework of the P-FIT that can be valuable for further, network based, neuroimaging inquiries regarding the neural underpinnings of intelligence. PMID- 25284304 TI - Age trajectories of functional activation under conditions of low and high processing demands: an adult lifespan fMRI study of the aging brain. AB - We examined functional activation across the adult lifespan in 316 healthy adults aged 20-89years on a judgment task that, across conditions, drew upon both semantic knowledge and ability to modulate neural function in response to cognitive challenge. Activation in core regions of the canonical semantic network (e.g., left IFG) were largely age-invariant, consistent with cognitive aging studies that show verbal knowledge is preserved across the lifespan. However, we observed a steady linear increase in activation with age in regions outside the core network, possibly as compensation to maintain function. Under conditions of increased task demands, we observed a stepwise reduction across the lifespan of modulation of activation to increasing task demands in cognitive control regions (frontal, parietal, anterior cingulate), paralleling the neural equivalent of "processing resources" described by cognitive aging theories. Middle-age was characterized by decreased modulation to task-demand in subcortical regions (caudate, nucleus accumbens, thalamus), and very old individuals showed reduced modulation to task difficulty in midbrain/brainstem regions (ventral tegmental, substantia nigra). These novel findings suggest that aging of activation to demand follows a gradient along the dopaminergic/nigrostriatal system, with earliest manifestation in fronto-parietal regions, followed by deficits in subcortical nuclei in middle-age and then to midbrain/brainstem dopaminergic regions in the very old. PMID- 25284308 TI - Autologous cranioplasty following decompressive craniectomy in the trauma setting. AB - Background. Decompressive craniectomy (DC) is an option for the treatment of increased intracranial pressure resulting from an acute neurological insult, including insults caused by trauma. When the brain swelling has receded, the skull is reconstructed with a wide choice of materials, each with its own advantages and disadvantages in terms of cost, cosmetic appearance, biocompatibility, implant strength and complication rate. Autologous cranioplasty (AC), where the patient's own bone flap is stored and reutilised, is common in many countries. No outcome studies have, however, been published on this technique for traumatic injuries. Methods. A retrospective study was conducted including all AC operations performed following DC due to traumatic brain injury. All operations were performed in one institution during a 4-year time period. Results were analysed for complication rates. Results. 44 cases were included. The mean time from craniotomy to cranioplasty was 86 (95% CI: 63-109) days. Complications severe enough to warrant readmission or further surgery were found in 13 cases (30%). No statistically significant predictor of complication from cranioplasty was detected. The complication rate was similar to published data on cranioplasty using artificial prosthetic materials. Conclusions. AC in the trauma setting is a valid treatment option with a complication rate that seems no worse than other alternatives. PMID- 25284306 TI - Quantification of microscopic diffusion anisotropy disentangles effects of orientation dispersion from microstructure: applications in healthy volunteers and in brain tumors. AB - The anisotropy of water diffusion in brain tissue is affected by both disease and development. This change can be detected using diffusion MRI and is often quantified by the fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Although FA is sensitive to anisotropic cell structures, such as axons, it is also sensitive to their orientation dispersion. This is a major limitation to the use of FA as a biomarker for "tissue integrity", especially in regions of complex microarchitecture. In this work, we seek to circumvent this limitation by disentangling the effects of microscopic diffusion anisotropy from the orientation dispersion. The microscopic fractional anisotropy (MUFA) and the order parameter (OP) were calculated from the contrast between signal prepared with directional and isotropic diffusion encoding, where the latter was achieved by magic angle spinning of the q-vector (qMAS). These parameters were quantified in healthy volunteers and in two patients; one patient with meningioma and one with glioblastoma. Finally, we used simulations to elucidate the relation between FA and MUFA in various micro-architectures. Generally, MUFA was high in the white matter and low in the gray matter. In the white matter, the largest differences between MUFA and FA were found in crossing white matter and in interfaces between large white matter tracts, where MUFA was high while FA was low. Both tumor types exhibited a low FA, in contrast to the MUFA which was high in the meningioma and low in the glioblastoma, indicating that the meningioma contained disordered anisotropic structures, while the glioblastoma did not. This interpretation was confirmed by histological examination. We conclude that FA from DTI reflects both the amount of diffusion anisotropy and orientation dispersion. We suggest that the MUFA and OP may complement FA by independently quantifying the microscopic anisotropy and the level of orientation coherence. PMID- 25284307 TI - Impact of extraneous proteins on the gastrointestinal fate of sunflower seed (Helianthus annuus) oil bodies: a simulated gastrointestinal tract study. AB - In this study, we examined the physicochemical nature of sunflower seed oil bodies (in the absence and presence of added protein) exposed to gastrointestinal conditions in vitro: crude oil bodies (COB); washed oil bodies (WOB); whey protein isolate-enriched oil bodies (WOB-WPI); and, sodium caseinate enriched-oil bodies (WOB-SC). All oil body emulsions were passed through an in vitro digestion model that mimicked the stomach and duodenal environments, and their physicochemical properties were measured before, during, and after digestion. Oil bodies had a positive charge under gastric conditions because the pH was below the isoelectric point of the adsorbed protein layer, but they had a negative charge under duodenal conditions which was attributed to changes in interfacial composition resulting from adsorption of bile salts. Oil bodies were highly susceptible to flocculation and coalescence in both gastric and duodenal conditions. SDS-PAGE analysis indicated degradation of oleosin proteins (ca. 18 21 kDa) to a greater or lesser extent (dependent on the emulsion) during the gastric phase in all emulsions tested; there is evidence that some oleosin remained intact in the crude oil body preparation during this phase of the digestion process. Measurements of protein displacement from the surface of COBs during direct exposure to bile salts, without inclusion of a gastric phase, indicated the removal of intact oleosin from native oil bodies. PMID- 25284309 TI - DYT1 directly regulates the expression of TDF1 for tapetum development and pollen wall formation in Arabidopsis. AB - The tapetum plays a critical role during the development and maturation of microspores. DYSFUNCTIONAL TAPETUM 1 (DYT1) is essential for early tapetal development. Here, we determined that the promoter region (-550 to -463 bp) contains indispensable cis-elements for DYT1 expression. Although DYT1 transcripts can be detected in both meiocytes and tapetal cells, localization of DYT1-GFP demonstrated that DYT1 is strictly located in tapetal cells during microsporogenesis. Chromatin immunoprecipitation (ChIP) analysis revealed that DYT1 directly binds the promoter region of Defective in Tapetal Development and Function 1 (TDF1), a transcription factor essential for tapetum development. When TDF1 driven by the DYT1 promoter is expressed in a dyt1 mutant, the expression of the transcription factors AMS, MS188/MYB80, TEK and MS1 and the pollen wall related genes are restored. Although the pollen wall is not formed and the microspores are ruptured, DIOC2 staining showed that fatty acids, the precursors of the pollen wall, were synthesized in the transgenic lines. These results indicate that DYT1 regulates the expression of AMS, MS188/MYB80, TEK and MS1 for pollen wall formation, primarily via TDF1. PMID- 25284311 TI - Instrument-free control of the standard potential of potentiometric solid-contact ion-selective electrodes by short-circuiting with a conventional reference electrode. AB - A simple, instrument-free method to control the standard potential (E degrees ) of potentiometric solid-contact ion-selective electrodes (SC-ISE) is described. In this method, the electrode potential of a SC-ISE is reset by short-circuiting the electrode with a metallic wire to a conventional Ag/AgCl/3 M KCl reference electrode (RE) in a solution containing primary ions. The method is studied experimentally for SC-ISEs where the conducting polymer poly(3,4 ethylenedioxythiophene) doped with the bulky anion poly(sodium 4 styrenesulfonate), PEDOT(PSS), is used as the solid contact. Three different types of ion-selective membranes (ISMs) are studied: two potassium-selective membranes, with and without the lipohilic additive tetradodecylammonium tetrakis(4-chlorophenyl)borate (ETH-500) and a cation-sensitive membrane without an ionophore. When the SC-ISE is short-circuited with the RE, the PEDOT(PSS) layer is oxidized or reduced, thereby shifting the potential of the SC-ISE to the proximity of the potential of the RE so that the potential difference between these two electrodes becomes zero or close to zero. The slope of the calibration curve is preserved after the short-circuit treatment of the SC-ISEs. The short circuiting method is an important step toward calibration-free potentiometric analysis. PMID- 25284310 TI - Phylogenetic analysis and the evolution of the 18S rRNA gene typing system of Acanthamoeba. AB - Species of Acanthamoeba were first described using morphological characters including cyst structure and cytology of nuclear division. More than 20 nominal species were proposed using these methods. Morphology, especially cyst shape and size, has proven to be plastic and dependent upon culture conditions. The DNA sequence of the nuclear small-subunit (18S) rRNA, the Rns gene, has become the most widely accepted method for rapid diagnosis and classification of Acanthamoeba. The Byers-Fuerst lab first proposed an Rns typing system in 1996. Subsequent refinements, with an increasing DNA database and analysis of diagnostic fragments within the gene, have become widely accepted by the Acanthamoeba research community. The development of the typing system, including its current state of implementation is illustrated by three cases: (i) the division between sequence types T13 and T16; (ii) the diversity within sequence supertype T2/T6, and (iii) verification of a new sequence type, designated T20. Molecular studies make clear the disconnection between phylogenetic relatedness and species names, as applied for the genus Acanthamoeba. Future reconciliation of genetic types with species names must become a priority, but the possible shortcomings of the use of a single gene when reconstructing the evolutionary history of the acanthamoebidae must also be resolved. PMID- 25284312 TI - Structural identification of modified amino acids on the interface between EPO and its receptor from EPO BRP, human recombinant erythropoietin by LC/MS analysis. AB - Protein modifications of recombinant pharmaceuticals have been observed both in vitro and in vivo. These modifications may result in lower efficacy, as well as bioavailability changes and antigenicity among the protein pharmaceuticals. Therefore, the contents of modification should be monitored for the quality and efficacy of protein pharmaceuticals. The interface of EPO and its receptor was visualized, and potential amino acids interacting on the interface were also listed. Two different types of modifications on the interface were identified in the preparation of rHu-EPO BRP. A UPLC/Q-TOF MS method was used to evaluate the modification at those variants. The modification of the oxidized variant was localized on the Met54 and the deamidated variants were localized on the Asn47 and Asn147. The extent of oxidation at Met54 was 3.0% and those of deamidation at Asn47 and Asn147 were 2.9% and 4.8%, respectively. PMID- 25284314 TI - Loop-mediated isothermal amplification assay targeting the blaCTX-M9 gene for detection of extended spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. AB - Extended-spectrum beta-lactamases (ESBLs) produced by Enterobacteriaceae are one of the resistance mechanisms to most beta-lactam antibiotics. ESBLs are currently a major problem in both hospitals and community settings worldwide. Rapid and reliable means of detecting ESBL-producing bacteria is necessary for identification, prevention and treatment. Loop-mediated isothermal amplification (LAMP) is a technique that rapidly amplifies DNA with high specificity and sensitivity under isothermal conditions. This study was aimed to develop a convenient, accurate and inexpensive method for detecting ESBL-producing bacteria by a LAMP technique. ESBLs-producing Escherichia coli and Klebsiella pneumoniae were isolated from a tertiary hospital in Bangkok, Thailand and reconfirmed by double-disk synergy test. A set of four specific oligonucleotide primers of LAMP for detection of bla(CTX-M9) gene was designed based on bla(CTX-M9) from E. coli (GenBank Accession No. AJ416345). The LAMP reaction was amplified under isothermal temperature at 63 degrees C for 60 min. Ladder-like patterns of band sizes from 226 bp of the bla(CTX-M9) DNA target was observed. The LAMP product was further analyzed by restriction digestion with MboI and TaqI endonucleases. The fragments generated were approximately 168, 177 and 250 bp in size for MboI digestion and 165, 193, 229, 281 and 314 bp for TaqI digestion, which is in agreement with the predicted sizes. The sensitivity of the LAMP technique to bla(CTX-M9) was greater than that of the PCR method by at least 10,000-fold. These results showed that the LAMP primers specifically amplified only the bla(CTX-M9) gene. Moreover, the presence of LAMP amplicon was simply determined by adding SYBR Green I in the reaction. In conclusion, this technique for detection of ESBLs is convenient, reliable and easy to perform routinely in hospitals or laboratory units in developing countries. PMID- 25284313 TI - Dax1 and Nanog act in parallel to stabilize mouse embryonic stem cells and induced pluripotency. AB - Nanog expression is heterogeneous and dynamic in embryonic stem cells (ESCs). However, the mechanism for stabilizing pluripotency during the transitions between Nanog(high) and Nanog(low) states is not well understood. Here we report that Dax1 acts in parallel with Nanog to regulate mouse ESC (mESCs) identity. Dax1 stable knockdown mESCs are predisposed towards differentiation but do not lose pluripotency, whereas Dax1 overexpression supports LIF-independent self renewal. Although partially complementary, Dax1 and Nanog function independently and cannot replace one another. They are both required for full reprogramming to induce pluripotency. Importantly, Dax1 is indispensable for self-renewal of Nanog(low) mESCs. Moreover, we report that Dax1 prevents extra-embryonic endoderm (ExEn) commitment by directly repressing Gata6 transcription. Dax1 may also mediate inhibition of trophectoderm differentiation independent or as a downstream effector of Oct4. These findings establish a basal role of Dax1 in maintaining pluripotency during the state transition of mESCs and somatic cell reprogramming. PMID- 25284315 TI - XPO1/CRM1-selective inhibitors of nuclear export (SINE) reduce tumor spreading and improve overall survival in preclinical models of prostate cancer (PCa). AB - BACKGROUND: Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus. AIM AND METHODS: To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT- 330) and KPT 251, were tested in preclinical models known to generate bone lesions and systemic tumor spread. RESULTS: In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor- and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor- and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor- and KPT-251-treated animals when compared to controls. CONCLUSIONS: Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa. PMID- 25284316 TI - How fragility makes phase-change data storage robust: insights from ab initio simulations. AB - Phase-change materials are technologically important due to their manifold applications in data storage. Here we report on ab initio molecular dynamics simulations of crystallization of the phase change material Ag4In3Sb67Te26 (AIST). We show that, at high temperature, the observed crystal growth mechanisms and crystallization speed are in good agreement with experimental data. We provide an in-depth understanding of the crystallization mechanisms at the atomic level. At temperatures below 550 K, the computed growth velocities are much higher than those obtained from time-resolved reflectivity measurements, due to large deviations in the diffusion coefficients. As a consequence of the high fragility of AIST, experimental diffusivities display a dramatic increase in activation energies and prefactors at temperatures below 550 K. This property is essential to ensure fast crystallization at high temperature and a stable amorphous state at low temperature. On the other hand, no such change in the temperature dependence of the diffusivity is observed in our simulations, down to 450 K. We also attribute this different behavior to the fragility of the system, in combination with the very fast quenching times employed in the simulations. PMID- 25284318 TI - Excitatory synaptic function and plasticity is persistently altered in ventral tegmental area dopamine neurons after prenatal ethanol exposure. AB - Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VTA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to enhanced excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LTP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhancement in amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders. PMID- 25284317 TI - The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease. AB - The proteins alpha-synuclein (alphaSyn) and leucine rich repeat kinase 2 (LRRK2) are both key players in the pathogenesis of the neurodegenerative disorder Parkinson's disease (PD), but establishing a functional link between the two proteins has proven elusive. Research studies for these two proteins have traditionally and justifiably focused in neuronal cells, but recent studies indicate that each protein could play a greater pathological role elsewhere. alphaSyn is expressed at high levels within neurons, but they also secrete the protein into the extracellular milieu, where it can have broad ranging effects in the nervous system and relevance to disease etiology. Similarly, low neuronal LRRK2 expression and activity suggests that LRRK2-related functions could be more relevant in cells with higher expression, such as brain-resident microglia. Microglia are monocytic immune cells that protect neurons from noxious stimuli, including pathological alphaSyn species, and microglial activation is believed to contribute to neuroinflammation and neuronal death in PD. Interestingly, both alphaSyn and LRRK2 can be linked to microglial function. Secreted alphaSyn can directly activate microglia, and can be taken up by microglia for clearance, while LRRK2 has been implicated in the intrinsic regulation of microglial activation and of lysosomal degradation processes. Based on these observations, the present review will focus on how PD-associated mutations in LRRK2 could potentially alter microglial biology with respect to neuronally secreted alphaSyn, resulting in cell dysfunction and neurodegeneration. PMID- 25284320 TI - Paradoxical neurobehavioral rescue by memories of early-life abuse: the safety signal value of odors learned during abusive attachment. AB - Caregiver-associated cues, including those learned in abusive attachment, provide a sense of safety and security to the child. Here, we explore how cues associated with abusive attachment, such as maternal odor, can modify the enduring neurobehavioral effects of early-life abuse. Two early-life abuse models were used: a naturalistic paradigm, where rat pups were reared by an abusive mother; and a more controlled paradigm, where pups underwent peppermint odor-shock conditioning that produces an artificial maternal odor through engagement of the attachment circuit. Animals were tested for maternal odor preference in infancy, forced swim test (FST), social behavior, and sexual motivation in adulthood-in the presence or absence of maternal odors (natural or peppermint). Amygdala odor evoked local field potentials (LFPs) via wireless electrodes were also examined in response to the maternal odors in adulthood. Both early-life abuse models induced preference for the maternal odors in infancy. In adulthood, these early life abuse models produced FST deficits and decreased social behavior, but did not change sexual motivation. Presentation of the maternal odors rescued FST and social behavior deficits induced by early-life abuse and enhanced sexual motivation in all animals. In addition, amygdala LFPs from both abuse animal models showed unique activation within the gamma frequency (70-90 Hz) bands in response to the specific maternal odor present during early-life abuse. These results suggest that attachment-related cues learned during infancy have a profound ability to rescue neurobehavioral dysregulation caused by early-life abuse. Paradoxically, abuse-associated cues seem to acquire powerful and enduring antidepressive properties and alter amygdala modulation. PMID- 25284319 TI - Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes. PMID- 25284321 TI - Volumetric-modulated arc therapy for oropharyngeal carcinoma: a dosimetric and delivery efficiency comparison with static-field IMRT. AB - The purpose of this study is to evaluate the treatment plan adequacy and delivery efficiency among volumetric-modulated arc therapy (VMAT) with one or two arcs and the conventional static-field dynamic multileaf collimator (dMLC) intensity modulated radiation therapy (IMRT) in patients undergoing oropharyngeal carcinoma. Fifteen patient cases were included in this investigation. Each of the cases was planned using step-and-shoot IMRT, VMAT with a single arc (Arc1) and VMAT with double arcs (Arc2). A two-dose level prescription for planning target volumes (PTVs) was delivered with 70 Gy/56 Gy in 30 fractions. Comparisons were performed of the dose-volume histograms (DVH) for PTVs, the DVH for organs at risk (OARs), the monitor units per fraction (MU/fx), and delivery time. IMRT and Arc2 achieved similar target coverage, but superior to Arc1. Apart from the oral cavity, Arc1 showed no advantage in sparing of OARs compared with IMRT, while Arc2 obtained equivalent or better sparing of OARs among the three techniques. VMAT reduced MU/fx and shortened delivery time remarkably compared with IMRT. Our results demonstrated that for oropharyngeal cases, Arc2 can achieve superior target coverage and normal tissue sparing, as well as a significant reduction in treatment time. PMID- 25284322 TI - Biofilm formation is not a prerequisite for production of the antibacterial compound tropodithietic acid in Phaeobacter inhibens DSM17395. AB - AIMS: The goal of this study was to investigate if biofilm formation on population level is a physiological requirement for antagonism in Phaeobacter inhibens DSM17395, since the antibiotic compound tropodithietic acid (TDA) is produced by several Roseobacter clade species during growth as multicellular aggregates or biofilms at the air-liquid interface and is induced on single cell level upon attachment. METHODS AND RESULTS: A mutant library was created by Tn5 transposon insertion and 22 TDA-positive (brown) mutants with decreased biofilm formation or adhesion, and eight TDA-negative (white) mutants with increased biofilm formation or adhesion were selected. None of the selected biofilm overproducing white mutants showed any antibiotic activity, while all brown mutants with reduced or disabled biofilm formation produced the antibacterial compound. Sequencing analysis indicated that genes that are likely involved in EPS/LPS production, motility and chemotaxis, and redox regulation play a role in biofilm formation and/or adhesion in P. inhibens DSM17395. CONCLUSIONS: Cell aggregation and biofilm formation are not physiological prerequisites for TDA production. SIGNIFICANCE AND IMPACT OF THE STUDY: This study contributes to the understanding of TDA production in P. inhibens, which has great potential as a probiotic in marine larviculture. PMID- 25284325 TI - Novel EP4 receptor agonist-bisphosphonate conjugate drug (C1) promotes bone formation and improves vertebral mechanical properties in the ovariectomized rat model of postmenopausal bone loss. AB - Current treatments for postmenopausal osteoporosis aim to either promote bone formation or inhibit bone resorption. The C1 conjugate drug represents a new treatment approach by chemically linking the antiresorptive compound alendronate (ALN) with the anabolic agent prostanoid EP4 receptor agonist (EP4a) through a linker molecule (LK) to form a conjugate compound. This enables the bone targeting ability of ALN to deliver EP4a to bone sites and mitigate the systemic side effects of EP4a, while also facilitating dual antiresorptive and anabolic effects. In vivo hydrolysis is required to release the EP4a and ALN components for pharmacological activity. Our study investigated the in vivo efficacy of this drug in treating established bone loss using an ovariectomized (OVX) rat model of postmenopausal osteopenia. In a curative experiment, 3-month-old female Sprague Dawley rats were OVX, allowed to lose bone for 7 weeks, then treated for 6 weeks. Treatment groups consisted of C1 conjugate at low and high doses, vehicle-treated OVX and sham, prostaglandin E2 (PGE2 ), and mixture of unconjugated ALN-LK and EP4a to assess the effect of conjugation. Results showed that weekly administration of C1 conjugate dose-dependently increased bone volume in trabecular bone, which partially or completely reversed OVX-induced bone loss in the lumbar vertebra and improved vertebral mechanical strength. The conjugate also dose-dependently stimulated endocortical woven bone formation and intracortical resorption in cortical bone, with high-dose treatment increasing the mechanical strength but compromising the material properties. Conjugation between the EP4a and ALN-LK components was crucial to the drug's anabolic efficacy. To our knowledge, the C1 conjugate represents the first time that a combined therapy using an anabolic agent and the antiresorptive compound ALN has shown significant anabolic effects which reversed established osteopenia. PMID- 25284326 TI - Measurement of middle cerebral artery diameter as a method for assessment of brain sparing in intra-uterine growth-restricted discordant twins. AB - OBJECTIVES: Blood vessel resistance is assessed by flow velocity indexes. However, the actual resistance should be more strongly correlated with vessel diameter rather than variations in flow velocity. We aimed to determine the utility of middle cerebral artery (MCA) diameter measurement as a tool for evaluating brain sparing effect in intrauterine growth-restricted (IUGR) discordant twins. METHODS: Ten dichorionic-diamniotic twin pairs with weight discordance were included in the study. Fetal assessment included estimated fetal weight, umbilical artery flow, MCA flow and MCA diameter. Paired statistical analysis was used to compare MCA diameter and MCA pulsatility index (PI) between the discordant twins. RESULTS: MCA diameter was significantly larger in the smaller twin (mean diameter 3.55 +/- 0.26 vs 2.71 +/- 0.22, P = 0.018, mean ratio 1.39 +/- 0.14). There was no significant difference in MCA PI values within the twin pairs (mean PI 1.51 +/- 0.13 vs 1.57 +/- 0.07, P = 0.878, mean ratio 0.99 +/ 0.11). CONCLUSIONS: Measurement of MCA diameter can potentially be used as a tool for assessing vessel resistance. Further studies are needed to assess the feasibility and sensitivity of this method as well as the clinical significance of MCA dilatation in the presence of normal Doppler flow indexes. PMID- 25284323 TI - Early life seizures: evidence for chronic deficits linked to autism and intellectual disability across species and models. AB - Recent work in Exp Neurol by Lugo et al. (2014b) demonstrated chronic alterations in sociability, learning and memory following multiple early life seizures (ELS) in a mouse model. This work adds to the growing body of evidence supporting the detrimental nature of ELS on the developing brain to contribute to aspects of an autistic phenotype with intellectual disability. Review of the face validity of behavioral testing and the construct validity of the models used informs the predictive ability and thus the utility of these models to translate underlying molecular and cellular mechanisms into future human studies. PMID- 25284324 TI - Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease. AB - The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme beta-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials. PMID- 25284327 TI - The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation. AB - Multiple epigenetic factors play a critical role in cell proliferation and differentiation. However, their function in embryogenesis, especially in neural development, is currently unclear. The Trithorax group (TrxG) homolog KMT2A (MLL1) is an important epigenetic regulator during development and has an especially well-defined role in hematopoiesis. Translocation and aberrant expression of KMT2A is often observed in many tumors, indicating its proto oncogenic character. Here, we show that Kmt2a was essential for neural development in zebrafish embryos. Disrupting the expression of Kmt2a using morpholino antisense oligonucleotides and a dominant-negative variant resulted in neurogenic phenotypes, including downregulated proliferation of neural progenitors, premature differentiation of neurons, and impaired gliogenesis. This study therefore revealed a novel function of Kmt2a in cell proliferation and differentiation, providing further insight into the function of TrxG proteins in neural development and brain tumors. PMID- 25284328 TI - Carboxyl group (-CO2 H) functionalized coordination polymer nanoparticles as efficient platforms for drug delivery. AB - Functionalization of nanoparticles can significantly influence their properties and potential applications. Although researchers can now functionalize metal, metal oxide, and organic polymer nanoparticles with a high degree of precision, controlled surface functionalization of nanoscale coordination polymer particles (CPPs) has remained a significant challenge. The lack of methodology is perhaps one of the greatest roadblocks to the advancement of CPPs into high added-value drug delivery applications. Here, we report having achieved this goal through a stepwise formation and functionalization protocol. We fabricated robust nanoparticles with enhanced thermal and colloidal stabilities by incorporation of carboxyl groups and these surface carboxyl groups could be subsequently functionalized through well-known peptide coupling reactions. The set of chemistries that we employed as proof-of-concept enabled a plethora of new functional improvements for the application of CPPs as drug delivery carriers, including enhanced colloidal stabilities and the incorporation of additional functional groups such as polyethylene glycol (PEG) or fluorescent dyes that enabled tracking of their cellular uptake. Finally, we ascertained the cytotoxicity of the new CPP nanoparticles loaded with camptothecin to human breast adenocarcinoma (MCF-7). Efflux measurements show that the encapsulation of camptothecin enhances the potency of the drug 6.5-fold and increases the drug retention within the cell. PMID- 25284329 TI - Application of new guidelines for the primary prevention of atherosclerotic cardiovascular disease in a Korean population. AB - AIM: We investigated the proportion of people who would qualify for statin treatment with an atherosclerotic cardiovascular disease (ASCVD) 10-year risk of >=7.5% and who exhibit an LDL cholesterol (LDL-C) of 70 to 189 mg/dL according to the new ACC/AHA guidelines for the treatment of increased cardiovascular risk. METHODS: The study population (8,742 subjects) included individuals who underwent health examinations at Kangbuk Samsung Hospital in South Korea in 2010. We also evaluated the data obtained from the 2008-2010 Korea National Health and Nutrition Examination Survey (KNHANES) of 16,892 adults. RESULTS: Approximately 90% of men >=60 years of age and women >=70 years of age had an ASCVD 10-year risk of >=7.5% and LDL-C level of >=70 mg/dL. The proportions of subjects with a Framingham 10-year risk of >=10%, coronary artery calcium score of >20 and >100 and fatty liver each increased in association with an increasing ASCVD 10-year risk quartile in both sexes. Furthermore, age was significantly associated with the ASCVD 10-year risk in both sexes (all p-value <0.001). The KNHANES data also showed that over 85.0% of men >=60 years of age and 95.0% of women >=70 years of age had an ASCVD 10-year risk of >=7.5% and an LDL-C level of >=70 mg/dL. CONCLUSIONS: Adopting the new ASCVD prevention guidelines would result in the treatment of almost all Korean men and women (>=60 years and >=70 years of age, respectively) without evidence of cardiovascular disease. Therefore, Asian specific guidelines are needed to avoid unnecessary over treatment in an aging global population. PMID- 25284330 TI - An embedded automaton to monitor the glycolysis process in pancreatic beta-cells. AB - An embedded automaton is introduced to monitor the whole glycolysis process in pancreatic beta-cell and it is a hybridization of both non-deterministic finite automaton and push-down automaton. The set of irreversible and reversible reactions in the glycolysis process are related to non-deterministic finite automaton and push-down automaton respectively. The embedded automaton is used to observe the glucose metabolism with the states of acceptance and rejection. The acceptance state of the embedded automaton depicts the normal level of glycolysis and insulin secretion. The rejection state of this machine shows inhibition of glycolysis which obstructs the secretion of insulin. The subsequent low level of insulin leads to the high blood glucose level also known as hyperglycemia. In this study, the designed machine can be used to regulate the process of glycolysis through a group of regulatory glycolytic enzymes for the treatment of Diabetes mellitus at molecular level. PMID- 25284331 TI - Celiac disease and drug absorption: implications for cardiovascular therapeutics. PMID- 25284332 TI - Synthesis of indoles using visible light: photoredox catalysis for palladium catalyzed C-H activation. AB - A combined palladium- and photoredox-catalyzed C-H olefination enables the synthesis of indoles. By using visible light, the direct C-H activation of aromatic enamines can be achieved and a variety of indole derivatives can be obtained in good yields under mild reaction conditions. PMID- 25284333 TI - Suppression of LPS-induced transcription and cytokine secretion by the dietary isothiocyanate sulforaphane. AB - SCOPE: Diets rich in cruciferous vegetables are associated with lower levels of pro-inflammatory cytokines, which may contribute to potential health-promoting properties of these vegetables. We investigate whether sulforaphane (SF), an isothiocyanate (ITC) obtained from broccoli, could suppress LPS-induced transcription and subsequent pro-inflammatory cytokine secretion at a physiologically relevant concentration using in vitro models of chronic inflammation. METHODS AND RESULTS: We find that exposure of the LPS receptor Toll like receptor-4 (TLR4) to physiologically appropriate concentrations of SF under non-reducing conditions results in covalent modification of cysteine residues 246 and 609. We further demonstrate that the changes in expression of 1210 genes (p <= 0.01) in THP-1 monocytes and the secretion of pro-inflammatory cytokines in both human peripheral blood mononuclear cells (PBMCs) and THP-1 monocytes induced by LPS exposure can be completely suppressed through exposure with physiologically appropriate concentrations of SF. Finally, we show that in vivo exposure of human PBMCs to ITCs within human circulation reduces secretion of pro inflammatory cytokines following subsequent ex vivo LPS challenge (p < 0.001). CONCLUSION: Covalent modification of TLR4 by ITCs and resultant suppression of LPS-induced cell signalling could lead to reductions in levels of pro inflammatory cytokines in people with chronic diseases who consume diets rich in cruciferous vegetables. PMID- 25284334 TI - Childhood abuse in the etiological continuum underlying psychosis from first episode psychosis to psychotic experiences. AB - GOAL: The present study aimed to examine the prevalence of child abuse across the continuum of psychosis. PATIENTS AND METHODS: The sample consisted of 198 individuals divided in three groups: (1) 48 FEP patients, (2) 77 individuals scoring high in Community Assessment of Psychic Experiences (CAPE), classified as "High CAPE" group and (3) 73 individuals scoring low, classified as "Low CAPE" group. Childhood abuse was assessed using self-report instruments. Chi(2) tests and logistic regression models controlling by sex, age and cannabis were used to perform three comparisons: (i) FEP vs. Low CAPE; (ii) FEP vs. High CAPE and (iii) High CAPE vs. Low CAPE. RESULTS: The frequency of individuals exposed to childhood abuse for FEP, High CAPE and Low CAPE groups were 52.1%, 41.6% and 11%, respectively. FEP and High CAPE group presented significantly higher rates of childhood abuse compared to Low CAPE group, however, no significant differences were found between FEP and High CAPE groups regarding the frequency of childhood abuse. CONCLUSION: There is an increasing frequency of childhood abuse from low subclinical psychosis to FEP patients. However, childhood abuse is equally common in FEP and at risk individuals. PMID- 25284335 TI - Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia. AB - Clozapine treatment is associated with weight gain and cardio-metabolic consequences among patients with schizophrenia. Polymorphisms of leptin, serotonin receptor HTR2C and adiponectin genes have been associated with antipsychotic-induced weight gain and metabolic comorbidity. However, the results of the studies so far are inconclusive. The aim of the present study was first to test for a possible role of serum leptin and adiponectin levels as a marker of weight gain in association with inflammatory cytokines/adipokines (IL-6, IL-1Ra, hs-CRP and adipsin), and second to study associations between SNPs LEP rs7799039 (-2548 A/G), ADIPOQ rs1501299 and HTR2C rs1414334 and weight gain and levels of leptin and adiponectin, in 190 patients with schizophrenia on clozapine treatment, with retrospectively assessed weight change and cross-sectionally measured cytokine levels. A strong association was found between serum levels of leptin and weight gain and cytokines/adipokines related to metabolic comorbidity, especially among female patients (in women leptin vs. weight gain, IL-6 and IL 1Ra, P<0.001; in men leptin vs. weight gain, P=0.026, leptin vs. IL-1Ra, P<0.001). In male patients low adiponectin level was a more specific marker of clozapine-induced weight gain (P=0.037). The results of the present study do not support a major role of SNPs LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of weight gain or association of serum levels of leptin and adiponectin and corresponding studied SNPs in patients with schizophrenia on clozapine treatment. PMID- 25284336 TI - How do Australian maternity and early childhood health services identify and respond to the settlement experience and social context of refugee background families? AB - BACKGROUND: Refugees have poor mental, social and physical health related to experiences of trauma and stresses associated with settlement, however little is known about how refugee families experience maternity and early childhood services. The aim of this study was to explore the responsiveness of health services to the social and mental health of Afghan women and men at the time of having a baby. METHOD: Participatory methods including community engagement and consultation with the Afghan community and service providers in Melbourne, Australia. Bicultural researchers conducted interviews with Afghan women and men who had recently had a baby. Interviews and focus groups were also conducted with health professionals working in the region. RESULTS: Thirty interviews were conducted with Afghan women and men who had recently had a baby. Thirty-four health professionals participated in an interview or focus group.Afghan women and men reported significant social hardship during the period before and after having a baby in Australia, but were rarely asked about their social health by maternity and early childhood services.Most health professionals recognised that knowledge and understanding of their client's migration history and social circumstances was relevant to the provision of high quality care. However, inquiring about refugee background, and responding to non-clinical needs of refugee families was challenging for many health professionals. Factors that made it more difficult for health professionals to engage with Afghan families in pregnancy included limited understanding of the context of migration, dependency of many Afghan women on their husband for interpreting, short appointments, and the high likelihood of seeing different health professionals at each antenatal visit. Community-based maternal and child health nurses had more scope to work with interpreters, and build relationships with families, providing a stronger foundation for identifying and responding to complex social circumstances. CONCLUSION: There are significant challenges in providing comprehensive, high quality primary health care for Afghan families accessing Australian maternity and early childhood services. The limited capacity of public maternity services to identify families of refugee background and provide tailored service responses are contributing to inequitable maternal and child health outcomes for families of refugee background. PMID- 25284337 TI - Oral somatosensory awareness. AB - Oral somatosensory awareness refers to the somatic sensations arising within the mouth, and to the information these sensations provide about the state and structure of the mouth itself, and objects in the mouth. Because the oral tissues have a strong somatosensory innervation, they are the locus of some of our most intense and vivid bodily experiences. The salient pain of toothache, or the habit of running one's tongue over one's teeth when someone mentions "dentist", provide two very different indications of the power of oral somatosensory awareness in human experience and behaviour. This paper aims to review the origins and structure of oral somatosensory awareness, focussing on quantitative, mechanistic studies in humans. We first extend a model of levels of bodily awareness to the specific case of the mouth. We then briefly summarise the sensory innervation of oral tissues, and their projections in the brain. We next describe how these peripheral inputs give rise to perceptions of objects in the mouth, such as foods, liquids and oral devices, and also of the mouth tissues themselves. Finally, we consider the concept of a conscious mouth image, and the somatosensory basis of "mouth feel". The theoretical framework outlined in this paper is intended to facilitate scientific studies of this important site of human experience. PMID- 25284338 TI - Water confined in the local field of ions. AB - Interionic distances are shorter in concentrated ionic solutions, thus instigating the interaction and overlap of hydration shells, as ions become separated by only one or two layers of water molecules. The simultaneous interaction of water with two oppositely charged ions has, so far, only been investigated by computer simulation studies, because the isolated vibrational spectroscopic signature of these molecules remains undetected. Our combined near infrared spectroscopic and molecular dynamics simulation studies of alkali halide solutions present a distinct spectral feature, which is highly responsive to depletion of bulk water and merging of hydration shells. The analysis of this spectral feature demonstrates that absorption trends are in good agreement with the law of matching affinities, thus providing the first successful vibrational spectroscopic treatment of this topic. Combined with commonly observed near infrared bands, this feature provides a spectral pattern that describes some relevant aspects of ionic hydration. PMID- 25284339 TI - A neural mass model of place cell activity: theta phase precession, replay and imagination of never experienced paths. AB - Recent results on hippocampal place cells show that the replay of behavioral sequences does not simply reflect previously experienced trajectories, but may also occur in the reverse direction, or may even include never experienced paths. In order to elucidate the possible mechanisms at the basis of this phenomenon, we have developed a model of sequence learning. The present model consists of two layers of place cell units. Long-range connections among units implement heteroassociation between the two layers, trained with a temporal Hebb rule. The network was trained assuming that a virtual rat moves within a virtual maze. This training leads to the formation of bidirectional synapses between the two layers, i.e. synapses connecting a neuron both with its previous and subsequent element in the path. Subsequently, two distinct conditions were simulated with the trained network. During an exploratory phase, characterized by a similar consideration to the external environment and to the internal representation, the model simulates the occurrence of theta precession in the forward path and the temporal compression. During an imagination phase, when there is no consideration to the external location, the model produces trains of gamma oscillations, without the presence of a theta rhythm, and simulates the occurrence of both direct and reverse replay, and the imagination of never experienced paths. The new paths are built by combining bunches of previous trajectories. The main mechanisms at the basis of this behavior are explained in detail, and lines for future improvements (e.g., to simulate preplay) are discussed. PMID- 25284340 TI - Encoding whisker deflection velocity within the rodent barrel cortex using phase delayed inhibition. AB - The primary sensory feature represented within the rodent barrel cortex is the velocity with which a whisker has been deflected. Whisker deflection velocity is encoded within the thalamus via population synchrony (higher deflection velocities entail greater synchrony among the corresponding thalamic population). Thalamic (TC) cells project to regular spiking (RS) cells within the barrel cortex, as well as to inhibitory cortical fast-spiking (FS) neurons, which in turn project to RS cells. Thus, TC spikes result in EPSPs followed, with a small time lag, by IPSPs within an RS cell, and hence the RS cell decodes TC population synchrony by employing a phase-delayed inhibition synchrony detection scheme. As whisker deflection velocity is increased, the probability that an RS cell spikes rises, while jitter in the timing of RS cell spikes remains constant. Furthermore, repeated whisker deflections with fixed velocity lead to system adaptation--TC ->RS, TC ->FS, and FS ->RS synapses all weaken substantially, leading to a smaller probability of spiking of the RS cell and increased jitter in the timing of RS cell spikes. Interestingly, RS cell activity is better able to distinguish among different whisker deflection velocities after adaptation. In this work, we construct a biophysical model of a basic 'building block' of barrel cortex - the feedforward circuit consisting of TC cells, FS cells, and a single RS cell - and we examine the ability of the purely feedforward circuit to explain the experimental data on RS cell spiking probability, jitter, adaptation, and deflection velocity discrimination. Moreover, we study the contribution of the phase-delayed inhibition network structure to the ability of an RS cell to decode whisker deflection velocity encoded via TC population synchrony. PMID- 25284341 TI - Anabolic steroids for rehabilitation after hip fracture in older people. AB - BACKGROUND: Hip fracture occurs predominantly in older people, many of whom are frail and undernourished. After hip fracture surgery and rehabilitation, most patients experience a decline in mobility and function. Anabolic steroids, the synthetic derivatives of the male hormone testosterone, have been used in combination with exercise to improve muscle mass and strength in athletes. They may have similar effects in older people who are recovering from hip fracture. OBJECTIVES: To examine the effects (primarily in terms of functional outcome and adverse events) of anabolic steroids after surgical treatment of hip fracture in older people. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (10 September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013 Issue 8), MEDLINE (1946 to August Week 4 2013), EMBASE (1974 to 2013 Week 36), trial registers, conference proceedings, and reference lists of relevant articles. The search was run in September 2013. SELECTION CRITERIA: Randomised controlled trials of anabolic steroids given after hip fracture surgery, in inpatient or outpatient settings, to improve physical functioning in older patients with hip fracture. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials (based on predefined inclusion criteria), extracted data and assessed each study's risk of bias. A third review author moderated disagreements. Only very limited pooling of data was possible. The primary outcomes were function (for example, independence in mobility and activities of daily living) and adverse events, including mortality. MAIN RESULTS: We screened 1290 records and found only three trials involving 154 female participants, all of whom were aged above 65 years and had had hip fracture surgery. All studies had methodological shortcomings that placed them at high or unclear risk of bias. Because of this high risk of bias, imprecise results and likelihood of publication bias, we judged the quality of the evidence for all primary outcomes to be very low.These trials tested two comparisons. One trial had three groups and contributed data to both comparisons. None of the trials reported on patient acceptability of the intervention.Two very different trials compared anabolic steroid versus control (no anabolic steroid or placebo). One trial compared anabolic steroid injections (given weekly until discharge from hospital or four weeks, whichever came first) versus placebo injections in 29 "frail elderly females". This found very low quality evidence of little difference between the two groups in the numbers discharged to a higher level of care or dead (one person in the control group died) (8/15 versus 10/14; risk ratio (RR) 0.75, 95% confidence interval (CI) 0.42 to 1.33; P = 0.32), time to independent mobilisation or individual adverse events. The second trial compared anabolic steroid injections (every three weeks for six months) and daily protein supplementation versus daily protein supplementation alone in 40 "lean elderly women" who were followed up for one year after surgery. This trial provided very low quality evidence that anabolic steroid may result in less dependency, assessed in terms of being either dependent in at least two functions or dead (one person in the control group died) at six and 12 months, but the result was also compatible with no difference or an increase in dependency (dependent in at least two levels of function or dead at 12 months: 1/17 versus 5/19; RR 0.22, 95% CI 0.03 to 1.73; P = 0.15). The trial found no evidence of between-group differences in individual adverse events.Two trials compared anabolic steroids combined with another nutritional intervention ('steroid plus') versus control (no 'steroid plus'). One trial compared anabolic steroid injections every three weeks for 12 months in combination with daily supplement of vitamin D and calcium versus calcium only in 63 women who were living independently at home. The other trial compared anabolic steroid injections every three weeks for six months and daily protein supplementation versus control in 40 "lean elderly women". Both trials found some evidence of better function in the steroid plus group. One trial reported greater independence, higher Harris hip scores and gait speeds in the steroid plus group at 12 months. The second trial found fewer participants in the anabolic steroid group were either dependent in at least two functions, including bathing, or dead at six and 12 months (one person in the control group died) (1/17 versus 7/18; RR 0.15, 95% CI 0.02 to 1.10; P = 0.06). Pooled mortality data (2/51 versus 3/51) from the two trials showed no evidence of a difference between the two groups at one year. Similarly, there was no evidence of between-group differences in individual adverse events. Three participants in the steroid group of one trial reported side effects of hoarseness and increased facial hair. The other trial reported better quality of life in the steroid plus group. AUTHORS' CONCLUSIONS: The available evidence is insufficient to draw conclusions on the effects, primarily in terms of functional outcome and adverse events, of anabolic steroids, either separately or in combination with nutritional supplements, after surgical treatment of hip fracture in older people. Given that the available data points to the potential for more promising outcomes with a combined anabolic steroid and nutritional supplement intervention, we suggest that future research should focus on evaluating this combination. PMID- 25284342 TI - Arctigenin but not arctiin acts as the major effective constituent of Arctium lappa L. fruit for attenuating colonic inflammatory response induced by dextran sulfate sodium in mice. AB - The crude powder of the fruit of Arctium lappa L. (ALF) has previously been reported to attenuate experimental colitis in mice. But, its main effective ingredient and underlying mechanisms remain to be identified. In this study, ALF was extracted with ethanol, and then successively fractionated into petroleum ether, ethyl acetate, n-butanol and water fraction. Experimental colitis was induced by dextran sulfate sodium (DSS) in mice. Among the four fractions of ALF, the ethyl acetate fraction showed the most significant inhibition of DSS-induced colitis in mice. The comparative studies of arctigenin and arctiin (the two main ingredients of ethyl acetate fraction) indicated that arctigenin rather than arctiin could reduce the loss of body weight, disease activity index and histological damage in the colon. Arctigenin markedly recovered the loss of intestinal epithelial cells (E-cadherin-positive cells) and decreased the infiltration of neutrophils (MPO-positive cells) and macrophages (CD68-positive cells). Arctigenin could down-regulate the expressions of TNF-alpha, IL-6, MIP-2, MCP-1, MAdCAM-1, ICAM-1 and VCAM-1 at both protein and mRNA levels in colonic tissues. Also, it markedly decreased the MDA level, but increased SOD activity and the GSH level. Of note, the efficacy of arctigenin was comparable or even superior to that of the positive control mesalazine. Moreover, it significantly suppressed the phosphorylation of MAPKs and the activation of NF-kappaB, including phosphorylation of IkappaBalpha and p65, p65 translocation and DNA binding activity. In conclusion, arctigenin but not arctiin is the main active ingredient of ALF for attenuating colitis via down-regulating the activation of MAPK and NF-kappaB pathways. PMID- 25284344 TI - Zeolites with continuously tuneable porosity. AB - Zeolites are important materials whose utility in industry depends on the nature of their porous structure. Control over microporosity is therefore a vitally important target. Unfortunately, traditional methods for controlling porosity, in particular the use of organic structure-directing agents, are relatively coarse and provide almost no opportunity to tune the porosity as required. Here we show how zeolites with a continuously tuneable surface area and micropore volume over a wide range can be prepared. This means that a particular surface area or micropore volume can be precisely tuned. The range of porosity we can target covers the whole range of useful zeolite porosity: from small pores consisting of 8-rings all the way to extra-large pores consisting of 14-rings. PMID- 25284345 TI - Lipoic acid and lipoic acid analogs in cancer metabolism and chemotherapy. AB - The lipoic acid (lipoate) coenzyme is unique in all of mammalian metabolism. It is not only crucial to the function of some of the major enzymes feeding carbon into the tricarboxylic acid cycle, but also generates dynamic regulatory information about the metabolic status of the mitochondrial matrix, ultimately functioning to control these metabolic fluxes. Moreover, these lipoate-sensitive regulatory processes are apparently systematically redesigned in tumor cells and the affected enzymes commonly become especially central to cancer metabolism. Thus, lipoate-sensitive regulatory processes constitute potentially uniquely valuable targets for chemotherapeutic attack. Our goal here is to review the current status of our knowledge relevant to the use of lipoate and lipoate analogs to therapeutically attack malignant disease. PMID- 25284343 TI - Combination therapy with dendritic cell vaccine and IL-2 encapsulating polymeric micelles enhances intra-tumoral accumulation of antigen-specific CTLs. AB - Dendritic cell (DC) vaccine is a promising immunotherapy for cancer due to its ability to induce antigen-specific CTLs efficiently. However, a number of clinical studies have implied insufficient therapeutic benefits with the use of MHC class 1 restricted peptide-pulsed DC vaccine. To enhance the clinical efficacy, we examined combination therapy of DC vaccine pulsed with OVA peptide and intravenous low dose unmodified IL-2 (IL-2 solution) administration against EG7 tumor-bearing mice. Unexpectedly, no additional effects of IL-2 solution were observed on CTL induction and the therapeutic effects of DC vaccine, possibly because of the short half-life of IL-2 in plasma. Therefore, we generated IL-2 encapsulating polymeric micelles (IL-2 micelle), which showed prolonged IL-2 retention in the circulation after intravenous administration compared with IL-2 solution. When mice were treated with OVA peptide-pulsed DCs in combination with IL-2 micelle, OVA-specific CTLs were efficiently induced in the spleen in comparison with DC vaccine combined with IL-2 solution or DC vaccine alone. In addition, combination therapy of DC vaccine and IL-2 micelle against EG7 tumor bearing mice induced the efficient accumulation of antigen-specific CTLs into the tumor and marked anti-tumor effects. Thus, the administration of IL-2 micelle can significantly enhance DC vaccine efficacy against tumors. PMID- 25284346 TI - Radiation exposure to comforters and carers during paediatric molecular radiotherapy. AB - BACKGROUND: To show whether the incidental radiation exposure received by comforters and carers of children undergoing molecular radiotherapy was kept as low as reasonably achievable and was within English national dose constraints. PROCEDURE: The radiation exposure of adult comforters and carers was routinely monitored with a whole body personal dose meter while the child was in hospital. Data were collected on iodine-131 meta-iodobenzylguanidine (131 I-mIBG), lutetium 177 DOTATATE (177 Lu-DOTATATE), and iodine-131 sodium iodide (131 I-NaI) treatments. RESULTS: Data were available for 50 treatments with high-administered activity double-infusion 131 I-mIBG and 12 single administrations; 15 177 Lu DOTATATE treatments and 28 131 I-NaI administrations. The median age was 7 years (1-18). The median administered activity of: 131 I-mIBG was 16.2 GBq (6.8-59 GBq) for double infusion patients and 8.1 GBq (5.26-16.25 GBq) for single administrations; 177 Lu-DOTATATE was 7.2 GBq (2.5-7.5 GBq); and 131 I-NaI was 3 GBq for thyroid remnant ablation and 5.5 GBq for cancer therapy. The median number of comforters and carers for all administrations was 2 (range 1-9). The median exposure values for comforters and carers for high-administered activity 131 I-mIBG administrations was 302 uSv (0-5282 uSv); for single fraction 131 I mIBG 163 uSv (3-3104 uSv); 177 Lu-DOTATATE 6 uSv (1-79 uSv); and 131 I-NaI 37 uSv (0-274 uSv). Only one of the comforters and carers exceeded the dose constraint of 5 mSv. CONCLUSIONS: Doses to comforters and carers were in all but one case within the dose constraint nationally recommended by the Health Protection Agency, now part of Public Health England. New evidence is presented which show that comforter and carer radiation exposure levels from paediatric molecular radiotherapy in routine clinical practice are acceptably low. Pediatr Blood Cancer 2015;62:235-239. (c) 2014 Wiley Periodicals, Inc. PMID- 25284347 TI - Classification and characterization of a laboratory chicken rotavirus strain carrying G7P[35] neutralization antigens on the genotype 4 backbone gene configuration. AB - The laboratory rotavirus strain, BRS/115, has been used for more than two decades to monitor rotaviruses in specific pathogen free flocks of laying hens. However, the virus strain has not been characterized in detail. Therefore we aimed at the description of molecular features of BRS115 by using random primed reverse transcription-PCR of the genomic RNA followed by massive parallel sequencing using the semiconductor sequencing technology. Over 64,000 trimmed reads mapped to reference sequences obtained from GenBank. The strain classified into the species Rotavirus A and genotyped G7-P[35]-I4-R4-C4-M4-A16-N4-T4-E11-H4 according to guidelines of the Rotavirus Classification Working Group. Phylogenetic analysis identified shared features with chicken, turkey and pigeon origin rotaviruses. This study demonstrates the robustness of next generation sequencing in the characterization of reference virus materials used in specialized laboratories. PMID- 25284348 TI - Spectrum of Newcastle disease virus stability in gradients of temperature and pH. AB - Newcastle disease (ND) is one of the highly pathogenic viral diseases of avian species. The disease is endemic in many developing countries where agriculture serves as the primary source of national income. Newcastle disease virus (NDV) belongs to the family Paramyxoviridae and is well characterized member among the avian paramyxovirus serotypes. The failure of vaccination is one of the major causes of NDV outbreaks in field condition. The present study gives a brief picture about the biology of NDV genome and its proteins under different conditions of temperature and pH. Our results indicate that the NDV is non infective above 42 degrees C and unstable above 72 degrees C. The study will be useful in defining an optimum storage condition for NDV without causing any deterioration in its viability. PMID- 25284349 TI - The effect of programed physical activity measured with levels of body balance maintenance. AB - Background The aim of the research was an evaluation of 2 training programs covering the same standard physical activity in the initial stage (warm-up) and the main (motor exercises) as well as a separate end part in Program A of stretching and in Programme B of vibration training designed to improve the level of body balance. Material and Methods We tested 40 randomly chosen students of the Academy of Physical Education and Sport in Gdansk, subsequently divided into two 20-person groups: C (average age 21.3+/-1.2), and E (average age 21.8+/-1.1). The training of body balance was conducted for 8 weeks: we used in Group C Program A and in group E Program B. The evaluation of body balance was done 3 times: at the beginning, at midway point, and at the end of the experiment. The stabilographic tests with posture-graphical method and the task of 1-leg balance standing with eyes closed was used. Results It was found that in the first examination both groups did not significantly differ in terms of the tested parameters of balance. During the training process we obtained increased time of maintaining balance on 1 leg. This difference was significant between tests 1 and 2 both for Group C (p=0.0002) and for E (p=0.0034), while between the tests 2 and 3 in Group E (p=0.0213) only. Conclusions The training Program B is more effective to maintain balance on 1 leg when compared to Program A. PMID- 25284350 TI - Epidermolysis bullosa pruriginosa: two novel mutations (A2054V and G2233R) in the COL7A1 gene. PMID- 25284351 TI - Sodium Butyrate Prevents Memory Impairment by Re-establishing BDNF and GDNF Expression in Experimental Pneumococcal Meningitis. AB - Pneumococcal meningitis is a serious infection of the central nervous system (CNS) with high fatality rates that causes reduced psychomotor performance, slight mental slowness, impairments in attention executive functions and learning and memory deficiencies. Previously, we demonstrated a correlation between memory impairment and decreased levels of brain-derived neurotropic factor (BDNF) in the hippocampi of rats subjected to pneumococcal meningitis. Emerging evidence demonstrates that histone acetylation regulates neurotrophins; therefore, a potential molecular intervention against cognitive impairment in bacterial meningitis may be the histone deacetylase (HDAC) inhibitor, sodium butyrate, which stimulates the acetylation of histones and increases BDNF expression. In this study, animals received either artificial cerebrospinal fluid as a placebo or a Streptococcus pneumoniae suspension at a concentration of 5 * 10(9) colony forming units (CFU/mL). The animals received antibiotic treatment as usual and received saline or sodium butyrate as an adjuvant treatment. Ten days after, meningitis was induced; the animals were subjected to open-field habituation and the step-down inhibitory avoidance task. Immediately after these behavioural tasks, the animals were killed, and their hippocampi were removed to evaluate the expression of BDNF, nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF). In the meningitis group that received saline, the animals presented memory impairment in both behavioural tasks, and hippocampal BDNF and GDNF expression was decreased. Sodium butyrate was able to prevent memory impairment and re-establish hippocampal neurotrophin expression in experimental pneumococcal meningitis. PMID- 25284352 TI - Cardiophrenic lymph nodes in liver transplant candidates with hepatocellular carcinoma: imaging characteristics and post-transplant outcomes. AB - BACKGROUND: No guidelines exist for the management of cardiophrenic lymph nodes in patients with hepatocellular carcinoma (HCC) being evaluated for liver transplantation. METHODS: One hundred and seventy-eight patients with HCC listed for liver transplant received both pre-transplant computed tomography (CT) and follow-up CT scans. Enlarged cardiophrenic lymph nodes on CT were characterized and followed on subsequent scans; lymph node outcomes were assigned to "reduced" and "not reduced" categories. Tumor and patient characteristics were also recorded. RESULTS: Seventy-one of one hundred and seventy-eight patients (39.9%) had at least one cardiophrenic lymph node larger than 8 mm in diameter on pre transplant CT. One hundred and sixty-six total lymph nodes were characterized. Six lymph nodes (3.6%) in two patients increased in size on follow-up imaging; all six cardiophrenic lymph nodes were presumed to represent metastases. There was a statistically significant reduction in lymph node size in patients who were transplanted vs. those who were not transplanted. Furthermore, a statistically significant association was found between increasing Model for End-Stage Liver Disease score and lymph node size reduction. There were no significant differences in post-transplant survival between patients with different lymph node outcomes. CONCLUSION: In the absence of metastatic disease in other sites, these lymph nodes are probably reactive; further workup is likely not necessary. PMID- 25284353 TI - [Reduction of 137caesium contamination in wild boars by supplementing offered food with ammonium-iron-hexa-cyanoferrate]. AB - OBJECTIVE: This replication study investigated whether the 137caesium (137Cs) contamination of wild boars could be relevantly reduced under field conditions by adding ammonium-iron-hexa-cyanoferrate (AFCF; Prussian blue) to the food. MATERIAL AND METHODS: In 285 wild boars that had been shot in six Bavarian hunting territories during the season (November until May) between 01 November 2010 and 10 December 2011 137Cs contamination was analysed. Thirty-five animals originated from two hunting territories in which offered food had been supplemented with 1250 mg AFCF per kilogram food. RESULTS: The control animals showed a mean 137Cs contamination of 522 Bq/kg lean skeletal muscle meat. Direct (univariable) comparisons of the two experimental territories with the four control territories yielded a mean reduction in 137Cs contamination due to Prussian bluefeeding by -211 Bq/kg (p < 0.001). Multivariable models that took potential confounders into account (age, weight, sex, hunting date, territory) estimated the effect to be -344 Bq/kg (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: This replication study confirmed the finding of Kienzle et al. (12) who described a statistically significant reduction in 137Cs contamination by 380 Bq/kg due to the feeding of Prussian blue in other territories. PMID- 25284354 TI - Association between frailty and carotid central structure changes: the Three-City Study. AB - OBJECTIVES: To demonstrate the association between carotid central structure changes and frailty. DESIGN: Cross-sectional study. SETTING: The Three-City Study, a French prospective cohort designed to evaluate the risk of cognitive decline attributable to vascular risk factors. PARTICIPANTS: Community-dwelling individuals aged 65 to 95 (N = 4,257). MEASUREMENTS: Frailty was defined as proposed by Fried and colleagues. Carotid intima-media thickness (IMT), diameter of the common carotid arteries, and the presence of plaques in both carotid arteries were determined using carotid Doppler ultrasonography. Multinomial logistic regression models, including adjustment for traditional cardiovascular and dementia risk factors, were used to evaluate the independent association between the central arterial structure and frailty. RESULTS: 6.8% of participants were classified as frail. Multivariate regression models showed an independent association between carotid IMT and frailty and between carotid diameter and frailty after adjusting for sociodemographic factors, cardiovascular risk factors, disability, and apolipoprotein E epsilon4 genotype. A 1-standard deviation (SD) increase in IMT (odds ratio (OR) = 1.15; P = .04) and a 1-SD increase in carotid diameter (OR = 1.23; P = .006) were associated with greater probability of being frail. CONCLUSION: The association between carotid structure changes and frailty suggests that frail elderly adults have vascular damage, which may explain, at least partly, why several adverse health-related outcomes are frequently observed in frail elderly adults. PMID- 25284355 TI - Chemical preparation of graphene materials results in extensive unintentional doping with heteroatoms and metals. AB - Chemical synthesis of graphene relies on the usage of various chemical reagents. The initial synthesis step, in which graphite is oxidized to graphite oxide, is achieved by a combination of chemical oxidants and acids. A subsequent chemical reduction step eliminates/reduces most oxygen functionalities to yield graphene. We demonstrate here that these chemical treatments significantly contaminate graphene with heteroatoms/metals, depending on the procedures followed. Contaminations with heteroatoms (N, B, Cl, S) or metals (Mn, Al) were present at relatively high concentrations (up to 3 at%), with their chemical states dependent on the procedures. Such unintentional contaminations (unwanted doping) during chemical synthesis are rarely anticipated and reported, although the heteroatoms/metals may alter the electronic and catalytic properties of graphene. In fact, the levels of unintentionally introduced contaminants on graphene are often higher than typical levels found on intentionally doped graphene. Our findings are important for scientists applying chemical methods to prepare graphene. PMID- 25284356 TI - Delayed-type hypersensitivity reaction against Nexplanon(r). AB - Nexplanon(r) is an etonogestrel implant with a long-acting contraceptive effect. Although several studies underlined its safety profile, its implant can rarely lead to moderate or severe adverse event. Here, we presented a case of delayed type hypersensitivity reaction against Nexplanon(r) that resolved after its removal. PMID- 25284357 TI - Molecular evolution and functional divergence of X-intrinsic protein genes in plants. AB - X-intrinsic proteins (XIPs) are a novel class of major intrinsic proteins found in diverse organisms. Recently, XIP genes have been reported to be involved in the transport of a wide range of hydrophobic solutes; however, the evolutionary forces driving their structural and functional divergence in plants are poorly understood. In the present study, comprehensive bioinformatics analyses were performed to gain insight into the molecular and evolutionary mechanisms driving this structural and functional diversification. Phylogenetic analyses have revealed the major lineage-specific expansions of XIP genes in plants. Within the eudicots, XIP genes have diverged into Asterid and Rosid-specific phylogenetic lineages and have also undergone several independent duplications during the course of evolution. Investigation of functional divergence at the protein level showed evidence for shifting evolutionary rate and/or altered constraints on the physiochemical properties of specific amino acid sites following gene duplication. Selection pressure analyses suggest that purifying selection is the predominant evolutionary force acting on the XIP gene subfamily, along with episodic positive selection. However, only a few amino acid sites were found to be subjected to such episodic positive selection. Furthermore, protein functional divergence analysis has identified critical amino acid residues, which must be validated by future experimental studies, that could provide new insights into the role of XIPs in transport of a wide range solutes of physiological importance. PMID- 25284358 TI - Earlier depression and later-life self-reported chewing difficulties: results from the Whitehall II study. AB - This study aimed to assess, whether depression in adulthood was associated with self-reported chewing difficulties at older age, and examine whether the strength of the association differed according to the number of depression episodes in earlier adult life. We used Whitehall II study data from 277 participants who completed a questionnaire in 2011. Depression was measured with the Center for Epidemiologic Studies Depression Scale (CES-D) in 2003 and 2008. The association between CES-D depression and self-reported chewing ability was assessed using regression models adjusted for some socio-demographic factors. Participants with depression at some point in their earlier adulthood had an odds ratio (95% CI) of 2.01 (1.06, 3.82) for reporting chewing difficulties in older adulthood, compared to those without depression. The respective odds ratios were 1.42 (0.66, 3.04) for individuals with depression in only one phase, but 3.53 (1.51, 8.24) for those with depression in two phases. In conclusion, while further research is required, there was an association between depression and chewing difficulty that was independent of demographic and socio-economic characteristics. Furthermore, this increased odds for chewing difficulties was primarily among adults that experienced two episodes or a prolonged period of depression. PMID- 25284360 TI - 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) as a novel and effective solvent to facilely prepare cyclodextrin-assembled materials. AB - We found that cyclodextrins (CDs) have a high solubility in 1,1,1,3,3,3 hexafluoro-2-propanol (HFIP). Evaporating HFIP from CD solutions on a glass plate gave crystalline solids composed of channel-type CD assemblies, and electrospinning with an HFIP solution of CDs fabricated CD microfibers. PMID- 25284359 TI - Expression of epithelial markers by human umbilical cord stem cells. A topographical analysis. AB - INTRODUCTION: Human umbilical cord stem cells have inherent differentiation capabilities and potential usefulness in regenerative medicine. However, the epithelial differentiation capability and the heterogeneity of these cells have not been fully explored to the date. METHODS: We analyzed the expression of several undifferentiation and epithelial markers in cells located in situ in different zones of the umbilical cord -in situ analysis- and in primary ex vivo cell cultures of Wharton's jelly stem cells by microarray and immunofluorescence. RESULTS: Our results demonstrated that umbilical cord cells were heterogeneous and had intrinsic capability to express in situ stem cell markers, CD90 and CD105 and the epithelial markers cytokeratins 3, 4, 7, 8, 12, 13, 19, desmoplakin and zonula occludens 1 as determined by microarray and immunofluorescence, and most of these markers remained expressed after transferring the cells from the in situ to the ex vivo cell culture conditions. However, important differences were detected among some cell types in the umbilical cord, with subvascular zone cells showing less expression of stem cell markers and cells in Wharton's jelly and the amnioblastic zones showing the highest expression of stem cells and epithelial markers. CONCLUSIONS: These results suggest that umbilical cord mesenchymal cells have intrinsic potential to express relevant epithelial markers, and support the idea that they could be used as alternative cell sources for epithelial tissue engineering. PMID- 25284361 TI - Does it always feel good to get what you want? Young children differentiate between material and wicked desires. AB - One line of research on children's attributions of guilt suggests that 3-year olds attribute negative emotion to self-serving victimizers, slightly older children attribute happiness, and with increasing age, attributions become negative again (i.e., a three-step model; Yuill et al., 1996, Br. J. Dev. Psychol., 14, 457). Another line of research provides reason to expect that 3 year-olds may be predisposed to view self-serving moral transgression as leading to positive emotion; this is a linear developmental model in which emotion attributions to transgressors become increasingly negative over the course of childhood (e.g., Nunner-Winkler & Sodian, 1988, Child Dev., 59, 1323). However, key differences in methodology make it difficult to compare across these findings. The present study was designed to address this problem. We asked how 3- to 9-year-old children (n = 111) reason about transgression scenarios that involve satisfying wicked desires (wanting to cause harm and doing so successfully) versus material desires (wanting an object and getting it successfully via harmful behaviour). Three-year-old children reasoned differently about desire and emotion across these two types of transgressions, attributing negative emotion in the case of wicked desires and positive emotion in the case of material desires. This pattern of emotion attribution by young children provides new information about how young children process information about desires and emotions in the moral domain, and it bridges a gap in the existing literature on this topic. PMID- 25284362 TI - Secular trends in physical fitness of Mozambican school-aged children and adolescents. AB - OBJECTIVE: This study presents information about secular trends in physical fitness (PF) levels among Mozambican youth. METHODS: The sample comprises 3,851 subjects (1,791 boys; 2,060 girls) aged 8-15 years who were evaluated at three time points (1992, 1999, 2012). PF tests included handgrip strength, 10 m * 5 m shuttle-run, sit-and-reach, and 1-mile run/walk. Biological maturity was assessed by sexual characteristics, and percentage body fat was predicted using triceps and subscapular skinfolds. ANCOVA (controlling for age, maturity status, and percentage body fat) was used to compare mean differences in PF tests among the three time points, by sex. RESULTS: Children in 1992 were more flexible than those from 2012; boys handgrip strength increased from 1992 to 2012, while girls decreased their handgrip strength; youth in 1992 were faster and more agile than their 2012 peers; and a decrease was observed in cardiorespiratory fitness between 1992 and 1999 and between 1992 and 2012 for both sexes. CONCLUSIONS: A negative secular trend among Mozambican children's PF was observed over the last two decades, suggesting that socio-political, educational, and economical changes occurring during this period had a relevant effect on their PF. This negative trend suggests that development of intervention programs/strategies to improve PF among youth is warranted. PMID- 25284363 TI - Elevation of biomarkers and long-term outcome after percutaneous coronary intervention. AB - BACKGROUND/OBJECTIVES: The impact of an elevation of cardiac biomarkers occurring after percutaneous coronary intervention (PCI) on long-term outcome remains controversial. Most available data are based on observational registries using multivariable analysis. In this study, a case-control approach was used to assess separately the impact of post-PCI elevation of CK-MB on the short-term in hospital outcome and on the long-term outcome after hospital discharge. METHODS: Between 1 January 1996 and 31 December 2008, a postprocedural rise of CK-MB was observed in 363 among 8346 consecutive PCI procedures (4.3%). The overall in hospital mortality for patients with or without CK-MB elevation after PCI was 8.5% and 1.5%, respectively (P < 0.001). For 245 hospital survivors with CK-MB elevation, we found 245 control cases matched for 9 relevant clinical parameters in our PCI database during the same period. The long-term survival of these patients was assessed by KM estimates. RESULTS: Despite an increased in-hospital mortality among patients with periprocedural elevation of CK-MB, the long-term outcome of patients who are discharged alive is independent of CK-MB release, curves of overall survival and of survival free of recurrence of myocardial infarction being similar up to 10 years after hospital discharge. CONCLUSIONS: In our population, the elevation of CK-MB after PCI identified a high-risk subgroup for in-hospital mortality but had no impact on the long-term prognosis, once the patient is discharged alive from the hospital. PMID- 25284364 TI - Characterization of the second HFE gross deletion highlights the potential importance of Alu-mediated recombination in haemochromatosis. PMID- 25284365 TI - Pyridine-NHC: effective ligand in Pd-catalyzed cyclopropanation of esters with substituted allyl carbonates. AB - By consideration of the mechanism of Pd-catalyzed cyclopropanation and allylation, NHC-pyridine compounds were adopted as the ligand in Pd-catalyzed cyclopropanation of esters and monosubstituted allylic reagents. The corresponding cyclopropanes were afforded as major products in moderate to good yields with high cyclopropane/allylation selectivity. PMID- 25284366 TI - INPP4B is highly expressed in prostate intermediate cells and its loss of expression in prostate carcinoma predicts for recurrence and poor long term survival. AB - BACKGROUND: Phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in prostate carcinoma due to the loss of tumor suppressor PTEN, which leads to increased Akt activity. Expression of INPP4B, another negative regulator of the PI3K/Akt pathway, is also reduced in prostate carcinoma. However, uncertainty exists regarding the association of INPP4B expression and biochemical and clinical relapse of prostate carcinoma. METHODS: INPP4B expression in benign prostate acini was analyzed by co-immunofluorescence with cytokeratins (CK) 5, 8, 19, androgen receptor (AR), c-MET, chromogranin A and Ki67. INPP4B expression in prostate carcinoma was analyzed in two independent cohorts (n = 406). The association of INPP4B with biochemical and clinical prostate carcinoma relapse was assessed by Kaplan-Meier and Cox proportional hazards modeling. RESULTS: INPP4B was expressed in luminal epithelium within benign ducts, and was highly expressed in CK5+/CK8+/CK19+/AR-/c-MET+/Ki67- intermediate cells in proliferative inflammatory atrophic acini. Overall, INPP4B expression was reduced in prostate carcinoma compared to benign epithelium. Absent/low INPP4B expression was associated with reduced biochemical relapse-free survival (P = 0.01) and increased risk of clinical relapse (P = 0.01). Absence of INPP4B expression was an independent predictor of clinical relapse free survival (P = 0.004) when modeled with Gleason score (P = 0.027) and pathologic stage (P = 0.07). CONCLUSIONS: INPP4B is highly expressed in intermediate cells within proliferative inflammatory atrophic ducts, and expression is reduced in prostate carcinoma. Absence of INPP4B expression is associated with poor outcome following radical prostatectomy, and represents an independent prognostic marker of prostate carcinoma clinical recurrence. PMID- 25284367 TI - [Weight loss and fever in a 83-year-old man]. PMID- 25284368 TI - NMR structure of the water soluble Abeta17-34 peptide. AB - Alzheimer's disease is the most common neurodegenerative disorder in the world. Its most significant symptoms are memory loss and decrease in cognition. Alzheimer's disease is characterized by aggregation of two proteins in the brain namely Abeta (amyloid beta) and tau. Recent evidence suggests that the interaction of soluble Abeta with nAChR (nicotinic acetylcholine receptors) contributes to disease progression. In this study, we determine the NMR structure of an Abeta17-34 peptide solubilized by the addition of two glutamic acids at each terminus. Our results indicate that the Abeta peptide adopts an alpha helical structure for residues 19-26 and 28-33. The alpha-helical structure is broken around residues S26, N27 and K28, which form a kink in the helical conformation. This alpha-helix was not described earlier in an aqueous solution without organic solvents, and at physiological conditions (pH 7). These data are in agreement with Abeta adopting an alpha-helical conformation in the membrane before polymerizing into amyloid beta-sheets and provide insight into the intermediate state of Abeta in Alzheimer's disease. PMID- 25284369 TI - A PH domain in ACAP1 possesses key features of the BAR domain in promoting membrane curvature. AB - The BAR (Bin-Amphiphysin-Rvs) domain undergoes dimerization to produce a curved protein structure, which superimposes onto membrane through electrostatic interactions to sense and impart membrane curvature. In some cases, a BAR domain also possesses an amphipathic helix that inserts into the membrane to induce curvature. ACAP1 (Arfgap with Coil coil, Ankyrin repeat, and PH domain protein 1) contains a BAR domain. Here, we show that this BAR domain can neither bind membrane nor impart curvature, but instead requires a neighboring PH (Pleckstrin Homology) domain to achieve these functions. Specific residues within the PH domain are responsible for both membrane binding and curvature generation. The BAR domain adjacent to the PH domain instead interacts with the BAR domains of neighboring ACAP1 proteins to enable clustering at the membrane. Thus, we have uncovered the molecular basis for an unexpected and unconventional collaboration between PH and BAR domains in membrane bending. PMID- 25284371 TI - Regression of retinal capillaries following N-methyl-D-aspartate-induced neurotoxicity in the neonatal rat retina. AB - Degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA) induced retinal neurotoxicity, and the degree of capillary degeneration decreases in an age-dependent manner. To determine the role of vascular endothelial growth factor (VEGF) in the high susceptibility of capillaries to neuronal damage during the early postnatal stage, this study compares the vascular regression patterns between NMDA-treated retinas and retinas treated with N-[2-chloro-4-{(6,7 dimethoxy-4-quinazolinyl)oxy}phenyl]-N'-propylurea (KRN633), a VEGF receptor tyrosine kinase inhibitor, in neonatal rats. Two days after a single intravitreal injection of NMDA (200 nmol/eye) on postnatal day (P) 7, substantial retinal neuron loss and delayed expansion of the retinal vascular bed were observed. The reduction in the capillary density in the central retina reached statistical significance 4 days after NMDA treatment. In retinas of rats injected subcutaneously with KRN633 (10 mg/kg) on P7 and P8, simplified vasculature attributable to capillary regression and prevention of endothelial cell growth were seen on P9, whereas no visible changes in the morphology of the retinal layers were observed. The degree of capillary degeneration in NMDA-treated retinas was less than that in KRN633-treated retinas. No apparent changes in immunoreactivities for VEGF were found 2 days after NMDA treatment. These results indicate that neuronal cell loss in the retina precedes retinal capillary degeneration following NMDA treatment, and VEGF-dependent immature capillaries might be more susceptible to NMDA-induced neuronal damage. PMID- 25284370 TI - Combining genetic perturbations and proteomics to examine kinase-phosphatase networks in Drosophila embryos. AB - Connecting phosphorylation events to kinases and phosphatases is key to understanding the molecular organization and signaling dynamics of networks. We have generated a validated set of transgenic RNA-interference reagents for knockdown and characterization of all protein kinases and phosphatases present during early Drosophila melanogaster development. These genetic tools enable collection of sufficient quantities of embryos depleted of single gene products for proteomics. As a demonstration of an application of the collection, we have used multiplexed isobaric labeling for quantitative proteomics to derive global phosphorylation signatures associated with kinase-depleted embryos to systematically link phosphosites with relevant kinases. We demonstrate how this strategy uncovers kinase consensus motifs and prioritizes phosphoproteins for kinase target validation. We validate this approach by providing auxiliary evidence for Wee kinase-directed regulation of the chromatin regulator Stonewall. Further, we show how correlative phosphorylation at the site level can indicate function, as exemplified by Sterile20-like kinase-dependent regulation of Stat92E. PMID- 25284372 TI - Association between abnormal gastric function risk and Helicobacter pylori infection assessed by ELISA and 14C-urea breath test. AB - OBJECTIVE: Epidemiological studies found a significant correlation between Helicobacter pylori infection and elevated serum pepsinogen, especially pepsinogen II (PGII), and reduced pepsinogen I (PGI)/PGII ratio. The study aimed to evaluate the association between abnormal gastric function risk and H. pylori infection assessed by H. pylori IgG assay and (14)C-urea breath test (UBT). METHODS: A total of 1555 subjects who underwent a health check were enrolled. Serum PGI, serum PGII, PGI/PGII ratio, gastrin 17 (G17), H. pylori IgG antibody titer, and UBT results were collected. RESULTS: Median PGII and G17 levels were higher, but PGI/PGII ratio was lower in H. pylori-seropositive compared with seronegative participants (P<0.001, respectively). Similar effects were demonstrated by UBT. The consistency between H. pylori IgG assay, and UBT results were 86.9%, 82.29%, and 84.64% in individuals with normal gastric function, but only 73.4%, 67.98%, and 74.6% in those with abnormal gastric function. The correlation coefficients for H. pylori infection and abnormal gastric function diagnosed by PGI/PGII <7 were 0.336 (P<0.001) by H. pylori IgG assay and 0.231 (P<0.001) by UBT, diagnosed by PGII >= 8.25 ug/L were 0.594(P<0.001) by H. pylori IgG assay and 0.493 (P<0.001) by UBT, diagnosed by G17 >3 pmol/L was 0.469 (P<0.001) by H. pylori IgG assay and 0.394 (P<0.001) by UBT. The odds ratios (ORs) (95% confidence intervals) of abnormal gastric function were 7.477 (5.278 10.594), 19.204 (14.526-25.387), and 7.921 (6.286-9.982) comparing positive versus negative by H. pylori IgG assay and 4.084 (2.98-5.598), 9.552 (7.494 12.174), and 5.402 (4.335-6.731) comparing positive versus negative by UBT. CONCLUSIONS: H. pylori infection assessments by antibody-based or bacterial component-based detection are both related with abnormal gastric function. Moreover, serum H. pylori IgG assay was stronger associated with abnormal gastric function than UBT assay. PMID- 25284373 TI - Overestimation of the Legionella spp. load in environmental samples by quantitative real-time PCR: pretreatment with propidium monoazide as a tool for the assessment of an association between Legionella concentration and sanitary risk. AB - Quantitative polymerase chain reaction (qPCR) offers rapid, sensitive, and specific detection of Legionella in environmental water samples. In this study, qPCR and qPCR combined with propidium monoazide (PMA-qPCR) were both applied to hot-water system samples and compared to traditional culture techniques. In addition, we evaluated the ability of PMA-qPCR to monitor the efficacy of different disinfection strategies. Comparison between the quantification obtained by culture and by qPCR or PMA-qPCR on environmental water samples confirms that the concentration of Legionella estimated by GU/L is generally higher than that estimated in CFU/L. Our results on 57 hot-water-system samples collected from 3 different sites show that: i) qPCR results were on average 178-fold higher than the culture results (Delta log10=2.25), ii) PMA-qPCR results were on average 27 fold higher than the culture results (Delta log10=1.43), iii) propidium monoazide induced signal reduction in qPCR were nearly 10-fold (Delta log10=0.95), and that iv) different degrees of correlations between the 3 methods might be explained by different matrix properties, but also by different disinfection methods affecting cultivability of Legionella. In our study, we calculated the logarithmic differences between the results obtained by PMA-qPCR and those obtained by culture, and we suggested an algorithm for the interpretation of PMA-qPCR results for the routine monitoring of healthcare water systems using a commercial qPCR system (iQ-check real-time PCR kit; Bio-Rad, Marnes-la-Coquette, France). PMID- 25284374 TI - Turnover of strains and intraclonal variation amongst Pseudomonas aeruginosa isolates from paediatric CF patients. AB - Transmissible strains of Pseudomonas aeruginosa in cystic fibrosis (CF) have been well documented. Our longitudinal survey of P. aeruginosa isolates from 45 paediatric CF patients indicated strain persistence and intraclonal diversity, but not cross infection. This study demonstrates the need for regular P. aeruginosa strain surveillance using genotyping. PMID- 25284375 TI - IncI1/ST113 and IncI1/ST114 conjugative plasmids carrying blaCTX-M-8 in Escherichia coli isolated from poultry in Brazil. AB - Extended-spectrum beta-lactamase-producing Escherichia coli isolated from poultry in Brazil showed blaCTX-M-8 gene. IS10 was found upstream of blaCTX-M-8, harbored on plasmids IncI1, ST113/ST114 subtypes. Genomic relationship revealed a heterogeneous E. coli population. The gene blaCTX-M-8 is established in South America in food-producing animals, which represent risk of dissemination for other countries. PMID- 25284376 TI - Red blood cell distribution width as a useful indicator to predict systemic vasculitis in patients with cutaneous vasculitis. AB - Cutaneous vasculitis can be limited to skin or a manifestation of primary systemic vasculitis. However, there are no definite markers to predict systemic involvements. Recent studies have shown that a higher red blood cell distribution width (RDW) is associated with disease activity in various disorders. We evaluated whether RDW can be used as an indicator for predicting systemic disease in patients with initial cutaneous involvements. We reviewed clinical and laboratory information of 143 patients with cutaneous vasculitis and 15 pigmented purpuric dermatosis patients seen at single academic hospital in Korea. Various parameters, including RDW, were evaluated in patients with primary cutaneous vasculitis and primary systemic vasculitis with initial cutaneous manifestations. The RDW value between cutaneous and systemic vasculitis patients was compared and RDW level was also investigated whether it can indicate systemic vasculitis in patients with cutaneous involvements. The mean age was 32.0 years, and 102 (64.6 %) patients were female. A total of 132 patients were patients with primary cutaneous vasculitis, and 11 were primary systemic vasculitis. Higher ratio of patients with high RDW was detected in systemic vasculitis group compared with cutaneous vasculitis group (36.4 vs. 7.6 %, P < 0.05). The mean RDW was significantly higher in systemic vasculitis patients (P < 0.05). RDW had the strongest association with systemic vasculitis (P < 0.05, OR 1.834). In conclusion, elevated level of RDW was significantly associated with systemic vasculitis. RDW can be used as one of the marker to predict systemic disease in patients with cutaneous vasculitis. PMID- 25284377 TI - Comment on: levels of dipeptidyl peptidase IV/CD26 substrates neuropeptide Y and vasoactive intestinal peptide in rheumatoid arthritis patients. PMID- 25284378 TI - Living on the edge: the role of geography and environment in structuring genetic variation in the southernmost populations of a tropical oak. AB - Understanding the factors determining genetic diversity and structure in peripheral populations is a long-standing goal of evolutionary biogeography, yet little empirical information is available for tropical species. In this study, we combine information from nuclear microsatellite markers and niche modelling to analyse the factors structuring genetic variation across the southernmost populations of the tropical oak Quercus segoviensis. First, we tested the hypothesis that genetic variability decreases with population isolation and increases with local habitat suitability and stability since the Last Glacial Maximum (LGM). Second, we employed a recently developed multiple matrix regression with randomisation (MMRR) approach to study the factors associated with genetic divergence among the studied populations and test the relative contribution of environmental and geographic isolation to contemporary patterns of genetic differentiation. We found that genetic diversity was negatively correlated with average genetic differentiation with other populations, indicating that isolation and limited gene flow have contributed to erode genetic variability in some populations. Considering the relatively small size of the study area (<120 km), analyses of genetic structure indicate a remarkable inter population genetic differentiation. Environmental dissimilarity and differences in current and past climate niche suitability and their additive effects were not associated with genetic differentiation after controlling for geographic distance, indicating that local climate does not contribute to explain spatial patterns of genetic structure. Overall, our data indicate that geographic isolation, but not current or past climate, is the main factor determining contemporary patterns of genetic diversity and structure within the southernmost peripheral populations of this tropical oak. PMID- 25284379 TI - Lutetium-methanediide-alkyl complexes: synthesis and chemistry. AB - The first four-coordinate methanediide/alkyl lutetium complex (BODDI)Lu2 (CH2 SiMe3 )2 (MU2 -CHSiMe3 )(THF)2 (BODDI=ArNC(Me)CHCOCHC(Me)NAr, Ar=2,6-iPr2 C6 H3 ) (1) was synthesized by a thermolysis methodology through alpha-H abstraction from a Lu-CH2 SiMe3 group. Complex 1 reacted with equimolar 2,6-iPrC6 H3 NH2 and Ph2 C+O to give the corresponding lutetium bridging imido and oxo complexes (BODDI)Lu2 (CH2 SiMe3 )2 (MU2 -N-2,6-iPr2 C6 H3 )(THF)2 (2) and (BODDI)Lu2 (CH2 SiMe3 )2 (MU2 -O)(THF)2 (3). Treatment of 3 with Ph2 C=O (4 equiv) caused a rare insertion of Lu-MU2 -O bond into theC=O group to afford a diphenylmethyl diolate complex 4. Reaction of 1 with PhN=C=O (2 equiv) led to the migration of SiMe3 to the amido nitrogen atom to give complex (BODDI)Lu2 (CH2 SiMe3 )2 -MU {PhNC(O)CHC(O)NPh(SiMe3 )-kappa(3) N,O,O}(THF) (5). Reaction of 1 withtBuN=C formed an unprecedented product (BODDI)Lu2 (CH2 SiMe3 ){MU2 -[eta(2) :eta(2) tBuN=C(=CH2 )SiMe2 CHC=NtBu-kappa(1) N]}(tBuN=C)2 (6) through a cascade reaction of N=C bond insertion, sequential cyclometalative gamma-(sp(3) )-H activation, C=C bond formation, and rearrangement of the newly formed carbene intermediate. The possible mechanistic pathways between 1, PhN=C=O, and tBuN=C were elucidated by DFT calculations. PMID- 25284380 TI - Special issue featuring Zoological Society Award reviews. PMID- 25284381 TI - Chronobiology of crickets: a review. AB - Crickets provide a good model for the study of mechanisms underlying circadian rhythms and photoperiodic responses. They show clear circadian rhythms in their overt behavior and the sensitivity of the visual system. Classical neurobiological studies revealed that a pair of optic lobes is the locus of the circadian clock controlling these rhythms and that the compound eye is the major photoreceptor necessary for synchronization to environmental light cycles. The two optic lobe clocks are mutually coupled through a neural pathway and the coupling regulates an output circadian waveform and a free-running period. Recent molecular studies revealed that the cricket's clock consists of cyclic expression of so-called clock genes and that the clock mechanism is featured by both Drosophila-like and mammalian-like traits. Molecular oscillation is also observed in some extra-optic lobe tissues and depends on the optic lobe clock in a tissue dependent manner. Interestingly, the clock is also involved in adaptation to seasonally changing environment. It fits its waveform to a given photoperiod and may be an indispensable part of a photoperiodic time-measurement mechanism. With adoption of modern molecular technologies, the cricket becomes a much more important and promising model animal for the study of circadian and photoperiodic biology. PMID- 25284382 TI - Functional diversity of axonemal dyneins as assessed by in vitro and in vivo motility assays of Chlamydomonas mutants. AB - This review outlines the current knowledge of the functional diversity of axonemal dyneins, as revealed by studies with the model organism Chlamydomonas. Axonemal dyneins, which comprise outer and inner dynein arms, power cilia and flagella beating by producing sliding movements between adjacent outer-doublet microtubules. Outer- and inner-arm dyneins have traditionally been considered similar in structure and function. However, recent evidence suggests that they differ rather strikingly in subunit composition, axonemal arrangement, and molecular motor properties. We posit that these arms make up two largely independent motile systems; whereas outer-arm dynein can generate axonemal beating by itself under certain conditions, inner-arm dynein can generate beating only in cooperation with the central pair/radial spokes. This conclusion is supported by genome analyses of various organisms. Outer-arm dynein appears to be particularly important for nodal cilia of mammalian embryos that function for determination of left-right body asymmetry. PMID- 25284383 TI - Cell lineages and fate maps in tunicates: conservation and modification. AB - Comparison of features of the cell lineages and fate maps of early embryos between related species is useful in inferring developmental mechanisms and amenable to evolutionary considerations. We present cleavage patterns, cell lineage trees, and fate maps of ascidian and appendicularian embryos side by side to facilitate comparison. This revealed a number of significant differences in cleavage patterns and cell lineage trees, whereas the fate maps were found to be conserved. This fate map similarity can be extended to vertebrates, thus representing the fate map characteristics of chordates. Cleavage patterns and cell lineages may have been modified during evolution without any drastic changes in fate maps. Selective pressures that constrain developmental mechanisms at early embryonic stages might not be so strong as long as embryos are still able to generate a chordate-type fate map. Aquatic chordates share similar fate maps and morphogenetic movements during gastrulation and neurulation, eventually developing into tadpole-shaped larvae. As swimming by tail beats, and not by cilia, is advantageous, selective pressure may maintain the basic elements of the tadpole shape. We also discuss the evolutionary origin of the vertebrate neural crest and the embryonic origin of the appendicularian heart to illustrate the usefulness of cell lineage data. From an evolutionary standpoint, cell lineages behave like other characteristics such as morphology or protein sequences. Both novel and primitive features are present in extant organisms, and it is of interest to identify the relative degree of evolutionary conservation as well as the level at which homology is inferred. PMID- 25284384 TI - Functional properties of opsins and their contribution to light-sensing physiology. AB - Many animals have developed systems for sensing environmental conditions during evolution. In sensory cells, receptor molecules are responsible for their sensing abilities. In light sensing, most animals capture light information via rhodopsin like photoreceptive proteins known as opsin-based pigments. A body of evidence from comparisons of amino acid sequences and in vitro experiments demonstrates that opsins have phylogenetically and functionally diversified during evolution and suggests that the phylogenetic diversity in opsins correlates with the variety of molecular properties of opsin-based pigments. In this review, we discuss the various molecular properties of opsin-based pigments and their contribution to light-sensing ability by providing two examples: i) contribution of photoregeneration ability and Chromophore retinal binding property of an Opn3 homolog to non-visual photoreception, and ii) contribution of an absorption characteristic of a visual pigment to depth perception in jumping spiders. PMID- 25284385 TI - Phylogeography of the salmonid fish, Dolly Varden Salvelinus malma: multiple glacial refugia in the North Pacific Rim. AB - The geographic distribution pattern of mitochondrial DNA (control region) sequence polymorphisms from 73 populations of a salmonid fish, Dolly Varden Salvelinus malma, over most of its range in the North Pacific rim, was examined to assess how its spatial population genetic structure has been molded. The observed 68 haplotypes were grouped into three main lineages, which correspond to western, central, and eastern regions in the North Pacific. The two outlier haplotype groups gave close agreement with DNA types from two congeneric species, white-spotted charr S. leucomaenis and Arctic charr S. alpinus, respectively. These results suggest that the present-day genetic structure of S. malma reflects historical patterns of isolation and re-colonization, and also historical hybridization with co-distributed species. We also placed the haplotypes of S. malma within our study areas into a pre-existing evolutionary relationship of S. alpinus and S. malma throughout the Northern Hemisphere. Phylogenetic analysis revealed that the Western Lineage S. malma was basal to all other lineages of S. malma and S. alpinus. Our data serve as a biogeographic hypothesis for salmonid fishes that the Sea of Japan and/or Sea of Okhotsk regions represents a place of origin for S. malma and S. alpinus groups currently distributed in circumpolar regions. PMID- 25284386 TI - Phylogeographical analysis of a cold-temperate freshwater fish, the Amur sleeper (Perccottus glenii) in the Amur and Liaohe River basins of Northeast Asia. AB - The Amur sleeper Perccottus glenii (Perciformes, Gobioidei, Odontobutidae) is well known as an invasive fish in the river basins of Eastern and Central Europe, but its genetic background is unavailable across its native habitats in northeast Asia. In this study, we used the mitochondrial cytochrome b gene by sampling 19 populations of P. glenii across its native distributional areas of Liaohe and Amur River basins to explore its evolutionary history. Phylogenetic analyses identified three major clades within P. glenii, among which Clade A and Clade B were co-distributed in the Liaohe and Amur River basins, and Clade C was restricted to the latter. Molecular dating showed that the splits of Clades A, B and C have happened in the late Early-early Middle Pleistocene and the most recent common ancestors of these clades have been presented in the late Middle early Late Pleistocene. The P. glenii showed very high levels of genetic structure among populations (PhiST = 0.801), probably due to the characters of its life histories with very limited dispersal ability. The admixture of different clades in some populations of P. glenii probably reflects historical secondary contact. These findings indicate that Pleistocene climatic oscillation and river capture were major determinants for genetic variations and evolutionary history of the P. glenii. PMID- 25284387 TI - Divergence preceding island formation among Aegean insular populations of the freshwater snail genus Pseudorientalia (Caenogastropoda: Truncatelloidea). AB - Freshwater snails that inhabit islands are excellent model organisms for testing relationships between geological events and phylogeography, especially in the Aegean region. Although many Aegean islands were searched in the present study, species of the genus Pseudorientalia were only found on Lesvos, Samos, and Chios. Phylogenetic relationships between specimens living on these three islands were analysed using COI and 16S rRNA molecular markers and morphological data. A high level of diversity was found between islands. Genetic distances between clades showed differences high enough for the samples from different islands to be considered distinct species (p-distance: 0.105-0.133). These results are also supported by obvious morphological differences in shell morphology between islands. The mean divergence time between the Lesvos clade and Samos/Chios clade was 24.13 +/- 3.30 Mya; between the Samos and Chios clades the divergence time was 14.80 +/- 1.11 Mya. Our data suggest that high divergence may have occurred between Pseudorientalia populations during the Upper and Middle Miocene, when the Aegean region was part of a united landmass. It is possible that the observed highly divergent Pseudorientalia clades are relicts of high regional diversity that existed in the past. PMID- 25284388 TI - Morphological and molecular sexing of the monochromatic Barbados bullfinch, Loxigilla barbadensis. AB - The bullfinch Loxigilla barbadensis is an endemic passerine on the Caribbean island of Barbados that has only recently been taxonomically split from the Lesser Antillean bullfinch L. noctis. The trait that most clearly distinguishes L. barbadensis from L. noctis is the absence in the male of sexually dimorphic coloration of the body and throat feathers, with L. barbadensis males and females sharing the same dull brown plumage. Here we report, in 64 individuals netted throughout the island, the results of a discriminant analysis on two (wing length and tail length) to four morphological traits showing very high (97%) concordance with sexing via PCR using blood samples. Females also show a paler lower mandible, a trait that yields an 80% concordance with PCR sexing. We found one L. barbadensis male that had a noctis-like reddish throat patch, supporting the idea that sexual dichromatism is the ancestral condition and that male Barbados bullfinches have evolved cryptic coloration that now makes the species monochromatic. PMID- 25284389 TI - Morphological and genetic diversity of Briareum (Anthozoa: Octocorallia) from the Ryukyu Archipelago, Japan. AB - The primary problem hindering the study of octocorals is the disordered situation regarding their taxonomy, chiefly caused by insufficient knowledge of valid morphological taxonomic characters. Briareum is an octocoral genus found in the Atlantic and Pacific in shallow tropical and subtropical waters, and occurs in both encrusting and branching colony forms. Their simple morphology and morphological plasticity have hindered taxonomic understanding of this genus. In this study three morphologically distinct types (= type-1, -2, and -3) of Briareum from the Ryukyu Archipelago and their genetic diversity were examined. Colony, anthostele morphology, and sclerite length were examined for each type. Four molecular markers (mitochondrial cytochrome c oxidase subunit 1, mitochondrial mismatch repair gene, nuclear 18S ribosomal DNA, internal transcribed spacer 2 (ITS2)) were used to evaluate molecular phylogenetic status of these variations. Although one morphological type ("deep" small colonies, = type-3) showed small differences in nuclear ITS2 sequences compared to the other two types, the remaining types had identical sequences for all molecular markers examined. The results suggest extremely low genetic diversity despite highly variable morphology of Briareum species in Okinawa. Nevertheless, considering the distribution patterns and discontinuous morphology of type-3 compared to the other two morphotypes, genetic isolation of type-3 is plausible. In Briareum, small variances in nuclear ITS2 sequences of type-3 may have much more importance than in molecular phylogenies of other octocorals. Further phylogenetic investigations and comparison with Briareum specimens from other regions are necessary to conclusively taxonomically identify the three types. PMID- 25284391 TI - Effects of salt on the expansion of starchy snacks: a multiscale analysis. AB - We investigate the effect of salt on the expansion of starchy snacks during frying by means of a multiscale simulation model. This model has been developed earlier for starchy snacks without salt. The simulation results are analysed by means of the supplemented state diagram. We have found that the optimal expansion for salty snacks occurs under the same conditions as for snacks without salt. This occurs at the moisture content where the 4 bar boiling line intersects the critical isoviscosity line of 1 MPa s. Salt is shown to influence both the boiling line and the critical isoviscosity line, via a change of the glass transition. The optimal moisture content for salty snacks is lower than that of unsalted snacks. We view our findings as important for reformulations of starchy snacks with lower salt levels. Furthermore, the presented tools of the multiscale simulations and supplemented state diagram can generally be used for reformulation problems in structured foods. PMID- 25284392 TI - Taxonomic studies on the Neotropical Landrevinae with description of new taxa (Orthoptera, Grylloidea, Gryllidae). AB - The understanding of the subfamily Landrevinae has been modified by different authors since its creation. In the neotropics three genera are known to the present: Odontogryllus Saussure, 1877 (one from Mexico, the others amazonian), Brasilodontus de Mello, 1992 with two species (from Brazilian Atlantic Forest), e Valchica de Mello, 1992 with one species (from Costa Rica). De Mello (1992) erroneously created the tribe Odontogryllini for this cluster of neotropical genera, here suppressed. In the present paper we revise and add new species to Brasilodontus and describe two monotypic genera, Xulavuna n. gen. and Yarrubura, n. gen. An identification key to the genera of neotropical Landrevinae is presented as well as one for the species of Brasilodontus. The male fore wings of Xulavuna adenoptera n. sp. is remarkable regarding its shape and its glandular condition. PMID- 25284390 TI - Anger proneness, gender, and the risk of heart failure. AB - BACKGROUND: Evidence regarding the association of anger proneness with incidence of heart failure is lacking. METHODS AND RESULTS: Anger proneness was ascertained among 13,171 black and white participants of the Atherosclerosis Risk in Communities (ARIC) study cohort with the use of the Spielberger Trait Anger Scale. Incident heart failure events, defined as occurrence of ICD-9-CM code 428.x, were ascertained from participants' medical records during follow-up in the years 1990-2010. Relative hazard of heart failure across categories of trait anger was estimated with the use of Cox proportional hazard models. Study participants (mean age 56.9 [SD 5.7] years) experienced 1,985 incident HF events during 18.5 (SD 4.9) years of follow-up. Incidence of HF was greater among those with high, as compared to those with low or moderate trait anger, with higher incidence observed for men than for women. The relative hazard of incident HF was modestly high among those with high trait anger, compared with those with low or moderate trait anger (age-adjusted hazard ratio for men: 1.44 (95% confidence interval [CI] 1.23-1.69). Adjustment for comorbidities and depressive symptoms attenuated the estimated age-adjusted relative hazard in men to 1.26 (95% CI 1.00 1.60). CONCLUSIONS: Assessment of anger proneness may be necessary in successful prevention and clinical management of heart failure, especially in men. PMID- 25284393 TI - A taxonomic mystery for more than 150 years: Identity, systematic position and Malagasy origin of the snake Elapotinus picteti Jan, 1862, and synonymy of Exallodontophis Cadle, 1999 (Serpentes: Lamprophiidae). AB - Elapotinus picteti Jan, 1862 is an enigmatic snake taxon that has been described without locality data. Genus and species, both based on the unique holotype, were considered to belong to the venomous African Aparallactinae for more than a century, but although this taxon was never rediscovered it was accepted as a valid species until present. To clarify the taxonomic status of E. picteti its characters were compared with literature and determination keys for the whole world. This literature survey and the subsequent study of type specimens revealed that the monotypic Elapotinus is a subjective senior synonym of the monotypic Malagasy pseudoxyrhophiine snake genus Exallodontophis Cadle, 1999 which is characterized by its unique aglyphous dentition. We therefore transfer Elapotinus from the lamprophiid subfamily Aparallactinae to the subfamily Pseudoxyrhophiinae. Furthermore, Elapotinus picteti strongly resembles the Malagasy species Exallodontophis albignaci (Domergue, 1984) in external morphology, coloration and dentition. As a consequence we consider Elapotinus picteti a subjective senior synonym of Exallodontophis albignaci. PMID- 25284394 TI - Three new species of the salamander genus Hynobius (Amphibia, Urodela, Hynobiidae) from Kyushu, Japan. AB - Three new species of lotic breeding Hynobius, formerly assigned to H. boulengeri, are described from the Kyushu region, southwestern Japan. They differ from all the known congeners by a unique combination of body size, character ratios, coloration, mtDNA, and allozymic characteristics. Together with H. stejnegeri they form a clade, which is not a sister group of H. boulengeri, and their speciation in Kyushu is surmised to have occurred at the end of Miocene, accompanied by differentiations in larval period and metamorphosing size. Measures of conservation of these new species are discussed briefly. PMID- 25284395 TI - Two new species of Piaroa (Arachnida: Schizomida, Hubbardiidae) from Colombia, with comments on the genus taxonomy and the flagellar setae pattern of Hubbardiinae. AB - Two new species of the genus Piaroa Villarreal, Tourinho & Giupponi, 2008, P. escalerete sp. nov. and P. bacata sp. nov. are described from Valle del Cauca, and Cundinamarca departments, Colombia, respectively. The female flagellum is fully illustrated for a Piaroa species for the first time; the generic diagnosis is also emended and the relationships of the new species with those previously described are discussed. New characters for Piaroa species, a new nomenclature for the chitinized arch and a reinterpretation of the Hubbardiinae flagellar setae pattern are proposed. A distribution map of the known species of Piaroa is provided. PMID- 25284396 TI - Tisaniba, a new genus of marpissoid jumping spiders from Borneo (Araneae: Salticidae). AB - Six new species of marpissoid jumping spiders from Sarawak, Borneo, are described in the new genus Tisaniba Zhang & Maddison. They are the type species, T. mulu Zhang & Maddison sp. nov., as well as the species T. bijibijan Zhang & Maddison sp. nov., T. dik Zhang & Maddison sp. nov., T. kubah Zhang & Maddison sp. nov., T. selan Zhang & Maddison sp. nov., and T. selasi Zhang & Maddison sp. nov. The spiders are small and brown to black, living in leaf litter in the tropical forest. Phylogenetic analyses based on 28s and 16sND1 genes indicate that they are a distinctive group within the marpissoids. Diagnostic illustrations and photographs of living spiders are provided for all species. PMID- 25284397 TI - First records of Ochrotrichia Mosely, 1934 (Trichoptera: Hydroptilidae) in Northeastern Brazil: Five new species and two new geographical records. AB - About 170 species have been assigned to the New World genus Ochrotrichia, only two of which were previously recorded from Brazil. Material collected in Bahia and Ceara states represent the first records of this genus from Northeastern Brazil and reveal five new species of Ochrotrichia. These are described and illustrated in this paper: O. caatinga sp. nov. (O. aldama group, from Ceara), O. priapo sp. nov. (O. aldama group, from Bahia); O. limeirai sp. nov. (O. aldama group, from Ceara), O. constricta sp. nov. (undetermined group, from Bahia), and O. igrapiuna sp. nov. (O. xena group, from Bahia). Ochrotrichia manuensis Flint & Bueno-Soria 1999 is firstly recorded from Brazil and O. patulosa (Wasmund & Holzenthal 2007) is firstly recorded from Northeastern Brazil. PMID- 25284398 TI - A new genus of cardinalfish from tropical Australia and southern New Guinea (Percomorpha: Apogonidae). AB - Ozichthys is described as a new monotypic genus, type species Apogon albimaculosus. This species is restricted to tropical Australia and southern New Guinea. The combination of first dorsal fin with VIII visible spines, fused first and second hypurals, epineural on ninth rib, ossified lower preopercle edge, serrated edge of the preopercle, more than three flute canals on post orbit, 23 24 pored lateral- line scales, elongate last lateral-line scale, and sixteen rows of free neuromasts on principal caudal fin-rays will identify this genus from other brownish ground-colored apogonids. This genus is placed in the clade with Apogonichthys, Foa, Fowleria, and Neamia based on color patterns present on the head, body and vertical fins and in having a single pore above and below the raised median canal on each pored lateral-line scale. PMID- 25284399 TI - The genera Luzonimyia and Pararhinoleucophenga from China (Diptera: Drosophilidae), with DNA barcoding information. AB - Four new species are described from Yunnan, China, which belong to two different genera within the subfamily Steganinae: Luzonimyia hirsutina sp. nov., Luzonimyia setocauda sp. nov., Pararhinoleucophenga amnicola sp. nov. and Pararhinoleucophenga sylvatica sp. nov. The DNA sequences and GenBank accession numbers of the mitochondrial COI gene among Chinese species are provided. PMID- 25284400 TI - New species of Afrotropical Muscidae (Diptera: Muscoidea). AB - The study of recently collected Afrotropical Muscidae (Diptera) from Burundi, Democratic Republic of the Congo, Kenya and South Africa has revealed ten new species which are described herein: Coenosia duomaculata sp. nov., C. nigromaculata sp. nov., C. fragilis sp. nov., Helina harrisorum sp. nov., H. ferfriniorum sp. nov., Hydrotaea tantula sp. nov., Limnophora diminuta sp. nov., L. antennalis sp. nov., Spilogona brunnea sp. nov. and S. bella sp. nov. Coenosia, Helina and Limnophora are speciose muscid genera, found throughout the Afrotropical Region, while Hydrotaea and Spilogona have a more restricted geographic distribution and include some 20 species each. PMID- 25284401 TI - Morphological differentiation of seven species of the genus Heterocypris Claus, 1892 (Ostracoda, Crustacea) based on the upper lip. AB - Morphological differences of upper lip shape were analyzed in seven Heterocypris species occurring in the Mediterranean region. Descriptive observations and morphometric analysis of upper lip length, height and maximum height position are given for 17 populations from the Pannonian Plain, Balkan Peninsula and Iberian Peninsula. We found high variation in relative upper lip measurements between the species, indicating that upper lip traits can be used as additional taxonomic characters. The most distinctive upper lip shapes were noted in H. exigua and H. gevgelica, while the greatest intraspecific variability was present in H. barbara, H. incongruens and H. rotundata. Previously described qualitative characters in the form of differently arranged patches of pseudochaetae on the upper lip surface were also observed. PMID- 25284402 TI - Additional slipper lobsters of the subfamily Scyllarinae Latreille, 1825 (Crustacea, Achelata, Scyllaridae) from Taiwan. AB - Five scyllarine lobsters are recorded from Taiwan for the first time. They are Bathyarctus rubens (Alcock & Anderson, 1894), Biarctus sordidus (Stimpson, 1860), Chelarctus aureus (Holthuis, 1963), Crenarctus bicuspidatus (De Man, 1905) and Petrarctus veliger Holthuis, 2002. The distributions of B. rubens, C. aureus and P. veliger are extended northwards to Taiwan. Distinguishing characters of these five species are illustrated and color photographs of all but B. sordidus are provided. Altogether, nine genera and 17 species of scyllarine lobsters are now known from Taiwan. PMID- 25284403 TI - First Harvestman Record for the Juan Fernandez Archipelago, Chile, with Morphological Notes on Acropsopilio chilensis (Opiliones: Caddidae: Acroposopilioninae). AB - Acropsopilio chilensis Silvestri, 1904 (Eupnoi: Caddidae: Acropsopilioninae), is recorded for Robinson Crusoe Island, Chile. This is the first harvestman species recorded for the Juan Fernandez Archipelago and also the first extra-continental record for this species. During the comparison with continental co-specific specimens, some previously unknown, remarkable morphological characteristics were discovered, among them: the absence of ovipositor seminal receptacles and tracheal system, small and probably imperforate spiracles and the presence of a subdistal spiny structure, maybe a stylus, in the major branch of the penis. PMID- 25284404 TI - Description of four new species of the genus Ptilocerembia Friederichs, 1923 (Embioptera: Ptilocerembiidae) from Thailand. AB - Four new species of webspinners in the genus Ptilocerembia Friederichs (Ptilocerembiidae) are described including Ptilocerembia thaidina sp. n., P. senathami sp. n., P. catherinae sp. n. and P. rossi sp. n. . from Thailand. Illustrations of heads, genitalia and papilla of adult males, sternite pattern of adult females together with photographs of adult males, females and their galleries for each species are provided. Notes on field observations and egg mass structure are given for P. catherinae sp. n. A distribution map and a dichotomous key to the Thai species in the genus Ptilocerembia are also included. PMID- 25284405 TI - Alaskan Heteroptera (Hemiptera): new records, associated data, and deletions. AB - Twenty-seven species of Heteroptera are recorded new to Alaska. Specimen data for ten additional species reported from Alaska without previously published data are also provided. Additionally, four species previously reported from the state are removed from the Alaska list of Heteroptera. PMID- 25284406 TI - Burrowing crickets endemic to summits in Mauritius (Orthoptera, Gryllidae): occupation of similar niches by species possibly derived from Australasian and African colonists. AB - Two ground burrowing crickets are described from the oceanic island of Mauritius (South Western Indian Ocean): Gialaia (Eugialaia) strasbergi n. sp. belongs to a subgenus that was only known from Papua-New Guinea, and Taciturna baiderae n.sp. belongs to a genus that was only known from South Africa. Taciturna baiderae n. sp. displays a maternal care behavior to clutch of eggs and offspring. Elements of the biology of these two new species are given and their conservation status is assessed. PMID- 25284407 TI - Lamprologus markerti, a new lamprologine cichlid (Teleostei: Cichlidae) endemic to the lower Congo River in the Democratic Republic of Congo, west-central Africa. AB - A new Lamprologus is described from the lower Congo River (LCR) in the Democratic Republic of Congo. Lamprologus markerti, new species, is readily distinguished from L. tigripictilis and L. werneri, the LCR endemic lamprologines with which it was once taxonomically conflated, in the possession of a reduced number of gill rakers on the first arch (9-11 versus 12-17), a longer head (32.1-34.7% SL versus 29.3-31.9 and 29.1-32.9% SL, respectively), and a longer predorsal length (33.0 35.9% SL versus 29.3-32.7 and 28.5-32.6% SL, respectively). Further, L. markerti lacks a second intestinal loop present in both L. tigripictilis and L. werneri, and has a highly reduced infraorbital series often consisting of a single first infraorbital (lachrymal) element. PMID- 25284408 TI - Survey of demersal fishes from southern Saudi Arabia, with five new records for the Red Sea. AB - During a survey of demersal fishes of the southern Red Sea coast of Saudi Arabia off Jizan, 98 species were collected by trawling. Five of these represent new records for the Red Sea: Saurida longimanus, Dactyloptena gilberti, Jaydia novaeguineae, Pomadasys maculatus and Parapercis maculata. Additionally a specimen of the rare moray Gymnothorax reticularis, previously known from only three specimens, was collected. Records of two species, Parastromateus niger and Pseudorhombus arsius, that formerly were considered questionable, are confirmed by collection of new voucher specimens. Validity of Laeops sinusarabici is confirmed. This study documents parts of the diversity of the demersal fish communities on sandy areas of the southern Red Sea, but also emphasizes that a large proportion of this area has not been explored. PMID- 25284409 TI - Two new species of Glyphocrangon (Decapoda: Caridea: Glyphocrangonidae) from the East China Sea and the Philippines. AB - The present paper reports two new species of Glyphocrangon (Crustacea, Caridea, Glyphocrangonidae) collected respectively from the East China Sea and the Philippines. G. singularis sp. nov., from the East China Sea, is similar to G. fimbriata Komai & Takeuchi, 1994 with the presence of fringe of setae on dactyl of the third to fifth pereopods, but differs from G. fimbriata by the rostrum shape and the armature on the carapace; G. denticulata sp. nov., from the Philippines, is similar to G. pugnax De Man, 1918 with the entire anterior third carina, but differs from G. pugnax by armatures of the antennal scaphocerite and carapace, the lengths of rostrum and the spines of fifth abdominal somite, and the colouration of carapace. PMID- 25284410 TI - Review of the genus Ammobatoides Radoszkowski, 1867 (Hymenoptera: Apidae, Nomadinae) from Russia and neighbouring countries . AB - Three species of Ammobatoides are reviewed. One new species, Ammobatoides radoszkowskii sp. nov. (Russia and North China) is described and illustrated. A male lectotype is designated for Paidia melectoides Radoszkowski, 1872. One new subjective synonym is established: Ammobatoides scriptus (Gerstaecker, 1869) =Paidia melectoides Radoszkowski, 1872, syn. nov. A key to species for both sexes is given. PMID- 25284411 TI - Review of the genus Mesosaimia Breuning with description of a new species (Coleoptera: Cerambycidae: Lamiinae: Mesosini). AB - The genus Mesosaimia Breuning, 1938 is reviewed. The genus Trichipocregyes Breuning, 1950 is synonymized with Mesosaimia. Trichomesosa similis Breuning, 1950 is transferred to Mesosaimia. A new species, M. wakaharai sp. nov., is described from Laos. Four species, M. robusta Breuning, 1938, M. mausoni (Breuning, 1950) comb. nov., M. similis (Breuning) comb. nov. and M. wakaharai sp. nov., are included in the genus. Habitus photographs, drawings of diagnostic male genitalia, and a key to all species of Mesosaimia are provided. PMID- 25284412 TI - Morphometry and redescription of Parahelichus granulosus (Deleve, 1974) with description of P. pseudogranulosus, a new cryptic species of Long-toed Water Beetles (Coleoptera: Dryopidae) from Indochinese peninsula, and proposal of a new synonym for Praehelichus sericatus (Waterhouse, 1881) from China. AB - A new species of Parahelichus Lobl & Smetana, 2006 is described from Laos and Thailand: P. pseudogranulosus. A similar species, P. granulosus Deleve, 1974, which was originally described only from a single specimen, is redescribed and morphometric data are provided from 442 specimens from Vietnam and Laos. Habitus views, illustrations of important characters as well as results of morphometric analyses are presented and discussed. Praehelichus sinensis (Fairmaire, 1888) is proposed as a new junior synonym of P. sericatus (Waterhouse, 1881). PMID- 25284413 TI - Salmoneus yoyo nov. sp., a peculiar new infaunal shrimp from Lombok, Indonesia (Decapoda, Caridea, Alpheidae). AB - An unusual new species of the alpheid shrimp genus Salmoneus Holthuis, 1955 is described from Sekotong Bay, southwestern Lombok, Indonesia. The holotype and single known specimen of Salmoneus yoyo sp. nov. was collected with a suction pump from a burrow of unknown host, on a seagrass flat partly exposed at low tide. The new species presents three characters on the chelipeds that are unique within Salmoneus: a conspicuous, mesially curved, hook-like process on the distomesial margin of the merus, a row of blunt teeth on the ventromesial margin of the merus, and a series of blunt teeth on the ventromesial margin of the propodus. Salmoneus yoyo sp. nov. also has a characteristic colour pattern consisting of bright red chromatophores occupying most of the carapace surface, except for the frontal and post-frontal areas. PMID- 25284414 TI - Paolaltica eocenica new genus and new species of flea beetle (Coleoptera: Chrysomelidae: Galerucinae: Alticini) from Baltic amber. AB - Paolaltica eocenica new genus and new species (Coleoptera: Chrysomelidae: Galerucinae: Alticini) is described and illustrated from Upper Eocene Baltic amber. The new taxon is compared with fossil and recent flea beetle genera. PMID- 25284415 TI - New species of Oropezella Collin (Diptera, Hybotidae, Ocydromiinae) from Brazil and Costa Rica, with comments on the relationships among species-groups. AB - The following sixteen new species of Oropezella from Brazil and Costa Rica are described and illustrated: Oropezella aquila sp. nov., O. arcuata sp. nov., O. bicolor sp. nov., O. bipunctata sp. nov., O. clavata sp. nov., O. costaricensis sp. nov., O. falcata sp. nov., O. flavida sp. nov., O. granulosa sp. nov., O. longifrons sp. nov., O. planti sp. nov., O. plaumanni sp. nov., O. rafaeli sp. nov., O. spathula sp. nov., O. uncata sp. nov. and O. undulata sp. nov. A new combination is proposed: Oropezella amazonica (Rafael & Ale-Rocha, 1990) is transferred from Ocydromia. Additionally, an identification key to all 25 Neotropical and Andean species of Oropezella is provided. A cladistic analysis of Oropezella using 29 species from the Neotropical, Andean, Palearctic and Neozelandic regions is performed and its results and implications discussed. PMID- 25284416 TI - Review of Solier's Mecorhopalus species (Coleoptera: Staphylinidae: Aleocharinae). AB - Antoine Joseph Jean Solier, a French naturalist, described 53 species of Staphylinidae of the Chilean fauna, among them three species in a new genus Mecorhopalus (M. ater, M. bipustulatus and M. elongatus). Today these species are regarded as Aleochara atra, A. solieri and A. mutare , respectively. The objective of this study is to provide an updated description and nomenclatural status of these species. Mecorhopalus remains as junior synonym of Aleochara with one species in the subgenus Aleochara and another in Coprochara. Through study of the type material, A. mutare is synonymized with A. solieri as junior subjective synonym. PMID- 25284417 TI - A new species of Trisecodes from the Afrotropics (Hymenoptera, Eulophidae) . AB - The first Afrotropical species of Trisecodes Delvare & LaSalle, 2000, T. africanum Gumovsky, sp. n., is described from localities in Uganda, Guinea and Cameroon. The new species differs from the type species of the genus, T. agromyzae, which was described from the Neotropical region in Belize, mostly by having longitudinally strigate sculpture on the mesosoma dorsally and by the fore wing being somewhat darkened in its basal three-fifths. A possible Gondwanan origin of the genus is postulated. PMID- 25284418 TI - New province record of Rhinagrion for Thailand and description of the larva of R. mima (Odonata: Zygoptera: Philosinidae). AB - The Oriental damselfly genus Rhinagrion includes 10 known species, but the larva of only R. philippinum has been described in any detail, while the larva of R. viridatum has been well-illustrated and features summarized. The larvae of the other eight species were unknown. Here, the larva of Rhinagrion mima is described and illustrated by supposition, based upon an F0 larva collected in Phetchabun Province in Thailand. It is compared with the larvae of R. philippinum and R. viridatum. This represents the first record of the genus for Phetchabun Province. PMID- 25284419 TI - Jerzego, a new hisponine jumping spider from Borneo (Araneae: Salticidae). AB - A new genus and species of hisponine jumping spider from Sarawak, Jerzego corticicola Maddison sp. nov. are described, representing one of the few hisponine jumping spiders known from Asia, and the only whose male is known. Although similar to the primarily-Madagascan genus Hispo in having an elongate and flat body, sequences of 28s and 16sND1 genes indicate that Jerzego is most closely related to Massagris and Tomomingi, a result consistent with morphology. Females of Jerzego and other genera of Hisponinae were found to have an unusual double copulatory duct, which appears to be a synapomorphy of the subfamily. Two species are transferred from Hispo, Jerzego bipartitus (Simon) comb. nov. and Jerzego alboguttatus (Simon) comb. nov. Diagnostic illustrations and photographs of living spiders are provided. PMID- 25284420 TI - The cicada genus Karenia Distant, 1888 (Hemiptera: Cicadidae), with description of a new species. AB - The cicadas of the genus Karenia are reviewed, and Karenia tibetensis sp.nov. (Hemiptera: Cicadidae) is described from Tibet, China. Pictures of the male adult and illustrations of the male genitalia are provided. A key to the species of Karenia is presented and the distribution of the Karenia species is discussed. PMID- 25284421 TI - A new Protzia species and the first description of the female Atractides (Polymegapus) persicus Pesic & Asadi 2010 from Turkey. PMID- 25284422 TI - Redescription of Ypsolopha kotzschi (Toll, 1947) (Lepidoptera, Ypsolophidae). PMID- 25284423 TI - Synopsis of the genus Pseudosparna Mermudes & Monne (Coleoptera, Cerambycidae, Lamiinae), with description of two new species . AB - Two new species of Pseudosparna Mermudes & Monne, 2009 are described: P. tucurui sp. nov. from Brazil (Para) and P. pichincha sp. nov. from Ecuador (Pichincha). A key to the species of Pseudosparna is also included. PMID- 25284424 TI - Correction of the spelling of Trichomycterus eichhorniarum Miranda Ribeiro, 1912 (Siluriformes: Trichomycteridae). PMID- 25284426 TI - Ureteral obstruction following renal transplantation: causes, diagnosis and management. AB - Renal transplantation, first performed successfully in the 1950s, is the treatment of choice for most patients with end-stage renal failure. It confers longer term survival and a better quality of life than do both haemodialysis and peritoneal dialysis. The success of renal transplantation is dependent on the preservation of renal graft function and despite the many advances in surgical techniques, immunosuppressive regimens and supportive therapies, many challenges remain including post-operative ureteral obstruction. This complication can pose a risk to graft, and, occasionally, to patient survival. In this pictorial review, we describe the causes of ureteral obstruction following renal transplantation and illustrate the pivotal role of radiology in both diagnosing and managing these complications. PMID- 25284428 TI - Improving testicular blood flow with electroacupuncture-like percutaneous nerve stimulation in an experimental rat model of testicular torsion. AB - INTRODUCTION: The purpose of this study was to determine the blood-flow-enhancing effect of electroacupuncture (EA) in an experimental rat model of testicular torsion. METHODS: At the first stage, 3D color Doppler ultrasound (3D-CDUS) scans were made to detect baseline perfusion of each testicle in 12 male albino Wistar rats. Then, the left testicles of all rats were twisted 180 degrees clockwise, and 3D-CDUS recordings were repeated. In the next step, 10-Hz EA was applied for 5 min over the T13 and L4 dermatome territories in the study group of six rats. In the control group of six rats, acupuncture needles were inserted in the same manner, but EA was not applied. Baseline, posttorsion, and postintervention (EA and manual needling) 3D-CDUS perfusion recordings were interpreted as volumetric data, and group comparisons were performed. RESULTS: After EA, we observed statistically significant perfusion improvements in both the ipsilateral torsed and contralateral nontorsed testicles. In the control group, testicular perfusion did not show a significant change after manual needling. CONCLUSION: EA can improve testicular blood flow bilaterally in a rat model of unilateral testicular torsion at 180 degrees . PMID- 25284427 TI - SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. AB - Mechanisms that coordinate different metabolic pathways, such as glucose and lipid, have been recognized. However, a potential interaction between amino acid and lipid metabolism remains largely elusive. Here we show that during starvation of Caenorhabditis elegans, proline catabolism is coupled with lipid metabolism by SKN-1. Mutation of alh-6, a conserved proline catabolic enzyme, accelerates fat mobilization, enhances the expression of genes involved in fatty acid oxidation and reduces survival in response to fasting. This metabolic coordination is mediated by the activation of the transcription factor SKN-1/Nrf2, possibly due to the accumulation of the alh-6 substrate P5C, and also requires the transcriptional co-regulator MDT-15. Constitutive activation of SKN-1 induces a similar transcriptional response, which protects animals from fat accumulation when fed a high carbohydrate diet. In human cells, an orthologous alh-6 enzyme, ALDH4A1, is also linked to the activity of Nrf2, the human orthologue of SKN-1, and regulates the expression of lipid metabolic genes. Our findings identify a link between proline catabolism and lipid metabolism, and uncover a physiological role for SKN-1 in metabolism. PMID- 25284429 TI - Pyrone derivatives from the endophytic fungus Alternaria tenuissima SP-07 of Chinese herbal medicine Salvia przewalskii. AB - Three new pyrones, solanapyrones P-R (1-3), were afforded by the extracts of the endophytic fungus Alternaria tenuissima SP-07 isolated from the fresh root of Chinese herbal medicine Salvia przewalskii, along with the known solanapyrones (4 6) and benzopyrones (7-9). Solanapyrones P (1) and Q (2) possess an unprecedented nor-solanapyrone skeleton as natural products. Their structures were determined on the basis of NMR and HR-ESI-MS analysis. The plausible biosynthetic pathways to those unknown compounds were discussed. All the isolated compounds were evaluated for their antibacterial activities against six bacteria. PMID- 25284431 TI - Enhanced electroanalysis in lithium potassium eutectic (LKE) using microfabricated square microelectrodes. AB - Molten salts (MSs) are an attractive medium for chemical and electrochemical processing and as a result there is demand for MS-compatible analysis technologies. However, MSs containing redox species present a challenging environment in which to perform analytical measurements because of their corrosive nature, significant thermal convection and the high temperatures involved. This paper outlines the fabrication and characterization of microfabricated square microelectrodes (MSMs) designed for electrochemical analysis in MS systems. Their design enables precise control over electrode dimension, the minimization of stress because of differential thermal expansion through design for high temperature operation, and the minimization of corrosive attack through effective insulation. The exemplar MS system used for characterization was lithium chloride/potassium chloride eutectic (LKE), which has potential applications in pyrochemical nuclear fuel reprocessing, metal refining, molten salt batteries and electric power cells. The observed responses for a range of redox ions between 400 and 500 degrees C (673 and 773 K) were quantitative and typical of microelectrodes. MSMs also showed the reduced iR drop, steady-state diffusion-limited response, and reduced sensitivity to convection seen for microelectrodes under ambient conditions and expected for these electrodes in comparison to macroelectrodes. Diffusion coefficients were obtained in close agreement with literature values, more readily and at greater precision and accuracy than both macroelectrode and previous microelectrode measurements. The feasibility of extracting individual physical parameters from mixtures of redox species (as required in reprocessing) and of the prolonged measurement required for online monitoring was also demonstrated. Together, this demonstrates that MSMs provide enhanced electrode devices widely applicable to the characterization of redox species in a range of MS systems. PMID- 25284430 TI - Antioxidant neolignan and phenolic glucosides from the fruit of Euterpe oleracea. AB - Three new glucosides, namely, (-)-7R8S-7',8'-dihydroxy-dihydrodehydroconiferyl alcohol-9-O-beta-D-glucopyranoside (1), (+)-7S8R-7',8'-dihydroxy dihydrodehydroconiferyl alcohol-9-O-beta-D-glucopyranoside (2) and 4-hydroxy-2 methoxyphenyl 1-O-[6-(hydrogen 3-hydroxy-3-methylpentanedioate)]-beta-D glucopyranoside (3), along with 6 known compounds were isolated from the fruit of Euterpe oleracea Mart. Their structures were elucidated based on spectroscopic analyses including NMR, HR-ESI-MS and CD. All the isolated compounds demonstrated significant antioxidant activity and 2 displayed moderate cytotoxicity against HL 60 cells. PMID- 25284432 TI - Coupled ferroelectric polarization and magnetization in spinel FeCr2S4. AB - One of the core issues for multiferroicity is the strongly coupled ferroelectric polarization and magnetization, while so far most multiferroics have antiferromagnetic order with nearly zero magnetization. Magnetic spinel compounds with ferrimagnetic order may be alternative candidates offering large magnetization when ferroelectricity can be activated simultaneously. In this work, we investigate the ferroelectricity and magnetism of spinel FeCr2S4 in which the Fe(2+) sublattice and Cr(3+) sublattice are coupled in antiparallel alignment. Well defined ferroelectric transitions below the Fe(2+) orbital ordering temperature Too = 8.5 K are demonstrated. The ferroelectric polarization has two components. One component arises mainly from the noncollinear conical spin order associated with the spin-orbit coupling, which is thus magnetic field sensitive. The other is probably attributed to the Jahn-Teller distortion induced lattice symmetry breaking, occurring below the orbital ordering of Fe(2+). Furthermore, the coupled ferroelectric polarization and magnetization in response to magnetic field are observed. The present work suggests that spinel FeCr2S4 is a multiferroic offering both ferroelectricity and ferrimagnetism with large net magnetization. PMID- 25284433 TI - Updating the definition and role of public health nursing to advance and guide the specialty. AB - National changes in the context for public health services are influencing the nature of public health nursing practice. Despite this, the document that defines public health nursing as a specialty--The Definition and Role of Public Health Nursing--has remained in wide use since its publication in 1996 without a review or update. With support from the American Public Health Association (APHA) Public Health Nursing Section, a national Task Force, was formed in November 2012 to update the definition of public health nursing, using processes that reflected deliberative democratic principles. A yearlong process was employed that included a modified Delphi technique and various modes of engagement such as online discussion boards, questionnaires, and public comment to review. The resulting 2013 document consisted of a reaffirmation of the one-sentence 1996 definition, while updating supporting documentation to align with the current social, economic, political, and health care context. The 2013 document was strongly endorsed by vote of the APHA Public Health Nursing Section elected leadership. The 2013 definition and document affirm the relevance of a population-focused definition of public health nursing to complex systems addressed in current practice and articulate critical roles of public health nurses (PHN) in these settings. PMID- 25284434 TI - [Haemovigilance and blood safety in overseas military]. AB - The French military blood institute (FMBI) is the only military blood supplier in France. FMBI operates independently and autonomously under the Ministry of Defense's supervision, and accordingly, to the French, European and NATO technical and safety guidelines. FMBI is in charge of the collection, preparation and distribution of blood products to supply transfusion support to armed forces, especially during overseas operations. In overseas military, a primary physician is responsible for haemovigilance in permanent relation with an expert in the FMBI to manage any adverse reaction. Additionally, traceability of delivered or collected blood products during overseas operation represents a priority, allowing an appropriate management of transfusion inquiries and assessment of practices aiming to improve and update procedures and training. Transfusion safety in overseas operation is based on regular and specific training of people concerned by blood supply chain in exceptional situation. PMID- 25284435 TI - Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical. AB - Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images. We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls. PMID- 25284436 TI - Corticotropin-releasing factor receptor densities vary with photoperiod and sociality. AB - Life in social groups relies on prosocial behaviors as well as on reduction of antisocial behaviors such as aggression and territoriality. The mechanisms supporting variation in behaviors that give rise to group living (sociality) are largely unknown. Female meadow voles exhibit natural seasonal variation in sociality: females are aggressive and territorial in summer, while in winter they share burrows and nest in mixed-sex groups. This behavioral shift is paralleled in the lab by day length-dependent variation in partner preference formation and social huddling. We exploit natural variation in meadow vole sociality in order to examine changes in neural pathways that coincide with environmental and behavioral variations. Mounting evidence suggests that the corticotropin releasing factor system, encompassing multiple peptides and two receptor subtypes (CRF1 and CRF2), may play an important role in regulating social behaviors. We report day-length dependent variation in CRF1 and CRF2 receptor binding in female meadow voles, and relate these findings to previously collected oxytocin receptor (OTR) binding data and behavioral data for the same individuals. CRF1 receptor binding was greater in summer-like long day lengths (LD), particularly in the hippocampus, while CRF2 receptor binding was greater in winter-like short day lengths (SD) in the cingulate cortex and hippocampus. OTR varied with day length in the bed nucleus of the stria terminalis, nucleus accumbens, and hippocampus. SD voles huddled more extensively than LD voles, and greater huddling time was associated with more CRF1 receptor binding and less CRF2 receptor binding in subregions of the lateral septum. CRF2 receptor associations with behavior mirrored those of OTR in the lateral septum. Finally, estradiol treatment affected density of CRF receptors in multiple brain regions. CRF receptors and their ligands are promising candidates for enhancing understanding of the regulation of non-sexual social behavior between group living peers. PMID- 25284437 TI - Cinnamon in a mouse model of PD: Khasnavis S, Pahan K. Cinnamon protects dopaminergic neurons in a mouse model of Parkinson's disease. J Neuroimmune Pharmacol 2014;9:569-581. PMID- 25284438 TI - Flow cytometry is a promising and rapid method for differentiating between freely suspended Escherichia coli and E. coli attached to clay particles. AB - AIM: A standard procedure does not exist to distinguish between attached and unattached micro-organisms. In this study, we compared two methods to quantify between Escherichia coli attached to clay particles and E. coli freely suspended in solution: flow cytometry (attachment assay and viability assay) and settling (or centrifugation followed by settling). METHODS AND RESULTS: Methods were tested using three environmental strains collected from swine facilities (A, B and C) and one purchased modified pathogenic strain (ATCC 43888); four clay particles: Hectorite, Kaolinite, Ca-Montmorillonite, Montmorillonite K-10; and a range of surface area ratios (particle surface area to E. coli surface area). When comparing the two methods, the per cent attached obtained from the flow cytometry was lower, but not significantly different from the per cent attached obtained from the settling method for all conditions except when the particle was Hectorite or Montmorillonite K-10; when the strain was C; and when the surface area ratio was below 100. Differences between the methods are likely because traditional culture-based methods cannot detect the viable but nonculturable (VBNC) population, whereas flow cytometry can detect the fraction of VBNC with intact membranes. CONCLUSION: Our results indicate that flow cytometry is a rapid and culture-independent method for differentiating between attached and unattached micro-organisms. SIGNIFICANCE AND IMPACT OF THE STUDY: Flow cytometry is useful for laboratory-based studies of micro-organism-particle interactions. PMID- 25284439 TI - Green colorants based on energetic azole borates. AB - The investigation of green-burning boron-based compounds as colorants in pyrotechnic formulations as alternative for barium nitrate, which is a hazard to health and to the environment, is reported. Metal-free and nitrogen-rich dihydrobis(5-aminotetrazolyl)borate salts and dihydrobis(1,3,4-triazolyl)borate salts have been synthesized and characterized by NMR spectroscopy, elemental analysis, mass spectrometry, and vibrational spectroscopy. Their thermal and energetic properties have been determined as well. Several pyrotechnic compositions using selected azolyl borate salts as green colorants were investigated. Formulations with ammonium dinitramide and ammonium nitrate as oxidizers and boron and magnesium as fuels were tested. The burn time, dominant wavelength, spectral purity, luminous intensity, and luminous efficiency as well as the thermal and energetic properties of these compositions were measured. PMID- 25284440 TI - Prenatal diagnosis of osteopathia striata with cranial sclerosis. PMID- 25284441 TI - Development of virtual platelets implementing the functions of three platelet membrane proteins with different adhesive characteristics. AB - AIM: Computer simulation is a new method for understanding biological phenomena. In this report, we developed a simple platelet simulator representing platelet adhesion under blood flow conditions. METHODS: We generated virtual platelets based on the functions of three key adhesive proteins: glycoprotein (GP) Ibalpha, GPIIb/IIIa and collagen receptors. The adhesive force between GPIbalpha and von Willebrand factor (VWF) was set to increase in association with increments in the fluid shear stress. GPIIb/IIIa acquires an adhesive force to bind with ligands only when platelets are activated following multiple GPIbalpha stimulation by VWF or collagen receptors. RESULTS: Upon perfusion over the area of virtual endothelial injury, the virtual platelets adhered and became activated to form platelet thrombi. A total of 286/mm(2) of activated platelets was found to have accumulated downstream of the flow obstacle within 30 seconds, with 59/mm(2) platelets adhering upstream. The results obtained with the virtual model were consistent with those for real platelets in human blood in the presence of similarly shaped flow obstacles. CONCLUSIONS: Our computer platelet simulator, which employs the functions of three key platelet membrane proteins, shows similar findings for adhesion in the presence and absence of blood flow obstacles. PMID- 25284442 TI - Environmental policy constraints for acidic exhaust gas scrubber discharges from ships. AB - Increasingly stringent environmental legislation on sulphur oxide emissions from the combustion of fossil fuels onboard ships (International Maritime Organization (IMO) Regulation 14) can be met by either refining the fuel to reduce sulphur content or by scrubbing the exhaust gases. Commonly used open loop marine scrubbers discharge warm acidic exhaust gas wash water into the sea, depressing its pH. The focus on this paper is on the physics and chemistry behind the disposal of acidic discharges in seawater. The IMO Marine Environment Protection Committee (MEPC 59/24/Add.1 Annex 9) requires the wash water to reach a pH greater than 6.5 at a distance of 4m from the point of discharge. We examine the engineering constraints, specifically size and number of ports, to identify the challenges of meeting regulatory compliance. PMID- 25284443 TI - An analysis of organic matter sources for surface sediments in the central South Yellow Sea, China: evidence based on macroelements and n-alkanes. AB - By analyzing the composition of n-alkane and macroelements in the surface sediments of the central South Yellow Sea of China, we evaluated the influencing factors on the distribution of organic matter. The analysis indicates that the distribution of total organic carbon (TOC) was low in the west and high in the east, and TOC was more related to Al2O3 content than medium diameter (MD). The composition of n-alkanes indicated the organic matter was mainly derived from terrestrial higher plants. Contributions from herbaceous plants and woody plants were comparable. The comprehensive analysis of the parameters of macroelements and n-alkanes showed the terrestrial organic matter in the central South Yellow Sea was mainly from the input of the modern Yellow River and old Yellow River. However, some samples exhibited evident input characteristics from petroleum sources, which changed the original n-alkanes of organic matter in sediments. PMID- 25284444 TI - Background values for evaluation of heavy metal contamination in sediments in the Parnaiba River Delta estuary, NE/Brazil. AB - This study establishes regional background levels and upper thresholds (geochemical baseline) for Zn, Cu, Pb, Cr, Mn, and Fe from surface samples and profiles taken in 16 sedimentary environments of the Parnaiba River Delta estuary, NE-Brazil. Three approaches were applied to evaluate metal contamination: normalization to Fe, statistical analysis and sediment quality guidelines or environmental assessment criteria (TEL-PEL). Metal concentrations in sediments ranged from 2.4 to 31 mg Zn kg(-1), 1.5 to 48 mg Cu kg(-1), 1.3 to 28 mg Pb kg(-1), 1.5 to 38 mg Cr kg(-1); 145 to 1,356 mg Mn kg(-1), and 0.3% to 2.5% for Fe. All metals showed positive correlations with the <0.63 MUm sediment fraction, indicating a significant association with rich lithogenic sources of iron oxide-hydroxides. Results suggest a low probability of adverse effects to the local aquatic biota. The background values of the area were lower than those reported for other areas of the northeastern coast of Brazil. PMID- 25284445 TI - Stabilization of liquid foams through the synergistic action of particles and an immiscible liquid. AB - Liquid foams are familiar from beer, frothed milk, or bubble baths; foams in general also play important roles in oil recovery, lightweight packaging, and insulation. Here a new class of foams is reported, obtained by frothing a suspension of colloidal particles in the presence of a small amount of an immiscible secondary liquid. A unique aspect of these foams, termed capillary foams, is the particle-mediated spreading of the minority liquid around the gas bubbles. The resulting mixed particle/liquid coating can stabilize bubbles against coalescence even when the particles alone cannot. The coated bubbles are further immobilized by entrapment in a network of excess particles connected by bridges of the minority liquid. Capillary foams were prepared with a diverse set of particle/liquid combinations to demonstrate the generality of the phenomenon. The observed foam stability correlates with the particle affinity for the liquid interface formed by spreading the minority liquid at the bubble surface. PMID- 25284446 TI - Incremental cost-effectiveness of percutaneous versus surgical closure of atrial septal defects in children under a public health system perspective in Brazil. AB - INTRODUCTION: Cost-effectiveness (CE) studies of percutaneous (PC) versus surgical (SC) atrial septal defect closure are lacking. METHODS: A systematic literature review in children and a CE analysis based on a model of long-term outcomes were performed. Direct costs of PC and SC were US$8700 (defined arbitrarily) and US$5700 (actually paid), respectively. Three-times the Brazilian GDI (US$28,700) per year of life saved (with a discount rate of 5%) was used as a limit for willingness-to-pay. DISCUSSION: PC had a high (US$104,500) incremental CE ratio despite lower complication rates, shorter hospital stay and better (nonsignificant) adjusted life expectancy. PC would be cost-effective if it cost US$6400 or SC had an 8% loss of utility or its indirect costs were US$2250. Costs of PC should be reduced to be cost-effective in the Brazilian public health system. Indirect costs and impact on quality of life should be further assessed. PMID- 25284447 TI - Laryngeal tuberculosis: a diagnosis not to be overlooked. PMID- 25284449 TI - Computational cogitation of Cn@Al12 clusters. AB - A variety of novel Cn Al12 core-shell nanoclusters have been investigated using density functional calculations. A series of Cn cores (n=1-4) have been encapsulated by icosahedral Al12 , with characteristic physical properties (energetics and stabilities, ionisation energies, electron affinities) calculated for each cluster. Other isomers, with the Cn moiety bound externally to the Al12 shell, have also been studied. For both series, a peak in stability was found for n(C)=2, a characteristic that appears to be inextricably linked with the relaxation of the constituent parts upon dissociation. Analysis of trends for ionisation energies and electron affinities includes evaluation of contributions from the carbon and aluminium components, which highlights the effects of composition and morphology on cluster properties. PMID- 25284448 TI - New considerations on hormetic response against oxidative stress. AB - In order to survive living organisms have developed multiple mechanisms to deal with tough environmental conditions. Hormesis is defined as a process in which exposure to a low dose of a chemical agent or environmental factor that is damaging at higher doses induces an adaptive beneficial effect on the cell or organism. In this paper, we examine several ideas that might be taken into consideration before using hormesis as a therapeutic tool to improve health and life span, and hopefully will open the discussion for new and interesting debates regard hormesis. The first one is to understand that the same stressor or inductor can activate different pathways in a parallel or dual response, which might lead to diverse outcomes. Another idea is related to the mechanisms involved in activating Nrf2, which might be different and have diverse hormetic effects.Last, we discuss mild oxidative stress in association to low-grade chronic inflammation as a stimulating avenue to be explored and the unexpected effects proposed by the obesity paradox theory. All the previous might help to clarify the reasons why centenarians are able to reach the extreme limits of human life span, which could probably be related to the way they deal with homeostasis maintenance, providing an opportunity for hormesis to intervene significantly. PMID- 25284450 TI - Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: the Rotterdam Study. AB - Some studies suggest a favorable role of antioxidants on breast cancer risk but this is still inconclusive. The aim of this study was to assess whether overall dietary antioxidant capacity, as assessed by dietary ferric reducing antioxidant potential (FRAP), and individual dietary antioxidant intake were associated with breast cancer risk. Data was used from women participating in the Rotterdam Study, a prospective cohort study among subjects aged 55 years and older (N = 3,209). FRAP scores and antioxidant intake (i.e., vitamin A, C, E, selenium, flavonoids and carotenoids) was assessed at baseline by a food frequency questionnaire. Incident cases of breast cancer were confirmed through medical reports. During a median follow-up of 17 years, 199 cases with breast cancer were identified. High dietary FRAP score was associated with a lower risk of breast cancer [hazard ratio (HR): 0.68; 95% confidence intervals (CI): 0.49, 0.96]. No overall association between individual antioxidant intake and breast cancer risk was found. However, low intake of alpha carotene and beta carotene was associated with a higher risk of breast cancer among smokers (HR: 2.48; 95% CI: 1.21, 5.12 and HR: 2.31; 95% CI: 1.12, 4.76 for alpha and beta carotene, respectively) and low intake of flavonoids was associated with breast cancer risk in women over the age of 70 (HR: 1.80; 95% CI: 1.09, 2.99). These results suggest that high overall dietary antioxidant capacity is associated with a lower risk of breast cancer. Individual effects of dietary carotenoids and dietary flavonoids may be restricted to subgroups such as smokers and elderly. PMID- 25284453 TI - Anaesthetic digital block with epinephrine vs. tourniquet in ingrown toenail surgery: a clinical trial on efficacy. AB - BACKGROUND: Current evidence shows that anaesthetic digital block with epinephrine is safe in surgical selected patients. There are no controlled studies that have examined the efficacy of local anaesthesia with vasoconstrictor in chemical matricectomy without using tourniquet to control bleeding. OBJECTIVES: A controlled, prospective and randomized study was conducted to examine primarily the rate of recurrence after segmental phenolization matricectomy with anaesthetic digital block with epinephrine vs. tourniquet. As secondary aims, duration of anaesthetic effect, post-operative bleeding and pain were analysed in both groups. METHODS: Forty-four healthy subjects with ingrown hallux nails (70 toes) were enrolled. A total of 34 toes were anaesthetized with a solution of 2% mepivacaine with (1 : 100,000) epinephrine and operated without tourniquet (experimental group) vs. 36 toes anesthetized with a solution of 2% mepivacaine without epinephrine and operated with tourniquet (control group). RESULTS: There was no statistically significant difference in recurrence rates (P = 0.478). Post-operative bleeding was significantly higher in the group with anaesthetic digital block without vasoconstrictor and with tourniquet (P = 0.001). Anaesthetic effect was higher in the group with anaesthetic digital block with vasoconstrictor and without tourniquet (P = 0.001). No post-operative complications occurred in any of the treatment groups. CONCLUSIONS: The use of local anaesthetic with vasoconstrictor to perform chemical matricectomy likely to be an effective procedure to reduce the disadvantages of using digital tourniquet (post-operative bleeding and lower anaesthetic effect) without increasing the risk of recurrence. The addition of epinephrine may reduce the need for a tourniquet and produce better and longer perioperative pain control. PMID- 25284455 TI - A postal screener for pain and need for treatment in older persons in primary care. AB - OBJECTIVES: To test the Pain intensity, Enjoyment in life, General activity questionnaire (PEG) as a postal screener for pain in older persons. DESIGN: Population-based survey. Postal screening questionnaires followed by an interview of a sample of participants. SETTING: Family practices. PARTICIPANTS: Persons aged 75 and older (N = 243; 95 interviewed). MEASUREMENTS: Screening included the PEG, a three-item abbreviated version of the Brief Pain Inventory (BPI), plus an additional question on treatment need. Pain severity and related interference was assessed (BPI) during the interview, as was the current (need for) pain treatment. RESULTS: The median PEG score of the 243 persons participating in the screening (response 76%) was 2.0 (interquartile range 0-4.7). Seventy-nine (35%) had moderate to severe pain (PEG score >= 4), of whom 56% reported current pain treatment and 15% stated that they might ask for help. For a PEG score cutoff of 4 or greater, sensitivity was 0.81 and specificity was 0.78 to find scores of 4 or greater on one or both BPI subscales during the interview. For the question on need for treatment, replies on the screener and the interview were not always consistent. Of the 43 interviewed participants with a PEG score of 4 or greater, 60% received treatment. Of the 17 without current pain treatment, 10 still reported pain, three of whom said that they might ask for help. CONCLUSION: The PEG can be used as a postal screener to detect the presence of pain in older persons, but treatment needs cannot be established using the PEG alone or in combination with a simple additional question. PMID- 25284454 TI - Genetic analysis and clinical picture of severe congenital neutropenia in Israel. AB - BACKGROUND: The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN. PROCEDURES: Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype. RESULTS: Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation. CONCLUSIONS: We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS. PMID- 25284456 TI - Multistimuli-responsive supramolecular assembly of cucurbituril/cyclodextrin pairs with an azobenzene-containing bispyridinium guest. AB - A linear supramolecular architecture was successfully constructed by the inclusion complexation of alpha-cyclodextrin with azobenzene and the host stabilized charge-transfer interaction of naphthalene and a bispyridinium guest with cucurbit[8]uril in water, which was comprehensively characterized by (1)H NMR spectroscopy, UV/Vis absorption, fluorescence, circular dichroism spectroscopy, dynamic laser scattering, and microscopic observations. Significantly, because it benefits from the photoinduced isomerization of the azophenyl group and the chemical reduction of bispyridinium moiety with noncovalent connections, the assembly/disassembly process of this supramolecular nanostructure can be efficiently modulated by external stimuli, including temperature, UV and visible-light irradiation, and chemical redox. PMID- 25284458 TI - Hypotonic male infant and MCT8 deficiency - a diagnosis to think about. AB - BACKGROUND: Thyroid hormone is crucial in the development of different organs, particularly the brain. MCT8 is a specific transporter of triiodothyronine (T3) hormone and MCT8 gene mutations cause a rare X-linked disorder named MCT8 deficiency, also known as Allan-Herndon-Dudley syndrome, characterized by psychomotor retardation and hypotonia. Typically, elevation of T3 and delayed myelination in cerebral magnetic resonance imaging are found. CASE PRESENTATION: We present a 24-month-old boy, born from non-consanguineous healthy parents, with severe motor and cognitive delay and global hypotonia, being unable to hold head upright or sit without support. Deep tendon reflexes were absent bilaterally at the ankles. T3 was elevated and thyroxine slightly decreased, consistent with MCT8 deficiency. Genetic studies confirmed the diagnosis. CONCLUSIONS: Although a rare disease (MCT8 mutations have been reported in about 50 families all around the world), we illustrate the importance of excluding Allan-Herndon-Dudley syndrome in the evaluation of floppy male infants with development delay, without history of perinatal asphyxia. The simple evaluation of thyroid status, including T3, T4 and TSH can guide the diagnosis, avoiding a number of useless, expensive and invasive investigations and allowing appropriate genetic counseling to the affected families. PMID- 25284457 TI - Emerging role of HMGB1 in fibrotic diseases. AB - High-mobility group box 1 (HMGB1) is originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be passively released from necrotic cells or actively secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 is a multifunctional cytokine that contributes to the process of infection, injury, inflammation, apoptosis, and immune responses by binding to specific cell-surface receptors. Recently, emerging studies indicate that HMGB1 is closely involved in fibrotic disorders including cystic fibrosis, liver fibrosis and pulmonary fibrosis, while HMGB1 signal inhibitions protect against the experimental models of fibrotic diseases. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses. This review focuses on the crucial role of HMGB1 in the pathogenesis of fibrotic diseases and inhibition of which may represent a promising clinical approach for treating tissue fibrosis. PMID- 25284459 TI - Genomic prediction based on runs of homozygosity. AB - BACKGROUND: Genomic prediction is based on the accurate estimation of the genomic relationships among and between training animals and selection candidates in order to obtain accurate estimates of the genomic estimated breeding values (GEBV). Various methods have been used to predict GEBV based on population-wide linkage disequilibrium relationships (G IBS ) or sometimes on linkage analysis relationships (G LA ). Here, we propose a novel method to predict GEBV based on a genomic relationship matrix using runs of homozygosity (G ROH ). Runs of homozygosity were used to derive probabilities of multi-locus identity by descent chromosome segments. The accuracy and bias of the prediction of GEBV using G ROH were compared to those using G IBS and G LA . Comparisons were performed using simulated datasets derived from a random pedigree and a real pedigree of Italian Brown Swiss bulls. The comparison of accuracies of GEBV was also performed on data from 1086 Italian Brown Swiss dairy cattle. RESULTS: Simulations with various thresholds of minor allele frequency for markers and quantitative trait loci showed that G ROH achieved consistently more accurate GEBV (0 to 4% points higher) than G IBS and G LA . The bias of GEBV prediction for simulated data was higher based on the real pedigree than based on a random pedigree. In the analyses with real data, G ROH and G LA had similar accuracies. However, G LA achieved a higher accuracy when the prediction was done on the youngest animals. The G IBS matrices calculated with and without standardized marker genotypes resulted in similar accuracies. CONCLUSIONS: The present study proposes G ROH as a novel method to estimate genomic relationship matrices and predict GEBV based on runs of homozygosity and shows that it can result in higher or similar accuracies of GEBV prediction than G LA , except for the real data analysis with validation of young animals. Compared to G IBS , G ROH resulted in more accurate GEBV predictions. PMID- 25284460 TI - Effectiveness of Behavior Change Communications for Reducing Transmission Risks Among People Living with HIV in 6 Countries in Central America. AB - This first region-wide study (N = 2,818) aims to estimate prevalence of HIV related risks (sexual behavior, HIV disclosure, number of sex partners, violence) and factors associated with these risks as well as evaluate a behavior change communications program targeted to PLHIV in 6 countries in Central America. After 2 years, the program achieved moderate coverage, with 21 % of the sample reporting exposure to interpersonal communications (IPC) and 52 % to mass media program components. The odds of condom use, HIV disclosure, and participation in a self-help group increased by 1.4-1.8 times with exposure to mass media. Exposure to IPC increased odds of condom use by 2.7 and participation in self help groups by 4.4 times. In addition, being in HIV care or taking ART was associated with condom use and HIV-status disclosure. About 30 % experienced physical or sexual violence, and those who did were 4 times less likely to use condoms. Findings suggest that behavioral interventions for PLHIV can reduce HIV transmission risks and increase access to care. PMID- 25284461 TI - Total synthesis of (-)-haouamine B pentaacetate and structural revision of haouamine B. AB - The enantiocontrolled total synthesis of (-)-haouamine B pentaacetate was accomplished via an optically active indane-fused beta-lactam, which was prepared by a newly developed Friedel-Crafts reaction. Subsequent cleavage of the beta lactam and an intramolecular McMurry coupling reaction provided the core indane fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zubia. PMID- 25284462 TI - NMR-based structural biology enhanced by dynamic nuclear polarization at high magnetic field. AB - Dynamic nuclear polarization (DNP) has become a powerful method to enhance spectroscopic sensitivity in the context of magnetic resonance imaging and nuclear magnetic resonance spectroscopy. We show that, compared to DNP at lower field (400 MHz/263 GHz), high field DNP (800 MHz/527 GHz) can significantly enhance spectral resolution and allows exploitation of the paramagnetic relaxation properties of DNP polarizing agents as direct structural probes under magic angle spinning conditions. Applied to a membrane-embedded K(+) channel, this approach allowed us to refine the membrane-embedded channel structure and revealed conformational substates that are present during two different stages of the channel gating cycle. High-field DNP thus offers atomic insight into the role of molecular plasticity during the course of biomolecular function in a complex cellular environment. PMID- 25284463 TI - Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study. AB - Cataract was prospectively assessed by serial slip lamp tests in 271 patients included in the Leucemie Enfants Adolescents (LEA) programme, the French cohort of childhood leukaemia survivors. All had received haematopoietic stem cell transplantation (HSCT) after total body irradiation (TBI, n = 201) or busulfan based (n = 70) myeloablative conditioning regimen. TBI was fractionated in all but six patients. The mean duration of follow-up from HSCT was 10.3 years. Cataract was observed in 113/271 patients (41.7%); 9/113 (8.1%) needed surgery. Cumulative incidence after TBI increased over time from 30% at 5 years to 70.8% and 78% at 15 and 20 years, respectively, without any plateau thereafter. The 15 year cumulative incidence was 12.5% in the Busulfan group. A higher cumulative steroid dose appeared to be a cofactor of TBI for cataract risk, in both univariate and multivariate Cox analysis. In the multivariate analysis, cataract had an impact in two quality of life domains: 'the role limitation due to physical problems' and 'the role limitation due to emotional problems'. These data suggest that with increasing follow-up, nearly all patients who receive TBI, even when fractionated, will suffer from cataract that can impact on their quality of life and that high cumulative steroid dose is a cofactor. PMID- 25284465 TI - Involvement of the sodium-calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity. AB - Ziram is a dimethyldithiocarbamate fungicide which can cause intraneuronal calcium (Ca(2+)) dysregulation and subsequently neuronal death. The signaling mechanisms underlying ziram-induced Ca(2+) dyshomeostasis and neurotoxicity are not fully understood. NCX3 is the third isoform of the sodium-calcium exchanger (NCX) family and plays an important role in regulating Ca(2+) homeostasis in excitable cells. We previously generated a mouse model deficient for the sodium calcium exchanger 3 and showed that NCX3 is protective against ischemic damage. In the present study, we aim to examine whether NCX3 exerts a similar role against toxicological injury caused by the pesticide ziram. Our data show baby hamster kidney (BHK) cells stably transfected with NCX3 (BHK-NCX3) are more susceptible to ziram toxicity than cells transfected with the empty vector (BHK WT). Increased toxicity in BHK-NCX3 was associated with a rapid rise in cytosolic Ca(2+) concentration [Ca(2+)]i induced by ziram. Profound mitochondrial dysfunction and ATP depletion were also observed in BHK-NCX3 cells following treatment with ziram. Lastly, primary dopaminergic neurons lacking NCX3 (NCX3(-/ )) were less sensitive to ziram neurotoxicity than wildtype control dopaminergic neurons. These results demonstrate that NCX3 genetic deletion protects against ziram-induced neurotoxicity and suggest NCX3 and its downstream molecular pathways as key factors involved in ziram toxicity. Our study identifies new molecular events through which pesticides (e.g. ziram) can lead to pathological features of degenerative diseases such as Parkinson's disease and indicates new targets to slow down neuronal degeneration. PMID- 25284467 TI - [Pathologic-anatomic and morphometric examinations on the heart in feral cockatoos]. AB - OBJECTIVE: To evaluate the heart of free-living psittacine birds macroscopically and morphologically, and to compare the results to findings published for psittacine birds living in captivity to obtain information on the influence of bird keeping in a human environment on the psittacine heart. MATERIAL AND METHODS: In total, 84 wild-living cockatoos were examined, including 50 sulphur crested cockatoos (Cacatua galerita), 31 galahs (Eolophus roseicapilla) and three long-billed corellas (Cacatua tenuirostris). The birds were euthanized because of a local cockatoo control program in Australia, and were examined pathologically within 8 hours of euthanasia. A macroscopic necropsy was performed, and the heart was assessed morphologically. Furthermore, a histological organ screening was conducted. RESULTS: The birds demonstrated good body condition and excellent muscle condition. Except for some paleness of the heart muscle, none of the animals showed any pathological alteration of the heart or large vessels. The mean heart mass was 8.7 g for the sulphur-crested cockatoos, 5.3 g for the galahs and 8.6 g for the long-billed corellas. Independent of the species examined, a highly significant correlation was found between the heart and body masses (r = 0.91; p < 0.001), which was also confirmed as significant within the sulphur crested cockatoo (r = 0.59; p < 0.001) and galah groups (r = 0.52; p = 0.003). This correlation can be used to calculate the expected heart mass based on the body mass, using the formula: heart mass (g) = 2.9 + 0.01 x body mass (g). In comparison to reports on Australian parakeets, the relative thickness of the heart muscle wall of the left ventricle found in this study was greater. CONCLUSION: In comparison to psittacine birds kept in captivity, wild-living cockatoos have good body condition and rarely suffer from macroscopically detectable diseases of the heart or large vessels. The cardiac fitness level is superior in comparison to that found in healthy appearing psittacine birds kept in captivity. CLINICAL RELEVANCE: The results can serve as a basis for the assessment of the heart in psittacine birds, because in contrast to earlier reports, the heart of healthy psittacine birds not previously exposed to any human influence could be assessed. PMID- 25284468 TI - Occlusion on oral implants: current clinical guidelines. AB - Proper implant occlusion is essential for adequate oral function and the prevention of adverse consequences, such as implant overloading. Dental implants are thought to be more prone to occlusal overloading than natural teeth because of the loss of the periodontal ligament, which provides shock absorption and periodontal mechanoreceptors, which provide tactile sensitivity and proprioceptive motion feedback. Although many guidelines and theories on implant occlusion have been proposed, few have provided strong supportive evidence. Thus, we performed a narrative literature review to ascertain the influence of implant occlusion on the occurrence of complications of implant treatment and discuss the clinical considerations focused on the overloading factors at present. The search terms were 'dental implant', 'dental implantation', 'dental occlusion' and 'dental prosthesis'. The inclusion criteria were literature published in English up to September 2013. Randomised controlled trials (RCTs), prospective cohort studies and case-control studies with at least 20 cases and 12 months follow-up interval were included. Based on the selected literature, this review explores factors related to the implant prosthesis (cantilever, crown/implant ratio, premature contact, occlusal scheme, implant-abutment connection, splinting implants and tooth-implant connection) and other considerations, such as the number, diameter, length and angulation of implants. Over 700 abstracts were reviewed, from which more than 30 manuscripts were included. We found insufficient evidence to establish firm clinical guidelines for implant occlusion. To discuss the ideal occlusion for implants, further well-designed RCTs are required in the future. PMID- 25284464 TI - MEK inhibition prevents tumour-shed transforming growth factor-beta-induced T regulatory cell augmentation in tumour milieu. AB - Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+) CD25(+) FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-beta (TGF-beta) production in tumour cells that essentially blocked TGF-beta-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor alpha on CD4(+) T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-beta-induced Treg cell augmentation. PMID- 25284469 TI - ISVI-IUA consensus document diagnostic guidelines of vascular anomalies: vascular malformations and hemangiomas. PMID- 25284466 TI - Refinement of schizophrenia GWAS loci using methylome-wide association data. AB - Recent genome-wide association studies (GWAS) have made substantial progress in identifying disease loci. The next logical step is to design functional experiments to identify disease mechanisms. This step, however, is often hampered by the large size of loci identified in GWAS that is caused by linkage disequilibrium between SNPs. In this study, we demonstrate how integrating methylome-wide association study (MWAS) results with GWAS findings can narrow down the location for a subset of the putative casual sites. We use the disease schizophrenia as an example. To handle "data analytic" variation, we first combined our MWAS results with two GWAS meta-analyses (N = 32,143 and 21,953), that had largely overlapping samples but different data analysis pipelines, separately. Permutation tests showed significant overlapping association signals between GWAS and MWAS findings. This significant overlap justified prioritizing loci based on the concordance principle. To further ensure that the methylation signal was not driven by chance, we successfully replicated the top three methylation findings near genes SDCCAG8, CREB1 and ATXN7 in an independent sample using targeted pyrosequencing. In contrast to the SNPs in the selected region, the methylation sites were largely uncorrelated explaining why the methylation signals implicated much smaller regions (median size 78 bp). The refined loci showed considerable enrichment of genomic elements of possible functional importance and suggested specific hypotheses about schizophrenia etiology. Several hypotheses involved possible variation in transcription factor-binding efficiencies. PMID- 25284470 TI - Hyperbilirubinemia, hemolysis, and increased bilirubin neurotoxicity. AB - Increased hemolysis in the presence of severe neonatal hyperbilirubinemia appears to augment the risk of bilirubin neurotoxicity. The mechanism of this intensifying effect is uncertain. In direct antiglobulin titer (DAT) positive, isoimmune hemolytic disease, the bilirubin threshold at which neurotoxicity occurs appears to be lower than in DAT-negative hyperbilirubinemia. In other hemolytic conditions, the hemolysis may simply facilitate the development of extremely high serum bilirubin levels. Whether the hemolytic process per se exerts an independent effect or whether a very rapid rise in serum bilirubin might lead to greater penetration of the blood-brain barrier is unclear. In this review, we survey the synergistic role of hemolysis associated with severe hyperbilirubinemia in the potentiation of bilirubin-induced neurotoxicity and suggest methods of identifying at-risk babies with increased hemolysis to allow for their increased surveillance. PMID- 25284471 TI - Visuospatial working memory for locations, colours, and binding in typically developing children and in children with dyslexia and non-verbal learning disability. AB - This study examined forward and backward recall of locations and colours and the binding of locations and colours, comparing typically developing children - aged between 8 and 10 years - with two different groups of children of the same age with learning disabilities (dyslexia in one group, non-verbal learning disability [NLD] in the other). Results showed that groups with learning disabilities had different visuospatial working memory problems and that children with NLD had particular difficulties in the backward recall of locations. The differences between the groups disappeared, however, when locations and colours were bound together. It was concluded that specific processes may be involved in children in the binding and backward recall of different types of information, as they are not simply the resultant of combining the single processes needed to recall single features. PMID- 25284472 TI - The aerosol assisted chemical vapour deposition of SnSe and Cu2SnSe3 thin films from molecular precursors. AB - Tin selenide (SnSe) and copper tin selenide (Cu2SnSe3) thin films have been deposited onto glass substrates by AACVD using [Sn(Ph2PSe2)2] or a mixture of [Sn(Ph2PSe2)2] and [Cu(acac)2] respectively. PMID- 25284473 TI - The digit ratio (2D:4D) in China: A meta-analysis. AB - OBJECTIVES: To explore the 2D:4D in China (mainland and Taiwan) and to analyze the influences of ethnicity, digit measurement methods, age, and latitude on Chinese 2D:4D. METHODS: We here conducted a meta-analysis of the results of 28 studies. A total of 112 independent samples and 19,093 participants were included. RESULTS: The sex difference in left 2D:4D only approached significance when outliers were removed (P = 0.078), whereas the right 2D:4D was significantly lower in males compared to females, showing that the magnitude of sex difference was greater for the right hand than for the left hand. No significant differences were found in the 2D:4D between Han and ethnic minorities. The 2D:4D of samples measured using indirect digit measurement tended to be lower than in samples measured using direct digit measurement. Moreover, there were no effects of age and latitude on the 2D:4D in China. CONCLUSIONS: We concluded that the sex differences in Chinese 2D:4D are consistent with the results from western studies, and that genetic pool differences rather than latitude-related environmental variables affect the 2D:4D in China. In addition, 2D:4D measurements obtained by different digit measurement techniques should not be combined within one study, or used together in comparative studies. PMID- 25284474 TI - Salvadenosine, a 5'-deoxy-5'-(methylthio) nucleoside from the Bahamian tunicate Didemnum sp. AB - Salvadenosine, (1) a rare 5'-deoxy-5'-(methylthio) nucleoside, was isolated from the deep-water Bahaman tunicate Didemnum sp. The structure was solved by integrated analysis of MS and 1D and 2D NMR data. We revise the structure of the known natural product, hamiguanosinol, which is a constitutional isomer of 1, to 5 by interpretation of the spectroscopic data and comparison with synthesized nucleosides. PMID- 25284475 TI - Ellagic acid, a component of pomegranate fruit juice, suppresses androgen dependent prostate carcinogenesis via induction of apoptosis. AB - BACKGROUND: Ellagic acid (EA), a component of pomegranate fruit juice (PFJ), is a plant-derived polyphenol and has antioxidant properties. PFJ and EA have been reported to suppress various cancers, including prostate cancer. However, their chemopreventive effects on development and progression of prostate cancer using in vivo models have not been established yet. METHODS: The transgenic rat for adenocarcinoma of prostate (TRAP) model was used to investigate the modulating effects of PFJ and EA on prostate carcinogenesis. Three-week-old male transgenic rats were treated with EA or PFJ for 10 weeks. In vitro assays for cell growth, apoptosis, and Western blot were performed using the human prostate cancer cell lines, LNCaP (androgen-dependent), PC-3 and DU145 (androgen-independent). RESULTS: PFJ decreased the incidence of adenocarcinoma in lateral prostate, and both EA and PFJ suppressed the progression of prostate carcinogenesis and induced apoptosis by caspase 3 activation in the TRAP model. In addition, the level of lipid peroxidation in ventral prostate was significantly decreased by EA treatment. EA was able to inhibit cell proliferation of LNCaP, whereas this effect was not observed in PC-3 and DU145. As with the in vivo data, EA induced apoptosis in LNCaP by increasing Bax/Bcl-2 ratio and caspase 3 activation. Cell cycle related proteins, p21(WAF) , p27(Kip) , cdk2, and cyclin E, were increased while cyclin D1 and cdk1 were decreased by EA treatment. CONCLUSIONS: The results indicate that PFJ and EA are potential chemopreventive agents for prostate cancer, and EA may be the active component of PFJ that exerts these anti-cancer effects. PMID- 25284476 TI - Ten years later. PMID- 25284479 TI - Fibrin as a delivery system in wound healing tissue engineering applications. AB - Fibrin is formed in the body upon initiation of the clotting cascade and is produced commercially for use as a tissue sealant and hemostasis device during surgical procedures. Experimentally fibrin is being increasingly used as a vector to deliver growth factors, cells, drugs and genes in tissue engineering applications mimicking aspects of the extra cellular matrix. Growth factors (GFs) are central to wound healing, inducing cell proliferation, migration and differentiation. Attempts have been made to augment wound healing with GFs, however widespread clinical use has been hindered in vivo due to their rapid metabolism within the body. Fibrin hydrogels protect GFs from rapid degradation and the composition of which can be altered to achieve their optimal release. This article reviews the use of fibrin for the delivery of GFs and details the various strategies that have evolved to alter the release rate so as to enhance the regenerative process, including bi-domain peptides, plasmin degradation sequences and heparin incorporation. This paper also reviews other recent advances in this field, such as dual delivery of cells and GF or sequential release of multiple GF. PMID- 25284481 TI - IRF5rs2004640 single nucleotide polymorphism is associated with susceptibility to rheumatoid arthritis in South Indian Tamils. AB - Polymorphism of interferon regulatory factor 5 (IRF5), a latent transcription factor gene has been associated with various auto-immune diseases. Our aim was to study the IRF5rs2004640 gene polymorphism and its association with disease susceptibility, disease phenotype and treatment response in South Indian Tamil patients with rheumatoid arthritis (RA).The study was conducted on 217 RA patients fulfilling the American College of Rheumatology (ACR) 2010 criteria and 482 healthy controls (HCs) without family history of autoimmune disease. The IRF5rs2004640 genotyping was performed using a TaqMan 5' allelic discrimination assay. We found that the IRF5rs2004640T allele [P < 0.0001, odds ratio (OR) 3.25, 95% confidence interval (CI) 2.55-4.12] and TT genotype (P < 0.0001, OR 4.60, 95% CI 3.23-6.57) were significantly more frequent in RA patients as compared with HCs. No association was found between IRF5rs2004640 polymorphism, clinical manifestations, autoantibody profile and treatment response. IRF5rs2004640 T (mutant) allele may be a susceptibility factor conferring risk for RA in South Indian Tamils, whereas G allele (wild type) may be protective. PMID- 25284480 TI - Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. AB - PIK3R1 (p85alpha regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1(R348*) and a nearby mutation PIK3R1(L370fs), in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors in vitro and in vivo. Consistent with the response to inhibitors, PIK3R1(R348*) and PIK3R1(L370fs) unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85alpha R348(*) and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1(R348*) and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors. PMID- 25284482 TI - Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news? AB - Originally studied in lymphoid diseases, cladribine (CdA) is an adenosine deaminase resistant analog of adenosine that was later discovered to induce myeloid cell apoptosis. The activity of CdA in myeloid malignancies was first reported in relapsed/refractory (RR) pediatric acute myeloid leukemia (AML) with complete response (CR) rates of up to 47%. Consequently, several studies have confirmed the efficacy of single agent CdA or CdA combination regimens in AML. Established CR rates for combination regimens in RR adults are approximately 50%, while CR rates for newly diagnosed (ND) adults are approximately 70% and show similar toxicity profiles to previously used regimens. Despite these promising data, many centers have yet to adopt CdA combination regimens for these difficult to treat populations. We review the pharmacology, pharmacokinetics, clinical data, and safety of CdA monotherapy and combination regimens for the management of pediatric and adult ND and RR-AML. PMID- 25284483 TI - Validating a human immunodeficiency virus risk score. PMID- 25284484 TI - National specialty trends in billable diagnostic ultrasound in the ED: analysis of Medicare claims data. AB - OBJECTIVE: To assess recent national specialty trends in the use of diagnostic ultrasound (US) services in the Emergency Department (ED) setting. METHODS: We searched aggregated 1998-2012 Medicare Part B Master Files for ED diagnostic US studies, excluding cardiac and ophthalmic examinations. Studies were classified by body part and interpreting specialty. Subsequent analysis was performed for higher-volume services rendered by emergency physicians for which discrete codes were present longitudinally for complete vs limited examinations. National trends were analyzed. RESULTS: From 1998 to 2012, paid ED US studies interpreted by radiologists, emergency physicians, and all other physicians increased by 332% (from 221,712 to 735,858 examinations), 4454% (from 561 to 24,992), and 251% (from 26,961 to 67,787), respectively. The fraction of ED US examinations interpreted remained around 90% for radiologists, increased from 0.2% to 3% for emergency physicians, and decreased from 11% to 8% for other physicians. The fraction of complete abdominal and complete retroperitoneal studies interpreted by emergency physicians remained less than 1% from 1998 through 2012. However, emergency physicians experienced disproportionate growth in limited examinations (from 1% to 9% for abdominal studies and from <1% to 20% for retroperitoneal studies). Likewise, the fraction of (typically targeted) chest studies interpreted by emergency physicians increased from less than 1% to 63%. CONCLUSION: From 1998 to 2012, there was substantial growth in ED US studies for Medicare beneficiaries interpreted by radiologists and emergency physicians alike. For more commonly performed services distinguishable as complete vs limited in nature, growth in services by emergency physicians was most dramatic for less complex services. PMID- 25284485 TI - Optic nerve sheath diameter and lumbar puncture opening pressure in nontrauma patients suspected of elevated intracranial pressure. AB - OBJECTIVE: The purpose of this study was to determine if patients with nontraumatic causes of elevated intracranial pressure (ICP) could be identified by ultrasound measurement of optic nerve sheath diameter (ONSD). It was hypothesized that an ONSD greater than or equal to 5 mm would identify patients with elevated ICP. METHOD: This was a prospective observational trial comparing ONSD with ICP measured by opening pressure manometry on lumbar puncture (LP). The cohort consisted of a convenience sample of adult patients presenting to the emergency department, requiring LP. The ONSD measurement was performed before computed tomography and LP. The physician performing the LP was blinded to the result of the ONSD measurement. An opening pressure on manometry of greater than or equal to 20 cm H2O and an ONSD greater than or equal to 5 mm were considered elevated. RESULTS: Fifty-one patients were included in our study, 24 (47%) with ICP greater than or equal to 20 cm H2O and 27 (53%) with ICP less than 20 cm H2O. The sensitivity of ONSD greater than or equal to 5 for identifying elevated ICP was 75% (95% confidence interval, 53%-90%) with specificity of 44% (25%-65%). The area under the receiver operator characteristic curve was 0.69 (0.54-0.84), suggesting a relationship between ONSD and ICP. CONCLUSION: An ONSD greater than or equal to 5 mm was associated with elevated ICP in nontraumatic causes of elevated ICP. Although a relationship exists, a sensitivity of 75% does not make ONSD measurement an adequate screening examination for elevated ICP in this patient population. PMID- 25284486 TI - Metabolite changes during the life history of Porphyra haitanensis. AB - Plant metabolomics is essentially the comprehensive analysis of complex metabolites of plant extracts. Metabolic fingerprinting is an important part of plant metabolomics research. In this study, metabolic fingerprinting of different stages of the life history of the red alga Porphyra haitanensis was performed. The stages included conchocelis filaments, sporangial branchlets, conchosporangia, discharged conchospores and conchosporangial branchlets after conchospore discharge. Metabolite extracts were analysed with ultra-performance liquid chromatography coupled with electrospray ionisation quadrupole-time of flight mass spectrometry. Analyses profiles were subjected to principal components analysis and orthogonal projection to latent structures discriminant analysis using the SIMCA-P software for biomarker selection and identification. Based on the MS/MS spectra and data from the literature, potential biomarkers, mainly of phosphatidylcholine and lysophosphatidylcholine, were identified. Identification of these biomarkers suggested that plasma membrane phospholipids underwent major changes during the life history of P. haitanensis. The levels of phosphatidylcholine and lysophosphatidylcholine increased in sporangial branchlets and decreased in discharged conchospores. Moreover, levels of sphingaine (d18:0) decreased in sporangial branchlets and increased in discharged conchospores, which indicates that membrane lipids were increasingly synthesised as energy storage in sporangial branchlets, while energy was consumed in sporangial branchlets to discharged conchospores. A metabolomic study of different growth phases of P. haitanensis will enhance our understanding of its physiology and ecology. PMID- 25284488 TI - Polyimido sulfur(VI) phosphanyl ligand in metal complexation. AB - Herein, new complexes containing the [Ph2PCH2S(NtBu)3](-) anion are presented, supplying three imido nitrogen atoms and a remote phosphorus atom as potential donor sites to main group and transition-metal cations. The lithiated complex [(tmeda)Li{(NtBu)3SCH2PPh2}] (1) is an excellent starting material in transmetalation reactions. Herein, the transition-metal complexes [M{(NtBu)3SCH2PPh2}2] (M=Mn (2), Ni (3), Zn (4)) were synthesized and structurally characterized. Their isotypical molecules show SN2 chelation and no employment of the adjacent phosphorus atom in coordination. The third pendent imido group is always twisted toward the vacant face of the tetrahedrally coordinated sulfur atom. PMID- 25284487 TI - Inflammatory dysregulation of blood monocytes in Parkinson's disease patients. AB - Despite extensive effort on studying inflammatory processes in the CNS of Parkinson's disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a "second hit". These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation. PMID- 25284489 TI - Therapy-related myelodysplastic syndrome/acute leukemia after multiple myeloma in the era of novel agents. AB - Survival for patients with multiple myeloma has increased. Both melphalan and lenalidomide are associated with subsequent development of myelodysplasia. We reviewed the cases of all patients with multiple myeloma who had subsequent development of myelodysplastic syndrome (MDS) or acute non-lymphoblastic leukemia (ANLL) during a 12-year period in three centers. Of 55 patients identified, two received only lenalidomide before myelodysplasia developed. The median time between the diagnoses of multiple myeloma and MDS/ANLL was 52.7 months. Median survival after the diagnosis of MDS or ANLL was 6.7 months. Treatment of MDS comprised allogeneic stem cell transplant in eight patients (median survival, 219 days; one patient alive at 624 days) and a hypomethylating agent in 21 patients (response of stable or better in five patients). Myelodysplasia remains a devastating complication of therapy for multiple myeloma, with short survival and poor response rates to available modalities. PMID- 25284490 TI - Health utilities in relation to treatment response and adverse events in relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. AB - New therapies for relapsing/refractory Hodgkin lymphoma (R/R HL) and R/R systemic anaplastic large-cell lymphoma (sALCL) have emerged. This study captured utility values for R/R HL and sALCL to support economic evaluation. Health state "vignettes" were developed describing states associated with R/R HL and sALCL: treatment response (complete or partial response), stable and progressive disease and treatment-related adverse events (B-symptoms, acute/chronic graft-versus-host disease [GVHD] and peripheral neuropathy). Vignettes were evaluated by members of the public in the UK, Australia, Taiwan, Thailand, South Korea, Brazil and Mexico using the time trade-off method. Mean utilities varied substantially. Complete response utility scores were UK: 0.906, Australia: 0.889, Taiwan: 0.597, Thailand: 0.728, South Korea: 0.827, Brazil: 0.764, Mexico: 0.728. Adverse events were associated with disutility: acute GVHD, lowest mean utility value: Thailand 0.124; highest value: Mexico 0.467. Societal evaluation of health states for R/R HL and sALCL revealed a marked perceived benefit of a treatment response. PMID- 25284491 TI - Combining MYC, BCL2 and TP53 gene and protein expression alterations improves risk stratification in diffuse large B-cell lymphoma. AB - Translocations affecting both MYC and BCL2 are associated with a poor prognosis in diffuse large B-cell lymphomas. We have examined genetic aberrations combined with analyses of protein expression of respective gene products. Fluorescence in situ hybridization (FISH) for translocations of BCL2 and MYC and del17p13 was performed. Immunohistochemistry analyses included BCL2, MYC and TP53 protein expression. Sixty-seven patients with high-risk DLBCL participating in a prospective multicenter study were included. Six patients with simultaneous translocations of BCL2 and MYC had impaired overall (OS) (p = 0.009) and progression-free survival (PFS) (p = 0.009). Six patients with high coexpression of MYC and BCL2 proteins also had impaired OS (p = 0.004) and PFS (p = 0.002). Combining these groups identified nine patients with impaired OS (p = 0.004) and PFS (p = 0.005). Sixteen patients had double-hit translocation or protein expression and/or del17p13 and/or high TP53. This combined endpoint was associated with impaired OS (p = 0.008) and PFS (p = 0.036), and identified 70% of all deaths. PMID- 25284492 TI - High-sensitivity flow cytometric analysis of mast cell clustering in systemic mastocytosis: a quantitative and statistical analysis. AB - We characterized recently identified event clusters in systemic mastocytosis (SM) by calculating the coefficient of variation (CV, %) of CD117 and side scatter (SSC), based on the mean fluorescence intensity of mast cells using flow cytometry. Seventy-five samples were from patients with SM and 124 samples from patients negative for SM (non-SM). Discrete cluster formation seen in 50 cases correlated with significantly lower CV for SSC (46.1% vs. 61.0%, p < 0.0001) and CD117 (64.5% vs. 80.5%, p < 0.0001) for SM vs. non-SM samples. A combined CVCD117 + SSC of < 125 showed a sensitivity of 80% and specificity of 80% for SM with PPV of 67% and NPV of 80%. Probability scores of having SM, generated based on CVs for SSC and CD117, were significantly higher in patients with SM than non-SM (0.55 vs. 0.17, respectively; p < 0.001). Flow cytometric-based quantitative analysis of event clustering is a useful approach for diagnosing and monitoring patients with SM. PMID- 25284493 TI - A case of CD5-positive mature B-cell neoplasm with t(10;14)(q24;q11.2) and trisomy 12. PMID- 25284494 TI - Spontaneous remission of acute myeloid leukemia. AB - Spontaneous remission (SR) of acute myeloid leukemia (AML) is rare. We collected all 46 reported cases of AML with SR. Fever occurred in 91.3% of cases before remission, which was largely due to pneumonia (54.5%) and bacteremia (24.2%). Pneumonia and bacteremia were significantly more common among those who achieved complete remission (CR) compared to those who achieved only a partial remission (p = 0.032). Although 88.6% of remissions were CR, the median duration of remission was only 5 months. Eight cases did not relapse during the follow-up period. The mechanism of SR in AML likely involves the stimulatory effect of systemic febrile infection on the immune system. Immediate treatment of infections and fever may contribute to the rarity of SR in AML. The results of this review improve our understanding of the important role of the immune system in countermanding AML and may provide new ideas for immunotherapy. PMID- 25284495 TI - Comparative effectiveness analysis of different salvage therapy intensities used for diffuse large B-cell lymphoma in Northern or Southern Alberta: an instrumental variable analysis. AB - To date, no clinical trial has addressed salvage therapy intensity for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We sought to determine whether the more intensive salvage chemotherapy approach used in Southern Alberta (SAB) compared to the conventional dose salvage approach used in Northern Alberta (NAB) affects the rates of autologous stem cell transplant (ASCT) and survival in patients with relapsed DLBCL. Using instrumental variable analysis, we examined 147 consecutive patients with relapsed/refractory DLBCL from 2004 to 2010 who received salvage therapy in SAB (n = 70) or NAB (n = 77). Patients treated in SAB had higher rates of: salvage chemotherapy response (85.0% vs. 54.0%, p = 0.001), ASCT (61.4% vs. 41.6%, p = 0.016) and 4-year overall survival (41% vs. 20%, p = 0.002) than those in NAB, respectively. This study supports the hypothesis that selective use of intensive salvage chemotherapy leads to higher rates of ASCT and survival in this population. PMID- 25284496 TI - The prognostic impact of peripheral blood progenitor cell dose following high dose therapy and autologous stem cell transplant for hematologic malignancies. AB - High-dose chemotherapy (HDT) followed by autologous peripheral blood progenitor cell transplant (PBPCT) has become a standard intervention in certain clinical settings of hematologic malignancies, particularly multiple myeloma and relapsed/refractory lymphoma. While the minimal required PBPCs infused, as defined by number of CD34 + cells, has been relatively well delineated for adequate hematopoietic recovery post-HDT, optimal PBPC dose has not been clearly defined. This is particularly relevant in the context of retrospective data suggesting improved survival outcomes with increased PBPC doses. The potential confounding of these data as they relate to disease risk is discussed within this review. Additionally, other retrospective data have suggested that enhanced quantitative lymphocyte subset reconstitution post-HDT-PBPCT may confer progression-free and overall survival advantage. These reported series herein reviewed may inform discussion of future, prospective clinical trials with the intent of defining optimal autologous PBPC dose following HDT, especially as it may relate to metrics beyond hematopoietic recovery. PMID- 25284497 TI - Waldenstrom macroglobulinemia and autoimmunity: what's the connection? PMID- 25284498 TI - Overcoming treatment challenges in imatinib-resistant chronic myelogenous leukemia. PMID- 25284499 TI - Primary central nervous system lymphoma: three linked questions in the situation puzzle of radiotherapy. PMID- 25284500 TI - Is the cure the poison? The evolving story of therapy-related myeloid malignancies. PMID- 25284501 TI - Vasodilatory effects of homologous adrenomedullin 2 and adrenomedullin 5 on isolated blood vessels of two species of eel. AB - In mammals, adrenomedullin (AM) is a potent vasodilator through signalling pathways that involve the endothelium. In teleost fishes, a family of five AMs are present (AM1/4, AM2/3 and AM5) with four homologous AMs (AM1, AM2/3 and AM5) recently cloned from the Japanese eel, Anguilla japonica. Both AM2 and AM5 have been shown to be strong in vivo vasodepressors in eel, but the mechanism of action of homologous AMs on isolated blood vessels has not been examined in teleost fish. In this study, both eel AM2 and AM5 caused a marked vasodilation of the dorsal aorta. However, only AM5 consistently dilated the small gonadal artery in contrast to AM2 that had no effect in most preparations. Neither AM2 nor AM5 had any effect when applied to the first afferent branchial artery; in contrast, eel ANP always caused a large vasodilation of the branchial artery. In the dorsal aorta, indomethacin significantly reduced the AM2 vasodilation, but had no effect on the AM5 vasodilation. In contrast, removal of the endothelium significantly enhanced the AM5 vasodilation only. In the gonadal artery, 1H [1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) significantly reduced the AM5 vasodilation suggesting a role for soluble guanylyl cyclase in the dilation, but l-NNA and removal of the endothelium had no effect. The results of this study indicate that AM2 and AM5 have distinct vasodilatory effects that may be due to the peptides signalling via different receptors to regulate vascular tone in eel. PMID- 25284502 TI - A multi-scale PDMS fabrication strategy to bridge the size mismatch between integrated circuits and microfluidics. AB - In recent years there has been great progress harnessing the small-feature size and programmability of integrated circuits (ICs) for biological applications, by building microfluidics directly on top of ICs. However, a major hurdle to the further development of this technology is the inherent size-mismatch between ICs (~mm) and microfluidic chips (~cm). Increasing the area of the ICs to match the size of the microfluidic chip, as has often been done in previous studies, leads to a waste of valuable space on the IC and an increase in fabrication cost (>100*). To address this challenge, we have developed a three dimensional PDMS chip that can straddle multiple length scales of hybrid IC/microfluidic chips. This approach allows millimeter-scale ICs, with no post-processing, to be integrated into a centimeter-sized PDMS chip. To fabricate this PDMS chip we use a combination of soft-lithography and laser micromachining. Soft lithography was used to define micrometer-scale fluid channels directly on the surface of the IC, allowing fluid to be controlled with high accuracy and brought into close proximity to sensors for highly sensitive measurements. Laser micromachining was used to create ~50 MUm vias to connect these molded PDMS channels to a larger PDMS chip, which can connect multiple ICs and house fluid connections to the outside world. To demonstrate the utility of this approach, we built and demonstrated an in-flow magnetic cytometer that consisted of a 5 * 5 cm(2) microfluidic chip that incorporated a commercial 565 * 1145 MUm(2) IC with a GMR sensing circuit. We additionally demonstrated the modularity of this approach by building a chip that incorporated two of these GMR chips connected in series. PMID- 25284503 TI - An annotated checklist of the Italian butterflies and skippers (Papilionoidea, Hesperiioidea). AB - We present here an updated checklist of the Italian butterflies (Lepidoptera: Hesperioidea and Papilionoidea) organised in the following sections (tables):1. Introduction, providing a broad outline of the paper.2. Checklist proper, summarised in a table, listing, in separate columns:a. Indications of endemicity (sub-endemic, Italian endemic).b. The relevant Annex in the Habitats Directive (legally protected species).c. Threat levels (in Europe: for threatened species only).d. A serial number (whose format is uniform across all Italian animal groups). This number runs throughout all the following tables (see 3, 4).e. Name, author, date of publication.f. Schematic overall indication of each specie's Italian range (N[orth], S[outh], Si[icily], Sa[rdinia]).3. Nomenclature, containing basic nomenclatural details for all listed genera, species and some of the generally or historically recognised subspecies and synonyms.4. Notes, where a variety of other information is provided, on a name by name (family, subfamily, genus, species, subspecies) basis. All remaining doubts as concerns each individual case are clearly stated. The number of nominal species listed in the previous edition of this checklist, published almost 20 years ago, was 275, whereas it has raised to 290 in the current list. The status of about a dozen of these remains controversial, as discussed in the text. The present checklist is meant to provide an update of the Italian butterfly fauna, taking into account all relevant publications, and tries to explain all nomenclatural changes that had to be introduced, in the appropriate section. Many detailed comments are offered, when necessary or useful, in the notes. PMID- 25284504 TI - Revision of the cricket genus Cardiodactylus (Orthoptera, Eneopterinae, Lebinthini): the species from both sides of the Wallace line, with description of 25 new species. AB - The genus Cardiodactylus is the most speciose and widely distributed genus of the cricket subfamily Eneopterinae and of the Lebinthini tribe. Along with diverse acoustic features, this genus is also characterized by a wide distribution area running from Japan to Southeast Asia, Northern Australia and in many archipelagos in the Western Pacific, with a high contrast in species distributions. In this paper we start revising Cardiodactylus by focusing on the western region of its wide distribution and the Novaeguineae species group. We describe 25 new species of Cardiodactylus, redescribe 3 species and bring new signalizations for 5 species. Whenever possible, information is provided about species distribution, male calling song and male and female genitalia, forewing venation and habitat. PMID- 25284505 TI - Annotated checklist and distribution of the lizards of Iran. AB - We present a comprehensive summary of the distribution of the lizards of Iran accompanied by an annotated checklist. The updated maps of distribution of all 146 species of 41 genera of 11 families are based on all available bibliographic records, catalogues of museum collections and our own field observations. The final dataset used for the distribution maps contains 8525 georeferenced records and cover 41% of the country when plotted on a grid of 0.25 degrees * 0.25 degrees resolution. The dataset is publicly accessible through GBIF portal (http://www.gbif.org/dataset/7db4f705-61ae-4c6e-9de2-06674e7d46b2). Following the latest biogeographic division of the country, ~53% of the species (76 species) inhabit the Iranian Province, ~41% (60 species) the Western Asian mountain transition zone, ~9% (13 species) the Turanian Province, and ~18% (27 species) the Arabian Province. In addition, ~2% (3 species) reach Iran from the Indo-Malay biogeographic region and ~2% (3 species) are believed to have been introduced to Iran by humans. Endemic species (46) represent ~32% of the known species diversity. The most species-rich family of lizards in Iran is Lacertidae with 47 species, followed by Gekkonidae (41), Agamidae (18), Scincidae (15), Phyllodactylidae (10), Sphaerodactylidae (4), Eublepharidae and Uromastycidae (3), Anguidae and Varanidae (2), and Trogonophidae with one representative. PMID- 25284507 TI - Enzyme activity in liquid lipase melts as a step towards solvent-free biology at 150 degrees C. AB - Water molecules play a number of critical roles in enzyme catalysis, including mass transfer of substrates and products, nucleophilicity and proton transfer at the active site, and solvent shell-mediated dynamics for accessing catalytically competent conformations. The pervasiveness of water in enzymolysis therefore raises the question concerning whether biocatalysis can be undertaken in the absence of a protein hydration shell. Lipase-mediated catalysis has been undertaken with reagent-based solvents and lyophilized powders, but there are no examples of molecularly dispersed enzymes that catalyse reactions at sub solvation levels within solvent-free melts. Here we describe the synthesis, properties and enzyme activity of self-contained reactive biofluids based on solvent-free melts of lipase-polymer surfactant nanoconjugates. Desiccated substrates in liquid (p-nitrophenyl butyrate) or solid (p-nitrophenyl palmitate) form can be mixed or solubilized, respectively, into the enzyme biofluids, and hydrolysed in the solvent-free state. Significantly, the efficiency of product formation increases as the temperature is raised to 150 degrees C. PMID- 25284508 TI - Deep brain stimulation of the pallidum internum for Gilles de la Tourette syndrome: a patient-specific model-based simulation study of the electric field. AB - OBJECTIVES: The aim of this study was to investigate the deep brain stimulation (DBS) electric field distribution in proton-density MRI scans visualizing the globus pallidus internus (GPi) of patients with Gilles de la Tourette syndrome (GTS), along with its relation to the anatomy. METHODS: Patient-specific brain tissue models (n = 7) with bilateral DBS electrodes in the GPi were set up using the finite element method in five patients who had undergone stereotactic proton density MRI-guided surgery and showed variable improvement with DBS. Simulations (n = 27) of the electric field were performed and the results visualized on the respective preoperative stereotactic MRI scans. The mean electric field volumes (n = 81) within the 0.1, 0.15, and 0.2 V/mm isosurfaces were calculated and compared with the anatomy. RESULTS: Visualization of the simulated electric field confirmed that the anteromedial limbic GPi was the main stimulated target for four of the patients and the posteromedial sensorimotor GPi for one. Larger volumes extended asymmetrically, with parts of fields stretching into the lamina between GPi and globus pallidus externus and into the internal capsule. There was a high correlation (r = 0.994, n = 54) between volumes and brain sides, but with a systematic shift toward the right side, especially for the larger volumes. Simulations with homogeneous tissue models showed no differences. CONCLUSIONS: Patient-specific DBS electric field simulations in the GPi as visualized on proton-density MR scans can be implemented in patients with GTS. Visualization of electric fields together with stereotactic thin-slice MRI can provide further support when predicting anatomical structures possibly influenced by DBS in this complex disorder. PMID- 25284509 TI - Macro and micro full field x-ray fluorescence with an X-ray pinhole camera presenting high energy and high spatial resolution. AB - This work describes a tabletop (50 cm * 25 cm * 25 cm) full field X-ray pinhole camera (FF-XPC) presenting high energy- and high spatial-resolution. The FF-XPC consists of a conventional charge-coupled device (CCD) detector coupled, in a coaxial geometry, to a pinhole collimator of small diameter. The X-ray fluorescence (XRF) is induced on the samples with an external low-power X-ray tube. The use of the CCD as an energy dispersive X-ray detector was obtained by adopting a multi-image acquisition in single photon counting and by developing a processing algorithm to be applied in real-time to each of the acquired image frames. This approach allowed the measurement of X-ray spectra with an energy resolution down to 133 eV at the reference value of 5.9 keV. The detection of the X-ray fluorescence through the pinhole-collimator allowed the two-dimensional elemental mapping of the irradiated samples. Two magnifications (M), determined by the relative sample-pinhole-CCD distances, are used in the present setup. A low value of M (equal to 0.35*) allows the macro-FF-XRF of large area samples (up to 4 * 4 cm(2)) with a spatial resolution down to 140 MUm; a large magnification (M equal to 6*) is used for the micro-FF-XRF of small area samples (2.5 * 2.5 mm(2)) with a spatial resolution down to 30 MUm. PMID- 25284510 TI - Comparative insight into expression of recombinant human VEGF111b, a newly identified anti-angiogenic isoform, in eukaryotic cell lines. AB - VEGF-A is a critical growth factor in tumor growth and progression. Two families of VEGF-A isoforms are produced through alternative splicing including VEGFxxx pro-angiogenic and VEGFxxxb anti-angiogenic isoforms. VEGF111b is a new member of the VEGFxxxb family that is induced by mitomycin C and doesn't express in normal conditions. The potent anti-angiogenic properties of VEGF-111b and its remarkable resistance to proteolysis make it an interesting alternative candidate for therapeutic use in all types of cancers. Here, the recombinant VEGF-111b cDNA with insertion of intronic sequence was constructed by using a class IIs restriction enzyme-based method. The recombinant pBud-VEGF111b was transfected into CHO dhfr(-) and HEK 293 cell lines which are currently the standard hosts for the production of candidate therapeutic proteins. Then, the VEGF-111b expression was evaluated in two cell lines using the Real-time PCR. The production of VEGF-111b protein was also investigated here by dot blotting. The VEGF expression was increased about 109 and 185-folds in transfected CHO-dhfr(-) and HEK 293 cells, respectively, in comparison with the un-transfected cells. Dot blotting approach confirmed that both cell lines have successfully produced the VEGF-111b protein. PMID- 25284512 TI - Orthodontic treatment complexity and need in a Nigerian teaching hospital. AB - OBJECTIVE: The aim of this study was to assess the orthodontic treatment need and complexity in a major referral orthodontic centre in Lagos, Nigeria. METHOD: Pre treatment dental casts of 150 consecutive patients were assessed using the Index of Complexity, Outcome and Need (ICON). RESULTS: Fifty-seven (38%) of the population needed orthodontic treatment. Twenty-five (16.7%) cases were classified as difficult or very difficult, 14.7% moderate and 68.6% belonged to the easy/mild categories. The overall mean ICON score was 43 +/- 17.8 SD. There were no significant age or gender differences in the pre-treatment ICON score. There was a significant association (p<0.05) between treatment need and social class: more subjects from the lower social class needed orthodontic treatment than subjects from the higher social class. CONCLUSIONS: More than one third of the population had a need for orthodontic treatment, of which close to one fifth were in the difficult to very difficult category. Patients in the lower socio economic class had greater need for orthodontic treatment than those from the higher class. PMID- 25284513 TI - Alternative coinitiators applicable to photocurable resin composites. AB - This review aimed to examine the evolution of the composite resins's photoinitiator system, with emphasis on those developed in recent years. This review covered literature from 1990 to 2013 and only papers with the key words of interest were included: "coinitiators", "amines", "composite resins", "photopolymerization". The search used full-text papers from PubMed and Science Direct databasis. It was included only English papers, and meeting abstracts and short communications were excluded. Hand search of the references completed the review. A total of 29 articles were studied. Many coinitiators are being researched as an alternative to traditional tertiary amines, particularly in order to improve the physical and mechanical properties of the final polymer and its biocompatibility with oral tissues. Polymerizable amines, natural compounds, and coinitiators with low toxicity and antiseptic properties were studied, and the results found they would be promising substitutes. These materials must present appropriate concentration and reactivity to obtain adequate physical and mechanical properties and high biocompatibility. However, further in vivo studies are required to verify the performance of these alternative coinitiators in the composite materials, mainly when in contact with oral tissues and the stomatognathic system. PMID- 25284511 TI - Identification and characterization of 5'-flanking region of the human riboflavin transporter 1 gene (SLC52A1). AB - The human SLC52A1 gene encodes the riboflavin transporter-1 (RFVT-1), a plasma membrane protein that transports vitamin B2 (riboflavin, RF) into cells, and thus, plays a role in controlling cellular homeostasis of RF in those tissues that express the carrier protein (e.g. placenta and intestine). Currently, there is nothing known about transcriptional regulation of the SLC52A1 gene, therefore, we aimed to clone and characterize its 5'-flanking region. Using rapid amplification of the cDNA ends (5'-RACE), we identified one transcription start site (TSS). A 579 bp segment of the 5'-flanking region of this gene was cloned which exhibited robust promoter activity upon transfection in human intestinal epithelial cells. Deletion analysis revealed that the core promoter activity to be embedded in a region between -234 and -23 that lacked TATA element, was GC rich, and harbored several putative cis-regulatory sites including KLFs, AP-2, EGRF and Sp-1. Mutating each of these sites led to a significant decrease in promoter activity (which was highest for the Sp-1 site), suggesting their possible involvement in regulating SLC52A1 transcription. Focusing on the Sp-1 site, EMSA, super-shift and ChIP analysis was performed that established the interaction of the Sp-1 transcription factor with the SLC52A1 promoter; also, co transfection of the minimal SLC52A1 promoter with an Sp-1 containing vector in Drosophila SL-2 cells led to significant promoter activation. These results are the first to reveal the identity of the minimal SLC52A1 promoter and to establish an important role for Sp-1 in its activity. PMID- 25284514 TI - Alterations in serum lipid profile patterns in oral cancer: correlation with histological grading and tobacco abuse. AB - Albeit alterations in serum lipid profile patterns have long been associated with malignancies, still role of these alterations remains controversial. It has been suggested a causative relationship might exist between plasma lipid levels and oral cancer patients. Further, the habit of tobacco consumption is on the rise and most often the oral cancer patients are afflicted with this menace. As a matter of fact, tobacco contains carcinogens capable of damaging the cell membrane components including lipids. Thus, the purpose of the present review is to discuss the basics of lipids and to evaluate alterations in plasma lipid profile in oral cancer patients and its association with histological grading and tobacco abuse. Pertinent literature was searched in PubMed and Medline by using key words such as serum lipid profile, oral cancer, histological grades and tobacco abuse. PMID- 25284515 TI - Comparison of two chair-side tests for enumeration of Mutans Streptococci in saliva. AB - AIM: To compare the prevalence and levels of salivary Mutans Streptococci (MS) assessed with two commercial chair-side methods based on culture growth or monoclonal antibodies, respectively. MATERIAL AND METHODS: The study group consisted of a convenience sample of 89 adults, 23-72 years of age, referred to a maxillofacial hospital clinic with a caries history. Stimulated whole saliva samples were collected and the number of MS was assessed with the Dentocult-SM Strip Mutans (DSM) and the Saliva-Check Mutans (SCM). The outcome was compared with conventional anaerobic laboratory cultivation on selective MSB agar. RESULTS: The prevalence of >= 5 * 10(5) CFU was 21%, 62%, and 73% with the SCM, DSM and MSB-cultivation, respectively. The correlation between DSM and SCM tests was r = 0.49 (p < 0.05) but the agreement on the high levels was fair. In comparison with the MSB agar, DSM provided acceptable levels of sensitivity and specificity while the SCM displayed a poor sensitivity but a perfect specificity. Both chair-side methods were significantly related to the prevalence of active root caries lesions (p < 0.05). CONCLUSIONS: The two chair-side salivary tests were significantly correlated and due their high specificity, they may be sensitive enough for screening purposes and for patient-centered promotion of oral health. PMID- 25284516 TI - International Oral Care: a proposed model for the humanitarian dental missions. AB - The creation of a good "field hospital" operating in the humanitarian missions has ever been the main aim to reach in any humanitarian missions. The Authors want to propose a model for all the humanitarian dental missions, so to standardize the activities and to make the results predictable in all the missions: this model has been named "International Oral Care" project. In the light of the experiences in the previous humanitarian missions, we have developed and standardized a protocol that provides a complex organizational planning for each phase of the mission. Our strengths are the "Dental-Marquee", the"Dental Ambulance", the "Dental-Roulotte" and a well-tested operative workflow. In the last 3 years of activity on the field, International Oral Care has achieved an increase of treated patients, certainly consequential to the increase of operators on the field, but also due to the optimization of internal processes and the improvement of organizational structures. IOC has achieved in recent years an organization optimized and highly predictable: this makes it a model for humanitarian missions in the field of dentistry, a model that could be adopted also by international NGOs operating in war zones, or in the major natural disasters. PMID- 25284517 TI - Prevalence and associated factors to developmental defects of enamel in primary and permanent dentition. AB - BACKGROUND: The disturbances during enamel formation manifesting as Developmental Defects of Enamel (DDE) present important clinical significance since they are responsible for aesthetic problems, dental sensitivity and may act as predisposing factor for dental caries. The aim of the present study was to examine the prevalence of DDE and associated etiological factors. MATERIALS AND METHODS: A total of 1550 children was examined, using a mouth mirror and a CPI probe. Diagnosis of DDE was established according to the modified DDE index. Relationships between DDE and body mass index (BMI), socioeconomic status (SES), childhood illness and birth weight were assessed using the multivariable logistic regression. Difference in proportion was tested using Kruskal-Wallis H, followed by Mann-Whitney U test for inter group comparison, and Chi-Square tests. RESULTS: The prevalence of DDE was 42.19%. The logistic regression model showed that there was a significant association of DDE with age (p<0.05), gender (p<0.05), low SES (p<0.05) and obesity (p<0.001). Demarcated opacity was the most frequent type of DDE both in primary and permanent dentition. Prevalence was more frequent in permanent dentition compared to primary dentition, with the permanent maxillary central incisor and primary maxillary second molars being the teeth affected most commonly. CONCLUSIONS: Prevalence of DDE was more in permanent teeth compared to primary teeth. A significant association of DDE with gender, low SES and BMI was demonstrated in the present study. PMID- 25284518 TI - Removal of refractory erosive-atrophic lichen planus by the CO2 laser. AB - AIM, STUDY AND BACKGROUND: The erosive-atrophic form of Oral lichen Planus (OLP) is often associated with severe pain and burning sensation. This study investigated the efficacy of CO2 laser surgery for management of refractory erosive-atrophic OLP. METHODS: Ten patients with thirteen erosive-atrophic OLP resistant to standard therapy participated in this study. The size and clinical scores of the lesions and the level of pain/discomfort were recorded before treatment. The lesions were then removed with a CO2 laser device (10600 nm, continuous wave, 5 W, slightly defocused). The subjects were evaluated 1 month and 3 months later and the response rate was assessed according to the decrease in pain, sign scores and size of the lesions. RESULTS: There was a significant reduction in pain and lesion size at 1 and 3 months following laser treatment (p<0.05). The sign scores of the lesions were also significantly improved at follow-up periods compared to the pretreatment state (p<0.05). At the end of the follow-up period, 54% of the lesions showed 3 or 4 degrees of improvement in the clinical score and 23% improved 1 or 2 degrees, whereas 23% remained unchanged post-operatively compared to the pretreatment evaluation. CONCLUSION: The present results indicate that the CO2 laser surgery is an effective modality for management of erosive-atrophic OLP and can be considered as a suitable alternative to standard treatment. PMID- 25284519 TI - Influence of surface sealant on the color-stability of a composite resin immersed in different beverages. AB - AIM: This study evaluated the influence of surface sealant (Fortify-Bisco) on the color-stability of a composite resin (Charisma-3M) immersed in different beverages. METHODS: It was prepared resin specimens with 10 mm-diameter X 2 mm thickness for each beverage (soft drink, coffee, tea and artificial saliva=control). Specimens were divided in 2 groups (with or without surface sealant) and afterwards divided in 4 subgroups (n=7) according to the immersion solution. After 24 hours, it was started the cycling in the solutions 3 times/day during 5 minutes for 90 days. Opacity (DeltaL) and color change (DeltaE) of specimens were analyzed with a spectrophotometer (BYK-Gardner) in the different groups in relation to the control group. This handheld portable equipment is unique. RESULTS: Composite resin showed statistically significant difference (p<0.05) in the solutions, and coffee promoted the higher color change, followed by tea and soft drink. There was no difference between specimens sealed or not. CONCLUSIONS: Therefore, surface sealant was inefficient on the protection against color change and coffee promoted the higher darkening of the specimens. PMID- 25284520 TI - Evaluation of pemphigus cases involving oral mucosa. AB - PURPOSE: Pemphigus, defines a group of disorders in autoimmune etiology which could be life-threatening and clinical manifestations are mainly epithelial blistering affecting cutaneous and/or mucosal surfaces including oral mucosa. The aim of our study is to evaluate the clinical appearance of pemphigus with oral involvement by reported 15 pemphigus cases. MATERIAL AND METHODS: This retrospective study of 15 cases of pemphigus obtained over a period of 7 years from 2006 to 2013 in Istanbul University, Dentistry Faculty, Oral Medicine and Surgery Department was designed. RESULTS: Age distribution of pemphigus was from 15 to 59 years with an average age of 41.3 years. Of the 15 patients, the male:female ratio was 1:2.75 (4 male, 11 female). The most common clinical various of pemphigus was pemphigus vulgaris, diagnosed in all patients. The buccal mucosa (34.3%) was the most commonly affected site followed by tongue (20%), gingiva (17.1%), palate (11.4%), lips (11.4%) and floor of mouth (5.7%). CONCLUSION: Our explanation of this conclusion, while speculative, is that socioeconomic situation related stress in males and hormonal changes like pregnancy and menostasis in females; systemic disease and using drugs; dental trauma and bruxism could be responsible for flare up in the disease. PMID- 25284521 TI - A comparative evaluation of antibacterial efficacy of 'Activ points' and 'Combi points' as intra-canal medicaments against Enterococcus faecalis: an ex vivo study. AB - BACKGROUND: Enterococcus faecalis has been found to be one of the most predominant bacterial species associated with failed endodontic cases. The ability of this microbe to form biofilms; penetrate into dentinal tubules; survival in low pH, high salinity and high temperatures and resistance to many intracanal medicaments, makes it one of the most resistant pathogen of all the root canal flora. Studies have shown that chlorhexidine is relatively more effective against E. faecalis as compared to other intra canal medicaments. But its placement in solution form or gel form up to the root apex is not only difficult but uncertain as well. The purpose of this study was to compare the antimicrobial efficacy of chlorhexidine releasing Activ pointsTM chlorhexidine and calcium hydroxide releasing Combi pointsTM with that of standard 2% chlorhexidine solution. MATERIALS AND METHODS: Thirty McKonkey agar plates were inoculated with Enterococcus faecalis and were divided into three groups. Test specimens (paper points soaked in 2% chlorhexidine solution chlorhexidine releasing Activ pointsTM and chlorhexidine and calcium hydroxide releasing Combi pointsTM; 20 each) were placed in the plates and the zone of inhibition was measured around the specimen after 24 and 48 hrs. The results so obtained were subjected to statistical analysis. RESULTS: Statistically significant difference was found in terms of zone of inhibition in between the three groups greatest being for Combi pointsTM. CONCLUSION: The findings of the present study suggest that Combi pointsTM and Activ pointsTM can be used safely as an alternative to 2% chlorhexidine solution as intra canal medicament with the additional advantage of availability of these points in ISO standard sizes easy placement up to the root apex and easy retrieval from the root canal system. PMID- 25284522 TI - Dental and maxillofacial alterations in patients affected from odontochondrodysplasia: a rare case report and review of literature. AB - INTRODUCTION: This paper has evaluated the dental and or facial disorders associated to Goldblatt syndrome, also known as odontochondrodysplasia. AIM: We report the analysis performed on a female young patient affected by this disease. We analyzed her dental and or facial features. MATERIALS AND METHODS: We adopted several diagnostic criteria: firstly, we performed radiographic investigations, followed by rhinomanometric measurements and by clinical analysis performed in order to determine the salivary flow in this typology of patients. The evidences obtained after a careful clinical, anamnestic, and radiographic analysis of our female patient allowed us to identify a number of odontostomatologic features, which are very likely to be related to this syndrome. Our patient showed some pathognomonic signs of odontochondrodysplasia already identified in the literature, that is, pectus carinatum, joint hyperextensibility, coxa valga and genu valgum, upper and lower limb asymmetry, and vertebral abnormalities. Moreover, we focused our attention on those odontostomatologic aspects that had never been analyzed by other reports in the literature: dentinogenesis imperfecta, ligamentous hyperlaxity of all joints and of temporomandibular joints in particular, poor lip competence, ogival palate, and oral respiration. Besides these, dental crowding and other important elements were identified through cephalometric measurements. DISCUSSION AND CONCLUSIONS: In the light of all these elements and of their comparison with the existing literature, it is possible to stereotype a few recurrent odontostomatologic and systemic-generalized features in patients with odontochondrodysplasia, which can be considered as closely associated with this syndrome. PMID- 25284523 TI - Conventional versus Papanicolaou-stained cytobrush biopsy in the diagnosis of oral squamous cell carcinoma. AB - AIMS: Squamous Cell Carcinoma (SCC) is the most frequent malignancy of the oral cavity which is known to have a high mortality rate. Early diagnosis of this cancer has a major role in the prevention of its progression and can help increase patient survival. Conventional biopsy is considered the gold standard for diagnosis of oral SCC. However oral brush biopsy is less invasive, quicker and easier than surgical method. The aim of this study was to assess the sensitivity of oral brush biopsy in patients with oral SCC. METHODS: Thirty-five oral SCC subjects underwent. Cyrtobrush sampling followed by conventional biopsy and the latter was used as gold standard to determine the sensitivity of the brush biopsy technique. Papanicolaou and hematoxylin/eosin staining were used for cytopathologic and histopathologic assessments, respectively. RESULTS: Only one patient was excluded due to inadequate sample material. A total of six of cytobrush specimens had the same diagnosis as their conventional biopsies (20.6% true positive), while 27 samples (79.4%) showed false negativity. CONCLUSIONS: According to the results obtained in the present study, sampling with cytobrush followed by Papanicolaou staining may not be a good alternative for conventional biopsy in oral SCC cases. PMID- 25284524 TI - Dental management of patients with epidermolysis bullosa. AB - Epidermolysis Bullosa (EB) is a group of rare, genetic skin disorders characterized by fragility and blistering to minimal trauma. All oral surfaces may be involved, including the tongue, buccal mucosa, palate, floor of the mouth and gingiva. Common oral findings of the disease include microstomia, intraoral ulcerations and bullae formation, ankyloglossia, tongue atrophy, elimination of buccal and vestibular sulci, lingual depapillation and atrophy of the palatal folds. In these case reports; systemic findings, oral manifestations and preventive measures are described for 3 patients with EB, all of whom required extensive oral management. Early dental management and preventive care to minimize caries development and improve oral health is very important for patients with EB. Pediatric dentists play an especially important role in early intervention. In describing the dental management of three EB cases, this article stresses the importance of an aggressive dental preventive programme with strict oral hygiene instructions for patients and parents along with frequent professional cleaning and fluoride therapy. PMID- 25284525 TI - Assessment of periodontal status among eunuchs residing in Bhopal city, Madhya Pradesh, India: a cross-sectional study. AB - AIM: To assess the periodontal status among eunuchs residing in Bhopal city, Madhya Pradesh, India. MATERIALS AND METHODS: Based on convenient non-probability snow ball sampling technique, all the self-identifi ed eunuchs residing in the city of Bhopal along with a matched control consisting of cross section of the general population residing in the same locality where these eunuchs live was examined to assess the periodontal status of the population by using WHO oral health assessment proforma 1997. All the obtained data was entered into a personal computer on Microsoft excel sheet and analyzed by using a software; SPSS version 20. Data comparison was done by applying chi square test, ANOVA and multiple logistic regression analysis. RESULTS: A total of 639 subjects comprised of 207 eunuchs, 218 males and 214 females. The overall gingival and periodontal disease prevalence was 87.3% with calculus and shallow pocket contributing a major part i.e., 67%. Among study participants, 56.9% males were having highest prevalence for calculus. Whereas, eunuchs were having highest prevalence for bleeding (17.4%), shallow pocket (22.7%) and deep pocket (9.7%). However, highest of 19.7% males and 10.1% eunuchs were having attachment loss of 4-5 mm and 6-8 mm respectively. However, 6.3% eunuchs were having attachment loss of 12 mm or more. CONCLUSION: The results of the current study showed poor periodontal status among eunuch population with most of the population requiring simple therapy. This indicates that comprehensive oral hygiene instruction and dental prophylaxis need to be initiated. PMID- 25284526 TI - Preservation of a tooth related with central giant cell granuloma with non invasive curettage: 7 years followed-up case report. AB - Central Giant Cell Granuloma (CGCG) is defined by the World Health Organization as an intraosseous lesion consisting of cellular fibrous tissue containing multiple foci of hemorrhage, aggregations of multinucleated giant cells, and occasionally trabeculae of woven bone. An 8-year-old patient presented with painless swelling and bleeding in his upper right canine region was referred to our clinic. Incisional biopsy was confirmed that this was a CGCG. The patient was treated with non-invasive curettage and secondary intention healing. Seven-year follow-up of the patient revealed a complete resolution of the lesion and uneventful eruption of the permanent canine tooth. In this case report, a successful long-term outcome of the conservative treatment of the CGCG was presented. PMID- 25284527 TI - Peripheral giant cell reparative granuloma of maxilla in a patient with aggressive periodontitis. AB - Peripheral giant cell reparative granuloma is a reactive and rare lesion of oral cavity with unknown etiology which is derived from periosteum and periodontal ligament and occurs frequently in young adults. Inflammation or trauma is underlying causative factor of reactive proliferation. In the present case report, a 35 year-old male with aggressive periodontitis and peripheral giant cell reparative granuloma is presented. The patient applied to our clinic with a complaining about a big nodule at his palate. The lesion was pedunculated and localized at his right maxilla between #16 and #17 which arose from distal aspect of #16, and the surface of the lesion was hyperkeratotic and the lesion was measured 22 x 30 mm at the largest diameter. He also had severe generalized aggressive periodontitis and hypertension. Amoxicillin clavulanate 625 mg, three times a day, metronidazole 500 mg three times a day and 0.2% chlorhexidine digluconate oral rinse, twice a day for a week, were prescribed to the patient. Then, scaling and root planing were performed along with systemic antibiotic treatment and he scheduled for surgery. The lesion was excised completely and #16 was extracted. After the healing period, periodontal surgery was planned for the treatment of aggressive periodontitis. Obtained tissue specimen was sent for histopathological examination. The diagnosis of peripheral giant cell reparative granuloma was confirmed with histopathological examination. No intra- and post operative complications were seen. PMID- 25284528 TI - Microleakage evaluation of class V restorations with conventional and resin modified glass ionomer cements. AB - The aim of this study was to evaluate in vitro the marginal microleakage of conventional Glass Ionomer Cements (GIC) and Resin Modified Glass Ionomer Cements (RMGIC). The tested materials were grouped as follows: GIC category - G1 (Vidrion R - SSWhite); G2 (Vitro Fill - DFL); G3 (Vitro Molar - DFL); G4 (Bioglass R - Biodinamica); and G5 (Ketac Fill - 3M/ESPE); and RMGIC category - G6 (Vitremer - 3M/ESPE); G7 (Vitro Fill LC - DFL); and G8 (Resiglass - Biodinamica). Therefore, 80 class V cavities (2.0X2.0 mm) were prepared in bovine incisors, either in the buccal face. The samples were randomly divided into 8 groups and restored using each material tested according to the manufacturer. The root apices were then sealed with acrylic resin. The teeth were stored for 24 h in 100% humidity at 37 degrees C. After storage, the specimens were polished with extra-slim burs and silicon disc (Soft-lex - 3M/ESPE), then were isolated with cosmetic nail polish up to 1 mm around the restoration. Then, the samples were immersed in 50% AgNO3 solution for 12 h and in a developing solution for 30 min. They were rinsed and buccal-lingual sectioned. The evaluation of the microleakage followed scores from 0 to 3. The Kruskal-Wallis test and Dunn method test were applied (a=0.05). The results showed that there was no difference between the enamel and dentin margins. However, GIC materials presented more microleakage than RMGIC. PMID- 25284529 TI - Early treatment of class III malocclusion with modified tandem traction bow appliance and a brief literature review. AB - The accurate diagnosis and clinical management of class III malocclusion continues to be a challenging task for the pediatric dentist due to the poor compliance of patient and high rate of relapse. Two cases of early treatment of class III malocclusion are presented which were treated by modified tandem traction bow appliance. The correction in the cross bite was achieved in six to seven months. Children's compliance and acceptance for the appliance was good. Follow up of two years and one years showed no relapse. PMID- 25284530 TI - Prevalence of hepatitis B vaccination among oral health care personnel in Mysore city, India. AB - BACKGROUND: The transmission of blood borne virus in health care workers is a potential occupational hazard to patients as well as to the Oral Health Care Personnel (OHCP). Hepatitis B remains a serious threat to dental team. PATIENTS AND METHODS: To assess the vaccination status and post vaccination antibody status of oral health care personnel against Hepatitis B Virus (HBV) infection. Descriptive Cross-sectional questionnaire study was conducted among the oral health care personnel of Mysore city. RESULTS: Out of 300 oral health care personnel 256 (85.4%) were vaccinated for HBV infection and 44 (14.6%) had not taken vaccination. Highest frequency of vaccination was seen among dentists and least amongst dental lab technicians and other workers. This difference was highly significant among the different occupation groups (p= 0.001). CONCLUSION: Majority of the OHCP of Mysore city have been vaccinated. Among them, dentists formed the majority group of vaccinated. But there was ignorance and less awareness regarding Hepatitis B vaccination among dental lab technicians and other workers like dental assistants and cleaning staff. Awareness amongst OHCPS against Hepatitis B vaccination has increased significantly over the years, but there are few who do not intend to get vaccinated. PMID- 25284531 TI - Esthetic and functional rehabilitation of missing anterior teeth with a conservative treatment approach: a clinical case series. AB - The current scenario in dentistry proposes several treatment modalities for the esthetic and functional replacement of a congenitally or traumatically missing anterior tooth in young and adult patients which includes implant supported single crown, conventional FPD, Resin Bonded FPD (RBFPD) or RPD. However when certain clinical conditions or unwillingness of the patient preclude the replacement of missing tooth with any of these prostheses, in such cases, a more conservative treatment modality, fiber reinforce composite resin fixed partial denture with composite resin, porcelain fused to metal, all ceramic or natural tooth pontic can be consider as a definitive treatment alternative in certain clinical conditions. This article describes successful rehabilitation of three different patients with three types of pontics by this technique. PMID- 25284532 TI - Relationship between oral health status and oral health related quality of life in adults attending H.P Government Dental College, Shimla, Himachal Pradesh- India. AB - OBJECTIVES: To describe Oral Health Related Quality of Life (OHRQoL) in adults attending the Outpatient Department (OPD) of Public health Dentistry, H.P Government Dental College, Shimla, and to assess the relationship between clinical measures of oral health status and oral health related quality of life. METHODS: A cross sectional study was carried out for a period of three months on 351 subjects reporting to the OPD of Public health Dentistry, H.P Government Dental College, Shimla. Subjects were examined systemically for dental caries, periodontal disease using DMFT index and CPI index. OHRQoL was measured using the 14 - item Oral Health Impact Profile questionnaire (OHIP-14). Also the data on education, socio economic status and reasons for seeking dental care was collected. RESULTS: There were 158 males and 193 females participating in the study. The mean age of study population was 35.7 +/- 9.33. The mean total OHP-14 score was 9.5 +/- 9.4; 35.6% of the subjects reported one or more OHIP problems 'fairly often or very often'. When the prevalence of impacts fairly /very often was modeled using logistic regression, presence of decayed teeth, presence of periodontal disease (CPI score >2) and number of missing teeth remained significantly associated with OHRQoL after adjusting for gender and episodic dental care. CONCLUSION: OHIP-14 scores were significantly associated with the clinical oral health status indicators, independently of gender and socio economic inequalities in oral health. PMID- 25284533 TI - Prevalence of traumatic injuries and knowledge regarding emergency care among 11 14 years government school children in rural area, Dehra, Kangra district, Himachal Pradesh. AB - OBJECTIVE: To assess the prevalence of traumatic injuries and the knowledge regarding the emergency care among school children in rural area Dehra, Kangra district, Himachal Pradesh. MATERIALS AND METHODS: A cross-sectional survey was carried out in 13 government schools among 1041 subjects aged 11- 14 years. The demographic details and knowledge regarding emergency care was recorded on a structured questionnaire. The data regarding the traumatic injuries was recorded using modified Ellis' classification. RESULTS: Prevalence of Traumatic Dental Injuries (TDI) was found to be 5.12 %. Maxillary central incisor was the most common tooth to be affected (58.1%). The main cause for TDI was found to be due to falls (51.2%). Enamel with dentin fracture with pulp exposure was the main type of TDI (46.7%). The awareness regarding emergency care revealed that 63.4% of subjects were aware of emergency care. The knowledge regarding TDI increased with increase in age. CONCLUSION: The prevalence of dental trauma was found to be low and the awareness level regarding emergency care was found to be fair. Hence it is highly recommended to plan a community wide trauma prevention campaign targeting parents, children and dental care providers. PMID- 25284534 TI - Mandibular incisor re-crowding: is it different in extraction and non-extraction cases? AB - INTRODUCTION: Relapse of anterior crowding after retention phase is a major complication in orthodontic treatment. It is the most unpredictable phenomena. This study is aimed to compare anterior crowding relapse in patients treated with non-extraction and extraction of upper and lower first premolars related to changes of selected variables. MATERIALS AND METHODS: "Irregularity Index" of dental arch of 40 patients (Extraction group = 21, Non-extraction group = 19) were measured on study models before treatment (T1), post-treatment (T2), and at post-retention (T3). The changes within each group were evaluated using the Wilcoxon test and the Mann-Whitney test was used for inter-group evaluation. RESULTS: The mean initial irregularity index was 7.23 mm in extraction group and 6.13 mm in non-extraction group which decreased to 0 mm with treatment. Finally, crowding relapsed to 2.11 mm in extraction group and 1.65 mm in non-extraction group at the post-retention period. These changes were equally statistically significant within both groups. (P-value = 0.001) However, no preference exists between studies groups concerning fewer incisors relapse. (P-value = 0.138) CONCLUSION: Extraction and non-extraction protocols are two different methods of treatment but they show similar tendency to incisor relapse. PMID- 25284535 TI - Dental students' perceived barriers in geriatric dental care active involvement. AB - OBJECTIVES: The present study assessed dental students' perceived barriers to geriatric dental care provision. METHODS: Out of 512 dental students in Iranian dental schools were participated in the study 464 were completed the questionnaire. The mean age of the dental students was 25.5 +/- 2.8 years; 67% were women. RESULTS: Most of the participants (79%) did not have any training focused on geriatric dental care, and the vast majority (more than 83%) had no experience with geriatric dental care. The primary barriers to provide dental care to the elderly that dental student mentioned included insufficient knowledge of geriatric dental care and perceived lack of communication skills and self confidence in managing elderly patients. CONCLUSION: Increased emphasis on geriatric dental education in the undergraduate dental curriculums needed to minimize the barriers and improving dental students' willingness to serve older people. PMID- 25284537 TI - Necrotizing sialometaplasia: a diagnostic dilemma. AB - Necrotizing sialometaplasia is a benign self-limiting lesion of both major and minor salivary glands although more commonly the latter. The clinical and histological similarity between this entity and a malignant lesion implies a risk of unnecessary radical treatment. We report a case of necrotizing sialometaplasia in middle aged women presenting as a non-ulcerated swelling. This case illustrates the need for careful analysis of a biopsy specimen for a correct diagnosis. PMID- 25284536 TI - Tobacco abuse amongst the school going students of 15 to 18 years of Almora district, Uttarakhand: a cross sectional study. AB - PURPOSE: The present study was done to assess the prevalence of tobacco abuse among school going students of the age group 15 to 18 year old in the rural areas of Almora district, Uttrakhand state, India. MATERIALS AND METHODS: Schools were grouped into 4 zones north, south and east, west based on their location in district, respectively. Second stage one private and one government school was randomly selected from each zone of rural Almora. All students belonging to age 15 to 18 year were selected from the selected schools. Data was collected by a pretested, closed ended questionnaire. RESULTS: Overall, the prevalence of tobacco consumption among the adolescents was 45.42%. 63% male and 47.1% female adolescents were habituated to it. All female and majority of the male adolescents predominantly consumed a smokeless form of tobacco. CONCLUSION: The prevalence of tobacco consumption indicates a downward shift in the age for the uptake of tobacco habit by adolescents and a rising prevalence among girls. Our findings suggest that tobacco use prevention and control measures are warranted and should be started very early preferably at primary education level. PMID- 25284538 TI - Orbital prosthesis: a novel reconstructive approach. AB - Rehabilitation of facial defects is a daunting task, requiring an individualized design of the technique for each patient. The disfigurement associated with the loss of an eye may result in significant physical and emotional problems. Various treatment modalities are available, one of which is the use of implants. Although implant-supported orbital prosthesis has a superior outcome, it may not be advisable in all the patients due to economic factors. The present article describes a reconstructive approach for a patient with exenterated right eye using silicone orbital prosthesis which improved his psychological, physical, social, functional, emotional and spiritual needs. Multidisciplinary management and team approach are essential in providing accurate and effective rehabilitation. PMID- 25284539 TI - Social factors affecting education quality of Iranian medical & dental students. AB - PURPOSE: Positive social behavior of student is an important factor in the integrity of educational quality. Unbalanced behavior can disrupt the progress of students in learning. The present study evaluates the effect of social factors on education quality of dental and medical students. MATERIALS & METHODS: This descriptive cross-sectional study was conducted on 227 randomly selected students (109 dental and 118 medical). The questionnaire contained three domains of cultural collectivism, self-concept, and social adjustment adapted from California Test of Personality. It also included demographic questions like; field of study, gender and home city of residence. Data was analyzed using SPSS (version#19) software. Pearsons' correlation coefficient and independent t-test were used at the P-value of 0.05. RESULTS: Generally, girl students showed higher cultural collectivism (P=0.028) and social adjustment (P=0.04). On the contrary, boys were better in self-concept behavior (P=0.34). Home city of residence evidenced with no significant effect on any aspects of social attitudes of subjects. Pearsons' correlation coefficient test showed a weak correlation between cultural collectivism and self-concept (r=0.134, P=0.04) and between cultural collectivism and social adjustment, as well. (r=0.252, P=0.001) Independent t-test showed a significant difference between male and female students concerning cultural collectivism and social adjustment. Reliability of cultural collectivism, self-concept and social adjustment scales ranged from very good to moderate, alpha=0.83, alpha=0.63, and alpha=0.54 respectively. CONCLUSIONS: The results of this study indicated that female students show better cultural collectivism and social adjustment skills. It also proved that home city of residence has no significant effect upon social behavior of either medical or dental students. PMID- 25284540 TI - Oral antiseptic and periodontitis: a clinical and microbiological study. AB - PURPOSE: This study evaluated the efficacy of a xanthan-based chlorhexidine gel (Xan-CHX) used as antiseptic in periodontal pockets after scaling and root planing in patients with generalized mild-severe chronic periodontitis. MATERIALS AND METHODS: 30 systemically healthy patients, 15 males and 15 females (mean age 54,1 +/- 6,9 years), diagnosed for chronic periodontitis were enrolled in this study. For each patient, in the 1(st) and 4(th) quadrant was applied antiseptic (Test sites); while the 2nd and 3rd were treated with the only mechanical causal therapy without using chemical agents (Control sites). Sub gingival plaque, gingival bleeding (BOP+), plaque index (PI-Plaque Control Record) and Probing Depths (PD) were evaluated at baseline (prior to any treatment) and after 4 weeks (21 days after treatment). RESULTS: The results showed that the mechanical causal therapy has a good effect in reducing the clinical indices, but the addition of antiseptics provides a significantly improvement in the PI, BOP and frequency of periodontopathic bacteria. CONCLUSION: The application of xanthan-based chlorhexidine (Xan-CHX) gel offers a great benefit in improving of the indices of periodontal disease, proving to be essential as adjunctive therapy in patients with a serious or moderate high chronic periodontitis, and of course as part of a program of periodontal treatment. PMID- 25284541 TI - Mucormycosis: a challenge for diagnosis and treatment--2 case reports and review of literature. AB - To present two clinical rare case reports of mucormycosis, an opportunistic fungal infection of maxilla presenting as necrosis in palate. The cases reported were two females with known immunodefficeancies. One patient was uncontrolled type 1 diabetic and the other was acute myloid leukemic patient on chemotherapy. Both the patients showed necrosis of hard palate. After histopathologic and culture report confirmation with a diagnosis of mucormycosis, they underwent surgical resection of involved bone and amphotericin B therapy. There was complete cure of disease. The oral physicians and surgeons play an important role in early detection of disease. Apt multimodal treatment strategy and prophylaxis for mucormycosis in all immune-deficient patients will help us to combat this dreaded disease. The antifungal prophylaxis for all chemotherapy patients should be reviewed so that prophylaxis for mucormycosis should also be included. PMID- 25284542 TI - Comparing government (school) vs. private (non-school) dental laboratories in marginal adaptation of single porcelain-fused-to-metal crowns. AB - AIM: The purpose of this study was to compare school and non-school dental laboratories in marginal adaptation of single Porcelain-Fused-to-Metal (PFM) crowns. METHOD: Six dental laboratories (three school- and three non-school laboratories) participated in this study. Each dental laboratory was requested to fabricate PFM crowns for three different ivorine teeth on different typodont jaw models (n=18). The crowns received from the laboratories and fitted in their abutments using fit-checker under uniform pressure. We examined 162 sites viewed under a scanning electron microscope to measure the vertical and horizontal marginal discrepancy. RESULTS: The mean vertical marginal discrepancy for school dental laboratories was 208.9 um, while for non-school dental laboratories was 182.8 um. For the horizontal marginal discrepancy, the median values were 48.5 um for school dental laboratories and 50 um for non-school dental laboratories. CONCLUSIONS: There was no statistically significant difference in the mean vertical and median horizontal values between school and non-school dental laboratories. However, a significant difference was observed within the non school laboratories. PMID- 25284543 TI - A verruciform xanthoma of the lower lip and review of the differential diagnosis. AB - A careful examination of lips is often neglected by the members of the medical and dental professions; yet the lips reveal a heterogeneous group of lesions ranging from congenital abnormalities to benign and malignant neoplasms. Verruciform Xanthoma (VX) is an uncommon benign inflammatory mucocutaneous condition that occurs in the oral cavity which was first described by Shafer in 1971. It is often associated with pre-existing epithelial and/or inflammatory disorder and is characterized histopathologically by papillary epithelial hyperplasia and the presence of foamy macrophages in connective tissue papillae. We report a case with VX which presented as a well-defined, soft, painless swelling on the lower lip having different clinical features. PMID- 25284544 TI - Restoration of primary canines with porcelain laminate veneers: a clinical report. AB - This article describes treatment of a young adult patient with porcelain laminate veneers for restoring unaesthetic maxillary anterior teeth with two retained primary canines. The patient had experienced an approximately two-year orthodontic treatment and had received both fixed and removable retainers for the upper arch. The patient could not afford implant supported restorations for his missing premolar teeth and was not pleased by the appearance of his smile. Using porcelain laminate veneers is a proper treatment option that could be taken into consideration in these situations. PMID- 25284545 TI - Long-term remission of adenoid cystic tongue carcinoma with low dose naltrexone and vitamin D3--a case report. AB - Naltrexone (ReVia(r)) is a long-acting oral pure opiate antagonist which is approved for the treatment of alcohol addiction as a 50mg per day tablet. The mechanism of action is complete opiate blockade, which removes the pleasure sensation derived from drinking alcohol (created by endorphins). Low Dose Naltrexone ("LDN") in the range of 3-4.5 mg per day has been shown to have the opposite effect - brief opiate receptor blockade with resulting upregulation of endogenous opiate production. Through the work of Bihari and Zagon, it has been determined that the level of the endogenous opiate methionine-enkephalin is increased by LDN. Met-enkephalin is involved in regulating cell proliferation and can inhibit cancer cell growth in multiple cell lines. Increased met-enkepahlin levels created by LDN thus have the potential to inhibit cancer growth in humans. Phase II human trials of met-enkephalin, case reports published by Berkson and Rubin, and the clinical experience of Bihari confirmed the potential role of LDN in treating pancreatic and other cancers. However, large scale trials are lacking and are unlikely to be funded given the current non-proprietary status of naltrexone. A case report is presented of successful treatment of adenoid cystic carcinoma as further evidence of LDN's potential as a unique non-toxic cancer therapy. PMID- 25284546 TI - Dental management in an encephalotrigeminal angiomatosis patient: a case report. AB - Sturge-Weber Syndrome (SWS) is a rare, non-hereditary, congenital neuro cutaneous disorder characterized by vascular hamartomatous proliferations affecting classically, the leptomeninges and the skin of the face and may be associated with glaucoma, seizures and mental retardation. Intraoral findings are variable. A case of Roach type II Sturge Weber syndrome is reported here that did not show any neurological disorder but revealed a prominent angiomatous enlargement of the ipsilateral maxillary gingiva. SWS is a condition where dental management and surgical procedures of the patient can be risky, thus a sound knowledge of the disease and its management protocols better equips the clinician to avoid serious complications. PMID- 25284547 TI - Kohlschutter-Tonz syndrome in siblings without ROGDI mutation. AB - BACKGROUND: Kohlschutter-Tonz syndrome is a rare neurodegenerative disorder presenting with intractable seizures, developmental regression, and characteristic hypoplastic dental enamel indicative of amelogenesis imperfecta. Recently, mutations in ROGDI were identified in part of Kohlschutter-Tonz syndrome cases, but the siblings reported here do not have a mutation in the ROGDI gene, showing that there is genetic heterogeneity in Kohlschutter-Tonz syndrome. AIM: Report two siblings that have Kohlschutter-Tonz syndrome. CONCLUSION: Early onset of seizures and lack of the ability to walk without support may be signs of non-ROGDI mutations in Kohlschutter-Tonz syndrome patients. PMID- 25284548 TI - Endodontic management of a young patient with avulsion and root fracture: a case report with 4 years follow-up. AB - Avulsion and root fractures are complications may be seen after a traumatic accident. These should be diagnosed and treated as soon as possible because the time elapsed between the trauma and start of the treatment is considered as the most important factor in the prognosis. All treatment protocols should be directed toward the management of the pulp and periodontal ligament. The present case report reviews a 22-year-old male patient which was visited with 5 hours delay after accident and avulsion of right central incisor. The avulsed tooth soaked in 2.4% fluoride solution for 20 minutes. Extra-oral root canal treatment was performed and it was immediately replanted. Anterior maxillary teeth were splinted by a semi-rigid splint. After 10 days, an intra-oral sinus tract was observed on the oral mucosa of the left central incisor, its tracing revealed a root fracture on this tooth. The coronal section of this tooth was endodontically treated. Four years follow-up revealed no radiographic or clinical signs and symptoms. PMID- 25284549 TI - Analysis of carious dentine using FTIR and ToF-SIMS. AB - Apart from the Maillard reaction, other processes, such as esterification, take place in carious tissue. The aim of the present study was to analyse sound and carious dentine in terms of ester groups and their reaction with hydrazine derivate using Fourier Transform Infrared Spectroscopy (FTIR) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). Carious and sound dentine from human premolars were excavated in three series (Experimental Parts I-III) and separated into inner and outer layers of carious dentine. The excavated tooth material was analysed with FTIR (Part I). Carious and sound dentine were also exposed to different chemical treatments and analysed with FTIR-Attenuated Total Reflectance (FTIR-ATR; Part II) and ToF-SIMS (Part III). The FTIR absorption spectra showed that the carious tissue contained ester groups, not detected in sound dentine. The results also indicated a higher occurrence of ester groups in the inner dental caries layer than in the outer ones. Potential binding to these ester groups by hydrazine derivative was observed after different chemical treatments with both FTIR-ATR and ToF-SIMS. The results of the present study revealed ester groups unique to the carious dentine which, after reaction with hydrazine derivative, form a covalent bond not found in sound dentine. The staining of carious unique groups would be clinically helpful in detection and prevention unnecessary removal of sound dentine. PMID- 25284550 TI - Are you willing to treat patients with HIV/AIDS? An anonymous survey among staff and students of dental institution. AB - BACKGROUND: India is one of the largest and most populated country in the world, with over one billion inhabitants. Of this number, it is estimated that around 23.9 lakh people are currently suffering with HIV. People living with HIV/AIDS (PLWHA) require increasingly competent and compassionate health care, including oral health care. OBJECTIVES: The present study was conducted with the objective of evaluating the response of dental health care professionals (staff and students) in willingness to provide treatment to HIV/AIDS patients and whether the training and education provided to them is sufficient to handle such patients, or whether there is necessity for advanced curriculum to be implemented. MATERIALS AND METHODS: An anonymous survey with the permission from ethical committee of dental institution was conducted with the use self administered questionnaire eliciting information on self-rated HIV/AIDS knowledge, attitudes, infection control practices, occupational risk perception and willingness to treat HIV/AIDS patients. RESULTS: An increase in level of knowledge was observed with the increase in year of study from first BDS to post graduation and MDS staff. It was observed that interns and post graduate students were willing to treat patients with HIV/AIDS. Staff of the institution showed greater concern to undergo training to provide efficient treatment to patients with HIV/AIDS. CONCLUSION: It was concluded that there was a positive attitude and willingness of staff and students to treat a patient suffering with HIV/AIDS. Also, there was willingness and interest of the staff and students of the dental institution to participate in training programmes to provide better and more efficient treatment to HIV/AIDS patients. PMID- 25284551 TI - Effect of long term 900 MHz radiofrequency radiation on enamel microhardness of rat's teeth. AB - PURPOSE: Oral tissues are important parts of body that absorbs radiation emitted from mobile phones which is the most popular technological equipment in the world. Because of the limited studies in this field, we aimed to investigate the effect of Radio Frequency (RF) radiation emitted from 900 MHz mobile phones on the enamel micro hardness of rat teeth. MATERIALS AND METHODS: The study was carried out on twenty one Wistar Albino adult male rats which were divided into two groups such as control and experiment groups. For the study group (n: 14), rats exposed to the radiation 2 h per day (7 days in a week) for 10 months. For the control group (n: 7), rats were placed into the carousel and the same procedure was applied except that the generator was turned off. At the end of the study, enamel micro hardness of rat's teeth was measured. RESULTS: The results of this study showed that 900 MHz RF radiation did not alter the enamel micro hardness of rats' teeth (p>0.05). CONCLUSIONS: Exposure of 900 MHz RF radiation for 2 hours per day during ten months does not alter enamel micro hardness of rats' teeth. However, further studies are necessary to clarify this topic. PMID- 25284552 TI - Effects of oxidative irrigants on root dentin structure: Attenuated Total Reflection Fourier Transform Infrared Spectroscopy study. AB - AIM: The aim of this study was to compare the effect of oxidative irrigants on the organic and inorganic structure of root canal dentin. METHODOLOGY: Fifty human 2nd premolar roots were used in the study. The dentin specimens prepared from those teeth were immersed in liquid nitrogen for 15 min. The frozen composition was titrated in a mixer and the obtained dentin powder was kept frozen at -70 degrees C until use. Ten groups of 50mg dentin powder were immersed in agents (A: Ozone for 100 or 200 sec, B: 5.25% NaOCl, C: 2.25% NaOCl, D: 2% Chlorhexidine, E: 0.9% NaCl (control)) for 5 or 10 min. An Attenuated Total Reflection Fourier Transform Infrared Spectrophotometer (ATR FT-IR) was used to analyze dentin powder. The data were statistically analyzed by using Kruskall Wallis analysis of variance. RESULTS: In all groups, collagen degradation was significantly increased compared to the control and 2% CHX groups (p<0.05). The use of ozone increased collagen degradation significantly compared to the use of 2.25% NaOCl and 2% Chlorhexidine for 5 min (p < 0.05). No significant differences were observed between ozone and 5.25% NaOCl-treated groups (p > 0.05). CONCLUSIONS: The structural composition of human dentin was significantly affected by the use of oxidative irrigants at higher concentrations. PMID- 25284553 TI - Methods for evaluation of masticatory efficiency in conventional complete denture wearers: a systematized review. AB - The objective of this study was to present a systematized review of different methods used to evaluate the masticatory efficiency in conventional complete denture wearers. A survey was conducted in the databases PubMed, Scopus, and Cochrane, seeking scientific articles according to the previously selected terms: "Masticatory performance", "Masticatory efficiency" and "Chewing ability complete denture". Moreover, complementary studies have been carried out with library manual search/databases, which included studies related to different ways to assess masticatory efficiency, specifically as it related to conventional complete denture wearers. Forty three papers were selected to be used in the present review. Despite the wide variety of methodologies in the literature, the sieves method is currently considered the gold standard method to evaluation of conventional complete denture wearers masticatory efficiency, since it is the simplest, does not depend on specific devices (beyond the set of sieves), allows for a rational assessment, and it has been widely reproduced in various types of oral rehabilitation. More, the almond, as natural test food, and the optocal (made from the molding material Optosil), as artificial test food, are the most constantly employed test foods to evaluate masticatory efficiency. PMID- 25284554 TI - Access of children to the oral health service. AB - BACKGROUND: Dental caries still affect a considerable proportion of children, however the epidemiological profile of oral diseases is changing, social inequalities cause different disease patterns. The same problems occur for the use of services, which damage those who are more susceptible to oral diseases in numerous ways. AIM: To verify the association between the variables: socioeconomic condition, oral health and access to dental services providing oral health care for preschool children. METHODS: The study population consisted of 2,759 children up to 6 years-old. The clinical exams followed the World Health Organization (WHO) criteria. The data were collected using a self-applied questionnaire, answered by the carers of children, with questions about socioeconomic variables and access to dental services. RESULTS: In terms of social class, a majority of the subjects came from the middle socioeconomic level (babies, 84.7%; children, 82.8%). Babies who had caries, 48.4% and 67.2% of the children that had decayed teeth had access to dental service. There was a association between the variables: the reason for the last dental appointment and the parent's perception of the treatment need of their children (babies p=0.0004 and children p < 0.0001); the parent's perception of the treatment need of their children and the oral health condition (babies p=0.0008 and children p < 0.0001); access to dental services and oral health condition (babies p=0.0021 and children p < 0.0001). CONCLUSION: The majority of the population studied sought care from public dental service and was from the middle class. PMID- 25284555 TI - Tuberculosis--frequency and differential diagnosis--analysis of cases in Pakistan. AB - BACKGROUND: Tuberculosis is highly prevalent in Pakistan and the numbers are on increase each year. Cervical lymphadenopathy, a common finding in tuberculosis and other inflammatory, infectious and malignant etiologies, is commonly encountered in hospital setting in Karachi, Pakistan. Signs and symptoms of tuberculosis are blood tinged sputum, weight loss, night sweats, loss of appetite and weakness. A through history, complete physical examination and investigations are needed to diagnose tuberculosis. OBJECTIVE: To determine the burden of tuberculosis in cases of cervical lymphadenopathy and to find the most common etiologies of cervical lymphadenopathy in hospital setup in Karachi, Pakistan. METHODS AND MATERIALS: Patients with cervical lymphadenopathy attending the surgical outpatient department of Jinnah Post Graduate Center, Karachi, Pakistan were conveniently sampled for this study without age and gender limitations. This cross sectional, descriptive study was conducted from January 2010 to January 2011. RESULTS: A total of 250 patient cases with cervical lymphadenopathy were studied. The age group with the highest number of patients was between 21 to 40 years, which included 97 females and 21 males. The patients with unilateral single cervical lymph node swelling were found to be 13.2%, while 86.8 % patients had multiple bilateral lymph node swellings. Tuberculosis was found in majority of patients, 63.6% followed by inflammatory hyperplasia which was present in 28.4% patients, other causes included lymphoma 5.2% and metastasis 2.8%. CONCLUSION: Tuberculosis is the most common etiology of cervical lymphadenopathy, followed by inflammatory hyperplasia, lymphoma and metastasis. PMID- 25284556 TI - Practical application of a method for assessing the progression of gingival recessions in orthodontically treated patients--a pilot study. AB - AIMS: The objective of the present study was to discuss the practical application of a new method for measuring bone width in the anterior section of the mandible to assess the progression of gingival recessions after orthodontic treatment based on a description of case studies. METHODS: Three cases with skeletal classes I, II and III aged 20-29 were presented. We assessed the risk of gingival recessions around lower incisors by analysing cephalograms before and after orthodontic treatment. The following values were analysed: the angle of buccal bone thickness in the anterior section of the mandible (API-CEJ2-B), the height of bone dehiscence (CEJ2-Id) and the width of the mentalis (B-D). Recession height (RD) and width (RW) were clinically measured using calibrated 1mm periodontometer. RESULTS: The mean baseline angle of API-CEJ2-B[ degrees ] was 22.23 degrees before and no lower than 16 degrees after treatment. In all patients CEJ2-Id was 0.56 mm before and greater than 1.4 mm following treatment. This was reflected clinically in the absence of new gingival recessions or the progression of an already existing recession in the area of the lower incisors in the first two cases. In the third case, height of recessions was increased to 1.25 mm average value. The mean baseline width for B-D was 13.46 mm; in all cases it increased up to 14.5 mm after treatment, most significantly in the case of a female patient with skeletal class II. CONCLUSIONS: An analysis of cephalometric images, including basic cranio- and gnathometric measurements together with a careful assessment of bone, mucosal and dental parameters of the alveolar ridge, can be a useful instrument to determine the risk of gingival recessions and to choose the right orthodontic treatment option, ensuring the highest possible aesthetic-functional treatment outcome. PMID- 25284557 TI - An evaluation of 0.2% hyaluronic acid gel (Gengigel (r)) in the treatment of gingivitis: a clinical & microbiological study. AB - AIM: Hyaluronic acid is a glycosaminoglycan with anti-inflammatory & anti edematous properties. This study is seeking to ascertain whether Hyaluronic acid gel formulation is clinically and microscopically effective in treatment of gingivitis. METHODS: In longitudinal, randomized, and placebo-controlled clinical trial, 105 patients with chronic plaque induce gingivitis were randomly divided into three groups; negative control group, placebo control group and test group. Patients were instructed to apply gel on inflamed gingiva twice daily in addition with routine oral hygiene maintenance. The clinical parameters Plaque Index (PI), Gingival Index(GI) and Papilla Bleeding Index (PBI) were determined at intervals of 1 week, 2 weeks and 4 weeks from baseline, microbiological parameters were monitored at the interval of 4 weeks from baseline. RESULTS: An improvement of all clinical variables was observed (p<0.05) for all treatment modalities. Clinically, There is significant difference (p<0.05) for GI & PBI in test group as compared to other groups, but reduction in PI was non-significant. In negative control and placebo control groups, the difference between clinical parameters was non-significant. Statistically significant (p<0.05) reduction in percentage of anaerobic gram negative bacilli and relative increase of gram positive coccoid cells was seen in all treatment groups at 4 weeks as compared to baseline. However, results were not statistically significant (p>0.05) in pair wise comparison in between groups. CONCLUSION: Local application of 0.2 % HA gel adjunct to non surgical periodontal treatment provided a significant improvement in clinical parameters than placebo control and negative control groups. Microbiologically experimental group does not showed any spastically significant results. PMID- 25284558 TI - Malocclusion in individuals with mental subnormality--a review. AB - The occurrence of malocclusion in individuals with mental disability poses an additional obstacle to social acceptance; not only from an esthetic point of view, but also in that it compromises all aspects of oral function. This review examines the reported prevalence of malocclusion in individuals with mental subnormality including Down syndrome, from 1981 to 2013, assessed according to Angle's classification, the Dental Aesthetic Index (DAI), the Index of Orthodontic Treatment Need (IOTN) and certain malocclusions. Although widely reported in many studies, it is still quite difficult to compare the exact proportion of occlusal anomalies and orthodontic treatment need among mentally challenged individuals. This is due partly to the multiplicity of measurement methods and the difficulty in standardizing criteria. Several studies have reported higher prevalence of malocclusion including anterior open bite, anterior cross bite, severe malocclusions in mentally challenged individuals, especially those with Down syndrome. The findings have been varied and attributed to musculoskeletal abnormalities, altered cranial-base relationships, premature tooth loss or eruption, lip incompetence, etc. Future research needs to be devoted to determining exactly why malocclusion is higher among individuals with mental subnormalities. It will be a challenge to identify the preventable factors among multiple complex etiologies to reduce these disparities. PMID- 25284559 TI - Knowledge of mothers with different education levels about the emergency management of avulsed teeth. AB - PURPOSE: The present study was undertaken to evaluate and assess, through questionnaire, the knowledge of mothers with different education levels regarding the emergency management of avulsed permanent teeth. BACKGROUND: The replantation is the preferred treatment for avulsed tooth. The prognosis depends upon the handling of the periodontal ligament and speed of replantation. Mothers are commonly taking care of children and are around them when such injuries can occur. Their knowledge about emergency management of avulsed tooth is important; that can vary upon the level of education of mothers. METHODS: The 800 mothers were divided into two groups of 400 each depending upon two different educational levels- primary and higher/technical education. After obtaining the consent, they filled 10 item questionnaire containing both correct and wrong answers related to emergency management of avulsed teeth. Collected data was statistically analyzed. RESULTS: The results indicated highly significant difference in the knowledge of mothers of two groups regarding emergency management of avulsed teeth with better knowledge and awareness in mothers with higher/technical education. CONCLUSION: Mothers with technical school education had better knowledge than mothers with primary school education. However, mothers of both the groups were severely lacking in the complete and accurate knowledge. PMID- 25284560 TI - Social factors and dental health in the urban adolescents of Isfahan, Iran. AB - AIM: The aim of this study is to determine the dental caries and oral health behavior status of urban adolescents in Iran. Also it assesses the influence of the socioeconomic background on their oral health outcomes. METHODS: A cross sectional study was conducted in the students living in the city of Isfahan, Iran. 597 adolescents by 13 to 17 years old participated in the study. The asset based wealth index, household income and parents' educational history were the indicators of socioeconomic status. Data on tooth brushing frequency and smoking experience were collected, and the adolescents were examined for their dental health status. The index of DMFT was recorded by two calibrated examiners considering the criteria of World Health Organization. Bivariate analysis and multivariate regressions were employed to explore the association between dental caries status and socioeconomic variables. RESULTS: The DMFT mean (SD) of the study population was 2.79(2.7) with attributable 50, 4 and 46 percent to D, M and F components and 26% caries- free prevalence. Nearly 19% of the students presented twice daily brushing and 3% of respondents had smoking experience. Dental caries did not show any linear relationship with the social indicators when the DMFT was modeled by the wealth index, parents' educational level and family income adjusted for age and gender. Without adjustment, lower income has increased the chance of untreated tooth decay, 2.5 times among the students. CONCLUSION: Despite the supporting findings on inequalities in oral health, this study did not show a direct association between socio economic backgrounds of the adolescents with their dental health/disease. The hypothesized balanced risk exposure is considered to justify the results, but it needs to be studied by further comprehensive analysis. PMID- 25284561 TI - Dental caries experience among secondary school children in the Vardar region of the Republic of Macedonia. AB - AIM: The aim of this study was to assess the dental caries in 15-year-old children attending regular public secondary schools in Veles. METHODS: The study has been carried out during 2013 on adolescents aged 15.01(+/- 0.42).In this cross-sectional study, the secondary school children from first grades (N = 127) have been selected from 2 Secondary Schools in Veles. The dental status of the participants was evaluated on the basis of the 1997 World Health Organization caries diagnostic criteria for Decayed, Missing or Filled Teeth (DMFT) by 2 calibrated examiners. P value <= 0.05 was considered statistically significant. RESULTS: The total number of children in the exercise was 127, consisting of 59 (46.46%) female and 68 (53.54.2%) male. The mean DMFT was 4.9768, with standard deviation (SD) of 3.5084 and 95% confidence interval (CI) of 4.3603-5.5925. Significant Caries (SiC) index was 8.9302. The prevalence of caries-free children was 9.45%. The percentage of untreated caries or the ration of D/DMFT was 0.5601 (56.01%). CONCLUSIONS: The present study provides some evidence of relatively high caries prevalence and severity in comparison with the Western European countries. It is necessary to dedicate more attention to the oral health of children and adolescents in our country. PMID- 25284562 TI - Intentional replantation of a mandibular canine with multiple iatrogenic endodontic complications. AB - Teeth being exposed to multiple iatrogenic complications during root canal treatment are usually extracted and replaced with a dental implant. This case report presents the treatment of a mandibular canine that had multiple endodontic complications using an intentional replantation technique. The case was showing swelling and pain, unusual canal anatomy, periapical lesion, broken instruments, and root perforation in association with overfilling. After extraction of the root, the resected root end and perforation were sealed using mineral trioxide aggregate. The root was replanted extrusively, fixed and restored with a crown. Appearances of slowly progressing replacement resorption were detected radio graphically at 6-, 12- and 24-month recalls. The tooth was functioning successfully without showing clinical symptoms at 6-, 12-and 24-month recalls. PMID- 25284563 TI - Exploring the predictors of quitting tobacco usage among patients attending a private dental institution--a survey from Jodhpur, India. AB - BACKGROUND: Burden of tobacco epidemic has swiftly moved to developing countries making the exploration of predictors of quitting tobacco usage extremely important. AIM: To assess the willingness to quit tobacco use and to ascertain the predictors of quitting tobacco as well as tobacco dependency by employing Fagerstrom scale. METHODS: The study consisted of 252 subjects visiting the Public Health Dentistry department in a Dental institution JDCGH (Jodhpur Dental College General Hospital), Rajasthan, India. Data on demographic information, tobacco usage and quitting, information on reasons for quitting like; self concepts, social concerns, legal issues, and health concern was collected by interview schedule method. RESULTS: Overall 76% of the study participants were planning to quit. Demographic variables like age, marital status and religion were significant predictors of planning to quit tobacco usage (p <= 0.05). Significant relationship was observed on Fagerstrom Scale with place of residence, type of tobacco use and frequency of tobacco use (p <= 0.05). The most frequent cited reason for quitting tobacco usage was spitting and ash dropping which was embarrassing in-front of others (75.65%) and least reported reason was future health concerns (33.16%). CONCLUSIONS: Most of the respondents had favourable attitude towards quitting tobacco usage and social concern was the main predictor of quitting tobacco usage. Less reported reasons like legal issues and health concerns have to be explored in depth. The present study highlights the need for more researches exploring the predictors of quitting tobacco usage in India and further nationwide study. PMID- 25284564 TI - Diagnostic utility of galium 67 SPECT/CT and role of pentoxifylline-tocopherol in chronic multifocal osteomyelitis. AB - Advances in radiology have helped in early diagnosis, surveillance and proper management of disease processes. SPECT scintigraphy is an imaging modality that helps in the detection & diagnosis of facial & skull osteomyelitis and is also useful for detecting silent lesions. Pentoxifylline-tocopherol together helps in faster healing of diseased bone. Pentoxifylline reduces blood viscosity and thus improves microcirculation. Tocopherol has a synergistic action with pentoxifylline and increases the oxygenation of tissues. Here, a case of chronic multifocal osteomyelitis, involving the mandible and occipital bone is presented which was diagnosed with conventional radiographs and gallium 67 bones SPECT. Simultaneous treatment with pentoxifylline-tocopherol and antibiotics relieved the patient's symptoms. PMID- 25284565 TI - A survey on radiographic prescription practices in dental implant assessment among dentists in Kerala, India. AB - AIMS AND OBJECTIVES: To conduct a survey of the current radiographic prescription practices among implant practitioners in the state of Kerala, India. METHODS: 300 dentists were interviewed by employing a questionnaire which enquired about the radiographic evaluation methods prescribed by practitioners in implant site assessment in their implantology practice. Other reasons for choosing particular imaging modalities were also enquired. The data collected from the survey was analysed using Epi-Info 7.1.3 software. RESULTS: Around 87.33% of the dentists prescribed only OPG for the implant site assessment and only 4.66% ordered Orthopantomograph (OPG) in combination with an Intra Oral Periapical Radiograph (IOPAR) and 4.33% ordered OPG with Computed Tomography (CT). Only 0.02% of the practitioners ordered CT as a single examination and 1% ordered it in conjunction with other modalities. 0.066% individuals ordered IOPAR as the sole imaging modality and none of them ever prescribed conventional or Cone beam computed tomography. CONCLUSIONS: Our study has conclusively proven that most of the dentists prescribe OPG followed by a combination of OPG and Intraoral periapical radiographs in their implant practices. Many of them were not aware and did not follow the American Academy of Oral and Maxillofacial Radiology, European Academy of Dentomaxillofacial Radiology, European Association of Osseointegration and International Congress of Oral Implantology recommendations regarding cross sectional imaging. PMID- 25284566 TI - Revascularization procedure induced maturogenesis of upper permanent incisor. AB - Treatment of carious or traumatized teeth with open apex is usually a challenge to a dentist. Recently, some case reports have shown that revascularization process induced maturogenesis of immature non-vital teeth. This case report describes the successful revascularization process of an immature central incisor. The upper left central incisor of 14-year-old boy was treated by revascularization process induced maturogenesis procedures. The tooth was symptomatic and caused a mucogingival swelling before the treatment. 3 years follow-up radiographs show a root elongation and an apical closure in the tooth treated with revascularization process. Revascularization procedure induced maturogenesis have several advantages over conventional apexification procedure. PMID- 25284567 TI - Workplace bullying: an emergent issue. AB - All companies, including dentists, rely on their staff to represent their firms in the most positive and effective manner. Today's managers face a multitude of issues, and as such, they must walk a fine line of fostering a productive, harmonious and safe working environment for their employees. Over the last several decades it is apparent that on the- job sexual harassment is no longer the leading issue of employee complaints. Rather, the organization issue which was investigated is workplace bullying, also commonly referred to as employee harassment. Risk management is no longer limited to avoiding malpractice issues but also preventing litigation created by poor organizational behavior. The primary purpose of this paper is to explore the background of workplace bullying and how it affects today's managers and their employees, customers and suppliers. In other words, the scope of this paper will feature research on past studies, results and conclusions. Since workplace bullying affects all levels of a corporation, it must be stated that the concern and focus of this paper is for today's manager to understand the background and history of workplace bullying, and what they can do to foster a safe working environment and prevent the bully from creating mental and physical harm to their employees. This paper details the history of workplace bullying and how management, employees and suppliers deal with and address the issue. Lastly, this treatise looks at risk management from a manger/dentist's perspective, the assessment/conclusion summarizes the implications for managers regarding how they must handle the issue or risk harm to the employee and/or serious legal ramifications. PMID- 25284568 TI - Self-perception and oral health in pregnant adolescents. AB - OBJECTIVE: To evaluate the oral health indicators by determining the experience of dental caries and periodontal disease and identification of self-perceived oral health status of pregnant adolescents and to assess the association between the studied variables. MATERIALS AND METHODS: A transversal study, survey type and survey of the oral health status of 127 adolescents, 10-19 years of age, pregnant, accompanied by the Unified Health System of Aracatuba-SP was performed. The self-perceived oral health and socio-demographic data were recorded using an adapted questionnaire. The oral health statuses were analyzed using the DMFT and CPI indices in accordance with the criteria established by the WHO for epidemiological survey. Descriptive statistical analyzes and the Fisher's exact test with a significance level of 5% was performed, as well as a logistic regression analysis to verify the association between the variables. RESULTS: Of the total, 41.0% reported having satisfactory oral health, while 63.0% believed they had problems with their teeth and gums. The DMFT index was 12.51 (SD = 4.21). The percentage of caries-free was 6.3%, and 91.3% had periodontal problems. A statistically significant association was found between the variables: self-perceived oral health and periodontal disease p = 0.0166 and self reported gum disease and periodontal disease p = 0.0039. CONCLUSION: Most patients considered their oral health as poor and reported having dental and gum problems, which can also be observed in the clinical examination since the caries experience of the pregnant women examined was considered high and the symptoms of periodontal disease were observed in most of the volunteers. PMID- 25284569 TI - Phenytoin effects on inflammatory mediator's production by gingival fibroblasts: a comparative study in children and adults. AB - BACKGROUND: About 30 to 50% of patients taking Phenytoin develop significant gingival alternations especially in buccal anterior part of oral cavity. This study was done to compare the synthesis of its inflammatory mediators and related gingival overgrowth in different ages. METHODS: Samples were collected from biopsy of a healthy gingival of four adults in 35-42 years old through crown lengthening surgery and four children in 4-11 years old through impact tooth surgery, after local anesthesia and from the keratinized soft tissues around the teeth. Gingival biopsies were transferred to a medium which containing DMEM and cultured on specific plates 25 cm2 and put on incubator containing CO2 with temperature of 37 degrees C. MTT was used to compare the Proliferation rate of fi broblasts. Supernatant of culture medium of test and control sinks were collected by sampler and concentration of IL1beta, PGE2, IL6, TGFbeta, TNFalpha and IL8 were analyzed by ELISA. RESULTS: Different proliferation rate of Phenytoin induced gingival fibroblasts in adults (0.073 +/- 0.177) as compared to children (0.056 +/- 0.028) was not significant. Production of PGE2, TGFbeta and IL6 by Phenytoin induced gingival fibroblasts in children was increased as compared to adults (p < 0.05). Production of IL8 by Phenytoin induced gingival fibroblasts in children was decreased compared to adults (P = 0.02). CONCLUSION: Phenytoin induced gingival fibroblasts of children produce more amounts of IL1beta, PGE2, IL6, TGFbeta and IL8 as compared to adults' fibroblasts. More Comprehensive studies with well-documented designs using other methods are recommended to verify these results. PMID- 25284570 TI - Accidental ingestion of an inter-occlusal device used for the restoration of occlusion: a case report. AB - The accidental swallowing of prosthetic devices has been discussed in the relevant literature as an unusual, although ordinary, event in clinical practice. This article aims at reporting the ingestion of an inter-occlusal device used to restore the Vertical Dimension of Occlusion (VDO) which, during the ingestion of an analgesic pill, was accidentally swallowed. The patient was sent to the Clinics Hospital UFMG where, upon taking radiographs, the device was located in the upper third of the esophagus. The device was removed during an endoscopic exam with the help of forceps for removing foreign objects. Dealing with a relevant situation, one may conclude that patients who use removable intra-oral devices must take part in a reevaluation protocol in order to detect adaptation and retention of these devices, as well as proper instruction for the patient. PMID- 25284571 TI - Orthodontic treatment need in Dubai school adolescents: a study of 20,000 school age adolescents in 66 public and private schools comparing orthodontic treatment need by gender and ethnicity. AB - AIM: The purpose of the study was to compare and contrast the orthodontic treatment needs of Dubai school-age school age children as a function of gender and ethnicity. METHODS: A total of 20,880 subjects were screened in 66 public and private school located in Dubai, United Arab Emirates. The study sample was grouped according to seven geographic regions. The total sample included 9,765 females and 11,115 males. Ages ranged from 9.08 years to 24.4 years with an overall mean age of 14.5 years. Calibrated dentists examined school age children using Peer Assessment Rating Index (PAR). PAR scores were translated to Index for Orthodontic Treatment Need (IOTN) scores based upon the description of each of the 31 IOTN line item descriptions that constitute IOTN grades from 1 to 5. Upon completion, statistical comparison of the study variables by gender and ethnicity was applied. RESULTS: Evaluation of IOTN grade by gender demonstrated significantly higher male (2.52) than female (2.47, p=0.002) grade; comparison of IOTN grade by region showed South Asia (2.58) significantly higher than Middle East (2.43). IOTN grade was highest for South Asia males (2.62) which was significantly higher than South Asia females (2.55, p=0.023) and higher than both Middle East males and females (2.45 and 2.41, p=.000). Moreover, average South Asia female IOTN grade was significantly higher (p=0.000) than for both Middle East males and females. Conclusions 1. In Dubai school-aged adolescents, 53.2% of the study sample would benefit from orthodontic treatment and 14.4% were profiled as "treatment require". 2. Within the Middle East region, UAE subjects had higher mean IOTN grade than subjects from Iran, Syria and Yemen. 3. India males had significantly higher mean IOTN grades than Middle East male and female subjects from UAE, Iran, Syria, and Yemen. 4. India females had significantly higher mean IOTN grades than Middle East female subjects from UAE, Iran, Syria, and Yemen. It may be concluded that males and females from India have the greatest orthodontic treatment need in Dubai public and private schools. PMID- 25284572 TI - Micro leakage of composite resin restorations following contamination with primary teeth root canal filling materials: an in vitro study. AB - AIM: The aim of this in vitro study was to assess the microleakage of composite restorations following contamination of access cavity with root canal filling materials of primary teeth. MATERIALS AND METHODS: Forty primary canines were selected for this study. Standardized access cavity on the lingual surface of the canine was prepared. The margins of preparation were ended on enamel. The teeth were randomly assigned into 4 groups (10 teeth/group). Teeth in group 1 served as a control, no material applied. For the other 3 groups the access cavity was filled with one of the following root canal filling material: Zinc Oxide and Eugenol (ZOE), calcium hydroxide (Ca(OH)2) and Vitapex. The root canal filling paste was left for two minutes in the cavity then washed out. The access cavity then restored with composite resin. After thermocycling for 500 cycles, teeth were immersed in 1% methylene blue for 24 hours, and then sectioned longitudinally in bucco lingual direction. The microleakage evaluation was carried under stereo-microscope and the worst result for each section was recorded. The data were statistically analyzed using Kruskal-Wallis and Post Hoc tests. RESULTS: All samples in the ZOE group showed leakage. However, the control, Ca(OH)2 and Vitapex groups showed leakage in 30%, 40% and 50% of the tested samples respectively. Microleakage occurred more significantly in ZOE group in comparison to the other test groups (p=0.00). Nevertheless, there was no significant difference in microleakage between the control group, Ca(OH)2 and Vitapex groups. CONCLUSIONS: Contamination of the access cavity with primary teeth root canal filling materials showed different levels of leakage in composite resin restoration and the ZOE group showed the highest microleakage scores. PMID- 25284573 TI - The bone splitting stabilisation technique--a modified approach to prevent bone resorption of the buccal wall. AB - The aim of this case series was to clinically demonstrate successful prevention of bone resorption of the buccal wall after alveolar bone splitting by additional stabilization of the lateral bone plate using a biphasic ceramic bone substitute. In three patients alveolar bone splitting was performed with a piezoelectric device. Clinical as well as radiological results after two and five years revealed stable hard and soft tissue conditions with no soft tissue recessions and peri-implant bone loss in three patients. The advantage of this one-stage procedure was the ability to insert dental implants into a very compromised bony site in a simultaneous procedure. Yet the bone splitting stabilisation technique appeared to be a more user-sensitive method. PMID- 25284574 TI - Oral cavity squamous cell carcinoma--an overview. AB - Inhaled or chewed tobacco is equally addictive and harmful and used daily by over 1 billion people. In addition to increased rates of coronary artery disease, stroke, peripheral vascular disease, congestive heart failure, chronic obstructive pulmonary disease and lung cancers, tobacco is the leading preventable cause of oral cavity squamous cell carcinoma. In addition to tobacco, consumption and abuse of alcohol, and betel nut quid significantly contribute to the burden of oral cavity squamous cell carcinoma. Dental visits are excellent opportunities to identify primary lesions in the oral cavity. This review highlights relevant anatomy, epidemiology, pathogenesis, evaluation and treatment options for oral cavity squamous cell carcinoma. PMID- 25284575 TI - We stop for no storm: coping with an environmental disaster and public health research. AB - Coping with natural disasters is part of the public nurses' role, and the public health nursing (PHN) researcher is doubly challenged with continuing to conduct community-based research in the midst of the disaster. The PHN may provide service along with attempting to continue the research. The challenges faced by public/community health nurse researchers as a result of hurricane Ike are discussed to provide lessons for other public/community health researchers who may be affected by natural disasters in the future. It is important to consider challenges for recruitment and retention of research subjects after a disaster, impact of natural disasters on ongoing research, and opportunities for research to be found in coping with natural disasters. A community-based study that was in progress at the time of hurricane Ike will be used as an example for coping with a natural disaster. We will present "lessons learned" in the hope of helping researchers consider what can go wrong with research studies in the midst of natural disasters and how to proactively plan for keeping research reliable and valid when natural disasters occur. We will also discuss the opportunities for collaborations between researchers and the community following any disaster. PMID- 25284576 TI - Obituary: professor ignacio v. Ponseti (1914-2009). PMID- 25284577 TI - ASAMI 2009 Abstracts. PMID- 25284579 TI - Rapid determination of IL-6 specific activity by flow cytometry. AB - Current methods to measure the specific activity of cytokines are based on the time-consuming determination of the growth curve of a sensitive cell line. Here, we present a faster alternative based on flow cytometry, by determining the dose response curve of cellular response to a cytokine. By using World Health Organization (WHO) cytokine standards, rapid determination of cytokine specific activity is now possible, as it takes only a few hours to achieve, in comparison to days with the classical method thus allowing laboratories to rapidly and easily assess the potency of their cytokines. PMID- 25284578 TI - A family history of diabetes determines poorer glycaemic control and younger age of diabetes onset in immigrants from the Middle East compared with native Swedes. AB - AIMS: Immigrant populations from the Middle East develop diabetes earlier than indigenous European populations; however, the underlying etiology is poorly understood. This study looked at the risk factors associated with early diabetes onset and, in non-diabetics, glycaemic control in immigrants from Iraq compared with native Swedes. METHODS: This cross-sectional population-based study comprised 1398 Iraqi immigrants and 757 Swedes (ages 30-75years) residing in the same area of Malmo, Sweden. Outcomes were age at diabetes onset and glycaemic control (HbA1c) as assessed by Cox proportional hazards and linear regression, respectively. RESULTS: In Iraqis vs Swedes, clustering in the family history (in two or more relatives) was more prevalent (23.2% vs 3.6%, P<0.001) and diabetes onset occurred earlier (47.6years vs 53.4years, P=0.001). Having an Iraqi background independently raised the hazard ratio (HR) for diabetes onset. Diabetes risk due to family history was augmented by obesity, with the highest HRs observed in obese participants with clustering in the family history (HR: 5.1, 95% CI: 3.2-8.2) after adjusting for country of birth and gender. In participants without previously diagnosed diabetes (Iraqis: n=1270; Swedes: n=728), HbA1c levels were slightly higher in Iraqis than in Swedes (4.5% vs 4.4%, P=0.038). This difference was explained primarily by clustering in the family history rather than age, obesity, lifestyle or socioeconomic status. CONCLUSION: The study shows that the greater predisposition to diabetes in Middle Eastern immigrants may be explained by a more extensive family history of the disorder; clinical interventions tailored to Middle Eastern immigrants with such a family history are thus warranted. PMID- 25284580 TI - The rabbit brachial plexus as a model for nerve repair surgery--histomorphometric analysis. AB - One of the most devastating injuries to the upper limb is trauma caused by the avulsion. The anatomical structure of the rabbit's brachial plexus is similar to the human brachial plexus. The aim of our study was to analyze the microanatomy and provide a detailed investigation of the rabbit's brachial plexus. The purpose of our research project was to evaluate the possibility of utilizing rabbit's plexus as a research model in studying brachial plexus injury. Studies included histomorphometric analysis of sampled ventral branches of spinal nerves C5, C6, C7, C8, and Th1, the cranial trunk, the medial part of the caudal trunk, the lateral part of the caudal trunk and peripheral nerve. Horizontal and vertical analysis was done considering following features: the axon diameter, fiber diameter and myelin sheath. The number of axons, nerve area, myelin fiber density and minimal diameter of myelin fiber, minimal axon diameter and myelin area was marked for each element. The changes between ventral branches of spinal nerves C5 Th1, trunks and peripheral nerve in which the myelin sheath, axon diameter and fiber diameter was assessed were statistically significant. It was found that the g-ratio has close value in the brachial plexus as in the peripheral nerve. The peak of these parameters was found in nerve trunks, and then decreased coherently with the nerves travelling peripherally. PMID- 25284581 TI - Functional/psychogenic movement disorders: do we know what they are? PMID- 25284582 TI - Differential roles of STAT3 in the initiation and growth of lung cancer. AB - Signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including pulmonary adenocarcinoma. However, the role of STAT3 in lung cancer pathogenesis has not been determined. Using lung epithelial-specific inducible knockout strategies, we demonstrate that STAT3 has contrasting roles in the initiation and growth of both chemically and genetically induced lung cancers. Selective deletion of lung epithelial STAT3 in mice before cancer induction by the smoke carcinogen, urethane, resulted in increased lung tissue damage and inflammation, K-Ras oncogenic mutations and tumorigenesis. Deletion of lung epithelial STAT3 after establishment of lung cancer inhibited cancer cell proliferation. Simultaneous deletion of STAT3 and expression of oncogenic K-Ras in mouse lung elevated pulmonary injury, inflammation and tumorigenesis, but reduced tumor growth. These studies indicate that STAT3 prevents lung cancer initiation by maintaining pulmonary homeostasis under oncogenic stress, whereas it facilitates lung cancer progression by promoting cancer cell growth. These studies also provide a mechanistic basis for targeting STAT3 to lung cancer therapy. PMID- 25284583 TI - CLIP2 as radiation biomarker in papillary thyroid carcinoma. AB - A substantial increase in papillary thyroid carcinoma (PTC) among children exposed to the radioiodine fallout has been one of the main consequences of the Chernobyl reactor accident. Recently, the investigation of PTCs from a cohort of young patients exposed to the post-Chernobyl radioiodine fallout at very young age and a matched nonexposed control group revealed a radiation-specific DNA copy number gain on chromosomal band 7q11.23 and the radiation-associated mRNA overexpression of CLIP2. In this study, we investigated the potential role of CLIP2 as a radiation marker to be used for the individual classification of PTCs into CLIP2-positive and -negative cases-a prerequisite for the integration of CLIP2 into epidemiological modelling of the risk of radiation-induced PTC. We were able to validate the radiation-associated CLIP2 overexpression at the protein level by immunohistochemistry (IHC) followed by relative quantification using digital image analysis software (P=0.0149). Furthermore, we developed a standardized workflow for the determination of CLIP2-positive and -negative cases that combines visual CLIP2 IHC scoring and CLIP2 genomic copy number status. In addition to the discovery cohort (n=33), two independent validation cohorts of PTCs (n=115) were investigated. High sensitivity and specificity rates for all three investigated cohorts were obtained, demonstrating robustness of the developed workflow. To analyse the function of CLIP2 in radiation-associated PTC, the CLIP2 gene regulatory network was reconstructed using global mRNA expression data from PTC patient samples. The genes comprising the first neighbourhood of CLIP2 (BAG2, CHST3, KIF3C, NEURL1, PPIL3 and RGS4) suggest the involvement of CLIP2 in the fundamental carcinogenic processes including apoptosis, mitogen activated protein kinase signalling and genomic instability. In our study, we successfully developed and independently validated a workflow for the typing of PTC clinical samples into CLIP2-positive and CLIP2-negative and provided first insights into the CLIP2 interactome in the context of radiation-associated PTC. PMID- 25284584 TI - USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. AB - The oncoprotein c-Myc is frequently overexpressed in many cancers and is essential for cancer cell proliferation. Ubiquitin-proteasome-dependent degradation is one of the main ways in which cells control c-Myc abundance at a post-translational level. However, the underlying mechanism by which c-Myc is directly deubiquitinated is not fully understood. In this study, by screening ubiquitin-specific proteases (USPs) that may regulate c-Myc stability, we identified USP37 as a novel deubiquitinating enzyme (DUB) that stabilizes c-Myc via direct binding. The overexpression of USP37 markedly increases c-Myc abundance by blocking its degradation, whereas the depletion of USP37 promotes c Myc degradation and reduces c-Myc levels. Further studies indicate that USP37 directly interacts with c-Myc and deubiquitinates c-Myc in a DUB activity dependent manner. Functionally, USP37 regulates cell proliferation and the Warburg effect by regulating c-Myc levels. Clinically, USP37 is significantly upregulated in human lung cancer tissues, where its expression is positively correlated with c-Myc protein expression. Thus, our findings uncover a previously unrecognized role for USP37 in the regulation of c-Myc stability in lung cancer and suggest that USP37 might be a potential therapeutic target for the treatment of lung cancer. PMID- 25284585 TI - P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer. AB - Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells. PMID- 25284586 TI - Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress. AB - Although previous studies suggest that myeloid zinc-finger 1 (MZF-1) is a multifaceted transcription factor that may function as either an oncogene or a tumor suppressor, the molecular bases determining its different traits remain elusive. Increasing evidence suggests that disorders in iron metabolism affect tumorigenesis and tumor behaviors, and that excess tumor iron stimulates tumor progression through various mechanisms such as enhancing DNA replication and energy metabolism. Ferroportin (FPN) is the only known iron exporter in mammalian cells, and it determines global iron egress out of cells. FPN reduction leads to decreased iron efflux and increased intracellular iron that consequentially aggravates the oncogenic effects of iron. MZF-1 was recently identified as a transcription factor that regulates FPN expression. Thus far, however, the molecular mechanisms underlying the MZF-1-FPN signaling in cancers are largely unknown. Here, we found a significant reduction of FPN levels in prostate tumors relative to adjacent tissues, and demonstrated a crucial role of FPN in tumor growth through controlling tumor iron concentration. Inhibition of MZF-1 expression led to reduced FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth. In contrast, increase of MZF-1 expression restrained tumor cell growth by promoting FPN-driven iron egress. Importantly, we demonstrated that AP4 and c-Myb jointly modulated MZF-1 transcription, and that miR-492 was also directly involved in regulating MZF-1 concentration through binding to the 3' untranslated regions of its mRNA. These results correlate with reduced AP4 and c Myb expression and elevated miR-492 expression found in prostate tumors as compared with adjacent tissues that resulted in diminished MZF-1 and FPN. Moreover, we demonstrated that alterations of AP4, c-Myb and miR-492 levels significantly affected tumor cell growth. Targeting molecules within the MZF-1 FPN signaling thus appears to be a promising approach to restrain prostate cancer. PMID- 25284587 TI - Genomic interaction between ER and HMGB2 identifies DDX18 as a novel driver of endocrine resistance in breast cancer cells. AB - Breast cancer resistance to endocrine therapies such as tamoxifen and aromatase inhibitors is a significant clinical problem. Steroid receptor coactivator-1 (SRC 1), a coregulatory protein of the oestrogen receptor (ER), has previously been shown to have a significant role in the progression of breast cancer. The chromatin protein high mobility group box 2 (HMGB2) was identified as an SRC-1 interacting protein in the endocrine-resistant setting. We investigated the expression of HMGB2 in a cohort of 1068 breast cancer patients and found an association with increased disease-free survival time in patients treated with endocrine therapy. However, it was also verified that HMGB2 expression could be switched on in endocrine-resistant tumours from breast cancer patients. To explore the function of this poorly characterized protein, we performed HMGB2 ChIPseq and found distinct binding patterns between the two contexts. In the resistant setting, the HMGB2, SRC-1 and ER complex are enriched at promoter regions of target genes, with bioinformatic analysis indicating a switch in binding partners between the sensitive and resistant phenotypes. Integration of binding and gene expression data reveals a concise set of target genes of this complex including the RNA helicase DDX18. Modulation of DDX18 directly affects growth of tamoxifen-resistant cells, suggesting that it may be a critical downstream effector of the HMGB2:ER complex. This study defines HMGB2 interactions with the ER complex at specific target genes in the tamoxifen resistant setting. PMID- 25284588 TI - Metabolic reprogramming during TGFbeta1-induced epithelial-to-mesenchymal transition. AB - Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFbeta1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFbeta1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFbeta1-induced EMT and metastasis. PMID- 25284589 TI - Loss of the tumor suppressor Hace1 leads to ROS-dependent glutamine addiction. AB - Cellular transformation is associated with altered glutamine (Gln) metabolism. Tumor cells utilize Gln in the tricarboxylic acid (TCA) cycle to maintain sufficient pools of biosynthetic precursors to support rapid growth and proliferation. However, Gln metabolism also generates NADPH, and Gln-derived glutamate is used for synthesis of glutathione (GSH). As both NADPH and GSH are antioxidants, Gln may also contribute to redox balance in transformed cells. The Hace1 E3 ligase is a tumor suppressor inactivated in diverse human cancers. Hace1 targets the Rac1 GTPase for degradation at Rac1-dependent NADPH oxidase complexes, blocking superoxide generation by the latter. Consequently, loss of Hace1 increases reactive oxygen species (ROS) levels in vitro and in vivo. Given the link between Hace1 loss and increased ROS, we investigated whether genetic inactivation of Hace1 alters Gln metabolism. We demonstrate that mouse embryonic fibroblasts (MEFs) derived from Hace1(-/-) mice are highly sensitive to Gln withdrawal, leading to enhanced cell death compared with wild-type (wt) MEFs, and Gln depletion or chemical inhibition of Gln uptake blocks soft agar colony formation by Hace1(-/-) MEFs. Hace1(-/-) MEFs exhibit increased Gln uptake and ammonia secretion, and metabolic labeling using (13)C-Gln revealed that Hace1 loss increases incorporation of Gln carbons into the TCA cycle intermediates. Gln starvation markedly increases ROS levels in Hace1(-/-) but not in wt MEFs, and treatment with the antioxidant N-acetyl cysteine or the TCA cycle intermediate oxaloacetate efficiently rescues Gln starvation-induced ROS elevation and cell death in Hace1(-/-) MEFs. Finally, Gln starvation increases superoxide levels in Hace1(-/-) MEFs, and NADPH oxidase inhibitors block the induction of superoxide and cell death by Gln starvation. Together, these results suggest that increased ROS production due to Hace1 loss leads to Gln addiction as a mechanism to cope with increased ROS-induced oxidative stress. PMID- 25284591 TI - Efficient and simple approaches towards direct oxidative esterification of alcohols. AB - The present article describes novel oxidative protocols for direct esterification of alcohols. The protocols involve successful demonstrations of both "cross" and "self" esterification of a wide variety of alcohols. The cross-esterification proceeds under a simple transition-metal-free condition, containing catalytic amounts of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)/TBAB (tetra-n butylammonium bromide) in combination with oxone (potassium peroxo monosulfate) as the oxidant, whereas the self-esterification is achieved through simple induction of Fe(OAc)2 /dipic (dipic=2,6-pyridinedicarboxylic acid) as the active catalyst under an identical oxidizing environment. PMID- 25284590 TI - Radiofrequency ablation versus transarterial chemoembolization for unresectable solitary hepatocellular carcinomas sized 5-8 cm. AB - OBJECTIVES: This retrospective review was conducted to compare the efficacy of radiofrequency ablation (RFA) with that of transarterial chemoembolization (TACE) in treating large (5-8 cm) unresectable solitary hepatocellular carcinomas (HCCs). METHODS: Patients with large unresectable solitary HCCs primarily treated by RFA or TACE were reviewed. The primary endpoint was overall survival. Secondary endpoints were tumour response, time to disease progression, and treatment-related morbidity and mortality. RESULTS: There were 15 patients in the RFA group. Of these, 12 achieved complete ablation, one had ablation site recurrence, and five developed complications. Median disease-free survival in this group was 13.0 months (range: 2.8-38.0 months). The TACE group included 26 patients, of whom four obtained a partial response, none achieved a complete response, and five developed complications. The median time to disease progression in this group was 8.0 months (range: 1.0-68.0 months). There were no hospital deaths in this series. Median survival was 39.8 months in the RFA group and 19.8 months in the TACE group (P = 0.257). Rates of 1-, 2- and 5-year survival were 93.3%, 86.2% and 20.9%, respectively, in the RFA group and 73.1%, 40.6% and 18.3%, respectively, in the TACE group. CONCLUSIONS: Both RFA and TACE are feasible treatments for large unresectable solitary HCCs. Both modes show comparable rates of complications and longterm survival, but RFA achieves better initial tumour control and results in better short-term survival. PMID- 25284592 TI - Managing fetuses at high risk of retinoblastoma: lesion detection on screening MRI. AB - OBJECTIVE: This study aimed to describe tumour identification on magnetic resonance imaging (MRI) in a 35-week fetus with familial retinoblastoma (RB) and report the use of prenatal ultrasound (US) and MRI screening in the management of fetuses at high risk of RB. METHOD: This is a retrospective review of the prenatal course and immediate postnatal findings in all children considered at high risk of RB who had prenatal imaging with both US and MRI at our institution over a 5-year period. RESULTS: Five patients met the inclusion criteria. No lesions were identified on US in any patients. Fetal MRI identified bilateral posterior pole lesions in one patient at 35 weeks' gestation. Of the four remaining patients, three developed lesions by 5 weeks of age. Only one fetus was delivered early following detection of RB. CONCLUSION: We present the first reported case of RB detected in a high-risk fetus on screening MRI at 35 weeks' gestation. A protocol for screening this population using both imaging modalities is presented. PMID- 25284593 TI - Characterization of a multicomponent lithium lithiate from a combined x-ray diffraction, NMR spectroscopy, and computational approach. AB - An unusual lithium lithiate [Li(diglyme)2][(diglyme)Li2(C4H3S)3], made up from three carbanions, two lithium cations, and a single donor base molecule in the anion and a single lithium cation, coordinated by two donor base molecules, is investigated in a combined study including X-ray diffraction, NMR spectroscopy and computational approaches in solution and the solid state. While the multicomponent lithiate is the only species present in the solid state, solution NMR spectroscopy and computational methods were employed to identify a second species in solution. The dimer [(diglyme)Li(C4H3S)]2 coexists with the lithiate in solution in a 1:1 ratio, the more the higher the polarity of the solvent is. Only the combination of this multitude of methods provides a firm picture of the whole. PMID- 25284594 TI - Evidence of skeletal treponematosis from the medieval burial ground of St. Mary Spital, London, and implications for the origins of the disease in Europe. AB - Treponematosis is a syndrome of chronic infectious diseases. There has been much debate on its origins and spread, particularly with regard to venereal syphilis, an unsightly and debilitating disease in preantibiotic populations. The osteological analysis of 5,387 individuals excavated by Museum of London Archaeology from the medieval burial ground of St. Mary Spital in London (dated c 1120-1539) provided an unprecedented opportunity to investigate the nature and prevalence of disease over a period of time. Twenty-five individuals were found with suspected treponematosis, originating from all but the earliest period of the burial ground. Descriptions of affected individuals from each period, together with supporting images, are provided. In this work, particular emphasis was given to the distribution of lesions on the skeleton and the variation in patterns by sex and over time. Little change was observed in the distribution of bony change between individuals dated to pre- and post-Columbian periods. However, a dramatic rise in the prevalence of the disease in the final period (c 1400-1539) may reflect documentary reports of a European epidemic from the late 15th century. PMID- 25284595 TI - Utility values for pre-menopausal women suffering from symptomatic uterine fibroids. AB - BACKGROUND: Uterine fibroids (UF) represent the most common benign uterine tumor in women of reproductive age. Symptoms including heavy, prolonged menstrual bleeding, pelvic pain/pressure, and/or urinary frequency have a substantial impact on women's quality of life and utility values for UF have not been published. METHODS: Health state descriptions associated with UF symptoms and treatment side effects were developed based on patient focus groups; validated using expert clinical input; and pilot tested for understandability. Using a web based questionnaire, 909 community-dwelling, Canadian women were surveyed to assess their perceived value associated with these states. RESULTS: Utility for uncontrolled bleeding was 0.55 (95% CI: 0.54, 0.57) and the decrement associated with hot flashes was 0.06 (95% CI: -0.07, -0.04). Utility improvement associated with bleeding control was 0.18 (95% CI: 0.17, 0.19) and with smaller fibroid size was 0.03 (95% CI: 0.02, 0.04). CONCLUSION: These values illustrate the high utility associated with control of excessive menstrual bleeding. PMID- 25284596 TI - [Treatment of moderate and severe hallux valgus by performing percutaneous double osteotomy of the first metatarsal bone]. AB - OBJECTIVE: To evaluate the clinical and radiological results in the surgical treatment of moderate and severe hallux valgus by performing percutaneous double osteotomy. MATERIAL AND METHOD: A retrospective study was conducted on 45 feet of 42 patients diagnosed with moderate-severe hallux valgus, operated on in a single centre and by the same surgeon from May 2009 to March 2013. Two patients were lost to follow-up. Clinical and radiological results were recorded. RESULTS: An improvement from 48.14 +/- 4.79 points to 91.28 +/- 8.73 points was registered using the American Orthopedic Foot and Ankle Society (AOFAS) scale. A radiological decrease from 16.88 +/- 2.01 to 8.18 +/- 3.23 was observed in the intermetatarsal angle, and from 40.02 +/- 6.50 to 10.51 +/- 6.55 in hallux valgus angle. There was one case of hallux varus, one case of non-union, a regional pain syndrome type I, an infection that resolved with antibiotics, and a case of loosening of the osteosynthesis that required an open surgical refixation. DISCUSSION: Percutaneous distal osteotomy of the first metatarsal when performed as an isolated procedure, show limitations when dealing with cases of moderate and severe hallux valgus. The described technique adds the advantages of minimally invasive surgery by expanding applications to severe deformities. CONCLUSIONS: Percutaneous double osteotomy is a reproducible technique for correcting severe deformities, with good clinical and radiological results with a complication rate similar to other techniques with the advantages of shorter surgical times and less soft tissue damage. PMID- 25284597 TI - Squamous cell carcinoma of parotid gland associated with concurrent lymphoepithelial cysts and lymphoepithelial lesion: case report and proposed histogenesis. AB - Lymphoepithelial cyst and lymphoepithelial lesion have similar histologic features and an affinity for the parotid gland. Though considered as different entities, both conditions arise from heterotopic salivary epithelial rests or inclusions in intra- or peri-parotid lymph nodes. We present a case of squamous cell carcinoma of parotid gland associated with concurrent lymphoepithelial cyst and lymphoepithelial lesion in a patient who was not infected with human immunodeficiency virus. We propose that lymphoepithelial cyst and lymphoepithelial lesion have a similar histogenesis. PMID- 25284598 TI - Quality of life in elderly kidney transplant recipients. AB - OBJECTIVES: To evaluate quality of life (QOL) in kidney transplant recipients aged 65 and older, identify predictors of impaired physical and mental QOL cross sectionally and compare QOL over time with that of younger transplant recipients and general population controls. DESIGN: Comparison of serial Medical Outcomes Study 36-item Short-Form Survey (SF-36) QOL scores in transplant recipients aged 65 and older with those of transplant recipients younger than 65 and with those of general population controls from the National Health Measurement Study (NHMS). SETTING: University of Minnesota. PARTICIPANTS: Individuals aged 65 and older (n = 150) and younger than 65 (n = 1,544) who received a primary kidney transplant between 1963 and 2009. MEASUREMENTS: Two-sample t-tests and logistic regression were used to assess the risk of significant impairment in physical and mental QOL, defined as 1 standard deviation below the general population norms (<40 points) for the SF-36 Physical (PCS) and Mental Component Subscale (MCS) scores. RESULTS: PCS scores were 39.3 for transplant recipients aged 65 and older, 43.5 for recipients younger than 65, and 49.2 for NHMS controls (P < .005 for each pairwise comparison). MCS scores were 54.6 for transplant recipients aged 65 and older, 51.0 for recipients younger than 65, and 53.8 for NHMS controls (P < .005 for >= 65 vs <65 and NHMS vs <65). These scores did not change significantly from the first (3.6 years after transplant) to the last (6.2 years after transplant) survey. Longer time since transplantation in elderly participants was associated with having significantly impaired physical QOL, but no predictors were associated with significantly impaired mental QOL. In younger recipients, rejection, diabetes mellitus, delayed graft function, coronary artery disease, and longer time on dialysis were associated with impaired physical QOL. Rejection, smoking, diabetes mellitus, and longer time on dialysis were predictors of impaired mental QOL. CONCLUSION: Physical QOL is lower in elderly recipients but mental QOL is maintained and is higher than in younger recipients. PMID- 25284599 TI - Effectiveness of a two-stage strategy with HPV testing followed by visual inspection with acetic acid for cervical cancer screening in a low-income setting. AB - The World Health Organization recently advocated a two-stage strategy with human papillomavirus (HPV) testing followed by visual inspection of the cervix with acetic acid (VIA) as a suitable option for cervical cancer screening. However, its accuracy has never been directly assessed in the context of primary screening. To evaluate effectiveness of HPV testing on self-obtained specimens (self-HPV) followed by VIA (sequential testing) in a low-income setting, we recruited 540 women aged between 30 and 65 years in two Cameroonian periurban areas. Eligible women were counseled about cervical cancer and how to perform self-sampling. HPV positive and a random sample of HPV-negative women were called back for VIA and biopsy. Disease was defined by interpretation of cervical intraepithelial neoplasia Grade 2 or worse (CIN2+). Performances of VIA, self-HPV and sequential testing were determined after adjustment for verification bias. HPV prevalence was 27.0%. VIA positivity was 12.9% and disease prevalence was 5%. Sensitivity and specificity of VIA for CIN2+ were 36.4% [95% confidence interval (CI): 15.2-64.6%] and 90.4% (95% CI: 85.4-93.7%), respectively. Sensitivity of self-HPV [100.0% (95% CI: 79.6-100.0%)] was 66% higher than that of sequential testing [33.3% (95% CI: 15.2-58.3%)]. Meanwhile, specificity of self-HPV [74.5% (95% CI: 70.6-78.1%)] was 22% lower than that of sequential testing [96.7% (95% CI: 94.8-97.9%)]. A two-stage screening strategy with self-HPV followed by VIA improves specificity of cervical cancer screening, but at the cost of an important loss of sensitivity. Ways to improve VIA performance or other tools are needed to increase positive predictive value of HPV testing. PMID- 25284600 TI - Successful transplantation of extended criteria lungs after prolonged ex vivo lung perfusion performed on a portable device. PMID- 25284601 TI - High-dose-rate brachytherapy for vaginal rhabdomyosarcoma using a personalized mold in a 20-month old patient. AB - Treatment of vaginal rhabdomyosarcoma (RMS) with conservative approaches is presently the standard of care. Intravaginal high-dose rate brachytherapy is a very effective treatment while sparing the normal tissue to preserve growth, fertility and prevent organ dysfunction. In this report, we describe the management of an infant with Stage I vaginal RMS, treated with chemotherapy, maximal safe resection and intravaginal brachytherapy using a customized mold and MRI and CT-based three-dimensional (3D) conformal planning, followed by a critical review of the literature. PMID- 25284602 TI - Mechanistic study of silver-mediated furan formation by oxidative coupling. AB - Density functional calculations and experiments have been carried out to unravel the mechanism of a silver-mediated furan formation by oxidative coupling. Various possible reaction paths were considered and the most favorable channel has been identified on the basis of the calculated solvent-corrected Gibbs free-energy profiles. The mechanism represented by this route consists of a radical and a subsequent ionic route. The silver cation has a double role in the mechanism: it is the oxidant in the radical steps and the catalyst for the ionic steps, which is in accordance with the experimental observations. The two most important aspects of the optimal route are the formation of a silver-acetylide, reacting subsequently with the enolate radical, and the aromatic furan-ring formation in a single step at the latter, ionic segment of the reaction path. Our findings could explain several experimental observations, including the "key-promoter role" of silver, the preference for ionic cyclization, and the reduced reactivity of internal acetylides. PMID- 25284603 TI - Does an educational intervention improve parents' knowledge about immunization? Experience from Malaysia. AB - BACKGROUND: Parents' knowledge about immunization is an important predictor factor for their children's immunization status. The aims of this study were to assess parents' knowledge and to evaluate the effect of a short educational intervention on improving parents' knowledge of childhood immunization. METHODS: A cross-sectional study using a pre- and post-test intervention survey of a single group was conducted among Malaysian parents. Changes in total knowledge score before and after the intervention were measured using a validated questionnaire. The intervention consisted of an animated movie and lecture using simple understandable language. Wilcoxon signed ranks test and the McNemar x2 test were applied to compare the differences in knowledge before and after the intervention. RESULTS: Seventy-three parents were enrolled in this study; the majority were mothers (n = 64, 87.7%). Parents' knowledge about childhood immunization increased significantly after the intervention compared to the baseline results (p < 0.001). There were significant differences between parents' knowledge and their educational level and monthly income (p < 0.001 and p = 0.005), respectively. CONCLUSIONS: A short educational intervention designed for parents had a positive effect on their knowledge about immunization. Educational interventions targeting parents with low levels of education and income are needed. Further studies investigating the actual effectiveness of such interventions on immunization rates and statuses are required. PMID- 25284604 TI - Hb Wilde and Hb Patagonia: two novel elongated beta-globin variants causing dominant beta-thalassemia. AB - We describe here the molecular and hematological characteristics of novel frameshift mutations in exon 2 of the HBB gene (in heterozygous state) found in two Argentinean pediatric patients with dominant beta-thalassemia-like features. In Hb Wilde, HBB:c.270_273delTGAG(p.Glu90Cysfs*67), we detected the deletion of the third base of the codon 89 (T) and the codon 90 (GAG), whereas in Hb Patagonia, HBB:c.296_297dupGT(p.Asp99Trpfs*59), the frameshift mutation was due to a duplication of a 'GT' dinucleotide after the second base of codon 98 (GTG). The Hb Patagonia and Hb Wilde mutations would result in elongated beta-globin chains with modified C-terminal sequences and a total of 155 and 157 amino acids residues, respectively. Based on bioinformatics and structural analysis, as well as protein modeling, we predict that the elongated beta-globins would affect the formation of the alphabeta dimers and their stability, which would further support the mechanism for the observed clinical features in both patients. PMID- 25284605 TI - An ylide transformation of rhodium(I) carbene: enantioselective three-component reaction through trapping of rhodium(I)-associated ammonium ylides by beta nitroacrylates. AB - The chiral Rh(I)-diene-catalyzed asymmetric three-component reaction of aryldiazoacetates, aromatic amines, and beta-nitroacrylates was achieved to obtain gamma-nitro-alpha-amino-succinates in good yields and with high diastereo- and enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of Rh(I)-associated ammonium ylides by nitroacrylates. This new transformation represents the first example of Rh(I)-carbene-induced ylide transformation. PMID- 25284606 TI - Aspen (Populus tremuloides Michx.) intake and preference by mammalian herbivores: the role of plant secondary compounds and nutritional context. AB - Aspen (Populus tremuloides Michx.) has evolved a chemical defense system comprised of phenolic glycosides (PG), which effectively deter insect herbivory. However, much less is known about the role of PG and the nutritional quality of the associated plant community on aspen browse susceptibility to mammalian herbivores. In three successive periods during the growing season, we conducted experiments with sheep by offering leaves from two aspen stands with different concentrations of PG (LOW, HIGH) or aspen leaves vs. leaves from a forb (Utah pea, Lathyrus pauciflorus) or a grass (smooth brome, Bromus inermis Leyss.) growing in an aspen understory. Intake of aspen (19 to 35 % PG) was low in all periods (1 to 6 g/Kg(0.75) in 2 hr) supporting the notion that aspen's defense system may contribute to its ecological success. However, lambs ate larger amounts of LOW than of HIGH suggesting that sheep could discriminate between aspen stands with different concentrations of PG, even when both stands were relatively well defended. Concentration of nutrients and chemical defenses in aspen leaves remained fairly stable across the growing season, and preference for aspen increased over the growing season. In contrast, preference for the forb and the grass decreased across the growing season in concert with a decline in the nutritional quality of these plants. The data suggest that nutritional context of aspen and associated forage species drove preference more than contrasts in defense chemistry of aspen. There may be periods of "susceptibility" of aspen use by mammalian herbivores, despite high concentrations of chemical defenses, which can potentially be targeted by management to reduce aspen herbivory. PMID- 25284607 TI - CD8+ T-cell recognition of a synthetic epitope formed by t-butyl modification. AB - We set out to clone Bax-specific CD8+ T-cells from peripheral blood samples of primary chronic lymphocytic leukemia patients. A number of clones were generated using a Bax peptide pool and their T-cell epitope was mapped to two peptides sharing a common 9-aa sequence (LLSYFGTPT), restricted by HLA-A*0201. However, when these T-cell clones were tested against highly purified syntheses (>95%) of the same peptide sequence, there was no functional response. Subsequent mass spectrometric analysis and HPLC fractionation suggested that the active component in the original crude peptide preparations (77% pure) was a peptide with a tert butyl (tBu) modification of the tyrosine residue. This was confirmed by modification of the inactive wild type (wt) sequence to generate functionally active peptides. Computer modeling of peptide:HLA-A*0201 structures predicted that the tBu modification would not affect interactions between peptide residues and the HLA binding site. However these models did predict that the tBu modification of tyrosine would result in an extension of the side chain out of the peptide-binding groove up towards the TCR. This modified product formed <1% of the original P603 crude peptide preparation and <0.05% of the original 23 peptide mixture used for T-cell stimulation. The data presented here, illustrates the potential for chemical modifications to change the immunogenicity of synthetic peptides, and highlights the exquisite capacity of TCR to discriminate between structurally similar peptide sequences. Furthermore this study highlights potential pitfalls associated with the use of synthetic peptides for the monitoring and modulating of human immune responses. This article is protected by copyright. All rights reserved. PMID- 25284608 TI - Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways. PMID- 25284609 TI - The atrial fibrillation epidemic is approaching the physician's door: will mobile technology improve detection? AB - The rising numbers of people with atrial fibrillation (AF) carry a heavy toll on our graying population. Epidemiological data suggest that AF exists in 1 in 10 individuals aged older than 80 years. The risk of embolic stroke increases along with well-known cardiovascular risk factors. Should there be systematic screening for the elderly? Although 1 in 10 is a huge hit rate in screening for any major illness, the initiative for such programs in AF remains in 'research and development'.At present, cardiologists can utilize implantable loop recorders in patients referred for specialist consultation. Novel technologies are also available, including cloud-based, algorithm-assisted, non-invasive monitoring patches, which allow extended observation periods. What about people in the community without a recognized need for cardiologic investigation? Mobile technology has made detection of pulse irregularity possible without medical attention. Smartphone apps enable opportunistic rhythm monitoring, but true arrhythmias need to be medically verified. AF may be the first common disorder to be effectively screened for by mobile technology. In the spirit of proactive campaigns such as 'Know Your Pulse', we should prepare for rapidly increasing reports of various pulse irregularities. PMID- 25284610 TI - Linking genetic variation in human Toll-like receptor 5 genes to the gut microbiome's potential to cause inflammation. AB - Immunodeficiencies can lead to alterations of the gut microbiome that render it pathogenic and capable of transmitting disease to naive hosts. Here, we review the role of Toll-like receptor (TLR) 5, the innate receptor for bacterial flagellin, in immune responses to the normal gut microbiota with a focus its role on adaptive immunity. Loss of TLR5 has profound effects on the microbiota that include greater temporal instability of major lineages and upregulation of flagellar motility genes that may be linked to the reduced levels of anti flagellin antibodies in the TLR5(-/-) host. A variety of human TLR5 gene alleles exist that also associated with inflammatory conditions and may do so via effects on the gut microbiome and altered host-microbial crosstalk. PMID- 25284611 TI - Endocrine regulation of predator-induced phenotypic plasticity. AB - Elucidating the developmental and genetic control of phenotypic plasticity remains a central agenda in evolutionary ecology. Here, we investigate the physiological regulation of phenotypic plasticity induced by another organism, specifically predator-induced phenotypic plasticity in the model ecological and evolutionary organism Daphnia pulex. Our research centres on using molecular tools to test among alternative mechanisms of developmental control tied to hormone titres, receptors and their timing in the life cycle. First, we synthesize detail about predator-induced defenses and the physiological regulation of arthropod somatic growth and morphology, leading to a clear prediction that morphological defences are regulated by juvenile hormone and life history plasticity by ecdysone and juvenile hormone. We then show how a small network of genes can differentiate phenotype expression between the two primary developmental control pathways in arthropods: juvenoid and ecdysteroid hormone signalling. Then, by applying an experimental gradient of predation risk, we show dose-dependent gene expression linking predator-induced plasticity to the juvenoid hormone pathway. Our data support three conclusions: (1) the juvenoid signalling pathway regulates predator-induced phenotypic plasticity; (2) the hormone titre (ligand), rather than receptor, regulates predator-induced developmental plasticity; (3) evolution has favoured the harnessing of a major, highly conserved endocrine pathway in arthropod development to regulate the response to cues about changing environments (risk) from another organism (predator). PMID- 25284612 TI - Aboveground endophyte affects root volatile emission and host plant selection of a belowground insect. AB - Plants emit specific blends of volatile organic compounds (VOCs) that serve as multitrophic, multifunctional signals. Fungi colonizing aboveground (AG) or belowground (BG) plant structures can modify VOC patterns, thereby altering the information content for AG insects. Whether AG microbes affect the emission of root volatiles and thus influence soil insect behaviour is unknown. The endophytic fungus Neotyphodium uncinatum colonizes the aerial parts of the grass hybrid Festuca pratensis * Lolium perenne and is responsible for the presence of insect-toxic loline alkaloids in shoots and roots. We investigated whether endophyte symbiosis had an effect on the volatile emission of grass roots and if the root herbivore Costelytra zealandica was able to recognize endophyte-infected plants by olfaction. In BG olfactometer assays, larvae of C. zealandica were more strongly attracted to roots of uninfected than endophyte-harbouring grasses. Combined gas chromatography-mass spectrometry and proton transfer reaction-mass spectrometry revealed that endophyte-infected roots emitted less VOCs and more CO2. Our results demonstrate that symbiotic fungi in plants may influence soil insect distribution by changing their behaviour towards root volatiles. The well known defensive mutualism between grasses and Neotyphodium endophytes could thus go beyond bioactive alkaloids and also confer protection by being chemically less apparent for soil herbivores. PMID- 25284613 TI - Enhanced glycogen synthase kinase-3beta activity mediates podocyte apoptosis under diabetic conditions. AB - Glycogen synthase kinase-3beta (GSK-3beta) is involved in the pathogenesis of various kidney diseases. This study was undertaken to examine the changes in GSK 3beta activity in podocytes under diabetic conditions and to elucidate the functional role of GSK-3beta in podocyte apoptosis. In vivo, 32 rats were injected with either diluent (n = 16, C) or with streptozotocin intraperitoneally (n = 16, DM), and 8 rats from each group were treated with 6-bromoindirubin-3' oxime (BIO) for 3 months. In vitro, immortalized mouse podocytes were exposed to 5.6 mM glucose or 30 mM glucose (HG) with or without 10 MUM BIO. Western blot analysis and TUNEL or Hoechst 33342 staining were performed to identify apoptosis. Urinary albumin excretion was significantly higher in DM rats, and this increase was significantly abrogated in DM rats by BIO treatment. The protein expression of Tyr216-phospho-GSK-3beta was significantly increased in DM glomeruli and in cultured podocytes exposed to HG. Western blot analysis revealed that the protein expression of Bax and active fragments of caspase-3 were significantly increased, whereas phospho-Akt, beta-catenin, and Bcl-2 protein expression were significantly decreased in DM glomeruli and HG-stimulated podocytes. Apoptosis, determined by TUNEL assay and Hoechst 33342 staining, was also significantly increased in podocytes under diabetic conditions. The changes in the expression of apoptosis-related molecules and the increase in the number of apoptotic cells in DM glomeruli as well as in HG-stimulated podocytes were significantly ameliorated by BIO. These findings suggest that enhanced GSK-3beta activity within podocytes under diabetic conditions is associated with podocyte loss in diabetic nephropathy. PMID- 25284614 TI - Effect of length post and remaining root tissue on fracture resistance of fibre posts relined with resin composite. AB - To investigate the influence of post length and amount of remaining root tissue on the fracture resistance of roots restored with fibre posts relined with resin composite. Ninety upper canine teeth were divided into nine groups (n = 10). The post spaces were prepared resulting in different lengths, as follows: group 2/3, preparations with lengths of 10 mm; group 1/2, preparations with lengths of 7.5 mm; and group 1/3, preparations with lengths of 5 mm. Each group was divided into 3 subgroups according to amount of remaining root tooth tissue (2, 1 mm or 0.5 mm of thick root). Fibre posts relined with resin composite were cemented, and all teeth were restored with metal crowns. The samples were submitted to the fracture resistance test in a universal testing machine, at an angle of 135 degrees and speed of 0.5 mm min(-1) . Failure modes were observed and the data of fracture resistance were submitted to the anova and Tukey's (alpha = 0.05). No statistically significant difference in fracture resistance was found among different post lengths (P > 0.05). Remaining dentin thickness of 2 and 1 mm did not differ statistically in fracture resistance (P > 0.05), which was higher than of 0.5 mm dentin thickness (P < 0.05). A prevalence of repairable failure was observed in all groups. It can be concluded that the length of fibre post relined with resin composite did not influence fracture resistance, but thickness was an important factor for the restoration of endodontically treated teeth. PMID- 25284616 TI - Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. AB - In cirrhosis, portal vein thrombosis (PVT) could be a cause or a consequence of the progression of liver disease. We analyzed data from a prospective trial of ultrasound screening for hepatocellular carcinoma in order to identify risk factors for and the impact of PVT in patients with cirrhosis. In all, 1,243 adults with cirrhosis without PVT were enrolled from 43 liver units in France and Belgium between June 2000 and March 2006. The mean follow-up was 47 months. Doppler ultrasonography was used to check the portal vein. Progression of liver disease was defined by the development of: ascites, hepatic encephalopathy, variceal bleeding, prothrombin <45%, serum bilirubin >45 MUmol/L, albumin <28 g/L, and/or creatinine >115 MUmol/L. G20210A prothrombin and factor V gene mutations were assessed in sera stored at three large centers. The 5-year cumulative incidence of PVT was 10.7%. PVT was mostly partial and varied over time. The development of PVT was independently associated with baseline esophageal varices (P = 0.01) and prothrombin time (P = 0.002), but not with disease progression before PVT, or prothrombotic mutations. Disease progression was independently associated with baseline age (hazard ratio [HR] 1.55; 95% confidence interval [CI]: 1.11-2.17), body mass index (HR 1.40; 95% CI: 1.01 1.95), prothrombin time (HR 0.79; 95% CI: 0.70-0.90), serum albumin (HR 0.97; 95% CI: 0.94-0.99), and esophageal varices (HR 1.70; 95% CI: 1.21-2.38) but not with the prior development of PVT (HR 1.32; 95% CI: 0.68-2.65). CONCLUSION: In patients with cirrhosis, the development of PVT is associated with the severity of liver disease at baseline, but does not follow a recent progression of liver disease. There is no evidence that the development of PVT is responsible for further progression of liver disease. PMID- 25284615 TI - MiRNA-30a inhibits AECs-II apoptosis by blocking mitochondrial fission dependent on Drp-1. AB - Apoptosis of type II alveolar epithelial cells (AECs-II) is a key determinant of initiation and progression of lung fibrosis. However, the mechanism of miR-30a participation in the regulation of AECs-II apoptosis is ambiguous. In this study, we investigated whether miR-30a could block AECs-II apoptosis by repressing mitochondrial fission dependent on dynamin-related protein-1 (Drp-1). The levels of miR-30a in vivo and in vitro were determined through quantitative real-time PCR (qRT-PCR). The inhibition of miR-30a in AECs-II apoptosis, mitochondrial fission and its dependence on Drp-1, and Drp-1 expression and translocation were detected using miR-30a mimic, inhibitor-transfection method (gain- and loss-of function), or Drp-1 siRNA technology. Results showed that miR-30a decreased in lung fibrosis. Gain- and loss-of-function studies revealed that the up-regulation of miR-30a could decrease AECs-II apoptosis, inhibit mitochondrial fission, and reduce Drp-1 expression and translocation. MiR-30a mimic/inhibitor and Drp-1 siRNA co-transfection showed that miR-30a could inhibit the mitochondrial fission dependent on Drp-1. This study demonstrated that miR-30a inhibited AECs-II apoptosis by repressing the mitochondrial fission dependent on Drp-1, and could function as a novel therapeutic target for lung fibrosis. PMID- 25284617 TI - [Classification of canine intervertebral disc degeneration using high-field magnetic resonance imaging and computed tomography]. AB - OBJECTIVE: Although the classification of canine intervertebral disc degeneration using magnetic resonance imaging (MRI) has been described in the literature, there is no such classification using computed tomographic imaging. Because computed tomography (CT) is a frequently used diagnostic imaging tool in veterinary medicine, the aim of this study was the introduction and validation of such a scoring system. T2-weighted magnetic resonance images were available for comparative analysis. MATERIAL AND METHODS: A total of 43 dogs were examined using CT and MRI. Image data records of 144 intervertebral discs were blinded, randomized and evaluated twice by three observers. CT data were analyzed using a self-developed scoring system, while MRI data sets were evaluated using the Pfirrmann scoring system. Intra- and interobserver agreement were determined using Statistical Analysis Software (SAS). RESULTS: Intra- and interobserver agreement were mostly substantial in the Pfirrmann (0.58-0.77) and self-developed (0.60-0.81) scoring systems. A slight agreement was found between both classification systems (kappa scores 0.26-0.29). CONCLUSION AND CLINICAL RELEVANCE: The self-developed scoring system allows a reliable assessment of canine intervertebral disc degeneration using CT imaging. Therefore, further diagnostic and prognostic information can be obtained. Degenerative changes in the intervertebral discs could be identified at an earlier stage when using MRI in comparison with CT. PMID- 25284618 TI - Aberrant TP53 detected by combining immunohistochemistry and DNA-FISH improves Barrett's esophagus progression prediction: a prospective follow-up study. AB - Barrett's esophagus (BE) goes through a sequence of low grade dysplasia (LGD) and high grade dysplasia (HGD) to esophageal adenocarcinoma (EAC). The current gold standard for BE outcome prediction, histopathological staging, can be unreliable. TP53 abnormalities may serve as prognostic biomarkers. TP53 protein accumulation detected by immunohistochemistry (IHC) indirectly assesses TP53 mutations. DNA fluorescent in situ hybridization (FISH) on brush cytology specimens directly evaluates gene locus loss. We evaluated if IHC and FISH are complementary tools to assess TP53 abnormalities and tested their prognostic value in a long-term prospective follow-up of a BE cohort. TP53 IHC on tissue sections and FISH on brush cytology specimens were evaluated for 116 BE patients with respect to the different histological stages. The TP53 abnormalities were further studied in a panel of cell lines representative of the Barrett's carcinogenic sequence. For 91patients, the predictive value of TP53 abnormalities with respect to progression to HGD/EAC was tested after long term follow-up. The frequency of IHC and FISH TP53 abnormalities increased significantly with increasing histological stage (P < 0.001, Chi(2) -test). Combining the techniques detected TP53 abnormalities in 100% of patients with LGD, HGD, and EAC. Multivariate analysis showed that IHC (hazard ratio: 17, 95% CI: 3.2-96, P = 0.001) and FISH (hazard ratio: 7.3, 95% CI: 1.3-41, P = 0.02) were both independent significant predictors of progression. Combining FISH and IHC in assessing TP53 abnormalities leads to an increased detection rate of TP53 aberrations and improved accuracy for predicting BE progression. PMID- 25284619 TI - Familial gigantiform cementoma: distinctive clinical features of a large Chinese pedigree. AB - Familial gigantiform cementoma is a rare benign fibrocemento-osseous lesion of the jaws that can cause severe facial deformity. It has an autosomal dominant mode of inheritance, but varies in its phenotype. It is more common in white, African, and East-Asian patients. Here we report what is to our knowledge the first distinctive Chinese family with familial gigantiform cementoma involving 4 generations and 13 patients, and which suggests that the tumour presents with 3 distinctive growth phrases. PMID- 25284620 TI - Editorial comment. PMID- 25284621 TI - Intima-media thickness: correlation between carotids, vertebral artery, aorta and femoral arteries. AB - AIM: Compare the intima-media thickness (IMT) of the internal carotid artery with the IMT of the common and external carotid, vertebral and femoral arteries and the abdominal aorta to assess the possibility of using these arteries as markers of atherosclerotic disease. METHODS: Fifty patients with atherosclerosic risk factors were examined and the IMT was determined in the carotid arteries and compared with the values of IMT of the vertebral and femoral arteries and the abdominal aorta. The Spearman correlation coefficient and Kappa index were used for statistical analysis. RESULTS: Considering IMT equal or greater than 0,8mm, there was positive and significant correlation between the values obtained for the examined arteries. The best agreement was found between the external and common carotid artery as compared to the internal carotid. (accuracy of 73.5% and 79.2%, respectively). For all arteries the was a positive correlation of the values of the EMI. CONCLUSION: There is positive and significant correlation between the IMT of the internal carotid artery and the vertebral and femoral arteries and abdominal aorta. Routine examinations of either one of these arteries can ad important findings regarding early diagnosis for higher risk patients concerning atherosclerotic disease. PMID- 25284622 TI - Surgical and endovascular intervention on internal carotid artery near occlusion. AB - Therapeutic strategy for treating carotid artery near occlusion (CANO) has been controversial. The aim of this study was to review the literature concerning the invasive treatment of atherosclerotic CANO. A review was conducted of the English medical literature from 1980 to 2013 using PubMedand EMBASE database to find studies involving open or endovascular management of CANO. The search identified 20 reports describing invasive treatment of CANO encompassing 770 patients (77.7% men; mean age 66.3+/-5.2 years). A typical appearance of string sign was noted in nearly 60% of the patients. The vast majority (92.6%) were symptomatic. 479 (62.2%) patients underwent an open procedure, while 291 (38.8%) were treated endovascularly. The technical success rate for the endovascular procedures was 99%, while distal embolic protection devices were applied in most patients (66%). The 30 days procedural stroke rate was 2.1% and 2.4% for open and endovascular repair respectively. During a follow-up period spanning an average of approximately two years the ipsilateral cerebrovascular event rate was 5% and 1.2% for open and endovascular treatmentrespectively. Twenty five (5.2%) restenosis or occlusions were reported for the open procedures, while 13 (5.4%) were also documented for endovascular repair. The current literature concerning the invasive treatment of CANO is weak and cannot support any evidence based recommendation. The necessity to intervene as well as the best therapeutic strategy remains controversial. This review shows that the interventionon symptomatic CANO may consist a relatively safe and effective therapeutic strategy with low perioperative cerebrovascular morbidity for both treatment modalities, although durability and long-term outcomes should be further affirmed. The low incidence of this entity and the dearth of clear evidence support the need for a large multicenter registry to clarify the absolute indications for intervention and define the best therapeutic approach. PMID- 25284623 TI - Identification of a novel HLA allele, HLA-A*11:101, in a platelet donor from China. AB - HLA-A*11:101 has one nucleotide change from HLA-A*11:02:01 where 120 Q is changed to R. PMID- 25284624 TI - Bone-conduction hearing and seismic sensitivity of the Late Permian anomodont Kawingasaurus fossilis. AB - An investigation of the internal cranial anatomy of the anomodont Kawingasaurus from the Upper Permian Usili Formation in Tanzania by means of neutron tomography revealed an unusual inner and middle ear anatomy such as extraordinarily inflated vestibules, lateroventrally orientated stapes with large footplates, and a small angle between the planes of the anterior and lateral semicircular canals. The vestibule has a volume, which is about 25 times larger than the human vestibule, although Kawingasaurus has only a skull length of approximately 40 mm. Vestibule inflation and enlarged stapes footplates are thought to be functionally correlated with bone-conduction hearing; both morphologies have been observed in fossorial vertebrates using seismic signals for communication. The firmly fused triangular head with spatulate snout was probably used for digging and preadapted to seismic signal detection. The quadrate-quadratojugal complex was able to transmit sound from the articular to the stapes by small vibrations of the quadrate process, which formed a ball and socket joint with the squamosal. Mechanical considerations suggest that the ventrolaterally orientated stapes of Kawingasaurus was mechanically better suited to transmit seismic sound from the ground to the fenestra vestibuli than a horizontal orientated stapes. The low sound pressure level transformer ratio of 2-3 in Kawingasaurus points to a seismic sensitivity of the middle ear and a vestigial or reduced sensitivity to airborne sound. Three hypothetical pathways of bone conduction in Kawingasaurus are discussed: 1) sound transmission via the spatulate snout and skull roof to the otic capsules, 2) relative movements resulting from the inertia of the mandible if sound is percepted with the skull, and 3) bone conduction from the substrate via mandible, jaw articulation, and stapes to the inner ear. PMID- 25284625 TI - Quantitative proteomics reveals that peroxidases play key roles in post-flooding recovery in soybean roots. AB - Soybean is an important legume crop that exhibits markedly reduced growth and yields under flooding conditions. To unravel the mechanisms involved in recovery after flooding in soybean root, gel-free proteomic analysis was performed. Morphological analysis revealed that growth suppression was more severe with increased flooding duration. Out of a total of 1645 and 1707 identified proteins, 73 and 21 proteins were changed significantly during the recovery stage following 2 and 4 days flooding, respectively. Based on the proteomic, clustering, and in silico protein-protein interaction analyses, six key enzymes were analyzed at the mRNA level. Lipoxygenase 1, which was increased at the protein level during the recovery period, was steadily down-regulated at the mRNA level. The peroxidase superfamily protein continuously increased in abundance during the course of recovery and was up-regulated at the mRNA level. HAD acid phosphatase was decreased at the protein level and down-regulated at the transcript level, while isoflavone reductase and an unknown protein were increased at both the protein and mRNA levels. Consistent with these findings, the enzymatic activity of peroxidase was decreased under flooding stress but increased significantly during the recovery sage. These results suggest that peroxidases might play key roles in post-flooding recovery in soybean roots through the scavenging of toxic radicals. PMID- 25284626 TI - Social cognition in patients following surgery to the prefrontal cortex. AB - Impaired social cognition, including emotion recognition, may explain dysfunctional emotional and social behaviour in patients with lesions to the ventromedial prefrontal cortex (VMPFC). However, the VMPFC is a large, poorly defined area that can be sub-divided into orbital and medial sectors. We sought to investigate social cognition in patients with discrete, surgically circumscribed prefrontal lesions. Twenty-seven patients between 1 and 12 months post-neurosurgery were divided into groups based on Brodmann areas resected, determined by post-surgical magnetic resonance imaging. We hypothesised that patients with lesions to the VMPFC (n=5), anterior cingulate cortex (n=4), orbitofrontal cortex (n=7) and dorsolateral prefrontal cortex (DLPFC, n=11) would perform worse than a control group of 26 extra-cerebral neurosurgery patients on measures of dynamic facial emotion recognition, theory of mind (ToM) and empathy. Results indicated the VMPFC-lesioned group performed significantly worse than the control group on the facial emotion recognition task overall, and for fear specifically, and performed worse on the ToM measure. The DLPFC group also performed worse on the ToM and empathy measures, but DLPFC lesion location was not a predictor of performance in hierarchical multiple regressions that accounted for other variables, including the reduced estimated verbal IQ in this group. It was concluded that isolated orbital or medial prefrontal lesions are not sufficient to produce impairments in social cognition. This is the first study to demonstrate that it is the combination of lesions to both areas that affect social cognition, irrespective of lesion volume. While group sizes were similar to other comparable studies that included patients with discrete, surgically circumscribed lesions to the prefrontal cortex, future large, multi site studies are needed to collect larger samples and confirm these results. PMID- 25284627 TI - Cu2O mesoporous spheres with a high internal diffusion capacity and improved catalytic ability for the aza-Henry reaction driven by visible light. AB - Mesoporous Cu2O spheres with a large pore size (LP-Cu2O) bring out a better performance towards the photocatalytic aza-Henry reaction than Cu2O spheres with a small pore size (SP-Cu2O). This work highlights the internal diffusion coefficient as a critical parameter for the fabrication of porous photocatalysts. PMID- 25284628 TI - Erratum to: Tumor markers in mature cystic teratomas of the ovary. PMID- 25284630 TI - Endovascular brachytherapy for renal artery in-stent restenosis. AB - OBJECTIVE: Renal artery in-stent restenosis (RAISR) is not an infrequent occurrence and may be in part responsible for the failure of renal stents to improve clinical outcome. A variety of treatments have been used to restore patency, with mixed results. These include repeated percutaneous transluminal renal angioplasty (PTRA), repeated PTRA with bare-metal stents, and repeated PTRA with drug-eluting stents or covered stents. Endovascular brachytherapy (EVBT) has been proven effective in preventing recurrent neointimal hyperplasia in coronary bare-metal stents. This prompted our group to study the effect of EVBT on RAISR. METHODS: From 2004 to 2012, 21 patients (23 renal arteries) developed RAISR <= 30 months after the initial procedure and were subsequently treated with EVBT. Five patients had at least one prior PTRA for recurrent restenosis. Renal artery duplex scanning was performed as a baseline study within a few days of the EVBT and then every 6 months. All patients who had EVBT were concurrently treated by PTRA and EVBT on the basis of existing protocols. Patency of the treated stents was evaluated by Kaplan-Meier survival curves. RESULTS: The average onset of the original RAISR was 11 +/- 9 months (range, 2-30 months; median, 8 months). The initial technical success of combined PTRA and EVBT was 100%. Mean follow-up was 44 +/- 18 months (range, 14-84 months). Of five patients who had PTRA before EVBT, four were available for long-term follow-up. These four patients had a combined total number of five PTRAs before EVBT, with recurrent stenosis developing on average by 12 months. After EVBT, three stents were patent at 39, 48, and 65 months, and one stent restenosed at 42 months. This was the only patient in the entire series to develop restenosis after EVBT. CONCLUSIONS: This retrospective experience with a relatively small number of patients undergoing concurrent EVBT/PTRA for recurrent stenosis in stents placed to treat atherosclerotic renal artery stenosis suggests that EVBT is safe and provides long-term freedom from recurrent stenosis. PMID- 25284629 TI - Analysis of EndoAnchors for endovascular aneurysm repair by indications for use. AB - OBJECTIVE: The proximal aortic neck remains one of the challenges of endovascular aneurysm repair (EVAR), and the risk of type Ia endoleak and endograft migration is increased in patients with short, large-diameter, or highly angulated necks. EndoAnchors have been used as an adjunct to EVAR in such patients, and the aim of this study was to assess their benefit analyzed by indication for use. METHODS: During a 2-year period, 319 patients were enrolled at 43 sites in the Aneurysm Treatment Using the Heli-FX Aortic Securement System Global Registry (ANCHOR) study. This prospective, multinational, real-world analysis of EndoAnchors comprised two groups of patients, those undergoing first-time EVAR (primary arm, 242) and those with proximal neck complications remote from the time of an initial endograft implantation (revision arm, 77). The primary arm was further subdivided into patients undergoing prophylactic EndoAnchor use for hostile proximal neck anatomy (178), with a type Ia endoleak evident during initial endograft deployment (60), and in conjunction with extender cuffs after unsatisfactory endograft deployment distally in the neck (four). The revision arm was subdivided into patients presenting with a type Ia endoleak alone (45), endograft migration alone (11), and migration with endoleak (21). Technical success was site reported as satisfactory deployment of the desired number of EndoAnchors without fracture or loss of integrity. Procedural success was defined as technical success without type Ia endoleak at completion arteriography. Core laboratory analysis was performed on 249 baseline and 192 follow-up computed tomographic studies, 66 of which were available within the 1-year window. RESULTS: Technical and procedural success rates were highest in the prophylactically treated subset (172 of 178; 96.6%). Whereas the technical success of EndoAnchor deployment was also high in the other subsets, residual type Ia endoleaks were more frequent at completion angiography when the indication for EndoAnchor use was type Ia endoleak, both in the primary arm (17 of 60; 28%) and in the revision arm (9 of 45; 20%). During a median imaging follow-up of 7 months, 183 of 202 patients (90.1%) remained free of type Ia endoleaks. Primary prophylactic patients were free from type Ia endoleak in 110 of 114 cases (96.5%). The most challenging subset was revision patients treated for type Ia endoleak; type Ia endoleaks were evident during follow-up in 10 of 29 of the cases (34%). Sac regression >5 mm in patients with 1-year imaging was observed in 26 of 66 patients (39%) and was highest in the primary prophylaxis subset (20 of 43; 47%). CONCLUSIONS: EndoAnchor implantation can be a useful adjunct to EVAR as prophylaxis against proximal attachment site complications in patients with hostile aortic neck anatomy, as treatment for early and late type Ia endoleaks, or, in conjunction with aortic extension cuffs, for endograft migration. Whereas the most challenging patients are those who present with type Ia endoleaks remote from initial EVAR, EndoAnchors are still effective in treating the majority of these cases. PMID- 25284631 TI - A review of the current state of the male circumcision literature. AB - INTRODUCTION: Male circumcision is one of the most commonly performed surgical procedures worldwide and a subject that has been the center of considerable debate. Recently, the American Association of Pediatrics released a statement affirming that the medical benefits of neonatal circumcision outweigh the risks. At present, however, the majority of the literature on circumcision is based on research that is not necessarily applicable to North American populations, as it fails to take into account factors likely to influence the interpretability and applicability of the results. AIMS: The purpose of this review is to draw attention to the gaps within the circumcision literature that need to be addressed before significant changes to public policy regarding neonatal circumcision are made within North America. METHODS: A literature review of peer reviewed journal articles was performed. MAIN OUTCOME MEASURES: The main outcome measure was the state of circumcision research, especially with regard to new developments in the field, as it applies to North American populations. RESULTS: This review highlights considerable gaps within the current literature on circumcision. The emphasis is on factors that should be addressed in order to influence research in becoming more applicable to North American populations. Such gaps include a need for rigorous, empirically based methodologies to address questions about circumcision and sexual functioning, penile sensitivity, the effect of circumcision on men's sexual partners, and reasons for circumcision. Additional factors that should be addressed in future research include the effects of age at circumcision (with an emphasis on neonatal circumcision) and the need for objective research outcomes. CONCLUSION: Further research is needed to inform policy makers, health-care professionals, and stakeholders (parents and individuals invested in this debate) with regard to the decision to perform routine circumcision on male neonates in North America. PMID- 25284632 TI - Wafer-scale fabrication of glass-FEP-glass microfluidic devices for lipid bilayer experiments. AB - We report a wafer-scale fabrication process for the production of glass-FEP-glass microdevices using UV-curable adhesive (NOA81) as gluing material, which is applied using a novel "spin & roll" approach. Devices are characterized for the uniformity of the gluing layer, presence of glue in the microchannels, and alignment precision. Experiments on lipid bilayers with electrophysiological recordings using a model pore-forming polypeptide are demonstrated. PMID- 25284633 TI - Biophysical Modeling of Alpha Rhythms During Halothane-Induced Unconsciousness. AB - During the induction of general anesthesia there is a shift in power from the posterior regions of the brain to the frontal cortices; this shift in power is called anteriorization. For many anesthetics, a prominent feature of anteriorization is a shift specifically in the alpha band (8-13 Hz) from posterior to frontal cortices. Here we present a biophysical computational model that describes thalamocortical circuit-level dynamics underlying anteriorization of the alpha rhythm in the case of halothane. Halothane potentiates GABAA and increases potassium leak conductances. According to our model, an increase in potassium leak conductances hyperpolarizes and silences the high-threshold thalamocortical (HTC) cells, a specialized subset of thalamocortical cells that fire at the alpha frequency at relatively depolarized membrane potentials (>-60 mV) and are thought to be the generators of quiet awake occipital alpha. At the same time the potentiation of GABAA imposes an alpha time scale on both the cortical and the thalamic component of the frontal portion of our model. The alpha activity in the frontal component is further strengthened by reciprocal thalamocortical feedback. Thus, we argue that the dual molecular targets of halothane induce the anteriorization of the alpha rhythm by increasing potassium leak conductances, which abolishes occipital alpha, and by potentiating GABAA, which induces frontal alpha. These results provide a computational modeling formulation for studying highly detailed biophysical mechanisms of anesthetic action in silico. PMID- 25284634 TI - Development of a Social Activities Scale for Community-Dwelling Older Women Requiring Support in Japan: A Preliminary Study. AB - OBJECTIVE: The purpose of this study was to develop a scale for measuring the social activities of community-dwelling older women requiring support in Japan. DESIGN AND SAMPLE: A methodological study was performed of 118 older women (>65 years old) requiring support and residing in region A of Japan. MEASURES: An anonymous questionnaire was administered through individual interviews, and valid responses were obtained from 110 people. The construct validity of the resulting scale was assessed by exploratory factor analysis. Criterion-related validity was tested by calculating Spearman's rank correlation coefficient between the resulting scale and the existing Social Activity Index for Elderly People (SAI E). Reliability was tested by Cronbach's alpha coefficient. RESULTS: The Social Activity Scale for Community-Dwelling Older Women Requiring Support (SASOWS) was created. This scale comprised the following three subscales: "interactions with familiar people," "consulting with care service providers," and "performing proactive creative activities at home". Correlation of SASOWS with the existing SAI-E resulted in a correlation coefficient of .521 (p < .01). Cronbach's alpha for the entire scale was .772, and internal consistency was observed. CONCLUSIONS: SASOWS appears to be a reliable, valid, and useful scale to measure social activities specific for older women requiring support. Future studies should continue to examine the items and usefulness of this scale. PMID- 25284636 TI - The Impact of Health Insurance Exchanges in Radiology, Today and Tomorrow. PMID- 25284635 TI - [Low-grade adenocarcinoma of nasal cavities: a case report]. AB - Low-grade sinonasal adenocarcinomas are uncommon and recently described entities. Its histologic diagnosis is challenging. This tumour is characterized by a tendency to local invasion, and rare distant metastases. Well treated, the prognosis is excellent. We describe a case of low-grade nasal cavity adenocarcinoma and discuss the anatomoclinical, therapeutic and evolutionary characteristics of this malignant tumour. A 54-year-old female patient presented with a 10 years history of right-sided nasal obstruction and recurrent epistaxis. On examination the patient had a large, firm mass in the right nasal cavity. Endoscopic sinonasal surgery was performed. The lesion was found to originate from the posteriolateral wall of the right nasal cavity. Histopathology analysis identified a low-grade sinonasal adenocarcinoma. Upon follow-up 4 years after surgery, the patient exhibited no clinical evidence of recurrence. Low-grade sinonasal adenocarcinomas are poorly defined neoplasms, accounting for 4 to 20% of all sinonasal malignancies. The nasal cavity is the most frequently involved site. Low-grade sinonasal adenocarcinomas pose a diagnostic challenge for the pathologist because they must be distinguished from benign tumours, especially adenomas. The primary treatment of sinonasal adenocarcinoma is complete surgical excision. PMID- 25284637 TI - Creative culture: the lessons of Florence. PMID- 25284638 TI - The effect of Glutathione-S-transferases in the susceptibility to bladder cancer. AB - BACKGROUND: Urinary bladder cancer is a quite common cancer type in men and women all over the world. Genetic polymorphisms of xenobiotic-metabolizing enzymes could increase individual susceptibility to various cancer types. AIMS: The aim of our study is to evaluate the rate of these polymorphisms in a group of patients from Central Anatolia. METHODS: Our study subjects consist of 65 men with histopathologically confirmed bladder TCC and 70 cancer-free control subjects. Restriction fragment length polymorphism (RFLP) method was used for the detection of polymorphisms of GSTT1 and GSTM1. RESULTS: There was no association between bladder cancer and GSTM1 polymorphism (ORs = 0.64, 95% CI = 0.32-1.29), but the probability of bladder cancer in patients with GSTT1 null genotype (67.9%), was significantly higher from the probability of bladder cancer with GSTT1 normal genotype (43.0%) statistically (ORs = 2.8, 95% CI = 1.16-6.75). CONCLUSION: Polymorphisms of these genes have been assessed to evaluate the relative risk of various cancers. Our intention is to continue this study with larger series of bladder cancer patients in a group of Turkish population from Central Anatolia. PMID- 25284639 TI - Bakri balloon tamponade as first step to manage severe post partum haemorrhage. PMID- 25284640 TI - Isolation and identification of dexamethasone sodium phosphate degrading Pseudomonas alcaligenes. AB - Glucocorticosteroids such as dexamethasone have polluted hospital wastewater, urban sewage, and river water in varying degrees. However, dexamethasone degradation by bioremediation technology is less understood. This study aims to isolate bacteria that could degrade dexamethasone and to identify their degradation characteristics. Hospital wastewater contaminated by dexamethasone was collected. After culturing in inorganic salt medium and in carbon deficient medium containing dexamethasone sodium phosphate, a bacterial strain with dexamethasone sodium phosphate as the sole carbon and energy source was enriched and isolated from the contaminated wastewater. The strain was identified as Pseudomonas alcaligenes by morphology, Gram staining, biochemical test, and 16S rDNA sequencing. Isolated bacteria were domesticated. Then its degradation characteristic was determined by high-performance liquid chromatography method. The degradation rate of P. alcaligenes on dexamethasone sodium phosphate was 50.86%. Of the degraded dexamethasone sodium phosphate, 75.23% of dexamethasone sodium phosphate was degraded to dexamethasone and 23.63% was degraded to other metabolites. In conclusion, the isolated P. alcaligenes in this study would provide experimental evidence for further research on the bioremediation technology to treat dexamethasone sodium phosphate and dexamethasone polluted water and further for the elimination of side effects of dexamethasone. PMID- 25284641 TI - Use of a modified Delphi approach to develop research priorities for the association of coloproctology of Great Britain and Ireland. AB - AIM: The modified Delphi approach is an established method for reaching a consensus opinion among a group of experts in a particular field. We have used this technique to survey the entire membership of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) to reach a consensus on prioritizing clinical research questions in colorectal disease. METHOD: Three rounds of surveys were conducted using a web-based tool. In the first, the ACPGBI membership was invited to submit research questions. In Rounds 2 and 3 they were asked to score questions on priority. A steering group analysed the results of each round to identify those questions ranked as being of highest priority. RESULTS: Five hundred and two questions were submitted in Round 1. Following two rounds of voting and analysis, a list of 25 priority questions was produced, including 15 cancer-related and 10 noncancer-related questions. CONCLUSION: It is anticipated that these results will: (i) set the research agenda over the next few years for the study of colorectal disease in the United Kingdom, (ii) promote development and (iii) define funding of new research and prioritize areas of unmet clinical need where the potential clinical impact is greatest. PMID- 25284642 TI - Prevalence and geographic distribution of edentulism among older Ghanaians. AB - OBJECTIVES: Edentulism has important health implications for aging individuals and is used as an indicator of the oral health of a population. Its distribution is unequal within populations, with the greatest burden on disadvantaged and socially marginalized populations. With an increasing older adult population in Ghana, its burden may increase; however, there is no nationwide information on edentulism in Ghana. Focusing on adults 50 years and older, this study assessed the prevalence of edentulism among older Ghanaians and its distribution across the country. METHODS: Secondary analysis of WHO's Study on global AGEing and adult health (SAGE) Wave 1 in Ghana was conducted using self-reported edentulism as the dependent variable. RESULTS: The overall prevalence was 2.8%, varying by sex (men had lower rates; OR = 0.67, 95% CI = 0.47-0.97); by location, being more prevalent in urban areas (3.6%) and the Western Region (4.7%); by education levels (rates were higher among those with no formal education; OR = 1.626, 95% CI = 1.111-2.380); and by marital status (those living without a partner had higher rates; OR = 1.980, 95% CI =1.366-2.870). On multivariate logistic regression, the variables positively associated with edentulism were older age (OR = 0.945) and urban residence (OR = 0.582). Living in the Brong Ahafo (OR = 3.138), Central (OR = 2.172), Eastern (OR = 2.257), or Volta regions (OR = 3.333) was negatively associated with edentulism. CONCLUSION: Edentulism is unequally distributed across Ghana. Future aged cohorts are likely to follow the same patterns of geographic and social disadvantage if needed interventions are not carried out. This study provides nationwide data to assist service planning. PMID- 25284643 TI - Conversion of adult Nucleus(r) 5 cochlear implant users to the Nucleus(r) 6 system. AB - OBJECTIVES: Cochlear's new sound processor system (Nucleus((r)) 6) features a new noise reduction algorithm called SNR-NR (signal-to-noise ratio), and an environmental classifier called SCAN, which activates the appropriate sound coding algorithms for a given listening environment. In addition, the sound processors (CP910 and CP920) have a data logging feature with data visually summarized using clinical programing software and come with two remote controls, CR210 and CR230. The objective of this clinical study was to conduct a field acceptance study comparing the user experience with the Nucleus((r)) 6 to the Nucleus((r)) 5 system and to evaluate the benefits of Nucleus((r)) 6 in an adult population currently equipped with the previous generation Nucleus((r)) 5 sound processor. Our primary objective was to compare speech recognition in speech weighted noise using Nucleus((r)) 6 with SCAN (activating SNR-NR) with the default Nucleus((r)) 5 'Noise' Program. Secondary objectives included comparisons of speech recognition in quiet, subjective performance feedback via questionnaires and diaries, and recipient preference for device and program type. METHODS: A prospective controlled trial was conducted with 30 adult Nucleus CI recipients using the Nucleus((r)) 5 sound processor (condition A). The Nucleus((r)) 6 sound processor (condition B) was evaluated in a within-subject ABBA design, with repeated speech in noise (S0N0, LIST sentence test), and speech in quiet testing (S0, NVA words). The remote controls were randomly given during the two B intervals. In addition, recipients had to complete questionnaires and diaries on the use of their current as well as new sound processors and remotes. RESULTS: The group mean speech reception threshold in noise (SRT50) with Nucleus((r)) 6 SCAN was significantly better (1.2 dB SNR) than with the Nucleus((r)) 5 'Noise' Program. Mean speech recognition scores in quiet were not significantly different between the processors. Subjective performance feedback (APHAB) did not show a significant difference between Nucleus((r)) 6 and Nucleus((r)) 5 with high satisfaction scores being reported for both sound processors. Recipients preferred the SCAN program in noise and reported a clear overall preference for the Nucleus((r)) 6 system. Clinicians were satisfied with the conversion process from Nucleus((r)) 5 to Nucleus((r)) 6. DISCUSSION AND CONCLUSION: SNR-NR provides a significant benefit in noise. Recipients were easily converted from Nucleus((r)) 5 to Nucleus((r)) 6 requiring little or no sound quality adjustment period. The Nucleus((r)) 6 SCAN program was well accepted by the majority of recipients for use during their daily life. PMID- 25284644 TI - Anostracan (Crustacea: Branchiopoda) zoogeography II. Relating distribution to geochemical substrate properties in the USA . AB - Anostracan zoogeography, biogeography, and habitat preferences have predominately been studied as related to the water quality parameters of their seasonally astatic wetland habitats. However, since water quality in seasonally astatic wetlands can fluctuate dramatically over a range of time scales, water quality data are generally of limited usefulness. Anostracan taxa occurrences in each of the nine North American anostracan bioregions across the United States of America were examined in relation to basic substrate geochemistry parameters (%CaSO*H2O, %CaCO, salinity, and dominate salt cations), and substrate type. Relationships between these parameters and the distributions of all 63 US species were discovered. Most anostracan species occurred only in habitats with specific geochemical ranges and attributes unique to that species. Additionally, three widespread species were found to occur in very different habitat types in different regions. Upon closer examination, these three taxa were each found to be comprised of more than one species. PMID- 25284645 TI - Five new species of the feather mite genus Trouessartia Canestrini from South America (Acari: Trouessartiidae). AB - Five new feather mite species of the genus Trouessartia Canestrini are described from South American birds: Trouessartia latiducta sp. nov. from Phylloscartes kronei (Tyrannidae), T. basileuteri sp. nov. from Basileuterus culicivorus (Parulidae), T. sicaliae sp. nov. from Sicalis flaveola (Emberizidae), T. savanae sp. nov. from Tyrannus savana (Tyrannidae), and T. picumni from Picumnus fulvescens (Picidae). The latter species is the first representative of the genus described from a bird of the order Piciformes. PMID- 25284646 TI - A review of Luxiaria Walker and its allied genus Calletaera Warren (Lepidoptera, Geometridae, Ennominae) from China. AB - The genus Luxiaria Walker and its allied genus Calletaera Warren in China, including 16 species in all, are reviewed. Five new species are described: C. obvia sp. nov., C. acuticornuta sp. nov., C. rotundicornuta sp. nov., C. dentata sp. nov., C. trigonoprocessus sp. nov. The species L. acutaria (Snellen, 1877) and L. tephrosaria (Moore, 1868) are newly recorded for China. Two new combinations are established: C. obliquata (Moore, 1888) comb. nov. and C. consimilaria (Leech, 1897) comb. nov. Four new synonyms are established: Eutoea Walker, 1860 (= Bithiodes Warren, 1894 syn. nov.); Calletaera Warren, 1895 (=Bithiodes Warren, 1899 syn. nov.), based on the fixation of nominal type Acidalia inexactata Walker, 1861, for the genus name Bithiodes Warren, 1894; L. emphatica Prout, 1925 (= L. costinota Inoue, 1978 syn. nov.); C. subexpressa (Walker, 1861) (= C. digrammata Wehrli, 1925 syn. nov.). Diagnoses for all Chinese species are provided. Illustrations of external features and genitalia are presented. PMID- 25284647 TI - Bryozoans from RV Sonne deep-sea cruises SO 167 'Louisville' and SO 205 'Mangan'. AB - The German research vessel Sonne is operating in the Pacific, Southern and Indian Oceans. In the current stage of development in Pacific deep-sea mining projects, prior understanding of biodiversity patterns in the affected regions is one of the major research goals of the RV Sonne cruises. In the present study, nine bryozoan species are reported from the Equatorial East Pacific and the Kermadec Tonga Ridge, collected during RV Sonne cruises SO 167 "Louisville" and SO 205 "Mangan", from 356-4007 m. Two new species, Raxifabia oligopora n. sp. and Opaeophora triangula n. sp., are described. PMID- 25284648 TI - Descriptions of four species of grenadier fishes of the genera Hymenocephalus and Hymenogadus (Teleostei, Gadiformes, Macrouridae) from the New Zealand region and Tasman Sea, including two new species of Hymenocephalus. AB - Two new species of Hymenocephalus are described from the New Zealand region and Tasman Sea. Hymenocephalus fuscus sp. n. has 11-12 pelvic fin rays, is darkly pigmented, with enlarged bony ridges on the dorsal aspects of head, lacks a chin barbel, has few (16-19) gill rakers on inner side of first arch and is similar to other species in the H. aterrimus species group. Hymenocephalus maculicaudus sp. n. has 8 pelvic fin rays, a mid-lateral line of melanophores on body and tail that extends about a head length posterior to anal fin origin, a short (7-16 % HL) chin barbel and is similar to other species in the H. megalops species group. Hymenocephalus nascens has 12-14 pelvic fin rays, lacks a chin barbel, has a mid lateral stripe of silvery (fresh) or brownish (preserved) pigment running along trunk and tail. Hymenogadus gracilis has a serrated (weak, near tip) first dorsal fin spine, 7-9 pelvic fin rays, long (20-30% HL) chin barbel, and one row of enlarged melanophores along lateral mid-line of the tail. Hymenocephalus nascens and Hymenogadus gracilis are recorded for the first time from the New Zealand region. A key to the known New Zealand species of Hymenocephalus and Hymenogadus is provided. PMID- 25284649 TI - Relict populations of Diaphanosoma (Cladocera: Ctenopoda) in the Chadian Sahara, with the description of a new species . AB - We record two species of Diaphanosoma from Ounianga and Tibesti in Northern Chad, the first ctenopods to be found in the Sahara desert. One species, from a freshwater guelta on the south flanks of the Tibesti (D. excisum) is tropical; the second species, found in a freshwater lake in a largely saline environment (the Ounianga plateau) is new to science (D. bopingi sp.nov.) and is here described, with special attention to some previously unnoticed structures on the postabdomen. Its relatives are northern species that may transgress into the tropics but largely live outside of them. They are also more salt-tolerant than the tropical D. excisum. The latter is considered a relict of Megachad times, while the new species is considered a relict of more humid but also cooler times in the desert. PMID- 25284650 TI - A new species of Bryophila Treitschke, 1825 from Mongolia (Lepidoptera, Noctuidae, Bryophilinae). AB - A new species of the Bryophila (Scythobrya) salomonis species-group, B. kaszabi sp. n. is described. A diagnostic comparison is made with B. miltophaea Hampson, 1908 and B. plumbeola Staudinger, 1881. Adults, male and female genitalia of the new and related species are illustrated. PMID- 25284651 TI - Nomenclatural changes for the genus Discophorellus Tsaur & Hsu, 1991 and new replacement name for Numata Matsumura, 1935 (Hemiptera: Fulgoromorpha). PMID- 25284652 TI - Checklist of helminth parasites of Goodeinae (Osteichthyes: Cyprinodontiformes: Goodeidae), an endemic subfamily of freshwater fishes from Mexico. AB - From August 2008 to July 2010, 1,471 fish belonging to the subfamily Goodeinae (representing 28 species) were collected from 47 localities across central Mexico and analyzed for helminth parasites. In addition, a database with all available published accounts of the helminth parasite fauna of goodeines was assembled. Based on both sources of information, a checklist containing all the records was compiled as a necessary first step to address future questions in the areas of ecology, evolutionary biology and biogeography of this host-parasite association. The checklist is presented in two tables, a parasite-host list and a host parasite list. The checklist contains 51 nominal species, from 34 genera and 26 families of helminth parasites. It includes 8 species of adult digeneans, 9 metacercarie, 6 monogeneans, 3 adult cestodes, 9 metacestodes, 1 adult acanthocephalan, 1 cystacanth, 6 adult nematodes and 8 larval nematodes. Based on the amount of information contained in the checklist, we pose that goodeines, a subfamily of viviparous freshwater fishes endemic to central Mexico, might be regarded as the first group of wildlife vertebrate for which a complete inventory of their helminth parasite fauna has been completed. PMID- 25284653 TI - A brief look at the Odonata from the Paramo ecosystems in Colombia, with the descriptions of Oxyallagma colombianum sp. nov. and Rhionaeschna caligo sp. nov. (Odonata: Coenagrionidae, Aeshnidae, Libellulidae). AB - Here I present the results of field work and collections of Odonata made in several paramos of Colombia between 2007 and 2014. Two undescribed species, in the genera Oxyallagma Kennedy, 1920, and Rhionaeschna Forster, 1909, respectively, were found, as well as two species not previously recorded from Colombia: Rhionaeschna peralta (Ris, 1918) and Oxyallagma dissidens (Selys, 1876). Descriptions and diagnoses of the new species, photographs, maps, illustrations, natural history notes, and comments on morphological plasticity are presented. PMID- 25284654 TI - Two new species and a new record of Scale-worms (Polychaeta) from Southwest Atlantic deep-sea coral mounds . AB - Two new species of scale-worms, Harmothoe ruthae sp. nov. (Polynoidae) and Pholoides sinepapillatus sp. nov. (Sigalionidae) are described. In addition, we expand the description of Harmothoe gilchristi and extend its distribution to the Southwest Atlantic. The three species were found among the species of corals Lophelia pertusa, Solenosmilia variabilis, Enallopsammia rostrata, Madrepora oculata and Errina sp., a total of 257 samples of these corals were taken between 570 m and 1040 m depth, at the North-East coast of Rio de Janeiro, Brazil. PMID- 25284655 TI - Two new species and a new synonym in the Pardosa nebulosa-group (Lycosidae: Pardosa) from China. AB - The Pardosa nebulosa-group consists of at least 66 species, including 14 species recorded from the South China. In this paper, we describe two new species of this group, P. tuberosa sp. nov. and P. parathompsoni sp. nov. from Yunnan Province of China. Also, P. shuangjiangensis Yin et al., 1997 is newly synonymised with P. pusiola (Thorell, 1891), based on the examination of specimens mainly from Yunnan. Detailed figures and photos of genitalia, photos of habitus of these three species and SEM photos of male bulb of P. pusiola are given. PMID- 25284656 TI - Review of the planthopper genus Ommatissus Fieber (Hemiptera: Fulgoromorpha: Tropiduchidae) with descriptions of three new species from China. AB - The tropiduchid planthopper genus Ommatissus Fieber, 1875 is reviewed to include six species in China: O. binotatus Fieber, 1875 (Taiwan), O. chinsanensis Muir, 1913 (Hong Kong, Macao, Guangdong), O. fuscus sp. nov. (Guizhou, Yunnan, Hunan), O. lateralis sp. nov. (Yunnan, Guizhou), O. lofouensis Muir, 1913 (Guizhou, Shandong, Shanxi, Hunan, Zhejiang, Fujian, Taiwan) and O. trimaculatus sp. nov. (Yunnan). Except O. chinsanensis and O. binotatus, four species are described or redescribed and illustrated. The generic characters are redefined. A checklist and key to all species in the genus are provided. PMID- 25284657 TI - The genus Scirtothrips (Thysanoptera: Thripidae) in Malaysia, with four new species and comments on Biltothrips, a related genus . AB - Species of the genus Scirtothrips are studied from Malaysia for the first time. Six species of this genus are here recorded from Malaysia: S. dobroskyi is newly recorded, and four new species: S. lantanae sp.n., S. lixinae sp.n., S. hitam sp.n. and S. malayensis sp.n. are described together with an illustrated identification key. Relationships were examined between S. dorsalis and the closely related S. hitam sp.n., based on the mitochondrial gene COI, and a redescription of the widespread pest species, dorsalis, is provided. Biltothrips minutus (Bhatti) is reported from Malaysia for the first time, and illustrations provided to distinguish this genus from Scirtothrips. PMID- 25284658 TI - Hesionidae Grube, 1850 (Annelida: Polychaeta) from South-Southeastern Brazil, with descriptions of four new species. AB - On the basis of extensive intertidal and subtidal samplings in South-Southeastern Brazil, five hesionid species were found; four are newly described and Podarkeopsis levisfuscina Perkins, 1984 is redescribed. Micropodarke pleijeli n. sp. differs from the other species because it lacks eyes, and by having a large number of pharynx papillae and by neurochaetal features; this species differs from M. dubia (Hessle, 1925) by lacking eyes, having a pharynx with more papillae, and by the neurochaetal features. Syllidia amaralae n. sp. resembles more closely S. armata sensu Day, 1967 (non S. armata de Quatrefages, 1865) because both have dorsal and tentacular cirri annulated or moniliform, and 10-15 pharyngeal papillae. However, S. amaralae n. sp. specimens differ from Day's ones because they have a quadrangular prostomium, by the relative size and arrangement of eyes, and by a reduced number of chaetae which are disposed in two bundles; these features are consistent and present in juveniles and mature specimens. Neogyptis nonatoi n. sp. is distinguishable from the others by having four types of neurochaetae; this species resembles N. crypta (Pleijel, 1993), and N. plurisetis (Hilbig, 1992). It differs from N. crypta by having a few acicular notochaetae with blunt tip, a small number of compound neurochaetae, simple capillary neurochaetae distally curved, and much slender notopodial and neuropodial lobes. The new species also differs from N. plurisetis by having four types of neurochaetae instead of having only falciger chaetae; there are less pharyngean papillae and they are far apart to each other, conical and shorter in N. plurisetis when compared to those of N. nonatoi n. sp., which are fringed, longer and closer among them, having some other longer lateral papillae. Oxydromus lanai n. sp. resembles O. obscurus (Verrill, 1873) as recorded by Uebelacker (1984), O. pugettensis by Hilbig (1994), O. guanicus by Hoagland (1919), and O. cf. guanicus by Hartman (1951). The pharynx of O. obscurus does not have fringe or papilla on its border, and it has two types of neurochaetae, differing from O. lanai n. sp. which has a single furcate notochaeta, with its shorter tine serrated. Oxydromus pugettensis and O. cf. guanicus also have usually two, instead of one, furcate notochaeta, differing from O. lanai n. sp. Oxydromus guanicus differs from our new species in having a characteristic pigmentation pattern, to be very large, its median antenna is less than one-third as long as lateral antennae, and its cirrophores are distally constricted producing a colorless ring, whereby the cirrostyle is inserted. These species are the first Brazilian records for the genera Podarkeopsis and Syllidia, and for Micropodarke, it is newly recorded from the Atlantic Ocean. Keys are included to identify hesionid genera and the species of Syllidia, Micropodarke, Neogyptis, and Podarkeopsis. PMID- 25284659 TI - A new Perigrapha Lederer, 1857 from South Kazakhstan (Lepidoptera, Noctuidae). AB - A new species of the genus Perigrapha, P. yasawii sp. n. is described from Syrdarya river valley, South Kazakhstan. The adults and male genitalia of the new and related species are illustrated. PMID- 25284660 TI - Redescription of Ypsolopha nervosella (Zerny, 1940) (Lepidoptera, Ypsolophidae) with first description of the female genitalia . PMID- 25284661 TI - Revision of Nearctic Phthinia Winnertz (Diptera: Mycetophilidae). AB - The Nearctic species of Phthinia Winnertz are revised. Eight species are recognized, of which four are newly described; P. tanypus Loew (= P. carolina Fisher n. syn., and P. catawbiensis Shaw n. syn.), P. lobata Zaitzev, P. miranda Zaitzev, P. ramificans Zaitzev, P. nepunei n. sp., P. cascadica n. sp., P. meicigama n. sp. and P. mikmaqi n. sp. A key to these species is also provided. PMID- 25284662 TI - Nematodes from galls on Myrtaceae. VI. Fergusobia from galls on Angophora in Australia, with description of F. colbrani n. sp. and key. AB - Collection data and biological information is presented on the Fergusobia (Nematoda: Neotylenchidae)/ Fergusonina (Diptera: Fergusoninidae) mutualism inducing galls on Angophora in Australia. Three species and two morphospecies have been recognised. Fergusobia colbrani Davies n. sp. is described from soft spheroid leaf galls on Angophora floribunda. It is characterised by a combination of morphological characters including a small C-shaped parthenogenetic female with a short broadly conoid tail, an arcuate infective female with an almost hemispherical tail tip, and an arcuate to barely J-shaped male with an angular spicule having a notched tip and mid-length leptoderan bursa. A key to the species and morphospecies of nematodes collected from Angophora is presented. Possible relationships of these organisms are discussed based on evidence from the nematode morphology, gall forms, and the morphology of the dorsal shield of the associated Fergusonina fly larvae. PMID- 25284663 TI - A Critically Endangered new dragonfly species from Morocco: Onychogomphus boudoti sp. nov. (Odonata: Gomphidae). AB - Both sexes of Onychogomphus boudoti sp. nov. Ferreira (Odonata: Anisoptera: Gomphidae) and exuviae are described and illustrated from a single locality in Morocco. This newly discovered species differs markedly from other Onychogomphus species by the morphology of the male epiproct and the female vulvar scale. It is genetically distinct in the mitochondrial DNA and the nuclear PRMT gene from all other Western Palaearctic Onychogomphus species. The known distribution of the new species is confined to a small stream with unusual habitat characteristics in the vicinity of Khenifra, in the Middle Atlas, where it experiences low population size and limited genetic diversity. We suggest listing this species both locally and globally as "Critically Endangered" [CR (B1, B2 + abiii)] following the IUCN Red List Categories and Criteria. PMID- 25284664 TI - Paracomesoma minor sp. n. and Microlaimus validus sp. n. (Nematoda) from the coast of Vietnam. AB - Two nematode species isolated from sediments of the littoral zone of South China Sea on the coast of Vietnam are described and illustrated. Paracomesoma minor sp. n. is closely related to P. elegans Gagarin & Thanh, 2009 and P. lissum Gagarin & Thanh, 2009. It differs from the former species in the shorter body, longer and more slender tail, longer cephalic setae and shorter spicules, and from the latter species in the shorter body, longer cephalic setae, presence of cervical setae and smaller number of precloacal supplements in males. Microlaimus validus sp. n. is morphologically closest to M. citrus Gerlach, 1959 and M. nanus Blome, 1982 and differs from both species in the longer body, relatively shorter pharynx and relatively shorter and thicker tail. PMID- 25284665 TI - A new genus of trechine beetles, Puertrechus gen. n., with two new species and a new species of Dactylotrechus Belousov et Kabak, 2003 from Southern China (Coleoptera: Carabidae: Trechinae). AB - Puertrechus gen. n., related to both Dactylotrechus and Quiennectrechus Deuve, 1992 is established to accommodate two new trechine species: P. mengsaensis sp. n. (type species of the genus, type locality: Mountains East of Mengsa City, Lincang Prefecture, Yunnan, China) and P. daxueshanicus sp. n. (type locality: Daxueshan Mount, the same prefecture). Likewise, the second species of the genus Dactylotrechus Belousov & Kabak, 2003, D. yalongensis sp. n., is described from the right bank of the Yalong River, SW of Mianing, southern Sichuan, China. This species differs from the only known species of the genus in some important characters including the elytral chaetotaxy and the male genitalia structure. Some adjustments of the genus diagnosis are made to embrace the new species. Keys to species of Dactylotrechus and Puertrechus gen. n. are included and their distribution is mapped. A key is provided to differentiate Puertrechus , Dactylotrechus and Quiennectrechus. PMID- 25284666 TI - Comparison of the structure and musculature of male terminalia in the tribe Cidariini Duponchel (Lepidoptera: Geometridae: Larentiinae) once again throws into doubt a sister relationship with the Xanthorhoini. AB - The structure and musculature of the male terminalia are described and illustrated in 11 genera of the tribe Cidariini (Lepidoptera, Geometridae, Larentiinae) from the Holarctic and Oriental regions. Nine genital muscles were identified: m1, m2(10), m3(2), m4, m5(7), m6(5), m7(6), m8(3) and m21. Variation in the insertion of the muscles m1, m3(2), m4, m5(7), m6(5) and m8(3) on the sclerites in several generic groups of the tribe Cidariini is discussed, revealing that the Thera species group does not share some apparently cidariine characters. A comparative analysis of the musculature in the tribes Cidariini and Xanthorhoini questions the sister relationship of these tribes that was suggested by earlier studies. The application of the terms 'anellus lobes' and 'labides' is discussed. PMID- 25284667 TI - First records of Croatian and Serbian Tetrigidae (Orthoptera: Caelifera) with description of a new subspecies of Tetrix transsylvanica (Bazyluk & Kis, 1960). AB - A review of the Croatian and Serbian Tetrigidae is given and first records of Tetrix undulata (Sowerby, 1806) for Croatia and Serbia as well as Tetrix tuerki (Krauss, 1876) and Tetrix transsylvanica (Bazyluk & Kis, 1960) comb. nov. for Croatia are presented. The status of the genus Uvarovitettix Bazyluk & Kis, 1960 and the taxonomic position of T. transsylvanica comb. nov. are discussed. The genus Uvarovitettix Bazyluk & Kis, 1960 syn. nov. is synonymised with the genus Tetrix Latreille, 1802. A new subspecies from Croatia and Slovenia, Tetrix transsylvanica hypsocorypha Skejo, 2014 subspecies nova, is described. Tetrix pseudodepressa (Ingrisch, 2006) comb. nov. and Tetrix depressa (Brisout de Barneville, 1848) comb. nov. are moved to the genus Tetrix and the genus Depressotetrix Karaman, 1960 syn. nov. is synonymised with the genus Tetrix. Tetrix gibberosa (Wang & Zheng, 1993) inc. sed. and T. nodulosa (Fieber, 1853) inc. sed. are now considered to be species of uncertain placement within the genus Tetrix. New combination is also given to Paratettix tuberculata (Zheng & Jiang, 1997), primarily placed within the genus Mishtshenkotetrix: Tetrix tuberculata (Zheng & Jiang, 1997) comb. nov., but its placement within the genus Tetrix is also uncertain. PMID- 25284668 TI - Plecoptera from Minas Gerais State, southeastern Brazil. AB - Specimens of Plecoptera collected in Minas Gerais State, Brazil were studied. Twelve previously described species were identified, Anacroneuria boraceiensis Froehlich, 2004, A. debilis (Pictet, 1841), A. itatiaiensis Baldin et al., 2013, A. polita (Burmeister, 1839), A. singularis Righi-Cavallaro & Lecci, 2010, A. stanjewetti Froehlich, 2002, A. terere Righi-Cavallaro & Lecci, 2010, A. vanini Froehlich, 2004, Kempnyia neotropica (Jacobson and Bianchi, 1905), K. obtusa Klapalek, 1916, Tupiperla gracilis (Burmeister, 1839) and T. robusta Froehlich, 1998. Additionally, two new species of Anacroneuria are described, A. paprockii n. sp. and A. mineira n. sp., and a list of species from Minas Gerais State is presented. PMID- 25284669 TI - A new species of wolf-spider (Alopecosa ogorodica sp.n.) from the Russian Mountain Altai with remarks on Arctosa meitanensis Yin et al., 1993 (Araneae: Lycosidae). AB - Alopecosa ogorodica sp.n. (??), a new wolf-spider species (Lycosidae) from the Russian Mountain Altai is described. New data, diagnosis, description and drawings on Arctosa meitanensis Yin et al., 1993 are provided. PMID- 25284670 TI - The bees of the genus Colletes (Hymenoptera: Apoidea: Colletidae) from China. AB - Available information about the bees of the genus Colletes from China is summarized. Currently, 66 species are recorded from China, of which two species, Colletes linzhiensis sp. nov. and C. spinatus sp. nov., are described as new. Type specimens are deposited in the Insect Collection of the Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Thirteen species are recorded for China for the first time: C. edentuloides Kuhlmann, 2011, C. pauljohni Kuhlmann, 2002, C. tuberculatus Morawitz, 1894, C. annapurnensis Kuhlmann, 2002, C. laevigena Noskiewicz, 1936, C. annejohnae Kuhlmann, 2003, C. eous Morice, 1904, C. squamosus Morawitz, 1879, C. wollmanni Noskiewicz, 1936, C. bhutanicus Kuhlmann, 2003, C. kaszabi Kuhlmann, 2002, C. uralensis Noskiewicz, 1936, and C. dorni Kuhlmann, 2002. The male of C. edentuloides Kuhlmann, 2011 and the female of C. pseudolaevigena Kuhlmann, 2002 are described for the first time. Colletes dudgeonii Bingham, 1897 was erroneously recorded from China and is removed from the list of Chinese species. PMID- 25284671 TI - Parapercis nigrodorsalis (Perciformes: Pinguipedidae), a new species of sandperch from northern New Zealand and the Norfolk Ridge, Tasman Sea and remarks on P. binivirgata (Waite, 1904). AB - A new species of pinguipedid fish, Parapercis nigrodorsalis, is described from 17 specimens collected off the North Island of New Zealand and Wanganella Bank, Norfolk Ridge, Tasman Sea, in depths of 56-280 m. The species has also been photographed underwater off the Poor Knights Islands Reserve and Burgess Island, Mokohinau Group, in New Zealand. It is most similar to Parapercis binivirgata (Waite, 1904) in morphology, coloration and meristic values, but is unique among the genus in having a combination of dorsal-fin rays V, 23, anal-fin rays I, 19, lateral-line scales 57-63, vomer with 1-2 irregular rows of robust conical teeth, palatines with 1-2 rows of small teeth, angle of subopercle smooth, 10 abdominal and 22 caudal vertebrae, and coloration, including seven broad reddish-brown bands on the upper body between the spinous dorsal-fin and the caudal peduncle, most bands bifurcated into close-set double bars with black smudge-like blotches below, and membrane of the spinous dorsal fin black. Comparison of the mitochondrial cytochrome c oxidase subunit 1 (CO 1) genetic marker utilised in DNA barcoding produced a genetic divergence of 5.38% and 7.63% between the new species and its two closest sampled congeners. The holotype of P. binivirgata is identified from two specimens previously regarded as syntypes, some revisions are made to meristic data in the original description of the latter, and a detailed description of the revised geographic range of P. binivirgata is provided. PMID- 25284672 TI - Integrative taxonomy in the Liolaemus fitzingerii complex (Squamata: Liolaemini) based on morphological analyses and niche modeling. AB - It has long been considered sufficient a single method or only a descriptive diagnosis to propose a new species. Recently, many works have proposed new theoretical paradigms to consider multiple sources of evidence to support the hypothesis of new taxa within an integrative approach. Despite this, many new described species continue to be merely descriptive and without any reproducible statistical analysis to support these descriptions. We tested whether five species described as members of a species complex of the lizard genus Liolaemus from Patagonia, can be differentiated based on classical morphometric analyses and ecological niche modeling. Individuals were sampled from their type localities. Our results showed that the univariate tests and Principal Component Analyses (PCA) were more accurate to differentiate species compared to the Linear Discriminant Analyses (LDA). However, there were almost no morphometric differences between two of the analyzed species. Major differences were found in bioclimatic variables of four of the species through Maxent ENMs and PCA using the original worldclim variables. Our results partially support the hypothesis that species can be differentiated by classical morphometric analyses, and found a strong support for the hypothesis that these taxa can be differentiated through their bioclimatic niches. These two approaches based on repeatable statistical basis, can supplement qualitative descriptive diagnoses of new species of the genus Liolaemus. PMID- 25284673 TI - Nematodes from galls on Myrtaceae. VII. Fergusobia from 'leafy' leaf bud galls in Australia, with re-description of Fergusobia tumifaciens (Currie 1937) Wachek 1955 and descriptions of Fergusobia planchonianae n. sp. and Fergusobia viminalisae n. sp. AB - Fergusobia tumifaciens (Currie 1937) Wachek 1955, the type species for the genus Fergusobia, is re-described from specimens collected from 'leafy' leaf bud galls on Eucalyptus bridgesiana near Albury in New South Wales, Australia. It is morphologically characterized by the combination of an open C-shaped parthenogenetic female with a small broadly conoid tail, a C-shaped infective female with a bluntly rounded tail tip, and an arcuate to J-shaped male with angular spicules, not heavily sclerotised, and short to mid-length peloderan bursa. Two new species of Fergusobia, collected from 'leafy' leaf bud galls on, respectively, Eucalyptus planchoniana in Queensland, and E. viminalis in South Australia, Australia, are described. Fergusobia planchonianae Davies n. sp. is characterised by the combination of a C-shaped parthenogenetic female with a conoid tail, an arcuate infective female with an hemispherical tail tip, and an almost straight to arcuate to C-shaped male with an angular spicule, a long peloderan bursa and a narrow tail. Fergusobia viminalisae Davies n. sp. is characterised by the combination of an open C-shaped parthenogenetic female with a broadly conoid tail, a C-shaped infective female with a bluntly rounded tail tip, and an arcuate to J-shaped male with an angular (not heavily sclerotised) spicule and short to mid-length peloderan bursa. The shield morphologies of the fly larvae associated with the 'leafy' leaf bud galls and their possible relationships are outlined. Possible evolutionary relationships of the Fergusobia nematodes from these galls are discussed, considering their morphology, DNA sequences, and the relationships of the associated Fergusonina flies and host plants. PMID- 25284674 TI - Mexorchestia: a new genus of talitrid amphipod (Crustacea, Amphipoda, Talitridae) from the Gulf of Mexico and Caribbean Sea, with the description of a new species and two new subspecies. AB - Two species of supralittoral Tethorchestia were reported by Bousfield (1984) to occur on the shores of the Gulf of Mexico and closely adjacent waters: T. antillensis Bousfield, 1984 from Quintana Roo, Mexico and an undescribed species, Tethorchestia sp. B of Bousfield (1984), from Florida and the U.S. Gulf coast. In this paper, we rediagnose and illustrate the former taxon based on material from Goodland Bay, Florida, which represents a range extension for that species. We examined the latter taxon from many locations throughout the Gulf of Mexico using classical morphology, epidermal pigment pattern recognition and allometry, reinforced by molecular markers (mitochondrial cytochrome oxidase I, Radulovici 2012), determining that Tethorchestia sp. B represents a new genus and species, comprising two subspecies. The nominate subspecies, Mexorchestia carpenteri carpenteri n. gen., sp. and subsp., is described from Tiger Tail Beach, Florida, based on conventional morphological criteria and its distinctive epidermal pigment patterns. The Tiger Tail Beach ecotope of M. c. carpenteri n. gen., sp. and subsp. was distinct from that of other locations examined in Florida and was associated with epidermal pigment pattern polymorphism, absent at other locations. A second subspecies, distinguished by differences in size, number of articles in the flagellum of antenna 2, the number of marginal setae on oostegite 2 of the female and the number of distal dorsolateral robust setae on the telson, was found in samples from Belize and Mexico. This subspecies is described from material collected at Turneffe Island, Belize, as Mexorchestia carpenteri raduloviciae n. gen., sp. and subsp. Like M. c. carpenteri n. gen., sp. and subsp., this taxon is also associated with epidermal pigment pattern polymorphism. A key is provided for the three currently described species of Tethorchestia (two extant) and two new subspecies of Mexorchestia n.gen. PMID- 25284675 TI - Paramoguai kavieng, a new genus and species of camptandriid crab from Papua New Guinea (Crustacea: Brachyura). AB - Paramoguai kavieng is recognised as a new genus and species of camptandriid crab, recently discovered in Papua New Guinea. The new genus closely resembles Moguai Tan & Ng, 1999, from the western Pacific, sharing similar carapace and pereopod structure, but is distinguished chiefly by the fusion of the maxilliped 3 ischiomerus, features of the epistome and front, and position of the anterolateral margins of the carapace. The new genus is unique in the Camptandriidae Stimpson, 1858, in having an epistome with a bilobed buccal margin. Moguai pyriforme Naruse, 2005, from Japan, which differs from P. kavieng primarily in carapace ornamentation and gonopod morphology, is transferred to Paramoguai. PMID- 25284676 TI - Lectotype designations and new synonymies in the Neotropical bee genus Centris Fabricius, 1804 (Hymenoptera: Apidae). AB - Ten name-bearing specimens of Centris Fabricius deposited in the Hungarian Natural History Museum are examined and nine lectotypes are designated for the following species: C. atripes Mocsary, 1899; C. flavilabris boliviensis Mocsary, 1899; C. facialis Mocsary, 1899; C. fusciventris Mocsary, 1899; C. mariae Mocsary, 1896; C. minuta Mocsary, 1899; C. obsoleta pleuralis Friese, 1901; C. proxima Friese, 1899, and C. vidua Mocsary, 1899. Two names are newly established as synonyms: C. nitida geminata Cockerell, 1914 syn. nov. = C. facialis Mocsary, 1899; C. pleuralis Friese, 1901 syn. nov. = C. obsoleta Lepeletier de Saint Fargeau, 1841. Comments on the repository of the holotype of C. horvathi Friese are also provided. PMID- 25284677 TI - A new species of Phanerotoma Wesmael (Hymenoptera: Braconidae: Cheloninae) from the Andaman Islands, India. AB - A new species Phanerotoma andamanensis Gupta & van Achterberg sp. nov. is described from the Andaman Islands, India. Differences of the new species from the other Oriental species are discussed. Phanerotoma agarwali Varshney & Shujauddin, 1999, is a junior synonym of P. syleptae Zettel, 1990, syn. nov. PMID- 25284678 TI - Development of a novel task for investigating decision making in a social context following traumatic brain injury. AB - OBJECTIVE: Examination of social cognition as a target for assessment and intervention is beginning to gain momentum in a number of illnesses and acquired disorders. One facet of social cognition is decision making within interpersonal situations. This skill forms an important part of our everyday lives and is commonly impaired in those with neurological and mental health conditions. A novel task was developed to allow the assessment of decision making specifically within a social context and was examined within a group known to experience this difficulty. METHOD: Participants with severe traumatic brain injury (TBI) were compared to healthy control participants on the Social Decision Making Task (SDMT), which required the participant to learn who the "friendly" players were in a game of toss. Participants also completed a nonsocial decision-making task, the Iowa Gambling Task (IGT) as well as a battery of neuropsychological tests and social cognition tasks. Current social functioning was also examined. RESULTS: Consistent with predictions, the TBI group made poorer decisions on the SDMT than the control group; however, group differences were not evident on the IGT. No significant relationships were observed between the SDMT and either measures of executive functioning (including working memory and reversal learning) or social cognition (including emotion recognition and theory of mind). Performance on the SDMT and the IGT were not associated, suggesting that the two tasks measure different constructs. CONCLUSIONS: The SDMT offers a novel way of examining decision making within a social context following TBI and may also be useful in other populations known to have specific social cognition impairment. Future research should aim to provide further clarification of the mechanisms of action and neuroanatomical correlates of poor performance on this task. PMID- 25284679 TI - The glycemic efficacies of insulin analogue regimens according to baseline glycemic status in Korean patients with type 2 diabetes: sub-analysis from the A(1)chieve((r)) study. AB - AIMS: In this study, we compared the glucose-lowering effectiveness of insulin analogues and their combination according to baseline glycemic status in patients with type 2 diabetes (T2D) from the A1 chieve((r)) study conducted in Korea. METHODS: This sub-analysis from the A1 chieve((r)) study was a 24-week prospective, multicenter, non-interventional, open-labelled study. Of the 4058 patients, 3074 patients who had their HbA1c level measured at baseline were included in this sub-analysis. We classified patients into three groups according to baseline HbA1c levels: group I (HbA1c < 7.5%), group II (7.5% <= HbA1c < 9.0%) and group III (HbA1c >= 9.0%). RESULTS: Patients in group I showed no significant HbA1c reduction with any insulin regimens (detemir, aspart, detemir and aspart or biphasic aspart 30 (Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark) after 24 weeks of treatment. In group II, although HbA1c was decreased for all insulin regimens, there was no difference in mean HbA1c reduction among the four insulin regimens. In patients with a high baseline HbA1c level (group III), mean HbA1c reduction was the greatest in patients on a basal-bolus regimen (detemir and aspart, -3.50%) and lowest in patients on a bolus regimen (aspart, -1.81%; p < 0.001). CONCLUSION: For optimal glycaemic control, a basal-bolus regimen may be adequate for Korean patients with poorly controlled T2D (HbA1c >= 9.0%). PMID- 25284680 TI - Resonance Raman spectroscopic measurements delineate the structural changes that occur during tau fibril formation. AB - The aggregation of the microtubule-associated protein, tau, into amyloid fibrils is a hallmark of neurodegenerative diseases such as the tauopathies and Alzheimer's disease. Since monomeric tau is an intrinsically disordered protein and the polymeric fibrils possess an ordered cross-beta core, the aggregation process is known to involve substantial conformational conversion besides growth. The aggregation mechanism of tau in the presence of inducers such as heparin, deciphered using probes such as thioflavin T/S fluorescence, light scattering, and electron microscopy assays, has been shown to conform to ligand-induced nucleation-dependent polymerization. These probes do not, however, distinguish between the processes of conformational conversion and fibril growth. In this study, UV resonance Raman spectroscopy is employed to look directly at signatures of changes in secondary structure and side-chain packing during fibril formation by the four repeat functional domain of tau in the presence of the inducer heparin, at pH 7 and at 37 degrees C. Changes in the positions and intensities of the amide Raman bands are shown to occur in two distinct stages during the fibril formation process. The first stage of UVRR spectral changes corresponds to the transformation of monomer into early fibrillar aggregates. The second stage corresponds to the transformation of these early fibrillar aggregates into the final, ordered, mature fibrils and during this stage; the processes of conformational conversion and the consolidation of the fibril core occur simultaneously. Delineation of these secondary structural changes accompanying the formation of tau fibrils holds significance for the understanding of generic and tau-specific principles of amyloid assembly. PMID- 25284681 TI - Innate immune sensing of nucleic acids from mycobacteria. AB - Endosomal and cytosolic receptors engage recognition of mycobacterial-derived nucleic acids (MyNAs). In contrast, virulent mycobacteria may utilize nucleic acid recognition pathways to escape the host immune system. This short review will summarize the mechanisms by which MyNAs are sensed and how they influence host protective responses. PMID- 25284682 TI - The induction of Staphylococcus aureus biofilm formation or Small Colony Variants is a strain-specific response to host-generated chemical stresses. AB - Staphylococcus aureus is extremely versatile. It has a capacity to persist within its host by switching to the alternative lifestyles of biofilm or Small Colony Variants (SCV). The induction of this switch has been presumed to be in response to stressed conditions, however the environmental basis has not been thoroughly investigated. We assessed the response of numerous strains to chemicals that are present in human host. There were some that induced a biofilm or SCV phenotype and indeed some inducing both lifestyles. This result illustrates the diversity within a population and a strain-specific adaptation to the presence of host generated stresses. PMID- 25284684 TI - Copper-catalyzed arylation of nitrogen heterocycles from anilines under ligand free conditions. AB - The arylation of pyrazole and derivatives can be achieved by coupling arenediazonium species (formed in situ from anilines) by using a catalytic system that employs low-toxicity and inexpensive copper metal under very mild and ligand free conditions (T=20 degrees C). From other nitrogen heterocycles, the presence of an additive (NBu4 I) significantly improves the efficiency of the catalytic system. These results represent the first examples of C?N bond formation from arenediazonium species. PMID- 25284683 TI - Investigation of avian influenza virus in poultry and wild birds due to novel avian-origin influenza A(H10N8) in Nanchang City, China. AB - Multiple reassortment events within poultry and wild birds had resulted in the establishment of another novel avian influenza A(H10N8) virus, and finally resulted in human death in Nanchang, China. However, there was a paucity of information on the prevalence of avian influenza virus in poultry and wild birds in Nanchang area. We investigated avian influenza virus in poultry and wild birds from live poultry markets, poultry countyards, delivery vehicles, and wild-bird habitats in Nanchang. We analyzed 1036 samples from wild birds and domestic poultry collected from December 2013 to February 2014. Original biological samples were tested for the presence of avian influenza virus using specific primer and probe sets of H5, H7, H9, H10 and N8 subtypes by real-time RT-PCR. In our analysis, the majority (97.98%) of positive samples were from live poultry markets. Among the poultry samples from chickens and ducks, AIV prevalence was 26.05 and 30.81%, respectively. Mixed infection of different HA subtypes was very common. Additionally, H10 subtypes coexistence with N8 was the most prevalent agent during the emergence of H10N8. This event illustrated a long-term surveillance was so helpful for pandemic preparedness and response. PMID- 25284685 TI - Core-shell nanoreactors for efficient aqueous biphasic catalysis. AB - Water-borne phosphine-functionalized core-cross-linked micelles (CCM) consisting of a hydrophobic core and a hydrophilic shell were obtained as stable latexes by reversible addition-fragmentation chain transfer (RAFT) in water in a one-pot, three-step process. Initial homogeneous aqueous-phase copolymerization of methacrylic acid (MAA) and poly(ethylene oxide) methyl ether methacrylate (PEOMA) is followed by copolymerization of styrene (S) and 4-diphenylphosphinostyrene (DPPS), yielding P(MAA-co-PEOMA)-b-P(S-co-DPPS) amphiphilic block copolymer micelles (M) by polymerization-induced self-assembly (PISA), and final micellar cross-linking with a mixture of S and diethylene glycol dimethacrylate. The CCM were characterized by dynamic light scattering and NMR spectroscopy to evaluate size, dispersity, stability, and the swelling ability of various organic substrates. Coordination of [Rh(acac)(CO)2 ] (acac=acetylacetonate) to the core confined phosphine groups was rapid and quantitative. The CCM and M latexes were then used, in combination with [Rh(acac)(CO)2 ], to catalyze the aqueous biphasic hydroformylation of 1-octene, in which they showed high activity, recyclability, protection of the activated Rh center by the polymer scaffold, and low Rh leaching. The CCM latex gave slightly lower catalytic activity but significantly less Rh leaching than the M latex. A control experiment conducted in the presence of the sulfoxantphos ligand pointed to the action of the CCM as catalytic nanoreactors with substrate and product transport into and out of the polymer core, rather than as a surfactant in interfacial catalysis. PMID- 25284686 TI - Enhanced NLRP3, caspase-1, and IL- 1beta levels in degenerate human intervertebral disc and their association with the grades of disc degeneration. AB - The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays an important role in a variety of diseases. However, the role of NLRP3 in the human intervertebral disc (IVD) degeneration remains unknown. In the present study, we assessed the expression levels of the NLRP3 inflammasome and its downstream targets caspase-1 and IL-1beta in 45 degenerate and seven nondegenerate IVD samples. The correlation between the degeneration scores and expression levels of NLRP3, caspase-1, and IL-1beta were also analyzed. The mRNA expression levels of the three molecules (NLRP3, caspase-1, and IL-1beta) were higher in the degenerate IVDs group than the controls (nondegenerate IVDs group). Immunohistochemistry showed that the expression levels of all three molecules were markedly increased in the nucleus pulposus of degenerate IVDs compared with nondegenerate IVDs. There was a positive correlation between the degeneration scores and the expression levels of the NLRP3 inflammasome as well as its downstream targets caspase-1 and IL-1beta. The findings suggest that excessive activation of the NLRP3 inflammasome results in overproduction of downstream IL 1beta, which participates in the pathogenesis of human IVD degeneration. Therefore, the NLRP3 inflammasome might serve as a potential therapeutic target for the prevention and treatment of IVD degeneration. PMID- 25284687 TI - Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease. AB - Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naive PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [(123) I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD. PMID- 25284688 TI - In-situ observation and atomic resolution imaging of the ion irradiation induced amorphisation of graphene. AB - Ion irradiation has been observed to induce a macroscopic flattening and in-plane shrinkage of graphene sheets without a complete loss of crystallinity. Electron diffraction studies performed during simultaneous in-situ ion irradiation have allowed identification of the fluence at which the graphene sheet loses long range order. This approach has facilitated complementary ex-situ investigations, allowing the first atomic resolution scanning transmission electron microscopy images of ion-irradiation induced graphene defect structures together with quantitative analysis of defect densities using Raman spectroscopy. PMID- 25284689 TI - Orphan nuclear receptor Nur77 is a novel negative regulator of endothelin-1 expression in vascular endothelial cells. AB - Endothelin-1 (ET-1) produced by vascular endothelial cells plays essential roles in the regulation of vascular tone and development of cardiovascular diseases. The objective of this study is to identify novel regulators implicated in the regulation of ET-1 expression in vascular endothelial cells (ECs). By using quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), we show that either ectopic expression of orphan nuclear receptor Nur77 or pharmacological activation of Nur77 by 6-mercaptopurine (6-MP) substantially inhibits ET-1 expression in human umbilical vein endothelial cells (HUVECs), under both basal and thrombin-stimulated conditions. Furthermore, thrombin stimulated ET expression is significantly augmented in both Nur77 knockdown ECs and aort from Nur77 knockout mice, suggesting that Nur77 is a negative regulator of ET-1 expression. Inhibition of ET-1 expression by Nur77 occurs at gene transcriptional levels, since Nur77 potently inhibits ET-1 promoter activity, without affecting ET-1 mRNA stability. As shown in electrophoretic mobility shift assay (EMSA), Nur77 overexpression markedly inhibits both basal and thrombin stimulated transcriptional activity of AP-1. Mechanistically, we demonstrate that Nur77 specially interacts with c-Jun and inhibits AP-1 dependent c-Jun promoter activity, which leads to a decreased expression of c-Jun, a critical component involved in both AP-1 transcriptional activity and ET-1 expression in ECs. These findings demonstrate that Nur77 is a novel negative regulator of ET-1 expression in vascular ECs through an inhibitory interaction with the c-Jun/AP-1 pathway. Activation of Nur77 may represent a useful therapeutic strategy for preventing certain cardiovascular diseases, such as atherosclerosis and pulmonary artery hypertension. PMID- 25284690 TI - Comparison of radioactive iodide uptake in the rat thyroid between oral and intravenous bolus administration. AB - OBJECTIVE: Radioiodide is commonly used to diagnose and treat hyperthyroidism and thyroid carcinoma. However, we could not find any experimental data that strictly compared the biodistribution and thyroid uptake of radioactive iodide between the oral and intravenous (iv) routes with time. This prompted us to compare (123)I biodistribution and thyroid uptake to clarify the differences between oral and iv bolus administration in rats. METHODS: The rats were divided into two groups, A and B (n = 5, each). In the first imaging experiment, Na(123)I solution (35 MBq/200 MUL) was administered as a bolus to the rats orally in group A and intravenously in group B. Two weeks later, the second imaging experiment was performed as a crossover experiment. (123)I biodistribution was evaluated visually and quantitatively with a gamma camera at 10 min, 3, 6, 12, 24, and 48 h after (123)I administration. Thyroid uptake was compared between oral and iv groups. Correlation of (123)I thyroid uptake and whole-body excretion was evaluated. The area under the curve (AUC) of thyroid uptake was also calculated. RESULTS: (123)I biodistribution differed visually during 6 h between the two groups. (123)I thyroid uptake was significantly higher in the iv group at 10 min (P < 0.05) and in the oral group at 6 or more hour time points (P < 0.005-P < 0.0001) and peaked at 12 h in both groups (oral: 24.4 +/- 2.8 %ID, iv: 15.2 +/- 2.8 %ID). (123)I thyroid uptake showed significant inverse correlations with whole-body excretion from 6 h (r = -0.799, P < 0.0001), and thereafter [12 h (r = -0.957, P < 0.0001), 24 h (r = -0.905, P < 0.0001) and 48 h (r = -0.893, P < 0.0001)], respectively. (123)I whole-body excretion was significantly higher in the iv group at each time point (P < 0.0001). The AUC of (123)I thyroid uptake was 1.6 times higher in the oral group than the iv group. CONCLUSIONS: These results suggest that radioiodide accumulates in the rat thyroid more effectively by oral than iv administration probably due to slower and lower (123)I clearance from the body in the oral administration when administered in a bolus fashion. PMID- 25284691 TI - Methotrexate for ectopic pregnancy: success rates and avoidance of embryopathy. PMID- 25284692 TI - Reply: To PMID 24657132. PMID- 25284693 TI - cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases. AB - INTRODUCTION: PDEs are key enzymes in the adenosine and guanosine cyclic nucleotides (cAMP and cGMP) signaling cascade. Their inhibition increases cyclic nucleotide levels inside the cell. Thus, pharmacological modulation of PDE activity can have profound effects on the function of cells and organ systems throughout the body. AREAS COVERED: Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. cAMP is an important second messenger not only by its involvement in a vast number of physiological processes but also by activation of protein kinase A, exchange protein activated by cAMP (Epac) and cAMP response element-binding (CREB) or cyclic nucleotide-gated channels. Clearly, such enzymes represent ideal drug targets for the pharmacological treatment of many pathologies. The discovery and development of small molecules targeting cAMP-specific PDEs reported in the last 5 years is the focus of the present review. EXPERT OPINION: The first PDE4 inhibitors recently reached the market, having avoided, by different strategies, their dose-limiting side effects (after more than two decades of drug development). Meanwhile, new cAMP-specific PDE7 and PDE8 inhibitors emerged as effective and safe drugs for severe unmet diseases. The therapeutic potential of these inhibitors will be tested in the near future, as many of these drug candidates are ready to start clinical trials. PMID- 25284695 TI - Diabetes and chronic kidney disease: concern, confusion, clarity? PMID- 25284694 TI - Reversibly controlling preferential protein adsorption on bone implants by using an applied weak potential as a switch. AB - A facile method is needed to control the protein adsorption onto biomaterials, such as, bone implants. Herein we doped taurocholic acid (TCA), an amphiphilic biomolecule, into an array of 1D nano-architectured polypyrrole (NAPPy) on the implants. Doping TCA enabled the implant surface to show reversible wettability between 152 degrees (superhydrophobic, switch-on state) and 55 degrees (hydrophilic, switch-off state) in response to periodically switching two weak electrical potentials (+0.50 and -0.80 V as a switch-on and switch-off potential, respectively). The potential-switchable reversible wettability, arising from the potential-tunable orientation of the hydrophobic and hydrophilic face of TCA, led to potential-switchable preferential adsorption of proteins as well as cell adhesion and spreading. This potential-switchable strategy may open up a new avenue to control the biological activities on the implant surface. PMID- 25284696 TI - My patient's diabetic kidney disease has progressed to stage 4; should I discontinue metformin? PMID- 25284697 TI - Optimal medication dosing in patients with diabetes mellitus and chronic kidney disease. AB - Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in Canada. As rates of diabetes rise, so does the prevalence of CKD. Diabetes and CKD are chronic diseases that require multiple medications for their management. Many of the anticipated effects of these medications are altered by the physiologic changes that occur in CKD. Failure to individualize drug dosing in this population may lead to toxicity or decreased therapeutic response, leading to treatment failure. At times this can be challenging for a multitude of reasons, including the limitations of available calculations for estimating renal function, inconsistent dosing recommendations and the lack of dosing recommendations for some medications. Clinicians caring for these patients need to consider an approach of individualized drug therapy that will ensure optimal outcomes. The better understanding that clinicians have of these challenges, the more effective they will be at using the available information as a guide together with their own professional judgement to make appropriate dosing changes. This article discusses the following: 1) physiologic changes that occur in CKD and its impact on drug dosing; 2) advantages and disadvantages of various calculations used for estimating renal function; 3) pharmacokinetic and pharmacodynamic changes of some commonly used medications in diabetes, and finally, 4) an approach to individualized drug dosing for this patient population. PMID- 25284698 TI - The Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch (iCARE) Cohort Study: rationale and Protocol. AB - BACKGROUND: Youth-onset type 2 diabetes is associated with a high burden of renal complications, culminating with end stage kidney disease in early adulthood. The establishment of relevant bioclinical determinants of albuminuria and ultimately progression of chronic kidney disease in youth is critically important to facilitate patient risk stratification and aid in the development of treatment targets and tailored prevention strategies. In response to the important gaps in knowledge, we created a prospective cohort study of youth with type 2 diabetes titled the Improving Renal Complications in Adolescents with Type 2 Diabetes through the REsearch (iCARE) Study. METHODS: iCARE is a prospective observational cohort study of individuals with type 2 diabetes diagnosed prior to 18 years of age; the recruitment target was 400 patients. Phase 1 entailed a detailed phenotypic assessment of youth, including anthropometrics, biochemistry, 24-hour ambulatory blood pressure monitoring, overnight urine collections for albumin excretion, renal ultrasound and iohexol-derived glomerular filtration rate. Phase 2 of the study is an evaluation of psychological factors, including hair-derived cortisol; validated questionnaires for perceived stress, distress and resiliency; and a detailed evaluation of systemic and urine inflammatory biomarkers. Annual follow up is planned to assess temporal associations between clinical risk factors and renal outcomes, including progression of albuminuria. CONCLUSION: This study will provide novel insight into the risk factors for albuminuria and progression of chronic kidney disease in youth with type 2 diabetes. New knowledge generated by this study will inform clinical care, and the infrastructure developed will provide a framework for future intervention studies. PMID- 25284699 TI - Blood pressure-lowering effects of incretin-based diabetes therapies. AB - Glucagon-like peptide-1 receptor (GLP-1) agonists and dipeptidyl-peptidase-4 (DPP 4) inhibitors are therapies that are used to treat hyperglycemia in patients with type 2 diabetes mellitus. Although both of these medication types primarily lower prandial and fasting blood glucose levels by enhanced GLP-1 receptor signalling, they have distinct mechanisms of action. Whereas DPP-4 inhibitors boost patient levels of endogenously produced GLP-1 (and glucose-dependent insulinotropic peptide) by preventing its metabolism by DPP-4 enzymatic activity, GLP-1 receptor agonists are either synthetic analogues of human GLP-1 or exendin-4 based molecules. They are tailored to resist hydrolysis by DPP-4 activity and to provide longer durability in the circulation compared with native GLP-1. Several roles for incretin-based diabetes therapies beyond the endocrine pancreas and their glycemic-lowering properties have now been described, including attenuation of cardiac myocyte injury and reduction in post-ischemic infarction size after cardiovascular insult. Favourable outcomes have also been observed on systolic blood pressure reduction, postprandial intestinal lipoprotein metabolism, endothelial cell function, modulation of innate immune-mediated inflammation and surrogate markers of renal function. As hypertension is an independent risk factor for premature death in patients with type 2 diabetes, potential favourable extrapancreatic actions, particularly within the heart, blood vessels and kidney, for this drug class are of considerable clinical interest. Herein, we highlight and provide critical appraisal of the clinical data supporting the antihypertensive effects of GLP-1 receptor agonists and DPP-4 inhibitors and link possible mechanisms of action to clinical outcomes reported for this drug class. PMID- 25284700 TI - Testing for albuminuria in 2014. AB - Routine quantification of urinary albumin levels is recommended for all Canadians with diabetes, yet many controversies remain when interpreting these tests. Elevated levels of albuminuria have traditionally been labeled as either microalbuminuria, representing 30 to 300 mg of albuminuria per day (a range not reliably picked up by conventional urine dipsticks), or as overt nephropathy, representing more than 300 mg per day and usually identifiable by dipstick. The random urine albumin-to-creatinine ratio is a convenient test that can predict reliably the total daily protein excretion. The 30 mg per day upper limit of normal was selected to be a threshold far above the normal albumin excretion seen in healthy people. However, recent studies have shown that elevations of albumin excretion below the microalbuminuria threshold are associated with increased cardiorenal risk, suggesting that the 30 mg per day level may be set too high. Recently, the Canadian Diabetes Association Clinical Practice Guidelines changed the threshold for abnormal urine albumin-to-creatinine ratios to be 2.0 mg/mmol for both men and women. As a result, more women will be identified as having abnormal levels of albuminuria. However, these women will be correctly identified as having increased cardiorenal risk. It is important to note that people with diabetes who have abnormal levels of albuminuria are among patients at the highest risk for cardiorenal disease. These risks can be reduced by using the strategies outlined in the guidelines put forth by the Canadian Diabetes Association. PMID- 25284701 TI - Morphological relationship between the cranial and supraorbital regions in Homo sapiens. AB - Although some hypotheses that attempt to explain the variation in supraorbital region morphology in modern humans have been proposed, this issue is still not well understood. In this study, the craniofacial size and spatial models were tested using a sample of modern human crania from geographically diverse populations, and the co-occurrence of the degrees of glabella (GL) and superciliary arch (ST) expression were analyzed. The two supraorbital structures were examined by visual assessment, and eight quantitative variables were included in the three-way ANOVA, canonical variates analysis and partial rank correlation. The influences of sex and the region of origin of the cranial samples on the relationships between the examined variables and the degrees of supraorbital structures expression were also considered. The results only partially supported the craniofacial size and spatial models and suggested that GL and ST experienced separate influences during development. In the sample of all crania, the neurocranial size more strongly influenced the morphological variation of the ST than of the GL, and sex influenced both of these structures the most. The results suggest that sex may be the main factor (having an influence independent of the other traits) on the morphological variation of the GL and ST. PMID- 25284703 TI - Thyroid cancer mortality and incidence: a global overview. AB - In most areas of the world, thyroid cancer incidence has been appreciably increasing over the last few decades, whereas mortality has steadily declined. We updated global trends in thyroid cancer mortality and incidence using official mortality data from the World Health Organization (1970-2012) and incidence data from the Cancer Incidence in Five Continents (1960-2007). Male mortality declined in all the major countries considered, with annual percent changes around -2/-3% over the last decades. Only in the United States mortality declined up to the mid 1980s and increased thereafter. Similarly, in women mortality declined in most countries considered, with APCs around -2/-5% over the last decades, with the exception of the UK, the United States and Australia, where mortality has been declining up to the late 1980s/late 1990s to level off (or increase) thereafter. In 2008-2012, most countries had mortality rates (age-standardized, world population) between 0.20 and 0.40/100,000 men and 0.20 and 0.60/100,000 women, the highest rates being in Latvia, Hungary, the Republic of Moldova and Israel (over 0.40/100,000) for men and in Ecuador, Colombia and Israel (over 0.60/100,000) for women. In most countries, a steady increase in the incidence of thyroid cancer (mainly papillary carcinomas) was observed in both sexes. The declines in thyroid cancer mortality reflect both variations in risk factor exposure and changes in the diagnosis and treatment of the disease, while the increases in the incidence are likely due to the increase in the detection of this neoplasm over the last few decades. PMID- 25284702 TI - Gastroprotective agent underuse in high-risk older daily nonsteroidal anti inflammatory drug users over time. AB - OBJECTIVES: To examine whether older adults taking nonsteroidal anti-inflammatory drugs (NSAIDs) decreased the underuse of gastroprotective agents over time. DESIGN: Before-and-after study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Daily users of a NSAID (prescription and over the counter (OTC)) at visits in 2002-03 (preperiod; n = 404) and 2006-07 (postperiod; n = 172). The sample had a mean +/- standard deviation age of 78.2 +/- 2.7 at the preperiod visit and 81.9 +/- 2.7 at the postperiod visit. The majority were white and female and had 12 or more years of education. MEASUREMENTS: Underusers were defined as persons taking nonselective NSAIDs who were at risk of peptic ulcer disease (PUD; because of current warfarin or glucocorticoid use or history of PUD) and not using a proton pump inhibitor (PPI) or persons taking cyclooxygenase 2 (COX-2) selective NSAIDs and aspirin who were at risk of PUD (having at least one risk factor) and not using a PPI. RESULTS: Daily NSAID use decreased from 17.6% to 11.3% (P < .001), and gastroprotective agent underuse decreased from 23.5% to 15.1% (P = .008). Controlling for important covariates, having prescription insurance was somewhat protective against underuse in the preperiod (adjusted odds ratio (AOR) = 0.78, 95% confidence interval (CI) = 0.46-1.34; P = .37), but more so and significantly in the postperiod (AOR = 0.41, 95% CI = 0.18 0.93; P = .03). Having prescription insurance was more protective in the post- than in the preperiod (less gastroprotective agent underuse; adjusted ratio of OR = 0.53, 95% CI = 0.22-1.29; P = .16), but this increased protection was not statistically significant. CONCLUSION: In older daily NSAID users at high risk of PUD, having prescription insurance and adequate gastroprotective use was more common in the post- than in the preperiod. PMID- 25284705 TI - Expression of hypoxia-inducible factor-1alpha and hepatocyte growth factor in development of fibrosis in the transplanted kidney. AB - Late renal graft loss is associated with interstitial fibrosis. Hypoxia-inducible factor-1alpha (HIF-1alpha) is thought to facilitate fibrosis through interaction with TGF-beta1, while hepatocyte growth factor (HGF) may act antifibrotic in the kidney allograft. The aim of this study was to investigate the expression of HIF 1alpha and HGF in protocol biopsies as possible prognostic biomarkers for renal fibrosis. Thirty-nine renal transplant recipients were included in the study. Protocol biopsies performed 1 and 2 years after transplantation were used for immunohistochemistry analysis. The correlation between HIF-1alpha/HGF and the Banff score was analysed. In addition, progression in renal fibrosis and graft survival among recipients with high or low expression of HIF-1alpha/HGF after transplantation was compared. There was no significant correlation between fibrosis and the HIF-1alpha expression 1 and 2 years after transplantation, but an inverse significant correlation between the HGF expression and the fibrosis score 1 year after transplantation was shown. Even when adjusting for human leucocyte antigen mismatches, there was a significant relationship between fibrosis and HGF expression. Graft survival was not significantly correlated to HIF-1alpha or HGF at 1 year, although the trend was towards better graft survival with high HGF. HGF may have antifibrotic effects in human renal transplants. (Central.Denmark.Region.Committee number: 1-10-72-318-13). PMID- 25284704 TI - Interaction of noradrenergic pharmacological manipulation and subthalamic stimulation on movement initiation control in Parkinson's disease. AB - BACKGROUND: Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic). OBJECTIVE: To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. METHODS: Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (?2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 MUg oral dose of clonidine (ON- or OFF-DBS). RESULTS: In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON DBS state. CONCLUSIONS: Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency. PMID- 25284706 TI - A universal approach for the reversible phase transfer of hydrophilic nanoparticles. AB - The ability to engineer the surface properties of magnetic nanoparticles is important for their various applications, as numerous physical and chemical properties of nanoscale materials are seriously affected by the chemical constitution of their surfaces. For some specific applications, nanoparticles need to be transferred from a polar to a nonpolar environment (or vice versa) after synthesis. In this work we have developed a universal method for the phase transfer of magnetic nanoparticles that preserves their shape and size. Octadecyltrimethoxysilane was used to cap the surfaces of the aqueous magnetic nanoparticles, thereby allowing their transfer into nonpolar solution. The resulting hydrophobic magnetic nanoparticles were transferred back into aqueous solution by subsequently covering them with an egg-PC lipid monolayer. The superparamagnetic properties of the particles were retained after the phase transfer. The maximum transfer yields are dependent on their particle size with a maximum value of 93.16 +/- 4.75% for magnetic nanoparticles with a diameter of 100 nm. The lipid-modified magnetic particles were stable over 1 week, and thus they have potential applications in the field of biomedicine. This work also provides a facile strategy for the controllable engineering of the surface properties of nanoparticles. PMID- 25284707 TI - Loading characteristics and chemical stability of headgroup-functionalized poly(ethylene glycol)-lipid ligand tethers on polypropylene capillary-channeled polymer fibers. AB - Polypropylene capillary-channeled polymer fibers have been modified by adsorption of headgroup-functionalized poly(ethylene glycol)-lipids to generate a species specific stationary phase. In order to study ligand binding characteristics, a fluorescein-labeled poly(ethylene glycol)-lipid was used as a model system. Breakthrough curves and frontal analysis were employed to characterize the surface loading characteristics across a range of lipid concentrations and mobile phase flow rates. Efficient mass transfer and fluid transport yield a linear adsorption isotherm up to the maximum loading concentration of 3 mg/mL, at a linear velocity of 57.1 mm/s. Under these conditions, the dynamic binding capacity was found to be 1.52 mg/g of fiber support. Variation of the linear velocity from 8.6 to 57.1 mm/s showed only small changes in breakthrough volume. The maximum capacity of 1.8 mg/g is found under conditions of a load velocity of 34.2 mm/s and a concentration of 3 mg/mL lipid. Exposure of the lipid modified fibers to several challenge solvents reveals a chemically robust system, with only 50% acetonitrile and hexanes able to disrupt the lipid adsorption. The straightforward capillary-channeled polymer fiber surface modification with headgroup-functionalized lipids provides both a diverse yet practically robust ligand tethering system. PMID- 25284709 TI - Time to rethink the unthinkable: upfront biopsy of children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). PMID- 25284708 TI - Embedding sustainable physical activities into the everyday lives of adults with intellectual disabilities: a randomised controlled trial. AB - BACKGROUND: Adults with intellectual disability (ID) are physically very inactive. This study will compare two approaches to increasing physical activity in adults with ID: a lifestyle physical activity (light-moderate intensity) approach and a structured exercise (moderate-vigorous intensity) approach. The trial will compare the short-term (3-month) and long-term (9-month) outcomes and sustainability of each approach with a usual-care control group. METHODS/DESIGN: A three-arm randomised controlled trial (RCT) will be conducted. Ninety adults with ID aged 18-55 will be randomly assigned to one of three groups: 1) a lifestyle physical activity group (n = 30), 2) a structured exercise group (n = 30), or 3) a usual care control group (n = 30). Participants in both groups will receive a 12-week intervention delivered by exercise specialists in the community with disability service staff, after which intervention will continue for 6 months, delivered by disability service staff only. Primary outcomes are aerobic fitness, 12-hour energy expenditure, and proxy-reported everyday physical activity. Secondary outcomes include objectively assessed physical activity and sedentary behaviour, intervention compliance, functional walking capacity, participation in domestic activities, muscle strength, body composition, psychosocial outcomes, quality of life and health care costs. DISCUSSION: The trial results will determine the effectiveness and sustainability of two approaches to increasing physical activity and exercise among adults with ID. TRIAL REGISTRATION: ISRCTN77889248 (18 April 2012). PMID- 25284711 TI - Increasing the size of an aromatic helical foldamer cavity by strand intercalation. AB - The postsynthetic modulation of capsules based on helical aromatic oligoamide foldamers would be a powerful approach for controlling their receptor properties without altering the initial monomer sequences. With the goal of developing a method to increase the size of a cavity within a helix, a single-helical foldamer capsule was synthesized with a wide-diameter central segment that was designed to intercalate with a second shorter helical strand. Despite the formation of stable double-helical homodimers (K(dim)>10(7) M(-1)) by the shorter strand, when it was mixed with the single-helical capsule sequence, a cross-hybridized double helix was formed with K(a)>10(5) M(-1). This strategy makes it possible to direct the formation of double-helical heterodimers. On the basis of solution- and solid state structural data, this intercalation resulted in an increase in the central cavity size to give a new interior volume of approximately 150 A(3). PMID- 25284710 TI - High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. AB - Downregulation of cereblon (CRBN) gene expression is associated with resistance to the immunomodulatory drug lenalidomide and poor survival outcomes in multiple myeloma (MM) patients. However, the importance of CRBN gene expression in patients with myelodysplastic syndrome (MDS) and its impact on lenalidomide therapy are not clear. In this study, we evaluate cereblon expression in mononuclear cells isolated from bone marrow [23 lower risk MDS patients with isolated 5q deletion (5q-), 37 lower risk MDS patients with chromosome 5 without the deletion of long arms (non-5q-), and 24 healthy controls] and from peripheral blood (38 patients with 5q-, 52 non-5q- patients and 25 healthy controls) to gain insight into, firstly, the role of cereblon in lower risk MDS patients with or without 5q deletion and, secondly, into the mechanisms of lenalidomide action. Patients with 5q- lower risk MDS have the highest levels of CRBN mRNA in comparison with both lower risk MDS without the deletion of long arms of chromosome 5 and healthy controls. CRBN gene expression was measured using the quantitative TaqMan real-time PCR. High levels of CRBN mRNA were detected in all lenalidomide responders during the course of therapy. A significant decrease of the CRBN mRNA level during lenalidomide treatment is associated with loss of response to treatment and disease progression. These results suggest that, similar to the treatment of MM, high levels of full-length CRBN mRNA in lower risk 5q- patients are necessary for the efficacy of lenalidomide. PMID- 25284712 TI - Synthesis and properties of salicyladehyde salicyhydrazone derivatives and their europium complexes. AB - Four novel salicyladehyde salicyhydrazone derivatives and their corresponding europium (Eu(3+)) complexes were synthesized and characterized. The formulas of the complexes were [EuL(a-d)(NO3)2](NO3) . H2O. The investigatoin of fluoresence properties of the Eu(3+) complexes showed that the salicyladehyde salicyhydrazone derivatives were efficient sensitizers for the fluoresence of Eu(3+) ions. The fluorescence intensity of the complex substituted by methyl (-CH3) was the strongest among all the Eu(3+) complexes. The exploration of the electrochemical properties of the Eu(3+) complexes showed that the introduction of electron donating groups methyl and methoxyl (-CH3 and -OCH3) could increase the oxidation potential and the highest occupied molecular orbital (HOMO) energy level of the Eu(3+) complex; however, the results of introduction of electron-withdrawing group were just opposite. PMID- 25284713 TI - Phenalenone fluorophores-synthesis, photophysical properties and DFT study. AB - Three new fluorescent phenalenone derivatives incorporating bexozazolyl, benzothiazolyl and benzimidazolyl rings have been synthesized from the intermediate 3-(1,3-benzazol-2-yl) naphthalen-2-ol by reacting with glycerol. The synthesized phenalenone derivatives were well characterized by using FT-IR, (1)HNMR, (13)CNMR and Mass spectroscopy. The photophysical properties of these phenalenone derivatives show that these dyes absorb in the range of 300-429 nm and emitted in the range of 348-578 nm. The relative fluorescence quantum yields of these derivatives were determined by using fluorescein, tinopal and anthracene as the reference standards. Photophysical properties of the synthesized phenalenone dyes were evaluated by UV-Visible spectroscopy and compared with the computed vertical excitations obtained from TD-DFT. Thermal stability of the compounds were studied by using thermo gravimetric analysis and results show that compounds are thermally stable up to 298-347 degrees C. PMID- 25284714 TI - Human Th1 dichotomy: origin, phenotype and biologic activities. AB - The great variety of pathogens present in the environment has obliged the immune system to evolve different mechanisms for tailored and maximally protective responses. Initially, two major types of CD4+ T helper (Th) effector cells were identified, and named as type 1 (Th1) and type (Th2) cells because of the different cytokines they produce. More recently, a third type of CD4+ Th effectors has been identified and named as Th17 cells. Th17 cells, however, have been found to exhibit high plasticity because they rapidly shift into the Th1 phenotype in the inflammatory sites. Therefore, in these sites usually there is a dichotomic mixture of classic and non classic (Th17-derived) Th1 cells. In humans, non classic Th1 cells express CD161, as well as the retinoic acid orphan receptor C, IL-17 receptor E, IL-1RI, CCR6, and IL-4-induced gene 1 and Tob-1, which are all virtually absent from classic Th1 cells. The possibility to distinguish these two cell subsets may allow the opportunity to better establish their respective pathogenic role in different chronic inflammatory disorders. In this review, we discuss the different origin, the distinctive phenotypic features and the major biologic activities of classic and non classic Th1 cells. This article is protected by copyright. All rights reserved. PMID- 25284715 TI - A longitudinal intergenerational analysis of executive functions during early childhood. AB - Despite the importance of executive function (EF) in both clinical and educational contexts, the aetiology of individual differences in early childhood EF remains poorly understood. This study provides the first longitudinal intergenerational analysis of mother-child EF associations during early childhood. A group of children and their mothers (n = 62) completed age appropriate EF tasks. Mother and child EFs were modestly correlated by 24 months of age, and this association was stable through 48 months. Importantly, maternal child EF associations were still robust after controlling for verbal ability (potential indicator of verbal/crystallized intelligence) and maternal education (correlate of socio-economic status and verbal intelligence). Potential implications of these findings as well as underlying mechanisms of the maternal child EF association (gene-environment interplay) are discussed. PMID- 25284716 TI - GTF2I-RARA is a novel fusion transcript in a t(7;17) variant of acute promyelocytic leukaemia with clinical resistance to retinoic acid. PMID- 25284717 TI - Seasonal differences and circadian variation in stroke occurrence and stroke subtypes. AB - BACKGROUND: India is a subtropical country with clear seasonal variations in weather conditions. Seasonal and circadian variation in occurrence of subtypes of cerebrovascular disease has been of interest in several studies from different countries and climate zones, but discrepant results have made the conclusions unclear. The aim of the present study was to observe the seasonal and circadian variation in the occurrence of stroke and its subtypes among our population. METHODS: This was a cross-sectional observational study based on new cases and past cases of stroke on follow-up, conducted between January 2011 and December 2012 in the Department of Neurology, at the All India Institute of Medical Sciences, New Delhi, India. The date and time of onset of the stroke was recorded. The categorization of months into season was in accordance with the Indian Meteorological Department guidelines. The time of onset was distributed into 6 hourly intervals. Statistical calculations were performed using Stata version 12.1 and SPSS version 20. RESULTS: A total of 583 patients were included for the study. The rate of occurrence of stroke was highest in the late morning 0600-1159 hours (P value <.001) compared with other times of the day, regardless of gender or age for both ischemic and hemorrhagic strokes. It was lowest in late evening (1800-2359 hours) quadrant compared with other quadrants. Although there was no significant difference found by dichotomizing the groups into two 6-month periods, there was an increasing trend in number of patients with stroke during the months November-February. There was no difference in stroke occurrence between the types of stroke or within each type among different seasons with different temperatures. Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification of ischemic strokes also did not show any association with season or circadian rhythm. CONCLUSIONS: There is a significant increase in occurrence of strokes between 0600 and 1159 hours and lowest between 1800-2359 hours. No significant variation in stroke occurrence or subtype for any of the seasons was observed. PMID- 25284718 TI - Diffusion tensor imaging and neuropsychologic assessment in aphasic stroke. AB - With the recent advances in neuroimaging it has become possible to characterize the cerebral reorganization that occurs in response to therapy and the conditions under which this reorganization occurs. Diffusion tensor imaging (DTI) is a neuroimaging technique that allows us to visualize white matter tracts and potential changes associated with different treatments. To date, only few data on structural neuroplasticity related to the recovery of poststroke aphasia were reported. We describe a case of aphasic stroke patient, who was studied before and after the intense rehabilitative treatment by using neuropsychologic evaluation and DTI examination, to assess the integrity of the arcuate fasciculus related to motor, language, and cognitive recovery. PMID- 25284719 TI - Global fibrinolytic activity, PAI-1 level, and 4G/5G polymorphism in Thai children with arterial ischemic stroke. AB - BACKGROUND: Prolonged euglobulin clot lysis time (ECLT) and increased level of plasminogen activator inhibitor-1 (PAI-1) were reported to be risk factors of arterial ischemic stroke (AIS) by some studies; however, these findings were not supported by other studies. The objective of this study was to determine the association of ECLT, PAI-1 level, and polymorphisms of 4G and 5G of PAI-1 gene to the development of AIS in Thai children. METHODS: This study included patients aged 1-18 years old. Diagnosis of AIS was confirmed by imaging study. The control group was age- and sex-matched healthy subjects. Demographic data were recorded, and blood was tested for ECLT, PAI-1 level, lipid profiles, fasting blood sugar (FBS), and 4G and 5G polymorphisms of PAI-1 gene. RESULTS: There were 70 subjects participating in this study, consisting of 30 patients and 40 controls. Demographic data, lipid profiles, and FBS were similar between the 2 groups. Furthermore, ECLT and PAI-1 level did not differ between patient and control groups; however, both showed significant correlation (r = .352, P = .006). The 4G/5G polymorphism was the most common genotype in both patient and control groups (69.0% vs. 80.0%). However, 4G and 5G polymorphisms of PAI-1 gene did not correlate with PAI-1 level in this study (P = .797). CONCLUSIONS: The PAI-1 level and 4G/5G polymorphism may not be a risk factor of AIS in this population. It was also found that the 4G/5G polymorphism was the most common PAI-1 genotype in this study. PMID- 25284720 TI - Cervical spinal epidural arteriovenous fistula with coexisting spinal anterior spinal artery aneurysm presenting as subarachnoid hemorrhage--case report. AB - Hemorrhagic presentation of spinal epidural arteriovenous fistulas (AVFs) is rare in patients with cervical spinal vascular lesions. The present report describes a patient with cervical spine epidural AVFs associated with anterior spinal artery aneurysm at the same vertebral level presenting with subarachnoid hemorrhage. A 54-year-old man presented with sudden onset of headache. Computed tomography of the head showed subarachnoid hemorrhage. Diagnostic angiography revealed an epidural AVF located at the C1-2 level that was fed mainly by the dorsal somatic branches of the segmental arteries from the radicular artery and anterior spinal artery. This AVF drained only into the epidural veins without perimedullary venous reflux. Further, there was a 4-mm anterior spinal artery aneurysm in the vicinity of the fistula that was thought to be the cause of the hemorrhage. Endovascular transarterial fistulas embolization from the right radicular artery was performed to eliminate the AVF and to reduce hemodynamic stress on the aneurysm. No new symptoms developed after the treatment and discharged without neurological deficits. The aneurysm was noted to be reduced in size after the treatment and totally disappeared by 1 year later, according to follow-up angiography. Anterior spinal artery aneurysm from a separate vascular distribution may coexist with spinal epidural AVFs. In the setting of spinal subarachnoid hemorrhage, comprehensive imaging is indicated to rule out such lesions. PMID- 25284721 TI - Efficacy, effectiveness and safety of long-acting granulocyte colony-stimulating factors for prophylaxis of chemotherapy-induced neutropenia in patients with cancer: a systematic review. AB - PURPOSE: Pegfilgrastim was introduced over a decade ago. Other long-acting granulocyte colony-stimulating factors (G-CSFs) have recently been developed. We systematically reviewed the efficacy, effectiveness and safety of neutropenia prophylaxis with long-acting G-CSFs in cancer patients receiving chemotherapy. METHODS: We performed a systematic literature search of the MEDLINE, EMBASE and Cochrane Library databases, and abstracts from key congresses. Studies of long acting G-CSFs for prophylaxis of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) were identified by two independent reviewers. Abstracts and full texts were assessed for final inclusion; risk of bias was evaluated using the Cochrane's tool. Effectiveness and safety results were extracted according to study type and G-CSF used. RESULTS: Of the 839 articles identified, 41 articles representing different studies met the eligibility criteria. In five randomised controlled trials, 11 clinical trials and 17 observational studies across several tumour types and chemotherapy regimens, pegfilgrastim was used alone or compared with daily G-CSF, no G-CSF, no upfront pegfilgrastim or placebo. Studies generally reported lower incidence of CIN (4/7 studies), FN (11/14 studies), hospitalisations (9/13 studies), antibiotic use (6/7 studies) and adverse events (2/5 studies) with pegfilgrastim than filgrastim, no upfront pegfilgrastim or no G-CSF. Eight studies evaluated other long-acting G-CSFs; most (5/8) were compared to pegfilgrastim and involved patients with breast cancer receiving docetaxel-based therapy. Efficacy and safety profiles of balugrastim and lipegfilgrastim were comparable to pegfilgrastim in phase 3 studies. Efficacy and safety of other long-acting G-CSFs were mixed. CONCLUSIONS: Pegfilgrastim reduced the incidence of FN and CIN compared with no prophylaxis. Most studies showed better efficacy and effectiveness for pegfilgrastim than filgrastim. Efficacy and safety profiles of lipegfilgrastim and balugrastim were similar to pegfilgrastim. PMID- 25284722 TI - Granulocyte colony-stimulating factors as prophylaxis against febrile neutropenia. AB - Myelosuppression secondary to chemotherapy remains a serious adverse effect of cancer therapy that causes high morbidity and mortality. Several current European and American guidelines recommend consideration of primary prophylaxis with colony-stimulating factors (CSFs) when the risk of febrile neutropenia is higher than 20 %. The main factors associated with a high risk of febrile neutropenia include the chemotherapy regimen, tumor type, and patient-related factors such as old age and/or comorbidities. The purpose of this paper is to summarize the most relevant clinical trials and updated recommendations of the main guidelines on the role of granulocyte colony-stimulating factors (G-CSFs) in febrile neutropenia, examining whether the combination of G-CSF with chemotherapy improves overall survival. Future directions for G-CSF use are also discussed. PMID- 25284725 TI - Autophagy in acute leukemias: a double-edged sword with important therapeutic implications. AB - Macroautophagy, usually referred to as autophagy, is a degradative pathway wherein cytoplasmatic components such as aggregated/misfolded proteins and organelles are engulfed within double-membrane vesicles (autophagosomes) and then delivered to lysosomes for degradation. Autophagy plays an important role in the regulation of numerous physiological functions, including hematopoiesis, through elimination of aggregated/misfolded proteins, and damaged/superfluous organelles. The catabolic products of autophagy (amino acids, fatty acids, nucleotides) are released into the cytosol from autophagolysosomes and recycled into bio-energetic pathways. Therefore, autophagy allows cells to survive starvation and other unfavorable conditions, including hypoxia, heat shock, and microbial pathogens. Nevertheless, depending upon the cell context and functional status, autophagy can also serve as a death mechanism. The cohort of proteins that constitute the autophagy machinery function in a complex, multistep biochemical pathway which has been partially identified over the past decade. Dysregulation of autophagy may contribute to the development of several disorders, including acute leukemias. In this kind of hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context. Therefore, strategies exploiting autophagy, either for activating or inhibiting it, could find a broad application for innovative treatment of acute leukemias and could significantly contribute to improved clinical outcomes. These aspects are discussed here after a brief introduction to the autophagic molecular machinery and its roles in hematopoiesis. PMID- 25284723 TI - Lineage-dependent effects of aryl hydrocarbon receptor agonists contribute to liver tumorigenesis. AB - Rodent cancer bioassays indicate that the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD), causes increases in both hepatocytic and cholangiocytic tumors. Effects of AHR activation have been evaluated on rodent hepatic stem cells (rHpSCs) versus their descendants, hepatoblasts (rHBs), two lineage stages of multipotent, hepatic precursors with overlapping but also distinct phenotypic traits. This was made possible by defining the first successful culture conditions for ex vivo maintenance of rHpScs consisting of a substratum of hyaluronans and Kubota's medium (KM), a serum-free medium designed for endodermal stem/progenitor cells. Supplementation of KM with leukemia inhibitory factor elicited lineage restriction to rHBs. Cultures were treated with various AHR agonists including TCDD, 6-formylindolo [3,2-b]carbazole (FICZ), and 3-3'-diindolylmethane (DIM) and then analyzed with a combination of immunocytochemistry, gene expression, and high-content image analysis. The AHR agonists increased proliferation of rHpSCs at concentrations producing a persistent AHR activation as indicated by induction of Cyp1a1. By contrast, treatment with TCDD resulted in a rapid loss of viability of rHBs, even though the culture conditions, in the absence of the agonists, were permissive for survival and expansion of rHBs. The effects were not observed with FICZ and at lower concentrations of DIM. CONCLUSION: Our findings are consistent with a lineage-dependent mode of action for AHR agonists in rodent liver tumorigenesis through selective expansion of rHpSCs in combination with a toxicity-induced loss of viability of rHBs. These lineage-dependent effects correlate with increased frequency of liver tumors. PMID- 25284724 TI - Pigment epithelium-derived factor (PEDF) inhibits breast cancer metastasis by down-regulating fibronectin. AB - Pigment epithelium-derived factor (PEDF) plays an important role in the tumor growth and metastasis inhibition. It has been reported that PEDF expression is significantly reduced in breast cancer, and associated with disease progression and poor patient outcome. However, the exact mechanism of PEDF on breast cancer metastasis including liver and lung metastasis remains unclear. The present study aims to reveal the impact of PEDF on breast cancer. The orthotopic tumor mice model inoculated by MDA-MB-231 cells stably expressing PEDF or control cells was used to assess liver and lung metastasis of breast cancer. In vitro, migration and invasion experiments were used to detect the metastatic abilities of MDA-MB 231 and SKBR3 breast cancer cells with or without overexpression of PEDF. The metastatic-related molecules including EMT makers, fibronectin, and p-AKT and p ERK were detected by qRT-PCR, Western blot, and Fluorescent immunocytochemistry. PEDF significantly inhibited breast cancer growth and metastasis in vivo and in vitro. Mechanically, PEDF inhibited breast cancer cell migration and invasion by down-regulating fibronectin and subsequent MMP2/MMP9 reduction via p-ERK and p AKT signaling pathways. However, PEDF had no effect on EMT conversion in the breast cancer cells which was usually involved in cancer metastasis. Furthermore, the study showed that laminin receptor mediated the down-regulation of fibronectin by PEDF. These results reported for the first time that PEDF inhibited breast cancer metastasis by down-regulating fibronectin via laminin receptor/AKT/ERK pathway. Our findings demonstrated PEDF as a dual effector in limiting breast cancer growth and metastasis and highlighted a new avenue to block breast cancer progression. PMID- 25284726 TI - Reliability of intra-oral quantitative sensory testing (QST) in patients with atypical odontalgia and healthy controls - a multicentre study. AB - The reliability of comprehensive intra-oral quantitative sensory testing (QST) protocol has not been examined systematically in patients with chronic oro-facial pain. The aim of the present multicentre study was to examine test-retest and interexaminer reliability of intra-oral QST measures in terms of absolute values and z-scores as well as within-session coefficients of variation (CV) values in patients with atypical odontalgia (AO) and healthy pain-free controls. Forty-five patients with AO and 68 healthy controls were subjected to bilateral intra-oral gingival QST and unilateral extratrigeminal QST (thenar) on three occasions (twice on 1 day by two different examiners and once approximately 1 week later by one of the examiners). Intra-class correlation coefficients and kappa values for interexaminer and test-retest reliability were computed. Most of the standardised intra-oral QST measures showed fair to excellent interexaminer (9-12 of 13 measures) and test-retest (7-11 of 13 measures) reliability. Furthermore, no robust differences in reliability measures or within-session variability (CV) were detected between patients with AO and the healthy reference group. These reliability results in chronic orofacial pain patients support earlier suggestions based on data from healthy subjects that intra-oral QST is sufficiently reliable for use as a part of a comprehensive evaluation of patients with somatosensory disturbances or neuropathic pain in the trigeminal region. PMID- 25284727 TI - Extending the time window of mammalian heart regeneration by thymosin beta 4. AB - Recent studies demonstrated that the heart of 1-day-old neonatal mice could regenerate, with Wt1(+) EPDCs migrating into myocardial regions after partial surgical resection, but this capacity was lost by 7 days of age. By treatment with Tbeta4 to maintain Wt1 expression and retain the migrating feature of EPDCs in neonatal mice, we explored the possibility of restoring the cardiac regeneration potential of mice. We intraperitoneally injected Tbeta4 into 1-day old mice on daily basis and then apical resection was performed on the mice 7 days later. Twenty one days after the resection, morphological analysis revealed that the Tbeta4-treated mice regenerated the resected ventricular apex, while the mice in PBS control group developed significant fibrosis without apical regeneration. The Tbeta4-treated mice had significantly better ventricular ejection fraction and fractional shortening than controls. During the process of regeneration, Wt1(+) EPDCs migrated into myocardial region and some of them expressed Islet1 and the markers for mature cardiomyocytes, such as cTnT and SalphaA. These characteristics of Wt1(+) EPDCs were also seen in the heart regeneration of mice subjected to apical resection 1 day after birth. Tbeta4 has no essential effect on cell cycle activity as no disruption of actin filaments was observed in Tbeta4-treated hearts. These results revealed that the cardiac regeneration potential of neonatal mice could be extended to the 7th post-natal day by Tbeta4 and Wt1(+) EPDCs mobilization might play an important role in the extension. PMID- 25284728 TI - The geometry of taking flight: limb morphometrics in Mesozoic theropods. AB - Theropoda was one of the most successful dinosaurian clades during the Mesozoic and has remained a dominant component of faunas throughout the Cenozoic, with nearly 10,000 extant representatives. The discovery of Archaeopteryx provides evidence that avian theropods evolved at least 155 million years ago and that more than half of the tenure of avian theropods on Earth was during the Mesozoic. Considering the major changes in niche occupation for theropods resulting from the evolution of arboreal and flight capabilities, we have analyzed forelimb and hindlimb proportions among nonmaniraptoriform theropods, nonavian maniraptoriforms, and basal avialans using reduced major axis regressions, principal components analysis, canonical variates analysis, and discriminant function analysis. Our study is the first analysis on theropod limb proportions to apply phylogenetic independent contrasts and size corrections to the data to ensure that all the data are statistically independent and amenable to statistical analyses. The three ordination analyses we performed did not show any significant groupings or deviations between nonavian theropods and Mesozoic avian forms when including all limb elements. However, the bivariate regression analyses did show some significant trends between individual elements that suggested evolutionary trends of increased forelimb length relative to hindlimb length from nonmaniraptoriform theropods to nonavian maniraptoriforms to basal avialans. The increase in disparity and divergence away from the nonavian theropod body plan is well documented within Cenozoic forms. The lack of significant groupings among Mesozoic forms when examining the entire theropod body plan concurrently suggests that nonavian theropods and avian theropods did not substantially diverge in limb proportions until the Cenozoic. PMID- 25284729 TI - Type 2 diabetes mellitus and fracture risk. AB - Increased fracture risk, traditionally associated with type 1 diabetes, has lately been of great concern in patients with type 2 diabetes. A variable increase in fracture risk has been reported, ranging from 20% to 3-fold, depending on skeletal site, diabetes duration and study design. Longer disease duration, the presence of diabetic complications, inadequate glycemic control, insulin use and increased risk for falls are all reported to increase fracture risk. Patients with type 2 diabetes display a unique skeletal phenotype with either normal or more frequently increased, bone mineral density and impaired structural and geometric properties. Recently, alterations in bone material properties seem to be the predominant defect leading to increased bone fragility. Accumulation of advanced glycation end-products and changes in collagen cross linking along with suppression of bone turnover seem to be significant factors impairing bone strength. FRAX score has been reported to underestimate fracture risk and lumbar spine BMD is inadequate in predicting vertebral fractures. Anti diabetic medications, apart from thiazolidinediones, appear to be safe for the skeleton, although more data are needed. Optimal strategies to reduce skeletal fragility in type 2 diabetic patients are yet to be determined. PMID- 25284730 TI - Genomic full-length sequence of two HLA-A alleles, A*02:05:01 and A*02:06:01 identified by cloning and sequencing. AB - Genomic full-length sequences of HLA-A*02:05:01 and A*02:06:01, were identified by cloning and sequencing from two Chinese donors. PMID- 25284731 TI - [Life-threatening Panton-Valentine leukocidin-associated staphylococcal infections in children. A broad spectrum of clinical presentations]. AB - Panton-Valentine leukocidin (PVL) is a major toxic virulence factor secreted by community-acquired methicillin-sensitive or methicillin-resistant Staphylococcus aureus (SA). SA-PVL can be responsible for life-threatening infections in healthy children with a wide spectrum of clinical presentations involving lung, skin, and soft tissues or bones and joints. PVL production should always be considered in severe SA infections. The pediatric medicine community remains poorly informed regarding the therapeutic management of this infection, which should be early and aggressive. Intravenous empiric antibiotics against SA and its toxins must be given with early and sometimes iterative surgical procedures to drain abscesses and to stop bacterial proliferation and necrosis in the tissues. Here, we report the cases of three patients admitted for SA-PVL infections to the pediatric intensive care unit. Initial clinical presentation in the three patients was multifocal osteomyelitis associated with necrotizing pneumonia; severe skin infection with septic shock; and non-necrotic pneumonia with pleural and pericardial effusion. Appropriate treatments resulted in a good outcome in all cases. Following these illustrations, we describe a number of practical key points in the optimal medical and surgical management of severe SA-PVL infections, with a review of the literature. PMID- 25284732 TI - [Clonidine poisoning in a child: a case report]. AB - Clonidine poisoning's clinical feature is well documented in the medical literature, but the minimal toxic dose has not yet been established. The effectiveness of naloxone is also controversial. The authors describe a clonidine overdose in a 9-year-old boy (25 kg) during a growth hormone test: he received tenfold the prescribed clonidine dose (0.23 mg instead of 0.023 mg) with 6.2 mg betaxolol. About 40 min later, he became drowsy and then complained of low blood pressure, bradycardia, and myosis. By maintaining the Trendelenburg position, administering fluids as well as salbutamol and naloxone (three doses of 0.2 mg were required), he recovered and was discharged from the hospital on day 2. The minimal clonidine toxic dose, the clinical picture, and the effectiveness of naloxone administration are discussed in this paper. PMID- 25284733 TI - [Value of routine identification of respiratory infectious agents in children hospitalized with an acute asthma exacerbation]. AB - BACKGROUND: Asthma is the most common chronic disease in childhood. With its high economic burden, it is considered a disease of major public health importance by the World Health Organization. The link between respiratory tract infections and acute exacerbation has been recognized for a long time. The aim of this retrospective study in routine care was to evaluate our practices concerning microbiological prescriptions in children hospitalized for asthma exacerbation. STUDY DESIGN: All children aged from 2 to 15 years hospitalized for asthma exacerbation between January 2010 and December 2011 in our unit were included in the study. Microbiological prescriptions, their indications, their results, and their cost were studied. RESULTS: One hundred ninety-seven children were included in the study. A potential causative agent was sought in 79.7% of the children (n=157) by immunofluorescence assay (IFA) and/or polymerase chain reaction (PCR). The main indications were upper airway infections, hypoxemia, and pneumonia. Viruses were detected in 23.8% of them (30/126). Mycoplasma pneumoniae was detected by PCR in only 3.2% of these patients (4/125). No other bacterial agent was identified. There was no correlation between the severity of asthma exacerbation and the microbiological diagnosis of infection. The results did not influence the therapy given. These prescriptions represented a substantial cost for each child. CONCLUSION: These analyses do not seem to have a real advantage for the patient except for epidemiology. It would be important to conduct a new study analyzing the role of rhinovirus, and of other viruses such as coronavirus, bocavirus, and enterovirus, not routinely investigated in our hospital, and to question the value of these costly microbiological tests. PMID- 25284734 TI - [Science, conscience, and adolescence... Comments on the article "The emergency department: an appropriate place for identifying troubled teens"]. PMID- 25284735 TI - [The jokes are vectors of stereotypes. Example of the medical profession from 220 jokes]. AB - INTRODUCTION: Sociological studies have shown the link between humor and unconscious ideas that we have of the society in which we evolve. We conducted a survey to answer the question: "What were the stereotypes of our medical profession that emerge from a transcript of jokes collected in a medical population?" METHODS: Recruitment of the source population (doctors and medical students) was done through different personal and professional mailing lists, Twitter, Facebook, medical press. The inclusion period was six weeks (from June 6 to July 14, 2013). Each physician recruited received the link to our blog: http://humourmedical.overblog.com which contained a link to the questionnaire. Physicians responded to the following proposition: "tell the joke involving doctors you laugh the most". Analysis of jokes was made by three investigators. Firstly, two investigators (DM and CP) and pooled of results to generate a stereotype for each joke. Then a triangulation was made with a third investigator (BG), to determine the final stereotype. RESULTS: Five hundred and twelve jokes have been collected on the site and 448 were included in the analysis, representing 220 jokes. The gender of respondents was 284 men (63%) and 164 women (37%), a ratio of 1.7. One hundred and fifty-six different stereotypes were classified into six themes: 46 stereotypes 'the vicissitudes of the medical profession'; 45 'hospital', the war of the block; 34 'personality traits doctor'; 14 'psychiatrist'; 12 'physician and sexuality'; 5 'medical studies and carabin woes'. Anesthetists were represented as lazy, inveterate coffee drinkers and less awakened than their sleeping patients. Surgeons were seen as megalomaniacal, tyrannical with other professions, operating without thinking, as their brain down to a neuron. Medical students appeared docile and absurd. Psychiatrists were as crazy as their patients, sometimes passing them to the consultation and looking only at their past relationship. Other stereotypes of doctors were used: the venality, the salacious, cynicism. CONCLUSION: We showed that the stereotypes contained in the medical jokes were quite caricatured and portrayed an unflattering picture of doctors in general. These traits were necessarily marked to emphasize the humorous effect of a joke. We have not entered into the reality of these stereotypes or their social role in the relationship between doctors. PMID- 25284736 TI - Decarboxylative acylation of indolines with alpha-keto acids under palladium catalysis: a facile strategy for the synthesis of 7-substituted indoles. AB - Palladium-catalyzed decarboxylative acylation of highly substituted indolines with alpha-keto acids via C-H bond activation is described. This protocol provides efficient access to C7-carbonylated indoles known to have diverse biological profiles. PMID- 25284737 TI - A unique anal hepatoid adenoma in a human. PMID- 25284738 TI - OnabotulinumtoxinA (Botox) nerve blocks provide durable pain relief for men with chronic scrotal pain: a pilot open-label trial. AB - INTRODUCTION: Chronic scrotal pain (CSP) is a common, often debilitating, condition affecting approximately 4.75% of men. While nerve blocks using local anesthetics usually provide temporary pain relief, there are no publications on the use of longer acting nerve blocks to provide more durable pain relief for men with CSP. AIM: The aim of this study was to determine if onabotulinumtoxinA (Botox) cord blocks provide durable pain relief for men with CSP. METHODS: In this pilot open-label study, men with CSP who had failed medical management but experienced temporary pain relief from a standard cord block underwent a cord block with 100U Botox. MAIN OUTCOME MEASURES: The outcomes measured were changes 1, 3, and 6 months post-Botox injection in (i) a 10-point visual analog scale (VAS) pain score; (ii) scrotal tenderness on a three-point scale as rated by physical examination; and (iii) the Chronic Epididymitis Symptom Index (CESI) to measure the severity and impact of scrotal pain on men. Paired t-tests were used to compare groups. RESULTS: Eighteen patients with CSP seen between April and September 2013 had Botox injected as a cord block. At the 1-month follow-up, pain reduction was reported by 72% of patients (mean VAS score: 7.36 vs. 5.61, P < 0.003), while by physical examination 44 and 34% of the men had either complete or partial resolution of scrotal tenderness. In addition, there was also a significant reduction in CESI scores (22.19 vs. 19.25, P < 0.04). At 3 months, 56% had both sustained pain reduction and reduced tenderness based on the VAS score (mean: 7.36 vs. 6.02, P < 0.05) and physical exam. The CESI score continued to be significantly lower. Unfortunately, by 6 months, most men had a return to their baseline levels of pain and tenderness. CONCLUSIONS: Our pilot study found that Botox cord blocks provide pain reduction for 3 months or more for most men with CSP. PMID- 25284740 TI - Comparison between neck pain disability and cervical range of motion in patients with episodic and chronic migraine: a cross-sectional study. AB - OBJECTIVE: The purpose of this study was to evaluate neck pain-related disability and cervical range of motion (CROM) in patients with episodic migraine (EM) and chronic migraine (CM) and to examine the correlation of both outcomes. METHODS: This cross-sectional study consisted of 91 patients with EM and 34 with CM. Cervical range of motion was measured with the CROM device, and pain during the cervical movement was recorded. Self-reported disability related to neck pain was assessed with the Neck Disability Index. RESULTS: Patients with CM showed higher Neck Disability Index scores and more moderate and severe disability (P = .01). Severe disability as a result of neck pain was associated with 7.6-fold risk of developing CM (P = .003). No significant differences in CROM were identified between groups. Moderate negative correlations between CROM and disability were found for 4 motions within the CM group (-0.60 .05). There were no observed changes in pain sensitivity, or an association between primary and secondary outcome measures. CONCLUSION: These results suggest that MTs (chiropractic spinal manipulation, spinal mobilization, and therapeutic touch) have an immediate effect on the FC between brain regions involved in processing and modulating the pain experience. This suggests that neurophysiologic changes after MT may be an underlying mechanism of pain relief. PMID- 25284742 TI - Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. AB - Suppression of mitochondrial function promoting proliferation and apoptosis suppression has been described in the pulmonary arteries and extrapulmonary tissues in pulmonary arterial hypertension (PAH), but the cause of this metabolic remodeling is unknown. Mice lacking sirtuin 3 (SIRT3), a mitochondrial deacetylase, have increased acetylation and inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial function. Sirt3KO mice develop spontaneous PAH, exhibiting previously described molecular features of PAH pulmonary artery smooth muscle cells (PASMC). In human PAH PASMC and rats with PAH, SIRT3 is downregulated, and its normalization with adenovirus gene therapy reverses the disease phenotype. A loss-of-function SIRT3 polymorphism, linked to metabolic syndrome, is associated with PAH in an unbiased cohort of 162 patients and controls. If confirmed in large patient cohorts, these findings may facilitate biomarker and therapeutic discovery programs in PAH. PMID- 25284743 TI - Avulsion fracture of the extensor carpi radialis longus carpal insertion due to a basketball injury: case report and literature review. AB - Articular fractures of the base of the 2nd metacarpal involving the extensor carpi radialis longus insertion are unusual and poorly understood. There is no consensus as to how these fractures should be treated. We report the case of a 2nd metacarpal base fracture in a professional basketball player that was treated surgically with open reduction and internal fixation using cannulated screws. The management of this case is compared to similar cases in the literature. PMID- 25284744 TI - Antifungal properties of an actinomycin D-producing strain, Streptomyces sp. IA1, isolated from a Saharan soil. AB - An actinomycete strain named IA1, which produced an antimicrobial compound, was isolated from a Saharan soil in In Amenas, Algeria. The study of the 16S rDNA sequence of this strain permitted to relate it to Streptomyces mutabilis NBRC 12800(T) (99.93% of similarity). Strain IA1 exhibited strong activity against a wide range of plant pathogenic fungi. One bioactive compound produced in large amounts (46.7 mg L(-1) day(-1) ), named YA, was isolated and purified by TLC and reverse phase HPLC. The structure elucidation of the pure substance, using combined data from UV visible, NMR spectra, and mass spectrometry, permitted to identify it as actinomycin D, and was thus found for the first time in S. mutabilis related species. The biocontrol abilities of the strain IA1 and compound YA were evaluated through two diseases, i.e., chocolate spot of field bean and Fusarium wilt of flax. The occurrence of the two fungal diseases was effectively reduced. The reduction of chocolate spot disease symptoms reached 80 and 91.7% with IA1 and YA seedlings pretreatments, respectively. Soil pretreatment with IA1 or YA also allowed to reduce Fusarium wilt disease impact by almost 60%. PMID- 25284745 TI - Gracilis muscle interposition for rectovaginal and anovaginal fistula repair: a systematic literature review. AB - BACKGROUND: Repair of rectovaginal fistula (RVF) is associated with high recurrence. For this reason gracilis muscle interposition is increasingly being used. AIM: To evaluate the efficacy of this procedure for RVF repair. METHOD/SEARCH STRATEGY: A search of PubMed and Medline databases was performed in November 2013 using the text terms and MESH headings 'rectovaginal fistula/fistulation', and 'gracilis muscle', spanning 1980-2013. The search strategy was restricted to articles written in English with available abstracts. Sample size, aetiology of RVF, previous repair attempts, follow-up period, healing rates and complications were recorded and analysed. RESULTS: Seventeen studies involving 106 patients were analysed. The cause of RVF included inflammatory bowel disease (n = 37 [34.9%]: Crohn's disease [34], ulcerative colitis [3]), pelvic surgery (37 [34.9%]), obstetric injury (9 [8.5%]), malignancy (7 [6.6%]), trauma (5 [4.7%]), miscellaneous (idiopathic, endometriosis, radiation: 11 [10.4%]). Patients had undergone a median number of two previous unsuccessful repairs. At a median follow-up of 21 months, healing had occurred in 33-100% (median 100%) with the largest studies reporting rates between 60% and 90%. Thirteen studies did not report any complications, with the remainder reporting only minor morbidity. CONCLUSION: Gracilis interposition appears to have a reasonable success rate for RVF repair with acceptable morbidity. It may be considered as one of the first-line treatment options for recurrent RVF. PMID- 25284746 TI - Relations between fine motor skill and parental report of attention in young children with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders presenting in approximately 1 in 3,500 live births. NF1 is a highly variable condition with a large number of complications. A common complication is neuropsychological problems, including developmental delays and learning difficulties that affect as many as 60% of patients. Research has suggested that school-aged children with NF1 often have poorer fine motor skills and are at greater risk for attention difficulties than the general population. Thirty-eight children with NF1 and 23 unaffected children between the ages of 4 and 6 years, who are enrolled in a study of early development in NF1, were included in the present study. Varying levels of fine motor functioning were examined (simple to complex fine motor tasks). For children with NF1, significant difficulties were demonstrated on lab-based mid-level and complex fine motor tasks, even after controlling for nonverbal reasoning abilities, but not on simple fine motor tasks. Parental report also indicated difficulties in everyday adaptive fine motor functioning. No significant correlations were found between complex fine motor ability and attention difficulties. This study provides much needed descriptive data on the early emergence of fine motor difficulties and attention difficulties in young children with NF1. PMID- 25284747 TI - Persistence with solifenacin add-on therapy in men with benign prostate obstruction and residual symptoms of overactive bladder after tamsulosin monotherapy. AB - AIMS: In spite of the reported efficacy and safety of antimuscarinics in men with OAB (overactive bladder) and BPO (benign prostatic obstruction), many patients do not persist with the treatment. We aimed to evaluate persistence and the reasons for the discontinuation of solifenacin add-on therapy in men with residual symptoms of OAB after tamsulosin monotherapy for BPO in a real clinical environment. METHODS: Men aged >= 45 years with IPSS >= 12 and symptoms of OAB (OAB-V8 >= 8, micturition >= 8/24 h, urgency >= 2/24 h) were prescribed tamsulosin 0.2 mg. After 4 weeks, men who had residual symptoms of OAB (OAB-V8 >= 8, micturition >= 8/24 h, urgency >= 1/24 h) and reported that they were 'dissatisfied' or 'a little satisfied' with the therapy were enrolled and prescribed solifenacin 5 mg in combination with tamsulosin. After 52 weeks, persistence and the reasons for the discontinuation of solifenacin were evaluated. Factors related to persistence were analysed. RESULTS: Of the 305 men who had been treated with tamsulosin, 176 were prescribed solifenacin. After 52 weeks, 44 (25%) remained on solifenacin therapy. Of the 132 who discontinued solifenacin, 85 were evaluated on the reason for discontinuation. The three most common reasons for discontinuation were adverse events (AEs) (35%), lack of efficacy (33%), and improvement in symptoms (16%). The aggravation of voiding symptoms was the most common AE leading to discontinuation. Retention was observed in 11 men. None of the demographical or clinical characteristics were significantly related to persistence. CONCLUSIONS: Only 25% men with OAB and BPO remained on antimuscarinic add-on therapy after 1 year, mostly because of AEs and lack of efficacy. Realistic data should be added to what is already known about antimuscarinic treatment in men by including patients who were excluded or who dropped out of well-designed clinical trials. PMID- 25284749 TI - A well-defined monomeric aluminum complex as an efficient and general catalyst in the Meerwein-Ponndorf-Verley reduction. AB - The metal-catalyzed Meerwein-Ponndorf-Verley (MPV) reduction allows for the mild and sustainable reduction of aldehydes and ketones but has not found widespread application in organic synthesis due to the high catalyst loading often required to obtain satisfactory yields of the reduced product. We report here on the synthesis and structure of a sterically extremely overloaded siloxide-supported aluminum isopropoxide capable of catalytically reducing a wide range of aldehydes and ketones (52 examples) in excellent yields under mild conditions and with low catalyst loadings. The unseen activity of the developed catalyst system in MPV reductions is due to its unique monomeric nature and the neutral donor isopropanol weakly coordinating to the aluminum center. The present work implies that monomeric aluminum alkoxide catalysts may be attractive alternatives to transition-metal-based systems for the selective reduction of aldehydes and ketones to primary and secondary alcohols. PMID- 25284748 TI - Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery. AB - Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable. PMID- 25284750 TI - Mapping of the modular closthioamide architecture reveals crucial motifs of polythioamide antibiotics. AB - Closthioamide, the first known secondary metabolite from an anaerobic microorganism (Clostridium cellulolyticum), represents a highly potent antibiotic that is active against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE) at nanomolar concentrations. To unveil structure-activity relationships of the unusual polythioamide natural product we have designed a synthetic grid to access analogues with altered terminal aromatic moieties, diverse p-phenyl substituents, different types and sizes of aliphatic spacers, varying numbers of thioamide residues, and diverse sizes and symmetries of the poly-beta-thioalanyl backbone. A library of 28 closthioamide analogues was tested against a panel of human pathogenic bacteria. We found that aromatic terminal groups, the defined length of the spacer groups, the presence of all six thioamide residues and the modular arrangement of the beta-thioalanyl units play essential roles for the antibiotic activity of closthioamide, yet there is a degree of freedom in the symmetry of the molecule. This study yields the first insights into pivotal structural motifs and the structural space of this new family of antibiotics, a prerequisite for the development of these promising antibiotics. PMID- 25284751 TI - Efficacy and safety of Korean red ginseng for cold hypersensitivity in the hands and feet: a randomized, double-blind, placebo-controlled trial. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Korean medicine, the steamed root of Panax ginseng C.A. Meyer, known as Korean red ginseng (KRG), is used to invigorate the body, enhance qi, and improve blood flow. It is a potential treatment for cold hypersensitivity in the hands and feet (CHHF), a common complaint among Asians, especially women. However, few studies of its efficacy and safety for CHHF have been conducted. MATERIALS AND METHODS: This randomized, double-blind, placebo controlled trial included 80 female patients with CHHF at Kyung Hee University Hospital at Gangdong, Seoul, Korea. The participants took six capsules of 500-mg KRG powder or placebo twice daily for 8 weeks and were followed up for 4 weeks. The primary outcome measure was change in skin temperature of the hands. The secondary outcome measures included change in skin temperature of the feet, visual analog scale (VAS) scores of CHHF severity, recovered temperature (RT) of the hands after cold stress test, distal-dorsal difference (DDD) in temperature of the hands, power variables of heart rate variability (HRV), and 36-item Short Form Health Survey (SF-36) scores. RESULTS: The KRG group had significantly higher skin temperature of the hands and feet, lower VAS scores, higher RT of the right 5th finger, and less parasympathetic activity than the placebo group at 8 weeks. No significant differences were noted in DDD of the hands and SF-36 scores. No serious adverse events were reported during the study. CONCLUSIONS: Peripheral vasodilation by KRG may alleviate CHHF. Further controlled studies are required to elucidate the effects of KRG on the autonomic nervous system. PMID- 25284752 TI - Anabolic steroids detected in bodybuilding dietary supplements - a significant risk to public health. AB - Twenty-four products suspected of containing anabolic steroids and sold in fitness equipment shops in the United Kingdom (UK) were analyzed for their qualitative and semi-quantitative content using full scan gas chromatography-mass spectrometry (GC-MS), accurate mass liquid chromatography-mass spectrometry (LC MS), high pressure liquid chromatography with diode array detection (HPLC-DAD), UV-Vis, and nuclear magnetic resonance (NMR) spectroscopy. In addition, X-ray crystallography enabled the identification of one of the compounds, where reference standard was not available. Of the 24 products tested, 23 contained steroids including known anabolic agents; 16 of these contained steroids that were different to those indicated on the packaging and one product contained no steroid at all. Overall, 13 different steroids were identified; 12 of these are controlled in the UK under the Misuse of Drugs Act 1971. Several of the products contained steroids that may be considered to have considerable pharmacological activity, based on their chemical structures and the amounts present. This could unwittingly expose users to a significant risk to their health, which is of particular concern for naive users. PMID- 25284753 TI - Precise and efficient antibody epitope determination through library design, yeast display and next-generation sequencing. AB - The ability of antibodies to bind an antigen with a high degree of affinity and specificity has led them to become the largest and fastest growing class of therapeutic proteins. Clearly identifying the epitope at which they bind their cognate antigen provides insight into their mechanism of action and helps differentiate antibodies that bind the same antigen. Here, we describe a method to precisely and efficiently map the epitopes of a panel of antibodies in parallel over the course of several weeks. This method relies on the combination of rational library design, quantitative yeast surface display and next generation DNA sequencing and was demonstrated by mapping the epitopes of several antibodies that neutralize alpha toxin from Staphylococcus aureus. The accuracy of this method was confirmed by comparing the results to the co-crystal structure of one antibody and alpha toxin and was further refined by the inclusion of a lower-affinity variant of the antibody. In addition, this method produced quantitative insight into the epitope residues most critical for the antibody antigen interaction and enabled the relative affinities of each antibody toward alpha toxin variants to be estimated. This affinity estimate serves as a predictor of neutralizing antibody potency and was used to anticipate the ability of each antibody to effectively bind and neutralize naturally occurring alpha toxin variants secreted by strains of S. aureus, including clinically relevant strains. Ultimately this type information can be used to help select the best clinical candidate among a set of antibodies against a given antigen. PMID- 25284755 TI - Phosphorylation and prolyl isomerization independently regulate the signal adapter function of CrkII. AB - The signaling protein CrkII switches between forms with high or low binding affinity. Both phosphorylation and native-state prolyl isomerization were suggested to regulate the transition between these forms. Here we analyzed how phosphorylation at Tyr222 and Tyr252 and the Pro238Ala substitution affect signal transfer of human and chicken CrkII to a downstream target. Human CrkII is regulated by phosphorylation only, but chicken CrkII is regulated by Pro238 trans >cis isomerization and by Tyr222 phosphorylation. Surprisingly, they act in an independent fashion. Apparently, the allosteric transition to a low-activity form can be induced by phosphorylation or prolyl isomerization located at distant sites in CrkII. PMID- 25284754 TI - Structural and functional mechanisms of CRAC channel regulation. AB - In many animal cells, stimulation of cell surface receptors coupled to G proteins or tyrosine kinases mobilizes Ca(2+) influx through store-operated Ca(2+)-release activated Ca(2+) (CRAC) channels. The ensuing Ca(2+) entry regulates a wide variety of effector cell responses including transcription, motility, and proliferation. The physiological importance of CRAC channels for human health is underscored by studies indicating that mutations in CRAC channel genes produce a spectrum of devastating diseases including chronic inflammation, muscle weakness, and a severe combined immunodeficiency syndrome. Moreover, from a basic science perspective, CRAC channels exhibit a unique biophysical fingerprint characterized by exquisite Ca(2+) selectivity, store-operated gating, and distinct pore properties and therefore serve as fascinating model ion channels for understanding the biophysical mechanisms of Ca(2+) selectivity and channel opening. Studies in the last two decades have revealed the cellular and molecular choreography of the CRAC channel activation process, and it is now established that opening of CRAC channels is governed through direct interactions between the pore-forming Orai proteins and the endoplasmic reticulum Ca(2+) sensors STIM1 and STIM2. In this review, we summarize the functional and structural mechanisms of CRAC channel regulation, focusing on recent advances in our understanding of the conformational and structural dynamics of CRAC channel gating. PMID- 25284758 TI - Primary familial brain calcification: Genetic analysis and clinical spectrum. AB - BACKGROUND: Primary familial brain calcification (PFBC) is a rare autosomal dominant disorder with bilateral calcification of basal ganglia and other cerebral regions, movement disorders, and neuropsychiatric disturbances. So far, three causative genes have been discovered: SLC20A2, PDGFRB and PDGFB, accounting for approximately 50% of cases. METHODS: Seven unrelated families with primary brain calcification were recruited to undergo clinical and genetic analysis, including Sanger sequencing of SLC20A2, PDGFRB, and PDGFB, and copy number analysis of SLC20A2. RESULTS: Mutations in SLC20A2 have been detected in three families: p.Glu368Glyfs*46, p.Ser434Trp, and p.Thr595Met. Intrafamilial phenotype variability has been observed. In spite of this, we found similar neuroimaging pattern among members of the same family. CONCLUSIONS: This molecular analysis expands the mutational spectrum of SLC20A2, which remains the major causative gene of primary familial brain calcification, and suggests the existence of disease-causing mutations in at least another, still unknown gene. PMID- 25284756 TI - Structural and functional divergence of the aldolase fold in Toxoplasma gondii. AB - Parasites of the phylum Apicomplexa are highly successful pathogens of humans and animals worldwide. As obligate intracellular parasites, they have significant energy requirements for invasion and gliding motility that are supplied by various metabolic pathways. Aldolases have emerged as key enzymes involved in these pathways, and all apicomplexans express one or both of fructose 1,6 bisphosphate (F16BP) aldolase and 2-deoxyribose 5-phosphate (dR5P) aldolase (DERA). Intriguingly, Toxoplasma gondii, a highly successful apicomplexan parasite, expresses F16BP aldolase (TgALD1), d5RP aldolase (TgDERA), and a divergent dR5P aldolase-like protein (TgDPA) exclusively in the latent bradyzoite stage. While the importance of TgALD1 in glycolysis is well established and TgDERA is also likely to be involved in parasite metabolism, the detailed function of TgDPA remains elusive. To gain mechanistic insight into the function of different T. gondii aldolases, we first determined the crystal structures of TgALD1 and TgDPA. Structural analysis revealed that both aldolases adopt a TIM barrel fold accessorized with divergent secondary structure elements. Structural comparison of TgALD1 and TgDPA with members of their respective enzyme families revealed that, while the active-site residues are conserved in TgALD1, key catalytic residues are absent in TgDPA. Consistent with this observation, biochemical assays showed that, while TgALD1 was active on F16BP, TgDPA was inactive on dR5P. Intriguingly, both aldolases are competent to bind polymerized actin in vitro. Altogether, structural and biochemical analyses of T. gondii aldolase and aldolase-like proteins reveal diverse functionalization of the classic TIM barrel aldolase fold. PMID- 25284757 TI - Mechanistic basis of plasmid-specific DNA binding of the F plasmid regulatory protein, TraM. AB - The conjugative transfer of bacterial F plasmids relies on TraM, a plasmid encoded protein that recognizes multiple DNA sites to recruit the plasmid to the conjugative pore. In spite of the high degree of amino acid sequence conservation between TraM proteins, many of these proteins have markedly different DNA binding specificities that ensure the selective recruitment of a plasmid to its cognate pore. Here we present the structure of F TraM RHH (ribbon-helix-helix) domain bound to its sbmA site. The structure indicates that a pair of TraM tetramers cooperatively binds an underwound sbmA site containing 12 base pairs per turn. The sbmA is composed of 4 copies of a 5-base-pair motif, each of which is recognized by an RHH domain. The structure reveals that a single conservative amino acid difference in the RHH beta-ribbon between F and pED208 TraM changes its specificity for its cognate 5-base-pair sequence motif. Specificity is also dictated by the positioning of 2-base-pair spacer elements within sbmA; in F sbmA, the spacers are positioned between motifs 1 and 2 and between motifs 3 and 4, whereas in pED208 sbmA, there is a single spacer between motifs 2 and 3. We also demonstrate that a pair of F TraM tetramers can cooperatively bind its sbmC site with an affinity similar to that of sbmA in spite of a lack of sequence similarity between these DNA elements. These results provide a basis for the prediction of the DNA binding properties of the family of TraM proteins. PMID- 25284759 TI - Effect of high temperature on grain filling period, yield, amylose content and activity of starch biosynthesis enzymes in endosperm of basmati rice. AB - BACKGROUND: High temperature during grain filling affects yield, starch amylose content and activity of starch biosynthesis enzymes in basmati rice. To investigate the physiological mechanisms underpinning the effects of high temperature on rice grain, basmati rice was grown under two temperature conditions - 32 and 22 degrees C - during grain filling. RESULTS: High temperature decreased the grain filling period from 32 to 26 days, reducing yield by 6%, and caused a reduction in total starch (3.1%) and amylose content (22%). Measurable activities of key enzymes involved in sucrose to starch conversion, sucrose synthase, ADP-glucose pyrophosphorylase, starch phosphorylase and soluble starch synthase in endosperms developed at 32 degrees C were lower than those at 22 degrees C compared with similar ripening stage on an endosperm basis. In particular, granule-bound starch synthase (GBSS) activity was significantly lower than corresponding activity in endosperms developing at 22 degrees C during all developmental stages analyzed. CONCLUSION: Results suggest changes in amylose/amylopectin ratio observed in plants grown at 32 degrees C was attributable to a reduction in activity of GBSS, the sole enzyme responsible for amylose biosynthesis. PMID- 25284760 TI - Caffeic acid derivatives, analogs and applications: a patent review (2009-2013). AB - INTRODUCTION: Caffeic acid (CA) is broadly distributed in several species of the plant kingdom and is widely consumed in human diet. CA and derivatives have been extensively studied in the past years, which unveiled a broad spectrum of biological activities and potential therapeutic applications. As a result, there has been an upsurge in the development of new chemical entities based on the CA scaffold. AREAS COVERED: The scope of this review is to revisit the therapeutic potential of CA and derivatives. It provides an overview of patented processes and applications thereof between 2009 and 2013. EXPERT OPINION: The phenylpropanoid framework is currently considered a valid structure for drug discovery programs. Actually, CA has been widely used as a template for the development of new chemical entities with potential therapeutic interest in human diseases associated with oxidative stress. Additionally, the applicability of CA derivatives expands to the realms of cosmetic industry due to its stabilizing properties. The synthesis of esters, amides and hybrids with currently marketed drugs is a trending strategy for the development of derivatives with therapeutic application. It is our opinion that the innovative artwork currently being developed involving this chemical scaffold will yield new and effective therapeutic agents in a foreseeable future. PMID- 25284763 TI - Superior versus temporal approach in descemet membrane endothelial keratoplasty. AB - PURPOSE: To compare superior vs temporal approach in patients who underwent Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Monocentric, prospective nonmasked study. METHODS: A prospective analysis of 53 DMEKs between January and September 2013 was performed at the Charite-Universitatsmedizin Berlin. Only DMEK cases with an incision size of 2.3 mm and with at least 1 month of follow-up were included. The surgically induced astigmatism (SIA), changes in corneal aberrations and in spherical equivalent, visual acuity, endothelial cell density, and complications were evaluated. RESULTS: Visual acuity improved significantly (0.70 +/- 0.39 logMAR vs 0.32 +/- 0.31 logMAR after 1 month (n = 48), 0.19 +/- 0.15 logMAR after 3 months (n = 46), and 0.16 +/- 0.17 logMAR after 6 months (n = 47) (P < .001)) regardless of the approach. SIA was significantly lower after temporal than after superior approach (1.42 +/- 0.91 diopters [D] [n = 13] vs 0.81 +/- 0.68 D [n = 13], P = .038). Change in total root mean square of all aberrations (RMS) (P = .046) at 6 mm pupil diameter, and change in total RMS (P = .019), third-order aberrations (P = .007), and fourth-order aberrations (P = .041) at 4 mm pupil diameter, demonstrated significantly lower results after temporal compared to superior approach. A higher rate of eyes after temporal approach underwent at least 1 rebubbling (39.1% vs 26.7%, P = .252). The endothelial cell density (P = .053) and the change in spherical equivalent (P = .145) did not differ significantly. CONCLUSIONS: The temporal approach induces significantly less SIA and corneal aberration. There are no significant differences between superior and temporal approach according to the change in spherical equivalent, visual acuity, and endothelial cell density. The need for rebubbling is higher using the temporal approach. PMID- 25284762 TI - Reevaluating the definition of intraretinal microvascular abnormalities and neovascularization elsewhere in diabetic retinopathy using optical coherence tomography and fluorescein angiography. AB - PURPOSE: To evaluate the agreement between clinical examination, spectral-domain ocular coherence tomography (SD OCT), and fluorescein angiography (FA) in diagnosing intraretinal microvascular abnormality (IRMA) and neovascularization elsewhere (NVE) and define the SD OCT features that differentiate NVEs from IRMAs. DESIGN: Retrospective study. METHODS: Data were collected from 23 lesions from 8 diabetic patients, seen from July 2012 through October 2013 at Moorfields Eye Hospital, United Kingdom. Main outcomes were SD OCT features and FA leakage of IRMA and neovascular complex. The agreement between 3 evaluations was analyzed by Fleiss' kappa. RESULTS: The following 5 SD OCT features significantly differentiated IRMAs from NVEs: (1) hyperreflective dots in superficial inner retina (P = .002); (2) the outpouching of internal limiting membrane (ILM) (P = .004); (3) the breach of ILM (P = .004); (4) the breach of posterior hyaloid (P = .0005); (5) hyperreflective dots in vitreous (P = .008). The agreement was moderate between 3 evaluations (kappa = 0.48, P = 7.11 * 10(-5)) but substantial between clinical and SD OCT evaluation (kappa = 0.72, P = .00055). There was no significant agreement between OCT evaluation and FA leakage (kappa = 0.249, P = .232). CONCLUSIONS: SD OCT will be a valuable adjunct in evaluating IRMA and NVE, since it can verify the histopathologic correlate. SD OCT provides subtle anatomic insights and may be more accurate than clinical examination or leakage on FA, our current method of diagnosing this important endpoint, which has implications in future trial design for proliferative diabetic retinopathy prevention. PMID- 25284761 TI - The reduction of serum soluble Flt-1 in patients with neovascular age-related macular degeneration. AB - PURPOSE: To evaluate serum soluble Flt-1 (sFlt-1) in age-related macular degeneration (AMD) patients. DESIGN: Case-control study. METHODS: Study involved 56 non-AMD participants, 53 early AMD patients, and 97 neovascular AMD patients from Belfast in Northern Ireland. Serum samples were collected from each patient. Serum sFlt-1 was measured by human sVEGFR1/sFlt-1 ELISA kit. The results were analyzed by Excel and SPSS. RESULTS: Serum sFlt-1 concentration of non-AMD, early AMD, and neovascular AMD were 90.8 +/- 2.9 pg/mL (+/- standard error of the mean), 88.2 +/- 2.6 pg/mL, and 79.9 +/- 2.2 pg/mL. sFlt-1 from neovascular AMD patients was significantly decreased compared to non-AMD and early AMD patients (ANOVA, P < .01). For each 10-point increase in sFlt-1, the odds for having neovascular AMD compared with non-AMD and neovascular AMD decrease by 27.8%, odds ratio (OR) = 0.722 (95% confidence interval [CI]: 0.588-0.888, P = .002) and 27.0%, OR = 0.730 (95% CI: 0.594-0.898, P = .003), respectively. In patients over 73 years of age, serum sFlt-1 <80 pg/mL was associated with a >6-fold higher risk of neovascular AMD. CONCLUSIONS: Reduced serum sFlt-1 differentiates those patients with neovascular AMD from both early AMD and non-AMD participants. In those aged over 73, serum sFlt <80 pg/mL seems to indicate a particularly high risk of neovascular AMD. Our results indicate serum sFlt-1 could be a biomarker for development of neovascular AMD. PMID- 25284764 TI - Meaning of visualizing retinal cone mosaic on adaptive optics images. AB - PURPOSE: To explore the anatomic correlation of the retinal cone mosaic on adaptive optics images. DESIGN: Retrospective nonconsecutive observational case series. METHODS: A retrospective review of the multimodal imaging charts of 6 patients with focal alteration of the cone mosaic on adaptive optics was performed. Retinal diseases included acute posterior multifocal placoid pigment epitheliopathy (n = 1), hydroxychloroquine retinopathy (n = 1), and macular telangiectasia type 2 (n = 4). High-resolution retinal images were obtained using a flood-illumination adaptive optics camera. Images were recorded using standard imaging modalities: color and red-free fundus camera photography; infrared reflectance scanning laser ophthalmoscopy, fluorescein angiography, indocyanine green angiography, and spectral-domain optical coherence tomography (OCT) images. RESULTS: On OCT, in the marginal zone of the lesions, a disappearance of the interdigitation zone was observed, while the ellipsoid zone was preserved. Image recording demonstrated that such attenuation of the interdigitation zone co localized with the disappearance of the cone mosaic on adaptive optics images. In 1 case, the restoration of the interdigitation zone paralleled that of the cone mosaic after a 2-month follow-up. CONCLUSION: Our results suggest that the interdigitation zone could contribute substantially to the reflectance of the cone photoreceptor mosaic. The absence of cones on adaptive optics images does not necessarily mean photoreceptor cell death. PMID- 25284766 TI - Functional dynamics of deuterated beta2 -adrenergic receptor in lipid bilayers revealed by NMR spectroscopy. AB - G-protein-coupled receptors (GPCRs) exist in conformational equilibrium between active and inactive states, and the former population determines the efficacy of signaling. However, the conformational equilibrium of GPCRs in lipid bilayers is unknown owing to the low sensitivities of their NMR signals. To increase the signal intensities, a deuteration method was developed for GPCRs expressed in an insect cell/baculovirus expression system. The NMR sensitivities of the methionine methyl resonances from the beta2 -adrenergic receptor (beta2 AR) in lipid bilayers of reconstituted high-density lipoprotein (rHDL) increased by approximately 5-fold upon deuteration. NMR analyses revealed that the exchange rates for the conformational equilibrium of beta2 AR in rHDLs were remarkably different from those measured in detergents. The timescales of GPCR signaling, calculated from the exchange rates, are faster than those of receptor tyrosine kinases and thus enable rapid neurotransmission and sensory perception. PMID- 25284767 TI - Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of alphavbeta5 integrin. AB - During melanoma progression, tumour cells show increased adhesiveness to the vascular wall, invade the extracellular matrix (ECM) and frequently form functional channels similar to vascular vessels (vasculogenic mimicry). These properties are mainly mediated by the interaction of integrins with ECM components. Since we had previously identified neuropilin 1 (NRP-1), a coreceptor of vascular endothelial growth factor A (VEGF-A), as an important determinant of melanoma aggressiveness, aims of this study were to identify the specific integrins involved in the highly invasive phenotype of NRP-1 expressing cells and to investigate their role as targets to counteract melanoma progression. Melanoma aggressiveness was evaluated in vitro as cell ability to migrate through an ECM layer and to form tubule-like structures using transfected cells. Integrins relevant to these processes were identified using specific blocking antibodies. The alphavbeta5 integrin was found to be responsible for about 80% of the capability of NRP-1 expressing cells to adhere on vitronectin. In these cells alphavbeta5 expression level was twice higher than in low-invasive control cells and contributed to the ability of melanoma cells to form tubule-like structures on matrigel. Cilengitide, a potent inhibitor of alphanu integrins activation, reduced ECM invasion, vasculogenic mimicry and secretion of VEGF-A and metalloproteinase 9 by melanoma cells. In conclusion, we demonstrated that alphanubeta5 integrin is involved in the highly aggressive phenotype of melanoma cells expressing NRP-1. Moreover, we identified a novel mechanism that contributes to the antimelanoma activity of the alphav integrin inhibitor cilengitide based on the inhibition of vasculogenic mimicry. PMID- 25284768 TI - Development of self-powered wireless high temperature electrochemical sensor for in situ corrosion monitoring of coal-fired power plant. AB - Reliable wireless high temperature electrochemical sensor technology is needed to provide in situ corrosion information for optimal predictive maintenance to ensure a high level of operational effectiveness under the harsh conditions present in coal-fired power generation systems. This research highlights the effectiveness of our novel high temperature electrochemical sensor for in situ coal ash hot corrosion monitoring in combination with the application of wireless communication and an energy harvesting thermoelectric generator (TEG). This self powered sensor demonstrates the successful wireless transmission of both corrosion potential and corrosion current signals to a simulated control room environment. PMID- 25284765 TI - Copy number variations of TBK1 in Australian patients with primary open-angle glaucoma. AB - PURPOSE: To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. DESIGN: A retrospective cohort study. METHODS: DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. RESULTS: Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. CONCLUSION: We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma. PMID- 25284769 TI - Understanding ocular surface disease from uncommon to extremely common afflictions. PMID- 25284770 TI - Clinical and genetic aspects of the TGFBI-associated corneal dystrophies. AB - Corneal dystrophies are a group of inherited disorders localized to various layers of the cornea that affect corneal transparency and visual acuity. The deposition of insoluble protein materials in the form of extracellular deposits or intracellular cysts is pathognomic. Mutations in TGFBI are responsible for superficial and stromal corneal dystrophies. The gene product, transforming growth factor beta induced protein (TGFBIp) accumulates as insoluble deposits in various forms. The severity, clinicopathogenic variations, age of the onset, and location of the deposits depend on the type of amino acid alterations in the protein. Until 2006, 38 different pathogenic mutants were reported for the TGFBI associated corneal dystrophies. This number has increased to 63 mutants, reported in more than 30 countries. There is no effective treatment to prevent, halt, or reverse the deposition of TGFBIp. This review presents a complete mutation update, classification of phenotypes, comprehensive reported incidents of various mutations, and current treatment options and their shortcomings. Future research directions and possible approaches to inhibiting disease progression are discussed. PMID- 25284771 TI - The precorneal tear film as a fluid shell: the effect of blinking and saccades on tear film distribution and dynamics. AB - We conducted a series of experiments to elucidate the behavior of the human precorneal tear film (PCTF) during blinking and horizontal and vertical saccades. Methodology included video-interferometry with subsequent image cross-correlation (tear film lipid layer [TFLL]) and video-microscopy (mucoaqueous subphase [MAS]). We observed that the TFLL interference pattern deteriorates rapidly with successive blinks and degrades slowly with repeated horizontal saccades during blink suppression when dark arcs of thinning appear in the fluorescein-stained PCTF. Furthermore, after full downgaze and a return to the primary position, a transient horizontal bright band appears, deep to the spreading TFLL. It may be followed by local disturbances in the interference pattern. Two horizontal dark bands form in the stained PCTF after the return saccade. PCTF disruption may occur below the lower band during blink suppression. We concluded that shearing during horizontal saccades is insufficient to disturb the tear film structure greatly. The MAS and TFLL move together as a fluid shell. The dark arcs/bands are caused by meniscus-induced thinning, imprinted onto the PCTF at the lid margin. Their stability during blink suppression suggests that the MAS has gel-like properties. The horizontal bright bands are probably due to transient corneal indentation in downgaze. In downgaze, the disturbance of the TFLL and MAS below the dark bands is possibly due to shearing across the MAS in the return phase. This could cause desiccating stress in everyday activities, such as working at a computer. PMID- 25284772 TI - Recurrence or re-emergence of keratoconus--what is the evidence telling us? Literature review and two case reports. AB - Keratoconus may recur following penetrating or lamellar keratoplasty, but latency is considerably longer in the former. Since keratoplasty involves only partial excision of the cornea, and recent research strongly indicates the presence of the pathology in the peripheral host cornea, the reappearance of the pathology after a latency period is most likely due to migration of the disease from host to donor cornea. This notion is further corroborated by the shorter latency period in partial thickness keratoplasty, where more of the diseased host cornea remains in place. Other proposed causes for the recurrence of keratoconus, such as eye rubbing and contact lens wear, were reportedly not associated with a significant number of cases, and, therefore, are not the primary factor. Based on existing literature, it is concluded that, in post-keratoplasty keratoconus, the etiology stems from re-emergence of the disease rather than recurrence. Keratoconus patients in need of keratoplasty should be counseled on the possibility of the disease re-emerging. PMID- 25284773 TI - Treatment of blepharitis: recent clinical trials. AB - Blepharitis is a chronic inflammatory disease of the eyelids that is frequently encountered in clinical practice. The etiology of the disorder is complex and not fully understood, but the general consensus is that bacteria and inflammation contribute to the pathology. Blepharitis can be classified into anterior blepharitis, involving the anterior lid margin and eyelashes, and posterior blepharitis, characterized by dysfunction of the meibomian glands. Long-term management of symptoms may include daily eyelid cleansing routines and the use of therapeutic agents that reduce infection and inflammation. A cure is not possible in most cases, and subjective symptoms may persist even when a clinical assessment of signs indicates that the condition has improved. There are no established guidelines regarding therapeutic regimens, but recent clinical trials have shown that antibiotics and topical corticosteroids can produce significant improvement in signs and symptoms of blepharitis. Fixed combinations of a topical antibiotic and a corticosteroid offer an effective and convenient treatment modality that addresses both infectious and inflammatory components of the disease. Further clinical trials are needed to determine optimal therapies for managing blepharitis. PMID- 25284774 TI - En-face optical coherence tomography as a novel tool for exploring the ocular surface: a pilot comparative study to conventional B-scans and in vivo confocal microscopy. AB - PURPOSE: To explore the potential of spectral-domain optical coherence tomography (SD-OCT) using the en-face technology for the imaging of ocular surface diseases and to correlate the findings with in vivo confocal microscopy (IVCM) images. PATIENTS AND METHODS: 113 eyes of 75 subjects with various ocular surface diseases were investigated with the RTVue((r)) anterior-segment en face OCT. En face OCT images were compared to B-scan OCT and IVCM images. RESULTS: Patients with corneal dystrophies, corneal deposits, keratitis, pterygium, conjunctivochalasis, or ocular surface squamous neoplasia and patients who underwent lamellar corneal surgeries were included. En-face OCT images showed ocular surface tissue changes that were not discernible using conventional B-scan OCT. Nevertheless, there was a good correlation with IVCM analysis. Compared with IVCM, the major advantages of en-face OCT included easy operation and rapid image acquisition, with minimal operator experience required. In addition, the non contact method avoided patient discomfort and external pressure on the globe, which was especially useful in patients with corneal dystrophies, ulcers, or corneal abscesses. Although the resolution of en-face OCT was lower than that of IVCM, it allowed useful overall visualization of corneal lesions due to the larger areas analyzed. CONCLUSION: En-face SD-OCT is a novel, valuable tool to assess a wide variety of ocular surface diseases. It can provide additional information and new insight into different ocular surface conditions with no corneal contact. PMID- 25284775 TI - Phases of clinical development. PMID- 25284776 TI - Preparation and evaluation of o-phenanthroline immobilized on a hybrid silica monolith modified with ionic liquids for reversed-phase pressurized capillary electrochromatography. AB - A novel o-phenanthroline-immobilized ionic-liquid-modified hybrid monolith for capillary electrochromatography was synthesized based on chloropropyl-silica, which was prepared by the in situ polymerization of tetramethoxysilane and 3 chloropropyltrimethoxysilane via a sol-gel process. The morphology of the hybrid monolith was characterized by scanning electron microscopy, and relatively stable anodic electroosmotic flow was observed under a broad pH ranged from pH 3.0 to 9.0. The separation mechanism was investigated by separating four neutral molecules (toluene, dimethylformamide, formamide, and thiourea). The obtained hybrid monolith possessed an obviously reversed-phase retention mechanism, but when the acetonitrile content in the mobile phase was >90% v/v, a weak hydrophilic mechanism was observed on the resultant o-phenanthroline-modified chloropropyl-silica hybrid monolith. The reproducibility of the column was also investigated by measuring relative standard deviations of the migration time for four neutral molecules. Relative standard deviations of run to run (n = 3), day to day (n = 3), and column to column (n = 3) were in the range of 0.4-0.7, 0.9 2.1, and 1.4-3.3%, respectively. Basic separations of various polar analytes including phenols and aromatic amines were successfully achieved. PMID- 25284777 TI - Supramolecular engineering of oligothiophene nanorods without insulators: hierarchical association of rosettes and photovoltaic properties. AB - Supramolecular rosettes of oligothiophenes that do not bear long aliphatic tails have been designed as semiconducting nanomaterials for solution-processable bulk heterojunction solar cells. The rosettes consist of six barbiturated thienyl[oligo(hexylthiophene)] units (Bar-T-hTn ; n=3,4,5) aggregated by multiple hydrogen bonds, which have been directly visualized by scanning tunneling microscopy (STM) at a solid-liquid interface. (1) H NMR spectroscopy in [D8 ]toluene showed that Bar-T-hTn exists as a mixture of monomers and small hydrogen bonded aggregates. Hierarchical organization of the hydrogen-bonded aggregates took place through pi-pi stacking interactions upon casting their toluene solutions, resulting in the growth of highly ordered nanorods whose widths are consistent with the diameters of the rosettes. The nanorods could be generated in the presence of soluble fullerene derivatives via solution casting or the annealing of the resulting thin films. The solar cells fabricated based on these bulk heterojunction films showed power conversion efficiencies of 1-3 %, which are far higher than those of the non-hydrogen-bonded reference oligothiophene and the derivative that possesses long aliphatic tails. PMID- 25284778 TI - Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease linked mutant causes temperature-sensitive defect in exocytosis. AB - Munc18-1 is a critical component of the core machinery controlling neuroexocytosis. Recently, mutations in Munc18-1 leading to the development of early infantile epileptic encephalopathy have been discovered. However, which degradative pathway controls Munc18-1 levels and how it impacts on neuroexocytosis in this pathology is unknown. Using neurosecretory cells deficient in Munc18, we show that a disease-linked mutation, C180Y, renders the protein unstable at 37 degrees C. Although the mutated protein retains its function as t-SNARE chaperone, neuroexocytosis is impaired, a defect that can be rescued at a lower permissive temperature. We reveal that Munc18-1 undergoes K48 linked polyubiquitination, which is highly increased by the mutation, leading to proteasomal, but not lysosomal, degradation. Our data demonstrate that functional Munc18-1 levels are controlled through polyubiquitination and proteasomal degradation. The C180Y disease-causing mutation greatly potentiates this degradative pathway, rendering Munc18-1 unable to facilitate neuroexocytosis, a phenotype that is reversed at a permissive temperature. PMID- 25284780 TI - Transforming growth factor beta/activin signaling functions as a sugar-sensing feedback loop to regulate digestive enzyme expression. AB - Organisms need to assess their nutritional state and adapt their digestive capacity to the demands for various nutrients. Modulation of digestive enzyme production represents a rational step to regulate nutriment uptake. However, the role of digestion in nutrient homeostasis has been largely neglected. In this study, we analyzed the mechanism underlying glucose repression of digestive enzymes in the adult Drosophila midgut. We demonstrate that glucose represses the expression of many carbohydrases and lipases. Our data reveal that the consumption of nutritious sugars stimulates the secretion of the transforming growth factor beta (TGF-beta) ligand, Dawdle, from the fat body. Dawdle then acts via circulation to activate TGF-beta/Activin signaling in the midgut, culminating in the repression of digestive enzymes that are highly expressed during starvation. Thus, our study not only identifies a mechanism that couples sugar sensing with digestive enzyme expression but points to an important role of TGF beta/Activin signaling in sugar metabolism. PMID- 25284779 TI - Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. AB - Deficiencies in DNA-degrading nucleases lead to accumulation of self DNA and induction of autoimmunity in mice and in monogenic and polygenic human diseases. However, the sources of DNA and the mechanisms that trigger immunity remain unclear. We analyzed mice deficient for the lysosomal nuclease Dnase2a and observed elevated levels of undegraded DNA in both phagocytic and nonphagocytic cells. In nonphagocytic cells, the excess DNA originated from damaged DNA in the nucleus based on colocalization studies, live-cell imaging, and exacerbation by DNA-damaging agents. Removal of damaged DNA by Dnase2a required nuclear export and autophagy-mediated delivery of the DNA to lysosomes. Finally, DNA was found to accumulate in Dnase2a(-/-) or autophagy-deficient cells and induce inflammation via the Sting cytosolic DNA-sensing pathway. Our results reveal a cell-autonomous process for removal of damaged nuclear DNA with implications for conditions with elevated DNA damage, such as inflammation, cancer, and chemotherapy. PMID- 25284781 TI - Circulating AIM prevents hepatocellular carcinoma through complement activation. AB - Hepatocellular carcinoma (HCC) is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM(-/-) mice were highly susceptible to steatosis-associated HCC development, whereas no AIM(+/+) mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM(-/-) mice, and HCC induction by diethylnitrosamine was more prominent in AIM(-/-) than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC. PMID- 25284782 TI - Cadherin-7 regulates mossy fiber connectivity in the cerebellum. AB - To establish highly precise patterns of neural connectivity, developing axons must stop growing at their appropriate destinations and specifically synapse with target cells. However, the molecular mechanisms governing these sequential steps remain poorly understood. Here, we demonstrate that cadherin-7 (Cdh7) plays a dual role in axonal growth termination and specific synapse formation during the development of the cerebellar mossy fiber circuit. Cdh7 is expressed in mossy fiber pontine nucleus (PN) neurons and their target cerebellar granule neurons during synaptogenesis and selectively mediates synapse formation between those neurons. Additionally, Cdh7 presented by mature granule neurons diminishes the growth potential of PN axons. Furthermore, knockdown of Cdh7 in PN neurons in vivo severely impairs the connectivity of PN axons in the developing cerebellum. These findings reveal a mechanism by which a single bifunctional cell-surface receptor orchestrates precise wiring by regulating axonal growth potential and synaptic specificity. PMID- 25284783 TI - GIT1 and betaPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission. AB - Effective inhibitory synaptic transmission requires efficient stabilization of GABA(A) receptors (GABA(A)Rs) at synapses, which is essential for maintaining the correct excitatory-inhibitory balance in the brain. However, the signaling mechanisms that locally regulate synaptic GABA(A)R membrane dynamics remain poorly understood. Using a combination of molecular, imaging, and electrophysiological approaches, we delineate a GIT1/betaPIX/Rac1/PAK signaling pathway that modulates F-actin and is important for maintaining surface GABA(A)R levels, inhibitory synapse integrity, and synapse strength. We show that GIT1 and betaPIX are required for synaptic GABA(A)R surface stability through the activity of the GTPase Rac1 and downstream effector PAK. Manipulating this pathway using RNAi, dominant-negative and pharmacological approaches leads to a disruption of GABA(A)R clustering and decrease in the strength of synaptic inhibition. Thus, the GIT1/betaPIX/Rac1/PAK pathway plays a crucial role in regulating GABA(A)R synaptic stability and hence inhibitory synaptic transmission with important implications for inhibitory plasticity and information processing in the brain. PMID- 25284784 TI - De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. AB - Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 * 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. PMID- 25284785 TI - Functional diversification of maize RNA polymerase IV and V subtypes via alternative catalytic subunits. AB - Unlike nuclear multisubunit RNA polymerases I, II, and III, whose subunit compositions are conserved throughout eukaryotes, plant RNA polymerases IV and V are nonessential, Pol II-related enzymes whose subunit compositions are still evolving. Whereas Arabidopsis Pols IV and V differ from Pol II in four or five of their 12 subunits, respectively, and differ from one another in three subunits, proteomic analyses show that maize Pols IV and V differ from Pol II in six subunits but differ from each other only in their largest subunits. Use of alternative catalytic second subunits, which are nonredundant for development and paramutation, yields at least two subtypes of Pol IV and three subtypes of Pol V in maize. Pol IV/Pol V associations with MOP1, RMR1, AGO121, Zm_DRD1/CHR127, SHH2a, and SHH2b extend parallels between paramutation in maize and the RNA directed DNA methylation pathway in Arabidopsis. PMID- 25284786 TI - Transformation resistance in a premature aging disorder identifies a tumor protective function of BRD4. AB - Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) provides a unique opportunity for studying the interplay between DNA damage and aging associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis. PMID- 25284787 TI - HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. AB - Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, and SHARPIN, is the only known ubiquitin ligase that generates linear ubiquitin linkages. HOIP is the catalytically active LUBAC component. Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation. Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation. HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha), and aberrant complex-II formation is responsible for sensitization to TNFR1-mediated cell death in the absence of HOIP. Finally, we show that HOIP's catalytic activity is necessary for preventing TNF-induced cell death. Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1 mediated endothelial cell death. PMID- 25284788 TI - Rewiring of an epithelial differentiation factor, miR-203, to inhibit human squamous cell carcinoma metastasis. AB - Metastatic colonization of distant organs underpins the majority of human-cancer related deaths, including deaths from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that triggers differentiation in multilayered epithelia, inhibits multiple postextravasation events during HNSCC lung metastasis. Inducible reactivation of miR-203 in already established lung metastases reduces the overall metastatic burden. Using an integrated approach, we reveal that miR-203 inhibits metastasis independently of its effects on differentiation. In vivo genetic reconstitution experiments show that miR-203 inhibits lung metastasis by suppressing the prometastatic activities of three factors involved in cytoskeletal dynamics (LASP1), extracellular matrix remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream effectors correlates with HNSCC overall survival outcomes, indicating the therapeutic potential of targeting this signaling axis. PMID- 25284790 TI - Cooperativity, specificity, and evolutionary stability of Polycomb targeting in Drosophila. AB - Metazoan genomes are partitioned into modular chromosomal domains containing active or repressive chromatin. In flies, Polycomb group (PcG) response elements (PREs) recruit PHO and other DNA-binding factors and act as nucleation sites for the formation of Polycomb repressive domains. The sequence specificity of PREs is not well understood. Here, we use comparative epigenomics and transgenic assays to show that Drosophila domain organization and PRE specification are evolutionarily conserved despite significant cis-element divergence within Polycomb domains, whereas cis-element evolution is strongly correlated with transcription factor binding divergence outside of Polycomb domains. Cooperative interactions of PcG complexes and their recruiting factor PHO stabilize PHO recruitment to low-specificity sequences. Consistently, PHO recruitment to sites within Polycomb domains is stabilized by PRC1. These data suggest that cooperative rather than hierarchical interactions among low-affinity sequences, DNA-binding factors, and the Polycomb machinery are giving rise to specific and strongly conserved 3D structures in Drosophila. PMID- 25284789 TI - 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. AB - The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5 hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes. PMID- 25284791 TI - TOR signaling couples oxygen sensing to lifespan in C. elegans. AB - Metazoans adapt to a low-oxygen environment (hypoxia) through activation of stress-response pathways. Here, we report that transient hypoxia exposure extends lifespan in C. elegans through mitochondrial reactive oxygen species (ROS) dependent regulation of the nutrient-sensing kinase target of rapamycin (TOR) and its upstream activator, RHEB-1. The increase in lifespan during hypoxia requires the intestinal GATA-type transcription factor ELT-2 downstream of TOR signaling. Using RNA sequencing (RNA-seq), we describe an ELT-2-dependent hypoxia response that includes an intestinal glutathione S-transferase, GSTO-1, and uncover that GSTO-1 is required for lifespan under hypoxia. These results indicate mitochondrial ROS-dependent TOR signaling integrates metabolic adaptations in order to confer survival under hypoxia. PMID- 25284792 TI - Modeling cerebrovascular pathophysiology in amyloid-beta metabolism using neural crest-derived smooth muscle cells. AB - There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Abeta) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Abeta metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest derived SMCs to mediate Abeta uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Abeta clearance by suppressing LRP1 expression. This enabled us to develop an assay of Abeta uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden. PMID- 25284793 TI - The prognostic ease and difficulty of invasive breast carcinoma. AB - Breast carcinoma (BC) has been extensively profiled by high-throughput technologies for over a decade, and broadly speaking, these studies can be grouped into those that seek to identify patient subtypes (studies of heterogeneity) or those that seek to identify gene signatures with prognostic or predictive capacity. The sheer number of reported signatures has led to speculation that everything is prognostic in BC. Here, we show that this ubiquity is an apparition caused by a poor understanding of the interrelatedness between subtype and the molecular determinants of prognosis. Our approach constructively shows how to avoid confounding due to a patient's subtype, clinicopathological profile, or treatment profile. The approach identifies patients who are predicted to have good outcome at time of diagnosis by all available clinical and molecular markers but who experience a distant metastasis within 5 years. These inherently difficult patients (~7% of BC) are prioritized for investigations of intratumoral heterogeneity. PMID- 25284794 TI - Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution. AB - Age-associated thymic involution results in diminished T cell output and function in aged individuals. However, molecular mediators contributing to the decline in thymic function during early thymic involution remain largely unknown. Here, we present transcriptional profiling of purified thymic stromal subsets from mice 1, 3, and 6 months of age spanning early thymic involution. The data implicate unanticipated biological functions for a subset of thymic epithelial cells. The predominant transcriptional signature of early thymic involution is decreased expression of cell-cycle-associated genes and E2F3 transcriptional targets in thymic epithelial subsets. Also, expression of proinflammatory genes increases with age in thymic dendritic cells. Many genes previously implicated in late involution are already deregulated by 3-6 months of age. We provide these thymic stromal data sets, along with thymocyte data sets, in a readily searchable web based platform, as a resource for investigations into thymocyte:stromal interactions and mechanisms of thymic involution. PMID- 25284796 TI - Understanding the role of gold nanoparticles in enhancing the catalytic activity of manganese oxides in water oxidation reactions. AB - The Earth-abundant and inexpensive manganese oxides (MnOx) have emerged as an intriguing type of catalysts for the water oxidation reaction. However, the overall turnover frequencies of MnOx catalysts are still much lower than that of nanostructured IrO2 and RuO2 catalysts. Herein, we demonstrate that doping MnOx polymorphs with gold nanoparticles (AuNPs) can result in a strong enhancement of catalytic activity for the water oxidation reaction. It is observed that, for the first time, the catalytic activity of MnOx/AuNPs catalysts correlates strongly with the initial valence of the Mn centers. By promoting the formation of Mn(3+) species, a small amount of AuNPs (<5%) in alpha-MnO2/AuNP catalysts significantly improved the catalytic activity up to 8.2 times in the photochemical and 6 times in the electrochemical system, compared with the activity of pure alpha-MnO2. PMID- 25284795 TI - Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. AB - Hypothalamic endoplasmic reticulum (ER) stress is a key mechanism leading to obesity. Here, we demonstrate that ceramides induce lipotoxicity and hypothalamic ER stress, leading to sympathetic inhibition, reduced brown adipose tissue (BAT) thermogenesis, and weight gain. Genetic overexpression of the chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) in the ventromedial nucleus of the hypothalamus (VMH) abolishes ceramide action by reducing hypothalamic ER stress and increasing BAT thermogenesis, which leads to weight loss and improved glucose homeostasis. The pathophysiological relevance of this mechanism is demonstrated in obese Zucker rats, which show increased hypothalamic ceramide levels and ER stress. Overexpression of GRP78 in the VMH of these animals reduced body weight by increasing BAT thermogenesis as well as decreasing leptin and insulin resistance and hepatic steatosis. Overall, these data identify a triangulated signaling network involving central ceramides, hypothalamic lipotoxicity/ER stress, and BAT thermogenesis as a pathophysiological mechanism of obesity. PMID- 25284797 TI - Bone marrow transplantation for non-malignant diseases using treosulfan-based conditioning. AB - BACKGROUND: Treosulfan (treo) is an alkylating agent with a low acute toxicity profile that is increasingly used in hematopoietic stem cell transplantation, predominantly in non-malignant diseases. Treosulfan is usually combined with additional agents, but there is scant evidence to allow comparison between different conditioning protocols using treosulfan. We present the experience of three pediatric transplantation centers in Israel using different treosulfan based conditioning regimens. PROCEDURE: Data were collected retrospectively on 44 children who underwent 45 hematopoietic stem cell transplantations using treosulfan in combination with either fludarabine (flu) and thiotepa (tt) (n = 20), cyclophosphamide (cy) (n = 6) or fludarabine alone (n = 19). RESULTS: Overall survival (OS) was 70.5%. Disease free survival (DFS) was 54.6%. There was no statistically significant difference between treatment groups in either OS or DFS. Overall survival in patients younger than one year was higher (88.2%). There were significantly more patients with 100% donor chimerism transplanted with flu/treo/tt compared with flu/treo or treo/cy (94.7% compared to 66.7% and 16.7%, respectively). Further prospective studies are required to determine the optimal treosulfan-based preparative regimen for children with non-malignant diseases. Pediatr Blood Cancer 2015;62:299-304. (c) 2014 Wiley Periodicals, Inc. PMID- 25284798 TI - Are horse paddocks threatening water quality through excess loading of nutrients? AB - The Baltic Sea is one of the most eutrophied water bodies in northern Europe and more than 50% of its total anthropogenic waterborne phosphorus (P) and nitrogen (N) loads derive from agricultural sources. Sweden is the second largest contributor of waterborne N and the third largest contributor of waterborne P to the Baltic Sea. Horse farms now occupy almost 10% of Swedish agricultural land, but are not well investigated with regard to their environmental impact. In this study, potential P, N and carbon (C) leaching losses were measured from two representative horse paddock topsoils (0-20 cm; a clay and a loamy sand) following simulated rainfall events in the laboratory. Results showed that the leachate concentrations and net release of P, N and dissolved organic C (DOC) from paddock topsoils were highest in feeding and excretion areas and considerably higher from the loamy sand than the clay paddock topsoil. Leaching losses of dissolved reactive P (DRP) were significantly (p < 0.05) correlated with concentrations of water-soluble P and ammonium acetate lactate-extractable P (P-AL) in the soil, while leaching losses of dissolved organic P and total organic N were significantly correlated with DOC concentration in leachate. Leaching loads of P and N from paddock topsoils greatly exceeded average figures for Swedish agricultural topsoils. It was concluded that: i) horse paddocks pose a potential threat to water quality via leaching of excess P and N, ii) feeding and excretion areas are potential hotspots for highly enhanced leaching losses, and iii) paddocks established on sandy soils are particularly susceptible to high N leaching losses. PMID- 25284799 TI - Enhancement of azo dye Acid Orange 7 removal in newly developed horizontal subsurface-flow constructed wetland. AB - Horizontal subsurface-flow (HSF) constructed wetland incorporating baffles was developed to facilitate upflow and downflow conditions so that the treatment of pollutants could be achieved under multiple aerobic, anoxic and anaerobic conditions sequentially in the same wetland bed. The performances of the baffled and conventional HSF constructed wetlands, planted and unplanted, in the removal of azo dye Acid Orange 7 (AO7) were compared at the hydraulic retention times (HRT) of 5, 3 and 2 days when treating domestic wastewater spiked with AO7 concentration of 300 mg/L. The planted baffled unit was found to achieve 100%, 83% and 69% AO7 removal against 73%, 46% and 30% for the conventional unit at HRT of 5, 3 and 2 days, respectively. Longer flow path provided by baffled wetland units allowed more contact of the wastewater with the rhizomes, microbes and micro-aerobic zones resulting in relatively higher oxidation reduction potential (ORP) and enhanced performance as kinetic studies revealed faster AO7 biodegradation rate under aerobic condition. In addition, complete mineralization of AO7 was achieved in planted baffled wetland unit due to the availability of a combination of aerobic, anoxic and anaerobic conditions. PMID- 25284800 TI - Manganese ore tailing: optimization of acid leaching conditions and recovery of soluble manganese. AB - Manganese recovery from industrial ore processing waste by means of leaching with sulfuric acid was the objective of this study. Experimental conditions were optimized by multivariate experimental design approaches. In order to study the factors affecting leaching, a screening step was used involving a full factorial design with central point for three variables in two levels (2(3)). The three variables studied were leaching time, concentration of sulfuric acid and sample amount. The three factors screened were shown to be relevant and therefore a Doehlert design was applied to determine the best working conditions for leaching and to build the response surface. By applying the best leaching conditions, the concentrations of 12.80 and 13.64 %w/w of manganese for the global sample and for the fraction -44 + 37 MUm, respectively, were found. Microbeads of chitosan were tested for removal of leachate acidity and recovering of soluble manganese. Manganese recovery from the leachate was 95.4%. Upon drying the leachate, a solid containing mostly manganese sulfate was obtained, showing that the proposed optimized method is efficient for manganese recovery from ore tailings. PMID- 25284801 TI - Evaluation of the improvement of sonication pre-treatment in the anaerobic digestion of sewage sludge. AB - Sewage sludge is a polluting and hazardous waste generated in wastewater treatment plants with severe management problems. The high content in heavy metal, pathogens and micropolluting compounds limit the implementation of the available management methods. Anaerobic digestion could be an interesting treatment method, but must be improved since the biomethanisation of sewage sludge entails low biodegradability and low methane production. A sonication pre treatment at lab scale is proposed to increase the organic matter solubilisation of sewage sludge and enhance the biomethanisation yield. Sonication time was optimised by analysing the physicochemical characteristics of sewage sludge (both total and soluble fraction) at different pre-treatment times. The pre-treatment time was fixed at 45 min under the study conditions given that the solubilisation of organic matter did not increase significantly at lower sonication times, whereas the concentration of total nitrogen increased markedly at higher times. The volatile fatty acids generation rate was also evaluated for the pre-treatment conditions. The anaerobic digestion of untreated and pre-treated sewage sludge was subsequently compared and promising results were obtained for loads of 1.0 g VS/L (VS, total volatile solids). The methane yield coefficient increased from 88 to 172 mLSTP/g VS (STP, 0 degrees C, 1 atm) after the pre-treatment, while biodegradability was found to be around 81% (in VS). Moreover, the allowed organic loading rate and methane production rate observed for the sewage sludge reached values of up to 4.1 kg VS/m(3).d and 1270 LSTP/m(3).d, respectively. PMID- 25284802 TI - Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. AB - Radiofrequency ablation (RFA) is considered a curative treatment option for hepatocellular carcinoma (HCC). Growing data have demonstrated that cryoablation represents a safe and effective alternative therapy for HCC, but no randomized controlled trial (RCT) has been reported to compare cryoablation with RFA in HCC treatment. The present study was a multicenter RCT aimed to compare the outcomes of percutaneous cryoablation with RFA for the treatment of HCC. In all, 360 patients with Child-Pugh class A or B cirrhosis and one or two HCC lesions <= 4 cm, treatment-naive, without metastasis were randomly assigned to cryoablation (n = 180) or RFA (n = 180). The primary endpoints were local tumor progression at 3 years after treatment and safety. Local tumor progression rates at 1, 2, and 3 years were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (P = 0.043). For lesions >3 cm in diameter, the local tumor progression rate was significantly lower in the cryoablation group versus the RFA group (7.7% versus 18.2%, P = 0.041). The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 40% for cryoablation and 97%, 66%, and 38% for RFA, respectively (P = 0.747). The 1-, 3-, and 5-year tumor-free survival rates were 89%, 54%, and 35% in the cryoablation group and 84%, 50%, and 34% in the RFA group, respectively (P = 0.628). Multivariate analyses demonstrated that Child Pugh class B and distant intrahepatic recurrence were significant negative predictors for overall survival. Major complications occurred in seven patients (3.9%) following cryoablation and in six patients (3.3%) following RFA (P = 0.776). CONCLUSION: Cryoablation resulted in a significantly lower local tumor progression than RFA, although both cryoablation and RFA were equally safe and effective, with similar 5-year survival rates. PMID- 25284803 TI - Reprint of "versatile and stable vectors for efficient gene expression in Ralstonia eutropha H16". AB - The Gram-negative beta-proteobacterium Ralstonia eutropha H16 is primarily known for polyhydroxybutyrate (PHB) production and its ability to grow chemolithoautotrophically by using CO2 and H2 as sole carbon and energy sources. The majority of metabolic engineering and heterologous expression studies conducted so far rely on a small number of suitable expression systems. Particularly the plasmid based expression systems already developed for the use in R. eutropha H16 suffer from high segregational instability and plasmid loss after a short time of fermentation. In order to develop efficient and highly stable plasmid expression vectors for the use in R. eutropha H16, a new plasmid design was created including the RP4 partitioning system, as well as various promoters and origins of replication. The application of minireplicons derived from broad-host-range plasmids RSF1010, pBBR1, RP4 and pSa for the construction of expression vectors and the use of numerous, versatile promoters extend the range of feasible expression levels considerably. In particular, the use of promoters derived from the bacteriophage T5 was described for the first time in this work, characterizing the j5 promoter as the strongest promoter yet to be applied in R. eutropha H16. Moreover, the implementation of the RP4 partition sequence in plasmid design increased plasmid stability significantly and enables fermentations with marginal plasmid loss of recombinant R. eutropha H16 for at least 96h. The utility of the new vector family in R. eutropha H16 is demonstrated by providing expression data with different model proteins and consequently further raises the value of this organism as cell factory for biotechnological applications including protein and metabolite production. PMID- 25284804 TI - The medial temporal lobes are critical for reward-based decision making under conditions that promote episodic future thinking. AB - In the present study, we investigated the effect of medial temporal lobe (MTL) damage on human decision making in the context of reward-based intertemporal choice. During intertemporal choice, humans typically devalue (or discount) a future reward to account for its delayed arrival (e.g., preferring $30 now over $42 in 2 months), but this effect is attenuated when participants engage in episodic future thinking, i.e., project themselves into the future to imagine a specific event. We hypothesized that this attenuation would be selectively impaired in amnesic patients, who have deficits in episodic future thinking. Replicating previous work, in a standard intertemporal choice task, amnesic patients showed temporal discounting indices similar to healthy controls. Consistent with our hypothesis, while healthy controls demonstrated attenuated temporal discounting in a condition that required participants first to engage in episodic future thinking (e.g., to imagine spending $42 at a theatre in 2 months), amnesic patients failed to demonstrate this effect. Moreover, as expected, amnesic patients' narratives were less episodically rich than those of controls. These findings extend the range of tasks that are shown to be MTL dependent to include not only memory-based decision-making tasks but also future oriented ones. PMID- 25284806 TI - The past and future of heart institutes: having moved beyond the one-trick pony. PMID- 25284805 TI - Can protons or altered fractionation decrease neurotoxicity after chemoradiation in head and neck cancer? PMID- 25284807 TI - Surgical treatments for patients with terminal heart failure: mechanical support compared with transplantation. AB - Heart transplantation remains the gold standard treatment for patients with terminal end-stage heart failure. Although results reported have been excellent, older recipients and donors associated with significant comorbidities are now the rule rather than the exception. Moreover, heart failure has become a significant public health problem with a growing population of patients in countries unable to answer the demand for transplantation. An emerging answer to this dilemma comes from results reported with the use of continuous flow pumps where patient survival approaches 80% one and 2 years after implantation in selected patients. Is it time to triage patients to continuous flow pumps? Should we recommend continuous flow pump implantations in patients with various comorbidities, and offer transplantation to a selected group of patients who will reach the long term benefit of the procedure? PMID- 25284808 TI - Comparison of sirolimus- and paclitaxel-eluting stents in patients with moderate renal insufficiency: results from the J-DESsERT trial. AB - BACKGROUND: It is unclear whether there are differences in clinical outcomes between sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) in patients with moderate renal insufficiency (RI). METHODS: The Japan-Drug Eluting Stents Evaluation; a Randomized Trial (J-DESsERT) was a prospective, randomized multicenter trial which compared 1:1 coronary stenting between SES and PES patients. Patient with serious RI (serum creatinine value 2mg/dL or higher) were excluded. Patients were classified into 2 arms according to renal function: a non RI arm of 2220 patients (SES 1094 and PES 1126 patients with estimated glomerular filtration rate (eGFR) >=60 mL min(-1) 1.73 m(-2)) and an RI arm of 1206 patients (SES 613, PES 593 with 30<=eGFR <60 mL min(-1) 1.73 m(-2)). RESULTS: At 12 months, the primary endpoint of target vessel failure in the non-RI arm occurred in 6.0% in the SES group and 8.7% in the PES group (p=0.02). In the RI arm, this occurred in 5.7% and 8.1% (p=0.10). Mortality rates were 0.8% vs 0.7% (p=0.78) in the non-RI arm, and 2.2% vs 2.1% (p=0.90) in the RI arm. Cardiac death was 0.4% vs 0.1% (p=0.17) in the non-RI arm, and 1.0% vs 1.0% (p=0.96) in the RI arm. Mortality was higher in patients with RI than those without RI (2.1% vs 0.8%; p<0.01). Cardiac death rates increased in the RI arm compared with those in the non-RI arm (1.0% vs 0.2%; p<0.01). CONCLUSIONS: Regardless of the presence or absence of moderate RI, differences in outcomes between SES and PES change little except mortality and cardiac death. PMID- 25284809 TI - Primary non-interventional operator vascular access choice is associated with lower use of radial PCI: insights from the VA CART. PMID- 25284810 TI - Can the rolling cross-sectional survey design be used to estimate the effectiveness of influenza vaccines? AB - INTRODUCTION: Observational studies of influenza vaccine effectiveness often study persons seeking medical care for acute respiratory infection (ARI). We conducted a pilot study to determine if vaccine effectiveness could be estimated in the general population with a novel rolling cross-sectional survey sampling design and laboratory confirmation of influenza. METHODS: Cross-sectional samples were selected weekly from defined populations in Marshfield, Wisconsin and Monroe County, New York from January through April, 2011 (12 weeks). Persons were telephoned and asked about the occurrence of ARI in the past week. Nasal and throat swabs were obtained from consenting individuals with ARI and tested by real-time reverse transcription polymerase chain reaction (RT-PCR). Vaccine effectiveness (VE) was defined as (100*[1-OR]) for vaccination in a logistic regression model that adjusted for age, calendar week, and site. The comparison group included all study participants without RT-PCR confirmed influenza, including those who were not ill. RESULTS: Study personnel contacted 9537 (62%) of 15,303 persons sampled; the primary analysis included 5678 subjects. Of these, 193 (3%) reported an ARI and agreed to be tested for influenza; 13 (7%) were influenza positive. The adjusted effectiveness of the influenza vaccine was 1% (95% confidence limits -239-70%). CONCLUSIONS: The rolling cross-sectional design is methodologically feasible and may be useful as a complement to clinic-based VE studies. This pilot study did not have sufficient power to detect significant vaccine effectiveness during a mild influenza season, but this approach may facilitate rapid estimation of VE in a pandemic setting when normal patterns of health care utilization are disrupted. PMID- 25284811 TI - H5 N-terminal beta sheet promotes oligomerization of H7-HA1 that induces better antibody affinity maturation and enhanced protection against H7N7 and H7N9 viruses compared to inactivated influenza vaccine. AB - Initiation of mass vaccination is critical in response to influenza pandemic. There is an urgent need of a simple, rapid method for production of influenza vaccine that is more effective than current traditional influenza vaccines. Recent H7N9 transmissions to humans in China with high morbidity/mortality initiated extensive vaccine evaluation. We produced the HA1 domains (amino acids 1-320) from H7N9 and H7N7 strains in E. coli. Both were found to contain primarily monomers/trimers with low oligomeric content. However, when residues from the N-terminal beta sheet (first 8 amino acid) of H7 HA1 domains were swapped with the corresponding amino acids from H5N1, functional oligomeric H7 HA1 were produced (HA1-DS), demonstrating strong receptor binding and hemagglutination. In rabbits, the HA1-DS from either H7N9 or H7N7 generated high neutralization titers against both homologous and heterologous H7 strains, superior to the unmodified H7 HA1 proteins. In ferrets, HA1-DS from H7N7 elicited higher (and faster) HI titers, better protected ferrets from lethality, weight loss, and reduced viral loads following challenge with wild-type highly pathogenic H7N7 virus compared with inactivated H7N7 subunit vaccine. HA1-DS vaccinated ferrets were also better protected from weight loss after challenge with the heterologous H7N9 virus compared with inactivated H7N7 subunit vaccine. Importantly, the H7N7 HA1-DS vaccine induced antibody affinity maturation far superior to the inactivated H7N7 subunit vaccine, which strongly correlated with control of viral loads in the nasal washes after challenge with either H7N7 or H7N9 strains. We conclude that N-terminus beta sheet domain-swap can be used to produce stable functional oligomeric forms of better recombinant HA1 vaccines in simple, inexpensive bacterial system for rapid response to emerging pandemic threat for the global population. PMID- 25284812 TI - Multiple IgE recognition on the major allergen of the Parietaria pollen Par j 2. AB - The interaction between IgE antibodies and allergens is a key event in triggering an allergic reaction. The characterization of this region provides information of paramount importance for diagnosis and therapy. Par j 2 Lipid Transfer Protein is one of the most important allergens in southern Europe and a well-established marker of sensitization in Parietaria pollen allergy. The main aim of this study was to map the IgE binding regions of this allergen and to study the pattern of reactivity of individual Parietaria-allergic patients. By means of gene fragmentation, six overlapping peptides were expressed in Escherichia coli, and their IgE binding activity was evaluated by immunoblotting in a cohort of 79 Parietaria-allergic patients. Our results showed that Pj-allergic patients display a heterogeneous pattern of IgE binding to the different recombinant fragments, and that patients reacted simultaneously against several protein domains spread all the over the molecule, even in fragments which do not contain structural features resembling the native allergen. Our results reveal the presence of a large number of linear and conformational epitopes on the Par j 2 sequence, which probably explains the high allergenic activity of this allergen. PMID- 25284813 TI - Effect of thioredoxin peroxidase-1 gene disruption on the liver stages of the rodent malaria parasite Plasmodium berghei. AB - Phenotypic observation of thioredoxin peroxidase-1 (TPx-1) gene-disrupted Plasmodium berghei (TPx-1 KO) in the liver-stage was performed with an in vitro infection system in order to investigate defective liver-stage development in a mouse infection model. Indirect immunofluorescence microscopy assay with anti circumsporozoite protein antibody revealed that in the liver schizont stage, TPx 1 KO parasite cells were significantly smaller than cells of the wild-type parent strain (WT). Indirect immunofluorescence microscopy assay with anti-merozoite surface protein-1 antibody, which was used to evaluate late schizont-stage development, indicated that TPx-1 KO schizont development was similar to WT strain development towards the merozoite-forming stage (mature schizont). However, fewer merozoites were produced in the mature TPx-1 KO schizont than in the mature WT schizont. Taken together, the results suggest that TPx-1 may be involved in merozoite formation during liver schizont development. PMID- 25284814 TI - Expression characteristics and specific antibody reactivity of diverse cathepsin F members of Paragonimus westermani. AB - Paragonimiasis, caused by the lung fluke Paragonimus, is a major food-borne helminthic disease. Differential diagnosis of paragonimiasis from tuberculosis and other infectious granulomas in the lung is a prerequisite to proper management of patients. Cysteine proteases of Paragonimus westermani (PwCPs) invoke specific antibody responses against patient sera, while antibody capturing activity of different PwCPs has not been comparatively analyzed. In this study, we observed the expressional regulation of 11 species of different PwCPs (PwCP1 11). We expressed recombinant PwCPs and assessed diagnostic reliability employing sera from patients with P. westermani (n=138), other trematodiases (n=80), cestodiases (n=60) and pulmonary tuberculosis (n=20), and those of normal controls (n=20). PwCPs formed a monophyletic clade into cathepsin F and showed differential expression patterns along with developmental stages of worm. Bacterially expressed recombinant PwCPs (rPwCPs) exhibited variable sensitivity of 38.4-84.5% and specificity of 87.2-100% in diagnosing homologous infection. rPwCPs recognized specific antibodies of experimental cat sera as early as 3 or 6weeks after infection. Patient sera of fascioliasis, Schistosomiasis japonicum and clonorchiasis demonstrated weak cross-reactions. Our results demonstrate that diverse PwCPs of the cathepsin F family participate in inducing specific antibody responses. Most P. westermani cathepsin F, except for PwCP2 (AAF21461), which showed negligible antibody responses, might be applicable for paragonimiasis serodiagnosis. PMID- 25284815 TI - Abnormal behavior during influenza in Japan during the last seven seasons: 2006 2007 to 2012-2013. AB - A few mortalities and cases of severe abnormal behavior have been reported after oseltamivir administration for influenza, thus increasing medical and public concerns regarding the drug's safety. We investigated the association between oseltamivir and abnormal behavior for seven years. All outpatient clinics and hospitals all over the country were requested to report severe abnormal behavior that could have resulted in a fatality if nobody intervened, such as abrupt running outside the home or intention of jumping off a building. The survey was performed prospectively between the 2007-2008 and 2012-2013 seasons, and retrospectively for the 2006-2007 season. As the result of the investigation, eight-hundred fifty-eight cases were reported and among of them 95.7% were positive by the influenza rapid diagnosis test. The epidemic curve of severe abnormal behavior showed a pattern similar to influenza-like illness. The same pattern was observed regardless of age group, gender, or timing of the incidents after waking. Consequently, specific association between the types of medications used or the types of antiviral and abnormal behavior was not observed clearly. The reported abnormal behaviors include fatal cases that would have died if nobody had stopped. This suggested that patients with influenza should be observed with caution for possible abnormal behavior whether taking oseltamivir or other neuraminidase inhibitor anti-influenza drugs. PMID- 25284816 TI - Delayed presence of alternatively activated macrophages during a Francisella tularensis infection. AB - Francisella tularensis is an intracellular bacterium that has the ability to multiply within the macrophage. The phenotype of a macrophage can determine whether the infection is cleared or the host succumbs to disease. Previously published data has suggested that F. tularensis LVS actively induces the alternative phenotype as a survival mechanism. In these studies we demonstrate that this is not the case for the more virulent strain of F. tularensis SCHU-S4. During an intranasal mouse model of infection, immuno-histochemistry identified that iNOS positive ("classical") macrophages are present at 72 h post-infection and remain high (supported by CCL-5 release) in numbers. In contrast, arginase/FIZZ-1 positive ("alternative") cells appear later and in low numbers during the development of the disease tularemia. PMID- 25284817 TI - Copper-mediated/catalyzed oxyalkylation of alkenes with alkylnitriles. AB - A copper-promoted oxyalkylation of alkenes with alkylnitriles has been developed. The protocol provides rapid access to phthalides (gamma-lactones) or isochromanones (delta-lactones) via the formation of a C(sp(3) )?C(sp(3) ) and a C(sp(3) )?O bond with the generation of up to two quaternary carbon atoms. Mechanistic studies suggest that this reaction is initiated by the formation of the C(sp(3) )?C(sp(3) ) bond rather than the C(sp(3) )?O bond. Catalytic conditions were subsequently developed using carboxylic acid as an internal nucleophile. PMID- 25284818 TI - Galectin-1 dysregulation independently predicts disease specific survival in bladder urothelial carcinoma. AB - PURPOSE: Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. Our previous proteomics investigation demonstrated that galectin-1 is up-regulated in high compared to nonhigh grade lesions. Thus, in the current cohort study we clarified the correlation of galectin-1 over expression with various clinicopathological features and prognosis. MATERIALS AND METHODS: We selected 185 cases of consecutively treated primary localized bladder urothelial carcinoma for study. Transurethral resection of bladder tumor was performed in all patients followed by radical cystectomy in those with T2 to T4 tumors. Pathological slides were examined to determine cytoplasmic galectin-1 immuno-expression and correlate galectin-1 dysregulation with various clinicopathological factors and disease specific survival. RESULTS: Positive galectin-1 immuno-expression in tumors was significantly linked to pT status (p = 0.0295), histological grade (p = 0.037), vascular invasion (p = 0.0287) and nodal status (p = 0.0012). Galectin-1 over expression in tumors significantly predicted disease specific survival at the univariate (p = 0.0002) and multivariate levels (p = 0.03, HR 2.438, 95% CI 1.090-5.451). In situ hybridization indicated that the LGALS1 gene was amplified in 43 specimens in an independent cohort of 56 snap frozen tumor specimens. Association analysis showed that an increased LGALS1 mRNA level was linked to bladder urothelial carcinoma invasiveness (p = 0.016) and LGALS1 gene amplification was significantly associated the amount of GAL-1 protein in tumors (p <0.0001). On the univariate level gene amplification was also closely linked to disease specific survival (p = 0.0006). CONCLUSIONS: These results reveal that galectin-1 over expression is a possible independent factor for bladder cancer prognosis. PMID- 25284819 TI - [Goal directed fluid therapy controversies in non-cardiac surgery]. PMID- 25284820 TI - Efficient, dual-stimuli responsive cytosolic gene delivery using a RGD modified disulfide-linked polyethylenimine functionalized gold nanorod. AB - Controlled-release systems capable of responding to external stimuli and/or unique internal environments have received great interests in site-specific gene and/or drug delivery. In this work, a functionalized gene nanocarrier for dual stimuli triggered cytosolic gene delivery is developed and showing high gene delivery efficacy with low cytotoxicity. The nanocarrier is prepared by conjugating gold nanorod (GNR) with multiple disulfide cross-linked short PEIs to harness the advantageous properties of GNR based near infrared (NIR) laser induced photothermal heating and intracellular stimuli-triggered degradability of disulfide cross-linked short PEIs (DSPEI). The DSPEI is further grafted with a poly(ethylene glycol) (PEG) section to afford high carrier stability in cell cultures and a terminal RGD peptide for specific targeting of cancer cells. The nanocarrier is found to effectively condense plasmid DNA to form a highly stable GNR-DSPEI-PEG-RGD/DNA complex with tumor cell-targeting ability that can be efficiently uptaken by cancer cells. Moreover, the loaded genes can be effectively released from the complex triggered by the high intracellular glutathione content and/or by photothermal effect of NIR irradiation at 808 nm. Interestingly, the GNRs-based complex can easily escape from intracellular endo /lyso-somal compartments and release the gene load into the cytosol upon exposure to NIR irradiation, resulting in significantly improved gene transfection efficiency. Our new gene carrier exhibits high gene transfection efficiency, comparable to or even better than that of high MW PEIs, but with a much lower cytotoxicity. Additionally, neither the GNR-based carrier nor the laser treatment shows any significant evidence of cytotoxicity. This work demonstrates a promising strategy for intracellular stimuli triggered, photothermal controllable gene delivery system, which can be further applied to many other nanomedicine fields. PMID- 25284821 TI - Abstractions for Genomics. PMID- 25284823 TI - Hadamard's Determinant Inequality. AB - This note is devoted to a short, but elementary, proof of Hadamard's determinant inequality. PMID- 25284822 TI - New Partners, More Kids: Multiple-Partner Fertility in the United States. AB - Declining rates of marriage and overall increases in union instability, combined with high levels of unintended and nonmarital fertility, create the possibility for parents to have children with more than one partner, called multiple-partner fertility, or MPF. The unique characteristics of families with MPF present data and other logistical challenges to researchers studying the phenomenon. Drawing from recent studies and updated data, I present new estimates of MPF that show that about 13 percent of men aged 40 to 44 and 19 percent of women aged 41 to 49 have children with more than one partner, with a higher prevalence among the disadvantaged. Compared to parents with two or more children by only one partner, people with MPF become parents at younger ages, largely with unintended first births, and often do so outside of marriage. This article touches on the implications of MPF for families and concludes by discussing the theoretical difficulties in studying MPF and the challenges it presents to public policy. PMID- 25284824 TI - Relative Dispersion: A Characterizing Feature of Specific Vascular Beds. PMID- 25284825 TI - Modeling the Complex Dynamics and Changing Correlations of Epileptic Events. AB - Patients with epilepsy can manifest short, sub-clinical epileptic "bursts" in addition to full-blown clinical seizures. We believe the relationship between these two classes of events-something not previously studied quantitatively-could yield important insights into the nature and intrinsic dynamics of seizures. A goal of our work is to parse these complex epileptic events into distinct dynamic regimes. A challenge posed by the intracranial EEG (iEEG) data we study is the fact that the number and placement of electrodes can vary between patients. We develop a Bayesian nonparametric Markov switching process that allows for (i) shared dynamic regimes between a variable number of channels, (ii) asynchronous regime-switching, and (iii) an unknown dictionary of dynamic regimes. We encode a sparse and changing set of dependencies between the channels using a Markov switching Gaussian graphical model for the innovations process driving the channel dynamics and demonstrate the importance of this model in parsing and out of-sample predictions of iEEG data. We show that our model produces intuitive state assignments that can help automate clinical analysis of seizures and enable the comparison of sub-clinical bursts and full clinical seizures. PMID- 25284826 TI - A biomolecular electrostatics solver using Python, GPUs and boundary elements that can handle solvent-filled cavities and Stern layers. AB - The continuum theory applied to biomolecular electrostatics leads to an implicit solvent model governed by the Poisson-Boltzmann equation. Solvers relying on a boundary integral representation typically do not consider features like solvent filled cavities or ion-exclusion (Stern) layers, due to the added difficulty of treating multiple boundary surfaces. This has hindered meaningful comparisons with volume-based methods, and the effects on accuracy of including these features has remained unknown. This work presents a solver called PyGBe that uses a boundary-element formulation and can handle multiple interacting surfaces. It was used to study the effects of solvent-filled cavities and Stern layers on the accuracy of calculating solvation energy and binding energy of proteins, using the well-known apbs finite-difference code for comparison. The results suggest that if required accuracy for an application allows errors larger than about 2% in solvation energy, then the simpler, single-surface model can be used. When calculating binding energies, the need for a multi-surface model is problem dependent, becoming more critical when ligand and receptor are of comparable size. Comparing with the apbs solver, the boundary-element solver is faster when the accuracy requirements are higher. The cross-over point for the PyGBe code is in the order of 1-2% error, when running on one gpu card (nvidia Tesla C2075), compared with apbs running on six Intel Xeon cpu cores. PyGBe achieves algorithmic acceleration of the boundary element method using a treecode, and hardware acceleration using gpus via PyCuda from a user-visible code that is all Python. The code is open-source under MIT license. PMID- 25284827 TI - Household Task Delegation among High-Fertility Forager-Horticulturalists of Lowland Bolivia. AB - Human kin cooperation is universal, leading researchers to label humans as "cooperative breeders." Despite widespread interest in human cooperation, there has been no systematic study of how household economic decision making occurs. We document age and sex profiles of task delegation by parents to children ages 4-18 among Bolivian forager-horticulturalists. We test for sex differences in the probability of delegation and examine whether tasks are more likely delegated as household labor demand increases. We also test whether food acquisition tasks are more likely delegated to higher producers. We find mixed support for the prediction that girls are more likely delegated domestic and alloparenting tasks than boys (n = 173 children). Both sexes are more likely delegated tasks during rice harvest months; number of coresident young children is also associated with greater probability of delegated allocare, although the effect retains significance for girls only. For both sexes, father absence is associated with greater probability of delegation, particularly for food acquisition tasks. Children delegated rice harvesting achieve 45% higher mean daily caloric returns from harvesting than children not delegated harvesting. Our results therefore suggest that delegation increases household economic efficiency. We find mixed support for the hypothesis that delegation prepares children for sex-specific adult roles. PMID- 25284828 TI - Treatment of Esophageal and Hypopharyngeal Squamous Cell Carcinoma. PMID- 25284829 TI - Single-Incision Slings (SIS) - a New Option for the Surgical Treatment of Female Stress Urinary Incontinence. AB - The new development of single-incision slings (SIS) for the treatment of female stress urinary incontinence offers comparable results with only minimal side effects and will find wide acceptance in modern incontinence surgery. This mini sling is inserted over a single vaginal incision and fixed on both sides to the pelvic wall tissue with special anchors, without passing through the groin and avoiding a blind tape passage. Compared with the established sub-urethral tapes, there are comparable success rates with fewer complications. Randomised prospective studies are needed to evaluate whether, in the long run, the benefits of the single incision technique can be correlated with satisfying continence results. PMID- 25284830 TI - The Patients' View On Accredited Breast Cancer Centers: Strengths and Potential for Improvement. AB - Breast Care Centers that were accredited according to the German Cancer Society criteria were offered to participate in a standardized patient survey in 2010, which was conducted by the Institute for Medical Sociology, Health Services Research and Rehabilitation Science, Faculty of Human Science and Faculty of Medicine, University of Cologne. Patients were included consecutively between March and November 2010. The Cologne Patient Questionnaire-Breast Cancer (CPQ-BC) was used, which assesses a number of aspects of hospital care as perceived by the patients, among them provider-patient interaction, the disease-specific information provided, the quality of organization, and room amenities. 128 of 195 Breast Care Centers and 160 of 251 hospitals participated in the study. 8226 patients consented to the survey. The questionnaires of 7301 patients could be included in the analyses (89 %). Overall, the results showed that patients are satisfied with their hospital stay and that the accreditation criteria are implemented in a way that serves the patients. However, there is room for improvement for a number of issues, for example with regard to the provision of information and patient involvement in decision making. In addition, for a number of indicators substantial differences were found between the hospitals. The results of the survey provide information on the breast centers' development and can be used by the centers' surgery locations for benchmarking purposes, to identify strengths and weaknesses, and to take actions. PMID- 25284831 TI - Accuracy of Fetal Weight Estimation in Women with Diet Controlled Gestational Diabetes. AB - Purpose: To evaluate whether ultrasound accuracy of estimated fetal weight (EFW) differs in women with diet controlled gestational diabetes mellitus (GDM) compared to nondiabetic pregnant women. Material and Methods: We included 363 patients, 121 patients with diet controlled GDM and 242 patients with a normal oral glucose tolerance test (oGTT). Each case of diet controlled GDM was matched with 2 unaffected controls. All patients were screened/diagnosed for GDM by means of an oGTT. Both groups received ultrasound examination including fetal biometry, using Hadlock's Formula, within 7 days to delivery. After birth, gestational age, birthweight and Apgar scores were collected from each newborn. Results: There was a good correlation between EFW and birth weight (coefficient = 0.747, p < 0.001 by Pearson correlation, even after adjustment for glucose status). Regression analyses, including noGDM/GDM, maternal age, maternal body mass index, birth weight and time interval between ultrasound and delivery revealed that only fetal birth weight significantly influences weight difference between ultrasound EFW and actual birth weight at term. Conclusion: Our data suggests that ultrasound accuracy of EFW using Hadlock's Formula at term does not differ in women with diet controlled GDM compared to women with normal glucose tolerance. PMID- 25284832 TI - Serum Folate and Cobalamin Levels in Women Using Combined Contraceptive Vaginal Ring. AB - Purpose: The aim of our study was to evaluate the effects of combined contraceptive vaginal rings on serum concentrations of folate and cobalamin in healthy users. Material and Methods: Case-control study on cobalamin and folate status of 45 healthy female nulligravidae using a combined contraceptive vaginal ring for > 3 months and 45 healthy controls. Factors interfering with vitamin metabolism were thoroughly controlled. Results: Cobalamin and folate levels did not differ between the groups. Vegetarian diet, smoking or obesity did not have a significant influence. Conclusions: The use of a combined contraceptive vaginal ring provides an appropriate hormonal contraception in women with pre-existing cobalamin deficiency or restrictive diet habit in order to avoid interferences between vitamin B12 metabolism and exogenously applied estrogens. PMID- 25284833 TI - The Danger of Time-Consuming Operative Laparoscopies: Avoiding Severe Complications. PMID- 25284834 TI - Axillary Dissection in the Case of Positive Sentinel Lymph Nodes: Results of the Innsbruck Consensus Conference. AB - The prognosis of breast cancer is most heavily influenced by the status of the axillary nodes. Until a few years ago, this knowledge was gained through radical axillary lymph node clearance. In the meantime, sentinel lymph node clearance has become an established part of the surgical treatment of breast cancer. With the development of this procedure, the morbidity caused by axillary dissection has been reduced significantly. Although comprehensive prospective, randomised data regarding the safe use of the sentinel concept are only now available, the focus currently, however, is on the question of whether in the case of positive sentinel lymph nodes, an axillary dissection can be done away with altogether without having any negative impact on the risk of loco-regional recurrence or on progression-free survival and overall survival. The results of the American ACOSOG-Z001 study have changed the fundamental perspective of this. In this study on the advantages of axillary dissection following the confirmation of tumour tissue in the sentinel lymph nodes, there were no statistically significant advantages from axillary dissection for women with a favourable overall risk profile who had received radiotherapy and systemic therapy. If this concept takes hold, the surgical treatment of node-positive breast cancer, at least in the axilla, would be reduced to a minimum, and the focus of treatment would in future lie more on the systemic treatment of this condition. As part of an interdisciplinary consensus meeting, a standardised approach for Austria with regard to this question was decided upon. PMID- 25284836 TI - Differences in the Incidence of Gestational Diabetes between Women of Turkish and German Origin: An Analysis of Health Insurance Data From a Statutory Health Insurance in Berlin, Germany (AOK), 2005-2007. AB - Background: Gestational diabetes increases the risk of maternal and infant complications and long-term health effects. A study of differences in the incidence of gestational diabetes between women of Turkish and German origin can identify high risk groups and may indicate the need for culturally sensitive diabetes information and treatment during pregnancy. Method: We analysed all pregnancy related health insurance data from the AOK Berlin (a statutory health insurance in Berlin) based on data from 2005 to 2007, using a name algorithm to identify cases with Turkish migrant background. A group of German women insured with the AOK Berlin served as a comparison group. Results: After exclusion of miscarriages and multiple births the data set comprised 3338 pregnancies in total. The incidence of gestational diabetes was significantly higher in women of Turkish origin with 183 per 1000 pregnancies than in German women (138 per 1000 pregnancies). Regression analyses showed that women of Turkish origin with obesity were at the highest risk of gestational diabetes (OR = 2.67; 95 % confidence interval 1.97-3.60). Conclusion: Obesity is an important factor in explaining the higher incidence of gestational diabetes in women of Turkish origin, especially among young Turkish women. These findings should stimulate discussion as to whether or not information about risk factors such as diabetes within the scope of prenatal care adequately addresses the needs of migrant women. Further research is needed to identify potential differences in undetected and primarily in insufficiently treated gestational diabetes between Turkish and German women. PMID- 25284835 TI - Is Patient Education About Adhesions a Requirement in Abdominopelvic Surgery? AB - Background: Over the past decades, our knowledge and understanding of adhesions and adhesion-related complications has increasingly grown and it has become evident that adhesions have significant implications for patients, physicians and the healthcare system. The question arises whether this has resulted in greater awareness of adhesion-related problems among practicing physicians and appropriate patient education on this topic in daily practice. The following article provides a brief overview of the important subject of adhesions, discusses current awareness of adhesions among patients and doctors and addresses the consequences of failure to provide patient education and consent from a medical perspective. Methods: Selective literature searches were conducted in PubMed and the Cochrane Library. A patient information and consent form was developed based on several years' experience and expertise in the field of adhesions. Results: Adhesions are the most common type of complication in abdominopelvic surgery today, with devastating consequences for some patients. Surveys investigating the awareness of adhesions among physicians and patients clearly showed that even well-informed physicians fail to educate their patients adequately. Such failure could potentially lead to successful medical malpractice lawsuits against doctors. Conclusion: Considering their clear clinical impact, adhesions and related consequences should always be discussed with patients preoperatively. A newly developed consent form that specifically addresses adhesion formation may serve to thoroughly educate patients preoperatively and to adequately document the process of doing so. PMID- 25284837 TI - Prevalence, Trend and Determining Factors of Gestational Diabetes in Germany. AB - Purpose: The true prevalence of gestational diabetes in Germany is unknown. Thus, the study's purposes were to estimate the prevalence of gestational diabetes as well as to describe the temporal prevalence trend and to identify determinants. Material and Methods: We calculated prevalence estimates based on two datasets: the register-based German perinatal statistic (n = 650 232) and the maternal self reports from the German children and youth health survey (KiGGS; n = 15 429). Differences between prevalence estimates were analysed using chi2 and trend tests, and determinants were identified using logistic regression. Results: According to the perinatal statistic, gestational diabetes was present in 3.7 % of pregnant women in Germany in 2010. The prevalence across the years 2001 to 2006 was estimated at 1.9 % which differed significantly from the prevalence estimate derived from the KiGGS dataset for the same period of time (5.3 %; 95 % confidence interval: 4.6-6.1 %). Both datasets show an increasing trend of gestational diabetes (p < 0.001). The risk for gestational diabetes was mainly associated with age, BMI and social class of pregnant women as well as with multiple pregnancies. Conclusion: The lack of significant screening studies among representative samples hampers a sound estimation of the true prevalence of gestational diabetes in Germany. The increasing trend in gestational diabetes might continue due to the projected increase of important risk factors (e.g., maternal age, obesity). Our analyses support the current consensus recommendations regarding standardised gestational diabetes screening. PMID- 25284839 TI - Pathophysiology of Bone Remodelling and Current Therapeutic Approaches. AB - Different metabolic bone parameters such as RANK (receptor activator of nuclear factor-kappaB), RANK ligand (receptor activator of nuclear factor-kappaB ligand) and OPG (osteoprotegerin) control physiological bone remodelling. The pathophysiology of these factors in bone diseases and osseous metastases is becoming clearer. In metastatic breast cancer, osteolytic bone metastases are the result of increased osteoclastic activity caused either by increased RANK ligand or decreased OPG expression of metastatic osseous tumour cells. These findings may lead to new therapeutic options for the treatment of breast cancer patients. The aim of this work is to provide an overview of physiological bone remodelling and of the interaction between tumour cells and bone environment. Current therapy approaches and the mechanisms of action of drugs are described. PMID- 25284838 TI - Change of Spectral Analysis of Fetal Heart Rate During Clinical Hypnosis: a Prospective Randomised Trial from the 20th Week of Gestation Till Term. AB - Objective: To investigate the functional adaptive process of the fetal autonomic nervous system during hypnosis from the 20th week of gestation till term. Are there changes in the power spectrum analysis of fetal heart rate when the mother is having a clinical hypnosis or control period? Study Design: Fourty-nine FHR recordings were analysed. Included recordings were from singletons and abdominal fetal ECG-monitored pregnancies. All women were randomised to receive clinical hypnosis followed by a period with no intervention or vice versa. Statistical analyses were performed with the Wilcoxon signed ranks and Spearman rho correlation tests. Results: There was a significant difference found between fetal heart rate at baseline (144.3 +/- 6.0) and hypnosis (142.1 +/- 6.4). A difference was also detected between the standard deviation of the heart rate between baseline (6.7 +/- 1.9) and hypnosis (6.8 +/- 3.5). LFnu was smaller during baseline (80.2 +/- 5.3) than during hypnosis (82.1 +/- 5.7), whereas HFnu was significantly larger (19.8 +/- 5.3 vs. 17.9 +/- 5.7). There was no correlation between the gestation age and the change in LFnu, HFnu or ratio LF/HF due to the hypnosis intervention. Conclusion: The functional adaptive process of the fetal autonomic system during hypnosis is reflected by a sympathovagal shift towards increased sympathetic modulation. PMID- 25284840 TI - Epidemiological Follow-up 15 Years after the Breast Cancer Scandal in Essen. AB - Purpose: In the years 1993-1996 a number of presumably false-positive breast cancer diagnoses were made by a pathologist in Essen. A follow-up, undertaken 15 years later, investigated how many women had tumour recurrence and/or metastasis or had died from breast cancer. Material and Methods: A total of 151 (68 %) out of 222 women could be traced. One hundred and forty-seven (66.2 %) of the 222 women were alive. The observed survival rate, number of recurrences and/or metastases, and number of deaths from breast cancer were compared with data from the Munich Tumour Registry. The number of breast cancer cases among daughters of the affected women was ascertained. Results: The total observed survival rate at follow-up after 15 years was 93 %, a much higher figure than the survival rate of 45 % given by the Munich Tumour Registry. Recurrence and/or metastasis or death from breast cancer occurred in 9/222 cases (4.1 %). The incidence for these events calculated according to data from the Munich Tumour Registry is 13 %. Two daughters (2.2 %) out of a total of 90 were diagnosed with breast cancer whereas, according to the German Cancer Research Centre, the expected rate would have been between 5 and 10 %. Conclusions: The results of our follow-up after 15 years show that more women survived than expected and that the number of recurrences and/or metastases and deaths due to breast cancer was lower than expected. Fewer daughters of affected women were diagnosed with breast cancer than expected. These results support our suspicion that not all women diagnosed with breast cancer by a pathologist in Essen actually had breast cancer. PMID- 25284841 TI - Impact of Phytoestrogens on Serum Lipids in Postmenopausal Women. AB - Objectives: The aim of the study was to assess the impact of soy- and red clover derived isoflavones on serum lipid levels in postmenopausal women and to compare the effects to the lipid levels of healthy postmenopausal women without phytoestrogen supplementation. Materials and Methods: Blood levels of triglycerides, total cholesterol and cholesterol fractions were assessed. Measurements were performed before treatment and at 6-month intervals over a period of 18 months. The investigation included 74 healthy postmenopausal women randomized into three groups according to treatment. The first group of 23 patients received soy-derived isoflavones, the second group (26 patients) was given red clover-derived phytoestrogens, while the third control group (25 patients) received no supplements. Results: Mean triglyceride, cholesterol and LDL levels of patients in the control group were significantly higher than in both the soy and the red clover groups (p < 0.001) at all three time points, while mean values did not differ significantly between the soy and the red clover groups. The mean HDL levels of patients in the control group was significantly lower than in both the soy and the red clover groups (p < 0.001). Conclusions: Phytoestrogen supplementation had a positive metabolic effect on serum lipid levels in postmenopausal women. The impact on serum lipids levels was similar for soy and red clover. PMID- 25284842 TI - Preoperative Uterine Artery Embolisation for Large Uterine Fibroids with Subsequent Uterus Preservation - Three Case Histories and Review of the Literature. AB - Uterine artery embolisation (UAE) is an established procedure to treat uterine fibroids as an alternative to surgery. The combination of both approaches is reserved for only a few cases. A preoperative UAE (PUAE) contributes to reducing bleeding complications and helps preserve the uterus. We report here on 3 patients, each with very large fibroid (all > 1100 g), who were successfully treated by interdisciplinary hybrid intervention (embolisation followed by surgery). Preserving the uterus was a "sine qua non" for all 3 patients. As discussed in some articles, PUAE should be considered when treating patients who wish to preserve their uterus at all costs but who are considered preoperatively to be at increased risk of bleeding and/or patients who are considered to be at high risk of requiring a hysterectomy "for technical reasons". The additional costs of embolisation can be set against the potentially shorter hospitalisation times due to the more favourable intraoperative and postoperative course, the savings arising from the reduced need for blood transfusions, and the greater patient satisfaction. PMID- 25284843 TI - Supervisor Work/Life Training Gets Results. PMID- 25284844 TI - Breast self-examination beliefs and practices, ethnicity, and health literacy: Implications for health education to reduce disparities. AB - OBJECTIVE: This study aimed to quantitatively and qualitatively examine breast cancer screening practices, including breast self-examination (BSE), and health literacy among patients with chronic disease. DESIGN: A prospective, multi-method study conducted with a targeted purposive sample of 297 patients with diabetes and/or hypertension from four ethnic groups (Latino, Vietnamese, African American, White-American) at an urban community health center. SETTING: A federally qualified health center in Western Massachusetts. METHODS: In our four year study, 297 participants completed cancer knowledge, beliefs, attitudes and screening utilization scales and measures of health literacy. In addition to survey data collection, we conducted in-depth interviews, focus groups, home visits, and chronic disease diaries (n=71). RESULTS: In focus groups, African American, Vietnamese and Latina participants offered interviewers an unprompted demonstration of BSE, reported regular BSE use at particular times of the month, and shared positive feelings about the screening method. In a sample where approximately 93% of women have had a mammogram, many also had performed BSE (85.2%). Women with adequate health literacy were more likely than those with inadequate health literacy to rely on it. Despite being positively inclined toward BSE, Vietnamese women, who had the lowest health literacy scores in our sample, were less likely to perform BSE regularly. CONCLUSIONS: BSE seemed to be an appealing self-care practice for many women in our study, but we conclude that proper BSE practices may not be reinforced equally across ethnic groups and among patients with low health literacy. PMID- 25284846 TI - Evaluation of pH of Bathing Soaps and Shampoos for Skin and Hair Care. AB - BACKGROUND: Normal healthy skin has potential of hydrogen (pH) range of 5.4-5.9 and a normal bacterial flora. Use of soap with high pH causes an increase in skin pH, which in turn causes an increase in dehydrative effect, irritability and alteration in bacterial flora. The majority of soaps and shampoos available in the market do not disclose their pH. AIMS AND OBJECTIVES: The aim of this study was to assess the pH of different brands of bathing soaps and shampoos available in the market. MATERIALS AND METHODS: The samples of soaps and shampoos were collected from shops in the locality. The samples of different brands are coded before the analysis of the pH. Solution of each sample was made and pH was measured using pH meter. RESULTS: Majority of the soaps have a pH within the range of 9-10. Majority of the shampoos have a pH within the range of 6-7. CONCLUSIONS: The soaps and shampoos commonly used by the population at large have a pH outside the range of normal skin and hair pH values. Therefore, it is hoped that before recommending soap to patient especially those who have sensitive and acne prone skin, due consideration is given to the pH factor and also that manufacturers will give a thought to pH of soaps and shampoos manufactured by them, so that their products will be more skin and hair friendly. PMID- 25284847 TI - Analysis of food allergy in atopic dermatitis patients - association with concomitant allergic diseases. AB - BACKGROUND: A few reports demonstrate the comorbidity of food allergy and allergic march in adult patients. AIMS AND OBJECTIVES: To evaluate, if there is some relation in atopic dermatitis patients at the age 14 years and older who suffer from food allergy to common food allergens to other allergic diseases and parameters as bronchial asthma, allergic rhinitis, duration of atopic dermatitis, family history and onset of atopic dermatitis. MATERIALS AND METHODS: Complete dermatological and allergological examination was performed; these parameters were examined: food allergy (to wheat flour, cow milk, egg, peanuts and soy), the occurrence of bronchial asthma, allergic rhinitis, duration of atopic dermatitis, family history and onset of atopic dermatitis. The statistical evaluation of the relations among individual parameters monitored was performed. RESULTS: Food allergy was altogether confirmed in 65 patients (29%) and these patients suffer significantly more often from bronchial asthma and allergic rhinitis. Persistent atopic dermatitis lesions and positive data in family history about atopy are recorded significantly more often in patients with confirmed food allergy to examined foods as well. On the other hand, the onset of atopic dermatitis under 5 year of age is not recorded significantly more often in patients suffering from allergy to examined foods. CONCLUSION: Atopic dermatitis patients suffering from food allergy suffer significantly more often from allergic rhinitis, bronchial asthma, persistent eczematous lesions and have positive data about atopy in their family history. PMID- 25284848 TI - Topical corticosteroid misuse: the Indian scenario. AB - Topical corticosteroids (TC) have been available for more than six decades during which they have completely changed the face of therapy of dermatological disorders. Despite being the most useful drug for such treatment they are known to produce serious local, systemic and psychological side-effects when overused or misused. Though the drug has been misused sporadically earlier, the menace has become more acute during the last two decades. In India, damaging effects to the human body particularly the skin have been reported regularly during the last decade. The misuse occurs at various levels such as manufacturing, marketing, prescription, sales and end-use by patients and laymen. During the last decade dermatologists in India have been regularly campaigning against such misuse. However, the menace keeps on increasing alarmingly. The need to accelerate the momentum of the campaign against TC misuse has been increasingly felt by dermatologists all over India. This symposium aims to contribute significantly to the campaign against misuse of TC. PMID- 25284849 TI - Topical steroid-damaged skin. AB - Topical steroids, commonly used for a wide range of skin disorders, are associated with side effects both systemic and cutaneous. This article aims at bringing awareness among practitioners, about the cutaneous side effects of easily available, over the counter, topical steroids. This makes it important for us as dermatologists to weigh the usefulness of topical steroids versus their side effects, and to make an informed decision regarding their use in each individual based on other factors such as age, site involved and type of skin disorder. PMID- 25284850 TI - Systemic side-effects of topical corticosteroids. AB - With the introduction of topical corticosteroids, a milestone has been achieved in dermatologic therapy; owing to its potent anti-inflammatory and ant proliferative effects, it became possible to treat some hitherto resistant dermatoses. But this magic drug can cause enough mischief if used inappropriately. Children are more susceptible to the systemic adverse effects because of enhanced percutaneous absorption through their tender skin. So, systemic side effects should be kept in mind while prescribing this therapeutically valuable topical medicament. PMID- 25284851 TI - Topical corticosteroid addiction and phobia. AB - Corticosteroids, one of the most widely prescribed topical drugs, have been used for about six decades till date. However, rampant misuse and abuse down the years has given the drug a bad name. Topical steroid abuse may lead to two major problems which lie at the opposing ends of the psychosomatic spectrum. Topical steroid addiction, a phenomenon that came to be recognized about a decade after the introduction of the molecule is manifested as psychological distress and rebound phenomenon on stoppage of the drug. The rebound phenomenon, which can affect various parts of the body particularly the face and the genitalia has been reported by various names in the literature. TC phobia which lies at the opposite end of the psychiatric spectrum of steroid abuse has been reported particularly among parents of atopic children. Management of both conditions is difficult and frustrating. Psychological counseling and support can be of immense help in both the conditions. PMID- 25284845 TI - Biologics in dermatology: an integrated review. AB - The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use. It is therefore imperative to succinctly comprehend their pharmacokinetics for their apt use. A concerted endeavor has been made to delve on this subject. The major groups of biologics have been covered and include: Drugs acting against TNF-alpha, Alefacept, Ustekinumab, Rituximab, IVIG and Omalizumab. The relevant pharmacokinetic characteristics have been detailed. Their respective label (approved) and off-label (unapproved) indications have been defined, highlighting their dosage protocol, availability and mode of administration. The evidence level of each indication has also been discussed to apprise the clinician of their current and prospective uses. Individual anti-TNF drugs are not identical in their actions and often one is superior to the other in a particular disease. Hence, the section on anti-TNF agents mentions the literature on each drug separately, and not as a group. The limitations for their use have also been clearly brought out. PMID- 25284852 TI - Ethical use of topical corticosteroids. AB - Dermatologists rely very heavily on corticosteroids for treating many common dermatoses. Concerns about their incorrect use are widely expressed both in lay public and specialist discourse. From the point of view of medical ethics, issues of autonomy, beneficence and non-maleficence are all raised frequently when we prescribe topical corticosteroids to our patients. We need to be aware of situations when conflicts between these issues arise and have a clear thought process about resolving them. This can only be achieved if we have a thorough understanding of the skin disease being treated coupled with expertise in the use of the varied potencies and available dosage forms of topical corticosteroids. A good understanding of human psychology and effective communication is also needed to use these agents optimally. PMID- 25284853 TI - Development of a guideline to approach plagiarism in Indian scenario. PMID- 25284854 TI - The First Report of KRT5 Mutation Underlying Acantholytic Dowling-Degos Disease with Mottled Hypopigmentation in an Indian Family. AB - Galli Galli disease (GGD) is the name given to a rare form of acantholytic Dowling-Degos disease. (DDD), the latter itself being a rare condition. We believe we are describing for the first time in Indian dermatologic literature a case of GGD in a family where 25 persons have DDD and have been able to document a KRT5 mutation in four members of the family. Whereas reticulate pigmentation is a hallmark of DDD there are rare reports of mottled pigmentation with multiple asymptomatic hypopigmented macules scattered diffusely along with the pigmentation. All the cases described here show a mottled pigmentation comprising hypo and hyperpigmented asymptomatic macules. After the clinical diagnosis was made by one of the authors (SV) in India, the German authors repeated histological examination and successfully demonstrated a heterozygous nonsense mutation, c.C10T (p.Gln4X), in exon 1 of the KRT5 gene, from various centers in Munich, Bonn, Dusseldorf and Friedrichschafen in Germany. PMID- 25284855 TI - Giant cells in dermatology. PMID- 25284856 TI - Efficacy of targeted narrowband ultraviolet B therapy in vitiligo. AB - BACKGROUND: Phototherapy is one of the most effective treatment options in vitiligo. Targeted phototherapy devices are becoming more popular as they offer a lot of advantages over the conventional whole-body phototherapy units. AIMS AND OBJECTIVES: The present study was conducted to assess the efficacy and safety of a targeted narrowband ultraviolet B (NBUVB) device in vitiligo. MATERIALS AND METHODS: A total of 40 patients of vitiligo were treated with a targeted NBUVB device twice-weekly for a maximum of 30 sessions or until 100% repigmentation, whichever was reached first. The extent of repigmentation achieved was assessed and adverse effects, if any, were also noted down. RESULTS: There were 31 responders (77.5%) who achieved repigmentation ranging from 50% to 100%. The onset of repigmentation was seen as early as the 3(rd) dose in some cases and by the 10(th) dose in all responders. A total of 97 lesions were treated out of which 45 lesions (46.6%) achieved 90-100% repigmentation. Lesions showing 75% and 50% repigmentation were 14 and 15 in number respectively. 23 lesions failed to show any significant repigmentation at the end of 30 doses. Best response was seen on the face and neck with 20 of the 31 lesions achieving 90-100% repigmentation in this area. Duration of vitiligo was seen to have no statistically significant impact on the repigmentation achieved. CONCLUSION: Targeted NBUVB phototherapy seems to be an effective treatment option in localized vitiligo with a rapid onset of repigmentation seen as early as 2(nd) week of treatment. PMID- 25284857 TI - Epidermal inclusion cyst embedded in a recurrent benign fibrous histiocytoma. AB - Epidermal infundibular cysts have been known to arise from implantation of epidermis in the dermis or subcutaneous tissues. The present case illustrates the theory of implantation in an epidermal inclusion cyst in a previously operated case of recurrent benign fibrous histiocytoma. PMID- 25284858 TI - A case of disseminated superficial porokeratosis associated with giant porokeratosis in pregnancy. AB - A 23-year-old pregnant lady presented with dark raised lesions over face, axillae, and upper limbs of 15-day duration. She was 35 weeks pregnant at the time of onset of the lesions. Dermatological examination revealed hyperpigmented plaques on the face and papules with raised borders in the axillae and proximal arms. Skin biopsy from both the lesions revealed a diagnosis of porokeratosis. She was treated with emollients alone and the lesions regressed four weeks following delivery. This case is being reported for the rare occurrence of the combination of disseminated superficial porokeratosis with giant porokeratosis in pregnancy. PMID- 25284859 TI - Extensive Infection of Face by Mycobacterium chelonae: An Unusual Presentation. AB - Mycobacterium chelonae is a rapidly growing mycobacteria, causes cutaneous, soft tissue, and rarely lung infections. Here we present a rare case of extensive infection of face at multiple sites by Mycobacterium chelonae, with an unusual presentation, diagnosed by using conventional methods. PMID- 25284860 TI - Lymphocytic thrombophilic arteritis: an enigma. AB - A 55-year-old woman presented with a 5-year history of livedo racemosa on her limbs. Histology showed vasculitis of medium-sized arteries with a circumferential, hyalinised, intraluminal fibrin ring. Her laboratory investigations did not indicate any underlying systemic disease. The findings were consistent with lymphocytic thrombophilic arteritis (LTA), alias macular arteritis, which is a recently described entity. The importance of LTA lies in the fact that it is a close clinical and microscopic mimic of polyarteritis nodosa (PAN). LTA is believed to be a distinct entity by some and as a form of PAN by others. We have discussed this case in our report. PMID- 25284861 TI - Multiple carboxylase deficiency (late onset) due to deficiency of biotinidase. AB - Biotinidase is a ubiquitous mammalian cell enzyme occurring in liver, serum and kidney. It cleaves biotin from biocytin, which is a cofactor for biotin dependent enzymes, namely the human carboxylases. Biotinidase deficiency is associated with a wide spectrum of neurological, dermatological, immunological and ophthalmological abnormalities. This is a case of a 3-year-old boy presenting with delayed developmental milestones, tachypnea, progressively increasing ataxia, alopecia and dermatitis, all which dramatically responded to high doses of biotin. PMID- 25284862 TI - Psoriasis sparing the polio-affected limb: is it merely the koebner phenomenon? AB - Psoriasis being a common skin condition, atypical forms and unusual localizations of this disease are quite frequently seen. However, psoriasis sparing a polio affected limb is extremely rare. We report a case of an adult male, who presented with psoriasis distributed all over the body but with almost complete sparing of the polio-affected left lower limb. PMID- 25284863 TI - Chondroid syringoma of the forearm: a case report of a rare localization. AB - Chondroid syringoma (CS) is an uncommon benign adnexal tumor of the skin with eccrine and apocrine origin, which usually involves the head and neck region. The presentation of CS in other areas of the body is rare. A 45-year-old male patient presented to the dermatology clinic with a chief complaint of a painless, slow growing mass on his left forearm, which gradually developed over the course of 2 years. A solitary, firm, purple, mobile, non-tender nodule was located in the distal part of left dorsal forearm, which was 1.8 cm in diameter. The tumor was surgically excised and sent for the histopathological evaluation. Results of biopsy and hematoxylin and eosin staining confirmed the diagnosis of CS and showed no evidence of malignancy. Although CS is an uncommon tumor in uppr limb region, it should be considered as one of the differential diagnoses, when dealing with tumors of this area. PMID- 25284864 TI - Epitheloid hemangioma: a report of two cases. AB - We report two cases of epitheloid hemangioma presented with multiple nodular lesions over head and neck region. One of them gave history of bleeding on minor trauma. Pyogenic granuloma was considered as a differential diagnosis from the morphological appearance and history of bleeding. Nodular leprosy, sarcoidosis, and secondary syphilis were also considered. Histopathological examination of both was typical of epitheloid hemangioma, an entity commonly overlooked clinically due to its rarity. PMID- 25284865 TI - Eccrine spiradenoma in knee. AB - Eccrine spiradenoma is an uncommon benign adnexal tumor of the eccrine sweat glands. Although it can occur at any age, it is most common in young adults without any sex predilection. Malignant transformation is rare, presenting as rapid increase in size of a long-standing lesion. Here, we report a case of eccrine spiradenoma in a 35-year-old man who presented with swelling over the right knee, with cytological atypia but no recurrence until date. PMID- 25284866 TI - Severity of Psoriasis Among Adult Males is Associated with Smoking, Not with Alcohol Use. PMID- 25284867 TI - Authors' reply. PMID- 25284868 TI - Hypersensitivity with ayurvedic oils under inappropriate use. PMID- 25284869 TI - Author's Reply. PMID- 25284870 TI - Chronic expanding hematoma showing fluid-fluid level. PMID- 25284871 TI - Phenytoin induced pellagroid dermatitis. PMID- 25284872 TI - Sebaceoma of the conjunctiva presenting as a chalazion. PMID- 25284873 TI - Addition of cyclosporine to adalimumab improved psoriasis and adalimumab-induced injection site reaction. PMID- 25284874 TI - A case of scleromyxoedema with thyroid dysfunction. PMID- 25284875 TI - Unilateral blepharochalasis of right eye. PMID- 25284876 TI - Absence of skin over scalp and short digits in a newborn. PMID- 25284877 TI - Mycetoma in iran: causative agents and geographic distribution. AB - BACKGROUND: Mycetoma is a chronic granulomatous disease caused by true fungi (eumycetoma) or filamentous bacteria (actinomycetoma). It usually involves the subcutaneous tissue after a traumatic inoculation of the causative organism. We reviewed retrospectively 13 patients with mycetoma. MATERIALS AND METHODS: This study reports the etiologic agents and distribution of mycetoma in 35 cases from 1994 to2009 in Iran. The diagnostic of mycetoma were confirmed by histopathology and direct preparation, culture techniques, and histopathology of granules and surgical biopsies, radiological examination of the affected site. RESULTS: Mycetoma was identified in 35 patients of 168 suspected patients (20.8%). They occurred in 22 male and 13 females. Their ages ranged from 14 to 80 years. The duration of the disease ranged from two months to 38 years. Sixteen patients had eumycetoma, and 19 patients had actinomycetoma, one of them had mix infections by eumycetoma and actinomycetoma. The majority of the patients were from central and states in south and north of Iran. The feet were most affected site (65.7%) of the cases, followed by hands (25.7%), face (2.8%), and trunk (2.8%), and buttock (2.8%). Most patients (68.5%) were more than 40 year-old. The male to female ratio was 5:3. The disease was abundant among housewife in urban and farmer in rural area of Iran. The most common prevalent mycetoma agents in this study were Actinomyces sp. There was a history of risk factors in 28.6% of patients in this study. CONCLUSION: Mycetoma occasionally occurs particularly in the South, Central, and North of Iran, and seen most often in persons, who live in hot, humid climates. If there are risk factors for invasive fungal infections traumatic inoculation with any fungus may result in rapid local spread and systemic disease, often with fatal outcome. PMID- 25284878 TI - Solitary superficial acral angiomyxoma: an infrequently reported soft tissue tumor. AB - Superficial angiomyxomas (SA) are clinically variable, infrequent, benign skin lesions. They are usually located on the trunk, but can also appear on the lower limbs, head, and neck. The present case, hence, is unusual, because the lesion developed on the toe. They are diagnosed histologically, and are characterized by being poorly delimited tumors with the presence of interstitial myxoid material and scanty cellularity. We discuss the clinical and histological features of digital SA as well as a brief outline of other myxoid lesions. PMID- 25284879 TI - Incidence of Skin Rash in the New H7N9 Influenza. PMID- 25284880 TI - Primary hydatid cysts in the soft tissue. PMID- 25284881 TI - Adverse reactions to tattoos. PMID- 25284882 TI - Painful skin tumor over the back. PMID- 25284883 TI - Multiple painful nodules in a segmental distribution in a middle-aged woman. PMID- 25284884 TI - On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution. AB - The native bases of RNA and DNA are prominent examples of the narrow selection of organic molecules upon which life is based. How did nature "decide" upon these specific heterocycles? Evidence suggests that many types of heterocycles could have been present on the early Earth. It is therefore likely that the contemporary composition of nucleobases is a result of multiple selection pressures that operated during early chemical and biological evolution. The persistence of the fittest heterocycles in the prebiotic environment towards, for example, hydrolytic and photochemical assaults, may have given some nucleobases a selective advantage for incorporation into the first informational polymers. The prebiotic formation of polymeric nucleic acids employing the native bases remains, however, a challenging problem to reconcile. Hypotheses have proposed that the emerging RNA world may have included many types of nucleobases. This is supported by the extensive utilization of non-canonical nucleobases in extant RNA and the resemblance of many of the modified bases to heterocycles generated in simulated prebiotic chemistry experiments. Selection pressures in the RNA world could have therefore narrowed the composition of the nucleic acid bases. Two such selection pressures may have been related to genetic fidelity and duplex stability. Considering these possible selection criteria, the native bases along with other related heterocycles seem to exhibit a certain level of fitness. We end by discussing the strength of the N-glycosidic bond as a potential fitness parameter in the early DNA world, which may have played a part in the refinement of the alphabetic bases. PMID- 25284886 TI - The FDA And ABCs: Unintended Consequences Of Antidepressant Warnings On Human Capital. AB - Using annual cross-sectional data on over 100,000 adolescents aged 12-17, we studied academic and behavioral outcomes among those who were and were not likely affected by FDA warnings regarding the safety of antidepressants. Compared to other adolescents, adolescents with probable depression experienced a relative decline in grade point average of .14 points following the FDA warnings. The FDA warnings also coincided with increased delinquency, use of tobacco and use of illicit drugs. Together, our results stress the importance of mental health and its treatment as an input into cognitive and non-cognitive aspects of human capital. PMID- 25284887 TI - Marital Dissolution Among Interracial Couples. AB - Increases in interracial marriage have been interpreted as reflecting reduced social distance among racial and ethnic groups, but little is known about the stability of interracial marriages. Using six panels of Survey of Income and Program Participation (N = 23,139 married couples), we found that interracial marriages are less stable than endogamous marriages, but these findings did not hold up consistently. After controlling for couple characteristics, the risk of divorce or separation among interracial couples was similar to the more-divorce prone origin group. Although marital dissolution was found to be strongly associated with race/ethnicity, the results failed to provide evidence that interracial marriage is associated with an elevated risk of marital dissolution. PMID- 25284885 TI - Sources of Individual Differences in Emerging Competence With Numeration Understanding Versus Multidigit Calculation Skill. AB - This study investigated contributions of general cognitive abilities and foundational mathematical competencies to numeration understanding (i.e., base-10 structure) versus multidigit calculation skill. Children (n = 394, M = 6.5 years) were assessed on general cognitive abilities and foundational numerical competencies at start of 1st grade; on the same numerical competencies, multidigit calculation skill, and numeration understanding at end of 2nd grade; and on multidigit calculation skill and numeration understanding at end of 3rd grade. Path-analytic mediation analysis revealed that general cognitive predictors exerted more direct and more substantial effects on numeration understanding than on multidigit calculations. Foundational mathematics competencies contributed to both outcomes, but largely via 2nd-grade mathematics achievement, and results suggest a mutually supportive role between numeration understanding and multidigit calculations. PMID- 25284888 TI - Parental Migration and Education of Left-Behind Children: A Comparison of Two Settings. AB - The out-migration of parents has become a common childhood experience worldwide. It can confer both economic benefits and social costs on children. Despite a growing literature, the circumstances under which children benefit or suffer from parental out-migration are not well understood. The present study examined how the relationship between parental out-migration and children's education varies across migration streams (internal vs. international) and across 2 societies. Data are from the Mexican Family Life Survey (N = 5,719) and the Indonesian Family Life Survey (N = 2,938). The results showed that children left behind by international migrant parents are worse off in educational attainment than those living with both parents. Internal migration of parents plays a negative role in some cases, though often to a lesser degree than international migration. In addition, how the overall relationship between parental migration and education balances out varies by context: It is negative in Mexico but generally small in Indonesia. PMID- 25284889 TI - Quantitative Thermodynamic Analyses of Spectroscopic Titration Curves. AB - Elucidation of ligand - macromolecule interactions requires detailed knowledge of energetics of the formed complexes. Spectroscopic methods are most commonly used in characterizing molecular interactions in solution. The methods do not require large quantities of material and most importantly, do not perturb the studied reactions. However, spectroscopic methods absolutely require the determination of the relationship between the observed signal and the degree of binding in order to obtain meaningful interaction parameters. In other words, the meaningful, thermodynamic interaction parameters can be only determined if the relationship between the observed signal and the degree of binding is determined and not assumed, based on an ad hoc model of the relationship. The approaches discussed here allow an experimenter to quantitatively determine the degree of binding and the free ligand concentration, i.e., they enable to construct thermodynamic binding isotherms in a model-independent fashion. PMID- 25284891 TI - 'Fight TB with BCG': mass vaccination campaigns in the British Caribbean, 1951-6. AB - Based on a wide range of primary materials, including WHO reports and Colonial Office correspondence, this article examines the UNICEF/WHO-funded mass BCG campaigns that were carried out in seven Caribbean colonies between 1951 and 1956. It explores the reasons behind them, their nature and aftermath and also compares them to those in other non-European countries and discusses them within a context of decolonisation. In doing so, it not only adds to the scholarship on TB in non-European contexts, which had tended to focus on Africa and Asia, but also to the relatively new field of Caribbean medical history and the rapidly expanding body of work on international health, which has paid scant attention to the Anglophone Caribbean and the pre-independence period. PMID- 25284890 TI - Gold-Catalyzed Oxidation of Propargylic Ethers with Internal C-C Triple Bonds: Impressive Regioselectivity Enabled by Inductive Effect. AB - Inductive perturbations of C-C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C-C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of beta alkoxy-alpha,beta-unsaturated ketones (up to >50/1 selectivity) via alpha-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a alpha-phenyl-beta-alkoxy-alpha,beta-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity. PMID- 25284892 TI - 'Recharge my exhausted batteries': Overbeck's Rejuvenator, Patenting, and Public Medical Consumers, 1924-37. AB - Although historians have shown that there has been a complex and multi-layered relationship between the body, medicine and the force of electricity, many avenues remain to be explored. One of the most prominent of these is the way in which electrotherapy technologies were marketed to a wide variety of different end users and intermediaries. This paper offers the first historical analysis of one such device - the Overbeck Rejuvenator - a 1920s electrotherapy machine designed for use by the general public. Its inventor, Otto Overbeck, was not a medical man and this enabled him to use aggressive strategies of newspaper advertising, using testimonials to market his product alongside appeals to his own scientific authority. He commissioned the prestigious Ediswan Company to manufacture the Rejuvenator on a large scale, and took out patents in eleven countries to persuade users of the efficacy of the device. In response to Overbeck's activities, the British Medical Association enlisted an electrical engineer to examine the Rejuvenator, contacted practitioners whose endorsements were being used in publicity material, and denied Overbeck permission to advertise in the British Medical Journal. Despite this, the Rejuvenator brought its inventor wealth and notoriety, and helped redefine the concept of 'rejuvenation', even if the professional reception of such a device was almost universally hostile. This paper shows how the marketing, patenting and publishing of Overbeck combined to persuade members of the laity to try the Rejuvenator as an alternative form of therapy, bypassing the medical profession in the process. PMID- 25284894 TI - Constructing new expertise: private and public initiatives for safe food (Brussels in the first half of the nineteenth century). AB - In 1856, the mayor of Brussels proposed the establishment of a municipal laboratory with a chemist to analyse food and beverages to restrain fraud. His proposal was accepted and a laboratory - possibly one of the first municipal laboratories in Europe - was set up. The laboratory still exists today. This paper aims at tracing the conditions in which it emerged, situating it within the laissez-faire context of the time. It was brought into existence by a liberal administration, in a period of little interventionism replete with unencumbered private interests (those of bakers, butchers, grocers, millers, pharmacists, doctors and so on). What will be considered here is the general mood with regard to food fraud, fair trade, correct price, and the quality of food in the first half of the nineteenth century. On a broader level, this contribution addresses the frictions between private and public initiative, while focusing on the process of construction of expertise. The paper makes use of contemporary documents such as reviews, newspapers, association reports and city council chronicles. PMID- 25284893 TI - 'Shell shock' revisited: an examination of the case records of the National Hospital in London. AB - During the First World War the National Hospital for the Paralysed and Epileptic, in Queen Square, London, then Britain's leading centre for neurology, took a key role in the treatment and understanding of shell shock. This paper explores the case notes of all 462 servicemen who were admitted with functional neurological disorders between 1914 and 1919. Many of these were severe or chronic cases referred to the National Hospital because of its acknowledged expertise and the resources it could call upon. Biographical data was collected together with accounts of the patient's military experience, his symptoms, diagnostic interpretations and treatment outcomes. Analysis of the notes showed that motor syndromes (loss of function or hyperkinesias), often combined with somato-sensory loss, were common presentations. Anxiety and depression as well as vegetative symptoms such as sweating, dizziness and palpitations were also prevalent among this patient population. Conversely, psychogenic seizures were reported much less frequently than in comparable accounts from German tertiary referral centres. As the war unfolded the number of physicians who believed that shell shock was primarily an organic disorder fell as research failed to find a pathological basis for its symptoms. However, little agreement existed among the Queen Square doctors about the fundamental nature of the disorder and it was increasingly categorised as functional disorder or hysteria. PMID- 25284895 TI - Matters of priority: Herbert Mayo, Charles Bell and discoveries in the nervous system. AB - Between 1822 and the late 1830s a highly personal priority dispute was fought between the celebrated surgeon and anatomist Sir Charles Bell and his ex-student Herbert Mayo. The dispute was over the motor and sensory functions of the Vth and VIIth cranial nerves. Over the course of the 1820s and the 1830s, the competing claims of Bell and Mayo were presented in newspapers, journals, and textbooks. But by the time of Bell's death in 1842, Mayo had been discredited, a seemingly tragic footnote in the history of nervous discovery. And yet, with the benefit of hindsight, Bell's case was at best disingenuous. His success was not due to any intrinsic scientific merit in his argument, but rather his ability to create a narrative that undermined the credibility of Mayo. However, only when Mayo's public performances elided with Bell's descriptions did this ploy succeed. As a result, the dispute illuminates the importance of credibility to the creation of an idealised scientific medical practitioner. PMID- 25284896 TI - Psychotherapy and moralising rhetoric in Galen's newly discovered Avoiding Distress (Peri Alypias). AB - In this article, I examine Galen's credentials as an ethical philosopher on the basis of his recently discovered essay Avoiding Distress (Peri alypias). As compensation for the scholarly neglect from which Galen's ethics suffers, I argue that his moral agenda is an essential part of his philosophical discourse, one that situates him firmly within the tradition of practical ethics of the Roman period. Galen's engagement with Stoic psychotherapy and the Platonic-Aristotelian educational model affirms his ethical authority; on the other hand, his distinctive moralising features such as the autobiographical perspective of his narrative and the intimacy between author and addressee render his Avoiding Distress exceptional among other essays, Greek or Latin, treating anxiety. Additionally, I show that Galen's self-projection as a therapist of the emotions corresponds to his role as a practising physician, especially as regards the construction of authority, the efficacy of his therapy and the importance of personal experience as attested in his medical accounts. Finally, the diligence with which Galen retextures his moral advice in his On the Affections and Errors of the Soul - a work of different nature and intent in relation to Avoiding Distress - is a testimony to the dynamics of his ethics and more widely to his philosophical medicine. The philosopher's lecture room is a 'hospital': you ought not to walk out of it in a state of pleasure, but in pain; for you are not in good condition when you arrive. Epictetus, Discourses 3.23.30. PMID- 25284899 TI - Ordinal latent variable models and their application in the study of newly licensed teenage drivers. AB - In a unique longitudinal study of teen driving, risky driving behavior and the occurrence of crashes or near crashes are measured prospectively over the first 18 months of licensure. Of scientific interest is relating the two processes and developing a predictor of crashes from previous risky driving behavior. In this work, we propose two latent class models for relating risky driving behavior to the occurrence of a crash or near crash event. The first approach models the binary longitudinal crash/near crash outcome using a binary latent variable which depends on risky driving covariates and previous outcomes. A random effects model introduces heterogeneity among subjects in modeling the mean value of the latent state. The second approach extends the first model to the ordinal case where the latent state is composed of K ordinal classes. Additionally, we discuss an alternate hidden Markov model formulation. Estimation is performed using the expectation-maximization (EM) algorithm and Monte Carlo EM. We illustrate the importance of using these latent class modeling approaches through the analysis of the teen driving behavior. PMID- 25284900 TI - Asymmetric Synthesis of Functionalized Dihydro- and Tetrahydropyrans via an Organocatalytic Domino Michael-Hemiacetalization Reaction. AB - Starting from alpha-hydroxymethyl nitroalkenes and various 1,3-dicarbonyl compounds, a one-pot organocatalyzed diastereo- and enantioselective synthesis of polyfunctionalized dihydro- and tetrahydropyran derivatives via a domino Michael hemiacetalization sequence is reported. The title compounds bearing a variety of functional groups can be synthesized in this way in good yields (59-91%) and with moderate to excellent diastereoselectivities (26-98% de) and enantioselectivities (71-99% ee). PMID- 25284901 TI - Direct Ras Inhibitors Identified from a Structurally Rigidified Bicyclic Peptide Library. AB - A one-bead-two-compound (OBTC) library of structurally rigidified bicyclic peptides was chemically synthesized on TentaGel microbeads (90 MUm), with each bead displaying a unique bicyclic peptide on its surface and a linear encoding peptide of the same sequence in its interior. Screening of the library against oncogenic K-Ras G12V mutant identified two classes of Ras ligands. The class I ligands apparently bind to the effector-binding site and inhibit the Ras-Raf interaction, whereas the class II ligand appears to bind to a yet unidentified site different from the effector-binding site. These Ras ligands provide useful research tools and may be further developed into therapeutic agents. PMID- 25284902 TI - Conditional Density Estimation in Measurement Error Problems. AB - This paper is motivated by a wide range of background correction problems in gene array data analysis, where the raw gene expression intensities are measured with error. Estimating a conditional density function from the contaminated expression data is a key aspect of statistical inference and visualization in these studies. We propose re-weighted deconvolution kernel methods to estimate the conditional density function in an additive error model, when the error distribution is known as well as when it is unknown. Theoretical properties of the proposed estimators are investigated with respect to the mean absolute error from a "double asymptotic" view. Practical rules are developed for the selection of smoothing parameters. Simulated examples and an application to an Illumina bead microarray study are presented to illustrate the viability of the methods. PMID- 25284903 TI - Decision Making for Postpartum Depression Treatment. PMID- 25284904 TI - Land Use Specific Ammonia Deposition Velocities: a Review of Recent Studies (2004 2013). AB - Land use specific deposition velocities of atmospheric trace gases and aerosols particularly of reactive nitrogen compounds-are a fundamental input variable for a variety of deposition models. Although the concept is known to have shortcomings-especially with regard to bi-directional exchange-the often limited availability of concentration data and meteorological input variables make it a valuable simplification for regional modeling of deposition fluxes. In order to meet the demand for an up-to-date overview of recent publications on measurements and modeling studies, we compiled a database of ammonia (NH3) deposition velocities published from 2004 to 2013. Observations from a total of 42 individual studies were averaged using an objective weighing scheme and classified into seven land use categories. Weighted average and median deposition velocities are 2.2 and 2.1 cm s-1 for coniferous forests, 1.5 and 1.2 cm s-1 for mixed forests, 1.1 and 0.9 cm s-1 for deciduous forests, 0.9 and 0.7 cm s-1 for semi-natural sites, 0.7 and 0.8 cm s-1 for urban sites, 0.7 and 0.6 cm s-1 for water surfaces, and 1.0 and 0.4 cm s-1 for agricultural sites, respectively. Thus, values presented in this compilation were considerably lower than those found in former studies (e.g., VDI 2006). Reasons for the mismatch were likely due to different land use classification, different averaging methods, choices of measurement locations, and improvements in measurement and in modeling techniques. Both data and code used for processing are made available as supplementary material to this article. PMID- 25284905 TI - Comparing Spatial and Multilevel Regression Models for Binary Outcomes in Neighborhood Studies. AB - The standard multilevel regressions that are widely used in neighborhood research typically ignore potential between-neighborhood correlations due to underlying spatial processes, and hence produce inappropriate inferences about neighborhood effects. In contrast, spatial models make estimations and predictions across areas by explicitly modeling the spatial correlations among observations in different locations. A better understanding of the strengths and limitations of spatial models as compared to the standard multilevel model is needed to improve the research on neighborhood and spatial effects. This research systematically compares model estimations and predictions for binary outcomes between (distance- and lattice-based) spatial and the standard multilevel models in the presence of both within- and between-neighborhood correlations, through simulations. Results from simulation analysis reveal that the standard multilevel and spatial models produce similar estimates of fixed effects, but different estimates of random effects variances. Both the standard multilevel and pure spatial models tend to overestimate the corresponding random effects variances, compared to hybrid models when both non-spatial within neighborhood and spatial between-neighborhood effects exist. Spatial models also outperform the standard multilevel model by a narrow margin in case of fully out-of-sample predictions. Distance-based spatial models provide extra spatial information and have stronger predictive power than lattice-based models under certain circumstances. These merits of spatial modeling are exhibited in an empirical analysis of the child mortality data from 1880 Newark, New Jersey. PMID- 25284906 TI - Does mindfulness attenuate thoughts emphasizing negativity, but not positivity? AB - The current research investigated whether mindfulness is differentially associated with thoughts that emphasize positive or negative valence. In Study 1, trait mindfulness was inversely associated with negative rumination but unassociated with positive rumination, controlling for state affect. In Study 2, participants completed either a mindful breathing meditation or a comparable control exercise, followed by a thought listing while viewing affective images. Compared to the control condition, the mindfulness condition listed proportionately fewer negative thoughts, particularly in response to negative images, and more non-valenced thoughts. The conditions did not differ in their proportions of positive thoughts. These results suggest that mindfulness may attenuate thoughts that emphasize negativity but not those that emphasize positivity. PMID- 25284907 TI - Interrogation of EGFR Targeted Uptake of TiO2 Nanoconjugates by X-ray Fluorescence Microscopy. AB - We are developing TiO2 nanoconjugates that can be used as therapeutic and diagnostic agents. Nanoscale TiO2 can be surface conjugated with various molecules and has the unique ability to induce the production of reactive oxygen species after radiation activation. One way to improve the potential clinical usefulness of TiO2 nanoparticles is to control their delivery to malignant cells by targeting them to cancer cell specific antigens. Epidermal Growth Factor Receptor is one potential target that is enriched in epithelial cancers and is rapidly internalized after ligand binding. Hence, we have synthesized TiO2 nanoparticles and functionalized them with a short EGFR binding peptide to create EGFR-targeted NCs. X-ray Fluorescence Microscopy was used to image nanoconjugates within EGFR positive HeLa cells. Further labeling of fixed cells with antibodies against EGFR and Protein A nanogold showed that TiO2 nanoconjugates can colocalize with receptors at the cell's plasma membrane. Interestingly, with increased incubation times, EGFR targeted nanoconjugates could also be found colocalized with EGFR within the cell nucleus. This suggests that EGFR-targeted nanoconjugates can bind the receptor at the cell membrane, which leads to the internalization of NC-receptor complexes and the subsequent transport of nanoconjugates into the nucleus. PMID- 25284908 TI - Can a Static Nonlinearity Account for the Dynamics of Otoacoustic Emission Suppression? AB - This study investigates whether time-dependent compression mechanisms in the cochlea are necessary to explain dynamic properties of otoacoustic emissions (OAEs). Dynamic properties of click-evoked OAEs (CEOAEs) have been observed in temporal suppression; the effect where the CEOAE magnitude is reduced when a click is presented less than 10 ms before the test click. A time-domain model of the cochlea that represented the basilar membrane (BM) as a cascade of coupled bandpass filters was used to investigate the cochlear origin of temporal suppression in CEOAEs. The model, implemented with a time-invariant nonlinearity, was able to simulate temporal suppression, but was unable to account for the exact time scale and magnitude of the effect. The results suggest that temporal overlap of BM impulse responses can account for suppression in CEOAEs, but that an additional time-dependent cochlear gain mechanism may be needed to account the high suppression maxima at inter-click intervals larger than zero. PMID- 25284909 TI - Tracing Distortion Product (DP) Waves in a Cochlear Model. AB - In many cases a cochlear model suffices to explain (by simulation) the properties of waves in the cochlea. This is not so in the case of a distortion product (DP) set up by presenting two primary tones to the cochlea. A three-dimensional model predicts, apart from a DP wave traveling in the apical direction, a DP wave that travels from the region of overlap of the two tone patterns towards the stapes setting the stapes in motion so as to produce an otoacoustic emission at the DP frequency. Experimental research has shown, however, that the actual DP wave in the cochlea appears to travel in the opposite direction, from near the stapes to the overlap region. This feature has been termed "inverted direction of wave propagation" (IDWP). The forward wave could result from an unknown process such as a "hidden source" near the stapes. In the present study we have disproved this notion, by using a one-dimensional model of the cochlea. It is found that both reverse and forward waves are set up by the source of nonlinearity, in the same way as has been published in an earlier work. The present results reveal that IDWP in the data corresponds to the region where the DP wave, originally created as a reverse wave but reflected from the stapes, has received so much amplification that it starts to dominate over the reverse wave. Hence we conclude that IDWP in a one-dimensional model is a direct manifestation of cochlear amplification. PMID- 25284910 TI - Ice barriers promote supercooling and prevent frost injury in reproductive buds, flowers and fruits of alpine dwarf shrubs throughout the summer. AB - Over-wintering reproductive buds of many woody plants survive frost by supercooling. The bud tissues are isolated from acropetally advancing ice by the presence of ice barriers that restrict ice growth. Plants living in alpine environments also face the risk of ice formation in summer months. Little knowledge exists, how reproductive structures of woody alpine plants are protected from frost injury during episodic summer frosts. In order to address this question, frost resistance of three common dwarf shrubs, Calluna vulgaris, Empetrum hermaphroditum and Loiseleuria procumbens was measured and ice formation and propagation were monitored in twigs bearing reproductive shoots during various stages of reproductive development (bud, anthesis, and fruit) throughout the alpine summer. Results indicated that, in the investigated species, ice barriers were present at all reproductive stages, isolating the reproductive shoots from ice advancing from the subtending vegetative shoot. Additionally, in the reproductive stems ice nucleating agents that are active at warm, sub-zero temperatures, were absent. The ice barriers were 100% effective, with the exception of L. procumbens, where in 13% of the total observations, the ice barrier failed. The ice barriers were localized at the base of the pedicel, at the anatomical junction of the vegetative and reproductive shoot. There, structural aspects of the tissue impede or prevent ice from advancing from the frozen stem into the pedicel of the reproductive shoot. Under the experimental conditions used in this study, ice nucleation initially occurred in the stem of the vegetative shoot at species-specific mean temperatures in the range of -4.7 to -5.8 degrees C. Reproductive shoots, however, remained supercooled and ice free down to a range of -7.2 to -18.2 degrees C or even below -22 degrees C, the lowest temperature applied in the study. This level of supercooling is sufficient to prevent freezing of reproductive structures at the lowest air temperature occurring at the altitude of the upper distribution boundary of the natural habitat of the investigated species which is between -8 and -10 degrees C in summer. Frost resistance assays indicated that reproductive shoots are much less frost resistant than vegetative stems, and in contrast to vegetative shoots, are not ice tolerant. Supercooling of reproductive shoots in alpine, woody plant species is an effective mechanism that protects developing offspring from potential frost damage resulting from episodic summer freezing events. PMID- 25284911 TI - Parental Efficacy, Experience of Stressful Life Events, and Child Externalizing Behavior as Predictors of Filipino Mothers' and Fathers' Parental Hostility and Aggression. AB - This study assessed relations of parental efficacy, experience of stressful life events, and child externalizing behavior to Filipino mothers and fathers' parental hostility and aggression. Orally-administered surveys were conducted with 117 mothers and 98 fathers for the first year of data collection, and again a year later with 107 mothers and 83 fathers. Path analyses showed that mothers' report of child externalizing behavior predicted subsequent parental hostility and aggression. For fathers, child externalizing behavior and experience of stressful life events predicted parental hostility and aggression. Additionally, fathers' parental efficacy was found to moderate the relationship between experience of stressful life events and parental hostility and aggression. Results suggest that child externalizing behavior and experience of stressful life events have direct relations to parental hostility and aggression, while parental efficacy has a moderating effect to it. The differences between the results for fathers and mothers are explained in the context of distinct parenting roles and parenting in the local context. PMID- 25284912 TI - Ecoepidemiologia del dengue: relevancia de dos vectores invasores. PMID- 25284913 TI - HIV/AIDS knowledge and occupational risk in primary care health workers from Chile. AB - OBJECTIVE: To explore the relationship between knowledge level and occupational risk exposure to HIV/AIDS in primary care health workers. METHODOLOGY: Analytical cross-sectional study. 720 health workers from Santiago answered a survey about HIV/AIDS that included: knowledge level (appropriate, inappropriate), occupational risk (with or without risk), and control variables (age, gender, health center, education and marital status). Descriptive and association analysis were performed. Odds Ratio (OR) was estimated through simple and multiple regressions logistics. RESULTS: 58.7% of the participants reported HIV occupational risk. 63.8% of the participants from the exposed group reported an appropriate level of knowledge, versus 36.1% of the non-exposed group (Adjusted OR of 3.1, IC95%OR: 2.0-4.8, p<0.0001). Technicians and cleaning staff reported a lower proportion of appropriate level of knowledge compared to the employees with college education (p<0.0001). CONCLUSION: The level of HIV/AID occupational risk is directly associated with the level of knowledge of the disease. PMID- 25284915 TI - [An Interdisciplinary Theory-Based ESL Curriculum to Teach English as a Second Language.] PMID- 25284914 TI - [Knowledge and Self Efficacy Related with HIV Prevention among Chilean Women]. AB - OBJECTIVE: To assess the relationship between knowledge and self efficacy associated to HIV/AIDS in women from Chile with social disadvantages. METHODOLOGY: Correlation study that uses the baseline assessment of the "Testing an HIV and AIDS intervention in Chilean women" study, carried out between 2006 and 2008, with a sample of 496 women between 18 and 49 years old, in 2 neighborhoods of Santiago de Chile. Participants answered a structured survey conducted by trained interviewers. The survey included questions about sociodemographic information, risk behaviors and a self-efficacy knowledge scale among others. RESULTS: The average age was 32.3+/-9.1 years, 72.2% live with their partner and 42.7% have completed high school education. The mean score of HIV infection knowledge was 8.9+/-2.5, while the mean score for the three scales used to measure self-efficacy were: "Peer rules" =9.8+/-3.6, "Risk reduction intentions =12.2+/-3.6 and "Self Efficacy Form"=20.2+/-4.7. HIV knowledge had a weak positive correlation with the "Risk reduction intentions" scale (r=0.19; p<0.0001) and the "Self Efficacy Form" scale (r=0.34; p<0.0001), however there was no correlation with the "Safe sex peer rules" (r=0.13;p=0.78). CONCLUSION: There is a weak positive correlation between the HIV/AIDS related knowledge and self-efficacy among Chilean with social disadvantages. PMID- 25284916 TI - Differentiating Worry and Rumination: Evidence from Heart Rate Variability During Spontaneous Regulation. AB - Worry is the defining feature of generalized anxiety disorder (GAD), and rumination is a central process in depression. GAD and depression are highly comorbid, and worry and rumination reflect similar perseverative cognitive processes. Prior studies have largely assessed these emotion regulation strategies at the trait level, which has resulted in a limited understanding of their phasic characteristics, including associated physiological processes. We addressed this limitation by examining the relationship between spontaneous state level worry and rumination and heart rate variability (HRV)-a physiological measure of emotion regulation-in response to emotion-eliciting film clips. We found differential associations between worry and rumination in relation to HRV, such that, worry was more consistently associated with HRV across emotional contexts than rumination was. Findings highlight functional distinctions between worry and rumination that have implications for understanding their associations with mood and anxiety disorders and, more broadly, for theories of emotion regulation and psychopathology. PMID- 25284917 TI - Expanding the Circle: Decreasing American Indian Mental Health Disparities through Culturally Competent Teaching about American Indian Mental Health. PMID- 25284918 TI - Targeted Local Support Vector Machine for Age-Dependent Classification. AB - We develop methods to accurately predict whether pre-symptomatic individuals are at risk of a disease based on their various marker profiles, which offers an opportunity for early intervention well before definitive clinical diagnosis. For many diseases, existing clinical literature may suggest the risk of disease varies with some markers of biological and etiological importance, for example age. To identify effective prediction rules using nonparametric decision functions, standard statistical learning approaches treat markers with clear biological importance (e.g., age) and other markers without prior knowledge on disease etiology interchangeably as input variables. Therefore, these approaches may be inadequate in singling out and preserving the effects from the biologically important variables, especially in the presence of potential noise markers. Using age as an example of a salient marker to receive special care in the analysis, we propose a local smoothing large margin classifier implemented with support vector machine (SVM) to construct effective age-dependent classification rules. The method adaptively adjusts age effect and separately tunes age and other markers to achieve optimal performance. We derive the asymptotic risk bound of the local smoothing SVM, and perform extensive simulation studies to compare with standard approaches. We apply the proposed method to two studies of premanifest Huntington's disease (HD) subjects and controls to construct age-sensitive predictive scores for the risk of HD and risk of receiving HD diagnosis during the study period. PMID- 25284919 TI - The Impact of Adolescent Deviance on Marital Trajectories. AB - Marriage is a key life event that has numerous benefits. Recent research extends these benefits to include desistance from crime and drug use yet there has been little investigation regarding whether deviant behavior in adolescence impacts long-term marital patterns. Since rates of marriage are low among African Americans and rates of adolescent deviance and crime are high, we investigate the long-term relationship between the two drawing on longitudinal data from the Woodlawn cohort of urban African Americans. This article investigates whether serious adolescent delinquency and marijuana use predict marital trajectories, controlling for known correlates. Multivariate findings indicate that within this African-American population, deviance predicts the probability of marriage, stability of marriage, and timing of marriage for men yet deviance relates solely to the probability of marriage for women. PMID- 25284920 TI - "I don't feel shy because I will be among others who are just like me...": The role of support groups for children perinatally infected with HIV in Zimbabwe. AB - As access to paediatric antiretroviral therapy (ART) continues to improve in sub Saharan Africa, a new historically specific cohort of HIV-perinatally infected children surviving into adolescent has emerged. Although remarkable successes have been made clinically in keeping this cohort alive and in reasonable health, their social support experiences are still unknown. The research being reported here sought to explore peer social support experiences of HIV-perinatally infected children in Harare, Zimbabwe. In this article, we draw on 56 repeat in depth interviews (IDIs) conducted in three phases and two focus group discussions (FGDs) with HIV-infected children (11-13 years). Additional interviews were held with 10 carers. Study findings suggested that both children and carers perceive support groups as a safe social space for learning and acquiring HIV information as well as gaining confidence. Additionally, findings highlighted the importance of consistency of participation. Structural and personal barriers to access and participation in support group were also identified. We conclude that support groups are a useful resource for HIV-infected children and therefore should be supported by stable funding. PMID- 25284921 TI - Internalizing Symptoms and Safe Sex Intentions among Adolescents in Mental Health Treatment: Personal Factors as Mediators. AB - Little is known about why some adolescents with internalizing symptoms engage in sexual behaviors that increase their risk for HIV. This study tested a mediation model of internalizing symptoms and safe sex intentions among adolescents receiving mental health treatment. Self-efficacy for HIV prevention, HIV knowledge, and worry about HIV were hypothesized to mediate associations between internalizing symptoms and safe sex intentions among sexually active and non active adolescents receiving mental health treatment (N = 893, M age = 14.9). Significant indirect effects from internalizing symptoms to safe sex intentions varied according sexual experience: for sexually non-active adolescents, HIV worry and knowledge mediated this link, whereas for sexually active adolescents, HIV self-efficacy was the significant mediator. Increasing both HIV knowledge and self-efficacy for HIV prevention are important targets for HIV prevention with adolescents with internalizing symptoms, and careful attention should be paid towards targeting these interventions to sexually experienced and inexperienced youth. PMID- 25284922 TI - Explicating the Social Mechanisms Linking Alcohol Use Behaviors and Ecology to Child Maltreatment. AB - This paper begins to describe and explicate the specific mechanisms by which alcohol use and the alcohol use environment contribute to specific types of child maltreatment. These mechanisms relating alcohol outlet densities to child maltreatment described here include effects on social disorganization, parent's drinking behaviors, and parental supervision. By investigating potential mechanisms, new information could be obtained on the importance and role of alcohol and their availability in the etiology of child maltreatment. This knowledge can be used to further tailor interventions to those conditions most likely to prevent and reduce maltreatment. PMID- 25284923 TI - Hepatoprotective Effect of Houttuynia cordata Thunb Extract against Carbon Tetrachloride-induced Hepatic Damage in Mice. AB - Houttuynia cordata Thunb (Saururaceae) is a traditional medicinal herb used to treat several disease symptoms. The present study was focused on the hepatoprotective effects of H. cordata ethyl acetate extract in experimental mice. Further the antioxidant potential of the extract was also evaluated to substantiate its hepatoprotective properties. Carbon tetrachloride-induced hepatic damage in mice was used to measure the serum biochemical parameters. Morphological changes in hepatocyte architecture were studied by haematoxylin and eosin staining. In vitro alkyl and hydroxyl free radical scavenging assays were performed to evaluate the antioxidant effect. Administration of H. cordata extract significantly reduced the elevated serum levels and regulated the altered levels of serum cholesterol in carbon tetrachloride-treated mice (P<0.05). The morphological changes in hepatocyte architecture were also reversed by H. cordata treatment. Further, the extract showed significant antioxidant actions by scavenging the alkyl and hydroxyl free radicals. The concentration of the extract necessary for 50% scavenging of alkyl and hydroxyl radicals was 15.5 and 410 MUg/ml, respectively. H. cordata extract exhibited significant hepatoprotective property in carbon tetrachloride-induced hepatotoxicity in mice. The strong antioxidant activities possessed by the extract might be responsible for such actions. PMID- 25284924 TI - Olea europaea Linn. Fruit Pulp Extract Protects against Carbon Tetrachloride induced Hepatic Damage in Mice. AB - The present study we investigated the hepatoprotective effects of Olea europaea fruit pulp extract against carbon tetrachloride-induced hepatic damage in experimental mice. Further we explored the antioxidant potential of the extract to substantiate the hepatoprotective properties. Biochemical parameters were analyzed in the serum of experimental mice using respective diagnostic kits. Antioxidant activities were measured following alkyl and hydroxyl radical scavenging assays. Compared with control groups, administration of the extract to carbon tetrachloride-treated mice significantly reduced the elevated serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. The carbon tetrachloride-treated morphological changes in hepatocyte architecture were also reversed by extract pretreatment. Further, the carbon tetrachloride-treated increased serum cholesterol levels such as triglyceride and low density/very low-density lipoprotein in the liver were reversed in acute and chronic carbon tetrachloride-treated mice. The extract was also found to significantly increase the serum level of high-density lipoproteins in carbon tetrachloride-treated mice. Furthermore, the extract showed significant in vitro antioxidant actions by scavenging the alkyl and hydroxyl free radicals, substantiating its use in hepatoprotection. The concentration of the extract necessary for 50% inhibition of alkyl and hydroxyl radicals was 72.41 and 52.24 MUg/ml, respectively. In conclusion, data from our study suggest that Olea europaea fruit pulp extract could prevent carbon tetrachloride-treated acute and chronic liver degeneration and attenuated the lipid levels elevated by carbon tetrachloride. The hepatoprotective activity exhibited by Olea europaea extract might possibly be through its antioxidant defense mechanisms. PMID- 25284925 TI - Pharmacogenetic selection of volunteers increases stringency of bioequivalence studies; the case of clopidogrel. AB - Clinical response to clopidogrel varies widely due to under-dosing, drug interactions and intrinsic interindividual differences resulting from genetic polymorphisms. Cytochrome P450-2C19 is the principal enzyme involved in the activation of the prodrug and loss-of-function alleles have been described. Upon expiration of the pharmaceutical patent of clopidogrel, generic manufacturers have started to subject interchangeable formulations to bioequivalence studies. The purpose of the current investigation was to study the effect of selection of volunteers homozygous for the CYP2C19*1 haplotype on the bioavailability of clopidogrel. A regular 2*2 bioequivalence study between two formulations of clopidogrel was performed in volunteers selected and unselected for relevant CYP2C19 haplotypes for the Mexican population. It was found that selection of volunteers homozygous for the CYP2C19*1 haplotype, increased the stringency of bioequivalence statistics and resulted in bioinequivalence of a generic clopidogrel compound that otherwise proved equivalent when tested in an open unselected population. Augmentation of bioequivalence strictness is expected to result from pharmacogenetic selection of volunteers. PMID- 25284926 TI - Relationship between Antifungal Activity against Candida albicans and Electron Parameters of Selected N-Heterocyclic Thioamides. AB - Due to the increasing demand for new pharmaceuticals showing biological activity against pathogenic microorganisms, there is increasing search for new compounds with predicted biological activity. Variously substituted thioamide derivatives with 1.3 and 1.2 ring of thiazole and 1,3,4-thiadiazole, as well as pyrazole were assessed for their activity against Candida albicans. Activity of majority of tested thioamides was larger as compared with that of the reference drugs. The electron parameters of obtained N-heterocyclic thioamides were determined and dependencies on their biological activity against Candida albicans were studied. The best electron compliance of produced bindings with the activity against Candida albicans was observed for the derivatives containing 1,3,4-thiadiazole ring. PMID- 25284927 TI - Synthesis and antiinflammatory activity of newer pyrazolinylbenzidines and isoxazolinylbenzidines. AB - In an effort to search for more active antiinflammatory agent, a series of pyrazolinylbenzidines and isoxazolylbenzidines was designed, synthesized, and screened for their potential as novel orally inflammation inhibitors. Compounds 4,4'-bis-(1"-acetyl-5"-substitutedaryl-2"-pyrazolin-3"-yl)benzidines (8-13) and 4,4'-bis-(2"-substitutedaryl-isoxazolin-4'-yl)benzidines (14-19) have been synthesized from 4,4'-bis-(substituted benzylidenyl-acetyl)benzidines (2-7). The structures of the products have been delineated by spectral and elemental analysis. Compounds 2-19 evaluated for antiinflammatory activity and acute toxicity and results are reported. The compound 4,4'-bis-[1"-acetyl-5"-(p methoxyphenyl)-2"-pyrazolin-3'-yl)benzidine (9) showed more potent and dose dependent antiinflammatory activity in comparison to reference drug. PMID- 25284928 TI - Drug utilisation study in a tertiary care center: recommendations for improving hospital drug dispensing policies. AB - Drug therapy accounts for a major portion of health expenditure. A useful strategy for achieving cost efficient healthcare is drug utilisation research as it forms the basis for making amendments in drug policies and helps in rational drug use. The present observational study was conducted to generate data on drug utilization in inpatients of our tertiary care hospital to identify potential targets for improving drug prescribing patterns. Data was collected retrospectively from randomly selected 231 medical records of patients admitted in various wards of the hospital. WHO Anatomical Therapeutic Chemical/Defined Daily Dose methodology was used to assess drug utilisation data and drug prescriptions were analysed by WHO core drug indicators. Antibiotics were prescribed most frequently and also accounted for majority of drug costs. The prescribed daily dose for most of the antibiotics corresponded to defined daily dose reflecting adherence to international recommendations. Brand name prescribing and polypharmacy was very common.78% of the total drugs prescribed were from the National List of Essential Medicines 2003. Restricting the use of newer and costlier antibiotics, branded drugs and number of drugs per prescription could be considered as targets to cut down the cost of drug therapysignificantly. PMID- 25284929 TI - Protective Effect of Gymnema sylvestre Ethanol Extract on High Fat Diet-induced Obese Diabetic Wistar Rats. AB - Obesity is associated with numerous co-morbidities such as cardiovascular diseases, type 2 diabetes, hypertension and others. Therefore, the present study was planned to investigate the effect of water- soluble fraction of Gymnema sylvestre ethanol extract on biochemical and molecular alterations in obese diabetic rats. Diabetes was induced by single i.v. injection of streptozotocin (45 mg/kg) via tail vein. Obesity was induced by oral feeding of high fat diet for a period of 28 days in diabetic rats. Body weight gain, food intake, water intake, hemodynamic parameters (systolic, diastolic, mean arterial blood pressures and heart rate), serum biochemical parameters (leptin, insulin, lipid levels, apolipoprotein B and glucose), cardiomyocyte apoptosis (cardiac caspase 3, Na(+)/K(+) ATPase activity and DNA fragmentation) organs and visceral fat pad weight and oxidative stress parameters were measured. Oral treatment with water soluble fraction of Gymnema sylvestre ethanol extracts (120 mg/kg/p.o.) for a period of 21 days, resulted in significant reduction in heart rate, mean arterial pressure, serum leptin, insulin, apolipoprotein B, lipids, glucose, cardiac caspase-3 levels, Na(+)/K(+) ATPase activity and DNA laddering, visceral fat pad and organ's weight and improved the antioxidant enzymes levels in the high fat diet induced obesity in diabetic rats. The results of present study reveal that water soluble fraction of Gymnema sylvestre ethanol extract could be useful intervention in the treatment of obesity and type-2 diabetes mellitus. PMID- 25284930 TI - Antihyperglycemic Activity of Petroleum Ether Leaf Extract of Ficus krishnae L. on Alloxan-induced Diabetic Rats. AB - The petroleum ether leaf extract of Ficus krishnae has been evaluated for the management of diabetes in alloxan induced diabetic rats. Phytochemical screening of the leaf extract for various chemical compounds has also been carried out. Leaf extract was administered continuously for 21 days orally at a dose of 200 mg/kg. Along with this, the blood glucose level was monitored at regular intervals to understand the activity of the extract. The leaf extract has decreased the blood glucose level of diabetic rats which was comparable to an antidiabetic standard drug, glibenclamide, given at a dose of 2.5 mg/kg. It has been observed that the leaves of Ficus krishnae possess antidiabetic activity and it reduces the blood glucose level significantly. The phytochemical screening of leaf has revealed the presence of carbohydrates, flavonoids, tannins, glycosides, terpenoids, steroids, alkaloids, gums and mucilage, phlobatannins, reducing sugars and phenolic compounds. The Fourier Transform Infrared analysis of glibenclamide and leaf powder has displayed some common absorption spectra. This shows that leaf powder has a molecule which is close to glibenclamide. Wavelength Dispersive X-Ray Fluorescence spectroscopy have shown the presence of cellulose, Ca, Si, K, Cl, Mg, P, S, Al, Fe, Na, Sr, Pd, Zn, Mn, Cr, Mo, Br, Ni, Rb and Zr. It is assumed that these elements alongwith other chemical compounds of the plant species may play a role in the management of diabetes. The Raman Specta of both glibenclamide and leaf powder has also shown some similarities. The results obtained during the present investigation have revealed the antidiabetic activity of Ficus krishnae leaves. The phytochemical screening has indicated the various chemical constituents likely to be responsible for this activity. The Fourier Transform Infrared, Wavelength Dispersive X-Ray Fluorescence and Raman Specta of the leaf powder suggested that there is some glibenclamide like molecule or its derivatives which is imparting antidiabetic activity. PMID- 25284931 TI - Synthesis of Pyrimidine Incorporated Piperazine Derivatives and their Antimicrobial Activity. AB - Thiophene substituted chalcones (1a-e) were cyclised with thiourea in presence of potassium hydroxide to get 4-substituted-6-(thiophen-2-yl)pyrimidine-2-thiols (2a e) which were then stirred with methyl iodide to obtain 4-substituted-2 (methylsulfanyl)-6-(thiophen-2-yl)pyrimidines (3a-e). Compounds (3a-e) were refluxed with different N-methylpiperazine and N-phenylpiperazine to afford 4 substituted-2-(4-methylpiperazin-1-yl)-6-(thiophen-2-yl)pyrimidines (4a-e) and 4 substituted-2-(4-phenylpiperazin-1-yl)-6-(thiophen-2-yl)pyrimidines (5a-e). The structures of all the newly synthesised compounds 4b, 4d, 5a and 5b showed good antibacterial activity at 40MUg/mlconcentration. Compounds 4a, 4d, 4e, 5c and 5e showed significant antifungal activity at 40 MUg/ml concentration compared with standard drugs. PMID- 25284932 TI - Synthesis, in vitro Anticancer and Antimicrobial Evaluation of Novel Substituted Dihydropyrimidines. AB - A series of 1,4-dihydropyrimidine derivatives 3(a-t) were prepared from Biginelli reactions by using ethyl acetoacetate, substituted benzaldehyde and thiourea in the presence of piperidine and ethanol. The compounds 3(a-t) were reacted with dimethylsulphate, diethylsulphate, butyl bromide and benzyl chloride to give the new series of compounds 4(a-t). The structures of the newly synthesized compounds 4(a-t) were established by IR, (1)H NMR, Mass spectra and elemental analysis. The synthesized compounds were evaluated for their in vitro anticancer activity by using Sulforhodamine B assay method against the growth of four humans cancer cell lines, antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli and for antifungal activity against Candida albicans and Aspergillus niger. The compounds exhibited good anticancer activity and moderate antibacterial and antifungal activities. Compounds 4b, 4c, 4d, 4g, 4i, 4n, 4o, 4q and 4s showed significant anticancer activity when compared with the doxorubicin as a standard reference drug. PMID- 25284933 TI - Standardization of in vitro Cell-based Model for Renal Ischemia and Reperfusion Injury. AB - Renal ischemia reperfusion injury contributes patho-physiological imbalance of acute renal failure that comprises of generation of reactive oxygen species, nitric oxide and peroxynitrite and inflammation involving cytokine/adhesion molecule cascade, finally leads to cell death. Oxygen deprival associated with ischemia that in turn lead to decline ATP production is the characteristic feature usually addressed in the development of in vitro cell based ischemic model. In order to create oxygen deficit in the cell lines different approaches like chemical induction, enzymatic induction and anaerobic chamber models are widely used. However efficiencies of these models were varied and the present study was aimed to compare the suitability of these models in creating in vitro ischemia reperfusion in cell culture. In the chemical induced method we used different concentrations of rotenone, antimycin and sodium azide to inhibit electron transport chain and thereby reduced the ATP production, measured indirectly by cell viability assay. Among the chemical induced model, antimycin mediated cell injury was more reliable for ischemia reperfusion study. In the enzymatic model, comprises of glucose oxidase (3mM/s) and catalase (998 s(-1) at 10:1 ratio) was used and found to be best among the three approaches as it can create injury in short experimental time and are reproducible. However anaerobic chamber method was not suitable for ischemia reperfusion study as it need more time to induce significant cell injury. PMID- 25284934 TI - Formulation Design, Optimization and Pharmacodynamic Evaluation of Sustained Release Mucoadhesive Microcapsules of Venlafaxine HCl. AB - The objective of present research work was to design and characterize the venlafaxine HCl-loaded sodium alginate-based mucoadhesive microcapsules by ionic gelation technique using HPMC K100M as mucoadhesive polymer. The Placket-Burman Design was applied for preliminary screening of the formulations and systematic optimization by using Box-Behnken Design. The prepared microcapsules were characterized for drug content, entrapment efficiency, micromeritic properties, particle size, swelling index, mucoadhesive strength, in vitro drug release and in vivo antidepressant activity. FTIR and differential scanning calorimetry studies showed no incompatibility. Surface morphology studies revealed spherical nature of the prepared microcapsules. In vitro drug release studies revealed sustained release by diffusion mechanism. Further, the microcapsules were effective in reducing the depression induced by forced swimming test in Sprague Dawley rats compared to the pure drug. The microcapsules were found to be stable under accelerated stability conditions, which suggest them as better alternative delivery systems for enhanced therapeutic efficacy of antidepressant drug, venlafaxine HCl. PMID- 25284935 TI - Assessment of Bioautography and Spot Screening of TLC of Green Tea (Camellia) Plant Extracts as Antibacterial and Antioxidant Agents. AB - This study was carried out as a prerequisite to evaluate the therapeutic potential of Camellia varieties. The crude extracts of six different plants of green tea Camellia assamica and Camellia sinensis were tested against three Gram positive and four Gram-negative bacteria using agar disk diffusion method at 50 mg/ml concentration. 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) and diphenyl-(2,4,6-trinitrophenyl)iminoazanium free radical scavenging methods were performed to evaluate the antioxidant potential. Phytochemical constituents and trace metals were detected through thin layer chromatography and Inductively Coupled Plasma Atomic Emission Spectrophotometer, respectively. The maximum inhibition of Staphylococcus aureus was recorded by dimethyl sulphoxide extracts of green tea varieties. The measured zone of inhibition of dimethyl sulphoxide extracts by Qimen was (10.00+/-0.0 mm), Japanese (10.00+/-0.0 mm), Turkish (10.00+/-0.0 mm), Indonesian (8.33+/-1.0 mm), P3 clone (10.00+/-0.0 mm) and Sri Lankan (10.00+/-0.0 mm). Maximum scavenging potential activity was found with ethanol, methanol and dimethyl sulphoxide extracts. Spot screening of TLC developed plates indicated that the presence of active biological compounds such as flavonoids, proteins, phenols, alkaloids and glycosides also exhibited strong activity against tested bacterial strains. This study reveals the potential biological activities of Camellia assamica and Camellia sinensis having massive phytochemical constituents and trace elements. PMID- 25284936 TI - Comparative in vitro Cytotoxic Studies of Novel 8-(4'/2'-Methoxy/Unsubstituted phenylcarbamoyl)bicyclo[3.3.1]nonane Derivatives on Ehrlich Ascites Carcinoma Cell Line. AB - Novel bicyclo[3.3.1]nonane derivatives were synthesized by an efficient methodology from acetoacetanilide, 2-methoxy and 4-methoxyacetoacetanilides, 1,3,5-trinitrobenzene and triethylamine. The structures of the compounds were characterized by UV/Visible, FTIR, (1)H NMR and 2D-correlation spectroscopy analysis. The in vitro cytotoxic studies were performed using Ehrlich Ascites Carcinoma cell line by Trypan blue dye exclusion assay and 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay. The IC50 values of the 8-(4'-/2'-methoxy/unsubstituted phenylcarbamoyl)bicyclo[3.3.1]nonanes were found to be 110.65 MUg/ml, 148.23 MUg/ml and 151.71 MUg/ml, respectively. Thus (4 methoxyphenylcarbomyl)bicyclo[3.3.1]nonane was more potent compared to other two bicyclic adducts. PMID- 25284938 TI - Subjective well-being and health: A potential field for scientific enquiry into the foundational concepts of Ayurveda. PMID- 25284937 TI - Evaluation of skin colouring properties of curcuma longa extract. AB - The aim of this study was to evaluate the skin colouring properties of curcuma extract in cosmetic formulations. Objective measurements of the skin colour changes were done by Chromameter using the CIE L*a*b* colour space parameters. These measurements were correlated with the results of the sensory analysis. The observations showed permanent, visible and statistically significant changing of b* component after one application of emulsions containing 12% and 25% of turmeric extract. The change of skin color remained also after removing the emulsion. Sensory analysis indicated that the tested emulsions with curcuma extract have a significant impact on skin smoothness, spreadability, cosmetic absorption and pillow effect. PMID- 25284939 TI - In vitro cytotoxic activity of menispermaceae plants against HeLa cell line. AB - BACKGROUND: Menispermaceae, a family of flowering plants, is a medium-sized family of 70 genera totaling 420 extant species, mostly of climbing plants. It has various medicinal properties, which are used in the Ayurvedic system of medicine. Plants belonging to this family are rich in alkaloids, especially bisbenzylisoquinoline type. The hypothesis of this study is that the bisbenzylisoquinoline alkaloids present in the selected plants may exhibit in vitro cytotoxic property. AIM: The present study is aimed at estimating the total alkaloidal content of methanolic extract of Cocculus hirsutus and Cissampelos pareira and evaluating the in vitro cytotoxic activity of both the extracts on the HeLa cell line. SETTINGS AND DESIGN: Methanolic extracts of both the plants in the concentrations of 500, 250, 125, 62.5, and 31.25 MUg/ml were assessed for its cytotoxic activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MATERIALS AND METHODS: Total alkaloidal content was studied for both the plants using ultraviolet-visible spectroscopy method. Methanol extracts of both the plants were tested for its inhibitory effect on HeLa cell line. Cytotoxicity of the plant extracts was evaluated by MTT assay. Nonlinear regression graph was plotted between % cell inhibition and Log10 concentration, and IC50 was determined using GraphPad Prism software. RESULTS: Preliminary phytochemical studies confirm the presence of alkaloids in both the plants. The total alkaloids present in C. hirsutus and C. pareira were found to be 0.252%w/w and 0.1656%w/w respectively. The IC50 values of C. hirsutus and C. pareria were found to be 111 MUg/ml and 129.3 MUg/ml respectively. CONCLUSION: From this study, it is observed that C. hirsutus and C. pareira have in vitro cytotoxic activity against HeLa cell line. PMID- 25284940 TI - A self-rating scale to measure tridosas in children. AB - BACKGROUND: Self - rating inventories to assess the Prakrti (constitution) and personality have been developed and validated for adults. To analyze the effect of personality development programs on Prakrti of the children, standardized scale is not available. Hence, present study was carried out to develop and standardize Caraka Child Personality inventory (CCPI). MATERIALS AND METHODS: The 77- item CCPI scale was developed on the basis of translation of Sanskrit verses describing vataja (a), pittaja (b) and kaphaja prakrti (c) characteristics described in Ayurveda texts and by taking the opinions of 5 Ayurveda experts and psychologists. The scale was administered on children of the age group 8-12 years in New Generation National public school, Bangalore. RESULTS: This inventory was named CCPI and showed excellent internal consistency. The Cronbach's alpha for A, B and C scales were 0.54, 0.64 and 0.64 respectively. The Split - Half reliability scores for A, B and C subscales were 0.64. 0.60 and 0.66 respectively. Factor validity coefficient Scores on each item was above 0.4. Scores on vataja, pittaja and kaphaja scales were inversely correlated. Test retest reliability scores for A,B and C scales were 0.87,0.88 and 0.89 respectively. The result of CCPI was compared with a parent rating scale Ayurveda Child Personality Inventory (ACPI). Subscales of CCPI correlated significantly highly (above 0.80) with subscales of ACPI which was done for the purpose of cross-validation with respect to ACPI. CONCLUSIONS: The prakrti of the children can be measured consistently by this scale. Correlations with ACPI pointed toward concurrent validity. PMID- 25284941 TI - The folklore medicinal orchids of Sikkim. AB - BACKGROUND: Orchids are well-known for decorative and aromatic values than its medicinal properties. Jivanti, Jivaka, Rsabhaka, Rasna, Manakanda, Pancagula are used in Ayurveda are said to be orchids. There are 50 species of orchids in medicine. Sikkim has identified 523 species of wild orchids so far. AIM: The aim of this study is to determine the folklore medicinal use of orchids in Sikkim. MATERIALS AND METHODS: To assess the traditional medicinal uses of orchid species, close contacts were made with native people particularly, traditional healers, religious leaders, nursery growers and villagers of Sikkim. The information was gathered with the help of the questionnaire and personal interviews with various knowledgeable respondents during the field visit in between August 2009 and December 2011. RESULTS AND CONCLUSION: We found that 36 species of orchids are used as medicines for different purposes of health. The botanical and ayurvedic name, phenology, parts used and medicinal uses of 36 orchids are presented in this paper along with its local distribution. PMID- 25284942 TI - Pharmaceutical standardization of Svarna vanga. AB - BACKGROUND: Kupipakva Rasayana is a category of Rasausadhis (herbomineral medicines) prepared by unique pharmaceutical process explained in Rasasastra. Svarna Vanga (SV) is one such medicament indicated mainly in diseases such as Madhumeha (diabetes mellitus), Svasa (respiratory disorders), Pradara (menorrhagia), and as a Vrsya (aphrodisiac). AIMS AND OBJECTIVES: The aim of this study is to establish the standard manufacturing process for SV and analyze its organoleptic and physicochemical properties. DESIGN: Pharmaceutical standardization. MATERIALS AND METHODS: Sodhita Vanga was melted and triturated with purified Parada (mercury) to form an amalgam. The amalgam so formed was mixed with Saindhava Lavana and levigated with Nimbu Svarasa (Citrus medica Var.) and washed until blackness of the mixture disappeared. On drying, suddha Gandhaka (Sulfur) and Navasadara (Ammonium chloride) were added and ground into a fine powder. The powder thus formed was filled in the Kupi and processed in an electrical muffle furnace for 18 h. On cooling, the product formed at the bottom of the Kupi was collected. Organoleptic and physicochemical parameters of SV were analyzed and tabulated. RESULTS AND CONCLUSION: SV is a Talastha Kupipakva Rasayana. It requires Mrdu (<250 C) and Madhyama Agni (250-500 C) for a period of 9 h each to prepare SV with 42.9% yield and having 63.2 and 34.4% tin and sulfur, respectively. PMID- 25284943 TI - Evaluation of implementation status of national policy on Indian systems of medicine and homeopathy 2002: Stakeholders' perspective. AB - BACKGROUND: National Policy on Indian systems of medicine and homoeopathy (ISM and H policy) was formulated in 2002 to encourage the development of Ayurveda, Sidhha, Unani, Yoga, Naturopathy and Homoeopathy in India. This study proposes to assess the views of public health experts on current implementation of ISM and H Policy. METHODS: An online questionnaire was designed to ascertain the views of public health experts on ISM and H Policy and mailed to 100 public health experts. The tool was tested for content validity and a pilot study was done. Results were analyzed with the help of SPSS version 16. RESULTS AND CONCLUSION: Response rate was 61%. Majority of experts considered implementation status of ISM and H Policy as poor. Lack of quality education was mentioned as major factor responsible for current scenario of ISM and H Policy by most of experts. Lack of funds and government support were emerged as major bottlenecks in implementation of ISM and H Policy. PMID- 25284944 TI - In-vitro antioxidant and antibacterial activities of Xanthium strumarium L. extracts on methicillin-susceptible and methicillin-resistant Staphylococcus aureus. AB - BACKGROUND AND AIMS: The excessive and repeated use of antibiotics in medicine has led to the development of antibiotic-resistant microbial strains, including Staphylococcus aureus whose emergence of antibiotic-resistant strains has reduced the number of antibiotics available to treat clinical infections caused by this bacterium. In this study, antioxidant and antimicrobial activities of methanolic extract of Xanthium strumarium L. leaves were evaluated on methicillin susceptible and methicillin-resistant Staphylococcus aureus (MRSA) spp. MATERIALS AND METHODS: Antiradical and antioxidant activities X. strumarium L. leaf extract were evaluated based on its ability to scavenge the synthetic 1,1-diphenyl-2 picrylhydrazyl (DPPH) free radical and by the paired diene method, respectively, whereas the antimicrobial activity was assayed by the disc diffusion method. STATISTICAL ANALYSIS: Data were subjected to analysis of variance following an entirely random design to determine the least significant difference at P < 0.05 using SPSS v. 11.5. RESULTS AND CONCLUSIONS: The IC50 values of the extract were 0.02 mg/mL and 0.09 mg/mL for the antioxidant and DPPH-scavenging capacity, respectively. X. strumarium extract affected both methicillin-sensitive Staphylococcus aureus and MRSA, though antibacterial activity was more effective on methicillin-susceptible S. aureus spp. The antibacterial and antioxidant activities exhibited by the methanol extract may justify the traditional use of this plant as a folk remedy worldwide. PMID- 25284945 TI - Studies on in vitro interaction of ampicillin and fresh garlic extract against Staphylococcus aureus by checkerboard method. AB - OBJECTIVE: Staphylococcus aureus has largely developed resistance to the multiple antimicrobial agents. Garlic (Allium sativum) is claimed to retard development of resistance and produce synergy with conventional antimicrobial agents. The aim of the present study was to evaluate the effect of combination of ampicillin with fresh garlic extract (FGE) against S. aureus by using in vitro method. MATERIALS AND METHODS: Antimicrobial activity of FGE was studied by well diffusion and broth dilution methods. The effect of combination of ampicillin with FGE was studied by using checkerboard method against the clinical isolates of S. aureus. The organisms were exposed to individual antimicrobial as well the different combinations of the two agents and minimum inhibitory concentration was measured. RESULTS: Synergistic interaction was observed by the combination of FGE with ampicillin for all the strains of S. aureus. Mean minimum inhibitor concentration (MIC) of ampicillin per se was 24 MUg/ml. Addition of 30-60 mg/ml of FGE reduced MIC of ampicillin to <2 MUg/ml. CONCLUSION: This in vitro study indicates synergism between FGE and ampicillin against S. aureus. Evaluation of these combinations in vivo may be warranted. PMID- 25284946 TI - Evaluation of a Unani polyherbal formulation (Tiryaqe wabai) as an immunostimulator in elderly persons. AB - BACKGROUND AND AIMS: Elderly subjects have a dysregulation of immune response mainly due to the changes in cell - mediated immunity. Due to their weakened immune response, the elderly are at increased risk of infection and related complications. In Unani medicine Tiryaq wabai was used for the prevention of epidemic diseases during outbreaks, but it has not been explored scientifically so far. The study was aimed to evaluate the immune-stimulating effect of Tiryaq wabai in elderly. MATERIALS AND METHODS: A randomized placebo controlled trial was conducted at National Institute of Unani Medicine Hospital, Bangalore. Thirty immunocompromised elderly persons were selected on the basis of clinical examination considering parameters like history of recurrent infection, unexplained weight loss, persistent diarrhea etc. They were randomly assigned, 20 in test and 10 in the control group. Tiryaq wabai was given to test group 500 mg orally thrice in a week for 45 days. Placebo was given orally to the control group at a dose of 500 mg thrice in a week for 45 days. Response was assessed by total leucocyte count (TLC), lymphocyte percentage, absolute lymphocyte count (ALC), CD4 and CD8 count. The results were analyzed statistically using Graph Pad InStat 3. RESULTS: The test drug showed statistically significant increase in TLC (P < 0.001), lymphocyte percentage (P < 0.001),ALC (P < 0.001), CD4 count (P < 0.001) in comparison to control group, but increase in CD8 count was not statistically significant. No major adverse effect was observed throughout the study. CONCLUSION: The findings outlined above indicate immune- stimulating activity of Tiryaq wabai and supports its use in conditions where immunostimulation is required and thus is suggestive of therapeutic usefulness. PMID- 25284947 TI - Evaluation of Brahmi ghrtam in children suffering from Attention Deficit Hyperactivity Disorder. AB - INTRODUCTION: Attention Deficit Hyperactivity Disorder (ADHD) is characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. In view of the adverse effects associated with psycho-stimulants used for the treatment of this disorder, efficacy of Brahmi ghrtam was evaluated in this condition. MATERIALS AND METHODS: After following due ethical considerations, children of either sex between the age group of 6 and 12 years diagnosed to be suffering from mixed variety of ADHD as per The Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria irrespective of other co-morbid psychiatric illnesses were recruited in the study. Initially a pilot study (n = 10) was carried out to confirm the efficacy of the identified dose of Brahmi ghrtam. Using this dose, further therapeutic confirmatory study (n = 27) was carried out, wherein Brahmi ghrtam was compared with methylphenidate. Effect on ADHD symptoms was assessed using the Dupaul ADHD rating scale and this was the main efficacy parameter. RESULTS: In the pilot exploratory study, Brahmi ghrtam showed 66% decrease in total ADHD score. In the therapeutic confirmatory study, only 16% improvement was seen with Brahmi ghrtam, which was similar to methylphenidate, standard treatment for ADHD that was used as a comparator in the present study. No side-effects were reported in both studies. CONCLUSION: Our study thus has adequately demonstrated efficacy and safety of Brahmi ghrtam in ADHD. PMID- 25284949 TI - Merremia emarginata (Burm. F.) Hall. F.: A substituted market source for Centella asiatica (L.) Urban: An observation from Salem district, Tamil Nadu. PMID- 25284948 TI - Pharmacological and therapeutic effects of Mentha Longifolia L. and its main constituent, menthol. AB - Mentha longifolia (wild mint) is a popular folk remedy. Some parts of this plant have been used in traditional medicine of Iran and other countries. Many studies have shown various pharmacological and therapeutic effects of the plant. Our aim in preparing this study was to review the traditional uses of M. longifolia together with the pharmacological and therapeutic effects of its entire extract and major compounds. Mentha longifolia is an herb with a wide range of pharmacological properties such as antimicrobial, gastrointestinal, and nervous system effects. Pulegone is the main compound of the plant responsible for most of its pharmacological effects followed by menthone, isomenthone, menthol, 1, 8 cineole, borneol, and piperitenone. Moreover, the plant may dose-dependently exert toxic effects in different systems of the body. Based on the review of various studies, it can be concluded that M. longifolia is a potential natural source for the development of new drugs. However, further studies are required to determine the precise quality and safety of the plant to be used by clinicians. PMID- 25284950 TI - Shear rheology and filament stretching behaviour of xanthan gum and carboxymethyl cellulose solution in presence of saliva. AB - The objective of the work reported in this paper is to determine if saliva addition has an effect on the rheology of xanthan gum solutions. The reasons for the interest was that it has been previously reported that flavour release from high viscosity xanthan thickened foods is not reduced in the same way as foods thickened by other hydrocolloids at comparable viscosities. It was previously postulated that this could be due to an interaction between saliva and xanthan that could change the microstructure and rheology of xanthan solutions. In this work the effect of saliva on the rheology of CMC and xanthan solutions was compared. Solutions of molecularly dissolved xanthan gum and CMC mixed with water or human whole saliva at a ratio of 5:1 showed little impact of the presence of saliva on steady shear or dynamic viscosity for the two hydrocolloids. In filament thinning experiments saliva addition significantly increased filament break-up time for xanthan gum while it had little effect on the break-up time of the CMC filament. Also, filament thinning appeared a lot less even and was not as reproducible in the case of xanthan gum. Addition of CMC and hydroxypropyl methylcellulose (HPMC) to xanthan gum solutions showed a similar increase in break-up time to saliva, but to see this effect the viscosity of the added CMC or HPMC solution had to be very much higher than the viscosity of saliva. The results are discussed in the context of the structure of xanthan gum and the reported extensional rheology of saliva. PMID- 25284951 TI - Aceptabilidad del diagnostico rapido casero para HIV entre hombres gay y otros hombres que tienen sexo con hombres (G&HSH) de la Ciudad de Buenos Aires. AB - El uso del diagnostico rapido para HIV en Argentina, asi como otros paises de Latinoamerica, ha sido limitado hasta el momento. Este trabajo reporta los resultados provenientes de un estudio cualitativo realizado entre hombres gays y otros hombres que tienen sexo con hombres (G&HSH) de la Ciudad de Buenos Aires, Argentina. El objetivo principal del mismo fue conocer las ventajas y desventajas que los hombres G&HSH perciben en relacion al diagnostico rapido casero para HIV. Se realizaron ocho grupos focales con 73 participantes en los cuales se discutio acerca de las ventajas y desventajas del uso de los diagnosticos rapidos. Las respuestas fueron codificadas utilizando un programa para analisis de datos cualitativos (NVivo) y analizadas tematicamente. Los participantes describieron numerosas ventajas sobre el uso del diagnostico rapido casero, aunque algunos reportaron importantes preocupaciones dentro de las cuales se destaca la posibilidad de impulsos suicidas si alguien recibe un resultado positivo estando solo. En terminos generales se observo una gran aceptabilidad para el uso del diagnostico rapido si el mismo es realizado por personal de salud en lugares acondicionados para este fin. PMID- 25284952 TI - Rehabilitation Program Integrating Virtual Environment to Improve Orientation and Mobility Skills for People Who Are Blind. AB - This paper presents the integration of a virtual environment (BlindAid) in an orientation and mobility rehabilitation program as a training aid for people who are blind. BlindAid allows the users to interact with different virtual structures and objects through auditory and haptic feedback. This research explores if and how use of the BlindAid in conjunction with a rehabilitation program can help people who are blind train themselves in familiar and unfamiliar spaces. The study, focused on nine participants who were congenitally, adventitiously, and newly blind, during their orientation and mobility rehabilitation program at the Carroll Center for the Blind (Newton, Massachusetts, USA). The research was implemented using virtual environment (VE) exploration tasks and orientation tasks in virtual environments and real spaces. The methodology encompassed both qualitative and quantitative methods, including interviews, a questionnaire, videotape recording, and user computer logs. The results demonstrated that the BlindAid training gave participants additional time to explore the virtual environment systematically. Secondly, it helped elucidate several issues concerning the potential strengths of the BlindAid system as a training aid for orientation and mobility for both adults and teenagers who are congenitally, adventitiously, and newly blind. PMID- 25284953 TI - CuPc/Au(1 1 0): Determination of the azimuthal alignment by a combination of angle-resolved photoemission and density functional theory. AB - Here we report on a combined experimental and theoretical study on the structural and electronic properties of a monolayer of Copper-Phthalocyanine (CuPc) on the Au(1 1 0) surface. Low-energy electron diffraction reveals a commensurate overlayer unit cell containing one adsorbate species. The azimuthal alignment of the CuPc molecule is revealed by comparing experimental constant binding energy (kxky )-maps using angle-resolved photoelectron spectroscopy with theoretical momentum maps of the free molecule's highest occupied molecular orbital (HOMO). This structural information is confirmed by total energy calculations within the framework of van-der-Waals corrected density functional theory. The electronic structure is further analyzed by computing the molecule-projected density of states, using both a semi-local and a hybrid exchange-correlation functional. In agreement with experiment, the HOMO is located about 1.2 eV below the Fermi level, while there is no significant charge transfer into the molecule and the CuPc LUMO remains unoccupied on the Au(1 1 0) surface. PMID- 25284954 TI - Lexical Retrieval is not by Competition: Evidence from the Blocked Naming Paradigm. AB - A central issue in research on speech production is whether or not the retrieval of words from the mental lexicon is a competitive process. An important experimental paradigm to study the dynamics of lexical retrieval is the blocked naming paradigm, in which participants name pictures of objects that are grouped by semantic category ('homogenous' or 'related' blocks) or not grouped by semantic category ('heterogeneous' or 'unrelated' blocks). Typically, pictures are repeated multiple times (or cycles) within both related and unrelated blocks. It is known that participants are slower in related than in unrelated blocks when the data are collapsed over all within-block repetitions. This semantic interference effect, as observed in the blocked naming task, is the strongest empirical evidence for the hypothesis of lexical selection by competition. Here we show, contrary to the accepted view, that the default polarity of semantic context effects in the blocked naming paradigm is facilitation, rather than interference. In a series of experiments we find that interference arises only when items repeat within a block, and only because of that repetition: What looks to be 'semantic interference' in the blocked naming paradigm is actually less repetition priming in related compared to unrelated blocks. These data undermine the theory of lexical selection by competition and indicate a model in which the most highly activated word is retrieved, regardless of the activation levels of nontarget words. We conclude that the theory of lexical selection by competition, and by extension the important psycholinguistic models based on that assumption, are no longer viable, and frame a new way to approach the question of how words are retrieved in spoken language production. PMID- 25284955 TI - The Autodigestion Hypothesis in Shock and Multi-Organ Failure: Degrading Protease Activity. AB - Shock and multi-organ failure have one of the highest levels of inflammatory markers, morbidities and mortality. The underlying mechanisms are currently unknown and no effective intervention exists. We present evidence for a previously untested mechanism due to autodigestion by the digestive enzymes synthesized in the pancreas and transported in the lumen of the intestine as normal part of food digestion. We summarize experimental evidence in support of the autodigestion hypothesis and a new approach for possible intervention against multi-organ failure that is currently entering clinical trials. PMID- 25284956 TI - Feasibility trial of a film-based educational intervention for increasing boys' and girls' intentions to avoid teenage pregnancy: Study protocol. AB - The World Health Organisation, amongst others, recognises that adolescent men have a vital yet neglected role in reducing teenage pregnancies and that there is a pressing need for educational interventions designed especially for them. This study seeks to fill this gap by determining the feasibility of conducting an effectiveness trial of the If I Were Jack intervention in post-primary schools. This 4-week intervention aims to increase teenagers' intentions to avoid unintended pregnancy and addresses gender inequalities in sex education by explicitly focusing on young men. A cluster randomised feasibility trial with embedded process evaluation will determine: recruitment, participation and retention rates; quality of implementation; acceptability and feasibility of the intervention and trial procedures; and costs. PMID- 25284957 TI - Parental Writing Support and Preschoolers' Early Literacy, Language, and Fine Motor Skills. AB - The current study examines the nature and variability of parents' aid to preschoolers in the context of a shared writing task, as well as the relations between this support and children's literacy, vocabulary, and fine motor skills. In total, 135 preschool children (72 girls) and their parents (primarily mothers) in an ethnically diverse, middle-income community were observed while writing a semi-structured invitation for a pretend birthday party together. Children's phonological awareness, alphabet knowledge, word decoding, vocabulary, and fine motor skills were also assessed. Results revealed that parents provided variable, but generally low-level, support for children's approximation of sound-symbol correspondence in their writing (i.e., graphophonemic support), as well as for their production of letter forms (i.e., print support). Parents frequently accepted errors rather than asking for corrections (i.e., demand for precision). Further analysis of the parent-child dyads (n = 103) who wrote the child's name on the invitation showed that parents provided higher graphophonemic, but not print, support when writing the child's name than other words. Overall parental graphophonemic support was positively linked to children's decoding and fine motor skills, whereas print support and demand for precision were not related to any of the child outcomes. In sum, this study indicates that while parental support for preschoolers' writing may be minimal, it is uniquely linked to key literacy-related outcomes in preschool. PMID- 25284959 TI - Typology of historical sources and the reconstruction of long-term historical changes of riverine fish: a case study of the Austrian Danube and northern Russian rivers. AB - Historical data are widely used in river ecology to define reference conditions or to investigate the evolution of aquatic systems. Most studies rely on printed documents from the 19th century, thus missing pre-industrial states and human impacts. This article discusses historical sources that can be used to reconstruct the development of riverine fish communities from the Late Middle Ages until the mid-20th century. Based on the studies of the Austrian Danube and northern Russian rivers, we propose a classification scheme of printed and archival sources and describe their fish ecological contents. Five types of sources were identified using the origin of sources as the first criterion: (i) early scientific surveys, (ii) fishery sources, (iii) fish trading sources, (iv) fish consumption sources and (v) cultural representations of fish. Except for early scientific surveys, all these sources were produced within economic and administrative contexts. They did not aim to report about historical fish communities, but do contain information about commercial fish and their exploitation. All historical data need further analysis for a fish ecological interpretation. Three case studies from the investigated Austrian and Russian rivers demonstrate the use of different source types and underline the necessity for a combination of different sources and a methodology combining different disciplinary approaches. Using a large variety of historical sources to reconstruct the development of past fish ecological conditions can support future river management by going beyond the usual approach of static historical reference conditions. PMID- 25284958 TI - The Cognitive Development of Young Dual Language Learners: A Critical Review. AB - Dual language exposure and bilingualism are relatively common experiences for children. The present review set out to synthesize the existing research on cognitive development in bilingual children and to identify the gaps and the methodological concerns present in the existing research. A search of major data bases for research conducted with typically-developing, preschool-age dual language learners between 2000-2013 yielded 102 peer-reviewed articles. The existing evidence points to areas of cognitive development in bilingual children where findings are robust or inconclusive, and reveals variables that influence performance. The present review also identifies areas for future research and methodological limitations. PMID- 25284960 TI - Comparing supervised and unsupervised multiresolution segmentation approaches for extracting buildings from very high resolution imagery. AB - Although multiresolution segmentation (MRS) is a powerful technique for dealing with very high resolution imagery, some of the image objects that it generates do not match the geometries of the target objects, which reduces the classification accuracy. MRS can, however, be guided to produce results that approach the desired object geometry using either supervised or unsupervised approaches. Although some studies have suggested that a supervised approach is preferable, there has been no comparative evaluation of these two approaches. Therefore, in this study, we have compared supervised and unsupervised approaches to MRS. One supervised and two unsupervised segmentation methods were tested on three areas using QuickBird and WorldView-2 satellite imagery. The results were assessed using both segmentation evaluation methods and an accuracy assessment of the resulting building classifications. Thus, differences in the geometries of the image objects and in the potential to achieve satisfactory thematic accuracies were evaluated. The two approaches yielded remarkably similar classification results, with overall accuracies ranging from 82% to 86%. The performance of one of the unsupervised methods was unexpectedly similar to that of the supervised method; they identified almost identical scale parameters as being optimal for segmenting buildings, resulting in very similar geometries for the resulting image objects. The second unsupervised method produced very different image objects from the supervised method, but their classification accuracies were still very similar. The latter result was unexpected because, contrary to previously published findings, it suggests a high degree of independence between the segmentation results and classification accuracy. The results of this study have two important implications. The first is that object-based image analysis can be automated without sacrificing classification accuracy, and the second is that the previously accepted idea that classification is dependent on segmentation is challenged by our unexpected results, casting doubt on the value of pursuing 'optimal segmentation'. Our results rather suggest that as long as under-segmentation remains at acceptable levels, imperfections in segmentation can be ruled out, so that a high level of classification accuracy can still be achieved. PMID- 25284961 TI - The Teenage Brain: Self Control. AB - Adolescence refers to the transition from childhood to adulthood that begins with the onset of puberty and ends with successful independence from the parent. A paradox for human adolescence is why, during a time when the individual is probably faster, stronger, of higher reasoning capacity and more resistant to disease, there is such an increase in mortality relative to childhood. These untimely deaths are not due to disease, but rather to preventable forms of death (accidental fatalities, suicide and homicide) associated with adolescents putting themselves in harm's way due, in part, to diminished self control - the ability to suppress inappropriate emotions, desires and actions. This paper highlights how self control varies as a function of age, context and the individual and delineates its neurobiological basis. PMID- 25284962 TI - Comprehensive peptidomic and glycomic evaluation reveals that sweet whey permeate from colostrum is a source of milk protein-derived peptides and oligosaccharides. AB - Whey permeate is a co-product obtained when cheese whey is passed through an ultrafiltration membrane to concentrate whey proteins. Whey proteins are retained by the membrane, whereas the low-molecular weight compounds such as lactose, salts, oligosaccharides and peptides pass through the membrane yielding whey permeate. Research shows that bovine milk from healthy cows contains hundreds of naturally occurring peptides - many of which are homologous with known antimicrobial and immunomodulatory peptides - and nearly 50 oligosaccharide compositions (not including structural isomers). As these endogenous peptides and oligosaccharides have low-molecular weight and whey permeate is currently an under-utilized product stream of the dairy industry, we hypothesized that whey permeate may serve as an inexpensive source of naturally occurring functional peptides and oligosaccharides. Laboratory fractionation of endogenous peptides and oligosaccharides from bovine colostrum sweet whey was expanded to pilot scale. The membrane fractionation methodology used was similar to the methods commonly used industrially to produce whey protein concentrate and whey permeate. Pilot-scale fractionation was compared to laboratory-scale fractionation with regard to the identified peptides and oligosaccharide compositions. Results were interpreted on the basis of whether industrial whey permeate could eventually serve as a source of functional peptides and oligosaccharides. The majority (96%) of peptide sequences and the majority (96%) of oligosaccharide compositions found in the laboratory-scale process were mirrored in the pilot-scale process. Moreover, the pilot-scale process recovered an additional 33 peptides and 1 oligosaccharide not identified from the laboratory-scale extraction. Both laboratory- and pilot-scale processes yielded peptides deriving primarily from the protein beta-casein. The similarity of the laboratory-and pilot-scale's resulting peptide and oligosaccharide profiles demonstrates that whey permeate can serve as an industrial-scale source of bovine milk peptides and oligosaccharides. PMID- 25284963 TI - N-glycan Cryptic Antigens as Active Immunological Targets in Prostate Cancer Patients. AB - Although tumor-associated abnormal glycosylation has been recognized for decades, information regarding host recognition of the evolving tumor glycome remains elusive. We report here a carbohydrate microarray analysis of a number of tumor associated carbohydrates for their serum antibody reactivities and potential immunogenicity in humans. These are the precursors, cores and internal sequences of N-glycans. They are usually masked by other sugar moieties and belong to a class of glyco-antigens that are normally "cryptic". However, viral expression of these carbohydrates may trigger host immune responses. For examples, HIV-1 and SARS-CoV display Man9 clusters and tri- or multi-antennary type II (Galbeta1 >4GlcNAc) chains (Tri/m-II), respectively; viral neutralizing antibodies often target these sugar moieties. We asked, therefore, whether prostate tumor expression of corresponding carbohydrates triggers antibody responses in vivo. Using carbohydrate microarrays, we analyzed a panel of human sera, including 17 samples from prostate cancer patients and 12 from men with Benign Prostatic Hyperplasia (BPH). We observed that IgG antibodies targeting the Man9- or Tri-/m II-autoantigens are readily detectable in the sera of men with BPH, as well as those with cancer. Importantly, these antibody activities were selectively increased in prostate cancer patients. Thus, human immune systems actively recognize these N-glycan cryptic carbohydrates and produce targeting antibodies. This finding shads a light on a class of previously less studied immunological targets of human cancers. Identifying the diagnostic, prognostic and therapeutic values of these targets will require further investigation. PMID- 25284965 TI - Current status of drug use and HIV/AIDS prevention in drug users in China. AB - The objective of this paper is to review the current status of drug use and HIV/AIDS prevention for drug users in China and provide scientific evidence for HIV/AIDS prevention and control in drug users. Literature and articles related to drug abuse in China, as well as the results of prevention efforts and successful cases regarding HIV/AIDS prevention in drug users, are reviewed. Lessons learned are drawn out for the future improvement of work and the sustainable development of treatment programs. The number of drug users in China is increasing. Even though the number of opioid-type drug users is growing more slowly than in the past, the number of amphetamine-type stimulant users has increased sharply. It has been proven that methadone maintenance treatment and syringe exchange programs gradually and successfully control HIV/AIDS transmission in drug users. However, it is necessary to enhance these prevention methods and expand their coverage. In addition, the strengthening of antiretroviral therapy (ART) treatment for HIV-infected drug users is crucial for HIV/AIDS prevention and control. The rapidly growing number of amphetamine-type stimulant users, along with their high-risk behavior, poses a hidden danger of greater HIV/AIDS transmission through sexual intercourse in the near future. PMID- 25284964 TI - A Proteomic Study of Human Merkel Cell Carcinoma. AB - Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin. The incidence has been quadrupled with a 5-year mortality rate of 46%, presently there is no cure for metastatic disease. Despite the contribution of Merkel cell polyomavirus, the molecular events of MCC carcinogenesis are poorly defined. To better understand MCC carcinogensis, we have performed the first quantitative proteomic comparison of formalin-fixed, paraffin-embedded (FFPE) MCC tissues using another neuroendocrine tumor (carcinoid tumor of the lung) as controls. Bioinformatic analysis of the proteomic data has revealed that MCCs carry distinct protein expression patterns. Further analysis of significantly over expressed proteins suggested the involvement of MAPK, PI3K/Akt/mTOR, wnt, and apoptosis signaling pathways. Our previous study and that from others have shown mTOR activation in MCCs. Therefore, we have focused on two downstream molecules of the mTOR pathway, lactate dehydrogenase B (LDHB) and heterogeneous ribonucleoprotein F (hnRNPF). We confirm over-expression of LDHB and hnRNPF in two primary human MCC cell lines, 16 fresh tumors, and in the majority of 80 tissue microarray samples. Moreover, mTOR inhibition suppresses LDHB and hnRNPF expression in MCC cells. The results of the current study provide insight into MCC carcinogenesis and provide rationale for mTOR inhibition in pre-clinical studies. PMID- 25284966 TI - Functional network reorganization in motor cortex can be explained by reward modulated Hebbian learning. AB - The control of neuroprosthetic devices from the activity of motor cortex neurons benefits from learning effects where the function of these neurons is adapted to the control task. It was recently shown that tuning properties of neurons in monkey motor cortex are adapted selectively in order to compensate for an erroneous interpretation of their activity. In particular, it was shown that the tuning curves of those neurons whose preferred directions had been misinterpreted changed more than those of other neurons. In this article, we show that the experimentally observed self-tuning properties of the system can be explained on the basis of a simple learning rule. This learning rule utilizes neuronal noise for exploration and performs Hebbian weight updates that are modulated by a global reward signal. In contrast to most previously proposed reward-modulated Hebbian learning rules, this rule does not require extraneous knowledge about what is noise and what is signal. The learning rule is able to optimize the performance of the model system within biologically realistic periods of time and under high noise levels. When the neuronal noise is fitted to experimental data, the model produces learning effects similar to those found in monkey experiments. PMID- 25284967 TI - Multiplicative Forests for Continuous-Time Processes. AB - Learning temporal dependencies between variables over continuous time is an important and challenging task. Continuous-time Bayesian networks effectively model such processes but are limited by the number of conditional intensity matrices, which grows exponentially in the number of parents per variable. We develop a partition-based representation using regression trees and forests whose parameter spaces grow linearly in the number of node splits. Using a multiplicative assumption we show how to update the forest likelihood in closed form, producing efficient model updates. Our results show multiplicative forests can be learned from few temporal trajectories with large gains in performance and scalability. PMID- 25284968 TI - Wavelet based multi-scale shape features on arbitrary surfaces for cortical thickness discrimination. AB - Hypothesis testing on signals defined on surfaces (such as the cortical surface) is a fundamental component of a variety of studies in Neuroscience. The goal here is to identify regions that exhibit changes as a function of the clinical condition under study. As the clinical questions of interest move towards identifying very early signs of diseases, the corresponding statistical differences at the group level invariably become weaker and increasingly hard to identify. Indeed, after a multiple comparisons correction is adopted (to account for correlated statistical tests over all surface points), very few regions may survive. In contrast to hypothesis tests on point-wise measurements, in this paper, we make the case for performing statistical analysis on multi-scale shape descriptors that characterize the local topological context of the signal around each surface vertex. Our descriptors are based on recent results from harmonic analysis, that show how wavelet theory extends to non-Euclidean settings (i.e., irregular weighted graphs). We provide strong evidence that these descriptors successfully pick up group-wise differences, where traditional methods either fail or yield unsatisfactory results. Other than this primary application, we show how the framework allows performing cortical surface smoothing in the native space without mappint to a unit sphere. PMID- 25284969 TI - WAFER-SCALE, SOLID FREEFORM FABRICATION OF FULLY-ASSEMBLED METAL MICRO-MECHANISMS FOR MINIMALLY-INVASIVE MEDICAL DEVICES. AB - The EFAB process was first presented at the SFF Symposium in 1998, at a very early stage of its development. Currently, the technology is able to produce complex 3-D devices-including mechanisms built pre-assembled-in production volumes, using a three-step process of selective electrodeposition of one metal, blanket electrodeposition of another metal, and planarization. Layer thickness is as small as 4 MUm, minimum feature size is down to 10 MUm, and linear tolerances are ~2 MUm. Metals are biocompatible materials with mechanical properties similar to stainless steel. The technology enables new instruments for minimally-invasive surgical and interventional procedures. PMID- 25284970 TI - Electrochemical Assay of GSTP1-related DNA Sequence for Prostrate Cancer Screening. PMID- 25284971 TI - OLDER ADULTS' PREFERENCES FOR AND ACCEPTANCE OF ROBOT ASSISTANCE FOR EVERYDAY LIVING TASKS. AB - Many older adults value their independence and prefer to age in place. Robots can be designed to assist older people with performing everyday living tasks and maintaining their independence at home. Yet, there is a scarcity of knowledge regarding older adults' attitudes toward robots and their preferences for robot assistance. Twenty-one older adults (M = 80.25 years old, SD = 7.19) completed questionnaires and participated in structured group interviews investigating their openness to and preferences for assistance from a mobile manipulator robot. Although the older adults were generally open to robot assistance for performing home-based tasks, they were selective in their views. Older adults preferred robot assistance over human assistance for many instrumental (e.g., housekeeping, laundry, medication reminders) and enhanced activities of daily living (e.g., new learning, hobbies). However, older adults were less open to robot assistance for some activities of daily living (e.g., shaving, hair care). Results from this study provide insight into older adults' attitudes toward robot assistance with home-based everyday living tasks. PMID- 25284972 TI - Interleukin-17 Induces Expression of Chemokines and Cytokines in Prostatic Epithelial Cells but Does Not Stimulate Cell Growth In Vitro. AB - BACKGROUND: Interleukin-17 (IL-17A) expression is increased in prostate cancer. This study investigated the expression of IL-17A receptor C (IL-17RC) in prostatic intraepithelial neoplasia (PIN) lesions and the effects of IL-17A on prostatic epithelial cells in in-vitro studies. METHODS: IL-17RC expression in human and rodent prostate tissues was detected by immunohistochemistry. Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot analyses were used to determine mRNA and protein expression in human and mouse prostatic epithelial cell lines. RESULTS: IL-17RC protein was increased in human and rodent PIN lesions, compared to the normal human and rodent prostatic epithelium. IL-17A treatment activated the Nuclear Factor-kappaB (NF-kappaB) and/or Extracellular signal-Regulated Kinase (ERK) pathways in human PIN and LNCaP cell lines as well as mouse prostate cancer cell line TRAMP-C1. IL 17A treatment did not affect cell growth of the cell lines studied. However, IL 17A induced expression of CXCL1, CXCL2, CCL2, CCL5, and IL-6 in human and mouse prostatic epithelial cell lines. When the full-length IL-17RC was over-expressed in human PIN and LNCaP cell lines, activation of NF-kappaB and/or ERK pathways and expression of CXCL1, CXCL2, and CCL5 chemokines were significantly enhanced upon IL-17A treatment. CONCLUSION: These findings suggest that the prostatic epithelial cells in PIN lesions may respond to IL-17A stimuli with augmented synthesis of chemokines, due to increased IL-17RC expression. PMID- 25284973 TI - Evaluating the Responsiveness of Accelerometry to Detect Change in Physical Activity. AB - The responsiveness to change of the Actical and ActiGraph accelerometers was assessed in children and adolescents. Participants (n=208) aged 6-16 years completed two simulated free-living protocols, one with primarily light-to moderate physical activities (PA) and one with mostly moderate-to-vigorous PA. Time in sedentary, light, moderate, and vigorous PA was estimated using 8 previously developed cut-points (4 for Actical and 4 for ActiGraph) and 15-s and 30-s epochs. Accelerometer responsiveness for detecting differences in PA between protocols was assessed using standardized response means (SRM). SRM values >=0.8 represented high responsiveness to change. Both accelerometers showed high responsiveness for all PA intensities (SRMs = 1.2-4.7 for Actical and 1.1-3.3 for ActiGraph). All cut-points and epoch lengths yielded high responsiveness, and choice of cut-points and epoch length had little effect on responsiveness. Thus, both the Actical and ActiGraph can detect change in PA in a simulated free-living setting, irrespective of cut-point selection or epoch length. PMID- 25284974 TI - Retrospective study of threshold time for the conventional treatment of branch retinal artery occlusion. AB - PURPOSE: To investigate the medical backgrounds of patients and the treatment periods from the onset of branch retinal artery occlusion to obtaining improved final visual acuity. METHODS: This was a retrospective case series study. A total of 68 consecutive patients (69 eyes) with branch retinal artery occlusion who visited Tokyo Medical University Hospital from 2007 to 2012 were included in this study. All patients underwent ophthalmic examinations and visual acuity tests. We reviewed their medical records for systemic conditions, as well as the periods from onset of symptoms to treatment. Participants were categorized into 2 groups: group A (n=36), which received any treatment within 24 hours from onset, and group B (n=33), which visited our hospital after 24 hours from onset. Best corrected visual acuity (BCVA) changes from the first to final visit and the relationships between systemic condition and visiting time to BCVA were assessed. RESULTS: At the first visit, 59% of the patients had BCVA over 20/40; the ratio was increased to 74% at the final visit. BCVA improved more than 2 lines for 35% of the patients and was unchanged for 57% of those receiving conventional treatment. BCVA over 20/40 was significantly lower in hyperlipidemia patients. Hypertension, diabetes mellitus, and significant carotid stenosis were not correlated. The mean BCVA at baseline (0.91+/-1.03) significantly recovered to 0.35+/-0.91 after treatment in group A (P<0.001, Student's t-test). The mean BCVA at baseline (0.30+/-0.64) was 0.25+/-0.61 at the final visit in group B (no significant change). CONCLUSION: Conventional treatment within 24 hours from onset was acceptable for branch retinal artery occlusion. PMID- 25284975 TI - Femtosecond laser versus mechanical microkeratome-assisted flap creation for LASIK: a prospective, randomized, paired-eye study. AB - PURPOSE: To compare a femtosecond laser with a microkeratome for flap creation during laser in situ keratomileusis (LASIK) in terms of flap thickness predictability and visual outcomes. PATIENTS AND METHODS: This was a prospective, randomized, masked, paired-eye study. Forty-four patients (34 females) who received bilateral LASIK were included. Patients were stratified by ocular dominance, and they then underwent randomization of flap creation using the femtosecond laser on one eye and undergoing the microkeratome procedure on the other one. The visual outcome differences between the corrected distance visual acuity (CDVA) at baseline and the uncorrected distance visual acuity (UDVA) on the first day postoperatively were set as the efficiency index for both groups. All visual acuity outcome results and the deviation of flap thickness were evaluated. P-values <0.05 were considered statistically significant. RESULTS: The index of efficiency regarding the postoperative visual outcomes in the microkeratome group was lower (P<0.0001). This result was correlated with the difference between intended and achieved flap thickness (P=0.038; r=0.28), and a negative relationship in the regression analysis was confirmed (P<0.04; R (2)=0.1428). The UDVA in the microkeratome group improved significantly by the end of the first month (P<0.0271) in comparison to the baseline CDVA. The deviation between intended and postoperative flap thickness using either optical coherence pachymetry or Heidelberg Retinal Tomography II confocal microscopy was statistically significant (paired t-test; P<0.001) between the groups. The flap thickness deviation in the microkeratome group was higher. In the femtosecond laser group, the efficiency index was stable postoperatively (P=0.64) The UDVA improved significantly by the end of the first postoperative week (P=0.0043) in comparison to the baseline CDVA. Six months after surgery, improvement in the UDVA was significant in both groups (all P<0.001; one way analysis of variance). CONCLUSION: Femtosecond laser was superior to microkeratome-assisted LASIK in terms of flap thickness predictability and the speed of visual acuity recovery. A negative relationship in the regression analysis between increasing flap thickness deviation and visual acuity recovery was confirmed. PMID- 25284977 TI - Projected changes in age-related macular degeneration and driving license holders in Finland. AB - PURPOSE: The aim of the study was to approximate the occurrence of all forms of age-related macular degeneration (AMD) of the retina among the driving license holders aged 80 or more, and to project the changes to 2030 in Finland. AMD, destroying the visual cells in the central part of the retina, is a common disease of older age: one out of three individuals aged 70 or older shows early signs of AMD progressing later to relentless loss of vision. This eye disease can be detected only by an ophthalmologist. In general, little is known about the prevalence of AMD among driving license holders aged 80 or older. METHODS: At first the prevalence of individuals with either drusen or AMD in Finland among those 80 or older was approximated. Then the number of license holders in this age group was extracted from the statistics of the Finnish Transport Safety Agency and Eurostat provided us with the demographical data. The changes were projected to 2030. RESULTS: In Finland, with a population of 5.35 million, the number of those aged 80 or over will increase by 175,000 by 2030. The total number of individuals with either drusen or AMD will increase from 118,000 to 193,000 by the year 2030 and an increasing proportion of them will have a driving license. The proportion of women in 2012 having a driving license in the groups 60 or younger is about 45%, while in those aged 80 or older it is only 20%. CONCLUSION: The number of people aged 80 years or older will increase in Finland by 2030. The number of those in this age group having a driving license will increase more rapidly as the population ages because the proportion of women with a driving license will increase in this age group. As the prevalence of drusen and AMD among women aged 80 or over is higher than among men at comparable age, this means that AMD will increase even more rapidly among drivers in this age group. PMID- 25284978 TI - Homonymous hemianopia: challenges and solutions. AB - Stroke is the most common cause of homonymous hemianopia (HH) in adults, followed by trauma and tumors. Associated signs and symptoms, as well as visual field characteristics such as location and congruity, can help determine the location of the causative brain lesion. HH can have a significant effect on quality of life, including problems with driving, reading, or navigation. This can result in decreased independence, inability to enjoy leisure activities, and injuries. Understanding these restrictions, as well as the management options, can aid in making the best use of remaining vision. Treatment options include prismatic correction to expand the remaining visual field, compensatory training to improve visual search abilities, and vision restoration therapy to improve the vision itself. Spontaneous recovery can occur within the first months. However, because spontaneous recovery does not always occur, methods of reducing visual disability play an important role in the rehabilitation of patients with HH. PMID- 25284979 TI - Hemifield pattern electroretinogram in ocular hypertension: comparison with frequency doubling technology and optical coherence tomography to detect early optic neuropathy. AB - BACKGROUND: To assess the sensitivity and specificity of hemifield pattern electroretinogram (HF-PERG) for detecting early retinal ganglion cell (RGC) damage in ocular hypertensive (OH) patients. METHODS: Fifty-two OH patients (mean age 56+/-9.6 years) with an intraocular pressure (IOP) .21 mmHg were assessed. All subjects underwent HF-PERG, optical coherence tomography (OCT), and frequency doubling technology (FDT) visual field. RESULTS: OH patients showed a significant increase of peak-time of the N95 (P=0.027) compared to controls. The amplitude of the N95 of the lower and upper HF-PERG showed significant differences (P=0.037 and P=0.023, respectively) between the two groups. A significant intraocular (P=0.006) and interocular (P=0.018) asymmetry of N95 amplitude was found. Receiver operating characteristic (ROC) curve analysis revealed a sensitivity of 93% for the N95 of the lower HF-PERG, whereas full-field pattern electroretinogram (PERG) N95 peak-time had a sensitivity of 88%. In OH patients, we found a thinning of OCT - retinal nerve fiber layer (RNFL), especially in the superior and inferior quadrant, although not statistically significant, and a significantly higher FDT pattern standard deviation (FDT-PSD; P=0.001). In the OCT-RNFL inferior quadrant, a sensitivity of 82% was recorded. Finally, the sensitivity of the FDT-PSD was 92%. CONCLUSION: Our study shows that HF-PERG is a very sensitive test for detecting early damage of the RGC. PMID- 25284980 TI - iStent trabecular micro-bypass stent for open-angle glaucoma. AB - Trabecular micro-bypass stents, commonly known as iStents, are micro-invasive glaucoma surgery (MIGS) devices used to treat open-angle glaucoma. Like other MIGS procedures that enhance trabecular outflow, the iStent lowers intraocular pressure (IOP) by creating a direct channel between the anterior chamber and Schlemm's canal. iStents are typically implanted at the time of phacoemulsification for patients with open-angle glaucoma and visually significant cataracts. This review summarizes the published data regarding the efficacy, safety, and cost considerations of trabecular micro-bypass stents. Most studies found statistically significant reductions in mean IOP and ocular medication use after combined phacoemulsification with single or double iStent implantation. The devices were found to be very safe, with a safety profile similar to that of cataract surgery. Complications were infrequent, with the most common complications being temporary stent obstruction or malposition, which resolved with observation or secondary procedures. Future studies are needed to evaluate long-term outcomes, patient satisfaction, cost effectiveness, and expanded indications. PMID- 25284981 TI - Effect of low-addition soft contact lenses with decentered optical design on myopia progression in children: a pilot study. AB - PURPOSE: To investigate the effect of low-addition soft contact lenses (CLs) with decentered optical design on the progression of myopia in children in a pilot study. SUBJECTS AND METHODS: Twenty-four Japanese children age 10-16 years with baseline myopia of -0.75 to -3.50 D sphere and <=1.00 D cylinder were studied. The new CLs were designed to have a nasal decentration with the optical center centered on the line of sight, and with progressive-addition power of +0.5 D peripherally. Monofocal soft CLs were used as controls. A pair of new CLs or control CLs was randomly assigned to the children, and they wore the lenses for 12 months during the first phase. Then, the type of CLs was changed, ie, a crossover design, and the children were observed for another 12 months during the second phase. The end points were changes in axial length and refractive error (spherical equivalent) under cycloplegia. RESULTS: The change of axial length in the new-CL and control-CL groups was not different between 12 months and baseline, the change of axial length between 12 months and 1 month in the new-CL group (0.09+/-0.08 mm) was significantly smaller (47%) than that in the control CL group (0.17+/-0.08 mm, P<0.05). During the same period, the change of refractive error in the new-CL group was not significantly different from that in the control group. Neither the change in axial length nor refractive error in the new-CL group was significantly different from those in the control-CL group in the second phase. CONCLUSION: This pilot study suggests that low-addition soft CLs with decentered optical design can reduce the degree of axial elongation in myopic children after an initial transient phase of CL wear. The reduction of the progression of myopia by low-addition soft CLs warrants further investigations. PMID- 25284976 TI - Pharmacotherapy for uveitis: current management and emerging therapy. AB - Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects. PMID- 25284983 TI - A randomized control trial to evaluate the effect of adjuvant selective laser trabeculoplasty versus medication alone in primary open-angle glaucoma: preliminary results. AB - BACKGROUND: The objective of this study was to investigate the effects of adjuvant selective laser trabeculoplasty (SLT) versus medication alone on intraocular pressure (IOP) control, medication use, and quality of life in patients with primary open-angle glaucoma. METHODS: This prospective, randomized control study recruited 41 consecutive primary open-angle glaucoma subjects with medically-controlled IOP <=21 mmHg. The SLT group (n=22) received a single 360 degree SLT treatment. The medication-only group (n=19) continued with their usual treatment regimen. In both groups, medication was titrated to maintain a target IOP defined as a 25% reduction from baseline IOP without medication, or <18 mmHg, whichever was lower. Outcomes, which were measured at baseline and at 6 months, included the Glaucoma Quality of Life-15 (GQL-15) and Comparison of Ophthalmic Medications for Tolerability (COMTOL) survey scores, IOP, and the number of antiglaucoma medicines. RESULTS: The baseline IOP was 15.8+/-2.7 mmHg and 14.5+/ 2.5 mmHg in the SLT and medication-only groups, respectively (P=0.04). Both groups had a comparable number of baseline medication (P=0.2), GQL-15 (P=0.3) and COMTOL scores (P=0.7). At 6 months, the SLT group had a lower IOP (P=0.03) and required fewer medications compared with both baseline (P<0.0001) and with the medication-only group (P=0.02). There was no statistically significant difference in the 6-month GQL-15 or COMTOL score as compared to baseline (P>=0.4) or between the two treatment groups (P>=0.2). CONCLUSION: A single session of adjuvant SLT provided further reductions in IOP and medication without substantial changes in quality of life or medication tolerability at 6 months. PMID- 25284982 TI - Cataract formation following vitreoretinal procedures. AB - PURPOSE: To evaluate the incidence and prevalence of cataract formation, progression, and extraction in patients that underwent vitreoretinal procedures and to evaluate factors that can potentially predispose patients to postoperative cataracts. MATERIALS AND METHODS: The medical records of consecutive patients who underwent vitreoretinal surgery at the Yale Eye Center with at least 6 months of follow-up and no prior intraocular surgery were obtained. Preoperative, intraoperative, and postoperative data were recorded and analyzed in this retrospective observational study. The main outcome measures were defined as cataract extraction, formation, and progression after vitreoretinal procedures. The lens status of the surgical eye was recorded preoperatively and at 1 month, 3 months, 6 months, 12 months, 24 months, and 36 months postoperatively. RESULTS: A total of 193 eyes of 180 patients fulfilled the inclusion criteria. The percentages of eyes with mild lens change were 96% after 20-gauge pars plana vitrectomy (PPV), 72% after small gauge (23- and 25-gauge) PPV, 38% after scleral buckle (SB), 38% after pneumatic retinopexy (PR), and 91% after PPV plus SB (PPV+SB). Posterior subcapsular and nuclear sclerotic cataracts were the most common with almost all developing within 24 months. There was no statistically significant difference (P=1.00) between the rate of cataract extraction after 20 gauge (41%) and small gauge PPV (42%), but there was a statistically significant difference between PPV and non-PPV (SB, 6%; PR, 7%; P<0.001) and PPV and PPV+SB groups (69%; P=0.0063). CONCLUSION: Cataracts were common following PPV regardless of the gauge. SB and PR led to the lowest while PPV+SB led to the highest risk of postoperative cataracts. PMID- 25284984 TI - Synthesis and antibacterial activities of acylide derivatives bearing an aryl tetrazolyl chain. AB - Seventeen acylides bearing an aryl-tetrazolyl alkyl-substituted side chain were synthesized, starting from clarithromycin, via several reactions including hydrolysis, acetylating, esterification, carbamylation, and Michael addition. The structures of all new compounds were confirmed by (1)H nuclear magnetic resonance spectroscopy, (13)C nuclear magnetic resonance spectroscopy, and mass spectrometry. All these synthesized acylides were evaluated for in vitro antimicrobial activities against gram-positive pathogens (Staphylococcus aureus, Staphylococcus epidermidis) and gram-negative pathogens (Pseudomonas aeruginosa, Escherichia coli), using the broth microdilution method. Results showed that compounds 10 e, 10 f, 10 g, 10 h, 10 o have good antibacterial activities. PMID- 25284985 TI - Interferon-gamma and celecoxib inhibit lung-tumor growth through modulating M2/M1 macrophage ratio in the tumor microenvironment. AB - Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFNgamma and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFNgamma alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFNgamma alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFNgamma and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFNgamma and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFNgamma and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFNgamma and celecoxib have potential to be further optimized into a new anticancer therapy. PMID- 25284986 TI - Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development. AB - The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r(2)) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%-72.4% of the 29 drugs on the dataset, and for 81.82%-90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7 degrees C) could replace the experimental values, with similar results. The in silico methods classified 20.76% (+/- 3.07%) as Class 1, 41.51% (+/- 3.32%) as Class 2, 30.49% (+/- 4.47%) as Class 3, and 6.27% (+/- 4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development. PMID- 25284987 TI - Phyllostachys edulis extract induces apoptosis signaling in osteosarcoma cells, associated with AMPK activation. AB - OBJECTIVE: Bamboo is distributed worldwide, and its different parts are used as foods or as a traditional herb. Recently, antitumoral effects of bamboo extracts on several tumors have been increasingly reported; however, antitumoral activity of bamboo extracts on osteosarcoma remains unclear. In the present study, we investigated effects of an aqueous Phyllostachys edulis leaf extract (PEE) on osteosarcoma cells and the underlying mechanism of inhibition. METHODS: The growth of human osteosarcoma cell lines 143 B and MG-63 and lung fibroblast MRC-5 cells was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Apoptosis was demonstrated using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay and flow cytometric analysis. Phosphorylation and protein levels were determined by immunoblotting. RESULTS: After treatment with PEE, viability of 143 B and MG-63 cells was dose-dependently reduced to 36.3% +/- 1.6% of control values, which were similar to AICAR (5 aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside) treatments. In parallel, ratios of apoptotic cells and cells in the sub-G1 phase were significantly increased. Further investigation showed that PEE treatments led to activation of caspase cascades and changes of apoptotic mediators Bcl2, Bax, and p53. Consistently, our results revealed that PEE activated adenosine monophosphate activated protein kinase (AMPK) signaling, and the AMPK activation was associated with the induction of apoptotic signaling. CONCLUSION: Our results indicated that PEE suppressed the growth of 143 B and MG-63 cells but moderately affected MRC-5 cells. PEE-induced apoptosis may attribute to AMPK activation and the following activation of apoptotic signaling cascades. These findings revealed that PEE possesses antitumoral activity on human osteosarcoma cells by manipulating AMPK signaling, suggesting that PEE alone or combined with regular antitumor drugs may be beneficial as osteosarcoma treatments. PMID- 25284988 TI - Bioactive protein fraction DLBS1033 containing lumbrokinase isolated from Lumbricus rubellus: ex vivo, in vivo, and pharmaceutic studies. AB - DLBS1033 is a bioactive protein fraction isolated from Lumbricus rubellus that tends to be unstable when exposed to the gastrointestinal environment. Accordingly, appropriate pharmaceutical development is needed to maximize absorption of the protein fraction in the gastrointestinal tract. In vitro, ex vivo, and in vivo stability assays were performed to study the stability of the bioactive protein fraction in gastric conditions. The bioactive protein fraction DLBS1033 was found to be unstable at low pH and in gastric fluid. The "enteric coating" formulation showed no leakage in gastric fluid-like medium and possessed a good release profile in simulated intestinal medium. DLBS1033 was absorbed through the small intestine in an intact protein form, confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) analysis. This result confirmed that an enteric coating formula using methacrylic acid copolymer could protect DLBS1033 from the acidic condition of the stomach by preventing the release of DLBS1033 in the stomach, while promoting its release when reaching the intestine. From the blood concentration-versus-time curve, (99m)Tc-DLBS1033 showed a circulation half-life of 70 minutes. This relatively long biological half-life supports its function as a thrombolytic protein. Thus, an enteric delivery system is considered the best approach for DLBS1033 as an oral thrombolytic agent. PMID- 25284989 TI - Acceptability of bone antiresorptive therapy among HIV-infected adults at different stages of antiretroviral therapy. AB - PURPOSE: Both HIV infection and antiretroviral therapy (ART) are associated with significant decreases in bone mineral density (BMD) and increased fracture rates. To prepare for a randomized controlled trial of prophylactic bone antiresorptive therapy during ART initiation, we assessed the acceptability of this strategy, bone health knowledge, and fracture risk among HIV-infected adults. METHODS: HIV infected adults with no history of osteoporosis were recruited from one tertiary and one primary care HIV clinic. Participants completed a questionnaire and underwent chart review. The primary outcome was the proportion of respondents expressing interest in taking prophylactic bone antiresorptive therapy in conjunction with ART. RESULTS: Of 112 respondents, 25.0% were ART naive, 23.2% had been taking ART for <=1 year, and 51.8% had been taking ART for >1 year. Half (51.9%) indicated interest in taking short-course prophylactic bone antiresorptive therapy; this did not differ by ART status (53.6% among ART-naive, 51.3% among ART-treated; P=0.84, chi-square test). In exploratory multivariable analysis adjusted for ART status, a greater number of pills taken per day was positively associated with this outcome (adjusted odds ratio [OR] =1.12 per pill, 95% confidence limit [CL] =1.01, 1.25), while male sex was inversely associated (adjusted OR =0.05, 95% CL =0.01, 0.24). Among those willing to take therapy, most (80.4%) were willing to do so for "as long as needed" and preferred weekly dosing (70.9%) to daily dosing (12.7%). CONCLUSIONS: Half of this sample would be willing to take bone antiresorptive therapy together with ART, with preferences for weekly dosing and for whatever duration may be required. These data will inform the design of future trials to protect bone health in HIV. PMID- 25284990 TI - Pharmacological interventions for ADHD: how do adolescent and adult patient beliefs and attitudes impact treatment adherence? AB - Adherence to medication can be problematic for patients, especially so for patients with attention deficit hyperactivity disorder (ADHD). Effective medications are available for the treatment of ADHD; however, nonadherence rates for ADHD medication range from 13.2%-64%. The reasons for nonadherence can be complex. This review aims to look at how the beliefs and attitudes of adolescents and adults impact ADHD treatment adherence. PMID- 25284991 TI - Medication adherence and its determinants among psychiatric patients in an Ethiopian referral hospital. AB - BACKGROUND: The degree to which an individual follows medical advice is a major concern in every medical specialty. Non-adherence to psychiatric treatment regimens has a profound impact on the disease course, relapse, future recovery, cost of health care, and the outcome for the patient. The aim of this study was to assess medication adherence and its correlates among psychiatric patients at Ayder Referral Hospital, Northern Ethiopia. METHODS: A cross-sectional study was conducted from June to September 2013 at Ayder Referral Hospital, where 423 patients were selected by a systematic random sampling technique from all patients attending the psychiatric clinic at the hospital. Data were collected by trained data collectors through interview of the patients using a structured questionnaire. The collected data were entered into Epi Info version 7 and analyzed by Statistical Package for the Social Sciences version 16 software. Logistic regression was used to assess independent predictors of adherence. RESULTS: A total of 387 patients completed the interview. Two hundred and sixteen (55.8%) and 113 (29.2%) were patients with a diagnosis of schizophrenia and mood disorder, respectively, while 35 (9%) and 23 (5.9%) had a diagnosis of drug addiction and autistic disorder. Two hundred and seven (71.6%) patients were found to be adherent to their medication. When adherence rates were observed according to type of disorder, 60 (53.1%), 24 (68.6%), 149 (69%), and 18 (78.3%) of patients with mood disorder, drug addiction, schizophrenia, and autism, respectively, were adherent to their medications. Female gender (adjusted odds ratio [AOR] 2.34; 95% confidence interval [CI] 1.45-3.74), tertiary education (AOR 2.69; 95% CI 1.46-4.85), living with family (AOR 2.57; 95% CI 1.66-4.58), and shorter treatment duration (AOR 1.82; 95% CI 1.21-2.84) were among the variables associated with better adherence. CONCLUSION: Suboptimal adherence was observed among psychiatric patients in this study. Health professionals in the psychiatric clinic and pharmacists need to focus on and counsel patients about adherence and its implications for their clinical outcome. PMID- 25284992 TI - Comparison of hybrid procedure and open surgical revascularization for multilevel infrainguinal arterial occlusive disease. AB - OBJECTIVE: To compare outcomes of hybrid (combined surgical and endovascular) procedures (HYBRID) with open surgical reconstructions (OPEN) in patients with multilevel infrainguinal artery occlusive diseases. DESIGN: Case series study with retrospective analysis of prospectively collected nonrandomized data. METHODS: Between 2008 and 2012, 64 patients underwent OPEN and 43 underwent HYBRID. Patient characteristics, technique success, clinical improvement, and procedure-related morbidity were reviewed and compared. Patency rates and limb salvages were analyzed and compared using Kaplan-Meier life tables. Cox regression analyses were used to assess the influence of various risk factors on primary patency. RESULTS: HYBRID patients were older and presented with worse New York Heart Association function compared with OPEN patients. The increase in the ankle-brachial index and improvement of Ruthford category after procedures were equivalent between two groups, but HYBRID patients had shorter hospital length of stay (7.6+/-12.0 versus 15.5+/-17.3; P= 0.018) and less overall perioperative morbidity (12% versus 28%; P=0.042) compared with OPEN patients. No statistically significant difference in 36-month primary (47.1%+/-7.1% versus 50.1%+/-9.4%; P=0.418), assisted primary (57.0%+/-7.9% versus 62.4%+/-9.2%; P=0.517), or secondary (82.0%+/-6.8% versus 83.1%+/-7.3%; P=0.445) patency was seen between the two groups. Limb salvage rates of HYBRID vs OPEN at 3 years were similar (76.3%+/-9.3% versus 80.4%+/-8.2%; P=0.579). Critical limb ischemia was a negative predictor of long-term patency of patients in both the HYBRID and OPEN groups (P=0.012 and P<0.001, respectively), and the presence of diabetes and renal insufficiency were another two independent predictors of decreased primary patency for HYBRID (P=0.017 and P=0.019, respectively). CONCLUSION: Multilevel infrainguinal artery occlusive diseases could be treated by hybrid procedure, with shorter hospitalization, less perioperative morbidity, and similar early- and long-term efficacy compared with open revascularization. A hybrid procedure should be considered for patients with high surgical risk, but critical limb ischemia, diabetes, and renal insufficiency could compromise its long-term patency. PMID- 25284993 TI - Feasibility and efficacy of cognitive telerehabilitation in early Alzheimer's disease: a pilot study. AB - BACKGROUND: This pilot study compared the effects of lexical-semantic stimulation through telecommunication technology (LSS-tele) with in-person LSS (LSS-direct) and unstructured cognitive treatment (UCS) in patients with early Alzheimer's disease. METHODS: Twenty-seven patients with Alzheimer's disease in the very early stage (Mini-Mental State Examination [MMSE] >26/30) were divided into three groups: seven patients received LSS-tele treatment, ten received standard LSS direct intervention, and ten participants underwent UCS as control condition. Intervention treatments consisted of two weekly sessions of LSS (through teleconference or face to face depending on group assignment) or UCS exercises administered to small groups throughout a 3-month period. The main outcome measures were changes of global cognitive performance, language abilities, and memory function. Secondary outcome measures were changes in attention, working memory, executive functions, and visual-spatial abilities tests. RESULTS: The mean MMSE score improved significantly in LSS-tele and LSS-direct treatments; LSS tele improved language abilities, both phonemic and semantic, and stabilized delayed verbal episodic memory with respect to an improved performance after the LSS-direct intervention and to a memory decline observed in the control group. Improvement was not achieved in any neuropsychological test score after UCS. CONCLUSION: Clinical application of telecommunication technology to cognitive rehabilitation of elderly patients with neurodegenerative cognitive impairment is feasible and may improve global cognitive performance. Technical aspects to ameliorate efficacy of delivery may further improve its impact on domain-specific cognitive abilities. PMID- 25284994 TI - The clinical features of foreign body aspiration into the lower airway in geriatric patients. AB - PURPOSE: To analyze the clinical features of foreign-body aspiration into the lower airway in geriatric patients. PATIENTS AND METHODS: The clinical data of 17 geriatric patients with foreign-body aspiration were retrospectively analyzed and compared with 26 nongeriatric adult patients. The data were collected from Peking University First Hospital and Anhui Chest Hospital between January 2000 and June 2014. RESULTS: (1) In the geriatric group, the most common symptoms were cough and sputum (15 cases, 88%), dyspnea (six cases, 35%), and hemoptysis (four cases, 24%). Five patients (29%) in the geriatric group could supply the history of aspiration on their first visit to doctor, a smaller percentage than in the nongeriatric group (13 cases, 50%). Only three cases in the geriatric group were diagnosed definitely without delay. Another 14 cases were misdiagnosed as pneumonia or lung cancer, and the time of delayed diagnosis ranged from 1 month to 3 years. Complications due to delay in diagnosis included obstructive pneumonitis, atelectasis, lung abscess, and pleural effusion. (2) Chest computed tomography demonstrated the foreign body in three cases (21%) in the geriatric group, which was lower than the positive proportion of detection in the nongeriatric group (nine cases, 35%). The most common type of foreign body in the geriatric group was food, such as bone fragments (seven cases, 41%) and plants (seven cases, 41%), and the foreign body was most often lodged in the right bronchus tree (eleven cases, 65%), especially the right lower bronchus (seven cases, 41%). Flexible bronchoscopy removed the foreign body successfully in all patients. CONCLUSION: The clinical features of foreign-body aspiration in geriatric patients are usually more obscure than in nongeriatric adults, which may lead to long delay in diagnosis. Flexible bronchoscopy is safe and useful for early diagnosis and effective management in geriatric patients. We suggest flexible bronchoscopy as the first-line approach to similar patients, especially those with aspiration history and unexplained pneumonia. PMID- 25284995 TI - General anesthetic and the risk of dementia in elderly patients: current insights. AB - In this review, we aim to provide clinical insights into the relationship between surgery, general anesthesia (GA), and dementia, particularly Alzheimer's disease (AD). The pathogenesis of AD is complex, involving specific disease-linked proteins (amyloid-beta [Abeta] and tau), inflammation, and neurotransmitter dysregulation. Many points in this complex pathogenesis can potentially be influenced by both surgery and anesthetics. It has been demonstrated in some in vitro, animal, and human studies that some anesthetics are associated with increased aggregation and oligomerization of Abeta peptide and enhanced accumulation and hyperphosphorylation of tau protein. Two neurocognitive syndromes that have been studied in relation to surgery and anesthesia are postoperative delirium and postoperative cognitive dysfunction, both of which occur more commonly in older adults after surgery and anesthesia. Neither the route of anesthesia nor the type of anesthetic appears to be significantly associated with the development of postoperative delirium or postoperative cognitive dysfunction. A meta-analysis of case-control studies found no association between prior exposure to surgery utilizing GA and incident AD (pooled odds ratio =1.05, P=0.43). The few cohort studies on this topic have shown varying associations between surgery, GA, and AD, with one showing an increased risk, and another demonstrating a decreased risk. A recent randomized trial has shown that patients who received sevoflurane during spinal surgery were more likely to have progression of preexisting mild cognitive impairment compared to controls and to patients who received propofol or epidural anesthesia. Given the inconsistent evidence on the association between surgery, anesthetic type, and AD, well-designed and adequately powered studies with longer follow-up periods are required to establish a clear causal association between surgery, GA, and AD. PMID- 25284996 TI - Divergent effects of obesity on fragility fractures. AB - Obesity was commonly thought to be advantageous for maintaining healthy bones due to the higher bone mineral density observed in overweight individuals. However, several recent studies have challenged the widespread belief that obesity is protective against fracture and have suggested that obesity is a risk factor for certain fractures. The effect of obesity on fracture risk is site-dependent, the risk being increased for some fractures (humerus, ankle, upper arm) and decreased for others (hip, pelvis, wrist). Moreover, the relationship between obesity and fracture may also vary by sex, age, and ethnicity. Risk factors for fracture in obese individuals appear to be similar to those in nonobese populations, although patterns of falling are particularly important in the obese. Research is needed to determine if and how visceral fat and metabolic complications of obesity (type 2 diabetes mellitus, insulin resistance, chronic inflammation, etc) are causally associated with bone status and fragility fracture risk. Vitamin D deficiency and hypogonadism may also influence fracture risk in obese individuals. Fracture algorithms such as FRAX((r)) might be expected to underestimate fracture probability. Studies specifically designed to evaluate the antifracture efficacy of different drugs in obese patients are not available; however, literature data may suggest that in obese patients higher doses of the bisphosphonates might be required in order to maintain efficacy against nonvertebral fractures. Therefore, the search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with obesity might be considered a clinical priority which could improve the prevention of fracture in obese individuals. PMID- 25284997 TI - Oral health status, dental treatment needs, and barriers to dental care of elderly care home residents in Lodz, Poland. AB - OBJECTIVES: To determine oral health status, dental treatment needs, and to identify barriers that prevent easy access to dental care by elderly care home residents in Lodz. BACKGROUND: Studies in many countries show that oral health status of elderly care home residents is poor and there is an urgent need to improve it. METHODS: The study included 259 care home residents, aged 65 years and older. The oral examination was performed. In face-to-face interviews, subjects were asked about frequency of cleaning teeth and/or dentures, whether they needed assistance, and whether the assistance was available; they were also asked about the perceived dental needs, and about the time since their last visit to a dentist and the purpose of the visit. If they had not visited the dentist in the past 12 months, they were asked about reasons for failing to visit the dentist. RESULTS: Forty-six percent of the subjects were edentulous. Only 5.8% of all participants had a sufficient number of functional natural teeth. Dental treatment was found to be necessary in 59.8% of the respondents. One in four subjects reported reduced ability of correctly cleaning teeth and dentures themselves, of whom only one-third were helped by others. An insufficient level of hygiene was found in every other subject. About 42% of residents had not visited a dentist for over 5 years, mainly due to organizational reasons. CONCLUSION: Expanding the current scope of medical care for the elderly care home residents to include dental care would improve their currently poor oral health status. PMID- 25284998 TI - Volumetric capnography for the evaluation of chronic airways diseases. AB - BACKGROUND: Obstructive lung diseases of different etiologies present with progressive peripheral airway involvement. The peripheral airways, known as the silent lung zone, are not adequately evaluated with conventional function tests. The principle of gas washout has been used to detect pulmonary ventilation inhomogeneity and to estimate the location of the underlying disease process. Volumetric capnography (VC) analyzes the pattern of CO2 elimination as a function of expired volume. OBJECTIVE: To measure normalized phase 3 slopes with VC in patients with non-cystic fibrosis bronchiectasis (NCB) and in bronchitic patients with chronic obstructive pulmonary disease (COPD) in order to compare the slopes obtained for the groups. METHODS: NCB and severe COPD were enrolled sequentially from an outpatient clinic (Hospital of the State University of Campinas). A control group was established for the NCB group, paired by sex and age. All subjects performed spirometry, VC, and the 6-Minute Walk Test (6MWT). Two comparisons were made: NCB group versus its control group, and NCB group versus COPD group. The project was approved by the ethical committee of the institution. Statistical tests used were Wilcoxon or Student's t-test; P<0.05 was considered to be a statistically significant difference. RESULTS: Concerning the NCB group (N=20) versus the control group (N=20), significant differences were found in body mass index and in several functional variables (spirometric, VC, 6MWT) with worse results observed in the NCB group. In the comparison between the COPD group (N=20) versus the NCB group, although patients with COPD had worse spirometric and 6MWT values, the capnographic variables mean phase 2 slope (Slp2), mean phase 3 slope normalized by the mean expiratory volume, or mean phase 3 slope normalized by the end-tidal CO2 concentration were similar. CONCLUSION: These findings may indicate that the gas elimination curves are not sensitive enough to monitor the severity of structural abnormalities. The role of normalized phase 3 slope may be worth exploring as a more sensitive index of small airway disease, even though it may not be equally sensitive in discriminating the severity of the alterations. PMID- 25284999 TI - Comparison of disease-severity measures within severe and very severe COPD patients: results from a nationally representative chart review and patient survey. AB - OBJECTIVE: This study aimed to compare spirometry- and risk + symptom-based classification systems to physician-based severity assessment and find which system is most predictive of patient-reported health status, as measured by the St George's Respiratory Questionnaire for COPD (chronic obstructive pulmonary disease; SGRQ-C). MATERIALS AND METHODS: In this chart review/patient survey, 99 physicians recruited patients with physician-assessed severe or very severe COPD who had recently experienced a moderate or severe exacerbation. A cross tabulation was undertaken comparing physician report, spirometry (mild/moderate, forced expiratory volume in 1 second [FEV1] >=50%; severe, 30% <= FEV1 <50%; very severe, FEV1 <30% predicted), and risk + symptom-based (A, low risk/fewer symptoms; B, low risk/more symptoms; C, high risk/fewer symptoms; D, high risk/more symptoms) severity systems. Analysis of covariance models were run for SGRQ-C, varying COPD-severity systems. RESULTS: Of 244 patients, 58.6% were severe and 34.8% very severe by physician report, 70% had FEV1 <=50% at their most recent visit, and 86% fell into quadrant D. Spirometry and physician report had 57.4% agreement, with physicians often indicating higher severity. Physician report and risk + symptom agreement was high (81.2% severe/very severe and D). Physician-reported severity, risk + symptoms, exacerbations in the previous year, and symptoms were significant SGRQ-C predictors, while spirometry was not. CONCLUSION: For recently exacerbating severe or very severe COPD patients, risk + symptoms more closely aligned with physician-reported severity and SGRQ-C versus spirometry. PMID- 25285000 TI - Health status in patients with coexistent COPD and heart failure: a validation and comparison between the Clinical COPD Questionnaire and the Minnesota Living with Heart Failure Questionnaire. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both common diseases that coexist frequently. Patients with both diseases have worse stable state health status when compared with patients with one of these diseases. In many outpatient clinics, health status is monitored routinely in COPD patients using the Clinical COPD Questionnaire (CCQ) and in HF patients with the Minnesota Living with Heart Failure Questionnaire (MLHF-Q). This study validated and compared which questionnaire, ie, the CCQ or the MLHF-Q, is suited best for patients with coexistent COPD and HF. METHODS: Patients with both COPD and HF and aged >=40 years were included. Construct validity, internal consistency, test-retest reliability, and agreement were determined. The Short Form 36 was used as the external criterion. All questionnaires were completed at baseline. The CCQ and MLHF-Q were repeated after 2 weeks, together with a global rating of change. RESULTS: Fifty-eight patients were included, of whom 50 completed the study. Construct validity was acceptable. Internal consistency was adequate for CCQ and MLHF-Q total and domain scores, with a Cronbach's alpha >=0.70. Reliability was adequate for MLHF-Q and CCQ total and domain scores, and intraclass correlation coefficients were 0.70-0.90, except for the CCQ symptom score (intraclass correlation coefficient 0.42). The standard error of measurement on the group level was smaller than the minimal clinical important difference for both questionnaires. However, the standard error of measurement on the individual level was larger than the minimal clinical important difference. Agreement was acceptable on the group level and limited on the individual level. CONCLUSION: CCQ and MLHF-Q were both valid and reliable questionnaires for assessment of health status in patients with coexistent COPD and HF on the group level, and hence for research. However, in clinical practice, on the individual level, the characteristics of both questionnaires were not as good. There is room for a questionnaire with good evaluative properties on the individual level, preferably tested in a setting of patients with COPD or HF, or both. PMID- 25285001 TI - A simple semipaced 3-minute chair rise test for routine exercise tolerance testing in COPD. AB - The functional work capacity of chronic obstructive pulmonary disease (COPD) patients is usually assessed with walk tests such as the 6-minute walk test (6MWT) or the shuttle test. Because these exercise modalities require a controlled environment which limits their use by pulmonologists and severely restricts their use among general practitioners, different modalities of a short (1 minute or less) sit-to-stand test were recently proposed. In this study, we evaluated a new modality of a semipaced 3-minute chair rise test (3CRT) in 40 patients with COPD, and compared the reproducibility of physiological responses and symptoms during the 3CRT and their interchangeability with the 6MWT. The results demonstrate that physiological variables, heart rate, pulse oxygen saturation, work done, and symptoms (Borg dyspnea and fatigue scores), during the 3CRT were highly reproducible, and that the physiological responses and symptoms obtained during the 3CRT and the 6MWT were interchangeable for most patients. Moreover, these preliminary data suggest that patients able to perform more than 50 rises during 3 minutes had no significant disability. The simplicity and ease of execution of the 3CRT will facilitate the assessment of exercise symptoms and disability in COPD patients during routine consultations with pulmonologists and general practitioners, and will thus contribute to the improved management of COPD patients. PMID- 25285002 TI - Characteristics of patients with COPD newly prescribed a long-acting bronchodilator: a retrospective cohort study. AB - INTRODUCTION: This study aimed to characterize patients with chronic obstructive pulmonary disease (COPD) newly prescribed a long-acting bronchodilator (LABD), and to assess changes in medication over 24 months. METHODS: A cohort of patients with COPD aged >=40 years newly prescribed an LABD between January 1, 2007 and December 31, 2009 were identified from the Truven Marketscan((r)) Commercial Database (Truven Health Analytics, Ann Arbor, MI, USA) and followed for 24 months. Inclusion criteria included no prior prescription for an LABD or inhaled corticosteroids for 12 months prior to the LABD index date (baseline). Patient characteristics were examined. As LABDs were mainly long-acting muscarinic antagonists (LAMAs), additions, switches, discontinuation, adherence to (medication possession ratio), and persistence (proportion of days covered) with LAMA monotherapy were assessed for 24 months following the index date. Adherence and persistence with long-acting beta2-agonists (LABAs) were also assessed. RESULTS: A cohort of 3,268 patients aged 40-65 years was identified (mean age 55.8 years, 48% male). LAMA monotherapy was prescribed to 93% of patients who received an LABD. During the 24-month follow-up, 16% of these patients added COPD medication, 10% switched to an inhaled corticosteroid-containing medication, and 25% discontinued after one LAMA prescription at baseline. Over 12 and 24 months, adherence to LAMA was 40% and 33%, respectively, and adherence to LABA was 29% and 24%, respectively. Over the same time periods, persistence with LAMA monotherapy was 19% and 15%, respectively, and persistence with LABA was 9% and 7%, respectively. CONCLUSION: Adherence to newly initiated LAMA monotherapy was low, with one in four patients adding to or switching from LAMA and many patients discontinuing therapy. Adherence to LABA was also low. These results suggest that additional medication to a single LABD may be required in some patients with COPD to achieve optimal disease control. PMID- 25285003 TI - Oxygen supersaturated fluid using fine micro/nanobubbles. AB - Microbubbles show peculiar properties, such as shrinking collapse, long lifetime, high gas solubility, negative electric charge, and free radical production. Fluids supersaturated with various gases can be easily generated using microbubbles. Oxygen microbubble fluid can be very useful for oxygen delivery to hypoxic tissues. However, there have been no reports of comparative investigations into adding fluids containing oxygen fine micro/nanobubbles (OFM NBs) to common infusion solutions in daily medical care. In this study, it was demonstrated that OFMNBs can generate oxygen-supersaturated fluids, and they may be sufficiently small to infuse safely into blood vessels. It was found that normal saline solution is preferable for generating an oxygen-rich infusion fluid, which is best administered as a 30-minute intravenous infusion. It was also concluded that dextran solution is suitable for drug delivery substances packing oxygen gas over a 1-hour intravenous infusion. In addition, normal saline solution containing OFMNBs was effective for improving blood oxygenation. Thus, the use of OFMNB-containing fluids is a potentially effective novel method for improving blood oxygenation in cases involving hypoxia, ischemic diseases, infection control, and anticancer chemoradiation therapies. PMID- 25285004 TI - Silk fibroin nanoparticles constitute a vector for controlled release of resveratrol in an experimental model of inflammatory bowel disease in rats. AB - PURPOSE: We aimed to evaluate the intestinal anti-inflammatory properties of silk fibroin nanoparticles, around 100 nm in size, when loaded with the stilbene compound resveratrol, in an experimental model of rat colitis. METHODS: Nanoparticles were loaded with resveratrol by adsorption. The biological effects of the resveratrol-loaded nanoparticles were tested both in vitro, in a cell culture of RAW 264.7 cells (mouse macrophages), and in vivo, in the trinitrobenzenesulfonic acid model of rat colitis, when administered intracolonically. RESULTS: The resveratrol liberation in 1* phosphate-buffered saline (PBS; pH 7.4) was characterized by fast liberation, reaching the solubility limit in 3 hours, which was maintained over a period of 80 hours. The in vitro assays revealed immunomodulatory properties exerted by these resveratrol loaded nanoparticles since they promoted macrophage activity in basal conditions and inhibited this activity when stimulated with lipopolysaccharide. The in vivo experiments showed that after evaluation of the macroscopic symptoms, inflammatory markers, and intestinal barrier function, the fibroin nanoparticles loaded with resveratrol had a better effect than the single treatments, being similar to that produced by the glucocorticoid dexamethasone. CONCLUSION: Silk fibroin nanoparticles constitute an attractive strategy for the controlled release of resveratrol, showing immunomodulatory properties and intestinal anti inflammatory effects. PMID- 25285005 TI - Use of electrical impedance spectroscopy to detect malignant and potentially malignant oral lesions. AB - The electrical properties of tissues depend on their architecture and cellular composition. We have previously shown that changes in electrical impedance can be used to differentiate between different degrees of cervical dysplasia and cancer of the cervix. In this proof-of-concept study, we aimed to determine whether electrical impedance spectroscopy (EIS) could distinguish between normal oral mucosa; benign, potentially malignant lesions (PML); and oral cancer. EIS data were collected from oral cancer (n=10), PML (n=27), and benign (n=10) lesions. EIS from lesions was compared with the EIS reading from the normal mucosa on the contralateral side of the mouth or with reference spectra from mucosal sites of control subjects (n=51). Healthy controls displayed significant differences in the EIS obtained from different oral sites. In addition, there were significant differences in the EIS of cancer and high-risk PML versus low-risk PML and controls. There was no significant difference between benign lesions and normal controls. Study subjects also deemed the EIS procedure considerably less painful and more convenient than the scalpel biopsy procedure. EIS shows promise at distinguishing among malignant, PML, and normal oral mucosa and has the potential to be developed into a clinical diagnostic tool. PMID- 25285007 TI - Development and validation of the Pictorial Cognitive Screening Inventory for illiterate people with dementia. AB - PURPOSE: The purpose of this study was to develop and validate a tool called the Pictorial Cognitive Screening Inventory (PCSI), which consists of pictorial memory and attention tests that are not influenced by literacy level. PATIENTS AND METHODS: PCSI, Mini Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) questionnaires were administered to 80 elderly participants (20 illiterate normal, 20 illiterate with dementia, 20 literate normal, and 20 literate with dementia). RESULTS: PCSI scores were highly correlated with those of the MMSE (r 0.51) and the CDR (r -0.71). In addition, the PCSI scores differed significantly between the normal group and the dementia group (mean difference 1.71, standard error [SE] 0.14, P<0.001), while no such difference was observed between the illiterate group and the literate group (mean difference 0.00, SE 0.24, P=0.997). Diagnostic validity of the PCSI is excellent, with a sensitivity of 90% and a specificity of 98% for screening dementia, whereas the MMSE has a sensitivity of 85% and a specificity of 60%. CONCLUSION: These results indicate that the PCSI is a sensitive and reliable test for screening dementia, regardless of an individual's literacy skills. The PCSI meets the increasing needs for screening of dementia in illiterate elderly populations in developing countries. PMID- 25285006 TI - Kynurenine and depressive symptoms in a poststroke population. AB - BACKGROUND AND PURPOSE: Depression is a commonly occurring and persistent sequel of stroke affecting approximately 29% of patients. An immunological hypothesis has been put forward, and synthesis of kynurenine from tryptophan has been proposed to link inflammatory activity with neurotoxicity and neurotransmitter dysfunction. This study assessed the relationship between peripheral blood kynurenine and poststroke depressive symptoms. PATIENTS AND METHODS: This was a multisite cross-sectional observational cohort study of patients with ischemic stroke. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression (CES-D) scale and divided into high, medium, and low depressive symptom tertiles. Concentrations of kynurenine and tryptophan were assayed from fasting serum samples, and the kynurenine/tryptophan ratio was compared between tertiles. Serum cytokine concentrations were assayed in a subgroup of patients, and the ratio of proinflammatory (IL-6, IL-18, IFNgamma, TNF, IL-1beta) to anti-inflammatory (IL-10) cytokines compared. NLM IDENTIFIER: NCT00254020. RESULTS: In these patients (n=86, 52.3% male, mean age 71.7+/-14.2 years), there were no differences in kynurenine/tryptophan ratios between CES-D scale tertiles (F 2,76=0.04, P=0.96) controlling for relevant covariates. For cytokines (n=53), serum IL-1beta concentrations (F 2,52=3.55, P=0.037) and serum ratios of IL-18/IL-10 (F 2,52=3.30, P=0.046), IFNgamma/IL-10 (F 2,52=4.02, P=0.025), and IL-1beta/IL-10 (F 2,52=4.34, P=0.019) were elevated in the middle CES-D tertile. Post hoc analyses suggested that serum ratios of IL-18/IL-10 (rho=0.28, P=0.04), and IL-1beta/IL-10 (rho=0.43, P=0.001), as well as IL-1beta (rho=0.29, P=0.04), were significantly associated with fatigue. CONCLUSION: Peripheral kynurenine/tryptophan ratios were not associated with depressive symptoms in a poststroke population. However, in exploratory analyses a proinflammatory bias was identified specifically in patients with mild depressive symptoms and associated with poststroke fatigue, suggesting an avenue for future research. PMID- 25285008 TI - Propofol prevents electroconvulsive-shock-induced memory impairment through regulation of hippocampal synaptic plasticity in a rat model of depression. AB - BACKGROUND: Although a rapid and efficient psychiatric treatment, electroconvulsive therapy (ECT) induces memory impairment. Modified ECT requires anesthesia for safety purposes. Although traditionally found to exert amnesic effects in general anesthesia, which is an inherent part of modified ECT, some anesthetics have been found to protect against ECT-induced cognitive impairment. However, the mechanisms remain unclear. We investigated the effects of propofol (2,6-diisopropylphenol) on memory in depressed rats undergoing electroconvulsive shock (ECS), the analog of ECT in animals, under anesthesia as well as its mechanisms. METHODS: Chronic unpredictable mild stresses were adopted to reproduce depression in a rodent model. Rats underwent ECS (or sham ECS) with anesthesia with propofol or normal saline. Behavior was assessed in sucrose preference, open field and Morris water maze tests. Hippocampal long-term potentiation (LTP) was measured using electrophysiological techniques. PSD-95, CREB, and p-CREB protein expression was assayed with Western blotting. RESULTS: Depression induced memory damage, and downregulated LTP, PSD-95, CREB, and p CREB; these effects were exacerbated in depressed rats by ECS; propofol did not reverse the depression-induced changes, but when administered in modified ECS, propofol improved memory and reversed the downregulation of LTP and the proteins. CONCLUSION: These findings suggest that propofol prevents ECS-induced memory impairment, and modified ECS under anesthesia with propofol improves memory in depressed rats, possibly by reversing the excessive changes in hippocampal synaptic plasticity. These observations provide a novel insight into potential targets for optimizing the clinical use of ECT for psychiatric disorders. PMID- 25285009 TI - Early prediction of blonanserin response in Japanese patients with schizophrenia. AB - BACKGROUND: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia in Japan and Korea. The present study aimed to examine early prediction of blonanserin in patients with schizophrenia. METHODS: An 8 week, prospective, single-arm, flexible-dose clinical trial of blonanserin in patients with schizophrenia was conducted under real-world conditions. The inclusion criteria were antipsychotic naive, and first-episode schizophrenia patients or schizophrenia patients with no consumption of any antipsychotic medication for more than 4 weeks before enrollment in this study. The positive predictive value, negative predictive value, sensitivity, specificity, and predictive power were calculated for the response status at week 4 to predict the subsequent response at week 8. RESULTS: Thirty-seven patients were recruited (56.8% of them had first-episode schizophrenia), and 28 (75.7%) completed the trial. At week 8, blonanserin was associated with a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score (P<0.0001) and in positive (P<0.0001), negative (P<0.0001), and general subscale scores (P<0.0001). In terms of percentage improvement of PANSS total scores from baseline to week 8, 64.9% of patients showed a >=20% reduction in the PANSS total score and 48.6% showed a >=30% reduction. However, 8.1% of patients experienced at least one adverse event. Using the 20% reduction in the PANSS total score at week 4 as a definition of an early response, the negative predictive values for later responses (ie, reductions of >=30 and >=40 in the PANSS total scores) were 88.9% and 94.1%, respectively. The specificities were 80.0% and 51.6%, respectively. CONCLUSION: Our results suggest that the blonanserin response at week 4 could predict the later response at week 8. PMID- 25285011 TI - Efficacy of tramadol as a preincisional infiltration anesthetic in children undergoing inguinal hernia repair: a prospective randomized study. AB - BACKGROUND: Preincisional local anesthetic infiltration at the surgical site is a therapeutic option for postoperative pain relief for pediatric inguinal hernia. Additionally, tramadol has been used as an analgesic for postoperative pain in children. Recently, the local anesthetic effects of tramadol have been reported. The aim of this study was to determine both the systemic analgesic and the local anesthetic effects of tramadol and to determine how it differs from bupivacaine when administered preincisionally. METHODS: Fifty-two healthy children, aged 2-7 years, who were scheduled for elective herniorrhaphy were randomly allocated to receive either preincisional infiltration at the surgical site with 2 mg/kg tramadol (Group T, n=26) or 0.25 mL/kg 0.5% bupivacaine (Group B, n=26). At the time of anesthetic administration, perioperative hemodynamic parameters were recorded. The pain assessments were performed 10 minutes after the end of anesthesia and during the first 6-hour period, using pain scores. The time of first dose of analgesia and need for additional analgesia were recorded. RESULTS: Between T and B groups, the anesthesia time, perioperative hemodynamic changes, and pain scores were not statistically different. However, in group B, the postoperative analgesic requirement was higher than in group T. CONCLUSION: Tramadol shows equal analgesic effect to bupivacaine and decreases additional analgesic requirement, when used for preincisional infiltration anesthesia in children undergoing inguinal herniorrhaphy. PMID- 25285010 TI - Towards a framework for treatment effectiveness in schizophrenia. AB - INTRODUCTION: Prompt administration of antipsychotic treatment that is adhered to is essential for the optimal treatment of schizophrenia. Many patients have benefited from the advent of second-generation antipsychotics, which can offer good symptomatic control with reduced incidence of extrapyramidal symptoms, although with higher risk of metabolic side effects. It is unsurprising that accounts as to whether first- and second-generation antipsychotics differ in their efficacy vary, since treatment effectiveness is a broad notion and difficult to define. OBJECTIVES: Numerous factors may be used to gauge treatment effectiveness and, while it has largely been defined in terms of improvements in four domains (symptoms of disease, treatment burden, disease burden, and health and wellness), the real-world clinical utility of this consensus is unclear. Therefore, this article aims to provide a framework that can aid psychiatrists in making assessments about treatment effectiveness. METHODS AND RESULTS: A panel of 12 psychiatrists and psychopharmacologists convened to develop and propose an accessible and globally-applicable framework for assessing the effectiveness of antipsychotic treatments in patients with schizophrenia. Following presentation of a preliminary proposal to a wider group of psychiatrists from across Europe, it was refined into a framework comprising five domains: symptomatic remission and retention of treatment; affective symptoms; cognitive functioning; treatment satisfaction; and personal and social functioning - each of which is discussed in this article. CONCLUSIONS: This article provides a framework that can aid psychiatrists in making assessments about treatment effectiveness. It is anticipated that the framework outlined here may contribute to improving clinical practice through the promotion of a patient-centered approach to the assessment of treatment effectiveness, using five specified domains, in patients with schizophrenia. PMID- 25285012 TI - Educating future leaders in patient safety. AB - Education of health care professionals has given little attention to patient safety, resulting in limited understanding of the nature of risk in health care and the importance of strengthening systems. The World Health Organization developed the Patient Safety Curriculum Guide: Multiprofessional Edition to accelerate the incorporation of patient safety teaching into higher educational curricula. The World Health Organization Curriculum Guide uses a health system focused, team-dependent approach, which impacts all health care professionals and students learning in an integrated way about how to operate within a culture of safety. The guide is pertinent in the context of global educational reforms and growing recognition of the need to introduce patient safety into health care professionals' curricula. The guide helps to advance patient safety education worldwide in five ways. First, it addresses the variety of opportunities and contexts in which health care educators teach, and provides practical recommendations to learning. Second, it recommends shared learning by students of different professions, thus enhancing student capacity to work together effectively in multidisciplinary teams. Third, it provides guidance on a range of teaching methods and pedagogical activities to ensure that students understand that patient safety is a practical science teaching them to act in evidence-based ways to reduce patient risk. Fourth, it encourages supportive teaching and learning, emphasizing the need to establishing teaching environments in which students feel comfortable to learn and practice patient safety. Finally, it helps educators incorporate patient safety topics across all areas of clinical practice. PMID- 25285013 TI - Dental anxiety: a comparison of students of dentistry, biology, and psychology. AB - INTRODUCTION: Dental anxiety is an important challenge for many patients and clinicians. It is thus of importance to know more about dental students' own experiences with dental anxiety and their understanding of dental anxiety. The aim was to investigate differences in dental anxiety levels between dental students, psychology students, and biology students at a Norwegian university. MATERIALS AND METHODS: A total of 510 students of dentistry, psychology, and biology at the University of Tromso received a questionnaire consisting of the Modified Dental Anxiety Scale, demographic questions, and questions relating to their last visit to the dentist/dental hygienist; 169 students gave complete responses. Nonparametric tests were used to investigate differences between the student groups. RESULTS: The respondents were 78% female and 22% male; their mean age was 24 years. The dental students showed a significantly lower degree of dental anxiety than the psychology (P<0.001) and biology students (P<0.001). A significant decrease in dental anxiety levels was found between novice and experienced dentistry students (P<0.001). DISCUSSION: The dental students had less dental anxiety compared to psychology students and biology students. Experienced dental students also had less dental anxiety than novice dental students. This could indicate that the dentistry program structure at the university may influence dental anxiety levels. CONCLUSION: Dental anxiety seemed to be less frequent in dentistry students compared to students of biology or clinical psychology. The practice-oriented dentistry education at the university might contribute to the differences in anxiety levels between new and experienced dentistry students. PMID- 25285014 TI - The target therapy of ovarian clear cell carcinoma. AB - Clear cell adenocarcinoma (CCC) of the ovary accounts for 10% of epithelial ovarian cancer and is a distinct entity from other epithelial ovarian carcinomas. It arises from the endometriosis. CCC has specific biological and clinical behavior. Compared with other histological types, CCC shows a chemoresistant phenotype, which leads to poorer prognosis. Thus, development of new target-based therapies remains an unmet need for these patients. Mutations in the gene ARID1A have been found to occur in high frequency in CCC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex and considered as a bona fide tumor suppressor. Upregulation of the PIK3/AKT/mTOR pathway, particularly through mutations of PIK3CA and inactivation of PTEN, is involved in tumorigenesis of CCC. Targeting angiogenesis, the Met protooncogene pathway, and HER2 are also discussed in this review. PMID- 25285015 TI - Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. AB - PURPOSE: The primary aim of this research was to investigate the association between uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms and the toxicities of irinotecan-based regimens in Chinese patients with metastatic colorectal cancer. METHODS: The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The adverse reactions and tumor response were evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0, and Response Evaluation Criteria In Solid Tumors, Version 1.0, criteria, respectively. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia was analyzed. The influences of UGT1A1*6/*28 polymorphisms on response rate and progression-free survival were also analyzed. Survival analysis was performed by the Kaplan-Meier method, and we used the log rank test to analyze the effect of genotypes on progression-free survival, the logistic regression model for multivariate analysis, and the Cox regression model for multivariate survival analysis. RESULTS: A total of 167 patients with metastatic colorectal cancer who were treated with irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. The rate of UGT1A1*28 homozygous wild-type TA6/6, heterozygous mutant-type TA6/7, and homozygous mutant-type TA7/7 was 65.3% (109/167), 32.3% (54/167), and 2.4% (4/167), respectively; the incidence of UGT1A1*6 wild-type G/G was 67.1% (112/167), heterozygous mutant-type G/A accounted for 28.7% (48/167), and seven cases were homozygous mutant-type A/A (4.2%; 7/167). The incidence of grade 3 or 4 delayed diarrhea in patients carrying UGT1A1*6 (G/A and A/A) was higher than that in the wild-type (G/G) (P=0.021). The rate was significantly lower in patients with the UGT1A1*28 TA6/6 wide-type genotype than those with TA6/7 and TA7/7 mutant-type genotypes (P=0.027). However, neither UGT1A1*6 (P=0.34) nor UGT1A1*28 (P=0.232) variants were significantly associated with severe neutropenia. Our study found no significant differences of severe neutropenia in patients with different numbers of mutational alleles (P=0.354), but patients with two alleles or single allele variants had more chances to develop severe diarrhea than patients with wild-type (P=0.027). No significant differences of either response rate or progression-free survival were found among different genotypes (P>0.05). CONCLUSION: For irinotecan-based regimens in metastatic colorectal cancer, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for irinotecan-associated severe delayed diarrhea, whereas no association between UGT1A1 gene polymorphisms and severe neutropenia was observed. We also found that neither clinical response nor prognosis were significantly associated with UGT1A1 gene polymorphisms. PMID- 25285018 TI - Tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group proteins. AB - PURPOSE: To investigate tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group (PcG) proteins. METHODS: Tissue microarrays containing matched primary and recurrent ovarian tumors from the same patients were constructed for detection of PcG protein expression. Survival analyses of clinicopathological parameters and expression of PcG proteins were performed on progression-free survival (PFS) and overall survival (OS) of patients. Genetic and epigenetic heterogeneity was explored in aspects of gene copy number and microRNA (miRNA) profiling. RESULTS: PcG proteins were heterogeneously expressed in primary versus recurrent tumors (P<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of BMI1 and EZH2 in first-onset lymph node metastases with shortened PFS was demonstrated (P=0.010, P=0.019); and a significant association of intensive expression of BMI1 and EZH2 in recurrent tumors with shortened OS was demonstrated (P=0.042, P=0.047). Importantly, BMI1 and EZH2 expression provided significant independent prognostic parameters in multivariate analyses (P<0.05). Gene amplification did not always coincide with PcG protein expression. Eight miRNAs were found to be downregulated in recurrent tumors, among which miR-298 might indirectly regulate the expression of EZH2 through transcription factor ILF3. CONCLUSION: Tumor heterogeneity exists in the recurrence of epithelial ovarian cancer, manifested by PcG protein expression and underlying genetic and epigenetic alterations. Intensive expression of BMI1 and EZH2 are predictors of earlier relapse and shorter OS, independent of grade and chemotherapy sensitivity. EZH2 and miR-298 have great potential to be new targets for treatment of recurrent ovarian cancer. PMID- 25285019 TI - Budget impact analysis of antiretroviral less drug regimen simplification in HIV positive patients on the Italian National Health Service. AB - BACKGROUND: Deintensification and less drug regimen (LDR) antiretroviral therapy (ART) strategies have proved to be effective in terms of maintaining viral suppression in human immunodeficiency virus (HIV)-positive patients, increasing tolerability, and reducing toxicity of antiretroviral drugs administered to patients. However, the economic impact of these strategies have not been widely investigated. The aim of the study is to evaluate the economic impact that ART LDR could have on the Italian National Health Service (INHS) budget. METHODS: A budget impact model was structured to assess the potential savings for the INHS by the use of ART LDR for HIV-positive patients with a 3 year perspective. Data concerning ART cost, patient distribution within different ARTs, and probabilities for patients to change ART on a yearly basis were collected within four Italian infectious diseases departments, providing ART to 13.7% of the total number of patients receiving ART in Italy. RESULTS: The LDR investigated (protease inhibitor-based dual and monotherapies) led to savings for the hospitals involved when compared to the "do nothing" scenario on a 3 year basis, between 6.7% (23.11 million ?) and 12.8% (44.32 million ?) of the total ART expenditures. The mean yearly cost per patient is reduced from 9,875 ? in the do nothing scenario to a range between 9,218 ? and 8,615 ?. The use of these strategies within the four departments involved would have led to a reduction of ART expenditures for the INHS of between 1.1% and 2.1% in 3 years. CONCLUSION: ART LDR simplification would have a significant impact in the reduction of ART related costs within the hospitals involved in the study. These strategies could therefore be addressed as a sustainable answer to the public financing reduction observed within the INHS in the last year, allowing therapies to be dispensed without affecting the quality of the services provided. PMID- 25285020 TI - Effect of BMI on cardiovascular and metabolic syndrome risk factors in an Appalachian pediatric population. AB - BACKGROUND: The purpose of this study was to characterize cardiovascular risk factors in a rural pediatric population by body mass index (BMI) category and the presence of the metabolic syndrome. METHODS: Data on 13,018 children and adolescents (aged younger than 20 years) from West Virginia and Ohio in 2005-2006 were obtained from the C8 Health Project to determine the prevalence of overweight/obesity and the metabolic syndrome, which was then compared with National Health and Nutrition Examination Survey 2005-2006 data. Cardiovascular risk factors were assessed by age-standardized and sex-standardized BMI category (<85th, 85th-95th, >95th percentiles) and the presence of metabolic syndrome, defined as the presence of three or more of the following criteria: BMI >97th percentile, triglycerides >110 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, and fasting blood glucose >110 mg/dL. RESULTS: The population was 51% male and 95% white. The prevalence of overweight/obesity was 38% and metabolic syndrome was 4.6% in the C8 population, compared with a prevalence of 30% and 3.4%, respectively, within the National Health and Nutrition Examination Survey population. In our Appalachian population, a significant adverse trend across BMI categories was observed for lipids, insulin, inflammatory markers, white blood cell count, and C-reactive protein. Significant differences in these risk factors were seen among those with metabolic syndrome compared with those without metabolic syndrome. CONCLUSION: The increased prevalence of overweight/obesity and the metabolic syndrome along with the increase in cardiovascular risk factors in Appalachian children and adolescents, suggests a cohort that may develop earlier onset and possibly increased severity of cardiovascular disease and other complications associated with metabolic syndrome and obesity. PMID- 25285017 TI - Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nonsmall cell lung cancer: challenges and perspectives. AB - Lung cancer, mostly nonsmall cell lung cancer, continues to be the leading cause of cancer-related death worldwide. With the development of tyrosine kinase inhibitors that selectively target lung cancer-related epidermal growth factor receptor mutations, management of advanced nonsmall cell lung cancer has been greatly transformed. Improvements in progression-free survival and life quality of the patients were observed in numerous clinical studies. However, overall survival is not prolonged because of later-acquired drug resistance. Recent studies reveal a heterogeneous subclonal architecture of lung cancer, so it is speculated that the tumor may rapidly adapt to environmental changes via a Darwinian selection mechanism. In this review, we aim to provide an overview of both spatial and temporal tumor heterogeneity as potential mechanisms underlying epidermal growth factor receptor tyrosine kinase inhibitor resistance in nonsmall cell lung cancer and summarize the possible origins of tumor heterogeneity covering theories of cancer stem cells and clonal evolution, as well as genomic instability and epigenetic aberrations in lung cancer. Moreover, investigational measures that overcome heterogeneity-associated drug resistance and new assays to improve tumor assessment are also discussed. PMID- 25285022 TI - More than meets the eye: visual attention biases in individuals reporting chronic pain. AB - The present study used eye-tracking technology to assess whether individuals who report chronic pain direct more attention to sensory pain-related words than do pain-free individuals. A total of 113 participants (51 with chronic pain, 62 pain free) were recruited. Participants completed a dot-probe task, viewing neutral and sensory pain-related words while their reaction time and eye movements were recorded. Eye-tracking data were analyzed by mixed-design analysis of variance with group (chronic pain versus pain-free) as the between-subjects factor, and word type (sensory pain versus neutral) as the within-subjects factor. Results showed a significant main effect for word type: all participants attended to pain related words more than neutral words on several eye-tracking parameters. The group main effect was significant for number of fixations, which was greater in the chronic pain group. Finally, the group by word type interaction effect was significant for average visit duration, number of fixations, and total late-phase duration, all greater for sensory pain versus neutral words in the chronic pain group. As well, participants with chronic pain fixated significantly more frequently on pain words than did pain-free participants. In contrast, none of the effects for reaction time were significant. The results support the hypothesis that individuals with chronic pain display specific attentional biases toward pain-related stimuli and demonstrate the value of eye-tracking technology in measuring differences in visual attention variables. PMID- 25285021 TI - Long-term efficacy and safety of once-daily mesalazine granules for the treatment of active ulcerative colitis. AB - In 1977, 5-aminosalicylic acid (5-ASA) was discovered as a therapeutically active moiety of sulfasalazine (SASP) and was launched for topical and oral therapy of ulcerative colitis (UC) in 1984. As a first-step, delivery systems had to be developed to protect 5-ASA against absorption in the upper gastrointestinal tract, resulting in different and competing strategies (azo compounds, controlled release, and pH-dependent release). In a second step, at the beginning of the new century, coinciding with the expiration of patent protection for the first 5-ASA formulations, two component composite release mechanisms (pH-dependent and controlled release) were developed. Furthermore, the drug was formulated as granules instead of tablets, allowing higher unit strengths compared with tablets. Neither Salofalk Granu-Stix((r)), nor MMX 5-ASA, nor Pentasa((r)) granules have initially been developed for once-daily (OD) dosing. A review of the achievements of 20 years of 5-ASA development has demonstrated that 5-ASA has equal efficacy compared with SASP at best, that there are no measurable differences in efficacy between various 5-ASA preparations, and that in a group of patients tolerating SASP, adverse event profiles of SASP and 5-ASA did not differ significantly, with SASP being the far cheaper substance. Therefore, drug adherence came into focus as a new goal for improving UC therapy. Although adherence is a complex and multifactorial construct, a simple dosing schedule may contribute to higher drug adherence and better efficacy of treatment. Simultaneously, the US 5-ASA market, estimated to be worth US$1.4 billion, is expected to grow continuously. Naturally, this very competitive market is not only driven by scientific progress but also by commercial interests. Thus, patents for minor changes to the formulation may serve as protection against drug companies trying to launch generic versions. Randomized controlled trials performed on OD dosing in induction of remission have demonstrated that OD administration of 5-ASA is as effective as conventional dosing in mild to moderate active UC. The three 5-ASA products MMX, Salofalk((r)), and Pentasa((r)) employed in those studies so far have not shown differences in efficacy between OD and conventional dosing. No differences regarding safety outcomes have been detected between OD and conventional dosing, including incidence of adverse events, serious adverse events, or withdrawal from treatment due to an adverse event. Although the majority of patients prefer OD dosing to conventional dosing, it was not possible to detect differences in adherence between OD and multiple dose regimens in the clinical trial setting. Well-designed and controlled large scale community-based studies are necessary to further investigate and prove the point of improved long-term adherence and treatment efficacy in OD dosing. PMID- 25285016 TI - The emerging role of class-3 semaphorins and their neuropilin receptors in oncology. AB - The semaphorins, discovered over 20 years ago, are a large family of secreted or transmembrane and glycophosphatidylinositol -anchored proteins initially identified as axon guidance molecules crucial for the development of the nervous system. It has now been established that they also play important roles in organ development and function, especially involving the immune, respiratory, and cardiovascular systems, and in pathological disorders, including cancer. During tumor progression, semaphorins can have both pro- and anti-tumor functions, and this has created complexities in our understanding of these systems. Semaphorins may affect tumor growth and metastases by directly targeting tumor cells, as well as indirectly by interacting with and influencing cells from the micro environment and vasculature. Mechanistically, semaphorins, through binding to their receptors, neuropilins and plexins, affect pathways involved in cell adhesion, migration, invasion, proliferation, and survival. Importantly, neuropilins also act as co-receptors for several growth factors and enhance their signaling activities, while class 3 semaphorins may interfere with this. In this review, we focus on the secreted class 3 semaphorins and their neuropilin co receptors in cancer, including aspects of their signaling that may be clinically relevant. PMID- 25285023 TI - Assessment of adnexal masses using ultrasound: a practical review. AB - Pelvic ultrasound is commonly used as part of the routine gynecologic exams, resulting in diagnosis of adnexal masses, the majority of which are functional or benign. However, due to the possible complications involving benign adnexal cysts (ie, adnexal torsion, pelvic pain) and the utmost importance of early diagnosis and treatment of ovarian cancer, the correct ultrasound diagnosis of adnexal masses is essential in clinical practice. This review will describe the typical ultrasound appearance of the common physiologic, benign, and malignant adnexal masses with the aim of aiding the clinician to reach the correct diagnosis. PMID- 25285024 TI - Unusual presentation of spinal lipomatosis. AB - Spinal epidural lipomatosis (SEL) is a rare condition characterized by overgrowth of normal adipose tissue in the extradural space within the spinal canal that can lead to significant spinal cord compression. It is most commonly reported in patients receiving chronic glucocorticoid therapy. Other causes can include obesity and hypercortisolism. Occasionally, idiopathic SEL will occur in patients with no known risk factors, but cases are more generally reported in obesity and males. We present the case of a 35 year-old non-obese woman found to have rapidly progressive SEL that was not associated with any of the common causes of the disorder. PMID- 25285027 TI - Evidence from the national health account: the case of Dubai. AB - INTRODUCTION: National health accounts (NHAs) provide useful information to aid in understanding the health care financing system. This article aims to present a profile of health system financing in Dubai using data from the NHA. We also aim to compare the provider structure of financing schemes in Dubai with those of the State of Qatar and selected Organization for Economic Cooperation and Development (OECD) countries. METHODS: The author analyzed secondary data published in NHAs for Dubai and Qatar, and data collected by the OECD countries and publicly available from the Statistical Office of the European Union (Eurostat), for 25 OECD countries for comparative analysis. All health financing measures used are as defined in the international System of Health Accounts (SHA). RESULTS: In Dubai, only 33% of current health expenditure (CHE) is funded by the government. However, the public sector is the main source of health funding in Qatar and most OECD countries, with an average of 79% and 72%, respectively. Households in Dubai spent about 22% of CHE, equivalent to an average US$187 per capita, ranking the highest among Gulf Cooperation Council (GCC) countries, and compared with 20% of CHE across OECD countries. Hospitals in Dubai accounted for 48% of CHE, which is much higher than Qatar (40%) and the OECD average (36%). CONCLUSION: The Dubai health care financing system differs substantially from that in OECD countries, as it is more private oriented. The findings point to several potential opportunities for growth and improvement. Policy areas that may be addressed using the information presented in this article are broad and include the following: shift from hospital care to ambulatory and day care, sustainability of health finance, shift the cost of health care to the private sector, introduce cost-containment measures, revise payment systems for health providers, and produce subnational accounts for non-communicable diseases. More investment in the translation of national health account data into policy is suggested for future researchers. PMID- 25285025 TI - Methodological choices for the clinical development of medical devices. AB - Clinical evidence available for the assessment of medical devices (MDs) is frequently insufficient. New MDs should be subjected to high quality clinical studies to demonstrate their benefit to patients. The randomized controlled trial (RCT) is the study design reaching the highest level of evidence in order to demonstrate the efficacy of a new MD. However, the clinical context of some MDs makes it difficult to carry out a conventional RCT. The objectives of this review are to present problems related to conducting conventional RCTs and to identify other experimental designs, their limitations, and their applications. A systematic literature search was conducted for the period January 2000 to July 2012 by searching medical bibliographic databases. Problems related to conducting conventional RCTs of MDs were identified: timing the assessment, eligible population and recruitment, acceptability, blinding, choice of comparator group, and learning curve. Other types of experimental designs have been described. Zelen's design trials and randomized consent design trials facilitate the recruitment of patients, but can cause ethical problems to arise. Expertise-based RCTs involve randomization to a team that specializes in a given intervention. Sometimes, the feasibility of an expertise-based randomized trial may be greater than that of a conventional trial. Cross-over trials reduce the number of patients, but are not applicable when a learning curve is required. Sequential trials have the advantage of allowing a trial to be stopped early depending on the results of first inclusions, but they require an independent committee. Bayesian methods combine existing information with information from the ongoing trial. These methods are particularly useful in situations where the number of subjects is small. The disadvantage is the risk of including erroneous prior information. Other types of experimental designs exist when conventional trials cannot always be applied to the clinical development of MDs. PMID- 25285026 TI - Taste perception analysis using a semantic verbal fluency task. AB - A verbal fluency (VF) task is a test used to examine cognitive perception. The main aim of this study was to explore a possible relationship between taste perception in the basic taste categories (sweet, salty, sour, and bitter) and subjects' taste preferences, using a VF task in healthy and dysphagic subjects. In addition, we correlated the results of the VF task with body mass index (BMI). The hypothesis is that categorical preferences would be consistent with the number of verbal responses. We also hypothesized that higher BMI (>30 kg/m(2)) would correlate with more responses in either some or all four categories. VF tasks were randomly administered. Analysis criteria included number of verbally produced responses, number of clusters, number of switches, number and type of errors, and VF consistency with taste preferences. Sixty Greek-speaking individuals participated in this study. Forty-three healthy subjects were selected with a wide range of ages, sex, and education levels. Seventeen dysphagic patients were then matched with 17 healthy subjects according to age, sex, and BMI. Quantitative one-way analysis of variance (between groups as well as repeated measures), post hoc, and chi-square, and qualitative analyses were performed. In the healthy subjects' group, the differences among the mean number of responses for the four taste categories were statistically significant. When comparing the two matched groups of healthy and dysphagic subjects, there were no statistically significant differences in the mean number of responses in the four basic taste categories. However, for both groups, most responses were generated in the following descending order: sweet, salty, sour, and bitter. The bitter category presented the majority of errors for both groups. Obese subjects produced a greater mean number of responses for the "sweet," "sour," and "bitter" categories; conversely, underweight subjects produced a larger mean number of responses for the "salty" category, even though these differences were not statistically significant. The relationship of VF with taste perception and BMI could contribute to evidence-based knowledge that can be used for clinical practice. PMID- 25285028 TI - Factors Associated with Body Mass Index(BMI) Among Older Adults: A Comparison Study of the U.S., Japan, and Korea. AB - This study examined BMI distributions among older adults in three different countries: the U.S., Japan, and Korea. The paper also explored differences in the factors predicting BMI in the three countries using three data sets: the U.S. Longitudinal Study of Aging (LSOA II, 8,589 persons), the Nihon University Japanese Longitudinal Study of Aging (NUJLSOA, 2,888 persons), and the Korean Longitudinal Study of Ageing (KLoSA, 2,397 persons). Descriptive analysis and multiple regression were performed. Japanese older adults were somewhat lighter than Koreans with fewer people at the upper end of the BMI distribution. Distributions of BMI among both Koreans and Japanese are shifted leftward relative to Americans. There is less dispersion in the distribution of BMI for Koreans and Japanese than among Americans. The association between socioeconomic variables and BMI is stronger in the U.S. and Japan than in Korea. Demographic variables are strong predictors of BMI in Korea. In Japan, all health behaviors have significant effects on BMI. It is concluded that the relationships between behavioral, demographical, and socioeconomic factors and BMI are not the same across countries. Results have policy implications for the involvement of health practitioners in helping older adults to control weight. PMID- 25285030 TI - Group Differences in Suppression Skill. AB - It is proposed that there are group differences in suppression skill, and one such grouping is the distinction between more versus less skilled university-aged comprehenders. Experiments supporting this proposal and demonstrating that university-aged adults differ in their ability to suppress irrelevant, inappropriate, potentially interfering information are reviewed. Many of these experiments have been replicated with other groups, which also hypothetically differ in their ability to suppress inappropriate information. Two new sets of experiments are reviewed. In one, the prediction that less skilled comprehenders- because they are less skilled at suppression- should be better at comprehending puns is evaluated. In the other, the prediction that less skilled comprehenders- because they are less skilled at suppression- are better able to shift to a different meaning of a homonym is evaluated. Both sets of data are evaluated with respect to a general slowing explanation and scaling artifacts. PMID- 25285029 TI - The EVB as a quantitative tool for formulating simulations and analyzing biological and chemical reactions. AB - Recent years have seen dramatic improvements in computer power, allowing ever more challenging problems to be approached. In light of this, it is imperative to have a quantitative model for examining chemical reactivity, both in the condensed phase and in solution, as well as to accurately quantify physical organic chemistry (particularly as experimental approaches can often be inconclusive). Similarly, computational approaches allow for great progress in studying enzyme catalysis, as they allow for the separation of the relevant energy contributions to catalysis. Due to the complexity of the problems that need addressing, there is a need for an approach that can combine reliability with an ability to capture complex systems in order to resolve long-standing controversies in a unique way. Herein, we will demonstrate that the empirical valence bond (EVB) approach provides a powerful way to connect the classical concepts of physical organic chemistry to the actual energies of enzymatic reactions by means of computation. Additionally, we will discuss the proliferation of this approach, as well as attempts to capture its basic chemistry and repackage it under different names. We believe that the EVB approach is the most powerful tool that is currently available for studies of chemical processes in the condensed phase in general and enzymes in particular, particularly when trying to explore the different proposals about the origin of the catalytic power of enzymes. PMID- 25285032 TI - 7Be-recoil radiolabelling of industrially manufactured silica nanoparticles. AB - Radiolabelling of industrially manufactured nanoparticles is useful for nanoparticle dosimetry in biodistribution or cellular uptake studies for hazard and risk assessment. Ideally for such purposes, any chemical processing post production should be avoided as it may change the physico-chemical characteristics of the industrially manufactured species. In many cases, proton irradiation of nanoparticles allows radiolabelling by transmutation of a tiny fraction of their constituent atoms into radionuclides. However, not all types of nanoparticles offer nuclear reactions leading to radionuclides with adequate radiotracer properties. We describe here a process whereby in such cases nanoparticles can be labelled with 7Be, which exhibits a physical half-life of 53.29 days and emits gamma-rays of 478 keV energy, and is suitable for most radiotracer studies. 7Be is produced via the proton-induced nuclear reaction 7Li(p,n)7Be in a fine-grained lithium compound with which the nanoparticles are mixed. The high recoil energy of 7Be atoms gives them a range that allows the 7Be recoils to be transferred from the lithium compound into the nanoparticles by recoil implantation. The nanoparticles can be recovered from the mixture by dissolving the lithium compound and subsequent filtration or centrifugation. The method has been applied to radiolabel industrially manufactured SiO2 nanoparticles. The process can be controlled in such a way that no alterations of the 7Be-labelled nanoparticles are detectable by dynamic light scattering, X-ray diffraction and electron microscopy. Moreover, cyclotrons with maximum proton energies of 17-18 MeV that are available in most medical research centres could be used for this purpose. PMID- 25285031 TI - Silibinin inhibits fibronectin induced motility, invasiveness and survival in human prostate carcinoma PC3 cells via targeting integrin signaling. AB - Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths among men in the United States. Preventing or inhibiting metastasis-related events through non-toxic agents could be a useful approach for lowering high mortality among PCA patients. We have earlier reported that natural flavonoid silibinin possesses strong anti-metastatic efficacy against PCA however, mechanism/s of its action still remains largely unknown. One of the major events during metastasis is the replacement of cell-cell interaction with integrins-based cell-matrix interaction that controls motility, invasiveness and survival of cancer cells. Accordingly, here we examined silibinin effect on advanced human PCA PC3 cells' interaction with extracellular matrix component fibronectin. Silibinin (50-200 MUM) treatment significantly decreased the fibronectin (5 MUg/ml)-induced motile morphology via targeting actin cytoskeleton organization in PC3 cells. Silibinin also decreased the fibronectin-induced cell proliferation and motility but significantly increased cell death in PC3 cells. Silibinin also inhibited the PC3 cells invasiveness in Transwell invasion assays with fibronectin or cancer associated fibroblasts (CAFs) serving as chemoattractant. Importantly, PC3-luc cells cultured on fibronectin showed rapid dissemination and localized in lungs following tail vein injection in athymic male nude mice; however, in silibinin treated PC3-luc cells, dissemination and lung localization was largely compromised. Molecular analyses revealed that silibinin treatment modulated the fibronectin-induced expression of integrins (alpha5, alphaV, beta1 and beta3), actin-remodeling (FAK, Src, GTPases, ARP2 and cortactin), apoptosis (cPARP and cleaved caspase 3), EMT (E-cadherin and beta-catenin), and cell survival (survivin and Akt) related signaling molecules in PC3 cells. Furthermore, PC3 xenograft tissue analyses confirmed the inhibitory effect of silibinin on fibronectin and integrins expression. Together, these results showed that silibinin targets PCA cells' interaction with fibronectin and inhibits their motility, invasiveness and survival; thus further supporting silibinin use in PCA intervention including its metastatic progression. PMID- 25285033 TI - Quantification of Al2O3 nanoparticles in human cell lines applying inductively coupled plasma mass spectrometry (neb-ICP-MS, LA-ICP-MS) and flow cytometry-based methods. AB - In order to quantify and compare the uptake of aluminum oxide nanoparticles of three different sizes into two human cell lines (skin keratinocytes (HaCaT) and lung epithelial cells (A549)), three analytical methods were applied: digestion followed by nebulization inductively coupled plasma mass spectrometry (neb-ICP MS), direct laser ablation ICP-MS (LA-ICP-MS), and flow cytometry. Light and electron microscopy revealed an accumulation and agglomeration of all particle types within the cell cytoplasm, whereas no particles were detected in the cell nuclei. The internalized Al2O3 particles exerted no toxicity in the two cell lines after 24 h of exposure. The smallest particles with a primary particle size (xBET) of 14 nm (Alu1) showed the lowest sedimentation velocity within the cell culture media, but were calculated to have settled completely after 20 h. Alu2 (xBET = 111 nm) and Alu3 (xBET = 750 nm) were calculated to reach the cell surface after 7 h and 3 min, respectively. The internal concentrations determined with the different methods lay in a comparable range of 2-8 ug Al2O3/cm2 cell layer, indicating the suitability of all methods to quantify the nanoparticle uptake. Nevertheless, particle size limitations of analytical methods using optical devices were demonstrated for LA-ICP-MS and flow cytometry. Furthermore, the consideration and comparison of particle properties as parameters for particle internalization revealed the particle size and the exposure concentration as determining factors for particle uptake. PMID- 25285034 TI - Nanocommunication design in graduate-level education and research training programs at Osaka University. AB - After more than ten years of strategic investment research and development supported by government policies on science and technology, nanotechnology in Japan is making a transition from the knowledge creation stage of exploratory research to the stage of making the outcomes available for the benefit of society as a whole. Osaka University has been proactive in discussions about the relationship between nanotechnology and society as part of graduate and continuing education programs. These programs are intended to fulfill the social accountability obligation of scientists and corporations involved in R&D, and to deepen their understanding of the relationship between science and society. To meet those aims, the program has covered themes relating to overall public engagement relating to nanotechnology governance, such as risk management of nanomaterials, international standardization for nanotechnology, nanomeasurement, intellectual property management in an open innovation environment, and interactive communication with society. Nanotechnology is an emerging field of science and technology. This paper reports and comments on initiatives for public engagement on nanotechnology at Osaka University's Institute for NanoScience Design, which aims to create new technologies based on nanotechnology that can help realize a sustainable society. PMID- 25285036 TI - Co-expression analysis of fetal weight-related genes in ovine skeletal muscle during mid and late fetal development stages. AB - BACKGROUND: Muscle development and lipid metabolism play important roles during fetal development stages. The commercial Texel sheep are more muscular than the indigenous Ujumqin sheep. RESULTS: We performed serial transcriptomics assays and systems biology analyses to investigate the dynamics of gene expression changes associated with fetal longissimus muscles during different fetal stages in two sheep breeds. Totally, we identified 1472 differentially expressed genes during various fetal stages using time-series expression analysis. A systems biology approach, weighted gene co-expression network analysis (WGCNA), was used to detect modules of correlated genes among these 1472 genes. Dramatically different gene modules were identified in four merged datasets, corresponding to the mid fetal stage in Texel and Ujumqin sheep, the late fetal stage in Texel and Ujumqin sheep, respectively. We further detected gene modules significantly correlated with fetal weight, and constructed networks and pathways using genes with high significances. In these gene modules, we identified genes like TADA3, LMNB1, TGF beta3, EEF1A2, FGFR1, MYOZ1, and FBP2 correlated with fetal weight. CONCLUSION: Our study revealed the complex network characteristics involved in muscle development and lipid metabolism during fetal development stages. Diverse patterns of the network connections observed between breeds and fetal stages could involve some hub genes, which play central roles in fetal development, correlating with fetal weight. Our findings could provide potential valuable biomarkers for selection of body weight-related traits in sheep and other livestock. PMID- 25285037 TI - Transcriptome characterization analysis of Bactrocera minax and new insights into its pupal diapause development with gene expression analysis. AB - Bactrocera minax is a major citrus pest distributed in China, Bhutan and India. The long pupal diapause duration of this fly is a major bottleneck for artificial rearing and underlying mechanisms remain unknown. Genetic information on B. minax transcriptome and gene expression profiles are needed to understand its pupal diapause. High-throughput RNA-seq technology was used to characterize the B. minax transcriptome and to identify differentially expressed genes during pupal diapause development. A total number of 52,519,948 reads were generated and assembled into 47,217 unigenes. 26,843 unigenes matched to proteins in the NCBI database using the BLAST search. Four digital gene expression (DGE) libraries were constructed for pupae at early diapause, late diapause, post-diapause and diapause terminated developmental status. 4,355 unigenes showing the differences expressed across four libraries revealed major shifts in cellular functions of cell proliferation, protein processing and export, metabolism and stress response in pupal diapause. When diapause was terminated by 20-hydroxyecdysone (20E), many genes involved in ribosome and metabolism were differentially expressed which may mediate diapause transition. The gene sets involved in protein and energy metabolisms varied throughout early-, late- and post-diapause. A total of 15 genes were selected to verify the DGE results through quantitative real-time PCR (qRT-PCR); qRT-PCR expression levels strongly correlated with the DGE data. The results provided the extensive sequence resources available for B. minax and increased our knowledge on its pupal diapause development and they shed new light on the possible mechanisms involved in pupal diapause in this species. PMID- 25285035 TI - Preclinical and clinical investigations of mood stabilizers for Huntington's disease: what have we learned? AB - Huntington's disease (HD) is a lethal, autosomal dominant neurodegenerative disorder caused by CAG repeat expansions at exon 1 of the huntingtin (Htt) gene, which encodes for a mutant huntingtin protein (mHtt). Prominent symptoms of HD include motor dysfunction, characterized by chorea; psychiatric disturbances such as mood and personality changes; and cognitive decline that may lead to dementia. Pathologically multiple complex processes and pathways are involved in the development of HD, including selective loss of neurons in the striatum and cortex, dysregulation of cellular autophagy, mitochondrial dysfunction, decreased neurotrophic and growth factor levels, and aberrant regulation of gene expression and epigenetic patterns. No cure for HD presently exists, nor are there drugs that can halt the progression of this devastating disease. Therefore, the need to discover neuroprotective modalities to combat HD is critical. In basic and preclinical studies using cellular and animal HD models, the mood stabilizers lithium and valproic acid (VPA) have shown multiple beneficial effects, including behavioral and motor improvement, enhanced neuroprotection, and lifespan extension. Recent studies in transgenic HD mice support the notion that combined lithium/VPA treatment is more effective than treatment with either drug alone. In humans, several clinical studies of HD patients found that lithium treatment improved mood, and that VPA treatment both stabilized mood and moderately reduced chorea. In contrast, other studies observed that the hallmark features of HD were unaffected by treatment with either lithium or VPA. The current review discusses preclinical and clinical investigations of the beneficial effects of lithium and VPA on HD pathophysiology. PMID- 25285038 TI - Deletion of Fgfr1 in osteoblasts enhances mobilization of EPCs into peripheral blood in a mouse endotoxemia model. AB - Endothelial progenitor cells (EPCs) contribute to neovascularization and vascular repair, and may exert a beneficial effect on the clinical outcome of sepsis. Osteoblasts act as a component of "niche" in bone marrow, which provides a nest for stem/progenitor cells and are involved in the formation and maintenance of stem/progenitor cells. Fibroblast growth factor receptor 1 (FGFR1) can regulate osteoblast activity and influence bone mass. So we explored the role of FGFR1 in EPC mobilization. Male mice with osteoblast-specific knockout of Fgfr1 (Fgfr1(fl/fl);OC-Cre) and its wild-type littermates (Fgfr1(fl/fl) ) were used in this study. Mice intraperitoneally injected with lipopolysaccharide (LPS) were used to measure the number of circulating EPCs in peripheral blood and serum stromal cell-derived factor 1alpha (SDF-1alpha). The circulating EPC number and the serum level of SDF-1alpha were significantly higher in Fgfr1(fl/fl);OC-Cre mice than those in Fgfr1(fl/fl) mice after LPS injection. In cell culture system, SDF-1alpha level was also significantly higher in Fgfr1(fl/fl);OC-Cre osteoblasts compared with that in Fgfr1(fl/fl) osteoblasts after LPS treatment. TRAP staining showed that there was no significant difference between the osteoclast activity of septic Fgfr1(fl/fl) and Fgfr1(fl/fl);OC-Cre mice. This study suggests that targeted deletion of Fgfr1 in osteoblasts enhances mobilization of EPCs into peripheral blood through up-regulating SDF-1alpha secretion from osteoblasts. PMID- 25285041 TI - Bayesian Analysis of the Effect of Intentional Weight Loss on Mortality Rate. AB - The effect of weight loss on mortality rate is widely studied and of importance in the field of obesity. Separating the effects of intentional weight loss (IWL) from unintentional weight loss (UWL) has been a challenge. Most studies addressing this issue have used weight loss among people intending to lose weight as a surrogate of IWL. Coffey et al. (2005) [1] showed that these were not equivalent and developed a preliminary model to separate the effects of IWL from those of UWL. In this study we construct and implement Bayesian latent-variable linear models that allow the separation of the effects of IWL and UWL. The key idea of our method is to augment the unobserved UWL by using the information of observed weight loss among individuals not intending to lose weight. This data augmentation approach offers a way to estimate the effects of IWL and UWL as well as any parameters of interest. We applied our method to a real data set of rodent caloric restriction studies: our results suggest that IWL has a beneficial effect on mouse lifespan in contrast to UWL. Extensions to human data involving censored outcomes are discussed. PMID- 25285040 TI - Linking patient satisfaction with nursing care: the case of care rationing - a correlational study. AB - BACKGROUND: Implicit rationing of nursing care is the withholding of or failure to carry out all necessary nursing measures due to lack of resources. There is evidence supporting a link between rationing of nursing care, nurses' perceptions of their professional environment, negative patient outcomes, and placing patient safety at risk. The aims of the study were: a) To explore whether patient satisfaction is linked to nurse-reported rationing of nursing care and to nurses' perceptions of their practice environment while adjusting for patient and nurse characteristics. b) To identify the threshold score of rationing by comparing the level of patient satisfaction factors across rationing levels. METHODS: A descriptive, correlational design was employed. Participants in this study included 352 patients and 318 nurses from ten medical and surgical units of five general hospitals. Three measurement instruments were used: the BERNCA scale for rationing of care, the RPPE scale to explore nurses' perceptions of their work environment and the Patient Satisfaction scale to assess the level of patient satisfaction with nursing care. The statistical analysis included the use of Kendall's correlation coefficient to explore a possible relationship between the variables and multiple regression analysis to assess the effects of implicit rationing of nursing care together with organizational characteristics on patient satisfaction. RESULTS: The mean score of implicit rationing of nursing care was 0.83 (SD = 0.52, range = 0-3), the overall mean of RPPE was 2.76 (SD = 0.32, range = 1.28 - 3.69) and the two scales were significantly correlated (tau = 0.234, p < 0.001). The regression analysis showed that care rationing and work environment were related to patient satisfaction, even after controlling for nurse and patient characteristics. The results from the adjusted regression models showed that even at the lowest level of rationing (i.e. 0.5) patients indicated low satisfaction. CONCLUSIONS: The results support the relationships between organizational and environmental variables, care rationing and patient satisfaction. The identification of thresholds at which rationing starts to influence patient outcomes in a negative way may allow nurse managers to introduce interventions so as to keep rationing at a level at which patient safety is not jeopardized. PMID- 25285042 TI - Text Detection in Natural Scene Images by Stroke Gabor Words. AB - In this paper, we propose a novel algorithm, based on stroke components and descriptive Gabor filters, to detect text regions in natural scene images. Text characters and strings are constructed by stroke components as basic units. Gabor filters are used to describe and analyze the stroke components in text characters or strings. We define a suitability measurement to analyze the confidence of Gabor filters in describing stroke component and the suitability of Gabor filters on an image window. From the training set, we compute a set of Gabor filters that can describe principle stroke components of text by their parameters. Then a K means algorithm is applied to cluster the descriptive Gabor filters. The clustering centers are defined as Stroke Gabor Words (SGWs) to provide a universal description of stroke components. By suitability evaluation on positive and negative training samples respectively, each SGW generates a pair of characteristic distributions of suitability measurements. On a testing natural scene image, heuristic layout analysis is applied first to extract candidate image windows. Then we compute the principle SGWs for each image window to describe its principle stroke components. Characteristic distributions generated by principle SGWs are used to classify text or nontext windows. Experimental results on benchmark datasets demonstrate that our algorithm can handle complex backgrounds and variant text patterns (font, color, scale, etc.). PMID- 25285043 TI - Accurate Measurement of RF Power Deposition During 3T MRI. PMID- 25285039 TI - Caspases: a molecular switch node in the crosstalk between autophagy and apoptosis. AB - Autophagy and apoptosis are two important catabolic processes contributing to the maintenance of cellular and tissue homeostasis. Autophagy controls the turnover of protein aggregates and damaged organelles within cells, while apoptosis is the principal mechanism by which unwanted cells are dismantled and eliminated from organisms. Despite marked differences between these two pathways, they are highly interconnected in determining the fate of cells. Intriguingly, caspases, the primary drivers of apoptotic cell death, play a critical role in mediating the complex crosstalk between autophagy and apoptosis. Pro-apoptotic signals can converge to activate caspases to execute apoptotic cell death. In addition, activated caspases can degrade autophagy proteins (i.e., Beclin-1, Atg5, and Atg7) to shut down the autophagic response. Moreover, caspases can convert pro autophagic proteins into pro-apoptotic proteints to trigger apoptotic cell death instead. It is clear that caspases are important in both apoptosis and autophagy, thus a detailed deciphering of the role of caspases in these two processes is still required to clarify the functional relationship between them. In this article, we provide a current overview of caspases in its interplay between autophagy and apoptosis. We emphasized that defining the role of caspases in autophagy-apoptosis crosstalk will provide a framework for more precise manipulation of these two processes during cell death. PMID- 25285044 TI - A Multi-Channel, High Dynamic Range, Real Time RF Power Deposition Monitor. PMID- 25285045 TI - Measuring energy diffusion: phosphocreatine in human skeletal muscle. PMID- 25285046 TI - Graphical-model Based Multiple Testing under Dependence, with Applications to Genome-wide Association Studies. AB - Large-scale multiple testing tasks often exhibit dependence, and leveraging the dependence between individual tests is still one challenging and important problem in statistics. With recent advances in graphical models, it is feasible to use them to perform multiple testing under dependence. We propose a multiple testing procedure which is based on a Markov-random-field-coupled mixture model. The ground truth of hypotheses is represented by a latent binary Markov random field, and the observed test statistics appear as the coupled mixture variables. The parameters in our model can be automatically learned by a novel EM algorithm. We use an MCMC algorithm to infer the posterior probability that each hypothesis is null (termed local index of significance), and the false discovery rate can be controlled accordingly. Simulations show that the numerical performance of multiple testing can be improved substantially by using our procedure. We apply the procedure to a real-world genome-wide association study on breast cancer, and we identify several SNPs with strong association evidence. PMID- 25285047 TI - A Mixed Methods Approach to Network Data Collection. AB - There is a growing interest in examining network processes with a mix of qualitative and quantitative network data. Research has consistently shown that free recall name generators entail recall bias and result in missing data that affects the quality of social network data. This study describes a mixed methods approach for collecting social network data, combining a free recall name generator in the context of an online survey with network relations data coded from transcripts of semi-structured qualitative interviews. The combined network provides substantially more information about the network space, both quantitatively and qualitatively. While network density was relatively stable across networks generated from different data collection methodologies, there were noticeable differences in centrality and component structure across networks. The approach presented here involved limited participant burden and generated more complete data than either technique alone could provide. We make suggestions for further development of this method. PMID- 25285048 TI - Do Actions Speak Louder Than Words?: Adolescent Interpretations of Parental Substance Use. AB - Parents are powerful socialization agents for children and as children reach adolescence parental role models, among other sources of influence, become particularly salient in adolescents' decision-making regarding initiation of substance use. Open parent-adolescent communication about substances is associated with less substance use by adolescents; however, it is unclear how youth interpret anti-drug use messages from their parents, especially if the parents engage in legal and/or illicit substance use themselves. Framed by social learning theory and social constructionism, this study analyzed in-depth interviews with 108 adolescents about personal experiences with substance use, family communication about substance use, and adolescent interpretations of parental use. Emergent themes in the data include: positive parental influence, parentalcontradictions, and negative outcomes of use. Prevalence of parental use regardless of legality, rarity of explicit communication about parental use, and various interpretations of parental use are discussed. PMID- 25285049 TI - X-ray Transparent Microfluidic Chip for Mesophase-Based Crystallization of Membrane Proteins and On-Chip Structure Determination. AB - Crystallization from lipidic mesophase matrices is a promising route to diffraction-quality crystals and structures of membrane proteins. The microfluidic approach reported here eliminates two bottlenecks of the standard mesophase-based crystallization protocols: (i) manual preparation of viscous mesophases and (ii) manual harvesting of often small and fragile protein crystals. In the approach reported here, protein-loaded mesophases are formulated in an X-ray transparent microfluidic chip using only 60 nL of the protein solution per crystallization trial. The X-ray transparency of the chip enables diffraction data collection from multiple crystals residing in microfluidic wells, eliminating the normally required manual harvesting and mounting of individual crystals. We validated our approach by on-chip crystallization of photosynthetic reaction center, a membrane protein from Rhodobacter sphaeroides, followed by solving its structure to a resolution of 2.5 A using X-ray diffraction data collected on-chip under ambient conditions. A moderate conformational change in hydrophilic chains of the protein was observed when comparing the on-chip, room temperature structure with known structures for which data were acquired under cryogenic conditions. PMID- 25285050 TI - Supramolecular Assembly of Ag(I) Centers: Diverse Topologies Directed by Anionic Interactions. AB - Ag(I)-Ag(I) interactions in supramolecular structures have been achieved through the use of structural support from the ligand frames. In structures involving simple ligands like pyridine, strong pi-pi interaction leads to spatial ordering of the individual [Ag(L)2]+ units. In such structures anions also play a crucial role in dictating the final arrangement of the [Ag(L)2]+ synthons. In order to determine whether the anions can solely dictate the arrangement of the [Ag(L)2]+ synthons in the supramolecular structure, four Ag(I) complexes of 4 pyridylcarbinol (PyOH), namely, [Ag(PyOH)2]X (X = NO3- (1), BF4- (2), CF3SO3- (3), and ClO4- (4)) have been synthesized and structurally characterized. Gradual transformation of the extended structures observed in 1-3 eventually merges into a unique linear alignment of the [Ag(PyOH)2]+ units in 4 along the c axis, a feature that results in strong argentophilic interactions. Complex 4 is sensitive to light and is inherently less stable than the other three analogues. The structural variations in this set of extended assemblies are solely dictated by the anions, since pi-pi interaction between the substituted pyridine ligands is significantly diminished due to disposition of the -CH2OH substituent at the 4 position and H-bonding throughout the structure. PMID- 25285051 TI - Using Visualizations to Explore Network Dynamics. AB - Network analysis has become a popular tool to examine data from online social networks to politics to ecological systems. As more computing power has become available, new technology-driven methods and tools are being developed that can support larger and richer network data, including dynamic network analysis. This timely merger of abundant data and cutting edge techniques affords researchers the ability to better understand networks over time, accurately show how they evolve, find patterns of growth, or study models such as the diffusion of innovation. We combine traditional methods in social network analysis with new innovative visualizations and methods in dynamic network studies to explore an online tobacco-control community called GLOBALink, using almost twenty years of longitudinal data. We describe the methods used for the study, and perform an exploratory network study that links empirical results to real-world events. PMID- 25285052 TI - Algorithms for Discovery of Multiple Markov Boundaries. AB - Algorithms for Markov boundary discovery from data constitute an important recent development in machine learning, primarily because they offer a principled solution to the variable/feature selection problem and give insight on local causal structure. Over the last decade many sound algorithms have been proposed to identify a single Markov boundary of the response variable. Even though faithful distributions and, more broadly, distributions that satisfy the intersection property always have a single Markov boundary, other distributions/data sets may have multiple Markov boundaries of the response variable. The latter distributions/data sets are common in practical data analytic applications, and there are several reasons why it is important to induce multiple Markov boundaries from such data. However, there are currently no sound and efficient algorithms that can accomplish this task. This paper describes a family of algorithms TIE* that can discover all Markov boundaries in a distribution. The broad applicability as well as efficiency of the new algorithmic family is demonstrated in an extensive benchmarking study that involved comparison with 26 state-of-the-art algorithms/variants in 15 data sets from a diversity of application domains. PMID- 25285053 TI - What exactly do numbers mean? AB - Number words are generally used to refer to the exact cardinal value of a set, but cognitive scientists disagree about their meanings. Although most psychological analyses presuppose that numbers have exact semantics (two means EXACTLY TWO), many linguistic accounts propose that numbers have lower-bounded semantics (AT LEAST TWO), and that speakers restrict their reference through a pragmatic inference (scalar implicature). We address this debate through studies of children who are in the process of acquiring the meanings of numbers. Adults and 2- and 3-year-olds were tested in a novel paradigm that teases apart semantic and pragmatic aspects of interpretation (the covered box task). Our findings establish that when scalar implicatures are cancelled in the critical trials of this task, both adults and children consistently give exact interpretations for number words. These results, in concert with recent work on real-time processing, provide the first unambiguous evidence that number words have exact semantics. PMID- 25285054 TI - Exact and Asymptotic Weighted Logrank Tests for Interval Censored Data: The interval R package. AB - For right-censored data perhaps the most commonly used tests are weighted logrank tests, such as the logrank and Wilcoxon-type tests. In this paper we review several generalizations of those weighted logrank tests to interval-censored data and present an R package, interval, to implement many of them. The interval package depends on the perm package, also presented here, which performs exact and asymptotic linear permutation tests. The perm package performs many of the tests included in the already available coin package, and provides an independent validation of coin. We review analysis methods for interval-censored data, and we describe and show how to use the interval and perm packages. PMID- 25285055 TI - Dichloro(1,2-Diaminocyclohexane)Platinum(II) (DACHPt) Loaded Polymer Micelles with Cross-Linked Core: Preparation and Characterization. PMID- 25285056 TI - Luliconazole for the treatment of fungal infections: an evidence-based review. AB - Luliconazole is an imidazole antifungal agent with a unique structure, as the imidazole moiety is incorporated into the ketene dithioacetate structure. Luliconazole is the R-enantiomer, and has more potent antifungal activity than lanoconazole, which is a racemic mixture. In this review, we summarize the in vitro data, animal studies, and clinical trial data relating to the use of topical luliconazole. Preclinical studies have demonstrated excellent activity against dermatophytes. Further, in vitro/in vivo studies have also shown favorable activity against Candida albicans, Malassezia spp., and Aspergillus fumigatus. Luliconazole, although belonging to the azole group, has strong fungicidal activity against Trichophyton spp., similar to that of terbinafine. The strong clinical antifungal activity of luliconazole is possibly attributable to a combination of strong in vitro antifungal activity and favorable pharmacokinetic properties in the skin. Clinical trials have demonstrated its superiority over placebo in dermatophytosis, and its antifungal activity to be at par or even better than that of terbinafine. Application of luliconazole 1% cream once daily is effective even in short-term use (one week for tinea corporis/cruris and 2 weeks for tinea pedis). A Phase I/IIa study has shown excellent local tolerability and a lack of systemic side effects with use of topical luliconazole solution for onychomycosis. Further studies to evaluate its efficacy in onychomycosis are underway. Luliconazole 1% cream was approved in Japan in 2005 for the treatment of tinea infections. It has recently been approved by US Food and Drug Administration for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis. Topical luliconazole has a favorable safety profile, with only mild application site reactions reported occasionally. PMID- 25285057 TI - On Quantitative Comparative Research in Communication and Language Evolution. AB - Quantitative comparison of human language and natural animal communication requires improved conceptualizations. We argue that an infrastructural approach to development and evolution incorporating an extended interpretation of the distinctions among illocution, perlocution, and meaning (Austin 1962; Oller and Griebel 2008) can help place the issues relevant to quantitative comparison in perspective. The approach can illuminate the controversy revolving around the notion of functional referentiality as applied to alarm calls, for example in the vervet monkey. We argue that referentiality offers a poor point of quantitative comparison across language and animal communication in the wild. Evidence shows that even newborn human cry could be deemed to show functional referentiality according to the criteria typically invoked by advocates of referentiality in animal communication. Exploring the essence of the idea of illocution, we illustrate an important realm of commonality among animal communication systems and human language, a commonality that opens the door to more productive, quantifiable comparisons. Finally, we delineate two examples of infrastructural communicative capabilities that should be particularly amenable to direct quantitative comparison across humans and our closest relatives. PMID- 25285058 TI - Near-infrared optical absorption enhanced in black silicon via Ag nanoparticle induced localized surface plasmon. AB - Due to the localized surface plasmon (LSP) effect induced by Ag nanoparticles inside black silicon, the optical absorption of black silicon is enhanced dramatically in near-infrared range (1,100 to 2,500 nm). The black silicon with Ag nanoparticles shows much higher absorption than black silicon fabricated by chemical etching or reactive ion etching over ultraviolet to near-infrared (UV VIS-NIR, 250 to 2,500 nm). The maximum absorption even increased up to 93.6% in the NIR range (820 to 2,500 nm). The high absorption in NIR range makes LSP enhanced black silicon a potential material used for NIR-sensitive optoelectronic device. PACS: 78.67.Bf; 78.30.Fs; 78.40.-q; 42.70.Gi. PMID- 25285059 TI - Investigation of the effect of the structure of large-area carbon nanotube/fuel composites on energy generation from thermopower waves. AB - Thermopower waves are a recently developed energy conversion concept utilizing dynamic temperature and chemical potential gradients to harvest electrical energy while the combustion wave propagates along the hybrid layers of nanomaterials and chemical fuels. The intrinsic properties of the core nanomaterials and chemical fuels in the hybrid composites can broadly affect the energy generation, as well as the combustion process, of thermopower waves. So far, most research has focused on the application of new core nanomaterials to enhance energy generation. In this study, we demonstrate that the alignment of core nanomaterials can significantly influence a number of aspects of the thermopower waves, while the nanomaterials involved are identical carbon nanotubes (CNTs). Diversely structured, large-area CNT/fuel composites of one-dimensional aligned CNT arrays (1D CNT arrays), randomly oriented CNT films (2D CNT films), and randomly aggregated bulk CNT clusters (3D CNT clusters) were fabricated to evaluate the energy generation, as well as the propagation of the thermal wave, from thermopower waves. The more the core nanostructures were aligned, the less inversion of temperature gradients and the less cross-propagation of multiple thermopower waves occurred. These characteristics of the aligned structures prevented the cancellation of charge carrier movements among the core nanomaterials and produced the relative enhancement of the energy generation and the specific power with a single-polarity voltage signal. Understanding this effect of structure on energy generation from thermopower waves can help in the design of optimized hybrid composites of nanomaterials and fuels, especially designs based on the internal alignment of the materials. More generally, we believe that this work provides clues to the process of chemical to thermal to electrical energy conversion inside/outside hybrid nanostructured materials. PMID- 25285061 TI - Factors Associated with Suicide and Bankruptcy in Japanese Pathological Gamblers. AB - Pathological gambling can lead to a number of deleterious consequences, including bankruptcy and suicide. The present study examined the correlation between clinical characteristics of pathological gamblers and history of bankruptcy and suicide attempts. Subjects (141; 124 male) were outpatients at a psychiatric hospital from 2007 to 2010. Demographic and medical variables including age, gender, age of gambling onset, psychiatric complications, suicide attempts, and bankruptcy were assessed. Positive correlations were observed between suicide attempt and female gender, family history of addiction, and unemployment (p < 0.05). Similar variables correlated with bankruptcy (p < 0.05). Multivariate analysis revealed that a family history of addiction was the strongest independent predictor of suicide and bankruptcy. Results suggest that treatment for pathological gambling should address the patient's past experience with addict family members, especially if the patient reports a history of bankruptcy or suicidal ideation. PMID- 25285060 TI - Sleep and Emotional Memory Processing. AB - Cognitive neuroscience continues to build meaningful connections between affective behavior and human brain function. Within the biological sciences, a similar renaissance has taken place, focusing on the role of sleep in various neurocognitive processes, and most recently, the interaction between sleep and emotional regulation. In this article, we survey an array of diverse findings across basic and clinical research domains, resulting in a convergent view of sleep-dependent emotional brain processing. Based on the unique neurobiology of sleep, we outline a model describing the overnight modulation of affective neural systems and the (re)processing of recent emotional experiences, both of which appear to redress the appropriate next-day reactivity of limbic and associated autonomic networks. Furthermore, a REM sleep hypothesis of emotional-memory processing is proposed, the implications of which may provide brain-based insights into the association between sleep abnormalities and the initiation and maintenance of mood disturbances. PMID- 25285062 TI - Synthesis and Evaluation of an O-Aminated Naphthol AS-E as a Prodrug of CREB mediated Gene Transcription Inhibition. AB - An O-aminated naphthol AS-E was designed as a prodrug to achieve reductive activation and improved aqueous solubility. During the synthesis of this designed compound, a novel transformation from aryl triflates and ethyl acetohydroximate to oxazoles was discovered. Although the initially designed O-amino naphthol AS-E was not made successfully, the eventually synthesized O-tert-butylamino derivative was found to be biologically inactive, suggesting that reductive N-O cleavage in this compound was not facile due to unfavorable steric and electronic effects. PMID- 25285064 TI - Comparative Identification of Differential Interactions from Trajectories of Dynamic Biological Networks. AB - It is often challenging to reconstruct accurately a complete dynamic biological network due to the scarcity of data collected in cost-effective experiments. This paper addresses the possibility of comparatively identifying qualitative interaction shifts between two dynamical networks from comparative time course data. An innovative approach is developed to achieve differential interaction detection by statistically comparing the trajectories, instead of numerically comparing the reconstructed interactions. The core of this approach is a statistical heterogeneity test that compares two multiple linear regression equations for the derivatives in nonlinear ordinary differential equations, statistically instead of numerically. In detecting any shift of an interaction, the uncertainty in estimated regression coefficients is taken into account by this test, while it is ignored by the reconstruction-based numerical comparison. The heterogeneity test is accomplished by assessing the gain in goodness-of-fit from using a single common interaction to using a pair of differential interactions. Compared with previous numerical comparison methods, the proposed statistical comparison always achieves higher statistical power. As sample size decreases or noise increases in a certain range, the improvement becomes substantial. The advantage is illustrated by a simulation study on the statistical power as functions of the noise level, the sample size, and the interaction complexity. This method is also capable of detecting interaction shifts in the oscillated and excitable domains of a dynamical system model describing cdc2-cyclin interactions during cell division cycle. Generally, the described approach is applicable to comparing dynamical systems of additive nonlinear ordinary differential equations. PMID- 25285063 TI - Comparative Generalized Logic Modeling Reveals Differential Gene Interactions during Cell Cycle Exit in Drosophila Wing Development. AB - A comparative interaction detection paradigm is proposed to study the complex gene regulatory networks that control cell proliferation during development. Instead of attempting to reconstruct the entire cell cycle regulatory network from temporal transcript data, differential interactions - represented by generalized logic - are detected directly from time course transcript data under two distinct conditions. This comparative approach is scale- and shift-invariant and is capable of detecting nonlinear differential interactions. Simulation studies on E. coli circuits demonstrated that the proposed comparative method has substantially increased statistical power over the intuitive reconstruct-then compare approach. This method was therefore applied to a microarray experiment, profiling gene expression in the fruit fly wing as cells exit the cell cycle, and under a condition which delays this exit, over-expression of the cell cycle regulator E2F. One statistically significant differential interaction was identified between two gene clusters that is strongly influenced by E2F activity, and suggests the involvement of the Hippo signaling pathway in response to E2F, a finding that may provide additional insights on cell cycle control mechanisms. Furthermore, the comparative modeling can be applied to both static and dynamic gene expression data, and is extendible to deal with more than two conditions, useful in many biological studies. PMID- 25285065 TI - De-noising with a SOCK can improve the performance of event-related ICA. AB - Event-related ICA (eICA) is a partially data-driven analysis method for event related fMRI that is particularly suited to analysis of simultaneous EEG-fMRI of patients with epilepsy. EEG-fMRI studies in epileptic patients are typically analyzed using the general linear model (GLM), often with assumption that the onset and offset of neuronal activity match EEG event onset and offset, the neuronal activation is sustained at a constant level throughout the epileptiform event and that associated fMRI signal changes follow the canonical HRF. The eICA method allows for less constrained analyses capable of detecting early, non canonical responses. A key step of eICA is the initial deconvolution which can be confounded by various sources of structured noise present in the fMRI signal. To help overcome this, we have extend the eICA procedure by utilizing a fully standalone and automated fMRI de-noising procedure to process the fMRI data from an EEG-fMRI acquisition prior to running eICA. Specifically we first apply ICA to the entire fMRI time-series and use a classifier to remove noise-related components. The automated objective de-noiser, "Spatially Organized Component Klassificator" (SOCK) is used; it has previously been shown to distinguish a substantial fraction of noise from true activation, without rejecting the latter, in resting-state fMRI. A second ICA is then performed, this time on the event related response estimates derived from the denoised data (according to the usual eICA procedure). We hypothesize that SOCK + eICA has the potential to be more sensitive than eICA alone. We test the effectiveness of SOCK by comparing activation obtained in an eICA analysis of EEG-fMRI data with and without the use of SOCK for 14 patients with rolandic epilepsy who exhibited stereotypical IEDs arising from a focus in the rolandic fissure. PMID- 25285066 TI - Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro. AB - The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5 HT4 receptor agonist, 1 MUM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 MUM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 MUM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity. PMID- 25285068 TI - New perspectives in neurosteroid action: open questions for future research. PMID- 25285067 TI - Biology of adeno-associated viral vectors in the central nervous system. AB - Gene therapy is a promising approach for treating a spectrum of neurological and neurodegenerative disorders by delivering corrective genes to the central nervous system (CNS). In particular, adeno-associated viruses (AAVs) have emerged as promising tools for clinical gene transfer in a broad range of genetic disorders with neurological manifestations. In the current review, we have attempted to bridge our understanding of the biology of different AAV strains with their transduction profiles, cellular tropisms, and transport mechanisms within the CNS. Continued efforts to dissect AAV-host interactions within the brain are likely to aid in the development of improved vectors for CNS-directed gene transfer applications in the clinic. PMID- 25285069 TI - Correlation of the electrophysiological profiles and sodium channel transcripts of individual rat dorsal root ganglia neurons. AB - Voltage gated sodium channels (Nav channels) play an important role in nociceptive transmission. They are intimately tied to the genesis and transmission of neuronal firing. Five different isoforms (Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) have been linked to nociceptive responses. A change in the biophysical properties of these channels or in their expression levels occurs in different pathological pain states. However, the precise involvement of the isoforms in the genesis and transmission of nociceptive responses is unknown. The aim of the present study was to investigate the synergy between the different populations of Nav channels that give individual neurons a unique electrophysical profile. We used the patch-clamp technique in the whole-cell configuration to record Nav currents and action potentials from acutely dissociated small diameter DRG neurons (<30 MUm) from adult rats. We also performed single cell qPCR on the same neurons. Our results revealed that there is a strong correlation between Nav currents and mRNA transcripts in individual neurons. A cluster analysis showed that subgroups formed by Nav channel transcripts by mRNA quantification have different biophysical properties. In addition, the firing frequency of the neurons was not affected by the relative populations of Nav channel. The synergy between populations of Nav channel in individual small diameter DRG neurons gives each neuron a unique electrophysiological profile. The Nav channel remodeling that occurs in different pathological pain states may be responsible for the sensitization of the neurons. PMID- 25285072 TI - Cognitive reappraisal and expressive suppression strategies role in the emotion regulation: an overview on their modulatory effects and neural correlates. AB - Individuals regulate their emotions in a wide variety of ways. In the present review it has been addressed the issue of whether some forms of emotion regulation are healthier than others by focusing on two commonly used emotion regulation strategies: cognitive reappraisal (changing the way one thinks about potentially emotion-eliciting events) and expressive suppression (changing the way one behaviorally responds to emotion-eliciting events). In the first section, experimental findings showing that cognitive reappraisal has a healthier profile of short-term affective, cognitive, and social consequences than expressive suppression are briefly reported. In the second section, individual-difference findings are reviewed showing that using cognitive reappraisal to regulate emotions is associated with healthier patterns of affect, social functioning, and well-being than is using expressive suppression. Finally, brain structural basis and functional activation linked to the habitual usage of cognitive reappraisal and expressive suppression are discussed in detail. PMID- 25285070 TI - Circadian gating of neuronal functionality: a basis for iterative metaplasticity. AB - Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory. PMID- 25285071 TI - Spiking in auditory cortex following thalamic stimulation is dominated by cortical network activity. AB - The state of the sensory cortical network can have a profound impact on neural responses and perception. In rodent auditory cortex, sensory responses are reported to occur in the context of network events, similar to brief UP states, that produce "packets" of spikes and are associated with synchronized synaptic input (Bathellier et al., 2012; Hromadka et al., 2013; Luczak et al., 2013). However, traditional models based on data from visual and somatosensory cortex predict that ascending sensory thalamocortical (TC) pathways sequentially activate cells in layers 4 (L4), L2/3, and L5. The relationship between these two spatio-temporal activity patterns is unclear. Here, we used calcium imaging and electrophysiological recordings in murine auditory TC brain slices to investigate the laminar response pattern to stimulation of TC afferents. We show that although monosynaptically driven spiking in response to TC afferents occurs, the vast majority of spikes fired following TC stimulation occurs during brief UP states and outside the context of the L4>L2/3>L5 activation sequence. Specifically, monosynaptic subthreshold TC responses with similar latencies were observed throughout layers 2-6, presumably via synapses onto dendritic processes located in L3 and L4. However, monosynaptic spiking was rare, and occurred primarily in L4 and L5 non-pyramidal cells. By contrast, during brief, TC-induced UP states, spiking was dense and occurred primarily in pyramidal cells. These network events always involved infragranular layers, whereas involvement of supragranular layers was variable. During UP states, spike latencies were comparable between infragranular and supragranular cells. These data are consistent with a model in which activation of auditory cortex, especially supragranular layers, depends on internally generated network events that represent a non-linear amplification process, are initiated by infragranular cells and tightly regulated by feed-forward inhibitory cells. PMID- 25285074 TI - Assimilative and non-assimilative color spreading in the watercolor configuration. AB - A colored line flanking a darker contour will appear to spread its color onto an area enclosed by the line (watercolor effect). The watercolor effect has been characterized as an assimilative effect, but non-assimilative color spreading has also been demonstrated in the same spatial configuration; e.g., when a black inner contour (IC) is paired with a blue outer contour (OC), yellow color spreading can be observed. To elucidate visual mechanisms underlying these different color spreading effects, this study investigated the effects of luminance ratio between the double contours on the induced color by systematically manipulating the IC and the OC luminance (Experiment 1) as well as the background luminance (Experiment 2). The results showed that the luminance conditions suitable for assimilative and non-assimilative color spreading were nearly opposite. When the Weber contrast of the IC to the background luminance (IC contrast) was smaller in size than that of the OC (OC contrast), the induced color became similar to the IC color (assimilative spreading). In contrast, when the OC contrast was smaller than or equal to the IC contrast, the induced color became yellow (non-assimilative spreading). Extending these findings, Experiment 3 showed that bilateral color spreading, i.e., assimilative spreading on one side and non-assimilative spreading on the other side, can also be observed in the watercolor configuration. These results suggest that the assimilative and the non assimilative spreading were mediated by different visual mechanisms. The properties of the assimilative spreading are consistent with the model proposed to account for neon color spreading (Grossberg and Mingolla, 1985) and extended for the watercolor effect (Pinna and Grossberg, 2005). However, the present results suggest that additional mechanisms are needed to account for the non assimilative color spreading. PMID- 25285073 TI - Memantine prevents memory consolidation failure induced by soluble beta amyloid in rats. AB - It has been well documented that beta-amyloid (Abeta) peptide accumulation and aggregation in the brain plays a crucial role in the pathophysiology of Alzheimer's disease (AD). However, a new orientation of the amyloid cascade hypothesis has evidenced that soluble forms of the peptide (sAbeta) are involved in Abeta-induced cognitive impairment and cause rapid disruption of the synaptic mechanisms underlying memory. The primary aim of this study was to elucidate the effects of sAbeta, acutely injected intracerebrally (i.c.v., 4 MUM), on the short term and long term memory of young adult male rats, by using the novel object recognition task. Glutamatergic receptors have been proposed as mediating the effect of Abeta on synaptic plasticity and memory. Thus, we also investigated the effects of sAbeta on prefrontal cortex (PFC) glutamate release and the specific contribution of N-methyl-D-aspartate (NMDA) receptor modulation to the effects of sAbeta administration on the cognitive parameters evaluated. We found that a single i.c.v. injection of sAbeta 2 h before testing did not alter the ability of rats to differentiate between a familiar and a novel object, in a short term memory test, while it was able to negatively affect consolidation/retrieval of long term memory. Moreover, a significant increase of glutamate levels was found in PFC of rats treated with the peptide 2 h earlier. Interestingly, memory deficit induced by sAbeta was reversed by a NMDA-receptor antagonist, memantine (5 mg/kg i.p), administered immediately after the familiarization trial (T1). On the contrary, memantine administered 30 min before T1 trial, was not able to rescue long term memory impairment. Taken together, our results suggest that an acute i.c.v. injection of sAbeta peptide interferes with the consolidation/retrieval of long term memory. Moreover, such sAbeta-induced effect indicates the involvement of glutamatergic system, proposing that NMDA receptor inhibition might prevent or lead to the recovery of early cognitive impairment. PMID- 25285075 TI - Preliteracy signatures of poor-reading abilities in resting-state EEG. AB - The hereditary character of dyslexia suggests the presence of putative underlying neural anomalies already in preliterate age. Here, we investigated whether early neurophysiological correlates of future reading difficulties-a hallmark of dyslexia-could be identified in the resting-state EEG of preliterate children. The children in this study were recruited at birth and classified on the basis of parents' performance on reading tests to be at-risk of becoming poor readers (n = 48) or not (n = 14). Eyes-open rest EEG was measured at the age of 3 years, and the at-risk children were divided into fluent readers (n = 24) and non-fluent readers (n = 24) after reading assessment at their third grade of school. We found that fluent readers and non-fluent readers differed in normalized spectral amplitude. Non-fluent readers were characterized by lower amplitude in the delta 1 frequency band (0.5-2 Hz) and higher amplitude in the alpha-1 band (6-8 Hz) in multiple scalp regions compared to control and at-risk fluent readers. Interestingly, across groups these EEG biomarkers correlated with several behavioral test scores measured in the third grade. Specifically, the performance on reading fluency, phonological and orthographic tasks and rapid automatized naming task correlated positively with delta-1 and negatively with alpha-1. Together, our results suggest that combining family-risk status, neurophysiological testing and behavioral test scores in a longitudinal setting may help uncover physiological mechanisms implicated with neurodevelopmental disorders such as the predisposition to reading disabilities. PMID- 25285076 TI - Recovery after aerobic exercise is manipulated by tempo change in a rhythmic sound pattern, as indicated by autonomic reaction on heart functioning. AB - Physical prowess is associated with rapid recovery from exhaustion. Here we examined whether recovery from aerobic exercise could be manipulated with a rhythmic sound pattern that either decreased or increased in tempo. Six men and six women exercised repeatedly for six minutes on a cycle ergometer at 60 percent of their individual maximal oxygen consumption, and then relaxed for six minutes while listening to one of two sound pattern conditions, which seemed to infinitely either decrease or increase in tempo, during which heart and breathing activity was measured. Participants exhibited more high-frequent heart rate variability when listening to decreasing tempo than when listening to increasing tempo, accompanied by a non-significant trend towards lower heart rate. The results show that neuropsychological entrainment to a sound pattern may directly affect the autonomic nervous system, which in turn may facilitate physiological recovery after exercise. Applications using rhythmic entrainment to aid physical recovery are discussed. PMID- 25285077 TI - Pediatric stroke and transcranial direct current stimulation: methods for rational individualized dose optimization. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated mainly in adults and doses may not be appropriate in pediatric applications. In perinatal stroke where potential applications are promising, rational adaptation of dosage for children remains under investigation. OBJECTIVE: Construct child specific tDCS dosing parameters through case study within a perinatal stroke tDCS safety and feasibility trial. METHODS: 10-year-old subject with a diagnosis of presumed perinatal ischemic stroke and hemiparesis was identified. T1 magnetic resonance imaging (MRI) scans used to derive computerized model for current flow and electrode positions. Workflow using modeling results and consideration of dosage in previous clinical trials was incorporated. Prior ad hoc adult montages vs. de novo optimized montages provided distinct risk benefit analysis. Approximating adult dose required consideration of changes in both peak brain current flow and distribution which further tradeoff between maximizing efficacy and adding safety factors. Electrode size, position, current intensity, compliance voltage, and duration were controlled independently in this process. RESULTS: Brain electric fields modeled and compared to values previously predicted models (Datta et al., 2011; Minhas et al., 2012). Approximating conservative brain current flow patterns and intensities used in previous adult trials for comparable indications, the optimal current intensity established was 0.7 mA for 10 min with a tDCS C3/C4 montage. Specifically 0.7 mA produced comparable peak brain current intensity of an average adult receiving 1.0 mA. Electrode size of 5 * 7 cm(2) with 1.0 mA and low-voltage tDCS was employed to maximize tolerability. Safety and feasibility confirmed with subject tolerating the session well and no serious adverse events. CONCLUSION: Rational approaches to dose customization, with steps informed by computational modeling, may improve guidance for pediatric stroke tDCS trials. PMID- 25285079 TI - Comparative studies between mice molars and incisors are required to draw an overview of enamel structural complexity. AB - In the field of dentistry, the murine incisor has long been considered as an outstanding model to study amelogenesis. However, it clearly appears that enamel from wild type mouse incisors and molars presents several structural differences. In incisor, exclusively radial enamel is observed. In molars, enamel displays a high level of complexity since the inner part is lamellar whereas the outer enamel shows radial and tangential structures. Recently, the serotonin 2B receptor (5-HT2BR) was shown to be involved in ameloblast function and enamel mineralization. The incisors from 5HT2BR knockout (KO) mice exhibit mineralization defects mostly in the outer maturation zone and porous matrix network in the inner zone. In the molars, the mutation affects both secretory and maturation stages of amelogenesis since pronounced alterations concern overall enamel structures. Molars from 5HT2BR KO mice display reduction in enamel thickness, alterations of inner enamel architecture including defects in Hunter Schreger Bands arrangements, and altered maturation of the outer radial enamel. Differences of enamel structure were also observed between incisor and molar from other KO mice depleted for genes encoding enamel extracellular matrix proteins. Thus, upon mutation, enamel analysis based exclusively on incisor defects would be biased. In view of the functional relationship between enamel structure and tooth morphogenesis, identification of molecular actors involved in amelogenesis requires comparative studies between mice molars and incisors. PMID- 25285078 TI - The Cerebrovascular Basement Membrane: Role in the Clearance of beta-amyloid and Cerebral Amyloid Angiopathy. AB - Cerebral amyloid angiopathy (CAA), the accumulation of beta-amyloid (Abeta) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer's disease (AD) brains and is thought to be due to a failure of the aging brain to clear Abeta. Perivascular drainage of Abeta along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Abeta is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA. PMID- 25285080 TI - Effect of an anti-human Co-029/tspan8 mouse monoclonal antibody on tumor growth in a nude mouse model. AB - New therapeutic agents are needed in digestive tract tumors. Co-029/tspan8 is a tetraspanin frequently expressed on human colorectal tumors, In this work, we report the effects of the monoclonal antibody Ts29.2, targeting Co-029/tspan8, on colorectal tumor cells in vitro and after implantation in nude mice. HT29, Isreco1 and SW480 colorectal tumor cell lines were used for this study. HT29 has a strong endogenous expression of Co-029/tspan8, whereas Isreco1 cells don't express Co-029/tspan8 and SW480 has only a weak expression. Isreco1 and SW480 were transduced to express Co-029/tspan8 at the same level as HT29. In order to check the specificity of the effect of monoclonal antibody Ts29.2, low Co 029/tspan8 expressing SW480 cells were injected simultaneously with transduced cells in the back, on the left and right sides of the mice. With an early treatment, Ts29.2 mAb inhibited growth of tumors expressing Co-029/tspan8 up to 70%, whereas a delayed treatment was less efficient. No effect of the antibody on cell proliferation or apoptosis induction was detected in vitro. No increase of activated caspase 3 labeling was observed in vivo and areas occupied by vessels were not significantly different between treated mice and controls. This suggests that the action of Ts29.2 is linked neither to cellular toxicity nor to the inhibition of the previously reported angiogenic properties of Co-029/tspan8. An inhibition of cell proliferation in vivo is demonstrated by a reduction of the mitotic index in HT29 tumors of Ts29.2 treated mice. The discrepancy between in vitro and in vivo data on cell proliferation suggests that the binding of Ts29.2 to tumor cells may modify their response to signals issued from the microenvironment. Given the restricted pattern of tissue expression of the tetraspanin Co-029/tspan8, these preliminary results put forth for consideration the antibody targeting of this tetraspanin in further investigations for therapeutic applications. PMID- 25285081 TI - Reading performance is predicted by more than phonological processing. AB - WE COMPARED THREE PHONOLOGICAL PROCESSING COMPONENTS (PHONOLOGICAL AWARENESS, RAPID AUTOMATIZED NAMING AND PHONOLOGICAL MEMORY), VERBAL WORKING MEMORY, AND ATTENTION CONTROL IN TERMS OF HOW WELL THEY PREDICT THE VARIOUS ASPECTS OF READING: word recognition, pseudoword decoding, fluency and comprehension, in a mixed sample of 182 children ages 8-12 years. Participants displayed a wide range of reading ability and attention control. Multiple regression was used to determine how well the phonological processing components, verbal working memory, and attention control predict reading performance. All equations were highly significant. Phonological memory predicted word identification and decoding. In addition, phonological awareness and rapid automatized naming predicted every aspect of reading assessed, supporting the notion that phonological processing is a core contributor to reading ability. Nonetheless, phonological processing was not the only predictor of reading performance. Verbal working memory predicted fluency, decoding and comprehension, and attention control predicted fluency. Based upon our results, when using Baddeley's model of working memory it appears that the phonological loop contributes to basic reading ability, whereas the central executive contributes to fluency and comprehension, along with decoding. Attention control was of interest as some children with ADHD have poor reading ability even if it is not sufficiently impaired to warrant diagnosis. Our finding that attention control predicts reading fluency is consistent with prior research which showed sustained attention plays a role in fluency. Taken together, our results suggest that reading is a highly complex skill that entails more than phonological processing to perform well. PMID- 25285082 TI - An approximate measurement invariance approach to within-couple relationship quality. AB - This study aimed at demonstrating the usefulness and flexibility of the Bayesian structural equation modeling approximate measurement invariance (BSEM-AMI) approach to within-couple data. The substantive aim of the study was investigating partner differences in the perception of relationship quality (RQ) in a sample of intact couples (n = 435) drawn from the first sweep of the Millenium Cohort Study. Configural, weak and strong invariance models were tested using both maximum likelihood (ML) and BSEM approaches. As evidence of a lack of strong invariance was found, full and partial AMI models were specified, allowing nine different prior variances or "wiggle rooms." Although we could find an adequately fitting BSEM-AMI model allowing for approximate invariance of all the intercepts, the two-step approach proposed by Muthen and Asparouhov (2013b) for identifying problematic parameters and applying AMI only to them provided less biased results. Findings similar to the ML partial invariance model, led us to conclude that women reported a higher RQ than men. The results of this study highlight the need to inspect parameterization indeterminacy (or alignment) and support the efficacy of the two-step approach to BSEM-AMI. PMID- 25285083 TI - I like it when my partner holds my hand: development of the Responses and Attitudes to Support during Pain questionnaire (RASP). AB - Social support can have beneficial effects on psychological and physiological well-being. During acute bodily pain, however, the effects of social support on pain are mixed. This variability may be due to the multifaceted nature of both pain and social support, as well as individual differences. In this paper, we present the development, psychometric assessment, and initial validation of the first self-report measure designed to address this variability in the general population; the Responses and Attitudes to Support during Pain questionnaire (RASP). The RASP includes questions on social support from the romantic partner as well as healthcare professionals (HCPs) and addresses different types of social support and pain responses. The development and validation of the RASP comprised four studies. In Study 1, a preliminary RASP version was completed by 179 healthy individuals regarding any type of acute pain. In Study 2, the reduced RASP was completed by 256 women with experiences of menstrual pain. Principal component analysis indicated a 22-item solution with five underlying dimensions reflecting General Partner Support, Emotional Support from HCPs, Anxiety in the Context of HCPs, Pain Behaviors during Partner Support, and Distraction by the Partner. Construct validity was assessed using a measure of adult attachment style. The RASP showed good validity and test-retest reliability. In Study 3, the 5-factor model received initial support through confirmatory factor analysis in a new sample of 120 individuals with recent musculoskeletal pain. Study 4 provided additional validation of the RASP in a sample of 180 individuals responding in reference to acute back pain. Overall, the RASP is a valid and reliable measure for assessing individual differences in attitudes and responses to social support in relation to acute pain. PMID- 25285084 TI - Aesthetic perception and its minimal content: a naturalistic perspective. AB - Aesthetic perception is one of the most interesting topics for philosophers and scientists who investigate how it influences our interactions with objects and states of affairs. Over the last few years, several studies have attempted to determine "how aesthetics is represented in an object," and how a specific feature of an object could evoke the respective feelings during perception. Despite the vast number of approaches and models, we believe that these explanations do not resolve the problem concerning the conditions under which aesthetic perception occurs, and what constitutes the content of these perceptions. Adopting a naturalistic perspective, we here view aesthetic perception as a normative process that enables agents to enhance their interactions with physical and socio-cultural environments. Considering perception as an anticipatory and preparatory process of detection and evaluation of indications of potential interactions (what we call "interactive affordances"), we argue that the minimal content of aesthetic perception is an emotionally valued indication of interaction potentiality. Aesthetic perception allows an agent to normatively anticipate interaction potentialities, thus increasing sense making and reducing the uncertainty of interaction. This conception of aesthetic perception is compatible with contemporary evidence from neuroscience, experimental aesthetics, and interaction design. The proposed model overcomes several problems of transcendental, art-centered, and objective aesthetics as it offers an alternative to the idea of aesthetic objects that carry inherent values by explaining "the aesthetic" as emergent in perception within a context of uncertain interaction. PMID- 25285085 TI - Examining cultural drifts in artworks through history and development: cultural comparisons between Japanese and western landscape paintings and drawings. AB - Research on cultural products suggest that there are substantial cultural variations between East Asian and European landscape masterpieces and contemporary members' landscape artwork (Masuda et al., 2008c), and that these cultural differences in drawing styles emerge around the age of 8 (Senzaki et al., 2014b). However, culture is not static. To explore the dynamics of historical and ontogenetic influence on artistic expressions, we examined (1) 17 20th century Japanese and Western landscape masterpieces, and (2) cross-sectional adolescent data in landscape artworks alongside previous findings of elementary school-aged children, and undergraduates. The results showed cultural variations in artworks and masterpieces as well as substantial "cultural drifts" (Herskovits, 1948) where at certain time periods in history and in development, people's expressions deviated from culturally default patterns but occasionally returned to its previous state. The bidirectional influence of culture and implications for furthering the discipline of cultural psychology will be discussed. PMID- 25285086 TI - Numerical development-from cognitive functions to neural underpinnings. PMID- 25285087 TI - A unified signal of attentional control. PMID- 25285089 TI - Is the frontal lobe involved in conscious perception? PMID- 25285088 TI - Outlines of a multiple trace theory of temporal preparation. AB - We outline a new multiple trace theory of temporal preparation (MTP), which accounts for behavior in reaction time (RT) tasks in which the participant is presented with a warning stimulus (S1) followed by a target stimulus (S2) that requires a speeded response. The theory assumes that during the foreperiod (FP; the S1-S2 interval) inhibition is applied to prevent premature response, while a wave of activation occurs upon the presentation of S2. On each trial, these actions are stored in a separate memory trace, which, jointly with earlier formed memory traces, starts contributing to preparation on subsequent trials. We show that MTP accounts for classic effects in temporal preparation, including mean RT FP functions observed under a variety of FP distributions and asymmetric sequential effects. We discuss the advantages of MTP over other accounts of these effects (trace-conditioning and hazard-based explanations) and suggest a critical experiment to empirically distinguish among them. PMID- 25285090 TI - Sync or sink? Interpersonal synchrony impacts self-esteem. AB - Synchronized behavior has significant social influence both in terms of everyday activities (e.g., walking and talking) as well as via more historical contexts (e.g., cultural rituals). Grounded in the science of coordination dynamics, previous research has revealed that interpersonal synchrony has numerous affiliative and pro-social consequences, such as enhanced rapport, cooperation, and social-cognitive functioning. The current study sought to explore the impact of intentional synchrony versus asynchrony on an individual's self-esteem and their feelings of social connection with a partner. The results revealed that individuals felt better about themselves following a period of synchronous compared to asynchronous movement, while they also perceived a greater self-other overlap with their partner. These findings not only extend previous research on social connections following interpersonal synchrony, but also provide the first demonstration of an influence on self-evaluations. Overall, it appears that moving in time with others may result in us feeling better about ourselves compared to moving to our own rhythm. PMID- 25285091 TI - The perspectival shift: how experiments on unconscious processing don't justify the claims made for them. PMID- 25285092 TI - The other-race and other-species effects in face perception - a subordinate-level analysis. AB - The ability of face discrimination is modulated by the frequency of exposure to a category of faces. In other words, lower discrimination performance was measured for infrequently encountered faces as opposed to frequently encountered ones. This phenomenon has been described in the literature: the own-race advantage, a benefit in processing own-race as opposed to the other-race faces, and the own species advantage, a benefit in processing the conspecific type of faces as opposed to the heterospecific type. So far, the exact parameters that drive either of these two effects are not fully understood. In the following we present a full assessment of data in human participants describing the discrimination performances across two races (Asian and Caucasian) as well as a range of non human primate faces (chimpanzee, Rhesus macaque and marmoset). We measured reaction times of Asian participants performing a delayed matching-to-sample task, and correlated the results with similarity estimates of facial configuration and face parts. We found faster discrimination of own-race above other-race/species faces. Further, we found a strong reliance on configural information in upright own-species/-race faces and on individual face parts in all inverted face classes, supporting the assumption of specialized processing for the face class of most frequent exposure. PMID- 25285093 TI - Computer modeling of anterior circulation stroke: proof of concept in cerebrovascular occlusion. AB - BACKGROUND: Current literature emphasizes the role of the Circle of Willis (CoW) in salvaging ischemic brain tissue but not that of leptomeningeal anastomoses (LA). We developed a computational model of the cerebral circulation to (1) evaluate the roles of the CoW and LA in restoring flow to the superficial compartment of the middle cerebral artery (MCA) territory and (2) estimate the size of the LA required to maintain flow above the critical ischemic threshold (>30% of baseline) under simulated occlusion. METHODS: Cerebral vasculature was modeled as a network of junctions connected by cylindrical pipes. The experiments included occlusion of successive distal branches of the intracranial arteries while the diameters of LA were varied. RESULTS: The model showed that the region of reduced flow became progressively smaller as the site of occlusion was moved from the large proximal to the smaller distal arteries. There was no improvement in flow in the MCA territory when the diameters of the inter-territorial LA were varied from 0.0625 to 0.5 mm while keeping the intra-territorial LA constant. By contrast, the diameter of the inter-territorial LA needed to be >1.0 mm in order to provide adequate (>30%) flow to selected arteries in the occluded MCA territory. CONCLUSION: The CoW and inter-territorial LA together play important supportive roles in intracranial artery occlusion. Computational modeling provides the ability to experimentally investigate the effect of arterial occlusion on CoW and LA function. PMID- 25285094 TI - Isotopic insights into microbial sulfur cycling in oil reservoirs. AB - Microbial sulfate reduction in oil reservoirs (biosouring) is often associated with secondary oil production where seawater containing high sulfate concentrations (~28 mM) is injected into a reservoir to maintain pressure and displace oil. The sulfide generated from biosouring can cause corrosion of infrastructure, health exposure risks, and higher production costs. Isotope monitoring is a promising approach for understanding microbial sulfur cycling in reservoirs, enabling early detection of biosouring, and understanding the impact of souring. Microbial sulfate reduction is known to result in large shifts in the sulfur and oxygen isotope compositions of the residual sulfate, which can be distinguished from other processes that may be occurring in oil reservoirs, such as precipitation of sulfate and sulfide minerals. Key to the success of this method is using the appropriate isotopic fractionation factors for the conditions and processes being monitored. For a set of batch incubation experiments using a mixed microbial culture with crude oil as the electron donor, we measured a sulfur fractionation factor for sulfate reduction of -300/00. We have incorporated this result into a simplified 1D reservoir reactive transport model to highlight how isotopes can help discriminate between biotic and abiotic processes affecting sulfate and sulfide concentrations. Modeling results suggest that monitoring sulfate isotopes can provide an early indication of souring for reservoirs with reactive iron minerals that can remove the produced sulfide, especially when sulfate reduction occurs in the mixing zone between formation waters (FW) containing elevated concentrations of volatile fatty acids (VFAs) and injection water (IW) containing elevated sulfate. In addition, we examine the role of reservoir thermal, geochemical, hydrological, operational and microbiological conditions in determining microbial souring dynamics and hence the anticipated isotopic signatures. PMID- 25285095 TI - Effect of mono- and dichromatic light quality on growth rates and photosynthetic performance of Synechococcus sp. PCC 7002. AB - Synechococcus sp. PCC 7002 was grown to steady state in optically thin turbidostat cultures under conditions for which light quantity and quality was systematically varied by modulating the output of narrow-band LEDs. Cells were provided photons absorbed primarily by chlorophyll (680 nm) or phycocyanin (630 nm) as the organism was subjected to four distinct mono- and dichromatic regimes. During cultivation with dichromatic light, growth rates were generally proportional to the total incident irradiance at values <275 MUmol photons m(-2) . s(-1) and were not affected by the ratio of 630:680 nm wavelengths. Notably, under monochromatic light conditions, cultures exhibited similar growth rates only when they were irradiated with 630 nm light; cultures irradiated with only 680 nm light grew at rates that were 60-70% of those under other light quality regimes at equivalent irradiances. The functionality of photosystem II and associated processes such as maximum rate of photosynthetic electron transport, rate of cyclic electron flow, and rate of dark respiration generally increased as a function of growth rate. Nonetheless, some of the photophysiological parameters measured here displayed distinct patterns with respect to growth rate of cultures adapted to a single wavelength including phycobiliprotein content, which increased under severely light-limited growth conditions. Additionally, the ratio of photosystem II to photosystem I increased ~40% over the range of growth rates, although cells grown with 680 nm light only had the highest ratios. These results suggest the presence of effective mechanisms which allow acclimation of Synechococcus sp. PCC 7002 acclimation to different irradiance conditions. PMID- 25285099 TI - Deleterious Effects of Molting on the Morpho-physiology of Japanese Quail Layers (Coturnix japonica). AB - Molting is a natural physiological phenomenon involving the periodic replacement of old feathers with new ones in the avian species. During mid-November an extensive loss of feathers in Japanese quail was observed in our breeding colony. The cause of molting could not be established, however, lower ambient temperatures may have played a major role and the decrease in day length could not be ruled out as a contributing factor. This study was conducted to correlate some aspects of the molting process using various physiological and morphometric parameters. Forty healthy 125-days old layers, hatch-mates, of approximately similar body weights (130.0+/-3.9 g) and in peak production were used for cohort evaluation of the molting process. Most of the birds lost feathers extensively from the cervical, thorax and dorsum areas, while some did not molt and continued laying eggs as usual, serving as a premolting control group. The molting birds drastically lost body weight weighing on average 117.5 g compared to 130.0 g in the control group and ceased egg production completely. There was a significant increase in blood glucose (293.03 mg/dL vs. 222.11 mg/dL), an increase in PCV values (47.14% vs. 41.43%) and a decrease in total plasma proteins (3.5 g/dl vs. 5.56 g/dl) and oviducts (1.55 g vs. 5.78 g, a decrease of 73.2%). Ovarian follicles underwent atresia and resorption. Birds that recovered from the molt resumed egg production and regained their body weights showing similar morpho physiological measures of the control values, which changed during the molting phase. Scientists working with Japanese quail should be fully aware of the physiology of the molting process and its impact on on-going studies involving growth, physiology, endocrinology, nutrition, reproduction and toxicology. PMID- 25285097 TI - Generalized framework for context-specific metabolic model extraction methods. AB - Genome-scale metabolic models (GEMs) are increasingly applied to investigate the physiology not only of simple prokaryotes, but also eukaryotes, such as plants, characterized with compartmentalized cells of multiple types. While genome-scale models aim at including the entirety of known metabolic reactions, mounting evidence has indicated that only a subset of these reactions is active in a given context, including: developmental stage, cell type, or environment. As a result, several methods have been proposed to reconstruct context-specific models from existing genome-scale models by integrating various types of high-throughput data. Here we present a mathematical framework that puts all existing methods under one umbrella and provides the means to better understand their functioning, highlight similarities and differences, and to help users in selecting a most suitable method for an application. PMID- 25285100 TI - Association Between Body Weight Growth and Selected Physiological Parameters in Male Japanese Quail (Coturnrix japonica). AB - Japanese quail is very popular research animal model. Its continued characterization for various norms is highly desirable for obtaining accurate and reliable results. This study was designed to assess various physiological parameters which are associated with body growth and development. Among various physiological parameters, blood constituents and hormones are commonly used as diagnostic tools in both physiological and pathological evaluations of humans and animals. Japanese quail hatchlings were housed in the temperature controlled brooders up to 3 weeks of age and then shifted to hanging cages in air conditioned room at ~74 F under 14L:10D lighting system and free access to feed and fresh water. Starting d8, a group of birds of uniform size and weight were selected randomly and euthanized at 4-day intervals up to d52 of age. The birds were weighed and blood sampled from the brachial vein for measuring Blood Glucose (BGL), Total Plasma Proteins (PP) and Packed Cell Volume (PCV). It was found that starting d36 all the three physiological parameters altered with approaching sexual maturity (d48-52): BGL decreased (252 vrs. 182 mg/dl, p<0.05), PCV% increased (43.6 vrs. 49.6%, p<0.05) and PP also increased (2.7 vrs. 3.2 gm/dl, p>0.05). Accordingly, BGL, PCV and PP values demonstrated significant potential to predict approaching sexual maturity in male Japanese quail. PMID- 25285096 TI - Granule protein processing and regulated secretion in neutrophils. AB - Neutrophils are part of a family of granulocytes that, together with eosinophils and basophils, play an essential role in innate immunity. Neutrophils are the most abundant circulating leukocytes and are vital for rapid immune responses, being recruited to sites of injury or infection within minutes, where they can act as specialized phagocytic cells. However, another prominent function of neutrophils is the release of pro-inflammatory compounds, including cytokines, chemokines, and digestive enzymes, which are stored in intracellular compartments and released through regulated exocytosis. Hence, an important feature that contributes to rapid immune responses is capacity of neutrophils to synthesize and store pre-formed pro-inflammatory mediators in specialized intracellular vesicles and thus no new synthesis is required. This review will focus on advancement in three topics relevant to neutrophil secretion. First, we will examine what is known about basal level pro-inflammatory mediator synthesis, trafficking, and storage in secretory compartments. Second, we will review recent advancements in the mechanisms that control vesicle mobilization and the release of pre-formed mediators. Third, we will examine the upregulation and de novo synthesis of pro-inflammatory mediators by neutrophils engaged at sites of infection. PMID- 25285101 TI - Quantitative and Morphological Measures May Predict Growth and Mortality During Prenatal Growth in Japanese Quails. AB - Growth pattern and mortality rate during the embryonic phase of avian species are difficult to recognize and predict. Determination of such measures and associated events may enhance our understanding of characteristics involved in the growth and hatching process. Furthermore, some quantitative measures could validate morphological determinants during the embryonic phase and predict the course of normal growth and alterations. Our aim was to characterize quantitative growth of embryos and to establish baseline embryonic standards for use in comparative and pathological research during the prenatal life of Japanese quail. Day 10 was a landmark timeline for initiation of extensive anatomical changes in growth and transformation. Wet and dry weights were positively correlated with each other and inversely correlated with water content (p = 0.05). Following d10, the water content decreased progressively, whereas, dry and wet weights increased with increasing age. Velocity of growth in wet and dry weights was evident starting d6, spiked at d11 and d15 and then declined before hatching on d16. Organic and inorganic contents of embryos were positively associated with age. Progressive increase in the organic to inorganic ratio with age was evident after d5, spiked on d9, d13 and d16. Accurate determinations of prenatal growth processes could serve as valuable tools in identifying morphological developments and characterization of prenatal growth and mortality, thus enhancing the reproductive efficiency of the breeding colony and the postnatal robustness of the offspring. PMID- 25285102 TI - Community-university Research Liaisons: Translating the Languages of Research and Culture. AB - This article describes the experiences of six individuals employed as community university research liaisons in a grant-funded centre for health disparities research. The liaisons were located in Native American communities and bridged the communities and the university, providing information between these groups, expanding understanding and knowledge of how research can address health disparities, and assisting in the development and ongoing work of partnerships using CBPR approaches. While tribal communities within the state may face similar health disparities, the approach to solving these disparities must be based on an understanding of the context and environment of the specific tribal community. In this paper, the tribal liaisons share their stories of negotiating and navigating their unique positions. Suggestions for utilizing tribal community-university positions to support community and partnership development are offered. PMID- 25285104 TI - 2014 dr lindsay e nicolle award. PMID- 25285103 TI - A Unique Partnership for Health Promotion in Native Communities Salish Kootenai College and University of Arizona. PMID- 25285105 TI - Ebola virus disease. PMID- 25285106 TI - What is new from the Canadian Paediatric Society Committee on Infectious Diseases and Immunization? PMID- 25285107 TI - Renal failure, hepatitis and myocarditis in a previously healthy man. PMID- 25285108 TI - Canadian consensus statement on HIV and its transmission in the context of criminal law. AB - INTRODUCTION: A poor appreciation of the science related to HIV contributes to an overly broad use of the criminal law against individuals living with HIV in cases of HIV nondisclosure. METHOD: To promote an evidence-informed application of the law in Canada, a team of six Canadian medical experts on HIV and transmission led the development of a consensus statement on HIV sexual transmission, HIV transmission associated with biting and spitting, and the natural history of HIV infection. The statement is based on a literature review of the most recent and relevant scientific evidence (current as of December 2013) regarding HIV and its transmission. It has been endorsed by >70 additional Canadian HIV experts and the Association of Medical Microbiology and Infectious Disease Canada. RESULTS: Scientific and medical evidence clearly indicate that HIV is difficult to transmit during sex. For the purpose of informing the justice system, the per-act possibility of HIV transmission through sex, biting or spitting is described along a continuum from low possibility, to negligible possibility, to no possibility of transmission. This possibility takes into account the impact of factors such as the type of sexual acts, condom use, antiretroviral therapy and viral load. Dramatic advances in HIV therapy have transformed HIV infection into a chronic manageable condition. DISCUSSION: HIV physicians and scientists have a professional and ethical responsibility to assist those in the criminal justice system to understand and interpret the science regarding HIV. This is critical to prevent miscarriage of justice and to remove unnecessary barriers to evidence based HIV prevention strategies. PMID- 25285109 TI - Vaccine knowledge in students in Paris, France, and surrounding regions. AB - INTRODUCTION: In France, young adults are legally freed from parental authority at the age of 18 years and are, thus, responsible for their own vaccine record. This young adult population is more frequently exposed to vaccine-preventable infectious diseases. OBJECTIVE: To determine the factors associated with students' knowledge of the interval between two antitetanus boosters and their report of having up-to-date vaccinations. METHODS: In April 2009, a survey was conducted involving a random sample of students between 18 and 25 years of age eating lunch at university dining facilities in Paris and its suburbs (Ile de France). RESULTS: Among the 677 students approached, 583 agreed to participate. Only 207 (36%) of respondents knew the recommended dosing interval between two doses of tetanus vaccine booster (10 years). The majority of students (69%) reported having up-to-date vaccinations. Declaring having up-to-date vaccinations was significantly associated with having a general practitioner (OR 3.03 [95% CI 1.69 to 5.55]). Health care students were significantly more likely to know the decennial interval between two antitetanus boosters (OR 2 [95% CI 1.28 to 3.25]). Most of responding students (n=519 [89%]) believed that vaccines were very useful. CONCLUSIONS: An overall lack of knowledge of vaccines was observed among this student population. Health care providers, such as GPs and university medical practice staff, who interact with these young individuals have an essential role to promote better vaccination coverage in this population. PMID- 25285110 TI - How many individuals with asthma need to be vaccinated to prevent one case of invasive pneumococcal disease? AB - BACKGROUND: The American Advisory Committee on Immunization Practices recommended the inclusion of adults with asthma in the high-risk category for pneumococcal vaccination based on a twofold increase in risk of invasive pneumococcal disease (IPD). OBJECTIVE: To determine whether, among individuals with asthma, the number needed to vaccinate (NNV) using pneumococcal conjugate vaccine (PCV)-13 or 23 valent pneumococcal polysaccharide vaccine (PPV-23) warrants its addition to the high-risk category for pneumococcal vaccination in Canada. METHODS: Using IPD incidence (per 10,000 individuals) figures from published articles (4.2 in high risk asthmatics, 2.3 in low-risk asthmatics and 1.2 in healthy individuals), the NNV to prevent one case of IPD in asthmatics five to 17 years of age and 18 to 50 years of age was calculated, factoring in the proportion of pneumococcal serotypes included in vaccines (based on data from Quebec) and accounting for the possibility of waning vaccine efficacy (VE) using four scenarios. RESULTS: Assuming a VE of 65% for PCV-13 in asthmatics, the NNV would be 704 to 820 in low risk and 386 to 449 in high-risk children; and 355 to 1532 in low-risk and 195 to 839 in high-risk adults (range depends on waning scenario). Assuming a VE of 65% for PPV-23 in asthmatics, the NNV would be 581 to 677 in low-risk and 318 to 371 in high-risk children; and 246 to 1059 in low-risk and 135 to 580 in high-risk adults. CONCLUSION: The NNV with both PCV-13 and PPV-23 in asthmatic children and adults is comparable with that of other high-risk conditions such as age >=65 years. Therefore, the addition of asthma to the list of high-risk conditions for pneumococcal vaccination is warranted. PMID- 25285111 TI - Real-time polymerase chain reaction for microbiological diagnosis of parapneumonic effusions in Canadian children. AB - BACKGROUND: Community-acquired pneumonia (CAP) complicated by parapneumonic effusion/empyema is an infectious syndrome commonly encountered by physicians caring for children in Canada. OBJECTIVE: To investigate the incremental benefit of novel molecular testing for the microbiological diagnosis of pediatric CAP complicated by parapneumonic effusion/empyema in Canada. METHODS: A convenience sample of pleural fluid from 56 children who had been admitted to hospital in Ontario with CAP complicated by parapneumonic effusion between 2009 and 2011 was examined. Multiple uniplex real-time polymerase chain reaction (PCR) testing was performed on these pleural fluids and compared with traditional culture-based testing of blood and pleural fluid samples. RESULTS: Molecular methods detected a pathogen in 82% of cases, whereas traditional cultures of blood and pleural fluids detected a pathogen in only 25%. The majority of parapneumonic effusions were associated with pneumococcal infection; Streptococcus pneumoniae was detected in 62% of the samples using molecular methods but in only 14% of samples using culture-based methods. Streptococcus pyogenes, detected in 16% of samples using PCR, was the second most common pathogen found. No patients were found to have empyema caused by Staphylococcus aureus. DISCUSSION: The results showed that multiple uniplex real-time PCR performed substantially better than traditional culture methods for microbiological diagnosis of CAP complicated by effusion/ empyema. S pneumoniae and S pyogenes were found to be responsible for the majority of infections. The approach detected pathogens in a similar proportion of pleural fluid samples as previously reported nested PCR assays; furthermore, the real-time closed-well approach also minimized the risk of nonspecificity due to cross-contamination relative to nested PCR. CONCLUSIONS: Real-time PCR for the detection of bacterial DNA in pleural fluids has the potential to better define the microbiological cause of pediatric CAP. This approach could help clinicians provide targeted antimicrobial therapy. PMID- 25285112 TI - Susceptibility of clinical Moraxella catarrhalis isolates in British Columbia to six empirically prescribed antibiotic agents. AB - BACKGROUND: Moraxella catarrhalis is a commensal organism of the respiratory tract that has emerged as an important pathogen for a variety of upper and lower respiratory tract infections including otitis media and acute exacerbations of chronic bronchitis. Susceptibility testing of M catarrhalis is not routinely performed in most diagnostic laboratories; rather, a comment predicting susceptibility based on the literature is attached to the report. The most recent Canadian report on M catarrhalis antimicrobial susceptibility was published in 2003; therefore, a new study at this time was of interest and importance. OBJECTIVE: To determine the susceptibility of M catarrhalis isolates from British Columbia to amoxicillin-clavulanate, doxycycline, clarithromycin, cefuroxime, levofloxacin and trimethoprimsulfamethoxazole. METHODS: A total of 117 clinical M catarrhalis isolates were isolated and tested from five Interior hospitals and two private laboratory centres in British Columbia between January and December 2012. Antibiotic susceptibility of M catarrhalis isolates was characterized using the Etest (E-strip; bioMerieux, USA) according to Clinical Laboratory Standards Institute guidelines. RESULTS: All isolates were sensitive to amoxicillin clavulanate, doxycycline, clarithromycin, levofloxacin and trimethoprimsulfamethoxazole. One isolate was intermediately resistant to cefuroxime, representing a 99.15% sensitivity rate to the cephem agent. Cefuroxime minimum inhibitory concentrations (MICs) inhibiting 50% and 90% of organisms (MIC50 and MIC90) were highest among the antibiotics tested, and the MIC90 (3 MUg/mL) of cefuroxime reached the Clinical Laboratory Standards Institute breakpoint of susceptibility. DISCUSSION: The antibiotic susceptibility of M catarrhalis isolates evaluated in the present study largely confirms the findings of previous surveillance studies performed in Canada. Cefuroxime MICs are in the high end of the sensitive range and the MIC50 and MIC90 observed in the present study are the highest ever reported in Canada. CONCLUSION: Although cefuroxime MICs in M catarrhalis are high, all agents tested showed antimicrobial activity, supporting their continued therapeutic and empirical use. PMID- 25285113 TI - HIV and liver transplantation: The British Columbia experience, 2004 to 2013. AB - BACKGROUND: The demand for definitive management of end-stage organ disease in HIV-infected Canadians is growing. Until recently, despite international evidence of good clinical outcomes, HIV-infected Canadians with end-stage liver disease were ineligible for transplantation, except in British Columbia (BC), where the liver transplant program of BC Transplant has accepted these patients for referral, assessment, listing and provision of liver allograft. There is a need to evaluate the experience in BC to determine the issues surrounding liver transplantation in HIV-infected patients. METHODS: The present study was a chart review of 28 HIV-infected patients who were referred to BC Transplant for liver transplantation between 2004 and 2013. Data regarding HIV and liver disease status, initial transplant assessment and clinical outcomes were collected. RESULTS: Most patients were BC residents and were assessed by the multidisciplinary team at the BC clinic. The majority had undetectable HIV viral loads, were receiving antiretroviral treatments and were infected with hepatitis C virus (n=16). The most common comorbidities were anxiety and mood disorders (n=4), and hemophilia (n=4). Of the patients eligible for transplantation, four were transplanted for autoimmune hepatitis (5.67 years post-transplant), nonalcoholic steatohepatitis (2.33 years), hepatitis C virus (2.25 years) and hepatitis B-delta virus coinfection (recent transplant). One patient died from acute renal failure while waiting for transplantation. Ten patients died during preassessment and 10 were unsuitable transplant candidates. The most common reason for unsuitability was stable disease not requiring transplantation (n=4). CONCLUSIONS: To date, interdisciplinary care and careful selection of patients have resulted in successful outcomes including the longest living HIV-infected post-liver transplant recipient in Canada. PMID- 25285114 TI - Prevalence of plasmid-mediated quinolone resistance genes among ciprofloxacin nonsusceptible Escherichia coli and Klebsiella pneumoniae isolated from blood cultures in Korea. AB - OBJECTIVES: To analyze the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants in ciprofloxacin-nonsusceptible Escherichia coli and Klebsiella pneumoniae isolated from patients at a tertiary care hospital in Korea. METHODS: A total of 102 nonduplicate isolates of ciprofloxacin intermediate or ciprofloxacin-resistant E coli (n=80) and K pneumoniae (n=22) from blood cultures were obtained. The qnr (qnrA, qnrB, qnrS), aac(6')-Ib-cr, qepA and oqxAB genes were detected using polymerase chain reaction (PCR) and confirmed using direct sequencing. To determine whether the PMQR-positive plasmid was horizontally transferable, conjugation experiments were performed. RESULTS: Of the 102 isolates, 81 (79.4%) had one or more PMQR genes; these consisted of 59 (73.8%) E coli and 22 (100%) K pneumoniae isolates. The qnr genes were present in 15 isolates (14.7%): qnrB4 was detected in 10.8% and qnrS1 was detected in 3.9%. The aac(6')-Ib-cr, qepA and oqxAB genes were detected in 77.5%, 3.9% and 10.8%, respectively. In conjugation experiments, PMQR genes were successfully transferred from seven (8.6%) isolates. The range of minimum inhibitory concentrations of ciprofloxacin for these seven transconjugants increased to 0.5 mg/L to 1 mg/L, which was 16- to 33-fold that of the recipient E coli J53 bacteria. CONCLUSIONS: PMQR genes were highly prevalent among ciprofloxacin nonsusceptible E coli and K pneumoniae from blood cultures in the authors' hospital. Therefore, it is necessary to monitor for the spread of PMQR genes of clinical isolates and to ensure careful antibiotic use in a hospital setting. PMID- 25285115 TI - Human herpesvirus 6 is associated with status epilepticus and hyponatremia after umbilical cord blood transplantation. AB - Status epilepticus after allogeneic hematopoietic cell transplantation (alloHCT) is rare. The authors report a case involving a 65-year-old man with nonconvulsive status epilepticus 34 days after umbilical cord blood transplantion for chronic lymphocytic leukemia. Cerebrospinal fluid and serum were positive for human herpesvirus 6 (HHV6). Magnetic resonance imaging of the brain showed symmetric T2 hyper-intensity bilaterally in the mesial temporal lobes, and T2 hyperintensi ties and restricted diffusion of bilateral putamina. Despite aggressive anticonvulsive therapy, his seizures only abated with initiation of ganciclovir therapy. The patient completed six weeks of combination antiviral therapy (ganciclovir and foscarnet). His cognitive function gradually improved and, after prolonged rehabilitation, the patient was discharged home with residual intermittent memory loss but otherwise functional. HHV6 should be considered in the differential diagnosis of nonconvulsive status epilepticus after alloHCT, especially in patients with hyponatremia. Empirical antiviral therapy targeting HHV6 should be administered to these patients. PMID- 25285116 TI - A confusing case - Weissella confusa prosthetic joint infection: A case report and review of the literature. AB - The authors describe the first case of Weissella confusa infection of a prosthetic joint. Identification of the pathogen required 16S ribosomal RNA sequencing of isolates obtained on two separate occasions during the assessment of an elderly woman with a painful, swollen knee following total knee arthroplasty. A review of reported human infections due to W confusa are summarized, and risk factors and pitfalls in the application of empirical antimicrobial therapy pending definitive microbiological identification are discussed. PMID- 25285118 TI - The cellulitis season is open. PMID- 25285117 TI - Community-associated methicillin-resistant Staphylococcus aureus necrotizing pneumonia without evidence of antecedent viral upper respiratory infection. AB - BACKGROUND: USA300 community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains causing necrotizing pneumonia have been reported in association with antecedent viral upper respiratory tract infections (URI). METHODS: A case series of necrotizing pneumonia presenting as a primary or coprimary infection, secondary to CA-MRSA without evidence of antecedent viral URI, is presented. Cases were identified through the infectious diseases consultation service records. Clinical and radiographic data were collected by chart review and electronic records. MRSA strains were isolated from sputum, bronchoalveolar lavage, pleural fluid or blood cultures and confirmed using standard laboratory procedures. MRSA strains were characterized by susceptibility testing, pulsed-field gel electrophoresis, spa typing, agr typing and multilocus sequence typing. Testing for respiratory viruses was performed by appropriate serological testing of banked sera, or nucleic acid testing of nasopharyngeal or bronchoalveloar lavage specimens. RESULTS: Ten patients who presented or copresented with CA necrotizing pneumonia secondary to CA-MRSA from April 2004 to October 2011 were identified. The median length of stay was 22.5 days. Mortality was 20.0%. Classical risk factors for CA-MRSA were identified in seven of 10 (70.0%) cases. Chest tube placement occurred in seven of 10 patients with empyema. None of the patients had historical evidence of antecedent URI. In eight of 10 patients, serological or nucleic acid testing testing revealed no evidence of acute viral coinfection. Eight strains were CMRSA-10 (USA300). The remaining two strains were a USA300 genetically related strain and a USA1100 strain. CONCLUSION: Pneumonia secondary to CA-MRSA can occur in the absence of an antecedent URI. Infections due to CA-MRSA are associated with significant morbidity and mortality. Clinicians need to have an awareness of this clinical entity, particularly in patients who are in risk groups that predispose to exposure to this bacterium. PMID- 25285119 TI - The particulars on parechovirus. PMID- 25285120 TI - A 55-year-old male immigrant with lymphoma and Gram-negative sepsis. PMID- 25285121 TI - A 48-year-old male immigrant with a painful foot mass. PMID- 25285122 TI - Fever in the returning traveller: A forgotten culprit. PMID- 25285123 TI - From the mouth of babes: Getting vaccinated doesn't have to hurt. AB - BACKGROUND: Analgesic interventions are not commonly administered during childhood vaccination, despite the fact that two-thirds of children are afraid of needles and one-tenth are noncompliant with immunization. OBJECTIVE: To explore children's experiences of vaccination and preferences for analgesia. METHODS: A total of 17 children (four to 14 years of age) at an independent school in Toronto (Ontario) participated in three focus-group interviews. The majority had previous experience with pain management interventions during vaccination. Thematic content analysis was used to analyze interview transcripts. RESULTS: THE FINDINGS WERE CATEGORIZED INTO THREE MAIN THEMES: experience of vaccination; roles and responsibilities regarding pain management; and impact of pain management. Children easily recalled previous vaccinations and discussed fear and distress experienced by themselves and others. Children believed that parents and immunizers should prepare them ahead of time and use interventions to manage and monitor pain. They also wanted adults to support their efforts to lead pain management. Children discussed benefits of managing pain, including reduced unnecessary suffering, improved vaccination experience, reduced risk of developing needle fears and reduced noncompliant behaviours. They were knowledgeable about strategies for reducing pain including distraction, topical anesthetics and injection techniques. They contrasted vaccination with and without pain management, and indicated a preference for pain management. CONCLUSION: Children reported that managing vaccination pain is important and that analgesic interventions should routinely be used. Incorporating pain management in the process of vaccination has the potential to improve children's experiences with vaccination and promote more positive attitudes and behaviours. PMID- 25285124 TI - Acceptability, predictors and attitudes of Canadian women in labour toward point of-care HIV testing at a single labour and delivery unit. AB - OBJECTIVE: To assess attitudes and opinions surrounding point-of-care HIV testing among Canadian women, and to determine predictors for acceptance of testing. METHODS: A survey assessing acceptability and attitudes toward rapid HIV testing was distributed on the labour and delivery unit in an academic hospital (St Michael's Hospital) in Toronto, Ontario, in 2011. Information collected included demographic data, health and pregnancy history, willingness to undergo rapid HIV testing while in labour and barriers to testing. RESULTS: Responses in 92 completed questionnaires were analyzed. The mean age of respondents was 32 years and all were HIV negative. Twelve percent of patients reported having at least one risk factor for HIV transmission. The study showed that only 59% of women were willing to be tested at the time of survey completion, and these women stated that they would accept saliva, urine or serum testing. If found to be positive, 96% would accept antiretroviral treatment and 94% would formula feed their infants. Of the 41% who were not willing to be tested, their reasons for refusal included "don't want to know" (39%) and being in "too much labour pain" (29%). Regardless of willingness to be tested, the most frequently cited barriers to testing were social stigma (64%) and reaction from partners (69%). CONCLUSIONS: Canadian women in labour were willing to undergo rapid HIV testing via urine, saliva or serum. If found to be positive, women were willing to undergo treatment and to formula feed to prevent mother-to-child transmission of HIV. PMID- 25285125 TI - Determination of real-time polymerase chain reaction uncertainty of measurement using replicate analysis and a graphical user interface with Fieller's theorem. AB - BACKGROUND: Disease monitoring of viruses using real-time polymerase chain reaction (PCR) requires knowledge of the precision of the test to determine what constitutes a significant change. Calculation of quantitative PCR confidence limits requires bivariate statistical methods. OBJECTIVE: To develop a simple-to use graphical user interface to determine the uncertainty of measurement (UOM) of BK virus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) real-time PCR assays. METHODS: Thirty positive clinical samples for each of the three viral assays were repeated once. A graphical user interface was developed using a spreadsheet (Excel, Microsoft Corporation, USA) to enable data entry and calculation of the UOM (according to Fieller's theorem) and PCR efficiency. RESULTS: The confidence limits for the BK virus, CMV and EBV tests were ~0.5 log, 0.5 log to 1.0 log, and 0.5 log to 1.0 log, respectively. The efficiencies of these assays, in the same order were 105%, 119% and 90%. The confidence limits remained stable over the linear range of all three tests. DISCUSSION: A >5 fold (0.7 log) and a >3-fold (0.5 log) change in viral load were significant for CMV and EBV when the results were <=1000 copies/mL and >1000 copies/mL, respectively. A >3-fold (0.5 log) change in viral load was significant for BK virus over its entire linear range. PCR efficiency was ideal for BK virus and EBV but not CMV. Standardized international reference materials and shared reporting of UOM among laboratories are required for the development of treatment guidelines for BK virus, CMV and EBV in the context of changes in viral load. PMID- 25285126 TI - Safety and immunogenicity of two doses of quadrivalent meningococcal conjugate vaccine or one dose of meningococcal group C conjugate vaccine, both administered concomitantly with routine immunization to 12- to 18-month-old children. AB - OBJECTIVES: To describe the immunogenicity and safety of a two-dose series of a quadrivalent meningococcal (serogroups A, C, Y and W) polysaccharide diphtheria toxoid conjugate vaccine (MenACYW-D) administered to toddlers. METHODS: Children were randomly assigned (1:1) at study entry to receive MenACYW-D at 12 and 18 months of age (group 1; n=61) or meningococcal serogroup C conjugate vaccine (MCC) at 12 months of age (group 2; n=62). All received routine childhood immunizations. A, C, Y and W antibody titres were measured in group 1 before and one month after the 18-month MenACYW-D vaccination and were measured in group 2 at one and seven months post-MCC vaccination. Antibodies elicited by diphtheria and tetanus toxoids, and acellular pertussis vaccine adsorbed combined with inactivated poliomyelitis vaccine and Haemophilus influenzae b conjugate (DTaP IPV-Hib) vaccine coadministered at the 18-month vaccination were measured one month later. Safety data were collected. RESULTS: At 19 months of age, >=96% in group 1 achieved protective titres for the four meningococcal serogroups after dose 2; 67% in group 2 exhibited protective titres against serogroup C 28 days after MCC vaccination at 12 months of age, declining to 27% seven months later. DTaP-IPV-Hib elicited high antibody concentrations/titres in groups 1 and 2, consistent with historical values. The safety profiles after each dose generated no unexpected safety signals; no serious adverse events were related to vaccination. DISCUSSION: A two-dose series of MenACYW-D given concomitantly with a DTaP-IPV-Hib booster dose at 18 months of age demonstrated a good immunogenicity and safety profile. A two-dose series of MenACYW-D can be used as an alternative to one dose of MCC and provides protection against additional serogroups (NCT ID: NCT01359449). PMID- 25285127 TI - Evaluation of amplification targets for the specific detection of Bordetella pertussis using real-time polymerase chain reaction. AB - BACKGROUND: Bordetella pertussis infections continue to be a major public health challenge in Canada. Polymerase chain reaction (PCR) assays to detect B pertussis are typically based on the multicopy insertion sequence IS481, which offers high sensitivity but lacks species specificity. METHODS: A novel B pertussis real-time PCR assay based on the porin gene was tested in parallel with several previously published assays that target genes such as IS481, ptx-promoter, pertactin and a putative thialase. The assays were evaluated using a reference panel of common respiratory bacteria including different Bordetella species and 107 clinical nasopharyngeal specimens. Discrepant results were confirmed by sequencing the PCR products. RESULTS: Analytical sensitivity was highest for the assay targeting the IS481 element; however, the assay lacked specificity for B pertussis in the reference panel and in the clinical samples. False-positive results were also observed with assays targeting the ptx-promoter and pertactin genes. A PCR assay based on the thialase gene was highly specific but failed to detect all reference strains of B pertussis. However, a novel assay targeting the porin gene demonstrated high specificity for B pertussis both in the reference panel and in clinical samples and, based on sequence-confirmed results, correctly predicted all B pertussis-positive cases in clinical samples. According to Probit regression analysis, the 95% detection limit of the new assay was 4 colony forming units/reaction. CONCLUSION: A novel porin assay for B pertussis demonstrated superior performance and may be useful for improved molecular detection of B pertussis in clinical specimens. PMID- 25285128 TI - Personalized genetic testing and norovirus susceptibility. AB - BACKGROUND: The availability of direct-to-consumer personalized genetic testing has enabled the public to access and interpret their own genetic information. Various genetic traits can be determined including resistance to norovirus through a nonsense mutation (G428A) in the FUT2 gene. Although this trait is believed to confer resistance to the most dominant norovirus genotype (GII.4), the spectrum of resistance to other norovirus strains is unknown. The present report describes a cluster of symptomatic norovirus GI.6 infection in a family identified to have norovirus resistance through personalized genetic testing. CASE PRESENTATION: In January 2013, four members of a family determined by a direct-to-consumer genetic test to be homozygous for the norovirus resistance trait (A/A genotype for single nucleotide polymorphism rs601338) developed symptoms consistent with acute viral gastroenteritis. Stool and vomitus samples were submitted for enteric viral pathogen testing. Samples were positive for norovirus GI.6 in three of the four cases. CONCLUSIONS: The present report is the first to describe norovirus GI.6 infection in patients with the G428A nonsense mutation in FUT2; this cluster of cases suggests that the G428A mutation in FUT2 may not confer resistance to norovirus GI.6. Direct-to-consumer genetic testing is empowering members of the public to identify novel associations with their genetic traits. Expert consultation is important for the interpretation of personalized genetic test results, and follow-up laboratory testing can confirm any potentially novel associations. PMID- 25285129 TI - Melioidosis in a returned traveller. AB - Melioidosis is an infection endemic to Southeast Asia and Northern Australia, and is associated with significant morbidity and mortality. The present report describes a case of chronic melioidosis in a returning traveller from the Philippines. Clinical suspicion of this illness is warranted in individuals with a history of travel to endemic regions. Safety in handling clinical specimens is paramount because laboratory transmission has been described. PMID- 25285130 TI - An unusual case of vaccine-associated paralytic poliomyelitis. AB - The present article reports a case involving an immunocompetent, previously well child who, despite two previous doses of inactivated poliovirus vaccine, developed severe flaccid paralysis consistent with polio after receiving oral polio vaccine. PMID- 25285131 TI - Osteomyelitis due to multiple carbapenemase-producing Gram-negative bacteria: The first case report of a GES-13-producing Pseudomonas aeruginosa isolate in Canada. AB - A case of osteomyelitis in an infant following a burn injury sustained in Pakistan caused by a GES-13-producing Pseudomonas aeruginosa (the first reported in Canada) and an OXA-48 producing Klebsiella pneumoniae is described. The present case serves to highlight the importance of international travel as a risk factor for infection with carbapenemase-producing bacteria and the challenges in the laboratory detection of these organisms. PMID- 25285132 TI - Letter to the editor. PMID- 25285133 TI - Raoultella planticola bacteremia following consumption of seafood. AB - Raoultella planticola is a Gram-negative bacillus commonly found in water, soil and aquatic environments. There have only been 16 cases of R planticola infection documented in the literature to date. R planticola possesses the ability to convert histidine to histamine and can produce symptoms of scombroid poisoning when poorly prepared seafood is consumed in large amounts. The present report describes a case involving a 56-year-old woman who presented with R planticola bacteremia and symptoms consistent with cholangitis four days after consuming a seafood salad containing squid and octopus. She was successfully treated with intravenous ceftriaxone followed by oral ciprofloxacin. Recent chemotherapy, proton pump inhibitor use and altered biliary flow secondary to hepatic metastases may have been contributing factors to the pathogenesis of disease. PMID- 25285134 TI - From the Editor-in-Chief. PMID- 25285135 TI - Bone disorders in children and adolescents with chronic HCV infection. AB - BACKGROUND AND AIMS: Although several studies have demonstrated a higher incidence of bone disorders in HCV-infected adults, the bone turnover alterations occurring in children and adolescents with chronic hepatitis C has not been thoroughly focused yet. We performed a study on a cohort of 30 HCV infected caucasian children and adolescents to assess the prevalence of osteodystrophy and evaluate a possible prophylactic and therapeutic approach. METHODS: Data regarding biochemical markers of bone metabolism were collected. Moreover, results of ultra-sonographic bone densitometry yearly performed were evaluated in comparison with data obtained from more than 500 healthy children and adolescents. RESULTS: Osteocalcin and telopeptide of the collagen molecule type 1, CTX, appeared higher than normal in 8/30 and in 7/30 cases respectively; the 25OH vitamin D values were normal in 25/28 cases. By densitometry osteoporosis was detected in 2 patients and osteopenia in other 5. After stratification of cases by age groups, the incidence of osteopenia/osteoporosis appeared higher among children than among adolescents. Osteocalcin levels tended to be higher in cases where hepatic fibrosis were not detected. CONCLUSIONS: The higher number of cases of osteopenia/osteoporosis in children than in adolescents is worthy of note, although not statistically significant. Ultrasound densitometry confirmed its important early diagnostic role in asymptomatic HCV infected children; moreover, also the increase in serum levels of osteocalcin may be considered as early marker of osteodystrophy of complementary value. Larger studies will be needed to confirm the efficacy and safety of antiviral and supportive care in these patients. PMID- 25285136 TI - Orthopaedic surgeons' strategies in pharmacological treatment of fragility fractures. AB - Fragility fractures are the most severe complications of osteoporosis and the poor mechanical properties of bone can make fixation and healing of these fracture extremely difficult. The role of orthopaedic surgeons does not end in skillful fixation of the fractures, but they have the unique opportunity to prevent complications which can negatively affect the patient's quality of life. The best practice for preventing the risk of further fractures in patients presenting fragility fractures includes fall prevention, investigation of possible causes underlying osteoporosis, attention to exercise, calcium and vitamin D supplementation as well as prescription of drugs. Actually two classes of agents can be used for their effect on fracture prevention: antiresorptive and bone forming agents. Systemic therapy reduces the risk of vertebral (30-70%) and non-vertebral fractures (12-53%), depending on agents and patients' compliance. Preclinical and clinical studies have shown that pharmacological agents involved in osteoporosis can also influence the phases of fracture repair. Preclinical studies and evidences from case reports showed a positive effect of anabolic drugs on bone healing and implant osseointegration. The interventions in the process of fracture healing had evolved from a diamond to a pentagon concept, with interactions between the mechanical environment, the local therapies, the vascularity of the fracture site, the biology of the host and the systemic therapy which has the potential to represent the fifth interaction factor. The orthopaedic surgeon plays a central role in clinical setting to evaluate the efficacy of systemic anti-fracture drugs for improving fracture repair and preventing complications. PMID- 25285137 TI - Management options of breast cancer related osteoporosis. AB - Breast cancer therapy after surgery has been improved in recent years. Adjuvant therapies like aromatase inhibitors are being extensively used among breast cancer survivors. This leaded to cancer related and iatrogenic osteoporosis. Management of these patients needs to be focused and differentiated from the standard age related osteoporosis in women. All guidelines consider mandatory to assess fracture risk periodically in all breast cancer survivors. Risk assessment diagnostic FRAX tool is the most used but it's not born specifically for cancer related osteoporosis. The therapeutic management of this kind of osteoporosis has been studied by different societies. Since breast cancer survivors are at risk of osteopenia and osteoporosis, counseling regarding modifiable risk factors is mandatory and advocated. The beginning of the treatment should be tailored in each patient. PMID- 25285138 TI - Towards the identification of early stage osteoarthritis. AB - A variety of genetic and environmental factors contribute to the progressive develop of OA. It is necessary to identify people who are developing initial changes in cartilage and/or subchondral bone before onset of classical radiological features in order to detect early phase of OA. Recent quantitative MRI techniques can evaluate the structural, mechanical and biochemical characteristics of cartilage. T2 mapping is able to assess cartilage volume and defects measurement, delayed gadolinium enhanced MRI (dGEMRIC) and Contrast Enhanced Computed Tomography (CECT) can reveal Cartilage GAG content. Accurate and reliable serum, urine and synovial fluid biomarkers are also requested. Several biomarkers have been studied and proposed, but there are many critical issues to consider for inferring useful data from studies on biomarkers in early OA such as phase of disease, specific joint sites, systemic concentrations, circadian rhythm, their clearance from the joint, etc. Recently proteomics has produced great expectations to improve the early diagnosis of OA. These discoveries may open opportunities for the identification of early stage of OA leading to manage the symptoms and ultimately slow the progression of OA. PMID- 25285139 TI - Correlation between osteoporosis and cardiovascular disease. AB - Several evidences have shown in the last years a possible correlation between cardiovascular diseases and osteoporosis. Patients affected with osteoporosis, for example, have a higher risk of cardiovascular diseases than subjects with normal bone mass. However, the heterogeneous approaches and the different populations that have been studied so far have limited the strength of the findings. Studies conducted in animal models show that vascular calcification is a very complex mechanism that involves similar pathways described in the normal bone calcification. Proteins like BMP, osteopontin, osteoprotegerin play an important role at the bone level but are also highly expressed in the calcified vascular tissue. In particular, it seems that the OPG protect from vascular calcification and elevated levels have been found in patients with CVD. Other factors like oxidative stress, inflammation, free radicals, lipids metabolism are involved in this complex scenario. It is not a case that medications used for treating osteoporosis also inhibit the atherosclerotic process, acting on blood pressure and ventricular hypertrophy. Given the limited amount of available data, further studies are needed to elucidate the underlying mechanisms between osteoporosis and cardiovascular disease which may be important in the future also for preventive and therapeutic approaches of both conditions. PMID- 25285140 TI - General Practitioner and FRAX((r)) (computer-based algorithm). AB - Osteoporotic fractures became the most important cause of disability and an increasing burden to the public health costs in Italy and in many regions of the world. Health professionals play a central role in identifying people at high risk of osteoporosis and osteoporotic fractures. However it is important to have available methods that allow to identify patients showing high risk of fragility fractures, with lower costs and high sensitivity than those currently adopted, e.g. Dual Energy X-ray Absorptiometry (DEXA). The computer-based algorithm (FRAX(r)) developed by WHO shows some barriers in primary care, for instance the difficulty to access this tool by General Practitioners (since it is not available in their DATABASE). Moreover, since the incidence of fracture and the prevalence of associated risk factors change over time, risk prediction algorithms need to be dynamic, so that they can be remodelled over time. In Italy, the Health Search - CSD Longitudinal Patients Database (HSD) could potentially provide the data needed to support the development and validation of an applicable prediction tool in primary care. In this framework we aim to develop and validate a prognostic score for osteoporotic fractures in Italian General Practice and to establish a risk map. PMID- 25285141 TI - Alendronate soluble solution: a higher adherence rate in the treatment of osteoporosis. AB - INTRODUCTION: Since low adherence to a long-term therapy results in a poor clinical outcome and significantly increases healthcare costs, adherence to the treatment of chronic disorders is an issue of great interest. This is particularly true of the treatment of osteoporosis (OP). PURPOSE OF STUDY: Adherence to the osteoporosis therapy in patients treated with bisphosphonates in tablet form has been evaluated in comparison with the adherence of those taking alendronate in soluble solution. METHODS AND MATERIALS: Here we present a retrospective study of 245 patients treated with alendronate, risedronate and ibandronate tablets and a prospective study of 118 patients treated with soluble alendronate. In both studies, patients have been observed for a period of 12 months. RESULTS: The analysis of patients' persistence with the treatment plan, assessed at three, six and 12 months, revealed a significantly higher adherence (p < 0.005) in the cohort of patients treated with soluble alendronate (92.37% at 12 months) compared with those who followed the course of treatment with tablets (65.4 %, 12 months). CONCLUSIONS: The investigation showed higher adherence to the oral therapy with soluble alendronate, demonstrating that a formulation obtained by this method can contribute to a higher level of persistence with the treatment of a disease such as osteoporosis, which requires a long-term therapeutic plan. PMID- 25285142 TI - Vgamma9Vdelta2 T lymphocytes activation in osteoporotic patients treated with bisphosphonates. AB - Treatment with bisphosphonates induces differentiation and activation of Vgamma9Vdelta2 T lymphocytes obtained from peripheral blood showing also an antitumoral effect in both in vitro and in vivo models. Aim of the present study was to determine in vivo the effect of BPs treatment in patients affected with osteoporosis on Vgamma9Vdelta2 T lymphocytes. We have studied Vgamma9Vdelta2 T lymphocytes expansion and differentiation from PBMC obtained from osteoporotic patients treated with one of the following bisphosphonates zoledronate, alendronate, neridronate or risedronate. We have found that zoledronic acid, followed by alendronate was the most effective on reducing CM population (100%) and increasing TEM and TEMRA gammadelta population. Our results indicate that in vivo treatment with BPs induces Vgamma9Vdelta2 cells to mature toward the effector phenotype, which may induce more antiresorptive responses. PMID- 25285143 TI - Osteoporosis and risk of fracture, analysis on a population admitted in rehabilitation post-acute. AB - In the context of osteoporosis the presence of a fragility fracture (vertebral or non-vertebral) constitutes a condition of severe osteoporosis; the most common fractures due to this disease are the responsibility of the proximal femur (hip), spine and wrist representing one of the leading causes of disability in the elderly population, as well as one of the greatest contributions to health care costs. By analyzing a population of patients hospitalized at a rehabilitation ward for post-acute outcomes of hip fracture fragility it was able to observe the effectiveness of preventive intervention, the risk of vertebral fractures and the importance of comorbidity. PMID- 25285144 TI - Motorised mobility scooters; upper limb fractures in elderly novice users. AB - We describe three upper limb injuries admitted in one year to our institution resulting from falls from motorised mobility scooters (MMS) where all three users were novices, using their MMS for less than 6 weeks. They sustained injuries in close proximity to their homes, necessitating admission to hospital. None had received any formal training before commencing use of their respective devices. Use of MMS devices increases independence in mobility, enhances quality of life, improves self-esteem, facilitating social participation in everyday life. Use of these devices is not without risks, and no clear safety guidelines or competency testing exists for users. We believe these injuries in novice users highlights this deficiency, and should alert prescribers of these devices to advocate some form of driver training for new users. PMID- 25285145 TI - Osteoporosis with vertebral fractures associated with pregnancy: two case reports. AB - Pregnancy and lactation-associated osteoporosis (PAO) is a rare condition characterized by the occurrence of fragility fractures, most commonly vertebral, in late pregnancy or the early postpartum period. The prevalence, etiology and pathogenesis of this osteoporosis are unknown, although there are several hypotheses attempting to explain the etiopathogenesis of pregnancy associated osteoporosis. In this paper we present two cases of young women who developed severe PAO with vertebral fractures: a 42-year-old woman with a family history of osteoporosis, and a 21-year-old woman affected with myasthenia gravis. The case 1 presented fragility fracture of D12, L2, and L3. She did not have any disease causing osteoporosis. However, she had a positive familial history for osteoporosis and during pregnancy (12th week) she had a detached placenta, so bed rest was prescribed for two months. The case 2 presented multiple vertebral fracture. She was affected by myasthenia gravis, which was diagnosed two years before pregnancy, and treated with corticosteroid. In summary, pregnancy and lactation-induced osteoporosis, although it is a rare disorder, should be kept in mind when pregnant women or women in postpartum period develop persistent back pain and it is important to monitor the patients with risk factors or secondary causes of osteoporosis. PMID- 25285146 TI - Pregnancy-associated osteoporosis with seven vertebral compression fractures, a case treated with strontium ranelate. AB - This paper shows a case of pregnancy-associated osteoporosis (PAO) with seven vertebral compression fractures treated with strontium ranelate and supplementation of calcium and cholecalciferol. Clinical evaluation, laboratory and radiological results are analyzed in the case-report to demonstrate that strontium ranelate is a good option to restore quickly the value of bone mineral density in the treatment of a case of PAO. PMID- 25285147 TI - A case report of defective endogenous vitamin D: a new clinical entity. AB - OBJECTIVE: To report a case of defective endogenous vitamin D with excellent response to low dose calcitriol replacement therapy. METHODS: We describe the patient's clinical presentation, biochemical workup, and clinical course. RESULTS: The patient initially presented with severe symptomatic hypocalcemia and was diagnosed with pseudohypoparathyroidism type 1b at an outside hospital and started on calcitriol 2.25 mcg twice daily with good response but calcitriol was stopped later for cost concerns which led to recurrence of symptoms, worsening hypocalcemia and increased parathormone levels. On review of her case it was noted that her 1,25 dihydroxy: vitamin D level was within normal limits even before she started taking calcitriol, which is not consistent with pseudohypoparathyroidism type 1b. Restarting low dose calcitriol (0.25 mcg twice daily) improved the patient's calcium level to 10.1 mg/dl and decreased the parathormone level to 17 pg/ml and symptoms resolved. Conditions associated with low serum calcium and high parathormone include pseudohypoparathyroidism, vitamin D deficiency and vitamin D resistance. This patient does not fit into any of the known entities causing hypocalcemia and elevated parathormone. CONCLUSIONS: We hypothesize that this patient had an inadequate number of vitamin D receptors that was corrected by exogenous administration of vitamin D. PMID- 25285148 TI - Case report: late subtrochanteric fracture post radiofrequency ablation of osteoid osteoma. AB - Osteoid osteoma is a benign tumor especially affecting young males generally treated with radiofrequency ablation. This is a non-invasive and safe procedure, major complications are very rare, most of them consisting in local skin burns. The present case shows a late subtrochanteric fracture in a young boy after CT guided termoablation of osteoid osteoma of proximal femur and short review of the literature. PMID- 25285149 TI - A case of bilateral stress fractures in an old woman: three years of pain. AB - In elderly patients frequent episodes of joint pain of lower limbs exacerbated by stress and resistant to treatment occur frequently. This paper reports a case of a long lasting bilateral atraumatic knee pain with a final diagnosis of bilateral stress fractures of proximal tibia in osteoporotic postmenopausal woman. The distinctive trait of this case is that the fracture has set in bilaterally and associated with an isthmic L4-L5 spondylolisthesis in a patient afflicted by a decline in mood. This particular clinical picture has delayed the diagnosis and the suitable treatment for 3 years. Therapy for this type of patients must aim in the acute phase at pain relief and only after must be settled in a long term antiosteoporotic therapy. We choose clodronate acyd for pain relief and after strontium ranelate for osteoporosis prevention. PMID- 25285150 TI - INTERSECTIONALITY: Mapping the Movements of a Theory. PMID- 25285151 TI - Cross-cultural adaptation of instruments assessing breastfeeding determinants: a multi-step approach. AB - BACKGROUND: Cross-cultural adaptation is a necessary process to effectively use existing instruments in other cultural and language settings. The process of cross-culturally adapting, including translation, of existing instruments is considered a critical set to establishing a meaningful instrument for use in another setting. Using a multi-step approach is considered best practice in achieving cultural and semantic equivalence of the adapted version. We aimed to ensure the content validity of our instruments in the cultural context of KwaZulu Natal, South Africa. METHODS: The Iowa Infant Feeding Attitudes Scale, Breastfeeding Self-Efficacy Scale-Short Form and additional items comprise our consolidated instrument, which was cross-culturally adapted utilizing a multi step approach during August 2012. Cross-cultural adaptation was achieved through steps to maintain content validity and attain semantic equivalence in the target version. Specifically, Lynn's recommendation to apply an item-level content validity index score was followed. The revised instrument was translated and back translated. To ensure semantic equivalence, Brislin's back-translation approach was utilized followed by the committee review to address any discrepancies that emerged from translation. RESULTS: Our consolidated instrument was adapted to be culturally relevant and translated to yield more reliable and valid results for use in our larger research study to measure infant feeding determinants effectively in our target cultural context. CONCLUSIONS: Undertaking rigorous steps to effectively ensure cross-cultural adaptation increases our confidence that the conclusions we make based on our self-report instrument(s) will be stronger. In this way, our aim to achieve strong cross-cultural adaptation of our consolidated instruments was achieved while also providing a clear framework for other researchers choosing to utilize existing instruments for work in other cultural, geographic and population settings. PMID- 25285152 TI - Nanotoxoid Vaccines. AB - To improve innate defense against diseases, vaccine formulations are routinely administered to mount immune responses against disease-causing organisms or their associated toxins. These formulations are typically prepared with weakened forms of microbes, their surface proteins, or their virulence factors, which can train the immune system to recognize and neutralize similar infectious threats in later exposures. Owing to many unique properties of nanoparticles in enhancing vaccine potency, nanoscale carriers are drawing increasing interest as a platform for developing safer and more effective vaccine formulations. Notably, a nanoparticle based strategy was recently demonstrated to safely deliver intact, non-denatured protein toxins to mount a potent anti-toxin immune response. A biomimetic nanoparticle cloaked in biological membranes was used to sequester membrane active toxins. Upon interaction with the nanoparticles, the toxins become retrained and lose their toxicity as they are precluded from interacting with cellular targets. The resulting particle/toxin complex adopts a nanoparticulate morphology that facilitates the toxins' intracellular delivery. This sequestration approach has immense immunological implications owing to its ability in enabling structurally preserved toxins for immune processing. This technique offers opportunities in novel toxoid vaccine designs that promise more effective anti-toxin immune responses and contrasts the existing paradigm in toxoid preparation, in which toxins are antigenically altered to ensure virulence removal. The potent nanotoxoid formulations provide a viable anti-virulence measure in combating microbial infections that involve membrane-damaging toxins, including methicillin-resistant Staphylococcus aureus (MRSA) and Group A streptococcal infections. PMID- 25285153 TI - Graph-distance distribution of the Boltzmann ensemble of RNA secondary structures. AB - BACKGROUND: Large RNA molecules are often composed of multiple functional domains whose spatial arrangement strongly influences their function. Pre-mRNA splicing, for instance, relies on the spatial proximity of the splice junctions that can be separated by very long introns. Similar effects appear in the processing of RNA virus genomes. Albeit a crude measure, the distribution of spatial distances in thermodynamic equilibrium harbors useful information on the shape of the molecule that in turn can give insights into the interplay of its functional domains. RESULT: Spatial distance can be approximated by the graph-distance in RNA secondary structure. We show here that the equilibrium distribution of graph distances between a fixed pair of nucleotides can be computed in polynomial time by means of dynamic programming. While a naive implementation would yield recursions with a very high time complexity of O(n (6) D (5)) for sequence length n and D distinct distance values, it is possible to reduce this to O(n (4)) for practical applications in which predominantly small distances are of of interest. Further reductions, however, seem to be difficult. Therefore, we introduced sampling approaches that are much easier to implement. They are also theoretically favorable for several real-life applications, in particular since these primarily concern long-range interactions in very large RNA molecules. CONCLUSIONS: The graph-distance distribution can be computed using a dynamic programming approach. Although a crude approximation of reality, our initial results indicate that the graph-distance can be related to the smFRET data. The additional file and the software of our paper are available from http://www.rna.uni-jena.de/RNAgraphdist.html. PMID- 25285154 TI - Bullying of youth with autism spectrum disorder, intellectual disability, or typical development: Victim and parent perspectives. AB - In-depth interviews conducted separately with 13-year-olds with autism spectrum disorder (ASD), intellectual disability (ID), or typical development (TD) and their mothers investigated the experiences of victimization in the form of bullying. Coded constructs from the interviews were utilized to compare groups on the frequency, type, and impact of victimization. Youth with ASD were victimized more frequently than their ID or TD peers, and the groups differed with regard to the type of bullying and the impact it had, with ASD youth faring the worst. Higher internalizing problems and conflict in friendships were found to be significant predictors of victimization, according to both youth- and mother reports. These predictors were found to be more salient than ASD status alone. Implications for practice are discussed. PMID- 25285156 TI - An iteration normalization and test method for differential expression analysis of RNA-seq data. AB - BACKGROUND: Next generation sequencing technologies are powerful new tools for investigating a wide range of biological and medical questions. Statistical and computational methods are key to analyzing massive and complex sequencing data. In order to derive gene expression measures and compare these measures across samples or libraries, we first need to normalize read counts to adjust for varying sample sequencing depths and other potentially technical effects. RESULTS: In this paper, we develop a normalization method based on iterating median of M-values (IMM) for detecting the differentially expressed (DE) genes. Compared to a previous approach TMM, the IMM method improves the accuracy of DE detection. Simulation studies show that the IMM method outperforms other methods for the sample normalization. We also look into the real data and find that the genes detected by IMM but not by TMM are much more accurate than the genes detected by TMM but not by IMM. What's more, we discovered that gene UNC5C is highly associated with kidney cancer and so on. PMID- 25285155 TI - Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation. AB - Although kidney transplantation has been an important means for the treatment of patients with end stage of renal disease, the long-term survival rate of the renal allograft remains a challenge. The cause of late renal allograft loss, once known as chronic allograft nephropathy, has been renamed "interstitial fibrosis and tubular atrophy" (IF/TA) to reflect the histologic pattern seen on biopsy. The mechanisms leading to IF/TA in the transplanted kidney include inflammation, activation of renal fibroblasts, and deposition of extracellular matrix proteins. Identifying the mediators and factors that trigger IF/TA may be useful in early diagnosis and development of novel therapeutic strategies for improving long-term renal allograft survival and patient outcomes. In this review, we highlight the recent advances in our understanding of IF/TA from three aspects: pathogenesis, diagnosis, and treatment. PMID- 25285157 TI - Should we disclose amyloid imaging results to cognitively normal individuals? AB - Demonstration of brain accumulation of fibrillar amyloid beta protein via positron emission tomography (PET) with amyloid specific ligands may support the diagnosis of Alzheimer's disease (AD). There is increasing recognition of the potential use of amyloid imaging to detect in vivo the pathology of AD in individuals with no ostensible cognitive impairment. Research use of amyloid PET in cognitively normal patients will be key to pursuit of therapies able to delay cognitive impairment and dementia due to AD. We review the pros and cons of disclosing amyloid imaging results to cognitively normal individuals in clinical and research settings and provide draft recommendations. PMID- 25285158 TI - Left ventricular diastolic function in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor- a pilot study. AB - BACKGROUND: Blood glucose control is fundamental albeit not enough to prevent diabetic macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in improving metabolic parameters in patients with type 2 diabetes mellitus (T2DM) but little is known about its cardiovascular effects. We compared the DPP-4 inhibitor sitagliptin with bedtime NPH insulin (NPH) as add-on therapy in patients with T2DM, aiming to ascertain which drug would have additional cardioprotective effects. METHODS: Thirty-five T2DM patients inadequately controlled with metformin plus glyburide were randomized to receive sitagliptin (n = 18) or NPH (n = 17) for 24 weeks. Fasting plasma glucose, HbA1c, lipid profile, C-reactive protein, active glucagon-like peptide (aGLP-1) levels, 24 hour ambulatory blood pressure measurement and comprehensive 2-dimensional echocardiogram were determined before and after treatments. RESULTS: Both sitagliptin and NPH therapies decreased HbA1c levels after 24 weeks. Fasting plasma glucose and triglyceride levels decreased in the NPH group whereas only sitagliptin increased aGLP-1 levels. Left ventricular diastolic dysfunction (LVDD) was detected in 58.6% of twenty-nine patients evaluated. Beneficial effects in LVDD were observed in 75% and 11% of patients treated with sitagliptin and NPH, respectively (p = 0.015). Neither therapy changed C-reactive protein or blood pressure. CONCLUSIONS: Sitagliptin and bedtime NPH were similarly effective on glucose control. Improvement in LVDD in T2DM patients treated with sitagliptin was suggested, probably related to the increase of aGLP-1 levels. Therefore, DPP 4 inhibitor seems to have cardioprotective effects independent of glucose control and may have a role in the prevention of diabetic cardiomyopathy. PMID- 25285159 TI - Metabolic syndrome-breast cancer link varies by intrinsic molecular subtype. AB - BACKGROUND: Metabolic syndrome (MS) has been shown to increase the risk of breast cancer. Existing data suggest that the strength of metabolic syndrome-breast cancer link varies by intrinsic molecular subtype, but results from worldwide literature are controversial. Primary endpoint of the study was to assess whether MS is a predictor of specific breast cancer (BC) subtype. Secondary endpoint was to determine whether components of MS can individually increase the risk of specific breast cancer subtype. METHODS: Anthropometric and metabolic variables were correlated to breast cancer specific subgroups, retrospectively. Statistical significance was considered when p <= 0.05 and 95% CI. RESULTS: Data analysis suggests that MS per se represents a modifiable risk factor for BC in postmenopausal [OR 6.28 (95% CI 2.79-14.11) p < 0.00001]. MS per se prevalence is higher among Luminal breast cancers in postmenopausal [OR 1.37 (95% CI 1.07-2.80) p = 0.03]. Body Mass Index (BMI) alone is associated to Luminal A subtype breast cancer risk [OR 1.12 (95% CI 0.96-2.196 p = 0.2]. Waist Circumference > 88 cm has been shown to be specifically and statistically significant associated to HER-2+ breast cancer subtypes in postmenopausal [OR 2.72 (95% CI 1.69- 10.72) p = 0.01], whilst in Luminal B it was only marginally statistical associated [OR 2.21 (95% CI 0.77-2.60) p = 0.1]. Insulin resistance showed statistical significant association to HER-2+ and Luminal B tumors [OR 2.11 (95% CI 1.66-6.69) p = 0.05] and [OR 2.33 (95% CI 1.2-4.2) p = 0.006], respectively. Hence, it has emerged that BMI is weakly associated to Luminal A breast cancers in this case series, whereas visceral obesity and insulin resistance are likely to be linked to more aggressive breast cancer subtypes. CONCLUSIONS: New molecular biomarkers unveiling metabolic syndrome related breast carcinogenesis need to be detected to further stratify breast cancer risk by subtypes. PMID- 25285160 TI - Machine learning methods in chemoinformatics. AB - Machine learning algorithms are generally developed in computer science or adjacent disciplines and find their way into chemical modeling by a process of diffusion. Though particular machine learning methods are popular in chemoinformatics and quantitative structure-activity relationships (QSAR), many others exist in the technical literature. This discussion is methods-based and focused on some algorithms that chemoinformatics researchers frequently use. It makes no claim to be exhaustive. We concentrate on methods for supervised learning, predicting the unknown property values of a test set of instances, usually molecules, based on the known values for a training set. Particularly relevant approaches include Artificial Neural Networks, Random Forest, Support Vector Machine, k-Nearest Neighbors and naive Bayes classifiers. PMID- 25285161 TI - Multiparametric spectroscopic photoacoustic imaging of breast cancer development in a transgenic mouse model. AB - OBJECTIVE: To evaluate the potential of multiparametric spectroscopic photoacoustic imaging using oxygen saturation, total hemoglobin, and lipid content to differentiate among four different breast histologies (normal, hyperplasia, ductal carcinoma in situ (DCIS), and invasive breast carcinoma) in a transgenic mouse model of breast cancer development. MATERIALS AND METHODS: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mammary glands (n=251) of a transgenic mouse model of breast cancer development (FVB/N-Tg(MMTV-PyMT)634Mul) were imaged using B-mode ultrasound and spectroscopic photoacoustic imaging, analyzed for oxygen saturation, total hemoglobin, and lipid content, and processed for histological analysis. Statistical analysis was performed using one-way ANOVA, two-sample t tests, logistic regression, and ROC analysis. RESULTS: Eighty-two normal, 12 hyperplastic, 96 DCIS, and 61 invasive breast carcinoma mammary glands were analyzed. Based on spectroscopic photoacoustic imaging, the oxygen saturation of hyperplasia (50.6%), DCIS (43.0%), and invasive carcinoma (46.2%) significantly increased compared to normal glands (35.5%, P <0.0001), while both total hemoglobin (P<0.01), and lipid content (P<0.0008) significantly decreased with advancing histology. In differentiating normal and hyperplasia from DCIS and invasive breast carcinoma, multiparametric imaging of oxygen saturation, lipid content, and raw photoacoustic signal at 750 nm provided an AUC value of 0.770. CONCLUSION: Multiparametric spectroscopic photoacoustic imaging is feasible and allows detection of differences in concentration of tissue chromophores among different histologies in a transgenic mouse model of breast cancer development. PMID- 25285162 TI - Enhancing therapeutic effects of docetaxel-loaded dendritic copolymer nanoparticles by co-treatment with autophagy inhibitor on breast cancer. AB - Dendrimers are synthetic nanocarriers that comprise a highly branched spherical polymer as new, efficient tools for drug delivery. However, the fate of nanocarriers after being internalized into cells has seldom been studied. Docetaxel loaded dendritic copolymer H40-poly(D,L-lactide) nanoparticles, referred to as "DTX-H40-PLA NPs", were prepared and used as a model to evaluate whether the NPs were sequestered by autophagy and fused with lysosomes. Besides being degraded through the endolysosomal pathway, the DTX-loaded H40-PLA NPs were also sequestered by autophagosomes and degraded through the autolysosomal pathway. DTX-loaded H40-PLA NPs may stop exerting beneficial effects after inducing autophagy of human MCF-7 cancer cells. Co-delivery of autophagy inhibitor such as chloroquine and chemotherapeutic drug DTX by dendritic copolymer NPs greatly enhanced cancer cell killing in vitro, and decreased both the volume and weight of the tumors in severe combined immunodeficient mice. These findings provide valuable evidence for development of nanomedicine such as dendritic copolymer NPs for clinical application. PMID- 25285163 TI - Co-delivery of doxorubicin and Bmi1 siRNA by folate receptor targeted liposomes exhibits enhanced anti-tumor effects in vitro and in vivo. AB - Bmi1 gene overexpression is found in various human tumors and has been shown as a potential target for gene treatment. However, siRNA-based treatments targeting Bmi1 gene have been restricted to limited delivery, low bioavailability and hence relatively reduced efficacy. To overcome these barriers, we developed a folate receptor targeted co-delivery system folate-doxorubicin/Bmi1 siRNA liposome (FA DOX/siRNA-L). The FA-DOX/siRNA-L was prepared through electrostatic interaction between folate doxorubicin liposome (FA-DOX-L) and Bmi1 siRNA. In vitro and in vivo studies showed that FA-DOX/siRNA-L inhibited tumor growth by combinatory role of Bmi1 siRNA and doxorubicin (DOX). Co-delivery of Bmi1 siRNA and DOX by FA DOX/siRNA-L showed significantly higher efficacy than sole delivery of either DOX or Bmi1 siRNA. Real-time PCR and western blot analysis showed that FA-DOX/siRNA-L silenced the expression of Bmi1 gene. In addition, higher accumulation of the siRNA and DOX in tumor cells indicated that folate ligand displayed tumor targeting effect. These results suggest that Bmi1 is an effective therapeutic target for siRNA based cancer treatment that can be further improved by co delivery of DOX through targeted liposomes. PMID- 25285164 TI - Photostimulable near-infrared persistent luminescent nanoprobes for ultrasensitive and longitudinal deep-tissue bio-imaging. AB - In vivo fluorescence imaging suffers from suboptimal signal-to-noise ratio and shallow detection depth, which is caused by the strong tissue autofluorescence under constant external excitation and the scattering and absorption of short wavelength light in tissues. Here we address these limitations by using a novel type of optical nanoprobes, photostimulable LiGa5O8:Cr(3+) near-infrared (NIR) persistent luminescence nanoparticles, which, with very-long-lasting NIR persistent luminescence and unique photo-stimulated persistent luminescence (PSPL) capability, allow optical imaging to be performed in an excitation-free and hence, autofluorescence-free manner. LiGa5O8:Cr(3+) nanoparticles pre-charged by ultraviolet light can be repeatedly (>20 times) stimulated in vivo, even in deep tissues, by short-illumination (~15 seconds) with a white light-emitting diode flashlight, giving rise to multiple NIR PSPL that expands the tracking window from several hours to more than 10 days. Our studies reveal promising potential of these nanoprobes in cell tracking and tumor targeting, exhibiting exceptional sensitivity and penetration that far exceed those afforded by conventional fluorescence imaging. PMID- 25285165 TI - Glycoproteomic study reveals altered plasma proteins associated with HIV elite suppressors. AB - HIV elite suppressors (ES) or controllers are individuals achieving control of viremia by their natural immunological mechanisms without highly active antiretroviral therapy (HAART). Study of the mechanisms responsible for the immunological suppression of viremia in ES may lead to the detection of individuals with ES and the effective control of HIV infection. We hypothesize that plasma glycoproteins play essential roles in the immune system of ES since plasma proteins are critical and highly relevant in anti-viral immunity and most plasma proteins are glycoproteins. To examine glycoproteins associated with ES, plasma samples from ES individuals (n=20), and from individuals on HAART (n=20), with AIDS (n=20), and no HIV infection (n=10) were analyzed by quantitative glycoproteomics. We found that a number of glycoproteins changed between ES versus HAART, AIDS and HIV- individuals. In sharp contrast, the level of plasma glycoproteins in the HAART cohort showed fewer changes compared with AIDS and HIV individuals. These results showed that although both ES and HAART effectively suppress viremia, ES appeared to profoundly affect immunologically relevant glycoproteins in plasma as consequence of or support for anti-viral immunity. Bioinformatic analysis revealed that altered proteins in ES plasma were mainly associated with inflammation. This analysis suggests that overlapping, while distinguishable, glycoprotein profiles for inflammation and immune activation appeared to be present between ES and non-ES (HAART+AIDS) cohorts, indicating different triggers for inflammation and immune activation between natural and treatment-related viral suppression. PMID- 25285166 TI - Quantitative proteomics analysis identifies mitochondria as therapeutic targets of multidrug-resistance in ovarian cancer. AB - Doxorubicin is a widely used chemotherapeutic agent for the treatment of a variety of solid tumors. However, resistance to this anticancer drug is a major obstacle to the effective treatment of tumors. As mitochondria play important roles in cell life and death, we anticipate that mitochondria may be related to drug resistance. Here, stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic strategy was applied to compare mitochondrial protein expression in doxorubicin sensitive OVCAR8 cells and its doxorubicin-resistant variant NCI_ADR/RES cells. A total of 2085 proteins were quantified, of which 122 proteins displayed significant changes in the NCI_ADR/RES cells. These proteins participated in a variety of cell processes including cell apoptosis, substance metabolism, transport, detoxification and drug metabolism. Then qRT-PCR and western blot were applied to validate the differentially expressed proteins quantified by SILAC. Further functional studies with RNAi demonstrated TOP1MT, a mitochondrial protein participated in DNA repair, was involved in doxorubicin resistance in NCI_ADR/RES cells. Besides the proteomic study, electron microscopy and fluorescence analysis also observed that mitochondrial morphology and localization were greatly altered in NCI_ADR/RES cells. Mitochondrial membrane potential was also decreased in NCI_ADR/RES cells. All these results indicate that mitochondrial function is impaired in doxorubicin resistant cells and mitochondria play an important role in doxorubicin resistance. This research provides some new information about doxorubicin resistance, indicating that mitochondria could be therapeutic targets of doxorubicin resistance in ovarian cancer cells. PMID- 25285169 TI - Multidisciplinary efforts driving translational theranostics. AB - This themed issue summarizes significant efforts aimed at using "biological language" to discern between "friends" and "foes" in the context of theranostics for true clinical application. It is expected that the success of theranostics depends on multidisciplinary efforts, combined to expedite our understanding of host responses to "customized" theranostic agents and formulating individualized therapies. PMID- 25285168 TI - MiR-194 deregulation contributes to colorectal carcinogenesis via targeting AKT2 pathway. AB - Recent studies have increasingly linked microRNAs to colorectal cancer (CRC). MiR 194 has been reported deregulated in different tumor types, whereas the function of miR-194 in CRC largely remains unexplored. Here we investigated the biological effects, mechanisms and clinical significance of miR-194. Functional assay revealed that overexpression of miR-194 inhibited CRC cell viability and invasion in vitro and suppressed CRC xenograft tumor growth in vivo. Conversely, block of miR-194 in APC(Min/+) mice promoted tumor growth. Furthermore, miR-194 reduced the expression of AKT2 both in vitro and in vivo. Clinically, the expression of miR-194 gradually decreased from 20 normal colorectal mucosa (N-N) cases through 40 colorectal adenomas (CRA) cases and then to 40 CRC cases, and was negatively correlated with AKT2 and pAKT2 expression. Furthermore, expression of miR-194 in stool samples was gradually decreased from 20 healthy cases, 20 CRA cases, then to 28 CRC cases. Low expression of miR-194 in CRC tissues was associated with large tumor size (P=0.006), lymph node metastasis (P=0.012) and shorter survival (HR =2.349, 95% CI = 1.242 to 4.442; P=0.009). In conclusion, our data indicated that miR-194 acted as a tumor suppressor in the colorectal carcinogenesis via targeting PDK1/AKT2/XIAP pathway, and could be a significant diagnostic and prognostic biomarker for CRC. PMID- 25285167 TI - MicroRNAs associated with HBV infection and HBV-related HCC. AB - Hepatitis B virus (HBV) infection is a global problem and a major risk factor for hepatocellular carcinoma (HCC). microRNAs (miRNAs) comprise a group of small noncoding RNAs regulating gene expression at the posttranslational level, thereby participating in fundamental biological processes, including cell proliferation, differentiation, and apoptosis. In this review, we summarize the roles of miRNAs in HBV infection, the recently identified mechanism underlying dysregulation of miRNAs in HBV-associated HCC, and their association with hepatocarcinogenesis. Moreover, we discuss the recent advances in the use of circulating miRNAs in the early diagnosis of HCC as well as therapies based on these aberrantly expressed miRNAs. PMID- 25285170 TI - Functional nanostructures for effective delivery of small interfering RNA therapeutics. AB - Small interfering RNA (siRNA) has proved to be a powerful tool for target specific gene silencing via RNA interference (RNAi). Its ability to control targeted gene expression gives new hope to gene therapy as a treatment for cancers and genetic diseases. However, siRNA shows poor pharmacological properties, such as low serum stability, off-targeting, and innate immune responses, which present a significant challenge for clinical applications. In addition, siRNA cannot cross the cell membrane for RNAi activity because of its anionic property and stiff structure. Therefore, the development of a safe, stable, and efficient system for the delivery of siRNA therapeutics into the cytoplasm of targeted cells is crucial. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major hurdles facing the therapeutic uses of siRNA. This review covers a broad spectrum of non-viral siRNA delivery systems developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and discusses their characteristics and opportunities for clinical applications of therapeutic siRNA. PMID- 25285171 TI - A highly specific probe for sensing hydrogen sulfide in live cells based on copper-initiated fluorogen with aggregation-induced emission characteristics. AB - Here we reported the first fluorescent probe with aggregation-induced emission characteristics, namely AIE-S, for the detection of hydrogen sulfide (H2S) in live cells. The detection system is selective for complicated biological application and the response is fast enough to complete within seconds. Moreover, the probe exhibits the unique advantage of being immune to aggregation-caused quenching which is a detrimental phenomenon limiting the application of most current available H2S fluorescent probes. The detection mechanism was investigated and postulated to be S(2-) initiated de-coordination and thereafter aggregation of the AIE-S complex. PMID- 25285174 TI - An approach to automatic evaluate registration performance for image guided navigation. PMID- 25285172 TI - Rapid and quantitative detection of zoonotic influenza A virus infection utilizing coumarin-derived dendrimer-based fluorescent immunochromatographic strip test (FICT). AB - Great efforts have been made to develop robust signal-generating fluorescence materials which will help in improving the rapid diagnostic test (RDT) in terms of sensitivity and quantification. In this study, we developed coumarin-derived dendrimer-based fluorescent immunochromatographic strip test (FICT) assay with enhanced sensitivity as a quantitative diagnostic tool in typical RDT environments. The accuracy of the proposed FICT was compared with that of dot blot immunoassay techniques and conventional RDTs. Through conjugation of coumarin-derived dendrimers with latex beads, fluorescent emission covering broad output spectral ranges was obtained which provided a distinct advantage of easy discrimination of the fluorescent emission of the latex beads with a simple insertion of a long-pass optical filter away from the excitation wavelength. The newly developed FICT assay was able to detect 100 ng/10 MUL of influenza A nucleoprotein (NP) antigen within 5 minutes, which corresponded to 2.5-fold higher sensitivity than that of the dot blot immunoassay or conventional RDTs. Moreover, the FICT assay was confirmed to detect at least four avian influenza A subtypes (H5N3, H7N1, H7N7, and H9N2). On applying the FICT to the clinical swab samples infected with respiratory viruses, our FICT assay was confirmed to differentiate influenza H1N1 infection from other respiratory viral diseases. These data demonstrate that the proposed FICT assay is able to detect zoonotic influenza A viruses with a high sensitivity, and it enables the quantitation of the infection intensity by providing the numerical diagnostic values; thus demonstrating enhanced detectability of influenza A viruses. PMID- 25285173 TI - The architecture and biological function of dual antibody-coated dendrimers: enhanced control of circulating tumor cells and their hetero-adhesion to endothelial cells for metastasis prevention. AB - Dissemination of circulating tumor cells (CTCs) in blood and their hetero adhesion to vascular endothelial bed of distant metastatic secondary organs are the critical steps to initiate cancer metastasis. The rarity of CTCs made their in vivo capture technically challenging. Current techniques by virtue of nanostructured scaffolds monovalently conjugated with a single antibody and/or drug seem less efficient and specific in capturing CTCs. Here, we report a novel platform developed to re-engineer nanoscale dendrimers for capturing CTCs in blood and interfering their adhesion to vascular endothelial bed to form micrometastatic foci. The nanoscale dendrimers were spatiotemporally accommodated with dual antibodies to target two surface biomarkers of colorectal CTCs. Physiochemical characterization, including spectra, fluorescence, electron microscope, dynamic light scattering, electrophoresis, and chromatography analyses, was conducted to demonstrate the successful conjugation of dual antibodies to dendrimer surface. The dual antibody conjugates were able to specifically recognize and bind CTCs, moderately down-regulate the activity of the captured CTCs by arresting them in S phase. The related adhesion assay displayed that the dual antibody conjugates interfered the hetero-adhesion of CTCs to fibronectin (Fn)-coated substrates and human umbilical vein endothelial cells (HUVECs). The dual antibody conjugates also showed the enhanced specificity and efficiency in vitro and in vivo in restraining CTCs in comparison with their single antibody counterparts. The present study showed a novel means to effectively prevent cancer metastatic initiation by binding, restraining CTCs and inhibiting their hetero-adhesion to blood vessels, not by traditional cytotoxic killing of cancer cells. PMID- 25285175 TI - Selective hypertrophy of the lobus caudatus as a novel approach enabling extended right hepatectomy in the presence of a non-perfused left lateral liver lobe. AB - INTRODUCTION: Portal vein embolization (PVE) is a well-established technique to enhance functional hepatic reserves of segments II and III before curative extended right hepatectomy for tumors of the right liver lobe. However, an adequate hepatopetal flow of the left lateral portal vein branches is required for a sufficient PVE-associated hypertrophy. CASE REPORT: Here, we report a 65 year old patient suffering from a locally advanced intrahepatic cholangiocarcinoma in the right liver lobe and segment IV. A curative extended right hepatectomy after preoperative PVE of liver segments IV-VIII was initially impossible because of partial thrombosis of the left lateral portal vein branches resulting in an ischemic-type atrophy of segments II and III. However, due to a massive hypertrophy of the caudate lobe following PVE of liver segments IV-VIII, subsequent extended right hepatectomy with intraoperative thrombectomy of segments II and III was made possible. CONCLUSIONS: To our knowledge this is the first case in which an extended right hepatectomy for a liver malignancy, in the presence of atrophic left lateral section, was made possible by a massive PVE associated hypertrophy of the caudate lobe. PMID- 25285177 TI - Introduction to Pediatric Sepsis. AB - Sepsis is a significant health problem in both critically ill children and adults. While the mortality rate from sepsis is much lower in children, sepsis is directly responsible for over 4,000 childhood deaths per year in the United States alone. At face value, this number suggests that more children die per year in the United States from sepsis as the primary cause than from cancer. Unfortunately, there are few studies on the epidemiology, pathophysiology, and management of sepsis in children. Moreover, extrapolation of adult data to critically ill children is probably not appropriate due to several key developmental differences in the host response to infection and response to therapy. Therefore, additional studies targeting sepsis in the pediatric population are urgently required. PMID- 25285178 TI - Targeting TRPV3 for the Development of Novel Analgesics. AB - Decades of characterization of the transient receptor potential vanilloid subtype 1 (TRPV1) has led to the realization of its central role in thermosensation and pain perception. A large number of pharmaceutical companies have had interest in developing TPRV1 antagonists for the treatment of pain. The subsequent discovery of multiple other members of this TRPV family has not gone unnoticed. TRPV3 exhibits approximately 40% homology to TRPV1, and has common as well as distinct features from TRPV1 in channel physiology, expression and function. Here we review the current understanding of TRPV3 channel biology, activation, sensitization and the consequences of TRPV3 manipulation for thermosensation and nociception, as well as additional considerations regarding the expression of TRPV3 in the skin. We weigh in on the available evidence in the context of potential development of TRPV3 modulating agents as analgesics. PMID- 25285179 TI - Omega-3 Fatty Acid Blood Levels Clinical Significance Update. AB - The potential benefit of fish oil (omega-3 fatty acids) consumption to reduce cardiovascular disease (CVD) risk remains controversial. Some investigations report reduced CVD risk associated with fish or fish oil consumption while others report no benefit. This controversy is in part resolved when consideration is given to omega-3 blood levels in relation to CVD risk as well as blood levels achieved in clinical trials of omega-3 supplementation and CVD benefit. There is a wide variation in omega-3 blood levels achieved between individuals in response to a given dose of an omega-3 supplement. Many studies tested a daily dose of 1 gram omega-3 supplementation. The individual variation in blood omega-3 levels achieved in response to a fixed daily dose helps to explain why some individuals may obtain CVD protection benefit while others do not due to failure to achieve a therapeutic threshold. Recent development of a population range in a United States population helps to provide clinical guidance since population omega-3 blood level ranges may vary due to environmental and genetic reasons. Omega-3 supplementation may also be of benefit in reducing the adverse impact of air pollution on CVD risk. PMID- 25285180 TI - Marine n-3 Fatty Acids and Gene Expression in Peripheral Blood Mononuclear Cells. AB - Intake of marine n-3 fatty acids has been shown to have beneficial effects on cardiovascular disease. Gene expression analyses in peripheral blood mononuclear cells (PBMCs) are used to understand the underlying mechanisms of action of marine n-3 fatty acids. The aim of this review was to summarize the effects mediated by marine n-3 fatty acids on gene expression in PBMCs. A systematic literature search was conducted in PubMed in May 2014 and 14 papers were included. Targeted gene expression studies were reported in 9 papers and focused on genes involved in lipid metabolism and inflammation. Whole genome transcriptome analyses were conducted in 5 papers, and processes and pathways related to atherosclerotic plaque formation such as inflammation, oxidative stress response, cell cycle, cell adhesion, and apoptosis were modulated after fish oil supplementation. PBMC gene expression profiling has a potential to clarify further the molecular effects of fish oil consumption on human health. PMID- 25285181 TI - Informal Care and Inter-vivos Transfers: Results from the National Longitudinal Survey of Mature Women. AB - Informal care is the largest source of long-term care for elderly, surpassing home health care and nursing home care. By definition, informal care is unpaid. It remains a puzzle why so many adult children give freely of their time. Transfers of time to the older generation may be balanced by financial transfers going to the younger generation. This leads to the question of whether informal care and inter-vivos transfers are causally related. We analyze data from the 1999 and 2003 waves of National Longitudinal Survey of Mature Women. We examine whether the elderly parents give more inter-vivos monetary transfers to adult children who provide informal care, by examining both the extensive and intensive margins of financial transfers and of informal care. We find statistically significant results that a child who provides informal care is more likely to receive inter-vivos transfers than a sibling who does not. If a child does provide care, there is no statistically significant effect on the amount of the transfer. PMID- 25285176 TI - Sugar glues for broken neurons. AB - Proteoglycans (PGs) regulate diverse functions in the central nervous system (CNS) by interacting with a number of growth factors, matrix proteins, and cell surface molecules. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major glycosaminoglycans present in the PGs of the CNS. The functionality of these PGs is to a large extent dictated by the fine sulfation patterns present on their glycosaminoglycan (GAG) chains. In the past 15 years, there has been a significant expansion in our knowledge on the role of HS and CS chains in various neurological processes, such as neuronal growth, regeneration, plasticity, and pathfinding. However, defining the relation between distinct sulfation patterns of the GAGs and their functionality has thus far been difficult. With the emergence of novel tools for the synthesis of defined GAG structures, and techniques for their characterization, we are now in a better position to explore the structure-function relation of GAGs in the context of their sulfation patterns. In this review, we discuss the importance of GAGs on CNS development, injury, and disorders with an emphasis on their sulfation patterns. Finally, we outline several GAG-based therapeutic strategies to exploit GAG chains for ameliorating various CNS disorders. PMID- 25285183 TI - Sample Complexity Bounds for Differentially Private Learning. AB - This work studies the problem of privacy-preserving classification - namely, learning a classifier from sensitive data while preserving the privacy of individuals in the training set. In particular, the learning algorithm is required in this problem to guarantee differential privacy, a very strong notion of privacy that has gained significant attention in recent years. A natural question to ask is: what is the sample requirement of a learning algorithm that guarantees a certain level of privacy and accuracy? We address this question in the context of learning with infinite hypothesis classes when the data is drawn from a continuous distribution. We first show that even for very simple hypothesis classes, any algorithm that uses a finite number of examples and guarantees differential privacy must fail to return an accurate classifier for at least some unlabeled data distributions. This result is unlike the case with either finite hypothesis classes or discrete data domains, in which distribution free private learning is possible, as previously shown by Kasiviswanathan et al. (2008). We then consider two approaches to differentially private learning that get around this lower bound. The first approach is to use prior knowledge about the unlabeled data distribution in the form of a reference distribution chosen independently of the sensitive data. Given such a reference , we provide an upper bound on the sample requirement that depends (among other things) on a measure of closeness between and the unlabeled data distribution. Our upper bound applies to the non-realizable as well as the realizable case. The second approach is to relax the privacy requirement, by requiring only label-privacy - namely, that the only labels (and not the unlabeled parts of the examples) be considered sensitive information. An upper bound on the sample requirement of learning with label privacy was shown by Chaudhuri et al. (2006); in this work, we show a lower bound. PMID- 25285182 TI - Synthesis and Biological Evaluation of Novel N-phenyl-5-carboxamidyl Isoxazoles as Potential Chemotherapeutic Agents for Colon Cancer. AB - A new series of isoxazole derivatives, N-phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. Six N phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by the in vitro disk-diffusion assay and IC50 cytotoxicity determination. The results showed that one of the derivatives, compound 3,N-(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC50 of 2.5 MUg/mL for both cell lines. Western blot analysis showed that compound 3 significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound 3 may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound 3 is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound 3 is a new N-phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound 3 inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer. PMID- 25285184 TI - Statistical Learning Methods for Longitudinal High-dimensional Data. AB - Recent studies have collected high-dimensional data longitudinally. Examples include brain images collected during different scanning sessions and time-course gene expression data. Because of the additional information learned from the temporal changes of the selected features, such longitudinal high-dimensional data, when incorporated with appropriate statistical learning techniques, are able to more accurately predict disease status or responses to a therapeutic treatment. In this article, we review recently proposed statistical learning methods dealing with longitudinal high-dimensional data. PMID- 25285185 TI - Predictors of discordance among Chilean families. AB - Parent-youth agreement on parental behaviors can characterize effective parenting. Although discordance in families may be developmentally salient and harmful to youth outcomes, predictors of discordance have been understudied, and existing research in this field has been mostly limited to North American samples. This paper addressed this literature gap by using data from a community based study of Chilean adolescents. Analysis was based on 1,068 adolescents in Santiago, Chile. The dependent variable was discordance which was measured by the difference between parent and youth's assessment of parental monitoring. Major independent variables for this study were selected based on previous research findings that underscore youth's developmental factors, positive parental and familial factors and demographic factors. Descriptive and multivariate analyses were conducted to examine the prevalence and associations between youth, parental and familial measures with parent-youth discordance. There was a sizable level of discordance between parent and youth's report of parental monitoring. Youth's gender and externalizing behavior were significant predictors of discordance. Warm parenting and family involvement were met with decreases in discordance. The negative interaction coefficients between parental warmth and youth's gender indicated that positive parental and familial measures have a greater effect on reducing parent-youth discordance among male youths. Results support the significance of positive family interactions in healthy family dynamics. Findings from this study inform the importance of services and interventions for families that aim to reduce youth's problem behavior and to create a warm and interactive family environment. PMID- 25285187 TI - A COMPARISON OF MODEL BASED AND DIRECT OPTIMIZATION BASED FILTERING ALGORITHMS FOR SHEARWAVE VELOCITY RECONSTRUCTION FOR ELECTRODE VIBRATION ELASTOGRAPHY. AB - Tissue stiffness estimation plays an important role in cancer detection and treatment. The presence of stiffer regions in healthy tissue can be used as an indicator for the possibility of pathological changes. Electrode vibration elastography involves tracking of a mechanical shear wave in tissue using radio frequency ultrasound echoes. Based on appropriate assumptions on tissue elasticity, this approach provides a direct way of measuring tissue stiffness from shear wave velocity, and enabling visualization in the form of tissue stiffness maps. In this study, two algorithms for shear wave velocity reconstruction in an electrode vibration setup are presented. The first method models the wave arrival time data using a hidden Markov model whose hidden states are local wave velocities that are estimated using a particle filter implementation. This is compared to a direct optimization-based function fitting approach that uses sequential quadratic programming to estimate the unknown velocities and locations of interfaces. The mean shear wave velocities obtained using the two algorithms are within 10%of each other. Moreover, the Young's modulus estimates obtained from an incompressibility assumption are within 15 kPa of those obtained from the true stiffness data obtained from mechanical testing. Based on visual inspection of the two filtering algorithms, the particle filtering method produces smoother velocity maps. PMID- 25285188 TI - Life Satisfaction of U.S. Counties Predicts Population Growth. AB - Subjective well-being reflects an overall evaluation of the quality of a person's life from his or her perspective. Although subjective well-being is typically studied at the individual level, social scientists have become increasingly interested in the well-being of broader regions like cities, states, or nations. The current study examines the association between aggregate well-being and an important behavioral indicator of regional success: migration and population growth. Using life satisfaction data from over 2 million respondents, along with population data from 2000 to 2010, I show that U.S. counties with higher levels of life satisfaction grew at substantially faster rates than did counties with low life satisfaction. Supplemental analyses showed that this association was not due to regional differences in birth or death rates. Instead, counties with high life satisfaction experienced high levels of domestic migration. These results show the validity and utility of life satisfaction measures at the regional level. PMID- 25285186 TI - Therapeutic Considerations in Treating HER2-Positive Metastatic Breast Cancer. AB - Despite advances in detection and treatment, metastatic breast cancer (MBC) remains the second highest cause of cancer-related death for women in the United States. Human epidermal growth factor receptor-2 (HER2) is amplified in 25-30% of breast cancers and is associated with aggressive disease and, historically, with poorer outcomes. The advent of trastuzumab, a monoclonal antibody to HER2, revolutionized the management of HER2-positive breast cancer (BC) in the metastatic and adjuvant settings. However, relapse despite adjuvant trastuzumab and resistance to trastuzumab in the metastatic setting remain substantial clinical problems for many patients with HER2-positive BC. As such, analyzing the mechanisms of trastuzumab resistance and developing new therapy to overcome trastuzumab resistance are research priorities. There has been progress, with the approval of three additional HER2-targeted agents in the last six years: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Other HER2-targeted therapies, including neratinib and afatinib, are in clinical development, and trials of novel agents such as heat shock protein-90 (HSP90) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and HER2-targeted vaccines are ongoing. In addition to developing new therapy, research is addressing several unique challenges in the management of HER2-positive MBC. In this article, we discuss advances in the treatment of HER2-positive MBC, with a focus on novel HER2-targeted therapy and HER2-targeted agents recently approved by the United States Food and Drug Administration (FDA). Additionally, we also address the management of brain metastases (BM) and hormone receptor (HR) - positive, HER2 positive MBC. PMID- 25285189 TI - In Vivo Imaging and Quantification of Iron Oxide Nanoparticle Uptake and Biodistribution. AB - Recent advances in nanotechnology have allowed for the effective use of iron oxide nanoparticles (IONPs) for cancer imaging and therapy. When activated by an alternating magnetic field (AMF), intra-tumoral IONPs have been effective at controlling tumor growth in rodent models. To accurately plan and assess IONP based therapies in clinical patients, noninvasive and quantitative imaging technique for the assessment of IONP uptake and biodistribution will be necessary. Proven techniques such as confocal, light and electron microscopy, histochemical iron staining, ICP-MS, fluorescent labeled mNPs and magnetic spectroscopy of Brownian motion (MSB), are being used to assess and quantify IONPs in vitro and in ex vivo tissues. However, a proven noninvasive in vivo IONP imaging technique has not yet been developed. In this study we have demonstrated the shortcomings of computed tomography (CT) and magnetic resonance imaging (MRI) for effectively observing and quantifying iron/IONP concentrations in the clinical setting. Despite the poor outcomes of CT and standard MR sequences in the therapeutic concentration range, ultra-short T2 MRI methods such as, Sweep Imaging With Fourier Transformation (SWIFT), provide a positive iron contrast enhancement and a reduced signal to noise ratio. Ongoing software development and phantom and in vivo studies, will further optimize this technique, providing accurate, clinically-relevant IONP biodistribution information. PMID- 25285190 TI - Imaging and modification of the tumor vascular barrier for improvement in magnetic nanoparticle uptake and hyperthermia treatment efficacy. AB - The predicted success of nanoparticle based cancer therapy is due in part to the presence of the inherent leakiness of the tumor vascular barrier, the so called enhanced permeability and retention (EPR) effect. Although the EPR effect is present in varying degrees in many tumors, it has not resulted in the consistent level of nanoparticle-tumor uptake enhancement that was initially predicted. Magnetic/iron oxide nanoparticles (mNPs) have many positive qualities, including their inert/nontoxic nature, the ability to be produced in various sizes, the ability to be activated by a deeply penetrating and nontoxic magnetic field resulting in cell-specific cytotoxic heating, and the ability to be successfully coated with a wide variety of functional coatings. However, at this time, the delivery of adequate numbers of nanoparticles to the tumor site via systemic administration remains challenging. Ionizing radiation, cisplatinum chemotherapy, external static magnetic fields and vascular disrupting agents are being used to modify the tumor environment/vasculature barrier to improve mNP uptake in tumors and subsequently tumor treatment. Preliminary studies suggest use of these modalities, individually, can result in mNP uptake improvements in the 3-10 fold range. Ongoing studies show promise of even greater tumor uptake enhancement when these methods are combined. The level and location of mNP/Fe in blood and normal/tumor tissue is assessed via histopathological methods (confocal, light and electron microscopy, histochemical iron staining, fluorescent labeling, TEM) and ICP-MS. In order to accurately plan and assess mNP-based therapies in clinical patients, a noninvasive and quantitative imaging technique for the assessment of mNP uptake and biodistribution will be necessary. To address this issue, we examined the use of computed tomography (CT), magnetic resonance imaging (MRI), and Sweep Imaging With Fourier Transformation (SWIFT), an MRI technique which provides a positive iron contrast enhancement and a reduced signal to noise ratio, for effective observation and quantification of Fe/mNP concentrations in the clinical setting. PMID- 25285191 TI - Implementation of an endoscopy safety checklist. AB - Patient safety and quality improvement are increasingly prioritised across all areas of healthcare. Errors in endoscopy are common but often inconsequential and therefore go uncorrected. A series of minor errors, however, may culminate in a significant adverse event. This is unsurprising given the rising volume and complexity of cases coupled with shift working patterns. There is a growing body of evidence to suggest that surgical safety checklists can prevent errors and thus positively impact on patient morbidity and mortality. Consequently, surgical checklists are mandatory for all procedures. Many UK hospitals are mandating the use of similar checklists for endoscopy. There is no guidance on how best to implement endoscopy checklists nor any measure of their usefulness in endoscopy. This article outlines lessons learnt from innovating service delivery in our unit. PMID- 25285194 TI - One bad apple: experimental effects of psychological conflict on social resilience. AB - Past research suggests that small groups are self-organizing systems, and that social resilience may be measured as the meta-flexibility of group dynamics: the ability to shift back and forth from flexiblity to rigidity in response to conflict. This study extends these prior results, examining the impact of experimentally induced internal conflict and group-level conflict resolution on group dynamics-whether one bad apple can spoil the bunch. Six experimental groups with four members each participated in a series of four 25 min discussions. The first two discussions served as a baseline condition. Internal conflict was induced to one or more group members prior to discussion three, with the prediction that higher levels of conflict induction would lead to significant drops in group flexibility-creating a press on the group's resilience, whereas conflict resolution in discussion four was expected to allow for a rebound in group flexibility. Consistent with prior research, the turn-taking dynamics of each the 24 groups were distributed as inverse power laws (R (2) = 0.86-0.99) providing evidence for self-organization. Furthermore, there were significant study-wise negative correlation between levels of personality conflict and two measures of flexibility: information entropy (r = -0.47, p = 0.019) and fractal dimension (r = -0.42, p = 0.037). Altogether, these results suggest that: (i) small groups are self-organizing systems with structure and flexibility providing social resilience and (ii) individual conflict is able to spread to higher level social dynamics, creating pressure on social resilience. Practical implications for assessment of, and intervention with, psychosocial resilience are discussed. PMID- 25285193 TI - Trifluoromethylated Nucleic Acid Analogues Capable of Self-Assembly through Hydrophobic Interactions. AB - An artificial nucleic acid analogue capable of self-assembly into duplex merely through hydrophobic interactions is presented. The replacement of Watson-Crick hydrogen bonding with strictly hydrophobic interactions has the potential to confer new properties and facilitate the construction of complex DNA nanodevices. To study how the hydrophobic effect works during the self-assembly of nucleic acid bases, we have designed and synthesized a series of fluorinated nucleic acids (FNA) containing 3,5-bis(trifluoromethyl) benzene (F) and nucleic acids incorporating 3,5-dimethylbenzene (M) as hydrophobic base surrogates. Our experiments illustrate that two single-stranded nucleic acid oligomers could spontaneously organize into a duplex entirely by hydrophobic base pairing if the bases were size-complementary and the intermolecular forces were sufficiently strong. PMID- 25285192 TI - Non-alcoholic fatty liver disease: a practical approach to treatment. AB - Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis. PMID- 25285195 TI - Computational modelling of the inflammatory response in trauma, sepsis and wound healing: implications for modelling resilience. AB - Resilience refers to the ability to recover from illness or adversity. At the cell, tissue, organ and whole-organism levels, the response to perturbations such as infections and injury involves the acute inflammatory response, which in turn is connected to and controlled by changes in physiology across all organ systems. When coordinated properly, inflammation can lead to the clearance of infection and healing of damaged tissues. However, when either overly or insufficiently robust, inflammation can drive further cell stress, tissue damage, organ dysfunction and death through a feed-forward process of inflammation -> damage -> inflammation. To address this complexity, we have obtained extensive datasets regarding the dynamics of inflammation in cells, animals and patients, and created data-driven and mechanistic computational simulations of inflammation and its recursive effects on tissue, organ and whole-organism (patho)physiology. Through this approach, we have discerned key regulatory mechanisms, recapitulated in silico key features of clinical trials for acute inflammation and captured diverse, patient-specific outcomes. These insights may allow for the determination of individual-specific tolerances to illness and adversity, thereby defining the role of inflammation in resilience. PMID- 25285196 TI - Resilience in the aftermath of war trauma: a critical review and commentary. AB - The resilience construct has received a great deal of attention as a result of the long wars in Iraq and Afghanistan. The discourse about resilience, especially the promise of promoting it and mitigating risk for serious post-traumatic negative outcomes among service members and veterans, is hopeful and encouraging. Remarkably, most service members exposed to horrific war trauma are not incapacitated by the experience. Yet, resilience is elusive and fleeting for many veterans of war. In this paper, I address some of the complexities about resilience in the context of exposure to war stressors and I offer some assumptions and heuristics that stem from my involvement in the dialogue about resilience and from experiences helping prevent post-traumatic stress disorder among active-duty service members with military trauma. My goal is to use my observations and applied experiences as an instructive context to raise critical questions for the field about resilience in the face of traumatic life-events. PMID- 25285197 TI - Sleep and inflammation in resilient aging. AB - Sleep quality is important to health, and increasingly viewed as critical in promoting successful, resilient aging. In this review, the interplay between sleep and mental and physical health is considered with a focus on the role of inflammation as a biological pathway that translates the effects of sleep on risk of depression, pain and chronic disease risk in aging. Given that sleep regulates inflammatory biologic mechanisms with effects on mental and physical health outcomes, the potential of interventions that target sleep to reduce inflammation and promote health in aging is also discussed. PMID- 25285198 TI - The hypothalamic-pituitary-adrenal-leptin axis and metabolic health: a systems approach to resilience, robustness and control. AB - Glucocorticoids contribute to obesity and metabolic syndrome; however, the mechanisms are unclear, and prognostic measures are unavailable. A systems level understanding of the hypothalamic-pituitary-adrenal (HPA)-leptin axis may reveal novel insights. Eighteen obese premenopausal women provided blood samples every 10 min over 24 h, which were assayed for cortisol, adrenocorticotropin releasing hormone (ACTH) and leptin. A published personalized HPA systems model was extended to incorporate leptin, yielding three parameters: (i) cortisol inhibitory feedback signalling, (ii) ACTH-adrenal signalling, and (iii) leptin cortisol antagonism. We investigated associations between these parameters and metabolic risk profiles: fat and lean body mass (LBM; using dual-energy X-ray absorptiometry), and insulin resistance. Decreased cortisol inhibitory feedback signalling was significantly associated with greater fat (kg; p = 0.01) and insulin resistance (p = 0.03) but not LBM. Leptin significantly antagonized cortisol dynamics in eight women, who exhibited significantly lower 24 h mean leptin levels, LBM and higher ACTH-adrenal signalling nocturnally (all p < 0.05), compared with women without antagonism. Traditional neuroendocrine measures did not predict metabolic health, whereas a dynamic systems approach revealed that lower central inhibitory cortisol feedback signalling was significantly associated with greater metabolic risk. While exploratory, leptin-cortisol antagonism may reflect a 'neuroendocrine starvation' response. PMID- 25285200 TI - The mathematician's control toolbox for management of type 1 diabetes. AB - Blood glucose levels are controlled by well-known physiological feedback loops: high glucose levels promote insulin release from the pancreas, which in turn stimulates cellular glucose uptake. Low blood glucose levels promote pancreatic glucagon release, stimulating glycogen breakdown to glucose in the liver. In healthy people, this control system is remarkably good at maintaining blood glucose in a tight range despite many perturbations to the system imposed by diet and fasting, exercise, medications and other stressors. Type 1 diabetes mellitus (T1DM) results from loss of the insulin-producing cells of the pancreas, the beta cells. These cells serve as both sensor (of glucose levels) and actuator (insulin/glucagon release) in a control physiological feedback loop. Although the idea of rebuilding this feedback loop seems intuitively easy, considerable control mathematics involving multiple types of control schema were necessary to develop an artificial pancreas that still does not function as well as evolved control mechanisms. Here, we highlight some tools from control engineering used to mimic normal glucose control in an artificial pancreas, and the constraints, trade-offs and clinical consequences inherent in various types of control schemes. T1DM can be viewed as a loss of normal physiologic controls, as can many other disease states. For this reason, we introduce basic concepts of control engineering applicable to understanding pathophysiology of disease and development of physiologically based control strategies for treatment. PMID- 25285202 TI - The net return from animal activity in agro-ecosystems: trading off benefits from ecosystem services against costs from crop damage. AB - Animals provide benefits to agriculture through the provision of ecosystem services, but also inflict costs such as damaging crops. These benefits and costs are mostly examined independently, rather than comparing the trade-offs of animal activity in the same system and quantifying the net return from beneficial minus detrimental activities. Here, I examine the net return associated with the activity of seed-eating birds in almond orchards by quantifying the economic costs and benefits of bird consumption of almonds. Pre-harvest, the consumption of harvestable almonds by birds cost growers AUD$57.50 ha (-1) when averaged across the entire plantation. Post-harvest, the same bird species provide an ecosystem service by removing mummified nuts from trees that growers otherwise need to remove to reduce threats from fungal infection or insect pest infestations. The value of this ecosystem service ranged from AUD$82.50 ha (-1) $332.50 ha (-1) based on the replacement costs of mechanical or manual removal of mummified nuts, respectively. Hence, bird consumption of almonds yielded a positive net return of AUD$25-$275 ha (-1) averaged across the entire plantation. However, bird activity varied spatially resulting in positive net returns occurring primarily at the edges of crops where activity was higher, compared to negative net returns in crop interiors. Moreover, partial mummy nut removal by birds meant that bird activity may only reduce costs to growers rather than replace these costs completely. Similar cost-benefit trade-offs exist across nature, and quantifying net returns can better inform land management decisions such as when to control pests or promote ecosystem service provision. PMID- 25285201 TI - Glucocorticoid-related predictors and correlates of post-traumatic stress disorder treatment response in combat veterans. AB - The identification of biomarkers for post-traumatic stress disorder (PTSD) and resilience/recovery is critical for advancing knowledge about pathophysiology and treatment in trauma-exposed persons. This study examined a series of glucocorticoid-related biomarkers prior to and in response to psychotherapy. Fifty-two male and female veterans with PTSD were randomized 2 : 1 to receive either prolonged exposure (PE) therapy or a weekly minimal attention (MA) intervention for 12 consecutive weeks. Psychological and biological assessments were obtained prior to and following treatment and after a 12-week naturalistic follow-up. Response was defined dichotomously as no longer meeting criteria for PTSD at post-treatment based on the Clinician Administered PTSD Scale for DSM-IV (CAPS). Clinical improvement on the CAPS was apparent for both PE and MA, with no significant difference according to treatment condition. Biomarkers predictive of treatment gains included the BCLI polymorphism of the glucocorticoid receptor gene. Additional predictors of treatment response were higher bedtime salivary cortisol and 24 h urinary cortisol excretion. Pre-treatment plasma dehydroepiandrosterone/cortisol ratio and neuropetide Y (NPY) levels were predictors of reductions in PTSD symptoms, and, for NPY only, of other secondary outcomes as well, including anxiety and depression ratings. Glucocorticoid sensitivity changed in association with symptom change, reflecting clinical state. It is possible to distinguish prognostic and state biomarkers of PTSD using a longitudinal approach in the context of treatment. Identified markers may also be relevant to understanding mechanisms of action of symptom reduction. PMID- 25285203 TI - Mutation extraction tools can be combined for robust recognition of genetic variants in the literature. AB - As the cost of genomic sequencing continues to fall, the amount of data being collected and studied for the purpose of understanding the genetic basis of disease is increasing dramatically. Much of the source information relevant to such efforts is available only from unstructured sources such as the scientific literature, and significant resources are expended in manually curating and structuring the information in the literature. As such, there have been a number of systems developed to target automatic extraction of mutations and other genetic variation from the literature using text mining tools. We have performed a broad survey of the existing publicly available tools for extraction of genetic variants from the scientific literature. We consider not just one tool but a number of different tools, individually and in combination, and apply the tools in two scenarios. First, they are compared in an intrinsic evaluation context, where the tools are tested for their ability to identify specific mentions of genetic variants in a corpus of manually annotated papers, the Variome corpus. Second, they are compared in an extrinsic evaluation context based on our previous study of text mining support for curation of the COSMIC and InSiGHT databases. Our results demonstrate that no single tool covers the full range of genetic variants mentioned in the literature. Rather, several tools have complementary coverage and can be used together effectively. In the intrinsic evaluation on the Variome corpus, the combined performance is above 0.93 in F measure, while in the extrinsic evaluation the combined recall performance is above 0.71 for COSMIC and above 0.62 for InSiGHT, a substantial improvement over the performance of any individual tool. Based on the analysis of these results, we suggest several directions for the improvement of text mining tools for genetic variant extraction from the literature. PMID- 25285199 TI - Biological mechanisms underlying the role of physical fitness in health and resilience. AB - Physical fitness, achieved through regular exercise and/or spontaneous physical activity, confers resilience by inducing positive psychological and physiological benefits, blunting stress reactivity, protecting against potentially adverse behavioural and metabolic consequences of stressful events and preventing many chronic diseases. In this review, we discuss the biological mechanisms underlying the beneficial effects of physical fitness on mental and physical health. Physical fitness appears to buffer against stress-related disease owing to its blunting/optimizing effects on hormonal stress responsive systems, such as the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. This blunting appears to contribute to reduced emotional, physiological and metabolic reactivity as well as increased positive mood and well-being. Another mechanism whereby regular exercise and/or physical fitness may confer resilience is through minimizing excessive inflammation. Chronic psychological stress, physical inactivity and abdominal adiposity have been associated with persistent, systemic, low-grade inflammation and exert adverse effects on mental and physical health. The anti-inflammatory effects of regular exercise/activity can promote behavioural and metabolic resilience, and protect against various chronic diseases associated with systemic inflammation. Moreover, exercise may benefit the brain by enhancing growth factor expression and neural plasticity, thereby contributing to improved mood and cognition. In summary, the mechanisms whereby physical fitness promotes increased resilience and well-being and positive psychological and physical health are diverse and complex. PMID- 25285204 TI - Abnormal hemostatic function one year after orthotopic liver transplantation can be fully attributed to endothelial cell activation. AB - BACKGROUND: The long-term risk of thrombotic and vascular complications is elevated in liver transplant recipients compared to the general population. Patients with cirrhosis are in a hypercoagulable status during and directly after orthotopic liver transplantation, but it is unclear whether this hypercoagulability persists over time. AIM: We aimed to investigate the hemostatic status of liver transplant recipients one year after transplantation. METHODS: We prospectively collected blood samples of 15 patients with a functioning graft one year after orthotopic liver transplantation and compared the hemostatic status of these patients with that of 30 healthy individuals. RESULTS: Patients one year after liver transplantation had significantly elevated plasma levels of von Willebrand factor (VWF). Thrombin generation, as assessed by the endogenous thrombin potential, was decreased in patients, which was associated with increased plasma levels of the natural anticoagulants antithrombin and tissue factor pathway inhibitor. Plasma fibrinolytic potential was significantly decreased in patients and correlated inversely with levels of plasminogen activator inhibitor-1. CONCLUSION: One year after liver transplantation, liver graft recipients have a dysregulated hemostatic system characterised by elevation of plasma levels of endothelial-derived proteins. Increased levels of von Willebrand factor and decreased fibrinolytic potential may (in part) be responsible for the increased risk for vascular disease seen in liver transplant recipients. PMID- 25285205 TI - Thiolation-enhanced substrate recognition by D-alanyl carrier protein ligase DltA from Bacillus cereus. AB - D-alanylation of the lipoteichoic acid on Gram-positive cell wall is dependent on dlt gene-encoded proteins DltA, DltB, DltC and DltD. The D-alanyl carrier protein ligase DltA, as a remote homolog of acyl-(coenzyme A) (CoA) synthetase, cycles through two active conformations for the catalysis of adenylation and subsequent thiolation of D-alanine (D-Ala). The crystal structure of DltA in the absence of any substrate was observed to have a noticeably more disordered pocket for ATP which would explain why DltA has relatively low affinity for ATP in the absence of any D-alanyl carrier. We have previously enabled the thiolation of D-alanine in the presence of CoA as the mimic of D-alanyl carrier protein DltC which carries a 4'-phosphopantetheine group on a serine residue. Here we show that the resulting Michaelis constants in the presence of saturating CoA for both ATP and D-alanine were reduced more than 10 fold as compared to the values obtained in the absence of CoA. The presence of CoA also made DltA ~100-fold more selective on D-alanine over L-alanine. The CoA-enhanced substrate recognition further implies that the ATP and D-alanine substrates of the adenylation reaction are incorporated when the DltA enzyme cycles through its thiolation conformation. PMID- 25285206 TI - enhancedGraphics: a Cytoscape app for enhanced node graphics. AB - enhancedGraphics ( http://apps.cytoscape.org/apps/enhancedGraphics) is a Cytoscape app that implements a series of enhanced charts and graphics that may be added to Cytoscape nodes. It enables users and other app developers to create pie, line, bar, and circle plots that are driven by columns in the Cytoscape Node Table. Charts are drawn using vector graphics to allow full-resolution scaling. PMID- 25285207 TI - The effects of extremes of pH on the growth and transcriptomic profiles of three haloarchaea. AB - The halophilic archaea (haloarchaea) live in saline environments which are found across the globe. In addition to salinity, these niches can be quite dynamic and experience extreme conditions such as low oxygen content, radiation (gamma and UV), pH and temperature. However, of all the naturally occurring stresses faced by the haloarchaea, only one, pH, has not been previously reported on. Therefore, we endeavored to determine the responses of the transcriptomes of three haloarchaea (Hla, Hvo, and NRC-1) to growth under acidic and alkaline pH. Our observations showed that the transcriptomes of Hvo and NRC-1 respond in a similar manner to each other as well as other prokaryotes when grown in an acidic environment, while the pattern for Hla was dissimilar. For alkaline stress, all three haloarchaea responded in a manner similar to well-studied archaea and bacteria and had four-times more significantly regulated transcripts in common, compared to acidic growth. Additionally, we performed an analysis on the changes in the transcriptomes of the three haloarchaea when shifting from one pH extreme to the other. The results showed that the transcriptomes of all three haloarchaea respond more similarly when moving from alkaline to acidic conditions compared to moving from an acidic to alkaline environment. Interestingly, our studies also showed that individual genes of multiple paralogous gene families ( tbp, tfb, orc/ cdc6, etc.) found in the haloarchaea were regulated under specific stresses thereby providing evidence that they modulate the response to various environmental stresses. The studies described here are the first to catalog the changes in the haloarchaeal transcriptomes under growth in extreme pH and help us understand how life is able to thrive under all conditions present on Earth and, if present, on extraterrestrial bodies as well. PMID- 25285208 TI - shinyMethyl: interactive quality control of Illumina 450k DNA methylation arrays in R. AB - We present shinyMethyl, a Bioconductor package for interactive quality control of DNA methylation data from Illumina 450k arrays. The package summarizes 450k experiments into small exportable R objects from which an interactive interface is launched. Reactive plots allow fast and intuitive quality control assessment of the samples. In addition, exploration of the phenotypic associations is possible through coloring and principal component analysis. Altogether, the package makes it easy to perform quality assessment of large-scale methylation datasets, such as epigenome-wide association studies or the datasets available through The Cancer Genome Atlas portal. The shinyMethyl package is implemented in R and available via Bioconductor. Its development repository is at https://github.com/jfortin1/shinyMethyl. PMID- 25285209 TI - A revised method for measuring distraction by tactile stimulation. AB - Sensory hypersensitivity (SH) refers to the tendency to attend to subtle stimuli, to persist in attending to them, and to find them noxious. SH is relatively common in several developmental disorders including Tourette Syndrome and Chronic Tic Disorder (TS/CTD). This study was an attempt to quantify the extent to which a mild tactile stimulus distracts one's attention in TS/CTD. Fourteen adults with TS/CTD and 14 tic-free control subjects completed questionnaires regarding SH and ADHD, and TS/CTD subjects completed self-report measures of current and past tic disorder symptoms and of current obsessions and compulsions. All subjects performed a sustained attention choice reaction time task during alternating blocks in which a mildly annoying stimulus (von Frey hair) was applied to the ankle ("ON") or was not applied ("OFF"). We present here the clinical and cognitive task data for each subject. PMID- 25285210 TI - Self-assembled insect muscle bioactuators with long term function under a range of environmental conditions. AB - The use of mammalian muscles as device actuators is severely limited by their sensitivity to environmental conditions and short lifetime. To overcome these limitations insect muscle stem cells were used to generate organized 3D muscle constructs with significant enhancements in environmental tolerance and long term function. These tissues self-assembled, self-repaired, survived for months in culture without media replenishment and produced stresses of up to 2 kPa, all under ambient conditions. The muscle tissues continued to function for days even under biologically extreme temperature and pH. Furthermore, the dimensions and geometry of these tissues can be easily scaled to MEMS or meso-scale devices. The versatility, environmental hardiness and long term function provide a new path forward for biological actuators for device needs. PMID- 25285211 TI - Retraction: Measles-mumps-rubella vaccination timing and autism among young African American boys: a reanalysis of CDC data. PMID- 25285212 TI - The feasibility of using dose-banded syringes to improve the safety and availability of patient-controlled opioid analgesic infusions in children. PMID- 25285214 TI - The use of haplotype-specific transcripts improves sample annotation consistency. AB - BACKGROUND: Exact sample annotation in expression microarray datasets is essential for any type of pharmacogenomics research. RESULTS: Candidate markers were explored through the application of Hartigans' dip test statistics to a publically available human whole genome microarray dataset. The marker performance was tested on 188 serial samples from 53 donors and of variable tissue origin from five public microarray datasets. A qualified transcript marker panel consisting of three probe sets for human leukocyte antigens HLA-DQA1 (2 probe sets) and HLA-DRB4 identified sample donor identifier inconsistencies in six of the 188 test samples. About 3% of the test samples require root-cause analysis due to unresolvable inaccuracies. CONCLUSIONS: The transcript marker panel consisting of HLA-DQA1 and HLA-DRB4 represents a robust, tissue-independent composite marker to assist control donor annotation concordance at the transcript level. Allele-selectivity of HLA genes renders them good candidates for "fingerprinting" with donor specific expression pattern. PMID- 25285213 TI - Nanostructured diamond coatings for orthopaedic applications. AB - With increasing numbers of orthopaedic devices being implanted, greater emphasis is being placed on ceramic coating technology to reduce friction and wear in mating total joint replacement components, in order to improve implant function and increase device lifespan. In this chapter, we consider ultra-hard carbon coatings, with emphasis on nanostructured diamond, as alternative bearing surfaces for metallic components. Such coatings have great potential for use in biomedical implants as a result of their extreme hardness, wear resistance, low friction and biocompatibility. These ultra-hard carbon coatings can be deposited by several techniques resulting in a wide variety of structures and properties. PMID- 25285215 TI - Acute affective responses to prescribed and self-selected exercise sessions in adolescent girls: an observational study. AB - BACKGROUND: Positive affective responses can lead to improved adherence to exercise. This study sought to examine the affective responses and exercise intensity of self-selected exercise in adolescent girls. METHODS: An observational study where twenty seven females (Age M = 14.6 +/- 0.8 years) completed three 20-minute exercise sessions (2 self-selected and 1 prescribed intensity) and a graded exercise test. The intensity of the prescribed session was matched to the first self-selected session. Intensity, affective responses and ratings of perceived exertion were recorded throughout the sessions and differences examined. Repeated measures ANOVAs were conducted to examine differences. RESULTS: There were no significant differences in intensity between the prescribed and self-selected sessions, but affective responses were significantly more positive (p < .01) during the self-selected session. Ratings of perceived exertion were significantly lower (p < .01) during the self-selected session than the prescribed session. On average participants worked at 72% [Formula: see text] peak; well within the intensity recommended by the American College of Sports Medicine. CONCLUSION: Even though the intensity did not differ between the self-selected and prescribed sessions, there was a significant impact on affective responses, with more positive affective responses being elicited in the self-selected session. This highlights the importance of autonomy and self paced exercise for affective responses and may have potential long-term implications for adherence. PMID- 25285216 TI - The electronic cigarette: a knight in shining armour or a Trojan horse? AB - Electronic cigarettes have caused a sharp debate in the public health community, with some promoting them as a means of harm reduction for tobacco users and some taking a strong stand against them because of fear of renormalising smoking behaviour and interrupting tobacco control progress. People with mental health problems smoke at high rates and e-cigarettes seem a potentially attractive method of cessation in this population, and their use should be studied carefully. PMID- 25285217 TI - Using virtual worlds for role play simulation in child and adolescent psychiatry: an evaluation study. AB - Aims and method To develop and evaluate a novel teaching session on clinical assessment using role play simulation. Teaching and research sessions occurred sequentially in computer laboratories. Ten medical students were divided into two online small-group teaching sessions. Students role-played as clinician avatars and the teacher played a suicidal adolescent avatar. Questionnaire and focus group methodology evaluated participants' attitudes to the learning experience. Quantitative data were analysed using SPSS, qualitative data through nominal group and thematic analyses. Results Participants reported improvements in psychiatric skills/knowledge, expressing less anxiety and more enjoyment than role-playing face to face. Data demonstrated a positive relationship between simulator fidelity and perceived utility. Some participants expressed concern about added value over other learning methods and non-verbal communication. Clinical implications The study shows that virtual worlds can successfully host role play simulation, valued by students as a useful learning method. The potential for distance learning would allow delivery irrespective of geographical distance and boundaries. PMID- 25285218 TI - Delayed discharge from intellectual disability in-patient units. AB - Aims and method We undertook a cross-sectional service evaluation of the reasons and extent of delay in the discharge process in an intellectual disability hospital over a 12-month period. Delays at each stage of the discharge process are also quantified in this study. Results We found that discharge was delayed for 29% of patients during the study period. The majority (78.5%) was due to awaiting completion of assessment of future care needs and waiting for public funding. Clinical implications Commissioners (health and social), provider trusts, regulators and community providers should consider the reasons for delay in the discharge process and adopt a whole systems approach to discharge planning. This is highly relevant in light of recommendations by the Department of Health following the Winterbourne View scandal, which has raised concern about patients staying in intellectual disability in-patient units too long and for the wrong reasons. PMID- 25285219 TI - Severe and enduring mental health problems within an established substance misuse treatment partnership. AB - Aims and method The study reports findings of an investigation into the presence of severe and enduring mental health problems within the four statutory and non statutory teams of an established substance misuse treatment partnership. Results Of a total of 772 clients in the four teams surveyed, 69 (8.9%) were identified as having severe and enduring mental health problems and problem substance use in the past 12 months. Alcohol was the most prevalent substance used by this predominantly male group. Different rates were found across the four teams, with higher numbers in the non-statutory teams. The clients displayed significant levels of self-harm and suicide risk and were responsible for 131 acute service contacts over the past 12 months. Clinical implications Clients with severe and enduring mental health problems engaged with substance misuse services display high levels of complex need. It is important to identify the best and most effective service response to this group. PMID- 25285220 TI - A new service model for the treatment of severe anorexia nervosa in the community: the Anorexia Nervosa Intensive Treatment Team. AB - Aims and method A community intensive treatment service for severe anorexia nervosa is described. The service is multidisciplinary but driven by a focus on psychological formulation. Psychological and dietetic interventions are grounded in a process of active risk management. Evaluations of safety, cost and acceptability of the service are described. Results Patients are highly satisfied with their care. A relatively low mortality rate for such a high-risk population was observed. In-patient bed use and costs were substantially reduced. Clinical implications There is a case for greater use of intensive community care for patients with severe anorexia nervosa, as it can be acceptable to patients, relatively safe and cost less than admission. PMID- 25285221 TI - Electronic cigarettes in mental health settings - solving a conundrum? AB - Electronic cigarettes (e-cigarettes), have recently been the focus of much attention and debate. This article attempts to highlight their relevance and potential importance for mental health settings, with a focus on in-patient units. To do so, the complexities involved in smoking among people with mental disorder, the debate surrounding e-cigarettes, and their potential to be utilised as a smoking cessation or temporary abstinence aid in the context of smoke-free policies and new National Institute for Health and Care Excellence guidance for smoking cessation in mental health settings, will be discussed and synthesised below. PMID- 25285222 TI - Private in-patient psychiatry in the USA. AB - The US healthcare system is in the midst of major changes driven by four forces: the growing consensus in the country that the current system is financially unsustainable; managed care and parity legislation; the Affordable Care Act 2010; and the ageing of the 'baby boomer' generation. How these forces will combine and interact is unclear. The current state of in-patient psychiatric care and trends affecting the private practice of in-patient psychiatry over the next few years will be described. PMID- 25285223 TI - Teaching and learning the mental state exam in an integrated medical school. Part I: Student perceptions. AB - Aims and method To investigate medical students' performance at and perceptions of the mental state examination (MSE) at a medical school with a modern integrated curriculum. We undertook an evaluative case study comprising a survey and analysis of performance data. The study is presented in two parts: part 1 discusses the students' perceptions of the MSE and the teaching, learning and practising of it. Results Most students in the study group considered the MSE an important examination in medicine. Other perceptions grouped in themes are presented. Unsurprisingly, most students found psychiatric attachments the most useful part of the course for learning about the MSE. About a half of students had witnessed an MSE being undertaken in clinical practice. Clinical implications Although students appear to recognise the importance of this examination in medicine, the teaching and learning of it possibly needs greater emphasis in the undergraduate curriculum, and teaching and learning opportunities improved throughout the course. PMID- 25285224 TI - Teaching and learning the mental state exam in an integrated medical school. Part II: Student performance. AB - Aims and method To investigate medical students' performance at and perceptions of the mental state examination (MSE) at a medical school with a modern integrated curriculum. We undertook an evaluative case study comprising a survey and analysis of performance data. The study is presented in two parts: part 2 reports the students' performance data as assessed by integrated structured clinical examination (ISCE). Results About a third of students (32.7%) thought that the MSE ISCE was more difficult than the non-MSE ISCE from the questionnaire data. The evidence from the ISCE performance data indicates that there are no significant differences between the scores of students in the MSE station and the non-MSE stations. Clinical implications Most studnets do not find the MSE ISCE station more difficult than other ISCE stations. Perhaps therefore students should be reassured that assessments in psychiatry are just like other assessments in medicine. For some students, however, performing at the MSE ISCE station is a more complex challenge. PMID- 25285225 TI - Bulletin comment: Smoking, mental ill health and electronic cigarettes. PMID- 25285226 TI - How can a young person wait over 90 hours in an emergency department for a bed? PMID- 25285227 TI - I prescribe, therefore I am? PMID- 25285228 TI - The capacity to attain subjectivity and emotion: the value of continuity of care. PMID- 25285229 TI - Challenges and opportunities in (neuro)psychiatry. PMID- 25285230 TI - Reflections on the management of medically unexplained symptoms. PMID- 25285232 TI - Reprogramming immune responses via microRNA modulation. AB - It is becoming increasingly clear that there are unique sets of miRNAs that have distinct governing roles in several aspects of both innate and adaptive immune responses. In addition, new tools allow selective modulation of the expression of individual miRNAs, both in vitro and in vivo. Here, we summarize recent advances in our understanding of how miRNAs drive the activity of immune cells, and how their modulation in vivo opens new avenues for diagnostic and therapeutic interventions in multiple diseases, from immunodeficiency to cancer. PMID- 25285233 TI - Tai Ji Quan for the aging cancer survivor: Mitigating the accelerated development of disability, falls, and cardiovascular disease from cancer treatment. AB - Currently there are more than 13.7 million cancer survivors living in the U.S., and that figure is projected to increase by 31% in the next decade, adding another 4 million cancer survivors into the healthcare system. Cancer is largely a disease of aging, and the aging of the population will sharply raise the proportion of older cancer survivors, many of whom will be long-term survivors (5+ years post diagnosis). This review will address the potential utility of exercise to address three health problems that are of particular concern for the aging cancer survivor and the healthcare system, i.e., disability, falls, and cardiovascular disease, because the development of these age-related problems may be accelerated by cancer treatment. While there are many different modes of exercise that each produce specific adaptations, Tai Ji Quan may be a particularly suitable strategy to mitigate the development of age- and cancer treatment-related problems. Based on studies in older adults without cancer, Tai Ji Quan produces musculoskeletal and cardiometabolic adaptations and is more easily performed by older adults due to its low energy cost and slower movement patterns. Since cancer survivors are mostly older, inactive, and often physically limited by the lingering side effects of treatment, they need to engage in safe, practical, and effective modes of exercise. The dearth of published controlled trials examining the efficacy of Tai Ji Quan to mitigate cancer-treatment-related musculoskeletal and cardiovascular side effects points to ample research opportunities to explore the application of this non-Western exercise modality to improve long-term outcomes for aging cancer survivors. PMID- 25285234 TI - Redefining Human Vitamin D Sufficiency: Back to the Basics. PMID- 25285235 TI - Nurses' uniforms: How many bacteria do they carry after one shift? AB - This pilot study investigated the pathogens that nurses are potentially bringing into the public and their home when they wear work uniforms outside of the work environment. To achieve this, sterilized uniforms were distributed to 10 nurses at a local hospital in Washington State at the beginning of their shift. Worn uniforms were collected at the end of the shifts and sent to a laboratory for analysis. Four tests were conducted: 1) a heterotrophic growth plate count, 2) methicillin-resistant Staphylococcus aureus (MRSA) growth, 3) vancomycin resistant Enterococci (VRE), and 4) identification of the heterotrophic plate counts. Each participant completed a questionnaire and a survey. The results showed that the average bacteria colony growth per square inch was 1,246 and 5,795 for day and night shift, respectively. After 48 h, MRSA positives were present on 4 of the day shift and 3 of the night shift uniforms. Additional bacteria identified include: Bacillus sp., Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, and Micrococcus roseus. The significant presence of bacteria on the uniforms 48 h after the shift ended necessitates further study, discussions and policy consideration regarding wearing health care uniforms outside of the work environment. PMID- 25285236 TI - The Myth of Community Differences as the Cause of Variations Among IRBs. AB - BACKGROUND: Although variations among institutional review boards (IRBs) have been documented for 30 years, they continue, raising crucial questions as to why they persist as well as how IRBs view and respond to these variations. METHODS: In-depth, 2-hour interviews were conducted with 46 IRB chairs, administrators, and members. The leadership of 60 U.S. IRBs were contacted (every fourth one in the list of the top 240 institutions by NIH funding). IRB leaders from 34 of these institutions were interviewed (response rate = 55%). RESULTS: The interviewees suggest that differences often persist because IRBs think these are legitimate, and regulations permit variations due to differing "community values." Yet, these variations frequently appear to stem more from differences in institutional and subjective personality factors, and from "more eyes" examining protocols, trying to foresee all potential future logistical problems, than from the values of the communities from which research participants are drawn. However, IRBs generally appear to defend these variations as reflecting underlying differences in community norms. CONCLUSIONS: These data pose critical questions for policy and practice. Attitudinal changes and education among IRBs, principal investigators (PIs), policymakers, and others and research concerning these issues are needed. PMID- 25285237 TI - weHelp: A Reference Architecture for Social Recommender Systems. AB - Recommender systems have become increasingly popular. Most of the research on recommender systems has focused on recommendation algorithms. There has been relatively little research, however, in the area of generalized system architectures for recommendation systems. In this paper, we introduce weHelp: a reference architecture for social recommender systems - systems where recommendations are derived automatically from the aggregate of logged activities conducted by the system's users. Our architecture is designed to be application and domain agnostic. We feel that a good reference architecture will make designing a recommendation system easier; in particular, weHelp aims to provide a practical design template to help developers design their own well-modularized systems. PMID- 25285238 TI - Nef-M1, a CXCR4 Peptide Antagonist, Enhances Apoptosis and Inhibits Primary Tumor Growth and Metastasis in Breast Cancer. AB - Results from studies with animal models suggest that, in many cancers, CXCR4 is an important therapeutic target and that CXCR4 antagonists may be promising treatments for primary cancers and for metastases. The Nef protein effectively competes with CXCR4's natural ligand, SDF-1alpha, and induces apoptosis. As described in this report, the Nef-M1 peptide (Nef protein amino acids 50 - 60) inhibits primary tumor growth and metastasis of breast cancer (BC). Four BC cell lines (MDA-MB-231, MDA-MB-468, MCF 7, and DU4475) and primary human mammary epithelium (HME) cells were evaluated for their response to the Nef protein and to the Nef-M1 peptide. The presence of CXCR4 receptors in these cells was determined by RT-PCR, Western blot (WB), and immunohistochemical analyses. The apoptotic effect of Nef-M1 was assessed by terminal transferase dUTP nick-end labeling (TUNEL). WBs was used to assess caspase 3 activation. BC xenografts grown in SCID mice were evaluated for the presence of CXCR4 and for their metastatic potential. CXCR4 was presented in MDA-MB-231, MCF 7, and DU 4475 BC cells but not in MDA-MB-468 BC or HME cells. Cells expressing CXCR4 and treated with Nef-M1 peptide or the Nef protein had higher rates of apoptosis than untreated cells. Caspase-3 activation increased in MDA-MB 231 cells treated with the Nef protein, the Nef 41 - 60 peptide, or Nef-M1. Nef-M1, administered to mice starting at the time of xenograft implantation, inhibited growth of primary tumors and metastatic spread. Untreated mice developed diffuse intraperitoneal metastases. We conclude that, in BCs, Nef-M1, through interaction with CXCR4, inhibits primary tumor growth and metastasis by causing apoptosis. PMID- 25285239 TI - Partner-Specific Anger Management as a Mediator of the Relation between Mindfulness and Female Perpetrated Dating Violence. AB - OBJECTIVE: The current study examined the relationship between facets of mindfulness, partner-specific anger management, and female perpetrated dating violence. In addition, we examined whether anger management mediated the relation between mindfulness and psychological and physical aggression perpetration. METHOD: Female undergraduate students (N = 481) completed self-report measures of mindfulness, partner-specific anger management, and dating violence perpetration. RESULTS: The mindfulness facets of nonreactivity, act with awareness, and nonjudging, as well as anger management, were associated with dating violence perpetration. After controlling for dating violence victimization, structural equation modeling (SEM) demonstrated that anger management fully mediated the relation between nonreactivity and act with awareness and psychological and physical aggression perpetration. Moreover, specific anger management components (escalating strategies and negative attributions) were largely responsible for the mediation findings. CONCLUSIONS: This is one of the first studies to demonstrate a relation between mindfulness and aggression perpetration, and the first to examine theoretically proposed mechanisms responsible for this relationship. Dating violence prevention programs may benefit from including mindfulness-based interventions to improve anger management and reduce aggressive behavior. PMID- 25285240 TI - A Proposal for an Individualized Pharmacogenetic-Guided Warfarin Dosage Regimen for Puerto Rican Patients Commencing Anticoagulation Therapy. AB - Warfarin is the current standard of care in oral anticoagulation therapy. It is commonly prescribed to treat venous thromboembolism, pulmonary embolism, acute myocardial infarction, and to decrease the risk of stroke in atrial fibrillation. Warfarin therapy is challenging because of marked and often unpredictable inter individual dosing variations that effectively reach and maintain adequate anticoagulation. Several researchers have developed pharmacogenetic-guided maintenance dose algorithms that incorporate genetics and individual patient characteristics. However, there is limited information available concerning dosing during warfarin initiation. This is considered the most clinically challenging therapeutic phase. In such, the risk of recurrent thromboembolism and hemorrhage are elevated. The objective of this retrospective study is to predict the individual initial doses for Puerto Rican patients (n=175) commencing anticoagulation therapy at Veterans Affairs Caribbean Healthcare System (VACHS) using pharmacogenetic/pharmacokinetic-driven model. A pharmacogenetic driven model (R2=0.4809) was developed in Puerto Rican patients and combined with pharmacokinetic formulas that enabled us to predict the individual initial doses for patients (n=121) commencing anticoagulation therapy. WinNonlin(r) pharmacokinetic-pharmacodynamic simulations were carried out to determine the predictability of this model. This model demonstrated promising results with few (n=10) simulations outside of their respective therapy range. A customized pharmacogenetic-based warfarin maintenance dose algorithm (R2=0.7659) was developed in a derivation cohort of 131 patients. The predictability of this developed pharmacogenetic algorithm was compared with the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm and it demonstrated superior predictability within our study population. PMID- 25285241 TI - Triple Negative Breast Cancer - An Overview. AB - Triple Negative Breast Cancer (TNBC) is a heterogeneous disease that based on immunohistochemistry (IHC) is estrogen receptor (ER) negative, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative. TNBC is typically observed in young AA women and Hispanic women who carry a mutation in the BRCA1 gene. TNBC is characterized by a distinct molecular profile, aggressive nature and lack of targeted therapies. The purpose of this article is to review the current and future novel signalling pathways as therapeutic approaches to TNBC. Recent Identification of a new BRCA1 trafficking pathway holds promise in the future for the development of targeted therapies for TNBC. PMID- 25285242 TI - Photo-selective delivery of model therapeutics from hydrogels. AB - Hydrogels are commonly used in biomedical applications to sequester and release therapeutics. Covalently tethering therapeutic agents to a hydrogel through a degradable linkage allows their controlled release, but temporally separating the release of multiple therapeutics from a single hydrogel remains a major challenge. In this report, we use of a series of photodegradable ortho nitrobenzyl (o-NB) groups with varying structures to link model therapeutic agents (fluorescein, rhodamine and aminomethylcoumarin acetate) to poly(ethylene glycol) macromers. We polymerized the macromers into hydrogel networks via redox polymerization and quantified the apparent rate constants of degradation (kapp) of each of the photoreleasable compounds. By exploiting differences in reactivity of the different o-NB groups, we are able to create complex, multi-stage release profiles. We demonstrate the ability to switch between concurrent and biased release of model therapeutics simply by switching wavelengths. We also demonstrate a complex four-stage release profile in which the release of three separate model therapeutics is controlled by varying wavelength, intensity and exposure time. This is the first report of photo-selective release of therapeutics from a hydrogel, allowing user-dictated real-time spatial and temporal control over multiple chemical signals in a cell microenvironment in 2D and 3D. PMID- 25285243 TI - Magnetic Resonance Imaging Estimation of Longitudinal Relaxation Rate Change (DeltaR1) in Dual Gradient Echo Sequences Using an Adaptive Model. AB - Magnetic Resonance Imaging (MRI) estimation of contrast agent concentration in fast pulse sequences such as Dual Gradient Echo (DGE) imaging is challenging. An Adaptive Neural Network (ANN) was trained with a map of contrast agent concentration estimated by Look-Locker (LL) technique (modified version of inversion recovery imaging) as a gold standard. Using a set of features extracted from DGE MRI data, an ANN was trained to create a voxel based estimator of the time trace of CA concentration. The ANN was trained and tested with the DGE and LL information of six Fisher rats using a K-Fold Cross-Validation (KFCV) method with 60 folds and 10500 samples. The Area Under the Receiver Operator Characteristic Curve (AUROC) for 60 folds was used for training, testing and optimization of the ANN. After training and optimization, the optimal ANN (4:7:5:1) produced maps of CA concentration which were highly correlated (r =0.89, P < 0.0001) with the CA concentration estimated by the LL technique. The estimation made by the ANN had an excellent overall performance (AUROC = 0.870). PMID- 25285244 TI - Utilizing Healthcare Developments, Demographic Data with Statistical Techniques to Estimate the Diarrhoea Prevalence in India. AB - Diarrhoea is one of the leading causes of morbidity and mortality in developing countries in Africa and South Asia such as India. Prevalence of diarrheal diseases in those countries is higher than developed western world and largely has been associated with socio-economic and sanitary conditions. However, present available data has not been sufficiently evaluated to study the role of other factors like healthcare development, population density, sex and regional influence on diarrheal prevalence pattern. Study was performed to understand the relationship of diarrheal prevalence with specific measures namely; healthcare services development, demographics, population density, socio-economic conditions, sex, and regional prevalence patterns in India. Data from Annual national health reports and other epidemiological studies were included and statistically analyzed. Our results demonstrate significant correlation of the disease prevalence pattern with certain measures like healthcare centers, population growth rate, sex and region-specific morbidity. Available information on sanitation like water supply and toilet availability and socioeconomic conditions like poverty and literacy measures could only be associated as trends of significance. This study can be valuable for improvisation of appropriate strategies focused on important measures like healthcare resources, population growth and regional significances to evaluate prevalence patterns and management of the diarrhoea locally and globally. PMID- 25285245 TI - Measurement of Aerobic Capacity Using Mouthpiece vs. Mask for Data Collection. AB - Measurement of aerobic capacity is an important task that must be done accurately in order for data to be worthwhile. Measurement is traditionally obtained through the use of a nose-clip, mouthpiece, and headgear apparatus. This method of collecting gas has proven to be difficult due to the high incidence of losing the nose clip during exercise, the awkwardness and discomfort of the apparatus, and the loss of oral communication. This study compares this method with using a gas collection mask for physiological measurement. Masks have been avoided due to leakage that causes errors in data. Maximal and submaximal values for Ve, VO2, HR, and RER were compared for both methods of collection. Results show that the mask produced values equal to those of the mouthpiece, nose clip, and headgear. Significantly more discomfort, as well as influence on running economy, was reported with the headgear. The data show that leakage is not a significant problem. Based on preliminary studies and data from this study, using the mask is recommended. Data suggests that further studies look at facial shape, as well as masks of different size and material, with regards to eliminating any data errors occurring in the mask. PMID- 25285246 TI - Guest Editors' message: American College of Physicians, Hawai'i Chapter, Annual Meeting 2014. PMID- 25285247 TI - Bodily fluid analysis of non-serum samples using point-of-care testing with iSTAT and Piccolo analyzers versus a fixed hospital chemistry analytical platform. AB - INTRODUCTION: Forward deployed military medical units can provide sophisticated medical care with limited resources. Point-of-Care Testing (POCT) may facilitate care and expedite diagnosis. This study assessed the accuracy of results for POCT for non-serum samples (pleural, peritoneal, and cerebrospinal fluid) using iSTAT and Piccolo hand-held devices compared with results obtained using a hospital chemistry analyzer. METHODS: Pleural, peritoneal, and cerebrospinal fluids obtained during routine care were simultaneously analyzed on a Vitros 5600 automated clinical chemistry hospital analyzer, iSTAT, and Piccolo POCT devices. RESULTS: POCT results were highly correlated with the Vitros 5600 for pleural fluid LDH, glucose, and triglycerides (TG); for peritoneal fluid bilirubin, TG, glucose, albumin, and protein; and glucose for cerebrospinal fluid. CONCLUSION: POCT results for non-serum samples from pleural, peritoneal, and cerebrospinal fluid correlate with standard hospital chemistry analysis. The results of this study demonstrate potential for possible new diagnostic roles for POCT in resource-limited environments. PMID- 25285248 TI - Aeroallergen sensitivity in Hawai'i: association with asthma and increased prevalence of sensitivity to indoor allergens since 1966. AB - Asthma and allergic diseases have increased globally. Earlier studies suggest a history of excess asthma morbidity and mortality in Hawai'i, with high prevalence of sensitization to outdoor aeroallergens among atopic children. This study was undertaken to test the hypotheses that specific allergens are more associated with asthma, and that sensitivity to common aeroallergens has increased in Hawai'i since 1966. Adult participants were recruited between 2001-2013, according to approved protocols. Data from 211 adults who reported physician diagnosed asthma and 404 non-asthmatic controls are included in this analysis. Skin test responses to 8 common aeroallergens were assessed, and association between specific aeroallergen response and asthma diagnosis evaluated, using Chi squared analysis. P-values < .05 were considered statistically significant. Compared to non-asthmatic controls, asthmatic participants were older, more likely to be of Mixed and non-White race, and more likely to be obese. Allergen sensitivity (atopy) was found in 85% of asthmatic and 72% of the controls. Prevalence (%) of positive responses to specific aeroallergens in asthmatic, non asthmatic, and all atopic subjects, were: D. farinae (74, 59, 83), D. pteronyssinus (68, 52, 75), roach (42, 31, 46), cat (45, 19, 37), dog (27, 15, 25), grasses (34, 26, 37), weeds (22, 18, 25), and molds (18, 11, 17). Adjusted for age, race, and BMI, highest prevalence ratios [PR (95% CI)] were: D. farinae [1.16 (1.1-1.2)], D. pteronyssinus [1.16 (1.1-1.3)], cat [1.34 (1.2-1.5)], and dog [1.19 (1.1-1.3)]. This data indicates a strong association with asthma, and an increased prevalence in sensitivity to indoor allergens. PMID- 25285249 TI - Streptococcus suis meningoencephalitis with seizure from raw pork ingestion: a case report. AB - BACKGROUND: Streptococcus suis meningoencephalitis is a rare but increasingly important condition. Good history taking will give clues to the diagnosis. This is the fourth case report in the United States. CASE: A 52-year-old Filipino man who recently returned from a trip to the Philippines was admitted with classic symptoms of bacterial meningitis. His cerebrospinal fluid culture grew Streptococcus suis. His clinical course was complicated by seizures, hearing loss, and permanent tinnitus. CONCLUSION: Clinicians should be aware of this emerging disease especially in patients with recent travel history to endemic areas. Early recognition and appropriate management could potentially prevent complications. PMID- 25285250 TI - Mycobacterium avium complex empyema in a patient with interferon gamma autoantibodies. AB - Interferon gamma (IFN-gamma) autoantibodies are a relatively recently discovered clinical entity, which have been shown to be associated with disseminated non tuberculous mycobacterial (NTM) infections and other opportunistic infections. Interestingly, isolated NTM infections (without disseminated NTM infection) have not been shown to be a good predictor of the presence of IFN-gamma autoantibodies. This case describes an isolated NTM empyema in a patient with IFN gamma autoantibodies and makes the argument that the development of an NTM empyema in a patient with no known immunodeficiency should prompt consideration for IFN-gamma testing. Additionally, this case underscores the importance for clinicians to recognize that an unusual infection without the typical cause of impairment in immunity should prompt a more thorough investigation of the patient's immune system. PMID- 25285251 TI - Lupus erythematosus tumidus: a unique disease entity. AB - Lupus erythematosus tumidus (LET) is a photosensitive skin disease characterized by succulent, edematous, and non-scarring plaques. Histologic features include perivascular and periadnexal lymphocytic infiltration and interstitial mucin deposition. Despite being first described in 1909, there are few case reports in the current literature describing this disease and even fewer that discuss treatment. We describe a case of a 22-year-old woman with systemic lupus erythematosus (SLE) and secondary class V lupus nephritis. She was referred to Dermatology for an intermittent pruritic facial eruption that was clinically and histologically consistent with LET. There is much controversy in literature as to whether or not LET is a unique variant of cutaneous lupus erythematosus. Interestingly, the mainstay of treatment for LET, in the limited case reports and series that exist, is with antimalarial drugs, which our patient had already been taking for SLE. This case exemplifies the need for complete disease characterization, evidence-based treatment, and a multidisciplinary approach. PMID- 25285252 TI - Diagnosis of atypical hemolytic uremic syndrome and response to eculizumab therapy. AB - Atypical hemolytic uremic syndrome (aHUS) has a high mortality rate if not detected and treated early. While in the past, it was associated with renal failure in children, today, it has become increasingly identified among adults. Due to recent advances in the pathogenesis of aHUS and other major thrombotic microangiopathies (TMA), diagnosing it has become a lot easier. We present a case of a 62-year-old man who was initially thought to have thrombotic thrombocytopenic purpura (TTP), but after further evaluation was diagnosed with aHUS. We will discuss how to distinguish aHUS from other major TMA and the role of eculizumab in the management of aHUS. PMID- 25285253 TI - Group B streptococcal (GBS) bacteremia with mycotic thoracic aortic aneurysm and suppurative pericardial effusion. AB - Mycotic aortic aneurysm associated with suppurative pericardial effusion is a rare and serious clinical phenomenon that is linked with significant morbidity and mortality. We report a case of a 78-year-old man who presented with purulent pericardial effusion with tamponade physiology in association with a progressively enlarging, transverse aortic arch, mycotic aneurysm due to group B streptococci. To our knowledge, this is only the second reported case of this nature. Despite advances in the current era of antibiotics and surgical techniques, early diagnosis and aggressive treatment remain sentinel to successful management of the cardiovascular complications of group B streptococcus bacteremia. PMID- 25285254 TI - Hospital visits due to domestic violence from 1994 to 2011 in the Solomon Islands: a descriptive case series. AB - The Solomon Islands has one of the highest rates of domestic violence in the world. This paper is a descriptive case series of all cases of domestic violence presenting to the Solomon Islands National Referral Hospital (NRH) over 18 years. Data were routinely collected from a database of all patients who were treated by NRH general surgery and orthopedic clinicians between 1994 and 2011, inclusive. The total number of cases in the injury database as a result of domestic violence was 387. The average number of cases in the database per year from 1994 to 2011 was 20. There were 6% more female patients (205 of 387; 53%) than male (182 of 387; 47%). Of the cases in which the perpetrator of the violence against a female patient was specified (111 of 205 female cases), 74% (82 of 111) were the patient's husband. Only 5% (5 of 111) of cases in females were inflicted by another female. This analysis provides the best available information on domestic violence cases requiring a visit to a tertiary hospital in a Pacific Island in the specified time period and is undoubtedly an under-estimate of the total cases of domestic violence. Preventing and treating domestic violence in the Solomon Islands and in the Pacific is an important challenge and there is a significant role for secondary and tertiary health services in screening for and preventing domestic violence. PMID- 25285255 TI - Marijuana use and maternal experiences of severe nausea during pregnancy in Hawai'i. AB - Recreational use of marijuana is relatively common in the United States, and medicinal use is gaining popular and legal support. Marijuana has been proposed as a potential treatment for hyperemesis gravidarum. Research into this topic is complicated by associations between marijuana use and poor birth outcomes. Cannabinoid hyperemesis syndrome, which can cause severe nausea and vomiting in marijuana users, is another complicating factor. Hawai'i Pregnancy Risk Assessment Monitoring System data from 4,735 respondents were used to estimate prevalence of self-reported marijuana use during and in the month before pregnancy, as well as severe nausea during pregnancy. Data were weighted to be representative of all pregnancies resulting in live births in Hawai'i between 2009 and 2011. Prevalence ratios (PR) and 95% confidence intervals (CI) were computed to estimate associations. Of recently-pregnant women in Hawai'i, 6.0% reported using marijuana in the month before pregnancy, and 2.6% reported using marijuana during pregnancy. Approximately 21.2% reported severe nausea during pregnancy. Women who reported severe nausea during pregnancy were significantly more likely to report marijuana use during pregnancy (3.7% vs 2.3%; PR=1.63, 95% CI: 1.08-2.44). More research is needed to investigate the relationship between marijuana use and severe nausea during pregnancy, and to quantify associated risks to mother and fetus. PMID- 25285257 TI - Medical school hotline: Educating current and future seniors: the mini-medical school on healthy aging; University of Hawai'i at Manoa, John A. Burns School of Medicine. PMID- 25285256 TI - Atypical antipsychotic usage among Asian Americans and Pacific Islanders. AB - Previous studies have shown significant ethnic differences in prescribing patterns of two or more antipsychotics. This study examined changes in atypical and typical antipsychotic prescriptions among Asian Americans and Pacific Islanders. Five hundred consecutive charts were reviewed for antipsychotics at the time of admission and discharge from each of two inpatient psychiatric facilities in Hawai'i. Multiple antipsychotic prescription rates were 9% at intake and 6% at discharge. For the ethnic groups studied, there were no statistically significant differences by patient ethnicity regarding antipsychotics at intake (chi(2) = 29.2, df = 21, P = .110) or discharge (chi(2) = 20.5, df = 24, P = .667). There were no significant differences in prescription and polypharmacy patterns among Asian Americans and Pacific Islanders ethnic groups in this study. PMID- 25285258 TI - Insights in public health: The Special Supplemental Nutrition Program for Women, Infants and Children: strengthening families for 40 years. AB - The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) is a proven, cost-effective investment in strengthening families. As part of the United States Department of Agriculture's (USDA) 15 federal nutrition assistance programs for the past 40 years, WIC has grown to be the nation's leading public health nutrition program. WIC serves as an important first access point to health care and social service systems for many limited resource families, serving approximately half the births in the nation as well as locally. By providing nutrition education, breastfeeding promotion and foods in addition to referrals, WIC plays a crucial role in promoting lifetime health for women, infants and children. WIC helps achieve national public health goals such as reducing premature births and infant mortality, increasing breastfeeding, and reducing maternal and childhood overweight. Though individuals and families can self-refer into WIC, physicians and allied health professionals have the opportunity and are encouraged to promote awareness of WIC and refer families in their care. PMID- 25285260 TI - Evaluation of health determinants for sustaining workability in aging US workforce. AB - Growth of older population in United States requires multi-generational evaluation to characterize health measures for sustaining workability. Investigation of measures that working population would need and use with their work-life in an attempt to stay healthy and fit, could potentially reveal significant association that could extend workability and enhance work productivity such as performance, presenteeism, job satisfaction. Evaluation with selective longitudinal health profiling; employment prerequisites; socio-economic and psychological scales could characterize health measures significantly associated with work sustainability. Such health measures could potentially be employed by US working population early in their life and occupation to sustain and improve workability in their later epoch. PMID- 25285261 TI - Repeated applications of cold atmospheric pressure plasma does not induce resistance in Staphylococcus aureus embedded in biofilms. AB - INTRODUCTION: The increasing microbial resistance against antibiotics complicates the therapy of bacterial infections. Therefore new therapeutic options, particularly those causing no resistance, are of high interest. Cold atmospheric plasma is one possible option to eradicate multidrug resistant microorganisms, and so far no resistance development against physical plasma is known. METHOD: We tested 6-fold repeated plasma applications on a Staphylococcus aureus strain embedded in biofilm and compared the reduction of the colony forming units between the different treatment periods to asses a possible development of resistance. RESULT: For all treatment periods, the control biofilms were reduced by plasma in average by 1.7 log10 CFU, and decreased from 7.6 to 5.8 log10 (CFU/cm(2)) within 5 hours. The results demonstrated that repeated plasma doses not induce resistance or habituation against plasma applied within short time periods. CONCLUSION: The repeated application of cold plasma is a promising option for the treatment of infected wounds without the risk of development of resistance against plasma. PMID- 25285262 TI - Compliance with infection control practices in an university hospital dental clinic. AB - AIM: Compliance with infection control practices is the key to quality care and excellence in dentistry. Infection control remains one of the most cost beneficial interventions available. However, implementing control procedures requires full compliance of the whole dental team. The aim of our study was to measure the compliance in daily clinical practice. METHODS: The compliance with infection control practices in dentistry by dental health care personnel (DHCP) in a German university dental clinic was observed during clinical work. In addition, a survey was conducted to assess the individual knowledge about infection control procedures. Contamination of the workplace during invasive dental procedures was tested, as well. RESULTS: A total of 58 invasive dental treatments implying close contacts between HCWs and patients were scrutinized. All HCWs (100%) wore gloves during dental work, but in some cases (female dentists: 14.3%; dental assistants: 28.6%) gloves were neither changed nor hands were disinfected between different activities or patient contacts (female dentists: 68.6%; male dentists: 60.9%; dental assistants: 93%). Only 31.4% of female and 39.1% of male dentists carried out adequate hygienic hand disinfection after removing gloves. Male dentists wore significantly more often (100%) protective eyewear compared to 77.1% of female dentists (p<0.05). In addition, most of female dentists (62.9%) and dental assistants (80.7%) wore jewelry during dental procedures. CONCLUSION: Despite the knowledge of distinct hygiene procedures only a small percentage of dental staff performs hygiene practices according to recommended guidelines. Strict audit is clearly needed in the dental setting to ensure compliance with infection control guidelines to prevent transmission of pathogens. Our results provide insights for the development of a targeted education and training strategy to enhance compliance of dental staff especially of dental assistants with infection control procedures. PMID- 25285263 TI - Can post-sternotomy mediastinitis be prevented by a closed incision management system? AB - Post-sternotomy mediastinitis is a serious complication after cardiothoracic surgery and contribute significantly to post-operative morbidity, mortality, and healthcare costs. Negative pressure wound therapy is today's golden standard for post-sternotomy mediastinitis treatment. A systematic literature search was conducted at PubMed until October 2012 to analyse whether vacuum-assisted closure technique prevents mediastinitis after clean surgical incisions closure. Today's studies showed reduction of post-sternotomy mediastinitis including a beneficial socio-economic impact. Current studies, however included only high-risk patients, hence furthermore, larger randomised controlled trials are warranted to clarify the benefit for using surgical incision vacuum management systems in the general patient population undergoing sternotomy and clarify risk factor interaction. PMID- 25285264 TI - Successful implementation of infection control strategies prevents P. aeruginosa transmission among cystic fibrosis patients inside the hospital. AB - BACKGROUND: The aim of this study was to characterise the epidemiology of P. aeruginosa isolated from cystic fibrosis (CF) patients at the Vienna General Hospital (VGH) by molecular genetic fingerprinting in order to understand transmission ways and to evaluate the established infection control protocols. METHODS: The outpatient clinic for CF patients at the VGH cares for children and adolescents up to the age of 18 years. Among an average of 139 patients cared for at the clinic, 41 were tested positive for P. aeruginosa during the study period. Fifty P. aeruginosa isolates, obtained between August 2010 and March 2012 from routine examinations of CF patients, were subject to molecular characterization using the DiversiLab((r)) method. RESULTS: 42 distinguishable molecular biological patterns were identified, 7 of which were found multiple times. 40 out of 42 genotypes were retrieved from single patients only, while two patterns were present in two patients each. Nine patients presented with two or more phenotypically diverse P. aeruginosa isolates. In five of these cases the retrieved isolates belonged to the same genotype. CONCLUSION: The broad genetic heterogeneity of P. aeruginosa in the studied patient population suggests that the majority of CF patients cared for at the VGH acquire P. aeruginosa from environmental sources. It may be concluded that implemented infection control guidelines have been successful in preventing nosocomial transmission of P. aeruginosa among CF patients within the VGH and patient-to-patient transmission outside the hospital. Chronic polyclonal infection/colonization was rare in the study population. PMID- 25285266 TI - Multiresistant pathogens in geriatric nursing - infection control in residential facilities for geriatric nursing in Germany. AB - BACKGROUND: The increase of multidrug-resistant organisms (MDROs) causes problems in geriatric nursing homes. Older people are at increased a growing risk of infection due to multimorbidity and frequent stays in hospital. A high proportion of the elderly require residential care in geriatric nursing facilities, where hygiene requirements in nursing homes are similar to those in hospitals. For this reason we examined how well nursing homes are prepared for MDROs and how effectively protect their infection control residents and staff. METHODS: A cross sectional study was performed on infection control in residential geriatric nursing facilities in Germany 2012. The questionnaire recorded important parameters of hygiene, resident and staff protection and actions in case of existing MDROs. RESULTS: The response was 54% in Hamburg and 27% in the rest of Germany. Nursing homes were generally well equipped for dealing with infection control: There were standards for MDROs and regular hygiene training for staff. The facilities provided adequate protective clothing, affected residents are usually isolated and hygienic laundry processing conducted. There are deficits in the communication of information on infected residents with hospitals and general practitioners. 54% of nursing homes performed risk assessments for staff infection precaution. CONCLUSION: There is a growing interest in MDROs and infection control will be a challenge in for residential geriatric nursing facilities in the future. This issue has also drawn increasing attention. Improvements could be achieved by improving communication between different participants in the health service, together with specific measures for staff protection at work. PMID- 25285268 TI - Using Animal Instincts to Design Efficient Biomedical Studies via Particle Swarm Optimization. AB - Particle swarm optimization (PSO) is an increasingly popular metaheuristic algorithm for solving complex optimization problems. Its popularity is due to its repeated successes in finding an optimum or a near optimal solution for problems in many applied disciplines. The algorithm makes no assumption of the function to be optimized and for biomedical experiments like those presented here, PSO typically finds the optimal solutions in a few seconds of CPU time on a garden variety laptop. We apply PSO to find various types of optimal designs for several problems in the biological sciences and compare PSO performance relative to the differential evolution algorithm, another popular metaheuristic algorithm in the engineering literature. PMID- 25285265 TI - Mini-review: Epidemiology and zoonotic potential of multiresistant bacteria and Clostridium difficile in livestock and food. AB - AIM: Information on the epidemiology of multiresistant bacteria (MRB) with zoonotic potential is growing but still remains quite incomplete. This narrative mini-review provides a general overview of the epidemiology of the most important zoonotic MRB in cattle, swine and poultry in Europe. METHODS: A literature search was conducted mainly on the PubMed website including articles published until April 2012. RESULTS: Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) especially poses a zoonotic risk to people working in close contact with livestock. These people may become carriers themselves and the hazard of transmission into health-care facilities needs surveillance. Extended spectrum beta-lactamases (ESBL) producing bacteria are widely spread in both humans and livestock, sharing similar genotypes, especially of the CTX-M-group, which makes a zoonotic transfer very likely. Identical strains of vancomycin resistant enterococci (VRE) were found both in humans and animals, after ingestion of animal strains transient colonization of the human gut may be possible. Only a few data are available on the transmission of methicillin resistant coagulase-negative staphylococci (MR-CoNS) between humans and animals. Direct contact to colonized animals may be a risk factor as well as the exchange of resistance genes between human and animal staphylococci. Clostridium difficile (C. difficile) ribotype 078 emerges in livestock and humans and a zoonotic transmission seems probable as genotypes and diseases resemble each other. CONCLUSION: All discussed MRB and C. difficile are important nosocomial agents which also occur in livestock and were found in foods of animal origin. Further analysis is needed to reveal the exact transmission routes and to perform a reliable risk assessment. PMID- 25285267 TI - Clinical characteristics of Staphylococcus epidermidis: a systematic review. AB - Staphylococci are known as clustering Gram-positive cocci, nonmotile, non-spore forming facultatively anaerobic that classified in two main groups, coagulase positive and coagulase-negative. Staphylococcus epidermidis with the highest percentage has the prominent role among coagulase-negative Staphylococci that is the most important reason of clinical infections. Due to various virulence factors and unique features, this microorganism is respected as a common cause of nosocomial infections. Because of potential ability in biofilm formation and colonization in different surfaces, also using of medical implant devices in immunocompromised and hospitalized patients the related infections have been increased. In recent decades the clinical importance and the emergence of methicillin-resistant Staphylococcus epidermidis strains have created many challenges in the treatment process. PMID- 25285269 TI - Serial pulmonary function tests to diagnose COPD in chronic heart failure. AB - BACKGROUND: It is unknown whether serial pulmonary function tests are necessary for the correct diagnosis of chronic obstructive pulmonary disease (COPD) in patients with stable non-congested chronic heart failure (CHF). The aim of this study was to determine the prevalence of COPD in outpatients with stable CHF without pulmonary congestion using initial as well as confirmatory spirometry three months after treatment for COPD. METHODS: Spirometry was performed in 187 outpatients with stable CHF without pulmonary congestion on chest radiograph who had a left ventricular ejection fraction < 40% (mean age 69 +/- 10 years, 78% men). COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease guidelines. The diagnosis of COPD was confirmed three months after treatment with tiotropium in newly diagnosed COPD patients. RESULTS: Using a three month follow-up spirometry to confirm initial diagnosis of de novo COPD did not change COPD prevalence significantly: 32.6% initially versus 32.1% after three months of follow-up. Only 1 of 25 (4%) patients with newly diagnosed COPD was not reproducibly obstructed at follow-up. COPD was greatly under- (19%) and overdiagnosed (32%). CONCLUSIONS: Spirometry should be used under stable and euvolemic conditions to decrease the burden of undiagnosed or overdiagnosed COPD in patients with CHF. Under these conditions, a confirmatory spirometry is unnecessary, as it does not change a newly established diagnosis of COPD in the vast majority of patients with CHF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01429376. PMID- 25285270 TI - Doing Damage in Delirium: The Hazards of Antipsychotic Treatment in Elderly Persons. PMID- 25285272 TI - Vitamin D supplementation in pregnancy. PMID- 25285273 TI - Medication counselling with sodium glucose transporter 2 inhibitor therapy. PMID- 25285271 TI - Near-infrared fluorescence and nuclear imaging and targeting of prostate cancer. AB - Despite advances in the treatment of castration-resistant and bone metastatic prostate cancer (PCa), there is still no clear demonstration that PCa growth and metastases can be unambiguously detected. We review recent advances including our own development of near-infrared fluorescence (NIRF) and near-infrared nuclear (NIRN) imaging approaches. We validated our results in experimental models of PCa bone and soft tissue metastases including PCa colonization at metastatic sites by injecting PCa cells either intratibially or intracardiacally. We describe our experience using noninvasive imaging and targeting modalities to probe PCa tumors grown at metastatic sites, molecular studies to understand the multiple molecular and cellular processes within tumor cells and their interactions with the tumor microenvironment, and targeting tumor growth at metastatic bone site. In this review, current knowledge and emerging technologies based on NIRF and NIRN disciplines will be summarized. Additionally the mechanisms of differential uptake of these agents by normal and cancerous cells will be described. PMID- 25285274 TI - Challenges in Type 1 diabetes management in South East Asia: Descriptive situational assessment. AB - Treatment of type 1 diabetes is a challenging issue in South East Asia. Unlike in the developed countries, patients have to procure insulin, glucometer strips and other treatment facilities from their own pockets. Coupled with poor resources are the difficulties with diagnosis, insulin initiation, insulin storage, marital and emotional challenges. Being a disease affecting only a minority of people, it is largely ignored by the governments and policy makers. Comprehensive diagnostic, treatment and team based educational facilities are available only in the speciality diabetes centers in the private sector whereas majority of the subjects with type 1 diabetes are from a poor socio-economic background. Unlike in the Western world, being known as a diabetes patient is a social sigma and poses huge emotional burden living with the disease and getting married. Even with best of the resources, long-term treatment of type 1 diabetes still remains a huge challenge across the globe. In this review, authors from India, Pakistan, Nepal, Sri Lanka, Myanmar and Bangladesh detail the country-specific challenges and discuss the possible solutions. PMID- 25285276 TI - Deciding oral drugs after metformin in type 2 diabetes: An evidence-based approach. AB - The most commonly used oral drug in treating type 2 diabetes (T2DM) after metformin are sufonylureas (SUs) based on the confidence gained over the several decades and because of its cheaper cost. Unfortunately, SUs are associated with secondary failure and sometimes associated with therapy related severe hypoglycaemia limiting its compliance and wider utility in current clinical practice. Although large randomised trials could not associate SUs with any obvious increase in cardiovascular (CV) mortality, some recent larger databases showing divergent results suggesting increasingly CV signals and this might put SUs in difficulty given the availability of other safer alternatives. In recent years, incretin-based therapies like dipeptidyl peptidase-4 inhibitors (DPP-4I) and glucagon-like peptide-1 (GLP-1) agonist (GLP-1A) are gaining popularity primarily because of their advantage of weight reduction/neutrality and minimal hypoglycemia along with the perception of possible pleiotropic CV benefit mainly derived from pooled CV data of their trials. Sodium glucose transporter 2 inhibitors (SGLT-2I) are another new promising molecule currently looking for its space in the management of T2DM. Insulin could be utilized at any place when required and in this regard outcomes reduction with an initial glargine intervention (ORIGIN) study also suggested that basal insulin glargine could be safely used even in early stage. This review will discuss what could be possibly be the best option as a second line oral agent, once metformin monotherapy becomes ineffective. PMID- 25285275 TI - Chronic obstructive pulmonary disease and the metabolic syndrome: Consequences of a dual threat. AB - The metabolic syndrome is found to be more frequent in chronic obstructive pulmonary disease (COPD). The presence of inflammatory markers in circulation, sputum, and broncho-alveolar fluid suggest systemic inflammation is one of the potential mechanisms responsible for both COPD and metabolic syndrome. Physical inactivity, skeletal muscle dysfunction, hypogonadism, and steroid use are also important causes of the metabolic syndrome in COPD. Obesity and insulin resistance is found to be more common in mild to moderate stages (I and II) of COPD. Patients with COPD and the metabolic syndrome have increase risk of morbidity and mortality due to cardiovascular disease. This review describes in details the various components of metabolic syndrome and its impact on long outcomes in COPD patients. PMID- 25285277 TI - Association of dietary fiber intake with serum total cholesterol and low density lipoprotein cholesterol levels in Urban Asian-Indian adults with type 2 diabetes. AB - CONTEXT: There is little data correlating dietary fibre (DF) intake and cardiovascular risk in Asian Indians with diabetes. AIM: To assess the DF intake and its association with lipid profile (total serum cholesterol and low density lipoprotein [LDL] - cholesterol levels) in urban Asian Indians with diabetes. SUBJECTS AND METHODS: Dietary assessment using validated Food Frequency Questionnaire was conducted in 1191 free-living adults with known diabetes in the Chennai Urban Rural Epidemiology Study. Subjects taking medication for dyslipidemia, and those with cardiovascular disease and implausible energy intake (n = 262) were excluded, leaving 929 participants. Anthropometric and relevant biochemical parameters were measured using standardized techniques. RESULTS: Diabetic individuals who consumed DF < median intake (29 g/day) had a higher prevalence of hypercholesterolemia (49.5% vs. 40.1% [P = 0.01]) and higher LDL cholesterol (46.2% vs. 35.5% [P = 0.001]) than those in the > median intake of DF group. The risk of hypercholesterolemia (odds ratio [OR] =1.38 [95% confidence interval [CI]: 1.02-1.85], P = 0.04), and high LDL cholesterol (OR: 1.43 [95% CI: 1.06-1.94], P = 0.02) was higher among those whose DF intake was less than the median. Serum triglycerides and high density lipoprotein cholesterol were not associated with DF intake. The main sources of DF were vegetables and legumes. CONCLUSION: In urban Asian Indians with diabetes, lower DF intake is positively related to total cholesterol and LDL cholesterol levels. PMID- 25285278 TI - Atherogenic index of plasma in highly active antiretroviral therapy-naive patients with human immunodeficiency virus infection in Southeast Nigeria. AB - INTRODUCTION: Metabolic abnormalities are often common among human immunodeficiency virus (HIV) patients. The atherogenic index of plasma (AIP) is increasingly being used as a screening tool for dyslipidemia as it predicts the presence of small, dense, and highly atherogenic low density lipoprotein (LDL) and high density lipoprotein (HDL) particles. The aim of this study was to identify the pattern and predictors of an abnormal atherogenic index in highly active antiretroviral therapy (HAART)-naive HIV patients. MATERIALS AND METHODS: HAART-naive patients with HIV infection were recruited for this cross-sectional study. Anthropometric indices, blood pressure, CD4 count, viral load, fasting blood glucose, and lipid profiles were determined. Total cholesterol (TCH)/HDL, triglyceride (TG)/HDL, and LDL/HDL ratios were calculated. The AIP was calculated as log (TG/HDL). The correlations between AIP and the other lipoprotein ratios and predictors of AIP were determined using stepwise multiple linear regression. P < 0.05 was considered as significant. RESULTS: A total of 353 patients with a mean age of 37.3 (9.6) years were recruited for this study. Low HDL level was the most common abnormality in 222 (62.9%) patients while elevated TCH was seen in 54 (15.3%) patients. Those with medium risk (AIP 0.1-0.24) and high risk category (AIP > 0.24) constituted up to 226 (64%) of the patients. There were significant correlations between AIP and CD4 count, body mass index, LDL, TCH/HDL, and LDL/HDL. Predictors of AIP were CD4 count, TCH/HDL, and LDL/HDL. CONCLUSION: Abnormal AIP is frequent in HAART-naive HIV patients and is inversely related to their level of immunity. We recommend that AIP estimation should be part of baseline assessment of HIV patients before the commencement of therapy. PMID- 25285279 TI - Thyroid abnormalities in Egyptian children and adolescents with type 1 diabetes mellitus: A single center study from Upper Egypt. AB - BACKGROUND: The aim of this study was to detect the prevalence of thyroid abnormalities among children and adolescents with type 1 diabetes mellitus (T1DM) in Upper Egypt and its relationship with disease-related variables. DESIGN: Cross sectional controlled study. PATIENTS AND METHODS: The study included 94 children and adolescents with T1DM (Group 1) attending for regular follow-up in the diabetes clinic of Assiut Children University Hospital, Assiut, Egypt were enrolled in the study and 60 healthy subjects matching in age and sex were taken as a control (Group 2). History taking, clinical examination, measurement of thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti Tg) antibodies levels as well as HbA1c were measured. RESULTS: Mean TSH levels were significantly higher in (Group 1) when compared to control (P < 0.01). Six children (6.3%) were found to have subclinical hypothyroidism in Group 1 compared with two children (2.1%) in the control group (P < 0.001) two children (2.1%) were found to have clinical hypothyroidism in Group 1 compared with non in the control group. Positive levels of anti-TPOAb and anti-TgAb were found in 9 (9.5%) and 6 (6.3%) in Group 1 compared with 2 (3.3)% and 1 (1.6%) of controls respectively (P < 0.01). Cases with hypothyroidism were significantly older, had longer duration of DM, higher body mass index and higher HbA1c compared with those without hypothyroidism. TSH had significant positive correlations to age (r = 0.71, P < 0.001), diabetes duration (r = 0.770, P < 0.001), Anti-TPO level (r = 0.678, P < 0.01), HbAIc level (r = -0.644, P < 0.01) and significant negative correlation with FT4 (r = -0.576, P = 0.01). CONCLUSION: The present study reported high prevalence of thyroid abnormalities in children and in children and adolescents with type 1 diabetes in Upper Egypt. The study recommended yearly evaluation thyroid function tests and thyroid antibodies in all children and adolescents with type 1 diabetes commencing from the onset of diabetes. PMID- 25285280 TI - Prevalence of dyslipidemia in adult Indian diabetic patients: A cross sectional study (SOLID). AB - CONTEXT: India leads the world with largest number of diabetic patients and is often referred to as the diabetes capital of the world. Diabetic dyslipidemia in India is one of the main cause for Coronary Artery Disease (CAD) mortality. Although diabetes continues to be a major lifestyle condition in India, there is a lack of studies in India on whether dyslipidemia in Indian diabetics is being adequately controlled. Our study provides critical insights into the insights into proportion of diabetes patients achieving lipid goal in India. AIMS: The primary objective of our study was to assess the control of dyslipidemia in the Indian diabetic population treated with lipid lowering drugs (LLDs), as per American Diabetes Association (ADA) 2010 guidelines. SETTINGS AND DESIGN: The study was carried out in a real world Indian clinical setting involving 178 sites. This is a multicenter, noninterventional, and cross-sectional observational study. MATERIALS AND METHODS: A total of 5400 adult subjects with established type-2 diabetes mellitus (T2DM) and dyslipidemia were recruited for the study. Patients in the study were on LLD at a stable dose for at least last 3 months before the designated study visit. Routine lipid profile tests were conducted for all patients. STATISTICAL ANALYSIS USED: Descriptive statistics was used to analyze qualitative and discrete variables. Chi-square test and t-test were conducted to assess the existence of statistically significant association between the variables. RESULTS: A total of 5400 patients with T2DM from 178 centers across India were recruited. Out of the total population, 56.75% (N = 3065) of them were males. Primary end-point of low-density lipoprotein cholesterol (LDL-C) level below ADA 2010 target was achieved in a total of 48.74% (N = 2632) patients. Gender was significantly associated with lipid levels and age was significantly (P < 0.05) correlated with all lipid levels. Control rates of other lipid parameters like high-density lipoprotein cholesterol, triglyceride, and total cholesterol in the study were 60.48% (N = 3236), 57.54% (N = 3107), and 92.24% (N = 4981) respectively. Among those with overt cardiovascular disease (CVD), target LDL-C level of < 70 mg/dL was achieved in 22.87% (70 out of 306) patients. The LDL-C levels of 49.03% (N = 1768) patients who were on statin therapy were within target levels, while 53.46% (N = 634) patients who were on statin and their combinations with other LLDs had their LDL C levels within the stipulated range. CONCLUSIONS: This study has reveled that dyslipidemia control in Indian T2DM patients is very poor with almost half of them not reaching their LDL -C goal. Dyslipidemia being one of the main risk factors for CVD in T2DM patients there is a need to treat dyslipidemia aggressively to reduce risk of future CV events. PMID- 25285281 TI - Comparison of clinical outcome after a fixed dose versus dosimetry-based radioiodine treatment of Graves' disease: Results of a randomized controlled trial in Indian population. AB - OBJECTIVE: Two approaches are used to treat Graves' disease with radioiodine ((131)I)-the fixed dose approach and the other based on dosimetry. A prospective study was performed to compare the results of these two approaches in a randomized patient population, as such study is lacking in the Indian population till date. MATERIALS AND METHODS: Patients with Graves' disease were randomized into two groups: (1) Fixed dose group and the (2) Calculated dose group, each comprising of 20 patients. All the patients underwent detailed clinical and biochemical evaluation. Thyroid mass was determined by high resolution ultrasound machine with linear transducer of 7-11 MHz. Patients were given 185-370 kBq (5-10 uCi) of (131)I and 24 hr radioiodine uptake (RAIU) was calculated using thyroid uptake probe and thyroid phantom. Fixed dose group patients were administered 185MBq of (131)I. Calculated dose group patients were given (131)I as per the following formula: Calculated dose = [3700 kBq/g * estimated thyroid wt. (g)] / 24 hr RAIU (%). Success of first dose of radioiodine was defined as clinically/biochemically euthyroid/hypothyroid status at the end of 3 months without the need for further therapy. RESULTS: In the fixed dose group, eight patients were hyperthyroid, four were euthyroid, and eight were hypothyroid after the first dose at 3 months. Success rate of first dose was 60%. In calculated dose group, seven patients were hyperthyroid, eight were euthyroid, and five were hypothyroid. Success rate of first dose was 65%. CONCLUSIONS: There is no statistically significant difference between the success rates of the two methods at 3 months. Hence, fixed dose approach may be used for treatment of Graves' disease as it is simple and convenient for the patient. Longer follow-up with higher number of patients should be done to confirm or contradict our findings. PMID- 25285282 TI - A randomized controlled trial of cholecalciferol supplementation in patients on maintenance hemodialysis. AB - BACKGROUND: Vitamin D deficiency is common in Indian patients with chronic kidney disease (CKD) on maintenance hemodialysis (MHD), but optimal dose of cholecalciferol is unclear. MATERIALS AND METHODS: A total of 45 consenting patients were randomized to intervention and control groups. In the intervention group, patients (n = 35) with serum 25-hydroxy vitamin D (25(OH)D) < 30 ng/mL (n = 33), received oral cholecalciferol 60,000 units/week for 6 weeks. The serum levels of 25(OH)D, calcium, phosphorus, albumin, and parathyroid hormone (PTH) were measured at 0, 6, and 12 weeks. In the control group (n = 10), these were estimated at 0 and 6 weeks. RESULTS: In the intervention group, 25/35 patients completed the supplementation at 6 weeks and 20/35 were available at 12 weeks. The mean baseline level of 25(OH)D was 9.59 +/- 7.59 ng/mL, and after 6 weeks 19.51 +/- 4.27 ng/mL, mean increase being 9.99 +/- 6.83 ng/mL, which was highly significant (P < 0.0001). After discontinuing supplementation at 6 weeks, serum 25(OH)D level dropped significantly from 6 to 12 weeks [-2.84 +/- 6.25 ng/mL (P = 0.04)]. However, it was still significantly higher at 12 weeks (16.08 +/- 8.27 ng/mL) as compared with the baseline. PTH and calcium did not change significantly with supplementation. The change in serum 25(OH)D level from baseline to 6 weeks in the intervention group was inversely related to baseline 25(OH)D levels and patient's weight. In the control group, change in 25(OH)D from baseline to 6 weeks was not significant. CONCLUSION: Supplementation with cholecalciferol 60,000 unit/week for 6 weeks was insufficient to achieve optimal levels of 25(OH)D in Indian patients with CKD on MHD. PMID- 25285283 TI - Percutaneous ethanol ablation in managing predominantly cystic thyroid nodules: An eastern India perspective. AB - AIMS: Percutaneous aspiration and ethanol injection (PEI) is effective in managing predominantly cystic (>50% cystic) thyroid nodules with efficacy ranging from 38-85%. We aimed to evaluate efficacy, safety, and factors determining outcomes of PEI in managing simple cystic (purely cystic) vs. complex cystic (having both cystic and solid components) thyroid nodules. MATERIALS AND METHODS: Predominantly cystic thyroid nodules, without any ultrasonography and/or fine needle aspiration, evidence of malignancy were aspirated ultrasonography guided. Sterile 100% ethanol (50-100% volume aspirated) was injected and reviewed monthly for 3 months and thereafter 3 monthly. Responders were defined as >= 50% reduction in nodule volume. RESULTS: Sixty-five patients out of 152 considered underwent PEI. Sixty patients [simple cystic (42) and complex cystic (18)] with mean follow-up of 12.3 +/- 2.88 months were analyzed. Response rate of PEI was 78.33% [simple cystic (92.86%) and complex cystic (44.44%) nodules; P < 0.001]. Also, 31.67% patients achieved remission at 1(st) month. And, 46.67% patients achieved remission between 1-6-months follow-up. Kaplan Meier analysis showed significantly improved outcomes in patients with simple cystic nodules (P < 0.001). Cox-regression revealed type of nodule (simple cystic vs. complex cystic) to be predictive of outcome (P = 0.034). Complex cystic nodules were 67.6% less likely to go into remission, compared to simple cystic nodules. Baseline nodule size, aspirate, or volume of ethanol injected did not predict outcome. CONCLUSIONS: PEI is safe and should be treatment of choice for simple cystic thyroid nodules. PEI for complex cystic thyroid nodules are associated with lower response, increased recurrence, and need for repeated PEI. PMID- 25285284 TI - Impact of lithium on radioactive iodine therapy for hyperthyroidism. AB - CONTEXT: Radioactive Iodine (RAI) is a common therapy for hyperthyroidism. However hyperthyroidism recurs or persists in 15-18% of patients after RAI. Studies report variable percentage of failure after RAI therapy depending on several variables including I(131). Lithium enhances efficacy of treatment by increasing RAI retention in the thyroid. AIMS: To evaluate the efficacy of Lithium to RAI therapy in terms of cure, reduction of mean thyroid volume, and its safety. SETTINGS AND DESIGN: A prospective comparative study. SUBJECTS AND METHODS: Forty hyperthyroid patients were assigned to two groups, RAI alone and RAI plus lithium and followed for 1 year. Lithium was given in a dose of 900 mg/day in three divided doses for 6 days starting on the day of RAI therapy. Total T3, total T4, and thyroid-stimulating hormone (TSH) were done at baseline, 2,4,6,9, and 12 months. Ultrasound of thyroid was done at baseline and at the end of 1 year. Monitoring was done for side effects of lithium and RAI therapy. STATISTICAL ANALYSIS: Cure rate and time to cure were assessed by Chi-square test. Mean change in thyroid volume was compared by student's t-test. P < 0.05 was considered significant. RESULTS: RAI combined with lithium had a trend towards better cure rate (90%) compared to RAI alone (70%) (P 0.11). Mean time taken to cure was 4.69 months in RAI plus lithium and 7.12 months in RAI alone (P 0.001). Mean change in thyroid volume was similar in both the groups (P = 0.75). There were no side effects of Lithium or RAI. CONCLUSIONS: RAI therapy combined with lithium showed a trend towards higher cure rate, safe and time to cure was less than RAI alone. Hence RAI combined with lithium is a better option in the management of hyperthyroidism than RAI alone. PMID- 25285285 TI - Correlation of abdominal adiposity with components of metabolic syndrome, anthropometric parameters and Insulin resistance, in obese and non obese, diabetics and non diabetics: A cross sectional observational study. (Mysore Visceral Adiposity in Diabetes Study). AB - OBJECTIVES: To measure Visceral Fat (VF) and Subcutaneous Fat (SCF) by ultrasound, in obese and non-obese diabetics and obese and non-obese non diabetics, in a South Indian (Asian Indian) Population and correlate them with Body Mass Index (BMI), Waist Circumference (WC), components of metabolic syndrome and Insulin Resistance (IR). RESEARCH DESIGN AND METHODS: This was a prospective observational study, 80 diabetics (40 obese and 40 non obese) and 80 non diabetics (40 obese and 40 non obese) a total of 160 subjects were enrolled, out of whom 153 completed the study. The subjects were evaluated with respect to BMI, WC, Blood Pressure (BP); Fasting Blood Sugar (FBS) Fasting Insulin levels (FIL), HbA1C and Lipid profile. The SCF and VF were measured by Ultrasonography.The results were statistically analyzed. RESULTS: WC correlated significantly with VF in all the groups. Diabetics had more VF compared to non-diabetics. Insulin resistance was significant in all the groups; however diabetics had greater levels of IR, BMI, WC, VF and SCF had no correlation with IR and had no significant correlation with metabolic parameters. CONCLUSIONS: In this study population, WC was found to be a useful surrogate measure of VF conforming to its well established applicability in other populations. Contrary to other studies elsewhere, SCF and VF were found to be poor indicators of Insulin Resistance. BMI, WC, VF and SCF were not useful in the prediction of metabolic syndrome. Ultrasound was found to be an easier and economic method of measuring abdominal adiposity and actual measurement of abdominal fat was more informative than anthropometric measurements. PMID- 25285286 TI - Impact of breakfast skipping on the health status of the population. AB - BACKGROUND: Obesity has become a worldwide epidemic and its prevalence continues to increase at a rapid rate in various populations and across all age-group. The effect of meal skipping, both behaviorally and physiologically, may have an impact on the outcome of weight-loss efforts. AIMS AND OBJECTIVES: Therefore, the aim of this study was to examine the prevalence of breakfast skipping and obesity in subjects. MATERIALS AND METHODS: A retrospective analysis of the patients visited to a metabolic clinic of the city was done. RESULTS: One hundred and eighty-six eligible subjects were included for the study. A questionnaire was used for data collection which included information regarding dietary factors and exercise schedule/physical activity. A 24-hour dietary recall method was used to assess the amount of food consumed. Anthropometric measurements were taken. CONCLUSION: The higher prevalence of overweight and obesity in the present study could be because of imbalance in the diet and faulty food habits prevalent in the region. PMID- 25285287 TI - Radioiodine therapy in patients with Graves' disease and the effects of prior carbimazole therapy. AB - The use of radioiodine as the first line of treatment in Graves' disease is restricted in India because of its limited availability and an unrealistic risk perception associated with it. Additionally, the effectiveness of radioiodine ablation in Graves' disease is influenced by many factors. Prior medical antithyroid therapy is one such important factor. AIMS: To analyze the efficacy of low dose radioiodine therapy (5 mCi) in treatment of naive patients of Graves' disease in comparison to that in which it was already primed with an antithyroid drug, carbimazole. SETTINGS AND DESIGN: A non-randomized, interventional study conducted in the Department of Medicine and Endocrinology of a tertiary care institute in South India. MATERIALS AND METHODS: The study had two groups; Group A (36 treatment naive, uncomplicated Graves' disease patients) and B (34 Graves' disease patients on carbimazole prior to radioiodine therapy). Both groups had baseline clinical, biochemical evaluation and were reassessed at 3 and 6 months for evaluating the clinical status for possible documentation of cure. RESULTS: The cure rate was 61.1% in drug naive group and 58.8% in pretreated group at 6 months following radioiodine (P = 0.845). Higher baseline 999m technicium (99m Tc) uptake, male gender, BMI and higher baseline free thyroxine (fT4) level predicted treatment failure following radioiodine therapy. CONCLUSIONS: Administration of carbimazole prior to low dose radioiodine therapy does not alter the efficacy of radioiodine. Low fixed dose (5 mCi) of radioactive iodine may be a safe and effective primary therapeutic option in Graves' disease patients pretreated with antithyroid drugs. PMID- 25285288 TI - Association of helicobacter pylori infection with type 2 diabetes. AB - INTRODUCTION: Helicobacter pylori (H. pylori) infection has been associated with increased levels of inflammatory cytokines and subsequent insulin resistance and epidemiologically linked to type 2 diabetes. OBJECTIVES: To study the prevalence rate of H. pylori infection in type 2 diabetes and its relation with HbA1C levels. MATERIALS AND METHODS: In this cross-sectional case-control study, 80 patients (>=18 years) who met the Americans with Disabilities Act (ADA) criteria for diabetes were recruited. Similarly, 60 age, sex, and education matched healthy controls were taken. They were tested for H. pylori infection by rapid urease test, histological examination of antral endoscopic biopsy specimens and serology. The relationship between H. pylori infection and levels of plasma glucose and HbA1C was assessed. RESULTS: Out of the 80 patients of type 2 diabetes, H. pylori infection was found in 62 (77.5%) while it was present in only 35 (58.3%) of 60 controls, which was found to be significant (Chi-square test: 5.919, df = 1, P value = 0.015). Mean HbA1C among diabetics with H. pylori infection was 8.19 +/- 1.16% and without H. pylori infection was 6.9 +/- 0.84% (t = 4.3872, P value = 0.0001). CONCLUSIONS: Prevalence of H. pylori infection was significantly higher in diabetes as compared to controls. Presence of H. pylori infection significantly correlated with the level of HbA1C. PMID- 25285289 TI - Bone mineral status in Egyptian children with classic congenital adrenal hyperplasia. A single-center study from Upper Egypt. AB - AIM OF THE STUDY: To evaluate bone mineral density (BMD) and levels of bone turnover markers in Egyptian children with classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency and its relationship with disease related variables. PATIENTS AND METHODS: The study population consisted of 28 children from Upper Egypt with classic CAH, their mean age 8.3 +/- 2.4 years and 28 age and sex matched healthy control. They were subjected to measurement of BMD of lumbar spines (L1-L4) and femoral neck using dual-energy-X-ray absorptiometry (DXA) and laboratory evaluation of bone turnover markers including Osteocalcin and serum receptor activator of nuclear factor kappaB-ligand (RANKL). RESULT: Children with CAH had significantly lower bone-mineral density (BMD) for both, vertebrae and femoral neck than controls. This difference is more obvious in children with poor control and in those receiving prednisone therapy. There was a significantly lower serum osteocalcin, and significantly higher serum RANKL levels in patients with CAH than the healthy controls. This differences is more obvious in children with poor control and in those receiving prednisone therapy. Total bone mineral content (BMC [gm]) have significant negative correlations to age (r = -0.81, P < 0.001), disease duration (r = -0.881, P < 0.001), 17 OH Progesterone level (r = -0.543, P < 0.05), RANKL level (r = -0.635, P < 0.05), and significant positive correlation with osteocalcin (r = 0.576, P < 0.001). CONCLUSIONS: Children from Upper Egypt with classic CAH may have reduced BMD and increase bone turnover compared with controls. This difference is more obvious in children with poor control and in those receiving prednisone therapy. RECOMMENDATIONS: Active monitoring of BMD in CAH children using Dual-energy X-ray absorptiometry (DEXA) scanning. Furthermore, effort should be done to bring hydrocortisone to Upper Egypt to replace prednisone in children with classic congenital adrenal hyperplasia. PMID- 25285290 TI - Does fasting or postprandial state affect thyroid function testing? AB - BACKGROUND: Thyroid stimulating hormone (TSH) levels vary with the time of the day and probably in relation to food. In this study, we addressed the question of whether a fasting or non-fasting sample would make a clinically significant difference in the interpretation of thyroid function tests. MATERIALS AND METHODS: Fifty seven adult ambulatory patients were selected from our laboratory database and were divided into Group A [Normal free thyroxine (T4) and TSH], Group B (subclinical hypothyroid with increased TSH and normal free T4) and Group C (overt hypothyroid with low free T4 and high TSH). Thyroid functions (free T4 and TSH) were done in fasting state and 2 hours postprandially. RESULTS: TSH was suppressed in all subjects after food irrespective of the fasting levels. Free T4 values did not change significantly. This resulted in reclassification of 15 out of 20 (75%) subjects as subclinical hypothyroidism (SCH) based on fasting values whose TSH values were otherwise within range in the postprandial sample. This may have an impact on the diagnosis and management of hypothyroidism especially where even marginal changes in TSH may be clinically relevant as in SCH and in pregnancy. CONCLUSION: TSH levels showed a statistically significant decline postprandially in comparison to fasting values. This may have clinical implications in the diagnosis and management of hypothyroidism, especially SCH. PMID- 25285292 TI - Clinical experience of switching from glargine or neutral protamine Hagedorn insulin to insulin detemir in type 2 diabetes: Observations from the Indian cohort in the A1chieve study. AB - AIM: To explore the clinical safety and effectiveness of insulin detemir (IDet) in a subgroup of Indian patients with type 2 diabetes (T2D) switched from either insulin glargine (IGlar) or neutral protamine Hagedorn (NPH) insulin in the 24 week, non-interventional A1chieve study. MATERIALS AND METHODS: Indian patients with T2D switching from pre-study IGlaror NPH insulin to IDet were included. Safety and effectiveness outcomes were evaluated by the physicians in local clinical settings. RESULTS: A total of 102 patients switched from IGlar to IDet (GLA group) and 39 patients switched from NPH insulin to IDet (NEU group). At baseline, the mean glycated hemoglobin A1c (HbA1c) levels were 9.9 +/- 1.8% in the GLA group and 9.1 +/- 1.2% in the NEU group. No serious adverse drug reactions, serious adverse events, or major hypoglycemic events were reported in either group throughout the study. At baseline and Week 24, 11.8% and 7.5% of patients, respectively, reported overall hypoglycemic events in the GLA group. No hypoglycemic events were reported at Week 24 in the NEU group. At Week 24, the mean HbA1c levels were 7.6 +/- 0.9% in the GLA group and 7.3 +/- 0.7% in the NEU group. The mean fasting plasma glucose, postprandial plasma glucose and quality of life also appeared to improve over 24 weeks. CONCLUSION: Switching to IDet therapy from IGlar and NPH insulin was well-tolerated and appeared to be associated with improved glycogenic control in Indian patients. PMID- 25285291 TI - Association of metabolic syndrome with severity of coronary artery disease. AB - BACKGROUND: South Asians are more prone to develop metabolic syndrome (MetS). The additive predictive value of components of MetS for cardiovascular diseases is still debated. We undertook this study to evaluate the association of MetS and its components with severity of coronary artery disease (CAD). MATERIALS AND METHODS: Three hundred patients with known coronary disease above the age of 25 years were included in this study. Blood samples were collected for biochemical markers. Patients were stratified into subjects with and without MetS (International Diabetes Federation, IDF, criteria) and severity of CAD (number of vessel involved). RESULTS: Mean age of the patient in the study was 60.9 +/- 12.4 years (male, M: 72%; female, F: 28%). MetS was present in 64% patients. Patients with MetS had more severe CAD compared to those without MetS. Triple vessel disease (TVD) was present in 62.5% of patients with MetS compared to 34.3% among without MetS (P < 0.0001). The percent number of patients with TVD showed increasing trend with increasing number of components of MetS (0-0%; 1-20%; 2 27.5%; 3-47.8%; 4-72.6%; 5-78.3%; Chi square for trend < 0.0001). Inflammatory markers [interleukin (IL) 6: 77.67 +/- 79.48 vs. 41.21 +/- 60.72 pg/ml, P < 0.0001; tumor nuclear factor (TNF)-alpha: 28.0 +/- 47.49 vs 20.43 +/- 24.5 pg/ml, P < 0.0001; high sensitive C-reactive protein (hsCRP): 14.30 +/- 9.91 vs. 7.02 +/ 7.18 mg/L, P < 0.0001], insulin resistance [homeostatic model analysis insulin resistance (HOMA-IR): 22.33 +/- 23.37 vs. 10.86 +/- 13.90, P < 0.0001] were higher and insulin sensitivity [quantitative insulin check index (QUICKI): 0.26 +/- 0.03 vs. 0.30 +/- 0.04, P < 0.0001] was significantly lower in subjects with MetS compared to subjects without MetS. Among lipids, total cholesterol were comparable but triglyceride (175 +/- 42 vs. 179 +/- 48 vs. 180 +/- 47 mg/dl, P < 0.0001) was high and high-density lipoprotein (HDL; 44.72 +/- 7.63 vs. 39.96 +/- 8.70 vs. 36.05 +/- 8.84, P < 0.0001) was low in subjects with TVD compared to others. Similarly, percentage of patients with diabetes (7.5% vs. 26.3% vs. 63.7%, P < 0.0001) and hypertension (34.3% vs. 56.6% vs. 77.7%, P < 0.0001) were higher in subjects with TVD compared to others. CONCLUSIONS: There is a strong correlation of MetS and its components with severity of CAD. PMID- 25285293 TI - Vitamin D status and risk of ischemic stroke in North Indian patients. AB - CONTEXT: Accumulating evidence suggests that vitamin D deficiency is associated with increased risk of stroke. Contributing mechanisms have been linked to the association of vitamin D deficiency with the presence of hypertension, diabetes mellitus, and atherosclerosis, however, the evidence is conflicting. AIMS: This study sought to determine the association of vitamin D deficiency with ischemic stroke and its risk factors. SETTINGS AND DESIGN: Cross-sectional case control study. SUBJECTS AND METHODS: We measured serum 25-hydroxyvitamin D [25(OH) D] and intact parathyroid hormone (iPTH) levels in 73 patients of ischemic stroke, presenting within 7 days of onset of stroke and compared with 70 age and gender matched controls. STATISTICAL ANALYSIS USED: The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 17.0 for Windows). RESULTS: The mean age of patients and controls was 59.9 +/- 11.2 years and 57.9 +/- 9.7 years, respectively (P = 0.26). Of 67.1% patients were men as compared to 65.7% controls (P = 0.86). There was no significant difference in the prevalence of vitamin D deficiency/insufficiency (P = 0.25), mean 25(OH) D levels (P = 0.75), and iPTH levels (P = 0.10) between cases and controls. No association of vitamin D deficiency/insufficiency was found with the prevalent risk factors in cases of ischemic stroke. CONCLUSIONS: Vitamin D deficiency does not bear an association with ischemic stroke or its risk factors. PMID- 25285294 TI - Pattern of 25 hydroxy vitamin D status in North Indian people with newly detected type 2 diabetes: A prospective case control study. AB - BACKGROUND: Vitamin D deficiency (VDD) has been linked to impaired glucose tolerance and type 2 diabetes (T2D) in humans. The aim of the present study was to find the vitamin D status in newly detected T2D patients compared with healthy controls. MATERIALS AND METHODS: One hundred and two, newly detected T2D patients and similar number of age, body mass index (BMI), and gender matched healthy controls without diabetes were studied. In addition to basic information, metabolic parameters and serum 25 hydroxy vitamin D (25HD) were measured in both the groups. RESULTS: Overall 25HD, was lower (mean +/- SD, 18.81 +/- 15.18 ng/ml) in patients with T2D as compared to healthy controls (28.46 +/- 18.89 ng/ml) (P = 0.00). Taking a cut of 30 ng/ml, 81% of T2D patients had either VDD or insufficiency compared to 67% of healthy control subjects. Severe VDD (25HD of < 5 ng/ml) was seen in 16.2% of patients with diabetes and 2.5% of control subjects. Levels of 25HD had a negative correlation with HbA1c, fasting plasma glucose. CONCLUSIONS: VDD is common in people with new onset T2D. PMID- 25285295 TI - Diabetes mellitus: Trends in northern India. AB - Diabetes mellitus is becoming a global health issue with more than 80% diabetics living in developing countries. India accounts for 62.4 million diabetics (2011). Indian Council of Medical Research India Diabetes Study (ICMR-INDIAB) study showed highest weighted prevalence rate in the north India among all studied regions. Diabetes in north India has many peculiarities in all aspects from risk factors to control programmers. North Indians are becoming more prone for diabetes and dyslipidemia because rapid westernization of living style and diet due rapid migration to metropolitan cities for employment. North Indian diabetes is plagued with gender bias against females, poor quality of health services, myths, and lack of disease awareness compounded with small number of prevention and awareness programmers that too are immature to counteract the growing pandemic. PMID- 25285296 TI - Importance of Universal screening for thyroid disorders in first trimester of pregnancy. AB - OBJECTIVE: To determine the importance of screening for Thyriod disorders in the first trimester of pregnancy. MATERIALS AND METHODS: The Study was conducted on 305 patients which were were randomly selected and screened on OPD basis by TSH levels (cut off level 0.10-2.50 mIU/ml). RESULTS: In the 305 women screened mean age was 24.46 years, mean gestational age was 9.09 weeks, 89.83% were euthyroid, 9.8%were hypothyroid, 0.32% were hyperthyroid. Incidence of hypothyroidism in high risk population was 20.58% and in normal population was 6.7%. There was significant association of thyroid disorders with high risk factors (P < 0.001). In hypothyroid women 46% had adverse perinatal outcomes and 53.33% had normal outcomes. This shows statistically significant association abnormal TSH values with adverse pregnancy outcomes (P < 0.001). In abnormal perinatal outcomes 6.2% women had Caesarean section out of them 73.68% were euthyroid, 26.31% were hypothyroid 1.9% had preterm labour, out of them 50% were euthyroid, 50% were hypothyroid. Out of 2.2% spontaneous abortions 28.5% were in euthyroid group while 71.4% were in hypothyroid group. There was 1 term stillbirth in hypothyroid group. This study showed significant association between abnormal thyroid stimulating hormone (TSH) values and adverse perinatal outcomes (P < 0.001). CONCLUSION: There is significant correlation between risk factors and hypothyroidism. So high risk screening is mandatory in early pregnancy. But if we screen only high risk population we would miss 4.6% cases which could have been diagnosed and treated earlier. Therefore it is important to screen all pregnant women in the first trimester, it should be made mandatory. PMID- 25285297 TI - Acanthosis nigricans in insulinoma. PMID- 25285298 TI - Tools as a means to achieve person-centered patient education? PMID- 25285299 TI - Response to the "Endocrinology and the arts at the feet of the dancing Lord: Parathyroid hormone resistance in an Indian icon". PMID- 25285300 TI - Author reply. PMID- 25285301 TI - A case of "pseudo-ketoacidosis". PMID- 25285302 TI - The Niemann-Pick C1 and caveolin-1 proteins interact to modulate efflux of low density lipoprotein-derived cholesterol from late endocytic compartments. AB - The Niemann-Pick C1 (NPC1) protein has a central role in regulating the efflux of lipoprotein-derived cholesterol from late endosomes/lysosomes and transport to other cellular compartments. Since the NPC1 protein has been shown to regulate the transport of cholesterol to cellular compartments enriched with the ubiquitous cholesterol-binding and transport protein caveolin-1, the present study was performed to determine whether the NPC1 and caveolin-1 proteins interact and function to modulate efflux of low density lipoprotein (LDL)-derived cholesterol from endocytic compartments. To perform these studies, normal human fibroblasts were grown in media with lipoprotein-deficient serum (LPDS) or media with LPDS supplemented with purified human LDL. The results indicated reciprocal co-immunoprecipitation and partial co-localization of the NPC1 and caveolin-1 proteins that was decreased when fibroblasts were grown in media with LDL. Consistent with interaction of the NPC1 and caveolin-1 proteins, a highly conserved caveolin-binding motif was identified within a cytoplasmic loop located adjacent to the sterol-sensing domain (SSD) of the NPC1 protein. To examine the functional relevance of this interaction, fibroblasts were transfected with caveolin-1 siRNA and found to accumulate increased amounts of LDL-derived cholesterol within late endosomes/ lysosomes. Together, this report presents novel results demonstrating that the NPC1 and caveolin-1 proteins interact to modulate efflux of LDL-derived cholesterol from late endocytic compartments. PMID- 25285304 TI - Blood Pressure, Heart Rate, and CNS Stimulant Medication Use in Children with and without ADHD: Analysis of NHANES Data. AB - It is estimated that 2-3% of children in the US have hypertension (HTN) and 8% of children ages 4-17 carry the diagnosis of attention-deficit hyperactivity disorder (ADHD). The prevalence of HTN and cardiovascular (CV) risk factors in children with ADHD on CNS stimulant treatment (stimulants) compared to no treatment and compared to their healthy counterparts is not well described. Using National Health and Nutrition Survey data, we examined demographic, blood pressure (BP) and CV risk factors of 4,907 children aged 12-18 years with and without the diagnosis of ADHD, and further examined the CV risk in a subgroup of ADHD patients on stimulants. Three hundred eighty-three (10.7%) children were reported to have ADHD, of whom 111 (3.4%) were on stimulants. Children with ADHD on stimulants were significantly younger, male, and white compared to those with ADHD not on medication and those without ADHD. Body mass index (BMI), eGFR, cholesterol, the prevalence of albuminuria, and poverty were not significantly different between the three groups. One hundred sixty (2.7%) had BP in the hypertensive and 637 (12.4%) in the pre-hypertensive range. The prevalence of elevated BP (HTN and/or pre-HTN range) was not different between children with ADHD on stimulants compared to ADHD without medication and those without ADHD. Heart rate (HR) was significantly higher in the ADHD group on stimulants vs. the groups ADHD on no stimulants and without ADHD. When the relationship between stimulants and the risk of abnormal BP was examined, there was a significant interaction between having BP in the HTN range and sex. After adjusting for BMI, race, and age, females with ADHD on stimulants tended to be older and had significantly more BP in the hypertensive range. On the other hand, males were more likely to be of a white race and older, but not hypertensive. Children with ADHD on stimulants have significantly higher HR than children with ADHD on no stimulants and children without ADHD. On the other hand, the prevalence of abnormal BP classification is comparable between the three groups. PMID- 25285303 TI - Alzheimer's Disease in Down Syndrome. AB - A key challenge to adults with Down syndrome (DS) as they age is an increased risk for cognitive decline, dementia, and Alzheimer disease (AD). In DS persons ranging from 40-49 years of age, 5.7-55% may be clinically demented and between 50-59 years, dementia prevalence ranges from 4-55% (reviewed in [1]). Despite the wide ranges reported for dementia prevalence, a consistent feature of aging in DS is the progressive accumulation of AD brain pathologies. By the age of 40 years, virtually all have sufficient senile plaques and neurofibrillary tangles for a neuropathological diagnosis of AD [2]. Thus, there is dissociation between the age of onset of AD neuropathology (40 years) and increasing signs of clinical dementia. We discuss the hypothesis that frontal impairments are a critical factor affecting cognitive function and are associated with white matter (WM) and AD neuropathology. While these may be an early sign of conversion to dementia, we also review several other clinical comorbidities that may also contribute to dementia onset. PMID- 25285305 TI - Genetic and Morphometric Variability of Triatoma sordida (Hemiptera: Reduviidae) from the Eastern and Western Regions of Paraguay. AB - Triatoma sordida is widely distributed throughout the Chaco and the Eastern Region of Paraguay. It is associated to palm trees and artificial ecotopes located in peridomestic environments. The aim of this work was to determine genetic and morphometric variability and feeding behavior among population of T. sordida captured in domicile and peridomicile areas of Paraguay. Feeding contents and levels of genetic and morphometric variation were determined in 124 T. sordida from domicile and peridomicile populations of San Pedro and Paraguari departments of the Eastern Region and Boqueron and Presidente Hayes departments of the Western region using Double Diffusion Gel, random amplified polymorphic DNA (RAPD), and head and wings morphometry. Morphometric analysis revealed isolation of populations by geographic region and larger size in triatomine populations from the Western Region. RAPD showed no specific patterns for domicile and peridomicile populations. The estimator of diversity (F ST; 0.08) and high gene flow obtained (N m; 5.7) did not allow the establishment of genetic differentiation within the same region. The blood meal source showed that poultry feeding was 38% of host preferences, and human blood was the second feeding preference (24%) in the insects from the Eastern Region while poultry feeding was predominant in those from the Western Region (30%). This work showed homogeneity between T. sordida populations of the same region and between domicile and peridomicile. The genetic diversity was determined among T. sordida populations of both geographical regions suggesting differentiation associated to eco geographical isolation by distance. It is important to notice that pattern feedings were different between the two regions. Further studies should be focused on how phenetic and genetic variations could be related to the adaptation capacity of these triatomine populations to domicile, increasing their vector potentiality in the transmission of Chagas disease. PMID- 25285306 TI - Race, age, and obesity disparities in adult physical activity levels in breast cancer patients and controls. AB - Physical activity has been shown to be inversely associated with breast cancer recurrence and survival. Although physical activity is known to decline with age, rates of change in physical activity have not been well characterized in breast cancer patients and subgroups with known disparities in breast cancer survival, especially in minorities, the elderly, and the obese. We evaluated moderate and strenuous physical activity from high school through diagnosis in 1,220 breast cancer patients, and from high school to recruitment in 935 controls. We compared the proportion of patients and controls meeting the American Cancer Society (ACS) guidelines for physical activity and differences in declines in level of physical activity by race, age, and obesity. At diagnosis, only 33.2% of breast cancer patients met the ACS physical activity guidelines. Only 13.2, 24.7, and 30.5% of African-American (AA), obese, and older (>=65 years) patients met the guidelines, respectively. Controls showed slightly higher rates, with 36.4% overall, 23.7% of AA, 29.0% of obese, and 32.4% of older women meeting the guidelines. AA patients were less likely to meet guidelines compared to White patients (p < 0.0001). Obese patients were less likely to meet guidelines compared to non-obese (p < 0.0001). We found that both moderate and strenuous physical activity declined after high school in patients and controls. AA patients reported steeper declines in strenuous (p = 0.0027), and total (p = 0.0009) physical activity compared to Whites. Obese patients reported steeper declines in total physical activity compared to non-obese (p = 0.022). Differences in average slopes of declines in physical activity were not observed by age. Our results suggest that strategies and programs to encourage women to maintain recommended levels of physical activity after high school are needed. Furthermore, breast cancer patients, particularly AA and obese patients, should be targeted to help reduce disparities. PMID- 25285308 TI - How Reliable Are Hematological Parameters in Predicting Uncomplicated Plasmodium falciparum Malaria in an Endemic Region? AB - BACKGROUND: Malaria remains endemic in Sub-Saharan Africa. Hematological changes that occur have been suggested as potential predictors of malaria. This study was aimed at evaluating the diagnostic relevance of hematological parameters in predicting malaria. METHODS: A cross-sectional study involving 370 patients with signs and symptoms of malaria was conducted at Mulago Hospital, Kampala, from May, 2012 to February, 2013. Thin and thick blood films were prepared for each patient and stained with Giemsa to aid the detection of malaria parasites. Patients' hematological parameters were determined. RESULTS: Out of the 370 patients, 61 (16.5%) had malaria. Significant differences in the hematological parameters between P. falciparum malaria parasitemic patients and nonparasitemic patients were only observed in mean (+/-SD) of the differential monocyte count (10.89 +/- 6.23% versus 8.98 +/- 5.02%, p = 0.01) and the platelet count (172.43 (+/- 80.41) *103 cells/MUl versus 217.82 +/- (95.96) *103 cells/MUl p = 0.00). The mean (+/-SD) values of the red blood cell indices (hemoglobin count, MCV, MCH, and MCHC), the differential neutrophil and lymphocyte counts, and the mean platelet volume (MPV) did not significantly differ between the two groups. CONCLUSION: Hematological changes are unreliable laboratory indicators of malaria in acute uncomplicated Plasmodium falciparum malaria. PMID- 25285309 TI - ENCOURAGING RECORD USE FOR FINANCIAL ASSET QUESTIONS IN AWEB SURVEY. AB - We report on two experiments to encourage record use by respondents in an Internet survey. The experiments were conducted in the 2009 Health and Retirement Study (HRS) Internet Survey, administered to those in the HRS panel with Internet access, and in the 2011 HRS Internet Survey. Encouraging respondents to consult records at the relevant point in the questionnaire significantly increased reported record use (from 39 percent to 47 percent), but was insufficient to produce significant changes in the precision (amount of rounding) of the information reported. Including the encouragement in the mailed invitation to the Web survey in 2011 resulted in a lower response rate (77 percent with encouragement, 80 percent without), but increased reported record use among respondents (from 46 percent to 55 percent). In neither case was the increase in reported record use large enough to produce significant differences in the precision of the information reported between the groups with and without encouragement. PMID- 25285307 TI - Amygdala Kindling Alters Estrus Cycle and Ovarian Morphology in the Rat. AB - The objective of this study is to explore the effects of amygdala kindling on estrus cycle and ovarian morphology. Thirty-five female rats at the age of 8 weeks were randomly designated to electrode kindled, sham-kindled, and normal controls. Kindled rats were implanted with kindling electrodes in the left basolateral amygdala and kindled by brief suprathreshold stimulations with a bipolar electrode. Estrous cycles were daily monitored through vaginal smears. Electrographic and behavioral seizures were recorded and ovarian morphology was evaluated by light and electron microscopies. Our results showed that the kindled rats lost their ovarian periodicity displayed significant ovarian enlargement. H&E staining revealed increased number of growing follicles and total follicles, as well as polycysts in the ovaries of the kindled animals compared to sham and control animals. Ultrastructural study detected numerous apoptotic granulosa cells in growing follicles and thecal cell hyperplasia with secretary granules in the thecal cells in the kindled rats. The results suggest that amygdala kindling is a risk factor for the development of polycystic ovary syndrome. PMID- 25285310 TI - Next Generation of the Java Image Science Toolkit (JIST): Visualization and Validation. AB - Modern medical imaging analyses often involve the concatenation of multiple steps, and neuroimaging analysis is no exception. The Java Image Science Toolkit (JIST) has provided a framework for both end users and engineers to synthesize processing modules into tailored, automatic multi-step processing pipelines ("layouts") and rapid prototyping of module development. Since its release, JIST has facilitated substantial neuroimaging research and fulfilled much of its intended goal. However, key weaknesses must be addressed for JIST to more fully realize its potential and become accessible to an even broader community base. Herein, we identify three core challenges facing traditional JIST (JIST-I) and present the solutions in the next generation JIST (JIST-II). First, in response to community demand, we have introduced seamless data visualization; users can now click 'show this data' through the program interfaces and avoid the need to locating files on the disk. Second, as JIST is an open-source community effort by design; any developer may add modules to the distribution and extend existing functionality for release. However, the large number of developers and different use cases introduced instability into the overal JIST-I framework, causing users to freeze on different, incompatible versions of JIST-I, and the JIST community began to fracture. JIST-II addresses the problem of compilation instability by performing continuous integration checks nightly to ensure community implemented changes do not negatively impact overall JIST-II functionality. Third, JIST-II allows developers and users to ensure that functionality is preserved by running functionality checks nightly using the continuous integration framework. With JIST-II, users can submit layout test cases and quality control criteria through a new GUI. These test cases capture all runtime parameters and help to ensure that the module produces results within tolerance, despite changes in the underlying architecture. These three "next generation" improvements increase the fidelity of the JIST framework and enhance utility by allowing researchers to more seamlessly and robustly build, manage, and understand medical image analysis processing pipelines. PMID- 25285311 TI - Enabling ITK-based processing and 3D Slicer MRML scene management in ParaView. AB - This paper documents on-going work to facilitate ITK-based processing and 3D Slicer scene management in ParaView. We believe this will broaden the use of ParaView for high performance computing and visualization in the medical imaging research community. The effort is focused on developing ParaView plug-ins for managing VTK structures from 3D Slicer MRML scenes and encapsulating ITK filters for deployment in ParaView. In this paper, we present KWScene, an open source cross-platform library that is being developed to support implementation of these types of plugins. We describe the overall design of the library and provide implementation details and conclude by presenting a concrete example that demonstrates the use of the KWScene library in computational anatomy research at Johns Hopkins Center for Imaging Science. PMID- 25285312 TI - Life Expectancy Estimates in the Life Care Plan: Accounting for Economic Factors. AB - OBJECTIVE: The purpose of this study was to summarize the existing scientific literature on the relationship between economic factors and life expectancy (LE) after spinal cord injury (SCI), present new data on the relationship between household income and LE, and present a revised theoretical risk model to account for the observed relationships. RESEARCH DESIGN: Data were from a prospective cohort study of 1386 participants with SCI which began in 1997. Mortality status was determined 10 years later. Person year logistic regression was used to evaluate predictors of mortality and to generate LE estimates, as each year of follow-up was treated as a separate observation (rather than a single observation per person). RESULTS: Results indicated significant relationships between age, injury severity, household income and LE, which suggest the need for more refined models of economic factors and LE. CONCLUSIONS: LE estimates in life care plans need to account for economic factors in order to improve accuracy. It is important to allocate resources to meet all healthcare needs throughout the lifecycle to ensure that LE is not compromised. PMID- 25285313 TI - Molecular mechanism underlying the impact of vitamin D on disease activity of MS. AB - OBJECTIVE: Some previous studies suggest modest to strong effects of 25 hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D. METHODS: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs). RESULTS: The number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene-gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b. INTERPRETATION: Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b. PMID- 25285315 TI - Role of Bone Marrow in Pathogenesis of Viral Infections. PMID- 25285316 TI - Improving Pain Recognition Through Better Utilisation of Temporal Information. AB - Automatically recognizing pain from video is a very useful application as it has the potential to alert carers to patients that are in discomfort who would otherwise not be able to communicate such emotion (i.e young children, patients in postoperative care etc.). In previous work [1], a "pain-no pain" system was developed which used an AAM-SVM approach to good effect. However, as with any task involving a large amount of video data, there are memory constraints that need to be adhered to and in the previous work this was compressing the temporal signal using K-means clustering in the training phase. In visual speech recognition, it is well known that the dynamics of the signal play a vital role in recognition. As pain recognition is very similar to the task of visual speech recognition (i.e. recognising visual facial actions), it is our belief that compressing the temporal signal reduces the likelihood of accurately recognising pain. In this paper, we show that by compressing the spatial signal instead of the temporal signal, we achieve better pain recognition. Our results show the importance of the temporal signal in recognizing pain, however, we do highlight some problems associated with doing this due to the randomness of a patient's facial actions. PMID- 25285317 TI - Action Anticipation and Interference: A Test of Prospective Gaze. AB - In the current study we investigate the proposal that one aspect of social perception, action anticipation, involves the recruitment of representations for self-produced action. An eye tracking paradigm was implemented to measure prospective gaze to a goal while performing either a motor or working memory task. Results indicate an effect of the motor task, suggesting the interference of a shared motor and action perception representation. PMID- 25285318 TI - ATTENTION MAINTENANCE IN NOVICE DRIVERS: ASSESSMENT AND TRAINING. AB - All programs assessing attention maintenance inside the vehicle have required eye trackers and either a driving simulator or a specially equipped field vehicle. Ideally, one would like a way to assess attention maintenance that could be implemented on a desktop PC. Additionally, one would like to have a program that could be used to train novice drivers to maintain their attention more safely on the forward roadway. An experiment was run (a) to determine whether a program FOCAL (Focused Concentration and Attention Learning) using a desktop PC could differentiate between the attention maintenance skills of novice and experienced drivers and (b) to determine whether a program that improved the hazard anticipation skills of novice drivers might also improve their attention maintenance skills. FOCAL was able to differentiate between the attention maintenance skills of novice and experienced drivers. However, hazard anticipation training did not improve the attention maintenance skills of the novice drivers. PMID- 25285314 TI - Multiple Mechanisms Contribute To Telomere Maintenance. AB - The unlimited growth potential of tumors depends on telomere maintenance and typically depends on telomerase, an RNA-dependent DNA polymerase, which reverse transcribes the telomerase RNA template, synthesizing telomere repeats at the ends of chromosomes. Studies in various model organisms genetically deleted for telomerase indicate that several recombination-based mechanisms also contribute to telomere maintenance. Understanding the molecular basis of these mechanisms is critical since some human tumors form without telomerase, yet the sequence is maintained at the telomeres. Recombination-based mechanisms also likely contribute at some frequency to telomere maintenance in tumors expressing telomerase. Preventing telomere maintenance is predicted to impact tumor growth, yet inhibiting telomerase may select for the recombination-based mechanisms. Telomere recombination mechanisms likely involve altered or unregulated pathways of DNA repair. The use of some DNA damaging agents may encourage the use of these unregulated pathways of DNA repair to be utilized and may allow some tumors to generate resistance to these agents depending on which repair pathways are altered in the tumors. This review will discuss the various telomere recombination mechanisms and will provide rationale regarding the possibility that L1 retrotransposition may contribute to telomere maintenance in tumors lacking telomerase. PMID- 25285319 TI - Disease mapping. PMID- 25285320 TI - The Use of Genetic Programming for Learning 3D Craniofacial Shape Quantifications. AB - Craniofacial disorders commonly result in various head shape dysmorphologies. The goal of this work is to quantify the various 3D shape variations that manifest in the different facial abnormalities in individuals with a craniofacial disorder called 22q11.2 Deletion Syndrome. Genetic programming (GP) is used to learn the different 3D shape quantifications. Experimental results show that the GP method achieves a higher classification rate than those of human experts and existing computer algorithms [1], [2]. PMID- 25285321 TI - Discriminating Tissue Stiffness with a Haptic Catheter: Feeling the Inside of the Beating Heart. AB - Catheter devices allow physicians to access the inside of the human body easily and painlessly through natural orifices and vessels. Although catheters allow for the delivery of fluids and drugs, the deployment of devices, and the acquisition of the measurements, they do not allow clinicians to assess the physical properties of tissue inside the body due to the tissue motion and transmission limitations of the catheter devices, including compliance, friction, and backlash. The goal of this research is to increase the tactile information available to physicians during catheter procedures by providing haptic feedback during palpation procedures. To accomplish this goal, we have developed the first motion compensated actuated catheter system that enables haptic perception of fast moving tissue structures. The actuated catheter is instrumented with a distal tip force sensor and a force feedback interface that allows users to adjust the position of the catheter while experiencing the forces on the catheter tip. The efficacy of this device and interface is evaluated through a psychophyisical study comparing how accurately users can differentiate various materials attached to a cardiac motion simulator using the haptic device and a conventional manual catheter. The results demonstrate that haptics improves a user's ability to differentiate material properties and decreases the total number of errors by 50% over the manual catheter system. PMID- 25285322 TI - Cancer Cell: Linking Oncogenic Signaling to Molecular Structure. AB - A multiscale strategy is presented for constructing models of intracellular signaling networks in which the oncogenic behavior of the network is encoded through alternate parameterization of the kinetic and structural properties of mutant oncoproteins. The approach uses molecular dynamics and docking simulations to quantify altered topologies of interactions as well as to provide the missing parameters for network models of both wild-type and oncogenic signaling. Through simulation of the resulting signaling networks, the global behavior of these networks may then be compared and functional roles may be assigned to the mutant oncoproteins. An example of this approach is presented in which structural alterations found in a mutant form of the epidermal growth factor receptor are represented as kinetic perturbations in a model of growth factor signaling. Based on network parameters estimated from molecular-level simulations, simulations at the network level show that small perturbations in molecular structure can lead to profoundly altered cellular phenotype. PMID- 25285323 TI - Long Term Effects of Hazard Anticipation Training on Novice Drivers Measured on the Open Road. AB - (a) The purpose of this study was to determine whether novice drivers that were trained to anticipate hazards did so better than novice drivers who were not so trained immediately after training and up to one year after training occurred. (b) Novice drivers who had held their restricted license for about one month were randomly assigned to a PC-based hazard anticipation training program (RAPT) or a placebo (control) training program. The programs took about one hour to complete. The effects of training were assessed in a field drive by using patterns of eye movements to assess whether drivers anticipated a potential unseen hazard. (c) The effects of training persisted over time. In the field test immediately after training, the RAPT group anticipated the hazards 65.8% of the time whereas; the control group anticipated them only 47.3% of the time. Six or more months later, the groups were brought back for a second field test and the effects of training did not diminish; the RAPT group anticipated the hazards 61.9% of the time compared to 37.7% for the control group. PMID- 25285324 TI - Passive and In-situ Assessment of Mental and Physical Well-being using Mobile Sensors. AB - The idea of continuously monitoring well-being using mobile-sensing systems is gaining popularity. In-situ measurement of human behavior has the potential to overcome the short comings of gold-standard surveys that have been used for decades by the medical community. However, current sensing systems have mainly focused on tracking physical health; some have approximated aspects of mental health based on proximity measurements but have not been compared against medically accepted screening instruments. In this paper, we show the feasibility of a multi-modal mobile sensing system to simultaneously assess mental and physical health. By continuously capturing fine grained motion and privacy sensitive audio data, we are able to derive different metrics that reflect the results of commonly used surveys for assessing well-being by the medical community. In addition, we present a case study that highlights how errors in assessment due to the subjective nature of the responses could potentially be avoided by continuous sensing and inference of social interactions and physical activities. PMID- 25285325 TI - Recognizing Clothes Patterns for Blind People by Confidence Margin based Feature Combination. AB - Clothes pattern recognition is a challenging task for blind or visually impaired people. Automatic clothes pattern recognition is also a challenging problem in computer vision due to the large pattern variations. In this paper, we present a new method to classify clothes patterns into 4 categories: stripe, lattice, special, and patternless. While existing texture analysis methods mainly focused on textures varying with distinctive pattern changes, they cannot achieve the same level of accuracy for clothes pattern recognition because of the large intra class variations in each clothes pattern category. To solve this problem, we extract both structural feature and statistical feature from image wavelet subbands. Furthermore, we develop a new feature combination scheme based on the confidence margin of a classifier to combine the two types of features to form a novel local image descriptor in a compact and discriminative format. The recognition experiment is conducted on a database with 627 clothes images of 4 categories of patterns. Experimental results demonstrate that the proposed method significantly outperforms the state-of-the-art texture analysis methods in the context of clothes pattern recognition. PMID- 25285327 TI - Virtual Exertions: a user interface combining visual information, kinesthetics and biofeedback for virtual object manipulation. AB - Virtual Reality environments have the ability to present users with rich visual representations of simulated environments. However, means to interact with these types of illusions are generally unnatural in the sense that they do not match the methods humans use to grasp and move objects in the physical world. We demonstrate a system that enables users to interact with virtual objects with natural body movements by combining visual information, kinesthetics and biofeedback from electromyograms (EMG). Our method allows virtual objects to be grasped, moved and dropped through muscle exertion classification based on physical world masses. We show that users can consistently reproduce these calibrated exertions, allowing them to interface with objects in a novel way. PMID- 25285326 TI - Modeling Response Times in the Go/No-Go Discrimination Task. AB - The work presented here uses a simple stochastic model as a cognitive psychometric tool for analyzing response time data in the Go/No-Go Discrimination task with motivationally distinct conditions. The parameters of the model inform us of underlying cognitive mechanisms because they have an established psychological meaning and allow us to quantify a subjects ability and response caution. Using these model parameters, we focus on the differences between subjects with varying degrees of substance abuse and antisocial behavioral disorders and show that there are reliable differences between the decision mechanisms of these subjects. Using data from executive working memory tasks, we postulate that these differences in cognitive processes might be due to differences in working memory capacity. Ultimately, we show that formal cognitive modeling has the potential to provide valuable insights into clinical phenomena that cannot be captured by traditional data analysis techniques. PMID- 25285328 TI - Predicting accurate probabilities with a ranking loss. AB - In many real-world applications of machine learning classifiers, it is essential to predict the probability of an example belonging to a particular class. This paper proposes a simple technique for predicting probabilities based on optimizing a ranking loss, followed by isotonic regression. This semi-parametric technique offers both good ranking and regression performance, and models a richer set of probability distributions than statistical workhorses such as logistic regression. We provide experimental results that show the effectiveness of this technique on real-world applications of probability prediction. PMID- 25285329 TI - Demand-Driven Clustering in Relational Domains for Predicting Adverse Drug Events. AB - Learning from electronic medical records (EMR) is challenging due to their relational nature and the uncertain dependence between a patient's past and future health status. Statistical relational learning is a natural fit for analyzing EMRs but is less adept at handling their inherent latent structure, such as connections between related medications or diseases. One way to capture the latent structure is via a relational clustering of objects. We propose a novel approach that, instead of pre-clustering the objects, performs a demand driven clustering during learning. We evaluate our algorithm on three real-world tasks where the goal is to use EMRs to predict whether a patient will have an adverse reaction to a medication. We find that our approach is more accurate than performing no clustering, pre-clustering, and using expert-constructed medical heterarchies. PMID- 25285330 TI - A General Iterative Shrinkage and Thresholding Algorithm for Non-convex Regularized Optimization Problems. AB - Non-convex sparsity-inducing penalties have recently received considerable attentions in sparse learning. Recent theoretical investigations have demonstrated their superiority over the convex counterparts in several sparse learning settings. However, solving the non-convex optimization problems associated with non-convex penalties remains a big challenge. A commonly used approach is the Multi-Stage (MS) convex relaxation (or DC programming), which relaxes the original non-convex problem to a sequence of convex problems. This approach is usually not very practical for large-scale problems because its computational cost is a multiple of solving a single convex problem. In this paper, we propose a General Iterative Shrinkage and Thresholding (GIST) algorithm to solve the nonconvex optimization problem for a large class of non-convex penalties. The GIST algorithm iteratively solves a proximal operator problem, which in turn has a closed-form solution for many commonly used penalties. At each outer iteration of the algorithm, we use a line search initialized by the Barzilai-Borwein (BB) rule that allows finding an appropriate step size quickly. The paper also presents a detailed convergence analysis of the GIST algorithm. The efficiency of the proposed algorithm is demonstrated by extensive experiments on large-scale data sets. PMID- 25285332 TI - Elevated high sensitivity C-reactive protein and uric acid levels in coronary artery ectasia. AB - AIM: The aim of this study is to examine uric asid (UA) and high sensitive C Reactive protein (Hs-CRP) levels in patients with coronary artery ectasia (CAE). MATERIALS AND METHODS: Ninety-eight patients with isolated CAE (mean age 57.5+/ 10.3), (group-I), 110 patients with CAD but without CAE (mean age 56.3+/-10.7), (group-II), and 105 patients with normal coronary angiographies (mean age 58.1+/ 10.8), (group-III) were included in the study. Blood samples of all individual were taken after coronary angiography from an antecubital vein, the patients uric acid and Hs-CRP levels were assessed. The severity of ectasia was evaluated and categorized according to Markis. RESULTS: A significant difference was not seen in serum uric acid and Hs-CRP levels between CAE and CAD groups. However, relative to the control group, uric acid and Hs-CRP levels in CAE and CAD groups were higher to a significant degree (p=0.001, p<0.001, respectively), (p<0.001, p<0.001, respectively). The statistical significant was detected between subgroups type I and type IV, Hs-CRP and UA were statistically high in subgroup type I. (p=0.012, p=0.033, respectively) In multiple regression analysis, CAE and CAD were independently associated with UA (beta=0.76; p<0.001, beta=0.68; p<0.001, respectively) and Hs-CRP (beta=0.66; p<0.01, beta=0.62; p<0.01, respectively) along with diabetes mellitus (beta=0.61; p=0.039, beta=0.94; p=0.028, respectively). CONCLUSION: In conclusion, the blood uric acid and Hs-CRP values in our study have been observed to be higher in the individuals with coronary arteri ectasia in comparison to normal individuals, and the increase in these values were found to be parallel to the extent of the ectasia. PMID- 25285331 TI - Amygdala Volume in Offspring from Multiplex for Alcohol Dependence Families: The Moderating Influence of Childhood Environment and 5-HTTLPR Variation. AB - BACKGROUND: The increased susceptibility for developing alcohol dependence seen in offspring from families with alcohol dependence may be related to structural and functional differences in brain circuits that influence emotional processing. Early childhood environment, genetic variation in the serotonin transporter linked polymorphic region (5-HTTLPR) of the SLCA4 gene and allelic variation in the Brain Derived Neurotrophic Factor (BDNF) gene have each been reported to be related to volumetric differences in the temporal lobe especially the amygdala. METHODS: Magnetic resonance imaging was used to obtain amygdala volumes for 129 adolescent/young adult individuals who were either High-Risk (HR) offspring from families with multiple cases of alcohol dependence (N=71) or Low-Risk (LR) controls (N=58). Childhood family environment was measured prospectively using age-appropriate versions of the Family Environment Scale during a longitudinal follow-up study. The subjects were genotyped for Brain-Derived Neurotrophic Factor (BDNF) Val66Met and the serotonin transporter polymorphism (5-HTTLPR). Two family environment scale scores (Cohesion and Conflict), genotypic variation, and their interaction were tested for their association with amygdala volumes. Personal and prenatal exposure to alcohol and drugs were considered in statistical analyses in order to more accurately determine the effects of familial risk group differences. RESULTS: Amygdala volume was reduced in offspring from families with multiple alcohol dependent members in comparison to offspring from control families. High-Risk offspring who were carriers of the S variant of the 5-HTTLPR polymorphism had reduced amygdala volume in comparison to those with an LL genotype. Larger amygdala volume was associated with greater family cohesion but only in Low-Risk control offspring. CONCLUSIONS: Familial risk for alcohol dependence is an important predictor of amygdala volume even when removing cases with significant personal exposure and covarying for prenatal exposure effects. The present study provides new evidence that amygdala volume is modified by 5-HTTLPR variation in High-Risk families. PMID- 25285333 TI - Two-photon AgNP/DNA-TP dye nanosensing conjugate for biothiol probing in live cells. AB - A novel silver nanoparticle (AgNP)/DNA-two-photon dye (TP dye) conjugate was fabricated as a two-photon nanoprobe for biothiol imaging in live cells. DNA templated silver nanoparticles are efficient quenchers and also provide a biocompatible nanoplatform for facile delivery of DNA into living cells. In the presence of biothiols (Cys, Hcy, or GSH), the strong interaction between the thiol group and silver results in the release of TP dye-labeled single-stranded DNA (ssDNA) from the AgNP surface and the subsequent fluorescence emission of the TP dye, thus enabling biothiols to be assayed. Our results reveal that the AgNP/DNA-TP dye nanosensing conjugate not only is a robust, sensitive, and selective sensor for quantitative detection of biothiols in the complex biological environment but also can be efficiently delivered into live cells and act as a "signal-on" sensor for specific, high-contrast imaging of target biomolecules. Our design provides a methodology for the development of future DNA templated silver nanoparticle-based two-photon fluorescent probes for use in vitro or in vivo as biomolecular sensors for live-cell imaging. PMID- 25285334 TI - 3D printed metal columns for capillary liquid chromatography. AB - Coiled planar capillary chromatography columns (0.9 mm I.D. * 60 cm L) were 3D printed in stainless steel (316L), and titanium (Ti-6Al-4V) alloys (external dimensions of ~5 * 30 * 58 mm), and either slurry packed with various sized reversed-phase octadecylsilica particles, or filled with an in situ prepared methacrylate based monolith. Coiled printed columns were coupled directly with 30 * 30 mm Peltier thermoelectric direct contact heater/cooler modules. Preliminary results show the potential of using such 3D printed columns in future portable chromatographic devices. PMID- 25285335 TI - Colorimetric and ratiometric pH responses by the protonation of phenolate within hemicyanine. AB - Compared to the nitrogen-reaction based pH optical responsive compounds, oxygen reaction related pH sensors have attracted less attention. In this paper, hemicyanine based pH probes are designed by establishing the equilibrium between phenolate and phenol, and their reversible absorption and emission responses towards pH are evaluated. The indolium-phenol based tetramethylene hemicyanine (1a) has colorimetric responses at 455 and 578 nm due to the protonating and deprotonating processes; its emission spectra shows ratiometric changes at 594 and 654 nm with large Stokes shifts under acidic (139 nm) and basic conditions (76 nm). The bromide substituent of the hemicyanine (1b) has a lower pKa value compared with unsubstituted hemicyanine (1a), which suggests that adjustable pKa can be achieved by the modification of electron withdrawing groups. The theoretical calculations based on the density functional theory (DFT) were also used to explain the optical properties. Moreover, the in cellulo fluorescence imaging shows that the hemicyanine (1a) can be used for the detection of intracellular pH levels. PMID- 25285336 TI - High-yield synthesis and crystal structure of a green Au30 cluster co-capped by thiolate and sulfide. AB - A green gold-cluster, Au30S(StBu)18, was successfully prepared in high yield and crystallographically characterized. Each cluster consists of an Au22 core capped by a mixed layer of staple Au-thiolate units, bridging thiolates and a MU3-S(2-). PMID- 25285337 TI - Disulfide reshuffling triggers the release of a thiol-free anti-HIV agent to make up fast-acting, potent macromolecular prodrugs. AB - The release of azidothymidine from macromolecular prodrugs was designed to respond to the intracellular disulfide reshuffling. This drug has no thiol groups, and a response to this trigger was engineered using a self-immolative linker. The resulting formulations were fast-acting, efficacious, and highly potent with regards to suppressing the infectivity of the virus. PMID- 25285338 TI - Rescuing DNA repair activity by rewiring the H-atom transfer pathway in the radical SAM enzyme, spore photoproduct lyase. AB - The radical SAM enzyme, spore photoproduct lyase, requires an H-atom transfer (HAT) pathway to catalyze DNA repair. By rational engineering, we demonstrate that it is possible to rewire its HAT pathway, a first step toward the development of novel catalysts based on the radical SAM enzyme scaffold. PMID- 25285339 TI - Methylation of secondary amines with dialkyl carbonates and hydrosilanes catalysed by iron complexes. AB - Methylation of secondary amines was achieved using dimethyl carbonate or diethyl carbonate as the C1 source under the catalysis of well-defined half-sandwich iron complexes bearing an N-heterocyclic carbene ligand. The reaction proceeded under mild conditions in the presence of hydrosilanes as the reductants, and the amines were obtained with good to excellent isolated yields. PMID- 25285340 TI - Multiple band light trapping in ultraviolet, visible and near infrared regions with TiO2 based photonic materials. AB - TiO2 based photonic materials (TiO2 PMs) with hierarchical top-nanonet/bottom nanotube structures were fabricated by a facile two-step electrochemical anodization method. The TiO2 PMs demonstrated multiple band light trapping activity not only in the ultraviolet and visible regions, but also in the near infrared region. PMID- 25285341 TI - A lithium anode protection guided highly-stable lithium-sulfur battery. AB - A Li3N protection layer is fabricated on the surface of a Li anode by an in situ method to suppress the shuttle effect on the basis of anode protection. The discharge capacity is retained at 773 mA h g(-1) after 500 cycles with an average coulombic efficiency of 92.3% in the electrolyte without LiNO3, while the sulfur loading of the simple sulfur cathode was 2.5-3 mg cm(-2). PMID- 25285342 TI - Probing the importance of pi-stacking interactions in DNA-templated self-assembly of bisfunctionalized guanidinium compounds. AB - Bisfunctionalized guanidinium compounds displaying aromatic side groups of varying size are shown to self-assemble in aqueous solution with single-stranded DNA through phosphodiester backbone recognition. Competition experiments indicate the importance of pi-stacking interactions in the stabilization of these DNA templated supramolecular self-assemblies. PMID- 25285343 TI - World Association for the Advancement of Veterinary Parasitology (WAAVP): Guideline for the evaluation of drug efficacy against non-coccidial gastrointestinal protozoa in livestock and companion animals. AB - The current guideline was written to aid in the design, implementation and interpretation of studies for the assessment of drug efficacy against non coccidial gastrointestinal protozoan parasites, with Giardia spp. as the leading example. The information provided in this guideline deals with aspects of how to conduct controlled studies using experimental infection models (dose determination and dose confirmation) and efficacy studies in commercial facilities (field effectiveness studies). Furthermore, the selection of suitable animals, housing, infection procedure, choice of diagnostic technique and data analysis are discussed. This guideline is intended to assist investigators in conducting specific studies, to provide specific information for registration authorities involved in the decision-making process, to assist in the approval and registration of new drugs and to facilitate the worldwide adoption of uniform procedures. The primary parameter for drug efficacy is the reduction in either parasite excretion or parasite counts and a minimum efficacy of 90% is required against non-coccidial gastrointestinal protozoa. A supporting efficacy parameter is a significant difference in the proportion of infected animals between treated and non-treated groups. Persistent efficacy is considered as an additional claim to therapeutic efficacy. PMID- 25285344 TI - Alemtuzumab for relapsing-remitting multiple sclerosis. PMID- 25285345 TI - Use of bisphosphonates in children: authors' reply. PMID- 25285346 TI - Reply: To PMID 24174631. PMID- 25285347 TI - A plasma cell ribbon. PMID- 25285348 TI - Schistosomal eggs identified on bone marrow biopsy. PMID- 25285349 TI - Medicolegal--malpractice and ethical issues in radiology. PMID- 25285350 TI - Heartland virus disease--United States, 2012-2013. PMID- 25285351 TI - In memoriam - Paola Loria (1951-2014). PMID- 25285352 TI - Three drugstore giants expand their health system partnerships. PMID- 25285353 TI - Health plans' success mixed in managing cancer care programs. PMID- 25285354 TI - Degradation of the neonicotinoid insecticide acetamiprid via the N-carbamoylimine derivate (IM-1-2) mediated by the nitrile hydratase of the nitrogen-fixing bacterium Ensifer meliloti CGMCC 7333. AB - The metabolism of the widely used neonicotinoid insecticide acetamiprid (ACE) has been extensively studied in plants, animals, soils, and microbes. However, hydration of the N-cyanoimine group in ACE to the N-carbamoylimine derivate (IM-1 2) by purified microbes, the enzyme responsible for this biotransformation, and further degradation of IM-1-2 have not been studied. The present study used liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy to determine that the nitrogen-fixing bacterium Ensifer meliloti CGMCC 7333 transforms ACE to IM-1-2. CGMCC 7333 cells degraded 65.1% of ACE in 96 h, with a half-life of 2.6 days. Escherichia coli Rosetta (DE3) overexpressing the nitrile hydratase (NHase) from CGMCC 7333 and purified NHase converted ACE to IM-1-2 with degradation ratios of 97.1% in 100 min and 93.9% in 120 min, respectively. Interestingly, IM-1-2 was not further degraded by CGMCC 7333, whereas it was spontaneously hydrolyzed at the N-carbamoylimine group to the derivate ACE-NH, which was further converted to the derivative ACE-NH2. Then, ACE NH2 was cleaved to the major metabolite IM-1-4. IM-1-2 showed significantly lower insecticidal activity than ACE against the aphid Aphis craccivora Koch. The present findings will improve the understanding of the environmental fate of ACE and the corresponding enzymatic mechanisms of degradation. PMID- 25285355 TI - Combination of everolimus and tacrolimus: a potentially effective regimen for recalcitrant psoriasis. AB - Severe forms of psoriasis that are refractory to conventional therapies are often difficult to manage. The mammalian target of rapamycin (mTOR) inhibitors potentially have versatile effects toward putative psoriatic pathologic pathways. Therefore, mTOR inhibitors may offer a range of new therapeutic options for patients with psoriasis. We describe a 55-year-old male renal transplant patient with refractory psoriasis. We adjusted his antirejection regimen and put him on everolimus (Certican((r)); Novartis, Basel, Switzerland; a semisynthetic macrolide, belonging to the mTOR inhibitors family) with low-dose tacrolimus. This combination regimen maintained his graft function and successfully controlled his psoriasis. His skin lesions never recurred in the next 18 months. To our knowledge, this is the first report showing that the combination of everolimus and tacrolimus could be used to treat recalcitrant psoriasis. The relative benefit-risk profiles of such therapies worth further investigation. PMID- 25285356 TI - Differential transcriptional activity of kidney genes in hypertensive ISIAH and normotensive WAG rats. AB - Transcriptional activity of the kidney genes was compared in hypertensive ISIAH and normotensive WAG rats using the oligonucleotide microarray technique. Most of differentially expressed genes were downregulated in ISIAH kidney both in renal cortex and medulla. According to functional annotation the kidney function in ISIAH rats is based on altered expression of many genes working in stress-related mode. The alterations in gene expression are likely related to both pathophysiological and compensatory mechanisms. The further studies of genes differentially expressed in ISIAH and WAG kidney will help to reveal new hypertensive genes and mechanisms specific for stress-induced arterial hypertension. PMID- 25285357 TI - Multivalent dendrimer vectors with DNA intercalation motifs for gene delivery. AB - Poly(amido amine) (PAMAM) dendrimers constitute an important class of nonviral, cationic vectors in gene delivery. Here we report on a new concept for dendrimer vector design based on the incorporation of dual binding motifs: DNA intercalation, and receptor recognition for targeted delivery. We prepared a series of dendrimer conjugates derived from a fifth generation (G5) PAMAM dendrimer, each conjugated with multiple folate (FA) or riboflavin (RF) ligands for cell receptor targeting, and with 3,8-diamino-6-phenylphenanthridinium ("DAPP")-derived ligands for anchoring a DNA payload. Polyplexes of each dendrimer with calf thymus dsDNA were made and characterized by surface plasmon resonance (SPR) spectroscopy, dynamic light scattering (DLS) and zeta potential measurement. These studies provided evidence supporting polyplex formation based on the observation of tight DNA-dendrimer adhesion, and changes in particle size and surface charge upon coincubation. Further SPR studies to investigate the adhesion of the polyplex to a model surface immobilized with folate binding protein (FBP), demonstrated that the DNA payload has only a minimal effect on the receptor binding activity of the polyplex: KD = 0.22 nM for G5(FA)(DAPP) versus 0.98 nM for its polyplex. Finally, we performed in vitro transfection assays to determine the efficiency of conjugate mediated delivery of a luciferase-encoding plasmid into the KB cancer cell line and showed that RF-conjugated dendrimers were 1 to 2 orders of magnitude more effective in enhancing luciferase gene transfection than a plasmid only control. In summary, this study serves as a proof of concept for DNA-ligand intercalation as a motif in the design of multivalent dendrimer vectors for targeted gene delivery. PMID- 25285358 TI - Comparative permeability studies with radioactive and nonradioactive risedronate sodium from self-microemulsifying drug delivery system and solution. AB - The purpose of this work is to prepare a self-microemulsifying drug delivery system (SMEDDS) for risedronate sodium (RSD) and to compare the permeability with RSD solution. The solubility of RSD was determined in different vehicles. Phase diagrams were constructed to determine the optimum concentration of oil, surfactant, and cosurfactant. RSD SMEDDS was prepared by using a mixture of soybean oil, cremophor EL, span 80, and transcutol (2.02:7.72:23.27:61.74, w/w, respectively). The prepared RSD SMEDDS was characterized by droplet size value. In vitro Caco-2 cell permeability studies were performed for SMEDDS and solution of radioactive ((99 m)Tc-labeled RSD) and nonradioactive RSD. The experimental results indicated that RSD SMEDDS has good stability and its droplet size is between 216.68 +/- 3.79 and 225.26 +/- 7.65 during stability time. In addition, RSD SMEDDS has higher permeability value than the RSD solution for both radioactive and nonradioactive experiments. The results illustrated the potential use of SMEDDS for delivery of poorly absorbed RSD. PMID- 25285359 TI - Estimating site-specific muscle loss: a valuable tool for early sarcopenia detection? AB - Currently, sarcopenia is commonly diagnosed using the appendicular lean mass calculation derived from the dual-energy X-ray absorptiometry (DXA) estimate. However, the DXA estimate of lean mass only gives a regional estimate of body composition and cannot differentiate different muscle groups. In contrast, diagnostic B-mode ultrasound can provide reliable estimates of individual muscle groups and may provide a method for earlier detection of sarcopenia. This may be important because it appears that the loss of skeletal muscle with age appears pronounced in certain muscle groups of the lower leg, while only minimally affecting others. This has been demonstrated in several large cross-sectional studies as well as a longitudinal investigation. In addition, this site-specific loss of muscle mass is associated with declines in muscle performance. We wish to suggest that the ultrasound estimate of muscle thickness may be a useful measurement to include when quantifying the age-related loss of muscle mass. Although the DXA is commonly used, changes in the anterior portion of the thigh may be occurring but may not necessarily be detected by the DXA estimate. This site-specific estimate coupled with a measure of muscle strength/performance may provide clinicians with a more complete picture of muscular changes with age. PMID- 25285361 TI - The structural conversion of multinuclear titanium(IV) MU-oxo-complexes. AB - For the first time we report the structural conversion processes of hexanuclear MU-oxo-Ti(IV) complexes into tetranuclear ones. Single-crystal X-ray diffraction studies reveal that metastable hexanuclear MU-oxo complexes ([Ti6O6(O(t)Bu)(O2CR')6]) are formed in the first stage of reactions between [Ti(O(t)Bu)4] and branched carboxylic acids R'COOH (R' = C(Me)2Et, CH2(t)Bu, (t)Bu). In the next stage they convert into tetranuclear MU-oxo-Ti(IV) complexes of the formula [Ti4O4(O(t)Bu)4(O2CR')4]. Spectroscopic investigations ((13)C NMR, IR, and MS) proved that the conversion of hexanuclear clusters relies on the attachment of smaller units (e.g., [Ti3O(O(t)Bu)8(O2CR')2] or [Ti4O2(O(t)Bu)6(O2CR')6]) and intermediate species formation (e.g., [Ti9O8(O(t)Bu)14(O2CR')6]). The decomposition of intermediate systems in the next reaction stage leads to the formation of tetranuclear clusters. The type of solvent used in the synthesis of multinuclear oxo-Ti(IV) complexes is an important factor, which influences the kind of clusters formed. PMID- 25285360 TI - Chronic obstructive pulmonary disease, cognitive impairment, and development of disability: the health and retirement study. AB - RATIONALE: The relationship between chronic obstructive pulmonary disease (COPD) and cognitive impairment in leading to disability has not been characterized. OBJECTIVES: We aimed to investigate the prevalence and cumulative incidence of disability among adults with and without COPD and the association of COPD and cognitive impairment with disability. METHODS: We analyzed 2006-2008 waves of the Health and Retirement Study, a nationally representative longitudinal health survey. COPD was self-reported. Prevalent disability was defined as baseline dependency in one or more activities of daily living (ADLs) and incident disability as one or more additional ADL dependencies. We used a validated performance-based measure of cognition to identify dementia and mild cognitive impairment. Covariates included seven chronic diseases, four geriatric syndromes, and sociodemographics. We used logistic regression to test associations between COPD, cognitive status, and prevalent/incident disability. MEASUREMENTS AND MAIN RESULTS: Of 17,535 participants at least 53 years of age in wave 2006 (representing 77.7 million Americans), 9.5% reported COPD and 13.5% mild cognitive impairment; 17.5% of those with COPD had mild cognitive impairment. Prevalent disability for COPD was 12.8% (5.2% for no-COPD, P < 0.001). An additional 9.2% with COPD developed incident disability at 2 years (4.0% for no COPD, P < 0.001). In adjusted models, COPD was associated with baseline (odds ratio, 2.0) and incident disability (odds ratio, 2.1; adjusted for baseline disability). Cognitive impairment had an additive effect to COPD. The COPD disability association, prevalent/incident, was of similar or greater magnitude than that of other chronic diseases (e.g., stroke, diabetes). The associations were maintained in sensitivity analyses using alternative definitions of disability (dependency in two or more ADLs, dependency in instrumental ADLs), and in analysis excluding respondents with dementia. CONCLUSIONS: Both COPD and mild cognitive impairment increase the risk of disability. The risk conferred by COPD is significant and similar or higher than other chronic diseases. PMID- 25285362 TI - Mass spectrometry approach and ELISA reveal the effect of codon optimization on N linked glycosylation of HIV-1 gp120. AB - The genes encoding many viral proteins such as HIV-1 envelope glycoprotein gp120 have a tendency for codons that are poorly used by the human genome. Why these codons are frequently present in the HIV genome is not known. The presence of these codons limits expression of HIV-1 gp120 for biochemical studies. The poor codons are replaced by synonymous codons that are frequently present in the highly expressed human genes to overexpress this protein. Whether this codon optimization affects functional properties of gp120 such as its N-linked glycosylation is unknown. We applied a bottom-up mass-spectrometry-based workflow for the direct measurement of deglycosylated and unglycosylated peptides with putative N-linked glycosylation sites, that is, NxS/T motifs. Using this mass spectrometry approach in combination with ELISA, it is found that codon optimization significantly reduces the frequency with which the dolichol pyrophosphate-linked oligosaccharide is added by the catalytic subunits of oligosaccharide transferase complex to the glycosylation sites. This reduction affects binding of glycan-dependent broadly neutralizing antibodies. These data are essential for biochemical studies of gp120 and successful development of a vaccine against HIV-1. Furthermore, they demonstrate a mass-spectrometry approach for studying the site-specific N-linked glycosylation efficiency of glycoproteins. PMID- 25285364 TI - Pharmacoepidemiology of Immune Thrombocytopenia: protocols of FAITH and CARMEN studies. AB - Immune thrombocytopenia (ITP) is a rare condition. Its epidemiology is not well known. First-line treatment is based on corticosteroids. ITP leads to persistency (lasting more than 3 months) in 70% of adult cases. Then, several second-line treatments (SLTs) are available, mainly splenectomy, rituximab (off-label) and thrombopoietin-receptor agonists. Their efficacy and safety have not been compared, particularly in the long-term. FAITH (French Adult primary Immune Thrombocytopenia: a pHarmacoepidemiological study) is dedicated to the building and follow-up of the cohort of all adults with primary ITP in France persistently treated (>3 months) through the database of French Health Insurance system (systeme national d'information interregimes d'Assurance maladie, SNIIRAM), in order to assess the benefit-to-risk balance of SLTs in real-life practice. CARMEN (Cytopenies Auto-immunes : Registre Midi-PyreneEN) is a clinical registry of all incident adult ITP patients in the Midi-Pyrenees region. It is aimed at describing ITP clinical features, assessing SLT benefit-to-risk balance and adherence to guidelines for ITP management. FAITH is registered n degrees ENCEPP/SDPP/4574. PMID- 25285363 TI - Resting State Functional Connectivity in Mild Traumatic Brain Injury at the Acute Stage: Independent Component and Seed-Based Analyses. AB - Mild traumatic brain injury (mTBI) accounts for more than 1 million emergency visits each year. Most of the injured stay in the emergency department for a few hours and are discharged home without a specific follow-up plan because of their negative clinical structural imaging. Advanced magnetic resonance imaging (MRI), particularly functional MRI (fMRI), has been reported as being sensitive to functional disturbances after brain injury. In this study, a cohort of 12 patients with mTBI were prospectively recruited from the emergency department of our local Level-1 trauma center for an advanced MRI scan at the acute stage. Sixteen age- and sex-matched controls were also recruited for comparison. Both group-based and individual-based independent component analysis of resting-state fMRI (rsfMRI) demonstrated reduced functional connectivity in both posterior cingulate cortex (PCC) and precuneus regions in comparison with controls, which is part of the default mode network (DMN). Further seed-based analysis confirmed reduced functional connectivity in these two regions and also demonstrated increased connectivity between these regions and other regions of the brain in mTBI. Seed-based analysis using the thalamus, hippocampus, and amygdala regions further demonstrated increased functional connectivity between these regions and other regions of the brain, particularly in the frontal lobe, in mTBI. Our data demonstrate alterations of multiple brain networks at the resting state, particularly increased functional connectivity in the frontal lobe, in response to brain concussion at the acute stage. Resting-state functional connectivity of the DMN could serve as a potential biomarker for improved detection of mTBI in the acute setting. PMID- 25285365 TI - Changes in genotype and fluconazole susceptibility of isolates from patients with Candida glabrata in Tunisia. AB - Candida glabrata has emerged as an opportunistic pathogen of considerable importance in invasive and superficial infections. AIMS: To analyze the development of fluconazole resistance in patients under treatment through epidemiological survey in our hospital. PATIENTS AND METHODS: Twenty two patients (89 clinical strains) were collected. Molecular typing of isolates was performed by polymorphic markers. Analysis of gene expression was realized by reverse transcriptase-real time polymerase chain reactions (RT-qPCR). RESULTS: Genetic analysis showed that 63% persists with apparently unchanged strains (n=14). Among them, four showed fluconazole resistance development. A strain replacement was observed in 6 patients and two patients selected more resistant isolates during the course of treatment. An analysis of Candida glabrata cerebellar degeneration related protein 1 (CgCDR1), Candida glabrata cerebellar degeneration-related protein 2 (CgCDR2) and Candida glabrata sterol 14 alpha-demetylase Erg 11 (CgERG11) expression revealed an over-expression in 10 resistant isolates. CONCLUSION: This study demonstrated that C. glabrata strain undergo frequent changes in vivo. The increase in CgCDR1 and CgCDR2 expression was the most mechanism associated with fluconazole resistance. PMID- 25285366 TI - [Weight gain during treatment with thalidomide: a case report]. AB - We report a case of weight gain induced by thalidomide in a 39-year-old female patient with Behcet's disease treated for an indication of severe, bipolar, aphthous stomatitis. PMID- 25285367 TI - The circadian changes of intraocular pressure and ocular perfusion pressure after tafluprost compared with travoprost in normal tension glaucoma. AB - PURPOSE: To compare the 24-h changes of intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) obtained with tafluprost versus travoprost in patients with normal-tension glaucoma (NTG). METHODS: This study is a randomized crossover study of 50 patients newly diagnosed with NTG who received either tafluprost or travoprost given once at 9 PM for 2 months, after which they were crossed over to the other medication for another 2 months. IOP and blood pressure were measured for 24 h before starting the treatment and after finishing the first and second treatment periods. RESULTS: Forty-one patients completed the study. The mean (+/-standard deviation) 24-h IOP was 16.8+/-2.0 mmHg at baseline, 14.4+/-2.2 mmHg on tafluprost, and 13.6+/-1.8 mmHg on travoprost. Both prostaglandin monotherapies significantly reduced mean 24-h IOP as compared with baseline (P<0.001, P<0.001, respectively), and travoprost demonstrated a lower mean 24-h IOP than tafluprost (P=0.044). Both treatments significantly reduced the IOP from baseline at every point over 24 h. At 3 individual time points, travoprost provided a lower IOP than tafluprost: at 4 PM (13.8+/-2.7 vs. 14.8+/ 2.6 mmHg, P=0.041), at 6 PM (13.5+/-2.5 vs. 14.4+/-2.5 mmHg, P=0.006), and at 8 PM (13.3+/-2.5 vs. 14.5+/-2.4 mmHg, P=0.029). Both tafluprost and travoprost significantly increased the 24-h MOPP (P=0.008, P=0.002, respectively), and travoprost demonstrated a greater 24-h MOPP than tafluprost (P=0.027). CONCLUSIONS: Both tafluprost and travoprost were effective in lowering IOP and increasing MOPP throughout 24 h in NTG. However, travoprost reduced IOP greater than tafluprost in the late afternoon and evening. PMID- 25285368 TI - Thinking ahead about where something is needed: new insights about episodic foresight in preschoolers. AB - We explored 3-, 4-, and 5-year-olds' capacity to draw on a past experience that entailed the lack of a particular resource (in this case, toys) in one room, but not in another, to make an adaptive choice (i.e., place toys in the room where there were none) for a subsequent visit to the two rooms. Children's memory for which room had toys and which room did not was explicitly assessed. Children were then queried about where they should place a new set of toys for their next visit to the rooms. In Experiment 1, where children were asked about the "distant" future, 4- and 5-year-olds, but not 3-year-olds, placed the toys in the "no-toy" room at a rate significantly higher than chance. In Experiment 2, where children were asked about the "immediate" future, correct responses of 3-year-olds were still no different from chance, those of 5-year-olds were above chance, and those of 4-year-olds trended in this direction. Our discussion centers on the importance of assessing both "memory" and "foresight" on tasks purported to assess children's episodic foresight, the role of "temporal distance" on children's future-oriented behavior, and implications for future research. PMID- 25285369 TI - Cross-cultural evidence for multimodal motherese: Asian Indian mothers' adaptive use of synchronous words and gestures. AB - In a quasi-experimental study, 24 Asian Indian mothers were asked to teach novel (target) names for two objects and two actions to their children of three different levels of lexical mapping development: prelexical (5-8 months), early lexical (9-17 months), and advanced lexical (20-43 months). Target naming (n=1482) and non-target naming (other, n=2411) were coded for synchronous spoken words and object motion (multimodal motherese) and other naming styles. Indian mothers abundantly used multimodal motherese with target words to highlight novel word-referent relations, paralleling earlier findings from American mothers. They used it with target words more often for prelexical infants than for advanced lexical children and to name target actions later in children's development. Unlike American mothers, Indian mothers also abundantly used multimodal motherese to name target objects later in children's development. Finally, monolingual mothers who spoke a verb-dominant Indian language used multimodal motherese more often than bilingual mothers who also spoke noun-dominant English to their children. The findings suggest that within a dynamic and reciprocal mother-infant communication system, multimodal motherese adapts to unify novel words and referents across cultures. It adapts to children's level of lexical development and to ambient language-specific lexical dominance hierarchies. PMID- 25285370 TI - Development of an ELP-Z based mAb affinity precipitation process using scaled down filtration techniques. AB - In this work, a proof of concept elastin-like polypeptide-Z domain fusion (ELP-Z) based monoclonal antibody (mAb) affinity precipitation process is developed using scaled-down filtration techniques. Tangential flow filtration (TFF) is examined for the recovery of ELP-Z-mAb precipitates formed during the mAb binding step and the ELP-Z precipitates formed during the mAb elution step. TFF results in complete precipitate recovery during both stages of the process and high host cell protein and DNA impurity clearance after diafiltration. Total recycle TFF experiments are then employed to determine permeate flux as a function of the precipitate concentration for both stages of the process. While the ELP-Z-mAb precipitate recovery step resulted in high permeate flux (550-600L/m(2)/h/bar), the ELP-Z precipitates are shown to severely foul the TFF membrane, causing rapid flux decay. Confocal microscopy of the ELP-Z-mAb and ELP-Z precipitates suggests significant differences in the morphology and the kinetics of formation of these precipitates, which is likely responsible for their different behavior during TFF. Finally, an alternative normal flow filtration strategy is developed for the ELP-Z precipitate recovery step during mAb elution, using a combination of 5MUm and a 0.45/0.2MUm filters. Using this approach, the ELP-Z precipitates are separated from the final mAb elution pool at high volumetric throughputs and high ELP-Z recovery (96%) is obtained after resolubilization from the filter. This study demonstrates that the ELP-Z affinity precipitation process can be readily scaled up using conventional membrane processing. PMID- 25285371 TI - Synthesis and evaluation of imidazole-4,5- and pyrazine-2,3-dicarboxamides targeting dengue and yellow fever virus. AB - The results of a high-throughput screening assay using the dengue virus-2 replicon showed that the imidazole 4,5-dicarboxamide (I45DC) derivative (15a) has a high dengue virus inhibitory activity. Based on 15a as a lead compound, a novel class of both disubstituted I45DCs and the resembling pyrazine 2,3-dicarboxamides (P23DCs) were synthesized. Here, we report on their in vitro inhibitory activity against dengue virus (DENV) and yellow fever virus (YFV). Some of these first generation compounds have shown activity against both viruses in the micromolar range. Within this series, compound 15b was observed to display the highest antiviral potency against YFV with an EC50 = 1.85 MUM. In addition, compounds 20a and 20b both potently inhibited replication of DENV (EC50 = 0.93 MUM) in Vero cells. PMID- 25285372 TI - Effect of Present-on-Admission (POA) Reporting Accuracy on Hospital Performance Assessments Using Risk-Adjusted Mortality. AB - OBJECTIVE: To evaluate how the accuracy of present-on-admission (POA) reporting affects hospital 30-day acute myocardial infarction (AMI) mortality assessments. DATA SOURCES: A total of 2005 California patient discharge data (PDD) and vital statistics death files. STUDY DESIGN: We compared hospital performance rankings using an established model assessing hospital performance for AMI with (1) a model incorporating POA indicators of whether a secondary condition was a comorbidity or a complication of care, and (2) a simulation analysis that factored POA indicator accuracy into the hospital performance assessment. For each simulation, we changed POA indicators for six major acute risk factors of AMI mortality. The probability of POA being changed depended on patient and hospital characteristics. PRINCIPAL FINDINGS: Comparing the performance rankings of 268 hospitals using the established model with that using the POA indicator, 67 hospitals' (25 percent) rank differed by >=10 percent. POA reporting inaccuracy due to overreporting and underreporting had little additional impact; POA overreporting contributed to 4 percent of hospitals' difference in rank compared to the POA model and POA underreporting contributed to <1 percent difference. CONCLUSION: Incorporating POA indicators into risk-adjusted models of AMI care has a substantial impact on hospital rankings of performance that is not primarily attributable to inaccuracy in POA hospital reporting. PMID- 25285373 TI - What you see is what you eat: an ALE meta-analysis of the neural correlates of food viewing in children and adolescents. AB - Food cues are omnipresent and may enhance overconsumption. In the last two decades the prevalence of childhood obesity has increased dramatically all over the world, largely due to overconsumption. Understanding children's neural responses to food may help to develop better interventions for preventing or reducing overconsumption. We aimed to determine which brain regions are concurrently activated in children/adolescents in response to viewing food pictures, and how these relate to adult findings. Two activation likelihood estimation (ALE) meta-analyses were performed: one with studies in normal weight children/adolescents (aged 8-18, 8 studies, 137 foci) and one with studies in normal weight adults (aged 18-45, 16 studies, 178 foci). A contrast analysis was performed for children/adolescents vs. adults. In children/adolescents, the most concurrent clusters were in the left lateral orbitofrontal cortex (OFC), the bilateral fusiform gyrus, and the right superior parietal lobule. In adults, clusters in similar areas were found. Although the number of studies for a direct statistical comparison between the groups was relatively low, there were indications that children/adolescents may not activate areas important for cognitive control. Overall, the number of studies that contributed to the significant clusters was moderate (6-75%). In summary, the brain areas most consistently activated in children/adolescents by food viewing are part of the appetitive brain network and overlap with those found in adults. However, the age range of the children studied was rather broad. This study offers important recommendations for future research; studies making a direct comparison between adults and children in a sufficiently narrow age range would further elucidate how neural responses to food cues change during development. PMID- 25285375 TI - Microsaccade-related brain potentials signal the focus of visuospatial attention. AB - Covert shifts of visuospatial attention are traditionally assumed to occur in the absence of oculomotor behavior. In contrast, recent behavioral studies have linked attentional cueing effects to the occurrence of microsaccades, small eye movements executed involuntarily during attempted fixation. Here we used a new type of electrophysiological marker to explore the attention-microsaccade relationship, the visual brain activity evoked by the microsaccade itself. By shifting the retinal image, microsaccades frequently elicit neural responses throughout the visual pathway, scalp-recordable in the human EEG as a microsaccade-related potential (mSRP). Although mSRPs contain similar signal components (P1/N1) as traditional visually-evoked potentials (VEPs), it is unknown whether they are also influenced by cognition. Based on established findings that VEPs are amplified for visual inputs at currently attended locations, we expected a selective gain-modulation also for mSRPs. Eye movements and EEG were coregistered in a classic spatial cueing task with an endogenous cue. Replicating behavioral findings, the direction of early microsaccades 200 400ms after cue onset was biased towards the cued side. However, for microsaccades throughout the cue-target interval, mSRPs were systematically enhanced at occipital scalp sites contralateral to the cued hemifield. This attention effect resembled that in a control condition with VEPs and did not interact with the direction of the underlying microsaccade, suggesting that mSRPs reflect the focus of sustained visuospatial attention, which remains fixed at the cued location, despite microsaccades. Microsaccades are not merely an artifact source in the EEG; instead, they are followed by cognitively modulated brain potentials that can serve as non-intrusive electrophysiological probes of attention. PMID- 25285376 TI - Why training and specialization is needed for peer review: a case study of peer review for randomized controlled trials. AB - BACKGROUND: The purpose and effectiveness of peer review is currently a subject of hot debate, as is the need for greater openness and transparency in the conduct of clinical trials. Innovations in peer review have focused on the process of peer review rather than its quality. DISCUSSION: The aims of peer review are poorly defined, with no evidence that it works and no established way to provide training. However, despite the lack of evidence for its effectiveness, evidence-based medicine, which directly informs patient care, depends on the system of peer review. The current system applies the same process to all fields of research and all study designs. While the volume of available health related information is vast, there is no consistent means for the lay person to judge its quality or trustworthiness. Some types of research, such as randomized controlled trials, may lend themselves to a more specialized form of peer review where training and ongoing appraisal and revalidation is provided to individuals who peer review randomized controlled trials. Any randomized controlled trial peer reviewed by such a trained peer reviewer could then have a searchable 'quality assurance' symbol attached to the published articles and any published peer reviewer reports, thereby providing some guidance to the lay person seeking to inform themselves about their own health or medical treatment. SUMMARY: Specialization, training and ongoing appraisal and revalidation in peer review, coupled with a quality assurance symbol for the lay person, could address some of the current limitations of peer review for randomized controlled trials. PMID- 25285378 TI - A chiroptical switch based on DNA/layered double hydroxide ultrathin films. AB - A highly oriented film was fabricated by layer-by-layer self-assembly of DNA and MgAl-layered double hydroxide nanosheets, and its application in chiroptical switch was demonstrated via intercalation and deintercalation of an achiral molecule into the DNA cavity. DNA molecules are prone to forming an ordered and dispersive state in the interlayer region of rigid layered double hydroxide (LDH) nanosheets as confirmed by scanning electron microscopy and atomic force microscopy. The induced chiroptical ultrathin film (UTF) is achieved via the intercalation of an achiral chromophore [5,10,15,20-tetrakis(4-N methylpyridyl)porphine tetra(p-toluenesulfonate) (TMPyP)] into the spiral cavity of DNA stabilized in the LDH matrix [denoted as TMPyP-(DNA/LDH)20]. Fluorescence and circular dichroism spectroscopy are utilized to testify the intercalation of TMPyP into (DNA/LDH)20 UTF that involves two steps: the electrostatic binding of TMPyP onto the surface of (DNA/LDH)20 followed by intercalation into base pairs of DNA. In addition, the TMPyP-(DNA/LDH)20 UTF exhibits good reversibility and repeatability in induced optical chirality, based on the intercalation and deintercalation of TMPyP by alternate exposure to HCl and NH3/H2O vapor, which can be potentially used as a chiroptical switch in data storage. PMID- 25285380 TI - JAMA patient page. Ebola virus disease. PMID- 25285379 TI - Dissection and immunostaining of imaginal discs from Drosophila melanogaster. AB - A significant portion of post-embryonic development in the fruit fly, Drosophila melanogaster, takes place within a set of sac-like structures called imaginal discs. These discs give rise to a high percentage of adult structures that are found within the adult fly. Here we describe a protocol that has been optimized to recover these discs and prepare them for analysis with antibodies, transcriptional reporters and protein traps. This procedure is best suited for thin tissues like imaginal discs, but can be easily modified for use with thicker tissues such as the larval brain and adult ovary. The written protocol and accompanying video will guide the reader/viewer through the dissection of third instar larvae, fixation of tissue, and treatment of imaginal discs with antibodies. The protocol can be used to dissect imaginal discs from younger first and second instar larvae as well. The advantage of this protocol is that it is relatively short and it has been optimized for the high quality preservation of the dissected tissue. Another advantage is that the fixation procedure that is employed works well with the overwhelming number of antibodies that recognize Drosophila proteins. In our experience, there is a very small number of sensitive antibodies that do not work well with this procedure. In these situations, the remedy appears to be to use an alternate fixation cocktail while continuing to follow the guidelines that we have set forth for the dissection steps and antibody incubations. PMID- 25285381 TI - Creating anatomically accurate and reproducible intracranial xenografts of human brain tumors. AB - Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live animal - particularly in sites with unique physiological and architectural qualities such as the brain. In vitro and ectopic models cannot account for features such as vasculature, blood brain barrier, metabolism, drug delivery and toxicity, and a host of other relevant factors. Orthotopic models have their limitations too, but with proper technique tumor cells of interest can be accurately engrafted into tissue that most closely mimics conditions in the human brain. By employing methods that deliver precisely measured volumes to accurately defined locations at a consistent rate and pressure, mouse models of human brain tumors with predictable growth rates can be reproducibly created and are suitable for reliable analysis of various interventions. The protocol described here focuses on the technical details of designing and preparing for an intracranial injection, performing the surgery, and ensuring successful and reproducible tumor growth and provides starting points for a variety of conditions that can be customized for a range of different brain tumor models. PMID- 25285382 TI - A new acetophenone derivative from flowers of Helichrysum italicum (Roth) Don ssp. italicum. AB - A new acetophenone derivative named gnaphaliol 9-O-propanoate (1) was isolated from the chloroform fraction of EtOH extract of Helichrysum italicum ssp. italicum flowers along with the five known acetophenones 12-acetoxytremetone (2), 13-(2-methylpropanoyloxy)toxol (3), [2,3-dihydro-2-[1-(hydroxymethyl)ethenyl]-5 benzofuranyl]-ethanone (4), 1-[2-[1-[(acetyloxy)methyl]ethenyl]-2,3-dihydro-3 hydroxy-5-benzofuranyl]-ethanone (5) and gnaphaliol (6). The structures of compounds 1-6 were elucidated by extensive spectroscopic methods including 1D- ((1)H and (13)C) and 2D-NMR (DQF-COSY, HSQC, HMBC, TOCSY and ROESY) experiments as well as ESIMS analysis. The isolated compounds were investigated for their cytotoxicity, anti-inflammatory and antioxidant properties. Biological assays on human colonic epithelial cells showed that compound 2 possessed antioxidant effects reducing reactive oxygen species (ROS) production. PMID- 25285384 TI - Putting judging situations into situational judgment tests: evidence from intercultural multimedia SJTs. AB - Although the term situational judgment test (SJT) implies judging situations, existing SJTs focus more on judging the effectiveness of different response options (i.e., response judgment) and less on how people perceive and interpret situations (i.e., situational judgment). We expand the traditional SJT paradigm and propose that adding explicit assessments of situational judgment to SJTs will provide incremental information beyond that provided by response judgment. We test this hypothesis across 4 studies using intercultural multimedia SJTs. Study 1 uses verbal protocol analysis to discover the situational judgments people make when responding to SJT items. Study 2 shows situational judgment predicts time lagged, peer-rated task performance and interpersonal citizenship among undergraduate seniors over and above response judgment and other established predictors. Study 3 shows providing situational judgment did not affect the predictive validity of response judgment. Study 4 replicates Study 2 in a working adult sample. We discuss implications for SJT theory as well as the practical implications of putting judging situations back into SJTs. PMID- 25285383 TI - Dissecting a neuron network: FIB-SEM-based 3D-reconstruction of the visual neuropils in the sea spider Achelia langi (Dohrn, 1881) (Pycnogonida). AB - BACKGROUND: The research field of connectomics arose just recently with the development of new three-dimensional-electron microscopy (EM) techniques and increasing computing power. So far, only a few model species (for example, mouse, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster) have been studied using this approach. Here, we present a first attempt to expand this circle to include pycnogonids, which hold a key position for the understanding of arthropod evolution. The visual neuropils in Achelia langi are studied using a focused ion beam-scanning electron microscope (FIB-SEM) crossbeam workstation, and a three-dimensional serial reconstruction of the connectome is presented. RESULTS: The two eyes of each hemisphere of the sea spider's eye tubercle are connected to a first and a second visual neuropil. The first visual neuropil is subdivided in two hemineuropils, each responsible for one eye and stratified into three layers. Six different neuron types postsynaptic to the retinula (R-cells) axons are characterized by their morphology: five types of descending unipolar neurons and one type of ascending neurons. These cell types are also identified by Golgi impregnations. Mapping of all identifiable chemical synapses indicates that the descending unipolar neurons are postsynaptic to the R cells and, hence, are second-order neurons. The ascending neurons are predominantly presynaptic and sometimes postsynaptic to the R-cells and may play a feedback role. CONCLUSIONS: Comparing these results with the compound eye visual system of crustaceans and insects - the only arthropod visual system studied so far in such detail - we found striking similarities in the morphology and synaptic organization of the different neuron types. Hence, the visual system of pycnogonids shows features of both chelicerate median and mandibulate lateral eyes. PMID- 25285385 TI - The chicken or the egg? A meta-analysis of panel studies of the relationship between work-family conflict and strain. AB - Does work-family conflict predict strain, does strain predict work-family conflict, or are they reciprocally related? To answer these questions, we used meta-analytic path analyses on 33 studies that had repeatedly measured work interference with family (WIF) or family interference with work (FIW) and strain. Additionally, this study sheds light on whether relationships between WIF/FIW and work-specific strain support the popular cross-domain perspective or the less popular matching perspective. Results showed reciprocal effects; that is, that WIF predicted strain (beta = .08) and strain predicted WIF (beta = .08). Similarly, FIW and strain were reciprocally related, such that FIW predicted strain (beta = .03) and strain predicted FIW (beta = .05). These findings held for both men and women and for different time lags between the 2 measurement waves. WIF had a stronger effect on work-specific strain than did FIW, supporting the matching hypothesis rather than the cross-domain perspective. PMID- 25285386 TI - Painless pediatric priapism and cough. AB - Pediatric priapism can be a medical emergency but is not a common complaint seen in pediatric emergency department. Priapism in a previously healthy child is also rare. We report a case of painless stuttering priapism associated with an acute Mycoplasma pneumoniae infection in a previously healthy boy. PMID- 25285387 TI - Pediatric tea tree oil aspiration treated with surfactant in the emergency department. AB - Tea tree oil is an essential oil containing a mixture of aromatic hydrocarbons. We describe an 18-month-old male patient who ingested tea tree oil, developed central nervous system depression, respiratory distress, and received early emergency department treatment with surfactant. Early treatment of hydrocarbon pneumonitis with surfactant has not been previously described. Early administration of surfactant should be further evaluated for treatment of hydrocarbon aspiration. PMID- 25285388 TI - An unusual case of hematemesis in a 12-month-old. AB - A 12-month-old male with a history of failure to thrive and hypothyroidism presented to a pediatric emergency department twice in a 24-hour period with complaint of hematemesis. The patient had a recent upper endoscopy and biopsy as part of a work-up for failure to thrive, but had no other pertinent positives in clinical history. Ultrasound demonstrated findings concerning for an intramural duodenal hematoma. The patient was admitted to the gastroenterology service for intravenous hydration and nasogastric decompression. He did not require any invasive management or blood products. Duodenal hematoma is a known, but very uncommon complication of upper endoscopy. PMID- 25285389 TI - Columbia-suicide severity rating scale: predictive validity with adolescent psychiatric emergency patients. AB - OBJECTIVE: Despite the high prevalence of psychiatric emergency (PE) visits for attempted suicide and nonsuicidal self-injury (NSSI) among adolescents, we have limited information about assessment tools that are helpful in predicting subsequent risk for suicide attempts among adolescents in PE settings. This study examined the predictive validity of a highly promising instrument, the Columbia Suicide Severity Rating Scale (C-SSRS). METHOD: Participants were 178 adolescents (44.4% male; ages 13-17 years) seeking PE services. The C-SSRS interview and selected medical chart data were collected for the index visit and subsequent visits during a 1-year follow-up. RESULTS: A suicide risk concern was the most common chief complaint (50.6%) in this sample, and nearly one third of the adolescents (30.4%) reported a lifetime history of suicide attempt at index visit. Sixty-two adolescents (34.8%) had at least one return PE visit during follow-up. Lifetime history of NSSI predicted both return PE visits and a suicide attempt at return visit. The C-SSRS intensity scale score was a significant predictor of a suicide attempt at return visit for both the full sample of adolescents and the subsample who reported suicidal ideation at their index visit. In this subsample, one specific item on the intensity scale, duration, was also a significant predictor of both a return PE visit and a suicide attempt at return visit. CONCLUSIONS: The C-SSRS intensity scale and NSSI had predictive validity for suicide attempts at return visit. Results also suggest that duration of adolescents' suicidal thoughts may be particularly important to risk for suicidal behavior, warranting further study. PMID- 25285390 TI - Cervical Spine Motion During Airway Management Using Two Manual In-line Immobilization Techniques: A Human Simulator Model Study. AB - OBJECTIVE: The aim of this study is to evaluate cervical spine motion using 2 manual inline immobilization techniques with the use of a human simulator model. METHODS: Medical students, pediatric and family practice residents, and pediatric emergency medicine fellows were recruited to maintain cervical manual in line immobilization above the head of the bed and across the chest of a human simulator while orotracheal intubation was performed. Participants were then instructed on appropriate holding techniques after the initial session took place. Orotracheal intubation followed. A tilt sensor measured time to intubation and cervical extension and rotation angle. RESULTS: Seventy-one subjects participated in a total of 284 successful orotracheal intubations. No change in cervical spine movement or time to intubation was observed when using 2 different inline manual immobilization techniques with no training. However, a statistically significant difference with assistants above the head versus across the chest was observed after training in: extension 2.1 degrees (95% confidence interval [95% CI], 1.15 to 3.00; P < 0.0001); rotation 0.7 degrees (95% CI, 0.26 to 1.19; P = 0.003) and intubation time of -1.9 seconds (95% CI, -3.45 to -0.13; P = 0.035) after training. CONCLUSIONS: Cervical spine movement did not change when maintaining cervical spine immobilization from above the head versus across the chest before training. There was a statistically significant change in extension and rotation when assistants were above the head and in time to intubation when assistants were across the chest after training. The clinical significance of these results is unclear. PMID- 25285391 TI - QTc Prolongation in Acute Pediatric Migraine. AB - OBJECTIVES: Migraine headache is common in pediatrics and is frequently assessed in emergency departments. Altered cardiac conduction, including prolongation of the QTc interval on electrocardiogram, has been observed in adults during migraine headache and resolves interictally. Prolonged QTc is associated with life-threatening arrhythmia, and many acute and prophylactic therapies for migraine can further prolong the QTc interval. It is the objective of this prospective cohort study to examine whether the QTc interval prolongs significantly during periods of acute migraine headache in children. METHODS: Patients ages 6 to 17 years presenting to the emergency department with acute migraine headache were recruited prospectively. Exclusion criteria included the use of QTc-prolonging medications and medical illnesses, including cardiovascular abnormalities, infection, or head injury. Paired, one-tailed Student t tests compared QTc intervals with and without headache and evaluated for QTc prolongation of 30 ms or longer during headache. RESULTS: Thirteen patients with migraine (mean age, 11.6 +/- 2.6 years) were evaluated. Mean QTc interval during headache was significantly longer than the QTc interval in the absence of headache (437.9 +/- 27.7 ms compared with 419.3 +/- 29.9 ms; p = 0.04). Three patients (23%) had unequivocal prolongation of the QTc (>460 ms) during the migraine, two of which normalized with headache resolution. The mean increase in QTc during headache did not reach or exceed 30 ms (p = 0.86) CONCLUSIONS: This study is the first to illustrate a connection between QTc prolongation and acute migraine headache in children. If confirmed in future studies, children should be monitored for QTc prolongation during the acute treatment of migraine in the emergency department when using medications that can lengthen the QTc interval. PMID- 25285392 TI - A Novel Approach to Combining Pediatric Emergency Medicine and Global Health Fellowships. AB - OBJECTIVES: To describe the creation of the first known combined Pediatric Emergency Medicine-Global Health (PEM-GH) fellowship for graduates of pediatric or emergency medicine residency programs. METHODS: We detail the necessary infrastructure for a successfully combined PEM-GH fellowship including goals, objectives, curriculum, timeline, and funding. The fellowship is jointly supported by the department of pediatrics, section of pediatric emergency medicine (PEM), and the hospital. Fellows complete all requirements for the PEM fellowship and Global Health, the latter requiring an additional 12 months of training. Components of the Global Health fellowship include international fieldwork, scholarly activity abroad, advanced degree coursework, disaster training, and didactic curricula. RESULTS: Since 2005, 9 fellows (8 pediatric trained and 1 emergency medicine-trained) have completed or are enrolled in the PEM-GH fellowship; 3 have graduated. All fellows have completed or are working toward advanced degrees and have or will participate in the disaster management course. Fellows have had 7 presentations at national or international meetings and have published 6 articles in peer-reviewed journals. Of the three graduates, all are working in academic PEM-GH programs and work internationally in Africa and/or Latin America. CONCLUSIONS: Our response to a global trend toward improvement in PEM care was the development of the first combined PEM-GH fellowship program. Recognizing the value of this program within our own institution, we now offer it as a model for building such programs in the future. This fellowship program promises to be a paradigm that can be used nationally and internationally, and it establishes a foundation for a full-fledged accredited and certified subspecialty. PMID- 25285374 TI - Studying ventricular abnormalities in mild cognitive impairment with hyperbolic Ricci flow and tensor-based morphometry. AB - Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and dementia and people with MCI are at high risk of progression to dementia. MCI is attracting increasing attention, as it offers an opportunity to target the disease process during an early symptomatic stage. Structural magnetic resonance imaging (MRI) measures have been the mainstay of Alzheimer's disease (AD) imaging research, however, ventricular morphometry analysis remains challenging because of its complicated topological structure. Here we describe a novel ventricular morphometry system based on the hyperbolic Ricci flow method and tensor-based morphometry (TBM) statistics. Unlike prior ventricular surface parameterization methods, hyperbolic conformal parameterization is angle-preserving and does not have any singularities. Our system generates a one-to-one diffeomorphic mapping between ventricular surfaces with consistent boundary matching conditions. The TBM statistics encode a great deal of surface deformation information that could be inaccessible or overlooked by other methods. We applied our system to the baseline MRI scans of a set of MCI subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI: 71 MCI converters vs. 62 MCI stable). Although the combined ventricular area and volume features did not differ between the two groups, our fine-grained surface analysis revealed significant differences in the ventricular regions close to the temporal lobe and posterior cingulate, structures that are affected early in AD. Significant correlations were also detected between ventricular morphometry, neuropsychological measures, and a previously described imaging index based on fluorodeoxyglucose positron emission tomography (FDG-PET) scans. This novel ventricular morphometry method may offer a new and more sensitive approach to study preclinical and early symptomatic stage AD. PMID- 25285393 TI - Tetragonal phase of 6-oxoverdazyl bent-core derivatives with photoinduced ambipolar charge transport and electrooptical effects. AB - Bent-core mesogens containing 6-oxoverdazyl radical as the angular central unit exhibit rich polymorphism that includes isotropic-isotropic transition, re-entant isotropic (I(re)), and a novel 3D tetragonal (Tet) phases. Surprisingly, the paramagnetic Tet phase interacts linearly with applied electric field and exhibits photoinduced ambipolar charge transport (MU ~ 10(-3) cm(2) V(-1) s(-1)). Magnetic analysis showed gradual increase of antiferromagnetic interactions upon cooling. PMID- 25285394 TI - Use and prescription of antibiotics in primary health care settings in China. AB - IMPORTANCE: Appropriate antibiotic use is a key strategy to control antibacterial resistance. The first step in achieving this is to identify the major problems in antibiotic prescription in health care facilities, especially in primary health care settings, which is where most patients receive medical care. OBJECTIVE: To identify current patterns of antibiotic use and explore the reasons for inappropriate prescription in primary health care settings in China. DESIGN, SETTING, AND PARTICIPANTS: A total of 48 primary health care facilities in China were randomly selected from 6 provinces at various levels of economic development. Data for the years 2009 through 2011 from 39 qualifying facilities (23 city and 16 rural primary health care centers) were analyzed retrospectively. The study sample consisted of prescription records for 7311 outpatient visits and 2888 inpatient hospitalizations. MAIN OUTCOMES AND MEASURES: General health center information, drug usage, disease diagnoses, and antibiotic use by outpatients and inpatients were surveyed. Cases of inappropriate antibiotic prescription were identified. RESULTS: Most staff in the primary health care facilities had less than a college degree, and the medical staff consisted primarily of physician assistants, assistant pharmacists, nurses, and nursing assistants. The median (range) governmental contribution to each facility was 34.0% (3.6%-92.5%) of total revenue. The facilities prescribed a median (range) of 28 (8-111) types of antibiotics, including 34 (10-115) individual agents. Antibiotics were included in 52.9% of the outpatient visit prescription records: of these, only 39.4% were prescribed properly. Of the inpatients, 77.5% received antibiotic therapy: of these, only 24.6% were prescribed properly. Antibiotics were prescribed for 78.0% of colds and 93.5% of cases of acute bronchitis. Of the antibiotic prescriptions, 28.0% contained cephalosporins and 15.7% fluoroquinolones. A total of 55.0% of the antibiotic prescriptions were for antibiotic combination therapy with 2 or more agents. In nonsurgical inpatients in cities, the mean (SD) duration of antibiotic therapy was 10.1 (7.8) days. Of the surgical patients, 98.0% received antibiotics, with 63.8% of these prescriptions for prophylaxis. CONCLUSIONS AND RELEVANCE: Antibiotics are frequently prescribed in Chinese primary health care facilities, and a large proportion of these prescriptions are inappropriate. Frequent and inappropriate use of antibiotics in primary health care settings in China is a serious problem that likely contributes to antimicrobial resistance worldwide. PMID- 25285395 TI - Neuromodulation of the conscious state following severe brain injuries. AB - Disorders of consciousness (DOC) following severe structural brain injuries globally affect the conscious state and the expression of goal-directed behaviors. In some subjects, neuromodulation with medications or electrical stimulation can markedly improve the impaired conscious state present in DOC. We briefly review recent studies and provide an organizing framework for considering the apparently widely disparate collection of medications and approaches that may modulate the conscious state in subjects with DOC. We focus on neuromodulation of the anterior forebrain mesocircuit in DOC and briefly compare mechanisms supporting recovery from structural brain injuries to those underlying facilitated emergence from unconsciousness produced by anesthesia. We derive some general principles for approaching the problem of restoration of consciousness after severe structural brain injuries, and suggest directions for future research. PMID- 25285396 TI - Challenges facing HIV-positive persons who use drugs and their families in Vietnam. AB - It is hypothesized that persons who use drugs (PWUD) in Vietnam who are also HIV positive may face additional challenges in psychosocial outcomes, and these challenges may extend to their family members. In this study, we examined depressive symptoms, stigma, social support, and caregiver burden of HIV-positive PWUD and their family members, compared to the outcomes of HIV-negative PWUD and their family members. Baseline, 3-month, and 6-month assessment data were gathered from 83 PWUD and 83 family members recruited from four communes in Phu Tho Province, Vietnam. For PWUD, although we observed a general decline in overall stigma over time for both groups, HIV-positive PWUD consistently reported significantly higher overall stigma for all three periods. Depressive symptoms among family members in both groups declined over time; however, family members of HIV-positive PWUD reported higher depressive symptoms across all three periods. In addition, family members of HIV-positive PWUD reported lower levels of tangible support across all three periods. Caregiver burden among family members of HIV-positive PWUD increased significantly over time, whereas the reported burden among family members of HIV-negative PWUD remained relatively unchanged. The findings highlight the need for future interventions for PWUD and family members, with targeted and culturally specific strategies to focus on the importance of addressing additional stigma experienced by PWUD who are HIV positive. Such challenges may have direct negative impact on their family members' depressive symptoms, tangible support, and caregiver burden. PMID- 25285397 TI - Vertebrate estrogen regulates the development of female characteristics in silkworm, Bombyx mori. AB - The vertebrate estrogens include 17-beta-estradiol (E2), which has an analog in silkworm ovaries. In this study, the Bombyx mori vitellogenin gene (BmVg) was used as a biomarker to analyze the function of the E2 in silkworm. In most oviparous animals, Vg has female-specific expression. However, BmVg expression was also detected in B. mori males. Stage specific fluctuation of BmVg expression was similar in males and females, but expression levels in males were lower than in females. E2 treatment by injection or feeding of male larvae in the final instar stage induced and stimulated male BmVg transcription and protein synthesis. When silkworm ovary primordia were transplanted into males, BmVg was induced in male fat bodies. Transplanted ovaries primordia were also able to develop into ovaries and produce mature eggs. When females were treated with E2 promoted BmVg/BmVn protein accumulation in hemolymph, ovaries and eggs. However, BmVg transcription was decreased in female fat bodies. An E2 analog was identified in the hemolymph of day 3 wandering silkworms using high-performance liquid chromatography. Estradiol titers from fifth late-instar larvae to pupal stage were determined by enzyme-linked immunosorbent assay. The results suggested that silkworms synthesized a vertebrate E2 analog. This study found that E2 promoted the synthesis of BmVg, a female typical protein in silkworms. PMID- 25285399 TI - Neonatal vermiform appendicopathy. AB - OBJECTIVE: A neonate with a perforated appendix vermiformis in our neonatal intensive care unit (NICU) (case 1) prompted us to review our cases of exploratory laparotomy due to spontaneous intestinal perforation (SIP), surgical necrotizing enterocolitis (NEC), and other neonatal abdominal emergencies to identify additional cases of pathological appendiceal involvement (appendicopathy). METHODS: A retrospective chart review was done for all the cases of exploratory laparotomy in our 16-bed community level-3 NICU between June 2003 and May 2014. RESULTS: A total of 34 patients with exploratory laparotomies were identified. Among the 11 cases with histopathology of the appendix available, only 3 cases had appendicopathy. Of these, only one was conclusive regarding the etiology. CONCLUSIONS: A perforated and/or inflamed appendix does not equal a diagnosis of true appendicitis. The term appendicopathy is in our opinion, therefore preferable because it can be either primary or secondary to more common diagnoses, such as NEC and SIP. The possibility of perforation of the appendix must be considered in all cases of appendicopathy but this diagnosis is difficult to make. Once appendicopathy is found, attempts should be made to identify its etiology to optimize treatment and prognosis. We thus propose an etiologic classification of neonatal appendicopathy. PMID- 25285398 TI - Using the threat probability task to assess anxiety and fear during uncertain and certain threat. AB - Fear of certain threat and anxiety about uncertain threat are distinct emotions with unique behavioral, cognitive-attentional, and neuroanatomical components. Both anxiety and fear can be studied in the laboratory by measuring the potentiation of the startle reflex. The startle reflex is a defensive reflex that is potentiated when an organism is threatened and the need for defense is high. The startle reflex is assessed via electromyography (EMG) in the orbicularis oculi muscle elicited by brief, intense, bursts of acoustic white noise (i.e., "startle probes"). Startle potentiation is calculated as the increase in startle response magnitude during presentation of sets of visual threat cues that signal delivery of mild electric shock relative to sets of matched cues that signal the absence of shock (no-threat cues). In the Threat Probability Task, fear is measured via startle potentiation to high probability (100% cue-contingent shock; certain) threat cues whereas anxiety is measured via startle potentiation to low probability (20% cue-contingent shock; uncertain) threat cues. Measurement of startle potentiation during the Threat Probability Task provides an objective and easily implemented alternative to assessment of negative affect via self-report or other methods (e.g., neuroimaging) that may be inappropriate or impractical for some researchers. Startle potentiation has been studied rigorously in both animals (e.g., rodents, non-human primates) and humans which facilitates animal to-human translational research. Startle potentiation during certain and uncertain threat provides an objective measure of negative affective and distinct emotional states (fear, anxiety) to use in research on psychopathology, substance use/abuse and broadly in affective science. As such, it has been used extensively by clinical scientists interested in psychopathology etiology and by affective scientists interested in individual differences in emotion. PMID- 25285400 TI - A clinical scoring system to predict the development of bronchopulmonary dysplasia. AB - OBJECTIVE: This study aims to develop a scoring system for the prediction of bronchopulmonary dysplasia (BPD). METHODS: Medical records of 652 infants whose gestational age and birth weight were below 32 weeks and 1,500 g, respectively, and who survived beyond 28th postnatal day were reviewed retrospectively. Logistic regression methods were used to determine the clinical and demographic risk factors within the first 72 hours of life associated with BPD, as well as the weights of these factors on developing BPD. Predictive accuracy of the scoring system was tested prospectively at the same unit. RESULTS: Birth weight, gestational age, gender, presence of respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, hypotension were the most important risk factors for BPD. Therefore, a scoring system (BPD-TM score) ranging from 0 to 13 and grouped in four tiers (0-3: low, 4-6: low intermediate, 7-9: high intermediate, and 10-13: high risk) was developed based on these factors. Below the score of 4, 4.1% of infants (18/436), above the score of 9, 100% (29/29) of the infants developed BPD. The score was validated successfully in 172 infants. CONCLUSION: With this easy to use scoring system, one can predict the neonate at risk for BPD at 72 hours of life and direct preventive measures toward these infants. PMID- 25285402 TI - Normalization to specific gravity prior to analysis improves information recovery from high resolution mass spectrometry metabolomic profiles of human urine. AB - Extraction of meaningful biological information from urinary metabolomic profiles obtained by liquid-chromatography coupled to mass spectrometry (MS) necessitates the control of unwanted sources of variability associated with large differences in urine sample concentrations. Different methods of normalization either before analysis (preacquisition normalization) through dilution of urine samples to the lowest specific gravity measured by refractometry, or after analysis (postacquisition normalization) to urine volume, specific gravity and median fold change are compared for their capacity to recover lead metabolites for a potential future use as dietary biomarkers. Twenty-four urine samples of 19 subjects from the European Prospective Investigation into Cancer and nutrition (EPIC) cohort were selected based on their high and low/nonconsumption of six polyphenol-rich foods as assessed with a 24 h dietary recall. MS features selected on the basis of minimum discriminant selection criteria were related to each dietary item by means of orthogonal partial least-squares discriminant analysis models. Normalization methods ranked in the following decreasing order when comparing the number of total discriminant MS features recovered to that obtained in the absence of normalization: preacquisition normalization to specific gravity (4.2-fold), postacquisition normalization to specific gravity (2.3-fold), postacquisition median fold change normalization (1.8-fold increase), postacquisition normalization to urinary volume (0.79-fold). A preventative preacquisition normalization based on urine specific gravity was found to be superior to all curative postacquisition normalization methods tested for discovery of MS features discriminant of dietary intake in these urinary metabolomic datasets. PMID- 25285404 TI - A two rotor model with spin for magnetic nanoparticles. AB - We argue that a kind of magnetic nanoparticle might exist characterized by the locking of the constituent spins with the density profile of the macrospin. We represent such a nanoparticle by two interacting rigid rotors, one of which has a large spin attached to the body, namely a two rotor model with spin. By this model we can describe in a unified way the cases of nanoparticles free and stuck in an elastic or a rigid matrix. We evaluate the magnetic susceptibility for the latter case and under some realistic assumptions we get results in closed form. A crossover between thermal and purely quantum hopping occurs at a temperature much higher than that at which tunneling becomes important. Agreement with some experimental data is remarkable. PMID- 25285401 TI - Transsynaptic trophic effects of steroid hormones in an avian model of adult brain plasticity. AB - The avian song control system provides an excellent model for studying transsynaptic trophic effects of steroid sex hormones. Seasonal changes in systemic testosterone (T) and its metabolites regulate plasticity of this system. Steroids interact with the neurotrophin brain-derived neurotrophic factor (BDNF) to influence cellular processes of plasticity in nucleus HVC of adult birds, including the addition of newborn neurons. This interaction may also occur transsynpatically; T increases the synthesis of BDNF in HVC, and BDNF protein is then released by HVC neurons on to postsynaptic cells in nucleus RA where it has trophic effects on activity and morphology. Androgen action on RA neurons increases their activity and this has a retrograde trophic effect on the addition of new neurons to HVC. The functional linkage of sex steroids to BDNF may be of adaptive value in regulating the trophic effects of the neurotrophin and coordinating circuit function in reproductively relevant contexts. PMID- 25285405 TI - Metabolism of palmatine by human hepatocytes and recombinant cytochromes P450. AB - In this study, we developed a new liquid chromatography-mass spectrometry (LC-MS) method for analysis of the protoberberine alkaloid palmatine and its metabolites with separation performed on a cyanopropyl-modified stationary phase. Palmatine (10 MUM) was metabolized using suspensions of human hepatocytes and human recombinant cytochrome P450 (CYP) enzymes. Our analyses using electrospray ionization-quadrupole time-of-flight mass spectrometry revealed that palmatine was relatively resistant to the metabolic activity of human hepatocytes and recombinant CYP enzymes. However, we found that the biotransformation of palmatine in human hepatocytes included O-demethylation or hydroxylation, and that the product of palmatine demethylation was conjugated by glucuronidation or sulfation. Moreover, we found that human recombinant CYP2D6 and, to a lesser extent, CYP1A2 can mediate O-demethylation of palmatine. These results provide fundamental insights into the biotransformation of palmatine in human in vitro models and, together with the LC-MS method, can be applied for further studies on the biotransformation of palmatine and other protoberberine alkaloids. PMID- 25285406 TI - LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6. AB - Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer. PMID- 25285407 TI - Comparative effectiveness research: ethical and regulatory guidance. PMID- 25285408 TI - Pushing the pedal to the metal: should we accelerate infliximab therapy for patients with severe ulcerative colitis? PMID- 25285409 TI - The role for dietary omega-3 fatty acids supplementation in older adults. AB - Optimal nutrition is one of the most important determinants of healthier ageing, reducing the risk of disability, maintaining mental and physical functions, and thus preserving and ensuring a better quality of life. Dietary intake and nutrient absorption decline with age, thus increasing the risk of malnutrition, morbidity and mortality. Specific nutrients, particularly long-chain omega-3 polyunsaturated fatty acids (PUFAs), might have the potential of preventing and reducing co-morbidities in older adults. Omega-3 PUFAs are able to modulate inflammation, hyperlipidemia, platelet aggregation, and hypertension. Different mechanisms contribute to these effects, including conditioning cell membrane function and composition, eicosanoid production, and gene expression. The present review analyzes the influence of omega-3 PUFAs status and intake on brain function, cardiovascular system, immune function, muscle performance and bone health in older adults. Omega-3 FAs may have substantial benefits in reducing the risk of cognitive decline in older people. The available data encourage higher intakes of omega-3 PUFAs in the diet or via specific supplements. More studies are needed to confirm the role of omega-3 FAs in maintaining bone health and preventing the loss of muscle mass and function associated with ageing. In summary, omega-3 PUFAs are now identified as potential key nutrients, safe and effective in the treatment and prevention of several negative consequences of ageing. PMID- 25285410 TI - Micronutrient intakes among children and adults in Greece: the role of age, sex and socio-economic status. AB - The aim of the present study was to report the usual nutrient intakes of sixteen micronutrients by schoolchildren, adults and the elderly in Greece and to further explore the role of age, sex and socio-economic status (SES) on meeting the recommended nutrient intakes. Dietary intake, demographic and SES data from three existing studies conducted in Greece (in 9-13-year-old children; 40-60-year-old adults; and 50-75-year-old women) were collected. The prevalence of study participants with inadequate micronutrient intakes were assessed using the estimated average requirement (EAR) cut-point method. Regarding sex and age differences, the highest prevalences of inadequate nutrient intakes occurred in post-menopausal women. In both sexes and all age groups, the prevalence of vitamin D intake below EAR reached 100%. Furthermore, nutrient intakes of 75% or more below EAR were found for vitamin E in all age groups, folate in women and for calcium and magnesium in post-menopausal women (p < 0.05). Regarding SES differences, the prevalences of inadequate calcium and vitamin C intakes were higher for children and postmenopausal women of lower SES compared to their higher SES counterparts (p < 0.05). The current study reported the highest prevalences of inadequate intakes for both sexes and all age and SES groups for calcium, folate and vitamins D and E. These findings could provide guidance to public health policy makers in terms of updating current dietary guidelines and fortifying foods to meet the needs of all population subgroups. PMID- 25285411 TI - Immunodetection of outer membrane proteins by flow cytometry of isolated mitochondria. AB - Methods to detect and monitor mitochondrial outer membrane protein components in animal tissues are vital to study mitochondrial physiology and pathophysiology. This protocol describes a technique where mitochondria isolated from rodent tissue are immunolabeled and analyzed by flow cytometry. Mitochondria are isolated from rodent spinal cords and subjected to a rapid enrichment step so as to remove myelin, a major contaminant of mitochondrial fractions prepared from nervous tissue. Isolated mitochondria are then labeled with an antibody of choice and a fluorescently conjugated secondary antibody. Analysis by flow cytometry verifies the relative purity of mitochondrial preparations by staining with a mitochondrial specific dye, followed by detection and quantification of immunolabeled protein. This technique is rapid, quantifiable and high-throughput, allowing for the analysis of hundreds of thousands of mitochondria per sample. It is applicable to assess novel proteins at the mitochondrial surface under normal physiological conditions as well as the proteins that may become mislocalized to this organelle during pathology. Importantly, this method can be coupled to fluorescent indicator dyes to report on certain activities of mitochondrial subpopulations and is feasible for mitochondria from the central nervous system (brain and spinal cord) as well as liver. PMID- 25285416 TI - Using microwave and macroscopic samples of dielectric solids to study the photonic properties of disordered photonic bandgap materials. AB - Recently, disordered photonic materials have been suggested as an alternative to periodic crystals for the formation of a complete photonic bandgap (PBG). In this article we will describe the methods for constructing and characterizing macroscopic disordered photonic structures using microwaves. The microwave regime offers the most convenient experimental sample size to build and test PBG media. Easily manipulated dielectric lattice components extend flexibility in building various 2D structures on top of pre-printed plastic templates. Once built, the structures could be quickly modified with point and line defects to make freeform waveguides and filters. Testing is done using a widely available Vector Network Analyzer and pairs of microwave horn antennas. Due to the scale invariance property of electromagnetic fields, the results we obtained in the microwave region can be directly applied to infrared and optical regions. Our approach is simple but delivers exciting new insight into the nature of light and disordered matter interaction. Our representative results include the first experimental demonstration of the existence of a complete and isotropic PBG in a two dimensional (2D) hyperuniform disordered dielectric structure. Additionally we demonstrate experimentally the ability of this novel photonic structure to guide electromagnetic waves (EM) through freeform waveguides of arbitrary shape. PMID- 25285418 TI - Synthesis of oligonucleotides containing N,N-disubstituted 3-deazacytosine nucleobases by post-elongation modification and their triplex-forming ability with double-stranded DNA. AB - A phosphoramidite of a 2'-O,4'-C-methylene-bridged nucleoside, bearing 4-(2,4,6 triisopropylbenzenesulfonyloxy)pyridin-2-one as a nucleobase precursor, was synthesized and introduced into an oligonucleotide. Treatment with various secondary amines after elongating the oligonucleotide on an automated DNA synthesizer enabled facile and mild conversion of the precursor into the corresponding N,N-disubstituted 3-deazacytosine nucleobases. The evaluation of the triplex-forming ability of the synthesized oligonucleotides with double stranded DNA showed that the nucleobase possessing the (3S)-3 guanidinopyrrolidine moiety can recognize a CG base pair with high sequence selectivity and binding-affinity. PMID- 25285417 TI - Shock wave lithotripsy does not impair renal function in a Swine model of metabolic syndrome. AB - PURPOSE: To determine whether shock wave lithotripsy (SWL) may be a risk factor for renal functional impairment in a swine model of metabolic syndrome (MetS). MATERIALS AND METHODS: Nine-month-old female Ossabaw pigs were fed an excess calorie atherogenic diet to induce MetS. At 15 months of age, the MetS pigs were treated with 2000 SWs or an overtreatment dose of 4000 SWs targeted at the upper pole calyx of the left kidney (24 kV at 120 SWs/min using the unmodified Dornier HM3 lithotripter; n=5-6 per treatment group). Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured in conscious pigs before and ~60 days after SWL to provide a qualitative assessment of how well both kidneys were filtering (glomerular filtration rate [GFR]). Bilateral renal function was assessed at ~65 days post-SWL in anesthetized pigs with GFR and effective renal plasma flow (ERPF) quantified by the renal clearance of inulin and para-amino hippurate, respectively. RESULTS: Cr and BUN values were within normal limits before SWL and remained unchanged after lithotripsy in both the 2000 SW- and 4000 SW-treated pigs. GFR and ERPF of kidneys treated with SWL at either SW dose were similar to the contralateral nontreated kidney. Chronic histological changes in the SW-treated pole of the kidney included interstitial fibrosis, sclerotic glomeruli, and dilated and atrophic tubules. CONCLUSIONS: Our results are consistent with the view that a single SWL session does not result in renal impairment, even in the presence of MetS. PMID- 25285419 TI - The characterization of the saddle shaped nickel(III) porphyrin radical cation: an explicative NMR model for a ferromagnetically coupled metallo-porphyrin radical. AB - Ni(III)(OETPP)(Br)2 is the first Ni(III) porphyrin radical cation with structural and (1)H and (13)C paramagnetic NMR data for porphyrinate systems. Associating EPR and NMR analyses with DFT calculations as a new model is capable of clearly determining the dominant state from two controversial spin distributions in the ring to be the Ni(III) LS coupled with an a1u spin-up radical. PMID- 25285420 TI - Separation and enhanced detection of anesthetic compounds using solid phase micro extraction (SPME)-Raman spectroscopy. AB - Polydimethylsiloxane (PDMS)-based solid-phase micro-extraction (SPME) was used along with Raman spectroscopy (RS) to separate and enhance the detection of five anesthetic compounds (halothane, propofol, isoflurane, enflurane, and etomidate) from aqueous and serum phases. Raman signals in the spectral ranges 250-450 cm( 1) and 950-1050 cm(-1) allowed the unique characterization of all five compounds when extracted into the PDMS phase. The SPME-RS detection of clinically relevant concentrations of aqueous propofol (6.5 MUM) and halothane (200 MUM) is shown. We quantify the partition coefficient for aqueous halothane in PDMS as log K = 1.9 +/- 0.2. Solid-phase micro-extraction of the anesthetics makes their detection possible without the strong autofluorescent interference of serum proteins. Because of low solubility and/or weak Raman scattering, we found it challenging to detect enflurane, isoflurane, and etomidate directly from the aqueous phase, but could we do so with SPME enhancement. These studies show the potential of SPME-RS as a method for the direct detection of anesthetics in blood. PMID- 25285421 TI - Validation of Bacteroidales quantitative PCR assays targeting human and animal fecal contamination in the public and domestic domains in India. AB - We compared host-associated Bacteroidales qPCR assays developed in the continental United States and Europe for the purpose of measuring the effect of improved sanitation on human fecal exposure in rural Indian communities where both human and animal fecal loading are high. Ten candidate Bacteroidales qPCR assays were tested against fecal samples (human, sewage, cow, buffalo, goat, sheep, dog and chicken) from a test set of 30 individual human, 5 sewage, and 60 pooled animal samples collected in coastal Odisha, India. The two universal/general Bacteroidales assays tested (BacUni, GenBac3) performed equally well, achieving 100% sensitivity on the test set. Across the five human associated assays tested (HF183 Taqman, BacHum, HumM2, BacH, HF183 SYBR), we found low sensitivity (17 to 49%) except for HF183 SYBR (89%), and moderate to high cross-reactivity with dog (20 to 80%) and chicken fecal samples (60 to 100%). BacHum had the highest accuracy (67%), amplified all sewage samples within the range of quantification (ROQ), and did not cross-react with any fecal samples from cows, the most populous livestock animal in India. Of the ruminant- and cattle-associated assays tested (BacCow, CowM2), BacCow was more sensitive in detecting the full range of common Indian livestock animal fecal sources, while CowM2 only detected cow sources with 50% sensitivity. Neither assay cross-reacted with human sources. BacCan, the dog-associated assay tested, showed no cross reactivity with human sources, and high sensitivity (90%) for dog fecal samples. Overall, our results indicate BacUni, BacHum, HumM2, BacCan and BacCow would be the most suitable MST assays to distinguish and quantify relative amounts of human-associated and livestock/domestic animal-associated contributions to fecal contamination in Odisha, India. PMID- 25285423 TI - Effectiveness of various irrigation activation protocols and the self-adjusting file system on smear layer and debris removal. AB - The purpose of the present study is to evaluate smear layer generation and residual debris after using self-adjusting file (SAF) or rotary instrumentation and to compare the debris and smear layer removal efficacy of the SAF cleaning/shaping irrigation system against final agitation techniques. One hundred and eight maxillary lateral incisor teeth were randomly divided into nine experimental groups (n = 12), and root canals were prepared using ProTaper Universal rotary files, with the exception of the SAF instrumentation group. During instrumentation, root canals were irrigated with a total of 16 mL of 5% NaOCl. For final irrigation, rotary-instrumented groups were irrigated with 10 mL of 17% EDTA and 10 mL of 5% NaOCl using different irrigation agitation regimens (syringe irrigation with needles, NaviTip FX, manual dynamic irrigation, CanalBrush, EndoActivator, EndoVac, passive ultrasonic irrigation (PUI), and SAF irrigation). In the SAF instrumentation group, root canals were instrumented for 4 min at a rate of 4 mL/min with 5% NaOCl and received a final flush with same as syringe irrigation with needles. The surface of the root dentin was observed using a scanning electron microscope. The SAF instrumentation group generated less smear layer and yielded cleaner canals compared to rotary instrumentation. The EndoActivator, EndoVac, PUI, and SAF irrigation groups increased the efficacy of irrigating solutions on the smear layer and debris removal. The SAF instrumentation yielded cleaner canal walls when compared to rotary instrumentation. None of the techniques completely removed the smear layer from the root canal walls. PMID- 25285425 TI - Effect of nanovaccine chemistry on humoral immune response kinetics and maturation. AB - Acute respiratory infections represent a significant portion of global morbidity and mortality annually. There is a critical need for efficacious vaccines against respiratory pathogens. To vaccinate against respiratory disease, pulmonary delivery is an attractive route because it mimics the route of natural infection and can confer both mucosal and systemic immunity. We have previously demonstrated that a single dose, intranasal vaccine based on polyanhydride nanoparticles elicited a protective immune response against Yersinia pestis for at least 40 weeks after immunization with F1-V. Herein, we investigate the effect of nanoparticle chemistry and its attributes on the kinetics and maturation of the antigen-specific serum antibody response. We demonstrate that manipulation of polyanhydride nanoparticle chemistry facilitated differential kinetics of development of antibody titers, avidity, and epitope specificity. The results provide new insights into the underlying role(s) of nanoparticle chemistry in providing long-lived humoral immunity and aid in the rational design of nanovaccine formulations to induce long-lasting and mature antibody responses. PMID- 25285426 TI - Health-related quality of life for chronically ill children. AB - Approximately 43% of children in the United States (32 million) are currently living with at least 1 of 20 common chronic childhood illnesses. The most common chronic childhood illnesses are asthma, cystic fibrosis, diabetes, obesity, malnutrition, developmental disabilities, cerebral palsy, consequences of low birthweight, and mental illness. For all chronically ill pediatric populations, the outcome of health-related quality of life (HRQOL) is particularly important because many of these children have not and will not be cured, and will continue to manage their chronic illness into adulthood. Advances in biomedical science and technology continue to improve efficacy of treatments and care for chronically ill children, adolescents, and their families, which highlight the importance measurement of HRQOL as a treatment and health status outcome. The construct of HRQOL is subjective, multidimensional, dynamic, and unique to each individual. It includes aspects of physical, psychological, social function, and goal attainment. Outcomes of HRQOL now include the financial implications for these children and their families, as well as financial and organizational consequences for healthcare planning and delivery of services.This article reviews the importance of HRQOL as a health outcome for chronically ill children. A historical overview and synthesis of the conceptualization and measurement of HRQOL for the chronically ill pediatric population is provided. Current research investigations that have measured health outcomes using individual scales tailored to children's specific symptoms health outcomes, such as PROMIS(r) Patient Reported Outcomes Measurement Information System-are reviewed. The clinical applications of HRQOL outcomes research include facilitation of patient healthcare provider communication, improved patient satisfaction, identification of hidden morbidities, a positive impact on clinical decision making, and improvement of patient outcomes over time. PMID- 25285424 TI - Experimental scleral cross-linking increases glaucoma damage in a mouse model. AB - The purpose of this study was to assess the effect of a scleral cross-linking agent on susceptibility to glaucoma damage in a mouse model.CD1 mice underwent 3 subconjunctival injections of 0.5 M glyceraldehyde (GA) in 1 week, then had elevated intraocular pressure (IOP) induced by bead injection. Degree of cross linking was measured by enzyme-linked immunosorbent assay (ELISA), scleral permeability was measured by fluorescence recovery after photobleaching (FRAP), and the mechanical effects of GA exposure were measured by inflation testing. Control mice had buffer injection or no injection in 2 separate glaucoma experiments. IOP was monitored by Tonolab and retinal ganglion cell (RGC) loss was measured by histological axon counting. To rule out undesirable effects of GA, we performed electroretinography and detailed histology of the retina. GA exposure had no detectable effects on RGC number, retinal structure or function either histologically or electrophysiologically. GA increased cross-linking of sclera by 37% in an ELISA assay, decreased scleral permeability (FRAP, p = 0.001), and produced a steeper pressure-strain behavior by in vitro inflation testing. In two experimental glaucoma experiments, GA-treated eyes had greater RGC axon loss from elevated IOP than either buffer-injected or control eyes, controlling for level of IOP exposure over time (p = 0.01, and 0.049, multivariable regression analyses). This is the first report that experimental alteration of the sclera, by cross-linking, increases susceptibility to RGC damage in mice. PMID- 25285427 TI - Pillars of judgment: how memory abilities affect performance in rule-based and exemplar-based judgments. AB - Making accurate judgments is an essential skill in everyday life. Although how different memory abilities relate to categorization and judgment processes has been hotly debated, the question is far from resolved. We contribute to the solution by investigating how individual differences in memory abilities affect judgment performance in 2 tasks that induced rule-based or exemplar-based judgment strategies. In a study with 279 participants, we investigated how working memory and episodic memory affect judgment accuracy and strategy use. As predicted, participants switched strategies between tasks. Furthermore, structural equation modeling showed that the ability to solve rule-based tasks was predicted by working memory, whereas episodic memory predicted judgment accuracy in the exemplar-based task. Last, the probability of choosing an exemplar-based strategy was related to better episodic memory, but strategy selection was unrelated to working memory capacity. In sum, our results suggest that different memory abilities are essential for successfully adopting different judgment strategies. PMID- 25285428 TI - Emodiversity and the emotional ecosystem. AB - [Correction Notice: An Erratum for this article was reported in Vol 143(6) of Journal of Experimental Psychology: General (see record 2014-49316-001). There is a color coding error in Figure 2. The correct color coding is explained in the erratum.] Bridging psychological research exploring emotional complexity and research in the natural sciences on the measurement of biodiversity, we introduce -and demonstrate the benefits of--emodiversity: the variety and relative abundance of the emotions that humans experience. Two cross-sectional studies across more than 37,000 respondents demonstrate that emodiversity is an independent predictor of mental and physical health--such as decreased depression and doctor's visits--over and above mean levels of positive and negative emotion. These results remained robust after controlling for gender, age, and the 5 main dimensions of personality. Emodiversity is a practically important and previously unidentified metric for assessing the health of the human emotional ecosystem. PMID- 25285430 TI - A hedonic story has a transmission advantage over a eudaimonic story. AB - We examined (a) whether a hedonic story (story full of hedonic activities) is better remembered and transmitted compared with a eudaimonic story (story full of eudaimonic activities), and (b) whether the hedonic story's memory and transmission advantage varies depending on contextual cues, as indexed by the day of the week. Study 1 showed that college students are surrounded with more party announcements on Wednesdays through Fridays than on Mondays and Tuesdays. Study 2 showed that the hedonic story and the eudaimonic story we created were equally interesting, rich in plot, surprising, and arousing, yet the hedonic story was rated as more disturbing, real, and newsworthy. In Studies 3 and 4, we used a serial reproduction method and found that the hedonic story was better recalled and transmitted to others than was the eudaimonic story, and that this effect was particularly strong when participants completed the study later in the week. Our findings suggest that a hedonic story is more communicable than a eudaimonic story, particularly when supported by environmental cues. PMID- 25285429 TI - The value of vengeance and the demand for deterrence. AB - Humans will incur costs to punish others who violate social norms. Theories of justice highlight 2 motives for punishment: a forward-looking deterrence of future norm violations and a backward-looking retributive desire to harm. Previous studies of costly punishment have not isolated how much people are willing to pay for retribution alone, because typically punishment both inflicts damage (satisfying the retributive motive) and communicates a norm violation (satisfying the deterrence motive). Here, we isolated retributive motives by examining how much people will invest in punishment when the punished individual will never learn about the punishment. Such "hidden" punishment cannot deter future norm violations but was nevertheless frequently used by both 2nd-party victims and 3rd-party observers of norm violations, indicating that retributive motives drive punishment decisions independently from deterrence goals. While self-reports of deterrence motives correlated with deterrence-related punishment behavior, self-reports of retributive motives did not correlate with retributive punishment behavior. Our findings reveal a preference for pure retribution that can lead to punishment without any social benefits. PMID- 25285431 TI - Complexity matching in dyadic conversation. AB - Recent studies of dyadic interaction have examined phenomena of synchronization, entrainment, alignment, and convergence. All these forms of behavioral matching have been hypothesized to play a supportive role in establishing coordination and common ground between interlocutors. In the present study, evidence is found for a new kind of coordination termed complexity matching. Temporal dynamics in conversational speech signals were analyzed through time series of acoustic onset events. Timing in periods of acoustic energy was found to exhibit behavioral matching that reflects complementary timing in turn-taking. In addition, acoustic onset times were found to exhibit power law clustering across a range of timescales, and these power law functions were found to exhibit complexity matching that is distinct from behavioral matching. Complexity matching is discussed in terms of interactive alignment and other theoretical principles that lead to new hypotheses about information exchange in dyadic conversation and interaction in general. PMID- 25285432 TI - Anisotropic temperature sensitive chitosan-based injectable hydrogels mimicking cartilage matrix. AB - In this study, chitosan-based hydrogels were formulated with material similarities to three of the four zones of articular cartilage. Gelatin, hyaluronic acid (HA), and beta-tricalcium phosphate for the superficial, radial, and calcified zones, were blended in different amounts and tested for formation of uniform solution, gelability, and rheological characteristics. Confined compression in two configurations (series and parallel to anisotropy), and cyclical tests were performed at the physiological conditions. In vivo gelation and systemic effects were evaluated in male BALB/c mice subcutaneous model. At day 5, hydrogels were harvested along with the adjoining skin and analyzed by histology. Formulations that produced solutions after pH adjustments were selected for each zone. Anisotropic hydrogels were formed by mixing solutions from each zone, which showed uniform gradation. Addition of HA improved structural integrity relative to other formulations. When hydrogels were in series, combined hydrogel modulus was the average of all zones while that in parallel orientation was half of that series orientation. Cyclical tests demonstrated repeatable strength and durability. All formulations were injectable into the subcutaneous region. H/E stained tissues showed minimal invasion of inflammatory cells in radial and calcified zones. Structural integrity of the hydrogel is suggested to be the resultant of the presence of HA. PMID- 25285433 TI - Chemical reaction dynamics I and electron dynamics in molecules: general discussion. PMID- 25285434 TI - Acute lurasidone overdose. PMID- 25285435 TI - Size dependent disruption of tethered lipid bilayers by functionalized polystyrene nanoparticles. AB - Molecular interactions between engineered nanomaterials (ENM) and biomembranes are not well understood. This study investigated the effects of particle size and surface functional group on polystyrene nanoparticles' (PNPs) potency for biomembrane disruption. Electrochemical impedance spectroscopy was used to measure changes in the electrical resistance (Rm) of a tethered bilayer lipid membrane BLM (tBLM) composed of 1,2-dioleoyl-sn-glycero-phosphocholine (DOPC) following PNP exposure. All PNPs tested triggered a decline in the Rm that could be described using an exponential-decay model. Statistical hierarchical clustering analysis of two model parameters (exponential rate constant and fractional loss of Rm) could distinguish between the PNPs based on both size and surface functional group. For COOH modified nanoparticles, 20nm PNPs were more potent in reducing Rm than 100nm PNP. However, for amidine modified nanoparticles, 120nm PNPs were more potent in reducing Rm than 23nm PNP. The COOH modified PNPs were more potent in reducing Rm than amidine modified PNP, which tended to aggregate following exposure to a tBLM. Ultra performance liquid chromatography-mass spectroscopy analysis suggested that the aggregation may have been triggered by DOPC that was removed from the tBLM by the amidine PNP. PMID- 25285437 TI - NIR persistent luminescence of lanthanide ion-doped rare-earth oxycarbonates: the effect of dopants. AB - A series of luminescent rare-earth ion-doped hexagonal II-type Gd oxycarbonate phosphors Gd2-xRExO2CO3 (RE = Eu(3+), Yb(3+), Dy(3+)) have been successfully synthesized by thermal decomposition of the corresponding mixed oxalates. The Yb(3+) doped Gd-oxycarbonate has evidenced a high persistent luminescence in the NIR region, that is independent from the temperature and makes this materials particular attractive as optical probes for bioimaging. PMID- 25285436 TI - Early effects of reward anticipation are modulated by dopaminergic stimulation. AB - The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predicting rewards of high and low magnitudes and probability (2 * 2 factorial design), while neural activity was scanned using magnetoencephalography. Importantly, one group of participants received 150 mg of the dopamine precursor levodopa prior to the experiment, while another group received a placebo. For the placebo group, neural signals of reward probability (but not magnitude) emerged at ~ 100 ms after cue presentation at occipital sensors in the event-related magnetic fields. Importantly, these probability signals were absent in the levodopa group indicating a close link. Moreover, levodopa administration reduced oscillatory power in the high (20-30 Hz) and low (13-20 Hz) beta band during both reward anticipation and delivery. Taken together, our findings indicate that visual brain regions are involved in coding prospective reward probability but not magnitude and that these effects are modulated by dopamine. PMID- 25285438 TI - Improving access to emergency contraception pills through strengthening service delivery and demand generation: a systematic review of current evidence in low and middle-income countries. AB - OBJECTIVES: Emergency contraception pills (ECP) are among the 13 essential commodities in the framework for action established by the UN Commission on Life Saving Commodities for Women and Children. Despite having been on the market for nearly 20 years, a number of barriers still limit women's access to ECP in low- and middle-income countries (LMIC) including limited consumer knowledge and poor availability. This paper reports the results of a review to synthesise the current evidence on service delivery strategies to improve access to ECP. METHODS: A narrative synthesis methodology was used to examine peer reviewed research literature (2003 to 2013) from diverse methodological traditions to provide critical insights into strategies to improve access from a service delivery perspective. The studies were appraised using established scoring systems and the findings of included papers thematically analysed and patterns mapped across all findings using concept mapping. FINDINGS: Ten papers were included in the review. Despite limited research of adequate quality, promising strategies to improve access were identified including: advance provision of ECP; task shifting and sharing; intersectoral collaboration for sexual assault; m health for information provision; and scale up through national family planning programs. CONCLUSION: There are a number of gaps in the research concerning service delivery and ECP in LMIC. These include a lack of knowledge concerning private/commercial sector contributions to improving access, the needs of vulnerable groups of women, approaches to enhancing intersectoral collaboration, evidence for social marketing models and investment cases for ECP. PMID- 25285439 TI - Simple quantitative PCR approach to reveal naturally occurring and mutation induced repetitive sequence variation on the Drosophila Y chromosome. AB - Heterochromatin is a significant component of the human genome and the genomes of most model organisms. Although heterochromatin is thought to be largely non coding, it is clear that it plays an important role in chromosome structure and gene regulation. Despite a growing awareness of its functional significance, the repetitive sequences underlying some heterochromatin remain relatively uncharacterized. We have developed a real-time quantitative PCR-based method for quantifying simple repetitive satellite sequences and have used this technique to characterize the heterochromatic Y chromosome of Drosophila melanogaster. In this report, we validate the approach, identify previously unknown satellite sequence copy number polymorphisms in Y chromosomes from different geographic sources, and show that a defect in heterochromatin formation can induce similar copy number polymorphisms in a laboratory strain. These findings provide a simple method to investigate the dynamic nature of repetitive sequences and characterize conditions which might give rise to long-lasting alterations in DNA sequence. PMID- 25285440 TI - The impact of climate change on infectious disease transmission: perceptions of CDC health professionals in Shanxi Province, China. AB - There have been increasing concerns about the challenge of emerging and re emerging infectious diseases due to climate change, especially in developing countries including China. Health professionals play a significant role in the battle to control and prevent infectious diseases. This study therefore aims to investigate the perceptions and attitudes of health professionals at the Centers for Disease Control and Prevention (CDC) in different levels in China, and to consider adaptation measures to deal with the challenge of climate change. In 2013, a cross-sectional questionnaire survey was undertaken among 314 staff in CDCs in Shanxi Province, China, whose routine work involves disease control and prevention. Data were analyzed using descriptive methods and logistic regression. A majority of the CDC staff were aware of the health risks from climate change, especially its impacts on infectious disease transmission in their jurisdictions, and believed climate change might bring about both temporal and spatial change in transmission patterns. It was thought that adaptation measures should be established including: strengthening/improving currently existing disease surveillance systems and vector monitoring; building CDC capacity in terms of infrastructure and in-house health professional training; development and refinement of relevant legislation, policies and guidelines; better coordination among various government departments; the involvement of the community in infectious disease interventions; and collaborative research with other institutions. This study provides a snapshot of the understanding of CDC staff regarding climate change risks relevant to infectious diseases and adaptation in China. Results may help inform future efforts to develop adaptation measures to minimize infectious disease risks due to climate change. PMID- 25285441 TI - FEV1 is a better predictor of mortality than FVC: the PLATINO cohort study. AB - OBJECTIVE: To determine whether the presence of chronic obstructive lung disease (COPD) and reduction of lung function parameters were predictors of mortality in a cohort. MATERIALS/PATIENTS AND METHODS: Population based cohorts were followed in Montevideo, Santiago and Sao Paulo during 5, 6 and 9 years, respectively. Outcomes included all-cause, cardiovascular, respiratory and cancer mortality; exposures were COPD, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Cox regression was used for analyses. Sensitivity, specificity, positive and negative predictive values, receiver operator characteristics curves and Youden's index were calculated. RESULTS: Main causes of death were cardiovascular, respiratory and cancer. Baseline COPD was associated with overall mortality (HR = 1.43 for FEV1/FVC=10 years followed from 1st January 1997 until diagnosis of sarcoidosis, death or 31st December 2011. Patients with a history of psoriasis and/or sarcoidosis at baseline were excluded. Information on comorbidity and concomitant medication was identified by individual-level linkage of administrative registers. Incidence rates of sarcoidosis were calculated and adjusted hazard ratios (HRs) were estimated by multivariable Cox regression models adjusted for age, gender, comorbidity, medications and socioeconomic status. RESULTS: A total of 6,043,518 subjects were eligible for analysis. In the study period 70,125 patients with new onset psoriasis, including 11,834 patients with severe psoriasis, were identified. The overall incidence rates of sarcoidosis were 1.18, 2.22, and 4.06 per 10,000 person-years for the reference population (9,717 cases), mild psoriasis (78 cases) and severe psoriasis (22 cases), respectively. Compared to the reference population, the age- and gender-adjusted HRs for sarcoidosis were increased in patients with psoriasis with HR 1.49 (95% confidence interval [CI] 1.18-1.87) and HR 2.51 (CI 1.64-3.85) for those with mild and severe disease, respectively. CONCLUSION: In this nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of sarcoidosis. PMID- 25285444 TI - Exserohilum rostratum: characterization of a cross-kingdom pathogen of plants and humans. AB - Pathogen host shifts represent a major source of new infectious diseases. There are several examples of cross-genus host jumps that have caused catastrophic epidemics in animal and plant species worldwide. Cross-kingdom jumps are rare, and are often associated with nosocomial infections. Here we provide an example of human-mediated cross-kingdom jumping of Exserohilum rostratum isolated from a patient who had received a corticosteroid injection and died of fungal meningitis in a Florida hospital in 2012. The clinical isolate of E. rostratum was compared with two plant pathogenic isolates of E. rostratum and an isolate of the closely related genus Bipolaris in terms of morphology, phylogeny, and pathogenicity on one C3 grass, Gulf annual rye grass (Lolium multiflorum), and two C4 grasses, Japanese stilt grass (Microstegium vimineum) and bahia grass (Paspalum notatum). Colony growth and color, as well as conidia shape and size were the same for the clinical and plant isolates of E. rostratum, while these characteristics differed slightly for the Bipolaris sp. isolate. The plant pathogenic and clinical isolates of E. rostratum were indistinguishable based on morphology and ITS and 28S rDNA sequence analysis. The clinical isolate was as pathogenic to all grass species tested as the plant pathogenic strains that were originally isolated from plant hosts. The clinical isolate induced more severe symptoms on stilt grass than on rye grass, while this was the reverse for the plant isolates of E. rostratum. The phylogenetic similarity between the clinical and plant-associated E. rostratum isolates and the ability of the clinical isolate to infect plants suggests that a plant pathogenic strain of E. rostratum contaminated the corticosteroid injection fluid and was able to cause systemic disease in the affected patient. This is the first proof that a clinical isolate of E. rostratum is also an effective plant pathogen. PMID- 25285445 TI - Label-free and sensitive fluorescent detection of sequence-specific single-strand DNA based on S1 nuclease cleavage effects. AB - The ability to detect sequence-specific single-strand DNA (ssDNA) in complex, contaminant-ridden samples, using a fluorescent method directly without a DNA extraction and PCR step could simplify the detection of pathogens in the field and in the clinic. Here, we have demonstrated a simple label-free sensing strategy to detect ssDNA by employing its complementary ssDNA, S1 nuclease and nucleic acid fluorescent dyes. Upon clearing away redundant complementary ssDNA and possibly mismatched double strand DNA by using S1 nuclease, the fluorescent signal-to-noise ratio could be increased dramatically. It enabled the method to be adaptable to three different types of DNA fluorescent dyes and the ability to detect target ssDNA in complex, multicomponent samples, like tissue homogenate. The method can distinguish a two-base mismatch from avian influenza A (H1N1) virus. Also, it can detect the appearance of 50 pM target ssDNA in 0.5 ug . mL( 1) Lambda DNA, and 50 nM target ssDNA in 5 ug . mL(-1) Lambda DNA or in tissue homogenate. It is facile and cost-effective, and could be easily extended to detect other ssDNA with many common nucleic acid fluorescent dyes. PMID- 25285446 TI - Expression cloning of camelid nanobodies specific for Xenopus embryonic antigens. AB - Developmental biology relies heavily on the use of conventional antibodies, but their production and maintenance involves significant effort. Here we use an expression cloning approach to identify variable regions of llama single domain antibodies (known as nanobodies), which recognize specific embryonic antigens. A nanobody cDNA library was prepared from lymphocytes of a llama immunized with Xenopus embryo lysates. Pools of bacterially expressed cDNAs were sib-selected for the ability to produce specific staining patterns in gastrula embryos. Three different nanobodies were isolated: NbP1 and NbP3 stained yolk granules, while the reactivity of NbP7 was predominantly restricted to the cytoplasm and the cortex. The isolated nanobodies recognized specific protein bands in immunoblot analysis. A reverse proteomic approach identified NbP1 target antigen as EP45/Seryp, a serine protease inhibitor. Given the unique stability of nanobodies and the ease of their expression in diverse systems, we propose that nanobody cDNA libraries represent a promising resource for molecular markers for developmental biology. PMID- 25285447 TI - Trithorax maintains the functional heterogeneity of neural stem cells through the transcription factor buttonhead. AB - The mechanisms that maintain the functional heterogeneity of stem cells, which generates diverse differentiated cell types required for organogenesis, are not understood. In this study, we report that Trithorax (Trx) actively maintains the heterogeneity of neural stem cells (neuroblasts) in the developing Drosophila larval brain. trx mutant type II neuroblasts gradually adopt a type I neuroblast functional identity, losing the competence to generate intermediate neural progenitors (INPs) and directly generating differentiated cells. Trx regulates a type II neuroblast functional identity in part by maintaining chromatin in the buttonhead (btd) locus in an active state through the histone methyltransferase activity of the SET1/MLL complex. Consistently, btd is necessary and sufficient for eliciting a type II neuroblast functional identity. Furthermore, over expression of btd restores the competence to generate INPs in trx mutant type II neuroblasts. Thus, Trx instructs a type II neuroblast functional identity by epigenetically promoting Btd expression, thereby maintaining neuroblast functional heterogeneity. PMID- 25285449 TI - Phosphatidic acid modulation of Kv channel voltage sensor function. AB - Membrane phospholipids can function as potent regulators of ion channel function. This study uncovers and investigates the effect of phosphatidic acid on Kv channel gating. Using the method of reconstitution into planar lipid bilayers, in which protein and lipid components are defined and controlled, we characterize two effects of phosphatidic acid. The first is a non-specific electrostatic influence on activation mediated by electric charge density on the extracellular and intracellular membrane surfaces. The second is specific to the presence of a primary phosphate group, acts only through the intracellular membrane leaflet and depends on the presence of a particular arginine residue in the voltage sensor. Intracellular phosphatidic acid accounts for a nearly 50 mV shift in the midpoint of the activation curve in a direction consistent with stabilization of the voltage sensor's closed conformation. These findings support a novel mechanism of voltage sensor regulation by the signaling lipid phosphatidic acid. PMID- 25285448 TI - The Drosophila Sp8 transcription factor Buttonhead prevents premature differentiation of intermediate neural progenitors. AB - Intermediate neural progenitor cells (INPs) need to avoid differentiation and cell cycle exit while maintaining restricted developmental potential, but mechanisms preventing differentiation and cell cycle exit of INPs are not well understood. In this study, we report that the Drosophila homolog of mammalian Sp8 transcription factor Buttonhead (Btd) prevents premature differentiation and cell cycle exit of INPs in Drosophila larval type II neuroblast (NB) lineages. We show that the loss of Btd leads to elimination of mature INPs due to premature differentiation of INPs into terminally dividing ganglion mother cells. We provide evidence to demonstrate that Btd prevents the premature differentiation by suppressing the expression of the homeodomain protein Prospero in immature INPs. We further show that Btd functions cooperatively with the Ets transcription factor Pointed P1 to promote the generation of INPs. Thus, our work reveals a critical mechanism that prevents premature differentiation and cell cycle exit of Drosophila INPs. PMID- 25285450 TI - Regulation of food intake by mechanosensory ion channels in enteric neurons. AB - Regulation of food intake is fundamental to energy homeostasis in animals. The contribution of non-nutritive and metabolic signals in regulating feeding is unclear. Here we show that enteric neurons play a major role in regulating feeding through specialized mechanosensory ion channels in Drosophila. Modulating activities of a specific subset of enteric neurons, the posterior enteric neurons (PENs), results in sixfold changes in food intake. Deficiency of the mechanosensory ion channel PPK1 gene or RNAi knockdown of its expression in the PENS result in a similar increase in food intake, which can be rescued by expression of wild-type PPK1 in the same neurons. Finally, pharmacological inhibition of the mechanosensory ion channel phenocopies the result of genetic interrogation. Together, our study provides the first molecular genetic evidence that mechanosensory ion channels in the enteric neurons are involved in regulating feeding, offering an enticing alternative to current therapeutic strategy for weight control. PMID- 25285451 TI - Visibly emissive and responsive extended 6-aza-uridines. AB - A family of extended 5-modified-6-aza-uridines was obtained via Suzuki coupling reactions with a common brominated precursor. Extending the conjugated-6-aza uridines with substituted aryl rings increases the push-pull interactions yielding enhanced bathochromic shifts and solvatochromism compared to the parent nucleosides. For example, the methoxy substituted derivative 1d displays lambdamax abs around 375 nm, with visible emission maxima at 486 nm (Phi = 0.74) and 525 nm (Phi = 0.02) in dioxane and water, respectively. PMID- 25285452 TI - Integrating a triplet-triplet annihilation up-conversion system to enhance dye sensitized solar cell response to sub-bandgap light. AB - The poor response of dye-sensitized solar cells (DSCs) to red and infrared light is a significant impediment to the realization of higher photocurrents and hence higher efficiencies. Photon up-conversion by way of triplet-triplet annihilation (TTA-UC) is an attractive technique for using these otherwise wasted low energy photons to produce photocurrent, while not interfering with the photoanodic performance in a deleterious manner. Further to this, TTA-UC has a number of features, distinct from other reported photon up-conversion technologies, which renders it particularly suitable for coupling with DSC technology. In this work, a proven high performance TTA-UC system, comprising a palladium porphyrin sensitizer and rubrene emitter, is combined with a high performance DSC (utilizing the organic dye D149) in an integrated device. The device shows an enhanced response to sub-bandgap light over the absorption range of the TTA-UC sub-unit resulting in the highest figure of merit for up-conversion assisted DSC performance to date. PMID- 25285453 TI - Transferring cognitive tasks between brain imaging modalities: implications for task design and results interpretation in FMRI studies. AB - As cognitive neuroscience methods develop, established experimental tasks are used with emerging brain imaging modalities. Here transferring a paradigm (the visual oddball task) with a long history of behavioral and electroencephalography (EEG) experiments to a functional magnetic resonance imaging (fMRI) experiment is considered. The aims of this paper are to briefly describe fMRI and when its use is appropriate in cognitive neuroscience; illustrate how task design can influence the results of an fMRI experiment, particularly when that task is borrowed from another imaging modality; explain the practical aspects of performing an fMRI experiment. It is demonstrated that manipulating the task demands in the visual oddball task results in different patterns of blood oxygen level dependent (BOLD) activation. The nature of the fMRI BOLD measure means that many brain regions are found to be active in a particular task. Determining the functions of these areas of activation is very much dependent on task design and analysis. The complex nature of many fMRI tasks means that the details of the task and its requirements need careful consideration when interpreting data. The data show that this is particularly important in those tasks relying on a motor response as well as cognitive elements and that covert and overt responses should be considered where possible. Furthermore, the data show that transferring an EEG paradigm to an fMRI experiment needs careful consideration and it cannot be assumed that the same paradigm will work equally well across imaging modalities. It is therefore recommended that the design of an fMRI study is pilot tested behaviorally to establish the effects of interest and then pilot tested in the fMRI environment to ensure appropriate design, implementation and analysis for the effects of interest. PMID- 25285454 TI - Protein isolation from the developing embryonic mouse heart valve region. AB - Western blot analysis is a commonly employed technique for detecting and quantifying protein levels. However, for small tissue samples, this analysis method may not be sufficiently sensitive to detect a protein of interest. To overcome these difficulties, we examined protocols for obtaining protein from adult human cardiac valves and modified these protocols for the developing early embryonic mouse counterparts. In brief, the mouse embryonic aortic valve regions, including the aortic valve and surrounding aortic wall, are collected in the minimal possible volume of a Tris-based lysis buffer with protease inhibitors. If required based on the breeding strategy, embryos are genotyped prior to pooling four embryonic aortic valve regions for homogenization. After homogenization, an SDS-based sample buffer is used to denature the sample for running on an SDS-PAGE gel and subsequent western blot analysis. Although the protein concentration remains too low to quantify using spectrophotometric protein quantification assays and have sample remaining for subsequent analyses, this technique can be used to successfully detect and semi-quantify phosphorylated proteins via western blot from pooled samples of four embryonic day 13.5 mouse aortic valve regions, each of which yields approximately 1 MUg of protein. This technique will be of benefit for studying cell signaling pathway activation and protein expression levels during early embryonic mouse valve development. PMID- 25285455 TI - Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Women's Health Study. AB - IMPORTANCE: While the pooled cohort equations from the recent American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Assessment of Cardiovascular Risk have overestimated cardiovascular risk in multiple external cohorts, the reasons for the discrepancy are unclear. OBJECTIVE: To determine whether increased use of statins over time, incident coronary revascularization procedures, or underascertainment of vascular events explain overestimation of risk in a more contemporary population. DESIGN, SETTING, AND PARTICIPANTS: The Women's Health Study (WHS) is a nationwide cohort of US women free of cardiovascular disease, cancer, or other major illness at baseline from 1992 to 1995. A total of 27 542 women ages 45 to 79 years with complete ascertainment of plasma lipids and other risk factors were followed for a median of 10 years. MAIN OUTCOME AND MEASURE: Atherosclerotic cardiovascular disease (ASCVD), defined as any myocardial infarction, any stroke, or death due to cardiovascular cause. RESULTS: A total of 632 women experienced an ASCVD event over the course of the follow-up. The average predicted risk from the pooled cohort equations was 3.6% over 10 years, compared with an actual observed risk of 2.2%. Ratios of predicted to observed rates were 1.90 or higher in the groups with 0 to less than 5.0% and 5.0% to less than 7.5% risk and were over 1.40 in the groups with 7.5% to less than 10.0% and 10.0% or higher risk. Rates of statin use and revascularizations increased over follow-up time and by risk group, and in sensitivity analyses, we estimated the hypothetical rates if no women were prescribed statins or underwent revascularization procedures. After adjustment for intervention effects of statins and revascularization as well as hypothetical confounding by indication, ratios of predicted to observed rates remained 1.80 or higher in the lower 2 risk groups and over 1.30 higher in the upper 2 risk groups. Underascertainment is unlikely since follow-up rates in the WHS were 97.2%, and overall we would need approximately 60% more events to match the numbers predicted using the pooled cohort equations. CONCLUSIONS AND RELEVANCE: Statin use, revascularization procedures, and underascertainment of events do not explain the discrepancy between observed rates of ASCVD in the WHS and those predicted by the ACC/AHA pooled cohort equations. Other explanations include changing patterns of risk within more contemporary populations. PMID- 25285457 TI - Circadian food anticipatory activity: Entrainment limits and scalar properties re examined. AB - Rats can anticipate a daily feeding time. This has been interpreted as a rhythm controlled by food-entrainable circadian oscillators, because the rhythm persists during several cycles of total food deprivation and fails to track mealtimes if the feeding schedule deviates substantially from 24. These and other properties distinguish anticipation of daily meals from anticipation of food rewards provided at intervals in the seconds-to-minutes range, suggesting distinct mechanisms. It has been reported that rats can anticipate meals at long, but noncircadian, intervals if they are required to work for food, and that anticipation of daily meals, expressed in operant behavior, shows the scalar property, a hallmark of timing intervals in the seconds-to-minutes range. These observations raise the possibility of a universal timing system, rather than unique mechanisms for circadian and noncircadian intervals. To test whether circadian constraints on daily meal timing depend on the measure of behavior, we re-examined formal properties of food anticipation using lever pressing and motion sensors. We observed robust anticipation in both measures to meals at 24 hr intervals but no anticipation of meals at 18-hr intervals in light-dark or constant light and no evidence that the duration of anticipation scales with the interval between lighting transitions and mealtime. We are therefore unable to confirm reports that operant measures can reveal timing at long, but noncircadian, intervals. If timing processes exist that do permit anticipation of events at long, but noncircadian, intervals, the conditions under which these can be revealed are evidently highly constrained. PMID- 25285456 TI - The contribution of medial prefrontal cortical regions to conditioned inhibition. AB - Few studies have considered the process by which individuals learn to omit a response, which is an essential aspect of adaptive behavior. Several lines of evidence indicate that two regions of the medial prefrontal cortex have disparate roles in behavioral flexibility. In particular, the prelimbic cortex (PL) is thought to facilitate the generation of a strategy to inhibit a prepotent response, whereas the infralimbic cortex (IL) appears to be more important for maintaining extensively trained inhibitory behaviors. The present experiments were designed to elucidate the contributions of PL and IL to the acquisition and maintenance of Pavlovian conditioned inhibition. In Experiment 1, damage to PL before training in a compound feature negative discrimination task impaired inhibitory learning. By comparison, lesions of IL had little effect. In Experiment 2, lesions of PL or IL occurred after overtraining, and damage to IL significantly impaired subsequent performance in the task, suggesting that this region is involved in the continued expression of Pavlovian conditioned inhibition after thorough training. PL may also be involved in maintaining inhibition, as evidenced by a marginally significant lesion-induced performance deficit. These data support the notion that PL and IL have distinguishable roles in modulating inhibition, while contributing important information about the specific role for PL in acquisition of an inhibitory response and IL in performance. PMID- 25285458 TI - A preclinical murine model of hepatic metastases. AB - Numerous murine models have been developed to study human cancers and advance the understanding of cancer treatment and development. Here, a preclinical, murine pancreatic tumor model of hepatic metastases via a hemispleen injection of syngeneic murine pancreatic tumor cells is described. This model mimics many of the clinical conditions in patients with metastatic disease to the liver. Mice consistently develop metastases in the liver allowing for investigation of the metastatic process, experimental therapy testing, and tumor immunology research. PMID- 25285459 TI - The Ebola outbreak, fragile health systems, and quality as a cure. PMID- 25285460 TI - Generation of transgenic Hydra by embryo microinjection. AB - As a member of the phylum Cnidaria, the sister group to all bilaterians, Hydra can shed light on fundamental biological processes shared among multicellular animals. Hydra is used as a model for the study of regeneration, pattern formation, and stem cells. However, research efforts have been hampered by lack of a reliable method for gene perturbations to study molecular function. The development of transgenic methods has revitalized the study of Hydra biology(1). Transgenic Hydra allow for the tracking of live cells, sorting to yield pure cell populations for biochemical analysis, manipulation of gene function by knockdown and over-expression, and analysis of promoter function. Plasmid DNA injected into early stage embryos randomly integrates into the genome early in development. This results in hatchlings that express transgenes in patches of tissue in one or more of the three lineages (ectodermal epithelial, endodermal epithelial, or interstitial). The success rate of obtaining a hatchling with transgenic tissue is between 10% and 20%. Asexual propagation of the transgenic hatchling is used to establish a uniformly transgenic line in a particular lineage. Generating transgenic Hydra is surprisingly simple and robust, and here we describe a protocol that can be easily implemented at low cost. PMID- 25285461 TI - The effect of different Global Navigation Satellite System methods on positioning accuracy in elite alpine skiing. AB - In sport science, Global Navigation Satellite Systems (GNSS) are frequently applied to capture athletes' position, velocity and acceleration. Application of GNSS includes a large range of different GNSS technologies and methods. To date no study has comprehensively compared the different GNSS methods applied. Therefore, the aim of the current study was to investigate the effect of differential and non-differential solutions, different satellite systems and different GNSS signal frequencies on position accuracy. Twelve alpine ski racers were equipped with high-end GNSS devices while performing runs on a giant slalom course. The skiers' GNSS antenna positions were calculated in three satellite signal obstruction conditions using five different GNSS methods. The GNSS antenna positions were compared to a video-based photogrammetric reference system over one turn and against the most valid GNSS method over the entire run. Furthermore, the time for acquisitioning differential GNSS solutions was assessed for four differential methods. The only GNSS method that consistently yielded sub decimetre position accuracy in typical alpine skiing conditions was a differential method using American (GPS) and Russian (GLONASS) satellite systems and the satellite signal frequencies L1 and L2. Under conditions of minimal satellite signal obstruction, valid results were also achieved when either the satellite system GLONASS or the frequency L2 was dropped from the best configuration. All other methods failed to fulfill the accuracy requirements needed to detect relevant differences in the kinematics of alpine skiers, even in conditions favorable for GNSS measurements. The methods with good positioning accuracy had also the shortest times to compute differential solutions. This paper highlights the importance to choose appropriate methods to meet the accuracy requirements for sport applications. PMID- 25285462 TI - Thalidomide in the treatment of immune reconstitution inflammatory syndrome in HIV patients with neurological tuberculosis. PMID- 25285463 TI - Gender differences in survival in old age. AB - BACKGROUND: Although increased survival among females is observed throughout much of adult life, supporting evidence among the oldest old is lacking. OBJECTIVE: We examined the hypothesis that gender differences in survival diminish with advancing age. METHODS: The Jerusalem Longitudinal Study follows a representative cohort born 1920-1921, comprehensively assessed at ages 70, 78, 85, and 90 (n=463, 927, 1224, and 673, respectively). Mortality data were collected during 1990-2013. Kaplan-Meier survival curves and mortality hazards ratios (HRs) were determined, adjusting for gender, marital status, education, loneliness, self rated health, physical activity, functional status, neoplasm, diabetes mellitus, hypertension, and ischemic heart disease. RESULTS: Survival between ages 70-78 was 77.3% (n=358/463), 78-85 was 68.9% (n=635/927), 85-90 years was 71.1% (n=870/1224), and 90-93 years was 80.5% (n=542/673). With advancing age, the survival advantage among females versus men declined-at ages 70-78 (85.6% vs. 71%, p<0.0001), 78-85 (74% vs. 63%, p=0.001), 85-90 (74% vs. 67.5%, p=0.06), and 90-93 (80% vs. 81%, p=0.92). Compared to females (HR=1.0), the adjusted HR for male mortality at ages 70-78 was 2.93 (95% confidence interval [CI] 1.75-4.91), ages 78-85 was 2.1 (95% CI 1.5-2.92), ages 85-90 was 1.6 (95% CI 1.2-2.2), and ages 90-93 was 1.1 (95% CI 0.7-1.8). CONCLUSIONS: Our findings confirm the hypothesis that the increased longevity observed among females at age 70 gradually diminishes with advancing age, and disappears beyond age 90. PMID- 25285465 TI - Reliability of intravitreal nepafenac in rabbits. AB - PURPOSE: The purpose of this experiment was to investigate the possible toxic effects of Nepafenac, a nonsteroidal anti-inflammatory molecule, after its intravitreal application in various concentrations. METHODS: Forty pigmented rabbits were randomly divided into 4 groups, each including 10 rabbits. The active ingredient Nepafenac was prepared to be applied in different doses, for intravitreal use. Under topical anesthesia, following pupil dilatation, 0.3, 0.5, 0.75, and 1.5 mg doses of Nepafenac was applied intravitreally into the right eye. In each rabbit, the right eye was considered to be the study group. Saline was injected intravitreally into the left eye of each rabbit, and these eyes were considered to be the control group. Immediately after the injection and at the 1st, 4th, and 8th weeks, fundus examination by indirect ophthalmoscopy and intraocular pressure measurement were conducted. Furthermore, electroretinographic (ERG) recordings were taken at the 4th and 8th weeks. At the end of the 8th week, eyes of the surviving 26 rabbits were enucleated, and then animals were sacrificed. Following necessary fixation procedures, histopathological investigations were conducted by using a light and electron microscope. In the histological cross sections, differences between the eyes with injection and the control group were evaluated, and total retinal thickness, inner nuclear layer thickness, and outer nuclear layer thickness were measured. RESULTS: No pathology was found by clinical examination of either group. In the photopic and scotopic full-field ERG, conducted before the injection and in the 4th and 8th weeks after the injection, no statistically significant difference was determined between the study group and the control group. In the histological evaluation of the preparations, there were no statistically significant differences in the retina thickness of control and study groups. In the electron microscopic examinations, there were no toxicity findings in the eyes with injection. CONCLUSIONS: Our data show that intravitreal application of 0.3, 0.5, 0.75, and 1.5 mg doses of Nepafenac active substance is nontoxic to the rabbit retina. PMID- 25285464 TI - Communication technology use and mHealth acceptance among HIV-infected men who have sex with men in Peru: implications for HIV prevention and treatment. AB - The HIV epidemic in Peru is concentrated among men who have sex with men (MSM). Given that MSM have been documented as early adopters of emerging technology, we examined communication technology access and utilization, and mobile health (mHealth) acceptance among Peruvian MSM and transgender women (TGW) in order to gauge opportunities for mHealth-enabled HIV interventions. A convenience sample of 359 HIV-infected MSM and TGW recruited from three sites in Lima, Peru completed standardized assessments of alcohol use disorders (AUDs), risky sexual behavior, and antiretroviral therapy (ART) adherence along with self-constructed measures of communication technology access and utilization, and mHealth acceptance. Most participants (86%) had daily access to any cell phone, including smartphones (30%). The most frequent communication activities were receiving and making calls, and receiving and sending text messages using cell phones. On a 5 point Likert scale, participants expressed interest in using mHealth for medication reminders (M = 3.21, SD = 1.32) and engaging in anonymous online interactions with health professionals to discuss HIV-related issues (M = 3.56, SD = 1.33). Importantly, no significant differences were found in communication technology use and mHealth acceptance among participants with AUDs, depression, and suboptimal ART adherence, all of which are associated with poor HIV treatment outcomes. Findings show support for implementing mHealth-based intervention strategies using cell phones to assess and reduce HIV-risk behaviors among HIV infected MSM and TGW. PMID- 25285466 TI - DNA extraction methods for panbacterial and panfungal PCR detection in intraocular fluids. AB - PURPOSE: Three different methods of DNA extraction from intraocular fluids were compared with subsequent detection for bacterial and fungal DNA by universal PCR amplification. MATERIAL AND METHODS: Three DNA extraction methods, from aqueous and vitreous humors, were evaluated to compare their relative efficiency. Bacterial (Gram positive and negative) and fungal strains were used in this study: Escherichia coli, Staphylococcus epidermidis and Candida albicans. The quality, quantification, and detection limit for DNA extraction and PCR amplification were analyzed. Validation procedures for 13 aqueous humor and 14 vitreous samples, from 20 patients with clinically suspected endophthalmitis were carried out. RESULTS: The column-based extraction method was the most time effective, achieving DNA detection limits >=10(2) and 10(3 )CFU/100 uL for bacteria and fungi, respectively. PCR amplification detected 100 fg, 1 pg and 10 pg of genomic DNA of E. coli, S. epidermidis and C. albicans respectively. PCR detected 90.0% of the causative agents from 27 intraocular samples collected from 20 patients with clinically suspected endophthalmitis, while standard microbiological techniques could detect only 60.0%. The most frequently found organisms were Streptococcus spp. in 38.9% (n = 7) of patients and Staphylococcus spp. found in 22.2% (n = 4). CONCLUSIONS: The column-based extraction method for very small inocula in small volume samples (50-100 uL) of aqueous and/or vitreous humors allowed PCR amplification in all samples with sufficient quality for subsequent sequencing and identification of the microorganism in the majority of them. PMID- 25285467 TI - Comparison of body composition techniques before and after a 161-km ultramarathon using DXA, BIS and BIA. AB - The low cost, ease of application and portability of bioelectrical impedance analysis (BIA) and spectroscopy (BIS) devices make them attractive tools for measuring acute changes in body composition before and after exercise, despite potential limitations from active compartmental fluid shifts. The primary study aim was to evaluate use of dual energy x-ray absorptiometry (DXA) against BIA and BIS in measurements of percent body fat (%BF) and percent total body water (%TBW) before and after prolonged endurance exercise. 10 runners were measured pre-race and at race finish. Significant linear relationships were noted pre-race between DXA vs. BIS for %BF (r(2)=0.76; p<0.01) and %TBW (r(2)=0.74; p<0.01). Significant correlations were noted at race finish between DXA vs. BIS for %BF (r(2)=0.64; p<0.01) and %TBW (r(2)=0.66; p<0.05), but only when one outlier was removed. Limits of agreement (LOA) between DXA vs. BIS were wide for both %BF (mean difference of -3.6, LOA between 5.4 and -12.6) and %TBW (mean difference 2.4, LOA between 0.4 and -4.6). LOA was closer between the DXA vs. BIA with DXA measuring slightly higher than BIA for %BF (mean difference of 0.5, LOA between 2.1 and 3.1) and slightly lower than BIA for %TBW (mean difference 0.3, LOA between 3.3 and -2.7). Linear correlations between DXA vs. BIA were not statistically significant for %BF or %TBW before or after the race. DXA measurement of acute changes in %BF and %TBW are not congruent with BIA or BIS measurements. These 3 techniques should not be utilized interchangeably after prolonged endurance running. PMID- 25285468 TI - Caffeinated nitric oxide-releasing lozenge improves cycling time trial performance. AB - Boosting nitric oxide production during exercise by various means has been found to improve exercise performance. We investigated the effects of a nitric oxide releasing lozenge with added caffeine (70 mg) on oxygen consumption during steady state exercise and cycling time trial performance using a double-blinded randomized, crossover experimental design. 15 moderately trained cyclists (7 females and 8 males) were randomly assigned to ingest the caffeinated nitric oxide lozenge or placebo 5 min before exercise. Oxygen consumption and blood lactate were assessed at rest and at 50%, 65% and 75% maximal oxygen consumption. Exercise performance was assessed by time to complete a simulated 20.15 km cycling time-trial course. No significant treatment effects for oxygen consumption or blood lactate at rest or during steady-state exercise were observed. However, time-trial performance was improved by 2.1% (p<0.01) when participants consumed the nitric oxide lozenge (2,424+/-69 s) compared to placebo (2,476+/-78 s) and without a significant difference in rating of perceived exertion. These results suggest that acute supplementation with a caffeinated nitric oxide releasing lozenge may be a practical and effective means of improving aerobic exercise performance. PMID- 25285469 TI - The effects of evening bright light exposure on subsequent morning exercise performance. AB - We investigated the effects of evening bright light on the circadian timing of core temperature and morning exercise performance under conditions of high thermal stress. At 20:00 h, 8 males were exposed to a standardised light protocol and thereafter to either polychromatic bright light (2,500 lux at 50 cm, BL) or no light (0 lux, NL) for 30 min. The following morning, intermittent cycling exercise was undertaken followed by a 10 km time-trial in an environmental chamber set to 35 degrees C and 60% relative humidity. Core body temperature was measured throughout. Data were analysed using a within-subjects model and presented as mean+/-SD. Time of the sleep-trough in core temperature occurred ~1.75 h later following BL (P=0.07). Prior to time-trial, core temperature was 0.27+/-0.42 degrees C lower in BL (95%CI: -0.02 to 0.57, P=0.07). The time-trial was completed 1.43+/-0.63 min (0.98-1.87) faster in BL (P=0.001). Post time trial, intestinal temperature was 38.21+/-0.56 degrees C (37.84-38.57) in BL compared to 38.64+/-0.42 degrees C (38.34-38.93) in NL (P=0.10). These data provide the first evidence that a 30-min exposure to bright light prior to sleep can influence exercise performance under hot conditions during the subsequent early morning. PMID- 25285470 TI - Muscular adaptations to short-term low-frequency downhill walking training. AB - This study examined muscular adaptations of knee extensors following short-term low-frequency downhill walking training. 22 young males (training group: TG, n=12; control group: CG, n=10) participated. TG conducted 40-min downhill treadmill walking (load: 10% of body mass, gradient: 28%, velocity: 5 km/h) 1 session/week for 4 weeks. Before and after the intervention, muscle thickness of knee extensors and maximal knee extension torques in eccentric (- 120, - 60, - 30 degrees /s), isometric (0 degrees /s), and concentric (30, 60, 120, 240 degrees /s) conditions were measured. For TG, muscle damage markers were also measured before and up to 72 h following each session. After the intervention, CG did not show any changes in all variables. TG had significant increases in maximal knee extension torques at all angular velocities, with higher relative gains in eccentric torques (+ 24% on average) than isometric (+ 13%) and concentric (+ 12% on average) torques. No changes were found in the muscle thickness. Although considerable muscle damage was observed after the first training session in TG, the magnitudes of changes in all markers following the second to fourth sessions were minimal. These results indicate that even with relatively short-term and low frequency, downhill walking training can increase the strength capacity of knee extensors, especially in eccentric strength. PMID- 25285471 TI - Neuromuscular fatigue following isometric contractions with similar torque time integral. AB - Torque time integral (TTI) is the combination of intensity and duration of a contraction. The aim of this study was to compare neuromuscular alterations following different isometric sub-maximal contractions of the knee extensor muscles but with similar TTI. Sixteen participants performed 3 sustained contractions at different intensities (25%, 50%, and 75% of Maximal Voluntary Contraction (MVC) torque) with different durations (68.5+/-33.4 s, 35.1+/-16.8 s and 24.8+/-12.9 s, respectively) but similar TTI value. MVC torque, maximal voluntary activation level (VAL), M-wave characteristics and potentiated doublet amplitude were assessed before and immediately after the sustained contractions. EMG activity of the vastus lateralis (VL) and -rectus femoris (RF) muscles was recorded during the sustained contractions. MVC torque reduction was similar in the 3 conditions after the exercise (-23.4+/-2.7%). VAL decreased significantly in a similar extent (-3.1+/-1.3%) after the 3 sustained contractions. Potentiated doublet amplitude was similarly reduced in the 3 conditions (-19.7+/-1.5%), but VL and RF M-wave amplitudes remained unchanged. EMG activity of VL and RF muscles increased in the same extent during the 3 contractions (VL: 54.5+/-40.4%; RF: 53.1+/-48.7%). These results suggest that central and peripheral alterations accounting for muscle fatigue are similar following isometric contractions with similar TTI. TTI should be considered in the exploration of muscle fatigue during sustained isometric contractions. PMID- 25285472 TI - Interactions between space-based and feature-based attention. AB - Although early research suggested that attention to nonspatial features (i.e., red) was confined to stimuli appearing at an attended spatial location, more recent research has emphasized the global nature of feature-based attention. For example, a distractor sharing a target feature may capture attention even if it occurs at a task-irrelevant location. Such findings have been used to argue that feature-based attention operates independently of spatial attention. However, feature-based attention may nonetheless interact with spatial attention, yielding larger feature-based effects at attended locations than at unattended locations. The present study tested this possibility. In 2 experiments, participants viewed a rapid serial visual presentation (RSVP) stream and identified a target letter defined by its color. Target-colored distractors were presented at various task irrelevant locations during the RSVP stream. We found that feature-driven attentional capture effects were largest when the target-colored distractor was closer to the attended location. These results demonstrate that spatial attention modulates the strength of feature-based attention capture, calling into question the prior evidence that feature-based attention operates in a global manner that is independent of spatial attention. PMID- 25285473 TI - Functional reconstitution of cellulose synthase in Escherichia coli. AB - Cellulose is a high molecular weight polysaccharide of beta1 -> 4-d-glucan widely distributed in nature-from plant cell walls to extracellular polysaccharide in bacteria. Cellulose synthase, together with other auxiliary subunit(s) in the cell membrane, facilitates the fibrillar assembly of cellulose polymer chains into a microfibril. The gene encoding the catalytic subunit of cellulose synthase is cesA and has been identified in many cellulose-producing organisms. Very few studies, however, have shown that recombinant CesA protein synthesizes cellulose polymer, but the mechanism by which CesA protein synthesizes cellulose microfibrils is not known. Here we show that cellulose-synthesizing activity is successfully reconstituted in Escherichia coli by expressing the bacterial cellulose synthase complex of Gluconacetobacter xylinus: CesA and CesB (formerly BcsA and BcsB, respectively). Cellulose synthase activity was, however, only detected when CesA and CesB were coexpressed with diguanyl cyclase (DGC), which synthesizes cyclic-di-GMP (c-di-GMP), which in turn activates cellulose synthesizing activity in bacteria. Direct observation by electron microscopy revealed extremely thin fibrillar structures outside E. coli cells, which were removed by cellulase treatment. This fiber structure is not likely to be the native crystallographic form of cellulose I, given that it was converted to cellulose II by a chemical treatment milder than ever described. We thus putatively conclude that this fine fiber is an unprecedented structure of cellulose. Despite the inability of the recombinant enzyme to synthesize the native structure of cellulose, the system described in this study, named "CESEC (CEllulose-Synthesizing E. Coli)", represents a useful tool for functional analyses of cellulose synthase and for seeding new nanomaterials. PMID- 25285474 TI - Responses of the spleen to intraamniotic lipopolysaccharide exposure in fetal sheep. AB - BACKGROUND: Intrauterine inflammation activates the fetal immune system and can result in organ injury and postnatal complications in preterm infants. As the spleen is an important site for peripheral immune activation, we asked how the fetal spleen would respond to intrauterine inflammation over time. We hypothesized that intraamniotic lipopolysaccharide (IA LPS) exposure induces acute and persistent changes in the splenic cytokine profile and T-cell composition that may contribute to the sustained fetal inflammatory response after chorioamnionitis. METHODS: Fetal sheep were exposed to IA LPS 5, 12, and 24 h and 2, 4, 8, or 15 d before delivery at 125 d of gestational age (term = 150 d). Splenic cytokine mRNA levels and cleaved caspase-3, CD3, and Foxp3 expression were evaluated. RESULTS: IA LPS increased interleukin (IL)1, IL4, IL5, and IL10 mRNA by twofold 24 h after injection. Interferon gamma increased by fivefold, whereas IL23 decreased 15 d post-LPS exposure. Cleaved caspase-3-positive cells increased 2 and 8 d after LPS exposure. CD3 immunoreactivity increased within 5 h with increased Foxp3-positive cells at 12 h. CONCLUSION: Intrauterine inflammation induced a rapid and sustained splenic immune response with persistent changes in the cytokine profile. This altered immune status may drive sustained inflammation and injury in other fetal organs. PMID- 25285475 TI - Interleukin-31 promotes helper T cell type-2 inflammation in children with allergic rhinitis. AB - BACKGROUND: Interleukin-31 (IL-31) is a recently described cytokine that is involved in helper T cell type-2 (Th2)-mediated diseases. However, its regulatory effect in the pathogenesis of children allergic rhinitis (AR) needs to be further characterized. This study sought to evaluate the expression and role of IL-31 in children with AR. METHODS: Sixty children with AR and 20 normal controls were included. IL-31 and Th2 cytokines production in tissue, serum, and nasal lavage was examined by immunohistochemistry, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay, respectively. Peripheral blood mononuclear cells (PBMCs) were purified for in vitro regulation experiment of IL 31. Nasal epithelial cells (NECs) were cultured and stimulated by recombinant IL 31. RESULTS: The IL-31 mRNA and protein levels in both serum and nasal lavage were significantly enhanced in AR compared with normal controls, especially in children with asthma. The nasal IL-31 was associated with enhanced local Th2 cytokines and mucin 5AC (MUC5AC) expression. In vitro study showed that IL-31 promotes Th2 cytokines expression and MUC5AC upregulation and thus amplified Th2 inflammation. CONCLUSION: Our results demonstrate that IL-31 expression in AR aggravated and amplified Th2 inflammation as well as mucin production, and provide a possible explanation for IL-31's regulatory role in the pathogenesis of AR. PMID- 25285476 TI - Formation of self-assembled defect-free Zn2SnO4 nanostructures from binary oxides without the Kirkendall effect. AB - In this Communication, we report a facile approach to synthesize a technologically important oxide Zn2SnO4 (ZTO) by a temperature-dependent solid state reaction without the Kirkendall effect. Single-phase defect-free ZTO was formed upon calcination of a homogeneous 2:1 mixture of reactive ZnO rods and SnO2 nanoparticles at 1000 degrees C. We also observed interesting photocatalytic and photovoltaic properties from the synthesized ZTO material. PMID- 25285477 TI - Multiblock copolymer solutions in contact with a surface: self-assembly, adsorption, and percolation. AB - Amphiphilic copolymers are often used as compatibilizing or stabilizing agents, either in solution or at surfaces. In the special case of multiblock copolymers the connectivity of the blocks combines with the antagonistic behavior of the different types of blocks. Here we report on the behavior of solutions of amphiphilic multiblock copolymers with a large number of blocks and a low fraction of solvophobic monomers in contact with an attractive surface. Using lattice Monte Carlo simulations, the influence on the structures of the solvent quality and the type of surface from noninteracting to strongly attractive to the solvophobic monomers can be assessed. In the presence of a surface bulk micelles are formed that are not different in size and shape from the micelles observed in the absence of a surface. When increasing the surface attraction, solvophobic monomers tend to adsorb either as isolated blocks or forming surface micelles. Evidence is given of a surface concentration threshold above which surface micelles can form due to microphase separation. These surface micelles are in equilibrium with bulk micelles, some of which are connected to the surface through a path of either hydrophobic and/or hydrophilic blocks or hydrophobic cross-links, or both. The size distributions of bulk and connected micelles are similar. With increasing surface concentration surface micelles get organized due to the steric repulsion between core-shell surface micelles. Moreover, these organized surface micelles percolate. The connected micelles form a concentrated layer parallel to the attractive surface. In addition, these systems are governed by two very different time scales: The fast one leads to micellar self-assembly in the bulk and at the surface while the slow one prevents the system from reaching equilibrium in the course of the simulations and corresponds to the transfer of copolymers from the bulk to the attractive surface. PMID- 25285478 TI - Almost fooled again: new insights into cesium dodecyl sulfate micelle structures. AB - Replacing sodium with cesium as the counterion for dodecyl sulfate in aqueous solution results in stronger complexation and charge shielding, which should lead to larger micelles and ultimately to a cylindrical structure (cf. spheres for sodium dodecyl sulfate), but small angle X-ray scattering (SAXS) and small angle neutron scattering patterns previously have been interpreted with ellipsoidal micelle models. We directly image CsDS micelles via cryo-transmission electron microscopy and report large core-shell spherical micelles at low concentrations (<=2 wt %) and cylindrical micelles at higher concentrations (5.0 and 8.1 wt %). These structures are shown to be consistent with SAXS patterns modeled using established form factors. These findings highlight the importance of combining real and reciprocal space imaging techniques in the characterization of self assembled soft materials. PMID- 25285479 TI - Which three-dimensional characteristics make efficient inhibitors of protein protein interactions? AB - The specific properties of protein-protein interactions (PPI) (flat, large and hydrophobic) make them harder to tackle with low-molecular-weight compounds. Learning from the properties of successful examples of PPI interface inhibitors (iPPI) at earlier stages of developments, has been pinpointed as a powerful strategy to circumvent this trend. To this end, we have computationally analyzed the bioactive conformations of iPPI and those of inhibitors of conventional targets (e.g enzymes) to highlight putative iPPI 3D characteristics. Most noticeably, the essential property revealed by this study illustrates how efficiently iPPI manages to bind to the hydrophobic patch often present at the core of protein interfaces. The newly identified properties were further confirmed as characteristics of iPPI using much larger data sets (e.g iPPI-DB, www.ippidb.cdithem.fr ). Interestingly, the absence of correlation of such properties with the hydrophobicity and the size of the compounds opens new ways to design potent iPPI with better pharmacokinetic features. PMID- 25285481 TI - Effect of acid adaptation and acid shock on thermal tolerance and survival of Escherichia coli O157:H7 and O111 in apple juice. AB - Gradual exposure to moderate acidic environments may enhance the thermal tolerance and survival of Escherichia coli O157:H7 in acid and acidified foods. Limited studies comparing methodologies to induce this phenomenon have been performed. The effects of strain and physiological state on thermal tolerance and survival of E. coli in apple juice were studied. The decimal reduction time (D value) at 56 degrees C [D56 degrees C] was determined for E. coli O157:H7 strains C7927 and ATCC 43895 and E. coli O111 at four physiological states: unadapted, acid-shocked (two methodologies used), and acid-adapted cells. The effect of acidulant was also evaluated by determining the D56 degrees C for the O157:H7 strains subjected to acid shock during 18 h in Trypticase soy broth (TSB), with pH 5 adjusted with hydrochloric, lactic, and malic acids. Survival of the three strains at four physiological states was determined at 1 +/- 1 degrees C and 24 +/- 2 degrees C. Experiments were performed in triplicate. For thermal inactivation, a significant interaction was found between strain and physiological state (P < 0.0001). Highest thermal tolerance was observed for the 43895 strain subjected to acid shock during 18 h in TSB acidified with HCl (D56 degrees C of 3.0 +/- 0.1 min) and the lowest for the acid-shocked C7927 strain treated for 4 h in TSB acidified with HCl (D56 degrees C of 0.45 +/- 0.06 min). Acidulants did not alter the heat tolerance of strain C7927 (D56 degrees C of 1.9 +/- 0.1 min; P > 0.05) but significantly affected strain 43895 (P < 0.05), showing the greatest tolerance when malic acid was used (D56 degrees C of 3.7 +/- 0.3 min). A significant interaction between strain, storage temperature, and physiological state was noted during the survival experiments (P < 0.05). E. coli O111 was the most resistant strain, surviving 6 and 23 days at 24 and 1 degrees C, respectively. Our findings may assist in designing challenge studies for juices and other pH-controlled products, where Shiga toxin-producing E. coli represents the pathogen of concern. PMID- 25285480 TI - Amplifying dynamic nuclear polarization of frozen solutions by incorporating dielectric particles. AB - There is currently great interest in understanding the limits on NMR signal enhancements provided by dynamic nuclear polarization (DNP), and in particular if the theoretical maximum enhancements can be achieved. We show that over a 2-fold improvement in cross-effect DNP enhancements can be achieved in MAS experiments on frozen solutions by simply incorporating solid particles into the sample. At 9.4 T and ~105 K, enhancements up to epsilonH = 515 are obtained in this way, corresponding to 78% of the theoretical maximum. We also underline that degassing of the sample is important to achieve highest enhancements. We link the amplification effect to the dielectric properties of the solid material, which probably gives rise to scattering, diffraction, and amplification of the microwave field in the sample. This is substantiated by simulations of microwave propagation. A reduction in sample heating at a given microwave power also likely occurs due to reduced dielectric loss. Simulations indicate that the microwave field (and thus the DNP enhancement) is inhomogeneous in the sample, and we deduce that in these experiments between 5 and 10% of the solution actually yields the theoretical maximum signal enhancement of 658. The effect is demonstrated for a variety of particles added to both aqueous and organic biradical solutions. PMID- 25285482 TI - Effect of high hydrostatic pressure on Salmonella inoculated into creamy peanut butter with modified composition. AB - Peanut butter has been associated with several large foodborne salmonellosis outbreaks. This research investigates the potential of high hydrostatic pressure processing (HPP) for inactivation of Salmonella in peanut butter of modified composition, both by modifying its water activity as well by the addition of various amounts of nisin. A cocktail of six Salmonella strains associated with peanut butter and nut-related outbreaks was used for all experiments. Different volumes of sterile distilled water were added to peanut butter to increase water activity, and different volumes of peanut oil were added to decrease water activity. Inactivation in 12% fat, light roast, partially defatted peanut flour, and peanut oil was also quantified. Nisaplin was incorporated into peanut butter at four concentrations corresponding to 2.5, 5.0, 12.5, and 25.0 ppm of pure nisin. All samples were subjected to 600 MPa for 18 min. A steady and statistically significant increase in log reduction was seen as added moisture was increased from 50 to 90%. The color of all peanut butter samples containing added moisture contents darkened after high pressure processing. The addition of peanut oil to further lower the water activity of peanut butter further reduced the effectiveness of HPP. Just over a 1-log reduction was obtained in peanut flour, while inactivation to below detection limits (2 log CFU/g) was observed in peanut oil. Nisin alone without HPP had no effect. Recovery of Salmonella after a combined nisin and HPP treatment did show increased log reduction with longer storage times. The maximum log reduction of Salmonella achieved was 1.7 log CFU/g, which was comparable to that achieved by noncycling pressure treatment alone. High pressure processing alone or with other formulation modification, including added nisin, is not a suitable technology to manage the microbiological safety of Salmonella-contaminated peanut butter. PMID- 25285483 TI - Impact of organic load on Escherichia coli O157:H7 survival during pilot-scale processing of iceberg lettuce with acidified sodium hypochlorite. AB - Chemical sanitizers are routinely used during commercial flume washing of fresh cut leafy greens to minimize cross-contamination from the water. This study assessed the efficacy of three chlorine treatments against Escherichia coli O157:H7 on iceberg lettuce, in wash water, and on surfaces of a pilot-scale processing line using flume water containing various organic loads. Iceberg lettuce (5.4 kg) was inoculated to contain 10(6) CFU/g of a 4-strain cocktail of nontoxigenic, green fluorescent protein-labeled, ampicillin-resistant E. coli O157:H7 and held for 24 h at 4 degrees C before processing. Lettuce was shredded using a Urschel TransSlicer, step conveyed to a flume tank, washed for 90 s using water alone or one of three different sanitizing treatments (50 ppm of total chlorine either alone or acidified to pH 6.5 with citric acid or T-128) in water containing organic loads of 0, 2.5, 5, or 10% (wt/vol) blended iceberg lettuce, and then dried using a shaker table and centrifugal dryer. Next, three 5.4-kg batches of uninoculated iceberg lettuce were processed identically. Various product (25 g), water (50 ml), and equipment surface swab (100 cm(2)) samples were homogenized in neutralizing buffer, diluted appropriately, and plated on tryptic soy agar containing 0.6% (wt/vol) yeast extract and 100 ppm of ampicillin without prior 0.45- m m membrane filtration to quantify E. coli O157:H7. Organic load negatively impacted the efficacy of all three chlorine treatments (P < 0.05) at the end of processing, with typical E. coli O157:H7 reductions of >5 and 0.9 to 3.7 log CFU/ml for organic loads of 0 and 10%, respectively. Organic load rarely had a significant impact (P < 0.05) on the efficacy of chlorine, chlorine plus citric acid, or chlorine plus T-128 against E. coli O157:H7 on iceberg lettuce. Reduced sanitizer efficacy generally corresponded to changes in total solids, chemical oxygen demand, turbidity, and maximum filterable volume, indicating that these tests may be effective alternatives to the industry standard of oxygen/reduction potential. PMID- 25285484 TI - Method-dependent variability in determination of prevalence of Campylobacter jejuni and Campylobacter coli in Canadian retail poultry. AB - Campylobacter is the most frequent cause of bacterial gastroenteritis in Canada, and the illness is commonly associated with poultry consumption. Whereas Canadian retail poultry is often contaminated with campylobacters, studies on the prevalence of this organism are inconsistent due to variability in sampling and microbiological methodology. To determine the current microbiological status of Canadian poultry, and to evaluate two commonly used microbiological methods, 348 raw poultry samples were collected at retail across Canada over a period of 3 years (2007 to 2010) and were analyzed for the presence of thermophilic Campylobacter species. The overall prevalence of Campylobacter spp. was found to be 42.8% by a combination of the two testing methods, with 33.9% of the samples positive for C. jejuni, 3.7% of the samples positive for C. coli, and 5.2% of the samples positive for both. Variability in Campylobacter spp. prevalence was observed in samples obtained from different regions across Canada and from poultry with or without skin, but this was not statistically significant. In co contaminated samples, C. jejuni was preferentially recovered from Preston agar compared with mCCDA and Campy-Cefex agar, with an increase in recovery of C. coli on all selective media after 48 h of enrichment. A subset of 214 of the poultry rinses were analyzed by both Health Canada's standard method, MFLP-46 (enrichment in Park and Sanders broth), and a second method requiring enrichment in Bolton broth. Significantly more positive samples were obtained with the MFLP-46 method (40.6%) than with the alternate method (35.0%). This improved recovery with MFLP 46 may be due to the omission of cycloheximide from this method. These results demonstrate that determination of prevalence of Campylobacter spp. on poultry products may be significantly impacted by the choice of microbiological methods used. Canadian poultry continues to be a source of exposure to Campylobacter spp. PMID- 25285485 TI - Inactivation and sublethal injury kinetics of Staphylococcus aureus in broth at low temperature storage. AB - Low temperatures are widely used to ensure food quality and safety. However, sublethally injured Staphylococcus aureus is an important microbiological safety concern in low temperature food. The objective of this study was to develop predictive inactivation kinetic models for the inactivation and sublethal injury of S. aureus in broth at different temperatures (4 to -18 degrees C) and time points. S. aureus was diluted in tryptic soy broth plus 0.6% (wt/vol) yeast extract (TSBYE) to obtain approximately 10(8) CFU/ml and was stored separately at 4, -3, -11, and -18 degrees C. After specific time points within 96 days, survival of S. aureus was determined on TSBYE and TSBYE agar plus 10% NaCl for enumeration of the total viable and noninjured cell numbers, respectively. Linear, Weibull, and modified Gompertz models were applied to determine survival curve regression. The combination of low temperature and time resulted in S. aureus inactivation, although the cells were able to survive in this sublethal state. Storage temperature was the critical parameter in survival of S. aureus. The modified Weibull model successfully described a second model of noninjured S. aureus cell survival at different low temperatures, whereas only the linear model was able to fit the total viable cells. The predictive model may be used to estimate the level of S. aureus contamination in food at low storage temperatures and times, and it provides new insight into the sublethally injured survival state of S. aureus in low temperature food. PMID- 25285486 TI - Modeling the effects of temperature, sodium chloride, and green tea and their interactions on the thermal inactivation of Listeria monocytogenes in turkey. AB - The interactive effects of heating temperature (55 to 65 degrees C), sodium chloride (NaCl; 0 to 2%), and green tea 60% polyphenol extract (GTPE; 0 to 3%) on the heat resistance of a five-strain mixture of Listeria monocytogenes in ground turkey were determined. Thermal death times were quantified in bags that were submerged in a circulating water bath set at 55, 57, 60, 63, and 65 degrees C. The recovery medium was tryptic soy agar supplemented with 0.6% yeast extract and 1% sodium pyruvate. D-values were analyzed by second-order response surface regression for temperature, NaCl, and GTPE. The data indicated that all three factors interacted to affect the inactivation of the pathogen. The D-values for turkey with no NaCl or GTPE at 55, 57, 60, 63, and 65 degrees C were 36.3, 20.8, 13.2, 4.1, and 2.9 min, respectively. Although NaCl exhibited a concentration dependent protective effect against heat lethality on L. monocytogenes in turkey, addition of GTPE rendered the pathogen more sensitive to the lethal effect of heat. GTPE levels up to 1.5% interacted with NaCl and reduced the protective effect of NaCl on heat resistance of the pathogen. Food processors can use the predictive model to design an appropriate heat treatment that would inactivate L. monocytogenes in cooked turkey products without adversely affecting the quality of the product. PMID- 25285487 TI - Behavior of Staphylococcus aureus in culture broth, in raw and thermized milk, and during processing and storage of traditional Greek Graviera cheese in the presence or absence of Lactococcus lactis subsp. cremoris M104, a wild, novel nisin A-producing raw milk isolate. AB - This study was conducted to evaluate the behavior of Staphylococcus aureus during processing, ripening, and storage of traditional Greek Graviera cheese in accordance with European Union Regulation 1441/2007 for coagulase-positive staphylococci in thermized milk cheeses. Lactococcus lactis subsp. cremoris M104, a wild, novel nisin A-producing (NisA+) strain, also was evaluated as an antistaphylococcal adjunct. A three-strain cocktail of enterotoxigenic (Ent+) S. aureus increased by approximately 2 log CFU/ml when co-inoculated (at approximately 3 log CFU/ml) in thermized Graviera cheese milk (TGCM; 63 degrees C for 30 s) with commercial starter culture (CSC) and/or strain M104 at approximately 6 log CFU/ml and then incubated at 37 degrees C for 3 h. However, after 6 h at 37 degrees C, significant retarding effects on S. aureus growth were noted in the order TGCM + M104 > TGCM + CSC = TGCM + CSC + M104 > TGCM. Additional incubation of TGCM cultures at 18 degrees C for 66 h resulted in a 1.2 log reduction (P < 0.05) of S. aureus populations in TGCM + M104. The Ent + S. aureus cocktail did not grow but survived during ripening and storage when inoculated (at approximately 3 log CFU/g) postcooking into Graviera mini cheeses prepared from TGCM + CSC or TGCM + CSC + M104, ripened at 18 degrees C and 90% relative humidity for 20 days, and stored at 4 degrees C in vacuum packages for 2 months. A rapid 10-fold decrease (P < 0.05) in S. aureus populations occurred within the first 24 h of cheese fermentation. Reductions of S. aureus were greater by approximately 0.4 log CFU/g in CSC + M104 than in CSC only cheeses, concomitantly with the presence of NisA + M104 colonies and nisin-encoding genes in the CSC plus M104 cheeses and their corresponding microbial consortia only. A high level of selective survival of a naturally nisin-resistant EntC z S. aureus strain from the cocktail was noted in CSC + M104 cheeses and in coculture with the NisA + M104 strain in M-17 broth. In conclusion, although S. aureus growth inhibition is assured during Graviera cheese ripening, early growth of the pathogen during milk curdling and curd cooking operations may occur. Nisin resistant S. aureus strains that may contaminate Graviera cheese milks postthermally may be difficult to control even by the application of the NisA + L. lactis subsp. cremoris strain M104 as a bioprotective adjunct culture. PMID- 25285488 TI - Hypervariable pili and flagella genes provide suitable new targets for DNA high resolution melt-based genotyping of dairy Geobacillus spp. AB - Although nonpathogenic in nature, spores of Geobacillus are able to attach to surfaces, germinate, and form biofilms, allowing rapid multiplication and persistence within milk powder processing plants, causing final product contamination, and eventually leading to a loss of revenue in terms of downgraded product quality. As a result, Geobacillus spp. have been found to be common contaminants of milk powder worldwide. Genotyping methods can help in gaining insight into the ecology and transmission of these thermophilic bacteria within and between dairy processing plants. The objective of this study was to use the assembled draft genomes of two Geobacillus spp. to identify and test new hypervariable genotyping targets for differentiating closely related dairy Geobacillus isolates. The two Geobacillus spp. strains obtained from high spore count powders were obtained in 2010 (isolate 7E) and in 1995 (isolate 126) and were previously shown to be of same genotype based on a variable number tandem repeat genotyping method. Significant nucleotide sequence variation was found in genes encoding pili and flagella, which were further investigated as suitable loci for a new high-resolution melt analysis (HRMA)-based genotyping method. Three genes encoding pulG (containing prepilin-type N-terminal cleavage domain), pilT (pili retraction protein), and fliW (flagellar assembly protein) were selected as targets for the new pili/flagella gene (PilFla) HRMA genotyping method. The three-gene-based PilFla-HRMA genotyping method differentiated 35 milk powder Geobacillus spp. isolates into 19 different genotype groups (D = 0.93), which compared favorably to the previous method (which used four variable number tandem repeat loci) that generated 16 different genotype groups (D = 0.90). In conclusion, through comparative genomics of two closely related dairy Geobacillus strains, we have identified new hypervariable regions that prove to be useful targets for highly discriminatory genotyping. PMID- 25285489 TI - Decontamination of hard cheeses by pulsed UV light. AB - Cheese is a ready-to-eat food that may be contaminated on the surface by undesirable spoilage and pathogenic microorganisms during production, packaging, and postpackaging processes. Penicillium roqueforti is commonly found on cheese surfaces at refrigeration temperatures and is one of the most common spoilage fungal species. Consumption of cheese contaminated with Listeria monocytogenes can result in foodborne listeriosis. Therefore, cheese should be decontaminated at postprocessing stages. Pulsed UV light is a nonthermal method for food preservation that involves the use of intense short pulses to ensure microbial decontamination on the surface of foods or packaging materials. In this study, the efficacy of pulsed UV light for inactivation of P. roqueforti and L. monocytogenes inoculated onto packaged and unpackaged hard cheeses was investigated. Treatment times and the distance from the UV strobe were evaluated to determine optimum treatment conditions. Packaged and unpackaged cheeses were treated at distances of 5, 8, and 13 cm for up to 60 s. For P. roqueforti, maximum reduction after 40 s at 5 cm was 1.32 log CFU/cm(2) on unpackaged cheese and 1.24 log CFU/cm(2) on packaged cheese. Reductions of L. monocytogenes under the same treatment conditions were about 2.9 and 2.8 log CFU/cm(2) on packaged and unpackaged cheeses, respectively. The temperature changes and total energy increases were directly proportional to treatment time and inversely proportional to distance between the UV lamp and the samples. The changes in color and lipid oxidation were determined at mild (5 s at 13 cm), moderate (30 s at 8 cm), and extreme (40 s at 5 cm) treatments. The color and chemical quality of cheeses were not significantly different after mild treatments (P > 0.05). The mechanical properties of the plastic packaging material (polypropylene) also were evaluated after mild, moderate, and extreme treatments. A decreasing trend was noted for elastic modulus; however, no significant differences were found between untreated samples and those given mild and moderate treatments (P > 0.05). Overall, these results indicate that pulsed UV light can inactivate P. roqueforti and L. monocytogenes on the surface of hard cheeses. PMID- 25285490 TI - Antibacterial activity of hen egg white lysozyme modified by heat and enzymatic treatments against oenological lactic acid bacteria and acetic acid bacteria. AB - The antimicrobial activity of heat-denatured and hydrolyzed hen egg white lysozyme against oenological lactic acid and acetic acid bacteria was investigated. The lysozyme was denatured by heating, and native and heat denatured lysozymes were hydrolyzed by pepsin. The lytic activity against Micrococcus lysodeikticus of heat-denatured lysozyme decreased with the temperature of the heat treatment, whereas the hydrolyzed lysozyme had no enzymatic activity. Heat-denatured and hydrolyzed lysozyme preparations showed antimicrobial activity against acetic acid bacteria. Lysozyme heated at 90 degrees C exerted potent activity against Acetobacter aceti CIAL-106 and Gluconobacter oxydans CIAL-107 with concentrations required to obtain 50% inhibition of growth (IC50) of 0.089 and 0.013 mg/ml, respectively. This preparation also demonstrated activity against Lactobacillus casei CIAL-52 and Oenococcus oeni CIAL-91 (IC50, 1.37 and 0.45 mg/ml, respectively). The two hydrolysates from native and heat-denatured lysozyme were active against O. oeni CIAL-96 (IC50, 2.77 and 0.3 mg/ml, respectively). The results obtained suggest that thermal and enzymatic treatments increase the antibacterial spectrum of hen egg white lysozyme in relation to oenological microorganisms. PMID- 25285491 TI - Chemical composition, antibacterial activity, and mechanism of action of the essential oil from Amomum kravanh. AB - Amomum kravanh is widely cultivated and used as a culinary spice. In this work, the chemical composition of the essential oil obtained by hydrodistillation of A. kravanh fruits was analyzed by gas chromatography-mass spectrometry, and 34 components were identified. 1,8-Cineole (68.42%) was found to be the major component, followed by alpha-pinene (5.71%), alpha-terpinene (2.63%), and beta pinene (2.41%). The results of antibacterial tests showed that the sensitivities to the essential oil of different foodborne pathogens tested were different based on the Oxford cup method, MIC, and MBC assays, and the essential oil exhibited the best antibacterial activity against Bacillus subtilis, a gram-positive bacterium, and Escherichia coli, a gram-negative bacterium. Growth in the presence of Amomum kravanh at the MIC, as measured by monitoring optical density over time, demonstrated that the essential oil was bacteriostatic after 12 h to both B. subtilis and E. coli. Observations of cell membrane permeability, cell constituent release assay, and transmission electron microscopy indicated that this essential oil may disrupt the cell wall and cell membrane permeability, leading to leakage of intracellular constituents in both B. subtilis and E. coli. PMID- 25285492 TI - Detection and survival of Toxoplasma gondii in milk and cheese from experimentally infected goats. AB - The consumption of unpasteurized goat cheese and goat's milk has been suggested as a risk factor for toxoplasmosis in humans. In the present study, detection and survival of Toxoplasma gondii in milk and cheese was studied by bioassay in mice (milk) and in cats (cheese). Eight goats were inoculated orally with 300 to 10,000 oocysts of T. gondii strain TgGoatUS26. Milk samples were collected daily up to 30 days postinoculation and bioassayed in mice and cats. For mouse bioassay, 50 ml of milk samples were centrifuged, and the sediment was inoculated subcutaneously into mice. Mice were tested for T. gondii infection by seroconversion and by the demonstration of parasites. By mouse bioassay, T. gondii was detected in milk from all eight goats. The T. gondii excretion in milk was intermittent. For cat bioassay, 400 ml (100 ml or more from each goat) of milk from four goats from 6 to 27 days postinoculation were pooled daily, and cheese was made using rennin. Ten grams of cheese was fed daily to four cats, and cat feces were examined for oocyst shedding. One cat fed cheese shed oocysts 7 to 11 days after consuming cheese. Attempts were made to detect T. gondii DNA in milk of four goats; T. gondii was detected by PCR more consistently, but there was no correlation between detection of viable T. gondii by bioassay in mice and T. gondii DNA by PCR. Results indicate that T. gondii can be excreted in goat's milk and can survive in fresh cheese made by cold-enzyme treatment. To prevent transmission to humans or animals, milk should not be consumed raw. Raw fresh goat cheese made by cold-enzyme treatment of unpasteurized milk also should not be consumed. PMID- 25285493 TI - Cross-reactivity of antibodies with phenolic compounds in pistachios during quantification of ochratoxin A by commercial enzyme-linked immunosorbent assay kits. AB - Ochratoxin A (OTA), a nephrotoxic mycotoxin, naturally occurs in wide range of agricultural commodities. Typical screening of OTA involves various enzyme-linked immunosorbent assay (ELISA) methods. Pistachio (Pistacia vera L.) is a rich source of phenolic compounds that may result in a false positive due to structural similarities to OTA. The present study investigated the cross reactivity profiles of phenolic compounds using two commercial ELISA test kits. High-performance liquid chromatography was used to confirm the concentration of OTA in the pistachio samples and compared with the results obtained from ELISA. When the degree of interaction and 50 % inhibitory concentration of phenolic compounds were determined, the cross-reactivity showed a pattern similar to that observed with the commercial ELSIA kits, although quantitatively different. In addition, the degree of interaction increased with the increasing concentration of phenolic compounds. The ELISA value had stronger correlations with the content of total phenolic compound, gallic acid, and catechin (R(2) = 0.757, 0.732, and 0.729, respectively) compared with epicatechin (R(2) = 0.590). These results suggest that phenolic compounds in pistachio skins may cross-react with the OTA antibody and lead to a false positive or to an overestimation of OTA concentration in ELISA-based tests. PMID- 25285494 TI - Removal of aflatoxin B1 and inhibition of Aspergillus flavus growth by the use of Lactobacillus plantarum on olives. AB - Olives can be contaminated with a wide variety of molds (Aspergillus and/or Penicillium) that can be occurring naturally on fresh and processed olives and could support mycotoxin production. The aim of this work was to investigate aflatoxin B1 (AFB1) production by fungi and its bioaccumulation in olives during storage and to study the impact of the application of Lactobacillus plantarum on the inhibition of mold development and production of AFB1. Two different treatments were applied: (i) olives with natural microflora and (ii) olives inoculated with Aspergillus flavus after elimination of natural microflora. AFB1 has been extracted from olives and quantitated by high-performance liquid chromatography using a fluorescence detector. Results showed the absence of this metabolite in the olives for the season 2008 to 2009. In 2009 to 2010, AFB1 was detected at the level of 11 MUg/kg. The application of L. plantarum during the storage of olives favors the reduction of the level of AFB1 to 5.9 MUg/kg correlated with a decrease in the amount of molds (86.3%). The images obtained by environmental scanning electron microscopy showed that L. plantarum was able to adhere to the olive surface and probably produce a biofilm that inhibits the multiplication of yeast and fungi by oxygen competition. Results showed an increase of antioxidant activity and amount of total phenolic compounds of olives, respectively, by 24 and 8.6%. In many olives contaminated with A. flavus, AFB1 was present at an initial level of 5.15 MUg/kg and increased to 6.55 MUg/kg after 8 days of storage. The biological detoxification of AFB1 in olives by L. plantarum is confirmed by the reduction of the level of AFB1 to 2.12 MUg/kg on day 0 and its absence after 4 days of storage. PMID- 25285495 TI - Effect of gamma radiation on the reduction of Salmonella strains, Listeria monocytogenes, and Shiga toxin-producing Escherichia coli and sensory evaluation of minimally processed spinach (Tetragonia expansa). AB - This study evaluated the effects of irradiation on the reduction of Shiga toxin producing Escherichia coli (STEC), Salmonella strains, and Listeria monocytogenes, as well as on the sensory characteristics of minimally processed spinach. Spinach samples were inoculated with a cocktail of three strains each of STEC, Salmonella strains, and L. monocytogenes, separately, and were exposed to gamma radiation doses of 0, 0.2, 0.4, 0.6, 0.8, and 1.0 kGy. Samples that were exposed to 0.0, 1.0, and 1.5 kGy and kept under refrigeration (4 degrees C) for 12 days were submitted to sensory analysis. D10 -values ranged from 0.19 to 0.20 kGy for Salmonella and from 0.20 to 0.21 for L. monocytogenes; for STEC, the value was 0.17 kGy. Spinach showed good acceptability, even after exposure to 1.5 kGy. Because gamma radiation reduced the selected pathogens without causing significant changes in the quality of spinach leaves, it may be a useful method to improve safety in the fresh produce industry. PMID- 25285496 TI - Presence and antimicrobial susceptibility of Escherichia coli recovered from retail chicken in China. AB - The aim of this study was to determine the prevalence and antimicrobial susceptibility of Escherichia coli in retail whole chicken in the People 9 s Republic of China. Five hundred seventy-six raw whole chicken samples, randomly purchased from 146 farmers' markets or supermarkets in four provinces from March through December 2010, were analyzed for E. coli contamination, and the E. coli isolates were further tested for the presence of virulence genes and antimicrobial susceptibility. The overall positive rate for E. coli in retail chicken was 69.1%. E. coli prevalence was the highest in Beijing (86.8%), followed by Henan province (78.5%), Shaanxi province (65.3%), and the lowest prevalence was found in Sichuan province (45.8%). Among 398 isolates recovered, only the eae gene was detected in one isolate; no other virulence genes were detected. Resistance was most common to tetracycline (84.4%), followed by nalidixic acid (74.1%), ampicillin (71.1%), trimethoprim-sulfamethoxazole (70.1%), amoxicillin-clavulanic acid (68.8%), and streptomycin (58.5%). Lower resistance was detected to chloramphenicol (43.7%), kanamycin (42.7%), ciprofloxacin (30.2%), gentamicin (29.4%), cefoperazone (13.6%), amikacin (12.6%), gatifloxacin (8%), and cefoxitin (7.8%). Only 3.8% of the isolates were susceptible to all tested antimicrobials. Six percent of the isolates displayed resistance to one antimicrobial, 6.3% to two, and 83.9% to three or more of the antimicrobials. Our findings indicate that retail chicken in China was commonly contaminated with E. coli, and many E. coli strains exhibited multiple drug resistance. The implementation of good manufacturing practices throughout the poultry production chain is necessary to reduce E. coli contamination in retail chicken, and the prudent use of antibiotics is imperative in poultry production in China. PMID- 25285497 TI - A comparison of the BAX system method to the U.S. Food and Drug Administration's Bacteriological Analytical Manual and International Organization for Standardization reference methods for the detection of Salmonella in a variety of soy ingredients. AB - The performances of two DuPont BAX System PCR assays for detecting Salmonella on a variety of low-moisture soy ingredients were evaluated against the U. S. Food and Drug Administration's Bacteriological Analytical Manual (FDA BAM) method or the International Organization for Standardization (ISO) 6579 reference method. These evaluations were conducted as a single laboratory validation at an ISO 17025 accredited third-party laboratory. Validations were conducted on five soy ingredients: isolated soy protein (ISP), soy fiber, fluid soy lecithin, deoiled soy lecithin, and soy nuggets, using a paired-study design. The ISP was analyzed as both 25- and 375-g composite test portions, whereas all other sample matrices were analyzed as 375-g composite test portions. To evaluate 25-g test portions of ISP, the test material was inoculated using Salmonella enterica subsp. enterica serovar Mbandaka (Q Laboratories isolate 11031.1). Salmonella enterica subsp. enterica serovar Tennessee (Q Laboratories isolate 11031.3) was used for all other trials. For each trial of the method comparison, 25 samples were analyzed for each matrix: 5 uninoculated controls and 20 samples inoculated at low levels (0.2 to 2 CFU per test portion) that were targeted to achieve fractionally positive results (25 to 75%). Using McNemar's chi-square analysis, no significant difference at P >= 0.05 (chi(2) <= 3.84) was observed between the number of positives obtained by the BAX System and the reference methods for all five test matrices evaluated. These studies indicate that the BAX System PCR assays, in combination with the single buffered peptone water primary enrichment and subsequent brain heart infusion regrowth step, demonstrate equivalent sensitivity and robustness compared with the FDA BAM and ISO reference methods for both 25- and 375-g composite samples. Moreover, there was no observed reduction of sensitivity in the larger 375-g composite samples for all five matrices. PMID- 25285498 TI - Occurrence of Vibrio vulnificus and toxigenic Vibrio parahaemolyticus on sea catfishes from Galveston Bay, Texas. AB - Dorsal and pectoral fin spines from two species of sea catfishes (Bagre marinus and Ariopsis felis) landed at 54 sites in Galveston Bay, Texas, and its sub-bays from June to October 2005 were screened with traditional cultivation-based assays and quantitative PCR assays for Vibrio vulnificus and Vibrio parahaemolyticus. V. vulnificus was present on 51.2% of fish (n = 247), with an average of 403 +/- 337 SD cells g(-1). V. parahaemolyticus was present on 94.2% (n = 247); 12.8% tested positive for the virulence-conferring tdh gene, having an average 2,039 +/- 2,171 SD cells g(-1). The increasing trend in seafood consumption of "trash fishes" from lower trophic levels, such as sea catfishes, warrants evaluation of their life histories for association with pathogens of concern for human consumption. PMID- 25285499 TI - Inhibition of Listeria monocytogenes in deli-style turkey breast formulated with cultured celery powder and/or cultured sugar-vinegar blend during storage at 4 degrees c. AB - Fermentation-derived nitrite (NO2) from vegetable sources is increasingly used as a "clean label" alternative to conventional NaNO2. Previous results suggested that processed meats cured with NO2 derived from a "natural" source had lower antimicrobial activity than did meats produced with chemical NaNO2; however, the differences were likely due to NO2 concentration rather than source. The objective of this study was to compare the antilisterial properties of traditional and clean label alternative curing approaches when combined with antimicrobials in deli-style turkey. Listeria monocytogenes inhibition by NO2 from synthetic and natural sources was validated in deli-style turkey (73 to 74% moisture, 1.8% salt, pH 6.4). Products were prepared with 0, 80, or 120 mg/kg NO2 using purified NaNO2 or cultured celery powder. Additional treatments were supplemented with 3.8% lactate-diacetate blend (LD) or 1% cultured sugar-vinegar blend (DF). Sliced cooked products were surface inoculated with L. monocytogenes at 3 log CFU/g, vacuum packaged, and stored at 4 degrees C for 12 weeks. Results revealed an average 2.4-log increase in L. monocytogenes at 3 weeks in the control without antimicrobials, a 1.3-log increase at 4 weeks for both 80 mg/kg NO2 treatments, and a 1.5-log increase at 6 weeks for the 120 mg/kg NO2 treatments. No significant difference (P > 0.05) in growth inhibition was found between NO2 sources when equivalent concentrations were added. In uncured turkey with 3.8% LD or 1% DF, growth was delayed until 6 weeks, whereas supplementation with LD or DF and 80 mg/kg NO2 from either source delayed listerial growth through 12 weeks. This study confirmed that the concentration of NO2, rather than the source, is a primary factor in enhancing the safety of ready-to-eat meats. Both conventional NO2 treatments and a clean label solution consisting of a fermentation-derived antimicrobial combined with 80 mg/kg naturally derived NO2 inhibited L. monocytogenes through 12 weeks of storage at 4 degrees C. PMID- 25285500 TI - Gene-related strain variation of Staphylococcus aureus for homologous resistance response to acid stress. AB - This study investigated the effect of adaptation of Staphylococcus aureus strains to the acidic condition of tomato in response to environmental stresses, such as heat and acid. S. aureus ATCC 13565, ATCC 14458, ATCC 23235, ATCC 27664, and NCCP10826 habituated in tomato extract at 35 degrees C for 24 h were inoculated in tryptic soy broth. The culture suspensions were then subjected to heat challenge or acid challenge at 60 degrees C and pH 3.0, respectively, for 60 min. In addition, transcriptional analysis using quantitative real-time PCR was performed to evaluate the expression level of acid-shock genes, such as clpB, zwf, nuoF, and gnd, from five S. aureus strains after the acid habituation of strains in tomato at 35 degrees C for 15 min and 60 min in comparison with that of the nonhabituated strains. In comparison with the nonhabituated strains, the five tomato-habituated S. aureus strains did not show cross protection to heat, but tomato-habituated S. aureus ATCC 23235 showed acid resistance. In quantitative real-time-PCR analysis, the relative expression levels of acid-shock genes (clpB, zwf, nuoF, and gnd) were increased the most in S. aureus ATCC 23235 after 60 min of tomato habituation, but there was little difference in the expression levels among the five S. aureus strains after 15 min of tomato habituation. These results indicate that the variation of acid resistance of S. aureus is related to the expression of acid-shock genes during acid habituation. PMID- 25285501 TI - Effects of modified atmosphere packaging on shelf life of Turkish delight (lokum). AB - Turkish delight is a sugar-based jellylike confection that has been produced for hundreds of years. In this study, four different modified atmospheres were created in order to extend the shelf life of Turkish delight. Microbiological analyses and sensory evaluations were conducted at the beginning of storage and at 7-day intervals thereafter. Microbiological analyses showed that the numbers of total mesophilic aerobic bacteria within samples stored in a modified atmosphere of 30% CO2 plus 70% N2 were lower than in the other modified atmospheres. According to sensory evaluations, the samples kept in a modified atmosphere of 50% CO2 plus 50% N2 were unacceptable after the 21st day of storage, whereas those kept in modified atmospheres of both 25% CO2 plus 75% N2 and 30% CO2 plus 70% N2 were found to be acceptable even after 30 days of storage. PMID- 25285502 TI - Effects of storage temperature on tyramine production by Enterococcus faecalis R612Z1 in water-boiled salted ducks. AB - Tyramine production by Enterococcus faecalis R612Z1 in water-boiled salted ducks was evaluated during storage at different temperatures. The results showed that E. faecalis R612Z1 could produce tyramine in meat samples when the storage temperature was no less than 4 degrees C. The E. faecalis R612Z1 counts of the meat samples reached 10(8) CFU/g on day 7 at 4 degrees C and on day 4 at 10 degrees C. However, the tyramine content of the meat samples stored at 10 degrees C increased to 23.73 MUg/g (on day 10), which was greater than the level in the samples stored at 4 degrees C (7.56 MUg/g). Reverse transcription quantitative PCR detection of the expression level of the tyrDC gene in E. faecalis R612Z1 in the meat samples revealed no significant changes at different storage temperatures. Thus, the changes in tyramine production of E. faecalis R612Z1 may be due to the different enzymatic activities at different storage temperatures. PMID- 25285503 TI - Peroxide test strips detect added hydrogen peroxide in raw milk at levels affecting bacterial load. AB - Hydrogen peroxide (H2O2) has a long-established history of use as a preservative in milk worldwide. The use of H2O2 to activate the inherent lactoperoxidase enzyme system has dramatically improved the quality of raw dairy products in areas in which cooling is not widely available. In the United States, however, where refrigeration is widely available, the addition of H2O2 to milk is not permitted, with the exception of certain applications prior to cheesemaking and during the preparation of modified whey. Due to the relatively quick deterioration of H2O2 in fluid milk, the detection of raw milk adulterated with the compound can be challenging. In this study we evaluated (i) total aerobic bacterial counts and (ii) ability of peroxide test strips to detect H2O2 in raw milk with various concentrations (0, 100, 300, 500, 700, and 900 ppm) of added H2O2, incubated at both 6 and 21 degrees C for 0, 24, and 48 h. Results showed that at both 6 and 21 degrees C the H2O2 concentration and time had a significant effect on bacterial loads in raw milk. Additionally, commercially available test strips were able to detect H2O2 in raw milk, with predicted probability of >90%, immediately after addition and after 24 and 48 h for the higher concentrations used, offering a viable method for detecting raw milk adulteration with H2O2. PMID- 25285504 TI - Natural occurrence of aflatoxins in peanuts and peanut butter from Bulawayo, Zimbabwe. AB - Mycotoxins are toxic secondary metabolites produced by filamentous fungi that may contaminate food and pose a health risk, especially in developing countries, where there is a lack of food security and quality is subsumed by food insufficiency. Aflatoxins are the most toxic known mycotoxins and are a significant risk factor for liver and kidney cancer, teratogenicity, undernutrition, and micronutrient malabsorption in both humans and animals. The main aim of the study was to determine the extent of fungal and aflatoxin contamination in peanuts and peanut butter being sold in both the formal and informal markets in Bulawayo, Zimbabwe. Eighteen peanut samples and 11 peanut butter samples were purchased from retail shops and the informal market. Fungal contamination was determined using standard mycology culture methods, while aflatoxin contamination was determined using high-performance liquid chromatography-fluorescence detection. Four of the six peanut samples tested for fungal contamination were infected with Aspergillus flavus/parasiticus, ranging from 3 to 20% of the kernels examined, while 27% (3 of 11) of the peanut butter samples were infected with A. flavus/parasiticus. Ninety-one percent (10 of 11) of the peanut butter samples were contaminated with aflatoxins (mean, 75.66 ng/g, and range, 6.1 to 247 ng/g), and aflatoxin B1 was the most prevalent (mean, 51.0 ng/g, and range, 3.7 to 191 ng/g). Three of the 18 peanut samples were contaminated with aflatoxins (range, 6.6 to 622 ng/g). The commercial peanut butter samples had very high aflatoxin levels, and manufacturers should be sensitized to the detrimental effects of aflatoxins and measures to reduce contamination. PMID- 25285505 TI - Acaricidal activity of constituents derived from peppermint oil against Tyrophagus putrescentiae. AB - The acaricidal activities of peppermint oil and menthol isomers against mites in stored food were evaluated using fumigant and contact bioassays and were compared with the activity of benzyl benzoate as a synthetic acaricide. Based on the 50% lethal dose (LD50) values against Tyrophagus putrescentiae in the fumigant bioassay, menthol (0.96 MUg/cm(2)) was approximately 12.18 times more effective than benzyl benzoate (11.70 MUg/cm(2)), followed by (+)-neomenthol (1.33 MUg/cm(2)), (-)-menthol (1.60 MUg/cm(2)), and (+)-menthol (1.90 MUg/cm(2)). In the filter paper bioassay, menthol (0.55 MUg/cm(2)) was about 15.18 times more active than benzyl benzoate (8.35 MUg/cm(2)), followed by (-)-menthol (0.84 MUg/cm(2)), (+)-menthol (0.92 MUg/cm(2)), and (+)-neomenthol (1.72 MUg/cm(2)). However, (+)-isomenthol did not exhibit any acaricidal activity against T. putrescentiae in the fumigant and filter paper bioassays. These results indicate that peppermint oil and menthol isomers could be effective natural acaricides for managing mites in stored food. PMID- 25285506 TI - Lateral-flow assay for rapid quantitative detection of clorprenaline residue in swine urine. AB - Clorprenaline (CLP), a beta2-adrenergic agonist, was first found in veterinary drugs for cold treatment in China in 2013. It is a potential new lean meat boosting feed additive because it can promote animal muscular mass growth and decrease fat accumulation. A competitive colloidal gold-based lateral flow immunoassay system with a portable strip reader was successfully developed for rapid quantitative detection of CLP residue in swine urine. The detection system was optimized so that the detection can be completed within 9 min with a limit of detection of 0.15 MUg . liter(-1). The assay exhibited good linear range from 3.0 to 20.0 MUg . liter(-1), with reliable correlation of 0.9970 and with no obvious cross-reaction with five other beta2-agonist compounds. Twenty spiked swine urine samples were tested by lateral flow immunoassay and liquid chromatography-tandem mass spectrometry to confirm the accuracy of the system. Results show good correlation between the two methods. This method is rapid, sensitive, specific, and convenient. It can be applied in the field for on-site detection of CLP in urine samples. PMID- 25285507 TI - Gluten contamination in foods labeled as "gluten free" in the United States. AB - Gluten is the main storage protein in grains and consists of gliadin and glutenin occurring in the same ratio. Persons suffering from intolerances, including celiac disease, must avoid foods containing gluten or products containing wheat, barley, and rye. Accordingly, gluten detection is of high interest for the food safety of celiac patients. This study was designed to determine the concentrations of gluten in foods labeled "gluten free" available in the United States. Seventy-eight samples labeled gluten free were collected and analyzed using a gliadin competitive enzyme-linked immunosorbent assay. The gluten content was calculated based on the assumption of the same ratio between gliadin and glutenin. Forty-eight (61.5%) of the 78 samples contained less than the limit of quantification of 10 mg/kg for gluten. In addition, 14 (17.9%) of the 78 samples labeled gluten free contained less gluten than the guidelines established by the Codex Alimentarius for gluten-free labeling (20 mg/kg). However, 16 samples (20.5%) did contain gluten levels of >=20 mg/kg, ranging from 20.3 to 60.3 mg/kg. In particular, five of eight breakfast cereal samples showed gluten contents higher than 20 mg/kg. These results may be of concern, as gluten sensitivity is known to vary among celiac disease patients. PMID- 25285508 TI - Space-charge-mediated anomalous ferroelectric switching in P(VDF-TrEE) polymer films. AB - We report on the switching dynamics of P(VDF-TrEE) copolymer devices and the realization of additional substable ferroelectric states via modulation of the coupling between polarizations and space charges. The space-charge-limited current is revealed to be the dominant leakage mechanism in such organic ferroelectric devices, and electrostatic interactions due to space charges lead to the emergence of anomalous ferroelectric loops. The reliable control of ferroelectric switching in P(VDF-TrEE) copolymers opens doors toward engineering advanced organic memories with tailored switching characteristics. PMID- 25285509 TI - A two-stage multiplex method for quantitative analysis of botulinum neurotoxins type A, B, E, and F by MALDI-TOF mass spectrometry. AB - In this publication, we report on the development of a quantitative enzymatic method for the detection of four botulinum neurotoxin (BoNT) serotypes responsible for human botulism by MALDI-TOF mass spectrometry. Factors that might affect the linearity and dynamic range for detection of BoNT cleavage products were initially examined, including the amount of peptide substrate and internal standard, the timing of cleavage reaction, and the components in the reaction solution. It was found that a long incubation time produced sensitive results, but was not capable of determining higher toxin concentrations, whereas a short incubation time was less sensitive so that lower toxin concentrations were not detected. In order to overcome these limitations, a two-stage analysis strategy was applied. The first stage analysis involved a short incubation period (e.g., 30 min). If no toxin was detected at this stage, the cleavage reaction was allowed to continue and the samples were analyzed at a second time point (4 h), so that toxin levels lower than 1 mouse LD50 or 55 attomoles per milliliter (55 amol/mL) could be quantified. By combining the results from two-stage quantification, 4 or 5 orders of magnitude in dynamic range were achieved for the detection of the serotypes of BoNT/A, BoNT/B, BoNT/E, or BoNT/F. The effect of multiplexing the assay by mixing substrates for different BoNT serotypes into a single reaction was also investigated in order to reduce the numbers of the cleavage reactions and save valuable clinical samples. PMID- 25285510 TI - Cardiovascular Collapse After Induction. PMID- 25285511 TI - Relapsed metachronous pancreatic metastasis from renal cell carcinoma (RCC): report of a case and review of literature. AB - AIM: The pancreas is a preferred site of metastasis from renal cell carcinoma (RCC), that may occur even after many years from a radical nephrectomy. Surgical R0 resection remains the only potentially curative treatment for solitary tumor. The possibility of a multifocality of the lesions (20-45%) must be considered. MATERIAL OF STUDY: We report a case of metachronous pancreatic metastasis from RCC that occurred twice. After five years from a right polar inferior nephrectomy for a RCC, two nodular lesions were identified in the body-tail of the pancreas and were treated with distal pancreatectomy and splenectomy. After six months the CT imaging revealed a nodular lesion of few millimeters in the residual pancreatic body; we followed the slow growth and in October 2012, when the size reached 2 cm, the patient was operated to remove the residual portion of pancreatic body. After 16 months of follow-up the patient is well and there isn't relapse of disease. DISCUSSION: Patients with metachronous pancreatic lesions represent a particular group with a more indolent course of RCC, the appearance of metastases after a prolonged interval from nephrectomy is related to a more favorable prognosis. Radical lymph-node dissection is not necessary for the uncommon involvement of peripancreatic nodes, condition that explains the positive outcomes achieved with surgery. CONCLUSION: Patients with resected metastasis present an 88% survival rate at 5 years versus 47% observed in nonoperated patients; studies provide encouraging results in survival and quality of life of surgically treated patients. PMID- 25285513 TI - Weighing projections of physical decline in lung cancer surgery decisions. AB - BACKGROUND: Patients with early-stage lung cancer often have comorbid illnesses and fear debility and death when contemplating surgery. However, data that compare physical function of patients who receive surgery with similar patients who do not are sparse. The authors report 1-year outcome results for surgical and nonsurgical patients in a prospective lung cancer cohort to address this gap. METHODS: The authors enrolled 386 patients with early-stage lung cancer. A 106 item survey was completed at the time of enrollment including the Short-Form 12 (SF-12) Health Survey to assess functional status. Patients were followed for a year. Chart abstractions were obtained to determine comorbid illnesses and surgical status. Death was ascertained through vital records. The SF-12 was repeated 1 year after the enrollment. Regression models were constructed to identify predictors of 1-year mortality and decline in physical function. RESULTS: Fifty-nine patients (15.3%) died before 1-year follow-up. Mortality in the surgical group was 10.8% compared with 22.8% in the nonsurgical group (P < 0.001). In regression analysis controlling for age and comorbidities, surgical treatment was associated with a reduction in 1-year mortality (odds ratio: 0.5 and 95% confidence interval: 0.3-1.0) but did not worsen physical function relative to the untreated group (average decrease in physical component score of SF-12 = 1.9 for surgery group and 2.5 for no surgery group, P = 0.66). CONCLUSIONS: Functional decline between surgically treated and untreated patients did not differ. This result casts doubt on its value as a treatment determinant. Cancer mortality seems to be a more essential issue in treatment decisions. PMID- 25285512 TI - Physician's fear of anticoagulant therapy in nonvalvular atrial fibrillation. AB - Despite the availability of predictive tools and treatment guidelines, anticoagulant therapies are underprescribed and many patients are undertreated for conditions that predispose to thromboembolic complications, including stroke. This review explores reasons for which physicians fear that the risks of anticoagulation may be greater than the potential benefit. The results of numerous clinical trials confirm that patients benefit from judiciously managed anticoagulation and that physicians can take various approaches to minimize risk. Use of stratification scores for patient selection and accurate estimation of stroke risk may improve outcomes; bleeding risk is less important than stroke risk. Adoption of newer anticoagulants with simpler regimens may help physicians allay their fears of anticoagulant use in patients with atrial fibrillation. These fears, although not groundless, should not overtake caution and hinder the delivery of appropriate evidence-based care. PMID- 25285514 TI - High-flow nasal cannula oxygen in adult patients: a narrative review. AB - High-flow nasal cannula oxygen (HFNC) is a relatively new therapeutic innovation being used in adults with severe respiratory disease. It delivers heated humidified oxygen through short nasal prongs and supplies much higher flow rates than traditional nasal cannula systems. These higher flows match patient flow demands better, reduce anatomic dead space and provide a slightly positive pressure in the upper airway. Randomized trials, nonrandomized prospective trials and case series using HFNC in adults were identified in the PubMed, Google Scholar and Cochrane databases for the period of June 1981 to December 2013. Fifteen studies meeting our inclusion criteria were analyzed; 5 were randomized controlled studies. These studies included 943 patients managed in intensive care units. Common clinical diagnoses included postoperative status, cancer and pneumonia. These studies demonstrated that HFNC provided better or comparable oxygenation when compared with conventional face masks and nasal cannulas. Side effects included epistaxis, nasal discomfort and dryness. No unexpected side effects were reported in the studies reviewed. Current studies demonstrate that HFNC can improve oxygenation adults with hypoxemic respiratory failure. In some patients, it is superior to traditional oxygen delivery systems and may obviate the need for positive pressure ventilation. More studies are needed to compare HFNC with noninvasive ventilation. PMID- 25285515 TI - Dining local: the microbial diet of a snail that grazes microbial communities is geographically structured. AB - Achatinella mustelina is a critically endangered tree snail that subsists entirely by grazing microbes from leaf surfaces of native trees. Little is known about the fundamental aspects of these microbe assemblages: not taxonomic composition, how this varies with host plant or location, nor whether snails selectively consume microbes. To address these questions, we collected 102 snail faecal samples as a proxy for diet, and 102 matched-leaf samples from four locations. We used Illumina amplicon sequencing to determine bacterial and fungal community composition. Microbial community structure was significantly distinct between snail faeces and leaf samples, but the same microbes occurred in both. We conclude that snails are not 'picky' eaters at the microbial level, but graze the surface of whatever plant they are on. In a second experiment, the gut was dissected from non-endangered native tree snails in the same family as Achatinella to confirm that faecal samples reflect gut contents. Over 60% of fungal reads were shared between faeces, gut and leaf samples. Overall, location, sample type (faeces or leaf) and host plant identity all significantly explained the community composition and variation among samples. Understanding the microbial ecology of microbes grazed by tree snails enables effective management when conservation requires captive breeding or field relocation. PMID- 25285516 TI - Isolation of distinct cell populations from the developing cerebellum by microdissection. AB - Microdissection is a novel technique that can isolate specific regions of a tissue and eliminate contamination from cellular sources in adjacent areas. This method was first utilized in the study of Nestin-expressing progenitors (NEPs), a newly identified population of cells in the cerebellar external germinal layer (EGL). Using microdissection in combination with fluorescent-activated cell sorting (FACS), a pure population of NEPs was collected separately from conventional granule neuron precursors in the EGL and from other contaminating Nestin-expressing cells in the cerebellum. Without microdissection, functional analyses of NEPs would not have been possible with the current methods available, such as Percoll gradient centrifugation and laser capture microdissection. This technique can also be applied for use with various tissues that contain either recognizable regions or fluorescently-labeled cells. Most importantly, a major advantage of this microdissection technique is that isolated cells are living and can be cultured for further experimentation, which is currently not possible with other described methods. PMID- 25285518 TI - In-hospital delirium while awaiting temporal artery biopsy: a teachable moment. PMID- 25285519 TI - Stimulus-dependent modulation of visual neglect in a touch-screen cancellation task. AB - OBJECTIVE: Patients with left-sided neglect frequently show omissions and repetitive behavior on cancellation tests. Using a touch-screen-based cancellation task, we tested how visual feedback and distracters influence the number of omissions and perseverations. METHOD: Eighteen patients with left-sided visual neglect and 18 healthy controls performed four different cancellation tasks on an iPad touch screen: no feedback (the display did not change during the task), visual feedback (touched targets changed their color from black to green), visual feedback with distracters (20 distracters were evenly embedded in the display; detected targets changed their color from black to green), vanishing targets (touched targets disappeared from the screen). RESULTS: Except for the condition with vanishing targets, neglect patients had significantly more omissions and perseverations than healthy controls in the remaining three subtests. Both conditions providing feedback by changing the target color showed the highest number of omissions. Erasure of targets nearly diminished omissions completely. The highest rate of perseverations was observed in the no-feedback condition. The implementation of distracters led to a moderate number of perseverations. Visual feedback without distracters and vanishing targets abolished perseverations nearly completely. CONCLUSIONS: Visual feedback and the presence of distracters aggravated hemispatial neglect. This finding is compatible with impaired disengagement from the ipsilesional side as an important factor of visual neglect. Improvement of cancellation behavior with vanishing targets could have therapeutic implications. PMID- 25285517 TI - Identification of KMU-3, a novel derivative of gallic acid, as an inhibitor of adipogenesis. AB - Differentiation of preadipocyte, also called adipogenesis, leads to the phenotype of mature adipocyte. Excessive adipogenesis, however, is largely linked to the development of obesity. Herein we investigated a library of 53 novel chemicals, generated from a number of polyphenolic natural compounds, on adipogenesis. Strikingly, among the chemicals tested, KMU-3, a derivative of gallic acid, strongly suppressed lipid accumulation during the differentiation of 3T3-L1 preadipocytes into adipocytes. On mechanistic levels, KMU-3 inhibited expressions of CCAAT/enhancer-binding protein-alpha (C/EBP-alpha), peroxisome proliferator activated receptor-gamma (PPAR-gamma), and fatty acid synthase (FAS) during adipocyte differentiation. Moreover, KMU-3 reduced expressions of adipokines, including retinol binding protein-4 (RBP-4), leptin, and regulated on activation, normal T cell expressed and secreted (RANTES) during adipocyte differentiation. Of further note, KMU-3 rapidly blocked the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) during the early stage of adipogenesis. Importantly, pharmacological inhibition studies revealed that AG490, a JAK-2/STAT 3 inhibitor suppressed adipogenesis and STAT-3 phosphorylation, implying that early blockage of STAT-3 activity is crucial for the KMU-3-mediated anti adipogenesis. These findings demonstrate firstly that KMU-3 inhibits adipogenesis by down-regulating STAT-3, PPAR-gamma, C/EBP-alpha, and FAS. This work shows that KMU-3 is an inhibitor of adipogenesis and thus may have therapeutic potential against obesity. PMID- 25285520 TI - "Ipsilesional neglect: Behavioral and anatomical correlates": Correction to Sacchetti et al. (2014). AB - Reports an error in "Ipsilesional Neglect: Behavioral and Anatomical Correlates" by Daniela L. Sacchetti, Kelly M. Goedert, Anne L. Foundas and A. M. Barrett (Neuropsychology, Advanced Online Publication, Sep 1, 2014, np). The funding source information was missing from the author note, and A. M. Barrett's institutional affiliation was incorrect. The funding source information and Barrett's correct institutional affiliation are provided in the erratum. (The following abstract of the original article appeared in record 2014-35685-001.) OBJECTIVE: The sparse existing research on ipsilesional neglect supports an association of this disorder with damage to the right frontal and subcortical brain networks. It is believed that dysfunction in these networks may result in primarily "aiming" motor-intentional spatial errors. The purpose of this study was to confirm whether frontal-subcortical circuits are indeed commonly affected in ipsilesional neglect and to determine the relative presence of "aiming" motor intentional versus "where" perceptual-attentional spatial errors in these individuals. METHODS: We identified 12 participants with ipsilesional neglect based on a computerized line bisection task and used the line bisection data to quantify participants' perceptual-attentional and motor-intentional errors. We were able to discriminate between these 2 biases using the algebraic solutions for 2 separate equations, one for "aiming" and one for "where" biases. Lesion mapping was conducted for all participants using MRIcron software; lesion checklist and overlap analysis were created from these images. RESULTS: A greater percentage of participants with ipsilesional neglect had frontal/subcortical damage (83%) compared with the expected percentage (27%) observed in published patient samples with contralesional neglect. We observed the greatest area of lesion overlap in frontal lobe white matter pathways. Nevertheless, participants with ipsilesional neglect made primarily "where" rather than "aiming" spatial errors. CONCLUSION: Our data confirm previous research suggesting that ipsilesional neglect may result from lesions to the right frontal-subcortical networks. Furthermore, in our group, ipsilesional neglect was also strongly associated with primarily "where" perceptual-attentional bias, and less so with "aiming" motor-intentional spatial bias. PMID- 25285523 TI - Numerical and functional responses of forest bats to a major insect pest in pine plantations. AB - Global change is expected to modify the frequency and magnitude of defoliating insect outbreaks in forest ecosystems. Bats are increasingly acknowledged as effective biocontrol agents for pest insect populations. However, a better understanding is required of whether and how bat communities contribute to the resilience of forests to man- and climate-driven biotic disturbances.We studied the responses of forest insectivorous bats to a major pine defoliator, the pine processionary moth Thaumetopoea pityocampa, which is currently expanding its range in response to global warming [corrected]. We used pheromone traps and ultrasound bat recorders to estimate the abundance and activity of moths and predatory bats along the edge of infested pine stands. We used synthetic pheromone to evaluate the effects of experimentally increased moth availability on bat foraging activity. We also evaluated the top-down regulation of moth population by estimating T. pityocampa larval colonies abundance on the same edges the following winter. We observed a close spatio-temporal matching between emergent moths and foraging bats, with bat activity significantly increasing with moth abundance. The foraging activity of some bat species was significantly higher near pheromone lures, i.e. in areas of expected increased prey availability. Furthermore moth reproductive success significantly decreased with increasing bat activity during the flight period of adult moths. These findings suggest that bats, at least in condition of low prey density, exhibit numerical and functional responses to a specific and abundant prey, which may ultimately result in an effective top-down regulation of the population of the prey. These observations are consistent with bats being useful agents for the biocontrol of insect pest populations in plantation forests. PMID- 25285521 TI - Genetic and dietary determinants of insulin-like growth factor (IGF)-1 and IGF binding protein (BP)-3 levels among Chinese women. AB - BACKGROUND: Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations. METHODS: From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (>= 40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1 to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels. RESULTS: Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] ug/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] ug/L). CONCLUSIONS: IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more. PMID- 25285525 TI - Corneal donor tissue preparation for Descemet's membrane endothelial keratoplasty. AB - Descemet's Membrane Endothelial Keratoplasty (DMEK) is a form of corneal transplantation in which only a single cell layer, the corneal endothelium, along with its basement membrane (Descemet's membrane) is introduced onto the recipient's posterior stroma(3). Unlike Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK), where additional donor stroma is introduced, no unnatural stroma-to-stroma interface is created. As a result, the natural anatomy of the cornea is preserved as much as possible allowing for improved recovery time and visual acuity(4). Endothelial Keratoplasty (EK) is the procedure of choice for treatment of endothelial dysfunction. The advantages of EK include rapid recovery of vision, preservation of ocular integrity and minimal refractive change due to use of a small, peripheral incision(1). DSAEK utilizes donor tissue prepared with partial thickness stroma and endothelium. The rapid success and utilization of this procedure can be attributed to availability of eye-bank prepared precut tissue. The benefits of eye-bank preparation of donor tissue include elimination of need for specialized equipment in the operating room and availability of back up donor tissue in case of tissue perforation during preparation. In addition, high volume preparation of donor tissue by eye-bank technicians may provide improved quality of donor tissue. DSAEK may have limited best corrected visual acuity due to creation of a stromal interface between the donor and recipient cornea. Elimination of this interface with transplantation of only donor Descemet's membrane and endothelium in DMEK may improve visual outcomes and reduce complications after EK(5). Similar to DSAEK, long term success and acceptance of DMEK is dependent on ease of availability of precut, eye-bank prepared donor tissue. Here we present a stepwise approach to donor tissue preparation which may reduce some barriers eye-banks face in providing DMEK grafts. PMID- 25285524 TI - Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. AB - Stathmin 1 performs a critical function in cell proliferation by regulating microtubule polymerization. This proliferative function is thought to explain the frequent overexpression of stathmin in human cancer and its correlation with a bad prognosis. Whether stathmin also functions in cell death pathways is unclear. Stathmin regulates microtubules in part by binding free tubulin, a process inhibited by stathmin phosphorylation from kinases including c-Jun N-terminal kinase (JNK). The involvement of JNK activation both in stathmin phosphorylation, and in hepatocellular resistance to oxidative stress, led to an examination of the role of stathmin/JNK crosstalk in oxidant-induced hepatocyte death. Oxidative stress from menadione-generated superoxide induced JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes. A stathmin knockdown sensitized hepatocytes to both apoptotic and necrotic cell death from menadione without altering levels of oxidant generation. The absence of stathmin during oxidative stress led to JNK overactivation that was the mechanism of cell death as a concomitant knockdown of JNK1 or JNK2 blocked death. Hepatocyte death from JNK overactivation was mediated by the effects of JNK on mitochondria. Mitochondrial outer membrane permeabilization occurred in stathmin knockdown cells at low concentrations of menadione that triggered apoptosis, whereas mitochondrial beta-oxidation and ATP homeostasis were compromised at higher, necrotic menadione concentrations. Stathmin therefore mediates hepatocyte resistance to death from oxidative stress by down regulating JNK and maintaining mitochondrial integrity. These findings demonstrate a new mechanism by which stathmin promotes cell survival and potentially tumor growth. PMID- 25285528 TI - Social values and preschool behavioral adjustment: A comparative investigation of Latino and European American preschool children. AB - The present article explored relationships between social values (cooperative, individualistic, and competitive) and the behavioral adjustment of Latino and European American preschoolers within the preschool setting. Of interest was whether relationships between social values and behavioral adjustment differed as a function of cultural background. Assessments of social values and teacher reports of child behavioral adjustment were obtained for 254 preschoolers from collectivist (Spanish-speaking Latino Americans), individualist (English-speaking European Americans), and mixed cultural backgrounds (English-Speaking Latino Americans). Cooperative values were more prevalent among collectivist background children, but did not predict behavioral adjustment. Individualistic values did not differ across groups, but predicted better behavioral adjustment for individualist children. Competitive values did not differ across groups, but predicted positive behavioral adjustment for collectivist children and negative behavioral adjustment for individualist children. These findings suggest that a competitive social orientation constitutes a resilience factor for children from collectivist cultural backgrounds and a risk factor for children from individualist cultural backgrounds, and that a cooperative social orientation is undervalued within school settings. Discussion focuses on facilitating the behavioral adjustment of children by raising teacher awareness of collectivist social values and, selectively, fostering or encouraging competitive social values. In sum, the results support the notion that the functionality and meaning of social values differ across social and cultural contexts. PMID- 25285526 TI - Cost-effectiveness of colorectal cancer screening protocols in urban Chinese populations. AB - Colorectal cancer (CRC) takes a second and fourth position in the incidence and mortality lists respectively among all malignant tumors in urban populations in China. This study was designed to evaluate the cost-effectiveness of two different CRC screening protocols: faecal occult blood test (FOBT) alone, and FOBT plus a high-risk factor questionnaire (HRFQ) as the respective initial screens, followed by colonoscopy. We developed a Markov model to simulate the progression of a cohort of 100,000 average risk asymptomatic individuals moving through a defined series of states between the ages of 40 to 74 years. The parameters used for the modeling came from the CESP (Comparison and Evaluation of Screening Programs for Colorectal Cancer in Urban Communities in China) study and published literature. Eight CRC screening scenarios were tested in the Markov model. The cost-effectiveness of CRC screening under each scenario was measured by an incremental cost-effectiveness ratio (ICER) compared with a scenario without CRC screening. The study revealed that a combined use of FOBT and HRFQ is preferable in CRC screening programs as an initial screening instrument. Annual FOBT+HRFQ screening is recommended for those who have a negative initial result and those who have a positive result but have failed to continue to colonoscopic examination. Repeated colonoscopy (for those with a positive result in initial screening but a negative colonoscopy result) should be performed at a ten-year interval instead of one-year. Such a protocol would cost 7732 Yuan per life year saved, which is the most cost-effective option. In conclusion, the current Chinese Trial Version for CRC Screening Strategy should be revised in line with the most cost-effective protocol identified in this study. PMID- 25285527 TI - Cognitive behavioral therapy: a meta-analysis of race and substance use outcomes. AB - Cognitive behavioral therapy (CBT) is an effective intervention for reducing substance use. However, because CBT trials have included predominantly White samples caution must be used when generalizing these effects to Blacks and Hispanics. This meta-analysis compared the impact of CBT in reducing substance use between studies with a predominantly non-Hispanic White sample (hereafter NHW studies) and studies with a predominantly Black and/or Hispanic sample (hereafter BH studies). From 322 manuscripts identified in the literature, 16 met criteria for inclusion. Effect sizes between CBT and comparison group at posttest had similar effects on substance abuse across NHW and BH studies. However, when comparing pre-posttest effect sizes from groups receiving CBT between NHW and BH studies, CBT's impact was significantly stronger in NHW studies. T-test comparisons indicated reduced retention/engagement in BH studies, albeit failing to reach statistical significance. Results highlight the need for further research testing CBT's impact on substance use among Blacks and Hispanics. PMID- 25285529 TI - A microfluidic-based electrochemical biochip for label-free DNA hybridization analysis. AB - Miniaturization of analytical benchtop procedures into the micro-scale provides significant advantages in regards to reaction time, cost, and integration of pre processing steps. Utilizing these devices towards the analysis of DNA hybridization events is important because it offers a technology for real time assessment of biomarkers at the point-of-care for various diseases. However, when the device footprint decreases the dominance of various physical phenomena increases. These phenomena influence the fabrication precision and operation reliability of the device. Therefore, there is a great need to accurately fabricate and operate these devices in a reproducible manner in order to improve the overall performance. Here, we describe the protocols and the methods used for the fabrication and the operation of a microfluidic-based electrochemical biochip for accurate analysis of DNA hybridization events. The biochip is composed of two parts: a microfluidic chip with three parallel micro-channels made of polydimethylsiloxane (PDMS), and a 3 x 3 arrayed electrochemical micro-chip. The DNA hybridization events are detected using electrochemical impedance spectroscopy (EIS) analysis. The EIS analysis enables monitoring variations of the properties of the electrochemical system that are dominant at these length scales. With the ability to monitor changes of both charge transfer and diffusional resistance with the biosensor, we demonstrate the selectivity to complementary ssDNA targets, a calculated detection limit of 3.8 nM, and a 13% cross-reactivity with other non-complementary ssDNA following 20 min of incubation. This methodology can improve the performance of miniaturized devices by elucidating on the behavior of diffusion at the micro-scale regime and by enabling the study of DNA hybridization events. PMID- 25285530 TI - Streptomyces coelicolor SCO4226 is a nickel binding protein. AB - The open reading frame SCO4226 of Streptomyces coelicolor A3(2) encodes an 82 residue hypothetical protein. Biochemical assays revealed that each SCO4226 dimer binds four nickel ions. To decipher the molecular function, we solved the crystal structures of SCO4226 in both apo- and nickel-bound (Ni-SCO4226) forms at 1.30 and 2.04 A resolution, respectively. Each subunit of SCO4226 dimer adopts a canonical ferredoxin-like fold with five beta-strands flanked by two alpha helices. In the structure of Ni-SCO4226, four nickel ions are coordinated at the surface of the dimer. Further biochemical assays suggested that the binding of Ni2+ triggers the self-aggregation of SCO4226 in vitro. In addition, RT-qPCR assays demonstrated that the expression of SCO4226 gene in S. coelicolor is specifically up-regulated by the addition of Ni2+, but not other divalent ions such as Cu2+, Mn2+ or Co2+. All these results suggested that SCO4226 acts as a nickel binding protein, probably required for nickel sequestration and/or detoxification. PMID- 25285532 TI - Fundamental technical elements of freeze-fracture/freeze-etch in biological electron microscopy. AB - Freeze-fracture/freeze-etch describes a process whereby specimens, typically biological or nanomaterial in nature, are frozen, fractured, and replicated to generate a carbon/platinum "cast" intended for examination by transmission electron microscopy. Specimens are subjected to ultrarapid freezing rates, often in the presence of cryoprotective agents to limit ice crystal formation, with subsequent fracturing of the specimen at liquid nitrogen cooled temperatures under high vacuum. The resultant fractured surface is replicated and stabilized by evaporation of carbon and platinum from an angle that confers surface three dimensional detail to the cast. This technique has proved particularly enlightening for the investigation of cell membranes and their specializations and has contributed considerably to the understanding of cellular form to related cell function. In this report, we survey the instrument requirements and technical protocol for performing freeze-fracture, the associated nomenclature and characteristics of fracture planes, variations on the conventional procedure, and criteria for interpretation of freeze-fracture images. This technique has been widely used for ultrastructural investigation in many areas of cell biology and holds promise as an emerging imaging technique for molecular, nanotechnology, and materials science studies. PMID- 25285533 TI - The importance of the ladder diagram in the evaluation of tachyarrhythmia: jumping to conclusions. PMID- 25285534 TI - Four into one: organocatalyzed stereoselective conjugate addition of unprotected and unactivated carbohydrates. AB - This paper proposes a new and stereoselective access to glycosides. This operationally simple approach achieved via base-catalyzed conjugate additions of unprotected and unactivated carbohydrates to activated alkenes or alkynes is described. PMID- 25285531 TI - A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24 hour infusion in older patients with previously untreated acute myeloid leukemia. AB - PURPOSE: An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (>= 70 yr) with untreated acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h * 3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h * 3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h * 3 d) if <= 1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h * 3 d) if DLT occurred in >= 2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h * 3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h * 3 d) to determine the morphologic complete response rate. RESULTS: In phase I, two of three patients receiving obatoclax 30 mg/day (3 h * 3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h * 3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h * 3 d; n = 7) and 60 mg/day (24 h * 3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient. CONCLUSIONS: Obatoclax 20 mg/day was the MTD (3 h * 3 d) in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00684918. PMID- 25285535 TI - Abnormal excess capacity of conjugated dicarboxylates in lithium-ion batteries. AB - Lithium-ion batteries (LIBs) are considered to be key energy storage systems needed to secure reliable, sustainable, and clean energy sources. Redox-active organic compounds have been proposed as interesting candidates for electrode materials for the next-generation LIBs because of their flexible molecular design, recyclability, and low production cost. Despite wide interest, a molecular-level understanding of the electrochemical lithiations/delithiations of those materials remains rudimentary. We synthesized a set of pi-conjugated dicarboxylates and discovered unprecedented excess capacities for inverse-Wurster type nonfused aromatic compounds (dilithium terephthalate and dilithium thiophene 2,5-dicarboxylate). Molecular structural investigations based on solid-state CP/MAS (13)C NMR combined with the stable isotope labeling method and ex situ X ray diffraction were carried out to elucidate the origin of the excess reversible capacity. Interestingly, an open-chain-type dilithium muconate did not show an analogous behavior, signifying the key role played by the cyclic moiety in the electrochemical reaction. PMID- 25285536 TI - High-throughput titration of luciferase-expressing recombinant viruses. AB - Standard plaque assays to determine infectious viral titers can be time consuming, are not amenable to a high volume of samples, and cannot be done with viruses that do not form plaques. As an alternative to plaque assays, we have developed a high-throughput titration method that allows for the simultaneous titration of a high volume of samples in a single day. This approach involves infection of the samples with a Firefly luciferase tagged virus, transfer of the infected samples onto an appropriate permissive cell line, subsequent addition of luciferin, reading of plates in order to obtain luminescence readings, and finally the conversion from luminescence to viral titers. The assessment of cytotoxicity using a metabolic viability dye can be easily incorporated in the workflow in parallel and provide valuable information in the context of a drug screen. This technique provides a reliable, high-throughput method to determine viral titers as an alternative to a standard plaque assay. PMID- 25285537 TI - The impact of spgM, rpfF, rmlA gene distribution on biofilm formation in Stenotrophomonas maltophilia. AB - BACKGROUND: Stenotrophomonas maltophilia is emerging as one of the most frequently found bacteria in chronic pulmonary infection. Biofilm is increasingly recognized as a contributing factor to disease pathogenesis. In the present study, a total of 37 isolates of S. maltophilia obtained from chronic pulmonary infection patients were evaluated to the relationship between biofilm production and the relative genes expression. METHODS: The clonal relatedness of isolates was determined by pulse-field gel electrophoresis. Biofilm formation assays were performed by crystal violet assay, and confirmed by Electron microscopy analysis and CLSM analysis. PCR was employed to learn gene distribution and expression. RESULTS: Twenty-four pulsotypes were designated for 37 S. maltophilia isolates, and these 24 pulsotypes exhibited various levels of biofilm production, 8 strong biofilm-producing S. maltophilia strains with OD492 value above 0.6, 14 middle biofilm-producing strains with OD492 average value of 0.4 and 2 weak biofilm producing strains with OD492 average value of 0.19. CLSM analysis showed that the isolates from the early stage of chronic infection enable to form more highly structured and multilayered biofim than those in the late stage. The prevalence of spgM, rmlA, and rpfF genes was 83.3%, 87.5%, and 50.0% in 24 S. maltophilia strains, respectively, and the presence of rmlA, spgM or rpfF had a close relationship with biofilm formation but did not significantly affect the mean amount of biofilm. Significant mutations of spgM and rmlA were found in both strong and weak biofilm-producing strains. CONCLUSION: Mutations in spgM and rmlA may be relevant to biofilm formation in the clinical isolates of S. maltophilia. PMID- 25285538 TI - Effect of bacteriophage infection in combination with tobramycin on the emergence of resistance in Escherichia coli and Pseudomonas aeruginosa biofilms. AB - Bacteriophage infection and antibiotics used individually to reduce biofilm mass often result in the emergence of significant levels of phage and antibiotic resistant cells. In contrast, combination therapy in Escherichia coli biofilms employing T4 phage and tobramycin resulted in greater than 99% and 39% reduction in antibiotic and phage resistant cells, respectively. In P. aeruginosa biofilms, combination therapy resulted in a 60% and 99% reduction in antibiotic and PB-1 phage resistant cells, respectively. Although the combined treatment resulted in greater reduction of E. coli CFUs compared to the use of antibiotic alone, infection of P. aeruginosa biofilms with PB-1 in the presence of tobramycin was only as effective in the reduction of CFUs as the use of antibiotic alone. The study demonstrated phage infection in combination with tobramycin can significantly reduce the emergence of antibiotic and phage resistant cells in both E. coli and P. aeruginosa biofilms, however, a reduction in biomass was dependent on the phage-host system. PMID- 25285540 TI - Support from hospital to home for elders: a randomized trial. AB - BACKGROUND: Hospitals are implementing discharge support programs to reduce readmissions, and these programs have had mixed success. OBJECTIVE: To examine whether a peridischarge, nurse-led intervention decreased emergency department (ED) visits or readmissions among ethnically and linguistically diverse older patients admitted to a safety-net hospital. DESIGN: Randomized, controlled trial using computer-generated randomization with 1:1 allocation, stratified by language. (Clinical Trials.gov: NCT01221532). SETTING: Publicly funded urban hospital in Northern California. PATIENTS: Hospitalized adults aged 55 years or older with anticipated discharge to the community who spoke English, Spanish, or Chinese (Mandarin or Cantonese). INTERVENTION: Usual care versus in-hospital, one on-one, self-management education given by a dedicated language-concordant registered nurse combined with a telephone follow-up after discharge from a nurse practitioner. MEASUREMENTS: Staff blinded to the study groups determined ED visits or readmissions to any facility at 30, 90, and 180 days after initial hospital discharge using administrative data from several hospitals. RESULTS: There were 700 low-income, ethnically and linguistically diverse patients with a mean age of 66.2 years (SD, 9.0). The primary outcome of ED visits or readmissions did not differ between the intervention and usual care groups (hazard ratio, 1.26 [95% CI, 0.89 to 1.78] at 30 days, 1.21 [CI, 0.91 to 1.62] at 90 days, and 1.11 [CI, 0.86 to 1.43] at 180 days). LIMITATIONS: This study was done at a single acute-care hospital. There were fewer outcomes than expected, which may have caused the study to be underpowered. CONCLUSION: A nurse-led, in hospital discharge support intervention did not show a reduction in readmissions or ED visits among diverse, low-income older adults at a safety-net hospital. Although wide CIs preclude firm conclusions, the intervention may have increased ED visits. Alternative readmission prevention strategies should be tested in this population. PRIMARY FUNDING SOURCE: Gordon and Betty Moore Foundation. PMID- 25285542 TI - Financial conflicts of interest and conclusions about neuraminidase inhibitors for influenza: an analysis of systematic reviews. AB - BACKGROUND: Industry funding and financial conflicts of interest may contribute to bias in the synthesis and interpretation of scientific evidence. OBJECTIVE: To examine the association between financial conflicts of interest and characteristics of systematic reviews of neuraminidase inhibitors. DESIGN: Retrospective analysis. SETTING: Reviews that examined the use of neuraminidase inhibitors in the prophylaxis or treatment of influenza, were published between January 2005 and May 2014, and used a systematic search protocol. MEASUREMENTS: Two investigators blinded to all information regarding the review authors independently assessed the presentation of evidence on the use of neuraminidase inhibitors as favorable or not favorable. Financial conflicts of interest were identified using the index reviews, other publications, and Web-based searches. Associations between financial conflicts of interest, favorability assessments, and presence of critical appraisals of evidence quality were analyzed. RESULTS: Twenty-six systematic reviews were identified, of which 13 examined prophylaxis and 24 examined treatment, accounting for 37 distinct assessments. Among assessments associated with a financial conflict of interest, 7 of 8 (88%) were classified as favorable, compared with 5 of 29 (17%) among those without a financial conflict of interest. Reviewers without financial conflicts of interest were more likely to include statements about the quality of the primary studies than those with financial conflicts of interest. LIMITATIONS: The heterogeneity in populations and outcomes examined in the reviews precluded analysis of the contribution of selective inclusion of evidence on the discordance of the assessments made in the reviews. Many of the systematic reviews had overlapping authorship. CONCLUSION: Reviewers with financial conflicts of interest may be more likely to present evidence about neuraminidase inhibitors in a favorable manner and recommend the use of these drugs than reviewers without financial conflicts of interest. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council. PMID- 25285541 TI - Physician decision making and trends in the use of cardiac stress testing in the United States: an analysis of repeated cross-sectional data. AB - BACKGROUND: Cardiac stress testing, particularly with imaging, has been the focus of debates about rising health care costs, inappropriate use, and patient safety in the context of radiation exposure. OBJECTIVE: To determine whether U.S. trends in cardiac stress test use may be attributable to population shifts in demographics, risk factors, and provider characteristics and evaluate whether racial/ethnic disparities exist in physician decision making. DESIGN: Analyses of repeated cross-sectional data. SETTING: National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (1993 to 2010). PATIENTS: Adults without coronary heart disease. MEASUREMENTS: Cardiac stress test referrals and inappropriate use. RESULTS: Between 1993 to 1995 and 2008 to 2010, the annual number of U.S. ambulatory visits in which a cardiac stress test was ordered or performed increased from 28 per 10,000 visits to 45 per 10,000 visits. No trend was found toward more frequent testing after adjustment for patient characteristics, risk factors, and provider characteristics (P = 0.134). Cardiac stress tests with imaging comprised a growing portion of all tests, increasing from 59% in 1993 to 1995 to 87% in 2008 to 2010. At least 34.6% were probably inappropriate, with associated annual costs and harms of $501 million and 491 future cases of cancer. Authors found no evidence of a lower likelihood of black patients receiving a cardiac stress test (odds ratio, 0.91 [95% CI, 0.69 to 1.21]) than white patients, although some evidence of disparity in Hispanic patients was found (odds ratio, 0.75 [CI, 0.55 to 1.02]). LIMITATION: Cross sectional design with limited clinical data. CONCLUSION: National growth in cardiac stress test use can largely be explained by population and provider characteristics, but use of imaging cannot. Physician decision making about cardiac stress test use does not seem to contribute to racial/ethnic disparities in cardiovascular disease. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute and the National Center for Advancing Translational Sciences. PMID- 25285543 TI - Sesame Street goes to jail: physicians should follow. PMID- 25285539 TI - Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor sparing antiretroviral regimens for treatment-naive volunteers infected with HIV 1: a randomized, controlled equivalence trial. AB - BACKGROUND: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING: 57 sites in the United States and Puerto Rico. PATIENTS: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION: The trial was open-label, and ritonavir was not provided. CONCLUSION: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases. PMID- 25285544 TI - Thinking outside the box: hospitals promoting employment for formerly incarcerated persons. PMID- 25285545 TI - Improvement interventions are social treatments, not pills. PMID- 25285546 TI - Air hunger. PMID- 25285547 TI - N-of-1 (single-patient) trials for statin-related myalgia. PMID- 25285548 TI - N-of-1 (single-patient) trials for statin-related myalgia. PMID- 25285549 TI - Raising the bar for the U.S. Preventive Services Task Force. PMID- 25285550 TI - Gender differences in time spent on parenting and domestic responsibilities. PMID- 25285551 TI - Gender differences in time spent on parenting and domestic responsibilities. PMID- 25285552 TI - Gender differences in time spent on parenting and domestic responsibilities. PMID- 25285553 TI - Gender differences in time spent on parenting and domestic responsibilities. PMID- 25285554 TI - Gender differences in time spent on parenting and domestic responsibilities. PMID- 25285557 TI - Summaries for patients. Nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1. PMID- 25285558 TI - Summaries for patients. Trends in the use of stress testing to diagnose coronary heart disease. PMID- 25285559 TI - In the clinic. Insomnia. AB - This issue provides a clinical overview of Insomnia focusing on prevention, diagnosis, treatment, practice improvement, and patient information. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://mksap.acponline.org, and other resources referenced in each issue of In the Clinic. PMID- 25285560 TI - Functional roles of 10 Hz alpha-band power modulating engagement and disengagement of cortical networks in a complex visual motion task. AB - Alpha band power, particularly at the 10 Hz frequency, is significantly involved in sensory inhibition, attention modulation, and working memory. However, the interactions between cortical areas and their relationship to the different functional roles of the alpha band oscillations are still poorly understood. Here we examined alpha band power and the cortico-cortical interregional phase synchrony in a psychophysical task involving the detection of an object moving in depth by an observer in forward self-motion. Wavelet filtering at the 10 Hz frequency revealed differences in the profile of cortical activation in the visual processing regions (occipital and parietal lobes) and in the frontoparietal regions. The alpha rhythm driving the visual processing areas was found to be asynchronous with the frontoparietal regions. These findings suggest a decoupling of the 10 Hz frequency into separate functional roles: sensory inhibition in the visual processing regions and spatial attention in the frontoparietal regions. PMID- 25285562 TI - Effect of alkaline pretreatment on delignification of wheat straw. AB - This study was conducted to analyse structural changes through scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) after alkaline pretreatment of wheat straw for optimum steaming period. During the study, 2 mm size of substrate was soaked in 2.5% NaOH for 1 h at room temperature and then autoclaved at 121 degrees C for various steaming time (30, 60, 90 and 120 min). Results revealed that residence time of 90 min at 121 degrees C has strong effect on substrate, achieving a maximum cellulose content of 83%, delignification of 81% and hemicellulose content of 10.5%. Further SEM and FTIR spectroscopy confirmed structural modification caused by alkaline pretreatment in substrate. Maximum saccharification yield of 52.93% was achieved with 0.5% enzyme concentration using 2.5% substrate concentration for 8 h of incubation at 50 degrees C. This result indicates that the above-mentioned pretreatment conditions create accessible areas for enzymatic hydrolysis. PMID- 25285561 TI - Nutrition potential of biogas residues as organic fertilizer regarding the speciation and leachability of inorganic metal elements. AB - Biogas residues (BRs) are prospective organic fertilizer sources for agricultural cultivation. Besides N and P, however, other inorganic metal elements, such as K, Fe, Cu, Zn and so on, also affect the nutritional level of BRs significantly. In this study, a sequential extraction procedure (SEP) combined with a toxicity characteristic leaching procedure (TCLP) was conducted to investigate the speciation and leachability of metal components in BRs. The results showed that element K was the most effective nutrient component due to its largest available fraction and highest mobility factor (MF) of 78.4, whereas phytotoxic Al was the most stable and inert element in terms of its 96.68% residual fraction. Ca and Mg could be viewed as potential nutrient sources because their MFs exceeded 60. TCLP results revealed that these BRs could be classed as non-toxic organic waste but Cu and Zn should be paid more attention in that their total contents were beyond the permissible values. Meanwhile, more concerns should be given to Ni and Pb due to their large TCLP extractable fraction. In conclusion, these BRs can be used as a prospective nutrient pool for agricultural cultivation. SEP combined with TCLP can be effectively applied for assessing the nutrient level of the BRs as organic fertilizer for agricultural use. PMID- 25285564 TI - Trial participation disclosure and gel use behavior in the CAPRISA 004 tenofovir gel trial. AB - Disclosure, or open communication, by female microbicide trial participants of their trial participation and use of an investigational HIV prevention drug to a sexual partner may affect participants' trial product usage behavior and contribute to poor adherence. With mixed results from recent microbicide clinical trials being linked to differing participant adherence, insights into the communication dynamics between trial participants and their sexual partners are particularly important. We examined the quantitative association between (1) communication of trial participation to a partner and participant adherence to gel and (2) communication of trial participation to a partner and participant HIV status. An in-depth adherence and product acceptability assessment was administered to the women participating in the CAPRISA 004 trial. Additionally, we collected qualitative data related to communication of trial participation and gel use. Qualitatively, among 165 women who had reported that they had discussed trial participation with others, most (68%) stated that they communicated participation to their sexual partner. Most of the women who had communicated study participation with their partners had received a positive/neutral response from their partner. Some of these women stated that gel use was easy; only a small number said that gel use was difficult. Among women who did not communicate their study participation to their partners, difficulty with gel use was more common and some women stated that they feared communicating their participation. Quantitatively, there was no statistically significant difference in the proportions of women who had communicated study participation to a partner across different adherence levels or HIV status. A deeper knowledge of the dynamics surrounding trial participation communication to male partners will be critical to understanding the spectrum of trial product usage behavior, and ultimately to designing tailored strategies to assist trial participants with product adherence. PMID- 25285568 TI - Association of cataract with chronic rhinosinusitis: a population-based case control study. AB - PURPOSE: To assess the association between cataract and chronic rhinosinusitis (CRS) using a population-based database. METHODS: The study sample for this case control study was retrieved from Taiwan's Longitudinal Health Insurance Database 2000. The study included 3045 patients who had undergone cataract surgery as cases and 9135 subjects without cataract as controls. Conditional logistic regression was performed to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) of having a prior diagnosis of CRS in cases versus controls. RESULTS: In the total study sample, the prevalence of prior CRS was 3.88%; 5.16% among cases and 3.45% among controls (p < 0.001). Conditional logistic regression suggested that the unadjusted OR for prior CRS among cases was 1.52 (95% CI 1.25-1.85, p < 0.001) compared to controls. After adjusting for monthly income, residential urbanization and geographic region, the OR for prior CRS among cases was 1.58 (95% CI 1.30-1.94, p < 0.001) compared to controls. Furthermore, the results consistently suggested that cases had higher adjusted ORs for prior CRS than controls across all age groups (40-59, 60-69, and >69 years). It is particularly noteworthy that younger groups demonstrated higher ORs for prior CRS among cases compared to controls. In particular, the adjusted OR for cases aged 40-50 years was 1.71 (95% CI 1.09~2.66; p < 0.05) compared to controls. CONCLUSION: While the true relationship between CRS and cataract remains to be further investigated, the result of this present study demonstrated CRS may be associated with cataract. PMID- 25285569 TI - Polymorphisms of DNA repair genes XPD (Lys751Gln) and XRCC1 (Arg399Gln), and the risk of age-related cataract: a meta-analysis. AB - PURPOSE: A meta-analysis of available studies was used to test the association between two DNA repair genes and age-related cataract. MATERIALS AND METHODS: A systematic search of the Chinese National Knowledge Infrastructure, EMBASE and PubMed databases identified six studies that were analyzed. Meta-analysis was used to evaluate single nucleotide polymorphisms (SNP) of the DNA repair gene xeroderma pigmentosum complementation group D (XPD) (Lys751Gln) and the X-ray repair cross-complementing gene 1 (XRCC1) (Arg399Gln). Only articles published before June 6, 2014, were included. The quality of the studies was determined using Newcastle-Ottawa Scale tools. The summary odds ratio (OR) and corresponding confidence interval (CI) for XPD Lys751Gln and XRCC1 Arg399Gln polymorphisms and risk of age-related cataract were estimated by random and fixed-effects models. Sensitivity analysis was employed to determine the robustness of the conclusions. RESULTS: Six studies, with a total of 1518 patients with cataractous lenses and 1437 subjects with clear lenses, were included in the meta-analysis. XRCC1 Arg399Gln polymorphisms were associated with cataract risk (recessive model: ORfixed = 0.79, 95% CI: 0.67-0.93; dominant model: ORfixed = 0.84, 95% CI: 0.64 1.11; additive model: ORfixed = 0.82, 95% CI: 0.72-0.92). Analysis of Chinese, but not non-Chinese subgroups, confirmed this association. The OR of XPD Lys751Gln polymorphisms for cataract was not significant. The associations remained significant after sensitivity analysis. CONCLUSIONS: This meta-analysis indicates that XRCC1 Arg399Gln polymorphisms, but not XPD Lys751Gln polymorphisms, are associated with risk of age-related cataract. PMID- 25285570 TI - [Optic neuritis]. AB - Optic neuritis is a frequent neuro-ophthalmological disease in which the diagnosis can be based on just a few symptoms and findings. It is not only important to differentiate from other optic nerve disorders but also to recognise special types of optic neuritis, which is mostly only possible during the course of the disease. This article presents a review of the current state in diagnosis and therapy from the authors' personal point of view. PMID- 25285571 TI - Influence of BHT inclusion on post-thaw attributes of human semen. AB - The aim of this study was to determine the effect of butylated hydroxytoluene (BHT) supplemented cryopreservation medium on sperm parameters during the freeze thaw process. In addition, sperm lipid peroxidation, DNA damage, and the amount of reactive oxygen species (ROS) were determined. Semen samples were obtained from 75 donors. Fifteen semen samples were used for optimizing BHT concentration and incubation time and 60 samples were used for the final experiments. After the determination of basic parameters, groups of three sample with similar parameters were pooled and processed by Pure Sperm gradient centrifugation. The semen samples were then diluted with normal freezing medium (control) or a medium containing 0.5 mM BHT (test) for 5 minute and stored in liquid nitrogen. Frozen cryovials were thawed individually for 20 seconds in a water bath (37 degrees C) for evaluation. Freezing extenders supplemented with 0.5 mM BHT led to higher sperm motility and viability compared with control samples (p < 0.001). Furthermore, the addition of BHT decreased malondialdehyde (MDA) formation, DNA fragmentation, and ROS content compared with controls (p < 0.001). Our results showed that the addition of BHT to the freezing medium could be of advantage in reducing ROS and preventing the detrimental effect of ROS on the human sperm function. PMID- 25285573 TI - Nanofibrillar chitin aerogels as renewable base catalysts. AB - We demonstrate the fabrication of chitin nanofibril aerogels and their successful application as base catalysts for the production of useful chemicals. Squid-pen chitin nanofibrils (ChNF) with primary C2-amine groups on their crystalline surfaces were fabricated into highly porous aerogels with high specific surface areas up to 289 m(2) g(-1) using freeze-drying or a supercritical drying process. The prepared ChNF aerogel was used in the aqueous Knoevenagel-condensation reaction and acted as a highly efficient base catalyst, suggesting that the combination of the nanofibrous aerogel structure and primary C2-amines exposed on the crystalline ChNF surface was effective for continuous flow catalysis. Because the ChNF aerogel can be easily prepared from abundant and renewable chitin present in nature, this strategy is a gateway to promoting and conducting green and sustainable chemistry. PMID- 25285572 TI - The effect of protease inhibitors on the cervical mucus of HIV-positive women taking norethindrone contraception. AB - OBJECTIVE: To compare cervical mucus score (CMS) with and without protease inhibitors (PI) before and after taking norethindrone (NET). STUDY DESIGN: This two-arm, researcher blinded, non-randomised, prospective study was conducted to evaluate cervical mucus quality in HIV-positive women taking progestin only pills. The study group was taking a PI, and compared to women taking ARV regimens that have demonstrated no significant interaction with NET in prior pharmacokinetic trials with combined oral contraceptives. The women had a cervical mucus score prior to NET administration. Mucus Scoring was repeated after 21 days of steady state exposure to oral NET 0.35 milligrams. Cervical mucus quality was quantified according to the World Health Organisation criteria, which include: volume, consistency, cellularity, spinnbarkeit, and ferning. RESULTS: Sixteen women took PI and 17 were controls. Baseline CMS were similar (p >= 0.1). After 21 days CMS were similar among the two groups (p = 1). CONCLUSIONS: HIV-positive women taking PI demonstrated thickened cervical mucus with oral norethindrone 0.35 mg and are similar to HIV-positive women taking no PI therapy. This may suggest no difference in contraceptive efficacy of progestin only pills in HIV-positive women taking PI. PMID- 25285574 TI - A semiempirical model for adsorption of binary mixtures. AB - The statistical thermodynamics of polyatomic species mixtures adsorbed on two dimensional lattices was developed based on generalization of the semiempirical approximation for the adsorption of single components [Roma, F. et al., Langmuir, 2006, 22, 3192-3197]. In this scheme, the partial adsorption isotherms are obtained using a correction function C[combining tilde], which relates to the conditional probability of finding the ith empty site to a lattice with i- 1 already vacant sites. This approximation allows us to write a new theoretical model using a combination of the correction functions corresponding to exact 1-D calculations and the Guggenheim-DiMarzio approach. Finally, comparisons with MC simulations and experimental data of methane-ethane and ethane-propylene mixtures on activated carbon are used to test the accuracy and reliability of the proposed model. The obtained results indicate that the new thermodynamic description is significantly better than the existing theoretical models developed to treat adsorption of interacting binary mixtures of polyatomics. PMID- 25285576 TI - One pot and selective intermolecular aryl- and heteroaryl-trifluoromethylation of alkenes by photoredox catalysis. AB - We report herein the first photoredox-catalyzed intermolecular aryl- and heteroaryltrifluoromethylation of alkenes. Under the optimized conditions using Umemoto's reagent as a CF3 source, a wide range of styrenes can be readily difunctionalized, affording the corresponding trifluoromethylated adducts in up to 99% yield. PMID- 25285577 TI - The effect of self-sorting and co-assembly on the mechanical properties of low molecular weight hydrogels. AB - Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties. PMID- 25285575 TI - Protein backbone engineering as a strategy to advance foldamers toward the frontier of protein-like tertiary structure. AB - A variety of non-biological structural motifs have been incorporated into the backbone of natural protein sequences. In parallel work, diverse unnatural oligomers of de novo design (termed "foldamers") have been developed that fold in defined ways. In this Perspective article, we survey foundational studies on protein backbone engineering, with a focus on alterations made in the context of complex tertiary folds. We go on to summarize recent work illustrating the potential promise of these methods to provide a general framework for the construction of foldamer mimics of protein tertiary structures. PMID- 25285578 TI - Chemical reaction dynamics II and correlated systems, surfaces and catalysis: general discussion. PMID- 25285579 TI - Homoleptic organocobalt(III) compounds with intermediate spin. AB - Homoleptic organocobalt(III) compounds with formula [NBu4][Co(III)(C6X5)4] [X = F (3), Cl (4)] were obtained in reasonable yields by chemical oxidation of the corresponding divalent species [NBu4]2[Co(II)(C6X5)4] [X = F (1), Cl (2)]. The [Co(III)(C6X5)4](-)/[Co(II)(C6X5)4](2-) couples are electrochemically related by quasi-reversible, one-electron exchange processes at moderate potential: E1/2 = 0.29 (X = F) and -0.36 V (X = Cl) versus saturated calomel electrode. The [Co(III)(C6X5)4](-) anions in salts 3 and 4 show an unusual square-planar geometry as established by single-crystal X-ray diffraction methods. According to their stereochemistry, these Co(III) derivatives (d(6)) are paramagnetic non Kramers systems with a large zero-field splitting contribution and no observable electron paramagnetic resonance (EPR) spectrum. The thermal dependence of their magnetic susceptibilities can be explained in terms of a spin-Hamiltonian formalism with S = 1 ground state (intermediate spin) and substantial spin-orbit contribution. The magnetic properties of the square-planar d(7) parent species [NBu4]2[Co(II)(C6X5)4] were also thoroughly studied both at microscopic (EPR) and macroscopic levels (alternating current and direct current magnetization measurements). They behave as S = 1/2 (low spin) systems with mainly (dz(2))(1) electron configuration and a certain degree of s-orbital admixture that has been quantified. The electronic structures of all four open-shell [Co(C6X5)4](q-) compounds (q = 1, 2) accounting for their respective magnetic properties are based on a common orbital energy-level diagram. PMID- 25285580 TI - Advances in treating HER2-positive breast cancer: an interview with Sunil Verma. AB - In this podcast, we talk to Dr Sunil Verma about the evolution of HER2 as a therapeutic target in breast cancer, and about how targeted therapy has revolutionized breast cancer treatment. We also discuss new agents in clinical development and the ways in which advances in treating HER2-positive breast cancer can be used to inform treatment decisions in other areas of medicine. PMID- 25285582 TI - Degradation of chlorophenols by supported Co-Mg-Al layered double hydrotalcite with bicarbonate activated hydrogen peroxide. AB - Toxic and bioresistant compounds have attracted researchers to develop more efficient and cost-effective technologies for degradation of organic compounds in wastewater. This work demonstrates the degradation of 4-chlorophenol, 2,4 dichlorophenol, 2,4,6-trichlorophenol, and phenol as model compounds using bicarbonate-activated H2O2 oxidation system in the presence of supported catalysts. The catalytic activity of the catalyst was investigated in term of degradation of target compounds, chemical oxygen demand (COD), and total organic carbon (TOC) removals both for batch mode and in fixed bed reactor using CoMgAl HTs and CoMgAl-SHTs, respectively. The leaching of cobalt ion was efficiently prohibited because of the presence of a weakly basic medium provided by bicarbonate, and the CoMgAl-SHTs catalyst was found to retain its stability and good catalytic activity in fixed bed reactor for over 300 h. Extensive chemical probing, fluorescence, and electron paired resonance (EPR) studies were conducted to identify the actual reactive species in the degradation pathway, which revealed that the reaction proceeds through generation of superoxide, hydroxyl radical along with carbonate radical. PMID- 25285581 TI - Ubiquitinated proteins in exosomes secreted by myeloid-derived suppressor cells. AB - We provide evidence at the molecular level that ubiquitinated proteins are present in exosomes shed by myeloid-derived suppressor cells (MDSC). Ubiquitin was selected as a post-translational modification of interest because it is known to play a determinant role in the endosomal trafficking that culminates in exosome release. Enrichment was achieved by two immunoprecipitations, first at the protein level and subsequently at the peptide level. Fifty ubiquitinated proteins were identified by tandem mass spectrometry filtering at a 5% spectral false discovery rate and using the conservative requirement that glycinylglycine modified lysine residues were observed in tryptic peptides. Thirty five of these proteins have not previously been reported to be ubiquitinated. The ubiquitinated cohort spans a range of protein sizes and favors basic pI values and hydrophobicity. Five proteins associated with endosomal trafficking were identified as ubiquitinated, along with pro-inflammatory high mobility group protein B1 and proinflammatory histones. PMID- 25285583 TI - Mechanistic study of laser desorption/ionization of small molecules on graphene oxide multilayer films. AB - Graphene and graphene oxide (GO) films have been explored to develop an efficient laser desorption/ionization mass spectrometry (LDI-MS) platform for the analysis of chemically and biologically important small molecules. The GO films were prepared by layer-by-layer (LBL) assembly cycles (one to ten layers) with precisely controlled thickness and surface roughness which are important structural factors for laser energy absorption capacity and laser energy transfer for efficient LDI-MS analysis. Amino acids, saccharides, and pyrenylated molecules were analyzed by LDI-MS on the LBL assembled GO films to reveal their structural influence on LDI-MS analysis of small molecules. Then, the structural influence of LBL assembled GO films on synergistic effect was investigated to develop an efficient and widely applicable LDI-MS analysis platform with an additional multiwalled carbon nanotube (MWCNT) layer. We found that the optimum number of GO film layers for LDI-MS analysis was dependent on the chemical structures of small molecules, and the laser energy threshold needed for LDI of small molecules on GO/MWCNT films could be lowered as the number of LBL assembled GO films increased underneath the MWCNT layer. PMID- 25285584 TI - Cardiovascular magnetic resonance characterization of left ventricular non compaction provides independent prognostic information in patients with incident heart failure or suspected cardiomyopathy. AB - BACKGROUND: With recent advances in imaging methods, detection of LVNC is increasingly common. Concomitantly, the prognostic importance of LVNC is less clear. METHODS: We followed 42 patients (63% male, age 44 +/- 15 years) with incident heart failure or suspected cardiomyopathy, in whom cardiovascular magnetic resonance (CMR) yielded a diagnosis of LVNC, for 27 +/- 16 months. RESULTS: LVNC was preferentially distributed among posterolateral segments, with apical predominance. Patients with maximum non-compacted-to-compacted thickness ratio (NC:C) < 3 improved by 0.9 +/- 0.7 NYHA Class, compared to 0.3 +/- 0.8 for patients with NC:C > 3 (p = 0.001). In 29 patients with baseline LVEF < 0.40, there was an inverse correlation between NC:C ratio, and the change in LVEF during follow-up. Tachyarrhythmias were observed in 42% of patients with LGE, and in 0% of patients without LGE (p = 0.02). In multivariate analysis, arrhythmia incidence was significantly higher in patients with LGE, even when adjusted for LVEF and RVEF. CONCLUSIONS: CMR assessments of myocardial morphology provide important prognostic information for patients with LVNC who present with incident heart failure or suspected cardiomyopathy. PMID- 25285585 TI - Solution-processable LaZrOx/SiO2 gate dielectric at low temperature of 180 degrees C for high-performance metal oxide field-effect transistors. AB - Although solution-processable high-k inorganic dielectrics have been implemented as a gate insulator for high-performance, low-cost transition metal oxide field effect transistors (FETs), the high-temperature annealing (>300 degrees C) required to achieve acceptable insulating properties still limits the facile realization of flexible electronics. This study reports that the addition of a 2 dimetylamino-1-propanol (DMAPO) catalyst to a perhydropolysilazane (PHPS) solution enables a significant reduction of the curing temperature for the resulting SiO2 dielectrics to as low as 180 degrees C. The hydrolysis and condensation of the as-spun PHPS film under humidity conditions were enhanced greatly by the presence of DMAPO, even at extremely low curing temperatures, which allowed a smooth surface (roughness of 0.31 nm) and acceptable leakage characteristics (1.8 * 10(-6) A/cm(2) at an electric field of 1MV/cm) of the resulting SiO2 dielectric films. Although the resulting indium zinc oxide (IZO) FETs exhibited an apparent high mobility of 261.6 cm(2)/(V s), they suffered from a low on/off current (ION/OFF) ratio and large hysteresis due to the hygroscopic property of silazane-derived SiO2 film. The ION/OFF value and hysteresis instability of IZO FETs was improved by capping the high-k LaZrOx dielectric on a solution-processed SiO2 film via sol-gel processing at a low temperature of 180 degrees C while maintaining a high mobility of 24.8 cm(2)/(V s). This superior performance of the IZO FETs with a spin-coated LaZrOx/SiO2 bilayer gate insulator can be attributed to the efficient intercalation of the 5s orbital of In(3+) ion in the IZO channel, the good interface matching of IZO/LaZrOx and the carrier blocking ability of PHPS-derived SiO2 dielectric film. Therefore, the solution processable LaZrOx/SiO2 stack can be a promising candidate as a gate dielectric for low-temperature, high-performance, and low-cost flexible metal oxide FETs. PMID- 25285586 TI - Recurrence of granular corneal dystrophy type I deposits within host stroma after non-descemet baring anterior lamellar keratoplasty. AB - PURPOSE: The aim of this study was to describe a case of recurrent granular deposits after non-Descemet baring anterior lamellar keratoplasty (nDALK). METHODS: A 28-year-old male with granular corneal dystrophy type I, found to have deposits throughout the anterior and midstroma, underwent nDALK. Three years later, he had a recurrence of the deposits. Slit-lamp photographs and optical coherence tomography were used to document the level of recurrence. Full thickness penetrating keratoplasty was performed, and the residual host stroma was sent for pathology. RESULTS: Slit-lamp photographs and anterior segment optical coherence tomography confirmed that the recurrent hyaline deposits were confined to the residual host stroma just anterior to Descemet membrane. The anterior lamellar graft and epithelium remained clear. Pathology showed positive staining with Masson trichrome in the host stroma just anterior to Descemet membrane. CONCLUSIONS: Previous studies suggest that the recurrence of granular deposits after keratoplasty is usually anterior and may even be epithelial in origin. This case report documents the recurrence of granular dystrophy entirely within the residual host stroma after nDALK. These findings suggest that residual keratocytes may still be a source of recurrence. PMID- 25285587 TI - In vivo imaging of coin-shaped lesions in cytomegalovirus corneal endotheliitis by anterior segment optical coherence tomography. AB - PURPOSE: The aim of this study was to investigate in vivo corneal changes of coin shaped lesions in cytomegalovirus corneal endotheliitis using anterior segment optical coherence tomography (AS-OCT). METHODS: Two eyes of 2 patients (69- and 71-year-old men), with polymerase chain reaction-proven CMV corneal endotheliitis presenting coin-shaped lesions, were included in this study. AS-OCT examination was performed on the initial visit and at follow-up visits by paying special attention to the coin-shaped lesions. Selected AS-OCT images of the cornea were evaluated qualitatively for changes in the shape and degree of light reflection. RESULTS: In both cases, coin-shaped lesions were observed at the corneal endothelial surface as clusters of fine precipitates using slit-lamp biomicroscopy. Using AS-OCT, high-resolution images of the putative coin-shaped lesions were successfully obtained in both patients as an irregularly thickened highly reflective endothelial cell layer. After anti-CMV treatment, the coin shaped lesions were resolved as assessed by slit-lamp biomicroscopy and AS-OCT in both patients. CONCLUSIONS: High-resolution AS-OCT provides novel and detailed visual information of coin-shaped lesions in patients with CMV corneal endotheliitis. Visualization of coin-shaped lesions by AS-OCT may be a useful adjunct to the diagnosis and follow-up of CMV corneal endotheliitis. PMID- 25285588 TI - Medium-term outcomes of boston type 1 keratoprosthesis implantation in Bangkok, Thailand. AB - PURPOSE: The aim of this study was to investigate the medium-term outcomes after Boston type 1 keratoprosthesis surgery in patients with poor prognosis for standard keratoplasty. METHODS: A prospective study of a case series was conducted at a university-based referral center from 2006 to 2013. Forty-two eyes of 40 patients with a minimum follow-up of 4 years were recruited. The main outcome measures included best spectacle-corrected visual acuity (BSCVA), keratoprosthesis retention, and complications. RESULTS: The mean follow-up was 64.9 +/- 15.2 months (range, 48-88 months). At 1 week, 90.5% had an improvement in BSCVA by >=2 lines compared with that in preoperative BSCVA. The best-ever vision was reached by the end of 6 months. Nevertheless, 39.5% (15/38) could not maintain the improved vision. The major etiology of visual deterioration after initial gains was glaucoma (60%). The initial keratoprosthesis retention rate was 80.9%, corresponding to a failure rate of 4 per 100 eye-years or 0.04/eye-year. Autoimmune diagnosis was the independent risk factor for keratoprosthesis failure (hazard ratio, 5.68; 95% confidence interval, 1.41-22.85; P = 0.014). The common postoperative complications were glaucoma, retroprosthetic membrane, corneal melting, infectious keratitis, and endophthalmitis. CONCLUSIONS: Boston type 1 keratoprosthesis is an alternative for patients who are not candidates for corneal transplants. However, there was a trend toward visual loss over time most commonly because of progressive glaucoma. Therefore, appropriate patient selection, lifelong follow-up, and early aggressive treatment of complications are recommended. PMID- 25285589 TI - Corneal densitometry in keratoconus. AB - PURPOSE: The aim of this study was to compare corneal densitometry measured by Scheimpflug tomography in normal and keratoconic eyes and to assess the differences in densitometry values among the stages of keratoconus. METHODS: Keratoconic and normal corneas were examined using the Pentacam. Corneal densitometry was measured over a 12-mm diameter area, divided by annular concentric zones and depths. Keratoconus was classified according to the topographic keratoconus classification. RESULTS: We enrolled 1 eye randomly selected from each of 172 patients with normal corneas (N) and 98 patients with bilateral keratoconus (KC). There were significant differences between the groups for densitometry measurements in 2 annuli: central 2.0 mm in diameter (N = 16.85 +/- 2.42, KC = 18.93 +/- 2.78, P = 0.0001) and annulus 2.0 to 6.0 mm in diameter (N = 15.18 +/- 2.18, KC = 16.16 +/- 1.71, P = 0.005), and total diameter (N = 24.89 +/- 6.18, KC = 16.71 +/- 2.3, P = 0.033). Divided by layers, the inner parts of anterior (120 MUm), central (from 120 MUm to the last 60 MUm), and posterior (last 60 MUm) layers were also higher in the KC group (P < 0.001). There were differences according to the stages of KC for corneal densitometry of the central annuli at total thickness, anterior and central layers. More advanced cases presented a higher backscatter (P < 0.05). The anterior layer presented the smallest overlap between groups and KC stages. CONCLUSIONS: The densitometry map reveals that light backscatter was higher in the central portion of the anterior keratoconic cornea than in the normal cornea. The densitometry level is higher in more advanced stages. PMID- 25285592 TI - Reference values for hematology and plasma biochemistry variables, and protein electrophoresis of healthy Hermann's tortoises (Testudo hermanni ssp.). AB - BACKGROUND: Hermann's tortoise, Testudo hermanni, is currently on the International Union for Conservation of Nature (IUCN) red list of endangered species. Reptile medicine relies also on laboratory analyses to evaluate health status, but reference ranges for hematology and biochemistry variables and protein electrophoresis in plasma of healthy tortoises are not available. OBJECTIVE: The purposes of this study were to establish reference ranges for select hematologic and biochemical variables in clinically healthy Hermann's tortoises, and evaluate the impact of sex and season. METHODS: Blood samples were collected from 34 healthy tortoises at the end of September and beginning of July. Blood smears, HCT, concentrations of HGB and select plasma biochemical analytes, select enzyme activities, and plasma protein fractions were evaluated. Reference ranges were determined and checked for influence of sex and sampling time point. RESULTS: Typical reptilian RBC and WBC were observed in blood smears. HCT and concentrations of HGB, uric acid and urea, and ALT and AST activities were significantly higher in males than in females. Concentrations of glucose, uric acid, and phosphate, and AST activity were significantly higher at the beginning of July, whereas concentrations of urea and Cl were higher at the end of September prior to hibernation. The electrophoretic protein fractions included albumin, and alpha, beta, and gamma globulins. CONCLUSIONS: The reference ranges defined in the present study are useful for clinical tortoise medicine and conservation. Sex and seasonal sampling were identified as factors significantly affecting hematology and blood chemistry analytes; they should be taken into consideration when assessing tortoise health status. PMID- 25285593 TI - Induced systemic resistance responses in perennial ryegrass against Magnaporthe oryzae elicited by semi-purified surfactin lipopeptides and live cells of Bacillus amyloliquefaciens. AB - The suppressive ability of several strains of cyclic lipopeptide-producing Bacillus rhizobacteria to grey leaf spot disease caused by Magnaporthe oryzae has been documented previously; however, the underlying mechanism(s) involved in the induced systemic resistance (ISR) activity in perennial ryegrass (Lolium perenne L.) remains unknown. Root-drench application of solid-phase extraction (SPE) enriched surfactin and live cells of mutant Bacillus amyloliquefaciens strain FZB42-AK3 (produces surfactin, but not bacillomycin D and fengycin) significantly reduced disease incidence and severity on perennial ryegrass. The application of the treatments revealed a pronounced multilayered ISR defence response activation via timely and enhanced accumulation of hydrogen peroxide (H2O2), elevated cell wall/apoplastic peroxidase activity, and deposition of callose and phenolic/polyphenolic compounds underneath the fungal appressoria in naive leaves, which was significantly more intense in treated plants than in mock treated controls. Moreover, a hypersensitive response (HR)-type reaction and enhanced expression of LpPrx (Prx, peroxidase), LpOXO4 (OXO, oxalate oxidase), LpPAL (PAL, phenylalanine ammonia lyase), LpLOXa (LOX, lipoxygenase), LpTHb (putative defensin) and LpDEFa (DEFa, putative defensin) in perennial ryegrass were associated with SPE-enriched surfactin and live AK3 cell treatments, acting as a second layer of defence when pre-invasive defence responses failed. The results indicate that ISR activity following surfactin perception may sensitize H2O2 -mediated defence responses, thereby providing perennial ryegrass with enhanced protection against M. oryzae. PMID- 25285594 TI - The effect of a creative art program on self-esteem, hope, perceived social support, and self-efficacy in individuals with multiple sclerosis: a pilot study. AB - BACKGROUND: Creative art has been found to be beneficial to some patients with chronic illness. Little is understood about how creative art can benefit individuals living with multiple sclerosis (MS). OBJECTIVES: The purpose of the pilot study was to determine if there was a difference in self-esteem, hope, perceived social support, and self-efficacy in individuals with MS after a 4-week creative art program. METHODS: A one-group, pretest/posttest design was used. The convenience sample of 14 individuals was recruited from MS Centers and the National MS Society. They ranged in age from 29 to 70 years (M = 51.3 years, SD = 12.5 years). Participants included 14 women. The creative art program included week 1-watercolor, week 2-collage making, week 3-beading, and week 4-knitting. Each of the four weekly sessions was facilitated by a registered nurse with expertise in MS and lasted 2 hours. Creative artists instructed participants and provided a hands-on experience for each of the creative projects. Participants were free to share thoughts, experiences, and words of support and encouragement during each session. The variables were measured before starting the creative art program and after the final session. The instruments included the Rosenberg Self Esteem Scale, the Herth Hope Index, the Modified Social Support Survey, the MS Self-Efficacy Scale, and a sociodemographic questionnaire. The Statistical Package for the Social Sciences Version 16.0 was used to analyze the data. RESULTS: There was a significant increase in all variables after the creative art program as follows: self-esteem (t = -3.05, p = 009), hope (t = -3.96, p = .002), social support (t = -2.21, p = .046), self-efficacy to function with MS (t = 2.68, p = .019), and self-efficacy to control MS (t = 3.22, p = .007). The power analysis revealed a large effect size for hope (d = 1.06), self-esteem (d = 0.82), and self-efficacy (control; d = 0.86). A medium effect size was found for self-efficacy (function; d = 0.72) and social support (d = 0.59). CONCLUSIONS: The creative art program was found to be effective and had a positive influence on self-esteem, hope, social support, and self-efficacy to function and control MS. Creative art has the potential to enhance the lives of those living with MS and should be investigated with a larger sample of participants. PMID- 25285596 TI - The effect of oral care on intracranial pressure in critically ill adults. AB - A major goal in the care of patients with neurological problems is to prevent or minimize episodes of increased intracranial pressure (ICP). Elevations in ICP in response to nursing interventions have been acknowledged since the 1960s when ICP monitoring was first introduced in the clinical setting. Until recently, few studies have specifically examined the effect of oral care on ICP, and oral care and other hygiene measures were combined or not specified, prohibiting a direct interpretation of the influence of oral care alone on ICP. The purpose of this study was to describe the relationship between routine oral care interventions and the changes in ICP specifically focusing on the effect of intensity and duration of this intervention. Twenty-three patients with a clinical condition requiring ICP monitoring were enrolled over a 12-month period. Oral care provided by neuroscience intensive care nurses was observed and videotaped. Characteristics of the intervention were documented including products used, patient positioning, and duration of the intervention. A 1-5 subjective scale was used to score intensity of oral care. Wrist actigraphy data were collected from the nurses to provide an objective measure of intensity. Patient physiologic data were collected at 12-second epochs 5 minutes before, during, and 5 minutes after oral care. The mixed-effect repeated measures analysis of variance model indicated that there was a statistically significant increase in ICP in response to oral care (p = .0031). There was, however, no clinically significant effect on ICP. This study provides evidence that oral care is safe to perform in patients in the absence of preexisting elevated ICP. PMID- 25285595 TI - Acceptance of the extracare program by Beta interferon-treated patients with multiple sclerosis: results of the explore study. AB - BACKGROUND: To gain full benefit from disease-modifying therapies such as interferon beta-1b, patients with multiple sclerosis (MS) need to adhere to treatment in the long term. Treatment adherence requires high patient satisfaction with treatment and care. OBJECTIVES: Our aim was to evaluate the satisfaction of patients with MS receiving interferon beta-1b Extavia with the patient care program Extracare. Efficacy and safety of treatment were evaluated as secondary objectives. METHODS: In this prospective, noninterventional 1-year study, data on the satisfaction of 174 patients with MS with Extracare were obtained by questionnaires. Disability and symptom severity as well as patients' reported activity limitations, quality of life, and fatigue were recorded. RESULTS: We observed high levels of patients' satisfaction with MS nurses, telephonic care, and information provided by Extracare (values <= 1.53 on a Likert scale ranging from 1 [very good] to 6 [insufficient]). Patient reported quality of life (Patient Reported Indices for MS QoL) improved from 11.82 +/- 11.36 at baseline to 9.74 +/- 10.94 at the end of the study (p = .02), whereas clinical parameters of disease progression remained unchanged. Rate of adverse events was as expected. CONCLUSIONS: This study provides the basis for further improvements of care programs to increase treatment adherence of patients with MS. PMID- 25285597 TI - In vivo and in vitro rearing of entomopathogenic nematodes (Steinernematidae and Heterorhabditidae). AB - Entomopathogenic nematodes (EPN) (Steinernematidae and Heterorhabditidae) have a mutualistic partnership with Gram-negative Gamma-Proteobacteria in the family Enterobacteriaceae. Xenorhabdus bacteria are associated with steinernematids nematodes while Photorhabdus are symbionts of heterorhabditids. Together nematodes and bacteria form a potent insecticidal complex that kills a wide range of insect species in an intimate and specific partnership. Herein, we demonstrate in vivo and in vitro techniques commonly used in the rearing of these nematodes under laboratory conditions. Furthermore, these techniques represent key steps for the successful establishment of EPN cultures and also form the basis for other bioassays that utilize these organisms for research. The production of aposymbiotic (symbiont-free) nematodes is often critical for an in-depth and multifaceted approach to the study of symbiosis. This protocol does not require the addition of antibiotics and can be accomplished in a short amount of time with standard laboratory equipment. Nematodes produced in this manner are relatively robust, although their survivorship in storage may vary depending on the species used. The techniques detailed in this presentation correspond to those described by various authors and refined by P. Stock's Laboratory, University of Arizona (Tucson, AZ, USA). These techniques are distinct from the body of techniques that are used in the mass production of these organisms for pest management purposes. PMID- 25285598 TI - Wound piercing: a novel approach for deep cutaneous ulcer cleansing. AB - AIM: To achieve healing of cutaneous deep and complicated ulcers, along with adequate ulcer debridement and microbespecific antibiotics, any fluid and/or exudate stasis should be avoided. METHODS: We have designed a surgical procedure of ulcer piercing and drainage with silastic tube which allows a continuous or daily cleansing of any pierced hidden tract by positive pressure irrigation. This procedure has been utilize in a series of 11 patients with deep infected recess of a sacral pressure ulcer (n=5), of 2 posttraumatic leg ulcers (n=2), of a deep perianal fistula (n=1) and dehiscence of a laparatomic surgical wound (n=3). RESULTS: In these patients deep ulcer recess completely recovered within 2, 3.5, 1.5 and 2.5 months with ulcer piercing procedure. CONCLUSION: Therefore, taking into consideration the advantages and the lack of advers, side effects or contraindications, the ulcer piercing procedure represents a small but effective step toward a better, safer and conservative approach in the treatment of deep complicated cutaneous ulcers. PMID- 25285599 TI - The use of interval ratios in consonance perception by rats (Rattus norvegicus) and humans (Homo sapiens). AB - Traditionally, physical features in musical chords have been proposed to be at the root of consonance perception. Alternatively, recent studies suggest that different types of experience modulate some perceptual foundations for musical sounds. The present study tested whether the mechanisms involved in the perception of consonance are present in an animal with no extensive experience with harmonic stimuli and a relatively limited vocal repertoire. In Experiment 1, rats were trained to discriminate consonant from dissonant chords and tested to explore whether they could generalize such discrimination to novel chords. In Experiment 2, we tested if rats could discriminate between chords differing only in their interval ratios and generalize them to different octaves. To contrast the observed pattern of results, human adults were tested with the same stimuli in Experiment 3. Rats successfully discriminated across chords in both experiments, but they did not generalize to novel items in either Experiment 1 or Experiment 2. On the contrary, humans not only discriminated among both consonance-dissonance categories, and among sets of interval ratios, they also generalized their responses to novel items. These results suggest that experience with harmonic sounds may be required for the construction of categories among stimuli varying in frequency ratios. However, the discriminative capacity observed in rats suggests that at least some components of auditory processing needed to distinguish chords based on their interval ratios are shared across species. PMID- 25285600 TI - Restless genital syndrome in Parkinson disease. AB - IMPORTANCE: Symptoms in the genital region, such as pain, discomfort, tingling, and burning sensations, have rarely been reported in Parkinson disease (PD), and the previous cases were attributed to nonmotor off symptoms. We report a patient with PD and severe genital discomfort unrelated to motor fluctuations but compatible with restless genital syndrome. OBSERVATIONS: A 65-year-old woman with PD experienced a disabling discomfort in her pelvis and genital region for 3 years. The episodes occurred in the evening and were triggered by sitting or lying down for a period. Gynecological investigation was unrevealing. She experienced improvement with a low dose of a dopamine agonist. CONCLUSION AND RELEVANCE: Restless genital syndrome is a rare disorder that can be a source of distress and disability. In patients with PD, restless genital syndrome should be included in the differential diagnosis of genital symptoms and restlessness, along with nonmotor wearing off and akathisia. A detailed clinical history is essential for this diagnosis and treatment with dopamine agonists can provide benefit. PMID- 25285601 TI - Organic nanowire fabrication and device applications. AB - Organic nanowires (ONWs) are flexible, stretchable, and have good electrical properties, and therefore have great potential for use in next-generation textile and wearable electronics. Analysis of trends in ONWs supports their great potential for various stretchable and flexible electronic applications such as flexible displays and flexible photovoltaics. Numerous methods can be used to prepare ONWs, but the practical industrial application of ONWs has not been achieved because of the lack of reliable techniques for controlling and patterning of individual nanowires. Therefore, an "individually controllable" technique to fabricate ONWs is essential for practical device applications. In this paper, three types of fabrication methods of ONWs are reviewed: non alignment methods, massive-alignment methods, and individual-alignment methods. Recent research on electronic and photonic device applications of ONWs is then reviewed. Finally, suggestions for future research are put forward. PMID- 25285603 TI - New synthesis of a Foamlike Fe3O4/C composite via a self-expanding process and its electrochemical performance as anode material for lithium-ion batteries. AB - A novel foamlike Fe3O4/C composite is prepared via a sol-gel type method with gelatin as the carbon source and ferric nitrate as the iron source, following a postannealing treatment. Its lithium storage properties as anode material for a lithium-ion battery are thoroughly investigated in this work. With the interaction between ferric nitrate and gelatin, the foamlike architecture is attained through a unique self-expanding process. The Fe3O4/C composite possesses abundant porous structure along with highly dispersed Fe3O4 nanocrystal embedment in the carbon matrix. In the constructed architecture, the 3D porous network property ensures electrolyte accessibility; meanwhile, nanosized Fe3O4 promotes lithiation/delithiation, owing to numerous active sites, large electrolyte contact area, and a short lithium ion diffusion path. As a result, this Fe3O4/C composite electrode demonstrates an excellent cycling stability with a reversible capacity of 1008 mA h g(-1) over 400 cycles at 0.2C (1C = 1000 mA g(-1)), as well as a superior rate performance with reversible capacity of 660 and 580 mA h g(-1) at 3C and 5C, respectively. PMID- 25285604 TI - Prevention guidelines: bad process, bad outcome. PMID- 25285602 TI - An in vitro adult mouse muscle-nerve preparation for studying the firing properties of muscle afferents. AB - Muscle sensory neurons innervating muscle spindles and Golgi tendon organs encode length and force changes essential to proprioception. Additional afferent fibers monitor other characteristics of the muscle environment, including metabolite buildup, temperature, and nociceptive stimuli. Overall, abnormal activation of sensory neurons can lead to movement disorders or chronic pain syndromes. We describe the isolation of the extensor digitorum longus (EDL) muscle and nerve for in vitro study of stretch-evoked afferent responses in the adult mouse. Sensory activity is recorded from the nerve with a suction electrode and individual afferents can be analyzed using spike sorting software. In vitro preparations allow for well controlled studies on sensory afferents without the potential confounds of anesthesia or altered muscle perfusion. Here we describe a protocol to identify and test the response of muscle spindle afferents to stretch. Importantly, this preparation also supports the study of other subtypes of muscle afferents, response properties following drug application and the incorporation of powerful genetic approaches and disease models in mice. PMID- 25285605 TI - Determination of protein-ligand interactions using differential scanning fluorimetry. AB - A wide range of methods are currently available for determining the dissociation constant between a protein and interacting small molecules. However, most of these require access to specialist equipment, and often require a degree of expertise to effectively establish reliable experiments and analyze data. Differential scanning fluorimetry (DSF) is being increasingly used as a robust method for initial screening of proteins for interacting small molecules, either for identifying physiological partners or for hit discovery. This technique has the advantage that it requires only a PCR machine suitable for quantitative PCR, and so suitable instrumentation is available in most institutions; an excellent range of protocols are already available; and there are strong precedents in the literature for multiple uses of the method. Past work has proposed several means of calculating dissociation constants from DSF data, but these are mathematically demanding. Here, we demonstrate a method for estimating dissociation constants from a moderate amount of DSF experimental data. These data can typically be collected and analyzed within a single day. We demonstrate how different models can be used to fit data collected from simple binding events, and where cooperative binding or independent binding sites are present. Finally, we present an example of data analysis in a case where standard models do not apply. These methods are illustrated with data collected on commercially available control proteins, and two proteins from our research program. Overall, our method provides a straightforward way for researchers to rapidly gain further insight into protein-ligand interactions using DSF. PMID- 25285606 TI - Enrichment for chemoresistant ovarian cancer stem cells from human cell lines. AB - Cancer stem cells (CSCs) are defined as a subset of slow cycling and undifferentiated cells that divide asymmetrically to generate highly proliferative, invasive, and chemoresistant tumor cells. Therefore, CSCs are an attractive population of cells to target therapeutically. CSCs are predicted to contribute to a number of types of malignancies including those in the blood, brain, lung, gastrointestinal tract, prostate, and ovary. Isolating and enriching a tumor cell population for CSCs will enable researchers to study the properties, genetics, and therapeutic response of CSCs. We generated a protocol that reproducibly enriches for ovarian cancer CSCs from ovarian cancer cell lines (SKOV3 and OVCA429). Cell lines are treated with 20 uM cisplatin for 3 days. Surviving cells are isolated and cultured in a serum-free stem cell media containing cytokines and growth factors. We demonstrate an enrichment of these purified CSCs by analyzing the isolated cells for known stem cell markers Oct4, Nanog, and Prom1 (CD133) and cell surface expression of CD177 and CD133. The CSCs exhibit increased chemoresistance. This method for isolation of CSCs is a useful tool for studying the role of CSCs in chemoresistance and tumor relapse. PMID- 25285607 TI - Stabilizing hepatocellular phenotype using optimized synthetic surfaces. AB - Currently, one of the major limitations in cell biology is maintaining differentiated cell phenotype. Biological matrices are commonly used for culturing and maintaining primary and pluripotent stem cell derived hepatocytes. While biological matrices are useful, they permit short term culture of hepatocytes, limiting their widespread application. We have attempted to overcome the limitations using a synthetic polymer coating. Polymers represent one of the broadest classes of biomaterials and possess a wide range of mechanical, physical and chemical properties, which can be fine-tuned for purpose. Importantly, such materials can be scaled to quality assured standards and display batch-to-batch consistency. This is essential if cells are to be expanded for high through-put screening in the pharmaceutical testing industry or for cellular based therapy. Polyurethanes (PUs) are one group of materials that have shown promise in cell culture. Our recent progress in optimizing a polyurethane coated surface, for long-term culture of human hepatocytes displaying stable phenotype, is presented and discussed. PMID- 25285608 TI - Isolating primary melanocyte-like cells from the mouse heart. AB - We identified a novel population of melanocyte-like cells (also known as cardiac melanocytes) in the hearts of mice and humans that contribute to atrial arrhythmia triggers in mice. To investigate the electrical and biological properties of cardiac melanocytes we developed a procedure to isolate them from mouse hearts that we derived from those designed to isolate neonatal murine cardiomyocytes. In order to obtain healthier cardiac melanocytes suitable for more extensive patch clamp or biochemical studies, we developed a refined procedure for isolating and plating cardiac melanocytes based on those originally designed to isolate cutaneous melanocytes. The refined procedure is demonstrated in this review and produces larger numbers of healthy melanocyte-like cells that can be plated as a pure population or with cardiomyocytes. PMID- 25285609 TI - Targeted chelation therapy with EDTA-loaded albumin nanoparticles regresses arterial calcification without causing systemic side effects. AB - BACKGROUND AND AIMS: Elastin-specific medial arterial calcification (MAC) is an arterial disease commonly referred as Monckeberg's sclerosis. It causes significant arterial stiffness, and as yet, no clinical therapy exists to prevent or reverse it. We developed albumin nanoparticles (NPs) loaded with disodium ethylene diaminetetraacetic acid (EDTA) that were designed to target calcified elastic lamina when administrated by intravenous injection. METHODS AND RESULTS: We optimized NP size, charge, and EDTA-loading efficiency (150-200 nm, zeta potential of -22.89--31.72 mV, loading efficiency for EDTA~20%) for in vivo targeting in rats. These NPs released EDTA slowly for up to 5 days. In both ex vivo study and in vivo study with injury-induced local abdominal aortic calcification, we showed that elastin antibody-coated and EDTA-loaded albumin NPs targeted the damaged elastic lamina while sparing healthy artery. Intravenous NP injections reversed elastin-specific MAC in rats after four injections over a 2 week period. EDTA-loaded albumin NPs did not cause the side effects observed in EDTA injection alone, such as decrease in serum calcium (Ca), increase in urine Ca, or toxicity to kidney. There was no bone loss in any treated groups. CONCLUSION: We demonstrate that elastin antibody-coated and EDTA-loaded albumin NPs might be a promising nanoparticle therapy to reverse elastin-specific MAC and circumvent side effects associated with systemic EDTA chelation therapy. PMID- 25285610 TI - Development of lipid nanoparticle formulations of siRNA for hepatocyte gene silencing following subcutaneous administration. AB - Recently developed lipid nanoparticle (LNP) formulations of siRNA have proven to be effective agents for hepatocyte gene silencing following intravenous administration with at least three LNP-siRNA formulations in clinical trials. The aim of this work was to develop LNP-siRNA systems for hepatocyte gene silencing that can be administered subcutaneously (s.c.). Three parameters were investigated, namely LNP size, residence time of the polyethylene glycol (PEG) lipid coating and the influence of hepatocyte-specific targeting ligands. LNP sizes were varied over the range of 30 to 115 nm in diameter and PEG-lipid that dissociates rapidly (PEG-DMG) and slowly (PEG-DSG) were employed. In mice, results show that large (~80 nm) LNP exhibited limited accumulation in the liver and poor Factor VII (FVII) gene silencing at 1mg siRNA/kg body weight. Conversely, small (~30 nm) LNP systems showed maximal liver accumulation yet still had minimal activity. Interestingly, intermediate size (~45 nm) LNP containing PEG-DSG exhibited nearly equivalent liver accumulation as the smaller systems following s.c. administration but reduced FVII levels by 80% at 1mg siRNA/kg body weight. Smaller systems (~35 nm diameter) containing either PEG-DMG or PEG-DSG were less active; however addition of 0.5 mol.% of a GalNAc-PEG lipid to these smaller systems improved activity to levels similar to that observed for the ~45 nm diameter systems. In summary, this work shows that appropriately designed LNP-siRNA systems can result in effective hepatocyte gene silencing following s.c administration. PMID- 25285611 TI - Microprojection arrays to immunise at mucosal surfaces. AB - The buccal mucosa (inner cheek) is an attractive site for delivery of immunotherapeutics, due to its ease of access and rich antigen presenting cell (APC) distribution. However, to date, most delivery methods to the buccal mucosa have only been topical-with the challenges of: 1) an environment where significant biomolecule degradation may occur; 2) inability to reach the APCs that are located deep in the epithelium and lamina propria; and 3) salivary flow and mucous secretion that may result in removal of the therapeutic agent before absorption has taken place. To overcome these challenges and achieve consistent, repeatable targeted delivery of immunotherapeutics to within the buccal mucosa (not merely on to the surface), we utilised microprojection arrays (Nanopatches 110 MUm length projections, 3364 projections, 16 mm2 surface area) with a purpose built clip applicator. The mechanical application of Nanopatches bearing a dry coated vaccine (commercial influenza vaccine, as a test case immunotherapeutic) released the vaccine to a depth of 47.8+/-14.8 MUm (mean+/-SD, n=4), in the mouse buccal mucosa (measured using fluorescent delivered dyes and CryoSEM). This location is in the direct vicinity of APCs, facilitating antigenic uptake. Resultant systemic immune responses were similar to systemic immunization methods, and superior to comparative orally immunised mice. This confirms the Nanopatch administered vaccine was delivered into the buccal mucosa and not ingested. This study demonstrates a minimally-invasive delivery device with rapid (2 min of application time), accurate and consistent release of immunotherapeutics in to the buccal mucosa-that conceptually can be extended in to human use for broad and practical utility. PMID- 25285612 TI - Endosulfan, pentachlorobenzene and short-chain chlorinated paraffins in background soils from Western Europe. AB - Soils are major reservoirs for many persistent organic pollutants (POPs). In this study, "newly" regulated POPs i.e. Sigmaendosulfans (alpha-endosulfan, beta endosulfan, endosulfan sulfate), pentachlorobenzene (PeCB), and short-chain chlorinated paraffins (SCCPs) were determined in background samples from woodland (WL) and grassland (GL) surface soil, collected along an existing latitudinal UK Norway transect. Statistical analysis, complemented with plots showing the predicted equilibrium distribution and mobility potential, was then explored to discuss factors controlling their spatial distribution. SCCPs were detected with the highest average concentrations (35 +/- 100 ng/g soil organic matter (SOM)), followed by Sigmaendosulfans (3 +/- 3 ng/g SOM) and PeCB (1 +/- 1 ng/g SOM). PeCB and Sigmaendosulfans share many similarities in their distribution in these background soils as well as with several legacy POPs. A steep decline in concentrations of SCCPs with increasing latitude indicates that their occurrence is dictated by proximity to source regions, while concentrations of Sigmaendosulfans peaked in regions experiencing elevated precipitation rates. PMID- 25285613 TI - Spatial and temporal patterns of diversification on the Amazon: A test of the riverine hypothesis for all diurnal primates of Rio Negro and Rio Branco in Brazil. AB - The role of Amazonian rivers as drivers of speciation through vicariance remains controversial. Here we explore the riverine hypothesis by comparing spatial and temporal concordances in pattern of diversification for all diurnal primates of Rio Negro and its largest tributary, Rio Branco. We built a comprehensive comparative phylogenetic timetree to identify sister lineages of primates based on mitochondrial cytochrome b DNA sequences from 94 samples, including 19 of the 20 species of diurnal primates from our study region and 17 related taxa from elsewhere. Of the ten primate genera found in this region, three had populations on opposite banks of Rio Negro that formed reciprocally monophyletic clades, with roughly similar divergence times (Cebus: 1.85 Ma, HPD 95% 1.19-2.62; Callicebus: 0.83 Ma HPD 95% 0.36-1.32, Cacajao: 1.09 Ma, 95% HPD 0.58-1.77). This also coincided with time of divergence of several allopatric species of Amazonian birds separated by this river as reported by other authors. Our data offer support for the riverine hypothesis and for a Plio-Pleistocene time of origin for Amazonian drainage system. We showed that Rio Branco was an important geographical barrier, limiting the distribution of six primate genera: Cacajao, Callicebus, Cebus to the west and Pithecia, Saguinus, Sapajus to the east. The role of this river as a vicariant agent however, was less clear. For example, Chiropotes sagulata on the left bank of the Rio Branco formed a clade with C. chiropotes from the Amazonas Department of Venezuela, north of Rio Branco headwaters, with C. israelita on the right bank of the Rio Branco as the sister taxon to C. chiropotes+C. sagulata. Although we showed that the formation of the Rio Negro was important in driving diversification in some of our studied taxa, future studies including more extensive sampling of markers across the genome would help determine what processes contributed to the evolutionary history of the remaining primate genera. PMID- 25285614 TI - Roseoloviruses in transplant recipients: clinical consequences and prospects for treatment and prevention trials. AB - Roseoloviruses frequently reactivate in transplant recipients. We review the impact of Roseoloviruses in transplant recipients and highlight research priorities. Human herpesvirus 6A (HHV-6A) and HHV-6B were recently classified as distinct species with important differences. Both viruses can result in inherited chromosomally integrated HHV-6, which may cause complications after transplant. HHV-6B is the primary species associated with disease and appears to have pleiotropic effects on the central nervous system. Small preemptive and prophylactic studies have not shown a statistically significant impact on HHV-6 disease. Although Roseoloviruses are associated with diverse complications in transplant patients, studies providing strong evidence for a causal role are lacking. Trials focusing on prevention and treatment will be important to inform the significance of Roseolovirus reactivation. PMID- 25285616 TI - Mythbusting in Orthopedics challenges our desire for meaning. PMID- 25285615 TI - Traditions and myths in hip and knee arthroplasty. AB - BACKGROUND AND PURPOSE: Traditions are passed on from experienced surgeons to younger fellows and become "the right way to do it". Traditions associated with arthroplasty surgery may, however, not be evidence-based and may be potentially deleterious to both patients and society, increasing morbidity and mortality, slowing early functional recovery, and increasing cost. METHODS: We identified selected traditions and performed a literature search using relevant search criteria (June 2014). We present a narrative review grading the studies according to evidence, and we suggest some lines of future research. RESULTS: We present traditions and evaluate them against the published evidence. Preoperative removal of hair, urine testing for bacteria, use of plastic adhesive drapes intraoperatively, and prewarming of the operation room should be abandoned-as should use of a tourniquet, a space suit, a urinary catheter, and closure of the knee in extension. The safety and efficacy of tranexamic acid is supported by meta-analyses. Postoperatively, there is no evidence to support postponement of showering or postponement of changing of dressings to after 48 h. There is no evidence to recommend routine dental antibiotic prophylaxis, continuous passive motion (CPM), the use of compression stockings, cooling for pain control or reduction of swelling, flexion of at least 90 degrees as a discharge criterion following TKA, or having restrictions after THA. We present evidence supporting the use of NSAIDs, early mobilization, allowing early travel, and a low hemoglobin trigger for transfusion. INTERPRETATION: Revision of traditions and myths surrounding hip and knee arthroplasty towards more contemporary evidence based principles can be expected to improve early functional recovery, thus reducing morbidity, mortality, and costs. PMID- 25285617 TI - Have cementless and resurfacing components improved the medium-term results of hip replacement for patients under 60 years of age? AB - BACKGROUND AND PURPOSE: The optimal hip replacement for young patients remains unknown. We compared patient-reported outcome measures (PROMs), revision risk, and implant costs over a range of hip replacements. METHODS: We included hip replacements for osteoarthritis in patients under 60 years of age performed between 2003 and 2010 using the commonest brand of cemented, cementless, hybrid, or resurfacing prosthesis (11,622 women and 13,087 men). The reference implant comprised a cemented stem with a conventional polyethylene cemented cup and a standard-sized head (28- or 32-mm). Differences in implant survival were assessed using competing-risks models, adjusted for known prognostic influences. Analysis of covariance was used to assess improvement in PROMs (Oxford hip score (OHS) and EQ5D index) in 2014 linked procedures. RESULTS: In males, PROMs and implant survival were similar across all types of implants. In females, revision was statistically significantly higher in hard-bearing and/or small-stem cementless implants (hazard ratio (HR) = 4) and resurfacings (small head sizes (< 48 mm): HR = 6; large head sizes (>= 48 mm): HR = 5) when compared to the reference cemented implant. In component combinations with equivalent survival, women reported significantly greater improvements in OHS with hybrid implants (22, p = 0.006) and cementless implants (21, p = 0.03) (reference, 18), but similar EQ5D index. For men and women, National Health Service (NHS) costs were lowest with the reference implant and highest with a hard-bearing cementless replacement. INTERPRETATION: In young women, hybrids offer a balance of good early functional improvement and low revision risk. Fully cementless and resurfacing components are more costly and do not provide any additional benefit for younger patients. PMID- 25285618 TI - Maternal methyl-enriched diet in rat reduced the audiogenic seizure proneness in progeny. AB - Audiogenic epilepsy proneness was analyzed in the progeny of rats from two strains (audiogenic seizure prone-strain "4"-and audiogenic seizure non-prone, strain "0"). Females were fed by a diet which contained substances enriched with methyl-groups during 1week before mating (MED), during pregnancy period and 1week after the delivery. This MED treatment resulted in a decrease of audiogenic seizure fit intensity, which was more evident in rats of strain "0". Control rats of strain "4" displayed intense seizures (tonic seizure, 3.85 arbitrary units). Med "4" rats seizures were less intense (3.23, tonic seizure of lower intensity), control "0" strain rats demonstrated the seizure with mean 3.09 arbitrary units, "0" MED rats only 2.03 arbitrary unit intensity (only clonic seizures, significantly, p<0.05, different from controls). Methyl-enriched diet resulted in the significant changes in methylation status of several genes (Cpne6, Gtf2i, Sctr,1 Sfmbt, Phe2). These genes among others were chosen for analysis as their expression was analyzed in other methylation study. These genes were hypermethylated after "epileptic tolerance". Due to this procedure, the intensity of status epilepticus, produced by kainate in mice, decreased (Miller-Delaney et al., 2012). The modulation of audiogenic seizure intensity as the result of methyl-enriched diet during prenatal and early postnatal ontogeny was demonstrated for the first time. PMID- 25285619 TI - Novel inhibitory effects of cardamonin on thromboxane A2-induced scratching response: Blocking of Gh/transglutaminase-2 binding to thromboxane A2 receptor. AB - Alpinia katsumadai is known to suppress thromboxane A2 (TXA2) receptor agonist induced scratching in mice. The specific components of A. katsumadai responsible for these biological effects, however, are not known. In the present study, we investigated whether cardamonin (CDN), one of major principles of A. katsumadai, has suppressive effects on TXA2-induced scratching in mice. Scratching induced by U46619 (the TXA2 receptor agonist) at a dose of 10nmol/site was shown to be suppressed by CDN (0.1nmol-0.5nmol/site). Suppression of the U46619-induced scratching response by CDN was found to be unrelated to competition with the ligand at the TXA2 receptor, since CDN did not suppress [(3)H] SQ29548 (the TXA2 receptor antagonist) binding to TXA2 receptor. TXA2 receptor expression in A549, HaCaT, and SH-SY5Y cell lines was examined and determined to be significant in the A549 and SH-SY5Y cell lines. Further, binding of high molecular G protein Gh/transglutaminase-2 (Gh/Tgase-2) to TXA2 receptor was confirmed in the A549 and SH-SY5Y cells by co-immunoprecipitation. CDN suppressed the binding of TXA2 receptor with Gh/Tgase-2, which also acts as a G protein involved in TXA2 signaling. These results suggested that CDN suppresses TXA2 receptor agonist induced scratching by suppressing TXA2 signaling, specifically via blocking of the binding of Gh/Tgase-2 to TXA2 receptor. PMID- 25285621 TI - Electric-acoustic interactions in the hearing cochlea: single fiber recordings. AB - The present study investigates interactions of simultaneous electric and acoustic stimulation in single auditory nerve fibers in normal hearing cats. First, the auditory nerve was accessed with a microelectrode and response areas of single nerve fibers were determined for acoustic stimulation. Second, response thresholds to extracochlear sinusoidal electric stimulation using ball electrodes positioned at the round window were measured. Third, interactions that occurred with combined electric-acoustic stimulation were investigated in two areas: (1) the spectral domain (frequency response areas) and (2) the temporal domain (phase locking to each stimulus) at moderate stimulus intensities (electric: 6 dB re threshold, acoustic: 20-40 dB re threshold at the characteristic frequency, CF). For fibers responding to both modalities responses to both electric and acoustic stimulation could be clearly identified. CFs, thresholds, and bandwidth (Q10dB) of acoustic responses were not significantly affected by simultaneous electric stimulation. Phase-locking of electric responses decreased in the presence of acoustic stimulation. Indication for electric stimulation of inner hair cells with 125 and 250 Hz were observed. However, these did not disturb the acoustic receptive fields of auditory nerve fibers. There was a trade-off between these responses when the intensities of the stimulation were varied: Relatively more intense stimulation dominated less intense stimulation. The scarcity of interaction between the different stimulus modalities demonstrates the ability of electric-acoustic stimulation to transfer useful information through both stimulation channels at the same time despite cochlear electrophonic effects. Application of 30 Hz electric stimulation resulted in a strong suppression of acoustic activity in the anodic phase of the stimulus. An electric stimulation like this might thus be used to control acoustic responses. This article is part of a Special Issue entitled . PMID- 25285620 TI - Decreased peripheral and central responses to acupuncture stimulation following modification of body ownership. AB - Acupuncture stimulation increases local blood flow around the site of stimulation and induces signal changes in brain regions related to the body matrix. The rubber hand illusion (RHI) is an experimental paradigm that manipulates important aspects of bodily self-awareness. The present study aimed to investigate how modifications of body ownership using the RHI affect local blood flow and cerebral responses during acupuncture needle stimulation. During the RHI, acupuncture needle stimulation was applied to the real left hand while measuring blood microcirculation with a LASER Doppler imager (Experiment 1, N = 28) and concurrent brain signal changes using functional magnetic resonance imaging (fMRI; Experiment 2, N = 17). When the body ownership of participants was altered by the RHI, acupuncture stimulation resulted in a significantly lower increase in local blood flow (Experiment 1), and significantly less brain activation was detected in the right insula (Experiment 2). This study found changes in both local blood flow and brain responses during acupuncture needle stimulation following modification of body ownership. These findings suggest that physiological responses during acupuncture stimulation can be influenced by the modification of body ownership. PMID- 25285622 TI - Cellular immunologic responses to cochlear implantation in the human. AB - A cochlear implant array consists of biomaterials, including metal and polymeric in type which are biocompatible, but not necessarily bio-inert. Histologic evidence of a foreign body reaction has been described in temporal bones in patients who in life had undergone cochlear implantation. In the current study, the cellular immune response was characterized using immunohistochemical stains for B-cell lymphocytes (CD20), T-cell lymphocytes (CD3), and macrophages (CD68). In addition, energy dispersive spectroscopy by scanning electron microscopy (EDS SEM) was performed to characterize the nature of particulate foreign material seen near the electrode array. Infiltrations of B-cell and Tcell lymphocytes and macrophages were identified immunohistochemically. The track of the electrode array was frequently lined by multi-nucleated foreign body giant cells. Energy dispersive X-ray spectroscopy identified the particulate material found in the fibrous sheeth surrounding the cochlear implant to be consistent with platinum. In conclusion, a cochlear implant generates a vigorous cellular immune response consisting of B and T lymphocytes, foreign body giant cells, and macrophages. Platinum was identified as one of the antigens likely responsible for this cellular response. This foreign body response may in certain cases result in migration or even extrusion of an implant device. PMID- 25285623 TI - An examination of the effects of broadband air-conduction masker on the speech intelligibility of speech-modulated bone-conduction ultrasound. AB - Ultrasound can be heard by bone-conduction, and speech-modulated bone-conducted ultrasound (BCU) delivers the speech information to the human ear. One of the recognition mechanisms is the demodulation of the signals. Because some of the profoundly deaf can also hear speech-modulated BCU, another mechanism may also contribution to the recognition of speech-modulated BCU. In this study, eight volunteers with normal hearing participated. The intelligibilities of speech modulated BCU were measured using a numeral word list under masking conditions. Because the masker can mask the demodulated sounds, the evaluation of the masking reveals the contribution of the demodulation to the recognition of speech modulated BCU. In the current results, the masking of speech-modulated BCU differed from that of original non-modulated speech. Although the masking shifted the recognition curve for the original speech upward, the same results were not observed for the speech-modulated BCU. The masking generated the difference in the correct answers among the words for the speech-modulated BCU. The current results suggested the importance of the envelope of the modulated ultrasonic signal to the recognition under masking condition. Both demodulation and direct ultrasonic stimulation contribute to the recognition of speech-modulated BCU for the normal hearing individuals, and the direct ultrasonic stimulation plays an important role in the recognition for the profoundly deaf. PMID- 25285624 TI - Factors constraining the benefit to speech understanding of combining information from low-frequency hearing and a cochlear implant. AB - Many studies have documented the benefits to speech understanding when cochlear implant (CI) patients can access low-frequency acoustic information from the ear opposite the implant. In this study we assessed the role of three factors in determining the magnitude of bimodal benefit - (i) the level of CI-only performance, (ii) the magnitude of the hearing loss in the ear with low-frequency acoustic hearing and (iii) the type of test material. The patients had low frequency PTAs (average of 125, 250 and 500 Hz) varying over a large range (<30 dB HL to >70 dB HL) in the ear contralateral to the implant. The patients were tested with (i) CNC words presented in quiet (n = 105) (ii) AzBio sentences presented in quiet (n = 102), (iii) AzBio sentences in noise at +10 dB signal-to noise ratio (SNR) (n = 69), and (iv) AzBio sentences at +5 dB SNR (n = 64). We find maximum bimodal benefit when (i) CI scores are less than 60 percent correct, (ii) hearing loss is less than 60 dB HL in low-frequencies and (iii) the test material is sentences presented against a noise background. When these criteria are met, some bimodal patients can gain 40-60 percentage points in performance relative to performance with a CI. This article is part of a Special Issue entitled . PMID- 25285626 TI - Collagen-derived dipeptide prolyl-hydroxyproline promotes differentiation of MC3T3-E1 osteoblastic cells. AB - Prolyl-hydroxyproline (Pro-Hyp) is one of the major constituents of collagen derived dipeptides. The objective of this study was to investigate the effects of Pro-Hyp on the proliferation and differentiation of MC3T3-E1 osteoblastic cells. Addition of Pro-Hyp did not affect MC3T3-E1 cell proliferation and matrix mineralization but alkaline phosphatase activity was significantly increased. Furthermore, cells treated with Pro-Hyp significantly upregulated gene expression of Runx2, Osterix, and Col1alpha1. These results indicate that Pro-Hyp promotes osteoblast differentiation. This study demonstrates for the first time that Pro Hyp has a positive effect on osteoblast differentiation with upregulation of Runx2, Osterix, and Collalpha1 gene expression. PMID- 25285625 TI - Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study. AB - Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4*10(-4), Bonferroni corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18 1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30-1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7*10(-4), Pc = 0.037, OR 1.53, 95%CI 1.19-1.96) and rs62339994 (dominant model, P = 9.0*10(-4), Pc = 0.043, OR 1.46, 95%CI 1.17 1.82). The haplotype carrying both of the risk alleles (rs66801661A-rs62339994A) was significantly increased in SLE (P = 9.9*10(-4)), while the haplotype constituted by both of the non-risk alleles (rs66801661G-rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNgamma stimulation (Tukey's test, P = 1.2*10(-4)). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2. PMID- 25285627 TI - Caspase-9 activation and Apaf-1 cleavage by MMP-3. AB - We have previously demonstrated that matrix metalloprotease-3 (MMP-3) can act inside the cell to trigger apoptosis in response to various cell stresses in dopaminergic neuronal cells. However, the mechanism by which MMP-3 activity leads to caspase-3 activation in apoptotic signaling was not known. In the present study, we found that MMP-3 acts upstream of caspase-9. Overexpression of wild type MMP-3, but not mutant MMP-3, generated the enzymatically active 35kD caspase 9. The caspase-9 activation was absent in MMP-3 knockout cells, but was present when these cells were transfected with wild type MMP-3 cDNA. It was elevated in cells that were under a MMP-3-inducing ER stress condition, and this was attenuated by pharmacologic inhibition and gene knockdown of MMP-3. Incubation of recombinant catalytic domain of MMP-3 (cMMP-3) with procaspase-9 was not sufficient to cause caspase-9 activation, and an additional cytosolic factor was required. cMMP-3 was found to bind to the cytosolic protein Apaf-1, as determined by changes in surface plasmon resonance, and to cleave Apaf-1. Pharmacological inhibition, knockout, and knockdown of MMP-3 attenuated the cleavage. Taken together, the present study demonstrates that MMP-3 leads to caspase-9 activation and suggests that this occurs indirectly via a cytosolic protein, possibly involving Apaf-1. PMID- 25285628 TI - Inhibition of autophagy promoted sphingosylphosphorylcholine induced cell death in non-small cell lung cancer cells. AB - Sphingosylphosphorylcholine (SPC) is a bioactive lipid mediated popular cell apoptosis in cancer cells. As a cell-specific sphingolipid, its function in lung cancer cells is unknown. Here we showed that SPC treatment triggered necrosis and autophagy but inhibited apoptosis in two non-small cell lung cancer cell lines: A549 cell line and H157 cell line. Then 3-methyladenine (3-MA), an autophagy inhibitor, was introduced to clarify the relationships between autophagy and necrosis or apoptosis. 3MA suppressed the survival furtherly by promoting apoptosis while had no influence on necrosis. Subsequent studies revealed that activity of AKT and mammalian target of rapamycin (mTOR) complex 1 (mTORC1) were downregulated during autophagy. Furthermore, SPC failed to promote autophagy in p53 deleted cells. Thus SPC induced autophagy in non-small cell lung cancer cells was through AKT/mTORC1 and P53 signal pathway. Besides, SPC reduced both the mitochondria membrane potential and ROS level in A549 cells. These findings provided a molecular basis of SPC-stimulated A549 cell death and support the notion that inhibition of autophagy is likely a novel anticancer mechanism. PMID- 25285629 TI - GDC-0980-induced apoptosis is enhanced by autophagy inhibition in human pancreatic cancer cells. AB - Pancreatic cancer remains fatal to the fast majority of affected patients. Activation of phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway plays an important role in pancreatic cancer progression and chemo resistance. In the present study, we examined the activity of GDC-0980, a novel class I PI3K/mTOR kinase inhibitor, against pancreatic cancer cells in vitro. GDC 0980 inhibited AKT-mTOR activation and pancreatic cancer cell (PANC-1 and Capan-1 lines) survival. In both cancer cell lines, GDC-0980 simultaneously activated apoptosis and autophagy, the latter was detected by p62 degradation, Beclin-1 upregulation and light chain 3B (LC3B) conversion from a cytosolic (LC3B-I) to a membrane-bound (LC3B-II) form. Autophagy inhibitors including 3-methyladenine, hydroxychloroquine, NH4Cl and bafilomycin A1 enhanced apoptosis and cytotoxicity by GDC-0980, such an effect was reversed by caspase inhibitors (z-VAD-FMK and z ITED-FMK). Furthermore, knockdown of LC3B or Beclin-1 through siRNA increased GDC 0980-induced anti-pancreatic cancer cell activity. Thus, inhibition of autophagy sensitizes GDC-0980-induced anti-pancreatic cancer activity, suggesting a novel therapeutic strategy for GDC-0980 sensitization. PMID- 25285630 TI - Long noncoding RNA expression in dermal papilla cells contributes to hairy gene regulation. AB - Dermal papilla (DP) cells may be the source of dermal-derived signaling molecules involved in hair-follicle development and postnatal hair cycling. Early-passage DP cells can induce hair growth in vivo, but, on further culture, this ability is lost. The cellular mechanisms underlying the hair-follicle induction property of early-passage DP cells are unclear. Long noncoding RNAs (lncRNAs) are an important class of genes involved in various biological functions. They are aberrantly expressed and play roles in the regulation of the Wnt signaling pathway, a critical point in maintaining hair-induction activity. LncRNA microarray revealed 1683 upregulated and 1773 downregulated lncRNAs in passage-4 DP cells compare with passage-10 DP cells. To investigate the relation between lncRNAs and coding genes in WNT signaling, we constructed a coding-noncoding gene co-expression network using lncRNAs and coding genes that were differentially expressed between the passage-4 and -10 DP cells. RP11-766N7.3, H19 and HOTAIR are specific lncRNAs that were aberrantly expressed in DP cells and played an important role in regulating Wnt signaling. This study may provide potential targets for discovering the hair-follicle induction mechanism of early-passage DP cells. PMID- 25285631 TI - Deacetylation of the mitotic checkpoint protein BubR1 at lysine 250 by SIRT2 and subsequent effects on BubR1 degradation during the prometaphase/anaphase transition. AB - Mitotic catastrophe, a form of cell death that occurs during mitosis and after mitotic slippage to a tetraploid state, plays an important role in the efficacy of cancer cell killing by microtubule inhibitors. Prolonged mitotic arrest at the spindle assembly checkpoint (SAC) is a well-known requirement for mitotic catastrophe and, thus, for conferring sensitivity to microtubule inhibitors. We previously reported that downregulation of SIRT2, a member of the sirtuin family of NAD+-dependent deacetylases, confers resistance to microtubule inhibitors by abnormally prolonging mitotic arrest and thus compromising the cell death pathway after mitotic slippage. Thus, turning off SAC activation after a defined period is an additional requirement for efficient post-slippage death. Here, we investigated whether SIRT2 deacetylates BubR1, which is a core component of the SAC; acetylation of BubR1 at lysine 250 (K250) during prometaphase inhibits its APC/C-dependent proteolysis and thus regulates timing in anaphase entry. We showed that SIRT2 deacetylates BubR1 K250 both in vitro and in vivo. We also found that SIRT2 knockdown leads to increased levels of BubR1 acetylation at prometaphase; however, this increase is not substantial to elevate the levels of total BubR1 or delay the transition from prometaphase to anaphase. The present study shows that SIRT2 is a deacetylase for BubR1 K250, although the abnormally prolonged SAC activation observed in SIRT2 knockdown cells is not accompanied by a change in BubR1 levels or by delayed progression from prometaphase to anaphase. PMID- 25285632 TI - An IL6-STAT3 loop mediates resistance to PI3K inhibitors by inducing epithelial mesenchymal transition and cancer stem cell expansion in human breast cancer cells. AB - Recently, a new generation of PI3K-specific inhibitors, such as GDC0941 and BKM120, are being investigated in clinical trials for treatment against tumors harboring PIK3CA mutations. Nevertheless, not all patients benefit from such treatment, suggesting that their tumors may be resistant to PI3K inhibitors. The investigation of the underlying mechanisms and efficacious personalized treatment remain a large unmet need. In this study, we revealed an IL6-STAT3 positive feedback loop that mediated the resistance to PI3K inhibitors. We found that breast cancer cells with acquired resistance to PI3K inhibitors displayed epithelial-mesenchymal transition (EMT) features and an highly enriched cancer stem cells (CSCs), secreting ~1000-fold more IL6 than parental cells. Further studies elucidated that activation of the IL6-STAT3 signaling effectively triggered EMT action, expanded the CSCs population, and reduced sensitivity to PI3K inhibitors. Pharmacological inhibition of STAT3 disrupted the IL6-STAT3 signaling and overcome resistance to PI3K inhibitors partially due to increased apoptosis induction. Taken together, our results demonstrated that feedback activation of the IL6-STAT3 loop lead to acquired resistance to PI3K inhibitors by promoting EMT and CSC-like features, and suggested that targeting this loop may be an efficient strategy to overcome resistance to PI3K inhibitors. PMID- 25285633 TI - Mitochondrial DNA common deletion increases susceptibility to noise-induced hearing loss in a mimetic aging rat model. AB - Noise-induced hearing loss (NIHL) is an important occupational health hazard. However, susceptibility to NIHL remains poorly understood. The present study was designed to investigate whether mitochondrial DNA common deletion (CD) increases the susceptibility of individuals to NIHL. A mimetic aging rat model harboring increased CD in the inner ear was established by chronic d-galactose administration, and the synergic effect of CD and noise on hearing sensitivity was assessed. We determined that although developed the same magnitude of temporary threshold shifts and hair cell loss, the d-galactose treated rats with increased CD in the inner ear exhibited a longer hearing recovery process and experienced higher permanent hearing threshold shifts at high frequencies than the saline-treated control rats. Greater supporting cell damage and stria vascularis ultrastructural changes were observed in d-galactose treated rats three weeks after recovery. The results suggested that the elevated CD in the inner ear could increase an individual's susceptibility to NIHL, which likely through a reduction in the self-repairing capability within the cochlea after acoustic injury. PMID- 25285634 TI - Specific inhibition of Wee1 kinase and Rad51 recombinase: a strategy to enhance the sensitivity of leukemic T-cells to ionizing radiation-induced DNA double strand breaks. AB - Present-day oncology sees at least two-thirds of cancer patients receiving radiation therapy as a part of their anticancer treatment. The objectives of the current study were to investigate the effects of the small molecule inhibitors of Wee1 kinase II (681641) and Rad51 (RI-1) on cell cycle progression, DNA double strand breaks repair and apoptosis following ionizing radiation exposure in human leukemic T-cells Jurkat and MOLT-4. Pre-treatment with the Wee1 681641 or Rad51 RI-1 inhibitor alone increased the sensitivity of Jurkat cells to irradiation, however combining both inhibitors together resulted in a further enhancement of apoptosis. Jurkat cells pre-treated with inhibitors were positive for gammaH2AX foci 24h upon irradiation. MOLT-4 cells were less affected by inhibitors application prior to ionizing radiation exposure. Pre-treatment with Rad51 RI-1 had no effect on apoptosis induction; however Wee1 681641 increased ionizing radiation-induced cell death in MOLT-4 cells. PMID- 25285635 TI - Motor domain-based motility system and motile properties of alpha heavy chain in Tetrahymena outer arm dynein. AB - Axonemal dynein plays an essential role in ciliary motility, and impaired ciliary motility causes human diseases such as primary ciliary dyskinesia (PCD). The motor domain of axonemal dynein powers ciliary motility and its function is regulated by several accessary proteins bound to the tail region. Therefore, to understand the essential properties of dynein motility, examining the motile properties of the motor domain without the tail is necessary. In this study, the functional motor domain of the alpha heavy chain in Tetrahymena outer arm dynein was purified, and its motile properties were examined using an in vitro motility system. The purified protein caused microtubules to glide at a velocity of 5.0MUm/s with their minus-end trailing, and motility was inhibited in an ATP concentration-dependent manner, which is in contrast with kinesin1. This method could be applicable to other axonemal dyneins and will enable further molecular studies on diverse axonemal dyneins and ciliary motility. PMID- 25285637 TI - Synergistic inhibition of cancer cell proliferation with a combination of delta tocotrienol and ferulic acid. AB - Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly delta-tocotrienol (delta-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of delta-T3 and FA markedly reduced cell proliferation relative to delta-T3 alone, and FA had no effect when used alone. Although delta-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of delta-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of delta-T3 by FA. Our results suggest that the combination of delta-T3 and FA may present a new strategy for cancer prevention and therapy. PMID- 25285636 TI - Crystal structure of archaeal homolog of proteasome-assembly chaperone PbaA. AB - Formation of the eukaryotic proteasome is not a spontaneous process but a highly ordered process assisted by several assembly chaperones. In contrast, archaeal proteasome subunits can spontaneously assemble into an active form. Recent bioinformatic analysis identified the proteasome-assembly chaperone-like proteins, PbaA and PbaB, in archaea. Our previous study showed that the PbaB homotetramer functions as a proteasome activator through its tentacle-like C terminal segments. However, a functional role of the other homolog PbaA has remained elusive. Here we determined the 2.25-A resolution structure of PbaA, illustrating its disparate tertiary and quaternary structures compared with PbaB. PbaA forms a homopentamer in which the C-terminal segments, with a putative proteasome-activating motif, are packed against the core. These findings offer deeper insights into the molecular evolution relationships between the proteasome assembly chaperones and the proteasome activators. PMID- 25285638 TI - Role of resveratrol in regulation of membrane transporters and integrity of human erythrocytes. AB - An altered ion homeostasis due to impaired membrane transporters is known to be involved in the pathophysiology of many chronic diseases. Resveratrol, a phytoalexin, has been reported to elicit pleiotropic health-promoting effects, however, the mechanism(s) which underlie these effects remain speculative. The present study investigate the modulatory role of resveratrol on erythrocyte membrane Ca(2+)ATPase (PMCA pump), Na(+)/K(+)-ATPase (NKA pump), and Na(+)/H(+) exchanger (NHE) in control and experimental-oxidative stress conditions. Results suggest that resveratrol is a potent modulator of membrane transporters evidenced by stimulation of PMCA and NKA pumps and down-regulation of NHE. The observed effects on membrane transporters correlated with susceptibility of erythrocyte membrane to oxidative damage. The findings provide an insight into the role of membrane transporters and their involvement in the health beneficial effects of resveratrol. PMID- 25285639 TI - COP9 signalosome subunit 6 binds and inhibits avian leukosis virus integrase. AB - The retroviral integrase plays an essential role in the integration of reverse transcribed retroviral cDNA into the host cell genome, and serves as an important target for anti-viral therapeutics. In this study, we identified the COP9 signalosome subunit 6 (CSN6) as a novel avian leukosis virus (ALV) integrase binding protein. Co-immunoprecipitation and GST pull-down assays showed that CSN6 bound to ALV integrase likely through direct interaction of CSN6 to the catalytic core of the integrase. We further demonstrated CSN6 inhibited integrase activity in vitro; knockdown of CSN6 in DF-1 promoted ALV production. These results indicated that CSN6 may be a negative regulator of ALV replication by binding to and inhibiting integrase. Our findings provided the insight into the integrase based host defense system and may have implications in the development of integrase-based anti-viral strategies. PMID- 25285640 TI - Cbl regulates the activity of SIRT2. AB - SIRT2 is a member of the sirtuin family of NAD(+)-dependent protein deacetylases. It is involved in metabolic homeostasis and has been linked to the progression of age-related diseases. Casitas B-lineage lymphoma (Cbl) proteins regulate signal transduction through many pathways and, consequently, regulate cell function and development. Cbl proteins are ubiquitin ligases that ubiquitinate and target many signaling molecules for degradation. The function of SIRT2 is modulated by post translational modifications. However, the precise molecular signaling mechanism of SIRT2 through interactions with Cbl proteins has not yet been established. In this study, we investigated the potential regulation of SIRT2 function by the Cbl mammalian family members Cbl-b and c-Cbl. We found that Cbl-b and c-Cbl increased the protein level and stability of SIRT2 and that Cbl-b and c-Cbl interact with SIRT2. They were also found to regulate the deacetylase activity of SIRT2. Further investigation revealed that Cbl-mediated SIRT2 regulation occurred via ubiquitination of SIRT2. PMID- 25285641 TI - Environmental temperature affects the dynamics of ingestion in the nectivorous ant Camponotus mus. AB - Environmental temperature influences physiology and behavior in animals in general and is particularly determinant in ectotherms. Not least because temperature defines metabolism and body temperature, muscle activity in insects also strongly depends on this factor. Here, we analyzed how environmental temperature influences the dynamics of ingestion due to its effect on the sucking pump muscles in the nectivorous ants Camponotus mus. Feeding behavior and sucking pump activity during sucrose solution ingestion were first recorded in a natural environment in an urban setting throughout the day and in different seasons. Then, controlled temperature experiments were performed in the laboratory. In both situations, feeding time decreased and pumping frequency increased with temperature. However, different pumping frequencies under a same temperature were also observed in different seasons. Besides, in the laboratory, the volume of solution ingested increased with temperature. Consequently, intake rate increased when temperature rose. This change was exclusively promoted by a variation in the pumping frequency while volume taken in per pump contraction was not affected by temperature. In summary, environmental temperature modified the dynamics of ingestion and feeding behavior by directly affecting pumping frequency. PMID- 25285642 TI - Criminal offending among males and females between ages 15 and 30 in a population based nationwide 1981 birth cohort: results from the FinnCrime Study. AB - We describe the epidemiology of crime between ages 15 and 30 in a population based sample. We received police register data for 5405 males and females, representing the children born in Finland in 1981. We classified crimes into drug, violent, property, traffic, drunk driving, and sexual crimes, excluding minor traffic offenses. Of males, 60% and of females, 25% were registered for offending. For males, prevalence peaked in late adolescence, while for females, there was no peak age. Offending frequency remained stable for male offenders but was lower among adolescent female offenders. All crime types overlapped each other. Crime accumulated: 1% committed 34% of male and 56% of female offenses. In conclusion, the adolescent peak in offending reflects peaking prevalence among males, not females, nor frequency of offending among offenders. The crime problem is focused on two key groups: late adolescent males and the few males and females in whom crime concentrates. PMID- 25285643 TI - PVCs arising from the moderator band: An under-recognized trigger for idiopathic VF? PMID- 25285644 TI - Catheter ablation of scar-based ventricular tachycardia: Relationship of procedure duration to outcomes and hospital mortality. AB - BACKGROUND: Ablation has become an important option for treatment of ventricular tachycardia (VT). The influence of procedure duration on outcomes remains unexamined. OBJECTIVE: The purpose of this study was to determine the influence of procedure duration on outcomes and complications over an 8-year period METHODS: Patients referred for scar-mediated VT ablation from 2004 to 2011 were retrospectively analyzed. Procedure duration was defined as the time from the insertion of catheters through the femoral vein to the time of their withdrawal. Procedure duration was analyzed in relationship with baseline and intraoperative covariates, acute procedural outcomes, complications, and 6-month clinical outcomes. RESULTS: One hundred forty-eight patients underwent VT ablation with mean procedure duration of 5.7 +/- 1.8 hours. VT recurrence and survival at 6 months were 46% and 82%, respectively, and were not associated with procedure duration. Hospital mortality increased with intraoperative intraaortic balloon pump insertion (adjusted odds ratio [OR] 13.7, 95% confidence interval [CI] 2.35 79.94, P = .004) and was improved with successful ablation of the clinical VT as a procedural end-point (adjusted OR 0.13, 95% Cl 0.03-0.54, P = .005). The association between procedure duration and hospital mortality remained after adjusting for significant baseline variables (adjusted OR 1.75, 95% CI 1.14-2.68, P = .0098) and intraoperative variables (adjusted OR 1.6, 95% CI 1.12-2.29, P = .0104). CONCLUSION: Hospital mortality was significantly increased by unsuccessful clinical VT ablation as a procedural end-point and intraoperative intraaortic balloon pump insertion. However, after adjusting for significant baseline and intraoperative covariates, procedure duration still was associated with increased hospital mortality. Procedure duration had no impact on VT recurrence and survival at 6 months. PMID- 25285645 TI - Use of a novel fragmentation map to identify the substrate for ventricular tachycardia in postinfarction cardiomyopathy. AB - BACKGROUND: Substrate ablation is commonly performed in patients with postinfarction cardiomyopathy and ventricular tachycardia (VT). Recognition of fragmented and late potentials during sinus rhythm is a tedious process subject to operator fatigue. OBJECTIVE: The purpose of this study was to assess the value of automated analysis to quantify electrogram fragmentation and to determine the relationship of fragmented regions to the VT isthmus. METHODS: Detailed left ventricular (LV) mapping was performed in 2 groups: (1) 14 patients with previous myocardial infarction and tolerated VT and (2) 14 controls with structurally normal hearts. In patients with VT, mid-isthmus sites were identified using entrainment mapping. Sinus rhythm endocardial LV electrograms underwent time- and frequency-domain analysis and were displayed as fragmentation or frequency maps. The region of fractionated electrograms and their relation to the VT isthmus sites were determined. RESULTS: Cutoffs for abnormal electrogram fragmentation were ventricular fractionation index >= 7 and fast Fourier transform ratio >= 14%, respectively. In the time domain, LV surface area with fractionated electrograms was significantly smaller than the total scar surface area (27.3% +/ 7.1% vs 42.1% +/- 12.3%, P <.001), yet contained 100% of VT isthmus sites. In the frequency domain, areas of abnormal fractionation occupied 9.7% +/- 6.9% of total LV surface area and included only 60% of the VT isthmus sites. CONCLUSION: Automated electrogram fractionation analysis represents an objective tool to rapidly quantify electrogram fragmentation and guide substrate-based ablation of VT. Empiric ablation of these regions may be a new strategy for substrate-guided VT ablation. PMID- 25285646 TI - Detailed analysis of ventricular activation sequences during right ventricular apical pacing and left bundle branch block and the potential implications for cardiac resynchronization therapy. AB - BACKGROUND: Left bundle branch block (LBBB) leads to prolonged left ventricular (LV) total activation time (TAT) and ventricular electrical uncoupling (VEU; mean LV activation time minus mean right ventricular [RV] activation time); both have been shown to be preferential targets for cardiac resynchronization therapy (CRT). Whether right ventricular apical pacing (RVAP) produces similar ventricular activation patterns has not been well studied. OBJECTIVE: The purpose of this study was to compare electrical ventricular activation patterns during RVAP and LBBB. METHODS: We performed ECG mapping during sinus rhythm, RVAP, and CRT in 24 patients with LBBB. RESULTS: We observed differences in the electrical activation pattern with RVAP compared to LBBB. During LBBB, RV activation occurred rapidly; in contrast, RV activation was prolonged during RVAP (46 +/- 21 ms vs 69 +/- 17 ms, P <.001). There was no significant difference in LVTAT; however, differences in conduction pattern were observed. During LBBB, LV activation was circumferential, whereas with RVAP, LV activation proceeded from apex to base. Differences in the number, size, and orientation of lines of slow conduction also were observed. With LBBB, VEU was nearly twice as long as during RVAP (73 +/- 12 ms vs 38 +/- 21 ms, P <.001). CRT resulted in a greater reduction in VEU relative to LBBB activation (P <.001). CONCLUSION: RVAP produces significant differences in ventricular activation characteristics compared to LBBB. Significantly less VEU occurs with RVAP, and as a result CRT produces a smaller relative reduction in VEU. This may explain the finding that CRT appears to be more effective in patients with LBBB than in those who were upgraded because of high percentages of RV pacing. PMID- 25285648 TI - Modest agreement in ECG interpretation limits the application of ECG screening in young athletes. AB - BACKGROUND: Athlete ECG screening has been recommended by several international sporting bodies; however, a number of controversies remain regarding the accuracy of ECG screening. An important component that has not been assessed is the reproducibility of ECG interpretation. OBJECTIVE: The purpose of this study was to assess the variability of ECG interpretation among experienced physicians when screening a large number of athletes. METHODS: A sports cardiologist, a sports medicine physician, and an electrophysiologist analyzed 440 consecutive screening ECGs from asymptomatic athletes and were asked to classify the ECGs according to the 2010 European Society of Cardiology criteria as normal (or demonstrating training related ECG changes) or abnormal. When an abnormal ECG was identified, they were asked to outline what follow-up investigations they would recommend. RESULTS: The reported prevalence of abnormal ECGs ranged from 13.4% to 17.5%. Agreement on which ECGs were abnormal ranged from poor (kappa = 0.297) to moderate (kappa = 0.543) between observers. Suggested follow-up investigations were varied, and follow-up costs ranged from an additional A$30-A$129 per screening episode. Neither of the 2 subjects (0.45%) in the cohort with significant pathology diagnosed as a result of screening were identified correctly by all 3 physicians. CONCLUSION: Even when experienced physicians interpret athletes' ECGs according to current standards, there is significant interobserver variability that results in false-positive and false-negative results, thus reducing the effectiveness and increasing the social and economic cost of screening. PMID- 25285647 TI - Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1. AB - BACKGROUND: Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT). OBJECTIVE: The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1. METHODS: Hearts were perfused retrogradely, and action potentials were recorded using a voltage sensitive dye and CMOS cameras. RESULTS: Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n = 16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na(+) current (INa)-mediated fast conduction and L-type Ca(2+) current (ICa)-mediated slow conduction coexist, manifesting as pVT. Addition of 2 MUM tetrodotoxin to reduce INa converted pVT into monomorphic VT. Reducing late INa in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results. CONCLUSION: Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by INa and slow wavefronts driven by ICa co-exist during pVT. PMID- 25285649 TI - Cryptogenic stroke: Is silent atrial fibrillation the culprit? AB - BACKGROUND: Stroke without an identifiable cause is frightening to patients and their families and is frustrating for the caring physician. Approximately 30% of patients with cardiac implanted electronic devices have some evidence of atrial fibrillation (AF), and much of it is silent: asymptomatic, and previously unrecognized. OBJECTIVE: The purpose of this review is to examine "silent AF" as a potential cause of cryptogenic stroke. METHODS/RESULTS: We begin by reviewing most of the published literature on screening for AF with different monitoring technologies in the setting of cryptogenic stroke. We present the results of 2 recent large randomized trials, CRYSTAL AF and EMBRACE, which compare standard of care monitoring in cryptogenic stroke patients to invasive and noninvasive monitoring strategies, respectively. Finally, we review the relationship of silent AF to stroke in the cardiac implanted electronic device population. Patient selection, duration of monitoring, sensitivity and specificity of monitoring technology, patient compliance, and several other factors affect the yield of AF detection during monitoring. CONCLUSION: Data suggest that silent AF is identified in approximately 30% of cryptogenic stroke patients and has important therapeutic implications. Oral anticoagulation likely should be prescribed when silent AF is detected. PMID- 25285650 TI - Pancreatic islet neuropeptide Y overexpression has minimal effect on islet morphology and beta-cell adaptation to high-fat diet. AB - Neuropeptide Y (NPY) is highly expressed in the hypothalamus, where it regulates feeding and energy homeostasis. Interestingly, NPY and its receptors are also expressed in peripheral tissues with roles in metabolism, including pancreatic islets. In islets, NPY is known to suppress insulin secretion acutely. In addition, the role of NPY in beta-cell de-differentiation has been postulated recently. Therefore, we studied transgenic mice expressing NPY under rat insulin promoter (TG) to determine the effects of chronic up-regulation of NPY on islet morphology and function. NPY levels were 25 times higher in islets of TG mice compared with wild-type (WT) littermates, whereas no differences in NPY expression were noted in the brains of TG and WT mice. Islet NPY secretion was 2.3-fold higher in TG compared with WT mice. There were no significant changes in body weight, glucose tolerance, or insulin sensitivity in TG mice fed regular rodent diet or high-fat diet (HF). Islet beta-cell area was comparable between TG and WT mice both on regular rodent and HF diets, indicating that NPY overexpression is insufficient to alter beta-cell maturation or the compensatory increase of beta-cell area on HF. One abnormality noted was that the glucose stimulated insulin secretion in islets isolated from TG was reduced compared with those from WT mice on HF diet. Overall, an increase in islet NPY level has little impact on islet function and is insufficient to affect glucose homeostasis in mice. PMID- 25285651 TI - Is there a paraneoplastic ALS? AB - Our objective was to examine the strength of evidence in support of the paraneoplastic syndrome (PNS) as one cause of ALS and, if the association appears more likely than chance, determine which features of ALS imply concurrent malignancy. We reviewed the literature on concurrent ALS and neoplasia assessing the strength of evidence for the association. Most accounts of ALS and neoplasm are case reports or small uncontrolled series. In order of strength of evidence, three clinical situations that support a paraneoplastic aetiology for ALS are: 1) laboratory evidence of well-characterized onconeuronal antibodies, most often anti-Hu, anti-Yo or anti-Ri; 2) co-occurrence of ALS and a neoplasm known to cause PNS, usually lymphoma or cancer of the breast; and 3) combined ALS and a neoplasm not classically associated with PNS, without detectable onconeuronal antibodies. Clinical features that warrant evaluation of neoplasm include upper motor neuron disease in elderly females, rapid progression, non-motor signs, and young onset. In conclusion, most examples of ALS and neoplasm do not constitute a classically established PNS. Rare instances of elevated onconeuronal antibody titres or typical neoplasm, implies that, albeit rare, the PNS is one of a multitude of causes of ALS. PMID- 25285653 TI - Modulation of active site electronic structure by the protein matrix to control [NiFe] hydrogenase reactivity. AB - Control of the reactivity of the nickel center of the [NiFe] hydrogenase and other metalloproteins commonly involves outer coordination sphere ligands that act to modify the geometry and physical properties of the active site metal centers. We carried out a combined set of classical molecular dynamics and quantum/classical mechanics calculations to provide quantitative estimates of how dynamic fluctuations of the active site within the protein matrix modulate the electronic structure at the catalytic center. Specifically we focused on the dynamics of the inner and outer coordination spheres of the cysteinate-bound Ni Fe cluster in the catalytically active Ni-C state. There are correlated movements of the cysteinate ligands and the surrounding hydrogen-bonding network, which modulate the electron affinity at the active site and the proton affinity of a terminal cysteinate. On the basis of these findings, we hypothesize a coupling between protein dynamics and electron and proton transfer reactions critical to dihydrogen production. PMID- 25285654 TI - Nanoscale and bio imaging: general discussion. PMID- 25285655 TI - Optimization, purification, and characterization of L-asparaginase from Actinomycetales bacterium BkSoiiA. AB - Actinobacteria are promising source of a wide range of important enzymes, some of which are produced in industrial scale, with others yet to be harnessed. L Asparaginase is used as an antineoplastic agent. The present work deals with the production and optimization of L-asparaginase from Actinomycetales bacterium BkSoiiA using submerged fermentation in M9 medium. Production optimization resulted in a modified M9 medium with yeast extract and fructose as carbon and nitrogen sources, respectively, at pH 8.0, incubated for 120 hr at 30 +/- 2 degrees C. The crude enzyme was purified to near homogeneity by ammonium sulfate precipitation following dialysis, ion-exchange column chromatography, and finally gel filtration. The sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) revealed an apparent molecular weight of 57 kD. The enzyme was purified 95.06-fold and showed a final specific activity of 204.37 U/mg with 3.49% yield. The purified enzyme showed maximum activity at a pH 10.0 and was stable at pH 7.0 to 9.0. The enzyme was activated by Mn(2+) and strongly inhibited by Ba(2+). All these preliminary characterization suggests that the L asparaginase from the source may be a tool useful to pharmaceutical industries after further research. PMID- 25285657 TI - Adhesion switch on a gecko-foot inspired smart nanocupule surface. AB - A gecko-foot inspired nanocupule surface prepared by an AAO template covering method was composed of poly(N-isopropylacrylamide) and polystyrene blend. Both superhydrophobicity and high adhesion force were exhibited on the PNIPAm/PS film at room temperature. Moreover, by controlling the temperature, the wettability of the film could be switched between 138.1 +/- 5.5 degrees and 150.6 +/- 1.5 degrees , and the adhesion force could also be correspondingly tuned accurately by temperature. This reversibility in both wettability and adhesion force could be used to construct smart devices for fine selection of water droplets. The proof-of-concept was demonstrated by the selective catching of precise weight controlled water droplets at different temperatures. This work could help us to design new type of devices for blood bioanalysis or lossless drug transportation. PMID- 25285656 TI - Quantification of left ventricular torsion and diastolic recoil using cardiovascular magnetic resonance myocardial feature tracking. AB - OBJECTIVES: Cardiovascular magnetic resonance feature tracking (CMR-FT) offers quantification of myocardial deformation from routine cine images. However, data using CMR-FT to quantify left ventricular (LV) torsion and diastolic recoil are not yet available. We therefore sought to evaluate the feasibility and reproducibility of CMR-FT to quantify LV torsion and peak recoil rate using an optimal anatomical approach. METHODS: Short-axis cine stacks were acquired at rest and during dobutamine stimulation (10 and 20 ug . kg(-1) . min(-1)) in 10 healthy volunteers. Rotational displacement was analysed for all slices. A complete 3D-LV rotational model was developed using linear interpolation between adjacent slices. Torsion was defined as the difference between apical and basal rotation, divided by slice distance. Depending on the distance between the most apical (defined as 0% LV distance) and basal (defined as 100% LV distance) slices, four different models for the calculation of torsion were examined: Model 1 (25-75%), Model-2 (0-100%), Model-3 (25-100%) and Model-4 (0-75%). Analysis included subendocardial, subepicardial and global torsion and recoil rate (mean of subendocardial and subepicardial values). RESULTS: Quantification of torsion and recoil rate was feasible in all subjects. There was no significant difference between the different models at rest. However, only Model-1 (25-75%) discriminated between rest and stress (Global Torsion: 2.7 +/- 1.5 degrees cm( 1), 3.6 +/- 2.0 degrees cm(-1), 5.1 +/- 2.2 degrees cm(-1), p<0.01; Global Recoil Rate: -30.1 +/- 11.1 degrees cm(-1) s(-1),-46.9 +/- 15.0 degrees cm(-1) s(-1),-68.9 +/- 32.3 degrees cm(-1) s(-1), p<0.01; for rest, 10 and 20 ug . kg( )1 . min(-1) of dobutamine, respectively). Reproducibility was sufficient for all parameters as determined by Bland-Altman analysis, intraclass correlation coefficients and coefficient of variation. CONCLUSIONS: CMR-FT based derivation of myocardial torsion and recoil rate is feasible and reproducible at rest and with dobutamine stress. Using an optimal anatomical approach measuring rotation at 25% and 75% apical and basal LV locations allows effective quantification of torsion and recoil dynamics. Application of these new measures of deformation by CMR-FT should next be explored in disease states. PMID- 25285658 TI - Statistics of natural binaural sounds. AB - Binaural sound localization is usually considered a discrimination task, where interaural phase (IPD) and level (ILD) disparities at narrowly tuned frequency channels are utilized to identify a position of a sound source. In natural conditions however, binaural circuits are exposed to a stimulation by sound waves originating from multiple, often moving and overlapping sources. Therefore statistics of binaural cues depend on acoustic properties and the spatial configuration of the environment. Distribution of cues encountered naturally and their dependence on physical properties of an auditory scene have not been studied before. In the present work we analyzed statistics of naturally encountered binaural sounds. We performed binaural recordings of three auditory scenes with varying spatial configuration and analyzed empirical cue distributions from each scene. We have found that certain properties such as the spread of IPD distributions as well as an overall shape of ILD distributions do not vary strongly between different auditory scenes. Moreover, we found that ILD distributions vary much weaker across frequency channels and IPDs often attain much higher values, than can be predicted from head filtering properties. In order to understand the complexity of the binaural hearing task in the natural environment, sound waveforms were analyzed by performing Independent Component Analysis (ICA). Properties of learned basis functions indicate that in natural conditions soundwaves in each ear are predominantly generated by independent sources. This implies that the real-world sound localization must rely on mechanisms more complex than a mere cue extraction. PMID- 25285659 TI - Photoisomerization and structural dynamics of two nitrosylruthenium complexes: a joint study by NMR and nonlinear IR spectroscopies. AB - In this work, the photoisomerization and structural dynamics of two isomeric nitrosylruthenium(ii) complexes [Ru(OAc)(2cqn)2NO] (H2cqn = 2-chloro-8 quinolinol) in CDCl3 and DMSO are examined using NMR and IR spectroscopic methods. The two N atoms in the 2cqn ligand are in trans position in the synthesized cis-1 isomer, while they are in cis position in the cis-2 isomer. Kinetics monitored by NMR spectroscopy shows that the rate constant of photoisomerization from cis-2 to cis-1 isomer depends on the wavelength of irradiation and solvent polarity; it proceeds faster on irradiating near the absorption peak in the UV-Vis region, and also in more polar solvents (DMSO). Density functional theory computation indicates that the peculiarity of [Ru(ii) NO(+)] group affects the structure and reactivity of the nitrosylruthenium complexes. Using the nitrosyl stretching (nuNO) to be vibrational probe, the structural dynamics and structural distributions of the cis-1 and cis-2 isomers are examined by steady-state linear infrared and ultrafast two-dimensional infrared (2D IR) spectroscopies. The structural and photochemical aspects of the observed spectroscopic parameters are discussed in terms of solute-solvent interactions for the two nitrosylruthenium complexes. PMID- 25285660 TI - Molecular cloning, characterization and expression analysis of the SAMS gene during adventitious root development in IBA-induced tetraploid black locust. AB - S-Adenosylmethionine synthetase (SAMS) catalyzes the synthesis of S adenosylmethionine (SAM), a precursor for ethylene and polyamine biosynthesis. Here, we report the isolation of the 1498 bp full-length cDNA sequence encoding tetraploid black locust (Robinia pseudoacacia L.) SAMS (TrbSAMS), which contains an open reading frame of 1179 bp encoding 392 amino acids. The amino acid sequence of TrbSAMS has more than 94% sequence identity to SAMSs from other plants, with a closer phylogenetic relationship to SAMSs from legumes than to SAMS from other plants. The TrbSAMS monomer consists of N-terminal, central, and C-terminal domains. Subcellular localization analysis revealed that the TrbSAMS protein localizes mainly to in the cell membrane and cytoplasm of onion epidermal cells and Arabidopsis mesophyll cell protoplasts. Indole-3-butyric acid (IBA) treated cuttings showed higher levels of TrbSAMS transcript than untreated control cuttings during root primordium and adventitious root formation. TrbSAMS and its downstream genes showed differential expression in shoots, leaves, bark, and roots, with the highest expression observed in bark. IBA-treated cuttings also showed higher SAMS activity than control cuttings during root primordium and adventitious root formation. These results indicate that TrbSAMS might play an important role in the regulation of IBA-induced adventitious root development in tetraploid black locust cuttings. PMID- 25285662 TI - Organocatalytic Michael addition-lactonisation of carboxylic acids using alpha,beta-unsaturated trichloromethyl ketones as alpha,beta-unsaturated ester equivalents. AB - Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2 alkenylacetic acids and alpha,beta-unsaturated trichloromethyl ketones. Ring opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high diastereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative. PMID- 25285663 TI - Dinuclear rhenium complexes as redox-active pendants in a novel electrodeposited polycyclopentadithiophene material. AB - The novel [Re2(MU-H)(MU-OOC-CPDT)(CO)6(MU-3-Me-pydz)] complex (1; OOC-CPDT = 4H cyclopenta[2,1-b:3,4-b']dithiophene-4-carboxylate, 3-Me-pydz = 3 methylpyridazine) has been prepared and characterized by single-crystal X-ray diffraction, density functional theory (DFT), and time-dependent DFT computations, UV-vis absorption and emission spectroscopy, and cyclic voltammetry (CV). The measured properties indicate the lack of electronic communication in the ground state between the CPDT and the rhenium diazine moieties. Oxidative electropolymerization of 1, achieved by repeated potential cycling (-0.4 to +1.0 V vs Fc(+)/Fc, in acetonitrile) with different supporting electrolytes, on different electrodes, afforded an electroactive and stable metallopolymer (poly 1). In situ measurements of the mass of the growing film (on a gold electrode, with an electrochemical quartz microbalance) confirmed the regularity of the polymerization process. The polymer exhibits two reversible oxidation peaks of the thiophene chain and a broad irreversible reduction peak (-1.4 V, quite close to that observed for the reduction of monomer 1), associated with a remarkably delayed sharp return peak, of comparable associated charge, appearing in close proximity (+0.3 V) to the first oxidation peak of the neutral polythiophene chain. This charge-trapping effect can be observed upon repeated cycles of p and n doping, and the negative charge is maintained even if the charged electrode is removed from the solution for many hours. Electrochemical impedance spectroscopy showed that the main CV oxidation peak corresponds to facile charge transfer, combined with very fast diffusion of both electrons and ions within the polymer. In summary, poly-1 provides a new example of a metallopolymer, in which the conductive properties of the pi-conjugated system are added to the redox behavior of the pendant-isolated complexes. PMID- 25285661 TI - Structural basis for resistance to diverse classes of NAMPT inhibitors. AB - Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development of drug resistance commonly limits the efficacy of cancer therapeutics. This study identifies mutations in NAMPT that confer resistance to a novel NAMPT inhibitor, GNE-618, in cell culture and in vivo, thus demonstrating that the cytotoxicity of GNE-618 is on target. We determine the crystal structures of six NAMPT mutants in the apo form and in complex with various inhibitors and use cellular, biochemical and structural data to elucidate two resistance mechanisms. One is the surprising finding of allosteric modulation by mutation of residue Ser165, resulting in unwinding of an alpha-helix that binds the NAMPT substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The other mechanism is orthosteric blocking of inhibitor binding by mutations of Gly217. Furthermore, by evaluating a panel of diverse small molecule inhibitors, we unravel inhibitor structure activity relationships on the mutant enzymes. These results provide valuable insights into the design of next generation NAMPT inhibitors that offer improved therapeutic potential by evading certain mechanisms of resistance. PMID- 25285664 TI - Next-generation sequencing analysis of miRNA expression in control and FSHD myogenesis. AB - Emerging evidence has demonstrated that miRNA sequences can regulate skeletal myogenesis by controlling the process of myoblast proliferation and differentiation. However, at present a deep analysis of miRNA expression in control and FSHD myoblasts during differentiation has not yet been derived. To close this gap, we used a next-generation sequencing (NGS) approach applied to in vitro myogenesis. Furthermore, to minimize sample genetic heterogeneity and muscle-type specific patterns of gene expression, miRNA profiling from NGS data was filtered with FC >= 4 (log(2)FC >= 2) and p-value<0.05, and its validation was derived by qRT-PCR on myoblasts from seven muscle districts. In particular, control myogenesis showed the modulation of 38 miRNAs, the majority of which (34 out 38) were up-regulated, including myomiRs (miR-1, -133a, -133b and -206). Approximately one third of the modulated miRNAs were not previously reported to be involved in muscle differentiation, and interestingly some of these (i.e. miR 874, -1290, -95 and -146a) were previously shown to regulate cell proliferation and differentiation. FSHD myogenesis evidenced a reduced number of modulated miRNAs than healthy muscle cells. The two processes shared nine miRNAs, including myomiRs, although with FC values lower in FSHD than in control cells. In addition, FSHD cells showed the modulation of six miRNAs (miR-1268, -1268b, 1908, 4258, -4508- and -4516) not evidenced in control cells and that therefore could be considered FSHD-specific, likewise three novel miRNAs that seem to be specifically expressed in FSHD myotubes. These data further clarify the impact of miRNA regulation during control myogenesis and strongly suggest that a complex dysregulation of miRNA expression characterizes FSHD, impairing two important features of myogenesis: cell cycle and muscle development. The derived miRNA profiling could represent a novel molecular signature for FSHD that includes diagnostic biomarkers and possibly therapeutic targets. PMID- 25285667 TI - Exploring the activation modes of a rotaxane-based switchable organocatalyst. AB - The reactivity of a rotaxane that acts as an aminocatalyst for the functionalization of carbonyl compounds through HOMO and LUMO activation pathways has been studied. Its catalytic activity is explored for C-C and C-S bond forming reactions through iminium catalysis, in nucleophilic substitutions and additions through enamine intermediates, in Diels-Alder reactions via trienamine catalysis, and in a tandem iminium-ion/enamine reaction. The catalyst can be switched "on" or "off", effectively controlling the rate of all of these chemical transformations, by the in situ change of the position of the macrocycle between two different binding sites on the rotaxane thread. PMID- 25285666 TI - An international comparison of deceased and living organ donation/transplant rates in opt-in and opt-out systems: a panel study. AB - BACKGROUND: Policy decisions about opt-in and opt-out consent for organ donation are based on limited evidence. To fill this gap we investigated the difference between deceased and living organ donation rates in opt-in and opt-out consent systems across a 13 year period. We controlled for extensive covariates and estimated the causal effect of consent with instrumental variables analysis. METHOD: This panel study used secondary data analysis to compare organ donor and transplant rates in 48 countries that had either opt-in or opt-out consent. Organ donation data were obtained over a 13-year period between 2000 and 2012. The main outcome measures were the number of donors, number of transplants per organ and total number (deceased plus living) of kidneys and livers transplanted. The role of consent on donor and transplant rates was assessed using multilevel modeling and the causal effect estimated with instrumental variables analysis. RESULTS: Deceased donor rates (per-million population) were higher in opt-out (M = 14.24) than opt-in consent countries (M = 9.98; Beta = -4.27, 95% confidence interval (CI) = -8.08, -0.45, P = .029). However, the number of living donors was higher in opt-in (M = 9.36) than opt-out countries (M = 5.49; B = 3.86, 95% CI = 1.16, 6.56, P = .006). Importantly, the total number of kidneys transplanted (deceased plus living) was higher in opt-out (M = 28.32) than opt-in countries (M = 22.43; B = -5.89, 95% CI = -11.60, -0.17, P = .044). Similarly, the total number of livers transplanted was higher in opt-out (M = 11.26) than opt-in countries (M = 7.53; B = -3.73, 95% CI = -7.47, 0.01, P = .051). Instrumental variables analysis suggested that the effect of opt-in versus opt-out consent on the difference between deceased and living donor rates is causal. CONCLUSIONS: While the number of deceased donors is higher than the number of living donors, opt-out consent leads to a relative increase in the total number of livers and kidneys transplanted. PMID- 25285668 TI - Oxaloacetate acetylhydrolase gene mutants of Sclerotinia sclerotiorum do not accumulate oxalic acid, but do produce limited lesions on host plants. AB - The oxaloacetate acetylhydrolase (OAH, EC 3.7.1.1)-encoding gene Ss-oah1 was cloned and functionally characterized from Sclerotinia sclerotiorum. Ss-oah1 transcript accumulation mirrored oxalic acid (OA) accumulation with neutral pH induction dependent on the pH-responsive transcriptional regulator Ss-Pac1. Unlike previously characterized ultraviolet (UV)-induced oxalate-deficient mutants ('A' mutants) which retain the capacity to accumulate OA, gene deletion Deltass-oah1 mutants did not accumulate OA in culture or during plant infection. This defect in OA accumulation was fully restored on reintroduction of the wild type (WT) Ss-oah1 gene. The Deltass-oah1 mutants were also deficient in compound appressorium and sclerotium development and exhibited a severe radial growth defect on medium buffered at neutral pH. On a variety of plant hosts, the Deltass oah1 mutants established very restricted lesions in which the infectious hyphae gradually lost viability. Cytological comparisons of WT and Deltass-oah1 infections revealed low and no OA accumulation, respectively, in subcuticular hyphae. Both WT and mutant hyphae exhibited a transient association with viable host epidermal cells at the infection front. In summary, our experimental data establish a critical requirement for OAH activity in S. sclerotiorum OA biogenesis and pathogenesis, but also suggest that factors independent of OA contribute to the establishment of primary lesions. PMID- 25285669 TI - Development of a ReaxFF reactive force field for tetrabutylphosphonium glycinate/CO2 mixtures. AB - Carbon dioxide interacts with the ionic liquid tetrabutylphosphonium glycinate, [P(C4)4][Gly], through both physical and chemical absorption. We present a parametrization of the ReaxFF force field for this system that accounts for both chemical and physical interactions. The parametrization was developed from an extensive training set including periodic density functional theory (DFT) calculations of reaction pathways between CO2 and the anion [Gly](-) in the condensed phase, condensed-phase molecular dynamics (MD) configurations, gas phase CO2-anion and CO2-cation interactions, and gas-phase cluster calculations for intra-ion interactions. The optimized ReaxFF parameters capture the essential features of both physical and chemical interactions between CO2 and [P(C4)4][Gly] as compared with experiments, van der Waals-corrected DFT calculations, or, in the case of physical interactions, classical force field calculations. The probability distributions of the distance between C (from CO2) and N (from the anion) and the CO2 bend angles calculated from MD simulations with the optimized ReaxFF force field are in good general agreement with those from DFT-based MD simulations. We predict that the density of CO2/[P(C4)4][Gly] mixtures increases with increasing CO2 concentration up to at least 50 mol % CO2. We attribute the significant increase in density to the small effective volume occupied by chemically bound CO2 in the mixture. The predicted increase in density may be tested experimentally. PMID- 25285670 TI - Polycation-b-polyzwitterion copolymer grafted luminescent carbon dots as a multifunctional platform for serum-resistant gene delivery and bioimaging. AB - Nanomaterials that integrate functions of imaging and gene delivery have been of great interest due to their potential use in simultaneous diagnosis and therapy. Herein, polycation-b-polysulfobetaine block copolymer, poly[2-(dimethylamino) ethyl methacrylate]-b-poly[N-(3-(methacryloylamino) propyl)-N,N-dimethyl-N-(3 sulfopropyl) ammonium hydroxide] (PDMAEMA-b-PMPDSAH) grafted luminescent carbon dots (CDs) were prepared via surface-initiated atom transfer radical polymerization (ATRP) and investigated as a multifunctional gene delivery system (denoted as CD-PDMA-PMPD) in which the CD cores acted as good multicolor cell imaging probes, the cationic PDMAEMA acted as a DNA condensing agent, and the outer shell of zwitterionic PMPDSAH block protected the vector against nonspecific interactions with serum components. As revealed by the fluorescent spectrum study, the photoluminescent attributes, especially the tunable emission property, were well inherited from the parent CDs. The CD-PDMA-PMPD could condense plasmid DNA into nanospheres with sizes of approximate 50 nm at a proper complex ratio, posing little cytotoxicity at higher ratios. It was shown that the hybrid vector exhibited significantly suppressed BSA protein adsorption and superior hemocompatibility compared to those of the widely used PEI25k. In the in vitro transfection assay, an increased serum concentration from 10 to 50% caused a dramatic drop in PEI25k transfection performance, whereas the transfection efficiency of CD-PDMA-PMPD was well maintained; CD-PDMA80-PMPD40 showed 13 and 28 times higher transfection efficiencies than PEI25k at 30 and 50% serum concentration, respectively. Intriguingly, the carbon dots in the transfected cells displayed excitation-dependent fluorescent emissions, portending that this polycation-polyzwitterion modified CD will be a promising theranostic vector with excellent stealth performance. PMID- 25285671 TI - Plasmapheresis for Preventing Complication of Hypertriglyceridemia: A Case Report and Review of Literature. AB - Severe hypertriglyceridemia is a common indication for the need of plasma exchange in treatment of hypertriglyceridemic-induced pancreatitis when normal therapies fail to garner a response. Application of plasmapheresis to prevent complication of hypertriglyceridemia is limited because of its cost and availability. We present a case of a 44-year-old man with metabolic syndrome and a medical history of secondary polycythemia in obesity hypoventilation syndrome, whose laboratory tests revealed a triglycerides value of 3965 mg/dL. To prevent the complication of pancreatitis due to hypertriglyceridemia, we performed plasma exchange 3 times when conventional treatments did not sufficiently reduce the high level of triglycerides. A review of the current available literature was therefore conducted to provide an overview of the present data on apheretic treatment for patients with severe hypertriglyceridemia. Several case reports and case series have used plasmapheresis in acute treatment of hypertriglyceridemia pancreatitis related. In our case, the choice of plasmapheresis was applied in prevention of possible complications of hypertriglyceridemia. PMID- 25285672 TI - A Prognostic Index to Identify Patients With Intrahepatic Cholangiocarcinoma Who Could Benefit From Gemcitabine Plus Cisplatin. AB - Biliary tract cancer is a heterogenous group. Gemcitabine plus cisplatin has been the standard chemotherapy for advanced biliary tract cancer, but there is lack of evidence on treatment in patients with intrahepatic cholangiocarcinoma (IHC). We analyzed 29 patients with only IHC who received gemcitabine plus cisplatin between June 2010 and February 2013. The median age was 63 years (range, 40-78 years), and Eastern Cooperative Oncology Group performance status of all patients was <2. The median progression-free survival and median overall survival (OS) were 4.3 and 7.3 months, respectively. Multivariate analysis showed that platelet count (<=180 * 10 per liter), metastatic site of more than 2, and albumin level (<=3.5 g/dL) were independent prognostic factors for decreased OS. OS was estimated based on the number of adverse prognostic factors: zero or 1 (good prognostic group), 2 (intermediate group), or 3 (poor prognostic group). The median OS for good (n = 15), intermediate (n = 10), and poor (n = 4) prognostic group was 10.5, 6.1, and 1.6 months, respectively (P < 0.005). Relatively better prognosis of the good prognosis group comparing to other prognosis groups can be expected from the prognostic model established in this study by analyzing patients with IHC treated with gemcitabine. PMID- 25285673 TI - Katayama et Al.: therapeutic window of lamotrigine for mood disorders: a naturalistic retrospective study. Pharmacopsychiatry 2014; 47: 111-114. AB - Katayama and colleagues proposed in their article a therapeutic window for lamotrigine in affective disorders between 5 and 11 MUg/mL. Despite potential differences in lamotrigine metabolism, the results of their retrospective study in a Japanese population match nicely with what we have previously reported in a Caucasian population with rapid cycling bipolar disorder. It is suggested that not only in epilepsy, but also in mood-disordered patients clinicians should rather consider lamotrigine plasma levels than dosage when in doubt about the efficacy of treatment. PMID- 25285674 TI - Modeling the lifecycle of Ebola virus under biosafety level 2 conditions with virus-like particles containing tetracistronic minigenomes. AB - Ebola viruses cause severe hemorrhagic fevers in humans and non-human primates, with case fatality rates as high as 90%. There are no approved vaccines or specific treatments for the disease caused by these viruses, and work with infectious Ebola viruses is restricted to biosafety level 4 laboratories, significantly limiting the research on these viruses. Lifecycle modeling systems model the virus lifecycle under biosafety level 2 conditions; however, until recently such systems have been limited to either individual aspects of the virus lifecycle, or a single infectious cycle. Tetracistronic minigenomes, which consist of Ebola virus non-coding regions, a reporter gene, and three Ebola virus genes involved in morphogenesis, budding, and entry (VP40, GP1,2, and VP24), can be used to produce replication and transcription-competent virus-like particles (trVLPs) containing these minigenomes. These trVLPs can continuously infect cells expressing the Ebola virus proteins responsible for genome replication and transcription, allowing us to safely model multiple infectious cycles under biosafety level 2 conditions. Importantly, the viral components of this systems are solely derived from Ebola virus and not from other viruses (as is, for example, the case in systems using pseudotyped viruses), and VP40, GP1,2 and VP24 are not overexpressed in this system, making it ideally suited for studying morphogenesis, budding and entry, although other aspects of the virus lifecycle such as genome replication and transcription can also be modeled with this system. Therefore, the tetracistronic trVLP assay represents the most comprehensive lifecycle modeling system available for Ebola viruses, and has tremendous potential for use in investigating the biology of Ebola viruses in future. Here, we provide detailed information on the use of this system, as well as on expected results. PMID- 25285675 TI - Human neurons derived from induced pluripotent stem cells as a new platform for preclinical drug screening and development. PMID- 25285676 TI - Molecular investigation of distal renal tubular acidosis in Tunisia, evidence for founder mutations. AB - BACKGROUND: Distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H+ ions in the intercalated cells of the collecting duct. Both autosomal dominant and recessive forms have been described; the latter is also associated with sensorineural hearing loss. METHODS: Twenty-two Tunisian families were analyzed for mutations in the ATP6V1B1 and ATP6V0A4 genes by direct sequencing. Dating of the founder mutations was performed. RESULTS: Two founder mutations in the ATP6V1B1 gene were found in 16/27 dRTA cases. The p.Ile386Hisfs*56 founder mutation was estimated to be older than 2400 years and no correlations were found with deafness. For the remaining patients, two mutations in the ATP6V0A4 gene, one of them being novel, were found in three Tunisian cases. The presence of a heterozygous missense mutation p.T30I, of the ATP6V1B1 gene, was identified in six patients, while no mutations of the second gene were detected. No deleterious mutations of either ATP6V1B1 or ATP6V0A were found for the two probands. CONCLUSION: Our study gives evidence of phenotypic and genotypic heterogeneity of dRTA in the Tunisian population. Five different mutations were found, two of them were due to a founder effect, and screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA. PMID- 25285677 TI - An evaluation of SERI surgical scaffold for soft-tissue support and repair in an ovine model of two-stage breast reconstruction. AB - This study was designed to evaluate the SERI Surgical Scaffold, a silk-derived bioresorbable scaffold, in an ovine model of two-stage breast reconstruction. Sheep were implanted bilaterally with either SERI or sham sutures during the stage 1 procedure. The SERI group underwent an exchange procedure for a breast implant at 3 months; animals in the sham group were killed at 3 months. The sham samples were significantly weaker than the SERI plus tissue samples by 3 months. At all endpoints, SERI plus tissue samples were greater than or equal to 150 percent of native ovine fascial strength. Histologic evaluation of SERI samples showed evidence of bioresorption through 12 months. SERI provided adequate soft tissue support with progressive bioresorption. By 12 months, newly formed tissue had assumed the majority of load-bearing responsibility. PMID- 25285678 TI - Flap coverage outcomes following vascular injury and repair: chronicling a decade of severe war-related extremity trauma. AB - BACKGROUND: Combat-related extremity injuries frequently require vascular repair within the combat theater before undergoing definitive reconstruction. This study examines the outcomes of early vascular repair with secondary soft-tissue extremity reconstruction over the past decade of war trauma. METHODS: War-related extremity injuries necessitating a downrange vascular procedure followed by a definitive limb reconstruction were reviewed. Patient demographics, type and location of vascular injuries, vascular intervention, and soft-tissue reconstruction procedures were examined. Outcomes of vascular repair, tissue transfer, and limb salvage were analyzed. RESULTS: From 2003 to 2012, 79 extremities in 78 patients had a vascular injury requiring in-theater intervention followed by 87 staged flap reconstructions performed distal to the vascular repair. Of the 74 arterial injuries requiring intervention, 27 were proximally located, with 73 percent requiring bypass. The early primary patency rate was 66 percent and the early primary-assisted patency rate was 93 percent for proximal artery repair procedures. The flap complication rate was 31 percent. Overall complications were examined by subtype and were not significantly different compared with flaps performed without a proximal vascular injury in the same limb. The flap success rate (93 percent) and the limb salvage rate (81 percent) were similar to the comparison cohort. CONCLUSIONS: This represents one of the largest series of traumatic extremity injuries requiring secondary limb reconstruction with tissue transfer following a vascular intervention. The authors identified no significant difference in outcomes related to flap coverage or limb salvage for patients with or without vascular injuries. Reconstructive options in combat extremity trauma are not limited by proximal vascular injury. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25285679 TI - Does water-jet force make a difference in fat grafting? In vitro and in vivo evidence of improved lipoaspirate viability and fat graft survival. AB - BACKGROUND: Recent literature has revealed that water-jet-assisted liposuction offers a new method of conventional liposuction techniques by using the gentle spray of fluid. However, there has not yet been a systematic, randomized, controlled study to demonstrate its effect on the vitality and postoperative fat survival of fresh lipoaspirates. In this study, the authors compared liposuction with or without water-jet assistance in a blinded fashion. METHODS: Human lipoaspirates were obtained from healthy Chinese female volunteers for body shaping. Lipoaspirates were harvested by a single surgeon using the same material and machine; water-jet assistance was the only variance in this study. At the beginning of surgery, the authors randomly performed conventional manual liposuction without water-jet assistance for one side to obtain 50 ml of lipoaspirate (group B). At the corresponding area of the other side, the authors used water-jet-assisted liposuction to obtain another 50 ml of lipoaspirate (group A). All of the harvested lipoaspirates were used in the in vitro and in vivo experiments to evaluate the effect of water-jet force on the vitality and postoperative fat survival of fresh lipoaspirates. RESULTS: Fresh lipoaspirates from group A had greater viability and a higher percentage of CD34/CD45 cells than group B. Grafted lipoaspirates in group A had better weight retention, less apoptosis, and greater angiogenesis. CONCLUSIONS: The fate of grafted lipoaspirates was affected by water-jet force. With the assistance of water-jet force during the harvesting procedure, the authors could obtain more viable lipoaspirates and achieve better fat survival. PMID- 25285680 TI - Financial conflicts of interest in plastic surgery: background, potential for bias, disclosure, and transparency. AB - Relationships between physicians and industry, whether it be pharmaceutical companies, medical device manufacturers, or purveyors of medical technology, contain both an element of potential for good and a potential for harm. Certainly, the potential for good is realized when the collaboration results in improved plastic surgery patient care due to product and technology development. If the collaboration contains a financial component, the potential for harm exists in the form of a financial conflict of interest on the part of the physician. Recently, considerable discussion has been directed toward the pervasiveness of financial conflict of interest in all three arenas of the profession of medicine: education, research, and clinical practice, although an overlap exists among all three with respect to the issue of conflict of interest. This article will focus on conflict of interest in plastic surgery education, both continuing medical education for practitioners and graduate medical education for plastic surgery residents, as well as conflict of interest in research, such as conflicts related to publications in our literature. PMID- 25285681 TI - Comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA at the 1: 3 conversion ratio for the treatment of asymmetry after long-term facial paralysis. AB - BACKGROUND: Botulinum toxin A injection into the nonparalyzed side is used to treat asymmetry resulting from facial palsy. OnabotulinumtoxinA and abobotulinumtoxinA units are not equivalent. The authors compared the conversion ratio of 1:3 in patients with facial palsy. METHODS: Fifty-five patients (age, 16 to 67 years; 43 women) with longstanding facial palsy were randomly treated with either onabotulinumtoxinA (n = 25) or abobotulinumtoxinA (n = 30) injections into the nonparalyzed side. Adverse effects, facial symmetry, subjective satisfaction, and Facial Disability Index were assessed after 1 and 6 months. RESULTS: The incidence of adverse effects was higher with abobotulinumtoxinA (93.3 percent versus 64.0 percent; p = 0.007). Clinical scores of the nonparalyzed side decreased after 1 month and increased again at 6 months, with no between-group differences. Scores of the paralyzed side were lower in the onabotulinumtoxinA group before treatment, but similar in both groups thereafter. The paralyzed side scores increased after 1 month, and at 6 months were still higher than the pretreatment scores in both groups. Subjective assessment improved at all time points compared with pretreatment scores and differed between the two groups only at 1 month, when the abobotulinumtoxinA group was a bit too paralyzed. The physical function and social/well-being function subscales of the Facial Disability Index did not differ between the two groups. CONCLUSIONS: Both toxins efficiently reduced asymmetry in patients with facial palsy. Adverse effects were higher with abobotulinumtoxinA at an equivalence ratio of 1:3. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25285682 TI - Deep inferior epigastric artery perforator flap donor-site closure with cannula assisted, limited undermining, and progressive high-tension sutures versus standard abdominoplasty: complications, sensitivity, and cosmetic outcomes. AB - BACKGROUND: In deep inferior epigastric artery perforator (DIEP) flap breast reconstruction, abdominal donor-site cosmetic and sensibility outcomes and the closure technique have drawn little attention in the literature, with many surgeons still following the principles of standard abdominoplasty. In this article, the authors report their experience with the cannula-assisted, limited undermining, and progressive high-tension suture ("CALP") technique of DIEP donor site closure compared with standard abdominoplasty. METHODS: Between December of 2008 and January of 2013, 137 consecutive women underwent DIEP flap breast reconstruction. Of these, 82 patients (between December of 2008 and November of 2011) underwent DIEP flap donor-site closure by means of standard abdominoplasty (control group) and 55 patients (from December of 2011 to January of 2013) by means of cannula-assisted, limited undermining, and progressive high-tension suture (study group). The abdominal drainage daily output, donor-site complications, abdominal skin sensitivity at 1-year follow-up, cosmetic outcomes, and patient satisfaction were recorded and analyzed statistically. RESULTS: Daily drainage output was significantly lower in the study group. Donor-site complications were significantly higher in the control group (37.8 percent versus 9 percent). Seroma and wound healing problems were experienced in the control group. Abdominal skin sensibility was better preserved in the study group. Overall, abdominal wall aesthetic outcomes were similar in both groups, except for scar quality (better in the study group). CONCLUSION: According to the authors' experience, cannula-assisted, limited undermining, and progressive high tension suture should be always preferred to standard abdominoplasty for DIEP donor-site closure to reduce the complication rate to improve abdominal skin sensitivity and scar quality. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25285683 TI - Reverse lymphatic mapping: a new technique for maximizing safety in vascularized lymph node transfer. AB - BACKGROUND: The authors introduce the technique of reverse lymphatic mapping for vascularized lymph node transfer. This physiologic technique allows one to identify which lymph nodes drain the trunk as opposed to the extremity, to minimize the risk of iatrogenic lymphedema. METHODS: A prospective study of patients undergoing vascularized lymph node transfer using the reverse lymphatic mapping technique was conducted. Patients received technetium injections in the first and second webspaces of the foot and intradermal indocyanine green injections in the lower abdomen. Lymphatic vessels were traced to the lymph nodes draining the lower abdomen that were harvested; a gamma probe was used to localize lymph nodes draining the lower extremity, which were avoided. In cases of vascularized axillary lymph node transfer, technetium was injected into the hand and indocyanine green was injected into the back and lateral chest. Ten second counts were recorded of the lymph node flap and the sentinel node draining the extremity for comparison. RESULTS: Thirty-five patients underwent vascularized lymph node transfer (19 groin and 16 axillary lymph node transfers) guided by reverse lymphatic mapping. Follow-up time was 1 to 30 months. Mean 10 second count using the gamma probe for all lymph node flaps was 88.6 (SD, 123; median, 39); mean 10-second count of extremity sentinel nodes was 2462 (SD, 2115; median, 2000). On average, 10-second signal strength of the lymph node flap was 6.0 percent that of the extremity sentinel node. CONCLUSION: Reverse lymphatic mapping guides vascularized lymph node flap harvest based on physiologic drainage patterns of the trunk and limb that may minimize the risk of iatrogenic lymphedema. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25285684 TI - Nonsurgical periorbital and brow rejuvenation. AB - BACKGROUND: There is a high patient demand for periorbital rejuvenation because the periorbita are often the first facial areas to show visible signs of aging. In addition to rhytides and skin laxity, aging appearance of the periorbital area is caused by changes in tissue volume resulting from soft-tissue atrophy and bone loss in the aging face. These changes are among the easiest areas to correct using several noninvasive techniques. The author uses three different techniques in his practice. METHODS: The author shares his experience using three different techniques for nonsurgical periorbital rejuvenation. RESULTS: Patients develop unique crow's feet lines, and treatment with toxins should be adapted to each particular pattern. Low doses generally produce a more natural appearance than high doses. Using hyaluronic acid fillers, three tissue layers within the periorbita can be injected to produce maximally beneficial results and minimize the risk of adverse events. Filling tear troughs depends on whether they occurred early in life or are age-related. The key to avoiding complications is a careful patient analysis and a slow technique. CONCLUSIONS: One deformity should not be singled out when rejuvenating the periorbita. The best results are obtained when the entire periorbital area is treated at the same time. PMID- 25285685 TI - The management of midline frontonasal dermoids: a review of 55 cases at a tertiary referral center and a protocol for treatment. AB - BACKGROUND: The incidence of midline frontonasal dermoid cysts is one in 20,000 to one in 40,000. These lesions may have intracranial extension. This is explained by the anatomy and embryology of nasofrontal development. Skin involvement may also be extensive. Incomplete excision frequently leads to recurrence. The authors report their experience and pathway for management of midline dermoids. METHODS: Databases were searched to identify patients who had undergone surgery for removal of a dermoid cyst. Preoperative imaging and indications for surgery were reviewed. Cases were grouped according to surgical approach, and outcomes and complications were identified. RESULTS: Fifty-five patients were treated. Magnetic resonance imaging or computed tomography was used to delineate the anatomy, and surgical excision was expedited if there was a history of infection, especially if imaging suggested intracranial extension. Twelve patients were treated endoscopically (one was converted to open). Eleven required transcranial approaches for intracranial extension (20 percent). Of these, one lesion breached the dura. The remaining 32 patients had dermoids excised with an open approach (direct, bicoronal, or rhinoplasty). There were no recurrences in the open group and there was one recurrence in the transcranial group. This was treated by reexcision. CONCLUSION: Midline dermoid cysts are relatively uncommon. However, knowledge of the pathogenesis of these lesions together with the authors' experience over 15 years has allowed them to develop a protocol-driven approach, with a low incidence of complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25285686 TI - Disorders of the distal radioulnar joint. AB - The distal radioulnar joint is responsible for stable forearm rotation. Injury to this joint can occur following a variety of mechanisms, including wrist fractures, ligamentous damage, or degenerative wear. Accurate diagnosis requires a clear understanding of the anatomy and mechanics of the ulnar aspect of the wrist. Injuries can be divided into three major categories for diagnostic purposes, and these include pain without joint instability, pain with joint instability, and joint arthritis. New advancements in imaging and surgical technique can allow for earlier detection of injuries, potentially preserving joint function. In this article, the authors review the pertinent anatomy, biomechanics, and major abnormality involving the distal radioulnar joint. PMID- 25285687 TI - Propagation of Homalodisca coagulata virus-01 via Homalodisca vitripennis cell culture. AB - The glassy-winged sharpshooter (Homalodisca vitripennis) is a highly vagile and polyphagous insect found throughout the southwestern United States. These insects are the predominant vectors of Xylella fastidiosa (X. fastidiosa), a xylem limited bacterium that is the causal agent of Pierce's disease (PD) of grapevine. Pierce's disease is economically damaging; thus, H. vitripennis have become a target for pathogen management strategies. A dicistrovirus identified as Homalodisca coagulata virus-01 (HoCV-01) has been associated with an increased mortality in H. vitripennis populations. Because a host cell is required for HoCV 01 replication, cell culture provides a uniform environment for targeted replication that is logistically and economically valuable for biopesticide production. In this study, a system for large-scale propagation of H. vitripennis cells via tissue culture was developed, providing a viral replication mechanism. HoCV-01 was extracted from whole body insects and used to inoculate cultured H. vitripennis cells at varying levels. The culture medium was removed every 24 hr for 168 hr, RNA extracted and analyzed with qRT-PCR. Cells were stained with trypan blue and counted to quantify cell survivability using light microscopy. Whole virus particles were extracted up to 96 hr after infection, which was the time point determined to be before total cell culture collapse occurred. Cells were also subjected to fluorescent staining and viewed using confocal microscopy to investigate viral activity on F-actin attachment and nuclei integrity. The conclusion of this study is that H. vitripennis cells are capable of being cultured and used for mass production of HoCV-01 at a suitable level to allow production of a biopesticide. PMID- 25285688 TI - In Vitro Model for Predicting the Protective Effect of Ultraviolet-Blocking Contact Lens in Human Corneal Epithelial Cells. AB - PURPOSE: To develop an in vitro method to determine the protective effect of UV blocking contact lenses (CLs) in human corneal epithelial (HCE) cells exposed to UV-B radiation. MATERIALS AND METHODS: SV-40-transformed HCE cells were covered with non-UV-blocking CL, UV-blocking CL or not covered, and exposed to UV-B radiation. As control, HCE cells were covered with both types of CLs or not covered, but not exposed to UV-B radiation. Cell viability at 24, 48 and 72 h, after UV-B exposure and removing CLs, was determined by alamarBlue((r)) assay. Percentage of live, dead and apoptotic cells was also assessed by flow cytometry after 24 h of UV-B exposure. Intracellular reactive oxygen species (ROS) production after 1 h of exposure was assessed using the dye H(2)DCF-DA. RESULTS: Cell viability significantly decreased, apoptotic cells and intracellular ROS production significantly increased when UVB-exposed cells were covered with non UV-blocking CL or not covered compared to non-irradiated cells. When cells were covered with UV-blocking CL, cell viability significantly increased and apoptotic cells and intracellular ROS production did not increase compared to exposed cells. CONCLUSIONS: UV-B radiation induces cell death by apoptosis, increases ROS production and decreases viable cells. UV-blocking CL is able to avoid these effects increasing cell viability and protecting HCE cells from apoptosis and ROS production induced by UV-B radiation. This in vitro model is an alternative to in vivo methods to determine the protective effect of UV-blocking ophthalmic biomaterials because it is a quicker, cheaper and reliable model that avoids the use of animals. PMID- 25285689 TI - Hapalindoles from the cyanobacterium fischerella: potential sodium channel modulators. AB - Hapalindoles make up a large group of bioactive metabolites of the cyanobacterial order Stigonematales. 12-epi-Hapalindole E isonitrile, 12-epi-hapalindole C isonitrile, 12-epi-hapalindole J isonitrile, and hapalindole L from Fischerella are acutely toxic for insect larvae; however, the biochemical targets responsible for the biological activities of hapalindoles are not understood. We describe here the electron impact mass spectra of these four hapalindole congeners; their structures were confirmed by nuclear magnetic resonance spectroscopy. In combination with the presented mass spectra of (15)N-labeled species and their retention times on a gas chromatography capillary column, a rapid and reliable determination should be possible in future research. The bioactivity of these hapalindoles was tested on mammalian cells focusing on their effects in the BE(2) M17 excitable human neuroblastoma cell line. The fluorescent dye Alamar Blue was applied to monitor cytotoxicity, fura-2 to evaluate changes in the cytosolic calcium concentrations, and bis-oxonol to detect effects on membrane potential. Data showed that the hapalindoles did not affect cell viability of the neuroblastoma cells, even when they were incubated for 72 h. Neither depolarization nor initiation of calcium influx was observed in the cells upon hapalindole treatment. However, the data provide evidence that hapalindoles are sodium channel-modulating neurotoxins. They inhibited veratridine-induced depolarization in a manner similar to that of neosaxitoxin. Our data suggest hapalindoles should be added to the growing number of neurotoxic secondary metabolites, such as saxitoxins and anatoxins, already known in freshwater cyanobacteria. As stable congeners, hapalindoles may be a risk in freshwater ecosystems or agricultural water usage and should therefore be considered in water quality assessment. PMID- 25285690 TI - Long-term outcome of local excision after preoperative chemoradiation for ypT0 rectal cancer. AB - BACKGROUND: Local excision, as an alternative to radical resection for patients with pathological complete response (ypT0) after preoperative chemoradiation, is under investigation. OBJECTIVE: The aim of the present study was to evaluate the long-term clinical outcome of a selected group of patients with ypT0 rectal cancer who underwent local excision with transanal endoscopic microsurgery as a definitive treatment. PATIENTS: Between 1993 and 2013, 43 patients with rectal adenocarcinoma underwent complete full-thickness local excision with a transanal endoscopic microsurgery procedure after a regimen of chemoradiation. In all patients, rectal wall penetration was preoperatively assessed by endorectal ultrasound and/or magnetic resonance. Chemoradiation and transanal endoscopic microsurgery were indicated in patients refusing radical procedures or patients unfit for major abdominal procedures. MAIN OUTCOME MEASURES: Patient characteristics, operative record, pathology report, and tumor recurrence were analyzed at a median follow-up of 81 months. The potential prognostic factors for recurrence, screened in univariate analysis, were analyzed by multivariate analysis by using the Cox regression model. RESULTS: Thirteen patients (30.2%), without residual tumor in the surgical specimen (ypT0), were treated with transanal endoscopic microsurgery only. In this ypT0 group, 2 patients (15.4%) had postoperative complications: 1 bleeding and 1 suture dehiscence. Postoperative mortality was nil. No local and distal recurrences were observed, and no tumor-related mortality occurred. In 30 patients (69.8%), partial tumor chemoradiation response or the absence of tumor chemoradiation response was observed. In this group, recurrence occurred in 17 patients (56.7%). LIMITATIONS: The study was limited by its retrospective nature, different protocols of chemoradiation and preoperative staging over time, and the small sample size. CONCLUSIONS: Local excision with transanal endoscopic microsurgery can be considered a definitive therapeutic option in patients with rectal cancer treated with preoperative chemoradiation, when no residual tumor is found in the specimen. In this selected group, local excision offers excellent results in terms of survival and recurrence rates. In the presence of residual tumor, transanal endoscopic microsurgery should be considered as a large excisional biopsy (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A157). PMID- 25285691 TI - Transanal local excision for distal rectal cancer and incomplete response to neoadjuvant chemoradiation - does baseline staging matter? AB - BACKGROUND: Local excision may offer the possibility of organ preservation for the management of select patients after neoadjuvant chemoradiation. The oncological outcomes of this strategy have been largely associated with the risk of nodal metastases. Therefore, in addition to final ypT status, baseline staging has been suggested to potentially influence the outcomes of this treatment modality. OBJECTIVE: The aim of this study is to compare the pathological and oncological outcomes of patients following neoadjuvant chemoradiation and incomplete clinical response managed by transanal endoscopic microsurgery according to baseline staging. DESIGN: This study is a retrospective review of prospectively collected data. SETTINGS: The study was conducted at a single center. PATIENTS: Forty-six patients with distal rectal cancer cT2-4N0-2M0 underwent 5-fluorouracil-based neoadjuvant chemoradiation. Assessment of response was performed at least 8 weeks from radiotherapy completion. Patients with a complete clinical response were not operated on immediately. Patients with an incomplete clinical response were managed by surgery. Those with small (<=3 cm) residual cancers (ycT1-2N0M0) were managed by transanal endoscopic microsurgery. MAIN OUTCOME MEASURES: Patients undergoing local excision following chemoradiation were compared according to baseline staging. RESULTS: Fifteen patients (32%) were cT2N0 at baseline. Final ypT status was ypT0 in 3 (20%) patients, ypT1 in 2 (13%) patients, ypT2 in 9 (60%) patients, and ypT3 in 1 (7%) patient. There were no differences in final ypT status in comparison with patients with baseline cT3-4 or cN+ undergoing chemoradiation followed by transanal endoscopic microsurgery (p = 0.38). Local recurrence was observed in 1 patient with baseline cT2N0 (7%) and in 7 patients (23%) with stage II and III (p = 0.18). LIMITATIONS: This study was limited by the short follow-up, its limited sample size, and its retrospective and nonrandomized nature. CONCLUSIONS: Patients with baseline cT2N0 that do not develop complete response to chemoradiation (ycT0-2N0; <=3 cm) frequently present unfavorable pathological features for transanal local excision (ypT2 or 3 in >66%). In the presence of incomplete clinical response following chemoradiation, patients with baseline cT2N0 have pathological and oncological outcomes similar to patients with baseline stage II or III and are probably not ideal candidates for local excision (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A159). PMID- 25285692 TI - Preoperative staging CT thorax in patients with colorectal cancer: its clinical importance. AB - BACKGROUND: Recent studies suggest that there is little benefit to routine preoperative staging CT of the thorax in colorectal cancer. OBJECTIVE: The current study hypothesized that staging CT of the thorax is not mandated in all patients with colorectal cancer. DESIGN: This study was a tertiary-care center retrospective observational study. PATIENTS: Patients with a diagnosis of colon and rectal adenocarcinoma during 2006 to 2011 were included in a hospital database. Demographic, pathological, radiological, survival, and clinical factors were recorded. Three hundred eighty-two patients were included in the analysis (234 male, 148 female). INTERVENTIONS: All patients underwent preoperative staging CT of the thorax to determine the presence of pulmonary metastasis and/or indeterminate lesions. MAIN OUTCOME MEASURES: Patients demographics were reviewed, and the factors associated with pulmonary metastasis and indeterminate lesions were evaluated. RESULTS: Distant metastases were evident in 61 patients (16%). CT scans revealed pulmonary metastasis in 23 patients (6%), and indeterminate lesions in 33 (8.6%). Only one-third of pulmonary lesions were evident on chest x-ray. On logistic regression analysis, nodal positivity was associated with an increased risk for pulmonary metastasis (p = 0.03). There was no difference in overall survival between patients with pulmonary metastasis and indeterminate lesions (p = 0.35, Kaplan-Meier estimate, log rank analysis). Pulmonary metastasis developed during postoperative surveillance in 7 patients with indeterminate lesions (21.2%). LIMITATIONS: This is a retrospective, single center study with a relatively small sample size. CONCLUSIONS: Pulmonary metastasis is relatively rare in colorectal cancer, and staging CT of the thorax may not be mandated in low-risk patients. PMID- 25285693 TI - Defunctioning cannula ileostomy after lower anterior resection of rectal cancer. AB - BACKGROUND AND OBJECTIVE: Most surgeons suggest the use of fecal diversion in patients undergoing low anterior resections of rectal tumors at high risk for anastomotic leakage. We describe an exploratory study to evaluate the efficacy and safety of a new diversion method called a spontaneously closing cannula ileostomy, which was designed to protect rectal anastomoses in patients at high risk for anastomotic leakage. The outcomes of patients treated with cannula ileostomy were compared to those of patients treated with loop ileostomy. MAIN OUTCOME MEASURES: Outcomes included the rates of anastomotic leakage, reoperation and other complications, as well as length of hospital stay and cost. DESIGN AND PATIENTS: From January 2011 to December 2012, 294 patients undergoing low colorectal or coloanal anastomosis were treated with ileum diversion using cannula ileostomy or traditional loop ileostomy. Demographics, clinical features, and operational data were recorded. RESULTS: The anastomotic leakage rates were 8.1% (12/149) in the cannula ileostomy group and 8.3% (12/145) in the loop ileostomy group (p = 1.0). The reoperation rate was 3% (4/149) in patients treated with a cannula ileostomy and 3.4% (5/145) in those who underwent a loop ileostomy (p = 0.75). The median length of the hospital stay was 8.6 days in the cannula ileostomy group and 17.1 days (p < 0.01) in the loop ileostomy group, including time for the initial and reversal operations. In the cannula ileostomy group, the median time to defecation from the anus was 16.5 days after the operation. During the follow-up period, 13 patients in the loop ileostomy group retained their stoma, as compared to 2 in the cannula ileostomy group (p < 0.01). LIMITATIONS: This study was a nonrandomized design and lacked contrast enema data to identify anastomotic leaks. CONCLUSIONS: Cannula ileostomy is a safe and effective diverting technique that protects low colorectal and coloanal anastomoses. Patients receiving a cannula ileostomy had shorter hospital stays and lower rates of permanent stoma than those receiving a loop ileostomy. PMID- 25285694 TI - Twenty-year-old stapled pouches for ulcerative colitis without evidence of rectal cancer: implications for surveillance strategy? AB - BACKGROUND: The risk of anal transition zone dysplasia/cancer after stapled IPAA for ulcerative colitis might be cumulative over time. OBJECTIVE: The purpose of this work was to assess the long-term incidence and risk factors of anal transition zone dysplasia. DESIGN: This was a retrospective study from a prospectively maintained database. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Participants included those in our surveillance program of serial anal transition zone biopsies after stapled IPAA from 1986 to 1992. MAIN OUTCOME MEASURES: Anal transition zone dysplasia was the main measured outcome. RESULTS: Of 532 patients, 285 had 2 or more anal transition zone surveillance biopsies, including 73 with >=20 years of regular follow-up. No adenocarcinoma was detected, and 15 patients died of unrelated causes after a median follow-up of 13.4 years (range, 2.9-19.5 years) without dysplasia. The estimated survival rates at 10, 15, and 20 years were 99.6% (95% CI, 96.9-99.9), 98.9% (95% CI, 95.7-99.7), and 92.6% (95% CI, 86.5-96.0). The estimated rates of anal transition zone dysplasia based on the 9 patients were 2.9% (95% CI, 1.5-5.7) and 3.4% (95% CI, 1.8-6.4) at 10 and 15 years. No new onset dysplasia was identified beyond 125 months. Postoperative anal transition zone dysplasia was significantly associated with both preoperative and pathology findings of colorectal dysplasia (p < 0.001 for each) or cancer (p = 0.025 and p <0.001) and was managed expectantly or with mucosectomy (5 and 4 patients), depending on the number of positive biopsies and degree of dysplasia. Continued surveillance after detection of anal transition zone dysplasia showed no evidence of recurrent dysplasia during a median follow-up of 125 months (range, 9-256 months). LIMITATIONS: Approximately half of the eligible patients were excluded from the analysis because of insufficient follow-up. CONCLUSIONS: Long-term follow-up data corroborate the use of stapled IPAA for ulcerative colitis. Future studies should assess whether a less intensive surveillance strategy is safe 10 years after surgery. PMID- 25285695 TI - Pursestring closure of the stoma site leads to fewer wound infections: results from a multicenter randomized controlled trial. AB - BACKGROUND: Surgical site infection after stoma reversal is common. The optimal skin closure technique after stoma reversal has been widely debated in the literature. OBJECTIVE: We hypothesized that pursestring near-complete closure of the stoma site would lead to fewer surgical site infections compared with conventional primary closure. DESIGN: This study was a parallel prospective multicenter randomized controlled trial. SETTINGS: This study was conducted at 2 university medical centers. PATIENTS: Patients (N = 122) presenting for elective colostomy or ileostomy reversal were selected. INTERVENTIONS: Pursestring versus conventional primary closure of stoma sites were compared. MAIN OUTCOME MEASURES: Stoma site surgical site infection within 30 days of surgery, overall surgical site infection, delayed healing (open wound for >30 days), time to wound epithelialization, and patient satisfaction were the primary outcomes measured. RESULTS: The pursestring group had a significantly lower stoma site infection rate (2% vs 15%, p = 0.01). There was no difference in delayed healing or patient satisfaction between groups. Time to epithelialization was measured in only 51 patients but was significantly longer in the pursestring group (34.6 +/- 20 days vs 24.1 +/- 17 days, p = 0.02). LIMITATIONS: This study was limited by the variability in procedures and surgeons, the limited follow-up after 30 days, and the inability to perform blinding. CONCLUSION: Pursestring closure after stoma reversal has a lower risk of stoma site surgical site infection than conventional primary closure, although wounds may take longer to heal with the use of this approach. REGISTRATION NUMBER: NCT01713452 (www.clinicaltrials.gov). PMID- 25285696 TI - The effect of transversus abdominis plane blocks on postoperative pain in laparoscopic colorectal surgery: a prospective, randomized, double-blind trial. AB - BACKGROUND: Superior early pain control has been suggested with transversus abdominis plane blocks, but evidence-based recommendations for transversus abdominis plane blocks and their effects on patient outcomes are lacking. OBJECTIVE: The aim of this study was to determine whether transversus abdominis plane blocks improve early postoperative outcomes in patients undergoing laparoscopic colorectal resection already on an optimized enhanced recovery pathway. DESIGN: This study is based on a prospective, randomized, double-blind controlled trial. SETTINGS: The trial was conducted at a tertiary referral center. PATIENTS: Patients undergoing elective laparoscopic colorectal resection were selected. INTERVENTIONS(S): Patients were randomly assigned to receive either a transversus abdominis plane block or a placebo placed intraoperatively under laparoscopic guidance. All followed a standardized enhanced recovery pathway. Patient demographics, perioperative procedures, and postoperative outcomes were collected. MAIN OUTCOME MEASURES: Postoperative pain and nausea/vomiting scores in the postanesthesia care unit and department, opioid use, length of stay, and 30-day readmission rates were measured. RESULTS: The trial randomly assigned 41 patients to the transversus abdominis plane block group and 38 patients to the control group. Demographic, clinical, and procedural data were not significantly different. In the postanesthesia care unit, the transversus abdominis plane block group had significantly lower pain scores (p < 0.01) and used fewer opioids (p < 0.01) than the control group; postoperative nausea/vomiting scores were comparable (p = 0.99). The transversus abdominis plane group had significantly lower pain scores on postoperative day 1 (p = 0.04) and throughout the study period (p < 0.01). There was no significant difference between groups in postoperative opioid use (p = 0.65) or nausea/vomiting (p = 0.79). The length of stay (median, 2 days experimental, 3 days control; p = 0.50) and readmission rate (7% experimental, 5% control, p = 0.99) was similar across cohorts. LIMITATIONS: This study was conducted a single center. CONCLUSIONS: Transversus abdominis plane blocks improved immediate short-term opioid use and pain outcomes. Pain improvement was durable throughout the hospital stay. However, the blocks did not translate into less overall narcotic use, shorter length of stay, or lower readmission rates. PMID- 25285697 TI - Clinical outcomes of perineal proctectomy among patients of advanced age. AB - BACKGROUND: Rectal prolapse occurs primarily in older patients who often have significant comorbidities. With the aging population, increasing numbers of elderly patients are presenting with rectal prolapse. The perineal approach is preferred for these patients because it involves less perioperative risk than an abdominal procedure, but the outcomes of this procedure in elderly patients are unknown. OBJECTIVE: The aim of this study was to examine whether clinical outcomes after perineal proctectomy are similar among elderly patients versus patients of younger age. DESIGN: This study was a retrospective review. SETTING: This study was conducted in mixed academic and private practice; the operations were performed at 16 hospitals. PATIENTS: Patients who had perineal proctectomy for rectal prolapse from 1994 to 2012 were grouped according to age: <70 (group A), 70 to 79 (group B), 80 to 89 (group C), and >=90 years (group D). INTERVENTIONS: Perineal proctectomy with or without concurrent levatorplasty was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were postoperative complications, recurrence, and survival after perineal proctectomy. RESULTS: Four hundred patients underwent 518 perineal proctectomies: group A, N = 113; group B, N = 113; group C, N = 208; and group D, N = 84. The immediate and late complication rates were 5.6% and 3.5% and did not vary by age. Recurrence was 22.6% and was significantly different between groups, with the lowest recurrence in group D, 14.3% (p = 0.007). Reoperation after recurrence was less likely in group D. The main type of reoperation was perineal proctectomy (41.5%), but, for group D, recurrence was usually managed nonoperatively (58.3%). Median survival after operation was more than 4 years in the advanced age group. LIMITATIONS: Retrospective data, which did not allow analysis of patients with rectal prolapse who did not undergo surgery, were used in this study. CONCLUSIONS: When selected appropriately, patients 90 years of age or older have outcomes similar to younger patients; therefore, age alone should not be a contraindication to surgery. In addition, elderly patients have a median survival of more than 4 years after surgery, so the operative risk can be worth the benefit accrued. PMID- 25285698 TI - Outcomes after operations for anal fistula: results of a prospective, multicenter, regional study. AB - BACKGROUND: There are various surgical techniques used treat anal fistulas. The adoption and success rates of newer techniques have not been clearly established. OBJECTIVE: The purpose of this study was to determine the healing rate after operations for anal fistulas in New England colorectal surgery practices. DESIGN: We conducted a retrospective review of a prospectively collected database. SETTINGS: The study was conducted at colorectal surgery practices in New England. PATIENTS: A prospective, multicenter registry was created by the New England Society of Colon and Rectal Surgeons. Surgeons were invited to collect data prospectively regarding patients operated on for anal fistulas between January 1, 2011, and August 1, 2013. Fistula classification, surgical intervention, continence scores, and healing were determined by the treating surgeon. INTERVENTION: Operation for anal fistula was performed. MAIN OUTCOME MEASURES: We measured the proportion of patients with healed fistulas at 3 months. RESULTS: Sixteen surgeons submitted data regarding 240 operations for fistula with curative intent. Mean patient age was 45 +/- 14 years. A total of 158 patients (66%) were men, and 110 (46%) had undergone an anorectal operation. Twenty-nine (12%) had Crohn's disease. The healing rates of fistulotomy, advancement flap, and fistula plugs at 3 months were 94% (95% CI, 89-97), 60% (95% CI, 33-77), and 20% (95% CI, 5-50). The healing rate of the ligation of intersphincteric fistula tract procedure at 3 months was 79% (95% CI, 65-88). Hospital site was the only variable associated with healing (p < 0.05). Hospitals that performed more ligation of intersphincteric fistula tract procedures had higher healing rates at 3 months (p < 0.0001). LIMITATIONS: This study was limited by selection bias and reporting bias. CONCLUSIONS: A wide variety of techniques are used to treat anal fistulas in our region. Fistulotomy continues to have excellent results. There has been enthusiastic early adoption of the ligation of intersphincteric fistula tract technique. Early healing rates after the ligation of intersphincteric fistula tract procedure appear to be excellent. PMID- 25285699 TI - Postdischarge occurrences after colorectal surgery happen early and are associated with dramatically increased rates of readmission. AB - BACKGROUND: Postoperative occurrences have been associated with an increased risk of readmission, yet these occurrences and their timing have not been well characterized. OBJECTIVE: We sought to analyze patients undergoing colorectal surgery as a model for general surgical readmissions. DESIGN: In a retrospective analysis, the impact of a postoperative occurrence on readmission was examined in a multivariable model with adjustment for potential confounders. The timing and type of postoperative occurrence were further characterized. SETTINGS: This study was conducted at a tertiary care hospital. PATIENTS: Patients undergoing colorectal surgery in the American College of Surgeons National Surgical Quality Improvement Program database (fiscal year 2011-2012) were analyzed. MAIN OUTCOME MEASURES: The main outcome measure was admission within 30 days of operation. RESULTS: A total of 54,823 patients undergoing colorectal surgery were identified, with 24% of patients experiencing a postoperative occurrence, and 12% of patients readmitted. The readmission rate in those who experienced an occurrence was 30% compared with 6% in those without an occurrence (p < 0.0001). After an occurrence during the index admission, the readmission rate was 18% compared with 57% if the occurrence happened postdischarge (p < 0.0001). In a multivariable analysis, postdischarge occurrence (risk ratio, 7.5 [95% CI, 7.3 7.8]) was associated with the largest risk of readmission. The median time to postdischarge occurrence was 8 days for organ space infection and wound complication and 7 days for sepsis. By day 14 postdischarge, 74% of organ space infections, 79% of wound complications, and 81% of sepsis had already occurred. LIMITATIONS: This analysis was limited to the variables available in the American College of Surgeons National Surgical Quality Improvement Program. Most significantly, readmission is captured for 30 days postoperatively rather than for 30 days postdischarge. CONCLUSIONS: Readmission occurs frequently (12%) after colorectal surgery and is strongly associated with a postdischarge occurrence. The most frequent postdischarge occurrences are infectious in nature and happen early postdischarge. The majority of postdischarge occurrences have already occurred by day 14, a standard time for the postoperative appointment. PMID- 25285700 TI - The effect of hysterectomy on colonoscopy completion: a systematic review and meta-analysis. AB - BACKGROUND: The primary aim of colonoscopy is a complete and thorough examination of the colon. There are a number of factors, however, that can potentially increase the difficulty of completing a colonoscopy. A significant proportion of women eligible for colorectal cancer screening have undergone hysterectomy. A history of hysterectomy is frequently considered to make colonoscopy more difficult, although there is no consensus in the literature. OBJECTIVE: The aim of this study is to assess the effect of hysterectomy on colonoscopy completion. DATA SOURCES: A systematic search of PubMed, Embase, and the Cochrane database identified 6 eligible studies. STUDY SELECTION: Studies that compared colonoscopy completion rates in women with a previous history of hysterectomy and women with no history of pelvic surgery were selected for review. INTERVENTION: Meta analysis was performed by using random-effects methods. MAIN OUTCOME MEASURES: The primary outcome used was colonoscopy completion rate. The outcomes were calculated as odds ratio with 95% CI. RESULTS: A total of 5947 patients were included in the final analysis. The average hysterectomy rate was 26.3% +/- 14.5%. The colonoscopy completion rate was significantly reduced in patients with a history of hysterectomy compared with those with no history of pelvic surgery (87.1% vs 95.5%) (OR, 0.28; 95% CI, 0.16-0.49; p < 0.001). Analysis of the funnel plot demonstrated nonsignificant across-study publication bias. There was significant across-study heterogeneity (Cochran Q, 19.6; p = 0.002). LIMITATIONS: The endoscopist's experience is poorly defined in some studies. Indication for colonoscopy was not provided in all cases. There is significant across-study heterogeneity. CONCLUSION: Colonoscopy completion rates appear decreased in women with a history of hysterectomy, but the available literature is heterogenous. Further studies in this area are warranted. PMID- 25285701 TI - Apex technique in the treatment of obstructed defecation syndrome associated with rectal intussusception and full rectal mucosa prolapse. AB - BACKGROUND: The aim of the current study was to demonstrate the use of a modified stapling technique, called the apex technique, to treat rectal intussusception and full rectal mucosal prolapse. It was conducted as a retrospective study at 3 centers (2 in Brazil and 1 in Chile). TECHNIQUE: The apex technique is performed by using a HEM/EEA-33 stapler. A pursestring suture is placed at the apex of the prolapse, on the 4 quadrants, independent of the distance to the dentate line. A second pursestring is then placed to define the band of rectal mucosa to be symmetrically resected. MAIN OUTCOME MEASURES: Outcome measures included width of the resected full-thickness rectal wall; the intensity of postoperative pain on a visual analog scale from 1 to 10; full mucosal prolapse and rectal intussusception assessed by physical examination, cinedefecography, or echodefecography; and change in the constipation scale. RESULTS: Forty-five patients (30 women/15 men; mean age, 59.5 years) with rectal intussusception and full mucosal prolapse were included. The median operative time was 17 (range, 15 30) minutes. Bleeding after stapler fire requiring manual suture occurred in 3 patients (6.7%); 25 (55.6%) patients reported having no postoperative pain. Hospital stay was 24 hours. The mean width of the resected rectal wall was 5.9 (range, 5.0-7.5) cm. Stricture at the staple line was seen in 4 patients, of whom 1 required dilation under anesthesia. The median follow-up time was 120 (range, 90-120) days. A small residual prolapse was identified in 6 (13.3%) patients. Imaging demonstrated complete disappearance of rectal intussusception in all patients, and the mean postoperative constipation score decreased from 13 (range, 8-15) to 5 (range, 3-7). CONCLUSIONS: The apex technique appears to be a safe, quickly performed, and low-cost method for the treatment of rectal intussusception. In this series, imaging examinations showed the disappearance of rectal intussusception, and a significant decrease in constipation score suggested improvement in functional outcomes. PMID- 25285702 TI - Robotic-assisted abdominoperineal resection with obturator lymph node dissection: a multidisciplinary approach. PMID- 25285705 TI - Complexes of XeHXe+ with simple ligands: a theoretical investigation on (XeHXe+)L (L = N2, CO, H2O, NH3). AB - The structure, stability, and harmonic frequencies of the (XeHXe(+))L complexes (L = N2, CO, H2O, NH3) were investigated by ab initio and density functional theory (DFT) calculations. Their bonding situation was also assayed by natural bond orbital (NBO), atoms-in-molecules (AIM), and energy decomposition (EDA) analyses. For any L, we located a linear and a T-shaped isomer, whose energy difference progressively increases in the order N2 < CO < H2O < NH3 and ranges from nearly 0 to 4.5 kcal mol(-1). The absolute complexation energies of both the linear and the T-shaped isomers also increase in the same order, and their EDA analysis revealed the prevailing contribution of electrostatic interactions. The noncovalent character of the bonding between XeHXe(+) and L was confirmed by the AIM analysis. In particular, we based our investigation on the joint use of numerical AIM indices and graphic examination of the local Hamiltonian kinetic energy density, K(r). Interestingly, this function visually identifies the "covalent" regions occupied by XeHXe(+) and L and the "noncovalent" zones existing between them, which include, in particular, the bond critical point located on the Xe-L bond paths. Only for the linear (XeHXe(+))NH3 did the AIM analysis suggest an onset of covalency in the xenon-nitrogen interaction. Further work is in progress to examine the effectiveness of K(r), and its plotted forms, as a function of the bonding situation of noble-gas compounds. PMID- 25285706 TI - Kinetic and sensitive analysis of tyrosinase activity using electron transfer complexes: in vitro and intracellular study. AB - Tyrosinase is an important marker of human diseases such as the neurodegeneration associated with Parkinson's disease and melanoma. Sensitive detection of tyrosinase activity in vitro and inside cells is of great significance to medical diagnostics and skin disorder treatments. With unique photophysical properties, semiconductor quantum dots (QDs) are employed as photoluminescent platforms for various biosensing, in particular for the detection of enzyme activities. In this work, QDs are functionalized with tyrosine and zwitterionic molecules to construct a nanometer-scale scaffold (QD-Tyr conjugate), and this is used to test tyrosinase activity in vitro and inside cells. Tyrosinase oxidizes tyrosine to dopachrome and switches on the electron-transfer access, which relates to fluorescence quenching. High quenching efficiency is achieved by shortening the distance between the electron donors and acceptors, which is attributed to the small size of the conjugated tyrosine. Enzymatic process curves reveal the enhanced enzymatic activity on the conjugated nanoparticle substrate, which leads to highly sensitive detection of tyrosinase (as low as 1 nM). It is also demonstrated that QD-Tyr conjugates can sensitively probe intracellular tyrosinase in melanoma cells, which promises great potential in disease monitoring and medical diagnostics. PMID- 25285708 TI - A neuroscience agenda for counseling psychology research. AB - Recent advances in the field of neuroscience have dramatically changed our understanding of brain-behavior relationships. In this article, we illustrate how neuroscience can provide a conceptual and methodological framework to understand our clients within a transdiagnostic developmental perspective. We provide directions for integrating neuroscience into future process and outcome research. We present examples on how neuroscience can be integrated into researching the effects of contextual counseling interventions. We posit that interpersonal and environmental factors, such as neurotoxic factors (e.g., emotional neglect, stress), positive neurodevelopmental factors (e.g., nurturing and caring, environmental enrichment), and therapeutic interventions influence psychological processes (executive control, behavioral flexibility, reinforcement learning and approach motivation, emotional expression and regulation, self-representation and theory of mind). These psychological processes influence brain networks (attention, motivational, emotional regulation, social cognition), which influence cognitive, social, emotional, identity, and vocational development. PMID- 25285707 TI - ICan: an optimized ion-current-based quantification procedure with enhanced quantitative accuracy and sensitivity in biomarker discovery. AB - The rapidly expanding availability of high-resolution mass spectrometry has substantially enhanced the ion-current-based relative quantification techniques. Despite the increasing interest in ion-current-based methods, quantitative sensitivity, accuracy, and false discovery rate remain the major concerns; consequently, comprehensive evaluation and development in these regards are urgently needed. Here we describe an integrated, new procedure for data normalization and protein ratio estimation, termed ICan, for improved ion-current based analysis of data generated by high-resolution mass spectrometry (MS). ICan achieved significantly better accuracy and precision, and lower false-positive rate for discovering altered proteins, over current popular pipelines. A spiked in experiment was used to evaluate the performance of ICan to detect small changes. In this study E. coli extracts were spiked with moderate-abundance proteins from human plasma (MAP, enriched by IgY14-SuperMix procedure) at two different levels to set a small change of 1.5-fold. Forty-five (92%, with an average ratio of 1.71 +/- 0.13) of 49 identified MAP protein (i.e., the true positives) and none of the reference proteins (1.0-fold) were determined as significantly altered proteins, with cutoff thresholds of >= 1.3-fold change and p <= 0.05. This is the first study to evaluate and prove competitive performance of the ion-current-based approach for assigning significance to proteins with small changes. By comparison, other methods showed remarkably inferior performance. ICan can be broadly applicable to reliable and sensitive proteomic survey of multiple biological samples with the use of high-resolution MS. Moreover, many key features evaluated and optimized here such as normalization, protein ratio determination, and statistical analyses are also valuable for data analysis by isotope-labeling methods. PMID- 25285709 TI - Neurosciences of infant mental health development: recent findings and implications for counseling psychology. AB - This article is about the neural correlates of infant mental health and their correspondences to social emotional development. These correspondences are organized in terms of the definition of infant mental provided by Zero to Three (2001), centered on infants' capacities regarding the experience and expression of emotions, interpersonal relationships, and learning. We conclude with implications of these correspondences for counseling psychology-namely, working with children's caregivers to maximize children's healthy social and emotional development. PMID- 25285711 TI - Neuroscience of child and adolescent health development. AB - Recent advances in technology and neuroscience have increased our understanding of human neurodevelopment. In particular, research on neuroplasticity and psychosocial genomics lends compelling support to a biopsychosocial perspective by elucidating mechanisms through which psychosocial forces and environments shape neurobiology. This article summarizes selected results from recent investigations of neuroplasticity and psychosocial genomics, which demonstrate complex interaction between genes, epigenetic processes, and environmental experience that confers neural growth into adulthood. Counseling psychologists working with children and adolescents need to be familiar with recent literature to be more effective in their work so that they can provide developmentally appropriate counseling services. Social cognitive theory and resilience theory are introduced to illustrate how counseling psychologists can incorporate neuroscience research findings in a counseling context and hypotheses are proposed for future counseling psychology research. PMID- 25285712 TI - Neurosciences and adult health behaviors: recent findings and implications for counseling psychology. AB - The current review comprehensively examines recent advances in 2 innovative areas of neuroscience research on healthy adults regarding neuropsychosocial interactions on human cognition and behavior, as well as implications for counseling psychologists conducting research and in practice. Advances in how oxytocin influences prosocial behavior and the mitigation of social stress, and the influence of environmentally mediated gene expressions on the development of attachment disorders are surveyed and discussed in terms of how counseling psychologists might best integrate recent neuroscience research into a framework for therapeutic intervention. PMID- 25285713 TI - Neuroscience research on aging and implications for counseling psychology. AB - The advances in neuroscience have led to an increase in scientific understanding of the aging process, and counseling psychologists can benefit from familiarity with the research on the neuroscience of aging. In this article, we have focused on the cognitive neuroscience of aging, and we describe the progression of healthy aging to Alzheimer's disease, given its high prevalence rate among older adults (Alzheimer's Association, 2013). Common techniques used to study the cognitive neuroscience of aging are explained in regards to measuring age-related changes in the brain and the role of biomarkers in identifying cognitive decline related to Alzheimer's disease. Using this information and in collaboration with cognitive neuroscientists, it is our hope that counseling psychologists may further pursue research areas on aging as well as design appropriate interventions for older individuals who may be experiencing cognitive impairment. PMID- 25285714 TI - Neurosciences, empathy, and healthy interpersonal relationships: recent findings and implications for counseling psychology. AB - In this article, we define the construct of empathy and its relevance for counseling psychology. The importance of deficits in empathic processes for most of the psychological disorders is presented within the context of the social brain hypothesis (Frith, 2007). We provide a review of empirical research about the neural correlates of empathy in terms of both the central and peripheral nervous system. We present recent evidence on the cortical and subcortical regions involved in different dimensions of empathy-emotional contagion, cognitive and emotional empathy, and self-regulation. Regarding the autonomic correlates of empathy, we present evidence about the correlates of sympathetic arousal associated with empathic processes and review data supporting the idea of the physiological linkage or synchrony as indicator of empathy in interpersonal relationships. The implications of these findings for counseling psychology, particularly for the psychotherapist-client relationship and for context of intimate relationships or couples therapy, are discussed. PMID- 25285716 TI - A psychometric study of the Suicide Cognitions Scale with psychiatric inpatients. AB - The cognitive model of suicide makes specific predictions about the role of cognition in suicide risk. This study examined psychometric properties of the Suicide Cognitions Scale (SCS), an instrument designed to measure suicide specific cognitions, in a sample of 150 patients (age range, 18-75 years, SD = 14.42; 56% female, 94% White) hospitalized for suicide risk associated with multiple, treatment-resistant psychiatric conditions. Findings revealed strong psychometric properties, including internal consistency and test-retest reliability. Incremental validity beyond depression and hopelessness was demonstrated in the prediction of suicidal ideation. Confirmatory factor analysis examining previously reported factor solutions suggested more consistency with a three-factor solution (Unlovability, Unbearability, and Unsolvability) relative to a two-factor solution. Good sensitivity to treatment response over the course of hospitalization also was demonstrated. The hypothesis of residual risk, derived from cognitive theory and predicting that lack of change in suicide schemas would be associated with higher suicide risk at discharge, was supported. Overall, these findings suggest considerable promise for the SCS as a measure of suicide risk that adds predictive utility to measures of depression and hopelessness, with potential usefulness in planning and monitoring treatment for suicidal individuals. PMID- 25285717 TI - Invariance in the Reynolds Intellectual Assessment Scales for Black and White referred students. AB - An important part of validity evidence for a test's scores is that they are invariant-measuring the same constructs the same way across different groups. Although published a decade ago, no independent investigation of invariance has been conducted on the Reynolds Intellectual Assessment Scales (RIAS). In the current study, we investigated invariance of the RIAS's measurement of general cognitive ability (g) between Black and White students who were referred for special education services. Results indicated that the subtest scores showed strict invariance, but g's variance was not the same across groups. Specifically, the White group exhibited a higher mean (d = 0.60) and almost twice the variability in g as the Black group did. Thus, although the between-group mean differences in subtest scores and the Composite Intelligence Index are due to between-group differences in g, the Black group used a narrower range of g than the White group did in answering the RIAS items. PMID- 25285718 TI - Development and validation of the Sociocultural Attitudes Towards Appearance Questionnaire-4 (SATAQ-4). AB - The Sociocultural Attitudes Towards Appearance Questionnaire-3 (SATAQ-3) and its earlier versions are measures designed to assess societal and interpersonal aspects of appearance ideals. Correlational, structural equation modeling, and prospective studies of the SATAQ-3 have shown consistent and significant associations with measures of body image disturbance and eating pathology. In the current investigation, the SATAQ-3 was revised to improve upon some conceptual limitations and was evaluated in 4 U.S. and 3 international female samples, as well as a U.S. male sample. In Study 1, exploratory and confirmatory factor analyses for a sample of women from the Southeastern United States (N = 859) indicated a 22-item scale with 5 factors: Internalization: Thin/Low Body Fat, Internalization: Muscular/Athletic, Pressures: Family, Pressures: Media, Pressures: Peers. This scale structure was confirmed in 3 independent and geographically diverse samples of women from the United States (East Coast N = 440, West Coast N = 304, and North/Midwest N = 349). SATAQ-4 scale scores demonstrated excellent reliability and good convergent validity with measures of body image, eating disturbance, and self-esteem. Study 2 replicated the factorial validity, reliability, and convergent validity of the SATAQ-4 in an international sample of women drawn from Italy, England, and Australia (N = 362). Study 3 examined a sample of college males from the United States (N = 271); the 5-factor solution was largely replicated, yet there was some evidence of an underlying structure unique to men. Future research avenues include additional item testing and modification of the scale for men, as well as adaptation of the measure for children and adolescents. PMID- 25285719 TI - Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. AB - The distribution, phenotype, and requirement of macrophages for fracture associated inflammation and/or early anabolic progression during endochondral callus formation were investigated. A murine femoral fracture model [internally fixed using a flexible plate (MouseFix)] was used to facilitate reproducible fracture reduction. IHC demonstrated that inflammatory macrophages (F4/80(+)Mac 2(+)) were localized with initiating chondrification centers and persisted within granulation tissue at the expanding soft callus front. They were also associated with key events during soft-to-hard callus transition. Resident macrophages (F4/80(+)Mac-2(neg)), including osteal macrophages, predominated in the maturing hard callus. Macrophage Fas-induced apoptosis transgenic mice were used to induce macrophage depletion in vivo in the femoral fracture model. Callus formation was completely abolished when macrophage depletion was initiated at the time of surgery and was significantly reduced when depletion was delayed to coincide with initiation of early anabolic phase. Treatment initiating 5 days after fracture with the pro-macrophage cytokine colony stimulating factor-1 significantly enhanced soft callus formation. The data support that inflammatory macrophages were required for initiation of fracture repair, whereas both inflammatory and resident macrophages promoted anabolic mechanisms during endochondral callus formation. Overall, macrophages make substantive and prolonged contributions to fracture healing and can be targeted as a therapeutic approach for enhancing repair mechanisms. Thus, macrophages represent a viable target for the development of pro-anabolic fracture treatments with a potentially broad therapeutic window. PMID- 25285721 TI - ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. AB - Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of nerve growth factor (proNGF) is overexpressed in prostate cancer and involved in the ability of prostate cancer cells to induce axonogenesis. A series of 120 prostate cancer and benign prostate hyperplasia (BPH) samples were analyzed by IHC for proNGF. ProNGF was mainly localized in the cytoplasm of epithelial cells, with marked expression in cancer compared with BPH. Importantly, the proNGF level positively correlated with the Gleason score (n = 104, tauB = 0.51). A higher level of proNGF was observed in tumors with a Gleason score of >=8 compared with a Gleason score of 7 and 6 (P < 0.001). In vitro, proNGF was detected in LNCaP, DU145, and PC-3 prostate cancer cells and BPH-1 cells but not in RWPE-1 immortalized nontumorigenic prostate epithelial cells or primary normal prostate epithelial cells. Co-culture of PC12 neuronal-like cells or 50B11 neurons with PC-3 cells resulted in neurite outgrowth in neuronal cells that was inhibited by blocking antibodies against proNGF, indicating that prostate cancer cells can induce axonogenesis via secretion of proNGF. These data reveal that ProNGF is a biomarker associated with high-risk prostate cancers and a potential driver of infiltration by nerves. PMID- 25285720 TI - Lethal factor, but not edema factor, is required to cause fatal anthrax in cynomolgus macaques after pulmonary spore challenge. AB - Inhalational anthrax is caused by inhalation of Bacillus anthracis spores. The ability of B. anthracis to cause anthrax is attributed to the plasmid-encoded A/B type toxins, edema toxin (edema factor and protective antigen) and lethal toxin (lethal factor and protective antigen), and a poly-d-glutamic acid capsule. To better understand the contribution of these toxins to the disease pathophysiology in vivo, we used B. anthracis Ames strain and isogenic toxin deletion mutants derived from the Ames strain to examine the role of lethal toxin and edema toxin after pulmonary spore challenge of cynomolgus macaques. Lethal toxin, but not edema toxin, was required to induce sustained bacteremia and death after pulmonary challenge with spores delivered via bronchoscopy. After intravenous challenge with bacilli to model the systemic phase of infection, lethal toxin contributed to bacterial proliferation and subsequent host death to a greater extent than edema toxin. Deletion of protective antigen resulted in greater loss of virulence after intravenous challenge with bacilli than deletion of lethal toxin or edema toxin alone. These findings are consistent with the ability of anti-protective antigen antibodies to prevent anthrax and suggest that lethal factor is the dominant toxin that contributes to the escape of significant numbers of bacilli from the thoracic cavity to cause anthrax after inhalation challenge with spores. PMID- 25285722 TI - Human skeletal muscle biopsy procedures using the modified Bergstrom technique. AB - The percutaneous biopsy technique enables researchers and clinicians to collect skeletal muscle tissue samples. The technique is safe and highly effective. This video describes the percutaneous biopsy technique using a modified Bergstrom needle to obtain skeletal muscle tissue samples from the vastus lateralis of human subjects. The Bergstrom needle consists of an outer cannula with a small opening ('window') at the side of the tip and an inner trocar with a cutting blade at the distal end. Under local anesthesia and aseptic conditions, the needle is advanced into the skeletal muscle through an incision in the skin, subcutaneous tissue, and fascia. Next, suction is applied to the inner trocar, the outer trocar is pulled back, skeletal muscle tissue is drawn into the window of the outer cannula by the suction, and the inner trocar is rapidly closed, thus cutting or clipping the skeletal muscle tissue sample. The needle is rotated 90 degrees and another cut is made. This process may be repeated three more times. This multiple cutting technique typically produces a sample of 100-200 mg or more in healthy subjects and can be done immediately before, during, and after a bout of exercise or other intervention. Following post-biopsy dressing of the incision site, subjects typically resume their activities of daily living right away and can fully participate in vigorous physical activity within 48-72 hr. Subjects should avoid heavy resistance exercise for 48 hr to reduce the risk of herniation of the muscle through the incision in the fascia. PMID- 25285723 TI - Homonymous Ganglion Cell Layer Thinning After Isolated Occipital Lesion: Macular OCT Demonstrates Transsynaptic Retrograde Retinal Degeneration. AB - A 48-year-old man was examined 24 months after medial and surgical treatment of an isolated well-circumscribed right occipital lobe abscess. An asymptomatic residual left homonymous inferior scotoma was present. Fundus examination revealed temporal pallor of both optic discs, and optical coherence tomography (OCT) revealed mild temporal loss of retinal nerve fiber layer in both eyes. No relative afferent pupillary defect was present. Assessment of the retinal ganglion cell layer demonstrated homonymous thinning in a pattern corresponding to the homonymous visual field loss. There were no abnormalities of the lateral geniculate nuclei or optic tracts on review of the initial brain computed tomography and follow-up magnetic resonance imaging. We believe our patient showed evidence of transsynaptic retrograde degeneration after an isolated right occipital lobe lesion, and the homonymous neuronal loss was detected on OCT by assessing the retinal ganglion cell layer. PMID- 25285724 TI - Association between single nucleotide polymorphisms in the ADD3 gene and susceptibility to biliary atresia. AB - BACKGROUND AND OBJECTIVES: Based on the results of previous studies, the ADD3 gene, located in the 10q24.2 region, may be a susceptibility gene of biliary atresia (BA). In this study, two single nucleotide polymorphisms (SNPs) in the ADD3 gene, rs17095355 C/T and rs10509906 G/C, were selected to investigate whether there is an association between these SNPs and susceptibility to BA in a Chinese population. METHODS: A total of 752 Han Chinese (134 BA cases and 618 ethnically matched healthy controls) were included in the present study. The ADD3 gene polymorphisms were genotyped using a TaqMan genotyping assay. RESULTS: Positive associations were found for the SNP rs17095355 in the codominant model; specifically, the frequencies of the CT and TT genotypes and the T allele were higher in the cases than the controls, demonstrating a significant risk for BA (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.02-2.58; OR = 2.89, 95% CI = 1.72-4.86; and OR = 1.75, 95% CI = 1.34-2.29, respectively). Regarding rs10509906, the per-C-allele conferred an OR of 0.70 (95% CI = 0.49-1.00) under the additive model. A greater risk of BA was associated with the T(a)-G(b) (a for rs17095355 and b for rs10509906) haplotype (OR = 1.82, 95% CI = 1.27-2.61) compared with the C(a)-C(b) haplotype. CONCLUSION: This study suggests that the ADD3 gene plays an important role in BA pathogenesis and reveals a significant association between two SNPs, rs17095355 and rs10509906, and BA. PMID- 25285725 TI - Rare extra-adrenal paraganglioma mimicking a painful Schwannoma: case report. AB - INTRODUCTION: Paragangliomas originate from chromaffin tissue primarily found in the Zuckerkandl body. A 53 years old man, was investigated with abdominal MRI for chronic backache, that had lasted for 2 years. CASE REPORT: MRI revealed an incidental mass in para-aortic region, at the adrenal lodge, with characteristics of a solid nodular mass, which did not seem to arise from the adrenal gland. An abdominal CT showed a mass localized prior to left adrenal gland; the radiologist reported this mass as a malignant peripheral nerve sheath tumor (Schwannoma). During his stay in hospital, tumoral markers chromogranin and neuron-specific enolase were dosed, with a concentration of 187.00 ng/mL and 7.7 ng/mL. Patient's back pain was treated first with ketorolac, without any resolution of the problem, then with ketorolac plus tramadol in elastomeric pump, again with no relief, and finally with a continuous infusion of morphine. Since the exact nature of the neoplasm was not known and a CT guided biopsy was not technically feasible to do, a laparoscopic excision of the mass, with transperitoneal anterior submesocolic approach, as well as for the left adrenalectomy, was planned. After surgery, the patient no longer needed morphine. The postoperative course was uneventful. RESULTS: Histopathological findings consisted of periadrenal paraganglioma. Extra-adrenal paragangliomas are rarely recognized during preoperative study. This is often due to its capacity of mimicking other type of tumors. CONCLUSIONS: Paragangliomas could be successfully resected by laparoscopy, they are difficult to distinguish from other tumor and they should be investigated even if preoperative findings argue for something else. PMID- 25285726 TI - Antibiotic misuse: a global crisis. PMID- 25285727 TI - Compact bis-adduct fullerenes and additive-assisted morphological optimization for efficient organic photovoltaics. AB - Bis-adduct fullerenes surrounded by two insulating addends sterically attenuate intermolecular interaction and cause inferior electron transportation. In this research, we have designed and synthesized a new class of bis-adduct fullerene materials, methylphenylmethano-C60 bis-adduct (MPC60BA), methylthienylmethano-C60 bis-adduct (MTC60BA), methylphenylmethano-C70 bis-adduct (MPC70BA), and methylthienylmethano-C70 bis-adduct (MTC70BA), functionalized with two compact phenylmethylmethano and thienylmethylmethano addends via cyclopropyl linkages. These materials with much higher-lying lowest unoccupied molecular orbital (LUMO) energy levels successfully enhanced the Voc values of the P3HT-based solar cell devices. The compact phenylmethylmethano and thienylmethylmethano addends to promote fullerene intermolecular interactions result in aggregation-induced phase separation as observed by the atomic force microscopy (AFM) and transmission electron microscopy (TEM) images of the poly(3-hexylthiophene-2,5-diyl) (P3HT)/bis-adduct fullerene thin films. The device based on the P3HT/MTC60BA blend yielded a Voc of 0.72 V, a Jsc of 5.87 mA/cm(2), and a fill factor (FF) of 65.3%, resulting in a power conversion efficiency (PCE) of 2.76%. The unfavorable morphologies can be optimized by introducing a solvent additive to fine-tune the intermolecular interactions. 1-Chloronaphthalene (CN) having better ability to dissolve the bis-adduct fullerenes can homogeneously disperse the fullerene materials into the P3HT matrix. Consequently, the aggregated fullerene domains can be alleviated to reach a favorable morphology. With the assistance of CN additive, the P3HT/MTC60BA-based device exhibited enhanced characteristics (a Voc of 0.78 V, a Jsc of 9.04 mA/cm(2), and an FF of 69.8%), yielding a much higher PCE of 4.92%. More importantly, the additive-assisted morphological optimization is consistently effective to all four compact bis-adduct fullerenes regardless of the methylphenylmethano or methylthienylmethano scaffolds as well as C60 or C70 core structures. Through the extrinsic additive treatment, these bis-adduct fullerene materials with compact architectures show promise for high-performance polymer solar cells. PMID- 25285728 TI - A multi-modal approach to assessing recovery in youth athletes following concussion. AB - Concussion is one of the most commonly reported injuries amongst children and youth involved in sport participation. Following a concussion, youth can experience a range of short and long term neurobehavioral symptoms (somatic, cognitive and emotional/behavioral) that can have a significant impact on one's participation in daily activities and pursuits of interest (e.g., school, sports, work, family/social life, etc.). Despite this, there remains a paucity in clinically driven research aimed specifically at exploring concussion within the youth sport population, and more specifically, multi-modal approaches to measuring recovery. This article provides an overview of a novel and multi-modal approach to measuring recovery amongst youth athletes following concussion. The presented approach involves the use of both pre-injury/baseline testing and post injury/follow-up testing to assess performance across a wide variety of domains (post-concussion symptoms, cognition, balance, strength, agility/motor skills and resting state heart rate variability). The goal of this research is to gain a more objective and accurate understanding of recovery following concussion in youth athletes (ages 10-18 years). Findings from this research can help to inform the development and use of improved approaches to concussion management and rehabilitation specific to the youth sport community. PMID- 25285729 TI - Heterotopic auxiliary rat liver transplantation with flow-regulated portal vein arterialization in acute hepatic failure. AB - In acute hepatic failure auxiliary liver transplantation is an interesting alternative approach. The aim is to provide a temporary support until the failing native liver has regenerated.(1-3) The APOLT-method, the orthotopic implantation of auxiliary segments- averts most of the technical problems. However this method necessitates extensive resections of both the native liver and the graft.(4) In 1998, Erhard developed the heterotopic auxiliary liver transplantation (HALT) utilizing portal vein arterialization (PVA) (Figure 1). This technique showed promising initial clinical results.(5-6) We developed a HALT-technique with flow regulated PVA in the rat to examine the influence of flow-regulated PVA on graft morphology and function (Figure 2). A liver graft reduced to 30 % of its original size, was heterotopically implanted in the right renal region of the recipient after explantation of the right kidney. The infra-hepatic caval vein of the graft was anastomosed with the infrahepatic caval vein of the recipient. The arterialization of the donor's portal vein was carried out via the recipient's right renal artery with the stent technique. The blood-flow regulation of the arterialized portal vein was achieved with the use of a stent with an internal diameter of 0.3 mm. The celiac trunk of the graft was end-to-side anastomosed with the recipient's aorta and the bile duct was implanted into the duodenum. A subtotal resection of the native liver was performed to induce acute hepatic failure. (7) In this manner 112 transplantations were performed. The perioperative survival rate was 90% and the 6-week survival rate was 80%. Six weeks after operation, the native liver regenerated, showing an increase in weight from 2.3+/-0.8 g to 9.8+/-1 g. At this time, the graft's weight decreased from 3.3+/-0.8 g to 2.3+/-0.8 g. We were able to obtain promising long-term results in terms of graft morphology and function. HALT with flow-regulated PVA reliably bridges acute hepatic failure until the native liver regenerates. PMID- 25285730 TI - Direct oxidative coupling of enamines and electron-deficient amines: TBAI/TBHP mediated synthesis of substituted diaminoalkenes under metal-free conditions. AB - A metal-free cross-coupling of enamines and electron-deficient amines through oxidative C(sp(2))-N bond formation has been realized by using TBAI as catalyst and TBHP as oxidant. This novel strategy allows for an efficient organocatalytic synthesis of the synthetically useful diaminoalkene derivatives and is highlighted by appealing features such as readily available of the starting materials, wide substrate scope and transition-metal-free characteristics. PMID- 25285732 TI - Direct comparison of postoperative monitoring of free flaps with microdialysis, implantable cook-swartz Doppler probe, and clinical monitoring in 20 consecutive patients. AB - BACKGROUND: There is an increasing demand for successful free tissue transfer, with postoperative monitoring of flaps a key to early salvage. Monitoring methods have ranged from clinical techniques to invasive options, of which two are particularly applicable to buried flaps (Cook-Swartz Doppler probe and microdialysis). The evidence for these options has been represented largely in separate cohort studies, with no single study comparing these three techniques. We aim to perform this comparison in a single cohort of patients. METHODS: A prospective, consecutive cohort study comparing clinical monitoring, microdialysis and the implantable Doppler probe was undertaken. In 20 patients receiving 22 flaps, 21 flaps were monitored with microdialysis, 18 flaps with clinical observation, and 21 flaps with the Cook-Swartz Implantable Doppler probe. Exclusion was based on applicability and availability intra-operatively. Efficacy was assessed through sensitivity, specificity, positive, and negative predictive values. RESULTS: Nineteen of 22 flaps had no suspected anastomotic problems; 3 of 22 flaps were explored for anastomotic problems, with two salvaged and one lost. The implantable Doppler and microdialysis were found to detect flap statistically earlier than clinical assessment, with microdialysis better at detecting flap compromise: 100% specificity (confidence interval 31-100%) when compared to the implantable probe and clinical assessment (67%: 13-98% and 33%: 2 87%, respectively). CONCLUSIONS: Each of the Cook-Swartz Doppler probe, microdialysis and clinical assessment was found suitable for monitoring in free tissue transfer. The implantable Doppler and microdialysis offer the potential for earlier detection of flap compromise. PMID- 25285731 TI - Maternal cadmium levels during pregnancy associated with lower birth weight in infants in a North Carolina cohort. AB - Cadmium (Cd) is a ubiquitous environmental contaminant, a known carcinogen, and understudied as a developmental toxicant. In the present study, we examined the relationships between Cd levels during pregnancy and infant birth outcomes in a prospective pregnancy cohort in Durham, North Carolina. The study participants (n = 1027) had a mean Cd level of 0.46 ug/L with a range of <0.08 to 2.52 ug/L. Multivariable models were used to establish relationships between blood Cd tertiles and fetal growth parameters, namely birth weight, low birth weight, birth weight percentile by gestational age, small for gestational age, pre-term birth, length, and head circumference. In multivariable models, high maternal blood Cd levels (>=0.50 ug/L) during pregnancy were inversely associated with birth weight percentile by gestational age (p = 0.007) and associated with increased odds of infants being born small for gestational age (p<0.001). These observed effects were independent of cotinine-defined smoking status. The results from this study provide further evidence of health risks associated with early life exposure to Cd among a large pregnancy cohort. PMID- 25285733 TI - Self-assembled phases of block copolymer blend thin films. AB - The patterns formed by self-assembled thin films of blended cylindrical and lamellar polystyrene-b-poly(methyl methacrylate) block copolymers can be either a spatially uniform, single type of nanostructure or separate, coexisting regions of cylinders and lamellae, depending on fractional composition and molecular weight ratio of the blend constituents. In blends of block copolymers with different molecular weights, the morphology of the smaller molecular weight component more strongly dictates the resulting pattern. Although molecular scale chain mixing distorts microdomain characteristic length scales from those of the pure components, even coexisting morphologies exhibit the same domain spacing. We quantitatively account for the phase behavior of thin-film blends of cylinders and lamellae using a physical, thermodynamic model balancing the energy of chain distortions with the entropy of mixing. PMID- 25285736 TI - Diagnostic value of adenosine conversion of wide complex tachycardia. PMID- 25285737 TI - Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use and renal outcomes: prevalent user designs may overestimate benefit. PMID- 25285738 TI - Diagnostic value of adenosine conversion of wide complex tachycardia-reply. PMID- 25285740 TI - Improving medication adherence and helping patients make lifestyle changes. PMID- 25285739 TI - Angiotensin-converting enzyme inhibitor or Angiotensin receptor blocker use and renal outcomes-reply. PMID- 25285741 TI - Improving medication adherence and helping patients make lifestyle changes. PMID- 25285742 TI - Improving medication adherence and helping patients make lifestyle changes-reply. PMID- 25285744 TI - Regarding the acute care of the elderly model. PMID- 25285745 TI - Biochemical and molecular characterization of potential phosphate-solubilizing bacteria in acid sulfate soils and their beneficial effects on rice growth. AB - A study was conducted to determine the total microbial population, the occurrence of growth promoting bacteria and their beneficial traits in acid sulfate soils. The mechanisms by which the bacteria enhance rice seedlings grown under high Al and low pH stress were investigated. Soils and rice root samples were randomly collected from four sites in the study area (Kelantan, Malaysia). The topsoil pH and exchangeable Al ranged from 3.3 to 4.7 and 1.24 to 4.25 cmol(c) kg(-1), respectively, which are considered unsuitable for rice production. Total bacterial and actinomycetes population in the acidic soils were found to be higher than fungal populations. A total of 21 phosphate-solubilizing bacteria (PSB) including 19 N2-fixing strains were isolated from the acid sulfate soil. Using 16S rRNA gene sequence analysis, three potential PSB strains based on their beneficial characteristics were identified (Burkholderia thailandensis, Sphingomonas pituitosa and Burkholderia seminalis). The isolated strains were capable of producing indoleacetic acid (IAA) and organic acids that were able to reduce Al availability via a chelation process. These PSB isolates solubilized P (43.65%) existing in the growth media within 72 hours of incubation. Seedling of rice variety, MR 219, grown at pH 4, and with different concentrations of Al (0, 50 and 100 uM) was inoculated with these PSB strains. Results showed that the bacteria increased the pH with a concomitant reduction in Al concentration, which translated into better rice growth. The improved root volume and seedling dry weight of the inoculated plants indicated the potential of these isolates to be used in a bio-fertilizer formulation for rice cultivation on acid sulfate soils. PMID- 25285746 TI - Directed dopaminergic neuron differentiation from human pluripotent stem cells. AB - Dopaminergic (DA) neurons in the substantia nigra pars compacta (also known as A9 DA neurons) are the specific cell type that is lost in Parkinson's disease (PD). There is great interest in deriving A9 DA neurons from human pluripotent stem cells (hPSCs) for regenerative cell replacement therapy for PD. During neural development, A9 DA neurons originate from the floor plate (FP) precursors located at the ventral midline of the central nervous system. Here, we optimized the culture conditions for the stepwise differentiation of hPSCs to A9 DA neurons, which mimics embryonic DA neuron development. In our protocol, we first describe the efficient generation of FP precursor cells from hPSCs using a small molecule method, and then convert the FP cells to A9 DA neurons, which could be maintained in vitro for several months. This efficient, repeatable and controllable protocol works well in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) from normal persons and PD patients, in which one could derive A9 DA neurons to perform in vitro disease modeling and drug screening and in vivo cell transplantation therapy for PD. PMID- 25285747 TI - Cardiac biomarkers and clinical scores for risk stratification in elderly patients with non-high-risk pulmonary embolism. AB - OBJECTIVE: To determine the prognostic accuracy of cardiac biomarkers alone and in combination with clinical scores in elderly patients with non-high-risk pulmonary embolism (PE). DESIGN: Ancillary analysis of a Swiss multicentre prospective cohort study. SUBJECTS: A total of 230 patients aged >=65 years with non-high-risk PE. MAIN OUTCOME MEASURES: The study end-point was a composite of PE-related complications, defined as PE-related death, recurrent venous thromboembolism or major bleeding during a follow-up of 30 days. The prognostic accuracy of the Pulmonary Embolism Severity Index (PESI), the Geneva Prognostic Score (GPS), the precursor of brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) was determined using sensitivity, specificity, predictive values, receiver operating characteristic (ROC) curve analysis, logistic regression and reclassification statistics. RESULTS: The overall complication rate during follow-up was 8.7%. hs-cTnT achieved the highest prognostic accuracy [area under the ROC curve: 0.75, 95% confidence interval (CI): 0.63-0.86, P < 0.001). At the predefined cut-off values, the negative predictive values of the biomarkers were above 95%. For levels above the cut-off, the risk of complications increased fivefold for hs-cTnT [odds ratio (OR): 5.22, 95% CI: 1.49-18.25] and 14-fold for NT-proBNP (OR: 14.21, 95% CI: 1.73-116.93) after adjustment for both clinical scores and renal function. Reclassification statistics indicated that adding hs-cTnT to the GPS or the PESI significantly improved the prognostic accuracy of both clinical scores. CONCLUSION: In elderly patients with nonmassive PE, NT-proBNP or hs-cTnT could be an adequate alternative to clinical scores for identifying low-risk individuals suitable for outpatient management. PMID- 25285748 TI - A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with moderately reduced left ventricular ejection fraction and a narrow QRS duration: study rationale and design. AB - Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the cardiac absolute refractory period that enhance the strength of cardiac muscular contraction. The FIX-HF-5 study was a prospective randomized study comparing CCM plus optimal medical therapy (OMT) to OMT alone that included 428 New York Heart Association (NYHA) functional class III or IV heart failure patients with ejection fraction (EF) <=45% according to core laboratory assessment. The study met its primary safety end point, but did not reach its primary efficacy end point: a responders analysis of changes in ventilatory anaerobic threshold (VAT). However, in a prespecified subgroup analysis, significant improvements in primary and secondary end points, including the responder VAT end point, were observed in patients with EFs ranging from 25% to 45%, who constituted about one-half of the study subjects. We therefore designed a new study to prospectively confirm the efficacy of CCM in this population. A hierarchic bayesian statistical analysis plan was developed to take advantage of the data already available from the first study. In addition, based on technical difficulties encountered in reliably quantifying VAT and the relatively large amount of nonquantifiable studies, the primary efficacy end point was changed to peak VO2, with significant measures incorporated to minimize the influence of placebo effect. In this paper, we provide the details and rationale of the FIX-HF-5C study design to study CCM plus OMT compared with OMT alone in subjects with normal QRS duration, NYHA functional class III or IV, and EF 25%-45%. This study is registered on www.clinicaltrials.gov with identifier no. NCT01381172. PMID- 25285749 TI - Relationships between biomarkers and left ventricular filling pressures at rest and during exercise in patients after myocardial infarction. AB - BACKGROUND: Increased pulmonary capillary wedge pressure (PCWP) is an independent prognostic predictor after myocardial infarction (MI), but PCWP is difficult to assess noninvasively in subjects with preserved ejection fraction (EF). We hypothesized that biomarkers would provide information regarding PCWP at rest and during exercise in subjects with preserved EF after MI. METHODS AND RESULTS: Seventy-four subjects with EF >45% and recent MI underwent right heart catheterization at rest and during a symptom-limited semisupine cycle exercise test with simultaneous echocardiography. Plasma samples were collected at rest for assessment of midregional pro-A-type natriuretic peptide (MR-proANP), N terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), copeptin, and midregional pro-adrenomedullin (MR-proADM). Plasma levels of MR proANP and PCWP were associated at rest (r = 0.33; P = .002) and peak exercise (r = 0.35; P = .002) as well as with changes in PCWP (r = 0.26; P = .03). Plasma levels of NT-proBNP and PCWP were weakly associated at rest (r = 0.23; P = .03) and peak exercise (r = 0.28; P = .02) but not with changes in PCWP (r = 0.20; P = .09). In a multivariable analysis, plasma levels of MR-proANP remained associated with rest and exercise PCWP (P < .01), whereas NT-proBNP did not. Plasma levels of Gal-3, copeptin, and MR-proADM were not associated with PCWP at rest or peak exercise. CONCLUSIONS: In subjects recovering from an acute MI with preserved EF, plasma levels of natriuretic peptides, particularly MR-proANP, are associated with filling pressures at rest and during exercise. PMID- 25285750 TI - How far from home? The locations of physical activity in an urban U.S. setting. AB - Little is known about where physical activity (PA) occurs, or whether different demographic groups accumulate PA in different locations. METHOD: Objective data on PA and location from 611 adults over 7days were collected in King County, WA in 2008-2009. The relative amounts of time spent in sedentary-to-low and moderate to-vigorous PA (MVPA) were quantified at three locations: "home" (<125m from geocoded home locations); "near" home (125-1666m, defining the home neighborhood); and "away" from home (>1666m). Differences in MVPA by demographics and location were examined. The percent of daily time in MVPA was estimated using a mixed model adjusted for location, sex, age, race/ethnicity, employment, education, BMI, and income. RESULTS: Most MVPA time occurred in nonhome locations, and disproportionately "near" home; this location was associated with 16.46% greater time in MVPA, compared to at-home activity (p<0.001), whereas more time spent at "away" locations was associated with 3.74% greater time in MVPA (p<0.001). Location was found to be a predictor of MVPA independent of demographic factors. CONCLUSION: A large proportion of MVPA time is spent at "near" locations, corresponding to the home neighborhood studied in previous PA research. "Away" locations also host time spent in MVPA and should be the focus of future research. PMID- 25285752 TI - More than add-on: chemoselective reactions for the synthesis of functional peptides and proteins. AB - The quest to enlarge the molecular space of functional biomolecules has led to the discovery of selective, mild and high-yielding chemical reactions for the modification of peptides and proteins. These conjugation methods have recently become even more advanced with the advent of modern biochemical techniques such as unnatural protein expression or enzymatic reactions that allow the site specific modification of proteins. Within this overview, we will highlight recent examples that describe the site-specific functionalization of proteins. These examples go beyond the straightforward attachment of a given functional moiety to the protein backbone by employing either an innovative linker-design or by novel conjugation chemistry, where the modification reaction itself is responsible for the (altered) functional behaviour of the biomolecule. The examples covered herein include 'turn-on' probes for cellular imaging with low levels of background fluorescence, branched or cleavable polymer-protein conjugates of high stability within a cellular environment, the installation of natural occurring posttranslational modifications to help understand their role in complex cellular environments and finally the engineering of novel antibody drug conjugates to facilitate target specific drug release. PMID- 25285753 TI - Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins. AB - Native chemical ligation continues to play a pivotal role in the synthesis of increasingly complex peptide and protein targets twenty years after its initial report. This opinion article will highlight a number of recent, powerful extensions of the technology that have expanded the scope of the reaction, accelerated ligation rates, enabled chemoselective post-ligation modifications, and streamlined the ligation of multiple peptide fragments. These advances have facilitated the synthesis of a number of impressive protein targets to date and hold great promise for the continued application of native chemical ligation for the detailed study of protein structure and function. PMID- 25285751 TI - Effectiveness of a 12-month randomized clinical trial to increase physical activity in multiethnic postpartum women: results from Hawaii's Na Mikimiki Project. AB - OBJECTIVE: Few postpartum ethnic minority women perform leisure-time moderate-to vigorous physical activity (MVPA). The study tested the effectiveness of a 12 month tailored intervention to increase MVPA in women with infants 2-12months old. METHODS: From 2008 to 2011, women (n=311) with infants (average age=5.7months) from Honolulu, Hawaii were randomly assigned to receive tailored telephone calls and access to a mom-centric website (n=154) or access to a standard PA website (n=157). MVPA was measured at baseline, 6, and 12months using self-report and acclerometers. RESULTS: Controlling for covariates, the tailored condition significantly increased self-reported MVPA from an average of 44 to 246min/week compared with 46 to 156min/week for the standard condition (p=0.027). Mothers with>=2 children had significantly greater increases in MVPA in response to the tailored intervention than those with one child (p=0.016). Accelerometer measured MVPA significantly increased over time (p=0.0001), with no condition differences. There was evidence of reactivity to initially wearing accelerometers; the tailored intervention significantly increased MVPA among women with low baseline accelerometer MVPA minutes, but not among those with high minutes (pinteraction=0.053). CONCLUSION: A tailored intervention effectively increased MVPA over 12months in multiethnic women with infants, particularly those with more than one child. PMID- 25285754 TI - Towards applications of synthetic genetic polymers in diagnosis and therapy. AB - Aptamers are a class of single-stranded nucleic acid ligands that can bind their targets with high specificity and affinities rivalling those of antibodies. First described over 20 years ago by Tuerk & Gold [1] and Ellington & Szostak [2] (who coined the name), their promise as both diagnostic and therapeutic agents remains to be realised. Key problems include the generally low biostability of the standard DNA/RNA or mixed RNA/2'F-DNA backbones under physiological conditions, limited chemical diversity of functional groups on the natural nucleobases, and the difficulty in reliably discovering aptamer ligands to some therapeutic targets. This review will describe recent progress in developing aptamer selection technology as well as expanding aptamer chemistry and informational complexity to improve aptamer discovery and properties. PMID- 25285755 TI - Integration of biological parts toward the synthesis of a minimal cell. AB - Various approaches are taken to construct synthetic cells in the laboratory, a challenging goal that became experimentally imaginable over the past two decades. The construction of protocells, which explores scenarios of the origin of life, has been the original motivations for such projects. With the advent of the synthetic biology era, bottom-up engineering approaches to synthetic cells are now conceivable. The modular design emerges as the most robust framework to construct a minimal cell from natural molecular components. Although significant advances have been made for each piece making this complex puzzle, the integration of the three fundamental parts, information-metabolism-self organization, into cell-sized liposomes capable of sustained reproduction has failed so far. Our inability to connect these three elements is also a major limitation in this research area. New methods, such as machine learning coupled to high-throughput techniques, should be exploited to accelerate the cell-free synthesis of complex biochemical systems. PMID- 25285757 TI - Rapid clearance of HCV-related splenic marginal zone lymphoma under an interferon free, NS3/NS4A inhibitor-based treatment. A case report. AB - Chronic infection with hepatitis C virus (HCV) may lead to B cell activation and transformation into non-Hodgkin lymphoma (NHL). Molecular mechanisms of B cell transformation by HCV are poorly understood. One of the most common lymphoproliferative disorders in HCV-infected patients is splenic marginal zone lymphoma (SMZL). A case of a 42-years old man, affected by HCV-related SMZL, effectively treated with an IFN-free, NS3-NS4A inhibitor-based regimen, is hereby described. The patient was treated for 16 weeks with faldaprevir, deleobuvir, and ribavirin, achieving a very rapid viral eradication without relevant toxicities. A rapid haematologic response was noted as well, with a statistically significant correlation between viral decay and lymphocyte improvement (coefficient r = 0.55, p = 0.042). The viral clearance led to SMZL cure, even without the use of IFN. Thus, the causative role, played by HCV in SMZL development, is once again reinforced, whereby the antiviral, rather than the anti-proliferative activity of IFN is indirectly proven. A regimen including DAAs should be considered when treating a HCV-related extra-hepatic disease. PMID- 25285756 TI - Language lateralization shifts with learning by adults. AB - For the majority of the population, language is a left-hemisphere lateralized function. During childhood, a pattern of increasing left lateralization for language has been described in brain imaging studies, suggesting that this trait develops. This development could reflect change due to brain maturation or change due to skill acquisition, given that children acquire and refine language skills as they mature. We test the possibility that skill acquisition, independent of age-associated maturation can result in shifts in language lateralization in classic language cortex. We imaged adults exposed to an unfamiliar language during three successive fMRI scans. Participants were then asked to identify specific words embedded in Norwegian sentences. Exposure to these sentences, relative to complex tones, resulted in consistent activation in the left and right superior temporal gyrus. Activation in this region became increasingly left lateralized with repeated exposure to the unfamiliar language. These results demonstrate that shifts in lateralization can be produced in the short term within a learning context, independent of maturation. PMID- 25285758 TI - Perspectives on engineering strategies for improving biofuel production from microalgae--a critical review. AB - Although the potential for biofuel production from microalgae via photosynthesis has been intensively investigated, information on the selection of a suitable operation strategy for microalgae-based biofuel production is lacking. Many published reports describe competitive strains and optimal culture conditions for use in biofuel production; however, the major impediment to further improvements is the absence of effective engineering strategies for microalgae cultivation and biofuel production. This comprehensive review discusses recent advances in understanding the effects of major environmental stresses and the characteristics of various engineering operation strategies on the production of biofuels (mainly biodiesel and bioethanol) using microalgae. The performances of microalgae-based biofuel-producing systems under various environmental stresses (i.e., irradiance, temperature, pH, nitrogen depletion, and salinity) and cultivation strategies (i.e., fed-batch, semi-continuous, continuous, two-stage, and salinity-gradient) are compared. The reasons for variations in performance and the underlying theories of the various production strategies are also critically discussed. The aim of this review is to provide useful information to facilitate development of innovative and feasible operation technologies for effectively increasing the commercial viability of microalgae-based biofuel production. PMID- 25285759 TI - Effects of various organic carbon sources on the growth and biochemical composition of Chlorella pyrenoidosa. AB - The aim of this study was to investigate the effects of various organic carbon sources (glucose, galactose, fructose, sucrose, maltose, lactose and starch) on the growth and biochemical composition of Chlorella pyrenoidosa. Monosaccharides were found to exert stronger stimulative effects on the algal growth than disaccharides and starch. After 10-day culture, addition of 0.5-5.0 g L(-1) glucose and galactose significantly reduced the cellular protein contents by 27.7 63.7% and 22.6-60.5%, respectively, and significantly increased the carbohydrate contents by 103.2-266.5% and 91.9-240.0%, respectively. However, addition of 0.5 5.0 g L(-1) disaccharides and starch did not significantly affect the contents of lipid, protein and carbohydrate. Similar to the normal nitrogen condition, the cellular biochemical composition was not significantly affected by addition of 3.0 g L(-1) disaccharides and starch under the low nitrogen condition. Finally, the significance of this work in the biotechnological application of mixotrophic cultivation of C. pyrenoidosa was further discussed. PMID- 25285760 TI - Impact of enzymatic pretreatment on corn stover degradation and biogas production. AB - Corn stover is an agricultural residue consisting of lignocellulose, cellulose and hemicellulose polymers, sheeted in a lignin barrier. Corn stover can be used as feedstock for biogas production. Previous studies have shown biological pretreatment of lignocellulose materials can increase digestibility of the substrate improving hydrolysis, the rate-limiting step in biogas production. The impact of pretreating with different enzymes (laccase, manganese peroxidase and versatile peroxidase) and different incubation times, (0, 6 and 24 h) was studied. The effect on the matrix and biomethane production was determined. Pretreatments did not yield high concentrations of phenolic compounds, inhibitors of biogas production. The laccase enzyme showed an increase in biomethane production of 25% after 24 h of incubation. Pretreatment with peroxidase enzymes increased biomethane production with 17% after 6 h of incubation. As such it can be concluded that by introducing the different enzymes at different stages during pretreatment an increased biomethane production can be obtained. PMID- 25285761 TI - Role of transparent exopolymer particles on membrane fouling in a full-scale ultrafiltration plant: feed parameter analysis and membrane autopsy. AB - Ultrafiltration (UF) is widely used for water purification, but membrane fouling remains an important issue. In this study, the role of transparent exopolymer particles (TEPs), recently put forward as possible major foulants, was investigated in the fouling process of a full-scale UF installation. Algae, TEPs and other parameters in the UF feed were monitored and correlated during an 8 months long full-scale operation. Results revealed a complex fouling mechanism involving interactions mainly between algae, Fe (flocculant) and TEPs. Algae related parameters rather that TEP concentrations correlated stronger with irreversible fouling rates, suggesting that the overall role of TEPs in membrane fouling seems limited for this application. Finally, membrane autopsy showed the formation of a thick Fe-rich fouling layer on top of the fouled membranes, which could mostly be removed via cleaning-in-place. It remained partly irremovable in the form of some Fe-organic complexes. PMID- 25285762 TI - Inhibition of methane production in microbial fuel cells: operating strategies which select electrogens over methanogens. AB - Methanogenesis may diminish coulombic efficiency of microbial fuel cells (MFCs), although its importance is application dependent; e.g., suppression of methanogenesis may improve MFC sensing accuracy, but may be tolerable in COD removal from wastewaters. Suppression of methanogenesis was investigated in three H-type MFCs, enriched and acclimated with acetate, propionate and butyrate substrates and subsequently operated under open and closed circuit (OC/CC) regimes. Altering the polarisation state of the electrode displaces microorganisms from the anodic biofilm and leads to observable methane inhibition. The planktonic archeal community was compared to the electrode biofilm whilst under the OC/CC regimes. Semi-quantitative DNA analyses indicate a shift in some dominant species, from the electrode to the solution, during OC operation. The effect of prolonged starvation on anodic species was also studied. The results indicate progressive inhibition of methanogenesis from OC/CC operations; and virtual cessation of methanogenesis when an MFC was starved for a significant period. PMID- 25285763 TI - Carbon cloth stimulates direct interspecies electron transfer in syntrophic co cultures. AB - This study investigated the possibility that the electrical conductivity of carbon cloth accelerates direct interspecies electron transfer (DIET) in co cultures. Carbon cloth accelerated metabolism of DIET co-cultures (Geobacter metallireducens-Geobacter sulfurreducens and G.metallireducens-Methanosarcina barkeri) but did not promote metabolism of co-cultures performing interspecies H2 transfer (Desulfovibrio vulgaris-G.sulfurreducens). On the other hand, DIET co cultures were not stimulated by poorly conductive cotton cloth. Mutant strains lacking electrically conductive pili, or pili-associated cytochromes participated in DIET only in the presence of carbon cloth. In co-cultures promoted by carbon cloth, cells were primarily associated with the cloth although the syntrophic partners were too far apart for cell-to-cell biological electrical connections to be feasible. Carbon cloth seemingly mediated interspecies electron transfer between the distant syntrophic partners. These results suggest that the ability of carbon cloth to accelerate DIET should be considered in anaerobic digester designs that incorporate carbon cloth. PMID- 25285764 TI - Performance of a pilot scale microbial electrolysis cell fed on domestic wastewater at ambient temperatures for a 12 month period. AB - A 100-L microbial electrolysis cell (MEC) was operated for a 12-month period fed on raw domestic wastewater at temperatures ranging from 1 degrees C to 22 degrees C, producing an average of 0.6 L/day of hydrogen. Gas production was continuous though decreased with time. An average 48.7% of the electrical energy input was recovered, with a Coulombic efficiency of 41.2%. COD removal was inconsistent and below the standards required. Limitations to the cell design, in particular the poor pumping system and large overpotential account for many of the problems. However these are surmountable hurdles that can be addressed in future cycles of pilot scale research. This research has established that the biological process of an MEC will to work at low temperatures with real wastewater for prolonged periods. Testing and demonstrating the robustness and durability of bioelectrochemical systems far beyond that in any previous study, the prospects for developing MEC at full scale are enhanced. PMID- 25285765 TI - Possible causes of excess sludge reduction adding metabolic uncoupler, 3,3',4',5 tetrachlorosalicylanilide (TCS), in sequence batch reactors. AB - Two parallel sequence batch reactors (SBRs) were operated, with and without TCS addition, to research the causes of sludge reduction by uncouplers. Three possible mechanisms of sludge reduction by TCS were studied: (1) occurrence of metabolic uncoupling, (2) consumption of more energy to resist the infection of TCS, (3) promotion of lysis-cryptic growth by TCS addition. Results showed the remarkable reduction of electronic transport system (ETS) activity and specific cellular ATP (SATP) in TCS reactor, which proved the occurrence of metabolic uncoupling. The increasing amounts of extracellular polymeric substances (EPS), as measured by chemical methods and excitation-emission matrix (EEM) fluorescence spectra, implied microorganisms consumed more energy to resist TCS. The similar DNA concentrations of the effluents in two reactors indicated sludge lysis was not intensified by TCS. Therefore, uncoupler might not only cause metabolic uncoupling but also induce more energy consumption in the production of some substances to resist uncoupler. PMID- 25285768 TI - Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL induced cancer cell apoptosis via stimulation of mitochondrial pathway. AB - In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action. PMID- 25285767 TI - Temperature control during therapeutic hypothermia for newborn encephalopathy using different Blanketrol devices. AB - Therapeutic hypothermia improves the survival and neurodevelopmental outcome of infants with newborn encephalopathy of a hypoxic-ischemic origin. The NICHD Neonatal Research Network (NRN) Whole Body Cooling trial used the Cincinnati Sub Zero Blanketrol II to achieve therapeutic hypothermia. The Blanketrol III is now available and provides additional cooling modes that may result in better temperature control. This report is a retrospective comparison of infants undergoing hypothermia using two different cooling modes of the Blanketrol device. Infants from the NRN trial were cooled with the Blanketrol II using the Automatic control mode (B2 cohort) and were compared with infants from two new NRN centers that adopted the NRN protocol and used the Blanketrol III in a gradient mode (B3 cohort). The primary outcome was the percent time the esophageal temperature stayed between 33 degrees C and 34 degrees C (target 33.5 degrees C) during maintenance of hypothermia. Cohorts had similar birth weight, gestational age, and level of encephalopathy at the initiation of therapy. Baseline esophageal temperature differed between groups (36.6 degrees C +/- 1.0 degrees C for B2 vs. 33.9 degrees C +/- 1.2 degrees C for B3, p<0.0001) reflecting the practice of passive cooling during transport prior to initiation of active device cooling in the B3 cohort. This difference prevented comparison of temperatures during induction of hypothermia. During maintenance of hypothermia the mean and standard deviation of the percent time between 33 degrees C and 34 degrees C was similar for B2 compared to B3 cohorts (94.8% +/- 0.1% vs. 95.8% +/- 0.1%, respectively). Both the automatic and gradient control modes of the Blanketrol devices appear comparable in maintaining esophageal temperature within the target range during maintenance of therapeutic hypothermia. PMID- 25285769 TI - The association between HbA1c, fasting glucose, 1-hour glucose and 2-hour glucose during an oral glucose tolerance test and cardiovascular disease in individuals with elevated risk for diabetes. AB - OBJECTIVE: To determine the association between HbA1c, fasting plasma glucose (FPG), 1-hour (1 hPG) and 2-hour (2 hPG) glucose after an oral glucose tolerance test (OGTT) and cardiovascular disease in individuals with elevated risk for diabetes. DESIGN: We studied the relationship between baseline, updated mean and updated (last) value of HbA1c, FPG, 1 hPG and 2 hPG after an oral 75 g glucose tolerance test (OGTT) and acute CVD events in 504 individuals with impaired glucose tolerance (IGT) at baseline enrolled in the Finnish Diabetes Prevention Study. SETTING: Follow-up of clinical trial. PARTICIPANTS: 504 individuals with IGT were followed with yearly evaluations with OGTT, FPG and HbA1c. MAIN OUTCOME MEASURE: Relative risk of CVD. RESULTS: Over a median follow-up of 9.0 years 34 (6.7%) participants had a CVD event, which increased to 52 (10.3%) over a median follow-up of 13.0 years when including events that occurred among participants following a diagnosis of diabetes. Updated mean HbA1c, 1 hPG and 2 hPG, HR per 1 unit SD of 1.57 (95% CI 1.16 to 2.11), p = 0.0032, 1.51 (1.03 to 2.23), p = 0.036 and 1.60 (1.10 to 2.34), p = 0.014, respectively, but not FPG (p = 0.11), were related to CVD. In analyses of the last value prior to the CVD event the same three glycaemic measurements were associated with the CVD events, with HRs per 1 unit SD of 1.45 (1.06 to 1.98), p = 0.020, 1.55 (1.04 to 2.29), p = 0.030 and 2.19 (1.51 to 3.18), p<0.0001, respectively but only 2 hPG remained significant in pairwise comparisons. Including the follow-up period after diabetes onset updated 2 hPG (p = 0.003) but not updated mean HbA1c (p = 0.08) was related to CVD. CONCLUSIONS AND RELEVANCE: Current 2 hPG level in people with IGT is associated with increased risk of CVD. This supports its use in screening for prediabetes and monitoring glycaemic levels of people with prediabetes. PMID- 25285770 TI - Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice. AB - Systemic deletion of the gene encoding for adipose triglyceride lipase (ATGL) in mice leads to severe cardiac dysfunction due to massive accumulation of neutral lipids in cardiomyocytes. Recently, impaired peroxisome proliferator-activated receptor alpha (PPARalpha) signaling has been described to substantially contribute to the observed cardiac phenotype. Disturbances of the ubiquitin proteasome system (UPS) have been implicated in numerous cardiac diseases including cardiomyopathy, ischemic heart disease, and heart failure. The objective of the present study was to investigate the potential role of UPS in cardiac ATGL deficiency. Our results demonstrate prominent accumulation of ubiquitinated proteins in hearts of ATGL-deficient mice, an effect that was abolished upon cardiomyocyte-directed overexpression of ATGL. In parallel, cardiac protein expression of the ubiquitin-activating enzyme E1a, which catalyzes the first step of the ubiquitination cascade, was significantly upregulated in ATGL-deficient hearts. Dysfunction of the UPS was accompanied by activation of NF-kappaB signaling. Moreover, the endoplasmic reticulum (ER) resident chaperon protein disulfide isomerase was significantly upregulated in ATGL-deficient hearts. Chronic treatment of ATGL-deficient mice with the PPARalpha agonist Wy14,643 improved proteasomal function, prevented NF-kappaB activation and decreased oxidative stress. In summary, our data point to a hitherto unrecognized link between proteasomal function, PPARalpha signaling and cardiovascular disease. PMID- 25285771 TI - Chronic PFOS exposure alters the expression of neuronal development-related human homologues in Eisenia fetida. AB - PFOS is a toxic, persistent environmental pollutant which is widespread worldwide. PFOS contamination has entered the food chain and is interfering with normal development in man and is neurotoxic, hepatotoxic and tumorigenic. The earthworm, Eisenia fetida is one of the organisms which can help to diagnose soil health and contamination at lower levels in the food chain. Studying the chronic effects of sub-lethal PFOS exposure in such an organism is therefore appropriate. As PFOS bioaccumulates and is not easily biodegraded, it is biomagnified up the food chain. Gene expression studies will give us information to develop biomarkers for early diagnosis of soil contamination, well before this contaminant passes up the food chain. We have carried out mRNA sequencing of control and chronically PFOS exposed E. fetida and reconstructed the transcripts in silico and identified the differentially expressed genes. Our findings suggest that PFOS up/down regulates neurodegenerative-related human homologues and can cause neuronal damage in E. fetida. This information will help to understand the links between neurodegenerative disorders and environmental pollutants such as PFOS. Furthermore, these up/down regulated genes can be used as biomarkers to detect a sub-lethal presence of PFOS in soil. Neuronal calcium sensor-2, nucleoside diphosphate kinase, polyadenylate-binding protein-1 and mitochondrial Pyruvate dehydrogenase protein-X component, could be potential biomarkers for sub lethal concentrations of PFOS. PMID- 25285772 TI - Heavy metals in selected tissues and histopathological changes in liver and kidney of common moorhen (Gallinula chloropus) from Anzali Wetland, the south Caspian Sea, Iran. AB - The present study aimed to measure the concentrations of Sn, Pb, Zn, Hg, Cu, Ni and Cd in the muscle and liver of 40 Common Moorhens (Gallinula chloropus) hunted from four stations in Anzali Wetland (Pirbazar, Ghalam-Koudeh, Selkeh and Abkenar). The histopathologic alteration index (HAI) of liver and kidney was also assessed in these birds. The highest concentrations of selected metals were measured in the liver of birds collected from Ghalam-Koudeh (Pb: 4.59+/-0.21, Sn: 6.663+/-0.282, Zn: 29.867+/-2.011, Cu: 24.07+/-1.84, Hg: 7.5+/-0.257, Ni: 6.85+/ 0.52, Cd: 1.879+/-0.4mg kg(-1) dw). The lowest concentrations of metals were measured in the muscle of birds caught from Abkenar (Pb: 0.799+/-0.207, Sn: 1.873+/-0.066, Zn: 18.533+/-1.582, Hg: 0.86+/-0.08, Ni: 0.53+/-0.117, Cu: 6.63+/ 1.114, Cd: 0.08+/-0.002mg kg(-1) dw). Also the highest and lowest concentrations of metals were recorded in sediment of Ghalam-Koudeh and Abkenar stations, respectively. These stations were located next to multi-industry Anzali Port. However, the concentration of Sn and Zn in sediment and tissues of Common Moorhens collected from different stations was lower than the permissible limit suggested by WHO and Canadian Council of Ministers of the Environment (CCME). But, Pb, Hg and Ni concentration in sediment and birds caught from all stations was higher than the permissible limit defined by WHO and CCME. Cu and Cd concentration in tissue samples and sediment of Ghalam-Koudeh and Pirbazar was also higher than the permissible limit defined by WHO and CCME. Hemorrhage, melanomacrophage aggregations, sinusoidal congestion and hepatocyte vacuolation were the most pathological changes found in the liver. Reduction of the Bowman space, melanomacrophage aggregations and hemorrhage also were observed in the kidney. The HAI means of G. chloropus collected from Ghalam-Koudeh and Pirbazar were significantly higher than other sites. Based on the HAI values and metal bioaccumulation in the tissues of G. chloropus, Ghalam-Koudeh and Pirbazar could be considered as having the worst environmental quality. PMID- 25285773 TI - Hysteroscopic treatment of symptomatic cesarean-induced isthmocele: a prospective study. AB - An isthmocele, also known as a cesarean scar defect, is an emerging condition that typically affects women with a history of previous cesarean section, and its presence is a novel under-recognized cause of postmenstrual abnormal uterine bleeding and/or pelvic pain. The incidence of symptoms and their resolution after hysteroscopic surgery were evaluated prospectively in 120 consecutive isthmocele patients. Patients included only symptomatic premenopausal women. Transvaginal ultrasound and office hysteroscopy were used to diagnose isthmocele. Operative hysteroscopy was performed to correct the cesarean scar defect, and histologic findings were evaluated. Correction of an isthmocele via operative hysteroscopy was successful in all cases evaluated. Isthmoplasty resulted in the resolution of postmenstrual abnormal uterine bleeding and suprapubic pelvic pain in 80% of patients. In the remaining cases, 7% of patients had an improvement of symptoms, whereas 13% did not obtain any relief. Considering the recent diagnostic recognition of isthmoceles, we conclude that surgical treatment of this pathology by operative hysteroscopy may represent the best choice in symptomatic women because of its minimal invasiveness and beneficial therapeutic results. PMID- 25285774 TI - Laparoscopic supracervical hysterectomy with transcervical morcellation: our experience. AB - STUDY OBJECTIVE: To present our experience with laparoscopic supracervical hysterectomy with transcervical morcellation (LSH-TM). DESIGN: A retrospective observational study (Canadian Task Force Classification III). SETTING: Gynecologic Department at Brunico Hospital, Brunico, Italy. PATIENTS: Three hundred sixty-five patients affected by gynecologic benign diseases who underwent LSH-TM. INTERVENTIONS: A minimally invasive surgical technique for supracervical hysterectomy that involves extraction of the morcellated uterus through the cervical canal. MEASUREMENTS AND MAIN RESULTS: We performed LSH-TM successfully in 365 patients; the mean (standard deviation) operating time was 72.24 (23.21) minutes. We registered no intraoperative complications. The main postoperative complications resulted in 2 cases of second-look laparoscopy because of internal bleeding, 5 cases of asymptomatic hematoma around the cervical stump, and 7 cases of pelvic pain. CONCLUSION: Our experience shows that LSH-TM is a safe and easy to perform technique and that it ensures minimal blood loss. PMID- 25285775 TI - Treatment of benign prostatic hyperplasia using transurethral split of the prostate with a columnar balloon catheter. AB - Transurethral dilation of the prostate (TUDP) with a spherical balloon catheter is a traditional treatment for patients with benign prostatic hyperplasia (BPH). TUDP, however, has been abandoned in clinical application because of its unsatisfying treatment benefit and severe complications. In this study, we redesigned an improved TUDP surgical procedure-transurethral split of the prostate (TUSP)-by replacing the spherical balloon with a columnar balloon. To evaluate the clinical therapeutic effect, we compared the lower urinary tract symptoms (LUTS) of patients with BPH after TUSP treatment and analyzed the urethra through CT films. Animal experiments were performed on aged dogs to investigate the urine function and electromyography (EMG) changes. Histopathology was used to evaluate the inflammation and injury. In addition, collagen content was detected by Trichrome Masson. TUSP attenuated LUTS and reconstructed the urethra in patients with BPH. The attenuation of LUTS was reflected in terms of LUTS parameters such as peak urine flow rate, postvoid residual urine volume, quality of life score, and International Prostate Symptom Score. TUSP expanded the urethra in experimental dogs by splitting the prostate tissues and decreasing the collagen content, with maintenance of normal urinary function and EMG characteristics. The successful clinical application of TUSP with significant therapeutic effect and limited complications made TUSP an ideal choice for the patients with BPH. PMID- 25285776 TI - Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: broadening the clinical and neuropsychological phenotype. AB - In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation. PMID- 25285778 TI - Promising anchoring groups for single-molecule conductance measurements. AB - The understanding of the charge transport through single molecule junctions is a prerequisite for the design and building of electronic circuits based on single molecule junctions. However, reliable and robust formation of such junctions is a challenging task to achieve. In this topical review, we present a systematic investigation of the anchoring group effect on single molecule junction conductance by employing two complementary techniques, namely scanning tunneling microscopy break junction (STM-BJ) and mechanically controllable break junction (MCBJ) techniques, based on the studies published in the literature and important results from our own work. We compared conductance studies for conventional anchoring groups described earlier with the molecular junctions formed through pi interactions with the electrode surface (Au, Pt, Ag) and we also summarized recent developments in the formation of highly conducting covalent Au-C sigma bonds using oligophenyleneethynylene (OPE) and an alkane molecular backbone. Specifically, we focus on the electron transport properties of diaryloligoyne, oligophenyleneethynylene (OPE) and/or alkane molecular junctions composed of several traditional anchoring groups, (dihydrobenzo[b]thiophene (BT), 5 benzothienyl analogue (BTh), thiol (SH), pyridyl (PY), amine (NH2), cyano (CN), methyl sulphide (SMe), nitro (NO2)) and other anchoring groups at the solid/liquid interface. The qualitative and quantitative comparison of the results obtained with different anchoring groups reveals structural and mechanistic details of the different types of single molecular junctions. The results reported in this prospective may serve as a guideline for the design and synthesis of molecular systems to be used in molecule-based electronic devices. PMID- 25285777 TI - Azo dye biodecolorization enhanced by Echinodontium taxodii cultured with lignin. AB - Lignocellulose facilitates the fungal oxidization of recalcitrant organic pollutants through the extracellular ligninolytic enzymes induced by lignin in wood or other plant tissues. However, available information on this phenomenon is insufficient. Free radical chain reactions during lignin metabolism are important in xenobiotic removal. Thus, the effect of lignin on azo dye decolorization in vivo by Echinodontium taxodii was evaluated. In the presence of lignin, optimum decolorization percentages for Remazol Brilliant Violet 5R, Direct Red 5B, Direct Black 38, and Direct Black 22 were 91.75% (control, 65.96%), 76.89% (control, 43.78%), 43.44% (control, 17.02%), and 44.75% (control, 12.16%), respectively, in the submerged cultures. Laccase was the most important enzyme during biodecolorization. Aside from the stimulating of laccase activity, lignin might be degraded by E. taxodii, and then these degraded low-molecular-weight metabolites could act as redox mediators promoting decolorization of azo dyes. The relationship between laccase and lignin degradation was investigated through decolorization tests in vitro with purified enzyme and dozens of aromatics, which can be derivatives of lignin and can function as laccase mediators or inducers. Dyes were decolorized at triple or even higher rates in certain laccase-aromatic systems at chemical concentrations as low as 10 uM. PMID- 25285779 TI - Instrumentation and methods: general discussion. PMID- 25285780 TI - Plasmonic-enhanced Raman scattering of graphene on growth substrates and its application in SERS. AB - We detail a facile method for enhancing the Raman signals of as-grown graphene on Cu foils by depositing gold nanoislands (Au Nis) onto the surface of graphene. It is found that an enhancement of up to 49 fold in the graphene Raman signal has been achieved by depositing a 4 nm thick Au film. The enhancement is considered to be related to the coupling between graphene and the plasmon modes of Au Nis, as confirmed by the finite element simulations. The plasmonic effect of the Au/graphene/Cu hybrid platform leads to a strong absorption at the resonant wavelength whose position shifts from visible light (640 nm) to near-infrared (1085 nm) when the thickness of Au films is increased from 2 nm to 18 nm. Finally, we demonstrate that hybrid substrates are reliable surface-enhanced Raman scattering (SERS) systems, showing an enhancement factor of ~10(6) for dye molecules Rhodamine B and Rhodamine 6G with uniform and stable response and a detection limit of as low as 0.1 nM for Sudan III and Sudan IV. PMID- 25285781 TI - Phomalactone optimization and production of entomopathogenic fungi by Ophiocordyceps communis BCC 1842 and BCC 2763. AB - Phomalactone, an antibacterial, insecticidal, and herbicidal compound, was produced by insect pathogenic fungi, Ophiocordyceps communis BCC 1842 and BCC 2763, in bioreactors using different carbon and nitrogen sources. Glucose and fructose were preferable for growth and phomalactone production. The highest specific growth rate (MU) of 0.012 hr(-1), the highest biomass yield (Ysx) of 0.38 g DW g(-1) sugar, the highest volumetric sugar consumption rate (qs) of 0.036 g (L hr)(-1), the maximum phomalactone concentration ([Formula: see text]) of 93.30 mg L(-1) at 127 hr, and the highest volumetric production rate of phomalactone (qp) of 0.46 +/- 0.12 mg (L d)(-1) were obtained on glucose and sodium nitrate as the sole carbon and nitrogen sources, respectively, by O. communis BCC 1842. In contrast, O. communis BCC 2763 gave lower phomalactone production. This mass phomalactone production is useful for the biological synthesis of a precursor for more broad-range potent analogs such as antitumor, antifungal, and others and for its further biological studies. PMID- 25285782 TI - External electric field induced hydrogen storage/release on calcium-decorated single-layer and bilayer silicene. AB - Hydrogen storage and release are two essential parameters that define the efficiency of a hydrogen storage medium. Herein, we investigate the effects of the external electric field F on the adsorption-desorption of H2 on a Ca decorated silicene system (Ca-silicene) based on density functional theory calculations. Our study demonstrates that nine H2 molecules per Ca atom can be adsorbed and 6.4 wt% H2 can be adsorbed on Ca-silicene with an average binding energy of 0.19 eV per H2, while the appropriate F can be used to effectively enhance the hydrogen storage-release on the Ca-silicene system. The high synergetic effect may be attributed to the observation that F induces an enhancement of the charge transfer between H2 molecules and the Ca-silicene system. Thus, the Ca-silicene system together with the synergy of F can efficiently facilitate H2 adsorption-desorption, completing the whole hydrogen storage-release cycle. PMID- 25285783 TI - Synthesis of functionalized fulvenes: [3 + 2] annulation of ethyl alpha chlorocyclopropaneformates with 1,3-dicarbonyl compounds. AB - A base-promoted [3 + 2] annulation reaction of ethyl alpha chlorocyclopropaneformates with 1,3-dicarbonyl compounds is described. This method provides an efficient and straightforward route to acidic multi substituted fulvenes with distinctive properties. PMID- 25285784 TI - Multifunctional SiO2@Gd2O3:Yb/Tm hollow capsules: controllable synthesis and drug release properties. AB - A series of hollow and luminescent capsules have been fabricated by covering luminescent Gd2O3:Yb/Tm nanoparticles on the surface of uniform hollow mesoporous silica capsules (HMSCs), which were obtained from an etching process using Fe3O4 as hard templates. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), up-conversion (UC) fluorescence spectra, and N2 adsorption desorption were used to characterize these samples. It is found that the as prepared products have mesoporous pores, large specific surface, and high dispersity. In particular, the size, shape, surface area, and interior space of the composites can be finely tuned by adjusting the size and morphology of the magnetic cores. Under 980 nm near-infrared (NIR) laser irradiation, the composites show characteristic blue UC emissions of Tm(3+) even after carrying doxorubicin hydrochloride (DOX). The drug-release test reveals that the capsules showed an apparent sustained release character and released in a pH-sensitive manner. Interestingly, the UC luminescence intensity of the drug-carrying system increases with the released DOX, realizing the possibility to track or monitor the released drug by the change of UC fluorescence simultaneously, which should be highly promising in anticancer drug delivery and targeted cancer therapy. PMID- 25285785 TI - Could atomoxetine improve sluggish cognitive tempo symptoms? PMID- 25285787 TI - Diatom mimics: directing the formation of biosilica nanoparticles by controlled folding of lysine-leucine peptides. AB - Silaffins, long chain polyamines, and other biomolecules found in diatoms are involved in the assembly of a large number of silica nanostructures under mild, ambient conditions. Nanofabrication researchers have sought to mimic the diatom's biosilica production capabilities by engineering proteins to resemble aspects of naturally occurring biomolecules. Such mimics can produce monodisperse biosilica nanospheres, but in vitro production of the variety of intricate biosilica nanostructures that compose the diatom frustule is not yet possible. In this study we demonstrate how LK peptides, composed solely of lysine (K) and leucine (L) amino acids arranged with varying hydrophobic periodicities, initiate the formation of different biosilica nanostructures in vitro. When L and K residues are arranged with a periodicity of 3.5 the alpha-helical form of the LK peptide produces monodisperse biosilica nanospheres. However, when the LK periodicity is changed to 3.0, corresponding to a 310 helix, the morphology of the nanoparticles changes to elongated rod-like structures. beta-strand LK peptides with a periodicity of 2.0 induce wire-like silica morphologies. This study illustrates how the morphology of biosilica can be changed simply by varying the periodicity of polar and nonpolar amino acids. PMID- 25285786 TI - Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials. AB - Breast cancers over-express the human epidermal growth factor receptor 2 (HER2) in about 15% of patients. This transmembrane tyrosine kinase receptor activates downstream signaling pathways and leads to proliferation of cancer cells. Trastuzumab, an anti-HER2 monoclonal antibody, improves outcome in women with early and metastatic breast cancer. Resistance to trastuzumab involves the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, truncation of the Her2 receptor or lack of immune response. The last decade has seen major advances in strategies to overcome resistance to trastuzumab. This includes the development of antibody-drug conjugates, dual HER2 inhibition strategies, inhibition of PI3K/mTOR pathway and development of modulators of immune checkpoints. PMID- 25285789 TI - Control of astrocyte progenitor specification, migration and maturation by Nkx6.1 homeodomain transcription factor. AB - Although astrocytes are the most abundant cell type in the central nervous system (CNS), little is known about their molecular specification and differentiation. It has previously been reported that transcription factor Nkx6.1 is expressed in neuroepithelial cells that give rise to astrocyte precursors in the ventral spinal cord. In the present study, we systematically investigated the function of Nkx6.1 in astrocyte development using both conventional and conditional Nkx6.1 mutant mice. At early postnatal stages, Nkx6.1 was expressed in a subpopulation of astrocytes in the ventral spinal cord. In the conventional Nkx6.1KO spinal cord, the initial specification of astrocyte progenitors was affected by the mutation, and subsequent migration and differentiation were disrupted in newborn mice. In addition, the development of VA2 subtype astrocytes was also inhibited in the white matter. Further studies with Nkx6.1 conditional mutants revealed significantly delayed differentiation and disorganized arrangement of fibrous astrocytes in the ventral white matter. Together, our studies indicate that Nkx6.1 plays a vital role in astrocyte specification and differentiation in the ventral spinal cord. PMID- 25285790 TI - Factors associated with hospital length of stay among cancer patients with febrile neutropenia. AB - PURPOSE: This study sought to evaluate factors associated with hospital length of stay in cancer patients with febrile neutropenia. METHODS: A prospective cohort study was performed at a single tertiary referral hospital in southern Brazil from October 2009 to August 2011. All adult cancer patients with febrile neutropenia admitted to the hematology ward were evaluated. Stepwise random effects negative binomial regression was performed to identify risk factors for prolonged length of hospital stay. RESULTS: In total, 307 cases of febrile neutropenia were evaluated. The overall median length of hospital stay was 16 days (interquartile range 18 days). According to multiple negative binomial regression analysis, hematologic neoplasms (P = 0.003), high-dose chemotherapy regimens (P<0.001), duration of neutropenia (P<0.001), and bloodstream infection involving Gram-negative multi-drug-resistant bacteria (P = 0.003) were positively associated with prolonged hospital length of stay in patients with febrile neutropenia. The condition index showed no evidence of multi-collinearity effect among the independent variables. CONCLUSIONS: Hematologic neoplasms, high-dose chemotherapy regimens, prolonged periods of neutropenia, and bloodstream infection with Gram-negative multi-drug-resistant bacteria are predictors of prolonged length hospital of stay among adult cancer patients with febrile neutropenia. PMID- 25285791 TI - Conception and evolution of stereocontrolled strategies toward functionalized 8 aryloctanoic acids related to the total synthesis of aliskiren. AB - A detailed account is given describing the approaches used toward the total synthesis of aliskiren. In particular, ring-closing metathesis with the Hoveyda Grubbs catalyst accelerates the formation of a 9-membered lactone from an (R) ester. The diastereomeric (S)-ester leads to the formation of dimeric dilactones, which were characterized by X-ray analysis and chemical conversions. PMID- 25285792 TI - Evolutionarily conserved repulsive guidance role of slit in the silkworm Bombyx mori. AB - Axon guidance molecule Slit is critical for the axon repulsion in neural tissues, which is evolutionarily conserved from planarians to humans. However, the function of Slit in the silkworm Bombyx mori was unknown. Here we showed that the structure of Bombyx mori Slit (BmSlit) was different from that in most other species in its C-terminal sequence. BmSlit was localized in the midline glial cell, the neuropil, the tendon cell, the muscle and the silk gland and colocalized with BmRobo1 in the neuropil, the muscle and the silk gland. Knock down of Bmslit by RNA interference (RNAi) resulted in abnormal development of axons and muscles. Our results suggest that BmSlit has a repulsive role in axon guidance and muscle migration. Moreover, the localization of BmSlit in the silk gland argues for its important function in the development of the silk gland. PMID- 25285793 TI - Clinical effectiveness and cost-effectiveness of HIV pre-exposure prophylaxis in men who have sex with men: risk calculators for real-world decision-making. AB - BACKGROUND: Oral pre-exposure prophylaxis (PrEP) can be clinically effective and cost-effective for HIV prevention in high-risk men who have sex with men (MSM). However, individual patients have different risk profiles, real-world populations vary, and no practical tools exist to guide clinical decisions or public health strategies. We introduce a practical model of HIV acquisition, including both a personalized risk calculator for clinical management and a cost-effectiveness calculator for population-level decisions. METHODS: We developed a decision analytic model of PrEP for MSM. The primary clinical effectiveness and cost effectiveness outcomes were the number needed to treat (NNT) to prevent one HIV infection, and the cost per quality-adjusted life-year (QALY) gained. We characterized patients according to risk factors including PrEP adherence, condom use, sexual frequency, background HIV prevalence and antiretroviral therapy use. RESULTS: With standard PrEP adherence and national epidemiologic parameters, the estimated NNT was 64 (95% uncertainty range: 26, 176) at a cost of $160,000 (cost saving, $740,000) per QALY--comparable to other published models. With high (35%) HIV prevalence, the NNT was 35 (21, 57), and cost per QALY was $27,000 (cost saving, $160,000), and with high PrEP adherence, the NNT was 30 (14, 69), and cost per QALY was $3,000 (cost saving, $200,000). In contrast, for monogamous, serodiscordant relationships with partner antiretroviral therapy use, the NNT was 90 (39, 157) and cost per QALY was $280,000 ($14,000, $670,000). CONCLUSIONS: PrEP results vary widely across individuals and populations. Risk calculators may aid in patient education, clinical decision-making, and cost-effectiveness evaluation. PMID- 25285794 TI - Optimal Stroke Prevention in the Geriatric Patient with Atrial Fibrillation: Position Paper of an Interdisciplinary Expert Panel. AB - The present position paper summarises the outcomes of an expert panel discussion held by hospital-based and office-based physicians with ample experience in the treatment of geriatric patients. The optimal approach to stroke prevention in geriatric patients with atrial fibrillation (AF) has not been adequately clarified. Despite their high risk of stroke and clear indication for anticoagulation according to established risk scores, in practice geriatric AF patients often are withheld treatment because of comorbidities and comedications, concerns about low treatment adherence or fear of bleeding events, in particular due to falls. The panel agreed that geriatric patients should receive oral anticoagulation as a rule, unless a comprehensive neurological and geriatric assessment (including clinical examination, gait tests and validated instruments such as Modified Rankin Scale, Mini-mental state examination or Timed Test of Money Counting) provides sound reasons for refraining from treatment. All patients with a history of falls should be thoroughly evaluated for further evaluation of the causes. Patients with CHADS2 score >= 2 should receive anticoagulation even if at high risk for falls. The novel oral anticoagulants (NOAC) facilitate management in the geriatric population with AF (no INR monitoring needed, easier bridging during interventions) and have, based on available data, an improved benefit-risk ratio compared to vitamin K antagonists. Drugs with predominantly non-renal elimination are safer in geriatric patients and should be preferred. PMID- 25285795 TI - Are Hemoglobin-Based Oxygen Carriers Being Withheld Because of Regulatory Requirement for Equivalence to Packed Red Blood Cells? PMID- 25285796 TI - Near Fatal Asthma in an Inner City Population. AB - Near-fatal asthma (NFA) is highly prevalent in inner city population. Patients who present with NFA require timely intervention, which necessitates knowledge of appropriate associated risk factors. The purpose of the study was to look and identify the salient features of an asthma exacerbation that are more likely to be associated with NFA in inner city population. We conducted a retrospective analysis of patients who were discharged from the hospital with a diagnosis of acute asthma exacerbation. Two hundred eighteen patients were included in the study. Patients who required intubation during the course of their hospitalization were defined as NFA and the rest were defined as non-near-fatal asthma (NNFA). Multiple patient parameters were compared between the 2 groups; 60 patients met the definition of NFA. There was no difference between NFA and NNFA groups with respect to sex, race, and history of smoking and asthma treatment modalities before presentation. NFA was seen more commonly in heroin (40% vs. 25.9%; P < 0.05) and cocaine users (28.3% vs. 16.5%; P < 0.05). A history of exacerbation requiring intensive care unit (ICU) care was more common among the NFA patients (55% vs. 40.5%; P = 0.05). A history of intubation for an exacerbation was more commonly seen in patients presenting with NFA (51.7% vs. 35.4%; P < 0.05). The NNFA group was more likely to have a primary care physician and to be discharged home (65.6% vs. 51.7%, P < 0.05; and 71.7 vs. 79.1%, P < 0.05). In a multi-logistic regression model, including age, sex, race, heroin and cocaine use, history of intubation and ICU admission, medications, use of noninvasive ventilation, primary care physician, and pH <7.35, PCO2 >45 mm Hg, and FiO2 >40% on initial blood gas, NFA was predicted only by PaCO2 >45 [odds ratio (OR = 6.7; P < 0.001)] and FiO2 >40% (OR = 3.5; P = 0.002). Use of noninvasive ventilation was a negative predictor of NFA (OR = 0.2; P < 0.001). Asthmatic patients who carry a history of intubation with mechanical ventilation for an asthma exacerbation, admissions to the ICU, or those who indulge in recreational drugs like cocaine or heroin should be closely monitored for clinical deterioration. PMID- 25285797 TI - Acute Mastoiditis Before Pneumococcal Vaccination: The Experience of a Large Tertiary Care Pediatric Hospital. AB - To report the experience of a large tertiary care pediatric center during a period of increasing Streptococcus pneumoniae antimicrobial resistance before the introduction of pneumococcal vaccine in Israel. Retrospective chart review of children diagnosed acute mastoiditis (AM) between January 1997 and December 2007. The children were divided into 4 age groups (6-11, 12-23, 24-35, and 36-40 months), and each group was compared with the others. A total of 198 AM episodes were recorded during the 10-year study period. The most prevalent pathogen was S. pneumonia, with a very low (15%) penicillin resistance rate (minimal inhibitory concentration >= 2). Complications were more prevalent in the 12- to 23-month age group. The number of AM cases increased during the study period. Penicillin resistance did not play an important role in determining the morbidity before the introduction of pneumococcal conjugate vaccine. PMID- 25285799 TI - Reduction-triggered aromatic to aromatic electronic structure switching in tribenzotetraazachlorin-fullerene conjugates. AB - Absorption spectral changes observed during sodium mirror reduction of tribenzotetraazachlorin-fullerene (TBTAC-C60) conjugates have clarified that electronic communication between the TBTAC and C60 moieties is switched off upon reduction of the conjugates. Spectroscopy has suggested that the anionic species retains its aromatic character. PMID- 25285798 TI - Honey bee hemocyte profiling by flow cytometry. AB - Multiple stress factors in honey bees are causing loss of bee colonies worldwide. Several infectious agents of bees are believed to contribute to this problem. The mechanisms of honey bee immunity are not completely understood, in part due to limited information about the types and abundances of hemocytes that help bees resist disease. Our study utilized flow cytometry and microscopy to examine populations of hemolymph particulates in honey bees. We found bee hemolymph includes permeabilized cells, plasmatocytes, and acellular objects that resemble microparticles, listed in order of increasing abundance. The permeabilized cells and plasmatocytes showed unexpected differences with respect to properties of the plasma membrane and labeling with annexin V. Both permeabilized cells and plasmatocytes failed to show measurable mitochondrial membrane potential by flow cytometry using the JC-1 probe. Our results suggest hemolymph particulate populations are dynamic, revealing significant differences when comparing individual hive members, and when comparing colonies exposed to diverse conditions. Shifts in hemocyte populations in bees likely represent changing conditions or metabolic differences of colony members. A better understanding of hemocyte profiles may provide insight into physiological responses of honey bees to stress factors, some of which may be related to colony failure. PMID- 25285800 TI - Efficacy, toxicity and mortality of autologous SCT in multiple myeloma patients with dialysis-dependent renal failure. AB - Numerous studies have reported the feasibility and safety of autologous SCT (ASCT) in patients with multiple myeloma (MM) and mild to moderate renal impairment, but there are limited data in dialysis-dependent patients. In this retrospective study, we reviewed the toxicities and efficacy outcomes of 33 MM patients with dialysis-dependent renal failure who underwent ASCT at our institution from 1998 to 2012. The most common grade 3 non-hematologic toxicities were mucositis (49%), infection (15%) and bleeding (6%). Atrial dysrhythmias (24%) and delirium (30%) of all grades were also common. Hematologic toxicities included febrile neutropenia (88%); and RBC and platelet transfusions were required by 71 and 100% of patients, respectively. Transplant-related mortality (TRM) was high at 15%, predominantly caused by septic shock. Response to ASCT was at least VGPR (very good PR) in 50%, PR in 46.2% and stable disease (SD) in 3.8%. Median OS was 5.6 years, comparable to our overall institutional data. Overall, seven patients became dialysis independent. We conclude that ASCT can be an effective treatment for dialysis-dependent MM patients, with high response rates and survival. However, toxicities and a high TRM are observed indicating that further studies are needed to enhance the safety of this approach. PMID- 25285802 TI - Haploidentical hematopoietic SCT for acquired severe aplastic anemia using post transplant high-dose CY. PMID- 25285801 TI - Impact of pre-transplant co-morbidities on outcome after alemtuzumab-based reduced intensity conditioning allo-SCT in elderly patients: a British Society of Blood and Marrow Transplantation study. AB - The advent of reduced intensity conditioning (RIC) regimens has permitted the extension of allo-SCT to selected patients into their eighth decade but GVHD remains a major cause of morbidity and mortality. Alemtuzumab is increasingly used to reduce the risk of severe GVHD, but there are concerns that T-cell depletion may compromise outcome particularly in older patients. We therefore studied the impact of pre-transplant factors on the outcome of 187 patients with a haematological malignancy over the age of 60 transplanted using an alemtuzumab based RIC regimen of whom co-morbidity scoring was possible in 169. Of the patients, 120 had a haematopoietic cell transplantation co-morbidity index (HCT CI) of 0 or 1 and 49 had a score of 2 or more. The 5-year OS was 33%. In multivariable analysis, OS was determined by co-morbidity score (P=0.001) and disease status at transplant (P=0.004) but not by patient age. Non-relapse mortality was determined by co-morbidity score (P=0.001). Two-year OS for patients with a HCT-CI of 0-1 was 59 versus 6% for patients with a higher score. Alemtuzumab-based RIC allografts can be delivered safely in patients aged over 60 but co-morbidity scoring is mandatory to identify patients who will benefit. PMID- 25285803 TI - Severe weight loss in 3 months after allogeneic hematopoietic SCT was associated with an increased risk of subsequent non-relapse mortality. AB - Patients after allogeneic hematopoietic SCT (HSCT) are at risk of malnutrition. To assess the impact of malnutrition after allogeneic HSCT on transplant outcomes, we conducted a retrospective study. Adult patients who received allogeneic HSCT from 2000 to 2009 for standard-risk leukemia and achieved disease free survival up to 3 months after allogeneic HSCT were included. From participating centers, 145 patients were enrolled. Median age was 46 years (19 68). Patients were classified based on weight loss during 3 months after allogeneic HSCT as follows: normal group (weight loss <5%, n=53), mild malnutrition group (5%?weight loss<10%, n=47), severe malnutrition group (10% ?weight loss, n=45). The cumulative incidences of 2-year nonrelapse mortality (NRM) were 3.8% in the normal group, 8.5% in the mild malnutrition group and 27.3% in the severe malnutrition group. The probabilities of a 2-year OS were 73.2% in the normal group, 74.5% in the mild malnutrition group and 55.3% in the severe malnutrition group. In multivariate analysis, severe malnutrition was associated with an increased risk of NRM and a worse OS. In conclusion, weight loss ?10% was associated with a worse clinical outcome. Prospective studies that identify patients at risk of malnutrition and intervention by a nutritional support team are warranted. PMID- 25285804 TI - Low-dose antithymocyte globulin enhanced the efficacy of tacrolimus and mycophenolate for GVHD prophylaxis in recipients of unrelated SCT. AB - We performed a retrospective analysis of the outcome of 197 consecutive unrelated donor transplant recipients who received GVHD prophylaxis either TM regimen (tacrolimus and mycophenolate) (121 patients) or TM/ATG-G regimen (TM with low dose antithymocyte globulin (ATG) of 4.5 mg/kg, ATG-G, Genzyme) (76 patients). Cumulative incidences of grade II-IV acute GVHD for the TM and TM/ATG-G cohorts were 49% and 61% (P=0.11) and grade III-IV acute GVHD for the TM and TM/ATG-G cohorts were 27% and 14% (P=0.02), respectively. There was no difference in the incidence of relapse or disease progression between TM and TM/ATG-G-16% and 23% (P=0.64). TM/ATG-G cohort had lower incidence of non-relapse mortality (NRM; 37% vs 20%, P=0.01), chronic GVHD (56% vs 43%, P<0.001) and more favorable global chronic GVHD severity (P<0.001). Univariate analyses showed improved OS and PFS of patients who received TM/ATG-G. Multivariate analysis confirmed TM/ATG-G had a favorable influence on OS (P=0.05) but not on PFS (P=0.07). We concluded that low dose ATG of 4.5 mg/kg given in conjunction with TM improved GVHD prophylaxis without increased risk of relapse. Lower NRM, lower incidence and severity of chronic GVHD could potentially improve survival. PMID- 25285805 TI - Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling. PMID- 25285806 TI - Quantitative evaluation of DNA dissociation from liposome carriers and DNA escape from endosomes during lipid-mediated gene delivery. AB - Nonviral vectors are highly attractive for gene therapy from a clinical point of view, and cationic lipid nanoparticles in particular have generated considerable interest. However, despite considerable recent advances, problems associated with low transfection efficiencies remain to be resolved to fully meet the potential of these vectors. The trafficking of plasmid DNA (pDNA) from the extracellular space up to the nucleus is prevented by several barriers, including liposome/pDNA dissociation within the endosome and pDNA escape into the cytosol. The aim of this work was to develop and optimize a tool that could offer simultaneous quantitative information both on the intracellular dissociation of oligonucleotides from lipid nanoparticles, and on the DNA escape from endocytic compartments. The ability to follow in real time both of these processes simultaneously (in a quantitative manner) is expected to be of high value in the rationalization and conception of new lipid nanoparticle vectors for gene delivery for therapeutic purposes. To this effect, a combination of Forster resonance energy transfer (FRET) and colocalization microscopy was employed. We show that it is possible to distinguish between liposome/pDNA dissociation and depletion of DNA within endosomes, providing resolution for the detection of intermediate species between endocytic particles with intact lipoplexes and endosomes devoid of DNA because of DNA escape or degradation. We demonstrate that after endocytosis, exceptionally few endocytic particles are found to exhibit simultaneously DNA/lipid colocalization and low FRET (DNA/lipid dissociation). These results clearly point to an extremely short-lived state for free plasmid within endosomes, which either escapes at once to the cytosol or is degraded within the endocytic compartment (because of exposure of DNA). It is possible that this limitation greatly contributes to reduction in probability of successful gene delivery through cationic lipid particles. PMID- 25285807 TI - Advances in the electrochemical simulation of oxidation reactions mediated by cytochrome p450. AB - Combining electrochemistry with mass spectrometry constitutes an increasingly useful approach for simulating reactions catalyzed by cytochrome P450 (CYP450). In this review, we discuss the ability of the electrochemical cell to act as a reliable tool to mimic CYP450. The electrochemical oxidation process and CYP450 catalyzed reactions are compared in terms of mechanistic pathways, chemical structures of reactive intermediate metabolites, and final chemical structures of oxidation products. The oxidation reactions mediated by CYP450 are known to occur by either a single electron transfer (SET) or a hydrogen atom transfer (HAT) mechanism. The similarities between the reactions mediated electrochemically or by CYP450 are discussed in terms of SET and HAT mechanisms. PMID- 25285808 TI - Gender difference in the pathophysiology and treatment of glaucoma. AB - Glaucoma is the principal cause of irreversible blindness in the world, the second leading cause of blindness in the United States, and it results in optic nerve head axonal degeneration and corresponding visual field deficits. Intraocular pressure (IOP) is the only known modifiable risk factor in glaucoma. Non-modifiable risk factors for glaucoma include age, ethnicity, central corneal thickness, and family history. While our understanding of the role of gender as a risk factor in glaucoma development and progression remains nascent, multiple observations have shown gender differences in the incidence and prevalence of glaucoma. Depending on the type of glaucoma, hormone therapy, oral contraceptive use and menopausal status have also been associated with glaucoma. In addition, pregnancy leads to changes in IOP, while the treatment of glaucoma must be tailored based on the systemic effects of topical therapeutics on the mother and fetus. This review will focus on the epidemiologic, anatomic and endocrinologic differences in male and female glaucoma patients. In addition, this review will discuss treatment modalities that may be more appropriate for one gender than the other, especially with respect to a woman's pregnancy status. PMID- 25285809 TI - Embolic middle cerebral artery occlusion (MCAO) for ischemic stroke with homologous blood clots in rats. AB - Clinically, thrombolytic therapy with use of recombinant tissue plasminogen activator (tPA) remains the most effective treatment for acute ischemic stroke. However, the use of tPA is limited by its narrow therapeutic window and by increased risk of hemorrhagic transformation. There is an urgent need to develop suitable stroke models to study new thrombolytic agents and strategies for treatment of ischemic stroke. At present, two major types of ischemic stroke models have been developed in rats and mice: intraluminal suture MCAO and embolic MCAO. Although MCAO models via the intraluminal suture technique have been widely used in mechanism-driven stroke research, these suture models do not mimic the clinical situation and are not suitable for thrombolytic studies. Among these models, the embolic MCAO model closely mimics human ischemic stroke and is suitable for preclinical investigation of thrombolytic therapy. This embolic model was first developed in rats by Overgaard et al.(1) in 1992 and further characterized by Zhang et al. in 1997(2). Although embolic MCAO has gained increasing attention, there are technical problems faced by many laboratories. To meet increasing needs for thrombolytic research, we present a highly reproducible model of embolic MCAO in the rat, which can develop a predictable infarct volume within the MCA territory. In brief, a modified PE-50 tube is gently advanced from the external carotid artery (ECA) into the lumen of the internal carotid artery (ICA) until the tip of the catheter reaches the origin of the MCA. Through the catheter, a single homologous blood clot is placed at the origin of the MCA. To identify the success of MCA occlusion, regional cerebral blood flow was monitored, neurological deficits and infarct volumes were measured. The techniques presented in this paper should help investigators to overcome technical problems for establishing this model for stroke research. PMID- 25285810 TI - Intraocular pressure trends after intravitreal injections of anti-vascular endothelial growth factor agents for diabetic macular edema. AB - PURPOSE: To study intraocular pressure (IOP) trends and risk factors of IOP elevation after intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema. METHODS: A retrospective review of 760 eyes treated with intravitreal anti-vascular endothelial growth factor injections for diabetic macular edema was performed. The rate and risk factors of IOP elevation were assessed. Intraocular pressure elevation was defined as an increase above baseline IOP by >= 6 mmHg, increase above baseline by > 20%, or IOP elevation to > 24 mmHg on 2 or more consecutive visits after treatment. When more than one pretreatment IOP reading was available, baseline IOP was calculated as the mean of the available pretreatment IOP readings (up to a maximum of three last IOP readings). Intraocular pressure elevation was considered transient unless it was maintained throughout the follow-up or required treatment (persistent elevation). RESULTS: Over a mean follow-up of 18 months, persistent and transient IOP elevation occurred in 44 (5.8%) and 53 (7%) eyes, respectively. The majority of eyes with persistent IOP elevation (70.4%) showed IOP elevation of > 20% from baseline. Only 13 eyes (1.71%) met the more strict criteria (> 6 mmHg from baseline or an IOP elevation > 24 mmHg). Final IOP was higher in the persistent IOP elevation group than the rest of the eyes (P < 0.001). Only the number of injections was associated with IOP elevation (P < 0.001). CONCLUSION: Persistent IOP elevation after intravitreal anti-vascular endothelial growth factor injections for diabetic macular edema is uncommon but may be associated with a higher number of injections. PMID- 25285811 TI - Bow-string technique for iris pupilloplasty and posterior iris-claw artisan intraocular lens implant in traumatic aphakia with associated iris defects. PMID- 25285813 TI - The anatomical location of postoperative forehead flap pedicle bleeding. PMID- 25285812 TI - Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. AB - IMPORTANCE: Repeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometimes referred to as intermediate) have been identified as modifiers of amyotrophic lateral sclerosis (ALS) risk. Prior studies have used thresholding considering various cutoffs for ATXN2 repeat length. OBJECTIVE: To calculate association between ATXN2 CAG repeat alleles and increased risk of ALS across multiple ethnic groups. DATA SOURCES: The MEDLINE database was searched for studies published by December 29, 2013, reporting ATXN2 CAG repeat length in patients with ALS and controls. STUDY SELECTION: Studies were included if they reported original data on relative risks or odds ratios (ORs) from ALS and control populations for individual ATXN2 alleles. Review articles that reported no new data were not included in the analysis. DATA EXTRACTION AND SYNTHESIS: Analysis of allele distribution was performed to ensure that all studies followed identical allele sizing. The ORs, 95% confidence intervals, and population attributable risk percentages were calculated according to standard procedures. MAIN OUTCOMES AND MEASURES: Occurrence of ALS associated with ATXN2 repeat alleles, expressed as ORs. RESULTS: Nine studies were analyzed, including 7505 controls and 6151 sporadic ALS cases. The ALS and control cohorts were recruited from different geographical and ethnic regions including the United States, French Canada/Canada, Belgium and the Netherlands, Germany, Italy, mainland China, Turkey, and Flanders-Belgium. The ATXN2 CAG repeat lengths ranged from 13 to 39 in patients with ALS and from 13 to 34 in controls. The ORs were less than 1.00 for alleles with 25 to 28 repeats. The OR was 1.55 for 30 repeats, but this elevation was not statistically significant (95% CI, 0.88-2.73). The ORs were 2.70 (95% CI, 1.47-4.93) for 31 CAG repeats, 11.09 (95% CI, 4.16-29.57) for 32 repeats, and 5.76 (95% CI, 1.79-18.57) for 33 repeats. CONCLUSIONS AND RELEVANCE: In contrast to prior studies with smaller numbers, risk for ALS associated with long-normal alleles is complex. Alleles with 27 and 28 repeats lower ALS risk slightly. The risk for ALS increases beginning with 29 repeats and reaches a maximum at 32 and 33 repeats. Of note, alleles with repeats of these lengths are known to be predisposed to meiotic expansion to full-penetrance mutant alleles. In patients with ALS, alleles with 31 to 33 repeats may have undergone preferential expansion in motor neurons during mitosis or DNA repair. Our meta analysis provides a framework for counseling individuals with long-normal ATXN2 repeats. PMID- 25285814 TI - Use of the standing cone allows for subunit repair of a large composite cheek and nose defect. PMID- 25285815 TI - Treatment of digital mucous cysts with intralesional sodium tetradecyl sulfate injection. AB - BACKGROUND: Digital mucous cysts (DMCs) are benign myxoid cysts typically involving the distal interphalangeal joint or over the proximal nail fold. There are various treatment modalities for DMCs, and intralesional sodium tetradecyl sulfate injection has been reported as an alternative treatment. OBJECTIVE: To assess the efficacy and safety of intralesional sodium tetradecyl sulfate injection in treating DMCs. MATERIALS AND METHODS: We performed intralesional injection of sodium tetradecyl sulfate in 17 patients (6 men and 11 women) with 20 DMCs. At each session, 1% to 3% sodium tetradecyl sulfate of 0.2 to 0.5 mL was injected into a lesion and repeated every 4 weeks if the cyst persisted. Changes in lesions and adverse reactions were recorded, and therapeutic efficacy was evaluated. RESULTS: Of the 20 lesions treated with intralesional sodium tetradecyl sulfate injection, 80% responded. Recurrences were observed in 2 patients, and 2 patients did not respond well to the treatment. No patient reported any major adverse effects. CONCLUSION: Intralesional sodium tetradecyl sulfate injection is a simple, safe, and effective modality for distal mucous cyst. Treatment was well tolerated with few side effects and favorable cure rate. Therefore, we believe that intralesional sodium tetradecyl sulfate injection should be considered an alternative treatment of DMCs. PMID- 25285816 TI - Commentary on porcine xenografts for the optimization of pedicle care in interpolation flaps. PMID- 25285817 TI - Chemical matricectomy with sodium hydroxide: long-term follow-up results. AB - BACKGROUND: Chemical matricectomy with sodium hydroxide is a method being used successfully in the treatment of ingrown toenail. OBJECTIVE: In this study, it was aimed to evaluate long-term recurrence rates after chemical matricectomy using sodium hydroxide application of different durations. MATERIALS AND METHODS: Two hundred two patients with ingrown nail edges were treated with either 1 minute (Group 1) or 2-minute (Group 2) applications of sodium hydroxide matricectomy. All patients were followed for at least 2 years. RESULTS: Chemical matricectomy with sodium hydroxide was applied to a total of 585 nail edges of 202 cases. The overall recurrence rates in Group 1 and Group 2 were 6.4% and 7.1%, respectively, during the average 7.5-year follow-up period. No statistically significant differences were detected in terms of recurrence between the 2 groups (p = .73). CONCLUSION: Chemical matricectomy with sodium hydroxide is an easy method in the treatment of ingrown nails, with low morbidity and high success rates. There was no difference between 1-minute and 2-minute applications in terms of recurrence during the long-term follow-up. Chemical matricectomy with 1-minute application of sodium hydroxide showed high success in terms of long-term follow-up results. PMID- 25285818 TI - Evolution of laser skin resurfacing: from scanning to fractional technology. AB - BACKGROUND: Laser skin resurfacing was popularized for photoaged and scarred skin 2 decades ago. Since then, several technologic advancements have led to a new generation of delivery systems that produce excellent clinical outcomes with reduced treatment risks and faster recovery times. OBJECTIVES: To review the evolution of laser skin resurfacing from pulsed and scanned infrared laser technology to the latest techniques of nonablative and ablative fractional photothermolysis. MATERIALS AND METHODS: All published literature regarding laser skin resurfacing was analyzed and collated. RESULTS: A comprehensive review of laser skin resurfacing was outlined and future developments in the field of fractionated laser skin treatment were introduced. CONCLUSION: Laser skin resurfacing has evolved such that excellent clinical outcomes in photodamaged and scarred skin are achieved with rapid wound healing. As newer devices are developed, the applications of this technology will have a dramatic effect on the delivery of medical and aesthetic dermatology. PMID- 25285819 TI - Toward molecular mechanism of xenon anesthesia: a link to studies of xenon complexes with small aromatic molecules. AB - The present study illustrates the steps toward understanding molecular mechanism of xenon anesthesia by focusing on a link to the structures and spectra of intermolecular complexes of xenon with small aromatic molecules. A primary cause of xenon anesthesia is attributed to inhibition of N-methyl-D-aspartate (NMDA) receptors by an unknown mechanism. Following the results of quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) calculations we report plausible xenon action sites in the ligand binding domain of the NMDA receptor, which are due to interaction of xenon atoms with aromatic amino-acid residues. We rely in these calculations on computational protocols adjusted in combined experimental and theoretical studies of intermolecular complexes of xenon with phenol. Successful reproduction of vibrational shifts in molecular species upon complexation with xenon measured in low-temperature matrices allowed us to select a proper functional form in density functional theory (DFT) approach for use in QM subsystems, as well as to calibrate force field parameters for MD simulations. The results of molecular modeling show that xenon atoms can compete with agonists for a place in the corresponding protein cavity, thus indicating their active role in anesthetic action. PMID- 25285820 TI - Virus capture and destruction by label-free graphene oxide for detection and disinfection applications. AB - Graphene oxide (GO) can efficiently capture viruses, destroy their surface proteins, and extract viral RNA in an aqueous environment by using the superficial bioreduction of GO. It follows from these phenomena that GO is an excellent nanomaterial for the high-throughput detection and disinfection of viruses, demonstrating its great potential for the prevention of environmental infections. PMID- 25285821 TI - The impact of high-fat diet on metabolism and immune defense in small intestine mucosa. AB - Improved procedures for sample preparation and proteomic data analysis allowed us to identify 7700 different proteins in mouse small intestinal mucosa and calculate the concentrations of >5000 proteins. We compared protein concentrations of small intestinal mucosa from mice that were fed for two months with normal diet (ND) containing 34.4% carbohydrates, 19.6% protein, and 3.3% fat or high-fat diet (HFD) containing 25.3% carbohydrates, 24.1% protein, and 34.6% fat. Eleven percent of the quantified proteins were significantly different between ND and HFD. After HFD, we observed an elevation of proteins involved in protein synthesis, protein N-glycosylation, and vesicle trafficking. Proteins engaged in fatty acid absorption, fatty acid beta-oxidation, and steroid metabolism were also increased. Enzymes of glycolysis and pentose phosphate cycle were decreased, whereas proteins of the respiratory chain and of ATP synthase were increased. The protein concentrations of various nutrient transporters located in the enterocyte plasma membrane including the Na(+)-d-glucose cotransporter SGLT1, the passive glucose transporter GLUT2, and the H(+)-peptide cotransporter PEPT1 were decreased. The concentration of the Na(+),K(+)-ATPase, which turned out to be the most strongly expressed enterocyte transporter, was also decreased. HFD also induced concentration changes of drug transporters and of enzymes involved in drug metabolism, which suggests effects of HFD on pharmacokinetics and toxicities. Finally, we observed down-regulation of antibody subunits and of components of the major histocompatibility complex II that may reflect impaired immune defense and immune tolerance in HFD. Our work shows dramatic changes in functional proteins of small intestine mucosa upon excessive fat consumption. PMID- 25285822 TI - Flow and heat transfer in Sisko fluid with convective boundary condition. AB - In this article, we have studied the flow and heat transfer in Sisko fluid with convective boundary condition over a nonisothermal stretching sheet. The flow is influenced by non-linearly stretching sheet in the presence of a uniform transverse magnetic field. The partial differential equations governing the problem have been reduced by similarity transformations into the ordinary differential equations. The transformed coupled ordinary differential equations are then solved analytically by using the homotopy analysis method (HAM) and numerically by the shooting method. Effects of different parameters like power law index n, magnetic parameter M, stretching parameter s, generalized Prandtl number Pr and generalized Biot number gamma are presented graphically. It is found that temperature profile increases with the increasing value of M and gamma whereas it decreases for Pr. Numerical values of the skin-friction coefficient and local Nusselt number are tabulated at various physical situations. In addition, a comparison between the HAM and exact solutions is also made as a special case and excellent agreement between results enhance a confidence in the HAM results. PMID- 25285823 TI - The health of young US workers. AB - OBJECTIVES: To provide an overview of the health status of young US workers across four domains: functional health, physical and psychological health, health behavior, and health care utilization. METHODS: Pooled data from the 2004 to 2010 National Health Interview Survey were analyzed for 11,279 US workers aged 18 to 24 years, representing an estimated 16.9 million workers annually. Thirty-nine health indicators were examined and compared across nine occupational groups. RESULTS: Compared with other occupational groups, craft workers and laborers and helpers had the highest prevalence of risky health behaviors, including current smoking and risky drinking, as well as fewer reported visits to a primary care physician in the past year. CONCLUSIONS: Young workers engage in risky health behaviors, and may benefit from targeted workplace interventions to mitigate the potentially negative long-term effects on health and well-being. PMID- 25285824 TI - Outdoor air pollution and out-of-hospital cardiac arrest in Okayama, Japan. AB - OBJECTIVES: We evaluated the association between short-term exposure to outdoor air pollution and out-of-hospital cardiac arrest in Japan. METHODS: We studied 558 residents of Okayama, Japan, who visited hospital emergency departments between January 2006 and December 2010 for out-of-hospital cardiac arrest using a time-stratified case-crossover design. We calculated city-representative average concentrations of different air pollutants and examined the association between air pollution and cardiac arrest. RESULTS: Exposure to air pollution was associated with an elevated risk of cardiac arrest; for example, odds ratios was 1.17 (95% confidence interval, 1.02 to 1.33) per interquartile-range increase in suspended particulate matter concentrations in the previous 48 to 72 hours. We also observed different susceptibilities to suspended particulate matter and ozone exposures by age category. CONCLUSIONS: Short-term exposure to outdoor air pollution was associated with increased risk of cardiac arrest. PMID- 25285825 TI - Crude oil spill exposure and human health risks. AB - OBJECTIVE: The objective of this study was to review and summarize published studies on human health effects of oil spill exposure. METHODS: A systematic literature search was conducted for articles published on health effects of oil spill exposure. More than 250 articles were examined, and only those articles that dealt with health effects on human populations were included. The methodology, results, discussion, and conclusions for each study were reviewed and summarized. RESULTS: Published studies are helpful in identifying acute and, to some extent, chronic health effects related to major oil spills. Nevertheless, many of these reports were focused on the behavioral health effects of the oil spill exposures in the affected population. CONCLUSIONS: These published studies clearly support the need for further assessment of the potential short- and long term repercussions in human populations exposed to oil spills. PMID- 25285826 TI - Workaholism and mental health problems among municipal middle managers in Norway. AB - OBJECTIVE: To provide empirical knowledge about the antecedents and outcomes of workaholism among municipal middle managers within the framework of the job demands-resources model. METHODS: We used a self-administered questionnaire to collect cross-sectional data (n = 118) on job demands, job resources, work engagement, workaholism, and mental health problems. RESULTS: Workaholism correlated positively with both work engagement and mental health problems. Job demands affected workaholism and mental health problems more strongly than did job resources. The results indicate that workaholism does not mediate the effects of certain work characteristics on mental health problems, but rather that workaholics create excessive job demands that harm their health. CONCLUSIONS: Preventing workaholism should be a central concern of municipal stakeholders because workaholic behavior among middle managers may harm organizational performance and employee health and middle managers' own health. PMID- 25285827 TI - Diabetes wellness care: a successful employer-endorsed program for employees. AB - OBJECTIVE: A 12-month wellness program was provided for employees of a major employer in the Orlando area. METHODS: The program involved screening and measurement of baseline indices, educational sessions, telephonic support, quarterly laboratory monitoring, and provision of glucometers and test strips. RESULTS: For the 73 enrolled employees with prediabetes, serum hemoglobin A1c levels-mean (standard deviation)-decreased from 6.10% (0.53%) to 5.42% (0.51%) (P < 0.0001). For the 151 enrolled employees with diabetes, mean serum hemoglobin A1c levels-mean (standard deviation)-decreased from 8.03% (1.91%) to 7.48% (1.52%) (P < 0.0001). In the 12 months before, during, and after the program, 27, 15, and 27 diabetic employees required hospitalization, respectively. Health insurance per member per month claims costs for employees with diabetes rose only 1.2% over the prior 12 months, and self-reported presenteeism increased (P < 0.0001). CONCLUSIONS: This employer-endorsed program achieved favorable outcomes for employees with prediabetes and diabetes. PMID- 25285828 TI - Blood lead, manganese, and aluminum levels in a regional Italian cohort of ALS patients: does aluminum have an influence? AB - OBJECTIVES: To study aluminum (Al), manganese (Mn), and lead (Pb) influence on amyotrophic lateral sclerosis (ALS) development. METHODS: A total of 34 patients (10% of the regional ALS population) and 25 controls of an Italian region were enrolled. Metal concentrations were determined by atomic absorption spectroscopy. RESULTS: Serum Al concentrations in patients and controls were similar and lower than those provided by the Italian Society of Reference Values. No differences were observed in serum Mn concentrations, while, as expected, blood Pb levels were significantly higher in patients with ALS than those in controls. CONCLUSIONS: Results confirmed the association between high Pb blood levels and ALS; on the contrary, Al and Mn did not differ significantly in patients and controls, suggesting that Mn and especially Al may play a less important role in the ALS pathogenesis. PMID- 25285829 TI - Occupational injury trends derived from trauma registry and hospital discharge records: lessons for surveillance and research. AB - OBJECTIVE: The suitability of the Washington State Trauma Registry (WTR) for occupational injury surveillance was assessed via comparing estimated rates and trends with those derived from state hospital discharge data. METHODS: Descriptive methods and negative binomial regression were used to model occupational injury trends (1998 to 2009). RESULTS: Nonlinear trends based on WTR data closely tracked those based on hospital discharge data, beginning about 2002. Rate estimates differed somewhat by data source and were most similar when a severity threshold was applied. Conclusions regarding temporal trends in work related injury rates were the same using either data source. CONCLUSIONS: This study found substantial similarity between occupational injury trends estimated using either WTR or hospital discharge data. We conclude that a mature state trauma registry with mandatory reporting requirements can be used for surveillance of severe work-related traumatic injuries. PMID- 25285830 TI - Relationship between domain-specific physical activity and different body composition measures in a working population. AB - OBJECTIVE: With respect to the overweight epidemic, this study aimed to investigate the association between domain-specific physical activity and body composition measures in Swiss male employees. METHODS: A total of 192 healthy male adults in full-time employment were investigated. Height, weight, and waist circumference were measured and body mass index was calculated. Relative fat mass and relative muscle mass were determined by bioelectric impedance analysis. Physical activity was assessed by the validated International Physical Activity Questionnaire. RESULTS: In multiple linear regressions, leisure-time activity showed an inverse association with waist circumference and relative fat mass and a positive correlation with relative muscle mass. Work activity was positively related to waist circumference and body mass index. CONCLUSIONS: This study shows that leisure-time activity may be the most effective physical activity domain for body composition. Work activity does not seem to be protective against overweight. PMID- 25285831 TI - Worksite safety climate, smoking, and the use of protective equipment by blue collar building workers enrolled in the MassBUILT smoking cessation trial. AB - OBJECTIVE: To assess potential contributors to high injury rates and smoking prevalence among construction workers, we investigated the association of safety climate with personal protective equipment use, and smoking behaviors. METHODS: Logistic regression models estimated risk ratios for personal protective equipment use and smoking using data from participants in MassBUILT smoking cessation intervention (n = 1725). RESULTS: Contractor safety climate was negatively associated with the use of dust masks (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.83 to 0.94), respirators (RR, 0.82; 95% CI, 0.75 to 0.89), general equipment (RR, 0.98; 95% CI, 0.95 to 1.00), and fall protection (RR, 0.94; 95% CI, 0.91 to 0.98) and positively associated with current smoking (RR, 1.12; 95% CI, 1.01 to 1.25) but not smoking cessation. Coworker safety climate was negatively associated with the use of dust masks (RR, 0.87; 95% CI, 0.82 to 0.92), respirators (RR, 0.80; 95% CI, 0.74 to 0.87), general equipment (RR, 0.96; 95% CI, 0.94 to 0.98), fall (RR, 0.92; 95% CI, 0.89 to 0.96), and hearing protection (RR, 0.88; 95% CI, 0.83 to 0.93) but not smoking. CONCLUSIONS: Worksite safety climate may be important for personal protective equipment use and smoking, but further research is needed. PMID- 25285832 TI - Prevalence of chronic obstructive pulmonary disease among US working adults aged 40 to 70 years. National Health Interview Survey data 2004 to 2011. AB - OBJECTIVE: To estimate the prevalence and prevalence odds ratios of chronic obstructive pulmonary disease (COPD) among US workers by major occupational groups. METHODS: The 2004 to 2011 National Health Interview Survey data for working adults 40 to 70 years old was analyzed to estimate the prevalence of COPD by major occupational groups. Logistic regression models were used to evaluate the associations between COPD (chronic bronchitis or emphysema) and occupations. RESULTS: The estimated overall COPD prevalence was 4.2% (95% CI, 4.0 to 4.3). The odds of COPD were highest among workers in health care support occupations (prevalence odds ratio, 1.64; 95% CI, 1.25 to 2.14) followed by food preparation and serving-related occupations (prevalence odds ratio, 1.57; 95% CI, 1.20 to 2.06). CONCLUSIONS: Prevalence varied by occupations, suggesting workplace exposures may contribute to COPD. Preventive measures such as interventions to reduce smoking may reduce the prevalence of COPD. PMID- 25285833 TI - The relationship between workplace environment and employee health behaviors in a South African workforce. AB - OBJECTIVE: To determine the relationship between the availability of wellness facilities at worksites and self-reported employee health behaviors (physical activity [PA] and nutrition [NUT]). METHODS: Employers (n = 71) and employees (n = 11472) participated in the South African Healthy Company Index survey. The survey included self-reported clinical measures and lifestyle behaviors. A facility score was calculated, ranging from 0 to 100. Hierarchical linear models were used to calculate the relationship between facility scores and whether employees met PA and NUT guidelines. RESULTS: The mean total facility score was 58.5 +/- 25.5. The number of facilities at each worksite accounted for 5.4% of the variance in PA among employees (r = 0.054; P = 0.036). Higher facility scores were associated with better NUT habits among employees. CONCLUSIONS: Employers providing wellness facilities are likely to have employees with better PA and NUT habits. PMID- 25285836 TI - Healthy-worker effect led to an overestimation of the concentration threshold value for respirable quartz. PMID- 25285837 TI - An attempt to estimate an exposure threshold is not a scientific exercise-example of silicosis from exposure to quartz dust. PMID- 25285838 TI - Response to: An attempt to estimate an exposure threshold is not a scientific exercise-example of silicosis from exposure to quartz dust. PMID- 25285839 TI - Response to: Healthy-worker effect led to an overestimation of the concentration threshold value for respirable quartz. PMID- 25285840 TI - Effect of a smoking ban on respiratory health in nonsmoking hospitality workers: a prospective cohort study. AB - OBJECTIVE: The aim of this study was to examine the effect of a smoking ban on lung function, fractional exhaled nitric oxide, and respiratory symptoms in nonsmoking hospitality workers. METHODS: Secondhand smoke exposure at the workplace, spirometry, and fractional exhaled nitric oxide were measured in 92 nonsmoking hospitality workers before as well as twice after a smoking ban. RESULTS: At baseline, secondhand smoke-exposed hospitality workers had lung function values significantly below the population average. After the smoking ban, the covariate-adjusted odds ratio for cough was 0.59 (95% confidence interval, 0.36 to 0.93) and for chronic bronchitis 0.75 (95% confidence interval, 0.55 to 1.02) compared with the preban period. CONCLUSIONS: The below-average lung function before the smoking ban indicates chronic damages from long-term exposure. Respiratory symptoms such as cough decreased within 12 months after the ban. PMID- 25285841 TI - Effects of low concentrations of benzene exposure on levels of platelet associated antibodies and platelet parameters. AB - OBJECTIVE: To evaluate the impact of exposure to low concentrations of benzene on the platelet-associated antibodies and platelet parameters. METHODS: We carried out an analysis on 121 benzene-exposed workers and 110 healthy workers whose blood samples were collected and the levels of platelet-associated antibodies and platelet parameters were assessed. Benzene emissions were monitored over 5 years. RESULTS: Large-platelet cell ratios (P-LCR), platelet distribution width (PDW), and mean platelet volume (MPV) were significantly higher in benzene-exposed participants than in control participants. In participants who smoke cigarettes or drank alcohol, P-LCR, PDW, and MPV were more significantly elevated in the benzene-exposed group than in nonsmokers and nondrinkers. Platelet-associated immunoglobulin (PAIg) levels in benzene-exposed participants were higher than those in the control group, and PAIgA and PAIgM levels correlated with cumulative benzene exposure. CONCLUSIONS: Exposure to low concentrations of benzene can induce changes in PAIg levels and platelet parameters. PMID- 25285842 TI - Association between individual PM2.5 exposure and DNA damage in traffic policemen. AB - OBJECTIVE: The aim of this study was to explore the association between individual PM2.5 and DNA damage in traffic policemen. METHODS: The participants included 110 traffic policemen and 101 common populations. The continuous 24-hour individual PM2.5 measurement was performed in participants. BPDE (benzo[a]pyrene 7,8-diol-9,10-epoxide)-DNA adducts and 1-OHP were detected. RESULTS: The average concentration of 24-hour personal PM2.5 for traffic policemen was significantly higher than that in the control group. PM2.5 exposure is associated with a 1.1% increase in 1-OHP and 0.8% increase in BPDE-DNA adducts after adjusted for body mass index, educational time period, and alcohol intake. Exposure group has 2.04 times higher of 1-OHP and 1.25 times higher of BPDE-DNA adducts when compared to the control group. CONCLUSIONS: These results demonstrated that traffic policemen have been a high-risk group suffering DNA damage because of the high PM2.5 exposure. PMID- 25285843 TI - Combination of microstereolithography and electrospinning to produce membranes equipped with niches for corneal regeneration. AB - Corneal problems affect millions of people worldwide reducing their quality of life significantly. Corneal disease can be caused by illnesses such as Aniridia or Steven Johnson Syndrome as well as by external factors such as chemical burns or radiation. Current treatments are (i) the use of corneal grafts and (ii) the use of stem cell expanded in the laboratory and delivered on carriers (e.g., amniotic membrane); these treatments are relatively successful but unfortunately they can fail after 3-5 years. There is a need to design and manufacture new corneal biomaterial devices able to mimic in detail the physiological environment where stem cells reside in the cornea. Limbal stem cells are located in the limbus (circular area between cornea and sclera) in specific niches known as the Palisades of Vogt. In this work we have developed a new platform technology which combines two cutting-edge manufacturing techniques (microstereolithography and electrospinning) for the fabrication of corneal membranes that mimic to a certain extent the limbus. Our membranes contain artificial micropockets which aim to provide cells with protection as the Palisades of Vogt do in the eye. PMID- 25285844 TI - The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats. AB - Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs. PMID- 25285845 TI - Investigating correlates of synthetic marijuana and Salvia use in light and intermittent smokers and college students in a predominantly Hispanic sample. AB - Few studies have examined correlates related to the use of synthetic cannabinoids (e.g., Spice, K2) and Salvia divinorum. Two studies were conducted to investigate whether demographic, smoking-related, and substance-related variables were associated with the use of synthetic cannabinoids and Salvia. In Study 1, 185 participants (50% female; 83% Hispanic; Mage = 32 years; SD = 13.68) were recruited from a local health clinic and a university on the U.S./Mexico border for a smoking-cessation study targeting light and intermittent smokers. In Study 2, 675 participants (62.4% female; 89.1% Hispanic; Mage = 21.0, SD = 8.56) were recruited from a university on the U.S./Mexico border for an online study. In Study 1, 10% of the sample indicated they had ever used either synthetic cannabinoids or Salvia in their lifetime. Being male and dual/multiple use of tobacco products were significantly associated with having ever used synthetic cannabinoids or Salvia. In Study 2, 9%, 5%, and 3% of the sample indicated lifetime, past-year, and past 30-day use of synthetic cannabinoids, respectively. Five percent, 2%, and 1% of the sample indicated lifetime, past-year, and past 30 day use of Salvia, respectively. Logistic regression analyses revealed that past 30-day marijuana use and past 30-day ecstasy use were significantly associated with use of synthetic cannabinoids and Salvia in one's lifetime. These findings suggest that the assessment of synthetic marijuana and Salvia use is warranted in studies of other addictive behaviors, particularly among current marijuana and ecstasy users. PMID- 25285846 TI - Virtual quality: the failure of public reporting and pay-for-performance programs. PMID- 25285847 TI - Copper-catalyzed aerobic synthesis of 2-arylpyridines from acetophenones and 1,3 diaminopropane. AB - A copper-catalyzed reaction providing direct access to 2-arylpyridines from acetophenones and 1,3-diaminopropane is described. A range of electronically diverse acetophenones undergo this transformation, affording 2-arylpyridines in good yields. PMID- 25285848 TI - Radical scavenging and antioxidant effects of Matricaria chamomilla polyphenolic polysaccharide conjugates. AB - Matricaria chamomilla L. (MC), a member of the Asteraceae family, is one of the oldest medicinal plants, widely used worldwide for a variety of healing applications. Its recommendations, derived from both traditional and modern medicine, include numerous disorders such as inflammation, ulcers, wounds, gastrointestinal disorders, stomach ache, pharyngitis, rheumatic pain, as well as the other ailments. This work is focused on another aspect of the biological activity of chamomile polyphenolic-polysaccharide conjugates--their antioxidant properties in the protection of blood plasma components against in vitro oxidative stress. Measurements of DPPH and ABTS radical scavenging indicated considerable anti-free radical action of MC. Pre-incubation of blood plasma with MC considerably diminished the extent of ONOO(-)-induced oxidative modifications such as protein carbonyl groups, SH groups, 3-nitrotyrosine, as well as the formation of lipid hydroperoxides. The analysis of the FRAP assay result shows a considerable increase of ferric reducing ability of blood plasma in the presence of MC. The results obtained in this study indicate that polyphenolic polysaccharide conjugates isolated from M. chamomilla substances possess antioxidant properties. The M. chamomilla macromolecular glycoconjugates may be useful in the creation of new natural-based medications or dietary supplements, helpful in the prevention and treatment of oxidative stress-mediated disorders. PMID- 25285849 TI - Pro-apoptotic properties of (1,3)(1,4)-beta-D-glucan from Avena sativa on human melanoma HTB-140 cells in vitro. AB - In this study, the growth-inhibitory effect of polysaccharide (1,3)(1,4)-beta-D glucan from oat, Avena sativa L. grains was explored on the human skin melanoma HTB-140 cells in vitro. The oat beta-D-glucan (OBG) exerted cytotoxic action on HTB-140 cells. After 24h of incubation, LD50 (concentration at which 50% of the cells were found dead) was obtained of 194.6 +/- 9.8 MUg/mL. The oat beta-D glucan caused a concentration-dependent increase of caspase-3/-7 activation and appearance of phosphatidylserine on the external surface of cellular membranes where it was bound to annexin V-FITC, demonstrating the induction of apoptosis. Intracellular ATP level decreased along with the mitochondrial potential, which suggested a mitochondrial pathway of apoptosis. A cell cycle analysis showed increase in the number of apoptotic cells, increase in the number of cells in G1 phase and decrease in the number of cells in G2/M. Although the detailed mechanism for the anti-tumor activity of the oat beta-D-glucan still needs further investigation, this study provides preliminary insights into this direction along with perspectives of developing it as an anti-tumor agent. PMID- 25285850 TI - Conformation of bovine submaxillary mucin layers on hydrophobic surface as studied by biomolecular probes. AB - In the present study, the conformational changes of bovine submaxillary mucin (BSM) adsorbed on a hydrophobic surface (polystyrene (PS)) as a function of concentration in bulk solution (up to 2mg/mL) have been investigated with biomolecular probe-based approaches, including bicinchoninic acid (BCA), enzyme linked immunosorbent assay (EIA), and enzyme-linked lectin assay (ELLA). The conformation and hydrodynamic diameter of highly purified BSM molecules, as characterized by circular dichroism (CD) spectroscopy and dynamic light scattering (DLS), respectively, showed a slight, yet gradual coiling and compaction in response to the increase in BSM concentration in bulk solution. Adsorbed masses of BSM onto hydrophobic surface, as probe by BCA, showed a continuously increasing trend up to 2mg/mL. But, the signals from EIA and ELLA, which probe the concentration of available unglycosylated C-terminals and the central glycosylated regions, respectively, showed complicated non-linear responses with increasing surface concentration. The results from this study support the conventional amphiphilic, triblock model of BSM in the adsorption onto hydrophobic surface from aqueous solution. The biomolecular probe-based approaches employed in this study, however, provided further details on the conformational changes of BSM on surface, in particular the accessibility of glycosylated and unglycosylated domains with increasing surface concentration. PMID- 25285851 TI - High intrachain order promotes triplet formation from recombination of long-lived polarons in poly(3-hexylthiophene) J-aggregate nanofibers. AB - Photoluminescence (PL) of single poly(3-hexylthiophene) (P3HT) J-aggregate nanofibers (NFs) exhibits strong quenching under intensity-modulated pulsed excitation. Initial PL intensities (I(0)) decay to steady-state levels (ISS) typically within ~ 1-10 MUs, and large quenching depths (I(0)/I(SS) >2) are observed for ~ 70% of these NFs. Similar studies of polymorphic, H-aggregate type P3HT NFs show much smaller PL quenching depths (I(0)/I(SS) <= 1.2). P3HT chains in J-type NF pi-stacks possess high intrachain order, which has been shown previously to promote the formation of long-lived, delocalized polarons. We propose that these species recombine nongeminately to triplets on time scales of >1 ns. The identity of triplets as the dominant PL quenchers was confirmed by subjecting NFs to oxygen, resulting in an instantaneous loss of triplet PL quenching (I(0)/I(SS) ~ 1). The lower intrachain order in H-type NFs, similar to P3HT thin-film aggregates, localizes excitons and polarons, leading to efficient geminate recombination that suppresses triplet formation at longer time scales. Our results demonstrate the promise of self-assembly strategies to control intrachain ordering within multichromophoric polymeric aggregate assemblies to tune exciton coupling and interconversion processes between different spin states. PMID- 25285852 TI - In situ determination of the liquid/solid interface thickness and composition for the Li ion cathode LiMn(1.5)Ni(0.5)O4. AB - Using neutron reflectometry, we have determined the thickness and scattering length density profile of the electrode-electrolyte interface for the high voltage cathode LiMn(1.5)Ni(0.5)O4 in situ at open circuit voltage and fully delithiated. Upon exposure to a liquid electrolyte, a thin 3.3 nm Li-rich interface forms due to the ordering of the electrolyte on the cathode surface. This interface changes in composition, as evident by an increase in the scattering length density of the new layer, with charging as the condensed layer evolves from being lithium rich to one containing a much higher concentration of F from the LiPF6 salt. These results show the surface chemistry evolves as a function of the potential. PMID- 25285853 TI - Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study. AB - BACKGROUND: Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population. METHODS: We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes. RESULTS: During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14-1.70), coronary heart disease (HR 1.72, 95%CI 1.11-2.66), heart failure (HR 2.87, 95%CI 2.17-3.80), stroke (HR 1.56, 95%CI 0.99-2.46), AF (HR 5.75, 95%CI 4.43-7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9 67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51-2.66), AF (HR 4.25, 95%CI 3.28-5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8-32.1). CONCLUSION: Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation. PMID- 25285854 TI - First Hungarian case of an infection caused by multidrug-resistant Bacteroides fragilis strain. AB - We report a case caused by a multidrug-resistant (MDR) Bacteroides fragilis strain isolated from abdominal fluid of a male patient with complex underlying diseases. The patient had received antibiotics prior to the presented case. As far as we know, this case with a MDR B. fragilis is the first from Hungary, and Eastern-Europe, as well. PMID- 25285855 TI - Comparison of centric and reverse-centric trajectories for highly accelerated three-dimensional saturation recovery cardiac perfusion imaging. AB - PURPOSE: Highly undersampled three-dimensional (3D) saturation-recovery sequences are affected by k-space trajectory since the magnetization does not reach steady state during the acquisition and the slab excitation profile yields different flip angles in different slices. This study compares centric and reverse-centric 3D cardiac perfusion imaging. METHODS: An undersampled (98 phase encodes) 3D ECG gated saturation-recovery sequence that alternates centric and reverse-centric acquisitions each time frame was used to image phantoms and in vivo subjects. Flip angle variation across the slices was measured, and contrast with each trajectory was analyzed via Bloch simulation. RESULTS: Significant variations in flip angle were observed across slices, leading to larger signal variation across slices for the centric acquisition. In simulation, severe transient artifacts were observed when using the centric trajectory with higher flip angles, placing practical limits on the maximum flip angle used. The reverse-centric trajectory provided less contrast, but was more robust to flip angle variations. CONCLUSION: Both of the k-space trajectories can provide reasonable image quality. The centric trajectory can have higher CNR, but is more sensitive to flip angle variation. The reverse-centric trajectory is more robust to flip angle variation. PMID- 25285856 TI - Visualization of ATP synthase dimers in mitochondria by electron cryo-tomography. AB - Electron cryo-tomography is a powerful tool in structural biology, capable of visualizing the three-dimensional structure of biological samples, such as cells, organelles, membrane vesicles, or viruses at molecular detail. To achieve this, the aqueous sample is rapidly vitrified in liquid ethane, which preserves it in a close-to-native, frozen-hydrated state. In the electron microscope, tilt series are recorded at liquid nitrogen temperature, from which 3D tomograms are reconstructed. The signal-to-noise ratio of the tomographic volume is inherently low. Recognizable, recurring features are enhanced by subtomogram averaging, by which individual subvolumes are cut out, aligned and averaged to reduce noise. In this way, 3D maps with a resolution of 2 nm or better can be obtained. A fit of available high-resolution structures to the 3D volume then produces atomic models of protein complexes in their native environment. Here we show how we use electron cryo-tomography to study the in situ organization of large membrane protein complexes in mitochondria. We find that ATP synthases are organized in rows of dimers along highly curved apices of the inner membrane cristae, whereas complex I is randomly distributed in the membrane regions on either side of the rows. By subtomogram averaging we obtained a structure of the mitochondrial ATP synthase dimer within the cristae membrane. PMID- 25285857 TI - A next-generation tissue microarray (ngTMA) protocol for biomarker studies. AB - Biomarker research relies on tissue microarrays (TMA). TMAs are produced by repeated transfer of small tissue cores from a 'donor' block into a 'recipient' block and then used for a variety of biomarker applications. The construction of conventional TMAs is labor intensive, imprecise, and time-consuming. Here, a protocol using next-generation Tissue Microarrays (ngTMA) is outlined. ngTMA is based on TMA planning and design, digital pathology, and automated tissue microarraying. The protocol is illustrated using an example of 134 metastatic colorectal cancer patients. Histological, statistical and logistical aspects are considered, such as the tissue type, specific histological regions, and cell types for inclusion in the TMA, the number of tissue spots, sample size, statistical analysis, and number of TMA copies. Histological slides for each patient are scanned and uploaded onto a web-based digital platform. There, they are viewed and annotated (marked) using a 0.6-2.0 mm diameter tool, multiple times using various colors to distinguish tissue areas. Donor blocks and 12 'recipient' blocks are loaded into the instrument. Digital slides are retrieved and matched to donor block images. Repeated arraying of annotated regions is automatically performed resulting in an ngTMA. In this example, six ngTMAs are planned containing six different tissue types/histological zones. Two copies of the ngTMAs are desired. Three to four slides for each patient are scanned; 3 scan runs are necessary and performed overnight. All slides are annotated; different colors are used to represent the different tissues/zones, namely tumor center, invasion front, tumor/stroma, lymph node metastases, liver metastases, and normal tissue. 17 annotations/case are made; time for annotation is 2-3 min/case. 12 ngTMAs are produced containing 4,556 spots. Arraying time is 15-20 hr. Due to its precision, flexibility and speed, ngTMA is a powerful tool to further improve the quality of TMAs used in clinical and translational research. PMID- 25285861 TI - Continuing evolution at JAMA pediatrics. PMID- 25285858 TI - Fabrication and implantation of miniature dual-element strain gages for measuring in vivo gastrointestinal contractions in rodents. AB - Gastrointestinal dysfunction remains a major cause of morbidity and mortality. Indeed, gastrointestinal (GI) motility in health and disease remains an area of productive research with over 1,400 published animal studies in just the last 5 years. Numerous techniques have been developed for quantifying smooth muscle activity of the stomach, small intestine, and colon. In vitro and ex vivo techniques offer powerful tools for mechanistic studies of GI function, but outside the context of the integrated systems inherent to an intact organism. Typically, measuring in vivo smooth muscle contractions of the stomach has involved an anesthetized preparation coupled with the introduction of a surgically placed pressure sensor, a static pressure load such as a mildly inflated balloon or by distending the stomach with fluid under barostatically controlled feedback. Yet many of these approaches present unique disadvantages regarding both the interpretation of results as well as applicability for in vivo use in conscious experimental animal models. The use of dual element strain gages that have been affixed to the serosal surface of the GI tract has offered numerous experimental advantages, which may continue to outweigh the disadvantages. Since these gages are not commercially available, this video presentation provides a detailed, step-by-step guide to the fabrication of the current design of these gages. The strain gage described in this protocol is a design for recording gastric motility in rats. This design has been modified for recording smooth muscle activity along the entire GI tract and requires only subtle variation in the overall fabrication. Representative data from the entire GI tract are included as well as discussion of analysis methods, data interpretation and presentation. PMID- 25285862 TI - Grouped hemorrhagic vesicles. PMID- 25285863 TI - Concerns about concussion rates in female youth soccer. PMID- 25285864 TI - Concerns about concussion rates in female youth soccer. PMID- 25285865 TI - Infants and interactive media use. PMID- 25285866 TI - Concerns about concussion rates in female youth soccer-reply. PMID- 25285867 TI - Infants and interactive media use. PMID- 25285868 TI - Infants and interactive media use-reply. PMID- 25285869 TI - Does newborn screening have 100% sensitivity to detect salt-wasting congenital adrenal hyperplasia?: A word of caution. PMID- 25285872 TI - Does newborn screening have 100% sensitivity to detect salt wasting congenital adrenal hyperplasia?-Reply. PMID- 25285873 TI - Gastroesophageal reflux disease. PMID- 25285874 TI - Sildenafil may elevate melanoma risk. PMID- 25285875 TI - Grey matter alterations in patients with depersonalization disorder: a voxel based morphometry study. AB - BACKGROUND: To our knowledge, no whole brain investigation of morphological aberrations in dissociative disorder is available to date. Previous region-of interest studies focused exclusively on amygdalar, hippocampal and parahippocampal grey matter volumes and did not include patients with depersonalization disorder (DPD). We therefore carried out an explorative whole brain study on structural brain aberrations in patients with DPD. METHODS: We acquired whole brain, structural MRI data for patients with DPD and healthy controls. Voxel-based morphometry was carried out to test for group differences, and correlations with symptom severity scores were computed for grey matter volume. RESULTS: Our study included 25 patients with DPD and 23 controls. Patients exhibited volume reductions in the right caudate, right thalamus and right cuneus as well as volume increases in the left dorsomedial prefrontal cortex and right somatosensory region that are not a direct function of anxiety or depression symptoms. LIMITATIONS: To ensure ecological validity, we included patients with comorbid disorders and patients taking psychotropic medication. CONCLUSION: The results of this first whole brain investigation of grey matter volume in patients with a dissociative disorder identified structural alterations in regions subserving the emergence of conscious perception. It remains unknown if these alterations are best understood as risk factors for or results of the disorder. PMID- 25285877 TI - Low-grade temporal gliomas: surgical strategy and long-term seizure outcome. AB - Low-grade gliomas (LGGs) are generally located in temporal lobe and cause medically-intractable seizure so that surgical treatment becomes inevitable. This study includes a retrospective analysis of our patients with temporal LGGs retrieved from our epilepsy surgery data base and tries to present appropriate surgical approach and long-term seizure and anti-epileptic drug (AED) outcomes. Fifty-three patients including children and adults underwent surgery on temporal lobe LGGs and 35 patients were reached to report seizure and AED outcomes. On the non-dominant temporal lobe, anterior temporal resection with hippocampectomy whether mesial structure are involved or not is the appropriate approach. On the dominant temporal lobe mesial structures should be respected. However, total resection of the tumor should be the goal of surgery. Mean follow-up period was 8.3 years and favorable seizure outcome was found to be 91.4%. Surgery decreased AED usage and mean number of AED significantly decreased. Children also benefited from surgery as adults. Surgical treatment of tumor-related epilepsy from temporal lobe controls seizures, and total removal should be the main goal of surgery as neuropsychological testing permit. PMID- 25285878 TI - Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase. AB - The paracaspase MALT1 is an Arg-specific protease that cleaves multiple substrates to promote lymphocyte proliferation and survival. The catalytic activity of MALT1 is normally tightly regulated by antigen receptor triggering, which promotes MALT1 activation by its inducible monoubiquitination-dependent dimerization. Constitutive MALT1 activity is a hallmark of specific subsets of B cell lymphomas, which are characterized by chromosomal translocations or point mutations that activate MALT1 or its upstream regulators. Recent findings suggest that such lymphomas may be sensitive to treatment with MALT1 inhibitors. Here we review recent progress in the understanding of MALT1 function and regulation, and the development of small molecule MALT1 inhibitors for therapeutic applications. PMID- 25285876 TI - Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology. AB - BACKGROUND: Despite more than 60 years of research in the role of serotonin (5 HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development. METHODS: Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists. RESULTS: Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region-specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms. LIMITATIONS: There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain. CONCLUSION: A multidisciplinary and longitudinal approach in designing studies on the role of 5 HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology. PMID- 25285879 TI - Inhibition and destruction of Pseudomonas aeruginosa biofilms by antibiotics and antimicrobial peptides. AB - Pseudomonas aeruginosa is one of the major nosocomial pathogen that can causes a wide variety of acute and chronic infections P. aeruginosa is a dreaded bacteria not just because of the high intrinsic and acquired antibiotic resistance rates but also the biofilm formation and production of multiple virulence factors. We investigated the in vitro activities of antibiotics (ceftazidime, tobramycin, ciprofloxacin, doripenem, piperacillin and colistin) and antimicrobial cationic peptides (AMPs; LL-37, CAMA: cecropin(1-7)-melittin A(2-9) amide, melittin, defensin and magainin-II) alone or in combination against biofilms of laboratory strain ATCC 27853 and 4 clinical strains of P. aeruginosa. The minimum inhibitory concentrations (MIC), minimum bactericidal concentration (MBC) and minimum biofilm eradication concentrations (MBEC) were determined by microbroth dilution technique. The MBEC values of antibiotics and AMPs were 80->5120 and 640 >640mg/L, respectively. When combined with the LL-37 or CAMA at 1/10* MBEC, the MBEC values of antibiotics that active against biofilms, were decreased up to 8 fold. All of the antibiotics, and AMPs were able to inhibit the attachment of bacteria at the 1/10* MIC and biofilm formation at 1* or 1/10* MIC concentrations. Time killing curve studies showed 3-log10 killing against biofilms in 24h with almost all studied antibiotics and AMPs. Synergism were seen in most of the studied combinations especially CAMA/LL-37+ciprofloxacin against at least one or two strains' biofilms. Since biofilms are not affected the antibiotics at therapeutic concentrations, using a combination of antimicrobial agents including AMPs, or inhibition of biofilm formation by blocking the attachment of bacteria to surfaces might be alternative methods to fight with biofilm associated infections. PMID- 25285880 TI - Evaluation of avian influenza virus isolated from ducks as a potential live vaccine candidate against novel H7N9 viruses. AB - Recent outbreaks of a novel H7N9 avian influenza virus in humans in China raise pandemic concerns and underscore an urgent need to develop effective vaccines. Theoretically, live influenza vaccines are of multiple advantages over traditional inactivated influenza vaccines to be used in a pandemic, because they can be produced rapidly, safely, and inexpensively. However, studies on live vaccines against the novel H7N9 virus are limited. In this study, we evaluated a potential live influenza vaccine candidate using an H7N3 avian influenza virus isolated from ducks with controls of two recombinant viruses generated through reverse genetics. The potential candidate could be produced efficiently using chicken embryonated eggs, and is homogenous to the novel H7N9 virus in their viral hemagglutinin genes. The potential candidate is likely low pathogenic to birds and mammals, and likely sensitive to oseltamivir and amantadine, as suggested by its genomic sequences. Its low pathogenicity was further supported through inoculation in mice, chicken embryonated eggs and chickens. Specific antibodies elicited in mice were detectable at least during the period between day 14 and day 56 after intranasal administration of the candidate for one time. Titers of the specific antibodies increased significantly with a boost intranasal administration or a higher inoculation dose. The induced specific antibodies were of substantial cross-reactivity with the novel H7N9 virus. These primary but promising evaluation data suggest that the duck influenza virus could be used as a potential live vaccine candidate, favorably through a prime-boost route, to mitigate the severity of the possible pandemic caused by the newly emerging H7N9 virus, and is valuable to be further evaluated. PMID- 25285881 TI - Elevated serum anti-phosphatidylcholine IgG antibodies in patients with influenza vaccination-associated optic neuritis. AB - INTRODUCTION: Because the optic nerve is mainly comprised from phospholipids such as phosphatidylcholine, the association between optic neuritis, anti phospholipids antibodies and vaccination was examined. SUBJECTS: Two female pediatric patients suddenly presented bilateral optic neuritis after administration of trivalent inactivated influenza vaccine. METHODS: These two patients and another 11 patients with central nervous system demyelinating diseases were examined these anti-phospholipids antibodies. And immune histopathology was examined using serum derived from a patient with optic neuritis. RESULTS: High serum titer of anti-phosphatidylcholine antibody levels were detected during acute phase in patients with optic neuritis. The patient's serum IgG antibodies were found to have stained the capillary endotheliums in the preserved autopsied optic nerve. Patients with optic neuritis had significantly elevated serum levels of anti-phosphatidylcholine antibody in comparison to the other patients without optic neuritis. CONCLUSION: Anti-phosphatidylcholine antibodies may be one of the causes of optic neuritis. PMID- 25285882 TI - Inpatient admission for febrile seizure and subsequent outcomes do not differ in children with vaccine-associated versus non-vaccine associated febrile seizures. AB - INTRODUCTION: Recent data suggest that the risk factors for febrile seizure (FS) can differ depending on whether the FS was vaccine-associated (VA) or not. As such, there also may be differences in the risk of inpatient admission and/or the incidence of FS-related subsequent outcomes following the index FS depending on whether it was VA or non-vaccine associated (NVA). This could have useful clinical implications including caregiver education and planning for follow-up care. METHODS: This cohort study consisted of 3348 children who experienced an index FS between 6 months up to 3 years of age from July 1, 2003 through December 31, 2011. The index FS was determined to be VA-FS or NVA-FS; inpatient admission for FS, recurrent FS, and diagnosis of epilepsy were compared between exposure groups. Hazard ratios and relative risk estimates comparing between VA-FS and NVA FS were estimated by Cox proportional models and Robust Poisson regression models, adjusted for race, sex, age at first FS, birth weight, gestational age, maternal age, and 1- and 5-min Apgar scores. RESULTS: The mean age at index FS was 1.5 years; the mean length of follow-up was 2.3 years. Of all index FS, 383 (11.4%) were VA and 2965 were NVA. Among index FS, 264 (7.9%) were admitted as inpatients. Subsequently, 703 (21.0%) children developed at least one recurrent FS, where the number of recurrences ranged from 0 to 9 events. Overall, 144 (4.3%) children were diagnosed with epilepsy during the follow-up period. In adjusted analyses, VA-FS did not differ in the risk for any of the outcomes of interest compared with NVA-FS. DISCUSSION: The risk of hospitalization for index FS or select subsequent FS outcomes did not differ between VA or NVA-FS. This suggests that the follow-up care of children with VA-FS does not warrant attention beyond that for NVA-FS. PMID- 25285883 TI - Safety of immunization during pregnancy: a review of the evidence of selected inactivated and live attenuated vaccines. AB - Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus. This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines. PMID- 25285884 TI - Safety of inactivated monovalent pandemic (H1N1) 2009 vaccination during pregnancy: a population-based study in Taiwan. AB - BACKGROUND: Pregnant women were prioritized for H1N1 vaccination during the 2009 2010 pandemic. Safety concerns exist with vaccinating pregnant women, particularly in their first trimesters. METHODS: We linked computerized data on H1N1 vaccination, National Health Insurance, and Taiwan Birth Registry and identified events of spontaneous abortions (SABs) and all singleton births that occurred/delivered during November 1, 2009-September 30, 2010. The observation period for each case of SAB (6-19 weeks gestation) was divided into period at risk (1-28 days after vaccination) and control periods (the remaining person-days until SAB). The self-controlled case series method for truncated observational periods assessed the incidence rate ratio (IRR) of SAB during the 1-28 days compared with those in the control period. The case-control design matched each case of adverse fetal outcomes to up to 10 controls on fetal sex and year/month of pregnancy onset, and calculated matched odds ratio (OR) on H1N1 vaccination at <14 or >=14 weeks gestation. RESULTS: Sixty-five women with SAB had received H1N1 vaccination at 6-19 weeks gestation. The IRR of SAB for the risk period 1-28 days was 1.03 (95% confidence interval [CI] 0.55-1.93). Among the 147,294 live births and 1354 stillbirths, maternal H1N1 vaccine receipt at <14 weeks gestation was associated with significantly reduced likelihood of small for gestational age (SGA) birth (OR 0.72, 95% CI 0.61-0.84) and birth defect (OR 0.46, 95% CI 0.22 1.00), whereas receipt at >=14 weeks gestation was associated with significantly reduced likelihood of stillbirth (OR 0.63, 95% CI 0.46-0.86), prematurity (OR 0.90, 95% CI 0.83-0.97), low birth weight (OR 0.81, 95% CI 0.74-0.88), and SGA birth (OR 0.90, 95% CI 0.84-0.97). CONCLUSIONS: H1N1 vaccination during pregnancy did not increase risk of SAB or adverse fetal outcomes. PMID- 25285885 TI - Pulmonary immunization of chickens using non-adjuvanted spray-freeze dried whole inactivated virus vaccine completely protects against highly pathogenic H5N1 avian influenza virus. AB - Highly pathogenic avian influenza (HPAI) H5N1 virus is a major threat to public health as well as to the global poultry industry. Most fatal human infections are caused by contact with infected poultry. Therefore, preventing the virus from entering the poultry population is a priority. This is, however, problematic in emergency situations, e.g. during outbreaks in poultry, as there are currently no mass application methods to effectively vaccinate large numbers of birds within a short period of time. To evaluate the suitability of needle-free pulmonary immunization for mass vaccination of poultry against HPAI H5N1, we performed a proof-of-concept study in which we investigated whether non-adjuvanted spray freeze-dried (SFD) whole inactivated virus (WIV) can be used as a dry powder aerosol vaccine to immunize chickens. Our results show that chickens that received SFD-WIV vaccine as aerosolized powder directly at the syrinx (the site of the tracheal bifurcation), mounted a protective antibody response after two vaccinations and survived a lethal challenge with HPAI H5N1. Furthermore, both the number of animals that shed challenge virus, as well as the level of virus shedding, were significantly reduced. Based on antibody levels and reduction of virus shedding, pulmonary vaccination with non-adjuvanted vaccine was at least as efficient as intratracheal vaccination using live virus. Animals that received aerosolized SFD-WIV vaccine by temporary passive inhalation showed partial protection (22% survival) and a delay in time-to-death, thereby demonstrating the feasibility of the method, but indicating that the efficiency of vaccination by passive inhalation needs further improvement. Altogether our results provide a proof-of-concept that pulmonary vaccination using an SFD-WIV powder vaccine is able to protect chickens from lethal HPAI challenge. If the efficacy of pulmonary vaccination by passive inhalation can be improved, this method might be suitable for mass application. PMID- 25285886 TI - Efficacy of Type 2 PRRSV vaccine against Chinese and Vietnamese HP-PRRSV challenge in pigs. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant reproductive losses in the sow herd and respiratory disease in growing pigs. The virus belongs to the family Arteriviridae and there are two major genotypes. Type 1 is represented by Lelystad virus, the European prototype virus, and Type 2 is represented by the North American prototype virus, VR-2332. Depending on husbandry, immune status of the herd, and virulence of the isolate, the severity of disease and magnitude of economic loss can be variable. Vaccine use is not always successful indicating a lack of cross-protection between vaccine strains and circulating wild-type viruses. To date, there is no clear method to demonstrate if a vaccine confers protection against a specific isolate except for empirical animal studies. In 2006, a new lineage of Type 2 PRRSV emerged in Chinese swine herds that were suffering dramatic losses resulting in those viruses being described as "Highly Pathogenic PRRSV" (HP-PRRSV). Experimental reproduction of severe disease with HP-PRRSV isolates and virus derived from HP PRRSV clones demonstrated the causal role of this virus. Recently, partial heterologous protection has been reported for Type 1 and Type 2 attenuated PRRSV vaccines against challenge by different Chinese HP-PRRSV isolates providing some hope for reducing economic loss. This paper reports the efficacy of a commercially available Type 2 attenuated vaccine in young pigs against heterologous challenge with a Chinese and Vietnamese HP-PRRSV isolate. When compared to unvaccinated pigs, vaccination decreased the length of viremia and viral titer, diminished the time of high fever and reduced macroscopic lung scores following homologous and heterologous PRRSV challenge. These results demonstrate the potential use of vaccine as an aid in the control of HP-PRRSV outbreaks. PMID- 25285888 TI - BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. AB - BACKGROUND: Mutations of v-raf murine sarcoma viral oncogene homolog B (BRAF) are commonly identified in papillary and anaplastic thyroid carcinoma and are associated with worse prognosis compared with the wild type. BRAF inhibition in papillary thyroid carcinoma cell lines and xenografts inhibits proliferation and decreases downstream phosphorylation. Our objectives were to analyze safety and efficacy of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid carcinoma. METHODS: We present the subset of patients with BRAF-mutant thyroid carcinoma enrolled in a larger phase 1 study, the main results of which are reported elsewhere. RESULTS: Fourteen patients with BRAF(V600E)-mutant thyroid carcinoma were enrolled, of whom 13 (93%) had received prior radioactive iodine. The median duration on treatment was 8.4 months, and seven (50%) patients received treatment for >=10 months. The most common treatment-related adverse events were skin papillomas (n=8, 57%), hyperkeratosis (n=5, 36%), and alopecia (n=4, 29%), all of which were grade 1. Treatment-related adverse events grade >=3 included grade 4 elevated lipase and grade 3 elevated amylase, fatigue, febrile neutropenia, and cutaneous squamous cell carcinoma (n=1 for each). Four (29%) partial responses were observed, and nine (64%) patients achieved at least 10% decrease. Only one responder progressed while on the study drug after a response duration of 9.3 months. The other three responders had not progressed, with response duration of 4.6+, 10.4+, and 21.4+ months. With seven (50%) patients showing no progression at the time of study completion, the median progression-free survival was 11.3 months. CONCLUSIONS: Dabrafenib was well tolerated and resulted in durable responses in BRAF-mutant differentiated thyroid carcinoma patients. PMID- 25285889 TI - Response to drought and salt stress in leaves of poplar (Populus alba * Populus glandulosa): expression profiling by oligonucleotide microarray analysis. AB - Drought and salt stresses are major environmental constraints on forest productivity. To identify genes responsible for stress tolerance, we conducted a genome-wide analysis in poplar (Populus alba * Populus glandulosa) leaves exposed to drought and salt (NaCl) stresses. We investigated gene expression at the mRNA level using oligonucleotide microarrays containing 44,718 genes from Populus trichocarpa. A total of 1604 and 1042 genes were up-regulated (>=2-fold; P value < 0.05) by drought and salt stresses, respectively, and 765 genes were up regulated by both stresses. In addition, 2742 and 1685 genes were down-regulated by drought and salt stresses, respectively, and 1564 genes were down-regulated by both stresses. The large number of genes regulated by both stresses suggests that crosstalk occurs between the drought and salt stress responses. Most up-regulated genes were involved in functions such as subcellular localization, signal transduction, metabolism, and transcription. Among the up-regulated genes, we identified 47 signaling proteins, 65 transcription factors, and 43 abiotic stress related genes. Several genes were modulated by only one of the two stresses. About 25% of the genes significantly regulated by these stresses are of unknown function, suggesting that poplar may provide an opportunity to discover novel stress-related genes. PMID- 25285887 TI - Neonatal intrahippocampal HIV-1 protein Tat(1-86) injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation. AB - Pediatric AIDS caused by human immunodeficiency virus type 1 (HIV-1) remains one of the leading worldwide causes of childhood morbidity and mortality. HIV-1 proteins, such as Tat and gp120, are believed to play a crucial role in the neurotoxicity of pediatric HIV-1 infection. Detrimental effects on development, behavior, and neuroanatomy follow neonatal exposure to the HIV-1 viral toxins Tat1-72 and gp120. The present study investigated the neurobehavioral effects induced by the HIV-1 neurotoxic protein Tat1-86, which encodes the first and second exons of the Tat protein. In addition, the potential effects of HIV-1 toxic proteins Tat1-86 and gp120 on inflammatory pathways were examined in neonatal brains. Vehicle, 25 MUg Tat1-86 or 100 ng gp120 was injected into the hippocampus of male Sprague-Dawley pups on postnatal day 1 (PD1). Tat1-86 induced developmental neurotoxic effects, as witnessed by delays in eye opening, delays in early reflex development and alterations in prepulse inhibition (PPI) and between-session habituation of locomotor activity. Overall, the neurotoxic profile of Tat1-86 appeared more profound in the developing nervous system in vivo relative to that seen with the first exon encoded Tat1-72 (Fitting et al., 2008b), as noted on measures of eye opening, righting reflex, and PPI. Neither the direct PD1 CNS injection of the viral HIV-1 protein variant Tat1-86, nor the HIV-1 envelope protein gp120, at doses sufficient to induce neurotoxicity, necessarily induced significant expression of the inflammatory cytokine IL-1beta or inflammatory factors NF-kappabeta and I-kappabeta. The findings agree well with clinical observations that indicate delays in developmental milestones of pediatric HIV-1 patients, and suggest that activation of inflammatory pathways is not an obligatory response to viral protein-induced neurotoxicity that is detectable with behavioral assessments. Moreover, the amino acids encoded by the second tat exon may have unique actions on the developing hippocampus. PMID- 25285890 TI - Prevalence of suicidal ideation in Chinese college students: a meta-analysis. AB - BACKGROUND: About 1 million people worldwide commit suicide each year, and college students with suicidal ideation are at high risk of suicide. The prevalence of suicidal ideation in college students has been estimated extensively, but quantitative syntheses of overall prevalence are scarce, especially in China. Accurate estimates of prevalence are important for making public policy. In this paper, we aimed to determine the prevalence of suicidal ideation in Chinese college students. OBJECTIVE AND METHODS: Databases including PubMed, Web of Knowledge, Chinese Web of Knowledge, Wangfang (Chinese database) and Weipu (Chinese database) were systematically reviewed to identify articles published between 2004 to July 2013, in either English or Chinese, reporting prevalence estimates of suicidal ideation among Chinese college students. The strategy also included a secondary search of reference lists of records retrieved from databases. Then the prevalence estimates were summarized using a random effects model. The effects of moderator variables on the prevalence estimates were assessed using a meta-regression model. RESULTS: A total of 41 studies involving 160339 college students were identified, and the prevalence ranged from 1.24% to 26.00%. The overall pooled prevalence of suicidal ideation among Chinese college students was 10.72% (95%CI: 8.41% to 13.28%). We noted substantial heterogeneity in prevalence estimates. Subgroup analyses showed that prevalence of suicidal ideation in females is higher than in males. CONCLUSIONS: The prevalence of suicidal ideation in Chinese college students is relatively high, although the suicide rate is lower compared with the entire society, suggesting the need for local surveys to inform the development of health services for college students. PMID- 25285891 TI - Hemispheric lateralization of posterior alpha reduces distracter interference during face matching. AB - Previous M/EEG studies on visuospatial attention have shown that attending to one hemifield, while ignoring the other, leads to a decrease in occipito-parietal alpha power contralateral to the target and a concurrent ipsilateral alpha increase. Here, we tested whether this alpha modulation facilitates the processing of attended faces in the presence of distracters. Face processing was tested in a match-to-sample task, in which participants matched a target face in a cued hemifield to a previously seen sample face. The target faces in the cued hemifield were presented together with a distracter face (intact or scrambled faces) in the other hemifield. The behavioral data indicated a larger impairment of matching performance when the distracter was another face, rather than a scrambled face. We hypothesized that enhanced alpha power contralateral to the distracter would enhance target matching by decreasing the interference from similar distracters. We found this effect, but only in the left hemisphere. Moreover, we found that with targets contralateral from the left hemisphere, a down-regulation of relative alpha power in the left hemisphere also correlated with increased target matching performance. Hence, the left hemisphere could protect the target from distracter interference either by decreasing alpha power in response to a contralateral target, or increasing alpha power to a contralateral distracter. Remarkably, alpha power in the right hemisphere was not predictive for matching performance. These findings support the hypothesis that alpha modulations contribute to the suppression of task-irrelevant information, but suggest a dominant role herein of the left hemisphere during face matching in the presence of distracters. PMID- 25285892 TI - The possible mechanism of Parkinson's disease progressive damage and the preventive effect of GM1 in the rat model induced by 6-hydroxydopamine. AB - The progressive pathogenesis and prevention of Parkinson's disease (PD) remains unknown at present. Therefore, the present study aimed to investigate the possible progressive pathogenesis and prevention of PD. Our study investigated the content of glutamate, mitochondria calcium, calmodulin, malonaldehyde and trace elements in striatum, cerebral cortex and hippocampus tissues; and the expression of bcl-2, bax and neuronal nitric oxide synthase (nNOS) in substantia nigra and striatum; and the change of apomorphine induced rotation behavior; and the treatmental effect of monosialotetrahexosylganglioside (GM1) intraperitoneal administration for 14 days in a PD rat model induced by 6-hydroxydopamine. The results revealed that the content of glutamate significantly decreased, and that of mitochondria calcium, calmodulin, malonaldehyde and ferrum significantly increased in striatum, cerebral cortex and hippocampus tissues; the content of magnesium significantly decreased, and that of cuprum and zinc significantly increased in cerebral cortex; the expression of bcl-2 significantly decreased, and that of bax and nNOS significantly increased in substantia nigra and striatum in PD rat. GM1 can partially improve the apomorphine induced rotation behavior and changes of glutamate, mitochondria calcium, calmodulin content in striatum of PD rat. Data suggested that dysfunction of excitatory amino acids neurotransmitter, calcium homeostasis disorder, abnormal metabolism of oxygen free radicals, abnormal trace elements distribution and/or deposition and excessive apoptosis participated in the progressive process of PD, and that GM1 could partially prevent the progressive damage. PMID- 25285893 TI - Hippocampus remodeling by chronic stress accompanied by GR, proteasome and caspase-3 overexpression. AB - Chronic stress is a threat to homeostasis for many brain regions. While hippocampal formation is one of the most stress-sensitive areas of the cortex, molecular changes occurring as a result of increased glucocorticoid neurotoxicity in hippocampus are largely unknown. The aim of these studies was to investigate mRNA expression of mineralocorticoid and glucocorticoid receptors (MR, GR), proteasome subunits beta5 (constitutive subunit) and beta1i (inducible immunoproteasome subunit), mTOR (mammalian target of rapamycin), bcl-2; as well as caspase-3 immunoreactivity (confocal microscopy) in adult Wistar rat hippocampus following 10-day restraint stress (plastic restrainers, 6h daily). Chronic restraint led to a significant reduction in number of neuronal and astroglial cells in hippocampal regions CA1-3. This reaction was combined with substantial increase in GR and decrease in MR mRNA levels with the greatest response - 1.5-fold amplitude increase - observed in dentate gyrus and CA3 correspondingly. Stress did not change the expression of constitutive beta5 subunit but dramatically enhanced expression of inducible beta1i subunit and increased mTOR, and bcl-2 mRNA expression. Multiple scattered cells demonstrating caspase-3(+) profile were found in hippocampus of stressed animals. The study demonstrates that hippocampal remodeling induced by chronic restraint stress is associated with GR, immunoproteasome, mTOR, caspase-3 and bcl-2 overexpression in hippocampus. PMID- 25285894 TI - Osteocytes as a record of bone formation dynamics: a mathematical model of osteocyte generation in bone matrix. AB - The formation of new bone involves both the deposition of bone matrix, and the formation of a network of cells embedded within the bone matrix, called osteocytes. Osteocytes derive from bone-synthesising cells (osteoblasts) that become buried in bone matrix during bone deposition. The generation of osteocytes is a complex process that remains incompletely understood. Whilst osteoblast burial determines the density of osteocytes, the expanding network of osteocytes regulates in turn osteoblast activity and osteoblast burial. In this paper, a spatiotemporal continuous model is proposed to investigate the osteoblast-to osteocyte transition. The aims of the model are (i) to link dynamic properties of osteocyte generation with properties of the osteocyte network imprinted in bone, and (ii) to investigate Marotti's hypothesis that osteocytes prompt the burial of osteoblasts when they become covered with sufficient bone matrix. Osteocyte density is assumed in the model to be generated at the moving bone surface by a combination of osteoblast density, matrix secretory rate, rate of entrapment, and curvature of the bone substrate, but is found to be determined solely by the ratio of the instantaneous burial rate and matrix secretory rate. Osteocyte density does not explicitly depend on osteoblast density nor curvature. Osteocyte apoptosis is also included to distinguish between the density of osteocyte lacuna and the density of live osteocytes. Experimental measurements of osteocyte lacuna densities are used to estimate the rate of burial of osteoblasts in bone matrix. These results suggest that: (i) burial rate decreases during osteonal infilling, and (ii) the control of osteoblast burial by osteocytes is likely to emanate as a collective signal from a large group of osteocytes, rather than from the osteocytes closest to the bone deposition front. PMID- 25285895 TI - Stochastic gene expression with delay. AB - The expression of genes usually follows a two-step procedure. First, a gene (encoded in the genome) is transcribed resulting in a strand of (messenger) RNA. Afterwards, the RNA is translated into protein. We extend the classical stochastic jump model by adding delays (with arbitrary distributions) to transcription and translation. Already in the classical model, production of RNA and protein comes in bursts by activation and deactivation of the gene, resulting in a large variance of the number of RNA and proteins in equilibrium. We derive precise formulas for this second-order structure with the model including delay in equilibrium. PMID- 25285896 TI - Effect of postcall fatigue on surgical skills measured by a robotic simulator. AB - PURPOSE: To examine the effect of a 24-hour call on residents' performance of a suturing task using the objective results calculated by the da Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA). SUBJECTS AND METHODS: Residents from urology and general surgery completed a single suturing skill immediately before and after a 24-hour call. Residents completed the task at least twice and were scored on three measures: time to complete the exercise, time to load the needle, and time to tie the knot. These scores were correlated with previous simulator experience, trainee level, and level of postcall fatigue. RESULTS: Thirteen residents (four senior and nine junior) participated; six had no simulator experience. All time measures were significantly longer when residents were postcall (p<0.05). In the precall measures, previous robotic simulator experience was associated with improved time for completion of the exercise, needle loading, and knot tying (p<0.05). In the postcall measures, however, the difference in performance between residents with and without previous simulator experience was no longer statistically significant (p>0.05). When examining factors that predicted an increased task time on multivariate analysis, being postcall consistently increased the time to complete the exercises, while previous simulator experience and trainee level decreased the time to complete tasks. CONCLUSIONS: Previous studies have shown that postcall-related fatigue is associated with decreased surgical skills in the operative room. We demonstrate this effect by having residents test their skills, precall and postcall, using a novel easily reproducible technique. Time to complete the three measures analyzed was significantly increased following a 24-hour call for all participants. Fatigue acts as an equalizer of abilities in that the effects of fatigue nullify the benefits of having previous robotic simulator experience. PMID- 25285897 TI - Cannabis use and mania symptoms: a systematic review and meta-analysis. AB - BACKGROUND: Whilst cannabis use appears to be a causal risk factor for the development of schizophrenia-related psychosis, associations with mania remain relatively unknown. This review aimed to examine the impact of cannabis use on the incidence of manic symptoms and on their occurrence in those with pre existing bipolar disorder. METHODS: A systematic review of the scientific literature using the PRISMA guidelines. PsychINFO, Cochrane, Scopus, Embase and MEDLINE databases were searched for prospective studies. RESULTS: Six articles met inclusion criteria. These sampled 2391 individuals who had experienced mania symptoms. The mean length of follow up was 3.9 years. Studies support an association between cannabis use and the exacerbation of manic symptoms in those with previously diagnosed bipolar disorder. Furthermore, a meta-analysis of two studies suggests that cannabis use is associated with an approximately 3-fold (Odds Ratio: 2.97; 95% CI: 1.80-4.90) increased risk for the new onset of manic symptoms. LIMITATIONS: We were only able to identify a small number of studies of variable quality, thus our conclusions remain preliminary. CONCLUSIONS: Our findings whilst tentative, suggest that cannabis use may worsen the occurrence of manic symptoms in those diagnosed with bipolar disorder, and may also act as a causal risk factor in the incidence of manic symptoms. This underscores the importance of discouraging cannabis use among youth and those with bipolar disorder to help prevent chronic psychiatric morbidity. More high quality prospective studies are required to fully elucidate how cannabis use may contribute to the development of mania over time. PMID- 25285898 TI - Transgenerational transmission of trauma in families of Holocaust survivors: the consequences of extreme family functioning on resilience, sense of coherence, anxiety and depression. AB - BACKGROUND: The psychological transmission of the noxious effects of a major trauma from one generation to the next remains unclear. The present study aims to identify possible mechanisms explaining this transmission among families of Holocaust Survivors (HS). We hypothesized that the high level of depressive and anxiety disorders (DAD) among HS impairs family systems, which results in damaging coping strategies of their children (CHS) yielding a higher level of DAD. METHODS: 49 CHS completed the Resilience Scale for Adults, the Hopkins Symptom Check List-25, the 13-Item Sense of Coherence (SOC) scale, and the Family Adaptability and Cohesion Scale. We test a mediation model with Family types as the predictor; coping strategies (i.e. Resilience or SOC) as the mediator; and DAD as the outcome variable. RESULTS: Results confirm that the CHS' family types are more often damaged than in general population. Moreover, growing in a damaged family seems to impede development of coping strategies and, therefore, enhances the occurrence of DAD. LIMITATIONS: The present investigation is correlational and should be confirmed by other prospective investigations. CONCLUSIONS: At a theoretical level we propose a mechanism of transmission of the noxious effects of a major trauma from one generation to the next through family structure and coping strategies. At a clinical level, our results suggest to investigate the occurrence of trauma among parents of patients consulting for DAD and to reinforce their coping strategies. PMID- 25285899 TI - Neurostructural impact of co-occurring anxiety in pediatric patients with major depressive disorder: a voxel-based morphometry study. AB - BACKGROUND: Depressive and anxiety disorders are among the most frequently occurring psychiatric conditions in children and adolescents and commonly present occur together. Co-occurring depression and anxiety is associated with increased functional impairment and suicidality compared to depression alone. Despite this, little is known regarding the neurostructural differences between anxiety disorders and major depressive disorder (MDD). Moreover, the neurophysiologic impact of the presence of anxiety in adolescents with MDD is unknown. METHODS: Using voxel-based morphometry, gray matter volumes were compared among adolescents with MDD (and no co-morbid anxiety disorders, n=14), adolescents with MDD and co-morbid anxiety ("anxious depression," n=12), and healthy comparison subjects (n=41). RESULTS: Patients with anxious depression exhibited decreased gray matter volumes in the dorsolateral prefrontal cortex (DLPFC) compared to patients with MDD alone. Compared to healthy subjects, adolescents with anxious depression had increased gray matter volumes in the pre- and post-central gyri. LIMITATIONS: The current sample size was small and precluded an analysis of multiple covariates which may influence GMV. CONCLUSIONS: Gray matter deficits in the DLPFC in youth with anxious depression compared to patients with MDD and no co-occurring anxiety may reflect the more severe psychopathology in these patients. Additionally, the distinct gray matter fingerprints of MDD and anxious depression (compared to healthy subjects) suggest differing neurophysiologic substrates for these conditions, though the etiology and longitudinal trajectory of the differences remain to be determined. PMID- 25285900 TI - Cognitive styles and future depressed mood in early adulthood: the importance of global attributions. AB - BACKGROUND: Cognitive theories of depression suggest that beliefs of low self worth and the tendency to attribute negative events to causes that are global (widespread rather than specific) and stable (will persist rather than change in the future) are associated with the development of depressed mood. Such theories are supported by evidence from prospective studies and have guided the development of successful treatment and prevention strategies such as CBT. However, the relative importance of different psychological constructs within cognitive theories is unknown. This is important to refine cognitive theories and develop more efficient prevention strategies. METHOD: We used prospective data from over 3500 young adults from the Avon Longitudinal Study for Parents and Children (ALSPAC) cohort in the UK to investigate the association between cognitive style, measured by short forms of the Dysfunctional Attitudes Scale (DAS) and Cognitive Styles Questionnaire-Short Form (CSQ-SF) at age 18, and future depressed mood at age 19. Structural equation modelling techniques were used to separate cognitive style constructs. RESULTS: Cognitive styles were associated with future depressed mood, independently of baseline mood, both as measured by the DAS-SF and the CSQ-SF. Of the different CSQ-SF constructs, only global attributions were associated with both baseline and future mood independently of other constructs. LIMITATIONS: The study was subject to attrition and the follow-up was relatively short (10 months). CONCLUSION: The findings suggest that the tendency to attribute negative events specifically to global causes could be particularly important for depression. Reducing global attributions is potentially important in the prevention and treatment of depression. PMID- 25285902 TI - Health and social care costs of managing amyotrophic lateral sclerosis (ALS): an Irish perspective. AB - The aim of this study was to quantify the health and social care costs associated with managing amyotrophic lateral sclerosis (ALS) in Ireland. Resource use of a representative group of deceased ALS patients attending a multidisciplinary ALS clinic was identified from a retrospective chart review and telephone interview with the main caregiver. Unit cost estimates were applied to each resource to identify the cost per patient. Cost drivers were identified using multivariate linear regression. Results showed that from time of diagnosis to death, the cost per month was ?1795, 21% of which was attributable to costs associated with the multidisciplinary clinic, 72% to community based care and 7% to aids and appliances. Higher monthly cost was associated with shorter survival and use of gastrostomy and non-invasive ventilation. In conclusion, ALS imposes a significant cost burden on the health services. More work is required to quantify the costs in other sectors, including informal care and productivity losses. PMID- 25285901 TI - Rating scales in general practice depression: psychometric analyses of the clinical interview for depression and the Hamilton rating scale. AB - BACKGROUND: Our objective was to investigate to what extent the Clinical Interview for Depression (CID) used in the general practice setting covers clinically valid subscales (depression, anxiety, and apathy) which can measure outcome of antidepressant therapy as well as identifying subsyndromes within major depressive disorder. The CID was compared to the Hamilton Depression Rating Scale (HAM-D17). METHODS: 146 patients from a previous study in general practice with the CID were investigated. The item response theory model established by Rasch was used to investigate the scalability (a scale's psychometric adequacy) of the subscales, and principal component analysis was used to identify subsyndromes with the symptoms of major depression according to DSM-5 or ICD-10. RESULTS: Whereas the HAM-D17 was found not to have an acceptable scalability, the three brief CID subscales for depression (six items), anxiety (five items), and apathy (five items) all had an acceptable scalability. Within the major depressive symptoms, principal component analysis identified the CID items of hypersomnia, increased appetite or weight gain as defining the subsyndrome of atypical depression. In total 29 patients (approximately 20%) had an atypical depression. LIMITATIONS: The samples were derived from a single study and were all rated by a single rater. CONCLUSION: The CID contains subscales of depression, anxiety, and apathy with an acceptable scalability for use in general practice. A subsyndrome of atypical depression is also a useful identifier in the treatment of depressed patients in general practice. PMID- 25285903 TI - Association study between salivary levels of interferon (IFN)-gamma, interleukin (IL)-17, IL-21, and IL-22 with chronic periodontitis. AB - OBJECTIVE: To investigate if the salivary levels of IL-17, IL-21, IL-22, and its ratio regarding salivary IFN-gamma may be linked with the periodontal clinical status. DESIGN: One hundred and five chronic periodontitis (CP) subjects and 44 healthy controls (HC) were recruited. Periodontal status was assessed based on full-mouth clinical periodontal measurements. Cytokine salivary levels were analyzed by ELISA. The association between the analytes with CP was analyzed using a binary logistic regression model. RESULTS: A statistically significant increase in salivary levels of IFN-gamma and IFN-gamma/IL-22 ratio in CP group could be detected, but there was no significant domination of any Th17 cytokine that could be of predictive value for health/disease status. Univariate and binary logistic regression analyses revealed a strong and independent association of IFN-gamma salivary levels and IFN-gamma/IL-22 ratio with disease status. An interaction effect of ageing on IFN-gamma levels also could be noted. CONCLUSION: While salivary levels of IFN-gamma and IFN-gamma/IL-22 ratio may act as strong/independent indicators of the amount and extent of periodontal breakdown, the low detection frequency of Th17 cytokines in saliva samples make these determinations useless for the detection of disease presence and/or its severity. PMID- 25285904 TI - Odontometric sex estimation on three populations of the Iron Age from Abruzzo region (central-southern Italy). AB - BACKGROUND: In archaeological contexts, sex identification is a necessary step for a complete reconstruction of the biological profile of the individuals and to know demographic patterns of the population, nutritional stress, diseases, growth and development, and distribution of pathological conditions. METHODS: This study is based on the skeletal remains of 149 individuals from three protohistoric populations in close temporal and geographic proximity in Abruzzo region (central southern Italy): Opi, Alfedena and Bazzano. It has been possible to develop logistic regression equations based on dental measurements of permanent teeth of adult individuals whose sex had previously been estimated based on pelvic and cranial features. These equations were subsequently applied to the permanent dentition of immature individuals and adult individuals whose sex was estimated as uncertain or unknown in order to estimate their sex. RESULTS: The mandibular canine is the tooth with the greatest sexual dimorphism in adults, followed by both maxillary and mandibular first and second molars, providing a correct assignment of sex ranging from 83.7% and 95.9% of cases, depending on the dimensions used for the construction of these equations. Of the 29 individuals in the target sample (14 adultus, 10 juvenilis and 5 infans), sex estimation was possible for 23 (10 adultus, 8 juvenilis and 5 infans), representing an applicability rate of 79.31% of the individuals. CONCLUSIONS: The results indicate that odontometrics is a useful tool for sex estimation and allows to increase the data to perform more complete paleodemographic studies on archaeological populations. PMID- 25285905 TI - Hybrid platforms of graphane-graphene 2D structures: prototypes for atomically precise nanoelectronics. AB - First-principles calculations demonstrate that line/ribbon defects, resulting from a controlled dehydrogenation in graphane, lead to the formation of low dimensional electron-rich tracks in a monolayer. The present simulations point out that hybrid graphane-graphene nanostructures exhibit important elements, greatly required for the fabrication of efficient electronic circuits at the atomic level. PMID- 25285906 TI - Molecular simulations and visualization: introduction and overview. AB - Here we provide an introduction and overview of current progress in the field of molecular simulation and visualization, touching on the following topics: (1) virtual and augmented reality for immersive molecular simulations; (2) advanced visualization and visual analytic techniques; (3) new developments in high performance computing; and (4) applications and model building. PMID- 25285907 TI - Ultrasonication assisted preparation of carbonaceous nanoparticles modified polyurethane foam with good conductivity and high oil absorption properties. AB - In this work, we report a facile, low cost and time-saving method for the fabrication of compressible, electrically conductive, oil absorptive, cost effective and flexible polyurethane (PU) foam through ultrasonication induced carbonaceous nanoparticles (CNP) onto flexible PU foam (CNP-PU foam). SEM images showed that the CNP could be firmly anchored onto the PU foam, and made the PU foam surface much rougher. Zero-dimensional carbonaceous nanoparticles were easier to anchor onto the PU foam surface than one-dimensional nanoparticles (e.g., carbon nanotube) or two-dimensional nanoparticles (e.g., graphene oxide). The CNP-PU foam exhibited excellent elasticity and high mechanical durability even when it was subjected to 500 cyclic compression. The CNP-PU foam had excellent absorption of organic solvents up to 121 times the weight of the initial PU foam. In addition, the electrical conductivity of PU foams was considerably increased with the anchoring of CNP onto the matrix. In addition, compression experiments confirmed that the electrical conductivity of CNP-PU foams changed with their compression ratios, thus exhibiting excellent pressure sensitivity. The as-prepared materials have significant potential as oil absorbents, elastic conductors, flexible electrodes, pressure sensors, etc. PMID- 25285909 TI - Novel application of pH-sensitive firefly luciferases as dual reporter genes for simultaneous ratiometric analysis of intracellular pH and gene expression/location. AB - Firefly luciferases are widely used as bioluminescent reporter genes for bioimaging and biosensors. Aiming at simultaneous analyses of different gene expression and cellular events, luciferases and GFPs that exhibit distinct bioluminescence and fluorescence colors have been coupled with each promoter, making dual and multicolor reporter systems. Despite their wide use, firefly luciferase bioluminescence spectra are pH-sensitive, resulting in a typical large red shift at acidic pH, a side-effect that may affect some bioanalytical purposes. Although some intracellular pH-indicators employ dual color and fluorescent dyes, none has been considered to benefit from the characteristic spectral pH-sensitivity of firefly luciferases to monitor intracellular pH associated stress, an important indicator of cell homeostasis. Here we demonstrate a linear relationship between the ratio of intensities in the green and red regions of the bioluminescence spectra and pH using firefly luciferases cloned in our laboratory (Macrolampis sp2 and Cratomorphus distinctus), allowing estimation of E. coli intracellular pH, thus providing a new analytical method for ratiometric intracellular pH-sensing. This is the first dual reporter system that employs a single luciferase gene to simultaneously monitor intracellular pH using spectral changes, and gene expression and/or ATP concentration using the bioluminescence intensity, showing great potential for real time bioanalysis of intracellular processes associated with metabolic changes such as apoptosis, cell death, inflammation and tissue acidification, among the other physiological changes. PMID- 25285908 TI - Trunk muscle activity is modified in osteoporotic vertebral fracture and thoracic kyphosis with potential consequences for vertebral health. AB - This study explored inter-relationships between vertebral fracture, thoracic kyphosis and trunk muscle control in elderly people with osteoporosis. Osteoporotic vertebral fractures are associated with increased risk of further vertebral fractures; but underlying mechanisms remain unclear. Several factors may explain this association, including changes in postural alignment (thoracic kyphosis) and altered trunk muscle contraction patterns. Both factors may increase risk of further fracture because of increased vertebral loading and impaired balance, which may increase falls risk. This study compared postural adjustments in 24 individuals with osteoporosis with and without vertebral fracture and with varying degrees of thoracic kyphosis. Trunk muscle electromyographic activity (EMG) associated with voluntary arm movements was recorded and compared between individuals with and without vertebral fracture, and between those with low and high thoracic kyphosis. Overall, elderly participants in the study demonstrated co-contraction of the trunk flexor and extensor muscles during forwards arm movements, but those with vertebral fractures demonstrated a more pronounced co-contraction than those without fracture. Individuals with high thoracic kyphosis demonstrated more pronounced alternating flexor and extensor EMG bursts than those with less kyphosis. Co contraction of trunk flexor and extensor muscles in older individuals contrasts the alternating bursts of antagonist muscle activity in previous studies of young individuals. This may have several consequences, including altered balance efficacy and the potential for increased compressive loads through the spine. Both of these outcomes may have consequences in a population with fragile vertebrae who are susceptible to fracture. PMID- 25285910 TI - Streptomyces sp. TEM 33 possesses high lipolytic activity in solid-state fermentation in comparison with submerged fermentation. AB - Solid-state fermentation (SSF) is a bioprocess that doesn't need an excess of free water, and it offers potential benefits for microbial cultivation for bioprocesses and product development. In comparing the antibiotic production, few detailed reports could be found with lipolytic enzyme production by Streptomycetes in SSF. Taking this knowledge into consideration, we prefer to purify Actinomycetes species as a new source for lipase production. The lipase producing strain Streptomyces sp. TEM 33 was isolated from soil and lipase production was managed by solid-state fermentation (SSF) in comparison with submerged fermentation (SmF). Bioprocess-affecting factors like initial moisture content, incubation time, and various carbon and nitrogen additives and the other enzymes secreted into the media were optimized. Lipase activity was measured as 1.74 +/- 0.0005 U/g dry substrate (gds) by the p-nitrophenylpalmitate (pNPP) method on day 6 of fermentation with 71.43% final substrate moisture content. In order to understand the metabolic priority in SSF, cellulase and xylanase activity of Streptomyces sp. TEM33 was also measured. The microorganism degrades the wheat bran to its usable form by excreting cellulases and xylanases; then it secretes the lipase that is necessary for degrading the oil in the medium. PMID- 25285911 TI - Molecular dynamics study of coagulation in silica-nanocolloid-water-NaCl systems based on the atomistic model. AB - In the present work, large scale molecular dynamics (MD) simulations of nanocolloidal silica in aqueous NaCl solutions were performed using a fully atomistic model to study the microscopic structures and dynamics of the systems that lead to aggregation or gelation. Our attention is focused on the self organizations that occur in the structures of the colloidal silica and water for various concentrations of NaCl. As the salt concentration increased, coagulation developed through the direct bonding of SiO4 units. The trend was explained by the systematic changes in the pair correlation functions related to the barrier height in the potential of mean force [J. G. Kirkwood, J. Chem. Phys., 1935, 3, 300]. Network structures of silica were visualised, and their fractal dimensions were examined by computing the running coordination numbers of Si-Si pairs and also by the analysis of two dimensional images. The calculated dimension by the former method was comparable to the experimental observations for the aggregation of silica colloids, and at longer length scales, super-aggregation was evident in the gelation process. The result from the 2D images is found to be insensitive to the differences in the structure. Clear changes in both the structure and mobility of the water were observed as the NaCl concentration increased, suggesting the importance of the solvent structures to these processes, although such a feature is lacking in the conventional models and most simulations of colloids. PMID- 25285912 TI - Models for B12-conjugated radiopharmaceuticals. Cobaloxime binding to new fac [Re(CO)3(Me2bipyridine)(amidine)]BF4 complexes having an exposed pyridyl nitrogen. AB - New mononuclear amidine complexes, fac-[Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4 [(4,4'-Me2bipy (1), 5,5'-Me2bipy (2), and 6,6'-Me2bipy (3)] (bipy = 2,2' bipyridine), were synthesized by treating the parent fac [Re(I)(CO)3(Me2bipy)(CH3CN)]BF4 complex with the C2-symmetrical amine 1-(4 pyridyl)piperazine (pyppzH). The axial amidine ligand has an exposed, highly basic pyridyl nitrogen. The reaction of complexes 1-3 with a B12 model, (py)Co(DH)2Cl (DH = monoanion of dimethylglyoxime), in CH2Cl2 yielded the respective dinuclear complexes, namely, fac-[Re(CO)3(Me2bipy)(MU (HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 [(4,4'-Me2bipy (4), 5,5'-Me2bipy (5), and 6,6' Me2bipy (6)]. (1)H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for 2, 3, 5, and 6 established that the amidine had only the E configuration in both the solid and solution states and that the pyridyl group is bound to Co in 4-6. Comparison of the NMR spectra of 1-3 with spectra of 4-6 reveals an unusually large "wrong-way" upfield shift for the pyridyl H2/6 signal for 4-6. The wrong-way H2/6 shift of (4-Xpy)Co(DH)2Cl (4-Xpy = 4-substituted pyridine) complexes increased with increasing basicity of the 4 Xpy derivative, a finding attributed to the influence of the magnetic anisotropy of the cobalt center on the shifts of the (1)H NMR signals of the pyridyl protons closest to Co. Our method of employing a coordinate bond for conjugating the fac [Re(I)(CO)3] core to a vitamin B12 model could be extended to natural B12 derivatives. Because B12 compounds are known to accumulate in cancer cells, such an approach is a very attractive method for the development of (99m)Tc and (186/188)Re radiopharmaceuticals for targeted tumor imaging and therapy. PMID- 25285913 TI - Visuospatial tasks affect locomotor control more than nonspatial tasks in older people. AB - BACKGROUND: Previous research has shown that visuospatial processing requiring working memory is particularly important for balance control during standing and stepping, and that limited spatial encoding contributes to increased interference in postural control dual tasks. However, visuospatial involvement during locomotion has not been directly determined. This study examined the effects of a visuospatial cognitive task versus a nonspatial cognitive task on gait speed, smoothness and variability in older people, while controlling for task difficulty. METHODS: Thirty-six people aged >=75 years performed three walking trials along a 20 m walkway under the following conditions: (i) an easy nonspatial task; (ii) a difficult nonspatial task; (iii) an easy visuospatial task; and (iv) a difficult visuospatial task. Gait parameters were computed from a tri-axial accelerometer attached to the sacrum. The cognitive task response times and percentage of correct answers during walking and seated trials were also computed. RESULTS: No significant differences in either cognitive task type error rates or response times were evident in the seated conditions, indicating equivalent task difficulty. In the walking trials, participants responded faster to the visuospatial tasks than the nonspatial tasks but at the cost of making significantly more cognitive task errors. Participants also walked slower, took shorter steps, had greater step time variability and less smooth pelvis accelerations when concurrently performing the visuospatial tasks compared with the nonspatial tasks and when performing the difficult compared with the easy cognitive tasks. CONCLUSIONS: Compared with nonspatial cognitive tasks, visuospatial cognitive tasks led to a slower, more variable and less smooth gait pattern. These findings suggest that visuospatial processing might share common networks with locomotor control, further supporting the hypothesis that gait changes during dual task paradigms are not simply due to limited attentional resources but to competition for common networks for spatial information encoding. PMID- 25285914 TI - High-throughput 3D cell invasion chip enables accurate cancer metastatic assays. AB - Chemotaxis is the phenomenon by which the migration and invasion of cells is directed in response to an extracellular chemical gradient. Chemotaxis of tumor cells and tumor-associated inflammatory and stromal cells is mediated by chemokines, chemokine receptors, growth factors, and growth factor receptors. Current techniques used to study chemotactic driven cell invasion and metastasis utilize two-dimensional migration assays involving imaging and analyzing tumor cells on glass slides or plastic surfaces, which requires large numbers of cells and often lacks real-time monitoring of vertical cell movement and systematically controlled chemotactic gradients, leading to contradictory results compared to those from clinical investigations and animal models. We addressed such challenges by developing a high-throughput microdevice with 4000 ultraminiaturized wells to monitor real-time, three-dimensional cell invasion over a wide range of cell densities and also screen drugs that inhibit cell invasion and potentially prevent metastatic malignancy. Additionally, this microdevice generates opposing gradients for two types of cells on the same chip, which builds a controlled system with sequentially changing components to study environmental effects from basal and immune cells. PMID- 25285915 TI - Effect of methylphenidate on height and weight in Korean children and adolescents with attention-deficit/hyperactivity disorder: a retrospective chart review. AB - OBJECTIVE: The purpose of this study was to investigate the effect of methylphenidate (MPH) on growth in Korean children and adolescents with attention deficit/hyperactivity disorder (ADHD). METHODS: The medical records of 157 subjects (mean age 8.9+/-2.2 years; 134 boys) with ADHD who received treatment with MPH for at least 1 year at the Department of Psychiatry at Asan Medical Center were retrospectively reviewed. Height and weight were prospectively obtained and retrospectively gathered. Height and weight were converted to age- and gender-corrected standard scores (z scores) using norms from the Korean population. Growth changes were analyzed from the starting to the end of treatment using random coefficients models with change in weight or height z score as the dependent variable. RESULTS: Weight (beta = -0.109, p<0.001) and height (beta = -0.072, p<0.001) z scores significantly decreased during treatment. Weight z score decreased more in girls (beta = -0.247, p<0.001) than in boys (beta = -0.090, p<0.001). Weight z score decreased during the 1st year of medication (beta = -0.327, p<0.001 for boys; beta = -0.646, p<0.001 for girls), and did not change or increase after the 1st year. Height z score significantly decreased during treatment (beta = -0.072, p<0.001) after controlling for the effect of age at treatment, gender, mean daily mg/kg dose, and comorbid depressive disorder. Height z score also decreased during the 1st year of medication (beta = -0.089, p<0.001) but did not change after the 1st year. CONCLUSIONS: These results suggest that MPH could be related to weight and height deficit in Korean children and adolescents, although the effects were minor, and disappeared after the 1st year. Because of the limitations of this study such as retrospective design, selection bias, and high attrition rate, further prospective studies are needed. PMID- 25285916 TI - Dissolution dominating calcification process in polar pteropods close to the point of aragonite undersaturation. AB - Thecosome pteropods are abundant upper-ocean zooplankton that build aragonite shells. Ocean acidification results in the lowering of aragonite saturation levels in the surface layers, and several incubation studies have shown that rates of calcification in these organisms decrease as a result. This study provides a weight-specific net calcification rate function for thecosome pteropods that includes both rates of dissolution and calcification over a range of plausible future aragonite saturation states (Omega(ar)). We measured gross dissolution in the pteropod Limacina helicina antarctica in the Scotia Sea (Southern Ocean) by incubating living specimens across a range of aragonite saturation states for a maximum of 14 days. Specimens started dissolving almost immediately upon exposure to undersaturated conditions (Omega(ar) ~ 0.8), losing 1.4% of shell mass per day. The observed rate of gross dissolution was different from that predicted by rate law kinetics of aragonite dissolution, in being higher at Omega(ar) levels slightly above 1 and lower at Omega(ar) levels of between 1 and 0.8. This indicates that shell mass is affected by even transitional levels of saturation, but there is, nevertheless, some partial means of protection for shells when in undersaturated conditions. A function for gross dissolution against Omega(ar) derived from the present observations was compared to a function for gross calcification derived by a different study, and showed that dissolution became the dominating process even at Omega(ar) levels close to 1, with net shell growth ceasing at an Omega(ar) of 1.03. Gross dissolution increasingly dominated net change in shell mass as saturation levels decreased below 1. As well as influencing their viability, such dissolution of pteropod shells in the surface layers will result in slower sinking velocities and decreased carbon and carbonate fluxes to the deep ocean. PMID- 25285917 TI - Investigation of climate change impact on water resources for an Alpine basin in northern Italy: implications for evapotranspiration modeling complexity. AB - Assessing the future effects of climate change on water availability requires an understanding of how precipitation and evapotranspiration rates will respond to changes in atmospheric forcing. Use of simplified hydrological models is required because of lack of meteorological forcings with the high space and time resolutions required to model hydrological processes in mountains river basins, and the necessity of reducing the computational costs. The main objective of this study was to quantify the differences between a simplified hydrological model, which uses only precipitation and temperature to compute the hydrological balance when simulating the impact of climate change, and an enhanced version of the model, which solves the energy balance to compute the actual evapotranspiration. For the meteorological forcing of future scenario, at-site bias-corrected time series based on two regional climate models were used. A quantile-based error correction approach was used to downscale the regional climate model simulations to a point scale and to reduce its error characteristics. The study shows that a simple temperature-based approach for computing the evapotranspiration is sufficiently accurate for performing hydrological impact investigations of climate change for the Alpine river basin which was studied. PMID- 25285918 TI - The hunt for protective correlates of immunity to Plasmodium falciparum malaria. AB - Determining an immunologic correlate of protection against Plasmodium falciparum malaria has been the holy grail of natural infection studies, and sought after as an endpoint for malaria vaccine trials. An in vitro assay that provides an accurate and precise assessment of protective immunity to malaria would make smaller, short-duration studies feasible, rather than the currently powered study designs that use morbidity or mortality as outcomes. Such a biomarker would be especially desirable in situations where malaria control measures that result in decreases in clinical endpoints and putatively waning protective immunity have been implemented. In an article published in BMC Medicine, Osier and colleagues addressed this problem, and demonstrated that antibodies promoting opsonic phagocytosis of merozoites provide a functional link between antigen-specific responses and protection. Understanding the mechanisms conferring protection against malaria not only improves our knowledge of basic human immunology, but promises to help in the design of an effective malaria vaccine. PMID- 25285919 TI - Molecular dynamics simulation of protein crystal with polarized protein-specific force field. AB - Two 250 ns molecular simulations have been carried out to study the structure and dynamics of crystal toxin protein II from the scorpion Androctonus australis Hector employing the polarized protein-specific charge (PPC), as well as the standard AMBER99SB force field, to investigate the electrostatic polarization on the simulated crystal stability. Results show that under PPC, the monomers in unit cell as well as the lattice in supercell are more stable with smaller root mean-square deviations and more accurate lattice atomic fluctuations compared with the crystallographic B-factors than under AMBER99SB force field. Most of the interactions at interfaces in the X-ray structure are quite well-preserved, underscoring the important effect of polarization on maintaining the crystal stability. However, the results also show that the hydrogen bond between Asp53 and Gln37 and the cation-pi interaction between Arg56 and His64 are not stable, indicating that further optimization of force field, especially the van der Waals interaction parameters, is desired. PMID- 25285920 TI - A gain-of-function mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family. PMID- 25285921 TI - IgE anti-LJM11 sand fly salivary antigen may herald the onset of fogo selvagem in endemic Brazilian regions. PMID- 25285925 TI - Who's buying? Who's selling? PMID- 25285922 TI - PKK suppresses tumor growth and is decreased in squamous cell carcinoma of the skin. AB - Non-melanoma skin cancer represents the most common cancer in the United States. Squamous cell carcinoma (SCC) of the skin is a subtype of NMSC that shows a greater potential for invasion and metastasis. The current study identifies the protein kinase C-associated kinase (PKK), which is also known as the receptor interacting protein kinase 4, as a suppressor of tumor growth in SCC of the skin. We show that expression of PKK is decreased in human SCC of the skin compared with normal skin. Further, suppression of PKK in human keratinocytes leads to increased cell proliferation. The use of RNA interference to reduce PKK expression in keratinocytes leads to an increase in S phase and in proteins that promote cell cycle progression. Consistent with the results obtained from cell culture, there is a marked increased tumorigenesis after PKK knockdown in a xenotransplant model and in soft agar assays. The loss of tumor suppression involves the NF-kappaB and p63 pathways. NF-kappaB is inhibited through inhibition of inhibitor of NF-kappaB kinase function and there is increased nuclear TP63 activity after PKK knockdown. This study opens new avenues both in the discovery of disease pathogenesis and for potential treatments. PMID- 25285926 TI - Thoughts on "human-centered veterinary medicine". PMID- 25285927 TI - What is your diagnosis? Noncoagulopathic spontaneous hemothorax. PMID- 25285928 TI - Diagnostic imaging in veterinary dental practice. PMID- 25285929 TI - Pathology in practice. Cryptococcus sp in a dog. PMID- 25285930 TI - Pathology in practice. Effusive FIP with fibrinous epicarditis in a cat. PMID- 25285931 TI - Factors that affect the supply price-quantity relationship. PMID- 25285932 TI - International survey of veterinarians to assess the importance of competencies in professional practice and education. AB - OBJECTIVE: To determine the perceived importance of specific competencies in professional veterinary practice and education among veterinarians in several countries. DESIGN: Survey-based prospective study. SAMPLE: 1,137 veterinarians in 10 countries. PROCEDURES: Veterinarians were invited via email to participate in the study. A framework of 18 competencies grouped into 7 domains (veterinary expertise, communication, collaboration, entrepreneurship, health and welfare, scholarship, and personal development) was used. Respondents rated the importance of each competency for veterinary professional practice and for veterinary education by use of a 9-point Likert scale in an online questionnaire. Quantitative statistical analyses were performed to assess the data. RESULTS: All described competencies were perceived as having importance (with overall mean ratings [all countries] >= 6.45/9) for professional practice and education. Competencies related to veterinary expertise had the highest ratings (overall mean, 8.33/9 for both professional practice and education). For the veterinary expertise, entrepreneurship, and scholarship domains, substantial differences (determined on the basis of statistical significance and effect size) were found in importance ratings among veterinarians in different countries. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated a general consensus regarding the importance of specific types of competencies in veterinary professional practice and education. Further research into the definition of competencies essential for veterinary professionals is needed to help inform an international dialogue on the subject. PMID- 25285933 TI - Association between oral health status and retrovirus test results in cats. AB - OBJECTIVE: To determine associations between oral health status and seropositivity for FIV or FeLV in cats. DESIGN: Cross-sectional survey. ANIMALS: 5,179 cats. PROCEDURES: Veterinarians at veterinary clinics and animal shelters completed online training on oral conditions in cats and then scored oral health status of cats with no known history of vaccination against FIV. Age, sex, and results of an ELISA for retroviruses were recorded. Results were analyzed by means of standard logistic regression with binary outcome. RESULTS: Of 5,179 cats, 237 (4.6%) and 186 (3.6%) were seropositive for FIV and FeLV, respectively, and of these, 12 (0.2%) were seropositive for FIV and FeLV. Of all 5,179 cats, 1,073 (20.7%) had gingivitis, 576 (11.1%) had periodontitis, 203 (3.9%) had stomatitis, and 252 (4.9%) had other oral conditions (overall oral disease prevalence, 2,104/5,179 [40.6%]). Across all age categories, inflammatory oral disease was associated with a significantly higher risk of a positive test result for FIV, compared with the seropositivity risk associated with other oral diseases or no oral disease. Stomatitis was most highly associated with risk of FIV seropositivity. Cats with any oral inflammatory disease were more likely than orally healthy cats to have a positive test result for FeLV. Increasing age was associated with a higher prevalence of oral disease in retrovirus-seronegative cats. CONCLUSIONS AND CLINICAL RELEVANCE: Inflammatory oral disease was associated with an increased risk of seropositivity for retroviruses in naturally infected cats. Therefore, retroviral status of cats with oral inflammatory disease should be determined and appropriate management initiated. PMID- 25285934 TI - Review of gunshot injuries in cats and dogs and utility of a triage scoring system to predict short-term outcome: 37 cases (2003-2008). AB - OBJECTIVE: To describe the signalment, wound characteristics, and treatment of gunshot injuries in cats and dogs in urban and rural environments, and to evaluate the utility of the animal trauma triage (ATT) score as an early predictor of survival to discharge from the hospital. DESIGN: Retrospective case series. ANIMALS: 29 dogs and 8 cats. PROCEDURES: Medical records of cats and dogs evaluated for gunshot wounds from 2003 and 2008 at a private urban referral practice in Cedar Rapids, Iowa, and an urban veterinary teaching hospital in Ames, Iowa, were reviewed. Information collected included signalment, chief reason for evaluation, circumstance of the injury, general physical examination findings, wound characteristics, treatments provided, cost of care, survival to discharge from the hospital (yes vs no), and duration of hospital stay. For each animal, ATT scores were calculated and evaluated as a prognostic tool. RESULTS: 37 animals met study inclusion criteria. Animals with higher ATT scores had a greater likelihood of poor outcome following gunshot injury. Animals with higher ATT scores, classified as low (< 4.5) or high (> 4.5), were found to have a longer duration of stay, classified as zero (0 days), short (1 to 3 days), or long (> 3 days). Young male dogs generally considered working breeds were overrepresented (29/37 [78.4%]). A preference for low-velocity, low-kinetic energy firearms was identified (19/37 [52%]). The most numerous wounds were those inflicted to the limbs (12/37 [32.4%]), during low-visibility hours or hunting excursions. Calculated ATT scores on admission were higher in animals requiring blood products or surgical procedures and in nonsurvivors. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggested that regional preferences in breed ownership and firearm choice are responsible for variation in gunshot injury characteristics and management in animals sustaining injuries in rural and urban settings in Iowa. In cats and dogs, calculation of an ATT score may provide a useful predictor of the need for surgery or blood products, duration of stay, and likelihood of survival to discharge from the hospital. PMID- 25285935 TI - Outcome and prognostic factors for osteosarcoma of the maxilla, mandible, or calvarium in dogs: 183 cases (1986-2012). AB - OBJECTIVE: To describe the biological behavior, clinical outcome, and prognostic factors of osteosarcoma of the maxilla, mandible, or calvarium in dogs. DESIGN: Retrospective case series. ANIMALS: 183 client-owned dogs with osteosarcoma of the maxilla, mandible, or calvarium. PROCEDURES: Medical records for dogs treated for osteosarcoma of the maxilla, mandible, or calvarium from 1986 through 2012 were reviewed. Dogs with a histopathologic diagnosis of osteosarcoma and treated for a primary tumor arising from these bones of the head were included. RESULTS: Mean age was 9.3 years, and body weight was 31.8 kg (70.0 lb). Most dogs (124/183 [67.8%]) were purebred, and the most common primary tumor site was the maxilla (80 [43.7%]). Treatments included palliative medical treatment only (11/183 [6.0%]), coarsely fractionated radiation therapy (RT; 12 [6.6%]), fractionated or stereotactic RT (18 [9.8%]), surgery (135 [73.8%]), and both surgery and fractionated RT (7 [3.8%]). Eighty-three (45.4%) dogs received adjuvant chemotherapy. Local recurrence or progression occurred in 80 of 156 (51.3%) dogs, and 60 of 156 (38.5%) dogs developed distant metastases. Median survival time for all dogs was 239 days. Dogs that underwent surgery had a median survival time of 329 days. Histologically tumor-free surgical margins were associated with significantly decreased hazards of progression or recurrence (hazard ratio [HR], 0.4) and death (HR, 0.5). Dogs with osteosarcoma of the calvarium had a significantly greater hazard of local recurrence or progression (HR, 2.0). CONCLUSIONS AND CLINICAL RELEVANCE: In this study, tumor excision in dogs with histologically tumor-free margins resulted in better local control and longer survival time than did other treatment types. PMID- 25285936 TI - Ultrasonographic visualization of the liver in sites recommended for blind percutaneous liver biopsy in horses. AB - OBJECTIVE: To ascertain the frequency of ultrasonographic identification of liver at sites recommended for blind percutaneous liver biopsy in middle-aged horses and to determine whether the liver is obscured by other organs or too thin for safe sample collection at recommended locations. DESIGN: Prospective case series. ANIMALS: 36 healthy middle-aged (between 3 and 18 years old) Quarter Horses or Quarter Horse crosses [Corrected]. PROCEDURES: Blood samples were collected from each horse and submitted for evaluation of liver function. Horses with any indication of liver dysfunction on serum biochemical analysis were excluded. The region just below a line drawn between the dorsal aspect of the tuber coxae and the point of the elbow joint in the right 11th, 12th, 13th, and 14th intercostal spaces (ICSs) was imaged by ultrasonography for the presence of liver. In each ICS, liver thickness and whether there was partial obstruction in viewing the liver caused by other abdominal or thoracic organs were recorded. RESULTS: 39% (14/36) of horses had liver imaged on ultrasonographic examination in all of the 11th to 14th ICSs. None of the 36 horses had liver of adequate thickness (ie, liver thickness >= 3.5 cm) for biopsy in all of the imaged ICSs. For 22 horses in which the liver was not visible on ultrasonographic examination of an ICS, lung was imaged instead in 12 (55%) horses, intestine in 8 (36%), and both intestine and lung in 2 (9%). CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of the results of this study, the practice of blind percutaneous liver biopsy in horses is not recommended because of the risk of serious complications. PMID- 25285937 TI - Comparison of a single dose of moxidectin and a five-day course of fenbendazole to reduce and suppress cyathostomin fecal egg counts in a herd of embryo transfer recipient mares. AB - OBJECTIVE: To compare larvicidal regimens of fenbendazole and moxidectin for reduction and suppression of cyathostomin fecal egg counts (FEC) in a transient herd of embryo transfer-recipient mares. DESIGN: Randomized, complete block, clinical trial. ANIMALS: 120 mares from 21 states, residing on 1 farm. PROCEDURES: An initial fecal sample was collected from each mare; mares with an FEC >= 200 eggs/g were assigned to treatment groups. Eighty-two horses received fenbendazole (10.0 mg/kg [4.5 mg/lb], PO, q 24 h for 5 days) or moxidectin (0.4 mg/kg [0.18 mg/lb], PO, once); FEC data were analyzed 14, 45, and 90 days after treatment. RESULTS: Mean FEC reduction was 99.9% for moxidectin-treated mares and 41.9% for fenbendazole-treated mares 14 days after treatment. By 45 days, mean FEC of fenbendazole-treated mares exceeded pretreatment counts; however, FECs of moxidectin-treated mares remained suppressed below pretreatment values for the duration of the 90-day study. Fecal egg counts were significantly different between groups at 14, 45, and 90 days after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Failure of the 5-day regimen of fenbendazole to adequately reduce or suppress FEC suggested inadequate adulticidal and larvicidal effects. In contrast, a single dose of moxidectin effectively reduced and suppressed FEC for an extended period. Given the diverse geographic origins of study mares, these results are likely representative of cyathostomin-infected mares in much of the United States, confirming previous findings indicating that fenbendazole resistance in cyathostomins is widespread and that moxidectin remains an effective treatment for control of these important parasites. PMID- 25285938 TI - High prevalence of metallo-beta-lactamase among carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China. AB - The aim of this study was to characterize the carbapenemases in carbapenem resistant Klebsiella pneumoniae (CR-KP) from a Chinese teaching hospital. A total of 40 CR-KPs were screened for the presence of carbapenemases. Minimum inhibitory concentrations were determined by agar dilution. The modified Hodge test was used for the detection of carbapenemase production. Carbapenemase, extended-spectrum beta-lactamase, and AmpC genes were detected using polymerase chain reaction (PCR) and sequencing. A conjugation test was performed using a broth culture mating method, transferred plasmids were typed by PCR-based replicon typing, and clonal relatedness was investigated by enterobacterial repetitive intergenic consensus sequences PCR (ERIC-PCR) and multilocus sequence typing (MLST). The results revealed that modified Hodge test was positive for 28 CR-KPs, and CR-KPs exhibited high resistance rates against various antibiotics, except colistin (5.0%) and tigecycline (22.5%). ERIC and MLST profiles showed no clonal outbreak. PCR demonstrated a high prevalence rate (55.0%, 22/40) of metallo-beta-lactamases (MBLs) in CR-KPs. IMP-4, IMP-8, NDM-1, and KPC-2 were identified in 14 (35.0%), 7 (17.5%), 2 (5.0%), and 7 (17.5%) isolates, respectively. Notably, 2 CR-KPs coproduced 2 carbapenemases simultaneously (IMP-8/NDM-1 and IMP-4/KPC-2). In vitro transfer of carbapenem resistance was successful for 11 MBL-producing CR KPs. The extended spectrum beta-lactamase genes were detected in 30 (75.0%) of these CR-KPs. To the best of our knowledge, this is the first report focusing on carbapenem resistance in K. pneumoniae due to metalloenzymes in China. Screening and surveillance of MBLs in Enterobacteriaceae is urgently needed in this region to control and prevent the spread of these resistance determinants. PMID- 25285939 TI - Planar chiral phosphoric acids with biphenylene-tethered paracyclophane scaffolds: synthesis, characterization, and catalytic screening. AB - Phosphoric acids with planar chiral paracyclophane scaffolds have been prepared in optically pure form starting from 1,8-dibromobiphenylene, by means of a chiral phosphorodiamidate as the phosphorylating agent. Structural characterization and configurational assignment have been performed by X-ray diffraction studies. The acids promote the organocatalytic enantioselective H-transfer reduction of alpha arylquinolines with up to 90% enantiomeric excess. PMID- 25285940 TI - First report of human Trypanosoma cruzi infection attributed to TcBat genotype. AB - Chagas disease is an endemic disease of the American continent caused by Trypanosoma cruzi and divided into six discrete typing units (TcI - TcVI). Nearly 10 million people harbour the infection representing a serious issue in public health. Epidemiological surveillance allowed us to detect a bat-related T. cruzi genotype (henceforth named TcBat) in a 5-year-old female living in a forest area in northwestern Colombia. Molecular tools determined a mixed infection of T. cruzi I and TcBat genotypes. This represents the first report of TcBat infection in humans; the epidemiological consequences of this finding are discussed herein. PMID- 25285941 TI - Ongoing activity of Toscana virus genotype A and West Nile virus lineage 1 strains in Turkey: a clinical and field survey. AB - Toscana virus (TOSV), West Nile virus (WNV) and tickborne encephalitis virus (TBEV) are among major viral pathogens causing febrile disease and meningitis/encephalitis. The impact of these viruses was investigated at a referral centre in Ankara Province, Central Anatolia in 2012, where previous reports suggested virus circulation but with scarce information on clinical cases and vector activity. Serum and/or cerebrospinal fluid samples from 94 individuals were evaluated, in addition to field-collected arthropod specimens that included 767 sandflies and 239 mosquitoes. Viral nucleic acids in clinical samples and arthropods were sought via specific and generic nested/real-time PCRs, and antibody responses in clinical samples were investigated via commercial indirect immunofluorescence tests (IIFTs) and virus neutralization. A WNV antigen assay was also employed for mosquitoes. WNV neuroinvasive disease has been identified in a 63-year-old male via RNA detection, and the WNV strain was characterized as lineage 1. TOSV infections were diagnosed in six individuals (6.3%) via RNA or IgM detection. Partial sequences in a 23-year-old female, presented with fever and transient pancytopenia, were characterized as TOSV genotype A. Febrile disease with arthralgia and/or peripheral cranial nerve involvement was noted in cases with TOSV infections. Previous WNV and TOSV exposures have been observed in 5.3% and 2.1% of the subjects, respectively. No confirmed TBEV exposure could be identified. Morphological identification of the field-collected mosquitoes revealed Culex pipiens sensu lato (74.4%), Anopheles maculipennis (20.9%), An. claviger (2.1%) and others. Sandfly species were determined as Phlebotomus papatasi (36.2%), P. halepensis (27.3%), P. major s. l. (19.3%), P. sergenti (8.9%), P. perfiliewi (4.4%), P. simici (2.6%) and others. Viral infections in arthropods could not be demonstrated. TOSV genotype A and WNV lineage 1 activity have been demonstrated as well as serologically proven exposure in patients. Presence of sandfly and mosquito species capable of virus transmission has also been revealed. PMID- 25285944 TI - Fabrication of folate bioconjugated near-infrared fluorescent silver nanoclusters for targeted in vitro and in vivo bioimaging. AB - Thiolpolyethyleneimine stabilized silver nanoclusters (SH-PEI-AgNCs) with intense NIR fluorescence and chemical stability were fabricated in aqueous solution. The SH-PEI-AgNCs were subsequently bioconjugated with folate for targeted in vitro and in vivo bioimaging. PMID- 25285942 TI - Effect of potent gamma-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. AB - IMPORTANCE: Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells. OBJECTIVE: To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of gamma-secretase inhibitor and gamma-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L). DESIGN, SETTING, AND PARTICIPANTS: Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with gamma-secretase inhibitor or GSM. Comparisons of total beta-amyloid (Abeta) and Abeta peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures. MAIN OUTCOMES AND MEASURES: Soluble Abeta levels in the media were measured by enzyme-linked immunosorbent assay. RESULTS: As predicted, mutant PS1 neurons exhibited an elevated Abeta42:Abeta40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Abeta42, Abeta40, and Abeta38 and in the Abeta42:Abeta40 ratio, with no change in the total Abeta levels. CONCLUSIONS AND RELEVANCE: This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment. PMID- 25285945 TI - Paired whole cell recordings in organotypic hippocampal slices. AB - Pair recordings involve simultaneous whole cell patch clamp recordings from two synaptically connected neurons, enabling not only direct electrophysiological characterization of the synaptic connections between individual neurons, but also pharmacological manipulation of either the presynaptic or the postsynaptic neuron. When carried out in organotypic hippocampal slice cultures, the probability that two neurons are synaptically connected is significantly increased. This preparation readily enables identification of cell types, and the neurons maintain their morphology and properties of synaptic function similar to that in native brain tissue. A major advantage of paired whole cell recordings is the highly precise information it can provide on the properties of synaptic transmission and plasticity that are not possible with other more crude techniques utilizing extracellular axonal stimulation. Paired whole cell recordings are often perceived as too challenging to perform. While there are challenging aspects to this technique, paired recordings can be performed by anyone trained in whole cell patch clamping provided specific hardware and methodological criteria are followed. The probability of attaining synaptically connected paired recordings significantly increases with healthy organotypic slices and stable micromanipulation allowing independent attainment of pre- and postsynaptic whole cell recordings. While CA3-CA3 pyramidal cell pairs are most widely used in the organotypic slice hippocampal preparation, this technique has also been successful in CA3-CA1 pairs and can be adapted to any neurons that are synaptically connected in the same slice preparation. In this manuscript we provide the detailed methodology and requirements for establishing this technique in any laboratory equipped for electrophysiology. PMID- 25285946 TI - 49 Mathoura Road: Geoffrey Kaye's letters to Paul M. Wood, 1939-1955. AB - From 1930 to 1955, Geoffrey Kaye, M.B.B.S., was one of the most influential anesthetists in Australia. In 1951, he opened a center of excellence for Australian anesthesia at 49 Mathoura Road, Toorak, Melbourne, which Kaye affectionately called "The Anaesthestists' Castle" and "49." "49" was designed to foster the educational, research, and administrative activities that would allow Australian anesthesia to reach the level of practice and professionalism found in Europe and America. Kaye wholly financed the venture and lived on the second floor of the building. During his world-wide travels, Kaye had developed a friendship with Paul M. Wood, M.D., the originator of the American Library-Museum now known eponymously as the Wood Library-Museum of Anesthesiology. Through the letters Kaye sent to Wood, the authors see Kaye's perception of the events surrounding the rise and fall of "49." Kaye's early letters were optimistic as he discussed the procurements and provisions he made for "49." His later letters exhibit frustration at the lack of participation by members of the Australian Society of Anaesthetists. Kaye was truly a visionary for his time. He believed that the diffusion center which "49" was to become was not only realistic and achievable but also necessary if Australian anesthesia was to gain international prominence comparable to anesthesia in Europe and North America. In the end, the failure of "49" left Kaye estranged from Australian anesthesia for many years. How this estrangement affected Australian anesthesia is unknown. PMID- 25285947 TI - p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder. AB - BACKGROUND: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 +/- 4.5 mV to -30.9 +/- 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 +/- 5.6 ms to 2.2 +/- 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD. PMID- 25285948 TI - Leukocyte Toll-like receptor 2-mitochondria axis in sepsis: unraveling immune response sophistication. PMID- 25285949 TI - Images in anesthesiology: bedside lung ultrasonography: a tool for rapid assessment of pneumothorax. PMID- 25285950 TI - Be able, available, and especially affable if you want team success. PMID- 25285953 TI - Delayed introduction of tacrolimus postliver transplant with intravenous mycophenolate mofetil preserves renal function without incurring rejection. PMID- 25285951 TI - Pro-inflammatory cytokines reduce the proliferation of NG2 cells and increase shedding of NG2 in vivo and in vitro. AB - Neuron glial 2 (NG2) cells become strongly activated in injured brain areas. The activation is characterized by increased proliferation as well as increased expression and shedding of the proteoglycan NG2 expressed on their cell surface. It is currently not known how these cells respond to low-grade neuroinflammation provoked by systemic inflammation. To investigate this, we analyzed NG2 cell proliferation as well as soluble NG2 (sNG2) in cerebrospinal fluid (CSF) from rats treated with an acute intraperitoneal (i.p) injection of lipopolysaccharides (LPS) or saline and sacrificed after 2 or 24 hours. The systemically induced neuroinflammation was confirmed as elevated levels of cytokines, including interleukin (IL)-6 and IL-1beta, and MHCII expressing microglia were found 24 h after LPS treatment. At this time point NG2 cell proliferation was significantly decreased in both amygdala and hippocampus and sNG2 levels in CSF were increased twofold. We also exposed human NG2 cells in culture to IL-6 and IL-1beta for 24 h and found, in line with our in vivo study, a direct impact of these cytokines reducing cell proliferation and increasing shedding of NG2. We conclude that LPS induced systemic inflammation significantly affects NG2 cell proliferation and shedding and that these two events at least in in part are mediated by IL-6 and IL-1beta. PMID- 25285954 TI - Incidence of non-Hodgkin lymphomas and the ten most commonly diagnosed cancers after heart transplantation: a nationwide population-based study in Taiwan. PMID- 25285955 TI - Medication regimen complexity in kidney and liver transplant recipients. PMID- 25285956 TI - Belatacept maintenance in a heart transplant recipient. PMID- 25285957 TI - Successful rescue of transplant ureteral obstruction by Boari flap. PMID- 25285958 TI - Short hairpin RNA library-based functional screening identified ribosomal protein L31 that modulates prostate cancer cell growth via p53 pathway. AB - Androgen receptor is a primary transcription factor involved in the proliferation of prostate cancer cells. Thus, hormone therapy using antiandrogens, such as bicalutamide, is a first-line treatment for the disease. Although hormone therapy initially reduces the tumor burden, many patients eventually relapse, developing tumors with acquired endocrine resistance. Elucidation of the molecular mechanisms underlying endocrine resistance is therefore a fundamental issue for the understanding and development of alternative therapeutics for advanced prostate cancer. In the present study, we performed short hairpin RNA (shRNA) mediated functional screening to identify genes involved in bicalutamide-mediated effects on LNCaP prostate cancer cells. Among such candidate genes selected by screening using volcano plot analysis, ribosomal protein L31 (RPL31) was found to be essential for cell proliferation and cell-cycle progression in bicalutamide resistant LNCaP (BicR) cells, based on small interfering RNA (siRNA)-mediated knockdown experiments. Of note, RPL31 mRNA is more abundantly expressed in BicR cells than in parental LNCaP cells, and clinical data from ONCOMINE and The Cancer Genome Altas showed that RPL31 is overexpressed in prostate carcinomas compared with benign prostate tissues. Intriguingly, protein levels of the tumor suppressor p53 and its targets, p21 and MDM2, were increased in LNCaP and BicR cells treated with RPL31 siRNA. We observed decreased degradation of p53 protein after RPL31 knockdown. Moreover, the suppression of growth and cell cycle upon RPL31 knockdown was partially recovered with p53 siRNA treatment. These results suggest that RPL31 is involved in bicalutamide-resistant growth of prostate cancer cells. The shRNA-mediated functional screen in this study provides new insight into the molecular mechanisms and therapeutic targets of advanced prostate cancer. PMID- 25285960 TI - Communication patterns in audiologic rehabilitation history-taking: audiologists, patients, and their companions. AB - OBJECTIVES: The nature of communication between patient and practitioner influences patient outcomes. Specifically, the history-taking phase of a consultation plays a role in the development of a relationship and in the success of subsequent shared decision making. There is limited research investigating patient-centered communication in audiology, and this study may be the first to investigate verbal communication in an adult audiologic rehabilitation context. This research aimed, first, to describe the nature of verbal communication involving audiologists, patients, and companions in the history-taking phase of initial audiology consultations and, second, to determine factors associated with communication dynamics. DESIGN: Sixty-three initial audiology consultations involving patients over the age of 55, their companions when present, and audiologists were audio-video recorded. Consultations were coded using the Roter Interaction Analysis System and divided into three consultation phases: history, examination, and counseling. This study analyzed only the history-taking phase in terms of opening structure, communication profiles of each speaker, and communication dynamics. Associations between communication dynamics (verbal dominance, content balance, and communication control) and 11 variables were evaluated using Linear Mixed Model methods. RESULTS: The mean length of the history-taking phase was 8.8 min (range 1.7 to 22.6). A companion was present in 27% of consultations. Results were grouped into three areas of communication: opening structure, information exchange, and relationship building. Examination of the history opening structure revealed audiologists' tendency to control the agenda by initiating consultations with a closed-ended question 62% of the time, followed by interruption of patient talk after 21.3 sec, on average. The aforementioned behaviors were associated with increased verbal dominance throughout the history and increased control over the content of questions. For the remainder of the history, audiologists asked 97% of the questions and did so primarily in closed-ended form. This resulted in the audiologist talking as much as the patient and much more than the companions when they were present. Questions asked by the audiologist were balanced in topic: biomedical and psychosocial/lifestyle; however, few emotionally focused utterances were observed from any speaker (less than 5% of utter ances). CONCLUSIONS: Analysis of verbal communication involving audiologists, patients, and companions in the history taking phase in 63 initial audiology consultations revealed a communicative exchange that was audiologist-controlled and structured, but covered both medical and lifestyle content. Audiologists often attempted to create a relationship with their patients; however, little emotional relationship building occurred, which may have implications later in the consultation when management decisions are being made. These results are not in line with patient-centered communication principles. Further research and changes to clinical practice are warranted to transform patient-centered communication from an ideal to a reality. PMID- 25285959 TI - Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding. AB - To predict structural and energetic effects of point mutations on ligand binding is of considerable interest in biochemistry and pharmacology. This is not only useful in connection with site-directed mutagenesis experiments, but could also allow interpretation and prediction of individual responses to drug treatment. For G-protein coupled receptors systematic mutagenesis has provided the major part of functional data as structural information until recently has been very limited. For the pharmacologically important A(2A) adenosine receptor, extensive site-directed mutagenesis data on agonist and antagonist binding is available and crystal structures of both types of complexes have been determined. Here, we employ a computational strategy, based on molecular dynamics free energy simulations, to rationalize and interpret available alanine-scanning experiments for both agonist and antagonist binding to this receptor. These computer simulations show excellent agreement with the experimental data and, most importantly, reveal the molecular details behind the observed effects which are often not immediately evident from the crystal structures. The work further provides a distinct validation of the computational strategy used to assess effects of point-mutations on ligand binding. It also highlights the importance of considering not only protein-ligand interactions but also those mediated by solvent water molecules, in ligand design projects. PMID- 25285962 TI - Formation and stability of C6H3+ isomers. AB - The stability of the five main isomers of C6H3(+) was investigated using quantum chemical calculations. The cyclic isomers are stabilized by two complementary aromatic effects, first 6-electron pi aromaticity, and second a more unusual three-center two-electron sigma aromaticity. Two cyclic isomers sit at the bottom of the potential energy surface with energies very close to each other, with a third cyclic isomer slightly higher. The reaction barriers for the interconversion of these isomers, as well as to convert to low-energy linear isomers, are found to be very high with transition states that break both the pi and the sigma aromaticities. Finally, possibilities for forming the cyclic isomers via association reactions are discussed. PMID- 25285961 TI - Synchrony of maternal auditory and visual cues about unknown words to children with and without cochlear implants. AB - OBJECTIVES: The purpose of this study was to compare types of maternal auditory visual input about word referents available to children with cochlear implants, children with normal hearing matched for age, and children with normal hearing matched for vocabulary size. Although other works have considered the acoustic qualities of maternal input provided to children with cochlear implants, this study is the first to consider auditory-visual maternal input provided to children with cochlear implants. DESIGN: Participants included 30 mother-child dyads from three groups: children who wore cochlear implants (n = 10 dyads), children matched for chronological age (n = 10 dyads), and children matched for expressive vocabulary size (n = 10 dyads). All participants came from English speaking families, with the families of children with hearing loss committed to developing listening and spoken language skills (not sign language). All mothers had normal hearing. Mother-child interactions were video recorded during mealtimes in the home. Each dyad participated in two mealtime observations. Maternal utterances were transcribed and coded for (a) nouns produced, (b) child directed utterances, (c) nouns unknown to children per maternal report, and (d) auditory and visual cues provided about referents for unknown nouns. Auditory and visual cues were coded as either converging, diverging, or auditory-only. RESULTS: Mothers of children with cochlear implants provided percentages of converging and diverging cues that were similar to the percentages of mothers of children matched for chronological age. Mothers of children matched for vocabulary size, on the other hand, provided a higher percentage of converging auditory-visual cues and lower percentage of diverging cues than did mothers of children with cochlear implants. Groups did not differ in provision of auditory only cues. CONCLUSIONS: The present study represents the first step toward identification of environmental input characteristics that may affect lexical learning outcomes of children with cochlear implants. Given that children with cochlear implants demonstrate slower rates of lexical growth than children with normal hearing, the findings from this study provide an important direction for further investigation of how environmental factors affect lexical outcomes for this population. If mothers can provide auditory and visual cues to increase the salience of a relevant object in word-learning contexts, they may be able to facilitate the language growth of their children. PMID- 25285963 TI - Quantum dot labelling of adenovirus allows highly sensitive single cell flow and imaging cytometry. AB - A quantum dot method for highly efficient labelling of single adenoviral particles is developed. The technique has no impact on viral fitness and allows the imaging and tracking of virus binding and internalisation events using a variety of techniques including imaging cytometry and confocal microscopy. The method is applied to characterise the tropism of different adenoviral vectors. PMID- 25285964 TI - Systematic proteomic approach to characterize the impacts of chemical interactions on protein and cytotoxicity responses to metal mixture exposures. AB - Chemical interactions have posed a big challenge in toxicity characterization and human health risk assessment of environmental mixtures. To characterize the impacts of chemical interactions on protein and cytotoxicity responses to environmental mixtures, we established a systems biology approach integrating proteomics, bioinformatics, statistics, and computational toxicology to measure expression or phosphorylation levels of 21 critical toxicity pathway regulators and 445 downstream proteins in human BEAS-2B cells treated with 4 concentrations of nickel, 2 concentrations each of cadmium and chromium, as well as 12 defined binary and 8 defined ternary mixtures of these metals in vitro. Multivariate statistical analysis and mathematical modeling of the metal-mediated proteomic response patterns showed a high correlation between changes in protein expression or phosphorylation and cellular toxic responses to both individual metals and metal mixtures. Of the identified correlated proteins, only a small set of proteins including HIF-1alpha is likely to be responsible for selective cytotoxic responses to different metals and metals mixtures. Furthermore, support vector machine learning was utilized to computationally predict protein responses to uncharacterized metal mixtures using experimentally generated protein response profiles corresponding to known metal mixtures. This study provides a novel proteomic approach for characterization and prediction of toxicities of metal and other chemical mixtures. PMID- 25285966 TI - Multiple numeric competencies: When a number is not just a number. AB - A growing body of evidence demonstrates the practical and theoretical importance of numeracy in evaluations and choices involving numeric information, an importance that goes beyond simple accuracy in performing mathematical computations. Numeric competency, however, may be multiply determined, but little research has examined potentially separable influences in evaluations and choice. In the present article, we describe 3 numeric competencies and begin to disentangle their effects. Participants (N = 111) completed a series of tasks in 4 1-hr sessions. We first examined relations between objective numeracy, subjective numeracy, and symbolic-number mapping abilities (thought to tap into internal representations of numeric magnitude and the mapping of symbolic numbers onto those representations) using a structural equation model. We then explored their dissociations in numeric and nonnumeric tasks. Higher vs. lower scores in objective numeracy were associated with explicit number operations, including number comparisons and calculations. Those with more vs. less exact mapping had better numeric memory (but not nonnumeric) and produced valuations that were closer to (but did not equal) a risky gamble's expected value, indicating a link with superior number intuitions. Finally, individuals lower vs. higher in subjective numeracy had more negative emotional reactions to numbers and were less motivated and/or confident in numeric tasks. It was less clear whether subjective numeracy might also relate to more general motivations and metacognitions involving nonnumeric information. We conclude that numeric competencies should be used in a more targeted fashion to understand their multiple mechanisms in people's evaluations, choices, and life outcomes. PMID- 25285965 TI - Child characteristics and parental educational expectations: evidence for transmission with transaction. AB - Parents' expectations for their children's ultimate educational attainment have been hypothesized to play an instrumental role in socializing academically relevant child behaviors, beliefs, and abilities. In addition to social transmission of educationally relevant values from parents to children, parental expectations and child characteristics may transact bidirectionally. We explore this hypothesis using both longitudinal and genetically informative twin data from the Early Childhood Longitudinal Study-Birth and Kindergarten cohorts. Our behavior genetic results indicate that parental expectations partly reflect child genetic variation, even as early as 4 years of age. Two classes of child characteristics were hypothesized to contribute to these child-to-parent effects: behavioral tendencies (approaches toward learning and problem behaviors) and achievement (math and reading). Using behavior genetic models, we find within twin-pair associations between these child characteristics and parental expectations. Using longitudinal cross-lagged models, we find that initial variation in child characteristics predicts future educational expectations above and beyond previous educational expectations. These results are consistent with transactional frameworks in which parent-to-child and child-to-parent effects co occur. PMID- 25285967 TI - Wherever I may roam: Processes of self-esteem development from adolescence to emerging adulthood in the context of international student exchange. AB - Previous studies on self-esteem development show substantial changes as well as interindividual differences in change from adolescence to young adulthood. However, the processes underlying these developmental trajectories are still not well understood. The aim of the present study was to shed light on the macro- and microprocesses of self-esteem development. We investigated a sample of 876 German high school students (M = 16.0 years at Time 1) participating in an international exchange year. Exchange students provided 3 waves of trait self-esteem data (shortly before they departed, immediately after return, and 1 year later), as well as 9 monthly state measures of self-esteem and social inclusion during their stay abroad. In addition, a control group of high school students who stayed in Germany (N = 714) provided 2 waves of trait self-esteem data. From a macroperspective, results showed an effect of student exchange on trait self esteem development: Exchange students showed a steeper mean-level increase and a lower rank-order stability compared with control students. Zooming in on the microprocesses underlying these developmental patterns, we found trait changes in exchange students to be mediated by state changes in self-esteem during their exchange. These fluctuations in state self-esteem were found to be predicted by feelings of social inclusion in the host country, and vice versa, providing support for both sociometer and self-broadcasting perspectives on self-esteem dynamics. In sum, our findings emphasize the importance of incorporating a microanalytical approach when investigating self-esteem development by showing that the environment triggers changes in this relatively stable personality trait through changes in states. PMID- 25285968 TI - Introduction to the supplement: clinical aspects of occupational and environmental lung disease. PMID- 25285969 TI - Military service and lung disease. AB - OBJECTIVE: Lung diseases associated with military service are often a reflection of the conditions seen in the local civilian population, and with a few notable exceptions, are often related to unique environmental and occupational exposures. METHODS: This article reviews important pulmonary diseases that have been associated with military service in the past 100 years in a question-and-answer format. RESULTS: Traditionally, bacterial and viral pneumonias were the most common sources of military morbidity and mortality. With improved preventive medicine and antimicrobial therapy, other diseases related to battlefield injuries or inhalational exposures have assumed greater importance. CONCLUSIONS: The etiology of military morbidity and mortality has evolved over the past century. Many of the discoveries related to vaccine efficacy, trauma resuscitation, interstitial lung disease, and even carcinomas have a strong military association. PMID- 25285970 TI - Respiratory diseases caused by coal mine dust. AB - OBJECTIVE: To provide an update on respiratory diseases caused by coal mine dust. METHODS: This article presents the results of a literature review initially performed for an International Conference on Occupational and Environmental Lung Disease held in summer 2013. RESULTS: Coal mine dust causes a spectrum of lung diseases collectively termed coal mine dust lung disease (CMDLD). These include Coal Workers' Pneumoconiosis, silicosis, mixed dust pneumoconiosis, dust-related diffuse fibrosis (which can be mistaken for idiopathic pulmonary fibrosis), and chronic obstructive pulmonary disease. CMDLD continues to be a problem in the United States, particularly in the central Appalachian region. Treatment of CMDLD is symptomatic. Those with end-stage disease are candidates for lung transplantation. Because CMDLD cannot be cured, prevention is critical. CONCLUSIONS: Coal mine dust remains a relevant occupational hazard and miners remain at risk for CMDLD. PMID- 25285972 TI - Outdoor air pollution: a global perspective. AB - Although the air quality in Western countries has continued to improve over the past decades, rapid economic growth in developing countries has left air quality in many cities notoriously poor. The World Health Organization estimates that urban outdoor air pollution is estimated to cause 1.3 million deaths worldwide per year. The primary health concerns of outdoor air pollution come from particulate matter less than 2.5 MUm (PM2.5) and ozone (O3). Short-term exposure to PM2.5 increases cardiopulmonary morbidity and mortality. Long-term exposure to PM2.5 has been linked to adverse perinatal outcomes and lung cancer. Excessive O3 exposure is known to increase respiratory morbidity. Patients with chronic cardiopulmonary diseases are more susceptible to the adverse effects of air pollution. Counseling these patients about air pollution and the associated risks should be part of the regular management plans in clinical practice. PMID- 25285971 TI - Performing a lung disability evaluation: how, when, and why? AB - OBJECTIVES: The objective of this review is to present a case-based clinical discussion on this topic. METHODS: The article represents part of the proceedings of the Occupational and Environmental Lung Disease conference held by the American College of Chest Physicians at Toronto, Ontario, Canada, in 2013, and is based upon a nonsystematic review of the current literature by the author. RESULTS: Although the American Medical Association Guides to the Evaluation of Permanent Impairment is the mainstay for evaluating respiratory impairment, many other impairment schemata are currently available in the United States. Impairment evaluation for a case with chronic respiratory disease and a separate case with asthma is discussed. CONCLUSIONS: Pulmonary function tests are the cornerstone for evaluating respiratory impairment. Impairment values differ between various impairment schemata. Impairment evaluation for asthma may be particularly difficult. PMID- 25285973 TI - Obstructive sleep apnea and World Trade Center exposure. AB - OBJECTIVES: To describe the proportion of at-risk World Trade Center (WTC) exposed rescue/recovery workers with polysomnogram-confirmed obstructive sleep apnea (OSA) and examine the relationship between WTC exposure, physician diagnosed gastroesophageal reflux disease (GERD), and rhinosinusitis and OSA. METHODS: A total of 636 male participants completed polysomnography from September 24, 2010, to September 23, 2012. Obstructive sleep apnea was classified as mild, moderate, or severe. Associations were tested using nominal polytomous logistic regression. RESULTS: Eighty-one percent of workers were diagnosed with OSA. Using logistic regression models, severe OSA was associated with WTC exposure on September 11, 2001 (odds ratio, 1.91; 95% confidence interval, 1.15 to 3.17), GERD (odds ratio, 2.75; 95% confidence interval, 1.33 to 5.70), and comorbid GERD/rhinosinusitis (odds ratio, 2.31; 95% confidence interval, 1.22 to 4.40). CONCLUSIONS: We found significant associations between severe OSA and WTC exposure, and with diseases prevalent in this population. Accordingly, we recommend clinical evaluation, including polysomnography, for patients with high WTC exposure, other OSA risk factors, and a physician diagnosis of GERD or comorbid GERD and rhinosinusitis. PMID- 25285974 TI - Silica exposure and silicosis in Alberta, Canada. AB - OBJECTIVES: To study potential exposures to crystalline silica and the number of work-related cases of silicosis occurring in Alberta. METHODS: Exposure data comprising 343 occupational samples were collected at 40 worksites across 13 industries. To assess silicosis reporting, cases reported to the Alberta government, claims accepted by the Workers' Compensation Board for work-related silicosis, and billings to Alberta Health for medical services with a diagnostic code for silicosis during a similar time period were compared. RESULTS: Workers potentially over-exposed to airborne respirable crystalline silica were identified at most of the worksites evaluated. There were large discrepancies in the number of silicosis cases found. CONCLUSIONS: Many Alberta workers may be over-exposed to airborne respirable crystalline silica, and the incidence of work related silicosis in Alberta may not be adequately represented by the official statistics. PMID- 25285975 TI - Clinical aspects of work-related asthma: past achievements, persistent challenges, and emerging triggers. AB - OBJECTIVE: The aim of this article was to address common clinical questions pertaining to work-related asthma (WRA). METHODS: This review is based on a presentation on WRA at the American College of Chest Physicians Course on Clinical Aspects of Occupational and Environmental Lung Disease, held in Toronto in 2013, and supplemented by a PubMed search of publications to 2013. RESULTS: Seven clinical questions are addressed in relation to definitions, causes, diagnosis, management and emerging triggers, and challenges of WRA. CONCLUSIONS: Although knowledge is expanding in this area, there remain challenges and uncertainties, particularly in the prevention of WRA. PMID- 25285976 TI - Advanced diagnostic studies: exhaled breath and sputum analyses. AB - AIM: : The present paper aims to review the advantages and limitations of sputum cell counts and exhaled nitric oxide (FeNO) levels in the investigation of occupational asthma (OA). METHODS: The American College of Chest physicians held a course on occupational and Environmental Lung Diseases in Toronto in 2013. A summary of the session on non-invasive measures of airway inflammation in OA is presented here. RESULTS: Occupational asthma is associated with an increase in sputum eosinophil percentage during periods at work or after positive specific inhalation challenges. Changes in FeNO are less sensitive than sputum eosinophil counts for predicting OA. CONCLUSIONS: In settings where this tool is available, sputum eosinophil counts may complement the current investigation of OA. The interpretation of FeNO remains sometimes difficult. The phenotypes of patients who may benefit from this measure needs to be better defined. PMID- 25285977 TI - Climate change and respiratory health. AB - OBJECTIVE: To discuss the nature of climate change and both its immediate and long-term effects on human respiratory health. METHODS: This review is based on information from a presentation of the American College of Chest Physicians course on Occupational and Environmental Lung Disease held in Toronto, Canada, June 2013. It is supplemented by a PubMed search for climate change, global warming, respiratory tract diseases, and respiratory health. It is also supplemented by a search of Web sites including the Environmental Protection Agency, National Oceanic and Atmospheric Administration, World Meteorological Association, National Snow and Ice Data Center, Carbon Dioxide Information Analysis Center, Inter-Governmental Panel on Climate Change, and the World Health Organization. RESULTS: Health effects of climate change include an increase in the prevalence of certain respiratory diseases, exacerbations of chronic lung disease, premature mortality, allergic responses, and declines in lung function. CONCLUSIONS: Climate change, mediated by greenhouse gases, causes adverse health effects to the most vulnerable patient populations-the elderly, children, and those in distressed socioeconomic strata. PMID- 25285978 TI - Clinical aspects of asbestos-related diseases--what are the unresolved topics? AB - OBJECTIVE: Despite awareness of the health risks associated with asbestos fiber inhalation and the decline in U.S. utilization (about 0.1% of the yearly peak amount), illnesses associated with exposure persist. Those with disease typically describe excessive exposures in the remote past, yet excessive exposures can occur today, most likely related to careless asbestos abatement procedures. The intent is to address unanswered questions associated with asbestos exposure. METHODS: The author summarizes clinical information addressing the case definition of asbestosis, the world-wide rate of mesothelioma, and clinical follow-up for those with exposure. RESULTS: The author describes information relevant to issues which remain unresolved. CONCLUSION: Perhaps somewhat surprisingly, even though there have been a great number of manuscripts reporting on the health risks of asbestos exposure, there remain unanswered questions regarding the pathogenesis of this disease. PMID- 25285979 TI - Metabolomic analysis of rat brain by high resolution nuclear magnetic resonance spectroscopy of tissue extracts. AB - Studies of gene expression on the RNA and protein levels have long been used to explore biological processes underlying disease. More recently, genomics and proteomics have been complemented by comprehensive quantitative analysis of the metabolite pool present in biological systems. This strategy, termed metabolomics, strives to provide a global characterization of the small-molecule complement involved in metabolism. While the genome and the proteome define the tasks cells can perform, the metabolome is part of the actual phenotype. Among the methods currently used in metabolomics, spectroscopic techniques are of special interest because they allow one to simultaneously analyze a large number of metabolites without prior selection for specific biochemical pathways, thus enabling a broad unbiased approach. Here, an optimized experimental protocol for metabolomic analysis by high-resolution NMR spectroscopy is presented, which is the method of choice for efficient quantification of tissue metabolites. Important strengths of this method are (i) the use of crude extracts, without the need to purify the sample and/or separate metabolites; (ii) the intrinsically quantitative nature of NMR, permitting quantitation of all metabolites represented by an NMR spectrum with one reference compound only; and (iii) the nondestructive nature of NMR enabling repeated use of the same sample for multiple measurements. The dynamic range of metabolite concentrations that can be covered is considerable due to the linear response of NMR signals, although metabolites occurring at extremely low concentrations may be difficult to detect. For the least abundant compounds, the highly sensitive mass spectrometry method may be advantageous although this technique requires more intricate sample preparation and quantification procedures than NMR spectroscopy. We present here an NMR protocol adjusted to rat brain analysis; however, the same protocol can be applied to other tissues with minor modifications. PMID- 25285980 TI - The debate on antibiotic therapy for patients hospitalized for pneumonia: where should we go from here? PMID- 25285981 TI - Bicyclic bridgehead phosphoramidite (briphos) ligands with tunable pi-acceptor ability and catalytic activity in the rhodium-catalyzed conjugate additions. AB - A new type of bicyclic bridgehead phosphoramidites (briphos) is reported, where the geometrical constraints significantly enhance the pi-acceptor ability compared with its monocyclic analogs. The briphos is shown to be highly efficient and tunable for Rh(I)-catalyzed conjugate additions of aryl boronic acids to alpha,beta-unsaturated ketones and N-tosyl ketimines. PMID- 25285983 TI - Fully solution-processed low-voltage aqueous In2O3 thin-film transistors using an ultrathin ZrO(x) dielectric. AB - We reported here "aqueous-route" fabrication of In2O3 thin-film transistors (TFTs) using an ultrathin solution-processed ZrOx dielectric thin film. The formation and properties of In2O3 thin films under various annealing temperatures were intensively examined by thermogravimetric analysis, Fourier transform infrared spectroscopy, and atomic force microscopy. The solution-processed ZrOx thin film followed by sequential UV/ozone treatment and low-temperature thermal annealing processes showed an amorphous structure, a low leakage-current density (~1 * 10(-9) A/cm(2) at 2 MV/cm), and a high breakdown electric field (~7.2 MV/cm). On the basis of its implementation as the gate insulator, the In2O3 TFTs based on ZrOx annealed at 250 degrees C exhibit an on/off current ratio larger than 10(7), a field-effect mobility of 23.6 cm(2)/V.s, a subthreshold swing of 90 mV/decade, a threshold voltage of 0.13 V, and high stability. These promising properties were obtained at a low operating voltage of 1.5 V. These results suggest that "aqueous-route" In2O3 TFTs based on a solution-processed ZrOx dielectric could potentially be used for low-cost, low-temperature-processing, high-performance, and flexible devices. PMID- 25285982 TI - Guanine-centric self-assembly of nucleotides in water: an important consideration in prebiotic chemistry. AB - Investigations of plausible prebiotic chemistry on early Earth must consider not only chemical reactions to form more complex products such as proto-biopolymers but also reversible, molecular self-assembly that would influence the availability, organization, and sequestration of reactant molecules. The self assembly of guanosine compounds into higher-order structures and lyotropic liquid crystalline "gel" phases through formation of hydrogen-bonded guanine tetrads (G tetrads) is one such consideration that is particularly relevant to an RNA-world scenario. G-tetrad-based gelation has been well studied for individual guanosine compounds and was recently observed in mixtures of guanosine with 5'-guanosine monophosphate (GMP) as well. The present work investigates the self-assembly of GMP in the presence of the other RNA nucleotides. Effects of the total concentration and relative proportion of the nucleotides in the mixtures, the form (disodium salt vs. free acid) of the nucleotides, temperature, pH, and salt concentration were determined by visual observations and circular dichroism (CD) spectroscopy. The results show that formation of cholesteric G-tetrad phases is influenced by interactions with other nucleotides, likely through association (e.g., intercalation) of the nucleotides with the G-tetrad structures. These interactions affect the structure and stability of the G-tetrad gel phase, as well as the formation of alternate self-assembled GMP structures such as a continuous, hydrogen-bonded GMP helix or dimers and aggregates of GMP. These interactions and multiple equilibria are influenced by the presence of cations, especially in the presence of K(+). This work could have important implications for the emergence of an RNA or proto-RNA world, which would require mixtures of nucleotides at sufficiently high, local concentrations for abiotic polymerization to occur. PMID- 25285984 TI - Selective growth and integration of silver nanoparticles on silver nanowires at room conditions for transparent nano-network electrode. AB - Recently, metal nanowires have received great research interests due to their potential as next-generation flexible transparent electrodes. While great efforts have been devoted to develop enabling nanowire electrodes, reduced contact resistance of the metal nanowires and improved electrical stability under continuous bias operation are key issues for practical applications. Here, we propose and demonstrate an approach through a low-cost, robust, room temperature and room atmosphere process to fabricate a conductive silver nano-network comprising silver nanowires and silver nanoparticles. To be more specific, silver nanoparticles are selectively grown and chemically integrated in situ at the junction where silver nanowires meet. The site-selective growth of silver nanoparticles is achieved by a plasmon-induced chemical reaction using a simple light source at very low optical power density. Compared to silver nanowire electrodes without chemical treatment, we observe tremendous conductivity improvement in our silver nano-networks, while the loss in optical transmission is negligible. Furthermore, the silver nano-networks exhibit superior electrical stability under continuous bias operation compared to silver nanowire electrodes formed by thermal annealing. Interestingly, our silver nano-network is readily peeled off in water, which can be easily transferred to other substrates and devices for versatile applications. We demonstrate the feasibly transferrable silver conductive nano-network as the top electrode in organic solar cells. Consequently, the transparent and conductive silver nano-networks formed by our approach would be an excellent candidate for various applications in optoelectronics and electronics. PMID- 25285985 TI - Electrically evoked compound action potentials artefact rejection by independent component analysis: procedure automation. AB - BACKGROUND: Independent-components-analysis (ICA) successfully separated electrically-evoked compound action potentials (ECAPs) from the stimulation artefact and noise (ECAP-ICA, Akhoun et al., 2013). NEW METHOD: This paper shows how to automate the ECAP-ICA artefact cancellation process. Raw-ECAPs without artefact rejection were consecutively recorded for each stimulation condition from at least 8 intra-cochlear electrodes. Firstly, amplifier-saturated recordings were discarded, and the data from different stimulus conditions (different current-levels) were concatenated temporally. The key aspect of the automation procedure was the sequential deductive source categorisation after ICA was applied with a restriction to 4 sources. The stereotypical aspect of the 4 sources enables their automatic classification as two artefact components, a noise and the sought ECAP based on theoretical and empirical considerations. RESULTS: The automatic procedure was tested using 8 cochlear implant (CI) users and one to four stimulus electrodes. The artefact and noise sources were successively identified and discarded, leaving the ECAP as the remaining source. The automated ECAP-ICA procedure successfully extracted the correct ECAPs compared to standard clinical forward masking paradigm in 22 out of 26 cases. COMPARISON WITH EXISTING METHOD(S): ECAP-ICA does not require extracting the ECAP from a combination of distinct buffers as it is the case with regular methods. It is an alternative that does not have the possible bias of traditional artefact rejections such as alternate-polarity or forward-masking paradigms. CONCLUSIONS: The ECAP-ICA procedure bears clinical relevance, for example as the artefact rejection sub-module of automated ECAP-threshold detection techniques, which are common features of CI clinical fitting software. PMID- 25285986 TI - Successful intracerebroventricular cannulation of a eusocial mammal. AB - BACKGROUND: Manipulating neural activity in live animals within a colony would allow researchers to more fully explore the neurobiology of complex social behaviors. However, some colony-living animals like the naked mole-rat (Heterocephalus glaber) cannot be reintroduced to a colony after the extended recovery time required following cranial surgery. Furthermore, the colony setting creates increased risk of infection and interruption of cranial surgical sites. NEW METHOD: A protocol for intracerebroventricular cannulations was developed for securing and minimizing exposure of the intracranial apparatus. We tested whether animals could be reintroduced to the colony immediately following surgery and whether they showed full recovery and expression of normal behavior a week later, after intracerebroventricular infusion of saline. RESULTS: Animals were successfully reincorporated into their home colony and showed normal behavior. No animals lost guide cannulae within their colony and loss of dummy cannulae was minimized. Any loss of animals was due to surgical complications or multiple intracerebroventricular infusions of saline rather than recovery in the colony, per se. COMPARISON WITH EXISTING METHODS: Standard cranial cannulation methods for small rodents were used with the addition of implanting a shortened guide cannula under the skin for limited exposure of cannulae to the external environment. Furthermore, dummy cannulae were sealed to guides to avoid loss in colony. CONCLUSION: The use of intracranial cannulations is a viable option for colony-living rodents when the proper care is taken to minimize cannula exposure and when animals are carefully and promptly reintroduced to the colony setting after surgery. PMID- 25285987 TI - Methodology for studying the transient effects of transcranial direct current stimulation combined with auditory residual inhibition on tinnitus. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) and auditory residual inhibition (RI) are short lasting non-invasive techniques that can suppress tinnitus in some people. A pilot study was undertaken to evaluate methods to measure a potential additive effect of these treatments. NEW METHOD: Ten participants (mean age 59 years) with chronic tinnitus underwent four sessions of anodal tDCS of the left temporoparietal area(LTA) combined with 1min of auditory stimulation (broadband noise presented at tinnitus minimum masking level [MML]+10 dB), either before, during or immediately after tDCS and in a sham controlled session. Participants continuously monitored and recorded their MML on custom software prior to stimulation, during 20 min of tDCS, and 30 min following tDCS. A tinnitus loudness rating was undertaken before and after completion of testing. RESULTS: Nine out of ten participants completed the study, one participant dropped out after two sessions due to self-reported worsening in tinnitus symptoms. Seven out of nine participants reported transient tinnitus suppression when sound stimulation was presented along with tDCS. No reliable change in MML was observed. COMPARISON WITH EXISTING METHOD: This is the first study to examine the feasibility of continuously measuring MML while providing a combination of auditory and noninvasive brain stimulation simultaneously. CONCLUSIONS: We propose modifications in the protocol used, to find ways to increase the duration of auditory RI and investigate its underlying mechanisms. Recommendations for further research are discussed. PMID- 25285988 TI - Luteolin inhibited the gene expression, production and secretion of MUC5AC mucin via regulation of nuclear factor kappa B signaling pathway in human airway epithelial cells. AB - Luteolin, a flavonoidal compound derived from Lonicera japonica Thunb. and Chrysanthemum indicum L., has been reported to show anti-inflammatory, anti oxidative and anti-carcinogenic effects. In this study, we investigated whether luteolin significantly affects the secretion, production and gene expression of airway mucin. Confluent NCI-H292 cells were pretreated with luteolin for 30 min and then stimulated with EGF (epidermal growth factor) or PMA (phorbol 12 myristate 13-acetate) for 24 h or the indicated periods. The MUC5AC mucin gene expression was measured by RT-PCR. Production and secretion of MUC5AC mucin protein were measured by ELISA. To elucidate the action mechanism of luteolin, effect of luteolin on PMA-induced NF-kappaB signaling pathway was investigated by western blot analysis. The results were as follows: (1) Luteolin inhibited the secretion of MUC5AC mucin protein induced by EGF or PMA; (2) Luteolin inhibited the production of MUC5AC mucin protein and the expression of MUC5AC mucin gene induced by EGF or PMA; (3) Luteolin inhibited PMA-induced phosphorylation and degradation of inhibitory kappa Balpha (IkappaBalpha); (4) Luteolin inhibited PMA induced phosphorylation and nuclear translocation of nuclear factor kappa B (NF kappaB) p65. This result suggests that luteolin can regulate the secretion, production and gene expression of mucin by acting on airway epithelial cells via regulation of NF-kB signaling pathway. PMID- 25285989 TI - Factors influencing childhood cancer patients to participate in a combined physical and psychosocial intervention program: Quality of Life in Motion. AB - BACKGROUND: For a multi-center randomized trial investigating the effects of a 12 week physical and psychosocial intervention program for children with cancer, we invited 174 patients (8-18 years old) on treatment or within 1 year after treatment; about 40% participated. Reasons for non-participation were investigated. METHODS: Eligible patients received written and verbal information about the study. Those declining to participate were asked to complete questionnaires concerning: reasons for non-participation, daily physical activity, health-related quality of life (HrQoL), and behavioral problems. Participants completed the same questionnaires at baseline (excluding 'reasons for non-participation'). RESULTS: Of 174 eligible patients, 106 did not participate; of these, 61 (57.5%) completed the one-time survey. The main reasons for non-participation as reported by the parents were 'too time consuming' and 'participation is too demanding for my child', while children most frequently reported 'too time consuming' and 'already frequently engaged in sports'. No differences between participants and non-participants were found for age, HrQoL, parental-reported behavior problems, sport participation, school type, BMI, and perceived health. A greater distance from home to hospital resulted in reduced participation (beta: -0.02; p = 0.01). Non-participants rated their fitness level higher (p = 0.03). Participating children (11-18 years old) reported more behavioral problems (p = 0.02), in particular internalizing problems (p = 0.06). CONCLUSIONS: Participation of childhood cancer patients in an intensive physical and psychosocial intervention program seems related to the burden of the intervention and the travel distance from home to hospital. In general, non participants rated their fitness level higher compared with participants. Patients with more (internalizing) behavioral problems seem more likely to participate in the study. PMID- 25285991 TI - Capsular Serotyping of Streptococcus pneumoniae by latex agglutination. AB - Latex agglutination reagents are widely used in microbial diagnosis, identification and serotyping. Streptococcus pneumoniae (the pneumococcus) is a major cause of morbidity and mortality world-wide. Current vaccines target the pneumococcal capsule, and there are over 90 capsular serotypes. Serotyping pneumococcal isolates is therefore important for assessing the impact of vaccination programs and for epidemiological purposes. The World Health Organization has recommended latex agglutination as an alternative method to the 'gold standard' Quellung test for serotyping pneumococci. Latex agglutination is a relatively simple, quick and inexpensive method; and is therefore suitable for resource-poor settings as well as laboratories with high-volume workloads. Latex agglutination reagents can be prepared in-house utilizing commercially-sourced antibodies that are passively attached to latex particles. This manuscript describes a method of production and quality control of latex agglutination reagents, and details a sequential testing approach which is time- and cost effective. This method of production and quality control may also be suitable for other testing purposes. PMID- 25285990 TI - Genome-based comparative analyses of Antarctic and temperate species of Paenibacillus. AB - Antarctic soils represent a unique environment characterised by extremes of temperature, salinity, elevated UV radiation, low nutrient and low water content. Despite the harshness of this environment, members of 15 bacterial phyla have been identified in soils of the Ross Sea Region (RSR). However, the survival mechanisms and ecological roles of these phyla are largely unknown. The aim of this study was to investigate whether strains of Paenibacillus darwinianus owe their resilience to substantial genomic changes. For this, genome-based comparative analyses were performed on three P. darwinianus strains, isolated from gamma-irradiated RSR soils, together with nine temperate, soil-dwelling Paenibacillus spp. The genome of each strain was sequenced to over 1,000-fold coverage, then assembled into contigs totalling approximately 3 Mbp per genome. Based on the occurrence of essential, single-copy genes, genome completeness was estimated at approximately 88%. Genome analysis revealed between 3,043-3,091 protein-coding sequences (CDSs), primarily associated with two-component systems, sigma factors, transporters, sporulation and genes induced by cold-shock, oxidative and osmotic stresses. These comparative analyses provide an insight into the metabolic potential of P. darwinianus, revealing potential adaptive mechanisms for survival in Antarctic soils. However, a large proportion of these mechanisms were also identified in temperate Paenibacillus spp., suggesting that these mechanisms are beneficial for growth and survival in a range of soil environments. These analyses have also revealed that the P. darwinianus genomes contain significantly fewer CDSs and have a lower paralogous content. Notwithstanding the incompleteness of the assemblies, the large differences in genome sizes, determined by the number of genes in paralogous clusters and the CDS content, are indicative of genome content scaling. Finally, these sequences are a resource for further investigations into the expression of physiological attributes that enable survival under extreme conditions and selection processes that affect prokaryotic genome evolution. PMID- 25285992 TI - Cell-based therapy for heart failure in rat: double thoracotomy for myocardial infarction and epicardial implantation of cells and biomatrix. AB - Cardiac cell therapy has gained increasing interest and implantation of biomaterials associated with cells has become a major issue to optimize myocardial cell delivery. Rodent model of myocardial infarction (MI) consisting of Left Anterior Descending Artery (LAD) ligation has commonly been performed via a thoracotomy; a second open-heart surgery via a sternotomy has traditionally been performed for epicardial application of the treatment. Since the description of LAD ligation model, post-surgery mortality rate has dropped from 35-13%, however the second surgery has remained critical. In order to improve post surgery recovery and reduce pain and infection, minimally invasive surgical procedures are presented. Two thoracotomies were performed, the initial one for LAD ligation and the second one for treatment epicardial administration. Biografts consisting of cells associated with solid or gel type matrices were applied onto the infarcted area. LAD ligation resulted in loss of heart function as confirmed by echocardiography performed after 2 and 6 weeks. Goldner trichrome staining performed on heart sections confirmed transmural scar formation. First and second surgeries resulted in less that 10% post-operative mortality. PMID- 25285993 TI - Luminescence resonance energy transfer to study conformational changes in membrane proteins expressed in mammalian cells. AB - Luminescence Resonance Energy Transfer, or LRET, is a powerful technique used to measure distances between two sites in proteins within the distance range of 10 100 A. By measuring the distances under various ligated conditions, conformational changes of the protein can be easily assessed. With LRET, a lanthanide, most often chelated terbium, is used as the donor fluorophore, affording advantages such as a longer donor-only emission lifetime, the flexibility to use multiple acceptor fluorophores, and the opportunity to detect sensitized acceptor emission as an easy way to measure energy transfer without the risk of also detecting donor-only signal. Here, we describe a method to use LRET on membrane proteins expressed and assayed on the surface of intact mammalian cells. We introduce a protease cleavage site between the LRET fluorophore pair. After obtaining the original LRET signal, cleavage at that site removes the specific LRET signal from the protein of interest allowing us to quantitatively subtract the background signal that remains after cleavage. This method allows for more physiologically relevant measurements to be made without the need for purification of protein. PMID- 25285994 TI - Evaluation of an oral supplement containing Phyllanthus emblica fruit extracts, vitamin E, and carotenoids in vitiligo treatment. AB - Phyllanthus emblica, vitamin E, and caroteinods are compounds showing antioxidative, anti-inflammatory, and repigmenting effects, whose role in vitiligo treatment has not been evaluated so far. Sixty-five subjects (group A) were treated with one tablet of an oral supplement containing P. emblica (100 mg), vitamin E (10 mg), and carotenoids (4.7 mg) three times/day for 6 months and compared with a control group (group B, 65 patients), which instead was not treated with antioxidants. Both groups were simultaneously treated with a comparable topical therapy and/or phototherapy. After a 6 months follow-up, a significantly higher number of patients in group A had a mild repigmentation on the head/neck regions (p = 0.019) and on the trunk (trend, p = 0.051). The number of patients who presented no repigmentation in head/neck, trunk, upper, and lower limbs was significantly higher in group B (respectively, p = 0.009, p = 0.001, p = 0.001, p = 0.025). Moreover, group B patients showed higher signs of inflammation (p = 0.002), a more rapid growth of the lesions (p = 0.039), a higher percentage of worsening disease (p = 0.003), and more erythema (p = 0.059), whereas group A patients showed a higher percentage of steady disease (p = 0.065). Our results suggest that the supplement with antioxidants in patients with vitiligo might represent a valuable instrument to increase the effectiveness of other vitiligo treatments. [Correction added after online publication 06-Oct 2014: the dosages of vitamin E and carotenoids have been updated.]. PMID- 25285995 TI - Where did it come from, where do you go? Direction sources influence navigation decisions during spatial uncertainty. AB - Previous research on route directions largely considers the case when a knowledgeable route-giver conveys accurate information. In the real world, however, route information is sometimes inaccurate, and directions can lead navigators astray. We explored how participants respond to route directions containing ambiguities between landmarks and turn directions, forcing reliance on one or the other. In three experiments, participants read route directions (e.g., To get to the metro station, take a right at the pharmacy) and then selected from destinations on a map. Critically, in half of the trials the landmark (pharmacy) and turn (right) directions were conflicting, such that the participant had to make a decision under conditions of uncertainty; under these conditions, we measured whether participants preferentially relied upon landmark- versus direction-based strategies. Across the three experiments, participants were either provided no information regarding the source of directions (Experiment 1), or told that the source of directions was a GPS device (Experiment 2), or a human (Experiment 3). Without information regarding the source of directions, participants generally relied on landmarks or turn information under conditions of ambiguity; in contrast, with a GPS source participants relied primarily on turn information, and with a human source on landmark information. Results were robust across gender and individual differences in spatial preference. We discuss these results within the context of spatial decision-making theory and consider implications for the design and development of landmark-inclusive navigation systems. PMID- 25285997 TI - Waste printed circuit board recycling techniques and product utilization. AB - E-waste, in particular waste PCBs, represents a rapidly growing disposal problem worldwide. The vast diversity of highly toxic materials for landfill disposal and the potential of heavy metal vapors and brominated dioxin emissions in the case of incineration render these two waste management technologies inappropriate. Also, the shipment of these toxic wastes to certain areas of the world for eco unfriendly "recycling" has recently generated a major public outcry. Consequently, waste PCB recycling should be adopted by the environmental communities as an ultimate goal. This article reviews the recent trends and developments in PCB waste recycling techniques, including both physical and chemical recycling. It is concluded that the physical recycling techniques, which efficiently separate the metallic and nonmetallic fractions of waste PCBs, offer the most promising gateways for the environmentally-benign recycling of this waste. Moreover, although the reclaimed metallic fraction has gained more attention due to its high value, the application of the nonmetallic fraction has been neglected in most cases. Hence, several proposed applications of this fraction have been comprehensively examined. PMID- 25285996 TI - Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels. AB - Metabolic syndrome, characterized by obesity, hyperglycemia, dyslipidemia and hypertension, increases the risks for cardiovascular disease, diabetes and stroke. Carboxylesterase 1 (CES1) is an enzyme that hydrolyzes triglycerides and cholesterol esters, and is important for lipid metabolism. Our previous data show that over-expression of mouse hepatic CES1 lowers plasma glucose levels and improves insulin sensitivity in diabetic ob/ob mice. In the present study, we determined the physiological role of hepatic CES1 in glucose homeostasis. Hepatic CES1 expression was reduced by fasting but increased in diabetic mice. Treatment of mice with glucose induced hepatic CES1 expression. Consistent with the in vivo study, glucose stimulated CES1 promoter activity and increased acetylation of histone 3 and histone 4 in the CES1 chromatin. Knockdown of ATP-citrate lyase (ACL), an enzyme that regulates histone acetylation, abolished glucose-mediated histone acetylation in the CES1 chromatin and glucose-induced hepatic CES1 expression. Finally, knockdown of hepatic CES1 significantly increased postprandial blood glucose levels. In conclusion, the present study uncovers a novel glucose-CES1-glucose pathway which may play an important role in regulating postprandial blood glucose levels. PMID- 25285998 TI - Fast photocatalytic degradation of methylene blue dye using a low-power diode laser. AB - This study focused on the application of diode lasers as alternative light sources for the fast photocatalytic degradation of methylene blue. The photocatalytic decomposition of methylene blue in aqueous solution under 443 nm laser light irradiation was found to be technically feasible using Ag/AgCl nanoparticles as photocatalysts. The effects of various experimental parameters, such as irradiation time, light source, catalyst loading, initial dye concentration, pH, and laser energy on decolorization and degradation were investigated. The mineralization of methylene blue was confirmed by chemical oxygen demand analysis. The results demonstrate that the laser-induced photocatalytic process can effectively degrade methylene blue under the optimum conditions (pH 9.63, 4 mg/L MB concentration, and 1.4 g/L Ag/AgCl nanoparticles). PMID- 25285999 TI - Statistical investigation of lead removal with various functionalized carboxylate ferroxane nanoparticles. AB - Four new types of carboxylate-ferroxane nanoparticles, namely; maleate ferroxane (MF), fumarateferroxane (FF), para-amino benzoate ferroxane (PABF) and para hydroxy benzoate ferroxane (PHBF) were synthesized, characterized and used for lead removal from aqueous solutions. Lepidocrocite nanoparticles were also synthesized and characterized asa precursorforcarboxylate-ferroxanes. FTIR, SEM and DLS analysis characterized the synthesized samplesand final Pb(II) concentration were analysed using inductively coupled plasma atomic emission spectrometer. Performance evaluation of the nanoparticlesin adsorption process was achieved using Taguchi experimental design. Variables in adsorption process were initial pH, contact time, adsorbent dose, adsorbent typeand initial concentration of Pb(2+) ions. The initial Pb(II) concentration was the most influential factor in the adsorption process among the five factors. Adsorption of lead was performed through two possible mechanisms; ion exchange and complex formation. Maleate ferroxane performed the best lead removal efficiency among the four types of ferroxane nanostructures studied. The adsorption kinetic data described well with a pseudo-second-order model and the equilibrium data fitted well to the Frendlich isotherm. PMID- 25286000 TI - Roles and regulation of plant cell walls surrounding plasmodesmata. AB - In plants, the intercellular transport of simple and complex molecules can occur symplastically through plasmodesmata. These are membranous channels embedded in cell walls that connect neighbouring cells. The properties of the cell walls surrounding plasmodesmata determine their transport capacity and permeability. These cell wall micro-domains are enriched in callose and have a characteristic pectin distribution. Cell wall modifications, leading to changes in plasmodesmata structure, have been reported to occur during development and in response to environmental signals. Cell wall remodelling enzymes target plasmodesmata to rapidly control intercellular communication in situ. Here we describe current knowledge on the composition of cell walls at plasmodesmata sites and on the proteins and signals that modify cell walls to regulate plasmodesmata aperture. PMID- 25286001 TI - Are ERM (ezrin/radixin/moesin) proteins targets for autoantibodies in demyelinating neuropathies? AB - Ezrin, radixin and moesin, which are strongly expressed in the Schwann cell microvilli, are putative targets for autoantibodies in acute or chronic inflammatory demyelinating polyneuropathy (AIDP or CIDP). An association between anti-moesin IgG antibodies and cytomegalovirus-related AIDP has been postulated. None of 41 AIDP patients, including 8 cytomegalovirus-related AIDP patients, and 23 CIDP had IgG or IgM antibodies to ezrin, radixin and moesin; whereas, one patient with cytomegalovirus-related AIDP had anti-ezrin IgM antibodies. Ezrin, radixin and moesin are unlikely targets for autoantibodies in AIDP and CIDP, and the association of anti-moesin antibodies with cytomegalovirus-related AIDP was not confirmed. PMID- 25286003 TI - Ultrasound surveillance for thyroid malignancies in survivors of childhood cancer following radiotherapy: a single institutional experience. AB - BACKGROUND: Survivors of childhood cancer (SCC) who have received radiotherapy to the head, neck, and upper thorax are at higher risk of developing subsequent thyroid malignancies. As part of the post treatment long-term follow-up protocol, the current Children's Oncology Group guideline recommends surveillance by annual palpation; however, thyroid nodules are difficult to detect by physical examinations alone, and potentially malignancy-harboring nodules may be undetected. Since thyroid ultrasound is a sensitive and noninvasive procedure, it was incorporated in our institutional follow-up protocol. The aim of this study was to examine the outcome of ultrasound screening in this high-risk population. The following describes our experience from 2007 to 2013. METHODS: A retrospective chart review was conducted on survivors enrolled in our follow-up program. SCC who have received direct or scattered radiation to the thyroid gland, and who were >=10 years from the diagnosis of primary childhood cancer were considered to be at-risk. RESULTS: Seventy-eight survivors met the inclusion criteria and were screened. Thyroid ultrasound detected thyroid nodule(s) in 46 patients (59%), 17 of which had nodule(s) between 5 and 10 mm (22%), and 15 patients had nodules >=10 mm (19%). Fourteen patients (18%) underwent fine-needle aspiration biopsy. Six patients (8%) underwent surgery, and 5 (6%) had confirmed papillary carcinoma. At the time of the first ultrasound, thyroid nodules of various sizes were found. However, over time, these nodules demonstrated slow growth rates. CONCLUSIONS: Incorporation of thyroid ultrasound into routine follow-up of high-risk SCC may aid in the detection of thyroid malignancies that are not clinically apparent. The use of ultrasound allows detailed characterization of the thyroid nodule and reliable monitoring of nodule progression. In SCC without suspicious nodule(s), it may be reasonable to perform screening ultrasounds less frequently due to the slow growth rate of thyroid nodules. However, in those with suspicious features, surgical work-up resulted in the removal of a high number of malignancies, with few unnecessary surgeries and complications. PMID- 25286002 TI - The frequency of HLA-B(*)57:01 and the risk of abacavir hypersensitivity reactions in the majority population of Costa Rica. AB - HLA-B(*)57:01 is a well-known and cost-effective pharmacogenetic marker for abacavir hypersensitivity. As with other HLA alleles, there is widespread variation in its frequency across populations. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA B(*)57:01 in this population has not been described yet. Thus, our aim was to determine the frequency of this allele in the CCVP. 200 unrelated healthy volunteer donors born in the CCVP were typed. HLA-B(*)57-positive samples identified by HLA intermediate resolution typing methods were further typed by SBT to high resolution. An HLA-B(*)57:01 carrier frequency of 5.00% was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B(*)57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment should be considered in this country. PMID- 25286004 TI - ABCB1 and ABCC4 efflux transporters are involved in methyl parathion detoxification in ZFL cells. AB - The multi-xenobiotics resistance (MXR) mechanisms are the first line of defense against toxic substances in aquatic organisms and present great importance in the adaptation related to contaminated environments. Methyl parathion (MP) is a widely used organophosphate pesticide, which has been associated to various toxic effects in organisms. In the present work, we studied the main genes related to efflux transporters in zebrafish liver (ZFL) cells exposed to MP with and without an inhibitor of ABC transporters (verapamil). The results concerning transporters activity showed that the MXR mechanism is activated to detoxify from methyl parathion. The toxic effects of MP on ZFL cells were increased in the presence of the efflux transporter inhibitor, once cell viability was significantly decreased in co-exposure experiments. The combined exposure to MP and the inhibitor caused an increase in gene expression of P-gp1 (Abcb1) and MRP4 (Abcc4), suggesting that these transporters isoforms are associated with MP efflux. In general, the expression of genes related to the antioxidant defense system (ADS) was significantly increased in ZFL cells co-exposed to MP and verapamil. These data provide useful insights for better understanding of MP detoxification mechanism in fish hepatocytes. PMID- 25286006 TI - Differences in reaction specificity toward lipoprotein X and abnormal LDL among 6 homogeneous assays for LDL-cholesterol. AB - BACKGROUND: We investigated the reaction specificity toward cholesterol in lipoprotein X (Lp-X) and abnormal LDL among 6 homogeneous assays for low-density lipoprotein cholesterol (LDL-C) based on different measurement principles. METHODS: The homogeneous LDL-C assays used were based on the liquid selective detergent, selective solubilization, elimination, enzyme-selective protection, calixarene complex, and phosphate complex inhibition methods. The fraction with a density of 1.006-1.063 kg/l was isolated from cholestatic sera, and the reactivity of cholesterol in the lipoprotein fractions by gel filtration for each homogeneous LDL-C assay was determined. RESULTS: The liquid selective detergent and elimination methods showed increased cholesterol reactivity in the Lp-X fraction in a concentration-dependent manner, while the selective solubilization and phosphate complex inhibition methods were less reactive toward Lp-X cholesterol. Meanwhile, the homogeneous LDL-C assays showed decreased reactivity against cholesterol in abnormal LDL, with increased ratios of phospholipids and triglycerides against cholesterol. CONCLUSION: The homogeneous LDL-C assays showed differential reactivity toward Lp-X and abnormal LDL. Our findings enable accurate interpretation of the LDL-C values in these homogeneous assays, and suggest that these methods should be improved to distinguish between normal LDL and abnormal LDL or Lp-X. PMID- 25286005 TI - Flavokawain A induces apoptosis in MCF-7 and MDA-MB231 and inhibits the metastatic process in vitro. AB - INTRODUCTION: The kava-kava plant (Piper methsyticum) is traditionally known as the pacific elixir by the pacific islanders for its role in a wide range of biological activities. The extract of the roots of this plant contains a variety of interesting molecules including Flavokawain A and this molecule is known to have anti-cancer properties. Breast cancer is still one of the leading diagnosed cancers in women today. The metastatic process is also very pertinent in the progression of tumorigenesis. METHODS: MCF-7 and MDA-MB231 cells were treated with several concentrations of FKA. The apoptotic analysis was done through the MTT assay, BrdU assay, Annexin V analysis, cell cycle analysis, JC-1 mitochondrial dye, AO/PI dual staining, caspase 8/9 fluorometric assay, quantitative real time PCR and western blot. For the metastatic assays, the in vitro scratch assay, trans-well migration/invasion assay, HUVEC tube formation assay, ex vivo rat aortic ring assay, quantitative real time PCR and western blot were employed. RESULTS: We have investigated the effects of FKA on the apoptotic and metastatic process in two breast cancer cell lines. FKA induces apoptosis in both MCF-7 and MDA-MB231 in a dose dependent manner through the intrinsic mitochondrial pathway. Additionally, FKA selectively induces a G2/M arrest in the cell cycle machinery of MDA-MB231 and G1 arrest in MCF-7. This suggests that FKA's anti-cancer activity is dependent on the p53 status. Moreover, FKA also halted the migration and invasion process in MDA-MB231. The similar effects can be seen in the inhibition of the angiogenesis process as well. CONCLUSIONS: FKA managed to induce apoptosis and inhibit the metastatic process in two breast cancer cell lines, in vitro. Overall, FKA may serve as a promising candidate in the search of a new anti-cancer drug especially in halting the metastatic process but further in vivo evidence is needed. PMID- 25286007 TI - Feasibility of noninvasive prenatal testing for common fetal aneuploidies in an early gestational window. AB - BACKGROUND: Noninvasive prenatal testing (NIPT) by massively parallel sequencing (MPS) of the circulating cell free fetal (cff) DNA during the second trimester of pregnancy is now a frontline test for detecting common fetal chromosomal abnormalities. However, the availability of an earlier test result in the first trimester would enable better clinical management of high-risk pregnancies. The aim of the study was to determine the feasibility of early gestational NIPT. METHODS: Plasma DNA libraries were subjected to MPS and chromosomal read counts normalized to reference. Chromosomal aneuploidy was determined by z-scores ( 3= 13) and low laser fluence (<5 mJ cm(-2)) conditions. Such nanostructured materials are promising candidates as photocatalysts or additives in nanocomposite materials with enhanced light absorption properties. PMID- 25286022 TI - Just in time-selection: A rapid semiautomated SELEX of DNA aptamers using magnetic separation and BEAMing. AB - A semiautomated two-step method for in vitro selection of DNA aptamers using magnetic separation and solid-phase emulsion polymerase chain reaction has been developed. The application of a magnetic separator allows the simultaneous processing of up to 12 SELEXs (systematic evolution of ligands by exponential enrichment) with different targets or buffer conditions. Using a magnetic separator and covalent target immobilization on magnetic beads, the selection process was simplified and the substeps of aptamer/target incubation, washing, and elution of the aptamers were merged into one automated procedure called "FISHing". Without further processing the resulting FISHing eluates are suitable for BEAMing (beads, emulsion, amplification, and magnetics), which includes the amplification by emPCR (emulsion polymerase chain reaction) and strand separation by the implementation of covalently immobilized reverse primers on magnetic beads. The novel selection process has been proved and validated by selecting and characterization of aptamers to the wine fining agent lysozyme. PMID- 25286023 TI - Role of water vapor desublimation in the adhesion of an iced droplet to a superhydrophobic surface. AB - The study of the adhesion of solid and liquid aqueous phases to superhydrophobic surfaces has become an attractive topic for researchers in various fields as a vital step in the design of icephobic coatings. The analysis of the available results shows that the experimentally measured values of adhesion strength for superhydrophobic substrates, which in some cases are quite small, are still essentially higher than might be expected from the portion of the actual wetted area. In this study we have considered the peculiarities of the three-phase contact zone between sessile supercooled water or ice droplets and a superhydrophobic coating at negative temperatures (below 0 degrees C) and during the water-ice phase transition. Two types of superhydrophobic coatings with very different textures were used to analyze the evolution of shape parameters of a sessile water droplet during droplet cooling and freezing. It was shown that the evolution of the contact angle and droplet contact diameter of a water droplet deposited on a superhydrophobic surface does not undergo essential changes when the droplet is cooled simultaneously with the substrate and the surrounding environment, and the humidity is maintained close to 100% during the cooling process. However, the phase transition from supercooled water to ice droplets leads to the growth of a metastable iced meniscus and a frost halo in the vicinity of the three-phase contact zone. The meniscus effectively increases the area of adhesive contact between the droplet and the substrate. This phenomenon is intrinsically related to the release of the heat of crystallization and is responsible for the enhancement of adhesion to a superhydrophobic substrate upon droplet transition from supercooled water to ice. At the same time, it was shown that the metastable state of the above meniscus leads to its spontaneous sublimation during exposure at negative temperatures. PMID- 25286024 TI - Role of HF in oxygen removal from carbon nanotubes: implications for high performance carbon electronics. AB - Oxygen removal from SWNTs is crucial for many carbon electronic devices. This work shows that HF treatment followed by current stimulation is a very effective method for oxygen removal. Using a procedure involving HF treatment, current stimulation and spin-casting AgNWs onto a SWNT thin film, record high efficiency SWNT/p-Si solar cells have been developed. PMID- 25286025 TI - Kinetically controlled nucleation of silver on surfactant-free gold seeds. AB - We report on the heterogeneous nucleation of Ag on Au seeds using a surfactant free synthesis where nanoparticle aggregation is nullified through the immobilization of bare Au seeds on the surface of a substrate. Requiring only silver nitrate, ascorbic acid, and Au seeds, the synthesis is facile and, from a mechanistic standpoint, far less convoluted than conventional protocols. The results reveal that, even in the absence of surfactants, highly anisotropic growth modes are achieved which result in a lone Ag structure emanating from a single (100) Au facet. Consistent with surfactant-based protocols is the ability to vary the product of the reaction by varying the reaction rate. It allows for kinetic control which is able to direct the reaction toward either a bimetallic heterodimer or a core-shell configuration. The observed growth modes cannot be explained in terms of those proposed for surfactant-based growth modes where surfactants, surface diffusion, and/or collision patterns are used to rationalize the reaction product. We, instead, propose a growth mode reliant on the formation of a space charge region around each seed consisting of a double layer of ions, where the integrity of the layer is dependent upon the facets expressed by the seed, the rate at which the reduced ions are being deposited, and the pH of the solution. Our work reveals the rich nature of surfactant-free heteroepitaxial growth modes as well as the utility of the substrate-based platform in defining growth pathways. PMID- 25286026 TI - Efficacy of guanfacine extended release assessed during the morning, afternoon, and evening using a modified Conners' Parent Rating Scale-revised: Short Form. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of once-daily guanfacine extended release (GXR) monotherapy administered either in the morning or evening, using a modified Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S) assessed three times/day in children with attention deficit/hyperactivity disorder (ADHD). METHODS: This multicenter, double-blind, placebo-controlled study randomized children 6-12 years of age with ADHD into three groups: GXR a.m. (GXR in the morning and placebo in the evening), GXR p.m. (placebo in the morning and GXR in the evening), or twice-daily placebo. The CPRS R:S, administered in the morning, afternoon, and evening prior to each study visit, was a secondary measure of efficacy. RESULTS: A total of 333 subjects were included in the analysis population (GXR a.m., n=107; GXR p.m., n=114; placebo, n=112). At visit 10, last observation carried forward (LOCF), subjects receiving GXR demonstrated significantly greater improvement from baseline in the daily mean CPRS-R:S total score, as well as in each of the morning, afternoon, and evening CPRS-R:S assessments, compared with placebo, regardless of the time of GXR administration (p<0.001 vs. placebo for GXR a.m. and GXR p.m.). In addition, subjects receiving GXR showed significantly greater improvements from baseline in each subscale score (oppositional, cognitive problems/inattention, hyperactivity, and ADHD index) compared with those receiving placebo, regardless of time of administration (p<0.003 vs. placebo across all subscales for GXR a.m. and GXR p.m.). CONCLUSIONS: These results provide further support for the demonstrated efficacy of once-daily GXR in reducing ADHD symptoms, and demonstrate that response is consistent throughout the day regardless of the time of administration, with improvement seen in ratings of oppositional as well as of ADHD symptoms. PMID- 25286027 TI - Associations between the duration of dialysis, endotoxemia, monocyte chemoattractant protein-1, and the effects of a short-dwell exchange in patients requiring continuous ambulatory peritoneal dialysis. AB - BACKGROUND: Endotoxemia is exaggerated and contributes to systemic inflammation and atherosclerosis in patients requiring continuous ambulatory peritoneal dialysis (CAPD). The risk of mortality is substantially increased in patients requiring CAPD for >2 years. However, little is known about the effects of long term CAPD on circulating endotoxin and cytokine levels. Therefore, the present study evaluated the associations between plasma endotoxin levels, cytokine levels, and clinical parameters with the effects of a short-dwell exchange on endotoxemia and cytokine levels in patients on long-term CAPD. METHODS: A total of 26 patients were enrolled and divided into two groups (short-term or long-term CAPD) according to the 2-year duration of CAPD. Plasma endotoxin and cytokine levels were measured before and after a short-dwell exchange (4-h dwell) during a peritoneal equilibration test (a standardized method to evaluate the solute transport function of peritoneal membrane). These data were analyzed to determine the relationship of circulating endotoxemia, cytokines and clinical characteristics between the two groups. RESULTS: Plasma endotoxin and monocyte chemotactic protein-1 (MCP-1) levels were significantly elevated in the long-term group. PD duration was significantly correlated with plasma endotoxin (r = 0.479, P = 0.016) and MCP-1 (r = 0.486, P = 0.012). PD duration was also independently associated with plasma MCP-1 levels in multivariate regression. Plasma MCP-1 levels tended to decrease (13.3% reduction, P = 0.077) though endotoxin levels did not decrease in the long-term PD group after the 4-h short-dwell exchange. CONCLUSION: Long-term PD may result in exaggerated endotoxemia and elevated plasma MCP-1 levels. The duration of PD was significantly correlated with circulating endotoxin and MCP-1 levels, and was an independent predictor of plasma MCP-1 levels. Short-dwell exchange seemed to have favorable effects on circulating MCP-1 levels in patients on long-term PD. PMID- 25286028 TI - Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer. AB - The polycomb complex protein Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog) mediates epigenetic transcriptional silencing by modifying chromatin structure and is critical for stem cell homeostasis and tumorigenesis. Bmi1 is frequently overexpressed in human malignancies and therefore has key diagnostic and prognostic significance, and holds potential as a therapeutic target. Here we sought to characterize the expression patterns and oncogenic roles of Bmi1 in tongue squamous cell carcinoma and to determine the anticancer effects of histone deacetylase inhibitors (HDACis) via Bmi1 inhibition against tongue cancer. Our data revealed that Bmi1 was aberrantly overexpressed in a significant portion of tongue cancers. Elevated Bmi1 is associated with cervical node metastasis, Ki-67 abundance and reduced overall survival, and also serves as an independent prognostic factor for patient outcomes. Short-hairpin RNA-mediated Bmi1 knockdown inhibited cell proliferation and migration, induced cell apoptosis and senescence, reduced colony formation and CD44(+)CD133(+) sub-population as well as enhanced cisplatin chemosensitivity, presumably by modulation of p16, p14 and E-cadherin. Moreover, HDACi chemicals Trichostatin A (TSA) and sodium butyrate (NaB) potently inhibited Bmi1 and triggered similar phenotypic changes reminiscent of Bmi1 silencing, although TSA treatment seemed paradoxically to induce some epithelial-mesenchymal transition-like changes in tongue cancer cells. Importantly, NaB-induced antitumor effects were partially attenuated by enforced Bmi1 overexpression in vitro. Genetic Bmi1 silencing and pharmacological inhibition of Bmi1 by NaB treatment significantly impaired tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that Bmi1 serves as a key driver and biomarker with multiple oncogenic functions underlying tongue tumorigenesis. Selected appropriate HDACi compounds like NaB may represent novel therapeutic agents against tongue cancer. PMID- 25286029 TI - miR-106b modulates cancer stem cell characteristics through TGF-beta/Smad signaling in CD44-positive gastric cancer cells. AB - Cancer stem cells have the capacity to form new tumors and are thus considered to be a cause of metastasis and tumor recurrence. However, many of the mechanisms determining cancer stem cell characteristics are still unknown. MicroRNAs (miRNAs) are possible modulators of cancer stem cell generation and may be involved in the retention of cancer stem cell characteristics. The aim of this study was to examine the miRNA expression profiles regulating the cancer stem like cell characteristics in gastric cancer. We sorted gastric cancer stem-like cells using the stem cell marker CD44 by fluorescence-activated cell sorting. CD44(+) cells formed more and larger spheres compared with CD44(-) cells. Cancer stem cell markers were overexpressed in CD44(+) cells. CD44(+) cells showed increased expression of mesenchymal cell markers, whereas epithelial markers were downregulated. In miRNA microarray, the miR-106b family comprising miR-106b, miR 93, and miR-25 was significantly upregulated in CD44(+) cells than in CD44(-) cells. Smad7, which inhibits transforming growth factor-beta (TGF-beta)/Smad signaling as a target of the miR-106b family, was downregulated in CD44(+) cells. Furthermore, expression of TGF-beta/Smad signal molecules was activated in CD44(+) cells, in accordance with the action of the miR-106b family. Inhibition of miR-106b showed suppression of the TGF-beta/Smad signaling pathway and decreased self-renewal capacity and cell invasiveness. Our study suggests that CD44(+) gastric cancer cells show cancer stem cell properties with epithelial mesenchymal transition (EMT). Increased miR-106b family expression regulated cancer stem-like cell properties, particularly EMT characteristics, through the TGF-beta/Smad signaling pathway in CD44(+) stem-like cells. Taken together, these results indicate that targeting miR-106b may be an effective form of cancer therapy in gastric cancer through the modulation of cancer stem cell characteristics. PMID- 25286031 TI - Next generation sequencing and tumor mutation profiling: are we ready for routine use in the oncology clinic? AB - Next generation sequencing (NGS) coupled with sophisticated bioinformatics tools yields an unprecedented amount of information regarding tumor genetics, with the potential to reveal insights into tumor behavior. NGS and other multiplex genomic assays are rapidly spilling from the laboratory into the clinic through numerous commercial and academic entities. This raises the important question as to whether we are ready to use these data in clinical decision-making. While genetic lesions are clearly targeted by a new generation of biological cancer therapies, and certain regulatory approvals are actually coupled to single gene assays, we still do not know if the vast information on other genomic alterations is worth the added cost, or even worse, the inappropriate and unproven assignment of patients to treatment with an unapproved drug carrying potentially serious side effects. On the other hand, the trend toward a precision medicine pathway is clearly accelerating, and clinical trials validating pathway-driven personalized cancer therapeutics will be necessary in both the community and academic settings. Lower cost and wider availability of NGS now raises a debate over the merit of routine tumor genome-wide analysis. PMID- 25286030 TI - Interactions of lipids and detergents with a viral ion channel protein: molecular dynamics simulation studies. AB - Structural studies of membrane proteins have highlighted the likely influence of membrane mimetic environments (i.e., lipid bilayers versus detergent micelles) on the conformation and dynamics of small alpha-helical membrane proteins. We have used molecular dynamics simulations to compare the conformational dynamics of BM2 (a small alpha-helical protein from the membrane of influenza B) in a model phospholipid bilayer environment with its behavior in protein-detergent complexes with either the zwitterionic detergent dihexanoylphosphatidylcholine (DHPC) or the nonionic detergent dodecylmaltoside (DDM). We find that DDM more closely resembles the lipid bilayer in terms of its interaction with the protein, while the short-tailed DHPC molecule forms "nonphysiological" interactions with the protein termini. We find that the intrinsic micelle properties of each detergent are conserved upon formation of the protein-detergent complex. This implies that simulations of detergent micelles may be used to help select optimal conditions for experimental studies of membrane proteins. PMID- 25286032 TI - Mobile money, smallholder farmers, and household welfare in Kenya. AB - The use of mobile phones has increased rapidly in many developing countries, including in rural areas. Besides reducing the costs of communication and improving access to information, mobile phones are an enabling technology for other innovations. One important example are mobile phone based money transfers, which could be very relevant for the rural poor, who are often underserved by the formal banking system. We analyze impacts of mobile money technology on the welfare of smallholder farm households in Kenya. Using panel survey data and regression models we show that mobile money use has a positive impact on household income. One important pathway is through remittances received from relatives and friends. Such remittances contribute to income directly, but they also help to reduce risk and liquidity constraints, thus promoting agricultural commercialization. Mobile money users apply more purchased farm inputs, market a larger proportion of their output, and have higher profits than non-users of this technology. These results suggest that mobile money can help to overcome some of the important smallholder market access constraints that obstruct rural development and poverty reduction. PMID- 25286033 TI - Laser-assisted lipolysis for neck and submental remodeling in Rohrich type IV patients: fact or fiction? AB - BACKGROUND: Since the first studies by Apfelberg in 1994 and the mathematical model of Mordon introduced in 2004, laser-assisted lipolysis (LAL) has been on the rise. In a previous study, we presented our results in patients treated with LAL for Rohrich type I to III aging neck. The average cervicomental angle decreased from 152.6 +/- 5.9 to 123.6 +/- 8.8 degrees after LAL. This demonstrated a systematic decrease in fat thickness, and improved skin tightening. OBJECTIVE: This new protocol focuses solely on LAL in the Rohrich type IV aging neck. METHODS: Between June 2012 and February 2013, a prospective study was performed on 10 patients treated with LAL for Rohrich type IV aging neck. The laser used in this study was a 1470 nm diode laser (Alma Lasers, Caesarea, Israel). Laser energy was transmitted through a 600 MUm optical fiber and delivered in a continuous mode, at 15 W power. Previous mathematical modeling suggested that 0.1 kJ was required in order to destroy 1 ml of fat. Patients were asked to fill out a satisfaction questionnaire. The cervicomental angle was measured 6 months postoperatively, and compared with the preoperative values. RESULTS: No seromas were observed, but prolonged edema was observed in two patients. Pain during anesthesia and discomfort after the procedure were minimal. The average cervicomental angle decreased from 191.5 +/- 5.7 to 164.9 +/- 14.2 degrees (p < 0.01). This demonstrated a systematic decrease in fat thickness and improved skin tightening. Even though the cervicomental angle was higher than 140 degrees in each case, the investigators, in agreement with the patients, decided to perform a complementary surgery with platysma muscle advancement and plication six months after LAL, in only two of the ten patients. This complementary surgery led to a mean cervicomental angle of 140.2 +/- 11.4, and fair satisfaction of both patients and investigators. CONCLUSION: LAL alone appears insufficient for complete remodeling in Rohrich type IV aging neck. While LAL alone is sufficient for Grade I to III, a complementary surgery must be added for Grade IV. PMID- 25286034 TI - Could alpha5-GABA-A receptor activation be used as a target for managing medulloblastomas? PMID- 25286037 TI - Retrospective analysis of safety and feasibility of a 3 days on/11 days off temozolomide dosing regimen in recurrent adult malignant gliomas. AB - AIMS: We report the safety and feasibility of a 3 days on/11 days off temozolomide regimen for the treatment of recurrent malignant gliomas. PATIENTS & METHODS: Fifteen adult patients were treated; 14 were treated with 300 mg/m(2) and one treated with 250 mg/m(2). RESULTS: We reviewed the toxicity, progression free survival (PFS), overall survival and objective response rate. Two patients (13%) experienced grade 3 nausea/vomiting and six patients (40%) experienced grade 3 lymphopenia. Dose reduction and treatment delay occurred in eight (53%) cases. One patient discontinued treatment due to uncontrolled nausea/vomiting. Median PFS for glioblastoma patients was 4.1 months and 6-month PFS was 25%. Twelve patients exhibited stable disease (86%), one patient (7%) had progressive disease and one patient (7%) showed a partial response. CONCLUSION: The '3 on/11 off' temozolomide regimen for recurrent high-grade gliomas was tolerable and warrants further study in a larger, prospective study. PMID- 25286038 TI - Incidence of Pneumocystis jirovecii pneumonia after temozolomide for CNS malignancies without prophylaxis. AB - AIMS: Prophylaxis against Pneumocystis jiroveci pneumonia (PJP) is currently recommended for patients receiving chemoradiation with temozolomide for newly diagnosed glioblastoma multiforme. At our institution, PJP prophylaxis during temozolomide treatment has not been routinely given because of the paucity of supporting data. We investigated the rate of PJP infections in our patients. PATIENTS & METHODS: We conducted a retrospective chart review of 240 brain tumor patients treated between 1999 and 2012 with temozolomide and no PJP prophylaxis, 127 of which received concurrent chemoradiation. RESULTS: One in 240 patients (0.4%; 95% CI: 0.01-2.00; median total dose: 7375 mg/m(2); interquartile range: 1300) were diagnosed with PJP. CONCLUSION: There was a <1% rate of PJP for brain tumor patients treated with temozolomide until progression without PJP prophylaxis. PMID- 25286039 TI - Validation of the Brain Symptom and Impact Questionnaire (BASIQ) to assess symptom and quality of life in brain metastases. AB - OBJECTIVE: To validate the Brain Symptom and Impact Questionnaire (BASIQ) version 1.0 for brain metastases. METHODS: Patients with brain metastases and their healthcare professionals (HCPs) assessed the relevance of the BASIQ on a 0-10 scale with 10 as extremely relevant. RESULTS: A total of 52 patients and 20 HCPs participated in this study. In total, 95% of HCPs and 85% of patients found all items relevant. Balance and walking ability were rated relevant by 100% of patients and HCPs. Headache, nausea, energy, memory and ability to do housework were also rated relevant by 100% of HCPs. Over 95% of patients determined the items of ability to do housework, tiredness, energy, vision, memory and putting ideas into words as relevant. There were no items rated below 7 by patients or below 5 by HCPs. CONCLUSION: This study indicates that BASIQ version 1.0 has valid content items encompassing disease-related symptom and impact on daily living. PMID- 25286040 TI - Novel approaches for quantifying protein biomarkers in gliomas: benefits and pitfalls. AB - The therapeutic paradigm of gliomas is changing from a general approach towards an individualized and targeted approach. Accordingly, the search for prognostic and predictive biomarkers, as well as the demand for quantitative, feasible and robust methods for biomarker analysis increases. We find that software classifiers can identify and quantify the expression of a given biomarker within different subcellular compartments and that such classifiers can exclude frequently occurring nontumor cells, thereby avoiding potential bias. The use of a quantitative approach provides a continuous measurement of the expression, allowing establishment of new cut-points and identification of patients with specific prognoses. However, some pitfalls must be noted. This article focuses on benefits and pitfalls of novel approaches for quantifying protein biomarkers in gliomas. PMID- 25286042 TI - The future of stroke treatment: bringing evaluation of behavior back to stroke neurology. PMID- 25286041 TI - Current and potential utility of transcranial magnetic stimulation in the diagnostics before brain tumor surgery. AB - This article describes the evolution and state-of-the-art of navigated transcranial magnetic stimulation for evaluation of patients with brain tumors in presumed eloquent location. Alternative noninvasive technologies for functional brain mapping are described and assessed in the context of their usability and clinical needs. In addition to the description of the current validation level and clinical application of navigated transcranial magnetic stimulation for motor and language mapping, the manuscript highlights ongoing research efforts and provides an outlook on upcoming developments in the field of noninvasive brain mapping. Finally, the clinical rationale for presurgical noninvasive brain mapping is discussed in the light of current developments in neurosurgery. PMID- 25286044 TI - A new SIR-based sigmoid power control game in cognitive radio networks. AB - Interference resulting from Cognitive Radios (CRs) is the most important aspect of cognitive radio networks that leads to degradation in Quality of Service (QoS) in both primary and CR systems. Power control is one of the efficient techniques that can be used to reduce interference and satisfy the Signal-to-Interference Ratio (SIR) constraint among CRs. This paper proposes a new distributed power control algorithm based on game theory approach in cognitive radio networks. The proposal focuses on the channel status of cognitive radio users to improve system performance. A new cost function for SIR-based power control via a sigmoid weighting factor is introduced. The existence of Nash Equilibrium and convergence of the algorithm are also proved. The advantage of the proposed algorithm is the possibility to utilize and implement it in a distributed manner. Simulation results show considerable savings on Nash Equilibrium power compared to relevant algorithms while reduction in achieved SIR is insignificant. PMID- 25286045 TI - Double oxidation of alpha-(alkylideneamino)nitriles to imides by molecular oxygen under mild basic conditions. AB - We reveal here the unique reactivity of alpha-(alkylideneamino)nitriles toward molecular oxygen. Thus, alpha-(alkylideneamino)nitriles can serve as the imide building block for the efficient synthesis of imides in the absence of transition metals under extremely mild conditions. PMID- 25286043 TI - The apolipoprotein-AI mimetic peptide L4F at a modest dose does not attenuate weight gain, inflammation, or atherosclerosis in LDLR-null mice. AB - OBJECTIVE: High density lipoprotein (HDL) cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein) mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/-) model fed a high fat high sucrose with cholesterol (HFHSC) diet. METHODS: Studies in differentiated 3T3-L1 adipocytes tested whether L4F could inhibit palmitate-induced adipocyte inflammation. In vivo studies used male Ldlr /- mice fed a HFHSC diet for 12 weeks and were injected daily with L4F (100 ug/mouse) subcutaneously during the last 8 weeks. Wild-type and apoA-I overexpressing Ldlr-/- mice were fed HFHSC diet for 16 weeks. RESULTS: Neither L4F administration nor apoA-I overexpression affected weight gain, total plasma cholesterol or triglycerides in our studies. While pre-treatment of 3T3-L1 adipocytes with either L4F or HDL abolished palmitate-induced cytokine expression in vitro, L4F treatment did not affect circulating or adipose tissue inflammatory markers in vivo. Neither L4F administration nor apoA-I overexpression affected glucose tolerance. ApoA-I overexpression significantly reduced atherosclerotic lesion size, yet L4F treatment did not affect atherosclerosis. CONCLUSION: Our results suggest that neither L4F (100 ug/day/mouse) nor apoA-I overexpression affects adiposity or insulin resistance in this model. We also were unable to confirm a reduction in atherosclerosis with L4F in our particular model. Further studies on the effect of apoA-I mimetics on atherosclerosis and insulin resistance in a variety of dietary contexts are warranted. PMID- 25286047 TI - Isolation and culture of dissociated sensory neurons from chick embryos. AB - Neurons are multifaceted cells that carry information essential for a variety of functions including sensation, motor movement, learning, and memory. Studying neurons in vivo can be challenging due to their complexity, their varied and dynamic environments, and technical limitations. For these reasons, studying neurons in vitro can prove beneficial to unravel the complex mysteries of neurons. The well-defined nature of cell culture models provides detailed control over environmental conditions and variables. Here we describe how to isolate, dissociate, and culture primary neurons from chick embryos. This technique is rapid, inexpensive, and generates robustly growing sensory neurons. The procedure consistently produces cultures that are highly enriched for neurons and has very few non-neuronal cells (less than 5%). Primary neurons do not adhere well to untreated glass or tissue culture plastic, therefore detailed procedures to create two distinct, well-defined laminin-containing substrata for neuronal plating are described. Cultured neurons are highly amenable to multiple cellular and molecular techniques, including co-immunoprecipitation, live cell imagining, RNAi, and immunocytochemistry. Procedures for double immunocytochemistry on these cultured neurons have been optimized and described here. PMID- 25286049 TI - Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders. AB - BACKGROUND: Recent studies suggest that exposure to traffic-related air pollutants, including particulate matter (PM), is associated with autism spectrum disorder (autism). METHODS: Children with autism were identified by records-based surveillance (n = 645 born in North Carolina in 1994, 1996, 1998, or 2000, and n = 334 born in the San Francisco Bay Area in California in 1996). They were compared with randomly sampled children born in the same counties and years identified from birth records (n = 12,434 in North Carolina and n = 2,232 in California). Exposure to PM less than 10 MUm (PM10) at the birth address was assigned to each child by a geostatistical interpolation method using daily concentrations from air pollution regulatory monitors. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for a 10 MUg/m increase in PM10 within 3 month periods from preconception through the child's first birthday, adjusting for year, state, maternal education and age, race/ethnicity, and neighborhood level urbanization and median household income, and including a nonparametric term for week of birth to account for seasonal trends. RESULTS: Temporal patterns in PM10 were pronounced, leading to an inverse correlation between the first- and third-trimester concentrations (r = -0.7). Adjusted ORs were, for the first trimester, 0.86 (95% CI = 0.74-0.99), second trimester, 0.97 (0.83-1.15), and third trimester, 1.36 (1.13-1.63); and, after simultaneously including first- and third-trimester concentrations to account for the inverse correlation, were: first trimester, 1.01 (0.81-1.27) and third trimester, 1.38 (1.03-1.84). CONCLUSIONS: Our study adds to previous work in California showing a relation between traffic-related air pollution and autism, and adds similar findings in an eastern US state, with results consistent with increased susceptibility in the third-trimester. PMID- 25286048 TI - A soybean C2H2-type zinc finger gene GmZF1 enhanced cold tolerance in transgenic Arabidopsis. AB - Zinc finger proteins were involved in response to different environmental stresses in plant species. A typical Cys2/His2-type (C2H2-type) zinc finger gene GmZF1 from soybean was isolated and was composed of 172 amino acids containing two conserved C2H2-type zinc finger domains. Phylogenetic analysis showed that GmZF1 was clustered on the same branch with six C2H2-type ZFPs from dicotyledonous plants excepting for GsZFP1, and distinguished those from monocotyledon species. The GmZF1 protein was localized at the nucleus, and has specific binding activity with EP1S core sequence, and nucleotide mutation in the core sequence of EPSPS promoter changed the binding ability between GmZF1 protein and core DNA element, implying that two amino acid residues, G and C boxed in core sequence TGACAGTGTCA possibly play positive regulation role in recognizing DNA-binding sites in GmZF1 proteins. High accumulation of GmZF1 mRNA induced by exogenous ABA suggested that GmZF1 was involved in an ABA-dependent signal transduction pathway. Over-expression of GmZF1 significantly improved the contents of proline and soluble sugar and decreased the MDA contents in the transgenic lines exposed to cold stress, indicating that transgenic Arabidopsis carrying GmZF1 gene have adaptive mechanisms to cold stress. Over-expression of GmZF1 also increased the expression of cold-regulated cor6.6 gene by probably recognizing protein-DNA binding sites, suggesting that GmZF1 from soybean could enhance the tolerance of Arabidopsis to cold stress by regulating expression of cold-regulation gene in the transgenic Arabidopsis. PMID- 25286050 TI - Integrating multi-scale knowledge on cardiac development into a computational model of ventricular trabeculation. AB - Insights into the mechanisms of development of the mammalian four-chambered heart are based on biological observations at organ, tissue, cell, and molecular levels, but the full integration of these experimental data awaits a systems biology approach. Such an approach can be employed to formulate and test conceptual models in a computational simulation. To illustrate how this can be applied to heart development, we used the process of trabeculation, which is the formation of muscular strands during chamber development. We selected this process because it is localized, involves a restricted number of cell types, and a range of experimental data is available. Trabeculation of the ventricles is based on the interplay between endocardial and myocardial cells and involves molecular pathways underlying cell-cell interactions and tissue-specific cell behavior. A cellular Potts model was used for the simulation of these multi-scale processes. With fairly simple inputs, of which the relative contributions are unknown, an iterative exploration achieved an outcome that resembles the trabeculation process and allows further investigation of contributing factors. The systems biology pipeline from biological observations and conceptual modeling to a mathematical model and computational algorithms is described and discussed. The multi-level biological observations provide the components and their connections of the conceptual model. However, the true strength of systems biology must be found in the biological test of the predictions that result from an experimental change in the computational model. These validated predictions will ultimately elucidate the functional role of a component or interaction in the process of heart development. PMID- 25286051 TI - Anti-interleukin 6 receptor antibodies attenuate antibody recall responses in a mouse model of allosensitization. AB - BACKGROUND: Interleukin (IL)-6 is a regulatory cytokine for T helper type 17 (Th17) and Treg cells and a potent stimulus for B/plasma cells. The current study evaluated the effect of IL-6 receptor (IL-6R) blockade with an antiYIL-6R monoclonal (mMR16-1) in alloantibody recall responses. METHODS: A mouse model of human leukocyte antigen (HLA).A2 sensitization was used for studies to evaluate the efficacy of antiYIL-6R on alloantibody recall responses and to examine the impact of IL-6R blockade on Th17, Treg, follicular T helper (Tfh) and plasma cells using multiparameter flow cytometry, flow antibody binding, and enzyme linked immunospot (ELISpot) assay. RESULTS: Re-exposure of C57BL/6 mice to HLA.A2(+) skin allografts resulted in a surge of donor-specific (antiYHLA.A2) immunoglobulin (Ig)G antibodies. AntiYIL-6R treatment significantly decreased but did not eliminate alloantibody responses (IgG mean fluorescence intensity, 486 T 153 vs. control 792 T 193, P = 0.0076). Flow cytometry analysis showed that antiYIL-6R treatment resulted in reduction of IL-21+CD4+ (Th17) cells (P = 0.006 vs. control) and CXCR5(+)CD4(+) Tfh cells (P = 0.04), but increased foxp3(+)CD4(+) (Treg) cells in the CD4(+) population (P =0.04 vs. control). The IgG ELISpot experiments showed a significant reduction of IgG spots in the bone marrow and the spleen cells from the antiYIL-6RYtreated mice. In vitro treatment of mouse hybridoma (PA2.1) cultures with antiYIL-6R decreased IgG spot formation but had limited effect on cell proliferation. CONCLUSION: The data indicate that antiYIL-6R therapy attenuates alloantibody recall responses by modulating a number of immune regulatory and effector cells, including Th17, Tfh, Treg, and importantly, the long-lived plasma cells in the bone marrow. PMID- 25286052 TI - Alloimmune responses and atherosclerotic disease after kidney transplantation. AB - BACKGROUND: Chronic exposure to exogenous antigens causes accumulation of proinflammatory CD57(+)CD28(-) hyperactivated CD8(+) T cells that may promote atherosclerosis. We hypothesized that persistent alloimmune responses may induce immune activation and contribute to posttransplant atherosclerosis. METHODS: This hypothesis was tested in a single-center cohort of 577 kidney transplant patients. Propensity score analysis was performed to address potential confounding variables by indication. Immune exhaustion was studied in subcohort of 103 patients. RESULTS: Five hundred seventy-seven consecutive renal transplant recipients were included. Seventy-seven atherosclerotic events (AE) (12.3%) occurred during a mean follow-up of 7 years. The cumulative incidence of AE increased with the number of human leukocyte antigen (HLA) mismatches (18%, 10%, and 5% in patients with 5-6, 3-4, and 0-2 mismatches, respectively; P=0.012). Human leukocyte antigen mismatch number (hazards ratio, 1.35; 95% confidence interval, 1.10-1.66, for each supplementary mismatch; P=0.005) was an independent risk factor for AE. In the propensity score match analysis, having received a well-matched kidney conferred a reduced risk of AE (hazards ratio, 0.22; 95% confidence interval, 0.05-0.95; P=0.044). We observed a significant correlation between HLA mismatch numbers and circulating CD57(+)CD28(-) CD8(+) T cells (R=0.31; P=0.017). These CD8(+) T cells were more frequent in patients with more HLA mismatches (P<0.0001). CONCLUSION: Overall, our results suggest that chronic allogeneic stimulation participates to accelerated atherosclerosis observed after transplantation. PMID- 25286053 TI - Calcineurin inhibitor-free immunosuppressive regimen in type 1 diabetes patients receiving islet transplantation: single-group phase 1/2 trial. AB - BACKGROUND: Our final objective is to develop an adoptive therapy with tolerogenic donor-specific type 1 T regulatory cells for patients with type 1 diabetes undergoing islet transplantation. The achievement of this objective depends on the availability of an immunosuppressive treatment compatible with the survival, function, and expansion of type 1 T regulatory cells. METHODS: For this purpose, we designed a single-group, phase 1 to 2 trial with an immunosuppression protocol including: (i) rapamycin treatment before the first islet infusion (starting >= 30 days before transplantation); (ii) induction therapy with anti thymocyte globulin (ATG) instead of anti-interleukin-2Ra monoclonal antibody (after the first islet infusion only); (iii) short-term treatment with steroids and interleukin-1Ra (right before and for 2 weeks after each infusion); rapamycin+mycophenolate mofetil treatment as maintenance therapy. The target enrollment was 10 patients. RESULTS: Ten of 15 patients who started the pretransplant rapamycin treatment completed it. Nine of 10 patients did not complete the induction therapy with ATG, and three of 10 required adaptation of maintenance immunosuppression caused by side effects. Four of 10 patients acquired insulin independence which can be maintained up to year 3 after last infusion. All six other patients have lost their graft, and the early graft loss was associated with lower dose of ATG during induction. CONCLUSION: This protocol resulted feasible, safe but less efficient in maintaining graft survival during the time than other T-cell depletion-based protocols. An adequate induction at the first infusion should be considered to improve the overall clinical outcome. PMID- 25286054 TI - Renal vein extension during living-donor kidney transplantation in the era of hand-assisted laparoscopic living-donor nephrectomy. AB - BACKGROUND: To evaluate retrospectively the clinical outcomes of living-donor kidney transplantations (LDKTs) using renal vein extension (RVE) for donor kidneys with short renal veins. METHODS: Between January 2007 and December 2010, a total of 576 LDKTs were performed with grafts generated by hand-assisted laparoscopic living-donor nephrectomy: 31 (5.4%) transplants with RVE and 545 (94.6%) without an additional vascular procedure for renal vein lengthening. Outcomes were compared in patients who did and did not undergo the RVE procedure during transplantation. RESULTS: The 31 transplantation patients that underwent RVE involved procured kidneys with short renal veins: 29 were right-sided kidneys (93.5%) and 2 were left-sided kidneys (6.5%) (P=0.00). The RVE grafts were obtained from allogenic gonadal veins from female donors (n=16, 51.6%) and iliac veins from deceased donors (n=15, 48.4%). There were no postoperative complications related to the RVE procedure. During a follow-up period of 45.6+/ 15.9 months, there were one (3.2%) graft failure among the 31 patients with RVE and four (0.7%) among the 545 patients without RVE. Delayed graft function was noted in one (3.2%) of the RVE patients and 22 (4.0%) of the patients without RVE. There was no statistically significant difference in graft failure (P=0.24) or delayed graft function (P=1.00) between the two groups. CONCLUSION: During LDKT, donor kidneys with exceptionally short renal veins, which may result in unavoidable tension during renal vein anastomosis, may be modified by RVE, thus facilitating a secure anastomosis and reducing postoperative complications. PMID- 25286055 TI - The diagnostic accuracy of tests for latent tuberculosis infection in hemodialysis patients: a systematic review and meta-analysis. AB - BACKGROUND: Reactivation of latent Mycobacterium tuberculosis infection is an important health concern for patients on hemodialysis because of their immunosuppressed state and in kidney transplant patients receiving immunosuppressive therapy to prevent organ rejection. There are several tests available to determine the presence of latent tuberculosis infection: the tuberculin skin test (TST), QuantiFERON-TB Gold (QFT-G), and T-SPOT.TB. The objective of this study is to evaluate the diagnostic accuracy of these tests in determining latent tuberculosis infection in the hemodialysis population. METHODS: The study design was a systematic review. We selected studies with adequate information to ascertain test sensitivity or specificity of the TST, QFT G, and TSPOT.TB with regards to determining latent tuberculosis infection in the hemodialysis population. RESULTS: One hundred two articles were selected for full review, and 17 were included in the meta-analysis. The TST had a pooled sensitivity of 31% (26%-36%, 95% confidence interval) and specificity of 63% (60% 65%) across eight studies. The QFT-G test had a pooled sensitivity of 53% (46% 59%) and specificity of 69% (65%-72%) across nine studies. The T-SPOT.TB test had a pooled sensitivity of 50% (42%-59%) and specificity of 67% (61%-73%) across three studies. CONCLUSION: The QFT-G and the T-SPOT.TB tests were more sensitive than the TST for diagnosis of latent tuberculosis infection in patients on hemodialysis while offering a comparable level of specificity. This systematic review calls into question the practice of using the TST to screen in this population, especially in patients considered for kidney transplantation. PMID- 25286056 TI - Natural killer cells play a critical role in cardiac allograft vasculopathy in an interleukin-6--dependent manner. AB - BACKGROUND: Approximately 50% of cardiac transplants fail in the long term, and currently, there are no specific treatments to prevent chronic rejection. In the clinic, donor cardiac graft ischemia time is limited to within a few hours and correlates with delayed graft function and organ failure. It is still unknown how ischemic injury negatively influences allograft function over the long term despite advances in immunosuppression therapy. METHODS: Allogeneic cardiac grafts were stored at 4 degrees C for 4 hr before being transplanted into T/B cell deficient Rag(-/-) mice or T/B/natural killer (NK) cell-deficient gammac(-/-)Rag( /-) mice. Grafts were harvested 60 days after transplantation and indicators of chronic allograft vasculopathy (CAV) were quantified. RESULTS: We have found that cold ischemia of cardiac grafts induces CAV after transplantation into Rag1(-/-) mice. Interestingly, cold ischemia-induced CAV posttransplantation was not seen in T/B/NK cell-deficient gammac(-/-)Rag(-/-) mice. However, cardiac grafts in gammac(-/-)Rag(-/-) mice that received an adoptive transfer of NK cells developed CAV, supporting the role of NK cells in CAV development. Analysis of various cytokines that contribute to NK cell function revealed high interleukin (IL)-6 expression in cardiac grafts with CAV. In addition, IL-6-deficient cardiac grafts did not develop CAV after transplantation into allogeneic Rag(-/-) mice. CONCLUSION: These data demonstrate that cold ischemia and NK cells play critical roles in the development CAV. Natural killer cells and injured grafts may play a reciprocal role for CAV development in an IL-6-independent manner. Specific therapeutic strategies may be required to attenuate NK cell contribution to chronic cardiac rejection. PMID- 25286057 TI - Changes in geographic disparity in kidney transplantation since the final rule. AB - BACKGROUND: The national organ allocation system for deceased-donor kidney transplant will endure increased burden as the waitlist expands and organ shortage persists. The Department of Health and Human Services issued the "Final Rule" in 1998 that states "Organs and tissues ought to be distributed on the basis of objective priority criteria and not on the basis of accidents of geography." However, it has not been addressed whether the rule was effective in encouraging regions to share the additional burden equitably. OBJECTIVE: To assess the significance of changes of geographic disparities for four metrics since the rule's adoption: waiting times, transplant rates, pretransplant mortality, and organ quality. METHODS: Using Organ Procurement and Transplant Network data from 1988 through 2009, annual ranges of the metrics were calculated for all donor service areas and United Network for Organ Sharing regions. Time series analyses were used to compare the metrics before and after the enactment of the Final Rule. RESULTS: A total of 412,127 kidney transplant candidates and 178,163 deceased-donor recipients were analyzed. Demographics varied significantly by region. The ranges of the four metrics have worsened by approximately 30% or more after the Final Rule at both the regional and donor service area levels. CONCLUSION: Increasing geographic disparity in allocation procedures may yield diverging outcomes and experiences in different locations for otherwise similar candidates. Consensus for measuring allocation discrepancies and policy interventions are required to mitigate the inequities. PMID- 25286058 TI - Bridging innate with adaptive immunity in transplantation: triggers, sensors, and modulators. AB - The molecular entities present on a cell or organ transplant that trigger the innate immune response and link to the adaptive immune system are increasingly recognized as a key influence on early graft function and for determining the microenvironment that will guide longer-term graft outcomes. The 2014 Beaune Seminar in Transplant Research discussed the evidence for triggers, sensors, and modulators of innate and adaptive immunity in response to alloantigens, challenged the conventional view, developed novel hypotheses, and highlighted the potential for therapeutic manipulation of these responses. PMID- 25286059 TI - The jury is out on the utilization of donors after cardiac death for simultaneous liver and kidney transplantation. PMID- 25286061 TI - To burn or not to burn? Effect of management strategy on North American prairie vegetation for public urban areas in Germany. AB - North American prairie vegetation has been a role model for designing highly attractive plantings for German urban green spaces for the past decade. In combination with gravel mulch top layers on planting sites and non-selective maintenance techniques like mowing or burning, prairie plantings are considered to be cost-effective and low-maintenance. This study was undertaken to assess the impact of different maintenance strategies and especially the necessity of fire management on the development success of ornamental prairie plantings in central Europe. A four factorial split-plot-block design was set up for investigation of different mixtures of prairie species under varying management conditions (mow only, mowing plus selective weeding, mowing plus weeding and burning) on two differing soil types (in-situ topsoil and in-situ topsoil with a graywacke gravel mulch top layer) over three years. Significant effects of maintenance strategy on mortality rates and vitality were documented for a number of target species, which responded species specifically, either being slightly affected by the burning or thriving on it. Those effects were mostly restricted to topsoil sites. A strong impact on weed species presence and abundance and resulting maintenance times was found on both soil types. On topsoil sites, mow-only treatment resulted in a short-term loss of the original planting due to extensive weed growth. Corresponding gravel mulch sites were generally less colonised and visually dominated by weeds. Differences between weeded and weeded plus burned sites were minor. Unexpectedly, weed species populations were mostly unaffected by the additional burning treatment, while maintenance times and costs increased. No overall benefit of fire management for the establishment of prairie plantings was documented. The most effective management combination proved to be mowing plus regular selective weeding measures on gravel mulched planting sites. PMID- 25286060 TI - A Bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer. AB - BACKGROUND: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. METHODS: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. RESULTS: Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50-1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. CONCLUSIONS: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons. PMID- 25286062 TI - Stereoselective construction of the 5-hydroxy diazabicyclo[4.3.1]decane-2-one scaffold, a privileged motif for FK506-binding proteins. AB - A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp(3)-sp(2) Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode. PMID- 25286064 TI - Re-CYCLing Rotavirus. PMID- 25286063 TI - Adalimumab therapy in children with Crohn disease previously treated with infliximab. AB - OBJECTIVES: Adalimumab, a humanised anti-tumour necrosis factor antibody, is an effective treatment in adult patients with refractory Crohn disease (CD). The available literature on its efficacy in children remains limited. We aimed to evaluate the real-world efficacy in paediatric patients with CD and compare the efficacy between infliximab (IFX) nonresponders and patients who lost response to IFX. METHODS: All Dutch patients with CD receiving adalimumab before the age of 18 years after previous IFX therapy were identified. We analysed longitudinal disease activity, assessed by the mathematically weighted Pediatric Crohn's Disease Activity Index (wPCDAI) or the physician global assessment (PGA), and adverse events (AEs). RESULTS: Fifty-three patients with CD were included. Twelve patients received monotherapy and the others received combination treatment with thiopurines (n = 21), methotrexate (n = 11), steroids (n = 7), or exclusive enteral nutrition (n = 2). Median follow-up was 12 months (interquartile range 5 23). Remission was reached in 34 patients (64%, wPCDAI < 12.5 or PGA = 0) after a median of 3.3 months, and maintained by 50% for 2 years. Eleven patients (21%) reached response but not remission (decrease in wPCDAI >= 17.5 or decrease in PGA). Eighteen patients (34%) failed adalimumab treatment because of nonresponse (n = 4), lost response (n = 11), or AEs (n = 3). More IFX nonresponders failed adalimumab treatment than patients who lost response to IFX (2/3 vs 8/34, hazard ratio 18.8, 95% confidence interval 1.1-303.6). Only 1 patient encountered a serious AE, a severe but nonfatal infection. CONCLUSIONS: In clinical practice, adalimumab induces remission in two-thirds of children with IFX refractory CD. PMID- 25286065 TI - Most probable distance between the nucleus and HOMO electron: the latent meaning of atomic radius from the product of chemical hardness and polarizability. AB - The simple relationship between size of an atom, the Pearson hardness, and electronic polarizability is described. The estimated atomic radius correlates well with experimental as well as theoretical covalent radii reported in the literature. Furthermore, the direct connection of atomic radius to HOMO electron density and important notions of conceptual DFT (such as frontier molecular orbitals and Fukui function) has been shown and interpreted. The radial maximum of HOMO density distribution at (alphaeta)(1/2) minimizes the system energy. Eventually, the knowledge of the Fukui function of an atom is sufficient to estimate its electronic polarizability, chemical potential, and hardness. PMID- 25286066 TI - Using client outcome monitoring as a tool for supervision. AB - A large body of research has supported the use of client outcome monitoring and client feedback in psychotherapy. However, discussions between supervisors and trainee clinicians in supervision are still largely based on subjective appraisals made by the trainees. In this article, we discuss 3 strategies for integrating client outcome data and feedback into the supervisory process: training students to obtain and use objective client feedback, using specific client data to inform discussions of clients, and identifying patterns of outcomes across clients to facilitate supervisee growth and development. PMID- 25286067 TI - Time of day and the decision to prescribe antibiotics. PMID- 25286068 TI - Emotion down-regulation diminishes cognitive control: a neurophysiological investigation. AB - Traditional models of cognitive control have explained performance monitoring as a "cold" cognitive process, devoid of emotion. In contrast to this dominant view, a growing body of clinical and experimental research indicates that cognitive control and its neural substrates, in particular the error-related negativity (ERN), are moderated by affective and motivational factors, reflecting the aversive experience of response conflict and errors. To add to this growing line of research, here we use the classic emotion regulation paradigm-a manipulation that promotes the cognitive reappraisal of emotion during task performance-to test the extent to which affective variation in the ERN is subject to emotion reappraisal, and also to explore how emotional regulation of the ERN might influence behavioral performance. In a within-subjects design, 41 university students completed 3 identical rounds of a go/no-go task while electroencephalography was recorded. Reappraisal instructions were manipulated so that participants either down-regulated or up-regulated emotional involvement, or completed the task normally, without engaging any reappraisal strategy (control). Results showed attenuated ERN amplitudes when participants down-regulated their emotional experience. In addition, a mediation analysis revealed that the association between reappraisal style and attenuated ERN was mediated by changes in reported emotion ratings. An indirect effects model also revealed that down regulation predicted sensitivity of error-monitoring processes (difference ERN), which, in turn, predicted poorer task performance. Taken together, these results suggest that the ERN appears to have a strong affective component that is associated with indices of cognitive control and behavioral monitoring. PMID- 25286069 TI - Why is happy-sad more difficult? Focal emotional information impairs inhibitory control in children and adults. AB - This study compared the relative difficulty of the happy-sad inhibitory control task (say "happy" for the sad face and "sad" for the happy face) against other card tasks that varied by the presence and type (focal vs. peripheral; negative vs. positive) of emotional information in a sample of 4- to 11-year-olds and adults (N = 264). Participants also completed parallel "name games" (direct labeling). All age groups made more errors and took longer to respond to happy sad compared to other versions, and the relative difficulty of happy-sad increased with age. The happy-sad name game even posed a greater challenge than some opposite games. These data provide insight into the impact of emotions on cognitive processing across a wide age range. PMID- 25286071 TI - Gratitude facilitates behavioral mimicry. AB - Recent theorists argue that gratitude, besides encouraging social exchange, serves an important function of relationship building. However, there is a lack of research exploring the specific behaviors through which gratitude promotes relationship building. Given that behavioral mimicry serves important affiliative needs, we explored whether gratitude promotes behavioral mimicry. We found that participants who received intentional help later mimicked the behavioral mannerisms of their benefactor. This mimicry tendency was not extended to a nonbenefactor. In contrast, participants who ended up with the same positive outcome, but believed that it was attributable to chance, did not exhibit a reliable level of mimicry. Our results suggest that nonconscious behavioral mimicry might be a subtle but important first step through which gratitude promotes communal relationships. PMID- 25286070 TI - Can't get it out of my head: age differences in affective responsiveness vary with preoccupation and elapsed time after daily hassles. AB - To better understand age differences in negative affective responses to daily hassles, the current study investigated how responses may depend on how much time has elapsed after the hassle and how much one still thinks about the hassle. In an experience-sampling approach with mobile phones, 397 participants aged 12 to 88 years reported their momentary activating (e.g., angry) and deactivating (e.g., disappointed) negative affect and occurrences of hassles, on average 55 times over 3 weeks. On measurement occasions when a hassle had occurred, participants also reported how long ago it occurred and how much they were currently preoccupied with thoughts about the hassle. Multilevel modeling results showed that, compared with more recent hassles, people across the entire age range of the sample reported lower activating, yet higher deactivating, negative affect when hassles occurred a longer time ago. Age differences only emerged in situations when individuals were still preoccupied with a past hassle. In these situations, deactivating negative affect was higher with stronger preoccupation and more elapsed time after the hassles; these effects were more pronounced with older age. Activating negative affect was higher the more people reported being preoccupied with the hassle and this effect was also more pronounced with age. The results foster an understanding of age differences in negative affective responses to daily hassles by considering preoccupation with hassles and investigating activating and deactivating negative affect separately. We discuss under which circumstances affective responsiveness and age differences therein are more or less pronounced. (PsycINFO Database Record PMID- 25286072 TI - Anxiety increases breakthrough of threat stimuli in continuous flash suppression. AB - Trait anxiety is associated with an excessive processing of danger-related stimuli, predisposing individuals to quickly detect threatening cues. Early, automatic mechanisms are believed to be responsible for the production of these cognitive biases; however, limitations in the paradigms most commonly used to achieve visual suppression or attentional unawareness have left open the possibility of strategic mechanisms influencing these early stages of information processing. Establishing whether symptoms of anxiety are associated with truly automatic biases in processing is an essential step in determining their etiology and in developing targeted cognitive interventions. We addressed this question using continuous flash suppression (CFS), a novel and robust method of visual suppression capable of rendering a stimulus invisible from awareness for extended durations. We specifically investigated the degree to which trait anxiety influenced the suppression of threatening, positive, and neutral faces. Forty nine individuals, with no reported history of psychological problems and varying levels of anxiety, were recruited. Higher trait anxiety scores were associated with an increased speed to detect fearful compared with happy faces. These results indicate that the bias toward threatening information associated with symptoms of anxiety operates, at least partly, at an early stage of information processing. This suggests that cognitive interventions for anxiety may benefit from directly targeting such early and potentially preconscious processes. PMID- 25286073 TI - Assessing the Impact of Anger State on the Three Attentional Networks with the ANT-I. AB - Anger is a negative and highly aroused emotion. Previous research has revealed that a high level of arousal can induce the participant in a physical preparation and self-awareness. The aim of this research was to study the influence of anger on the attentional network using the Attention Network Test-Interactions (ANT-I). This test has been developed in order to assess 3 attentional networks: alerting, orienting, and executive control. Here, participants were induced in anger using the autobiographic recall procedure or in a neutral mood before the realization of the ANT-I. As expected, the results showed a better alerting score for the angry group. The possible origin of this alerting gain related to the high level of arousal is discussed. The results obtained should enlighten the interaction between emotion and the functioning of the attentional system. They also may be relevant for applied fields related to anger. PMID- 25286074 TI - Reappraisal but not suppression downregulates the experience of positive and negative emotion. AB - The emotion regulation literature is growing exponentially, but there is limited understanding of the comparative strengths of emotion regulation strategies in downregulating positive emotional experiences. The present research made the first systematic investigation examining the consequences of using expressive suppression and cognitive reappraisal strategies to downregulate positive and negative emotion within a single design. Two experiments with over 1,300 participants demonstrated that reappraisal successfully reduced the experience of negative and positive affect compared with suppression and control conditions. Suppression did not reduce the experience of either positive or negative emotion relative to the control condition. This finding provides evidence against the assumption that expressive suppression reduces the experience of positive emotion. This work speaks to an emerging literature on the benefits of downregulating positive emotion, showing that suppression is an appropriate strategy when one wishes to reduce positive emotion displays while maintaining the benefits of positive emotional experience. PMID- 25286075 TI - Preschoolers and toddlers use ownership to predict basic emotions. AB - People's emotions often depend on ownership. We report 3 experiments showing that preschoolers and toddlers consider ownership in predicting basic emotions. In Experiment 1, 3-year-olds were sensitive to ownership when predicting how a character would feel when objects went missing. Experiment 2 found that 3- to 5 year-olds consider ownership when predicting emotional reactions to harmless violations of ownership rights, and Experiment 3 showed 2-year-olds also do this. For instance, preschoolers and toddlers predicted a girl would be upset when a boy played with her teddy bear without permission, but not when he played with his own. These findings show that preschoolers and toddlers understand basic causal relations between ownership and emotions, and are also the first to show that 2-year-olds are sensitive to other people's ownership rights. PMID- 25286076 TI - Facial expression influences face identity recognition during the attentional blink. AB - Emotional stimuli (e.g., negative facial expressions) enjoy prioritized memory access when task relevant, consistent with their ability to capture attention. Whether emotional expression also impacts on memory access when task-irrelevant is important for arbitrating between feature-based and object-based attentional capture. Here, the authors address this question in 3 experiments using an attentional blink task with face photographs as first and second target (T1, T2). They demonstrate reduced neutral T2 identity recognition after angry or happy T1 expression, compared to neutral T1, and this supports attentional capture by a task-irrelevant feature. Crucially, after neutral T1, T2 identity recognition was enhanced and not suppressed when T2 was angry-suggesting that attentional capture by this task-irrelevant feature may be object-based and not feature-based. As an unexpected finding, both angry and happy facial expressions suppress memory access for competing objects, but only angry facial expression enjoyed privileged memory access. This could imply that these 2 processes are relatively independent from one another. PMID- 25286077 TI - Attenuating fearful memories: effect of cued extinction on intrusions. AB - Exposure-based therapies for posttraumatic stress disorder are thought to reduce intrusive memories through extinction processes. Methods that enhance extinction may translate to improved treatment. Rat research suggests retrieving a memory via a conditioned stimulus (CS) cue, and then modifying the retrieved memory within a specific reconsolidation window may enhance extinction. In humans, studies (e.g., Kindt & Soeter, 2013; Schiller et al., 2010) using basic learning paradigms show discrepant findings. Using a distressing film paradigm, participants (N = 148) completed fear acquisition and extinction. At extinction, they were randomized to 1 of 3 groups: CS cue within reconsolidation window, CS cue outside window, or non-CS cue within window. Intrusions were assessed 24 hr after extinction. Participants receiving the CS cue and completing extinction within the reconsolidation window had more intrusions (M = 2.40, SD = 2.54) than those cued outside (M = 1.65, SD = 1.70) or those receiving a non-CS cue (M = 1.24, SD = 1.26), F(2, 145) = 4.52, p = .01, d = 0.55. Consistent with the reconsolidation hypothesis, presenting a CS cue does appear to activate a specific period of time during which a memory can be updated. However, the CS cue caused increased, rather than decreased, frequency of intrusions. Understanding parameters of preextinction cueing may help us better understand reconsolidation as a potential memory updating mechanism. PMID- 25286078 TI - Genetic variants of interleukin-4 gene in autoimmune thyroid diseases: an updated meta-analysis. AB - Autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are common autoimmune endocrine disorders. Interleukin-4 (IL-4), a cytokine secreted by T cells, plays a critical role in antigen-specific Th2 responses. The IL-4 gene is highly polymorphic and it has been reported that the polymorphism at -590 (T/C, rs2243250) in the promoter region of IL-4 may contribute to the development of AITDs. Recently, several case control studies have examined the association of genetic variants of IL-4 with AITDs. However, the results of these studies remain conflicting. To systematically study the role of IL-4 in the pathogenesis of AITDs, we conducted a meta-analysis including 11 eligible studies (1847 cases and 2068 healthy controls). Fixed-effect or random-effect models were used to calculate pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Our results revealed a significant association between the IL-4 genetic variant (-590, T/C, rs2243250) and the risk of developing AITDs (TC + TT versus TT genotype: OR = 1.83, 95% CI = 1.083-3.091, p = 0.024). These findings demonstrate that the IL-4 rs2243250 genetic variant might play a key role in the development of AITDs. PMID- 25286079 TI - Biological Effects of Anti-Granulocyte-Macrophage Colony-Stimulating Factor (GM CSF) Antibody Formation in Patients Treated With GM-CSF (Sargramostim) as Adjuvant Therapy of Melanoma. AB - OBJECTIVES: We investigated the development of binding and neutralizing antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving prolonged therapy with GM-CSF as adjuvant therapy of melanoma and the impact of these antibodies on biological effects. METHODS: Fifty-three patients with high-risk melanoma that had been surgically excised were treated with GM-CSF, 125 MUg/m daily for 14 days every 28 days for 1 year after surgical resection of disease. Serum samples for antibodies to GM-CSF were measured before treatment and on study days 155 and 351. Blood draws for testing biological effects were keyed to GM-CSF administration: days 0 (before), 15 (after 14 d on GM-CSF), 29 (after 14 d off GM-CSF), 155, and 351 (after 14 d on GM-CSF in the sixth and 13th cycle of treatment). RESULTS: Of 53 patients enrolled, 43 were evaluable for the development of anti-GM-CSF antibodies. Of these, 93% developed binding antibodies and 42% developed both binding and neutralizing antibodies. The increase in the white blood cell count, percent eosinophils, or neopterin levels engendered by GM-CSF administration was abrogated or markedly decreased in patients with neutralizing antibodies but not in patients who developed only binding antibodies. CONCLUSIONS: Ninety-three percent of patients with melanoma treated with GM-CSF as adjuvant therapy develop antibodies to GM-CSF. In those with neutralizing antibodies, a diminution of the biological effects of GM-CSF was observed. The development of neutralizing antibodies might also abrogate the potential clinical benefit of this treatment and should be considered in the design of future clinical trials. PMID- 25286080 TI - A qualitative examination of the GST proteome of the blow fly, Lucilia cuprina: use of cross-database matching of MALDI data. AB - This study was aimed at determining whether, in the absence of a full genetic database for the Sheep Blowfly (Lucilia cuprina) glutathione transferases from this insect could be characterized by cross-database matching of MALDI TOF data with the database for other metazoan organisms. Glutathione transferases of L. cuprina were partially purified by the sequential use of affinity chromatography media; first on glutathione immobilized on epichlorohydrin-activated Sepharose 6B and subsequently on dinitrophenyl-glutathione immobilized on the same matrix. The Proteins obtained were separated by 2D SDS-PAGE and tentatively characterized by MALDI-TOF analysis of tryptic peptides. The mass fragments were matched against the NCBInr "Other metazoa" database. The GSTs matched to other insect species were identified as coming from the Sigma, Delta and Epsilon classes. The relative abundance of most of these GSTs appeared to vary little during development, or across bodily segments, an exception being one group, (Zone E) tentatively identified as Epsilon class, which was most prominent in eggs and absent from adults and which is therefore assumed to play a specific role in development. PMID- 25286081 TI - Fluorescence imaging with one-nanometer accuracy (FIONA). AB - Fluorescence imaging with one-nanometer accuracy (FIONA) is a simple but useful technique for localizing single fluorophores with nanometer precision in the x-y plane. Here a summary of the FIONA technique is reported and examples of research that have been performed using FIONA are briefly described. First, how to set up the required equipment for FIONA experiments, i.e., a total internal reflection fluorescence microscopy (TIRFM), with details on aligning the optics, is described. Then how to carry out a simple FIONA experiment on localizing immobilized Cy3-DNA single molecules using appropriate protocols, followed by the use of FIONA to measure the 36 nm step size of a single truncated myosin Va motor labeled with a quantum dot, is illustrated. Lastly, recent effort to extend the application of FIONA to thick samples is reported. It is shown that, using a water immersion objective and quantum dots soaked deep in sol-gels and rabbit eye corneas (>200 um), localization precision of 2-3 nm can be achieved. PMID- 25286082 TI - Fisetin up-regulates the expression of adiponectin in 3T3-L1 adipocytes via the activation of silent mating type information regulation 2 homologue 1 (SIRT1) deacetylase and peroxisome proliferator-activated receptors (PPARs). AB - Adiponectin, an adipokine, has been described as showing physiological benefits against obesity-related malfunctions and vascular dysfunction. Several natural compounds that promote the expression and secretion of adipokines in adipocytes could be useful for treating metabolic disorders. This study investigated the effect of fisetin, a dietary flavonoid, on the regulation of adiponectin in adipocytes using 3T3-L1 preadipocytes. The expression and secretion of adiponectin increased in 3T3-L1 cells upon treatment with fisetin in a dose dependent manner. Fisetin-induced adiponectin secretion was inhibited by peroxisome proliferator-activated receptor (PPAR) antagonists. It was also revealed that fisetin increased the activities of PPARs and silent mating type information regulation 2 homologue 1 (SIRT1) in a dose-dependent manner. Furthermore, the up-regulation of adiponectin and the activation of PPARs induced by fisetin were prevented by a SIRT1 inhibitor. Fisetin also promoted deacetylation of PPAR gamma coactivator 1 (PGC-1) and its interaction with PPARs. SIRT knockdown by siRNA significantly decreased both adiponectin production and PPARs-PGC-1 interaction. These results provide evidence that fisetin promotes the gene expression of adiponectin through the activation of SIRT1 and PPARs in adipocytes. PMID- 25286083 TI - Mussel-inspired polydopamine coated hollow carbon microspheres, a novel versatile filler for fabrication of high performance syntactic foams. AB - Syntactic foams, which can be synthesized by mechanical mixing of hollow microspheres with a matrix material, are a special class of lightweight composite materials. Developing of high-performance syntactic foams remains challenges. In this work, a facile and environmentally friendly surface modification method employing polydopamine (PDA) as a surface treatment agent for hollow carbon microspheres (HCMs) was used, aiming to extend the application of syntactic foams to seldom touched areas. The PDA coating was used as a strategy for interfacial interaction enhancement and also as a platform for further metal coating meant for electromagnetic interference (EMI) shielding. The stronger interfacial interaction between microspheres and polymer matrix provided effective interfacial stress transfer, as a result of the syntactic foams with high strength to weight ratio. Furthermore, the PDA coating on HCMs served as a versatile platform for the growth of noble metals on the surface of PDA-HCMs. Silver nanoparticles was grown by PDA medium. The silver coated HCMs (Ag-PDA HCMs) impacted the complex permittivity of the syntactic foams leading to high EMI shielding effectiveness (SE). The specific EMI SE reached up to 46.3 dB.cm(3)/g, demonstrated the Ag-PDA-HCMs/epoxy syntactic foam as a promising candidate for lightweight high-performance EMI shielding material. PMID- 25286085 TI - Intracerebroventricular viral injection of the neonatal mouse brain for persistent and widespread neuronal transduction. AB - With the pace of scientific advancement accelerating rapidly, new methods are needed for experimental neuroscience to quickly and easily manipulate gene expression in the mouse brain. Here we describe a technique first introduced by Passini and Wolfe for direct intracranial delivery of virally-encoded transgenes into the neonatal mouse brain. In its most basic form, the procedure requires only an ice bucket and a microliter syringe. However, the protocol can also be adapted for use with stereotaxic frames to improve consistency for researchers new to the technique. The method relies on the ability of adeno-associated virus (AAV) to move freely from the cerebral ventricles into the brain parenchyma while the ependymal lining is still immature during the first 12-24 hr after birth. Intraventricular injection of AAV at this age results in widespread transduction of neurons throughout the brain. Expression begins within days of injection and persists for the lifetime of the animal. Viral titer can be adjusted to control the density of transduced neurons, while co-expression of a fluorescent protein provides a vital label of transduced cells. With the rising availability of viral core facilities to provide both off-the-shelf, pre-packaged reagents and custom viral preparation, this approach offers a timely method for manipulating gene expression in the mouse brain that is fast, easy, and far less expensive than traditional germline engineering. PMID- 25286084 TI - Cancer, coping, and cognition: a model for the role of stress reactivity in cancer-related cognitive decline. AB - BACKGROUND: Cognitive decline and accompanying neurological changes associated with non-CNS cancer diagnosis and treatment have been increasingly identified in a subset of patients. Initially believed to be because of neurotoxic effects of chemotherapy exposure, observation of cognitive decline in patients not treated with chemotherapy, cancer-diagnosed individuals prior to treatment, and patients receiving alternative treatment modalities (surgery, endocrine therapy, and radiation) has led to the investigation of additional potential etiologies and moderating factors. Stressful experiences have long been posited as a contributor to these cognitive changes. Through reciprocal connectivity with peripheral systems, the brain maintains a dynamic circuitry to adapt to stress (allostasis). However, overuse of this system leads to dysregulation and contributes to pathophysiology (allostatic load). At this time, little research has been conducted to systematically examine the role of allostatic load in cancer-related cognitive dysfunction. METHODS AND RESULTS: Here, we integrate theories of stress biology, neuropsychology, and coping and propose a model through which individuals with a high level of allostatic load at diagnosis may be particularly vulnerable to the neurocognitive effects of cancer. CONCLUSIONS: Opportunities for future research to test and extend proposed mechanisms are discussed in addition to points of prevention and intervention based on individual variation in stress reactivity and coping skills. PMID- 25286086 TI - Erythrocyte membrane is an alternative coating to polyethylene glycol for prolonging the circulation lifetime of gold nanocages for photothermal therapy. AB - Gold nanocages (AuNCs), which have tunable near-infrared (NIR) absorption and intrinsically high photothermal conversion efficiency, have been actively investigated as photothermal conversion agents for photothermal therapy (PTT). The short blood circulation lifetime of AuNCs, however, limits their tumor uptake and thus in vivo applications. Here we show that such a limitation can be overcome by cloaking AuNCs with red blood cell (RBC) membranes, a natural stealth coating. The fusion of RBC membranes over AuNC surface does not alter the unique porous and hollow structures of AuNCs, and the resulting RBC-membrane-coated AuNCs (RBC-AuNCs) exhibit good colloidal stability. Upon NIR laser irradiation, the RBC-AuNCs demonstrate in vitro photothermal effects and selectively ablate cancerous cells within the irradiation zone as do the pristine biopolymer-stealth coated AuNCs. Moreover, the RBC-AuNCs exhibit significantly enhanced in vivo blood retention and circulation lifetime compared to the biopolymer-stealth coated counterparts, as demonstrated using a mouse model. With integrated advantages of photothermal effects from AuNCs and long blood circulation lifetime from RBCs, the RBC-AuNCs demonstrate drastically enhanced tumor uptake when administered systematically, and mice that received PPT cancer treatment modulated by RBC-AuNCs achieve 100% survival over a span of 45 days. Taken together, our results indicate that the long circulating RBC-AuNCs may facilitate the in vivo applications of AuNCs, and the RBC-membrane stealth coating technique may pave the way to improved efficacy of PPT modulated by noble metal nanoparticles. PMID- 25286087 TI - Episcleral infantile hemangioma successfully treated with topical timolol. AB - Episcleral hemangiomas are usually associated with neonatal hemangiomatosis. Recently, propranolol has been described for the treatment of this entity. We present for the first time a patient with an episcleral hemangioma without neonatal hemangiomatosis successfully treated with topical timolol. PMID- 25286088 TI - A procedure to observe context-induced renewal of pavlovian-conditioned alcohol seeking behavior in rats. AB - Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues. PMID- 25286089 TI - Neuroprotection of a novel cyclopeptide C*HSDGIC* from the cyclization of PACAP (1-5) in cellular and rodent models of retinal ganglion cell apoptosis. AB - PURPOSE: To investigate the protective effects of a novel cyclopeptide C*HSDGIC* (CHC) from the cyclization of Pituitary adenylate cyclase-activating polypeptide (PACAP) (1-5) in cellular and rodent models of retinal ganglion cell apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: Double-labeling immunohistochemistry was used to detect the expression of Thy-1 and PACAP receptor type 1 in a retinal ganglion cell line RGC-5. The apoptosis of RGC-5 cells was induced by 0.02 J/cm(2) Ultraviolet B irradiation. MTT assay, flow cytometry, fluorescence microscopy were used to investigate the viability, the level of reactive oxygen species (ROS) and apoptosis of RGC-5 cells respectively. CHC attenuated apoptotic cell death induced by Ultraviolet B irradiation and inhibited the excessive generation of ROS. Moreover, CHC treatment resulted in decreased expression of Bax and concomitant increase of Bcl-2, as was revealed by western-blot analysis. The in vivo apoptosis of retinal ganglion cells was induced by injecting 50 mM N-methyl D-aspartate (NMDA) (100 nmol in a 2 uL saline solution) intravitreally, and different dosages of CHC were administered. At day 7, rats in CHC+ NMDA-treated groups showed obvious aversion to light when compared to NMDA rats. Electroretinogram recordings revealed a marked decrease in the amplitudes of a wave, b-wave, and photopic negative response due to NMDA damage. In retina receiving intravitreal NMDA and CHC co-treatment, these values were significantly increased. CHC treatment also resulted in less NMDA-induced cell loss and a decrease in the proportion of dUTP end-labeling-positive cells in ganglion cell line. CONCLUSIONS: C*HSDGIC*, a novel cyclopeptide from PACAP (1-5) attenuates apoptosis in RGC-5 cells and inhibits NMDA-induced retinal neuronal death. The beneficial effects may occur via the mitochondria pathway. PACAP derivatives like CHC may serve as a promising candidate for neuroprotection in glaucoma. PMID- 25286090 TI - Super-resolution imaging of the cytokinetic Z ring in live bacteria using fast 3D structured illumination microscopy (f3D-SIM). AB - Imaging of biological samples using fluorescence microscopy has advanced substantially with new technologies to overcome the resolution barrier of the diffraction of light allowing super-resolution of live samples. There are currently three main types of super-resolution techniques - stimulated emission depletion (STED), single-molecule localization microscopy (including techniques such as PALM, STORM, and GDSIM), and structured illumination microscopy (SIM). While STED and single-molecule localization techniques show the largest increases in resolution, they have been slower to offer increased speeds of image acquisition. Three-dimensional SIM (3D-SIM) is a wide-field fluorescence microscopy technique that offers a number of advantages over both single-molecule localization and STED. Resolution is improved, with typical lateral and axial resolutions of 110 and 280 nm, respectively and depth of sampling of up to 30 um from the coverslip, allowing for imaging of whole cells. Recent advancements (fast 3D-SIM) in the technology increasing the capture rate of raw images allows for fast capture of biological processes occurring in seconds, while significantly reducing photo-toxicity and photobleaching. Here we describe the use of one such method to image bacterial cells harboring the fluorescently labelled cytokinetic FtsZ protein to show how cells are analyzed and the type of unique information that this technique can provide. PMID- 25286092 TI - Overdiagnosis - overtreatment. PMID- 25286091 TI - One dose versus three weekly doses of benzathine penicillin G for patients co infected with HIV and early syphilis: a multicenter, prospective observational study. AB - BACKGROUND: One dose of benzathine penicillin G (BPG) has been recommended for HIV-infected patients with early syphilis (primary, secondary, and early latent syphilis) in the sexually transmitted diseases treatment guidelines, but clinical data to support such a recommendation are limited. METHODS: We prospectively observed the serological response to 1 or 3 weekly doses of BPG in HIV-infected adults who sought treatment of early syphilis at 8 hospitals around Taiwan. Rapid plasma reagin (RPR) titers were followed every 3-6 months after treatment. The serological response was defined as a 4-fold or greater decline in RPR titers at 12 months of treatment. The missing values were treated by following the last observed-carried-forward principle. We hypothesized that 1 dose was non-inferior to 3 weekly doses of BPG with the non-inferiority margin for the difference of serological response set to 10%. RESULTS: Between 2007 and 2012, 573 patients completed at least 12 months of follow-up: 295 (51.5%) receiving 1 dose of BPG (1 dose group) and 278 (48.5%) 3 doses (3-dose group). Overall, 198 patients (67.1%; 95% confidence interval [CI], 61.4-72.5%) in the 1-dose group achieved serological response at 12 months, as did 208 patients (74.8%; 95% CI, 69.3 79.8%) in the 3-dose group (one-sided 95% CI of the difference, 15.1%). In the multivariate analysis, secondary syphilis (adjusted odds ratio [AOR], 1.90; 95% CI 1.17-3.09), RPR titer >=32 (AOR, 1.93; 95% CI, 1.38-2.69), and 3 doses of BPG (AOR, 1.68; 95% CI, 1.20-2.36) were independently associated with a serological response. The time to the first episode of treatment failure was 1184 (standard deviation [SD], 70.5) and 1436 (SD, 80.0) days for 1- and 3-dose group, respectively. CONCLUSIONS: Single-dose BPG resulted in a higher serological failure rate and shorter time to treatment failure than 3 weekly doses of BPG in the treatment of early syphilis in HIV-infected patients. PMID- 25286093 TI - Prevalence and identification of Cryptosporidium species in paediatric patients with diarrhoea. AB - OBJECTIVES: To determine the prevalence of Cryptosporidium infection in children with diarrhoea, identify associated factors and identify the parasite using Polymerase Chain Reaction (PCR). METHODS: A total of 138 diarrhoeic faecal samples were collected between August 2011 and February 2013, from children under 12 years of age, admitted to paediatric units of Teaching Hospitals, Kandy and Peradeniya, Sirimawo Bandaranayake Childrens' Hospital, Peradeniya and District General Hospital, Matale. One hundred faecal samples collected from healthy children were used as controls. All control and test samples were screened for the presence of Cryptosporidium oocysts with Modified Ziehl-Neelsen (MZN) method and PCR. RESULTS: Prevalence of Cryptosporidium infection among children with diarrhoea was 5.7%. All the cases positive for Cryptosporidium were below 3 years of age. The majority (7 out of 8) of the positive cases had watery diarrhoea while none of the healthy children excreted Cryptosporidium oocysts in the faeces. Of the 8 positive cases, 6 had a history of animal contact. A large proportion of positive cases used pipe borne municipal water. The majority (66.6%) of positive cases did not consume boiled cooled water. We were able to identify C. parvum from one of the eight cases that had diarrhoea. CONCLUSIONS: The current study shows that Cryptosporidium is one of the aetiological agents responsible for childhood watery diarrhoea in Sri Lanka, thus stressing the importance of routine stool examination for Cryptosporidium oocysts. This study recommends boiling water as an important measure to prevent the transmission of Cryptosporidium oocysts. Further molecular studies are needed to determine the other species of Cryptosporidium responsible for cryptosporidiosis in children in Sri Lanka. PMID- 25286094 TI - Polymerase chain reaction - restriction fragment length polymorphism analysis for the differentiation of mycobacterial species in bronchial washings. AB - OBJECTIVES: To identify mycobacterial species in bronchoscopy specimens with a simple assay based on polymerase chain reaction and restriction enzyme digestion. METHODS: Sputum smear negative, bronchoscopy specimens (n=202) were collected from patients attending the Central Chest Clinic and the Teaching Hospital Kandy, Sri Lanka. DNA, extracted from the mycobacterial cultures (n=43) were amplified using known mycobacterial specific Sp1 and Sp2 primers. Resulting products were digested with HaeIII and CfoI restriction enzymes and DNA sequencing was performed for the selected isolates. RESULTS: Among the culture positive patients, PCR was able to distinguish 12 rapid growers (~280-320 bp), 15 slow (~200-220 bp) and 10 patients having both rapid and slow and one having two rapid growing mycobacteria. DNA Sequence analysis revealed the presence of M. intracellulare (n=3), M. phocaicum (n=7), M. tuberculosis complex (n=13), Nocardia (n=2), M. smegmatis (n=1) and Mycobacterium sp (n=12). The identified organisms got digested upon exposure to HaeIII restriction enzyme whereas when exposed to CfoI, only M. phocaicum yielded 80 bp and 230 bp DNA fragments while others remained undigested. Consequently, six patients were confirmed to have M. tuberculosis complex, seven had both M. tuberculosis and non-tuberculosis bacteria (NTM) in their bronchoscopy specimens while 21 had NTM. CONCLUSIONS: Optimised PCR-RFLP assay was able to differentiate M. tuberculosis complex bacteria from nontuberculosis mycobacteria and Nocardia. Molecular analysis confirmed the presence of NTM in bronchoscopy specimens and according to the study a significant proportion of patients (13% to 14%) of the study population were found to have NTM in their bronchial washings. PMID- 25286095 TI - Elder abuse among outpatient department attendees in a tertiary care hospital in Sri Lanka. AB - OBJECTIVES: Abuse of older people is a hidden problem. Some believe that it is less in Asian societies as the extended family is a protective factor. The real extent of the problem however, is not researched adequately in Sri Lanka. METHODS: A cross sectional descriptive study was conducted at the North Colombo Teaching Hospital on 530 consecutive adults above 60 years of age attending the out-patient department. The Hwalek-Sengstock elder abuse screening test with modifications to address socio-cultural differences was administered. A brief demographic questionnaire and questions on past and present abuse were also included. RESULTS: Out of 530 elders studied, 32 (6%) were above 80 years of age and the mean age was 68.5 years. Male to female ratio was 1:2. Abuse, either physical, psychological, verbal or neglect was reported by 239 (45%) elders. Physical abuse was reported by 5.6%. The screening test revealed that the study population was vulnerable to psychological and financial abuse. Total overall rate of abuse was 38.5%. Loneliness was reported by 26%. Of the caregivers, 22% were financially dependent on the elders. Having more than three children was a risk factor for psychological and financial abuse and being single was a risk factor for psychological abuse. CONCLUSIONS: Physical, emotional and financial abuse of elders were reported in our study population. A limitation of this study was that it studied elders who sought treatment at a tertiary care hospital. Community studies will be needed to establish the true prevalence of elder abuse. PMID- 25286096 TI - Identification of aero-allergen sensitization in children seeking treatment for bronchial asthma at a tertiary care hospital for children in Sri Lanka. AB - OBJECTIVES: Despite a significant rise in asthma globally as well as in Sri Lanka, data regarding allergen sensitization patterns and other risk factors for asthma are not available. Therefore, we set out to determine the allergen sensitization patterns in children with asthma in Sri Lanka. METHODS: Skin prick testing for common indoor aeroallergens (cockroach, cat, dog, house dust mite, moulds) were carried out in 156 children with bronchial asthma at Lady Ridgeway Hospital for Children. RESULTS: 49.1% of the patients were sensitized to at least one allergen and 6.4% were sensitized to three or more allergens. Of the children 37.8% tested positive to house dust mite, 23.7% to cockroach, 5.8% to indoor moulds, 12.2% to cats and 8.9% to dogs. Allergen sensitization was significantly less in children aged four years or younger than in older children (p<0.0001). A family history of asthma or allergic rhinitis (AR) was a significant risk factor (p<0.0001) for allergen sensitization (OR 10.9, 95% CI 3.9 to 30.1). Frequency of symptoms was significantly higher in those who used firewood alone compared to those who used other fuels (OR 2.5, 95% CI 1.1 to 5.8). CONCLUSIONS: Sensitization to aero-allergens was seen in a majority of children with asthma. Sensitization was significantly more in children above 4 years of age. Patients with more frequent symptoms and with AR were more likely to be sensitized to allergens. PMID- 25286097 TI - Chronic kidney disease in rural areas of Sri Lanka: an evolving catastrophe needing an urgent response. PMID- 25286098 TI - Cardiac toxicity with nodal bradycardia due to Panama rubber (Castilla elastica: Moraceae) poisoning. PMID- 25286099 TI - McArdle syndrome with recurrent rhabdomyolysis in a middle aged man. PMID- 25286100 TI - Myelitis and cerebral vasculopathy following neck irradiation. PMID- 25286101 TI - Two unusual features in a child with Berardinelli-Seip congenital generalised lipodystrophy. PMID- 25286102 TI - Genital piercing and beading; threat to life? PMID- 25286103 TI - Sexual violence against women: a challenge. PMID- 25286104 TI - Education in psychiatry: wider reforms needed--a reply. PMID- 25286105 TI - Platelet recovery in dengue--a reply. PMID- 25286106 TI - Raman spectroscopy of soft musculoskeletal tissues. AB - Tendon, ligament, and joint tissues are important in maintaining daily function. They can be affected by disease, age, and injury. Slow tissue turnover, hierarchical structure and function, and nonlinear mechanical properties present challenges to diagnosing and treating soft musculoskeletal tissues. Understanding these tissues in health, disease, and injury is important to improving pharmacologic and surgical repair outcomes. Raman spectroscopy is an important tool in the examination of soft musculoskeletal tissues. This article highlights exciting basic science and clinical/translational Raman studies of cartilage, tendon, and ligament. PMID- 25286107 TI - Ghrelin effects expression of several genes associated with depression-like behavior. AB - Ghrelin (Ghr) is an orexigenic peptide that is being investigated for its potential role in development of anxiety-like behavior and modulation of depressive-like symptoms induced by bilateral olfactory bulbectomy (OB) in rodents. Olfactory bulbectomy is an animal model useful to study of depression and Ghr could be an alternative therapeutic tool in depression therapy. We studied the effects of intracerebroventricular (i.c.v.) Ghr administration on the expression of hypothalamic genes related to depression and mood (delta opioid receptor (DOR), mu opioid receptor (MOR) and kappa opioid receptor (KOR), lutropin-choriogonadotropic hormone receptor (LHCGR), serotonin transporter (SERT), interleukin 1 beta (IL-1b), vasopressin (AVP) and corticotrophin releasing hormone (CRH)) in OB animals, as well as changes in plasma levels of AVP, CRH and adenocorticotropic hormone (ACTH). We found that acute Ghr 0.3 nmol/MUl administration increases gene expression of DOR, SERT and LHCGR in OB mice and decreased expression of IL-1b, suggesting that these genes could be involved in the antidepressant-like effects of Ghr. In addition, OB animals exhibit high AVP gene expression and elevated plasma concentrations of AVP and ACTH and acute Ghr 0.3 nmol/MUl administration reduces AVP gene expression and the concentration of these hormones, suggesting that peptide-effects on depressive-like behavior could be mediated at least in part via AVP. In conclusion, this study provides new evidence about genes, receptors and hormones involved in the antidepressant mechanism/s induced by Ghr in OB animals. PMID- 25286108 TI - Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C terminal tryptophan residues and lipid modification. AB - Aldehyde dehydrogenases (ALDHs) catalyse the conversion of toxic aldehydes into non-toxic carboxylic acids. Of the 21 ALDHs in mice, it is the ALDH3 family members (ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2 and ALDH3B3) that are responsible for the removal of lipid-derived aldehydes. However, ALDH3B2 and ALDH3B3 have yet to be characterized. In the present study, we examined the enzyme activity, tissue distribution and subcellular localization of ALDH3B2 and ALDH3B3. Both were found to exhibit broad substrate preferences from medium- to long-chain aldehydes, resembling ALDH3A2 and ALDH3B1. Although ALDH3B2 and ALDH3B3 share extremely high sequence similarity, their localizations differ, with ALDH3B2 found in lipid droplets and ALDH3B3 localized to the plasma membrane. Both were modified by prenylation at their C-termini; this modification greatly influenced their membrane localization and enzymatic activity towards hexadecanal. We found that their C-terminal regions, particularly the two tryptophan residues (Trp462 and Trp469) of ALDH3B2 and the two arginine residues (Arg462 and Arg463) of ALDH3B3, were important for the determination of their specific localization. Abnormal quantity and perhaps quality of lipid droplets are implicated in several metabolic diseases. We speculate that ALDH3B2 acts to remove lipid-derived aldehydes in lipid droplets generated via oxidative stress as a quality control mechanism. PMID- 25286109 TI - Genetic differentiation revealed by selective loci of drought-responding EST-SSRs between upland and lowland rice in China. AB - Upland and lowland rice (Oryza sativa L.) represent two of the most important rice ecotypes adapted to ago-ecosystems with contrasting soil-water conditions. Upland rice, domesticated in the water-limited environment, contains valuable drought-resistant characters that can be used in water-saving breeding. Knowledge about the divergence between upland and lowland rice will provide valuable cues for the evolution of drought-resistance in rice. Genetic differentiation between upland and lowland rice was explored by 47 Simple Sequence Repeats (SSRs) located in drought responding expressed sequence tags (ESTs) among 377 rice landraces. The morphological traits of drought-resistance were evaluated in the field experiments. Different outlier loci were detected in the japonica and indica subspecies, respectively. Considerable genetic differentiation between upland and lowland rice on these outlier loci was estimated in japonica (Fst = 0.258) and indica (Fst = 0.127). Furthermore, populations of the upland and lowland ecotypes were clustered separately on these outlier loci. A significant correlation between genetic distance matrices and the dissimilarity matrices of drought resistant traits was determined, indicating a certain relationship between the upland-lowland rice differentiation and the drought-resistance. Divergent selections occur between upland and lowland rice on the drought-resistance as the Qsts of some drought-resistant traits are significantly higher than the neutral Fst. In addition, the upland- and lowland-preferable alleles responded differently among ecotypes or allelic types under osmotic stress. This shows the evolutionary signature of drought resistance at the gene expression level. The findings of this study can strengthen our understanding of the evolution of drought-resistance in rice with significant implications in the improvement of rice drought-resistance. PMID- 25286111 TI - Aging, hypercoagulability, and leg necrosis in critical limb ischemia. AB - BACKGROUND: Aging is associated with changes in coagulation status and progression of arterial insufficiency. The purpose of this study was to identify interrelationships among aging, coagulation status, and leg necrosis in patients with critical limb ischemia (CLI). METHODS: Between March 2010 and February 2013, 103 consecutive patients with CLI were enrolled in this study. Retrospective analyses were performed on patient characteristics including age, gender, the presence or the absence of leg necrosis, diabetes mellitus (DM), hypertension, and smoking, and preoperatively measured baseline coagulability factors, which included measurements of coagulation factors anticardiolipin antibodies IgG and IgM, lupus anticoagulant and factor 8, the fibrinolytic factor tissue plasminogen activator (t-PA), and natural anticoagulants proteins C and S and antithrombin III. RESULTS: Among 103 patients with CLI, a total of 49 legs from 41 patients presented varying degrees of necrosis. CLI patients with DM and hypertension showed significantly increased incidences of leg necrosis compared with those without (P = 0.000, 0.039, respectively). Patients with CLI and leg necrosis were significantly older compared with the age of those without necrosis (P = 0.007). Blood levels of anticardiolipin antibodies IgG and IgM, factor 8, lupus anticoagulant, and t-PA tended to increase with age. However, blood levels of proteins C and S and antithrombin III decreased with patient age. Patients with CLI and leg necrosis showed significantly increased levels of lupus anticoagulant (P = 0.049) and significantly decreased levels of proteins C and S (P = 0.009 and 0.018, respectively) compared with patients without leg necrosis. CONCLUSIONS: Patients with CLI and leg necrosis were significantly older compared with those without necrosis; similarly, our results revealed age-related hypercoagulability, with significantly elevated coagulation factor lupus anticoagulant and decreased natural anticoagulants protein C and S levels. From these observations, we conclude that age-related hypercoagulability may be an important mechanism that may facilitate leg necrosis in patients with CLI. PMID- 25286110 TI - Appropriate use of D-dimer testing can minimize over-utilization of venous duplex ultrasound in a contemporary high-volume hospital. AB - BACKGROUND: The sensitivity of d-dimer (DD) in detecting deep venous thrombosis (DVT) is remarkably high; however, many institutions send patients immediately for a venous duplex ultrasound (VDU). This study was designed to examine the appropriate utilization of DD and VDU in a high-volume hospital. METHODS: A retrospective study was conducted on consecutive patients who presented to a high volume emergency department (ED) with lower extremity limb swelling/pain over a 30-day period, who were sent for VDU during an evaluation for DVT. VDU data were merged with electronic DD laboratory results. The enzyme-linked immunosorbent assay method was used to provide DD values and thresholds. Values above 0.60 mg/fibrinogen equivalent unit (FEU) were considered abnormal. RESULTS: We reviewed the medical records of 517 ED patients in the month of June 2013. After applying the Wells criteria, 157 patients (30.4%) were excluded because of a history of DVT or pulmonary embolism, having been screened for shortness of breath, or sent for surveillance-leaving 360 for analysis. The average age was 59.3 +/- 16.5 years with more women (210, 58.3%) and the majority reported limb pain or swelling (73.9%). DD was performed on 51 patients with an average value of 3.6 +/- 5.4 mg/FEU, of which 43 (84.3%) were positive. DD identified all positive and negative DVT patients (100% sensitivity and negative predictive value), but also included 40 false positives (16.7% specificity). On the other hand, 309 patients were sent directly to VDU without DD; of those, 43 (13.9%) were positive for DVT. However, 266 (86.1%) patients were negative for DVT by VDU without DD and these were deemed improper by our current study protocol. Potential charge savings were calculated as VDU for all (360 * $1000 = $360,000), DD for all (360 * $145 = $52,200), and VDU for both true and false positives (estimated to be about 25% of the cases; 90 * $1000 = $90,000); this equals a charge savings of $217,800 and would avoid unnecessary VDUs. CONCLUSIONS: Based on the results of our study, we suggest that the DD test be utilized during the initial work-up for patients with limb swelling/pain in the emergency room. Appropriate utilization of DD, as well as other clinical criteria, may limit the over-utilization and added cost of VDU, without a negative impact on patient care. The results of DD tests should be utilized to limit the number of patients sent for VDU to only those patients with a positive DD or other significant underlying concerns. PMID- 25286112 TI - Smoking cessation is the least successful outcome of risk factor modification in uninsured patients with symptomatic peripheral arterial disease. AB - BACKGROUND: Patients with peripheral arterial disease (PAD) have multiple atherosclerotic risk factors. Risk factor modification can reduce severity of disease at presentation and improve treatment outcomes. The Trans-Atlantic Inter Society Consensus II (TASC II) has issued several recommendations that are widely adopted by specialists. However, the ability to provide proper services to patients may depend on the specific patient's access to care, which is primarily determined by the presence of health insurance. The purpose of our study was to determine whether insurance status impairs the ability of patients with symptomatic PAD to meet select TASC II recommendations. METHODS: A retrospective review of patients with symptomatic PAD from August 2011 to May 2013 was conducted; demographic, preoperative, procedural, and standard outcome variables were collected. Patients were divided into the insured group (private insurance, Medicare, Medicaid) or the uninsured group (self-pay). Insurance status was analyzed for its association to select TASC II recommendations: smoking cessation, referral to smoking cessation program, low-density lipoprotein cholesterol <2.59 mmol/L (<100 mg/dL), low-density lipoprotein cholesterol <1.81 mmol/L (<70 mg/dL), patients with coexisting hyperlipidemia and diabetes, glycated hemoglobin <7%, systolic blood pressure <140 mm Hg, prescription of aspirin, and prescription of a statin. RESULTS: One hundred and forty-four patients with symptomatic PAD were identified. Insured patients were more likely to be African American, older at presentation, or have a diagnosis of congestive heart failure. There was no significant difference between insured and uninsured patients in success rates of low-density lipoprotein cholesterol targets (65.1% vs. 51.1% for <2.59 mmol/L; 24.3% vs. 19.1% for <1.81 mmol/L), glycated hemoglobin targets (61.9% vs. 61.1% for <7%), blood pressure control (51.1% vs. 50.0% for systolic blood pressure <140), aspirin use (72.8% vs. 59.6%), or statin use (77.2% vs. 63.5%). However, insured patients were more likely to quit smoking than uninsured patients (35.1% vs. 17.7%, P = 0.023). Furthermore, there was no difference in patterns of referral to a multidisciplinary smoking cessation program between the 2 groups (31.5% vs. 38.5%). CONCLUSIONS: Insurance status does not impair patients' ability to meet most TASC II guidelines to modify cardiovascular risk factors in patients who have access to health care. Uninsured patients are, however, less likely to cease smoking compared with insured patients, despite no significant difference in referral patterns between the 2 groups for multidisciplinary smoking cessation counseling. Future efforts to assist patients with symptomatic PAD with atherosclerotic risk factor modification should focus on aiding uninsured patients in smoking cessation efforts. PMID- 25286113 TI - A hybrid artificial neural network and particle swarm optimization for prediction of removal of hazardous dye brilliant green from aqueous solution using zinc sulfide nanoparticle loaded on activated carbon. AB - In the present study, zinc sulfide nanoparticle loaded on activated carbon (ZnS NP-AC) simply was synthesized in the presence of ultrasound and characterized using different techniques such as SEM and BET analysis. Then, this material was used for brilliant green (BG) removal. To dependency of BG removal percentage toward various parameters including pH, adsorbent dosage, initial dye concentration and contact time were examined and optimized. The mechanism and rate of adsorption was ascertained by analyzing experimental data at various time to conventional kinetic models such as pseudo-first-order and second order, Elovich and intra-particle diffusion models. Comparison according to general criterion such as relative error in adsorption capacity and correlation coefficient confirm the usability of pseudo-second-order kinetic model for explanation of data. The Langmuir models is efficiently can explained the behavior of adsorption system to give full information about interaction of BG with ZnS-NP-AC. A multiple linear regression (MLR) and a hybrid of artificial neural network and partial swarm optimization (ANN-PSO) model were used for prediction of brilliant green adsorption onto ZnS-NP-AC. Comparison of the results obtained using offered models confirm higher ability of ANN model compare to the MLR model for prediction of BG adsorption onto ZnS-NP-AC. Using the optimal ANN-PSO model the coefficient of determination (R(2)) were 0.9610 and 0.9506; mean squared error (MSE) values were 0.0020 and 0.0022 for the training and testing data set, respectively. PMID- 25286114 TI - Simultaneous removal of binary mixture of Brilliant Green and Crystal Violet using derivative spectrophotometric determination, multivariate optimization and adsorption characterization of dyes on surfactant modified nano-gamma-alumina. AB - The present study deals with the simultaneous removal of Brilliant Green (BG) and Crystal Violet (CV) by surfactant-modified alumina. The utilization of alumina nanoparticles with an anionic surfactant (sodium dodecyl sulfate (SDS)) as a novel and efficient adsorbent is successfully carried out to remove two cationic dyes from aqueous solutions in binary batch systems. A first-order derivative spectrophotometric method is developed for the simultaneous determination of BG and CV in binary solutions. The linear concentration range and limits of detection for the simultaneous determination of BG and CV were found to be: 1-20, 1-15 mg/L, 0.3 and 0.5 mg/L, respectively. The influence of various parameters, such as contact time, initial concentration of dyes and sorbent mass on the dye adsorption is investigated. A response surface methodology achieved through performing the Box-Behnken design is utilized to optimize the removal of dyes by surfactant-modified nanoparticle alumina through a batch adsorption process. The proposed quadratic model resulting from the Box-Behnken design approach fitted very well with the experimental data. The optimal conditions for dye removal were contact time t=50 min, sorbent dose=0.036 g, CBG (Initial BG concentration)=215 mg/L and CCV (Initial CV concentration)=170 mg/L. Furthermore, FT-IR analysis, the isotherms and kinetics of adsorption were also explored. PMID- 25286115 TI - Computational study of influence of diffuse basis functions on geometry optimization and spectroscopic properties of losartan potassium. AB - The work was aimed at investigating the influence of diffusion of basis functions on the geometry optimization of molecule of losartan in acidic and salt form. Spectroscopic properties of losartan potassium were also calculated and compared with experiment. Density functional theory method with various basis sets: 6 31G(d,p) and its diffused variations 6-31G(d,p)+ and 6-31G(d,p)++ was used. Application of diffuse basis functions in geometry optimization resulted in significant change of total molecule energy. Total molecule energy of losartan potassium decreased by 112.91kJ/mol and 114.32kJ/mol for 6-31G(d,p)+ and 6 31G(d,p)++ basis sets, respectively. Almost the same decrease was observed for losartan: 114.99kJ/mol and 117.08kJ/mol respectively for 6-31G(d,p)+ and 6 31G(d,p)++ basis sets. Further investigation showed significant difference within geometries of losartan potassium optimized with investigated basis sets. Application of diffused basis functions resulted in average 1.29A difference in relative position between corresponding atoms of three obtained geometries. Similar study taken on losartan resulted in only average 0.22A of dislocation. Extensive analysis of geometry changes in molecules obtained with diffused and non-diffuse basis functions was carried out in order to elucidate observed changes. The analysis was supported by electrostatic potential maps and calculation of natural atomic charges. UV, FT-IR and Raman spectra of losartan potassium were calculated and compared with experimental results. No crucial differences between Raman spectra obtained with different basis sets were observed. However, FT-IR spectra of geometry of losartan potassium optimized with 6-31G(d,p)++ basis set resulted in 40% better correlation with experimental FT-IR spectra than FT-IR calculated with geometry optimized with 6-31G(d,p) basis set. Therefore, it is highly advisable to optimize geometry of molecules with ionic interactions using diffuse basis functions when accuracy of results is a priority. PMID- 25286116 TI - Optical and thermal properties of azo derivatives of salicylic acid thin films. AB - N-acryloyl-4-aminosalicylic acid (4-AMSA), monomer (HL) and 5-(4'-alkyl phenylazo)-N-acryloyl-4-aminosalicylic acid (HLn) are synthesized and characterized with various physico-chemical techniques. Thin films of 5-(4'-alkyl phenylazo)-N-acryloyl-4-aminosalicylic acid (HLn) are prepared by spin coating technique. The X-ray diffraction (XRD) patterns of 4-aminosalicylic acid (4-ASA) and its derivatives are investigated in powder and thin film forms. Thermal properties of the compounds are investigated by thermogravemetric analysis (TGA). The optical energy gap and the type of optical transition are investigated in the wavelength range (200-2500 nm) for 4-ASA, HL and HLn. The values of fundamental energy gap (Eg) are in the range 3.60-3.69 eV for all compounds and the type of optical transition is found to be indirect allowed. The onset energy gap Eg(*) appeared only for azodye compounds is found to be in the range 0.95-1.55 eV depending on the substituent function groups. The refractive index, n, shows a normal dispersion in the wavelength range 650-2500 nm, while shows anomalous dispersion in the wavelength rang 200-650 nm. The dispersion parameters epsiloninfinity, epsilonL, Ed, Eo and N/m(*) are calculated. The photoluminescence phenomena (PL) appear for thin films of 4-ASA and its derivatives show three main emission transitions. PMID- 25286117 TI - Successful introduction of laparoendoscopic single-site donor nephrectomy after experience with laparoscopic single-site plus-one trocar donor nephrectomy. AB - PURPOSE: To assess the feasibility, safety, and efficacy of the laparoendoscopic single-site (LESS) donor nephrectomy (LESSDN) procedure after experience with the LESS-plus-one-trocar donor nephrectomy (LEPODN) procedure. PATIENTS AND METHODS: From 2009 to 2014, 126 left laparoscopic donor nephrectomies (LDNs) were performed, including 59 Standard (Std)-LDN, 30 LEPODN, and 37 LESSDN. In the LEPODN procedure, a 5-mm trocar was added as a right-hand working trocar to the LESSDN procedure. A GelPOINT((r)) platform was applied on a pararectal single incision in both LEPODN and LESSDN procedures. After performing the LEPODN procedure several times, each surgeon performed the LESSDN procedure. RESULTS: Std-LDN, LEPODN, and LESSDN procedures were performed by 10, 10, and 7 surgeons, respectively. The mean operative time, estimated blood loss, warm ischemia time, time to ambulation, and length of postoperative hospital stay were the shortest for the LESSDN procedure (P<0.012, P=0.007, P<0.001, P=0.027, and P=0.001, respectively). No significant difference in the complication rate, delayed graft function rate, and mean 7-day post-transplant serum creatinine levels was observed among the three procedures. Individual results of the operative time and estimated blood loss for the LESSDN procedure were not significantly inferior to those of Std-LDN and LEPODN procedures for each surgeon. CONCLUSIONS: The LESSDN procedure can be introduced safely and effectively without compromising the operative time, complication rate, and graft function after experience with the LEPODN procedure among multiple surgeons. The LEPODN procedure may be an effective bridge from standard multiport LDN to LESSDN. PMID- 25286118 TI - Sigma-1 (sigma1) receptor deficiency reduces beta-amyloid(25-35)-induced hippocampal neuronal cell death and cognitive deficits through suppressing phosphorylation of the NMDA receptor NR2B. AB - In early Alzheimer's disease (AD) brain, reduction of sigma-1 receptors (sigma1R) is detected. In this study, we employed male heterozygous sigma1R knockout (sigma1R(+/-)) mice showing normal cognitive performance to investigate association of sigma1R deficiency with AD risk. Herein we report that a single injection (i.c.v.) of Abeta(25-35) impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Abeta(25-35) WT mice), whereas it did not cause such impairments in sigma1R(+/-) mice (Abeta(25-35)-sigma1R(+/-) mice). Compared with WT mice, Abeta(25-35)-WT mice showed increased levels of NMDA-activated currents (INMDA) and NR2B phosphorylation (phospho-NR2B) in the hippocampal CA1 region at 48 h after Abeta25-35-injection (post-Abeta(25-35)) followed by approximately 40% decline at 72 h post-Abeta(25-35) of their respective control levels, which was inhibited by the sigma1R antagonist NE100. In Abeta(25-35)-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1-4 post-Abeta(25-35) attenuated the memory deficits and loss of pyramidal cells. By contrast, Abeta(25-35)-sigma1R(+/-) mice showed a slight increase in the INMDA density and the phospho-NR2B at 48 h or 72 h post-Abeta25-35 compared to sigma1R(+/-) mice. Treatment with sigma1R agonist PRE084 in Abeta(25-35)-sigma1R(+/-) mice caused the same changes in the INMDA density and the phospho-NR2B as those in Abeta(25-35)-WT mice. Furthermore, Abeta(25-35)-sigma1R(+/-) mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1-4 post-Abeta(25-35) showed a loss of neuronal cells and memory impairment. These results indicate that the sigma1R deficiency can reduce Abeta(25-35)-induced neuronal cell death and cognitive deficits through suppressing Abeta(25-35)-enhanced NR2B phosphorylation. PMID- 25286119 TI - Monoamine receptor agonists, acting preferentially at presynaptic autoreceptors and heteroreceptors, downregulate the cell fate adaptor FADD in rat brain cortex. AB - FADD is a crucial adaptor of death receptors that can engage apoptosis or survival actions (e.g. neuroplasticity) through its phosphorylated form (p-FADD). Although FADD was shown to participate in receptor mechanisms related to drugs of abuse, little is known on its role in the signaling of classic neurotransmitters (dopamine, noradrenaline, and serotonin) in brain. This study assessed the modulation of FADD (and p-FADD/FADD ratio, as an index of neuroplasticity) and FLIP-L (a neuroprotective FADD interacting partner), as well as the role of MEK ERK signaling, after activation of monoamine auto/heteroreceptors by selective agonists in rat cortex. Acute depletion of monoamines with reserpine, but not with AMPT or PCPA, reduced FADD (28%) and increased p-FADD/FADD ratio (1.34 fold). Activation of presynaptic alpha2A-adrenoceptors (UK-14304 and clonidine), 5-HT1A receptors (8-OH-DPAT), and D2 dopamine receptor (bromocriptine) dose dependently decreased FADD (up to 54%) and increased p-FADD (up to 29%) and p FADD/FADD ratios (up to 2.93-fold), through specific receptor mechanisms. Activation of rat 5-HT1B autoreceptor in axon terminals by CP-94253 did not modulate FADD forms. Activation of postsynaptic D1 dopamine receptor by SKF-81297 also reduced FADD (25%) and increased p-FADD (32%). Disruption of MEK-ERK activation with SL327 did not modify clonidine (alpha2A-adrenoceptor)-induced FADD inhibition, indicating that agonist effect was not dependent on ERK signaling. The various monoamine receptor agonists and antagonists did not alter FLIP-L content, or the activation of executioner caspase-3 and PARP-1 cleavage, indicating that the agonists attenuated apoptotic signals and promoted neuroplasticity through FADD regulation. These novel results indicate that inhibition of pro-apoptotic FADD adaptor could function as a common signaling step in the initial activation of monoamine receptors in the brain. PMID- 25286120 TI - A Smad3 transgenic reporter reveals TGF-beta control of zebrafish spinal cord development. AB - TGF-beta (TGFbeta) family mediated Smad signaling is involved in mesoderm and endoderm specifications, left-right asymmetry formation and neural tube development. The TGFbeta1/2/3 and Activin/Nodal signal transduction cascades culminate with activation of SMAD2 and/or SMAD3 transcription factors and their overactivation are involved in different pathologies with an inflammatory and/or uncontrolled cell proliferation basis, such as cancer and fibrosis. We have developed a transgenic zebrafish reporter line responsive to Smad3 activity. Through chemical, genetic and molecular approaches we have seen that this transgenic line consistently reproduces in vivo Smad3-mediated TGFbeta signaling. Reporter fluorescence is activated in phospho-Smad3 positive cells and is responsive to both Smad3 isoforms, Smad3a and 3b. Moreover, Alk4 and Alk5 inhibitors strongly repress the reporter activity. In the CNS, Smad3 reporter activity is particularly high in the subpallium, tegumentum, cerebellar plate, medulla oblongata and the retina proliferative zone. In the spinal cord, the reporter is activated at the ventricular zone, where neuronal progenitor cells are located. Colocalization methods show in vivo that TGFbeta signaling is particularly active in neuroD+ precursors. Using neuronal transgenic lines, we observed that TGFbeta chemical inhibition leads to a decrease of differentiating cells and an increase of proliferation. Similarly, smad3a and 3b knock-down alter neural differentiation showing that both paralogues play a positive role in neural differentiation. EdU proliferation assay and pH3 staining confirmed that Smad3 is mainly active in post-mitotic, non-proliferating cells. In summary, we demonstrate that the Smad3 reporter line allows us to follow in vivo Smad3 transcriptional activity and that Smad3, by controlling neural differentiation, promotes the progenitor to precursor switch allowing neural progenitors to exit cell cycle and differentiate. PMID- 25286122 TI - Co-operative Bmp- and Fgf-signaling inputs convert skin wound healing to limb formation in urodele amphibians. AB - Urodele amphibians have remarkable organ regeneration capability, and their limb regeneration capability has been investigated as a representative phenomenon. In the early 19th century, nerves were reported to be an essential tissue for the successful induction of limb regeneration. Nerve substances that function in the induction of limb regeneration responses have long been sought. A new experimental system called the accessory limb model (ALM) has been established to identify the nerve factors. Skin wounding in urodele amphibians results in skin wound healing but never in limb induction. However, nerve deviation to the wounded skin induces limb formation in ALM. Thus, nerves can be considered to have the ability to transform skin wound healing to limb formation. In the present study, co-operative Bmp and Fgf application, instead of nerve deviation, to wounded skin transformed skin wound healing to limb formation in two urodele amphibians, axolotl (Ambystoma mexicanum) and newt (Pleurodeles waltl). Our findings demonstrate that defined factors can induce homeotic transformation in postembryonic bodies of urodele amphibians. The combination of Bmp and Fgf(s) may contribute to the development of novel treatments for organ regeneration. PMID- 25286121 TI - Evolutionarily conserved role for SoxC genes in neural crest specification and neuronal differentiation. AB - Members of the Sox family of transcription factors play a variety of critical developmental roles in both vertebrates and invertebrates. Whereas SoxBs and SoxEs are involved in neural and neural crest development, respectively, far less is known about members of the SoxC subfamily. To address this from an evolutionary perspective, we compare expression and function of SoxC genes in neural crest cells and their derivatives in lamprey (Petromyzon marinus), a basal vertebrate, to frog (Xenopus laevis). Analysis of transcript distribution reveals conservation of lamprey and X. laevis SoxC expression in premigratory neural crest, branchial arches, and cranial ganglia. Moreover, morpholino-mediated loss of-function of selected SoxC family members demonstrates essential roles in aspects of neural crest development in both organisms. The results suggest important and conserved functions of SoxC genes during vertebrate evolution and a particularly critical, previously unrecognized role in early neural crest specification. PMID- 25286123 TI - Improving metacognitive accuracy: how failing to retrieve practice items reduces overconfidence. AB - People often exhibit inaccurate metacognitive monitoring. For example, overconfidence occurs when people judge that they will remember more information on a future test then they actually do. The present experiments examined whether a small number of retrieval practice opportunities would improve participants' metacognitive accuracy by reducing overconfidence. Participants studied Lithuanian-English paired associates and predicted their performance on an upcoming memory test. Then they attempted to retrieve one or more practice items (or none in the control condition) and made a second prediction. Experiment 1 showed that failing to retrieve a single practice item lead to improved subsequent performance predictions - participants became less overconfident. Experiment 2 directly manipulated retrieval failure and showed that again failure to retrieve a single practice item significantly improved subsequent predictions, relative to when participants successfully retrieved the practice item. Finally, Experiment 3 showed that additional retrieval practice opportunities reduced overconfidence and improved prediction accuracy. PMID- 25286124 TI - Spatial frequency filtered images reveal differences between masked and unmasked processing of emotional information. AB - High and low spatial frequency information has been shown to contribute differently to the processing of emotional information. In three priming studies using spatial frequency filtered emotional face primes, emotional face targets, and an emotion categorization task, we investigated this issue further. Differences in the pattern of results between short and masked, and short and long unmasked presentation conditions emerged. Given long and unmasked prime presentation, high and low frequency primes triggered emotion-specific priming effects. Given brief and masked prime presentation in Experiment 2, we found a dissociation: High frequency primes caused a valence priming effect, whereas low frequency primes yielded a differentiation between low and high arousing information within the negative domain. Brief and unmasked prime presentation in Experiment 3 revealed that subliminal processing of primes was responsible for the pattern observed in Experiment 2. The implications of these findings for theories of early emotional information processing are discussed. PMID- 25286125 TI - Digital dream analysis: a revised method. AB - This article demonstrates the use of a digital word search method designed to provide greater accuracy, objectivity, and speed in the study of dreams. A revised template of 40 word search categories, built into the website of the Sleep and Dream Database (SDDb), is applied to four "classic" sets of dreams: The male and female "Norm" dreams of Hall and Van de Castle (1966), the "Engine Man" dreams discussed by Hobson (1988), and the "Barb Sanders Baseline 250" dreams examined by Domhoff (2003). A word search analysis of these original dream reports shows that a digital approach can accurately identify many of the same distinctive patterns of content found by previous investigators using much more laborious and time-consuming methods. The results of this study emphasize the compatibility of word search technologies with traditional approaches to dream content analysis. PMID- 25286126 TI - Examining intention in simulated actions: are children and young adults different? AB - Previous work with adults provides evidence that 'intention' used in processing simulated actions is similar to that used in planning and processing overt movements. The present study compared young adults and children on their ability to estimate distance reachability using a NOGO/GO paradigm in conditions of imagery only (IO) and imagery with actual execution (IE). Our initial thoughts were that whereas intention is associated with motivation and commitment to act, age-related differences could impact planning. Results indicated no difference in overall accuracy by condition within groups, and as expected adults were more accurate. These findings support an increasing body of evidence suggesting that the neurocognitive processes (in this case, intention) driving motor imagery and overt actions are similar, and as evidenced here, functioning by age 7. PMID- 25286127 TI - Textures that we like to touch: an experimental study of aesthetic preferences for tactile stimuli. AB - We report two experiments designed to investigate the nature of aesthetic preferences for tactile textures in humans. In Experiment 1, the participants rated their preference for a range of actively and passively explored textures presented on their hands and on their cheeks. The results revealed that those textures that were subjectively-rated as smoother were preferred over those that were rated as rougher. Moreover, certain textures were disliked more during active than during passive stimulation. In Experiment 2, the speed of tactile stimulation was controlled in order to elicit vigorous responses from C-tactile fibers (present only in hairy skin), which are thought to play a central role in pleasant aspects of touch. The results revealed that textures were preferred when presented on the hairy skin of the forearm than on the glabrous palm of the hand. These results provide preliminary evidence regarding people's preferences for different attributes of tactile surface. PMID- 25286128 TI - Emotion as a boost to metacognition: how worry enhances the quality of confidence. AB - Emotion and cognition are known to interact during human decision processes. In this study we focus on a specific kind of cognition, namely metacognition. Our experiment induces a negative emotion, worry, during a perceptual task. In a numerosity task subjects have to make a two alternative forced choice and then reveal their confidence in this decision. We measure metacognition in terms of discrimination and calibration abilities. Our results show that metacognition, but not choice, is affected by the level of worry anticipated before the decision. Under worry individuals tend to have better metacognition in terms of the two measures. Furthermore understanding the formation of confidence is better explained with taking into account the level of worry in the model. This study shows the importance of an emotional component in the formation and the quality of the subjective probabilities. PMID- 25286129 TI - Dissociating electrophysiological correlates of subjective, objective, and correct memory in investigating the emotion-induced recognition bias. AB - Performance on tasks requiring discrimination of at least two stimuli can be viewed either from an objective perspective (referring to actual stimulus differences), or from a subjective perspective (corresponding to participant's responses). Using event-related potentials recorded during an old/new recognition memory test involving emotionally laden and neutral words studied either blockwise or randomly intermixed, we show here how the objective perspective (old versus new items) yields late effects of blockwise emotional item presentation at parietal sites that the subjective perspective fails to find, whereas the subjective perspective ("old" versus "new" responses) is more sensitive to early effects of emotion at anterior sites than the objective perspective. Our results demonstrate the potential advantage of dissociating the subjective and the objective perspective onto task performance (in addition to analyzing trials with correct responses), especially for investigations of illusions and information processing biases, in behavioral and cognitive neuroscience studies. PMID- 25286130 TI - Introspection during visual search. AB - Recent advances in the field of metacognition have shown that human participants are introspectively aware of many different cognitive states, such as confidence in a decision. Here we set out to expand the range of experimental introspection by asking whether participants could access, through pure mental monitoring, the nature of the cognitive processes that underlie two visual search tasks: an effortless "pop-out" search, and a difficult, effortful, conjunction search. To this aim, in addition to traditional first order performance measures, we instructed participants to give, on a trial-by-trial basis, an estimate of the number of items scanned before a decision was reached. By controlling response times and eye movements, we assessed the contribution of self-observation of behavior in these subjective estimates. Results showed that introspection is a flexible mechanism and that pure mental monitoring of cognitive processes is possible in elementary tasks. PMID- 25286131 TI - Subliminal primes for global or local processing influence judgments of vehicular traffic. AB - Previous studies on semantic priming show that briefly presented words can unconsciously manipulate subjects' mental states, behaviors, and attitudes. Here we evaluated whether semantic primes can also manipulate the breadth of subjects' visual attention. We primed participants with briefly presented words that indicate either broadness or narrowness; each prime was followed by either a large or a small picture of a street intersection with vehicles, and participants had to indicate in which order the vehicles were legally allowed to pass the intersection. Participants responded to large pictures faster when primed with words denoting broadness, and to small pictures faster when primed with words denoting narrowness. From this we concluded that semantic priming can be effectively applied to manipulate the breadth of attention, which could be exploited in real-world scenarios. PMID- 25286132 TI - Inhibitory mechanisms in single negative priming from ignored and briefly flashed primes: the key role of the inter-stimulus interval. AB - The influence of interstimulus intervals (ISIs) on priming effects was investigated using a single-prime negative priming (NP) paradigm. In all experiments, a brief (16ms), centrally displayed prime (a Chinese character, to be ignored) appeared, followed by a pattern mask and then a centrally displayed target (another semantically related or unrelated Chinese character); the task required semantic categorization (animate/inanimate) of the target. An ISI could occur either between prime and mask (Experiments 1 and 5) or between mask and target (Experiments 2-4). The results revealed NP when a 470ms ISI occurred between prime and mask (Experiments 1 and 5) and when a 700ms ISI occurred between mask and target (Experiments 3 and 4). In contrast, when a long prime target SOA was maintained but the mask-target ISI was shortened, NP disappeared (Experiment 4). The results indicated that a persisting mask/distractor (without ISI) located in the same position as the following target interfered with the buildup of inhibition, but an ISI between prime and mask or mask and target eliminated this interference, and that inhibition processes induced by an ignore instruction were implemented faster with an ISI placed between prime and mask than with an ISI placed between mask and target. PMID- 25286133 TI - Formation mechanism of (001) oriented perovskite SrTiO3 microplatelets synthesized by topochemical microcrystal conversion. AB - To develop a better understanding of the mechanism responsible for topochemical microcrystal conversion (TMC) from Aurivillius SrBi4Ti4O15 precursors to perovskite SrTiO3 microplatelets, compositional/structural evolutions, morphological development, and reaction interface evolution of the (001) oriented SrBi4Ti4O15 microplatelets were investigated during the conversion process. The results show that multiple topotactic nucleation events of SrTiO3 occurred directly on the surfaces of SrBi4Ti4O15 above 700 degrees C, while reacting zones of intermediate phase(s) with less Bi(3+) contents were observed to form in the interior of SrBi4Ti4O15. Extensive exfoliation of the precursors occurred generally parallel to the (001) surfaces above 775 degrees C. At 950 degrees C, the original single-crystal SrBi4Ti4O15 platelet was replaced by a polycrystalline aggregate consisting of (001) aligned SrTiO3 crystallites and poorly crystallized intermediate phase(s). With further increasing the temperature or holding time, the SrTiO3 phase formed from related intermediate phase(s), and the aligned crystallites were sintered to form dense SrTiO3 with strong (001) orientation. The obtained SrTiO3 microplatelets preserved the shape of SrBi4Ti4O15 and show high chemical and phase purity. This TMC mechanism has general applicability to a variety of compounds and will be very useful for the design and synthesis of novel anisotropic perovskite crystals with high quality in the future. PMID- 25286134 TI - Circadian analysis of large human populations: inferences from the power grid. AB - Few, if any studies have focused on the daily rhythmic nature of modern industrialized populations. The present study utilized real-time load data from the U.S. Pacific Northwest electrical power grid as a reflection of human operative household activity. This approach involved actigraphic analyses of continuously streaming internet data (provided in 5 min bins) from a human subject pool of approximately 43 million primarily residential users. Rhythm analyses reveal striking seasonal and intra-week differences in human activity patterns, largely devoid of manufacturing and automated load interference. Length of the diurnal activity period (alpha) is longer during the spring than the summer (16.64 h versus 15.98 h, respectively; p < 0.01). As expected, significantly more activity occurs in the solar dark phase during the winter than during the summer (6.29 h versus 2.03 h, respectively; p < 0.01). Interestingly, throughout the year a "weekend effect" is evident, where morning activity onset occurs approximately 1 h later than during the work week (5:54 am versus 6:52 am, respectively; p < 0.01). This indicates a general phase-delaying response to the absence of job-related or other weekday morning arousal cues, substantiating a preference or need to sleep longer on weekends. Finally, a shift in onset time can be seen during the transition to Day Light Saving Time, but not the transition back to Standard Time. The use of grid power load as a means for human actimetry assessment thus offers new insights into the collective diurnal activity patterns of large human populations. PMID- 25286135 TI - Feeding and adrenal entrainment stimuli are both necessary for normal circadian oscillation of peripheral clocks in mice housed under different photoperiods. AB - The mammalian circadian rhythm is entrained by multiple factors, including the light-dark cycle, the organism's feeding pattern and endocrine hormones such as glucocorticoids. Both a central clock (the suprachiasmatic nucleus, or SCN) and peripheral clocks (i.e. in the liver and lungs) in mice are entrained by photoperiod. However, the factors underlying entrainment signals from the SCN to peripheral clocks are not well known. To elucidate the role of entrainment factors such as corticosterone and feeding, we examined whether peripheral clock rhythms were impaired by adrenalectomy (ADX) and/or feeding of 6 meals per day at equal intervals under short-day, medium-day and long-day photoperiods (SP, MP and LP, respectively). We evaluated the waveform and phase of circadian rhythms in the liver, kidney and salivary gland by in vivo imaging of PER2::LUCIFERASE knock in mice. In intact mice, the waveforms of the peripheral clocks were similar among all photoperiods. The phases of peripheral clocks were well adjusted by the timing of the "lights-off"-operated evening (E) oscillator but not the "lights on"-operated morning (M) oscillator. ADX had almost no effect on the rhythmicity and phase of peripheral clocks, regardless of photoperiod. To reduce the feeding induced signal, we placed mice on a restricted feeding regimen with 6 meals per day (6 meals RF). This caused advances of the peripheral clock phase in LP-housed mice (2-5 h) and MP-housed mice (1-2 h) but not SP-housed mice. Thus, feeding pattern may affect the phase of peripheral clocks, depending on photoperiod. More specifically, ADX + 6 meals RF mice showed impairment of circadian rhythms in the kidney and liver but not in the salivary gland, regardless of photoperiod. However, the impairment of peripheral clocks observed in ADX + 6 meals RF mice was reversed by administration of dexamethasone for 3 days. The phase differences in the salivary gland clock among SP-, MP- and LP-housed mice became very small following treatment with ADX + 6 meals RF, suggesting that the effect of photoperiod was reduced by ADX and 6 meals RF. Because the SCN rhythm (as evaluated by PER2 immunohistochemistry) was not disrupted by ADX + 6 meals RF, impairment of peripheral clocks in these mice was not because of impaired SCN clock function. In addition, locomotor activity rhythm and modifications of the feeding pattern may not be completely responsible for determining the phase of peripheral clocks. Thus, this study demonstrates that the phase of peripheral clocks responds to a photoperiodic lights-off signal, and suggests that signals from normal feeding patterns and the adrenal gland are necessary to maintain the oscillation and phase of peripheral clocks under various photoperiods. PMID- 25286136 TI - Effects of N-acetylcysteine and imipramine in a model of acute rhythm disruption in BALB/c mice. AB - Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms. PMID- 25286137 TI - Circadian preference and trait impulsivity, sensation-seeking and response inhibition in healthy young adults. AB - Circadian preference has been considered related with impulsivity. The purpose of the present study was to evaluate the relationship between circadian typology and impulsivity measured by the Barratt Impulsivity Scale (BIS), sensation-seeking measured by the Sensation Seeking Scale - Form V (SSS-V) and response inhibition elicited by the GO/NO-GO paradigm. A total of 503 Korean healthy college students (288 males and 215 females) completed the Composite Scale of Morningness (CSM) for circadian typology and the BIS and SSS-V for impulsivity and risk taking, respectively. A subset of 142 subjects additionally performed the computerized GO/NO-GO task for motor response inhibition. A significant association was found between the circadian typology of the CSM and impulsivity of the BIS and disinhibition of SSS-V. In addition, there was a difference in trend level between the circadian typology and response inhibition elicited by the GO/NO-GO test. Regarding circadian preference, evening types were significantly associated with higher impulsivity on the BIS, disinhibition on the SSS-V and lower rate of successful inhibition on the GO/NO-GO task compared to morning types. The present results showed significant relationships between circadian preference and impulsivity and sensation-seeking personality traits. In particular, our findings suggest that high impulsivity, disinhibition and impaired response inhibition are more related to evening types. Circadian preference might be associated with psychiatric problems interacting with some aspects of personality traits such as inhibitory control. PMID- 25286138 TI - Effects of time of L-ornithine administration on the diurnal rhythms of plasma growth hormone, melatonin, and corticosterone levels in mice. AB - The synthesis and secretion of many hormones such as growth hormone (GH), melatonin, and corticosterone, exhibit temporal variations over each day and night. Oral administration of several nutritional factors, including L-ornithine, modulates these hormonal secretions and induces an acute increase in plasma GH levels. However, the impact of L-ornithine on the diurnal rhythms of hormone secretion remains unclear. In this study, we evaluated whether the diurnal rhythms of plasma GH, melatonin, and corticosterone secretion were altered by the daily administration of L-ornithine as well as the timing of the administration, in CBA/N mice. Our results showed that the plasma GH levels that peaked at light phase were amplified by L-ornithine (500 mg/kg) administered at Zeitgeber time (ZT) 22, but not at ZT10. Additionally, L-ornithine (1000 mg/kg) administered at ZT22 advanced the onset of the nocturnal rise of melatonin, which resulted in the elongation of the melatonin peak. On the other hand, L-ornithine (500 and 1000 mg/kg) administered at ZT10, but not at ZT22, suppressed the diurnal rhythm peaks of plasma corticosterone. The effects of L-ornithine on plasma GH rhythms lasted for at least 2 days after cessation of the daily administration. Running wheel activity during the active phase was slightly elevated by L-ornithine administration at ZT22, but the overall patterns were only slightly affected. L Ornithine levels in the plasma and hypophysis after a single administration of L ornithine at ZT22 were lower than those after administration at ZT10, suggesting that the metabolic rate of L-ornithine differs between day and night. In conclusion, our data suggest that a daily administration of L-ornithine regulates the diurnal rhythms of GH, melatonin, and corticosterone in a manner dependent on administration time, which might be related to the diurnal rhythms of L-ornithine metabolism. PMID- 25286139 TI - Chromatographic enrichment and subsequent separation of nickel and vanadyl porphyrins from natural seeps and molecular characterization by positive electrospray ionization FT-ICR mass spectrometry. AB - We report a novel chromatographic method to enrich and separate nickel and vanadyl porphyrins from a natural seep sample and combine molecular level characterization by positive-ion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Vanadyl and nickel porphyrin model compound elution from primary secondary amine (PSA) stationary phase combined with UV-vis spectroscopy confirms enrichment and subsequent fractionation of nickel and vanadyl porphyrins into polarity-based subfractions. A more than 100-fold increase in signal-to-noise ratio for nickel porphyrins enables unequivocal elemental composition assignment confirmed by isotopic fine structure for all isotopes >1% relative abundance, and the first mass spectral identification of (61)Ni porphyrin isotopologues derived from natural seeps. Oxygen-containing vanadyl porphyrins and sulfur-containing vanadyl porphyrins are isolated in the same fraction simultaneously from the same sample. We provide the first chromatographic evidence of carboxylic acid functionalities peripheral to the porphyrin core, in agreement with previous studies. PMID- 25286140 TI - First observation of HO reactivity in water under high energy ions at elevated temperature. AB - This communication reports the first observation of the formation of HO produced under two different High energy ion beams, (18)O(8+) and (36)Ar(18+) having Linear Energy Transfers (LET) of 65 and 350 eV nm(-1) respectively, at temperatures up to 411 K. Both scavenging with various concentrations of SCN(-) and heavy-ion pulse radiolysis methods are used with an original temperature and pressure regulated optical cell. Deconvolution of kinetics is used to analyze the evolution of HO track segment yields as a function of time and temperature. It takes care of involving the ionic strength effect and Arrhenius expression in the rate constants correction. The results show a fast decay of HO yields in the 10( 10)-10(-8) s range which denotes an efficient reactivity of this species in the track structure of the ion beam. This effect is enhanced with the lowest LET of O(8+). Increasing the temperature also accelerates the decays for both ions. These observations are discussed in terms of temperature activation of reactions and the track structure exhibiting the formation of HO in a "low LET" penumbra around the ionization tracks. HO track segment yields at 100 ns, of 0.4 * 10(-7) and 0.6 * 10(-7) mol J(-1), respectively for 350 and 65 eV nm(-1), are not affected by temperature. PMID- 25286142 TI - A proposal to use iterative, small clinical trials to optimize therapeutic HIV vaccine immunogens to launch therapeutic HIV vaccine development. AB - The HIV cure agenda has rekindled interest in the development of a therapeutic HIV vaccine. An iterative clinical trial strategy that proved successful for the development of effective cancer chemotherapies in the 1960s may be applicable to the development of a CD8 T lymphocyte-based therapeutic HIV vaccine. However, while cancer chemotherapy development could begin with iterative clinical trials to improve the use of active drugs, the first step in therapeutic HIV vaccine design should be discovery of immunogen constructs with potential for activity and their optimization to meet the challenges of HIV-1 sequence diversity and human polymorphism in T cell antigen presentation. A strategy for doing this is discussed in this article. The proposed strategy relies on a major commitment by funding organizations to fund organized and coordinated manufacture and clinical testing of a series of first- and second-generation constructs to test basic concepts in product design. This is presented as an alternative to funding a more traditional competition among private manufacturers and product champions of individual, already designed products. PMID- 25286143 TI - Structural evolvement and thermoelectric properties of Cu(3-x)Sn(x)Se3 compounds with diamond-like crystal structures. AB - Polycrystalline samples of Cu(3-x)Sn(x)Se3 were synthesized in the composition range x = 0.87-1.05. A compositionally induced evolvement from tetragonal via cubic to monoclinic crystal structures is observed, when the composition changes from a Cu-rich to a Sn-rich one. The Cu(3-x)Sn(x)Se3 materials show a metal-to semiconductor transition with increasing x. Electronic transport properties are governed by the charge-carrier concentration which is well described by a linear dispersion-band model. The lattice component of the thermal conductivity is practically independent of x which is attributed to the opposite influence of the atomic ordering and the inhomogeneous distribution of the Cu-Se or Sn-Se bonds with different polarities in the crystal structure. The highest thermoelectric figure of merit ZT of 0.34 is achieved for x = 1.025 at 700 K. PMID- 25286141 TI - Dimerization of the EphA1 receptor tyrosine kinase transmembrane domain: Insights into the mechanism of receptor activation. AB - EphA1 is a receptor tyrosine kinase (RTK) that plays a key role in developmental processes, including guidance of the migration of axons and cells in the nervous system. EphA1, in common with other RTKs, contains an N-terminal extracellular domain, a single transmembrane (TM) alpha-helix, and a C-terminal intracellular kinase domain. The TM helix forms a dimer, as seen in recent NMR studies. We have modeled the EphA1 TM dimer using a multiscale approach combining coarse-grain (CG) and atomistic molecular dynamics (MD) simulations. The one-dimensional potential of mean force (PMF) for this system, based on interhelix separation, has been calculated using CG MD simulations. This provides a view of the free energy landscape for helix-helix interactions of the TM dimer in a lipid bilayer. The resulting PMF profiles suggest two states, consistent with a rotation-coupled activation mechanism. The more stable state corresponds to a right-handed helix dimer interacting via an N-terminal glycine zipper motif, consistent with a recent NMR structure (2K1K). A second metastable state corresponds to a structure in which the glycine zipper motif is not involved. Analysis of unrestrained CG MD simulations based on representative models from the PMF calculations or on the NMR structure reveals possible pathways of interconversion between these two states, involving helix rotations about their long axes. This suggests that the interaction of TM helices in EphA1 dimers may be intrinsically dynamic. This provides a potential mechanism for signaling whereby extracellular events drive a shift in the repopulation of the underlying TM helix dimer energy landscape. PMID- 25286144 TI - Biodegradation of tetracycline by the yeast strain Trichosporon mycotoxinivorans XPY-10. AB - We investigated the behavior of tetracycline degradation and its degradation products upon treatment of isolated yeast that we termed "XPY-10." XPY-10 was isolated from wastewater and identified as Trichosporon mycotoxinivorans by morphological and physiological tests and 5.8S rRNA ITS sequencing. In our experiments, 78.28 +/- 0.8% of tetracycline was removed within 7 days with XPY 10. The degradation of tetracycline fitted well with the first-order kinetic model. We also speculated upon the biodegradation products formed during biodegradation. The possible structures of five products were determined using liquid chromatography-tandem mass spectrometry. During practical application, XPY 10 was shown to have an obvious influence on biodegradation, and 89.61% of tetracycline was removed in feedlot sewage after 7 days of reaction. The chemical oxygen demand removal reached 73.47%. PMID- 25286146 TI - Pancake bouncing: simulations and theory and experimental verification. AB - Drops impacting superhydrophobic surfaces normally spread, retract, and leave the surface in an approximately spherical shape, with little loss of energy. Recently, however, it was shown that drops can leave the substrate before retracting while still in an extended pancake-like form. We use mesoscale simulations and theoretical arguments, compared to experimental data, to show that such "pancake bouncing" occurs when impacting fluid that enters the surface is slowed and then expelled by capillary forces. For the drop to bounce as a pancake, two criteria must be satisfied: the fluid must return to the surface at the appropriate time, and it must do so with sufficient kinetic energy to lift the drop. We argue that this will occur for superhydrophobic surfaces with topological features having dimensions of ~200 MUm, larger than those normally considered. The contact time of pancake bouncing events is reduced by up to 5 fold compared to that of conventional bouncing, suggesting relevance to drop shedding and anti-icing applications. PMID- 25286147 TI - Boron dipyrromethene (BODIPY) functionalized carbon nano-onions for high resolution cellular imaging. AB - Carbon nano-onions (CNOs) are an exciting class of carbon nanomaterials, which have recently demonstrated a facile cell-penetration capability. In the present work, highly fluorescent boron dipyrromethene (BODIPY) dyes were covalently attached to the surface of CNOs. The introduction of this new carbon nanomaterial based imaging platform, made of CNOs and BODIPY fluorophores, allows for the exploration of synergetic effects between the two building blocks and for the elucidation of its performance in biological applications. The high fluorescence intensity exhibited by the functionalized CNOs translates into an excellent in vitro probe for the high resolution imaging of MCF-7 human breast cancer cells. It was also found that the CNOs, internalized by the cells by endocytosis, localized in the lysosomes and did not show any cytotoxic effects. The presented results highlight CNOs as excellent platforms for biological and biomedical studies due to their low toxicity, efficient cellular uptake and low fluorescence quenching of attached probes. PMID- 25286145 TI - Resting-state fMRI activity predicts unsupervised learning and memory in an immersive virtual reality environment. AB - In the real world, learning often proceeds in an unsupervised manner without explicit instructions or feedback. In this study, we employed an experimental paradigm in which subjects explored an immersive virtual reality environment on each of two days. On day 1, subjects implicitly learned the location of 39 objects in an unsupervised fashion. On day 2, the locations of some of the objects were changed, and object location recall performance was assessed and found to vary across subjects. As prior work had shown that functional magnetic resonance imaging (fMRI) measures of resting-state brain activity can predict various measures of brain performance across individuals, we examined whether resting-state fMRI measures could be used to predict object location recall performance. We found a significant correlation between performance and the variability of the resting-state fMRI signal in the basal ganglia, hippocampus, amygdala, thalamus, insula, and regions in the frontal and temporal lobes, regions important for spatial exploration, learning, memory, and decision making. In addition, performance was significantly correlated with resting-state fMRI connectivity between the left caudate and the right fusiform gyrus, lateral occipital complex, and superior temporal gyrus. Given the basal ganglia's role in exploration, these findings suggest that tighter integration of the brain systems responsible for exploration and visuospatial processing may be critical for learning in a complex environment. PMID- 25286148 TI - Unicentric Castleman disease: from screening mammography to PET/CT imaging. PMID- 25286149 TI - Laser-induced photo-polymerisation for creation of paper-based fluidic devices. AB - Paper-based microfluidics is a rapidly progressing inter-disciplinary technology driven by the need for low-cost alternatives to conventional point-of-care diagnostic tools. For transport of reagents/analytes, such devices often consist of interconnected hydrophilic fluid-flow channels that are demarcated by hydrophobic barrier walls that extend through the thickness of the paper. Here, we present a laser-based fabrication procedure that uses polymerisation of a photopolymer to produce the required fluidic channels in paper. Experimental results showed that the structures successfully guide the flow of fluids and allow containment of fluids in wells, and hence the technique is suitable for fabrication of paper-based microfluidic devices. The minimum width for the hydrophobic barriers that successfully prevented fluid leakage was ~120 MUm and the minimum width for the fluidic channels that can be formed was ~80 MUm, the smallest reported so far for paper-based fluidic patterns. PMID- 25286150 TI - Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists. AB - Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119. PMID- 25286151 TI - Light-induced changes in magnetism in a coordination polymer heterostructure, Rb0.24Co[Fe(CN)6]0.74@K0.10Co[Cr(CN)6]0.70.nH2O and the role of the shell thickness on the properties of both core and shell. AB - Particles of formula Rb0.24Co[Fe(CN)6]0.74@K0.10Co[Cr(CN)6]0.70.nH2O with a light responsive rubidium cobalt hexacyanoferrate (RbCoFe) core and a magnetic potassium cobalt hexacyanochromate (KCoCr) shell have been prepared and exhibit light-induced changes in the magnetization of the normally light-insensitive KCoCr shell, a new property resulting from the synergy between the core and shell of a coordination polymer heterostructure. A single batch of 135 +/- 12 nm RbCoFe particles are used as seeds to generate three different core@shell samples, with KCoCr shell thicknesses of approximately 11, 23 and 37 nm, to probe the influence of the shell thickness over the particles' morphology and structural and magnetic properties. Synchrotron powder X-ray diffraction reveals that structural changes in the shell accompany the charge transfer induced spin transition (CTIST) of the core, giving direct evidence that the photomagnetic response of the shell is magnetomechanical in origin. The depth to which the KCoCr shell contributes to changes in magnetization is estimated to be approximately 24 nm when using a model that assumes a constant magnetic response of the core within the series of particles. In turn, the presence of the shell changes the nature of the CTIST of the core. As opposed to the usually observed first order transition exhibiting hysteresis, the CTIST becomes continuous in the core@shell particles. PMID- 25286152 TI - Preventing and reducing violence against women: innovation in community-level studies. AB - Intimate partner violence is a serious global problem that damages the health and prosperity of individuals, their families, community, and society. WHO endorses an 'ecological model,' which states that there are multi-level intersecting factors enabling perpetration and victimization of violence. Intervention science to prevent or reduce the problem is in its infancy, and the few existing intervention studies have been targeted at the individual level. In a recent study published in BMC Medicine, Abramsky et al. bring innovation to the field, targeting their intervention trial "SASA!" in Kampala Uganda at all ecological levels, but particularly at the community level. Recruiting and training both male and female community leaders and activists who enabled group and media discussions, the authors focused on the beneficial and abusive detrimental uses of power rather than commencing with the central issue of gender inequality. SASA! successfully reduced community attitudes to tolerance of violence and inequality, men's sexual risk behaviors, and women's experience of physical violence. The study also improved the communities' response to victimized women. SASA! has promise for adaptation and replication in low, middle and high income countries. Please see related article: http://www.biomedcentral.com/1741 7015/12/122. PMID- 25286154 TI - Enzymatic minimum free energy path calculations using swarms of trajectories. AB - The development of approaches for simulating rare events in complex molecular systems is a central concern in chemical physics. In recent work, Roux and co workers proposed a novel, swarms of trajectories (SoT) method for determining the transition paths of such events. It consists of the dynamical refinement on the system's free energy surface of a putative transition path that is parametrized in terms of a set of collective variables (CVs) that are identified as being important for the transition. In this work, we have implemented the SoT method and used it to investigate the catalytic mechanisms of two enzymatic reactions using hybrid QM/MM potentials. Our aim has been to test the performance of SoT for enzyme systems and to devise robust simulation protocols that can be employed in future studies of this type. We identify the conditions under which converged results can be obtained using inertial and Brownian dynamical evolutions of the CVs, show that the inclusion of several CVs can give significant additional insight into the mechanisms of the reactions, and show that the use of minimum energy paths as starting guesses can greatly accelerate path refinement. PMID- 25286155 TI - Sodium ion diffusion in Al2O3: a distinct perspective compared with lithium ion diffusion. AB - Surface coating of active materials has been one of the most effective strategies to mitigate undesirable side reactions and thereby improve the overall battery performance. In this direction, aluminum oxide (Al2O3) is one of the most widely adopted coating materials due to its easy synthesis and low material cost. Nevertheless, the effect of Al2O3 coating on carrier ion diffusion has been investigated mainly for Li ion batteries, and the corresponding understanding for emerging Na ion batteries is currently missing. Using ab initio molecular dynamics calculations, herein, we first find that, unlike lithiation, sodiation of Al2O3 is thermodynamically unfavorable. Nonetheless, there can still exist a threshold in the Na ion content in Al2O3 before further diffusion into the adjacent active material, delivering a new insight that both thermodynamics and kinetics should be taken into account to describe ionic diffusion in any material media. Furthermore, Na ion diffusivity in NaxAl2O3 turns out to be much higher than Li ion diffusivity in LixAl2O3, a result opposite to the conventional stereotype based on the atomic radius consideration. While hopping between the O rich trapping sites via an Na-O bond breaking/making process is identified as the main Na ion diffusion mechanism, the weaker Na-O bond strength than the Li-O counterpart turns out to be the origin of the superior diffusivity of Na ions. PMID- 25286153 TI - Bisphenol a exposure and the development of wheeze and lung function in children through age 5 years. AB - IMPORTANCE: Bisphenol A (BPA), a prevalent endocrine-disrupting chemical, has been associated with wheezing in children, but few studies have examined its effect on lung function or wheeze in older children. OBJECTIVES: To test whether BPA exposure is associated with lung function, with wheeze, and with pattern of wheeze in children during their first 5 years. DESIGN, SETTING, AND PARTICIPANTS: A birth cohort study, enrolled during early pregnancy in the greater Cincinnati, Ohio, area among 398 mother-infant dyads. We collected maternal urine samples during pregnancy (at 16 and 26 weeks) and child urine samples annually to assess gestational and child BPA exposure. MAIN OUTCOMES AND MEASURES: We assessed parent-reported wheeze every 6 months for 5 years and measured child forced expiratory volume in the first second of expiration (FEV1) at age 4 and 5 years. We evaluated associations of BPA exposure with respiratory outcomes, including FEV1, child wheeze, and wheeze phenotype. RESULTS: Urinary BPA concentrations and FEV1 data were available for 208 children and urinary BPA concentrations and parent-reported wheeze data were available for 360 children. The mean maternal urinary BPA concentration ranged from 0.53 to 293.55 ug/g of creatinine. In multivariable analysis, every 10-fold increase in the mean maternal urinary BPA concentration was associated with a 14.2% (95% CI, -24.5% to -3.9%) decrease in the percentage predicted FEV1 at 4 years, but no association was found at 5 years. In multivariable analysis, every 10-fold increase in the mean maternal urinary BPA concentration was marginally associated with a 54.8% increase in the odds of wheezing (adjusted odds ratio, 1.55; 95% CI, 0.91-2.63). While the mean maternal urinary BPA concentration was not associated with wheeze phenotype, a 10 fold increase in the 16-week maternal urinary BPA concentration was associated with a 4.27-fold increase in the odds of persistent wheeze (adjusted odds ratio, 4.27; 95% CI, 1.37-13.30). Child urinary BPA concentrations were not associated with FEV1 or wheeze. CONCLUSIONS AND RELEVANCE: These results provide evidence suggesting that prenatal but not postnatal exposure to BPA is associated with diminished lung function and the development of persistent wheeze in children. PMID- 25286156 TI - Early Surgical Complications After Primary Cleft Lip Repair: A Report of 3108 Consecutive Cases. AB - OBJECTIVE: To analyze short term surgical complications after primary cleft lip repair. PATIENTS AND DESIGN: A total of 3108 consecutive lip repairs with 2062 follow-ups were reviewed retrospectively through medical records. Patients were aged 3 months to 75 years at the time of surgery, with a median of 7 years. SETTING: Guwahati Comprehensive Cleft Care Center, Assam, India. INTERVENTION: Primary cleft lip repair. MAIN OUTCOME MEASURES: Documented complications in terms of dehiscence, necrosis, infection, and suture granuloma were compiled. Logistic regression was used with dehiscence (yes/no) or infection (yes/no) as binary dependant variables. Age, cleft type, and surgeon (visiting/long term) were used as covariates. RESULTS: Among the 2062 patients who returned for early follow-up, 90 (4.4%) had one or more complications. Dehiscence (3.2%) and infection (1.1%) were the most common types of complication. Visiting surgeon, complete cleft, and bilateral cleft were significantly associated with wound dehiscence, and complete cleft was associated with wound infection according to the logistic regression analysis. Of patients with bilateral complete clefts, 6.9% suffered from some degree of wound dehiscence. CONCLUSION: In a setting where presurgical molding is unavailable and patients present at all ages, lip wound dehiscence is a relatively common complication in patients with bilateral complete clefts. The risk of dehiscence, however, is reduced when these cases are assigned to surgeons with experience with these types of clefts. We also found that the incidence of wound infection can be kept relatively low, even without the use of postoperative antibiotics. PMID- 25286157 TI - High performance surface-enhanced Raman scattering via dummy molecular imprinting onto silver microspheres. AB - A new strategy for achieving high performance SERS was proposed by using the dummy molecular imprinting technique. The obtained core-shell composite can effectively improve the signal-to-noise ratio and the veracity of trace analysis in SERS detection. PMID- 25286158 TI - Comparison of efficacy and toxicity of traditional Chinese medicine (TCM) herbal mixture LQ and conventional chemotherapy on lung cancer metastasis and survival in mouse models. AB - Unlike Western medicine that generally uses purified compounds and aims to target a single molecule or pathway, traditional Chinese medicine (TCM) compositions usually comprise multiple herbs and components that are necessary for efficacy. Despite the very long-time and wide-spread use of TCM, there are very few direct comparisons of TCM and standard cytotoxic chemotherapy. In the present report, we compared the efficacy of the TCM herbal mixture LQ against lung cancer in mouse models with doxorubicin (DOX) and cyclophosphamide (CTX). LQ inhibited tumor size and weight measured directly as well as by fluorescent-protein imaging in subcutaneous, orthotopic, spontaneous experimental metastasis and angiogenesis mouse models of lung cancer. LQ was efficacious against primary and metastatic lung cancer without weight loss and organ toxicity. In contrast, CTX and DOX, although efficacious in the lung cancer models caused significant weight loss, and organ toxicity. LQ also had anti-angiogenic activity as observed in lung tumors growing in nestin-driven green fluorescent protein (ND-GFP) transgenic nude mice, which selectively express GFP in nascent blood vessels. Survival of tumor-bearing mice was also prolonged by LQ, comparable to DOX. In vitro, lung cancer cells were killed by LQ as observed by time-lapse imaging, comparable to cisplatinum. LQ was more potent to induce cell death on cancer cell lines than normal cell lines unlike cytotoxic chemotherapy. The results indicate that LQ has non-toxic efficacy against metastatic lung cancer. PMID- 25286159 TI - Conformational evaluation of HIV-1 trimeric envelope glycoproteins using a cell based ELISA assay. AB - HIV-1 envelope glycoproteins (Env) mediate viral entry into target cells and are essential to the infectious cycle. Understanding how those glycoproteins are able to fuel the fusion process through their conformational changes could lead to the design of better, more effective immunogens for vaccine strategies. Here we describe a cell-based ELISA assay that allows studying the recognition of trimeric HIV-1 Env by monoclonal antibodies. Following expression of HIV-1 trimeric Env at the surface of transfected cells, conformation specific anti-Env antibodies are incubated with the cells. A horseradish peroxidase-conjugated secondary antibody and a simple chemiluminescence reaction are then used to detect bound antibodies. This system is highly flexible and can detect Env conformational changes induced by soluble CD4 or cellular proteins. It requires minimal amount of material and no highly-specialized equipment or know-how. Thus, this technique can be established for medium to high throughput screening of antigens and antibodies, such as newly-isolated antibodies. PMID- 25286160 TI - Purification and characterization of a mucin specific mycelial lectin from Aspergillus gorakhpurensis: application for mitogenic and antimicrobial activity. AB - BACKGROUND: Lectins are carbohydrate binding proteins or glycoproteins that bind reversibly to specific carbohydrates present on the apposing cells, which are responsible for their ability to agglutinate red blood cells, lymphocytes, fibroblasts, etc. Interest in lectins has been intensified due to their carbohydrate specificity as they can be valuable reagents for the investigation of cell surface sugars, purification and characterization of glycoproteins. The present study reports the purification, characterization and evaluation of mitogenic and antimicrobial potential of a mycelial lectin from Aspergillus gorakhpurensis. METHODS: Affinity chromatography on mucin-sepharose column was carried out for purification of Aspergillus gorakhpurensis lectin. The lectin was characterized for physico-chemical parameters. Mitogenic potential of the lectin was evaluated against splenocytes of Swiss albino mice by MTT assay. Antimicrobial activity of the purified lectin has also been evaluated by disc diffusion assay. RESULTS: Single-step affinity purification resulted in 18.6-fold purification of the mycelial lectin. The molecular mass of the lectin was found to be 70 kDa and it was composed of two subunits of 34.8 kDa as determined by gel filtration chromatography, SDS-PAGE and MALDI-TOF analysis. pH optima of the lectin was found to be 6.5-9.5, while optimum temperature for lectin activity was 20-30 degrees C. Lectin was stable within a pH range of 7.0-10.5 and showed fair thermostability. EDTA did not affect lectin activity whereas it was found susceptible to the denaturants tested. MTT assay revealed strong mitogenic potential of A. gorakhpurensis lectin at a concentration upto 150 ug/mL. Antimicrobial activity assay showed its potent antibacterial activity against Bacillus cereus, Staphylococcous aureus and Escherichia coli and marginal antifungal activity against Saccharomyces cerevisiae. CONCLUSION: This is the first report on the mitogenic and antimicrobial potential of Aspergillus gorakhpurensis lectin. The results will provide useful guidelines for further research in clinical applications of this lectin. PMID- 25286162 TI - PCB related effects thresholds as derived through gene transcript profiles in locally contaminated ringed seals (Pusa hispida). AB - Causal evidence linking toxic injury to polychlorinated biphenyl (PCB) exposure is typically confounded by the complexity of real-world contaminant mixtures to which aquatic wildlife are exposed. A local PCB "hotspot" on the Labrador coast provided a rare opportunity to evaluate the effects of PCBs on the health of a marine mammal as this chemical dominated their persistent organic pollutant (POP) burdens. The release of approximately 260 kg of PCBs by a military radar facility over a 30 year period (1970-2000) contaminated some local marine biota, including the ringed seal (Pusa hispida). The abundance profiles of eight health-related gene transcripts were evaluated in liver samples collected from 43 ringed seals in the affected area. The mRNA transcript levels of five gene targets, including aryl hydrocarbon receptor (Ahr), interleukin-1 beta (Il1b), estrogen receptor alpha (Esr1), insulin like growth factor receptor 1 (Igf1), and glucocorticoid receptor alpha (Nr3c1) correlated with increasing levels of blubber PCBs. PCB threshold values calculated using best-fit hockey-stick regression models for these five genes averaged 1,680+/-206 ng/g lw, with the lowest, most conservative, being 1,370 ng/g lw for Il1b. Approximately 14% of the seals in the region exceeded this threshold. The dominance of PCBs in the seals studied enabled an assessment of the effects of this chemical on gene transcripts involved in regulating the health of a highly mobile predator, something that is rarely possible in the world of complex mixtures. PMID- 25286161 TI - The interrelationship between promoter strength, gene expression, and growth rate. AB - In exponentially growing bacteria, expression of heterologous protein impedes cellular growth rates. Quantitative understanding of the relationship between expression and growth rate will advance our ability to forward engineer bacteria, important for metabolic engineering and synthetic biology applications. Recently, a work described a scaling model based on optimal allocation of ribosomes for protein translation. This model quantitatively predicts a linear relationship between microbial growth rate and heterologous protein expression with no free parameters. With the aim of validating this model, we have rigorously quantified the fitness cost of gene expression by using a library of synthetic constitutive promoters to drive expression of two separate proteins (eGFP and amiE) in E. coli in different strains and growth media. In all cases, we demonstrate that the fitness cost is consistent with the previous findings. We expand upon the previous theory by introducing a simple promoter activity model to quantitatively predict how basal promoter strength relates to growth rate and protein expression. We then estimate the amount of protein expression needed to support high flux through a heterologous metabolic pathway and predict the sizable fitness cost associated with enzyme production. This work has broad implications across applied biological sciences because it allows for prediction of the interplay between promoter strength, protein expression, and the resulting cost to microbial growth rates. PMID- 25286164 TI - Multimodality imaging and transcatheter coil embolization of an iatrogenic subclavian artery-internal jugular vein fistula. AB - A 69-year-old man was found to have a loud continuous bruit in the neck. Duplex carotid ultrasound showed high-velocity turbulent flow in the dilated and pulsatile right internal jugular vein. Computed tomography angiogram demonstrated markedly enlarged right internal jugular vein with a posteriorly located arteriovenous communication. Invasive angiography revealed an arteriovenous fistula originating from the right subclavian artery draining into the dilated and tortuous right internal jugular vein. An endovascular coil was successfully deployed in the fistula tract. Subclavian artery-internal jugular vein fistula is rare. Our case is most likely iatrogenic towing to previous central venous cannulation during coronary bypass grafting. The anatomic challenge of this fistula, being located in the thoracic outlet, makes endovascular repair particularly favourable. PMID- 25286165 TI - Understanding the role of histidine in the GHSxG acyltransferase active site motif: evidence for histidine stabilization of the malonyl-enzyme intermediate. AB - Acyltransferases determine which extender units are incorporated into polyketide and fatty acid products. The ping-pong acyltransferase mechanism utilizes a serine in a conserved GHSxG motif. However, the role of the conserved histidine in this motif is poorly understood. We observed that a histidine to alanine mutation (H640A) in the GHSxG motif of the malonyl-CoA specific yersiniabactin acyltransferase results in an approximately seven-fold higher hydrolysis rate over the wildtype enzyme, while retaining transacylation activity. We propose two possibilities for the reduction in hydrolysis rate: either H640 structurally stabilizes the protein by hydrogen bonding with a conserved asparagine in the ferredoxin-like subdomain of the protein, or a water-mediated hydrogen bond between H640 and the malonyl moiety stabilizes the malonyl-O-AT ester intermediate. PMID- 25286166 TI - Behavioral attitudes and preferences in cooking practices with traditional open fire stoves in Peru, Nepal, and Kenya: implications for improved cookstove interventions. AB - Global efforts are underway to develop and promote improved cookstoves which may reduce the negative health and environmental effects of burning solid fuels on health and the environment. Behavioral studies have considered cookstove user practices, needs and preferences in the design and implementation of cookstove projects; however, these studies have not examined the implications of the traditional stove use and design across multiple resource-poor settings in the implementation and promotion of improved cookstove projects that utilize a single, standardized stove design. We conducted in-depth interviews and direct observations of meal preparation and traditional, open-fire stove use of 137 women aged 20-49 years in Kenya, Peru and Nepal prior in the four-month period preceding installation of an improved cookstove as part of a field intervention trial. Despite general similarities in cooking practices across sites, we identified locally distinct practices and norms regarding traditional stove use and desired stove improvements. Traditional stoves are designed to accommodate specific cooking styles, types of fuel, and available resources for maintenance and renovation. The tailored stoves allow users to cook and repair their stoves easily. Women in each setting expressed their desire for a new stove, but they articulated distinct specific alterations that would meet their needs and preferences. Improved cookstove designs need to consider the diversity of values and needs held by potential users, presenting a significant challenge in identifying a "one size fits all" improved cookstove design. Our data show that a single stove design for use with locally available biomass fuels will not meet the cooking demands and resources available across the three sites. Moreover, locally produced or adapted improved cookstoves may be needed to meet the cooking needs of diverse populations while addressing health and environmental concerns of traditional stoves. PMID- 25286167 TI - Telephone-based adiposity prevention for families with overweight children (T.A.F.F.-Study): one year outcome of a randomized, controlled trial. AB - The one-year outcome of the randomized controlled T.A.F.F. (Telephone based Adiposity prevention For Families) study is presented. Screening of overweight (BMI-SDS > 90th centile) children 3.5-17.4 years was performed via the German CrescNet database, and candidates were randomized to an intervention group (IG) and control group (CG). The intervention consisted of computer-aided telephone counselling for one year, supported by mailed newsletters. The primary endpoint was change in BMI-SDS; secondary endpoints were eating behavior, physical activity, media consumption, quality of life. Data from 289 families (145 IG (51% females); 144 CG (50% females)) were analyzed (Full Analysis Set: FAS; Per Protocol Set: PPS). Successful intervention was defined as decrease in BMI-SDS >= 0.2. In the FAS, 21% of the IG was successful as compared to 16% from the CG (95% CI for this difference: (-4, 14), p = 0.3, mean change in BMI-SDS: -0.02 for IG vs. 0.02 for CG; p = 0.4). According to the PPS, however, the success rate was 35% in the IG compared to 19% in the CG (mean change in BMI-SDS: -0.09 for IG vs. 0.02 for CG; p = 0.03). Scores for eating patterns (p = 0.01), media consumption (p = 0.007), physical activity (p = 9 * 10-9), quality of life (p = 5 * 10-8) decreased with age, independent of group or change in BMI-SDS. We conclude that a telephone-based obesity prevention program suffers from well-known high attrition rates so that its effectiveness could only be shown in those who adhered to completion. The connection between lifestyle and weight status is not simple and requires further research to better understand. PMID- 25286171 TI - A photochemical one-pot three-component synthesis of tetrasubstituted imidazoles. AB - Tetrasubstituted imidazoles can be formed in a photochemical one-pot synthesis from aldehydes, alpha-aminonitriles, and isoxazoles. Condensation of the first two components produces alpha-(alkylideneamino)nitriles which react under basic conditions with the acylazirines formed in situ by photochemical ring transformation of the isoxazole component. This process includes an unusual cleavage of the C(2)-C(3) bond of the acylazirine. The reaction mechanism was studied by DFT calculations. PMID- 25286168 TI - Reasons for starting and stopping electronic cigarette use. AB - The aim of our study was to explore reasons for starting and then stopping electronic cigarette (e-cigarette) use. Among a national sample of 3878 U.S. adults who reported ever trying e-cigarettes, the most common reasons for trying were curiosity (53%); because a friend or family member used, gave, or offered e cigarettes (34%); and quitting or reducing smoking (30%). Nearly two-thirds (65%) of people who started using e-cigarettes later stopped using them. Discontinuation was more common among those whose main reason for trying was not goal-oriented (e.g., curiosity) than goal-oriented (e.g., quitting smoking) (81% vs. 45%, p < 0.001). The most common reasons for stopping e-cigarette use were that respondents were just experimenting (49%), using e-cigarettes did not feel like smoking cigarettes (15%), and users did not like the taste (14%). Our results suggest there are two categories of e-cigarette users: those who try for goal-oriented reasons and typically continue using and those who try for non-goal oriented reasons and then typically stop using. Research should distinguish e cigarette experimenters from motivated users whose decisions to discontinue relate to the utility or experience of use. Depending on whether e-cigarettes prove to be effective smoking cessation tools or whether they deter cessation, public health programs may need distinct strategies to reach and influence different types of users. PMID- 25286172 TI - Core self-evaluations and Snyder's hope theory in persons with spinal cord injuries. AB - OBJECTIVE: The objective of the study was to evaluate a motivational model of core self-evaluations (CSE), hope (agency and pathways thinking), participation, and life satisfaction in persons with spinal cord injuries. DESIGN: A cross sectional, correlational design with path analysis was used to evaluate the model. PARTICIPANTS: 187 adults with spinal cord injuries participated in this study. RESULTS: The results indicated an excellent fit between the data and the proposed model. Specifically, CSE was found to directly predict agency and pathways thinking, participation, and life satisfaction. CSE was also found to indirectly predict participation and life satisfaction through agency thinking. CONCLUSIONS: Although CSE contributes directly to participation and life satisfaction, it also has a unique role in increasing individuals' motivation to pursue goals, which also predicts participation and life satisfaction. Counseling interventions should be multifaceted and address the components of CSE to increase hope, participation, and life satisfaction. PMID- 25286173 TI - beta-Lactam monotherapy vs beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial. AB - IMPORTANCE: The clinical benefit of adding a macrolide to a beta-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE: To test noninferiority of a beta-lactam alone compared with a beta-lactam and macrolide combination in moderately severe community acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS: Patients were treated with a beta-lactam and a macrolide (combination arm) or with a beta-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES: Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0 degrees C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS: After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE: We did not find noninferiority of beta-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00818610. PMID- 25286174 TI - Safety-related moderators of a parent-based HIV prevention intervention in South Africa. AB - Our study examined factors influencing the effectiveness of a parent-based HIV prevention intervention implemented in Cape Town, South Africa. Caregiver-youth dyads (N = 99) were randomized into intervention or control conditions and assessed longitudinally. The intervention improved a parenting skill associated with youth sexual risk, parent-child communication about sex and HIV. Analyses revealed that over time, intervention participants (female caregivers) who experienced recent intimate partner violence (IPV) or unsafe neighborhoods discussed fewer sex topics with their adolescent children than caregivers in safer neighborhoods or who did not report IPV. Participants with low or moderate decision-making power in their intimate relationships discussed more topics over time only if they received the intervention. The effectiveness of our intervention was challenged by female caregivers' experience with IPV and unsafe neighborhoods, highlighting the importance of safety-related contextual factors when implementing behavioral interventions for women and young people in high risk environments. Moderation effects did not occur for youth-reported communication outcomes. Implications for cross-cultural adaptations of parent based HIV prevention interventions are discussed. PMID- 25286175 TI - A randomized clinical trial to test the efficacy of a family-focused, culturally informed therapy for schizophrenia. AB - Research strongly suggests that family interventions can benefit patients with schizophrenia, yet current interventions often fail to consider the cultural context and spiritual practices that may make them more effective and relevant to ethnic minority populations. We have developed a family focused, culturally informed treatment for schizophrenia (CIT-S) patients and their caregivers to address this gap. Sixty-nine families were randomized to either 15 sessions of CIT-S or to a 3-session psychoeducation (PSY-ED) control condition. Forty-six families (66.7%) completed the study. The primary aim was to test whether CIT-S would outperform PSY-ED in reducing posttreatment symptom severity (controlling for baseline symptoms) on the Brief Psychiatric Rating Scale. Secondary analyses were conducted to test whether treatment efficacy would be moderated by ethnicity and whether patient-therapist ethnic match would relate to efficacy and patient satisfaction with treatment. Patients included 40 Hispanic/Latinos, 14 Whites, 11 Blacks, and 4 patients who identified as "other." In line with expectations, results from an ANCOVA indicated that patients assigned to the CIT-S condition had significantly less severe psychiatric symptoms at treatment termination than did patients assigned to the PSY-ED condition. Patient ethnicity and patient therapist ethnic match (vs. mismatch) did not relate to treatment efficacy or satisfaction with the intervention. Results suggest that schizophrenia may respond to culturally informed psychosocial interventions. The treatment appears to work equally well for Whites and minorities alike. Follow-up research with a matched length control condition is needed. Further investigation is also needed to pinpoint specific mechanisms of change. PMID- 25286176 TI - Molecular dynamics of CYP2D6 polymorphisms in the absence and presence of a mechanism-based inactivator reveals changes in local flexibility and dominant substrate access channels. AB - Cytochrome P450 enzymes (CYPs) represent an important enzyme superfamily involved in metabolism of many endogenous and exogenous small molecules. CYP2D6 is responsible for ~ 15% of CYP-mediated drug metabolism and exhibits large phenotypic diversity within CYPs with over 100 different allelic variants. Many of these variants lead to functional changes in enzyme activity and substrate selectivity. Herein, a molecular dynamics comparative analysis of four different variants of CYP2D6 was performed. The comparative analysis included simulations with and without SCH 66712, a ligand that is also a mechanism-based inactivator, in order to investigate the possible structural basis of CYP2D6 inactivation. Analysis of protein stability highlighted significantly altered flexibility in both proximal and distal residues from the variant residues. In the absence of SCH 66712, *34, *17-2, and *17-3 displayed more flexibility than *1, and *53 displayed more rigidity. SCH 66712 binding reversed flexibility in *17-2 and *17 3, through *53 remained largely rigid. Throughout simulations with docked SCH 66712, ligand orientation within the heme-binding pocket was consistent with previously identified sites of metabolism and measured binding energies. Subsequent tunnel analysis of substrate access, egress, and solvent channels displayed varied bottle-neck radii. Taken together, our results indicate that SCH 66712 should inactivate these allelic variants, although varied flexibility and substrate binding-pocket accessibility may alter its interaction abilities. PMID- 25286178 TI - A simple centrifugation method for improving the detection of Ostreid herpesvirus 1 (OsHV-1) in natural seawater samples with an assessment of the potential for particulate attachment. AB - Ostreid herpesvirus-1 (OsHV-1) is responsible for massive mortality events in commercially farmed Pacific oysters (Crassostrea gigas) in Australia, New Zealand, Europe and the USA. Economic losses have been severe in many countries since 2008, associated with a strain known as OsHV-1MU-var. Despite intensive studies of the virus itself, there is almost no information on its detection in natural seawater, how it is spread over wide geographic distance in water or on how it is transmitted from oyster to oyster via seawater. The aim of the current work was to (1) assess and compare several centrifugation methods in order to detect OsHV-1 in natural seawater samples using real-time quantitative PCR, in such a way that large numbers of samples could be processed efficiently and (2) assess the potential for particulate attachment of OsHV-1 using filtration. Compared to testing unprocessed seawater samples, centrifugation of seawater at 1000*g for 20 min with testing of the pellet improved OsHV-1 detection rates by two fold. Results suggest that OsHV-1 may be attached to particles large enough to be pelleted at low g-force, as well as in the form of small particles, free virus or free viral DNA. Filtration of seawater using low protein binding filters could not be used to assess OsHV-1 particle attachment, due to interactions between particles, free virus or free viral DNA and the membranes. PMID- 25286177 TI - Sequencing human rhinoviruses: direct sequencing versus plasmid cloning. AB - Human rhinoviruses (RV) are associated with the majority of viral respiratory illnesses in infants, children and adults. Over the last several years, researchers have begun to sequence the many different species and strains of RV in order to determine if certain species were associated with increased disease severity. There are a variety of techniques employed to prepare samples for sequencing. One method utilizes plasmid-cloning, which is expensive and takes several hours to complete. Recently, some investigators have instead used direct sequencing to sequence RV strains, allowing for omission of the time- and labor intensive cloning step. This study formally compares and contrasts the sequencing results obtained from plasmid-cloning and direct Sanger sequencing of a 500 base pair PCR product covering the VP4/VP2 region of RV. A slightly longer sequence (by 65 base pairs on average) was obtained when specimens were plasmid-cloned, and the sequences were 86% similar. After trimming the extra base pairs from the cloned sequences, the sequences were 99.7% identical. Overall success of directly sequencing samples was similar to that of cloning, 5% on average failed for each technique. Therefore, in many instances, directly sequencing samples may be considered in lieu of the more expensive and time-consuming plasmid-cloning technique. PMID- 25286179 TI - Avian oncogenic virus differential diagnosis in chickens using oligonucleotide microarray. AB - Avian oncogenic viruses include the avian leukosis virus (ALV), reticuloendotheliosis virus (REV) and Marek's disease virus (MDV). Multiple oncogenic viral infections are frequently seen, with even Marek's disease vaccines reported to be contaminated with ALV and REV. The gross lesions caused by avian oncogenic viruses often overlap, making differentiation diagnosis based on histopathology difficult. The objective of this study is to develop a rapid approach to simultaneously differentiate, subgroup and pathotype the avian oncogenic viruses. The oligonucleotide microarray was employed in this study. Particular DNA sequences were recognized using specific hybridization between the DNA target and probe on the microarray, followed with colorimetric development through enzyme reaction. With 10 designed probes, ALV-A, ALV-E, ALV-J, REV, MDV pathogenic and vaccine strains were clearly discriminated on the microarray with the naked eyes. The detection limit was 27 copy numbers, which was 10-100 times lower than multiplex PCR. Of 102 field samples screened using the oligonucleotide microarray, 32 samples were positive for ALV-E, 17 samples were positive for ALV J, 6 samples were positive for REV, 4 samples were positive for MDV, 7 samples were positive for both ALV-A and ALV-E, 5 samples were positive for ALV-A, ALV-E and ALV-J, one sample was positive for both ALV-J and MDV, and 3 samples were positive for both REV and MDV. The oligonucleotide microarray, an easy-to-use, high-specificity, high-sensitivity and extendable assay, presents a potent technique for rapid differential diagnosis of avian oncogenic viruses and the detection of multiple avian oncogenic viral infections under field conditions. PMID- 25286180 TI - Relative quantitation goes viral: An RT-qPCR assay for a grapevine virus. AB - Accurate detection and quantitation of viruses can be beneficial to plant-virus interaction studies. In this study, three SYBR green real-time RT-PCR assays were developed to quantitate grapevine leafroll-associated virus 3 (GLRaV-3) in infected vines. Three genomic regions (ORF1a, coat protein and 3'UTR) were targeted to quantitate GLRaV-3 relative to three stably expressed reference genes (actin, GAPDH and alpha-tubulin). These assays were able to detect all known variant groups of GLRaV-3, including the divergent group VI, with equal efficiency. No link could be established between the concentration ratios of the different genomic regions and subgenomic RNA (sgRNA) expression. However, a significant lower virus concentration ratio for plants infected with variant group VI compared to variant group II was observed for the ORF1a, coat protein and the 3'UTR. Significant higher accumulation of the virus in the growth tip was also detected for both variant groups. The quantitation of viral genomic regions under different conditions can contribute to elucidating disease aetiology and enhance knowledge about virus ecology. PMID- 25286181 TI - Lyophilisation of influenza, rabies and Marburg lentiviral pseudotype viruses for the development and distribution of a neutralisation -assay-based diagnostic kit. AB - Pseudotype viruses (PVs) are chimeric, replication-deficient virions that mimic wild-type virus entry mechanisms and can be safely employed in neutralisation assays, bypassing the need for high biosafety requirements and performing comparably to established serological assays. However, PV supernatant necessitates -80 degrees C long-term storage and cold-chain maintenance during transport, which limits the scope of dissemination and application throughout resource-limited laboratories. We therefore investigated the effects of lyophilisation on influenza, rabies and Marburg PV stability, with a view to developing a pseudotype virus neutralisation assay (PVNA) based kit suitable for affordable global distribution. Infectivity of each PV was calculated after lyophilisation and immediate reconstitution, as well as subsequent to incubation of freeze-dried pellets at varying temperatures, humidities and timepoints. Integrity of glycoprotein structure following treatment was also assessed by employing lyophilised PVs in downstream PVNAs. In the presence of 0.5M sucrose PBS cryoprotectant, each freeze-dried pseudotype was stably stored for 4 weeks at up to 37 degrees C and could be neutralised to the same potency as unlyophilised PVs when employed in PVNAs. These results confirm the viability of a freeze-dried PVNA-based kit, which could significantly facilitate low-cost serology for a wide portfolio of emerging infectious viruses. PMID- 25286182 TI - FoxP3+ regulatory T cells determine disease severity in rodent models of inflammatory neuropathies. AB - Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies. PMID- 25286184 TI - Comparable efficacy of tenofovir versus entecavir and predictors of response in treatment-naive patients with chronic hepatitis B: a multicenter real-life study. AB - OBJECTIVE: To compare responses to tenofovir (TDF) and entecavir (ETV) therapy. METHODS: This was a multicenter retrospective study including treatment-naive patients with chronic hepatitis B (CHB) who received TDF or ETV. The primary end points were undetectable HBV-DNA at 48 weeks and serological and biochemical responses. RESULTS: Out of 195 CHB patients, 90 (46%) received TDF and 105 (54%) received ETV; 72% were male, their mean age was 43+/-12 years, and the mean duration of treatment was 30.2+/-15.7 months. Hepatitis B e antigen (HBeAg) seropositivity was 32% in the TDF group and 34% in the ETV group. HBeAg seroconversion rates in HBeAg-positive patients were 24% in the TDF group and 39% in the ETV group; the difference was not significant (p=0.2). The mean time to alanine aminotransferase (ALT) normalization and rates of ALT normalization at 3, 6, 12, 18, and 24 months were similar in the two groups (p > 0.05). The mean time to undetectable HBV-DNA levels in the TDF and ETV groups was 11.5+/-8.9 and 12.9+/-10.8 months, respectively (p=0.32). A significantly greater decline in HBV DNA levels at 12 and 18 months was observed in the TDF group (p=0.02 and p=0.03, respectively). Seven (7%) patients on ETV therapy had virological breakthrough (p=0.01). Only one patient in each group had hepatitis B surface antigen (HBsAg) clearance. None of the patients developed decompensation or hepatocellular carcinoma during treatment. CONCLUSIONS: The two drugs appear to have similar efficacy in CHB patients. However, 7% of patients on ETV therapy had virological breakthrough, while none of the patients on TDF therapy did. PMID- 25286185 TI - Tissue-simulating phantoms for assessing potential near-infrared fluorescence imaging applications in breast cancer surgery. AB - Inaccuracies in intraoperative tumor localization and evaluation of surgical margin status result in suboptimal outcome of breast-conserving surgery (BCS). Optical imaging, in particular near-infrared fluorescence (NIRF) imaging, might reduce the frequency of positive surgical margins following BCS by providing the surgeon with a tool for pre- and intraoperative tumor localization in real-time. In the current study, the potential of NIRF-guided BCS is evaluated using tissue simulating breast phantoms for reasons of standardization and training purposes. Breast phantoms with optical characteristics comparable to those of normal breast tissue were used to simulate breast conserving surgery. Tumor-simulating inclusions containing the fluorescent dye indocyanine green (ICG) were incorporated in the phantoms at predefined locations and imaged for pre- and intraoperative tumor localization, real-time NIRF-guided tumor resection, NIRF guided evaluation on the extent of surgery, and postoperative assessment of surgical margins. A customized NIRF camera was used as a clinical prototype for imaging purposes. Breast phantoms containing tumor-simulating inclusions offer a simple, inexpensive, and versatile tool to simulate and evaluate intraoperative tumor imaging. The gelatinous phantoms have elastic properties similar to human tissue and can be cut using conventional surgical instruments. Moreover, the phantoms contain hemoglobin and intralipid for mimicking absorption and scattering of photons, respectively, creating uniform optical properties similar to human breast tissue. The main drawback of NIRF imaging is the limited penetration depth of photons when propagating through tissue, which hinders (noninvasive) imaging of deep-seated tumors with epi-illumination strategies. PMID- 25286186 TI - Silver-enhanced block copolymer membranes with biocidal activity. AB - Silver nanoparticles were deposited on the surface and pore walls of block copolymer membranes with highly ordered pore structure. Pyridine blocks constitute the pore surfaces, complexing silver ions and promoting a homogeneous distribution. Nanoparticles were then formed by reduction with sodium borohydride. The morphology varied with the preparation conditions (pH and silver ion concentration), as confirmed by field emission scanning and transmission electron microscopy. Silver has a strong biocide activity, which for membranes can bring the advantage of minimizing the growth of bacteria and formation of biofilm. The membranes with nanoparticles prepared under different pH values and ion concentrations were incubated with Pseudomonas aeruginosa and compared with the control. The strongest biocidal activity was achieved with membranes containing membranes prepared under pH 9. Under these conditions, the best distribution with small particle size was observed by microscopy. PMID- 25286187 TI - Prevalence, associated factors and source of support concerning supportive care needs among Japanese cancer survivors. AB - BACKGROUND: The current study aimed to describe cancer survivors' supportive care needs in Japan, to identify associated factors of unmet needs, and to describe the source of support that are preferred and actually used by cancer survivors. METHODS: Using a web-based questionnaire, we examined unmet supportive needs and its associated factors among 628 adult Japanese cancer survivors. The questionnaire comprised 16 items representing five domains (medical psychological, financial, social-spiritual, sexual, and physical needs). RESULTS: Prevalence of unmet need ranged from 5 to 18%, depending on different domains. The prevalence was high in medical-psychological and financial domains and relatively low in physical and sexual domains. Poor performance status, psychiatric morbidity and low income status were associated with unmet needs of most domains. Most cancer survivors preferred and actually sought support from their family and friends. Financial needs were preferred to be provided by non medical professionals. Call for peer support was intense, especially for medical psychological, social-spiritual, and sexual needs; however, peer support was not well-provided. CONCLUSIONS: This study illustrated characteristics of Japanese cancer survivors who are likely to have unmet needs. The study demonstrated need for expanded involvement of non-medical professionals and peer support, especially in the domains of medical-psychological, social-spiritual, financial and sexual needs. PMID- 25286183 TI - Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives. AB - Saponins are widely distributed plant natural products with vast structural and functional diversity. They are typically composed of a hydrophobic aglycone, which is extensively decorated with functional groups prior to the addition of hydrophilic sugar moieties, to result in surface-active amphipathic compounds. The saponins are broadly classified as triterpenoids, steroids or steroidal glycoalkaloids, based on the aglycone structure from which they are derived. The saponins and their biosynthetic intermediates display a variety of biological activities of interest to the pharmaceutical, cosmetic and food sectors. Although their relevance in industrial applications has long been recognized, their role in plants is underexplored. Recent research on modulating native pathway flux in saponin biosynthesis has demonstrated the roles of saponins and their biosynthetic intermediates in plant growth and development. Here, we review the literature on the effects of these molecules on plant physiology, which collectively implicate them in plant primary processes. The industrial uses and potential of saponins are discussed with respect to structure and activity, highlighting the undoubted value of these molecules as therapeutics. PMID- 25286188 TI - Effect of processing on phenolic composition of dough and bread fractions made from refined and whole wheat flour of three wheat varieties. AB - This study investigated the effect of breadmaking on the assay of phenolic acids from flour, dough, and bread fractions of three whole and refined wheat varieties. Comparison of the efficacy of two commonly used methods for hydrolysis and extraction of phenoilc acids showed that yields of total phenolic acids (TPA) were 5-17% higher among all varieties and flour types when samples were directly hydrolyzed in the presence of ascorbate and EDTA as compared to the method separating free, soluble conjugates and bound, insoluble phenolic acids. Ferulic acid (FA) was the predominant phenolic acid, accounting for means of 59 and 81% of TPA among all refined and whole wheat fractions, respectively. All phenolic acids measured were more abundant in whole wheat than in refined samples. Results indicated that the total quantified phenolic acids did not change significantly when breads were prepared from refined and whole wheat flour. Thus, the potential phytochemical health benefits of total phenolic acids appear to be preserved during bread baking. PMID- 25286189 TI - Ex vivo culture of Drosophila pupal testis and single male germ-line cysts: dissection, imaging, and pharmacological treatment. AB - During spermatogenesis in mammals and in Drosophila melanogaster, male germ cells develop in a series of essential developmental processes. This includes differentiation from a stem cell population, mitotic amplification, and meiosis. In addition, post-meiotic germ cells undergo a dramatic morphological reshaping process as well as a global epigenetic reconfiguration of the germ line chromatin the histone-to-protamine switch. Studying the role of a protein in post-meiotic spermatogenesis using mutagenesis or other genetic tools is often impeded by essential embryonic, pre-meiotic, or meiotic functions of the protein under investigation. The post-meiotic phenotype of a mutant of such a protein could be obscured through an earlier developmental block, or the interpretation of the phenotype could be complicated. The model organism Drosophila melanogaster offers a bypass to this problem: intact testes and even cysts of germ cells dissected from early pupae are able to develop ex vivo in culture medium. Making use of such cultures allows microscopic imaging of living germ cells in testes and of germ-line cysts. Importantly, the cultivated testes and germ cells also become accessible to pharmacological inhibitors, thereby permitting manipulation of enzymatic functions during spermatogenesis, including post-meiotic stages. The protocol presented describes how to dissect and cultivate pupal testes and germ line cysts. Information on the development of pupal testes and culture conditions are provided alongside microscope imaging data of live testes and germ-line cysts in culture. We also describe a pharmacological assay to study post-meiotic spermatogenesis, exemplified by an assay targeting the histone-to-protamine switch using the histone acetyltransferase inhibitor anacardic acid. In principle, this cultivation method could be adapted to address many other research questions in pre- and post-meiotic spermatogenesis. PMID- 25286190 TI - Three-dimensional valency mapping in ceria nanocrystals. AB - Using electron tomography combined with electron energy loss spectroscopy (EELS), we are able to map the valency of the Ce ions in CeO2-x nanocrystals in three dimensions. Our results show a clear facet-dependent reduction shell at the surface of ceria nanoparticles; {111} surface facets show a low surface reduction, whereas at {001} surface facets, the cerium ions are more likely to be reduced over a larger surface shell. Our generic tomographic technique allows a full 3D data cube to be reconstructed, containing an EELS spectrum in each voxel. This possibility enables a three-dimensional investigation of a plethora of material-specific physical properties such as valency, chemical composition, oxygen coordination, or bond lengths, triggering the synthesis of nanomaterials with improved properties. PMID- 25286191 TI - Successful treatment of psoriasis with low-dose per os interleukins 4, 10, and 11. PMID- 25286193 TI - Is a sphygmomanometer a valid and reliable tool to measure the isometric strength of hip muscles? A systematic review. AB - BACKGROUND: Muscle strength measurement is a key component of physiotherapists' assessment and is frequently used as an outcome measure. A sphygmomanometer is an instrument commonly used to measure blood pressure that can be potentially used as a tool to assess isometric muscle strength. OBJECTIVE: To systematically review the evidence on the reliability and validity of a sphygmomanometer for measuring isometric strength of hip muscles. METHOD: A literature search was conducted across four databases. Studies were eligible if they presented data on reliability and/or validity, used a sphygmomanometer to measure isometric muscle strength of the hip region, and were peer reviewed. The individual studies were evaluated for quality using a standardized critical appraisal tool. RESULTS: A total of 644 articles were screened for eligibility, with five articles chosen for inclusion. The use of a sphygmomanometer to objectively assess isometric muscle strength of the hip muscles appears to be reliable with intraclass correlation coefficient values ranging from 0.66 to 0.94 in elderly and young populations. No studies were identified that have assessed the validity of a sphygmomanometer. CONCLUSION: The sphygmomanometer appears to be reliable for assessment of isometric muscle strength around the hip joint, but further research is warranted to establish its validity. PMID- 25286196 TI - Solid state mechanochemical processes for better electroceramics. AB - The present short overview focuses on the renovation of solid state processes toward phase pure and well-crystallized complex oxides centered on the electroceramic materials. Elevation of the reactivity and preservation of stoichiometry of the starting mixture or precursor are of universal importance. Mechanical activation, being considered as versatile, may also need reconsideration in view of contamination and process rationalization. After briefly reviewing mechanochemical processes for direct synthesis of complex oxides, solid state processes toward well crystallized fine particles of complex oxides are discussed by starting from mechanochemically derived precursors with subsequent optimized calcination. Case studies were cited from literatures for complex oxides, including author's own experimental studies mainly with BaBi(2)Ta(2)O(9) (BBT), Ba(Mg(1/3)Ta(2/3))O(3) (BMT) and KNbO(3) (KN). The substances discussed are mostly associated with ferroelectric materials, with a few exceptions of iron-containing magnetic materials. PMID- 25286194 TI - Real-time imaging of axonal transport of quantum dot-labeled BDNF in primary neurons. AB - BDNF plays an important role in several facets of neuronal survival, differentiation, and function. Structural and functional deficits in axons are increasingly viewed as an early feature of neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). As yet unclear is the mechanism(s) by which axonal injury is induced. We reported the development of a novel technique to produce biologically active, monobiotinylated BDNF (mBtBDNF) that can be used to trace axonal transport of BDNF. Quantum dot-labeled BDNF (QD BDNF) was produced by conjugating quantum dot 655 to mBtBDNF. A microfluidic device was used to isolate axons from neuron cell bodies. Addition of QD-BDNF to the axonal compartment allowed live imaging of BDNF transport in axons. We demonstrated that QD-BDNF moved essentially exclusively retrogradely, with very few pauses, at a moving velocity of around 1.06 MUm/sec. This system can be used to investigate mechanisms of disrupted axonal function in AD or HD, as well as other degenerative disorders. PMID- 25286197 TI - New Mg-based 4,4'-biphenyldicarboxylate coordination polymer with layered crystal structure. AB - New magnesium 4,4'-biphenyldicarboxylate (BPDC) was solvothermally synthesized in the presence of N,N'-dimethylformamide (DMF). The crystal structure with formula Mg(3)(BPDC)(3)(DMF)(4) and denoted as NICS-7 was solved in monoclinic symmetry with space group Pn (no. 7) and unit cell parameters a = 12.6433(7) A, b = 13.3950(5) A, c = 19.9230(8) A, beta = 107.131(5) degrees . The structure consists of MgO(6) linear arranged trimers with common vertices connected through BPDC ligands forming extended 2-dimensional layered hybrid structure. Each terminal Mg atom within trimeric clusters is coordinated by two dimethylformamide molecules, respectively. Layers of Mg(3)(BPDC)(3)(DMF)(4) are stabilized by non coordinated dimethylformamide molecules located within the voids in crystallographically disordered manner. Thermal properties of NICS-7 were determined by thermogravimetric and temperature-programmed X-ray diffraction. The structure remains stable only up to 50 degrees C. At higher temperatures, the removal of non-coordinated dimethylformamide molecules causes formation of amorphous Mg-BPDC phase. PMID- 25286198 TI - The novel crystal structure with Zr6O4(OH)4 core and hydrazine carboxylate ligands, and its thermal properties. AB - The title compound, [Zr(6)(OH)(4)O(4)(N(2)H(3)COO)(12)] . 14H(2)O, was prepared with a novel multi-step synthetic pathway. The structure contains a Zr(6)(u(3) OH)(4)(u(3)-O(4))(12+) core on which twelve hydrazine carboxylate anions are bound to form neutral coordination molecules. The coordination mode of carboxylate ligand is exclusively N,O-bidentate chelating, which is observed for the first time in this class of compounds. The title compound is also the first example of isolated Zr(IV) oxo clusters with cubic symmetry. The structure is stabilized with an extensive hydrogen bond network between coordination and water molecules, and amongst the solvent water molecules themselves. Thermogravimetric studies have shown that the prepared [Zr(6)(OH)(4)O(4)(N(2)H(3)COO)(12)] . (14)H(2)O decomposed in several consecutive steps characterized by evolution of H(2)O, CO, CO(2), N(2) and H(2), finally yielding ZrO(2). The decomposition mechanism is rather complex and includes the formation of a series of amorphous intermediates. PMID- 25286195 TI - Neuronal activity induces synaptic delivery of hnRNP A2/B1 by a BDNF-dependent mechanism in cultured hippocampal neurons. AB - Dendritic protein synthesis plays a critical role in several forms of synaptic plasticity, including BDNF (brain-derived neurotrophic factor)-mediated long-term synaptic potentiation (LTP). Dendritic transcripts are typically transported in a repressed state as components of large ribonucleoprotein complexes, and then translated upon stimulation at, or in the vicinity, of activated synapses. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) is a trans-acting factor involved in dendritic mRNA trafficking, but how the distribution of the protein in dendrites is regulated has not been characterized. Here we found that a fraction of hnRNP A2/B1 is present at the synapse under resting conditions in cultured hippocampal neurons. Accordingly, this ribonucleoprotein was detected in free mRNP, monosomal, and polyribosomal fractions obtained from synaptoneurosomes. Neuronal activity and BDNF treatment increased hnRNP A2/B1 protein levels in the cell body and dendritic compartments, and induced the delivery of this protein to synaptic sites. The activity-dependent accumulation of hnRNP A2/B1 at the synapse required, at least in part, the activation of TrkB receptors, presumably by BDNF. This neurotrophin also upregulated the hnRNP A2/B1 mRNA in the soma but was without effect on the abundance of neuritic hnRNP A2/B1 transcripts. These results show that the distribution of hnRNP A2/B1 is regulated by BDNF and by neuronal activity, an effect that may have a role in BDNF-induced synaptic plasticity events. PMID- 25286199 TI - Visible-light photoactivity of Bi-pyrochlores with high Fe contents. AB - Three Bi-pyrochlores with different Fe contents (Bi(2)Ti(2)O(7), Bi(1.65)Nb(1.12)Fe(1.16)O(7) and Bi(1.9)Te(0.58)Fe(1.52)O(6.87)) were synthesized in the form of nanopowders with similar morphological characteristics. All three nanopowders show an intensive visible-light photocatalytic activity. The analysis of their band gap and absorption characteristics has shown a strong correlation with the Fe-content indicating that a significant band gap reduction can be obtained by Fe incorporation. The photocatalytic activity has not followed this trend. The initial increase in the Fe-content has resulted in a significant enhancement of the photoactivity while with the further increase the photoactivity has slowly decreased. The reason for this behaviour has been proposed to be in an opposing influence of the increased exciton density and recombination rate. PMID- 25286200 TI - Strain engineering effects on electrical properties of lead-free piezoelectric thin films on Si wafers. AB - Using radio frequency - magnetron sputtering, calcium-doped barium zirconate titanate ((Ba(0.85)Ca(0.15))(Zr(0.1)Ti(0.9))O(3), BCZT) thin films were deposited on Si wafers with different bottom electrodes. The obtained BCZT thin film on a lanthanum nickel oxide (LNO) electrode had a highly c-axis preferred orientation, while the BCZT thin film on a Pt bottom electrode had (111) preferred orientation. Furthermore, the out-of-plane lattice constant of the BCZT on LNO/Si was 3.4% larger than that of the reported bulk material because of the compressive thermal stress from LNO with a large thermal expansion coefficient. This compressive thermal stress engenders an increase of the Curie temperature. The local piezoelectric response of the BCZT thin film on a LNO/Si structure was measured by piezoresponse force microscope. PMID- 25286201 TI - Protection of copper surface with phytic acid against corrosion in chloride solution. AB - Phytic acid (inositol hexaphosphate) was tested as a corrosion inhibitor for copper in 3% sodium chloride. Phytic acid is a natural compound derived from plants, it is not toxic and can be considered as a green inhibitor. Electrochemical methods of linear polarization and potentiodynamic polarization were used to study the electrochemical behaviour and evaluate the inhibition effectiveness. To obtain the optimal corrosion protection the following experimental conditions were investigated: effect of surface pre-treatment (abrasion and three procedures of surface roughening), pre-formation of the layer of phytic acid, time of immersion and concentration of phytic acid. To evaluate the surface pre-treatment procedures the surface roughness and contact angle were measured. Optimal conditions for formation of phytic layer were selected resulting in the inhibition effectiveness of nearly 80%. Morphology and composition of the layer were further studied by scanning electron microscopy, energy dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy. The layer of phytic acid with thickness in the nanometer range homogeneously covers the copper surface. The obtained results show that this natural compound can be used as a mildly effective corrosion inhibitor for copper in chloride solution. PMID- 25286202 TI - Gel-sol synthesis of rutile nanoparticles. AB - Titanium dioxide (TiO(2)) rutile nanoparticles were synthesized at temperatures below 100 degrees C using a gel-sol process that provides control of the final particles' characteristics, such as the nanoparticle size, morphology, crystal structure and crystallinity. The synthesized rutile nanoparticles were analyzed using X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results show that the gel-sol process allows control over the final nanoparticle characteristics with the proper choice of reaction parameters. The most profound influence on the nanoparticles' properties is achieved by the type and concentration of the acid used in the reaction mixture. The gel-sol synthesis resulted in anisotropic rutile nanoparticles that are 60-160 nm long, depending on the reaction parameters, and have an aspect ratio of about 5. A reaction mechanism is presented, explaining the influence of various reaction parameters on the characteristics of the TiO(2) nanoparticles. PMID- 25286203 TI - A method for fast estimation of the rate-limiting step in lithium-ion batteries. AB - Transport of charge in electrodes for lithium-ion batteries is complex. For accurate description one needs to use a multilevel approach which addresses processes on different scales - from the ones occurring inside active nanoparticles to those governing the transport in composite electrodes or in separators of sub-millimeter thickness. Here we attempt an approximation that allows for a fast estimation of the rate-limiting step in given electrochemical cell. Despite thoroughly simplified description of transport, the method gives suprisingly good prediction of polarisation resistance as a function of charge/discharge rate and of the electrode thickness. The method might be helpful for fast evaluation of new materials or new electrode designs in everyday laboratory testing. PMID- 25286204 TI - The magnetic and colloidal properties of CoFe2O4 nanoparticles synthesized by co precipitation. AB - Magnetic CoFe(2)O(4) nanoparticles were synthesized by co-precipitation at 80 degrees C. This co-precipitation was achieved by the rapid addition of a strong base to an aqueous solution of cations. The investigation of the samples that were quenched at different times after the addition of the base, using transmission electron microscopy (TEM) coupled with energy-dispersive X-ray spectroscopy (EDXS) and X-ray powder diffractometry, revealed the formation of a Co-deficient amorphous phase and Co(OH)(2), which rapidly reacted to form small CoFe(2)O(4) nanoparticles. The nanoparticles grew with the time of aging at elevated temperature. The colloidal suspensions of the nanoparticles were prepared in both an aqueous medium and in a non-polar organic medium, with the adsorption of citric acid and ricinoleic acid on the nanoparticles, respectively. The measurements of the room-temperature magnetization revealed the ferrimagnetic state of the CoFe(2)O(4) nanoparticles, while their suspensions displayed superparamagnetic behaviour. PMID- 25286205 TI - PMMA-b-PMAA diblock copolymer as a reactive polymeric surfactant for the functionalization of ZnO nanoparticles. AB - We investigated the efficiency of poly(methyl methacrylate)-b-poly(methacrylic acid) (PMMA-b-PMAA) diblock copolymers as reactive polymeric surfactants for the functionalization of ZnO nanoparticles (NPs) of diameters ranging from 20 to 80 nm. PMMA-b-PMAA with molar masses in the range of 20.000 and 30.000 g/mol and PMAA content between 3 and 30 mol % were prepared by reversible addition fragmentation chain transfer (RAFT) radical polymerization. Scanning transmission electron microscopy (STEM) showed efficient coverage of the particle surface with a polymer layer and infrared (IR) spectroscopy provided evidence of interaction of the PMAA segment (anchoring chains) with the NP surface. As demonstrated by dynamic light scattering (DLS) and UV-vis spectroscopy, the amphiphilic PMMA-b PMAA block copolymers prevented agglomeration of ZnO NPs to great extent and thus increased transparency of ZnO suspensions in tetrahydrofuran (THF) and PMMA/ZnO nanocomposites in the visible light region. We also demonstrated the importance of the length of PMAA segment for ZnO surface functionalization. Optimal UV-vis performance of suspensions of functionalized NPs in THF as well as of PMMA/ZnO nanocomposites was achieved with PMMA-b-PMAA block copolymers containing 3 and 15 mol % of anchoring PMAA segment. PMID- 25286206 TI - Tuning the photocatalytic activity of nanocrystalline titania by phase composition control and nitrogen doping, using different sources of nitrogen. AB - Titania nanoparticles were synthesized by employing the hydrothermal method and using TiOSO(4) as a titanium source. By varying pH between 0.5 and 1.0 and adding isopropanol to the hydrothermal reaction mixture, different mixtures of anatase, rutile, and brookite were obtained. The samples were also doped with nitrogen at different N concentrations using, respectively, urea, ammonium nitrate, and tripropylamine as nitrogen sources. The samples were characterized by X-ray powder diffraction, field emission scanning electron microscopy, infrared spectroscopy, UV-Vis diffuse reflectance spectroscopy and according to their specific surface area. Additionally, their photocatalytic activity was measured in a gas-solid reactor system. The results show that low pH favours rutile formation, whereas a higher pH yields mixed phase titania polymorphs. Isopropanol addition also favours rutile formation, and boosted the photocatalytic activity of the resulted particles. Contrary to most data in the literature, rutile turned out to be the more active phase in the present investigation. Nitrogen doping, on the other hand, did not contribute to higher photocatalytic activity, but was rather detrimental to it. PMID- 25286207 TI - Foil-based TiO2/gel electrolyte/Ni1-xO electrochromic device made of electrochromic pigment coatings. AB - Thin electrochromic coatings were obtained by co-grinding the mTiA particle aggregates (300 nm in size) with open-corner heptaisobutyl trisilanol POSS (T(8) IB(7)(OH)(3) POSS) acting as dispersant. After the addition of titanium tetraisopropoxide (3-5%) the mTiA pigment dispersion was deposited on FTO glass and plastic ITO PET foils and coatings were obtained by thermal treatment at 150 degrees C. Optical transmittance and luminous haze from 2 to 6% of the coatings were determined from the corresponding UV-Vis spectra. The achieved electrochromic effect was evaluated by electrochemical charging/discharging in 1 M LiClO(4)/PC electrolyte. Results revealed that the colouring/bleaching changes depended on the extent of grinding and the size of the milling zirconia beads, enabling to distinguish between the surface charging of the mTiA grains and the filling and emptying of the anatase density of states. mTiA pigment coatings deposited on plastic foil were used in combination with Ni(1-x)O pigment coatings for construction of foil-based electrochromic device employing novel gel electrolyte with ionic liquid co-solvent. PMID- 25286208 TI - Characterization of the alkoxide-based sol-gel derived La9.33Si6O26 powder and ceramic. AB - In this study, we report on the acid-catalysed synthesis of La(9.33)Si(6)O(26) from lanthanum nitrate or acetate and silicon ethoxide (TEOS) in the ethanol solvent, upon the transition from liquid to amorphous and crystalline phases. The similarity of the Fourier transform infrared spectra of the lanthanum-salt solutions and lanthanum-silicon sols indicates that the lanthanum environment is not changed in the reaction of the La-salt with TEOS. In the nitric-acid catalysed synthesis, the hydrolysis reaction was almost instantaneous, as a consequence of a higher amount of water in this system, which contributed to a high level of chemical heterogeneity in the product. The acetic acid-based synthesis ensured a good mixing of the reagents at the nanometre level, which gave rise to the formation of the pure La(9.33)Si(6)O(26) powder upon heating at 900 degrees C, and single phase ceramics with 94 % relative density after sintering at 1400 degrees C for 3 h in air, which is 200 degrees C lower temperature then usually reported for the apatite material. PMID- 25286209 TI - Silver(I) tetrafluoridooxidovanadate(V) - Ag[VOF4]. AB - Silver(I) tetrafluoridooxidovanadate(V) which contains the polymeric chain anion, [VOF(4)](nn-), has been prepared in reaction between AgNO(3) and VOF(3) in anhydrous HF solvent and characterised in the solid state by single-crystal X-ray diffraction and Raman spectroscopy. Pale yellow crystals of Ag[VOF(4)] crystallise in a monoclinic P2(1)/c space group with a = 5.5452(4) A, b = 5.0071(3) A, c = 13.6511(11) A, beta = 100.543(3) degrees , and V = 372.63(5) A(3) at 200 K with Z = 4. The most intense feature in the Raman spectrum is the V=O stretching band of the anion at 1008 cm-1. Solid-state conformational isomerism exists between [VOF(4)](-) anions in crystal structures of Ag[VOF(4)] and previously reported and structurally characterised K[VOF(4)] and Cs[VOF(4)] salts. PMID- 25286210 TI - Study of thermal decomposition of (K0.5Na0.5)NbO3 thin-films precursors with different amounts of alkali-acetate excess. AB - Liquid precursors of (K(0.5)Na(0.5))NbO(3) thin-films were prepared from alkali acetates and niobium ethoxide in 2-methoxyethanol solvent either in a stoichiometric ratio or with 5 or 10 mole % of potassium or sodium acetate excess. Fourier-transform infrared (FTIR) spectroscopy of the dried precursors confirmed the presence of acetate and hydroxyl groups. Thermal decompositions of the as-dried precursors in air occurred gradually. Between room temperature and ~200 degrees C, the weight loss of a few per cent was due to the evaporation of residual solvents. The major mass loss was due to thermal oxidation of organic group with the major exothermic events at about 250 degrees C and 450 degrees C, almost 200 degrees C below the onset of the chemical decomposition of alkali acetates, indicating that a heterometallic complex was formed in solution, in agreement with FTIR analysis. Both the amount and to a lesser extent the choice of alkali-acetate excess influenced the thermal decomposition of the organic groups predominantly in the temperature interval between ~200 degrees C and ~400 degrees C. PMID- 25286211 TI - An overview of the optical and electrochemical methods for detection of DNA - drug interactions. AB - A large number of inorganic and organic compounds is able to bind to DNA and form complexes. Among them, drugs are very important, especially chemotherapeutics. This paper presents the overview of DNA structural characteristics and types of interactions (covalent and non-covalent) between DNA molecule and drugs. Covalent binding of the drug is irreversible and leads to complete inhibition of DNA function, what conclusively, causes the cell death. On the other hand, non covalent binding is reversible and based on the principle of molecular recognition. Special attention is given to elucidation of the specific sites in DNA molecule for drug binding. According to their structural characteristics, drugs that react non-covalently with DNA are mainly intercalators, but also minor and major groove binders. When the complex between drug and DNA is formed, both the drug molecule, as well as DNA, experienced some modifications. This paper presents the overview of the methods used for the study of the interactions between DNA and drugs with the aim of detection and explanation of the resulting changes. For this purpose many spectroscopic methods like UV/VIS, fluorescence, infrared and NMR, polarized light spectroscopies like circular and linear dichroism, and fluorescence anisotropy or resonance is used. The development of the electrochemical DNA biosensors has opened a wide perspective using particularly sensitive and selective electrochemical methods for the detection of specific DNA interactions. The presented results summarize literature data obtained by the mentioned methods. The results are used to confirm the DNA damage, to determine drug binding sites and sequence preference, as well as conformational changes due to drug-DNA interaction. PMID- 25286212 TI - Efficient synthesis of spironaphthopyrano [2,3-d]pyrimidine-5,3'-indolines under solvent-free conditions catalyzed by SBA-Pr-SO3H as a nanoporous acid catalyst. AB - A green, simple one-pot synthesis of spironaphthopyrano[2,3-d]pyrimidine-5,3' indoline derivatives by a three-component reaction of isatins, 2-naphthol, and barbituric acids under solvent-free conditions in the presence of SBA-Pr-SO(3)H has been accomplished. Sulfonic acid functionalized SBA-15 (SBA-Pr-SO(3)H) as a heterogeneous nanoporous solid acid catalyst was found to be an efficient and recyclable acid catalyst in this synthesis. PMID- 25286213 TI - Bioanalytical method development and validation for simultaneous estimation of cefixime and dicloxacillin by RP-HPLC in human plasma. AB - An accurate, rapid and simple reversed-phase high performance liquid chromatography (RP-HPLC) bioanalytical method was developed and validated for simultaneous estimation of cefixime, dicloxacillin in human plasma using ezetimibe as an internal standard. The cefixime, dicloxacillin and internal standard were extracted by liquid-liquid extraction technique. Chromatographic separation is accomplished using CAPCELL PAK C18 (4.6 mm * 250 mm, 5 m) analytical column. The mobile phase consisted of phosphate buffer, acetonitrile and methanol in 42:55:03 proportions. Detection and quantification were performed by UV/Vis detection at 225 nm. The lower limit of quantification was 0.5 ug mL( 1) for both cefixime and dicloxacillin in human plasma. The calibration curves were linear over the concentration range 0.5 to 40 ug mL(-1) for both drugs in human plasma. The method was quantitatively evaluated in terms of linearity, precision, accuracy, recovery, selectivity, and stability. The method was found to be simple, convenient and suitable for the analysis of cefixime and dicloxacillin from biological fluids. PMID- 25286214 TI - The influence of nano-ZnO application methods on UV protective properties of cotton. AB - The influence of different application methods on UV protective properties of white and dyed cotton functionalized with ZnO nanoparticles (nano-ZnO) was investigated. The methods differ in application procedure, time of treatment and auxiliaries used in the treating bath. The ultraviolet protection factor (UPF) was determined for untreated and functionalized samples. The presence of nano-ZnO on fibres was investigated using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The content of Zn was determined with energy-dispersive X-ray spectroscopy (EDS) and inductively coupled plasma mass spectrometry (ICP-MS). Dynamic light scattering (DLS) was used for particle size measurements in the prepared solutions. The results show that UV protection of cotton increases with a higher content and uniform distribution of nano-ZnO on the samples and that dyeing increases the loading capacity of cotton towards nano ZnO. One of the methods (Method IV) gave remarkable results giving cotton an excellent UV protection whether it was dyed or not. PMID- 25286215 TI - Surface treated titanium dioxide nanoparticles as inorganic UV filters in sunscreen products. AB - TiO(2) nanoparticles were used in this research as an inorganic UV absorber for preparation of a sunscreen that ensures optically transparent films with adequate SPF. TiO(2) nanoparticles in rutile crystal form, produced in Cinkarna Celje, were used in this research. The elementary principle of the nanograde TiO(2) production is the sulphate synthesis process, which is upgraded for the synthesis of final nano product. TiO(2) nanoparticles were subsequently surface modified by coating with sodium silicate as the source of silica. The resulting silica coated TiO(2) nanoparticles were examined by scanning (SEM) and transmission electron microscopy (TEM). Uniform particles distribution and homogeneous amorphous coatings, formed in heterogeneous nucleation of silica molecules on the surface of TiO(2) nanoparticles, were observed. Sun-protection factor (SPF) of 28 was determined for sunscreen with incorporated 9.0 wt. % TiO(2) nanoparticles, surface treated with 5.0 wt. % silica according to the "Method for the In Vitro Determination of UVA Protection Provided by Sunscreen Products". PMID- 25286216 TI - The role of co-spray-drying procedure in the preformulation of intranasal propranolol hydrochloride. AB - The use of dry powder formulations presents an alternative through which to achieve better deposition and residence time in the nasal cavity, increased stability and possible absorption enhancement. The most important factors involved in the preformulation are particle size and physical stability. Propranolol hydrochloride a model drug was subjected to spray-drying technology to form an intranasal dry powder. Particle size reduction of the drug was carried out by integration (spray-drying) methods, using different excipients. The micrometric properties were characterized by size and morphology. The structure was determined through the use of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy investigations. It was concluded that the intranasal dry powder formulation of propranolol hydrochloride can be achieved with a suitable particle size without polymorph modification or chemical decomposition. PMID- 25286217 TI - Synthesis of Er- and Yb-doped gadolinium oxide polymorphs and influence of their structures on upconversion properties. AB - Nanocrystalline Gd(2)O(3) products doped with Er(3+) and Yb(3+) cations were synthesized by combustion method. We showed that the temperature of combustion can be tuned by using different types of organic fuels within reaction mixture. The combustion process is performed at lower temperature in the presence of urea as an organic fuel leading to pure cubic Gd(2)O(3):Er,Yb phase, on the other hand higher combustion temperature, yielding pure monoclinic Gd(2)O(3):Er,Yb polymorph is achieved in the mixture of urea and b-alanine. Effective doping of Er(3+) and Yb(3+) cations within Gd(2)O(3) were confirmed by XRD analysis. Both polymorphs show upconversion in green and red areas and possess strong dependence of fluorescence intensity ratios (I(525)/I(549) or I(525)/I(560) for monoclinic and cubic polymorphs, respectively) on temperature. This indicates that both phases can be applied for the temperature sensor devices based on upconversion intensity ratio changes. PMID- 25286218 TI - New assay for quantification of PEGylated proteins during in vitro permeability studies. AB - One of the major challenges when analyzing very low amounts of PEGylated proteins is finding a sensitive analytical method. Immunoassays are most frequently used, however, conjugation can partially or completely mask protein epitopes, which can substantially lower the response and influence the quantitation range. Here we describe a novel assay that allows quantification of low amounts of PEGylated or differently conjugated proteins. The basic principle is similar to the classic sandwich ELISA but there are no antibodies used neither for capture nor for detection. Instead, Ni(2+) chelation is exploited for capture and affinity between streptavidin and biotin for the detection step. The usefulness of the assay was proven in permeation studies (Caco-2 cell model) using diversely conjugated TNF-a protein. This approach could be extended to numerous other proteins eliminating the need to develop a separate assay for each protein/project. PMID- 25286219 TI - One-pot synthesis of indenonaphthopyrans catalyzed by copper(II) triflate: a comparative study of reflux and ultrasound methods. AB - An effective and environment-friendly protocol for the synthesis of indenonaphthopyrans has been developed by one-pot reaction of 2-naphthol, various aromatic aldehydes and 1,3-indandione, in the presence of copper(II) triflate as the catalyst while using reflux (Method A) and ultrasound (Method B). The Method B approach offers the advantages of a simple reaction method, short reaction time, excellent yield, and showcases the economic importance of the catalysts for such processes. PMID- 25286220 TI - Synthesis, crystal structures, and catalytic oxidation properties of oxidovanadium(V) complexes with hydrazone and hydroxamate ligands. AB - Two new oxidovanadium(V) complexes with hydrazone ligands and hydroxamate ligands were synthesized and characterized by IR and (1)H NMR spectroscopy, elemental analysis and single crystal X-ray diffraction. The coordination sphere of each V atom is octahedral, constructed from three donor atoms of the hydrazone ligand, two donor atoms of the hydroxamate ligand, and one oxido oxygen. Both complexes show effective catalytic oxidation properties for the oxidation of cyclohexene, cyclopentene and benzyl alcohol using H(2)O(2) as primary oxidant. PMID- 25286221 TI - Evaluation of Michael-type acceptor reactivity of 5-benzylidenebarbiturates, 5 benzylidenerhodanines, and related heterocycles using NMR. AB - Despite existing experimental and computational tools to assess the risk, the non specific chemical modification of protein thiol groups remains a significant source of false-positive hits, particularly in academic drug discovery. Herein, we describe the application of a simple NMR method in a systematic study on the reactivity of 5-benzylidenebarbiturates, 5-benzylidenerhodanines, and their related oxo-heterocycles, which have been associated with numerous biological activities and have recently gained a reputation as unselective promiscuous binders. Using this method, we confirmed the reactivity of 5 benzylidenebarbiturates, which are known to easily form Michael adducts with nucleophiles. In contrast, 5-benzylidene five-membered oxo-heterocycles revealed almost insignificant reactivity. We can conclude that the distinct binding profile of the most controversial compounds, 5-benzylidenerhodanines, is not necessarily related to their unspecific Michael acceptor reactivity. PMID- 25286222 TI - The unfolding process of apo-human serum transferrin in the presence of cetylpyridinium chloride: an isothermal titration calorimetry study. AB - Isothermal titration calorimetry (ITC) was utilized at conditions close to physiological (50 mM HEPES buffer, pH 7.4 and 160 mM NaCl) and at various temperatures of 25, 30, 35 and 40 degrees C to evaluate the thermodynamic parameters, enthalpy and heat capacity changes, and subsequently the unfolding process of apo-human serum tarnsferrin (apo-hTf) in the presence of cetylpyridinium chloride (CPC) as a cationic surfactant. The precise thermograms and heat capacity curves obtained and interpreted in terms of molecular events such as specific and non-specific binding and the unfolding process. The analysis of obtained enthalpograms and heat capacity changes profile showed a distinct extreme region close to [CPC]/[apo-hTf] mole ratio of 20 indicated that predominant cooperative unfolding occurs at this mole ratio via a two states mechanism. PMID- 25286223 TI - Slow-release drug delivery through Elvax 40W to the rat retina: implications for the treatment of chronic conditions. AB - Diseases of the retina are difficult to treat as the retina lies deep within the eye. Invasive methods of drug delivery are often needed to treat these diseases. Chronic retinal diseases such as retinal oedema or neovascularization usually require multiple intraocular injections to effectively treat the condition. However, the risks associated with these injections increase with repeated delivery of the drug. Therefore, alternative delivery methods need to be established in order to minimize the risks of reinjection. Several other investigations have developed methods to deliver drugs over extended time, through materials capable of releasing chemicals slowly into the eye. In this investigation, we outline the use of Elvax 40W, a copolymer resin, to act as a vehicle for drug delivery to the adult rat retina. The resin is made and loaded with the drug. The drug-resin complex is then implanted into the vitreous cavity, where it will slowly release the drug over time. This method was tested using 2 amino-4-phosphonobutyrate (APB), a glutamate analogue that blocks the light response of the retina. It was demonstrated that the APB was slowly released from the resin, and was able to block the retinal response by 7 days after implantation. This indicates that slow-release drug delivery using this copolymer resin is effective for treating the retina, and could be used therapeutically with further testing. PMID- 25286224 TI - Intimate partner violence and diurnal cortisol patterns in couples. AB - This study examined whether physical intimate partner violence (IPV) victimization was associated with diurnal patterns of salivary cortisol in a community sample of 122 couples in their 30s from predominantly lower socioeconomic status backgrounds. Findings indicate that women with higher levels of victimization exhibited flatter patterns of diurnal cortisol characterized by both higher midday levels and more attenuated decreases in cortisol levels across the day, compared to women with lower levels of victimization. However, men's victimization was not associated with their diurnal cortisol levels. This study advances our understanding of the association between physical IPV victimization and dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning in women, which is likely to have further implications for their subsequent mental and physical health. PMID- 25286225 TI - Noradrenergic influences in the basolateral amygdala on inhibitory avoidance memory are mediated by an action on alpha2-adrenoceptors. AB - The role of norepinephrine (NE) in the consolidation of inhibitory avoidance learning (IA) in rats is known to involve alpha1- and beta-adrenoceptor systems in the basolateral nucleus of the amygdala (BLA). However, the amygdala also contains alpha2-adrenoceptor subtypes, and local microinfusions of the selective alpha2-adrenoceptor antagonist idazoxan and agonist UK 14,304 respectively into the BLA enhance and inhibit IA performances when administered before acquisition. The present study investigated whether the effects of idazoxan and UK 14,304 on IA were associated with changes in NE release within the BLA before and after one trial inhibitory avoidance training. Male Sprague-Dawley rats were unilaterally implanted with a microdialysis probe in the BLA and were administered idazoxan (0.1mM) or UK 14,304 (10 MUM) by retrodialysis infusion 15 min before the acquisition of IA. Dialysates were collected every 15 min for analysis of NE. Retrodialysis of idazoxan potentiated the release of NE induced by footshock application, whereas UK 14,304 decreased NE release to the extent that the footshock failed to induce any measurable effect on NE levels. Idazoxan infusion enhanced IA retention tested 24h later and this effect was directly related to the level of NE release in the BLA measured during IA acquisition. In contrast, the infusion of UK 14,304 did not modify IA performances in comparison to control animals, possibly due to compensatory activity of the contralateral BLA. These results are consistent with previous evidence that amygdala NE is involved in modulating memory consolidation, and provide evidence for an involvement of presynaptic alpha2-autoceptors in the BLA in this process. PMID- 25286226 TI - Phospholipid ether analogs for the detection of colorectal tumors. AB - The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non invasive lesions (total radiant efficiency: 1.76*10(10) vs 3.27*10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease. PMID- 25286228 TI - Secreted phospholipases A2 in cancer: diverse mechanisms of action. AB - Secreted phospholipases A2 (sPLA2s) hydrolyse cell and lipoprotein phospholipid membranes to release free fatty acids and lysophospholipids, and can also bind to specific proteins. Several sPLA2s have been associated with various cancers, including prostate, colon, gastric, lung and breast cancers, yet, their role is controversial and seems to be dependent on the cancer type, the local microenvironment and the enzyme studied. There is strong evidence that the expression of some sPLA2s, most notably the group IIA, III and X enzymes, is dysregulated in various malignant tissues, where, as described in a number of in vitro and in vivo studies using mouse models and according to correlations between sPLA2 expression and patient survival, a particular enzyme may exert either a pro- or an anti-tumourigenic role. It is becoming clear that there are multiple, context-dependent mechanisms of action of sPLA2s in different cancers. First, the role of sPLA2s in cancer has traditionally been associated with their enzymatic activity and ability to participate in the release of potent biologically active lipid mediators, in particular arachidonic acid-derived eicosanoids, which promote tumourigenesis by stimulating cell proliferation and cell survival, by abrogating apoptosis and by increasing local inflammation and angiogenesis. Second, several biological effects of sPLA2s were found to be independent of sPLA2 enzymatic activity, arguing for a receptor-mediated mechanism of action. Finally, recent studies have implicated sPLA2s in the regulation of basal lipid metabolism, opening a new window to the understanding of the diverse roles of sPLA2s in cancer. In this short review, we highlight the newest findings on the biological roles of sPLA2s in cancer, with emphasis on their diverse mechanisms of action. PMID- 25286229 TI - Comparing score tests and other local dependence diagnostics for the graded response model. AB - Score tests for identifying locally dependent item pairs have been proposed for binary item response models. In this article, both the bifactor and the threshold shift score tests are generalized to the graded response model. For the bifactor test, the generalization is straightforward; it adds one secondary dimension associated only with one pair of items. For the threshold shift test, however, multiple generalizations are possible: in particular, conditional, uniform, and linear shift tests are discussed in this article. Simulation studies show that all of the score tests have accurate Type I error rates given large enough samples, although their small-sample behaviour is not as good as that of Pearson's Chi2 and M2 as proposed in other studies for the purpose of local dependence (LD) detection. All score tests have the highest power to detect the LD which is consistent with their parametric form, and in this case they are uniformly more powerful than Chi2 and M2 ; even wrongly specified score tests are more powerful than Chi2 and M2 in most conditions. An example using empirical data is provided for illustration. PMID- 25286227 TI - Controlling the switches: Rho GTPase regulation during animal cell mitosis. AB - Animal cell division is a fundamental process that requires complex changes in cytoskeletal organization and function. Aberrant cell division often has disastrous consequences for the cell and can lead to cell senescence, neoplastic transformation or death. As important regulators of the actin cytoskeleton, Rho GTPases play major roles in regulating many aspects of mitosis and cytokinesis. These include centrosome duplication and separation, generation of cortical rigidity, microtubule-kinetochore stabilization, cleavage furrow formation, contractile ring formation and constriction, and abscission. The ability of Rho proteins to function as regulators of cell division depends on their ability to cycle between their active, GTP-bound and inactive, GDP-bound states. However, Rho proteins are inherently inefficient at fulfilling this cycle and require the actions of regulatory proteins that enhance GTP binding (RhoGEFs), stimulate GTPase activity (RhoGAPs), and sequester inactive Rho proteins in the cytosol (RhoGDIs). The roles of these regulatory proteins in controlling cell division are an area of active investigation. In this review we will delineate the current state of knowledge of how specific RhoGEFs, RhoGAPs and RhoGDIs control mitosis and cytokinesis, and highlight the mechanisms by which their functions are controlled. PMID- 25286231 TI - Spectroscopic characterization of supramolecular chiral porphyrin homoassociates at the air-water interface. AB - The water-soluble 4-sulfonatophenyl meso-substituted porphyrin (TPPS) dye exhibits a transformation to a chiral self-aggregate from the non-aggregated species (diprotonated H4TPPS(2-)) at low concentration (no more than 1 * 10(-5) M). Immobilization of supramolecular chiral porphyrin homoassociates was mediated by the electrostatic interaction between the anionic TPPS molecule and cationic surfactant monolayer at the air-water interface. With the immobilization, a reversible transformation from monomeric TPPS to J-aggregate (M<->J) could be changed into an irreversible (M->J), which is desirable for stabilization of aggregation structure for a long period. The novel finding was achieved using a fine-tuned specialized solid-state circular dichroism (CD) spectrophotometer and derived analytical procedure to obtain artifact-free CD signals. To our knowledge, this is the first report achieving the chiral control of a homoassociate induced by a chiral surfactant at the air-water interface, indicating that the handedness of the formed homoassociate could be determined. PMID- 25286230 TI - Hyperhomocysteinemia is a result, rather than a cause, of depression under chronic stress. AB - BACKGROUND: Although the accumulation of homocysteine (Hcy) has been implicated in the pathogenesis of depression, whether Hcy is directly involved and acts as the primary cause of depressive symptoms remains unclear. The present study was designed to clarify whether increased Hcy plays an important role in stress induced depression. RESULTS: We employed the chronic unpredictable mild stress model (CUMS) of depression for 8 weeks to observe changes in the plasma Hcy level in the development of depression. The results showed that Wistar rats exposed to a series of mild, unpredictable stressors for 4 weeks displayed depression-like symptoms such as anhedonia (decreased sucrose preferences) and a decreased 5 Hydroxy Tryptophan (5-HT) concentration in the hippocampus. At the end of 8 weeks, the plasma Hcy level increased in the CUMS rats. The anti-depressant sertraline could decrease the plasma Hcy level and improve the depression-like symptoms in the CUMS rats. RhBHMT, an Hcy metabolic enzyme, could decrease the plasma Hcy level significantly, although it could not improve the depressive symptoms in the CUMS rats. CONCLUSIONS: The results obtained from the experiments did not support the hypothesis that the increased Hcy concentration mediated the provocation of depression in CUMS rats, and the findings suggested that the increased Hcy concentration in the plasma might be the result of stress-induced depression. PMID- 25286233 TI - Simple on-plastic/paper inkjet-printed solid-state Ag/AgCl pseudoreference electrode. AB - A miniaturized, disposable, and low cost Ag/AgCl pseudoreference electrode based on inkjet printing has been developed. Silver ink was printed and chlorinated with bleach solution. The reference electrodes obtained in this work showed good reproducibility and stability during at least 30 min continuous measurement and even after 30 days storage without special care. Moreover, the strategy used in this work can be useful for large scale production of a solid-state Ag/AgCl pseudoreference electrode with different designs and sizes, facilitating the coupling with different electrical/electrochemical microsensors and biosensors. PMID- 25286232 TI - Nonmodifiable factors and complications contribute to length of stay in robot assisted partial nephrectomy. AB - INTRODUCTION/OBJECTIVE: Robotic-assisted partial nephrectomy (RPN) offers a mean length of stay (LOS) of 2 to 3 days. The purpose of this study is to determine the impact of modifiable and nonmodifiable risk factors on hospital LOS after RPN. PATIENTS AND METHODS: We retrospectively reviewed our prospectively maintained database to identify all patients undergoing RPN for localized tumors at five US centers from 2007 to 2013. Patient and tumor characteristics were compared among hospital LOS groups. Associated factors were modeled using univariate and multivariate cumulative logistic regression to determine factors predictive of hospital LOS. RESULTS: One thousand five hundred thirty-two patients were grouped into LOS 1 to 3 days (1298, 84.1%), LOS=4 days (133, 8.6%), and LOS >4 days (110, 7.2%). Patient demographics were similar between groups. Patients in the LOS=4 and LOS >4 day groups were more likely to have a higher Charlson comorbidity index score (mean 2.2, 3.1 and 3.8; p<0.001), higher nephrometry score (mean 7.1, 7.6, 7.8; p=0.0002), and larger tumors (mean 2.9, 3.6 and 3.5 cm; p<0.0001) than those in the LOS 1 to 3 day group. Significant differences in complication rates were observed when comparing LOS 1-3 (116, 8.9%), LOS=4 (40, 30%), and LOS >4 (59, 54%). According to the Clavien-Dindo classification of surgical complications, 11 grade 3 and 11 grade 4 complications occurred in patients with an LOS of 4 or more days (p<0.0001). Postoperative transfusion, deep vein thrombosis, pulmonary embolism, atrial fibrillation, dyspnea/atelectasis, ileus, and acute renal failure each significantly predicted a hospital LOS >4 days (p<0.001). CONCLUSION: 15.8% of patients undergoing RPN have an LOS of 4 days or more. Longer LOS was independently associated with higher Charlson index, nephrometry score (nonmodifiable factors), and perioperative complications (potentially modifiable). These data may be useful in perioperative counseling and payer precertification. PMID- 25286234 TI - Alkali-metal ion coordination in uranyl(VI) poly-peroxide complexes in solution. Part 1: the Li+, Na+ and K+--peroxide-hydroxide systems. AB - The alkali metal ions Li(+), Na(+) and K(+) have a profound influence on the stoichiometry of the complexes formed in uranyl(VI)-peroxide-hydroxide systems, presumably as a result of a templating effect, resulting in the formation of two complexes, M[(UO2)(O2)(OH)]2(-) where the uranyl units are linked by one peroxide bridge, MU-eta(2)-eta(2), with the second peroxide coordinated "end-on", eta(2), to one of the uranyl groups, and M[(UO2)(O2)(OH)]4(3-), with a four-membered ring of uranyl ions linked by MU-eta(2)-eta(2) peroxide bridges. The stoichiometry and equilibrium constants for the reactions: M(+) + 2UO2(2+) + 2HO2(-) + 2H2O -> M[(UO2)(O2)(OH)]2(-) + 4H(+) (1) and M(+) + 4UO2(2+) + 4HO2(-) + 4H2O -> M[(UO2)(O2)(OH)]4(3-) + 8H(+) (2) have been measured at 25 degrees C in 0.10 M (tetramethyl ammonium/M(+))NO3 ionic media using reaction calorimetry. Both reactions are strongly enthalpy driven with large negative entropies of reaction; the observation that DeltaH(2) ~ 2DeltaH(1) suggests that the enthalpy of reaction is approximately the same when peroxide is added in bridging and "end on" positions. The thermodynamic driving force in the reactions is the formation of strong peroxide bridges and the role of M(+) cations is to provide a pathway with a low activation barrier between the reactants and in this way "guide" them to form peroxide bridged complexes; they play a similar role as in the synthesis of crown-ethers. Quantum chemical (QC) methods were used to determine the structure of the complexes, and to demonstrate how the size of the M(+)-ions affects their coordination geometry. There are several isomers of Na[(UO2)(O2)(OH)]2(-) and QC energy calculations show that the ones with a peroxide bridge are substantially more stable than the ones with hydroxide bridges. There are isomers with different coordination sites for Na(+) and the one with coordination to the peroxide bridge and two uranyl oxygen atoms is the most stable one. PMID- 25286235 TI - The complete mitochondrial genome of the Epinephelus lanceolatus (Perciformes: Serranidae). AB - The complete mitochondrial genome of the Epinephelus lanceolatus was presented in this study. The mitochondrial genome is 16,743 bp long and consists of 13 protein coding genes, two rRNA genes, 22 tRNA genes and a control region. The gene order and composition of E. lanceolatus mitochondrial genome was similar to that of most other vertebrates. The nucleotide compositions of the light strand are 26.55% of A, 15.02% of C, 29.67% of T and 28.76% of G. With the exception of the NADH dehydrogenase subunit 6 (ND6) and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. PMID- 25286236 TI - A simple method for the small scale synthesis and solid-phase extraction purification of steroid sulfates. AB - Steroid sulfates are a major class of steroid metabolite that are of growing importance in fields such as anti-doping analysis, the detection of residues in agricultural produce or medicine. Despite this, many steroid sulfate reference materials may have limited or no availability hampering the development of analytical methods. We report simple protocols for the rapid synthesis and purification of steroid sulfates that are suitable for adoption by analytical laboratories. Central to this approach is the use of solid-phase extraction (SPE) for purification, a technique routinely used for sample preparation in analytical laboratories around the world. The sulfate conjugates of sixteen steroid compounds encompassing a wide range of steroid substitution patterns and configurations are prepared, including the previously unreported sulfate conjugates of the designer steroids furazadrol (17beta-hydroxyandrostan[2,3 d]isoxazole), isofurazadrol (17beta-hydroxyandrostan[3,2-c]isoxazole) and trenazone (17beta-hydroxyestra-4,9-dien-3-one). Structural characterization data, together with NMR and mass spectra are reported for all steroid sulfates, often for the first time. The scope of this approach for small scale synthesis is highlighted by the sulfation of 1MUg of testosterone (17beta-hydroxyandrost-4-en 3-one) as monitored by liquid chromatography-mass spectrometry (LCMS). PMID- 25286238 TI - The role of lattice parameter in water adsorption and wetting of a solid surface. AB - Ice formation is a complex cooperative process that is almost invariably catalysed by the presence of an interface on which ice crystals nucleate. As yet there is no clear picture of what factors make a surface particularly good at nucleating ice, but the importance of having a template with a suitable lattice parameter has often been proposed. Here we report the contrasting wetting behaviour of a series of pseudomorphic surfaces, designed to form an ordered template that matches the arrangement of water in a bulk ice Ih(0001) bilayer. The close-packed M(111) surfaces (M = Pt, Pd, Rh, Cu and Ni) form a (?3 * ?3) R30 degrees Sn substitutional alloy surface, with Sn atoms occupying sites that match the symmetry of an ice bilayer. The lattice constant of the alloy changes from 4% smaller to 7% greater than the lateral spacing of ice across the series. We show that only the PtSn surface, with a lattice parameter some 7% greater than that of a bulk ice layer, forms a stable water layer, all the other surfaces being non-wetting and instead forming multilayer ice clusters. This observation is consistent with the idea that the repeat spacing of the surface should ideally match the O-O spacing in ice, rather than the bulk ice lattice parameter, in order to form a continuous commensurate water monolayer. We discuss the role of the lattice parameter in stabilising the first layer of water and the factors that lead to formation of a simple commensurate structure rather than an incommensurate or large unit cell water network. We argue that lattice match is not a good criteria for a material to give low energy nucleation sites for bulk ice, and that considerations such as binding energy and mobility of the surface layer are more relevant. PMID- 25286239 TI - Investigations on the role of proton-coupled electron transfer in hydrogen activation by [FeFe]-hydrogenase. AB - Proton-coupled electron transfer (PCET) is a fundamental process at the core of oxidation-reduction reactions for energy conversion. The [FeFe]-hydrogenases catalyze the reversible activation of molecular H2 through a unique metallocofactor, the H-cluster, which is finely tuned by the surrounding protein environment to undergo fast PCET transitions. The correlation of electronic and structural transitions at the H-cluster with proton-transfer (PT) steps has not been well-resolved experimentally. Here, we explore how modification of the conserved PT network via a Cys -> Ser substitution at position 169 proximal to the H-cluster of Chlamydomonas reinhardtii [FeFe]-hydrogenase (CrHydA1) affects the H-cluster using electron paramagnetic resonance (EPR) and Fourier transform infrared (FTIR) spectroscopy. Despite a substantial decrease in catalytic activity, the EPR and FTIR spectra reveal different H-cluster catalytic states under reducing and oxidizing conditions. Under H2 or sodium dithionite reductive treatments, the EPR spectra show signals that are consistent with a reduced [4Fe 4S]H(+) subcluster. The FTIR spectra showed upshifts of nuCO modes to energies that are consistent with an increase in oxidation state of the [2Fe]H subcluster, which was corroborated by DFT analysis. In contrast to the case for wild-type CrHydA1, spectra associated with Hred and Hsred states are less populated in the Cys -> Ser variant, demonstrating that the exchange of -SH with -OH alters how the H-cluster equilibrates among different reduced states of the catalytic cycle under steady-state conditions. PMID- 25286237 TI - Physical activity level of urban pregnant women in Tianjin, China: a cross sectional study. AB - OBJECTIVE: To determine the physical activity level and factors influencing physical activity among pregnant urban Chinese women. METHODS: This prospective cross-sectional study enrolled 1056 pregnant women (18-44 years of age) in Tianjin, China. Their socio-demographic characteristics were recorded, and the Pregnancy Physical Activity Questionnaire was used to assess their physical activity during pregnancy. The data were analyzed by multinomial logistic regression with adjustment for potential confounders. RESULTS: Median total energy expenditure of pregnant women in each of the three trimesters ranged from 18.50 to 21.90 metabolic equivalents of task (METs) h/day. They expended 1.76 1.85 MET h/day on moderate and vigorous activities and 0.11 MET h/day on exercise. Only 117 of the women (11.1%) met the international guideline for physical activity in pregnancy (>=150 min moderate intensity exercise per week). The most frequent reason given for not being more physically active was the fear of miscarriage. Higher education level (OR: 4.11, 95% CI: 1.59-10.62), habitual exercise before pregnancy (OR: 2.14, 95% CI: 1.39-3.28), and husbands who exercised regularly (OR: 2.21, 95% CI: 1.33-3.67) significantly increased the odds of meeting the guideline (p<0.001). A low pre gravid body mass index (OR: 0.42, 95% CI: 0.20-0.87) significantly decreased the odds (p<0.001). CONCLUSIONS: Few urban Chinese pregnant women met the recommended physical activity guideline. They also expended little energy exercising. Future interventions should be based on the clinic environment and targeting family members as well as the subjects. All pregnant women should be targeted, not just those in high-risk groups. PMID- 25286240 TI - Functional cortical network in alpha band correlates with social bargaining. AB - Solving demanding tasks requires fast and flexible coordination among different brain areas. Everyday examples of this are the social dilemmas in which goals tend to clash, requiring one to weigh alternative courses of action in limited time. In spite of this fact, there are few studies that directly address the dynamics of flexible brain network integration during social interaction. To study the preceding, we carried out EEG recordings while subjects played a repeated version of the Ultimatum Game in both human (social) and computer (non social) conditions. We found phase synchrony (inter-site-phase-clustering) modulation in alpha band that was specific to the human condition and independent of power modulation. The strength and patterns of the inter-site-phase-clustering of the cortical networks were also modulated, and these modulations were mainly in frontal and parietal regions. Moreover, changes in the individuals' alpha network structure correlated with the risk of the offers made only in social conditions. This correlation was independent of changes in power and inter-site phase-clustering strength. Our results indicate that, when subjects believe they are participating in a social interaction, a specific modulation of functional cortical networks in alpha band takes place, suggesting that phase synchrony of alpha oscillations could serve as a mechanism by which different brain areas flexibly interact in order to adapt ongoing behavior in socially demanding contexts. PMID- 25286241 TI - The spatial distance rule in the moving and classical rubber hand illusions. AB - The rubber hand illusion (RHI) is a perceptual illusion in which participants perceive a model hand as part of their own body. Here, through the use of one questionnaire experiment and two proprioceptive drift experiments, we investigated the effect of distance (12, 27.5, and 43cm) in the vertical plane on both the moving and classical RHI. In both versions of the illusion, we found an effect of distance on ownership of the rubber hand for both measures tested. Our results further suggested that the moving RHI might follow a narrower spatial rule. Finally, whereas ownership of the moving rubber hand was affected by distance, this was not the case for agency, which was present at all distances tested. In sum, the present results generalize the spatial distance rule in terms of ownership to the vertical plane of space and demonstrate that also the moving RHI obeys this rule. PMID- 25286242 TI - Self-referential memory in autism spectrum disorder and typical development: Exploring the ownership effect. AB - Owned objects occupy a privileged cognitive processing status and are viewed almost as extensions of the self. It has been demonstrated that items over which a sense of ownership is felt will be better remembered than other items (an example of the "self-reference effect"). As autism spectrum disorder (ASD) is characterised by an a typical self-concept, people with ASD may not demonstrate this "ownership effect". Two experiments were conducted which replicate and extend Cunningham, Turk, MacDonald, and Macrae (2008). In Experiment 1, neurotypical adults completed a card sorting task and cards belonging to the 'self' were better remembered than cards belonging to another person. In Experiment 2, adults with ASD recalled self- and other owned items equally well. These results shed light both on the relation between sense of self and the ownership effect, and the nature of the self-concept in ASD. PMID- 25286243 TI - Accounting for the phenomenology and varieties of auditory verbal hallucination within a predictive processing framework. AB - Two challenges that face popular self-monitoring theories (SMTs) of auditory verbal hallucination (AVH) are that they cannot account for the auditory phenomenology of AVHs and that they cannot account for their variety. In this paper I show that both challenges can be met by adopting a predictive processing framework (PPF), and by viewing AVHs as arising from abnormalities in predictive processing. I show how, within the PPF, both the auditory phenomenology of AVHs, and three subtypes of AVH, can be accounted for. PMID- 25286244 TI - CD8(+)IL-17(+) T Cells Mediate Neutrophilic Airway Obliteration in T-bet Deficient Mouse Lung Allograft Recipients. AB - Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet(-/-) recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T bet(-/-) recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8(+) T cells producing allospecific IL-17 and/or IFN-gamma, in contrast to IFN-gamma-dominant responses in WT mice. CD4(+) T cells produced IL-17 but not IFN-gamma responses in T-bet(-/-) recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8(+)IFN-gamma(+) responses in both T-bet(-/-) and WT mice but had no attenuating effect on lung rejection pathology in T-bet(-/-) recipients or on the development of obliterative airway inflammation that occurred only in T-bet(-/-) recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade resistant rejection pathology and airway inflammation in T-bet(-/-) recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet(-/-) allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet-deficient recipients of complete MHC mismatched lung allografts develop costimulation blockade-resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8(+)IL-17(+) T cells. Our data support T-bet deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation. PMID- 25286245 TI - Simultaneous deletion of p21Cip1/Waf1 and caspase-3 accelerates proliferation and partially rescues the differentiation defects of caspase-3 deficient hematopoietic stem cells. AB - Specialized blood cells are generated through the entire life of an organism by differentiation of a small number of hematopoietic stem cells (HSC). There are strictly regulated mechanisms assuring a constant and controlled production of mature blood cells. Although such mechanisms are not completely understood, some factors regulating cell cycle and differentiation have been identified. We have previously shown that Caspase-3 is an important regulator of HSC homeostasis and cytokine responsiveness. p21cip1/waf1 is a known cell cycle regulator, however its role in stem cell homeostasis seems to be limited. Several reports indicate interactions between p21cip1/waf1 and Caspase-3 in a cell type dependent manner. Here we studied the impact of simultaneous depletion of both factors on HSC homeostasis. Depletion of both Caspase-3 and p21cip1/waf1 resulted in an even more pronounced increase in the frequency of hematopoietic stem and progenitor cells. In addition, simultaneous deletion of both genes revealed a further increase of cell proliferation compared to single knock-outs and WT control mice, while apoptosis or self-renewal ability were not affected in any of the genotypes. Upon transplantation, p21cip1/waf1-/- bone marrow did not reveal significant alterations in engraftment of lethally irradiated mice, while Caspase 3 deficient HSPC displayed a significant reduction of blood cell production. However, when both p21cip1/waf1 and Caspase-3 were eliminated this differentiation defect caused by Caspase-3 deficiency was abrogated. PMID- 25286247 TI - AFM probing of polymer/nanofiller interfacial adhesion and its correlation with bulk mechanical properties in a poly(ethylene terephthalate) nanocomposite. AB - The interfacial adhesion between polymer and nanofiller plays an important role in affecting the properties of nanocomposites. The detailed relationship between interfacial adhesion and bulk properties, however, is unclear. In this work, we developed an atomic force microscopy (AFM)-based abrasive scanning methodology, as applied to model laminate systems, to probe the strength of interfacial adhesion relevant to poly(ethylene terephthalate) (PET)/graphene or clay nanocomposites. Graphite and mica substrates covered with ~2 nm thick PET films were abrasively sheared by an AFM tip as a model measurement of interfacial strength between matrix PET and dispersed graphene and clay, respectively. During several abrasive raster-scan cycles, PET was shear-displaced from the scanned region. At temperatures below the PET glass transition, PET on graphite exhibited abrupt delamination (i.e., full adhesive failure), whereas PET on mica did not; rather, it exhibited a degree of cohesive failure within the shear-displaced layer. Moreover, 100-fold higher force scanning procedures were required to abrade through an ultimate "precursor" layer of PET only ~0.2-0.5 nm thick, which must be largely disentangled from the matrix polymer. Thus, the adhesive interface of relevance to the strength of clay-filler nanocomposites is between matrix polymer and strongly bound polymer. At 90 degrees C, above the bulk PET glass transition temperature, the PET film exhibited cohesive failure on both graphite and mica. Our results suggest that there is little difference in the strength of the relevant interfacial adhesion in the two nanocomposites within the rubbery dynamic regime. Further, the bulk mechanical properties of melt mixed PET/graphene and PET/clay nanocomposites were evaluated by dynamic mechanical analysis. The glassy dynamic storage modulus of the PET/clay nanocomposite was higher than that of PET/graphene, correlating with the differences in interfacial adhesion probed by AFM. PMID- 25286246 TI - Protein engineering of the N-terminus of NEMO: structure stabilization and rescue of IKKbeta binding. AB - NEMO is a scaffolding protein that, together with the catalytic subunits IKKalpha and IKKbeta, plays an essential role in the formation of the IKK complex and in the activation of the canonical NF-kappaB pathway. Rational drug design targeting the IKK-binding site on NEMO would benefit from structural insight, but to date, the determination of the structure of unliganded NEMO has been hindered by protein size and conformational heterogeneity. Here we show how the utilization of a homodimeric coiled-coil adaptor sequence stabilizes the minimal IKK-binding domain NEMO(44-111) and furthers our understanding of the structural requirements for IKK binding. The engineered constructs incorporating the coiled coil at the N terminus, C-terminus, or both ends of NEMO(44-111) present high thermal stability and cooperative melting and, most importantly, restore IKKbeta binding affinity. We examined the consequences of structural content and stability by circular dichoism and nuclear magnetic resonance (NMR) and measured the binding affinity of each construct for IKKbeta(701-745) in a fluorescence anisotropy binding assay, allowing us to correlate structural characteristics and stability to binding affinity. Our results provide a method for engineering short stable NEMO constructs to be suitable for structural characterization by NMR or X-ray crystallography. Meanwhile, the rescuing of the binding affinity implies that a preordered IKK-binding region of NEMO is compatible with IKK binding, and the conformational heterogeneity observed in NEMO(44-111) may be an artifact of the truncation. PMID- 25286248 TI - Toxicity of ciprofloxacin and sulfamethoxazole to marine periphytic algae and bacteria. AB - Ciprofloxacin and sulfamethoxazole are two antibiotics commonly detected in the aquatic environment, but information on their toxicity towards natural microbial communities is largely absent. In particular no data are available for marine microorganisms. The aim of the current study was therefore to evaluate the chronic toxicity of ciprofloxacin and sulfamethoxazole to natural marine biofilms (periphyton), a complex ecological community comprising a variety of bacterial and algal species. The biofilms were sampled along the Swedish west coast and subsequently exposed over 4 days in a semi-static system to a concentration series of each antibiotic. Effects on the bacterial part of the periphyton community were assessed using Biolog Ecoplates, reflecting total respiration and functional diversity of the bacterial community. Exposure to either antibiotic resulted in a clear concentration-response relationship with EC10 and EC50 values for the inhibition of total carbon source utilization of 46.1nmol/L and 490.7nmol/L for ciprofloxacin, and 56nmol/L and 1073nmol/L for sulfamethoxazole. The NOEC for ciprofloxacin was 26nmol/L, with a minimum significant difference of 19.24%, for sulfamethoxazole it was 140nmol/L with a minimum significant difference of 14%. Multivariate data exploration of the whole carbon source utilization pattern confirmed these results. The data indicate that sulfamethoxazole leads to a general decrease in carbon source utilization, while ciprofloxacin exposure leads to a re-arrangement of the carbon-utilization pattern in the region of 20- 50% effect. This corresponds with the higher specificity of ciprofloxacin for certain bacterial species. Effects on the algal part of the communities were evaluated by analyzing the amount and composition of photosynthetic pigments, and neither ciprofloxacin nor sulfamethoxazole caused any inhibitory effects up to the maximum tested concentration of 9000nmol/L. However, sulfamethoxazole exposure did lead to a significant stimulation (75% above control level) of the total pigment content of the biofilm already at the lowest tested concentration of 5nmol/L. The stimulation then decreased with increasing concentrations to finally return to control level at 3000nmol/L. No shifts in the relative pigment composition were observed, indicating a generally increased algal biomass without major shifts in community composition. PMID- 25286249 TI - Domoic acid-induced seizures in California sea lions (Zalophus californianus) are associated with neuroinflammatory brain injury. AB - California sea lions (CSLs) exposed to the marine biotoxin domoic acid (DA) develop an acute or chronic toxicosis marked by seizures and act as sentinels of the disease. Experimental evidence suggests that oxidative stress and neuroinflammation are important mechanisms underlying the seizurogenic potential of environmental toxicants but these pathways are relatively unstudied in CSLs. In the current study, we investigated the role of glutamate-glutamine changes and gliosis in DA-exposed CSLs to better understand the neurotoxic mechanisms occurring during DA toxicity. Sections from archived hippocampi from control and CSLs diagnosed with DA toxicosis were immunofluorescently stained for markers of gliosis, oxidative/nitrative stress and changes in glutamine synthetase (GS). Quantitative assessment revealed increasing loss of microtubule associated protein-2 positive neurons with elevations in 4-hydroxynonenal correlating with chronicity of exposure, whereas the pattern of activated glia expressing nitric oxide synthase 2 and tumor necrosis factor followed pathological severity. There was no significant change in the amount of GS positive cells but there was increased 3-nitrotyrosine in GS expressing cells and in neurons, particularly in animals with chronic DA toxicosis. These changes were consistently seen in the dentate gyrus and in the cornu ammonis (CA) sectors CA3, CA4, and CA1. The results of this study indicate that gliosis and resultant changes in GS are likely important mechanisms in DA-induced seizure that need to be further explored as potential therapies in treating exposed wildlife. PMID- 25286250 TI - Eu-MOFs with 2-(4-carboxyphenyl)imidazo[4,5-f]-1,10-phenanthroline and ditopic carboxylates as coligands: synthesis, structure, high thermostability, and luminescence properties. AB - Hydrothermal reactions of europium(III) salt with 2-(4-carboxyphenyl)imidazo[4,5 f]-1,10-phenanthroline and dicarboxylic acid as coligands-benzene-1,4 dicarboxylic acid, 4,4'-biphenyldicarboxylic acid, 2,5-dibromoterephthalic acid, and naphthalene-1,4-dicarboxylic acid-lead to four europium fluorescent materials (1-4). Structural analyses reveal that 1-4 have binuclear 3D metal-organic frameworks with different channels, void volumes, and conjugated structures tuned by ditopic carboxylates. There are no latticed and coordinated water molecules occurring in 1-3, while the free water molecules fill in 1D channels of 4. 4' was readily obtained via water removal of 4. Thermal analyses of all compounds show the high thermal stability of the main framework up to 450 degrees C. Optical studies indicate that 1-4 and 4' show the characteristic red luminescence emission of the Eu(III) ion in the visible regions at room temperature. On the basis of emission spectra, their luminescence lifetimes were determined. In particular, compound 4' shows a longer lifetime (tau = 0.942 ms) and significantly enhanced quantum yield (39%) compared with those of 1 (11%, 0.770 ms), 2 (4%, 0.414 ms), 3 (18%, 0.807 ms), and 4 (26%, 0.858 ms). PMID- 25286251 TI - (99m)Tc-3P-RGD2 micro-single-photon emission computed tomography/computed tomography provides a rational basis for integrin alphavbeta3-targeted therapy. AB - PURPOSE: This study was to demonstrate the utility of (99m)Tc-3P-RGD2 micro single-photon emission computed tomography/computed tomography (SPECT/CT) for the integrin alphavbeta3 expression quantification in NCI-H446 and A549 lung cancer xenografts. MATERIALS AND METHODS: (99m)Tc-3P-RGD2 was prepared with high radiochemical purity (97%+/-2%) and showing high in vitro stability. The in vitro affinities of (99m)Tc-3P-RGD2 to NCI-H446 and A549 tumor cells were analyzed with gamma-counter, while the in vivo uptakes in NCI-H446 and A549 xenografts were evaluated with micro-SPECT/CT. The region of interest was drawn over the tumor site and contralateral muscle on the SPECT/CT image, and the tumor to nontumor (T/NT) ratio was calculated to estimate alphavbeta3 expression and tumor uptake. The expressions of integrin alphavbeta3 in vitro and in vivo were analyzed using a flow cytometer and immunofluorescence. RESULTS: Micro-SPECT/CT demonstrated focal uptake in the tumors. T/NT ratio in NCI-H446 xenografts was significantly higher compared with the A549 tumor model, as 5.92+/-0.82 and 3.62+/-0.91, respectively, with p<0.05. In addition, integrin alphavbeta3 expression in NCI H446 cells was significantly higher compared with the A549 cells, which was consistent with the imaging data. A linear relationship was observed between (99m)Tc-3P-RGD2 uptake and alphavbeta3 expression (R(2)=0.7667, p<0.001). CONCLUSION: (99m)Tc-3P-RGD2 SPECT/CT could be used to quantify integrin alphavbeta3 expression within tumors, providing a rational basis for integrin alphavbeta3-targeted cancer therapy. PMID- 25286252 TI - In silico identification and characterization of the MAPK family members of unicellular model eukaryote Tetrahymena thermophila. AB - The biological function and evolutionary diversity of the mitogen-activated protein kinase (MAPK) family have mostly been studied in fungi, animals and plants, with very limited information from lower eukaryotes. This study aimed to describe the MAPKs of unicellular Tetrahymena thermophila. Eight members of the T. thermophila MAPK (TtMPK) gene family, in addition to previously reported TtMPK1, TtMPK2 and TtMPK3, were identified bioinformatically using a T. thermophila genome database. Phylogenetic analysis assigned the TtMPKs into two major groups, ERK1/2-like (TtMPK1, 2, 3, 5, 6, 7, 8, and 9) as stress-responsive MAPKs for biotic and abiotic stresses, and ERK7/8-like (TtMPK4, 10, and 11) as cell-cycle-associated protein kinases for biotic factors. Semi-quantitative RT PCR analysis of the TtMPKs showed high mRNA expression at 30 degrees C; however, only TtMPK5 and TtMPK6 showed high expression at 37 degrees C. Osmotic shock by 100mM NaCl only increased the expression of TtMPK2, whereas 20mM NaCl reduced the expression of all MPKs to almost zero. The results suggested that T. thermophila MAPKs are among the closest representatives of the ancestors of the eukaryotic MAPK family. Although no functional characterization of MPKs was performed, this study is the first report of the genome-wide MAPK family in T. thermophila. PMID- 25286254 TI - General synthesis of substituted 1,2-dihydropyridines. AB - A general and practical metal-free protocol for the synthesis of 1,2 dihydropyridines with wide structural/functional diversity at the ring and featuring mono, double, or spiro substitution at the sp(3) position is described. The protocol entails a microwave-assisted domino reaction of a propargyl vinyl ether (secondary or tertiary) and a primary amine (aliphatic or aromatic) in toluene or methanol. PMID- 25286255 TI - Ten years in two dimensions: are graphene technologies ready for commercialization? PMID- 25286253 TI - Outer membrane protein A (OmpA) of Shigella flexneri 2a induces TLR2-mediated activation of B cells: involvement of protein tyrosine kinase, ERK and NF-kappaB. AB - B cells are critically important in combating bacterial infections and their differentiation into plasma cells and memory cells aids bacterial clearance and long-lasting immunity conferred by essentially all vaccines. Outer membrane protein A (OmpA) of Shigella flexneri 2a has been demonstrated to induce the production of IgG and IgA in vivo following immunization of mice through intranasal route, but the direct involvement of B cells in OmpA-mediated immune regulation was not determined. Consequently, we investigated whether OmpA can modulate B cell functions and identified the molecular events involved in OmpA induced B cell immune response in vitro. We show that OmpA of S. flexneri 2a activates B cells to produce protective cytokines, IL-6 and IL-10 as well as facilitates their differentiation into antibody secreting cells (ASCs). The immunostimulatory properties of OmpA are attributed to the increased surface expression of MHCII and CD86 on B cells. We also report here that B cell activation by OmpA is mediated strictly through recognition by TLR2, resulting in initiation of cascades of signal transduction events, involving increased phosphorylation of protein tyrosine kinases (PTKs), ERK and IkappaBalpha, leading to nuclear translocation of NF-kappaB. Importantly, a TLR2 antibody diminishes OmpA-induced upregulation of MHCII and CD86 on B cell surface as well as significantly inhibits B cell differentiation and cytokine secretion. Furthermore, we illustrate that B cell differentiation into ASCs and induction of cytokine secretion by OmpA are dependent on PTKs activity. Moreover, we identify that OmpA-induced B cell differentiation is entirely dependent on ERK pathway, whereas both NF-kappaB and ERK are essential for cytokine secretion by B cells. Overall, our data demonstrate that OmpA of S. flexneri 2a amplifies TLR signaling in B cells and triggers B cell immune response, which is critical for the development of an effective adaptive immunity to an optimal vaccine antigen. PMID- 25286256 TI - The global growth of graphene. PMID- 25286257 TI - Challenges and opportunities in graphene commercialization. PMID- 25286258 TI - Humanism from a chemist. PMID- 25286259 TI - Graphene for displays that bend. PMID- 25286261 TI - Electrifying inks with 2D materials. PMID- 25286262 TI - Charging graphene for energy. PMID- 25286263 TI - Graphene against corrosion. PMID- 25286264 TI - Sequencing with graphene pores. PMID- 25286265 TI - Graphene devices for life. PMID- 25286266 TI - Graphene in the sky and beyond. PMID- 25286268 TI - Public engagement: the benefits of communicating. PMID- 25286269 TI - Bacterial nanowires: an extended membrane. PMID- 25286270 TI - Semiconductor lasers: taken for a spin. PMID- 25286271 TI - 2D materials: valley currents controlled by light. PMID- 25286272 TI - Electronics based on two-dimensional materials. AB - The compelling demand for higher performance and lower power consumption in electronic systems is the main driving force of the electronics industry's quest for devices and/or architectures based on new materials. Here, we provide a review of electronic devices based on two-dimensional materials, outlining their potential as a technological option beyond scaled complementary metal-oxide semiconductor switches. We focus on the performance limits and advantages of these materials and associated technologies, when exploited for both digital and analog applications, focusing on the main figures of merit needed to meet industry requirements. We also discuss the use of two-dimensional materials as an enabling factor for flexible electronics and provide our perspectives on future developments. PMID- 25286276 TI - Engaging a wider audience. PMID- 25286273 TI - Photodetectors based on graphene, other two-dimensional materials and hybrid systems. AB - Graphene and other two-dimensional materials, such as transition metal dichalcogenides, have rapidly established themselves as intriguing building blocks for optoelectronic applications, with a strong focus on various photodetection platforms. The versatility of these material systems enables their application in areas including ultrafast and ultrasensitive detection of light in the ultraviolet, visible, infrared and terahertz frequency ranges. These detectors can be integrated with other photonic components based on the same material, as well as with silicon photonic and electronic technologies. Here, we provide an overview and evaluation of state-of-the-art photodetectors based on graphene, other two-dimensional materials, and hybrid systems based on the combination of different two-dimensional crystals or of two-dimensional crystals and other (nano)materials, such as plasmonic nanoparticles, semiconductors, quantum dots, or their integration with (silicon) waveguides. PMID- 25286277 TI - "While you still think, I already type": experienced social power reduces deliberation during e-mail communication. AB - E-mail allows individuals to deliberate on their communication before sending it off. For instance, communication partners can easily take their time to ponder how best to frame a request before they actually send a message. Individuals at times strategically exploit this opportunity to deliberate in order to tailor messages to their communication partner, such as when communicating with a relatively more powerful person. As social power reduces concerns about impression management, we predicted that individuals deliberate more while composing e-mail messages under low (vs. high) power. This assumption was tested with well-established power priming. As such, we expected that experienced power in one context would diminish deliberation times during a subsequent e-mail communication. An experiment manipulating the experience of (low vs. high) power and measuring deliberation times during e-mail composition supported this hypothesis. The findings thus indicate how social power alters deliberation times. More importantly, the results show that individuals not only strategically deliberate during e-mail communication in line with their current situation, but also in line with their social standing in a previous situation (here, their experience of power). PMID- 25286274 TI - Graphene spintronics. AB - The isolation of graphene has triggered an avalanche of studies into the spin dependent physical properties of this material and of graphene-based spintronic devices. Here, we review the experimental and theoretical state-of-art concerning spin injection and transport, defect-induced magnetic moments, spin-orbit coupling and spin relaxation in graphene. Future research in graphene spintronics will need to address the development of applications such as spin transistors and spin logic devices, as well as exotic physical properties including topological states and proximity-induced phenomena in graphene and other two-dimensional materials. PMID- 25286279 TI - Quercetin 3-O-rutinoside mediated inhibition of PBP2a: computational and experimental evidence to its anti-MRSA activity. AB - The PBP2a is a cell wall synthesizing protein, which causes resistivity in methicillin resistant Staphylococcus aureus (MRSA) from beta-lactam antibiotics but it is susceptible to 5th generation cephalosporin, ceftobiprole. Ceftobiprole inhibits the growth of MRSA by targeting the PBP2a-mediated cell wall synthesis, but it is reported to have adverse side effects. Due to this, there is a constant need to develop natural alternatives, which are generally free from adverse side effects. Hence in this study, in silico based docking analysis was performed with 37 quercetin derivatives towards PBP2a inhibition and their efficiencies were compared with beta-lactam antibiotic, ceftobiprole. The docking studies suggested that quercetin 3-O-rutinoside (ZINC5280805) interacted efficiently with PBP2a, attaining the highest LibDock score (187.32) compared to other quercetin derivatives. The structural stability and dynamics of the identified lead with PBP2a were validated through molecular dynamics simulation. Simulation results such as RMSD, RMSF, and Rg values indicated that the stability of quercetin 3-O rutinoside with PBP2a was better, with respect to the un-ligated PBP2a. Furthermore, the quercetin 3-O-rutinoside was subjected to an antibacterial susceptibility test and found to have antibacterial activity at 500, 700, and 900 MUM concentration. Also, morphological changes in the bacterial colony and bacterial surface were observed using a scanning electron microscope, when MRSA was treated with 900 MUM concentration of quercetin 3-O-rutinoside. Collectively, results from this study suggest that the quercetin 3-O-rutinoside has the capability to inhibit PBP2a and hence could be used as an alternative or in combination with other drugs in treating MRSA infection. PMID- 25286280 TI - Magnetic resonance imaging findings in atypical polypoid adenomyoma. AB - OBJECTIVES: This article describes magnetic resonance imaging (MRI) findings in 3 cases of atypical polypoid adenomyoma (APAM). METHODS: Clinical and MRI manifestations of 3 patients with APAM were evaluated. High b value diffusion weighted and dynamic contrast-enhanced images were performed. The size, shape, site of origin, and signal intensity (SI) of MRI findings were evaluated. RESULTS: All patients (age range, 37-47 years; mean age, 40 years) had a chief complaint of atypical genital bleeding with no history of pregnancy. In 2 cases, cytology of the endometrium was positive, and pathological analysis of curettage specimens indicated endometrioid adenocarcinoma. The MRI revealed an endometrial polypoid mass arising from the upper corpus (50%) or lower uterine segment (50%). Except for 1 tumor that seemed to invade the myometrium of the uterine wall due to its irregular margin, all tumors were well circumscribed. On T2-weighted MRI scans, the SI of the tumor was homogenous and marginally hyperintense, and contained markedly hyperintense cystic foci. On T1-weighted images, all the tumors were isointense relative to the myometrium, and in 1 case, a number of cystic foci showed high SIs. In a dynamic contrast-enhanced study, solid portions other than the cystic foci showed contrast enhancement in the arterial phase and demonstrated a washout pattern or plateau pattern in the late phase. All tumors demonstrated high SIs on diffusion-weighted images. CONCLUSIONS: Differentiating APAM from other malignant polypoid uterine endometrial tumors may still pose difficulties, especially when the tumor seems to invade the myometrium on MRI. Comprehensive clinical information about the patient including age, pathological assessment of the endometrium, and MRI findings should be essential to provide indication for a diagnosis of APAM. PMID- 25286281 TI - The role of quantum effects on structural and electronic fluctuations in neat and charged water. AB - In this work, we revisit the role of nuclear quantum effects on the structural and electronic properties of the excess proton in bulk liquid water using advanced molecular dynamics techniques. The hydronium ion is known to be a weak acceptor of a hydrogen bond which gives it some hydrophobic character. Quantum effects reduce the degree of this hydrophobicity which facilitates the fluctuations of the protons along the wires compared to the classical proton. Although the Eigen and Zundel species still appear to be dominant motifs, quantum fluctuations result in rather drastic events where both transient autoionization and delocalization over extended proton wires can simultaneously occur. These wild fluctuations also result in a significant change of the electronic properties of the system such as the broadening of the electronic density of states. An analysis of the Wannier functions indicate that quantum fluctuations of neat water molecules result in transient charging with subtle similarities and differences to that of the excess proton. PMID- 25286282 TI - Cost-effective choices of marine fuels in a carbon-constrained world: results from a global energy model. AB - The regionalized Global Energy Transition model has been modified to include a more detailed shipping sector in order to assess what marine fuels and propulsion technologies might be cost-effective by 2050 when achieving an atmospheric CO2 concentration of 400 or 500 ppm by the year 2100. The robustness of the results was examined in a Monte Carlo analysis, varying uncertain parameters and technology options, including the amount of primary energy resources, the availability of carbon capture and storage (CCS) technologies, and costs of different technologies and fuels. The four main findings are (i) it is cost effective to start the phase out of fuel oil from the shipping sector in the next decade; (ii) natural gas-based fuels (liquefied natural gas and methanol) are the most probable substitutes during the study period; (iii) availability of CCS, the CO2 target, the liquefied natural gas tank cost and potential oil resources affect marine fuel choices significantly; and (iv) biofuels rarely play a major role in the shipping sector, due to limited supply and competition for bioenergy from other energy sectors. PMID- 25286284 TI - Bioactive clerodane diterpenoids from the twigs of Casearia balansae. AB - Eight new clerodane diterpenes, balanspenes A-H (1-8), along with two known analogues (9 and 10), were isolated from the twigs of Casearia balansae. The structures of 1-8 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of compounds 1, 4, and 7 were confirmed by comparing their experimental CD spectra with those calculated by the time-dependent density functional theory method. Compounds 4-7, 9, and 10 were found to possess the property of being able to stimulate NGF mediated neurite outgrowth from PC12 cells. PMID- 25286283 TI - Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. AB - IMPORTANCE: Combination antiretroviral therapy initiated within several weeks of human immunodeficiency virus (HIV) infection in adults limits proviral reservoirs that preclude HIV cure. Biomarkers of restricted proviral reservoirs may aid in the monitoring of HIV remission or cure. OBJECTIVES: To quantify peripheral blood proviral reservoir size in perinatally HIV-infected (PHIV+) adolescents and to identify correlates of limited proviral reservoirs. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study including 144 PHIV+ youths (median age, 14.3 years) enrolled in the United States-based Pediatric HIV/AIDS Cohort Study and receiving durable (median duration, 10.2 years) combination antiretroviral therapy, stratified by age at virologic control. MAIN OUTCOMES AND MEASURES: The primary end point was peripheral blood mononuclear cell (PBMC) proviral load after virologic control at different ages. Correlations between proviral load and markers of active HIV production (ie, HIV-specific antibodies, 2-long terminal repeat circles) and markers of immune activation and inflammation were also assessed. RESULTS: Proviral reservoir size was markedly reduced in the PHIV+ youth who achieved virologic control before 1 year of age (4.2 [interquartile range, 2.6-8.6] copies per 1 million PBMCs) compared with those who achieved virologic control at 1 to 5 years of age (19.4 [interquartile range, 5.5-99.8] copies per 1 million PBMCs) or after 5 years of age (70.7 [interquartile range, 23.2-209.4] copies per 1 million PBMCs; P < .001). A proviral burden of less than 10 copies per 1 million PBMCs in PHIV+ youth was measured in 11 (79%), 20 (40%), and 13 (18%) participants with virologic control before 1 year, at 1 to 5 years, and after 5 years of age, respectively (P < .001). Lower proviral load was associated with undetectable 2-long terminal repeat circles (P < .001) and HIV negative or indeterminate serostatus (P < .001) but not with concentrations of soluble immune activation markers CD14 and CD163. CONCLUSIONS AND RELEVANCE: Early effective combination antiretroviral therapy with prolonged virologic suppression after perinatal HIV infection leads to negligible peripheral blood proviral reservoirs in adolescence and is associated with negative or indeterminate HIV serostatus. These findings highlight the long-term effect of early effective control of HIV replication on biomarkers of HIV persistence in perinatal infection and the utility of HIV serostatus as a biomarker for small proviral reservoir size, although not necessarily for cure. PMID- 25286285 TI - The global burden of liver disease: a challenge for methods and for public health. AB - New Global Burden of Disease estimates for liver cirrhosis, published in BMC Medicine, suggest that cirrhosis caused over a million deaths in 2010, with a further million due to liver cancer and acute hepatitis. Cause-specific mortality data were very sparse for some regions, particularly in Africa, with no relevant mortality data for 58/187 countries. Liver disease involves infectious, malignant and chronic aetiologies with overlapping symptoms. Where available mortality data come from verbal autopsies, separating different types of liver disease is challenging. Cirrhosis is a disease of rich and poor alike; key public health risk factors such as alcohol consumption play an important role. Risk-reduction strategies such as controlling the price of alcohol are being widely discussed. Since these estimates used alcohol consumption as a covariate, they cannot be used to explore relationships between alcohol consumption and cirrhosis mortality. There is hope: coming generations of adults will have been vaccinated against hepatitis B, and this is envisaged to reduce the burden of fatal liver disease. But more complete civil registration globally is needed to fully understand the burden of liver disease.Please see related article: http://www.biomedcentral.com/1741-7015/12/145/abstract. PMID- 25286286 TI - Sulfur-doped porous reduced graphene oxide hollow nanosphere frameworks as metal free electrocatalysts for oxygen reduction reaction and as supercapacitor electrode materials. AB - Chemical doping with foreign atoms is an effective approach to significantly enhance the electrochemical performance of the carbon materials. Herein, sulfur doped three-dimensional (3D) porous reduced graphene oxide (RGO) hollow nanosphere frameworks (S-PGHS) are fabricated by directly annealing graphene oxide (GO)-encapsulated amino-modified SiO2 nanoparticles with dibenzyl disulfide (DBDS), followed by hydrofluoric acid etching. The XPS and Raman spectra confirmed that sulfur atoms were successfully introduced into the PGHS framework via covalent bonds. The as-prepared S-PGHS has been demonstrated to be an efficient metal-free electrocatalyst for oxygen reduction reaction (ORR) with the activity comparable to that of commercial Pt/C (40%) and much better methanol tolerance and durability, and to be a supercapacitor electrode material with a high specific capacitance of 343 F g(-1), good rate capability and excellent cycling stability in aqueous electrolytes. The impressive performance for ORR and supercapacitors is believed to be due to the synergistic effect caused by sulfur doping enhancing the electrochemical activity and 3D porous hollow nanosphere framework structures facilitating ion diffusion and electronic transfer. PMID- 25286288 TI - The facile assembly of nanocrystals by optimizing humidity. AB - The ambient humidity and the nature of substrates are considered coordinately in the assembly of nano-sized crystals. The nanocrystal monolayers show large-area uniformity without any aggregates. Zeolite and hematite monolayers with thicknesses of 20-100 nm and excellent orientations are produced. PMID- 25286287 TI - Caspase-like activities accompany programmed cell death events in developing barley grains. AB - Programmed cell death is essential part of development and cell homeostasis of any multicellular organism. We have analyzed programmed cell death in developing barley caryopsis at histological, biochemical and molecular level. Caspase-1, -3, -4, -6 and -8-like activities increased with aging of pericarp coinciding with abundance of TUNEL positive nuclei and expression of HvVPE4 and HvPhS2 genes in the tissue. TUNEL-positive nuclei were also detected in nucellus and nucellar projection as well as in embryo surrounding region during early caryopsis development. Quantitative RT-PCR analysis of micro-dissected grain tissues revealed the expression of HvVPE2a, HvVPE2b, HvVPE2d, HvPhS2 and HvPhS3 genes exclusively in the nucellus/nucellar projection. The first increase in cascade of caspase-1, -3, -4, -6 and -8-like activities in the endosperm fraction may be related to programmed cell death in the nucellus and nucellar projection. The second increase of all above caspase-like activities including of caspase-9-like was detected in the maturating endosperm and coincided with expression of HvVPE1 and HvPhS1 genes as well as with degeneration of nuclei in starchy endosperm and transfer cells. The distribution of the TUNEL-positive nuclei, tissues-specific expression of genes encoding proteases with potential caspase activities and cascades of caspase-like activities suggest that each seed tissue follows individual pattern of development and disintegration, which however harmonizes with growth of the other tissues in order to achieve proper caryopsis development. PMID- 25286289 TI - Facile synthesis of highly porous Ni-Sn intermetallic microcages with excellent electrochemical performance for lithium and sodium storage. AB - Highly porous Ni3Sn2 microcages composed of tiny nanoparticles were synthesized by a facile template-free solvothermal method (based on Ostwald ripening and etching mechanism) for use as anode materials for high-capacity and high-rate capability Li-ion and Na-ion batteries. The Ni3Sn2 porous microcages exhibit highly stable and substantial discharge capacities of the amount to 700 mA h g( 1) after 400 cycles at 0.2C and 530 mA h g(-1) after 1000 cycles at 1C for Li-ion battery anode. For Na-ions storage performance, a reversible capacity of approximate 270 mA h g(-1) is stably maintained at 1C during the first 300 cycles. PMID- 25286290 TI - Lung cancer screening with low-dose computed tomography: an analysis of the MEDCAC decision. AB - Lung cancer is the leading cause of cancer death in the United States and worldwide. However, among the top 4 deadliest cancers, lung cancer is the only one not subject to routine screening. Optimism for an effective lung cancer screening examination soared after the release of the National Lung Screening Trial results in November 2011. Since then, nearly 40 major medical societies and organizations have endorsed low-dose computed tomography (LDCT) screening. In December 2013, the United States Preventive Services Task Force also endorsed LDCT. However, the momentum for LDCT screening slowed in April 2014 when the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) panel concluded that there was not enough evidence to justify the annual use of LDCT scans for the detection of early lung cancer. This article briefly reviews the epidemiology of lung cancer, the National Lung Screening Trial study results, and the growing national endorsement of LDCT from a variety of key stakeholder organizations. We subsequently analyze and offer our evidence-based counterpoints to the major assumptions underlying the MEDCAC decision. PMID- 25286291 TI - Beak sign. PMID- 25286292 TI - Computed tomography fluoroscopy versus conventional computed tomography guidance for biopsy of intrathoracic lesions: a retrospective review of 1143 consecutive procedures. AB - PURPOSE: To compare the success rates, complication rates, and radiation doses of conventional computed tomography (CCT) versus computed tomography with fluoroscopy (CTF) during image-guided percutaneous needle biopsies of intrathoracic lesions. MATERIALS AND METHODS: We conducted a retrospective analysis of 1143 consecutive intrathoracic biopsies performed under computed tomography guidance at a single tertiary care center. For each procedure we recorded patient age and sex, lesion size and location, and radiation dose administered to the patient. Thereafter, appropriate tests of statistical significance were applied to compare rates of success, complications, and radiation between CCT and CTF guidance. RESULTS: After correcting for lesion size, CTF was associated with an odds ratio (OR) of 6.07 [95% confidence interval (CI): 2.23-16.50] for technical procedural success, an OR of 0.79 (95% CI: 0.55 1.15) for fine-needle aspiration success, an OR of 2.11 (95% CI: 1.02-4.38) for core-needle biopsy success, and an OR of 1.45 (95% CI: 1.00-2.21) for overall success when compared with CCT. CTF was associated with an OR of 1.10 (95% CI: 0.35-3.48) for complications when compared with CCT. Mean dose-length product per procedure was 1332 mGy cm for CCT and 1730 mGy cm for CTF (P=0.027). CONCLUSIONS: CCT and CTF are both valuable tools for intrathoracic biopsy. CTF improves technical and core-needle biopsy success at the expense of higher radiation doses to the patient. Operator confidence with CCT and CTF in light of lesion characteristics should guide the choice to select one over the other. PMID- 25286294 TI - Curvulamine, a new antibacterial alkaloid incorporating two undescribed units from a Curvularia species. AB - The white croaker (Argyrosomus argentatus) derived Curvularia sp. IFB-Z10 produces curvulamine as a skeletally unprecedented alkaloid incorporating two undescribed extender units. Curvulamine is more selectively antibacterial than tinidazole and biosynthetically unique in the new extenders formed through a decarboxylative condensation between an oligoketide motif and alanine. PMID- 25286293 TI - High efficiency differentiation of human pluripotent stem cells to cardiomyocytes and characterization by flow cytometry. AB - There is an urgent need to develop approaches for repairing the damaged heart, discovering new therapeutic drugs that do not have toxic effects on the heart, and improving strategies to accurately model heart disease. The potential of exploiting human induced pluripotent stem cell (hiPSC) technology to generate cardiac muscle "in a dish" for these applications continues to generate high enthusiasm. In recent years, the ability to efficiently generate cardiomyogenic cells from human pluripotent stem cells (hPSCs) has greatly improved, offering us new opportunities to model very early stages of human cardiac development not otherwise accessible. In contrast to many previous methods, the cardiomyocyte differentiation protocol described here does not require cell aggregation or the addition of Activin A or BMP4 and robustly generates cultures of cells that are highly positive for cardiac troponin I and T (TNNI3, TNNT2), iroquois-class homeodomain protein IRX-4 (IRX4), myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v) and myosin regulatory light chain 2, atrial isoform (MLC2a) by day 10 across all human embryonic stem cell (hESC) and hiPSC lines tested to date. Cells can be passaged and maintained for more than 90 days in culture. The strategy is technically simple to implement and cost effective. Characterization of cardiomyocytes derived from pluripotent cells often includes the analysis of reference markers, both at the mRNA and protein level. For protein analysis, flow cytometry is a powerful analytical tool for assessing quality of cells in culture and determining subpopulation homogeneity. However, technical variation in sample preparation can significantly affect quality of flow cytometry data. Thus, standardization of staining protocols should facilitate comparisons among various differentiation strategies. Accordingly, optimized staining protocols for the analysis of IRX4, MLC2v, MLC2a, TNNI3, and TNNT2 by flow cytometry are described. PMID- 25286296 TI - Acute myocardial infarction during pregnancy. AB - Myocardial infarction complicating pregnancy is an important cause of maternal morbidity and mortality. The coexistence of obesity, diabetes, chronic hypertension, and delayed age at pregnancy is expected to increase the prevalence of myocardial infarction during pregnancy. Timely treatment in the form of percutaneous coronary intervention has dramatically improved outcomes. Early medical treatment with antiplatelet and antithrombotic agents is important, and maternal fetal medicine specialists must be familiar with it. In this article we will describe the basic initial medical management of patients with an acute coronary syndrome. PMID- 25286295 TI - The contraceptive CHOICE project round up: what we did and what we learned. AB - The Contraceptive CHOICE Project was a prospective cohort study of 9256 women in the St Louis area. The project provided no-cost reversible contraception to participants for 2 to 3 years with the goal of increasing uptake of long-acting reversible contraception and decreasing unintended pregnancy in the area. This manuscript will provide a brief summation of the major findings to date including the dramatic effect the project had on unintended pregnancy and abortion rates. PMID- 25286298 TI - Critical care obstetrics. PMID- 25286297 TI - Severe sepsis during pregnancy. AB - Severe sepsis is a major cause of mortality among critically ill patients. Early recognition accompanied by early initiation of broad-spectrum antibiotics with source control and fluid resuscitation improves outcomes. Hemodynamic resuscitation starts with fluid therapy followed by vasopressors if necessary. Cases refractory to first-line vasopressors (norepinephrine) will require second line vasopressors (epinephrine or vasopressin) and low-dose steroid therapy. Resuscitation goals should include optimization of central venous oxygenation and serum lactate. PMID- 25286299 TI - Contraceptive update: evidenced based optimism. PMID- 25286300 TI - Nanoscale adhesion forces of Pseudomonas aeruginosa type IV Pili. AB - A variety of bacterial pathogens use nanoscale protein fibers called type IV pili to mediate cell adhesion, a primary step leading to infection. Currently, how these nanofibers respond to mechanical stimuli and how this response is used to control adhesion is poorly understood. Here, we use atomic force microscopy techniques to quantify the forces guiding the adhesion of Pseudomonas aeruginosa type IV pili to surfaces. Using chemical force microscopy and single-cell force spectroscopy, we show that pili strongly bind to hydrophobic surfaces in a time dependent manner, while they weakly bind to hydrophilic surfaces. Individual nanofibers are capable of withstanding forces up to 250 pN, thereby explaining how they can resist mechanical stress. Pulling on individual pili yields constant force plateaus, presumably reflecting conformational changes, as well as nanospring properties that may help bacteria to withstand physiological shear forces. Analysis of mutant strains demonstrates that these mechanical responses originate solely from type IV pili, while flagella and the cell surface localized and proposed pili-associated adhesin PilY1 play no direct role. We also demonstrate that bacterial-host interactions involve constant force plateaus, the extension of bacterial pili, and the formation of membrane tethers from host cells. We postulate that the unique mechanical responses of type IV pili unravelled here enable the bacteria to firmly attach to biotic and abiotic surfaces and thus maintain attachment when subjected to high shear forces under physiological conditions, helping to explain why pili play a critical role in colonization of the host. PMID- 25286301 TI - The NTR domain of procollagen C-proteinase enhancer-1 (PCPE-1) mediates PCPE-1 binding to syndecans-1, -2 and -4 as well as fibronectin. AB - Procollagen C-proteinase enhancer 1 (PCPE-1) is an extracellular matrix glycoprotein that can stimulate procollagen processing by procollagen C proteinases (PCPs) such as bone morphogenetic protein-1 (BMP-1). PCPE-1 consists of two CUB domains that bind to the procollagen C-propeptide and are responsible for enhancing activity and a netrin-like (NTR) domain that binds to BMP-1 as well as heparin and heparan sulfate. The NTR domain also mediates binding of PCPE-1 to cells, an interaction inhibited by heparin, thus suggesting involvement of cell membrane heparan-sulfate proteoglycans (HSPGs). Using pull-down experiments and an ELISA type binding assay we show here that PCPE-1 binds to three cell membrane HSPGs, syndecans-1, -2 and -4. We also demonstrate that this binding is mediated by the NTR domain and depends on the glycosaminoglycan chains of the syndecans. Using co-immunoprecipitation and an ELISA type binding assay we show that PCPE-1 can also bind fibronectin (an established binding partner of BMP-1), another interaction involving the NTR domain. Consistently, fibronectin inhibits cell attachment to PCPE-1 although it does not affect PCPE-1 enhancing activity. PCPE 1 is not an adhesive protein since cell attachment to PCPE-1 is not associated with cell spreading and/or actin filaments formation. The results suggest that PCPE-1 binding to syndecans and/or fibronectin may control collagen fibril assembly on the cell surface. Further characterization of these interactions may pave the way for future design of new means to modulate collagen deposition in pathological conditions such as fibrosis. PMID- 25286302 TI - A novel centrosome and microtubules associated subcellular localization of Nogo A: implications for neuronal development. AB - Oligodendrocyte-derived neurite-outgrowth inhibitor Nogo-A and its restriction mechanism are well-known. Recently, Nogo-A is reported to be abundantly expressed in neurons, however, the concrete link between neuronal Nogo-A and neuronal development is poorly understood. In the present study, we used Neuro2A and COS7 cell lines to clarify that Nogo-A largely distributed in the centrosome and microtubules-rich regions. When endogenous Nogo-A was down-regulated with RNA interference, the percentage of cell differentiation and the total neurite length of Neuro2A exposed to valproic acid (VPA) decreased sharply. Furthermore, in primary neurons, acetylated alpha-tubulin decreased at the tips of neurites where endogenous Nogo-A was still highly expressed. In HEK293FT cell lines, Nogo-A overexpression could redistribute acetylated alpha-tubulin but not change the level of alpha-tubulin. Together, our data discovered that centrosome- and microtubules-localized Nogo-A positively regulates neuronal differentiation and neurite outgrowth of Neuro2A cell lines, implicating the essential roles of subcellular Nogo-A in neuronal development. PMID- 25286303 TI - Growing for different ends. AB - Tissue engineering and regenerative biology are usually discussed in relation to biomedical research and applications. However, hand in hand with developments of this field in the biomedical context, other approaches and uses for non-medical ends have been explored. There is a growing interest in exploring spin off tissue engineering and regenerative biology technologies in areas such as consumer products, art and design. This paper outlines developments regarding in vitro meat and leather, actuators and bio-mechanic interfaces, speculative design and contemporary artistic practices. The authors draw on their extensive experience of using tissue engineering for non-medical ends to speculate about what lead to these applications and their possible future development and uses. Avoiding utopian and dystopian postures and using the notion of the contestable, this paper also mentions some philosophical and ethical consideration stemming from the use of non-medical approaches to tissue constructs. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID- 25286304 TI - Gene therapy for eye as regenerative medicine? Lessons from RPE65 gene therapy for Leber's Congenital Amaurosis. AB - Recombinant virus mediated gene therapy of Leber's Congenital Amaurosis has provided a wide range of data on the utility of gene replacement therapy for recessive diseases. Studies to date demonstrate that gene therapy in the eye is safe and can result in long-term recovery of visual function, but they also highlight that further research is required to identify optimum intervention time points, target populations and the compatibility of associate therapies. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID- 25286305 TI - Structural analysis of glyceraldehyde-3-phosphate dehydrogenase functional diversity. AB - Multifunctional proteins provide a new mechanism to expand exponentially cell information and capability beyond that indicated by conventional gene analyses. As such, examination of their structure-function relationships provides a means to define the mechanisms through which cells accomplish critical yet disparate activities required for cell viability and survival. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) may be considered the quintessential multidimensional protein which exhibits a variety of functions unrelated to its classical role in energy production. This review discusses new insights into the structure-function mechanisms through which defined GAPDH amino acid domains are utilized for its diverse activities, the importance of its post-translational modification, and, intriguingly, the logic inherent in the presence or the absence of specific signaling domains. PMID- 25286306 TI - One-step immobilization of antibodies for alpha-1-fetoprotein immunosensor based on dialdehyde cellulose/ionic liquid composite. AB - A novel immunosensor for alpha-1-fetoprotein based on dialdehyde cellulose/ionic liquid composite film as a matrix has been developed. Microcrystalline cellulose was activated by sodium metaperiodate to produce dialdehyde cellulose. Antibodies can be immobilized on the electrode by a one-step method through covalent bonding of the aldehyde groups of dialdehyde cellulose with the amino groups of antibodies, in which no additional chemical cross-linking step is required. Moreover, ionic liquid added can improve the conductivity of the sensing interface and, therefore, can enhance the electrochemical signal. In this work, alpha-1-fetoprotein was detected within the range from 0.1 to 60ngml(-1) with a detection limit of 0.07ngml(-1) (signal/noise=3). The proposed immunosensor had good specificity and reproducibility. It was used to determine real samples with satisfactory results. PMID- 25286310 TI - Highly efficient layer-by-layer-assisted infiltration for high-performance and cost-effective fabrication of nanoelectrodes. AB - We present a novel cathode fabrication technique for improved performance and production efficiency of SOFCs based on an infiltration method assisted by layer by-layer (LbL) assembly of polyelectrolytes. Preparation of the electrode with LbL-assisted infiltration leads to a 6.5-fold reduction in the electrode fabrication time while providing uniform and small formation of Pr0.7Sr0.3CoO3 delta (PSC) particles on the electrode. The increased surface area by 24.5% and number of active sites of the prepared electrode exhibits superior electrochemical performance up to 36.1% while preserving the electrical properties of the electrode. Because of its versatility and tenability, the LbL assisted infiltration process may become a new route for fabrication of composite electrodes for other energy storage and conversion devices. PMID- 25286309 TI - Detection of very long antisense transcripts by whole transcriptome RNA-Seq analysis of Listeria monocytogenes by semiconductor sequencing technology. AB - The Gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a severe food-borne infection characterised by abortion, septicaemia, or meningoencephalitis. L. monocytogenes causes outbreaks of febrile gastroenteritis and accounts for community-acquired bacterial meningitis in humans. Listeriosis has one of the highest mortality rates (up to 30%) of all food-borne infections. This human pathogenic bacterium is an important model organism for biomedical research to investigate cell-mediated immunity. L. monocytogenes is also one of the best characterised bacterial systems for the molecular analysis of intracellular parasitism. Recently several transcriptomic studies have also made the ubiquitous distributed bacterium as a model to understand mechanisms of gene regulation from the environment to the infected host on the level of mRNA and non-coding RNAs (ncRNAs). We have used semiconductor sequencing technology for RNA-seq to investigate the repertoire of listerial ncRNAs under extra- and intracellular growth conditions. Furthermore, we applied a new bioinformatic analysis pipeline for detection, comparative genomics and structural conservation to identify ncRNAs. With this work, in total, 741 ncRNA locations of potential ncRNA candidates are now known for L. monocytogenes, of which 611 ncRNA candidates were identified by RNA-seq. 441 transcribed ncRNAs have never been described before. Among these, we identified novel long non-coding antisense RNAs with a length of up to 5,400 nt e.g. opposite to genes coding for internalins, methylases or a high-affinity potassium uptake system, namely the kdpABC operon, which were confirmed by qRT-PCR analysis. RNA-seq, comparative genomics and structural conservation of L. monocytogenes ncRNAs illustrate that this human pathogen uses a large number and repertoire of ncRNA including novel long antisense RNAs, which could be important for intracellular survival within the infected eukaryotic host. PMID- 25286311 TI - Peer-mediated check-in/check-out for students at-risk for internalizing disorders. AB - The present study investigated the effectiveness of peer-mediated check-in/check out (CICO) on the internalizing behaviors of elementary school students. A nonconcurrent multiple-baseline design across participants was utilized to evaluate the intervention's effectiveness for 3 students in 1st and 2nd grade. Two 5th grade students were trained to implement CICO under the supervision of an adult intervention specialist. The peer-mediated CICO procedure was effective for 2 of the 3 participants as evidenced by moderate to large effect sizes; however, all 3 participants were identified as "at-risk" on a universal screener for internalizing problems. The results suggest peer-mediated CICO may be a resource efficient Tier II strategy to meet the needs of students engaging in internalizing behavior within a multitiered framework of service delivery. PMID- 25286308 TI - The effect of tensile stress on the conformational free energy landscape of disulfide bonds. AB - Disulfide bridges are no longer considered to merely stabilize protein structure, but are increasingly recognized to play a functional role in many regulatory biomolecular processes. Recent studies have uncovered that the redox activity of native disulfides depends on their C-C-S-S dihedrals, chi2 and chi'2. Moreover, the interplay of chemical reactivity and mechanical stress of disulfide switches has been recently elucidated using force-clamp spectroscopy and computer simulation. The chi2 and chi'2 angles have been found to change from conformations that are open to nucleophilic attack to sterically hindered, so called closed states upon exerting tensile stress. In view of the growing evidence of the importance of C-C-S-S dihedrals in tuning the reactivity of disulfides, here we present a systematic study of the conformational diversity of disulfides as a function of tensile stress. With the help of force-clamp metadynamics simulations, we show that tensile stress brings about a large stabilization of the closed conformers, thereby giving rise to drastic changes in the conformational free energy landscape of disulfides. Statistical analysis shows that native TDi, DO and interchain Ig protein disulfides prefer open conformations, whereas the intrachain disulfide bridges in Ig proteins favor closed conformations. Correlating mechanical stress with the distance between the two a-carbons of the disulfide moiety reveals that the strain of intrachain Ig protein disulfides corresponds to a mechanical activation of about 100 pN. Such mechanical activation leads to a severalfold increase of the rate of the elementary redox S(N)2 reaction step. All these findings constitute a step forward towards achieving a full understanding of functional disulfides. PMID- 25286312 TI - Sensitivity to change and concurrent validity of direct behavior ratings for academic anxiety. AB - Multitiered frameworks of service delivery have traditionally underserved students with mental health needs. Whereas research has supported the assessment and intervention of social and academic behavior across tiers, evidence is limited with regard to mental health concerns including internalizing behaviors (e.g., anxiety and depression). In particular, there is a notable shortage of brief anxiety assessment tools to be used for progress monitoring purposes. Moreover, traditional omnibus rating scale approaches may fail to capture contextually dependent anxiety. The purpose of the present investigation is to examine the sensitivity to change and concurrent validity of Direct Behavior Ratings (DBR; Chafouleas, Riley-Tillman, & Christ, 2009; Chafouleas, Riley Tillman, & Sugai, 2007) of anxiety and traditional rating scales in measuring academic anxiety directly before, during, and after a potentially anxiety provoking stimulus. Research was conducted with 115 undergraduate students in a Southeastern university. Results indicated significant relationships between DBRs and pre- and postmeasures of anxiety. Change metrics suggested an overall lack of correspondence between DBR and the criterion measure, with DBR scales detecting greater change both across the testing situation and participants. The use of DBR for anxiety is considered within a multitiered, problem-solving framework. Feasibility and limitations associated with implementation are discussed. PMID- 25286314 TI - The neural bases of crossmodal object recognition in non-human primates and rodents: a review. AB - The ability to integrate information from different sensory modalities to form unique multisensory object representations is a highly adaptive cognitive function. Surprisingly, non-human animal studies of the neural substrates of this form of multisensory integration have been somewhat sparse until very recently, and this may be due in part to a relative paucity of viable testing methods. Here we review the historical development and use of various "crossmodal" cognition tasks for non-human primates and rodents, focusing on tests of "crossmodal object recognition", the ability to recognize an object across sensory modalities. Such procedures have great potential to elucidate the cognitive and neural bases of object representation as it pertains to perception and memory. Indeed, these studies have revealed roles in crossmodal cognition for various brain regions (e.g., prefrontal and temporal cortices) and neurochemical systems (e.g., acetylcholine). A recent increase in behavioral and physiological studies of crossmodal cognition in rodents augurs well for the future of this research area, which should provide essential information about the basic mechanisms of object representation in the brain, in addition to fostering a better understanding of the causes of, and potential treatments for, cognitive deficits in human diseases characterized by atypical multisensory integration. PMID- 25286307 TI - Intersection of AHR and Wnt signaling in development, health, and disease. AB - The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1) the roles of both AHR and Wnt signaling in development and disease, and (2) the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of Wnt signaling impairs fetal prostate development. PMID- 25286315 TI - Commentary: Omalizumab therapy for bullous pemphigoid by KK Yu, AB Crew, KAN Messingham, JA Fairley, DT Woodley. J Am Acad Dermatol 2014 Jun 20. pii: S0190 9622(14)01410-8. doi: 10.1016/j.jaad.2014.04.053. [Epub ahead of print]. PMID- 25286313 TI - Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. AB - The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial. PMID- 25286316 TI - Attitudes of hospital leaders toward publicly reported measures of health care quality. AB - IMPORTANCE: Public reporting of quality is considered a key strategy for stimulating improvement efforts at US hospitals; however, little is known about the attitudes of hospital leaders toward existing quality measures. OBJECTIVES: To describe US hospital leaders' attitudes toward hospital quality measures found on the Centers for Medicare & Medicaid Services' Hospital Compare website, assess use of these measures for quality improvement, and examine the association between leaders' attitudes and hospital quality performance. DESIGN, SETTING, AND PARTICIPANTS: We mailed a 21-item questionnaire from January 1 through September 31, 2012, to senior hospital leaders from a stratified random sample of 630 US hospitals, including equal numbers with better-than-expected, as-expected, and worse-than-expected performance on mortality and readmission measures. MAIN OUTCOMES AND MEASURES: We assessed levels of agreement with statements concerning quality measures, examined use of measures for improvement activities, and analyzed the association between leaders' attitudes and hospital performance. RESULTS: Of 630 hospitals surveyed, 380 (60.3%) responded. For each of the mortality, readmission, process, and patient experience measures, more than 70% of hospitals agreed with the statement that "public reporting stimulates quality improvement activity at my institution"; agreement for measures of cost and volume was 65.2% and 53.3%, respectively. A similar pattern was observed for the statement that "our hospital is able to influence performance on this measure"; agreement for processes of care and patient experience measures was 96.4% and 94.2%, respectively. A total of 89.7% of hospitals agreed that the hospital's reputation was influenced by patient experience measures; agreement was 77.4% for mortality, 69.9% for readmission, 76.3% for process measures, 66.1% for cost measures, and 54.0% for volume measures. A total of 87.1% of hospitals reported incorporating performance on publicly reported measures into their hospital's annual goals, whereas 90.2% reported regularly reviewing the results with the hospital's board of trustees and 94.3% with senior clinical and administrative leaders. When compared with chief executive officers and chief medical officers, respondents who identified themselves as chief quality officers or vice presidents of quality were less likely to agree that public reporting stimulates quality improvement and that measured differences are large enough to differentiate among hospitals. CONCLUSIONS AND RELEVANCE: Hospital leaders indicated that the measures reported on the Hospital Compare website exert strong influence over local planning and improvement efforts. However, they expressed concerns about the clinical meaningfulness, unintended consequences, and methods of public reporting. PMID- 25286317 TI - Offering variety: a subtle manipulation to promote healthy food choice throughout the day. AB - OBJECTIVE: Providing a variety of food generally increases consumption and enjoyment. This effect is typically associated with unhealthy behavior (e.g., overindulgence at a buffet) and studied during a single meal. Two studies tested whether this effect can be leveraged in a subtle, simple manipulation to promote healthy food choices over the course of a day. METHOD: In Studies 1 and 2, 188 and 187 participants, respectively, chose between a sweet and a piece of fruit in the afternoon. The fruit was either the same as or different from fruit that was selected in the morning; choice was not given in the morning. Study 1 tested this effect in the domain of expressed preferences and Study 2 examined actual choice. RESULTS: In both studies, a second piece of fruit was more likely to be selected in the afternoon if it was different from fruit that was selected in the morning. CONCLUSIONS: These results illustrate how a robust effect that is typically associated with unhealthy outcomes can be harnessed to promote healthy food choices and underscore the importance of conceptualizing eating as a series of interrelated behavioral decisions. This work has implications for applied settings, such as cafeterias, and is distinguished from other simple structural manipulations by its focus on sustaining healthy food choice over the course of the day. (PsycINFO Database Record PMID- 25286319 TI - Local tumour ablative therapies: opportunities for maximising immune engagement and activation. AB - The relationship between cancer and the immune system is a complex one. The immune system can prevent tumour growth by eliminating cancer cells but this editing process ultimately results in poorly immunogenic cells remaining allowing for unchallenged tumour growth. In light of this, the focus of cancer treatment should be to maximise cancer elimination and the prevention of escape mechanisms. In this review we will examine current and emerging ablative treatment modalities that induce Immunogenic Cell Death (ICD), a special type of cell death that allows for immune cell involvement and the generation of an anti-tumour specific immune response. When paired with immune modulating agents, capable of potentiating the immune response and reversing the immune-suppressive environment created by tumours, we may be looking at the future of anti-cancer therapy. PMID- 25286320 TI - Exploiting the cytoskeletal filaments of neoplastic cells to potentiate a novel therapeutic approach. AB - Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate filament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo efficacy, suggesting that cytoskeletal filaments may be exploited to supplement chemotherapeutic approaches currently used in the clinical setting. Therefore, this review is intended to expose academics and clinicians to the tremendous variety of cytoskeletal filament directed agents that are currently available for further chemotherapeutic evaluation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage malignant cells are discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents. PMID- 25286318 TI - The intrinsically disordered regions of the Drosophila melanogaster Hox protein ultrabithorax select interacting proteins based on partner topology. AB - Interactions between structured proteins require a complementary topology and surface chemistry to form sufficient contacts for stable binding. However, approximately one third of protein interactions are estimated to involve intrinsically disordered regions of proteins. The dynamic nature of disordered regions before and, in some cases, after binding calls into question the role of partner topology in forming protein interactions. To understand how intrinsically disordered proteins identify the correct interacting partner proteins, we evaluated interactions formed by the Drosophila melanogaster Hox transcription factor Ultrabithorax (Ubx), which contains both structured and disordered regions. Ubx binding proteins are enriched in specific folds: 23 of its 39 partners include one of 7 folds, out of the 1195 folds recognized by SCOP. For the proteins harboring the two most populated folds, DNA-RNA binding 3-helical bundles and alpha-alpha superhelices, the regions of the partner proteins that exhibit these preferred folds are sufficient for Ubx binding. Three disorder containing regions in Ubx are required to bind these partners. These regions are either alternatively spliced or multiply phosphorylated, providing a mechanism for cellular processes to regulate Ubx-partner interactions. Indeed, partner topology correlates with the ability of individual partner proteins to bind Ubx spliceoforms. Partners bind different disordered regions within Ubx to varying extents, creating the potential for competition between partners and cooperative binding by partners. The ability of partners to bind regions of Ubx that activate transcription and regulate DNA binding provides a mechanism for partners to modulate transcription regulation by Ubx, and suggests that one role of disorder in Ubx is to coordinate multiple molecular functions in response to tissue specific cues. PMID- 25286323 TI - Structured reporting of multiphasic CT for pancreatic cancer: potential effect on staging and surgical planning. AB - PURPOSE: To compare structured versus nonstructured reporting of multiphasic computed tomography (CT) for staging of pancreatic cancer and the effects of both types of reporting on subjective assessment of resectability. MATERIALS AND METHODS: This institutional review board-approved, HIPAA-compliant retrospective study with waiver of informed consent included all patients who were referred for presurgical multiphasic CT of the pancreas between December 2006 and April 2011 at one institution before and after implementation (April 2008) of a structured reporting template. The template was created specifically for reporting multiphasic CT results to stage pancreatic cancer in patients and contained specific information relevant to surgical and oncologic planning. Multiphasic CT reports were assessed for the presence of 12 key features required for staging and surgical planning, including location, size, enhancement, node status, and vascular involvement. Three pancreatic surgeons evaluated the reports to assess resectability, surgical planning, and ease of extracting information before and after reviewing the multiphasic CT images blinded to the patient identifiers. The Student t test and chi(2) test were used for statistical analysis. RESULTS: Forty eight (40%) structured and 72 (60%) nonstructured multiphasic CT reports were reviewed. Nonstructured reports contained a mean +/- standard deviation of 7.3 key features +/- 2.1 (range, 1-11) and structured reports contained 10.6 +/- 0.9 (range, 9-12) features (P < .001). Information for surgical planning was deemed easily accessible in 94%, 60%, and 98% of structured and 47%, 54%, and 32% of nonstructured reports by the three surgeons, respectively (P < .001, .79, < .001). Surgeons had sufficient information for surgical planning in 96%, 69%, and 98% of structured and 31%, 43%, and 25% of nonstructured reports (P < .001, .009, and < .001). When surgeons reviewed reports in combination with multiphasic CT images, they were more likely to convert an answer of "unsure" regarding resectability to a definitive answer (ie, resectable or unresectable) when the reports were structured than when they were nonstructured. CONCLUSION: Structured reporting of pancreatic multiphasic CT provided superior evaluation of pancreatic cancer and facilitated surgical planning. Surgeons were more confident regarding decisions about tumor resectability when they reviewed structured reports before review of multiphasic CT images. PMID- 25286322 TI - Assessment of carotid artery atherosclerotic disease by using three-dimensional fast black-blood MR imaging: comparison with DSA. AB - PURPOSE: To assess fast three-dimensional (3D) black-blood (BB) magnetic resonance (MR) imaging as a noninvasive alternative to intraarterial digital subtraction angiography (DSA) at quantifying moderate to severe carotid artery atherosclerotic disease. MATERIALS AND METHODS: Local ethics committee approval and written informed patient consent were obtained for this study. Sixty-five carotid arteries from 52 patients with at least 50% stenosis underwent 3D BB MR imaging and DSA. Quantitative measurements, including stenosis, lesion length, and the presence or absence of plaque ulceration, obtained with the two modalities were independently determined. Sensitivity and specificity, the intraclass correlation coefficient (ICC), Cohen kappa, and Bland-Altman analysis were used to assess the agreement. RESULTS: Excellent agreement in measuring luminal stenosis was found between 3D BB MR imaging and DSA (ICC, 0.96; 95% confidence interval [CI]: 0.93, 0.97). Three-dimensional BB MR imaging was also found to have high sensitivity (91.7%), specificity (96.2%), and agreement (Cohen kappa, 0.85; 95% CI: 0.66, 0.99) with DSA for detection of ulcers. Good agreement was found between lesion length measured by using 3D BB MR imaging and DSA (ICC, 0.75; 95% CI: 0.51, 0.84). However, lesion length measurements by using 3D BB MR imaging were, on average, 4.0 mm longer than those measured by using DSA (P < .001). CONCLUSION: Three-dimensional BB MR imaging is a noninvasive and accurate way to quantify moderate to severe carotid artery atherosclerotic disease. With fast acquisition and large coverage, 3D BB MR imaging has the potential to become an alternative imaging approach in evaluating the severity of atherosclerosis. PMID- 25286324 TI - Incremental value of liver MR imaging in patients with potentially curable colorectal hepatic metastasis detected at CT: a prospective comparison of diffusion-weighted imaging, gadoxetic acid-enhanced MR imaging, and a combination of both MR techniques. AB - PURPOSE: To prospectively compare diagnostic performance of diffusion-weighted (DW) imaging, gadoxetic acid-enhanced magnetic resonance (MR) imaging, both techniques combined (combined MR imaging), and computed tomography (CT) for detecting colorectal hepatic metastases and evaluate incremental value of MR for patients with potentially curable colorectal hepatic metastases detected with CT. MATERIALS AND METHODS: In this institutional review board-approved prospective study, with informed consent, 51 patients (39 men, 12 women; mean age, 62 years) with potentially resectable hepatic metastases detected with CT underwent liver MR, including DW imaging and gadoxetic acid-enhanced MR. Two independent readers reviewed DW, gadoxetic acid-enhanced, combined MR, and CT image sets to detect hepatic metastases. The figure-of-merit (FOM) value representing overall diagnostic performance, sensitivity, and positive predictive value (PPV) for each image set were analyzed by using free-response receiver operating characteristic analysis and generalized estimating equations. RESULTS: There were 104 hepatic metastases in 47 patients. The pooled FOM values, sensitivities, and PPVs of combined MR (FOM value, 0.93; sensitivity, 98%; and PPV, 88%) and gadoxetic acid enhanced MR (FOM value, 0.92; sensitivity, 95%; and PPV, 90%) were significantly higher than those of CT (FOM value, 0.82; sensitivity, 85%; and PPV, 73%) (P < .006). The pooled FOM value and sensitivity of combined MR (FOM value, 0.92; sensitivity, 95%) was also significantly higher than that of DW imaging (FOM value, 0.82; sensitivity, 79%) for metastases (<=1-cm diameter) (P <= .003). DW imaging showed significantly higher pooled sensitivity (79%) and PPV (60%) than CT (sensitivity, 50%; PPV, 33%) for the metastases (<=1-cm diameter) (P <= .004). In 47 patients with hepatic metastases, combined MR depicted more metastases than CT in 10 and 14 patients, respectively, according to both readers. CONCLUSION: Gadoxetic acid-enhanced MR and combined MR are more accurate than CT in detecting colorectal hepatic metastases, have an incremental value when added to CT alone for detecting additional metastases, and can be routinely performed in patients with potentially curable hepatic metastases detected with CT. PMID- 25286321 TI - Unmet needs of people with severe multiple sclerosis and their carers: qualitative findings for a home-based intervention. AB - BACKGROUND: Few data on services for people with severe multiple sclerosis (MS) are available. The Palliative Network for Severely Affected Adults with MS in Italy (PeNSAMI) developed a home palliative care program for MS patients and carers, preceded by a literature review and qualitative study (here reported). OBJECTIVE: To identify unmet needs of people with severe MS living at home by qualitative research involving key stakeholders, and theorize broad areas of intervention to meet those needs. METHOD: Data were collected from: at least 10 personal interviews with adults with severe MS (primary/secondary progressive, EDSS>=8.0); three focus group meetings (FGs) of carers of people with severe MS; and two FGs of health professionals (HPs). Grounded theory guided the analysis of interview and FG transcripts, from which the areas of intervention were theorized. RESULTS: Between October 2012 and May 2013, 22 MS patients, 30 carers and 18 HPs participated. Forty-eight needs themes were identified, grouped into 14 categories and four domains. Seven, highly interdependent intervention areas were theorized. Patients had difficulties expressing needs; experiences of burden and loneliness were prominent, chiefly in dysfunctional, less affluent families, and among parent carers. Needs differed across Italy with requirements for information and access to services highest in the South. All participants voiced a strong need for qualified personnel and care coordination in day-to-day home care. Personal hygiene emerged as crucial, as did the need for a supportive network and preservation of patient/carer roles within family and community. CONCLUSIONS: Unmet needs transcended medical issues and embraced organizational and psychosocial themes, as well as health policies. The high interdependence of the seven intervention areas theorized is in line with the multifaceted approach of palliative care. At variance with typical palliative contexts, coping with disability rather than end-of-life was a major concern of patients and carers. PMID- 25286325 TI - Electronic tongue generating continuous recognition patterns for protein analysis. AB - In current protocol, a combinatorial approach has been developed to simplify the design and production of sensing materials for the construction of electronic tongues (eT) for protein analysis. By mixing a small number of simple and easily accessible molecules with different physicochemical properties, used as building blocks (BBs), in varying and controlled proportions and allowing the mixtures to self-assemble on the gold surface of a prism, an array of combinatorial surfaces featuring appropriate properties for protein sensing was created. In this way, a great number of cross-reactive receptors can be rapidly and efficiently obtained. By combining such an array of combinatorial cross-reactive receptors (CoCRRs) with an optical detection system such as surface plasmon resonance imaging (SPRi), the obtained eT can monitor the binding events in real-time and generate continuous recognition patterns including 2D continuous evolution profile (CEP) and 3D continuous evolution landscape (CEL) for samples in liquid. Such an eT system is efficient for discrimination of common purified proteins. PMID- 25286326 TI - A novel method for localizing reporter fluorescent beads near the cell culture surface for traction force microscopy. AB - PA gels have long been used as a platform to study cell traction forces due to ease of fabrication and the ability to tune their elastic properties. When the substrate is coated with an extracellular matrix protein, cells adhere to the gel and apply forces, causing the gel to deform. The deformation depends on the cell traction and the elastic properties of the gel. If the deformation field of the surface is known, surface traction can be calculated using elasticity theory. Gel deformation is commonly measured by embedding fluorescent marker beads uniformly into the gel. The probes displace as the gel deforms. The probes near the surface of the gel are tracked. The displacements reported by these probes are considered as surface displacements. Their depths from the surface are ignored. This assumption introduces error in traction force evaluations. For precise measurement of cell forces, it is critical for the location of the beads to be known. We have developed a technique that utilizes simple chemistry to confine fluorescent marker beads, 0.1 and 1 um in diameter, in PA gels, within 1.6 MUm of the surface. We coat a coverslip with poly-D-lysine (PDL) and fluorescent beads. PA gel solution is then sandwiched between the coverslip and an adherent surface. The fluorescent beads transfer to the gel solution during curing. After polymerization, the PA gel contains fluorescent beads on a plane close to the gel surface. PMID- 25286327 TI - Stimulation of cytoplasmic DNA sensing pathways in vitro and in vivo. AB - In order to efficiently stimulate an innate immune response, DNA must be of sufficient length and purity. We present a method where double stranded DNA (dsDNA) which has the requisite characteristics to stimulate the cytoplasmic DNA sensing pathways can be generated cheaply and with ease. By the concatemerization of short, synthetic oligonucleotides (which lack CpG motifs), dsDNA can be generated to be of sufficient length to activate the cytosolic DNA sensing pathway. This protocol involves blunt end ligation of the oligonucleotides in the presence of polyethylene glycol (PEG), which provides an environment for efficient ligation to occur. The dsDNA concatemers can be used, following purification by phenol/chloroform extraction, to simulate the innate immune response in vitro by standard transfection protocols. This DNA can also be used to stimulate innate immunity in vivo by intradermal injection into the ear pinna of a mouse, for example. By standardizing the concatemerization process and the subsequent stimulation protocols, a reliable and reproducible activation of the innate immune system can be produced. PMID- 25286328 TI - A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors. AB - We have developed a new method for the building of pharmacophores for G protein coupled receptors, a major drug target family. The method is a combination of the ligand- and target-based pharmacophore methods and founded on the extraction of structural fragments, interacting ligand moiety and receptor residue pairs, from crystal structure complexes. We describe the procedure to collect a library with more than 250 fragments covering 29 residue positions within the generic transmembrane binding pocket. We describe how the library fragments are recombined and inferred to build pharmacophores for new targets. A validating retrospective virtual screening of histamine H1 and H3 receptor pharmacophores yielded area-under-the-curves of 0.88 and 0.82, respectively. The fragment-based method has the unique advantage that it can be applied to targets for which no (homologous) crystal structures or ligands are known. 47% of the class A G protein-coupled receptors can be targeted with at least four-element pharmacophores. The fragment libraries can also be used to grow known ligands or for rotamer refinement of homology models. Researchers can download the complete fragment library or a subset matching their receptor of interest using our new tool in GPCRDB. PMID- 25286330 TI - Perceptions of boundary ambiguity in the process of leaving an abusive partner. AB - The process of leaving an abusive partner has been theorized using the Stages of Change Model. Although useful, this model does not account for changes in relational boundaries unique to the process of leaving. Using family stress and feminist perspectives, this study sought to integrate boundary ambiguity into the Stages of Change Model. Boundary ambiguity is defined as a perception of uncertainty as to who is in or out of a family system (Boss & Greenberg, 1984). Twenty-five mothers who had temporarily or permanently left their abusers were interviewed. Data were analyzed using constructivist grounded theory methods. Results identify types, indicators of, and mothers' responses to boundary ambiguity throughout the five stages of change. Most mothers and abusers fluctuated between physical and psychological presence and absence over multiple separations. The integration of boundary ambiguity into the Stages of Change Model highlights the process of leaving an abusive partner as systemic, fluid, and nonlinear. PMID- 25286331 TI - Iridium complex catalyzed germylative coupling reaction between alkynes and iodogermanes--a new route to alkynylgermanium and alkynylgermasilicon compounds. AB - The new reaction of terminal alkynes with iodogermanes proceeding in the presence of an Ir(I)-complex [{Ir(MU-Cl)(CO)2}2] (I) and NEt((i)Pr)2, as a hydrogen iodide acceptor, leads to the formation of functionalized alkynylgermanes. This reaction occurs via direct activation of the C(sp)-H bond in the starting alkyne. Detailed stoichiometric experiments using [Ir(cod)(CCPh)(PCy3)] (IVa) and iodogermane were performed and resulted in a proposal of a reasonable mechanism for the germylative coupling reaction between alkynes and iodogermanes. PMID- 25286329 TI - Caerulomycin A suppresses immunity by inhibiting T cell activity. AB - BACKGROUND: Caerulomycin A (CaeA) is a known antifungal and antibiotic agent. Further, CaeA is reported to induce the expansion of regulatory T cell and prolongs the survival of skin allografts in mouse model of transplantation. In the current study, CaeA was purified and characterized from a novel species of actinomycetes, Actinoalloteichus spitiensis. The CaeA was identified for its novel immunosuppressive property by inhibiting in vitro and in vivo function of T cells. METHODS: Isolation, purification and characterization of CaeA were performed using High Performance Flash Chromatography (HPFC), NMR and mass spectrometry techniques. In vitro and in vivo T cell studies were conducted in mice using flowcytometry, ELISA and thymidine-[methyl-(3)H] incorporation. RESULTS: CaeA significantly suppressed T cell activation and IFN-gamma secretion. Further, it inhibited the T cells function at G1 phase of cell cycle. No apoptosis was noticed by CaeA at a concentration responsible for inducing T cell retardation. Furthermore, the change in the function of B cells but not macrophages was observed. The CaeA as well exhibited substantial inhibitory activity in vivo. CONCLUSION: This study describes for the first time novel in vitro and in vivo immunosuppressive function of CaeA on T cells and B cells. CaeA has enough potential to act as a future immunosuppressive drug. PMID- 25286332 TI - Biphasic influence of dexamethasone exposure on embryonic vertebrate skeleton development. AB - Dexamethasone (Dex) has anti-inflammatory and immunomodulatory properties against many conditions. There is a potential teratogenic risk, however, for pregnant women receiving Dex treatment. It has been claimed that Dex exposure during pregnancy could affect osteogenesis in the developing embryo, which still remains highly controversial. In this study, we employed chick embryos to investigate the effects of Dex exposure on skeletal development using combined in vivo and in vitro approach. First, we demonstrated that Dex (10(-8)-10(-6)MUmol/egg) exposure resulted in a shortening of the developing long bones of chick embryos, and it accelerated the deposition of calcium salts. Secondly, histological analysis of chick embryo phalanxes exhibited Dex exposure inhibited the proliferation of chondrocytes, increased apoptosis of chondrocytes and osteocytes, and led to atypical arranged hypertrophic chondrocytes. The expression of genes related to skeletogenesis was also analyzed by semi-quantitative RT-PCR. The expression of ALP, Col1a2 and Col2a1 was decreased in the Dex treated phalanxes. A detectable increase was observed in Runx-2 and Mmp-13 expression. We next examined how Dex affected the different stages of skeletogenesis in vitro. Utilizing limb bud mesenchyme micromass cultures, we determined that Dex exposure exerted no effect on apoptosis but impaired chondrogenic cell proliferation. Interestingly, low dose of Dex moderately prompted nodule formation as revealed by alcian blue staining, but higher doses of Dex significantly inhibited similar chondrogenic differentiation. Dex exposure did not induce apoptosis when the chondrogenic precursors were still at the mesenchymal stage, however, cell viability was suppressed when the mesenchyme differentiated into chondrocytes. Alizarin red staining revealed that the capacity to form mineralized bone nodules was correspondingly enhanced as Dex concentrations increased. The mRNA level of Sox-9 was slightly increased in mesenchymal cell mass treated by low concentration of Dex. Mmp-13 expression was obviously up-regulated by Dex in both mesenchymal cells and primary chondrocyte cultures. And Col10a1 expression was also increased by Dex exposure in chondrocyte. In summary, we have revealed that different concentrations of Dex exposure during early gestation could exert a biphasic effect on vertebrate skeletal development. PMID- 25286333 TI - Complete protocol for slow-spinning high-resolution magic-angle spinning NMR analysis of fragile tissues. AB - High-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) is an essential tool to characterize a variety of semisolid systems, including biological tissues, with virtually no sample preparation. The "non-destructive" nature of NMR is typically compromised, however, by the extreme centrifugal forces experienced under conventional HR-MAS frequencies of several kilohertz. These features limit the usefulness of current HR-MAS approaches for fragile samples. Here, we introduce a full protocol for acquiring high-quality HR-MAS NMR spectra of biological tissues at low spinning rates (down to a few hundred hertz). The protocol first consists of a carefully designed sample preparation, which yields spectra without significant spinning sidebands at low spinning frequency for several types of sample holders, including the standard disposable inserts classically used in HR-MAS NMR-based metabolomics. Suppression of broad spectral features is then achieved using a modified version of the recently introduced PROJECT experiment with added water suppression and rotor synchronization, which deposits limited power in the sample and which can be suitably rotor-synchronized at low spinning rates. The performance of the slow HR MAS NMR procedure is demonstrated on conventional (liver tissue) and very delicate (fish eggs) samples, for which the slow-spinning conditions are shown to preserve the structural integrity and to minimize intercompartmental leaks of metabolites. Taken together, these results expand the applicability and reliability of HR-MAS NMR spectroscopy. These results have been obtained at 400 and 600 MHz and suggest that high-quality slow HR-MAS spectra can be expected at higher magnetic fields using the described protocol. PMID- 25286334 TI - Perspectives on percutaneous penetration: Silica nanoparticles. AB - Nanotechnology is a rapidly expanding area of research involved in developing science-based solutions for innovative therapeutics. Silica nanoparticles (SNPs) have received wide attention in several industries and medicine and are being developed for biomedical and biotechnological applications such as drug delivery, DNA transfection, and targeted molecular imaging of cancer. Recently, they are emerging in the fields of cosmetics and dermal preparations. SNP may offer a revolutionized treatment of several skin diseases by controlled and sustained release of drugs to skin, as well as enhanced skin penetration of encapsulated drug ingredients. SNPs are candidates for transcutaneous vaccination and transdermal gene therapy, too. Yet there exist concerns that whilst the properties of SNPs have enabled numerous industrial and medical applications, their toxicological and environmental safety mandates evaluation. The knowledge of passage of SNPs through skin following skin exposure (intentionally or unintentionally) and subsequent effects is limited. This review surveys the key experiments on SNP-based formulations in the fields of dermatology and cosmetics with the goal of rationalizing data and informing public health concerns related to SNPs' toxicity among scientists and manufacturers handling them, while highlights the research gaps in dermal absorption of these compounds. PMID- 25286335 TI - Novel ureteroscopic technique for treatment of prolonged caliceal leak after partial nephrectomy. AB - INTRODUCTION AND OBJECTIVES: Caliceal leak after partial nephrectomy (PN) typically resolves with conservative management. However, persistent fistulae pose a formidable challenge that may require additional therapeutic actions. METHODS: We describe a case of a patient with a solitary kidney who suffered a persistent urine leak following PN. A novel retrograde ureteroscopic approach was taken that utilized the combined techniques of caliceal fulguration and fibrin glue injection. RESULTS: Imaging demonstrated resolution of the caliceal fistula at 13 months postoperatively. CONCLUSIONS: Persistent urine leak after PN remains a burdensome complication that often requires creative steps to resolve. Our case presents a solution using a novel ureteroscopic technique. PMID- 25286336 TI - Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP+ toxicity. AB - Exercise induces oxidative stress, which may activate adaptive antioxidant responses. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the defense of oxidative stress by regulating the expression of antioxidant enzymes, gamma-glutamylcysteine ligase (gammaGCL) and heme oxygenase 1 (HO-1). We investigated whether treadmill exercise protects dopaminergic neurons by regulating the Nrf2 antioxidant system in a 1-methyl-4-phenylpyridine (MPP(+))-induced parkinsonian rat model. We found that MPP(+) induced early decreases in total glutathione level and Nrf2/gammaGCLC (catalytic subunit of gammaGCL) expression, but late upregulation of HO-1 expression in association with loss of nigral dopaminergic neurons and downregulation of tyrosine hydroxylase and dopamine transporter expression in the striatum. Treadmill exercise for 4weeks induced upregulation of Nrf2 and gammaGCLC expression, and also prevented the MPP(+)-induced downregulation of Nrf2/gammaGCLC/glutathione, HO-1 upregulation, and nigrostriatal dopaminergic neurodegeneration. Moreover, the protective effect of exercise was blocked by the knockdown of Nrf2 using a lentivirus-carried shNrf2 delivery system. These results demonstrate an essential role of Nrf2 in the exercise-mediated protective effect that exercise enhances the nigrostriatal Nrf2 antioxidant defense capacity to protect dopaminergic neurons against the MPP(+)-induced toxicity. PMID- 25286337 TI - Associations between STAT3 rs744166 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. AB - BACKGROUND: Many studies have investigated the associations between the signal transducer and activator of transcription 3 (STAT3) in the susceptibility to ulcerative colitis (UC) and Crohn's disease (CD). However, the results remain inconsistent. This meta-analysis determined the risk of STAT3 rs744166 polymorphism-conferred UC and CD susceptibility. MATERIALS AND METHODS: Electronic databases, including PubMed, EMBASE and the Cochrane Library, were searched for all eligible studies that evaluated the association between STAT3 rs744166 polymorphisms with UC and CD risk up to August 21, 2014. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed- or random-effects models. RESULTS: Twelve studies containing 10298 patients with CD, 4244 patients with UC and 11191 controls were included in this meta-analysis. The results indicated that the STAT3 rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, OR = 1.20, 95%CI, 1.11-1.30, I2 = 0%, Punadjusted<0.00001, PBonferroni<0.00005, PFDR<0.00001; UC: GA+AA vs. GG, OR = 1.21, 95%CI, 1.08-1.36, I2 = 1%, Punadjusted = 0.001, PBonferroni = 0.005, PFDR = 0.00125). In subgroup analyses by ethnicity, the significant association was found only among Caucasians. However, when grouped by age of onset, positive associations were found both among adults and children. In addition, when stratified by study design and genotyping methods, the risk of CD was significantly associated with the STAT3 rs744166 polymorphism in hospital-based and population-based groups and in SNP Array and SNPlex groups. For UC, significant associations were also found in population-based, PCR-RFLP and SNPlex groups. Moreover, these findings were sufficiently robust to withstand the Bonferroni correction and false discovery rate (FDR). CONCLUSION: This meta analysis indicates that carriers of the STAT3 rs744166 'A' allele have a significantly greater risk of CD and UC, especially among Caucasians. PMID- 25286338 TI - Total synthesis and determination of the absolute configuration of rakicidin A. AB - Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target were consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547, and vinylamycin, and facilitates the investigations of rakicidin A as an anticancer stem cell agent. PMID- 25286339 TI - Spray deposited copper zinc tin sulphide (Cu2ZnSnS4) film as a counter electrode in dye sensitized solar cells. AB - Stoichiometric thin films of Cu2ZnSnS4 (CZTS) were deposited by the spray technique on a FTO coated glass substrate, with post-annealing in a H2S environment to improve the film properties. CZTS films were used as a counter electrode (CE) in Dye-Sensitized Solar Cells (DSCs) with N719 dye and an iodine electrolyte. The DSC of 0.25 cm(2) area using a CE of CZTS film annealed in a H2S environment under AM 1.5G illumination (100 mW cm(-2)) exhibited a short circuit current density (JSC) = 18.63 mA cm(-2), an open circuit voltage (VOC) = 0.65 V and a fill factor (FF) = 0.53, resulting in an overall power conversion efficiency (PCE) = 6.4%. While the DSC using as deposited CZTS film as a CE showed the PCE = 3.7% with JSC = 13.38 mA cm(-2), VOC = 0.57 V and FF = 0.48. Thus, the spray deposited CZTS films can play an important role as a CE in the large area DSC fabrication. PMID- 25286340 TI - Optimal asymmetric thread for orthodontic microimplants: Laboratory and clinical evaluation. AB - OBJECTIVES: To investigate the performance of microimplants incorporating a newly designed asymmetric thread. MATERIALS AND METHODS: Three microimplants were compared. The control group comprised microimplants with the original v-shaped thread. The two experimental groups (Taper 1.0 and Taper 1.25) comprised prototype microimplants constructed with the new asymmetric thread; the Taper 1.25 specimens had a 1.25-mm-long and sharper tip, while the Taper 1.0 and control groups had a less sharp 1-mm tip. Two specially designed artificial bone blocks mimicking soft (maxillary) and hard (mandibular) bone were used to evaluate the microimplant insertion characteristics and postinsertion lateral stability. The peak insertion torque, insertion time, Periotest value (PTV), and torsional strength were measured. Then the microimplants were evaluated clinically over a 3-month period. RESULTS: Significant differences in peak insertion torque, insertion time, and PTV were observed and favored the experimental groups. Although statistically insignificant, the clinical success rate was also higher in the Taper 1.25 experimental group than in the control group (87.2% vs 75.6%). CONCLUSIONS: The better performances of the experimental microimplant, under both laboratory and clinical conditions (although statistically insignificant in the latter), demonstrate the superiority of the new asymmetric thread. PMID- 25286341 TI - Maxillary arch changes with transpalatal arch treatment followed by full fixed appliances. AB - OBJECTIVE: To evaluate short- and long-term maxillary dental arch dimensional changes in patients treated with a transpalatal arch (TPA) during mixed dentition followed by full fixed appliances in the permanent dentition compared with an untreated sample. MATERIALS AND METHODS: Dental casts and lateral cephalograms obtained from 36 consecutively treated patients before TPA treatment (T0), after TPA treatment (T1), after fixed appliance treatment (T2), and a minimum of 3 years after fixed appliance treatment (T3) were analyzed. The control group was matched as closely as possible. Arch widths, perimeter, and length, as well as crowding and incisor proclination, were evaluated. RESULTS: In the treated group, intercanine, interpremolar, and intermolar widths and arch perimeter increased significantly at T1. At T2, only the intercanine width increase was still significant. At T3 all arch dimensions decreased, remaining larger than they were at T0. The arch length increased after T1, significantly decreased at T2, and slightly decreased at T3. The crowding decreased significantly at T1, was eliminated at T2, and increased at T3. At T3, 50% of the patients showed relapse with crowding ranging from 0.5 to 2 mm. In the control group at T1, only slight changes were noted but crowding increased. At T2, crowding and upper incisor inclination increased but arch length decreased. At T3, intercuspid width, arch perimeter, and arch length continued to decrease, thereby increasing crowding. CONCLUSION: Maxillary dental arch dimensions changed significantly after TPA followed by treatment with fixed appliances. Relapse occurred to some extent, especially in intercanine width and arch perimeter, but most of the dental arch changes remained stable. PMID- 25286342 TI - Supramolecular glycodendrimer-based hybrid drugs. AB - Specific noncovalent interactions are commonly used by nature to modulate numerous processes including cell recognition, viral adhesion, and transmembrane communications. Here we report on the design, synthesis, and preliminary characterization of new supramolecular glycodendrimer-based hybrid drugs based on adamantyl-modified glycodendrimers of third, fourth, or fifth generation (mPPI-G3 AdaB, mPPI-G4-AdaB, and mPPI-G5-AdaB) and a new heterobifunctional ligand. This component was tailored to bind through noncovalent interactions both the multimeric natural 5-HT3 receptor (through an optimized arylpiperazine pharmacophore) and the adamantyl groups located on the glycodendrimer surfaces (through a beta-cyclodextrin residue) giving rise to biorelevant supramolecular constructs. PMID- 25286343 TI - Total reflection X-ray spectrometry (TXRF) for trace elements assessment in edible clams. AB - The present contribution presents a preliminary investigation of the chemical composition with respect to major, minor, trace, and ultratrace elements in several clam species that are frequently used for human consumption in Portuguese markets and worldwide. In order to use a simple and rapid analytical methodology for clam analysis, energy dispersive X-ray fluorescence (EDXRF) spectrometry and total reflection X-ray fluorescence (TXRF) spectrometry were selected as analytical techniques. The analytical capabilities of TXRF spectrometry were evaluated for the determination of minor and trace elements in commercial edible clams. We compared the direct analysis of powdered suspensions (using different sample amounts and dispersant agents) with the analysis of the digested samples for trace element determination. Inductively coupled plasma mass spectrometry analysis of clam digests was also performed to evaluate the analytical possibilities of TXRF spectrometry for trace and ultratrace analysis. PMID- 25286344 TI - Formation of cholesterol-rich supported membranes using solvent-assisted lipid self-assembly. AB - This paper describes the application of a solvent-exchange method to prepare supported membranes containing high fractions of cholesterol (up to ~57 mol %) in an apparent equilibrium. The method exploits the phenomenon of reverse-phase evaporation, in which the deposition of lipids in alcohol (e.g., isopropanol) is followed by the slow removal of the organic solvent from the water-alcohol mixture. This in turn induces a series of lyotropic phase transitions successively producing inverse-micelles, monomers, micelles, and vesicles in equilibrium with supported bilayers at the contacting solid surface. By using the standard cholesterol depletion by methyl-beta-cyclodextrin treatment, a quartz crystal microbalance with dissipation monitoring assay confirms that the cholesterol concentration in the supported membranes is comparable to that in the surrounding bulk phase. A quantitative characterization of the biophysical properties of the resultant bilayer, including lateral diffusion constants and phase separation, using epifluorescence microscopy and atomic force microscopy establishes the formation of laterally contiguous supported lipid bilayers, which break into a characteristic domain-pattern of coexisting phases in a cholesterol concentration-dependent manner. With increasing cholesterol fraction in the supported bilayer, the size of the domains increases, ultimately yielding two dimensional cholesterol bilayer domains near the solubility limit. A unique feature of the approach is that it enables preparation of supported membranes containing limiting concentrations of cholesterol near the solubility limit under equilibrium conditions, which cannot be obtained using conventional techniques (i.e., vesicle fusion). PMID- 25286345 TI - Combined treatment of xenon and hypothermia in newborn rats--additive or synergistic effect? AB - BACKGROUND: Breathing the inert gas Xenon (Xe) enhances hypothermic (HT) neuroprotection after hypoxia-ischemia (HI) in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added) or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7) rats, showed that the combination of mild HT (35 degrees C) and low Xe concentration (20%), both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study. DESIGN/METHODS: After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT) NT37 degrees C, HT35 degrees C, HT32 degrees C) or Xe concentrations (0%, 20% or 50%) starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101) of P7 pups were exposed to either HT35 degrees C+Xe0%, NT+Xe20% or a combination of HT35 degrees C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side) brain tissue area loss after seven day survival. RESULTS: Immediate HT32 degrees C (p = 0.042), but not HT35 degrees C significantly reduced brain injury compared to NT37 degrees C. As previously shown, adding immediate Xe50% to HT32 degrees C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37 degrees C significantly reduced brain injury (p>0.050). In addition, neither 4 h-delayed HT35 degrees C alone, nor HT35 degrees C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model. CONCLUSIONS: Combining two treatments that individually were ineffective (delayed HT35 degrees C and delayed Xe20%) did not exert neuroprotection when combined, and therefore did not show a synergistic treatment effect. PMID- 25286346 TI - Intimate injection partnerships are at elevated risk of high-risk injecting: a multi-level longitudinal study of HCV-serodiscordant injection partnerships in San Francisco, CA. AB - BACKGROUND: It is increasingly recognized that the risk for HIV and hepatitis C (HCV) transmission among people who inject drugs (PWID), such as syringe sharing, occurs in the context of relationships between (at least) two people. Evidence suggests that the risk associated with injection behavior varies with injection partner types. METHODS: We utilized longitudinal dyad-level data from a study of young PWID from San Francisco (2006 to 2013) to investigate the relationship level factors influencing high-risk injecting within HCV-serodiscordant injection partners (i.e., individuals who injected together >=5 times in the prior month). Utilizing data from 70 HCV-serodiscordant injection partnerships, we used generalized linear models to examine relationship-level predictors (i.e., partnership composition, partnership closeness, and partnership dynamics) of: (1) receptive syringe sharing (RSS); and (2) receptive cooker use (RCU), as reported by the HCV-negative injection partner. RESULTS: As reported by the "at-risk" HCV negative injection partner, receptive syringe sharing (RSS) and receptive cooker use (RCU) were 19% and 33% at enrollment, and 11% and 12% over all visits (total follow-up time 55 person-years) resulting in 13 new HCV-infections (incidence rate: 23.8/100 person-years). Person-level factors, injection partnership composition, and partnership dynamics were not significantly associated with either RSS or RCU. Instead, intimate injection partnerships (those who lived together and were also in a sexual relationship) were independently associated with a 5-times greater risk of both RSS and a 7-times greater risk of RCU when compared to injecting only partnerships. CONCLUSION: Our findings suggest a positive, and amplified effect of relationship factors on injecting drug risk behaviors among young PWID injection partnerships. The majority of interventions to reduce injection drug use related harms focus on individual-based education to increase drug use knowledge. Our findings support the need to expand harm reduction strategies to relationship-based messaging and interventions. PMID- 25286347 TI - In vivo enzyme inhibition improves the targeting of [177Lu]DOTA-GRP(13-27) in GRPR-positive tumors in mice. AB - INTRODUCTION: Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N terminus for (111)In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with (177)Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [(177)Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine. METHODS: In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys. RESULTS AND DISCUSSION: Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [(177)Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios. PMID- 25286348 TI - Ebolavirus in West Africa, and the use of experimental therapies or vaccines. AB - Response to the current ebolavirus outbreak based on traditional control measures has so far been insufficient to prevent the virus from spreading rapidly. This has led to urgent discussions on the use of experimental therapies and vaccines untested in humans and existing in limited quantities, raising political, strategic, technical and ethical questions. PMID- 25286349 TI - Artificial vision support system (AVS(2)) for improved prosthetic vision. AB - State-of-the-art and upcoming camera-driven, implanted artificial vision systems provide only tens to hundreds of electrodes, affording only limited visual perception for blind subjects. Therefore, real time image processing is crucial to enhance and optimize this limited perception. Since tens or hundreds of pixels/electrodes allow only for a very crude approximation of the typically megapixel optical resolution of the external camera image feed, the preservation and enhancement of contrast differences and transitions, such as edges, are especially important compared to picture details such as object texture. An Artificial Vision Support System (AVS(2)) is devised that displays the captured video stream in a pixelation conforming to the dimension of the epi-retinal implant electrode array. AVS(2), using efficient image processing modules, modifies the captured video stream in real time, enhancing 'present but hidden' objects to overcome inadequacies or extremes in the camera imagery. As a result, visual prosthesis carriers may now be able to discern such objects in their 'field-of-view', thus enabling mobility in environments that would otherwise be too hazardous to navigate. The image processing modules can be engaged repeatedly in a user-defined order, which is a unique capability. AVS(2) is directly applicable to any artificial vision system that is based on an imaging modality (video, infrared, sound, ultrasound, microwave, radar, etc.) as the first step in the stimulation/processing cascade, such as: retinal implants (i.e. epi-retinal, sub-retinal, suprachoroidal), optic nerve implants, cortical implants, electric tongue stimulators, or tactile stimulators. PMID- 25286350 TI - Investigating the functional implications of reinforcing feedback loops in transcriptional regulatory networks. AB - Transcription factors (TFs) and microRNAs (miRNAs) can jointly regulate transcriptional networks in the form of recurrent circuits or motifs. A motif can be divided into a feedforward loop (FFL) and a feedback loop (FBL). Incoherent FFLs have been the recent focus due to their potential to dampen gene expression noise in maintaining physiological norms. However, a cell is not only able to manage noise but also able to exploit it during development or tumorigenesis to initiate radical transformation such as cell differentiation or metastasis. A plausible mechanism may involve reinforcing FBLs (rFBLs), which amplify changes to a sufficient level in order to complete the state transition. To study the behaviour of rFBLs, we developed a novel theoretical framework based on biochemical kinetics. The proposed rFBL follows a parsimonious design, involving two TFs and two miRNAs. A simulation study based on our model suggested that a system with rFBLs is robust to only a certain level of fluctuation but prone to a complete paradigm shift when the change exceeds a threshold level. To investigate the natural occurrence of rFBLs, we performed a rigorous network motif analysis using a recently available TF/miRNA regulatory network from the Encyclopedia of DNA Elements (ENCODE). Our analysis suggested that the rFBL is significantly depleted in the observed network. Nonetheless, we identified 9 rFBL instances. Among them, we found a double-rFBL involving three TFs SUZ12/BCLAF1/ZBTB33 and three miRNAs miR-9/19a/129-5p, which together serve as an intriguing toggle switch between nerve development and telomere maintenance. Additionally, we investigated the interactions implicated in the rFBLs using expression profiles of cancer patients from The Cancer Genome Atlas (TCGA). Together, we provided a novel and comprehensive view of the profound impacts of rFBLs and highlighted several TFs and miRNAs as the leverage points for potential therapeutic targets in cancers due to their eminent roles in the identified rFBLs. PMID- 25286351 TI - Fabrication of electrochemical interface based on boronic acid-modified pyrroloquinoline quinine/reduced graphene oxide composites for voltammetric determination of glycated hemoglobin. AB - A voltammetric sensor for determination of glycated hemoglobin (HbA1c) was developed based on the composites of phenylboronic acid-modified pyrroloquinoline quinine (PBA-PQQ) and reduced graphene oxide. After the electrodeposition of reduced graphene oxide (ERGO) on the glassy carbon (GC) electrode, PQQ multilayer was decorated on the surface of the ERGO/GC electrode via potential cycling. Further modification with PBA would lead to the formation of the working electrode, namely PBA-PQQ/ERGO/GC electrode. PQQ on the electrode exhibited a quasi-reversible electrode process with 2-electron transfer and 2-proton participation, and the electron transfer efficiency was further enhanced by the introduction of ERGO layer. The complexation of PBA with HbA1c through specific boronic acid-diol recognition could cause the change of the oxidation peak current of PQQ on the electrode, which was utilized for HbA1c detection. Under the optimized conditions, the PBA-PQQ/ERGO/GC electrode provided high selectivity and high sensitivity for HbA1c detection with a linear range of 9.4-65.8 MUg mL( 1) and a low detection limit of 1.25 MUg mL(-1). The fabricated sensor was also successfully applied to determine the percentages of HbA1c in whole blood of healthy individuals. PMID- 25286352 TI - Gelatin methacrylate (GelMA) mediated electrochemical DNA biosensor for DNA hybridization. AB - In this study, an electrochemical biosensor system for the detection of DNA hybridization by using gelatin methacrylate (GelMA) modified electrodes was developed. Electrochemical behavior of GelMA modified Pencil Graphite Electrode (PGE) that serve as a functional platform was investigated by using Cyclic Voltammetry (CV) and Electrochemical Impedance Spectroscopy (EIS) and compared with those of the bare PGE. Hybridization was achieved in solution phase and guanine oxidation signal changes were evaluated. The decrease in the guanine oxidation peak currents at around +1.0 V was used as an indicator for the DNA hybridization. Also, more interestingly GelMA intrinsic oxidation peaks at around +0.7 V changed substantially by immobilization of different oligonucleotides such as probe, hybrid and control sequences to the electrode surface. It is the first study of using GelMA as a part of an electrochemical biosensor system. The results are very promising in terms of using GelMA as a new DNA hybridization indicator. Additionally, GelMA modified electrodes could be useful for detecting ultra low quantity of oligonucleotides by providing mechanical support to the bio recognition layer. The detection limit of this method is at present 10(-12)mol. Signal suppressions were increased from 50% to 93% for hybrid with using GelMA when it was compared to bare electrode which facilitates the hybridization detection. PMID- 25286353 TI - A signal "on" photoelectrochemical biosensor for assay of protein kinase activity and its inhibitor based on graphite-like carbon nitride, Phos-tag and alkaline phosphatase. AB - A highly sensitive and selective photoelectrochemical (PEC) biosensor is fabricated for the detection of protein kinase activity based on visible-light active graphite-like carbon nitride (g-C3N4) and the specific recognition utility of Phos-tag for protein kinase A (PKA)-induced phosphopeptides. For assembling the substrate peptides, g-C3N4 and gold nanoparticles (g-C3N4-AuNPs) complex is synthesized and characterized. When the immobilized peptides on g-C3N4-AuNPs modified ITO electrode are phosphorylated under PKA catalysis, they can be specifically identified and binded with biotin functionalized Phos-tag (Phos-tag biotin) in the presence of Zn(2+). Then, through the specific interaction between biotin and avidin, avidin functionalized alkaline phosphatase (avidin-ALP) is further assembled to catalyze its substrate of l-ascorbic acid-2-phosphate trisodium salt (AAP) to produce electron donor of ascorbic acid (AA), resulting an increased photocurrent compared with the absence of phosphorylation event. Based on the specific identification effect of Phos-tag, the fabricated biosensor presents excellent selectivity for capturing the phosphorylated serine residues in the substrate peptides. With the good photoactivity of g-C3N4 and ALP catalyzed signal amplification, the fabricated biosensor presents high sensitivity and low detection limit (0.015 unit/mL, S/N = 3) for PKA. The applicability of this PEC biosensor is further testified by the evaluation of PKA inhibition by HA-1077 with the IC50 value of 1.18MUM. This new strategy is also successfully applied to detect the change of PKA activity in cancer cell lysate with and without drug stimulation. Therefore, the developed PEC method has great potential in screening of kinase inhibitors and highly sensitive detection of kinase activity. PMID- 25286354 TI - Real-time QCM-D monitoring of cancer cell death early events in a dynamic context. AB - Since a few years, the acoustic sensing of whole cell is the focus of increasing interest for monitoring the cytoskeletal cellular response to morphological modulators. We aimed at illustrating the potentialities of the quartz crystal microbalance with dissipation (QCM-D) technique for the real-time detection of the earliest morphological changes that occur at the cell-substrate interface during programmed cell death. Human breast cancer cells (MCF-7) grown on serum protein-coated gold sensors were placed in dynamic conditions under a continuous medium flow. The mass and viscoelasticity changes of the cells were tracked by monitoring the frequency and dissipation shifts during the first 4h of cell exposure to staurosporine, a well-known apoptosis inducer. We have identified a QCM-D signature characteristic of morphological modifications and cell detachment from the sensing surface that are related to the pro-apoptotic treatment. In particular, for low staurosporine doses below 1 uM, we showed that recording the dissipation shift allows to detect an early cell response which is undetectable after the same duration by the classical analytical techniques in cell biology. Furthermore, this sensing method allows quantifying the efficiency of the drug effect in less than 4h without requiring labeling and without interfering in the system, thus preventing any loss of information. In the actual context of targeted cancer therapy development, we believe that these results bring new insights in favor of the use of the non invasive QCM-D technique for quickly probing the cancer cell sensitivity to death inducer drugs. PMID- 25286355 TI - Highly-ordered perpendicularly immobilized FWCNTs on the thionine monolayer modified electrode for hydrogen peroxide and glucose sensors. AB - In this paper, we innovatively immobilized few-walled carbon nanotubes (FWCNTs) perpendicularly on Au surface through conductive thionine instead of aminoalkanethiols so as to improve electrochemical properties. Because FWCNTs own smaller aggregates, stronger chemical corrosion resistant, and higher conductivity than single-walled carbon nanotubes (SWCNTs), and thionine is a good electron transfer mediator can provide amino and sulfhydryl groups playing the same function as insulating aminoalkanethiols. The strategy for obtaining perpendicularly aligned FWCNTs (p-FWCNTs) is electrostatically assembled thionine and 11-amino-n-undecanethiol (AUT) on Au surface via Au-S bond to provide amino groups for covalently combining terminus-carboxylated FWCNTs, we confirmed and compared the results by AFM, Raman spectroscopy and electrochemical methods. In order to prove the constructed basement has excellent electrochemical properties can provide a good platform for sensors fabrication, we developed a novel non enzymatic hydrogen peroxide (H2O2) sensor by electrodepositing Pt nanoparticles (PtNPs) on p-FWCNTs/Thionine/Au electrode surface, and verified the result by TEM, EDX and electrochemical techniques. Furthermore, polyallylamine (PAA) and poly(vinyl sulfate) (PVS) permselective layer, poly(diallyldimethylammonium) (PDDA) and glucose oxidase (GOx) multilayer films were layer-by-layer self assembled on p-FWCNTs/Thionine/Au surface to fabricate a glucose biosensor. Either the non-enzymatic H2O2 sensor or the enzyme-based glucose biosensor showed good sensitivity, selectivity, reproducibility and stability, both them had been applied for biological sample analysis with satisfactory results. The results show that the p-FWCNTs/Thionine/Au electrode can work as an ideal platform for the development of highly sensitive sensors, coupled with p-FWCNTs are rich in functional groups could be used for fabricating diverse sensors. PMID- 25286356 TI - Mechanistic insight into aerobic alcohol oxidation using NOx-nitroxide catalysis based on catalyst structure-activity relationships. AB - The mechanism of an NOx-assisted, nitroxide(nitroxyl radical)-catalyzed aerobic oxidation of alcohols was investigated using a set of sterically and electronically modified nitroxides (i.e., TEMPO, AZADO (1), 5-F-AZADO (2), 5,7 DiF-AZADO (3), 5-MeO-AZADO (4), 5,7-DiMeO-AZADO (5), oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8)). The motivation for the present study stemmed from our previous observation that the introduction of an F atom at a remote position from the nitroxyl radical moiety on the azaadamantane nucleus effectively enhanced the catalytic activity under typical NOx-mediated aerobic-oxidation conditions. The kinetic profiles of the azaadamantane-N-oxyl-[AZADO (1)-, 5-F-AZADO (2)-, and 5,7 DiF-AZADO (3)]-catalyzed aerobic oxidations were closely investigated, revealing that AZADO (1) showed a high initial reaction rate compared to 5-F-AZADO (2) and 5,7-DiF-AZADO (3); however, AZADO-catalyzed oxidation exhibited a marked slowdown, resulting in ~90% conversion, whereas 5-F-AZADO-catalyzed oxidation smoothly reached completion without a marked slowdown. The reasons for the marked slowdown and the role of the fluoro group are discussed. Oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8) were designed and synthesized to confirm their comparable catalytic efficiency to that of 5-F-AZADO (2), providing supporting evidence for the electronic effect on the catalytic efficiency of the heteroatoms under NOx assisted aerobic-oxidation conditions. PMID- 25286358 TI - Current levels and composition profiles of emerging halogenated flame retardants and dehalogenated products in sewage sludge from municipal wastewater treatment plants in China. AB - Occurrence of new toxic chemicals in sludge from wastewater treatment plants (WWTPs) is of concern for the environment and human health. Alternative halogenated flame retardants (HFRs) are a group of potentially harmful organic contaminants in the environment. In this study, a nationwide survey was carried out to identify the occurrence of HFRs and their potential dehalogenated products in sewage sludge from 62 WWTPs in China. Of all 20 target chemicals analyzed, decabromodiphenyl ethane (DBDPE), hexabromocyclododecane (HBCD) and 1, 2-bis (2,4,6-tribromophenoxy)-ethane (BTBPE) were detected in all sludge samples, and the concentrations were in the range of 0.82-215, 0.09-65.8, and 0.10-2.26 ng g( 1) d.w., respectively. Dechlorane Plus (DP) was found in 60 of 62 samples, and the concentration ranged from nd-298 ng g(-1) with a mean of 18.9 ng g(-1) d.w. The anti-DP fractional abundance fanti (0.79) in the samples was much higher than the commercial DP composition (fanti=0.59), indicating a stereoselective degradation. Comparison with global sludge concentrations of HFRs indicate that China is at the medium pollution level in the world. Principal components analysis revealed that strong correlations existed between ln-transformed concentrations (natural logarithm) of the dominant BFRs and total organic carbon (TOC) as well as industrial wastewater proportion, influent volume and serving population. Significant linear relationships (R=0.360-0.893, p<0.01) were found among emerging brominated flame retardants (BFRs), suggesting their common commercial applications and release sources to the environment. Two kinds of dehalogenated products, pentabromocyclododecane (PBCD) and undecachloropentacyclooctadecadiene (Cl11-DP), derived from HBCD and DP, were also identified in sewage sludge for the first time. PMID- 25286359 TI - Targeting cardiac hypertrophy: toward a causal heart failure therapy. AB - Cardiac hypertrophy is commonly observed in conditions of increased hemodynamic or metabolic stress. This hypertrophy is not compensatory but rather reflects activation of maladaptive cellular processes that promote disease progression. Myocardial hypertrophy serves as a diagnostic and prognostic marker of cardiac remodeling, and underlying regulatory processes have provided effective therapeutic targets to slow disease progression and improve outcome. We review hypertrophic signaling pathways in cardiomyocytes and discuss established and novel targets for pharmacological intervention. New drugs in the pipeline include the third generation aldosterone antagonists (PF-03882845 and BAY94-8862) and biased angiotensin II receptor agonists. Furthermore, different approaches to stimulate cGMP-dependent protective signaling are currently evaluated in clinical trials, including the combination of the vasopeptidase neprilysin inhibitor and an angiotensin receptor blocker (ARNi). In an overview on cardiomyocyte hypertrophic signaling, we also highlight emerging experimental treatment concepts such as inhibition of Ca-mediated transcriptional regulation, adeno associated viruses for sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), PI3 kinase gene transfer and microRNA-based therapy. We conclude that antihypertrophic therapy extends beyond blocking the classical beta-adrenergic and renin-angiotensin-aldosterone system-dependent signaling cascades, although new therapies require clinical validation regarding outcome. PMID- 25286360 TI - Activation of IK1 channel by zacopride attenuates left ventricular remodeling in rats with myocardial infarction. AB - Activating IK1 channels is considered to be a promising antiarrhythmic strategy. Zacopride has been identified as a selective IK1 channel agonist and can suppress triggered arrhythmias. Whether this drug also exerts a beneficial effect on cardiac remodeling is unknown, and the present study sought to address this question. Cardiac remodeling was induced through coronary ligation-induced myocardial infarction (MI) in male Sprague-Dawley rats. Zacopride (15 ug/kg) was administered (intraperitoneally) daily for 28 days after MI to determine whether it could attenuate MI-induced cardiac remodeling. A 4-week treatment with zacopride attenuated post-MI cardiac remodeling, as shown by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension and the increased ejection fraction and fractional shortening in zacopride treated animals compared with animals treated with vehicle (all P < 0.05). Furthermore, zacopride significantly decreased myocardial collagen deposition, cardiomyocyte hypertrophy, the plasma level of brain natriuretic peptide, and cardiomyocyte ultrastructural injury. Zacopride also upregulated the expression of the IK1 channel protein and downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. These beneficial effects of zacopride were partially abolished by the IK1 channel blocker chloroquine. We conclude that the activation of IK1 channel by zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling. PMID- 25286361 TI - Effects of PP1-12, a novel protein phosphatase-1 inhibitor, on ventricular function and remodeling after myocardial infarction in rats. AB - : PP1-12, a new protein phosphatase-1 inhibitor, is designed and synthesized to modulate the endoplasmic reticulum (ER) stress apoptotic pathway, which is involved in various cardiovascular diseases. In this study, we examined the effect of PP1-12 on ventricular remodeling and heart function after myocardial infarction. Rats that survived within 24 hours after coronary ligation were randomly divided into 6 groups and treated with normal saline, vehicle, PP1-12 at 1, 3, and 10 mg.kg.d and perindopril at 2 mg.kg.d for 4 weeks, respectively. At the end of the follow-up point, we evaluated echocardiographic and hemodynamic parameters, myocardial pathomorphology, apoptosis, and interstitial fibrosis, as well as the expression levels of important proteins involved in ER stress and apoptosis. Left ventricular geometry and function were ameliorated by PP1-12. PP1 12 inhibited interstitial fibrosis and reduced apoptosis of cardiomyocytes in a dose-dependent manner. PP1-12 decreased GRP78 and caspase-12 expression and increased p-eIF2alpha and Bcl-2/Bax expression. These results suggest that PP1-12 efficiently inhibits left ventricular remodeling and improves heart function. The mechanism involved may be associated with the ability of PP1-12 to depress myocardial apoptosis induced by ER stress. PMID- 25286363 TI - Study of cytochrome c-DNA interaction--evaluation of binding sites on the redox protein. AB - Artificial assemblies consisting of the cationic cytochrome c (cyt c) and double stranded DNA are interesting for the field of biohybrid systems because of the high electro-activity of the incorporated redox protein. However, little is known about the interactions between these two biomolecules. Here, the complex of reduced cyt c and a 41 base pair oligonucleotide was characterized in solution as a function of pH and ionic strength. Persistent cyt c-DNA agglomerates were observed by UV-vis and DLS (dynamic light scattering) at pH 5.0 and low ionic strength. The strength of the interaction was attenuated by raising the pH or the ionic strength. At pH 7.0 agglomerates were not formed, allowing interaction analysis by NMR spectroscopy. Using TROSY (transverse relaxation-optimized spectroscopy)-HSQC (heteronuclear single quantum coherence) experiments it was possible to identify the DNA binding site on the cyt c surface. Numerous residues surrounding the exposed heme edge of cyt c were involved in transient binding to DNA under these conditions. This result was supported by SEC (size exclusion chromatography) experiments at pH 7.0 showing that the interaction is sufficient for co-elution of cyt c and DNA. PMID- 25286362 TI - Effects of extreme climate events on tea (Camellia sinensis) functional quality validate indigenous farmer knowledge and sensory preferences in tropical China. AB - Climate change is impacting agro-ecosystems, crops, and farmer livelihoods in communities worldwide. While it is well understood that more frequent and intense climate events in many areas are resulting in a decline in crop yields, the impact on crop quality is less acknowledged, yet it is critical for food systems that benefit both farmers and consumers through high-quality products. This study examines tea (Camellia sinensis; Theaceae), the world's most widely consumed beverage after water, as a study system to measure effects of seasonal precipitation variability on crop functional quality and associated farmer knowledge, preferences, and livelihoods. Sampling was conducted in a major tea producing area of China during an extreme drought through the onset of the East Asian Monsoon in order to capture effects of extreme climate events that are likely to become more frequent with climate change. Compared to the spring drought, tea growth during the monsoon period was up to 50% higher. Concurrently, concentrations of catechin and methylxanthine secondary metabolites, major compounds that determine tea functional quality, were up to 50% lower during the monsoon while total phenolic concentrations and antioxidant activity increased. The inverse relationship between tea growth and concentrations of individual secondary metabolites suggests a dilution effect of precipitation on tea quality. The decrease in concentrations of tea secondary metabolites was accompanied by reduced farmer preference on the basis of sensory characteristics as well as a decline of up to 50% in household income from tea sales. Farmer surveys indicate a high degree of agreement regarding climate patterns and the effects of precipitation on tea yields and quality. Extrapolating findings from this seasonal study to long-term climate scenario projections suggests that farmers and consumers face variable implications with forecasted precipitation scenarios and calls for research on management practices to facilitate climate adaptation for sustainable crop production. PMID- 25286364 TI - Synthesis of S,S,O-orthoesters and 1,1-difluoroalkyl ethers via reaction of peroxides with lithiated 1,3-dithianes. AB - Alkyl tetrahydropyranyl peroxides (ROOTHP) transfer alkoxide (OR) to lithiated 1,3-dithianes. The derived S,S,O-orthoesters undergo fluorodesulfurization with HF/pyridine and N-bromosuccinamide (NBS) to furnish difluoromethyl ethers. The overall protocol can be applied to synthesis of both terminal (ROCF2H) and internal (ROCF2R') ethers. Application of the same set of reactions to a lithiated tris(alkylthio)alkane is shown to generate a trifluoromethyl ether. PMID- 25286365 TI - Family history day: beyond talking turkey. PMID- 25286366 TI - Advance directives: empowering patients at the end of life. AB - Advance directives were conceived as a prospective means of empowering patients to direct their own end-of-life care. Unfortunately, these directives have been inadequately incorporated into healthcare decisions due to less-than-optimal execution and implementation. The authors explore challenges to implementing advance directives and propose potential solutions. PMID- 25286367 TI - Pediatric migraine: common, yet treatable. AB - Migraine headache is a common problem among children and adolescents that is now recognized as a significant and often debilitating condition in this population. Improved recognition and management of pediatric migraine in primary care is necessary, as there is a knowledge gap in understanding the unique features of this condition and a general reluctance to treat children. PMID- 25286368 TI - Preventing pre-eclampsia - are dietary factors the key? AB - Pre-eclampsia is a common pregnancy related condition, which contributes significantly both to maternal and perinatal morbidity and mortality. The precise pathophysiology of pre-eclampsia is uncertain, and the development of effective preventive strategies remains elusive. Schoenaker and colleagues conducted a systematic review and meta-analysis of observational studies reporting dietary intake and dietary patterns. The findings indicated that women with a low dietary calcium intake were more likely to be diagnosed with gestational hypertension, while there was a suggestion (although not statistically significant) of a beneficial effect of a diet rich in fruits and vegetables on risk of pre eclampsia. This is in contrast to the findings of systematic reviews and meta analyses of randomised trials in pregnancy evaluating calcium supplementation and anti-oxidant vitamin C and E supplementation. The validity of any systematic review is reliant on both the underlying methodology and the quality of each of the included studies; the review by Schoenaker and colleagues is limited by the observational nature of the included studies.Please see related article: http://www.biomedcentral.com/1741-7015/12/157/abstract. PMID- 25286369 TI - Aphrodisiac use associated with HIV infection in elderly male clients of low-cost commercial sex venues in Guangxi, China: a matched case-control study. AB - BACKGROUND: Rising HIV infection rates have been observed among elderly people in Guangxi, China. Inexpensive aphrodisiacs are available for purchase in suburban and rural areas. This study aims to investigate the association between aphrodisiac use and increased HIV risk for middle-aged and elderly men in Guangxi. METHODS: A matched case-control study of aphrodisiac use-associated HIV infection was performed among male subjects over 50 years old who were clients of low-cost commercial sex venues in Guangxi. The cases were defined as clients who were HIV-positive and two controls were selected for each case. The cases and the controls were matched on the visited sex venue, age (+/-3 years), number of years of purchasing sex (+/-3 years), and educational attainment. Subjects were interviewed and tested for HIV. Paired t-test or McNemar Chi-squared test were used to compare the characteristics between the cases and controls. A stepwise conditional logistic regression was used to identify risk factors associated with HIV infection. FINDINGS: This study enrolled 103 cases and 206 controls. Aphrodisiac use (P = 0.02, odds ratio (OR) = 1.81, 95% CI = 1.08-3.04), never using condom during commercial sex encounter (P = 0.03, odds ratio (OR) = 1.82, 95% CI = 1.08-3.07), and lacking a stable partner (P = 0.03, odds ratio (OR) = 1.76, 95% CI = 1.05-2.98) were found to be risk factors for HIV infection among the study groups. For subjects reporting aphrodisiac use, the frequency of purchasing sex was positively correlated with the frequency of aphrodisiac use (r = 0.3; p = 0.02). CONCLUSIONS: Aphrodisiac use was significantly associated with increased HIV infection risk in men over 50 years old who purchased commercial sex in the suburban and rural areas of Guangxi. Further research and interventions should address the links between aphrodisiac use, commercial sex work, condom use, and increased HIV transmission. PMID- 25286371 TI - The modal suicide decedent did not consume alcohol just prior to the time of death: An analysis with implications for understanding suicidal behavior. AB - We identified and analyzed a total of 92 studies, representing 167,894 suicide decedents, to determine if there is evidence to support what appears to be a widely held cultural, clinical, and scholarly view that many people who die by suicide had been drinking at the time of death. It was determined that, based on weighted averages, approximately 27% of suicide decedents had above-zero blood alcohol concentrations (BACs) at the time of death. We emphasize that it was not 27% who were intoxicated at the time of death; rather, 27% had above-zero BACs and 73% had BACs of 0.00%. Among studies of suicide decedents, BACs differed as a function of race (higher in non-White individuals). We conclude that the role of alcohol use at the time of death may be less than some assume, and this interpretation can inform clinical practice and theories of suicide. Important unanswered questions are posed which will help refine research in this area going forward. PMID- 25286372 TI - Performance monitoring in obsessive-compulsive disorder and social anxiety disorder. AB - Overactive performance monitoring, indexed by greater error-related brain activity, has been frequently observed in individuals with obsessive-compulsive disorder (OCD). Similar alterations have been found in individuals with major depressive and generalized anxiety disorders. The main objective was to extend these findings by investigating performance monitoring in individuals with social anxiety disorder (SAD) and to evaluate the specificity of performance-monitoring changes in OCD. Event-related potentials were used to examine error-related brain activity during a flanker task in 24 individuals with OCD, 24 individuals with SAD, and 24 healthy controls with no history of neurological or psychiatric disorders. Error-related negativity (ERN) and correct-related negativity served as electrophysiological indicators for performance monitoring. Enhanced ERN was expected for both clinical groups, but differential associations with clinical symptoms were explored. ERN amplitudes were larger in individuals with OCD and SAD than in healthy controls. Correlational analyses did not reveal significant associations between ERN and clinical symptomatology in OCD, but a significant correlation with depressive symptoms was found in the SAD group. These findings further strengthen the idea that overactive performance monitoring is independent of clinical symptoms in OCD. Furthermore, it may also represent a transdiagnostic vulnerability indicator, although the relationship with clinical symptoms observed in the SAD group needs additional evaluation. PMID- 25286370 TI - Computational systems biology approaches to anti-angiogenic cancer therapeutics. AB - Angiogenesis is an exquisitely regulated process that is required for physiological processes and is also important in numerous diseases. Tumors utilize angiogenesis to generate the vascular network needed to supply the cancer cells with nutrients and oxygen, and many cancer drugs aim to inhibit tumor angiogenesis. Anti-angiogenic therapy involves inhibiting multiple cell types, molecular targets, and intracellular signaling pathways. Computational tools are useful in guiding treatment strategies, predicting the response to treatment, and identifying new targets of interest. Here, we describe progress that has been made in applying mathematical modeling and bioinformatics approaches to study anti-angiogenic therapeutics in cancer. PMID- 25286373 TI - The temporal relationship between posttraumatic stress disorder and problem alcohol use following traumatic injury. AB - Chronic alcohol abuse is a major public health concern following trauma exposure; however, little is known about the temporal association between posttraumatic stress disorder (PTSD) symptoms and problem alcohol use. The current study examined the temporal relationship between PTSD symptom clusters (re experiencing, effortful avoidance, emotional numbing, and hyperarousal) and problem alcohol use following trauma exposure. This study was a longitudinal survey of randomly selected traumatic injury patients interviewed at baseline, 3 months, 12 months, and 24 months following injury. Participants were 1,139 injury patients recruited upon admission from 4 Level 1 trauma centers across Australia. Participants were assessed using the Clinician Administered PTSD Scale and Alcohol Use Disorders Identification Test. Results indicated that high levels of re-experiencing, effortful avoidance, and hyperarousal symptoms at 12 months were associated with greater increases (or smaller decreases) in problem alcohol use between 12 and 24 months. Findings also suggested that high levels of problem alcohol use at 12 months were associated with greater increases (or smaller decreases) in emotional numbing symptoms between 12 and 24 months. These findings highlight the critical importance of the chronic period following trauma exposure in the relationship between PTSD symptoms and problem alcohol use. PMID- 25286374 TI - Long-term results of multiple arterial bypass conduits. AB - PURPOSE OF REVIEW: Ongoing efforts to compare percutaneous coronary intervention with coronary bypass surgery for multivessel coronary disease mandate that surgeons reevaluate best practices for coronary surgery in order to maximize long term outcomes. This review presents recent data for the long-term outcomes of multiple arterial grafting in terms of patient selection, conduit choice, and technical considerations. RECENT FINDINGS: Multiple arterial grafting remains poorly utilized, with fewer than 10% of cases receiving more than one arterial graft. Bilateral internal thoracic artery grafting confers superior long-term survival and freedom from reoperation over single thoracic artery with saphenous vein. Use of a second internal thoracic artery graft is advantageous in diabetic patients despite higher risk of sternal wound complications. Routine use of skeletonized grafts and Y or T grafting to allow complete revascularization allows lower early complication rates and better long-term survival. Radial artery grafts confer superior long-term survival compared with saphenous vein grafts and should be considered in patients at high risk for sternal wound complications. SUMMARY: Multiple arterial grafting confers superior long-term outcomes in comparison with single internal thoracic artery grafting and should be considered as the standard of care. PMID- 25286376 TI - Na,K-ATPase reconstituted in ternary liposome: the presence of cholesterol affects protein activity and thermal stability. AB - Differential scanning calorimetry (DSC) was applied to investigate the effect of cholesterol on the thermotropic properties of the lipid membrane (DPPC and DPPE). The thermostability and unfolding of solubilized and reconstituted Na,K-ATPase in DPPC:DPPE:cholesterol-liposomes was also studied to gain insight into the role of cholesterol in the Na,K-ATPase modulation of enzyme function and activity. The tertiary system (DPPC:DPPE:cholesterol) (molar ratio DPPC:DPPE equal 1:1) when cholesterol content was increased from 0% up to 40% results in a slight decrease in the temperature of transition and enthalpy, and an increase in width. We observed that, without heating treatment, at 37 degrees C, the activity was higher for 20mol% cholesterol. However, thermal inactivation experiments showed that the enzyme activity loss time depends on the cholesterol membrane content. The unfolding of the enzyme incorporated to liposomes of DPPC:DPPE (1:1mol) with different cholesterol contents, ranging from 0% to 40% mol was also studied by DSC. Some differences between the thermograms indicate that the presence of lipids promotes a conformational change in protein structure and this change is enough to change the way Na,K-ATPase thermally unfolds. PMID- 25286377 TI - Lessons from chlorophylls: modifications of porphyrinoids towards optimized solar energy conversion. AB - Practical applications of photosynthesis-inspired processes depend on a thorough understanding of the structures and physiochemical features of pigment molecules such as chlorophylls and bacteriochlorophylls. Consequently, the major structural features of these pigments have been systematically examined as to how they influence the S1 state energy, lifetimes, quantum yields, and pigment photostability. In particular, the effects of the macrocyclic pi-electron system, central metal ion (CMI), peripheral substituents, and pigment aggregation, on these critical parameters are discussed. The results obtained confirm that the pi electron system of the chromophore has the greatest influence on the light energy conversion capacity of porphyrinoids. Its modifications lead to changes in molecular symmetry, which determine the energy levels of frontier orbitals and hence affect the S1 state properties. In the case of bacteriochlorophylls aggregation can also strongly decrease the S1 energy. The CMI may be considered as another influential structural feature which only moderately influences the ground-state properties of bacteriochlorophylls but strongly affects the singlet excited-state. An introduction of CMIs heavier than Mg2+ significantly improves pigments' photostabilities, however, at the expense of S1 state lifetime. Modifications of the peripheral substituents may also influence the S1 energy, and pigments' redox potentials, which in turn influence their photostability. PMID- 25286378 TI - "Mixed-charge self-assembled monolayers" as a facile method to design pH-induced aggregation of large gold nanoparticles for near-infrared photothermal cancer therapy. AB - The acidic microenvironment of tumor tissues has proven to be one of the major differences from other normal tissues. The near-infrared (NIR) light irradiation of aggregated gold nanoparticles in a tumor acidic pH-induced manner could then provide an effect approach to treat solid tumors with the advantage of minimizing the undesired damage to normal tissues. Although it is well-known the aggregation of larger nanoparticles will result in a better NIR photothermal effect, the preparation of pH-sensitive gold nanoparticles in large sizes remains a big challenge because of their worse dispersive stability. In this paper, we introduce a facile way to endow large gold nanoparticles with tunable pH aggregation behaviors by modifying the nanoparticle surface with mixed-charge self-assembly monolayers compromising positively and negatively charged thiol ligands. Four different size nanoparticles were used to study the general principle of tailoring the pH-induced aggregation behaviors of mixed-charge gold nanoparticles (MC-GNPs) by adjusting the surface ligand composition. With proper surface ligand composition, the MC-GNPs in four different sizes that all exhibited aggregation at tumor acidic pH were obtained. The biggest MC-GNPs showed the most encouraging aggregation-enhanced photothermal efficacy in vitro when they formed aggregates. The mixed-charge self-assembled monolayers were then proved as a facile method to design pH-induced aggregation of large gold nanoparticles for better NIR photothermal cancer therapy. PMID- 25286379 TI - Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases. AB - Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non transformed cell lines. Our results suggest that increased generation of misfolded proteasome substrates may contribute to the mechanism(s) underlying the increased sensitivity of tumor cells to inhibitors of the ubiquitin-proteasome system. PMID- 25286381 TI - Gene expression changes during Giardia-host cell interactions in serum-free medium. AB - Serial Analysis of Gene Expression (SAGE) was used to quantify transcriptional changes in Giardia intestinalis during its interaction with human intestinal epithelial cells (IECs, HT-29) in serum free M199 medium. Transcriptional changes were compared to those in trophozoites alone in M199 and in TYI-S-33 Giardia growth medium. In total, 90 genes were differentially expressed, mainly those involved in cellular redox homeostasis, metabolism and small molecule transport but also cysteine proteases and structural proteins of the giardin family. Only 29 genes changed their expression due to IEC interaction and the rest were due to M199 medium. Although our findings generated a small dataset, it was consistent with our earlier microarray studies performed under different interaction conditions. This study has confined the number of genes in Giardia to a small subset that specifically change their expression due to interaction with IECs. PMID- 25286380 TI - Reproducibility of functional connectivity and graph measures based on the phase lag index (PLI) and weighted phase lag index (wPLI) derived from high resolution EEG. AB - Functional connectivity (FC) and graph measures provide powerful means to analyze complex networks. The current study determines the inter-subject-variability using the coefficient of variation (CoV) and long-term test-retest-reliability (TRT) using the intra-class correlation coefficient (ICC) in 44 healthy subjects with 35 having a follow-up at years 1 and 2. FC was estimated from 256-channel EEG by the phase-lag-index (PLI) and weighted PLI (wPLI) during an eyes-closed resting state condition. PLI quantifies the asymmetry of the distribution of instantaneous phase differences of two time-series and signifies, whether a consistent non-zero phase lag exists. WPLI extends the PLI by additionally accounting for the magnitude of the phase difference. Signal-space global and regional PLI/wPLI and weighted first-order graph measures, i.e. normalized clustering coefficient (gamma), normalized average path length (lambda), and the small-world-index (SWI) were calculated for theta-, alpha1-, alpha2- and beta frequency bands. Inter-subject variability of global PLI was low to moderate over frequency bands (0.12Pyr), the application of S-nitroso-N-acetyl-dl penicillamine (SNAP, 100 MUM), an NO donor, suppressed uIPSC amplitudes in 31% of the connections, whereas 39% of the connections showed uIPSC facilitation. The remaining FS->Pyr connections showed little effect of SNAP on uIPSCs. An analysis of paired-pulse ratio (PPR) implied the involvement of presynaptic mechanisms in SNAP-induced effects on uIPSCs. Similar effects of SNAP were observed in FS >FS/non-FS connections; 33%, 54%, and 13% of the connections were facilitated, suppressed, and unchanged, respectively. In contrast, non-FS->Pyr or FS/non-FS showed constant uIPSC suppression by SNAP. PPR analysis supports the hypothesis that these SNAP-induced effects are mediated by presynaptic mechanisms in FS >FS/non-FS and non-FS->Pyr/FS/non-FS connections. The NO scavenger, 2-phenyl 4,4,5,5-tetramethylimidazolineoxyl-1-oxyl-3-oxide (PTIO), or the inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), abolished the SNAP-induced uIPSC modulation. These results suggest that NO regulation of inhibitory synaptic transmission is dependent on presynaptic cell subtypes and that, at least in part, the effects are mediated by presynaptic mechanisms. PMID- 25286389 TI - Improving Trichoderma reesei Cel7B thermostability by targeting the weak spots. AB - For proteins that denature irreversibly, the denaturation is typically triggered by a partial unfolding, followed by a permanent change (e.g., aggregation). The regions that initiate the partial unfolding are named "weak spots". In this work, a molecular dynamics (MD) simulation and data analysis protocol is developed to identify the weak spots of Trichoderma reesei Cel7B, an important endoglucanase in cellulose hydrolysis, through assigning the local melting temperature (Tmp) to individual residue pairs. To test the predicted weak spots, a total of eight disulfide bonds were designed in these regions and all enhanced the enzyme thermostability. The increased stability, quantified by DeltaT50 (which is the T50 difference between the mutant and the wild type enzyme), is negatively correlated with the MD-predicted Tmp, demonstrating the effectiveness of the protocol and highlighting the importance of the weak spots. Strengthening interactions in these regions proves to be a useful strategy in improving the thermostability of Tr. Cel7B. PMID- 25286390 TI - Simultaneous measurement of tabun, sarin, soman, cyclosarin, VR, VX, and VM adducts to tyrosine in blood products by isotope dilution UHPLC-MS/MS. AB - This work describes a new specific, sensitive, and rapid stable isotope dilution method for the simultaneous detection of the organophosphorus nerve agents (OPNAs) tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), VR, VX, and VM adducts to tyrosine (Tyr). Serum, plasma, and lysed whole blood samples (50 MUL) were prepared by protein precipitation followed by digestion with Pronase. Specific Tyr adducts were isolated from the digest by a single solid phase extraction (SPE) step, and the analytes were separated by reversed-phase ultra high performance liquid chromatography (UHPLC) gradient elution in less than 2 min. Detection was performed on a triple quadrupole tandem mass spectrometer using time-triggered selected reaction monitoring (SRM) in positive electrospray ionization (ESI) mode. The calibration range was characterized from 0.100-50.0 ng/mL for GB- and VR-Tyr and 0.250-50.0 ng/mL for GA-, GD-, GF-, and VX/VM-Tyr (R(2) >= 0.995). Inter- and intra-assay precision had coefficients of variation of <=17 and <=10%, respectively, and the measured concentration accuracies of spiked samples were within 15% of the targeted value for multiple spiking levels. The limit of detection was calculated to be 0.097, 0.027, 0.018, 0.074, 0.023, and 0.083 ng/mL for GA-, GB-, GD-, GF-, VR-, and VX/VM-Tyr, respectively. A convenience set of 96 serum samples with no known nerve agent exposure was screened and revealed no baseline values or potential interferences. This method provides a simple and highly specific diagnostic tool that may extend the time postevent that a confirmation of nerve agent exposure can be made with confidence. PMID- 25286391 TI - Meta-analysis of associations of IL1 receptor antagonist and estrogen receptor gene polymorphisms with systemic lupus erythematosus susceptibility. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that affects a number of different organs and tissues. Interleukin-1 (IL1) and estrogen are considered potential elements in the pathology of SLE. Recently, the variable number of tandem repeats (VNTR) polymorphism in the IL1 receptor antagonist gene (IL1-RN) and PvuII (rs2234693) and XbaI (rs9340799) polymorphisms in the estrogen receptor 1 gene (ESR1) have been associated with a predisposition to SLE. However, the evidence for these associations is inconclusive. We therefore conducted a meta analysis to validate the roles of these polymorphisms in SLE susceptibility. We searched four databases and identified a total of 17 eligible articles comprising 24 studies. The Newcastle-Ottawa quality assessment scale was used to assess the qualities of the selected studies. We assessed the strengths of the associations using odds ratios (ORs) with 95% confidence intervals (95% CIs). Regarding the IL 1RN VNTR, the 2 allele significantly increased SLE susceptibility (2 vs. L: OR = 1.34, 95% CI = 1.03-1.73, P = 0.03). The ESR1 PvuII CC/CT genotype was also associated with SLE susceptibility (CC/CT vs. TT: OR = 1.25, 95% CI = 1.06-1.47, P = 0.01), and the difference was especially pronounced among Asians (CC/CT vs. TT: OR = 1.33, 95% CI = 1.04-1.69, P = 0.02). No significant association between the ESR1 XbaI polymorphism and SLE susceptibility was observed in the overall analysis. However, a marginally significant association between the GG/GA genotype was found in individuals of Asian descent (GG/GA vs. AA: OR = 1.30, 95% CI = 1.01-1.67, P = 0.04). These results indicate that the IL1-RN VNTR 2 allele, ESR1 PvuII CC/CT genotype and ESR1 XbaI GG/GA genotype may increase SLE susceptibility, especially in Asian individuals. PMID- 25286392 TI - Thirdhand cigarette smoke: factors affecting exposure and remediation. AB - Thirdhand smoke (THS) refers to components of secondhand smoke that stick to indoor surfaces and persist in the environment. Little is known about exposure levels and possible remediation measures to reduce potential exposure in contaminated areas. This study deals with the effect of aging on THS components and evaluates possible exposure levels and remediation measures. We investigated the concentration of nicotine, five nicotine related alkaloids, and three tobacco specific nitrosamines (TSNAs) in smoke exposed fabrics. Two different extraction methods were used. Cotton terry cloth and polyester fleece were exposed to smoke in controlled laboratory conditions and aged before extraction. Liquid chromatography-tandem mass spectrometry was used for chemical analysis. Fabrics aged for 19 months after smoke exposure retained significant amounts of THS chemicals. During aqueous extraction, cotton cloth released about 41 times as much nicotine and about 78 times the amount of tobacco specific nitrosamines (TSNAs) as polyester after one hour of aqueous extraction. Concentrations of nicotine and TSNAs in extracts of terry cloth exposed to smoke were used to estimate infant/toddler oral exposure and adult dermal exposure to THS. Nicotine exposure from THS residue can be 6.8 times higher in toddlers and 24 times higher in adults and TSNA exposure can be 16 times higher in toddlers and 56 times higher in adults than what would be inhaled by a passive smoker. In addition to providing exposure estimates, our data could be useful in developing remediation strategies and in framing public health policies for indoor environments with THS. PMID- 25286394 TI - Decahydroquinolines from the venom of a formicinae ant, Oecophylla smaragdina. AB - Ecologically significant species in controlling pests, Oecophylla smaragdina uses its venom to paralyze their prey and to communicate with their colony mates. But no significant analysis of the ant's venom gland secretions has been carried out hitherto. This study describes the identification of venom constituents of Oecophylla smaragdina using coupled gas chromatography and mass spectroscopy (GC MS) analysis. The results indicate the anticipated presence of a neurotoxin i.e., 2, 5 dipropyl decahydroquinoline and phenol, 2, 4-bis (1, 1 dimethylethyl). This is the first report on presence of decahydroquinolines in the venom of formicinae ant species of genera Oecophylla. PMID- 25286393 TI - Mechanisms of GOLPH3 associated with the progression of gastric cancer: a preliminary study. AB - STUDY DESIGN: To investigate the specific mechanisms by which Golgi phosphoprotein 3 (GOLPH3) affects the progression of gastric cancer and to explore its clinical significance. METHODS: Immunohistochemical analysis was used to evaluate the correlations between GOLPH3, phosphorylated mTOR (p-mTOR), phosphorylated Akt (p-Akt), phosphorylated p70S6 (p-p70S6), phosphorylated 4E-BP1 (p-4E-BP1) and the clinicopathological features of gastric cancer. The mRNA expression levels of GOLPH3, mTOR, Akt, p70S6 and 4E-BP1 in gastric cancer, carcinoma-adjacent and paired normal tissue were analyzed using RT-PCR. Western blotting was used to determine the protein expression of GOLPH3, p-mTOR, p-Akt, p p70S6 and p-4E-BP1 in tissues. RESULTS: High expression protein levels of GOLPH3, p-AKT, p-mTOR, p70S6, p-4E-BP1 were positively associated with histological grade (p<0.05), depth of invasion (p<0.05), distant metastasis (p<0.05) and lymph node involvement (p<0.05). Compared with carcinoma-adjacent and paired normal tissues, the mRNA expression levels of GOLPH3, AKT, mTOR, p70S6 and 4EBP1 in gastric cancer tissues were significantly higher. The protein expression levels of GOLPH3, p-AKT, p-mTOR, p-p70S6 and p-4E-BP1 in gastric cancer tissues were also significantly higher than in carcinoma-adjacent and paired normal tissues. A strong positive correlation was observed between GOLPH3, p-mTOR, p-p70S6 and p 4EBP1 expression (r = 0.410, 0.303 and 0.276, respectively, p<0.05), but no significant correlation between the expression of GOLPH3 and p-Akt was observed. CONCLUSIONS: The GOPLH3 expression level is highly correlated with Akt/mTOR signaling in human gastric cancer samples. GOLPH3 combined with Akt/mTOR signaling activation may play an important role in the development, differentiation, invasion and metastasis of gastric cancer. PMID- 25286395 TI - Toxin and species identification of toxic octopus implicated into food poisoning in Taiwan. AB - A food poisoning incident due to ingestion of unknown octopus occurred in Taipei in December, 2010. The serum and urine from victims (male 38 and 43 years old) were collected, determined the toxicity, and identified tetrodotoxin (TTX) by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). It was found that only urine contained the trace of TTX. Then, two retained specimen (one without blue ring in the skin and another with small blue ring in the skin) were collected from victims and examined for the toxicity and toxin. Meanwhile, 6 specimens of octopus without blue ring in the skin and 4 specimens of octopus with blue ring in the skin were re-collected from the market. Both retained octopus samples were found to contain TTX. However, re-collected market's octopus without blue ring in the skin did not show to contain TTX the and was identified as Octopus aegina by using the analysis of cytochrome b gene (Cyt b) and cytochrome c oxidase subunit I gene (COI). Only octopus with blue ring in the skin contained TTX and was identified as Hapalochlaena fasciata by using the analysis of Cyt b and COI. Therefore, this octopus food poisoning was caused by toxic octopus H. fasciata and the causative agent was TTX. PMID- 25286397 TI - Bioactive toxins from stinging jellyfish. AB - Jellyfish blooms occur throughout the world. Human contact with a jellyfish induces a local reaction of the skin, which can be painful and leave scaring. Systemic symptoms are also observed and contact with some species is lethal. A number of studies have evaluated the in vitro biological activity of whole jellyfish venom or of purified fractions. Hemolytic, cytotoxic, neurotoxic or enzymatic activities are commonly observed. Some toxins have been purified and characterized. A family of pore forming toxins specific to Medusozoans has been identified. There remains a need for detailed characterization of jellyfish toxins to fully understand the symptoms observed in vivo. PMID- 25286398 TI - PbS sensitized TiO2 nanotube arrays with different sizes and filling degrees for enhancing photoelectrochemical properties. AB - PbS nanoparticles (PbS NPs), an efficient sensitizer for TiO2 nanotube arrays (TiO2 NAs), were fabricated by the method of sonication-assisted successive ionic layer adsorption and reaction (SILAR). The filling degree and size of PbS NPs can be tuned by changing the repeated cycles (N) of the SILAR process. TiO2 NAs can be fully covered with PbS NPs with a size ranging from less than 4 nm to 25 nm and large aggregates inside and outside the nanotubes when N reaches 15. The growth mechanism of PbS NPs in TiO2 NAs was expounded in great detail in this work. Ultraviolet-visible diffuse-reflectance spectra and surface photovoltage spectroscopy were used to investigate the light absorption properties and the transfer behavior of photogenerated charges in PbS-modified TiO2 NA heterostructures. Results show that the absorption range of TiO2 NAs is extended from the ultraviolet to the visible region by PbS NPs modification. A heterojunction is formed between PbS NPs and TiO2 NAs, facilitating the separation of photogenerated charge carriers. This PbS NPs fully-covered TiO2 NA electrode exhibits the best photoelectrochemical performance in all PbS sensitized TiO2 NA electrodes, due to a larger number of small PbS NPs (<4 nm). With AM 1.5G illumination at 100 mW cm(-2), its short-circuit current density, open-circuit voltage and photoelectric conversion efficiency are 9.55 mA cm(-2), 0.95 V and 2.83%, respectively. PMID- 25286396 TI - In vitro chronic effects on hERG channel caused by the marine biotoxin azaspiracid-2. AB - Azaspiracids (AZAs) are marine biotoxins produced by the dinoflagellate Azadinium spinosum that accumulate in many shellfish species. Azaspiracid poisoning caused by AZA-contaminated seafood consumption is primarily manifested by diarrhea in humans. To protect human health, AZA-1, AZA-2 and AZA-3 content in seafood has been regulated by food safety authorities in many countries. Recently AZAs have been reported as a low/moderate hERG channel blockers. Furthermore AZA-2 has been related to arrhythmia appearance in rats, suggesting potential heart toxicity. In this study AZA-2 in vitro effects on hERG channel after chronic exposure are analyzed to further explore potential cardiotoxicity. The amount of hERG channel in the plasma membrane, hERG channel trafficking and hERG currents were evaluated up to 12 h of toxin exposure. In these conditions AZA-2 caused an increase of hERG levels in the plasma membrane, probably related to hERG retrograde trafficking impairment. Although this alteration did not translate into an increase of hERG channel-related current, more studies will be necessary to understand its mechanism and to know what consequences could have in vivo. These findings suggest that azaspiracids might have chronic cardiotoxicity related to hERG channel trafficking and they should not be overlooked when evaluating the threat to human health. PMID- 25286399 TI - Characterization of homeobox genes reveals sophisticated regionalization of the central nervous system in the European cuttlefish Sepia officinalis. AB - Cephalopod mollusks possess a number of anatomical traits that often parallel vertebrates in morphological complexity, including a centralized nervous system with sophisticated cognitive functionality. Very little is known about the genetic mechanisms underlying patterning of the cephalopod embryo to arrive at this anatomical structure. Homeodomain (HD) genes are transcription factors that regulate transcription of downstream genes through DNA binding, and as such are integral parts of gene regulatory networks controlling the specification and patterning of body parts across lineages. We have used a degenerate primer strategy to isolate homeobox genes active during late-organogenesis from the European cuttlefish Sepia officinalis. With this approach we have isolated fourteen HD gene fragments and examine the expression profiles of five of these genes during late stage (E24-28) embryonic development (Sof-Gbx, Sof-Hox3, Sof Arx, Sof-Lhx3/4, Sof-Vsx). All five genes are expressed within the developing central nervous system in spatially restricted and largely non-overlapping domains. Our data provide a first glimpse into the diversity of HD genes in one of the largest, yet least studied, metazoan clades and illustrate how HD gene expression patterns reflect the functional partitioning of the cephalopod brain. PMID- 25286400 TI - Expression of bioactive soluble human stem cell factor (SCF) from recombinant Escherichia coli by coproduction of thioredoxin and efficient purification using arginine in affinity chromatography. AB - Stem cell factor (SCF) known as the c-kit ligand is a two disulfide bridge containing cytokine in the regulation of the development and function of hematopoietic cell lineages and other cells such as mast cells, germ cells, and melanocytes. The secreted soluble form of SCF exists as noncovalently associated homodimer and exerts its activity by signaling through the c-Kit receptor. In this report, we present the high level expression of a soluble recombinant human SCF (rhSCF) in Escherichia coli. A codon-optimized Profinity eXactTM-tagged hSCF cDNA was cloned into pET3b vector, and transformed into E. coli BL21(DE3) harboring a bacterial thioredoxin coexpression vector. The recombinant protein was purified via an affinity chromatography processed by cleavage with sodium fluoride, resulting in the complete proteolytic removal the N-terminal tag. Although almost none of the soluble fusion protein bound to the resin in standard protocol using 0.1M sodium phosphate buffer (pH 7.2), the use of binding buffer containing 0.5M l-arginine for protein stabilization dramatically enhanced binding to resin and recovery of the protein beyond expectation. Also pretreatment by Triton X-114 for removing endotoxin was effective for affinity chromatography. In chromatography performance, l-arginine was more effective than Triton X-114 treatment. Following Mono Q anion exchange chromatography, the target protein was isolated in high purity. The rhSCF protein specifically enhanced the viability of human myeloid leukemia cell line TF-1 and the proliferation and maturation of human mast cell line LAD2 cell. This novel protocol for the production of rhSCF is a simple, suitable, and efficient method. PMID- 25286401 TI - Highly efficient production of VHH antibody fragments in Brevibacillus choshinensis expression system. AB - Anti-IZUMO1PFF VHH (variable domain of camelid heavy chain antibody) clones, N6 and N15, from immunized alpaca (Lama pacos) phage library were efficiently expressed and their VHH products were secreted into the culture medium of Brevibacillus choshinensis HPD31-SP3, e.g., at a level of 26-95mg in 100ml conventional flask culture. With a 3-L scale fed-batch culture for 65h, the N15 VHH protein with C-terminal His-tag was produced at ~3g/l culture medium. The N6 and N15 proteins were easily purified to apparent homogeneity by cation exchange and Ni-affinity chromatographies. Both proteins showed specific antigen-binding activity by ELISA and high antigen binding affinity, KD=6.0-8.6nM, by surface plasmon resonance analysis. Size exclusion chromatography-multi-angle laser light scattering analysis revealed that N6 and N15 proteins purified were exclusively monomeric form in phosphate buffered saline. CD spectrum showed beta-sheet rich structure, consistent with a typical antibody structure and also suggested aromatic-aromatic interactions, as indicated by a positive peak at 232nm. Thermal melting analysis of the N15 protein with C-terminal His-tag demonstrated a clear thermal transition with a Tm at 67 degrees C. The heat-denatured sample recovered antigen binding activity upon cooling, indicating a reversible denaturation. PMID- 25286402 TI - Development of an improved mammalian overexpression method for human CD62L. AB - We have previously developed a glutamine synthetase (GS)-based mammalian recombinant protein expression system that is capable of producing 5-30mg/L recombinant proteins. The over expression is based on multiple rounds of target gene amplification driven by methionine sulfoximine (MSX), an inhibitor of glutamine synthetase. However, like other stable mammalian over expression systems, a major shortcoming of the GS-based expression system is its lengthy turn-around time, typically taking 4-6months to produce. To shorten the construction time, we replaced the multi-round target gene amplifications with single-round in situ amplifications, thereby shortening the cell line construction to 2months. The single-round in situ amplification method resulted in highest recombinant CD62L expressing CHO cell lines producing ~5mg/L soluble CD62L, similar to those derived from the multi-round amplification and selection method. In addition, we developed a MSX resistance assay as an alternative to utilizing ELISA for evaluating the expression level of stable recombinant CHO cell lines. PMID- 25286404 TI - Polymorphism dependent light induced spin transition. AB - A photomagnetic study of orthorhombic and tetragonal low spin polymorphs of compound [Fe(L)2](BF4)2 revealed different properties and thermal stability of their metastable high spin states. Furthermore, the reversible thermally induced phase/spin transition between low spin and high spin orthorhombic phases was studied by variable temperature UV/VIS spectroscopy. PMID- 25286405 TI - Thermal conductivity in nanostructured films: from single cellulose nanocrystals to bulk films. AB - We achieved a multiscale description of the thermal conductivity of cellulose nanocrystals (CNCs) from single CNCs (~0.72-5.7 W m(-1) K(-1)) to their organized nanostructured films (~0.22-0.53 W m(-1) K(-1)) using experimental evidence and molecular dynamics (MD) simulation. The ratio of the approximate phonon mean free path (~1.7-5.3 nm) to the lateral dimension of a single CNC (~5-20 nm) suggested a contribution of crystal-crystal interfaces to polydisperse CNC film's heat transport. Based on this, we modeled the thermal conductivity of CNC films using MD-predicted single crystal and interface properties along with the degree of CNC alignment in the bulk films using Hermans order parameter. Film thermal conductivities were strongly correlated to the degree of CNC alignment and the direction of heat flow relative to the CNC chain axis. The low interfacial barrier to heat transport found for CNCs (~9.4 to 12.6 m(2) K GW(-1)), and their versatile alignment capabilities offer unique opportunities in thermal conductivity control. PMID- 25286403 TI - Gut microbiome and the risk factors in central nervous system autoimmunity. AB - Humans are colonized after birth by microbial organisms that form a heterogeneous community, collectively termed microbiota. The genomic pool of this macro community is named microbiome. The gut microbiota is essential for the complete development of the immune system, representing a binary network in which the microbiota interact with the host providing important immune and physiologic function and conversely the bacteria protect themselves from host immune defense. Alterations in the balance of the gut microbiome due to a combination of environmental and genetic factors can now be associated with detrimental or protective effects in experimental autoimmune diseases. These gut microbiome alterations can unbalance the gastrointestinal immune responses and influence distal effector sites leading to CNS disease including both demyelination and affective disorders. The current range of risk factors for MS includes genetic makeup and environmental elements. Of interest to this review is the consistency between this range of MS risk factors and the gut microbiome. We postulate that the gut microbiome serves as the niche where different MS risk factors merge, thereby influencing the disease process. PMID- 25286406 TI - Low-level carotid baroreceptor stimulation suppresses ventricular arrhythmias during acute ischemia. AB - BACKGROUND: The autonomic imbalance during acute ischemia is involved in the occurrence of life-threatening arrhythmias. OBJECTIVE: To investigate the effect of autonomic nervous system (ANS) modulation by low-level carotid baroreceptor stimulation (LL-CBS) on ventricular ischemia arrhythmias. METHODS: Anesthetized dogs were received either sham treatment (SHAM group, n = 10) or LL-CBS treatment (LL-CBS group, n = 10). The voltage lowering the blood pressure was used as the threshold for setting LL-CBS at 80% below the threshold. Treatment started 1 hour before left anterior descending coronary (LAD) occlusion, and continued until the end of experience. Ventricular effective refractory periods (ERP), monophasic action potential duration at 90% (APD90), ventricular arrhythmias, indices of heart rate variability, left stellate ganglion nerve activity (LSGNA) and infarct sizes were measured and analyzed. RESULTS: Ventricular ischemia resulted in an acute reduction of blood pressure, which was not significantly affected by LL CBS. After 1 hour of LL-CBS, there was a progressive and significant increase in ERP, increase in APD90, and decrease in LSGNA vs the SHAM group (all P<0.05). LL CBS apparently reduced premature ventricular contractions (PVC, 264+/-165 in the SHAM group vs 60+/-37 in the LL-CBS group; P<0.01) during LAD occlusion. Number of episodes of ventricular fibrillation (VF) was 8 in the Control group versus 3 in the LL-CBS group (80% versus 30%, P<0.05). LL-CBS obviously increased high frequency (HF) component (P<0.05) and decreased low frequency/high frequency ratio (P<0.05) compared with the SHAM group. Ischemic size was not affected by LL CBS between the two groups. CONCLUSIONS: LL-CBS reduced the occurrences of ventricular arrhythmias during acute ischemia without affecting blood pressure. The procedure was associated with changes of electrophysiological characteristics, nerve activity and heart rate variability. Therefore, LL-CBS may protect from ventricular arrhythmias during acute ischemic events by modulating ANS. PMID- 25286407 TI - Effects of single injection of local anesthetic agents on intervertebral disc degeneration: ex vivo and long-term in vivo experimental study. AB - BACKGROUND: Analgesic discography (discoblock) can be used to diagnose or treat discogenic low back pain by injecting a small amount of local anesthetics. However, recent in vitro studies have revealed cytotoxic effects of local anesthetics on intervertebral disc (IVD) cells. Here we aimed to investigate the deteriorative effects of lidocaine and bupivacaine on rabbit IVDs using an organotypic culture model and an in vivo long-term follow-up model. METHODS: For the organotypic culture model, rabbit IVDs were harvested and cultured for 3 or 7 days after intradiscal injection of local anesthetics (1% lidocaine or 0.5% bupivacaine). Nucleus pulposus (NP) cell death was measured using confocal microscopy. Histological and TUNEL assays were performed. For in vivo study, each local anesthetic was injected into rabbit lumbar IVDs under a fluoroscope. Six or 12 months after the injection, each IVD was prepared for magnetic resonance imaging (MRI) and histological analysis. RESULTS: In the organotypic culture model, both anesthetic agents induced time-dependent NP cell death; when compared with injected saline solution, significant effects were detected within 7 days. Compared with the saline group, TUNEL-positive NP cells were significantly increased in the bupivacaine group. In the in vivo study, MRI analysis did not show any significant difference. Histological analysis revealed that IVD degeneration occurred to a significantly level in the saline- and local anesthetics-injected groups compared with the untreated control or puncture-only groups. However, there was no significant difference between the saline and anesthetic agents groups. CONCLUSIONS/SIGNIFICANCE: In the in vivo model using healthy IVDs, there was no strong evidence to suggest that discoblock with local anesthetics has the potential of inducing IVD degeneration other than the initial mechanical damage of the pressurized injection. Further studies should be performed to investigate the deteriorative effects of the local injection of analgesic agents on degenerated IVDs. PMID- 25286409 TI - Enhanced near-infrared emission from holmium-ytterbium co-doped phosphate glasses containing silver nanoparticles. AB - The fabrication and spectroscopic characterization of Ho(3+) and Yb(3+) co-doped phosphate glasses, also containing silver nanoparticles (SNPs), is reported. The nucleation and formation of nanoparticle structures in the samples are confirmed using transmission electron microscopy analyses. It is found that the Ho(3+) Yb(3+)-SNP phosphate glasses exhibit an enhancement of both the resonant absorption and the fluorescence properties when the SNP concentration is increased. PMID- 25286408 TI - Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes. AB - BACKGROUND: Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation. METHODS: Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance. RESULTS: Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR 181a, a marker of human PTB. CONCLUSIONS: The findings indicate that a family history of stress may program central and peripheral pathways regulating gestational length and maternal and newborn health outcomes in the maternal lineage. This new paradigm may model the origin of many human PTB causes. PMID- 25286410 TI - The role of population origin and microenvironment in seedling emergence and early survival in Mediterranean maritime pine (Pinus pinaster Aiton). AB - Understanding tree recruitment is needed to forecast future forest distribution. Many studies have reported the relevant ecological factors that affect recruitment success in trees, but the potential for genetic-based differences in recruitment has often been neglected. In this study, we established a semi natural reciprocal sowing experiment to test for local adaptation and microenvironment effects (evaluated here by canopy cover) in the emergence and early survival of maritime pine (Pinus pinaster Aiton), an emblematic Mediterranean forest tree. A novel application of molecular markers was also developed to test for family selection and, thus, for potential genetic change over generations. Overall, we did not find evidence to support local adaptation at the recruitment stage in our semi-natural experiment. Moreover, only weak family selection (if any) was found, suggesting that in stressful environments with low survival, stochastic processes and among-year climate variability may drive recruitment. Nevertheless, our study revealed that, at early stages of recruitment, microenvironments may favor the population with the best adapted life strategy, irrespectively of its (local or non-local) origin. We also found that emergence time is a key factor for seedling survival in stressful Mediterranean environments. Our study highlights the complexity of the factors influencing the early stages of establishment of maritime pine and provides insights into possible management actions aimed at environmental change impact mitigation. In particular, we found that the high stochasticity of the recruitment process in stressful environments and the differences in population specific adaptive strategies may difficult assisted migration schemes. PMID- 25286411 TI - Developmentally regulated sesquiterpene production confers resistance to Colletotrichum gloeosporioides in ripe pepper fruits. AB - Sesquiterpenoid capsidiol, exhibiting antifungal activity against pathogenic fungus, is accumulated in infected ripe pepper fruits. In this study, we found a negative relation between the capsidiol level and lesion size in fruits infected with Colletotrichum gloeosporioides, depending on the stage of ripening. To understand the developmental regulation of capsidiol biosynthesis, fungal-induced gene expressions in the isoprenoid biosynthetic pathways were examined in unripe and ripe pepper fruits. The sterol biosynthetic pathway was almost shut down in healthy ripe fruits, showing very low expression of hydroxymethyl glutaryl CoA reductase (HMGR) and squalene synthase (SS) genes. In contrast, genes in the carotenoid pathway were highly expressed in ripe fruits. In the sesquiterpene pathway, 5-epi-aristolochene synthase (EAS), belonging to a sesquiterpene cyclase (STC) family, was significantly induced in the ripe fruits upon fungal infection. Immunoblot and enzyme activity analyses showed that the STCs were induced both in the infected unripe and ripe fruits, while capsidiol was synthesized discriminatively in the ripe fruits, implying diverse enzymatic specificity of multiple STCs. Thereby, to divert sterol biosynthesis into sesquiterpene production, infected fruits were pretreated with an SS inhibitor, zaragozic acid (ZA), resulting in increased levels of capsidiol by more than 2-fold in the ripe fruits, with concurrent reduction of phytosterols. Taken together, the present results suggest that the enhanced expression and activity of EAS in the ripe fruits play an important role in capsidiol production, contributing to the incompatibility between the anthracnose fungus and the ripe pepper fruits. PMID- 25286412 TI - Rare circulating microRNAs as biomarkers of colorectal neoplasia. AB - BACKGROUND: MicroRNAs (miRNAs) are regulatory RNAs, stable in circulation, and implicated in colorectal cancer (CRC) etiology and progression. Therefore they are promising as early detection biomarkers of colorectal neoplasia. However, many circulating miRNAs are highly expressed in blood cells, and therefore may not be specific to colorectal neoplasia. METHODS: We selected 7 miRNA candidates with previously reported elevated expression in adenoma tissue but low expression in blood cells ("rare" miRNAs), 2 previously proposed as adenoma biomarkers, and 3 implicated in CRC. We conducted a colonoscopy-based case-control study including 48 polyp-free controls, 43 advanced adenomas, 73 non-advanced adenomas, and 8 CRC cases. miRNAs from plasma were quantified by qRT-PCR. Correlations between miRNA expression levels, adjusted for age and sex, were assessed. We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals quantifying the association between expression levels of miRNAs and case groups. We also conducted nonparametric receiver operating characteristic (ROC) analyses and estimated area under the curve (AUC). RESULTS: miRNAs with high expression levels were statistically significantly correlated with one another. No miRNAs were significantly associated with non-advanced or advanced adenomas. Strong (ORs >5) and significant associations with CRC were observed for 6 miRNA candidates, with corresponding AUCs significantly >0.5. CONCLUSIONS: These candidate miRNAs, assayed by qRT-PCR, are probably unsuitable as blood based adenoma biomarkers. Strong associations between miRNAs and CRC were observed, but primarily with miRNAs highly expressed in blood cells. These results suggest that rare miRNAs will require new detection methods to serve as circulating biomarkers of adenomas. PMID- 25286413 TI - Expression, purification, and structural insights for the human uric acid transporter, GLUT9, using the Xenopus laevis oocytes system. AB - The urate transporter, GLUT9, is responsible for the basolateral transport of urate in the proximal tubule of human kidneys and in the placenta, playing a central role in uric acid homeostasis. GLUT9 shares the least homology with other members of the glucose transporter family, especially with the glucose transporting members GLUT1-4 and is the only member of the GLUT family to transport urate. The recently published high-resolution structure of XylE, a bacterial D-xylose transporting homologue, yields new insights into the structural foundation of this GLUT family of proteins. While this represents a huge milestone, it is unclear if human GLUT9 can benefit from this advancement through subsequent structural based targeting and mutagenesis. Little progress has been made toward understanding the mechanism of GLUT9 since its discovery in 2000. Before work can begin on resolving the mechanisms of urate transport we must determine methods to express, purify and analyze hGLUT9 using a model system adept in expressing human membrane proteins. Here, we describe the surface expression, purification and isolation of monomeric protein, and functional analysis of recombinant hGLUT9 using the Xenopus laevis oocyte system. In addition, we generated a new homology-based high-resolution model of hGLUT9 from the XylE crystal structure and utilized our purified protein to generate a low resolution single particle reconstruction. Interestingly, we demonstrate that the functional protein extracted from the Xenopus system fits well with the homology based model allowing us to generate the predicted urate-binding pocket and pave a path for subsequent mutagenesis and structure-function studies. PMID- 25286414 TI - Pseudo-cyclic structures of mono- and di-azaderivatives of malondialdehydes. Synthesis and conformational disentanglement by computational analyses. AB - Mono- and diaza-derivatives of malondialdehydes, namely 3-alkyl(aryl)amino-2 arylacroleins and 1,5-dialkyl(aryl)-3-arylvinamidines are open-chain systems in which extended electron delocalization and pseudoaromaticity can be envisaged. A set of diversely functionalized compounds has been synthesized and characterized by spectroscopic data and X-ray diffractometry. Quantum-chemical calculations were performed for all possible neutral tautomers and conformers in the gas phase and compared to those in polar solvents (CHCl3, DMSO, and EtOH) at the M06-2X/6 311++G(d,p) level. Tautomeric equilibria and conformational preferences can be rationalized in terms of structural factors, which can be roughly estimated as summation or subtractions of intramolecular interactions. As expected, a key role is played by intramolecular hydrogen bonds whose strength varies from the gas phase to polar ethanol. This issue also delves into the concept of resonance assisted H-bond, where the donor and acceptor atoms are connected by a pi conjugated system. The most stable conformers (structures a and c) possess a high degree of pseudoaromaticity as inferred from HOMA indexes and other delocalization parameters. PMID- 25286415 TI - Single-walled carbon nanotubes as nano-electrode and nano-reactor to control the pathways of a redox reaction. AB - Single-walled carbon nanotubes have been demonstrated as effective nanoscale containers for a redox active organometallic complex Cp(Me)Mn(CO)3, acting simultaneously as nano-electrode and nano-reactor. Extreme spatial confinement of the redox reaction within the nanotubes changes its pathway compared to bulk solution due to stabilisation of a reactive intermediate. PMID- 25286417 TI - A method for quantifying visual field inhomogeneities. AB - It is well known that performance is not homogeneous across the visual field, even at isoeccentric locations. Several inhomogeneities in particular have been identified - a Horizontal-Vertical Anisotropy (HVA - better performance in the horizontal than in the vertical direction); a Vertical Asymmetry (VA - better performance in the lower than the upper visual field); and a Vertical Meridian Asymmetry (VMA - better performance below than above the point of fixation on the vertical meridian). Performance has also been reported to be particularly poor at the location directly above the point of fixation, i.e., the "North" (N) location and sometimes at the location directly below the point of fixation, i.e., the "South" (S) location. These phenomena are typically characterized by statistics that compare performance across the visual field to a homogeneous (circular) model. Here we propose an alternative method for assessing visual field inhomogeneities, which involves comparing performance to an elliptical model of the visual field. We maintain that this method provides a more robust analysis of visual field inhomogeneities because it does not overestimate the North and South effects. PMID- 25286416 TI - Stereomotion scotomas occur after binocular combination. AB - Stereomotion scotomas are a surprisingly common visual impairment that result in an observer's inability to accurately report the direction of an object's motion in depth in restricted parts of the visual field. In this study we investigated the role of binocular cues to motion in depth. Using stimuli containing only non stationary cues to stereomotion, we measured sensitivity across the visual field and identified areas of significant impairment in stereomotion processing in over 50% of otherwise healthy observers. These impairments vary idiosyncratically in extent and location between observers. We established that these impairments occur for a variety of visual stimuli, as long as they share the property that stimulus motion is exclusively defined by interocular and velocity differences. We tested for concordant impairments at relatively early stages along the visual pathway, i.e. changes in sensitivity across the visual field to local eye dominance, monocular motion or instantaneous binocular disparity. Although we find variability in sensitivity across the visual field of our observers for all visual tasks, this variability across visual field locations did not correlate with the impairments in stereomotion processing. We therefore conclude that these stereomotion scotomas are due to impaired processing of dynamic cues after the stage of binocular combination. PMID- 25286419 TI - Erratum: Autologous fat transfer with in-situ mediation (AIM): a novel and compliant method of adult mesenchymal stem cell therapy. PMID- 25286418 TI - Expansion of NK cells and reduction of NKG2D expression in chronic lymphocytic leukemia. Correlation with progressive disease. AB - The immune system may mediate anti-tumor responses in chronic lymphocytic leukemia (CLL) which may affect disease progression and survival. In this study, we analyzed the immune characteristics of 99 consecutive previously diagnosed CLL patients and 50 healthy controls. The distribution of lymphocyte subsets at diagnosis was retrospectively analyzed. Compared with controls, leukemia patients showed an expansion of NK and CD8 T cells at diagnosis. The relative number of CD8 T cells at diagnosis was associated with time to treatment, suggesting that CD8 T cells may modify disease progression. The distribution of lymphocyte subsets was analyzed again when patients were enrolled in this study. The median time since these patients were diagnosed was 277 weeks. Compared with diagnosis, the absolute number of CD8 T cells significantly decreased in these patients, reaching similar values to healthy controls; however NK cells kept significantly elevated overtime. Nevertheless, NK cells showed an impaired expression of NKG2D receptor and a defective cytotoxic activity. This down-regulation of NKG2D expression was further enhanced in patients with advanced and progressive disease. Additionally, membrane NKG2D levels significantly decreased on CD8 T cells, but a significant increase of NKG2D+CD4+ T cells was observed in CLL patients. The cytotoxic activity of NK cells was diminished in CLL patients; however the treatments with IL-2, IL-15, IL-21 and lenalidomide were able to restore their activity. The effect of IL-2 and IL-15 was associated with the increase of NKG2D expression on immune cells, but the effect of IL-21 and lenalidomide was not due to NKG2D up-regulation. The expansion of NK cells and the reversibility of NK cell defects provide new opportunities for the immunotherapeutic intervention in CLL. PMID- 25286420 TI - Metabolic engineering of Saccharomyces cerevisiae for production of butanol isomers. AB - Saccharomyces cerevisiae has decisive advantages in industrial processes due to its tolerance to alcohols and fermentation conditions. Butanol isomers are considered as suitable fuel substitutes and valuable biomass-derived chemical building blocks. Whereas high production was achieved with bacterial systems, metabolic engineering of yeast for butanol production is in the beginning. For isobutanol synthesis, combination of valine biosynthesis and degradation, and complete pathway re-localisation into cytosol or mitochondria gave promising results. However, competing pathways, co-factor imbalances and FeS cluster assembly are still major issues. 1-Butanol production via the Clostridium pathway seems to be limited by cytosolic acetyl-CoA, its central precursor. Endogenous 1 butanol pathways have been discovered via threonine or glycine catabolism. 2 Butanol production was established but was limited by B12-dependence. PMID- 25286421 TI - Testing for gluten sensitivity. AB - There has been both medical and lay interest in the association of gluten with gastrointestinal conditions. PMID- 25286422 TI - Coeliac disease: where are we in 2014? AB - BACKGROUND: Coeliac disease (CD) is an autoimmune condition affecting at least 1% of the population, many of whom remain undiagnosed. It is characterised by chronic inflammation of the small-intestinal mucosa and triggered by eating gluten. It is challenging to diagnose be-cause of the many and varied ways in which it may present. OBJECTIVE: To present up-to-date information on CD as we now understand it, with recommendations on whom to test and how to test them, and how to manage patients once they are diagnosed. DISCUSSION: Primary care practitioners have a crucial role in improving rates of CD diagnosis, and in the ongoing care of patients with CD. A blood test for coeliac-specific antibodies will identify most patients who need to undergo duodenal biopsy to make the diagnosis. Management encompasses supporting patients with adherence to the gluten-free diet and conducting a CD-focused clinical review every 1-2 years. PMID- 25286423 TI - Hot topics in paediatric immunology: IgE-mediated food allergy and allergic rhinitis. AB - BACKGROUND: The epidemic of allergic disease is a major public health crisis. The greatest burden of allergies is in childhood, when rapidly rising rates of disease are also most evident. General practitioners (GP) have a key role in recognising and addressing aller-gy-related problems and identifying whether a child requires referral to a paediatric allergist. OBJECTIVE: This article focuses on IgE-mediated food allergies and allergic rhinitis, the most commonly seen conditions in paediatric im-munology. We will discuss prevention, diagnosis, management and treatment strategies. DISCUSSION: Currently there is no cure for food allergy. Oral tolerance induction continues to be a significant focus of research. All children with a possible food allergy should be referred to an allergist for further testing and advice. Children who develop allergic rhinitis need a regular review by their GP. Immunotherapy should be discussed early in the disease process and needs to be com-menced by an allergist. PMID- 25286424 TI - The role of food intolerance in functional gastrointestinal disorders in children. AB - BACKGROUND: Functional gastrointestinal disorder (FGID) is a common, benign, chronic diagnosis that has a significant negative impact on quality of life. FGIDs that develop in childhood can persist into adulthood. Currently, there is no cure and few treatment options are available. OBJECTIVE: This article provides an outline of current research supporting the role of food intolerance in children with FGIDs. DISCUSSION: Food intolerances have long been reported by patients with FGIDs; however, randomised controlled trials are lacking in this area. Food intolerances that have been investigated include intolerance to food chemicals, lactose, fructose and, more recently, fer-mentable carbohydrates, termed FODMAPs. The low-FODMAP diet eliminates poorly absorbed short-chain carbohydrates and has a clearly defined mechanism of action. Emerging evidence suggests it alleviates symptoms in adults with irritable bowel syndrome and, potentially, also in children. However, more evidence is required for the efficacy of the diet in children and in oth-er subgroups of FGID. Any dietary restriction in growing children should be undertaken with clinical supervision by a dietitian. PMID- 25286425 TI - A positive approach to parents with concerns about vaccination for the family physician. AB - BACKGROUND: Vaccine hesitancy is becoming increasingly recognised as an issue in Australia and globally, as concerns about vaccines and their safety predominate over concerns about the risk of vaccine-preventable diseases. OBJECTIVE: This review provides an approach for primary care physicians to enable effective communication with parents who have differ-ent levels of concerns about vaccinations and awareness of currently available resources that may be used to support discussions. DISCUSSION: Clear and flexible communication strategies for healthcare providers to undertake effective discussions with vaccine-hesitant parents or clear referral pathways are the key to addressing concerns about vaccination in both primary and secondary care. PMID- 25286426 TI - Frontotemporal hair loss. PMID- 25286427 TI - Incidentally detected thrombocytopaenia in adults. AB - BACKGROUND: With the advent of automated counters, low platelet counts are a common incidental finding. The list of possible aetiologies is long and exhaustive (Figure 1, available online only). Platelet abnormalities range from having no clinical relevance to being the only initial manifestation of a serious underlying disorder. OBJECTIVE: This article provides general practitioners with an approach to differentiating the benign from the life-threatening causes of thrombocytopenia using routine pathology testing in adults. DISCUSSION: There are no specific laboratory tests that can conclusively identify the mechanism of thrombocytopenia - a thorough history, clinical examination, and blood results remain the initial means of diagnosis. PMID- 25286428 TI - Changes in mood, depression and suicidal ideation after commencing pregabalin for neuropathic pain. AB - BACKGROUND: Pregabalin is a treatment option for patients with persistent neuropathic pain. Its use has been associated with changes in mood and the development of depression and/or suicidal ideation. OBJECTIVE: Case presentations were reviewed of five patients reporting changes in mood, depression and suicidal ideation from the first 50 (approximately) patients commenced on pregabalin at the clinic. DISCUSSION: Although these patients had a history of depression, their mood had been stable before commencing pregabalin. Soon after commencement they reported changes in mood, and development of depression and/or suicidal ideation, which improved with dose reduction or cessation of pregabalin. Ultimately, all five patients ceased pregabalin treatment. Suicidal ideation is a recognised adverse effect of pregabalin. Patients should be warned of and monitored for deterioration in mood. PMID- 25286429 TI - Pruritus in the elderly - a guide to assessment and management. AB - BACKGROUND: Pruritus is the most common skin complaint in patients over the age of 65 years. These patients are in a unique population group that will require a comprehensive clinical approach. The symptoms of pruritus can be potentially debilitating and can have a significant impact on elderly patients by impairing their quality of life. OBJECTIVE: This article discusses the assessment and management of pruritus, with a specific focus on the elderly population. DISCUSSION: Pruritus in the elderly population remains both a diagnostic and therapeutic challenge. In the first instance, it has to be established whether the pruritus is arising from a primary dermatological condition or whether it is a manifestation of an underlying systemic disease. When a rash is present it could suggest an underlying primary dermatosis. Apart from lifestyle modifications, emollients, topical antipruritics (eg menthol 1% in aqueous cream), oral antihistamines, topical corticosteroids and phototherapy may prove useful. PMID- 25286430 TI - Diagnostic difficulties in skin cancer detection within tattoos. PMID- 25286431 TI - Online continuing medical education (CME) for GPs: does it work? A systematic review. AB - BACKGROUND: Numerous studies have assessed the effectiveness of online continuing medical education (CME) designed to improve healthcare professionals' care of patients. The effects of online educational interventions targeted at general practitioners (GP), however, have not been systematically reviewed. METHODS: A computer search was conducted through seven databases for studies assessing changes in GPs' knowledge and practice, or patient outcomes following an online educational intervention. RESULTS: Eleven studies met the eligibility criteria. Most studies (8/11, 72.7%) found a significant improvement in at least one of the following outcomes: satisfaction, knowledge or practice change. There was little evidence for the impact of online CME on patient outcomes. Variability in study design, characteristics of online and outcome measures limited conclusions on the effects of online CME. DISCUSSION: Online CME could improve GP satisfaction, knowledge and practices but there are very few well-designed studies that focus on this delivery method of GP education. PMID- 25286432 TI - The use of a global trigger tool to inform quality and safety in Australian general practice: a pilot study. AB - BACKGROUND: Systems to identify risks and adverse events (AEs) in Australia are limited. This study aims to explore whether general practice records contain information on AEs, and to conduct a pilot study on the type and frequency of AEs in general practice in Australia, using a global trigger tool (GTT). METHODS: Five practices were recruited and consented to collect data. Practice nurses were trained to collect data at their practices. Rec-ords from randomly sampled patients aged 75 years or older were reviewed. RESULTS: A total of 428 patient records were reviewed. A total of 44 AEs were detected in 41 records. The percentage of patients with an AE was 9.6%. Most low preventability AEs (21/29) were medication incidents. DISCUSSION: The study found that significant levels of information about AEs exist in general practice medical records and rates of harm are broadly in line with a similar study in Scotland. PMID- 25286433 TI - Accuracy of general practitioner medication histories for patients presenting to the emergency department. AB - BACKGROUND: Clinical handover and obtaining best possible medication histories (BPMH) at transition points in care are key patient safety pri-orities. This study aimed to determine the accuracy of medication histories documented on general practitioner (GP) referral letters for patients referred to emergency departments. METHODS: This was a multicentre prospective observational study in eight emergency departments. Patients taking >=1 regular medication, referred to the emergency department with a GP letter and seen by a pharmacist were included. GP medication regimens were compared with BPMH documented by the emergency department pharmacist. RESULTS: Of the GP letters (total 414), 361 (87%) had one or more discrepancies in the patients' regular medications and 62% had one or more regular medication discrepancies of moderate-high significance. Omission of medication was more prevalent in hand-written letters (P DISCUSSION: GP referral letters should not be used in isolation to determine the medication regimen taken before an emergency department presentation. Interventions are indicated to improve awareness and accuracy of medication documentation. PMID- 25286434 TI - Barcoding Fauna Bavarica: 78% of the Neuropterida fauna barcoded! AB - This publication provides the first comprehensive DNA barcode data set for the Neuropterida of Central Europe, including 80 of the 102 species (78%) recorded from Bavaria (Germany) and three other species from nearby regions (Austria, France and the UK). Although the 286 specimens analyzed had a heterogeneous conservation history (60% dried; 30% in 80% EtOH; 10% fresh specimens in 95% EtOH), 237 (83%) generated a DNA barcode. Eleven species (13%) shared a BIN, but three of these taxa could be discriminated through barcodes. Four pairs of closely allied species shared barcodes including Chrysoperla pallida Henry et al., 2002 and C. lucasina Lacroix, 1912; Wesmaelius concinnus (Stephens, 1836) and W. quadrifasciatus (Reuter, 1894); Hemerobius handschini Tjeder, 1957 and H. nitidulus Fabricius, 1777; and H. atrifrons McLachlan, 1868 and H. contumax Tjeder, 1932. Further studies are needed to test the possible synonymy of these species pairs or to determine if other genetic markers permit their discrimination. Our data highlight five cases of potential cryptic diversity within Bavarian Neuropterida: Nineta flava (Scopoli, 1763), Sympherobius pygmaeus (Rambur, 1842), Sisyra nigra (Retzius, 1783), Semidalis aleyrodiformis (Stephens, 1836) and Coniopteryx pygmaea Enderlein, 1906 are each split into two or three BINs. The present DNA barcode library not only allows the identification of adult and larval stages, but also provides valuable information for alpha-taxonomy, and for ecological and evolutionary research. PMID- 25286435 TI - Exploratory study of physical activity in persons with Charcot-Marie-Tooth disease. AB - OBJECTIVES: To explore and describe the perceived facilitators and barriers to physical activity, and to examine the physical activity correlates in people with Charcot-Marie-Tooth (CMT) disease. DESIGN: Cross-sectional survey study. SETTING: Community-living subjects. PARTICIPANTS: Swedish people with CMT disease (N=44; men, 54.5%; median age, 59.5 y [interquartile range, 45.3-64.8 y]). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The survey included open ended questions and standardized self-reported scales measuring physical activity, fatigue, activity limitation, self-efficacy for physical activity, fall related self-efficacy, social support, and enjoyment of physical activity. Physical activity was measured by the Physical Activity Disability Survey Revised. RESULTS: Qualitative content analysis revealed that personal factors such as fatigue, poor balance, muscle weakness, and pain were important barriers for physical activity behavior. Facilitators of physical activity were self efficacy for physical activity, activity-related factors, and assistive devices. Multiple regression analysis showed that self-efficacy for physical activity (beta=.41) and fatigue (beta=-.30) explained 31.8% of the variation in physical activity (F2,40=10.78, P=.000). CONCLUSIONS: Despite the well-known benefits of physical activity, physical activity in people with CMT disease is very sparsely studied. These new results contribute to the understanding of factors important for physical activity behavior in people with CMT disease and can guide health professionals to facilitate physical activity behavior in this group of patients. PMID- 25286436 TI - Parkinsonian gait ameliorated with a moving handrail, not with a banister. AB - OBJECTIVE: To determine whether haptic (touch and proprioception) cues from touching a moving handrail while walking can ameliorate the gait symptoms of Parkinson disease (PD), such as slowness and small stride length. DESIGN: Nonrandomized, controlled before-after trial. SETTING: Physical therapy clinic. PARTICIPANTS: People with PD (n=16) and healthy age-matched control subjects (n=16) with no neurologic disorders volunteered. No participants withdrew. INTERVENTIONS: We compared gait using a moving handrail as a novel assistive aid (speed self-selected) versus a banister and unassisted walking. Participants with PD were tested on and off dopaminergic medication. MAIN OUTCOME MEASURES: Mean gait speed, stride length, stride duration, double-support duration, and medial lateral excursion. RESULTS: With the moving handrail, participants with PD increased gait speed relative to unassisted gait by 16% (.166m/s, P=.009, d=.76; 95% confidence interval [CI], .054-.278m/s) and increased stride length by 10% (.053m, P=.022, d=.37; 95% CI, .009-.097m) without significantly changing stride or double-support duration. The banister reduced speed versus unassisted gait by 11% (-.097m/s, P=.040, d=.40; 95% CI, .002-.193m/s) and reduced stride length by 8% (.32m, P=.004, d=.26; 95% CI, .010-.054m), whereas it increased stride duration by 3% (.023s, P=.022, d=.21; 95% CI, .004-.041s) and double-support duration by 35% (.044s, P=.031, d=.58; 95% CI, .005-.083s). All medication * condition interactions were P>.05. CONCLUSIONS: Using haptic speed cues from the moving handrail, people with PD walked faster by spontaneously (ie, without specific instruction) increasing stride length without altering cadence; banisters slowed gait. Haptic cues from the moving handrail can be used by people with PD to engage biomechanical and neural mechanisms for interpreting tactile and proprioception changes related to gait speed to control gait better than static cues afforded by banisters. PMID- 25286437 TI - Subcellular distribution of Cd and Zn and MT mRNA expression in the hepatopancreas of Sinopotamon henanense after single and co-exposure to Cd and Zn. AB - The freshwater crab Sinopotamon henanense was exposed to Cd and Zn either on their own or in combination. At 14 and 28 days the hepatopancreas was taken and total metal and metallothionein MT) in transcript abundance were assessed. In addition, the subcellular contents of Cd and Zn also were examined following a differential centrifugation. The results showed that concentration of Cd was more responsive to waterborne metal exposures than the concentration of Zn; Zn was better regulated and exhibited only 2-3 fold increases relative to the control. Of the subcellular fractions, the heat stable protein (HSP) fraction was the predominant metal-binding compartment for Cd. The proportion and accumulation of Cd in this fraction increased with the single Cd exposures, which suggest that metallothionein-like proteins play a key role in metal detoxification in the hepatopancreas of S. henanense. Despite the increases in Cd in the HSP fraction during single Cd exposures, some accumulation of Cd was observed in metal sensitive fraction (MSF), which showed that metal detoxification was incomplete. The results demonstrated that the Cd content decreased in metal mixture groups especially when mixed with higher Zn, while the Cd accumulation in MSF was also reduced when Zn was added. MT mRNA expression was also determined in our report, the results showed that both Cd and Zn had the ability of inducing MT mRNA expression. Additionally, the MT mRNA transcription level was enhanced when Cd was mixed with Zn. PMID- 25286438 TI - Improving and testing geochemical speciation predictions of metal ions in natural waters. AB - The ability of WHAM VII and NICA-Donnan models to predict free-ion activities of Cu in natural waters was examined from two perspectives, (i) the presence of EDTA and NTA contaminants, (ii) the need to improve estimates of HA and FA concentrations. Potentiometric responses of a Cu(II) ion-selective electrode were investigated in five assays containing dissolved organic matter (DOM) isolated from a series of polluted (urban) and relatively unpolluted (upland) streams in northern England. The [Cu]/[DOC] ratio in these assays spanned an environmentally realistic range of ~1-500 MUmol/g. Reasonably good agreement between measured and predicted Cu(2+) activities was obtained with both WHAM VII and NICA-Donnan models, assuming 65% of DOM as fulvic acid and including the measured EDTA and NTA concentrations, but generally the models overestimated the activities by a factor of ~2. In contrast, the models over-predicted the Cu(2+) activities by up to 2 orders of magnitude at low [Cu]/[DOC] ratios in urban waters if anthropogenic ligands were not included in the model simulations. Three dimensional fluorescence excitation-emission matrix (EEM) spectroscopy was used to measure the functional properties of the isolated DOM and to estimate the fractions of FA and HA present. Using these fractions in the models gave improvements in predictions compared to the 65% FA assumption, as shown by higher correlations, reduced error and reduced bias. These results highlight various issues with the use of the available speciation models for predicting free ion concentrations in natural waters, such as the use of the Biotic Ligand Model (BLM) for the derivation of environmental standards. It is clearly necessary to measure EDTA and NTA in waters with urban influences, while fluorescence measurements offer the possibility of appreciably improving the accuracy of predictions. PMID- 25286439 TI - Ancient humans and the origin of modern humans. AB - Recent advances in sequencing technologies and molecular methods have facilitated the sequencing of DNA from ancient human remains which has, in turn, provided unprecedented insight into human history. Within the past 4 years the genomes of Neandertals and Denisovans, as well as the genomes of at least two early modern humans, have been sequenced. These sequences showed that there have been several episodes of admixture between modern and archaic groups; including admixture from Neandertals into modern human populations outside of Africa, and admixture from Denisovans into modern human populations in Oceania. Recent results indicate that some of these introgressed regions may have been advantageous for modern humans as they expanded into new regions outside of Africa. PMID- 25286440 TI - Ablation of Foxl1-Cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury. AB - BACKGROUND & AIMS: Foxl1(+) hepatic progenitor cells (HPCs) differentiate into cholangiocytes and hepatocytes after liver injury. We investigated the requirement for Foxl1(+) HPCs in recovery from liver injury in mice. METHODS: We developed mice in which we could trace and delete Foxl1-expressing HPCs and their descendants (Foxl1-Cre;Rosa(YFP/iDTR)-inducible diphtheria toxin receptor [iDTR] mice). Foxl1-Cre-negative mice were used as controls. Liver damage was induced in male mice by placing them on choline-deficient, ethionine-supplemented (CDE) diets for 15 days; mice then were placed on normal diets and allowed to recover. Liver damage was induced in female mice by placing them on 3,5-diethoxycarbonyl 1,4-dihydrocollidine (DDC)-containing diets, followed by a recovery period. Some mice were given injections of diphtheria toxin during the recovery phase to delete Foxl1-Cre-marked HPCs and their descendants. Livers were collected from all mice and analyzed by immunofluorescence, quantitative reverse-transcription polymerase chain reaction, flow cytometry, and histologic analyses. RESULTS: Foxl1-Cre-marked HPCs were required for the development of cholangiocytes and hepatocytes in livers after CDE diet-induced injury. A smaller percentage of yellow fluorescent protein-positive (YFP(+)) hepatocytes contained markers of oxidative stress, DNA damage, or cell death than YFP-negative hepatocytes, indicating that YFP(+) hepatocytes are newly formed cells. Injection of diphtheria toxin deleted YFP(+) cells from Foxl1-Cre;Rosa(YFP/iDTR) mice and prevented the resolution of hepatic steatosis. In mice recovering from DDC diet induced injury, most cholangiocytes arose from Foxl1-Cre-marked HPCs. Deletion of YFP(+) cells did not alter levels of markers of liver injury or liver function. CONCLUSIONS: Based on studies of Foxl1-Cre;Rosa(YFP/iDTR) mice, Foxl1(+) HPCs and/or their descendants are required for the development of cholangiocytes and hepatocytes in liver after CDE diet-induced injury. PMID- 25286442 TI - Simple and cost-effective 14-loci SNP assay designed for differentiation of European, East Asian and African samples. AB - During every criminal investigation, it is vital to extract as much information as possible from every piece of evidence. When it comes to DNA testing, simple short tandem repeat (STR) typing may soon become a relic because it is now possible to genotype more characteristics. Ancestry informative markers are receiving attention from the forensic community because individuals can be assigned to their population or territory of origin based on their analysis. Many panels of this kind have been proposed so far, yet most of them require typing of a large number of loci. In many cases it is crucial to pick a minimal set of the most informative markers due to the limited amount of material available for analysis. In this study, we demonstrate that 14 carefully picked SNPs combined in two multiplex assays are capable of fast, robust and cost effective three-way differentiation of East Asians, Europeans and Africans. PMID- 25286441 TI - Efficient cryoprotection of macromolecular crystals using vapor diffusion of volatile alcohols. AB - Macromolecular X-ray crystallography, usually done at cryogenic temperature to limit radiation damage, often requires liquid cryoprotective soaking that can be labor intensive and damaging to crystals. Here we describe a method for cryoprotection that uses vapor diffusion of volatile cryoprotective agents into loop-mounted crystals. The crystal is mounted into a vial containing a small volume of an alcohol-based cryosolution. After a short incubation with the looped crystal sitting in the cryosolution vapor, the crystal is transferred directly from the vial into the cooling medium. Effective for several different protein crystals, the approach obviates the need for liquid soaking and opens up a heretofore underutilized class of cryoprotective agents for macromolecular crystallography. PMID- 25286443 TI - Evaluation of the RapidHITTM 200, an automated human identification system for STR analysis of single source samples. AB - The RapidHITTM 200 Human Identification System was evaluated to determine its suitability for STR analysis of single source buccal swabs. Overall, the RapidHITTM 200 performed as well as our traditional capillary electrophoresis based method in producing useable profile information on a first-pass basis. General observations included 100% concordance with known profile information, consistent instrument performance after two weeks of buccal swab storage, and an absence of contamination in negative controls. When data analysis was performed by the instrument software, 95.3% of the 85 samples in the reproducibility study gave full profiles. Including the 81 full profiles, a total of 2682 alleles were correctly called by the instrument software, or 98.6% of 2720 possible alleles tested. Profile information was generated from as little as 10,000 nucleated cells, with swab collection technique being a major contributing factor to profile quality. The average peak-height-ratio for heterozygote profiles (81%) was comparable to conventional STR analysis, and while a high analytical threshold was required when offline profile analysis was performed (800 RFU), it was proportionally consistent with traditional methods. Stochastic sampling effects were evaluated, and a manageable approach to address limits of detection for homozygote profiles is provided. These results support consideration of the RapidHITTM 200 as an acceptable alternative to conventional, laboratory based STR analysis for the testing of single source buccal samples, with review of profile information as a requirement until an expert software system is incorporated, and when proper developmental and internal validation studies have been completed. PMID- 25286444 TI - Synthesis of "click" alginate hydrogel capsules and comparison of their stability, water swelling, and diffusion properties with that of Ca(+2) crosslinked alginate capsules. AB - Ionically crosslinked alginate hydrogels have been extensively explored for encapsulation and immunoisolation of living cells/tissues to develop implantable cell therapies, such as islet encapsulation for bioartificial pancreas. Chemical instability of these hydrogels during long-term implantation hinders the development of viable cell therapy. The exchange between divalent crosslinking ions (e.g., Ca(+2) ) with monovalent ions from physiological environment causes alginate hydrogels to degrade, resulting in exposure of the donor tissue to the host's immune system and graft failure. The goal of this study was to improve stability of alginate hydrogels by utilizing covalent "click" crosslinking while preserving other biomedically viable hydrogel properties. Alginate was first functionalized to contain either pendant alkyne or azide functionalities, and subsequently reacted via "click" chemistry to form "click" gel capsules. Alginate functionalization was confirmed by NMR and gel permeation chromatography. When compared with Ca(+2) capsules, "click" capsules exhibited superior stability in ionic media, while showing higher permeability to small size diffusants and similar molecular weight cut-off and water swelling. Physicochemical properties of "click" alginate hydrogels demonstrate their potential utility for therapeutic cell encapsulation and other biomedical applications. PMID- 25286445 TI - Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice. AB - BACKGROUND: Oxidative damage plays a pivotal role in the pathogenesis of cerebral ischemic stroke and may represent a target for treatment. Our previous studies have proved that nuclear factor E2-related factor 2 (Nrf2) and its downstream genes served as a key mechanism for protection against oxidative stress. Paeonol (PN) is reputed to possess a broad range of therapeutic properties probably by virtue of its antioxidative ability. However little is elucidated regarding the underlying mechanisms in ischemic stroke. The aim of this study was to explore PNs effect in ischemic injury and the role of the pAkt, Nrf2 and hemeoxygenase-1 (HO-1) in the mice brains of permanent middle cerebral artery occlusion (pMCAO). METHODS: Male CD-1 mice were subjected to pMCAO and randomly divided into five groups: Sham (sham-operated+0.9% saline), pMCAO (pMCAO+0.9% saline), Vehicle (pMCAO+vehicle), PN-L (pMCAO+PN 30 mg/kg) and PN-H (pMCAO+PN 60 mg/kg) groups. PN was pre-administered intragastrically once daily for 3 days and with the last administration at 30 min before the operation in the fourth day. Neurological deficit scores, brain water content and infarct volume were measured at 24h after pMCAO. Western blot and qRT-PCR were employed to determine the expressions of pAkt, Nrf2, HO-1 and claudin-5. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by spectrophotometer. RESULTS: Compared with Vehicle group, PN significantly alleviated neurological deficit, infarct volume and brain edema (P<0.05), upregulated the expression of pAkt, Nrf2, HO-1 and SOD (P<0.05), decreased the level of MDA (P<0.05). Meanwhile, the expression of claudin-5 was also enhanced. CONCLUSIONS: PN reduced ischemic brain injury after pMCAO; this effect may be accompanied with upregulation of pAkt, Nrf2, HO-1 and ameliorating BBB permeability. PMID- 25286446 TI - Genetic association with low concentrations of high density lipoprotein cholesterol in a pediatric population of the Middle East and North Africa: the CASPIAN-III study. AB - OBJECTIVE: Depressed high-density lipoprotein cholesterol (HDL-C) is prevalent the Middle East and North Africa. Some studies have documented associations between HDL-C and several single nucleotide polymorphisms (SNPs) in candidate gene polymorphisms. METHODS: We investigated the associations between SNP genotypes and HDL-C levels in Iranian students, aged 10-18 years. Genotyping was performed in 750 randomly selected participants among those with low HDL-C levels (below 5th percentile), intermediate HDL-C levels (5-95th) and high HDL-C levels (above the 95th percentile). Minor allele frequencies (MAFs) of the SNPs of interest were compared between the three HDL-C groups. RESULTS: The vast majority of pairwise comparisons of MAFs between HDL-C groups were significant. Pairwise comparisons between low and high HDL-C groups showed significant between-group differences in MAFs for all SNPs, except for APOC3 rs5128. Pairwise comparisons between low and intermediate HDL-C groups showed significant between-group differences in MAFs for all SNPs, except for APOC3 rs5128 and APOA1 rs2893157. Pairwise comparisons between intermediate and high HDL-C groups showed significant between-group differences in MAFs for all SNPs, except for ABCA1 APOC3 rs5128 and APOA1 rs2893157. After adjustment for confounding factors, including age, sex, body mass index, low physical activity, consumption of saturated fats, and socioeconomic status, ABCA1 r1587K and CETP A373P significantly increased the risk of depressed HDL-C, and CETP Taq1 had a protective role. CONCLUSION: This study replicated several associations between HDL-C levels and candidate gene SNPs from genome-wide associations with HDL-C in Iranians from the pediatric age group. PMID- 25286447 TI - In vivo evaluation of vascular-targeted spheroidal microparticles for imaging and drug delivery application in atherosclerosis. AB - OBJECTIVE: Vascular-targeting remains a promising strategy for improving the diagnosis and treatment of coronary artery disease (CAD) by providing localized delivery of imaging and therapeutic agents to atherosclerotic lesions. In this work we evaluate how size and shape affects the capacity for a vascular-targeted carrier system to bind inflamed endothelial cells over plaque using ApoE -/- mice with developed atherosclerosis. METHOD: We investigated the adhesion levels along mouse aortae of ellipsoidal and spherical particles targeted to the inflammatory molecules E-selectin and VCAM-1, as well as the biodistribution of targeted and untargeted particles in major organs following injection via tail-vein and a 30 min circulation time. RESULTS: We found that targeted ellipsoidal microparticles adhered to mouse aortae at higher levels than microspheres of similar volume, particularly at segments that contained atherosclerotic plaques. Moreover, both ellipsoidal and spherical nanoparticles displayed the same minimal adhesion levels compared to both types of microparticles evaluated, likely due to poor localization of nanoparticles to the vessel wall in blood flow. We found that microparticles targeted to plaque-associated inflammation were retained at higher levels in the lungs than untargeted particles, largely due to molecular interaction with the pulmonary endothelium. The level of the mechanical entrapment of ellipsoidal microparticles in the lungs was also not significantly different from that of microspheres of the same volume despite a ~3-fold higher major axis length for the ellipsoids. CONCLUSIONS: Particle shape and size should be considered in the design of carrier systems to target atherosclerosis, as these parameters can be tuned to improve carrier performance. PMID- 25286448 TI - Trajectories of the cortisol awakening responses during weight gain in anorexia nervosa patients with severe and less severe symptoms. AB - The aim of this study was to examine the features and changes of the cortisol awakening response (CAR) in patients with anorexia nervosa (AN) with severe and less severe symptoms over the course of inpatient treatment. Our study included n=20 AN patients who received treatment at the University Hospital, Heidelberg. N=11 patients were admitted at a psychosomatic and internal-medicine ward that specialized in the treatment of AN patients with a very low BMI (patient group with high symptom severity, HSS). The mean BMI of these patients was 13.2 kg/m(2) (SD=1.4) at the beginning of the study and 16.9 kg/m(2) (SD=1.7) at the end. N=9 patients were treated at a psychotherapeutic ward where AN patients with less severe symptoms are admitted (patient group with low symptom severity, LSS). The mean BMI of these latter patients was 16.3 kg/m(2) (SD=0.89) at the beginning of the study and 17.1 kg/m(2) (SD=0.65) at the end. Salivary cortisol was measured on two consecutive days respectively, both at the beginning and the end of the study. At the beginning of the study, patients with HSS had a significantly lower mean CAR compared to patients from the LSS group (3.4 nmol/l vs. 11.4 nmol/l). At the end of the study, the mean CAR of patients from the HSS group was still significantly lower compared to the mean CAR of patients with LSS (2.0 nmol/l vs. 9.2 nmol/l). Results indicate that AN patients with severe symptoms exhibit a lower CAR compared to AN patients with less severe symptoms. PMID- 25286449 TI - Quantitative analysis of wrist electrodermal activity during sleep. AB - We present the first quantitative characterization of electrodermal activity (EDA) patterns on the wrists of healthy adults during sleep using dry electrodes. We compare the new results on the wrist to the prior findings on palmar or finger EDA by characterizing data measured from 80 nights of sleep consisting of 9 nights of wrist and palm EDA from 9 healthy adults sleeping at home, 56 nights of wrist and palm EDA from one healthy adult sleeping at home, and 15 nights of wrist EDA from 15 healthy adults in a sleep laboratory, with the latter compared to concurrent polysomnography. While high frequency patterns of EDA called "storms" were identified by eye in the 1960s, we systematically compare thresholds for automatically detecting EDA peaks and establish criteria for EDA storms. We found that more than 80% of the EDA peaks occurred in non-REM sleep, specifically during slow-wave sleep (SWS) and non-REM stage 2 sleep (NREM2). Also, EDA amplitude is higher in SWS than in other sleep stages. Longer EDA storms were more likely to occur in the first two quarters of sleep and during SWS and NREM2. We also found from the home studies (65 nights) that EDA levels were higher and the skin conductance peaks were larger and more frequent when measured on the wrist than when measured on the palm. These EDA high frequency peaks and high amplitude were sometimes associated with higher skin temperature, but more work is needed looking at neurological and other EDA elicitors in order to elucidate their complete behavior. PMID- 25286451 TI - The diagnostic accuracy of the Revised Mini Nutritional Assessment Short Form for older people living in the community and in nursing homes. AB - OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of the CC-SF, which was developed to use calf circumference (CC) instead of BMI in the MNA-SF, for elderly people living in the community and in nursing homes. It also aimed separately to determine the correlation of CC-SF and BMI-SF with the full MNA. STUDY DESIGN AND METHODS: The study included 640 elderly people living in their community and 243 elderly people living in nursing homes. Accuracy was assessed by determining the sensitivity and selectivity of the nutritional assessments. The correlations between the MNA-SFs and the full MNA were analyzed. RESULTS: The correlation between MNA-SFs and full MNAs was strong, significant and almost identical both in the community and in nursing homes (r=0.86-0.88; p<0.001). The observed agreement between the BMI-SF and the full MNA was 82.2% in the community and 77.8% in the nursing homes. There was a substantial agreement by kappa values in the comparison of community and nursing homes (the Kappa value of the BMI-SF was 0.63 in the community and 0.62 in the nursing homes, and the kappa value of the CC-SF was 0.62 in the community and 0.63 in the nursing homes). When compared to the full MNA the MNA-SFs tended to underestimate nutritional status. Both MNA-SFs had similarly high sensitivity and selectivity, both in the community and nursing homes. (when dichotomized as "malnourished-at risk of malnutrition" versus " well nourished" and "malnourished" versus "at risk of malnutrition-well nourished") (over 80%). CONCLUSION: In cases where BMI cannot be determined, the CC-SF is a good substitute for the BMI-SF. PMID- 25286450 TI - The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction. AB - Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK-STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK-STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by ~85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK-STAT. Inhibition of JAK-STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK-STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK STAT inhibitors in ventilated ICU patients. PMID- 25286452 TI - Nutritional status of the elderly in rural North China: a cross-sectional study. AB - OBJECTIVES: This study aimed to describe the nutritional status of elderly people living in a rural area of North China. DESIGN: Community-based, cross-sectional prevalence survey. SETTING: 3 rural towns of Lvliang City, Shanxi Province, China. PARTICIPANTS: A sample of 1845 community residents (29.1% of those eligible) 55 years or older (birth before 1958-01-01). MEASUREMENTS: The participants were assessed regarding demographic characteristics, height, weight, as well as having a physical examination and blood sampling for serum cholesterol, total homocysteine (tHcy), folate, and vitamin B12 levels. RESULTS: 991 (53.7%) were female and 139 (7.5%) did not complete the anthropometric measurement. Prevalence of underweight and obesity was 3.5% and 24.9% in men and 6.7% and 31.0% in women (P = 0.003, P = 0.005, respectively). Prevalence of hypercholesterolemia and hypocholesterolemia was 13.5% and 52.6% in men and 25.0% and 34.3% in women (P < 0.001, P < 0.001, respectively). Prevalence of high LDL-c concentrations was 8.8% in men and 16.8% in women (P < 0.001). The mean serum tHcy in men (28.8 +/- 20.1 MUmmol/l) was significantly higher than in women (21.0 +/- 15.1 MUmmol/L, P < 0.001). Prevalence of hyperhomocysteinemia (defined as > 15MUmmol/L) was 79.7% in men and 65.5% in women (P < 0.001). Prevalence of low folate (defined as < 11 nmol/L) and vitamin B12 levels (defiend as < 185 pmol/L) was 70.8 % and 76.8% in men and 56.5% and 72.6% in women (P < 0.001, P = 0.036, respectively). Correlation coefficients between tHcy, folate, and vitamin B12 indicated an inverse linear correlation (r = -0.21, P < 0.001, r = -0.35, P < 0.001, respectively). CONCLUSIONS: As China's economic climate has developed, the nutritional status of elderly people in the rural parts of the country has improved in some aspects. However, the trend toward obesity will lead to a shift in the burden of obesity-related chronic diseases. In addition, rurally-located elderly people are at high risk of death that may be associated with abnormal serum cholesterol. The data also suggest that severe deficiencies in folate and vitamin B12 levels exist, as well as there being a high prevalence of hyperhomocysteinemia. Folate and vitamin B12 supplementation are necessary to prevent related diseases. PMID- 25286453 TI - Hyperglycemia is associated with relatively lower lean body mass in older adults. AB - BACKGROUND/OBJECTIVES: Older adults with known diabetes are vulnerable to accelerated loss of lean body mass. However, the relationship of hyperglycemia per se with lean body mass is not fully understood. We sought to examine the independent relationship of hyperglycemia with relative lean body mass in older persons without a reported history of diabetes. DESIGN: Cross-sectional nationally representative survey. SETTING: United States. PARTICIPANTS: We studied U.S. adults >50 years without known diabetes (n=5434) in the National Health and Nutrition Examination Survey (1999-2004). MEASUREMENTS: In linear regression models, we studied the relationship of measured HbA1c (<5.0%, 5.0 5.4%, 5.5-5.9%, 6.0-6.4%, >=6.5%) with percent lean body mass, measured by dual energy x-ray absorptiometry, after accounting for potential confounders. RESULTS: Among older U.S. men and women, progressively higher HbA1c was associated with relatively lower total, appendicular, and trunk percent lean mass, independent of demographics and height (all p<0.05). Accounting for physical activity, C reactive protein, and diabetes-related comorbidities (heart disease, peripheral arterial disease, arthritis, neuropathy, hip fracture, amputation, cancer, pulmonary disease), undiagnosed diabetes (i.e. HbA1c >=6.5%) versus reference (<5.0%) in both men and women was associated with lower total (-3.5+/-0.8% and 2.9+/-0.8%), appendicular (-1.8+/-0.5% and -1.2+/-0.4%), and trunk percent lean mass (-1.2+/-0.4% and -1.3+/-0.5%), respectively (all p<0.05). Persons at increased risk for diabetes (i.e. HbA1c 6.0-6.4%) also had significant decrements at these sites versus reference. CONCLUSIONS: Hyperglycemia is associated with relatively lower lean mass in a nationally representative population of older adults without history of diabetes. Future longitudinal studies are needed to investigate the relationship of hyperglycemia with the accelerated decline of skeletal muscle mass in older persons. PMID- 25286454 TI - Bioelectrical impedance analysis is more accurate than clinical examination in determining the volaemic status of elderly patients with fragility fracture and hyponatraemia. AB - OBJECTIVES: Management of hyponatraemia depends crucially on accurate determination of volaemic (hydration) status but this is notoriously challenging to measure in older people. Bioelectrical impedance analysis (BIA) provides a validated means of determining total body water (TBW), but its clinical utility in determining volaemic status in hyponatraemia has never been tested. This study assessed the utility of BIA in the clinical management of hyponatraemia in elderly patients with fragility fractures (EPFF), a group at high risk of hyponatraemia. DESIGN: Prospective observational study of consenting patients >=65 years with fragility fractures (N=127). SETTING: University teaching hospital in Scotland. PARTICIPANTS: Patients >=665 years with fragility fractures with capacity to consent to participation. MEASUREMENTS: BIA and standard clinical examination procedures (jugular venous distension, skin turgor, mouth and axillary moistness, peripheral oedema, capillary refill time, overall impression) were performed daily throughout each participant's hospital stay. Volaemic status of hyponatraemia was determined by an expert panel using clinical data (history, examination, nursing observations and laboratory tests) blinded to TBW readings. Cohen's kappa was calculated to assess the level of agreement between the expert panel and both BIA and standard clinical examination measures in determining the volaemic state of hyponatraemia. RESULTS: 26/33 (79%) cases of hyponatraemia had sufficient clinical information to allow determination of volaemic status by BIA. There was moderate level of agreement between BIA and the expert panel, kappa 0.52 (p<.001). All kappa values for standard clinical assessments of volaemic status neared zero, indicating nil to slight agreement. CONCLUSION: BIA outperformed all aspects of the standard clinical examination in determining the volaemic status of hyponatraemic EPFF, suggesting it may be useful in clinical practice. PMID- 25286455 TI - Sarcopenia according to the European Working Group on Sarcopenia in Older People (EWGSOP) versus dynapenia as a risk factor for mortality in the elderly. AB - BACKGROUND: Sarcopenia and dynapenia have been associated with poorer physical performance, disability and death. The aim of this study was to compare the association between sarcopenia and dynapenia with mortality. METHODS: We studied 1,149 Brazilians aged 60 years or older residing in Sao Paulo. Sarcopenia was defined according to the consensus of the European Working Group on Sarcopenia in Older People (EWGSOP), which includes three components: low muscle mass (LMM) assessed by skeletal muscle mass index <= 8.90kg/m2 (men) and <= 6.37kg/m2 (women); low muscle strength (LMS) assessed by handgrip strength <30kg (men) and < 20kg (women); and low physical performance (LPP) assessed by walking speed <= 0.8m/s. Diagnosis of sarcopenia required presence of LMM plus LMS or LPP. Dynapenia was defined as handgrip strength < 30kg (men) and < 20kg (women). Covariates included socio-demographic and behavioral variables, medical conditions, hospitalization, depressive symptoms, cognition, and disability in activities of daily living or instrumental activities of daily living. The outcome was all-cause mortality over five-year follow-up. RESULTS: During the five-year follow-up, 187 subjects died. The mortality rate for those with or without sarcopenia were 65.9/1,000 person/years and 20.1/1,000 person/years and for dynapenia were 44.3/1,000 person/years and 14.9/1,000 person/years. The adjusted model showed that sarcopenia (HR=1.52, 95%CI: 1.06 - 2.19) and dynapenia (HR=2.04, 95%CI: 1.24 - 3.37) are independent risk factors for death. CONCLUSIONS: The EWGSOP definition of sarcopenia and dynapenia can help to determine risk for mortality and can be used as a screening instrument in public health. PMID- 25286456 TI - Screening for frailty in elderly subjects living at home: validation of the Modified Short Emergency Geriatric Assessment (SEGAm) instrument. AB - OBJECTIVES: To validate the modified version of the Short Emergency Geriatric Assessment (SEGAm) frailty instrument in elderly people living at home. DESIGN: Longitudinal, prospective, multicentre study. SETTING: Four departments (Ardennes, Marne, Meurthe-et-Moselle, Meuse) in two French Regions (Champagne Ardenne and Lorraine). PARTICIPANTS: Subjects aged 65 years or more, living at home, who could read and understand French, with a degree of autonomy corresponding to groups 5, or 6 in the AGGIR autonomy evaluation scale. MEASUREMENTS: Assessment included demographic characteristics, comprehensive geriatric assessment, and the SEGAm instrument. Psychometric validation was used to study feasibility and acceptability, internal structure validity, reliability, and discriminant validity of the SEGAm instrument. RESULTS: Between July 1st 2012 and March 31st 2013, 167 patients were included in the study. Averaged age was 77+/-7 years, the majority were women (70.7%). Feasibility and acceptability of the SEGAm instrument were excellent: we observed no refusal to participate, no drop-out during administration, no missing items, no ceiling or floor effects, and the administration time was short (5.0+/-3.5 min). By factor analysis, the instrument proved to be unidimensional. It showed good internal consistency (Cronbach's alpha coefficient: 0.68) and good test-retest (intra-class correlation: 0.88) at 7 days interval. Discriminant validity showed a significant difference, mainly for nutritional status, fall risk, dependency, mood and depression risk, and comorbidities. CONCLUSION: Based on these psychometric properties, the SEGAm appears to be an easy-to-use instrument that is particularly suitable for use in the community to identify frail elderly people who could benefit from early targeted interventions. PMID- 25286457 TI - Depression as a correlate of functional status of community-dwelling older adults: utilizing a short-version of 5-item Geriatric Depression Scale as a screening tool. AB - Depression has been known to be associated with functional limitations in elderly populations and screening is an effective preventive approach. The purpose of this study was to examine the contribution of depression in explaining the functional status of community-dwelling older adults and to explore the utility of a short version 5-item Geriatric Depression Scale (GDS-5) as a screening tool. DESIGN: Cross-sectional survey Settings: Six hospitals and communities served by home-delivery meal programs Participants: 529 individuals aged 60 years and older. MEASUREMENTS: Using structured survey questionnaires, key variables including demographics, depression status, and two domains of functional status assessed by basic Activities of Daily Living (ADL) /Instrumental ADL (IADL) and mini-mental status (MMSE) were collected. To determine the unique contribution of depression in explaining functional status of participating older adults, hierarchical multiple regression was conducted. RESULTS: The model explained 18 % of the total variance in physical function and 21 % of the total variance in cognitive function. Race/ethnicity and depression were significant predictors of functional status. In particular, entry of the depression variable resulted in a significant R square change of 7%, accounting for a unique portion of the ADL/IADL variance. In terms of cognitive function measured by MMSE, entry of the depression variable showed a small, but significant change. Older adults who were ethnic minorities and had depression were significantly more likely to report poor perceived physical and cognitive function. Hierarchical multiple regressions revealed that some personal factors such as age, education, race/ethnicity contributed to the explanatory model, and depressive symptoms significantly explained additional variance. GDS-5 was less reliable (Cronbach's alpha= 0.5) to assess depressive symptoms in this study. CONCLUSION: Depression was a significant contributing factor to functional limitations of older adults. A short 5-item version of the GDS could be used to screen older adults, but two tiered GDS-5/15 would be better alternative tool. PMID- 25286458 TI - [Background to forefront: sensor channels for cell death and homeostasis]. PMID- 25286459 TI - Serum cholesterol response to changes in the diet: I. Iodine value of dietary fat versus 2S-P. AB - In men in calorie equilibrium, changes in dietary fat produce responses in the serum cholesterol level that, on the average, are predictable from the percentages of total calories provided by saturated (S) and polyunsaturated (P) fatty acid glycerides in the diets concerned. S and P have opposing actions and, in general, Delta Cholesterol (mg./100 ml.) = 2.7DeltaS - 1.3DeltaP, where Delta refers to the difference between 2 diets. Increasing the number of double bonds beyond 2 in polyunsaturated fatty acids does not result in proportionate increases in serum cholesterol-lowering effect. The mono-enes oleic and erucic acid have little or no effect on the serum cholesterol level when they are exchanged in the diet for equal calories of simple carbohydrate. Changes of fats in the diet produce serum cholesterol responses that are also correlated with the iodine values, or the square-roots of those values, of the fats concerned when the iodine value happens to be highly correlated with 2.7S - 1.3P. When changes in diet fats involve substantial differences in amounts of mono-enes, or of fatty acids containing more than 2 double bonds, the serum cholesterol response has a low or negligible correlation with the iodine value, or its square-root, of the fats. PMID- 25286460 TI - Serum cholesterol response to changes in the diet: II. The effect of cholesterol in the diet. AB - The series of metabolic ward experiments, with 22 physically healthy men in each, covered dietary cholesterol intakes from 50 to 1450 mg. daily, with all other variables controlled. The serum-cholesterol data, plus the data from comparable experiments reported from 4 other institutions, were analyzed in regard to average serum cholesterol response (Delta Chol., mg./100 ml.) to changed cholesterol intake. Least-squares solution, using serum cholesterol responses in 19 sets of dietary cholesterol comparisons, gives Delta Chol. = 1.5(Z2 - Z1), where the subscripts refer to the diets compared and Z is the square-root of the dietary cholesterol, measured as mg./1000 Cal. The correlation between the average Delta Chol. predicted and that observed is r = 0.95. The serum response was the same over a wide range of dietary fat composition. Ordinary American diets range from about about 150 to 350 mg. cholesterol/1000 Cal. These extremes correspond to an average difference of about 9 mg. of cholesterol/100 ml. of serum if all other variables are constant. Change from 250 mg./l000 Cal. to a cholesterol-free diet will cause an average fall of about 24 mg./100 ml. of serum. But a 50 per cent decrease in dietary cholesterol will produce an average decrease in the serum of only about 7 mg./100 ml. For the purpose of controlling the serum level, dietary cholesterol should not be completely ignored but attention to this factor alone accomplishes little. PMID- 25286461 TI - Preface. PMID- 25286462 TI - [Etiopathogenic factors and patterns of the electrical activity violations of the gastrointestinal tract in patients with critical conditions]. PMID- 25286463 TI - Concerted efforts to improve the understanding and treatment of anxiety disorders. Preface. PMID- 25286464 TI - Reply from the author. PMID- 25286465 TI - Serum cholesterol response to changes in the diet: III. Differences among individuals. AB - Data from 227 men in 10 sets of controlled dietary experiments in 5 institutions gave the least-squares solution: [see text] with S.E. of slope --+/-0.44, where X is the serum cholesterol level of an individual, X is the average for all men on the same diet, and Delta is the response to a given dietary change. Equations, a chart and a table are provided for the prediction of the serum cholesterol response when change is made from one diet to another when cholesterol and fatty acid compositions of the diets are known. Comparison of predicted with observed average values in recently published data on samples of free-living people changing diets on prescription designed to lower serum cholesterol gave, predicted versus observed Delta: -30.0 vs. -28.5 and -27.2 vs. -30.1 mg./l00 ml. in men and women in caloric balance. In a sample of men who were also losing weight on a low-fat, low-cholesterol diet a change of -33.5 was predicted versus 39.8 observed. PMID- 25286466 TI - Serum cholesterol response to changes in the diet: IV. Particular saturated fatty acids in the diet. AB - For many dietary changes satisfactory prediction of the average change in the serum cholesterol level of man in mg./100 ml., is given by Delta Chol. = 1.35(2DeltaS - DeltaP) + 1.5DeltaZ where S and P are percentages of total calories provided by glycerides of saturated and polyunsaturated fatty acids in the diet and Z2 = mg. of dietary cholesterol/1000 Cal. This formula fails, however, when the dietary change involves large amounts of cocoa butter and discrepancies also appear with beef tallow or hydrogenated coconut oil diets. Controlled dietary experiments at the University of Minnesota and at 2 other centers, provide 63 sets of comparisons of serum cholesterol averages for groups of men on each of 2 chemically characterized diets. Least-squares analysis indicates that stearic acid, as well as saturated fatty acids containing fewer than 12 carbon atoms, have little or no effect on serum cholesterol in man. The equation, Delta Chol. = 1.2(2DeltaS' - DeltaP) + 1.5DeltaZ, yields good correlation (r = 0.93) with the observed values in these 63 sets of data. This formulation also resolves heretofore puzzling discrepancies in the literature. PMID- 25286467 TI - Correlation of serum lipids with uric acid and blood sugar in normal males. AB - In a group of healthy adult males, the correlation of serum triglycerides with cholesterol, uric acid, blood sugar and obesity was not significant. The annual variation of these biochemical determinations was of a sufficient degree to warrant caution in designating an individual as being at risk of developing coronary artery disease on the basis of a single value. Until our knowledge concerning the basic factors predisposing to coronary artery disease is more fully developed, it would appear that multiple biochemical determinations related to lipid, protein and carbohydrate metabolism should be included at repeated intervals in any longitudinal study of this disease process. PMID- 25286468 TI - The effect of phenformin on "prediabetes". AB - Observations are presented on the cortisone glucose tolerance test in 568 relatives of diabetic patients. Twenty-one per cent showed a positive cortisone glucose tolerance curve, including 4.4 per cent who were regarded overtly diabetic from the conventional glucose tolerance curve. A double-blind study was carried out, on the effect of a 6 week course of phenformin on cortisone-induced glucose intolerance in 60 non-diabetic relations of diabetic persons. Following placebo administration, there was a progressive decline in the number of subjects whose cortisone glucose tolerance curve was rendered normal, to 42 per cent 1 year after discontinuing the agent. With phenformin there was a progressive rise to 71 per cent. The phenformin effect was statistically significantly greater than placebo (0.05 > p > 0.02). These subjects were comprised of 2 groups. In subjects designated "prediabetics," the conventional glucose tolerance curves were entirely normal. In "probable diabetics," the conventional glucose tolerance curve showed some abnormality, but not sufficient to be regarded as overt diabetes. In the probable diabetes group, 1 year following placebo marked deterioration of cortisone glucose tolerance occurred, while in the phenformin treated there was improvement. The differences were highly statistically significant 0.005 > p > 0.001). Not 1 of 7 phenformin treated persons became overtly diabetic, whereas 3 of 5 placebo treated showed overt diabetes after 1 year. Following 1 year of observation, no change occurred in the mean values of the cortisone glucose tolerance curve in a group of prediabetics. (p > .0.9). One year after placebo administration a slight fall occurred. (0.05 > p > 0.02), but following phenformin a marked and highly significant drop was observed (p < 0.001). Placebo appears to exert a significant but progressively wanning influence on the glucose intolerance of prediabetes, and no effect on probable diabetes. Phenformin results in marked amelioration of the cortisone-induced glucose intolerance of both prediabetes and probable diabetes, and appears to exert a retarding effect on the development of the diabetic syndrome. PMID- 25286469 TI - Electrolyte and renal changes in severe potassium depletion. AB - This report describes electrolyte changes and some clinical aspects of the renal disease associated with the loss of potassium through the gastrointestinal tract in 2 patients with diarrhea. In one of them, the diarrhea resulted from non tropical sprue, in the other, from non-beta islet-cell adenoma of pancreas. In both patients, some observations were repeated after potassium repletion. PMID- 25286470 TI - Magnesium metabolism in Huntington's chorea. AB - Human magnesium deficiency states are known to be associated with tremor, choreiform and athetoid movements, delirium and convulsions. In order to assess a recent report of altered magnesium metabolism in Huntington's chorea, 6 patients with the disease have been studied with complete balance studies, exchangeable magnesium studies, erythrocyte and ultrafiltrable magnesiums and 2 patients with spinal fluid magnesium determinations. Balance studies failed to suggest any abnormalities. Exchangeable magnesium28 values were within normal ranges (4.3 +/- 0.7 mEq./Kg. at 24 hrs.), as were erythrocyte magnesium determinations (5.29 +/- 0.42 mEq./L.). Ultrafiltrable magnesiums were normal and the 2 spinal fluids evaluated had normal magnesium values. These results are not compatible with the hypothesis of altered magnesium metabolism in Huntington's chorea. PMID- 25286471 TI - Effects of protein intake and growth hormone on utilization of N15 from ammonium citrate. AB - In experiments on dogs receiving diets containing either 12.3 per cent of casein and a supplement of methionine, or 36.2 per cent of casein, utilization of N15 from ingested ammonium citrate was larger when it was added to the low protein diet. Growth hormone induced nitrogen storage and gain in weight on the low protein diet, and increased utilization of N15 from ammonium citrate much more than it did when protein intake was high. Addition of sodium lactate, pyruvate, or alpha-ketoglutarate to either diet on the day that N15-labeled ammonium citrate was fed did not alter the amount of N15 retained. PMID- 25286472 TI - Effect of catecholamines, glucose, insulin, and changes of flow on the metabolism of free fatty acids by the myocardium. AB - Isolated rabbit hearts were perfused with a suspension of red blood cells in a buffer solution containing palmitate-1-C14 complexed to albumin. Arteriovenous differences of radioactivity in free fatty acids (FFA) and CO2 were measured after addition of epinephrine, norepinephrine, glucose and insulin under conditions of constant arterial concentration of FFA and rate of perfusion. Both norepinephrine and epinephrine increased the oxidation of free fatty acids to CO2 (48 and 53 per cent, respectively) but neither altered their extraction by the myocardium. Addition of glucose alone or glucose with insulin influenced neither the extraction nor the oxidation of FFA. Under the conditions of study, uptake of FFA by the heart was strictly proportional to the rate of perfusion. PMID- 25286473 TI - Total urinary hydroxyproline excretion in diabetics before and after hypophysectomy and after growth hormone in adult hypopituitarism. AB - Total urinary excretion of hydroxyproline has been found to be significantly decreased in adult diabetics and was increased after hypophysectomy for diabetic retinopathy. There was no change in hydroxyproline excretion after the administration of 53 mg. of human growth hormone to one patient with hypopituitarism over a 4 day period. PMID- 25286474 TI - The effect of nicotinic acid on adipose tissue metabolism in vitro. AB - Rat epididymal fat pads were incubated in vitro in the presence of norepinephrine and nicotinic acid. Nicotinic acid was found to inhibit the glycerol release induced by norepinephrine from the tissues. It also increased glucose uptake. The lipase activity in the tissue homogenate was increased by norepinephrine. This increase was more pronounced in the presence of norepinephrine and glucose. Nicotinic acid incubated with the intact tissue inhibited the norepinephrine induced increase. It had no effect when added to the homogenate. The results suggest that the ability of nicotinic acid to decrease fatty acid outflow from adipose tissue is caused by inhibition of the lipase activation by norepinephrine and possible also by increase of re-esterification of fatty acids. PMID- 25286475 TI - Circadian periodicity in thyroid stimulating hormone titer in the rat hypophysis and serum. AB - Thyroid stimulating hormone (TSH) activity in the hypophyses of euthyroid and hypothyroid rats and the sera of hypothyroid rats maintained under standardized conditions were assayed. The concentration of TSH in the gland and serum exhibited a circadian rhythm. PMID- 25286476 TI - ELECTROPHYSIOLOGY OF HIPPOCAMPAL NEURONS: III. FIRING LEVEL AND TIME CONSTANT. PMID- 25286477 TI - ELECTROPHYSIOLOGY OF HIPPOCAMPAL NEURONS: IV. FAST PREPOTENTIALS. PMID- 25286479 TI - Get your geek on. PMID- 25286478 TI - Changes. PMID- 25286480 TI - Dues diligence. PMID- 25286481 TI - Address to the House of Delegates, IDA President elect Dr. Steven Holm May 17, 2014. PMID- 25286482 TI - Resolutions briefing. PMID- 25286483 TI - IDPAC update. PMID- 25286484 TI - IDA leadership is in the AIR. PMID- 25286485 TI - Smiles for success: restoring functional dentition one mouth at a time. AB - Edentulism is the outcome of a multifactorial process involving biological factors and patient-related factors. Prosthodontics serves as a solution. Tooth replacement through prosthetic devices may be prohibitive for the underserved population due to barriers such as cost and lack of transportation. A community service project was developed as a response strategy to address these concerns in Fort Wayne, Indiana. With the help of Indiana University Purdue University (IPFW) Dental Laboratory Technology students and local dental professionals, the Smiles for Success: Restoring Functional Dentition One Mouth at a Time project assisted the underserved of Fort Wayne. Success was accomplished through the repair or reline of existing dentures, as well as the creation of new partial and complete oral prosthetic appliances. Working within the existing healthcare framework of an inner city clinic and local health fair for the underserved, the project completed work on 29 dentures and restored 22 patients to functioning dentitions. While the prosthetic appliances bring about new and restored smiles, it leads to a lifetime of new opportunities and improved health. PMID- 25286486 TI - The Irish priest. PMID- 25286487 TI - The summer of '64. PMID- 25286488 TI - IDA member healthcare benefits. PMID- 25286489 TI - WHO is responsible? PMID- 25286490 TI - Should dentistry be a profession or a retail industry? PMID- 25286491 TI - Oath of dentistry. PMID- 25286492 TI - Health care reform: preparing for the coming train wreck. PMID- 25286493 TI - Backyard wildlife. PMID- 25286494 TI - Component 140. PMID- 25286495 TI - Because it's Indiana... PMID- 25286496 TI - Smooth and fast to the finish line. PMID- 25286497 TI - Community--connected to patients through work and life. PMID- 25286498 TI - Governing decisions of your association. AB - Every association has some sort of internal structure to make decisions and to do the business of the association. Though the IDA is a member organization, we use a representative form of governing to allow selected members to represent the entire membership. For the Indiana Dental Association, there are two major parts to this governance structure: the administrative body in the Board of Trustees and a legislative body called the House of Delegates. Both are made up of representative members from each of the local component societies or districts. PMID- 25286499 TI - Hoosier smiles. PMID- 25286500 TI - Dentists making a difference--and making room for you. PMID- 25286501 TI - Including CAD/CAM dentistry in a dental school curriculum. PMID- 25286502 TI - Complications associated with the placement and restoration of dental implants. PMID- 25286503 TI - Be true to your teeth or they will be false to you . PMID- 25286504 TI - Who is your hero? PMID- 25286505 TI - [Effects of copper and zinc cations bound by gamma-globulin fraction in Staphylococcus aureus culture]. AB - AIM. Evaluation of Staphylococcus aureus culture growth dynamics in the presence of gamma-globulin: metal-complexes formed with copper and zinc cations as well as cations of metals used in isolation during the first 24 hours of exposition. MATERIALS AND METHOD: . Samples of human gamma-globulin metal-complexes with copper or zinc cations at a final concentration of 0.5 microg/ml were introduced into S. aureus bacteria suspensions containing approximately 10(3) CFU/ml. Suspension at the volume of 5.0 ml was incubated at 37 degrees C for 24 hours with sampling and CFU calculation in the culture at various exposure periods. An accepted micromethod for determination of viability of bacteria was used. RESULTS: The protein transformed by copper cation binding realizes bacteriostatic activity in the logarithmic growth phase of S. aureus culture from 3.0 to 6.0 hours of incubation. Free copper cations inhibit bacterial reproduction at a higher degree than the metal-complex. The protein transformed by zinc cation binding realizes bacteriostatic activity at 1.5 hours of S. aureus incubation. Free zinc cations do not have bacteriostatic effect against S. aureus. CONCLUSION: Proteins of the gamma-globulin fraction in the range of physiological concentrations forming metal-complexes with copper and zinc cations may be factors that have cytostatic effect against S. aureus bacteria. Zinc cations realize bacteriostatic activity only in gamma-gloulin bound state whereas copper cations--also in the free state. PMID- 25286506 TI - [The role of pro- and antioxidants of microorganisms in regulation of symbiosis homeostasis mechanisms (on the model of human vaginal biotope)]. AB - AIM: Study the production of bacterial pro- and antioxidants in vaginal biotope and analysis of their role in regulation of symbiosis homeostasis mechanisms. MATERIALS AND METHODS: Hydrogen peroxide, catalase inhibitors and antioxidant production in bacteria isolated from 63 women with vaginal eubiosis and 53--with dysbiosis were studied. Production of pro- and antioxidants was regulated by lactate, volatile fatty acids, polyamines and Lactobacillus plantarum and Corynebacterium minutissimum polysaccharides, metabolite bactericidity of peroxide producing lactobacilli was enhanced by addition of iron (II) ions. RESULT: A high level of pro- and antioxidant production was noted for eubiosis state, and their ratio was close to 1, for biotopes with dysbiosis a multiple predominance of microbial antioxidant levels over pro-oxidants was characteristic. Peroxide producing symbionts are an important component of system of generation of hydroxyl radicals that are highly effective wide specter disinfectants. CONCLUSION: Maintenance of balance of pro- and antioxidant production by symbionts determined vaginal biotope symbiosis homeostasis. The detected high biocidic activity of hydroxyl radicals that are formed from hydrogen peroxide of normoflora through the creation of optimal conditions for their generation by selection of the respective concentrations of iron (II) ions and H2O2 opens perspective of development of novel disinfection methods. PMID- 25286507 TI - [Activity of B and D factors of complement alternative pathway in children with atopic dermatitis]. AB - AIM: Development of enzyme immunoassay detection of B and D factors of complement alternative pathway functional activity for solving diagnostic and prognostic problems of patient therapy. Study activity of these factors in blood sera of children with atopic dermatitis before and after therapy for elucidation of the role of complement alternative pathway in pathogenesis of this disease. MATERIALS AND METHODS: Children aged 6 months to 18 years with atopic dermatitis were examined for functional activity of B and D factors in blood sera before and after therapy by the developed methods. RESULTS: The developed enzyme immunoassay methods for determination of functional activity of B and D complement alternative pathway showed high sensitivity and reliability. In children with atopic dermatitis factor B and D activity was significantly lower than normal before treatment. After treatment these activity increased significantly (p < 0.004) and in the case of D factor--up to normal. CONCLUSION: The data obtained in the study indicates the presence of complement alternative pathway activation in atopic dermatitis in children and the possibility of use of factor B and D functional activity analysis for diagnostic and prognostic purposes. PMID- 25286508 TI - [Comparative analysis of informative-diagnostic properties of mucosa immune reactivity parameters]. AB - AIM: Study the features of immune-reactivity expression in mucosa depending on their topicity and etiopathogenesis of the pathological process. MATERIALS AND METHODS: Data from 30 clinically healthy children and 77 children with acute and recurrent diseases of respiratory tract: 51--with acute and 15--with chronic bronchitis; as well as 132 women: 41--with active stage of acute urogenital chlamydia infection, 29--with recurrent chronic process, 30--with non-recurrent form and 32 clinically healthy women were analyzed. Saline and urogenital tract mucosa discharge was analyzed for IgG, sIgA and secretory component, IL-1beta, 4, 6, 8, 9, 10, 12, IFNgamma, TNFalpha and GM-CSF, TLR-2, TLR-3, TLR-4, TLR-8 gene expression levels as well as content of lysozyme, total protein and leucocytes. RESULTS: Solidity, universality and practically single-stage triggering of mucosa immune reaction mechanisms to intervention by foreign agents regardless of their localization was confirmed. A dependence of immune-reactivity expression on the form of pathologic process, its localization and qualitative and quantitative characteristics of the infectious agents was clearly seen. The highest level of clinical-laboratory and immunological parameters is inherent for patients with acute processes in urogenital tract (cervical canal and urethra), especially cause by mixed infections. CONCLUSION: Immune diagnostic parameters of mucosa among which TLR system is especially notable have high information properties allowing not only diagnostics of inflammatory process but also differentiating its form and character our course. PMID- 25286509 TI - [Immune diagnostics of disorders in the IFN-alpha/NK-cell system in patients with frequently recurrent herpes simplex]. AB - AIM: Study of features of NK-cell response to the effect of recombinant IFN-alpha in complex with evaluation of the ability to synthesize inherent IFN-alpha in patients with frequently recurrent herpes simplex (FRHS). MATERIALS AND METHODS: 48 patients with genital (n = 31), labial (n = 10) and mixed localization (n = 7) FRHS diagnosis were observed. 31 healthy donors composed the control group. MC were cultivated in the presence of a recombinant human IFN-alpha2b at the concentration of 10, 100 and 1000 U/ml for 24 hours. NK-cell response to the effect of IFN-alpha was evaluated after 24 hours using flow cytometry by degranulation reaction and in the NK-activity test. IFN-alpha synthesis was evaluated in HSV-1, HSV-2 and Newcastle disease virus stimulated cell supernatants by EIA method. RESULTS: Patients with FRHS were established to be a heterogeneous group by parameters in the IFN-alpha/NK-cell cytotoxicity system. 2 types of NK-cell response to the stimulation by recombinant IFN-alpha were identified. Type A is characterized by a decrease of NK-cell response to IFN alpha in the remission phase and does not have this defect in the exacerbation phase. Synthesis of inherent IFN-alpha in response to viral inductors for type A was comparable with the response in healthy donors in both phases. On the contrary type B having normal sensitivity of NK-cells to IFN-alpha in the remission phase is characterized by a decrease of this parameter in the exacerbation phase for more than 3 times. Synthesis of inherent IFN-alpha in response to viral inductors during type B is increased in the remission phase and decreased in the exacerbation phase. CONCLUSION: During immune-correcting therapy of FRHS a personalized approach taking into account features of NK-cell response to IFN-alpha is necessary, because types A and B have principal differences by cytotoxicity parameters of NK-cells and their change under the effect of IFN alpha, as well as by parameters of IFN-alpha synthesis in response to viral inductors at various phases of the clinical process. PMID- 25286510 TI - [Comparative characteristics of HLA system gene distribution in patients with lung tuberculosis of the Russian population of Chelyabinsk region]. AB - AIM: Study of distribution of genes and HLA system haplotypes A, B, DRB1, DQA1, DQB1 in healthy individuals and patients with lung tuberculosis, members of the Russian population of Chelyabinsk region for isolation of risk markers for the development of various forms of tuberculosis. MATERIALS AND METHODS: The study group consisted of 86 patients with lung tuberculosis of the Tuberculosis Dispensary No. 3 of Chelyabinsk of Russian nationality. 239 healthy donors of Chelyabinsk Hemotransfusion Station of Russian nationality composed the comparison group. HLA-typing was carried out by multi-primer polymerase chain reaction--PCR SSP, HLA II genotyping--by DNA technology (Russia) kits, HLA class I--by methods described in the article by Downing J.M.G. et al. (2004). Result detection was carried out by electrophoresis. RESULTS: In lung tuberculosis patients high frequency of detection of HLA haplotype DRB1*16-DQA1*01:02 DQB1*05:02/4 was established. In patients with fibrous-cavernous form B*08 and DRB1*03 gene frequency of detection increased and DRB1*07 and DQA1*02:01 genes did not occur. During focal form high frequency of HLA B*15 and HLA DRB1*15 alleles was determined compared with infiltrative form. HLA A*01-B*08-DRB1*03 DQA1*05:01-DQB1*02:01 haplotype only occurred ingroups of patients with more severe forms of tuberculosis. CONCLUSION: Markers of sensitivity to clinical phenotypes of tuberculosis were isolated. PMID- 25286511 TI - [Intestinal microflora, obesity and type 2 diabetes]. AB - The review of data of the literature on a role of intestinal microflora, genetic features of a macroorganism, exogenic factors and character of a food is presented at obesity and a type 2 diabetes. Researches establish, that development in experimental animals of the induced obesity and the type 2 diabetes, depends on a diet and presence of intestinal microflora. The factors increasing permeability mucous intestines, promote a translocation of intestinal automicroflora and its toxins into macroorganism and a system blood-circulation. Long introduction LPS (endotoxin) of gram-negative bacteria to the special laboratory animals led to development of inflammatory reaction, adiposity and resistance to insulin. The specified phenomena did not develop at LPS introduction to the animals, who have lost receptor CD14 which is necessary for linkage and endotoxin action. Data about change of intestinal microflora and a role of immune infringements are discussed at obesity and the type 2 diabetes occurring into background of low-grade chronic inflammation and metabolic disorders. PMID- 25286512 TI - [Intestine microbiota and allergic diseases]. AB - In industrialized countries an increased number of diseases due to immune system disorders including connected with allergy is noted. Allergic diseases generally proceed against the background of various common inflammatory diseases arising in childhood. The role of intestine microflora in its interaction with immune system and defining factors in allergization of children are actively studied. A decrease of risk of allergy development later in life for children who had grown up in the countryside was shown to be possibly related with microorganisms present in food. Thus the positive potential of farms is currently examined as a result of innate immunity activation by using microbial components. Acinetobacter lwoffii F78 isolated from cowsheds is able to protect mice from experimental allergy by activating Th1-polarization program of dendritic cells. Moreover, an important role in pathogenesis of allergic diseases belongs to mast cells. Probiotic lactobacilli may weaken activation of mast cells and release of inflammation mediators connected with allergic reactions. The ability of intestine microflora to influence immune response resulted in novel approaches in therapy that use these differences in microbiota for therapy and prophylaxis in allergy patients. And therefore on the basis of "hygiene hypothesis" of allergy emergence, a consideration is expressed that early manipulation with intestinal microbial communities may offer a new strategy of allergic sensibilization prevention. PMID- 25286513 TI - [Bronchial asthma pathogenesis and genetic prognosis development]. AB - The review is dedicated to an actual problem--genetic prognosis of risk of bronchial asthma development that is quite a complex aspect of studies from a methodological viewpoint. Bronchial asthma--heterogeneous disease by both etiology and clinical characteristics. At the same time genetic prognosis is based on the unity of pathogenetic mechanisms of development, though in immunological reactions that are the base of this disease, alternative variants are possible. The aim of this review is carrying out parallels between modern achievements in the field of deciphering trigger mechanisms of bronchial asthma pathogenesis and object of genetic studies based on these mechanisms. Among the examined conceptions--role of epithelial tissue in trigger mechanisms of bronchial asthma, variants of key role of immune system cells, first of all, T helpers of various types for further development of inflammatory-effector reactions with damage characteristic for this disease. Compliance of contemporary approaches of genetic studies and novel concepts of bronchial asthma pathogenesis is shown. PMID- 25286514 TI - [Pneumococcus pathogenicity factors and their protective properties]. AB - Owing to rapid development of molecular-biological and genetic methods of research in infectology as well as use of adequate models (tissue colonization of human respiratory epithelium, mice models of colonization, sepsis and meningitis), a significant progress in the field of pneumococcus pathogenicity factors has been made in the last decades. Aside from the well-known pathogenicity factor--capsule polysaccharide, to date several dozens of surface proteins providing adhesion, colonization and invasion have been detected in pneumococcus. Pneumolysin is a toxic factor and at the same time brain invasion factor. Many of the known pathogenicity factors play a role in formation of biofilm that facilitates prolonged colonization of nasopharynx. Protective activity has been proved for some of the surface proteins and pneumolysin that forms the base for development of novel rational pneumococcal vaccines as an alternative to polysaccharide. PMID- 25286515 TI - [Fc-receptor proteins of Streptococcus pyogenes and pathogenesis of post infection complications]. AB - Phenomenon and mechanism of non-immune binding of immunoglobulins G and A by various emm-genotypes of group A streptococcus and in particular M-family proteins--main factors of pathogenicity of this causative agent of widespread human diseases are examined. The role of these receptor proteins in pathogenesis of post-streptococcal damage of kidneys (glomerules) and heart (myocarditis) are proved. Results of long-term studies that confirm hypothesis of initiating function of Fc-receptor M proteins in genesis of immune inflammation in organ tissues that precede development of glomerulonephritis and myocarditis are provided. According to the basic position, Fc-binding of an immunoglobulin by M proteins initiates production of anti-IgG, immune complexes of various composition and complement activation, deposition of those in tissues results in lymphocyte infiltration and production of pro-inflammatory cytokines. Literature data on the role of Fc-binding proteins in genesis of IgA-nephropathies and rheumatoid factor is also examined. An important role of other factors of the microbe is discussed such as cross-reacting antigens, erythrogenic toxin B, system of streptokinase-plasmin receptor or endostreptosin in post-streptococcal processes in kidneys. Their participation in the process must be mediated by an inflammation reaction in the tissue that is initiated by interaction of immunoglobulins with Fc-binding proteins of the microbe. A novel approach to understanding the nature of this pathology allowed to establish the ability of Fc fragments of immunoglobulin G to suppress the development of the process. PMID- 25286516 TI - [From molecular to genomic and metagenomic epidemiology]. AB - The notion "molecular epidemiology" was introduced into scientific literature by Kilburn E. et al. in 1973. The first period of development of infectious diseases molecular epidemiology may be called "genotypic" (1980-1990s). During this period methodology of molecular marking of pathogens for purposes of monitoring of their spread and outbreak detection (novel nomenclature of diphtheria corynebacteria based on ribotyping; international network PulseNet for monitoring food source infections; international database of tuberculosis mycobacteria spoligotypes) was created. The second--"genomic" period started in the 2000s. Molecular epidemiology rapidly went through single markers (genotypes or single genes) to deciphering the whole genome of pathoge "mobileome", "resistome", "virulome" etc. took an important place in the studies of emerging and pandemic infections. Knowledge on genetic mechanisms leading to emergence and global dissemination of novel pathogens give molecular epidemiology its own scientific content and transforms it from a methodical approach to an independent field of epidemiology. The third--"metagenomic" period starts nowadays based on meta-genomic approach that allows to determine the whole set ofgenomes in the studied sample without the cultivation procedure. In the short-term this would lead to a change of a century-long paradigm of diagnostics and control of infections: instead of search of separate (key) pathogens--characteristics of the full specter of microorganisms in the material from patients and environmental samples with its identification up to any taxonomic depth. In the systems of regional and global epidemiologic control a universal monitoring of all known and re-emerging pathogens with construction and maintenance of metagenomic passports of human habitats will be realized. PMID- 25286517 TI - [Contemporary view on the role of bacteriophages in evolution of nosocomial strains and prophylaxis of healthcare associated infections]. AB - One of the actual problems of contemporary healthcare are healthcare associated infections (HAI). An important aspect of study of HAI problem is the study of evolution of hospital strains causing HAI. The knowledge accumulated to date in the field of bacteria genetics gives evidence on the significant role of phages in the mechanism of virulence obtaining by pathogenic and opportunistic microorganisms. The studies of the authors of this article show that bacteriophages may play a significant role in the formation of virulent properties in hospital conditions that in different hospitals with participation of phages form virulent and antibiotic resistant hospital strains of HAI causative agents. At the same time bacteriophages are effective means for HAI therapy and prophylaxis. Under the condition of mass and irrational use of antibiotics, HAI causative agents form multiple resistance to the existing antibacterial preparations. In this regard bacteriophages as antimicrobial agents become especially actual. To date in Russian and foreign literature considerable material has been accumulated that shows high effectiveness of bacteriophages under the conditions of rational use. The aim of this review is to evaluate contemporary achievements in the field of study of bacteriophage role in evolution of hospital strains and therapy and prophylaxis of healthcare associated infections. PMID- 25286518 TI - [Proteomic methods of protein separation and analysis]. AB - The review briefly presents principles and stages of execution of such highly effective methods of protein separation as capillary, 2D gel-electrophoresis, liquid chromatography, the possibility of their successful combination with tandem mass-spectrometry and application in various fields of proteomics. The main problems of proteomic analysis as well as ways of solving by using mass spectrometry are examined. 2 main approaches during protein identification are described in the review, characteristics and possibilities of various top-down and bottom-up proteomic analytical programs are provided. PMID- 25286519 TI - [Promising approaches of antiviral therapy of hemorrhagic fevers]. AB - Acceptable means of therapy and prophylaxis for most of the especially dangerous viral hemorrhagic fevers to present date are lacking. Analysis of the state of this problem shows that creation of a new generation of etiotropic preparations requires selection of additional targets for their effect that may be based on the use of molecular-biological features of pathogenesis of these infections. Literature data analysis has shown that during filovirus infection non-structural and structural proteins of the causative agents serve as pathogens during direct damaging effect of the virus and secondary immune reactions that in general pervert cell and humoral components of immunity converting its destructive effect on cells and tissues of the macro organism. Selection of promising approaches of antiviral therapy is possible based on molecular-biological analysis of interaction of micro- and macro organism with isolation of the most vulnerable for the effect of causative agent aggression factors. PMID- 25286520 TI - [Frequency of occurrence of ivyC and pliC lysozyme inhibitors genes in clinical klebsiella strains]. AB - AIM: Chromosomal ivyC and plasmid pliC lysozyme inhibitor genes frequency of occurrence detection in klebsiella strains of various origins. MATERIALS AND METHODS: 129 strains were studied including K. pneumoniae (n= 115) and K. oxytoca (n=14). Klebsiella strains were divided into 2 groups: group 1 - 62 strains (39 isolated in Kazan and 23 strains isolated from children with klebsiella infection in Moscow). Kazan strains were presented by isolates from young children receiving in-patient treatment regarding klebsiella (n=8), respiratory (n= 17), rotavirus (n=5) and purulent-inflammation infection ofnewborns (n=9). Group 2 (n=67) was composed of strains isolated from children that had received outpatient treatment regarding intestine dysbacteriosis in Kazan (n=37) and Moscow (n=30). ivyC and pliC gene detection was carried out by PCR (N.B. Perunova et al., 2012). RESULTS: Chromosomal ivyC gene determinants were isolated in 40.3% of cases (52 strains of 129), plasmid pliC gene - 6.9% (9 of 129). ivyC gene frequency of occurrence in klebsiella strains isolated from 39 ill children of Kazan was 46.6% of cases (18 of 39), in Moscow clinical strains - 95.5% (22 of 23) cases, wherein 6 strains had ivyC and pliC genes at the same time. Dysbiosis intestine strains had chromosomal ivyC gene at the frequency of 61.2% (41 of 67), 1 strain additionally had pliC gene. CONCLUSION: . The presence of ivyC and pliC lysozyme inhibitor genes in klebsiella clinical strains provides bacteria with selective advantages in various biotopes in the process of bacterial colonization of mucous membrane. PMID- 25286521 TI - [Sensitivity of corynebacterium diphtheriae strains to antibacterial preparations]. AB - AIM: Study the prevalence and mechanisms of resistance in circulating C. diphtheriae strains. MATERIALS AND METHODS: 664 C. diphtheriae strains isolated in 1987 - 2013 in various regions of Russia and sent to the reference center of Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology were the object of the study. Antibiotic sensitivity of the strains was studied by disk diffusion and E-test methods using 10 antimicrobial preparations. Nucleotide sequence analysis was carried out by using BLAST program and EMBL/GenBank database. RESULTS: Most of the studied strains turned out to be sensitive to all the antibacterial preparations used. 1.2% of C. diphtheriae strains turned out to be resistant to penicillin and 6.0% had intermediate level of resistance. 0.4 - 0.6% of the strains had intermediate level of resistance to macrolides, and 4.0 - 4.4% were resistant. 2.0% of the strains had multiple resistance. Erm(X)-specific PCR carried out in this study showed that all the C. diphtheriae strains resistant to macrolide antibiotics carry erm(X) gene. CONCLUSION: The results of the study indicate a fairly high level of prevalence for C. diphtheriae strains resistant to antibiotics. PMID- 25286522 TI - [Enterovirus non-poliomyelitis infections in Krasnodar region]. AB - AIM: Evaluation of epidemic situation by non-poliomyelitis enterovirus infections in Krasnodar region in multi-year dynamics and characterization of clinical course of enterovirus serous meningitis in hospitalize patients. MATERIALS AND METHODS: Retrospective analysis of non-poliomyelitis enterovirus infection epidemi process manifestations during 2002-2012 in Krasnodar region territory based on data of Center of Hygien and Epidemiology in Krasnodar Region. RESULTS: Clinical-epidemiologic characteristics of enterovirus infections in Krasnodar region are presented. Landscape ofenteroviruses isolated from the environment of some territories of the region and from the biological material of patients with various diseases is demonstrated. Clinical features ofenterovirus meningitis course are characterized. CONCLUSION: Enterovirus transmission b contact route was established to be the most frequent. A lack of pathognomonic symptoms and awareness o physicians of various specialties regarding diagnostics of this infection are the clinical problems of non-po liomyelitis enterovirus diseases. PMID- 25286523 TI - [Immunogenicity and safety of vaccine preparations based on circulating Bordetella pertussis strains]. AB - AIM: Study specific activity and safety ofvaccine preparations based on circulating B. pertussis strains with currently predominating allele variants of pertussis toxin (ptxA1) and pertactin (prn2) genes. MATERIALS AND METHODS: B. pertussis strains isolated from pertussis patients in Moscow in 2001-2010 were grown in dense and liquid media. The content of separate antigens in B. pertussis strains was determined by EIA. Immunogenicity and safety of the preparations was determined in F1(CBAxC57B16) line mice. RESULTS: All the studied circulating B. pertussis strains expressed pertussis toxin (PT), filamentous hemagglutinin (FHA) and agglutinogens corresponding to the serovar. Whole-cell and acellular pertussis vaccines were prepared based on the circulating strains, and a highly productive recently isolated toxigenic B.pertussis strain that could be used for production ofpertussis vaccines was selected as a result of studies ofimmunogenic, toxic and sensibilizing properties. CONCLUSION: Vaccine preparations based on a B. pertussis strain adapted to growth in liquid media with pertussis toxin and pertactin ptxAl1 - prn2 gene allele variation characteristic for contemporary population are specifically active and safe. PMID- 25286524 TI - [Immunogenicity and safety of a prototype chemical anthrax vaccine in laboratory animal models]. AB - AIM: Evaluation of immune stimulating and toxic effects of a vaccine prototype protein components. MATERIALS AND METHODS: Linear mice, guinea pigs and rabbits were immunized subcutaneously once or twice by recombinant protective antigen (rPA), S-layer protein (EA1) or their complex. Innate immunity structure activation was registered by changes in Toll-like receptor (TLR) expression. Adaptive immune response parameters were determined by established methods. Toxicity of the preparations was determined using flow cytofluorometry and densitomorphometry. RESULTS: The ability of rPA and EA1 to activate structures of innate immunity - TLR 2 and 6 - was established. Features of anti-PA antibody titer dynamics for each of the animal species was determined, a comparison with antibody formation during immunization with Bacillus anthracis STI- 1 was carried out. 2 immunizations ofbiomodels with a complex preparation combined with an adjuvant provides protection from infection by a test-strain that is comparable with protectivity of a live vaccine. Evidences regarding damaging effect of rPA and EAI on cells and tissues of macro organism were not detected throughout the study. CONCLUSION: Aprototype of a chemical anthrax vaccine under development has high immunogenicity and its protein components are not toxic for laboratory animals based on the results of complex testing. PMID- 25286525 TI - [Clinical significance of interleukin-28B and RNAse L gene polymorphism determination in patients with chronic viral hepatitis C]. AB - AIM: Determination of frequency of occurrence and clinical significance ofinterleukin-28B (IL28B) and RNAse L gene polymorphism in patients with chronic hepatitis C (CHC). MATERIALS AND METHODS: 104 hospital patients with CHC (65% male; 63% with genotype 1 hepatitis C virus - HCV) were examined. 70 patients received therapy with interferon (IFN) and ribavirin (RBV). Single nucleotide polymorphism (SNP) of IL28B gene 39743165T>G (rs8099917), SNP 39738787C>T (rs12979860) and RNAse Lgene (1385G>A) were determined by polymerase chain reaction. RESULTS: The frequency of detection of "favorable," SNP allele variants of IL28B gene in patients with CHC was lower than in population of the European region. In patients with genotype 1 HCV, mutant alleles in SNP 39743165T>G (p=0.045) and 39738787C>T (p=0.005) occurred more frequently than in patients with other virus genotypes. Highervalues of alanine aminotransferase in patients with genotype CC 39738787C>T were detected. Frequencies of SNP variants of IL28B and RNAse L gene did not differ depending on the speed of disease progression (p>0.5). Response to IFN/RBV therapy was higher in "favorable" TT (SNP 39743165T>G) and CC (SNP 39738787C>T) variants. CONCLUSION: Examination for IL28B gene SNP 39738787C>T is recommended before the start of IFN/RBV therapy in all the patients with genotype 1 HCV as a prognostic factor on the therapy response. RNAse L gene SNP 1385G>A does not have a clear clinical significance in CHC. PMID- 25286526 TI - [MALDI-TOF mass-spectrometric analysis of cell proteins during identification of leptospira genus members]. AB - AIM: Development of methodological approaches for identification of leptospira by using MALDI-TOF direct protein profiling technology. MATERIALS AND METHODS: Analysis of cell proteins of 34 leptospira strains was carried out in Microflex LT by using "MALDI Biotyper 3.0 for identification and classification of microorganisms" program. RESULTS: 19 reference spectra of reference leptospira strains from 7 species were generated and imported into MALDI Biotyper 3.0 database. Identification of 6 strains with undetermined taxonomic position was carried out. CONCLUSION: The approved method allows determination of leptospira species with accuracy that depends on their adaptation to nutrient media, preparation approach and sample storage conditions for mass-spectrometry. PMID- 25286527 TI - [Evaluation of real-time multiplex PCR effectiveness for group a rotavirus genotyping]. AB - AIM: Evaluate resolution and diagnostic significance of real-time multiplex PCR (MP RT-PCR) as a platform for group A rotavirus G/P genotyping test-systems. MATERIALS AND METHODS: Primer and DNA probe construction for an experimental test system based on MP RT-PCR was carried out by using specialized PC programs and sequence databases GenBank NCBI, EMBL Nucleotide Sequence Database etc. The experimental genotyping test-system was tested using 116 clinical samples with confirmed rotavirus infection and 14 biosamples negative for group A rotavirus RNA. Selective sequencing of VP7, VP6, VP4 gene mark-erloci was carried out as a reference method forverifying determination of rotavirus genotype. RESULTS: Specific interaction between primers and DNA probes with genotype-specific loci of retrovirus genome segments and a lack of false-negative signals, complete match ofgenotyping results obtained by MR RT-PCR and sequenc- ing methods were established. CONCLUSION: The resolution of MP RT-PCR methods allows designing test-systems that can confidently identify rotavirus genotypes with effectiveness of 90% and above. PMID- 25286528 TI - [Epidemiologic control for rubella in pregnant women]. AB - AIM: Evaluate effectiveness of measures specified by epidemiologic control for rubella in pregnant women. MATERIALS AND METHODS: 585 pregnant women with suspected measles were laboratory examined in 10 Regional Centers of Control for Measles and Rubella by EIA. RESULTS: 24 rubella infected pregnant women aged 16 36 years were detected among the examined pregnant women, most of those (91.7%) were either not immunized against rubella or had unknown immunization anamnesis: 16 women terminated pregnancy, in 8 women pregnancy ended with delivery at term. Of the 8 newborns only a single child had innate rubella infection (the child was clinically healthy). CONCLUSION: Epidemiologic investigation of each rubella case in pregnant women with obligatory laboratory examination of women and source of infection revealed a significant number of women at childbearing age susceptible to rubella virus that retains the possibility of birth of children with innate rubella syndrome. PMID- 25286529 TI - [Study of sensitivity of laboratory animals to a causative agent of argentine hemorrhagic fever]. AB - AIM: Study sensitivity of laboratory animals to a causative agent ofArgentine hemorrhagic fever. MATERIALS AND METHODS: Junin virus strain XJ P37 was obtained from the State Collection of Causative Agents of Viral Hemorrhagic Fevers of the Pathogenicity Group I of Scientific Research Center of the 33rd Central Scientific Research Test Institute (SRC of the 33rd CSRTI). Junin virus strain XJ P37 culture with biological activity of 5.2 1g PFU x ml was used in the experiments. Mice (2 - 4 and 7 - 14 days old), guinea pigs (250 - 300 g), 1.8 - 2.5 kg shinshilla breed rabbits, 2.0 - 3.0 kg javanese macaque monkeys were obtained from vivarium of the SRC of the 33rd CSRTI. Vero (B) and GMK-AH-1 (D) cell cultures were obtained from cell culture collection of the SRC of the 33rd CSRTI. Biological activity calculation of Junin virus was carried out by Kerber in I.P. Amsharin modification. RESULTS: Lethality in animals was from 12.5 to 50% after intranasal and intraperitoneal infection of guinea pigs, intramuscular, intraperitoneal and subcutaneous infection of rabbits, intracerebral and intranasal infection of mice at the doses from 0.4 to 1.0 x 10(5) PFU. Death of infected monkeys after intramuscular administration of the virus at 1.0 x 10(4) PFU dose was not observed. In 100% of surviving animals formation of virus neutralizing antibodies was registered. CONCLUSION: Evaluation of sensitivity of laboratory animals to Junin virus has shown that intracerebrally infected mice may be used to maintain causative agent culture, infected guinea pigs - to prepare virus-containing cultures and modelling infection exacerbation in humans. Intramuscularly infected rabbits may be used to obtain hyper-immune sera. PMID- 25286530 TI - [O3:K6 serogroup vibrio parahaemolyticus - the causative agent of food toxic infection outbreaks in Primorsky region of Russian federation]. AB - AIM: Comparative evaluation of biological properties of parahemolytic vibrios that had determined outbreaks and sporadic cases of food toxic infection in Primorsky Region in 2012 and previous years. Materials AND METHODS: 40 clinical strains of Vibrio parahaemolyticus isolated in 2012 were studied in comparison with 62 strains from this region that had been characterized by us previously. Virulence was evaluated by a complex method: hemolytic activitywas determined in Kanagawa test (KT), urease - in Kristensen medium. Serotyping was carried out by a commercial kit of O/K sera. PCR-genotyping was carried out by marker genes of 7 pathogenicity "islands" (VPaI-1-7). RESULTS: All the strains isolated from patients in 2012 had KT-positive and urease-negative phenotype, belonged to O3:K6 serogroup and contained marker genes of 7 VPal that allowed to consider them members of a "pandemic" clone as the other clinical strains from this region. However among 2012 strains an increase of number of antibiotic-resistant variants was established compared with 1997 isolates. CONCLUSION: The data obtained give evidence on the risk of spread of a "pandemic" clone of V. parahaemolyticus in the Far-Eastern region of Russia, a dangerous tendency of antibiotic-resistant variant formation and a necessity to monitor morbidity and the environment with mandatory PCR-detection of genes associated with virulence including integrated into pathogenicity "islands". PMID- 25286531 TI - [Sensitivity of nosocomial purulent-septic infection causative agents to disinfection agents and antibiotics]. AB - AIM: Study the sensitivity of nosocomial purulent-septic infection (PSI) causative agents to disinfectants (DA) and antibiotics (AB). MATERIALS AND METHODS: Sensitivity to DA and AB of 209 PSI causative agent strains isolated from patients and the environment of 2 obstetric and 3 surgical hospitals was studied in 2009-2011. Sensitivity to DA of 94 strains and to AB of 189 strains of Pseudomonas aeruginosa isolated from patients with signs of PSI of reanimation and intensive therapy and surgical departments of a multi-field hospital was studied in 2012. Sensitivity to DA was determined on test-surfaces and in solution according to guidelines by V.V. Shkarin et al., 2010; sensitivity to AB by disc-diffusion method. RESULTS: Among PSI causative agents resistant to DA the portion of poly-antibiotic resistant strains is higher than among microorganisms sensitive to DA, and among antibiotic resistant bacteria the number of strains resistant to DA is higher than among sensitive to antibiotics. The increase of resistance to DA and AB of P. aeruginosa strains is observed in parallel to the increase of volume of the antibacterial preparations used. CONCLUSION: The results obtained give evidence of the possibility of formation of combined (associated) resistance to DA and AB by nosocomial PSI causative agents against the background of increase of their consumption. PMID- 25286532 TI - [Indexes of immunity and local protection in humans with intestine dysbacteriosis]. AB - AIM: Study indexes of immunity and local protection in humans with intestine dysbacteriosis. MATERIALS AND METHODS: Qualitative and quantitative intestine microbiocenosis, content of gamma-interferon (EIA method) in coprofiltrates in 204 individuals were studied, data from immunograms of 123 individuals with bacteriologically confirmed dysbacteriosis were analyzed. RESULTS: The presence of immune deficiency mainly by T-cell type was established in 92.7+/-2.4% of individuals with intestine dysbacteriosis. Significant variations in -interferon content in coprofiltrates of examined individuals was detected (from no less than 5 pcg/ml to 240 pcg/ml), a statistically significant dependence of gamma interferon content in coprofiltrates on the number of opportunistic microbes and atypical escherichia (including hemolytic) in intestine microbiocenosis was determined. CONCLUSION: The presence of T-cell type immune deficiency in individuals with intestine dysbacteriosis combined with a reduced local protection, and the content of gamma-interferon in coprofiltrates gives evidence not only on the reduction of local protection but also to some extent mirrors the degree of this reduction. PMID- 25286533 TI - [Post-vaccination complications during administration of BCG and BCG-M in children of Krasnodar]. AB - AIM: Analysis of frequency and reasons of complications after BCG vaccination in 2008 - 2012 in Krasnodar Region for improvement of prevention measures. MATERIALS AND METHODS: Data on frequency and structure of post-vaccination complications during vaccination against tuberculosis of Centre of Hygiene and Epidemiology in Krasnodar Region and Regional Tuberculosis Hospital in 2008 - 2012 were used. Reasons of the complications were analyzed. RESULTS: During the observation period 16 complications related to immunization with tuberculosis vaccine were noted with frequency index of 5.1 - 40.4 per 100 000 immunized newborns and a tendency of decrease from 2008 to 2012. In the structure of complications cold abscesses (37.5%), lymphadenitis (31.25%) and ostitis (31.25%) occurred at a similar frequency. CONCLUSION: Predominance of cold abscesses in the structure of post-vaccination complications indicates violations in vaccination technologies in maternity hospitals and children's clinics in Krasnodar city, and late periods of post-vaccination ostitis diagnostics - a decrease of epidemiologic awareness of general medical network physicians regarding BCG-vaccination complications, that requires enhancement of immunization control and requalification of personnel carrying it out. PMID- 25286534 TI - [Antagonistic activity of novel green microalgae strain]. AB - AIM: Screening of novel microalgae strains for the presence of pronounced antagonistic (antibacterial) activity against opportunistic bacteria. MATERIALS AND METHODS: 11 pure cultures of green unicellular algae isolated from fresh and salt basins of Orenburg region were studied for the presence of antagonistic activity against 4 test-strains of opportunistic bacteria by a photometric method. The effect of water extracts of microalgae Astermonas gracilis on the speed of self-purification of brine from Escherichia coli as well as antibacterial activity of peloid were evaluated under co-cultivation conditions. RESULTS: Pure cultures of green unicellular algae Scenedesmus obliquus (Turpin) Kutz, Scenedesmus magnus Meyen var. magnus, Pediastru duplex Meyen var. duplex, Chlorella vulgaris Bory, Monoraphidium arcuatum (Korschikov) Hindak (=Ankistrodesmus arcuatus Korschikov), Dictyosphaerium sp. had the most pronounced antagonistic activit against opportunistic bacteria. Water extract ofA. gracilis microalgae accelerated brine self-purification fro E. coli due to antibacterial effect. Peloid containing extracts of microorganism cells had a pronounced antibacterial effect against opportunistic bacteria. CONCLUSION: Antagonistic substances localized inside cells of microalgae increased the speed of allochthonic microorganism elimination that is one of the mechanisms of self purification of a basin and antibacterial effect of peloid. The novel green microalgae strains studied due to the presence of pronounced antagonistic activity may have a wide practical application. PMID- 25286535 TI - [Cycloferon biological activity characteristics]. AB - AIM: Study the effect of cycloferon in experimental and clinical conditions on persistence properties of aurococci as well as features of their morpho functional reaction by atomic force microscopy. MATERIALS AND METHODS: The study was carried out in 12 Staphylococcus aureus clones isolated from mucous membrane of nose anterior part of a resident carrier. The effect of cycloferon in vivo was evaluated in 26 resident staphylococci carriers under the control of anti carnosine activity of staphylococci. Anti-carnosine activity was determined by O.V. Bukharin et al. (1999), biofilm formation -by G.A. O'Toole et al. (2000). Staphylococci treated with cycloferon were studied by atomic force microscopy in contact mode using scanning probe SMM-2000 microscope. RESULTS: The decrease of persistence properties of staphylococci under the effect of cycloferon in vitro and in vivo may be examined as one of the mechanisms of biological activity of the preparation. A significant increase of S. aureus surface roughness and changes in their morphology under the effect of cycloferon allow stating the disorder of barrier functions in the aurococci cell wall. CONCLUSION: The data obtained expand the understanding of cycloferon biological activity mechanisms. PMID- 25286536 TI - [Bacterial lipopolsaccharides in pathogenesis of gynecological diseases and obstetric complications]. AB - Analysis of literature data and author studies on the role of lipopolysaccharides (endotoxin) of Gram negative bacteria in women genital tract pathology and obstetric complications is presented. The role of endogenous infection associated with altered microecology of intestinal tract and vaginal biotopes of women in the development of endotoxinemia is discussed. The participation of endotoxin in embryo resorption, delay of intrauterine development and antenatal death of fetus, premature birth, pre-eclampsia, placental dysfunction is examined. The level of endotoxinema and pro-inflammatory cytokines is a marker of chronic endogenous infectious-inflammatory disease of various parts of genital tract with damage of a network of female reproduction system organs. PMID- 25286537 TI - [Ultrastructure of microbial biofilms during intercellular interactions of bacteria in communities]. AB - Analysis of summarized data obtained by us on ultrastructure of microbial biofilms of opportunistic bacteria is presented. A complex ultrathin organization of lactobacilli, enterobacteria, staphylococci and enterococci biofilms discovered during electron microscopy is described. The presence of surface film and polysaccharide matrix that determine increased resistance of intrabiofilm bacteria against the effect of protective immune factors of the organism and etiotropic preparations is demonstrated in all the studied comminutes. A varied response of bacterial cells contained in the biofilm during antagonistic effect of symbiont probiotic bacteria was discovered. PMID- 25286538 TI - [Molecular aspects of anthrax pathogenesis]. AB - A model of anthrax infection with the role determined for main pathogenicity factors of Bacillus anthracis exotoxin and capsule is presented. After spore phagocytosis by macrophages, synthesis of the main exotoxin component begins - a protective antigen that in oligomeric form disrupts phagosome membrane. This accelerates the transition of the pathogen from phagosome into the macrophage cytoplasm. Poly-D-glutamine capsule synthesized by the pathogen triggers the exit (exocytosis) of vegetative cells from macrophages and protects them from re phagocytosis in lymphatic node lumen. The vegetative cells, that actively and freely replicate in lymphatic node, secret an exotoxin that disrupts endothelial septum between lymph and blood due to cytotoxic activity. As a result the vegetative cells get into blood and bacteremia develops. Pathogenetic pattern during anthrax (multiple hemorrhages in various organs etc.) is associated with local microcirculation disorders of various organs caused by the effect of bacterial exoproteases via activation of Willebrand factor. This results in a rapid local increase of microbial mass and consequent powerful cytotoxic effect of exotoxin on the tissue cells of the affected organ. Death of the infected organism takes place at the final stage of infec- tion due to toxic shock caused by the exotoxin. A reduction of body temperature takes place after death and the process of spore formation begins in the dead animal: capsule depolymerization, chain shortening, peptidoglycan cortex formation. Spores in this form are the prolonged source of infectious agent conservation and spread of infection in nature. PMID- 25286539 TI - [Mechanisms of microorganism resistance to beta-lactam antibiotics]. AB - Literature data on molecular mechanisms of resistance to beta-lactam antibiotics have been summarized. The following mechanisms are examined: appearance ofpenicillin-binding proteins (PBP) with lower affinity to beta-lactam antibiotics; production by microorganisms of enzymes (beta-lactamases) that hydrolyze beta-lactam ring; disruption of microbial cell outer membrane permeability and active secretion of antibiotics from the microbial cell (effiux effect). Characterization of extended spectrum beta-lactamases (ESBL) as well as data on structure of SCCmec element of MRSA and bacterial efflux system (RND) is presented. PMID- 25286540 TI - [Adhesion of corynebacterium diphtheriae: the role of surface structures and formation mechanism]. AB - The paper is devoted to the study of surface structures including pili (fimbriae) 67-72p surface protein, DIP 1281 surface protein, lipoarabinomannan CdiLAM and their role in the adhesion and colonization of the mucous membrane of the throat by Corynebacterium diphtheriae. A description is offered for the main stages in the adhesion process of diphtheria causative agent and the ability of its adhesins to stimulate the effect of innate and acquired immunity factors. The paper stresses prospectiveness of the development of vaccines forming immunoprotection of the organism against adhesive activity of C. diphtheriae and also preventing their colonization and reproduction. That would facilitate a solution for the problem of diphtheria carrier state, which cannot be solved using the existing means of preventive vaccination. PMID- 25286541 TI - [Results of studies of human dirofilariasis in Russia]. AB - Human dirofilariasis is a pressing health problem in Russia. By 2014, there have been as many as 850 Dirofilaria repens-infested people living in 42 subjects of the Russian Federation. One of the favorable factors for circulation and spread of invasion is a temperature of above +20-24 degrees C; when the latter is maintained during at least 20 days there may be 1.-1.5 circulations of invasion in the carrier and a 2.8-fold increase in transmission intensity. The border ofa dirofilariasis area with a temperate climate is southward to 58 degrees N in European Russia and West Siberia and southward to 50 degrees N in the Far East. The conditions in the human body have been found to be more favorable for the development of Dirofilaria than considered before and allow the helminth to achieve sexual maturity and to propagate. If man has microfilaremia, he may be a source of invasion. It is necessary to examine venous blood by the enrichment method and, if possible, polymerase chain reaction and enzyme immunoassay, which make it possible to establish a diagnosis in occult invasion and to identify a pathogen species. PMID- 25286542 TI - [Entomological monitoring of an area to assess Dirofilaria transmission risk]. AB - As the basis for entomological monitoring, the authors first propose to investigate the structure of a season of D. repens invasion transmission in the carrier in relation to the ambient temperature, such as onset of a transmission season, terminaton of mosquito infection, the number of invasion circulations. A calculating procedure has been developed. It is shown that there is a need for entomological monitoring of each specific area irrespective of the latitude to study a risk for local dirofilariasis cases. PMID- 25286543 TI - [Microsymbiocenosis of Codiella mollusks as a basis for symbiotic relations in the parasite-host system in opisthorchiasis]. AB - The purpose of the first step of microparasitocenosis investigation was to study the microbiocenosis of the first intermediate hosts of O. felineus--prosobranch gastropods of the genus Codiella, as well as their habitats. Materials were collected in the Iryum River of the Ob-Irtysh basin. The microflora of mollusks, water, and soil from their habitats was examined. The predominant flora was Aeromonas species in the biocenosis of mollusks and Enterobacteriaceae in the microbiocenosis of the water basin and soil. Examination of the microbial communities in the mollusks and their habitats showed that the range of microbial populations of mollusks was wider in species composition as compared to the microbiocenosis of soil and water. PMID- 25286544 TI - [Possible sources of Trichinella infection in the indigenous population of Chukotka]. AB - Statistical methods confirmed that the dietary intake of traditionally made meat from marine mammals and polar bear could cause Trichinella infection in the residents of the communities of the Chukotka Peninsula. PMID- 25286545 TI - [Gastropods and their role in the transmission of Trichinella invasion]. AB - Gastropods were established to be able to absorb decapsulated and encapsulated Trichinella larvae located in muscle tissue. Trichinella larvae remain viable and infectious for 24 to 48 hours after passing through the gastrointenstinal tract of gastropods. PMID- 25286546 TI - [Spread of Lamblia (Giardia) sp. protozoa among dogs and cats in the city of Moscow]. PMID- 25286547 TI - [Assessment of Nanophyetus salmincola schikhobalowl (Skrjiabin et Podjiapolskaja, 1931) infestation of salmonlike fishes in the rivers of the Khabarovsk Territory]. AB - Parasitological investigations of 529 specimens of 7 fish species from the water basins of the Khabarovsk Territory in 2009-2013 revealed the high extensity (11.7 to 100%) and intensity (as many as 9341 larvae per fish) of invasion with N. s. schikhobalowi metacercaria in salmonlike fishes from the mountain tributaries (Khor, Anyui, and Manoma) of the Amur river. The examined specimens of four salmonlike fish species (Thymallus tugarinae, Hucho taimen, Brachymystax tumensis and B. lenok) showed an increase in all indicators of infestation: invasion extensity (IE), invasion intensity (II), and abundance index (AI) with age. Moreover, IE peaked just in a 3-4-year-old fish (and in 1-year-old B. lenok) and further remained virtually unchanged. N. s. schikhobalowi metacercaria accumulated in the fish trunk with age, by maintaining their viability. With very high II, practically 100% infestation in B. lenok makes the population run the maximum risk of Nanophyetus infection with the dietary intake of this fish species if it is not disinfected. Examination of the distribution of N. s. schikhobalowi metacercaria in the trunk of Thymallus tugarinae showed that over 50% of larvae were detectable in the kidneys. This peculiarity of their localization could propose a simple method to determine II for Nanophyetus larvae in salmonlike fishes. Recommendations for reducing the risk of human infection with trematodes are given. PMID- 25286548 TI - [A novel bromine-containing salicylanilide (the compound MST-18). Preparation and antihymenolepic activity]. PMID- 25286549 TI - [The preparation and antihymenolepic activity of a bromine-containing salicylanilide the compound MST-16)]. PMID- 25286550 TI - [The biological component of the professional standards and qualification characteristics of preventive medicine specialists (as exemplified by the specialty of parasitology)]. AB - In the context of theoretical analysis, the paper characterizes a specialist training system based on the biological component of the qualification characteristics and professional standard of preventive medicine specialists. Evidence is provided for the relationship between the components of the training system for preventive medicine specialists. The authors also specify the fact that the content of qualification characteristics and professional standards, besides general requirements, must take into account requirements for training the specialists in terms of natural and climatic and socioeconomic characteristics of regions. PMID- 25286551 TI - [In memory of the teacher (on the occasion of the 100th of Elena Semenovna Leikina)]. PMID- 25286552 TI - [Current treatments for clonorchiasis]. AB - The paper briefly reviews the current techniques for treatment for human clonorchiasis, which are both widely used in medical practice and developed at experimental research laboratories. It describes specific examples of chemotherapy, including combined therapy, clonorchiasis vaccines and drug resistance. Particular emphasis is placed on the prospects of use of minor interfering RNA as a source of new-generation diagnostic and remedial agents. PMID- 25286553 TI - [Use of geographic information systems in public health]. AB - To enhance the efficiency of epidemiological surveillance by the countrywide use of current information telecommunication technologies, diagnostic systems based on monitoring is one of the tasks of the Russian Federal Service for Consumer Rights Protection and Human Health Control in the control and prevention of parasitic diseases. The epidemiological surveillance system for parasitosis encompasses not only the monitoring and assessment of the situation, but also necessary measures if epidemic complications occur. Geographic information systems (GIS) may be successfully used for this purpose. GIS-based interactive health atlases have been created and put on the Internet and researches made. PMID- 25286554 TI - [The current status of the resistance of malaria pathogens to antimalarials]. AB - The review presents the results of trials of the clinical efficacy of a test antimalarial drug for each malarial parasite species, which were published in 2000-2013 and supplemented by the data of in vitro studies or investigations using the molecular markers of resistance. There are data on the resistance of each medicament since many of the drugs are used in combination with artermisinin derivatives. PMID- 25286555 TI - [Pecilomycosis: myth and reality]. PMID- 25286556 TI - [The historical experience of medical service in cooperation with state healthcare facilities during the Great Patriotic War 1941-1945]. AB - Cooperation issues between military-medical service and civil healthcare in the field of delivery of medical aid to patients in the rear of country are considered in the artic. The rear is a final stage of the care by echelon and the main medical reserve force for front and army areas. Wide hospital network in the rear consisted mainly of evacuation hospitals of the People's Commissariat of the USSR healthcare. Cooperation between military-medical service and civil healthcare facilities was required. Sometimes necessary cooperation failed and made mutual helming of evacuation hospitals difficult. But despite the problems the main problem - return of maximum wounded soldiers to active duty was solved during the Great Patriotic War. PMID- 25286557 TI - [ Microstructure of the hippocampus in brain injury caused by non-lethal weapons]. AB - Methods of histomorphometry and AFM investigation were used in research of hippocampus in acute phase of gunshot brain injury. Experimental sheep were used in research. Researches fired a shot in parietooccipital area with the gun "Makarych". It was found that shooting causes interstitial edema which disintegrates neuronal cytoarchitectonics of hippocampus in 30 minutes. Main factor for interstitial edema is peculiarities of microstructures of separate hippocampal layers. In surface tissue structures that have porous and viscous structure occurs infiltrative dissection of conduction structures. The energy of edema realizes as spalling and fragmentation in dense lamina of the fascia dentata. Independent from localization pressure cavitation occurs in interstitial tissue of hippocampus. Common pathogenic factors are acidotic picnosis and neuronal desynaptization. PMID- 25286558 TI - [Medical and social aspects of dermatoses morbidity in military personnel serving in a region of the Far North]. AB - Analysed the possibility of dermatosis as an adaptive health disorder in military personnel serving in a region of the Far North. 127 men took part in this research; the average age is 19,5+/-0,7 years. 89 patients with atopic dermatitis and 38 patients with psoriasis were examined and proceeded with the treatment. 50 healthy servicemen were in the experimental group. Each patient filled out a questionnaire for evaluation of anamnesis, contributory causes, social and psychological status. It is revealed that seamen break out in atopic dermatitis and psoriasis in first 2 months of service; flare-up was observed in autumn. Climate and geographic peculiarities of the region affect the course of skin disorders. The draft and first months of service are the main stressful factors affecting dysadaptation disorders. It is necessary to study preclinical sociopsychological factors in conscripts and compulsory-duty servicemen and to provide modern psychological prophylaxis. PMID- 25286559 TI - [Refractory hypertension: diagnosis and treatment optimization]. AB - Resistant hypertension occurs in up to 15% of patients with arterial hypertension in Russia. Medical treatment of resistant hypertension must include minimum 3 medications with maximum or maximum tolerated doses besides one of the medications must be diuretic. According to department of arterial hypertension of the Burdenko Main Military Clinical Hospital to achieve the target levels of arterial blood pressure it was necessary to prescribe 4-5 components antihypertension therapy in patients. Authors suggested an algorithm of diagnosis and treatment of patients with resistant hypertension with the help of surgical method. This method is based on decreasing of sympathic nervous system activity by selective break of neuronal connections with the help of interventional intravascular radio-wave ablation. Endovascular renal sympathetic denervation allows to effectively control arterial blood pressure, to optimize antihypertensive therapy, but this method does not cure from arterial hypertension. PMID- 25286560 TI - [Pharmacological tolerance to medical therapy of organophosphate poisoning and ways of tolerance management]. AB - Authors consider causes of low efficiency of antidote therapy and ways of pharmacological tolerance management during medical treatment of organophosphate poisoning. One of the promising ways is a preventive antidote on the base of enzyme agents and allosteric modulators of a cholinesterase activity. Authors showed a expediency of a study of new acetylcholinesterase reactivators, its compositions and ways of drug delivery. Authors specified ways of searching for anticonvulsants from classes of quick-closing benzodiatines and NMDA-antagonists. Authors defined ways of improvement of methods of special antidotes delivery with targeted transport system. Authors made an assumption about the necessity of symptomatic treatment. PMID- 25286561 TI - [The experience in organizing the medical support of allied convoys during the Great Patriotic War on the northern maritime theater]. AB - The medical support of allied convoys during the Great Patriotic War had a number of features. The Intensity of power of the fighting, the meteorological conditions, the composition of convoy's forces, the kind of enemy's weapon - had a significant impact on the structure of losses in personnel. The main type of medical care on the ships of 2-3rd rank was predoctor care. On the large and small antisubmarine ships and torpedo boats - it was first aid. The factor which has been affecting the amount of assistance - was a one-time inflow of a significant number of victims. Medical-evacuation provision of the convoys was carried out by the ships medical service without the use of amplification and sanitary ships. The most part of the wounded were taken to the coastal fleet hospitals later than 12 hours after the wound. The war experience has shown that in the distant convoys qualified surgical assistance may be provided in case of organizing it in this convoy and in case of using high-speed vehicles. PMID- 25286562 TI - [The current state and development prospectives of military nephrology]. AB - This article is dedicated to the current state and prospectives of military nephrology. Using as examples the nephrology services of the armed forces of Serbia, France, Great Britain and USA it is shown that this branch of military healthcare plays an important role abroad. The brief review of military nephrology formation and development history demonstrates the growing significance of military nephrology in the general system of medical care at the battlefield. PMID- 25286563 TI - [The Central Military Hospital of the People's Commissariat for Defence during the Great Patriotic War]. AB - The article is devoted to activity of the Central Military Hospital of the People's Commissariat for Defence during the Great Patriotic War. The research is based on declassified orders of PCD and orders of the chef of hospital. Authors presented the role of the hospital in organization of medical aid for officers of PCD, members of their families, Red Army soldiers, junior and senior Red Army commanders; the role of the hospital in organization of medical facilities for combat army; medical supply for evacuation of family members of PCD's officers ( en route and in evacuation places); delivery of child health care to children of officers of PCD in the hospital and education in kindergartens of PCD. PMID- 25286564 TI - [1st Naval Hospital during the Great Patriotic War]. AB - In the article about The First Naval Hospital, that became famous during the Great Patriotic War, the authors present the facts of the heroic work of the hospital and its staff under the hardest conditions of the Siege of Leningrad, in an atmosphere of constant shelling, its productive clinical and scientfic work during the war years (1941-1945). As a material for the preparation of this article were used documents of the Military-Medical Museum, factual information about the history of the hospital published in various sources. PMID- 25286565 TI - [The head of battlefronts medical service during the Great Patriotic War]. AB - The article is dedicated to unrenowned moments of life of the outstanding organizer of the system of military healthcare general-lieutenant of medical service Arsenii Yakovlevich Barabanov (1901-1952). His outstanding organizing skills and deep knowledge in the field of military medicine revealed during the Second World War, when he was the head of medical service of 31st Army of the Western Front and 34th Army of North-Western Front and since 1942 he has helmed medical service of Donskoy, Central, 1st Belorussian Fronts. His experience in organization of collecting of PW, system medical treatment for PW acquired during the battle of Stalingrad and afterwards was used and improved during further offensive operations, especially during the final stage of the Second World War and also in organization of medical aid for prisoners of war from the Soviet Union and allied states freed from Nazi extermination camps. PMID- 25286566 TI - [Military history of evacuation hospital No 3457 and the head of this hospital -- Porfirii Ivanovich Zabolotnyi]. AB - The article is devoted to publication of an archive document "History of evacuation hospital AN 3457". This archive document was found in one of the deserted country house in Sumy Oblast, Ukraine. 32 pages of text is bright and eloquent testimony of the period of the Great Patriotic War. Hospital was founded in 1941 in Sumy Oblast and then was deployed in Siberia, in the region of the Far North, again in Ukraine and in Hungary. Army medical officer Porfirii Zabolotnyi was the chef of evacuation hospital during this period. PMID- 25286567 TI - [Belarusian paramedics during the Nazi occupation]. AB - The article is devoted to Belarusian paramedics serving in occupational territories during the World War II. The article is focused on paramedical professional duties as a part of patriotic activities. This article also touches on their participation in anti-epidemic work. PMID- 25286568 TI - [Psychology and psychopathology of information warfare]. AB - Tension of information warfare as a form of modern war has a global character nowadays. Topicality of research of psychological reaction peculiarities and psychopathology phenomena developing during information warfare is determined by necessity of scientific development of the effective means of diagnosis and prophylaxis of these phenomena. The article is devoted to analytical review of modern articles about aim, goals and methods of information warfare, covering some signs of manipulative influence on people's mind. Authors set forward opinion about possible psychological peculiarities and psychopathological consequences of targeted aggressive information influence and also suggest some methods against this influence. PMID- 25286569 TI - [The experience in orginizing medical supply of the Belorussian operation 1944 "Bagration"]. AB - A research of some literary sources and archive materials relating to the Belorussian strategic offensive operation "Bagration" in 1944 in which the group of armies "Center" was defeated has been conducted. The article provides a notion of a character and work volume of operational higher formations medical service control bodies in the process of preparation for the medical provision and treatment and evacuation measures implementation by the all-medical service levels in the course of operation. Shortcomings were revealed both in the medical provision planning and predesigned measures implementation that could be of certain interest for military doctors. PMID- 25286570 TI - [Telemedical approach to the organization of the advisory dermatologic care]. AB - Considered the introduction to the health practice of the remote medical help by the information and Communication Technologies to improve the quality of diagnostics of dermatological patients in the remote garrisons. Developed the scheme and the map of teleconsultation, and also defined indications for its conduct. Given the example of online consultation resulted in a diagnosis of pathomimics (Munchausen's disease), and in the recommendations for survey and treatment of the patient. It is concluded that the development of remote consultation of the patients needing dermatovenereological medical care from any health care facility will bring closer the highly specialized dermatovenereological assistance to the remote garrisons and will significantly save the cost of such assistance. PMID- 25286571 TI - [The organization of emergency actions for ocular burns in conditions of military unit (of the ship)]. AB - Prehospital services for ocular burns are delivered by servicemen as self or mutual management and also by paramedic. Every case of ocular burn should be considered as severe one. The patient, shortly after the first aid, should be transported to the medical company or medical unit. Under conditions of medical unit military doctor has to organize an ophthalmological working space (ophthalmological comer) with the necessary equipment. Eye irrigation has to be made for chemical ocular burns. Military doctor should consider any previous irrigation as insufficient. For severe ocular burns during evacuation to the hospital it is necessary to perform a simple blepharorrhaphy or (if the condition of lids allows) to make a hermetic seal with aid of aid-band. Doctor's obligations should also include prophylaxis of ocular burns. PMID- 25286572 TI - [The use of plasma surgery in military medicine]. AB - Scientists have been carrying out plasma energy research with the aim to apply to surgical practice. Domestic plasma devices "SUPR-M", "Fakel-01", "Gemoplaz-VP" and "Plazon" passed tests and were approved not only in clinical practice but also in condition of armed conflicts. Biological influence of air-plasma flows on tissues was examined. Nitrogen oxide (NO) is continuously produced in humans and animals involving enzymatic NO-synthase (NOS), acting as a universal regulator of diverse biological and physiological processes. Comparative analysis of the treatment of gunshot wounds and infectious complications clearly demonstrated the efficacy of using plasma flows at the final stage of surgical treatment. Use in military surgery, oncology, urology and gynecology, thoracic and abdominal surgery should be considered as a promising direction of this technology. PMID- 25286573 TI - [Radiomitigators: prospects for use in medical radiation protection]. AB - Prospects of creation and use of radiomitigators--the treatment-and-prophylactic means intended for rendering medical care by the victim of influence of ionizing radiation in the earliest terms after irradiation (hours, days) are presented. It is shown that the most effective radiomitigators are found among natural biopolymers of a microbic origin (a vaccine from bacteria of enterotyphus group, preparations of lipopolysaccharide or protein-polysaccharide components of these microbes). Very perspective such preparations as desoxinate, translame and flagellin are represented. The expressed radiomitigate properties such antioxidants as a-tocopherole, xantosine, caffeine, selenium methionine, inosine, guanosine and antioxidant complexes are possess. Among steroids the greatest interest represents 5-androstenediol. Radiomitigate properties have some cytokines, for example interleukine-1beta (betaleukine), trombopoetin, stem cell factor, and also their combination with colony stimulated factors. Tasks of increase of efficiency of medical radiation protection at early stages of a radiation injures are formulated. PMID- 25286574 TI - [Health status of military men serving on the North Fleet]. AB - Authors analyzed data characterizing health status of military men serving on the North Fleet, peculiarities of changes in category of fitness for military service in 2002-2011. It was found that 75.1% of conscripts fell into first health group, 20.1%--fell into second health group, 4.8%--fell into third health group. Authors gave detailed characteristics of frequent diseases in military men. Authors formulated organizational solutions, ways of improvement of conscripts' health status. PMID- 25286575 TI - [Intravascular decompressive aerogenesis ultrasonography in a practice of diving medical physician]. AB - The aim of research was substantiation of necessity and accessibility of acoustic indication of intravascular decompressive aerogenesis in a practice of diving medical. Authors define possibilities of portable ultrasound blood flow indicator for location of decompressive gas bubbles. It was found that acoustic indication of intravascular decompressive gas bubbles made by simple portable ultrasonic blood flow meter allows to reveal moving gas bubble in blood flow. Authors came to conclusion that it is necessary to include portable ultrasonic diagnostic equipment into the norms of medical supply for ships, vessels and military units of the Armed Forces of the Russian Federation. PMID- 25286576 TI - [Modern ways of actualisation of military formulary system]. AB - Authors presented a historical summary about formation and development of military formulary system and quantitative and qualitative characteristics of the fifth edition of the Drug formulary. The new Drug formulary is a list of drugs developed on the basis of multi-criteria choice of optimal alternatives according clinical and pharmacoeconomic effectiveness, costs with due regard to possible pharmacological support for troops. The fifth edition of the Drug Formulary fully covers medical and social demands of military servicemen, of military retirees and members of their families for the effective drugs during the treatment of socially important and common aliments within the framework of established government guarantee. PMID- 25286577 TI - [Medical control over physical training in the US Armed Forces]. AB - The current article elucidates some novel trends in the field of medical control over the physical training process in the US Armed Forces. The high rate of injuries attributed to physical training calls for scientific medical research intensification of the physical training process. The main innovations are the following: avoidance of overtraining, personalization, gradual increase of loading. PMID- 25286578 TI - [Academy of medical sciences during the Great Patriotic War and first years after war]. AB - In the article presented the history of foundation of the Academy of Medical Sciences of the USSR and its activities during the World War Two and the early postwar years. According to the authors, the scientific development of many fundamental problems from domestic medicine experience during the war has retained its relevance in solving of the contemporary issues in health and medical science in modern Russia. PMID- 25286579 TI - [Military hospital in Komsomolsk-on-Amur celebrates 80th anniversary]. AB - In March of 1934 the Revolutionary Military Council of the Special Far Eastern Red Army decided to deploy a military hospital in the city of Komsomolsk-on-Amur which has been under construction. In June of 1934 there was a connection with the local hospital of Dalpromstroy, located in the barracks, with a total of 60 beds. This hospital began to serve all city construction workers and solders without any exception. June 11, 1934 is considered the day of the hospital foundation. The article presents a brief outline of the hospital's history from 2010 to the present time--Branch number 2 301st District of Military clinical Hospital. PMID- 25286580 TI - [Organization of anesthesia management and advanced life support at military medical evacuation levels]. AB - Anesthesia management and advanced life support for the severely wounded personnel at military medical evacuation levels in armed conflict (local war) is time-consuming and resource-requiring task. One of the mathematical modeling methods was used to evaluate capabilities of anesthesia and intensive care units at tactical level. Obtained result allows us to tell that there is a need to make several system changes of the existing system of anesthesia management and advanced life support for the severely wounded personnel at military medical evacuation levels. In addition to increasing number of staff of anesthesiology critical care during the given period of time another solution should be the creation of an early evacuation to a specialized medical care level by special means while conducting intensive monitoring and treatment. PMID- 25286581 TI - [Modern methods of examination of ballistic trauma after passing through the barrier]. AB - On the basis of experimental data were studied peculiarities of ballistic of wounds after passing barriers. Authors analyzed forensic medical examination reports concerned about murdered and wounded with gunshots in Saint Petersburg. As research objects were used: simulators of biological materials (block of glycerin soap) and experimental animals. The following bullets were used: automat cartridge 7H22, 7H24 - gauge 5,45x39 mm, pistol cartridge 7H29 - gauge 9,0x21 mm; gun reach - 50 and 100 meters; barriers - steel plates, glass, brickwork. The following assessment of exposure was used: in simulators - according to volumes of temporary cavity; in experimental animals - according to results of morphofunctional researches. Data about damaging action of pistol cartridge 7H22, 7H24 with gauge 5,45 mm and automat cartridges 7H29 and 9,0 mm is received. PMID- 25286582 TI - [Modem technologies in the express diagnosis of alcohol and drug intoxication]. AB - Presented domestic and foreign data of the methodological, organizational and legal aspects of express diagnosis of alcohol and drug intoxication. Shown that methods, which are in use for that in different countries, are basically identical. Differ significantly only the holding organizing, coverage breadth of population research, and used legal and material basis. To identify persons which are prone to addictive behavior it is important direction in modern screening surveys. For early detection of solders abusing alcohol or using drugs and psychotropic substances, the most informative scheduled and unexpected surveys using primarily immunochrmmatographic test systems and portable hardware systems. PMID- 25286583 TI - [Diagnosis and treatment of peripheral arterial aneurysms in lower limbs]. AB - Authors analyzed a five years experience of the diagnosis and treatment of peripheral arterial aneurysms in the Center of vascular surgery of the multidisciplinary military hospital. Authors give the assessment of different diagnostic instrumental methods and demonstrate results of surgical treatment. The possibility and effectiveness of endovascular-traumatic method of surgical correction of this pathology of lower limb arteries are given. PMID- 25286584 TI - [Applying of the multifaceted approach to the treatment of patients with a phlegmon of hand]. AB - Presented the experience of treatment of 189 patients with a phlegmon of hand. Conducted multifactorial analysis of the importance and influence on the outcome of disease and prognosis of each of the indicators used to determine the severity of the pathological process. Proved that individual determination of the severity and prognosis of the disease allows correcting choice of treatment methods, to evaluate the probability of complications development and to determine timing and amount of outpatient rehabilitation. Complex of clinical and laboratory methods and ray studies allowed to differentiate medical tactics depending on the location, extent and severity of the pathological process. Diferentiated approach allowed to optimize the schemes and determine indications for immunomodulators, systemic enzyme therapy, and indirect lymphotropic therapy. In 70,9% of cases good resonse to the treatment in patients'with a phlegmon of hand was obtained, in 22,7% satisfactory response to the treatment and only in 6,3% of cases response to the treatment was unsatisfactory (including deep and combined phlegmons). Obtained results allow to recommend developed treatment and diagnostic algorithm for using in clinical practice. PMID- 25286585 TI - [Peculiarities of medical backup of low flight course and nap-of-the-earth]. AB - Authors presented peculiarities of low flight course and nap-of-the-earth: quick change of orientation cues, ground proximity, possible bird collision, loss of radio signal, exposure of oscillating acceleration, caused by increased atmosphere turbulence. It is showed that low flight course and nap-of-the-earth require special health status of pilots, who must be ready to evaluate obstacle distance, obstacle position relative to aircraft plane, gain in altitude, flight elevation and closing speed, new obstacles and make a decision to fly-by or turn. These circumstances cause emotional tension that affects working capacity and professional reliance. Air medical officer should take additional measures for medical backup of these flight courses. PMID- 25286586 TI - [Evaluation of condition and factors affecting activity effectiveness and visual performance of pilots who use night vision goggles during the helicopter flights]. AB - According to analysis of questionnaire authors revealed factors, which affect activity effectiveness, and visual performance of pilots who use night vision goggles during the helicopter flights. These are: difficulty of flight tasks, flying conditions, illusion of attitude. Authors gave possible ways to reduce an impact of these factors. PMID- 25286587 TI - [Healthcare-associated infections. The current state of the problem]. AB - The current article elucidates some novel trends in the field of healthcare associated infections emerged in the foreign scientific medical publications over the last year and a half (January 2013 - June 2014). The following topics are covered: definition of the term, the body of publications bibliometrics, classification, statistics, patient-to-professional infection transmission, control and prevention, specialized national organizations, new guidelines and a new monograph on the theme. The conducted analysis demonstrates the significance of the topic and the high rate of research in the field. PMID- 25286588 TI - [Materials for the history of medical support of the White movement in Eastern Russia (1918-1920)]. AB - The article provides a brief description of the composition of the Eastern Front and the conditions of warfare affecting the organization of the first medical software. The data on the management of health-care de-scrap, the forces and means of health services, especially medical staff manning the troops, medical and sanitary institutions and their activities. Concluded that the command of the troops and the medical service of the White movement in the Russian East used in those conditions available forms of medical evacuation and anti-epidemic measures. Medical support was based on the experience acquired during the Russian German war, and adaptable to the new conditions of warfare. PMID- 25286589 TI - [Organization of medical supply for Russian troops during the Patriotic War of 1812]. AB - Pharmacists and pharmacy assistants made a significant contribution to the successful solution of problems for protection of life and health of soldiers of the Russian Army during the War of 1812. During this period Russia's military pharmacy received a new boost. The first legislatively authorized procedure for medical supplies was established, improved the regulatory framework and the system of training of pharmaceutical personnel, organizational principles of accumulation and the maintenance of a medical emergency reserve property, etc. PMID- 25286590 TI - [Clinical justification of medico-psychological care to the victims of technogenic accidents and catastrophes with prevalence of anxious and depressive symptoms of non-psychotic register]. AB - In the article the clinical justification of medico-psychological care to the victims of technogenic accidents and catastrophes with prevalence of anxious and depressive symptoms of non-psychotic register is described. The necessity of differentiated approach is analyzed in accomplishing of psychotherapy of this contingent of patients taking into account the high level of anxiety, emotional stress, decreased mood, low levels of the quality of life in the remote period of strong stressful factor's action. PMID- 25286591 TI - [Immune activation and inflammation in chronic heart failure]. AB - This survey shows that among chronic heart failure (CHF) and its characteristic inflammation observed mutual activation. Given the role of inflammation in the pathophysiology of heart failure, it is to study how the combination drug treatment of CHF, its variants influence on markers of inflammation. It is expedient to determine not only the level of cytokines, but also acute phase proteins (haptoglobin, seroglikoidy C3-complement, transferrin), reflecting inflammation and necrosis in the connective tissue, as well as IgA, IgG, IgM and protein spectrum. The importance of the study of haptoglobin due to its involvement in the metabolism of hemoglobin and transferrin--the exchange of iron. PMID- 25286592 TI - [Evaluation of systemic involving of the connective tissue in children with different localisation of isolated abnormal chords of the left ventricle (ACLV)]. AB - Evaluation of the systemic involving of the connective tissue (SICT) under the new Ghent nosology (2010) showed that in children with isolated ACLV born to parents exposed to the Chernobyl disaster, its expression is associated with their location and quantity. The degree of systemic involvement of connective tissue is confirmed by the results of the analysis of features echostructure of isolated ACLV (the presence of thickening and calcification), echomorphometry, assessment of systolic (hypokinetic organization of the central hemodynamics), and the relaxation functions of the heart (initiation of diastolic dysfunction). High level of SICT (score greater than 5) indicates systemic damage to the body and particularly the heart, which requires dynamic monitoring and preventive measures. Found that the diagnostic and monitoring of children with isolated ACLV may be based on registration of systemic involvement of connective tissue with the calculation of points under the new Ghent nosology of 2010. PMID- 25286593 TI - [Diagnostic markers of anthracycline-induced cardiomyopathy in children with acute leukemia]. AB - The results of the survey 16 children with acute lymphoblastic leukemia, in which the resulting protocol chemotherapy using doxorubicin developed toxic anthracycline-induced cardiomyopathy. The control group was 20 healthy children of similar age studied. Distribution of research groups included age status and cumulative dose of doxorubicin. Studies of the cardiovascular system in children with acute leukemia was conducted before and at the end of each protocol chemotherapy. It is noted that the complaints of the cardiovascular system as palpitations and disruptions in the heart, cardialgia, autonomic crises occurred at the end of the first phase I protocol chemotherapy. Severity of complaints prevalent in patients with higher cumulative dose of doxorubicin. Noted a decrease in left ventricular contractile capacity and the development of myocardial ischemia in patients with acute leukemia at the end of the first phase II protocol. The increase pro-brain natriuretic peptide in all patients with acute lymphoblastic leukemia at the end of the first phase I protocols that can be considered as an early diagnostic marker of myocardial injury in these patients. PMID- 25286594 TI - [Clinical features of atopic asthma and their relation to the T-regulatory cells and total immunoglobulin E]. AB - Allergic diseases are among the most popular in the world. Scientific hypothesis formation and multifactorial pathogenesis of atopic asthma (AA) is constantly updated. Our purpose of this study was to investigate the relationship of humoral and cellular immunity with features clinical and anamnestic data in patients AA. Found that AA is genetically determined disorders, mainly transmitted through the maternal line, characterized polisensibilization, most of household allergens. AA is often associated with other allergic nosology (62.2%) and gastrointestinal diseases (44.4%). In the absence of clinical evidence of disease at CD4+/CD25+/Foxp3+, IgE and IL-4 in patients with AA is higher than in healthy individuals. When polyvalent allergy has been a significant increase in IgE (199.3 +/- 22.2) and IL-4 (79.2 +/- 16.5) and reduced expression of molecules CD4+/CD25+/Foxp3+ compared with sensitization to one or two allergens. PMID- 25286595 TI - [The role of toxininduced autoimmune activity in formation of the endotoxemia during the lead exposure]. AB - Here presented the features of formation of endotoxemia at microsaturnism. Here are the results of the retrospective study of toxininduced autoimmune activity and their role in toxemia depending on the degree of exposure of lead. Investigated the mechanisms of production of toxins and damaging potentials activity, molecular size toxins and parameters of their distribution and accumulation in the blood stream, due to the strength of toxinbearing fractions depending on the degree of microsaturnism. PMID- 25286596 TI - [Special features of mild cognitive impairment in patients with metabolic syndrome]. AB - Aim: to establish special features of mild cognitive impairment (MCI) in patients with chronic insufficiency of cerebral circulation (CICC) with metabolic syndrome (MS) depending on the age of patients. Investigation involved 282 patients aged 45-89 with CICC. All the patients also were divided into three groups depending on age; each group was divided into two subgroups: with MS and without it. Total MMSE score in patients with MS and without it of all age groups was not significantly different. We found significant difference between groups of patients in some MMSE tests: orientation in time, orientation in space, remembering of three words, attention and count, words reproduction. Presence of MS in patients with MCI syndrome of all age groups negatively influenced on such cognitive functions as: storage and reproduction of information, attention, orientation in time (processes depicting state of executive functions). In patients with MS, comparing with those without MS, we found significantly worse characteristics of immediate and delayed memory for verbal stimuli, especially in old aged patients, the rate of sensorimotor reactions, mental capacity, the amount of active attention of patients on tables Schulte, information processing speed and attention according to SCWT for all age groups. PMID- 25286597 TI - [A clinic and pathway comorbidity aetiology of the somatoform disorder, abuse syndromes and addictions at adolescent age]. AB - The clinical features of forming of komorbydnoho combination of vegetative disfunction are studied with the displays of chronic pain. It examined 82 adolescents--48 girls (58.5%) and 34 boys (41.5%) aged 16-17 years. All teenagers have noted the presence of the dual problems of stress in their lives. Girls feel a greater impact of stressful factors than boys. The largest number of connected stressful factors were found in the subgroup of women with the syndrome tsefalhiyi, and the lowest was observed among boys with abdominalhiyi syndrome. PMID- 25286598 TI - [Methods for early detection of predisposition to abnormal increases in body weight of children and adolescents]. AB - This article presents the results of a special method designed for the early identification of children's and adolescents' propensity for abnormal weight gain. The basis of this technique is the principle of monitoring the actual values of body mass index for each child or young person at the age of dynamic changes in the index of the normal range. The weekly body weight of each child or adolescent who participates in the study is measured and the results are included in a special registry. Measurement of the body weight of the children and adolescents occurs in the morning at the same hour on an empty stomach after use of the toilet and performance of necessary hygiene. Afterwards, the obtained values of their body mass indices are compared with those considered normal for age, according to official data. In cases when the resulting body mass index of a child or young person exceeds the range of normal-for-age values, an in-depth medical examination of the child or adolescent is conducted together with the nature of their food intake and mode of physical activity, which may then be corrected. PMID- 25286599 TI - [Algorithm for the diagnosis of the vertebral artery compression syndrome based on sensitivity of ultrasound and angiographic methods]. AB - The results of sensitivity analysis and ultrasonic techniques hagiographic 150 patients with vertebral artery syndrome caused by compression extravasal (ECVA) segment V(p), who underwent surgery on clinical. In assessing the sensitivity by a static cross-vertebral artery, vessel diameter, the condition of the lumen- Ultrasonic and hagiographic (SAG and MRA) techniques showed the same high sensitivity in the range 85-89% (P > 0.05), and according to such criteria as the dynamic permeability (89.2% vs. 34.2 and 45.5%), the value of ripple vascular (86.3% vs. 58 and 67%), the state of the perivascular tissue USDG figures were significantly higher than the data angiography (82.2% vs. 0 and 29%) (P < 0.05 for all tests). Comparative analysis of selective angiography, enhanced magnetic resonance angiography and ultrasound proposed method allowed us to determine their sensitivity. Thus, the sensitivity of selective angiography in extravasal vertebral artery compression is 57.1%, magnetic resonance angiography--88% and triplex ultrasound-- 91.3%. PMID- 25286600 TI - [Modern methods of correction of systemic inflammation and insulin resistance by patients with coronary heart disease and diabetes mellitus type 2]. AB - Mediterranean diet and regular exercise are the best means to reduce the systemic smoldering inflammation (SI) and insulin resistance (IR). Of drugs prescribed to patients with diabetes mellitus type 2, have the greatest effect receptor agonists that activate the peroxisome proliferator (PPAR], activators of incretine and metformin. Debate the use of "submaximal" double and triple agonist PPAR. Sulfonylurea drugs have very weak anti-inflammatory effect and is not reduce insulin resistance, and insulin as monotherapy increases IR. PMID- 25286601 TI - [Features of respiratory dysfunction in patients with severe community acquired pneumonia]. AB - The article presents information about the features of violations of respiratory function in patients with severe community-acquired pneumonia, who were treated in the Department of Pulmonology (therapy), as well as the Department of intensive care unit and intensive care. It has been shown the correlation between the degree patients severity from the severity of the violation of external breathing. The results can serve as a basis for a more personal approach to the development of diagnostic and therapeutic programs for patients with severe community-acquired pneumonia. PMID- 25286602 TI - [Clinical use of 13C-breath tests in esophagogastroduodenal diseases]. AB - Investigations in new facilities of 13C-breath tests clinical use in gastroenterology is shown in the aricle. The urea and octanoate breath tests' clinical efficacy in dyspepsia, gastroesophageal reflux disease and H. pylori associated diseases was proven experimentally. PMID- 25286603 TI - [Effectiveness of medical rehabilitation of women of reproductive age with fatigue syndrome]. AB - Efficacy Erbisol in combination with Lymphomyosot and Echinacea compositum C in medical rehabilitation of women of reproductive age with fatigue syndrome and chronic gynecological pathology was studied. It was found that this complex of medications promotes faster and more effective reduction of the level of circulating immune complexes in the serum, achievement of persistent clinical remission of disease and liquidation of fatigue syndrome manifestations, what improves the quality of life of patients. PMID- 25286604 TI - [The effect of comorbid headaches in patients with epilepsy on clinical pathomorphosis of the disease]. AB - Of 404 adult patients with epilepsy (E) with a period of follow-up from 5 to 26 years (mean 8.5 +/- 3.0) a group of 168 people was distinguished by presence of comorbid headaches (HAs) of various types: by origin--primary and secondary, by relation to occurrence of epileptic seizures--inter- and periictal. In general, the presence of comorbid HA did not affect the prognosis for remission of epileptic seizures in patients of all etiologic groups (idiopathic, cryptogenic, and symptomatic). Primary HAs were mainly observed in cryptogenic and idiopathic E, and secondary--in symptomatic E. It is in the group of patients with symptomatic epilepsy and HAs the clinical pathomorphosis depending on the etiology of the disease has been marked. HA in patients with vascular E haven't worsen the prognosis of the disease: 86.7% of patients were in remission, indicating the positive clinical pathomorphosis of this form of E. At the same time, a negative long-term clinical pathomorphosis of symptomatic E was observed in comorbidity of HA with posttraumatic E, with mesial temporal sclerosis and with E due to the brain space-occupying lesions, or the consequences of their removal. In these cases the patients developed more often drug-resistance. Pseudo resistance was observed in patients with E and HA in multiple sclerosis and in alcoholic E. PMID- 25286605 TI - [Laparoscopy of the upper urinary tract]. AB - The upper urinary tract is a wide field for using of laparoscopy. The aim of this work was to analyze retrospectively our experience in the development of laparoscopic techniques of surgical treatment of upper urinary tract pathology. 137 patients with pathology of the upper urinary tract were operated laparoscopically in our department during three years (July 2010 - July 2013). There were performed: nephrectomy--75 (54.7%, nephroureterectomy--3, 2.2%, partial nephrectomy--12 (8.7%), adrenalectomy--11 (8%), resection of the adrenal gland--2 (1.5%), cystectomy--10 : (7.3%) ureterolithotomy--15 (11%) pelviolithotomy--3 (2.2%), pyeloplasty--4 (2.9%) nephropexy--2 (14%). The results were evaluated by the comparative analysis of laparoscopic surgery and similar open interventions that were performed in our clinic. The mean operative time after laparoscopic nephrectomy was 180 min (80-220), the mean blood loss during surgery was 150 ml (50-370). The patients discharged at 4-5 days after operation. Laparoscopic partial nephrectomy was performed at an average tumor size 2.7 cm (1.5-3.5). We used warm ischemia in 75% of cases. Its average time was 27 min (9 39), which was significantly greater than in the open resection--17 min (10-27). At the beginning of the development of laparoscopic adrenalectomy the average operative time was 140 min (110-270). In the future, as we got experience, it declined to 70 min (60-90) min. The mean blood loss was 70 ml (range 20-400). After laparoscopic cystectomy, ureterolithotomy, pelviolithotomy and pyeloplastic the patients discharged at 2-3 days. Intraoperative and postoperative complications were not noted. Laparoscopic surgery for treatment of pathology of the upper urinary tract is an alternative to the operations performed by the open approach. The oncological outcomes, functional results and complication rates are comparable for both types of surgery. PMID- 25286606 TI - [Spinal anesthesia with low doses of local anesthetic in patients with multiple trauma]. AB - The aim of the study was to compare the safety of low doses of local anesthetic spinal anesthesia with the traditional by frequency of hypotension and bradycardia in patients with polytrauma. We observed 144 patients with multiple injuries, including fractures of the lower limbs: I group patients 7.5-10 mg intrathecal bupivacaine group II--15-20 mg of bupivacaine. The relative risk (RR) of hypotension for the control group compared with the study was 9.3 (95 % CI 2.79-39.3). The relative risk (RR) of insufficient duration of anesthesia when using unilateral technique was not significantly higher--2.56 (95% CI 0.73 11.32). Found that spinal anesthesia with low doses of local anesthetic can significantly reduce the risk of hypotension and bradycardia in patients with multiple injuries, but during prolonged surgical interventions unilateral spinal anesthesia is advisable to combine with catheterization of the epidural space. PMID- 25286607 TI - [Clinical--anatomic ground of caudal approach in newborns with surgical pathology]. AB - Anatomic research have been done on 20 dead bodies of newborns for updating of caudal block level. For definition of caudal block level it was proved, that injection of coloring agent in volume of 0.5 ml/kg, 1 ml/kg and 1.2 ml/kg promotes reaching middle thoracic, high thoracic and highest level of epidural block. Analysis of hemodynamic and serum cortisol level in 25 newborns with surgical pathology showed the best analgesic effect in 15 newborns, who have got caudal-epidural anesthesia comparably with 10 newborns, who have got traditional multicomponent general anesthesia. PMID- 25286608 TI - [Justification for the study screening newborn hearing screening in terms of regionalization of perinatal care in Ukraine]. AB - Conducting research screening newborn hearing screening in terms of regional perinatal centers in Ukraine and further rehabilitation of children with hearing impairment is a key step in their integration into society. Universal newborn hearing screening should be mandatory, especially in perinatal centers, because it has significant medical, social and economic effects. It is also necessary to reorganize the existing regional offices surdologichesky and create on their bases and methodological Regional Medical Center hearing and speech problems, which will provide high-quality diagnosis, epidemiological data form, will hold the register of children diagnosed with hearing defects, organize them continuously active surveillance, hearing aids and effective rehabilitation, to ensure the quality of screening. Creating a distributed database for these patients, by far. Will achieve success in the integration of children with special needs in society. PMID- 25286610 TI - [Biochemical parameters of blood and morpho-functional state of the liver of experimental animals by the actions of lead sulfide nanoparticles in different time study]. AB - Biochemical studies revealed that alanine aminotransferase levels changing first during short action (30 injections) of lead sulfide nanoparticles of size 10 and 30 nm, and the ionic form of a 400 nm lead while the growth of both enzymes (aspartate aminotransferase and alanine aminotransferase) activity during long term exposure (60 injections) is the same intensity. It it confirmed by the value of de Ritis coefficient, which is statistically the same as control. Morphological studies also confirm these data--degenerative changes of hepatocytes, reactive changes of the stroma and vascular responses were detected. It is shown that the severity of metabolic and morphological damages in the liver increased with prolonging the duration of lead nanoparticles intake. PMID- 25286609 TI - [Comparative evaluation of the influence of calcium channel blockers of derivatives of 1,4-dihydropyridine--amlodipine and dimeodipine--on parameters of carbohydrate metabolism in the blood of rats with doxorubicin-induced cardiomyopathy]. AB - Presented are experimental data on the influence of calcium antagonists of the third-generation derivatives of 1,4-dihydropyridines--amlodipine (1.5 mg/kg), dimeodipine (1.5 mg/kg)--on parameters of carbohydrate metabolism in rat blood model doxorubicin-induced cardiomyopathy. The possibility for correcting carbohydrate metabolic disorders in the blood with the above drugs through a reduction of lactate, lactate/pyruvic retio, LDH activity, normalization of the level of glycogen, glucose, pyruvate. PMID- 25286611 TI - [Pharmacogenetic aspects of candesartan application for the treatment of arterial hypertension in patients with chronic pyelonephritis]. AB - Now necessity of the strict control arterial pressure (AP) is conventional at chronic diseases of kidneys. Inhibitors of receptors AT1R (BAR) are recognized all over the world as preparations of the first of some for treatment of renoparenchimal hypertensia. The purpose research--to study of clinical effect of Candesartan at patients with renoparenchimal hypertensia depending on a genotype. Survey 50 patients with inspected patients with renoparenchimal hypertensia on a background of chronic pyelonephritis, polymorphism of gene of angiotensin 11 of the first type is certain. Patients appointed Kandesartan in doses of 8-32 (Mg), observed in current of 12 months. By results of research the genotype AA is revealed at 46%, AC at 48%, CC at 6% of patients. Allel A it is revealed in a genotype of 94%, allel C - 54% of patients of renoparenchimal hypertensia. A target level the AP will reach at 94.,3% patients. Kandesartan has shown high clinical effect at all variants of polymorphism of gene AT1R. PMID- 25286612 TI - [Experience of using phytopreparation Alba (root extract of the Potentilla alba) in complex treatment of thyroid pathology in children and adolescents]. AB - This article presents the background for including phytopreparation Alba (root extract of the Potentilla alba) into complex treatment of thyroid pathology. The findings confirm visible reduction of size of the thyroid gland and normalizing its functions in children and adults with the thyroid gland with normal or enhanced function treated by Alba per oral. PMID- 25286613 TI - [Comparative hygienic assessment of potential risk to workers under application of fungicides of different classes]. AB - The comparative hygienic evaluation of working conditions in various application technologies of triazole fungicides (tebuconazole, dyfenoconazole, penconazole) strobilurine fungicides (azoxystrobin, pyraclostrobin, trifloxystrobin), ethylene bis-dytiocarbamate fungicides (metiram, mancozeb), cianopyrrole fungicide (fludioxonil), anilide fungicides (benalaxyl-M, boscalid), anilinopirymidyne fungicides (cyprodynil, valifenal, pirymetanil). Potential complex risk of possible harmful effects of the investigated compounds on workers by inhalation and percutaneous admission, as well as a comparative analysis of received values was assessed. Determination of active substances in the samples was carried out by gas-liquid and high performance liquid chromatography. In the air of the working area were found triazoles 0.005-0.01 mg/m3, ethylene-bis-dytiokarbamates- 0.01-0.02 mg/m3 at fan plants processing, anilinopirymidynes--0.19 mg/m3 at backpack plants processing. Listed values do not exceed the established hygienic standards in the air of the working area. Steam plants processing had not accompanied by the arrival of investigated compounds in the air of the working area. For all the studied crops processing technologies magnitude of the potential risk of possible harmful effects of study classes fungicides influence at the complex admission does not exceed the permissible level (was less than 1). Comparative analysis of complex risks for workers allowed to distribute fungicides according this criterion in the following order: cianopyrrole < strobilurynes < triazoles < anilides < anilinopirymidynes < ethylene-bis dytiokarbamates. PMID- 25286614 TI - [Features of interpersonal behavior among executives of healthcare institutions with different styles of resolving management decisions]. AB - The aim of this work is to study the influence of the type of interpersonal relationships between executives and subordinates in healthcare institutions on their style of resolving management decision. It was established that indulgent and autonomous style are formed against background of liberal interpersonal relationship by the following criteria, as the absence of dominant traits, expressed benevolence among executives with autonomous style, uncertainty and inexperience among executives with indulgent style. Authoritarian and marginal styles are formed against empowerment and dominance in relationship with subordinates by expressed dominance criteria, as leadership qualities among executives with authoritarian style or as a manifestation of social maladjustment among executives with marginal style. Type of interpersonal relationships determines the style of resolving management decisions, that should be considered at conducting professional selection of candidates for senior positions in healthcare institutions. PMID- 25286615 TI - [Analysis of functioning of system management by quality of Medicare]. AB - In the article the lighted up questions are in relation to the quality management of medicare. The analysis of world and home experience of creation of control system by quality is presented from position of acceptance of administrative decisions. PMID- 25286616 TI - [The medical activities of the first head of Sumy Children's Hospital St. Zinaida - A. F. Belousov]. AB - The article examines the work of the first head of the Children's Hospital St. Zinaida at Sumy--Alexander Fedorovich Belousov. We considered his contribution to the organization of the first children's hospital in Sumy region and the creation of specialized pediatric services for children population in the Sloboda Ukraine. The article describes the personal role of A. F. Belousov in improving medical and sanitary care in a difficult socio-economic situation of the majority of citizens of the Russian Empire in the late 19th-early 20th century. PMID- 25286617 TI - [To the memory of Anatoliy Rodionovich Uvarenko]. PMID- 25286618 TI - Healthcare DIY. PMID- 25286619 TI - Healthcare on demand. PMID- 25286620 TI - Who are you? PMID- 25286621 TI - HIPAA's place in court-ordered discovery. PMID- 25286622 TI - Accessing and using data from wearable fitness devices. PMID- 25286623 TI - How and why to preserve health records during litigation. PMID- 25286624 TI - Why standards should matter to HIM professionals. PMID- 25286626 TI - Defining the basics of health informatics for HIM professionals. PMID- 25286625 TI - Curing inherited EHR ailments. PMID- 25286627 TI - ACA risk adjustment models emerge in commercial care. PMID- 25286628 TI - Coding ICD-10-PCS procedures in the ancillary sections. PMID- 25286629 TI - [The Lancet crosses all boundaries]. PMID- 25286630 TI - [A hantavirus killed an Israeli researcher: hazards while working with wild animals]. AB - An Israeli researcher working in Finland with Bank Voles, contracted an infectious viral disease and died. This was a rare event, but it is important to learn about this class of viruses and to be aware of the hazards while working in the field in close contact with wild animals. The virus termed Puumala belongs to the genus Hanta from the Bunyaviridae family. The natural reservoir is rodents, mice, rats and Bank Votes for the Puuamala strain. The disease is termed HFRS (hemorrhagic fever with renal syndrome), is prevalent in Asia and Europe, affecting 200,000 people a year, with 5-15% percent mortality (although in Finland mortality rate is 0.1%). The New World strains cause HPS (hemorrhagic pulmonary syndrome) affecting 200 people a year with 40% mortality. Virus is present in all rodents excretions, and route of infection is by aerosols, hand to mucus membranes contamination, by rodents bites and by contaminated food or water. More than 226 work related infections were documented. Treatment with Ribavirin helps in HFRS but not in HPS. The virus is stable in the environment for long periods, and research must be carried out at biosafety level 3. Working outdoors in rodent infested area, should be carried out using protective clothing, gloves, googles and face mask whenever aerosol producing tasks are performed. Both indoor and outdoor, it is important to adhere to self-hygienic procedures, especially hand washing. PMID- 25286631 TI - [From the diary of the director of the Southern District of a community healthcare service in wartime]. PMID- 25286632 TI - [A case of Crohn's disease following an infection by Epstein-Barr virus]. AB - Infection by the Epstein-Barr virus (EBV) has been linked to the development of autoimmune diseases and recent studies have investigated its specific influence on inflammatory bowel diseases. This is a case report of a 20 year old patient who was diagnosed with Crohn's disease following a prolonged manifestation of infectious mononucleosis. The current information regarding the association between EBV and the development of inflammatory bowel diseases is discussed. PMID- 25286633 TI - [Robotic-assisted surgery in urogynecology--our experience with the first 100 cases: experience from a single institution]. AB - INTRODUCTION: The prevalence of surgery for pelvic organ prolapse repair is increasing. It is estimated that about 30% of women who underwent an operation for pelvic organ prolapse will need repeat surgery within a period of five years. The main reasons for surgical failure are attributed to difficulty in selecting the correct procedure for the type of prolapse and problems associated with the surgical technique. Sacrocolpopexy was originally described 55 years ago. However, expertise in laparoscopic sacrocolpopexy requires a relatively long learning curve. AIMS: To describe our experience in robotic sacrocolpopexy (RSC). METHODS: A retrospective study of the first 100 robotic sacrocolpopexy performed at a single medical center The primary outcomes examined were intraoperative bleeding, operative time, and hospitalization length. Secondary outcomes studied were surgical complications. Data were retrieved from patients electronic charts. RESULTS: The mean age and POPQ stage were 60 years 145-77 years) and median stage of III (II-IV), respectively. Estimated intraoperative blood loss was 41 ml (25 300 ml) and mean operative time was 177 minutes (range 114-299 minutes). The median length of hospital stay was 1 day (1-6 days). Adverse events were rare (4%) and not severe. CONCLUSIONS: Based on our experience with the first 100 cases, RSC is a feasible procedure with a low complication rate. RSC enables operating anatomically with a small amount of bleeding and a relatively short hospital stay following surgery. Long-term follow up is needed in order to evaluate the efficacy of RSC. PMID- 25286634 TI - [Prenatal diagnosis of trisomy 13 and trisomy 18: the experience of Assaf-Harofe Medical Center]. AB - INTRODUCTION: Trisomy 18 and 13 are the most common autosomal trisomies, after trisomy 21, and their frequency is rising due to the increased maternal age of pregnant women. The fetuses suffer from multi-organ damage that may lead to many gestational complications as well as short life expectancy. OBJECTIVE: To assess the indications for prenatal karyotyping of trisomy 13 (T-13, Patau syndrome) and trisomy 18 (T-18, Edwards syndrome) during pregnancy in our medical center. METHODS: This retrospective cohort study involved all singleton pregnancies locally diagnosed or referred to our Institute because of T-13 and T-18, during the years 1998-2011. RESULTS: There were 1879 cases of termination of pregnancies (TOPs) because of fetal indications, of them 53 cases of T-18 and 10 cases of T 13. The main indications for prenatal karyotyping in our study group were abnormal sonographic findings during anomaLy scans. In addition, 7 newborns with T-18 and 3 infants with T-13 were born in our hospital during the same period of time. We examined all cases that led to the Live birth of newborns with chromosomal anomalies, stemming from the Lack of extraction of the tests mentioned above and/or ignoring findings that raise suspicion that requires performing prenatal karyotyping during pregnancy. DISCUSSION: Our findings corresponded with other studies and showed that prenatal diagnosis of T-13/T-18 due to abnormal sonographic finding is rising. CONCLUSIONS: Our study shows that it was possible to identify the vast majority of T-13/T-18 among the pregnant women who had an increased risk based on a combination of the routine screening tests applied in Israel. PMID- 25286635 TI - [Familial spam (streptococcal pharyngitis associated myocarditis): is it a new entity or a coincidence?]. AB - BACKGROUND: Myocarditis is an inflammation of the myocardium. It is potentially life-threatening, with a wide range of clinical presentations and most often it is caused by various viral, bacterial or fungal infections. CASE PRESENTATION: A 27 year-old man, previously hospitalized due to streptococcal tonsillitis, was admitted to ED because of chest pain. He presented with pain, tightness irradiating to both shoulders and arms and associated sweating and vomiting. The ECG revealed ST elevations on Leads: V5-V6, V7-V9, II, III, AVF and ST depressions on Leads V1-V3. Laboratory results showed elevated Liver enzymes, and positive troponin-5.766 ng/mL The patient showed clinical improvement with NSAIDs and was diagnosed with myocarditis. His brother was admitted to the hospital a year earlier with a sore throat accompanied by chest pain and was diagnosed with perimyocarditis. CONCLUSIONS: The family history of myocarditis after a streptococcal infection, affecting two brothers a year apart from each other, raises the possibility that there is a genetic component responsible for an individuaLs susceptibility to develop myocarditis. PMID- 25286636 TI - [Intraoperative radiotherapy (IORT) in early breast cancer]. AB - BACKGROUND: Breast-conservation therapy is widely accepted as an effective treatment option for patients with early stage carcinoma of the breast. The proportion of patients with recurrence after receiving partial breast irradiation is the same as that seen in patients treated with whole breast irradiation. Therefore, the necessity of whole breast irradiation has been questioned, and partial breast irradiation has emerged as a reasonable alternative. METHODS: Since 2006, 468 women with early breast cancer (age > 60 years, T1, infiltrative duct carcinoma and with no clinical or sonographic suspicion of involved axillary lymph nodes) were treated in the Carmel Medical Center with intraoperative radiotherapy, using the INTRABEAM System giving 20 Gy at the tumor bed. We report the cohort of the first 100 patients who have had a follow up period of more than 3 years. RESULTS: The median age was 70 years (range 56-87 years). Twenty four patients had mild to moderate local complications, while nine patients experienced major local complications. Eighteen patients had metastatic involvement of the axillary lymph nodes, and in 16 of them, only one node was involved. Five patients had additional local therapy (one patient underwent mastectomy and four patients received whole breast irradiation). During the follow up period, four ipsilateral breast failures were observed: two new primary tumors (by location and histology) and two local recurrences. CONCLUSIONS: Intraoperative radiotherapy using the INTRABEAM system is feasible and may offer an alternative to whole breast radiotherapy, in low risk early breast cancer patients with a low rate of local recurrence and morbidity. Longer follow up is required in order to evaluate long term results and late toxicity. PMID- 25286637 TI - [Obsessive compulsive disorder (OCD) in the ultra-orthodox community--cultural aspects of diagnosis and treatment]. AB - Obsessive compulsive disorder (OCD) is reflected similarly in different communities, while symptoms are affected by the patient's cultural and spiritual world. An ultra-orthodox Jew with OCD will perform compulsive actions and will have obsessive thoughts related to the Jewish religious world. The religious symptoms do not necessarily correspond with the main commandments. Despite their significance, Shabbat or moral commandments such as respecting one's parents do not play a central role in the compulsive pattern. The religious compulsiveness of OCD patients focuses on commandments having to do with order and cleanliness and is characterized by repetition, checking and slowness. Obsessive thoughts and compulsive actions of ultra-orthodox OCD patients are usually based on the Jewish scriptures. One might assume that religion, as a framework with rules and dictated rituals, serves as a strong foundation for the development of OCD. However, it is estimated that the prevalence of OCD in the ultra-orthodox community is similar to the general population. Rabbis acknowledge OCD as a psychiatric illness and do not encourage the obsessive punctuality in following the commandments. An ultra-orthodox patient will first consult his rabbi, and after receiving his recommendation, will turn to psychiatric treatment. He might prefer to receive drug treatment rather than Cognitive Behavioral Therapy that may oppose his beliefs. Understanding the cultural background of the patient is essential, in particular when the patient is ultra-orthodox and the treatment is considered "secular". Therefore, cooperation with the patient's rabbi is important in order to obtain the patient's trust and develop a treatment plan. PMID- 25286638 TI - [Physical activity during pregnancy--facts and practical guidelines]. AB - Physical activity during pregnancy is known to have a positive effect on both the mother and the fetus/newborn, as long as there are no specific contraindications relating to maternal pathology. Physical activity during pregnancy is known to be associated with reduced incidence of several gestational pathologies, as well as boosting physical and mental capabilities. Furthermore, a positive effect was found in newborns whose mothers continued their physical activity habits throughout pregnancy. Nevertheless, the intensity and duration, and specifically their efforts against resistance, have not been adequately emphasized. Herein, we review the main recent findings and insights on physical activity during pregnancy, and provide a practical set of recommendations. PMID- 25286639 TI - [The incredible story about the cesarean section from ancient times till nowadays]. AB - During its evolution the cesarean section has meant different things to different people. The indications for it have changed throughout the course of history. From the initial purpose to retrieve an infant from a dead or dying mother in order to bury the child separately from his mother, to contemporary indications. This article strives to follow the roots of this common procedure--starting from the descriptions in the ancient Greek mythology, through the imperial Roman law, aspects of Judaism and the evolution of the procedure throughout modern history. Major improvements in the surgical techniques, the introduction of anesthesia and aseptic procedures contributed to the decline in mortality and morbidity rates. We will attempt to find the etymology for the expression "cesarean section" which has commonly been accounted to Julius Caesar's name, although history denies it. This review takes us on a historical journey, from ancient times to nowadays, in which we follow the course and nature of a procedure being performed daily in thousands of hospitals. PMID- 25286640 TI - [Is there a role for asymptomatic carotid artery stenosis screening?]. AB - Screening for asymptomatic carotid artery stenosis (CAS) is highly controversial Many surgeons routinely screen their patients for carotid disease prior to major operations, yet the benefit of such practice was never demonstrated. The treatment of symptomatic patients has not changed much during the last twenty years, since the publication of the North American Symptomatic Carotid Endarterectomy Trial (NASCET). However, in contrast, the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST) failed to get the same acceptance among the multidisciplinary group treating CAS.The prevalence of asymptomatic 60-99% carotid artery stenosis among the general population is about 1%. Neither ACAS nor ACST showed that stenosis severity was associated with increasing stroke risk. The 'realpolitik' is that mass interventions in asymptomatic patients will probably only ever prevent about 1% of all strokes. This is even truer regarding patients scheduLed for major operation, in which the incidence of stroke is less than 1%. Moreover the current evidence in the literature suggests that the best medicaL treatment (BMT) results in 0.5% strokes per year, better than resuLts which can be offered by surgery. According to the current evidence, it seems that asymptomatic carotid artery screening should be discontinued, since it is a major waste of resources. PMID- 25286641 TI - [Obesity, bariatric surgery and future fertility]. AB - Obesity is an increasingly widespread health problem. In addition to comorbidities such as diabetes, hypertension, dyslipidemia and cardiovascular disease, obesity has a significant impact on reproductive life, including infertility, miscarriages and high prevalence of pregnancy complications. The present review describes the possible benefits of bariatric surgery regarding fertility and pregnancy outcome. It is well established that bariatric surgery leads to regular ovulatory cycles and improves spontaneous conception rates in obese women. While pregnancy after bariatric surgery is safe and associated with reduced pregnancy complications, pregnant women following bariatric surgery are still at high risk for preterm births and small dimensions of gestational age offsprings. The optimal interval that should be kept between surgery and subsequent pregnancy is controversial, with recent studies emphasizing the importance of nutritional balance rather than the time from surgery to conception as being the most important determinant. Strict peri-conceptional surveillance is mandatory in order to prevent nutritional deficiencies and for the early diagnosis of abnormal fetal growth. PMID- 25286642 TI - [Two decades of progress in the diagnosis and treatment of differentiated thyroid cancer]. AB - The clinical presentation of differentiated thyroid cancer (DTC) has changed considerably over the last two decades. This is mainly due to improvements in our capabilities to make an early diagnosis. As a result of these changes, a huge increase in the incidence of DTC has been seen worldwide, with the appearance of a much more indolent disease. During this period, significant progress has also been made in our understanding of the disease and today our approach to the DCT patient has changed completely. As we are entering an era of new technologies, we aim to review the major deveLopments considered as the milestones of these changes. PMID- 25286644 TI - [Medicine, physicians and medical ethics in Jewish tradition through the ages]. AB - Medicine has always had a place of honor in the Jewish heritage. Since Biblical times, the sources of Judaism have valued the physician's activities and seen them as a partnership with God's deeds. Later, in the times of the Mishna and the Talmud, a model of scholars evolved who were not only learned sages but also had extensive medical and scientific knowledge. Their dealings with various issues in medical ethics were the basis for deliberation on questions that appeared throughout history on the advancement of medical science. The various sources from this period show the sages' sensitivity regarding the subject of human life, saving lives and the importance of the availability of medicine for all segments of the population. During the years following the completion of the Talmud, the medical profession was common among the Jews and they excelled in this field. Jewish doctors left behind a Legacy of values in medicine. Hebrew was considered a significant Language in the medical field and was cited in various medical texts such as in the book written by Vesalius, the "father" of modern anatomy. The rapid progress of medicine poses new challenges in bioethics. There is a need for physicians with extensive medical knowledge along with an understanding of ethical issues in order to offer solutions to new situations. Knowledge of the Jewish literature throughout the ages on a variety of subjects and the essential values which are their foundation can contribute to the modern discussion on biomedical questions. This is even more important in Israeli society where many of the laws are formed based on Jewish values. Engagement with Jewish medical ethics can help in educating physicians to have the ability to contribute to public debate and legislation in a way that would balance between the values and needs which an ethical issue raises. PMID- 25286643 TI - [Women pioneers: first female cardiothoracic surgeons in the USA and in Israel]. AB - At the beginning of the 1960's, three female doctors managed to break the glass ceiling and become the first female cardiothoracic surgeons in the USA. Since then, the number of certified female cardiothoracic surgeons has steadily increased. Nevertheless, females stilt only account for a minority of cardiothoracic surgeons in the USA. In Israel, three women have become specialists in cardiothoracic surgery over the last two decades, aLthough these surgeons are working as general thoracic surgery consultants, without any representative females in cardiac surgery. PMID- 25286645 TI - [Summary of the EPICOH 2013--epidemiology and occupational health--Utrecht 2013]. PMID- 25286646 TI - Distribution of classical enterotoxin genes in staphylococci from milk of cows with- and without mastitis and the cowshed environment. AB - The aim of this study was to analyze by PCR 185 isolates of Staphylococcus from milk of cows with- and without mastitis and from the cowsheds environment for their potential ability to produce five classical staphylococcal enterotoxins. Among S. aureus isolates 8 (32%) carried enterotoxin genes and only 2 of them had more than one gene. The enterotoxin genes were detected in 22 (13.7%) coagulase negative staphylococci (CNS) isolates, among them in 9 (11.4%) isolates of S. xylosus, 5 (16.7%) S. sciuri, 3 (10.3%) S. epidermidis and in 5 (22.7%) Staphylococcus spp. In some CNS 2 or 3 genes were detected simultaneously. Among the investigated enterotoxin genes, sec was the most prevalent (70%). The genes encoding enterotoxin B and D were detected in 5 (16.7%) and 6 (20%) isolates, respectively. The lowest number of isolates had sea and see genes. The genes encoding enterotoxins were often identified in staphylococci from milk of cows with mastitis (73.4% of detected genes), while only 6 (20%) isolates from milk of cows without mastitis and 2 (6.6%) isolates from cowshed environment were positive for enterotoxin genes. The results showed that CNS from bovine milk, like S. aureus, carried enterotoxin genes and may pose a risk for public health. PMID- 25286647 TI - Cytomorphometry of canine cutaneous histiocytoma. AB - A morphometric analysis of tumoral Langerhans cells and activated macrophages was conducted using canine cutaneous tumors (65 cases of canine cutaneous histiocytoma and 7 cases of pyogranuloma). The histiocytic origin of the tumor cells was confirmed using immunohistochemistry. The parameters of the morphometric analysis included cellular and nuclear size and shape and the nuclear:cytoplasmic ratio; the variability of these features was calculated separately for each tumor. The canine cutaneous histiocytoma group was divided into four stages of regression depending on the intensity of the lymphocytic infiltration. Statistical analysis revealed that the anisocytosis, anisokaryosis and cellular pleomorphism of tumoral Langerhans cells increased, while the cellular circularity and nuclear:cytoplasmic ratio decreased with tumor regression. Activated macrophages of the pyogranuloma were significantly larger, and had larger nuclei, than tumoral Langerhans cells. Furthermore, these activated macrophages showed greater anisocytosis and anisokaryosis and a lower nuclear:cytoplasmic ratio than tumoral Langerhans cells in the first stages of tumor regression. These results indicate that tumoral Langerhans cells undergo morphologic changes during the regression of canine cutaneous histiocytoma, reflecting their maturation and differentiation. Morphometry can be a useful method for distinguishing activated macrophages from tumoral Langerhans cells. PMID- 25286648 TI - B-cell and T-cell values in peripheral blood in Polish mixed-breed rabbits with addition of blood of meet breeds. AB - In Poland, rabbit is a highly valued animal, due to dietetic and flavour values of its meat, but above all, rabbits tend to be commonly used laboratory animals. The aim of the study was developing standards for counts of B-cells with CD19+ receptor, T-cells with CD5+ receptor, and their subpopulations, namely T-cells with CD4+, CD8+ and CD25+ receptor in the peripheral blood of mixed-breed Polish rabbits with addition of blood of meet breeds, including the assessment of the impact of four seasons of the year and animal sex on the values of the immunological parameters determined. The results showed that the counts of B- and T-cells and their subpopulations in peripheral blood remain within the following ranges: for CD19+ B-cells: 1.05 - 3.05%, for CD5+ T-cells: 34.00 - 43.07%, CD4+ T cells: 23.52 - 33.23%, CD8+ T-cells: 12.55 - 17.30%, whereas for CD25+ T-cells: 0.72 - 2.81%. As it comes to the season of the year, it was observed that it principally affects the values of CD25+ T-cells, while in the case of rabbit sex, more changes were found in females. PMID- 25286649 TI - Use of biochemical markers to evaluate the quality of fresh and cryopreserved semen from the arctic fox (Vulpes lagopus). AB - The aim of this study was to use biochemical markers to evaluate the quality of fresh and cryopreserved semen from the arctic fox (Vulpes lagopus). Twenty-three manually collected ejaculates were analysed for the main indicators of semen quality (sperm concentration and ejaculate volume). Sperm motility and percentage of morphologically normal and abnormal spermatozoa were determined according to the stage of cryopreservation (fresh--measurement A; equilibrated--measurement B; frozen/thawed--measurement C). Furthermore, the seminal plasma and supernatants were analysed after equilibration and freeze/thawing for the activity of the enzymes alkaline phosphatase (ALP), acid phosphatase (AcP), lactate dehydrogenase (LDH) and aspartate aminotransferase (AspAT), and for the activity of acrosin inhibitors (AP). The mean concentration of sperm was 625.1 million/cm3, and ejaculate volume averaged 1.6 cm3. Seminal plasma was characterized by the highest activity of alkaline phosphatase (3.43 x 10(3) U/l) and lowest activity of acrosin inhibitors (4.55 x 10(3) U/l). After equilibration, the supernatants showed the highest activity of acid phosphatase (94.9 U/l) and after freeze thawing, they showed a high activity of lactate dehydrogenase (535.8 U/l) and aspartate aminotransferase (577.1 U/l), which indicates that these proteins had leaked from spermatozoa into the extracellular medium during the biotechnique of semen cryopreservation. In addition, several significant relationships were found between some indicators of semen quality and plasma and/or supernatant enzyme activity. PMID- 25286650 TI - Oxidative parameters and expression of 70kDa heat shock proteins in pig heart tissue after transport and slaughter. AB - In view of the significant role of Hsp70 in protecting the organism against the destructive effects of stress, and the possibility of using this protein as a marker of the infarction process in the heart, the aim of this study was to conduct an evaluation of the expression of 70kDa heat shock proteins (Hsp70) and the concentration of TBARS (thiobarbituric acid reactive substances) and nitric oxide ions (NO), determined as nitrite ions, as markers of oxidative stress in hearts obtained from healthy pigs following slaughter and pigs which had died during or immediately after transport with symptoms of sudden cardiac death. The material consisted of hearts obtained from 90 pigs following slaughter and from pigs which had died. Oxidative stress was determined in heart lysates based on the concentration of TBARS and nitrite ions. Expression and concentration of Hsp70 were determined using SDS-PAGE, Western blotting, and ELISA. Expression of Hsp70 was observed in hearts lysates obtained from slaughtered pigs and from those which had died with symptoms of sudden death. The strongest reaction in the Western Blotting was noted in hearts lysates from pigs with no pathological changes. The highest TBARS concentration was observed in lysates from hearts in pigs which had died during or immediately after transport. The highest concentration of NO ions, determined as nitrite ions, was noted in hearts from pigs with myocardial infarction lesions. The significant decrease observed in Hsp70 concentration in heart tissue obtained from the pigs which had died in comparison to the hearts from healthy pigs indicates the important role of this protein in protecting the heart muscle against the destructive effects of stress, which limits the occurrence of post-stress cardiomyopathy in pigs following transport. PMID- 25286651 TI - Insight into behavior of epithelial cells of the feline conjunctiva in chronic conjunctivitis as a possible limitation in detection of Chlamydophila spp. AB - The aims of this work was documentation of the reactivity of feline conjunctival epithelial cells in chronic conjunctivitis and the investigation of a possible correlation of histological findings in conjunctiva with a limitation in detection of the pathogen. In this observational study, conjunctival swab samples collected from six cats suffering from chronic conjunctivitis were monitored for Chlamydophila spp. infection for one month, every ten days. Chlamydophilosis was diagnosed by conventional PCR, and confirmed by sequencing analysis. A lack of coherence with results in subsequent studies using PCR did not allow an accurate diagnosis. Additional bioptat samples of conjunctiva were collected for diagnostic purposes and stained in haematoxylin and eosin following the Giemsa method for light microscopic analysis. Additionally the samples were incubated for 15 min with IMAGEN Chlamydia conjugate (IMAGEN Chlamydia reagent kit, Dako, UK), allowing immunofluorescence detection of Chlamydophila spp. Within the epithelium an increased number of goblet cells, as well as general enlargement of the epithelium and a reduced number of normal epithelial cells, was observed. Only in areas of low epithelium could structures similar to the elementary bodies of Chlamydophila spp. be distinguished. The presented data document a possible limitation in molecular evidence for chlamydophila infection in some naturally infected cats, taking into account histological conditions in conjunctiva at the same time. PMID- 25286652 TI - Production of slime by coagulase-negative staphylococci (CNS) isolated from clinical and subclinical mastitis in cows. AB - The aim of the study was to evaluate the slime-producing ability of coagulase negative staphylococci (CNS) isolated from clinical and subclinical mastitis in cows. The study was carried out on 100 isolates of CNS obtained from milk of 86 cows from farms located in the Lublin region (Poland). Slime-producing ability was observed in over half of coagulase-negative staphylococci (54.0% of isolated CNS), including 19 isolates of methicillin-resistant staphylococci (95.5% of all MRCNS). Of 22 isolates of CNS responsible for the clinical form of mastitis, 20 isolates (90.9%) produced slime: S. xylosus (7 isolates), S. haemolyticus (6 isolates), S. chromogenes (4 isolates), and S. sciuri (3 isolates), including 9 isolates of MRCNS (45.0%). The remaining 34 isolates of CNS (43.6%) with the ability to produce this exopolysaccharide were isolated from the milk of cows with subclinical form of mastitis: S. xylosus (12 isolates), S. sciuri (9 isolates), S. chromogenes (6 isolates), S. haemolyticus (3 isolates), S. warneri (3 isolates) and S. saprophyticus (1 isolate), including 10 isolates of MRCNS (12.8%). PMID- 25286653 TI - The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity. AB - Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of kynurenic acid (12.5 microM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 microM and 25 microM) seems indicative of endogenous kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA. PMID- 25286654 TI - Evaluation of methods for Mycobacterium avium ssp. paratuberculosis detection in milk samples from the cattle herd showing low seroprevalence of Johne's disease. AB - Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of chronic gastroenteritis in cattle called the Johne's disease (JD). The disease causes significant economic losses in cattle production. MAP is also supposed to be involved in the Crohn's disease and inflammatory bowel disease (IBD) in people. The detection of the cattle infection based on investigations of milk samples and evaluation of the capacity of the methods used to detect the disease was the objective of the present study. Following methods were applied for milk samples testing: detection of MAP in bacterial culture, detection of the specific IS-900 fragment of MAP in the genetic material isolated directly and detection of MAP antibodies. The results obtained were compared with the "golden standard" results, i.e. the isolation of MAP from the faeces. PQStat-the program for diagnostic reliability estimation, was used for evaluation of the sensitivity, specificity and predictive value. The method based on detection of the specific IS-900 fragment of MAP in the genetic material isolated directly from milk samples was found to possess the highest sensitivity. Detection of anti-MAP antibodies on the other hand showed the lowest sensitivity. The method of detecting anti-MAP antibodies in milk was the most specific while detection of the IS-900 fragment in the genetic material was the least specific method. These results obtained may serve as a guide to choose the most appropriate method for diagnosis of MAP infections by milk sample testing. PMID- 25286655 TI - Toltrazuril (Baycox) treatment against coccidiosis caused by Eimeria sp. in Japanese quails (Coturnix coturnix japonica). AB - Coccidiosis is the most predominant parasitic disease affecting Japanese quails (Coturnix coturnix japonica) in commercial farms. Coccidiosis as a subclinical infection is difficult to diagnose without parasitological examinations. Oocysts of two Eimeria species, E. bateri and E. tsunodai, were determined in the analysed quail flock. Infected birds were administered Baycox 2.5% at the dose of: group I--7 mg toltrazuril/kg BW per day provided in drinking water (1.5 ml/0.5 1 H2O) that was available 24 h for 2 days, group II--14 mg/kg BW (3 ml/0.5 1 H2O), and group III-- 24.5 mg/kg BW (5 ml/0.5 1 H2O); in groups II and III, the solutions were available 8 h/24 h for 2 days. After the first day of the treatment, the number of excreted oocysts (OPG - oocysts per gram) increased, a steady decrease in oocyst counts began on the second day of Baycox administration and lasted until a three-day period when no oocyst were determined in faecal samples. Regardless of the dose applied, toltrazuril (Baycox) completely eliminated E. bateri coccidia and led to a highly significant reduction in the number of E. tsunodai oocysts. The results suggest that the effectiveness of toltrazuril varies depending on coccidia species and developmental stages of the parasite. From the clinical point of view, the treatment applied significantly reduces the number of coccidia oocysts in commercial flocks of Japanese quails. PMID- 25286656 TI - Expression of NK1 receptor at the protein and mRNA level in the porcine female reproductive system. AB - The presence and distribution of substance P (SP) receptor NK1 was studied in the ovary, the oviduct and the uterus (uterine horn and cervix) of the domestic pig using the methods of molecular biology (RT-PCR and immunoblot) and immunohistochemistry. The expression of NK1 receptor at mRNA level was confirmed with RT-PCR in all the studied parts of the porcine female reproductive system by the presence of 525 bp PCR product and at the protein level by the detection of 46 kDa protein band in immunoblot. Immunohistochemical staining revealed the cellular distribution of NK1 receptor protein. In the ovary NKI receptor was present in the wall of arterial blood vessels, as well as in ovarian follicles of different stages of development. In the tubular organs the NK1 receptor immunohistochemical stainings were observed in the wall of the arterial blood vessels, in the muscular membrane, as well as in the mucosal epithelium. The study confirmed the presence of NK1 receptor in the tissues of the porcine female reproductive tract which clearly points to the possibility that SP can influence porcine ovary, oviduct and uterus. PMID- 25286657 TI - Modeling the effect of temperature on survival rate of Salmonella Enteritidis in yogurt. AB - The aim of the study was to determine the inactivation rates of Salmonella Enteritidis in commercially produced yogurt and to generate primary and secondary mathematical models to predict the behaviour of these bacteria during storage at different temperatures. The samples were inoculated with the mixture of three S. Enteritidis strains and stored at 5 degrees C, 10 degrees C, 15 degrees C, 20 degrees C and 25 degrees C for 24 h. The number of salmonellae was determined every two hours. It was found that the number of bacteria decreased linearly with storage time in all samples. Storage temperature and pH of yogurt significantly influenced survival rate of S. Enteritidis (p < 0.05). In samples kept at 5 degrees C the number of salmonellae decreased at the lowest rate, whereas at 25 degrees C the reduction in number of bacteria was the most dynamic. The natural logarithm of mean inactivation rates of Salmonella calculated from primary model was fitted to two secondary models: linear and polynomial. Equations obtained from both secondary models can be applied as a tool for prediction of inactivation rate of Salmonella in yogurt stored under temperature range from 5 to 25 degrees C; however, polynomial model gave the better fit to the experimental data. PMID- 25286658 TI - Sonoelastography in differentiation of benign and malignant testicular lesion in dogs. AB - Present study aimed to evaluae the elasticity of tumorous testicular lesions and usefulness of the elastographic examination for diagnosing lesions in the testes. The study was carried out on nine dogs in which tumorous testicular lesions had been found in the ultrasonographic examination. In all the animals examined, the elastographic examination of the lesions was performed and then castration and the histopathological examination of specimens in order to determine the type of the changes. On the basis of the results of the histopathological examination the dogs were divided into two groups: group I--consisted of three dogs in which nonneoplastic testicular lesions were found and group II comprised six dogs in which neoplasic lesions that began in testicular interstitial cells (Leydigoma) were detected. The lesions observed in dogs of group I showed low stiffness (average 11.25 kPa, range 6.1 to 16.4 kPa), whereas the lesions found in dogs of group II were characterized by high stiffness (average 91.85 kPa, range 52.3 to 131.4 kPa). On the basis of a scale proposed by Goodie et al. (2012), the lesions in group I were in the range of SC1, and in turn, the lesions in group II were in the range of SC 3 inverted. Based on the results obtained, it can be stated that the sonoelastographic examination is useful method for the screening diagnostics of testicular lesions. PMID- 25286659 TI - Comparison of flunixin meglumine and meloxicam influence on postoperative and oxidative stress in ovariohysterectomized bitches. AB - The aim of this study was to compare the effect of flunixin meglumine (FM) and meloxicam (M) on postoperative and oxidative stress in ovariohysterectomized bitches. Twenty four bitches were divided into three groups (n = 8 in each) and treated during premedication as follows: FM (2.2 mg/kg, iv, Fluvil, Vilsan, Turkey), M (0.2 mg/kg, sc, Maxicam, Sanovel, Turkey) or 0.9% saline (1 ml, iv, IE, Turkey)--control (C) group. The concentrations of serum cortisol, nitric oxide (NO), malondialdehyde (MDA), antioxidant potential (AOP) and glutation (GSH) were measured in blood samples collected during incision (0 h), closure of incision line (0.5 h) and 1, 2.5, 12 and 24 hours after incision. It was observed that cortisol level was higher at 0.5, 1 and 2.5 h in group C (p < 0.05), 0.5 h in group FM (p < 0.001), and 1 and 2.5 h in group M (p < 0.01), as compared to that determine at 0 h. Group C showed higher cortisol level during 0.5 h (p < 0.05) than that found in the other groups. Group FM displayed lower levels during 1 h (p < 0.01) and 2.5 h (p < 0.05) as compared to those observed in other groups. Concentrations of MDA, AOP and GSH between all the groups did not show any significant differences. MDA level was higher at 0.5 and 1 h in group M (p < 0.05) than that found in group C and it was the lowest at 2.5 h in group C (p < 0.05). AOP was higher at 2.5 h in group FM and M (p < 0.05) than that observed in group C, and at 12 and 24 h in group M than that found in group C and FM. GSH did not show any significant differences between the groups. NO level in group FM after 12 h was higher (p < 0.05) than that at 0.5, 1 and 24 h. Moreover, NO level was lower at 0.5 (p < 0.01), 1 (p < 0.05) and 24 h (p < 0.05) in group FM than that observed in group C and M. In conclusion, flunixin meglumine decreases cortisol and NO levels more efficiently than meloxicam. Therefore, it is suggested that postoperative stress following ovariohysterectomy may be prevented by flunixin meglumine in bitches. PMID- 25286660 TI - Diagnostic performance of ID screen MVV-CAEV Indirect Screening ELISA in identifying small ruminant lentiviruses-infected goats. AB - Diagnostic performance of ID Screen MVV-CAEV Indirect Screening ELISA in identifying goats infected with small ruminant lentiviruses (SRLV) was evaluated. In total 299 serum samples from the collection of the Laboratory of Veterinary Epidemiology and Economics--109 truly positive and 190 truly negative--were used. To be enrolled in the study a serum sample had to come from at least 2 year-old goat which had reacted identically in two serological surveys preceding sample collection and was kept in a herd of stable serological status confirmed at least twice during preceding 5 years. Moreover, in seropositive herds at least 20% of goats had to be serologically positive at the moment when the serum sample was collected for the study. The test proved to have high accuracy. Area under curve was 98.8% (95% CI: 97.5%, 100%). Diagnostic performance of the test was almost identical (Youlden's index of 90%, sensitivity > 90% and specificity > 95%) within a fairly wide range of cut-off values--between 20% and 60%. At manufacturer's cut-off of 50% sensitivity and specificity were 91.7% (95% CI: 85.0%, 95.6%) and 98.9% (95% CI: 96.2%, 99.7%), respectively. For this cut-off positive likelihood ratio was 87 (95% CI: 22, 346) and negative likelihood ratio was 0.08 (95% CI: 0.04, 0.16). In conclusion, the results of this study indicate that ID Screen MVV-CAEV Indirect Screening ELISA is a highly accurate diagnostic test for SRLV infection. PMID- 25286661 TI - Commercial metal-based nanocolloids--lack of virucidal activity against ECBO virus. AB - Metallic nanoparticles, mainly silver ones, have been widely used as antibacterial agents, and some studies shown they also exert direct antiviral activity against both enveloped and non-enveloped viruses. The objective of this study has been to evaluate the virucidal activity of commercial silver, gold, copper and platinum nanocolloids, recommended by the manufacturer as antimicrobials, against the ECBO virus, according to Polish Standard PN-EN 14675:2006. The highest experimentally observed decrease in the viral load was 0.875 log, which--when contrasted with the reduction in virus titre of at least 4 log expected from disinfectants--indicates that none of the analyzed nanocolloids had a disinfectant power towards the ECBO virus under the conditions defined by the standard. PMID- 25286662 TI - Prostaglandin E2 inhibits IL-10 production by bovine CD4+ T cells. AB - Although prostaglandin E2 (PGE2) is a pro-inflammatory mediator, it also produces some effect which is anti-inflammatory in character. It is suggested that one of the mechanisms responsible for the latter effect is the increased synthesis of IL 10. The aim of this study has been to determine the influence of PGE2 on IL-10 production by bovine CD4+ and CD8+ T cells and NK cells. With this aim, peripheral blood mononuclear cells collected from 12-month-old heifers (n = 10) were treated without or with PGE2 (10(-6) M). Flow cytometric analysis showed that PGE2 caused a reduction in the percentage of IL-10 producing CD4+ T cells (P < 0.001), while leaving the secretion of this cytokine by CD8+ T cells and NK cells unaffected. This seems to indicate that PGE2 in cattle does not produce an anti-inflammatory effect by increasing the synthesis of IL-10; contrary to this, it may aggravate an inflammatory response by inhibiting the secretion of this cytokine by CD4+ T cells. PMID- 25286663 TI - Prevalence and distribution of Dirofilaria repens Railliet et Henry, 1911 in dogs in Poland. AB - In 2011-2013 1588 samples of dogs' blood were examined for dirofilariosis using Knott method, as well as the Kingston and Morton method. The species of microfilariae was determined on the basis of morphometric characteristics. Samples were also examined using the Canine Heartworm Antigen Test. Positive samples were examined using a multiplex PCR assay for species confirmation. Microfilariae belonging to the species D. repens were found in the blood samples of dogs from all the provinces of Poland. The mean prevalence of this species observed in Poland was 11.7%. The range of intensity of infection was counted using the number of microfilariae found in 60 microl of blood amounted to between 1 and 158, and the mean intensity was 18 microfilariae. Microfilariae and antigens of D. immitis were not found in any examined blood samples. PMID- 25286664 TI - Effect of 24 hour application of three hemostatic dressings to porcine thigh muscles. AB - The effectiveness of three types of hemostatic dressings, QuikClot Gauze, ChitoGauze PRO and Celox Gauze, was evaluated in nine pigs. The results indicated a strong influence of all examined dressings on porcine femoral muscle tissue evaluated 24 hours after direct contact. A histopathological analysis revealed pathological changes in muscle tissue specimens collected from all the animals. PMID- 25286665 TI - Molecular identification of Fascioloides magna (Bassi, 1875) from red deer from South-Western Poland (Lower Silesian wilderness) on the basis of internal transcribed spacer 2 (ITS-2). AB - The study was conducted in 2012-2013 on 75 fecal samples of red deer from the Lower Silesian Wilderness which were examined to determine the prevalence of Fascioloides magna in the game population. Finding liver fluke eggs in a single sample which were larger in size than Fasciola hepatica eggs indicated that further molecular analysis was necessarily. The partial sequence (116 bp long) of ITS-2 of the investigated eggs was identical to the sequences of F. magna from red deer (Cervus elaphus) (GenBank, EF534993; GenBank, EF534992) and from wapiti deer (Cervus elaphus canadensis) (GenBank, EF534994) from Slovakia, as well as from fallow deer (Dama dama) from the USA (GenBank, EF051080). This is the first molecular confirmation of the occurrence of F. magna in Poland. PMID- 25286666 TI - The influence of doxazosin, an alpha1-adrenergic receptor antagonist on the urinary bladder contractility in pigs. AB - In the present study influence of doxazosin on the porcine urinary bladder contractility has been examined. Immature pigs were treated for 30 days with: a) doxazosin (n = 5) per os at a dose of 0.1 mg/kg b.w. or b) placebo (n = 5; control group). Thereafter, animals were sacrificed and urinary bladder strips from the trigone were suspended in organ baths. The tension of the smooth musce was measured before and after exposition to acetylocholine (ACh; 10(-5) - 10(-3) M), norepinephrine (NE; 10(-9) - 10(-7) M) and 5-hydroxytryptamine (5-HT; 10(-7) 10(-5) M). Both the ACh and 5-HT at the highest doses significantly increased the contractility in each group, but this response was weaker in doxazosin treated animals. NE caused relaxation in both groups, but the effect was weaker in doxazosine-treated group. The results of our study have shown that long-term administration of doxazosin caused a desensitization of the detrusor smooth muscle for in vitro applied mediators of the autonomic nervous systems. PMID- 25286667 TI - The use of magnetic resonance imaging in diagnosing equine deep digital flexor tendinopathies--own experience. AB - Deep digital flexor tendinopathy is a common problem in horses of different athletic disciplines. Nowadays, the use of magnetic resonance imaging is considered to be a noninvasive and superior choice for recognizing bone and soft tissue pathologies especially related to difficult to access structures within the hoof capsule. PMID- 25286668 TI - Correlations between cholesterol content, fatty acid composition and health lipid indices in fat of chosen tissues and organs of finishing pigs. AB - The aim of this study was to estimate fatty acid composition, health related lipid indices (atherogenic-AI and thrombogenic-IT indices, h/H ratio) and the correlation between these traits and cholesterol content in various tissues of fatteners. The experiment involved 60 crossbred pigs (PL x PLW) x Duroc. The animals were slaughtered at 115 +/- 2.0 kg body weight. The tissue samples (backfat, m. longissimus, liver, heart) were collected to analyze fatty acid profile and cholesterol content. The highest PUFA level was determined in the fat of the heart and liver. Weak to moderate correlations were observed between cholesterol content and most of the studied indices of fatty acid profile of the analyzed tissues. Importantly, the most significant correlations were established between the examined traits in the heart fat. Generally, irrespective of tissue type, the cholesterol level was negatively correlated with total PUFA, n-3 and n 6 FA content and h/H ratio. PMID- 25286669 TI - Single nucleotide polymorphism within arylsulfatase D gene (ARSD) is associated with selected kinematic parameters of sperm motility in Holstein-Friesian bulls. AB - The aim of the study was to find out whether the single nucleotide polymorphism (SNP) within arylsulfatase D (ARSD) gene is associated with kinematic parameters of sperm motility in Holstein-Friesian bulls. 367 Holstein-Friesian bulls kept in one AI center were included in the study. Point mutation C/T at position 139037255 on chromosome X (rs42207167) was identified by PCR-RFLP method (Pflm I). Significant associations were found between ARSD genotypes and CASA-derived sperm motility parameters: average TM (Total Motility), average VSL (Straight Velocity), average VCL (Curvilinear Velocity) and for fraction of sperms showing progressive motility (a) of sperms (VSLa, VCLa and BCFa -Beat Cross Frequency). Most significant differences were observed between alternative homozygotes (CC vs TT). Our results suggest new role of arylsulfatase D gene as being involved in sperm motility. PMID- 25286670 TI - A retrospective study of the occurrence of chronic superficial keratitis in 308 German Shepherd dogs: 1999-2010. AB - Chronic Superficial Keratitis (CSK) is an autoimmune mediated inflammation of the cornea, that is usually bilateral but often with nonsymmetrical manifestation. The aim of this study was to determine the occurrence and appearance of clinical symptoms of CSK in German Shepherd dogs in Poland and Slovakia. CSK was diagnosed in 308 German Shepherds for a period of 11 years (from 1999 to 2010). The highest incidence of the CSK (p < 0.001) in Slovakia and in Poland was in dogs between the ages of 5-8 years. This study found similarity in gender ratio of affected patients with CSK in two neighboring countries. This disease occurs most often in males, with almost identical frequency in both countries, Slovakia 65.63% and Poland 61.32%, respectively. The incidence of depigmentation and thickening of the external surface of the third eyelid together with CSK was observed in 69.19% of dogs in Poland and in 63.15% of dogs in Slovakia. CSK is often recognized in advanced stage-affected areas with inflammatory process by CSK, obtained frequently from 2 to 3 quadrants. PMID- 25286671 TI - Endometrosis--significance for horse reproduction, pathogenesis, diagnosis, and proposed therapeutic methods. AB - Equine endometrosis is a multifactorial disease considered to be a one of the most important causes of equine infertility, especially in older mares. This article reviews the current knowledge of equine endometrosis: pathogenesis, diagnosis, and optional treatment. Also describes the histomorphological and immunohistochemical characterization of endometrosis as well as potential etiological factors which may influence disease progression. Unfortunately, the etiology and pathogenesis of endometrosis still remains unclear, and consequently no effective treatment has been proposed so far. Therefore future studies are needed for explanation of this disease. PMID- 25286672 TI - Two fundamentals of mammalian defense in fungal infections: endothermy and innate antifungal immunity. AB - The environment of animals is inhabited by enormous fungal species, but only a few hundreds are pathogenic for mammals. Most of potentially pathogenic fungal species, excluding dermatophytes, seldom cause the disease in immunocompetent hosts. Data from literature indicate, that an immune system and endothermy are foundations for this mammalian relative resistance to fungal systemic infections. Stable and high temperature of the body restricts invasion and growth of potentially pathogenic fungi. Together with elevated metabolism it supports the effectiveness of mammalian immunity. The innate immunity is assigned to prevent the invasion of various microbes (including fungi) to the hosts' organism. It consists of cellular receptors and several humoral factors as the Antimicrobial Peptides. If the physical barriers fail in stopping the invader, it is recognized as "alien" by multiple Pattern Recognition Receptors (PRRs) like Toll Like Receptors (TLRs) expressed by cells of innate immunity and/or C-type lectins. At the same time innate inflammation begins and the complement cascade is activated. These mechanisms are able to stop and clear some fungal infections. During existing infection the adaptive immunity is induced. This review aims to show the role of mammalian endothermy and to point the most important elements of innate antifungal immunity. PMID- 25286673 TI - [Construction of prokaryotic expression vector for Ag85A-HA2 fusion gene and studies on the immunity efficacy of fusion protein against influenza A virus]. AB - OBJECTIVE: To construct Ag85A-HA2 prokaryotic expression vector, express the fusion protein and study the immunity efficacy of fusion protein against influenza A virus. METHODS: Ag85A-HA2 prokaryotic expression vector was constructed and induced with IPTG. The fusion protein was identified by SDS-PAGE and purified with His-Tag affinity chromatography. The BALB/c mice were immunized with fusion protein. Then the pathological section, lung index, lung inhibitory rate and death-protection rate were tested to evaluate the immunity efficacy of fusion protein. RESULTS: pET-32a(+)/Ag85A-HA2 prokaryotic expression vector was constructed successfully. And SDS-PAGE indicated that fusion protein was expressed correctly with a molecular mass of 70 x 10(3). The lung index and death protection rate in experimental group were 39.30% and 80%, higher than that of control group. The pathological section also demonstrated that Ag85A-HA2 fusion protein had a protective effect on murine lungs. CONCLUSION: Ag85A-HA2 prokaryotic expression vector was successfully constructed, inducible expression and the fusion protein had an immunity efficacy against influenza A virus in animal experiment. PMID- 25286674 TI - [Leptin play the key role in astroglial differentiation of mouse neural stem cells and regulated the STAT3 signaling through Jak-STAT3 pathway]. AB - OBJECTIVE: To investigate the effect of Leptin on differentiation of nueral stem cell and explore the underline molecular mechanism. METHODS: Co-culture neural stem cell with different concentration of Leptin (0, 0.05, 0.2, 0.5, 1, 2 mg/L), the effect of Leptin on differentiation of nueral stem cell was analyzed. After treated the nueral stem cell with inhibitors of Jak-STAT3 (Janus family tyrosine kinases (Jak kinases) and signal transducers and activators of transcription (STAT proteins) and PI3k-Akt (phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)), the STAT3, phosphorylated-STAT3, Akt, phosphorylated-Akt levels and GFAP were detected with western blot and fluoroimmunoassay respectively. RESULTS: Morphology observation found nueral stem cell to change to astrocyte. An increased astrocyte marker (GFAP) in Leptin group but not Tuj-1 or MBP with fluoroimmunoassay and western blot detection was observed. The expression of GFAP began at 24 h after co-culture, and increased consistent with the concentration of Leptin. Jak-STAT3 inhibitors but not PI3k-Akt inhibitors decreased the expression of phosphorylated-STAT3, and accompanily decreased the expression of GFAP. CONCLUSION: Leptin may have an effect on the astroglial differentiation on neural stem cells through the JAK-STAT3 pathway but not PI3k-Akt pathway. PMID- 25286675 TI - [Expression of PAPP-A, IGF-I and their effects on the cytological functions of siRNA lentiviral vector of hCASMCs IGF-I after inflammatory factor]. AB - OBJECTIVE: To evaluate expression of PAPP-A, IGF-I and the effect of TNF-alpha, IL-1beta on the cytological functions of hCASMCs with IGF-I gene silencing after inflammatory factor, in order to further study on the action of IGF axis hormone in the rupture of astable atheroxclerosis plaque. METHODS: A RNA interference (RNAi) aimed at the gene of IGF-I was carried out to have an eukaryon transfection to hCASMCs. When the IGF- I-shRNA-hCASMC were treated by TNF-alpha, IL-1beta, IGFBP4, the expression of PAPP-A and IGF-I were detected with Western blot and ELISA. And then, the effect of TNF-alpha, IL-1beta, IGFBP4 on the proliferation of IGF-I-shRNA- hCASMC were assessed by MTT assay and changing in cell cycle and apoptosis were evaluated by using flow cytometry. RESULTS: Significant positive expression of PAPP-A in hCASMCs which were treated by TNF alpha + IL-1beta or TNF-alpha + IL-1beta + IGFBP4 in Blank control (CON), Negative control (NC) and RNAi group were observed, but lower expression in the RNAi group than that in CON and NC groups. However, there was no positive expression of PAPP-A in hCASMCs of CON, NC, RNAi group treating without TNF-alpha + IL-1beta or TNF-alpha + IL-1beta + IGFBP4. The expression of IGF-I in hCASMCs of CON, NC, RNAi group treated with TNF-alpha + IL-1beta + IGFBP4 were greater than that only with or without TNF-alpha + IL-1beta treatment. In RNAi group, the A570 decreased when the hCASMCs treated with TNF-alpha + IL-1beta + IGFBP4 and significant lower than that in hCASMCs treated with TNF-alpha + IL-1beta. When the hCASMCs were treated with TNF-alpha + IL-1beta or TNF-alpha + IL-1beta + IGFBP4, the rate of apoptosis significantly increased in RNAi group, which was significantly higher than that in CON group and NC group. In addition, in RNAi group, the rate of apoptosis in hCASMCs treated with TNF-alpha + IL-1beta + IGFBP4 was significant higher than that in hCASMCs treated only with TNF-alpha + IL-1beta. CONCLUSION: When the IGF-I-shRNA-hCASMCs were stimulated by some inflammation factors, its proliferation decreased but the apoptosis enhanced. So the activated IGF-I level in local microebvironnment increased, which may cause the descend of cell proliferation and the increasing of apoptosis. PMID- 25286676 TI - [Effect of hypoxia on the activation and visfatin expression in rat hepatic stellate cells]. AB - OBJECTIVE: To investigate the effect of hypoxia on the visfatin and the expression of smooth muscle-actin (alpha-SMA) and hypoxia-inducible factor-1alpha (HIF-1alpha) in rat hepatic stellate cells (HSCs). METHODS: Rat primary HSCs were isolated from SD rats by in situ perfusion of collagenase and pronase and single step Nycodenz density gradient centrifugation, and then cultured and activated. Completely activated primary HSCs were exposed to hypoxic conditions (37 degrees C, 5% CO2, 1% O2, 94% N2), or normoxic conditions (37 degrees C, 5% CO2, 21% O2, 74% N2), for 3, 6, 12 or 24 h respectively. The expression of alpha-SMA, the marker of HSC activation, and visfatin were assessed by Real time-PCR and Western blot. The Expression of HIF-1alpha was detected by Real time-PCR. RESULTS: HIF 1alpha mRNA in rat HSCs was induced after exposed to hypoxia for 3 h, and maintained elevated status up to 24 h. HSCs exposed to 1% O2 hypoxic conditions for 6 h increased alpha-SMA mRNA and protein expression. Visfatin mRNA expression was up-regulated after subjected to hypoxia for 12 h, and protein level was elevated after 6 h hypoxia. A positive linear correlation existed between alpha SMA and visfatin expression in responsible to hypoxia (r = 0.991 (genes) and r = 0.968 (proteins), P < 0.05). CONCLUSION: Microcirculation impairment could significantly induce alpha-SMA and visfatin expression in rat HSCs, which might potentate the activation process of HSCs. PMID- 25286677 TI - [Hypoxemia induced the changing structure of the lung tissue in SD rat though changing blood clotting and the effects of breviscapine's intervention]. AB - OBJECTIVE: To investigate the expressions of plasminogen activator inhibitor-1 (PAI-1), activated protein C (APC) and the histology structures of the rat lung tissues in the different hypoxia time; and to investigate the effects of breviscapine to the above changes. METHODS: Eighty SD rats were randomly divided into A (control), B (hypoxia), C (hypoxia + low-dose breviscapine) and D (hypoxia + high-dose breviscopine) groups with 20 rats in each group. Each hypoxia group placed daily pressure (101 kpa, 10% O2) environment for 8 h, low-dose and high dose breviscapine groups were given of 10 mg/kg, 40 mg/kg breviscapine by intraperitoneal injection. On the 3rd, 7th, 14th and 21st d, 5 rats were randomly taken from each group and were killed for examination. The hematoxylin and eosin stain (HE stain) was performed for observation on pathological changes in the rat lung tissues. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed for detection of the mRNA levels of transforming growth factor (TGF beta1) and Plasminogen activator inhibitor-1 (PAI-1). Western blot analysis was applied for detection of the expression of PAI-1. Besides, APC in the bronchoalveolar lavage fluid (BALF) was determined by ELISA. RESULTS: (1) The HE stain demonstrated that compared with A group, the degree of thickening of alveolar septal the mRNA expressions of TGF-beta1 and PA-1, and the protein expressions of PAI-1 in B group were increased (P < 0.05), and the expression of APC in the BALF was decreased (P < 0.05). And with prolonged hypoxia, the more significant of these changes were observed. Positive correlation was found between the mRNA levels of PAI-1 and TGF-beta1 (r = 0.936, P < 0.05). (2) Compared with B group, the increased thicknesses of alveolar septal in C and D groups were lightened, the mRNA expressions of TGF-beta1 and PAI-1, and the protein expression of PAI-1 were decreased (P < 0.05), and the expressions of APC in the BALF was increased (P < 0.05). With increasing dose, the expression levels of each factor gradually reduced or increased. CONCLUSION: Hypoxia may cause coagulant function abnormality to increase clotting activity and reduce fibrinolytic activity and the anticoagulant activity, inducing alveolar septal thickening, and the mechanism of above changes may related to the TGF-beta1 signaling pathways. Breviscapine could improve hypoxia-induced hypercoagulable state that alleviate alveolar septal thickening. PMID- 25286678 TI - [SIRT1 promote GTM cell DSBs repair and resist cellular senescence]. AB - OBJECTIVE: To study the relationship between SIRT1 and glaucoma trabecular meshwork cell (GTM) cell on DNA double-strand breaks (DSBs) repair capability and resist cellular senescence. METHODS: The expressions of SIRT1 in GTM and normal trabecular meshwork (HTM) cell detected by RT-RCR and Western blot; HTM and GTM cells divided into four groups separately: Res group (treat cells with 0.5 micromol/L Resveratrol for 24 h), SIRT1-ShRNA group (cells infected with recombinant SIRT1-ShRNA), microRNA34a group (cells infected with recombinant microRNA34a) and control group. The expression level of SIRT1 in groups was detected by Western blot. SA-beta-Gal staining was applied to each group of cells at 10 h, 32 h, 3 d and 6 d to evaluate the senescence of the cells. DSBs and the expression of gamma-H2AX after treated with 1.33 mol/L H2O2 at 0 h, 1 h, 2 h were detected by comet electrophoresis and Western blot. RESULTS: The expression of SIRT1 were observed in both HTM and GTM cells, but the expression level in HTM was higher than that of GTM cells have the ability to express SIRT1, however the expression of SIRT1 was lower than HTM. Expression levels of SIRT1 presented following treads: Res > Control > microRNA34a > SIRT1-ShRNA. The dgree of senescence in GTM was higher than that in HTM cells when detected at the same time point with SA-beta-Gal staining. In the same cell line, the signs of senescence were appeared firstly and seriously in the cells treated with SIRT1 ShRNA in a time-dependent manner. Differently, after 24 h treatment with Res, the degree of senescence was decreased. The DSBs in GTM group was more than that of HTM group after treatment with oxidant when detected with Comet Electrophoresis and the the trends of the change was SIRT1-ShRNA > microRNA34a > Control > Res. The similar results also observed in the expression of gamma-H2AX. CONCLUSION: SIRT1 may be useful in predicting the development and prognosis of glaucoma; Res promotes the expression of SIRT1 significantly, and the SIRT1 may protects GTM from oxidative stress-induced DSBs, aging even apoptosis, and promotes cell cycle arrest, which may provide a new target to treat glaucoma. PMID- 25286679 TI - [Notch signaling pathway blocked by gamma-secretase inhibitor and its effect on the growth and apoptosis of SKOV3 cells]. AB - OBJECTIVE: To determine the effect and mechanism of gamma-secretase inhibitor DAPT on the growth and apoptosis of human ovarian carcinoma SKOV3 cells. METHODS: The effect of gamma-secretase inhibitor DAPT was tested in vitro using SKOV3 cells. Its inhibition effect on cell proliferation was determined by CCK-8 assay. The cell apoptosis was detected by AO/EB double staining and flow cytometry. The expression of Notch1 mRNA and protein was detected by RT-PCR and Western blot. RESULTS: Compared with controls, 5 micromol/L, 10 micromol/L and 20 micromol/L of DAPT showed an effect of cell growth inhibition in a dose-dependent manner, with 19.87%, 28.38%, and 46.67% of 24 h inhibitory rates, respectively. Dose-dependent effect of DAPT on cell apoptosis was also evident, with (5.80 +/- 0.98)%, (12.96 +/- 4.99)%, (30.88 +/- 7.63)%, and (42.98 +/- 1.46)% apoptosis rates for the control, 5 micromol/L, 10 micromol/I, and 20 micromol/L DAPT groups, respectively. RT-PCR analysis demonstrated that the expression of Notch1 mRNA decreased significantly in the DAPT groups, with an inhibition rate of 10.23%, 20.50%, and 38.83% for the three DAPT groups, respectively. Western blot results demonstrated that the expression of Notch1 protein decreased significantly, with an inhibition rate of 12.89%, 27.47%, and 49.84% for the three DAPT groups, respectively. CONCLUSION: Gamma-secretase inhibitor DAPT can block Notch signaling pathway, inhibit proliferation, and induce apoptosis of SKOV3 cells through down-regulation of the expression of Notch1. PMID- 25286680 TI - [Expression of NKG2A and NKG2C receptors and their ligand HLA-E in decidua of preeclampsia patients]. AB - OBJECTIVE: To investigatethe expressions of NKG2A, NKG2C receptors and their ligand HLA-E in decidua of preeclampsia patients. METHODS: Decidua tissues were collected from 30 patients with mild preeclampsia, 42 patients with severe preeclampsia and 46 normal pregnancy as contrast. The expressions of NKG2A, NKG2C protein were detected by immunohistochemitry and mRNAs of NKG2A, NKG2C and HLA-E genes were detected by RT-PCR. RESULTS: The expression of HLA-E mRNA was significantly decreased in preeclampsia, especially in severe preeclampsia patients (P < 0.05); The mRNA and protein expression of NKG2A, NKG2C in severe preeclampsia group were significantly higher than that in normal pregnancy group (P < 0.05); In the severe preeclampsia group, the ratio of expression level of NKG2A and NKG2C was significantly lower than that of normal group and the mRNA and protein expression of NKG2C receptor were both significantly higher than that of NKG2A (P < 0.05); The mRNA expression level of HLA-E, NKG2A and NKG2C were closely related with clinical and biochemical indexes,such as blood pressure of late pregnancy and 24-hour proteinuria. CONCLUSION: The decreased expression of HLA-E and the unevenly increase of NKG2A and NKG2C may involve in the pathogenesis of preeclampsia. PMID- 25286681 TI - [Feverfew lactone induces autophagic death of hepatocellular carcinoma SMMC 7721 cells]. AB - OBJECTIVE: To explore the effect and mechanism of feverfew lactone on inducing autophagic death of hepatocellular carcinoma. METHODS: The proliferation of hepatocellular carcinoma SMMC 7721 cells treated with feverfew lactone was measured by MTT assay. The autophagy of SMMC 7721 induced with feverfew lactone was assessed by acridine orange staining, autophagic marker LC3 and p62 detecting and autophagic flows analyzing. In addition, a role of ROS in this process was stated by treatment with antioxidant agent N-acetyl-L-cysteine (NAC). RESULTS: The proliferation of SMMC 7721 cells were inhibited by feverfew lactone in a concentration dependence manner. The expression of LC3 and autophagic flows of SMMC 7721 cells were increased by feverfew lactone, while p62 was decreased, which implied that feverfew lactone could induce the autophagy of SMMC 7721 cells. Further more, the autophagy effect induced by feverfew lactone was declined obviously when treated with NAC suggested that ROS played an important role in this effect. CONCLUSION: Feverfew lactone induces autophagic death of SMMC 7721 cells by stimulating cells to produce ROS. The study will be helpful for the treatment of hepatocellular carcinoma and to provide theoretical basis for the clinical application of feverfew lactone. PMID- 25286682 TI - [DAB2IP expression in bladder transitional cell carcinoma and its correlation with clinical outcome]. AB - OBJECTIVE: To investigate the expression of DAB2IP in bladder transitional cell carcinoma (BTCC) and its correlation with clinical characteristics and prognosis of BTCC patients. METHODS: Immunohistochemical staining was applied to detect DAB2IP protein level in 79 cases of TCCB tissues and 11 cases of normal bladder tissues, and the relationships of the staining results with pathological grade, stage, lymph node metastasis, gender, age and the 3-year survival rate of the patients were analyzed. RESULTS: The expression of DAB2IP in BTCC tissues was significantly lower than that in normal bladder epithelium, and the expression score and rate of DAB2IP in the high-grade, invasive and metastatic BTCC were significantly lower than those in low-grade, superficial and non-metastatic BTCC (P < 0.05). The 3-year survival rate of the patients with high DAB2IP expression was significantly higher than that of the patients with low DAB2IP expression. CONCLUSION: DAB2IP may be one of the important inhibitory factors during the occurrence and progression of BTCC. PMID- 25286683 TI - [Effects of lingqijuangan capsule medicated serum on apoptosis of activated rat hepatic stellate cells]. AB - OBJECTIVE: To investigate the effects of LingQiJuanGan Capsule medicated serum on the apoptosis of and the expression of Bcl-2/Bax in hepatic stellate cell-T6 (HSC T6) activated by platelet-derived growth factor (PDGF). METHODS: Preparation of drug-medicated serum. 30 SD rats were randomly divided into three groups. Serum was obtained from the SD rats administrated intragastricly with saline (10 mL/kg, group A), Fufang Biejia Ruangan Tablet solution (1.5 g/kg, group B) and LingQiJuanGan Capsule solution respectively (4.25 g/kg, group C). Detection of cell apoptosis and the expression of Bcl-2/Bax. HSC-T6 cells were activated by 10 ng/mL PDGF and incubated with drug-medicated serum at 200 mL/L. Cell apoptosis and the expression of Bcl-2/Bax were measured by flow cytometry at 0, 12, 24 and 48 h. RESULTS: Significantly higher apoptotic rates of HSC-T6 in group B and group C were detected at 12, 24, 48 h compared with that of group A (P < 0.05), wheraus no significant difference was found between group B and group C (P > 0.05). With increase of exposure time, the apoptotic rates of HSC-T6 in group B and group C increased (P < 0.05). The levels of Bcl-2 expression in HSC-T6 in group B and C were lower than that of group A (P < 0.05) at 12, 24, 48 h (No significant difference between group B and group C, P > 0.05). The expression level of Bcl-2 decreased with increased exposure time (P > 0.05) in both group B and group C. However, no such trend was observed in group A (P > 0.05). In both group B and group C, the expression level of Bax increased in a time-dependent manner. CONCLUSION: LingQiJuanGan Capsule can induce apoptosis of PDGF activated HSC-T6 and inhibit hepatic fibrosis in a time-dependent manner by influencing the expression of Bcl-2/Bax. PMID- 25286684 TI - [Effects of "reinforcing Qi and activating blood" on stable chronic obstructive pulmonary disease (Qi deficiency and blood stasis syndrome]. AB - OBJECTIVE: To study the clinical effects of "Reinforcing Qi and Activating Blood" in the treatment of stable chronic obstructive pulmonary disease (Qi Deficiency and Blood Stasis Syndrome). METHODS: This study recruit 50 outpatients with stabe chronic obstructive pulmonary disease (Qi Deficiency and Blood Stasis Syndrome), who were randomly divided into 2 groups, control group and treatment of "Reinforcing Qi and Activating Blood" group. The patients in control group were given conventional treatment, while the patients in treatment group not only received conventional treatment but also the treatment of Yu-Ping-Feng capsules and Fu-Fang-Dan-Shen tablets for 3 months. The duration of follow up was 12 months, and chinese medicine (CM) symptoms, cellular immunity indexes and haemodynamics indexes were assessed every 3 months. RESULTS: The total effective rate in treatment group at 3 months treatment and 3 months follow-up were higher than that in control group (P < 0.05). The CM symptoms in treatment group were improved significantly (P < 0.05). In treatment group, the level of CD4 and the ratio of CD4/CD8 after therapy were higher than those before (P < 0.05), and the level of CD8 was lower than that before (P < 0.05). The level of NO was no significant difference (P > 0.05), while the level of endothelin (ET) was significantly different (P < 0.05). The frequency of suffering from cold, the admission due to acute exacerbation and hospital stay in treatment group were all lower than those in control group (P < 0.05). CONCLUSION: The "Reinforcing Qi and Activating Blood" therapy can improve the symptoms and clinical curative effect of TCM in the treatment of stable COPD (Qi Deficiency and Blood Stasis Syndrome), with the improvement of their cellular immunological function and vasomotor function. PMID- 25286685 TI - [Effects of hyperthermia combined platinum-based drugs on ovarian cancer cell lines SKOV3]. AB - OBJECTIVE: To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. METHODS: SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 microg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10.0, 20.0, 40 microg/mL) at a temperature of 42 degrees C for hyperthermia or 37 degrees C for normal temperature. Methyl thiazolyl tetrazolium (MTT) method was used to test growth ratios of ovarian cancer cell lines SKOV3. Real-time PCR was adopted to detect the expression level of excision repair cross-complementing group 1 (ERCC1) and Survivin mRNA in SKOV3 cells. RESULTS: DDP, CBP and OXA inhibited the growth of SKOV3 in a dose-dependent manner (P < 0.05). Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum, carboplatin and oxaliplatin (P < 0.05). The half inhibitory concentration (IC50) values of DDP, CBP and OXA were (7.271 +/- 0.096) microg/mL, (37.609 +/- 0.779) microg/mL and (28.328 +/- 0.698) microg/mL respectively. When combined with hyperthermia, the IC50 values of DDP, CBP, and OXA were (2.075 +/- 0.244) microg/mL, (19.591 +/- 0.453) microg/mL, (19.089 +/- 0.424) microg/mL (P < 0.05). The increased sensitivity index was 2.075 +/- 0.244 for cis-platinum, 1.92 +/- 0.044 for carboplatin, 1.484 +/- 0.039 for oxaliplatin. After the treatment of hyperthermia, the expression of ERCC1 and Survivin mRNA showed downward trend. ERCC1 decreased more significantly in the group of hyperthermia combined with carboplatin, and Survivin decreased more significantly in the group of hyperthermia combined with oxaliplatin (P < 0.05). CONCLUSION: Hyperthermia can enhance the sensitivity of ovarian cancer SKOV3 cells to platinum-based drugs, which may be related to the down regulation of ERCC1 and Survivin expression. PMID- 25286686 TI - [Expression of CLIC1 and IGFBP7 in complete hydatidiform mole]. AB - OBJECTIVE: To investigate the expression level of chloride intracellular channel 1 (CLIC1) and insulin-like growth factor binding protein 7 (IGFBP7) in complete hydatidiform mole (CHM) and estimate the relationship between the expression level and clinical prognosis. METHODS: Immunohistochemistry (IHC) method was used to detect the expression level of P57(KIP2) in order to differentiate CHM. CLIC1 and IGFBP7 expression level of CHM were measured by IHC method then. RESULTS: (1) According to the P57(KIP2) expression result 66 patients were diagnosed as CHM (85.71%). Fourteen of 66 patients progressed into gestational trophoblastic neoplasia (GTN), which accounted for 21.21%. (2) The results of IHC showed that CLIC1 significantly higher expressed in malignant group than spontaneous regressive group (P = 0.014). IGFBP7 significantly down-regulated in malignant group (P = 0.002). (3) Pearson correlation analysis results revealed that there were no relation between the expression of CLIC1 and IGFBP7 (P = 0.761). Logistic regression analysis indicated that down-regulation of IGFBP7 was the independent risk factors of CHM progression, P = 0.005, OR = 8.493 (95% confidence interval (CI): 1.878-38.401); Serum hCG > 5 x 10(5) mIU/mL was the independent risk factors of CHM progression too, P = 0.011, OR = 11.251 (95% CI: 1.731-73.151). (4) Receiver operator characteristic curve (ROC curve) results showed that the area under the curve (AUC) of CLIC1 was 0.707. The optimum cut off was 10.5, and correspondingly sensitivity was 42.90%, specificity 94.20%. AUC of IGFBP7 was 0.764. The optimum cut off was 7.0, and the correspondingly sensitivity and specificity were 64.30% and 78.80% respectively. Combining the two markers in series, the sensitivity of predicting the prognosis of CHM was 21.42%, while the specificity was 100%. When combining in parallel, the sensitivity and specificity were 85.71% and 71.15% respectively. CONCLUSION: Up-regulation of CLIC1 and down regulation of IGFBP7 might pay an important role in progression of CHM, but there was no relationship between the expression levels of them. The predictive values of malignance transformation of CHM with the two biomarkers were with certain accuracy, and combining them in parallel test could improve accuracy. They are promising to be candidate prognostic markers of CHM. PMID- 25286687 TI - [The change of CD4+ CD25+ regulatory T cells in patients with rheumatoid arthritis]. AB - OBJECTIVE: To investigate the change of CD4+ CD25+ FoxP3+ regulatory T cells (Treg)in peripheral blood (PB)and synovial fluid (SF) in patients with rheumatoid arthritis (RA) and its role in RA immune tolerance imbalance. METHODS: The frequency of CD4+ CD25+ FoxP3+ Treg in PB and SF cells in active RA patients and healthy volunteers were determined using flow cytometry. The expression of FoxP3 gene in mononuclear cells was analyzed by real-time PCR. The correlation between the frequency of CD4+ CD25+ FoxP3+ Treg in PB cells and disease activity indices was evaluated. RESULTS: (1) Active RA patients had a higher level of CD4+ CD25+ FoxP3+ Treg in SF cells (7.56% +/- 2.89%) than in PB cells (1.84% +/- 0.97%). Their level of CD4+ CD25+ FoxP3+ Treg in SF cells was also higher than that of healthy volunteers (2.19% +/- 0.54%). Anti-CCP antibody (ACPA) positive RA patients had a lower level of CD4+ CD25+ FoxP3+ Treg (1.40% +/- 0.63%) in PB cells compared with the ACPA negative RA patients (2.85 +/- 0.87%). (2) Active RA patients had a higher mRNA level of FoxP3 in SF mononuclear cells than those inactive RA patients and healthy volunteers (P < 0.01). (3) The frequency of CD4+ CD25+ FoxP3+ Treg in PB cells in active RA patients had no correlation with disease activity indices (P > 0.05). CONCLUSION: Altered frequency of CD4+ CD25+ FoxP3+ Treg in SF cells of RA patients might contribute to RA immune tolerance imbalance in inflammatory joints. PMID- 25286688 TI - [Characteristics of 72 h glucose profiles detected by continuous glucose monitoring system in patients with insulinoma]. AB - OBJECTIVE: To identify the characteristics of glucose profiles in patients with insulinoma using continuous glucose monitoring system (CGMS). METHODS: Six patients with insulinoma (All of the patients were diagnosed after operations with pathological tests) admitted to the Department of Endocrinology and Metabolism, West China Hospital of Sichuan University from October 2009 to November 2011 were recruited for this study (group A). They were compared with 71 patients with normal glucose tolerance (NGT) (group B) and 3 patients with responsive hypoglycemia (group C). All of the participants received 75 g oral glucose tolerance tests (OGTT), insulin release tests, and 72 h CGM. Glucose fluctuations and hypoglycemia risks were assessed by the following parameters obtained from CGMS: mean blood glucose (MBG) and standard deviation (SD), mean amplitude of glycemic excursion (MAGE), mean daily differences (MODD), low glucose index (LBGI), glycaemic Risk Assessment Diabetes Equation (GRADE) and M value. RESULTS: Group A had significantly lower levels of HbA1c, fasting blood glucose, and 2 h-BG than group B (P < 0.05). Compared with Group B, Group A had lower levels of 72 h-MBG (P < 0.001) and higher levels of LBGI, M-value, GRADE, SD and MODD (P < 0.05). The insulinoma patients had 27 occasions of hypoglycemia (glucose < 2.8 mmol/L), more likely in early morning, at a fasting state or preprandial periods. Such events were rare in the control groups (2 occasions in Group B and one occasion in Group C). CONCLUSION: Insulinoma patients present a greater level of glucose fluctuations and frequent hypoglycemia. Hypoglycemia risk detected by CGM is helpful for differentiating diagnosis of insulinoma. PMID- 25286689 TI - [Risk factors of hepatolithasis-associated intrahepatic cholangiocarcinoma and the value of serum tumor-related makers in its diagnosis]. AB - OBJECTIVE: To explore the risk factors of hepatolithasis-associated intrahepatic cholangiocarcinoma (HICC) and the clinical value of serum tumor-related markers for the detection of HICC. METHODS: Clinical data were collected from 58 patients pathologically diagnosed as HICC between 2005 and 2011 in West China Hospital of Sichuan University and 189 patients diagnosed as hepatolithiasis alone in the same period as matched control group. Logistic regression analysis was used to detect the independent risk factors of HICC and ROCs curve were constructed to assess the diagnostic value of CA199, CEA, GGT and ALP. RESULTS: The patients in both HICC group and control group presented similar clinical symptoms except weight loss. The results of univariate analysis suggested cholangioenterostomy (P < 0.001), early stone removal (OR = 0.001), family history of cancer (P = 0.001) were associated with the incidence of HICC. The results of Multivariate analysis suggested diabetes mellitus (OR = 3.621, 95% CI: 1.333-9.834, P = 0.012), family history of cancer (OR = 16.830, 95% CI: 1.937-146.21, P = 0.010), cholangioenterostomy (OR = 5.115, 95% CI: 1.733-15.098, P = 0.003), early removal of stone (OR = 0.315, 95% CI: 0.128-0.771, P = 0.011) and CA199 > 100 IU/mL (OR = 5.478, 95% CI: 2.539-11.820, P < 0.001) were independent risk factors for hICC. Serum CA199 and CEA level presented low diagnostic accuracy, a combined test (CA199 > 100 IU/mL or CEA > 5 ng/mL) showed better diagnostic performance with a 71.05% of sensitivity and 82.05% of specificity. CONCLUSION: Cholangioenterostomy, diabetes, early and complete stone removal were independent risk factors for hepatolithiasis-associated ICC. A combined test of CA199 and CEA could be an effective detecting tool for HICC. PMID- 25286690 TI - [Multivariate factors analysis on length of stay in Lushan earthquake victims]. AB - OBJECTIVE: To clarify the factors associate with the length of stay (LOS) in Lushan Earthquake victims. METHODS: We retrospectively analyzed the medical information of 263 traumatic patients admitted to West China Hospital, Sichuan University after the Lushan Earthquake. Ten variables extracted for the analysis, including gender, age, injuried time, multiple injury, infection, comorbidities, Injury Severity Score (ISS), Revised Trauma Score (RTS) CRAMS score, and Prehospital Index (PHI). Univariable analysis using multiple stepwise regression analysis was performed to identify the factors associated with extended LOS. RESULTS: Infection, ISS score, and Pre-hospital Time were associated with extended LOS, and infection was the most weighted factor. The regression equation is: LOS (h) = 498.36 + 671.41 x Infection + 43.87 x ISS score - 5.12 x Pre hospital Time. CONCLUSION: This study demonstrated that trauma patients with infections and high ISS scores were at increased risk for extended LOS and pre hospital time decreased the risk. PMID- 25286691 TI - [Phase I clinical trial on the safety of injectable cefetamet sodium with a single dose in healthy volunteers]. AB - OBJECTIVE: To investigate the safety and maximum tolerable dosage of injectable cefetamet sodium Sixty healthy volunteers were enrolled in this study. with a single infusion in Chinese healthy volunteers. METHODS: A double-blinded, randomized, placebo-controlled design was adopted. Eight dosages ranging from 100 mg to 5 000 mg were tested. The pharmacokinetics of the drug was analyzed using a Latin square three-cross self-controlled design, with 12 healthy volunteers receiving 500 mg, 1 000 mg and 2 000 mg of injectable cefetamet sodium in a randomized sequence. Blood and urine samples were collected and analyzed using high performance liquid chromatography with UV detection. The main pharmacokinetics parameters were calculated with DAS2.0 software. RESULTS: 59 healthy volunteers completed the tolerance tests. Clinical adverse reactions occurred in 22.73% of participants in the test group and 6.67% of participants in the placebo group; but the difference was not statistically significant. Common adverse events included infusion pain and dizziness. Rare adverse events such as palpitations, diarrhea and rash occurred in participants in the test group. All of the adverse reactions were mild. Abnormal laboratory test results occurred in 43.18% participants in the test group and 53.33% participants in the placebo group; again the difference was not statistically significant. Common abnormal laboratory test results included abnormal bowel flora, stool abnormalities, abnormal urine and elevated serum potassium. After a single infusion of 500 mg, 1 000 mg and 2 000 mg of injectable cefetamet sodium, peak concentration of the drug at 0.5 h reached (37.92 +/- 7.43), (74.90 +/- 10.67) and (148.54 +/- 31.63) mg/L, with areas under concentration-time curve of (72.08 +/- 14.98), (144.28 +/- 24.57) and (286.66 +/- 54.25) (mg x h)/L, respectively. Their elimination half life was (2.03 +/- 0.38), (2.04 +/- 0.26), and (2.12 +/- 0.26) h, respectively. The disposition of cefetamet was presented as a two-compartment model with linear kinetics. The 24-hour urinary accumulation excretion was 76.6%-67.5%. CONCLUSION: The maximum single tolerated dose of injectable cefetamet sodium is 5 000 mg. The pharmacokinetics is a two-compartment model with linear kinetics within a dose range 500-2 000 mg. PMID- 25286692 TI - [Advances in the target therapy of hematological malignancies]. AB - With the rapid development of modern bio-medical technology, the pathogenesis of hematological malignancies including leukemia, lymphoma, myeloma has been illustrated with more and more attractive details. The diagnosis of hematological malignancies now becomes more precisely and clarified based on the progress than ever before, and the treatments of hematological malignancies keep the evolution in the way of integrating the novel molecular target drugs with conventional chemotherapy, radiotherapy, hematopoietic stem cell transplantation. The pivotal progress in the target therapy of hematological malignancies includes tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia, CD20 monoclonal antibody treatment of B-cell lymphoma and CD20 positive leukemia, FLT3 inhibitors fo the treatment of FLT3 mutation positive high-risk acute myelogenous leukemia. The topics of this issue focus on the advances in this field, which reflects the new achievements in the research of hematological malignancies, and the trends of precise and stratified diagnosis as well as tailored target therapy in the future. PMID- 25286693 TI - [Efficacy of tyrosine kinase inhibitor in treatment of chronic myeloid leukemia patients]. AB - OBJECTIVE: To evaluate the effects of tyrosine kinase inhibitors (TKI) in the treatment of chronic myeloid leukemia. METHODS: There were total 655 cases of chronic myeloid leukemia treated in one single-institution enrolled in this study. The dosage of TKI Imatinib was 400 mg/d for chronic phase, 600 mg/d for accelerated and blast phase respectively. Complete blood count, cytogenetic and molecular studies were regularly monitored during the course of therapy. The therapeutic effect was evaluated and the survival analysis was performed. RESULTS: The total complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and major molecular response (MMR) rates were 92.1%, 75.8%, 73.1% and 47.9% respectively. 1-year, 3 year, 5-year and 10-year overall survival (OS) rates were (96.3 +/- 0.8)%, (86.3 +/-1.8)%, (79.0 +/- 2.4)% and (66.5 +/- 4.8)% respectively. 1 year, 3-year, 5 year and 10-year event-free survival (EFS) rates were (92.2 +/- 1.1)%, (77.9 +/- 2.1)%, (67.9 +/- 6.8)% and (35.8 +/- 6.0)% respectively. The proportion of the patients in chronic phase achieving CHR, MCyR, CCyR and MMR were 98.7%, 82.5%, 79.4% and 52.4% respectivly. Compared with chronic phase patients, the efficacy of IM in the treatment of accelerated phase and blast phase patients was significantly lower. The effect of TKI in early chronic phase was better than that in late chronic phase. Early molecular response was associated with a better 5-year EFS, but not OS. CONCLUSION: CML patients in chronic phase treated with TKI have a better outcome. The earlier TKI be used, the better the prognosis and efficacy be achieved. PMID- 25286694 TI - [A clinicopathologic and prognosis study of Epstein-Barr virus positive diffuse large B-cell lymphoma in west-southern China]. AB - OBJECTIVE: To investigate the clinicopathologic features, immunophenotype, and the prognosis related factors of Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) in west-southern China. METHODS: There were 42 cases of EBV+ DLBCL in a total 586 DLBCL, the clinical and pathologic profiles of these patients were evaluated. Immunohistochemical study and in situ hybridization (ISH) of EBER1/2 were performed on formalin fixed tissues by tissue chips. The prognosis related factors were analyzed. RESULTS: The median age of these 42 EBV+ DLBCL patients was 62.5 years. The male-to-female ratio was 2.23 : 1. The site of occurrence included lymph node (69.05%) and spleen, stomach, tonsil, nasal cavity and nasopharynx. The mostly common initial clinical presentations were non specific symptoms, such as lymphadenopathy, splenomegaly, hepatomegaly, fever, and fatigue. Morphologically, the majority (90.48%, 38/42) were pleomorphic subtypes and only 4 cases (9.52%) were simplex subtypes. Immunophenotype showed non-GCB type of DLBCL was predominance (83.33%, 35/42) by Hans classification. The expression of CD30, CD5, BCL-2, P53 and NF-kappaB/ P65 were 52.38% (22/42), 54.76% (23/42), 54.76% (23/42), 87.5% (35/40) and 0% (0/40) respectively. Follow up data was available in 23 (54.76%) patients, 14 (60.87%) patients died of the tumor. 5-years overall survival was 16.5%. The median survival time was 40 months. The expression of BCL-2, increased LDH level and starry-sky morphologic character were associated with a poor prognosis. CONCLUSION: EBV positive DLBCL is not uncommon. Most lesions locate in lymph nodes. Pleomorphic histologic subtype is predominant. The tumor has worse prognosis with increased LDH level, starry-sky morphologic character and BCL-2 expression. PMID- 25286695 TI - [Expression of CD20 in B-cell precursor acute lymphoblastic leukemia and its correlation with clinical outcomes]. AB - OBJECTIVE: To determine whether expression of CD20 is associated with clinical outcomes of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). METHODS: 271 newly diagnosed childhood BCP-ALL during January 2009 to May 2013 were enrolled in this study. The patients were treated in line with the Chinese Childhood Leukemia Group ALL 2008 protocol (CCLG-ALL 2008). The clinical feature, early therapeutic response and clinical outcomes of the patients with a CD20 positive (CD20+ BCP) expression were compared with those with a CD20 negative (CD20- BCP) expression. RESULTS: CD20- BCP accounted for 45.76% (124 cases) of all participants. There were no significant differences between CD20- BCP and CD20- BCP patients in gender distribution, age, WBC counts when diagnosis was made, proportion of prednisone poor responders, and distribution of risk categories (P > 0.05). Patients of 10 years or older comprised 25.81% and 14.29% of CD20+ BCP and CD20- BCP patients, respectively (P = 0.017). Pro-B and pre-B cases accounted for 43.55% and 59.86% of CD20- BCP patients respectively, compared with 56.45 and 40.14% in CD20- BCP patients (P = 0.007). CD20+ BCP patients had 12.20% Philadelphia positive ALL and 6.50% BCP-ALL with TEL-AML1 fusion gene, compared with 4.86% (P = 0.03) and 18.06% (P = 0.005) in those of CD20 BCP. No significant differences were found between the two groups of patients in 15-day (77.50% vs. 74.13%, P = 0.525) and 33-day (95.04% vs. 95.83%, P = 0.757) complete remission rates. No significant differences (P > 0.05) were found in predicted 4-year event-free survival CEFS (78.00% +/- 4.96%) vs. (79.05% +/- 5.40%)) and predicted 4-year overall survival (OS (83.01% +/- 6.13%) vs. (93.64% +/- 2.46%)) between the two groups of patients either. CONCLUSION: CD20 positivity was not found to be associated with worse prognosis of children with BCP-ALL. More studies are needed to validate the correlation between CD20 and unfavorable outcomes in BCP-ALL. PMID- 25286696 TI - [GATA-2 gene overexpression and its clinical significance in acute myeloid leukemia with AML1/ETO fusion gene]. AB - OBJECTIVE: To determine the expression level of GATA-2 gene in acute myeloid leukemia with maturation (AML-M2) patients carrying AML1/ETO fusion gene. METHODS: Bone marrow samples were collected from 23 patients with de novo adult AML-M2 carrying AML1/ETO fusion gene. GATA-2 gene expression was detected by real time quantitative polymerase chain reaction (RQ-PCR). We analyzed the correlation between GATA-2 gene expression and laboratorial features and clinical prognosis of patients. RESULTS: GATA-2 expression levels (GATA-2 gene copies/reference gene copies) in the patients were found to be 2.17%-1 260.65%. A GATA-2 expression over or equal to 82% was defined as HIGH (10 cases), while an expression level below 82% was defined as LOW (13 cases). No significant differences were found in age, sex, white blood cell count or the rate of bone marrow blasts between HIGH and LOW expression groups (P > 0.05). Although the difference in complete remission rate between the two groups was not statistical significant (P = 0.067 8), the HIGH expression group had higher relapse rate (71.43% vs. 15.38%, P = 0.022 3) and higher mortality rate (70.00% vs. 7.69%, P < 0.05). The DFS and OS of the HIGH group are statistically significantly lower than that of the LOW group (P < 0.01). In the HIGH group, the patients choosing HSCT (2/10) are all alive without relapse, while among those choosing chemotherapy only (8/10), seven out of eight patients died. CONCLUSION: High expression level of GATA-2 in AML-M2 patients with AML1/ETO is associated with high risk of relapse and poor prognosis. Therefore, AML-M2 patients with AML1/ETO fusion gene and high expression of GATA-2 would possibly benefit from additional treatments except for chemotherapy. PMID- 25286697 TI - [FLT3 mutation in acute promyelocytic leukemia patients with extramedullary relapse]. AB - OBJECTIVE: To evaluate the role of FLT3 gene mutation in acute promyelocytic leukemia (APL) patients with extramedullary relapse. METHODS: The blood and bone marrow samples were collected from 2 APL patients with extramedullary relapse and FLT3 gene mutation was detected with these samples. The correlation between FLT3 gene mutation and extramedullary relapse was analyzed. RESULTS: A rare point mutation Asn841Gly (A841G) of FLT3-TKD and a novel mutation (c. 1209_1210insT/p. K404X) of WT1 were detected in a APL patient who suffered CNS relapse, while a rare point mutation Asp839Gly (D839G) of FLT3-TKD and a novel mutation Arg458Pro (c. 1373G>C) of WT1 were found in another APL patient who suffered testicular relapse. CONCLUSION: The rare point mutation of FLT3 as well as the novel mutation of WT1 were found in APL with extramedullary relapse. PMID- 25286698 TI - [Comparing BFA with BuCyA as a myeloablative conditioning regimen for allogeneic stem cell transplantation in acute leukemias]. AB - OBJECTIVE: To compare BFA (busulfan, fludarabine plus cytarabine) with BuCyA (busulfan, cyclophoshpamide plus cytarabine) as the conditioning regimens in allogeneic stem cell transplantation for acute leukemias. METHODS: 83 patients with acute leukemia were allocated to BFA group (busulfan 3.2 mg/(kg x d), -9 d-6 d; fludarabine 30 mg/(m2 x d), -5 d(-) -1 d; cytarabine, 1 g/(m2 x d), -5 d(-) - 1 d) or BuCyA group (busulfan, 3.2 mg/(kg x d), -8 d(-) - 5 d; cyclophoshpamide 60 mg/(kg x d),-2 d(-) - 1 d; cytarabine, 3 g/(m2 x d), -4 d(-) - 3 d). Their three-year disease-free survival (DFS) rate, complete remission (CR) rate and incidences of acute graft versus host disease (aGVHD) and hemorrhagic cystitis were monitored. RESULTS: BuCyA group had lower DFS (40.0% vs 61.9%, P = 0.039 9) and lower CR (44.0% vs 71.6%, P = 0.031 0) than BFA group. About 20% of patients treated with BuCyA were not in remission, compared with 51.6% of those treated with BFA. aGVHD occurred in 46.7% patients in the BuCyA group and 50.9% patients in the BFA group, which were 23.3% and 9.4%, respectively, for those graded III - IV. Severe infection occurred in 23.3% patients in the BuCyA group and 22.9% patients in the BFA group. Severe bleeding occurred in 26.7% patients in the BuCyA group and 11.4% patients in the BFA group. The incidence of hemorrhagic cystitis in the BuCyA group and BFA group was 16.7% and 5.7%, respectively. CONCLUSION: BFA is a safer and more effective conditioning regimen compared with BuCyA. PMID- 25286699 TI - [Comparison of HyperCVAD regimen and CHOP regimen in treating patients with lymphoblastic lymphoma]. AB - OBJECTIVE: To compare the efficacy and safety of HyperCVAD regimen and CHOP regimen in treating patients with lymphoblastic lymphoma (LBL). METHODS: Seventy five LBL patients were enrolled from January 2002 to October 2013, with 44 being treated with HyperCVAD and 31 being treated with CHOP regimen. The patients were followed up until 31 December 2013. Factors associated with the prognosis of the patients were analyzed using Logistic and COX regression models. RESULTS: The complete remission rate (73% vs. 23%) and overall response rate (91% vs. 46%) were both significantly higher in the patients receiving HyperCVAD regimen compared with those receiving CHOP regimen (P < 0.000 1). The follow-up lasted on average (median) 9.9 months (ranging from 1.3 to 41 months). The patients receiving HyperCVAD regimen had significantly longer overall survival (OS) (median 31.5 vs. 11 months, P = 0.012 7) and progression-free survival (PFS) time (median 16 vs. 5 months, P= 0.000 4) than those receiving CHOP regimen. Complete remission (CR) was negatively associated with increased lactate dehydrogenase (LDH, standard partial regression coefficent (beta) = -0.4793 and international prognostic index (IPI score > or = 3, beta = -0.691) in the patients receiving HyperCVAD regimen. The only significant predictor for survival was CR (relative risk (RR) = 0.146, 95% confidence interval (CI): 0.044-0.488). Common adverse events of the two regimens were bone marrow suppression, pulmonary infection, liver dysfunction and hemorrhage. Patients receiving HyperCVAD regimen were more likely to suffer from bone marrow suppression (100% vs. 84%) and severe pulmonary infection (27% vs. 3%) than those receiving CHOP regimen (P < 0.05). No patient died of those adverse events. CONCLUSION: Compared with CHOP regimen, HyperCVAD regimen can improve response rates and survival of LBL patients. Its higher level of pulmonary infection can be managed. PMID- 25286700 TI - [A comparison of different estimation equations for glomerular filtration rate in Chinese diabetic patients]. AB - OBJECTIVE: To compare the accuracy and precision of C-G equation, simplified MDRD equation, the Chinese equation, Ruijin equation, and CKD-EPI equation for estimating glomerular filtration rate (GFR) in Chinese diabetic patients. METHODS: Diabetic patients visiting the West China Hospital (both outpatient and inpatient departments) of Sichuan University who were older than 18 years old were enrolled in this study. Their general health and clinical characteristics were recorded. The GFR of those patients were evaluated by 99mTc-DTPA dynamic renal imaging (rGFR). We compared the accuracy and precision of C-G equation, simplified MDRD equation, the Chinese equation, Ruijin equation and CKD-EPI equation for estimating GFR (eGFR). We also tested whether levels of GFR, plasma creatinine (Scr) and fasting plasma glucose (FPG) influenced the accuracy and precision of the equations. RESULTS: 217 diabetic patients (139 males and 78 females) were enrolled in this study. Compared with rGFR, C-G equation underestimated GFR slightly; whereas simplified MDRD equation, the Chinese equation, Ruijin equation and CKD-EPI equation overestimated GFR. Ruijin equation had the best accuracy and precision in all the equations, followed by CKD-EPI equation. When patients had lower than 133 microml/L Scr, Ruijin equation had the best accuracy and precision. When patients had 133-177 micromol/L Scr, CKD-EPI equation had the best accuracy and precision. When patients had higher than 177 micromol/L Scr, there was no obvious difference in accuracy and precision among the equations. Regardless of the level of FPG, Ruijin equation had the best accuracy and precision in all the equations. CONCLUSION: Ruijin equation is the best equation for estimating GFR, followed by CKD-EPI equation. PMID- 25286701 TI - [Causes of death in STZ-induced rat models of diabetes mellitus]. AB - OBJECTIVE: To identify conditions that may improve the successful rate of STZ induced rat models of diabetes mellitus (DM). METHODS: 100 male SD rats were randomly divided into control group (n = 10) and experimental group (n = 90). Rats in the experimental group were treated with intraperitoneal injection of STZ 65 mg/kg once, and were then categorized into succeeded DM model group and failed group. Their body masses and levels of fasting blood glucose (FBG), urine glucose (UG), urine protein (UP), urine routine, renal function, liver function, blood lipids and kidney hypertrophy index (KHI) were monitored and compared. Dead rats were dissected to observe diseased organs. Pathological changes of those diseased organs were examined by HE staining. RESULTS: DM rat models were established through a single intraperitoneal injection of STZ, with a success rate of 58.89%. During the experiment, 43.33% of rats died. Compared with the rats in the failed group, the DM rat models had significantly higher levels of body mass, food intake, water intake, urine output, FBG, creatinine, blood urea nitrogen, KHI, urinary tract infections, and mortality; but lower levels of total protein, albumin and cholesterol and triglyceride (P < 0.05). Nine rats died of pulmonary edema; 19 died of renal abscess. The causes of 11 dead rats were not clear. CONCLUSION: DM rat models can be established through a single intraperitoneal injection of STZ 65 mg/kg, but with high mortality rate. The deaths may be associated with infection, malnutrition, suffocation of lymphatic circulation, toxicity of STZ, and changes in environmental and climate conditions. PMID- 25286702 TI - [Evaluation of greenlight photoselective vaporization of prostate and plasmakinetic resection of prostate for the treatment of eldly benign prostatic hyperplasia men with high surgical risk: a prospective randomised control trial]. AB - OBJECTIVE: To compare the clinical effects and safety between greenlight photoselective vaporization of prostate (PVP) and plasmakinetic resection of prostate (PRP) in eldly benign prostatic hyperplasia (BPH) men with high surgical risk. METHODS; Fifty three eldly BPH patients, who had the indication of surgical treatment but complicated with at least one internal disease, were randomly divided into PVP group and PRP group. The clinical data of all the patients were collected and compared between the two groups, including pre-operative and post operative international prostate symptom score (IPSS), postvoid residual urine (PVR), urine flow rate (Qmax), quality of life (QOL) as well as prostate volume (PV), operational time, operative bleeding volume, postoperative recovery, peri operative complications. RESULTS: The complete follow-up data of 44 patients were achieved: 21 of PVP, 23 of PRP. There were significant differences between two groups in operative bleeding, bladder irrigation time, indwelling catheter time and hospital stay (P < 0.002). The peri-operative bleeding was lower in PVP group, while the bladder irrigation time, indwelling catheter time and hospital stay were shorter in PVP group. The operation time showed no difference (P = 0.12). No significant differences were found 3 months postoperatively between two groups in all the data associated with urination (IPSS, Qmax, PVR, QOL), P > 0.05. Complications (urethrostenosis, retrograde ejaculationwere acceptable in both groups. CONCLUSION: For surgical treatment of eldly men with high surgical risk, both PVP and PRP are safe and effective with the internal disease being sufficient control. PMID- 25286703 TI - [A clinical trial of ultrasound-guided facet joint block in the lumbar spine to treat facet joint related low back pain]. AB - OBJECTIVE: To determine the feasibility and clinical efficacy of ultrasound guided facet joint injection and nerve block in lumbar facet joint for the treatment of facet-joint related low back pain. METHODS: 20 patients with facet joint pain were randomized into two groups received block blindly (B group) or guided by ultrasound (US group) respectively. The location of needle tip was confirmed by CT in both groups, and the accuracy was computed afterwards. VAS score, puncture time and one-time puncture success rate (%) were recorded. VAS scores and pain remission rates in both groups were recorded at 30 min, 1 d, 2 d, 6 weeks after the block. RESULTS: The VAS scores were 3.3 +/- 0.4 in US group and 1.2 +/- 0.3 in B group (P < 0.05). The puncture time was (206 +/- 27) s in US group while (397 +/- 31) s in B group (P < 0.05). There were 37 facet joint blocks guided by ultrasound, in which 32 were correctly targeted with the first puncture. The success rate is 86.5%. There were 35 facet joint blocks blindly, in which 11 were correctly targeted with the first puncture. The success rate is 31.4%. The difference of one-time puncture success rate between the two groups was significant (P < 0.05). Differences of VAS and pain remission rate at half an hour after facet joint injection between B group and US group were significant (P < 0.05). There were 8, 9, 9, and 9 patients in US group obtaining a reduction in VAS scores > or = 3 at 30 min, 1 d, 2 d and 6 weeks after the procedure respectively, while the numbers of such patients were 5, 6, 5, 5 in B group (P > 0.05). After 6 weeks of follow-up, the overall remission rates were (72.3 +/- 14.0)% in US group, and (56.7 +/- 11.0)% in B group, there was no significant difference between the two groups (P > 0.05). CONCLUSION: The ultrasound-guided lumbar facet joint injection technique had a high feasibility and accuracy, and had better clinical efficacy than block blindly. PMID- 25286704 TI - [Quality of life of patients with gastric tube anastomosis after proximal gastrectomy in adenocarcinoma of esophagogastric junction]. AB - OBJECTIVE: To compare postoperative quality of life (QOL) of patients receiving proximal gastrectomy (PG) for adenocarcinoma of gastroesophagealjunction (AEG) throughgastric tube anastomosis and traditional esophagogastrostomy. METHODS: Between January 2010 and February 2011, 112 patients were diagnosed as AEG in our hospital. All patients underwent curative operations. Two post-PG alimentary tract reconstruction methods were adopted: gastric tube anastomosis (n = 60) and traditional direct anastomosis (n = 52). The European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire Core-30 (EORTC QLQ C30) and QLQ-STO22 were used to assess QOL of those patients before and two years after operations. RESULTS: There were no statistically significant differences between the two groups of patients in clinical and pathologic characteristics, clinical pathological characteristics and preoperative QOL (P > 0.05). Two years after operations, the patients receiving traditional direct anastomosis showed higher scores in reflux, body image, and nausea and vomiting compared with those receiving gastric tube anastomosis. No statistical differences were found between the two groups of patients in general health, physical function, role function, fatigue and pain (P > 0.05). CONCLUSION: Gastric tube reconstruction could improve the postoperative QOL of AEG patients. PMID- 25286705 TI - Annual Delegate Conferences. PMID- 25286706 TI - Nursing beyond the bush. PMID- 25286707 TI - Cultural safety and respect. PMID- 25286708 TI - Medical/surgical nursing in the home. PMID- 25286709 TI - Printing a new way to personalised health. PMID- 25286710 TI - Right to an assisted death in the spotlight. PMID- 25286711 TI - High flow nasal cannula oxygen therapy for infants and young children with bronchiolitis. PMID- 25286712 TI - Preventing infections through cleaner hospitals project. PMID- 25286713 TI - Nurses working to reduce infection and other complications for children with central venous access devices. PMID- 25286714 TI - Surveillance to reduce urinary tract infections: the STRUTI project. PMID- 25286715 TI - Minimum standard for wound dressing procedure in the home care environment. PMID- 25286716 TI - NSW hand hygiene campaign. PMID- 25286717 TI - Reducing catheter associated urinary tract infections. PMID- 25286718 TI - Preventing infections following caesarean section. PMID- 25286719 TI - Clinical waste in home healthcare: navigating the swamp. PMID- 25286720 TI - The challenges faced in infection prevention and control practices. PMID- 25286721 TI - The circle of life--the infection prevention and control program. PMID- 25286722 TI - Intern credentialing training at the Princess Alexandra Hospital. PMID- 25286723 TI - Stand up for aged care. PMID- 25286724 TI - Your professional conference. PMID- 25286725 TI - Whooping cough vaccine programme in pregnancy extended. PMID- 25286727 TI - UK first-time mothers 'oldest in the world'. PMID- 25286726 TI - Wales bans smoking in cars carrying under-18s. PMID- 25286728 TI - Rotavirus cases down by 70%. PMID- 25286729 TI - NHS finances reach 'tipping point'. PMID- 25286730 TI - Schools allowed to hold spare asthma inhalers for pupils. PMID- 25286732 TI - FGM prevention funding package announced. PMID- 25286733 TI - One million Scots now in poverty. PMID- 25286734 TI - NI child obesity 'top of the health agenda. PMID- 25286735 TI - Cochrane Review update: psychological and educational interventions for atopic eczema in children. PMID- 25286737 TI - Profiling parenting. PMID- 25286736 TI - Questioning development. PMID- 25286738 TI - School nurse 121 campaign. PMID- 25286739 TI - An analysis of Time 4U, a therapeutic group for women with postnatal depression. AB - This article examines the effectiveness of the Time4U therapeutic group for women with postnatal depression, introduced seven years ago in Bury. The group is facilitated by a health visitor and primary care mental health nurse, and offers a combination of group therapy, cognitive behavioural therapy, peer support and social support. This paper analyses the scores and evaluations of the mothers who attended in 2012 and shows that the mothers' depression, anxiety and social functioning improved. The reasons for the group's success are discussed and include partnership working between community services, primary mental health services and children's centres. PMID- 25286740 TI - Time to tackle domestic violence: identifying and supporting families. AB - Domestic violence and abuse (DVA) is a serious societal and public health issue that takes place within family-type intimate relationships and forms a pattern of coercive and controlling behaviours, which can escalate over time. DVA rarely exists in isolation from other social 'ills' and can have an enormous impact on people's health and wellbeing. Recently, family violence has become more visible to health visitors and increasingly presents challenges to practice. Some are practical challenges faced by practitioners who seek to comprehend the evolving phenomenon and others involve the clinical dilemmas surrounding service delivery. The deeply vexed question is how health visitors can work towards ending the cycle of DVA, especially where there are unclear parameters between the victim and perpetrator, and when clients are accepting of, and dismissive about, DVA. The recent government strategy-based move towards greater emphasis on prevention has provided an opportunity for health visitors to intervene in DVA. In light of the nature of safeguarding responsibilities, and a wider public health role as providers of universal health services, health visitors are well placed to offer early support to families. PMID- 25286741 TI - Maternal and infant health of Eastern Europeans in Bradford, UK: a qualitative study. AB - This qualitative study aimed to investigate maternal and infant health needs within Eastern European populations in Bradford. Evidence suggested that migrants from Eastern Europe had poor maternal and child health and increased rates of infant mortality. Health visitors, community midwives and specialist voluntary workers were involved. Eleven interviews took place. They were semi-structured and analysed using a thematic approach. A number of health needs were identified in Eastern European populations, including high rates of smoking and poor diet. Wider determinants of health such as poverty and poor housing were cited as commonplace for Eastern European migrants. There were numerous cultural barriers to health, such as discrimination, mobility, cultural practices regarding age at pregnancy, and disempowerment of women. Lastly, access to health services was identified as a significant issue and this was impacting on staff working with this population. This study demonstrated the complexity and interaction of health and social factors and their influence on utilisation of health services. PMID- 25286742 TI - The UK child and adolescent immunisation programme: an update. PMID- 25286744 TI - The effect of induction of CYP3A4 by St John's wort on ambrisentan plasma pharmacokinetics in volunteers of known CYP2C19 genotype. AB - To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (rs = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance. PMID- 25286743 TI - When to consider transfusion therapy for patients with non-transfusion-dependent thalassaemia. AB - Non-transfusion-dependent thalassaemia (NTDT) refers to all thalassaemia disease phenotypes that do not require regular blood transfusions for survival. Thalassaemia disorders were traditionally concentrated along the tropical belt stretching from sub-Saharan Africa through the Mediterranean region and the Middle East to South and South-East Asia, but global migration has led to increased incidence in North America and Northern Europe. Transfusionists may be familiar with beta-thalassaemia major because of the lifelong transfusions needed by these patients. Although patients with NTDT do not require regular transfusions for survival, they may require transfusions in some instances such as pregnancy, infection or growth failure. The complications associated with NTDT can be severe if not properly managed, and many are directly related to chronic anaemia. Awareness of NTDT is important, and this review will outline the factors that should be taken into consideration when deciding whether to initiate and properly plan for transfusion therapy in these patients in terms of transfusion interval and duration of treatment. PMID- 25286745 TI - The soil resistome: a critical review on antibiotic resistance origins, ecology and dissemination potential in telluric bacteria. AB - Soil is a large reservoir of microbial diversity and the majority of antimicrobial compounds used today in human and veterinary health care have been isolated from soil microorganisms. The Darwinian hypothesis of an 'arms-shields race' between antibiotic producers and resistant strains is often cited to explain antibiotic resistance gene determinants (ARGD) origins and diversity. ARGD abundance and antibiotic molecule exposure are, however, not systematically linked, and many other factors can contribute to resistance gene emergence, selection and dissemination in the environment. Soil is a heterogeneous habitat and represents a broad spectrum of different ecological niches. Soil harbours a large genetic diversity at small spatial scale, favouring exchange of genetic materials by means of horizontal gene transfer (HGT) that will contribute to ARGD dissemination between bacteria and eventually acquisition by pathogen genomes, therefore threatening antibiotic therapies. Our current knowledge on the extent of the soil resistome abundance and diversity has been greatly enhanced since the metagenomic revolution and help of high-throughput sequencing technologies. Different ecological hypotheses explaining their high prevalence in soil and questioning their transfer rate to pathogens, in respect to these recent experimental results, will be discussed in the present review. PMID- 25286746 TI - Oesophageal atresia with tracheo-oesophageal fistula in a preterm neonate in Limbe, Cameroon: case report & brief literature review. AB - BACKGROUND: Oesophageal atresia is a congenital anomaly in which there is interruption of the oesophageal lumen resulting in an upper and lower segment. We present the case of a rare sub-type of Oesophageal atresia with proximal trachea oesophageal fistula associated with Meconium Aspiration Syndrome. This is the first case reported in literature in the South West Region of Cameroon. CASE PRESENTATION: A 2 day old preterm male baby who presented as an emergency with difficulty breathing, fever and refusal to feed. Initially managed as early onset neonatal sepsis from meconium aspiration syndrome in which a diagnosis of oesophageal atresia was finally made. CONCLUSION: A high index of suspicion for Oesophageal atresia/trachea-oesophageal fistula should prevail when faced with a neonate with the triad: respiratory distress during feeds, regurgitation and persistent frothy salivation. The case discusses the diagnostic dilemma and management difficulties in a preterm neonate with the above association in a low income setting. PMID- 25286747 TI - Molecular characterization of complex chromosomal rearrangement: first report of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML-M2 case. AB - The strong association of diagnostic karyotype with clinical outcome has made cytogenetics one of the most valuable diagnostic and prognostic tools for acute myeloid leukemia (AML) till today. Complex chromosomal findings are reported to be seen in nearly 10-15% of adult AMLs and are generally associated with poor outcome. In the current report, we present the results of hematologic, immunophenotypic, cytogenetic, chromosomal microarray and molecular analyses of a 60-year-old female patient diagnosed with AML-M2. Cytogenetic analysis revealed complex chromosomal findings involving seven different chromosomes. However, cytogenetic analyses were not able to precisely unveil all karyotypic changes, hence chromosomal microarray was used for further characterization. The most interesting observation was identification of a t(7;12) (q11;q22) as part of this complex karyotype. To the best of our knowledge, this is the first report of identification of novel t(7;12) (q11;q22) as part of a complex karyotype in de novo AML-M2. PMID- 25286748 TI - Variant acute promyelocytic leukemia presenting with loss of visual acuity and extreme pancytopenia. PMID- 25286749 TI - Delayed flare reaction of draining vein due to subcutaneous bortezomib more likely to occur at the inner thigh. PMID- 25286750 TI - Cutaneous invasion of leukemia cells during blastic transformation in a post polycythemia vera myelofibrosis patient. PMID- 25286751 TI - Quantitative proteomic analysis of global effect of LLL12 on U87 cell's proteome: An insight into the molecular mechanism of LLL12. AB - Glioblastoma multiforme (GBM) is one of the most devastating and dreadful WHO grade IV brain tumors associated with poor survival rate and limited therapeutics. Signal transducer and activator of transcription factor 3 (STAT3) is persistently active in several cancers, including gliomas, and STAT3 inhibitors hold great promise for treatment of glioma. LLL12, a curcumin derivative, inhibits STAT3 functions, thereby reduces growth of GBM. However, the global effects of targeting STAT3 using LLL12 have not been studied well. To shed light on this aspect, we performed quantitative proteomic analyses using differential in-gel electrophoresis (2D-DIGE) and isobaric tags for relative and absolute quantitation (iTRAQ) as well as label-free mass spectrometric analysis with 0.5MUM (IC50) concentration of LLL12. Through this approach, we identified a total dataset of 1012 proteins with 1% FDR, of which 143 proteins were differentially expressed associated with various cellular functions. Results suggest that LLL12 influences central cellular metabolism and cytoskeletal proteins, in addition to its apoptosis inducing and anti-angiogenic activities, which altogether contribute to its anti-tumorigenic function. Interestingly, triose phosphate isomerase (TPI), phosphoglycerate mutase 1 (PGAM1), adaptor molecule (CRK2), protein DJ-1 (PARK7) and basic transcription factor 3 (BTF3) were found to be down-regulated and can be studied further to understand their therapeutic potential in gliomas. TPI1 and PGAM1 protein expressions were validated using immunoblot. Conclusively, our results suggest the therapeutic potential of LLL12 and it can be investigated further for a significant role in glioma treatment. BIOLOGICAL SIGNIFICANCE: LLL12 holds great promise for therapeutic development in gliomas with constitutive expression of STAT3. This study investigated the global effect of LLL12 on the proteome of U87 glioma cells using complementary proteomic approaches, and our findings suggest that LLL12 influences central metabolism, translation, transport processes, and cytoskeleton of a cell in addition to its anti-angiogenic and apoptosis inducing functions which altogether contributes to anti-tumorigenic activity of LLL12. This study leads to the identification of several proteins which may serve as prognostic or predictive markers in GBM. We identified TPI1, PGAM1, CRK and BTF3 as potential therapeutic targets and further investigations on these candidates may facilitate therapeutic development. PMID- 25286753 TI - Is single red cell distribution width without iron, folic acid and vitamin B12 enough to decide? PMID- 25286752 TI - A low-density SNP array for analyzing differential selection in freshwater and marine populations of threespine stickleback (Gasterosteus aculeatus). AB - BACKGROUND: The threespine stickleback (Gasterosteus aculeatus) has become an important model species for studying both contemporary and parallel evolution. In particular, differential adaptation to freshwater and marine environments has led to high differentiation between freshwater and marine stickleback populations at the phenotypic trait of lateral plate morphology and the underlying candidate gene Ectodysplacin (EDA). Many studies have focused on this trait and candidate gene, although other genes involved in marine-freshwater adaptation may be equally important. In order to develop a resource for rapid and cost efficient analysis of genetic divergence between freshwater and marine sticklebacks, we generated a low-density SNP (Single Nucleotide Polymorphism) array encompassing markers of chromosome regions under putative directional selection, along with neutral markers for background. RESULTS: RAD (Restriction site Associated DNA) sequencing of sixty individuals representing two freshwater and one marine population led to the identification of 33,993 SNP markers. Ninety-six of these were chosen for the low-density SNP array, among which 70 represented SNPs under putatively directional selection in freshwater vs. marine environments, whereas 26 SNPs were assumed to be neutral. Annotation of these regions revealed several genes that are candidates for affecting stickleback phenotypic variation, some of which have been observed in previous studies whereas others are new. CONCLUSIONS: We have developed a cost-efficient low-density SNP array that allows for rapid screening of polymorphisms in threespine stickleback. The array provides a valuable tool for analyzing adaptive divergence between freshwater and marine stickleback populations beyond the well-established candidate gene Ectodysplacin (EDA). PMID- 25286754 TI - Prognostic value of CD133 expression in cancer patients treated with chemoradiotherapy: a meta-analysis. AB - Many studies evaluated the correlations of CD133 expression with the clinical outcomes in patients treated with chemoradiotherapy (CRT) but yielded controversial results. This meta-analysis was performed to identify the impacts of CD133 expression on the prognosis of cancer patients treated with CRT. Electronic databases updated up to March 2014 were searched to find relevant studies. Relevant literatures without any language restrictions were searched via electronic databases as follows: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). STATA software was used for the current meta-analysis. Hazard ratios (HR) and its corresponding 95% confidence interval (95% CI) were calculated. Six studies were identified with a total of 470 cancer patients treated with CRT. The meta analysis results showed that CD133-positive patients had poorer overall survival (OS) than that of CD133-negative patients (HR = 2.13, 95% CI = 1.20 ~ 3.07, P < 0.001). Furthermore, CD133-positive patients displayed shorter disease-free survival (DFS) than that of CD133-negative patients (HR = 1.74, 95% CI = 0.08 ~ 3.40, P = 0.039). Ethnicity-stratified analysis indicated that CD133 expression positively correlated with shorter OS among the Japanese, Chinese, and Spanish populations (all P < 0.05). In conclusion, our findings suggest that CD133 expression may be positively correlated with poorer prognosis in cancer patients treated with CRT. PMID- 25286755 TI - Immunohistochemistry with a novel mutation-specific monoclonal antibody as a screening tool for the EGFR L858R mutational status in primary lung adenocarcinoma. AB - Epidermal growth factor receptor (EGFR) mutation status is the best predictor of patient response to treatments with tyrosine kinase inhibitors in primary lung adenocarcinoma and is typically analyzed by DNA-based techniques, such as direct DNA sequencing and allele-specific PCR. Recently, however, two mutation-specific antibodies against delE746-A750 in exon 19 and L858R in exon 21 have opened the door for a more convenient and more efficient strategy to determine EGFR mutation status. To evaluate the clinical application of a new mutation-specific mouse monoclonal antibody for EGFR (L858R), we performed immunohistochemistry (IHC) studies with tumor samples from primary lung adenocarcinoma in retrospective and validation settings. A total of 215 cases of primary lung adenocarcinoma were examined and compared using a combination of DNA-based techniques (direct DNA sequencing and/or allele-specific PCR) and protein-based IHC. IHC staining was assessed on a 0 to 3+ score scale, and a cutoff value of 2+ was used as positive by IHC. In the retrospective setting, statistical analyses of the data showed that the sensitivity of IHC was 90.9% and the specificity was 96.8%. Findings from the validation study demonstrated that the sensitivity and specificity of IHC were 88.2% and 100%, respectively. IHC with the novel mutation-specific antibody could be used as a screening method to assess the EGFR L858R mutation status in primary lung adenocarcinoma. PMID- 25286756 TI - Lactotransferrin could be a novel independent molecular prognosticator of nasopharyngeal carcinoma. AB - Lactotransferrin (LTF), also known as lactoferrin, is a key component of innate immune defense. We previously reported that LTF was downregulated in nasopharyngeal carcinoma (NPC) and could suppress NPC cell proliferation. However, the relevance of the relationship between LTF expression and NPC clinical outcome has not been reported. This study aims to assess the possible correlations between LTF expression and clinical parameters and its potential prognostic predictive ability in the outcomes of patients with NPC. Complementary DNA (cDNA) microarray, quantitative real-time PCR (qRT-PCR), and immunohistochemistry (IHC) results suggested that LTF expression was significantly downregulated in NPC tissues compared to non-NPC tissues. LTF was negatively correlated with lymph node metastasis (P = 0.042), T stage (P < 0.001), clinical tumor-node-metastasis (TNM) stage (P = 0.022), and EBV-encoded RNA 1 (EBER-1) expression (r = -.167, P = 0.016). A survival analysis of 108 patients with NPC revealed that positive expression of LTF could predict a good prognosis [disease-free survival (DFS): P = 0.043, overall survival (OS): P = 0.040]. Multivariable analysis revealed that LTF could independently predict prognosis (DFS: HR = 0.414, P = 0.003; OS: HR = 0.309, P = 0.005). These observations indicated that LTF is a potential prognostic factor of NPC. PMID- 25286757 TI - The impact of hepatitis B virus x protein and microRNAs in hepatocellular carcinoma: a comprehensive analysis. AB - microRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, approximately 22 nucleotides (nts) in length, widely found in animals, plants, and viruses. Mature miRNAs control gene expression at a post-transcriptional level through blocking protein translation or inducing mRNA degradation. Many recent studies have shown that hepatitis B virus x protein (HBx), a viral protein with a crucial role in hepatogenesis, is associated with the regulation of miRNAs. This interaction impacts fundamental tumor processes, such as cell proliferation, differentiation, and apoptosis. In this review, we summarized the recent literature on the roles of HBx-regulated miRNAs in the pathogenesis of hepatocellular carcinoma. PMID- 25286758 TI - Combined analysis of copy number alterations by single-nucleotide polymorphism array and MYC status in non-metastatic breast cancer patients: comparison according to the circulating tumor cell status. AB - Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC( ) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists. PMID- 25286759 TI - Serum C-reactive protein acted as a prognostic biomarker for overall survival in metastatic prostate cancer patients. AB - The aim of this study was to determine whether baseline serum C-reactive protein (CRP) levels were associated with overall survival in patients with metastatic prostate cancer in the Chinese population. A total of 135 patients with metastatic prostate cancer were retrospectively reviewed. Both Kaplan-Meier product-limit method and multivariable analysis by Cox regression model were used to assess the prognostic role of serum CRP levels on overall survival of patients with metastatic prostate cancer. There were 51 patients (37.8%) with higher values of baseline serum CRP levels (>=10 mg/L). Kaplan-Meier product-limit method and log-rank test showed that patients with high serum CRP level (>=10 mg/L) had significantly worse overall survival than those patients with normal serum CRP level (<10 mg/L) (P < 0.001). The multivariable analysis by Cox regression model further showed that high serum CRP level (>=10 mg/L) was a significantly independent predictor of overall survival (hazard ratio (HR) = 2.39; 95% confidence interval (95% CI) 1.56-2.39, P < 0.001). In addition, high Gleason score (>=8) also was an independent predictor of overall survival (HR = 1.80; 95% CI 1.16-2.79, P = 0.008). In conclusion, serum CRP level is useful to predict the prognosis of metastatic prostate cancer patients, and high serum CRP level is a significantly independent predictor of worse overall survival. PMID- 25286761 TI - CD105 promotes hepatocarcinoma cell invasion and metastasis through VEGF. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality. Tumor neovascularization is necessarily required for tumor progression and metastasis. CD105 and vascular endothelial growth factor (VEGF) have separately been identified as important contributors to angiogenesis; however, it is unclear if these factors interact to promote the progression of HCC. The goal of this study was to determine the interaction between CD105 and VEGF in HCC, using HCC tissue samples and the human HCC cell line SMMC-7721. In a survey of 89 HCC tumor samples, we determined that CD105 and VEGF expressions were positively correlated with each other and expressed at a higher level in tumor cells. Furthermore, the expression of CD105 was closely related to the tumor-node metastasis (TNM) staging of HCC, degree of tumor differentiation, portal vein invasion, and lymph node metastasis (P < 0.05). Next, we used a lentiviral system to stably overexpress CD105 in SMMC-7721 cells, which was confirmed at the messenger RNA (mRNA) and protein level. We observed that VEGF expression was increased in these cells, as was cell motility and migration, as assessed using a wound healing assay and Transwell chamber system, respectively. Using VEGF small interfering RNA (siRNA), we also demonstrated that elevated VEGF expression is required to promote increased cell motility and migration in CD105-overexpressing cells. In conclusion, we interpret our data to prove that CD105 promotes the invasion and metastases of liver cancer cells by increasing VEGF expression. These results provide a new theoretical and experimental basis for the treatment of liver cancer. PMID- 25286760 TI - Expression and clinical role of NF45 as a novel cell cycle protein in esophageal squamous cell carcinoma (ESCC). AB - NF45 (also known as ILF2), as one subunit of NF-AT (nuclear factor of activated T cells), repairs DNA breaks, inhibits viral replication, and also functions as a negative regulator in the microRNA processing pathway in combination with NF90. Recently, it was found that implicated in the mitotic control of HeLa cells and deletion of endogenous NF45 decreases growth of HeLa cells. While the role of NF45 in cancer biology remains under debate. In this study, we analyzed the expression and clinical significance of NF45 in esophageal squamous cell carcinoma ESCC. The expression of NF45 was evaluated by Western blot in 8 paired fresh ESCC tissues and immunohistochemistry on 105 paraffin-embedded slices. NF45 was highly expressed in ESCC and significantly associated with ESCC cells tumor stage and Ki-67. Besides, high NF45 expression was an independent prognostic factor for ESCC patients' poor survival. To determine whether NF45 could regulate the proliferation of ESCC cells, we increased endogenous NF45 and analyzed the proliferation of TE1 ESCC cells using Western blot, CCK8, flow cytometry assays and colony formation analyses, which together indicated that overexpression of NF45 favors cell cycle progress of TE1 ESCC cells. While knockdown of NF45 resulted in cell cycle arrest at G0/G1-phase and thus abolished the cell growth. These findings suggested that NF45 might play an important role in promoting the tumorigenesis of ESCC, and thus be a promising therapeutic target to prevent ESCC progression. PMID- 25286762 TI - MicroRNA-495 mimics delivery inhibits lung tumor progression. AB - MicroRNAs (miRNAs) can function as tumor suppressors and might provide an efficient strategy for annihilating cancer. Specific miRNAs can be reintroduced into tumor cells to elicit the tumor suppressor activities. We show that systemically delivered, synthetic miRNA mimics in complex with a novel neutral lipid emulsion are preferentially targeted to lung tumors and show therapeutic benefit in mouse models of lung cancer. The delivery was demonstrated using mimics of the tumor suppressor microRNA-495 which is found downregulated in most lung cancer. Systemic treatment of a Kras-activated autochthonous mouse model of non-small cell lung cancer (NSCLC) led to a significant decrease in tumor burden. Specifically, mice treated with microRNA-495 displayed a large reduction in tumor area compared to mice treated with a miRNA control. These findings provide direct evidence that systematically delivered synthetic miRNA mimics to the mammalian lung can inhibit tumor proliferation and support the promise of miRNAs as a targeted therapy for lung cancer in future. PMID- 25286763 TI - Evaluation of miR-720 prognostic significance in patients with colorectal cancer. AB - Aberrant expression of miR-720 had been reported in several cancers. However, the expression level and prognostic value of miR-720 in colorectal cancer (CRC) had not been addressed. In our study, we detected the expression level of miR-720 in 96 CRC tissues to evaluate its clinicopathological characteristics in colorectal cancer. Kaplan-Meier survival curve was performed to evaluate the prognostic role of miR-720 in patients with CRC. Furthermore, in vitro, we transfected the miR 720 mimics or inhibitors into the corresponding CRC cell lines and evaluated the effects on the abilities of cell growth, colony formation, migration, wound healing, and invasion in CRC cells. Our data showed that miR-720 level was significantly upregulated in CRC tissues than that in corresponding normal appearing tissues (NATs) (p < 0.05), and high miR-720 correlated with the tumor size (p = 0.014), tumor-node-metastasis (TNM) stage (p = 0.040), lymphatic metastasis (p = 0.008), and distant metastasis (p = 0.016), which led to a poorer 5-year overall survival rate in CRC patients (p < 0.05). Our experiments in vitro also confirmed that miR-720 could promote the cell growth (p < 0.05), abilities of colony formation (p < 0.05), wound healing (p < 0.05), migration (p < 0.05), and invasion of CRC cells (p < 0.05). We identified StarD13 gene as a putative target of miR-720 in colorectal cancer by bioinformatics analysis, and subsequent dual luciferase activity and Western blot assay further certified that miR-720 might specifically target the StarD13 3'-untranslated region (UTR) at the 795 region (p < 0.05). miR-720 might act as a promoting factor in the development of CRC and could be a prognostic indicator in the prognosis of CRC. Downregulation of miR-720 might be considered to be a potentially important molecular treatment strategy for early stage CRC patients. PMID- 25286766 TI - Reviewer's comment concerning "anterior cervical discectomy versus corpectomy for multilevel cervical spondylotic myelopathy: a meta-analysis" (ESJO-D-14-00408R2 by Shan-Wen Xiao, Hua Jiang, Li-Jing Yang and Zeng-Ming Xiao). PMID- 25286767 TI - Principles of hydrogen radical mediated peptide/protein fragmentation during matrix-assisted laser desorption/ionization mass spectrometry. AB - Matrix-assisted laser desorption/ionization in-source decay (MALDI-ISD) is a very easy way to obtain large sequence tags and, thereby, reliable identification of peptides and proteins. Recently discovered new matrices have enhanced the MALDI ISD yield and opened new research avenues. The use of reducing and oxidizing matrices for MALDI-ISD of peptides and proteins favors the production of fragmentation pathways involving "hydrogen-abundant" and "hydrogen-deficient" radical precursors, respectively. Since an oxidizing matrix provides information on peptide/protein sequences complementary to that obtained with a reducing matrix, MALDI-ISD employing both reducing and oxidizing matrices is a potentially useful strategy for de novo peptide sequencing. Moreover, a pseudo-MS(3) method provides sequence information about N- and C-terminus extremities in proteins and allows N- and C-terminal side fragments to be discriminated within the complex MALDI-ISD mass spectrum. The combination of high mass resolution of a Fourier transform-ion cyclotron resonance (FTICR) analyzer and the software suitable for MALDI-ISD facilitates the interpretation of MALDI-ISD mass spectra. A deeper understanding of the MALDI-ISD process is necessary to fully exploit this method. Thus, this review focuses first on the mechanisms underlying MALDI-ISD processes, followed by a discussion of MALDI-ISD applications in the field of proteomics. (c) 2014 Wiley Periodicals, Inc., Mass Spec Rev 35:535-556, 2016. PMID- 25286764 TI - Expression of microRNA-96 and its potential functions by targeting FOXO3 in non small cell lung cancer. AB - MicroRNAs are implicated in the regulation of various cellular processes, including proliferation, differentiation, cell death, and cell mobility, and can function either as oncogenes or tumor suppressors in tumor progression. The effects of the expression of miR-96 in non-small cell lung cancer (NSCLC) remain unclear. In our study, qRT-PCR (quantitative reverse transcription PCR) was performed to identify the miR-96 expression level in 68 paired NSCLC and adjacent normal lung tissues. Trans-well, cell counting kit-8, and apoptosis assays were used to evaluate the effects of miR-96 expression on cell invasion, proliferation, and apoptosis. Dual-luciferase reporter assay and Western blotting were used to verify whether FOXO3 was a potential major target gene of miR-96. Finally, the effect of FOXO3 on miR-96-induced cell survival was determined by transfection of the genes expressing FOXO3 lacking 3'UTR and miR-96. The expression level of miR-96 in NSCLC tissues was higher than that in adjacent normal lung tissues, and this increased expression was significantly associated with lymph node metastasis. In contrast to the cells in the blank and negative control groups, the number of cells migrating through the matrigel was significantly lower and the incidence of apoptosis was significantly higher in cells transfected with a miR-96 inhibitor. Western blotting and dual-luciferase reporter assays demonstrated that miR-96 can bind to the putative seed region in FOXO3 mRNA 3'UTR, and can significantly lower the expression of FOXO3. The introduction of FOXO3 cDNA without 3'UTR restored miR-96 induced cell apoptosis and invasion. MiR-96 is up-regulated in NSCLC tissues. Downregulation of miR-96 inhibits invasion and promotes apoptosis in NSCLC cells A549 and SPC-A-1 by targeting FOXO3. Therefore, our study improves our understanding of the mechanisms underlying NSCLC pathogenesis and may promote the development of novel targeted therapies. PMID- 25286768 TI - Autonomous self-pollination and insect visitors in partially and fully mycoheterotrophic species of Cymbidium (Orchidaceae). AB - Few studies have examined the reproductive ecology of mycoheterotrophic plants, but the existing literature hypothesizes that they adopt a self-pollinating strategy. Although growing evidence indicates that some rewarding mycoheterotrophic plants depend (at least partially) on an insect-mediated pollination system, it remains unclear whether some mycoheterotrophic plants can attract pollinators without nectar or other rewards. Moreover, in a broader evolutionary/ecological context, the question of whether the evolution of mycoheterotrophy induces a shift in pollination pattern is still unknown. Here I present a comparative investigation into the breeding system of two fully mycoheterotrophic orchids, Cymbidium macrorhizon and C. aberrans, and their closest extant relative, the mixotrophic C. lancifolium. Pollination experiments were conducted to determine the breeding system of these plants. In addition, flower visitors that might contribute to pollination were recorded. Flowers at different maturity stages were examined to investigate mechanisms enabling or limiting self-fertilization. While nectarless flowers of C. lancifolium and C. macrorhizon can successfully attract potential pollinator honeybees, all three Cymbidium possess an effective self-pollination system in which the rostellum that physically separates the stigma and pollinia is absent. Because mixotrophic and mycoheterotrophic Cymbidium occupy low-light niches, pollinator foraging would be negatively influenced by low-light intensity. In partial and fully mycoheterotrophic Cymbidium, autogamy would likely be favoured as a reproductive assurance to compensate for pollinator limitation due to their lack of nectar and pollinators' hostile habitat preferences. PMID- 25286769 TI - Applications of human-induced pluripotent stem cells in the investigation of inherited cardiomyopathy. PMID- 25286770 TI - Right on the mark, or may be migration? PMID- 25286771 TI - Paid- and family-carers' views on supporting women with intellectual disability through breast screening. AB - The cancer needs of people with intellectual disabilities are increasingly being debated. This paper explores the views and experiences of paid- and family-carers when supporting women with intellectual disabilities through breast screening. An ethnographic approach was drawn on and purposive sampling methods were employed. One-to-one semi-structured interviews with 13 carers (10 paid-carers, three family-carers) were undertaken and supported by periods of focused observation on behaviour related to breast awareness and breast screening. Findings indicated that most women with intellectual disabilities needed some support but the quality and quantity of support depended upon both the woman's level of intellectual disability and who was supporting them. In terms of breast screening, the findings suggested that the women were potentially being let down at all the different stages of the breast screening process, from the arrival of the invitation letter to the experience of having a mammogram. The conclusion drawn was that there was evidence of equality of service provision but inequality of service delivery and uptake. PMID- 25286772 TI - Prenatal diagnosis of giant left ventricular diverticulum: case report. AB - The distinction between a ventricular aneurysm and diverticulum is difficult. The differences between these two are based on anatomical, histological, and functional criteria. We present a case of prenatal diagnosis of a giant left ventricular outpouching at 28 weeks gestation. During the postnatal period, the neonate underwent surgical correction for the outpouching. Histopathological examination reported the resected segment was a cardiac diverticulum. Our case indicates that differentiating between the two diagnoses during the intrauterine period is not always straightforward and possible. Histopathological examinations are sometimes necessary to make a precise differentiation. Treatment should be individualized depending on the clinical presentation. PMID- 25286773 TI - Reversible Ca(2+) switch of an engineered allosteric antioxidant selenoenzyme. AB - A Ca(2+) -responsive artificial selenoenzyme was constructed by computational design and engineering of recoverin with the active center of glutathione peroxidase (GPx). By combining the recognition capacity for the glutathione (GSH) substrate and the steric orientation of the catalytic selenium moiety, the engineered selenium-containing recoverin exhibits high GPx activity for the catalyzed reduction of H2 O2 by glutathione (GSH). Moreover, the engineered selenoenzyme can be switched on/off by Ca(2+) -induced allosterism of the protein recoverin. This artificial selenoenzyme also displays excellent antioxidant ability when it was evaluated using a mitochondrial oxidative damage model, showing great potential for controlled catalysis in biomedical applications. PMID- 25286774 TI - Environmentally friendly method for the determination of acrylamide and trimethylolpropane in paper packaging materials by liquid chromatography with tandem mass spectrometry. AB - A simple, rapid, and environmentally friendly method was developed for the determination of acrylamide and trimethylolpropane in paper packaging materials. No organic solvent was used and the matrix effect was investigated. The extract was directly analyzed by liquid chromatography with tandem mass chromatography for quantification and confirmation. The chromatographic separations were performed on a ZORBAX HILIC Plus (2.1 mm * 150 mm, 3MUm; Agilent, USA) column with only one mobile phase (100% water). Calibration curves for acrylamide and trimethylopropane were achieved with concentrations ranging from 0.4 to 20 mg/kg and the corresponding r(2) values were 0.998 and 0.999, respectively. The recoveries were >85% with relative standard deviations <10%. The validated method was applied to the analysis of 50 real samples, and positive results were obtained for 30 samples. The result indicated that trimethylolpropane is associated with inks and printing activity and acrylamide is widely used as a papermaking additive in many paper packages. The concentrations of acrylamide and trimethylolpropane ranged from 0.41 to 7.5 and 0.50 to 8.8 mg/kg, respectively. The results of this study revealed that this method could be used accurately and precisely. PMID- 25286775 TI - Calcium micro-depositions in jugular truncular venous malformations revealed by Synchrotron-based XRF imaging. AB - It has been recently demonstrated that the internal jugular vein may exhibit abnormalities classified as truncular venous malformations (TVMs). The investigation of possible morphological and biochemical anomalies at jugular tissue level could help to better understand the link between brain venous drainage and neurodegenerative disorders, recently found associated with jugular TVMs. To this end we performed sequential X-ray Fluorescence (XRF) analyses on jugular tissue samples from two TVM patients and two control subjects, using complementary energies at three different synchrotrons. This investigation, coupled with conventional histological analyses, revealed anomalous micro formations in the pathological tissues and allowed the determination of their elemental composition. Rapid XRF analyses on large tissue areas at 12.74 keV showed an increased Ca presence in the pathological samples, mainly localized in tunica adventitia microvessels. Investigations at lower energy demonstrated that the high Ca level corresponded to micro-calcifications, also containing P and Mg. We suggest that advanced synchrotron XRF micro-spectroscopy is an important analytical tool in revealing biochemical changes, which cannot be accessed by conventional investigations. Further research on a larger number of samples is needed to understand the pathogenic significance of Ca micro-depositions detected on the intramural vessels of vein walls affected by TVMs. PMID- 25286776 TI - What is new in atopic dermatitis/eczema? AB - INTRODUCTION: Atopic eczema (AE) is a chronic relapsing inflammatory skin condition and one of the most common, potentially debilitating diseases with increasing incidence. AREAS COVERED: The complex etiology of AE with multiple systemic and local immunologic and inflammatory responses and interactions between susceptibility genes and environmental factors leading to defects in skin barrier function and eczematous skin lesions is presented. Knowledge of pathogenesis is important for understanding the more innovative treatment approaches discussed. EXPERT OPINION: Basic therapy consists of hydrating topical treatment and avoidance of specific and unspecific provocation factors. For acute eczematous skin lesions, anti-inflammatory treatment consists mainly of topical glucocorticoids and topical calcineurin inhibitors. Microbial colonization and superinfection may induce skin exacerbation, which can be treated by either topical or systemic antimicrobial treatment. Systemic anti-inflammatory therapy is limited to severe cases and consists of systemic steroids, cyclosporine A or mycophenolate mofetil. Novel anti-inflammatory concepts that go beyond corticosteroids are in the early phases of development. There are targeted therapeutic approaches, such as cytokine and chemokine modulators, and it remains to be investigated how effective they will be and what side effects they may carry. Existing treatment modalities such as barrier repair therapy, topical immunosuppressive agents, antiseptic treatment as well as systemic treatment options are discussed. PMID- 25286777 TI - Core needle biopsy is a safe and accurate initial diagnostic procedure for suspected lymphoma. AB - BACKGROUND: Excisional biopsy is currently recommended for the analysis of lymphadenopathy suspicious for lymphoma. This study aims to evaluate the efficacy and safety of image-guided core needle biopsy (IGCNB) for the diagnosis of lymphoma using a standard protocol for tissue acquisition and analysis. METHODS: All IGCNBs from 2008 to 2014 performed under the study protocol were included in analysis. Demographics, pathology results, additional studies, and follow-up information were recorded. RESULTS: Seventy-three IGCNBs were performed in 71 consecutive patients. Lymphoma was diagnosed in 37 patients (51%). All 37 patients (100%) were subtyped and treated based on IGCNB results. The remaining 36 IGCNBs in 34 patients did not have subsequent diagnosis of lymphoma in a mean follow-up of 15 months (range, 0 to 54 months). There were no complications. CONCLUSIONS: IGCNB performed under a standard protocol is effective and safe and should be considered as an initial diagnostic tool for the evaluation of lymphadenopathy suspicious for lymphoma. PMID- 25286778 TI - Late preterm births: an important issue but often neglected. PMID- 25286779 TI - Primary fallopian tube cancer: domestic data and up-to-date review. AB - Primary fallopian tube carcinoma (PFTC) is a rare gynecological malignancy with the following characteristics: its preoperative diagnosis is easy to miss or delay because of a lack of specific symptoms and signs; it is difficult to distinguish from serous epithelial ovarian cancer or primary peritoneal serous carcinoma during or even after operation because they have the same histopathological features; and there is uncertainty regarding the optimal management because of the lack of available standard guidelines. All of these factors contribute to the major challenge of undertaking a comprehensive study of this disease. To improve our understanding of this rare disease, the domestic data were summarized first. We searched PubMed on this topic, using the term "primary fallopian tube tumor and Taiwan" (from January 1, 1990 to November 3, 2013) and identified 15 published articles, but only 11 studies focused on the outcome of patients with PFTC in Taiwan. These limited data were not enough to increase our knowledge in dealing with this disease; therefore, the addition of large series or published review articles addressing this topic was needed. According to these reports, we concluded: (1) the main type of PFTC was serous type, often poorly differentiated; (2) the diagnosis of PFTC is frequently missed or delayed; (3) PFTC is often of an earlier International Federation of Gynecology and Obstetrics (FIGO) stage than is epithelial ovarian cancer (EOC), because of the appearance of earlier but nonspecific symptoms or signs, such as abdominal pain, vaginal bleeding, and watery discharge or mass; (4) the most important clinicopathological prognostic factor was FIGO stage; (5) the therapeutic strategy is still uncertain, but is often based on the guidelines for treating EOC. An intensive surgical effort such as a complete surgical resection or optimal cytoreduction surgery with a minimal residual tumor followed by a platinum-paclitaxel combination chemotherapy with/without targeted therapy (for example, antiangiogenesis agents) may provide the best possibility of disease free or overall survival. PMID- 25286780 TI - Enhanced myometrial autophagy in postpartum uterine involution. AB - OBJECTIVE: To understand the mechanisms of postpartum uterine involution, we investigated the uterine myometrial changes during pregnancy and the postpartum period. MATERIALS AND METHODS: Nine groups of uterine myometrial samples from mice (n = 4) were collected on gestational Day 0 (nonpregnant), Day 1, Day 2, Day 7, Day 14, and Day 21 and on postpartum Day 1, Day 2, and Day 7. Human samples of uterine myometrium on term (n = 1) and postpartum Day 1 (n = 2) were also collected. Ki-67 immunostaining was used to determine myometrial proliferation. For cell hypertrophy analysis, organelle proteins, beta-actin, prohibin, calnexin, and golgin-97 were analyzed by Western blotting. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and evaluation of activated caspase-3 expression by Western blot analysis assay were used to detect apoptosis. Autophagy was assayed via the evaluation of LC3 expression by Western blotting, immunohistochemistry, and autophagosomes by electron microscopy. RESULTS: Uterine myocytes proliferated during the early stage of gestation with a peak at Day 2, whereas myocyte hypertrophy with increased cellular organelle production occurred gradually in later stages of pregnancy. Postpartum autophagy developed abruptly in uterine myocytes without obvious apoptosis. CONCLUSION: Autophagy of myocytes may play an important role in uterine involution. These results have implications for our understanding of myometrial functional adaptations during pregnancy and the physiological role of autophagy in the uterine remodeling events in the postpartum period. PMID- 25286781 TI - Laparoscopic surgery for subfertility related to endometriosis: a meta-analysis. AB - OBJECTIVE: Endometriosis is the presence of an endometrial gland or stroma in sites other than the uterine cavity and it is frequently diagnosed in infertile women. It has not been well established whether laparoscopic surgery improves fertility. The objective of this study was to assess the effectiveness of laparoscopic surgery for subfertility related to endometriosis. MATERIALS AND METHODS: Main electronic databases were searched for randomized and nonrandomized controlled trials. Trials were included if they were randomized or nonrandomized controlled trials that compared the effectiveness of laparoscopic surgery in the treatment of subfertility associated with endometriosis versus other treatment methods or diagnostic laparoscopy only. Six studies were included in this meta analysis. Outcomes analyzed included live birth rate, pregnancy rate, fetal losses, and surgical complications. RESULTS: An overall advantage of laparoscopic surgery was demonstrated when analyzing live birth rate [relative risk (RR) 1.52, 95% confidence interval (CI) 1.26-1.84, p < 0.01]. An increase in pregnancy rate after laparoscopic surgery was seen (RR of 1.44, 95% CI 1.24-1.68, p < 0.01). No significant difference in foetal losses. CONCLUSION: The use of laparoscopic surgery in the treatment of subfertility related to minimal endometriosis may increase the chances of future pregnancy and live birth. PMID- 25286782 TI - Does magnesium sulfate delay the active phase of labor in women with premature rupture of membranes? A randomized controlled trial. AB - OBJECTIVE: Administration of many drugs including magnesium sulfate (MS) has considerable influences on pregnancy outcomes. The present study investigates the effects of MS administration on reaching the active phase of labor in women with premature rupture of membrane (PROM) and subsequent fetal complications. MATERIALS AND METHODS: A double blind, randomized, placebo-controlled trial was performed among primipara women referred to the PROM center in Tehran, Iran between March 2010 and August 2012. Patients were equally allocated into two groups; the intervention group who received MS (n = 46) and the control (placebo) group (n = 46). Both groups received a corticosteroid, 1g oral azithromycin (oral) and 2 g ampicillin (IV) every 6 hours for 48 hours, followed by amoxicillin (500 mg orally 3 times daily) for an additional 5 days. None of the research staff were aware of the treatment allocation of patients in order for blinding purposes. RESULTS: Administration of MS in intervention group increases this period 2.7 times compared to the control group. In women whose gestational age was <30 weeks, MS administration increased the active phase of labor up to 77%. Administration of magnesium sulfate reduced the risk of respiratory distress syndrome significantly (p = 0 .002), without producing any adverse pregnancy outcomes. CONCLUSION: Magnesium sulfate increases delay in reaching the active phase of labor in mothers with PROM, without producing adverse birth outcomes. (Registration ID in IRCT; IRCT2012091810876N1). PMID- 25286783 TI - Effects of anti-Mullerian hormone and follicle stimulating hormone levels on in vitro fertilization pregnancy rate. AB - OBJECTIVES: To analyze the relationship between in vitro fertilization (IVF) pregnancy rate and basal serum hormone levels before patients begin an IVF course. MATERIALS AND METHODS: In this retrospective study, we analyzed patients with anti-Mullerian hormone (AMH) data and IVF data from January 2009 to October 2012. Pregnancy rates were calculated by AMH and follicle stimulating hormone quartiles and analyzed using the independent samples t test. Furthermore, patients were divided into three groups by age. The Chi-square test was used to assess the association between the parameters and IVF pregnancy rates. RESULTS: From the 910 IVF treatment courses, 377 (41.4%) clinical pregnancies resulted. The pregnant and nonpregnant groups differed significantly in age and FSH and AMH levels. The pregnancy rate was 53.3% for patients aged <32 years and 22.1% for patients aged >38 years. The pregnancy rate was 53.4% for patients with FSH levels <5.6 mIU/mL and 25.8% for patients with FSH levels >8.9 mIU/mL. The pregnancy rate was 56.8% for patients with AMH levels >4.0 ng/mL and 20.0% for patients with AMH levels <1.1 ng/mL. Furthermore, among patients aged <40 years, AMH and FSH were significantly associated with pregnancy rate. Higher pregnancy rates were found among the groups with higher AMH levels than in groups with lower AMH levels. CONCLUSION: For patients aged <40 years, basal serum AMH level and FSH level affected the IVF pregnancy rate, and patients with higher AMH levels had better pregnancy rates. PMID- 25286784 TI - On the qi deficiency in traditional Chinese medicine. AB - OBJECTIVE: Qi deficiency (QD), one of the most common disorders in Traditional Chinese medicine (TCM), is relevant to many disorders in obstetrics and gynecology. This study aimed to identify the common processes and criteria for diagnosing QD among contemporary proficient TCM practitioners. MATERIALS AND METHODS: Steps of decision tree analysis and modified Delphi method were merged together into four-round postal questionnaires to collect qualitative and quantitative data. Open-ended questions and content analysis were used to explore the proficient TCM practitioners' cognitive activities used for diagnosis. The statements obtained from the qualitative responses were used to develop the items for subsequent questionnaires. Based on the TCM practitioners' responses, the diagnostic processes and criteria for making diagnosis were generated. RESULTS: Twenty-eight out of the 30 participants completed all four questionnaires from June 2007 to January 2010. The 11 diagnostic procedures identified in the returned first round of questionnaires were used as the alternatives to select and rank for all the steps to diagnose QD. After three more rounds of postal surveys, an algorithm with a five-stage diagnostic process as well as sets of decision criteria were identified. Although the priorities of procedures and descriptions of reasoning were varied, the content revealed the major themes in the model. The criteria to differentiate signs and symptoms (S/S) included five principles for correlating S/S with QD, and 17 S/S should be differentiated carefully. CONCLUSION: The results demonstrate that the TCM practitioners precisely diagnosed QD using a number of specific procedures and criteria that could be used as a reference to understand women complaining of S/S that could be similar to QD. PMID- 25286785 TI - Monozygotic twinning after in vitro fertilization/intracytoplasmic sperm injection treatment is not related to advanced maternal age, intracytoplasmic sperm injection, assisted hatching, or blastocyst transfer. AB - OBJECTIVE: To evaluate the effect of assisted reproductive techniques on the incidence of monozygotic twins (MZT) and the associated pregnancy outcomes. MATERIALS AND METHODS: This was a retrospective study of all in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles with MZT pregnancies in our center from January 2001 to December 2011. The diagnosis of MZT pregnancies with their respective placental configurations was based on the results of ultrasonographic examinations performed during either the first or second trimester. The treatment characteristics and outcomes of each IVF cycle were recorded and stored in a computer database. RESULTS: A total of 17 cycles with MZT pregnancies were identified, resulting in an overall incidence of MZT of 1.3%. The incidence of MZT for women aged <35 years and >=35 years were 1.5% and 0.8%, respectively (p = 0.319). The incidence was not significantly different between ICSI and non-ICSI cycles (1.4% vs. 1.0%; p = 0.620). In addition, the incidence was not increased in the assisted hatching (AH) group compared to those without AH (0.9% vs. 2.1%; p = 0.103). Finally, cycles with embryo transfer at the blastocyst stage had an MZT incidence that was not significantly different from those transferred at the cleavage stage (1.4% vs. 1.3%, respectively; p = 1.000). The incidence of each type of chorionicity, dichorionic-diamniotic, monochorionic-diamniotic, and monochorionic-monoamniotic, was 33.3%, 46.7%, and 20.0%, respectively. A total of 11 of 39 (28%) monozygotic babies and 16 of 19 (84%) coexisting heterozygotic babies were born alive. CONCLUSION: Until definite conclusions are drawn from larger trials, patients receiving IVF should not be overly concerned about the increase in MZT risk when proceeding to various assisted reproductive procedures (i.e., ICSI, AH, and blastocyst transfer). However, there is some evidence that the incidence of monochorionic-monoamniotic twins may be significantly increased after IVF/ICSI cycles. Patients should be informed about the possible obstetric complications regarding this rare type of MZT. PMID- 25286786 TI - Outcome of patients with bulky IB (>= 6 cm) cervical squamous cell carcinoma with and without cisplatin-based neoadjuvant chemotherapy. AB - OBJECTIVE: To study the surgical morbidity and outcomes of patients with markedly bulky cervical squamous cell carcinoma (>= 6 cm Cx-SCC) who underwent radical hysterectomy (RH) with and without neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: This retrospective study enrolled patients with International Federation of Gynecology and Obstetrics (FIGO) IB markedly bulky Cx-SCC who were treated with either three courses of weekly single agent cisplatin NACT (50 mg/m2) and subsequent radical hysterectomy (NACT-RH) or direct radical hysterectomy (RH) between 1996 and 2001. A total of 60 patients fulfilled the criteria, including 35 and 25 patients with NsACT-RH and RH, respectively. RESULTS: There was no statistically significant difference in basic characteristics between the two groups, except the smaller pathological tumor size, less blood loss, and lower immediate complication rate in the NACT-RH group. Median survival was 143.8 months in the NACT-RH group and 129.8 months in the RH group, respectively, without a statistically significant difference. Multivariate analysis showed that large pathological tumor size [hazard ratio (HR) 10.66, 95% confidence interval (CI) 2.93-38.80], the presence of para-aortic lymph node metastases and an immediate complication (HR 8.33 and 4.55, 95% CI 1.66-41.75 and 1.35-15.27, respectively) contributed to a worse outcome. CONCLUSION: Weekly single agent cisplatin NACT indeed reduced the pathological tumor size and immediate complication rate during the RH, supporting the feasibility of subsequent RH in the management of patients with bulky Cx-SCC. PMID- 25286787 TI - Factors that affect early recurrence after prolapse repair by a nonanchored vaginal mesh procedure. AB - OBJECTIVE: Prosima (Ethicon, Somerville, NJ, USA) is a novel procedure for treating pelvic organ prolapse (POP) that uses nonanchored vaginal mesh. However, nonfixation of the mesh may limit effectiveness. The aim of this study was to evaluate the safety, efficacy, and limitations of this procedure. MATERIALS AND METHODS: From January 2011 through to December 2011, 52 patients with symptomatic POP >= Stage 2 undergoing the Prosima procedure at a tertiary hospital were enrolled consecutively in this prospective study. A Data and Safety Monitoring Plan (DSMP) was developed to assess the results. RESULTS: Fifty of the 52 patients (96%) attended the 3-6-month postoperative assessment. Symptom and quality-of-life scores were found to have improved significantly after surgery (p < 0.05). Forty-two patients (84%) underwent successful treatment for POP (Stage 0 1). The other eight patients (16%) were found to have recurrent Stage 2 anterior vaginal wall prolapse, although most of them (5/8) were asymptomatic. The highest morbidity, namely vaginal mesh exposure, occurred in four patients (8%) and was managed as a minor issue. Statistical analysis showed that anatomic recurrence was significantly (p < 0.05) associated with a "preoperative Ba >= +4 cm" (odds ratio = 20.57), "conservation of the prolapsed uterus" (odds ratio = 10.56) and "use of a concomitant midurethral sling" (odds ratio = 0.076). CONCLUSION: Prosima seems to have limitations when used to manage severe anterior vaginal wall prolapse and concomitant surgery may further affect its effectiveness. The information obtained from this study's DSMP will contribute to developing a strategy to improve the use of nonanchored vaginal mesh for POP repair. PMID- 25286788 TI - Surgical outcome prediction in patients with advanced ovarian cancer using computed tomography scans and intraoperative findings. AB - OBJECTIVE: This study aimed to identify features on preoperative computed tomography (CT) scans that are predictive of suboptimal primary cytoreduction and to evaluate the correlation between CT findings and intraoperative findings in advanced ovarian cancer. MATERIALS AND METHODS: We retrospectively reviewed preoperative CT scans and operative findings from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction between 2003 and 2006. Fourteen criteria were assessed. Clinical data were extracted from medical records. Residual tumors measuring >=1 cm were considered suboptimal. RESULTS: We retrospectively identified 118 patients who met the study inclusion criteria. The rate of optimal cytoreduction (<=1 cm residual disease) was 40%. On preoperative CT scans, omental extension to the stomach or spleen and inguinal or pelvic lymph nodes >2 cm were predictors of suboptimal cytoreduction on univariate (p = 0.016 and p = 0.028, respectively) and multivariate analysis (p = 0.042 and p = 0.029, respectively). Involvement of both omental extension and inguinal or pelvic lymph nodes had a positive predictive value (PPV) of 100%, a specificity of 100%, and an accuracy of 45.8% in predicting suboptimal cytoreduction. We correlated the preoperative CT findings with the intraoperative findings. There were significant correlations between CT and intraoperative findings of omental extension (p = 0.007), inguinal or pelvic lymph nodes >2 cm (p < 0.001), and large bowel mesentery implants >2 cm (p = 0.001). CONCLUSION: The combination of omental extension to the stomach or spleen and involvement of inguinal or pelvic lymph nodes in preoperative CT scans is considered predictive of suboptimal cytoreduction. These patients may be more appropriately treated with neoadjuvant chemotherapy followed by surgical cytoreduction. PMID- 25286789 TI - Comparison of outcomes after vaginal reconstruction surgery between elderly and younger women. AB - OBJECTIVE: The objective of this study was to estimate the association of vaginal sacrospinous ligament fixation with anterior-transobturator mesh repair surgery for advanced pelvic organ prolapse in patients of two different age groups. MATERIALS AND METHODS: Vaginal sacrospinous ligament fixation with anterior mesh repair as primary prolapse surgery was performed on 225 patients with advanced pelvic organ prolapse (POP-Q >= stage III). POP-Q < stage II was objective cure and subjective cure was determined according to feedback of POPDI-6 (Questions 2 and 3). Patients provided responses to UDI-6, IIQ-7, POPDI-6, and PISQ-12 pre- and postsurgery. Outcome measures were observed in cohorts of two age groups (<75 years and >=75 years). RESULTS: Postoperative data of 217 patients were available. The cumulative objective cure rates were 93.0% and 92.5% for patients aged >=75 years and <75 years, respectively, with mean follow-up of 33.93 +/- 18.52 months and 36.44 +/- 19.34 months respectively. The UDI-6, IIQ-7, POPDI-6, and PISQ-12 scores within each of the two age groups improved significantly after surgery. Comparatively, the POPDI-6 score was better whereas the PISQ-12 score was poorer among patients aged >=75 years. Older women had significantly more preoperative comorbidities. The operative time, perioperative complications, and length of hospital stay showed no difference between the two groups. The intraoperative blood loss was significantly less in the older group and neither group had mortality. CONCLUSION: This study showed that adequately optimized older patients undergoing pelvic organ prolapse surgery experienced the same anatomical outcomes, comparable improved quality of life, morbidity, and mortality as their counterparts of younger age. PMID- 25286791 TI - Detection of endometrial and subendometrial vasculature on the day of embryo transfer and prediction of pregnancy during fresh in vitro fertilization cycles. AB - OBJECTIVES: Successful implantation depends on interaction between a blastocyst and a receptive endometrium. Endometrial vasculature is important in the early endometrial response to blastocyst implantation, and vascular changes can affect uterine receptivity. This study aims to investigate whether vascular parameters measured using three-dimensional power Doppler ultrasound (3D PD-US) could predict pregnancy following fresh in vitro fertilization and embryo transfer (IVF ET) using a gonadotropin releasing hormone (GnRH) agonist long protocol. MATERIALS AND METHODS: This prospective observational study enrolled 236 nulliparous women who underwent a first IVF-ET using a GnRH long protocol with stimulation by recombinant FSH (rFSH) from May 2009 to April 2012. After excluding two cases of tubal pregnancy, 234 women were in either a pregnant group (n = 113) or a nonpregnant group (n = 121). Color Doppler ultrasound and 3D PD-US examinations were performed on the day of embryo transfer. Main outcomes were pulsatility index (PI), resistance index (RI), systolic/diastolic ratio (S/D) of the uterine artery, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) of the endometrium and subendometrial region. Measurements were analyzed relative to IVF-ET outcome (pregnant vs. nonpregnant). RESULTS: No significant differences were observed in patient age, infertility duration, body mass index (BMI), basal FSH levels, number of retrieved oocytes or good quality embryos, or endometrial thickness or volume between the two groups. The pregnant group had higher endometrial VI, FI, and VFI scores than the nonpregnant group (p = 0.001, p = 0.000, p = 0.021, respectively). By contrast, neither subendometrial region VI, FI, and VFI scores (p = 0.770, p = 0.252, p = 0.451), nor uterine artery PI, RI, or S/D scores (p = 0.256, p = 0.527, p = 0.365) differed between groups. Cut-off values of endometrial VI, FI, and VFI scores were 0.95, 12.94, and 0.15 for pregnancy achievement. CONCLUSION: Three dimensional PD-US was a useful and effective method for assessing endometrial blood flow in IVF cycles. Good endometrial blood flow on the day of embryo transfer might be associated with high pregnancy success with a GnRH long protocol, because this is indicative of endometrial receptivity in fresh IVF cycles. PMID- 25286790 TI - Small cell neuroendocrine carcinoma of the endometrium: a clinicopathologic study of six cases. AB - OBJECTIVES: Primary small cell carcinoma of the endometrium is a rare disease that can only be diagnosed at an advanced stage, and thus has a poor prognosis. In this study, the clinicopathologic characteristics of endometrial small cell carcinoma are described and the survival outcomes are discussed. MATERIALS AND METHODS: The data from six patients from a single medical institution who were diagnosed with endometrial small cell carcinoma in the past 20 years were retrospectively reviewed. RESULTS: The median age of the six patients was 60 years. Vaginal bleeding was the most common symptom. All six patients underwent complete staging surgery, including hysterectomy, bilateral salpingoophorectomy, and systematic lymphadenectomy. Three of the patients were diagnosed with early stage disease, [International Federation of Gynecology and Obstetrics (FIGO) stage I or II], and the other three were in an advanced stage (FIGO stage III). Pathologically, deep myometrial invasion was observed in five (83.3%) of the patients, and lymphovascular invasion in six. As adjuvant therapy, four (66.7%) patients received platinum-based chemotherapy and one (16.7%) underwent concurrent chemoradiotherapy. During the median follow-up period of 16.2 months, recurrence developed in four patients (66.7%). There were disseminated recurrences on the peritoneum and lymph nodes in two cases, and distant metastasis to the brain in the other two cases. The median time to recurrence was 7.5 months (range, 315 months). One patient died of disease. CONCLUSION: Small cell carcinoma of the endometrium shows an aggressive clinical behavior, such as a disseminated disease and distant metastasis within a short time to recurrence. Initial active management with complete surgical resection and systemic chemotherapy might improve outcomes, although further large studies should be done to confirm this. PMID- 25286792 TI - Predictive factors related to the efficacy of pelvic arterial embolization for postpartum hemorrhage: a retrospective analysis of 21 cases. AB - OBJECTIVE: This retrospective study aimed to determine the predictive factors for the efficacy of pelvic arterial embolization for postpartum hemorrhage. MATERIALS AND METHODS: Twenty-one patients who underwent pelvic arterial embolization for postpartum hemorrhage of >1000 mL between September 2006 and September 2011 were enrolled in this study. The patients were divided into two subgroups according to the blood loss and time from the end of pelvic arterial embolization to complete hemostasis: good-response (16 patients) and poor-response groups (5 patients). The following predictive factors were compared between the groups: (1) patient characteristics; (2) blood loss; (3) time between delivery (or onset of bleeding) and pelvic arterial embolization; (4) obstetrical disseminated intravascular coagulation score comprising clinical background, clinical signs, and laboratory data; (5) individual disseminated intravascular coagulation score; (6) shock index; and (7) laboratory data including platelet count, prothrombin time international normalized ratio, fibrinogen, fibrin degradation products, and antithrombin-III at the time of pelvic arterial embolization. RESULTS: In the poor-response group, the obstetrical and individual disseminated intravascular coagulation scores and prothrombin time-international normalized ratio were higher than those in the good-response group (p < 0.05). Platelet count, fibrinogen, and fibrin degradation products were lower than those in the good response group (p < 0.05). All obstetrical disseminated intravascular coagulation scores in the poor-response group were >9 points. CONCLUSION: The efficacy of pelvic arterial embolization is related to the presence or absence of coagulation disorders. When the obstetrical disseminated intravascular coagulation score is high (>9 points), the efficacy may be poor. PMID- 25286793 TI - Comprehensive treatment for infertile women with severe Asherman syndrome. AB - OBJECTIVE: Many preoperative, intraoperative, and postoperative methods have been described that improve the outcomes of women with severe Asherman syndrome, and it is likely that an integrated application of all of these methods may provide better reproductive outcomes; however, there is as yet no report on this type of integrated approach. MATERIALS AND METHODS: The cases of four infertile women with severe Asherman syndrome were analyzed retrospectively. The comprehensive therapeutic plan for the four women included (1) preoperative office hysteroscopy to confirm the diagnosis and evaluate the severity of disease; (2) the use of ultrasound-guided intraoperative abdominal procedures during the surgical procedure, including hysteroscopic adhesiolysis to ensure the entire the hysteroscopic dissection, and placement of a Hyalobarrier((r)) gel and an intrauterine balloon catheter at the end of the surgery; (3) postoperative oral estrogen supplementation to enhance endometrial proliferation, removal of the balloon catheter, and a second-look office hysteroscopy; and (4) in vitro fertilization and embryo transfer (IVF & ET) for three of the four patients. RESULT: After treatment, the endometrium was significantly thicker than at baseline (median endometrial thickness, 7.5 mm versus 3.0 mm, p < 0.05). All the women (100%, 4/4) conceived successfully (three undergoing IVF & ET, and one had a spontaneous pregnancy), but only two patients had a term pregnancy with cesarean section (one placenta previa and the other placental abruption), contributing to 50% of successful term pregnancies. One patient had the complication of abortion after amniocentesis. The last one woman underwent an abortion because of thyroid problems. CONCLUSION: Comprehensive management offers promising reproductive outcomes for infertile women with severe Asherman syndrome. PMID- 25286794 TI - The risk of malignancy index (RMI) in women with adnexal masses in Wales. AB - OBJECTIVE: To evaluate the accuracy of the risk of malignancy index (RMI) which combines serum CA-125 levels, ultrasound score, and menopausal state, in discriminating between benign and malignant adnexal masses in the Welsh population. MATERIALS AND METHODS: Two hundred and forty-seven women with pelvic masses discussed consecutively at the South West Wales Gynaecological Oncology multidisciplinary meeting between January 2010 and June 2011 were included in this retrospective study. The main outcomes were surgical and pathological findings. RESULTS: The sensitivity and specificity of CA-125 at 35kU/L were 76% and 67%, respectively. CA-125 was found to be a relevant predictor of malignancy but the area under the receiver operating characteristic curve for each of the risk of malignancy indices was greater than the area for the CA-125 serum levels alone. Each of the RMIs has a different optimal threshold, however using a threshold of 200, RMI 1 had a sensitivity of 66% and a specificity of 91%; RMI 2 had a sensitivity of 74% and a specificity of 79%; and RMI 3 had a sensitivity of 68% and a specificity of 85%. CONCLUSION: This is the first study in Wales to evaluate the RMI in triaging women with pelvic masses. Overall, RMI 1 and RMI 2 are better malignancy predictors than RMI 3. It would be recommended that RMI 1 and RMI 2 be compared in a head-to-head prospective study, although we suspect that RMI 1 is likely to be the overall best malignancy predictor. PMID- 25286795 TI - Effectiveness of delayed absorbable monofilament suture in emergency cerclage. AB - OBJECTIVE: To determine the sustained effects of emergency cerclage using slowly absorbable monofilament sutures, changes in cervical length after cerclage were evaluated in six cases. MATERIALS AND METHODS: A delayed absorbable monofilament suture (1 PDS-Plus; Ethicon, Inc., Somerville, NJ, USA) has been used for emergency cerclage after 20 weeks of gestation at Juntendo University Hospital since January 2011. A retrospective chart review was conducted including all of the patients undergoing emergency cerclage between January 2011 and August 2013. The patients' characteristics, perinatal outcome, cervical length, and obstetric data were collected. RESULTS: Six cases were identified from our medical records. Their characteristics and perinatal outcomes are shown in Table 1. Of the six cases, four had an extremely short cervix, with an average cervical length of 7.85 +/- 3.38 mm, and two had prolapsed membranes. Fig. 1 shows the cervical length and the time elapsed after cerclage. There were no cases with shortening of the cervical length below the levels at the cerclage. CONCLUSION: This absorbable monofilament suture appears useful for emergency cerclage. PMID- 25286796 TI - Three-dimensional computed tomographic angiography in the diagnosis and conservative management of cesarean scar pregnancy with prominent neovascularization. AB - OBJECTIVE: Cesarean scar pregnancy (CSP) is a rare potentially life-threatening form of ectopic gestation. However, optimal management has not yet been established. Furthermore, there are limited reports on the diagnostic value of three-dimensional computed tomographic angiography (3D-CTA) for the conservative management of this disorder. CASE REPORT: A 33-year-old woman (gravida 3, para 2), with two previous deliveries by low segmental transverse cesarean section, was referred after 5 weeks of amenorrhea. Her serum beta-human chorionic gonadotropin (beta-hCG) value was 2921 mIU/mL. Cesarean scar pregnancy was diagnosed by ultrasonography and magnetic resonance imaging. On 3D-CTA, a prominent uteroplacental neovascularized mass was identified. It was supplied by the left uterine artery and a thick draining left ovarian vein. After three cycles of systemic methotrexate (MTX) administration, the serum beta-hCG value decreased to 142 mIU/mL. However, the gestational sac enlarged and peritrophoblastic blood flow persisted. In contrast to the ultrasonographic findings, marked reduction of uteroplacental neovascularization at the CSP site with regression of the draining ovarian vein was evident on 3D-CTA. The gestational products were thereafter successfully resected by hysteroscopic surgery without hemorrhagic complications. Fifty-seven days after the initial MTX administration, serum beta-hCG reached a normal level. CONCLUSION: This case emphasizes that, when selecting the method of intervention, 3D-CTA is potentially useful for evaluating uteroplacental neovascularization in a hemodynamically stable CSP. PMID- 25286797 TI - Ventral hernia with uterine rupture after vaginal delivery. AB - OBJECTIVE: Ventral hernia is uncommon during pregnancy and is extremely rare in postpartum women. It leads to a life-threatening emergency. CASE REPORT: A 33 year-old woman, gravida 2 para 1, was admitted to our institute with severe abdominal pain and overdistended abdomen immediately after a full-term vaginal delivery. She had a normal prenatal course and denied having any medical and surgical history. The primipara woman with no history of abdominal surgery was diagnosed with a ventral hernia with uterine rupture after vaginal delivery. We performed an emergency laparotomy and primary repair of the uterine rupture and abdominal wall defect. An abdominal binder was provided for the postoperative period. The patient's postoperative period was uncomplicated. She was discharged from the hospital after 12 days. CONCLUSION: If a patient has hernia-related symptoms or complications, the diagnosis and management of the hernia should be performed as soon as possible, regardless of the onset, to decrease maternal and fetal mortality. PMID- 25286798 TI - Iatrogenic parasitic myoma: a case report and review of the literature. AB - OBJECTIVE: To investigate the possible causes of iatrogenic parasitic myoma and methods to prevent its occurrence. CASE REPORT: A 27-year-old nulliparous unmarried patient underwent laparoscopic myomectomy with morcellation for a submucosal myoma at the National Taiwan University Hospital (Taipei, Taiwan). Seven years later, an asymptomatic pelvic tumor was noted during a regular annual follow up. Two pelvic tumors were detected and excised by laparoscopic surgery. The masses were confirmed by histopathology to be cellular leiomyomas. CONCLUSION: In the past 7 years, the incidence of iatrogenic parasitic myomas has increased because of the increased use of minimally invasive surgery using a morcellator. Forty-one cases of iatrogenic parasitic myoma were reviewed from 23 published studies. Parasitic myoma frequently occurs in the dependent part of the abdominal cavity, which suggests seeding of myometrial tissues during morcellation. In situ morcellation and vigorous irrigation with concomitant changes in position may decrease the incidence of retained myoma tissue in the abdomen during surgery. PMID- 25286799 TI - Term delivery of a complete hydatidiform mole with a coexisting living fetus followed by successful treatment of maternal metastatic gestational trophoblastic disease. AB - OBJECTIVE: A twin pregnancy consisting of a complete hydatidiform mole with a coexisting normal fetus is extremely rare with an incidence of 1/22,000 to 1/100,000. The incidence of preterm delivery is high and few pregnancies reach near term with a viable fetus. CASE REPORT: A 34-year-old woman presented at 20 weeks of gestation with increased levels of serum beta human chorionic gonadotropin (beta-HCG) at 4.74 multiples of the median (310277.7 mIU/mL). Ultrasonography showed a hydatidiform mole together with a normal fetus. Fetal karyotyping revealed 46XY. The serum beta-HCG levels were followed up throughout the remainder of the pregnancy. A male infant weighting 2260 g and the molar tissue were delivered at 37 weeks of gestation. The karyotype of the molar tissue showed 46XX and the histopathological report confirmed our diagnosis. At 4 months postpartum, metastatic gestational trophoblastic disease of the lung was diagnosed in the mother by a computed tomography scan due to increased beta-HCG levels. The patient received three unsuccessful cycles of methotrexate and folinate. Another four cycles of chemotherapy consisting of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA-CO) were initiated and the beta-HCG levels returned to normal. There was no evidence of recurrence in the subsequent 5 years of regular follow up. CONCLUSION: A pregnancy with a complete hydatidiform mole and a living cotwin can be a serious threat to the health of both the mother and the fetus. Early diagnosis depends on a combination of detecting an unusually high level of serum beta-HCG and ultrasound examination. We suggest that continuation of the pregnancy may be an acceptable option and that the pregnancy may continue until term if a normal fetal anatomy is assured and maternal complications are under control. Patients require careful postpartum follow up and any recurrent disease should be managed aggressively. PMID- 25286800 TI - Rupturing heterotopic pregnancy mimicking acute appendicitis. PMID- 25286801 TI - Prenatal diagnosis of Pallister Killian Syndrome in a fetus with congenital diaphragmatic hernia, short limbs, and increased nuchal translucency. PMID- 25286802 TI - Prenatal diagnosis of complete ring chromosome 22 without phenotypical abnormalities. PMID- 25286803 TI - Primary primitive neuroectodermal tumor of the ovary. PMID- 25286804 TI - Primary pure large cell neuroendocrine carcinoma of the ovary. PMID- 25286805 TI - Single-incision mesh repair for the treatment of neovaginal prolapse. PMID- 25286806 TI - Autoimmune progesterone dermatitis. PMID- 25286807 TI - Embryonal rhabdomyosarcoma of the uterine cervix in a pregnant woman. PMID- 25286808 TI - A rare case of endometriosis in Turner's syndrome. PMID- 25286809 TI - Left ventricular assist device for stress-induced cardiomyopathy after postpartum hemorrhage. PMID- 25286810 TI - Cavernous lymphangioma of fetal thigh. PMID- 25286812 TI - MBL and MASP-2 concentrations in serum and MBL2 promoter polymorphisms are associated to schizophrenia. PMID- 25286811 TI - Overview of fetal growth retardation/restriction. PMID- 25286813 TI - Effect of chronic variable stress on corticosterone levels and hippocampal extracellular 5-HT in rats with persistent differences in positive affectivity. PMID- 25286814 TI - Corticolimbic changes in acetylcholine and cyclic guanosine monophosphate in the Flinders Sensitive Line rat: a genetic model of depression. PMID- 25286815 TI - Safety and efficacy of electroconvulsive therapy for depression following cerebrovascular accident. PMID- 25286816 TI - Memory deficits and depression in patients with chronic epilepsy. PMID- 25286817 TI - Rorschach assessment of personality functioning in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. PMID- 25286818 TI - A false positive for clozapine using high-pressure liquid chromatography with ultraviolet detection. PMID- 25286819 TI - Sinus node dysfunction due to psychotropic agents' combination. PMID- 25286820 TI - Wild barley introgression lines revealed novel QTL alleles for root and related shoot traits in the cultivated barley (Hordeum vulgare L.). AB - BACKGROUND: Root is the prime organ that sucks water and nutrients from deep layer of soil. Wild barley diversity exhibits remarkable variation in root system architecture that seems crucial in its adaptation to abiotic stresses like drought. In the present study, we performed quantitative trait locus (QTL) mapping of root and related shoot traits under control and drought conditions using a population of wild barley introgression lines (ILs). This population (S42IL) comprising of genome-wide introgressions of wild barley accession ISR42-8 in the cultivar Scarlett background. Here, we aimed to detect novel QTL alleles for improved root and related shoot features and to introduce them in modern cultivars. RESULTS: The cultivar Scarlett and wild barley accession ISR42-8 revealed significant variation of root and related shoot traits. ISR42-8 showed a higher performance in root system attributes like root dry weight (RDW), root volume (RV), root length (RL) and tiller number per plant (TIL) than Scarlett. Whereas, Scarlett exhibited erect type growth habit (GH) as compared to spreading growth habit in ISR42-8. The S42IL population revealed significant and wide range of variation for the investigated traits. Strong positive correlations were found among the root related traits whereas GH revealed negative correlation with root and shoot traits. The trait-wise comparison of phenotypic data with the ILs genetic map revealed six, eight, five, five and four QTL for RL, RDW, RV, TIL and GH, respectively. These QTL were linked to one or several traits simultaneously and localized to 15 regions across all chromosomes. Among these, beneficial QTL alleles of wild origin for RL, RDW, RV, TIL and GH, have been fixed in the cultivar Scarlett background. CONCLUSIONS: The present study revealed 15 chromosomal regions where the exotic QTL alleles showed improvement for root and related shoot traits. These data suggest that wild barley accession ISR42-8 bears alleles different from those of Scarlett. Hence, the utility of genome-wide wild barley introgression lines is desirable to test the performance of individual exotic alleles in the elite gene pool as well as to transfer them in the cultivated germplasm. PMID- 25286821 TI - Long case or case vignettes: a comparison of two instructional methods in inpatient geriatrics for medical students. AB - The varied, atypical manifestations of geriatric syndromes make knowledge transfer the ability to extend knowledge from one context to another a particularly relevant concept. The authors hypothesized that multiple, contrasting short cases, by facilitating knowledge transfer, would improve knowledge more than a single long case in geriatric medicine. The authors' objective was to assess the impact of two instructional methods (a single long case vs. contrasting short cases) on knowledge and knowledge retention among 3rd year medical students on their Internal Medicine-Geriatrics Clerkship. They participated in the curriculum which consisted of four weekly mandatory sessions covering five content areas based on a systematic needs assessment. Instructional method alternated by month. Knowledge and knowledge retention were measured using an online multiple-choice question test administered before, immediately after, and one year following the curriculum. Students also completed a demographic survey prior to the curriculum and an evaluation of the curriculum following the curriculum. There was significant improvement in test scores from pre- to postcurriculum in both groups that persisted one year after the experience with no significant differences between the two groups. The two case-based instructional methods resulted in significant and enduring knowledge improvement, but one method was not better than the other. PMID- 25286822 TI - Nerve growth factor and proNGF simultaneously promote symmetric self-renewal, quiescence, and epithelial to mesenchymal transition to enlarge the breast cancer stem cell compartment. AB - The discovery of cancer stem cells (CSCs) fundamentally advanced our understanding of the mechanisms governing breast cancer development. However, the stimuli that control breast CSC self-renewal and differentiation have still not been fully detailed. We previously showed that nerve growth factor (NGF) and its precursor proNGF can stimulate breast cancer cell growth and invasion in an autocrine manner. In this study, we investigated the effects of NGF and proNGF on the breast CSC compartment and found that NGF or proNGF enrich for CSCs in several breast cancer cell lines. This enrichment appeared to be achieved by increasing the number of symmetric divisions of quiescent/slow-proliferating CSCs. Interestingly, in vitro NGF pretreatment of MCF-7 luminal breast cancer cells promoted epithelial to mesenchymal transition in tumors of severe combined immunodeficient mice. Furthermore, p75(NTR), the common receptor for both neurotrophins and proneurotrophins, mediated breast CSC self-renewal by regulating the expression of pluripotency transcription factors. Our data indicate, for the first time, that the NGF/proNGF/p75(NTR) axis plays a critical role in regulating breast CSC self-renewal and plasticity. PMID- 25286823 TI - Serum anti-Mullerian hormone levels across different ethnic groups: a cross sectional study. AB - OBJECTIVE: To assess whether ethnic differences in serum anti-Mullerian hormone (AMH) exist in a population of subfertile women presenting to a fertility clinic. DESIGN: Observational cross-sectional study. SETTING: Homerton University Hospital Fertility Centre, London, UK. POPULATION: A total of 865 women attending the fertility clinic for their first consultation appointment between September 2012 and September 2013. METHODS: Serum AMH was compared amongst women from five different ethnic groups. MAIN OUTCOME MEASURES: Serum AMH and ethnicity were the primary outcome variables. RESULTS: Although initial comparison showed South Asian women to have a higher serum AMH, compared with white European and Afro Caribbean women (F = 3.817; P < 0.005), South Asian women attending the clinic were significantly younger and less likely to be smokers than women from other ethnic groups. The prevalence of polycystic ovary syndrome (PCOS) was significantly higher in South Asian and South East Asian women than in other ethnic groups. Differences in serum AMH were no longer significant after controlling for confounding factors: age, body mass index (BMI), and smoking status with (P = 0.869) and without (P = 0.215) controlling for PCOS. CONCLUSION: The results from our study show that there was no independent association of ethnicity and serum AMH levels in an unselected population of women attending the fertility clinic. PMID- 25286824 TI - Effects of iRoot BP and white mineral trioxide aggregate on cell viability and the expression of genes associated with mineralization. AB - AIM: To evaluate the cytotoxicity and mineralization effects of iRoot BP in human dental pulp cells (hDPCs) and to compare them with those of white mineral trioxide aggregate (WMTA). METHODOLOGY: hDPCs were exposed to prepared dilutions (1 : 1-1 : 10) of the test materials. Cell viability was evaluated using the XTT assay after incubation periods of 24, 48 or 72 h. The expression of mineralization-related genes (bone morphogenic protein, osteonectin, bone sialoprotein, osteopontin, dentine sialophosphoprotein and collagen type 1) and heme oxygenase 1 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) at 24 and 72 h. Statistical differences between test materials were analysed with the Mann-Whitney test. RESULTS: The 1 : 1 and 1 : 2 dilutions of iRoot BP were associated with higher cell viability after 24 h (P < 0.05). Only the 1 : 1 dilution of iRoot BP had higher cell viability after 48 h (P < 0.05), and there was no difference between iRoot BP and WMTA after 72 h (P > 0.05). Although somewhat variable, according to the gene expression results, iRoot BP had a mineralization potential similar to that of WMTA. WMTA revealed a higher heme oxygenase 1 (HO-1) mRNA level than iRoot BP (P < 0.001). CONCLUSIONS: iRoot BP and WMTA were biocompatible and facilitated odontoblastic differentiation of hDPCs. PMID- 25286825 TI - An unusual cause of growth failure in cystic fibrosis: A salutary reminder of the interaction between glucocorticoids and cytochrome P450 inhibiting medication. AB - A 12 1/2 year old male with cystic fibrosis presented with growth failure after itraconazole was added to a treatment regimen including inhaled and intranasal glucocorticoids. Investigations showed severe adrenal suppression. This case demonstrates the potential for exogenous glucocorticoids to accumulate when their degradation is inhibited by a CYP3A4 inhibitor. PMID- 25286826 TI - Protease-antiprotease imbalances differ between Cystic Fibrosis patients' upper and lower airway secretions. AB - BACKGROUND: Balanced levels of proteases and anti-proteases are essential in host defense systems. In CF patients' lungs, elevated protease/anti-protease-ratios contribute to damage of airway tissue and premature death with the inherited disease. Little is known about upper airway protease equilibrium in CF. METHODS: Neutrophil elastase (NE), Secretory leukocyte protease inhibitor (SLPI), matrix metalloproteinase (MMP)9, tissue inhibitors of metalloproteinase (TIMP)1, cathepsin S (CTSS) and the corresponding cellular distribution were assessed in the nasal lavage (NL) and sputum of 40 CF patients. RESULTS: Concentrations of all proteases and anti-proteases were markedly higher in sputum than in NL (NE: 10-fold, SLPI: 5000-fold). Interestingly, the NE/SLPI ratio was 726-fold higher in NL compared to sputum, while the MMP9/TIMP1 ratio was 4.5-fold higher in sputum compared to NL. DISCUSSION: This first study to compare protease/anti protease networks of CF upper and lower airways by NL and sputum reveals substantial differences between both compartments' immunological responses. This finding may have implications for sinonasal and pulmonary treatment, possibly leading to new therapeutic approaches. PMID- 25286827 TI - Development of novel treatment with a bioabsorbable esophageal patch for benign esophageal stricture. AB - Using a large animal model, we examined whether circumferential stricture after esophageal endoscopic submucosal dissection (ESD) can be treated by grafting a bioabsorbable esophageal patch. Circumferential ESD was performed on the thoracic esophagus in pigs (n = 6) to create a stricture, for which one of the following interventions was performed: (1) the stricture site was longitudinally incised, and an artificial esophageal wall (AEW) was grafted after placing a bioabsorbable stent (AEW patch group, n = 3); (2) endoscopic balloon dilation (EBD) was performed every other week after stricture development (EBD group, n = 3). In both groups, esophageal fluoroscopy was performed 8 weeks after the interventions, and the esophagus was excised for histological examination of the patched site. In the AEW patch group, esophageal fluoroscopy revealed favorable passage through the patched site. Histologically, the mucosal epithelium and lamina propria had regenerated as in the normal area. In the EBD group, the circumferential stricture site showed marked thickening, and there were hypertrophic scars associated with epithelial defects on the luminal surface. Histologically, defects of the mucosal epithelium and full-thickness proliferation of connective tissue were observed. AEW patch grafting was suggested to be a potentially novel treatment strategy for post-ESD esophageal circumferential stricture. PMID- 25286828 TI - Combination of lithium chloride and pEGFP-N1-BmK CT effectively decreases proliferation and migration of C6 glioma cells. AB - Deleterious invasiveness of glioma cells into the normal brain tissue is endorsed by its inherent ability to regulate the receptor-mediated adhesive properties, extracellular matrix degradation and remodeling and elevated secretory ability of metalloproteinase (MMPs) such as MMP-2. By doing so, it will create an intercellular space for the invasion of glioma cells. Here, we reported that combination of gene therapy Buthus martensii Karsch (BmK) CT, a type of scorpion toxin peptide, with lithium chloride (LiCl), clinically used as mood stabilizer, could inhibit the migration and invasion of C6 glioma cells. The results showed that concomitant administration of LiCl and pEGFP-N1-BmK CT on glioma cells would hamper pro-MMP2 secretion and in the meantime, inhibited its proliferation in a synergistic manner. These results try to extrapolate the potential interplay between the combined treatment of LiCl and BmK CT with signaling pathways beta catenin, MMP, GSK-3 in C6 glioma cells. This strategy can stand for a novel approach designated for the development of a new method for glioma therapy. PMID- 25286829 TI - Monitoring of cerebral oxygen saturation during resuscitation in out-of-hospital cardiac arrest: a feasibility study in a physician staffed emergency medical system. AB - BACKGROUND: Despite recent advances in resuscitation algorithms, neurological injury after cardiac arrest due to cerebral ischemia and reperfusion is one of the reasons for poor neurological outcome. There is currently no adequate means of measuring cerebral perfusion during cardiac arrest. It was the aim of this study to investigate the feasibility of measuring near infrared spectroscopy (NIRS) as a potential surrogate parameter for cerebral perfusion in patients with out-of-hospital resuscitations in a physician-staffed emergency medical service. METHODS: An emergency physician responding to out-of-hospital emergencies was equipped with a NONIN cerebral oximetry device. Cerebral oximetry values (rSO2) were continuously recorded during resuscitation and transport. Feasibility was defined as >80% of total achieved recording time in relation to intended recording time. RESULTS: 10 patients were prospectively enrolled. In 89.8% of total recording time, rSO2 values could be recorded (213 minutes and 20 seconds), thus meeting feasibility criteria. 3 patients experienced return of spontaneous circulation (ROSC). rSO2 during manual cardiopulmonary resuscitation (CPR) was lower in patients who did not experience ROSC compared to the 3 patients with ROSC (31.6%, +/- 7.4 versus 37.2% +/- 17.0). ROSC was associated with an increase in rSO2. Decrease of rSO2 indicated occurrence of re-arrest in 2 patients. In 2 patients a mechanical chest compression device was used. rSO2 values during mechanical compression were increased by 12.7% and 19.1% compared to manual compression. CONCLUSIONS: NIRS monitoring is feasible during resuscitation of patients with out-of-hospital cardiac arrest and can be a useful tool during resuscitation, leading to an earlier detection of ROSC and re-arrest. Higher initial rSO2 values during CPR seem to be associated with the occurrence of ROSC. The use of mechanical chest compression devices might result in higher rSO2. These findings need to be confirmed by larger studies. PMID- 25286830 TI - Cranial nerve and cervical root enhancement in an infant with polymerase gamma mutation mitochondrial disease. AB - BACKGROUND: Nuclear polymerase gamma (POLG) mutations are the most common cause of inherited mitochondrial disease. POLG mutation diseases have a broad spectrum of clinical manifestations; the lethal infantile form is myocerebrohepatopathy spectrum. PATIENT: A 4-month-old boy was referred for poor feeding, emesis, failure to thrive, and hypotonia. RESULTS: Brain computed tomography was normal. Brain magnetic resonance imaging with and without contrast demonstrated bilateral enhancement of cranial nerves III, V-X, and the upper and midcervical nerve roots. Liver biopsy revealed early cirrhosis, steatosis, and focal necrosis. Muscle biopsy did not demonstrate specific abnormalities of mitochondrial morphology or number. Electron transport chain analysis of both fibroblasts and muscle demonstrated deficiencies. Because of suspected mitochondrial depletion disorder, testing was performed for mitochondrial abnormalities including analysis of the POLG gene, which revealed two pathogenic mutations, c.1399G>A (p.A467T) and c.3285C>G (p.S1095R). CONCLUSIONS: We report abnormal gadolinium enhancement of multiple cranial nerves and cervical nerve roots in an infant with myocerebrohepatopathy spectrum disease whose brain MRI otherwise revealed only mild atrophy. Mitochondrial disease should be included in the differential diagnosis of cranial nerve enhancement. Contrast-enhanced MRI aids in the diagnostic evaluation of infants with developmental delay and suspected neurological disease. PMID- 25286831 TI - A vermiculate tongue. PMID- 25286832 TI - A multi-institution pooled analysis of gastrostomy tube dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated radiotherapy. AB - BACKGROUND: Severe swallowing dysfunction necessitating enteral support is a well known late sequela of nonsurgical therapy for oropharyngeal cancer, but its incidence after intensity-modulated radiotherapy has not been quantified comprehensively outside of small single-institution series. METHODS: This was a multi-institution, institutional review board-approved, retrospective study. Consecutive patients with oropharyngeal squamous cell carcinoma who had received definitive intensity-modulated radiotherapy from 1998 to 2011 were identified from 3 academic centers. RESULTS: In total, 2315 patients were included. The American Joint Committee on Cancer staging distribution was as follows: stage I, 2.1%; stage II, 4.4%; stage III, 14.7%; and stage IV, 77.3%. Among 1459 patients (63%) who received a gastrostomy tube (g-tube), placement was prophylactic in 52% and reactive in 48%. Among patients with stage III and IV disease, 58% received concurrent chemotherapy. The median follow-up was 43.7 months (range, 0.1-164 months). The g-tube dependence rate was 7% at 1 year and 3.7% at 2 years. Among 1238 patients with stage III and IV disease who received concurrent chemotherapy, the 1-year and 2-year rates of g-tube dependence were 8.6% and 4.4%, respectively. The 1-year g-tube dependence rate was 5% for patients with stage I and II disease; 5.2% for patients with stage III and IV, T1-T2/N0-N2 disease; and 10.1% for patients with stage III and IV, T3-T4 or N3 disease. On multivariate analysis, advanced age (odds ratio [OR], 1.066; P<.001), greater number of smoking pack-years (OR, 1.008; P=.04), advanced N-category (OR, 1.13; P=.049), and receipt of cytotoxic chemotherapy (OR, 2.26; P=.02) were predictive of g-tube dependence at 1 year. CONCLUSIONS: This multi-institution series of 2315 patients treated at 3 institutions demonstrates that modern nonsurgical therapy for oropharyngeal cancer is associated with a low rate of long-term g-tube dependence. PMID- 25286834 TI - The enhanced photothermal effect of graphene/conjugated polymer composites: photoinduced energy transfer and applications in photocontrolled switches. AB - Composites prepared by grafting poly(3-hexylthiophene) (P3HT) onto the surfaces of reduced graphene oxide (RGO) (RGO-g-P3HT) exhibit an enhanced photothermal effect due to photoinduced energy transfer from P3HT to RGO. A remote photo controlled electrical switch was prepared using RGO-g-P3HT as a photothermal layer. PMID- 25286833 TI - Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China. AB - BACKGROUND: Mandibuloacral dysplasia type A (MADA) is a rare autosomal recessive disorder, characterized by growth retardation, skeletal abnormality with progressive osteolysis of the distal phalanges and clavicles, craniofacial anomalies with mandibular hypoplasia, lipodystrophy and mottled cutaneous pigmentation. Some patients may show progeroid features. MADA with partial lipodystrophy, more marked acral, can be caused by homozygous or compound heterozygous mutation in the gene encoding lamin A and lamin C (LMNA). MADA and Hutchinson-Gilford progeria syndrome are caused by the same gene and may represent a single disorder with varying degrees of severity. MAD patients characterized by generalized lipodystrophy (type B) affecting the face as well as extremities and severe progressive glomerulopathy present heterozygous compound mutations in the ZMPSTE24 gene. CASES PRESENTATIONS: We described a rare pedigree from Southern China, among them all three children presented with phenotypes of MADA associated progeria. The two elder sisters had developed severe mandibular hypoplasia associated progeria since the age of 1 year. The eldest sister showed a progressive osteolysis. The youngest son of 10 months showed severer lesions than those of his sisters at the same age, and presented possible muscle damage, and his symptoms progressed gradually. Three genes mutations including LMNA, ZMPSTE24 and BANF1 were tested in the family. LMNA gene sequencing revealed a homozygous missense mutation, c.1579C > T, p.R527C for all three siblings, and heterozygous mutations for their parents, whereas no mutations of ZMPSTE24 and BANF1 genes was detected among them. CONCLUSIONS: The same homozygous mutation of c.1579C > T of LMNA gene led to MADA associated progeria for the present family. The course of osteolysis for MADA is progressive. PMID- 25286835 TI - Archiving raw crystallographic data. AB - This article describes some of the activities of the IUCr Diffraction Data Deposition Working Group and introduces a collection of articles discussing the archiving of diffraction images. PMID- 25286836 TI - Experiences with making diffraction image data available: what metadata do we need to archive? AB - Recently, the IUCr (International Union of Crystallography) initiated the formation of a Diffraction Data Deposition Working Group with the aim of developing standards for the representation of raw diffraction data associated with the publication of structural papers. Archiving of raw data serves several goals: to improve the record of science, to verify the reproducibility and to allow detailed checks of scientific data, safeguarding against fraud and to allow reanalysis with future improved techniques. A means of studying this issue is to submit exemplar publications with associated raw data and metadata. In a recent study of the binding of cisplatin and carboplatin to histidine in lysozyme crystals under several conditions, the possible effects of the equipment and X ray diffraction data-processing software on the occupancies and B factors of the bound Pt compounds were compared. Initially, 35.3 GB of data were transferred from Manchester to Utrecht to be processed with EVAL. A detailed description and discussion of the availability of metadata was published in a paper that was linked to a local raw data archive at Utrecht University and also mirrored at the TARDIS raw diffraction data archive in Australia. By making these raw diffraction data sets available with the article, it is possible for the diffraction community to make their own evaluation. This led to one of the authors of XDS (K. Diederichs) to re-integrate the data from crystals that supposedly solely contained bound carboplatin, resulting in the analysis of partially occupied chlorine anomalous electron densities near the Pt-binding sites and the use of several criteria to more carefully assess the diffraction resolution limit. General arguments for archiving raw data, the possibilities of doing so and the requirement of resources are discussed. The problems associated with a partially unknown experimental setup, which preferably should be available as metadata, is discussed. Current thoughts on data compression are summarized, which could be a solution especially for pixel-device data sets with fine slicing that may otherwise present an unmanageable amount of data. PMID- 25286837 TI - Operation of the Australian Store.Synchrotron for macromolecular crystallography. AB - The Store.Synchrotron service, a fully functional, cloud computing-based solution to raw X-ray data archiving and dissemination at the Australian Synchrotron, is described. The service automatically receives and archives raw diffraction data, related metadata and preliminary results of automated data-processing workflows. Data are able to be shared with collaborators and opened to the public. In the nine months since its deployment in August 2013, the service has handled over 22.4 TB of raw data (~1.7 million diffraction images). Several real examples from the Australian crystallographic community are described that illustrate the advantages of the approach, which include real-time online data access and fully redundant, secure storage. Discoveries in biological sciences increasingly require multidisciplinary approaches. With this in mind, Store.Synchrotron has been developed as a component within a greater service that can combine data from other instruments at the Australian Synchrotron, as well as instruments at the Australian neutron source ANSTO. It is therefore envisaged that this will serve as a model implementation of raw data archiving and dissemination within the structural biology research community. PMID- 25286838 TI - How to make deposition of images a reality. AB - The IUCr Diffraction Data Deposition Working Group is investigating the rationale and policies for routine deposition of diffraction images (and other primary experimental data sets). An information-management framework is described that should inform policy directions, and some of the technical and other issues that need to be addressed in an effort to achieve such a goal are analysed. In the near future, routine data deposition could be encouraged at one of the growing number of institutional repositories that accept data sets or at a generic data publishing web repository service. To realise all of the potential benefits of depositing diffraction data, specialized archives would be preferable. Funding such an initiative will be challenging. PMID- 25286839 TI - Continuous mutual improvement of macromolecular structure models in the PDB and of X-ray crystallographic software: the dual role of deposited experimental data. AB - Accurate crystal structures of macromolecules are of high importance in the biological and biomedical fields. Models of crystal structures in the Protein Data Bank (PDB) are in general of very high quality as deposited. However, methods for obtaining the best model of a macromolecular structure from a given set of experimental X-ray data continue to progress at a rapid pace, making it possible to improve most PDB entries after their deposition by re-analyzing the original deposited data with more recent software. This possibility represents a very significant departure from the situation that prevailed when the PDB was created, when it was envisioned as a cumulative repository of static contents. A radical paradigm shift for the PDB is therefore proposed, away from the static archive model towards a much more dynamic body of continuously improving results in symbiosis with continuously improving methods and software. These simultaneous improvements in methods and final results are made possible by the current deposition of processed crystallographic data (structure-factor amplitudes) and will be supported further by the deposition of raw data (diffraction images). It is argued that it is both desirable and feasible to carry out small-scale and large-scale efforts to make this paradigm shift a reality. Small-scale efforts would focus on optimizing structures that are of interest to specific investigators. Large-scale efforts would undertake a systematic re-optimization of all of the structures in the PDB, or alternatively the redetermination of groups of structures that are either related to or focused on specific questions. All of the resulting structures should be made generally available, along with the precursor entries, with various views of the structures being made available depending on the types of questions that users are interested in answering. PMID- 25286840 TI - Multi-crystal native SAD analysis at 6 keV. AB - Anomalous diffraction signals from typical native macromolecules are very weak, frustrating their use in de novo structure determination. Here, native SAD procedures are described to enhance signal to noise in anomalous diffraction by using multiple crystals in combination with synchrotron X-rays at 6 keV. Increased anomalous signals were obtained at 6 keV compared with 7 keV X-ray energy, which was used for previous native SAD analyses. A feasibility test of multi-crystal-based native SAD phasing was performed at 3.2 A resolution for a known tyrosine protein kinase domain, and real-life applications were made to two novel membrane proteins at about 3.0 A resolution. The three applications collectively serve to validate the robust feasibility of native SAD phasing at lower energy. PMID- 25286841 TI - The structure of allophycocyanin B from Synechocystis PCC 6803 reveals the structural basis for the extreme redshift of the terminal emitter in phycobilisomes. AB - Allophycocyanin B (AP-B) is one of the two terminal emitters in phycobilisomes, the unique light-harvesting complexes of cyanobacteria and red algae. Its low excitation-energy level and the correspondingly redshifted absorption and fluorescence emission play an important role in funnelling excitation energy from the hundreds of chromophores of the extramembraneous phycobilisome to the reaction centres within the photosynthetic membrane. In the absence of crystal structures of these low-abundance terminal emitters, the molecular basis for the extreme redshift and directional energy transfer is largely unknown. Here, the crystal structure of trimeric AP-B [(ApcD/ApcB)3] from Synechocystis sp. PCC 6803 at 1.75 A resolution is reported. In the crystal lattice, eight trimers of AP-B form a porous, spherical, 48-subunit assembly of 193 A in diameter with an internal cavity of 1.1 * 10(6) A(3). While the overall structure of trimeric AP-B is similar to those reported for many other phycobiliprotein trimers, the chromophore pocket of the alpha-subunit, ApcD, has more bulky residues that tightly pack the phycocyanobilin (PCB). Ring D of the chromophores is further stabilized by close interactions with ApcB from the adjacent monomer. The combined contributions from both subunits render the conjugated rings B, C and D of the PCB in ApcD almost perfectly coplanar. Together with mutagenesis data, it is proposed that the enhanced planarity effectively extends the conjugation system of PCB and leads to the redshifted absorption (lambdamax = 669 nm) and fluorescence emission (679 nm) of the ApcD chromophore in AP-B, thereby enabling highly efficient energy transfer from the phycobilisome core to the reaction centres. PMID- 25286843 TI - A new family of beta-helix proteins with similarities to the polysaccharide lyases. AB - Microorganisms that degrade biomass produce diverse assortments of carbohydrate active enzymes and binding modules. Despite tremendous advances in the genomic sequencing of these organisms, many genes do not have an ascribed function owing to low sequence identity to genes that have been annotated. Consequently, biochemical and structural characterization of genes with unknown function is required to complement the rapidly growing pool of genomic sequencing data. A protein with previously unknown function (Cthe_2159) was recently isolated in a genome-wide screen using phage display to identify cellulose-binding protein domains from the biomass-degrading bacterium Clostridium thermocellum. Here, the crystal structure of Cthe_2159 is presented and it is shown that it is a unique right-handed parallel beta-helix protein. Despite very low sequence identity to known beta-helix or carbohydrate-active proteins, Cthe_2159 displays structural features that are very similar to those of polysaccharide lyase (PL) families 1, 3, 6 and 9. Cthe_2159 is conserved across bacteria and some archaea and is a member of the domain of unknown function family DUF4353. This suggests that Cthe_2159 is the first representative of a previously unknown family of cellulose and/or acid-sugar binding beta-helix proteins that share structural similarities with PLs. Importantly, these results demonstrate how functional annotation by biochemical and structural analysis remains a critical tool in the characterization of new gene products. PMID- 25286842 TI - Solving the RNA polymerase I structural puzzle. AB - Knowing the structure of multi-subunit complexes is critical to understand basic cellular functions. However, when crystals of these complexes can be obtained they rarely diffract beyond 3 A resolution, which complicates X-ray structure determination and refinement. The crystal structure of RNA polymerase I, an essential cellular machine that synthesizes the precursor of ribosomal RNA in the nucleolus of eukaryotic cells, has recently been solved. Here, the crucial steps that were undertaken to build the atomic model of this multi-subunit enzyme are reported, emphasizing how simple crystallographic experiments can be used to extract relevant biological information. In particular, this report discusses the combination of poor molecular replacement and experimental phases, the application of multi-crystal averaging and the use of anomalous scatterers as sequence markers to guide tracing and to locate the active site. The methods outlined here will likely serve as a reference for future structural determination of large complexes at low resolution. PMID- 25286844 TI - Metrics for comparison of crystallographic maps. AB - Numerical comparison of crystallographic contour maps is used extensively in structure solution and model refinement, analysis and validation. However, traditional metrics such as the map correlation coefficient (map CC, real-space CC or RSCC) sometimes contradict the results of visual assessment of the corresponding maps. This article explains such apparent contradictions and suggests new metrics and tools to compare crystallographic contour maps. The key to the new methods is rank scaling of the Fourier syntheses. The new metrics are complementary to the usual map CC and can be more helpful in map comparison, in particular when only some of their aspects, such as regions of high density, are of interest. PMID- 25286845 TI - The structure of a tetrameric alpha-carbonic anhydrase from Thermovibrio ammonificans reveals a core formed around intermolecular disulfides that contribute to its thermostability. AB - Carbonic anhydrase enzymes catalyse the reversible hydration of carbon dioxide to bicarbonate. A thermophilic Thermovibrio ammonificans alpha-carbonic anhydrase (TaCA) has been expressed in Escherichia coli and structurally and biochemically characterized. The crystal structure of TaCA has been determined in its native form and in two complexes with bound inhibitors. The tetrameric enzyme is stabilized by a unique core in the centre of the molecule formed by two intersubunit disulfides and a single lysine residue from each monomer that is involved in intersubunit ionic interactions. The structure of this core protects the intersubunit disulfides from reduction, whereas the conserved intrasubunit disulfides are not formed in the reducing environment of the E. coli host cytosol. When oxidized to mimic the environment of the periplasmic space, TaCA has increased thermostability, retaining 90% activity after incubation at 70 degrees C for 1 h, making it a good candidate for industrial carbon-dioxide capture. The reduction of all TaCA cysteines resulted in dissociation of the tetrameric molecule into monomers with lower activity and reduced thermostability. Unlike other characterized alpha-carbonic anhydrases, TaCA does not display esterase activity towards p-nitrophenyl acetate, which appears to result from the increased rigidity of its protein scaffold. PMID- 25286846 TI - Crystal structure and functional implications of LprF from Mycobacterium tuberculosis and M. bovis. AB - The Gram-positive bacteria Mycobacterium tuberculosis and M. bovis are causative agents of tuberculosis in humans and cattle. The lipoprotein LprF is found in M. tuberculosis and M. bovis but not in the nonpathogenic M. smegmatis. To date, the role of LprF remains to be elucidated. In this study, the crystal structure of LprF has been determined at 1.1 A resolution. The overall structure is similar to that of a homologue, LprG, with a central hydrophobic cavity that binds a triacylated glycolipid. LprF exhibited a central cavity structure similar to that of LprG, but with a smaller cavity that binds two alkyl chains. Consistently, subsequent mass-spectrometric analysis revealed that the bound ligand was a diacylated glycolipid, as found in the structure. Furthermore, an increased ratio of lipoarabinomannan to lipomannan in the mycobacterial cell wall was observed when lprF was introduced into M. smegmatis. These observations suggested that LprF transfers the diacylated glycolipid from the plasma membrane to the cell wall, which might be related to the pathogenesis of the bacteria. PMID- 25286847 TI - Visualization of a substrate-induced productive conformation of the catalytic triad of the Neisseria meningitidis peptidoglycan O-acetylesterase reveals mechanistic conservation in SGNH esterase family members. AB - Peptidoglycan O-acetylesterase (Ape1), which is required for host survival in Neisseria sp., belongs to the diverse SGNH hydrolase superfamily, which includes important viral and bacterial virulence factors. Here, multi-domain crystal structures of Ape1 with an SGNH catalytic domain and a newly identified putative peptidoglycan-detection module are reported. Enzyme catalysis was performed in Ape1 crystals and key catalytic intermediates along the SGNH esterase hydrolysis reaction pathway were visualized, revealing a substrate-induced productive conformation of the catalytic triad, a mechanistic detail that has not previously been observed. This substrate-induced productive conformation of the catalytic triad shifts the established dogma on these enzymes, generating valuable insight into the structure-based design of drugs targeting the SGNH esterase superfamily. PMID- 25286848 TI - Structural analysis of arabinose-5-phosphate isomerase from Bacteroides fragilis and functional implications. AB - The crystal structure of arabinose-5-phosphate isomerase (API) from Bacteroides fragilis (bfAPI) was determined at 1.7 A resolution and was found to be a tetramer of a single-domain sugar isomerase (SIS) with an endogenous ligand, CMP Kdo (cytidine 5'-monophosphate-3-deoxy-D-manno-oct-2-ulosonate), bound at the active site. API catalyzes the reversible isomerization of D-ribulose 5-phosphate to D-arabinose 5-phosphate in the first step of the Kdo biosynthetic pathway. Interestingly, the bound CMP-Kdo is neither the substrate nor the product of the reaction catalyzed by API, but corresponds to the end product in the Kdo biosynthetic pathway and presumably acts as a feedback inhibitor for bfAPI. The active site of each monomer is located in a surface cleft at the tetramer interface between three monomers and consists of His79 and His186 from two different adjacent monomers and a Ser/Thr-rich region, all of which are highly conserved across APIs. Structure and sequence analyses indicate that His79 and His186 may play important catalytic roles in the isomerization reaction. CMP-Kdo mimetics could therefore serve as potent and specific inhibitors of API and provide broad protection against many different bacterial infections. PMID- 25286851 TI - Low-dose X-ray radiation induces structural alterations in proteins. AB - X-ray-radiation-induced alterations to protein structures are still a severe problem in macromolecular crystallography. One way to avoid the influence of radiation damage is to reduce the X-ray dose absorbed by the crystal during data collection. However, here it is demonstrated using the example of the membrane protein bacteriorhodopsin (bR) that even a low dose of less than 0.06 MGy may induce structural alterations in proteins. This dose is about 500 times smaller than the experimental dose limit which should ideally not be exceeded per data set (i.e. 30 MGy) and 20 times smaller than previously detected specific radiation damage at the bR active site. To date, it is the lowest dose at which radiation modification of a protein structure has been described. Complementary use was made of high-resolution X-ray crystallography and online microspectrophotometry to quantitatively study low-dose X-ray-induced changes. It is shown that structural changes of the protein correlate with the spectroscopically observed formation of the so-called bR orange species. Evidence is provided for structural modifications taking place at the protein active site that should be taken into account in crystallographic studies which aim to elucidate the molecular mechanisms of bR function. PMID- 25286850 TI - Structures of human constitutive nitric oxide synthases. AB - Mammals produce three isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The overproduction of NO by nNOS is associated with a number of neurodegenerative disorders; therefore, a desirable therapeutic goal is the design of drugs that target nNOS but not the other isoforms. Crystallography, coupled with computational approaches and medicinal chemistry, has played a critical role in developing highly selective nNOS inhibitors that exhibit exceptional neuroprotective properties. For historic reasons, crystallography has focused on rat nNOS and bovine eNOS because these were available in high quality; thus, their structures have been used in structure-activity-relationship studies. Although these constitutive NOSs share more than 90% sequence identity across mammalian species for each NOS isoform, inhibitor-binding studies revealed that subtle differences near the heme active site in the same NOS isoform across species still impact enzyme-inhibitor interactions. Therefore, structures of the human constitutive NOSs are indispensible. Here, the first structure of human neuronal NOS at 2.03 A resolution is reported and a different crystal form of human endothelial NOS is reported at 1.73 A resolution. PMID- 25286849 TI - New methods for indexing multi-lattice diffraction data. AB - A new indexing method is presented which is capable of indexing multiple crystal lattices from narrow wedges of diffraction data. The method takes advantage of a simplification of Fourier transform-based methods that is applicable when the unit-cell dimensions are known a priori. The efficacy of this method is demonstrated with both semi-synthetic multi-lattice data and real multi-lattice data recorded from crystals of ~1 um in size, where it is shown that up to six lattices can be successfully indexed and subsequently integrated from a 1 degrees wedge of data. Analysis is presented which shows that improvements in data quality indicators can be obtained through accurate identification and rejection of overlapping reflections prior to scaling. PMID- 25286852 TI - A case study on the treatment of protein SIRAS data. AB - A case study has been made on the treatment of the SIRAS (single isomorphous replacement with anomalous scattering) data of the originally unknown protein LegC3N. An alternative treatment has been proposed which led to improved results in this particular test case. The treatment involves iterative direct-method SAD (single-wavelength anomalous diffraction) phasing and direct-method-aided model completion, both of which are implanted in the IPCAS (Iterative Protein Crystal structure Automatic Solution) pipeline. Apart from the experimental data, a simulated SIRAS data set for LegC3N with the derivative data truncated to 5.0 A resolution has also been tested. SAD phasing and phase/model extension in PHENIX without direct methods failed to solve the structure using these simulated SIRAS data. However, the procedure proposed here involving direct methods in both SAD phasing and phase/model extension led to a nearly complete structure model. This shows the potential ability of treating SIRAS data with a derivative diffracting to lower resolution. PMID- 25286853 TI - Structure of archaerhodopsin-2 at 1.8 A resolution. AB - Archaerhodopsin-2 (aR2), the sole protein found in the claret membrane of Halorubrum sp. Aus-2, functions as a light-driven proton pump. In this study, structural analysis of aR2 was performed using a novel three-dimensional crystal prepared by the successive fusion of claret membranes. The crystal is made up of stacked membranes, in each of which aR2 trimers are arranged on a hexagonal lattice. This lattice structure resembles that found in the purple membrane of H. salinarum, except that lipid molecules trapped within the trimeric structure are not distributed with perfect threefold symmetry. Nonetheless, diffraction data at 1.8 A resolution provide accurate structural information about functionally important residues. It is shown that two glutamates in the proton-release channel form a paired structure that is maintained by a low-barrier hydrogen bond. Although the structure of the proton-release pathway is highly conserved among proton-pumping archaeal rhodopsins, aR2 possesses the following peculiar structural features: (i) the motional freedom of the tryptophan residue that makes contact with the C13 methyl group of retinal is restricted, affecting the formation/decay kinetics of the L state, and (ii) the N-terminal polypeptide folds into an Omega-loop, which may play a role in organizing the higher-order structure. PMID- 25286854 TI - Using textons to rank crystallization droplets by the likely presence of crystals. AB - The visual inspection of crystallization experiments is an important yet time consuming and subjective step in X-ray crystallography. Previously published studies have focused on automatically classifying crystallization droplets into distinct but ultimately arbitrary experiment outcomes; here, a method is described that instead ranks droplets by their likelihood of containing crystals or microcrystals, thereby prioritizing for visual inspection those images that are most likely to contain useful information. The use of textons is introduced to describe crystallization droplets objectively, allowing them to be scored with the posterior probability of a random forest classifier trained against droplets manually annotated for the presence or absence of crystals or microcrystals. Unlike multi-class classification, this two-class system lends itself naturally to unidirectional ranking, which is most useful for assisting sequential viewing because images can be arranged simply by using these scores: this places droplets with probable crystalline behaviour early in the viewing order. Using this approach, the top ten wells included at least one human-annotated crystal or microcrystal for 94% of the plates in a data set of 196 plates imaged with a Minstrel HT system. The algorithm is robustly transferable to at least one other imaging system: when the parameters trained from Minstrel HT images are applied to a data set imaged by the Rock Imager system, human-annotated crystals ranked in the top ten wells for 90% of the plates. Because rearranging images is fundamental to the approach, a custom viewer was written to seamlessly support such ranked viewing, along with another important output of the algorithm, namely the shape of the curve of scores, which is itself a useful overview of the behaviour of the plate; additional features with known usefulness were adopted from existing viewers. Evidence is presented that such ranked viewing of images allows faster but more accurate evaluation of drops, in particular for the identification of microcrystals. PMID- 25286855 TI - Use of massively multiple merged data for low-resolution S-SAD phasing and refinement of flavivirus NS1. AB - An emergent challenge in macromolecular crystallography is the identification of the substructure from native anomalous scatterers in crystals that diffract to low to moderate resolution. Increasing the multiplicity of data sets has been shown to make previously intractable phasing problems solvable and to increase the useful resolution in model refinement. For the West Nile virus nonstructural protein 1 (NS1), a protein of novel fold, the utility of exceptionally high multiplicity data is demonstrated both in solving the crystal structure from the anomalous scattering of the native S atoms and in extending the useful limits of resolution during refinement. A high-multiplicity data set from 18 crystals had sufficient anomalous signal to identify sulfur sites using data to 5.2 A resolution. Phases calculated to 4.5 A resolution and extended to 3.0 A resolution were of sufficient quality for automated building of three-quarters of the final structure. Crystallographic refinement to 2.9 A resolution proceeded smoothly, justifying the increase in resolution that was made possible by combining multiple data sets. The identification and exclusion of data from outlier crystals is shown to result in more robust substructure determination. PMID- 25286856 TI - Crystallographic study of the phosphoethanolamine transferase EptC required for polymyxin resistance and motility in Campylobacter jejuni. AB - The foodborne enteric pathogen Campylobacter jejuni decorates a variety of its cell-surface structures with phosphoethanolamine (pEtN). Modifying lipid A with pEtN promotes cationic antimicrobial peptide resistance, whereas post translationally modifying the flagellar rod protein FlgG with pEtN promotes flagellar assembly and motility, which are processes that are important for intestinal colonization. EptC, the pEtN transferase required for all known pEtN cell-surface modifications in C. jejuni, is a predicted inner-membrane metalloenzyme with a five-helix N-terminal transmembrane domain followed by a soluble sulfatase-like catalytic domain in the periplasm. The atomic structure of the catalytic domain of EptC (cEptC) was crystallized and solved to a resolution of 2.40 A. cEptC adopts the alpha/beta/alpha fold of the sulfatase protein family and harbors a zinc-binding site. A phosphorylated Thr266 residue was observed that was hypothesized to mimic a covalent pEtN-enzyme intermediate. The requirement for Thr266 as well as the nearby residues Asn308, Ser309, His358 and His440 was ascertained via in vivo activity assays on mutant strains. The results establish a basis for the design of pEtN transferase inhibitors. PMID- 25286857 TI - Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2. AB - The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated beta-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors. PMID- 25286858 TI - Structure of the bifunctional aminoglycoside-resistance enzyme AAC(6')-Ie APH(2'')-Ia revealed by crystallographic and small-angle X-ray scattering analysis. AB - Broad-spectrum resistance to aminoglycoside antibiotics in clinically important Gram-positive staphylococcal and enterococcal pathogens is primarily conferred by the bifunctional enzyme AAC(6')-Ie-APH(2'')-Ia. This enzyme possesses an N terminal coenzyme A-dependent acetyltransferase domain [AAC(6')-Ie] and a C terminal GTP-dependent phosphotransferase domain [APH(2'')-Ia], and together they produce resistance to almost all known aminoglycosides in clinical use. Despite considerable effort over the last two or more decades, structural details of AAC(6')-Ie-APH(2'')-Ia have remained elusive. In a recent breakthrough, the structure of the isolated C-terminal APH(2'')-Ia enzyme was determined as the binary Mg2GDP complex. Here, the high-resolution structure of the N-terminal AAC(6')-Ie enzyme is reported as a ternary kanamycin/coenzyme A abortive complex. The structure of the full-length bifunctional enzyme has subsequently been elucidated based upon small-angle X-ray scattering data using the two crystallographic models. The AAC(6')-Ie enzyme is joined to APH(2'')-Ia by a short, predominantly rigid linker at the N-terminal end of a long alpha-helix. This alpha-helix is in turn intrinsically associated with the N-terminus of APH(2'')-Ia. This structural arrangement supports earlier observations that the presence of the intact alpha-helix is essential to the activity of both functionalities of the full-length AAC(6')-Ie-APH(2'')-Ia enzyme. PMID- 25286860 TI - Comment on Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights by Rona et al. (2013). AB - The authors comment on the article by Rona et al. [(2013), Acta Cryst. D69, 2495 2505]. PMID- 25286859 TI - Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex. AB - The structural characterization of the insulin-insulin receptor (IR) interaction still lacks the conformation of the crucial B21-B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26] insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms. PMID- 25286861 TI - Factors influencing nucleo-cytoplasmic trafficking: which matter? Response to Alvisi & Jans' comment on Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights. AB - The authors respond to a comment by Alvisi & Jans [(2014), Acta Cryst. D70, 2775 2776] on the article Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights [Rona et al. (2013), Acta Cryst. D69, 2495-2505]. PMID- 25286862 TI - On the prompt update of literature references in the Protein Data Bank. AB - Updating literature references in the Protein Data Bank is discussed. PMID- 25286863 TI - Response to On prompt update of literature references in the Protein Data Bank. AB - The wwPDB responds to the article On the prompt update of literature references in the Protein Data Bank [Wlodawer (2014), Acta Cryst. D70, 2779]. PMID- 25286864 TI - Gene module based regulator inference identifying miR-139 as a tumor suppressor in colorectal cancer. AB - Colorectal cancer is one of the most commonly diagnosed cancer types worldwide. Identification of the key regulators of the altered biological networks is crucial for understanding the complex molecular mechanisms of colorectal cancer. We proposed a gene module based approach to infer key miRNAs regulating the major gene network alterations in cancer tissues. By integrating gene differential expression and co-expression information with a protein-protein interaction network, the differential gene expression modules, which captured the major gene network changes, were identified for colorectal cancer. Then, several key miRNAs, which extensively regulate the gene modules, were inferred by analyzing their target gene enrichment in the modules. Among the inferred candidates, three miRNAs, miR-101, miR-124 and miR-139, are frequently down-regulated in colorectal cancers. The following computational and experimental analyses demonstrate that miR-139 can inhibit cell proliferation and cell cycle G1/S transition. A known oncogene ETS1, a key transcription factor in the gene module, was experimentally verified as a novel target of miR-139. miR-139 was found to be significantly down regulated in early pathological cancer stages and its expression remained at very low levels in advanced stages. These results indicate that miR-139, inferred by the gene module based approach, should be a key tumor suppressor in early cancer development. PMID- 25286865 TI - Design of a microscopic electrical impedance tomography system for 3D continuous non-destructive monitoring of tissue culture. AB - BACKGROUND: Non-destructive continuous monitoring of regenerative tissue is required throughout the entire period of in vitro tissue culture. Microscopic electrical impedance tomography (micro-EIT) has the potential to monitor the physiological state of tissues by forming three-dimensional images of impedance changes in a non-destructive and label-free manner. We developed a new micro-EIT system and report on simulation and experimental results of its macroscopic model. METHODS: We propose a new micro-EIT system design using a cuboid sample container with separate current-driving and voltage sensing electrodes. The top is open for sample manipulations. We used nine gold-coated solid electrodes on each of two opposing sides of the container to produce multiple linearly independent internal current density distributions. The 360 voltage sensing electrodes were placed on the other sides and base to measure induced voltages. Instead of using an inverse solver with the least squares method, we used a projected image reconstruction algorithm based on a logarithm formulation to produce projected images. We intended to improve the quality and spatial resolution of the images by increasing the number of voltage measurements subject to a few injected current patterns. We evaluated the performance of the micro-EIT system with a macroscopic physical phantom. RESULTS: The signal-to-noise ratio of the developed micro-EIT system was 66 dB. Crosstalk was in the range of -110.8 to -90.04 dB. Three-dimensional images with consistent quality were reconstructed from physical phantom data over the entire domain. From numerical and experimental results, we estimate that at least 20 * 40 electrodes with 120 MUm spacing are required to monitor the complex shape of ingrowth neotissue inside a scaffold with 300 MUm pore. CONCLUSION: The experimental results showed that the new micro-EIT system with a reduced set of injection current patterns and a large number of voltage sensing electrodes can be potentially used for tissue culture monitoring. Numerical simulations demonstrated that the spatial resolution could be improved to the scale required for tissue culture monitoring. Future challenges include manufacturing a bioreactor-compatible container with a dense array of electrodes and a larger number of measurement channels that are sensitive to the reduced voltage gradients expected at a smaller scale. PMID- 25286866 TI - Membrane potential bistability in nonexcitable cells as described by inward and outward voltage-gated ion channels. AB - The membrane potential of nonexcitable cells, defined as the electrical potential difference between the cell cytoplasm and the extracellular environment when the current is zero, is controlled by the individual electrical conductance of different ion channels. In particular, inward- and outward-rectifying voltage gated channels are crucial for cell hyperpolarization/depolarization processes, being amenable to direct physical study. High (in absolute value) negative membrane potentials are characteristic of terminally differentiated cells, while low membrane potentials are found in relatively depolarized, more plastic cells (e.g., stem, embryonic, and cancer cells). We study theoretically the hyperpolarized and depolarized values of the membrane potential, as well as the possibility to obtain a bistability behavior, using simplified models for the ion channels that regulate this potential. The bistability regions, which are defined in the multidimensional state space determining the cell state, can be relevant for the understanding of the different model cell states and the transitions between them, which are triggered by changes in the external environment. PMID- 25286867 TI - Context, Contrast, and Tone of Voice in Auditory Sarcasm Perception. AB - Four experiments were conducted to investigate the interplay between context and tone of voice in the perception of sarcasm. These experiments emphasized the role of contrast effects in sarcasm perception exclusively by means of auditory stimuli whereas most past research has relied on written material. In all experiments, a positive or negative computer-generated context spoken in a flat emotional tone was followed by a literally positive statement spoken in a sincere or sarcastic tone of voice. Participants indicated for each statement whether the intonation was sincere or sarcastic. In Experiment 1, a congruent context/tone of voice pairing (negative/sarcastic, positive/sincere) produced fast response times and proportions of sarcastic responses in the direction predicted by the tone of voice. Incongruent pairings produced mid-range proportions and slower response times. Experiment 2 introduced ambiguous contexts to determine whether a lower context/statements contrast would affect the proportion of sarcastic responses and response time. Results showed the expected findings for proportions (values between those obtained for congruent and incongruent pairings in the direction predicted by the tone of voice). However, response time failed to produce the predicted pattern, suggesting potential issues with the choice of stimuli. Experiments 3 and 4 extended the results of Experiments 1 and 2, respectively, to auditory stimuli based on written vignettes used in neuropsychological assessment. Results were exactly as predicted by contrast effects in both experiments. Taken together, the findings suggest that both context and tone influence how sarcasm is perceived while supporting the importance of contrast effects in sarcasm perception. PMID- 25286868 TI - Differential Language Functioning of Monolinguals and Bilinguals on Positive Negative Emotional Expression. AB - The present interdisciplinary research investigates the differential emotional expression between Persian monolinguals and Persian-English bilinguals. In other words, the article was an attempt to answer the questions whether bilinguals and monolinguals differ in the expression of positive and negative emotions elicited through sad and happy autobiographies and measured through UWIST Mood Adjective Checklist. The result of this pioneering work indicated no significant difference between Persian monolinguals and Persian-English bilinguals in expressing happy memories while differences were observed on sad memories. Bilinguals expressed more negative emotions in their L2 than L1. This outcome support the dominant claim that second language is the preferred language for the expression of sad emotions since it is the language of emotional detachment and distance. Further analysis on the number of words bilinguals and monolinguals used to express both sad and happy autobiographies indicated that bilinguals used more words in expressing both sad and happy autobiographies. PMID- 25286869 TI - Treatment agreements, informed consent, and the role of state medical boards in opioid prescribing. PMID- 25286872 TI - Population data for 22 autosomal STR loci from Estonia. AB - Allele frequencies and forensically relevant population statistics of 22 short tandem repeat (STR) loci were determined from 303 unrelated Estonian individuals. The samples were amplified with three kits: the AmpFlSTR((r)) Identifiler, the PowerPlex((r)) ESI 16 and the PowerPlex((r)) 16. No significant deviation from Hardy-Weinberg equilibrium was detected, except for locus D22S1045. Investigated loci are very discriminating in Estonian population, with a combined discrimination power of 0.9999999999999999999999999877. Furthermore, a comparison with previously published frequency data from other nearby populations is presented. PMID- 25286873 TI - Aptamer-based-sorbents for sample treatment--a review. AB - To improve selectivity during sample pretreatment, various selective tools inducing a molecular recognition mechanism during the extraction procedure have been developed, such as sorbents constituted of immobilized antibodies, i.e., immunosorbents, or molecularly imprinted polymers. More recently, as an alternative to both previous approaches, aptamers immobilized onto a solid support, i.e., oligosorbents, were proposed. Thanks to the high affinity and high selectivity of the interaction that some aptamers offer toward some target analytes, they also provide powerful techniques that make selective extraction and the concentration of a target analyte from liquid matrices in one step or sample purification of extracts from solid matrices possible. This review describes the development and the properties of these oligosorbents developed for different types of targets-pharmaceuticals, mycotoxins, proteins, cells, etc. After describing the immobilization procedures, we discuss different parameters characterizing the potential of aptamer-based supports as extraction sorbents. Close relations exist between extraction recoveries and the affinity and amounts of aptamers immobilized on the extraction device. In addition, analyte-aptamer interactions may be affected by matrix components and by additives in the samples. This may also lower extraction recoveries and affect the stability and the possible reusability of the aptamer-based sorbent. All these points are discussed and illustrated. Numerous examples of applications of these sorbents to the treatment of complex samples such as food samples, environmental samples, and biological fluids are also reported. Their association with analytical devices, from conventional to miniaturized analytical systems, is also discussed. PMID- 25286874 TI - Survey of pyrrolizidine alkaloids in teas and herbal teas on the Swiss market using HPLC-MS/MS. AB - Pyrrolizidine alkaloids (PAs) are a large class of natural compounds amongst which the esterified 1,2-unsaturated necine base is toxic for humans and livestock. In the present study, a method was developed and validated for the screening and quantification of nine PAs and one PA N-oxide in teas (Camellia sinensis (L.) O. Kuntze) and herbal teas (camomile, fennel, linden, mint, rooibos, verbena). Samples were analysed by HPLC on a RP-column, packed with sub 2 MUm core-shell particles, and quantified using tandem mass spectrometry operating in the positive electrospray ionisation mode. These PAs and some of their isomers were detected in a majority of the analysed beverages (50/70 samples). In 24 samples, PA concentrations were above the limit of quantification and the sum of the nine targeted PAs was between 0.021 and 0.954 MUg per cup of tea. Thus, in some cases, total concentrations exceed the maximum daily intake recommended by the German Federal Institute for Risk Assessment and the UK's Committee On Toxicity (i.e. 0.007 MUg kg(-1) bw). PMID- 25286875 TI - Fluorescence imaging of macromolecule transport in high molecular weight cut-off microdialysis. AB - When microdialysis (MD) membrane exceeds molecular weight cut-off (MWCO) of 100 kDa, the fluid mechanics are in the ultrafiltration regime. Consequently, fluidic mass transport of macromolecules in the perfusate over the membrane may reduce the biological relevance of the sampling and cause an inflammatory response in the test subject. Therefore, a method to investigate the molecular transport of high MWCO MD is presented. An in vitro test chamber was fabricated to facilitate the fluorescent imaging of the MD sampling process, using fluoresceinylisothiocyanate (FITC) dextran and fluorescence microscopy. Qualitative studies on dextran behavior inside and outside the membrane were performed. Semiquantitative results showed clear dextran leakage from both 40 and 250 kDa dextran when 100 kDa MWCO membranes were used. Dextran 40 kDa leaked out with an order of magnitude higher concentration and the leakage pattern resembled more of a convective flow pattern compared with dextran 250 kDa, where the leakage pattern was more diffusion based. No leakage was observed when dextran 500 kDa was used as a colloid osmotic agent. The results in this study suggest that fluorescence imaging could be used as a method for qualitative and semiquantitative molecular transport and fluid dynamics studies of MD membranes and other hollow fiber catheter membranes. PMID- 25286876 TI - LC-MS/MS determination of potential endocrine disruptors of cortico signalling in rivers and wastewaters. AB - A targeted analytical method was established to determine a large number of chemicals known to interfere with the gluco- and mineralocorticoid signalling pathway. The analytes comprise 30 glucocorticoids and 9 mineralocorticoids. Ten out of these corticosteroids were primary metabolites. Additionally, 14 nonsteroids were included. These analytes represent a broader range of possible adverse modes of action than previously reported. For the simultaneous determination of these structurally diverse compounds, a single-step multimode solid-phase extraction and pre-concentration was applied. Extracts were separated by a short linear HPLC gradient (20 min) on a core shell RP column (2.7 MUm particle size) and compounds identified and quantified by LC-MS/MS. The method provided excellent retention time reproducibility and detection limits in the low nanograms per litre range. Untreated hospital wastewater, wastewater treatment plant influent, treated effluent and river waters were analysed to demonstrate the applicability of the method. The results show that not all compounds were sufficiently eliminated by the wastewater treatment, resulting in the presence of several steroids (~20 ng/L) and nonsteroids in the final effluent, some of them at high concentrations up to 200 ng/L. Most of the detected mono-hydroxylated steroidal transformation products were found at significantly higher concentrations than their parent compounds. We therefore recommend to include these potentially bioactive metabolites in environmental toxicity assessment. PMID- 25286877 TI - A comparison of different chemometrics approaches for the robust classification of electronic nose data. AB - Accurate detection of certain chemical vapours is important, as these may be diagnostic for the presence of weapons, drugs of misuse or disease. In order to achieve this, chemical sensors could be deployed remotely. However, the readout from such sensors is a multivariate pattern, and this needs to be interpreted robustly using powerful supervised learning methods. Therefore, in this study, we compared the classification accuracy of four pattern recognition algorithms which include linear discriminant analysis (LDA), partial least squares-discriminant analysis (PLS-DA), random forests (RF) and support vector machines (SVM) which employed four different kernels. For this purpose, we have used electronic nose (e-nose) sensor data (Wedge et al., Sensors Actuators B Chem 143:365-372, 2009). In order to allow direct comparison between our four different algorithms, we employed two model validation procedures based on either 10-fold cross-validation or bootstrapping. The results show that LDA (91.56% accuracy) and SVM with a polynomial kernel (91.66% accuracy) were very effective at analysing these e-nose data. These two models gave superior prediction accuracy, sensitivity and specificity in comparison to the other techniques employed. With respect to the e nose sensor data studied here, our findings recommend that SVM with a polynomial kernel should be favoured as a classification method over the other statistical models that we assessed. SVM with non-linear kernels have the advantage that they can be used for classifying non-linear as well as linear mapping from analytical data space to multi-group classifications and would thus be a suitable algorithm for the analysis of most e-nose sensor data. PMID- 25286878 TI - Hemin-block copolymer micelle as an artificial peroxidase and its applications in chromogenic detection and biocatalysis. AB - Following an inspiration from the fine structure of natural peroxidases, such as horseradish peroxidase (HRP), an artificial peroxidase was constructed through the self-assembly of diblock copolymers and hemin, which formed a functional micelle with peroxidase-like activity. The pyridine moiety in block copolymer poly(ethylene glycol)-block-poly(4-vinylpyridine) (PEG-b-P4VP) can coordinate with hemin, and thus hemin is present in a five-coordinate complex with an open site for binding substrates, which mimics the microenvironment of heme in natural peroxidases. The amphiphilic core-shell structure of the micelle and the coordination interaction of the polymer to the hemin inhibit the formation of hemin MU-oxo dimers, and thereby enhance the stability of hemin in the water phase. Hemin-micelles exhibited excellent catalytic performance in the oxidation of phenolic and azo compounds by H2O2. In comparison with natural peroxidases, hemin-micelles have higher catalytic activity and better stability over wide temperature and pH ranges. Hemin-micelles can be used as a detection system for H2O2 with chromogenic substrates, and they anticipate the possibility of constructing new biocatalysts tailored to specific functions. PMID- 25286879 TI - Epidemiology of human infections with avian influenza A(H7N9) virus in the two waves before and after October 2013 in Zhejiang province, China. AB - We compared the epidemiological and clinical features of avian influenza A(H7N9) virus infections in the population in Zhejiang province, China, between March and April 2013 (first wave) and October 2013 and February 2014 (second wave). No statistical difference was found for age, sex, occupation, presence of underlying conditions, exposure history, white blood cell count, lymphocyte percentage and illness timeline and duration (all P > 0.05). The virus spread to 30 new counties compared to the first wave. The case-fatality rate was 22% in the first wave and 42% in the second (P = 0.023). Of those infected, 66% in the first wave and 62% in the second wave had underlying conditions. The proportion of those exposed to live poultry markets were 80% and 66%, respectively. We recommend permanent closure of live poultry markets and reformation of poultry supply and sales. PMID- 25286880 TI - A high-pressure-induced dense CO overlayer on a Pt(111) surface: a chemical analysis using in situ near ambient pressure XPS. AB - We investigated the high-density CO adsorption phase formed on a Pt(111) surface when exposed to CO gas of pressure ranging from UHV to 100 mTorr using near ambient-pressure (NAP)-XPS. Combined results from the NAP-XPS measurements and DFT calculations reveal the adsorption structure of CO molecules in the dense CO overlayer, which is stable under realistic conditions. PMID- 25286882 TI - Terpy(Pt-salphen)2 switchable luminescent molecular tweezers. AB - The design and synthesis of switchable molecular tweezers based on a luminescent terpy(Pt-salphen)2 (1; terpy=terpyridine) complex is reported. Upon metal coordination, the tweezers can switch from an open "W"-shaped conformation to a closed "U"-shaped form that is adapted for selective recognition of cations. Closing of the tweezers by metal coordination (M=Zn(2+), Cu(2+), Pb(2+), Fe(2+), Hg(2+)) was monitored by (1)H NMR and/or UV/Vis titrations. During the titration, exclusive formation of the 1:1 complex [M(1)] was observed, without appearance of an intermediate 1:2 complex [M(1)2]. The crystallographic structure of the 1:1 complex was obtained with Pb(2+) and showed a distorted helical structure. Selective intercalation of Hg(2+) cations by the closed "U" form was observed. The tweezers were reopened by selective metal decoordination of the terpyridine ligand by using tris(2-aminoethyl)amine (tren) as a competitive ligand without modification of the Pt-salphen complex. Detailed photophysical studies were performed on the open and closed tweezers. Structured emission was observed in the open form from the Pt-salphen moieties, with a high quantum yield and a long lifetime. The emission is slightly modified upon closing with 1 equivalent of Zn(2+) or Hg(2+), whereas a dramatic quenching was obtained upon intercalation of additional Hg(2+). PMID- 25286883 TI - Responses of blood pressure and lactate levels to various aquatic exercise movements in postmenopausal women. AB - AIM: Middle-aged and elderly women represent the main attending group in head-out aquatic exercise (HOAE). Blood pressure (BP) significantly increases both during water immersion and aquatic walking. Based on risk concerns, it is important to evaluate BP responses in postmenopausal women doing HOAE. The aim of this study was to determine BP, lactate levels, and rating of perceived exertion (RPE) changes associated with performing 3 different movements at 3 levels of exercise intensity in water. METHODS: Twelve postmenopausal women (59.9+/-0.6 years old) participated in 3 aquatic trials involving running (RU), rocking (RO), and scissor kicks (SK) on separate days. Systolic BP, mean arterial pressure (MAP), lactate levels, RPE, and motion cadence were measured at rest; upon reaching 50%, 65%, and 80% of heart rate reserve for 6 minutes; and 10 and 30 minutes after exercise. RESULTS: Under similar RPE responses at 3 levels of intensity, SK resulted in higher systolic BP, MAP, and lactate levels than RO at 10 minutes after exercise (P<0.05) and the lowest motion cadence (P<0.05). RO resulted in the lowest MAP and diastolic BP responses during exercise (P<0.05). RU resulted in lower responses of lactate levels at high exercise intensity (P<0.05). CONCLUSION: RO resulted in lower diastolic BP and MAP responses compared with RU and SK during exercise. These findings suggest that RO movement in aquatic exercises is more suitable for people at high risk for cardiovascular disease. PMID- 25286884 TI - The repeated bout effect: is the blunted creatine kinase response an effect of an altered enzyme inactivation kinetic? AB - AIM: If unaccustomed lengthening contractions are repeated within a certain period of time, muscle damage symptoms are blunted. This observation, often referred to as the repeated bout effect (RBE), also holds true for the response of muscle damage markers like creatine kinase (CK). However, measuring plasma enzyme activity rather than the concentration of enzyme protein might conceal the actual amount of damaged tissue. Therefore, the primary aim of the study was to investigate if the RBE of CK can partially be explained by enzyme inactivation. METHODS: Ten healthy male subjects performed two bouts of 100 drop-to-vertical jumps (DVJs) from a 70-cm high platform at an interval of three weeks. CK activity, CK concentration, and neutrophils were measured prior to, and on four consecutive days after the interventions. RESULTS: Besides significant main effects, there was a significant group by time interaction for the specific CK activity (CK activity in blood [U/L] divided by the enzyme concentration [ng/mL]). Higher values following the first bout (133.1+/-99.4 U/ug) than the second bout (94.7+/-63.0 U/ug) indicate that the ratio of inactive to active CK molecules increased. Neutrophil levels were similar following both bouts and differed only at 8 hours (7.0+/-2.5 bout 1, 5.1+/-1.6 bout 2). CONCLUSION: The findings of the present study support the hypothesis that the blunted response of CK activity after a repeated bout of eccentric exercise is not solely the result of tissue protection, but can be at least partially attributed to enzyme inactivation. PMID- 25286885 TI - The relationship between Shin Splints with anthropometric characteristics and some indicators of body composition. AB - AIM: Medial tibial stress syndrome (MTSS), commonly known as ''shin splints,'' is a frequent injury of the lower extremity and one of the most common causes of exertional leg pain in athletes. The aim of this study was to study the relationship between Shin splints, anthropometric characteristics and some indicators of body composition. METHOD: In this descriptive - comparative study, thirty--five students of physical education were evaluated in two groups: Shin Splints group [(n=17) , mean (+/- SD) height and weight, 161.52 +/- 5.32 and 56.85 +/- 9.30 respectively] and healthy group [(n=18) ,mean (+/- SD) height and weight, 162.75 +/- 3.85 and 54.73 +/- 6.36 respectively]. Anthropometric and body composition characteristic of both groups were studied under identical conditions. Independent t--test was performed in order to analyze the data. RESULTS: No significant differences were found in anthropometric parameters (thigh length, leg length, foot length and leg circumference) body composition (the amount of minerals and body fat percentage) between the healthy group and the Shin Splints group (P> 0/05). CONCLUSION: According to the results of this study, anthropometric characteristics and body composition indicators may not be regarded as a risk factor for shin splints. PMID- 25286881 TI - Novel antiplatelet agents in acute coronary syndrome. AB - For more than 10 years, dual antiplatelet therapy with aspirin and clopidogrel has remained the cornerstone of treatment for patients with acute coronary syndrome (ACS). The novel oral P2Y purinoceptor 12 (P2Y12)-receptor inhibitors prasugrel and ticagrelor were approved by the FDA for clinical use in 2009 and 2011, respectively. These agents have a faster-acting, more-potent, and more predictable antiplatelet effect than clopidogrel, which translates into improved clinical outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, some patients continue to experience adverse ischaemic events despite treatment with aspirin and a P2Y12-receptor antagonist, because platelets can remain activated via pathways not inhibited by these agents, such as the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin. Emerging antiplatelet therapies that might address these limitations include intravenous P2Y12 antagonists, oral PAR-1 antagonists, and thromboxane receptor inhibitors. In this Review, we provide an overview of these novel antiplatelet drugs, including newly approved agents and emerging compounds currently under clinical development, and also discuss evolving concepts and unmet needs related to antiplatelet therapy for the treatment of ACS. PMID- 25286886 TI - The effectiveness of chocolate milk as a post-climbing recovery aid. AB - AIM: Recovery is essential to effective performance in climbing competitions which often involve repeated bouts, and sport climbing where climbers may work a route over a number of days prior to a complete ascent. METHODS: This study employed a cross-over design to compare water with chocolate milk as recovery aids following an exhaustive bout of high intensity endurance climbing. Ten male climbers (age: 22+/-1 years; height: 178.5+/-7.9 cm; mass: 74.7+/-11.3 kg) climbed a Tredwall (Brewer Ledge M6) until volitional exhaustion. The participants consumed either water or chocolate milk 20 minutes after the climb and then again with their evening meal. The exercise protocol was repeated 24 hours after the original climb. The second condition was completed 7 days later. Workload indicators of heart rate, rate of perceived exertion (RPE), blood lactate and muscle soreness scores were recorded alongside climbing performance measures of duration and distance of the climb. A improved performance was found after the consumption of chocolate milk, with both a greater distance climbed (F(1,9)=11.704, P=0.008) and duration (F(1,9) =10.922, P=0.009), there were no differences in end of climb heart rate or RPE. RESULTS: Muscle soreness scores were lower three days after exercise following chocolate milk (t(8)=3.773, P=0.005). Chocolate milk as a recovery drink resulted in further sustained climbing, a decrease in muscle soreness, compared to water. It may be pertinent for climbers to consider its use as a recovery aid during repeated climbing bouts. Chocolate milk is a relatively unexplored recovery aid and warrants further attention. PMID- 25286887 TI - Five training sessions improves 3000 meter running performance. AB - AIM: The primary aim of the present study was to evaluate the effect of two weeks of endurance training on 3000-meter running performance. Secondary we wanted to assess the relationship between baseline running performance and change in running performance over the intervention period. METHODS: We assigned 36 military recruits to a training group (N.=28) and a control group. The training group was randomly allocated to one of three sub-groups: 1) a 3000 meter group (test race); 2) a 4x4-minutes high-intensity interval group; 3) a continuous training group. The training group exercised five times over a two-week period. RESULTS: The training group improved its 3000 meter running performance with 50 seconds (6%) compared to the control group (P=0.003). Moreover, all sub-groups improved their performance by 37 to 73 seconds (4-8%) compared to the control group (P<0.037). There was a significant relationship between pretest performance and improvement from pre- to post-test (rho=-0.65, P<0.001) in the training group. CONCLUSION: We conclude that five endurance training sessions improved 3000 meter running performance and the slowest runners achieved the greatest improvement in running performance. PMID- 25286888 TI - Oxygen consumption and heart rate responses during and after constant load and alternating intensity exercise at 105% of lactate threshold. AB - AIM: The purpose of this study was a secondary-analysis of previously published data, in order to compare the acute VO2 responses, the time spent at high percentage of VO2max and total VO2 consumed (TVO2) between constant and alternating intensity exercise of the same intensity and duration. This study also aimed to examine VO2 and heart rate (HR) responses one hour after both exercises. METHODS: Ten recreationally trained men (24.7+/-4.7 years) completed the following two exercise tests lasting an hour each and having the same mean intensity at 105% of lactate threshold (70% VO2max): 1) constant load cycling (CON), and 2) alternating intensity exercise (ALT), during which 40 seconds of light exercise (47% VO2max) were alternated with 20 seconds of supramaximal intensity at 120% of VO2max. RESULTS: TVO2 (69.89+/-7.02 vs. 58.22+/-9.13 mL/kg/min, P=0.03) and HR (142+/-16, 128+/-12, P=0.04) was higher in CON exercise compared to ALT. All participants reached 70% and 80% of VO2max irrespective of the exercise protocol. In ALT exercise the time spent at 90% was higher compared to CON exercise (70.81+/-21.37 vs. 36.88+/-11.88 seconds). Also, TVO2 recovery values after ALT exercise was higher compared to CON (11.1 +/-2.93 vs. 9.94+/ 3.54 mL/kg/min). CONCLUSION: ALT exercise allowed participants to spend longer time at 90% of VO2max, even if TVO2 in CON exercise was higher, suggesting that in ALT exercise greater aerobic stress (as based on exercise intensity) is imposed on the athletes. While VO2 recovery values were higher in ALT compared to CON, indicating different substrate utilization during and after exercise. PMID- 25286890 TI - The impact of a simulated grand tour on sleep, mood, and well-being of competitive cyclists. AB - AIM: Professional cycling is considered one of the most demanding of all endurance sports. The three major professional cycling stages races (i.e. Tour de France, Giro d'Italia and Vuelta a Espana) require cyclists to compete daily covering between ~150-200 km for three consecutive weeks. Anecdotal evidence indicates that such an event has a significant effect on the sleep, mood, and general well-being of cyclists, particularly during the latter stages of the event. The primary aim of this study was to simulate a grand tour and determine the impact a grand tour has on the sleep, mood, and general well-being of competitive cyclists. METHODS: Twenty-one male cyclists (M+/-SD, age 22.2+/-2.7 years) were examined for 39 days across three phases (i.e. baseline, simulated grand tour, and recovery). Sleep was assessed using sleep diaries and wrist activity monitors. Mood and general well-being were assessed using the Brunel Mood Scale (BRUMS) and Visual Analogue Scales (VAS). RESULTS: The amount and quality of sleep as assessed by the wrist activity monitors declined during the simulated grand tour. In contrast, self-reported sleep quality improved throughout the study. Cyclists' mood and general well-being as indicated by vigour, motivation, physical and mental state declined during the simulated tour. CONCLUSION: Future investigations should examine sleep, mood and well-being during an actual grand tour. Such data could prove instrumental toward understanding the sleep and psychological changes that occur during a grand tour. PMID- 25286889 TI - The temperature of water ingested ad libitum does not influence performance during a 40-km self-paced cycling trial in the heat. AB - AIM: The aim of the present study was to evaluate the effects of the temperature of ingested water on performance during a 40-km self-paced cycling trial in the heat (35o C and 60% relative humidity). METHODS: The study was randomized, counterbalanced, crossover and single-blinded. Ten well-trained male cycling athletes (cyclists, mountain bikers or triathletes) who were non-acclimatized to heat were subjected to four experimental situations divided into two sets. In the first set, the participants performed two trials, during which they were given either cold (10o C) or warm water (37o C) ad libitum. In these situations, the volume and timing of the water ingestion (when each bolus was ingested) were recorded and replicated in the second set, but the water temperature was reversed. RESULTS: The performance times were unaffected by the water intake volume (P=0.425), but the water at a temperature of 37o C tended to induce lower performance times (P=0.078) during the trials (AL10=93.0+/-3.5 min; AL37=94.4+/ 4.1 min; SC10=93.4+/-4.0; SC37=97.4+/-4.3 min). The water intake was greater when the water was cold (P<0.05), but the temperature did not affect the heat storage rate, rectal temperature, mean skin temperature, heart rate, blood glucose level, sweat loss, sweat rate, perceived exertion rate or plasma volume changes. However, a significant reduction in the plasma volume change from pre- to postexercise was observed (P<0.01). CONCLUSION: The performance, thermoregulatory, cardiovascular and metabolic responses during a 40-km self paced cycling trial in the heat were unaffected by different water temperatures. PMID- 25286891 TI - Changes in tissue oxygen saturation with calf compression sleeve: before, during and after a cycling exercise. AB - AIM: The purpose of this study was to examine the changes in tissue oxygen saturation (StO2) with calf compression sleeves, before, during and after a cycling exercise. METHODS: Eleven athletes came to the laboratory two times, to complete the same session with or without calf compression sleeves, in a randomized order. The session included a 15-min incremental cycling exercise: 3 min at each intensity - 40, 80, 120, 160 and 200 W, preceded (baseline) and followed (recovery) by a 10-min period at rest in seated position. Calf StO2 was recorded using near infrared spectroscopy during the three last min of the baseline period, during the cycling exercise and during the recovery period. RESULTS: Baseline StO2 was significantly increased with the compression sleeves (P<0.001; +24.8+/-3.5%). During the cycling exercise, StO2 was significantly increased with the compression sleeves only at 40 W (P<0.05; +8.2+/-3.7%) and 80 W (P<0.05; +7.9+/-3.7%). At 120 W (P=0.23; +5.0+/-4.0%), 160 W (P=0.38; +3.9+/ 4.1%) and 200 W (P=0.81; -0.1+/-4.9%), no significant difference was found with compression sleeves. During the recovery period, StO2 was significantly increased with the compression sleeves (1 to 10 min: P<0.001; +10.5+/-1.3%). CONCLUSION: This study shows that wearing calf compression sleeves increases StO2 at rest (before and after an exercise) and at low intensities in cycling (40 W and 80 W). At high intensities (120 W and more), compression sleeves is not useful to increase StO2. PMID- 25286892 TI - Effect of short-term heat acclimation training on kinetics of lactate removal following maximal exercise. AB - BACKGROUND: Heat acclimation (HA) evokes numerous physiological adaptations, improves heat tolerance and has also been shown to enhance lactate (LA) responses during exercise, similar to that seen with endurance training. The purpose of this study was to examine whether HA improves the body's ability to remove LA during recovery following maximal exercise. METHODS: Ten healthy men completed two trials of maximal treadmill exercise (pre- and post-HA) separated by 5 days of HA. Each day of HA consisted of two 45 minute periods of cycling at ~50% VO2max separated by a 15min rest period in an environmental chamber (T(db) 45 degrees C, RH 20%). In pre-/post-HA trials, venous blood was collected during 60 minutes of recovery to determine LA concentrations and removal kinetics (A2: amplitude and y2: velocity constant) using bi-exponential curve fitting. RESULTS: Physiological adaptation to heat was significantly developed during HA, as evidenced by end-exercise T(re) (DAY1 vs. 5) (38.89+/-0.56 vs. 38.66+/-0.44 degrees C), T(sk) (38.07+/-0.51 vs. 37.66+/-0.48 degrees C), HR (175.0+/-9.9 vs. 165.0+/-18.5 beats.min(-1)), and sweat rate (1.24 +/-.26 vs. 1.47 +/-0.27 L.min(-1)) (P<0.05). However, there was no significant difference in either LA concentrations (LA(0min): 8.78+/-1.08 vs. 8.69+/-1.23; LA(peak): 10.97+/-1.77 vs. 10.95+/-1.46; and La(60min); 2.88+/-0.82 vs. 2.96+/-0.93 mmol.L(-1)) or removal kinetics (A2: -13.05+/-7.05 vs -15.59+/-7.90 mmol.L(-1) and y2: 0.02+/-0.01 vs. 0.03+/-.01 min(-1)). CONCLUSIONS: The present study concluded that, while effective in inducing thermo-physiological adaptations to heat stress, short-term HA does not improve the body's ability to remove LA following maximal exercise. Therefore, athletes and workers seeking faster LA recovery from intense physical activity may not benefit from short-term HA. PMID- 25286893 TI - Glycemic control and hunger during recovery from high- and moderate-intensity Nordic skiing in well-trained skiers. AB - BACKGROUND: The aim of this paper was to study the effects of Nordic ski training on post-exercise blood glucose (BG) regulation. METHODS: Twenty-one (male N.=10; female N.=11) competitive college Nordic skiers (age 19.14+/-1.3 yrs; body fat percentage 14.9+/-6.2) completed two ski training conditions (high intensity [HI] and easy volume [MOD]) and one resting control (CON) condition on separate days. At rest on the control day and upon completion of ski training, a 75 g oral glucose tolerance test (OGTT) was administered. BG was measured prior to the OGTT and at 20-minute intervals for 80 minutes of passive rest. Hunger was assessed prior to the OGTT and at 40 and 80 minutes of rest via Visual Analog Scale. Data were analyzed using a two-way ANOVA with repeated measures and one-way ANOVA (SPSS v. 19). RESULTS: Significant time effects were present for BG. BG area under the curve (AUC) was significantly smaller (P<0.05) following HI (8825+/-149 arbitrary units [a.u.]) vs. CON (9493+/-168 a.u.), but not different from MOD (9087+/-227 a.u.). MOD AUC tended to be smaller than CON (P=0.064). Mean CON hunger was lower than MOD (P<0.05) and tended to be lower than HI (P=0.064). CONCLUSIONS: High-intensity Nordic skiing appears to enhance glycemic control when provided with an OGTT following acute exercise. The role that active muscle volume plays in this response should be investigated. PMID- 25286894 TI - A single set of exhaustive exercise before local muscular endurance training improves quadriceps strength and endurance in young men. AB - BACKGROUND: The purpose of this study was to examine the effects of an additional set of exhaustive exercise before local muscular endurance (LME) training on maximal dynamic strength and endurance of quadriceps muscle in young men. METHODS: Twenty-seven healthy men (age: 20.9+/-1.8 years) performed one repetition maximum (1RM), muscular endurance, and magnetic resonance imaging (MRI) tests on two separate occasions (before and after an 8-wk LME training program using a bilateral knee extensor machine). After baseline testing, the subjects were divided into three groups: untrained control (CO, N.=9), traditional training (TR, N.=9), and prior exhaustive training (PE, N.=9). Both the TR and PE groups trained using the same LME training protocol (2 d?wk-1; 3 sets of 15-20 repetitions at 50% of 1RM) throughout the 8-wk experimental period; the only difference was that the PE group performed an additional set of exhaustive exercise at 80% of 1RM immediately before each training session. RESULTS: After 8 wk, the PE group experienced a greater (P<0.05) increase in 1RM, endurance, and work efficiency than the TR group. Additionally, no changes (P>0.05) in cross-sectional area (CSA), body mass and daily dietary intake were observed from pre- to post-test in either group. CONCLUSIONS: These results suggest that the inclusion of a single set of exhaustive exercise at 80% of 1RM immediately before LME training can be a suitable strategy for inducing additional beneficial effects on quadriceps strength and endurance in young men. PMID- 25286895 TI - An evaluation of wheelchair basketball players' nutritional status and nutritional knowledge levels. AB - BACKGROUND: This study aimed to assess the nutritional status of women paralympic athletes and their nutritional knowledge. METHODS: Twenty two players of National Wheelchair Women Basketball Team (15-38 years) participated in this study and answered a questionnaire (76 questions) Players were at sport camp during the assessment where their body weight is measured regularly by the team coach. The waist, hip size and the height of the players who are able to stand have been used for the assessment, while the knee height of the players who are not able to stand have been measured for the study. SPSS 15.0 and BEBIS (Nutritional Data System) have been used for statistical assessment. RESULTS: The average age and sport years as a player of the participants are; respectively; 25.5+/-7.2 years and 3.9+/-2.8 years. The average daily energy consumption is 2867.8+/-523.6 kcal/day. The average proportion of energy, converted from carbohydrate, protein, fat are been calculated as, respectively; 42.7% (5.3+/-1.5 g/kg/day), 13.3% (1.6+/-0.3 g/kg/day), 44% (2.5+/-0.8 g/kg/day). It is also found that Vitamin B1, folic acid, magnesium, iron and fiber have not been consumed enough. The questions about sport nutrition have been mostly answered incorrectly. CONCLUSIONS: Athletes have inadequate food consumption and nutrition information. The athletes have to be educated more about nutrition and they should have nutritional counseling support. PMID- 25286896 TI - Acute effects of a high-volume resistance training session on lung function. AB - AIM: The purpose of this study was to examine whether a high--volume compared to a low--volume whole--body resistance exercise session acutely impairs lung function. METHODS: Fifteen competitive male bodybuilders (age 27.4 +/- 5.4 y; body mass 89.7 +/- 12.8 kg; stature 177.9 +/- 4.8 cm), in a crossover trial, completed two resistance training protocols (high--volume: 5 sets per exercise; low--volume: 2 sets per exercise) and a control session (no exercise) on 3 separate occasions. RESULTS: The physiological demands of the two resistance exercise sessions were significantly different as indicated by greater VE, VO2, and HR (P<0.05), and lower PETCO2 (P<0.05) responses for the majority of exercises during the high--volume compared to low--volume session. No significant differences were found for lung function measures (FVC, SVC, FEV1, FEV3, FEV6, IC, ERV, and MVV) between pre-- and post--session for the low--volume and high volume sessions. CONCLUSION: The findings suggest that the ventilatory muscle demands of a strenuous resistance exercise session are not great enough to acutely affect indices of lung function. PMID- 25286897 TI - Effects of creatine supplementation along with resistance training on urinary formaldehyde and serum enzymes in wrestlers. AB - BACKGROUND: Formaldehyde is a cytotoxic agent produced from creatine through a metabolic pathway, and in this regard, it has been claimed that creatine supplementation could be cytotoxic. Even though the cytotoxic effects of creatine supplementation have been widely studied, yet little is known about how resistance training can alter these toxic effects. This study aimed to determine the effects of short-term creatine supplementation plus resistance training on the level of urinary formaldehyde and concentrations of serum enzymes in young male wrestlers. METHODS: In a double-blind design twenty-one subjects were randomized into creatine supplementation (Cr), creatine supplementation plus resistance training (Cr + T) and placebo plus resistance training (Pl + T) groups. Participants ingested creatine (0.3 g/kg/day) or placebo for 7 days. The training protocol consisted of 3 sessions in one week, each session including three sets of 6-9 repetitions at 80-85% of one-repetition maximum for whole-body exercise. Urine and blood samples were collected at baseline and at the end of the supplementation. RESULTS: Creatine supplementation significantly increased the excretion rate of urinary formaldehyde in the Cr and Cr + T groups by 63.4% and 30.4%, respectively (P<0.05), indicating that resistance training could partially lower this rate by 17.7%. No significant differences were detected in the levels of serum enzymes across time and groups (P>0.05). CONCLUSIONS: These findings indicate that resistance training may lower the increase of urinary formaldehyde excretion induced by creatine supplementation, suggesting that creatine consumption could be relatively less toxic when combined with resistance training. PMID- 25286898 TI - Exercise-based rehabilitation improves cardiorespiratory fitness but does not modulate myeloperoxidase levels in coronary heart disease patients. PMID- 25286899 TI - Balance performance in older adults and its relationship with falling. AB - BACKGROUND AND AIMS: A normal consequence of aging is a general deterioration in a number of musculoskeletal and sensory systems that affect postural control and balance. The aim of this study was to evaluate history of falls among active older individuals in Iran, and estimate the risk factors for falls among this population. METHODS: A total of 448 active older subjects from rural region of Rasht city, Iran, were included. They were divided into three groups depending on their age: young-old (n = 266); middle-old (n = 154) and oldest-old (n = 28). We assessed balance performance by One-Leg Balance (OLB), Functional Reach (FR), Timed Up and Go (TUG) and Romberg tests. RESULTS: The fall rate (>2 in the last year) was 27.0 %. The cut-off point 13.75 s for TUG test showed 84.7 % sensitivity and 56 % specificity. Also the best cut-off point for OLB test was 12.7 s (63 % sensitivity and 83.5 % specificity). Logistic regression analysis revealed that age, BMI, diabetes, and failure in OLB, FR, and Romberg tests predicted fall risk. The decision tree classification of older individuals showed three categorical variables, which in their order of importance included diabetes, Romberg test, and OLB test. CONCLUSIONS: This study revealed the value of history taking about diabetes as a predictor for existing falling. Decision tree technique showed that Romberg and OLB tests help in identifying older adults with balance problems. Given the incidence and consequences of falls among older adults, large-scale prospective studies on older individuals to identify those prone to falls are warranted. PMID- 25286900 TI - Comparative study of lumbosacral alignment in elderly versus young adults: data on patients with low back pain. AB - BACKGROUND: Sagittal spinal alignment is an important determinant for proper spinal function. Alterations in spinal alignment may serve as leading factor for diminished body biomechanics. Although increased age is suggested to be associated with changes in lumbosacral alignment, in turn body posture, this is still a current issue in geriatrics which requires further research. AIMS: The aim of this study was to compare the spinal alignment of elderly to that of young adults. METHODS: A total of 402 (243 female and 159 male) patients with low back pain were included in the study. The mean ages of young adults (n = 205) and elderly (n = 197) were 29.15 +/- 6.46 and 71.97 +/- 6.48 years, respectively. The electronic medical record database was used to obtain the lumbar radiographs of the individuals retrospectively. Lumbar lordosis angle (LLA), lumbosacral lordosis angle (LSLA), sacral tilt (ST) and lumbosacral angle (LSA) were measured on lateral standing lumbar radiographs. RESULTS: Lumbar lordosis angle of elderly was significantly smaller than that of young adults (36.22 +/- 11.94 and 39.83 +/ 10.01 respectively, p = 0.001). When the data was analyzed according to sex, females had wider LLA, ST and LSA than males, whilst males had wider LSLA than females. DISCUSSION: This study reflects an age-related loss of lumbar lordosis along with sex-dependent alterations in lumbar sagittal alignment CONCLUSIONS: Aging is related with the loss of lumbar curvature, particularly in men. Longitudinal studies on this issue are needed to confirm the results of this study. PMID- 25286901 TI - Prevalence of porcine cysticercosis in the Lake Kyoga Basin, Uganda. AB - BACKGROUND: Taenia solium is a zoonotic helminth with the potential to cause life threatening epilepsy in people through the aberrant larval infection of the brain called Neurocysticercosis (NCC). The pig is the intermediate host for T. solium where the larval form, cysticercus cellulosae, normally develops after the pig eats eggs of the parasite. Humans are the definitive host where the adult tapeworm develops and are infected through the consumption of poorly cooked, infected meat. T. solium has been acknowledged by the World Health Organization (WHO), Food and Agriculture Organization (FAO) and UK Department for International Development (DFID) as being a neglected zoonotic disease, and was recently included in the WHO roadmap for control of neglected tropical diseases. This neglect encompasses a lack of epidemiological data and a lack of validated, effective control strategies being adopted. Understanding the epidemiology of this parasite in the intermediate host is the first step towards designing suitable intervention strategies for the improvement of public health. This study was undertaken to provide an accurate and up-to-date estimate for the prevalence of porcine cysticercosis in the Lake Kyoga basin. RESULTS: Sera from 378 pigs were analysed with the HP10 Antigen Enzyme Linked Immunosorbant Assay (ELISA) and the prevalence was found to be 25.7% (95% confidence interval 21.0% to 30.0%). Previous sero- surveillance in this region, using the B158/B60 Ag Elisa had indicated a prevalence of 8.6% in 2005 indicating a dramatic increase in prevalence (J. Parasitol Res, Article ID 375493, 2009) within a 6 year period. CONCLUSION: This increasing prevalence in the disease indicates to us that there is currently no effective control of this parasite and that in this region of Uganda at least; cysticercosis remains a neglected zoonotic disease. PMID- 25286902 TI - Ketoprofen-induced lamina lucida-type linear IgA bullous dermatosis. PMID- 25286903 TI - Endoplasmic reticulum stress is the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in liver fibrosis. AB - OBJECTIVE: The objective of the review is to examine the crossroads of autophagy, inflammation, and apoptosis signaling pathways and their participation in liver fibrosis. INTRODUCTION: Endoplasmic reticulum (ER) stress was emerged as a common feature relevant to the pathogenesis of diseases associated with organ fibrosis. However, the functional consequences of these alterations on ER stress and the possible involvement in liver fibrosis were currently largely unexplored. Here, we will survey the recent literature in the field and discuss recent insights focusing on some cellular models expressing mutant proteins involved in liver fibrosis. METHODS: A computer-based online search with PubMed, Scopus and Web of Science databases was performed for articles published, concerning ER stress, adaptation, inflammation and apoptosis with relevance to liver fibrosis. RESULTS AND CONCLUSIONS: Progression of liver fibrosis requires sustained inflammation leading to hepatocytes apoptosis through ER stress, whereas associated with activation of hepatic stellate cells (HSCs) into a fibrogenic and proliferative cell type. Faced with persistent and massive ER stress, HSCs adaptation starts to fail and apoptosis occurs in reversal of liver fibrosis, possibly mediated through calcium perturbations, unfolded protein response, and the pro-apoptotic transcription factor CHOP. Although limited in scope, current studies underscored that ER stress is tightly linked to adaptation, inflammation and apoptosis, and recent evidences suggested that these processes are related to the pathogenesis of liver fibrosis and its recovery. PMID- 25286904 TI - Colitis generates remote antinociception in rats: the role of the L arginine/NO/cGMP/PKG/KATP pathway and involvement of cannabinoid and opioid systems. AB - OBJECTIVE AND DESIGN: The aim of this study was to investigate the possible involvement of the NO/cGMP/PKG/KATP+ pathway, cannabinoids and opioids in remote antinociception associated with 2,4,6-trinitrobenzene sulph onic acid (TNBS) induced colitis. METHODS: TNBS-induced colitis was induced by intracolonic administration of 20 mg of TNBS in 50% ethanol. After induction, carrageenan (500 MUg/paw) or prostaglandin (PG) E2 (100 ng/paw) was injected in the rat's plantar surface and hypersensitivity was evaluated by the electronic von Frey test. Rats were pre-treated with L-Noarg one hour before carrageenan injection. L-Arginine was given 10 min before L-Noarg injections. ODQ, KT 5823, glibenclamide (Glib), naloxone and AM 251 or AM 630 were administered 30 min prior to carrageenan or PGE2 treatments. RESULTS: Colitis induction by TNBS reduced PGE2 or carrageenan induced hypersensitivity. Antinociception produced by TNBS-induced colitis was reversed significantly (P<0.05) by L-Noarg, ODQ, KT 5823, glibenclamide, naloxone, AM251 and AM630 treatments. CONCLUSIONS: TNBS-induced colitis causes antinociception in the rat paw. This disorder appears to be mediated by activation of the NO/cGMP/PKG/KATP pathway, endocannabinoids and endogenous opioids. This information may contribute to a better understanding of peripheral neurological dysfunctions occurring in Crohn's disease. PMID- 25286905 TI - Results of a cohort of 200 hormone-naive consecutive patients with prostate cancer treated with iodine 125 permanent interstitial brachytherapy by the same multidisciplinary team. AB - PURPOSE: To report survival and morbidity of a cohort of 200 hormone-naive consecutive patients with localized prostate cancer, treated by low-dose rate brachytherapy within the frame of multidisciplinary approach. PATIENTS AND METHODS: Between 2001 and 2011, 200 patients were treated by the same team with 125 iodine seeds: 167 low-risk and 33 intermediate risk according to the d'Amico classification; eligible patients had clinical stage T1/T2a-b, Gleason score 3+3 or 3+4, baseline prostate-specific antigen level below 15ng/mL, prostate volume less than 60cm(3). The median number of random biopsies was 12 (range 6-32) and the breakdown of positive cores was as follows: 1 (29%), 2 (35%), 3 or more (36%). Acute morbidity was assessed according to the Common Terminology Criteria for Adverse Events and late toxicity according to the EORTC/RTOG scale. Data were prospectively collected. RESULTS: The median follow-up was 69 months (range 16 to 135). The 5- and 10-year biochemical relapse free survivals were 95.6% (95% confidence interval [CI]: 91-98) and 89.7% (95% CI: 79.4-95.0). The 5-year and 10 year overall survival were respectively 96.4% (95% CI: 92-98.4) and 89.7% (95% CI: 80.8-94.6%) and the 10-year disease specific survival, 99.1% (95% CI: 93.0 99.9). The 5- and 10-year grade 3 acute toxicity cumulative rate were respectively 3.3% (95% CI: 1.4-6.6) and 4% (95% CI: 1.4-6.6) and the 5- and 10 year grades 3 cumulative late toxicity 2.5% (95% CI: 2.0-5.9) and 4% (95% CI: 2.0 5.9). CONCLUSION: Brachytherapy managed within the frame of a multidisciplinary approach - from diagnosis to evaluation - may offer optimized results with a reduced late toxicity rate, while remaining opened to dosimetry and technical improvements. PMID- 25286906 TI - New options for the adjuvant treatment of cutaneous melanoma? AB - High-dose interferon is the current standard of care for the adjuvant treatment of high-risk cutaneous melanoma. Despite numerous clinical trials using interferon in a variety of doses and schedules, none have demonstrated a meaningful clinical improvement relative to standard high-dose interferon. Recently however, a phase III trial using biochemotherapy demonstrated a superior relapse-free survival benefit over standard interferon. In addition, several agents approved for use in metastatic melanoma are being investigated in the adjuvant setting. PMID- 25286907 TI - Effects of supplementing cassava peels with cassava leaves and cowpea haulms on the performance, intake, digestibility and nitrogen utilization of West African Dwarf goats. AB - A 16-week experiment was conducted to determine the utilization of ratios of cassava leaf meal, cassava peel and cowpea haulms by West African Dwarf (WAD) goats. Thirty WAD bucks aged 8 +/- 1.3 months with body weights of 6-6.5 +/- 0.12 kg were divided into five groups of six animals and each group randomly assigned to one of the treatments in a completely randomized design. The five dietary treatments were formulated to contain cassava peels, leaves and cowpea haulms at different proportions of 700:100:175 (T1), 500:200:275 (T2), 300:300:375 (T3) and 100:400:475 (T4) g/kg dry matter (DM), respectively. A standard diet formulated to meet the nutrient requirement of the animals with no cassava and cowpea haulms was used as the control diet (T5). DM intake ranged from 316.16 to 458.73 g/day and significantly increased (linear (L), quadratic (Q), cubic (C): P < 0.05) as the inclusion of cassava peels reduced and cassava leaves and cowpea haulms increased in the diets. The crude protein (CP) intake significantly increased (L, Q, C: P < 0.05) as the inclusion of cassava peels reduced and cassava leaves and cowpea haulms increased in the diets. Growth rate values significantly (L: P < 0.05; Q: P < 0.01) ranged from 21.55 g/day in T1 to 43.09 g/day in T4. The feed conversion ratio was significantly (L, Q: P <0.01) lowest in T4 (11.35) and was highest in animals in T5 (14.33). Dry matter digestibility significantly (L, Q, C: P < 0.05) ranged from 78.94 to 89.52 %. The digestibility increased as the inclusion of cassava leaves and cowpea haulms increased and reduced cassava peels in the diets. The highest N intake of 14.75 g/day obtained in T4 was significantly (L: P < 0.01; Q, C: P < 0.05) different from the values of 9.26, 10.56, 11.31 and 12.02 in T1, T2, T3 and T5, respectively. Nitrogen balance values significantly (L, Q, C: P < 0.05) ranged from 2.75 g/day in T1 to 9.15 g/day in T4. It is recommended that cassava peels, leaves and cowpea haulms in the proportion of 100:400:475 g/kg DM improved the growth and digestibility of WAD goats and can therefore be used to sustain animal performance during the dry season in a total mixed ration. PMID- 25286908 TI - Health experts launch campaign to reverse NHS reforms. PMID- 25286909 TI - Nerve ultrasound in patients with CMT1C: description of 3 cases. PMID- 25286910 TI - Medication-overuse headache in China: clinical profile, and an evaluation of the ICHD-3 beta diagnostic criteria. AB - BACKGROUND: Although medication-overuse headache (MOH) is common in China, its clinical profile is not yet fully established. Meanwhile, ICHD-3 beta has been published, but its diagnostic criteria require further validation. METHODS: We retrospectively classified the clinical features of 240 consecutive patients with MOH (55 males, 185 females), whose demographic data, headache features, overused medications (type, quantity, frequency and duration of use), headache-attributed burden, and outcomes were reviewed. We then applied the criteria of the several versions of ICHD (II, IIR and 3-beta) to these patients. RESULTS: Compared with those with other headaches, patients with MOH were more likely to be less well educated (64.6% vs 42.0% for secondary school or lower, p < 0.0001), and on lower annual incomes (72.3% vs 56.0% for an income of Chinese yuan (CNY) 30,000 or less, p < 0.0001). Combination analgesics were the most commonly overused medications, and, caffeine (89.9%), aminopyrine (70.0%), phenacetin (53.9%) and phenobarbital (48.8%) were the most commonly used specific components of these. Only two patients (0.8%) had previously been given the diagnosis of MOH; accordingly, the median time to diagnosis after the estimated onset of the disorder was 4.0 years. The majority of patients (83.7%) improved with treatment. All 240 patients fulfilled the diagnostic criteria for MOH according to ICHD-3 beta; only 134 (55.8%) satisfied the diagnostic criteria for definite MOH according to ICHD-II, while 195 (81.2%) met those of ICHD-IIR. CONCLUSIONS: MOH in China is associated with lower educational level and annual income. MOH has rarely been diagnosed and correctly treated in China. ICHD-3 beta appears to be more appropriate for the diagnosis of MOH than previous versions. PMID- 25286911 TI - The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS. AB - The brain-blood barrier (BBB) tightly limits immune cell migration into the central nervous system (CNS), avoiding unwanted inflammation under the normal state. However, immune cells can traverse the BBB when inflammation occurs within the CNS, suggesting a certain signal that creates a gateway that bypasses the BBB might exist. We revealed the inflammation amplifier as a mechanism of this signal, and identified dorsal vessels of the fifth lumber (L5) spinal cord as the gateway. The inflammation amplifier is driven by a simultaneous activation of NF kappaB and STATs in non-immune cells, causing the production of a large amount of inflammatory chemokines to open the gateway at L5 vessels. It was found that the activation of the amplifier can be modulated by neural activation and artificially operated by electric pulses followed by establishment of new gateways, Gateway Reflex, at least in mice. Furthermore, genes required for the inflammation amplifier have been identified and are highly associated with various inflammatory diseases and disorders in the CNS. Thus, physical and/or pharmacological manipulation of the inflammation amplifier holds therapeutic value to control neuro-inflammation. PMID- 25286912 TI - Shifting liberal and conservative attitudes using moral foundations theory. AB - People's social and political opinions are grounded in their moral concerns about right and wrong. We examine whether five moral foundations--harm, fairness, ingroup, authority, and purity--can influence political attitudes of liberals and conservatives across a variety of issues. Framing issues using moral foundations may change political attitudes in at least two possible ways: (a) Entrenching: Relevant moral foundations will strengthen existing political attitudes when framing pro-attitudinal issues (e.g., conservatives exposed to a free-market economic stance) and (b) Persuasion: Mere presence of relevant moral foundations may also alter political attitudes in counter-attitudinal directions (e.g., conservatives exposed to an economic regulation stance). Studies 1 and 2 support the entrenching hypothesis. Relevant moral foundation-based frames bolstered political attitudes for conservatives (Study 1) and liberals (Study 2). Only Study 2 partially supports the persuasion hypothesis. Conservative-relevant moral frames of liberal issues increased conservatives' liberal attitudes. PMID- 25286913 TI - Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. AB - BACKGROUND: No treatment strategies have been demonstrated to be beneficial for the population for patients with heart failure (HF) and preserved ejection fraction (EF). METHODS AND RESULTS: The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial was a prospective, single-blinded, randomized controlled clinical trial testing the hypothesis that hemodynamically guided HF management decreases decompensation leading to hospitalization. Of the 550 patients enrolled in the study, 119 had left ventricular EF >=40% (average, 50.6%), 430 patients had low left ventricular EF (<40%; average, 23.3%), and 1 patient had no documented left ventricular EF. A microelectromechanical system pressure sensor was permanently implanted in all participants during right heart catheterization. After implant, subjects were randomly assigned in single-blind fashion to a treatment group in whom daily uploaded pressures were used in a treatment strategy for HF management or to a control group in whom standard HF management included weight-monitoring, and pressures were uploaded but not available for investigator use. The primary efficacy end point of HF hospitalization rate >6 months for preserved EF patients was 46% lower in the treatment group compared with control (incidence rate ratio, 0.54; 95% confidence interval, 0.38-0.70; P<0.0001). After an average of 17.6 months of blinded follow-up, the hospitalization rate was 50% lower (incidence rate ratio, 0.50; 95% confidence interval, 0.35-0.70; P<0.0001). In response to pulmonary artery pressure information, more changes in diuretic and vasodilator therapies were made in the treatment group. CONCLUSIONS: Hemodynamically guided management of patients with HF with preserved EF reduced decompensation leading to hospitalization compared with standard HF management strategies. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00531661. PMID- 25286914 TI - Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study. AB - BACKGROUND: Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure are unknown. METHODS AND RESULTS: In this double-blind, randomized, placebo controlled, multicenter study, patients with New York Heart Association Class II to III chronic heart failure, left ventricular ejection fraction <=45%, and estimated glomerular filtration rate (GFR) 30 to 89 mL/min per 1.73 m(2) received intravenous serelaxin 30 MUg/kg per day or placebo for 24 hours. Primarily, we assessed the difference between serelaxin and placebo on renal plasma flow (para aminohippuric acid clearance) and GFR (iothalamate clearance) over 8 to 24 hours. All 22 patients from 1 clinical site were excluded from primary analyses before unblinding because of implausible measurements. The primary analysis comprised 65 patients, mean age was 68 (+/-10) years, 89% were male, mean estimated GFR was 64 (+/-19) mL/min per 1.73 m(2), and 34% had New York Heart Association Class III symptoms. Renal plasma flow increased by 29% with serelaxin and 14% with placebo (13% relative increase with serelaxin; P=0.0386), whereas GFR changes did not differ significantly during 8 to 24 hours. Filtration fraction increased by 36% with serelaxin and 62% with placebo (16% relative decrease with serelaxin; P=0.0019) during 8 to 24 hours. Changes in systolic blood pressure were largely similar, and creatinine clearance did not differ between groups. Adverse event rates were similar with serelaxin (20.5%) and placebo (25.0%). CONCLUSIONS: In patients with chronic heart failure, serelaxin increased renal plasma flow and reduced the increase in filtration fraction compared with placebo, but did not affect GFR. These results suggest beneficial renal hemodynamic effects in patients with chronic heart failure. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01546532. PMID- 25286915 TI - Inter-reader agreement in HRCT detection of pleural plaques and asbestosis in participants with previous occupational exposure to asbestos. AB - OBJECTIVES: To investigate inter-reader agreement for the detection of pleural and parenchymal abnormalities using CT in a large cross-sectional study comprising information on individual cumulative exposure to asbestos. METHODS: The project was approved by the hospital ethics committee, and all patients received information on the study and gave their written informed consent. In 5511 CT scans performed in a cohort of retired workers previously exposed to asbestos and volunteering to participate in a multiregional survey programme (Asbestos Related Diseases Cohort, ARDCO), double randomised standardised readings, triple in case of disagreement, were performed by seven trained expert radiologists specialised in thoracic imaging and blind to the initial interpretation. Inter-reader agreement was evaluated by calculating the kappa weighted coefficient between pairs of expert readers and results of routine practice and final diagnosis after expert reading. RESULTS: kappa-Weighted coefficients between trained experts ranged from 0.28 to 0.52 (fair to good), 0.59 to 0.86 (good to excellent) and 0.11 to 0.66 (poor to good) for the diagnosis of asbestosis, pleural plaques and fibrosis of the visceral pleura, respectively. kappa-Weighted coefficients between results of routine practice and final diagnosis after expert reading were 0.13 (poor), 0.53 (moderate) and 0.11 (poor) for the diagnosis of asbestosis, pleural plaques and fibrosis of the visceral pleura, respectively. CONCLUSIONS: Interpretation of benign asbestos related thoracic abnormalities requires standardisation of the reading and trained readers, particularly for participants asking for compensation, and with a view to the longitudinal survey of asbestos-exposed workers. PMID- 25286916 TI - Low-level cadmium exposure and effects on kidney function. AB - OBJECTIVES: The nephrotoxicity of cadmium at low levels of exposure, measured by urinary cadmium, has recently been questioned since co-excretion of cadmium and proteins may have causes other than cadmium toxicity. The aim of this study was to explore the relation between kidney function and low or moderate cadmium levels, measured directly in kidney biopsies. METHODS: We analysed cadmium in kidney biopsies (K-Cd), blood (B-Cd) and urine (U-Cd) from 109 living kidney donors in a cross-sectional study. We measured glomerular filtration rate (GFR), cystatin C in serum, albumin, beta-2-microglobulin (B2M), retinol-binding protein (RBP), alpha-1-microglobulin (A1M), N-acetyl-beta-d-glucosaminidase and kidney injury molecule 1 (KIM-1) in 24 h and overnight urine. RESULTS: We found significant positive associations between A1M excretion and K-Cd in multiple regression models including age, sex, weight, smoking and urinary flow rate. This association was also present in never-smokers. A1M was also positively associated with B-Cd and U-Cd. GFR and the other biomarkers of kidney function were not associated with K-Cd. GFR estimated from serum cystatin C showed a very poor correlation with measured GFR. KIM-1, RBP and possibly albumin were positively associated with U-Cd, but only in overnight urine. No associations were found with B2M. CONCLUSIONS: Our results suggest that A1M in urine is a sensitive biomarker for effects of low-level cadmium exposure. A few associations between other renal biomarkers and U-Cd, but not K-Cd, were probably caused by physiological co-excretion or chance. PMID- 25286917 TI - Syncope. AB - Syncope is common representing approximately 3% of ED visits and up to 6% of hospital admissions, with a cost close to 2 billion dollars per year. Diagnostic testing is often poorly sensitive and evaluations commonly lack a standardized approach. A mindful and systematic approach can increase sensitivity and improve diagnostic accuracy. A thorough history and physical exam is paramount, as conclusions drawn from the history and exam will guide further assessment. Developing a strategy for the first and, if necessary, subsequent tests will improve the accuracy of identifying the etiology of syncope and reduce cost. Although syncope has a favorable prognosis, identification of patients with structural heart disease is critical, as these patients are at greatest risk for mortality. Several risk scoring systems have been developed to help separate high risk from low risk patients. PMID- 25286918 TI - Pheochromocytoma-Induced Inverted Takotsubo-Like Cardiomyopathy Leading to Cardiogenic Shock Successfully Treated With Extracorporeal Membrane Oxygenation. AB - Pheochromocytoma classically displays a variety of rather benign symptoms, such as headache, palpitations, and sweating, although severe cardiac manifestations have been described. We report a case of pheochromocytoma-induced inverted takotsubo-like cardiomyopathy leading to shock and cardiac arrest successfully treated with extracorporeal membrane oxygenation (ECMO) as a bridge to pharmacological therapy and curative adrenalectomy. A previously healthy 46-year old woman presented to the emergency department with abdominal pain, dyspnea, nausea, and vomiting. Clinical evaluation revealed cardiorespiratory failure with hypoxia and severe metabolic acidosis. Computed tomography (CT) scan showed pulmonary edema and a left adrenal mass. Transthoracic echocardiography (TTE) displayed severe left ventricular dysfunction with inverted takotsubo contractile pattern. Despite mechanical ventilation and inotropic and vasopressor support, asystolic cardiac arrest ensued. The patient was resuscitated using manual chest compressions followed by venoarterial ECMO. Repeated TTEs demonstrated resolution of the cardiomyopathy within a few days. Laboratory results indicated transient renal and hepatic dysfunction, and CT scan of the brain displayed occipital infarctions. Biochemical testing and radionuclide scintigraphy confirmed a pheochromocytoma. Pharmacological adrenergic blockade was instituted prior to delayed adrenalectomy after which the diagnosis was histopathologically verified. The patient recovered after rehabilitation. We conclude that pheochromocytoma should be considered in patients presenting with unexplained cardiovascular compromise, especially if they display (inverted) takotsubo contractile pattern. Timely, adequate management might involve ECMO as a bridge to pharmacological therapy and curative surgery. PMID- 25286919 TI - Computing autocatalytic sets to unravel inconsistencies in metabolic network reconstructions. AB - MOTIVATION: Genome-scale metabolic network reconstructions have been established as a powerful tool for the prediction of cellular phenotypes and metabolic capabilities of organisms. In recent years, the number of network reconstructions has been constantly increasing, mostly because of the availability of novel (semi )automated procedures, which enabled the reconstruction of metabolic models based on individual genomes and their annotation. The resulting models are widely used in numerous applications. However, the accuracy and predictive power of network reconstructions are commonly limited by inherent inconsistencies and gaps. RESULTS: Here we present a novel method to validate metabolic network reconstructions based on the concept of autocatalytic sets. Autocatalytic sets correspond to collections of metabolites that, besides enzymes and a growth medium, are required to produce all biomass components in a metabolic model. These autocatalytic sets are well-conserved across all domains of life, and their identification in specific genome-scale reconstructions allows us to draw conclusions about potential inconsistencies in these models. The method is capable of detecting inconsistencies, which are neglected by other gap-finding methods. We tested our method on the Model SEED, which is the largest repository for automatically generated genome-scale network reconstructions. In this way, we were able to identify a significant number of missing pathways in several of these reconstructions. Hence, the method we report represents a powerful tool to identify inconsistencies in large-scale metabolic networks. AVAILABILITY AND IMPLEMENTATION: The method is available as source code on http://users.minet.uni jena.de/~m3kach/ASBIG/ASBIG.zip. CONTACT: christoph.kaleta@uni-jena.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25286920 TI - Deviance residuals-based sparse PLS and sparse kernel PLS regression for censored data. AB - MOTIVATION: A vast literature from the past decade is devoted to relating gene profiles and subject survival or time to cancer recurrence. Biomarker discovery from high-dimensional data, such as transcriptomic or single nucleotide polymorphism profiles, is a major challenge in the search for more precise diagnoses. The proportional hazard regression model suggested by Cox (1972), to study the relationship between the time to event and a set of covariates in the presence of censoring is the most commonly used model for the analysis of survival data. However, like multivariate regression, it supposes that more observations than variables, complete data, and not strongly correlated variables are available. In practice, when dealing with high-dimensional data, these constraints are crippling. Collinearity gives rise to issues of over-fitting and model misidentification. Variable selection can improve the estimation accuracy by effectively identifying the subset of relevant predictors and enhance the model interpretability with parsimonious representation. To deal with both collinearity and variable selection issues, many methods based on least absolute shrinkage and selection operator penalized Cox proportional hazards have been proposed since the reference paper of Tibshirani. Regularization could also be performed using dimension reduction as is the case with partial least squares (PLS) regression. We propose two original algorithms named sPLSDR and its non linear kernel counterpart DKsPLSDR, by using sparse PLS regression (sPLS) based on deviance residuals. We compared their predicting performance with state-of-the art algorithms on both simulated and real reference benchmark datasets. RESULTS: sPLSDR and DKsPLSDR compare favorably with other methods in their computational time, prediction and selectivity, as indicated by results based on benchmark datasets. Moreover, in the framework of PLS regression, they feature other useful tools, including biplots representation, or the ability to deal with missing data. Therefore, we view them as a useful addition to the toolbox of estimation and prediction methods for the widely used Cox's model in the high-dimensional and low-sample size settings. AVAILABILITY AND IMPLEMENTATION: The R-package plsRcox is available on the CRAN and is maintained by Frederic Bertrand. http://cran.r-project.org/web/packages/plsRcox/index.html. CONTACT: pbastien@rd.loreal.com or fbertran@math.unistra.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25286921 TI - Chimera: a Bioconductor package for secondary analysis of fusion products. AB - SUMMARY: Chimera is a Bioconductor package that organizes, annotates, analyses and validates fusions reported by different fusion detection tools; current implementation can deal with output from bellerophontes, chimeraScan, deFuse, fusionCatcher, FusionFinder, FusionHunter, FusionMap, mapSplice, Rsubread, tophat fusion and STAR. The core of Chimera is a fusion data structure that can store fusion events detected with any of the aforementioned tools. Fusions are then easily manipulated with standard R functions or through the set of functionalities specifically developed in Chimera with the aim of supporting the user in managing fusions and discriminating false-positive results. PMID- 25286923 TI - High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation. AB - This study aimed to evaluate the long-term prognostic usefulness of (18)F-FDG PET for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEPNETs). METHODS: Thirty-eight patients with metastatic GEPNETs were prospectively enrolled. Initial check-up comprised CT scan, (111)In-pentetreotide scintigraphy (SRS), and (18)F-FDG PET. Only (18)F-FDG PET-positive lesions with a maximum standardized uptake value (SUVmax) greater than 4.5 or an SUV ratio (SUVmax tumor to SUVmax nontumoral liver tissue, or T/NT ratio) of 2.5 or greater were considered positive for prognosis-that is, indicating a poor prognosis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Factors associated with survival were assessed with univariate and multivariate analyses, using the Cox regression model. RESULTS: Median PFS and OS were significantly higher for patients with a negative (18)F FDG PET finding, with an OS of 119.5 mo (95% confidence interval [CI], 72 infinity), than for patients with a positive (18)F-FDG PET finding (only 15 mo [95% CI, 4-27]) (P < 10(-3)). Median PFS and OS were significantly higher for the patient group that had a positive SRS than the group with a negative SRS (P = 0.0002). For patients with a positive SRS, PFS and OS were significantly shorter when the (18)F-FDG PET finding was positive: 19.5 mo (95% CI, 4-37) for PFS and 119.5 mo (95% CI, 81-infinity) for OS (P < 10(-3)). In the patient group with a low-grade GEPNET and a positive SRS, PFS and OS were also significantly lower for patients with a positive (18)F-FDG PET. At 48-mo follow-up, 100% of patients who had a positive (18)F-FDG PET for disease progression (of which 47% were also SRS positive) were deceased, and 87% of patients with a negative (18)F-FDG PET were alive (P < 0.0001). The T/NT ratio was the only parameter associated with OS on multivariate analysis. CONCLUSION: Overall, (18)F-FDG PET appears to be of major importance in the prognostic evaluation of metastatic GEPNET. A positive (18)F FDG PET with an SUV ratio (T/NT) of 2.5 or greater was a poor prognostic factor, with a 4-y survival rate of 0%. A positive SRS does not eliminate the need for performing (18)F-FDG PET, which is of greater prognostic utility. PMID- 25286922 TI - Internal dose assessment of (-)-18F-flubatine, comparing animal model datasets of mice and piglets with first-in-human results. AB - (-)-(18)F-flubatine is a promising tracer for neuroimaging of nicotinic acetylcholine receptors (nAChRs), subtype alpha4beta2, using PET. Radiation doses after intravenous administration of the tracer in mice and piglets were assessed to determine the organ doses (ODs) and the effective dose (ED) to humans. The results were compared with subsequent clinical investigations in human volunteers. METHODS: Twenty-seven female CD1 mice (weight +/- SD, 28.2 +/- 2.1 g) received intravenous injection of 0.75 +/- 0.33 MBq of (-)-(18)F-flubatine. Up to 240 min after injection, 3 animals per time point were sacrificed and the organs harvested, weighed, and counted in a gamma counter to determine mass and activity, respectively. Furthermore, whole-body PET scans of 5 female piglets (age +/- SD, 44 +/- 3 d; weight +/- SD, 13.7 +/- 1.7 kg) and 3 humans (2 men and 1 woman; age +/- SD, 59.6 +/- 3.9 y; weight +/- SD, 74.3 +/- 3.1 kg) were obtained up to 236 min (piglets) and 355 min (humans) after injection of 186.6 +/ 7.4 and 353.7 +/- 10.2 MBq of (-)-(18)F-flubatine, respectively, using a PET/CT scanner. The CT was used for delineation of the organs. Exponential curves were fitted to the time-activity-data, and time and mass scales were adapted to the human anatomy. The ODs were calculated using OLINDA/EXM (version 1.0); EDs were calculated with the tissue-weighting factors of ICRP103. RESULTS: After the injection of (-)-(18)F-flubatine, there were no adverse or clinically detectable pharmacologic effects in any of the subjects. The highest activities after injection were found in the kidneys, urinary bladder, and liver. The urinary bladder receives the highest OD in all investigated species, followed by the kidneys and the liver for animals and humans, respectively. On the basis of mouse, piglet, and human kinetic data, the projected human ED of (-)-(18)F flubatine was estimated to be 12.5 MUSv/MBq in mice, 14.7 +/- 0.7 MUSv/MBq in piglets, and 23.4 +/- 0.4 MUSv/MBq in humans. CONCLUSION: As has been demonstrated for other PET radiotracers, preclinical (i.e., animal-derived) dosimetry underestimates the ED to humans, in the current case of (-)-(18)F flubatine by 34%-44%. PMID- 25286925 TI - Clinical genomics and the adult with congenital heart disease: new opportunities. PMID- 25286924 TI - 18F-FDG kinetics parameters depend on the mechanism of injury in early experimental acute respiratory distress syndrome. AB - PET with (18)F-FDG allows for noninvasive assessment of regional lung metabolism reflective of neutrophilic inflammation. This study aimed at determining during early acute lung injury whether local (18)F-FDG phosphorylation rate and volume of distribution were sensitive to the initial regional inflammatory response and whether they depended on the mechanism of injury: endotoxemia and surfactant depletion. METHODS: Twelve sheep underwent homogeneous unilateral surfactant depletion (alveolar lavage) and were mechanically ventilated for 4 h (positive end-expiratory pressure, 10 cm H2O; plateau pressure, 30 cm H2O) while receiving intravenous endotoxin (lipopolysaccharide-positive [LPS+] group; n = 6) or not (lipopolysaccharide-negative group; n = 6). (18)F-FDG PET emission scans were then acquired. (18)F-FDG phosphorylation rate and distribution volume were calculated with a 4-compartment model. Lung tissue expression of inflammatory cytokines was measured using real-time quantitative reverse transcription polymerase chain reaction. RESULTS: (18)F-FDG uptake increased in LPS+ (P = 0.012) and in surfactant-depleted sheep (P < 0.001). These increases were topographically heterogeneous, predominantly in dependent lung regions, and without interaction between alveolar lavage and LPS. The increase of (18)F-FDG uptake in the LPS+ group was related both to increases in the (18)F-FDG phosphorylation rate (P < 0.05) and to distribution volume (P < 0.01). (18)F-FDG distribution volume increased with infiltrating neutrophils (P < 0.001) and phosphorylation rate with the regional expression of IL-1beta (P = 0.026), IL-8 (P = 0.011), and IL-10 (P = 0.023). CONCLUSION: Noninvasive (18)F-FDG PET-derived parameters represent histologic and gene expression markers of early lung injury. Pulmonary metabolism assessed with (18)F-FDG PET depends on the mechanism of injury and appears to be additive for endotoxemia and surfactant depletion. (18)F FDG PET may be a valuable imaging biomarker of early lung injury. PMID- 25286926 TI - Recurrent blackouts in a 36-year-old woman: familial LQTS. PMID- 25286927 TI - Angiopoietin-2, its soluble receptor Tie-2 and subclinical cardiovascular disease in a population-based sample. AB - OBJECTIVE: Higher circulating Angiopoietin-2 (Ang-2) levels predict cardiovascular events and mortality in clinical samples and in the general population. To better understand the underlying mechanisms, we investigated the association of circulating Ang-2 and sTie-2 (the soluble form of the Ang-2 receptor) levels with various measures of subclinical cardiovascular disease. METHODS: Cross-sectional data of 3204 participants (1654 women) aged 25-88 years from the population-based Study of Health in Pomerania were analysed. LV mass (LVM) and fractional shortening were determined echocardiographically as indices of cardiac structure and function, respectively. Intima media thickness (IMT) of the common carotid artery, the number of carotid plaques and flow-mediated dilation (FMD) were used to characterise large and medium-sized arterial structure and function. RESULTS: Multivariable-adjusted linear and negative binomial regression models revealed an inverse association of circulating Ang-2 levels (independent variable) with fractional shortening (beta=-0.51 per 1 SD increment; 95% CI -0.86 to -0.16, p=0.005) and a positive association with number of carotid plaques (rate ratio=1.04 95% CI 1.01 to 1.07, p=0.019). No associations of Ang-2 or sTie-2 with LVM, IMT and FMD were found. CONCLUSIONS: Circulating Ang-2 levels were associated with select subclinical cardiovascular disease traits, consistent with the notion that the Ang-2-pathway plays a role in mediating cardiovascular morbidity. PMID- 25286928 TI - Emerging trends in diabetes care practice and policy in The Netherlands: a key informants study. AB - BACKGROUND: Effective self-management is viewed as the cornerstone of diabetes care. Many interventions and policies are available to support self-management, but challenges remain regarding reaching specific subgroups and effectively changing lifestyles. Here, our aim was to identify emerging policies and practices regarding diabetes care in The Netherlands. METHODS: Study with a purposeful sample of key informants, covering a range of stakeholders. They were individually interviewed, using a flexible and semi-structured approach. A thematic analysis was done, guided by an international framework, which resulted in 28 themes. RESULTS: After a decade of investing in diabetes care in The Netherlands, stakeholders seem to have shifted their focus towards a view that effective self-management is expected in most people. The expectation is that individuals' personal networks, community organizations and emerging information technologies will facilitate this. If support of self-management is required, this has to be provided by local coalitions of health and social care organizations, with involvement of municipalities. Poor reach in specific subgroups of the population, such as economically deprived people, is recognized but has not led to targeted policies. CONCLUSIONS: The role of healthcare providers in supporting patients' self-management in diabetes care seems to be changing in The Netherlands. PMID- 25286929 TI - Reduced interferon-alpha production by dendritic cells in type 1 diabetes does not impair immunity to influenza virus. AB - The increased risk and persistence of infections in diabetic condition is probably associated with defects in the cellular immune responses. We have previously shown a decrease in the production of interferon (IFN)-alpha by dendritic cells (DCs) in diabetic subjects. The basal level of IFN-alpha in splenic plasmacytoid DCs (pDCs) is also lower in non-obese diabetic (NOD) mice compared to prediabetic mice. The objective of this study was to analyse the ability of diabetic mice to mobilize innate and CD8(+) T cell-mediated immune response to influenza A virus (IAV) with the live influenza A/Puerto Rico/8/1934 H1N1 (PR8) strain or with its immunodominant CD8(+) T cell epitopes. We found that following immunization with IAV, the level of IFN-alpha in diabetic mice was increased to the level in prediabetic mice. Immunization of NOD mice with the immunodominant IAV PR8 peptide induced clonal expansion of IFN-gamma-producing CD8(+) T cells similar to the response observed in prediabetic mice. Thus, diabetic and prediabetic NOD mice have a similar capacity for IFN-alpha and IFN gamma production by pDCs and CD8(+) T cells, respectively. Therefore, the DC related immune defect in diabetic NOD mice does not impair their capacity to develop an effective immune response to IAV. Our results suggest that reduced IFN alpha production by diabetic human and mouse DCs is not an impediment to an effective immunity to IAV in type 1 diabetic subjects vaccinated with live attenuated influenza vaccine. PMID- 25286930 TI - A drunken search in crystallization space. AB - The REMARK280 field of the Protein Data Bank is the richest open source of successful crystallization information. The REMARK280 field is optional and currently uncurated, so significant effort needs to be applied to extract reliable data. There are well over 15 000 crystallization conditions available commercially from 12 different vendors. After putting the PDB crystallization information and the commercial cocktail data into a consistent format, these data are used to extract information about the overlap between the two sets of crystallization conditions. An estimation is made as to which commercially available conditions are most appropriate for producing well diffracting crystals by looking at which commercial conditions are found unchanged (or almost unchanged) in the PDB. Further analyses include which commercial kits are the most appropriate for shotgun or more traditional approaches to crystallization screening. This analysis suggests that almost 40% of the crystallization conditions found currently in the PDB are identical or very similar to a commercial condition. PMID- 25286931 TI - The structure of lactoferrin-binding protein B from Neisseria meningitidis suggests roles in iron acquisition and neutralization of host defences. AB - Pathogens have evolved a range of mechanisms to acquire iron from the host during infection. Several Gram-negative pathogens including members of the genera Neisseria and Moraxella have evolved two-component systems that can extract iron from the host glycoproteins lactoferrin and transferrin. The homologous iron transport systems consist of a membrane-bound transporter and an accessory lipoprotein. While the mechanism behind iron acquisition from transferrin is well understood, relatively little is known regarding how iron is extracted from lactoferrin. Here, the crystal structure of the N-terminal domain (N-lobe) of the accessory lipoprotein lactoferrin-binding protein B (LbpB) from the pathogen Neisseria meningitidis is reported. The structure is highly homologous to the previously determined structures of the accessory lipoprotein transferrin-binding protein B (TbpB) and LbpB from the bovine pathogen Moraxella bovis. Docking the LbpB structure with lactoferrin reveals extensive binding interactions with the N1 subdomain of lactoferrin. The nature of the interaction precludes apolactoferrin from binding LbpB, ensuring the specificity of iron-loaded lactoferrin. The specificity of LbpB safeguards proper delivery of iron-bound lactoferrin to the transporter lactoferrin-binding protein A (LbpA). The structure also reveals a possible secondary role for LbpB in protecting the bacteria from host defences. Following proteolytic digestion of lactoferrin, a cationic peptide derived from the N-terminus is released. This peptide, called lactoferricin, exhibits potent antimicrobial effects. The docked model of LbpB with lactoferrin reveals that LbpB interacts extensively with the N-terminal lactoferricin region. This may provide a venue for preventing the production of the peptide by proteolysis, or directly sequestering the peptide, protecting the bacteria from the toxic effects of lactoferricin. PMID- 25286932 TI - Structure of a short-chain dehydrogenase/reductase (SDR) within a genomic island from a clinical strain of Acinetobacter baumannii. AB - Over 15% of the genome of an Australian clinical isolate of Acinetobacter baumannii occurs within genomic islands. An uncharacterized protein encoded within one island feature common to this and other International Clone II strains has been studied by X-ray crystallography. The 2.4 A resolution structure of SDR WM99c reveals it to be a new member of the classical short-chain dehydrogenase/reductase (SDR) superfamily. The enzyme contains a nucleotide binding domain and, like many other SDRs, is tetrameric in form. The active site contains a catalytic tetrad (Asn117, Ser146, Tyr159 and Lys163) and water molecules occupying the presumed NADP cofactor-binding pocket. An adjacent cleft is capped by a relatively mobile helical subdomain, which is well positioned to control substrate access. PMID- 25286933 TI - Human carbonic anhydrase II-cyanate inhibitor complex: putting the debate to rest. AB - The binding of anions to carbonic anhydrase II (CA II) has been attributed to high affinity for the active-site zinc. An anion of interest is cyanate, for which contrasting binding modes have been reported in the literature. Previous spectroscopic data have shown cyanate behaving as an inhibitor, directly binding to the zinc, in contrast to previous crystallographic data that implied that cyanate acts as a substrate mimic that is not directly bound to the zinc but overlaps with the binding site of the substrate CO2. Wild-type and the V207I variant of CA II have been expressed and X-ray crystal structures of their cyanate complexes have been determined to 1.7 and 1.5 A resolution, respectively. The rationale for the V207I CA II variant was its close proximity to the CO2 binding site. Both structures clearly show that the cyanate binds directly to the zinc. In addition, inhibition constants (~40 uM) were measured using (18)O exchange mass spectrometry for wild-type and V207I CA II and were similar to those determined previously (Supuran et al., 1997). Hence, it is concluded that under the conditions of these experiments the binding of cyanate to CA II is directly to the zinc, displacing the zinc-bound solvent molecule, and not in a site that overlaps with the CO2 substrate-binding site. PMID- 25286934 TI - Structure of an Aspergillus fumigatus old yellow enzyme (EasA) involved in ergot alkaloid biosynthesis. AB - The Aspergillus fumigatus old yellow enzyme (OYE) EasA reduces chanoclavine-I aldehyde to dihydrochanoclavine aldehyde and works in conjunction with festuclavine synthase at the branchpoint for ergot alkaloid pathways. The crystal structure of the FMN-loaded EasA was determined to 1.8 A resolution. The active site amino acids of OYE are conserved, supporting a similar mechanism for reduction of the alpha/beta-unsaturated aldehyde. The C-terminal tail of one monomer packs into the active site of a monomer in the next asymmetric unit, which is most likely to be a crystallization artifact and not a mechanism of self regulation. PMID- 25286935 TI - Structure of Streptococcus agalactiae glyceraldehyde-3-phosphate dehydrogenase holoenzyme reveals a novel surface. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a conserved cytosolic enzyme, which plays a key role in glycolysis. GAPDH catalyzes the oxidative phosphorylation of D-glyceraldehyde 3-phosphate using NAD or NADP as a cofactor. In addition, GAPDH localized on the surface of some bacteria is thought to be involved in macromolecular interactions and bacterial pathogenesis. GAPDH on the surface of group B streptococcus (GBS) enhances bacterial virulence and is a potential vaccine candidate. Here, the crystal structure of GBS GAPDH from Streptococcus agalactiae in complex with NAD is reported at 2.46 A resolution. Although the overall structure of GBS GAPDH is very similar to those of other GAPDHs, the crystal structure reveals a significant difference in the area spanning residues 294-307, which appears to be more acidic. The amino-acid sequence of this region of GBS GAPDH is also distinct compared with other GAPDHs. This region therefore may be of interest as an immunogen for vaccine development. PMID- 25286936 TI - Structure of homoserine O-acetyltransferase from Staphylococcus aureus: the first Gram-positive ortholog structure. AB - Homoserine O-acetyltransferase (HTA) catalyzes the formation of L-O-acetyl homoserine from L-homoserine through the transfer of an acetyl group from acetyl CoA. This is the first committed step required for the biosynthesis of methionine in many fungi, Gram-positive bacteria and some Gram-negative bacteria. The structure of HTA from Staphylococcus aureus (SaHTA) has been determined to a resolution of 2.45 A. The structure belongs to the alpha/beta-hydrolase superfamily, consisting of two distinct domains: a core alpha/beta-domain containing the catalytic site and a lid domain assembled into a helical bundle. The active site consists of a classical catalytic triad located at the end of a deep tunnel. Structure analysis revealed some important differences for SaHTA compared with the few known structures of HTA. PMID- 25286937 TI - Expression, purification and preliminary crystallographic analysis of the cryptic polo-box domain of Caenorhabditis elegans ZYG-1. AB - ZYG-1 is a polo-like kinase essential for centriole assembly in Caenorhabditis elegans. The targeting of ZYG-1 to nascent centrioles is via its central cryptic polo-box (CPB) domain. To shed light on the molecular basis of ZYG-1 recruitment, it is necessary to obtain structural knowledge of the ZYG-1 CPB. Here, the expression, purification and preliminary crystallographic analysis of the ZYG-1 CPB are reported. The protein was overexpressed in Escherichia coli strain BL21 (DE3), purified by multi-step chromatography and crystallized using the vapour diffusion method. Crystals of the wild-type protein exhibited an order-disorder pathology, which was solved by reductive lysine methylation. A complete anomalous data set was collected to 2.54 A resolution at the Se K edge (lambda = 0.9792 A). The crystal belonged to space group P2, with unit-cell parameters a = 53.3, b = 60.09, c = 87.51 A, beta = 93.31 degrees . There were two molecules in the asymmetric unit. PMID- 25286938 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of human IL-18 and its extracellular complexes. AB - Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the interleukin 1 (IL-1) family, is involved in the pathogenesis of autoimmune/autoinflammatory and allergic diseases such as juvenile idiopathic arthritis and bronchial asthma. IL-18 forms a signalling complex with the IL-18 receptor alpha (IL-18Ralpha) and beta (IL-18Rbeta) chains; however, the detailed activation mechanism remains unclear. Here, the IL-18-IL-18Ralpha binary and IL-18-IL-18Ralpha-IL-18Rbeta ternary complexes were purified and crystallized as well as IL-18 alone. An X-ray diffraction data set for IL-18 was collected to 2.33 A resolution from a crystal belonging to space group P21, with unit-cell parameters a = 68.15, b = 79.51, c = 73.46 A, beta = 100.97 degrees . Crystals of both the IL-18 binary and ternary complexes belonging to the orthorhombic space groups P21212 and P212121, respectively, diffracted to 3.10 A resolution. Unit-cell parameters were determined as a = 135.49, b = 174.81, c = 183.40 A for the binary complex and a = 72.56, b = 111.56, c = 134.57 A for the ternary complex. PMID- 25286939 TI - Crystallization and preliminary X-ray diffraction analysis of the Pax9 paired domain bound to a DC5 enhancer DNA element. AB - Pax genes belong to a family of metazoan transcription factors that are known to play a critical role in eye, ear, kidney and neural development. The mammalian Pax family of transcription factors is characterized by a ~128-amino-acid DNA binding paired domain that makes sequence-specific contacts with DNA. The diversity in Pax gene activities emerges from complex modes of interaction with enhancer regions and heterodimerization with multiple interaction partners. Based on in vitro optimal binding-site selection studies and enhancer identification assays, it has been suggested that Pax proteins may recognize and bind their target DNA elements with different binding modes/topologies, however this hypothesis has not yet been structurally explored. One of the most extensively studied DNA target elements of the Pax6 paired domain is the eye-lens specific DC5 (delta-crystallin) enhancer element. In order to shed light on Pax6-DC5 DNA interactions, the related paired-domain prototype Pax9 was crystallized with the minimal delta-crystallin DC5 enhancer element and preliminary X-ray diffraction analysis was attempted. A 3.0 A resolution native data set was collected at the National Synchrotron Light Source (NSLS), Brookhaven from crystals grown in a solution consisting of 10%(w/v) PEG 20K, 20%(v/v) PEG 550 MME, 0.03 M NaNO3, 0.03 M Na2HPO4, 0.03 M NH2SO4, 0.1 M MES/imidazole pH 6.5. The data set was indexed and merged in space group C2221, with unit-cell parameters a = 75.74, b = 165.59, c = 70.14 A, alpha = beta = gamma = 90 degrees . The solvent content in the unit cell is consistent with the presence of one Pax9 paired domain bound to duplex DNA in the asymmetric unit. PMID- 25286940 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction of a lysine-specific permease from Pseudomonas aeruginosa. AB - The prokaryotic lysine-specific permease (LysP) belongs to the amino acid polyamine-organocation (APC) transporter superfamily. In the cell, members of this family are responsible for the uptake and recycling of nutrients, for the maintenance of a constant internal ion concentration and for cell volume regulation. The detailed mechanism of substrate selectivity and transport of L lysine by LysP is not understood. A high-resolution crystal structure would enormously facilitate such an understanding. To this end, LysP from Pseudomonas aeruginosa was recombinantly expressed in Escherichia coli and purified to near homogeneity by immobilized metal ion-affinity chromatography (IMAC) and size exclusion chromatography (SEC). Hexagonal- and rod-shaped crystals were obtained in the presence of L-lysine and the L-lysine analogue L-4-thialysine by vapour diffusion and diffracted to 7.5 A resolution. The diffraction data were indexed in space group P21, with unit-cell parameters a = 169.53, b = 169.53, c = 290.13 A, gamma = 120 degrees . PMID- 25286941 TI - Expression, crystallization and preliminary X-ray crystallographic analysis of cystathionine beta-lyase from Acinetobacter baumannii OXA-23. AB - Multidrug-resistant Acinetobacter baumannii (Ab) has emerged as a leading nosocomial pathogen because of its resistance to most currently available antibiotics. Cystathionine beta-lyase (CBL), a pyridoxal 5'-phosphate (PLP) dependent enzyme, catalyzes the second step in the transsulfuration pathway, which is essential for the metabolic interconversion of the sulfur-containing amino acids homocysteine and methionine. The enzymes of the transsulfuration pathway are considered to be attractive drug targets owing to their specificity to microbes and plants. As a potential target for the development of novel antibacterial drugs, the AbCBL protein was expressed, purified and crystallized. An AbCBL crystal diffracted to 1.57 A resolution and belonged to the trigonal space group P3112, with unit-cell parameters a = b = 102.9, c = 136.5 A. The asymmetric unit contained two monomers, with a corresponding VM of 2.3 A(3) Da( 1) and a solvent content of 46.9%. PMID- 25286942 TI - Purification and X-ray crystallographic analysis of 7-keto-8-aminopelargonic acid (KAPA) synthase from Mycobacterium smegmatis. AB - 7-Keto-8-aminopelargonic acid synthase (KAPA synthase; BioF) is an essential enzyme for mycobacterial growth that catalyses the first committed step in the biotin-synthesis pathway. It is a pyridoxal 5'-phosphate (PLP)-dependent enzyme and is a potential drug target. Here, the cloning, expression, purification and crystallization of KAPA synthase from Mycobacterium smegmatis (MsBioF) and the characterization of MsBioF crystals using X-ray diffraction are described. The crystals diffracted to 2.3 A resolution and belonged to the monoclinic space group P21, with unit-cell parameters a = 70.88, b = 91.68, c = 109.84 A, beta = 97.8 degrees . According to the molecular weight of MsBioF, the unit-cell parameters and the self-rotation function map, four molecules are present in each asymmetric unit with a VM value of 2.06 A(3) Da(-1) and a solvent content of 40.20%. PMID- 25286943 TI - Expression, purification, crystallization and preliminary X-ray crystallographic analysis of fructose-1,6-bisphosphate aldolase from Escherichia coli. AB - Fructose-1,6-bisphosphate aldolase is one of the most important enzymes in the glycolytic pathway and catalyzes the reversible cleavage of fructose-1,6 bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. The full-length fbaB gene encoding fructose-1,6-bisphosphate aldolase class I (FBPA I) was cloned from Escherichia coli strain BL21. FBPA I was overexpressed in E. coli and purified. Biochemical analysis found that the optimum reaction temperature of FBPA I is 330.5 K and that the enzyme has a high temperature tolerance. Crystals of recombinant FBPA I were obtained by the sitting-drop vapour-diffusion technique in a condition consisting of 19 mg ml(-1) FBPA I in 0.1 M Tris pH 9.0, 10%(w/v) polyethylene glycol 8000 and diffracted to 2.0 A resolution. The crystals belonged to the monoclinic space group C2, with unit cell parameters a = 217.7, b = 114.9, c = 183.9 A, beta = 124.6 degrees . The asymmetric unit of these crystals may contain ten molecules, giving a Matthews coefficient of 2.48 A(3) Da(-1) and a solvent content of 50.5%. PMID- 25286944 TI - Crystallization of the Ets1-Runx1-CBFbeta-DNA complex formed on the TCRalpha gene enhancer. AB - Gene transcription is regulated in part through the assembly of multiple transcription factors (TFs) on gene enhancers. To enable examination of the mechanism underlying the formation of these complexes and their response to a phosphorylation signal, two kinds of higher-order TF-DNA assemblies were crystallized composed of an unmodified or phosphorylated Ets1 fragment, a Runx1(L94K) fragment and a CBFbeta fragment on the T-cell receptor (TCR) alpha gene enhancer. Within these complexes, the Ets1 and Runx1 fragments contain intrinsically disordered regulatory regions as well as their DNA-binding domains. Crystals of the complex containing unmodified Ets1 belonged to space group P212121, with unit-cell parameters a = 78.7, b = 102.1, c = 195.0 A, and diffracted X-rays to a resolution of 2.35 A, and those containing phosphorylated Ets1 belonged to the same space group, with unit-cell parameters a = 78.6, b = 101.7, c = 194.7 A, and diffracted X-rays to a similar resolution. To facilitate crystallization, a Runx1 residue involved in a hydrophobic patch that was predicted to be engaged in crystal packing based on the previously reported structures of Runx1-containing crystals was mutated. PMID- 25286945 TI - Crystallization and preliminary X-ray crystallographic studies of CrArsM, an arsenic(III) S-adenosylmethionine methyltransferase from Chlamydomonas reinhardtii. AB - Arsenic is one the most toxic environmental substances. Arsenic is ubiquitous in water, soil and food, and ranks first on the Environmental Protection Agency's Superfund Priority List of Hazardous Substances. Arsenic(III) S adenosylmethionine methyltransferases (AS3MT in animals and ArsM in microbes) are key enzymes of arsenic biotransformation, catalyzing the methylation of inorganic arsenite to give methyl, dimethyl and trimethyl products. Arsenic methyltransferases are found in members of every kingdom from bacteria to humans (EC 2.1.1.137). In the human liver, hAS3MT converts inorganic arsenic into more toxic and carcinogenic forms. CrArsM, an ortholog of hAS3MT from the eukaryotic green alga Chlamydomonas reinhardtii, was purified by chemically synthesizing the gene and expressing it in Escherichia coli. Synthetic purified CrArsM was crystallized in an unliganded form. Crystals were obtained by the hanging-drop vapor-diffusion method. The crystals belonged to space group R3:H, with unit-cell parameters a = b = 157.8, c = 95.4 A, gamma = 120 degrees and two molecules in the asymmetric unit. Complete data sets were collected and processed to a resolution of 2.40 A. PMID- 25286946 TI - Crystallization and preliminary X-ray diffraction analysis of the BRPF1 bromodomain in complex with its H2AK5ac and H4K12ac histone-peptide ligands. AB - The bromodomain-PHD finger protein 1 (BRPF1) is an essential subunit of the monocytic leukemia zinc (MOZ) histone acetyltransferase (HAT) complex and is required for complex formation and enzymatic activation. BRPF1 contains a structurally conserved bromodomain, which recognizes specific acetyllysine residues on histone proteins. The MOZ HAT plays a direct role in hematopoiesis, and deregulation of its activity is linked to the development of acute myeloid leukemia. However, the molecular mechanism of histone-ligand recognition by the BRPF1 bromodomain is currently unknown. The 117-amino-acid BRPF1 bromodomain was overexpressed in Escherichia coli and purified to homogeneity. Crystallization experiments of the BRPF1 bromodomain in complex with its H4K12ac and H2AK5ac histone ligands yielded crystals that were suitable for high-resolution X-ray diffraction analysis. The BRPF1 bromodomain-H4K12ac crystals belonged to the tetragonal space group P43212, with unit-cell parameters a = 75.1, b = 75.1, c = 86.3 A, and diffracted to a resolution of 1.94 A. The BRPF1 bromodomain-H2AK5ac crystals grew in the monoclinic space group P21, with unit-cell parameters a = 60.9, b = 55.6, c = 82.1 A, beta = 93.6 degrees , and diffracted to a resolution of 1.80 A. Complete data sets were collected from both crystal forms using synchrotron radiation on beamline X29 at Brookhaven National Laboratory (BNL). PMID- 25286947 TI - Cloning, expression, purification and preliminary X-ray analysis of EstN2, a novel archaeal alpha/beta-hydrolase from Candidatus Nitrososphaera gargensis. AB - EstN2 is a novel alpha/beta-hydrolase originating from the ammonia-oxidizing thaumarchaeon Candidatus Nitrososphaera gargensis. The genome of the organism was sequenced and genes conferring putative lipolytic activity were amplified and cloned into Escherichia coli as a heterologous host. Through function-based screening, esterase and lipase activity was detected. A recombinant enzyme designated EstN2 was successfully expressed, purified and crystallized. The crystals belonged to space group I2, with one molecule per asymmetric unit, and diffracted X-rays to 1.5 A resolution. PMID- 25286949 TI - Expression, crystallization and preliminary X-ray analysis of McbB, a multifunctional enzyme involved in beta-carboline skeleton biosynthesis. AB - beta-Carboline alkaloids (betaCs), with tricyclic pyrido[3,4-b]indole rings, have important pharmacological and therapeutic value. In the biosynthesis of betaCs, the Pictet-Spengler (PS) cyclization reaction is responsible for the formation of ring structures. McbB is one of a few enzymes that are known to catalyse PS cyclization. It can also catalyse decarboxylation and oxidation. Here, the expression, crystallization and preliminary data analysis of McbB are reported. The crystals diffracted to 2.10 A resolution and belonged to the monoclinic space group P21, with unit-cell parameters a = 66.06, b = 85.48, c = 106.19 A, alpha = 90.00, beta = 106.77, gamma = 90.00 degrees . These results provide a basis for solving the crystal structure and elucidating the catalytic mechanism for McbB. PMID- 25286948 TI - Crystallization and preliminary X-ray diffraction analysis of Lin1840, a putative beta-glucosidase from Listeria innocua. AB - Lin1840 is a putative beta-glucosidase that is predicted to be involved in 1,2 beta-glucan metabolism since the lin1839 gene encoding a 1,2-beta-oligoglucan phosphorylase and the lin1840 gene are located in the same gene cluster. Here, Lin1840 was crystallized. The crystals of Lin1840 diffracted to beyond 1.8 A resolution. The crystal belonged to space group I121, with unit-cell parameters a = 89.75, b = 95.10, c = 215.00 A, alpha = 90.00, beta = 96.34, gamma = 90.00 degrees . PMID- 25286950 TI - Crystallization and preliminary X-ray diffraction analyses of the redox controlled complex of terminal oxygenase and ferredoxin components in the Rieske nonhaem iron oxygenase carbazole 1,9a-dioxygenase. AB - The initial reaction in bacterial carbazole degradation is catalyzed by carbazole 1,9a-dioxygenase, which consists of terminal oxygenase (Oxy), ferredoxin (Fd) and ferredoxin reductase components. The electron-transfer complex between reduced Oxy and oxidized Fd was crystallized at 293 K using the hanging-drop vapour diffusion method with PEG 3350 as the precipitant under anaerobic conditions. The crystal diffracted to a maximum resolution of 2.25 A and belonged to space group P21, with unit-cell parameters a = 97.3, b = 81.6, c = 116.2 A, alpha = gamma = 90, beta = 100.1 degrees . The VM value is 2.85 A(3) Da(-1), indicating a solvent content of 56.8%. PMID- 25286951 TI - Crystallization and preliminary X-ray diffraction analysis of cyclolavandulyl diphosphate synthase, a new member of the cis-isoprenyl diphosphate synthase superfamily. AB - Cyclolavandulyl diphosphate synthase (CLDS; estimated molecular weight 23.1 kDa) from the soil bacterium Streptomyces sp. CL190 is an enzyme that catalyzes both the condensation of two molecules of C5 dimethylallyl diphosphate (DMAPP) and the subsequent cyclization. CLDS was crystallized in the absence and the presence of the substrate DMAPP. Diffraction data were collected at a synchrotron source and the crystals diffracted to 2.00 and 1.73 A resolution, respectively. The crystal obtained in the absence of DMAPP belonged to space group P212121, with unit-cell parameters a = 39.0, b = 87.5, c = 113.6 A. The crystal obtained in the presence of DMAPP belonged to space group P1, with unit-cell parameters a = 46.9, b = 61.7, c = 82.2 A, alpha = 74.0, beta = 84.5, gamma = 86.0 degrees . PMID- 25286952 TI - Purification, crystallization and preliminary X-ray crystallographic studies of Drep2 CIDE domain. AB - Drep2 is a novel nuclease from the fruit fly that might have a similar function in apoptosis to DFF40 and DFF45, which are primary players in apoptotic DNA fragmentation. Drep2 contains a conserved CIDE domain of ~90 amino-acid residues that is involved in protein-protein interaction. In this study, the Drep2 CIDE domain was purified and crystallized by the hanging-drop vapour-diffusion method. X-ray diffraction data were then collected to a resolution of 2.3 A. The crystals were found to belong to the orthorhombic space group P212121, with unit-cell parameters a = 50.28, b = 88.70, c = 113.37 A. PMID- 25286953 TI - Crystallization and preliminary X-ray diffraction analysis of a novel sphingomyelinase D from Loxosceles gaucho venom. AB - Brown spider envenomation results in dermonecrosis, intravascular coagulation, haemolysis and renal failure, mainly owing to the action of sphingomyelinases D (SMases D), which catalyze the hydrolysis of sphingomyelin to produce ceramide 1 phosphate and choline or the hydrolysis of lysophosphatidylcholine to produce lysophosphatidic acid. Here, the heterologous expression, purification, crystallization and preliminary X-ray diffraction analysis of LgRec1, a novel SMase D from Loxosceles gaucho venom, are reported. The crystals belonged to space group P21212, with unit-cell parameters a = 52.98, b = 62.27, c = 84.84 A and diffracted to a maximum resolution of 2.6 A. PMID- 25286954 TI - Crystallization and preliminary crystallographic analysis of poly(3 hydroxybutyrate) depolymerase from Bacillus thuringiensis. AB - Poly[(R)-3-hydroxybutyrate] (PHB) is a microbial biopolymer that has been commercialized as biodegradable plastics. The key enzyme for the degradation is PHB depolymerase (PhaZ). A new intracellular PhaZ from Bacillus thuringiensis (BtPhaZ) has been screened for potential applications in polymer biodegradation. Recombinant BtPhaZ was crystallized using 25% polyethylene glycol 3350, 0.2 M ammonium acetate, 0.1 M bis-tris pH 6.5 at 288 K. The crystals belonged to space group P1, with unit-cell parameters a = 42.97, b = 83.23, c = 85.50 A, alpha = 73.45, beta = 82.83, gamma = 83.49 degrees . An X-ray diffraction data set was collected to 1.42 A resolution with an Rmerge of 6.4%. Unexpectedly, a molecular replacement solution was obtained using the crystal structure of Streptomyces lividans chloroperoxidase as a template, which shares 24% sequence identity to BtPhaZ. This is the first crystal structure of an intracellular poly(3 hydroxybutyrate) depolymerase. PMID- 25286955 TI - Production, crystallization and preliminary crystallographic analysis of Allochromatium vinosum thiosulfate dehydrogenase TsdA, an unusual acidophilic c type cytochrome. AB - The ability to perform the very simple oxidation of two molecules of thiosulfate to tetrathionate is widespread among prokaryotes. Despite the prevalent occurrence of tetrathionate formation and its well documented significance within the sulfur cycle, little is known about the enzymes that catalyze the oxidative condensation of two thiosulfate anions. To fill this gap, the thiosulfate dehydrogenase (TsdA) enzyme from the purple sulfur bacterium Allochromatium vinosum was recombinantly expressed in Escherichia coli, purified and crystallized, and a crystallographic data set was collected. The crystals belonged to the monoclinic space group C2, with unit-cell parameters a = 79.2, b = 69.9, c = 57.9 A, beta = 129.3 degrees , contained one monomer per asymmetric unit and diffracted to a resolution of 1.98 A. PMID- 25286956 TI - Crystallization and preliminary X-ray diffraction analysis of full-length spr1814, a response regulator of Streptococcus pneumoniae, in complex with a phosphoryl analogue. AB - Spr1814 of Streptococcus pneumoniae is a signal transduction response regulator belonging to the NarL/FixJ subfamily, which has a helix-turn-helix DNA-binding effector domain. To understand how the phosphorylation of the conserved aspartic acid residue induces conformational changes in spr1814 allowing binding to the target promoter, recombinant spr1814 expressed in Escherichia coli was crystallized with the phosphoryl analogue beryllium fluoride BeF3(-) by the hanging-drop vapour-diffusion method. The crystals diffracted to 1.9 A resolution and belonged to space group P21, with unit-cell parameters a = 40.2, b = 114.5, c = 50.1 A, beta = 92.1 degrees . Structure determination by the SAD method using the bromine derivative 5-amino-2,4,6-tribromoisophthalic acid (B3C) is under way. PMID- 25286957 TI - Crystallization and preliminary X-ray diffraction studies of the C-terminal domain of Chlamydia trachomatis CdsD. AB - The inner membrane ring of the bacterial type III secretion system (TTSS) is composed of two proteins. In Chlamydia trachomatis this ring is formed by CdsD (gene name CT_664) and CdsJ (gene name CTA_0609). CdsD consists of 829 amino acids. The last 400 amino acids at its C-terminal end relate it to the type III secretion system YscD/HrpQ protein family. The C-terminal domain, consisting of amino acids 558-771, of C. trachomatis CdsD was overexpressed in Escherichia coli and purified using immobilized metal-affinity chromatography (IMAC) and size exclusion chromatography. The protein was crystallized using the vapour-diffusion method. A data set was collected to 2.26 A resolution. The crystals have the symmetry of space group C2, with unit-cell parameters a = 106.60, b = 23.91, c = 118.65 A, beta = 104.95 degrees . According to the data analysis there is expected to be one molecule in the asymmetric unit, with a Matthews coefficient of 3.0 A(3) Da(-1). PMID- 25286958 TI - Enhancing ubiquitin crystallization through surface-entropy reduction. AB - Ubiquitin has many attributes suitable for a crystallization chaperone, including high stability and ease of expression. However, ubiquitin contains a high surface density of lysine residues and the doctrine of surface-entropy reduction suggests that these lysines will resist participating in packing interactions and thereby impede crystallization. To assess the contributions of these residues to crystallization behavior, each of the seven lysines of ubiquitin was mutated to serine and the corresponding single-site mutant proteins were expressed and purified. The behavior of these seven mutants was then compared with that of the wild-type protein in a 384-condition crystallization screen. The likelihood of obtaining crystals varied by two orders of magnitude within this set of eight proteins. Some mutants crystallized much more readily than the wild type, while others crystallized less readily. X-ray crystal structures were determined for three readily crystallized variants: K11S, K33S and the K11S/K63S double mutant. These structures revealed that the mutant serine residues can directly promote crystallization by participating in favorable packing interactions; the mutations can also exert permissive effects, wherein crystallization appears to be driven by removal of the lysine rather than by addition of a serine. Presumably, such permissive effects reflect the elimination of steric and electrostatic barriers to crystallization. PMID- 25286959 TI - Felix Frolow (1947-2014). PMID- 25286961 TI - Serum IgE-targeted elimination diets for treating eosinophilic esophagitis: things are not what they seem. PMID- 25286962 TI - Insulin resistance in patients on valproic acid: relation to adiponectin. AB - OBJECTIVES: To investigate the presence of insulin resistance in obese children with idiopathic epilepsy on valproic acid (VPA) monotherapy in comparison to obese otherwise healthy subjects. Secondary outcome was to explore the relation between adiponectin and insulin resistance among those patients. MATERIALS AND METHODS: Fifty obese children with generalized idiopathic epilepsy on VPA monotherapy and a control group of 49 obese clinically healthy age and sex matched children with simple obesity were recruited in the study. Anthropometric assessment, fasting plasma insulin (FI), fasting glucose (FG) and fasting adiponectin levels were measured. Fasting glucose insulin ratio (FGIR) and homoeostasis model assessment for insulin resistance (HOMA-IR) were calculated for both patients and control subjects. Measurement of serum VPA trough level was also performed in patients. RESULTS: Patients had significantly higher fasting blood glucose, fasting insulin, lower FGIR and higher HOMA-IR values, compared to controls. Mean adiponectin level was significantly lower in patients compared to controls. The duration of treatment with valproic acid negatively correlated with adiponectin (r = -0.285, P = 0.045), but did not correlate with fasting glucose, insulin, FGIR or HOMA-IR. Total daily VPA dose significantly correlated with fasting insulin (r = 0.495, P < 0.001), FGIR (r = -0.525, P < 0.001) and HOMA-IR (r = 0.404, P = 0.004). CONCLUSION: This study ascertains the relationship between dose and duration of VPA therapy, insulin resistance and the adipocytokine axis. We are reporting the novel proposal that obese VPA-treated children are more insulin resistant and have lower adiponectin levels than obese and otherwise healthy children. PMID- 25286963 TI - Host-microbe interactions via membrane transport systems. AB - Living organisms take in essential molecules and get rid of wastes effectively through the selective transport of materials. Especially in the digestive tract, advanced transport systems are indispensable for the absorption of nutrients and elimination of waste products. These transport pathways control physiological functions by modulating the ionic environment inside and outside the cells. Moreover, recent studies have shown the importance of the expression of trafficking-related molecules and the population of gut microbiota. We found that the molecules secreted from microorganisms are imported into the cells via transporters or endocytosis and that they activate cell survival pathways of intestinal epithelial cells. These findings indicate that the interactions between the gut microbiota and host cells are mediated, at least partly, by the membrane transport systems. In addition, it is well known that the breakdown of transport systems induces various diseases. This review highlights the significance of the transport systems as the pathogenic molecules and therapeutic targets in gastrointestinal disorders. For example, abnormal expression of the genes encoding membrane transport-related molecules is frequently involved in digestive diseases, such as colorectal cancer and inflammatory bowel disease. We herein review the significance of these molecules as pathogenic and therapeutic targets for digestive diseases. PMID- 25286960 TI - Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers. AB - BACKGROUND: Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown. RESULTS: Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium specific enhancers derived from specific TEs. CONCLUSIONS: DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers. PMID- 25286964 TI - Delivering kidney cancer care in rural Central and Southern Illinois: a telemedicine approach. AB - There is a growing body of experience and research suggesting that telemedicine (video conferencing, smart phones and online patient portals) could be the solution to addressing gaps in the provision of specialised healthcare in rural areas. The proposed role of telemedicine in providing needed services in hard to reach areas is not new. The United States Telecommunication Act of 1996 provided the initial traction for telemedicine by removing important economic and legal obstacles regarding the use of technology in healthcare delivery. This initial ruling has been supplemented by the availability of federal funding to support efforts aimed at developing telemedicine in underserved areas. In this paper, we explore one aspect of disease disparity pertinent to rural Illinois (kidney cancer incidence and mortality) and describe how we are planning to use an existing telemedicine program at Southern Illinois University School of Medicine (SIUSOM) to improve kidney cancer (Kca) care in rural Illinois. This represents an example of the possible role of telemedicine in addressing healthcare disparities in rural areas/communities and provides a description of general challenges and barriers to the implementation and maintenance of such systems. PMID- 25286965 TI - Cervical transforaminal epidural block using low-dose local anesthetic: a prospective, randomized, double-blind study. AB - OBJECTIVES: Intra-arterial injections of local anesthetic during cervical transforaminal epidural block (TFEB) can cause rare but fatal neurologic complications. We hypothesized that using a dose of local anesthetic lower than seizure threshold during cervical TFEB would not be associated with seizure activity in cases of accidental intra-arterial injection. METHODS: Patients were randomized to one of two groups: group I received injections of 1 mL of 1% lidocaine mixed with dexamethasone 2.5 mg (n = 15), and group II received 1 mL of 0.125% lidocaine mixed with dexamethasone 2.5 mg (n = 15). When the numeric rating scale (NRS) for pain was greater than 3, cervical TFEBs were performed three times at 2-week intervals. Patients were evaluated up to 3 months. RESULTS: Thirty patients with cervical radicular pain were enrolled in this study. The NRS pain score on the day of procedure and at 2 weeks, 4 weeks, 6 weeks, and 3 months following the initial procedure were similarly significantly reduced in both groups. The total number of procedures performed and the outcomes evaluated according to Odom's criteria at the 3-month follow-up visit were not different between groups. Overall, 73.3% and 80% patients in groups I and II, respectively, rated the degree of their symptom relief as excellent or good. CONCLUSION: Cervical TFEB performed using 0.125% lidocaine with dexamethasone achieved similar satisfactory effects as 1% lidocaine with dexamethasone for the treatment of cervical radicular pain. Therefore, the use of low-dose lidocaine with dexamethasone is reasonable for cervical TFEB, as this may reduce the incidence of rare but fatal complications. PMID- 25286966 TI - Gesture-controlled interactive three dimensional anatomy: a novel teaching tool in head and neck surgery. AB - BACKGROUND: There is a need for innovative anatomic teaching tools. This paper describes a three dimensional (3D) tool employing the Microsoft KinectTM. Using this instrument, 3D temporal bone anatomy can be manipulated with the use of hand gestures, in the absence of mouse or keyboard. METHODS: CT Temporal bone data is imported into an image processing program and segmented. This information is then exported in polygonal mesh format to an in-house designed 3D graphics engine with an integrated Microsoft KinectTM. Motion in the virtual environment is controlled by tracking hand position relative to the user's left shoulder. RESULTS: The tool successfully tracked scene depth and user joint locations. This permitted gesture based control over the entire 3D environment. Stereoscopy was deemed appropriate with significant object projection, while still maintaining the operator's ability to resolve image details. Specific anatomical structures can be selected from within the larger virtual environment. These structures can be extracted and rotated at the discretion of the user. Voice command employing the Kinect'sTM intrinsic speech library was also implemented, but is easily confounded by environmental noise. CONCLUSION: There is a need for the development of virtual anatomy models to complement traditional education. Initial development is time intensive. Nonetheless, our novel gesture-controlled interactive 3D model of the temporal bone represents a promising interactive teaching tool utilizing a novel interface. PMID- 25286967 TI - New diagnosis of chronic pancreatitis: risk of missing an underlying pancreatic cancer. AB - OBJECTIVES: Patients with pancreatic cancer (PaCa) sometimes present with symptoms suggestive of chronic pancreatitis (CP). We evaluated the prevalence of undiagnosed PaCa in patients with new CP diagnosis. METHODS: This is a retrospective study with data from Veterans Health Administration national medical care data sets from fiscal year 1998-2007. A 3-year washout period was used to identify patients with preexisting PaCa and preexisting CP diagnosis. RESULTS: Among 471,992 veterans included, 917 (0.19%) had PaCa, 2,557 (0.54%) had a preexisting CP, and 2,175 (0.46%) had a new diagnosis of CP. PaCa was diagnosed <=2 years following CP diagnosis in 44 patients, comprising 4.80% of patients with PaCa. Following a new diagnosis of CP, the risk of PaCa diagnosis was most marked in the first year (incidence 18.04 per 1,000 person-years (py), relative risk (RR) 63.43) and became similar to risk in patients with preexisting CP in the third year. The first-year incidence of PaCa was 7.33/1,000 py in the fifth decade and reached 36.91/1,000 py after seventh decade of life. Time to PaCa diagnosis following a CP diagnosis was <=60 days in 14 patients, 3-12 months in 25 patients, and 13-24 months in 5 patients. CONCLUSIONS: Approximately 5% of patients with PaCa are initially misdiagnosed as CP, and in two-thirds of these patients the cancer diagnosis is delayed by >2 months. PaCa should reliably be excluded before making a new CP diagnosis in patients who are >40 years old, especially in those without heavy smoking or alcohol history. PMID- 25286968 TI - Improved anti-emetic efficacy of 5-HT3 receptor antagonists in cancer patients with genetic polymorphisms of ABCB1 (MDR1) drug transporter. AB - Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti-emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti-emetic treatment with 5-HT3 receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti-emetic responses were recorded daily. The primary end-point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR-RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT-TT-TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT-TT-TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti-emetic response to 5-HT3 receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti-emetic efficacy of 5-HT3 antagonists. PMID- 25286969 TI - Epidemiological features of pertussis resurgence based on community populations with high vaccination coverage in China. AB - Active symptom surveillance was applied to three selected communities ( 160,147 persons) in Tianjin from 2010 to 2012. We examined 1089 individuals showing pertussis-like symptoms, of which 1022 nasopharyngeal specimens were tested for pertussis by polymerase chain reaction and 802 sera for anti-pertussis toxin antibodies. Of the total cases tested, 113 were confirmed, and their demographic, clinical, and vaccination-related data were collected. The annual incidence was 23.52 cases/100,000 persons among communities, which was 16.22 times that obtained via hospital reports for the same period (P < 0.001). The actual incidence in the 15-69 years age group was most significantly underestimated by hospitals, given that it was 43.08 times that of the reported hospital rate. Among the cases aged <15 years, 84.5% were individuals who had been fully vaccinated. The misdiagnosis rate was as high as 94.69%, and only 5.31% of the confirmed pertussis cases were properly diagnosed as pertussis at their first medical visit. Pertussis incidence in China has been severely underestimated and this was in part due to a high misdiagnosis rate. Adolescents and adults have become new high-risk populations. Future work should focus on reinforcing immunization programmes, especially among adolescents and adults. PMID- 25286970 TI - Formation of graphene grain boundaries on Cu(100) surface and a route towards their elimination in chemical vapor deposition growth. AB - Grain boundaries (GBs) in graphene prepared by chemical vapor deposition (CVD) greatly degrade the electrical and mechanical properties of graphene and thus hinder the applications of graphene in electronic devices. The seamless stitching of graphene flakes can avoid GBs, wherein the identical orientation of graphene domain is required. In this letter, the graphene orientation on one of the most used catalyst surface - Cu(100) surface, is explored by density functional theory (DFT) calculations. Our calculation demonstrates that a zigzag edged hexagonal graphene domain on a Cu(100) surface has two equivalent energetically preferred orientations, which are 30 degree away from each other. Therefore, the fusion of graphene domains on Cu(100) surface during CVD growth will inevitably lead to densely distributed GBs in the synthesized graphene. Aiming to solve this problem, a simple route, that applies external strain to break the symmetry of the Cu(100) surface, was proposed and proved efficient. PMID- 25286973 TI - Liver cancer: sorafenib resistance uncovered by novel RNAi screen. PMID- 25286971 TI - Bacterial associates of seed-parasitic wasps (Hymenoptera: Megastigmus). AB - BACKGROUND: The success of herbivorous insects has been shaped largely by their association with microbes. Seed parasitism is an insect feeding strategy involving intimate contact and manipulation of a plant host. Little is known about the microbial associates of seed-parasitic insects. We characterized the bacterial symbionts of Megastigmus (Hymenoptera: Torymidae), a lineage of seed parasitic chalcid wasps, with the goal of identifying microbes that might play an important role in aiding development within seeds, including supplementing insect nutrition or manipulating host trees. We screened multiple populations of seven species for common facultative inherited symbionts. We also performed culture independent surveys of larvae, pupae, and adults of M. spermotrophus using 454 pyrosequencing. This major pest of Douglas-fir is the best-studied Megastigmus, and was previously shown to manipulate its tree host into redirecting resources towards unfertilized ovules. Douglas-fir ovules and the parasitoid Eurytoma sp. were also surveyed using pyrosequencing to help elucidate possible transmission mechanisms of the microbial associates of M. spermotrophus. RESULTS: Three wasp species harboured Rickettsia; two of these also harboured Wolbachia. Males and females were infected at similar frequencies, suggesting that these bacteria do not distort sex ratios. The M. spermotrophus microbiome is dominated by five bacterial OTUs, including lineages commonly found in other insect microbiomes and in environmental samples. The bacterial community associated with M. spermotrophus remained constant throughout wasp development and was dominated by a single OTU - a strain of Ralstonia, in the Betaproteobacteria, comprising over 55% of all bacterial OTUs from Megastigmus samples. This strain was also present in unparasitized ovules. CONCLUSIONS: This is the first report of Ralstonia being an abundant and potentially important member of an insect microbiome, although other closely-related Betaproteobacteria, such as Burkholderia, are important insect symbionts. We speculate that Ralstonia might play a role in nutrient recycling, perhaps by redirecting nitrogen. The developing wasp larva feeds on megagametophyte tissue, which contains the seed storage reserves and is especially rich in nitrogen. Future studies using Ralstonia-specific markers will determine its distribution in other Megastigmus species, its mode of transmission, and its role in wasp nutrition. PMID- 25286972 TI - An update on PARP inhibitors--moving to the adjuvant setting. AB - Inhibition of poly(ADP-ribose) polymerase (PARP) enzymes is a potential synthetic lethal therapeutic strategy in cancers harbouring specific DNA-repair defects, including those arising in carriers of BRCA1 or BRCA2 mutations. Since the development of first-generation PARP inhibitors more than a decade ago, numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the stage at which adjuvant therapy with PARP inhibitors is now being considered as a viable treatment option for patients with breast cancer. Nevertheless, the available data do not provide clear proof that these drugs are efficacious in the setting of metastatic disease. Advancement of a therapy to the neoadjuvant and adjuvant settings without such evidence is exceptional, but seems reasonable in the case of PARP inhibitors because the target population that might benefit from this class of drugs is small and well defined. This Review describes the evolution of PARP inhibitors from bench to bedside, and provides an up-to-date description of the key published or otherwise reported clinical trials of these agents. The specific considerations and challenges that might be encountered when implementing these compounds in the adjuvant treatment of breast cancer in the clinic are also highlighted. PMID- 25286974 TI - Decade in review-targeted therapy: successes, toxicities and challenges in solid tumours. PMID- 25286975 TI - Decade in review--genomics: a decade of discovery in cancer genomics. PMID- 25286977 TI - Decade in review--clinical trials: shifting paradigms in cancer clinical trial design. PMID- 25286978 TI - Consequences of a screening programme on the prevalence of congenital hereditary sensorineural deafness in the Australian Cattle Dog. AB - Genetic disease testing programmes are used in domestic animal breeds to guide selective breeding with the aim of reducing disease prevalence. We assessed the change in the prevalence of canine congenital hereditary sensorineural deafness (CHSD) in litters of Australian Cattle Dogs following the introduction of a brainstem auditory evoked response (BAER) testing programme. We studied 608 pups from 122 litters from 10 breeding kennels. Despite 10 years of testing (1998 2008), no substantial reduction in prevalence of CHSD was evident in these 10 breeding kennels. Even for the subset of litters in which both parents were BAER tested as normal hearing (305 pups from 58 litters), there was no evidence of substantial reduction in prevalence. Odds ratios for CHSD in pups for each extra year since testing in the kennel commenced were 1.01 (95% CI, 0.88-1.17) and 1.03 (95% CI, 0.82-1.30) respectively for these populations. Amongst 284 dogs from 54 litters with extended pedigrees and both parents BAER-tested normal hearing, observed prevalences of CHSD were highest in pups with no BAER-tested normal grandparents (17% or 5/29) and lowest in pups with all four grandparents tested normal (0% or 0/9). In pups for which one, two and three grandparents tested negative, prevalences of CHSD were 12% (9/74), 9% (9/101) and 8% (6/71) respectively. Hence, testing programmes based on phenotypic screening may not lead to a substantial reduction in recessive genetic disease prevalence over the medium term, even when only tested normal parents are used. Exclusive breeding of litters in which both parents and all four grandparents are BAER-tested normal is expected to reduce CHSD prevalence in pups to the greatest extent over the long term. PMID- 25286979 TI - Formation of a superatom monolayer using gas-phase-synthesized Ta@Si16 nanocluster ions. AB - The controlled assembly of superatomic nanocluster ions synthesized in the gas phase is a key technology for constructing a novel series of functional nanomaterials. However, it is generally difficult to immobilize them onto a conductive surface while maintaining their original properties owing to undesirable modifications of their geometry and charge state. In this study, it has been shown that this difficulty can be overcome by controlling the donor acceptor interaction between nanoclusters and surfaces. Cations of Ta-atom encapsulated Si(16) cage nanoclusters (Ta@Si(16)) behaving as rare-gas-like superatoms are synthesized in the gas phase and deposited on conductive surfaces terminated with acceptor-like C(60) and donor-like alpha-sexithiophene (6 T) molecules. Scanning tunneling microscopy and spectroscopy have demonstrated that Ta@Si(16) cations can be densely immobilized onto C(60)-terminated surfaces while retaining their cage shape and positive charge, which is realized by creating binary charge transfer complexes (Ta@Si(16)(+)-C(60)(-)) on the surfaces. The Ta@Si(16) nanoclusters exhibit excellent thermal stability on C(60-)terminated surfaces similar to those in the gas phase, whereas the nanoclusters destabilize at room temperature on 6 T-terminated surfaces owing to the loss of electronic closure via a change in the charge state. PMID- 25286976 TI - Translational research in oncology--10 years of progress and future prospects. AB - International efforts to sequence the genomes of various human cancers have been broadly deployed in drug discovery programmes. Diagnostic tests that predict the value of the molecularly targeted anticancer agents used in such programmes are conceived and validated in parallel with new small-molecule treatments and immunotherapies. This approach has been aided by better preclinical cancer models; an enhanced appreciation of the complex interactions that exist between tumour cells and their microenvironment; the elucidation of interactions between many of the genetic drivers of cancer, including oncogenes and tumour suppressors; and recent insights into the genetic heterogeneity of human tumours made possible by extraordinary improvements in DNA-sequencing techniques. These advances are being employed in the first generation of genomic clinical trials that will examine the feasibility of matching a broad range of systemic therapies to specific molecular tumour characteristics. More-extensive molecular characterization of tumours and their supporting matrices are anticipated to become standard aspects of oncological practice, permitting continuous molecular re-evaluations of human malignancies on a patient-by-patient and treatment-by treatment basis. We review selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer our thoughts on future prospects for the next few years. PMID- 25286980 TI - Laser (755 nm) and cryotherapy as depigmentation treatments for vitiligo: a comparative study. AB - BACKGROUND: Depigmentation therapy can be an option in adults with extensive and refractory vitiligo. Remaining pigmented patches can be removed using depigmentation creams (monobenzyl ether of hydroquinone 20%), laser therapy or cryotherapy. In contrast to cream treatment, laser therapy and cryotherapy are fast and targeted methods, capable of destroying melanocytes selectively on one specific area. Up till now, controlled trials comparing laser and cryotherapy as depigmenting treatment in vitiligo are lacking. MATERIAL AND METHODS: We performed a retrospective comparative study in 22 generalized vitiligo patients. Thirty-one pigmented test regions were exposed to cryotherapy and 20 to 755 nm laser therapy. The mean surface area per test region was 3.55 cm2 and number of treatments per test region was limited to one single session in 84.3% and varied up to four sessions (2.0%). RESULTS: Overall no significant difference in the capacity to induce depigmentations was observed between cryotherapy (46.7%) and laser therapy (42.9%) after one treatment. The percentage of induced depigmentation was significantly different according to the body location (P = 0.005) with best results on the trunk, followed by the arms, face, neck and less on the hands. Variables that positively influenced depigmentation results were a younger age of vitiligo onset (P = 0.012), skin type V (P < 0.001) and clinical presence of Koebner's phenomenon (P = 0.039). Despite initial failure after one treatment, repetitive treatment sessions on eight test areas resulted in successful depigmentation. Side-effects were restricted to cryotherapy and concerned mainly hyperpigmentation in the face. CONCLUSION: To our knowledge, this is the first study comparing head-to-head depigmentation strategies intra- and inter-individually. We could demonstrate that in general laser and cryotherapy are equally effective in inducing depigmentations in generalized vitiligo patients. Retreatment of the same area may be required in case of initial failure. PMID- 25286981 TI - Preliminary evidence for good psychometric properties of the Norwegian version of the Brief Problems Monitor (BPM). AB - BACKGROUND: Methods to assess intervention progress and outcome for frequent use are needed. OBJECTIVE: To provide preliminary information about psychometric properties for the Norwegian version of the Brief Problems Monitor. METHOD: Cronbach's alpha scores and intra-class correlation coefficients as indicators for internal consistency (reliability) and Pearson correlation coefficients between corresponding subscales of the long and short ASEBA form versions as well as multiple regression coefficients to explore the predictive power of the reduced item-set related to the corresponding scale-scores of the long version were calculated in large, representative data sets of Norwegian children and adolescents. RESULTS: Cronbach's alpha scores of the Norwegian version of the BPM subscales varied between 0.67 (attention BPM-youth) and 0.88 (attention BPM teacher) and between 0.90 (BPM-youth) and 0.96 (BPM-teacher) for its total problem score. Corresponding subscales from the long versions and the BPM as well as the total problems scores were closely correlated with coefficients of high effect size (all r > 0.80). The variance of the items of the BPM explained about three-quarters or more of the variance in the corresponding subscales of the long version. CONCLUSIONS: The Norwegian BPM has good psychometric properties in terms of 1) being acceptable to good internal consistency and in terms of 2) regression coefficients of high effect size from the BPM items to the problem-scale scores of the long versions as validity indicators. Its use in clinical practice and research can be recommended. PMID- 25286982 TI - Bayesian prediction of treatment outcome in anorexia nervosa: a preliminary study. AB - BACKGROUND: Knowledge of the prognostic factors predicting treatment outcome in anorexia nervosa (AN) measured with health-related quality of life (HRQoL) is limited. AIMS: We performed a novel statistical analysis to identify factors predicting treatment outcome in AN. METHODS: 39 patients entering treatment of an ICD-10-defined AN completed the 15D HRQoL survey, the Eating Disorder Inventory (EDI) and a questionnaire evaluating self reported health status and eating habits before and 2 years after the start of treatment. The analysis was based on a Bayesian approach, which allows analyses of small data sets, and was performed using a naive Bayes classifier. RESULTS: An impaired follow-up HRQoL score was associated with three baseline risk factors: low self-reported vitality, high scores in eating control and a poor reported health status. Low baseline body mass index (BMI) and a high score in the eating dimension of the 15D predicted low follow-up BMI. CONCLUSIONS: In our preliminary study, we identified a set of variables predicting poor HRQoL in AN. An effort to treat these symptoms effectively in the beginning of AN treatment may influence the outcome. PMID- 25286983 TI - Effect of hydrosoluble vitamin E on erythrocyte membrane lipid composition in patients with advanced cirrhosis: An open-label pilot trial. AB - AIM: Deficiency in vitamin E, a natural antioxidant, participates in abnormal erythrocyte membrane lipids, structural alterations and hemolysis in advanced cirrhosis. Poor absorption of fat-soluble vitamins limits full correction of deficiency with standard formulations in cirrhosis with cholestasis. The aim of the present study was to examine safety and effects of tocofersolan, a water soluble derivative of vitamin E, on erythrocyte membrane lipids and anemia in patients with biopsy-proven advanced cirrhosis, vitamin E deficiency and hemolysis. METHODS: Twenty patients (age, 53 +/- 10 years; Child class B/C, 8/12), with low plasma vitamin E, chronic anemia and hemolysis, received oral tocofersolan 700 mg/day for 4 weeks. Erythrocyte membrane lipid composition (cholesterol [Chol], phospholipids [Phosph]) was determined by enzymatic assays. Total and conjugated bilirubin, hemoglobin and vitamin E were measured. RESULTS: Abdominal pain occurred in one patient. Five patients received blood transfusions due to severe anemia. After 4 weeks, both Chol and Phosph decreased, but changes were not significant. Both plasma vitamin E (P < 0.05) and hemoglobin (P < 0.05) increased, together with a decrease in total (P < 0.05) and conjugated (P < 0.05) bilirubin. CONCLUSION: In patients with advanced cirrhosis, low vitamin E plasma levels and chronic anemia with hemolysis, oral tocofersolan was overall well tolerated, but did not affect erythrocyte membrane lipid composition. PMID- 25286984 TI - Expression patterns of beta-defensin and cathelicidin genes in parenchyma of bovine mammary gland infected with coagulase-positive or coagulase-negative Staphylococci. AB - BACKGROUND: Mastitis is still considered to be the most economically important infectious disease in dairy cattle breeding. The immune response in mammary gland tissues could help in developing support strategies to combat this disease. The role of neutrophils and macrophages in the innate response of mammary gland is well known. However, the immune response in mammary gland tissues, including levels of antimicrobial peptide transcripts, has not been well recognized. Moreover, most studies are conducted in vitro, on cell cultures, or on artificially infected animals, with analysis being done within a several dozen hours after infection.The aim of the study was to examine the in vivo transcript levels of beta-defensin and cathelicidins genes in cow mammary gland secretory tissue (parenchyma) with the chronic, recurrent and incurable mammary gland inflammation induced by coagulase-positive or coagulase-negative Staphyloccoci vs. bacteria-free tissue. RESULTS: The mRNA of DEFB1, BNBD4, BNBD5, BNBD10 and LAP genes, but not of TAP gene, were detected in all investigated samples regardless of the animals' age and microbiological status of the mammary gland, but at different levels. The expression of most of the beta-defensin genes was shown to be much higher in tissues derived from udders infected with bacteria (CoPS or CoNS) than from bacteria-free udders, regardless of parity. Cathelicidins (CATH4, CATH5 and CATH6) showed expression patterns contrasting those of beta-defensins, with the highest expression in tissues derived from bacteria-free udders. CONCLUSION: Increased expression of genes encoding beta defensins in the infected udder confirms their crucial role in the defense of the cow mammary gland against mastitis. On the other hand, the elevated cathelicidin transcripts in non-infected tissues indicate their role in the maintenance of healthy mammary tissues. The expression levels of investigated genes are likely to depend on the duration of the infection and type of bacteria. PMID- 25286985 TI - Factors influencing local ecological knowledge maintenance in Mediterranean watersheds: Insights for environmental policies. AB - Local ecological knowledge (LEK) has been found to be one of the main bridges to manage biocultural diversity. We analyzed the factors affecting LEK maintenance and transmission in a Mediterranean watershed. We used a mixed methods approach to evaluate the agricultural LEK in three different dimensions: biological, soil and water management, and forecasting. We found that the main factors for its maintenance were the respondent's time living in the area and the social relationships established among farmers, which involved partner collaboration and farmer information exchanges. Protected areas also played a key role for maintaining the LEK associated with soil and water management. Finally, we found that outmigration and mechanization were the most important indirect drivers of change underlying LEK erosion. We suggest that environmental policies should focus on promoting this experiential knowledge, considering both intergenerational renewal and the gendered aspects of this knowledge. PMID- 25286986 TI - Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. AB - INTRODUCTION: Patients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown. METHODS: In total, 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either ATII infusion (N =10) or placebo (N =10) plus standard of care. ATII was started at a dose of 20 ng/kg/min, and titrated for a goal of maintaining a mean arterial pressure (MAP) of 65 mmHg. The infusion (either ATII or placebo) was continued for 6 hours then titrated off. The primary endpoint was the effect of ATII on the standing dose of norepinephrine required to maintain a MAP of 65 mmHg. RESULTS: ATII resulted in marked reduction in norepinephrine dosing in all patients. The mean hour 1 norepinephrine dose for the placebo cohort was 27.6 +/- 29.3 mcg/min versus 7.4 +/- 12.4 mcg/min for the ATII cohort (P =0.06). The most common adverse event attributable to ATII was hypertension, which occurred in 20% of patients receiving ATII. 30-day mortality for the ATII cohort and the placebo cohort was similar (50% versus 60%, P =1.00). CONCLUSION: Angiotensin II is an effective rescue vasopressor agent in patients with distributive shock requiring multiple vasopressors. The initial dose range of ATII that appears to be appropriate for patients with distributive shock is 2 to 10 ng/kg/min. TRIAL REGISTRATION: Clinicaltrials.gov NCT01393782. Registered 12 July 2011. PMID- 25286987 TI - Is there an age cutoff to apply adult formulas for GFR estimation in children? AB - BACKGROUND: Estimation of glomerular filtration rate (eGFR) using a common formula for both adult and pediatric populations is challenging. Using inulin clearances (iGFRs), this study aims to investigate the existence of a precise age cutoff beyond which the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or the Cockroft-Gault (CG) formulas, can be applied with acceptable precision. Performance of the new Schwartz formula according to age is also evaluated. METHOD: We compared 503 iGFRs for 503 children aged between 33 months and 18 years to eGFRs. To define the most precise age cutoff value for each formula, a circular binary segmentation method analyzing the formulas' bias values according to the children's ages was performed. Bias was defined by the difference between iGFRs and eGFRs. To validate the identified cutoff, 30% accuracy was calculated. RESULTS: For MDRD, CKD-EPI and CG, the best age cutoff was >=14.3, >=14.2 and <=10.8 years, respectively. The lowest mean bias and highest accuracy were -17.11 and 64.7% for MDRD, 27.4 and 51% for CKD-EPI, and 8.31 and 77.2% for CG. The Schwartz formula showed the best performance below the age of 10.9 years. CONCLUSION: For the MDRD and CKD-EPI formulas, the mean bias values decreased with increasing child age and these formulas were more accurate beyond an age cutoff of 14.3 and 14.2 years, respectively. For the CG and Schwartz formulas, the lowest mean bias values and the best accuracies were below an age cutoff of 10.8 and 10.9 years, respectively. Nevertheless, the accuracies of the formulas were still below the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target to be validated in these age groups and, therefore, none of these formulas can be used to estimate GFR in children and adolescent populations. PMID- 25286989 TI - Advances in the theoretical understanding of photon upconversion in rare-earth activated nanophosphors. AB - Photon upconversion in rare earth activated phosphors involves multiple mechanisms of electronic transitions. Stepwise optical excitation, energy transfer, and various nonlinear and collective light-matter interaction processes act together to convert low-energy photons into short-wavelength light emission. Upconversion luminescence from nanomaterials exhibits additional size and surface dependencies. A fundamental understanding of the overall performance of an upconversion system requires basic theories on the spectroscopic properties of solids containing rare earth ions. This review article surveys the recent progress in the theoretical interpretations of the spectroscopic characteristics and luminescence dynamics of photon upconversion in rare earth activated phosphors. The primary aspects of upconversion processes, including energy level splitting, transition probability, line broadening, non-radiative relaxation and energy transfer, are covered with an emphasis on interpreting experimental observations. Theoretical models and methods for analyzing nano-phenomena in upconversion are introduced with detailed discussions on recently reported experimental results. PMID- 25286990 TI - Epigenetic alterations related to early-life stressful events. PMID- 25286988 TI - Increased prevalence of MEFV exon 10 variants in Japanese patients with adult onset Still's disease. AB - Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still's disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6.1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non carriers with clinical manifestations, but the monocyclic clinical course of the AOSD disease phenotype was observed less frequently in patients without MEFV variants. AOSD patients had significantly higher frequencies of MEFV exon 10 mutations, suggesting that low-frequency variants of MEFV gene may be one of the susceptibility factors of AOSD. PMID- 25286991 TI - Placebo-controlled cross-over study of the monoaminergic stabiliser (-)-OSU6162 in mental fatigue following stroke or traumatic brain injury. PMID- 25286992 TI - Effects of maintenance electroshock on mitochondrial respiratory chain and creatine kinase activities in the rat brain. PMID- 25286993 TI - Neurochemical differences in two rat strains exposed to social isolation rearing. PMID- 25286994 TI - Acute administration of GLP-1 receptor agonists induces hypolocomotion but not anxiety in mice. PMID- 25286995 TI - Increased Na+,K+-ATPase activity in the rat brain after meningitis induction by Streptococcus pneumoniae. PMID- 25286996 TI - Fluoxetine-induced tardive dyskinesia in a patient with Parkinson's disease. PMID- 25286997 TI - Bilateral striopallidodentate calcinosis presenting with psychiatric symptoms and speech disorders. PMID- 25286998 TI - Long-term specificity and stability of somatic delusions in delusional disorder, somatic type. PMID- 25287000 TI - Exploring associations between exposure to sexy online self-presentations and adolescents' sexual attitudes and behavior. AB - Previous research suggests that adolescents' social network site use is related to their sexual development. However, the associations between adolescents' exposure to sexy self-presentations of others on social network sites and their sexual attitudes and experience have not yet been empirically supported. This study investigated reciprocal longitudinal relationships between adolescents' exposure to others' sexy self-presentations on social network sites and their sexual attitudes (i.e., sexual objectification of girls and instrumental attitudes towards sex) and sexual experience. We further tested whether these associations depended on adolescents' age and gender. Results from a representative two-wave panel study among 1,636 Dutch adolescents (aged 13-17, 51.5 % female) showed that exposure to sexy online self-presentations of others predicted changes in adolescents' experience with oral sex and intercourse 6 months later, but did not influence their sexual attitudes. Adolescents' instrumental attitudes towards sex, in turn, did predict their exposure to others' sexy online self-presentations. Sexual objectification increased such exposure for younger adolescents, but decreased exposure for older adolescents. In addition, adolescents' experience with genital touching as well as oral sex (only for adolescents aged 13-15) predicted their exposure to sexy self presentations of others. These findings tentatively suggest that the influence on adolescents' sexual attitudes previously found for sexual media content may not hold for sexy self-presentations on social network sites. However, exposure to sexy self-presentations on social network sites is motivated by adolescents' sexual attitudes and behavior, especially among young adolescents. PMID- 25287001 TI - Endoscopic Transpapillary Gallbladder Stent Placement Is Safe and Effective in High-Risk Patients Without Cirrhosis. AB - BACKGROUND: Endoscopic transpapillary gallbladder stent (ETGS) placement is a proposed minimally invasive alternative to cholecystectomy in high-risk patients with symptomatic gallbladder disease. AIMS: To describe the safety and efficacy of ETGS placement in 29 consecutive patients without cirrhosis. METHODS: A retrospective analysis of consecutive ETGS cases from 2005 to 2013 at a referral center was undertaken. RESULTS: The mean age was 70 years (range 40-91), and 62 % were hospitalized. The most common indication for ETGS was acute calculus cholecystitis (52 %). Comorbidities precluding cholecystectomy included advanced cancer (45 %), severe cardiopulmonary disease (21 %), and advanced age/frailty (17 %). Eighty-six percent of the patients had an ASA class of III or IV, and the Charlson comorbidity index was >3 in 55 %. An ETGS was successfully placed in 22 patients (76 %) with 18 being successful on the first attempt. A percutaneous rendezvous approach was required to obtain cystic duct access in six patients (21 %). During a mean follow-up of 376 days, a sustained clinical response was noted in 90 % of the patients with a stent placed. No peri-procedural complications were noted. However, two patients developed delayed complications of abdominal pain and cholangitis. Six patients were alive with their original stent still in place at a mean follow-up of 2.5 years. CONCLUSIONS: ETGS is an effective and safe alternative to cholecystectomy in high-risk patients. Technical success can be facilitated by a percutaneous rendezvous technique. Our data and those of others suggest that scheduled stent exchanges may not be required unless a clinical change occurs. PMID- 25287002 TI - Resect and discard approach to colon polyps: real-world applicability among academic and community gastroenterologists. AB - BACKGROUND: "Resect and discard" (RD) is a new paradigm for management of diminutive polyps. AIM: To compare concordance of surveillance interval recommendations and diagnostic performance between RD and standard of care in a hospital outpatient department with both academic and community gastroenterologists. METHODS: Prospective, observational study conducted at a single outpatient endoscopy center over 12 months. Patients with diminutive polyps on screening or surveillance colonoscopy were included. Histology predictions for all diminutive polyps (<=5 mm) were made based on endoscopic imaging. Concordance of recommended surveillance intervals and diagnostic performance of histology predictions were compared to histopathological review. RESULTS: A total of 606 diminutive polyps were found in 315 patients (mean age 62.4 years, 49 % female). Histological prediction was made in 95.7 % of polyps (97.4 % of patients), with high confidence in 74.3 %. The concordance for surveillance intervals was 82.1 % compared to histopathological review and was similar between community and academic gastroenterologists (80.2 vs. 76.3 %, p = 0.38). Overall, sensitivity, specificity, and accuracy of histological predictions made with high confidence were 0.81, 0.36, and 77.1 %. Predictions made with narrow-band imaging (NBI) had lower accuracy (73.9 % with NBI vs. 82.5 % with high-definition white light (HWDL) only, p = 0.017) as well as lower prediction confidence (score of 7.6 with NBI vs. 8.6 with HDWL only, p < 0.001). CONCLUSIONS: Our surveillance interval concordance was below the 90 % threshold deemed acceptable by the ASGE Preservation and Incorporation of Valuable Endoscopic Innovations statement. Diagnostic performance using optical imaging to predict histology was equal between community and academic endoscopists. PMID- 25287004 TI - The multi-faceted and continuous nature of education and training to improve healthcare of older persons. PMID- 25287003 TI - Bacterial translocation and endotoxemia after pringle maneuver in cirrhotic rats. AB - BACKGROUND: Pringle maneuver (Pm) is advocated for the reduction of blood loss during liver surgery, while postoperative infections continue to be a frequent complication after hepatic resection and liver transplantation. AIM: To investigate the effect of the Pringle maneuver on systemic bacterial translocation and endotoxemia in cirrhotic rats and cirrhotic rats with selective intestinal decontamination. METHODS: A total of 100 male Sprague-Dawley cirrhotic rats were randomly divided into five equal groups: sham operation, Pm of 10 min, Pm of 20 min, Pm of 30 min, and pretreatment. Tissue samples from mesenteric lymph nodes, liver, lungs, portal, and vena cava vein blood were obtained for culture after 30 min and 24 h of the operation. Endotoxin levels were measured in portal vein and vena cava blood. RESULTS: Portal vein and vena cava blood endotoxin concentrations increased significantly after 30 min, especially 24 h of operation in the Pm of 20 min and Pm of 30 min groups. A significant increase in contaminated mesenteric lymph nodes, liver, portal, and vena cava blood was noted 24 h later. The incidence of gut bacterial translocation increased with the duration extension of Pm. Escherichia coli was the most common bacteria isolated from the tissues. There was a significant decrease of portal vein and vena cava blood endotoxin concentrations and the incidence of bacterial translocation by selective intestinal decontamination. CONCLUSIONS: There is endotoxemia immediately after Pringle maneuver and gut bacteria translocation 24 h later. The incidence of gut bacterial translocation increases with the duration extension of Pm. Selective intestinal decontamination can decrease bacteria translocation and endotoxemia. PMID- 25287007 TI - Expression of klotho and beta-catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance. AB - Esophageal carcinoma is one of the most common types of cancers in the world; the molecular mechanism underlying its tumorigenesis is still not well understood. This study was aimed at investigating the expression of klotho and beta-catenin in patients with esophageal squamous cell carcinoma (ESCC) and analyzing their association with clinicopathological variables and their effects on prognosis. The expression patterns of klotho and beta-catenin were determined by tissue microarray and immunohistochemical technique in ESCC and normal tissues, and their correlations with clinicopathological characteristics were investigated using univariate and multivariate analysis. The serum klotho levels in 40 ESCC patients and controls were measured by sandwich enzyme-linked immunosorbent assay system (ELISA). The expression level of klotho was significantly lower in ESCC than in the adjacent noncancerous tissues (30 vs. 50%, P < 0.000), and the protein level was negative correlated with clinical staging, histological grade, lymph node metastasis, and invasion depth (P < 0.05). Whereas, the expression of beta-catenin was much higher in ESCC than their corresponding normal mucosa tissues (78.3 vs. 11.5%, P < 0.000), and the level of protein correlated only with histological grade and invasion depth (P < 0.05). Correlation analysis showed the expression level of klotho inversely correlated with that of beta catenin (r = -0.214, P < 0.01). Patients with klotho-positive tumors had longer survival than those with klotho-negative tumors (P < 0.01). Cox proportional hazards model analysis demonstrated that positive expression of klotho was an important factor indicating good prognosis (hazard ratio, 0.371; 95% confidence interval, 0.201-0.685; P < 0.01). ELISA showed that the level of serum klotho was markedly higher (461.50 +/- 43.30 pg/mL) than control group (239.37 +/- 20.65 pg/mL) (P < 0.001). Receiver operating characteristic analysis gave a cut-off value of 327.031 of serum klotho with a sensitivity of 81.3% and specificity of 81.2% (P < 0.000). Our present study demonstrated for the first time that klotho might be a novel biomarker candidate for predicting progression and prognosis in patients with ESCC. PMID- 25287008 TI - Transnasal insufflation or continuous positive airway pressure (CPAP) in acute stroke. The next step or a new dilemma? PMID- 25287009 TI - Atypical femur fractures: a review. AB - Bisphosphonates are one of the most commonly prescribed medications for the treatment of osteoporosis. Their use has greatly decreased the number of osteoporosis-related vertebral and nonvertebral fractures. Recently, however, a relationship between long-term bisphosphonate use and subtrochanteric and femoral shaft fractures has been elucidated. These low-energy fractures, termed atypical femur fractures, exhibit unique characteristics in their pathophysiology, presentation, and radiographic appearance compared with more traditional high energy femur fractures. Here we provide a review based on the most recent literature of the pathophysiology, presentation, evaluation, and management of these fractures. Despite an abundance of literature, atypical femur fractures remain difficult to treat, and surgeons must be aware of the tricks and complications associated with their management. PMID- 25287010 TI - Systematic review of parenting interventions in European countries aiming to reduce social inequalities in children's health and development. AB - BACKGROUND: Early child development influences many aspects of wellbeing, health, competence in literacy and numeracy, criminality, and social and economic participation throughout the life course. Children from disadvantaged groups have less possibilities of achieving full development. By providing a positive start for all children across the social gradient, improved developmental outcomes will be seen during later childhood and throughout their lives. The objective of this systematic review was to identify interventions during early childhood in countries from the World Health Organisation European Region in 1999-2013 which reduced inequalities in children's health and development. METHODS: A systematic review was carried out adhering to the PRISMA guidelines. The review examined universal, targeted and proportionate universalism interventions, programs and services using an electronic search strategy in PubMed and the International Bibliography of the Social Sciences [IBSS] databases. A further search was performed in the grey literature. Interventions were included only if they were aimed at children or their parents and had been evaluated. RESULTS: We identified 23 interventions in total: 6 in the PubMed data base, 5 in IBSS and 12 in grey literature. All but 1 intervention-delivered in Sweden-were carried out in the United Kingdom and the Republic of Ireland. These aimed to improve parenting abilities, however, some had additional components such as: day-care provision, improving housing conditions and speech or psychological therapies. Programmes offering intensive support, information and home visits using a psycho educational approach and aimed at developing parent's and children's skills showed more favourable outcomes. These were parenting behaviours, overall children's health and higher level of fine motor skills and cognitive functioning. Child injuries and abuse were also reduced. Two interventions were universally proportionate and all others were aimed at a specific target population. CONCLUSIONS: Interventions with better outcomes and a higher level of evidence combined workshops and educational programmes for both parents and children beginning during early pregnancy and included home visits by specialised staff. Further evaluation and publication of early years interventions should be carried out also within a wider range of countries than just the UK and Ireland. PMID- 25287011 TI - Pyrrolidine Dithiocarbamate Inhibits Nuclear Factor kappaB and Toll-Like Receptor 4 Expression in Rats with Acute Necrotizing Pancreatitis. AB - BACKGROUND/AIMS: To investigate the expression of Toll-like receptor 4 (TLR4) in the pancreases of rats with acute necrotizing pancreatitis (ANP) and any changes upon treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappaB (NF-kappaB), as well as to determine the relationship between TLR4 and NF-kappaB in ANP pathogenesis. METHODS: A total of 72 SD rats were randomly divided into three groups, namely, the control (sham-operation), ANP, and ANP with PDTC pretreatment groups. The PDTC-pretreated group was intraperitoneally injected with PDTC at a dose of 100 mg/kg 1 hour before the induction of ANP. The expressions of TLR4 and NF-kappaB in pancreatic tissue were evaluated by immunohistochemistry and Western blot analysis. The mRNA levels of cytokines tumor necrosis factor alpha, interleukin (IL)-beta, and IL-6 were measured by reverse transcription polymerase chain reaction. RESULTS: The expressions of TLR4, NF-kappaB, and cytokine (NF-kappaB target) genes in the pancreatic tissue increased more significantly in the ANP groups than in the sham-operation group at 3, 6, and 12 hours. Pretreatment with PDTC alleviated the inflammatory activation in the pancreas with ANP, causing a significant decrease in the expressions of TLR4, NF-kappaB, and cytokine genes in the pancreatic tissue. CONCLUSIONS: The expressions of TLR4 and NF-kappaB were increased in the pancreases of rats with ANP. PDTC not only inhibits NF-kappaB but also suppresses the expression of TLR4 and downregulates the expression of the related cytokine genes. PMID- 25287012 TI - Distinct HbA1c trajectories in a type 2 diabetes cohort. AB - AIMS: The aim of this study was to identify subgroups of type 2 diabetes mellitus patients with distinct hemoglobin A1c (HbA1c) trajectories. Subgroup characteristics were determined and the prevalence of microvascular complications over time was investigated. STUDY DESIGN AND SETTING: Data from a cohort of 5,423 type 2 diabetes patients from a managed primary care system were used [mean follow-up 5.7 years (range 2-9 years)]. Latent class growth modeling was used to identify subgroups of patients with distinct HbA1c trajectories. Multinomial logistic regression analyses were conducted to determine which characteristics were associated with different classes. RESULTS: Four subgroups were identified. The first and largest subgroup (83 %) maintained good glycemic control over time (HbA1c <=53 mmol/mol), the second subgroup (8 %) initially showed severe hyperglycemia, but reached the recommended HbA1c target within 2 years. Patients within this subgroup had significantly higher baseline HbA1c levels but were otherwise similar to the good glycemic control group. The third subgroup (5 %) showed hyperglycemia and a delayed response without reaching the recommended HbA1c target. The fourth subgroup (3.0 %) showed deteriorating hyperglycemia over time. Patients within the last two subgroups were significantly younger, had higher HbA1c levels and a longer diabetes duration at baseline. These subgroups also showed a higher prevalence of retinopathy and microalbuminuria. CONCLUSION: Four subgroups with distinct HbA1c trajectories were identified. More than 90 % reached and maintained good glycemic control (subgroup one and two). Patients within the two subgroups that showed a more unfavorable course of glycemic control were younger, had higher HbA1c levels and a longer diabetes duration at baseline. PMID- 25287013 TI - Co-existence of beta-lactamases in clinical isolates of Escherichia coli from Kathmandu, Nepal. AB - BACKGROUND: The trend of extended-spectrum beta-lactamases producing Escherichia coli (ESBL-EC) is increasing in Nepal. Limited studies have been reported investigating ESBL types and carbapenemases in E. coli. METHODS: A cross sectional study was conducted between June 2012 to January 2013 in Kathmandu Medical College and Teaching Hospital, Nepal. Non-repetitive clinical samples from out-patient department (OPD) and Intensive Care Units (ICU) were processed for bacteriological culture and identification of E. coli. Antibiotic susceptibility test, screening and phenotypic confirmation for ESBLs and carbapenemases and PCR (blaCTX-M, blaSHV and blaTEM-type ESBLs, blaVIM, blaIMP and blaNDM-1-type carbapenemases, and class 1 integron element integrase gene) were performed. Clones were resolved by PCR-Randomly Amplified Polymorphic DNA. RESULTS: Out of 332 non-repetitive clinical specimens processed for culture and identification 160 (48.2%) were culture positive. Of which, 93 (58.1%) were E. coli. Of these, 24 (25.8%) were phenotypically confirmed as ESBL-EC and 3 (12.50%) of 24 ESBL-EC were carbapenemase producers. blaCTX-M-type ESBL was most common (23, 95.8%) followed by blaTEM (7, 29.2%) and blaSHV (3, 12.5%). blaVIM, blaIMP and blaNDM-1 were present in 3, 2 and 2 ESBL-EC, respectively. Class 1 integron element was present in 18 (75.0%) ESBL-EC. Nine isolates possessed more than one type of beta-lactamases. Interestingly, all carbapenemase producers were isolated form ICU and co-existence of blaCTX-M, blaSHV, blaTEM, blaIMP, blaVIM and blaNDM-1 beta-lactamases was documented in one ESBL-EC (EC104). All most all isolates had different RAPD patterns. CONCLUSIONS: For the first time in Nepal, high prevalence of blaCTX-M-type ESBL and co-existence of ESBLs and carbapenemases has been described. Continuous monitoring and surveillance and proper infection control and prevention practices will limit the further spread of these super-bugs within this hospital and beyond. PMID- 25287014 TI - Integrative analysis of transcriptomics, proteomics, and metabolomics data of white adipose and liver tissue of high-fat diet and rosiglitazone-treated insulin resistant mice identified pathway alterations and molecular hubs. AB - The incidences of obesity and type 2 diabetes are rapidly increasing and have evolved into a global epidemic. In this study, we analyzed the molecular effects of high-fat diet (HFD)-induced insulin-resistance on mice in two metabolic target tissues, the white adipose tissue (WAT) and the liver. Additionally, we analyzed the effects of drug treatment using the specific PPARgamma ligand rosiglitazone. We integrated transcriptome, proteome, and metabolome data sets for a combined holistic view of molecular mechanisms in type 2 diabetes. Using network and pathway analyses, we identified hub proteins such as SDHB and SUCLG1 in WAT and deregulation of major metabolic pathways in the insulin-resistant state, including the TCA cycle, oxidative phosphorylation, and branched chain amino acid metabolism. Rosiglitazone treatment resulted mainly in modulation via PPAR signaling and oxidative phosphorylation in WAT only. Interestingly, in HFD liver, we could observe a decrease of proteins involved in vitamin B metabolism such as PDXDC1 and DHFR and the according metabolites. Furthermore, we could identify sphingosine (Sph) and sphingosine 1-phosphate (SP1) as a drug-specific marker pair in the liver. In summary, our data indicate physiological plasticity gained by interconnected molecular pathways to counteract metabolic dysregulation due to high calorie intake and drug treatment. PMID- 25287015 TI - Optimization of acquisition parameters and accuracy of target motion trajectory for four-dimensional cone-beam computed tomography with a dynamic thorax phantom. AB - Our purpose in this study was to evaluate the performance of four-dimensional computed tomography (4D-CBCT) and to optimize the acquisition parameters. We evaluated the relationship between the acquisition parameters of 4D-CBCT and the accuracy of the target motion trajectory using a dynamic thorax phantom. The target motion was created three dimensionally using target sizes of 2 and 3 cm, respiratory cycles of 4 and 8 s, and amplitudes of 1 and 2 cm. The 4D-CBCT data were acquired under two detector configurations: "small mode" and "medium mode". The projection data acquired with scan times ranging from 1 to 4 min were sorted into 2, 5, 10, and 15 phase bins. The accuracy of the measured target motion trajectories was evaluated by means of the root mean square error (RMSE) from the setup values. For the respiratory cycle of 4 s, the measured trajectories were within 2 mm of the setup values for all acquisition times and target sizes. Similarly, the errors for the respiratory cycle of 8 s were <4 mm. When we used 10 or more phase bins, the measured trajectory errors were within 2 mm of the setup values. The trajectory errors for the two detector configurations showed similar trends. The acquisition times for achieving an RMSE of 1 mm for target sizes of 2 and 3 cm were 2 and 1 min, respectively, for respiratory cycles of 4 s. The results obtained in this study enable optimization of the acquisition parameters for target size, respiratory cycle, and desired measurement accuracy. PMID- 25287016 TI - Ataxia and tremor due to lesions involving cerebellar projection pathways: a DTI tractographic study in six patients. AB - Focal lesions of brainstem, thalamus, and subcortical white matter may cause movement disorders that are clinically indistinguishable from cerebellar symptoms. It is suspected that ataxia in these cases is due to damage of efferent or afferent pathways of the cerebellum. However, the precise anatomical correlate often remains undefined. We used deterministic diffusion tensor magnetic resonance imaging (DTI) tractography to study the anatomical relationship between lesions causing ataxia and efferent cerebellar pathways. Study subjects were six male patients with focal lesions of different etiology (demyelination, hemorrhage, ischemia, neoplasm) outside the cerebellum. Five patients had cerebellar-like ataxia with prominent contralateral upper limb involvement. One patient with an almost midline mesencephalic lesion had a symmetrical ataxic syndrome. We used 3T MRI (Intera, Philips Medical Systems, Best, Netherlands) and DTI tractography (32 directions, StealthViz DTI, Medtronic Navigation, Louisville, USA) to delineate the dentato-rubro-thalamo-cortical tract (DRT). In all patients, tractography demonstrated focal lesions affecting the DRT in different locations. We conclude that in vivo mapping of cerebral pathways using DTI tractography in patients with focal extracerebellar brain lesions may provide direct evidence of circumscribed damage to the DRT, causing unilateral cerebellar like ataxia. Also, a unilateral mesencephalic lesion at the level of the crossing of the DRT may cause bilateral ataxia. PMID- 25287017 TI - Late onset hereditary sensory and autonomic neuropathy with cognitive impairment associated with Y163X prion mutation. PMID- 25287018 TI - Visual hallucinations: an unusual manifestation of sporadic Creutzfeldt-Jakob disease termed the 'Heidenhain variant'. PMID- 25287019 TI - Working memory capacity links cognitive reserve with long-term memory in moderate to severe TBI: a translational approach. AB - Traumatic brain injury (TBI) can have devastating negative consequences on an individuals' ability to remember information; however, there is variability among memory impairment resulting from TBI. Some individuals exhibit long-term memory (LTM) impairment while others do not. This variability has been explained, at least in part, by the theory of cognitive reserve (CR). The theory suggests that individuals who have spent significant time engaged in intellectually enriching activities (higher CR) are better able to withstand LTM impairment despite neurological injury. The cognitive mechanisms that underlie this relationship are not well-specified. Recent evidence suggests that working memory (WM) capacity may be one mediating variable that can help explain how/why cognitive reserve (CR) protects against LTM impairment. The present research tested this hypothesis in a sample of fifty moderate to severe TBI patients. Specific neuropsychological tests were administered to estimate CR, LTM and WM. The results were congruent with a recent theoretical model that implicates WM capacity as a mediating variable in the relationship between CR and LTM (Sobel's Z = 2.62, p = 0.009). These data corroborate recent findings in an alternate neurological population and suggest that WM is an underlying mechanism of CR. Additional research is necessary to establish whether (1) WM is an important individual difference variable to include in memory rehabilitation trials and (2) to determine whether rehabilitation and treatment strategies that specifically target WM may also lead to complimentary improvements on diagnostic tests of delayed LTM in TBI and other memory impaired populations. PMID- 25287020 TI - Maternal iron metabolism gene variants modify umbilical cord blood lead levels by gene-environment interaction: a birth cohort study. AB - BACKGROUND: Given the relationship between iron metabolism and lead toxicokinetics, we hypothesized that polymorphisms in iron metabolism genes might modify maternal-fetal lead transfer. The objective of this study was to determine whether maternal and/or infant transferrin (TF) and hemochromatosis (HFE) gene missense variants modify the association between maternal blood lead (MBL) and umbilical cord blood lead (UCBL). METHODS: We studied 476 mother-infant pairs whose archived blood specimens were genotyped for TF P570S, HFE H63D and HFE C282Y. MBL and UCBL were collected within 12 hours of delivery. Linear regression models were used to examine the association between log-transformed MBL and UCBL, examine for confounding and collinearity, and explore gene-environment interactions. RESULTS: The geometric mean MBL was 0.61 MUg/dL (range 0.03, 3.2) and UCBL 0.42 (<0.02, 3.9). Gene variants were common with carrier frequencies ranging from 12-31%; all were in Hardy-Weinberg equilibrium. In an adjusted linear regression model, log MBL was associated with log UCBL (beta = 0.92, 95% CI: 0.82, 1.03; p < 0.01) such that a 1% increase in MBL was associated with a 0.92% increase in UCBL among infants born to wild-type mothers. In infants born to C282Y variants, however, a 1% increase in MBL is predicted to increase UCBL 0.65% (beta(Main Effect) = -0.002, 95% CI: -0.09, -0.09; p = 0.97; beta(Interaction) = -0.27, 95% CI: -0.52, -0.01; p = 0.04), representing a 35% lower placental lead transfer among women with MBL 5 MUg/dL. CONCLUSIONS: Maternal HFE C282Y gene variant status is associated with greater reductions in placental transfer of lead as MBL increases. The inclusion of gene-environment interaction in risk assessment models may improve efforts to safeguard vulnerable populations. PMID- 25287021 TI - Genome-wide screening of Saccharomyces cerevisiae genes required to foster tolerance towards industrial wheat straw hydrolysates. AB - The presence of toxic compounds derived from biomass pre-treatment in fermentation media represents an important drawback in second-generation bio ethanol production technology and overcoming this inhibitory effect is one of the fundamental challenges to its industrial production. The aim of this study was to systematically identify, in industrial medium and at a genomic scale, the Saccharomyces cerevisiae genes required for simultaneous and maximal tolerance to key inhibitors of lignocellulosic fermentations. Based on the screening of EUROSCARF haploid mutant collection, 242 and 216 determinants of tolerance to inhibitory compounds present in industrial wheat straw hydrolysate (WSH) and in inhibitor-supplemented synthetic hydrolysate were identified, respectively. Genes associated to vitamin metabolism, mitochondrial and peroxisomal functions, ribosome biogenesis and microtubule biogenesis and dynamics are among the newly found determinants of WSH resistance. Moreover, PRS3, VMA8, ERG2, RAV1 and RPB4 were confirmed as key genes on yeast tolerance and fermentation of industrial WSH. PMID- 25287022 TI - Increased rate of hair keratin gene loss in the cetacean lineage. AB - BACKGROUND: Hair represents an evolutionary innovation that appeared early on mammalian evolutionary history, and presumably contributed significantly to the rapid radiation of the group. An interesting event in hair evolution has been its secondary loss in some mammalian groups, such as cetaceans, whose hairless phenotype appears to be an adaptive response to better meet the environmental conditions. To determine whether different repertoire of keratin genes among mammals can potentially explain the phenotypic hair features of different lineages, we characterized the type I and II clusters of alpha keratins from eight mammalian species, including the hairless dolphin and minke whale representing the order Cetacea. RESULTS: We combined the available genomic information with phylogenetic analysis to conduct a comprehensive analysis of the evolutionary patterns of keratin gene clusters. We found that both type I and II gene clusters are fairly conserved among the terrestrial mammals included in this study, with lineage specific gene duplication and gene loss. Nevertheless, there is also evidence for an increased rate of pseudogenization in the cetacean lineage when compared to their terrestrial relatives, especially among the hair type keratins. CONCLUSIONS: Here we present a comprehensive characterization of alpha-keratin genes among mammals and elucidate the mechanisms involved in the evolution of this gene family. We identified lineage-specific gene duplications and gene loss among the Laurasiatherian and Euarchontoglires species included in the study. Interestingly, cetaceans present an increased loss of hair-type keratin genes when compared to other terrestrial mammals. As suggested by the 'less-is-more' hypothesis, we do not rule out the possibility that the gene loss of hair-type keratin genes in these species might be associated to the hairless phenotype and could have been adaptive in response to new selective pressures imposed by the colonization of a new habitat. Our study provides support for the idea that pseudogenes are not simply 'genomic fossils' but instead have adaptive roles during the evolutionary process. PMID- 25287024 TI - Coronary flow velocity reserve in patients with ascending aorta aneurysm. AB - BACKGROUND: Ascending aorta aneurysms (AAA) are one of the leading causes of morbidity and mortality. Impairment in coronary flow may contribute to cardiovascular consequences in AAA patients. Coronary flow velocity reserve (CFVR) has been considered an important diagnostic index of the functional capacity of coronary arteries noninvasively. The aim of this study was to evaluate, by noninvasive CVFR, whether patients with AAA demonstrate significant coronary microvascular dysfunction in the absence of coronary artery disease (CAD). METHODS: We prospectively included 44 patients with thoracic AAA in the absence of concomitant CAD (30 men, 14 women; mean age 57.5 +/- 8.4 years). A total of 36 patients without aortic dilatation (mean age 55.2 +/- 9.9 years) were selected as the control group. Coronary flow velocities in the distal left anterior descending (LAD) artery were measured using transthoracic echocardiography. CFVR was calculated as the hyperemic to resting coronary diastolic peak velocities ratio. RESULTS: Compared with controls, patients with AAA had higher baseline LAD peak diastolic coronary flow velocities (28.3 +/- 5.8 vs. 25.2 +/- 4.5 cm/sec, P = 0.01), lower hyperemic LAD flow velocities (54.0 +/- 10.3 vs. 57.2 +/- 12.7 cm/sec, P = 0.220), and consequently lower CFVR (1.9 +/- 0.3 vs. 2.3 +/- 0.5, P < 0.001). Multivariate linear regression analysis showed that CFVR was independently associated only with aortic systolic diameter (AoSD) (beta = -0.679, P = <0.001). CONCLUSIONS: Our study demonstrates that noninvasive CFVR is significantly reduced in patients with AAA and AoSD is the most important determinant of impaired CFVR. PMID- 25287023 TI - Electroporation in food processing and biorefinery. AB - Electroporation is a method of treatment of plant tissue that due to its nonthermal nature enables preservation of the natural quality, colour and vitamin composition of food products. The range of processes where electroporation was shown to preserve quality, increase extract yield or optimize energy input into the process is overwhelming, though not exhausted; e.g. extraction of valuable compounds and juices, dehydration, cryopreservation, etc. Electroporation is--due to its antimicrobial action--a subject of research as one stage of the pasteurization or sterilization process, as well as a method of plant metabolism stimulation. This paper provides an overview of electroporation as applied to plant materials and electroporation applications in food processing, a quick summary of the basic technical aspects on the topic, and a brief discussion on perspectives for future research and development in the field. The paper is a review in the very broadest sense of the word, written with the purpose of orienting the interested newcomer to the field of electroporation applications in food technology towards the pertinent, highly relevant and more in-depth literature from the respective subdomains of electroporation research. PMID- 25287025 TI - Sonographic breast pattern in women in Ibadan, Nigeria. AB - BACKGROUND: Sonographic breast density pattern like mammography is dependent on the relative proportion of connective and glandular tissue. Breast density is a marker for breast cancer risk and has received wide spread interest in many countries in recent times. AIMS AND OBJECTIVES: This paper aims at describing the sonographic breast pattern in women in Ibadan using the American College of Radiology in its breast imaging reporting and data system (ACR-BI-RADS) lexicon. It will also estimate the prevalence of the different sonographic breast patterns and attempt to find any association between the breast patterns and various demographic variables in the women studied. MATERIALS AND METHODS: A prospective, descriptive study of the sonographic breast pattern in 573 women carried out at the Department of Radiology, University College Hospital, Ibadan. Nigeria. Breasts scans were performed with an Aloka SSD and Logiq P5 machine. RESULTS: A total of 573 women were recruited into the study. Their age ranged between 14 and 74 years (mean = 38.91 +/- 12.51 years and median = 38 years). The modal age group was 30-39 years (26.9%). The women attained menopause between 35 and 59 years (mean = 46.2 +/- 5.1 years) while the median age for menopause was 47 years. The majority of the women studied were either obese or overweight (66.9%). Sixty-one (10.6%) women had a positive family history of breast cancer with the heterogeneous fibroglandular (60.7%) breast pattern being commonest in this high risk group; and in the entire study population (52.7%). Significant associations between the sonographic breast pattern, age, menopausal status, parity, body mass index (BMI), and waist-hip ratio (WHR) was found. BI-RADS 2 breast pattern appeared to decrease with increasing age while BI-RADS I breast pattern increased with increasing age (P < 0.001). CONCLUSION: Ultrasonography like mammography, can define the parenchymal breast pattern accurately. Strong correlation exists between parenchymal breast pattern and demographic, parity variables, and breast cancer risk factors. PMID- 25287026 TI - Body mass index as a determinant of carotid intima-media thickness in Nigerian adults with primary hypertension. AB - BACKGROUND: Long standing hypertension may result in thickening of arterial walls and is reportedly strongly correlated with body mass index (BMI). B-mode ultrasound is a reproducible method for evaluating adaptive vascular changes. The aim of this study is to determine the relationship between body mass index and ultrasound measured carotid intima-media thickness (CIMT) among adults with primary hypertension. MATERIALS AND METHODS: One hundred and twenty adults of both genders diagnosed with primary hypertension at the University College Hospital (UCH), Ibadan underwent B-mode ultrasound evaluation of the walls of the common and extracranial internal carotid arteries bilaterally. Participants' height and weight were measured and body mass index (BMI) was calculated. RESULTS: Study population had gender distribution of 50 (41.7%) and 70 (58.3%) for males and females, respectively; and a mean age of 50.61 ? 10.94 years. Mean height, weight, and BMI were 1.66 m, 69.36 kg, and 24.92 kg/m 2 for male subjects and 1.59 m, 65.6 kg, and 25.6 kg/m 2 for female subjects, respectively. Normal/underweight and overweight/obese male participants had mean CIMT of 0.744 and 0.820 mm (P < 0.05) on the right side of the neck and 0.740 and 0.816 mm (P < 0.05) on the left side, respectively. However, female participants showed no statistically significant variation in CIMT values for both BMI groups. CONCLUSION: B-mode ultrasound demonstrates statistically significant variation in CIMT values between normal/underweight and overweight/obese male adults diagnosed with primary hypertension. PMID- 25287027 TI - Benin stroke score in the diagnosis of acute brain infarct: a pilot study in Senegalese Africans. AB - BACKGROUND: The Benin stroke score (BSS) is a validated tool in the diagnosis of intracerebral hemorrhage (ICH) but not in the diagnosis of brain infarct. The aim of this report is to specifically validate the BSS in the clinical diagnosis of acute brain infarct. MATERIALS AND METHODS: A total of 60 participants with a presumptive diagnosis of acute stroke in a busy tertiary neurologic care centre in Francophone West Africa were evaluated within 48 h of onset of symptoms with the BSS after basic data were obtained, before computed tomography or magnetic resonance imaging scans was used as gold standard. BSS is a three-item tool that scores age, supine diastolic blood pressure, and Glasgow coma scale with a minimum score of 0 and a maximum score of 3.5. A score of 2.5 or less is diagnostic for a brain infarct. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratios of BSS in the diagnosis of brain infarct were 83.78%, 69.56%, 81.57%, 72.72%, 2.75, and 0.23, respectively. BSS agreed with neuroimaging in the diagnosis of all stroke subtypes significantly on kappa statistics (k = 0.538, P < 0.001) and interrater and intrarater reliability between two cadres of medical personnel in the use of BSS were significant (r = 0.9. 0.95, 0.95, P < 0.001, <0.001, <0.001), respectively. CONCLUSION: BSS as a simple clinical tool could be used with appreciable levels of accuracy in the clinical diagnosis of acute brain infarct where neuroimaging may not be available or immediately inaccessible, much the same way it is being used for ICH. PMID- 25287028 TI - Human immunodeficiency virus screening in rural communities of Rivers State, Nigeria: challenges and potential solutions. AB - BACKGROUND: Human immunodeficiency virus (HIV) testing and counseling has remained significantly low in rural communities of Nigeria despite the huge benefits of early case detection and treatment. This study aims at evolving strategies based on the health-seeking attitudes of rural people in order to improve their HIV testing access. MATERIALS AND METHODS: A cross-sectional study was carried out between May and June 2011 among persons of reproductive ages, that is, 15 years and above for men and 15-49 years for women; normally resident in rural communities of Rivers State, Nigeria, selected using a multistage sampling technique. RESULTS: A total of 267 (42.0%) males and 368 (57.9%) females were interviewed. Most of the respondents (619, 97.5%) had heard about HIV, and 498 (78.4%) were aware of its transmission by sexual route. Condom use was low and non-use with a nonmarital partner 12 months preceding the survey was 33.8% (191). Only 242 (38.1%) had ever tested for HIV: 90 (37.2%) men and 152 (62.8%) women (chi2 = 15.14, degree of freedom (df) =1, P = 0.000), while only 33 (13.6%) had tested for HIV based on sexual risk perceptions. The commonest reasons for HIV testing were pregnancy, premarriages, and test for concordance. Reasons for not testing were lack of perception of HIV risk, fear of stigmatization, and discrimination from positive test result. CONCLUSION: This study highlights the persistence of low HIV testing culture in rural settings in Nigeria and underscores the need that HIV programs should look beyond the healthcare settings and involve the communities, using home and community-based testing approaches in order to expand HIV testing access. PMID- 25287029 TI - Out-patient percutaneous renal biopsy among children in Northern Nigeria: a single center experience. AB - BACKGROUND: The safety of percutaneous renal biopsy (PRB) has been debated. The primary aim of this study was to review the procedure and secondary aim is to evaluate the safety of PRB in children in a developing nephrology unit in Northern Nigeria. METHODS: Renal biopsies carried out in the renal unit of a teaching hospital in northern Nigeria between November 2011 and April 2013 were retrospectively reviewed. All biopsies were carried out electively and under real time ultrasound guidance using an automatic spring-loaded biopsy gun. Risk factors for complications were analyzed using logistic regression. RESULTS: A total of 24 biopsies were carried out in 20 children with nephrotic syndrome during the period under review. Mean age was 8.3 ? 3.0 years. Steroid resistant nephrotic syndrome was the most common indication for biopsy in 11 (55%) cases. Adequate tissue was obtained in 91.7%. Complications occurred in 2 (8.3%) cases. One required hospitalization with blood transfusion. Pre-biopsy hemoglobin concentration of <10 g/dL was found to be a significant predictor for the development of complications (P < 0.05). There was no significant difference in the rate of complications between the in-patient biopsies and day case biopsies. CONCLUSIONS: PRB can be safely carried out as an out-patient procedure in children. Low hemologlobin concentration was the major risk factor for complication. PMID- 25287030 TI - Clinical characteristics and outcome of management of Fournier's gangrene at the Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria. AB - BACKGROUND: Fournier's gangrene (FG) though a rare condition can be associated with significant mortality. There are few reports in our environment documenting the outcome of management of the condition. The aim of the following study was to describe the clinical characteristics and outcome of management of patients with FG in a tertiary hospital in Southwest Nigeria. PATIENTS AND METHODS: The clinical records of patients who presented with FG at a tertriary hospital over a 5 year period were reviewed. RESULTS: A total of 11 cases were reviewed and all patients were male. The scrotum alone was the most common site of involvement (54.5%). Late presentation was common with 9.6 days (range 1-21 days) being the average duration between the onset of symptoms and presentation at the hospital. Most of the patients (63.6%) did not have any identifiable systemic predisposing factor. There was no mortality or testicular loss recorded. CONCLUSION: Patients with FG still present late in our environment. However, appropriate aggressive treatment can help ameliorate the associated mortality and morbidity even in a resource poor setting. PMID- 25287031 TI - Tubal abnormalities in patients with intrauterine adhesion: evaluation using hysterosalpingography. AB - BACKGROUND: Intrauterine adhesion (IUA) represents scar tissue inside the uterine cavity. Many patients may experience recurrent miscarriages, menstrual dysfunction, and may also be unable to achieve pregnancy. Tubal abnormalities are a significant cause of infertility in women. Hysterosalpingography (HSG) is a useful screening test for the evaluation of the uterine cavity and provides information relating to the assessment of tubal morphology and patency. MATERIALS AND METHODS: The HSG radiographs of 92 patients with intrauterine adhesions, between November 2008 and October 2011, in the Lagos State University Teaching Hospital, were assessed and analyzed for tubal abnormality. RESULTS: Out of the 92 patients studied, 12 (13.04%) were diagnosed with primary infertility, while the rest of the 80 (86.96%) were referred for secondary infertility. The age range of the patients was between 27 and 42 years, with a mean age of 34.58 +/- SD years. The mean infertile period of all the study subjects was 5.78 +/- SD years. The prevalence of tubal abnormalities demonstrated in the study was 67.39%. Sixty-six (71.73%) patients presented with minor adhesions, while 26 (28.27%) patients presented with moderate adhesions. Conclusion : The prevalence of tubal abnormalities demonstrated in patients with intrauterine adhesion was 67.39%. PMID- 25287032 TI - Eye health seeking habits and barriers to accessing curative services among blind beggars in an urban community in Northern Nigeria. AB - OBJECTIVE: The aim of the following study was to determine the types of intervention sought by the blind street beggars and assess the barriers to accessing available eye care services. METHODS: This cross-sectional study was conducted among consenting blind street beggars in Sokoto, Nigeria between May and June, 2009. A semi-structured interview was conducted to probe issues on historical antecedents of the blindness and the eye heath seeking behavior including the use of traditional eye medications. Assessment of barriers to accessing curative services among the blind persons was explored. Questions were asked and the individual responses were recorded in the questionnaire under the appropriate sections. RESULTS: Two hundred and two of 216 (94.7%) of the examined subjects were found to be blind and included in the analysis. The principal cause of blindness was corneal opacity. Overall 82% of the blindness was due to avoidable causes with majority irreversibly blind. Only 38 subjects (18.8%) sought for intervention in hospitals, others resorted to self-medication (42.1%), medicine store (31.2%) and traditional facility (7.9%). Those that accessed treatment at a hospital did so mainly at a primary health center (50.0%) and General Hospitals (34.2%). The barriers to accessing treatment at the hospital were mainly due to "not taken to any hospital" by the parents/relatives (50.3%) and "services not available" (25.2%). CONCLUSION: Most respondents resorted to ocular self-medication particularly traditional eye medicines. We advocate for a provision of affordable, accessible and qualitative eye care services with a strong health education component on avoidable causes of blindness. PMID- 25287033 TI - Physical activity among type-2 diabetic adult Nigerians. AB - BACKGROUND: Regular participation in physical activity (PA) programs is a key concept included in current public health guidelines. Therefore, this study was aimed to determine PA level among adult with type 2 diabetes. METHODS: A cross section of 122 participants selected consecutively were categorized as physically inactive or active using International Physical Activity Questionnaire. Data was assessed using descriptive and inferential statistics. RESULTS: About 31% of the respondents were physically inactive. Residential areas were significantly associated with PA. A high proportion of those who lived in the metropolitan area were physically inactive. Less likely to be physically inactive were married (odds ratios [OR] =0.29, confidence interval [CI] =0.09-0.93) and living in an urban area (OR = 0.19, CI = 0.40-0.87). The degree holders are least physically inactive while the primary school leavers are highest. The median energy expenditure for walking, moderate and vigorous PA was 280.5, 80 and 0 MET min/week respectively. The sedentary behavior of the respondents was 288 min/day, behavior which increases with age. CONCLUSION: This study suggests that the prevalence of physical inactivity was high among type 2 diabetics and their sedentary behavior is over 4 h/day. This group of people should be encouraged to participate regularly in PA. PMID- 25287034 TI - Pattern and outcome of admissions in the medical wards of a tertiary health center in a rural community of Ekiti State, Nigeria. AB - OBJECTIVE: To determine the pattern and outcome of medical admissions as well as the basic demographic characteristics in medical wards of a tertiary health center located in a rural area. Materials and Methods : A retrospective analysis of medical wards admissions of the Federal Medical Centre, Ido-Ekiti, Ekiti State, southwest Nigeria, between January 2009 and December 2011. Data obtained was analyzed using SPSS Version 16 software. RESULT: The total number of patients admitted during the period was 1519, age ranged from 16 to 120 years, with a mean of 56.1 + 18.8 years. There were 823 (54.3%) males and 696 (45.7%) females in a ratio of 1.2:1.0; the highest number of age group admitted was the elderly. Disorders of the cardiovascular system topped the admission list (32.1%) in general, and noncommunicable diseases were also predominant (68.4%) on the admission list compared with communicable diseases (31.6%). The most common cause of death was cardiovascular diseases (33.0%). CONCLUSION: Male gender and elderly aged groups were predominant on admission. Noncommunicable diseases were of higher proportion on admission than communicable diseases. The most common cause of death was cardiovascular diseases of which stroke topped the list. PMID- 25287035 TI - Effect of demographic and injury etiologic factors on intensive care unit mortality after severe head injury in a low middle income country. AB - BACKGROUND: Low- and middle-income countries bear the mortality burden of head injury compared with high-income countries. Not much has been studied about predictors of poor outcome after head injury in these countries. This study describes and quantifies the effect of demographics and injury causative factors on mortality in a cohort managed in a Nigerian tertiary hospital intensive care. MATERIALS AND METHODS: A retrospective study was undertaken of all patients admitted into intensive care with severe head injury at the University of Port Harcourt Teaching Hospital, Nigeria between 1 st January, 1997 and 31 st December, 2006. Logistic regression analysis was performed to examine the effect of age, gender and injury etiology on risk of intensive care unit (ICU) mortality. RESULTS: The number of ICU admission for severe head injury was 231 patients with a male to female ratio of 2.8:1. Patients' mean age and standard deviation was 31.2 +/- 15.5 years. The mortality rate was 52.8%. Road traffic injury was the most common etiologic factor (84%). Logistic regression analysis indicated a 56% increase in the risk of ICU mortality between the ages of 21 and 40 years. The effect of age was found to be nonlinear (likelihood ratio P = 0.033). On multivariable analysis, patient's gender (odds ratio 1.07; 95% confidence interval: 0.56-1.97) and etiology of injury were not significantly associated with risk of mortality. Gender was not a modifier of the effect of age (P = 0.218). CONCLUSION: The study indicated a strong prognostic effect of age. Gender and etiology of injury had no effect on ICU mortality among study cohort. PMID- 25287036 TI - Sero-prevalence of hepatitis B and C among mentally ill patients attending a tertiary hospital in Nigeria. AB - BACKGROUND: Mentally ill persons are vulnerable to sexually transmitted infections including hepatitis B and C because of their high level risky behaviors. This study is aimed at establishing the sero-prevalence of hepatitis B and C among the mentally ill individuals (MII) attending psychiatric clinic of the University of Ilorin Teaching Hospital (UITH), Nigeria since it has not been documented. METHODS: A total of 350 MII were recruited. HBsAg testing was by immunoassay test strip (Grand Medical Diagnostic R USA) while hepatitis C was tested by commercially prepared kits from ACON, R USA. Healthy adults who presented as donors in the blood bank of the hospital were used as controls. RESULTS: A total of 700 participants including 350 MII and 350 blood donors (BDs) were recruited for the study. The mean ages of MII and control participants were 36.5 +/- 12.3 and 31.4 +/- 8.3, respectively.The sero-prevalence of hepatitis B and C among patients with mental illness was 10.0 and 12.6%, respectively, as compared to 10.9% and 1.1% of the blood donors. There was a significant difference in the prevalence of HCV among mentally ill when compared with the blood donors (P = 0.001, chi2 = 33.97; OR (CI) =12.44 (5.33-29.03). CONCLUSION: Mentally ill patients attending UITH were significantly infected with hepatitis C virus. There is need for interventional measures to reduce the prevalence of hepatitis C among the mentally ill population such as health education and early screening of mentally ill in our setting. PMID- 25287037 TI - Pattern of computerized tomography of the brain findings in stroke patients in Sokoto, northwestern Nigeria. AB - BACKGROUND: Stroke is a common cause of morbidity and mortality worldwide. Therapeutic decision regarding its management requires prompt and accurate diagnosis as well as exclusion of other conditions mimicking this condition. Computerized tomography (CT) scan has been found to be the gold standard in distinguishing primary intracerebral hemorrhage (ICH) from cerebral infarction (CI). METHODS: A retrospective review of CT findings in 128 patients who presented in the Radiology Department of Usmanu Danfodiyo University Teaching Hospital with clinical diagnosis of stroke was undertaken over a period of 1 year (from December 2008 to November 2009). The following data were recorded; age, sex, clinical diagnosis, and CT findings. All the CT examinations were performed on a Neusoft C3000 multidetector spiral CT. Evaluation was done by consultant radiologists in the department. RESULTS: Of the 128 patients seen within the period under review, 84 (65.6%) were males while 44 (34.4%) were females. Age range was 4-85 years (mean 49.52, standard deviation (SD) 15.11), while 61 (47.7%) of the patients were in the age group of 41-60 years. Eighty-six patients (67.1%) had cerebral infarction, 38 (29.7%) had intracerebral hemorrhage, while one (0.01%) had subarachnoid hemorrhage. Three patients (0.02%) had normal brain CT findings. CONCLUSION: Cerebral infarction is the most common form of stroke in this study. CT is essential in establishing the type of stroke, which subsequently determines the type of intervention as well as follow-up evaluation the patient may require. PMID- 25287038 TI - Eight year review of hemodialysis: treated patients in a tertiary center in Southern Nigeria. AB - BACKGROUND: Hemodialysis (HD) is the readily available modality of renal replacement therapy in Nigeria today. The number of centers for HD continues to increase, but the majority is still located in the big cities and towns. METHODS: A retrospective descriptive study in which records of patients on HD from 2004 to 2011 were reviewed. Data in respect of patients' sex, age, occupation and etiology of kidney disease were collected. Data were analyzed using Statistical Package for the Social Sciences statistical software version 16 (SPSS Inc, Chicago IL). RESULTS: A total of 1278 new patients were admitted for HD over the period of review; 60.9% (778) were males and 39.1% (500) females. Mean age of male patients was significantly higher than that of the females (P < 0.01). Those under the age of 40 years constituted 45.4% (580) of the study population, whereas 43.8% (560) were unskilled workers. Nearly 81.1% had CKD while 18.9% (241) had acute kidney injury (AKI). The most common cause of CKD and AKI were chronic glomerulonephritis (CGN) and sepsis respectively. CONCLUSION: This review showed a preponderance of males in the dialyzed population with males significantly older than the female patients. Patients aged <= 40 years and unskilled workers formed a large proportion of the population of HD treated patients. CGN and sepsis were the most common causes of CKD and AKI respectively. PMID- 25287039 TI - Foramen of Huschke (tympanicum) in a Nigerian male with articular soft-tissue herniation into the external auditory meatus. AB - The protrusion of articular soft-tissue from the temporomandibular joint (TMJ) into the external ear in the absence of trauma, neoplasm or inflammation is rare. We present below a Nigerian adult male with retrodiscal herniation of soft tissues of the TMJ into the external auditory meatus through a persistent foramen of Huschke. We are not aware of any reports of this developmental defect or its prevalence in the Nigerian medical literature. Therefore, this case is presented to heighten the index of suspicion of physicians when managing patients with otorrhea and otalgia; which is often primarily diagnosed or misdiagnosed as otitis externa. This will help avoid complications associated with the anomaly, some of which could be very serious. PMID- 25287040 TI - An usual cause of postextubation airway obstruction and its management in a low resource setting. PMID- 25287041 TI - The relationship between smoking, clinical manifestations, and HAART in Nigerian HIV-infected patients. PMID- 25287042 TI - Surgical management of nasolachrymal duct obstruction in children. PMID- 25287043 TI - The perils of bladder exstrophy repairs in Africa. PMID- 25287044 TI - Nanostructured Brownian surfaces prepared through two-photon polymerization: investigation of stem cell response. AB - Nondeterministic phenomena are at the base of plenty of biological processes that comprise physiological signaling, cellular communications, and biological architectures. Among them, natural surface topographies are often characterized by "chaotic" features that are not trivial to be recreated in vitro. Recently, some methods have been proposed to resemble the hierarchical organization of the extracellular microenvironment, through the chemical preparation of randomly rough and self-affine fractal surfaces. Notwithstanding, this approach does not allow the fractal dimension to be modulated at a desired value, being moreover the self-affinity maintained just for one decade of spatial frequencies. Here, we propose the replication of in silico generated Brownian surfaces through a two photon polymerization technique. As a result of the direct laser writing of the desired patterns, we were able to obtain highly reproducible self-affine (in a range of two spatial frequency decades) structures characterized by the desired predetermined Hurst exponents. Rat mesenchymal stem cells were moreover cultured on the obtained substrates, highlighting interesting phenomena concerning cell adhesion, cytoskeleton conformation, and actin polymerization, strictly depending on the fractal dimension of the surfaces. PMID- 25287045 TI - Flagellar-dependent motility in Mesorhizobium tianshanense is involved in the early stage of plant host interaction: study of an flgE mutant. AB - Bacterial motility is most likely a critical factor for rhizobium to chemotactically colonize on the root surface prior to infecting leguminous plant hosts. Several studies of the rhizobium flagellar filament have been reported, but little is known about the rhizobium flagellum hook. To investigate the roles of the hook protein in flagellum synthesis in Mesorhizobium tianshanense, the hook protein-encoding gene flgE of M. tianshanense was amplified by PCR and sequenced. Comparison of the deduced amino acid sequences revealed pronounced similarities in Domain 1 and lower similarities in Domain 2, which are supposed to be related to hook structure assembly and antigenic diversity, respectively. The level of transcription of flgE increased along with the cell growth and reached its maximum at the middle log phase. Disruption of the flgE gene caused a flagellar-less phenotype, thereby causing complete loss of swimming ability, modified nutrient-related swarming ability and biofilm formation. Moreover, the absence of flagellar caused decreased bacterial attachment on the root hair, suggesting that flagellar is involved in the early stage of symbiosis process. PMID- 25287047 TI - A new prodrug form of Affibody molecules (pro-Affibody) is selectively activated by cancer-associated proteases. AB - Affinity proteins have advanced the field of targeted therapeutics due to their generally higher specificity compared to small molecular compounds. However, side effects caused by on-target binding in healthy tissues are still an issue. Here, we design and investigate a prodrug strategy for improving tissue specificity of Affibody molecules in future in vivo studies. The prodrug Affibody (pro-Affibody) against the HER2 receptor was constructed by fusing a HER2-specific Affibody (ZHER2) to an anti-idiotypic Affibody (anti-ZHER2). The linker was engineered to comprise a substrate peptide for the cancer-associated matrix metalloprotease 1 (MMP-1). The hypothesis was that the binding surface of ZHER2 would thereby be blocked from interacting with HER2 until the substrate peptide was specifically hydrolyzed by MMP-1. Binding should thereby only occur where MMP-1 is overexpressed, potentially decreasing on-target toxicities in normal tissues. The pro-Affibody was engineered to find a suitable linker and substrate peptide, and the different constructs were evaluated with a new bacterial display assay. HER2 binding of the pro-Affibody was efficiently masked and proteolytic activation of the best variant yielded over 1,000-fold increase in apparent binding affinity. Biosensor analysis revealed that blocking of the pro-Affibody primarily affected the association phase. In a cell-binding assay, the activated pro-Affibody targeted native HER2 on cancer cells as opposed to the non-activated pro Affibody. We believe this prodrug approach with proteolytic activation is promising for improving tissue specificity in future in vivo targeting applications and can hopefully be extended to other Affibody molecules and similar affinity proteins as well. PMID- 25287048 TI - Phenotypic characterization and genetic diversity of Flavobacterium columnare isolated from red tilapia, Oreochromis sp., in Thailand. AB - Flavobacterium columnare is the aetiological agent of columnaris disease and severely affects various freshwater aquaculture fish species worldwide. The objectives of this study were to determine the phenotypic characteristics and genetic variability among F. columnare isolates isolated from red tilapia in Thailand. Forty-four F. columnare isolates were recovered from diseased fish in different geographical locations. The isolates exhibited homologous phenotypic characteristics but exhibited genetic diversity. One isolate was assigned to genomovar I, and the remainder were assigned to genomovar II, indicating the coexistence of these genomovars but predominance of genomovar II. Phylogenetic analysis of the 16S-23S ISR sequences revealed that a subset of the Thai isolates (n = 25) contained a smaller intergenic spacer region (ISR) (523-537 bp) and formed a unique ISR phylogenetic group. Phylogenetic analysis of the 16S rRNA gene supported the unique cluster of Thai isolates. This is the first description of the phenotypic and molecular characteristics of F. columnare isolated from red tilapia in Thailand as well as five isolates of F. columnare derived from other fish species including Nile tilapia, koi carp and striped catfish. PMID- 25287046 TI - Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics. AB - In absence of experimental 3D structures, several homology models, based on ABC exporter 3D structures, have provided significant insights into the molecular mechanisms underlying the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel whose defects are associated with cystic fibrosis (CF). Until now, these models, however, did not furnished much insights into the continuous way that ions could follow from the cytosol to the extracellular milieu in the open form of the channel. Here, we have built a refined model of CFTR, based on the outward-facing Sav1866 experimental 3D structure and integrating the evolutionary and structural information available today. Molecular dynamics simulations revealed significant conformational changes, resulting in a full-open channel, accessible from the cytosol through lateral tunnels displayed in the long intracellular loops (ICLs). At the same time, the region of nucleotide-binding domain 1 in contact with one of the ICLs and carrying amino acid F508, the deletion of which is the most common CF-causing mutation, was found to adopt an alternative but stable position. Then, in a second step, this first stable full-open conformation evolved toward another stable state, in which only a limited displacement of the upper part of the transmembrane helices leads to a closure of the channel, in a conformation very close to that adopted by the Atm1 ABC exporter, in an inward facing conformation. These models, supported by experimental data, provide significant new insights into the CFTR structure-function relationships and into the possible impact of CF-causing mutations. PMID- 25287049 TI - Are teleoncology models merely about avoiding long distance travel for patients? AB - Teleoncology models are used increasingly throughout the world as a means to provide access to quality cancer care for people in rural, remote and other disadvantaged settings. Some authors have suggested that teleoncology is merely about avoiding long distance travel. In this commentary we argue that the benefits of teleoncology extend beyond those of the patients and their families to the rural health system and beyond. We draw upon the literature and results of an evaluation of the Townsville Teleoncology Network (TTN) in North Queensland, Australia to support our arguments. PMID- 25287050 TI - Reactive oxygen species-responsive protein modification and its intracellular delivery for targeted cancer therapy. AB - Herein we report a convenient chemical approach to reversibly modulate protein (RNase A) function and develop a protein that is responsive to reactive oxygen species (ROS) for targeted cancer therapy. The conjugation of RNase A with 4 nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl carbonate (NBC) blocks protein lysine and temporarily deactivates the protein. However, the treatment of RNase A-NBC with hydrogen peroxide (one major intracellular ROS) efficiently cleaves the NBC conjugation and restores the RNase A activity. Thus, RNase A-NBC can be reactivated inside tumor cells by high levels of intracellular ROS, thereby restoring the cytotoxicity of RNase A for cancer therapy. Due to higher ROS levels inside tumor cells compared to healthy cells, and the resulting different levels of RNase A-NBC reactivation, RNase A-NBC shows a significant specific cytotoxicity against tumor cells. PMID- 25287051 TI - Climatic variability, hydrologic anomaly, and methane emission can turn productive freshwater marshes into net carbon sources. AB - Freshwater marshes are well-known for their ecological functions in carbon sequestration, but complete carbon budgets that include both methane (CH4 ) and lateral carbon fluxes for these ecosystems are rarely available. To the best of our knowledge, this is the first full carbon balance for a freshwater marsh where vertical gaseous [carbon dioxide (CO2 ) and CH4 ] and lateral hydrologic fluxes (dissolved and particulate organic carbon) have been simultaneously measured for multiple years (2011-2013). Carbon accumulation in the sediments suggested that the marsh was a long-term carbon sink and accumulated ~96.9 +/- 10.3 (+/-95% CI) g C m(-2) yr(-1) during the last ~50 years. However, abnormal climate conditions in the last 3 years turned the marsh to a source of carbon (42.7 +/- 23.4 g C m( 2) yr(-1) ). Gross ecosystem production and ecosystem respiration were the two largest fluxes in the annual carbon budget. Yet, these two fluxes compensated each other to a large extent and led to the marsh being a CO2 sink in 2011 (-78.8 +/- 33.6 g C m(-2) yr(-1) ), near CO2 -neutral in 2012 (29.7 +/- 37.2 g C m(-2) yr(-1) ), and a CO2 source in 2013 (92.9 +/- 28.0 g C m(-2) yr(-1) ). The CH4 emission was consistently high with a three-year average of 50.8 +/- 1.0 g C m( 2) yr(-1) . Considerable hydrologic carbon flowed laterally both into and out of the marsh (108.3 +/- 5.4 and 86.2 +/- 10.5 g C m(-2) yr(-1) , respectively). In total, hydrologic carbon fluxes contributed ~23 +/- 13 g C m(-2) yr(-1) to the three-year carbon budget. Our findings highlight the importance of lateral hydrologic inflows/outflows in wetland carbon budgets, especially in those characterized by a flow-through hydrologic regime. In addition, different carbon fluxes responded unequally to climate variability/anomalies and, thus, the total carbon budgets may vary drastically among years. PMID- 25287052 TI - Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages. AB - Although Fasudil has shown therapeutic potential in EAE mice, the mechanism of action are still not fully understood. Here, we examined the immunomodulatory effect of Fasudil on encephalitogenic mononuclear cells (MNCs), and tested the therapeutic potential of Fasudil-treated MNCs in active EAE. Fasudil inhibited expression of CCL20 on T cells and migration of T cells, decreased CD4(+) IFN gamma(+) and CD4(+) IL-17(+) T cells, but increased CD4(+) IL-10(+) and CD4(+) TGF-beta(+) T cells. Fasudil reduced expression of CD16/32 and IL-12, while elevating expression of CD206, CD23, and IL-10. Fasudil also decreased levels of iNOS/NO, enhanced levels of Arg-1, and inhibited the TLR-4/NF-kappaB signaling and TNF-alpha, shifting M1 macrophage to M2 phenotype. These modulatory effects of Fasudil on T cells and macrophages were not altered by adding autoantigen MOG35-55 to the culture, i.e., autoantigen-independent. Further, we observed that, in vitro, Fasudil inhibited the capacity of encephalitogenic MNCs to adoptively transfer EAE and reduced TLR-4/p-NF-kappaB/p65 and inflammatory cytokines in spinal cords. Importantly, Fasudil-treated encephalitogenic MNCs exhibited therapeutic potential when injected into actively induced EAE mice. Together, our results not only provide evidence that Fasudil mediates the polarization of macrophages and the regulation of T cells, but also reveal a novel strategy for cell therapy in MS. PMID- 25287053 TI - Pathways from childhood maltreatment to emerging adulthood: investigating trauma mediated substance use and dating violence outcomes among child protective services-involved youth. AB - Longitudinal survey data were used to examine the relationship between two types of childhood maltreatment, abuse/neglect and exposure to intimate partner violence (IPV), and two outcomes, substance use and dating violence, within the past year. Participants were youth (N = 158, aged 16-19 at Time 3) involved with child protective services (CPS). A parallel multiple mediator model was used to test the hypothesis that trauma symptoms would mediate the relationship between both types of maltreatment and dating violence, marijuana, and alcohol use outcomes. Although both types of maltreatment were not directly associated with dating violence and substance use outcomes, the indirect effects of anxiety, anger, and dissociation on the relationship between maltreatment and substance use/dating violence were significant. Direct effects of both types of maltreatment on past year use of dating violence + alcohol use and dating violence + marijuana use were not significant, but results demonstrated a significant indirect effect for anger on the relationship between exposure to IPV and past year dating violence + marijuana use. No other indirect effects were significant. Findings highlight the negative effects of exposure to IPV and have implications for the development of prevention programming for youth transitioning out of CPS. PMID- 25287054 TI - Comparison of different cleanup procedures for oil crops based on the development of a trace analytical method for the determination of pyraclostrobin and epoxiconazole. AB - The effects of different cleanup procedures in removing high-molecular-mass lipids and natural colorants from oil-crop extracts, including dispersive solid phase extraction, low-temperature precipitation and gel permeation chromatography, were studied. The pigment removal, lipid quantity, and matrix effects of the three cleanup methods were evaluated. Results indicated that the gel permeation chromatography method is the most effective way to compare the dispersive solid-phase extraction and low-temperature precipitation. Pyraclostrobin and epoxiconazole applied extensively in oil-crop production were selected as typical pesticides to study and a trace analytical method was developed by gel permeation chromatography and ultra high performance liquid chromatography with tandem mass spectrometry. Average recoveries of the target pesticides at three levels (10, 50, and 100 MUg/kg) were in the range of 74.7 96.8% with relative standard deviation values below 9.2%. The limits of detection did not exceed 0.46 MUg/kg, whereas the limits of quantification were below 1.54 MUg/kg and much lower than maximum residue limit in all matrices. This study may provide the essential data for optimizing the analytical method of pesticides in oil-crop samples. PMID- 25287055 TI - Non-proportional odds multivariate logistic regression of ordinal family data. AB - Methods to examine whether genetic and/or environmental sources can account for the residual variation in ordinal family data usually assume proportional odds. However, standard software to fit the non-proportional odds model to ordinal family data is limited because the correlation structure of family data is more complex than for other types of clustered data. To perform these analyses we propose the non-proportional odds multivariate logistic regression model and take a simulation-based approach to model fitting using Markov chain Monte Carlo methods, such as partially collapsed Gibbs sampling and the Metropolis algorithm. We applied the proposed methodology to male pattern baldness data from the Victorian Family Heart Study. PMID- 25287056 TI - Structure and biosynthetic assembly of gulmirecins, macrolide antibiotics from the predatory bacterium Pyxidicoccus fallax. AB - The gulmirecins constitute a new class of glycosylated macrolides that were isolated from the predatory bacterium Pyxidicoccus fallax HKI 727. Their structures were solved by a combination of NMR spectroscopic experiments and chemical derivatization. Analysis of the annotated gulmirecin gene cluster complemented the configurational assignment and provided insights into the stereochemical course of the biosynthetic assembly. The gulmirecins exhibit strong activity against staphylococci, including methicillin-resistant Staphylococcus aureus, but no cytotoxic effects on human cells. PMID- 25287057 TI - The influence of low-level laser on orthodontic relapse in rats. AB - SUMMARY OBJECTIVES: This study evaluated the effect of low-level laser therapy (LLLT) on the tendency of rat molars to relapse following orthodontic tooth movement (OTM). MATERIAL AND METHODS: Maxillary rat molars were moved mesially for 10 days. Animals were randomly assigned to group I (non-irradiated) or II (irradiation with LLLT). Appliances were removed, and the molars allowed to relapse for 1, 3, 5, 7, 14, or 21 days; rats in group II received LLLT according to a protocol. Bone density of periapical alveolar bone was measured using radiographs and Digora software. Dental supporting structures were examined histologically with haematoxylin and eosin and tartrate-resistant acid phosphatase. RESULTS: In both groups, first molar relapse was rapid 1 day after the end of active treatment; by 21 days percentage relapse was measured as 86.11 per cent in group I, and 72.22 per cent in group II. Osteoclast number was highest at the end of active OTM, and thereafter successively decreased during the relapse phase in both groups. Decrease in number, and redistribution of osteoclasts occurred more rapidly in the non-irradiated than the LLLT group. Whilst molar relapse was generally less and osteoclast numbers generally higher in group II compared to group I, the differences were not significant. There was no significant difference in bone density between the two groups. CONCLUSIONS: These results indicate that LLLT may reduce the relapse tendency, possibly due in part to bone formation in previous tension areas, and to redistribution of osteoclasts following removal of orthodontic force. The role of LLLT in the prevention of orthodontic relapse requires further study. PMID- 25287059 TI - Virus-induced double-membrane vesicles. AB - Many viruses that replicate in the cytoplasm compartmentalize their genome replication and transcription in specific subcellular microenvironments or organelle-like structures, to increase replication efficiency and protect against host cell defences. Recent studies have investigated the complex membrane rearrangements induced by diverse positive-strand RNA viruses, which are of two morphotypes : membrane invagination towards the lumen of the endoplasmic reticulum (ER) or other specifically targeted organelles and double-membrane vesicles (DMVs) formed by extrusion of the ER membrane. DMVs resemble small autophagosomes and the viruses inducing these intriguing organelles are known to promote autophagy, suggesting a potential link between DMVs and the autophagic pathway. In this review, we summarize recent findings concerning the biogenesis, architecture and role of DMVs in the life cycle of viruses from different families and discuss their possible connection to autophagy or other related pathways. PMID- 25287060 TI - Combined use of endometrial sample and magnetic resonance imaging in the preoperative risk-stratification of endometrial carcinomas. AB - OBJECTIVE: To compare two treatment strategies in women undergoing surgery for endometrial carcinoma. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. POPULATION: 1166 patients. Uterine biopsy/curettage was obtained in 1140 women, of whom 229 also had pelvic magnetic resonance imaging (MRI). METHODS: We compared two strategies: (i) routine pelvic lymphadenectomy and (ii) selective pelvic lymphadenectomy for women with high-risk carcinomas as determined from preoperative histology and MRI. High-risk carcinomas included grade 1-2 endometrioid carcinomas with >=50% myometrial invasion, grade 3 endometrioid carcinomas, and nonendometrioid carcinomas. Others were considered low-risk carcinomas. MAIN OUTCOME MEASURES: Diagnostic indices, treatment algorithms. RESULTS: Of the women who underwent lymphadenectomy, positive pelvic nodes were found in 2.3% of low-risk carcinomas and 18.3% of high-risk carcinomas. The combination of preoperative histology and MRI detected high-risk carcinomas with a sensitivity of 85.7%, a specificity of 75.0%, a positive predictive value of 74.4%, and a negative predictive value of 86.1%. Area under curve was 0.804. In the routine lymphadenectomy algorithm, 54.1% of lymphadenectomies were performed for low-risk carcinomas. In the selective lymphadenectomy algorithm, 14.3% of women with high-risk carcinomas did not receive lymphadenectomy. Missed positive pelvic nodes were estimated to occur in 2.1% of patients in the selective strategy. Similarly, the estimated risk for isolated para-aortic metastasis was 2.1%, regardless of treatment strategy. CONCLUSIONS: The combination of preoperative histology and MRI is moderately sensitive and specific in detecting high-risk endometrial carcinomas. The clinical utility of the method is hampered by the relatively high proportion of high-risk cases that remain unrecognized preoperatively. PMID- 25287058 TI - RNase L contributes to experimentally induced type 1 diabetes onset in mice. AB - The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon alpha (IFNalpha) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNalpha contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNalpha-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8(+)T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying beta-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L. PMID- 25287061 TI - Gene expression-based enrichment of live cells from adipose tissue produces subpopulations with improved osteogenic potential. AB - INTRODUCTION: Mesenchymal stem cells have been increasingly used for cell-based therapies. Adipose-derived stem/stromal cells (ASCs) from the stromal vascular fraction (SVF) of fat tissue are a particularly attractive option for cell based therapy given their accessibility and relative abundance. However, their application in both clinical and basic science investigations is complicated by the isolation of differentiable cells within the SVF. Current enrichment strategies, such as monolayer passaging and surface marker-based sorting, can be time-consuming or overly stringent. Ideally, a population of cells with great regenerative capacity could be isolated with high yields so that extensive in vitro manipulation is not necessary. The objective of this study was to determine whether SVF cells sorted based on expression of alkaline phosphatase liver/bone/kidney (ALPL) resulted in populations with increased osteogenic differentiation potential. METHODS: SVF samples were obtained from four, human donors and processed to isolate initial, heterogeneous cell populations. These SVF cells underwent a four day osteogenic priming period, after which they were treated with a fluorescent, oligodeoxynucleotide molecular beacon probe specific for ALPL mRNA. Cells were separated into positive and negative groups using fluorescence-activated cell sorting (FACS) then differentiated down the osteogenic lineage. Differentiation was assessed by measuring calcified matrix production in each sample. RESULTS: Cells positive for ALPL expression (ALPL+) represented approximately 34% of the gated population, while cells negative for ALPL expression (ALPL-) represented approximately 18%. ALPL+ cells produced 3.7 fold and 2.1-fold more calcified matrix than ALPL- and unsorted SVF cells, respectively, indicating a significant improvement in osteogenic differentiation. Further, ALPL+ cells showed increases in metabolite production for both adipogenesis and chondrogenesis, suggesting that the enrichment process yields an enhanced multipotent phenotype. Osteogenic differentiation response and cell yields for ALPL+ cells were markedly improved over surface marker-sorted samples. CONCLUSION: This study demonstrates a novel method to enrich heterogeneous SVF cells for increased osteogenic potential. The procedure requires less time and results in higher yields of therapeutically useful cells than other existing approaches. Gene expression-based sorting of MSCs is a potentially paradigm shifting approach that could benefit applications spanning from basic science to clinical therapy. PMID- 25287062 TI - A miR-208-Mef2 axis drives the decompensation of right ventricular function in pulmonary hypertension. AB - RATIONALE: Right ventricular (RV) failure is a major cause of morbidity and mortality in pulmonary hypertension, but its mechanism remains unknown. Myocyte enhancer factor 2 (Mef2) has been implicated in RV development, regulating metabolic, contractile, and angiogenic genes. Moreover, Mef2 regulates microRNAs that have emerged as important determinants of cardiac development and disease, but for which the role in RV is still unclear. OBJECTIVE: We hypothesized a critical role of a Mef2-microRNAs axis in RV failure. METHODS AND RESULTS: In a rat pulmonary hypertension model (monocrotaline), we studied RV free wall tissues from rats with normal, compensated, and decompensated RV hypertrophy, carefully defined based on clinically relevant parameters, including RV systolic and end diastolic pressures, cardiac output, RV size, and morbidity. Mef2c expression was sharply increased in compensating phase of RVH tissues but was lost in decompensation phase of RVH. An unbiased screening of microRNAs in our model resulted to a short microRNA signature of decompensated RV failure, which included the myocardium-specific miR-208, which was progressively downregulated as RV failure progressed, in contrast to what is described in left ventricular failure. With mechanistic in vitro experiments using neonatal and adult RV cardiomyocytes, we showed that miR-208 inhibition, as well as tumor necrosis factor-alpha, activates the complex mediator of transcription 13/nuclear receptor corepressor 1 axis, which in turn promotes Mef2 inhibition, closing a self limiting feedback loop, driving the transition from compensating phase of RVH toward decompensation phase of RVH. In our model, serum tumor necrosis factor alpha levels progressively increased with time while serum miR-208 levels decreased, mirroring its levels in RV myocardium. CONCLUSIONS: We describe an RV specific mechanism for heart failure, which could potentially lead to new biomarkers and therapeutic targets. PMID- 25287064 TI - Needs of informal caregivers during transition from home towards institutional care in dementia: a systematic review of qualitative studies. AB - BACKGROUND: Alongside providing care, informal caregivers of people with dementia often need support and guidance themselves, especially during difficult periods such as the care-transition from home towards a nursing home. Knowledge on needs of informal caregivers during this period is sparse. This study aims to provide insight into problems and needs of informal caregivers caring for people with dementia during care-transition from home-based care to institutional long-term care. METHODS: A systematic electronic search in CINAHL, Cochrane, Medline, PsycINFO, Pubmed and Web of Knowledge. All qualitative articles up to September 2013 were considered. The included articles underwent a quality appraisal. Thematic analysis was used to analyze problems and needs described in the articles. RESULTS: Thirteen publications were included providing 14 topics comprising needs and problems of informal caregivers during the care-transition period. The most stated topics were: "emotional concerns" (e.g. grief and shame about the decision), "knowledge/information" (e.g. understanding the care system) and "support" (e.g. need for counseling). Similar topics were found prior and after admission, with examples specific to the either the home or nursing home situation. CONCLUSIONS: The care-transition period should be considered a continuum, as similar needs and problems were identified prior and after admission. This should be kept in mind in developing support and guidance for informal caregivers during this process. Whereas currently the situation prior and post admission are seen and treated as adjacent stages, they should be considered one integrated stage. Multicomponent programmes should be offered that are designed in a continuous way, starting prior to admission, and continuing after. PMID- 25287065 TI - Attitudes toward straight, gay male, and transsexual parenting. AB - This study examined American attitudes toward transsexual and gay male parenting, compared to straight parenting. After reporting levels of transphobia, participants read a vignette regarding a couple seeking child adoption. Individuals high in transphobia perceived nontraditional couples as more emotionally unstable than straight couples and were less willing to grant custody of a child to the nontraditional couples vs. the straight couples. In addition, the transsexual couple faced more prejudice and discrimination than the gay male couple. Implications of these findings are discussed. PMID- 25287066 TI - Mild traumatic brain injury and motor vehicle crashes: limitations to our understanding. PMID- 25287063 TI - Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. AB - RATIONALE: Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes mellitus. OBJECTIVE: To test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. METHODS AND RESULTS: By using a ferric chloride (FeCl3)-induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp(-/-) and Tymp(+/-) mice compared with wild-type mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet TYMP was responsible for the antithrombotic phenomenon in the TYMP deficient mice. Collagen-, collagen-related peptide-, adenosine diphosphate-, or thrombin-induced platelet aggregation were significantly attenuated in Tymp(+/-) and Tymp(-/-) platelets, and in wild type or human platelets pretreated with TYMP inhibitor KIN59. Tymp deficiency also significantly decreased agonist-induced P selectin expression. TYMP contains an N-terminal SH3 domain-binding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn, and Yes in platelets. TYMP-associated Lyn was inactive in resting platelets, and TYMP trapped and diminished active Lyn after collagen stimulation. Tymp/Lyn double haploinsufficiency diminished the antithrombotic phenotype of Tymp(+/-) mice. TYMP deletion or inhibition of TYMP with KIN59 dramatically increased platelet endothelial cell adhesion molecule 1 tyrosine phosphorylation and diminished collagen-related peptide- or collagen-induced AKT phosphorylation. In vivo administration of KIN59 significantly inhibited FeCl3-induced carotid artery thrombosis without affecting hemostasis. CONCLUSIONS: TYMP participates in multiple platelet signaling pathways and regulates platelet activation and thrombosis. Targeting TYMP might be a novel antiplatelet and antithrombosis therapy. PMID- 25287067 TI - Psychometric Properties of the Korean Versions of Three Sleep Evaluation Questionnaires. AB - Psychometric properties of the Korean versions of three sleep evaluation questionnaires were described to provide tools for practitioners and researchers interested in transcultural studies in Korea. The Pittsburgh Sleep Quality Index (PSQI), the General Sleep Disturbance Scale (GSDS), and the Leeds Sleep Evaluation Questionnaire (LSEQ) were analyzed using data from 959 community dwelling adults in Korea. Furthermore, cut-off points and prevalence of sleep disturbance were identified. Reliability and concurrent validity for all measures were acceptable. Optimal cut-off points of PSQI, GSDS, and LSEQ with highest Youden's index were 5, 33, and 66, and prevalence of sleep disturbance was 22.1%, 26.3%, and 25.8%, respectively. The Korean PSQI, GSDS, and LSEQ are all valid and reliable tools for detecting sleep disturbance. We provide suggestions for selecting the right tools according to the purpose, setting, and participants of transcultural studies. PMID- 25287068 TI - Temperament and social behavior in pediatric brain tumor survivors and comparison peers. AB - OBJECTIVE: To examine the role of temperament (i.e., surgency/positive affect, negative affect, and effortful control) in the social behavior of pediatric brain tumor survivors and comparison classmates. METHODS: Parent-, peer-, and self report data were collected for 75 children after treatment for a brain tumor, and 67 comparison classmates. Tests of mediation and moderated mediation were run to examine whether effortful control accounted for group differences in social behavior and whether this indirect effect was moderated by surgency/positive or negative affectivity. RESULTS: Peers described survivors as lower in Leadership popularity and higher in Sensitivity-isolation and victimization than comparison classmates. Parent and self-report of surgency/positive affect revealed survivors were lower on this dimension. Survivors were rated by parents as demonstrating less effortful control. Effortful control did not consistently account for group differences in social behavior. There was limited evidence of moderated mediation. CONCLUSIONS: Research on the implications of potential changes in temperament following treatment is warranted. PMID- 25287070 TI - An evaluation of regulatory and commercial barriers to stratified medicine development and adoption. AB - Today, a range of products based on genomics, proteomics and metabolomics have facilitated the development of 'stratified' medicines and companion diagnostics. This investigation profiles a series of targeted medicines and corresponding diagnostics, and their role(s) in supporting evidence-based medicine. Despite their potential benefits we found that scientific, financial and regulatory barriers impede the development and adoption of companion diagnostics. Therefore, in order to realise improvements to the risk/benefit profiles of health-care interventions-notably reducing clinical uncertainty-conferred by the use of companion diagnostics, industry representatives, health-care providers and regulators will need a coordinated response to overcome these barriers. PMID- 25287069 TI - Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer. AB - Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with 'interplay between innate and adaptive immune responses' as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge, that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC. PMID- 25287071 TI - The first steps towards the era of personalised vaccinology: predicting adverse reactions. AB - Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccines has been ascribed to unpredictable stochastic processes. Recent advances in pharmacogenomics indicate that some features of host response to immunisation are influenced by genetic traits, henceforth predictable. The ability to predict the adverse reaction to vaccination would represent an important step towards the development of personalised vaccinology and could enhance public confidence in the safety of vaccines. Herein, we have reviewed all the available information on the association between genetic variants and the risk for healthy subjects to develop adverse reactions. PMID- 25287072 TI - The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients. AB - Tacrolimus, a dual substrate of CYP3A4 and CYP3A5 has a narrow therapeutic index and is characterized by high between-subject variability in oral bioavailability. This study investigated the effects of the recently described CYP3A4*22 intron 6 C>T single nucleotide polymorphism on in vivo CYP3A4 activity as measured by midazolam (MDZ) clearance and tacrolimus pharmacokinetics in two cohorts of renal allograft recipients, taking into account the CYP3A5*1/*3 genotype and other determinants of drug disposition. In CYP3A5 non-expressers, the presence of one CYP3A4*22T-allele was associated with a 31.7-33.6% reduction in MDZ apparent oral clearance, reflecting reduced in vivo CYP3A4 activity. In addition, at ?12 months after transplantation, steady-state clearance of tacrolimus was 36.8% decreased compared with homozygous CYP3A4*22CC-wild type patients, leading to 50% lower dose requirements. Both concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP3A4*22T-allele. PMID- 25287074 TI - Cost-effective development of highly polymorphic microsatellite in Japanese quail facilitated by next-generation sequencing. AB - Next-generation sequencing technologies permit rapid and cost-effective identification of numerous putative microsatellite loci. Here, from the genome sequences of Japanese quail, we developed microsatellite markers containing dinucleotide repeats and employed these for characterisation of genetic diversity and population structure. A total of 385 individuals from 12 experimental and one wild-derived Japanese quail lines were genotyped with newly developed autosomal markers. The maximum number of alleles, expected heterozygosity and polymorphic information content (PIC) per locus were 10, 0.80 and 0.77 respectively. Approximately half of the markers were highly informative (PIC >= 0.50). The mean number of alleles per locus and observed heterozygosity within a line were in the range of 1.3-4.1 and 0.11-0.53 respectively. Compared with the wild-derived line, genetic diversity levels were low in the experimental lines. Genetic differentiation (FST ) between all pairs of the lines ranged from 0.13 to 0.83. Genetic clustering analyses based on multilocus genotypes of individuals showed that most individuals formed clearly defined clusters corresponding to the origins of the lines. These results suggest that Japanese quail experimental lines are highly structured. Microsatellite markers developed in this study may be effective for future genetic studies of Japanese quail. PMID- 25287073 TI - Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERalpha-positive advanced breast cancer. AB - In patients with breast cancer (BC), deregulation of estrogen receptor (ERalpha) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERalpha modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERalpha+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERalpha+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERalpha signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERalpha+ BC treated with adjuvant TAM. PMID- 25287075 TI - Observer reliability of CT angiography in the assessment of acute ischaemic stroke: data from the Third International Stroke Trial. AB - INTRODUCTION: CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. METHODS: We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (<2 years experience) rated all 15 scans independently and blind to clinical data for: presence (versus absence) of any intracranial arterial abnormality (stenosis or occlusion), severity of arterial abnormality using relevant scales (IST-3 angiography score, Thrombolysis in Cerebral Infarction (TICI) score, Clot Burden Score), collateral supply and visibility of a perfusion defect on CTA source images (CTA-SI). Intra-observer reliability was assessed using independently repeated expert panel scan ratings. We assessed observer agreement with Krippendorff's-alpha (K-alpha). RESULTS: Among experienced observers, inter-observer agreement was substantial for the identification of any angiographic abnormality (K-alpha = 0.70) and with an angiography assessment scale (K-alpha = 0.60-0.66). There was less agreement for grades of collateral supply (K-alpha = 0.56) or for identification of a perfusion defect on CTA-SI (K-alpha = 0.32). Radiology trainees performed as well as expert readers when additional training was undertaken (neuroradiology specialist trainees). Intra-observer agreement among experts provided similar results (K alpha = 0.33-0.72). CONCLUSION: For most imaging characteristics assessed, CTA has moderate to substantial observer agreement in acute ischaemic stroke. Experienced readers and those with specialist training perform best. PMID- 25287076 TI - Quantitative T1 and T2 mapping in recurrent glioblastomas under bevacizumab: earlier detection of tumor progression compared to conventional MRI. AB - INTRODUCTION: Treatment with the humanized anti-vascular endothelial growth factor (VEGF) antibody bevacizumab in glioblastoma patients suppresses contrast enhancement via the reduction of vascular permeability, which does not necessarily indicate real reduction of tumor cell mass. Therefore, other imaging criteria are needed to recognize tumor growth under bevacizumab more reliably. It is still unknown, whether quantitative T1 mapping is useful to monitor the effects of anti-angiogenic therapy or to indicate a tumor progression earlier and more reliable compared to conventional magnetic resonance imaging (MRI) sequences. This raised the question whether quantitative T1 mapping is more suitable to monitor treatment effects of bevacizumab. METHODS: Conventional and quantitative MRI was performed on six consecutive patients with recurrent glioblastoma before treatment with bevacizumab and every 8 weeks thereafter until further tumor progression. Quantitative T1 maps before and after intravenous application of contrast agent and quantitative T2 maps were performed to calculate serial differential maps and subtraction maps from one time point, subtracting contrast-enhanced T1 maps from non-contrast T1 maps. RESULTS: In five illustrative cases, tumor progression was documented earlier in differential T1 relaxation time (DiffT1) and T2 relaxation time (DiffT2) maps before changes in the conventional MRI studies were obvious. Four patients showed previous prolongation of T1 relaxation time in the DiffT1 maps, suggesting tumor progression, and subtraction maps revealed faint contrast enhancement matching with the areas of T1 prolongation. CONCLUSION: Our results emphasize that quantitative relaxation time mapping could be a promising method for tumor monitoring in glioblastoma patients under anti-angiogenic therapy. Quantitative T1 mapping seems to detect enhancing tumor earlier than conventional contrast enhanced T1-weighted images. PMID- 25287077 TI - CalDAG-GEFI deficiency protects mice from FcgammaRIIa-mediated thrombotic thrombocytopenia induced by CD40L and beta2GPI immune complexes. AB - INTRODUCTION: Platelet activation via the Fcgamma receptor IIa (FcgammaRIIa) is implicated in the pathogenesis of immune complex (IC)-mediated thrombocytopenia and thrombosis (ITT). We previously showed that ICs composed of antigen and antibodies targeting CD40 ligand (CD40L) or beta2 Glycoprotein I (beta2GPI) induce ITT in mice transgenic for human FcgammaRIIa (hFcR) but not wild-type controls (which lack FcgammaRIIa). Here we evaluated the contribution of the guanine nucleotide exchange factor, CalDAG-GEFI, and P2Y12, key regulators of Rap1 signaling in platelets, to ITT induced by these clinically relevant ICs. METHODS: Pre-formed anti-CD40L or anti-beta2GPI ICs were injected into hFcR/Caldaggef1(+/+) or hFcR/Caldaggef1(-/-) mice, with or without clopidogrel pretreatment. Animals were observed for symptoms of shock for 30 min, during which time core body temperature was monitored. Platelet counts were obtained before and 30 min after IC injection. Lungs were assessed for thrombosis by histology or near-infrared imaging. RESULTS: Both CD40L and beta2GPI ICs rapidly induced severe thrombocytopenia, shock and a reduction in body temperature in hFcR/Caldaggef1(+/+) mice. hFcR/Caldaggef1(-/-) mice were protected from CD40L and beta2GPI IC-induced thrombocytopenia and shock, whereas P2Y12 inhibition had only a modest effect on IC-induced ITT. Consistent with these findings, IC induced integrin activation in vitro and the accumulation of activated platelets in the lungs of IC-challenged mice was strongly dependent on CalDAG-GEFI. CONCLUSIONS: Our studies demonstrate that CalDAG-GEFI plays a critical role in platelet activation, thrombocytopenia and thrombosis induced by clinically relevant ICs in mice. Thus, CalDAG-GEFI may be a promising target for the intervention of IC-associated, FcgammaRIIa-mediated thrombotic conditions. PMID- 25287078 TI - Right ventricular global longitudinal strain is an independent predictor of right ventricular function: a multimodality study of cardiac magnetic resonance imaging, real time three-dimensional echocardiography and speckle tracking echocardiography. AB - OBJECTIVES: Accurate assessment of right ventricular (RV) systolic function is important, as it is an established predictor of mortality in cardiac and respiratory diseases. We aimed to compare speckle tracking-derived longitudinal deformation measurements with traditional two-dimensional (2D) echocardiographic parameters, as well as real time three-dimensional echocardiography (RT3DE) and cardiac magnetic resonance imaging (CMR)-derived RV volumes and ejection fraction (EF). METHOD: Subjects referred for CMR also underwent echocardiography. On both RT3DE and CMR, we measured RV volumes and EF. On 2D echocardiography, we analyzed RV fractional area change, RV internal diastolic diameter, tricuspid annular plane systolic excursion, tricuspid annular tissue Doppler-derived velocity, myocardial performance index, and RV global longitudinal strain (RV GLS). RESULTS: Sixty subjects were recruited (mean age = 45 +/- 10 years; 60% male). RV GLS (R = -0.69, P < 0.001) and RT3DE RVEF (R = 0.56, P < 0.001) correlated well with CMR RVEF. RT3DE RV end-diastolic (RVEDV) and end-systolic (RVESV) volumes also correlated with CMR RV volumes: RVEDV, R = 0.74, P < 0.001 and RVESV, R = 0.84, P < 0.001. In addition, RV GLS best predicted the presence of RV dysfunction, defined as RVEF <48% on CMR (hazard ratio = 7.0 [1.5-31.7], P < 0.01). On receiver operator characteristic analysis, a RV GLS of -20% was the most sensitive and specific predictor of RV dysfunction (AUC 0.8 [0.57-1.0], P < 0.02). CONCLUSION: RVEF and volumes estimated on RT3DE were closely correlated with CMR measurements. When compared to more traditional markers of RV systolic function and RT3DE, RVGLS produced the highest correlation with CMR RVEF and was a good predictor of RV dysfunction. RV GLS should be considered a complementary modality to RT3DE and CMR in the assessment of RV systolic function. PMID- 25287080 TI - Mobile health: is it really a great advance? PMID- 25287079 TI - Delayed facial weakness in Guillain-Barre and Miller Fisher syndromes. AB - INTRODUCTION: Dr. C. Miller Fisher described the appearance of unilateral facial palsy after resolution of ataxia in a patient with the eponymic Miller Fisher syndrome (MFS). However, there have been very few reports of delayed appearance of facial weakness in Guillain-Barre syndrome (GBS) and MFS when the other neurological signs reached nadir or started improving. METHODS: In this study we reviewed the clinical and laboratory findings of consecutive patients with GBS (n=195) and MFS (n=68). RESULTS: Delayed facial weakness occurred in 12 (6%) GBS and 4 (6%) MFS patients and was unilateral in 5 (42%) GBS and 2 (50%) MFS patients. In those patients with delayed facial weakness, neither limb weakness nor ataxia progressed, and facial weakness disappeared without immunotherapy. CONCLUSIONS: Because facial weakness can lead to further morbidity, it would be prudent for clinicians to warn patients of this possibility, although additional immunotherapy is usually not required. PMID- 25287082 TI - Images of the month. Hydatid disease. PMID- 25287083 TI - Video of the month: A novel technique for treating cholangitis following EUS-CDS. PMID- 25287086 TI - Editorial: The importance of systematic reviews and meta-analyses of probiotics and prebiotics. AB - Irritable bowel syndrome (IBS) and chronic idiopathic constipation are prevalent and burdensome gastrointestinal disorders. A systematic review and meta-analysis of the evidence for probiotics, prebiotics, and synbiotics in IBS and chronic idiopathic constipation has recently been performed. By far, the most convincing evidence was for the use of probiotics in IBS, which reported that overall probiotics reduced the risk of symptom persistence by 21%. However, only a minority of the trials were at a low risk of bias, and some used small sample sizes. Meta-analysis is a powerful tool to combine individual small trials to improve the power to detect the direction, size, and consistency of an effect, but it can do little to overcome the poor design of individual trials. Many debate the use of meta-analysis to combine data from different probiotic species, strains, or combinations. It is recommended that all future meta-analyses of probiotics, in any clinical setting, perform subgroup analysis on specific species/strains and specific combinations. It is hoped that the current meta analysis will empower clinicians in making evidence-based decisions regarding whether probiotics should be recommended for IBS, which species/strain(s) to use, and for which symptoms. PMID- 25287089 TI - Editorial: Constipation and colorectal cancer risk: a continuing conundrum. AB - There are conflicting data regarding the association between bowel movement frequency, constipation, and colorectal cancer (CRC). In this issue, Citronberg et al. present data from a large prospective study that was designed to examine this issue. In addition to examining bowel habits, these authors included information about the participants' laxative use, distinguishing between fiber and non-fiber-based laxatives. The investigators also collected data with respect to CRC risk factors including demographics, family history, lower endoscopy exposure, smoking, medication use, and detailed dietary information. The results demonstrated no relationship between bowel movement frequency or constipation and CRC. The authors also observed an increased CRC risk in patients who were in either the low or high non-fiber laxative use groups as compared with individuals who never used these agents (low risk: hazard ratio (HR)=1.49; and high risk: HR=1.43; Ptrend=0.05). Conversely, there was a statistically significant lower risk for those patients who reported a high use of fiber laxatives (HR=0.44, 95% confidence interval: 0.21-0.95) as compared with the nonuse group. These data have implications for physicians who treat patients with constipation. PMID- 25287090 TI - Response to Surawicz et al. PMID- 25287091 TI - Response to Gorbach et al. PMID- 25287092 TI - Do male endoscopists have better adenoma detection rates than female endoscopists? PMID- 25287093 TI - Response to AlAmeel et al. PMID- 25287094 TI - How does length of stay in the United States affect colorectal cancer incidence among immigrant Asian populations in California? PMID- 25287095 TI - Response to Molakatalla and Kumar. PMID- 25287096 TI - Comment on Parikh et al. PMID- 25287097 TI - Response to Sage and Mogrovejo. PMID- 25287098 TI - Polypectomy to eradicate cap polyposis with protein-losing enteropathy. PMID- 25287099 TI - Immortal time bias: a likely alternate explanation for the purported benefits of DXA Screening in ulcerative colitis. PMID- 25287102 TI - The arsenic contamination of rice in Guangdong Province, the most economically dynamic provinces of China: arsenic speciation and its potential health risk. AB - Rice is a staple food in China, but it may contain toxic heavy metals. Hence, the concentrations of arsenic (As) species (As(III), As(V), MMA and DMA) were evaluated in 260 rice samples from 13 cities of Guangdong Province, the most economically dynamic provinces of China. The levels of sum concentrations of As species in rice samples varied from non-detect to 225.58 ng g(-1), with an average value of 57.27 ng g(-1). The mean concentrations of the major As species detected in rice samples were in the order As(III) (34.77 ng g(-1)) > As(V) (9.34 ng g(-1)) > DMA (8.33 ng g(-1)) > MMA (4.82 ng g(-1)). The rice samples of Guangdong Province were categorized as inorganic As type. Significant geographical variation of As speciation existed in rice samples of 13 cities of Guangdong Province by chi-square test (p < 0.05). The average human weekly intakes of inorganic As via rice consumption in Guangdong Province, southern China, were 1.91 ug kg(-1) body weight. Hazard quotients of total As via rice consumption of adults in 13 cities ranged from 0.06 to 0.30, indicating the As contents in rice from Guangdong Province had no potential adverse impact on human health. PMID- 25287103 TI - Bayesian estimation of cardiovascular autonomic neuropathy diagnostic test based on short-term heart rate variability without a gold standard. AB - OBJECTIVE: To evaluate the reference values for short-term heart rate variability (HRV), estimate the performance of cardiovascular autonomic neuropathy (CAN) diagnostic tests in the absence of a gold standard, and assess CAN prevalence in our dataset. SETTING: Community and hospital health centre. PARTICIPANTS: Of 2092 subjects available for data analysis, 371 healthy subjects were selected so the reference values for the short-term HRV test could be evaluated. An external dataset contained 88 subjects who completed both the short-term HRV test and Ewing's test. INTERVENTION: Collection of information on clinical outcome. PRIMARY AND SECOND OUTCOME MEASURES: Cardiovascular autonomic function evaluated by using the short-term HRV test and/or Ewing's test. RESULTS: Cut-off points of 356.13, 55.45 and 36.64 ms2 were set for total power, low frequency and high frequency (HF), respectively. The diagnostic test for CAN based on the mentioned reference value was created. The HRV test had a high sensitivity (80.01-85.09%) and specificity (82.30-85.20%) for CAN. In addition, the non-inferiority test rejected the null hypothesis that the performance of the HRV test was inferior to that of Ewing's test (p<0.05). The estimated CAN prevalence was 14.92% and 29.17% in the total sample and patients with diabetes, respectively. CONCLUSIONS: Our findings provided reference values for short-term HRV, which were used for the CAN diagnostic test with high sensitivity and specificity. The estimated CAN prevalence was high in the Chinese population. PMID- 25287104 TI - Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study. AB - OBJECTIVES: Although pain is a significant symptom in chronic fatigue syndrome (CFS), pain is poorly understood in adolescents with CFS. The aim of this study was to explore pain distribution and prevalence, pain intensity and its functional interference in everyday life, as well as pressure pain thresholds (PPT) in adolescents with CFS and compare this with a control group of healthy adolescents (HC). METHODS: This is a case-control, cross-sectional study on pain including 120 adolescents with CFS and 39 HCs, aged 12-18 years. We measured pain frequency, pain severity and pain interference using self-reporting questionnaires. PPT was measured using pressure algometry. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial. RESULTS: Adolescents with CFS had significantly lower PPTs compared with HCs (p<0.001). The Pain Severity Score and the Pain Interference Score were significantly higher in adolescents with CFS compared with HCs (p<0.001). Almost all adolescents with CFS experienced headache, abdominal pain and/or pain in muscles and joints. Moreover, in all sites, the pain intensity levels were significantly higher than in HCs (p<0.001). CONCLUSIONS: We found a higher prevalence of severe pain among adolescents with CFS and lowered pain thresholds compared with HCs. The mechanisms, however, are still obscure. Large longitudinal population surveys are warranted measuring pain thresholds prior to the onset of CFS. TRIAL REGISTRATION NUMBER: Clinical Trials, NCT01040429; The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) http://www.clinicaltrials.gov. PMID- 25287105 TI - Adolescents' physical activity trends over the years: a three-cohort study based on the Health Behaviour in School-aged Children (HBSC) Portuguese survey. AB - OBJECTIVE: Many young people do not practise enough physical activity (PA) to benefit their health. The three-cohort study aimed to investigate the prevalence of PA and understand the trends between 2002 and 2010, using a representative sample of Portuguese adolescents. DESIGN, SETTING AND PARTICIPANTS: The participants were 8483 adolescents (4067 boys, 4416 girls) who participated in the Health Behaviour in School-aged Children Portuguese survey in 2002, 2006 and 2010. DESIGN, SETTING AND PARTICIPANTS: A questionnaire was used to collect data of PA. Analyses were run separately for boys and girls. RESULTS: Boys aged 15-17 reported practising 3.5+/-1.9 times a week in 2002, 3.9+/-1.9 times a week in 2006 and 3.8+/-1.9 times a week in 2010, with a significant increase from 2002 to 2006/2010 (p<0.05). PA practice during the past 7 days decreased from 4.2+/-2.1 to 3.9+1.9 between 2002 and 2006 (p<0.001) and also decreased from 4.4+/-2.1 to 3.8+/-1.9 between 2006 and 2010 (p<0.001). Among girls, PA practices during the past 7 days declined significantly from 3.5+/-1.9 to 2.7+/-1.7 between 2002 and 2006 (p<0.001), and from 3.3+/-1.9 to 2.9+/-1.7 between 2006 and 2010 (p<0.001). CONCLUSIONS: The study points to age as a factor related to diminished PA participation. The study also revealed that the prevalence of PA has decreased over the years for the same age groups. PMID- 25287106 TI - The Esophageal Pressure-Guided Ventilation 2 (EPVent2) trial protocol: a multicentre, randomised clinical trial of mechanical ventilation guided by transpulmonary pressure. AB - INTRODUCTION: Optimal ventilator management for patients with acute respiratory distress syndrome (ARDS) remains uncertain. Lower tidal volume ventilation appears to be beneficial, but optimal management of positive end-expiratory pressure (PEEP) remains unclear. The Esophageal Pressure-Guided Ventilation 2 Trial (EPVent2) aims to examine the impact of mechanical ventilation directed at maintaining a positive transpulmonary pressure (PTP) in patients with moderate-to severe ARDS. METHODS AND ANALYSIS: EPVent2 is a multicentre, prospective, randomised, phase II clinical trial testing the hypothesis that the use of a PTP guided ventilation strategy will lead to improvement in composite outcomes of mortality and time off the ventilator at 28 days as compared with a high-PEEP control. This study will enrol 200 study participants from 11 hospitals across North America. The trial will utilise a primary composite end point that incorporates death and days off the ventilator at 28 days to test the primary hypothesis that adjusting ventilator pressure to achieve positive PTP values will result in improved mortality and ventilator-free days. ETHICS AND DISSEMINATION: Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approvals of the protocol as well as informed consent documents were also obtained from the Institutional Review Board of each participating institution prior to enrolling study participants at each respective site. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to PubMed Central in accordance with the National Institute of Health Public Access Policy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov under number NCT01681225. PMID- 25287108 TI - Remyelination in multiple sclerosis: cellular mechanisms and novel therapeutic approaches. AB - The myelin sheath that coats axons allows rapid propagation of electrical impulses across the nervous system. Oligodendrocytes (ODs) are myelin-producing cells of the central nervous system (CNS) responsible for wrapping the axons of neurons. Multiple sclerosis (MS) is a demyelinating disease of the CNS identifiable by white and gray matter lesions. These lesions consist of axons that have lost their myelin through an autoimmune response to myelin and ODs. Current treatments for MS target the autoimmune aspect of the disease. However, these immunomodulators do not directly enhance the process of remyelination. The ability to remyelinate lesions can be enhanced by neural progenitor cells that can differentiate into ODs and replace lost myelin, although successful remyelination is complex and dependent on multiple factors. The restoration of lost myelin might protect the axon from degeneration and restore optimal conduction of impulses in MS patients, requiring further research on proremyelinating therapies. The combination of immunomodulators and remyelinating enhancers might be the best course of treatment for many MS patients. This Review discusses demyelination in MS, the mechanisms of remyelination, and current therapies designed to promote remyelination in MS patients. PMID- 25287107 TI - Kinetics of cardiac myosin isoforms in mouse myocardium are affected differently by presence of myosin binding protein-C. AB - We tested whether cardiac myosin binding protein-C (cMyBP-C) affects myosin cross bridge kinetics in the two cardiac myosin heavy chain (MyHC) isoforms. Mice lacking cMyBP-C (t/t) and transgenic controls (WT(t/t)) were fed L-thyroxine (T4) to induce 90/10% expression of alpha/beta-MyHC. Non-transgenic (NTG) and t/t mice were fed 6-n-propyl-2-thiouracil (PTU) to induce 100% expression of beta-MyHC. Ca(2+)-activated, chemically-skinned myocardium underwent length perturbation analysis with varying [MgATP] to estimate the MgADP release rate (k(-ADP)) and MgATP binding rate (k(+ATP)). Values for (k(-ADP)) were not significantly different between t/t(T4) (102.2 +/- 7.0 s(-1)) and WT(t/t)(T4) (91.3 +/- 8.9 s( 1)), but k(+ATP)) was lower in t/t(T4) (165.9 +/- 12.5 mM(-1) s(-1)) compared to WT(t/t)(T4) (298.6 +/- 15.7 mM(-1) s(-1), P < 0.01). In myocardium expressing beta-MyHC, values for k(-ADP) were higher in t/t(PTU) (24.8 +/- 1.0 s(-1)) compared to NTG(PTU) (15.6 +/- 1.3 s(-1), P < 0.01), and k(+ATP) was not different. At saturating [MgATP], myosin detachment rate approximates k(-ADP), and detachment rate decreased as sarcomere length (SL) was increased in both t/t(T4) and WT(t/t)(T4) with similar sensitivities to SL. In myocardium expressing beta-MyHC, detachment rate decreased more as SL increased in t/t(PTU) (21.5 +/- 1.3 s(-1) at 2.2 MUm and 13.3 +/- 0.9 s(-1) at 3.3 MUm) compared to NTGPTU (15.8 +/- 0.3 s(-1) at 2.2 MUm and 10.9 +/- 0.3 s(-1) at 3.3 MUm) as detected by repeated-measures ANOVA (P < 0.01). These findings suggest that cMyBP C reduces MgADP release rate for beta-MyHC, but not for alpha-MyHC, even as the number of cMyBP-C that overlap with the thin filament is reduced to zero. Therefore, cMyBP-C appears to affect beta-MyHC kinetics independent of its interaction with the thin filament. PMID- 25287109 TI - [Operative hysteroscopy for myoma removal: Morcellation versus bipolar loop resection]. AB - OBJECTIVE: To evaluate the results associated with hysteroscopic morcellation for submucous myomas removal, and to compare with those observed associated with bipolar loop resection. MATERIELS AND METHODS: A retrospective comparative study was conducted in two universitary centers from January 2012 to December 2013. A total of 83 patients, who presented with submucous myomas type 0,1 and 2, were included. The number of myomas type 0,1 was 36 (71 %) and 15 (29 %) myomas type 2 in morcellation group versus 44 (59 %) myomas type 0,1 and 31 (41 %) type 2 in electrosurgical resection group (P=0.17). Hysteroscopic morcellation or electrosurgical resection with bipolar loop for removal submucous myomas were performed. RESULTS: Thirty-four patients underwent hysteroscopic morcellation using MyoSure((r)), and 49 had hysteroscopic resection using Versapoint-24F((r)) bipolar loop. The mean operative duration was 30minutes in morcellation group, compared to 31minutes in bipolar resection group (P=0.98). Complete myoma removal was achieved in 22 (64 %) patients in morcellation group, and in 34 (69 %) in bipolar resection group (P=0.65). There were no difference in the occuring of adverse events between the two. The prevalence of postoperative intra-uterine adherence was 10 % in morcellation group and 13.8 % in bipolar resection group (P=0.69). CONCLUSION: In the current short comparative series, hysteroscopic morcellation and bipolar loop resection were associated with comparable results for removal of submucous myomas. PMID- 25287110 TI - Nanoarchitectonics of biomolecular assemblies for functional applications. AB - The stringent processes of natural selection and evolution have enabled extraordinary structure-function properties of biomolecules. Specifically, the archetypal designs of biomolecules, such as amino acids, nucleobases, carbohydrates and lipids amongst others, encode unparalleled information, selectivity and specificity. The integration of biomolecules either with functional molecules or with an embodied functionality ensures an eclectic approach for novel and advanced nanotechnological applications ranging from electronics to biomedicine, besides bright prospects in systems chemistry and synthetic biology. Given this intriguing scenario, our feature article intends to shed light on the emerging field of functional biomolecular engineering. PMID- 25287112 TI - The concept of mobility in single- and double handed manipulation. AB - The concept of mobility describes an important property of the human body when performing manipulation tasks. It describes, in a sense, how easy it is to accelerate a link or a point on the manipulator. Most often it is calculated for the end-link or end-point of the manipulator, since these are important for the control objective of the manipulator. Mobility is the inverse of the inertia experienced by a force acting on the end-point, or a combined force and torque acting on the end-link. The concept has been used in studies of reaching tasks with one arm, but thus far not for bi-manual manipulation. We present here the concept for both single-handed and double-handed manipulation, in a general manner which includes any type of grip of the hands on the object. The use of the concept is illustrated with data on the left and right arm in a golf swing. PMID- 25287111 TI - Evolution of osmotic pressure in solid tumors. AB - The mechanical microenvironment of solid tumors includes both fluid and solid stresses. These stresses play a crucial role in cancer progression and treatment and have been analyzed rigorously both mathematically and experimentally. The magnitude and spatial distribution of osmotic pressures in tumors, however, cannot be measured experimentally and to our knowledge there is no mathematical model to calculate osmotic pressures in the tumor interstitial space. In this study, we developed a triphasic biomechanical model of tumor growth taking into account not only the solid and fluid phase of a tumor, but also the transport of cations and anions, as well as the fixed charges at the surface of the glycosaminoglycan chains. Our model predicts that the osmotic pressure is negligible compared to the interstitial fluid pressure for values of glycosaminoglycans (GAGs) taken from the literature for sarcomas, melanomas and adenocarcinomas. Furthermore, our results suggest that an increase in the hydraulic conductivity of the tumor, increases considerably the intratumoral concentration of free ions and thus, the osmotic pressure but it does not reach the levels of the interstitial fluid pressure. PMID- 25287114 TI - Frequency of and predictors for withholding patient safety concerns among oncology staff: a survey study. AB - Speaking up about patient safety is vital to avoid errors reaching the patient and to improve a culture of safety. This study investigated the prevalence of non speaking up despite concerns for safety and aimed to identify predictors for withholding voice among healthcare professionals (HCPs) in oncology. A self administered questionnaire assessed safety concerns, speaking up beliefs and behaviours among nurses and doctors from nine oncology departments. Multiple regression analysis was used to identify predictors for withholding safety concerns. A total of 1013 HCPs returned the completed survey (response rate 65%). Safety concerns were common among responders. Fifty-four per cent reported to recognise their colleagues making potentially harmful errors at least sometimes. A majority of responders reported at least some episodes of withholding concerns about patient safety. Thirty-seven per cent said they remained silent at least once when they had information that might have helped prevent an incident. Respondents believed that a high level of interpersonal, communication and coping skills are necessary to speak up about patient safety issues at their workplace. Higher levels of perceived advocacy for patient safety and psychological safety significantly decreased the frequency of withholding voice. Remaining silent about safety concerns is a common phenomenon in oncology. Improved strategies are needed to support staff in effective communication and make cancer care safer. PMID- 25287113 TI - Improved measurement of brain deformation during mild head acceleration using a novel tagged MRI sequence. AB - In vivo measurements of human brain deformation during mild acceleration are needed to help validate computational models of traumatic brain injury and to understand the factors that govern the mechanical response of the brain. Tagged magnetic resonance imaging is a powerful, noninvasive technique to track tissue motion in vivo which has been used to quantify brain deformation in live human subjects. However, these prior studies required from 72 to 144 head rotations to generate deformation data for a single image slice, precluding its use to investigate the entire brain in a single subject. Here, a novel method is introduced that significantly reduces temporal variability in the acquisition and improves the accuracy of displacement estimates. Optimization of the acquisition parameters in a gelatin phantom and three human subjects leads to a reduction in the number of rotations from 72 to 144 to as few as 8 for a single image slice. The ability to estimate accurate, well-resolved, fields of displacement and strain in far fewer repetitions will enable comprehensive studies of acceleration induced deformation throughout the human brain in vivo. PMID- 25287115 TI - Economic shocks, resilience, and male suicides in the Great Recession: cross national analysis of 20 EU countries. AB - BACKGROUND: During the 2007-11 recessions in Europe, suicide increases were concentrated in men. Substantial differences across countries and over time remain unexplained. We investigated whether increases in unaffordable housing, household indebtedness or job loss can account for these population differences, as well as potential mitigating effects of alternative forms of social protection. METHODS: Multivariate statistical models were used to evaluate changes in suicide rates in 20 EU countries from 1981-2011. Models adjusted for pre-existing time trends and country-fixed effects. Interaction terms were used to evaluate modifying effects. RESULTS: Changes in levels of unaffordable housing had no effect on suicide rates (P = 0.32); in contrast, male suicide increases were significantly associated with each percentage point rise in male unemployment, by 0.94% (95% CI: 0.51-1.36%), and indebtedness, by 0.54% (95% CI: 0.02-1.06%). Spending on active labour market programmes (ALMP) (-0.26%, 95% CI: 0.08 to -0.45%) and high levels of social capital (-0.048%, 95% CI: -0.0096 to 0.087) moderated the unemployment-suicide association. There was no interaction of the volume of anti-depressant prescriptions (P = 0.51), monetary benefits to unemployed persons (P = 0.77) or total social protection spending per capita (P = 0.37). Active labour market programmes and social capital were estimated to have prevented ~ 540 and ~ 210 male suicides, respectively, arising from unemployment in the countries studied. CONCLUSION: Job losses were a critical determinant of variations in male suicide risks in Europe's recessions. Greater spending on ALMP and levels of social capital appeared to mitigate suicide risks. PMID- 25287117 TI - Transverse testicular ectopia: a rare association with inguinal hernia. AB - Transverse testicular ectopia (TTE) is a rare anomaly that is commonly associated with inguinal hernia. Most of the reported cases are in children with very few reported cases in adults. We report a case of 42 years, fertile male, who presented with left reducible inguinal hernia. During surgery, he was found to have a left indirect inguinal hernia with TTE with both testes on the left side. Hernioplasty and bilateral orchidopexy were performed. He had an uneventful recovery. Most of these cases are diagnosed intraoperatively, but imaging (ultrasonography and magnetic resonance imaging) has emerged as a promising tool for preoperative diagnosis although ultrasound missed it in this case. PMID- 25287116 TI - Anti-inflammatory effect of rosmarinic acid and an extract of Rosmarinus officinalis in rat models of local and systemic inflammation. AB - Rosmarinic acid is a polyphenolic compound and main constituent of Rosmarinus officinalis and has been shown to possess antioxidant and anti-inflammatory properties. We aimed to evaluate the anti-inflammatory properties of rosmarinic acid and of an extract of R. officinalis in local inflammation (carrageenin induced paw oedema model in the rat), and further evaluate the protective effect of rosmarinic acid in rat models of systemic inflammation: liver ischaemia reperfusion (I/R) and thermal injury models. In the local inflammation model, rosmarinic acid was administered at 10, 25 and 50 mg/kg (p.o.), and the extract was administered at 10 and 25 mg/kg (equivalent doses to rosmarinic acid groups) to male Wistar rats. Administration of rosmarinic acid and extract at the dose of 25 mg/kg reduced paw oedema at 6 hr by over 60%, exhibiting a dose-response effect, suggesting that rosmarinic was the main contributor to the anti inflammatory effect. In the liver I/R model, rosmarinic acid was administered at 25 mg/kg (i.v.) 30 min. prior to the induction of ischaemia and led to the significant reduction in the serum concentration of transaminases (AST and ALT) and LDH. In the thermal injury model, rosmarinic acid was administered at 25 mg/kg (i.v.) 5 min. prior to the induction of injury and significantly reduced multi-organ dysfunction markers (liver, kidney, lung) by modulating NF-kappaB and metalloproteinase-9. For the first time, the anti-inflammatory potential of rosmarinic acid has been identified, as it causes a substantial reduction in inflammation, and we speculate that it might be useful in the pharmacological modulation of injuries associated to inflammation. PMID- 25287118 TI - Lichenoid dermatitis in three patients with metastatic melanoma treated with anti PD-1 therapy. AB - Therapies that activate the immune system through blocking the binding of programmed death ligand 1 (PD-L1) present on tumors and PD-1 (programmed death 1) present on activated immune cells are revolutionizing the care for patients with cancer. These therapies work by inhibiting negative regulators of the immune system, thereby decreasing a tumor's ability to evade the immune system. The side effects of anti-PD-1/PD-L1 therapies are generally mild and as expected are related to autoimmune reactions. Two of the most common side effects of anti-PD 1/PD-L1 therapies are rash and pruritus occurring in approximately 20% of patients. Although the rash is generally recognized to be immune mediated, the exact mechanisms of the rash remain unclear. Herein, we report three cases of lichenoid dermatitis in three patients treated with MK-3475 (anti-PD-1) that were characterized with marked T-cell infiltrates with few PD-1-positive cells. The rashes in all three patients were relatively mild, allowing treatment to continue despite the rashes. PMID- 25287119 TI - Diagnostic and therapeutic approach to obscure gastrointestinal bleeding in a patient with a jejunal gastrointestinal stromal tumor: a case report. AB - BACKGROUND: Gastrointestinal stromal tumors of the alimentary tract may present with severe bleeding. Localization and treatment of obscure gastrointestinal bleeding is challenging in cases of negative bi-directional endoscopy. CASE PRESENTATION: A previously healthy 64-year-old Caucasian female presented with clinical signs of active gastrointestinal bleeding. Esophagogastroduodenoscopy was normal, and colonoscopy revealed passage of blood from the small bowel. Computerized tomography angiography demonstrated a hypervascular lesion with active extravasation located in the jejunum. Angiography of the superior mesenteric artery revealed a focal hypervascular mass in the jejunum, and super selective distal coil embolization of the feeding vessel was performed. When the patient was taken for laparoscopic exploration, a 2.5 cm tumor arising from the anti-mesenteric border of the proximal jejunum was identified and resected with primary anastomosis. Pathological results demonstrated a gastrointestinal stromal tumor with a low proliferation index of 1%. Small erosions in the adjacent mucosa confirmed the locus of bleeding. CONCLUSIONS: Computerized tomography is a useful tool for initial diagnosis of submucosal alimentary tumors in patients with obscure but clinically overt gastrointestinal bleeding. Selective angiography, following positive computerized tomography findings, is an important modality to allow both localization and hemostasis in actively bleeding small bowel tumors, but the procedure carries the risk of bowel necrosis. Complete surgical resection remains the mainstay for treatment of gastrointestinal stromal tumors. PMID- 25287121 TI - Diversification of the C-TERMINALLY ENCODED PEPTIDE (CEP) gene family in angiosperms, and evolution of plant-family specific CEP genes. AB - BACKGROUND: Small, secreted signaling peptides work in parallel with phytohormones to control important aspects of plant growth and development. Genes from the C-TERMINALLY ENCODED PEPTIDE (CEP) family produce such peptides which negatively regulate plant growth, especially under stress, and affect other important developmental processes. To illuminate how the CEP gene family has evolved within the plant kingdom, including its emergence, diversification and variation between lineages, a comprehensive survey was undertaken to identify and characterize CEP genes in 106 plant genomes. RESULTS: Using a motif-based system developed for this study to identify canonical CEP peptide domains, a total of 916 CEP genes and 1,223 CEP domains were found in angiosperms and for the first time in gymnosperms. This defines a narrow band for the emergence of CEP genes in plants, from the divergence of lycophytes to the angiosperm/gymnosperm split. Both CEP genes and domains were found to have diversified in angiosperms, particularly in the Poaceae and Solanaceae plant families. Multispecies orthologous relationships were determined for 22% of identified CEP genes, and further analysis of those groups found selective constraints upon residues within the CEP peptide and within the previously little-characterized variable region. An examination of public Oryza sativa RNA-Seq datasets revealed an expression pattern that links OsCEP5 and OsCEP6 to panicle development and flowering, and CEP gene trees reveal these emerged from a duplication event associated with the Poaceae plant family. CONCLUSIONS: The characterization of the plant-family specific CEP genes OsCEP5 and OsCEP6, the association of CEP genes with angiosperm-specific development processes like panicle development, and the diversification of CEP genes in angiosperms provides further support for the hypothesis that CEP genes have been integral to the evolution of novel traits within the angiosperm lineage. Beyond these findings, the comprehensive set of CEP genes and their properties reported here will be a resource for future research on CEP genes and peptides. PMID- 25287123 TI - Label-free molecular beacons for biomolecular detection. AB - Biomolecular detection and imaging methods provide quantitative measurements essential for biological research. In this context, molecular beacon based sensors have emerged as powerful, no-wash imaging agents, providing target specific fluorescent activation for nucleic acids, proteins, and small molecules. Conventional molecular beacons require double-labeled DNA sequences, which are costly and time-consuming to prepare. To address this issue, we developed DNA based label-free molecular beacons consisting of two regions: a signal-generating region based on human telomeric G-quadruplex sequence that activates Thioflavin T fluorescence and a target recognition sequence designed to interact in a molecular beacon format. We demonstrated the utility of these probes for the selective detection of DNA, RNA, and protein. Multiple probes were applied against a single target to achieve improved brightness in fluorescence detection of nucleic acid targets. This label-free strategy provides a straightforward, cost-effective alternative to fluorescently labeled oligonucleotides in biomolecular detection and imaging. PMID- 25287122 TI - Effect of resistance training on neuromuscular junctions of young and aged muscles featuring different recruitment patterns. AB - To examine the effects of aging on neuromuscular adaptations to resistance training (i.e., weight lifting), young (9 months of age) and aged (20 months of age) male rats either participated in a 7-week ladder climbing protocol with additional weight attached to their tails or served as controls (n = 10/group). At the conclusion, rats were euthanized and hindlimb muscles were quickly removed and frozen for later analysis. Longitudinal sections of the soleus and plantaris muscles were collected, and pre- and postsynaptic features of neuromuscular junctions (NMJs) were visualized with immunofluorescence staining procedures. Cross-sections of the same muscles were histochemically stained to determine myofiber profiles (fiber type and size). Statistical analysis was by two-way ANOVA (main effects of age and treatment) with significance set at P <= 0.05. Results revealed that training-induced remodeling of NMJs was evident only at the postsynaptic endplate region of soleus fast-twitch myofibers. In contrast, aging was associated with pre- and postsynaptic remodeling in fast- and slow-twitch myofibers of the plantaris. Although both the soleus and the plantaris muscles failed to display either training or aging-related alterations in myofiber size, aged plantaris muscles exhibited an increased expression of type I (slow-twitch) myofibers in conjunction with a reduced percentage of type II (fast-twitch) myofibers, suggesting early stages of sarcopenia. These data demonstrate the high degree of specificity of synaptic modifications made in response to exercise and aging and that the sparsely recruited plantaris is more vulnerable to the effects of aging than the more frequently recruited soleus muscle. PMID- 25287124 TI - Combinatorial approaches for developing upconverting nanomaterials: high throughput screening, modeling, and applications. AB - Colloidal nanoparticles doped with lanthanide ions can upconvert near-infrared light to visible frequencies, enabling the application of such materials to biological imaging and luminescent solar concentration. The optical properties of upconverting nanomaterials are determined by their combination of lanthanide dopants, by their morphology, by their host matrices, and by their surface ligands. Identifying ideal compositions and synthesis conditions for these materials can be tedious and time-consuming due to the large number of parameters to optimize. This review surveys the use of combinatorial strategies to rapidly screen and optimize diverse libraries of upconverting nanomaterials. I will review high-throughput techniques for synthesizing and characterizing large libraries of nanocrystals, and I will discuss theoretical methods for modeling the optical properties of lanthanide-doped materials. Case studies will illustrate the use of these approaches for optimizing the physical properties of upconverting nanoparticles, including cases in which unexpected phenomena were revealed. Finally, this review will identify promising opportunities in which combinatorial techniques could accelerate on-going research or facilitate the discovery of novel upconverting nanomaterials that overcome fundamental limitations of current material designs. PMID- 25287120 TI - Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. AB - The use of nanoparticulate pharmaceutical drug delivery systems (NDDSs) to enhance the in vivo effectiveness of drugs is now well established. The development of multifunctional and stimulus-sensitive NDDSs is an active area of current research. Such NDDSs can have long circulation times, target the site of the disease and enhance the intracellular delivery of a drug. This type of NDDS can also respond to local stimuli that are characteristic of the pathological site by, for example, releasing an entrapped drug or shedding a protective coating, thus facilitating the interaction between drug-loaded nanocarriers and target cells or tissues. In addition, imaging contrast moieties can be attached to these carriers to track their real-time biodistribution and accumulation in target cells or tissues. Here, I highlight recent developments with multifunctional and stimuli-sensitive NDDSs and their therapeutic potential for diseases including cancer, cardiovascular diseases and infectious diseases. PMID- 25287125 TI - Tip-enhanced laser ablation sample transfer for biomolecule mass spectrometry. AB - Atomic force microscope (AFM) tip-enhanced laser ablation was used to transfer molecules from thin films to a suspended silver wire for off-line mass spectrometry using laser desorption ionization (LDI) and matrix-assisted laser desorption ionization (MALDI). An AFM with a 30 nm radius gold-coated silicon tip was used to image the sample and to hold the tip 15 nm from the surface for material removal using a 355 nm Nd:YAG laser. The ablated material was captured on a silver wire that was held 300 MUm vertically and 100 MUm horizontally from the tip. For the small molecules anthracene and rhodamine 6G, the wire was cut and affixed to a metal target using double-sided conductive tape and analyzed by LDI using a commercial laser desorption time-of-flight mass spectrometer. Approximately 100 fg of material was ablated from each of the 1 MUm ablation spots and transferred with approximately 3% efficiency. For larger polypeptide molecules angiotensin II and bovine insulin, the captured material was dissolved in saturated matrix solution and deposited on a target for MALDI analysis. PMID- 25287126 TI - Study of the association of adrenomedullin and basic-fibroblast growth factors with the peripheral arterial blood flow and endothelial dysfunction biomarkers in type 2 diabetic patients with peripheral vascular insufficiency. AB - BACKGROUND: Progressive micro-vascular vaso-degeneration is the major factor in progression of diabetic complications. Adrenomedullin (AM) and basic-Fibroblast growth factor (b-FGF) are strongly correlated with angiogenesis in vascular diseases. This study aims to provide base line data regarding the vascular effects and correlation of AM, and b-FGF with the peripheral blood flow in diabetic patients with peripheral vascular disease (PVD), and their effect on endothelial dysfunction markers. Ninety age- and sex matched females were enrolled in the study: 30 were controls, 30 had diabetes without complications (group II) and 30 had diabetes with PVD (group III) diagnosed by ankle/ brachial index (A/BI). Plasma levels of AM, b-FGF, intercellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured by indirect enzyme immunoassay (ELISA). RESULTS: There was a significant increase in plasma AM, VCAM-1and ICAM-1, while a significant decrease in plasma b-FGF in diabetic patients with PVD (p < 0.05). A positive correlation was observed between plasma AM, b-FGF and A/BI and a negative correlation with VCAM -1 and ICAM in diabetic PVD. AM was not a predictor, while b-FG, VCAM-1 and ICAM-1 could be predictors for peripheral blood flow in diabetic PVD. CONCLUSION: This study elucidates for the first time that AM and b-FGF are correlated and have a direct impact on the peripheral blood flow, the rise of AM in diabetic PVD may be a consecutive and compensatory vasculo-protective effect as its angiogenic and anti-inflammatory properties act to relief the endothelial insult. Down expression of b-FGF may be a predisposing factor for micro-vascular derangement. It is not clear if the rise of AM and the decline of b- FGF levels may be consequences or predisposing factors for VCAM-1 and ICAM-1 elevation as these endothelial dysfunction biomarkers could reduce peripheral blood flow and vascular integrity. It is optimistic to believe that drug intervention through AM and b-FGF administration together with reversing the endothelial inflammatory process by targeting VCAM and ICAM could reduce the prevalence of diabetic vascular complications, reduce the risk of cerebrovascular and cardiovascular morbidity in diabetes through normalizing vascular endothelium function and peripheral blood flow. PMID- 25287127 TI - Characterization of Vibrio parahaemolyticus causing acute hepatopancreatic necrosis disease in southern Thailand. AB - Vibrio parahaemolyticus was isolated from shrimp of five farms located in the Pattani and Songkhla provinces of southern Thailand. Using a PCR method targeted to the unique DNA sequences derived from the plasmid (AP2 primers) and the toxin gene (AP3 primers) of V. parahaemolyticus that caused acute hepatopancreatic necrosis disease (AHPND), a total of 33 of 108 isolates were positive. In contrast, all 63 and 66 isolates of clinical and environmental V. parahaemolyticus, respectively, obtained previously from 2008 to 2014 from the same area were negative. This implied that these strains were likely to be the cause of the outbreak of AHPND in this area. Intestinal samples proved to be a better source for the isolation of V. parahaemolyticus AHPND than the hepatopancreas. All isolates were investigated for haemolytic activity, virulence genes, serotypes, genotypes and antibiotic susceptibility. All the AHPND isolates had a unique O antigen, but small variations of the K antigens were detected from different farms. In addition, the DNA profiles of V. parahaemolyticus AHPND isolates were similar, but distinct from those clinical and environmental isolates. It is postulated that the causative agent of AHPND might have originated from one clone and then slightly different serotypes subsequently developed. PMID- 25287130 TI - Molecular characterization of a novel reovirus isolated from Pekin ducklings in China. AB - The complete genome sequence of a novel duck orthoreovirus, designated DRV strain TH11(DRV-TH11), was determined and characterized. The DRV-TH11 genome is comprised of 23,417 bp and its genome organization is more similar to that of avian orthoreoviruses (ARVs) of chicken origin than other reoviruses. The results of comparative sequence analysis and dendrograms based on the uB- and sigmaC encoding genes indicated that TH11 may be derived from the reassortment of ARVs and classic Muscovy duck reovirus (MDRV). A possible recombinant event was identified using the SimPlot program, and it occurred in the M2 segment. The results indicated that reassortment and mutation play a role in the evolution of duck reovirus. PMID- 25287128 TI - FOXM1: an emerging master regulator of DNA damage response and genotoxic agent resistance. AB - FOXM1 is a transcription factor required for a wide spectrum of essential biological functions, including DNA damage repair, cell proliferation, cell cycle progression, cell renewal, cell differentiation and tissue homeostasis. Recent evidence suggests that FOXM1 also has a role in many aspects of the DNA damage response. Accordingly, FOXM1 drives the transcription of genes for DNA damage sensors, mediators, signal transducers and effectors. As a result of these functions, it plays an integral part in maintaining the integrity of the genome and so is key to the propagation of accurate genetic information to the next generation. Preserving the genetic code is a vital means of suppressing cancer and other genetic diseases. Conversely, FOXM1 is also a potent oncogenic factor that is essential for cancer initiation, progression and drug resistance. An enhanced FOXM1 DNA damage repair gene expression network can confer resistance to genotoxic agents. Developing a thorough understanding of the regulation and function of FOXM1 in DNA damage response will improve the diagnosis and treatment of diseases including cancer, neurodegenerative conditions and immunodeficiency disorders. It will also benefit cancer patients with acquired genotoxic agent resistance. PMID- 25287129 TI - Complete genomic characterization of a potato mop-top virus isolate from the United States. AB - Potato mop-top virus (PMTV; family Virgaviridae) was reported recently in the Pacific Northwestern USA. To better understand the genetic diversity of this virus, the complete genome of an isolate from Washington State (WA), USA, was characterized. Sequence comparisons of the WA isolate with other known sequences revealed that the RNA-Rep-encoded RdRp protein and the RNA-CP-encoded coat protein displayed >99 % amino acid sequence identity to those of two Nordic (RdRp) and several European and North American isolates (CP), respectively. The RNA-TGB-encoded TGB 1 and TGB 3 protein sequences had >99 % amino acid sequence identity to the corresponding proteins of Czech and Danish isolates, whereas the TGB 2 protein is identical to those of Colombian isolates. Phylogenetic analysis of the viral genes of the WA isolate reflected the close relationship between WA and European isolates. RFLP analysis of corresponding DNA of RNA TGB and RNA CP revealed that the WA isolate has the RNA TGB-II and RNA CP-B types, which are prevalent in Europe and other parts of world. This is the first report of the complete genome characterization of PMTV from the Americas. PMID- 25287131 TI - Prediction of signaling pathways involved in enterovirus 71 infection by algorithm analysis based on miRNA profiles and their target genes. AB - Enterovirus 71 (EV71) causes major outbreaks of hand, foot, and mouth disease. Host factors and signaling pathways exhibit important functions in the EV71 life cycle. We conducted algorithm analysis based on miRNA profiles and their target genes to identify the miRNAs and downstream signaling pathways involved in EV71 infection. The miRNA profiles of human rhabdomyosarcoma cells treated with interferon (IFN-)-alpha or IFN-gamma were compared with those of cells infected with EV71. Genes targeted by differentially expressed miRNAs were identified and assigned to different signaling pathways according to public databases. The results showed that host miRNAs specifically responded to the viral infection and IFN treatment. Some miRNAs, including miR-124 and miR-491-3p, were regulated in opposite manners by the IFNs and EV71. Some signaling pathways regulated by both EV71 infection and IFN treatment were also predicted. These pathways included axon guidance, Wingless/Int1 (Wnt) signaling cascade, platelet-derived growth factor receptor (PDGFR)/PDGF, phosphatidylinositol 3-kinase (PI3K), Jun N terminal kinase (JNK)/mitogen-activated protein kinase (MAPK), transforming growth factor-beta receptor (TGF-betaR)/TGF-beta, SMAD2/3, insulin/insulin-like growth factor (IGF), bone morphogenetic protein (BMP), CDC42, ERB1, hepatocyte growth factor receptor (c-Met), eukaryotic translation initiation factor 4E (eIF4E), protein kinase A (PKA), and IFN-gamma pathways. The identified miRNA and downstream signaling pathways would help to elucidate the interaction between the virus and the host. The genomics method using algorithm analysis also provided a new way to investigate the host factors and signaling pathways critical for viral replication. PMID- 25287132 TI - Evaluation of the modified colorimetric resazurin microtiter plate-based antibacterial assay for rapid and reliable tuberculosis drug susceptibility testing. AB - BACKGROUND: The resazurin microtiter assay (classic REMA), a colorimetric liquid culture-based drug susceptibility assay for Mycobacterium tuberculosis (MTB), has been endorsed by the World Health Organization. The assay requires 8-16 days to obtain results, delaying management of drug resistant tuberculosis patients. A modified REMA which allows results in as little as 24 hours for bacterial strains, has been developed and validated using Staphylococcus aureus, but has not yet been evaluated for MTB. Therefore we assessed the performance of the modified REMA for rifampicin (RIF) and isoniazid (INH) susceptibility, using the classic REMA as the reference standard. We also compared simplicity (from the technicians' point of view), time taken to obtain results (rank-sum testing), specificity and Kappa statistics of the two methods. RESULTS: The modified REMA, which is a one-step procedure, was found to be simpler to perform and results were obtained in a significantly shorter time (5 versus 9 days, p < 0.0001) compared to the classic REMA due to addition of indicator and strain at the same time. The specificity of the modified REMA was low {46.8% (35.5% - 58.4%) for RIF and 13.9% (7.2% - 23.5%) for INH}. Kappa statistics were 16.0% for RIF and 2.0% for INH. Low specificity and kappa statistics are due to indicator reduction by the strains before complete drug activity. CONCLUSION: Although modified REMA is faster and simpler compared to classic REMA, it is not reliable for MTB drug susceptibility testing. PMID- 25287134 TI - Clinical outcomes of enjoying sexualization among lesbian women. AB - The Enjoyment of Sexualization Scale (ESS) was given to 150 lesbians in addition to measures of self-objectification, negative eating attitudes, and depression. The ESS was found to have acceptable levels of internal consistency reliability with a lesbian sample. Scores on the ESS were lower in this sample than in previously reported research with heterosexual women. Enjoying sexualization was found to moderate the relationship between body shame and both depressive symptomatology and negative eating attitudes. In contrast to findings from a heterosexual sample, lesbians who enjoyed sexualization had smaller relationships between these negative clinical outcomes and body shame than lesbians who did not. For lesbians, enjoying sexualization may serve a protective function against the negative effects of self-objectification. Findings are discussed in terms of body image and perceptions of ideal beauty among lesbians. PMID- 25287133 TI - Differential regulation of proteins in rice (Oryza sativa L.) under iron deficiency. AB - KEY MESSAGE: Sixty-three proteins were identified to be differentially accumulated due to iron deficiency in shoot and root. The importance of these proteins alterations on shoot physiology is discussed. Iron (Fe) is an essential micronutrient for plant growth and its accumulation affects the quality of edible plant organs. To investigate the adaptive mechanism of a Chinese rice variety grown under iron deficiency, proteins differentially accumulated in leaves and roots of Yangdao 6, an indica cultivar, under Fe deficiency growth condition, were profiled using a two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS). The accumulations of seventy-three proteins were detected to be increased or decreased upon iron deficiency, and sixty-three of them were successfully identified. Among the sixty-three proteins, a total of forty proteins were identified in rice leaves, and twenty-three proteins were in roots. Most of these proteins are involved in photosynthesis, C metabolism, oxidative stress, Adenosine triphosphate synthesis, cell growth or signal transduction. The results provide a comprehensive way to understand, at the level of proteins, the adaptive mechanism used by rice shoots and roots under iron deficiency. PMID- 25287135 TI - Hair cortisol concentration is unaffected by basic military training, but related to sociodemographic and environmental factors. AB - The analysis of hair cortisol concentrations (HCC) is a promising new biomarker for retrospective measurement of chronic stress. The effect of basic military training (BMT) on chronic stress has not yet been reported. The aim of this study was to investigate the effect of 10-week BMT on HCC, while further exploring the role of known and novel covariates. Young healthy male recruits of the Swiss Army participated twice, 10 weeks apart, in data collection (1st examination: n = 177; 2nd examination: n = 105). On two occasions, we assessed HCC, perceived stress and different candidate variables that may affect HCC (e.g. socioeconomic status, meteorological data). Military training increased perceived stress from the first to the second examination, but did not affect HCC. In line with this, there was no correlation between HCC and perceived stress ratings. This could be interpreted as a missing influence of mainly physical stress (e.g. exercise) on HCC. In contrast, significant correlations were found between HCC and ambient temperature, humidity and education. Future studies should control for meteorological data and educational status when examining HCC. PMID- 25287136 TI - The effects of chronic restraint on the morphology of ventral CA1 neurons in female Long Evans rats. AB - Women are more likely than men to develop psychopathology as a result of stress, but there is little research regarding the effects of a stressful condition and its treatment in female non-human animals, perhaps because of inherent hormonal activity. Recent studies have demonstrated that there are structural and functional differences between the dorsal and ventral hippocampus, but the effects of stress on the morphology of CA1 and CA3 neurons have been studied primarily in the dorsal hippocampus. This study assessed the effects of stress induced by restricted movement on the morphology of ventral hippocampal CA1 neurons in male and female rats. Male and female Long Evans (LE) rats were subjected to restraint stress for 6 h every day for 25 days. One group of rats was used to study the dendritic morphology of CA1 ventral hippocampal neurons using the Golgi-Cox stain. A second group of rats was used to analyze learning and memory using the Morris water maze. Stressed female rats exhibited a decrease in the density of basilar dendritic spines, an increase in the number of apical dendritic intersections and deficits in spatial memory. There were no apparent effects of stress on male rats. Our data support previous findings of a dimorphic response to chronic stress and indicate that the ventral hippocampus is not particularly susceptible to the effects of stress. PMID- 25287137 TI - Impact of a mindfulness stress management program on stress, anxiety, depression and quality of life in women with polycystic ovary syndrome: a randomized controlled trial. AB - Polycystic ovary syndrome (PCOS) is a common endocrine disorder with a significant psychological burden throughout the life course of affected women. Thus, use of mindful awareness may be beneficial as an adjunct to conventional medical management of women with PCOS. A randomized, controlled trial was conducted at the Evgenideion Hospital of the Athens University Medical School to explore the impact of an 8-week mindfulness stress management program on measures of depression, anxiety and stress as well as on the quality of life in reproductive age women with PCOS. The study was approved by the Research Ethics Committee. Twenty-three and 15 women with PCOS were randomly allocated to the intervention or control group, respectively. All participants were administered DASS21, PSS-14, PCOSQ, Daily Life and General Life Satisfaction Questionnaires and provided three-timed daily samples of salivary cortisol, before and after the intervention. Intervention group participants were provided with the Credibility/Expectancy Questionnaire at the day of enrolment, to check for possible placebo effect on the outcome. Post-intervention, between-group results revealed statistically significant reductions in stress, depressive and anxiety symptoms, as well as in salivary cortisol concentrations, along with an increase in Life Satisfaction and Quality of Life scores in the intervention group only. There was no significant "placebo" effect on the outcome measures. Mindfulness techniques seem promising in ameliorating stress, anxiety, depression and the quality of life in women with PCOS and could be used as an adjunct method to the conventional management of these women. PMID- 25287139 TI - Management and 2-year follow-up of children aged 29 days to 17 years hospitalized for a first stroke in France (2009-2010). AB - INTRODUCTION: Childhood stroke is a little-known disease in France. The objective of this study was to report the characteristics, management, treatment and outcome of stroke in terms of survival and 2-year recurrence rates. METHOD: The study population included children aged 29 days to 17 years, identified by their first hospitalization for stroke (excluding transient ischemic attack) in 2009 and 2010 and not hospitalized for stroke between 2005 and 2008. Data were derived from the systeme national d'information inter-regimes de l'assurance maladie (SNIIRAM) [national health insurance information system]. RESULTS: For the 428 children with stroke in 2009 and the 441 children with stroke in 2010, the mean annual hospitalization rate was 3/100,000 children, comprising 0.5/100,000 for cerebral infarction (CI) and 1.5/100,000 for intracerebral hemorrhage (ICH). The youngest children presented the highest ICH rate, while, to a lesser extent, adolescents presented a higher proportion of CI. A male predominance was observed for ICH. Comorbidities were relatively common among these children prior to hospitalization: 21% had already been granted an affection de longue duree (ALD) [chronic disease] status and 37% had been hospitalized at least once during the previous year. The mean length of the hospital stay was 7.2 days and the hospital mortality was 3.9% (3.4% for ICH, 3.2% for CI). The 1-year mortality rate was 5.7% and the 2-year mortality rate was 6.0% (6% for ICH and 5% for CI). The readmission rate for stroke was 13% during the 1st year and 2% during the 2nd year. At 1 year, 18% of children (26% for CI) had been admitted at least once to a rehabilitation unit. CONCLUSION: This is the first study to report the epidemiology of childhood stroke in France. The validity of this study is supported by the fact that it demonstrated homogeneous descriptive indicators to those obtained by means of various methodologies in other populations. The high mortality, recurrence, and disability rates observed during the year following the initial stroke encourage continuation of the ongoing process of standardizing the management of childhood stroke in France. PMID- 25287138 TI - DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival. AB - INTRODUCTION: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood. METHODS: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer. RESULTS: Consensus clustering using methylation (beta) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset. CONCLUSIONS: This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes. PMID- 25287140 TI - [Clinical and biochemical characterization of childhood urolithiasis]. AB - OBJECTIVES: Urolithiasis is rare in children, but the incidence has increased over the past few decades. This study aims at describing the clinical and biochemical characteristics, etiology, and treatment of urolithiasis in children. METHODS: This was a retrospective study of all children under 16 years of age seen at the Bordeaux University Children's Hospital with a diagnosis of urolithiasis. The diagnosis was confirmed either radiologically or clinically by the expulsion of the stone. RESULTS: A total of 186 children with a diagnosis of urolithiasis between 1994 and 2012 were included. The median age at diagnosis was 7.4 years. The male-to-female ratio was 1.9. The estimated annual incidence was around 5.5/100,000 children under 15 years of age in the past 5 years. The main presenting feature was nonspecific abdominal pain (71%). Metabolic calculi accounted for 48% of the patients with idiopathic hypercalciuria as the main cause. Genetic diseases accounted for 15% of cases. The proportion of infectious calculi was estimated at 33% and decreased in the past two decades. Stone fragments were sent for analysis in 86 children, and calcium oxalate was the major component (37%), followed by calcium phosphate (33%), purine (9%), and struvite (8%). At least 26% of patients experienced recurrence of stone passage. CONCLUSION: This retrospective study highlighted changes in characteristics of pediatric urolithiasis over time. Childhood-onset urolithiasis requires complete etiological work-up so that a metabolic cause with a high risk of recurrence does not go unrecognized. PMID- 25287141 TI - [Prolonged convulsive seizures in children: how are they managed outside the hospital?]. AB - CONTEXT AND OBJECTIVES: Guidelines recommend that any epileptic seizure that lasts more than 5 min (prolonged seizures) be treated immediately with benzodiazepines in order to prevent progression to status epilepticus. However, there is very little published information on how such seizures are managed outside of the hospital setting, for example in schools or at home. This paper presents the initial results, specific to France, of the Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy (PERFECT) Initiative, which was set up in 2011 to gain a better understanding of how prolonged convulsive seizures are managed and rescue medication is administered in out-of-hospital settings across Europe. METHODS: The PERFECT Initiative was conducted in six countries (France, Germany, Italy, Spain, Sweden, the United Kingdom) and consists of three phases. This paper reports on the first two phases of this study and focuses on findings for France. Phase I of the PERFECT initiative consisted of a review of existing clinical guidelines, guidance to schools, and relevant policy and legal frameworks in France, from both published and web-based sources. Phase II consisted in a telephone survey of 20 pediatricians, pediatric neurologists, and neurologists who treat children with prolonged convulsive seizures in France in order to obtain their views on how prolonged seizures are managed outside of hospitals. Phase III is ongoing and consists of a survey of children with prolonged seizures and their caregivers. RESULTS: Existing clinical guidelines pertain mainly to the hospital setting and contain very little informations on how prolonged seizures should be managed outside the hospital. Guidance to schools is unclear as to whether teachers are allowed to administer rescue medication to children and legal frameworks are full of contradictions. As a result, whether or not children who experience prolonged seizures receive their rescue medication during school hours depends mostly on the resources and training available in each school. Healthcare professionals stated that lack of information on prolonged seizures and their management, as well as a lack of up-to-date guidance specific to schools were considerable obstacles to a systematic approach to managing prolonged seizures outside of the hospital. DISCUSSION: In France and elsewhere, there has been growing recognition of substantial gaps in the provision of care to children with epilepsy in recent years. However, the issues that arise for children who require rescue medication for prolonged seizures outside of hospitals are conspicuously absent from policy documents or clinical guidelines. This lack of information, combined with insufficient training in schools on epilepsy, and inadequate guidelines create a situation in which schools are likely to call an ambulance every time a child has a prolonged seizure, therefore risking delays in treatment, and putting the child at risk of status epilepticus and clinical sequelae, not to mention stigmatization at school. CONCLUSION: There is a need for more explicit guidance covering educational and healthcare settings, clearer information to parents and schools, and more systematic training to be made available to caregivers in order to ensure that all children at risk of prolonged seizures receive their prescribed rescue medication as quickly as possible, regardless of where their seizure occurs. PMID- 25287142 TI - [Assessing early childhood vaccination coverage in France after 2013 vaccination schedule implementation]. PMID- 25287143 TI - [Simulation training: a pilot-study on reception of parents in a pediatric intensive care unit]. AB - BACKGROUND: Simulation training is gradually being integrated into the curriculum for caregivers in intensive care units. There are few training programs on communication with families. GOAL: This pilot-study evaluated the impact of a training protocol on professional practices including a protocol for the reception of the parents of a child admitted to a pediatric intensive care unit. MATERIALS AND METHODS: The training program lasted 3 months and included three parts: a theoretical contribution, a simulation session with debriefing, and a focus group. During the simulation session, a multi-professional team of three healthcare providers (physician, nurse, assistant nurse) must apply a protocol for the reception of the parents of a child who had just been admitted. The protocol lasted 35 min and included three sequences: reception and dressing by the assistant nurse, medical meeting conducted by the physician and the nurse, support of the parents in the room by the nurse and the assistant nurse. The child was simulated by a manikin (SimBabyTM, Laerdal) and the parents were prepared actors. The main objective of the pilot-study was to measure the rate of change in professional practices 1 year after the end of training. RESULTS: One year later, all healthcare providers (n=15) declared they had changed their professional practices and felt that half of these changes were due to the pilot study. New practices such as receiving parents in pairs in a dedicated room or managing a short interview with the parents before supporting the child were applied "always" or "if possible". CONCLUSION: The pilot-study showed that the training program induced half of the changes of professional practices for welcoming the parents of a child admitted to pediatric intensive care unit 1 year later. PMID- 25287144 TI - Diuretic response in patients with acute decompensated heart failure: characteristics and clinical outcome--an analysis from RELAX-AHF. AB - AIMS: We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF). METHODS AND RESULTS: RELAX-AHF was a double-blind, placebo controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 ug/kg per day) within 16 h from presentation. Diuretic response was defined as Delta weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was -0.42 ( 1.00, -0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507). CONCLUSIONS: In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response. TRIAL REGISTRATION: NCT00520806. PMID- 25287145 TI - [Cardiac rehabilitation after myocardial infarction in France: still not prescribed enough]. AB - Despite well-documented benefits for patients after myocardial infarction, cardiac rehabilitation is underutilized in most countries. In France, a recent study showed a participation rate of 22.7 %, with huge regional disparities for unknown reasons. In this paper, we analyze some demographic particularities for explaining these curious results. Then, we review in the literature the complex factors influencing patient's referral in cardiac rehabilitation (patient's believes, role of the physician, health system's organization...), and the best ways of improving cardiac rehabilitation rate or finding adequate alternatives. PMID- 25287146 TI - Comparative genomics reveals multiple genetic backgrounds of human pathogenicity in the Trypanosoma brucei complex. AB - The Trypanosoma brucei complex contains a number of subspecies with exceptionally variable life histories, including zoonotic subspecies, which are causative agents of human African trypanosomiasis (HAT) in sub-Saharan Africa. Paradoxically, genomic variation between taxa is extremely low. We analyzed the whole-genome sequences of 39 isolates across the T. brucei complex from diverse hosts and regions, identifying 608,501 single nucleotide polymorphisms that represent 2.33% of the nuclear genome. We show that human pathogenicity occurs across a wide range of parasite genotypes, and taxonomic designation does not reflect genetic variation across the group, as previous studies have suggested based on a small number of genes. This genome-wide study allowed the identification of significant host and geographic location associations. Strong purifying selection was detected in genomic regions associated with cytoskeleton structure, and regulatory genes associated with antigenic variation, suggesting conservation of these regions in African trypanosomes. In agreement with expectations drawn from meiotic reciprocal recombination, differences in average linkage disequilibrium between chromosomes in T. brucei correlate positively with chromosome size. In addition to insights into the life history of a diverse group of eukaryotic parasites, the documentation of genomic variation across the T. brucei complex and its association with specific hosts and geographic localities will aid in the development of comprehensive monitoring tools crucial to the proposed elimination of HAT by 2020, and on a shorter term, for monitoring the feared merger between the two human infective parasites, T. brucei rhodesiense and T. b. gambiense, in northern Uganda. PMID- 25287148 TI - Pesticide retailers' knowledge and handling practices in selected towns of Tanzania. AB - BACKGROUND: Approximately 300 pesticide retailers are currently registered in Tanzania. Inadequate knowledge and unsafe handling practices among retailers may contribute to human pesticide exposure and environmental contamination. This study investigated pesticide retailers' qualifications, work experience, safety practices and the products distributed so as to identify opportunities for preventing Acute Pesticide Poisoning (APP). METHODOLOGY: In 2005, employees of pesticide retail firms in six Tanzanian towns were surveyed using a semi structured questionnaire and physical inspection of premises. In addition, information on products distributed in 2004 and 2005 was collected from Arusha and Arumeru firms to assess potential risk posed for end-users. RESULTS: More than half of the participating firms (58.6%) were not registered. Most agents on sale in Arusha and Arumeru were hazardous products including WHO Class I and II products (61.7%) and the mean number of cholinesterase inhibiting agents was 5.8 (range 2-8). Major deficiencies found included semi-trained staff (52%), lack of first-aid kits (38.6%), repacking and decanting of pesticides into smaller unlabelled containers (25.3%), lack of fire-fighting equipment (22.6%) and distribution of unregistered products (9.3%). Compared to unregistered companies, those companies that were registered were more likely to report practicing safe container disposal (40% versus 19%; p = 0.06) and to have an absence of leaking containers (36% versus 15%; p = 0.04). CONCLUSION: Pesticide distribution in Tanzania was accompanied by many unsafe practices that may contribute to the burden from APP, not only affecting the distributors but also farmers who buy and use these products. Market pressures appear to be encouraging decanting of pesticides to enable retailers to make profits. Registration of firms appears to be associated with safer practices. Comprehensive interventions to strengthen enforcement mechanisms by increasing the number of pesticide inspectors, ensuring adequate financial support for enforcement activities and providing training opportunities for pesticide retailers and the end users are strongly recommended. PMID- 25287147 TI - Elucidating the genotype-phenotype relationships and network perturbations of human shared and specific disease genes from an evolutionary perspective. AB - To date, numerous studies have been attempted to determine the extent of variation in evolutionary rates between human disease and nondisease (ND) genes. In our present study, we have considered human autosomal monogenic (Mendelian) disease genes, which were classified into two groups according to the number of phenotypic defects, that is, specific disease (SPD) gene (one gene: one defect) and shared disease (SHD) gene (one gene: multiple defects). Here, we have compared the evolutionary rates of these two groups of genes, that is, SPD genes and SHD genes with respect to ND genes. We observed that the average evolutionary rates are slow in SHD group, intermediate in SPD group, and fast in ND group. Group-to-group evolutionary rate differences remain statistically significant regardless of their gene expression levels and number of defects. We demonstrated that disease genes are under strong selective constraint if they emerge through edgetic perturbation or drug-induced perturbation of the interactome network, show tissue-restricted expression, and are involved in transmembrane transport. Among all the factors, our regression analyses interestingly suggest the independent effects of 1) drug-induced perturbation and 2) the interaction term of expression breadth and transmembrane transport on protein evolutionary rates. We reasoned that the drug-induced network disruption is a combination of several edgetic perturbations and, thus, has more severe effect on gene phenotypes. PMID- 25287149 TI - Noninvasive diagnostics supporting system for choroidal melanoma: a pilot study. AB - PURPOSE: To examine the usefulness of a near-infrared hyperspectral imager (NIR HSI) system in discriminating uveal melanoma from other intraocular tumors. METHOD: The NIR-HSI, which had been developed as a screening system for age related macular degeneration, was used to measure near-infrared hyperspectral data (NIR-HSD) of a lesion located at the ocular fundus of 17 Japanese patients, including 5 with choroidal melanoma and 12 with other intraocular tumors. The index was derived from each NIR-HSD. Non-parametric statistical analysis was performed. RESULTS: Diagnostic accuracy of 94.1% was achieved when the threshold value of the index was set to minimize the average value of false-positive and negative fractions. CONCLUSIONS: The NIR-HSI system is useful as a noninvasive diagnostic supporting system for choroidal melanoma. PMID- 25287150 TI - Associations between the dietary intake of antioxidant nutrients and the risk of hip fracture in elderly Chinese: a case-control study. AB - The role of oxidative stress in skeletal health is unclear. The present study investigated whether a high dietary intake of antioxidant nutrients (vitamins C and E, beta-carotene, animal-derived vitamin A, retinol equivalents, Zn and Se) is associated with a reduced risk of hip fracture in elderly Chinese. This 1:1 matched case-control study involved 726 elderly Chinese with hip fracture and 726 control subjects, recruited between June 2009 and May 2013. Face-to-face interviews were conducted to determine habitual dietary intakes of the above mentioned seven nutrients based on a seventy-nine-item FFQ and information on various covariates, and an antioxidant score was calculated. After adjustment for potential covariates, dose-dependent inverse associations were observed between the dietary intake of vitamin C, vitamin E, beta-carotene, and Se and antioxidant score and the risk of hip fracture (P for trend <= 0.005). The OR of hip fracture for the highest (v. lowest) quartile of intake were 0.39 (95 % CI 0.28, 0.56) for vitamin C, 0.23 (95 % CI 0.16, 0.33) for vitamin E, 0.51 (95 % CI 0.36, 0.73) for beta-carotene, 0.43 (95 % CI 0.26, 0.70) for Se and 0.24 (95 % CI 0.17, 0.36) for the antioxidant score. A moderate-to-high dietary intake of retinol equivalents in quartiles 2-4 (v. 1) was found to be associated with a lower risk of hip fracture (OR range: 0.51-0.63, P< 0.05). No significant association was observed between dietary Zn or animal-derived vitamin A intake and hip fracture risk (P for trend >0.20). In conclusion, a higher dietary intake of vitamins C and E, beta-carotene, and Se and a moderate-to-high dietary intake of retinol equivalents are associated with a lower risk of hip fracture in elderly Chinese. PMID- 25287151 TI - Sexual function in women before and after surgery for pelvic organ prolapse. AB - OBJECTIVE: The aim of this study was to evaluate sexual function in women before and after surgery for pelvic organ prolapse (POP) using native tissue repair. DESIGN: A prospective observational study. SETTING: Danish university hospital, between December 2008 and May 2010. POPULATION: Eighty-one patients who had a POP operation with native tissue repair performed. METHODS: The patients completed a validated Danish questionnaire on prolapse, the Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire - 12 Short Form (PISQ-12-SF), and the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF) before undergoing surgery and six months postoperatively. MAIN OUTCOME MEASURES: Differences in PISQ-12-SF measures six months after the operation in different types of POP operations. RESULTS: Preoperatively, the PISQ 12-SF score (mean +/- SD) was 35.2 +/- 4.6 and postoperatively 38.3 +/- 3.9, giving a significant difference of 3.0 +/- 3.8. (p < 0.05). Thirty-seven women (72%) improved their PISQ-12-SF score postoperatively, nine (18%) had an equal score, and five (10%) reported a lower score. There was no significant difference in the PISQ-12-SF scores between different operations. The ICIQ-UI-SF showed an overall improvement in incontinence postoperatively with a small correlation to PISQ-12-SF. CONCLUSIONS: The majority of patients who undergo operation for different kinds of POP using native tissue repair, experience an improvement in their sexual life postoperatively. Most women with preoperative urinary incontinence experienced cure or improvement after POP surgery. PMID- 25287152 TI - Models for Access to Maternal Smoking cessation Support (MAMSS): a study protocol of a quasi-experiment to increase the engagement of pregnant women who smoke in NHS Stop Smoking Services. AB - BACKGROUND: Maternal smoking is a key cause of poor outcomes for mothers, babies and children and Wales has higher rates of smoking in pregnancy than any other UK country. Despite various improvements within the NHS Stop Smoking Service to strengthen the intervention for pregnant women, referrals and successful quit attempts for this group have continued to remain extremely low. A key element of UK national guidance for smoking cessation during pregnancy is to provide a flexible and tailored service to help increase levels of engagement. This study aims to test the effectiveness of three different models of service delivery to address the gap in the evidence base about how to deliver a flexible, tailored smoking cessation service to pregnant women. METHODS: This study will adopt a quasi-experimental design over a 12 month period. The setting is four of Wales' seven Health Boards using an integrated approach between maternity services, local public health teams and the NHS Stop Smoking Service. Core recommendations from UK public health guidance are being implemented across intervention and usual care sites. Stop smoking support for pregnant women in intervention sites is being delivered more flexibly than in usual care sites. Both qualitative and quantitative approaches will be adopted to capture important contextual information and consider multiple perspectives. A health economic analysis will be undertaken using a cost-consequences analysis approach. The primary outcome measure is engagement with stop smoking services (defined as having at least one face-to-face therapeutic contact with a clinician). DISCUSSION: Supporting pregnant women to stop smoking is a challenging area of public health. The proposed study will address several areas where there are key evidence gaps relating to smoking cessation interventions for pregnant women. Specifically, how best to encourage pregnant women to attend a specialist stop smoking support service, how to deliver the service and who should provide it. PMID- 25287153 TI - Direct identification of Streptococcus agalactiae and capsular type by real-time PCR in vaginal swabs from pregnant women. AB - Most group B streptococcus (GBS) infections in newborns are with capsular type Ia, Ib, or III. To prevent these infections more effectively, we developed a real time PCR method to simultaneously detect GBS species and identify these 3 capsular types in vaginal swab samples from women at 36-39 weeks of gestation. DNA to be detected included those of the dltS gene (encoding a histidine kinase specific to GBS) and cps genes encoding capsular types. PCR sensitivity was 10 CFU/well for a 33-35 threshold cycle. Results were obtained within 2 h. Direct PCR results were compared with results obtained from cultures. Samples numbering 1226 underwent PCR between September 2008 and August 2012. GBS positivity rates by direct PCR and after routine culture were 15.7% (n = 192) and 12.6% (n = 154), respectively. Sensitivity and specificity of direct PCR relative to culture were 96.1% and 95.9%. Of GBS positive samples identified by PCR, capsular types determined directly by real-time PCR were Ia (n = 24), Ib (n = 32), and III (n = 26). Real-time PCR using our designed cycling probe is a practical, highly sensitive method for identification of GBS in pregnant carriers, allowing use of prophylactic intrapartum antibiotics in time to cover the possibility of unexpected premature birth. PMID- 25287154 TI - Acinetobacter baumannii escape from neutrophil extracellular traps (NETs). AB - Acinetobacter baumannii and Pseudomonas aeruginosa are the same aerobic gram negative bacillus and are usually harmless but cause infectious diseases in compromised hosts. Neutrophils play a critical role in infective protection against the extracellular growth of bacteria. Recently, a new biological defense mechanism called neutrophil extracellular traps (NETs) has been attracting attention. In present study, we investigated the responsiveness of neutrophils to A. baumannii and P. aeruginosa, focusing on NET formation. Neutrophils were co cultured with A. baumannii or P. aeruginosa, and then DNA, histone and neutrophil elastase were stained, and the formation of NETs was evaluated. Neutrophils stimulated with A. baumannii had spread, but their shapes was maintained, and the nucleus was observed as clearly as that in non-stimulated neutrophils. However, neutrophils stimulated with P. aeruginosa did not maintain their cellular morphology, and the nucleus was disrupted with DNA, histones, and neutrophil elastase released into the extracellular space. These results suggest that A. baumannii does not induce NET formation, in contrast to P. aeruginosa. In addition, we measured expression of myeloperoxidase (MPO), reactive oxygen species (ROS) and superoxide in neutrophils, and we found that these expression in P. aeruginosa-stimulated neutrophils was stronger than that in A. baumannii stimulated neutrophils. Furthermore, A. baumannii was not killed by neutrophils, in contrast to P. aeruginosa. In this study, we show that the reactivity of neutrophils and their biological defense mechanism are different between A. baumannii and P. aeruginosa, which is important for understanding the pathogenicity of these bacteria. PMID- 25287155 TI - A correlation between reduced susceptibilities to vancomycin and daptomycin among the MRSA isolates selected in mutant selection window of both vancomycin and daptomycin. AB - Guidelines for the treatment of MRSA infection, recently published by the IDSA and JSC, recommend daptomycin for sepsis and skin and soft tissue infections comparably to or more strongly than vancomycin. Meanwhile MIC creeping with an increased isolation frequency of MRSA isolates with vancomycin MIC of 2 MUg/mL has become a problem. In the present study, the MIC creeping rate of MRSA strains in the Tohoku district, Japan in 2012 was 13%, a significantly higher value than 3.3% in 2008 (P < 0.01). Of these isolates, the MIC and mutant prevention concentration (MPC) values of daptomycin and vancomycin were determined for 30 clinical isolates of MRSA in 2012. The MIC50/MIC80 values of daptomycin and vancomycin were 0.125/0.5 MUg/mL and 0.125/1 MUg/mL, respectively. The MPC50/MPC80 values of daptomycin and vancomycin were both 32/64 MUg/mL. In the present study, the mutant selection window (MSW) of daptomycin and vancomycin was >=64 MIC. Of strains that selected in the MSW, daptomycin non-susceptible isolates accounted for 70.0%, while MRSA with vancomycin MIC of 2 MUg/mL accounted for 26.7%. On the other hand, 50% of the strains that selected in the vancomycin MSW were daptomycin non-susceptible strain. The detection rate of MRSA with vancomycin MIC of 2 MUg/mL that selected in the daptomycin MSW was 36.7%. These results showed that MRSA with vancomycin MIC of 2 MUg/mL and daptomycin non susceptible isolates were selected by exposure to both antibiotics. Therefore, though vancomycin is frequently used for treatment of MRSA infection, both antibiotics should be selected as a first-line drug appropriately. PMID- 25287156 TI - The predictive value of proteinuria in acute pancreatitis. AB - BACKGROUND/OBJECTIVES: Acute pancreatitis has a highly variable clinical course. Early and reliable predictors for the severity of acute pancreatitis are lacking. Proteinuria appears to be a useful predictor of disease severity and outcome in a variety of clinical conditions. This study aims to investigate the predictive value of proteinuria on admission for the severity of acute pancreatitis compared with other commonly used predictors; the APACHE II score, Modified Glasgow score and C-reactive protein (CRP). METHODS: This is a post-hoc analysis of 64 patients admitted with acute pancreatitis treated in one teaching hospital, who participated in a previous randomized trial. Proteinuria was defined as a Protein/Creatinine (P/C) ratio >23 mg/mmol. The primary endpoint was severe acute pancreatitis. Secondary endpoints included infectious complications, need for invasive intervention, ICU stay and in-hospital mortality. RESULTS: Proteinuria was present in 30/64 patients (47%). Eleven patients (17%) had severe acute pancreatitis. There was no difference in incidence of severe acute pancreatitis between patients with and without proteinuria: 6/30 patients (20%) versus 5/34 patients (15%) respectively (p = 0.58). Likewise, the occurrence of infectious complications, need for intervention and ICU stay and mortality did not differ significantly (p = 0.58, p = 0.99, p = 0.33 and p = 0.60 respectively). The diagnostic performance of the P/C ratio for the prediction of severe pancreatitis was inferior to the Modified Glasgow score (p = 0.04) and CRP (p = 0.03). CONCLUSION: Proteinuria on admission does not seem to be a reliable predictor for disease severity in acute pancreatitis. The diagnostic performance of the P/C ratio is inferior to the Modified Glasgow score and CRP. PMID- 25287157 TI - Single-operator pancreatoscopy is helpful in the evaluation of suspected intraductal papillary mucinous neoplasms (IPMN). AB - BACKGROUND AND OBJECTIVE: Even when advanced cross-sectional imaging modalities have been employed, endoscopic evaluation of intraductal papillary mucinous neoplasms (IPMN) is often required in order to assess the final character and extent of lesions. The current study addresses the use of SpyGlass single operator peroral pancreatoscopy in suspected IPMN. DESIGN: A prospective, non randomized exploratory cohort study. SETTING: Single-center. PATIENTS AND INTERVENTION: A prospective study-cohort of 44 consecutive patients in a single tertiary referral center who underwent ERCP and peroral pancreatoscopy, was prospectively collected between July 2007 and March 2013 because of a radiological signs of IPMN. These IPMN-findings were discovered incidentally in 44% of the cases. MAIN OUTCOME MEASUREMENTS: Diagnostic accuracy (specificity & sensitivity) and complications. RESULTS: The targeted region of the pancreatic duct was reached with the SpyGlass system in 41 patients (median age 65 years, 41% female). Three patients were excluded from analysis because of failed deep cannulation of the pancreatic duct. Brush cytology was taken in 88% and direct biopsies in 41%. IPMN with intermediate or high-grade dysplasia was the main final diagnosis (76%) in 22 patients who had surgery. Out of the 17 patients with a final diagnosis of MD-IPMN, 76% were correctly identified by pancreatoscopy. Of the 9 patients with a final diagnosis of BD-IPMN, the pancreatoscopy identified 78% of the cases correctly.The incidence of post-ERCP pancreatitis was 17%. Pancreatoscopy was found to have provided additional diagnostic information in the vast majority of the cases and to affect clinical decision-making in 76%. LIMITATIONS: Single-center study. CONCLUSIONS: Single-operator peroral pancreatoscopy contributed to the clinical evaluation of IPMN lesions and influenced decision-making concerning their clinical management. The problem of post-procedural pancreatitis needs further attention. PMID- 25287158 TI - Optimal duration of the early and late recurrence of pancreatic cancer after pancreatectomy based on the difference in the prognosis. AB - BACKGROUND: The term "early recurrence" of pancreatic cancer has not been well defined in most previous studies. METHODS: The clinical records of 86 patients who underwent macroscopic curative pancreatectomy for pancreatic cancer between 2000 and 2009 were retrospectively examined. We divided 55 patients who experienced disease recurrence into two groups, the early and late recurrence groups, using the minimum p value approach. The relationships between the interval prior to recurrence and clinical outcomes were investigated. RESULTS: The cumulative 5-year overall survival rates for all 86 patients were 30.2%. For 55 patients who experienced disease recurrence, the optimal cut-off value for differentiating early (n = 37) and late (n = 18) recurrence based on the overall survival was 12 months (p = 0.0000045). The Cox proportional hazard analysis identified carbohydrate antigen 19-9 > 100 U/ml (p = 0.017) and surgical margin (p = 0.007) as the independent prognostic factors associated with overall survival. Positive surgical margin (p = 0.037) and severe venous invasion (p = 0.005) were identified as independent factors associated with early recurrence. CONCLUSION: Twelve months after pancreatectomy is the optimal cut-off value for defining early versus late recurrence based on the overall survival. Early recurrence was related to the status of the surgical margin and venous invasion. PMID- 25287159 TI - Epidermoid Cyst of the Central Nervous System with Marked Lipid Content. PMID- 25287160 TI - NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use. AB - Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and nonmalignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in patients with bone cancer. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40% to 70%, depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late-stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight. PMID- 25287162 TI - Epsilon toxin from Clostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination. AB - Epsilon toxin (ET) is produced by Clostridium perfringens types B and D and causes severe neurological disorders in animals. ET has been observed binding to white matter, suggesting that it may target oligodendrocytes. In primary cultures containing oligodendrocytes and astrocytes, we found that ET (10(-9) M and 10(-7) M) binds to oligodendrocytes, but not to astrocytes. ET induces an increase in extracellular glutamate, and produces oscillations of intracellular Ca(2+) concentration in oligodendrocytes. These effects occurred without any change in the transmembrane resistance of oligodendrocytes, underlining that ET acts through a pore-independent mechanism. Pharmacological investigations revealed that the Ca(2+) oscillations are caused by the ET-induced rise in extracellular glutamate concentration. Indeed, the blockade of metabotropic glutamate receptors type 1 (mGluR1) prevented ET-induced Ca(2+) signals. Activation of the N-methyl-D aspartate receptor (NMDA-R) is also involved, but to a lesser extent. Oligodendrocytes are responsible for myelinating neuronal axons. Using organotypic cultures of cerebellar slices, we found that ET induced the demyelination of Purkinje cell axons within 24 h. As this effect was suppressed by antagonizing mGluR1 and NMDA-R, demyelination is therefore caused by the initial ET-induced rise in extracellular glutamate concentration. This study reveals the novel possibility that ET can act on oligodendrocytes, thereby causing demyelination. Moreover, it suggests that for certain cell types such as oligodendrocytes, ET can act without forming pores, namely through the activation of an undefined receptor-mediated pathway. PMID- 25287161 TI - Targeting the MYC and PI3K pathways eliminates leukemia-initiating cells in T cell acute lymphoblastic leukemia. AB - Disease relapse remains the major clinical challenge in treating T-cell acute lymphoblastic leukemia (T-ALL), particularly those with PTEN loss. We hypothesized that leukemia-initiating cells (LIC) are responsible for T-ALL development and treatment relapse. In this study, we used a genetically engineered mouse model of Pten(-/-) T-ALL with defined blast and LIC-enriched cell populations to demonstrate that LICs are responsible for therapeutic resistance. Unlike acute and chronic myelogenous leukemia, LICs in T-ALL were actively cycling, were distinct biologically, and responded differently to targeted therapies in comparison with their differentiated blast cell progeny. Notably, we found that T-ALL LICs could be eliminated by cotargeting the deregulated pathways driven by PI3K and Myc, which are altered commonly in human T-ALL and are associated with LIC formation. Our findings define critical events that may be targeted to eliminate LICs in T-ALL as a new strategy to treat the most aggressive relapsed forms of this disease. PMID- 25287163 TI - Sodium Picosulfate with Magnesium Citrate (SPMC) Plus Laxative Is a Good Alternative to Conventional Large Volume Polyethylene Glycol in Bowel Preparation: A Multicenter Randomized Single-Blinded Trial. AB - BACKGROUND/AIMS: We investigated whether sodium picosulfate with magnesium citrate (SPMC) plus bisacodyl compares favorably with conventional polyethylene glycol (PEG) with respect to bowel cleansing adequacy, compliance, and safety. METHODS: We performed a multicenter, prospective, single-blinded study in outpatients undergoing daytime colonoscopies. Patients were randomized into a split preparation SPMC/bisacodyl group and a conventional split PEG group. We compared preparation adequacy using the Boston bowel preparation scale (BBPS), ease of use using a modified Likert scale (LS), compliance/satisfaction level using a visual analogue scale (VAS), and safety by monitoring adverse events during the colonoscopy between the two groups. RESULTS: A total of 365 patients were evaluated by intention to treat (ITT) analysis, and 319 were evaluated by per protocol (PP) population analysis (153 for SPMC/bisacodyl, 166 for PEG). The mean total BBPS score was not different between the two groups in both the ITT and PP analyses (p>0.05). The mean VAS score for satisfaction and LS score for the ease of use were higher in the SPMC/bisacodyl group (p<0.001). The adverse event rate was lower in the SPMC/bisacodyl group than in the PEG group (p<0.05). CONCLUSIONS: The SPMC/bisacodyl treatment was comparable to conventional PEG with respect to bowel preparation adequacy and superior with respect to compliance, satisfaction, and safety. PMID- 25287164 TI - New technique of endoscopic sphincterotomy with iso-tome(r) to incise the distal papillary roof in patients with choledocholiths and choledochoduodenal fistula. AB - BACKGROUND/AIMS: It is sometimes difficult to incise the dis-tal papillary roof (PR) completely in patients with choledocho-liths and choledochoduodenal fistula (CDF). The Iso-Tome(r) (MTW-Endoskopie W. Haag KG), which is helpful in prevent ing electrical leakage, has good orientation capabilities and can be easily placed at the orifice of the CDF or ampulla of Vater (AV). We aimed to evaluate the efficacy of endoscopic sphincterotomy (ES) with the Iso-Tome(r) for cutting the distal PR. METHODS: Between May 2003 and July 2012, 35 pa-tients were analyzed retrospectively. The distal PR was cut downward and/or upward using the Iso-tome(r) until the pink intrapapillary mucosa was fully exposed. Downward incisions were performed from the opening of the CDF to the orifice of the AV; upward incisions were performed in reverse. RESULTS: Spontaneous or artificial CDF occurred in four and 31 pa-tients, respectively. The technical and therapeutic success rates were 94.3% (33/35) and 94.3% (33/35), respectively. There was no case of electrical damage to the pink intrapap-illary mucosa. Adverse events occurred in 2.9% (1/35; 1, mild bleeding) of patients. CONCLUSIONS: The new technique of ES with the Iso-tome(r) is feasible and useful for effectively incising the distal PR in patients with CDF and choledocho-liths. (Gut Liver, 2015;9231-238). PMID- 25287165 TI - Screening Colonoscopy among Uninsured and Underinsured Urban Minorities. AB - BACKGROUND/AIMS: Uninsured individuals have lower rates of screening colonoscopy (SC), and little is known regarding the pathology results obtained when they undergo colonoscopies. Since 2004, we have participated in a program that offers SC to uninsured New Yorkers; herein, we report our findings. METHODS: Uninsured, average-risk patients who were at least 50 years of age underwent SC at our institution between April 2004 and June 2011. We analyzed polyp pathology, location, size, incidence of adenomas, and incidence of adenomas with advanced pathology (AAP) with respect to ethnicity, gender, and age. RESULTS: Out of 493 referrals, 222 patients completed the colonoscopies. Polyps were identified in 21.2% of all patients; 14% had adenomas, and 4.5% had AAP. The rates of adenomas among African-Americans, Hispanics, and Whites were 24.3%, 12.1%, and 11.6%, respectively, and the corresponding rates of AAP were 10.8%, 3.5%, and 2.3%. Differences in the polyp type, location, and AAP did not reach statistical significance with respect to ethnicity or gender. Patients aged 60 and older were found to have a higher rate of advanced adenomas compared with younger patients (8.6% vs. 2.6%, p=0.047). CONCLUSIONS: Further efforts to fund screening colonoscopies for uninsured individuals will likely result in the identification of advanced lesions of the colon before they progress to colorectal cancer. PMID- 25287166 TI - The Effects of Broccoli Sprout Extract Containing Sulforaphane on Lipid Peroxidation and Helicobacter pylori Infection in the Gastric Mucosa. AB - BACKGROUND/AIMS: The aims of this study were to investigate whether a broccoli sprout extract containing sulforaphane (BSES) inhibited the Helicobacter pylori infection density and exerted an antioxidative effect on gastric mucosal damage. METHODS: The enrolled subjects were randomized in a double-blinded manner into three groups. Finally, 33 H. pylori (+) BSES treatment subjects (group A), 28 H. pylori (+) placebo subjects (group B), and 28 H. pylori (-) BSES treatment subjects (group C) were studied. H. pylori infection density was indirectly quantified by a (13)C-urea breath test (UBT), and the ammonia concentration in gastric juice aspirates was measured through gastroscopic examination. Malondialdehyde (MDA), an oxidative damage biomarker, and reduced glutathione (GSH), an antioxidant biomarker, were measured in the gastric mucosa by an enzyme linked immunosorbent assay. RESULTS: BSES treatment did not significantly affect the UBT values or ammonia concentration in group A (p=0.634 and p=0.505, respectively). BSES treatment did significantly reduce mucosal MDA concentrations in group A (p<0.05) and group C (p<0.001), whereas the gastric mucosal GSH concentrations did not differ before and after treatment in any of the groups. CONCLUSIONS: BSES did not inhibit the H. pylori infection density. However, BSES prevented lipid peroxidation in the gastric mucosa and may play a cytoprotective role in H. pylori-induced gastritis. PMID- 25287167 TI - A polymorphism in the microsomal triglyceride transfer protein can predict the response to antiviral therapy in Egyptian patients with chronic hepatitis C virus genotype 4 infection. AB - BACKGROUND/AIMS: A polymorphism in the microsomal triglyceride transfer protein (MTP) is associated with hepatic fibrosis, and carriers showed higher levels of steatosis, higher levels of hepatitis C virus (HCV) RNA and advanced fibrosis. The aim of this study was to study MTP expression pattern in HCV patients and impact of the MTP polymorphism on the response to antiviral therapy. METHODS: One hundred consecutive naive HCV genotype 4 patients were recruited to receive antiviral therapy, and 40 control subjects were also recruited. Demographic, laboratory, and histopathology data were collected. DNA was isolated, and the samples were subjected to polymerase chain reaction analysis and genotyping for MTP by restriction fragment length polymorphism analysis. RESULTS: Patients and controls were age- and sex-matched (male/female, 56/44, age, 39.2+/-7.8 years for patients with HCV; male/female, 18/22, age, 38.1+/-8.1 years for controls). MTP single nucleotide polymorphisms (SNPs) (GG, GT, TT) and alleles (G, T) in the patients versus the controls were 70%, 21%, 9% & 80.5%, 19.5% versus 10%, 87.5%, 2.5% & 53.8%, 46.3%, respectively (p=0.0001). The sustained viral response (SVR) of the patients was 60%. SNPs in MTP genotypes (GG, GT, and TT) and alleles (G and T) in the responders and nonresponders were 71.7%, 25%, 3.3% & 84.2%, 15.8% versus 67.5%, 15%, 17.5% & 75%, 25% (p=0.038 and p=0.109, respectively). A multivariate analysis showed that the GT genotype was an independent predictor of SVR (area under the curve 90% and p=0.0001). CONCLUSIONS: MTP could be a new predictor for SVR to antiviral therapy in patients with HCV genotype 4 infection. PMID- 25287168 TI - Lipase Supplementation before a High-Fat Meal Reduces Perceptions of Fullness in Healthy Subjects. AB - BACKGROUND/AIMS: Postprandial symptoms of fullness and abdominal discomfort are common after fatty meals. Gastric lipases hydrolyze 10% to 20% of dietary triglycerides during the stomach trituration period of digestion. The aim of this study was to evaluate the effects of acid-resistant lipase on upper gastrointestinal symptoms, including fullness and bloating, as well as on gastric myoelectrical activity after healthy subjects ingested a high-fat, liquid meal. METHODS: This study utilized a double-blind, placebo-controlled, crossover design with 16 healthy volunteers who ingested either a capsule containing 280 mg of acid-resistant lipase or a placebo immediately before a fatty meal (355 calories, 55% fat). Participants rated their stomach fullness, bloating, and nausea before and at timed intervals for 60 minutes after the meal. Electrogastrograms were obtained to assess the gastric myoelectrical activity. RESULTS: Stomach fullness, bloating, and nausea increased significantly 10 minutes after ingestion of the fatty meal (p<0.01), whereas normal gastric myoelectrical activity decreased and tachygastria increased (p<0.05). With lipase, reports of stomach fullness were significantly lower compared with placebo (p<0.05), but no effect on gastric myoelectrical activity or other upper gastrointestinal symptoms was observed. CONCLUSIONS: The high-fat meal induced transient fullness, bloating, nausea, and tachygastria in healthy individuals, consistent with postprandial distress syndrome. Acid-resistant lipase supplementation significantly decreased stomach fullness. PMID- 25287169 TI - High expression of aldo-keto reductase 1B10 is an independent predictor of favorable prognosis in patients with hepatocellular carcinoma. AB - BACKGROUND/AIMS: Upregulation of aldo-keto reductase 1B10 (AKR1B10) through the mitogenic activator protein-1 signaling pathway might promote hepatocarcinogenesis and tumor progression. The goal of this study was to evaluate the prognostic significance of AKR1B10 protein expression in patients with hepatocellular carcinoma after surgery. METHODS: A tissue microarray was used to detect the expression level of AKR1B10 protein in tumors from 255 patients with hepatocellular carcinoma who underwent curative hepatectomy. The impact of AKR1B10 expression on the survival of patients was analyzed. The median follow-up period was 119.8 months. RESULTS: High AKR1B10 protein expression was observed in 125 of the 255 patients with hepatocellular carcinoma (49.0%). High AKR1B10 expression was significantly associated with a lack of invasion of the major portal vein (p=0.022), a lack of intrahepatic metastasis (p=0.010), lower the American Joint Committee on Cancer T stage (p=0.016), lower the Barcelona Clinic Liver Cancer stage (p=0.006), and lower alpha-fetoprotein levels (p=0.020). High AKR1B10 expression was also correlated with a lack of early recurrence (p=0.022). Multivariate analyses of survival revealed that intrahepatic metastases and lower albumin levels were independent predictors of both shorter recurrence-free survival and shorter disease-specific survival. High AKR1B10 expression was an independent predictor of both longer recurrence-free survival (p=0.024) and longer disease-specific survival (p=0.046). CONCLUSIONS: High AKR1B10 protein expression might be useful as a marker of a favorable prognosis in patients with hepatocellular carcinoma after curative hepatectomy. PMID- 25287170 TI - Long-term outcomes and dynamics of mutants associated with lamivudine-adefovir rescue therapy in patients with lamivudine-resistant chronic hepatitis B. AB - BACKGROUND/AIMS: To investigate the association between the baseline profiles and dynamics of hepatitis B virus (HBV) DNA polymerase gene mutations and the long term virological response of lamivudine (LAM)-adefovir (ADV) combination therapy in patients with LAM-resistant chronic hepatitis B. METHODS: Seventy-five patients who received LAM-ADV combination therapy for more than 12 months were analyzed. Restriction fragment mass polymorphism assays were used to detect and monitor the dynamics of LAM- and ADV-resistant mutations. RESULTS: The median duration of LAMADV combination therapy was 26 months (range, 12 to 58 months). The baseline mutation profiles, rtM204I (p=0.992), rtM204I/V (p=0.177), and rtL180M (p=0.051), were not correlated with the cumulative virological response, and the baseline HBV DNA level (p=0.032) was the only independent predictive factor for cumulative virological response. Tests for LAM- and ADV-resistant mutations were performed in 12 suboptimal responders in weeks 48 and 96. The population of rtM204 mutants persisted or increased in 8 of 12 patients, and rtA181T mutants newly emerged as a minor population in four patients until 96 weeks. Nevertheless, the viral loads progressively decreased during rescue therapy, and these dynamics did not correlate with virological response. CONCLUSIONS: The baseline profile and dynamics of LAM-resistant mutations during LAM-ADV combination therapy are not associated with a virological response. PMID- 25287171 TI - Association between IPTA gene polymorphisms and hematological abnormalities in hepatitis C virus-infected patients receiving combination therapy. AB - BACKGROUND/AIMS: Hematological abnormalities during hepatitis C virus (HCV) combination therapy with pegylated interferon alpha and ribavirin often necessitate dose reduction. Variants of the ITPA gene have been reported to protect against anemia during the early stages of HCV combina-tion treatments but have also been associated with larger decreases in platelet counts. We aimed to identify the as-sociation between specific ITPA gene polymorphisms and hematological abnormalities in patients undergoing HCV combination therapy. METHODS: In this retrospective study, 175 patients treated with HCV combination therapy were enrolled at St. Martin De Porres Hospital in Taiwan between 2006 and 2012. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs1127354, rs6051702) were genotyped. We investigated the effect of ITPA gene variants on hematological abnormalities during the therapy. RESULTS: The ITPA rs1127354 minor variants were significantly associated with protection against anemia at week 4 (p=1.86*10(-6)) and with more severe decreases in platelet counts during HCV combination therapy. SNP rs6051702 was not associated with the hemoglobin decline to >3 g/dL at week 4 in our study (p=0.055). CONCLUSIONS: The ITPA SNP rs1127354 is a useful predictor of ribavirin-induced anemia in Taiwanese patients and may be related to more severe decreases in platelet counts during the early stage of HCV combination therapy. (Gut Liver, 2015;9214-223). PMID- 25287173 TI - Major depression is associated with cardiac autonomic dysregulation. PMID- 25287172 TI - Feasibility, efficacy, and predictive factors for the technical success of endoscopic nasogallbladder drainage: a prospective study. AB - BACKGROUND/AIMS: Several studies have shown the useful-ness of endoscopic nasogallbladder drainage (ENGBD) in patients with acute cholecystitis. However, the procedure is difficult, and factors that affect technical success have not yet been clarified. We conducted a prospective study to eval-uate the technical feasibility, efficacy, and predictive factors for the technical success of ENGBD in patients with acute cholecystitis. METHODS: All patients with moderate or severe acute cholecystitis who were enrolled underwent ENGBD between April 2009 and April 2011. Patients with surgically altered anatomy or pancreatobiliary malignancies were ex-cluded. The primary outcomes included technical success, clinical success, and complications. Factors that could affect the technical success were also examined. RESULTS: Of the 27 patients who underwent ENGBD during the study period, technical success was achieved in 21 (78%) and clinical improvement was achieved in 20 (95%). Early complications were encountered in four patients (15%). Gallbladder wall thickness (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.08 to 2.47) and age (OR, 1.16; 95% CI, 1.00 to 1.35) were effective predictors of technical failure. CONCLUSIONS: ENGBD was effective in resolving acute cholecystitis; however, this modality was technically challenging and had a limited suc-cess rate. Because of technical difficulties, ENGBD should be reserved for limited indications. (Gut Liver, 2015;9239-246). PMID- 25287174 TI - Computer-assisted cognitive remediation in adolescents with psychosis or at risk for psychosis: a 6-month follow-up. PMID- 25287175 TI - HTR2A gene polymorphisms and Inward and Outward Personal Meaning Organisations. PMID- 25287176 TI - Obstetric complications and neurological soft signs in male patients with schizophrenia. PMID- 25287177 TI - Impaired working memory and normal sustained attention in borderline personality disorder. PMID- 25287178 TI - Sleep quality in heroin addicts under methadone maintenance treatment. PMID- 25287179 TI - Risperidone and pulmonary embolism: a harmful association? Case series and review of the literature. PMID- 25287180 TI - Effects of combined treatment with clorgyline and selegiline on extracellular noradrenaline and serotonin levels. PMID- 25287181 TI - Graves' disease presenting with catatonia: a probable case of encephalopathy associated with autoimmune thyroid disease. PMID- 25287182 TI - Efficacy and tolerability of blonanserin in 48 patients with intractable schizophrenia. PMID- 25287183 TI - Plasma brain-derived neurotrophic factor level may contribute to the therapeutic response to eye movement desensitisation and reprocessing in complex post traumatic stress disorder: a pilot study. PMID- 25287184 TI - Oesophageal narrowing is common and frequently under-appreciated at endoscopy in patients with oesophageal eosinophilia. AB - BACKGROUND: Estimation of the prevalence of oesophageal narrowing and its clinical relevance in patients with oesophageal eosinophilia is probably underestimated by endoscopy. AIMS: To determine the sensitivity and specificity of oesophagogastroduodenoscopy (EGD) for oesophageal narrowing when compared to a structured oesophagram. METHODS: We conducted a retrospective chart review at Mayo Clinic, Rochester of adult patients with eosinophilic oesophageal infiltration of >15 eosinophils/hpf with symptomatic dysphagia, who underwent a structured barium oesophagram. The sensitivity and specificity of EGD were evaluated against the gold standard of oesophagram. Demographic and multiple clinical factors were evaluated as potential predictors of oesophageal narrowing. RESULTS: Of the 58 patients identified, 34 (58.6%) had a narrowed oesophageal diameter (<21 mm). EGD had poor sensitivity (14.7%, 95% CI 5.0-31.1%) for detection of a narrowed oesophagus and only modest specificity (79.2%, 95% CI 57.8-92.9%). Even at a cut-off diameter of EDmax <= 15 mm, EGD had a sensitivity of only 25.0% (95% CI 5.5-57.2%) for narrowed oesophagus. A history of >5 food impaction episodes, endoscopic rings, and female sex were the best predictors of oesophageal narrowing. 86% (6/7) patients with persistent dysphagia despite remission of histological eosinophilia responded to oesophageal dilation all of whom had radiological oesophageal narrowing and 71% of whom had no perceived oesophageal narrowing at EGD. CONCLUSIONS: Symptomatic oesophageal narrowing identified by barium oesophagography is common and under-recognised at endoscopy in patients with oesophageal eosinophilia. PMID- 25287185 TI - Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil. AB - Gaucher's disease (GD) is caused by a beta-glucocerebrosidase deficiency, leading to the accumulation of glucocerebroside in the reticuloendothelial system. The prevalence of GD in Tabuleiro do Norte (TN) (1:4000) is the highest in Brazil. The purpose of this study was to present evidence of consanguinity and founder effect for the G377S mutation (c.1246G>A) among GD patients in TN based on enzyme, molecular and genealogical studies. Between March 2009 and December 2010, 131 subjects at risk for GD (GC in dried blood <=2.19 nmol/h/ml) and 5 confirmed GD patients from the same community were submitted for molecular analysis to characterize the genetic profile of the population. Based on the enzymatic and molecular analysis, the subjects were classified into three categories: affected (n = 5), carrier (n = 20) and non-carrier (n = 111). All carriers were (G377S/wt). Affected subjects were homozygous (G377S/G377S). The identification of a single mutation in carriers and homozygotes from different generations, the history of the community and the genealogy study suggest that the high prevalence of GD in this population may be due to a combination of consanguinity and founder effect for the G377S mutation. PMID- 25287186 TI - Collagenous fibroma of the right coronary cusp: a case report and literature review. AB - Collagenous fibroma (desmoplastic fibroblastoma) is a rare benign tumor. This type of tumor mostly occurs in the subcutaneous tissues or skeletal muscle, and to the best of our knowledge, there is no unique case report of it occurring in the cardiac valves. This is the first description of collagenous fibroma in a human heart. PMID- 25287188 TI - Characterization and pollutant removal efficiency of biochar derived from baggase, bamboo and tyre. AB - Conversion of broad-spectrum organic waste into carbonaceous biochar has gained enormous interest in past few years. The present study aims to characterize feedstock (FS), i.e. bagasse (Bg), bamboo (Bm) and biochar (BC), i.e. baggase biochar (BBg), bamboo biochar (BBm) and tyre biochar (Ty). Significant changes in elemental composition, atomic ratio, proximate analyses, mineral content and heavy metal content were observed which was well supported by Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analysis. Impregnation with ferric hydroxide was done, and resultant modified biochars (MBC), i.e. iron impregnated baggase biochar (FeBBg), iron-impregnated bamboo biochar (FeBBm) and iron-impregnated tyre biochar (FeTy), along feedstock and biochar were used for PO4 (3-), Pb, Hg and Cu adsorption. In general, BBg, FeBBg, BBm, FeBBm, Ty and FeTy were found to adsorb PO4 (3-), Pb, Hg and Cu better than Bg and Bm, except in few cases. Results from adsorption experiments were fitted into Langmuir, Freundlich and Temkin models of isotherms and pseudo-first-order, pseudo-second order and Elovich models of kinetics. Result of batch study adsorption revealed that maximum adsorption of PO4 (3-), Pb, Hg and Cu was done by FeBBg (adsorption mechanism explained by Freundlich model), FeTy (Temkin model), Ty (Langmuir model) and BBm (Langmuir model) respectively. According to R (2) values, pseudo first-order reaction was well suited to PO4 (3-), Pb, Hg and Cu adsorption. The optimum pH for maximum adsorption was observed to be 7.4 for PO4 (3-), 5 for Cu and 6 for Pb and Hg respectively. PMID- 25287187 TI - Novel functions for the endocytic regulatory proteins MICAL-L1 and EHD1 in mitosis. AB - During interphase, recycling endosomes mediate the transport of internalized cargo back to the plasma membrane. However, in mitotic cells, recycling endosomes are essential for the completion of cytokinesis, the last phase of mitosis that promotes the physical separation the two daughter cells. Despite recent advances, our understanding of the molecular determinants that regulate recycling endosome dynamics during cytokinesis remains incomplete. We have previously demonstrated that Molecule Interacting with CasL Like-1 (MICAL-L1) and C-terminal Eps15 Homology Domain protein 1 (EHD1) coordinately regulate receptor transport from tubular recycling endosomes during interphase. However, their potential roles in controlling cytokinesis had not been addressed. In this study, we show that MICAL L1 and EHD1 regulate mitosis. Depletion of either protein resulted in increased numbers of bi-nucleated cells. We provide evidence that bi-nucleation in MICAL-L1 and EHD1-depleted cells is a consequence of impaired recycling endosome transport during late cytokinesis. However, depletion of MICAL-L1, but not EHD1, resulted in aberrant chromosome alignment and lagging chromosomes, suggesting an EHD1-independent function for MICAL-L1 earlier in mitosis. Moreover, we provide evidence that MICAL-L1 and EHD1 differentially influence microtubule dynamics during early and late mitosis. Collectively, our new data suggest several unanticipated roles for MICAL-L1 and EHD1 during the cell cycle. PMID- 25287189 TI - Colloid centrifugation of fresh stallion semen before cryopreservation decreased microorganism load of frozen-thawed semen without affecting seminal kinetics. AB - Freezability of equine semen may be influenced by microorganism population of semen. The objective of this study was to verify the effect of single-layer density gradient centrifugation (SLC) of fresh semen before cryopreservation on semen's microbial load (ML) and sperm cells kinetics after freezing-thawing. For that, one ejaculate was collected from 20 healthy stallions and split into control (C) samples (cryopreserved without previous SLC) and SLC samples (subjected to SLC). Semen cryopreservation was performed according to the same protocol in both groups. Microbial load of each microorganism species and total microbial load (TML) expressed in colony-forming units (CFU/mL) as well as frozen thawed sperm kinetics were assessed in both groups. Additional analysis of the TML was performed, subdividing the frozen-thawed samples in "suitable" (total motility >= 30%) and "unsuitable" (total motility < 30%) semen for freezing programs, and comparing the C and SLC groups within these subpopulations. After thawing, SLC samples had less (P < 0.05) TML (88.65 * 10(2) +/- 83.8 * 10(2) CFU/mL) than C samples (155.69 * 10(2) +/- 48.85 * 10(2) CFU/mL), mainly due to a reduction of Enterococcus spp. and Bacillus spp. A relationship between post-thaw motility and SLC effect on ML was noted, as only in samples with more than 30% total motility was ML reduced (P < 0.05) by SLC (from 51.33 * 10(2) +/- 33.26 * 10(2) CFU/mL to 26.68 * 10(2) +/- 12.39 * 10(2) CFU/mL in "suitable" frozen thawed semen vs. 240.90 * 10(2) +/- 498.20 * 10(2) to 139.30 * 10(2) +/- 290.30 * 10(2) CFU/mL in "unsuitable" frozen-thawed semen). The effect of SLC on kinetics of frozen-thawed sperm cells was negligible. PMID- 25287190 TI - Seroprevalence and risk factors of Toxoplasma gondii infection in sheep and goats slaughtered for human consumption in Central Ethiopia. AB - BACKGROUND: Toxoplasmosis is one of the most common parasitic zoonoses worldwide. Humans get infections with T. gondii after ingesting raw or undercooked meat or oocysts via contaminated soil, food or water; or congenitally by transplacental transmission of tachyzoites. The objectives of the present study were to estimate the seroprevalence and assess risk factors for T. gondii infection in sheep and goats slaughtered for human consumption in Central Ethiopia. METHODS: A cross sectional study was carried out from September, 2011 to November, 2012 in randomly selected small ruminants (n = 628). Direct Agglutination Test (DAT) was used to detect IgG antibodies specific to T. gondii. A titer of 1: 40 or 1: 4000 or both was considered indicative of T. gondii exposure. Logistic regression was used to assess potential risk factors. RESULTS: An overall seroprevalence of 17.68% (111/628) (95% confidence interval [CI]:14.77-20.89) was detected. Twenty percent (61/305) seroprevalence (95% CI: 15.6-624.94) in sheep was found with a reciprocal end titers of 60 in fourteen, 180 in three, 540 in two, 1620 in five, 6000 in nine, 18000 in six, 54000 in eleven and 162000 in eleven. Similarly, seroprevalence of 15.48% (50/323) (95% CI:11.71-19.89) in goats was found with a reciprocal end titers of 60 in eighteen, 180 in five, 540 in three, 1620 in seven, 6000 in four, 18,000 in four, 54,000 in five and 162,000 in four. Multivariable logistic regression analysis showed that the risk of T. gondii infection was significantly higher in adult sheep (adjusted Odd ratio (aOR) = 2.02, 95% CI: 1.10-3.70; P = 0.023) than in young sheep and in sheep sampled during the dry season (aOR = 4.19, 95% CI: 1.55-11.33, P = 0.005) than those sampled during wet season. CONCLUSIONS: The seroprevalence of T. gondii infection in small ruminants slaughtered for human consumption in Central Ethiopia is high. Age and season are significant predictors of seropositivity in sheep. The study highlighted the importance of meat of small ruminants as a potential source of infection for humans. Prevention of the spread of the disease through farm biosecurity measures is essential. PMID- 25287191 TI - Apoptotic effects of platelet factor VIII on megakaryopoiesis: implications for a modified human FVIII for platelet-based gene therapy. AB - BACKGROUND: Ectopically expressed B-domainless factor VIII in megakaryocytes is stored in alpha-granules, is effective in a number of murine hemostatic models, and is protected from circulating inhibitors. However, this platelet (p) FVIII has different temporal-spatial availability from plasma FVIII, with limited efficacy in other murine hemostatic models. OBJECTIVES AND METHODS: We sought to improve pFVIII hemostatic efficacy by expressing canine (c) FVIII, which has higher stability and activity than human (h) FVIII in FVIII(null) mice. RESULTS AND CONCLUSIONS: We found that pcFVIII was more effective than phFVIII at restoring hemostasis, but peak pcFVIII antigen levels were lower and were associated with greater megakaryocyte apoptosis than phFVIII. These new insights suggest that pFVIII gene therapy strategies should focus on enhancing activity rather than levels. We previously showed that modification of the PACE/furin cleavage site in hFVIII resulted in secretion of hFVIII primarily as a single chain molecule with increased biological activity. In megakaryocytes, this variant was expressed at the same level as phFVIII with a lentiviral bone marrow transplant approach to reconstitute FVIII(null) mice, but was more effective, resulting in near-normal hemostasis in the cremaster laser injury model. These studies may have implications for pFVIII gene therapy in hemophilia A. PMID- 25287192 TI - Hearing loss in the royal Norwegian Navy: a cross-sectional study. AB - OBJECTIVES: Prior studies have indicated a high prevalence of noise-induced hearing loss (NIHL) among Navy personnel; however, it is not clear whether this is caused by work on board. The present study aimed to assess the prevalence of hearing loss among Navy personnel in the Royal Norwegian Navy (RNoN), and to investigate whether there is an association between work on board RNoN vessels and occurrence of hearing loss. METHODS: Navy personnel currently working on board RNoN vessels were recruited to complete a questionnaire on noise exposure and health followed by pure tone audiometry. Hearing loss was defined as hearing threshold levels >=25 dB in either ear at the frequencies 3,000, 4,000 or 6,000 Hz. Hearing thresholds were adjusted for age and gender using ISO 7029. RESULTS: The prevalence of hearing loss among Navy personnel was 31.4 %. The work exposure variables: years of work in the Navy, years on vessel(s) in the Navy and years of sailing in the Navy were associated with reduced hearing after adjusting for age, gender and otitis as an adult. Among the work exposure variables, years of sailing in the Navy was the strongest predictor of reduced hearing, and significantly reduced hearing was found at the frequencies 1,000, 3,000 and 4,000 Hz. CONCLUSIONS: Our results indicate that time spent on board vessels in the RNoN is a predictor of reduced hearing. PMID- 25287193 TI - Plasmodesmata: channels for intercellular signaling during plant growth and development. AB - Plants have evolved strategies for short- and long-distance communication to coordinate plant development and to adapt to changing environmental conditions. Plasmodesmata (PD) are intercellular nanochannels that provide an effective pathway for both selective and nonselective movement of various molecules that function in diverse biological processes. Numerous non-cell-autonomous proteins (NCAP) and small RNAs have been identified that have crucial roles in cell fate determination and organ patterning during development. Both the density and aperture size of PD are developmentally regulated, allowing formation of spatial symplastic domains for establishment of tissue-specific developmental programs. The PD size exclusion limit (SEL) is controlled by reversible deposition of callose, as well as by some PD-associated proteins. Although a large number of PD associated proteins have been identified, many of their functions remain unknown. Despite the fact that PD are primarily membranous structures, surprisingly very little is known about their lipid composition. Thus, future studies in PD biology will provide deeper insights into the high-resolution structure and tightly regulated functions of PD and the evolution of PD-mediated cell-to-cell communication in plants. PMID- 25287194 TI - Plasmodesmata: channels for viruses on the move. AB - The symplastic communication network established by plasmodesmata (PD) and connected phloem provides an essential pathway for spatiotemporal intercellular signaling in plant development but is also exploited by viruses for moving their genomes between cells in order to infect plants systemically. Virus movement depends on virus-encoded movement proteins (MPs) that target PD and therefore represent important keys to the cellular mechanisms underlying the intercellular trafficking of viruses and other macromolecules. Viruses and their MPs have evolved different mechanisms for intracellular transport and interaction with PD. Some viruses move from cell to cell by interacting with cellular mechanisms that control the size exclusion limit of PD whereas other viruses alter the PD architecture through assembly of specialized transport structures within the channel. Some viruses move between cells in the form of assembled virus particles whereas other viruses may interact with nucleic acid transport mechanisms to move their genomes in a non-encapsidated form. Moreover, whereas several viruses rely on the secretory pathway to target PD, other viruses interact with the cortical endoplasmic reticulum and associated cytoskeleton to spread infection. This chapter provides an introduction into viruses and their role in studying the diverse cellular mechanisms involved in intercellular PD-mediated macromolecular trafficking. PMID- 25287195 TI - Imaging plasmodesmata with high-resolution scanning electron microscopy. AB - High-resolution scanning electron microscopy (HRSEM) is an effective tool to investigate the distribution of plasmodesmata within plant cell walls as well as to probe their complex, three-dimensional architecture. It is a useful alternative to traditional transmission electron microscopy (TEM) in which plasmodesmata are sectioned to reveal their internal substructures. Benefits of adopting an HRSEM approach to studies of plasmodesmata are that the specimen preparation methods are less complex and time consuming than for TEM, many plasmodesmata within a large region of tissue can be imaged in a single session, and three-dimensional information is readily available without the need for reconstructing TEM serial sections or employing transmission electron tomography, both of which are lengthy processes. Here we describe methods to prepare plant samples for HRSEM using pre- or postfixation extraction of cellular material in order to visualize plasmodesmata embedded within plant cell walls. PMID- 25287196 TI - Preparative methods for imaging plasmodesmata at super-resolution. AB - Much of our knowledge of plasmodesmata has come from the ability to visualize them. Light microscopy is a popular tool for exploring subcellular structures but is limited in its resolving power due to the diffractive properties of light. At 50 nm in diameter plasmodesmata are below this limit and so cannot be resolved. Super-resolution microscopy operates beyond the limits of conventional light microscopy affording a more detailed view. Although lacking the ultrastructural resolving power of the electron microscope (EM), super-resolution microscopy helps to bridge the gap between conventional light microscopy and EM.Here we present three preparative methods for studying plasmodesmata at super-resolution using 3D-structured illumination microscopy (3D-SIM). PMID- 25287197 TI - Isolation of plasmodesmata from Arabidopsis suspension culture cells. AB - Due to their position firmly anchored within the plant cell wall, plasmodesmata (PD) are notoriously difficult to isolate from plant tissue. Yet, getting access to isolated PD represents the most straightforward strategy for the identification of their molecular components. Proteomic and lipidomic analyses of such PD fractions have provided and will continue to provide critical information on the functional and structural elements that define these membranous nano pores. Here, we describe a two-step simple purification procedure that allows isolation of pure PD-derived membranes from Arabidopsis suspension cells. The first step of this procedure consists in isolating cell wall fragments containing intact PD while free of contamination from other cellular compartments. The second step relies on an enzymatic degradation of the wall matrix and the subsequent release of "free" PD. Isolated PD membranes provide a suitable starting material for the analysis of PD-associated proteins and lipids. PMID- 25287198 TI - Immunofluorescence detection of callose deposition around plasmodesmata sites. AB - Accumulation of callose (beta-1,3 glucans) at the plasmodesmata (PD) neck region dynamically regulates symplastic intercellular transport. Here we describe a 2-3 day immuno-labelling protocol to determine callose levels in the cell wall region at PD. The method relies on exposure of internal cell walls by hand-sectioning of the sample and digestion of the cell wall with enzymes in order to improve antibody penetration to deep tissue layers. By using this protocol, combined with high-resolution confocal imaging, we successfully detected PD-associated callose in Arabidopsis root apical meristem, vascular tissue, and developing lateral root primordia. PMID- 25287199 TI - Imaging callose at plasmodesmata using aniline blue: quantitative confocal microscopy. AB - Callose (beta-1,3-glucan) is both structural and functional component of plasmodesmata (Pd). The turnover of callose at Pd controls the cell-to-cell diffusion rate of molecules through Pd. An accurate assessment of changes in levels of Pd-associated callose has become a first-choice experimental approach in the research of intercellular communication in plants.Here we describe a detailed and easy-to-perform procedure for imaging and quantification of Pd associated callose using fixed plant tissue stained with aniline blue. We also introduce an automated image analysis protocol for non-biased quantification of callose levels at Pd from fluorescence images using ImageJ. Two experimental examples of Pd-callose quantification using the automated method are provided as well. PMID- 25287200 TI - Localization of fluorescently tagged protein to plasmodesmata by correlative light and electron microscopy. AB - Plasmodesmata (PD) are intercellular communication channels that form long, membrane-lined cylinders across cellular junctions. A fluorescent-tagging approach is most commonly used for an initial assessment to address whether a protein of interest may localize or associate with PD domain. However, owing to the dimension of PD being at nanoscale, PD-associated fluorescent signals are detected only as small spots scattered at the cell periphery, hence requiring additional confirmatory evidence. Immunogold labeling provides such information, but suitable antibodies are not always available and morphological preservation is often compromised with this approach. Here we describe an alternative approach using a correlative light and electron microscopy (CLEM) technique, which combines fluorescent imaging and transmission electron microscopy. By employing this method, a clear correlation between fluorescent speckles and the presence of individual or clusters of PD is achieved. PMID- 25287201 TI - Quantification of plant cell coupling with live-cell microscopy. AB - Movement of nutrients and signaling compounds from cell to cell is an essential process for plant growth and development. To understand processes such as carbon allocation, cell communication, and reaction to pathogen attack it is important to know a specific molecule's capacity to pass a specific cell wall interface. Transport through plasmodesmata, the cell wall channels that directly connect plant cells, is regulated not only by a fixed size exclusion limit, but also by physiological and pathological adaptation. The noninvasive approach described here offers the possibility of precisely determining the plasmodesmata-mediated cell wall permeability for small molecules in living cells.The method is based on photoactivation of the fluorescent tracer caged fluorescein. Non-fluorescent caged fluorescein is applied to a target tissue, where it is taken up passively into all cells. Imaged by confocal microscopy, loaded tracer is activated by UV illumination in a target cell and its spread to neighboring cells monitored. When combined with high-speed acquisition by resonant scanning or spinning disc confocal microscopy, the high signal-to-noise ratio of photoactivation allows collection of three-dimensional (3D) time series. These contain all necessary functional and anatomical data to measure cell coupling in complex tissues noninvasively. PMID- 25287202 TI - Drop-ANd-See: a simple, real-time, and noninvasive technique for assaying plasmodesmal permeability. AB - Gating of plasmodesmata (PD) is a highly dynamic cellular process spatiotemporally controlled by various physiological, developmental, and environmental conditions. Here, we describe a quantitative approach named Drop ANd-See (DANS), which allows for a real-time, in situ assessment of plasmodesmal permeability in an array of comparative studies. The power of the DANS assay lies in its simplicity: a membrane-permeable, non-fluorescent dye is loaded onto the adaxial epidermis of an intact leaf; the absorbed dye is cleaved by cellular esterases and become fluorescent yet membrane-impermeable; this symplasmic form then diffuses via PD through the mesophyll and into the abaxial epidermis, where the extent of fluorescent dye spreading can be imaged and quantified by confocal microscopy as a measure of cell-to-cell permeability. By employing this DANS assay, rapid changes in PD permeability upon chemical, biological, or environmental treatments can be easily analyzed. Furthermore, PD permeability as a phenotype or a trait of interest can be evaluated using various genetic backgrounds or mutants. We provide hereby an easy-to-follow visual guide of the DANS assay using Arabidopsis plants as an example along with a description of the step-by-step protocol. PMID- 25287203 TI - Mapping symplasmic fields at the shoot apical meristem using iontophoresis and membrane potential measurements. AB - Microinjections of fluorescent dyes have revealed that the shoot apical meristem (SAM) is dynamically partitioned into symplasmic fields (SFs), implying that plasmodesmata (Pd) are held shut at specific locations in the proliferating cellular matrix. The SFs are integrated into a coherent morphogenetic unit by exchange of morphogens and transcription factors via gating Pd between adjacent SFs, and by ligand-receptor interactions that operate across the extracellular space. We describe a method for the real-time mapping of SF in the SAM by iontophoresis and membrane potential measurements. PMID- 25287204 TI - Analysis of the conductivity of plasmodesmata by microinjection. AB - Pressure microinjection can be used to introduce fluorescent dyes and labeled macromolecules into single cells. The method allows measuring transport activity of macromolecules such as proteins and RNA molecules within and between cells. Routinely, plant mesophyll cells are injected with fluorescent dextran molecules of specific sizes to measure an increase of the size exclusion limit of plasmodesmata in the presence of a co-injected or expressed protein. The mobility of a macromolecule can also be addressed directly by injecting a recombinant protein that itself is labeled with fluorescent dye and following its transport to neighboring cells. This chapter describes a pressure microinjection protocol successfully applied to Nicotiana leaves. This protocol requires basic skills and experience in handling a microscope equipped with an imaging system, a micromanipulator, and a microinjection system attached to an upright microscope. Using this equipment, a trained person can inject approximately 10-20 mesophyll cells per hour. PMID- 25287205 TI - Investigating plasmodesmata genetics with virus-induced gene silencing and an agrobacterium-mediated GFP movement assay. AB - Plasmodesmata (PD) are channels that connect the cytoplasm of adjacent plant cells, permitting intercellular transport and communication. PD function and formation are essential to plant growth and development, but we still know very little about the genetic pathways regulating PD transport. Here, we present a method for assaying changes in the rate of PD transport following genetic manipulation. Gene expression in leaves is modified by virus-induced gene silencing. Seven to ten days after infection with Tobacco rattle virus carrying a silencing trigger, the gene(s) of interest is silenced in newly arising leaves. In these new leaves, individual cells are then transformed with Agrobacterium to express GFP, and the rate of GFP diffusion via PD is measured. By measuring GFP diffusion both within the epidermis and between the epidermis and mesophyll, the assay can be used to study the effects of silencing a gene(s) on PD transport in general, or transport through secondary PD specifically. Plant biologists working in several fields will find this assay useful, since PD transport impacts plant physiology, development, and defense. PMID- 25287206 TI - Probing plasmodesmata function with biochemical inhibitors. AB - To investigate plasmodesmata (PD) function, a useful technique is to monitor the effect on cell-to-cell transport of applying an inhibitor of a physiological process, protein, or other cell component of interest. Changes in PD transport can then be monitored in one of several ways, most commonly by measuring the cell to-cell movement of fluorescent tracer dyes or of free fluorescent proteins. Effects on PD structure can be detected in thin sections of embedded tissue observed using an electron microscope, most commonly a Transmission Electron Microscope (TEM). This chapter outlines commonly used inhibitors, methods for treating different tissues, how to detect altered cell-to-cell transport and PD structure, and important caveats. PMID- 25287207 TI - GAL4 transactivation-based assay for the detection of selective intercellular protein movement. AB - Several plant proteins function as intercellular messenger to specify cell fate and coordinate plant development. Such intercellular communication can be achieved by direct, selective, or nonselective (diffusion-based) trafficking through plasmodesmata (PD), the symplasmic membrane-lined nanochannels adjoining two cells. A trichome rescue trafficking assay was reported to allow the detection of protein movement in Arabidopsis leaf tissue using transgenic gene expression. Here, we provide a protocol to dissect the mode of intercellular protein movement in Arabidopsis root. This assay system involves a root ground tissue-specific GAL4/UAS transactivation expression system in combination with fluorescent reporter proteins. In this system, mCherry, a red fluorescent protein, can move cell to cell via diffusion, while mCherry-H2B is tightly cell autonomous. Thus, a protein fused to mCherry-H2B that can move out from the site of synthesis likely contains a selective trafficking signal to impart a cell-to cell gain-of-trafficking function to the cell-autonomous mCherry-H2B. This approach can be adapted to investigate the cell-to-cell trafficking properties of any protein of interest. PMID- 25287208 TI - Techniques for assessing the effects of pharmacological inhibitors on intercellular protein movement. AB - Intercellular protein movement is an important mechanism in plant development. Here we present an integrated protocol that utilizes an inducible system to block plasmodesmata-dependent movement and assessment of fluorescent recovery after photobleaching (FRAP) to identify compounds that influence intercellular protein movement. PMID- 25287209 TI - Probing protein targeting to plasmodesmata using fluorescence recovery after photo-bleaching. AB - Fluorescence recovery after photo-bleaching (FRAP) involves the irreversible bleaching of a fluorescent protein within a specific area of the cell using a high-intensity laser. The recovery of fluorescence represents the movement of new protein into this area and can therefore be used to investigate factors involved in this movement. Here we describe a FRAP method to investigate the effect of a range of pharmacological agents on the targeting of Tobacco mosaic virus movement protein to plasmodesmata. PMID- 25287210 TI - The tracking of intercellular small RNA movement. AB - RNA silencing is a regulatory mechanism that controls the expression of endogenous genes and exogenous molecular parasites such as viruses, transgenes, and transposable elements. The sequence specificity of these processes relies on small noncoding RNA (sRNA) molecules. In plants, one of the most fascinating aspects of RNA silencing is its mobile nature, in other words its ability to spread from the cell where it has been initiated to neighboring cells, through movement of sRNA molecules. To study this process, a key step is to directly monitor the spread of these nucleic acid species. Here we describe how this can be achieved through biolistic delivery of fluorescently labeled siRNA. PMID- 25287211 TI - Analysis of the role of myosins in targeting proteins to plasmodesmata. AB - Plasmodesmata (PD) are dynamic cell wall microchannels that facilitate the intercellular trafficking of RNA and protein macromolecules playing cell nonautonomous roles in the orchestration of plant development, growth, and plant defense. The trafficking of macromolecules and organelles within cells depends on cytoskeletal components and their associated motor proteins. Plant viruses evolved to hijack this transport system to move their infectious genomes to PD. Current efforts concentrate on dissecting the role of specific myosin motors in transporting plant or viral proteins to the channels. Here we describe a method that addresses the role of specific myosins by expression of myosin tails that cause the repression of myosin activity in a dominant-negative manner. As an example, we explain the use of myosin tails from Nicotiana benthamiana to address the role of N. benthamiana myosins in the targeting of PLASMODESMATA-LOCATED PROTEIN 1 (PDLP1) to PD. PMID- 25287212 TI - Pumilio-based RNA in vivo imaging. AB - Subcellular, sequence-specific detection of RNA in vivo is a powerful tool to study the macromolecular transport that occurs through plasmodesmata. The RNA binding domain of Pumilio proteins can be engineered to bind RNA sequences of choice and fused to fluorescent proteins for RNA imaging. This chapter describes the construction of a Pumilio-based imaging system to track the RNA of Tobacco mosaic virus in vivo, and practical aspects of RNA live-cell imaging. PMID- 25287213 TI - In vivo RNA labeling using MS2. AB - The trafficking and asymmetric distribution of cytoplasmic RNA is a fundamental process during development and signaling across phyla. Plants support the intercellular trafficking of RNA molecules such as gene transcripts, small RNAs, and viral RNA genomes by targeting these RNA molecules to plasmodesmata (PD). Intercellular transport of RNA molecules through PD has fundamental implications in the cell-to-cell and systemic signaling during plant development and in the systemic spread of viral disease. Recent advances in time-lapse microscopy allow researchers to approach dynamic biological processes at the molecular level in living cells and tissues. These advances include the ability to label RNA molecules in vivo and thus to monitor their distribution and trafficking. In a broadly used RNA labeling approach, the MS2 method, the RNA of interest is tagged with a specific stem-loop (SL) RNA sequence derived from the origin of assembly region of the bacteriophage MS2 genome that binds to the bacteriophage coat protein (CP) and which, if fused to a fluorescent protein, allows the visualization of the tagged RNA by fluorescence microscopy. Here we describe a protocol for the in vivo visualization of transiently expressed SL-tagged RNA and discuss key aspects to study RNA localization and trafficking to and through plasmodesmata in Nicotiana benthamiana plants. PMID- 25287214 TI - Effect of ponesimod, a selective S1P1 receptor modulator, on the QT interval in healthy individuals. AB - Ponesimod is an orally active selective sphingosine-1-phosphate receptor 1 modulator under investigation for the treatment of multiple sclerosis. This was a single-centre, double-blind, randomized, placebo- and positive-controlled parallel-group study investigating the effects of ponesimod on the QTc interval in healthy individuals. A nested cross-over comparison between moxifloxacin and placebo was included in the combined moxifloxacin/placebo treatment group. Subjects in group A received multiple doses of 10-100 mg ponesimod according to an uptitration regimen on days 2-23 and moxifloxacin-matching placebo on days 1 and 24. Subjects in group B received ponesimod-matching placebo on days 2-23 and were randomized to receive either a single dose of 400 mg moxifloxacin or matching placebo on days 1 and 24. The primary end-point was the baseline adjusted, placebo-corrected effect on the individually corrected QT interval (QTcI) on days 12 (after 5 days of 40 mg ponesimod) and 23 (after 5 days of 100 mg ponesimod). Ponesimod caused a mild QTcI prolongation with a largest effect of 6.9 ms (90% two-sided confidence interval (CI): 2.5-11.3) and 9.1 ms (90% CI: 4.1 14.0) for doses of 40 mg and 100 mg, respectively. A concentration-effect analysis confirmed the QTcI-prolonging effect of ponesimod with a shallow slope of 0.0053 ms per ng/mL. Using the concentration-effect analysis, the QTc prolongation caused by 20 mg ponesimod and the current highest therapeutic dose was predicted to be below the level of clinical concern (i.e. an upper bound of the two-sided 90% CI of >=10 ms). PMID- 25287215 TI - Job-related stress in psychiatric nurses in Japan caring for elderly patients with dementia. AB - OBJECTIVES: We investigated the specificity and structures of job-related stress in psychiatric dementia nurses (PDNs) caring for elderly patients with serious behavioral and psychological symptoms of dementia who required substantial assistance with activities of daily living, in order to obtain fundamental knowledge toward providing mental health care for these nurses. METHODS: Subjects were 244 nurses [63 PDNs and 181 other psychiatric nurses (OPNs)] RESULTS: Analysis of covariance to examine the specificity of job-related stress in PDNs revealed physical workload and work environment to be more significant stressors, and irritability and anxiety to be more significant stress reactions in PDNs than in OPNs. An examination of PDNs' job-related stress structures established in a structural equation model with two stress reactions confirmed as specific outcomes for PDNs revealed a significant positive influence of work environment on irritability; utilization of techniques for anxiety and physical workload influenced both stress reactions. CONCLUSIONS: Our findings highlight the importance of reducing physical workload and environment and establishing a structure for nursing techniques in psychiatric dementia wards to improve the mental health of PDNs. PMID- 25287216 TI - Advancing therapeutic discovery through phenotypic screening of the extracellular proteome using hydrodynamic intravascular injection. AB - OBJECTIVE: Although the human genome encodes ~ 20,000 protein-coding genes, only a very small fraction of these have been explored as potential targets for therapeutic development. The challenge of identifying and validating new protein targets has contributed to the significant reduction in the productivity of the pharmaceutical industry in the recent decade, highlighting the continued need to find new therapeutic targets. RESEARCH DESIGN AND METHODS: The traditional methods to discover new targets are expensive, low throughput and time consuming, usually taking years to validate or invalidate a target. To address these limitations, as a proof of concept, we explored the hydrodynamic tail vein (HTV) injection as a gene delivery method for direct in vivo phenotypic screening of novel secreted factor targets for Type II diabetes therapeutics. RESULTS: High levels and sustained expression of target proteins were observed in diabetic mouse models tested, allowing us to identify multiple novel hormones that may regulate glucose metabolism. CONCLUSIONS: These results suggest that HTV is a low cost, high-throughput method for direct in vivo phenotypic drug screening in metabolic disorders and could be applicable to many other disease areas as well. This method if combined with other approaches such as human genetic studies could provide a significant value to future drug discovery. PMID- 25287218 TI - Idiopathic inflammatory myopathies evaluated by near-infrared spectroscopy. AB - INTRODUCTION: In this study we evaluated whether near-infrared spectroscopy (NIRS) can determine the metabolic patterns of dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). METHODS: We enrolled 10 consecutive patients affected by DM, 11 by PM, and 9 by IBM, and 3 groups of healthy controls. We measured changes in oxygenated and deoxygenated hemoglobin/myoglobin in the extensor digitorum communis during venous and arterial occlusion testing (VOT) and post-occlusion hyperemia. RESULTS: DM showed lower oxygen consumption (P=0.04) during VOT and reduced oxygen supply after VOT (P=0.04) compared with controls. IBM patients showed higher oxygen consumption (P=0.04) during VOT and higher oxygen supply after VOT (P=0.03) than controls. DM patients showed reduced oxidative metabolism compared with IBM (P=0.001), and an impaired ability to supply oxygen compared with PM (P=0.03) and IBM (P=0.001) patients. CONCLUSIONS: NIRS differentiated samples of DM and IBM patients from controls, but it could not distinguish PM patients from a sample of healthy subjects. PMID- 25287217 TI - Disrupted structural connectome is associated with both psychometric and real world neuropsychological impairment in diffuse traumatic brain injury. AB - Traumatic brain injury (TBI) is likely to disrupt structural network properties due to diffuse white matter pathology. The present study aimed to detect alterations in structural network topology in TBI and relate them to cognitive and real-world behavioral impairment. Twenty-two people with moderate to severe TBI with mostly diffuse pathology and 18 demographically matched healthy controls were included in the final analysis. Graph theoretical network analysis was applied to diffusion tensor imaging (DTI) data to characterize structural connectivity in both groups. Neuropsychological functions were assessed by a battery of psychometric tests and the Frontal Systems Behavior Scale (FrSBe). Local connection-wise analysis demonstrated reduced structural connectivity in TBI arising from subcortical areas including thalamus, caudate, and hippocampus. Global network metrics revealed that shortest path length in participants with TBI was longer compared to controls, and that this reduced network efficiency was associated with worse performance in executive function and verbal learning. The shortest path length measure was also correlated with family-reported FrSBe scores. These findings support the notion that the diffuse form of neuropathology caused by TBI results in alterations in structural connectivity that contribute to cognitive and real-world behavioral impairment. PMID- 25287219 TI - Speckle tracking and myocardial tissue imaging in infant of diabetic mother with gestational and pregestational diabetes. AB - The aim of this study was to evaluate the myocardial changes in infants of diabetic mother either with gestational or pregestational diabetes and its relation to maternal diabetic control. The study included 45 infants of diabetic mother (IDMs) and 45 healthy newborn as a control group. IDMs were then categorized into 2 subgroups: twenty infants of mother with pregestational diabetes and twenty-five infants of mothers with gestational diabetes. The studied groups underwent measurement of the maternal and neonatal glycated Hb % (HbA1c), conventional echocardiography, tissue Doppler imaging (TDI) and two dimensional speckle tracking imaging (STI). The weight, the rate of complications, and the rate of cesarean section were significantly higher in the IDMs group than in the control group. Significant positive correlation was present between the levels of HbA1c of IDMs and HbA1c of their mothers (P < 0.05). A significant deterioration of both systolic and diastolic functions measured by both conventional echocardiography and TDI was present in IDMs with both pre-gestational and gestational diabetes compared with the control group. Also, the septal/posterior wall ratio (SW/PW) was significantly higher in pregestational (1.86 +/- 0.3) and gestational (2 +/- 0.4) groups than in the control group (1 +/- 0.06). Two-dimensional STI showed that the cardiac torsion was significantly impaired in pre-gestational (9.66 +/- 2.5) and gestational (8.66 +/- 3.9) groups when compared with the control group (5.4 +/- 2.4) [P < 0.0001]. It also showed that the global strain was significantly impaired in pre gestational (-10.4 +/- 3.2) and gestational (-13.1 +/- 4.7) groups when compared with the control group (-19 +/- 2) [P < 0.0001]. However, no significant differences were present among the two patients' subgroups in echocardiographic data except for a significant decrease of E'/A' ratio and S wave at tricuspid annulus derived by TDI and impaired global strain derived by STI in infants of mothers with pre-gestational DM than those with gestational DM [P = 0.02]. SW/PW and cardiac torsion were significantly higher in infant of diabetic mother than the normal newborn and on the contrary systolic function and global strain were significantly lower in IDMs especially in infants of mother with pre-gestational diabetes. All the previous TDI findings did not show any significant correlation to neither maternal nor fetal HbA1c. Also, there was no significant correlation between cardiac torsion and the rest of TDI data neither in IDMs group nor in the control group. TDI and two-dimensional STI were efficient and sensitive tools able to early detect cardiac dysfunction in IDMs even in the absence of morphologic cardiac changes. PMID- 25287220 TI - Health-related quality of life assessment in children followed in a cardiomyopathy clinic. AB - As our ability to diagnosis cardiomyopathy matures and genetic testing becomes more widespread, there has been an increase in the number of children followed for cardiomyopathy. The purpose of this study was to compare health-related quality of life (HRQoL) between children with cardiomyopathy and healthy controls and with children seen in clinic who are at risk for the development of cardiomyopathy. Patient and parent-proxy perspectives were obtained using the Pediatric Quality of Life Inventory (PedsQL(TM)) 4.0 Core Scales (ages 2-18 years) and the disease-specific Cardiac Module. Cardiomyopathy physicians' perceptions of the impact of cardiomyopathy on the functional status of the patients were collected. In addition, data regarding disease-specific medical and socioeconomic information were collected from chart review and parental report. The questionnaires were completed by 100 parent-proxies and 71 children. The PedsQL(TM) scores reported by children and their parent-proxies were compared to scores reported by pediatric norms. Compared to healthy controls, patients followed in a pediatric cardiomyopathy clinic scored lower in Total score when compared to pediatric norms (80.7 vs 86.4, p = 0.002). Interestingly, children with a family history of cardiomyopathy who are at risk for developing the disease scored similar to those children with a diagnosis of cardiomyopathy. Parental and patients perceptions were discrepant when compared, which may deter appropriate referral to behavioral health services. These results should encourage cardiomyopathy clinics to screen all patients for HRQoL impairments and to have behavioral services available to assist these children. PMID- 25287221 TI - Halogenated persistent organic pollutants in relation to trophic level in deep sea fish. AB - The bioaccumulation of persistent organic pollutants (POPs) in deep sea fish from the Rockall fishing area was investigated. Predator and prey species were analysed for stable isotopes, fatty acids, polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). delta(15)N indicated that black scabbard was at the highest trophic level and the prey the lowest. The fatty acid signatures indicated that black scabbard and black dogfish fed at a higher trophic level compared to the roundnose grenadier. PCBs and PBDEs were detected in the liver of all three predator species. PCB concentrations were significantly higher in the roundnose grenadier, possibly due to their longer life span. PCB concentrations were compared to OSPAR assessment criteria, concentrations were above background but below Environmental Assessment Criteria for all but one congener. PCB concentrations were below food safety levels in the flesh, but exceeded the limit for liver in the roundnose grenadier and black dogfish. PMID- 25287222 TI - Towards improving the representation of beaching in oil spill models: a case study. AB - Oil-shoreline interaction (or "beaching" as commonly referred to in literature) is an issue of major concern in oil spill modeling, due to the significant environmental, social and economic importance of coastal areas. The present work studies the improvement of the representation of beaching brought by the introduction of the Oil Holding Capacity approach to estimate oil concentration on coast, along with new approaches for coast type assignment to shoreline segments and the calculation of permanent oil attachment to the coast. The above were tested for the Lebanon oil spill of 2006, using a modified version of the open-source oil spill model MEDSLIK-II. The modified model results were found to be in good agreement with field observations for the specific case study, and their comparison with the original model results denote the significant improvement in the fate of beached oil brought by the proposed changes. PMID- 25287223 TI - The effect of suspended sediment on fertilization success in the urchin Evechinus chloroticus: analysis of experimental data using hierarchical Bayesian methods. AB - Terrestrial sediments are a significant stressor on coastal ecosystems, with both suspended and deposited sediment having adverse effects on aquatic organisms. However, information on the effect of suspended sediments on fertilization success for urchin species is lacking. Using sediment levels similar to those encountered in situ, a controlled experiment was conducted to test whether suspended sediment affects fertilization success in the urchin Evechinus chloroticus. Analyses used generalized linear mixed models (GLMMs) and hierarchical Bayesian (HB) regression. Both approaches showed a significant decrease in fertilization success with increased suspended sediment levels. Uncertainties in estimates were narrower for HB models, suggesting that this approach has advantages over GLMMs for sparse data problems sometimes encountered in laboratory experiments. Given future global change scenarios, this work is important for predicting the effects of stressors such as sedimentation that may ultimately impact marine populations. PMID- 25287224 TI - Mercury in the food chain of the Lagoon of Venice, Italy. AB - Sediments and biota samples were collected in a restricted area of the Lagoon of Venice and analysed for total mercury, monomethyl mercury (MMHg), and nitrogen and carbon isotopes. Results were used to examine mercury biomagnification in a complex food chain. Sedimentary organic matter (SOM) proved to be a major source of nutrients and mercury to primary consumers. Contrary to inorganic mercury, MMHg was strongly biomagnified along the food chain, although the lognormal relationship between MMHg and delta(15)N was less constrained than generally reported from lakes or coastal marine ecosystems. The relationship improved when logMMHg concentrations were plotted against trophic positions derived from baseline delta(15)N estimate for primary consumers. From the regression slope a mean MMHg trophic magnification factor of 10 was obtained. Filter-feeding benthic bivalves accumulated more MMHg than other primary consumers and were probably important in MMHg transfer from sediments to higher levels of the food chain. PMID- 25287225 TI - Monitoring of genotoxicity in marine zooplankton induced by toxic metals in Ennore estuary, Southeast coast of India. AB - The present study provides preliminary in-situ data on genetic integrity of marine zooplankton. Paracalanus parvus, Oithona rigida and Euterpina acutifrons were collected during four different seasons (summer, pre-monsoon, monsoon and post-monsoon) from 2011 to 2012 in Ennore and Kovalum estuaries. DNA damage levels in different zooplankton were analyzed by comet assay and were correlated with different environmental stressors. Spatial and temporal variations in DNA damage was observed in all the species. Zooplankton from Ennore estuary showed significantly lower genetic integrity. Particulate, sediment, and zooplankton fractions of Pb, Ni, Cu, Cr and Co were associated with high DNA damage during the period of lowest pH, salinity and dissolved oxygen. Zn and Cd showed lower genotoxic impact than the other metals. Feeding modes strongly influenced the genetic integrity in the zooplankton species studied. These results support the use of comet assay as a tool in effectively monitoring genotoxicity in marine plankton communities. PMID- 25287226 TI - Long-term seafloor monitoring at an open ocean aquaculture site in the western Gulf of Maine, USA: development of an adaptive protocol. AB - The seafloor at an open ocean finfish aquaculture facility in the western Gulf of Maine, USA was monitored from 1999 to 2008 by sampling sites inside a predicted impact area modeled by oceanographic conditions and fecal and food settling characteristics, and nearby reference sites. Univariate and multivariate analyses of benthic community measures from box core samples indicated minimal or no significant differences between impact and reference areas. These findings resulted in development of an adaptive monitoring protocol involving initial low cost methods that required more intensive and costly efforts only when negative impacts were initially indicated. The continued growth of marine aquaculture is dependent on further development of farming methods that minimize negative environmental impacts, as well as effective monitoring protocols. Adaptive monitoring protocols, such as the one described herein, coupled with mathematical modeling approaches, have the potential to provide effective protection of the environment while minimize monitoring effort and costs. PMID- 25287227 TI - Suffer the little children...! PMID- 25287228 TI - Selective transport of microplastics and mesoplastics by drifting in coastal waters. AB - The quantity and size distributions of small plastic fragments in the Seto Inland Sea, Japan were investigated using field surveys and a numerical particle tracking model. The model was used to interpret the distributions of small plastic fragments and the possible transport processes in coastal waters. Of note, the size and quantity of mesoplastics (approximately >5mm) gradually increased close to the coast irrespective of the existence of river mouths, which probably act as a major source of anthropogenic marine debris. Additionally, microplastics were more dominant as we moved further offshore. The numerical model reproduced the near-shore trapping of mesoplastics, suggesting that mesoplastics are selectively conveyed onshore by a combination of Stokes drift and terminal velocity, dependent on fragment sizes. It is suggested that mesoplastics washed ashore on beaches degrade into microplastics, and that the microplastics, which are free from near-shore trapping, are thereafter spread offshore in coastal waters. PMID- 25287229 TI - Indole derivatives inhibited the formation of bacterial biofilm and modulated Ca2+ efflux in diatom. AB - Marine biofouling is a serious environmental problem worldwide. As an effort to find environmental friendly antifoulants, indole derivatives were determined for their activities to inhibit the growth of bacteria and diatom. The minimum inhibitory concentrations (MICs) of indole derivatives against bacteria were very low, especially for 6-chloroindole. It was proved that 6-chloroindole obviously inhibited the growth of bacteria, interfered with the formation of bacterial biofilm, destroyed bacterial cell morphology and also inhibited the growth of diatom Cylindrotheca sp. as well. By using noninvasive micro-test technique (NMT), 6-chloroindole triggered algal cellular Ca(2+) efflux. The highest value was 72.03 pmol cm(-2)s(-1), 10.6 times of the control group. The present studies indicated that indole derivatives might have the potential to be new antifouling agents because of their excellent antibacterial and anti-algal activities. At the same time, Ca(2+) efflux might be one of the mechanisms that indole derivatives inhibited the growth of diatom. PMID- 25287230 TI - Effect of TiO2 microbead pore size on the performance of DSSCs with a cobalt based electrolyte. AB - Mesoporous TiO2 microbeads with well-defined intra-bead pore sizes (14 nm, 23 nm or 33 nm) were employed to investigate the effect of pore size on the performance of dye-sensitized solar cells constructed with an organic dye (MK2) and a [Co(bpy)3](2+/3+) (bpy = 2,2'-bipyridine)-based electrolyte. The TiCl4 post treatment and film thickness were optimized for the TiO2 electrodes made from beads with 33 nm intra-bead pores, and an overall energy conversion efficiency of 8.5% was achieved for a device with a 6.5 MUm thick TiO2 film treated with a 20 mM TiCl4 solution. Although beads with larger pores had a smaller specific surface area, devices derived from these beads produced better photovoltaic performance. This is attributed to the improved diffusion of cobalt species inside the working electrode, as evidenced by a higher electron lifetime and dye regeneration rate recorded on these solar cells. PMID- 25287231 TI - Low-volume cleansing regimens for colon capsule endoscopy: the answer to the million-dollar question? PMID- 25287232 TI - Effectiveness of entecavir treatment and predictive factors for virologic response. AB - INTRODUCTION: Entecavir (ETV) is a potent inhibitor of hepatitis B virus (HBV) replication. In patients adherent to treatment, virologic remission rates of > 95 % can be maintained with entecavir at 3-5 years. AIM AND METHODS: A cohort study was performed, including all subjects who received ETV for chronic hepatitis B, in the South- Eastern Romania. We assessed viral response, HBeAg loss and seroconversion, HBsAg loss and seroconversion, biochemical response. Comparison of categorical data was performed by Chi2-test or Fisher's exact where applicable. RESULTS: Data from 533 patients were available: predominantly males (64 %), 82.6 % nucleotide naive, 23.1 % HBe-Ag positive, 78.2 % with elevated ALT, 8 % with cirrhosis. The median follow up was 24 months (range 12-48 months). Rate of undetectable HBV DNA increased constantly from year 1 to 3, reaching 91.2 %. Positive predictive factors for virologic response were low score of fibrosis (p-0.006), low level of HBV DNA (p-0.003), while negative predictive factors were: HBe antigen positive status (p-value < 0.001), prior IFN therapy (p 0.015). Virologic rebound was found in 7.8 % (breakthrough in 0.8 %). Rate of HBe Ag loss increases with the therapy duration, reaching 47.83 % in year 3,with two positive predictive factors: Male sex (p = 0.007), and undetectable HBV DNA at 24 weeks (p = 0.002). The percentage of HBs Ag loss was 1.31 %. CONCLUSIONS: ETV maintained and even increased the high initial response rate (from 78 % to 91.2 %). Low score of fibrosis, low level of HBV DNA, HBe antigen negative status, absence of prior interferon therapy predict a good virologic response. Virologic rebound was found in a higher rate in our population, due probably to a poor drug compliance. Lamivudine-resistant patients usually respond well to ETV, but 15.62 % are non responders, suspect of Entecavir resistance. PMID- 25287233 TI - Preparations for colon capsule endoscopy. Prospective and randomized comparative study between two preparations for colon capsule endoscopy: PEG 2 liters + ascorbic acid versus PEG 4 liters. AB - INTRODUCTION: PillCam(c) colon capsule endoscopy (CCE) enables the study of colonic diseases in a safe and non-invasive way, although there are aspects that need to be improved. Current methods of bowel preparation lead to discordant rates of adequate cleansing and CCE excretion. AIMS: To compare the efficacy of colon cleansing using two different regimes (2L PEG plus ascorbic acid versus 4L PEG alone) for PillCam Colon (C2) capsule endoscopy. METHODS: Fifty eight patients included in this prospective study and randomized to: Group A, PEG plus ascorbic acid regimen (n = 28, 12 F/16 M) or group B, PEG alone regimen (n = 30, 14 F/16 M). The degree of cleansing was categorized into "excellent-good" or "fair-poor", according to Leighton's recently published preparation scale. CCE excretion rate and colon cleansing were assessed. Patients underwent to PillCam colon of second generation (C2). RESULTS: Cleansing was considered to be excellent-good in 78 % of cases in group A and in 64 % of cases in group B, with no significant difference between the groups (p = 0.252). Nevertheless, when the grade of cleansing was analyzed in segments, a significant difference was found in the cecum and transverse colon. No differences were observed in the bubble effect between preparations. The excretion rate was 93 % in group A versus 70 % in group B (p = 0.043). CONCLUSIONS: These results suggest that a 2L PEG plus ascorbic acid regimen is at least as effective as a 4L PEG regimen. This regimen may be considered an effective alternative which would improve compliance because a smaller volume is required. PMID- 25287234 TI - Prevalence and persistence of nausea and vomiting along the pregnancy. AB - BACKGROUND/AIMS: Nausea and vomiting of pregnancy (NVP) impact in the pregnant woman's quality of life, especially when are persistent or severe. The objective is to estimate the prevalence and factors associated with the persistence of NVP in each trimester of pregnancy. METHODS: We studied a cohort of 263 pregnant women with gestational age < 12 weeks. Data were collected using the Gastro- Esophageal Reflux Questionnaire validated for use in the Spanish population. Data were collected through telephone interviews at the end of each trimester of pregnancy. The main variable was the presence of NVP in each trimester and their persistence along the pregnancy. RESULTS: The prevalence of nausea in the each trimester was 63.5 %, 33.8 %, 26.2 %, and vomiting was 29.3 %, 22.1 %, 14.1 %, respectively. Factors associated with nausea in the first trimester were Latin American origin (OR: 3.60, 95 %IC 1.61- 80.5) and primary education (OR: 0.31; 0.13-0.73); vomiting was associated with Latin-American origin (OR: 13.80, 1.82 104.4) and was inversely associated with weight gain (OR: 0.58, 0.35-0.97). Persistence of NVP were only associated with suffering the symptom in the previous trimester (p < 0.01), and did not find other predictor factors. CONCLUSIONS: NVP's prevalence declines along pregnancy, is associated with race and inversely with weight gain, and its persistence over time cannot be predicted. PMID- 25287235 TI - MicroRNAs: an epigenetic tool to study celiac disease. AB - This article summarizes recent findings on the role of microRNAs (miRNAs) in biological processes associated with the regulation of chronic inflammation and autoimmunity. miRNAs are small non-coding RNA molecules that have been recently emerged as a new class of modulators of gene expression at the post transcriptional level. MiRNAs bind to complementary sequences of specific targets of messengers RNA, which can interfere with protein synthesis. We reviewed studies that evaluated the expression patterns of miRNAs in different autoimmune diseases, especially in celiac disease (CD). CD is a chronic enteropathy triggered by gluten proteins, characterized by altered immune responses in genetically susceptible individuals that results in damage to the bowel mucosa. CD has a high prevalence and an effective treatment by a specific diet ("gluten free diet"). Genetic factors confer susceptibility but do not explain the whole disease, suggesting that environmental factors do play a relevant role in the development of the condition.The evaluation of the potential role of miRNA is of particular interest in CD given that these epigenetic mechanisms in the pathogenesis of autoimmune and inflammatory diseases have been recently described. Improving our understanding of miRNAs in CD will contribute to clarify the role of altered epigenetic regulation in the development and course of this disease. PMID- 25287236 TI - Innate lymphoid cells and natural killer T cells in the gastrointestinal tract immune system. AB - The gastrointestinal tract is equipped with a highly specialized intrinsic immune system. However, the intestine is exposed to a high antigenic burden that requires a fast, nonspecific response -so-called innate immunity- to maintain homeostasis and protect the body from incoming pathogens. In the last decade multiple studies helped to unravel the particular developmental requirements and specific functions of the cells that play a role in innate immunity. In this review we shall focus on innate lymphoid cells, a newly discovered, heterogeneous set of cells that derive from an Id2-dependent lymphoid progenitor cell population. These cells have been categorized on the basis of the pattern of cytokines that they secrete, and the transcription factors that regulate their development and functions. Innate lymphoid cells play a role in the early response to pathogens, the anatomical contention of the commensal flora, and the maintenance of epithelial integrity.Amongst the various innate lymphoid cells we shall lay emphasis on a subpopulation with several peculiarities, namely that of natural killer T cells, a subset of T lymphocytes that express both T-cell and NK cell receptors. The most numerous fraction of the NKT population are the so called invariant NKT or iNKT cells. These iNKT cells have an invariant TCR and recognize the glycolipidic structures presented by the CD1d molecule, a homolog of class-I MHC molecules. Following activation they rapidly acquire cytotoxic activity and secrete both Th1 and Th2 cytokines, including IL-17. While their specific role is not yet established, iNKT cells take part in a great variety of intestinal immune responses ranging from oral tolerance to involvement in a number of gastrointestinal conditions. PMID- 25287237 TI - Gastric and duodenal pseudomelanosis: a propos of two cases. PMID- 25287238 TI - Acute cholangitis and hemobilia in a patient with liver cirrhosis and portal vein cavernomatous transformation. PMID- 25287239 TI - Can the vicious cycle of obscure or intractable gastrointestinal bleeding be broken in patients with atrial fibrillation subject to anticoagulant therapy? AB - Gastrointestinal bleeding of obscure origin or with an intractable cause is particularly common in patients with atrial fibrillation subject to oral anticoagulant therapy. This condition is highly recurrent and therefore gives rise to high morbidity and mortality rates, thus entailing a vicious cycle that is difficult to solve.Percutaneous left atrial appendage closure has become a therapeutic alternative for patients with atrial fibrillation and a contraindication for oral anticoagulation. This technique would allow the discontinuation of oral anticoagulants, thus helping to reduce the risk for gastrointestinal bleeding, and would also be protective against embolic events in this group of patients, thereby eventually breaking this vicious cycle.We report our experience with percutaneous left atrial appendage closure in the management of patients with atrial fibrillation who are subject to oral anticoagulation therapy and suffer from obscure or intractable gastrointestinal bleeding. PMID- 25287240 TI - Bowel ischaemia and cocaine consumption; case study and review of the literature. AB - BACKGROUND: Amongst others, cocaine consumption has a detrimental effect in the vascular supply to the mesenteric area causing abdominal ischemic changes. Early recognition of these changes and adequate treatment are essential to avoid serious complications and possible death of the patient from sepsis. CASE REPORT: In this case study, the subject is a 40-years-old gentleman presenting with acute abdominal pain due to multiple ischemic changes in both small bowel and sigmoid loops. The patient required emergency surgical intervention consisting of bowel resection and anastomosis. The pathologic analysis of the segment showed transmural necrosis and necrotizing phlebitis caused by the ingestion of drugs or toxic agents. The patient later confirmed the habitual consumption of cocaine. DISCUSSION: The increase in cocaine consumption and other recreational toxins substructed from erythroyilon coca alkaloids amongst young people have generated a large number of admissions to Hospital Accident and Emergency Departments with patients complaining of acute abdominal pain. In many of these cases, surgical intervention is required and in some cases patients will sadly die without a proper diagnosis. Some of the most common effects of cocaine and its compounds includes; hollow viscus perforation, gastro-intestinal bleed, and other vascular problems such as enteritis and ischemic colitis. It appears clear that there is a great need for an advance history taking of these patients and their habit to cocaine and other drugs together with a urine test for drug screening. These together with a suspicion of a non- occlusive ischemic bowel caused by the effects of cocaine in young adults with no cardiac risk factors will guide clinicians and establish, and plan the correct treatment for these categories of patients. PMID- 25287241 TI - [Hepatic abscesses]. PMID- 25287242 TI - Aceruloplasminemia: An entity to consider in patients with anemia. PMID- 25287243 TI - Severe colonic stricture related to acute pancreatitis. PMID- 25287244 TI - Derivative anastomotic gastrojejunostomic stenosis resolved with a yo-yo type stent. PMID- 25287245 TI - Retroperitoneal hematoma in Crohn's disease patient with warfarin therapy. PMID- 25287246 TI - Metastasis of lobular breast carcinoma in the sigmoid colon. PMID- 25287247 TI - Intraductal papillary neoplasm of the bile duct. PMID- 25287249 TI - Lignin depolymerisation strategies: towards valuable chemicals and fuels. AB - Research on lignin deconstruction has recently become the center of interest for scientists and companies worldwide, racing towards harvesting fossil-fuel like aromatic compounds which are so durably put together by plants as products of millions of years of evolution. The natural complexity and high stability of lignin bonds (also as an evolutionary adaptation by plants) makes lignin depolymerization a highly challenging task. Several efforts have been directed towards a more profound understanding of the structure and composition of lignin in order to devise pathways to break down the biopolymer into useful compounds. The present contribution aims to provide an overview of key advances in the field of lignin depolymerisation. Protocols and technologies will be discussed as well as critically evaluated in terms of possibilities and potential for further industrial implementation. PMID- 25287248 TI - MicroRNA-5p and -3p co-expression and cross-targeting in colon cancer cells. AB - BACKGROUND: Two mature miRNA species may be generated from the 5' and 3' arms of a pre-miRNA precursor. In most cases, only one species remains while the complementary species is degraded. However, co-existence of miRNA-5p and -3p species is increasingly being reported. In this work, we aimed to systematically investigate co-expression of miRNA-5p/3p in colon cancer cells in a genome-wide analysis, and to examine cross-targeting of the dysregulated miRNAs and 5p/3p species. RESULTS: Four colon cancer cell lines were examined relative to two normal colon tissues. Of the 1,190 miRNAs analyzed, 92 and 36 were found to be up or down-regulated, respectively, in cancer cells. Nineteen co-expressed miRNA 5p/3p pairs were further identified suggesting frequent 5p/3p co-accumulation in colon cancer cells. Of these, 14 pairs were co-up-regulated and 3 pairs were co down-regulated indicating concerted 5p/3p dysregulation. Nine dysregulated miRNA pairs fell into three miRNA gene families, namely let-7, mir-8/200 and mir-17, which showed frequent cross-targeting in the metastasis process. Focusing on the let-7d-5p/3p pair, the respectively targeted IGF1R and KRAS were shown to be in a reverse relationship with expression of the respective miRNA, which was confirmed in transient transfection assays using let-7d mimic or inhibitor. Targeting of KRAS by let-7d was previous reported; targeting of IGF1R by let-7d-5p was confirmed in luciferase assays in this study. The findings of let-7d-5p/3p and multiple other miRNAs targeting IGF1R, KRAS and other metastasis-related factors suggest that 5p/3p miRNAs contribute to cross-targeting of multiple cancer associated factors and processes possibly to evade functional abolishment when any one of the crucial factors are inactivated. CONCLUSIONS: miRNA-5p/3p species are frequently co-expressed and are coordinately regulated in colon cancer cells. In cancer cells, multiple cross-targeting by the miRNAs, including the co existing 5p/3p species, frequently occurs in an apparent safe-proof scheme of miRNA regulation of important tumorigenesis processes. Further systematic analysis of co-existing miRNA-5p/3p pairs in clinical tissues is important in elucidating 5p/3p contributions to cancer pathogenesis. PMID- 25287250 TI - Pregnancy intentions and maternal and child health: an analysis of longitudinal data in Oklahoma. AB - Better understanding of the impact of unintended childbearing on infant and early childhood health is needed for public health practice and policy. Data from the 2004-2008 Oklahoma Pregnancy Risk Assessment Monitoring System survey and The Oklahoma Toddler Survey 2006-2010 were used to examine associations between a four category measure of pregnancy intentions (intended, mistimed <2 years, mistimed >=2 years, unwanted) and maternal behaviors and child health outcomes up to age two. Propensity score methods were used to control for confounding. Births mistimed by two or more years (OR .58) and unwanted births (OR .33) had significantly lower odds than intended births of having a mother who recognized the pregnancy within the first 8 weeks; they were also about half as likely as intended births to receive early prenatal care, and had significantly higher likelihoods of exposure to cigarette smoke during pregnancy. Breastfeeding was significantly less likely among unwanted births (OR .68); breastfeeding for at least 6 months was significantly less likely among seriously mistimed births (OR .70). We find little association between intention status and early childhood measures. Measured associations of intention status on health behaviors and outcomes were most evident in the prenatal period, limited in the immediate prenatal period, and mostly insignificant by age two. In addition, most of the negative associations between intention status and health outcomes were concentrated among women with births mistimed by two or more years or unwanted births. Surveys should incorporate questions on the extent of mistiming when measuring pregnancy intentions. PMID- 25287251 TI - Prevalence of prescription medication use among non-pregnant women of childbearing age and pregnant women in the United States: NHANES, 1999-2006. AB - Many prescription medications have limited information regarding safety for use during pregnancy. In order to inform research on safer medication use during pregnancy, we examined prescription medication use among women in the United States. We analyzed data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) to estimate the prevalence of prescription medication use in the past 30 days among pregnant women and non-pregnant women of childbearing age (15-44 years) and to ascertain the most commonly reported prescription medications by women in these groups. We assessed how the most commonly reported medications differed among groups defined by selected demographic characteristics, including age, race/ethnicity, and markers of socioeconomic status. Prescription medication use in the past 30 days was reported by 22 % of pregnant women and 47 % of non-pregnant women of childbearing age. The most commonly reported prescription medications by NHANES participants differed somewhat by pregnancy status; allergy and anti-infective medications were more common among pregnant women, while oral contraceptives were more common among non-pregnant women. Use of prescription medication for asthma and thyroid disorders was reported by both groups. Although prescription medication use in the previous 30 days was less common among pregnant women than non-pregnant women, its use was reported among almost 1 in 4 pregnant women. Many of the most common medications reported were for the treatment of chronic medical conditions. Given the potential impact of medications on the developing fetus, our data underscore the importance of understanding the safety of these medications during pregnancy. PMID- 25287252 TI - Lateral trap-door window approach with maxillary sinus membrane lifting for dental implant placement in atrophied edentulous alveolar ridge. AB - One of the most challenging and technically sensitive surgical procedures in conjunction with dental implant rehabilitation is sinus membrane lifting to increase the bone height or volume from the maxillary sinus floor. This important preprosthetic surgical technique has been available for >15 years, making possible the creation of bone volume in the edentulous posterior maxilla for the placement of dental implants in surgically compromised cases. Substantial literature exists regarding the most efficacious way to increase the predictability of this surgical procedure, and reduce its associated complications. In this article, we describe the regional anatomy of the maxillary sinus, the evolution of the sinus membrane lifting procedure, the current surgical technique, its survival rate and associated complications, the need for bone graft or bone substitutes, and current advances in the lateral approach through a trap-door window for sinus membrane lifting for dental implants. PMID- 25287253 TI - Helicobacter pylori infection, chronic kidney disease, and peptic ulcer disease. PMID- 25287254 TI - Probiotics, immunostimulants, plant products and oral vaccines, and their role as feed supplements in the control of bacterial fish diseases. AB - There is a rapidly increasing literature pointing to the success of probiotics, immunostimulants, plant products and oral vaccines in immunomodulation, namely stimulation of the innate, cellular and/or humoral immune response, and the control of bacterial fish diseases. Probiotics are regarded as live micro organisms administered orally and leading to health benefits. However, in contrast with the use in terrestrial animals, a diverse range of micro-organisms have been evaluated in aquaculture with the mode of action often reflecting immunomodulation. Moreover, the need for living cells has been questioned. Also, key subcellular components, including lipopolysaccharides, have been attributed to the beneficial effect in fish. Here, there is a link with immunostimulants, which may also be administered orally. Furthermore, numerous plant products have been reported to have health benefits, namely protection against disease for which stimulation of some immune parameters has been reported. Oral vaccines confer protection against some diseases, although the mode of action is usually linked to humoral rather than the innate and cellular immune responses. This review explores the relationship between probiotics, immunostimulants, plant products and oral vaccines. PMID- 25287255 TI - Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells. AB - The integrity of intestinal barrier is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of various gastrointestinal diseases. Aside from serving as substrates for protein biosynthesis, amino acids also maintain the health of intestinal mucosal barrier. However, the underlying mechanisms remain unclear. We aimed to determine the effect and mechanism of non-essential amino acid (NEAA) deprivation on intestinal tight junction permeability using porcine intestinal epithelial cells as a model. We found that NEAA deprivation led to an impairment of barrier function as evidenced by increased permeability, decreased trans-epithelial resistance, and decreased expression of tight junction proteins claudin-1 and ZO-1. Importantly, NEAA deprivation induced both apoptosis and autophagy as shown by caspase-3 activation, and poly ADP-ribose polymerase cleavage; and LC3II lipidation and p62 degradation, hallmarks of apoptosis and autophagy, respectively. Importantly, we showed that the autophagy induced by NEAA deprivation counteracts apoptosis. Abrogation of autophagy by 3-methyladenine enhanced NEAA deprivation-induced barrier dysfunction and apoptosis; whereas, activation of autophagy by rapamycin partially rescued NEAA deprivation-induced barrier dysfunction and apoptosis. Taken together, our results demonstrate a critical role of NEAA on the mucosal integrity by regulating cell death and survival signaling pathways. PMID- 25287256 TI - Is D-aspartate produced by glutamic-oxaloacetic transaminase-1 like 1 (Got1l1): a putative aspartate racemase? AB - D-Aspartate is an endogenous free amino acid in the brain, endocrine tissues, and exocrine tissues in mammals, and it plays several physiological roles. In the testis, D-aspartate is detected in elongate spermatids, Leydig cells, and Sertoli cells, and implicated in the synthesis and release of testosterone. In the hippocampus, D-aspartate strongly enhances N-methyl-D-aspartate receptor dependent long-term potentiation and is involved in learning and memory. The existence of aspartate racemase, a candidate enzyme for D-aspartate production, has been suggested. Recently, mouse glutamic-oxaloacetic transaminase 1-like 1 (Got1l1) has been reported to synthesize substantially D-aspartate from L aspartate and to be involved in adult neurogenesis. In this study, we investigated the function of Got1l1 in vivo by generating and analyzing Got1l1 knockout (KO) mice. We also examined the enzymatic activity of recombinant Got1l1 in vitro. We found that Got1l1 mRNA is highly expressed in the testis, but it is not detected in the brain and submandibular gland, where D-aspartate is abundant. The D-aspartate contents of wild-type and Got1l1 KO mice were not significantly different in the testis and hippocampus. The recombinant Got1l1 expressed in mammalian cells showed L-aspartate aminotransferase activity, but lacked aspartate racemase activity. These findings suggest that Got1l1 is not the major aspartate racemase and there might be an as yet unknown D-aspartate-synthesizing enzyme. PMID- 25287257 TI - 2013-2014 updates in Peyronie's disease management. AB - The number of patients presenting with Peyronie's disease (PD) appears to be on the rise. This review provides an analysis of pertinent recent updates in the management of PD, focusing on data published within the past year. Objective benefit from injectable agents has been reported for years in mostly noncontrolled trials. The safety and efficacy of injectable collagenase clostridium histolyticum is now supported by data from a large-scale phase III randomized controlled trial. Other important advances have also been made in the surgical management of Peyronie's disease, including new modifications to proven surgical techniques and a variety of approaches that can help enhance and restore penile length. PMID- 25287258 TI - Mixed incontinence: what takes precedence in its management? AB - Mixed urinary incontinence is a commonly encountered condition for urologists, urogynecologists, and primary care providers. In this review, we discuss the approach to the evaluation and management of patients with simultaneous stress and urgency urinary incontinence. The available evidence for treatment modalities in the setting of mixed urinary incontinence is presented, and we discuss our treatment algorithm for this common but challenging clinical scenario. An accurate assessment of stress and urge symptoms and their relative impact on quality of life help guide the management plan, appropriate counseling, and appropriate appraisal of patient expectations for treatment. PMID- 25287259 TI - Hyperglycemia and insulin resistance and the risk of BPH/LUTS: an update of recent literature. AB - Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are highly prevalent in older men and represent a substantial challenge to public health. Increasing epidemiologic evidence suggests that diabetes and associated hyperglycemia and insulin resistance significantly increase the risks of BPH and LUTS. Plausible pathophysiologic mechanisms to explain these associations include increased sympathetic tone, stimulation of prostate growth by insulin and related trophic factors, alterations in sex steroid hormone expression, and induction of systemic inflammation and oxidative stress. This article presents a comprehensive update of the current understanding of clinical and epidemiologic research on diabetes and BPH/LUTS, describes hypothesized pathophysiologic mechanisms linking these conditions, and recommends future directions for research. PMID- 25287261 TI - "Not hiding, not shouting, just me": gay men negotiate their visual identities. AB - This study explored how British gay men make sense of their appearance and clothing practices and the pressures and concerns they attend to in discursively negotiating their visual identities. A convenience sample of 20 mostly young, White, and middle-class self-identified gay men responded to a qualitative survey on dress and appearance. The participants clearly understood the rules of compulsory heterosexuality and the risks of looking "too gay." In the data, there was both a strong resistance to the notion of gay as a "master status" and an orientation to the "coming out" imperative in gay communities. The analysis revealed the overriding importance of discourses of authentic individuality for making sense of visual identity and the reported cultivation of appearance and clothing practices that communicate the message that: "I'm not hiding (too closeted), I'm not shouting (too gay), I'm just me (an authentic individual who just happens to be gay)." PMID- 25287262 TI - Detection and quantification of the solid component in pulmonary subsolid nodules by semiautomatic segmentation. AB - OBJECTIVE: To determine whether semiautomatic volumetric software can differentiate part-solid from nonsolid pulmonary nodules and aid quantification of the solid component. METHODS: As per reference standard, 115 nodules were differentiated into nonsolid and part-solid by two radiologists; disagreements were adjudicated by a third radiologist. The diameters of solid components were measured manually. Semiautomatic volumetric measurements were used to identify and quantify a possible solid component, using different Hounsfield unit (HU) thresholds. The measurements were compared with the reference standard and manual measurements. RESULTS: The reference standard detected a solid component in 86 nodules. Diagnosis of a solid component by semiautomatic software depended on the threshold chosen. A threshold of -300 HU resulted in the detection of a solid component in 75 nodules with good sensitivity (90%) and specificity (88%). At a threshold of -130 HU, semiautomatic measurements of the diameter of the solid component (mean 2.4 mm, SD 2.7 mm) were comparable to manual measurements at the mediastinal window setting (mean 2.3 mm, SD 2.5 mm [p = 0.63]). CONCLUSION: Semiautomatic segmentation of subsolid nodules could diagnose part-solid nodules and quantify the solid component similar to human observers. Performance depends on the attenuation segmentation thresholds. This method may prove useful in managing subsolid nodules. KEY POINTS: * Semiautomatic segmentation can accurately differentiate nonsolid from part-solid pulmonary nodules * Semiautomatic segmentation can quantify the solid component similar to manual measurements * Semiautomatic segmentation may aid management of subsolid nodules following Fleischner Society recommendations * Performance for the segmentation of subsolid nodules depends on the chosen attenuation thresholds. PMID- 25287263 TI - A 16-channel MR coil for simultaneous PET/MR imaging in breast cancer. AB - OBJECTIVES: To implement and evaluate a dedicated receiver array coil for simultaneous positron emission tomography/magnetic resonance (PET/MR) imaging in breast cancer. METHODS: A 16-channel receiver coil design was optimized for simultaneous PET/MR imaging. To assess MR performance, the signal-to-noise ratio, parallel imaging capability and image quality was evaluated in phantoms, volunteers and patients and compared to clinical standard protocols. For PET evaluation, quantitative (18) F-FDG PET images of phantoms and seven patients (14 lesions) were compared to images without the coil. In PET image reconstruction, a CT-based template of the coil was combined with the MR-acquired attenuation correction (AC) map of the phantom/patient. RESULTS: MR image quality was comparable to clinical MR-only examinations. PET evaluation in phantoms showed regionally varying underestimation of the standardised uptake value (SUV; mean 22 %) due to attenuation caused by the coil. This was improved by implementing the CT-based coil template in the AC (<2 % SUV underestimation). Patient data indicated that including the coil in the AC increased the SUV values in the lesions (21 +/- 9 %). CONCLUSIONS: Using a dedicated PET/MR breast coil, state-of the-art MRI was possible. In PET, accurate quantification and image homogeneity could be achieved if a CT-template of this coil was included in the AC for PET image reconstruction. KEY POINTS: * State-of-the-art breast MRI using a dedicated PET/MR breast coil is feasible. * A multi-channel design facilitates shorter MR acquisition times via parallel imaging. * An MR coil inside a simultaneous PET/MR system causes PET photon attenuation. * Including a coil CT-template in PET image reconstruction results in recovering accurate quantification. PMID- 25287264 TI - Delayed coverage of drug-eluting stents after interventional revascularisation of chronic total occlusions assessed by optical coherence tomography: the ALSTER-OCT CTO registry. AB - AIMS: Following percutaneous coronary interventions (PCI) for revascularisation of chronic total occlusions (CTO) patients are at increased risk for stent thrombosis (ST). Delayed drug-eluting stent (DES) coverage has previously been shown to be related to ST. Using optical coherence tomography (OCT), we tested the hypothesis that CTO-PCI is associated with delayed DES coverage compared to non-CTO lesions. METHODS AND RESULTS: From 06/2010 to 11/2013, 105 patients (111 lesions) with clinically driven follow-up angiography after PCI with DES received an OCT analysis. Patients with successful CTO-PCI (19 patients/20 lesions, 6.5+/ 2.1 months post PCI) were included in the CTO group, and patients with non-CTO lesions and total stent length >24 mm (28 patients/28 lesions, 4.9+/-2.2 months post PCI) were used as a control group. Struts were analysed by OCT (CTO vs. control, mean+/-SD): covered: 68.9+/-21.9% vs. 89.6+/-10.4%, p<0.001; uncovered apposed: 20.2+/-16.2% vs. 7.5+/-8.7%, p=0.001; uncovered malapposed: 10.9+/-10.3% vs. 2.9+/-2.6%, p<0.001. Neointimal thickness was 92.0+/-61.2 m vs. 109.3+/-39.2 m, p=0.033. No differences concerning different CTO-PCI approaches were found. CONCLUSIONS: A significantly delayed DES coverage after CTO-PCI was observed. Given the known increased rate of ST following CTO-PCI and the known association between delayed DES coverage and ST, OCT may aid in determining the optimal duration of dual antiplatelet therapy after CTO-PCI. PMID- 25287265 TI - Improved endothelial function and decreased levels of endothelium-derived microparticles after transcatheter aortic valve implantation. AB - AIMS: Degenerative aortic valve stenosis (AVS) is independently associated with endothelial dysfunction and increased levels of circulating endothelium-derived microparticles (EMPs) as a marker of compromised endothelial integrity. The aim of this study was to investigate whether therapy for severe AVS by transcatheter aortic valve implantation (TAVI) improves endothelial function and decreases EMPs. METHODS AND RESULTS: Fifty-six patients with indication for TAVI due to symptomatic severe AVS were prospectively enrolled. Brachial wall shear stress (WSS), endothelial function and circulating microparticles (MPs) were measured before and three months following TAVI. Endothelial function was assessed as flow mediated dilation (FMD) using ultrasound. MP subpopulations were discriminated by flow cytometry according to the expression of established surface antigens: CD31+/CD41-, CD144+ and CD62E+ as EMPs and CD41+ as platelet-derived MPs (PMPs). In patients with severe AVS, decreased brachial WSS was an independent predictor of low FMD. At three-month follow-up after TAVI, WSS and FMD increased along with decreased levels of EMPs as compared to pre TAVI. Decrease of CD31+/CD41-, CD144+ and CD62E+ EMP levels correlated with the increase of FMD. CONCLUSIONS: Therapy for AVS by TAVI was associated with improved endothelial function and integrity indicating beneficial effects of TAVI on systemic arterial function. PMID- 25287260 TI - Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus. AB - The flaviviruses dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex spp.), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses. PMID- 25287266 TI - Analysis of antithyroid drugs in surface water by using liquid chromatography tandem mass spectrometry. AB - This paper describes development and validation of a new method for the simultaneous determination of six antithyroid drugs (ATDs) in surface waters by using liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS). Target compounds include two ATD classes: thiouracil derivatives (thiouracil (TU), methyl-thiouracil (MTU), propyl-thiouracil (PTU), phenyl-thiouracil (PhTU)) and imidazole derivatives (tapazole (TAP), and mercaptobenzimidazole (MBI)). Sensitivity and selectivity of the LC-multiple reaction monitoring (MRM) analysis allowed applying a simple pre-concentration procedure and "shooting" the concentrated sample into the LC-MS/MS system without any other treatment. Recoveries were higher than 75% for all analytes. Intra-day precision and inter day precision, calculated as relative standard deviation (RSD), were below 19 and 22%, respectively. Limits of detection (LODs) ranged from 0.05 to 0.25 MUg/L; limits of quantitation (LOQs) varied between 0.15 and 0.75 MUg/L. The validated method was successfully applied to the analysis of ATD residues in surface water samples collected from the Tiber River basin and three lakes of Lazio (central Italy). The analytes were quantified based on matrix-matched calibration curves with mercaptobenzimidazole-d4 (MBI-d4) as the internal standard (IS). The most widespread compound was TAP, one of the most common ATDs used in human medicine, but also TU and MBI were often detected in the analysed samples. PMID- 25287267 TI - Multi-residue analysis of emerging pollutants in benthic invertebrates by modified micro-quick-easy-cheap-efficient-rugged-safe extraction and nanoliquid chromatography-nanospray-tandem mass spectrometry analysis. AB - Aquatic ecosystems are continuously contaminated by agricultural and industrial sources. Although the consequences of this pollution are gradually becoming visible, their potential impacts on aquatic ecosystems are poorly known, particularly regarding the risk of bioaccumulation in different trophic levels. To establish a causality relationship between bioaccumulation and disease, experiments on biotic matrices must be performed. In this context, a multi residue method for the analysis of 35 emerging pollutants in three benthic invertebrates (Potamopyrgus antipodarum, Gammarus fossarum, and Chironomus riparius) has been developed. Because the variation in response of each individual must be taken into account in ecotoxicological studies, the entire analytical chain was miniaturised, thereby reducing the required sample size to a minimum of one individual and scaling the method accordingly. A new extraction strategy based on a modified, optimised and miniaturised "QuEChERS" approach is reported. The procedure involves salting out liquid-liquid extraction of approximately 10-20mg of matrix followed by nano-liquid chromatography-nano electospray ionisation coupled with tandem mass spectrometry. The validated analytical procedure exhibited recoveries between 40 and 98% for all the target compounds and enabled the determination of pollutants on an individual scale in the ng g(-1) concentration. The method was subsequently applied to determine the levels of target analytes in several encaged organisms which were exposed upstream and downstream of an effluent discharge. The results highlighted a bioaccumulation of certain targeted emerging pollutants in three freshwater invertebrates, as well as inter-species differences. 18 out of 35 compounds were detected and eight were quantified. The highest concentrations were measured for ibuprofen in G. fossarum, reaching up to 105 ng g(-1). PMID- 25287268 TI - Suppression of the sidewall effect in pillar array columns with radially elongated pillars. AB - An important bottleneck of pillar array columns designed for liquid chromatography is that small deviations of the target 'magical distance' at the sidewall region leads to detrimental sidewall effects, due to local differences of linear velocities at the sidewall region versus other locations in the pillar bed. In the present study, we demonstrate that a lateral elongation of the pillar significantly increases the tolerance for offsets of the magical distance. By shifting the sidewall distance 600 nm for 2 pillar aspect ratio (AR) designs (AR=3 and 9), only minor sidewall effects on the measured plate heights could be observed for the AR=9 columns, while the plate height was roughly doubled when using the wrong versus the correct sidewall distance for the AR=3 columns. Technologically, this constitutes a huge advantage because small deviations (order of 100 nm) between the set and the finally achieved value for the inter pillar distance are very common using mid-UV lithography based etching processes. PMID- 25287269 TI - Potential blood pressure thresholds and outcome in acute intracerebral hemorrhage. AB - BACKGROUND: Little is known about the relationships between different systolic blood pressure (SBP) thresholds and their outcomes in acute intracerebral hemorrhage (ICH). We aimed to determine the associations of potential systolic blood pressure (SBP) thresholds with hematoma growth (HG) and clinical outcome in patients with acute ICH. METHODS: 117 patients with acute (<6 h) spontaneous supratentorial ICH underwent blood pressure monitoring at 15 min interval over the first 24 h. SBP thresholds of 140, 150, 160, 170, 180, 190, and 200 mm Hg were assessed by means of the percentage of 24-hour values exceeding each threshold (SBP load). HG at 24 h, early neurological deterioration (END), 24-hour and 90-day mortality, and poor outcome were recorded. RESULTS: SBP 170, 180, 190, and 200 loads were significantly correlated with the amount of both absolute and relative hematoma enlargement at 24 h. In multivariate analyses, SBP 170 load was related to HG and END, while SBP 160 load was associated with mortality at 24 h. No thresholds were independently related to outcomes at 90 days. CONCLUSION: In patients with acute ICH, SBP lowering to at least less than 160 mm Hg threshold may be needed to minimize the deleterious effect of high SBP on 24-hour outcomes. PMID- 25287270 TI - Men's constructions of masculinity and male sexuality through talk of buying sex. AB - Commercial sex is an everyday occurrence across a range of contexts in South Africa. In this paper we turn our attention to the often-marginalised role of the buyers of sex by drawing on narrative interviews with male clients of female sex workers recruited through online advertisements in order to explore the ways in which heterosexual men construct, negotiate and perform their masculinity and sexuality through talking about their experiences of paying for sex. We highlight parallels between men's narratives of paying for sex and dominant discourses of gender and heterosexuality. We show how men draw on heteronormative sexual scripts in constructing and making sense of paid sexual encounters and how men are simultaneously able to construct and enact a particular idealised version of masculinity and male sexuality through their talk on paying for sex. Finally, we discuss how online resources could be used more extensively in future research with the male clients of sex workers. PMID- 25287272 TI - Local allograft irradiation as an adjunct for treating severe resistant rejection after liver transplantation in adults. AB - Acute rejection after liver transplantation occurs in one-third of all recipients and can be managed with conventional rejection therapy in the majority of cases. In rare instances, patients with severe acute rejection may be refractory to or have contraindications for conventional therapies. This case series evaluates the role of local allograft irradiation (LAI) as an adjunct for patients with rejection that is refractory to or contraindicated for conventional therapies. Additionally, the literature on the use of radiation therapy for reversing rejection in solid organ transplantation is reviewed. Five patients underwent 9 LAI treatments: 2 had refractory rejection, and 1 each had a malignancy, a concurrent life-threatening infection, and serum sickness with antibody therapy. Conventional rejection therapies included steroids, calcineurin inhibitors, and antithymocyte globulin. LAI consisted of 3 cycles of 1.5 Gy directed toward the liver allograft. Two of the 5 patients remained alive with excellent graft function. Six of the 9 treatments were successful in rescuing the liver allograft (reversing the rejection episode). Treatment success was associated with lower pretreatment serum bilirubin levels and higher pretreatment alanine aminotransferase levels. Compared with patients with immunosuppression-responsive severe acute rejection, those requiring LAI trended toward a later onset of first rejection. In conclusion, local irradiation of liver allografts can be a useful adjunct in patients for whom conventional options have been exhausted or cannot be used. The ability of LAI to reverse allograft dysfunction and promote patient survival appears to be greatest before the onset of severe cholestatic injury. PMID- 25287273 TI - Appropriate blood sampling sites for measuring Tg concentrations for forensic diagnosis. AB - Previous studies have reported that thyroglobulin (Tg) concentrations in heart blood are high in cases of asphyxia caused by neck compression such as hanging, strangulation, and throttling and in those with fatal traumatic brain injuries. However, even in cases without these findings presumed to increase the Tg concentration in the previous studies, we previously reported that in some cases the Tg concentration in right heart blood (RHB) and left heart blood (LHB) exceeded the standard value for diagnosis (200 ng/mL) defined in previous studies and the Tg concentration in RHB was significantly higher than that in LHB. In the present study, in our 46 forensic autopsy cases without findings presumed to increase Tg concentration, we separately collected external iliac venous blood (IVB) and external iliac arterial blood (IAB) in addition to RHB and LHB, measured Tg concentrations in RHB, LHB, IVB, and LAB (TRHB, TLHB, TIVB, and TIAB, respectively), and investigated the appropriate blood sampling site for measuring Tg concentrations for forensic diagnosis. TRHB, TLHB, TIVB, and TIAB were 386.3 +/- 674.1, 105.8 +/- 179.0, 109.2 +/- 166.8, and 43.7 +/- 90.9 ng/mL, respectively. There were statistically significant differences between TRHB and TLHB, TIVB and TIAB, TRHB and TIVB, and TLHB and TIAB. Tg is more readily diffused by the venous system (RHB, IVB) than by the arterial system (LHB, IAB) because the venous system retains more blood volume after death. Tg is more readily diffused to heart blood (RHB, LHB) than to peripheral blood (IVB, IAB) because of the proximity of the heart to the thyroid gland. Therefore, we conclude that Tg leaks into the vessels around the thyroid gland because of the influences of postmortem changes and subsequently diffuses through the blood after death, and therefore the Tg concentration increases after death. When Tg concentration values are used for forensic diagnosis, it is appropriate to measure them using peripheral arterial blood situated distant from the thyroid gland. PMID- 25287271 TI - Transcriptome sequencing of rhizome tissue of Sinopodophyllum hexandrum at two temperatures. AB - BACKGROUND: Sinopodophyllum hexandrum is an endangered medicinal herb, which is commonly present in elevations ranging between 2,400-4,500 m and is sensitive to temperature. Medicinal property of the species is attributed to the presence of podophyllotoxin in the rhizome tissue. The present work analyzed transcriptome of rhizome tissue of S. hexandrum exposed to 15 degrees C and 25 degrees C to understand the temperature mediated molecular responses including those associated with podophyllotoxin biosynthesis. RESULTS: Deep sequencing of transcriptome with an average coverage of 88.34X yielded 60,089 assembled transcript sequences representing 20,387 unique genes having homology to known genes. Fragments per kilobase of exon per million fragments mapped (FPKM) based expression analysis revealed genes related to growth and development were over expressed at 15 degrees C, whereas genes involved in stress response were over expressed at 25 degrees C. There was a decreasing trend of podophyllotoxin accumulation at 25 degrees C; data was well supported by the expression of corresponding genes of the pathway. FPKM data was validated by quantitative real time polymerase chain reaction data using a total of thirty four genes and a positive correlation between the two platforms of gene expression was obtained. Also, detailed analyses yielded cytochrome P450s, methyltransferases and glycosyltransferases which could be the potential candidate hitherto unidentified genes of podophyllotoxin biosynthesis pathway. CONCLUSIONS: The present work revealed temperature responsive transcriptome of S. hexandrum on Illumina platform. Data suggested expression of genes for growth and development and podophyllotoxin biosynthesis at 15 degrees C, and prevalence of those associated with stress response at 25 degrees C. PMID- 25287274 TI - Unravelling nonspecific adsorption of complex protein mixture on surfaces with SPR and MS. AB - Characterization of protein adsorption to surfaces has implications from biosensing to protective biocoatings. While research studies have principally focused on determining the magnitude of protein adsorption to surfaces, the proteins involved in the process remains only broadly identified and has not been investigated on several surfaces. To further elucidate the nonspecific adsorption process of serum to surfaces, surface plasmon resonance (SPR) and matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) were used in combination to obtain quantitative and qualitative information about the process of protein adsorption to surfaces. To validate the technique, crude serum was nonspecifically adsorbed on four self-assembled monolayer (SAM) on gold: 16 mercaptohexadecanoic acid (16-MHA), 11-mercaptoundecane(ethylene glycol)3-COOH (PEG), 3-MPA-LHDLHD-OH, and 3-MPA-HHHDD-OH. Direct MS analysis of the nonspecifically adsorbed proteins suggested the presence of a variety of protein (BSA, IgG, and apolipoprotein A-1). Performing a trypsin digestion of the nonspecifically adsorbed proteins confirmed the presence of BSA and apolipoprotein A-1 and further revealed the complexity of the process by detecting the presence of complement C3, SHC-transforming protein 1, and kininogen 2. The level of nonspecific adsorption on different surfaces measured by SPR sensing directly correlated with the intensity of the serum protein and indirectly with the tryptic peptides measured by MS. Detailed analysis of the BSA peptides digested on 16-MHA and for BSA digested in solution was used to investigate the orientation of BSA on this surface. The combination of SPR and MS allows the quantitative and qualitative understanding of protein adsorption processes to surfaces. PMID- 25287275 TI - Strategic threat management: an exploration of nursing strategies in the pediatric intensive care unit. AB - Part of the work of a critical care nurse is to manage the threats that arise that could impede efficient and effective job performance. Nurses manage threats by employing various strategies to keep performance high and workload manageable. We investigated strategic threat management by using the Threat-Strategy Interview. Threats frequently involved technology, staff, or organizational components. The threats were managed by a toolbox of multifaceted strategies, the most frequent of which involved staff-, treatment- (patient + technology), examination- (patient + clinician), and patient-oriented strategies. The profile of strategies for a particular threat often leveraged work facets similar to the work facet that characterized the threat. In such cases, the nurse's strategy was directed at eliminating the threat (not working around it). A description at both a domain invariant level - useful for understanding strategic threat management generally - and a description at an operational, specific level - useful for guiding interventions-- are presented. A structural description of the relationship among threats, strategies, and the cues that trigger them is presented in the form of an evidence accumulation framework of strategic threat management. PMID- 25287276 TI - Calcium concentration in hypoxic-ischemic encephalopathy during hypothermia. AB - BACKGROUND: The aim of this study was to investigate the relationship between prognosis and the changes in serum-ionized calcium concentration in neonates with hypoxic-ischemic encephalopathy (HIE) before and during brain hypothermia (BHT). METHODS: Serum samples were obtained from 16 HIE neonates who underwent BHT. All patients underwent developmental testing at 18 months of age. RESULTS: Mean serum ionized calcium concentration in the poor outcome group (developmental quotient [DQ], <80; nine infants) was significantly lower than in the good outcome group (DQ >80; seven infants), both immediately before and after 6 h of BHT. Mean serum ionized calcium concentration significantly decreased in both groups for 6 h, and the lowest adjusted serum-ionized calcium during 6 h of BHT was <1.05 mmol/L, known as the cut-off value for poor outcome, in 57.1% of the good outcome group. CONCLUSION: The influx of calcium into cells continues regardless of neurological prognosis during the early phase of BHT, but BHT might protect some high-risk patients against neurological damage at low adjusted serum-ionized calcium concentration. PMID- 25287277 TI - Conservative treatment for osteoid osteoma of the odontoid process of the axis: a case report. AB - BACKGROUND: Osteoid osteoma is a primary benign bone lesion, which constitutes about 10% of all primary benign bone tumors and 3% of all primary bone tumors. The spine is involved in 10% of the cases, and the lumbar spine is the most commonly affected whereas the tumor is rarely seen in the cervical spine. With regard to the osteoid osteoma being located at the odontoid process of the axis, limited cases have been reported in the literature. CASE PRESENTATION: An osteoid osteoma of the odontoid process of the axis was diagnosed by computed tomography in an 18-year-old male patient with a 3-month history of pain. The patient's parents refused surgery for fear of surgical risks and high expense. Considering the benign nature of osteoid osteoma, we prescribed celecoxib 200 mg per day to the patient. With the treatment, the patient's pain was alleviated gradually and the range of motion of the cervical spine also recovered to normal. At the two year phone follow-up, the patient was free of symptoms. CONCLUSIONS: For this kind of benign tumor, conservative treatment plus close follow-up is applicable whereas surgery bears significant risks and a heavy economic burden. PMID- 25287278 TI - Sequence specificity incompletely defines the genome-wide occupancy of Myc. AB - BACKGROUND: The Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes. Genome occupancy of Myc-Max is thought to be driven by Enhancer box (E-box) DNA elements, CACGTG or variants, to which the heterodimer binds in vitro. RESULTS: By analyzing ChIP-Seq datasets, we demonstrate that the positions occupied by Myc-Max across the human genome correlate with the RNA polymerase II, Pol II, transcription machinery significantly better than with E-boxes. Metagene analyses show that in promoter regions, Myc is uniformly positioned about 100 bp upstream of essentially all promoter proximal paused polymerases with Max about 15 bp upstream of Myc. We re evaluate the DNA binding properties of full length Myc-Max proteins. Electrophoretic mobility shift assay results demonstrate Myc-Max heterodimers display significant sequence preference, but have high affinity for any DNA. Quantification of the relative affinities of Myc-Max for all possible 8-mers using universal protein-binding microarray assays shows that sequences surrounding core 6-mers significantly affect binding. Compared to the in vitro sequence preferences,Myc-Max genomic occupancy measured by ChIP-Seq is largely, although not completely, independent of sequence specificity. CONCLUSIONS: We quantified the affinity of Myc-Max to all possible 8-mers and compared this with the sites of Myc binding across the human genome. Our results indicate that the genomic occupancy of Myc cannot be explained by its intrinsic DNA specificity and suggest that the transcription machinery and associated promoter accessibility play a predominant role in Myc recruitment. PMID- 25287279 TI - Moving Beyond Too Little, Too Late: Managing Emerging Infectious Diseases in Wild Populations Requires International Policy and Partnerships. PMID- 25287281 TI - Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload. AB - AIMS: Women with aortic stenosis develop a more concentric form of LV hypertrophy than men. However, the molecular factors underlying sex differences in LV remodelling are incompletely understood. We took an unbiased approach to identify sex-specific patterns in gene expression and pathway regulation, and confirmed the most prominent findings in human hearts. METHODS AND RESULTS: Echocardiography was performed in 104 patients (53.8% women) with aortic stenosis before aortic valve replacement. LV mass, LV end-diastolic diameter, and relative wall thickness were included in a factor analysis to generate an index classifying LV remodelling as adaptive or maladaptive. Maladaptive remodelling was present in 64.6% of male and in 32.7% of female patients (P < 0.01). Genome wide expression profiling of LV samples was performed in a representative subgroup of 19 patients (52.6% women) compared with samples from healthy controls (n = 18). Transcriptome characterization revealed that fibrosis-related genes/pathways were induced in male overloaded ventricles, while extracellular matrix-related and inflammatory genes/pathways were repressed in female overloaded ventricles (adjusted P < 0.05). We confirmed gene regulation by quantitative real-time reverse transcription-polymerase chain reaction and immunoblotting analysis, and we further demonstrate the relevance of our findings by histological documentation of higher fibrosis in men than in women. CONCLUSION: We conclude that in pressure overload distinct molecular processes are regulated between men and women. Maladaptive LV remodelling occurs more frequently in men and is associated with greater activation of profibrotic and inflammatory markers. Collectively, sex-specific regulation of these processes may contribute to sex differences in the progression to heart failure. PMID- 25287280 TI - Honeysuckle-encoded atypical microRNA2911 directly targets influenza A viruses. AB - Influenza A viruses (IAVs), particularly H1N1, H5N1 and H7N9, pose a substantial threat to public health worldwide. Here, we report that MIR2911, a honeysuckle (HS)-encoded atypical microRNA, directly targets IAVs with a broad spectrum. MIR2911 is highly stable in HS decoction, and continuous drinking or gavage feeding of HS decoction leads to a significant elevation of the MIR2911 level in mouse peripheral blood and lung. Bioinformatics prediction and a luciferase reporter assay showed that MIR2911 could target various IAVs, including H1N1, H5N1 and H7N9. Synthetic MIR2911 significantly inhibited H1N1-encoded PB2 and NS1 protein expression, but did not affect mutants in which the MIR2911-binding nucleotide sequences were altered. Synthetic MIR2911, extracted RNA from HS decoction and HS decoction all significantly inhibited H1N1 viral replication and rescued viral infection-induced mouse weight loss, but did not affect infection with a mutant virus in which the MIR2911-binding nucleotide sequences of PB2 and NS1 were altered. Importantly, the inhibitory effect of HS decoction on viral replication was abolished by an anti-MIR2911 antagomir, indicating that the physiological concentration of MIR2911 in HS decoction could directly and sufficiently suppress H1N1 viral replication. MIR2911 also inhibited H5N1 and H7N9 viral replication in vitro and in vivo. Strikingly, administration of MIR2911 or HS decoction dramatically reduced mouse mortality caused by H5N1 infection. Our results demonstrate that MIR2911 is the first active component identified in Traditional Chinese Medicine to directly target various IAVs and may represent a novel type of natural product that effectively suppresses viral infection. PMID- 25287282 TI - The efficacy of moderate-to-vigorous resistance exercise during pregnancy: a randomized controlled trial. AB - OBJECTIVES: To assess the effect and safety of moderate-to-vigorous resistance exercise during pregnancy. DESIGN: Randomized controlled study. SETTING: Two antenatal clinics in Gothenburg, Sweden. POPULATION: Ninety-two healthy pregnant women. METHODS: The intervention was administered during gestational weeks 14-25. The intervention group received supervised resistance exercise twice a week, performed at an activity level equivalent to within moderate-to-vigorous (n = 51). The control group received generalized exercise recommendation, a home-based training program and a telephone follow up (n = 41). MAIN OUTCOME MEASURES: Health-related quality of life, physical strength, pain, weight, blood pressure, functional status, activity level, and perinatal data. RESULTS: Functional status deteriorated during the intervention in both groups and pain increased. Significant differences between the groups were obtained only for birthweight. Newborns delivered by women who underwent resistance exercise during pregnancy were significantly heavier than those born to control women; 3561 (+/-452) g vs. 3251 (+/-437) g (p = 0.02), a difference that disappeared when adjustment was made for gestational age (p = 0.059). Both groups showed normal health-related quality of life, blood pressure, and perinatal data. CONCLUSIONS: These findings indicate that supervised, moderate-to-vigorous resistance exercise does not jeopardize the health status of healthy pregnant women or the fetus during pregnancy, but instead appears to be an appropriate form of exercise in healthy pregnancy. PMID- 25287286 TI - Reproductive endocrinology: circadian clock involved in embryo implantation. PMID- 25287283 TI - Regulation of the adrenocortical stem cell niche: implications for disease. AB - Stem cells are endowed with the potential for self-renewal and multipotency. Pluripotent embryonic stem cells have an early role in the formation of the three germ layers (ectoderm, mesoderm and endoderm), whereas adult tissue stem cells and progenitor cells are critical mediators of organ homeostasis. The adrenal cortex is an exceptionally dynamic endocrine organ that is homeostatically maintained by paracrine and endocrine signals throughout postnatal life. In the past decade, much has been learned about the stem and progenitor cells of the adrenal cortex and the multiple roles that these cell populations have in normal development and homeostasis of the adrenal gland and in adrenal diseases. In this Review, we discuss the evidence for the presence of adrenocortical stem cells, as well as the various signalling molecules and transcriptional networks that are critical for the embryological establishment and postnatal maintenance of this vital population of cells. The implications of these pathways and cells in the pathophysiology of disease are also addressed. PMID- 25287291 TI - Sasa quelpaertensis leaf extract suppresses dextran sulfate sodium-induced colitis in mice by inhibiting the proinflammatory mediators and mitogen-activated protein kinase phosphorylation. AB - Sasa quelpaertensis leaves exert anti-inflammatory and anticarcinogenic effects, although it remains unclear whether these leaves can suppress inflammation related intestinal diseases. This study hypothesized that Sasa quelpaertensis leaf extract (SQE) exerts a protective effect against inflammation in a dextran sulfate sodium (DSS)-induced colitis mouse model. Therefore, colon tissues of DSS induced colitis mice that were treated with SQE were assayed for levels of proinflammatory markers, mitogen-activated protein kinase signaling, and activation of nuclear factor kappaB. For this purpose, mice were pretreated with SQE (100 mg/kg or 300 mg/kg body weight) by gavage for a 2-week period. Mice then received either SQE or sulfasalazine (100 mg/kg body weight) with 2.5% DSS in drinking water for 7 days twice daily and 7 days of tap water ad libitum between DSS treatment. Treatment with SQE was found to attenuate the severity of DSS induced colitis, as assessed by disease activity index scores, shrinkage of colon length, and histopathologic changes. SQE reduced DSS-induced proliferation in distal colon tissues. It also significantly suppressed levels of tumor necrosis factor-alpha in serum and colon tissues, nitric oxide synthase, cyclooxygenase, and levels of phosphorylated c-Jun N-terminal kinases, p38, extracellular-signal regulated kinases 1/2, and IkappaBalpha in colon tissues. To our knowledge, this is the first study to demonstrate that SQE supplementation can exert an anti inflammatory effect on experimental chronic colitis. PMID- 25287289 TI - Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. AB - Hypoglycaemia is a frequent adverse effect of treatment of diabetes mellitus with insulin and sulphonylureas. Fear of hypoglycaemia alters self-management of diabetes mellitus and prevents optimal glycaemic control. Mild (self-treated) and severe (requiring help) hypoglycaemia episodes are more common in type 1 diabetes mellitus but people with insulin-treated type 2 diabetes mellitus are also exposed to frequent hypoglycaemic events, many of which occur during sleep. Hypoglycaemia can disrupt many everyday activities such as driving, work performance and leisure pursuits. In addition to accidents and physical injury, the morbidity of hypoglycaemia involves the cardiovascular and central nervous systems. Whereas coma and seizures are well-recognized neurological sequelae of hypoglycaemia, much interest is currently focused on the potential for hypoglycaemia to cause dangerous and life-threatening cardiac complications, such as arrhythmias and myocardial ischaemia, and whether recurrent severe hypoglycaemia can cause permanent cognitive impairment or promote cognitive decline and accelerate the onset of dementia in middle-aged and elderly people with diabetes mellitus. Prevention of hypoglycaemia is an important part of diabetes mellitus management and strategies include patient education, glucose monitoring, appropriate adjustment of diet and medications in relation to everyday circumstances including physical exercise, and the application of new technologies such as real-time continuous glucose monitoring, modified insulin pumps and the artificial pancreas. PMID- 25287292 TI - Conjugated linoleic acid improves glucose utilization in the soleus muscle of rats fed linoleic acid-enriched and linoleic acid-deprived diets. AB - The effect that conjugated linoleic acid (CLA) has on glucose metabolism in experimental animals depends on nutritional conditions. Therefore, we hypothesized that CLA improves glucose utilization and insulin sensitivity in rats fed different levels of dietary linoleic acid (LA). We investigated the effect of CLA on the uptake, incorporation, and oxidation of glucose and glycogen synthesis in the soleus muscle of rats who were fed either LA-enriched (+LA) or LA-deprived (-LA) diets, under basal conditions and in the absence or presence of insulin and/or palmitate. For 60 days, male Wistar rats were fed 1 of 4 diets consisting of +LA, -LA, or +LA and -LA supplemented with CLA. Nutritional parameters and soleus glucose metabolism were evaluated. Under basal conditions, CLA enhanced soleus glucose oxidation, whereas increased glucose uptake and incorporation were observed in the -LA + CLA group. Conjugated linoleic acid supplemented rats presented a lower response to insulin on glucose metabolism compared with non-CLA-supplemented rats. Palmitate partially inhibited the effect of insulin on the uptake and incorporation of glucose in the +LA and -LA groups but not in the +LA + CLA or -LA + CLA groups. Dietary CLA increased glucose utilization under basal conditions and prevented the palmitate-induced inhibition of glucose uptake and incorporation that is stimulated by insulin. The beneficial effects of CLA were better in LA-deprived rats. Conjugated linoleic acid may also have negative effects, such as lowering the insulin response capacity. These results demonstrate the complexities of the interactions between CLA, palmitate, and/or insulin to differentially modify muscle glucose utilization and show that the magnitude of the response is related to the dietary LA levels. PMID- 25287287 TI - Branched-chain amino acids in metabolic signalling and insulin resistance. AB - Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes beta-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. PMID- 25287294 TI - Salt appetite in the elderly. AB - The present study investigated whether salt appetite in the elderly is impaired similar to thirst because of the commonality of their physiological substrates and whether alterations in salt appetite are related to mood. Elderly (65-85 years, n 30) and middle-aged (45-58 years, n 30) men and women were compared in two test sessions. Thirst, psychophysical ratings of taste solutions, dietary Na and energy intakes, seasoning with salt and sugar, number of salty and sweet snacks consumed, preferred amounts of salt in soup and sugar in tea, and an overall measure of salt appetite and its relationship with mood, nocturia and sleep were measured. Elderly participants were found to be less thirsty and respond less to thirst. In contrast, no impairment of salt appetite was found in them, and although they had a reduced dietary Na intake, it dissipated when corrected for their reduced dietary energy intake. Diet composition and Na intake were found to be similar in middle-aged and elderly participants, despite the lesser intake in elderly participants. There were no age-related differences in the intensity of taste or hedonic profile of Na, in salting habits, in tests of salting soup, or number of salty snacks consumed. No relationship of any measure of salt appetite with mood measured by the Positive and Negative Affect Schedule, frequency of nocturia, or sleep duration was observed. The age-related impairment of the physiology of mineralofluid regulation, while compromising thirst and fluid intake, spares salt appetite, suggesting that salt appetite in humans is not regulated physiologically. Intact salt appetite in the elderly might be utilised judiciously to prevent hyponatraemia, increase thirst and improve appetite. PMID- 25287293 TI - Oligonucleotide treatment causes flax beta-glucanase up-regulation via changes in gene-body methylation. AB - BACKGROUND: Nowadays, the challenge for biotechnology is to develop tools for agriculture and industry to provide plants characterized by productivity and quality that will satisfy the growing demand for different kinds of natural products. To meet the challenge, the generation and application of genetically modified plants is justified. However, the strong social resistance to genetically modified organisms and restrictive regulations in European Union countries necessitated the development of a new technology for new plant types generation which uses the knowledge resulting from analysis of genetically modified plants to generate favourably altered plants while omitting the introduction of heterologous genes to their genome. Four-year experiments led to the development of a technology inducing heritable epigenetic gene activation without transgenesis. RESULTS: The method comprises the induction of changes in methylation/demethylation of the endogenous gene by the plant's treatment with short oligodeoxynucleotides antisense to the coding region. In vitro cultured plants and F3 generation flax plants overproducing the beta-1,3-glucanase gene (EMO-betaGlu flax) were characterized by up-regulation of beta-glucanase and chitinase genes, decreases in the methylation of CCGG sequences in the beta glucanase gene and in total DNA methylation and, more importantly, reasonable resistance against Fusarium infection. In addition, EMO-betaGlu flax obtained by this technology showed similar features as those obtained by genetic engineering. CONCLUSION: To our best knowledge, this is the first report on plant gene activation by treatment with oligodeoxynucleotides homologous to the coding region of the gene. Apart from the evident effectiveness, the most important issue is that the EMO method allows generation of favourably altered plants, whose cultivation makes the plant producer independent from the complicated procedure of obtaining an agreement on GMO release into the environment and whose products might be more easily introduced to the global market. PMID- 25287295 TI - Postoperative radiotherapy in human papilloma virus-positive oropharyngeal tumours-a survey of target volume delineation, dose prescription and treatment verification among UK oncologists. PMID- 25287296 TI - Neurobehavioral function and low-level metal exposure in adolescents. AB - An excessive metal exposure is harmful to the brain. However, many aspects of metal neurotoxicity remain unclear including the magnitude of the low-level exposure effects and the level of exposure that can be assumed safe. The aim of our study was to investigate the association between a low-level metal exposure and three neurobehavioral domains (sustained attention, short-term memory, and manual motor speed). We measured Cd, Cu, Mn, Pb, and Tl in blood, Cd, Ni, and toxicologically relevant As in urine and methyl Hg in hair in 606 adolescents between 13.6 and 17 years of age. A two-fold increase in blood Cu was associated with a 0.37 standard deviations decrease in sustained attention (95% CI: -0.67 to -0.07, p=0.02) and 0.39 standard deviations decrease in short-term memory (95% CI: -0.70 to -0.07, p=0.02), accounting for gender, age, smoking, passive smoking, household income per capita, occupation of the parents, and education level of the mother. None of the other metals was significantly associated with the neurobehavioral domains that were measured. The observed associations between blood Cu and neurobehavioral performance are in line with recent studies in elderly. However, the relevance of our results for public health remains to be elucidated. PMID- 25287297 TI - [Terminology in the context of anesthesia for preterm and term newborns and infants]. AB - An acceptable, standardized and mandatory terminology is important for the planning and implementation of anesthetic procedures on term and preterm newborns and infants. Contradictory use of perinatal terminology poses a problem in current medical practice. This article provides an overview of conventional definitions and technical terms. It also puts forward terminological principles for a model of risk stratification of anesthesia in the newborn period and infancy. PMID- 25287298 TI - "Together at school"--a school-based intervention program to promote socio emotional skills and mental health in children: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Schools provide a natural context to promote children's mental health. However, there is a need for more evidence-based, high quality school intervention programs combined with an accurate evaluation of their general effectiveness and effectiveness of specific intervention methods. The aim of this paper is to present a study protocol of a cluster randomized controlled trial evaluating the "Together at School" intervention program. The intervention program is designed to promote social-emotional skills and mental health by utilizing whole-school approach and focuses on classroom curriculum, work environment of school staff, and parent-teacher collaboration methods. METHODS/DESIGN: The evaluation study examines the effects of the intervention on children's socio-emotional skills and mental health in a cluster randomized controlled trial design with 1) an intervention group and 2) an active control group. Altogether 79 primary school participated at baseline. A multi-informant setting involves the children themselves, their parents, and teachers. The primary outcomes are measured using parent and teacher ratings of children's socio-emotional skills and psychological problems measured by the Strengths and Difficulties Questionnaire and the Multisource Assessment of Social Competence Scale. Secondary outcomes for the children include emotional understanding, altruistic behavior, and executive functions (e.g. working memory, planning, and inhibition). Secondary outcomes for the teachers include ratings of e.g. school environment, teaching style and well-being. Secondary outcomes for both teachers and parents include e.g. emotional self-efficacy, child rearing practices, and teacher-parent collaboration. The data was collected at baseline (autumn 2013), 6 months after baseline, and will be collected also 18 months after baseline from the same participants. DISCUSSION: This study protocol outlines a trial which aims to add to the current state of intervention programs by presenting and studying a contextually developed and carefully tested intervention program which is tailored to fit a national school system. Identification of effective intervention elements to promote children's mental health in early school years is crucial for optimal later development. TRIAL REGISTRATION: ClinicalTrials.gov register: NCT02178332. PMID- 25287299 TI - Multiple mechanisms determine the order of APC/C substrate degradation in mitosis. AB - The ubiquitin protein ligase anaphase-promoting complex or cyclosome (APC/C) controls mitosis by promoting ordered degradation of securin, cyclins, and other proteins. The mechanisms underlying the timing of APC/C substrate degradation are poorly understood. We explored these mechanisms using quantitative fluorescence microscopy of GFP-tagged APC/C(Cdc20) substrates in living budding yeast cells. Degradation of the S cyclin, Clb5, begins early in mitosis, followed 6 min later by the degradation of securin and Dbf4. Anaphase begins when less than half of securin is degraded. The spindle assembly checkpoint delays the onset of Clb5 degradation but does not influence securin degradation. Early Clb5 degradation depends on its interaction with the Cdk1-Cks1 complex and the presence of a Cdc20 binding "ABBA motif" in its N-terminal region. The degradation of securin and Dbf4 is delayed by Cdk1-dependent phosphorylation near their Cdc20-binding sites. Thus, a remarkably diverse array of mechanisms generates robust ordering of APC/C(Cdc20) substrate destruction. PMID- 25287300 TI - Dynamin and endocytosis are required for the fusion of osteoclasts and myoblasts. AB - Cell-cell fusion is an evolutionarily conserved process that leads to the formation of multinucleated myofibers, syncytiotrophoblasts and osteoclasts, allowing their respective functions. Although cell-cell fusion requires the presence of fusogenic membrane proteins and actin-dependent cytoskeletal reorganization, the precise machinery allowing cells to fuse is still poorly understood. Using an inducible knockout mouse model to generate dynamin 1- and 2 deficient primary osteoclast precursors and myoblasts, we found that fusion of both cell types requires dynamin. Osteoclast and myoblast cell-cell fusion involves the formation of actin-rich protrusions closely associated with clathrin mediated endocytosis in the apposed cell. Furthermore, impairing endocytosis independently of dynamin also prevented cell-cell fusion. Since dynamin is involved in both the formation of actin-rich structures and in endocytosis, our results indicate that dynamin function is central to the osteoclast precursors and myoblasts fusion process, and point to an important role of endocytosis in cell-cell fusion. PMID- 25287301 TI - The calcium-dependent ribonuclease XendoU promotes ER network formation through local RNA degradation. AB - How cells shape and remodel organelles in response to cellular signals is a poorly understood process. Using Xenopus laevis egg extract, we found that increases in cytosolic calcium lead to the activation of an endogenous ribonuclease, XendoU. A fraction of XendoU localizes to the endoplasmic reticulum (ER) and is required for nuclear envelope assembly and ER network formation in a catalysis-dependent manner. Using a purified vesicle fusion assay, we show that XendoU functions on the surface of ER membranes to promote RNA cleavage and ribonucleoprotein (RNP) removal. Additionally, RNA removal from the surface of vesicles by RNase treatment leads to increased ER network formation. Using human tissue culture cells, we found that hEndoU localizes to the ER, where it promotes the formation of ER tubules in a catalysis-dependent manner. Together, these results demonstrate that calcium-activated removal of RNA from membranes by XendoU promotes and refines ER remodeling and the formation of tubular ER. PMID- 25287303 TI - Hrr25 triggers selective autophagy-related pathways by phosphorylating receptor proteins. AB - In selective autophagy, degradation targets are specifically recognized, sequestered by the autophagosome, and transported into the lysosome or vacuole. Previous studies delineated the molecular basis by which the autophagy machinery recognizes those targets, but the regulation of this process is still poorly understood. In this paper, we find that the highly conserved multifunctional kinase Hrr25 regulates two distinct selective autophagy-related pathways in Saccharomyces cerevisiae. Hrr25 is responsible for the phosphorylation of two receptor proteins: Atg19, which recognizes the assembly of vacuolar enzymes in the cytoplasm-to-vacuole targeting pathway, and Atg36, which recognizes superfluous peroxisomes in pexophagy. Hrr25-mediated phosphorylation enhances the interactions of these receptors with the common adaptor Atg11, which recruits the core autophagy-related proteins that mediate the formation of the autophagosomal membrane. Thus, this study introduces regulation of selective autophagy as a new role of Hrr25 and, together with other recent studies, reveals that different selective autophagy-related pathways are regulated by a uniform mechanism: phosphoregulation of the receptor-adaptor interaction. PMID- 25287304 TI - Compositional and immunobiological analyses of extracellular vesicles released by Candida albicans. AB - The release of extracellular vesicles (EV) by fungal organisms is considered an alternative transport mechanism to trans-cell wall passage of macromolecules. Previous studies have revealed the presence of EV in culture supernatants from fungal pathogens, such as Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii, Malassezia sympodialis and Candida albicans. Here we investigated the size, composition, kinetics of internalization by bone marrow-derived murine macrophages (MO) and dendritic cells (DC), and the immunomodulatory activity of C. albicans EV. We also evaluated the impact of EV on fungal virulence using the Galleria mellonella larvae model. By transmission electron microscopy and dynamic light scattering, we identified two populations ranging from 50 to 100 nm and 350 to 850 nm. Two predominant seroreactive proteins (27 kDa and 37 kDa) and a group of polydispersed mannoproteins were observed in EV by immunoblotting analysis. Proteomic analysis of C. albicans EV revealed proteins related to pathogenesis, cell organization, carbohydrate and lipid metabolism, response to stress, and several other functions. The major lipids detected by thin-layer chromatography were ergosterol, lanosterol and glucosylceramide. Short exposure of MO to EV resulted in internalization of these vesicles and production of nitric oxide, interleukin (IL)-12, transforming growth factor-beta (TGF-beta) and IL-10. Similarly, EV-treated DC produced IL-12p40, IL-10 and tumour necrosis factor alpha. In addition, EV treatment induced the up-regulation of CD86 and major histocompatibility complex class-II (MHC-II). Inoculation of G. mellonella larvae with EV followed by challenge with C. albicans reduced the number of recovered viable yeasts in comparison with infected larvae control. Taken together, our results demonstrate that C. albicans EV were immunologically active and could potentially interfere with the host responses in the setting of invasive candidiasis. PMID- 25287306 TI - Burger or yogurt? Indulgent consumption in impression management contexts. AB - We conducted three studies to investigate indulgent choice in settings with and without impression management by public-private manipulation with evaluation. Study 1 showed that the participants were less indulgent under public scrutiny due to the employment of impression management. Study 2 focused on the impression management context to test the moderate effect of self-consciousness in two impression managed contexts. Study 3 focused on context without impression management to test the moderate effects of self-awareness on choices. We found that depending on differences in primed personality, individuals tended to make choices other than those they favoured privately when anticipating that others might form impressions of them based on the decisions made. The findings of all three studies support our basic prediction that people are less indulgent under impression management and suggest that people tend to manage their impression by eating healthier (less indulgently) in public. PMID- 25287305 TI - Additively manufactured 3D porous Ti-6Al-4V constructs mimic trabecular bone structure and regulate osteoblast proliferation, differentiation and local factor production in a porosity and surface roughness dependent manner. AB - Additive manufacturing by laser sintering is able to produce high resolution metal constructs for orthopedic and dental implants. In this study, we used a human trabecular bone template to design and manufacture Ti-6Al-4V constructs with varying porosity via laser sintering. Characterization of constructs revealed interconnected porosities ranging from 15-70% with compressive moduli of 2579-3693 MPa. These constructs with macro porosity were further surface-treated to create a desirable multi-scale micro-/nano-roughness, which has been shown to enhance the osseointegration process. Osteoblasts (MG63 cells) exhibited high viability when grown on the constructs. Proliferation (DNA) and alkaline phosphatase specific activity, an early differentiation marker, decreased as porosity increased, while osteocalcin, a late differentiation marker, as well as osteoprotegerin, vascular endothelial growth factor and bone morphogenetic proteins 2 and 4 increased with increasing porosity. Three-dimensional (3D) constructs with the highest porosity and surface modification supported the greatest osteoblast differentiation and local factor production. These results indicate that additively manufactured 3D porous constructs mimicking human trabecular bone and produced with additional surface treatment can be customized for increased osteoblast response. Increased factors for osteoblast maturation and differentiation on high porosity constructs suggest the enhanced performance of these surfaces for increasing osseointegration in vivo. PMID- 25287307 TI - Changes in methylation patterns of multiple genes from peripheral blood leucocytes of Alzheimer's disease patients. AB - BACKGROUND: Efforts aiming at identifying biomarkers and corresponding methods for early diagnosis of Alzheimer's disease (AD) might be the most appropriate strategy to initiate promising new treatments and/or prevention of AD OBJECTIVE: The aim of our study is to assess the association of DNA methylation pattern of various leucocyte genes with AD pathogenesis in order to find potential biomarkers and corresponding methods for molecular diagnosis of AD. METHODS: DNA methylation level of various genes in AD patients and normal population were compared by bisulphite sequencing PCR and methylation-specific PCR (MSP). Furthermore, real-time PCR was used to explore the effects of DNA methylation on the expression of target genes. RESULTS: Results showed significant hypermethylation of mammalian orthologue of Sir2 (SIRT1) gene in AD patients compared with normal population. Meanwhile, changes in methylation level of SIRT1 gene between different severities of AD were also found. Specific primers were designed from the SIRT1 CpG islands to differentiate AD and control group by MSP method. Besides, significant demethylation of beta-amyloid precursor protein (APP) gene was observed in AD patients, whereas no difference was observed in other AD-related genes. Moreover, significant decrease in expression of SIRT1 gene and increase in expression of APP gene were also found in AD patients. In addition, the expression level of SIRT1/APP genes was associated with the severity, but not with the age or gender, of AD patients. CONCLUSION: SIRT1 and APP might be the interesting candidate biomarkers and valuable for clinical diagnosis or treatment of AD. PMID- 25287308 TI - 5-HT depletion, but not 5-HT1A antagonist, prevents the anxiolytic-like effect of citalopram in rat contextual conditioned fear stress model. AB - OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety. METHODS: Rats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or dl-p chlorophenylalanine (PCPA), various subtype-selective serotonin (5-HT) receptor antagonists: the 5-HT1A receptor antagonist WAY 100635, the 5-HT2A receptor antagonist MDL 100907, the 5-HT2C receptor antagonist SB 242084, the 5-HT3 receptor antagonist tropisetron, the 5-HT4 receptor antagonist GR 125487, the 5 HT6 receptor antagonist SB 258585 or the 5-HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks. RESULTS: Citalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic-like effect of citalopram was prevented completely by pretreatment with the 5-HT-depleting agent PCPA, but not by the 5-HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype-selective 5-HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic-like effect of citalopram. CONCLUSION: The anxiolytic-like effect of citalopram in contextual CFS model depends on 5-HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic-like effect of citalopram. PMID- 25287309 TI - Pharmacoeconomic analysis of paliperidone palmitate versus olanzapine pamoate for chronic schizophrenia in Norway. AB - OBJECTIVE: Paliperidone palmitate long-acting injection (PP-LAI) has recently been approved for treatment of chronic schizophrenia. Its cost-effectiveness has not been established. The objective was to compare direct costs and outcomes between PP-LAI and olanzapine pamoate (OLZ-LAI) in treating chronic schizophrenia in Norway from the perspective of the government payer. METHODS: We used a decision analytic model over a 1-year time horizon. Clinical inputs were derived from the literature and an expert panel; costs were taken from standard lists, adjusted to 2010 Norwegian kroner (NOK). Discounting was not done. Main outcomes included average cost per patient treated, hospitalisations, emergency room (ER) visits and quality-adjusted life years (QALYs). The pharmacoeconomic outcome was the incremental cost per QALY. Robustness was examined using one-way sensitivity analyses on critical variables and a 5000-iteration probabilistic Monte Carlo sensitivity analysis with all variables included. RESULTS: PP-LAI generated 0.845 QALY at a cost of 151 336 NOK of which 23% was due to drugs; 25% of patients were hospitalised and another 12% required ER visits. OLZ-LAI cost 174 351 NOK (21% due to drugs); patient outcomes included 0.844 QALY, 27% hospitalisations and 14% ER visits. PP-LAI dominated OLZ-LAI in the base case. The analysis was reasonably robust against variations in drug cost but sensitive to small changes in adherence and hospitalisation rates. Overall, PP-LAI was dominant over OLZ-LAI in 54.5% of simulations. Replacing OLZ-LAI with PP-LAI would be cost saving for the Norwegian healthcare system. CONCLUSION: PP-LAI was cost-effective compared with OLZ-LAI in treating patients with chronic schizophrenia in Norway but sensitive to changes in adherence and hospitalisation rates. PMID- 25287310 TI - Evaluation of energetic metabolism in the rat brain after meningitis induction by Klebsiella pneumoniae. AB - BACKGROUND: Bacterial meningitis is an infection of the central nervous system characterised by strong inflammatory response. The brain is highly dependent on ATP, and the cell energy is obtained through oxidative phosphorylation, a process which requires the action of various respiratory enzyme complexes and creatine kinase (CK) as an effective buffering system of cellular ATP levels in tissues that consume high energy. OBJECTIVES: Evaluate the activities of mitochondrial respiratory chain complexes I, II, III, IV and CK activity in hippocampus and cortex of the Wistar rat submitted to meningitis by Klebsiella pneumoniae. METHODS: Adult Wistar rats received either 10 ul of sterile saline as a placebo or an equivalent volume of K. pneumoniae suspension. The animals were killed in different times at 6, 12, 24 and 48 h after meningitis induction. Another group was treated with antibiotic, starting at 16 h and continuing daily until their decapitation at 24 and 48 h after induction. RESULTS: In the hippocampus, the meningitis group without antibiotic treatment, the complex I was increased at 24 and 48 h, complex II was increased at 48 h, complex III was inhibited at 6, 12, 24 and 48 h and in complex IV all groups with or without antibiotic treatment were inhibited after meningitis induction, in the cortex there was no alteration. Discussion Although descriptive, our results show that antibiotic prevented in part the changes of the mitochondrial respiratory chain. The meningitis model could be a good research tool to study the biological mechanisms involved in the pathophysiology of the K. pneumoniae meningitis. PMID- 25287311 TI - Daytime sleepiness, sleep disturbance and functioning impairment in bipolar disorder. AB - OBJECTIVE: To verify the prevalence and clinical impact of excessive daytime sleepiness (EDS) in outpatients with bipolar disorder. METHODS: Eighty-one outpatients with bipolar disorder and 79 healthy control subjects were recruited. Patients were required not to be acutely manic or depressed. We used the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index and the Functioning Assessment Short Test to assess sleepiness, sleep problems and functioning, respectively. RESULTS: Patients had a higher prevalence of sleepiness (40%) than the control group (18%). Sleepiness and sleep disturbance had independent impacts on disability in the multivariable model. CONCLUSIONS: This study suggests that EDS is a relevant clinical dimension in patients with bipolar disorder. It is a frequent symptom that often overlaps with other sleep disturbances. This study also reveals that once present it has the potential to increase functional impairment. PMID- 25287312 TI - The influence of glutamatergic antagonism on motor variability, and comparison to findings in schizophrenia patients. AB - OBJECTIVE: The primary aim of this explorative study was to investigate the influence of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine on motor activity in healthy subjects. Secondarily, we wanted to compare these data to findings in a sample of schizophrenia patients. METHODS: The healthy subjects acted as their own controls in an open-within-subject design. Motor activity was recorded with an actigraph worn for 24 h in the drug free, and steady-state memantine conditions, respectively. Motor activity levels for 1-min intervals were analysed by means of both linear and nonlinear methods. The schizophrenia patients were monitored only once, without memantine manipulation. RESULTS: The root mean square successive differences (RMSSD) and the RMSSD/SD ratio were increased by memantine, and memantine was also associated with lower autocorrelation (lag 1) but in recordings from the right arm only. These movement patterns partly corresponded to those found in a sample of drug treated schizophrenia patients. Total activity level, standard deviation (SD) and sample entropy were not significantly different in the memantine versus drug-free condition. CONCLUSION: The findings suggest a role for the NMDA receptor in the regulation of motor activity in healthy individuals as memantine increased the variability in the motor recordings and the alterations between adjacent motor recordings. It is suggested that the findings may be relevant to the role played by glutamate and the NMDA receptor functioning to the motor disturbances in schizophrenia. PMID- 25287313 TI - The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. AB - OBJECTIVES: To examine and record the clinical antidepressant effect of exogenous agmatine, an amino acid derived central glutamaergic modulator in endogenously depressed subjects. It was also the author's intention to examine the effects of parachlorophenylalanine (PCPA) in therapeutic responders to determine if serotonergic mechanisms mediate agmatine's antidepressant effect. Methodology Exogenous agmatine was ingested in doses of 2-3mg/day by depressed subjects with Major Depresssive Disorder (MDD), clinically assessed using the 21 item Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS). Antidepressant responders volunteered to concommittantly ingest parachlorophenylalanine (PCPA) at starting doses of 250mg/day, and increased until depressive relapse, mitigating side effects, or a maximum dosage of 1250mg/day. RESULTS: Three depressed subjects showing total illness remission with exogenous agmatine did not relapse after concomitantly adding PCPA. Effective in relieving both psychomotor agitation and retardation, the antidepressant effect was free of physical or behavioural side effects: gastrointestinal discomfort and loose stools in one subject resolved spontaneously within days. All three subjects refused to risk depressive relapse by temporarily stopping agmatine after PCPA was stopped. CONCLUSION: The antidepressant effect of exogenous agmatine was documented in a small number of MDD subjects, and was not reversed/modified by PCPA confirming findings in animals that therapeutic response is not mediated by serotonergic mechanisms. A NAMDA (N-methyl-D-aspartate) receptor antagonist, agmatine's recognized function in brain as inhibitory modulator of excitatory glutamatergic transmission suggests a pivotal role for brain glutamate, contributing to the ripening glutamatergic basis of depression, and a rational basis for future antidepressant pharmacotherapy. PMID- 25287314 TI - Urinary incontinence and diarrhoea associated with the switch from oral to injectable risperidone. AB - OBJECTIVE: Urgency, urinary incontinence and bowel disturbances are distressing side effects that have been observed during treatment with risperidone and other antipsychotics probably due to the receptor affinity profile. This occurrence can lead to poor compliance and therefore impair clinical outcome. METHOD: We report the case of a 50 year-old lady, who experienced urinary incontinence and diarrhoea, when switching from oral to injectable risperidone, which ceased when discontinuing the drug. Results and conclusions It should be taken into account that some side effects can be revealed when switching from oral to depot formulations due to non-compliance to orals; nevertheless dose-dependent mechanisms and individual metabolic variability must be considered when observing idiosyncratic reactions to drugs. PMID- 25287315 TI - De novo Tardive Tourette-like syndrome after prolonged combination depot and oral neuroleptic therapy. AB - Introduction Tardive Tourette-like syndrome is recognised by the observation of several motor and vocal tics often in individuals receiving psychotropic medications and can happen within 1-3 months of treatment. Clinical case We report a case which is unique in its onset of Tardive Tourette-like syndrome comprising of vocal, motor tics and coprolalia after more than three decades of treatment with combination depot and oral neuroleptics. Discussion Use of the Naranjo Adverse Drug Reaction Probability Scale indicates a probable relationship between the onset of Tardive Tourettism and the antipsychotic therapy in this patient. This was in contrast to earlier reports which noted earlier onset and partial reversal with termination or change of medications. Clinicians need to pay heed to the emergence of late-onset Tourettism in order to better manage its manifestation and prevent its worsening in the context of holistic care for patients with neuropsychiatric conditions including schizophrenia. PMID- 25287316 TI - Neuroimaging in pediatric opsoclonus-myoclonus syndrome: beyond the search for neuroblastomas. PMID- 25287317 TI - Irisin: 'fat' or artefact. AB - Soon after the discovery of the muscle-derived factor irisin, a great controversy arose in the literature regarding certain inconsistencies in the regulation of the fibronectin type III domain containing 5 protein (FNDC5/irisin) after exercise, as well as the unpredicted association of circulating irisin levels with parameters of adiposity in humans. Due to these questionable findings, doubts as to the identity of the soluble portion of FNDC5 as well as the real role of irisin and its possible therapeutic applications in the treatment of obesity and diabetes have proliferated. We recently postulated that FNDC5/irisin is an adipokine expressed and secreted by white adipose tissue in rats and humans. Its circulating concentration correlates with adiposity in humans among independent cohorts of patients. Further analysis, focused on obesity-related metabolic disorders, has shown that irisin could play a role in promoting insulin resistance or act as an adaptive response to counteract disturbances in glucose and lipid homoeostasis in obesity. Overall, this leads us to raise the question whether the new factor, increased in circulation of obese patients, is really irisin-reflecting fat mass or it is an artefact. Therefore, the current review is focused on the potential participation of adipose tissue in irisin circulating levels, and the role of irisin in metabolic pathologies associated with obesity in an attempt to clarify the controversy generated by these recently published reports. PMID- 25287318 TI - Left Ventricular Mechanics in Untreated Normotensive Patients with Type 2 Diabetes Mellitus: A Two- and Three-dimensional Speckle Tracking Study. AB - BACKGROUND: Our aim was to investigate left ventricular (LV) mechanics estimated by two- (2DE) and three-dimensional echocardiography (3DE) strains in subjects with type 2 diabetes mellitus (DM). METHODS: This cross-sectional study included 50 untreated normotensive DM subjects and 50 healthy controls similar by sex and age. All the subjects underwent adequate laboratory analyses and complete 2DE and 3DE examination. RESULTS: Left ventricular mechanics, assessed by 2DE, was impaired in all three directions. Global longitudinal 3DE strain was significantly decreased in the DM group in comparison with the controls (-17.8 +/ 2.5 vs. -19.1 +/- 2.7%, P = 0.014). Similar results were found for 3DE global circumferential strain (-18.9 +/- 2.9 vs. -20.4 +/- 3.2%, P = 0.01), 3DE global radial strain (40.3 +/- 6.9 vs. 43.1 +/- 7.3%, P = 0.035), and 3DE global area strain (-29.2 +/- 3.7 vs. -31 +/- 4%, P = 0.024). LV torsion was similar between the DM patients and the controls (2.1 +/- 0.6 vs. 1.9 +/- 0.5 degrees /cm, P = 0.073); whereas LV untwisting rate was significantly increased in the DM subjects (-114 +/- 26 vs. -96 +/-23 degrees /s, P < 0.001). A multivariate analysis showed that 3DE global longitudinal and area myocardial functions were associated with HbA1c independently of 3DE LV mass index. CONCLUSION: Left ventricular deformation obtained by 3DE is significantly impaired in the type 2 DM patients. HbA1c is independently associated with LV mechanics that implies that early anti diabetic therapy and normalization of the fasting glucose level and HbA1c could impede further cardiac damage. PMID- 25287319 TI - Partial remission definition: validation based on the insulin dose-adjusted HbA1c (IDAA1C) in 129 Danish children with new-onset type 1 diabetes. AB - OBJECTIVE: To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c). SUBJECTS AND METHODS: The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset of type 1 diabetes (T1D). Receiver operating characteristic curve (ROC) analysis was used to evaluate the predictive value of IDAA1c and age on partial C-peptide remission (stimulated C-peptide, SCP > 300 pmol/L). RESULTS: PR (IDAA1c <= 9) in the Danish and Hvidoere cohorts occurred in 62 vs. 61% (3 months, p = 0.80), 47 vs. 44% (6 months, p = 0.57), 26 vs. 32% (9 months, p = 0.32) and 19 vs. 18% (12 months, p = 0.69). The effect of age on SCP was significantly higher in the Danish cohort compared with the Hvidoere cohort (p < 0.0001), likely due to higher attained Boost SCP, so the sensitivity and specificity of those in PR by IDAA1c <= 9, SCP > 300 pmol/L was 0.85 and 0.62 at 6 months and 0.62 vs. 0.38 at 12 months, respectively. IDAA1c with age significantly improved the ROC analyses and the AUC reached 0.89 +/- 0.04 (age) vs. 0.94 +/- 0.02 (age + IDAA1c) at 6 months (p < 0.0004) and 0.76 +/- 0.04 (age) vs. 0.90 +/- 0.03 (age + IDAA1c) at 12 months (p < 0.0001). CONCLUSIONS: The diagnostic and prognostic power of the IDAA1c measure is kept but due to the higher Boost stimulation in the Danish cohort, the specificity of the formula is lower with the chosen limits for SCP (300 pmol/L) and IDAA1c <=9, respectively. PMID- 25287320 TI - Multiple skin hamartomata: a possible novel clinical presentation of SUFU neoplasia syndrome. AB - Medulloblastoma tumours may arise sporadically or as part of an inherited syndrome. A subset of children with medulloblastoma carry germline and somatic mutations in the SUFU tumour suppressor gene located at 10q24. We report a 55 year old woman referred for investigation on the basis of skin lesions and a family history of two children from different unions with medulloblastoma. Examination of our patient revealed facial papules (classified as benign folliculosebaceous hamartomatous lesions) and dysmorphology (macrocephaly, hypertelorism and prognathism). She reported her father and her son share the same dermatological features; photographs of the son display hypertelorism. Sequencing in our patient revealed a splice-site mutation in intron 6 of SUFU (c. 756+1G>A), predicted to lead to skipping of exon 6. We suggest that the emerging phenotype in SUFU associated with familial medulloblastoma may include hamartomatous skin lesions. Consideration of these features, along with macrocephaly will alert clinicians to the likely genetic basis of the syndrome, affording the opportunity for genetic counselling, prenatal or pre-implantation genetic diagnosis in at-risk families. PMID- 25287321 TI - The importance of cone-beam computed tomography in the management of endodontic problems: a review of the literature. AB - INTRODUCTION: To obtain essential information in clinical endodontics, cone-beam computed tomographic (CBCT) imaging can be used in all phases of treatment including diagnosis, treatment planning, during the treatment phase, and through post-treatment assessment and follow-up. The purpose of this article was to review the use of CBCT imaging in the diagnosis, treatment planning, and assessing the outcome of endodontic complications. METHODS: Literature was selected through a search of PubMed electronic databases for the following keywords: tooth root injuries, tooth root radiography, tooth root perforation, tomography, cone-beam computed tomography, endodontic complications, tooth root internal/external resorption, root fractures, and broken instruments. The research was restricted to articles published in English. One hundred twelve articles met the inclusion criteria and were included in this review. RESULTS: Currently, intraoral radiography is the imaging technique of choice for the management of endodontic disease, but CBCT imaging appears to have a superior validity and reliability in the management of endodontic diagnosis and complications. CONCLUSIONS: Endodontic cases should be judged individually, and CBCT imaging should be considered in situations in which information from conventional imaging systems may not yield an adequate amount of information to allow the appropriate management of endodontic problems. CBCT imaging has the potential to become the first choice for endodontic treatment planning and outcome assessment, especially when new scanners with lower radiation doses will be available. PMID- 25287322 TI - Characteristics of the spatio-temporal network of cattle movements in France over a 5-year period. AB - A good knowledge of the specificities of the animal trade network is highly valuable to better control pathogen spread on a large regional to transnational scale. Because of their temporal dynamical nature, studying multi-annual datasets is particularly needed to investigate whether structural patterns are stable over the years. In this study, we analysed the French cattle movement network from 2005 to 2009 for different spatial granularities and temporal windows, with the three-fold objective of exploring temporal variations of the main network characteristics, computing proxies for pathogen spread on this network, which accounts for its time-varying properties and identifying specificities related to the main types of animals and farms (dairy versus beef). Network properties did not qualitatively vary among different temporal and spatial granularities. About 40% of the holdings and 80% of the communes were directly interconnected. The width of the aggregation time window barely impacted normalised distributions of indicators. A period of 8-16 weeks would suffice for robust estimation of their main trends, whereas longer periods would provide more details on tails. The dynamic nature of the network could be seen through the small overlap between consecutive networks with 65% of common active nodes for only 3% of common links over 2005-2009. To control pathogen spread on such a network, by reducing the largest strongly connected component by more than 80%, movements should be prevented from 1 to 5% of the holdings with the highest centrality in the previous year network. The analysis of breed-wise and herd-wise subnetworks, dairy, beef and mixed, reveals similar trends in temporal variation of average indicators and their distributions. The link-based backbones of beef subnetworks seem to be more stable over time than those of other subnetworks. At a regional scale, node reachability accounting for time-respecting paths, as proxy of epidemic burden, is greater for a dairy region than for a beef region. This highlights the importance of considering local specificities and temporal dynamics of animal trade networks when evaluating control measures of pathogen spread. PMID- 25287323 TI - Prevalence of the infectious hypodermal and hematopoietic necrosis virus in shrimp (Penaeus vannamei) broodstock in northwestern Mexico. AB - The Penaeus stylirostris densovirus (PstDNV or IHHNV) is the smallest of the known shrimp viruses. It causes severe mortalities in juveniles and sub-adults of the blue shrimp Penaeus stylirostris, while specimens of the white shrimp Penaeus vannamei infected by this virus exhibit reduced growth rates and negative effects on the feed-conversion rate (FCR). To date, no descriptive epidemiological surveys on the prevalence of this virus in shrimp broodstock have been performed. In this study, the prevalence of IHHNV in broodstock of the white shrimp P. vannamei from hatcheries on the northwest of Mexico region was estimated. Prevalence vary across different regions from high (63%) to low (6%) in shrimp broodstock. Several factors, as transport of pathogens by human activities, or the absence or implementation of ineffective biosecurity measures, may explain the observed differences. To the best of our knowledge, the present study is the first to examine the prevalence of IHHNV on broodstock. PMID- 25287325 TI - The relationship between observed signs of impairment and THC concentration in oral fluid. AB - BACKGROUND: Studies have shown that cannabis intake increases the risk of traffic accidents. Controlled experiments support these findings and have shown a positive dose-effect relationship. METHODS: In this retrospective cross-sectional study of data from a roadside survey, we investigated whether a police officer's judgment regarding signs of impairment is related to the concentration of delta-9 tetrahydrocannabinol (THC) in the oral fluid (OF). We investigated 2,632 cases from a representative sample of 3,302 Spanish drivers: 253 drivers positive for THC only, 32 positive for THC and ethanol, 201 with only ethanol detected in their breath, and 2,146 drivers who tested negative for ethanol in breath and drugs in OF. Recorded data comprised breath alcohol concentrations, THC concentrations in the OF, and the 31 observed signs of impairment. Subject groups were compared using the chi-square test, and logistic regression was used to examine the risk of being categorized as exhibiting signs of impairment. RESULTS: A relationship was found between the OF THC concentration and some observed signs of impairment. Eye signs were noticeable from a THC concentration >3.0 ng/ml in OF, and >25 ng/ml was related to behavior, facial expression, and speech signs. Alcohol and THC contribute to impairment independently and, when taken simultaneously, the effects are comparable to the sum of the effects when consumed separately. CONCLUSIONS: The observation of signs of impairment due to cannabis occurs in an OF concentration-related manner but, as a clinical test, OF has low sensitivity and specificity in a random roadside survey. PMID- 25287324 TI - A prospective study of marijuana use change and cessation among adolescents. AB - BACKGROUND: With marijuana use increasing among American adolescents, better understanding of the factors associated with decreasing use and quitting can help inform cessation efforts. This study evaluates a range of neighborhood, family, peer network, and individual factors as predictors of marijuana use, change, and non-use over one year, and cessation over six years. METHODS: Data come from adolescents in Waves I and II of the National Longitudinal Study of Adolescent Health (N=458, one-year sample), or Waves I and III (N=358, six-year sample), and reported using marijuana at least four times in the past month at Wave I. RESULTS: Eighteen percent of adolescents stopped using marijuana after six years. Results suggest neighborhood context affects overall use level, whereas neighborhood context and friends were critical to cessation vs. continuation of use. Decrease in use were more likely among adolescents in disadvantaged or less cohesive neighborhoods, or who moved between waves. Non-use after one year was more likely among adolescents who did not move, had fewer marijuana-using friends, and did not exclusively have outside-of-school friends. Cessation at six years was more likely among adolescents in less disadvantaged and more cohesive neighborhoods, and for those with within-school friends. CONCLUSIONS: Results highlight the importance of both objective and subjective neighborhood characteristics, as well as peer networks, on adolescent marijuana use. Factors associated with decreases in use appear distinct from those that predict quitting, suggesting that continuation vs. cessation is linked to peers as well as neighborhood context. Relocated and isolated individuals may face challenges with cessation. PMID- 25287326 TI - Hepatoid adenocarcinoma of the stomach: dual-time-point (18)F-FDG PET/CT findings. AB - Hepatoid adenocarcinoma of the stomach (HAS) is a rare distinct variant of gastric carcinoma with earlier metastases and worse prognosis compared to the more common intestinal types. It is often misdiagnosed as hepatocellular carcinoma, especially when primary HAS is insignificantly anatomically abnormal, produces high alpha-fetoprotein and develops early liver metastasis. In this case we show the significance of dual-time-point (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) in accurately diagnosing and staging HAS. PMID- 25287327 TI - Prof. Dr. Gerhard Seifert (1921-2014): a European pathologist from Germany. PMID- 25287329 TI - Modified cellulose nanocrystal for vitamin C delivery. AB - Cellulose nanocrystal grafted with chitosan oligosaccharide (CNC-CSOS) was used to encapsulate vitamin C and prepare CNCS/VC complexes using tripolyphosphte via ionic complexation. The stability of vitamin C and the antioxidant activity of the CNCS/VC complexes were elucidated. The formation of the complex was confirmed using DSC and UV-vis spectrophotometry, and TEM was used to study the morphology of the complexes. The encapsulation efficiency of vitamin C at pH 3 and 5 was 71.6% +/- 6.8 and 91.0 +/- 1.0, respectively. Strong exothermic peaks observed in isothermal titration calorimetric (ITC) studies at pH 5 could be attributed to additional electrostatic interactions between CNC-CSOS and vitamin C at pH 5. The in vitro release of vitamin C from CNCS/VC complexes showed a sustained release of up to 20 days. The vitamin C released from CNCS/VC complex displayed higher stability compared with the control vitamin C solution, and this was also confirmed from the ITC thermograms. CNC-CSOS possessed a higher scavenging activity and faster antioxidant activity compared with its precursors, i.e., oxidized CNC and CSOS and their physical mixtures. Complexing vitamin C into CNC CSOS particles yielded a dynamic antioxidant agent, where the vitamin C is released over time and displayed sustained antioxidant properties. Therefore, CNCS/VC can potentially be used in cosmeceutical applications as topical formulations. PMID- 25287328 TI - Protein kinase D1 regulates ERalpha-positive breast cancer cell growth response to 17beta-estradiol and contributes to poor prognosis in patients. AB - About 70% of human breast cancers express and are dependent for growth on estrogen receptor alpha (ERalpha), and therefore are sensitive to antiestrogen therapies. However, progression to an advanced, more aggressive phenotype is associated with acquisition of resistance to antiestrogens and/or invasive potential. In this study, we highlight the role of the serine/threonine-protein kinase D1 (PKD1) in ERalpha-positive breast cancers. Growth of ERalpha-positive MCF-7 and MDA-MB-415 human breast cancer cells was assayed in adherent or anchorage-independent conditions in cells overexpressing or depleted for PKD1. PKD1 induces cell growth through both an ERalpha-dependent manner, by increasing ERalpha expression and cell sensitivity to 17beta-estradiol, and an ERalpha independent manner, by reducing cell dependence to estrogens and conferring partial resistance to antiestrogen ICI 182,780. PKD1 knockdown in MDA-MB-415 cells strongly reduced estrogen-dependent and independent invasion. Quantification of PKD1 mRNA levels in 38 cancerous and non-cancerous breast cell lines and in 152 ERalpha-positive breast tumours from patients treated with adjuvant tamoxifen showed an association between PKD1 and ERalpha expression in 76.3% (29/38) of the breast cell lines tested and a strong correlation between PKD1 expression and invasiveness (P < 0.0001). In tamoxifen-treated patients, tumours with high PKD1 mRNA levels (n = 77, 50.66%) were significantly associated with less metastasis-free survival than tumours with low PKD1 mRNA expression (n = 75, 49.34%; P = 0.031). Moreover, PKD1 mRNA levels are strongly positively associated with EGFR and vimentin levels (P < 0.0000001). Thus, our study defines PKD1 as a novel attractive prognostic factor and a potential therapeutic target in breast cancer. PMID- 25287330 TI - p47phox and reactive oxygen species production modulate expression of microRNA 451 in macrophages. AB - The production of microRNAs (miRNA) is influenced by various stimuli, including environmental stresses. We hypothesized that reactive oxygen species (ROS) associated stress could regulate macrophage miRNA synthesis. miRNAs undergo unique steps of maturation processing through either one of two pathways of cytoplasmic processing. Unlike the canonical pathway, the regulation of alternative cytoplasmic processing of miRNA has not been fully elucidated yet. We cultured bone marrow derived macrophages (BMDM) from wild type (WT) and p47(phox /-) mice and profiled miRNA expression using microarrays. We analyzed 375 miRNAs including four endogenous controls to normalize the data. At resting state, p47(phox-/-) BMDM has the markedly reduced expression of miR-451 compared to WT BMDM, without other significant differences. Unlike majority of miRNAs, miR-451 goes through the unique alternative processing pathway, in which Ago2 plays a key role. In spite of significant reduction of mature miR-451, however, its precursor form, pre-mir-451, was similar in both BMDMs, suggesting that the processing of pre-mir-451 is impaired in p47(phox-/-) BMDM. Moreover, p47(phox-/-) BMDM expressed significantly reduced level of Ago2. In contrast, Ago2 mRNA levels were similar in WT and p47(phox-/-) BMDM, suggesting a post-transcriptional defect of Ago2 production in p47(phox-/-) macrophages, which resulted in impaired processing of pre-miR-451. In order to examine the functional significance of miR 451 in macrophages, we cultured BMDMs from miR-451 knock-out mice. Of interest, miR-451-deficient BMDM exhibited reduced ROS generation upon zymosan stimulation, compared to WT BMDM. Our studies suggest functional crosstalk between ROS and miR 451 in the regulation of macrophage oxidant stress. PMID- 25287331 TI - Adenosine receptors and renal ischaemia reperfusion injury. AB - One of the frequent clinical complications that results in billions of dollars in healthcare costs annually in the United States is acute kidney injury (AKI). Ischaemia reperfusion (IR) injury is a major cause AKI. Unfortunately, no effective treatment or preventive measure for AKI exists. With increased surgical complexity coupled with increasing number of elderly, the incidence of AKI is becoming more frequent. Adenosine is a metabolic breakdown product of adenosine triphosphate (ATP) and contributes to the regulation of multiple physiological events. Extracellular adenosine activates four subtypes of adenosine receptors (AR) including A1 AR, A2 A AR, A2 B AR and A3 AR. In the kidney, adenosine regulates glomerular filtration rate, vascular tone, renin release and is an integrative part of tubular glomerular feedback signal to the afferent arterioles. In addition, each AR subtype powerfully modulates renal IR injury. The A1 AR activation protects against ischaemic insult by reducing apoptosis, necrosis and inflammation. Activation of A2 A AR protects against renal injury by modulating leucocyte-mediated inflammation as well as directly reducing renal tubular inflammation. Activation of A2 B AR acts via direct activation of renal parenchymal as well as renovascular receptors and is important in kidney preconditioning. Finally, activation of A3 AR exacerbates renal damage following renal IR injury while A3 AR antagonism attenuates renal damage following ischaemic insult. Latest body of research suggests that kidney AR modulation may be a promising approach to treat ischaemic AKI. This brief review focuses on the signalling pathways of adenosine in the kidney followed by the role for various AR modulations in protecting against ischaemic AKI. PMID- 25287332 TI - Isoflavones extracted from chickpea Cicer arietinum L. sprouts induce mitochondria-dependent apoptosis in human breast cancer cells. AB - Isoflavones are important chemical components of the seeds and sprouts of chickpeas. We systematically investigated the effects of isoflavones extracted from chickpea sprouts (ICS) on the human breast cancer cell lines SKBr3 and Michigan Cancer Foundation-7 (MCF-7). 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays showed that ICS (10-60 ug/mL) significantly inhibited the proliferation of both cell lines in a time-dependent and dose dependent fashion. Wright-Giemsa staining as well as annexin V-fluorescein isothiocyanate and propidium iodide (Annexin V/PI) staining showed that ICS significantly increased cytoclasis and apoptotic body formation. Quantitative Annexin V/PI assays further showed that the number of apoptotic cells increased in a dose-dependent manner following ICS treatment. Semiquantitative reverse transcription PCR showed that ICS increased the expression of the apoptosis promoting gene Bcl-2-associated X protein and decreased the expression of the antiapoptotic gene Bcl-2. Western blot analysis showed that treatment of SKBr3 and MCF-7 cells with ICS increased the expression of caspase 7, caspase 9, P53, and P21 in a dose-dependent manner. Flow cytometry assays using the fluorescent probe 3,3'-dihexyloxacarbocyanine iodide showed a dose-dependent decrease in mitochondrial membrane potential following ICS treatment. Treatment using ICS also induced a dose-dependent increase in reactive oxygen species production. This is the first study to demonstrate that ICS may be a chemopreventive or therapeutic agent against breast cancer. PMID- 25287334 TI - Nuclear transfer in the mouse. AB - Nuclear transfer (NT) technique provides a powerful experimental tool to study the mechanisms of reprogramming processes and to derive NT-embryonic stem (ntES) cells from living or frozen animals. The Piezo-driven direct microinjection NT method has proved to be a valid technique to clone mice and other species. In addition, this method has been broadly used as a versatile tool for many fields of mouse micromanipulation. This chapter describes the "one step method" protocol of nuclear transfer in mouse, which combines injection of a donor cell nucleus and enucleation of MII metaphase in a single manipulation procedure. This protocol describes the isolation and collection of oocytes, treatment of donor cells, visualization of spindle-chromosomal complex, direct injection and enucleation, activation of reconstructed embryos and their in vitro culture and transfer into pseudopregnant mice. PMID- 25287333 TI - Chemoenzymatic synthesis of spinosyn A. AB - Following the biosynthesis of polyketide backbones by polyketide synthases (PKSs), post-PKS modifications result in a significantly elevated level of structural complexity that renders the chemical synthesis of these natural products challenging. We report herein a total synthesis of the widely used polyketide insecticide spinosyn A by exploiting the prowess of both chemical and enzymatic methods. As more polyketide biosynthetic pathways are characterized, this chemoenzymatic approach is expected to become readily adaptable to streamlining the synthesis of other complex polyketides with more elaborate post PKS modifications. PMID- 25287335 TI - Nuclear transfer in rabbit. AB - Since 2002, our INRA laboratory (Biologie du Developpement et de la Reproduction) has developed a method to produce live somatic clones in rabbit, one of the mammalian species considered as difficult to clone. This chapter presents the technical protocol used nowadays to achieve the goal to obtain cloned embryos able to develop to term using fresh somatic cumulus cells. PMID- 25287336 TI - Nuclear transfer in ruminants. AB - Ruminants were the first mammalian species to be cloned successfully by nuclear transplantation. Those experiments were designed to multiply high merit animals (Willadsen, Nature 320(6057):63-65, 1986; Prather et al., Biol Reprod 37(4):859 866, 1987; Wilmut et al., Nature 385(6619):810-813, 1997). Since then, cloning has provided us with a vast amount of knowledge and information on the reprogramming ability of somatic cells to different cell types which became an important basis for stem cell research and human medicine. Nowadays, the goals of most nuclear transfer work vary widely but in most cases the micromanipulation procedures remain the same. However, differences between species require different technical considerations. In this chapter, we describe in detail somatic cell nuclear transfer which is the foremost method for cloning ruminants with specific reference to sheep and cattle. PMID- 25287337 TI - Nuclear transfer and transgenesis in the pig. AB - Somatic cell nuclear transfer (SCNT) using genetically modified donor cells facilitates the generation of tailored pig models for biomedical research and for xenotransplantation. Up to now, SCNT is the main way to generate gene-targeted pigs, since germ line-competent pluripotent stem cells are not available for this species. In this chapter, we introduce our routine workflow for the production of genetically engineered pigs, especially focused on the genetic modification of somatic donor cells, SCNT using in vitro matured oocytes, and laparoscopic embryo transfer. PMID- 25287338 TI - Embryonic stem cell-somatic cell fusion and postfusion enucleation. AB - Embryonic stem (ES) cells are able to reprogram somatic cells following cell fusion. The resulting cell hybrids have been shown to have similar properties to pluripotent cells. It has also been shown that transcriptional changes can occur in a heterokaryon, without nuclear hybridization. However it is unclear whether these changes can be sustained following removal of the dominant ES nucleus. In this chapter, methods are described for the cell fusion of mouse tetraploid ES cells with somatic cells and enrichment of the resulting heterokaryons. We next describe the conditions for the differential removal of the ES cell nucleus, allowing for the recovery of somatic cells. PMID- 25287339 TI - Analysis of nuclear reprogramming following nuclear transfer to Xenopus oocyte. AB - Germinal vesicle of stage V-VI Xenopus Laevis oocytes (at the prophase I stage of meiosis) can be used to transplant mammalian nuclei. In this type of interspecies nuclear transfer no cell division occurs and no new cell types are generated. However, the transplanted nuclei undergo extensive transcriptional reprogramming. Here, it is first explained how to carry out transplantation of multiple mammalian cell nuclei to Xenopus oocytes. It is then described how to perform RT qPCR, Western Blot, Chromatin Immunoprecipitation, and live imaging analysis to monitor transcriptional reprogramming of the nuclei transplanted to oocytes. PMID- 25287340 TI - Assessing the quality of donor cells: karyotyping methods. AB - Somatic cell nuclear transfer (SCNT) has a low success rate that rarely exceeds 5 %. Moreover, SCNT requires highly technical skills and may be influenced by the biological material used (oocyte and donor cell quality). Hence, it is crucial to check the normality of the donor cell's karyotype. Numerical and structural chromosome abnormalities are detected by cytogenetic analysis at minimum using G banding to identify the chromosomes. Here, we describe the classical protocols that are needed to perform complete cytogenetic analyses, i.e., G-banding to identify chromosome aberrations, followed by Fluorescent In Situ Hybridization (FISH) of specific probes for a more sensitive detection and precise identification of the rearrangement. PMID- 25287341 TI - Treatment of donor cell/embryo with different approaches to improve development after nuclear transfer. AB - The successful production of cloned animals by somatic cell nuclear transfer (SCNT) is a promising technology with many potential applications in basic research, medicine, and agriculture. However, the low efficiency and the difficulty of cloning are major obstacles to the widespread use of this technology. Since the first mammal cloned from an adult donor cell was born, many attempts have been made to improve animal cloning techniques, and some approaches have successfully improved its efficiency. Nuclear transfer itself is still difficult because it requires an accomplished operator with a practiced technique. Thus, it is very important to find simple and reproducible methods for improving the success rate of SCNT. In this chapter, we will review our recent protocols, which seem to be the simplest and most reliable method to date to improve development of SCNT embryos. PMID- 25287342 TI - Fluorescent immunodetection of epigenetic modifications on preimplantation mouse embryos. AB - A common problem in research laboratories that study the mammalian embryo after nuclear transfer is the limited supply of material. For this reason, new methods are continually developed, and existing methods for cells in culture are adapted to suit this peculiar experimental model. Among them is the fluorescent immunodetection. Fluorescent immuno-detection on fixed embryos is an invaluable technique to detect and locate proteins, especially nuclear ones such as modified histones, in single embryos thanks to its specificity and its sensitivity. Moreover, with specific fixation procedures that preserve the 3D shape of the embryos, immunostaining can now be performed on whole-mount embryos. Target proteins are detected by specific binding of first antibody usually nonfluorescent, and revealed with a second antibody conjugated with a fluorochrome directed specifically against the host animal in which the first antibody was produced. The result can then be observed on a microscope equipped with fluorescent detection. Here, we describe the 3D fluorescent immunodetection of epigenetic modifications in mouse embryos. This procedure can be used on nuclear transferred embryos but also on in vivo-collected, in vitro-developed and in vitro-fertilized ones. PMID- 25287343 TI - Visualization of epigenetic modifications in preimplantation embryos. AB - Epigenetic modifications such as DNA methylation and posttranslational histone modifications change drastically during embryonic development. To visualize histone modifications in living embryos, a Fab-based live endogenous modification labeling (FabLEM) technique has been developed. Here we describe the methods required for FabLEM experiments, including Fab preparation from IgG, its conjugation with a fluorescent dye, loading into cultured cells or mouse embryos, and imaging. PMID- 25287344 TI - Live embryo imaging to follow cell cycle and chromosomes stability after nuclear transfer. AB - Nuclear transfer (NT) into mouse oocytes yields a transcriptionally and functionally heterogeneous population of cloned embryos. Most studies of NT embryos consider only embryos at predefined key stages (e.g., morula or blastocyst), that is, after the bulk of reprogramming has taken place. These retrospective approaches are of limited use to elucidate mechanisms of reprogramming and to predict developmental success. Observing cloned embryo development using live embryo cinematography has the potential to reveal otherwise undetectable embryo features. However, light exposure necessary for live cell cinematography is highly toxic to cloned embryos. Here we describe a protocol for combined bright-field and fluorescence live-cell imaging of histone H2b-GFP expressing mouse embryos, to record cell divisions up to the blastocyst stage. This protocol, which can be adapted to observe other reporters such as Oct4-GFP or Nanog-GFP, allowed us to quantitatively analyze cleavage kinetics of cloned embryos. PMID- 25287345 TI - Analysis of nucleolar morphology and protein localization as an indicator of nuclear reprogramming. AB - When a cell is reprogrammed to a new phenotype, the nucleolus undergoes more or less dramatic modulations, which can be used as a marker for the occurrence of the reprogramming. This phenomenon is most pronounced when differentiated cells are reprogrammed to totipotency when they are submitted to cloning by somatic cell nuclear transfer. However, when cells are reprogrammed by less fundamental means, as for example treatment by Xenopus extract or expression of pluripotency genes, more subtle nucleolar modulations can also be noted. The monitoring and understanding of the reprogramming-related nucleolar modulations are based upon detailed knowledge about the nucleolar changes that occur during normal development from the developing oocyte over oocyte maturation and fertilization to the activation of the embryonic genome in the early embryo. Below, the ultrastructural and molecular modulations of the nucleolus are summarized in this developmental context, but also as they occur in assisted reproductive technologies such as in vitro fertilization and somatic cell nuclear transfer. Moreover, detailed protocols for monitoring the nucleolar changes by transmission electron microscopy and immunocytochemistry are presented. PMID- 25287346 TI - Assessment of cell lineages and cell death in blastocysts by immunostaining. AB - During the last decade it has been shown that most mammalian blastocysts consisted of three cell lineages. Immunofluorescence with multiple antibodies enables to identify each cell type allowing an easy detection of eventual defects. It is complementary to RT-PCR experiments as this technique allows to look at cell position and to analyze and count the proportions between the different cell types. Thus after any kind of embryo manipulation such as nuclear transfer (NT), the analysis of the three cell lineages by immunofluorescence will provide criteria for good or poor development. PMID- 25287347 TI - Gene expression analysis in early embryos through reverse transcription quantitative PCR (RT-qPCR). AB - Real-time, reverse transcription quantitative PCR (RT-qPCR) is a highly sensitive and reproducible technology for the analysis of gene expression patterns. Its ability to detect minute quantities of nucleic acid from multifarious sources makes it an ideal technique for embryonic transcript quantification. However, complex cellular diversity and active transcriptome dynamics in early embryos necessitate particular caution to avoid erroneous results. This chapter is intended to outline basic methodology to design and execute RT-qPCR experiments in pre-implantation embryos. PMID- 25287348 TI - Studying bovine early embryo transcriptome by microarray. AB - Microarrays represent a significant advantage when studying gene expression in early embryo because they allow for a speedy study of a large number of genes even if the sample of interest contains small quantities of genetic material. Here we describe the protocols developed by the EmbryoGENE Network to study the bovine transcriptome in early embryo using a microarray experimental design. PMID- 25287349 TI - Methylation of specific regions: bisulfite-sequencing at the single oocyte or 2 cell embryo level. AB - To question the possible implication of an alteration of the DNA methylation of imprinted genes in normal development failure observed following fertilization in ART centers, it has been necessary to develop a reproducible and highly efficient method to perform analysis at the one cell level. We have thus developed a very efficient protocol for methylation studies on individual oocytes or cleavage stage embryos. All the different steps were optimized, from DNA extraction, to limit DNA degradation and give a high success rate of bisulfite converted DNA, to amplification of the bisulfite modified DNA. PMID- 25287350 TI - Micro chromatin immunoprecipitation (MUChIP) from early mammalian embryos. AB - Chromatin immunoprecipitation (ChIP) is a powerful method for mapping protein-DNA interactions in vivo. Genomic localization of histone modifications, transcription factors, and other regulatory proteins can be revealed by ChIP. However, conventional ChIP protocols require the use of large numbers of cells, which prevents the application of ChIP to rare cell types. We have developed ChIP assays suited for the immunoprecipitation of histone proteins or transcription factors from small cell numbers. Here we describe a rapid, yet sensitive micro (MU)ChIP protocol producing high signal to noise ratio output, suitable for as few as 100 cells. This chapter provides a detailed protocol for MUChIP from early mammalian embryos, also suitable for any sample of limited numbers of cells. Minor modifications of this optimized high signal to noise ChIP protocol make it a reliable tool for the use with any cell number (100-10(7)). PMID- 25287351 TI - Assessing reprogramming by chimera formation and tetraploid complementation. AB - Pluripotent stem cells can be evaluated by pluripotent markers expression, embryoid body aggregation, teratoma formation, chimera contribution and even more, tetraploid complementation. Whether iPS cells in general are functionally equivalent to normal ESCs is difficult to establish. Here, we present the detailed procedure for chimera formation and tetraploid complementation, the most stringent criterion, to assessing pluripotency. PMID- 25287352 TI - Whole-mount in situ hybridization to assess advancement of development and embryo morphology. AB - Whole-mount in situ hybridization (WISH) is widely used to visualize the site and dynamics of gene expression during embryonic development. Various methods of probe labeling and hybridization detection are available nowadays. Meanwhile the technique was adapted to be used on many different species and has evolved from a manual to a larger scale and automated procedure. Standardized automated protocols improve the chance to compare different experimental settings reliably. The high resolution of this method is ideally suited for examination of manipulated (e.g., cloned) embryos often displaying subtle changes only. Embedding and sectioning of in situ hybridized specimen further enhance the detailed examination of their gene expression and morphology. PMID- 25287353 TI - Genome-wide analysis of methylation in bovine clones by methylated DNA immunoprecipitation (MeDIP). AB - Methylated DNA immunoprecipitation (MeDIP), when coupled to high-throughput sequencing or microarray hybridization, allows for the identification of methylated loci at a genome-wide scale. Genomic regions affected by incomplete reprogramming after nuclear transfer can potentially be delineated by comparing the MeDIP profiles of bovine clones and non-clones. This chapter presents a MeDIP protocol largely inspired from Mohn and colleagues (Mohn et al., Methods Mol Biol 507:55-64, 2009), with PCR primers specific for cattle, and when possible, overviews of experimental designs adapted to the comparison between clones and non-clones. PMID- 25287354 TI - Addressing health disparities of lesbian and bisexual women: a grounded theory study. AB - BACKGROUND: Lesbian and bisexual (LB) women encounter numerous barriers to equitable health care services, such as lack of quality care and discriminatory health care settings. These barriers affect the well-being of LB women, presumably leading to disparities in health and health care. Despite these disparities, few published research studies explore health services of LB women. This qualitative, grounded theory study addressed that gap. METHODS: Purposive sampling was used to recruit 18- to 24-year-old women who identified as LB and who reported using health services as an adult. Participants (n = 9) were recruited from lesbian, gay, bisexual, and transgender student groups at universities in the Southwestern United States, and in-depth audio recorded interviews were performed. The nine participants represent 29 unique health care experiences. The transcriptions were uploaded into NVivo, and the constant comparison method was used to analyze the data. FINDINGS: Six themes were identified, including seeking health care, expectations, disclosure of sexual orientation, moment of truth (provider attributes), proximal outcomes, and health outcomes. These themes were sorted into an explanatory conceptual framework that represents three distinct phases of the health care experience: Pre-interaction, health care interaction, and outcomes. CONCLUSIONS: The women in this study identified disclosure of sexual orientation and provider attributes as major points in the health care experience. Creating health care environments that facilitate disclosure of sexual orientation and educating providers about LB appropriate care are strategies that may impact health and health care disparities of LB women. PMID- 25287355 TI - A myopathy with unusual features caused by PNPLA2 gene mutations. AB - INTRODUCTION: The PNPLA2 gene encodes the enzyme adipose triglyceride lipase (ATGL), which catalyzes the first step of triglyceride hydrolysis. Mutations in this gene are associated with an autosomal recessive lipid-storage myopathy, neutral lipid-storage disease with myopathy (NLSD-M). RESULTS: A 72-year-old woman had late-onset myopathy, with mild weakness, cramps, and exercise intolerance. Electromyography showed myotonic discharges. A few leukocytes showed lipid droplets (Jordan anomaly). Deltoid and quadriceps muscle biopsies showed no lipid storage. Genetic analysis of PNPLA2 detected 2 heterozygous mutations: c.497A>G (p.Asp166Gly) in exon 5 and c.1442C>T (p.Pro481Leu) in exon 10. Expression of mutant PNPLA2 plasmids in HeLa cells resulted in impaired enzyme activity, confirming the pathological effects of the mutations. CONCLUSIONS: In this case of NLSD-M, the myopathy may be due to a metabolic defect rather than to a mechanical effect of lipid storage. This suggests that more than 1 mechanism contributes to muscle damage in NLSD-M. PMID- 25287356 TI - Breakfast intake is associated with nutritional status, Mediterranean diet adherence, serum iron and fasting glucose: the CYFamilies study. AB - OBJECTIVE: To assess the association of breakfast intake with Mediterranean diet adherence, physical activity levels, obesity, selected cardiovascular risk markers and Fe status. DESIGN: Cross-sectional study. BMI, body fat percentage and waist circumference were assessed. Physical activity was assessed using a pedometer and diet quality was evaluated by applying the KIDMED index. Blood tests to assess blood lipids, high-sensitivity C-reactive protein, fasting glucose, serum Fe and ferritin, as well as Hb, were performed. SETTING: Primary school children of the Troodos mountainous area in Cyprus. SUBJECTS: Eighty-three Cypriot children (mean age 9.2 (sd 1.7) years). RESULTS: Compared with breakfast skippers, regular breakfast eaters were 40 % more likely to have a KIDMED score higher by one point on average (OR=1.41; 95 % CI 1.08, 1.84) after accounting for obesity levels and other confounders. Breakfast skippers, on the other hand, were by about 14 % more likely to have a body fat percentage value higher by one unit, as well as higher values for both BMI and waist circumference. The relationship was significantly strengthened when combining body fat percentage and waist circumference into a composite variable (OR=0.20; 95 % CI 0.06, 0.69). Fasting glucose was inversely correlated to breakfast intake in descriptive analyses, whereas serum Fe was positively correlated to breakfast intake after considering age, gender and diet quality. The latter relationship disappeared, however, after considering physical activity levels. CONCLUSIONS: Cypriot children who take breakfast regularly exhibit a higher adherence to the Mediterranean diet and have higher serum Fe concentrations and lower BMI, waist circumference, body fat percentage and fasting glucose levels, compared with children who skip breakfast. Public health professionals, educators and parents should prioritize on actions that will motivate children to regularly eat breakfast. PMID- 25287357 TI - ESPR adopts British guidelines for imaging in suspected non-accidental injury as the European standard. PMID- 25287358 TI - In utero and postnatal imaging findings of parasitic conjoined twins (ischiopagus parasiticus tetrapus). AB - Conjoined twins are a rare developmental anomaly with a reported prevalence of 1.47 per 100,000 births. We present an uncommon case of a parasitic ischiopagus tetrapus with a parasitic ischiopagus partial twin joined to the complete fetus at the level of the ischium diagnosed in utero by fetal MRI. The correct prenatal diagnosis led to birth by caesarean section. Prenatal MRI findings are presented and corroborated by postnatal imaging delineating the full extent and associated anomalies of this rare malformation. Differential diagnosis of duplicated lower extremities is discussed. PMID- 25287360 TI - Twenty cultural and learning principles to guide the development of pharmacy curriculum in Pacific Island countries. AB - INTRODUCTION: A lack of education capacity to support the development of medical supply management competency is a major issue affecting Pacific Islands countries (PICs). Limited human resources and underdeveloped medicines supply management competency are two significant impediments to reaching the health-related Millennium Development Goals in many countries in this rural and remote region. Two recent review publications have provided relevant background documenting factors affecting learning and teaching. These articles have presented available information regarding competency and training requirements for health personnel involved in essential medicine supply management in the region. This background research has provided a platform from which tangible principles can be developed to aid educators and professionals in PICs in the development and delivery of appropriate pharmacy curriculum. Specifically the aim of the present article is to identify culturally meaningful learning and teaching principles to guide the development and delivery of pharmaceutical curriculum in PICs. Subsequently, this information will be applied to develop and trial new pedagogical approaches to the training of health personnel involved in essential medicines supply management, to improve medicine availability for patients in their own environment. This article forms part of a wider research project involving the United Nations Population Fund Suva subregional office, the University of Canberra, Ministry of Health officials and health personnel within identified PICs. METHODS: Two previous reviews, investigating Pacific culture, learning approaches, and training requirements affecting pharmaceutical personnel, were synthesised into a set of principles that could be applied to the development of pharmaceutical curriculum. These principles were validated through focus groups of health personnel using action research methods. RESULTS: An initial set of 16 principles was developed from the synthesis of the two reviews. These principles were reviewed by two focus groups held in Fiji and the Solomon Islands to produce a set of 20 validated principles. These validated principles can be grouped under the headings of learning theory, structure and design, and learning and teaching methods. CONCLUSIONS: The 20 principles outlined in this article will be used to develop and trial culturally relevant training approaches for the development of medicine management competencies for various cadres of health personnel in PICs. These principles provide a practical framework for educators and health professionals to apply to health-based education and training in the Pacific, with potential application to other rural and remote environments. PMID- 25287361 TI - Forkhead factor FOXQ1 promotes TGF-beta1 expression and induces epithelial mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) promotes tumor invasion and metastasis, but the coordination and integration mechanisms of these processes are still not fully understood. In this study, we used a cross-species expression profiling strategy of Hela cells to determine an important genetic program transfers. In particular, we have discovered a new transfer function, which is not previously known about transcription factor forkhead box Q1 (FOXQ1). The shRNA anti-FOXQ1 gene was synthesized and transfected into the Hela and EpRas cells. RT-PCR assay was performed to detect the mRNA levels in cells. Cell adhesion and separation assay were used to examine the cell-cell adhesion and separation among cells. Wound healing assay was utilized to examine cell migration and invasion ability. Chromatin immunoprecipitation assay was used to investigate the interaction between E-cadherin and N-cadherin and FOXQ1 promoter region. The results indicated that ectopic expression of FOXQ1 increased cell migration and invasion in vitro, enhanced mammary epithelial cells in vivo lung metastasis, and triggered significant EMT. In contrast, the opposite effects in vitro and in vivo of FOXQ1 knockdown phenotypes were caused by these mechanisms. Notably, FOXQ1 repressed core EMT regulation of the expression of TGF-beta1. FOXQ1 protein directly interacts with E-cadherin and N-cadherin promoter region. And surveys show that FOXQ1 expression regulation by TGF-beta1 and blockade induced EMT both morphological and molecular levels. Our findings emphasize the feasibility of cross-species expression profiles, as a strategy to identify metastasis-related genes. The induction of EMT by FOXQ1 defines a new transfer function in promoting cancer behind possible mechanisms. PMID- 25287363 TI - Mitochondria-targeting phosphorescent iridium(III) complexes for living cell imaging. AB - Two phosphorescent iridium(III) complexes conjugated to a lipophilic triphenylphosphonium cation moiety, IrMitoOlivine and IrMitoNIR, were synthesized. The complexes show high mitochondria-specificity and relatively lower cytotoxicity. Time-lapse confocal imaging indicates that both complexes exhibit an excellent anti-photobleaching capability under continuous laser irradiation. PMID- 25287364 TI - NMR chemical shift study of the interaction of selected peptides with liposomal and micellar models of apoptotic cells. AB - The interaction between two peptides previously selected by phage display to target apoptotic cells and phospholipidic models of these cells (liposomes or micelles made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and/or 1,2 dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS, phosphatidylserine analog) was studied by the simple analysis of the changes induced on the proton NMR chemical shifts of the peptides. Our approach which does not need healthy and/or apoptotic cells for assessing the affinity of different peptides is fast and efficient and requires small amounts of peptide to determine the association constant, the interacting protons, and the number of interaction sites. The micellar model gave more reliable results than the liposomal one. The preferential interaction of the peptide with DPPS was evidenced by the change of the chemical shifts of specific amino acids of the peptides. Our micellar model is thus well suited to mimic apoptotic cells. PMID- 25287362 TI - Up-regulation of S100A16 expression promotes epithelial-mesenchymal transition via Notch1 pathway in breast cancer. AB - BACKGROUND: Our previous studies demonstrated that S100A16 promotes adipogenesis and is involved in weight gain attenuation induced by dietary calcium. Till now, the function of S100A16 in the breast cancer remains to be elucidated. RESULTS: In this study, we observed that S100A16 was expressed in higher levels in human breast cancer tissues compared with paired adjacent non-cancerous tissues. Further examination showed that overexpression of S100A16 in MCF-7 cells could increase cell proliferation and colony formation. One major mechanistic change was that S100A16 was able to up-regulate the transcription factors Notch1, ZEB1, and ZEB2, which had the capacities to directly repress the expression of epithelial markers E-cadherin and beta-catenin but increase mesenchymal markers N cadherin and vimentin, a characterized phenotype of epithelial-mensenchymal transition (EMT). In addition to display with morphologic change, migration and invasion were increased in S100A16 over-expressed MCF-7 cells. Importantly, knockdown of Notch1 by specific siRNA could reverse the EMT induced by S100A16 overexpression, which confirmed that Notch1 played a critical role in the process of EMT induced by S100A16. CONCLUSIONS: All together, our data indicated that S100A16 had a potential function to regulate some embryonic transcription factors to promote EMT in breast cancer cells which may be an important target site for the therapy of breast cancer. PMID- 25287365 TI - Insights into the structural determinants of substrate specificity and activity in mouse aldehyde oxidases. AB - In this work, a combination of homology modeling and molecular dynamics (MD) simulations was used to investigate the factors that modulate substrate specificity and activity of the mouse AOX isoforms: mAOX1, mAOX2 (previously mAOX3l1), mAOX3 and mAOX4. The results indicate that the AOX isoform structures are highly preserved and even more conserved than the corresponding amino acid sequences. The only differences are at the protein surface and substrate-binding site region. The substrate-binding site of all isoforms consists of two regions: the active site, which is highly conserved among all isoforms, and a isoform specific region located above. We predict that mAOX1 accepts a broader range of substrates of different shape, size and nature relative to the other isoforms. In contrast, mAOX4 appears to accept a more restricted range of substrates. Its narrow and hydrophobic binding site indicates that it only accepts small hydrophobic substrates. Although mAOX2 and mAOX3 are very similar to each other, we propose the following pairs of overlapping substrate specificities: mAOX2/mAOX4 and mAOX3/mAXO1. Based on these considerations, we propose that the catalytic activity between all isoforms should be similar but the differences observed in the binding site might influence the substrate specificity of each enzyme. These results also suggest that the presence of several AOX isoforms in mouse allows them to oxidize more efficiently a wider range of substrates. This contrasts with the same or other organisms that only express one isoform and are less efficient or incapable of oxidizing the same type of substrates. PMID- 25287366 TI - Comparison of conventional versus crossed monovision in pseudophakia. AB - AIMS: To compare the visual performances and patient satisfactions of conventional monovision, which corrects the dominant eye for distance vision, and crossed monovision, which corrects the non-dominant eye for distance vision in patients with pseudophakia. METHODS: This prospective randomised study was conducted in 59 patients who underwent implantation of different targets of monofocal intraocular lens for each eye at Konkuk University Medical Center between November 2009 and August 2012. The following were examined before bilateral cataract surgery and 2 months after the surgery: refractive error, binocular uncorrected distance visual acuity (UCDVA), uncorrected near visual acuity (UCNVA), best corrected visual acuity (BCVA) and stereopsis. Questionnaires to evaluate postoperative spectacle dependence and patient satisfaction were completed by all patients. RESULTS: The conventional monovision group and the crossed monovision group were composed of 28 and 31 patients, respectively. There were no significant differences in postoperative UCDVA, UCNVA, BCVA and stereopsis between the two groups. In addition, patient satisfaction with near and distant vision and spectacle dependence were not significantly different in the two groups. CONCLUSIONS: The clinical results of the crossed monovision were not significantly different from the results of conventional monovision. Therefore, crossed monovision can also be a valuable option for correcting postoperative presbyopia in patients considering bilateral cataract surgery. TRIAL REGISTRATION NUMBER: KCT0001065. PMID- 25287367 TI - Does cognitive impairment influence outcomes from cataract surgery? Results from a 1-year follow-up cohort study. AB - BACKGROUND/AIMS: To assess the impact of impaired cognition on visual outcomes 1 year following cataract surgery in a cohort of older people. METHODS: Participants aged 75 years or more with bilateral cataract and scheduled for cataract surgery were recruited consecutively. Cognition was assessed using the revised Addenbrooke's cognitive examination (ACE-R). Participants were divided into two groups: normal (ACE-R >=88) and impaired cognition (ACE-R <88). Visual quality of life (VQOL) and logarithm of minimum angle of resolution visual acuity (VA) were assessed at baseline and 1 year following cataract surgery. RESULTS: Of 112 participants, 48 (43%) had normal cognition and 64 (57%) had impaired cognition. One year following cataract surgery participants in both groups had significant improvements in VQOL and VA. Visual outcomes at 1 year were significantly better in participants with normal cognition than in those with impaired cognition (95% CIs for difference 0.4-7.0 and 0.02-0.1, for VQOL and VA, respectively). Regression analyses correcting for potential confounders showed a relationship between baseline cognition and VA at 1 year (R(2)=0.30, p=0.001) and a possible relationship between baseline cognition and VQOL at 1 year (R(2)=0.41, p=0.01, this became insignificant after removal of outliers). CONCLUSIONS: Patients with impaired cognition benefit from cataract surgery, but not to the same extent as patients with normal cognition. PMID- 25287368 TI - Serum-free medium and hydroxyethyl starch supports cell survival better than Minimal Essential Medium and dextran in organ-cultured mouse corneas. AB - BACKGROUND/AIMS: In a previous study, we observed a deleterious effect of serum supplemented Minimal Essential Medium (MEM) on human corneal endothelial cell survival in a cell culture model. Consequently, here we studied the effects of conventional, serum-supplemented MEM and a serum-free medium in combination with two different deswelling substances on cell survival in whole corneas in a mouse model. METHODS: Murine corneas were cultured for 4 days in MEM+2% fetal calf serum (FCS) or serum-free Human Endothelial-SFM (SFM), both supplemented with either 6% dextran T500 or 7.5% hydroxyethyl starch (HES) 130/0.4. Cells were examined by differential interference contrast microscopy, H&E staining, immunocytochemistry for cleaved caspase-3, Bcl-2, haem oxygenase-1 and immunoblotting for cleaved caspase-3. RESULTS: In MEM, endothelial cells were almost completely lost after 4 days and the number of epithelial cells was markedly reduced. The remaining cells showed fragmented nuclei and were positive for cleaved caspase-3 and strongly positive for Bcl-2. Corneas cultured in SFM retained an almost closed layer of endothelial cells. Fewer cells were positive for Bcl-2, and only a few cells were positive for cleaved caspase-3 even under staurosporine administration. HES supplementation was well tolerated by corneal cells over 4 days, while a 4-day supplementation with dextran resulted in the loss of endothelial and epithelial cells. CONCLUSIONS: Serum-free medium, Human Endothelial-SFM, promoted cell survival during corneal organ culture better than MEM+2% FCS. HES 130/0.4 appeared to be tolerated better by the cells than dextran T500. PMID- 25287369 TI - Measuring rates of structural and functional change in glaucoma. AB - Glaucoma is a progressive optic neuropathy. Hence, most glaucomatous eyes demonstrate signs of deterioration over time despite what may appear to be adequate treatment. The main goal of glaucoma treatment is to slow the rate of disease so that patients can prolong their functional vision. Therefore, it is important for clinicians caring for patients with glaucoma to be able to estimate rates of change with structural and functional outcomes in their patients. Various trend analysis models have been previously used to estimate rates of decay in glaucoma. The authors discuss the relevant issues and the inherent caveats related to estimating structural and functional rates of change in glaucoma. Patterns of deterioration, testing frequency, and combing structural and functional rates of change are also addressed. PMID- 25287370 TI - 1H and 13C NMR assignments of tricanguinas A-B, coumarin monoterpenes from Trichosanthes anguina L. PMID- 25287371 TI - Orally administered phenylbutazone causes oxidative stress in the equine gastric mucosa. AB - Phenylbutazone (PBZ) is widely used in equine medicine, and its side effects on the gastrointestinal tract are well known. The inhibition of prostaglandins and the oxidative stress induced by nonsteroidal anti-inflammatory drugs (NSAIDs) are described as mechanisms of gastric mucosal injury in humans. In horses, only the secondary effect of changes in cyclooxygenases is related to gastric mucosal injury. The objective of this study was to evaluate the effect of PBZ on certain antioxidative/oxidative parameters of the gastric mucosa. The concentrations of antioxidants and oxidants (superoxide dismutase, SOD; catalase, CAT; nitric oxide, NO; total glutathione, GSH; myeloperoxidase, MPO; and malondialdehyde, MDA), PGE2 levels, and the ulcerative lesions score were assessed. The results demonstrated decreased levels of antioxidant variables, increased levels of oxidant variables, and alterations in the prostaglandin E2 (PGE2 ), myeloperoxidase (MPO), and glutathione (GSH) levels. In conclusion, PBZ induces oxidative stress in the gastric glandular mucosa of horses by changing the antioxidant-oxidant balance of this surface, which might be regarded as another mechanism of injury in the horse stomach. PMID- 25287372 TI - From navigation to negotiation: an examination of the lived experiences of Black gay male alumni of historically Black colleges and universities. AB - This research presents an examination of Black gay men and their lived experiences while undergraduates at historically Black colleges and universities (HBCUs). Based on 10 in-depth interviews with self-identified Black gay men, the author presents four emergent themes, which reveal the complex ways in which Black gay men navigate and negotiate the intersections of their multiple identities as related to race, sexual orientation, and gender at HBCUs. The findings of this research have implications for larger discussions of community, Black masculinity, and gay identity in predominantly Black and non-Black contexts. PMID- 25287373 TI - Erratum to: Long non-coding RNAs in cancer: implications for personalized therapy. PMID- 25287375 TI - Clozapine-induced pericarditis: an overlooked adverse effect. PMID- 25287376 TI - Toleration and the Design of Norms. AB - One of the pressing challenges we face today-in a post-Westphalian order (emergence of the state as the modern, political information agent) and post Bretton Woods world (emergence of non-state multiagent systems or MASs as "hyperhistorical" players in the global economy and politics)-is how to design the right kind of MAS that can take full advantage of the socio-economic and political progress made so far, while dealing successfully with the new global challenges that are undermining the best legacy of that very progress. This is the topic of the article. In it, I argue that (i) in order to design the right kind of MAS, we need to design the right kind of norms that constitute them; (ii) in order to design the right kind of constitutive norms, we need to identify and adopt the right kind of principles of normative design; (iii) toleration is one of those principles; (iv) unfortunately, its role as a foundation for the design of norms has been undermined by the "paradox of toleration"; (v) however, the paradox can be solved; (vi) so toleration can be re-instated as the right kind of foundational principle for the design of the right kind of norms that can constitute the right kind of MAS that can operate across cultures, societies and states, to help us to tackle the new global challenges facing us. PMID- 25287377 TI - Antegrade continence enema (ACE): predictors of outcome in 111 patients. AB - PURPOSE: The antegrade continence enema (ACE) is used as a means of managing faecal incontinence and constipation with varying outcomes. We aim to evaluate our outcomes of ACEs and identify predictors of outcome. METHODS: A retrospective case-note review of patients <=16 years of age undergoing an ACE (March 2000 September 2013) was carried out. Data collected included: patient demographics, functional outcomes and complications. Data are quoted as median (range) and compared using Mann-Whitney and Fisher's exact test. Univariate analysis was performed to identify predictors of successful outcomes. P < 0.05 is significant. Successful outcome = total continence/occasional leakage and failed outcome = regular soiling and/or constipation. RESULTS: 111 patients with complete data sets underwent an ACE [59% male, median age = 9.5 years (3.4-16 years)] and median follow-up = 48 months (4 months-11 years 4 months). Underlying diagnoses were idiopathic constipation (n = 68), anorectal malformation (n = 27), neuropathic bowel (n = 7), Hirschsprung disease (n = 5) and gastrointestinal dysmotility (n = 4). Social continence was achieved in 87/111 (78%). Fifteen percent of patients underwent reversal of ACE due to resolution of symptoms. There was no difference in outcomes related to diagnosis, gender, age or follow up duration. Complication rate was 20.7% (23/111). CONCLUSIONS: The ACE is safe and effective in the management of intractable constipation and soiling. No predictors of outcome were identified. PMID- 25287379 TI - Nanoparticle-based polychemotherapy: optimizing drug synergy for efficacious cancer treatment. PMID- 25287380 TI - Overcoming barriers in the mucosal delivery of virus-like particle-based vaccines. PMID- 25287378 TI - Acoustic and perceptual correlates of faster-than-habitual speech produced by speakers with Parkinson's disease and multiple sclerosis. AB - Acoustic-perceptual characteristics of a faster-than-habitual rate (Fast condition) were examined for speakers with Parkinson's disease (PD) and multiple sclerosis (MS). Judgments of intelligibility for sentences produced at a habitual rate (Habitual condition) and at a faster-than-habitual rate (Fast condition) by 46 speakers with PD or MS as well as a group of 32 healthy speakers revealed that the Fast condition was, on average, associated with decreased intelligibility. However, some speakers' intelligibility did not decline. To further understand the acoustic characteristics of varied intelligibility in the Fast condition for speakers with dysarthria, a subgroup of speakers with PD or MS whose intelligibility did not decline in the Fast condition (no decline group, n=8) and a subgroup of speakers with significantly declined intelligibility (decline group, n=8) were compared. Acoustic measures of global speech timing, suprasegmental characteristics, and utterance-level segmental characteristics for vocalics were examined for the two subgroups. Results suggest acoustic contributions to intelligibility under rate modulation are complex. Potential clinical relevance and implications for the acoustic bases of intelligibility are discussed. LEARNING OUTCOMES: Readers will be able to (1) discuss existing evidence for the use of rate change to facilitate intelligibility, (2) describe acoustic-perceptual characteristics of a faster-than-habitual rate among speakers with mild dysarthria, (3) discuss the relationships between rate, intelligibility, suprasegmental variables, and segmental variables, (4) identify the need to further investigate the acoustic basis for intelligibility and its potential theoretical and clinical implications. PMID- 25287383 TI - Lost in translation: what is stopping inhaled nanomedicines from realizing their potential? PMID- 25287384 TI - Calcium-channel blocking and nanoparticles-based drug delivery for treatment of drug-resistant human cancers. AB - BACKGROUND: Cancer cell chemoresistance is one of the major limitations to successful cancer treatment and one of the factors that is responsible for the possible recurrence of the disease. Here, we aimed to combine a calcium-channel blocker, verapamil, with an alternative delivery of the anti-cancer drug, doxorubicin, using nanostructural materials. This approach could reduce the cellular resistance to chemotherapeutics agents. RESULTS: The outcome of this complex approach on cellular viability was investigated by using various assays in both a time- and concentration-dependent manner: WST-1, flow cytometry cell viability assay, fluorescence microscopy, DNA fragmentation, and TUNEL labeling of apoptotic cells. CONCLUSION: All of these analytical assays confirmed the ability to reduce the chemoresistance of the cancer cells based on the proposed procedure. PMID- 25287385 TI - Investigation of ethyl cellulose microsponge gel for topical delivery of eberconazole nitrate for fungal therapy. AB - BACKGROUND: The aim of the study was to investigate ethyl cellulose microsponges as topical carriers for the controlled release and cutaneous drug deposition of eberconazole nitrate (EB). MATERIALS & METHOD: EB microsponges were prepared using the quasiemulsion solvent diffusion method. The effect of formulation variables (drug:polymer ratio, internal phase volume and amount of emulsifier) and process variables (stirring time and stirring speed) on the physical characteristics of microsponges were investigated. The optimized microsponges were dispersed into a hydrogel and evaluated. RESULTS & DISCUSSION: Spherical and porous EB microsponge particles were obtained. The optimized microsponges possessed particle size, drug content and entrapment efficiency of 24.5 um, 43.31% and 91.44%, respectively. Microsponge-loaded gels demonstrated controlled release, nonirritancy to rat skin and antifungal activity. An in vivo skin deposition study demonstrated fourfold higher retention in the stratum corneum layer as compared with commercial cream. CONCLUSION: Developed ethyl cellulose microsponges could be potential pharmaceutical topical carriers of EB in antifungal therapy. PMID- 25287386 TI - Genuair((r)) in chronic obstructive pulmonary disease: a novel, user-friendly, multidose, dry-powder inhaler. AB - Inhaled corticosteroids and bronchodilators, which are pivotal to the management of respiratory diseases, are delivered by numerous devices, including pressurized metered-dose inhalers and dry-powder inhalers. However, patient adherence to these medications is suboptimal and incorrect inhaler technique is endemic, meaning that insufficient drug quantities are frequently delivered to the lungs. Genuair((r)) (Almirall SA, Spain) is a novel, breath-actuated, multidose dry powder inhaler designed to achieve reliable and effective delivery of inhaled medicines - including aclidinium bromide - to patients with chronic obstructive pulmonary disease. In addition to describing Genuair's design, which incorporates multiple feedback mechanisms in order to confirm effective medication uptake, this article discusses the performance characteristics of the inhaler, its efficiency in terms of drug deposition and the results of recent patient preference and satisfaction studies. PMID- 25287387 TI - Overview and appraisal of the current concept and technologies for improvement of sublingual drug delivery. AB - Sublingual drug delivery is capable of achieving high bioavailability by avoiding first-pass liver extraction and enzymatic degradation in the gastrointestinal tract, as well as achieving rapid onset of effect. Thus, this route of administration can offer attractive therapeutic advantages for certain drugs as a convenient substitute for parenteral administration and has been applied successfully to a number of therapeutic conditions, especially urgent cardiovascular conditions and acute severe pain control. However, due to inherent limitations such as small sublingual mucosa area for absorption, primarily passive mechanism of transport, short residence time, and potential local irritation, a relatively small number of sublingual products have been successfully developed to date. In this Review, key concepts and technologies for potential improvement of sublingual drug delivery are reviewed. The optimal application of these concepts and technologies, together with clinical need for non-parenteral delivery, will hopefully broaden the development of sublingual drug delivery in the future. PMID- 25287388 TI - Physical stabilization of low-molecular-weight amorphous drugs in the solid state: a material science approach. AB - Use of the amorphous state is considered to be one of the most effective approaches for improving the dissolution and subsequent oral bioavailability of poorly water-soluble drugs. However as the amorphous state has much higher physical instability in comparison with its crystalline counterpart, stabilization of amorphous drugs in a solid-dosage form presents a major challenge to formulators. The currently used approaches for stabilizing amorphous drug are discussed in this article with respect to their preparation, mechanism of stabilization and limitations. In order to realize the potential of amorphous formulations, significant efforts are required to enable the prediction of formulation performance. This will facilitate the development of computational tools that can inform a rapid and rational formulation development process for amorphous drugs. PMID- 25287390 TI - Strategies for delivering porphyrinoid-based photosensitizers in therapeutic applications. AB - Delivery strategies for porphyrinoid-based photosensitizers for use in therapeutic applications are based on a myriad of factors, which include porphyrinoid structure, solubility and cellular targets. These drug-delivery methods include encapsulation, hydrogels, protein carriers, nanoparticles and polymeric micelles among others. This article reviews the strategies for delivering porphyrinoids published to date and will focus on porphyrins, corroles, chlorins, bacteriochlorins, porphyrazines and phthalocyanines. Highlighted are the most recent and different strategies used for each of the corresponding porphyrinoid-based macrocycles. PMID- 25287389 TI - Ultrasound-enhanced transdermal delivery: recent advances and future challenges. AB - The skin is a formidable diffusion barrier that restricts passive diffusion to small (<500 Da) lipophilic molecules. Methods used to permeabilize this barrier for the purpose of drug delivery are maturing as an alternative to oral drug delivery and hypodermic injections. Ultrasound can reversibly and non-invasively permeabilize the diffusion barrier posed by the skin. This review discusses the mechanisms of ultrasound-permeability enhancement, and presents technological innovations in equipment miniaturization and recent advances in permeabilization capabilities. Additionally, potentially exciting applications, including protein delivery, vaccination, gene therapy and sensing of blood analytes, are discussed. Finally, the future challenges and opportunities associated with the use of ultrasound are discussed. It is stressed that developing ultrasound for suitable applications is key to ensure commercial success. PMID- 25287391 TI - Refluxing supernumerary kidney: easy to overlook. AB - Supernumerary kidney is a rare anomaly and most of the times it is incidentally detected. On occasions it may present with symptoms due to stones, tumours and infections. Supernumerary unit if small and dysplastic may easily escape detection. In this case report, supernumerary kidney presented as vesicoureteric reflux in a 4-year-old male child. PMID- 25287392 TI - Graft versus host disease following small bowel and abdominal wall transplantation. PMID- 25287393 TI - Benign sinonasal capillary haemangioma. AB - Haemangiomas are benign fibrovascular tumours relatively that are common in the head and neck, where 60% of them occur Among the various categories of haemangiomas, lobular capillary haemangiomas (LCH) occur frequently on the skin, lips, buccal mucosa, tongue and gingiva. However, they are vanishingly rare in the paranasal sinuses. The imaging features of LCH are non-specific. The histological characteristics of LCH can also make diagnosis difficult as sometimes resemble highly vascular malignant tumours. This leads to the false preoperative diagnosis of suspected malignancy in many cases, which places the patient under unnecessary distress and anxiety. We present a case of LCH appearing as a suspicious nasal lesion of the lateral nasal wall with unilateral nasal obstruction, necrotic centre and epistaxis. The tumour was excised endoscopically in one operation including endoscopic medial maxillectomy. Further education about this lesion is deemed important as preoperative embolisation may be needed for a safe operation. PMID- 25287395 TI - Cellular effects of low-intensity pulsed ultrasound and X-irradiation in combination in two human leukaemia cell lines. AB - Previously, we have shown that a combination between X-irradiation and low intensity pulsed ultrasound (US) could synergistically suppress cell survival post exposure (Buldakov et al., 2014). In this study, the cellular effects underlying the enhanced cell killing are investigated. U937 and Molt-4 cell lines were exposed to 1.0 MHz US with 50% duty factor at 0.3 W/cm(2) and pulsed at 1, 5 and 10 Hz immediately after exposure to X-rays at 0, 0.5, 2.5 and 5 Gy. The cells were assayed at different time points to depict the major cellular events that culminated in cell death. For instance, membrane damage and cell lysis were estimated immediately following exposure and 24 h later. Intracellular reactive oxygen species (ROS) were also determined flow cytometrically after treatment. Moreover, the extent of DNA damage and cell cycle progression were determined at 6 and 24 h, respectively. Despite the general trend for synergism, there was a disproportionation of mediating factors depending on the cell type and its specific biological makeup. Immediately, US could induce appreciable necrotic cell death through extensive membrane damage in U937 but induced cell lysis in Molt-4 cells. ROS might have contributed to cell killing in Molt-4 but not in U937 cells. Although both of the physical modalities are significantly DNA damaging alone, no additional damage was observed in combination. Moreover, override in some arrested cell cycle phases was also observed following combination. Collectively, the interaction between X-rays and US seems to depend mainly on the acoustic environment determined by the setup and this might explain the contradictory data among reports. PMID- 25287394 TI - Transcriptomic analysis of a psammophyte food crop, sand rice (Agriophyllum squarrosum) and identification of candidate genes essential for sand dune adaptation. AB - BACKGROUND: Sand rice (Agriophyllum squarrosum) is an annual desert plant adapted to mobile sand dunes in arid and semi-arid regions of Central Asia. The sand rice seeds have excellent nutrition value and have been historically consumed by local populations in the desert regions of northwest China. Sand rice is a potential food crop resilient to ongoing climate change; however, partly due to the scarcity of genetic information, this species has undergone only little agronomic modifications through classical breeding during recent years. RESULTS: We generated a deep transcriptomic sequencing of sand rice, which uncovers 67,741 unigenes. Phylogenetic analysis based on 221 single-copy genes showed close relationship between sand rice and the recently domesticated crop sugar beet. Transcriptomic comparisons also showed a high level of global sequence conservation between these two species. Conservation of sand rice and sugar beet orthologs assigned to response to salt stress gene ontology term suggests that sand rice is also a potential salt tolerant plant. Furthermore, sand rice is far more tolerant to high temperature. A set of genes likely relevant for resistance to heat stress, was functionally annotated according to expression levels, sequence annotation, and comparisons corresponding transcriptome profiling results in Arabidopsis. CONCLUSIONS: The present work provides abundant genomic information for functional dissection of the important traits in sand rice. Future screening the genetic variation among different ecotypes and constructing a draft genome sequence will further facilitate agronomic trait improvement and final domestication of sand rice. PMID- 25287397 TI - Blood pressure in relation to environmental lead exposure in the national health and nutrition examination survey 2003 to 2010. AB - In view of the declining environmental lead exposure in the United States, we analyzed the National Health and Nutrition Examination Survey (2003-2010) for association of blood pressure and hypertension with blood lead. The 12 725 participants included 21.1% blacks, 20.5% Hispanics, 58.4% whites, and 48.7% women. Blacks compared with non-Blacks had higher systolic and diastolic pressures (126.5 versus 123.9 and 71.9 versus 69.6 mm Hg) and higher hypertension prevalence (44.7 versus 36.8%). Blood lead was lower in whites than in non-whites (1.46 versus 1.57 MUg/dL) and in women than in men (1.25 versus 1.80 MUg/dL). In multivariable analyses of all participants, blood lead doubling was associated with higher (P<=0.0007) systolic and diastolic pressure (+0.76 mm Hg; 95% confidence interval, 0.38-1.13 and +0.43 mm Hg; 0.18-0.68), but not with the odds of hypertension (0.95; 0.90-1.01; P=0.11). Associations with blood lead were nonsignificant (P>=0.09) for systolic pressure in women and for diastolic pressure in non-whites. Among men, systolic pressure increased with blood lead (P<=0.060) with effect sizes associated with blood lead doubling ranging from +0.65 mm Hg in whites to +1.61 mm Hg in blacks. For systolic pressure, interactions of ethnicity and sex with blood lead were all significant (P<=0.019). In conclusion, small and inconsistent effect sizes in the associations of blood pressure with blood lead likely exclude current environmental lead exposure as a major hypertension cause in the United States. PMID- 25287398 TI - The arterial load and its role on the heart. PMID- 25287396 TI - Resistive and pulsatile arterial load as predictors of left ventricular mass and geometry: the multi-ethnic study of atherosclerosis. AB - Arterial load is composed of resistive and various pulsatile components, but their relative contributions to left ventricular (LV) remodeling in the general population are unknown. We studied 4145 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, who underwent cardiac MRI and radial arterial tonometry. We computed systemic vascular resistance (SVR=mean arterial pressure/cardiac output) and indices of pulsatile load including total arterial compliance (TAC, approximated as stroke volume/central pulse pressure), forward wave amplitude (Pf), and reflected wave amplitude (Pb). TAC and SVR were adjusted for body surface area to allow for appropriate sex comparisons. We performed allometric adjustment of LV mass for body size and sex and computed standardized regression coefficients (beta) for each measure of arterial load. In multivariable regression models that adjusted for multiple confounders, SVR (beta=0.08; P<0.001), TAC (beta=0.44; P<0.001), Pb (beta=0.73; P<0.001), and Pf (beta=-0.23; P=0.001) were significant independent predictors of LV mass. Conversely, TAC (beta=-0.43; P<0.001), SVR (beta=0.22; P<0.001), and Pf (beta= 0.18; P=0.004) were independently associated with the LV wall/LV cavity volume ratio. Women demonstrated greater pulsatile load than men, as evidenced by a lower indexed TAC (0.89 versus 1.04 mL/mm Hg per square meter; P<0.0001), whereas men demonstrated a higher indexed SVR (34.0 versus 32.8 Wood Units*m2; P<0.0001). In conclusion, various components of arterial load differentially associate with LV hypertrophy and concentric remodeling. Women demonstrated greater pulsatile load than men. For both LV mass and the LV wall/LV cavity volume ratio, the loading sequence (ie, early load versus late load) is an important determinant of LV response to arterial load. PMID- 25287399 TI - Periodic limb movements during sleep and prevalent hypertension in the multi ethnic study of atherosclerosis. AB - Periodic limb movements during sleep (PLMS) are associated with immediate increases in blood pressure. Both PLMS and hypertension have different distributions across racial/ethnic groups. We sought to determine whether PLMS is associated with hypertension among various racial/ethnic groups. A total of 1740 men and women underwent measurement of blood pressure and polysomnography with quantification of PLMS. Hypertension was defined as systolic blood pressure (SBP) >=140, diastolic BP >=90, or taking antihypertensive medication. For those taking antihypertensives, an estimated pretreatment SBP value was derived based on observed SBP and medication type/dose. Measures of PLMS, PLMS index, and PLMS arousal index were the main explanatory variables. Hypertension and SBP were modeled with logistic and multivariable regression adjusted for age, sex, body mass index, cardiovascular risk factors, lifestyle/habitual factors, apnea hypopnea index, and race/ethnicity. In the overall cohort, prevalent hypertension was modestly associated with PLMS index (10 U; odds ratio, 1.05; 95% confidence interval, 1.00-1.10) and PLMS arousal index (1 U; 1.05; 1.01-1.09) after adjusting for confounders. Association in the overall cohort was influenced by large effect sizes in blacks, in whom the odds of prevalent hypertension increased by 21% (1%-45%) for 10 U PLMS index increase and 20% (2%-42%) for 1-U PLMS arousal index increase. In blacks, every 1-U PLMS arousal index increase was associated with SBP 1.01 mm Hg higher (1.01; 0.04-1.98). Associations between PLMS and blood pressure outcomes were also suggested among Chinese-Americans but not in whites or Hispanics. In a multiethnic cohort of community-dwelling men and women, prevalent hypertension and SBP are associated with PLMS frequency in blacks. PMID- 25287401 TI - Masked hypertension: a phenomenon of measurement. PMID- 25287402 TI - Blood pressure in chronic kidney disease: does the emperor have new clothes? PMID- 25287400 TI - Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion. AB - We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the blood pressure (BP) responses to chronic L-NAME or angiotensin II (Ang II) infusion in Sprague-Dawley rats implanted with telemetry transmitters, venous catheters, and intracerebroventricular cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 MUg/kg/min IV, groups 1 and 2) or Ang II (10 ng/kg/min IV, groups 3 and 4) were infused for 24 days, and starting on day 7 of L-NAME or Ang II infusion, the MC3/4R antagonist SHU-9119 (24 nmol/d, n=6/group; groups 1 and 3) or vehicle (saline 0.5 MUL/h, n=6/group; groups 2 and 4) was infused intracerebroventricularly for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40+/-3 and 56+/-5 mm Hg, respectively, although heart rate was slightly reduced. MC3/4R blockade doubled food intake and reduced heart rate (~40 to ~50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mm Hg) and no change in rats receiving Ang II, although markedly reducing BP by 21+/-4 mm Hg in L-NAME-treated rats. After SHU-9119 infusion was stopped, food intake, heart rate, and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II. PMID- 25287403 TI - Relationship between cerebral blood flow and blood pressure in long-term heart transplant recipients. AB - Heart transplant recipients are at an increased risk for cerebral hemorrhage and ischemic stroke; yet, the exact mechanism for this derangement remains unclear. We hypothesized that alterations in cerebrovascular regulation is principally involved. To test this hypothesis, we studied cerebral pressure-flow dynamics in 8 clinically stable male heart transplant recipients (62+/-8 years of age and 9+/ 7 years post transplant, mean+/-SD), 9 male age-matched controls (63+/-8 years), and 10 male donor controls (27+/-5 years). To increase blood pressure variability and improve assessment of the pressure-flow dynamics, subjects performed squat stand maneuvers at 0.05 and 0.10 Hz. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal carbon dioxide were continuously measured during 5 minutes of seated rest and throughout the squat-stand maneuvers. Cardiac baroreceptor sensitivity gain and cerebral pressure-flow responses were assessed with linear transfer function analysis. Heart transplant recipients had reductions in R-R interval power and baroreceptor sensitivity low frequency gain (P<0.01) compared with both control groups; however, these changes were unrelated to transfer function metrics. Thus, in contrast to our hypothesis, the increased risk of cerebrovascular complication after heart transplantation does not seem to be related to alterations in cerebral pressure-flow dynamics. Future research is, therefore, warranted. PMID- 25287405 TI - The process of adapting a universal dating abuse prevention program to adolescents exposed to domestic violence. AB - Adolescents exposed to domestic violence are at increased risk of dating abuse, yet no evaluated dating abuse prevention programs have been designed specifically for this high-risk population. This article describes the process of adapting Families for Safe Dates (FSD), an evidenced-based universal dating abuse prevention program, to this high-risk population, including conducting 12 focus groups and 107 interviews with the target audience. FSD includes six booklets of dating abuse prevention information, and activities for parents and adolescents to do together at home. We adapted FSD for mothers who were victims of domestic violence, but who no longer lived with the abuser, to do with their adolescents who had been exposed to the violence. Through the adaptation process, we learned that families liked the program structure and valued being offered the program and that some of our initial assumptions about this population were incorrect. We identified practices and beliefs of mother victims and attributes of these adolescents that might increase their risk of dating abuse that we had not previously considered. In addition, we learned that some of the content of the original program generated negative family interactions for some. The findings demonstrate the utility of using a careful process to adapt evidence-based interventions (EBIs) to cultural sub-groups, particularly the importance of obtaining feedback on the program from the target audience. Others can follow this process to adapt EBIs to groups other than the ones for which the original EBI was designed. PMID- 25287406 TI - Understanding how advocates can affect sexual assault victim engagement in the criminal justice process. AB - Following a sexual assault, survivors may seek help from multiple community organizations including the criminal justice system (CJS). However, sexual assault survivors often feel apprehensive about participating in the CJS and thus, few report their victimizations to law enforcement. Of those who report, many withdraw their participation from the CJS. Rape crisis center advocates often are one of the first professionals victims encounter while seeking help after a victimization and thus, they may play a key role in reducing barriers to victim participation in the CJS. Qualitative interviews were conducted with forensic nurses and victim advocates at a Midwest Sexual Assault Nurse Examiner (SANE) program to examine how advocacy services may influence victim engagement with the CJS. This study found multiple components of advocacy services that may address common barriers to victim participation. Implications for research and practice are discussed. PMID- 25287407 TI - She said, he said, judge said: analyzing judicial decision making in civil protection order hearings. AB - A modest body of research has examined judicial decision making in civil protection order (CPO) cases. A major finding of this prior research is that the factors expected to shape judicial responses to CPO requests are often found to be insignificant. Because such decisions are often rendered in an environment of vast judicial discretion and competing allegations, the question of "what matters?" assumes added importance. This study examines permanent/final restraining order (PRO) outcomes for intimate partner violence on a number of variables. Specifically, chi-square analyses were performed examining the associations between granting/denying a PRO and demographic, relationship, hearing, and allegation characteristics associated with the petitioner and respondent. These tests helped to reveal relationships at the bivariate level and aided in further model-building using logistic regression and decision-tree analysis. The findings show that the factors most associated with PRO outcomes, namely, the denial of a PRO, are those reflecting the licit rather than illicit behavior of the respondent. PMID- 25287404 TI - Blood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the chronic renal insufficiency cohort study. AB - Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease, before starting hemodialysis. We determined the association between SBP and mortality at advanced chronic kidney disease and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort participants with advanced chronic kidney disease followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants (1) had an estimated glomerular filtration rate <30 mL/min/1.73 m2 (n=1705), (2) initiated hemodialysis and had dialysis-unit SBP measures (n=403), and (3) initiated hemodialysis and had out-of dialysis-unit SBP measured at a Chronic Renal Insufficiency Cohort study visit (n=326). Cox models were adjusted for demographics, cardiovascular risk factors, and dialysis parameters. A quadratic term for SBP was included to test for a U shaped association. At advanced chronic kidney disease, there was no association between SBP and mortality (hazard ratio, 1.02 [95% confidence interval, 0.98 1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (hazard ratio, 1.26 [95% confidence interval, 1.14-1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of dialysis-unit SBP, which may merit more consideration as a target for clinical management and in interventional trials. PMID- 25287408 TI - Issues and challenges in the application of Husserlian phenomenology to the lived experience of hate crime and its legal aftermath: an enlightenment prejudice against prejudice? AB - The field of hate crime research addresses the presence, sources, and impact of particular types of expressions of prejudice, often perceived as particularly damaging and hurtful forms of interpersonal abuse and violence. There is the reflexive question of the possibilities of researchers themselves ever being able to adopt a truly "unprejudiced" approach to the presence of such damaging prejudices. Can this goal be realized without a researcher necessarily losing an experientially grounded understanding of what these meanings, values and purposes have come to mean, and how they are themselves interpretively reconstituted anew, including within the lived experience of victims, witnesses, police, prosecutors, judges, and victim support workers? A possible philosophically informed approach to the dilemmas posed by this topic is offered by Husserl's phenomenology. This study critically explores the possibilities, reflective stages, and theoretical limitations of a sympathetically reconstructed Husserlian approach to hate crime. It argues that despite its manifest tensions, gaps, ambiguities, and internal contradictions, aspects of the Husserlian philosophical approach directed toward the different levels of experienced hate crime still retain the potential to both challenge and advance our understanding of this topic. PMID- 25287409 TI - Intimate partner violence perpetrators in a forensic psychiatric outpatient setting: criminal history, psychopathology, and victimization. AB - This study investigated criminological, psychopathological, and victimological profiles of intimate partner violence (IPV) perpetrators in a sample of 119 Dutch female and male forensic psychiatric outpatients aged 18 to 58 years. In addition, differences in criminological, psychopathological, and victimological factors between IPV perpetrators (n = 61, 51.3%) and non-intimate violence (NIV) perpetrators (n = 58, 48.7%) were examined. All data, including information on demographics, criminal history, history of psychological, sexual, and physical victimization during childhood or adolescence, family history of psychopathology, history of psychopathology in childhood and adolescence, and mental disorders, were derived from archival electronic medical records. Mental disorders were measured using structured psychiatric interviews and final consensus diagnoses were established during weekly case consultations. Both IPV and NIV perpetrators displayed high rates of criminal history, psychopathology, and previous victimization, but the two groups did not differ in these factors with two exceptions. IPV perpetrators were significantly more likely to have higher rates of previous physical victimization and intermittent explosive disorder than NIV perpetrators. The current study suggests that a history of physical victimization and intermittent explosive disorder are specific characteristics of IPV perpetrators in a forensic psychiatric outpatient setting. Future research should focus on mechanisms explaining the association of childhood victimization and IPV and increase our understanding of the role of intermittent explosive disorder in IPV. PMID- 25287410 TI - Men's Perceptions of an Acquaintance Rape: The Role of Relationship Length, Victim Resistance, and Gender Role Attitudes. AB - Sexual aggression is a persistent and prevalent issue in the United States, which often results in a number of psychological, emotional, and physical consequences for victims. The current study examined whether the length of relationship between the victim and perpetrator, level of victim resistance, and observers' gender role attitudes play a role in observers' perceptions of an alleged sexual assault. Participants included 297 male college students from a public university in the Northeastern United States. Contrary to hypotheses, there were no significant effects for length of relationship on participants' attributions. Relative to no resistance, verbal and physical strategies by the victim predicted higher levels of victim credibility, perpetrator culpability, and perpetrator guilt, as well as lower levels of victim culpability and perceived victim pleasure. Endorsement of traditional adversarial sex role beliefs and hostile sexist attitudes, as opposed to egalitarian attitudes, were associated with the attribution of less credibility to the victim, perceived victim trauma, perpetrator culpability, perpetrator guilt, and shorter recommended prison sentences, as well as greater victim culpability and perceived victim pleasure. Laypersons' perceptions of sexual assault merit further study, as they are relevant to juror decision making and third party responses to sexual victimization (e.g., peer support for victim) and can contribute to the secondary victimization and recovery of survivors of sexual assault. PMID- 25287412 TI - Lasting effect of intimate partner violence exposure during preschool on aggressive behavior and prosocial skills. AB - Intimate partner violence (IPV) exposure can negatively affect children's social behavior. However, it is unknown if the negative effects of IPV exposure during the preschool years are sustained through the early school years, if maladaptive behavior in one domain (e.g., aggressive behavior) is linked to subsequent maladaptive behavior in a different developmental domain (e.g., prosocial skill deficits), and if these relations differ by gender. This study addresses these gaps by using data from a sample of 1,125 children aged 3 to 4 at Time 1 and aged 5 to 7 at Time 2 from the National Survey of Child and Adolescent Well-Being. A series of nested longitudinal structural equation models were tested. Aggressive behavior and prosocial skills were stable across time. Time 1 IPV was associated with increased aggressive behavior at Time 1, which in turn was related to increased Time 2 aggressive behavior. Gender differences emerged; Time 2 IPV was associated with prosocial skills deficits for girls but not boys. A cross-domain relation existed between Time 1 aggressive behavior and Time 2 prosocial skills deficits for boys but not girls. These findings support that behavioral problems demonstrated later in childhood may emerge from earlier adverse developmental experiences and that difficulties in one domain may spill over into other developmental domains. Gender-specific interventions to promote competence in children may contribute to diverting children from maladaptive developmental outcomes. PMID- 25287411 TI - Fighting With Siblings and With Peers Among Urban High School Students. AB - Understanding the determinants of fighting is important for prevention efforts. Unfortunately, there is little research on how sibling fighting is related to peer fighting. Therefore, the aim of this study was to evaluate the association between sibling fighting and peer fighting. Data are from the Boston Youth Survey 2008, a school-based sample of youth in Boston, MA. To estimate the association between sibling fighting and peer fighting, we ran four multivariate regression models and estimated adjusted prevalence ratios and 95% confidence intervals. We fit generalized estimating equation models to account for the fact that students were clustered within schools. Controlling for school clustering, race/ethnicity, sex, school failure, substance use, and caregiver aggression, youth who fought with siblings were 2.49 times more likely to have reported fighting with peers. To the extent that we can confirm that sibling violence is associated with aggressive behavior, we should incorporate it into violence prevention programming. PMID- 25287413 TI - Violence exposure and teen dating violence among African American youth. AB - This study examines the relationships between exposure to violence in the community, school, and family with dating violence attitudes and behaviors among 175 urban African American youth. Age, gender, state support and experiences with neglect, school violence, and community violence were the most significant predictors of acceptance of dating violence. Experiences with community violence and age were important predictors of dating violence perpetration and victimization. Findings highlight the importance of planning prevention programs that address variables affecting attitudes and behaviors of high-risk youth who have already been exposed to multiple types of violence. PMID- 25287414 TI - Does Child Maltreatment Predict Adult Crime? Reexamining the Question in a Prospective Study of Gender Differences, Education, and Marital Status. AB - Bivariate analyses of adult crime and child maltreatment showed that individuals who had been maltreated as children, according to child welfare reports, subsequently committed more crime than others who had not been maltreated. Analyses of crimes by category-property, person, and society-provided further evidence of a link between child maltreatment and crime at the bivariate level. Tests of gender differences showed that crime generally is more prevalent among males, although females with a history of maltreatment were more likely than those in a no-maltreatment (comparison) group to report having had some prior involvement in crime. Surprisingly, multivariate analyses controlling for childhood socioeconomic status, gender, minority racial status, marital status, and education level showed that, with one exception (crimes against society), the significant association between child maltreatment and crime observed in bivariate tests was not maintained. Implications for future research are discussed. PMID- 25287415 TI - The Relationship Between Child Maltreatment and Partner Violence Victimization and Perpetration Among College Students: Focus on Auditory Status and Gender. AB - Partner violence is a pervasive public health concern that has received significant attention over the past three decades. Although a number of studies have reported that college students who are Deaf or hard of hearing are at an increased risk of experiencing partner violence compared with their hearing counterparts, little is known about partner violence perpetration among college students who are Deaf or hard of hearing. Furthermore, beyond disability, studies examining partner violence among students with disabilities tend to ignore other potential risk factors that may increase the risk of partner violence as a victim and/or a perpetrator. This exploratory study examines the extent of partner violence among male and female college students by auditory status and the relationship between experiencing and perpetrating partner abuse (i.e., physical abuse and psychological abuse) and child maltreatment (i.e., witnessing abuse and experiencing child physical abuse). The study also examines gender differences in the relationship between child maltreatment and physical and psychological abuse victimization and perpetration. Data were collected from a sample of approximately 680 college students at a northeastern university. Findings indicate that having witnessed interparental abuse as a child was only significant for being an adult victim of physical abuse. Having been a child victim of parental abuse was not significant for any of the abuse measures. Gender was only significant for being an adult victim of physical abuse. Deaf students were significantly more likely to report all abuse measures. Implications and directions for further research are discussed. PMID- 25287416 TI - An estimate of the incidence of influenza-like illness during the influenza pandemic of 2009. AB - INTRODUCTION: The influenza pandemic of 2009 had a great social impact. Many health resources were devoted to the care, prevention and surveillance of this disease. Epidemiological surveillance is based on the reporting of cases of influenza-like illness (ILI) and confirmed influenza cases. The objective was to estimate the true incidence of ILI during the influenza pandemic of 2009. METHODS: The capture-recapture method was applied during the month of highest influenza incidence in Castellon. Two notification systems were used: (i)electronic reporting of Notifiable Diseases (ND), and (ii)laboratory-based (LAB) data collection. Estimates were made by stratifying by age group and week. Independence coefficients were calculated for those strata. RESULTS: No dependence was found between stratification variables and the reporting system. A total of 7,181 ND cases and 524 LAB cases were identified, of which 211 were recorded in both systems. The estimated total of cases was 17,785 in a single month. In the study period, almost 4% of people in the area suffered flu symptoms (cumulative incidence), with 1% being affected each day (daily prevalence). The sensitivity of the ND system was 40%, i.e., the percentage of patients seeking primary care. CONCLUSIONS: To obtain an estimate of the actual incidence of influenza-like illness in the population during a pandemic period, the number of medical consultations should be multiplied by a factor of 2.5. This factor is lower than that estimated for periods without pandemic alert. PMID- 25287417 TI - Inflammation-based scores and hepatocellular carcinoma. PMID- 25287418 TI - Ileocolonic anastomosis after right hemicolectomy for colon cancer: functional end-to-end or end-to-side? AB - BACKGROUND: The purpose of this study was to compare short-term clinical outcomes of ileocolonic functional end-to-end anastomosis (FEEA) and end-to-side anastomosis (ESA) following resection of the right colon for cancer. METHODS: We enrolled 379 patients who underwent ileocolonic anastomosis following resection of the right colon for cancer by a single surgeon, from January 2009 through June 2012. Patient characteristics, operative results, and postoperative complications were analyzed. RESULTS: A total of 164 patients received ESA and 215 patients received FEEA. The FEEA group had a lower incidence of anastomotic error (0.9% versus 4.3%; P = 0.04) and a shorter operating time (140.4 +/- 14.9 min versus 150.5 +/- 20.1 min; P = 0.001). The length of hospital stay (10.9 +/- 3.5 days versus 11.3 +/- 4.0 days; P = 0.36) and anastomotic leakage (1.8% versus 0.5%; P = 0.20) were similar in both groups. No relevant differences between FEEA and ESA were observed for blood loss, retrieved lymph nodes, first flatus and postoperative complications. CONCLUSION: An FEEA after right hemicolectomy for colon cancer is a safe and reliable anastomotic technique, resulting in a favorable outcome in selected patients with the right colon cancer. PMID- 25287419 TI - Self-reported exercise and longitudinal outcomes in cystic fibrosis: a retrospective cohort study. AB - BACKGROUND: Cystic fibrosis (CF) is characterized by recurrent respiratory infections and progressive lung disease. Whereas exercise may contribute to preserving lung function, its benefit is difficult to ascertain given the selection bias of healthier patients being more predisposed to exercise. Our objective was to examine the role of self-reported exercise with longitudinal lung function and body mass index (BMI) measures in CF. METHODS: A total of 1038 subjects with CF were recruited through the U.S. CF Twin-Sibling Study. Questionnaires were used to determine exercise habits. Questionnaires, chart review, and U.S. CF Foundation Patient Registry data were used to track outcomes. RESULTS: Within the study sample 75% of subjects self-reported regular exercise. Exercise was associated with an older age of diagnosis (p = 0.002), older age at the time of ascertainment (p < 0.001), and higher baseline FEV1 (p = 0.001), but not CFTR genotype (p = 0.64) or exocrine pancreatic function (p = 0.19). In adjusted mixed models, exercise was associated with both a reduced decline in FEV1 (p < 0.001) and BMI Z-score (p = 0.001) for adults, but not children aged 10 17 years old. CONCLUSIONS: In our retrospective study, self-reported exercise was associated with improved longitudinal nutritional and pulmonary outcomes in cystic fibrosis for adults. Although prospective studies are needed to confirm these associations, programs to promote regular exercise among individuals with cystic fibrosis would be beneficial. PMID- 25287421 TI - Anti-Mullerian hormone reduction after ovarian cyst surgery is dependent on the histological cyst type and preoperative anti-Mullerian hormone levels. AB - OBJECTIVE: To investigate changes in serum anti-Mullerian hormone (AMH) concentrations following ovarian cyst surgery, and predictors of these changes. DESIGN: Prospective cohort study with follow up at 3 and 6 months. SETTING: University hospital. POPULATION: Women of reproductive age scheduled for ovarian cyst surgery. METHODS: Women were recruited between March 2011 and March 2012 (n = 75). Serum AMH concentrations were measured preoperatively and at 3 and 6 months postoperatively. MAIN OUTCOME MEASURES: Changes in AMH after surgery and predictors for these changes. RESULTS: After surgery, median AMH levels decreased significantly from 2.7 MUg/L (0.2-16.9) to 1.6 MUg/L (0.2-9.9) at 3 months and were still low, 1.6 MUg/L (0.2-8.3) at 6 months (both p < 0.001). In patients with unilateral cysts, a significant and more rapid AMH decrease was seen after enucleation of endometriomas (n = 19) vs. dermoid cysts (n = 22) (p = 0.010). The reduction was long-lasting at 6 months. In a multivariate regression analysis, a higher baseline AMH concentration was predictive of AMH reduction at 3 [odds ratio (OR) 1.9, 95% CI 1.1-3.1] and 6 months postoperatively (OR 2.5, 95% CI 1.2 5.2). Women with normal or elevated baseline AMH presented with a significant reduction of -23% and -43% at 3 and 6 months, respectively, whereas women with low or very low AMH had minimal or no changes over time. Patient's age, cyst size, duration of surgery or intraoperative bleeding were not predictive of a postoperative AMH decrease. CONCLUSIONS: Reduction of AMH was of greater magnitude and longer duration after enucleation of endometriomas and in women with normal and high preoperative AMH levels. PMID- 25287420 TI - Wolbachia lipoproteins: abundance, localisation and serology of Wolbachia peptidoglycan associated lipoprotein and the Type IV Secretion System component, VirB6 from Brugia malayi and Aedes albopictus. AB - BACKGROUND: Lipoproteins are the major agonists of Wolbachia-dependent inflammatory pathogenesis in filariasis and a validated target for drug discovery. Here we characterise the abundance, localisation and serology of the Wolbachia lipoproteins: Wolbachia peptidoglycan associated lipoprotein and the Type IV Secretion System component, VirB6. METHODS: We used proteomics to confirm lipoprotein presence and relative abundance; fractionation, immunoblotting and confocal and electron immuno-microscopy for localisation and ELISA for serological analysis. RESULTS: Proteomic analysis of Brugia malayi adult female protein extracts confirmed the presence of two lipoproteins, previously predicted through bioinformatics: Wolbachia peptidoglycan associated lipoprotein (wBmPAL) and the Type IV Secretion System component, VirB6 (wBmVirB6). wBmPAL was among the most abundant Wolbachia proteins present in an extract of adult female worms with wBmVirB6 only detected at a much lower abundance. This differential abundance was reflected in the immunogold-labelling, which showed wBmPAL localised at numerous sites within the bacterial membranes, whereas wBmVirB6 was present as a single cluster on each bacterial cell and also located within the bacterial membranes. Immunoblotting of fractionated extracts confirmed the localisation of wBmPAL to membranes and its absence from cytosolic fractions of C6/36 mosquito cells infected with wAlbB. In whole worm mounts, antibody labelling of both lipoproteins were associated with Wolbachia. Serological analysis showed that both proteins were immunogenic and raised antibody responses in the majority of individuals infected with Wuchereria bancrofti. CONCLUSIONS: Two Wolbachia lipoproteins, wBmPAL and wBmVirB6, are present in extracts of Brugia malayi with wBmPAL among the most abundant of Wolbachia proteins. Both lipoproteins localised to bacterial membranes with wBmVirB6 present as a single cluster suggesting a single Type IV Secretory System on each Wolbachia cell. PMID- 25287423 TI - Staphylococcus aureus DivIB is a peptidoglycan-binding protein that is required for a morphological checkpoint in cell division. AB - Bacterial cell division is a fundamental process that requires the coordinated actions of a number of proteins which form a complex macromolecular machine known as the divisome. The membrane-spanning proteins DivIB and its orthologue FtsQ are crucial divisome components in Gram-positive and Gram-negative bacteria respectively. However, the role of almost all of the integral division proteins, including DivIB, still remains largely unknown. Here we show that the extracellular domain of DivIB is able to bind peptidoglycan and have mapped the binding to its beta subdomain. Conditional mutational studies show that divIB is essential for Staphylococcus aureus growth, while phenotypic analyses following depletion of DivIB results in a block in the completion, but not initiation, of septum formation. Localisation studies suggest that DivIB only transiently localises to the division site and may mark previous sites of septation. We propose that DivIB is required for a molecular checkpoint during division to ensure the correct assembly of the divisome at midcell and to prevent hydrolytic growth of the cell in the absence of a completed septum. PMID- 25287424 TI - Proteins without unique 3D structures: biotechnological applications of intrinsically unstable/disordered proteins. AB - Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are functional proteins or regions that do not have unique 3D structures under functional conditions. Therefore, from the viewpoint of their lack of stable 3D structure, IDPs/IDPRs are inherently unstable. As much as structure and function of normal ordered globular proteins are determined by their amino acid sequences, the lack of unique 3D structure in IDPs/IDPRs and their disorder-based functionality are also encoded in the amino acid sequences. Because of their specific sequence features and distinctive conformational behavior, these intrinsically unstable proteins or regions have several applications in biotechnology. This review introduces some of the most characteristic features of IDPs/IDPRs (such as peculiarities of amino acid sequences of these proteins and regions, their major structural features, and peculiar responses to changes in their environment) and describes how these features can be used in the biotechnology, for example for the proteome-wide analysis of the abundance of extended IDPs, for recombinant protein isolation and purification, as polypeptide nanoparticles for drug delivery, as solubilization tools, and as thermally sensitive carriers of active peptides and proteins. PMID- 25287425 TI - [Recurrent nevus or recurrent melanoma]. PMID- 25287422 TI - Partial rescue of V1V2 mutant infectivity by HIV-1 cell-cell transmission supports the domain's exceptional capacity for sequence variation. AB - BACKGROUND: Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry. RESULTS: In a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the alpha4beta7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission. CONCLUSIONS: Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1. PMID- 25287428 TI - Acute kidney injury: acute kidney injury associated with burnt sugarcane harvesting. PMID- 25287429 TI - Transplantation: rituximab induction for prevention of HLA-antibody rebound. AB - Desensitization therapy enables HLA-incompatible transplantation. However, desensitized patients have an increased risk of antibody-mediated rejection, and the presence of donor-specific antibodies (DSAs) is associated with poor outcomes. A new study has assessed the effect of rituximab induction on DSA production in kidney transplant recipients with high immunological risk. PMID- 25287430 TI - Hypertension: dendritic cells: linking oxidation and hypertension. PMID- 25287434 TI - Constraining cyclic peptides to mimic protein structure motifs. AB - Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein-like structures in water. However, short peptides can be induced to fold into protein like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic peptides can have protein like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties. PMID- 25287435 TI - Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non-small-cell lung cancer. AB - Interstitial lung disease (ILD) occurrence and risk factors were investigated in the Japanese non-small-cell lung cancer, post-marketing, large-scale surveillance study, POLARSTAR. All patients with unresectable, recurrent/advanced non-small cell lung cancer who were treated with erlotinib in Japan between December 2007 and October 2009 were enrolled. Primary endpoints were patterns of ILD and risk factors for onset of ILD and ILD-related death. Overall survival, progression free survival, and occurrence of adverse drug reactions were secondary endpoints. Interstitial lung disease was confirmed in 429 (4.3%) patients. Concurrent/previous ILD (hazard ratio, 3.19), emphysema or chronic obstructive pulmonary disease (hazard ratio, 1.86), lung infection (hazard ratio, 1.55), smoking history (hazard ratio, 2.23), and period from initial cancer diagnosis to the start of treatment (<360 days; hazard ratio, 0.58) were identified as significant risk factors for developing ILD by Cox multivariate analysis. Logistic regression analysis identified Eastern Cooperative Oncology Group performance status 2-4 (odds ratio, 2.45 [95% confidence interval, 1.41-4.27]; P = 0.0016), <=50% remaining normal lung area (odds ratio, 3.12 [1.48-6.58]; P = 0.0029), and concomitant honeycombing with interstitial pneumonia (odds ratio, 6.67 [1.35-32.94]; P = 0.02) as poor prognostic factors for ILD death. Median overall survival was 277 days; median progression-free survival was 67 days. These data confirm the well-characterized safety profile of erlotinib. Interstitial lung disease is still an adverse drug reaction of interest in this population, and these results, including ILD risk factors, give helpful information for treatment selection and monitoring. Erlotinib efficacy was additionally confirmed in this population. (POLARSTAR trial ML21590.). PMID- 25287436 TI - Predictors of prostate-specific antigen biochemical recurrence in patients undergoing primary whole-gland prostate cryoablation. AB - PURPOSE: Cryoablation has been proven as a less invasive, safe, and effective treatment for localized prostate cancer. We attempted to identify the predictors of biochemical recurrence after prostate cryoablation for localized prostate cancer in this study. METHODS: We reviewed 114 patients who underwent primary whole-gland prostate cryoablation for localized prostate cancer from October 2008 to March 2013. The perioperative parameters included age >70 years, initial prostate-specific antigen (PSA), preoperative prostate volume, Gleason score, T stage, D'Amico risk group, postoperative PSA nadir, time to PSA nadir, and PSA biochemical recurrence, defined by Phoenix definition (nadir plus 2 ng/mL). Receiver operating characteristic (ROC) analysis was used for the best cutoff value of PSA nadir for PSA biochemical recurrence. The parameters were analyzed in binary logistic regression and Kaplan-Meier analysis for PSA biochemical recurrence. RESULTS: A total of 31.6 % (N = 36) patients had PSA biochemical recurrence during the median follow-up of 34.87 +/- 16.49 months. ROC analysis revealed that the best cutoff value for biochemical recurrence prediction was when the PSA nadir = 0.3 ng/mL. On multivariate analysis and Kaplan-Meier analysis, the D'Amico high-risk group [hazard ratio (HR) 6.552; p = 0.014], PSA nadir >0.3 ng/mL (HR 34.062; p < 0.001), and time to PSA nadir <3 months (HR 4.144; p = 0.021) were statistically significant for PSA biochemical recurrence. CONCLUSIONS: The D'Amico high-risk group, postoperative PSA nadir >0.3 ng/mL, and time to PSA nadir <3 months predict biochemical recurrence in primary whole-gland prostate cryoablation. PMID- 25287437 TI - Anesthetic selection and disease-free survival following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. AB - BACKGROUND: Previous studies have offered conflicting results regarding an association between perioperative epidural analgesia and disease-free survival (DFS) following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. A possible separate role for inhalational anesthetics has not been assessed. METHODS: We conducted a historical cohort study of all women undergoing optimal primary cytoreduction (<1 cm residual disease) for Stage III epithelial ovarian cancer between January 1, 2007, and December 31, 2011, at Brigham and Women's Hospital. Cohorts were defined by exposure to perioperative epidural analgesia or exposure to specific volatile anesthetics. The primary outcome was DFS. RESULTS: A total of 194 patients met study inclusion criteria. Addition of epidural analgesia was associated with a lower overall rate of ovarian cancer recurrence compared with general anesthesia alone (72 vs. 85 %, p = 0.028). Longer median DFS was associated with more than 48 h of epidural use (14.9 months) compared with fewer than 24 h (10.9 months) or 24-48 h of epidural use (10.0 months; p = 0.025). Use of desflurane was associated with a lower overall rate of ovarian cancer recurrence compared with sevoflurane (63 vs. 84 %, p = 0.01). In multivariate analysis, use of desflurane was independently associated with improved DFS (hazards ratio 0.563; 95% confidence interval 0.33 0.962). CONCLUSIONS: For patients with Stage III ovarian cancer, use of desflurane is associated with improved DFS following primary cytoreductive surgery compared with other volatile anesthetics. If epidural analgesia offers additional benefit, this effect appears limited to patients with more than 48 h of postoperative epidural use. PMID- 25287433 TI - Chronic kidney disease and premature ageing. AB - Chronic kidney disease (CKD) shares many phenotypic similarities with other chronic diseases, including heart failure, chronic obstructive pulmonary disease, HIV infection and rheumatoid arthritis. The most apparent similarity is premature ageing, involving accelerated vascular disease and muscle wasting. We propose that in addition to a sedentary lifestyle and psychosocial and socioeconomic determinants, four major disease-induced mechanisms underlie premature ageing in CKD: an increase in allostatic load, activation of the 'stress resistance response', activation of age-promoting mechanisms and impairment of anti-ageing pathways. The most effective current interventions to modulate premature ageing treatment of the underlying disease, optimal nutrition, correction of the internal environment and exercise training-reduce systemic inflammation and oxidative stress and induce muscle anabolism. Deeper mechanistic insight into the phenomena of premature ageing as well as early diagnosis of CKD might improve the application and efficacy of these interventions and provide novel leads to combat muscle wasting and vascular impairment in chronic diseases. PMID- 25287438 TI - Histopathologic correlation of residual mammographic microcalcifications after neoadjuvant chemotherapy for locally advanced breast cancer. AB - OBJECTIVE: This study was designed to determine the histopathologic correlation at surgery of residual mammographic calcifications in patients after neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC). METHODS: This single-institution, retrospective study was approved by the Institutional Review Board and was Health Insurance Portability and Accountability act compliant. Women with LABC who underwent NAC between January 1, 2004 and December 31, 2008 and had mammography performed before and after NAC available for review were included in this study. The extent of microcalcifications associated with cancer before and after the completion of NAC was correlated with histopathology and biomarker status. RESULTS: Of 494 patients who met the inclusion criteria, 106 demonstrated microcalcifications on pre-, post-chemotherapy, or both sets of mammograms and were included in this study. Of 106 women, 31 (29 %) had invasive ductal carcinoma (IDC) and 60 (57 %) had both IDC and ductal carcinoma in situ (DCIS). Microcalcifications decreased or remained stable in 76 (72 %) patients after completion of NAC. Correlation of microcalcifications with histopathology after NAC showed that 43 (40.6 %) patients had tumors associated with benign pathology. Of 32 patients with pathologic complete response, calcifications were associated with DCIS in 9 (9 %) and benign findings in 21 (22 %). The proportion of residual malignant calcifications was higher in ER+ versus ER- patients after NAC. CONCLUSIONS: The extent of calcifications on mammography following NAC does not correlate with the extent of residual disease in up to 22 % of women; this information may impact surgical planning in subsets of women with breast cancer. PMID- 25287439 TI - Cryoablation provides superior local control of primary hepatocellular carcinomas of >2 cm compared with radiofrequency ablation and microwave coagulation therapy: an underestimated tool in the toolbox. AB - BACKGROUND: Although cryoablation (Cryo) has been advocated as an effective locoregional therapy for hepatocellular carcinoma (HCC), few studies have compared the outcomes with those of radiofrequency ablation (RFA) and microwave coagulation therapy (MCT). METHODS: Consecutive patients with primary HCCs of <5 cm received Cryo or RFA/MCT between 1998 and 2011 and were monitored for local recurrence (defined as a recurrent tumor at or in direct contact with the ablated area) and overall complication rates. RESULTS: The median tumor size was 2.5 cm in the Cryo group (n = 55) and 1.9 cm in the RFA/MCT group (n = 64; P < 0.001), but other patient characteristics were similar. Multivariate Cox regression analysis revealed Cryo as the only independent factor for improved 2-year local recurrence-free survival, with a hazard ratio (HR) of 0.3 (95 % confidence interval, 0.1-0.9; P = 0.02). Tumor diameter was a negative indicator of local recurrence-free survival (HR, 2.0; 95 % confidence interval, 1.1-3.5; P = 0.02). Subgroup analysis of patients with tumors of >2 cm demonstrated significantly better local recurrence rates in the Cryo group compared with the RFA/MCT group (21 vs. 56 % at 2 years; P = 0.006). Overall complication rates and incidences of Clavien-Dindo classification grade >= III were identical (both P = 1.00). No in hospital mortality occurred. CONCLUSIONS: Appropriate use of Cryo, as shown in this series, is safe and provides significantly improved local control for the treatment of primary HCCs of >2 cm compared with RFA/MCT. PMID- 25287440 TI - Conditional survival after surgical resection of gastric cancer: a multi institutional analysis of the us gastric cancer collaborative. AB - BACKGROUND: Survival estimates following surgical resection of gastric adenocarcinoma are traditionally reported as survival from the date of surgery. Conditional survival (CS) estimates, however, may be more clinically relevant by accounting for time already survived. We assessed CS following surgical resection for gastric adenocarcinoma. METHODS: We analyzed 807 patients who underwent resection for gastric adenocarcinoma from 2000 to 2012 at seven participating institutions in the U.S. Gastric Cancer Collaborative. Cox proportional hazards models were used to evaluate factors associated with overall survival. Three-year CS estimates at "x" year after surgery were calculated as follows: CS3 = S(x+3)/S(x). RESULTS: Overall 1-, 3-, and 5-year overall survival rates after gastric resection were 42, 34, and 30 %, respectively. Using CS estimates, the probability of surviving an additional 3 years given that the patient had survived at 1, 3, and 5 years were 56, 71, and 82 %, respectively. Patients with higher risk at baseline (i.e., stage III or IV disease, lymphovascular invasion) demonstrated the greatest increase in CS over time. CONCLUSIONS: Survival estimates following surgical resection of gastric adenocarcinoma is dynamic; the probability of survival increases with time already survived. Patients with worse prognostic features at the time of surgery had the greatest increases in CS over time. Conditional survival estimates provide important information about the changing probability of survival over time and should be used among patients with resected gastric adenocarcinoma to guide subsequent follow-up strategies. PMID- 25287441 TI - Local low-dose thrombolysis for safe and effective treatment of venous port catheter thrombosis. AB - PURPOSE: Retrospective evaluation of local low-dose thrombolysis for treatment of venous port-catheter thrombosis. METHODS: A total of 1,031 patients with dysfunctional port systems underwent port angiography depicting 181 patients with thrombosis around the port-catheter. A total of 165 patients (male 35, female 130; age 57.3 +/- 12.9 [20-83] years) underwent thrombolysis by single injection of 3 mg alteplase into the port system. Patients were followed up by clinical and angiographic/radiological port controls the next day and 12.9 +/- 17.9 [1-81] months on the basis of regular oncologic staging examinations. RESULTS: Thrombosis occurred 10.1 +/- 19.3 [median 2.9] months after port implantation and was clinically suspected by difficult blood aspiration in 146 of 181 (80.7 %) and high resistance to injection fluids in 75 (41.4 %) patients. A predictor for angiographically confirmed port-catheter thrombosis was a combination of both (73, 40.3 % patients) (Fisher's exact test p < 0.0001; positive predictive value 0.8977), or suboptimal (not cavoatrial) port-catheter position (92, 50.8 % patients) (p = 0.0047; positive predictive value 0.8276). The cumulative success rate of thrombolysis was 92.7 % (153 of 165 patients). Initial thrombolysis was effective in 127 (77.0 %) patients. Repeated (up to 6 times) thrombolysis was effective in 26 of 31 patients after second or third thrombolysis. Extensive central venous thrombosis (9 patients) predicted ineffective thrombolysis (p < 0.0001). Primary patency of successfully treated devices was 92.8 % at 1 month and 84.9 % at 3 months. Rethrombosis occurred in 27 patients after 4.4 +/- 6.6 (median 1.8) months. Primary rethrombolysis was effective in 22 (81.5 %) patients. Cumulative patency was 100 % at 3 months. CONCLUSIONS: Difficult aspiration combined with high resistance to injection fluids or suboptimal port catheter position are strong independent predictors for port-catheter thrombosis. Local low-dose thrombolysis or repeat thrombolysis is safe and effective in the absence of large central venous thrombosis. PMID- 25287442 TI - p204-Mediated innate antiviral responses in mouse adipose cells and their effects on cell functions. AB - Viruses can infect adipose tissues. However, innate antiviral responses in adipose cells and their effects on adipocyte function have not yet been intensively investigated. In this study, p204-initiated innate antiviral responses in mouse adipose cells were examined. Cytosolic DNA sensor p204 and its signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in primary preadipocytes. Synthetic herpes simplex viral DNA (HSV60), a p204 ligand, induced type I IFN expression by activating IFN regulatory factor 3. Major antiviral proteins, including IFN-stimulating gene 15, 2',5'-oligoadenylate synthetase and Mx GTPase 1, in preadipocytes were upregulated by HSV60. HSV60-triggered innate antiviral responses were significantly reduced by inhibition of p204 signaling with specific small interfering RNA targeting p204 or STING. HSV60 inhibited the differentiation of preadipocytes to mature adipocytes and enhanced the proliferation of adipose cells. Moreover, HSV60 induced innate antiviral responses in mature adipocytes and inhibited expressions of several adipokines, including leptin, adiponectin and resistin. These results indicated that p204 initiated innate antiviral responses in adipose cells, thereby modulating adipocyte function. PMID- 25287443 TI - Overexpression of Jagged-1 combined with blockade of CD40 pathway prolongs allograft survival. AB - Dendritic cells (DCs) have the tolerogenic potential to regulate adaptive immunity and induce allografts acceptance. Here we investigated whether blockade of the CD40 pathway could enhance the immune tolerance induced by DC2.4 cells modified to express Jagged-1 (JAG1-DC) in heart transplantation. Results showed that JAG1-DC treatment combined with anti-CD40L monoclonal antibody (mAb) administration significantly prolonged cardiac allograft survival in mice, with long-term survival (>110 days) of 50% of the allografts in the recipients. The therapy specifically inhibited the immune response, induced alloantigen-specific T-cell hyporesponsiveness, upregulated transforming growth factor-beta synthesis and increased the population of regulatory T cells (Tregs) driven by Jagged-1 Notch activation. These results highlight the potential application of gene therapy to induce alloantigen-specific Tregs effectively by providing the Jagged 1 stimulation. PMID- 25287444 TI - The bullseye synapse formed between CD4+ T-cell and staphylococcal enterotoxin B pulsed dendritic cell is a suppressive synapse in T-cell response. AB - The immunological synapse (IS) is a supermolecular activation cluster formed between T cells and antigen-presenting cells. Although diverse IS structures have been reported, the function of the IS in T-cell activation remains unclear. Here, we found that the bullseye IS, one of IS types at the interface of CD4(+) T cells and staphylococcal enterotoxin B-pulsed dendritic cells, suppressed CD4(+) T-cell activation, whereas multifocal IS, another synapse type, stimulated CD4(+) T-cell activation. Consistent with these results, bullseye IS formation was accompanied by a low-level calcium response in T cells and a loss of T-cell receptor signalling molecules from the synapse, whereas multifocal IS exhibited the opposite. Furthermore, we found that CD4(+)CD25(+) regulatory T cells (T(regs)) more efficiently formed bullseye IS and promoted bullseye IS formation in CD4(+) CD25(-) T cells. Cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitory molecule expressed continuously on T(regs), was localised in bullseye IS. Moreover, blocking CTLA-4 reduced the percentage of bullseye IS formation and promoted T-cell activation. Our data thus indicate that bullseye IS formation is mediated by CTLA-4, and may negatively control T-cell activation as a suppressive synapse. PMID- 25287447 TI - DOES LOWER SUBJECTIVE SOCIAL STATUS YIELD RISKIER BIOMARKER PROFILES? AB - Both objective and, more recently, subjective measures of low social status have been linked to poor health outcomes. It is unclear, however, through which precise physiological mechanisms such standing may influence health, although it has been proposed that those of lower status may have biomarker profiles that are more dysregulated (and hence pose a greater risk for poorer health). The main objective of this study was to investigate whether lower subjective social standing is associated with riskier neuroendocrine biomarker profiles. Data were from the Social Environment and Biomarkers of Aging Study (SEBAS), a nationally representative survey of Taiwanese men and women (ages 54-91) conducted in Taiwan in 2000. Five neuroendocrine markers (cortisol, dehydroepiandrosterone sulphate (DHEAS), adrenaline, noradrenaline and dopamine) were analysed both separately and collectively in an index termed neuroendocrine allostatic load (NAL) in relation to status - both self-reported and as measured through objective socioeconomic status (SES) indicators. For the biomarker DHEAS, some connection was found between its levels and the measures of status, but for the other markers and the NAL index almost no connection was found. The overall negative finding of this paper would be further supported with more and different measures of neuroendocrine system function and a reordering of the subjective social status questions in the survey such that the one probing about status in the community (that has no prompt) was asked before the one probing about status in all of Taiwan (which has a SES prompt). PMID- 25287445 TI - Autophagy in T-cell development, activation and differentiation. AB - Autophagy is a vital catabolic process for degrading bulky cytosolic contents, which cannot be resorbed via the proteasome. First described as a survival mechanism during nutrient starvation conditions, recent reports have demonstrated that autophagy supports metabolic functions of T cells at various stages of maturation and effector function. Autophagy is crucial for T-cell development at the precursor stage as self-renewability and quiescence of hematopoietic stem cells depend on autophagy of the mitochondria and the endoplasmic reticulum. Later, during development in the thymus, autophagy regulates peptide presentation in stromal cells and professional antigen-presenting cells, which mediate thymocyte selection. Furthermore, the metabolic changes when mature T cells enter the periphery and when they are activated are both dependent on autophagy. Lastly, autophagy prevents early aging and, thus, ensures maintenance of memory T cells. PMID- 25287446 TI - Tubulin- and actin-associating GIMAP4 is required for IFN-gamma secretion during Th cell differentiation. AB - Although GTPase of the immunity-associated protein (GIMAP) family are known to be most highly expressed in the cells of the immune system, their function and role remain still poorly characterized. Small GTPases in general are known to be involved in many cellular processes in a cell type-specific manner and to contribute to specific differentiation processes. Among GIMAP family, GIMAP4 is the only member reported to have true GTPase activity, and its transcription is found to be differentially regulated during early human CD4(+) T helper (Th) lymphocyte differentiation. GIMAP4 has been previously connected mainly with T- and B-cell development and survival and T-cell apoptosis. Here we show GIMAP4 to be localized into cytoskeletal elements and with the component of the trans golgi network, which suggests it to have a function in cellular transport processes. We demonstrate that depletion of GIMAP4 with RNAi results in downregulation of endoplasmic reticulum localizing chaperone VMA21. Most importantly, we discovered that GIMAP4 regulates secretion of cytokines in early differentiating human CD4(+) Th lymphocytes and in particular the secretion of interferon-gamma also affecting its downstream targets. PMID- 25287448 TI - Paradoxical cardiac and cerebral arterial gas embolus during percutaneous lead extraction in a patient with a patent foramen ovale. AB - A 42 year-old man presented for elective percutaneous lead extraction for pacemaker redundancy. The procedure was performed supine under general anaesthesia via the right femoral vein and was complicated by acute inferior ST elevation and hypotension. Urgent transoesophageal echocardiogram showed inferior left ventricular hypokinesis, right ventricular impairment, a patent foramen ovale and air in the left ventricle. Coronary angiography demonstrated normal coronary arteries, the ST changes resolved and the leads were subsequently removed intact. Post-operatively the patient displayed nystagmus, was managed with hyperbaric oxygen therapy, and had complete resolution of his symptoms. An MRI brain confirmed an acute left cerebellar infarction, and a diagnosis of paradoxical air embolus to the coronary and cerebral circulations was made. This case illustrates the risks associated with paradoxical embolism in patients with PFOs undertaking percutaneous lead extractions. It also highlights the need for further consideration into techniques to avoid this complication in all high-risk percutaneous procedures. PMID- 25287449 TI - Maternal low-protein diet induces changes in the cardiovascular autonomic modulation in male rat offspring. AB - BACKGROUND AND AIMS: Maternal undernutrition induces development of the arterial hypertension. We investigated the effects of a maternal low-protein diet on cardiovascular autonomic control in the offspring. METHODS AND RESULTS: Male Wistar rats were divided into two groups according to the diets of their mothers during gestation and lactation: the control (normal protein, NP, 17% casein; n = 14) and low-protein (LP, 8% casein; n = 14) groups. Direct measurements of arterial pressure (AP) were recorded from wakeful 90-day-old male offspring. The LP offspring presented higher mean AP than did the NP rats (NP: 93 +/- 4 vs. LP: 113 +/- 2 mmHg; p < 0.05), whereas the heart rate (HR) was similar in the two groups. In the spectral analysis, the LP group showed higher power at low (NP: 1.98 +/- 0.25 vs. LP: 3.7 +/- 0.3 mmHg2; p < 0.05) and high (NP: 1.28 +/- 0.18 vs. LP: 2.13 +/- 0.42 mmHg2; p < 0.05) frequencies of systolic arterial pressure (SAP). In the pulse interval, the LP group presented an increase in the LF/HF ratio (NP: 0.32 vs. LP: 0.56; p < 0.05). After propranolol (4 mg/kg, intravenous (iv)), the bradycardia was higher in the LP group (NP: -36 +/- 8 vs. LP: -94 +/- 12 bpm; p < 0.05), after methylatropine (2 mg/kg, iv), the tachycardia was similar to NP group. After administration of the ganglionic blocker (hexamethonium; 25 mg/kg, iv), the LP animals showed larger delta variation in the AP (NP: -33.7 +/- 5 vs. LP: -53.6 +/- 4 mmHg; p < 0.05). CONCLUSION: The rats subjected to protein malnutrition presented an increase in the cardiovascular sympathetic tone, which contributed to the elevated AP observed in these animals. PMID- 25287451 TI - Grommets for otitis media with effusion in children with cleft palate: a systematic review. AB - BACKGROUND AND OBJECTIVE: No consensus has yet been reached with regard to the link between otitis media with effusion (OME), hearing loss, and language development in children with cleft palate. The objective of this study was to address the effectiveness of ventilation tube insertion (VTI) for OME in children with cleft palate. METHODS: A dual review process was used to assess eligible studies drawn from PubMed, Medline via Ovid, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, and reference lists between 1948 and November 2013. Potentially relevant papers were selected according to the full text of the articles. Relevant data were extracted onto a data extraction sheet. RESULTS: Nine high- or moderate-quality cohort studies were included in this study. VTI was administered in 38% to 53% of the OME cases, and more severe cases appeared more likely to undergo VTI. Compared with conservative forms of management (eg, watchful waiting), VTI has been shown to be beneficial to the recovery of hearing in children with cleft palate and OME. A growing body of evidence demonstrates the benefits of VTI in the development of speech and language in children with cleft palate and OME. These children face a higher risk of complications than those undergoing conservative treatments, the most common of which are eardrum retraction and tympanosclerosis, with an incidence of ~ 11% to 37%. CONCLUSIONS: This review provides evidence-based information related to the selection of treatment for OME in children with cleft palate. Additional randomized controlled trials are required to obtain bias-resistant evidence capable of reliably guiding treatment decisions. The conclusions in this review are based on underpowered cohort studies and very-low-strength evidence. PMID- 25287450 TI - GmFLD, a soybean homolog of the autonomous pathway gene FLOWERING LOCUS D, promotes flowering in Arabidopsis thaliana. AB - BACKGROUND: Flowering at an appropriate time is crucial for seed maturity and reproductive success in all flowering plants. Soybean (Glycine max) is a typical short day plant, and both photoperiod and autonomous pathway genes exist in soybean genome. However, little is known about the functions of soybean autonomous pathway genes. In this article, we examined the functions of a soybean homolog of the autonomous pathway gene FLOWERING LOCUS D (FLD), GmFLD in the flowering transition of A. thaliana. RESULTS: In soybean, GmFLD is highly expressed in expanded cotyledons of seedlings, roots, and young pods. However, the expression levels are low in leaves and shoot apexes. Expression of GmFLD in A. thaliana (Col) resulted in early flowering of the transgenic plants, and rescued the late flowering phenotype of the A. thaliana fld mutant. In GmFLD transgenic plants (Col or fld background), the FLC (FLOWERING LOCUS C) transcript levels decreased whereas the floral integrators, FT and SOC1, were up-regulated when compared with the corresponding non-transgenic genotypes. Furthermore, chromatin immuno-precipitation analysis showed that in the transgenic rescued lines (fld background), the levels of both tri-methylation of histone H3 Lys-4 and acetylation of H4 decreased significantly around the transcriptional start site of FLC. This is consistent with the function of GmFLD as a histone demethylase. CONCLUSIONS: Our results suggest that GmFLD is a functional ortholog of the Arabidopsis FLD and may play an important role in the regulation of chromatin state in soybean. The present data provides the first evidence for the evolutionary conservation of the components in the autonomous pathway in soybean. PMID- 25287452 TI - Videogames, here for good. PMID- 25287453 TI - Umbilical cord blood transplantation to treat Pelizaeus-Merzbacher Disease in 2 young boys. AB - Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longer-term follow-up will be necessary to assess the effect of this treatment on the variable natural disease course. PMID- 25287454 TI - Adherence to guidelines for glucose assessment in starting second-generation antipsychotics. AB - OBJECTIVES: In 2003, the US Food and Drug Administration issued warnings about hyperglycemia and diabetes with second-generation antipsychotics (SGAs); guidelines have recommended metabolic screening since 2004. However, little is known of contemporary practices of glucose screening among youth initiating SGAs. Our objective was to evaluate baseline glucose assessment among youth in the Mini Sentinel Distributed Database starting an SGA. METHODS: The cohort included youth ages 2 through 18 newly initiating SGAs January 1, 2006, through December 31, 2011, across 10 sites. Baseline glucose was defined as fasting/random glucose or hemoglobin A1c (GLU) measurement occurring relative to first SGA dispensing. Differences in GLU assessment were evaluated with chi(2) tests and logistic regression. RESULTS: The cohort included 16,304 youth; 60% boys; mean age 12.8 years. Risperidone was most commonly started (43%). Eleven percent (n = 1858) had GLU assessed between 90 days before and 3 days after first dispensing. Assessment varied across SGAs (olanzapine highest), sites (integrated health care systems higher), ages (16-18 highest), years (2007 highest), and gender (female higher; all P < .001). GLU assessment among those starting olanzapine was more likely than among those starting quetiapine (odds ratio [OR]: 1.72 [95% confidence interval (CI): 1.37-2.18]), aripiprazole (OR: 1.49 [95% CI: 1.18-1.87]), or risperidone (OR: 1.61 [95% CI: 1.28-2.03]). CONCLUSIONS: Few children and adolescents starting SGA have baseline glucose assessed. This is concerning because those at high diabetes risk may not be identified. Further, lack of screening impedes determining the contribution of SGAs to hyperglycemia development. PMID- 25287455 TI - School-based health centers as patient-centered medical homes. AB - OBJECTIVE: School-based health centers (SBHCs) have been suggested as possible patient-centered medical homes. Our objectives were to determine, in a low income, urban population, adolescents' reasons for visiting SBHCs and the value parents place on SBHC services, and adolescents' and parents' assessment of how well SBHCs fulfill criteria for a medical home as defined by the American Academy of Pediatrics. METHODS: A cross-sectional, mailed survey of a random sample of 495 adolescent SBHC users and 497 parents of SBHC users from 10 SBHCs in Denver, CO from May to October 2012. Eligible adolescents were registered in an SBHC with >= 1 visit during the 2011 to 2012 school year. RESULTS: Response rates were 40% (198/495) among adolescents and 36% (181/497) among parents. The top 3 reasons for visits were for illness (78%), vaccines (69%), and sexual health education (63%). Factors reported as very important by >75% of parents in the decision to enroll their adolescent in an SBHC included clinic offering sick or injury visits, sports physicals, and vaccinations. More than 70% of adolescents gave favorable responses (always or usually, excellent or good) to questions about American Academy of Pediatrics medical home criteria (accessibility, continuity, comprehensiveness, family-centeredness, coordination, and compassion). Most parents (83%) reported that they could always or usually trust the SBHC provider to take good care of their child; 82% were satisfied with provider-to-provider communication. CONCLUSIONS: In a low-income urban population, SBHCs met criteria of a medical home from adolescents' and parents' perspectives. Policymakers and communities should recognize that SBHCs play an important role in the medical community, especially for underserved adolescents. PMID- 25287456 TI - When is waiver of consent appropriate in a neonatal clinical trial? AB - It is difficult to do scientifically rigorous research on treatments that must be administered urgently or emergently. Therefore, such treatments are often provided without a strong evidence base. Research would be facilitated if it were permissible to waive the requirement for parental consent. However, that raises a different set of concerns. Federal regulations allow waiver of the requirement for consent but only if studies meet certain conditions. Institutional review boards must decide whether those conditions are met. Sometimes, reasonable people disagree. We present and analyze a protocol for which investigators request a waiver of consent. PMID- 25287457 TI - Prenatal and newborn screening for critical congenital heart disease: findings from a nursery. AB - BACKGROUND: Delayed diagnosis of critical congenital heart disease (CCHD) in neonates increases morbidity and mortality. The use of pulse oximetry screening is recommended to increase detection of these conditions. The contribution of pulse oximetry in a tertiary-care birthing center may be different from at other sites. METHODS: We analyzed CCHD pulse oximetry screening for newborns >= 35 weeks' gestation born at Brigham and Women's Hospital and cared for in the well infant nursery during 2013. We identified patients with prenatal diagnosis of CCHD. We also identified infants born at other medical centers who were transferred to Boston Children's Hospital for CCHD and determined if the condition was diagnosed prenatally. RESULTS: Of 6838 infants with complete pulse oximetry data, 6803 (99.5%) passed the first screening. One infant failed all 3 screenings and had the only echocardiogram prompted by screening that showed persistent pulmonary hypertension. There was 1 false-negative screening in an infant diagnosed with interrupted aortic arch. Of 112 infants born at Brigham and Women's Hospital with CCHD, 111 had a prenatal diagnosis, and none was initially diagnosed by pulse oximetry. Of 81 infants transferred to Boston Children's Hospital from other medical centers with CCHD, 35% were diagnosed prenatally. CONCLUSIONS: In our tertiary-care setting, pulse oximetry did not detect an infant with CCHD because of effective prenatal echocardiography screening. Pulse oximetry will detect more infants in settings with a lower prenatal diagnosis rate. Improving training in complete fetal echocardiography scans should also improve timely diagnosis of CCHD. PMID- 25287458 TI - Fragile X syndrome: a review of associated medical problems. AB - Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families. PMID- 25287459 TI - Longitudinal association between teen sexting and sexual behavior. AB - BACKGROUND: This study examines the temporal sequencing of sexting and sexual intercourse and the role of active sexting (sending a nude picture) in mediating the relationship between passive sexting (asking or being asked for a nude picture) and sexual behaviors. METHODS: Data are from Wave 2 (spring 2011) and Wave 3 (spring 2012) of an ongoing 6-year longitudinal study of high school students in southeast Texas. Participants included 964 ethnically diverse adolescents with a mean age of 16.09 years (56% female; 31% African American, 29% Caucasian, 28% Hispanic, 12% other). Retention rate for 1-year follow-up was 93%. Participants self-reported history of sexual activity (intercourse, risky sex) and sexting (sent, asked, been asked). Using path analysis, we examined whether teen sexting at baseline predicted sexual behavior at 1-year follow-up and whether active sexting mediated the relationship between passive sexting and sexual behavior. RESULTS: The odds of being sexually active at Wave 3 were 1.32 times larger for youth who sent a sext at Wave 2, relative to counterparts. However, sexting was not temporally associated with risky sexual behaviors. Consistent with our hypothesis, active sexting at Wave 2 mediated the relationship between asking or being asked for a sext and having sex over the next year. CONCLUSIONS: This study extends cross-sectional literature and supports the notion that sexting fits within the context of adolescent sexual development and may be a viable indicator of adolescent sexual activity. PMID- 25287461 TI - Intravenous immunoglobulin therapy for refractory recurrent pericarditis. AB - Recurrent pericarditis is a troublesome complication of idiopathic acute pericarditis and occurs more frequently in pediatric patients after cardiac surgery (postpericardiotomy syndrome). Conventional treatment with nonsteroidal antiinflammatory drugs, corticosteroids, and colchicine is not always effective or may cause serious adverse effects. There is no consensus, however, on how to proceed in those patients whose disease is refractory to conventional therapy. In such cases, human intravenous immunoglobulin, immunosuppressive drugs, and biological agents have been used. In this report we describe 2 patients with refractory recurrent pericarditis after cardiac surgery who were successfully treated with 3 and 5 monthly high-dose (2 g/kg) intravenous immunoglobulin until resolution of the effusion. Our experience supports the effectiveness and safety of this therapy. PMID- 25287460 TI - Transition care for children with special health care needs. AB - BACKGROUND: Approximately 750,000 children in the United States with special health care needs will transition from pediatric to adult care annually. Fewer than half receive adequate transition care. METHODS: We had conversations with key informants representing clinicians who provide transition care, pediatric and adult providers of services for individuals with special health care needs, policy experts, and researchers; searched online sources for information about currently available programs and resources; and conducted a literature search to identify research on the effectiveness of transition programs. RESULTS: We identified 25 studies evaluating transition care programs. Most (n = 8) were conducted in populations with diabetes, with a smaller literature (n = 5) on transplant patients. We identified an additional 12 studies on a range of conditions, with no more than 2 studies on the same condition. Common components of care included use of a transition coordinator, a special clinic for young adults in transition, and provision of educational materials. CONCLUSIONS: The issue of how to provide transition care for children with special health care needs warrants further attention. Research needs are wide ranging, including both substantive and methodologic concerns. Although there is widespread agreement on the need for adequate transition programs, there is no accepted way to measure transition success. It will be essential to establish consistent goals to build an adequate body of literature to affect practice. PMID- 25287462 TI - Overdiagnosis: how our compulsion for diagnosis may be harming children. AB - Overdiagnosis occurs when a true abnormality is discovered, but detection of that abnormality does not benefit the patient. It should be distinguished from misdiagnosis, in which the diagnosis is inaccurate, and it is not synonymous with overtreatment or overuse, in which excess medication or procedures are provided to patients for both correct and incorrect diagnoses. Overdiagnosis for adult conditions has gained a great deal of recognition over the last few years, led by realizations that certain screening initiatives, such as those for breast and prostate cancer, may be harming the very people they were designed to protect. In the fall of 2014, the second international Preventing Overdiagnosis Conference will be held, and the British Medical Journal will produce an overdiagnosis themed journal issue. However, overdiagnosis in children has been less well described. This special article seeks to raise awareness of the possibility of overdiagnosis in pediatrics, suggesting that overdiagnosis may affect commonly diagnosed conditions such as attention-deficit/hyperactivity disorder, bacteremia, food allergy, hyperbilirubinemia, obstructive sleep apnea, and urinary tract infection. Through these and other examples, we discuss why overdiagnosis occurs and how it may be harming children. Additionally, we consider research and education strategies, with the goal to better elucidate pediatric overdiagnosis and mitigate its influence. PMID- 25287463 TI - Off-hours admission to pediatric intensive care and mortality. AB - BACKGROUND: Critically ill patients are admitted to the pediatric ICU at all times, while staffing and other factors may vary by day of the week or time of day. The purpose of this study was to evaluate whether admission during off-hours is independently associated with mortality in PICUs. METHODS: A retrospective cohort study of admissions of patients <18 years of age to PICUs was performed using the Virtual PICU Systems (VPS, LLC) database. "Off-hours" was defined as nighttime (7:00 pm to 6:59 am) or weekend (Saturday or Sunday any time). Mixed effects multivariable regression was performed by using Pediatric Index of Mortality 2 (PIM2) to adjust for severity of illness. Primary outcome was death in the pediatric ICU. RESULTS: Data from 234,192 admissions to 99 PICUs from January 2009 to September 2012 were included. When compared with regular weekday admissions, off-hours admissions were less likely to be elective, had a higher risk for mortality by PIM2, and had a higher observed ICU mortality (off-hours 2.7% vs weekdays 2.2%; P < .001). Multivariable regression revealed that, after adjustment for other significant factors, off-hours admission was associated with lower odds of mortality (odds ratio, 0.91; 95% confidence interval, 0.85-0.97; P = .004). Post hoc multivariable analysis revealed that admission during the morning period 6:00 am to 10:59 am was independently associated with death (odds ratio, 1.27; 95% confidence interval, 1.16-1.39; P < .0001). CONCLUSIONS: Off hours admission does not independently increase odds of death in the PICU. Admission from 6:00 am to 10:59 am is associated with increased risk for death and warrants further investigation in the PICU population. PMID- 25287464 TI - Empathy, target distress, and neurohormone genes interact to predict aggression for others-even without provocation. AB - Can empathy for others motivate aggression on their behalf? This research examined potential predictors of empathy-linked aggression including the emotional state of empathy, an empathy target's distress state, and the function of the social anxiety-modulating neuropeptides oxytocin and vasopressin. In Study 1 (N = 69), self-reported empathy combined with threat to a close other and individual differences in genes for the vasopressin receptor (AVPR1a rs3) and oxytocin receptor (OXTR rs53576) to predict self-reported aggression against a person who threatened a close other. In Study 2 (N = 162), induced empathy for a person combined with OXTR variation or with that person's distress and AVPR1a variation led to increased amount of hot sauce assigned to that person's competitor. Empathy uniquely predicts aggression and may do so by way of aspects of the human caregiving system in the form of oxytocin and vasopressin. PMID- 25287465 TI - Is Weiner's attribution-help model stable across cultures? A test in Brazilian subcultures. AB - The effect of attribution of responsibility on the intention to help is a well studied effect. The Weiner model of attribution-emotion-help is the main theoretical development to describe the structural relation between these variables. Some research results have suggested that culture influences the relation between model variables. Collectivists tend to show more compassionate emotions independent of attribution of responsibility whereby emotion is no longer a mediator. The present research aims to test the Weiner model in Brazil, a country with established subcultures and clear distinctions in the collectivism individualism dimension across its regions. An experiment with 1,569 participants from all five Brazilian regions was conducted. Path analysis revealed that more socially oriented participants tended to feel more compassion for the experimental scenario's protagonist, independent of controllability manipulation, decreasing the effect of emotions in the model. These results depict the effect of culture on the model, questioning the stability of the model across cultures. PMID- 25287466 TI - Psychiatric phenomena as initial manifestation of encephalitis by anti-NMDAR antibodies. AB - OBJECTIVE: Autoimmune encephalitis associated with autoantibodies against the N methyl-d-aspartate receptor (NMDAR) often presents with behavioural change. Our objective was to describe in detail the psychiatric presentation and pathways to care in order to aid the early diagnosis of NMDAR encephalitis. METHODS: Sera and cerebrospinal fluid (CSF) from patients with suspected NMDAR encephalitis were tested on HEK 293 cells transfected with the NR1 subunit of the NMDAR. Clinical information was obtained from the referring psychiatrists and neurologists and by review of the clinical records. RESULTS: Samples from 15 patients (13 female, 2 male, mean age 24 years, range 5-56 years) tested anti-NMDAR positive. Twelve of the 15 patients (80%) presented with prominent psychiatric symptoms and 8 were initially referred to a psychiatric service. The most prominent initial psychiatric symptoms were anxiety in seven (47%), behavioural change (often bizarre) in six (40%) and agitation in five (33%). All patients developed psychiatric symptoms in the first 6 weeks of illness. Thirteen patients received psychotropic medications: antipsychotics in 12 and benzodiazepines in 11. Treating physicians considered the psychotropic medication not effective in 11 patients resulting in many drug switches. At nadir, all patients were in a very poor condition. However, eight patients (53%) recovered (almost) completely. Outcome tended to be better in patients who had received early immunotherapy or tumour removal. CONCLUSIONS: Autoimmune encephalitis and anti-NMDAR testing in serum and CSF should be considered in patients, especially young females, presenting with atypical psychiatric phenomena. Early diagnosis and treatment will likely improve the prognosis of NMDAR encephalitis. PMID- 25287467 TI - Proinflammatory cytokine levels in patients with conversion disorder. AB - OBJECTIVE: It was aimed to evaluate the relationship between proinflammatory cytokine levels and conversion disorder both commonly known as stress regulated. METHOD: Baseline proinflammatory cytokine levels-[Tumour necrosis factor alpha (TNF-alpha), Interleukin-1 beta (IL-1beta), Interleukin-6 (IL-6)]-were evaluated with enzyme-linked immunosorbent assay in 35 conversion disorder patients and 30 healthy controls. Possible changes in proinflammatory cytokine levels were evaluated again, after their acute phase in conversion disorder patients. RESULTS: Statistically significant decreased serum TNF-alpha levels were obtained in acute phase of conversion disorder. Those levels increased after acute conversion phase. There were no statistically significant difference observed between groups in serum IL-1beta and (IL-6) levels. CONCLUSIONS: Stress associated with conversion disorder may suppress immune function in acute conversion phase and may have diagnostic and therapeutic value. PMID- 25287468 TI - Working memory subsystems are impaired in chronic drug dependents. AB - BACKGROUND: A large body of research that has investigated substance dependence and working memory (WM) resources, yet no prior study has used a comprehensive test battery to examine the impact of chronic drug dependence on WM as a multi component system. OBJECTIVES: This study examined the efficiency of several WM components in participants who were chronic drug dependents. In addition, the functioning of the four WM components was compared among dependents of various types of drugs. METHOD: In total, 128 chronic drug dependents participated in this study. Their average age was 38.48 years, and they were classified into four drug-dependence groups. Chronic drug dependents were compared with a 36 participant control group that had a mean age of 37.6 years. A WM test battery that comprised eight tests and that assessed each of four WM components was administered to each participant. RESULTS: Compared with the control group, all four groups of drug dependents had significantly poorer test performance on all of the WM tasks. Among the four groups of drug users, the polydrug group had the poorest performance scores on each of the eight tasks, and the performance scores of the marijuana group were the least affected. Finally, the forward digit span task and the logical memory tasks were less sensitive than other tasks when differentiating between marijuana users and the normal participants. CONCLUSION: The four components of WM are impaired among chronic drug dependents. These results have implications for the development of tools, classification methods and therapeutic strategies for drug dependents. PMID- 25287469 TI - Cardiac autonomic dysregulation in acute schizophrenia. AB - OBJECTIVE: Altered cardiac autonomic function has been proposed in schizophrenia, but the results are mixed. Therefore, analyses with larger sample sizes and better methodology are needed. METHODS: To examine whether acute schizophrenia is associated with cardiac autonomic dysfunction, 314 unmedicated patients with acute schizophrenia and 409 healthy volunteers, aged 18-65 years, were recruited for a case-control analysis. The severity of schizophrenia symptoms was assessed with the Positive and Negative Syndrome Scale. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters during the supine standing-supine test. Frequency-domain indices of HRV were obtained. RESULTS: Unmedicated patients with acute schizophrenia consistently exhibited reduced mean RR interval and HRV levels in a supine rest and standing position compared with healthy volunteers. The severity of psychopathology, in particular positive symptoms, was negatively correlated with cardiac vagal control. CONCLUSION: These data suggest that acute schizophrenia is accompanied by cardiac autonomic dysregulation. In view of the higher risk for cardiac complications in these patients, one might also consider the antipsychotic treatment in favour of improving cardiac autonomic modulation. Further studies using larger patient groups and controlled therapeutics may better understand the influence of antipsychotic treatment on cardiac autonomic regulation in schizophrenia. PMID- 25287470 TI - Gender differences of axis I and II comorbidity in subjects diagnosed with attention-deficit hyperactivity disorder as adults. AB - OBJECTIVE: To investigate gender differences in psychiatric comorbidity patients diagnosed with attention-deficit hyperactivity disorder (ADHD) as adults. METHODS: Interviews about current ADHD symptoms and psychiatric comorbidity on axis I and II (Structured Clinical Interview for DSM-IV axis I and axis II) were conducted in a clinical cohort of 168 patients (78 women, 90 men). Independent information on childhood and current symptoms was collected from parents, partners and patient files. RESULTS: The lifetime prevalence of psychiatric comorbidity on axis I reached 92%, and current comorbidity, including autism spectrum disorders and Tourette's syndrome, was 47%. Women had a higher lifetime prevalence of mood and eating disorders compared with men, where substance-use disorders were more frequent. Ten per cent of patients fulfilled diagnostic criteria for a personality disorder. When excluding the general diagnostic criteria, 46% of the patients endorsed the specific criteria for at least one personality disorder. Gender differences were identified with predominance of histrionic personality traits in women and conduct disorder in men. CONCLUSION: Patients diagnosed with ADHD as adults display an extremely high lifetime axis I comorbidity with a gender-specific pattern similar to the general population. No gender differences were identified with regard to personality disorders; however, an increased prevalence of deviant personality traits was confirmed. This study stresses the importance of evaluating comorbidity among patients diagnosed with ADHD as adults to secure optimal treatment. PMID- 25287471 TI - Heart rate variability in junior high school students with depression and anxiety in Taiwan. AB - BACKGROUND: The impact of depression and anxiety on heart rate variability (HRV) is not clear in adolescents. We hypothesised that HRV investigation in adolescents may early prevent the mental diseases occurrence. METHODS: Three hundred and thirty-three seventh grade students participated in this study programme. HRV instrumental analysis and spectral with scale of depression were measured respectively. RESULTS: It showed that among the participants, the depression score of female was higher than male. The population with lower depression score present with lower high frequency and higher low frequency/high frequency ratio but not statistically significant. Oppositely, participants with higher depression score were increased with heart rate and present with lower standard deviation of heart rate. However, it is also not statistically significant. CONCLUSION: This study supported the positive relation between HRV and depression, especially in the female gender. Therefore, HRV in depression may be beneficial in the detection and prevention of mental disorder development, even suicide behaviour in teenagers. PMID- 25287472 TI - Seasonal variation in the occurrence of delirium in patients admitted to medical units of a general hospital in Italy. AB - OBJECTIVE: Delirium syndrome is common in the hospitalised population. However, data on its aetiological factors are scarce. Clinical observations suggest a relationship between delirium occurrence and seasons. The aim of study was to determine whether a seasonal variation exists in the occurrence of delirium events in-hospital patients. METHODS: The study included all admissions to the medical units of the Hospital of Ferrara, Italy, between January 2002 and December 2010. On the basis of date admission, cases have been analysed for seasonal variation (four 3-month intervals by seasons) by means of conventional statistics. Moreover, cases categorised into twelve 1-month intervals were also analysed by means of a validated chronobiologic inferential method (single cosinor) to search for cyclic variability. RESULTS: During the analysed period, the hospital database contained 74 379 records referring to 42 625 subjects (52.7% females). Delirium diagnoses were 1300 (1.7% of total sample), 668 of whom in females (51.4%) and 632 in males (48.6%). Events of delirium were more frequent in winter and autumn (26.6 and 26.5%, respectively) than in spring (23.5%) and summer (23.4%). Chronobiological analysis yielded a significant peak of delirium events in January, when considering both the total raw number of cases and the percent of admissions. CONCLUSIONS: The study seems to indicate in patients hospitalised in medical units, a higher rate of occurrence of delirium in autumn-winter, similar to that reported for acute medical diseases. The role of possible underlying favouring or triggering factors deserves further research. PMID- 25287473 TI - Can low-dose propranolol induce a manic syndrome? Case report of an unexpected side effect. AB - OBJECTIVES: Propranolol, the first discovered b-adrenergic receptor antagonist, has been prescribed by physicians in various fields for more than three decades. It has been applied for treating psychiatric disorders including schizophrenia, mania and anxiety disorders, as well as for controlling withdrawal symptoms or other side effects. METHODS: We describe the case of an 11-year-old boy with bipolar-I disorder comorbid with panic disorder who developed manic symptoms with a single dose of 10 mg of propranolol. Results and Conclusion Although depression is a better-known side effect of b-adrenergic antagonists, clinicians should take mania as a rare side effect into consideration as well. PMID- 25287474 TI - Familial trichotillomania: role of genetic factors in the determination of subtypes. AB - OBJECTIVES: Trichotillomania (TTM) is a psychiatric syndrome characterised by the inability to control repetitive hair pulling. Psychiatric data reveal that TTM is not usually prevalent among all family members of patients, and so far only one case of familial TTM has been reported. METHODS: In this study, we report a case of familial TTM that afflicted four sisters and discuss the importance of genetic factors in this disorder. RESULTS: This report suggests that, similar to many other psychiatric disorders, TTM can be detected in other family members and that genetic factors not only have a significant role in the development of such disorders but also in determination of the disorder subtype. This report also shows that the comorbidities in one member of the family might predict the existence of comorbidities in other members. On the basis of response to medication. CONCLUSION: the authors suggest that a genetic disorder like polymorphism in serotonin receptors or dopamine can cause such a disorder. PMID- 25287475 TI - Tuberculous pericarditis mimicking a pericardial tumor. PMID- 25287476 TI - Compensatory renal hypertrophy following uninephrectomy is calcineurin independent. AB - Calcineurin is a calcium-dependent phosphatase that is involved in many cellular processes including hypertrophy. Inhibition or genetic loss of calcineurin blocks pathological cardiac hypertrophy and diabetic renal hypertrophy. However, calcineurin does not appear to be involved in physiological cardiac hypertrophy induced by exercise. The role of calcineurin in a compensatory, non-pathological model of renal hypertrophy has not been tested. Therefore, in this study, we examined activation of calcineurin and the effect of calcineurin inhibition or knockout on compensatory hypertrophy following uninephrectomy (UNX). UNX induces ~15% increase in the size of the remaining kidney; the data show no change in the generation of reactive oxygen species (ROS), Nox4 or transforming growth factor beta expression confirming the model as one of compensatory hypertrophy. Next, analyses of the remaining kidney reveal that total calcineurin activity is increased, and, to a lesser extent, transcriptional activity of the calcineurin substrate nuclear factor of activated T cell is up-regulated following UNX. However, inhibition of calcineurin with cyclosporine failed to prevent compensatory renal hypertrophy. Likewise, hypertrophy was comparable to WT in mice lacking either isoform of the catalytic subunit of calcineurin (CnAalpha-/- or CnAbeta-/-). In conclusion, similar to its role in the heart, calcineurin is required for pathological but not compensatory renal hypertrophy. This separation of signalling pathways could therefore help further define key factors necessary for pathological hypertrophy including diabetic nephropathy. PMID- 25287478 TI - Capsule commentary on Edelman et al., Shared medical appointments for patients with diabetes mellitus: a systematic review. PMID- 25287477 TI - Carpal tunnel syndrome severity staging using sonographic and clinical measures. AB - INTRODUCTION: Ultrasonography may be valuable in staging carpal tunnel syndrome severity, especially by combining multiple measures. This study aimed to develop a preliminary severity staging model using multiple sonographic and clinical measures. METHODS: Measures were obtained in 104 participants. Multiple categorization structures for each variable were correlated to diagnostic severity based on nerve conduction. Goodness-of-fit was evaluated for models using iterative combinations of highly correlated variables. Using the best-fit model, a preliminary scoring system was developed, and frequency of misclassification was calculated. RESULTS: The severity staging model with best fit (rho 0.90) included patient-reported symptoms, functional deficits, provocative testing, nerve cross-sectional area, and nerve longitudinal appearance. An 8-point scoring scale classified severity accurately for 79.8% of participants. CONCLUSIONS: This severity staging model is a novel approach to carpal tunnel syndrome evaluation. Including more sensitive measures of nerve vascularity, nerve excursion, or other emerging techniques may refine this preliminary model. PMID- 25287479 TI - Laboratory monitoring for pharmaceuticals: familiarity does not breed contempt. PMID- 25287480 TI - Safety of fertility-sparing surgery in primary mucinous carcinoma of the ovary. AB - PURPOSE: The aim of this study is to evaluate the safety of fertility-sparing surgery as the treatment for patients with primary mucinous epithelial ovarian cancer. MATERIALS AND METHODS: A retrospective study of patients with mucinous ovarian cancer between 1991 and 2010 was performed. The demographics and survival outcomes were compared between patients who underwent fertility-sparing surgery and those who underwent radical surgery. RESULTS: A total of 110 patients underwent primary surgery. At the time of surgery, tumors appeared to be grossly confined to the ovaries in 90 patients, and evidence of metastasis was definite in 20 patients. Of the 90 patients with tumors that appeared to be grossly confined to the ovaries at surgical exploration, 35 (38.9%) underwent fertility sparing surgery. The Kaplan- Meier curve and the log rank test showed no difference in either recurrence-free survival (p=0.792) or disease-specific survival (p=0.706) between the two groups. Furthermore, there was no significant difference in recurrence-free survival (p=0.126) or disease-specific survival (p=0.377) between the two groups, even when the analysis was limited to women below the age of 40. In a multivariate Cox model, fertility-sparing surgery had no effect on either recurrence-free survival (recurrence hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.25 to 5.71) or disease-specific survival (death HR, 0.88; 95% CI, 0.17 to 4.60). CONCLUSION: Fertility-sparing surgery in primary mucinous cancer grossly confined to the ovaries may be a safe option and one not associated with an increase in recurrence or mortality. PMID- 25287481 TI - Congratulations! PMID- 25287482 TI - Implant and clinical characteristics for pediatric and congenital heart patients in the national cardiovascular data registry implantable cardioverter defibrillator registry. AB - BACKGROUND: In 2010, the National Cardiovascular Data Registry enhanced pediatric, nonatherosclerotic structural heart disease and congenital heart disease (CHD) data collection. This report characterizes CHD and pediatric patients undergoing implantable cardioverter defibrillator implantation. METHODS AND RESULTS: In this article, we report implantable cardioverter defibrillator procedures (April 2010 to December 2012) in the registry for 2 cohorts: (1) all patients with CHD (atrial septal defect, ventricular septal defect, tetralogy of Fallot, Ebstein anomaly, transposition of the great vessels, and common ventricle) and (2) patients <21 years. We evaluated indications and characteristics to include transvenous and nontransvenous lead implants, CHD type, and New York Heart Association class. There were 3139 CHD procedures, 1601 for patients <21 years and 126 for CHD <21 years. Implantable cardioverter defibrillator indications for patients with CHD were primary prevention in 1943 (61.9%) and secondary prevention in 1107 (35.2%). Pediatric patients had 935 (58.4%) primary prevention and 588 (36.7%) secondary prevention devices. Primary prevention had higher New York Heart Association class. Nontransvenous age (35.9 +/- 23.2 versus 40.1 +/- 24.6 years; P=0.05) and nontransvenous height (167.1 +/- 18.9 cm; range, 53-193 cm versus 170.4 +/- 13.1 cm; range, 61-203 cm; P<0.01) were lower than for transvenous patients. CHD and pediatrics had similar rates of transvenous (97%) and nontransvenous (3%) leads and did not differ from the overall registry. Transposition of the great vessels and common ventricle had higher rates of nontransvenous leads. CONCLUSIONS: Primary prevention exceeds secondary prevention for CHD and pediatrics. Nontransvenous lead patients were younger, with higher rates of transposition of the great vessels and common ventricle patients compared with transvenous lead patients. PMID- 25287483 TI - Inhibition of hepatitis C entry: too soon to dismiss while many are still being denied treatment. PMID- 25287484 TI - Feasibility of carbon ion radiotherapy for locally advanced sinonasal adenocarcinoma. AB - BACKGROUND AND PURPOSE: To evaluate the safety and efficacy of carbon ion radiotherapy (CIRT) for locally advanced sinonasal adenocarcinoma. MATERIAL AND METHODS: Twenty-two patients with sinonasal adenocarcinoma were treated with CIRT. CIRT was the primary treatment for 16 patients. Four patients received CIRT for local recurrence after surgery and two for residual tumour after surgery or chemotherapy. At the start of CIRT, 1 patient had T-classification (T) 2 disease, 2 had T3 disease, 5 had T4a disease, and 14 had T4b disease. Fourteen patients were treated with 57.6 Gy equivalent (GyE)/16 fractions, and 8, with 64.0 GyE/16 fractions. RESULTS: The median follow-up period was 43 months for all patients. The 3-year local control and loco-regional control rates for all patients were 76.9% (95% confidence interval [CI]=56.7-97.1%) and 61.3% (95% CI=38.5-84.1%), respectively. The 3-year overall survival and disease-specific survival rates were 59.1% (95% CI=38.6-79.6%) and 65.6% (95% CI=44.9-86.3%), respectively. Acute reactions of grade 3 of the skin and mucosa were observed in 2 and 4 patients, respectively. Late reactions included lateral visual loss (5 patients), mucosal ulceration (1 patient), and brain necrosis with clinical symptoms (1 patient). In the 5 patients who developed visual loss, the optic nerve was close to the tumour. CONCLUSIONS: CIRT was effective and generally safe for locally advanced sinonasal adenocarcinoma. PMID- 25287485 TI - Positron emission tomography/CT versus MRI in liver metastasis: is there a winner? PMID- 25287486 TI - Ian F 'Jock' Anderson (1941-2014). PMID- 25287487 TI - John Hamlyn Stewart (1922-2014). PMID- 25287490 TI - Ag[Fe(CO)5]2(+) : a bare silver complex with Fe(CO)5 as a ligand. AB - Attempts to prepare Fe(CO)5 (+) from Ag[Al(OR(F) )4 ] (R(F) =C(CF3 )3 ) and Fe(CO)5 in CH2 Cl2 yielded the first complex of a neutral metal carbonyl bound to a simple metal cation. The Ag[Fe(CO)5 ]2 (+) cation consists of two Fe(CO)5 molecules coordinating Ag(+) in an almost linear fashion. The nu(CO) modes are blue-shifted compared to Fe(CO)5 , with one band above 2143 cm(-1) indicating that back-bonding is heavily decreased in the Ag[Fe(CO)5 ]2 (+) cation. PMID- 25287489 TI - Paired box gene 8 (PAX8) expression is associated with sonic hedgehog (SHH)/wingless int (WNT) subtypes, desmoplastic histology and patient survival in human medulloblastomas. AB - AIMS: The paired box gene 8 (PAX8) plays crucial roles in organ patterning and cellular differentiation during development and tumorigenesis. Although its function is partly understood in vertebrate development, there is poor data concerning human central nervous system (CNS) development and brain tumours. METHODS: We investigated developing human (n = 19) and mouse (n = 3) brains as well as medulloblastomas (MBs) (n = 113) for PAX8 expression by immunohistochemistry. Human MB cell lines were assessed for PAX8 expression using polymerase chain reaction and immunoblotting and analysed for growth and migration following PAX8 knock-down by small interfering ribonucleic acid (siRNA). RESULTS: PAX8 protein expression was associated with germinal layers in human and murine forebrain and hindbrain development. PAX8 expression significantly decreased over time in the external granule cell layer but increased in the internal granule cell layer. In MB subtypes, we observed an association of PAX8 expression with sonic hedgehog (SHH) and wingless int subtypes but not with group 3 and 4 MBs. Beyond that, we detected high PAX8 levels in desmoplastic MB subtypes. Univariate analyses revealed high PAX8 levels as a prognostic factor associated with a significantly better patient prognosis in human MB (overall survival: Log-Rank P = 0.0404, Wilcoxon P = 0.0280; progression-free survival: Log-Rank P = 0.0225; Wilcoxon P = 0.0136). In vitro assays revealed increased proliferation and migration of MB cell lines after PAX8 siRNA knock-down. CONCLUSION: In summary, high PAX8 expression is linked to better prognosis in MBs potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio-temporal expression pattern of PAX8 during brain development might contribute to the understanding of distinct MB subtype histogenesis. PMID- 25287491 TI - Detection of plant viruses in mixed infection by a macroarray-assisted method. AB - The protocol for a simple, sensitive, and specific method using a cDNA macroarray to detect multiple viruses is provided. The method can be used even at the production sites for crops, which need a reliable routine diagnosis for mixed infection of plant viruses. The method consists of three steps: RNA extraction, duplex RT-PCR, and "microtube hybridization" (MTH). Biotinylated cDNA probes are prepared using RT-PCR and used to hybridize a nylon membrane containing target viral cDNAs by MTH. Positive signals can be visualized by colorimetric reaction and judged by eyes. We here demonstrate this method to detect asparagus viruses (Asparagus virus 1 and Asparagus virus 2) from latently infected asparagus plants. PMID- 25287492 TI - RT-PCR and real-time RT-PCR methods for the detection of potato virus Y in potato leaves and tubers. AB - Potato virus Y (PVY) is a major threat to potato crops around the world. It is an RNA virus of the family Potyviridae, exhibiting many different strains that cause a range of symptoms in potato. ELISA detection of viral proteins has traditionally been used to quantify virus incidence in a crop or seed lot. ELISA, however, cannot reliably detect the virus directly in dormant tubers, requiring several weeks of sprouting tubers to produce detectable levels of virus. Nor can ELISA fully discriminate between the wide range of strains of the virus. Several techniques for directly detecting the viral RNA have been developed which allow rapid detection of PVY in leaf or tuber tissue, and that can be used to easily distinguish between different strains of the virus. Described in this chapter are several protocols for the extraction of RNA from leaf and tuber tissues, and three detection methods based upon reverse-transcription-PCR (RT-PCR). First described is a traditional two-step protocol with separate reverse transcription of viral RNA into cDNA, then PCR to amplify the viral cDNA fragment. Second described is a one-step RT-PCR protocol combining the cDNA production and PCR in one tube and one step, which greatly reduces material and labor costs for PVY detection. The third protocol is a real-time RT-PCR procedure which not only saves on labor but also allows for more precise quantification of PVY titre. The three protocols are described in detail, and accompanied with a discussion of their relative advantages, costs, and possibilities for cost-saving modifications. While these techniques have primarily been developed for large scale screening of many samples for determining viral incidence in commercial fields or seed lots, they are also amenable to use in smaller-scale research applications. PMID- 25287493 TI - A new method to isolate total dsRNA. AB - When a diseased plant is suspected to be infected with unknown viruses, the approach of isolating double-stranded RNA (dsRNA) from diseased tissues and analyzing the sequence has been useful for detecting the viruses. This procedure owes its success to the majority of plant pathogenic viruses being RNA viruses, which accumulate dsRNAs as copies of their genome or as a replicative intermediate in infected cells. Conventional dsRNA isolation methods (e.g., chromatography using CF-11 cellulose) require a significant amount of plant material and are laborious and time consuming. Therefore, it has been impractical to isolate dsRNA from many samples at the same time. To overcome these problems, we developed a novel dsRNA isolation method involving a recombinant dsRNA-binding protein. Using this method, we can readily isolate viral dsRNA from a small amount of plant material, and can process numerous samples simultaneously. Purified dsRNA can be used as a template for cDNA synthesis and sequencing, enabling detection of both known and unknown viruses. PMID- 25287494 TI - Multiplex RT-PCR method for the simultaneous detection of nine grapevine viruses. AB - Viral diseases are a serious pathological problem for grapevines, and in recent years the need for increasingly specific and rapid diagnostic methods for the selection of propagation materials has grown. Arabis mosaic virus, Grapevine fanleaf virus, Grapevine virus A, Grapevine virus B, Grapevine rupestris stem pitting-associated virus, Grapevine fleck virus, and Grapevine leafroll associated viruses 1, 2, and 3 are nine of the most widespread viruses that naturally infect grapevines. A multiplex RT-PCR was developed for simultaneous detection of these nine grapevine viruses, in combination with a plant RNA internal control used as an indicator of the effectiveness of the reaction. One to ten fragments specific for the viruses and an internal control were simultaneously amplified from infected samples and identified by their specific molecular sizes in agarose gel. The protocol reported is an update of previously published protocols for RNA extraction and multiplex diagnosis of viruses. After several years of use and hundreds of samples tested, and following validation in several laboratories, this multiplex RT-PCR provides a reliable and rapid method for detecting grapevine viruses from a large number of samples. PMID- 25287495 TI - Detection methods for rice viruses by a reverse-transcription loop-mediated isothermal amplification (RT-LAMP). AB - Developing a quick and accurate method to diagnose rice viruses in host plants and in vector insects is very important to control virus diseases of rice. A reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay, one of the most promising molecular diagnostic methods, was established to detect nine viruses, including eight RNA viruses and one DNA virus, in infected rice plants and the viruliferous vector insects. The sensitivities of the assays were either higher than or similar to those of one-step RT-PCR. With a combination of rapid RNA extraction and a RT-LAMP assay, these nine viruses were detected within 2 h from infected rice plants and the viruliferous insects without expensive or unusual equipment. This RT-LAMP method for rice viruses can therefore be adopted not only for diagnosis but also to study the epidemiology and molecular pathology of rice viruses. PMID- 25287496 TI - Real-time PCR protocols for the quantification of the begomovirus tomato yellow leaf curl Sardinia virus in tomato plants and in its insect vector. AB - Tomato yellow leaf curl Sardinia virus (TYLCSV) (Geminiviridae) is an important pathogen, transmitted by the whitefly Bemisia tabaci, that severely affects the tomato production in the Mediterranean basin. Here, we describe real-time PCR protocols suitable for relative and absolute quantification of TYLCSV in tomato plants and in whitefly extracts. Using primers and probe specifically designed for TYLCSV, the protocols for relative quantification allow to compare the amount of TYLCSV present in different plant or whitefly samples, normalized to the amount of DNA present in each sample using endogenous tomato or Bemisia genes as internal references. The absolute quantification protocol allows to calculate the number of genomic units of TYLCSV over the genomic units of the plant host (tomato), with a sensitivity of as few as ten viral genome copies per sample. The described protocols are potentially suitable for several applications, such as plant breeding for resistance, analysis of virus replication, and virus-vector interaction studies. PMID- 25287497 TI - Detection and analysis of non-retroviral RNA virus-like elements in plant, fungal, and insect genomes. AB - Endogenous non-retroviral RNA like sequences (NRVSs) have been discovered in the genome of a wide range of eukaryotes. These are considered as fossil RNA viral elements integrated into host genomes by as-yet-known mechanisms, and in many cases, those fossils are estimated to be millions-of-years-old. It is likely that the number of NRVS records will increase rapidly due to the growing availability of whole-genome sequences for many kinds of eukaryotes. Discovery of the novel NRVSs and understanding of their phylogenetic relationship with modern viral relatives provide important information on deep evolutionary history of RNA virus host interactions. In this chapter, therefore, the common strategies for the identification and characterization of endogenous NRVSs from plants, insects, and fungi are described. PMID- 25287498 TI - Detection of plant viruses in natural environments by using RNA-Seq. AB - Sequencing of RNA by next generation sequencers, RNA-Seq, is revolutionizing virus detection. In addition to the unbiased detection of various viruses from wild plants in natural environments, RNA-Seq also allows for the parallel collection of host plant transcriptome data. Host transcriptome data are highly valuable for studying the responses of hosts to viral infections, as well as viral host manipulation. When detecting viruses using RNA-Seq, it is critical to choose appropriate methods for the removal of rRNA from total RNA. Although viruses with polyadenylated genomes can be detected by RNA-Seq following mRNA purification using oligo-dT beads, viruses with non-polyadenylated genomes are not effectively detected. However, such viruses can be detected by RNA-Seq using the rRNA selective depression method. The high-throughput and cost-effective method of RNA-Seq library preparation which is described here allows us to detect a broad range of viruses in wild plants. PMID- 25287499 TI - Cloning and profiling of small RNAs from cucumber mosaic virus satellite RNA. AB - RNA silencing is not only a gene regulation mechanism that is conserved in a broad range of eukaryotes but also an adaptive immune response against foreign nucleic acids including viruses in plants. A major feature of RNA silencing is the production of small RNA (sRNA) of 21-24 nucleotides (nt) in length from double-stranded (ds) or hairpin-like (hp) RNA by Dicer-like (DCL) proteins. These sRNAs guide the binding and cleavage of cognate single-stranded (ss) RNA by an RNA silencing complex. Like all plant viruses and subviral agents, replication of viral satellite RNAs (satRNAs) is associated with the accumulation of 21-24 nt viral small interfering RNA (vsiRNA) derived from the whole region of a satRNA genome in both plus and minus-strand polarities. These satRNA-derived siRNAs (satsiRNAs) have recently been shown to play an important role in the trilateral interactions among host plants, helper viruses and satRNAs. Here, we describe the cloning and profile analysis of satsiRNAs from satRNAs of Cucumber mosaic virus (CMV). We also describe a method to minimize the strand bias that often occurs during vsiRNA cloning and sequencing. PMID- 25287500 TI - Drawing siRNAs of viral origin out from plant siRNAs libraries. AB - Viruses are obligate intracellular entities that infect all forms of life. In plants, invading viral nucleic acids trigger RNA silencing machinery and it results in the accumulation of viral short interfering RNAs (v-siRNAs). The study of v-siRNAs population in biological samples has become a major part of many research projects aiming to identify viruses infecting them, including unknown viruses, even at extremely low titer. Currently, siRNA populations are investigated by high-throughput sequencing approaches, which generate very large data sets. The major difficulty in these studies is to properly analyze such huge amount of data. In this regard, easy-to-use bioinformatics tools to groom and decipher siRNA libraries and to draw out v-siRNAs are needed. Here we describe a workflow, which permit users with little experience in bioinformatics to draw out v-siRNAs from raw data sequences obtained by Illumina technology. Such pipeline has been released in the context of Galaxy, an open source Web-based platform for bioinformatics analyses. PMID- 25287501 TI - Viral detection by high-throughput sequencing. AB - We applied a high-throughput sequencing platform, Ion PGM, for viral detection in fecal samples from adult cows collected in Hokkaido, Japan. Random RT-PCR was performed to amplify RNA extracted from 0.25 ml of fecal specimens (N = 8), and more than 5 MUg of cDNA was synthesized. Unbiased high-throughput sequencing using the 318 v2 semiconductor chip of these eight samples yielded 57-580 K (average: 270 K, after data analysis) reads in a single run. As a result, viral genome sequences were detected in each specimen. In addition to bacteriophage, mammal- and insect-derived viruses, partial genome sequences of plant, algal, and protozoal viruses were detected. Thus, this metagenomic analysis of fecal specimens could be useful to comprehensively understand viral populations of the intestine and food sources in animals. PMID- 25287502 TI - Analysis and application of viroid-specific small RNAs generated by viroid inducing RNA silencing. AB - Viroids are noncoding RNA pathogens inducing severe to mild disease symptoms on agriculturally important crop plants. Viroid replication is entirely dependent on host transcription machinery, and their replication/accumulation in the infected cells can activate RNA silencing-a host defense mechanism that targets the viroid itself. RNA silencing produces in the cell large amounts of viroid-specific small RNAs of 21-24-nucleotides by cleaving (or "dicing") entire molecules of viroid RNA. However, viroid replication is resistant to the effects of RNA silencing and disrupts the normal regulation of host gene expression, finally resulting in the development of disease symptoms on infected plant. The molecular mechanisms of biological processes involving RNA silencing and underlying various aspects of viroid-host interaction, such as symptom expression, are of special interests to both basic and applied areas of viroid research. Here we present a method to create infectious viroid cDNA clones and RNA transcripts, the starting material for such analyses, using Hop stunt viroid as an example. Next we describe methods for the preparation and analysis of viroid-specific small RNAs by deep sequencing using tomato plants infected with Potato spindle tuber viroid as an example. Finally we introduce bioinformatics tools and methods necessary to process, analyze, and characterize these viroid-specific small RNAs. These bioinformatic methods provide a powerful new tool for the detection and discovery of both known and new viroid species. PMID- 25287503 TI - Detection and characterization of mycoviruses in arbuscular mycorrhizal fungi by deep-sequencing. AB - Fungal viruses (mycoviruses) often have a significant impact not only on phenotypic expression of the host fungus but also on higher order biological interactions, e.g., conferring plant stress tolerance via an endophytic host fungus. Arbuscular mycorrhizal (AM) fungi in the phylum Glomeromycota associate with most land plants and supply mineral nutrients to the host plants. So far, little information about mycoviruses has been obtained in the fungi due to their obligate biotrophic nature. Here we provide a technical breakthrough, "two-step strategy" in combination with deep-sequencing, for virological study in AM fungi; dsRNA is first extracted and sequenced using material obtained from highly productive open pot culture, and then the presence of viruses is verified using pure material produced in the in vitro monoxenic culture. This approach enabled us to demonstrate the presence of several viruses for the first time from a glomeromycotan fungus. PMID- 25287504 TI - SuperSAGE as an analytical tool for host and viral gene expression. AB - SuperSAGE is a tag-based transcript profiling method, which allows to analyze the expression of thousands of genes at a time. In SuperSAGE, 26 bp tags are extracted from cDNA using the type III restriction enzyme, EcoP15I. In SuperSAGE, the amount of transcripts was represented by tag counts. Taking advantage of uniqueness of the 26 bp tags, host and virus transcripts can be monitored in virus-infected cells. Combining next generation sequencing technology, we established High-throughput SuperSAGE (Ht-SuperSAGE), which allows the analysis of multiple samples with reduced time and cost. In this chapter, we present the protocol of Ht-SuperSAGE involving a recently available benchtop type next generation sequencer. PMID- 25287505 TI - Microarray analysis of R-gene-mediated resistance to viruses. AB - The complex process for host-plant resistance to viruses is precisely regulated by a number of genes and signaling compounds. Thus, global gene expression analysis can provide a powerful tool to grasp the complex molecular network for resistance to viruses. The procedures for comparative global gene expression profiling of virus-resistant and control plants by microarray analysis include RNA extraction, cDNA synthesis, cRNA labeling, hybridization, array scanning, and data mining steps. There are several platforms for the microarray analysis. Commercial services for the steps from cDNA synthesis to array scanning are now widely available; however, the data manipulation step is highly dependent on the experimental design and research focus. The protocols presented here are optimized for analyzing global gene expression during the R gene-conferred defense response using commercial oligonucleotide-based arrays. We also demonstrate a technique to screen for differentially expressed genes using Excel software and a simple Internet tool-based data mining approach for characterizing the identified genes. PMID- 25287506 TI - Construction of infectious cDNA clones derived from the potyviruses clover yellow vein virus and bean yellow mosaic virus. AB - Infectious cDNA clones are now indispensible tools for the genetic analysis of viral factors involved in viral virulence and host resistance. In addition, infectious cDNA-derived virus vectors that express foreign genes in infected plants enable the production of useful proteins at low cost and can confer novel crop traits. We constructed infectious cDNA clones derived from two potyviruses, Clover yellow vein virus and Bean yellow mosaic virus, which infect legume plants and cause disease. Here, we present our procedure for constructing these potyvirus infectious clones. PMID- 25287507 TI - Virus-induced gene silencing of N gene in tobacco by apple latent spherical virus vectors. AB - Virus infections induce an RNA-mediated defense that targets viral RNAs in a nucleotide sequence-specific manner in plants, commonly referred to as virus induced gene silencing (VIGS). When the virus carries sequences of plant genes, it triggers virus-induced gene silencing (VIGS) and results in the degradation of mRNA of endogenous homologous gene. VIGS has been shown to have great potential as a reverse-genetics tool for studying of gene functions in plants, and it has several advantages over other functional genomics approaches. Here, we describe VIGS of N gene in tobacco cv. Xanthi nc by ALSV vectors containing fragments of N gene from Nicotiana glutinosa. PMID- 25287508 TI - Simplified methods for the construction of RNA and DNA virus infectious clones. AB - Infectious virus clones are one of the most powerful tools in plant pathology, molecular biology, and biotechnology. The construction of infectious clones of RNA and DNA viruses, however, usually requires laborious cloning and subcloning steps. In addition, instability of the RNA virus genome is frequently reported after its introduction into the vector and transference to Escherichia coli. These difficulties hamper the cloning procedures, making it tedious and cumbersome. This chapter describes two protocols for a simple construction of infectious viruses, an RNA virus, the tobamovirus Pepper mild mottle virus, and a DNA virus, a bipartite begomovirus. For this purpose, the strategy of overlap extension PCR was used for the construction of infectious tobamovirus clone and of rolling circle amplification (RCA) for the construction of a dimeric form of the begomovirus clone. PMID- 25287509 TI - Efficient double-stranded RNA production methods for utilization in plant virus control. AB - Double-stranded RNA (dsRNA) is an inducer molecule of the RNA silencing (RNA interference, RNAi) pathway that is present in all higher eukaryotes and controls gene expression at the posttranscriptional level. This mechanism allows the cell to recognize aberrant genetic material in a highly sequence specific manner. This ultimately leads to degradation of the homologous target sequence, rendering the plant cell resistant to subcellular pathogens. Consequently, dsRNA-mediated resistance has been exploited in transgenic plants to convey resistance against viruses. In addition, it has been shown that enzymatically synthesized specific dsRNA molecules can be applied directly onto plant tissue to induce resistance against the cognate virus. This strongly implies that dsRNA molecules are applicable as efficacious agents in crop protection, which will fuel the demand for cost-effective dsRNA production methods. In this chapter, the different methods for dsRNA production-both in vitro and in vivo-are described in detail. PMID- 25287510 TI - Detection of plant virus in meristem by immunohistochemistry and in situ hybridization. AB - Most plant viruses do not infect the shoot apical meristem (SAM) of a host plant, and this virus-free region of meristem tissue has been used to obtain virus-free clones by meristem tip culture. Thus, the validation of viral distribution in meristem tissues is important for ensuring the appropriate excision of virus-free meristem tips. Although immunohistochemical microscopy and in situ hybridization are classical techniques, they allow us to determine the presence or absence of plant viruses in the shoot meristem tissues of a host plant. Briefly, meristem tissues are excised from infected plants, fixed, embedded in paraffin medium, and prepared in semithin sections (10-15 MUm). By treating these sections with an antibody against viral protein or with a probe complementary to viral RNA, the viral distribution in the meristem tissue can be clearly observed. Importantly, these procedures are broadly applicable to most virus (and viroid) and host plant combinations. PMID- 25287511 TI - Insights into the potential function and membrane organization of the TP0435 (Tp17) lipoprotein from Treponema pallidum derived from structural and biophysical analyses. AB - The sexually transmitted disease syphilis is caused by the bacterial spirochete Treponema pallidum. This microorganism is genetically intractable, accounting for the large number of putative and undercharacterized members of the pathogen's proteome. In an effort to ascribe a function(s) to the TP0435 (Tp17) lipoprotein, we engineered a soluble variant of the protein (rTP0435) and determined its crystal structure at a resolution of 2.42 A. The structure is characterized by an eight-stranded beta-barrel protein with a shallow "basin" at one end of the barrel and an alpha-helix stacked on the opposite end. Furthermore, there is a disulfide-linked dimer of the protein in the asymmetric unit of the crystals. Solution hydrodynamic experiments established that purified rTP0435 is monomeric, but specifically forms the disulfide-stabilized dimer observed in the crystal structure. The data herein, when considered with previous work on TP0435, imply plausible roles for the protein in either ligand binding, treponemal membrane architecture, and/or pathogenesis. PMID- 25287514 TI - Controlled gelation of poly(3-alkylthiophene)s in bulk and in thin-films using low volatility solvent/poor-solvent mixtures. AB - Low volatility solvent/non-solvent mixtures were utilized to engineer the structure of poly(3-alkylthiophene) (P3AT) organogels. The ratio of solvent to poor-solvent was manipulated to systematically control the kinetics of self assembly. Specific solvent mixtures were utilized to produce similar gelation kinetics with polymers of differing alkyl chain length. Simultaneous small angle neutron scattering (SANS) and dielectric spectroscopy was used to probe the structure and the electronic properties of isothermally self-assembled P3ATs. It was determined that alkyl chain length has a dominant effect on the relationship between fiber development and conductivity. Furthermore, using transmission electron microscopy (TEM) and SANS we demonstrate that, for P3HT organogels, lower poor-solvent content leads to fewer fibers with larger nucleation centers while higher poor-solvent amounts results in more fibers and nucleation centers that are smaller and more abundant. This leads to opposing effects in terms of the contribution of the solvent quality to the electrical conductivity. An optimum in conductivity is found at different amounts of poor-solvent for each type of polymer. It is also shown that low volatility solvent mixtures allow for the formation of thermoreversible conjugated polymer organogels in thin-films at room temperature. This work highlights the potential to engineer the structure of conjugated polymer organogels while enabling the use of interconnected gel structures in thin-film organic electronic devices. PMID- 25287512 TI - Basolateral amygdala volume and cell numbers in major depressive disorder: a postmortem stereological study. AB - Functional imaging studies consistently report abnormal amygdala activity in major depressive disorder (MDD). Neuroanatomical correlates are less clear: imaging studies have produced mixed results on amygdala volume, and postmortem neuroanatomic studies have only examined cell densities in portions of the amygdala or its subregions in MDD. Here, we present a stereological analysis of the volume of, and the total number of, neurons, glia, and neurovascular (pericyte and endothelial) cells in the basolateral amygdala in MDD. Postmortem tissues from 13 subjects with MDD and 10 controls were examined. Sections (~15/subject) taken throughout the rostral-caudal extent of the basolateral amygdala (BLA) were stained for Nissl substance and utilized for stereological estimation of volume and cell numbers. Results indicate that depressed subjects had a larger lateral nucleus than controls and a greater number of total BLA neurovascular cells than controls. There were no differences in the number or density of neurons or glia between depressed and control subjects. These findings present a more detailed picture of BLA cellular anatomy in depression than has previously been available. Further studies are needed to determine whether the greater number of neurovascular cells in depressed subjects may be related to increased amygdala activity in depression. PMID- 25287515 TI - Development and validation of a questionnaire (FASH--Functional Assessment Scale for Acute Hamstring Injuries): to measure the severity and impact of symptoms on function and sports ability in patients with acute hamstring injuries. AB - OBJECTIVE: To develop a condition-specific patient-reported outcome measure, the Functional Assessment Scale for Acute Hamstring Injuries (FASH), de novo in three languages, following distinct and rigorous methodology for content generation, analysis and validation and to assess its psychometric properties. BACKGROUND: To our knowledge, there is no patient-reported functional scale specific for acute hamstring injuries. METHODS: The development of the scale followed specific guidelines, as well as de novo construction in three languages (Greek, English and German). Item generation was accomplished by selecting three different sources of items: literature review, focus group and key informant interviews. Content analysis was conducted by an expert committee. The 21 items selected as appropriate were tested through a structured content analytic method and item content validity coefficient, and 10 were retained for the FASH. The validation and assessment of its psychometric properties followed theConsensus-based Standards for the selection of health status Measurement Instruments (COSMIN) recommendations to ensure quality, in a convenience sample of 140 participants. RESULTS: The face validity was adequate and tested by expert committees, authors and participants. Content validity was characterised as well addressed and conducted independently by experts and through specific content validation procedures. The dimensionality analysis indicated a one-factor solution explaining the 95.8% of total variance. Known group validity was demonstrated by significant differences between patients and controls (p<0.001). The FASH exhibited very good test-retest reliability (intraclass correlation coefficient=0.9, p<0.001), internal consistency (alpha=0.98) and responsiveness (3.81 and 5.23 using baseline and pooled SD, respectively; standardised response mean (SRD)=4.68). CONCLUSION: This study provides initial evidence for psychometric properties of the first scale assessing hamstring injuries. PMID- 25287513 TI - Multimodal MRI of the hippocampus in Parkinson's disease with visual hallucinations. AB - Visual hallucinations carry poor prognosis in Parkinson's disease. Here we tested the hypothesis that the hippocampus and visuospatial memory impairment play a central role in the pathology of PD with visual hallucinations. Multimodal magnetic resonance imaging of the brain was carried out in 12 people with PD and visual hallucinations; 15 PD individuals without hallucinations; and 14 healthy controls. Age, gender, cognitive ability, and education level were matched across the three groups. PD patients were taking dopaminergic medication. Hippocampal volume, shape, mean diffusivity (MD), and functional connectivity within the whole brain were examined. Visuospatial memory was compared between groups, and correlations with hippocampal MD, functional connectivity, and the severity of hallucinations were explored. There were no macrostructural differences across groups, but individuals with hallucinations had higher diffusivity in posterior hippocampus than the other two groups. Visuospatial memory was poorer in both PD groups compared to controls, and was correlated with hallucinations. Finally, hippocampal functional connectivity in the visual cortices was lower in those with hallucinations than other groups, and this correlated with visuospatial memory impairment. In contrast, functional connectivity between the hippocampus and default mode network regions and frontal regions was greater in the PD hallucinators compared to other groups. We suggest that hippocampal pathology, which disrupts visuospatial memory, makes a key contribution to visual hallucinations in PD. These findings may pave the way for future studies of imaging biomarkers to measure treatment response in those with PD who are most at risk of poor outcomes. PMID- 25287516 TI - Molecular adsorption on graphene. AB - Current studies addressing the engineering of charge carrier concentration and the electronic band gap in epitaxial graphene using molecular adsorbates are reviewed. The focus here is on interactions between the graphene surface and the adsorbed molecules, including small gas molecules (H(2)O, H(2), O(2), CO, NO(2), NO, and NH(3)), aromatic, and non-aromatic molecules (F4-TCNQ, PTCDA, TPA, Na NH(2), An-CH(3), An-Br, Poly (ethylene imine) (PEI), and diazonium salts), and various biomolecules such as peptides, DNA fragments, and other derivatives. This is followed by a discussion on graphene-based gas sensor concepts. In reviewing the studies of the effects of molecular adsorption on graphene, it is evident that the strong manipulation of graphene's electronic structure, including p- and n-doping, is not only possible with molecular adsorbates, but that this approach appears to be superior compared to these exploiting edge effects, local defects, or strain. However, graphene-based gas sensors, albeit feasible because huge adsorbate-induced variations in the relative conductivity are possible, generally suffer from the lack of chemical selectivity. PMID- 25287517 TI - International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. AB - The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands. PMID- 25287518 TI - Implementation of a risk assessment program in a breast-imaging community practice. AB - BACKGROUND: To review the initial results of the implementation of a risk assessment program in our outpatient community-based breast-imaging practice. METHODS: From May 1, 2011 through November 4, 2013 a total of 96,389 patients presented to our facility. Each patient was required to complete a health history form. 24,850 (25.7 %) were flagged through our radiology information system (RIS) as potentially being at increased risk for breast cancer per responses on the health history form. Patient flagging was based on a system we developed. Letters were generated informing flagged patients and her physician that the patient could be a candidate for further breast cancer risk assessment. Genetic testing performed was primarily for BRCA1/BRCA2; testing for other mutations was offered based on personal and family history of the patient. RESULTS: 1,088 genetic counseling appointments occurred during the time frame from the 24,850 patients flagged, leading to 887 genetic tests performed. Forty-three mutations were detected: 21 BRCA1, 19 BRCA2, 1 MLH1, 1 MSH6 and 1 CHEK2. There were 717 negative tests, 20 variants of unknown significance; the remaining cases were cancelled. 464 high-risk MRIs were performed after the patient was referred from the program, from which 52 biopsies were performed due to a finding on MRI revealing 14 malignancies. CONCLUSIONS: In our experience after implementation of a risk assessment program, 24,850 potential at-risk patients have been flagged, revealing 40 BRCA 1 or 2 mutations. Screening with breast MRI provided to at-risk patients revealed 14 cancers diagnosed that may have otherwise been undetected. PMID- 25287519 TI - CORR Insights(r): A new method for calculating femoral anterior cortex point location and its effect on component sizing and placement. PMID- 25287520 TI - What factors predict improvements in outcomes scores and reoperations after the Bernese periacetabular osteotomy? AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) has entered its fourth decade and is frequently used for corrective osteotomy in patients with acetabular dysplasia. Although our capacity to preserve the joint after corrective osteotomy is excellent, gaining a better understanding on how well patients function after this surgery is important as well. QUESTIONS/PURPOSES: (1) What changes in patient-reported outcomes scores occur in patients treated with PAO for hip dysplasia in the setting of a single-surgeon practice? (2) What are the predictors of clinical function and survivorship? METHODS: All 67 patients presenting to a single surgeon's clinic with hip dysplasia treated with PAO between October 2005 and January 2013 were prospectively followed. Baseline demographic data as well as pre- and postoperative radiographic and functional measurements were obtained with a minimum of 1-year followup. Radiographic criteria included Tonnis grade, Tonnis angle, minimum joint space width, center edge angle, presence of crossover sign, medial translation of the hip center, and alpha angle. We also used validated outcome measures including the WOMAC, the UCLA Activity Scale, and the SF-12. Multiple regression analysis was used to determine predictors of functional outcome scores. RESULTS: There were increases in WOMAC, UCLA, and SF-12 Physical scores. Higher preoperative alpha angle was associated with a lower postoperative WOMAC score (beta=-0.47; 95% confidence interval [CI], -0.92 to -0.02; R2=0.08; p=0.04). The 5-year Kaplan-Meier survivorship was 94.1% (95% CI, 90.7-97.5) with reoperation (ie, hip arthroscopy and/or total hip arthroplasty) used as the endpoint for failure. With the limited numbers available, we could not identify any demographic or radiographic factors associated with reoperation. CONCLUSIONS: Overall survivorship for the PAO at our center at 5 years is comparable to other clinical series with overall functional scores improving. A greater alpha angle preoperatively was associated with poorer patient-reported outcome scores. Further research is needed to determine how and when intraarticular cartilage damage associated with dysplasia needs to be addressed. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25287521 TI - Do 360-degree feedback survey results relate to patient satisfaction measures? AB - BACKGROUND: There is evidence that feedback from 360-degree surveys-combined with coaching-can improve physician team performance and quality of patient care. The Physicians Universal Leadership-Teamwork Skills Education (PULSE) 360 is one such survey tool that is used to assess work colleagues' and coworkers' perceptions of a physician's leadership, teamwork, and clinical practice style. The Clinician & Group-Consumer Assessment of Healthcare Providers and System (CG-CAHPS), developed by the US Department of Health and Human Services to serve as the benchmark for quality health care, is a survey tool for patients to provide feedback that is based on their recent experiences with staff and clinicians and soon will be tied to Medicare-based compensation of participating physicians. Prior research has indicated that patients and coworkers often agree in their assessment of physicians' behavioral patterns. The goal of the current study was to determine whether 360-degree, also called multisource, feedback provided by coworkers could predict patient satisfaction/experience ratings. A significant relationship between these two forms of feedback could enable physicians to take a more proactive approach to reinforce their strengths and identify any improvement opportunities in their patient interactions by reviewing feedback from team members. An automated 360-degree software process may be a faster, simpler, and less resource-intensive approach than telephoning and interviewing patients for survey responses, and it potentially could facilitate a more rapid credentialing or quality improvement process leading to greater fiscal and professional development gains for physicians. QUESTIONS/PURPOSES: Our primary research question was to determine if PULSE 360 coworkers' ratings correlate with CG-CAHPS patients' ratings of overall satisfaction, recommendation of the physician, surgeon respect, and clarity of the surgeon's explanation. Our secondary research questions were to determine whether CG-CAHPS scores correlate with additional composite scores from the Quality PULSE 360 (eg, insight impact score, focus concerns score, leadership-teamwork index score, etc). METHODS: We retrospectively analyzed existing quality improvement data from CG-CAHPS patient surveys as well as from a department quality improvement initiative using 360 degree survey feedback questionnaires (Quality PULSE 360 with coworkers). Bivariate analyses were conducted to identify significant relationships for inclusion of research variables in multivariate linear analyses (eg, stepwise regression to determine the best fitting predictive model for CG-CAHPS ratings). In all higher order analyses, CG-CAHPS ratings were treated as the dependent variables, whereas PULSE 360 scores served as independent variables. This approach led to the identification of the most predictive linear model for each CG-CAHPS' performance rating (eg, [1] overall satisfaction; [2] recommendation of the physician; [3] surgeon respect; and [4] clarity of the surgeon's explanation) regressed on all PULSE scores with which there was a significant bivariate relationship. Backward stepwise regression was then used to remove unnecessary predictors from the linear model based on changes in the variance explained by the model with or without inclusion of the predictor. RESULTS: The Quality PULSE 360 insight impact score correlated with patient satisfaction (0.50, p = 0.01), patient recommendation (0.58, p = 0.002), patient rating of surgeon respect (0.74, p < 0.001), and patient impression of clarity of the physician explanation (0.69, p < 0.001). Additionally, leadership-teamwork index also correlated with patient rating of surgeon respect (0.46, p = 0.019) and patient impression of clarity of the surgeon's explanation (0.39, p = 0.05). Multivariate analyses supported retention of insight impact as a predictor of patient overall satisfaction, patient recommendation of the surgeon, and patient rating of surgeon respect. Both insight impact and leadership-teamwork index were retained as predictors of patient impression of explanation. Several other PULSE 360 variables were correlated with CG-CAHPS ratings, but none were retained in the linear models post stepwise regression. CONCLUSIONS: The relationship between Quality PULSE 360 feedback scores and measures of patient satisfaction reaffirm that feedback from work team members may provide helpful information into how patients may be perceiving their physicians' behavior and vice versa. Furthermore, the findings provide tentative support for the use of team-based feedback to improve the quality of relationships with both coworkers and patients. The 360-degree survey process may offer an effective tool for physicians to obtain feedback about behavior that could directly impact practice reimbursement and reputation or potentially be used for bonuses to incentivize better team professionalism and patient satisfaction, ie, "pay-for professionalism." Further research is needed to expand on this line of inquiry, determine which interventions can improve 360-degree and patient satisfaction scores, and explain the shared variance in physician performance that is captured in the perceptions of patients and coworkers. PMID- 25287522 TI - Editor's Spotlight/Take 5: The 2014 ABJS Nicolas Andry Award: The puzzle of the thumb: mobility, stability, and demands in opposition. PMID- 25287523 TI - Conversion of stemmed hemi- or total to reverse total shoulder arthroplasty: advantages of a modular stem design. AB - BACKGROUND: If revision of a failed anatomic hemiarthroplasty or total shoulder arthroplasty is uncertain to preserve or restore satisfactory rotator cuff function, conversion to a reverse total shoulder arthroplasty has become the preferred treatment, at least for elderly patients. However, revision of a well fixed humeral stem has the potential risk of loss of humeral bone stock, nerve injury, periprosthetic fracture, and malunion or nonunion of a humeral osteotomy with later humeral component loosening. QUESTIONS/PURPOSES: The purposes of this study were to determine whether preservation of a modular stem is associated with (1) less blood loss and operative time; (2) fewer perioperative and postoperative complications, including reoperations and revisions; and/or (3) improved Constant and Murley scores and subjective shoulder values for conversion to a reverse total shoulder arthroplasty compared with stem revision. METHODS: Between 2005 and 2011, 48 hemiarthroplasties and eight total shoulder arthroplasties (total=56 shoulders; 54 patients) were converted to an AnatomicalTM reverse total shoulder arthroplasty system without (n=13) or with (n=43) stem exchange. Complications and revisions for all patients were tallied through review of medical and surgical records. The outcomes scores included the Constant and Murley score and the subjective shoulder value. Complete clinical followup was available on 80% of shoulders (43 patients; 45 of 56 procedures, 32 with and 13 without stem exchange) at a minimum of 12 months (mean, 37 months; range, 12-83 months). RESULTS: Blood loss averaged 485 mL (range, 300-700 mL; SD, 151 mL) and surgical time averaged 118 minutes (range, 90-160 minutes; SD, 21 minutes) without stem exchange and 831 mL (range, 350-2000 mL; SD, 400 mL) and 176 minutes (range, 120 300 minutes; SD, 42 minutes) with stem exchange (p=0.001). Intraoperative complications (8% versus 30%; odds ratio [OR], 5.2) and reinterventions (8% versus 14%; OR, 1.9) were substantially fewer in patients without stem exchange. The complication rate leading to dropout from the study was substantial in the stem revision group (six patients; 43 shoulders [14%]), but there were no complication-related dropouts in the stem-retaining group. If, however, such complications could be avoided, with the numbers available we detected no difference in the functional outcome between the two groups. CONCLUSIONS: Patients undergoing revision of stemmed hemiarthroplasty or total to reverse total shoulder arthroplasty without stem exchange had less intraoperative blood loss and operative time, fewer intraoperative complications, and fewer revisions than did patients whose index revision procedures included a full stem exchange. Therefore modularity of a shoulder arthroplasty system has substantial advantages if conversion to reverse total shoulder arthroplasty becomes necessary and should be considered as prerequisite for stemmed shoulder arthroplasty systems. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25287524 TI - Hydrophobicity of whey protein hydrolysates enhances the protective effect against oxidative damage on PC 12 cells. AB - The relationship between hydrophobicity and the protective effect of whey protein hydrolysates (WPHs) against oxidative stress was studied. Whey protein was first hydrolysed by pepsin and trypsin to obtain WPHs. After absorbed by macroporous adsorption resin DA201-C, three fractions named as M20, M40, and M60 were eluted by various concentrations of ethanol. The hydrophobicity showed a trend of increase from M20 to M60. Antioxidant ability test in vitro indicated that all the three components of WPHs displayed reasonably good antioxidant ability. Moreover, with the increase of hydrophobicity, antioxidant ability of WPHs improved significantly. Then rat pheochromocytoma line 12 (PC12) cells oxidative model was built to evaluate the suppression of oxidative stress of three components on PC12 cells induced by H2O2. Morphological alterations, cell viability, apoptosis rate, and intracellular antioxidase system tests all indicated that WPHs exert significant protection on PC cells against H2O2-induced damage. Among them, M60 had the highest protective effect by increasing 19.3% cell survival and reducing 28.6% cell apoptosis. These results suggested hydrophobicity of WPHs was contributing to the antioxidant ability and the protective effect against oxidative damage. PMID- 25287525 TI - Prolonged swimming promotes cellular oxidative stress and p66Shc phosphorylation, but does not induce oxidative stress in mitochondria in the rat heart. AB - Exercise-induced changes in p66Shc-dependent signaling pathway are still not fully understood. The p66Shc protein is one of the key players in cell signaling, particularly in response to oxidative stress. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the phosphorylation of p66Shc as well as the induction of mitochondrial and cellular oxidative stress in rat hearts. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their hearts were removed immediately for experiments. The exercise protocol caused increased levels of the following oxidative stress parameters in cardiac cells: DNA damage, protein carbonyls, and lipid dienes. There was also increased phosphorylation of p66Shc without any alterations in Akt and extracellular signal-regulated kinases. Changes in the ferritin L levels and the L to H subunit ratio were also observed in the exercised hearts compared with the control hearts. Despite increased phosphorylation of p66Shc, no significant increase was observed in either mitochondrial H2O2 release or mitochondrial oxidative stress markers. Regardless of the changes in phosphorylation of p66Shc, the antioxidant enzyme activities (superoxide dismutase and catalase) and anti-apoptotic (Bcl2), and pro-apoptotic (Bax) protein levels were not affected by prolonged swimming. Further studies are required to investigate whether p66Shc phosphorylation is beneficial or detrimental to cardiac cells after exercise cessation. PMID- 25287526 TI - Are tyrosine residues involved in the photoconversion of the water-soluble chlorophyll-binding protein of Chenopodium album? AB - Non-photosynthetic and hydrophilic chlorophyll (Chl) proteins, called water soluble Chl-binding proteins (WSCPs), are distributed in various species of Chenopodiaceae, Amaranthaceae, Polygonaceae and Brassicaceae. Based on their photoconvertibility, WSCPs are categorised into two classes: Class I (photoconvertible) and Class II (non-photoconvertible). Chenopodium album WSCP (CaWSCP; Class I) is able to convert the chlorin skeleton of Chl a into a bacteriochlorin-like skeleton under light in the presence of molecular oxygen. Potassium iodide (KI) is a strong inhibitor of the photoconversion. Because KI attacks tyrosine residues in proteins, tyrosine residues in CaWSCP are considered to be important amino acid residues for the photoconversion. Recently, we identified the gene encoding CaWSCP and found that the mature region of CaWSCP contained four tyrosine residues: Tyr13, Tyr14, Tyr87 and Tyr134. To gain insight into the effect of the tyrosine residues on the photoconversion, we constructed 15 mutant proteins (Y13A, Y14A, Y87A, Y134A, Y13-14A, Y13-87A, Y13-134A, Y14-87A, Y14-134A, Y87-134A, Y13-14-87A, Y13-14-134A, Y13-87-134A, Y14-87-134A and Y13-14 87-134A) using site-directed mutagenesis. Amazingly, all the mutant proteins retained not only chlorophyll-binding activity, but also photoconvertibility. Furthermore, we found that KI strongly inhibited the photoconversion of Y13-14-87 134A. These findings indicated that the four tyrosine residues are not essential for the photoconversion. PMID- 25287528 TI - Advances in functional electrical stimulation (FES). AB - This review discusses the advancements that are needed to enhance the effects of electrical stimulation for restoring or assisting movement in humans with an injury/disease of the central nervous system. A complex model of the effects of electrical stimulation of peripheral systems is presented. The model indicates that both the motor and sensory systems are activated by electrical stimulation. We propose that a hierarchical hybrid controller may be suitable for functional electrical stimulation (FES) because this type of controller acts as a structural mimetic of its biological counterpart. Specific attention is given to the neural systems at the periphery with respect to the required electrodes and stimulators. Furthermore, we note that FES with surface electrodes is preferred for the therapy, although there is a definite advantage associated with implantable technology for life-long use. The last section of the review discusses the potential need to combine FES and robotic systems to provide assistance in some cases. PMID- 25287527 TI - Infarct tissue heterogeneity by contrast-enhanced magnetic resonance imaging is a novel predictor of mortality in patients with chronic coronary artery disease and left ventricular dysfunction. AB - BACKGROUND: Strategies for prevention of sudden cardiac death focus on severe left ventricular (LV) dysfunction, although most sudden cardiac death postmyocardial infarction occurs in patients with mild/moderate LV dysfunction. We tested the hypothesis that infarct heterogeneity by cardiac magnetic resonance is associated with mortality beyond LV ejection fraction (LVEF) in patients with coronary artery disease and LV dysfunction. In addition, we examined the association between infarct heterogeneity and mortality in those with LVEF >35%. METHODS AND RESULTS: We studied 301 patients with coronary artery disease and LV dysfunction referred for cardiac magnetic resonance. We quantified total infarct mass, infarct core mass, and peri-infarct zone (PIZ) normalized for total infarct mass (%PIZ) using signal-intensity criteria of >2 SDs, >3 SDs, and 2- to -3 SDs above remote myocardium, respectively. Mean LVEF was 41 +/- 14%. After 3.9 years median follow-up, 66 (22%) patients died (13 sudden cardiac death; 33 with LVEF >35%). In patients with LVEF >35%, below-median %PIZ carried an annual death rate of 2.8% versus 12% in patients with above-median %PIZ (P<0.001). In a multivariable model, %PIZ maintained strong association with mortality adjusted to patient age, LVEF, right ventricular ejection fraction, prolonged QT interval, and total infarct size and resulted in improve risk reclassification 0.492 (95% confidence interval, 0.183-0.817). CONCLUSIONS: Cardiac magnetic resonance infarct heterogeneity has a strong association with mortality independent of LVEF in patients with coronary artery disease and LV dysfunction, particularly in patients with mild or moderate LV dysfunction. Further studies incorporating cardiac magnetic resonance in clinical decision making for defibrillator therapy are warranted. PMID- 25287529 TI - The role of trunk muscles in sitting balance control in people with low back pain. AB - The purpose of this study was to examine the muscular activities and kinetics of the trunk during unstable sitting in healthy and LBP subjects. Thirty-one healthy subjects and twenty-three LBP subjects were recruited. They were sat on a custom made chair mounted on a force plate. Each subject was asked to regain balance after the chair was tilted backward at 20 degrees , and then released. The motions of the trunk and trunk muscle activity were examined. The internal muscle moment and power at the hip and lumbar spine joints were calculated using the force plate and motion data. No significant differences were found in muscle moment and power between healthy and LBP subjects (p>0.05). The duration of contraction of various trunk muscles and co-contraction were significantly longer in the LBP subjects (p<0.05) when compared to healthy subjects, and the reaction times of the muscles were also significantly reduced in LBP subjects (p<0.05). LBP subjects altered their muscle strategies to maintain balance during unstable sitting, but these active mechanisms appear to be effective as trunk balance was not compromised and the internal moment pattern remained similar. The changes in muscle strategies may be the causes of LBP or the result of LBP with an attempt to protect the spine. PMID- 25287530 TI - Letter to the editor: A comparative study of three-year weight loss and outcomes after laparoscopic gastric bypass in patients with "yellow light" psychological clearance. PMID- 25287531 TI - Erratum to: Buttressing the Staple Line: A Randomized Comparison Between Staple Line Reinforcement Versus No Reinforcement During Sleeve Gastrectomy. PMID- 25287532 TI - Erratum to: Laparoscopic Sleeve Gastrectomy Versus Laparoscopic Roux-En-Y Gastric Bypass for Morbid Obesity and Related Comorbidities: A Meta-Analysis of 21 Studies. PMID- 25287533 TI - Changes induced by prenatal stress in behavior and brain morphology: can they be prevented or reversed? AB - This chapter presents a critical analysis of the behavioral alterations reported in the offspring of women exposed to stress and/or depression during pregnancy and the neurochemical and structural changes underlying them. Among the alterations attributed to prenatal stress in humans and experimental rats of both sexes is impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis, anxiety and exaggerated fear of novelty, and decreased social interaction. Learning and attention deficits are more prevalent in boys and male rats. Fear of novelty and anxiety are associated with enlargement of the amygdala and its corticotropin-releasing factor content, and decreased socialization, with lower oxytocin activity in the amygdala. Learning deficits are associated with a decrease in neurogenesis, dendritic complexity, and spine number in the dorsal hippocampus. Fostering prenatally stressed (PS) pups onto control mothers prevents the dysregulation of the HPA axis and heightened anxiety, indicating a role for postnatal factors in their etiology. By contrast, learning impairment and decreased socialization are not affected by this fostering procedure and are therefore prenatally mediated.In spite of their widespread use in depressed pregnant women, selective serotonin reuptake inhibitor (SSRI) antidepressants do not normalize the behavior of their children. When administered during gestation to stressed rats, SSRIs do not reduce anxiety or learning deficits in their offspring. Moreover, when given to unstressed mothers, SSRIs induce anxiety in the offspring. The detrimental effect of SSRIs may result from inhibition of the serotonin transporter exposing the brain to excess amounts of 5-hydroxytryptamine (5-HT) at a critical time during fetal development. PMID- 25287534 TI - Sleep in prenatally restraint stressed rats, a model of mixed anxiety-depressive disorder. AB - Prenatal restraint stress (PRS) can induce persisting changes in individual's development. PRS increases anxiety and depression-like behaviors and induces changes in the hypothalamo-pituitary-adrenal (HPA) axis in adult PRS rats after exposure to stress. Since adaptive capabilities also depend on temporal organization and synchronization with the external environment, we studied the effects of PRS on circadian rhythms, including the sleep-wake cycle, that are parameters altered in depression. Using a restraint stress during gestation, we showed that PRS induced phase advances in hormonal/behavioral circadian rhythms in adult rats, and an increase in the amount of paradoxical sleep, positively correlated to plasma corticosterone levels. Plasma corticosterone levels were also correlated with immobility in the forced swimming test, indicating a depressive-like profile in the PRS rats. We observed comorbidity with anxiety like profile on PRS rats that was correlated with a reduced release of glutamate in the ventral hippocampus. Pharmacological approaches aimed at modulating glutamate release may represent a novel therapeutic strategy to treat stress related disorders. Finally, since depressed patients exhibit changes in HPA axis activity and in circadian rhythmicity as well as in the paradoxical sleep regulation, we suggest that PRS could represent an original animal model of depression. PMID- 25287536 TI - Involvement of Nitric Oxide, Neurotrophins and HPA Axis in Neurobehavioural Alterations Induced by Prenatal Stress. AB - Several studies suggest that negative emotions during pregnancy generate adverse effects on the cognitive, behavioural and emotional development of the descendants. The psychoneuroendocrine pathways involve the transplacentary passage of maternal glucocorticoids in order to influence directly on fetal growth and brain development.Nitric oxide is a gaseous neurotransmitter that plays an important role in the control of neural activity by diffusing into neurons and participates in learning and memory processes. It has been demonstrated that nitric oxide is involved in the regulation of corticosterone secretion. Thus, it has been found that the neuronal isoform of nitric oxide synthase (nNOS) is an endogenous inhibitor of glucocorticoid receptor (GR) in the hippocampus and that nNOS in the hippocampus may participate in the modulation of hypothalamic-pituitary-adrenal axis activity via GR.Neurotrophins are a family of secreted growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4. Although initially described in the nervous system, they regulate processes such as cell survival, proliferation and differentiation in several other compartments. It has been demonstrated that the NO-citrulline cycle acts together with BDNF in maintaining the progress of neural differentiation.In the present chapter, we explore the interrelation between nitric oxide, glucocorticoids and neurotrophins in brain areas that are key structures in learning and memory processes. The participation of this interrelation in the behavioural and cognitive alterations induced in the offspring by maternal stress is also addressed. PMID- 25287535 TI - Hormonal modulation of catecholaminergic neurotransmission in a prenatal stress model. AB - Our laboratory has a long-standing interest in the effects of prenatal stress (PS) on various neurotransmitter pathways and the morphology of the developing brain as well as in behavioural aspects of the offspring. Employing a commonly used PS paradigm in which the dams were subjected to restraint stress during the last week of gestation, we observed that several of these pathways were altered in the offspring brain. In this chapter, we will summarize and discuss the results obtained with the main catecholaminergic pathways, namely dopamine (DA) and norepinephrine (NE). In our hands, PS produces an increase in dopamine D2 type receptors in limbic areas, a decreased DA release after amphetamine stimulation in prefrontal cortex (PFC) and an increase in NE release in the same area of the adult offspring brain. In addition, DA uptake is altered at prepubertal stages that persist through adulthood. However, the expression of the step-limiting enzyme of the DA synthesis, tyrosine hydroxylase (TH), is only impaired at early stages of development after PS in the neuronal bodies. At the nuclear regulation level, dopaminergic transcription factors Nurr1 and Ptx3 showed a high vulnerability to PS showing changes along the lifespan. It was striking to observe that many impairments observed in most of these pathways differed depending on whether they were tested before or after puberty indicating a particular sensitivity of the systems to variations in gonadal hormones peaks. In fact, we observed that PS induced long-term effects on the male offspring reproductive system and spermatogenesis development, particularly by inducing a long-term imbalance of circulating sexual hormone levels. Our findings suggest that PS exerts long-term effects on various neurotransmitter pathways altering the normal connectivity between brain areas. Since the developing forebrain was shown to be influenced by androgen exposure, and PS was shown to disrupt prenatal testosterone surges, our results suggest that prenatal insults might be affecting the organizational role of androgens during brain development and differentially modulating their activational role during pubertal brain maturation. PMID- 25287537 TI - Prenatal stress and adult drug-seeking behavior: interactions with genes and relation to nondrug-related behavior. AB - Addiction inflicts large personal, social, and economic burdens, yet its etiology is poorly defined and effective treatments are lacking. As with other neuropsychiatric disorders, addiction is characterized by a core set of symptoms and behaviors that are believed to be influenced by complex gene-environment interactions. Our group focuses on the interaction between early stress and genetic background in determining addiction vulnerability. Prior work by our group and others has indicated that a history of prenatal stress (PNS) in rodents elevates adult drug seeking in a number of behavioral paradigms. The focus of the present chapter is to summarize work in the area of PNS and addiction models as well as our recent studies of PNS on drug seeking in different strains of mice as a strategy to dissect gene-environment interactions underlying cocaine addiction vulnerability. These studies indicate that ability of PNS to elevate adult cocaine seeking is strain dependent. Further, PNS also alters other nondrug behaviors in a fashion that is dependent on different strains and independent from the strain dependence of drug seeking. Thus, it appears that the ability of PNS to alter behavior related to different psychiatric conditions is orthogonal, with similar nonspecific susceptibility to prenatal stress across genetic backgrounds but with the genetic background determining the specific nature of the PNS effects. Finally, the advent of recombinant inbred mouse strains is allowing us to determine the genetic bases of these gene-environment interactions. Understanding these effects will have broad implications to determining the nature of vulnerability to addiction and perhaps other disorders. PMID- 25287538 TI - A self-medication hypothesis for increased vulnerability to drug abuse in prenatally restraint stressed rats. AB - Stress-related events that occur in the perinatal period can permanently change brain and behavior of the developing individual and there is increasing evidence that early-life adversity is a contributing factor in the etiology of drug abuse and mood disorders. Neural adaptations resulting from early-life stress may mediate individual differences in novelty responsiveness and in turn contribute to drug abuse vulnerability. Prenatal restraint stress (PRS) in rats is a well documented model of early stress known to induce long-lasting neurobiological and behavioral alterations including impaired feedback mechanisms of the HPA axis, enhanced novelty seeking, and increased sensitiveness to psychostimulants as well as anxiety/depression-like behavior. Together with the HPA axis, functional alterations of the mesolimbic dopamine system and of the metabotropic glutamate receptors system appear to be involved in the addiction-like profile of PRS rats. PMID- 25287539 TI - How postnatal insults may program development: studies in animal models. AB - During the postnatal period, the nervous system is modified and shaped by experience, in order to adjust it to the particular environment in which the animal will live. This plasticity, one of the most remarkable characteristics of the nervous system, promotes adaptive changes, but it also makes brain more vulnerable to insults. This chapter will focus on the effects of interventions during the postnatal development in animal models of neonatal handling (usually up to 15 min of handling) and maternal separation (usually at least for 3 h). Sex specific changes and effects of prepubertal stress such as social isolation later on in life were also considered. These interventions during development induce long-lasting traces in the pups' nervous system, which will be reflected in changes in neuroendocrine functions, including the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes; anxiety and cognitive performance; and feeding, sexual, and social behavior. These enduring changes may be adaptive or maladaptive, depending on the environment in which the animal will live. The challenge researchers facing now is to determine how to reverse the deleterious effects that may result from early-life stress exposure. PMID- 25287540 TI - Perinatal positive and negative influences on the early neurobehavioral reflex and motor development. AB - Early life events are critical in the development of the central nervous system. Injuries in this period can cause severe damage with permanent disabilities. The early changes following a perinatal lesion have prognostic significance. The nervous system in young age has a potential for plasticity and regeneration, which can prevent the negative effects of neuronal damage, and the most important objective of rehabilitation is to enhance this inner potential of the developing brain. Experimental examination of the environmental factors affecting this regeneration and remodeling process is very important. Endogenous factors, such as neurotrophic factors, which play a role in neurogenesis, migration, and differentiation of neurons, and development of neuronal circuits, are also in the center of interest. Most studies concerning the effect of positive or negative perinatal treatments focus mainly on long-term effects, and most examinations are carried out on adult animals following perinatal injuries. Less data are available on short-term effects and early neurobehavioral changes. In the past several years, we have shown how different (positive or negative) perinatal events affect the early neuronal development. Applying different tests widely used for behavioral testing, we have established a standardized testing method. This includes measuring parameters of somatic growth and facial development, appearance of basic neurological reflexes and also reflex performance, more complex motor coordination tests, and open-field and novelty-seeking tests. In the present chapter, we summarize data on early neurobehavioral development of newborn rats subjected to negative (perinatal asphyxia, hypoxia, excitotoxic injury, stress) and positive (enriched environment, neurotrophic factor treatment) stimuli during early postnatal life. PMID- 25287541 TI - Short- and long-term consequences of perinatal asphyxia: looking for neuroprotective strategies. AB - Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. A primary insult is first produced by the length of the time without oxygenation, leading to hypoxia/ischemia and death if oxygenation is not promptly established. A second insult is produced by re-oxygenation, eliciting a cascade of biochemical events for restoring function, implying, however, improper homeostasis. The effects observed long after perinatal asphyxia can be explained by over-expression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for oxidised nicotinamide adenine dinucleotide (NAD(+)) during re-oxygenation. Asphyxia also induces transcriptional activation of pro-inflammatory factors, including nuclear factor kappaB (NFkappaB) and its subunit p65, whose translocation to the nucleus is significantly increased in brain tissue from asphyxia-exposed animals, in tandem with PARP-1 overactivation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. It is proposed that PARP-1 inhibition also down-regulates the expression of pro-inflammatory cytokines.Nicotinamide is a suitable PARP-1 inhibitor, whose effects have been studied in an experimental model of global perinatal asphyxia in rats, inducing the insult by immersing rat foetuses into a water bath for various periods of time. Following asphyxia, the pups are delivered, immediately treated, or given to surrogate dams for nursing, pending further experiments. Systemic administration of nicotinamide 1 h after the insult inhibited PARP-1 overactivity in peripheral and brain tissue, preventing several of the long-term consequences elicited by perinatal asphyxia, supporting the idea that it constitutes a lead for exploring compounds with similar or better pharmacological profiles. PMID- 25287542 TI - Affective, cognitive, and motivational processes of maternal care. AB - The present chapter reviews current knowledge of the neurobiology of maternal behavior in mammals. In the first section, we present existing information of the affective, motivational, and cognitive processes that characterize maternal behavior, primarily discussing research findings in rats and humans, because most of the work on the neurobiological basis of this behavior has been done in these species. The second section outlines the maternal neural circuitry, with a special emphasis on the mechanisms that underlie the affective, motivational, and cognitive processes of motherhood. Finally, we summarize some of the main themes raised in the chapter and issues yet to be explored. PMID- 25287543 TI - Role of sensory, social, and hormonal signals from the mother on the development of offspring. AB - For mammals, sensory, social, and hormonal experience early in life is essential for the continuity of the infant's development. These experiences come from the mother through maternal care, and have enduring effects on the physiology and behavior of the adult organism. Disturbing the mother-offspring interaction by maternal deprivation (neglect) or exposure to adverse events as chronic stress, maltreatment, or sexual abuse has negative effects on the mental, psychological, physiological, and behavioral health. Indeed, these kinds of negative experiences can be the source of some neuropsychiatric diseases as depression, anxiety, impulsive aggression, and antisocial behavior. The purpose of this chapter is to review the most relevant evidence that supports the participation of cues from the mother and/or littermates during the postnatal preweaning period for the development of nervous system of the offspring. These findings come from the most frequently utilized experimental paradigms used in animal models, such as natural variations in maternal behavior, handling, partial maternal deprivation, and total maternal deprivation and artificial rearing. Through the use of these experimental procedures, it is possible to positively (handling paradigm), or negatively (maternal deprivation paradigms), affect the offspring's development. Finally, this chapter reviews the importance of the hormones that pups ingest through the maternal milk during early lactation on the development of several physiological systems, including the immune, endocrine systems, as well as on the adult behavior of the offspring. PMID- 25287544 TI - Retrospective studies. AB - Large retrospective, epidemiological studies accumulated in the late 1980s, providing increasing evidence to the deeply rooted thought that perinatal events could persistently affect the individual's functioning and health/disease patterns throughout the lifetime. Evidences of such associations can be found in the literature since the beginning of the twentieth century, but studies from Barker, Hales, and colleagues serve as an important hallmark. They proposed the "thrifty phenotype" hypothesis, stating that poor nutrition in fetal and early infant life is detrimental to the development and function of the individuals' organism, predisposing them to the later development of adult chronic diseases. At first used to explain the increased risk for type 2 diabetes in low birth weight individuals, the hypothesis was soon adapted to other systems, becoming one of the core assumptions of the Developmental Origins of Adult Health and Disease (DOHaD) model. The central nervous system is also vulnerable to the effects of environmental variation during fetal or neonatal life. Many researchers have explored the effects of perinatal programming on the human neurodevelopment, and some aspects of the brain structure and/or functioning (such as cognitive function, physiological reactivity to stress, and the risk for behavioral disorders or psychopathology) were shown to be modifiable by the exposure to certain adverse events early in life such as neonatal infections, exposure to gestational psychosocial stress, nutrition during gestation, exposure to drugs, or tobacco smoking during pregnancy. Until recently, most studies focused on birth weight as a strong surrogate of the intrauterine environment, investigating the effects of low birth weight (as a marker of suboptimal fetal environment) on a variety of neurodevelopmental outcomes. Despite the fact that literature reviews on this topic are as old as 1940, the more recent retrospective studies are summarized in this chapter. PMID- 25287545 TI - Prenatal stress and its effects on the fetus and the child: possible underlying biological mechanisms. AB - Many prospective studies have shown that if a mother is depressed, anxious or stressed while pregnant, this increases the risk for her child having a wide range of adverse outcomes including emotional problems, symptoms of attention deficit hyperactivity disorder (ADHD) or impaired cognitive development. Although genetics and postnatal care clearly affect these outcomes, evidence for a prenatal causal component also is substantial. Prenatal anxiety/depression may contribute 10-15 % of the attributable load for emotional/behavioural outcomes.The mechanisms underlying these changes are just starting to be explored. One possible mediating factor is increased exposure of the fetus to cortisol, as has been shown in animal studies. However, the human hypothalamic pituitary-adrenal (HPA) axis which makes cortisol functions differently in human pregnancy from in most animals. The maternal HPA axis becomes gradually less responsive to stress as pregnancy progresses. And there is only a weak, if any, association between a mother's prenatal mood and her cortisol level, especially later in pregnancy. Cytokines are alternative possible mediators. An additional explanation is that stress or anxiety causes increased transfer of maternal cortisol across the placenta to the fetus. The placenta plays a crucial role in moderating fetal exposure to maternal factors and presumably in preparing the fetus for the environment in which it is going to find itself. There is some evidence in both rat models and in humans that prenatal stress can reduce placental 11beta-HSD2, the enzyme which metabolises cortisol to inactive cortisone. The level of cortisol in the amniotic fluid, surrounding the baby in the womb, has been shown to be inversely correlated with infant cognitive development. However, several other biological systems are likely to be involved. Serotonin is another possible mediator of prenatal stress induced programming effects on offspring neurocognitive and behavioural development. The role of epigenetic changes in mediating alterations in offspring outcome following prenatal stress is likely to be important and starting to be explored. PMID- 25287546 TI - Using natural disasters to study prenatal maternal stress in humans. AB - Animal studies of prenatal maternal stress permit random assignment of pregnant animals to stress and no-stress groups, and allow total control of the type, severity, and timing of the stressor in utero. Human studies have obvious constraints that make the use of experimental methods nearly impossible. Studying pregnant women who experience natural disasters during pregnancy, however, approximates the random assignment to groups enjoyed by animal studies, and can characterize the timing of the stressor in utero with great precision. In this chapter, we briefly describe our three ongoing prospective longitudinal studies of children exposed to prenatal maternal stress from natural disasters. We present results from Project Ice Storm in detail, showing effects of prenatal maternal stress on cognitive and neurodevelopment. We contrast these results with preliminary findings from the Iowa Flood Study and introduce the QF2011 Queensland Flood Project. In the "Discussion" section, we present conclusions to date and discuss the relative effects of the severity of maternal objective disaster exposure and maternal subjective distress levels, the moderating effects of fetal sex and the timing of the stressor in utero, and the longevity of the effects. Finally, we discuss some possible mechanisms that may mediate the effects of prenatal maternal stress on the neurodevelopment of children. PMID- 25287547 TI - Early life influences on cognition, behavior, and emotion in humans: from birth to age 20. AB - The long-lasting effects of fetal exposure to early life influences (ELI) such as maternal anxiety, stress, and micronutrient deficiencies as well as mediating and moderating factors are quite well established in animal studies, but remain unclear in humans. Here, we report about effects on cognition, behavior, and emotion in offspring aged 5-20 years old in two prospective longitudinal birth cohorts. PMID- 25287548 TI - Perinatal programming of neurodevelopment: epigenetic mechanisms and the prenatal shaping of the brain. AB - The recent years have witnessed an exponential growth in the knowledge of epigenetic mechanisms, and piling evidence now links DNA methylation and histone modifications with a wide range of physiological processes from embryonic development to memory formation and behavior. Not surprisingly, deregulation of epigenetic modifications is associated with human diseases as well.An important feature of epigenetics is the ability of transducing environmental input into biological signaling, mainly by modulation of the transcriptome in response to a particular scenario. This characteristic generates developmental plasticity and allows the manifestation of a variety of phenotypes from the same genome.The early-life years represent a period of particular susceptibility to epigenetic alteration, as active changes in DNA methylation and histone marks are occurring as part of developmental programs and in response to environmental cues, which notably include psychosocial stimulation and maternal behavior. Memory formation and storage, response to stress in adult life, behavior, and manifestation of neurodegenerative conditions can all be imprinted in the organism by epigenetic modifications that contribute to shape the brain during prenatal or early postnatal life. Moreover, if these epigenetic alterations are preserved in the germ line, changes induced in one generation are likely inherited by future offspring. Programming by transgenerational inheritance thus represents a central mechanism by which environmental conditions may influence disease risk across multiple generations.As novel techniques emerge and as genome-wide profiling of disease-associated methylomes is achieved, epigenetic marks open a new source for biomarker discovery. PMID- 25287549 TI - Epigenetic mechanisms of perinatal programming: translational approaches from rodent to human and back. AB - Perinatal life is a period of enhanced plasticity and susceptibility to environmental effects via the maternal environment or parental care. A variety of studies have indicated that epigenetic mechanisms, which can alter gene function without a change in gene sequence, play a role in setting developmental trajectories that impact health, including mental health. This chapter reviews examples of translational approaches to the study of biological embedding of mental health via differences in parental care. PMID- 25287550 TI - Perinatal administration of aromatase inhibitors in rodents as animal models of human male homosexuality: similarities and differences. AB - In this chapter we briefly review the evidence supporting the existence of biological influences on sexual orientation. We focus on basic research studies that have affected the estrogen synthesis during the critical periods of brain sexual differentiation in male rat offspring with the use of aromatase inhibitors, such as 1,4,6-androstatriene-3,17 (ATD) and letrozole. The results after prenatal and/or postnatal treatment with ATD reveal that these animals, when adults, show female sexual responses, such as lordosis or proceptive behaviors, but retain their ability to display male sexual activity with a receptive female. Interestingly, the preference and sexual behavior of these rats vary depending upon the circadian rhythm.Recently, we have established that the treatment with low doses of letrozole during the second half of pregnancy produces male rat offspring, that when adults spend more time in the company of a sexually active male than with a receptive female in a preference test. In addition, they display female sexual behavior when forced to interact with a sexually experienced male and some typical male sexual behavior when faced with a sexually receptive female. Interestingly, these males displayed both sexual behavior patterns spontaneously, i.e., in absence of exogenous steroid hormone treatment. Most of these features correspond with those found in human male homosexuals; however, the "bisexual" behavior shown by the letrozole-treated rats may be related to a particular human population. All these data, taken together, permit to propose letrozole prenatal treatment as a suitable animal model to study human male homosexuality and reinforce the hypothesis that human sexual orientation is underlied by changes in the endocrine milieu during early development. PMID- 25287551 TI - Impact of the Perinatal Environment on the Child's Development: Implications for Prevention Policies. AB - Basic emotional security is central to the construction of the child and has an impact on the brain's organisation, the personal autonomy and the capacity to explore the world. The key concept of the attachment theory is supported by recent neuroimaging findings of brain development and the structuring of the hypothalamic-pituitary-adrenal axonal regulatory systems.In addition to the child's potential, the essential variable lies in the quality of the environment's responses, and consequently in the quality of the maternal security, from the very early intrauterine life. The understanding of the effects of parental stress during the early developmental stages is advancing. In France, the emotional security of pregnant women and future parents has become a major stake of perinatal policies for the prevention of developmental disorders.Specific strategies are being developed to improve both the maternal and the infant well-being. These are not restricted only to mental health specialists but rather involve every health-care professional of the perinatal period. The mechanisms of change for vulnerable parents emerge from the prospective analysis of support methods. Continuity and coherence of such care serve as a holding function, which enables the restructuring of previous emotional traumas.A new interdisciplinary perinatal medicine is emerging, structured rigorously around a well-coordinated obstetrical and paediatric follow up. Considering the future of children, teenagers and adults, the stakes are enormous. PMID- 25287552 TI - Perinatal programming prevention measures. AB - Over the past 10 years, there has been outstanding scientific progress related to perinatal programming and its epigenetic effects in health, and we can anticipate this trend will continue in the near future. We need to make use and apply these achievements to human neurodevelopment via prevention interventions. Based on the concept of the interaction between genome and ambiome, this chapter proposes low cost easy-implementation preventive strategies for maternal and infant health institutions.Breastfeeding and human milk administration are the first preventive measures, as has been reviewed in the policy statement of the American Academy of Pediatrics. Another strategy is the Safe and Family-Centered Maternity Hospitals initiative that promotes and empowers the inclusion of the families and the respect for their rights, especially during pregnancy and birth. (This change of paradigm was approved and is recommended by both United Nations Children's Fund, UNICEF, and Pan American Health Organization, PAHO.) Then, there is also an important emphasis given to the sacred hour-which highlights the impact of bonding, attachment, and breastfeeding during the first hour of life-the pain prevention and treatment in newborns, the control of the "new morbidity" represented by late preterm infants, and finally, the importance of avoiding intrauterine and extrauterine growth restriction. (However, there are not yet clear recommendations about nutritional interventions in order to diminish the potential metabolic syndrome consequence in the adult.). PMID- 25287553 TI - Pregnancy Outcomes After a Maternity Intervention for Stressful Emotions (PROMISES): A Randomised Controlled Trial. AB - There is ample evidence from observational prospective studies that maternal depression or anxiety during pregnancy is a risk factor for adverse psychosocial outcomes in the offspring. However, to date no previous study has demonstrated that treatment of depressive or anxious symptoms in pregnancy actually could prevent psychosocial problems in children. Preventing psychosocial problems in children will eventually bring down the huge public health burden of mental disease. The main objective of this study is to assess the effects of cognitive behavioural therapy in pregnant women with symptoms of anxiety or depression on the child's development as well as behavioural and emotional problems. In addition, we aim to study its effects on the child's development, maternal mental health, and neonatal outcomes, as well as the cost-effectiveness of cognitive behavioural therapy relative to usual care.We will include 300 women with at least moderate levels of anxiety or depression at the end of the first trimester of pregnancy. By including 300 women, we will be able to demonstrate effect sizes of 0.35 or more on the total problems scale of the Child Behaviour Checklist 1.5 5 with alpha 5 % and power (1-beta) 80 %.Women in the intervention arm are offered 10-14 individual cognitive behavioural therapy sessions, 6-10 sessions during pregnancy and 4-8 sessions after delivery (once a week). Women in the control group receive care as usual.Primary outcome is behavioural/emotional problems at 1.5 years of age as assessed by the total problems scale of the Child Behaviour Checklist 1.5-5 years.Secondary outcomes are mental, psychomotor and behavioural development of the child at age 18 months according to the Bayley scales; maternal anxiety and depression during pregnancy and postpartum; and neonatal outcomes such as birth weight, gestational age and Apgar score, health care consumption and general health status (economic evaluation). TRIAL REGISTRATION: NTR2242. PMID- 25287555 TI - Reliability of intra-abdominal pressure measurements using the modified Kron technique. AB - OBJECTIVES: Assessment of intra-abdominal pressure (IAP) and the likelihood of abdominal compartment syndrome using valid and reliable measures is an important tool in the assessment of critically ill patients. The current method of relying on a single IAP per measurement period to determine patient clinical status raises the question: is a single intermittent IAP measurement an accurate indicator of clinical status or should more than one measurement be taken per measurement period? METHODS: This study sought to assess the reliability of IAP measurements. Measurements were taken using the modified Kron technique. A total of two transvesical intra-abdominal pressure measurements were undertaken per patient using a standardized protocol. Recordings were taken at intervals of 5 minutes. RESULTS: The majority of participants (58%) were surgical patients. Thirty-two were males and the mean age was 58 years (SD: 16.7 years). The concordance correlation coefficient between the two measurements was 0.95. Both the scatter and Bland-Altman plots demonstrate that the comparisons of two measurements are highly reproducible. CONCLUSION: The findings of this study suggest that conducting two IAP measurements on single patient produce comparable results; therefore, there appears to be no advantage in doing two IAP measurements on a single patient. The measurement of an IAP requires the implementation of a standardized protocol and competent and credentialed assessors trained in the procedure. PMID- 25287554 TI - Baseline brain activity predicts response to neuromodulatory pain treatment. AB - OBJECTIVES: The objective of this study was to examine the associations between baseline electroencephalogram (EEG)-assessed brain oscillations and subsequent response to four neuromodulatory treatments. Based on available research, we hypothesized that baseline theta oscillations would prospectively predict response to hypnotic analgesia. Analyses involving other oscillations and the other treatments (meditation, neurofeedback, and both active and sham transcranial direct current stimulation) were viewed as exploratory, given the lack of previous research examining brain oscillations as predictors of response to these other treatments. DESIGN: Randomized controlled study of single sessions of four neuromodulatory pain treatments and a control procedure. METHODS: Thirty individuals with spinal cord injury and chronic pain had their EEG recorded before each session of four active treatments (hypnosis, meditation, EEG biofeedback, transcranial direct current stimulation) and a control procedure (sham transcranial direct stimulation). RESULTS: As hypothesized, more presession theta power was associated with greater response to hypnotic analgesia. In exploratory analyses, we found that less baseline alpha power predicted pain reduction with meditation. CONCLUSIONS: The findings support the idea that different patients respond to different pain treatments and that between-person treatment response differences are related to brain states as measured by EEG. The results have implications for the possibility of enhancing pain treatment response by either 1) better patient/treatment matching or 2) influencing brain activity before treatment is initiated in order to prepare patients to respond. Research is needed to replicate and confirm the findings in additional samples of individuals with chronic pain. PMID- 25287556 TI - Polymer fluctuation lubrication in hydrogel gemini interfaces. AB - Interfacial sliding speed and contact pressure between the sub-units of particulate soft matter assemblies can vary dramatically across systems and with dynamic conditions. By extension, frictional interactions between particles may play a key role in their assembly, global configuration, collective motion, and bulk material properties. For example, in tightly packed assemblies of microgels colloidal microspheres made of hydrogel - particle stiffness controls the fragility of the glassy state formed by the particles. The interplay between particle stiffness and shear stress is likely mediated by particle-particle normal forces, highlighting the potential role of hydrogel-hydrogel friction. Here we study friction at a twinned "Gemini" interface between hydrogels. We construct a lubrication curve that spans four orders of magnitude in sliding speed, and find qualitatively different behaviour from traditional lubrication of engineering material surfaces; fundamentally different types of lubrication occur at the hydrogel Gemini interface. We also explore the role played by polymer solubility and hydrogel-hydrogel adhesion in hydrogel friction. We find that polymer network elasticity, mesh size, and single-chain relaxation times can describe friction at the gel-gel interface, including a transition between lubrication regimes with varying sliding speed. PMID- 25287557 TI - A decade of nutrition research in Africa: assessment of the evidence base and academic collaboration. AB - OBJECTIVE: Malnutrition in Africa has not improved compared with other regions in the world. Investment in the build-up of a strong African research workforce is essential to provide contextual solutions to the nutritional problems of Africa. To orientate this process, we reviewed nutrition research carried out in Africa and published during the last decade. DESIGN: We assessed nutrition research from Africa published between 2000 and 2010 from MEDLINE and EMBASE and analysed the study design and type of intervention for studies indexed with major MeSH terms for vitamin A deficiency, protein-energy malnutrition, obesity, breast-feeding, nutritional status and food security. Affiliations of first authors were visualised as a network and power of affiliations was assessed using centrality metrics. SETTING: Africa. SUBJECTS: Africans, all age groups. RESULTS: Most research on the topics was conducted in Southern (36%) and Western Africa (34%). The intervention studies (9%; n 95) mainly tested technological and curative approaches to the nutritional problems. Only for papers on protein-energy malnutrition and obesity did lead authorship from Africa exceed that from non African affiliations. The 10% most powerfully connected affiliations were situated mainly outside Africa for publications on vitamin A deficiency, breast feeding, nutritional status and food security. CONCLUSIONS: The development of the evidence base for nutrition research in Africa is focused on treatment and the potential for cross-African networks to publish nutrition research from Africa remains grossly underutilised. Efforts to build capacity for effective nutrition action in Africa will require forging a true academic partnership between African and non-African research institutions. PMID- 25287558 TI - Improving the thermoactivity and thermostability of pectate lyase from Bacillus pumilus for ramie degumming. AB - Thermostable alkaline pectate lyases can be potentially used for enzymatically degumming ramie in an environmentally sustainable manner and as an alternative to the currently used chemical-based ramie degumming processes. To assess its potential applications, pectate lyase from Bacillus pumilus (ATCC 7061) was cloned and expressed in Escherichia coli. Evolutionary strategies were applied to generate efficient ramie degumming enzymes. Obtained from site-saturation mutagenesis and random mutagenesis, the best performing mutant enzyme M3 exhibited a 3.4-fold higher specific activity on substrate polygalacturonic acid, compared with the wild-type enzyme. Furthermore, the half-life of inactivation at 50 degrees C for M3 mutant extended to over 13 h. In contrast, the wild-type enzyme was completely inactivated in less than 10 min under the same conditions. An upward shift in the optimal reaction temperature of M3 mutant, to 75 degrees C, was observed, which was 10 degrees C higher than that of the wild-type enzyme. Kinetic parameter data revealed that the catalysis efficiency of M3 mutant was higher than that of the wild-type enzyme. Ramie degumming with M3 mutant was also demonstrated to be more efficient than that with the wild-type enzyme. Collectively, our results suggest that the M3 mutant, with remarkable improvements in thermoactivity and thermostability, has potential applications for ramie degumming in the textile industry. PMID- 25287559 TI - Noninvasive prenatal testing: known knowns and known unknowns. PMID- 25287560 TI - Radical trachelectomy for early stage cervical cancer: the Queensland experience. AB - BACKGROUND: Radical trachelectomy and pelvic lymph node dissection are an increasingly recognised treatment for early cervical cancer in women wishing to retain their fertility. AIMS: To analyse and summarise the outcomes of women having undergone radical trachelectomies at the Queensland Centre for Gynaecological Cancer (QCGC) between June 2000 and June 2012. METHODS: Retrospective study of data collected on the QCGC database. RESULTS: 17 women underwent radical trachelectomies, with six subsequently giving birth to a total of seven live term babies, all delivered by caesarean section. There was one first trimester miscarriage, but no major obstetric complications. There have been no cancer recurrences, deaths or major complications. CONCLUSIONS: Radical trachelectomy should be offered as an alternative treatment for women with early stage cervical cancer who wish to preserve their fertility as long as they are aware of the increased risk of infertility and preterm birth. PMID- 25287561 TI - Prognostic significance of steroid receptor positivity and adjuvant progestogen use in endometrial stromal sarcoma. AB - BACKGROUND: The prognostic significance of oestrogen and progesterone receptors (ER/PR) in endometrial stromal sarcoma (ESS) has conflicting reports in the literature, and the routine use of adjuvant progestogen is of uncertain efficacy. AIMS: To examine the prognostic significance of ER/PR positivity and of primary adjuvant progestogen use with outcome in ESS. MATERIALS AND METHODS: All women with a diagnosis of ESS in our tertiary institution and associated private practices over the last 23 years were included. Primary variables were ER/PR positivity and adjuvant progestogen use. Other variables included high-grade disease and extrauterine disease. The primary outcome was survival, and the secondary outcome was recurrence-free survival (both overall and at 5 years). Survival was calculated using the Kaplan-Meier method. Univariate analyses were performed with t-test for means and chi-squared test for proportions, and multivariate analysis was used to control for age. RESULTS: 35 women were included. ER/PR positivity was associated with a survival benefit (OR death 0.22, P = 0.02), but primary adjuvant progestogen was not. High-grade disease (OR 13, P = 0.02) and extrauterine disease (OR 8.7, P = 0.04) were associated with decreased survival. No variable significantly affected recurrence-free survival. Eight of ten cases of recurrence treated with progestogen have survived more than 3 years. CONCLUSIONS: ER/PR positivity appears to be useful for prognosis, but routine administration of primary adjuvant progestogen is not supported. There may be a role for progestogen in ER/PR positive tumours with recurrence or incomplete surgical clearance, but further research is required. PMID- 25287563 TI - Can anyone screen for deep infiltrating endometriosis with transvaginal ultrasound? AB - BACKGROUND: Surgical treatment of deep infiltrating endometriosis (DIE) is complex, and preoperative diagnosis benefits both surgeon and patient. Studies in expert centres have reported high accuracy for transvaginal ultrasound (TVUS) diagnosis of DIE. External validation of these findings has been limited, and no information is available on how quickly these skills can be acquired. The aim of this study was to measure the learning curve of DIE-TVUS and to identify the causes for inaccuracies in the diagnosis of bowel lesions and Pouch of Douglas (POD) obliteration. METHODS: Following one week of training at the University of Sao Paulo (Brazil), 205 consecutive women with a history of endometriosis symptoms were prospectively assessed by TVUS after minimal bowel preparation. TVUS findings were correlated with laparoscopic findings in eighty-five cases to assess the accuracy. The LC-CUSUM and CUSUM were used to assess the learning curve and maintenance of competency, respectively. RESULTS: The sensitivity and specificity for DIE of the bladder, vagina and bowel were 33% and 100%, 80% and 100%, and 88% and 93%, respectively. The sensitivity and specificity for the presence of POD obliteration were 88% and 90%, respectively. LC-CUSUM analysis confirmed that competency for DIE-TVUS was achieved within 38 scans for the detection of POD obliteration and within 36 scans for the detection of bowel nodules. Competency was maintained for the remainder of the scans as assessed by the CUSUM. CONCLUSIONS: After one week of DIE-TVUS training, competency can be achieved within forty procedures, allowing diagnosis of DIE with similar diagnostic accuracy as reported by centres of excellence. PMID- 25287562 TI - Uterine cancer: exploring access to services in the public health system. AB - BACKGROUND: Maori are the indigenous peoples of New Zealand and experience higher rates of uterine cancer and poorer survival rates. Postmenopausal bleeding (PMB) is the most common presenting symptom for uterine cancer. Prompt investigation is essential with 28 days being viewed as an appropriate time from first medical contact (FMC) to first specialist appointment (FSA). AIMS: To compare access to services for the investigation of PMB between Maori and non-Maori women. MATERIALS AND METHODS: The time interval between FMC to FSA was obtained from medical records for women presenting to gynaecology clinics for PMB. Dates of first bleeding symptoms, knowledge and access issues were collected in a nurse administered questionnaire. RESULTS: A total of 154 women (n = 27 Maori and 127 non-Maori) participated in the study. 23% of women had their FSA from FMC within 28 days and 67% waited more than six weeks. The 75th percentile was approximately two weeks longer for Maori women. 25% (n = 37) of women were not aware that they needed to see a doctor about PMB, and this was significantly more common for Maori women (44%; 95% CI 25-65) than non-Maori women (20%; 95% CI 13-28; P = 0.011). CONCLUSIONS: The majority of women were not seen for FSA within 28 days of their FMC. Maori women were more likely to experience lengthy delays and to report that they did not know they should see a doctor about PMB. Further investigation into reasons for delays and initiatives to improve access to services and health information appears warranted. PMID- 25287564 TI - Single-dose methotrexate treatment for ectopic pregnancy and pregnancy of unknown location and progesterone as a predictor of success. AB - BACKGROUND: The use of single-dose intramuscular administration of methotrexate in the treatment of ectopic pregnancies (EP) is a well-established practice. This study evaluates its use at a novel dose of 40 mg/m(2) body surface area (BSA). OBJECTIVE: To evaluate the efficacy and safety of single-dose methotrexate treatment 40 mg/m(2) for tubal EP and persistent pregnancies of unknown location (PUL) and determine whether serum progesterone is a predictor of treatment success. MATERIALS AND METHODS: Retrospective cohort study of patients receiving intramuscular methotrexate 40 mg/m(2) for the treatment of EP or PUL at Royal Prince Alfred Hospital over five years. RESULTS: One hundred and eighteen women received single-dose methotrexate with an overall success of 84%. Surgical intervention was needed in 16.6%. Pretreatment beta-hCG level and ectopic diagnosis were independent variables predictive of the need for surgery (P = 0.003 and 0.02, respectively). Serum progesterone level was not predictive of the need for a second dose or surgery. The sensitivity and specificity at pretreatment beta-hCG of 1202 IU/L were 84% and 74%, respectively. Commonly reported side effects included nausea, abdominal pain and heavy vaginal bleeding. Significant treatment-related adverse effects were rare. CONCLUSION: Single-dose IM methotrexate at a novel dose of 40 mg/m(2) is a safe and effective treatment for selected EP and persistent PUL. The risk of surgery was positively correlated to serum beta-hCG level and the diagnosis of EP. Progesterone was not a risk factor for surgery. Further studies are required to confirm the efficacy of this dose regimen and explore the safety of expectant management as an alternative to methotrexate treatment. PMID- 25287565 TI - betahCG monitoring after single-dose methotrexate treatment of tubal ectopic pregnancy: is the Day 4 betahCG necessary? A retrospective cohort study. AB - BACKGROUND: In ectopic pregnancy (EP) management, failure of betahCG to fall more than 15% between Days 4 and 7 after methotrexate administration indicates the need for a second dose. Regimens preferring a 25% fall in betahCG between methotrexate administration and Day 7 have been proposed. AIMS: Our study analysed these and other regimens' performance in predicting treatment success. Secondarily, we investigated how each regimen guided the prescription of additional methotrexate doses. METHODS: Medical files of 88 women with ultrasound confirmed tubal EP and pretreatment betahCG <6000 IU/L, unsuitable for expectant management, were retrospectively analysed. The betahCG monitoring regimens studied were (i) 15% fall Day 4-7, (ii) 25% fall Day 0/1-7, (iii) any fall Day 0/1-7, (iv) any fall Day 0/1-4 and (v) 20% fall Day 0/1-4. Treatment success was defined if the EP resolved without surgical intervention. Statistical analysis was performed using McNemar's test. RESULTS: Overall, treatment success with methotrexate was 92% (n = 81/88). Predicting success of methotrexate (PPV 98 100%) and detecting those needing surgery (specificity 86-100%) were equivalent across all monitoring regimens. However, the 25% Day 0/1-7 fall (and the Day 0/1 4 regimens) over-selected women for a second dose of methotrexate (P < 0.05). CONCLUSION: The performance of each regimen is equivalent to the traditional 15% fall Day 4-7 regimen in predicting treatment success. However, a regimen aiming for a 25% fall in betahCG Day 0/1-7 over-selects patients for a second methotrexate dose. In comparison, any drop in betahCG Day 0/1-7 does not over select women and eliminates Day 4 testing. PMID- 25287566 TI - Relating historical variables at first presentation with operative findings at laparoscopy for endometriosis. AB - OBJECTIVES: To determine the correlation between historical variables at presentation with the phenotype and location of biopsy proven endometriosis at laparoscopy. METHODS: Prospective observational study. Consecutive women had laparoscopic surgery following clinical suspicion of endometriosis. Standardised history and clinical examination were taken, and the presenting complaints were evaluated within four subsets of women: (i) primary laparoscopy for endometriosis (ii) previous laparoscopically confirmed endometriosis (iii) biopsy positive for endometriosis and (iv) all biopsies negative for endometriosis. Historical pain variables within the four subsets were compared with disease location and phenotype (superficial, deep infiltrating, endometriomata) at laparoscopy. A stringent P-value of 0.01 was used as the cut-off for significance. RESULTS: Overall 104 consecutive women were included: mean age 34.3 years, 66/104 (63.5%) had reoperation and 38/104 (36.5%) had primary laparoscopy. 89/104 (85.6%) were biopsy positive for endometriosis, and 11/104 (10.6%) were biopsy negative. Superficial endometriosis was most common phenotype. Site of pain did not correlate with ipsilateral location of disease. Significant correlations included as follows: dyspareunia and endometrioma (P = 0.0009) in women undergoing reoperation; dyspareunia and posterior compartment (P = 0.0086) and lateral compartment (P = 0.0004) disease in women with histology proven endometriosis; left iliac fossa pain and biopsy proven posterior compartment endometriosis (P = 0.0041). CONCLUSIONS: Although a history of dyspareunia in women with previous endometriosis was significantly correlated with endometrioma, site-specific locations of pain symptoms did not correlate with ipsilateral locations of endometriosis at laparoscopy. The phenotype - combined deep and superficial endometriosis - was associated with dyspareunia among women with previous history of endometriosis. PMID- 25287567 TI - Noninvasive prenatal testing (NIPT) in Western Australia; considerations in clinical practice. AB - With the rapid uptake of noninvasive prenatal testing (NIPT), certain technical and ethical limitations are becoming more widely recognised; however, there are still some salient issues that seem to be left by the wayside. As the consumer driven push for NIPT increases, healthcare providers need to ensure that they are providing testing appropriately and that patients understand the potential limitations and results as well as the benefits. PMID- 25287568 TI - Maternal body weight and first trimester screening for chromosomal anomalies. AB - Prenatal risk ratios for Down syndrome adjust for maternal weight because maternal serum biomarker levels decrease with increasing maternal weight. This is accomplished by converting serum biomarker values into a multiple of the expected median (MoM) for women of the same gestational age. Weight is frequently not recorded, and the impact of using MoMs not adjusted for weight for calculating risk ratios is unknown. The aim of this study is to examine the effect of missing weight on first trimester Down syndrome risk ratios by comparing risk ratios calculated using weight-unadjusted-and-adjusted MoMs. Findings at the population level indicate that the impact of not adjusting for maternal weight on first trimester screening results for chromosomal anomalies would lead to under identification of 84 per 10,000 pregnancies. PMID- 25287569 TI - Is tissue an issue? Current practice and opinion in Western Australia for routine histopathology on products of conception. AB - An anonymous questionnaire-based survey was used to determine current practices and opinions of senior health professionals working in Western Australian (WA) hospitals performing gynaecological procedures, regarding the routine use of histopathology for products of conception (POC) obtained either from the surgical management of miscarriage or termination of pregnancy. Sixty-one senior health professionals completed the survey. Tissue histopathology on POC was routinely requested for miscarriage and termination of pregnancy (TOP) by 87 and 59% of respondents, respectively. Respondents listed the main reasons for requesting routine histopathology as avoidance of misdiagnosis, medico-legal and quality assurance. There were inconsistent practices among WA health professionals regarding sending POC for histopathology; 63% of gynaecology head of departments recommend the introduction of state or national guidelines for the use of histopathology in the surgical management of miscarriages or terminations of pregnancy. PMID- 25287570 TI - Utilisation of ART in single women and lesbian couples since the 2010 change in Victorian legislation. AB - Enactment of the Assisted Reproductive Treatment Act (Vic) 2008 in January 2010 allowed single persons and same sex couples in Victoria to access reproductive treatments. A retrospective cohort analysis of Monash IVF patients was conducted to identify trends in Assisted Reproductive Technology (ART) use amongst single women and lesbian couples after January 2010. A 102.8% increase in the utilisation of ART was observed amongst the single women group and a 248.8% increase in the lesbian couple population. PMID- 25287571 TI - The Power of Exercise and the Exercise of Power: The Harvard Fatigue Laboratory, Distance Running, and the Disappearance of Work, 1919-1947. AB - In the early twentieth century, fatigue research marked an area of conflicting scientific, industrial, and cultural understandings of working bodies. These different understandings of the working body marked a key site of political conflict during the growth of industrial capitalism. Many fatigue researchers understood fatigue to be a physiological fact and allied themselves with Progressive-era reformers in urging industrial regulation. Opposed to these researchers were advocates of Taylorism and scientific management, who held that fatigue was a mental event and that productivity could be perpetually increased through managerial efficiency. Histories of this conflict typically cease with the end of the First World War, when it is assumed that industrial fatigue research withered away. This article extends the history of fatigue research through examining the activities of the Harvard Fatigue Laboratory in the 1920s and 1930s. The Laboratory developed sophisticated biochemical techniques to study the blood of exercising individuals. In particular, it found that exercising individuals could attain a biochemically "steady state," or equilibrium, and extrapolated from this to assert that fatigue was psychological, not physiological, in nature. In contrast to Progressive-era research, the Laboratory reached this conclusion through laboratory examination, not of industrial workers, but of Laboratory staff members and champion marathon runners. The translation of laboratory research to industrial settings, and the eventual erasure of physiological fatigue from discussions of labor, was a complex function of institutional settings, scientific innovation, and the cultural meanings of work and sport. PMID- 25287573 TI - Time seizures and the self: institutional temporalities and self-preservation among homeless women. AB - This article documents temporalities of homelessness as experienced by many homeless people today, those living in the midst of an urban "services ghetto" where social service organizations abound, but such organizations fail to coordinate the provision or timing of services, producing an incoherent multiplicity of offerings and schedules. I analyzed distinct but related temporal modes by which institutional timetables controlled homeless women's existence, what I call empty time and overscheduled time. The paradoxes of institutionalized waiting and strict yet inconsistent timetables exacted profound material and psychological tolls. For homeless women in Chicago, many of whom experienced symptoms of severe mental illness, simply securing their daily needs was such a time-consuming endeavor that they had to focus on short-term self-preservation rather than seeking stable employment or housing. Using anthropological theories of self and subjectivity, I argue that what was at stake for many women was more than the exhaustion of shelter life-negotiating institutional timetables also threatened their sense of dignity and humanity. Through the everyday patterning of women's time, non-profit agencies whose stated aim was to eliminate homelessness paradoxically frustrated women's efforts to escape life on the streets. I conclude the analysis with policy suggestions to address these problems. PMID- 25287572 TI - A case-control study of brain structure and behavioral characteristics in 47,XXX syndrome. AB - Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under-recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age and sex-matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi-structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention-deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population-based studies of Trisomy X and also found in our sample. PMID- 25287574 TI - Heroin: from drug to ambivalent medicine : on the introduction of medically prescribed heroin and the emergence of a new space for treatment. AB - This article provides an anthropological analysis of the introduction of medically prescribed heroin as part of official substance abuse treatment. While anthropological inquiries of substance abuse treatment have mainly focused on providing the users perspectives on the (ab)use or unraveling the conflicts and negotiations between users and staff, the present article argues for the merits of paying attention to the spatial dimensions of substance abuse treatment. Focusing on the spatial and material ramification of the treatment can shed a nuanced light on the still vulnerable process of altering the heroin from drug to medicine, and thereby on the attempts to settle heroin in a new practical and semantic landscape. The heroin is anchored in some powerful discourses of crime, death, and pleasure, and the analysis shows how these discourses (re-)appear in the spatial textures of the clinic, contesting the attempts to medicalize the heroin. Further, the article argues that even though the treatment aims at a marginalization of the heroin in the life of the clients, the spatial arrangements and the practices within them simultaneously enforces a centralization of the heroin, making the space for treatment highly ambivalent. PMID- 25287575 TI - In vitro and in vivo evaluation of an in situ forming gel system for sustained delivery of Florfenicol. AB - The objective of this study was to develop an injectable in situ forming gel system based on Poloxamer for sustained release of Florfenicol (FFC). The formulations were prepared containing certain amounts of Poloxamer 407 (P407) and Poloxamer 188 (P188) alone or with hydroxylpropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), or polyvinyl pyrrolidone (PVP) as polymer additives. The optimal formulation was chosen according to in vitro parameters (gelation temperature, gelation time, pH value, viscosity, and in vitro release). Then the FFC in vivo pharmacokinetic character of the optimal formulation was investigated in dogs with a single dose of 50 mg/kg b.w. under s.c. injection. In vitro release studies, all formulations containing polymer additives had prolonged release time and decreased initial burst to some extent. The optimal formulation containing 0.15% HPMC showed a best sustained release profile for about 128 h with the lowest initial burst in vitro (<40% in 24 h). In vivo, the 20% FFC in situ forming gel provided prolonged drug release time within the therapeutic range for about 100 h, with stable plasma levels and elimination half life (t1/2lambdaz ) nine times higher than the control formulation. In conclusion, in situ forming gel is an attractive alternative for FFC sustained release system. PMID- 25287576 TI - Comparison of effective I-131 half-life between thyroid hormone withdrawal and recombinant human thyroid-stimulating hormone for thyroid cancer: a retrospective study. AB - INTRODUCTION: Preparation for postoperative radioiodine ablation for differentiated thyroid carcinoma is performed by either thyroid hormone withdrawal or recombinant human thyroid-stimulating hormone (rhTSH) administration. There is little information on the impact of the method of preparation with respect to whole-body effective I-131 half-life and its potential clinical implications in the Australian setting. METHODS: A retrospective study was performed on patients admitted for adjuvant radioiodine ablation for non-metastatic differentiated thyroid carcinoma at the Royal Adelaide Hospital over a 41/2-year period from 2009. Dose rate measurements were analysed for 19 rhTSH and 31 thyroid hormone withdrawal patients. RESULTS: The mean effective I-131 half-lives were 11.51 and 13.29 h for the rhTSH and thyroid hormone withdrawal groups, respectively, with no statistically significant difference between the two groups (P = 0.761). This result differs from previously published data where withdrawal periods were typically longer, resulting in slower renal clearance and longer half-lives for withdrawal patients. CONCLUSIONS: Our study did not demonstrate a significant difference in whole-body effective half-life of I-131 between the two methods of preparation for radioiodine ablation. This suggests that putative advantages of rhTSH over withdrawal in terms of whole-body radiation dose, duration of hospital admission and quality of life may be sensitive to duration of withdrawal. PMID- 25287577 TI - Emergent Power Hierarchies and Group Performance. AB - In newly formed groups, informal hierarchies emerge automatically and readily. In this study, we argue that emergent group hierarchies enhance group performance (Hypothesis 1) and we assume that the more the power hierarchy within a group corresponds to the task-competence differences of the individual group members, the better the group performs (Hypothesis 2). Twelve three-person groups and 28 four-person groups were investigated while solving the Winter Survival Task. Results show that emerging power hierarchies positively impact group performance but the alignment between task-competence and power hierarchy did not affect group performance. Thus, emergent power hierarchies are beneficial for group performance and although they were on average created around individual group members' competence, this correspondence was not a prerequisite for better group performance. PMID- 25287578 TI - Handling incidental findings in neuroimaging research in Japan: current state of research facilities and attitudes of investigators and the general population. AB - BACKGROUND: To establish appropriate measures that deal with incidental findings (IFs), the neuroscience community needs to address various ethical issues. The current state of research facilities regarding IFs and investigator attitudes as well as potentially eligible research participants must be assessed prior to future discussions and before the development of policies and guidelines. To this end, we conducted two questionnaire surveys to clarify i) how IFs are addressed at neuroimaging research facilities in Japan and ii) the views of investigators and potential research participants regarding the handling of IFs. METHODS: Thirty-one principal investigators (PIs) involved in the Strategic Research Program for Brain Sciences (SRPBS), a government-funded project, were asked to fill out a questionnaire regarding ways IFs were handled at the facility. A total of 110 investigators engaged in SRPBS tasks, including 31 PIs who participated in the research facility survey and researchers conducting studies under the management of the PIs, and 500 individuals from the general public (i.e., general population) were asked to select the most appropriate way to deal with IFs in two scenarios, namely the medical school and humanities and social sciences department scenarios. RESULTS: More than 40% of PIs responded that they did not know or were unsure of what type of approach was employed to handle IFs at their research facilities. Nevertheless, they were willing to improve the current status if sufficient resources were provided. With regard to specialist involvement, 37.7% of investigators responded that it was appropriate to have a specialist check all images in the medical school scenario, whereas 13.3% responded that such involvement was appropriate in the humanities and social sciences department scenario. In contrast, 76.1% and 61.0% of the general population indicated that specialist involvement was appropriate in the medical school and humanities and social sciences department scenarios, respectively. These results show that expectations of the general population exceed those of investigators regarding measures to address IFs. Both investigators and the general population demanded more responsibility from PIs at medical institutions, compared to PIs at non-medical institutions. CONCLUSIONS: Based on our preliminary results, we recommended that a licensed physician perform a screening test to appropriately examine clear abnormalities. These recommendations were implemented by the SRPBS as guidelines for handling IFs in national research projects in Japan. PMID- 25287579 TI - Reply: Comparison of 2-limb versus 3-limb electrodiagnostic studies in the evaluation of CIDP. PMID- 25287580 TI - Nucleoside triphosphate diphosphohydrolase1 (TcNTPDase-1) gene expression is increased due to heat shock and in infective forms of Trypanosoma cruzi. AB - BACKGROUND: Ecto-Nucleoside Triphosphate Diphosphohydrolases (Ecto-NTPDases) are enzymes that hydrolyze tri- and/or di-phosphate nucleotides. Evidences point to their participation in Trypanosoma cruzi virulence and infectivity. In this work, we evaluate TcNTPDase-1 gene expression in comparison with ecto-NTPDase activity, in order to study the role of TcNTPDase-1 in parasite virulence, infectivity and adaptation to heat shock. FINDINGS: Comparison between distinct T. cruzi isolates (Y, 3663 and 4167 strains, and Dm28c, LL014 and CL-14 clones) showed that TcNTPDase-1 expression was 7.2 +/- 1.5 times higher in the Dm28c than the CL-14 avirulent clone. A remarkable expression increase was also observed in the trypomastigote and amastigote forms (22.5 +/- 5.6 and 16.3 +/- 3.8 times higher than epimastigotes, respectively), indicating that TcNTPDase-1 is overexpressed in T. cruzi infective forms. Moreover, heat shock and long-term cultivation also induced a significant increment on TcNTPDase-1 expression. CONCLUSIONS: Our results suggest that TcNTPDase-1 plays an important role on T. cruzi infectivity and adaptation to stress conditions, such as long-term cultivation and heat shock. PMID- 25287581 TI - Long-term follow-up of large maxillary advancements with distraction osteogenesis in growing and non-growing cleft lip and palate patients. AB - BACKGROUND: Maxillary distraction osteogenesis (DO) in cleft lip and palate patients has been described by several authors, but most studies have a relatively short follow-up and do not clearly separate growing patients from non growing patients. METHOD: The records of 22 consecutive patients affected by cleft lip and palate, who underwent Le Fort I osteotomy and maxillary distraction with a rigid external distractor (RED), were reviewed. The sample was subdivided into a growing and a non-growing group. All patients had pre-DO cephalometric records, immediately post DO, 12 months post DO and long-term records with a long term follow-up of >5 years (range 5-13 years). As a control sample for the growing group, cleft children with a negative overjet not subjected to distraction or any protraction treatment during growth were followed up until the completion of growth. RESULTS: The average maxillary advancement in the growing group was 22.2 +/- 5.5 mm (range: 15-32 mm); in the non-growing group, it was 17.7 +/- 6.6 mm (range: 6-25 mm). Excellent post-surgical stability was recorded in the adult sample. On the other hand, growing children had an average 16% relapse in the first year post DO and an additional 26% relapse in the long-term follow-up. CONCLUSIONS: This study seems to point out that early Le Fort I DO allows for the correction of very severe deformities. It is followed by a relatively high amount of true skeletal relapse in children with cleft lip and palate. Prognosis should be discussed in depth with the family and true aesthetic and psychological needs assessed. PMID- 25287582 TI - Pleomorphic adenomas: post-operative radiotherapy is unnecessary following primary incomplete excision: a retrospective review. AB - BACKGROUND: Current standard treatment of Pleomorphic Salivary Adenoma (PSA) of the Parotid Gland is by surgical excision. The management of incomplete excision remains undecided with post-operative radiotherapy advocated by some and observation by others. METHODS: 190 patients who underwent resection of PSA of the parotid gland within the West of Scotland region from 1981 to 2008 were identified and data collected. RESULTS: 78/190 patients had a primary incomplete excision. 25/78 received post-operative radiotherapy and 53 were observed. Recurrences occurred in 11/53 in those observed and in 1/25 of those who received radiotherapy. 21/25 complained of significant side effects from the radiotherapy. 38 surgeons performed 190 procedures, with a range of experience from 1 to28 procedures. CONCLUSIONS: Radiotherapy does appear to reduce recurrence with incomplete excision, however it is associated with significant side effects. We therefore feel radiotherapy should not be routinely recommended. Subspecialisation should be adopted to increase the operating surgeon's experience. PMID- 25287583 TI - Beneficial effect of grape seed proanthocyanidin extract in rabbits with steroid induced osteonecrosis via protecting against oxidative stress and apoptosis. AB - BACKGROUND: Oxidative damage and apoptosis play dominant roles in the pathogenesis of steroid-induced osteonecrosis (ON). Grape seed proanthocyanidin extract (GSPE) demonstrates antioxidant and antiapoptotic properties. Our aim was to demonstrate the effects of GSPE in preventing steroid-induced ON in rabbits. METHODS: Osteonecrosis was induced by high-dose methylprednisolone (40 mg/kg). Rabbits in the preventive medicine group were treated with 100 mg/kg/day GSPE for 14 consecutive days, and the presence or absence of ON was examined histopathologically. Oxidative damage in bone tissue was assessed by immunohistochemical staining of 8-oxo-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA) levels, and activities of antioxidant enzymes Cu/Zn superoxide dismutase (SOD) and phospholipid hydroperoxide glutathione peroxidase (GSH-Px). Apoptosis was detected via quantitative terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate nick end labelling (TUNEL) staining and activated caspase 3 immunoblotting and activity. RESULTS: GSPE significantly attenuated the changes of immunohistochemical staining of 8-OHdG, MDA levels, and antioxidant enzymes activities, which were caused by methylprednisolone administration. Quantitative TUNEL and caspase 3 assay showed lower apoptosis with GSPE application. Simultaneously, GSPE reduced the incidence of steroid-induced ON in an established rabbit model to 17.6 %, compared with 87.5 % in the steroid-only group. CONCLUSION: These results reveal that GSPE treatment could inhibit oxidative damage and apoptosis to exert beneficial effects on reducing the incidence of steroid-induced ON in rabbit models. PMID- 25287584 TI - Up-regulation of hexokinase1 in the right ventricle of monocrotaline induced pulmonary hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown. METHODS: PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle. RESULTS: We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex alpha1 (PDHalpha1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle. CONCLUSIONS: There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention. PMID- 25287585 TI - Associations between positive parenting practices and child externalizing behavior in underserved Latino immigrant families. AB - This study examined whether five specific parenting practices (i.e., monitoring, discipline, skill encouragement, problem solving, and positive involvement) were associated with reduced child externalizing behaviors among a sample of Latino immigrant families. It utilized baseline data from 83 Latino couples with children participating in a larger randomized controlled trial of a culturally adapted parenting intervention. Results reveal that monitoring, discipline, skill encouragement, and problem solving each made independent contributions to the prediction of child externalizing behavior, although not all in the expected direction. Further analyses examining mothers and fathers separately suggest that mother-reported monitoring and father-reported discipline practices uniquely contributed to these findings. These results may have important implications for prevention and clinical intervention efforts with Latino immigrant families, including the cultural adaptation and implementation of parenting interventions with this underserved population. PMID- 25287586 TI - Can we predict clinical cardiotoxicity with cardiac biomarkers in patients after haematopoietic stem cell transplantation? AB - The long-term prognosis of patients after haematopoietic stem cell transplantation (HSCT) has greatly improved. Cardiac complications represent unresolved and potentially life-threatening conditions in these patients. We prospectively examined 37 consecutive patients with a median age of 28 years who underwent allogeneic HSCT. Biomarkers of cardiac injury were measured serially before the conditioning regimen, the first day after HSCT and then 14, 30, 90 and 180 days after HSCT. Echocardiography was performed before and 1 month after HSCT. Eleven patients (30%) had persistently increased NT-proBNP values, 14 patients (38%) had only transient elevations and 12 (32%) had no changes in NT proBNP concentrations for a period exceeding 14 days after HSCT. Elevated NT proBNP values at day 14 after HSCT remained an independent predictor of cardiotoxicity during the first 6 months after HSCT (P < 0.01). Patients with persistent elevations in NT-proBNP also had significant elevations in hs-cTnT concentrations (P < 0.01). Only patients with persistently increased NT-proBNP had a significant worsening in systolic and some diastolic echocardiographic parameters, and we observed in this group the highest values of both cardiomarkers during the 6-month period. Forty-five percent of these patients developed clinical manifestation of cardiotoxicity. Elevations in NT-proBNP concentrations at day 14 after HSCT can predict patients at risk of developing cardiac events during the first 6 months after HSCT. Simultaneous elevations of both cardiomarkers (NT-proBNP and hs-cTnT) persisting 14 days after HSCT had a sensitivity of 83% and a specificity of 80.69%. PMID- 25287588 TI - Rationale and evidence for human immunodeficiency virus treatment as prevention at the individual and population levels. AB - Individual health benefits of antiretroviral therapy (ART) are becoming clearer. In resource-rich countries, side effects of current ART regimens are minimal. US guidelines recommend ART regardless of CD4 count or viral load. Maintaining an undetectable viral load with ART comes close to eliminating the risk of HIV transmission, leading the US guidelines to recommend universal ART to reduce HIV transmission. Achieving population-level control through treatment as prevention (TasP) may be feasible, but requires considerable investment of resources devoted to HIV testing, linkage to care, ART accessibility, and retention in care. Ongoing studies of TasP will provide insight into achieving meaningful ART coverage. PMID- 25287587 TI - Human immunodeficiency virus vaccines. AB - Although some success was achieved in recent years in HIV prevention, an effective vaccine remains the means with the most potential of curtailing HIV-1 infections worldwide. Despite multiple failed attempts, a recent HIV vaccine regimen demonstrated modest protection from infection. Although the protective efficacy in this trial was not sufficient to warrant licensure, it spurred renewed optimism in the field and has provided valuable insights for improving future vaccine designs. This review summarizes the pertinent details of vaccine development and discusses ways the field is moving forward to develop a vaccine to prevent HIV infection and disease progression. PMID- 25287589 TI - Prevention of human immunodeficiency virus and AIDS: postexposure prophylaxis (including health care workers). AB - Postexposure prophylaxis (PEP), which is designed to prevent human immunodeficiency virus (HIV) infection after an exposure, is one of several strategies for HIV prevention. PEP was first used after occupational HIV exposures in the late 1980s, with the Centers for Disease Control and Prevention issuing the first set of guidelines that included considerations regarding the use of antiretroviral agents for PEP after occupational HIV exposures in 1990. Use of PEP has been extended to nonoccupational exposures, including after sexual contact or injection-drug use. This article provides a rationale for PEP, assessment of the need for PEP, and details of its implementation. PMID- 25287591 TI - Direct and indirect effects of a combination of adipose-derived stem cells and platelet-rich plasma on bone regeneration. AB - A key goal for successful bone regeneration is to bridge a bone defect using healing procedures that are stable and durable. Adipose-derived stem cells (ASCs) have the potential to differentiate into bone. Meanwhile, platelet-rich plasma (PRP) is an interesting biological means to repair tissue by inducing chemotactic, proliferative, and anabolic cellular responses. This study evaluated bone regeneration using a combination of ASCs and PRP in a rat calvarial defect model. ASCs were isolated from inguinal fat pads of F344 inbred rats, while PRP was prepared from these rats. ASCs were cultured in control medium supplemented with 10% fetal bovine serum or 5% PRP in vitro. After 1 week, levels of growth factors including insulin-like growth factor-1, transforming growth factor-beta1, hepatocyte growth factor, and vascular endothelial growth factor in the culture supernatant were measured by enzyme-linked immunosorbent assays. Moreover, the ASC/PRP admixture was transplanted into the rat calvarial defect. Microcomputed tomography, histological, and immunohistochemical (osteopontin and osteocalcin) analyses were performed at 4 and 8 weeks after transplantation. The in vitro study showed that the levels of growth factors secreted by ASCs were significantly increased by the addition of PRP. Transplantation of the ASC/PRP admixture had dramatic effects on bone regeneration overtime in comparison with rats that received other transplants. Furthermore, some ASCs directly differentiated into osteogenic cells in vivo. These findings suggest that the combination of ASCs and PRP has augmentative effects on bone regeneration. The ASC/PRP admixture may be a promising source for the clinical treatment of cranial defects. PMID- 25287590 TI - Metabolic profiling reveals altered sugar and secondary metabolism in response to UGPase overexpression in Populus. AB - BACKGROUND: UDP-glucose pyrophosphorylase (UGPase) is a sugar-metabolizing enzyme (E.C. 2.7.7.9) that catalyzes a reversible reaction of UDP-glucose and pyrophosphate from glucose-1-phosphate and UTP. UDP-glucose is a key intermediate sugar that is channeled to multiple metabolic pathways. The functional role of UGPase in perennial woody plants is poorly understood. RESULTS: We characterized the functional role of a UGPase gene in Populus deltoides, PdUGPase2. Overexpression of the native gene resulted in increased leaf area and leaf-to shoot biomass ratio but decreased shoot and root growth. Metabolomic analyses showed that manipulation of PdUGPase2 results in perturbations in primary, as well as secondary metabolism, resulting in reduced sugar and starch levels and increased phenolics, such as caffeoyl and feruloyl conjugates. While cellulose and lignin levels in the cell walls were not significantly altered, the syringyl to-guaiacyl ratio was significantly reduced. CONCLUSIONS: These results demonstrate that PdUGPase2 plays a key role in the tightly coupled primary and secondary metabolic pathways and perturbation in its function results in pronounced effects on growth and metabolism beyond cell wall biosynthesis of Populus. PMID- 25287592 TI - NMR spectroscopy to follow reaction progress in ionic liquids. AB - In order to understand reaction outcomes in ionic liquids, it is crucial to be able to follow the progress of these reactions. This review highlights the advantages of NMR spectroscopy over other analytical techniques in following reaction progress in ionic liquids, particularly addressing the practical aspects of the methodology and highlighting the range of processes that can be readily followed. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25287593 TI - Letter to the editor: rectal cancer in a 15-year-old female with a novel MLH1 and MSH6 biallelic inheritance. PMID- 25287596 TI - Multiple sclerosis: Blood-based biomarkers provide insight into progressive MS. PMID- 25287598 TI - CD34 measurement: setting standards. PMID- 25287599 TI - Mesenchymal stromal cells enhance wound healing by ameliorating impaired metabolism in diabetic mice. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been documented to improve delayed wound healing in diabetes, but the underlying mechanism remains obscure. We aimed to investigate whether the therapeutic effects on wounds was associated with metabolic alterations by paracrine action of MSCs. METHODS: MSCs from mice with high-fat diet/streptozotocin-induced diabetes or wild-type C57BL/6 mice were evaluated for their paracrine potential in vitro using enzyme-linked immunosorbent assay and immunohistochemical staining assay. MSCs were then evaluated for their therapeutic potential in vivo using an excisional cutaneous wound model in mice with diabetes. Metabolic alterations and glucose transporter four (GLUT4) as well as PI3K/Akt signaling pathway expression after wounding were also examined. RESULTS: MSCs from normal mice expressed even more insulin-like growth factor-1 (IGF-1) than mice with diabetes, suggesting putative paracrine action. Furthermore, compared with IGF-1 knockdown MSCs, normal MSCs markedly accelerated wound healing, as revealed by higher wound closure rate and better healing quality at 21 days post-wound. By contrast, MSCs administration increased the level of insulin as well as GLUT4 and PI3K/Akt signaling pathway expression but repressed the biochemical indexes of glucose and lipid, resulting in obvious metabolic improvement. CONCLUSIONS: These findings suggest that IGF-1 is an important paracrine factor that mediates the therapeutic effects of MSCs on wound healing in diabetes, and the benefits of MSCs may be associated with metabolism improvements, which would provide a new target for treatment. PMID- 25287600 TI - Is the subarachnoid administration of mesenchymal stromal cells a useful strategy to treat chronic brain damage? AB - BACKGROUND AIMS: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Developing effective protocols for the administration of mesenchymal stromal cells (MSCs) is a promising therapeutic strategy to treat TBI. It is important to develop alternatives to direct parenchymal injection at the injury site because direct injection is an expensive and invasive technique. Subarachnoid transplantation, a minimally invasive and low-risk procedure, may be an important and clinically applicable strategy. The aim of this study was to test the therapeutic effect of subarachnoid administration of MSCs on functional outcome 2 months after an experimental TBI in rats. METHODS: Two months after TBI, 30 female Wistar rats were divided into 3 groups (n = 10 in each group): sham, MSC (received 2 * 10(6) MSCs) and saline (received only saline) groups. Neurological function, brain and spinal cords samples and cerebrospinal fluid were studied. RESULTS: No significant differences were found in neurological evaluation and after histological analysis; differences in the expression of neurotrophins were present but were not statistically significant. MSCs survived in the host tissue, and some expressed neural markers. CONCLUSIONS: Similar to direct parenchymal injections, transplanted MSCs survive, migrate to the injury cavity and differentiate into mature neural cell types for at least 6 months after engraftment. These results open the possibility that MSC administration through subarachnoid administration may be a treatment for the consequences of TBI. The transplantation technique and cell number should be adjusted to obtain functional outcome and neurotrophin production differences. PMID- 25287597 TI - Brain connectivity in neurodegenerative diseases--from phenotype to proteinopathy. AB - Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases. PMID- 25287601 TI - Reprogramming human umbilical cord mesenchymal stromal cells to islet-like cells with the use of in vitro-synthesized pancreatic-duodenal homebox 1 messenger RNA. AB - BACKGROUND AIMS: Human umbilical cord mesenchymal stromal cells (hUC-MSCs) hold great potential as a therapeutic candidate to treat diabetes, owing to their unlimited source and ready availability. METHODS: In this study, we differentiated hUC-MSCs with in vitro-synthesized pancreatic-duodenal homebox 1 (PDX1) messenger (m)RNA into islet-like cell clusters. hUC-MSCs were confirmed by both biomarker detection and functional differentiation. In vitro-synthesized PDX1 messenger RNA can be transfected into hUC-MSCs efficiently. The upregulated expression of PDX1 protein can be detected 4 h after transfection and remains detectable for 36 h. RESULTS: The induction of islet-like structures was confirmed by means of morphology and dithizone staining. Reverse transcriptase polymerase chain reaction results revealed the expression of some key pancreatic transcription factors, such as PDX1, NeuroD, NKX6.1, Glut-2 and insulin in islet like cell clusters. Immunofluorescence analysis showed that differentiated cells express both insulin and C-peptide. Enzyme-linked immunosorbent assay analysis validated the insulin secretion of islet-like cell clusters in response to the glucose stimulation. CONCLUSIONS: Our results demonstrate the use of in vitro synthesized PDX1 messenger RNA to differentiate hUC-MSCs into islet-like cells and pave the way toward the development of reprogramming and directed differentiation methods for the expression of encoded proteins. PMID- 25287602 TI - A multimerized form of recombinant human CD40 ligand supports long-term activation and proliferation of B cells. AB - BACKGROUND AIMS: CD40-activated B cells have long been studied as potent antigen presenting cells that can potentially be used for cancer immunotherapy. Nevertheless, their use in human clinical trials has been limited by the lack of a Good Manufacturing Practice-grade soluble human CD40 ligand that is able to induce activation and proliferation of primary B cells. We describe an in vitro method to effectively generate and expand B cells through the use of a multimerized form of human recombinant CD40 ligand (rCD40L). METHODS: Human B cells were isolated from healthy donors and cultivated with either rCD40L or on a monolayer of murine NIH3T3 cells stably expressing human CD40L (NIH3T3/tCD40L) as a widely used standard method. Morphology, expansion rate, immune phenotype and antigen presentation function were assessed. RESULTS: B cells efficiently proliferated in response to rCD40L over 14 days of culture in comparable amounts to NIH3T3/tCD40L. B-cell division in response to CD40L was also confirmed by carboxyfluorescein succinimidyl ester dilution. Moreover, rCD40L induced on B cells upregulation of co-stimulatory molecules essential for antigen presentation. Additionally, proliferation of T cells from allogeneic healthy volunteers confirmed the immunostimulatory capacities of CD40-activated B cells. CONCLUSIONS: We demonstrated that B cells with potent antigen presentation capacity can be generated and expanded by use of a non-xenogeneic form of CD40L that could be implemented in future human clinical settings. PMID- 25287603 TI - Use of a transjugular intrahepatic portosystemic shunt combined with autologous bone marrow cell infusion in patients with decompensated liver cirrhosis: an exploratory study. AB - BACKGROUND AIMS: Currently, there is no treatment for decompensated liver cirrhosis except for liver transplantation. The safety and effect on liver function of a transjugular intrahepatic portosystemic shunt (TIPS) with and without autologous bone marrow cell (BMC) infusion in patients with decompensated liver cirrhosis were determined. METHODS: Ten patients who were diagnosed with decompensated liver cirrhosis during the period from September 2011 to July 2012 were enrolled in this study. The patients underwent TIPS (TIPS group) or combined treatment with TIPS and BMC infusion through the hepatic artery (TIPS+BMC group). All patients were monitored for adverse events, liver function and complications caused by portal hypertension during a period of 52 weeks. RESULTS: The number of infused BMCs was 2.65 +/- 1.20 *10(9). Significant improvements in the serum levels of albumin and total bilirubin and decreased Child-Pugh scores were observed in patients treated with both TIPS and BMCs (P < 0.05), whereas no such changes were observed in the TIPS group. Endoscopic findings showed that varices in the esophagus and the gastric fundus were alleviated after either treatment. All 10 patients showed a complete or partial resolution of ascites at 4 weeks. No major adverse effects were noted during the follow-up period for patients in either group. CONCLUSIONS: TIPS combined with BMC infusion is clinically safe; the treatment improved liver function and alleviated complications caused by portal hypertension; therefore, this combination has potential for treatment of patients with decompensated liver cirrhosis. PMID- 25287604 TI - Complete nationwide survey on umbilical cord blood freezing bag breakage in Japan. AB - BACKGROUND AIMS: Although umbilical cord blood (UCB) has now become a common stem cell source, UCB bag breakage is a known risk in UCB transplantation (UCBT). This survey provides the first comprehensive data on the frequency and causes of UCB bag breakage in Japan. METHODS: Data regarding UCB bag breakage from all causes, identified between April 1, 2010, and September 3, 2013, were collected from all transplant centers registered for UCBT (209 hospitals) and all public cord blood banks (CBBs) (8 CBBs) in Japan. RESULTS: Seventeen incidents of UCB bag breakage at CBBs were confirmed, none of which resulted in bags being shipped to transplant centers. From among 3836 UCBT, 16 incidents (0.4%) of UCB bag breakage were confirmed at transplant centers. Although all these bags were used for transplantation, no direct health hazard was reported. The major cause of UCB bag breakage confirmed at transplant centers was considered to be external force (75%). In addition, 11 incidents of unexplained UCB bag breakage at sealing between compartments were reported. CONCLUSIONS: UCB bag breakage was confirmed at both CBBs and transplant centers. UCB bags should be handled with particular care and attention. PMID- 25287605 TI - Grip strength ratio: a grip strength measurement that correlates well with DASH score in different hand/wrist conditions. AB - BACKGROUND: Grip strength correlates with personal factors such as gender, age and nutritional status and has a good inter-rater reliability. It reflects fairly well how much people can use their hands.The Disabilities of the Arm, Shoulder and Hand (DASH) Outcome Measure 3 is a 30-item, self-report, questionnaire that reflects the patients' opinion on their disability due to upper-limb disorders. We assessed if grip strength and grip strength ratio correlate with DASH score. METHODS: In 3 groups (20 healthy volunteers, 17 patients after distal radius fractures, 12 patients with different hand/wrist conditions) grip strength and DASH scores (items 1-21, 22-30 and total) were assessed. To exclude personal factors grip strengths in the injured or non-dominant hand and grip strength ratios (grip strength in the injured or non-dominant hand divided by grip strength in the non-injured or dominant hand) were assessed too. Results were analyzed groups using Pearson Correlation Coefficients and with a multivariate ANOVA. RESULTS: Grip strength ratio was 0.97 in healthy volunteers, 0.52 in patients after distal radius fracture and 0.74 in patients with various other hand/wrist disorders.Significant correlations were found between the grip strength ratio and DASH as well as DASH subsections in all groups and between DASH scores and grip strength in some. The correlations between the ratio of the grip strength (GSR) and DASH were much stronger than the correlation between grip strength and DASH. This emphasizes the value of the GSR. Age showed no correlation with grip strength ratio using a multivariate ANOVA. CONCLUSION: Grip strength ratio correlates well with the DASH score in different hand and wrist conditions. It is a valuable tool to assess patients that speak a different language and have problems with the non-dominant hand and probably easier to follow over time than the DASH score, which is time consuming to fill in and process. PMID- 25287606 TI - Crowning proteins: modulating the protein surface properties using crown ethers. AB - Crown ethers are small, cyclic polyethers that have found wide-spread use in phase-transfer catalysis and, to a certain degree, in protein chemistry. Crown ethers readily bind metallic and organic cations, including positively charged amino acid side chains. We elucidated the crystal structures of several protein crown ether co-crystals grown in the presence of 18-crown-6. We then employed biophysical methods and molecular dynamics simulations to compare these complexes with the corresponding apoproteins and with similar complexes with ring-shaped low-molecular-weight polyethylene glycols. Our studies show that crown ethers can modify protein surface behavior dramatically by stabilizing either intra- or intermolecular interactions. Consequently, we propose that crown ethers can be used to modulate a wide variety of protein surface behaviors, such as oligomerization, domain-domain interactions, stabilization in organic solvents, and crystallization. PMID- 25287607 TI - Evaluation of milk compositional variables on coagulation properties using partial least squares. AB - The aim of this study was to investigate the effects of numerous milk compositional factors on milk coagulation properties using Partial Least Squares (PLS). Milk from herds of Jersey and Holstein-Friesian cattle was collected across the year and blended (n=55), to maximise variation in composition and coagulation. The milk was analysed for casein, protein, fat, titratable acidity, lactose, Ca2+, urea content, micelles size, fat globule size, somatic cell count and pH. Milk coagulation properties were defined as coagulation time, curd firmness and curd firmness rate measured by a controlled strain rheometer. The models derived from PLS had higher predictive power than previous models demonstrating the value of measuring more milk components. In addition to the well-established relationships with casein and protein levels, CMS and fat globule size were found to have as strong impact on all of the three models. The study also found a positive impact of fat on milk coagulation properties and a strong relationship between lactose and curd firmness, and urea and curd firmness rate, all of which warrant further investigation due to current lack of knowledge of the underlying mechanism. These findings demonstrate the importance of using a wider range of milk compositional variables for the prediction of the milk coagulation properties, and hence as indicators of milk suitability for cheese making. PMID- 25287608 TI - The prognostic utility and the association of serum light chains (free and total) and absolute lymphocyte count in patients with newly diagnosed diffuse large B cell lymphoma. AB - In this study, serum free and total light chains (sFLC/sTLC) were measured in 108 serum samples of therapy-naive patients with DLBCL. Clinicopathologic data and survival outcomes were analyzed according to the results of sFLC/sTLC measurements. Moreover, the association of sFLC/sTLC with absolute monocyte count (AMC) and absolute lymphocyte count (ALC) was evaluated. Elevated sFLC and abnormal kappa/lambda ratio was present in 42.6% (51/108) and 4.6% (5/108) of patients, respectively. sTLC was successfully measured in 107 serum samples, abnormal sTLC and abnormal kappa/lambda ratio was found in 28.0% (30/107) and 26.2% (28/107) of patients, respectively. Patients with elevated sFLC more frequently displayed adverse clinical characteristics, including age (P=0.001), B symptoms (P=0.022), low ALC (P=0.024) and hyperglobulinemia (P=0.012). Patients with elevated sFLC had an inferior overall survival (OS) (P=0.012) and tended to have shorter progression-free survival (PFS) (P=0.061) compared to patients with normal sFLC. Abnormal sTLC or abnormal sTLC ratio showed no significant association with clinical outcomes, with exception of abnormal concurrent kappa and lambda. Only association of sFLC and ALC with survival remained significant after adjusting for the International Prognostic Index (IPI). The measurement of sFLC and ALC at diagnosis might be useful for the prognostic stratification of patients and sTLC measurement was of little prognostic utility in DLBCL. PMID- 25287609 TI - Prostaglandins and n-3 polyunsaturated fatty acids in the regulation of the hypothalamic-pituitary axis. AB - The hypothalamic-pituitary (H-P) axis integrates complex physiological and environmental signals and responds to these cues by modulating the synthesis and secretion of multiple pituitary hormones to regulate peripheral tissues. Prostaglandins are a component of this regulatory system, affecting multiple hormone synthesis and secretion pathways in the H-P axis. The implications of these actions are that physiological processes or disease states that alter prostaglandin levels in the hypothalamus or pituitary can impinge on H-P axis function. Considering the role of prostaglandins in mediating inflammation, the potential for neuroinflammation to affect H-P axis function in this manner may be significant. In addition, the mitigating effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on the inflammation-associated synthesis of prostaglandins and their role as substrates for pro-resolving lipid mediators may also include effects in the H-P axis. One context in which neuroinflammation may play a role is in the etiology of diet-induced obesity, which also correlates with altered pituitary hormone levels. This review will survey evidence for the actions of prostaglandins and other lipid mediators in the H-P axis, and will address the potential for obesity-associated inflammation and n-3 PUFA to impinge on these mechanisms. PMID- 25287610 TI - Potential biocontrol agents for biofouling on artificial structures. AB - The accumulation of biofouling on coastal structures can lead to operational impacts and may harbour problematic organisms, including non-indigenous species. Benthic predators and grazers that can supress biofouling, and which are able to be artificially enhanced, have potential value as augmentative biocontrol agents. The ability of New Zealand native invertebrates to control biofouling on marina pontoons and wharf piles was tested. Caging experiments evaluated the ability of biocontrol to mitigate established biofouling, and to prevent fouling accumulation on defouled surfaces. On pontoons, the gastropods Haliotis iris and Cookia sulcata reduced established biofouling cover by >55% and largely prevented the accumulation of new biofouling over three months. On wharf piles C. sulcata removed 65% of biofouling biomass and reduced its cover by 73%. C. sulcata also had better retention and survival rates than other agents. Augmentative biocontrol has the potential to be an effective method to mitigate biofouling on marine structures. PMID- 25287611 TI - On the selection of ordinary differential equation models with application to predator-prey dynamical models. AB - We consider model selection and estimation in a context where there are competing ordinary differential equation (ODE) models, and all the models are special cases of a "full" model. We propose a computationally inexpensive approach that employs statistical estimation of the full model, followed by a combination of a least squares approximation (LSA) and the adaptive Lasso. We show the resulting method, here called the LSA method, to be an (asymptotically) oracle model selection method. The finite sample performance of the proposed LSA method is investigated with Monte Carlo simulations, in which we examine the percentage of selecting true ODE models, the efficiency of the parameter estimation compared to simply using the full and true models, and coverage probabilities of the estimated confidence intervals for ODE parameters, all of which have satisfactory performances. Our method is also demonstrated by selecting the best predator-prey ODE to model a lynx and hare population dynamical system among some well-known and biologically interpretable ODE models. PMID- 25287612 TI - An interesting case of tricuspid aortic valve with a quadricuspid function. AB - Quadricuspid aortic valve (QAV) is a rare congenital heart defect, often related to severe aortic regurgitation, and usually detected by echocardiography or at the time of aortic valve surgery. We report a case of an interesting and extremely rare variant of "false" QAV, detected preoperatively by transthoracic and transesophageal echocardiography, in a severely symptomatic patient, admitted to our hospital for dyspnea. Three leaflets of aortic valve appeared quadricuspid, because the left coronary cusp was divided into 2 parts, as confirmed by MRI and pathology. Most frequently, QAV presents with all 4 leaflets equal in size. PMID- 25287613 TI - The effect of clonazepam mouthwash on the symptomatology of burning mouth syndrome: an open pilot study. PMID- 25287614 TI - Molecular mapping of restorer-of-fertility 2 gene identified from a sugar beet (Beta vulgaris L. ssp. vulgaris) homozygous for the non-restoring restorer-of fertility 1 allele. AB - KEY MESSAGE: By genetically eliminating the major restorer - of - fertility gene ( Rf ), a weak Rf gene was unveiled. It is an allele of Z , long known as an elusive Rf gene in sugar beet. In the hybrid breeding of sugar beet, maintainer genotype selection is a laborious process because of the dependence on test crossing, despite the very low occurrence of this genotype. Marker-assisted selection (MAS) of the maintainer genotype is highly desired by sugar beet breeders. The major restorer-of-fertility gene (Rf) was identified as Rf1, and its non-restoring allele (rf1) was discriminated at the DNA level; however, some of the rf1rf1 selections retained an as yet unidentified Rf, another target locus for MAS. The objective of this study was to identify this Rf. An rfrf1 plant was crossed to a cytoplasmic male-sterile sugar beet and then backcrossed to obtain progeny segregating the unidentified Rf. The progeny exhibited partial male fertility restoration that was unstable in single plants. The segregation ratio of restored vs. non-restored plants suggested the involvement of a single Rf in this male-fertility restoration, designated as Rf2. We confirmed the feasibility of molecular tagging of Rf2 by identifying four shared amplified fragment length polymorphism (AFLP) fragments specific to 17 restored plants. Bulked segregant analysis also was performed to screen the Rf2-linked AFLP markers, which were subsequently converted into 17 sequence-tagged site markers. All the markers, as well two additional chromosome-IV-assigned markers, were linked to each other to form a single linkage map, on which Rf2 was located. Our data suggested that Rf2 is likely an allele of Z, long known as an elusive Rf gene in sugar beet. We also discuss the importance of Rf2 for sugar beet breeding. PMID- 25287615 TI - The bacterial 'mitochondrium'. AB - Organelles are membrane-enclosed compartments that serve a dedicated physiological purpose. While eukaryotic organelles are common textbook knowledge, bacteria were long thought to lack such subcellular organization. However, Planctomycetes were proposed to comprise a compartmentalized cell plan, including membrane-enclosed organelles such as the paryphoplasm, the pirellulosome, a nucleus-like membrane system and the anammoxosome. The latter is the hallmark of anaerobic ammonium oxidizing (anammox) bacteria, which gain energy by coupling the oxidation of ammonium to the reduction of nitrite. Since calculations indicate that 50% of nitrogen gas in the earth atmosphere results from anammox activity, this process is key for the global nitrogen cycle. Despite strong evidence for a confined compartment housing this reaction, the concept of planctomycetal compartmentalization in general is currently under debate and the presence of organelles in these bacteria was questioned. However, Neumann et al. (2014) report the isolation of physiological functional anammoxosomes from 'Candidatus Kuenenia stuttgartiensis'. Subsequent proteomic and microscopic analysis revealed a confined organelle, paralleling eukaryotic mitochondria. This advance is of major importance for the understanding of bacterial compartmentalization in general and of the Planctomycetes in particular. Furthermore, the work of Neumann et al. leads to a better understanding of the anammox process. PMID- 25287616 TI - Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients. AB - The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy. PMID- 25287618 TI - Modulations of eye movement patterns by spatial filtering during the learning and testing phases of an old/new face recognition task. AB - In two experiments, we examined the effects of varying the spatial frequency (SF) content of face images on eye movements during the learning and testing phases of an old/new recognition task. At both learning and testing, participants were presented with face stimuli band-pass filtered to 11 different SF bands, as well as an unfiltered baseline condition. We found that eye movements varied significantly as a function of SF. Specifically, the frequency of transitions between facial features showed a band-pass pattern, with more transitions for middle-band faces (~5-20 cycles/face) than for low-band (~<5 cpf) or high-band (~>20 cpf) ones. These findings were similar for the learning and testing phases. The distributions of transitions across facial features were similar for the middle-band, high-band, and unfiltered faces, showing a concentration on the eyes and mouth; conversely, low-band faces elicited mostly transitions involving the nose and nasion. The eye movement patterns elicited by low, middle, and high bands are similar to those previous researchers have suggested reflect holistic, configural, and featural processing, respectively. More generally, our results are compatible with the hypotheses that eye movements are functional, and that the visual system makes flexible use of visuospatial information in face processing. Finally, our finding that only middle spatial frequencies yielded the same number and distribution of fixations as unfiltered faces adds more evidence to the idea that these frequencies are especially important for face recognition, and reveals a possible mediator for the superior performance that they elicit. PMID- 25287617 TI - Load-induced inattentional deafness. AB - High perceptual load in a task is known to reduce the visual perception of unattended items (e.g., Lavie, Beck, & Konstantinou, 2014). However, it remains an open question whether perceptual load in one modality (e.g., vision) can affect the detection of stimuli in another modality (e.g., hearing). We report four experiments that establish that high visual perceptual load leads to reduced detection sensitivity in hearing. Participants were requested to detect a tone that was presented during performance of a visual search task of either low or high perceptual load (varied through item similarity). The findings revealed that auditory detection sensitivity was consistently reduced with higher load, and that this effect persisted even when the auditory detection response was made first (before the search response) and when the auditory stimulus was highly expected (50 % present). These findings demonstrate a phenomenon of load-induced deafness and provide evidence for shared attentional capacity across vision and hearing. PMID- 25287619 TI - Bayesian principles or Gestalt perception for clinical judgment. PMID- 25287620 TI - An unusual diagnosis of increasing respiratory failure after lung resection. PMID- 25287621 TI - Zellweger syndrome and secondary mitochondrial myopathy. AB - Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning. We report on an 8-month-old female infant and a 6-month-old female infant with typical clinical, radiological and laboratory features of Zellweger syndrome; light microscopic and ultrastructural evidence of mitochondrial pathology in their muscle biopsies; and homozygous pathogenic mutations of the PEX16 gene (c.460 + 5G > A) and the PEX 12 gene (c.888_889 del p.Leu297Thrfs*12), respectively. Additionally, mitochondrial respiratory chain enzymology analysis in the first girl showed a mildly low activity in complexes II-III and IV. We also review five children previously reported in the literature with a presumptive diagnosis of ZS and additional mitochondrial findings in their muscle biopsies. In conclusion, this is the first study of patients with a molecularly confirmed peroxisomal disorder with features of a concomitant mitochondrial myopathy and underscores the role of secondary mitochondrial dysfunction in Zellweger syndrome, potentially contributing to the clinical phenotype. PMID- 25287623 TI - Adenocarcinoma developed from remnant cystic duct after cholecystectomy. AB - BACKGROUND: Cystic duct adenocarcinoma is a rare disease because the cystic duct has a short length and a narrow cavity. Cystic duct adenocarcinoma accounts for 8% of all gallbladder adenocarcinoma; of these, adenocarcinoma that develops from the remnant cystic duct after cholecystectomy is extremely rare. We report a case of incidentally detected adenocarcinoma that developed from the remnant cystic duct in a patient with history of cholecystectomy. CASE PRESENTATION: A 74-year old Korean woman visited our hospital with abdominal pain. Her past medical history included cholecystectomy for acute cholecystitis with gallstones 10 years previously. Imaging of the abdomen demonstrated inflammation of the remnant cystic duct with multiple impacted stones. Complete removal of the remnant cystic duct with stones was performed. The pathologic report showed severe inflammation with abscess formation and an unexpected adenocarcinoma that appeared to invade the perimuscular connective tissue. The second operation (confirmation of the resection margin of the remnant cystic duct, wedge resection of the liver, and lymphadenectomy) was performed due to suspicion of pT2. There were no cancer cells in the resection margin of the remnant cystic duct, liver, or lymph nodes (0/6). The final histopathological diagnosis was pT2N0M0. She recovered without any complications. The patient is still living 1 year after surgery without recurrence or metastasis. CONCLUSIONS: We report a rare case of adenocarcinoma that developed from the remnant cystic duct in a patient who underwent cholecystectomy. PMID- 25287622 TI - Double-strand break repair-adox: Restoration of suppressed double-strand break repair during mitosis induces genomic instability. AB - Double-strand breaks (DSBs) are one of the severest types of DNA damage. Unrepaired DSBs easily induce cell death and chromosome aberrations. To maintain genomic stability, cells have checkpoint and DSB repair systems to respond to DNA damage throughout most of the cell cycle. The failure of this process often results in apoptosis or genomic instability, such as aneuploidy, deletion, or translocation. Therefore, DSB repair is essential for maintenance of genomic stability. During mitosis, however, cells seem to suppress the DNA damage response and proceed to the next G1 phase, even if there are unrepaired DSBs. The biological significance of this suppression is not known. In this review, we summarize recent studies of mitotic DSB repair and discuss the mechanisms of suppression of DSB repair during mitosis. DSB repair, which maintains genomic integrity in other phases of the cell cycle, is rather toxic to cells during mitosis, often resulting in chromosome missegregation and aberration. Cells have multiple safeguards to prevent genomic instability during mitosis: inhibition of 53BP1 or BRCA1 localization to DSB sites, which is important to promote non homologous end joining or homologous recombination, respectively, and also modulation of the non-homologous end joining core complex to inhibit DSB repair. We discuss how DSBs during mitosis are toxic and the multiple safeguard systems that suppress genomic instability. PMID- 25287624 TI - Rapid pressure-to-flow dynamics of cerebral autoregulation induced by instantaneous changes of arterial CO2. AB - Continuous assessment of CA is desirable in a number of clinical conditions, where cerebral hemodynamics may change within relatively short periods. In this work, we propose a novel method that can improve temporal resolution when assessing the pressure-to-flow dynamics in the presence of rapid changes in arterial CO2. A time-varying multivariate model is proposed to adaptively suppress the instantaneous effect of CO2 on CBFV by the recursive least square (RLS) method. Autoregulation is then quantified from the phase difference (PD) between arterial blood pressure (ABP) and CBFV by calculating the instantaneous PD between the signals using the Hilbert transform (HT). A Gaussian filter is used prior to HT in order to optimize the temporal and frequency resolution and show the rapid dynamics of cerebral autoregulation. In 13 healthy adult volunteers, rapid changes of arterial CO2 were induced by rebreathing expired air, while simultaneously and continuously recording ABP, CBFV and end-tidal CO2 (ETCO2). Both simulation and physiological studies show that the proposed method can reduce the transient distortion of the instantaneous phase dynamics caused by the effect of CO2 and is faster than our previous method in tracking time-varying autoregulation. The normalized mean square error (NMSE) of the predicted CBFV can be reduced significantly by 38.7% and 37.7% (p<0.001) without and with the Gaussian filter applied, respectively, when compared with the previous univariate model. These findings suggest that the proposed method is suitable to track rapid dynamics of cerebral autoregulation despite the influence of confounding covariates. PMID- 25287626 TI - Validation and randomized control trial of the e-SAID, a computerized paediatric dental patient request form, to intervene in dental anxiety. AB - BACKGROUND: A rationale for, and pilot of a children's patient request form developed specifically for dental visits, has been previously reported. The SAID (survey of anxiety and information for dentists) is a questionnaire with three embedded subscales: dental anxiety, coping style and dental neglect. It includes children's requests for emotional support, information and treatment. The main, but not sole, response format is a facial image scale. A randomized control trial of a computer version is now reported. The aims were to validate items in the e SAID, and to assess it as an intervention in dental anxiety. METHOD: A total of 168 children aged 10-13, attending for routine dental checks in a community dental clinic, were randomly assigned to intervention (83) or control (85) groups. The intervention group completed the e-SAID, in which the first and last questions measured anxiety; and printed a summary of their responses for the dentist. Control group children completed the same anxiety questions, but with a time-lapse. RESULTS: Means and SD were summarized for the 11 items showing a generally positive skew on the seven point scale. After removing the two-item dental neglect subscale, the anxiety and coping subscales were shown to be relatively independent (r = 0.14) and factorially pure. The intervention group mean anxiety score decreased following completion of the e-SAID, while the control group mean anxiety score increased with a small significant interaction effect; however, much of the change occurred in the positive-affect end of the scale. CONCLUSIONS: Two problems are discussed: defining anxiety as a bipolar score; and some children being so keen to be assigned to the intervention group that they circumvented the computer allocation process. Children wanted to actively engage in discussion of their dental treatment. The e-SAID was an effective tool for that, regardless of initial low anxiety levels. PMID- 25287625 TI - Computational de novo design of a four-helix bundle protein--DND_4HB. AB - The de novo design of proteins is a rigorous test of our understanding of the key determinants of protein structure. The helix bundle is an interesting de novo design model system due to the diverse topologies that can be generated from a few simple alpha-helices. Previously, noncomputational studies demonstrated that connecting amphipathic helices together with short loops can sometimes generate helix bundle proteins, regardless of the bundle's exact sequence. However, using such methods, the precise positions of helices and side chains cannot be predetermined. Since protein function depends on exact positioning of residues, we examined if sequence design tools in the program Rosetta could be used to design a four-helix bundle with a predetermined structure. Helix position was specified using a folding procedure that constrained the design model to a defined topology, and iterative rounds of rotamer-based sequence design and backbone refinement were used to identify a low energy sequence for characterization. The designed protein, DND_4HB, unfolds cooperatively (Tm >90 degrees C) and a NMR solution structure shows that it adopts the target helical bundle topology. Helices 2, 3, and 4 agree very closely with the design model (backbone RMSD = 1.11 A) and >90% of the core side chain chi1 and chi2 angles are correctly predicted. Helix 1 lies in the target groove against the other helices, but is displaced 3 A along the bundle axis. This result highlights the potential of computational design to create bundles with atomic-level precision, but also points at remaining challenges for achieving specific positioning between amphipathic helices. PMID- 25287627 TI - Serum annexin A2 levels in patients with colon cancer in comparison to healthy controls and in relation to tumor pathology. AB - BACKGROUND: The deregulation and localization of the Annexins is consistently reported to have close relation to tumor cell malignancy, invasion, and metastasis as well as clinical progression of tumors. This study aimed to evaluate serum Annexin A2 (Anx A2) levels in patients with colon cancer in comparison to healthy controls and in relation to demographics and tumor pathology. MATERIAL AND METHODS: A total of 100 patients (mean (SD) age: 58 (5.8) years, 55.0% females) with colon cancer and 70 controls (mean (SD) age: 59 (5.4) years, 50.0% females) were included. Serum levels for Anx A2 were evaluated in relation to study group, demographics, and tumor pathology. RESULTS: Serum levels for Anx A2 were significantly lower in patients with colon cancer than in controls (13.1 (4.5) vs. 22.8 (2.1) ng/mL, p<0.001) and significantly decreased with increase in tumor size (p=0.003), and at higher stages of TNM (p=0.004), tumor invasion (p=0.005), lymph node metastasis (p=0.003), and distant metastasis (p=0.005). CONCLUSIONS: Our findings indicate a significant decrease in Anx A2 expression in colon cancer patients compared to healthy controls and in parallel with tumor progression. PMID- 25287628 TI - Hacking into the granuloma: could antibody antibiotic conjugates be developed for TB? AB - Alternatives to small molecule or vaccine approaches to treating tuberculosis are rarely discussed. Attacking Mycobacterium tuberculosis in the granuloma represents a challenge. It is proposed that the conjugation of small molecules onto a monoclonal antibody that recognizes macrophage or lymphocytes cell surface receptors, might be a way to target the bacteria in the granuloma. This antibody drug conjugate approach is currently being used in 2 FDA approved targeted cancer therapies. The pros and cons of this proposal for further research are discussed. PMID- 25287630 TI - Phylogenetic analysis of hepatitis E virus in domestic swine and wild boar in Germany. AB - Hepatitis E virus (HEV) is an emerging non-enveloped positive strand RNA virus with worldwide distribution that can cause acute liver disease in humans. The virus has also been detected in both domestic and wild animals. In this study we investigated the presence of HEV in free-living wild boar as well as in domestic swine. A total of 105 domestic swine fecal samples and 124 wild boar sera were tested for the presence of HEV RNA by RT-PCR. A 241 nucleotide (nt) fragment from the capsid gene of HEV from one domestic swine and from 18 wild boars were amplified and sequenced. In addition, the complete capsid of three HEV sequences found in wild boar and the complete genomic sequence of the domestic swine HEV were obtained. Phylogenetic analyses based on both the 241 nt fragments as well as four complete capsid gene sequences demonstrated that all sequences belong to genotype HEV-3. PMID- 25287629 TI - Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials. AB - BACKGROUND: Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT - Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. METHODS: This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset. RESULTS: In each study, RS-Total score was internally consistent (Cronbach alpha) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman's rho; p < 0.01, all comparisons listed here): FEV1% predicted (-0.19, -0.14, -0.15); St. George's Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (-0.30, -0.14) and incremental shuttle walk (ISWT) (-0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed. CONCLUSIONS: Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials. TRIAL REGISTRATION: MPEX: NCT00739648 ; AZ1: NCT00949975 ; AZ 2: NCT01023516. PMID- 25287631 TI - Physiotherapeutic interventions before and after surgery for degenerative lumbar conditions: a systematic review. AB - BACKGROUND: Physiotherapeutic management of patients immediately following lumbar spinal surgery is common. However, there is considerable variability in the interventions provided. OBJECTIVES: To assess the effect of peri-operative physiotherapeutic intervention in adults undergoing surgery for the management of degenerative lumbar conditions. DATA SOURCES: The Cochrane Library, Medline, Embase, CINAHL and PEDro were searched from inception to August 2012. STUDY SELECTION: Randomised controlled trials investigating physiotherapeutic interventions prior to and immediately following surgery for degenerative lumbar conditions were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data independently using a standardised form. Risk of bias was assessed using a modified version of the Cochrane Collaboration tool. The quality of evidence was assessed using the GRADE approach, and the treatment effect size was calculated where comparable outcome measures were used across multiple trials. RESULTS: Four studies were included. There is very-low-quality evidence that pre- and post operative exercise in addition to standard physiotherapeutic care may reduce pain, time taken to achieve post-operative functional milestones, and post operative time off work. Results from one study indicated that there is no clear benefit or risk of harm from performing either prone or side-lying transfers. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: Very-low-quality evidence suggests that physiotherapy may improve pain and function following lumbar surgery. Due to low numbers of included studies and variation in the interventions assessed, the current evidence provides limited guidance for physiotherapeutic practice. Further research is required to determine the effectiveness of physiotherapeutic interventions in this population. PMID- 25287632 TI - Water from fruit or the river? Examining hydration strategies and gastrointestinal illness among Tsimane' adults in the Bolivian Amazon. AB - OBJECTIVE: Water is an essential nutrient overlooked in many cross-cultural studies of human nutrition. The present article describes dietary water intake patterns among forager-horticulturalist adults in lowland Bolivia, compares daily intake with international references and examines if variation in how people acquire water relates to gastrointestinal illness. DESIGN: Cross-sectional observational study used survey, anthropometric and qualitative methods with Tsimane' adults selected by age and sex stratification sampling in one community. SETTING: Research occurred in one Tsimane' village in the Beni department, Bolivia with limited access to clean water. The 24 h diet and health recalls were conducted in July-August 2012 and qualitative interviews/ethnographic observation in September-October 2013. SUBJECTS: Forty-five Tsimane' household heads (49% men) took part in the first data collection and twenty-two Tsimane' (55% men) were included in the follow-up interviews. RESULTS: Men and women reported consuming 4.9 litres and 4.4 litres of water daily from all dietary sources, respectively. On average, water from foods represented 50 % of total water intake. Thirteen per cent of participants reported symptoms of gastrointestinal illness. In a logistic regression model adjusted for age, BMI, sex and raw water consumed, each percentage increase in water obtained from foods was associated with a reduced risk of gastrointestinal illness (OR=0.92; 95% CI 0.85, 0.99). CONCLUSIONS: Both total water intake and percentage of water from foods were higher than averages in industrialized countries. These findings suggest that people without access to clean water may rely on water-rich foods as a dietary adaptation to reduce pathogen exposures. PMID- 25287633 TI - Hippocampal volume and serotonin transporter polymorphism in major depressive disorder. AB - OBJECTIVE: The main aim of the present study was to replicate a previous finding in major depressive disorder (MDD) of association between reduced hippocampal volume and the long variant of the di- and triallelic serotonin transporter polymorphism in SLC6A4 on chromosome 17q11.2. Secondarily, we also hypothesised that 5-HTTLPR may be a risk factor for MDD. METHODS: Quantitative magnetic resonance imaging (MRI) of the hippocampus was studied in 23 inpatients suffering from MDD and in 33 healthy controls. Normalised volumetric MRI data of hippocampus were assessed with adjustment for total brain volume and tensor-based morphometry was used to elucidate structural brain differences. A triallelic genetic marker resulting from two SLC6A4 promoter region polymorphisms, 5-HTTLPR and rs25531, was analysed for association with MDD and quantitative traits. RESULTS: Healthy controls had a smaller relative hippocampal volume (relative to brain size) but a larger total brain volume compared with patients with MDD. For patients compared with healthy controls, atrophy was found in the right temporal lobe and pons medulla. Allele and genotype frequencies were strikingly different from the previous study that we aimed to replicate, and no significant associations with the serotonin transporter polymorphism were found. CONCLUSIONS: The present quantitative and morphometric MRI study was not able to replicate the previous finding of association between reduced hippocampal volume in depressed patients and the serotonin transporter polymorphism. PMID- 25287634 TI - Abnormalities in extracellular glycine and glutamate levels in the striatum of sandy mice. AB - OBJECTIVE: Glycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods. METHODS: We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration. RESULTS: The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice. CONCLUSIONS: These results suggest that dysbindin might modulate glycine and glutamate release in vivo. PMID- 25287635 TI - Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response. AB - OBJECTIVES: There has been increasing evidence that the gamma-aminobutyric acid (GABA)ergic system is involved in the neurobiology of anxiety. The present study aimed to investigate the role of GABAergic systems in the modulation of anxiety in the medial prefrontal cortex (mPFC) of rats using the elevated plus maze test. METHODS: Rats were anaesthetised with a mixture of ketamine and xylazine, and then special cannulae were inserted stereotaxically into the mPFC. After 5-7 days of recovery, the effects of intra-mPFC administration of GABAergic agents were studied. RESULTS: Bilateral injection of the GABAA receptor agonist muscimol (0.25, 0.5 and 1 MUg/rat) produces an anxiolytic-like effect, shown by significant increases in the percentage of open-arm time (%OAT) and percentage of open-arm entries (%OAE). Intra-mPFC administration of the GABAA receptor antagonist bicuculline (0.25, 0.5 and 1 MUg/rat) produces significant anxiogenic like behaviour. However, intra-mPFC injection of the GABAB receptor agonist baclofen (0.05, 0.1 and 0.2 MUg/rat) and the GABAB receptor antagonist CGP35348 (5, 10 and 15 MUg/rat) did not alter %OAT and %OAE significantly. CONCLUSION: The results of the present study demonstrate that the GABAergic system of the mPFC modulates anxiety-related behaviours of rats through GABAA receptors. PMID- 25287636 TI - The dopamine transporter gene possibly affects personality traits in patients with early-onset major depressive disorder. AB - OBJECTIVE: Comorbid personality pathologies may affect the outcome of patients with major depression (MD). The dopamine transporter gene DAT1 (SLC6A3) has been suggested to play a role in both depression and specific personality traits. The aim of this study was to assess five polymorphisms of the DAT1 gene (rs2550948, rs2975226, rs6347, rs27072, and 3'-VNTR) to determine whether this gene influences personality traits in patients with MD or its subgroups. METHODS: The DAT1 polymorphisms were analysed in 463 unrelated Han Chinese MD patients. The personality traits, novelty seeking (NS), and harm avoidance (HA), were examined using the Tridimensional Personality Questionnaire. The patients were also divided into four clinical subgroups on the basis of differences in their sex (male or female) and age at disease onset (early or late). RESULTS: There was no association between the DAT1 gene and either NS or HA in the total MD sample or in the sex-based subgroups. However, early-onset MD patients with the G/G genotype of rs2550948 and the T/T genotype of rs2975226 had lower NS scores than did patients with the other genotypes (p corrected = 0.05 for rs2550948 and p corrected = 0.005 for rs2975226). CONCLUSION: Our study suggests that DAT1 promoter variants possibly influence specific personality traits in the early onset subgroup of depressed patients in the Han Chinese population. Further prospective cohort studies are required to verify our preliminary finding and to confirm the effects of personality susceptibility on long-term disease outcomes. PMID- 25287637 TI - Methylphenidate treatment affects mitogen-activated protein kinase activation in the striatum of young rats. AB - OBJECTIVE: Methylphenidate (MPD) is a drug prescribed for the treatment of attention deficit/hyperactivity disorder and its therapeutic effect is attributed to the inhibition of dopamine. METHODS: Young male Wistar rats were administered MPD (1, 2, 5, or 10 mg/kg) once a day or an intraperitoneal injection of saline for 28 days (chronic treatment) or for 1 day (acute treatment). Two hours after the last administration the animals were decapitated and their striatum was dissected. RESULTS: In this work, we show that continued treatment with MPD is capable of modifying the levels of phosphorylation of proteins JNK1/2 (c-Jun amino-terminal kinases 1 and 2) and ERK1/2 (extracellular signal-regulated kinases 1 and 2). Whereas the level of phosphorylation of protein ERK increased significantly, that of proteins JNK1/2 diminished. CONCLUSION: The alteration in the level of activation of mitogen-activated protein kinases can be a molecular mechanism through which MPD exerts its therapeutic effect. PMID- 25287638 TI - Depressive symptomatology and pineal epidermoid cyst: a case report. AB - Introduction Intracranial epidermoid cysts are congenital cysts. They comprise 0.2-1.8% of primary intracranial tumours and are four to nine times as common as dermoid cysts. Case report We here in present the case of a 32-year-old man who reported sudden onset of symptoms of a depressive symptomatology and particularly severe headache, accompanied by fatigue, depressed mood most of the day, marked diminished interest or pleasure in all or almost all activities, insomnia and diminished ability to think or concentrate. Brain magnetic resolution imaging examination revealed a pineal epidermoid cystic lesion, visualised in the posterior part of the third ventricle, with a maximum diameter of ~2.8 cm and obstructing the aqueduct of Sylvius, causing obstructive hydrocephalus. Discussion Pineal cysts may enlarge over time, because of either increased cyst fluid or intracystic haemorrhage, and become symptomatic. Brain radiological investigations in patients with depressive symptomatology may be substantial. PMID- 25287639 TI - Neuropsychiatric complications in a patient with Marfan syndrome. AB - BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant disorder of fibrillin 1 gene mutations, with the involvement of cardiovascular, skeletal, and ocular systems. In addition to physical abnormalities, MFS patients are also found to be susceptible to schizophrenia and other psychiatric conditions. OBJECTIVES: Awareness of the association between MFS and psychiatric conditions would improve the clinical management of MFS patients to reduce the risk or even to prevent the development of psychiatric complications in MFS patients. METHODS: Here, we describe a male MFS patient who manifested incoherent speech and impaired cognitive and social function at the age of 40 years. Results and conclusion His mental dysfunction could be attributed to his bilateral cerebral infarction, which is a neurovascular complication associated with MFS. PMID- 25287640 TI - Depression as first manifestation of a large intracerebral lymphoma. AB - OBJECTIVE: The differentiation between a 'non-organic' depressive episode and an organic depressive disorder on the basis of clinical grounds might be challenging. METHODS: We report a case with an initially typical severe depressive episode without any focal neurological deficits. RESULTS: Only medical history from a third party raised doubts about this provisional diagnosis. Brain magnetic resonance imaging revealed a highly malignant diffuse large intracerebral B-cell lymphoma in the right frontal lobe changing the diagnosis into an organic depressive disorder. The patient recovered after neurosurgical resection, chemotherapy and autologous stem cell transplantation. CONCLUSION: This report helps to reduce possible errors in the differential diagnosis of depressive disorders by underlining the importance of a comprehensive medical history including anamnesis from a third party and neuroimaging, especially in first or atypical manifestation of depressive disorders. PMID- 25287641 TI - Height distribution of equipotential lines in a region confined by a rough conducting boundary. AB - This work considers the behavior of the height distributions of the equipotential lines in a region confined by two interfaces: a cathode with an irregular interface and a distant flat anode. Both boundaries, which are maintained at distinct and constant potential values, are assumed to be conductors. The morphology of the cathode interface results from the deposit of 2 * 10(4) monolayers that are produced using a single competitive growth model based on the rules of the Restricted Solid on Solid and Ballistic Deposition models, both of which belong to the Kadar-Parisi-Zhang (KPZ) universality class. At each time step, these rules are selected with probability p and q = 1 - p. For several irregular profiles that depend on p, a family of equipotential lines is evaluated. The lines are characterized by the skewness and kurtosis of the height distribution. The results indicate that the skewness of the equipotential line increases when they approach the flat anode and this increase has a non-trivial convergence to a delta distribution that characterizes the equipotential line in a uniform electric field. The morphology of the equipotential lines is discussed; the discussion emphasizes their features for different ranges of p that correspond to positive, null and negative values of the coefficient of the non linear term in the KPZ equation. PMID- 25287642 TI - Rational design of lower-temperature solid oxide fuel cell cathodes via nanotailoring of co-assembled composite structures. AB - A novel in situ co-assembled nanocomposite LSM-Bi1.6 Er0.4 O3 (ESB) (icn-LSMESB) was obtained by conjugated wet-chemical synthesis. It showed an enhancement of the cathode polarization at 600 degrees C by >140 times relative to conventional LSM-Y0.08 Zr0.84 O1.92 (YSZ) cathodes and exceptional solid oxide fuel cell (SOFC) performance of >2 W cm(-2) below 750 degrees C. This demonstrates that this novel cost-effective and broadly applicable process provides new opportunities for performance enhancement of energy storage and conversion devices by nanotailoring of composite electrodes. PMID- 25287644 TI - Neural correlates of sensory prediction errors in monkeys: evidence for internal models of voluntary self-motion in the cerebellum. AB - During self-motion, the vestibular system makes essential contributions to postural stability and self-motion perception. To ensure accurate perception and motor control, it is critical to distinguish between vestibular sensory inputs that are the result of externally applied motion (exafference) and that are the result of our own actions (reafference). Indeed, although the vestibular sensors encode vestibular afference and reafference with equal fidelity, neurons at the first central stage of sensory processing selectively encode vestibular exafference. The mechanism underlying this reafferent suppression compares the brain's motor-based expectation of sensory feedback with the actual sensory consequences of voluntary self-motion, effectively computing the sensory prediction error (i.e., exafference). It is generally thought that sensory prediction errors are computed in the cerebellum, yet it has been challenging to explicitly demonstrate this. We have recently addressed this question and found that deep cerebellar nuclei neurons explicitly encode sensory prediction errors during self-motion. Importantly, in everyday life, sensory prediction errors occur in response to changes in the effector or world (muscle strength, load, etc.), as well as in response to externally applied sensory stimulation. Accordingly, we hypothesize that altering the relationship between motor commands and the actual movement parameters will result in the updating in the cerebellum based computation of exafference. If our hypothesis is correct, under these conditions, neuronal responses should initially be increased--consistent with a sudden increase in the sensory prediction error. Then, over time, as the internal model is updated, response modulation should decrease in parallel with a reduction in sensory prediction error, until vestibular reafference is again suppressed. The finding that the internal model predicting the sensory consequences of motor commands adapts for new relationships would have important implications for understanding how responses to passive stimulation endure despite the cerebellum's ability to learn new relationships between motor commands and sensory feedback. PMID- 25287643 TI - Targeting NF-kappaB signaling with protein kinase C agonists as an emerging strategy for combating HIV latency. AB - Highly active antiretroviral therapy (HAART) is very effective in suppressing HIV 1 replication and restoring immune functions in HIV-infected individuals. However, it fails to eradicate the latent viral reservoirs and fully resolve chronic inflammation in HIV infection. The "shock-and-kill" strategy was recently proposed to induce latent HIV expression in the presence of HAART. Recent studies have shown that the protein kinase C (PKC) agonists are highly potent in inducing latent HIV expression from the viral reservoirs in vitro and ex vivo and in protecting primary CD4(+) T cells from HIV infection through down-modulation of their HIV coreceptor expression. The PKC agonists are excellent candidates for advancing to clinical HIV eradication strategies. This article will present a critical review of the structure and function of known PKC agonists, their mechanisms for the reactivation of latent HIV expression, and the potential of these compounds for advancing clinical HIV eradication strategies. PMID- 25287645 TI - Milk siblingship, religious and secular: History, applications, and implications for practice. AB - PROBLEM OR BACKGROUND: Milk kinship has religious and practical importance to Muslim families that is not well understood in Western cultures. The relationship occurs when an infant receives the milk of a woman other than the biological mother, creating familial relationships between the child and the woman whose milk is received. As milk siblings, her children and the recipient infant must never marry each other. Midwives in Western countries may encounter this in relation to human milk banking. AIM: This review provides a context for respectfully assisting families with their decision making when they are offered banked milk. METHODS: A database search was conducted and other publications were found manually. REVIEW/FINDINGS: Milk siblingship can be religious or secular. In Islam similar prohibitions on marriage exist to those for blood relations. The mothers therefore have to be known to each other to prevent an inappropriate marriage. This relationship has been a barrier to use of human milk banks by Muslim families as milk from several mothers is usually pooled. Nevertheless, donor milk has been used for premature neonates in two Islamic countries, applying the religious requirements. Recent interpretations by some Islamic scholars permitting milk banking may be acceptable to some families, but others will heed other rulings. CONCLUSION/IMPLICATIONS: NICU staff may encounter difficulties in providing banked human milk to infants from Muslim families. Different rulings exist and Muslim families in Western countries come from a variety of traditions. Sensitivity is required to explore these issues with families. PMID- 25287646 TI - Emerging trends in heart valve engineering: Part III. Novel technologies for mitral valve repair and replacement. AB - In this portion of an extensive review of heart valve engineering, we focus on the current and emerging technologies and techniques to repair or replace the mitral valve. We begin with a discussion of the currently available mechanical and bioprosthetic mitral valves followed by the rationale and limitations of current surgical mitral annuloplasty methods; a discussion of the technique of neo-chordae fabrication and implantation; a review the procedures and clinical results for catheter-based mitral leaflet repair; a highlight of the motivation for and limitations of catheter-based annular reduction therapies; and introduce the early generation devices for catheter-based mitral valve replacement. PMID- 25287647 TI - The combination of electric current and copper promotes neuronal differentiation of adipose-derived stem cells. AB - Damage to the nervous system can be caused by several types of insults, and it always has a great effect on the life of an individual. Due to the limited availability of neural transplants, alternative approaches for neural regeneration must be developed. Stem cells have a great potential to support neuronal regeneration. Human adipose-derived stem cells (hADSCs) have gained increasing interest in the fields of regenerative medicine due to their multilineage potential and easy harvest compared to other stem cells. In this study, we present a growth factor-free method for the differentiation of hADSCs toward neuron-like cells. We investigated the effect of electric current and copper on neuronal differentiation. We analyzed the morphological changes, the mRNA and protein expression levels in the stimulated cells and showed that the combination of current and copper induces stem cell differentiation toward the neuronal lineage with elongation of the cells and the upregulation of neuron specific genes and proteins. The induction of the neuronal differentiation of hADSCs by electric field and copper may offer a novel approach for stem cell differentiation and may be a useful tool for safe stem cell-based therapeutic applications. PMID- 25287648 TI - Cognitive workload assessment based on the tensorial treatment of EEG estimates of cross-frequency phase interactions. AB - The decoding of conscious experience, based on non-invasive measurements, has become feasible by tailoring machine learning techniques to analyse neuroimaging data. Recently, functional connectivity graphs (FCGs) have entered into the picture. In the related decoding scheme, FCGs are treated as unstructured data and, hence, their inherent format is overlooked. To alleviate this, tensor subspace analysis (TSA) is incorporated for the parsimonious representation of connectivity data. In addition to the particular methodological innovation, this work also makes a contribution at a conceptual level by encoding in FCGs cross frequency coupling apart from the conventional frequency-specific interactions. Working memory related tasks, supported by networks oscillating at different frequencies, are good candidates for assessing the novel approach. We employed surface EEG recordings when the subjects were repeatedly performing a mental arithmetic task of five cognitive workload levels. For each trial, an FCG was constructed based on phase interactions within and between Frontal (theta) and Parieto-Occipital (alpha2) neural activities, which are considered to reflect the function of two distinct working memory subsystems. Based on the TSA representation, a remarkably high correct-recognition-rate (96%) of the task difficulties was achieved using a standard classifier. The overall scheme is computational efficient and therefore potentially useful for real-time and personalized applications. PMID- 25287649 TI - Two, three, or four-limb testing? Or the difficulties of optimizing electrodiagnosis for suspected CIDP. PMID- 25287650 TI - The spatial-temporal characteristics of type I collagen-based extracellular matrix. AB - Type I collagen abounds in mammalian extracellular matrix (ECM) and is crucial to many biophysical processes. While previous studies have mostly focused on bulk averaged properties, here we provide a comprehensive and quantitative spatial temporal characterization of the microstructure of type I collagen-based ECM as the gelation temperature varies. The structural characteristics including the density and nematic correlation functions are obtained by analyzing confocal images of collagen gels prepared at a wide range of gelation temperatures (from 16 degrees C to 36 degrees C). As temperature increases, the gel microstructure varies from a "bundled" network with strong orientational correlation between the fibers to an isotropic homogeneous network with no significant orientational correlation, as manifested by the decaying of length scales in the correlation functions. We develop a kinetic Monte-Carlo collagen growth model to better understand how ECM microstructure depends on various environmental or kinetic factors. We show that the nucleation rate, growth rate, and an effective hydrodynamic alignment of collagen fibers fully determines the spatiotemporal fluctuations of the density and orientational order of collagen gel microstructure. Also the temperature dependence of the growth rate and nucleation rate follow the prediction of classical nucleation theory. PMID- 25287651 TI - Identification and characterisation of tobacco microRNA transcriptome using high throughput sequencing. AB - MicroRNAs (miRNAs) are post-transcriptional regulators that are involved in numerous biological processes in plants. In this study, we investigate miRNAs in Honghua Dajinyuan, an agronomically important species of tobacco in China. Here, we report a comprehensive analysis of miRNA expression profiles in the leaf, stem and root using a high-throughput sequencing approach. A total of 165 miRNAs, representing 55 conserved families, and 50 novel miRNAs, representing 19 families, were identified in three libraries. In addition, 12 miRNAs were randomly selected from a differentially expressed conserved miRNA family in three libraries with expression alterations and subjected to qRT-PCR validation. Of these, the expression level of nta-miR167d is highly enriched in the leaf tissue. In addition, the expression level of nta-miR319a is prominently enriched in the stem, while nta-miR160c is highly enriched in the root. Moreover, the target prediction showed that most of the targets coded for transcription factors that are involved in cellular and metabolic processes. GO analysis showed that most of the targets were involved in organelle function, served binding functions, and take part in cellular and metabolic processes. This study helps shed new light on understanding the role of miRNAs in different parts of the tobacco plant and adds a significant number of novel miRNAs to the tobacco miRNA transcriptome. PMID- 25287653 TI - Storage of male Glossina palpalis gambiensis pupae at low temperature: effect on emergence, mating and survival. AB - BACKGROUND: Procurement of sterile tsetse flies (Glossina palpalis gambiensis) from Burkina Faso for an eradication programme in Senegal that incorporates the sterile insect technique (SIT) required the development of transport and handling protocols that would allow retaining the female flies in the rearing facility and transport of the male flies as irradiated pupae. The proposed handling scheme included the chilling of the male pupae after the female emergence and transport to Senegal under low temperatures. The effect of exposing male pupae of G. p. gambiensis to low temperature immediately prior to emergence was investigated. METHODS: The parameters of interest were emergence rate, insemination potential, survival of adult male, male ability to participate in mating activities and productivity of females mated with these males. Production was assessed in laboratory rearing cages and mating behaviour in field cages. Male flies that emerged after the female emergence flush from pupae stored at 10 degrees C or 12.5 degrees C for 5 or 7 days were used in the investigations with flies that emerged under standard colony conditions as control. Males that were 3, 6 or 9 days old competed for mating opportunities with 3 day old females. RESULTS: The emergence of males after storage of pupae at low temperature (10 degrees C and 12.5 degrees C) for 3, 5, or 7 days was similar to those kept under standard colony conditions while emergence of flies stored at 15 degrees C started before the storage period was over. Survival of males that emerged from pupae stored at low temperature for varying periods was more than 60% at 30 days post emergence (control more than 75%). The fecundity of females inseminated by males that emerged from pupae stored at low temperature for varying periods ranged from 0.33+/-0.16 to 0.73+/-0.04 pupae per female per 10 days (control 0.60+/-0.16). The older males, irrespective of treatment, out-competed the younger males and 3 day-old males transferred lower amounts of seminal contents to the females. CONCLUSIONS: Storage of male pupae at low temperature for periods up to 7 days at the end of the male pupal period could not be directly associated with impairment of mating activity. PMID- 25287652 TI - Missing-in-Metastasis regulates cell motility and invasion via PTPdelta-mediated changes in SRC activity. AB - MIM (Missing-in-Metastasis), also known as MTSS1 (metastasis suppressor 1), is a scaffold protein that is down-regulated in multiple metastatic cancer cell lines compared with non-metastatic counterparts. MIM regulates cytoskeletal dynamics and actin polymerization, and has been implicated in the control of cell motility and invasion. MIM has also been shown to bind to a receptor PTP (protein tyrosine phosphatase), PTPdelta, an interaction that may provide a link between tyrosine phosphorylation-dependent signalling and metastasis. We used shRNA-mediated gene silencing to investigate the consequences of loss of MIM on the migration and invasion of the MCF10A mammary epithelial cell model of breast cancer. We observed that suppression of MIM by RNAi enhanced migration and invasion of MCF10A cells, effects that were associated with increased levels of PTPdelta. Furthermore, analysis of human clinical data indicated that PTPdelta was elevated in breast cancer samples when compared with normal tissue. We demonstrated that the SRC protein tyrosine kinase is a direct substrate of PTPdelta and, upon suppression of MIM, we observed changes in the phosphorylation status of SRC; in particular, the inhibitory site (Tyr527) was hypophosphorylated, whereas the activating autophosphorylation site (Tyr416) was hyperphosphorylated. Thus the absence of MIM led to PTPdelta-mediated activation of SRC. Finally, the SRC inhibitor SU6656 counteracted the effects of MIM suppression on cell motility and invasion. The present study illustrates that both SRC and PTPdelta have the potential to be therapeutic targets for metastatic tumours associated with loss of MIM. PMID- 25287654 TI - Hypofractionated radiation treatment following mastectomy in early breast cancer: the Christchurch experience. AB - INTRODUCTION: Although hypofractionated radiotherapy (HFRT) has become an accepted option for whole-breast irradiation after breast-conserving surgery, there is limited evidence to support HFRT to the chest wall following mastectomy. We retrospectively analysed post-mastectomy patients treated with HFRT in Christchurch to determine whether HFRT yields acceptable efficacy and toxicity. METHODS: The Christchurch oncology database was used to identify breast cancer patients treated with adjuvant HFRT to the chest wall following a mastectomy between 2003 and 2008. Eligible post-mastectomy patients were treated with 40 Gy in 16 daily fractions. Treatment outcomes assessed included local recurrence-free survival, breast cancer survival, overall survival and acute toxicities. RESULTS: One hundred thirty-three patients were identified. The median follow-up period was 5.03 years. Three patients had a local recurrence as a first event, resulting in 5-year local recurrence-free survival of 97.6%. Five-year overall survival and 5-year breast cancer survival were 74.7% and 77.7%, respectively. The prospectively assessed acute toxicities were mostly grade 1. In particular, the incidence of grade 2 skin toxicity was 10.7%, and no patients experienced grade 3 skin toxicity. CONCLUSION: The high local control rate with HFRT, combined with acceptable toxicity and the practical benefits of a shorter treatment time, supports its ongoing use in the eligible patient group. A randomised controlled trial would be necessary to more completely assess the acute and long-term toxicity of HFRT compared with standard fractionation. PMID- 25287655 TI - Prader-Willi syndrome and Tay-Sachs disease in association with mixed maternal uniparental isodisomy and heterodisomy 15 in a girl who also had isochromosome Xq. AB - Malsegregation of chromosomes during reproduction can result in uniparental disomy when associated with trisomy rescue, monosomy rescue or gamete complementation. Pathogenicity stemming from uniparental disomy in liveborns results from imprinting disorders or autozygosity for autosomal recessive disorders. We report on a girl with Prader-Willi syndrome and Tay-Sachs disease resulting from maternal uniparental disomy of chromosome 15. The child also had an isochromosome Xq. To further characterize the etiology of the aberrant chromosome 15 and the isochromosome Xq, SNP loci from both chromosomes were assessed in the proband and parents, and genome-wide DNA methylation analysis was performed. SNP and DNA methylation analysis confirmed maternal uniparental heterodisomy around the Prader-Willi locus, while the region around the HEXA locus showed maternal uniparental isodisomy. This result is consistent with trisomy rescue of a maternal meiosis l error in a chromosome 15 with two meiotic recombinations. SNP analysis of the X chromosomes is consistent with a maternal origin for the isochromosome. PMID- 25287656 TI - Prefrontal neuronal circuits of contextual fear conditioning. AB - Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories. PMID- 25287657 TI - Circulating microRNAs as novel potential biomarkers for early diagnosis of acute stroke in humans. AB - BACKGROUND: Many diseases include microRNAs (miRNAs) as reported biomarkers. The significance of circulating miRNAs for early diagnosis of acute stroke in humans is unknown. We aim to determine whether circulating miRNAs potentially serve as novel biomarkers for acute stroke. METHODS: We prospectively recruited patients with acute stroke and those with nonstroke disease. Patients with acute stroke were identified using magnetic resonance imaging (MRI) for early diagnosis. If the patient suffered from acute stroke that was detected with diffusion-weighted imaging, the patient was defined as an MRI(+) patient. Otherwise, it was defined as an MRI(-) patient. Circulating miRNAs were measured by miRNA microarray and real-time polymerase chain reaction (PCR) analysis. RESULTS: A total of 136 patients were included in the study. Testing by miRNA microarray and real-time PCR analyses showed that hsa-miR-106b-5P and hsa-miR-4306 were present with markedly high abundance in patients of acute stroke, whereas hsa-miR-320e and hsa miR-320d were present with quite low abundance in patients compared with healthy individuals. Compared with healthy individuals, the miRNAs were increased as in patients with acute stroke as follows: hsa-miR-106b-5P, 3.63-fold in MRI(-) patients and 23.90-fold in MRI(+) patients; hsa-miR-4306, 3.19-fold in MRI(-) patients and 5.30-fold in MRI(+) patients; hsa-miR-320e, .33-fold in MRI(-) patients and .13-fold in MRI(+) patients; and hsa-miR-320d, .23-fold in MRI(-) patients and .07-fold in MRI(+) patients. CONCLUSIONS: Elevated hsa-miR-106b-5P and hsa-miR-4306 and decreased hsa-miR-320e and hsa-miR-320d in plasma may be novel biomarkers for the early detection of acute stroke in humans. PMID- 25287659 TI - Blue-shift of Eu2+ emission in (Ba,Sr)3Lu(PO4)3:Eu2+ eulytite solid-solution phosphors resulting from release of neighbouring-cation-induced stress. AB - A series of iso-structural eulytite-type (Ba,Sr)3Lu(PO4)3:Eu(2+) solid-solution phosphors with different Sr/Ba ratios were synthesized by a solid-state reaction. Crystal structures of (Ba,Sr)3Lu(PO4)3:Eu(2+) were resolved by the Rietveld method, which shows an eulytite-type cubic Bi4(SiO4)3 structure with cations disordered in a single C3 site while the oxygen atoms were distributed over two partially occupied sites. The emission peaks of Ba((3-x))Sr(x)Lu(PO4)3:Eu(2+) (0 <= x <= 3) phosphors were blue-shifted, from 506 to 479 nm, with increasing Sr/Ba ratio upon the same excitation wavelength of 365 nm, and such interesting luminescence behaviours can also be found in other eulytite-type (Ba,Sr)3Ln(PO4)3:Eu(2+) (Ln = Y, Gd) solid-solution phosphors. The blue-shift of the Eu(2+) emission with increasing Sr/Ba ratio was ascribed to the variation of the crystal field strength that the 5d orbital of Eu(2+) ion experiences, and a new model based on the Eu-O bond length and released neighboring-cation stress in disordered Ba(2+)/Sr(2+)/Ln(3+) sites is proposed. PMID- 25287658 TI - Hospital readmission in heart failure, a novel analysis of a longstanding problem. AB - Acute decompensated heart failure is a significant source of morbidity and mortality in the USA. It is the most common reason for admission in the Medicare population and the greatest cause of hospital readmission in both medical and surgical patients. As many of these readmissions are considered preventable, providers and hospital systems are seeking novel strategies to reduce rehospitalization. Several specific interventions have been shown to decrease readmission for heart failure. However, these are typically narrow in scope, focusing on one aspect of patient care and providing a one-size-fits-all approach. We review the data and propose integrating some of these interventions into a comprehensive patient-centered model that is organized into six categories: quality of medical management, early reassessment, health literacy, neuropsychological status, financial means and functional status. By screening for deficiencies in each of these categories, providers and hospital systems can use resources more efficiently to make targeted interventions to improve health outcomes and mitigate readmissions. PMID- 25287660 TI - Computational analysis of human N-acetylgalactosamine-6-sulfate sulfatase enzyme: an update in genotype-phenotype correlation for Morquio A. AB - Mucopolysaccharidosis IV A (MPS IV A) is a lysosomal storage disease produced by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. Although genotype-phenotype correlations have been reported, these approaches have not enabled to establish a complete genotype-phenotype correlation, and they have not considered a ligand-enzyme interaction. In this study, we expanded the in silico evaluation of GALNS mutations by using several bioinformatics tools. Tertiary GALNS structure was modeled and used for molecular docking against galactose-6-sulfate, N-acetylgalactosamine-6-sulfate, keratan sulfate, chondroitin-6-sulfate, and the artificial substrate 4-methylumbelliferyl-beta-D galactopyranoside-6-sulfate. Furthermore, we considered the evolutionary residue conservation, change conservativeness, position within GALNS structure, and the impact of amino acid substitution on the structure and function of GALNS. Molecular docking showed that amino acids involved in ligand interaction correlated with those observed in other human sulfatases, and mutations within the active cavity reduced affinity of all evaluated ligands. Combination of several bioinformatics approaches allowed to explaine 90% of the missense mutations affecting GALNS, and the prediction of the phenotype for another 21 missense mutations. In summary, we have shown for the first time a docking evaluation of natural and artificial ligands for human GALNS, and proposed an update in genotype-phenotype correlation for Morquio A, based on the use of multiple parameters to predict the disease severity. PMID- 25287661 TI - The decreased frequency of SIGIRR-positive CD4+ T cells in peripheral blood of patients with SLE and its correlation with disease activity. AB - Recently, many studies have shown that Single immunoglobulin interleukin-1 receptor related protein (SIGIRR), a member of the IL-1R family acting as a negative regulator of TLR/IL-1R signaling, affects autoimmune responses in animal model of systemic lupus erythematosus (SLE). However, the role of SIGIRR in the pathogenesis of human SLE has not been widely explored. In this study, we analyzed the frequency of SIGIRR-positive CD4+ T cells in peripheral blood mononuclear cells (PBMCs) of SLE patients and its correlation with disease activity as well as the clinical data. Circulating SIGIRR-positive CD4+ T cells were quantified in 51 SLE patients and 38 healthy controls by using flow cytometer. Results showed that the percentages of SIGIRR-positive CD4+ T cells were decreased in the PBMCs of SLE patients compared with healthy controls (Z = 5.49, P < 0.001). The frequency of SIGIRR-positive CD4 + T cells were also significantly decreased in SLE patients with nephritis than those without nephritis (Z = -3.71, P < 0.001). In addition, there was significant correlation between the percentages of SIGIRR-positive CD4+ T cells and SLEDAI score (r s = 0.74, P < 0.001), 24-hour urine protein (r s = -0.62, P < 0.001), Scr (r s = 0.65, P < 0.001), ESR (r s = -0.60, P < 0.001), C3 (r s = 0.53, P < 0.001) as well as C4 (r s = 0.52, P < 0.001). However, there was no correlation between the proportion of SIGIRR-positive CD4+ T cells and glucocorticoid dose (P = 0.59). In summary, decreased numbers of SIGIRR-positive CD4+ T cells in SLE patients and its correlation with SLEDAI score as well as the clinical data suggest that SIGIRR may be involved in the pathogenesis of SLE. PMID- 25287663 TI - Erratum to: Identification of gene variants associated with hypoxia pathway in acute coronary syndrome: a pilot study. PMID- 25287662 TI - FLT3 expression and IL10 promoter polymorphism in acute myeloid leukemia with RUNX1-RUNX1T1. AB - We investigated the correlation between FLT3 expression and IL10 gene promoter polymorphism in acute myeloid leukemia with RUNX1-RUNX1T1 and their clinical significance. FLT3 mRNA expression was measured by real-time quantitative PCR (qPCR) and immunohistochemical staining (IHC) on bone marrow (BM) leukemic cells. IL10 gene promoter polymorphisms including rs1800896 (G-1082A), rs1800871 (C 819T), and rs1800872 (C-592T) were genotyped by direct sequencing. Among 45 enrolled patients, 32 (71.1 %) exhibited FLT3 overexpression, whose FLT3 mRNA level was higher than normal cut-off value (0.02). The IHC results also consisted with FLT3 mRNA expression data achieved by qPCR. The FLT3 mRNA level was significantly different among 3 IHC staining groups (P < 0.0001); 0.031 +/- 0.041, 0.106 +/- 0.097 and 0.588 +/- 0.573 in IHC negative, intermediate and positive group, respectively. Interestingly, the FLT3 expression level was correlated with the percentage of BM CD34 positive cells (R = 0.360, P = 0.016). The elevated FLT3 expression at initial BM were decreased after remission and maintained lower than the cut-off level. FLT3 expression was not dependent on IL10 gene promoter polymorphisms. FLT3 overexpression itself did not demonstrate significant effects on overall survival (OS). However, it is notable that IL10 rs1800896 GA genotype tended to have a lower estimated mean OS (20.1 months) compared to GG genotype (54.6 months), but the statistical significance was not derived because of limited number of patients in this study (P = 0.072). Further studies including more type of leukemia and patients may be helpful to understand the relations between cytokine genotype and FLT3 expression and their prognostic impact. PMID- 25287664 TI - The morality of larks and owls: unethical behavior depends on chronotype as well as time of day. PMID- 25287665 TI - Does the morning morality effect hold true only for morning people? PMID- 25287666 TI - Incorporating culture into the study of affect and health. PMID- 25287668 TI - Bioreducible guanidinylated polyethylenimine for efficient gene delivery. AB - Cationic polymers are known to afford efficient gene transfection. However, cytotoxicity remains a problem at the molecular weight for optimal DNA delivery. As such, optimized polymeric gene delivery systems are still a sought-after research goal. A guanidinylated bioreducible branched polyethylenimine (GBPEI-SS) was synthesized by using a disulfide bond to crosslink the guanidinylated BPEI (GBPEI). GBPEI-SS showed sufficient plasmid DNA (pDNA) condensation ability. The physicochemical properties of GBPEI-SS demonstrate that it has the appropriate size (~200 nm) and surface potential (~30 mV) at a nitrogen-to-phosphorus ratio of 10. No significant toxicity was observed, possibly due to bioreducibility and to the guanidine group delocalizing the positive charge of the primary amine in BPEI. Compared with the nonguanidinylated analogue, BPEI-SS, GBPEI-SS showed enhanced transfection efficiency owing to increased cellular uptake and efficient pDNA release by cleavage of disulfide bonds. This system is very efficient for delivering pDNA into cells, thereby achieving high transfection efficiency and low cytotoxicity. PMID- 25287669 TI - Gastroprotective effects of L-lysine salification of ketoprofen in ethanol injured gastric mucosa. AB - Ketoprofen L-lysine salt (KLS), a NSAID, is widely used for its analgesic efficacy and tolerability. L-lysine salification was reported to increase the solubility and the gastric absorption and tolerance of ketoprofen. Since the management of NSAIDs gastrotoxicity still represents a major limitation in prolonged therapies, mainly when gastric lesions are present, this study investigated the gastro-protective activity of L-lysine by using a well established model of gastric mucosa injury, the ethanol-gastric injury model. Several evidences show that the damaging action of ethanol could be attributed to the increase of ROS, which plays a key role in the increase of lipid peroxidation products, including malonyldialdehyde and 4-hydroxy-2-nonenal. With the aim to unravel the mechanism of L-lysine gastroprotection, cellular MDA levels and 4-HNE protein adducts as markers of lipid peroxidation and a panel of key endogenous gastro-protective proteins were assayed. The data obtained indicate a gastroprotective effect of L-lysine on gastric mucosa integrity. PMID- 25287667 TI - Replicability and robustness of genome-wide-association studies for behavioral traits. AB - A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ~ 0.02%), reached genome-wide significance (p < 5 * 10( 8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ~ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies. PMID- 25287671 TI - Mobilization with movement and elastic tape application for the conservative management of carpometacarpal joint osteoarthritis. AB - Carpometacarpal osteoarthritis can limit a person's ability to engage in desired activities. Many therapists utilize conservative approaches to assist these patients. These authors describe utilizing a combination of mobilization with movement and the use of elastic tape for patients with this arthritis. - Victoria Priganc, PhD, OTR, CHT, CLT, Practice Forum Editor. PMID- 25287670 TI - Adoption of electronic medical record-based decision support for otitis media in children. AB - OBJECTIVE: Substantial investment in electronic health records (EHRs) has provided an unprecedented opportunity to use clinical decision support (CDS) to increase guideline adherence. To inform efforts to maximize adoption, we characterized the adoption of an otitis media (OM) CDS system, the impact of performance feedback on adoption, and the effects of adoption on guideline adherence. STUDY SETTING: A total of 41,391 OM visits with 108 clinicians at 16 pediatric practices between February 2009 and August 2010. STUDY DESIGN: Prospective cohort study of EHR-based CDS adoption during OM visits, comparing clinicians receiving performance feedback to none. CDS was available to all physicians; use was voluntary. DATA COLLECTION: Extraction from a common EHR. PRINCIPAL FINDINGS: Clinicians and practices used the CDS system for a mean of 21 percent (range: 0-85 percent) and 17 percent (0-51 percent) of eligible OM visits, respectively. Clinicians who received performance feedback reports summarizing CDS use and guideline adherence had a relative increase in CDS use of 9.0 percentage points compared to others (p = .001). CDS adoption was associated with increased OM guideline adherence. Effects were greatest among clinicians with the lowest adherence prior to the study. CONCLUSIONS: Performance feedback increased CDS adoption, but additional strategies are needed to integrate CDS into primary care workflows. PMID- 25287672 TI - Heat shock protein 90 stimulates rat mesenchymal stem cell migration via PI3K/Akt and ERK1/2 pathways. AB - The objective of this study was to determine the role of Hsp90alpha in regulating the migration of mesenchymal stem cells (MSCs) and to investigate the underlying mechanisms of this effect. MSCs migration was assessed by wound healing assay and transwell migration assay. Hsp90alpha expression was silenced in MSC by siRNA (sirHsp90alpha). The activity of secreted metalloproteases MMP-2 and MMP-9, and their expression levels in MSC were evaluated using gelatin zymography, Western blot analysis and real-time PCR. Gene expression of VCAM-1 and CXCR4 cytokines was evaluated by real-time PCR. Akt and ERK activity were analyzed by Western blotting using antibodies against phosphorylated forms of these proteins. Treatment with Hsp90alpha significantly enhanced MSC migration, and this effect was blocked by transfecting MSC with sirHsp90alpha. Treating the cells with recombinant human Hsp90alpha (rhHsp90alpha) enhanced gene expression and protein levels of MMP-2 and MMP-9, as well as their secretion and activity. MSC incubated with rhHsp90alpha exhibited increased gene expression of CXCR4 and VCAM-1. Finally, the levels of phosphorylated Akt and Erk were markedly increased by rhHsp90alpha treatment. These findings indicate that Hsp90alpha promotes MSCs migration via PI3K/Akt and ERK signaling pathways, and that this effect is possibly mediated by MMPs, SDF-1/CXCR4 pathway, and VCAM-1. PMID- 25287673 TI - A retrospective study to compare the use of tacrolimus and cyclosporine in combination with adriamycin in post-transplant liver cancer patients. AB - The aim of this study was to compare the clinical effect of tacrolimus (TAC) versus cyclosporine (CycA) in post-transplant hepatic cancer patients undergoing adriamycin hydrochloride (ADM) chemotherapy. Patients with advanced hepatic cancer who underwent liver transplant and subsequent therapy between March 2007 and March 2009 in our hospital were selected for this study. All of these patients were treated with chemotherapeutic agent adriamycin, with respect to immunosuppressant, whereas they received either TAC or CycA, and hence represented two groups, TAC and controls, respectively. The short- and long-term outcomes of two therapies, ADM + TAC and ADM + CsA, were compared. The TAC group patients showed improved remission compared to the control group (40 cases with 46.0 % versus 32 cases with 31.1 % remission, respectively). The 5-year survival in TAC group was significantly prolonged (20.7 %) compared to that of the controls (8.7 %). The short-term outcomes, such as serum levels of calcium, biomarkers of cardiac toxicity/functioning, and regulatory T lymphocytes counts (markers of immune functioning), were found to be significantly more auspicious with TAC treatment than with CycA. Our study showed that use of TAC plus ADM resulted in improved patient survival, tolerance of the graft, and remission compared to CycA combined with ADM. The serum levels of various markers in the short follow-up analysis indicated a better cardiac and immune functioning with TAC than with CycA treatment. PMID- 25287674 TI - Erythropoietin (EPO) protects against high glucose-induced apoptosis in retinal ganglional cells. AB - The aim of this study was to investigate the protective effect and mechanism of EPO on the apoptosis induced by high levels of glucose in retinal ganglial cells (RGCs). High glucose-induced apoptosis model was established in RGCs isolated from SD rats (1-3 days old) and identified with Thy1.1 mAb and MAP-2 pAb. The apoptosis was determined by Hochest assay. The levels of ROS were quantitated by staining the cells with dichloro-dihydro-fluorescein diacetate (DCFH-DA) and measure by flow cytometry. The SOD, GSH-Px, CAT activities, and levels of T-AOC and MDA were determined by ELISA. Change in mitochondrial membrane potential (Deltapsim) was also assessed by flow cytometry, and expressions of Bcl-2, Bax, caspase-3, caspase-9, and cytochrome C were assessed by western blotting. The RGCs treated with high glucose levels exhibited significantly increased apoptotic rate and concentrations of ROS and MDA. Pretreatment of the cells with EPO caused a significant blockade of the high glucose-induced increase in ROS and MDA levels and apoptotic rate. EPO also increased the activities of SOD, GSH-Px, and CAT, and recovered the levels of T-AOC levels. As a consequence, the mitochondrial membrane potential was improved and Cyt c release into the cytoplasm was prevented which led to significantly suppressed up-regulation of Bax reducing the Bax/Bcl-2 ratio. The expressions of caspase-3 and caspase-9 induced by high glucose exposure were also ameliorated in the RGCs treated with EPO. The protective effect of EPO against apoptosis was mediated through its antioxidant action. Thus, it blocked the generation of pro-apoptotic proteins and apoptotic degeneration of the RGCs by preventing the mitochondrial damage. PMID- 25287676 TI - Structure elucidation and NMR assignments of two unusual isomeric aromatic monacolin analogs from Monascus purpureus. PMID- 25287675 TI - Optimal amount of basic fibroblast growth factor in gelatin sponges incorporating beta-tricalcium phosphate with chondrocytes. AB - BACKGROUND: A gelatin sponge with slowly releasing basic fibroblast growth factor (b-FGF) enhances chondrogenesis. This study investigated the optimal amount of b FGF in gelatin sponges to fabricate engineered cartilage. MATERIALS AND METHODS: b-FGF (0, 10, 100, 500, 1000, and 2000 MUg/cm(3))-impregnated gelatin sponges incorporating beta-tricalcium phosphate (beta-TCP) were produced. Chondrocytes were isolated from the auricular cartilage of C57B6J mice and expanded. The expanded auricular chondrocytes (10*10(6) cells/cm(3)) were seeded onto the gelatin sponges, which served as scaffolds. The construct assembly was implanted in the subcutaneous space of mice through a syngeneic fashion. Thereafter, constructs were retrieved at 2, 4, or 6 weeks. RESULTS: (1) Morphology: The size of implanted constructs was larger than the size of the scaffold with 500, 1000, and 2000 MUg/cm(3) b-FGF-impregnated gelatin sponges incorporating beta-TCP at 4 and 6 weeks after implantation. (2) The weight of the constructs increased roughly proportional to the increase in volume of the b-FGF-impregnated scaffold at 2, 4, and 6 weeks after implantation, except in the 2000 MUg/cm(3) b-FGF impregnated constructs group. (3) Histological examination: Extracellular matrix in the center of the constructs was observed in gelatin sponges impregnated with more than 100 MUg/cm(3) b-FGF at 4 weeks after implantation. The areas of cells with an abundant extracellular matrix were positive for cartilage-specific marker type 2 collagen in the constructs. (4) Protein assay: Glycosaminoglycan and collagen type 2 expression were significantly increased at 4 and 6 weeks on implantation of gelatin sponges impregnated with more than 100 MUg/cm(3) b-FGF. At 6 weeks after implantation, the ratio of type 2 collagen to type 1 collagen in constructs impregnated with 100 MUg/cm(3) or more b-FGF was higher than that in mice auricular cartilage. CONCLUSION: Gelatin sponges impregnated with more than 100 MUg/cm(3) b-FGF incorporating beta-TCP with chondrocytes (10*10(6) cells/cm(3)) can fabricate engineered cartilage at 4 weeks after implantation. PMID- 25287677 TI - [Potential cognitive alterations after treatment of benign prostate syndrome. Investigations on transurethral electroresection and 180 W GreenLight XPS laser therapy]. AB - OBJECTIVE: The study was carried out to detect possible changes in cognition after transurethral resection of the prostate (TURP) and 180 W GreenLight-XPS laser treatment of the prostate. METHODS: Cognitive capacity was assessed by the mini-mental state examination (MMSE) and the clock test preoperatively and on postoperative day 2 in addition to documentation of clinical parameters, such as patient age, prostate size, duration of surgery, comorbidities, co-medications and alterations in hemoglobin (Hb) and sodium concentrations. RESULTS: Patients treated with TURP (n = 88) and 180 W GreenLight-XPS laser treatment of the prostate (n = 114) were comparable regarding age, prostate size and duration of surgery. Baseline characteristics of the patients treated by laser showed an increased potential for postoperative cognitive changes with an average of 3.8 comorbidities (TURP 3.11, p = 0.005) and were using an average of 6.79 multiple medications (TURP 5.24, p < 0.001); however, neither the MMSE nor the clock test demonstrated a decrease in the average postoperative score (difference between postoperative and preoperative MMSE + 0.6 +/- 1.6 for 180 W GreenLight-XPS laser treatment and + 0.6 +/- 1.6 for TURP, p = 0.944; difference postoperative and preoperative clock test + 0.43 +/- 1.44 for 180 W GreenLight-XPS laser treatment and 0.13 +/- 1.17 for TURP, p = 0.097). Neither postoperative hemoglobin nor sodium concentrations, as safety relevant parameters, demonstrated clinically relevant changes. The differences between the surgical procedures were not statistically significant. DISCUSSION: Neither 180 W GreenLight-XPS laser treatment of the prostate nor TURP demonstrated changes in cognition by comparing the preoperative MMSE and the clock test scores. In this study, the baseline characteristics of laser-treated patients showed a higher number of comorbidities and a higher use of medications, particular those with anticholinergic potency; therefore, 180 W GreenLight-XPS laser treatment of the prostate appears particularly safe for elderly patients. PMID- 25287678 TI - [Approaches of general practitioners and patients to multimorbidity. Qualitative study]. AB - BACKGROUND: For general practioners (GP) the treatment of patients suffering from multimorbidity is an everyday challenge. For these patients guidelines which each focus on a specific chronic disease cannot be applied comprehensively and equally; therefore, it is necessary to prioritize. OBJECTIVE: Given this situation the study aimed at analyzing how GPs and patients deal with this challenge and what their priorities are. MATERIAL AND METHODS: Narrative interviews were conducted with 9 GPs and 19 of their multimorbid patients. The data were analyzed by means of content analysis. RESULTS: The majority of interviewed patients felt well or very well cared for by their GPs; however, GPs and multimorbid patients often had relatively different priorities. Whereas GPs mostly focused on the management of diseases that could lead to life-threatening situations, patients put an emphasis on maintaining autonomy and a social life. CONCLUSION: The results of this study suggest that there is room for development in the way GPs and multimorbid patients communicate with each other, particularly as far as shared priority setting is concerned. PMID- 25287679 TI - Hepatobiliary agents and their role in LI-RADS. AB - The Liver Imaging Reporting and Data System (LI-RADS) was introduced with the goal of standardizing the diagnosis of hepatocellular carcinoma. The 2014 version of LI-RADS incorporates the use of hepatobiliary contrast agents (HBAs) into the diagnostic algorithm, including gadoxetate disodium and gadobenate dimeglumine. Three new ancillary features are introduced: hepatobiliary phase (HBP) hypointensity and HBP hypointense rim favor malignancy, while HBP isointensity favors benignity. HBP hyperintensity favors neither malignancy nor benignity. In this review, we describe how to use these new features as well as numerous pitfalls associated with the use ofHBAs, including hemangiomas, cholangiocarcinomas, and focal confluent fibrosis. Importantly, findings on the HBP are not included as major criteria and therefore the criteria for the diagnosis of LI-RADS 5 observations remain unchanged, and so congruence with the Organ Procurement Transplant Network system remains intact. Additionally, we review how the major features in LI-RADS, arterial phase hyperenhancement, threshold growth, and washout and capsule appearance, may be affected with HBAs. Notably with HBAs, hypointensity on the delayed phase, termed the transitional phase, does not qualify as washout appearance due to the possibility of early parenchymal enhancement. It is hoped that the incorporation of HBAs into LI-RADS will help create consistency when interpreting HBA enhanced MRIs. PMID- 25287680 TI - Is the nonlipomatous component of dedifferentiated liposarcoma always soft tissue on CT? Analysis of CT densities and correlation with rate of growth in 60 patients. AB - PURPOSE: To define the various CT densities of nonlipomatous component of dedifferentiated liposarcoma (DDLPS) and to determine if the rate of growth varies with density. METHODS: This study identified 60 patients with DDPLS (38 men, 22 women; mean age at diagnosis 59 years, range, 35-82 years) who had one or more resections. CT scan immediately before the surgical resection (presurgery) and up to a maximum of one year before the surgery (baseline) was reviewed by two radiologists to note the density of the nonlipomatous elements and rate of growth during that period. Clinical and histopathological data were extracted from electronic medical records. Rate of growth of various densities was compared using Kruskal-Wallis test. RESULTS: Three distinct densities of the nonlipomatous component were noted: soft tissue density (SD), fluid density (FD), and mixed density (MD). Of 109 lesions on the presurgery scan (SD = 78; MD = 22; FD = 9), scans at baseline were available for 72/109 lesions (SD = 49; MD = 14; FD = 9). Median growth rate/month without treatment, with chemotherapy, and with radiotherapy were 40%, 24%, and 62%, respectively, for SD lesions and 28%, 61%, and 52% for MD lesions. For FD lesions, it was 72% and 35%, respectively, without treatment and with chemotherapy. There was no statistical difference in the rate of growth of various densities. Density changed over time in 8/72 (11%) lesions, including 2/49 SD lesions (to MD), 1/14 MD lesions (to SD), and 5/9 FD lesions (to SD). CONCLUSIONS: DDLPS has three distinct CT densities of which soft tissue density is the most common. Despite not being statistically significant, fluid density lesions had rapid growth rate and often converted to soft tissue density in our study. PMID- 25287683 TI - Osteoarthritis: Animal data show VEGF blocker inhibits post-traumatic OA. PMID- 25287681 TI - Detection of allele specific differences in IFNL3 (IL28B) mRNA expression. AB - BACKGROUND: Variants of the interferon-lambda3 (IFNL3) gene have been associated with both spontaneous and treatment induced clearance of HCV infection. Attempts to link polymorphisms of the IFNL3 gene with variation in the level of IFNL3 expression have been inconclusive. This is partially due to the difficulty to design assays distinguishing IFNL3 from IFNL2. METHODS: In this study an allele specific real-time PCR (RT-PCR) assay was developed which allows the relative quantification of the two IFNL3 transcripts in cells heterozygous for SNP IFNL3.rs4803217 in the 3'UTR of the IFNL3 gene. This SNP is in strong linkage disequilibrium (LD) with the predictive marker rs12979860. RESULTS: Raji cells showed two-fold increased levels of IFNL3.rs4803217 C-allele expression. In peripheral blood mononuclear cells (PBMCs) of eight uninfected donors, two donors showed increased IFNL3.rs4803217 C-allele expression. CONCLUSION: This indicates that allele specific differences in IFNL3 expression vary between individuals and might contribute to the variety of outcomes in HCV infected patients. PMID- 25287684 TI - Biphenyl-derived phosphepines as chiral nucleophilic catalysts: enantioselective [4+1] annulations to form functionalized cyclopentenes. AB - Because of the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. Introduced herein is a new family of chiral nucleophilic catalysts, biphenyl-derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation. A range of one-carbon coupling partners can be employed, thereby generating cyclopentenes which bear a fully substituted stereocenter [either all-carbon or heteroatom-substituted (sulfur and phosphorus)]. Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four carbon coupling partner is not the turnover-limiting step of the catalytic cycle. PMID- 25287685 TI - Quantitative radiology: applications to oncology. AB - Oncologists, clinician-scientists, and basic scientists collect computed tomography, magnetic resonance, and positron emission tomography images in the process of caring for patients, managing clinical trials, and investigating cancer biology. As we have developed more sophisticated means for noninvasively delineating and characterizing neoplasms, these image data have come to play a central role in oncology. In parallel, the increasing complexity and volume of these data have necessitated the development of quantitative methods for assessing tumor burden, and by proxy, disease-free survival. PMID- 25287687 TI - Recent advances in nanoparticle-based nuclear imaging of cancers. AB - Nuclear imaging techniques that include positron emission tomography (PET) and single-photon computed tomography have found great success in the clinic because of their inherent high sensitivity. Radionuclide imaging is the most popular form of imaging to be used for molecular imaging in oncology. While many types of molecules have been used for radionuclide-based molecular imaging, there has been a great interest in developing newer nanomaterials for use in clinic, especially for cancer diagnosis and treatment. Nanomaterials have unique physical properties which allow them to be used as imaging probes to locate and identify cancerous lesions. Over the past decade, a great number of nanoparticles have been developed for radionuclide imaging of cancer. This chapter reviews the different kinds of nanomaterials, both organic and inorganic, which are currently being researched for as potential agents for nuclear imaging of variety of cancers. Several radiolabeled multifunctional nanocarriers have been extremely successful for the detection of cancer in preclinical models. So far, significant progress has been achieved in nanoparticle structure design, in vitro/in vivo trafficking, and in vivo fate mapping by using PET. There is a great need for the development of newer nanoparticles, which improve active targeting and quantify new biomarkers for early disease detection and possible prevention of cancer. PMID- 25287688 TI - Molecular-genetic imaging of cancer. AB - Molecular-genetic imaging of cancer using nonviral delivery systems has great potential for clinical application as a safe, efficient, noninvasive tool for visualization of various cellular processes including detection of cancer, and its attendant metastases. In recent years, significant effort has been expended in overcoming technical hurdles to enable clinical adoption of molecular-genetic imaging. This chapter will provide an introduction to the components of molecular genetic imaging and recent advances on each component leading to safe, efficient clinical applications for detecting cancer. Combination with therapy, namely, generating molecular-genetic theranostic constructs, will provide further impetus for clinical translation of this promising technology. PMID- 25287690 TI - Cerenkov imaging. AB - Cerenkov luminescence (CL) has been used recently in a plethora of medical applications like imaging and therapy with clinically relevant medical isotopes. The range of medical isotopes used is fairly large and expanding. The generation of in vivo light is useful since it circumvents depth limitations for excitation light. Cerenkov luminescence imaging (CLI) is much cheaper in terms of infrastructure than positron emission tomography (PET) and is particularly useful for imaging of superficial structures. Imaging can basically be done using a sensitive camera optimized for low-light conditions, and it has a better resolution than any other nuclear imaging modality. CLI has been shown to effectively diagnose disease with regularly used PET isotope ((18)F-FDG) in clinical setting. Cerenkov luminescence tomography, Cerenkov luminescence endoscopy, and intraoperative Cerenkov imaging have also been explored with positive conclusions expanding the current range of applications. Cerenkov has also been used to improve PET imaging resolution since the source of both is the radioisotope being used. Smart imaging agents have been designed based on modulation of the Cerenkov signal using small molecules and nanoparticles giving better insight of the tumor biology. PMID- 25287686 TI - The intricate role of CXCR4 in cancer. AB - Chemokines mediate numerous physiological and pathological processes related primarily to cell homing and migration. The chemokine CXCL12, also known as stromal cell-derived factor-1, binds the G-protein-coupled receptor CXCR4, which, through multiple divergent pathways, leads to chemotaxis, enhanced intracellular calcium, cell adhesion, survival, proliferation, and gene transcription. CXCR4, initially discovered for its involvement in HIV entry and leukocytes trafficking, is overexpressed in more than 23 human cancers. Cancer cell CXCR4 overexpression contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. As such, CXCR4 is a target not only for therapeutic intervention but also for noninvasive monitoring of disease progression and therapeutic guidance. This review provides a comprehensive overview of the biological involvement of CXCR4 in human cancers, the current status of CXCR4 based therapeutic approaches, as well as recent advances in noninvasive imaging of CXCR4 expression. PMID- 25287689 TI - Real-time fluorescence image-guided oncologic surgery. AB - Medical imaging plays a critical role in cancer diagnosis and planning. Many of these patients rely on surgical intervention for curative outcomes. This requires a careful identification of the primary and microscopic tumors, and the complete removal of cancer. Although there have been efforts to adapt traditional-imaging modalities for intraoperative image guidance, they suffer from several constraints such as large hardware footprint, high-operation cost, and disruption of the surgical workflow. Because of the ease of image acquisition, relatively low-cost devices and intuitive operation, optical imaging methods have received tremendous interests for use in real-time image-guided surgery. To improve imaging depth under low interference by tissue autofluorescence, many of these applications utilize light in the near-infrared (NIR) wavelengths, which is invisible to human eyes. With the availability of a wide selection of tumor-avid contrast agents, advancements in imaging sensors, electronic and optical designs, surgeons are able to combine different attributes of NIR optical imaging techniques to improve treatment outcomes. The emergence of diverse commercial and experimental image guidance systems, which are in various stages of clinical translation, attests to the potential high impact of intraoperative optical imaging methods to improve speed of oncologic surgery with high accuracy and minimal margin positivity. PMID- 25287692 TI - Tracking cellular and immune therapies in cancer. AB - The field of tumor immunology has seen an explosion of renewed interest over the last decade. With the FDA approval of new immunotherapies for prostate cancer and melanoma, as well as several exciting new drugs in clinical trials, tumor immunology is becoming an increasingly important topic in preclinical studies and patient care. However, the current methods for assessing the immune status of a patient and tumor are limited, which has led to the development of novel molecular imaging methods for assessing tumor immunology. From cell tracking for cellular therapeutics to assessing the tumor immune microenvironment, these imaging methods have the potential to further preclinical understanding of immunotherapies and potentially translate into clinically useful tests to predict and assess therapeutic response of these exciting new agents. In this review, we first discuss the recent advances in cancer immunotherapy, followed by a detailed review of the current state of molecular imaging for tumor immunology. Finally, we discuss opportunities for further development and innovation in this rapidly growing field. PMID- 25287693 TI - Developing MR probes for molecular imaging. AB - Molecular imaging plays an important role in the era of personalized medicine, especially with recent advances in magnetic resonance (MR) probes. While the first generation of these probes focused on maximizing contrast enhancement, a second generation of probes has been developed to improve the accumulation within specific tissues or pathologies, and the newest generation of agents is also designed to report on changes in physiological status and has been termed "smart" agents. This represents a paradigm switch from the previously commercialized gadolinium and iron oxide probes to probes with new capabilities, and leads to new challenges as scanner hardware needs to be adapted for detecting these probes. In this chapter, we highlight the unique features for all five different categories of MR probes, including the emerging chemical exchange saturation transfer, (19)F, and hyperpolarized probes, and describe the key physical properties and features motivating their design. As part of this comparison, the strengths and weaknesses of each category are discussed. PMID- 25287691 TI - Molecular imaging of the tumor microenvironment for precision medicine and theranostics. AB - Morbidity and mortality from cancer and their associated conditions and treatments continue to extract a heavy social and economic global burden despite the transformative advances in science and technology in the twenty-first century. In fact, cancer incidence and mortality are expected to reach pandemic proportions by 2025, and costs of managing cancer will escalate to trillions of dollars. The inability to establish effective cancer treatments arises from the complexity of conditions that exist within tumors, the plasticity and adaptability of cancer cells coupled with their ability to escape immune surveillance, and the co-opted stromal cells and microenvironment that assist cancer cells in survival. Stromal cells, although destroyed together with cancer cells, have an ever-replenishing source that can assist in resurrecting tumors from any residual cancer cells that may survive treatment. The tumor microenvironment landscape is a continually changing landscape, with spatial and temporal heterogeneities that impact and influence cancer treatment outcome. Importantly, the changing landscape of the tumor microenvironment can be exploited for precision medicine and theranostics. Molecular and functional imaging can play important roles in shaping and selecting treatments to match this landscape. Our purpose in this review is to examine the roles of molecular and functional imaging, within the context of the tumor microenvironment, and the feasibility of their applications for precision medicine and theranostics in humans. PMID- 25287695 TI - Emerging applications of molecular imaging to oncology. Preface. PMID- 25287694 TI - Clinical translation of molecular imaging agents used in PET studies of cancer. AB - Over recent years, there has been a rapid expansion in our knowledge of the factors that regulate tumor growth; this has resulted in the identification of new therapeutic targets and improvements in the long-term survival of cancer patients. New noninvasive biomarkers of drug targets and pathway modulation in vivo are needed to guide therapy selection and detect drug resistance early so that alternative, more effective treatments can be offered. The translation of new therapeutics into the clinic is disappointingly slow, expensive, and subject to high rates of attrition often occurring at late stages (phase 3) of development. In an attempt to mitigate these delays and failures, there has been resurgence in the development of new molecular imaging probes for studies with positron emission tomography (PET) to characterize tumor biology. In the assessment of therapeutic effects, PET allows imaging of entire tumor burden in a noninvasive repeatable manner. This chapter focuses on the clinical translation of PET imaging agents from bench to bedside. New probes are being used to study a diverse range of processes such as angiogenesis, apoptosis, fatty acid metabolism, and growth factor receptor expression. In the future, validation of these novel imaging probes could allow more innovative therapies to be adapted earlier in the clinic leading to improved patient outcomes. PMID- 25287696 TI - Rapeseed and sunflower oilcake as supplements for dairy sheep: animal performance and milk fatty acid concentrations. AB - The influence of different amounts of oilseed cake (rapeseed and sunflower) on animal production parameters and fatty acid (FA) concentrations of the milk was studied in a Latxa dairy sheep experimental flock, both in winter (50% oilcakes; indoor feeding) and in spring (30% oilcakes; part-time grazing). The two different levels of the oilcakes tested did not affect animal production parameters or milk yield. Milk fat content and the fat/protein ratio decreased significantly with 30 and 50% sunflower cake. Yet, fat/protein ratio values were within the range for cheesemaking. Both levels of either type of oilcake tested significantly increased the concentrations of nutritionally interesting FA (CLA isomer C18:2cis-9, trans-11, vaccenic, oleic, and total unsaturated FA), while simultaneously decreasing the concentration of atherogenic FA. The atherogenicity indexes of milks from ewes fed 50 or 30% of either oilcake were significantly lower than those of their corresponding control. The use of cakes in winter increased the concentration of nutritionally interesting FA to the values obtained with part-time grazing. PMID- 25287698 TI - Data about (complementary and alternative) medicine are irrelevant, because we are all Bayesians. PMID- 25287699 TI - Resistant gram-positive infections: where have we been, where are we now, and where are we going? PMID- 25287700 TI - Examination of the role of the combination of alcohol and cannabis in South Australian road crashes. AB - OBJECTIVES: The aim of the present study was to examine the role of cannabis in road crashes in South Australia, with a particular focus on the extent to which crashes involving cannabis also involve alcohol. METHODS: Hospital data, police reported crash data, and the results of forensic tests of blood samples for drugs and alcohol were collected for 1,074 crash participants (drivers or motorcyclists) admitted to hospital. A sample of 135 coroners' reports was also examined to determine the role of alcohol and cannabis in fatal crashes. RESULTS: The 3 years of linked data for hospital admission cases revealed that alcohol played a greater role in road crashes than other drugs. Approximately 1 in 5 drivers or motorcyclists had a blood alcohol concentration (BAC) above the legal limit of 0.05. Routine testing for cannabis, methamphetamine, and MDMA revealed a drug-positive rate of approximately 1 in 10 of those tested, with over half of these positive to cannabis. More than a third of cannabis cases also involved alcohol. The majority of those who were positive for alcohol had a BAC above 0.15 g/100 mL. BACs were similarly high among drivers positive for both alcohol and cannabis. CONCLUSIONS: The findings of the hospital data and the coroners' reports were consistent with each other in terms of providing confirmation that alcohol is still the drug associated with the greatest level of road trauma on South Australian roads. Furthermore, alcohol was also present in around half of the cannabis cases and, when present, tended to be present at very high levels. The results of this study emphasize that, although drug driving is clearly a problem, the most important form of impaired driving that needs to be the target of enforcement is drink driving. Roadside drug testing is important but should not be conducted in such a way that reduces the deterrent value of random breath testing. PMID- 25287701 TI - Negative pressure wound therapy for skin grafts and surgical wounds healing by primary intention. AB - BACKGROUND: Indications for the use of negative pressure wound therapy (NPWT) are broadening with a range of systems now available on the market, including those designed for use on clean, closed incisions and skin grafts. Reviews have concluded that the evidence for the effectiveness of NPWT remains uncertain, however, it is a rapidly evolving therapy. Consequently, an updated systematic review of the evidence for the effects of NPWT on postoperative wounds expected to heal by primary intention is required. OBJECTIVES: To assess the effects of NPWT on surgical wounds (primary closure, skin grafting or flap closure) that are expected to heal by primary intention. SEARCH METHODS: We searched the following electronic databases to identify reports of relevant randomised clinical trials: the Cochrane Wounds Group Specialised Register (searched 28 January 2014); the Cochrane Central Register of Controlled Trials (CENTRAL; 2013, issue 12); Database of Abstracts of Reviews of Effects (2013, issue 12); Ovid MEDLINE (2011 to January 2014); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 24 January 2014); Ovid EMBASE (2011 to January 2014 Week 44); and EBSCO CINAHL (2011 to January 2014). We conducted a separate search to identify economic evaluations. SELECTION CRITERIA: We included trials if they allocated patients to treatment randomly and compared NPWT with any other type of wound dressing, or compared one type of NPWT with a different type of NPWT. DATA COLLECTION AND ANALYSIS: We assessed trials for their appropriateness for inclusion and for their quality. This was done by three review authors working independently, using pre-determined inclusion and quality criteria. MAIN RESULTS: In this first update, we included an additional four trials, taking the total number of trials included to nine (785 participants). Three trials involved skin grafts, four included orthopaedic patients and two included general surgery and trauma surgery patients; all the included trials had unclear or high risk of bias for one or more of the quality indicators we assessed. Seven trials compared NPWT with a standard dressing (two of these were 'home-made' NPWT devices), one trial compared one 'home-made' NPWT with a commercially available device. In trials where the individual was the unit of randomisation, there were no differences in the incidence of surgical site infections (SSI); wound dehiscence, re-operation (in incisional wounds); seroma/haematoma; or failed skin grafts. Lower re operation rates were observed among skin graft patients in the 'home-made' NPWT group (7/65; 10.8%) compared to the standard dressing group (17/66; 25.8%) (risk ratio (RR) 0.42; 95% CI 0.19 to 0.92). The mean cost to supply equipment for VAC(r) therapy was USD 96.51/day compared to USD 4.22/day for one of the 'home made' devices (P value 0.01); labour costs for dressing changes were similar for both treatments. Pain intensity score was also reported to be lower in the 'home made' group when compared with the VAC(r) group (P value 0.02). One of the trials in orthopaedic patients was stopped early because of a high incidence of fracture blisters in the NPWT group (15/24; 62.5%) compared with the standard dressing group (3/36; 8.3%) (RR 7.50; 95% CI 2.43 to 23.14). AUTHORS' CONCLUSIONS: Evidence for the effects of negative pressure wound therapy (NPWT) for reducing SSI and wound dehiscence remains unclear, as does the effect of NPWT on time to complete healing. Rates of graft loss may be lower when NPWT is used, but hospital-designed and built products are as effective in this area as commercial applications. There are clear cost benefits when non-commercial systems are used to create the negative pressure required for wound therapy, with no evidence of a negative effect on clinical outcome. In one study, pain levels were also rated lower when a 'home-made' system was compared with a commercial counterpart. The high incidence of blisters occurring when NPWT is used following orthopaedic surgery suggests that the therapy should be limited until safety in this population is established. Given the cost and widespread use of NPWT, there is an urgent need for suitably powered, high-quality trials to evaluate the effects of the newer NPWT products that are designed for use on clean, closed surgical incisions. Such trials should focus initially on wounds that may be difficult to heal, such as sternal wounds or incisions on obese patients. PMID- 25287697 TI - Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy. AB - INTRODUCTION: Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. METHODS: Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. RESULTS: 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p<0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p<0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p<0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02-229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03-2.06), with no differences in major bleeding rate. CONCLUSION: Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations. PMID- 25287702 TI - Application of Intravascular Ultrasound in the Emergency Diagnosis and Treatment of Patients with ST-Segment Elevation Myocardial Infarction. AB - PURPOSE: This study aimed to examine the application of intravascular ultrasound (IVUS) in ST-segment elevation myocardial infarction (STEMI) patients with high thrombus burden (thrombus grade >=3) undergoing emergency diagnosis and primary percutaneous coronary intervention. METHODS: Eighty STEMI patients were enrolled and randomly assigned to the IVUS-guided group (38 patients) or non-IVUS group (42 patients). Stent implantation was performed in non-IVUS group patients. IVUS group patients were further divided into low-risk and high-risk patients on the basis of IVUS evaluation for determining whether stenting should be performed. Major adverse cardiac event (MACE) rates, changes in the left ventricular end diastolic diameter (LVEDD) and ejection fraction (EF) values, and stent numbers were examined during hospitalization, and follow-up was performed at 1, 3, 6, and 12 months postoperatively. RESULTS: During hospitalization, there were no significant differences in the MACE rates, LVEDD, and EF values and in the follow up outcomes at 1, 3, 6, and 12 months postoperatively among the patients in the 2 groups (P > 0.05). A significantly lower number of stents were implanted in the IVUS group than in the non-IVUS group patients (P < 0.05). CONCLUSION: During the IVUS-guided emergency intervention, enhanced antithrombotic therapy and best medical care for low-risk STEMI patients may be feasible. PMID- 25287703 TI - Racial disparities across provider specialties in opioid prescriptions dispensed to medicaid beneficiaries with chronic noncancer pain. AB - OBJECTIVE: Chronic pain affects both psychological and physical functioning, and is responsible for more than $60 billion in lost productivity annually in the United States. Although previous studies have demonstrated racial disparities in opioid treatment, there is little evidence regarding disparities in treatment of chronic noncancer pain (CNCP) and the role played by physician specialty in these disparities. DESIGN: A retrospective cohort study. SETTING: We analyzed North Carolina Medicaid claims data, from July 1, 2009 to May 31, 2010, to examine disparities by different provider specialties in beneficiaries' dispensed prescriptions for opioids. SUBJECTS: The population included white and black North Carolina Medicaid beneficiaries with CNCP (N = 75,458). METHODS: We used bivariate statistics and logistic regression analysis to examine race-based discrepancies in opioid prescribing by physician specialty. RESULTS: Compared with white beneficiaries with CNCP (N = 49,197), black beneficiaries (N = 26,261) were less likely (odds ratio [OR] 0.91 [confidence interval {CI}: 0.88-0.94]) to fill an opioid prescription. Our hypothesis was partially supported: we found that race-based differences in beneficiaries' dispensed opioid prescriptions were more prominent in certain specialties. In particular, these differences were most salient among patients of specialists in obstetrics and gynecology (OR 0.78 [CI: 0.67-0.89]) and internal medicine (OR 0.86 [CI: 0.79-0.92]), as well as general practitioners/family medicine physicians (OR 0.91 [CI: 0.85-0.97]). CONCLUSIONS: Our findings suggest that, in our study population, black beneficiaries with CNCP are less likely than whites to fill prescriptions for opioid analgesics as a function of their provider's specialty. Although race-based differences in patients filling opioid prescriptions have been noted in previous studies, this is the first study that clearly demonstrates these disparities by provider specialty. PMID- 25287704 TI - A beta1-6/beta1-3 galactosidase from Bifidobacterium animalis subsp. lactis Bl-04 gives insight into sub-specificities of beta-galactoside catabolism within Bifidobacterium. AB - The Bifidobacterium genus harbours several health promoting members of the gut microbiota. Bifidobacteria display metabolic specialization by preferentially utilizing dietary or host-derived beta-galactosides. This study investigates the biochemistry and structure of a glycoside hydrolase family 42 (GH42) beta galactosidase from the probiotic Bifidobacterium animalis subsp. lactis Bl-04 (BlGal42A). BlGal42A displays a preference for undecorated beta1-6 and beta1-3 linked galactosides and populates a phylogenetic cluster with close bifidobacterial homologues implicated in the utilization of N-acetyl substituted beta1-3 galactosides from human milk and mucin. A long loop containing an invariant tryptophan in GH42, proposed to bind substrate at subsite + 1, is identified here as specificity signature within this clade of bifidobacterial enzymes. Galactose binding at the subsite - 1 of the active site induced conformational changes resulting in an extra polar interaction and the ordering of a flexible loop that narrows the active site. The amino acid sequence of this loop provides an additional specificity signature within this GH42 clade. The phylogenetic relatedness of enzymes targeting beta1-6 and beta1-3 galactosides likely reflects structural differences between these substrates and beta1-4 galactosides, containing an axial galactosidic bond. These data advance our molecular understanding of the evolution of sub-specificities that support metabolic specialization in the gut niche. PMID- 25287705 TI - Surgery for thoracic aortic disease in Japan: evolving strategies toward the growing enemies. AB - Recent advances in surgery for thoracic aorta have been described, including data by the annual survey of the Japanese Association for Thoracic Surgery. Current clinical problems in aortic root surgery, brain protection during aortic arch surgery, spinal cord protection during thoracoabdominal aortic surgery, acute aortic dissection and endovascular stenting have been discussed. PMID- 25287706 TI - Antioxidant N-acetyl-L-cysteine increases engraftment of human hematopoietic stem cells in immune-deficient mice. AB - Immunocompromised mice, such as the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, have been widely used to examine the self renewal and differentiation potential of human hematopoietic stem cells (HSCs) in vivo. However, the efficiency of human HSC engraftment remains very low. Here, we report that NOD/SCID mice had higher levels of reactive oxygen species (ROS) in their bone marrow (BM) than other commonly used mouse strains (C57BL/6 and BALB/C). Treatment with the antioxidant N-acetyl-l-cysteine (NAC) decreased ROS levels in the BM of NOD/SCID mice. Furthermore, the NAC-treated mice displayed a significant increase in human HSC engraftment and multilineage hematopoietic differentiation in the mice. In comparison with the control mice, NAC-treated recipients displayed a 10.8-fold increase in hematopoietic engraftment in the injected tibiae. A beneficial effect of NAC for human hematopoietic engraftment was also observed in an additional immunodeficient mouse strain, namely NOD.Cg Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NOD/SCID/gammac(-/-) or NSG). Thus, this study uncovers a previously unappreciated negative effect of ROS on human stem cell engraftment in immunodeficient mice. PMID- 25287707 TI - Update on the use of hydroxyurea therapy in sickle cell disease. PMID- 25287709 TI - The TAK1-NF-kappaB axis as therapeutic target for AML. AB - Development and maintenance of leukemia can be partially attributed to alterations in (anti)-apoptotic gene expression. Genome-wide transcriptome analyses revealed that 89 apoptosis-associated genes were differentially expressed between patient acute myeloid leukemia (AML) CD34(+) cells and normal bone marrow (NBM) CD34(+) cells. Among these, transforming growth factor-beta activated kinase 1 (TAK1) was strongly upregulated in AML CD34(+) cells. Genetic downmodulation or pharmacologic inhibition of TAK1 activity strongly impaired primary AML cell survival and cobblestone formation in stromal cocultures. TAK1 inhibition was mainly due to blockade of the nuclear factor kappaB (NF-kappaB) pathway, as TAK1 inhibition resulted in reduced levels of P-IkappaBalpha and p65 activity. Overexpression of a constitutive active variant of NF-kappaB partially rescued TAK1-depleted cells from apoptosis. Importantly, NBM CD34(+) cells were less sensitive to TAK1 inhibition compared with AML CD34(+) cells. Knockdown of TAK1 also severely impaired leukemia development in vivo and prolonged overall survival in a humanized xenograft mouse model. In conclusion, our results indicate that TAK1 is frequently overexpressed in AML CD34(+) cells, and that TAK1 inhibition efficiently targets leukemic stem/progenitor cells in an NF kappaB-dependent manner. PMID- 25287710 TI - Douglas L. Coleman, 1931-2014. PMID- 25287708 TI - The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation. AB - Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells for patients without HLA-matched adult donors. UCB contains a low number of nucleated cells and mostly naive T cells, resulting in prolonged time to engraftment and lack of transferred T-cell memory. Although the first phase of T cell reconstitution after UCB transplantation (UCBT) depends on peripheral expansion of transferred T cells, permanent T-cell reconstitution is mediated via a central mechanism, which depends on de novo production of naive T lymphocytes by the recipient's thymus from donor-derived lymphoid-myeloid progenitors (LMPs). Thymopoiesis can be assessed by quantification of recent thymic emigrants, T-cell receptor excision circle levels, and T-cell receptor repertoire diversity. These assays are valuable tools for monitoring posttransplantation thymic recovery, but more importantly they have shown the significant prognostic value of thymic reconstitution for clinical outcomes after UCBT, including opportunistic infections, disease relapse, and overall survival. Strategies to improve thymic entry and differentiation of LMPs and to accelerate recovery of the thymic stromal microenvironment may improve thymic lymphopoiesis. Here, we discuss the mechanisms and clinical implications of thymic recovery and new approaches to improve reconstitution of the T-cell repertoire after UCBT. PMID- 25287711 TI - SLC30A8 mutations in type 2 diabetes. AB - SLC30A8 encodes the secretory granule-resident and largely endocrine pancreas restricted zinc transporter ZnT8. Interest in this gene product was sparked amongst diabetologists in 2007 when the first genome-wide association study for type 2 diabetes identified polymorphisms in SLC30A8 as affecting disease risk. Thus, the common polymorphism rs13266634 was associated with lowered beta cell function and a 14% increase in diabetes abundance per risk (C) allele. This non synonymous variant encodes a tryptophan-to-arginine switch at position 325 in the protein's intracellular carboxy-terminal domain, resulting in reduced zinc transport activity and, consequently, decreased intragranular zinc levels. Whereas insulin secretion from isolated islets is most often increased in mice inactivated for Slc30a8, null animals usually show impaired glucose tolerance and lowered circulating insulin. Since Slc30a8 null animals display little, if any, zinc secretion from islets, the lower plasma insulin levels could be explained by increased hepatic clearance as a result of lowered local zinc levels, or less efficient insulin action on target tissues. Despite the emerging consensus on the role of ZnT8 in glucose homeostasis, a recent genetic study in humans has unexpectedly identified loss-of-function SLC30A8 mutants that are associated with protection from diabetes. Here, we attempt to reconcile these apparently contradictory findings, implicating (1) differing degrees of inhibition of ZnT8 activity in carriers of common variants vs rare loss-of-function forms, (2) effects dependent on age or hypoxic beta cell stress. We propose that these variables conspire to affect both the size and the direction of the effect of SLC30A8 risk alleles in man. PMID- 25287712 TI - Metabolic response to 36 hours of fasting in young men born small vs appropriate for gestational age. AB - AIMS/HYPOTHESIS: Being born small for gestational age (SGA) is associated with an increased risk of type 2 diabetes in an affluent society, but could confer an improved chance of survival during sparse living conditions. We studied whether insulin action and other metabolic responses to prolonged fasting differed between 21 young adults born SGA and 18 matched controls born appropriate for gestational age (AGA). METHODS: A frequently sampled IVGTT and indirect calorimetry measurements were performed after a 36 h fast. Endogenous glucose production, insulin sensitivity (SI), first-phase insulin secretion and glucose effectiveness were estimated by stable isotope tracer techniques and minimal modelling. Muscle and fat biopsies were obtained after 35 h of fasting. RESULTS: During fasting, SGA individuals experienced a more pronounced decrease in serum insulin and lower plasma triacylglycerol levels compared with AGA individuals. In addition, energy expenditure decreased in SGA but increased in AGA individuals. After fasting, SGA individuals displayed lower fat oxidation than AGA individuals. SG was reduced in SGA compared with AGA individuals, whereas hepatic or whole body insulin action (SI) did not differ between groups. SGA individuals had increased muscle PPARGC1A DNA methylation. We found no differences in adipose tissue PPARGC1A DNA methylation, muscle and adipose tissue PPARGC1A mRNA expression, or muscle glycogen levels between the groups. CONCLUSION: Compared with AGA individuals, SGA individuals displayed a more energy-conserving and potentially beneficial [corrected] cardiometabolic response to 36 h fasting. The role of increased muscle PPARGC1A DNA methylation in mediating this response requires further study. PMID- 25287713 TI - Thelohanellus wangi n. sp. (Myxozoa, Myxosporea), a new gill parasite of allogynogenetic gibel carp (Carassius auratus gibelio Bloch) in China, causing severe gill myxosporidiosis. AB - We describe here a new myxozoan, Thelohanellus wangi n. sp., infecting the allogynogenetic gibel carp, Carassius auratus gibelio (Bloch), in a fry nursery farm in Jiangsu Province, China. Polysporous gray white round or ovoid plasmodia, 500-1,500 MUm in size, were found exclusively in the gill filaments. The diagnostic characteristics of the myxospores are as follows: spore melon seed shaped in frontal view with smooth surface and asymmetrical valves; convex-shaped in sutural view with straight or slightly bent and thick sutural line, averaging 20.2 (16.5-22.3) * 9.9 (9.1-10.8) * 9.3 MUm (8.2-10.4) in size; and one elliptical polar capsules with subulate anterior end and round posterior end, averaging 10.1 (8.4-11.2) * 6.5 MUm (6.1-7.0) in size. Polar filaments coil six to seven turns and are slightly oblique to the longitudinal axis of the polar capsule. An elongate melon seed-shaped mucus envelope surrounds almost completely the spore, but with largest distance in posterior end between spore valve and mucus envelope. Granular sporoplasm contains two slightly oval nuclei, and no iodinophilous vacuole is observed. Histopathological analysis showed that the plasmodia embedded in the gill filaments and occasionally extended into the connective tissue of the gill arch. No significant inflammatory responses were provoked by the infection. The development of parasite is asynchronous, with mature spores centrally locating and trophozoites and pre-sporogonic stages peripherally locating within the plasmodia. Overall prevalence was 74% (37/50). Infection intensity was usually high, with about 10-30 cysts per fish. Phylogenetical analysis shows that T. wangi n. sp. is most closely related to several Thelohanellus species infecting cyprinid fish and formed a Thelohanellus clade based on the ribosomal DNA data. The cysts of this myxosporean were only found from fry seed with body length below 7 cm, generally from late April to early June when the fry fish of allogynogenetic gibel carp were nursed in the epizootic areas. PMID- 25287714 TI - Abnormal liver function in different patients with Schistosoma japonicum. AB - Schistosomiasis japonica, caused by Schistosoma japonicum, is still a serious public health problem in China. It is important for schistosomiasis control to prevent from infection and advanced patients. Recent years, however, the form of the prevalence of schistosomiasis japonica in China was changed these days. Paying attention to the quality of life of these patients already infected with S. japonicum becomes a new objective to schistosomiasis control program. Although most of the chronic infections with S. japonicum will finally appear as liver fibrosis symptoms, it is still unknown liver function abnormalities in patients with severe forms of schistosomiasis, and there is also no evidence whether S. japonicum infection will directly cause damage to liver cells. Thus, this study investigated 494 patients diagnosed with S. japonicum (87.7%) and 69 healthy subjects from a endemic areas belonging to Jiangxi Province of China and aimed to evaluate the liver function abnormalities in patients with severe forms of schistosomiasis and possible associations with coinfection with HBV. The results showed that the hepatic metabolism situation significantly changed in patients infected with S. japonicum; meanwhile, the abnormal rates of ALT and AST in patients with schistosomiasis were significantly higher than that in the control group, which confirmed that patients infected with S. japonicum not only had damaged liver function but also the hepatic cells were directly influenced. And the coinfection of CHB and schistosomiasis japonica can be a risk factor for more serious outcomes in patients from endemic areas. These results give us the advice that in the further treatment of patients infected with S. japonicum, especially these coinfections, we should better give the routine liver-protection treatment in advance. PMID- 25287715 TI - Impact of alcohol consumption on survival in patients with esophageal carcinoma: a large cohort with long-term follow-up. AB - Alcohol is a well-established cause of esophageal carcinoma, but its effect on survival is little known and contradictory. To clarify whether drinking is an independent predictor of survival in esophageal carcinoma, 2151 Chinese patients, receiving surgical resection from January 1997 to December 2008, were followed until March 2014. Cox proportional hazards analysis was applied to evaluate the prognostic effect of alcohol consumption. The median follow-up was 64 months. The median overall survival (OS; 42 months) and disease-free survival (DFS; 33 months) for never-drinkers were significantly higher than ever-drinkers (27 and 22 months, respectively). In the multivariate Cox model that was adjusted for age, weight loss, stage according to criteria set by the American Joint Committee on Cancer, radicality of surgery, adjuvant treatment, smoking status, and gender, the hazard ratios of ever-drinking were 1.22 (1.06-1.41, P = 0.005) on OS, and 1.16 (1.01-1.34, P = 0.037) on DFS. The hazardous effect on OS and DFS of drinking grew statistically significantly in a dose-dependent manner with increasing amount of alcohol consumption per day (both P-value for trend < 0.05). The predictive effect of drinking on OS (P = 0.596) or DFS (P = 0.207) was not significant in the subgroup with esophageal adenocarcinoma (n = 195). The current study revealed that the survival is shortened, of those patients who consume alcohol before diagnosis of esophageal squamous cell carcinoma, which are not attributable to differences in stage, smoking status, and gender. Alcohol control should be emphasized to reduce mortality of esophageal carcinoma, and further outcome studies should include alcohol as a potential prognosticator. PMID- 25287716 TI - miR-150 modulates cisplatin chemosensitivity and invasiveness of muscle-invasive bladder cancer cells via targeting PDCD4 in vitro. AB - BACKGROUND: Chemotherapeutic insensitivity and tumor cell invasiveness are major obstacles to effectively treating muscle-invasive bladder cancer (MIBC). Recent reports show that microRNAs (miRNAs) play an important role in the chemotherapeutic response and disease progression of MIBC. Therefore, here we investigated the role of miR-150 in MIBC cells in vitro. MATERIAL AND METHODS: miR-150 expression was quantified by qRT-PCR in two MIBC cell lines (5637 and T24). After successful miR-150 inhibition by transfection, MTS and transwell assays were used to assess the MIBC's cisplatin sensitivity and cell invasiveness, respectively. The TargetScan database and a luciferase reporter system were used to identify whether the programmed cell death 4 protein (PDCD4) is a direct target of miR-150 in MIBC cells. RESULTS: miR-150 expression was found to be significantly increased in both MIBC cell lines, and treatment with a miR-150 inhibitor significantly sensitized MIBC cells to cisplatin and inhibited MIBC cell invasiveness. PDCD4 was identified as a direct target of miR-150 in MIBC cells, and increased PDCD4 expression via transfection with the pLEX-PDCD4 plasmid efficiently sensitized MIBC cells to cisplatin chemotherapy and inhibited MIBC cell invasiveness. CONCLUSIONS: This study provides novel evidence that miR 150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via targeting PDCD4. Thus, modulation of the miR-150 PDCD4 axis shows promise as a therapeutic strategy for MIBC. PMID- 25287717 TI - High prevalence of HIV infection and unprotected anal intercourse among older men who have sex with men in China: a systematic review and meta-analysis. AB - BACKGROUND: China has the largest number of the elderly in the world. As the proportion of elderly is rapidly increasing among national reported HIV/AIDS cases, it is a concern about HIV epidemic among older MSM in China. However, studies on HIV prevalence and unprotected anal intercourse (UAI) among Chinese older MSM were relatively few or generally had small sample sizes. METHODS: English and Chinese articles published in peer-reviewed journals were identified by systematically searching 5 electronic databases including PubMed and through cross-referencing. Summary prevalence rates of HIV infection and UAI with male sexual partners were calculated, and analyses were performed using the software Comprehensive Meta-Analysis V2.0 and SPSS V17.0. Subgroup analyses were performed separately by sample size, study year, study location, recruitment settings and sampling method. RESULTS: Twenty eligible cross-sectional studies (3 in English and 17 in Chinese), published between 2005 and 2013, with a total of 2812 older MSM participants, were identified. Our meta-analyses showed that the prevalence of HIV, syphilis and UAI in the last 6 months were 11.6% (95% confidence interval [CI]: 8.0%-16.6%), 23.0% (95% CI: 15.8%-32.3%) and 79.5% (95% CI: 72.7%-84.9%), respectively. HIV prevalence increased over the study period (6.3% in 2003-2007; 8.6% in 2008-2009, and 11.5% in 2010-2011, trend test Chi-square = 7.02, p = 0.008). The pooled prevalence of HIV (11.6% vs. 5.2%, Chi-square value = 36.2, p < 0.001) and UAI (79.5% vs. 52.6%, Chi-square value = 440.04, p < 0.001) among older MSM were both significantly higher than among younger age group (age < 50 years). CONCLUSIONS: Older Chinese MSM have high prevalence of HIV and syphilis. Unprotected anal sex is common and further puts them at high risks of acquiring and transmitting HIV, which was one of reasons for the rapid increasing of national reported older male HIV/AIDS cases. Prevention intervention programs should be specially tailored for this high risk MSM subgroup. PMID- 25287718 TI - Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets. AB - Ebolaviruses are highly lethal filoviruses that cause hemorrhagic fever in humans and nonhuman primates. With no approved treatments or preventatives, the development of an anti-ebolavirus therapy to protect against natural infections and potential weaponization is an urgent global health need. Here, we describe the design, biophysical characterization, and validation of peptide mimics of the ebolavirus N-trimer, a highly conserved region of the GP2 fusion protein, to be used as targets to develop broad-spectrum inhibitors of ebolavirus entry. The N trimer region of GP2 is 90% identical across all ebolavirus species and forms a critical part of the prehairpin intermediate that is exposed during viral entry. Specifically, we fused designed coiled coils to the N-trimer to present it as a soluble trimeric coiled coil as it appears during membrane fusion. Circular dichroism, sedimentation equilibrium, and X-ray crystallography analyses reveal the helical, trimeric structure of the designed N-trimer mimic targets. Surface plasmon resonance studies validate that the N-trimer mimic binds its native ligand, the C-peptide region of GP2. The longest N-trimer mimic also inhibits virus entry, thereby confirming binding of the C-peptide region during viral entry and the presence of a vulnerable prehairpin intermediate. Using phage display as a model system, we validate the suitability of the N-trimer mimics as drug screening targets. Finally, we describe the foundational work to use the N trimer mimics as targets in mirror-image phage display, which will be used to identify D-peptide inhibitors of ebolavirus entry. PMID- 25287719 TI - Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid. AB - BACKGROUND: Severe Alpha-1 Antitrypsin (AAT) deficiency is a hereditary condition caused by mutations in the SERPINA1 gene, which predisposes to lung emphysema and liver disease. It is usually related to PI*Z alleles, and less frequent to rare and null (QO) alleles. Null-AAT alleles represent the end of a continuum of variants associated with profound AAT deficiency and extremely increased risk of emphysema. METHODS: A family with severe AAT deficiency was analyzed to achieve genetic diagnosis. The complete exons and introns of the SERPINA1 gene were sequenced and transcriptional analysis by RT-PCR was performed to characterize the effect of splicing variants found in the patients. In addition, a minigene MGserpa1_ex1b-1c was cloned into the pSAD vector to in vitro investigate the independent impact of variants on splicing process. RESULTS: We report a new identified null allele (PI*QOMadrid) in two adult siblings with practically no detectable serum AAT. The PI*QOMadrid allele consist of a duplication of the thymine (T) in position +2 of the donor splice site of exon 1C (+2dupT). In these two subjects, PI*QOMadrid occurred in compound heterozygote combination with the previously described variant PI*QOPorto. Both QOMadrid and QOPorto variants are located very close together in a regulatory region of the SERPINA1 gene. Analysis of transcripts revealed that QOMadrid variant prevented the expression of transcripts from exon 1C, and then normally spliced RNA products are not expected in the liver of these patients. In addition, aberrant splicing patterns of both variants were clearly distinguished and quantified by functional in vitro assays lending further support to their pathogenicity. CONCLUSION: Finding pathogenic mutations in non-coding regions of the SERPINA1 highlight the importance that regulatory regions might have in the disease. Regulatory regions should be seriously considered in discordant cases with severe AAT deficiency where no coding mutations were found. PMID- 25287720 TI - Journeys of adjustment: the experiences of adolescents living with juvenile idiopathic arthritis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is one of the most common diseases of childhood causing pain, swelling of joints and reduced mobility. Previous research has focused on the challenges and psychosocial impact of JIA, but there has been limited attention given to how young people adjust and adapt to living with a long-term condition such as JIA. The aim of this qualitative study was therefore to explore adolescents' experiences of living with JIA, with particular focus on the process of adjustment. METHODS: Ten adolescents (7 female, 3 male) aged 13-17 years with good treatment adherence were recruited from an adolescent arthritis clinic. In-depth interviews were conducted, and data were analysed by two researchers independently using interpretative phenomenological analysis. RESULTS: These adolescents described the physical and psychosocial 'burden of living with JIA' and the challenges faced by an underlying preoccupation 'to be a normal teenager'. However, their accounts also revealed ways in which they regained agency and developed 'resilience through taking control' over their lives. This resilience helped the adolescents re establish a sense of well-being through an ongoing process of 'acceptance and self-growth'. CONCLUSIONS: Although much research has adopted a deficit model that focuses on adjustment problems, the current study highlights the resourcefulness of young people in managing the challenges of living with a long term condition. These experiences of successful adjustment can be used as the basis of positive, strength-based intervention approaches for adolescents with arthritis to enhance resilience and well-being. PMID- 25287721 TI - Leishmaniasis in travelers: a literature review. AB - Leishmaniasis is a vector-borne protozoan infection whose clinical spectrum ranges from asymptomatic infection to fatal visceral leishmaniasis. Over the last decades, an increase in imported leishmaniasis cases in developed, non-endemic countries, have been pointed-out from a review of the international literature. Among the possible causes are increasing international tourism, influx of immigrants from endemic regions and military operations. The main area for the acquisition of cutaneous leishmaniasis, especially for adventure travelers on long-term trips in highly-endemic forested areas, is represented from South America, whereas popular Mediterranean destinations are emerging as the main areas to acquire visceral variant. Leishmaniasis should be considered in the diagnostic assessment of patients presenting with a compatible clinical syndrome and a history of travel to an endemic area, even if this occurred several months or years before. Adventure travelers, researchers, military personnel, and other groups of travelers likely to be exposed to sand flies in endemic areas, should receive counseling regarding leishmaniasis and appropriate protective measures. PMID- 25287722 TI - Fascioliasis: a worldwide parasitic disease of importance in travel medicine. AB - Fascioliasis is a foodborne zoonotic disease caused by the two parasite species Fasciola hepatica and Fasciola gigantica. This trematodiasis has never been claimed special relevance for travellers and migrants. However, the situation has drastically changed in the last two decades, in a way that fascioliasis should today be included in the list of diseases to be enhanced in Travel Medicine. Different kind of travellers have been involved in human infection reports: business travellers, tourists, migrants, expatriated workers, military personnel, religious missionaries, and refugees. Europe is the continent where more imported cases have been reported in many countries. More cases would have been probably reported in Europe if fascioliasis would be a reportable disease. In the Americas, most of the reports concern cases diagnosed in USA. Relative few patients have been diagnosed in studies on travellers performed in Asia. In Africa, most cases were reported in Maghreb countries. Blood eosinophilia and the ingestion of watercress or any other suggestive freshwater plant in anamnesis are extremely useful in guiding towards a fascioliasis diagnosis in a developed country, although may not be so in human endemic areas of developing countries. Several suggestive clinical presentation aspects may be useful, although the clinical polymorphism may be misleading in many cases. Non-invasive techniques are helpful for the diagnosis, although images may lead to confusion. Laparoscopic visualization should assist and facilitate procurement of an accurately guided biopsy. Endoscopic retrograde cholangiopancreatography (ERCP) is the first choice in patients in the chronic phase. ERCP and sphincterotomy are used to extract parasites from the biliary tree. Fluke egg finding continues to be the gold standard and enables for burden quantification and establishing of the drug dose. Many serological and stool antigen detection tests have been developed. Immunological techniques present the advantages of being applicable during all periods of the disease, but fundamentally during the invasive or acute period, as well as to other situations in which coprological techniques may present problems. Triclabendazole is the drug of choice at present, although the spread of resistance to this drug is challenging. Prevention mainly concerns measures to avoid individual infection by considering the different human infection sources. PMID- 25287723 TI - Parental motivation to change body weight in young overweight children. AB - OBJECTIVE: To determine what factors are associated with parental motivation to change body weight in overweight children. DESIGN: Cross-sectional study. SETTING: Dunedin, New Zealand. SUBJECTS: Two hundred and seventy-one children aged 4-8 years, recruited in primary and secondary care, were identified as overweight (BMI >= 85th percentile) after screening. Parents completed questionnaires on demographics; motivation to improve diet, physical activity and weight; perception and concern about weight; parenting; and social desirability, prior to being informed that their child was overweight. Additional measures of physical activity (accelerometry), dietary intake and child behaviour (questionnaire) were obtained after feedback. RESULTS: Although all children were overweight, only 42% of parents perceived their child to be so, with 36% indicating any concern. Very few parents (n 25, 8%) were actively trying to change the child's weight. Greater motivation to change weight was observed for girls compared with boys (P = 0.001), despite no sex difference in BMI Z-score (P = 0.374). Motivation was not associated with most demographic variables, social desirability, dietary intake, parenting or child behaviour. Increased motivation to change the child's weight was observed for heavier children (P < 0.001), those who were less physically active (P = 0.002) and more sedentary (P < 0.001), and in parents who were more concerned about their child's weight (P < 0.001) or who used greater food restriction (P < 0.001). CONCLUSIONS: Low levels of parental motivation to change overweight in young children highlight the urgent need to determine how best to improve motivation to initiate change. PMID- 25287724 TI - The fertility of the hybrid lineage derived from female Megalobrama amblycephala * male Culter alburnus. AB - Distant hybridization can combine together the genomes of different species, which leads to changes of the offspring in phenotypes and genotypes. In this study, we successfully establish a fertile hybrid lineage by intergeneric hybridization of female blunt snout bream (BSB, Megalobrama amblycephala) * male topmouth culter (TC, Culter alburnus) and investigate some important biological traits of this lineage including the morphological traits, chromosomal number, karyotype, DNA content, gonadal development, egg and milt yield, sperm shape and density, fertilization rate and early survival rate. The results show that: (1) the diploid and triploid hybrids coexist in F1 and only diploid hybrids are found in F2, in which the diploid hybrids of F1 and F2 possess 48 chromosomes with one chromosome set of BSB and one chromosome set of TC, and the triploid hybrids of F1 possess 72 chromosomes with two chromosome sets of BSB and one chromosome set of TC. (2) All the tested males and females of the diploid F1 and F2 hybrids have the normal gonadal development and produce mature sperm and egg, respectively, which are fertilized with each other to form F2 and F3 hybrids, respectively, and finally form a diploid hybrid lineage (F1-F3). (3) The good fertility of the F1 and F2 hybrids of female BSB * male TC potentially provides reproductive base to make the hybrid lineage propagate from one generation to another. The formation of the hybrid lineage (F1-F3) also provides an ideal model to research the reproductive rules of distant hybrid progeny. PMID- 25287726 TI - Aspects of metabolic changes in first-episode drug-naive schizophrenic patients. AB - Aim The aim of the study was to investigate the state of parameters characterising different sites of metabolism and the degree of endogenous intoxication in first-episode drug-naive schizophrenic [first episode of schizophrenia (FES)] patients. It is hypothesised that the FES is the initial step in the development of pathologically disturbed biochemical status that is characteristic of chronic schizophrenia. METHODS: Platelet monoamine oxidase (MAO) and serum semicarbazide-sensitive amine oxidase (SSAO) activities, serum concentrations of middle-mass endotoxic molecules (MMEM) and malondialdehyde and parameters of the serum albumin functional state were measured in 26 FES patients and 15 age-matched healthy controls. RESULTS: Severity of disorder before the treatment was 75.5 +/- 2.2, according to Positive and Negative Syndrome Scale score. FES patients were characterised by significant increase in MAO activity (99%) and MMEM concentration (124%) and significant decrease in SSAO activity (26%) as compared with controls. Changes of all other parameters were insignificant. Regression analysis has showed a significant relationship of three parameters - MAO, SSAO and MMEM, with values of PANNS score. Two methods of extraction of factor analysis revealed that MAO and SSAO belonged to Factor 1, whereas MMEM and albumin functional parameters belonged to Factor 2. CONCLUSION: Comparing our earlier data on chronic schizophrenic patients with present data, we hypothesise that FES patients are at the stage that leads to a stable, pathological state of metabolism. PMID- 25287725 TI - Transcriptional coactivator undifferentiated embryonic cell transcription factor 1 expressed in spermatogonial stem cells: a putative marker of boar spermatogonia. AB - Spermatogenesis is initiated from spermatogonial stem cells (SSCs), which are derived from gonocytes. Although some rodent SSC markers have been investigated, other species- and developmental stage-specific markers of spermatogonia have not been identified. The objective of this study was to characterize the expression of undifferentiated embryonic cell transcription factor 1 (UTF1) gene as a potential marker for spermatogonia and SSCs in the boar testis. In boar testis tissue at pre-pubertal stages (tissues collected at 5, 30, and 60 days of age), UTF1 gene expression was detected in almost all spermatogonia cells that expressed a protein gene product 9.5 (PGP9.5), and immunocytochemical analysis of isolated total testicular cells showed that 91.14% of cells staining for PGP9.5 also stained for UTF1. However, in boar testis tissue at pubertal and post pubertal stages (tissues collected at 90, 120, 150, and 180 days of age), UTF1 was not detected in all PGP9.5-positive cells in the basement membrane. While some PGP9.5-positive cells stained for UTF1, other cells stained only for PGP9.5 or UTF1. PGP9.5, UTF1, and NANOG was assessed in in vitro cultures of pig SSCs (pSSCs) from testes collected at 5 days of age. The relative amounts of PGP9.5, NANOG, and UTF1 mRNA were greater in pSSC colonies than in testis and muscle tissue. Thus, the UTF1 gene is expressed in PGP9.5-positive spermatogonia cells of pigs at 5 days of age, and its expression is maintained in cultured pSSC colonies, suggesting that UTF1 is a putative marker for early-stage spermatogonia in the pre-pubertal pig testis. These findings will facilitate the study of spermatogenesis and applications in germ cell research. PMID- 25287727 TI - Altered cingulum bundle microstructure in autism spectrum disorder. AB - OBJECTIVE: Here, we examined the cingulum bundle, a long-range white matter tract mediating dorsal limbic connectivity, using diffusion tensor imaging (DTI) tractography, in children and adolescents with autism spectrum disorder (ASD) versus controls. We hypothesised that cingulum bundle microstructure would be altered in ASD, based on evidence implicating abnormal white matter connectivity in this disorder. METHODS: DTI data were acquired for 19 ASD participants (IQ ? 70; 7-18 years; mean = 12.4 +/- 3.1) and 16 age-matched controls (7-18 years; mean = 12.3 +/- 3.6) on a 3 T magnetic resonance imaging system. Deterministic tractography was used to isolate the cingulum bundle. Left and right cingulum bundles were examined for differences in several DTI metrics in ASD children/adolescents versus controls, including: fractional anisotropy (FA), mean, axial, and radial diffusivity. RESULTS: Significant age * group interaction effects were found for all DTI metrics (mean diffusivity: F 1,28 = 9.5, p = 0.005, radial diffusivity: F 1,28 = 7.8, p = 0.009, axial diffusivity: F 1,28 = 5.2, p = 0.03, FA: F 1,28 = 4.4, p = 0.04). Interaction effects were driven by increases in cingulum bundle diffusivity (mean, radial, and axial diffusivity), and decreased FA, in younger ASD participants within our sample versus controls. CONCLUSION: Our results point to immature microstructural organisation of the cingulum bundle in ASD, particularly during the early years of life, with implications for limbic network synchronisation and complex socio-emotional performance. PMID- 25287728 TI - Relationship of oestrogen receptor status to depressive symptoms and quality of life in breast cancer patients. AB - OBJECTIVE: We investigated the relationship of oestrogen receptor (ER) status to the severity of depressive symptoms and quality of life (QOL) impairment in breast cancer patients. METHODS: Seventy-seven breast cancer patients with comorbid depression were evaluated with the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impression-Severity of Illness (CGI-S) for depression, and the Functional Assessment of Cancer Therapy-Breast (FACT-B). ER status was determined using immunohistochemical analysis. RESULTS: The ER positive group (n = 31) showed significantly higher scores compared with the ER negative group (n = 46) on HAMD total (p = 0.04) and somatic anxiety factor (p = 0.004) scores as well as CGI-S score (p = 0.03). As for QOL measured with the FACT-B, a significantly higher score was found on the Functional Well-Being (FWB) subscale in the ER-positive group (p = 0.001). The relationships were further analysed using generalised linear models (GLM), after controlling for the influence of the current anti-oestrogen treatment. The analysis revealed that ER status was still significantly related to the FWB subscale score of the FACT-B (p = 0.04). However, the HAMD and CGI-S scores were no longer significantly related to ER status after the influence of anti-oestrogen treatment was controlled for. CONCLUSION: These results suggest that ER status, which is a well-known biological prognostic factor in breast cancer, may be related to the severity of certain aspects of depressive symptoms or QOL impairment, implying a role of the ER in affective and behavioural regulation. However, anti-oestrogen treatments significantly influence these relationships. PMID- 25287729 TI - Differential ultrasonic indices of separation distress in the presence and absence of maternal cues in infant rats bred for high and low positive social affect. AB - OBJECTIVE: Preclinical models of human mood disorders commonly focus on the study of negative affectivity, without comparably stressing the role of positive affects and their ability to promote resilient coping styles. We evaluated the role of background constitutional affect of rats by studying the separation and reunion responses of infants from low and high positive affect genetic lines (i.e., differentially selected for High and Low 50 kHz ultrasonic vocalisations (USVs). METHODS: Infants from Low and High 50 kHz USV breeding lines were isolated from mothers and exposed to either social (familiar or unfamiliar bedding) or neutral (clean bedding) odour cues between two short isolation periods, and tested in homeothermic and hypothermic ambient temperatures. Negative affect was estimated by monitoring separation distress calls (35-45 kHz USVs). RESULTS: Low Line pups called at higher rates than High Line, and their rates were stable regardless of odour cue. In contrast, High Line pups increased vocalisations during the second compared with the first isolation periods and during exposure to both familiar and unfamiliar odour cues, but not to neutral odour. Furthermore, the greatest increase in USV emission was seen in the second isolation period following exposure to the unfamiliar odour. However, both lines showed comparable elevated distress USVs to the thermal stressor. CONCLUSION: High Line animals, selected for a positive affective phenotype (50 kHz USVs), exhibited reduced separation anxiety responses in infancy, making this a promising animal model for the role of constitutional affective states in emotional responsivity and potential resilience against emotional disorders. PMID- 25287730 TI - Functional recovery results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). AB - OBJECTIVE: ConstaTRE is an open-label, randomised, controlled, relapse prevention trial in patients with stable schizophrenia or schizoaffective disorder switched to risperidone long-acting injectable (RLAI) or oral quetiapine, and was designed to test the hypothesis that injectable antipsychotic treatment with risperidone would be more effective than oral therapy with quetiapine. Here we report the functional recovery results from the ConstaTRE trial. METHODS: Clinically stable adults previously treated with oral risperidone, olanzapine, or oral first generation antipsychotics were randomised to RLAI or quetiapine for 24 months. Functional recovery was assessed using the Social and Occupational Functioning Assessment Scale (SOFAS) and two quality-of-life (QoL) measures [Medical Outcomes Survey Short Form-12 (SF-12) and Schizophrenia Quality-of-Life Scale Revision 4 (SQLS-R4)]. RESULTS: A total of 666 patients were randomised and treated with RLAI (n = 329) or quetiapine (n = 337). Relapse occurred in 16.5% RLAI and 31.3% quetiapine patients. Significant improvements in SOFAS, SF-12, and SQLS-R4 scores were observed from baseline to month 24 with both RLAI and quetiapine. At months 6, and 12, and endpoint, improvement in SOFAS score was significantly greater for RLAI than quetiapine (p < 0.05). CONCLUSIONS: Among patients with stable schizophrenia or schizoaffective disorder, the likelihood of functional recovery appears to be higher in those switching to RLAI than to quetiapine, although improvements in functional status and QoL were observed with both treatments. PMID- 25287731 TI - Multi-electron oxygen reduction by a hybrid visible-light-photocatalyst consisting of metal-oxide semiconductor and self-assembled biomimetic complex. AB - Adsorption experiments and density functional theory (DFT) simulations indicated that Cu(acac)2 is chemisorbed on the monoclinic sheelite (ms)-BiVO4 surface to form an O2-bridged binuclear complex (OBBC/BiVO4) like hemocyanin. Multi-electron reduction of O2 is induced by the visible-light irradiation of the OBBC/BiVO4 in the same manner as a blue Cu enzyme. The drastic enhancement of the O2 reduction renders ms-BiVO4 to work as a good visible-light photocatalyst without any sacrificial reagents. As a model reaction, we show that this biomimetic hybrid photocatalyst exhibits a high level of activity for the aerobic oxidation of amines to aldehydes in aqueous solution and imines in THF solution at 25 degrees C giving selectivities above 99% under visible-light irradiation. PMID- 25287732 TI - An individual rehabilitation program: evaluation by Parkinsonian patients and their physiotherapists. AB - OBJECTIVES: The purpose of this work was to study the feasibility of an individual Parkinson disease (PD) rehabilitation program based on each patient's prevalent symptoms and to determine the effects of this program on patient's quality of life as well as the level of patient's and physiotherapist's satisfaction with the program. PATIENTS AND METHODS: In association with physiotherapists with expertise in PD, a physical medicine and rehabilitation physician, we elaborated a physical therapy program based on the core areas for physical therapy in PD: transfers; posture; balance and falls; physical capacity and inactivity. Within this program, we selected exercises tailored to each patient's main impairment and proposed this selection to their local physiotherapist for three months. Quality of life was evaluated with PDQ-39 at baseline and after three months of the individualized physical therapy program. We built an anonymous satisfaction questionnaire for patients and physiotherapists that was filled out at the end of the program. RESULTS: One hundred and three individuals with moderately advanced but clinically stable idiopathic PD were included. Significant improvement was found for the emotional well-being, bodily discomfort and stigma domain (P <= 0.05). No significant improvement was found for the other PDQ-39 domains. The mean global satisfaction figures for this program were 6.0 +/- 2.4 and 7.2 +/- 2.1 for patients and physiotherapists respectively. Most of the patients felt improved by the physiotherapy program and especially for transfer, balance, gait, and mobility. CONCLUSION: Our study found evidence of the potential benefits of a patient tailored physiotherapy program. Such a program was feasible and had a favorable impact on patients' quality of life and on physiotherapists' practices for PD patients. Specific physiotherapy may be effective to limit physical mobility impairment. Our results also pointed out that physiotherapy may be efficient to confine the negative impact of social isolation, pain and emotional reactions. Such a program should be associated with a therapeutic education intervention such as encouraging patients to perform physical therapy exercises alone. PMID- 25287733 TI - The internal time-giver role of melatonin. A key for our health. AB - Daily rhythms in physiological and behavioural processes are controlled by a network of circadian clocks. In mammals, at the top of the network is a master clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The nocturnal synthesis and release of melatonin by the pineal gland are tightly controlled by the SCN clock. Several roles of melatonin in the circadian system have been identified. As a major hormonal output, melatonin distributes temporal cues generated by the SCN to the multitude of tissues expressing melatonin receptors. In some target tissues, these melatonin signals can drive daily rhythmicity that would otherwise be lacking. In other target structures, melatonin signals are used for the synchronization (i.e., adjustment of the timing of existing oscillations) of peripheral oscillators. Due to the expression of melatonin receptors in the SCN, endogenous melatonin is also able to feedback onto the master clock. Of note, pharmacological treatment with exogenous melatonin can synchronize the SCN clock. From a clinical point of view, provided that the subject is not exposed to light at night, the daily profile of circulating melatonin provides a reliable estimate of the timing of the human SCN. During the past decade, a number of melatonin agonists have been developed. These drugs may target the SCN for improving circadian timing or act indirectly at some downstream level of the circadian network to restore proper internal synchronization. PMID- 25287734 TI - Systemic capillary leak syndrome in an 85-year-old man (Clarkson's syndrome). PMID- 25287735 TI - [Beneficial effect of preferred music on cognitive functions in minimally conscious state patients]. AB - Several studies have shown that music can boost cognitive functions in normal and brain-damaged subjects. A few studies have suggested a beneficial effect of music in patients with a disorder of consciousness but it is difficult to conclude since they did not use quantified measures and a control condition/group. The aim of the present study was to compare the effect of music to that of a continuous sound on the relational behavior of patients in a minimally conscious state (MCS). Behavioral responses of six MCS patients were evaluated using items from the Coma Recovery Scale-Revised. Weekly evaluation sessions were carried out, over four weeks, under two conditions: following the presentation of either the patient's preferred music, or following a continuous sound (control condition). Qualitative and quantitative analyses showed that twelve of the eighteen sessions (66.6%) showed a better result for the music condition than for the control condition. This new protocol suggests that preferred music has a beneficial effect on the cognitive abilities of MCS patients. The results further suggest that cerebral plasticity may be enhanced in autobiographical (emotional and familiar) contexts. These findings should now be further extended with an increased number of patients to further validate the hypothesis of the beneficial effect of music on cognitive recovery. PMID- 25287736 TI - Quantification of myocardial perfusion in clinical trials. PMID- 25287737 TI - Regadenoson provides perfusion results comparable to adenosine in heterogeneous patient populations: a quantitative analysis from the ADVANCE MPI trials. AB - BACKGROUND: Total and reversible left ventricular (LV) perfusion defect size (PDS) predict patient outcome. Limited data exist as to whether regadenoson induces similar perfusion abnormalities as observed with adenosine. We sought to determine whether regadenoson induces a similar LV PDS as seen with adenosine across varying patient populations. METHODS AND RESULTS: ADVANCE MPI were prospective, double-blind randomized trials comparing regadenoson to standard adenosine myocardial perfusion tomography (SPECT). Following an initial adenosine SPECT, patients were randomized to either regadenoson (N = 1284) or a second adenosine study (N = 660). SPECT quantification was performed blinded to randomization and image sequence. Propensity analysis was used to define comparability of regadenoson and adenosine perfusion results. Baseline clinical and SPECT results were similar in the two randomized groups. There was a close correlation between adenosine and regadenoson-induced total (r (2) = 0.98, P < .001) and reversible (r (2) = 0.92, P < .001) PDS. Serial differences in total (0.00 +/- 3.51 vs -0.11 +/- 3.46, P = .51) and reversible (0.15 +/- 3.79 vs 0.07 +/- 3.33, P = .65) PDS were also comparable in patients randomized to regadenoson vs adenosine, respectively, and irrespective of age, gender, diabetic status, body mass index, or prior cardiovascular history. By propensity analysis, regadenoson-induced total PDS was significantly larger than observed with adenosine. CONCLUSION: This is the first study to show that regadenoson induces similar, if not larger, perfusion defects than those observed with adenosine across different patient populations and demonstrates the value of quantitative analysis for defining serial changes in SPECT perfusion results. Regadenoson should provide comparable diagnostic and prognostic SPECT information to that obtained with adenosine. PMID- 25287738 TI - Diagnostic value of 99mTc-HMPAO-labeled leukocytes scintigraphy in suspicion of post-sternotomy mediastinitis relapse. AB - BACKGROUND: The diagnostic value of radiolabeled white blood cells (WBCs) scintigraphy in mediastinitis is well established, but data in the specific context of relapse are lacking. The present study aimed at evaluation of the diagnostic value of WBCs scintigraphy in suspicion of mediastinitis relapse after prior surgical revision. METHODS AND RESULTS: Multiple planar incidences of the chest were acquired 4 and 20 hours after injection of labeled WBC in 43 patients. In case of non-conclusive scintigraphy, a second scan was performed 2-3 weeks after the first one. The diagnosis of infection was based on positive bacteriological results; otherwise patients were followed up for at least 1 year. Out of 39 analyzable patients, 17 (44%) were diagnosed with mediastinitis relapse. After the first scan, 32 of 39 were correctly classified, 2 were false positive, and 5 were not conclusive. After completion of an additional scan in the latter 5 patients, 36 of 39 were correctly classified and 3 were false positive (100% sensitivity, 86% specificity, 85% positive predictive value, and 100% negative predictive value). CONCLUSIONS: In the specific context of suspicion of mediastinitis relapse, the optimal diagnostic value was achieved by repeating the scan when the first one was not conclusive. In this context, a negative WBC scintigraphy was able to rule out infection, with potential major impact on therapeutic management in patients with poor clinical status. PMID- 25287739 TI - "Neighborhood matters": assessment of neighborhood social processes. AB - Neighborhoods are important contexts for understanding development and behavior, but cost and difficulty have challenged attempts to develop measures of neighborhood social processes at the neighborhood level. This article reports the development, reliability, and validity of Neighborhood Matters, a collection of instruments assessing three aspects of neighborhood social processes, namely, norms (five subscales), informal social control (six subscales and total scale), social connection (two subscales), as well as individual scales for assessing neighborhood change, neighborhood resources, and neighborhood problems. Six hundred six residents of Chicago, chosen at random from 30 neighborhoods (defined by US Census tracts), completed the measures. Neighborhoods were selected randomly from pools that balanced poverty and predominant (African-American vs. Latino Hispanic) ethnicity. Within each neighborhood 20 individuals were selected at random, balanced by age (18-24 vs. 30+) and gender. Scaling and item analysis permitted reduction of the number of items in each scale. All subscales had individual-level internal consistency in excess of .7. Generalizability theory analysis using random effects regression models found significant shared variance at the neighborhood level for three norms subscales, four informal social control subscales, both social connection subscales, and the neighborhood change, resources and problems scales. Validity analyses found significant associations between neighborhood-level scores on multiple Neighborhood Matters scales and neighborhood levels of violent, property, and drug-related crime. Discussion focuses on potential applications of the Neighborhood Matters scales in community research. PMID- 25287740 TI - Preparation and evaluation of liver-targeting micelles loaded with oxaliplatin. AB - We prepared liver-targeting micelles loaded with oxaliplatin (OXA), using a polymer modified by a liver-targeting ligand, namely, glycyrrhetinic acid conjugated and stearic acid-grafted chitosan (GA-CS-SA). The particles had a uniform size, which was 138.6 +/- 0.72 nm. The encapsulation efficiency was up to 71.7 +/- 0.46%. The hepatic distribution of OXA in mice given OXA-GA-CS-SA was significantly superior to that in the controls (P < 0.05), which means that liver targeted delivery of OXA was achieved. These results reveal that OXA-GA-CS-SA could be a potential and promising candidate for efficiently targeted delivery of OXA. PMID- 25287741 TI - Density functional theory of freezing for binary mixtures of 2D superparamagnetic colloids. AB - Density functional theory of freezing is used to study the phase diagram of a binary mixture of superparamagnetic colloidal particles in two dimensions. The particles interact via a purely repulsive potential that scales as the inverse cube of the inter-particle separation. This corresponds to a magnetic dipole interaction where the dipoles are induced by an external magnetic field applied normal to the plane. The pair correlation functions needed as input information in the density functional theory are calculated by the hypernetted chain integral equation closure. Considering the freezing into a disordered triangular solid phase, a spindle phase diagram is found for the susceptibility ratio 0.9 of the species, which changes to an azeotrope at a ratio 0.8. A eutectic-like phase diagram with an intervening solid phase emerges for the susceptibility ratio 0.7. The results are verifiable in real-space experiments on superparamagnetic colloids in external magnetic fields. PMID- 25287742 TI - Which hand is worse? Concordance between patient perception and electrodiagnostic results in carpal tunnel syndrome. AB - INTRODUCTION: In patients with clinically diagnosed carpal tunnel syndrome (CTS) the more symptomatic hand may be different from the more severely affected hand on electrodiagnostic testing. This study aims to determine the level of agreement which should be expected between these measures and consequently the level of suspicion for co-occurring pathology which is warranted if there is discordance. METHODS: This was a single center retrospective review of 252 patients referred for upper extremity electrodiagnostic evaluation who were diagnosed subsequently with CTS. Comparison was made between the patient's perceived worst side and the more abnormal side on electrodiagnostic studies. RESULTS: We found a significant level of agreement (kappa = 0.676) between patient symptoms and electrodiagnostic testing when identifying the side with more severe CTS. CONCLUSIONS: Discordance between patient perception and electrodiagnostic results regarding which hand is affected more severely in patients with CTS should alert the clinician to possible coexisting nonneurologic pathology and prompt regional musculoskeletal examination as indicated. PMID- 25287743 TI - Intraocular pressure-lowering medications and long-term outcomes of selective laser trabeculoplasty. AB - BACKGROUND: To investigate the effects of current intraocular pressure-lowering medications on the efficacy of selective laser trabeculoplasty. DESIGN: Retrospective chart review of records from an urban glaucoma clinic in Sydney, Australia. PARTICIPANTS: Patients who received their first selective laser trabeculoplasty between 2002 and 2005 were studied (grouped from 0 to 3 according to the number of pre-selective laser trabeculoplasty medications, and followed for 5 years). Those with previous argon laser therapy, trabeculectomy or angle closure were excluded. METHODS: Selective laser trabeculoplasty (Ellex) used to deliver 180 or 360 degree of treatment, under the same protocol. MAIN OUTCOME MEASURES: Responders were defined by >=20% reduction from baseline intraocular pressure. Data were censored when pressure-lowering intervention was required. The mean intraocular pressure, survivor, response rate, number and type of medications were compared. RESULTS: There were 206 patients with ocular hypertension, primary, pseudo-exfoliation, or pigmentary glaucoma who used none (n = 20), one (n = 33), two (n = 61) or three or more (n = 92) pre-selective laser trabeculoplasty topical anti-glaucoma medications. The mean baseline intraocular pressures for each group was 23.7, 22.2, 20.7 and 20.4 mmHg, respectively (P = 0.061). Post-treatment mean intraocular pressure was 17.9, 17.7, 15.5, and 15.7 mmHg; percentage reduction was similar between groups (23.6 25.6%, P = 0.20). Kaplan-Meier survival analysis showed comparable survival rates across groups (P = 0.445). At 60 months, 11.1, 17.1, 30.5 and 11.5% of responders remained in each group. Higher proportions of patients in groups 2 and 3 required further laser or surgery. CONCLUSION: The number of pre-selective laser trabeculoplasty medications did not affect the intraocular pressure-lowering effectiveness of selective laser trabeculoplasty; however, groups on more medications required more pressure-lowering interventions. PMID- 25287744 TI - Neutral sphingomyelinase-2 is a redox sensitive enzyme: role of catalytic cysteine residues in regulation of enzymatic activity through changes in oligomeric state. AB - Neutral sphingomyelinase-2 (nSMase-2) is the major sphingomyelinase activated in response to pro-inflammatory cytokines and during oxidative stress. It is a membrane-bound 655 amino acid protein containing 22 cysteine residues. In this study, we expressed recombinant mouse nSMase-2 protein in Escherichia coli, and investigated whether nSMase-2 is a redox sensitive enzyme. Our results demonstrate that nSMase-2 exists as both monomers and multimers that are associated with high and low enzymatic activity respectively. Mutational analysis of nSMase-2 identified within its C-terminal catalytic domain several oxidant sensitive cysteine residues that were shown to be involved in enzyme oligomerization. Changing Cys(617) to Ser for example is a gain-of-function mutation associated with a decreased propensity for oligomerization. Alternatively, nSMase-2 expression in a bacterial strain that lacks endogenous thioredoxin, Rosetta-gami2, results in increased oligomer formation and lower enzyme activity. Phenotypic rescue was accomplished by treating nSMase-2 lysates with recombinant human thioredoxin. This indicates that nSMase-2 may be a novel substrate for thioredoxin. FRET analysis confirmed the presence of nSMase-2 multimers in mammalian HEK cells and their localization to the plasma membrane. In conclusion, our results identify nSMase-2 as a redox-sensitive enzyme, whose basal activity is influenced by thioredoxin-mediated changes in its oligomeric state. PMID- 25287746 TI - Evaluating the Effectiveness of Strategies for the Control of Equine Influenza Virus in the New Zealand Equine Population. AB - New Zealand has never experienced an equine influenza (EI) outbreak. The 2007 outbreak of EI in Australia showed that in a naive population EI spreads rapidly and substantial efforts (in terms of movement restrictions, mass vaccination and post-vaccination surveillance) were required to achieve eradication. To control EI, it is essential that animal health authorities have well-defined strategies for containment, control and eradication in place before an incursion occurs. A spatially explicit stochastic simulation model, InterSpread Plus, was used to evaluate EI control strategies for the New Zealand situation. The control strategies considered were movement restrictions alone and movement restrictions in combination with one of three vaccination strategies beginning on day 14; suppressive, protective or targeted. The suppressive strategy involved vaccination in a 3 km radius around infected properties, while the protective strategy involved vaccination in a 7-10 km ring around infected properties. Targeted vaccination involved the vaccination of all breeding and racing properties within 20 km of an infected property. Simulations were carried out to determine the impact of timing of vaccination and earlier detection on the size of and duration of the outbreak. All three vaccination strategies implemented on day 14 resulted in between 1028 and 2161 fewer infected properties (P < 0.001), and an epidemic that was between 42 and 90 days shorter (P < 0.001) compared with movement restrictions alone. Any vaccination strategy implemented on day 7 resulted in fewer infected properties, compared with vaccination implemented on days 14 or 21. Overall, the suppressive vaccination strategy resulted in fewer infected properties. Our findings indicate that any vaccination strategy, if combined with complete movement restrictions could be effective for the control of EI, if an outbreak was to occur in New Zealand. If an outbreak were to occur, a simulation model has now been created to assist in decision-making using data from the actual outbreak. PMID- 25287747 TI - UBE2A deficiency syndrome: a report of two unrelated cases with large Xq24 deletions encompassing UBE2A gene. AB - Intragenic mutations of the UBE2A gene, as well as larger deletions of Xq24 encompassing UBE2A have in recent years been associated with a syndromic form of X-linked intellectual disability called UBE2A deficiency syndrome or X-linked intellectual disability type Nascimento (OMIM#300860). Common clinical features in these patients include moderate to severe intellectual disability (ID), heart defects, dysmorphic features such as high forehead, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, wide mouth, myxedematous appearance, hirsutism, onychodystrophy, and genital anomalies. This study investigates clinical and molecular data of two unrelated, affected males with chromosome Xq24 deletions encompassing UBE2A. Both have been followed from birth until two years of age. A review of the previously published patients with deletions encompassing UBE2A is provided. Besides the common features, the two boys show anomalies not previously described, such as retinal coloboma, esophageal atresia with esophageal fistula, long fingers, camptodactyly, clinodactyly, and long broad toes. Analyses of the phenotype-genotype correlations suggest considerable prevalence of heart defects in the group of patients with larger deletions of Xq24 in comparison to the patients having intragenic UBE2A mutations. However, further studies are needed in order to establish statistically reliable phenotype-genotype correlations of this syndrome. PMID- 25287748 TI - How long is a transurethral catheter necessary in patients undergoing thoracotomy and receiving thoracic epidural analgesia? Literature review. PMID- 25287745 TI - Mass spectrometry assays of plasma biomarkers to predict radiographic progression of knee osteoarthritis. AB - INTRODUCTION: Biomarkers to identify osteoarthritis (OA) patients at risk for disease progression are needed. As part of a proteomic analysis of knee synovial fluid from normal and OA patients, differentially expressed proteins were identified that could represent potential biomarkers for OA. This study aimed to use mass spectrometry assays to identify representative peptides from several proteins in synovial fluid and peripheral blood, and assess their levels as biomarkers of OA progression. METHODS: Multiplexed high throughput selected reaction monitoring (SRM) assays were developed to measure tryptic peptides representative of 23 proteins in matched serum and synovial fluid samples from late OA subjects at the time of joint replacement. Subsequently plasma samples from the baseline visit of 173 subjects in an observational OA cohort were tested by SRM for peptides from nine of these proteins: afamin, clusterin, cartilage oligomeric matrix protein, hepatocyte growth factor, kallistatin, insulin-like growth factor binding protein, acid labile subunit, lubricin, lumican, and pigment epithelium-derived factor. Linear regression was used to determine the association between the peptide biomarker level at baseline and change in joint space width (DeltaJSW) from baseline to 30 months, adjusting for age and sex. RESULTS: In the matched cohort, 17 proteins could be identified in synovial fluid and 16 proteins were detected in serum. For the progression cohort, the average age was 62 and average DeltaJSW over 30 months was 0.68 mm. A high correlation between different peptides from individual proteins was observed, indicating our assays correctly measured their target proteins. Peptides representative of clusterin, lumican and lubricin showed statistically significant associations with joint space narrowing after adjustment for age and sex. Partial R2 values showed clusterin FMETVAEK and lubricin LVEVNPK peptide biomarkers explains about 2 to 3% of the variability of DeltaJSW, similar to that explained by age. A biomarker score combining normalized data for both lubricin and clusterin peptides increased the model R2 to 0.079. CONCLUSIONS: Our results suggest that when combined, levels of peptides representative of clusterin and lubricin in plasma are as predictive of OA progression as age. Replication of these findings in other prospective OA cohorts is planned. PMID- 25287749 TI - Anesthetics and cerebral protection in patients undergoing carotid endarterectomy. PMID- 25287751 TI - Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. AB - BACKGROUND: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. METHODS: In a randomized controlled trial, 52 healthy obese individuals were, after a diet induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. RESULTS: Soluble leptin receptor increase was 59% lower; 2.1+/-0.7 vs 5.1+/-0.8 ng ml(-1) (-3.0 (95% confidence interval (CI)=-0.5 to -5.5)), P<0.001 and free leptin index decrease was 43% smaller; -62+/-15 vs -109+/-20 (-47 (95% CI=-11 to -83)), P<0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (-2.3 kg (95% CI=-0.6 to -4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=-0.6 to -1)), P<0.001. Fasting glucose was decreased by an additional -0.2+/ 0.1 mmol l(-1) in the GLP-1RA group in contrast to the control group, where glucose increased 0.3+/-0.1 mmol l(-1) to the level before weight loss (-0.5mmol l(-1) (95% CI=-0.1 to -0.9)), P<0.005. Meal response of peptide PYY3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P<0.05. CONCLUSIONS: The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY3-36 response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity. PMID- 25287752 TI - Maternal weight gain in different periods of pregnancy and childhood cardio metabolic outcomes. The Generation R Study. AB - BACKGROUND: Excessive gestational weight gain seems to be associated with offspring cardio-metabolic risk factors. Little is known about the critical periods of gestational weight gain. We examined the associations of maternal weight gain in different periods of pregnancy with childhood cardio-metabolic risk factors. METHODS: In a population-based prospective cohort study from early pregnancy onwards among 5908 mothers and their children, we obtained maternal prepregnancy weight and weight in early, mid and late pregnancy. At the age of 6 years (median: 72.6 months; 95% range: 67.9, 95.8), we measured childhood body mass index (BMI), total body and abdominal fat distribution, blood pressure and blood levels of lipids, insulin and c-peptide. RESULTS: Overall, the associations of maternal prepregnancy weight with childhood outcomes were stronger than the associations of maternal gestational weight gain. Independent from maternal prepregnancy weight and weight gain in other periods, higher weight gain in early pregnancy was associated with higher childhood BMI, total fat mass, android/gynoid fat mass ratio, abdominal subcutaneous fat mass and systolic blood pressure (P-values<0.05). Independent associations of maternal weight gain in early pregnancy with childhood abdominal preperitoneal fat mass, insulin and c peptide were of borderline significance. Higher weight gain in mid pregnancy was independently associated with higher childhood BMI, total and abdominal subcutaneous fat mass and systolic blood pressure (P-values<0.05). The associations for childhood cardio-metabolic outcomes attenuated after adjustment for childhood BMI. Weight gain in late pregnancy was not associated with childhood outcomes. Higher weight gain in early, but not in mid or late pregnancy, was associated with increased risks of childhood overweight and clustering of cardio-metabolic risk factors (odds ratio (OR) 1.19 (95% confidence interval (CI): 1.10, 1.29) and OR 1.20 (95% CI: 1.07, 1.35) per standard deviation increase in early gestational weight gain, respectively). CONCLUSIONS: Higher weight gain in early pregnancy is associated with an adverse cardio metabolic profile in offspring. This association is largely mediated by childhood adiposity. PMID- 25287754 TI - Synthesis, structure and magnetic properties of phenylhydroxamate-based coordination clusters. AB - The strategic recombination of preformed coordination clusters in the presence of polymodal bridging ligands has successfully led to the characterisation of five new compounds of structural and magnetic interest. Indeed using the dinuclear complex [M2(H2O)(piv)4(Hpiv)4] (M = Co, Ni; Hpiv = pivalic acid) as starting material and reacting it with phenylhydroxamic acid (H2pha) has yielded the four tetrametallic coordination clusters [Co4(Hpha)2(piv)6(Hpiv)4] (1), [Ni4(Hpha)2(piv)6(Hpiv)2(DMF)2] (2), [Co4(Hpha)2(piv)6(EtOH)2(H2O)2] (3), [Ni4(Hpha)2(piv)6(EtOH)2(H2O)2] (4) and the hexanuclear complex [Co6(Hpha)4(piv)8(EtOH)2].EtOH (5). All the compounds have been structurally characterised revealing a particular binding mode for the hydroxamate ligand. The study of their magnetic properties has been performed and the modelling of these properties has been done using the appropriate hamiltonians for each compound. The experimental data and their modelling show non-zero spin ground states for compounds 4 and 5. PMID- 25287753 TI - Natural course of metabolically healthy abdominal obese adults after 10 years of follow-up: the Tehran Lipid and Glucose Study. AB - OBJECTIVE: This study aims to assess the natural course of metabolically healthy abdominal obese (MHAO) phenotype and determine the predictors of change in the metabolic status in this population over 10 years of follow-up. METHODS: A total of 916 MHAO subjects from the Tehran Lipid and Glucose Study were followed for changes in their metabolic health status. Anthropometric and metabolic indices were measured at baseline and were compared between subjects with healthy and unhealthy metabolic conditions at the end of follow-up. Predictors of change in metabolic health were assessed in logistic regression models. National waist circumference cutoffs were used for definition of abdominal obesity. Metabolic health was defined as ?1 metabolic components of metabolic syndrome according to the Joint Interim Statement criteria. RESULTS: At the end of the follow-up, nearly half of the MHAO subjects lost their metabolic health and 42.1% developed metabolic syndrome by definition. Low high-density lipoprotein cholesterol, hypertriglyceridemia and homeostasis model assessment-insulin resistance at baseline were significant predictors of change in metabolic health condition. CONCLUSION: MHAO is a relatively unstable condition and a considerable percentage of these individuals will lose their metabolic health as time passes. Baseline metabolic characteristics may be useful predictors of this change and should be considered in the care of these individuals. PMID- 25287755 TI - Advances against aspergillosis: biology, host response, diagnosis and treatment. PMID- 25287756 TI - Improvement of quality of life in patients with steroid-refractory chronic graft versus-host disease treated with the mTOR inhibitor everolimus. AB - Compromised quality of life (QoL) is a frequent consequence of treatment refractory chronic graft-versus-host disease (cGvHD). Here, we report on the assessment of QoL in a subgroup of 22 patients with a median age of 54 (17-70) yr receiving an everolimus-based salvage therapy at a single center for their steroid-refractory cGvHD. Five patients suffered from mild, 13 from moderate, and four from severe cGvHD according to NIH consensus criteria when everolimus was introduced. Median treatment duration was 390 d ranging from 86 to 814 d. We performed actual and retrospective assessments of QoL (EuroQol EQ-5D questionnaire) and degree of bother experienced by cGvHD symptoms (Lee cGvHD Symptom Scale). Seventeen of 22 patients showed an improved QoL according to the EQ-5D visual analog scale (37.5% vs. 70.0%; p < 0.001), and a decline in the median Lee cGvHD Symptom Scale was noted in 20 of 22 patients (28 vs. 17; p < 0.001). Furthermore, an improvement was noted in each of the five dimensions of the EQ-5D descriptive system. These data even when limited by their retrospective nature suggest that beyond physical responses everolimus may have contributed to the rebuilding of patients' QoL. PMID- 25287757 TI - Fully biobased and supertough polylactide-based thermoplastic vulcanizates fabricated by peroxide-induced dynamic vulcanization and interfacial compatibilization. AB - A fully biobased and supertough thermoplastic vulcanizate (TPV) consisting of polylactide (PLA) and a biobased vulcanized unsaturated aliphatic polyester elastomer (UPE) was fabricated via peroxide-induced dynamic vulcanization. Interfacial compatibilization between PLA and UPE took place during dynamic vulcanization, which was confirmed by gel measurement and NMR analysis. After vulcanization, the TPV exhibited a quasi cocontinuous morphology with vulcanized UPE compactly dispersed in PLA matrix, which was different from the pristine PLA/UPE blend, exhibiting typically phase-separated morphology with unvulcanized UPE droplets discretely dispersed in matrix. The TPV showed significantly improved tensile and impact toughness with values up to about 99.3 MJ/m(3) and 586.6 J/m, respectively, compared to those of 3.2 MJ/m(3) and 16.8 J/m for neat PLA, respectively. The toughening mechanisms under tensile and impact tests were investigated and deduced as massive shear yielding of the PLA matrix triggered by internal cavitation of VUPE. The fully biobased supertough PLA vulcanizate could serve as a promising alternative to traditional commodity plastics. PMID- 25287758 TI - Practical, modular, and general synthesis of 3-coumaranones through gold catalyzed intermolecular alkyne oxidation strategy. AB - A gold-catalyzed intermolecular alkyne oxidation for the preparation of 3 coumaranones has been developed. Using 8-isopropylquinoline N-oxides as oxidants, the reactions of o-ethynylanisoles afford versatile 3-coumaranones in moderate to good isolated yields. The synthetic utility of this chemistry is also indicated by the synthesis of the natural product sulfuretin. PMID- 25287759 TI - The relationships of physician practice characteristics to quality of care and costs. AB - BACKGROUND: Medical group practices are central to many of the proposals for health care reform, but little is known about the relationship between practice level characteristics and the quality and cost of care. METHODS: Practice characteristics from a 2009 national survey of 211 group practices were linked to Medicare claims data for beneficiaries attributed to the practices. Multivariate regression was used to examine the relationship between practice characteristics and claims-computable measures of screening and monitoring, avoidable utilization, risk-adjusted per-beneficiary per-year (PBPY) costs, and the practice's net revenue. RESULTS: Several characteristics of group practices are predictive of screening and monitoring measures. Those measures, in turn, are predictive of lower values of avoidable utilization measures that contribute to higher PBPY costs. The effects of group practice characteristics on avoidable utilization, cost, and practice net revenue appear to work primarily through improved screening and monitoring. CONCLUSIONS: Practice characteristics influence costs indirectly through a set of statistically significant relationships among screening and monitoring measures and avoidable utilization. However, these relationships are not the only pathways connecting practice characteristics to cost and those additional pathways contain substantial "noise" adding uncertainty to the estimated direct effects. Some of the attributes thought to be important characteristics of accountable care organizations and medical homes appear to be associated with lower quality and no improvement in cost. PMID- 25287760 TI - Human Chorionic Villous Mesenchymal Stem Cells Modify the Functions of Human Dendritic Cells, and Induce an Anti-Inflammatory Phenotype in CD1+ Dendritic Cells. AB - BACKGROUND: Mesenchymal stem cells derived from the chorionic villi of human term placenta (pMSCs) have drawn considerable interest because of their multipotent differentiation potential and their immunomodulatory capacity. These properties are the foundation for their clinical application in the fields of stem cell transplantation and regenerative medicine. Previously, we showed that pMSCs induce an anti-inflammatory phenotype in human macrophages. In this study, we determined whether pMSCs modify the differentiation and maturation of human monocytes into dendritic cells (DCs). The consequences on dendritic function and on T cell proliferation were also investigated. METHODS: Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF) were used to stimulate the differentiation of monocytes into immature dendritic cells (iDCs), which were subsequently co-cultured with pMSCs. Lipopolysaccharide (LPS) was used to induce maturation of iDCs into mature dendritic cells (mDCs). Flow cytometry and enzyme linked immunosorbent assays (ELISA) were used to quantify the effect pMSC co culturing on DC differentiation using CD1a, a distinctive marker of DCs, as well as other molecules important in the immune functions of DCs. The phagocytic activity of iDCs co-cultured with pMSCs, and the effects of iDCs and mDC stimulation on T cell proliferation, were also investigated. RESULTS: Monocyte differentiation into iDCs was inhibited when co-cultured with pMSCs and maturation of iDCs by LPS treatment was also prevented in the presence of pMSCs as demonstrated by reduced expression of CD1a and CD83, respectively. The inhibitory effect of pMSCs on iDC differentiation was dose dependent. In addition, pMSC co-culture with iDCs and mDCs resulted in both phenotypic and functional changes as shown by reduced expression of costimulatory molecules (CD40, CD80, CD83 and CD86) and reduced capacity to stimulate CD4(+) T cell proliferation. In addition, pMSC co-culture increased the surface expression of major histocompatibility complex (MHC-II) molecules on iDCs but decreased MHC-II expression on mDCs. Moreover, pMSC co-culture with iDCs or mDCs increased the expression of immunosuppressive molecules [B7H3, B7H4, CD273, CD274 and indoleamine-pyrrole 2,3-dioxygenase (IDO). Additionally, the secretion of IL-12 and IL-23 by iDCs and mDCs co-cultured with pMSCs was decreased. Furthermore, pMSC co-culture with mDCs decreased the secretion of IL-12 and INF-gamma whilst increasing the secretion of IL-10 in a T cell proliferation experiment. Finally, pMSC co-culture with iDCs induced the phagocytic activity of iDCs. CONCLUSIONS: We have shown that pMSCs have an inhibitory effect on the differentiation, maturation and function of DCs, as well as on the proliferation of T cells, suggesting that pMSCs can control the immune responses at multiple levels. PMID- 25287761 TI - Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. AB - The inability of current recommendations to control the epidemic of diabetes, the specific failure of the prevailing low-fat diets to improve obesity, cardiovascular risk, or general health and the persistent reports of some serious side effects of commonly prescribed diabetic medications, in combination with the continued success of low-carbohydrate diets in the treatment of diabetes and metabolic syndrome without significant side effects, point to the need for a reappraisal of dietary guidelines. The benefits of carbohydrate restriction in diabetes are immediate and well documented. Concerns about the efficacy and safety are long term and conjectural rather than data driven. Dietary carbohydrate restriction reliably reduces high blood glucose, does not require weight loss (although is still best for weight loss), and leads to the reduction or elimination of medication. It has never shown side effects comparable with those seen in many drugs. Here we present 12 points of evidence supporting the use of low-carbohydrate diets as the first approach to treating type 2 diabetes and as the most effective adjunct to pharmacology in type 1. They represent the best-documented, least controversial results. The insistence on long-term randomized controlled trials as the only kind of data that will be accepted is without precedent in science. The seriousness of diabetes requires that we evaluate all of the evidence that is available. The 12 points are sufficiently compelling that we feel that the burden of proof rests with those who are opposed. PMID- 25287762 TI - Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. AB - OBJECTIVE: Chronic heart failure (CHF) is characterized by several micronutrient deficits. Amino acid supplementation may have a positive effect on nutritional and metabolic status in patients with CHF. Levo-carnosine (beta-alanyl-L histidine) is expressed at a high concentration in myocardium and muscle. Preliminary studies with L-carnosine in healthy individuals have suggested a potential role in improving exercise performance. To our knowledge, no study has been conducted in patients with heart failure. The aim of this study was to test the oral supplementation of L-carnosine and its effects on quality of life and exercise performance in patients with stable CHF. METHODS: Fifty patients with stable CHF and severe left-ventricular systolic dysfunction on optimal medical therapy were randomized 1:1 to receive oral orodispersible L-carnosine (500 mg OD) or standard treatment. Left-ventricular ejection fraction (LVEF) was measured by echocardiography. Cardiopulmonary stress test, 6-minute walking test (6 MWT) and quality-of-life (visual analog scale score and the EuroQOL five dimensions questionnaire [EQ-5D]) were performed at baseline and after 6 mo. RESULTS: Patients receiving orodispersible L-carnosine had an improvement in 6 MWT distance (P = 0.014) and in quality-of-life (VAS score) (P = 0.039) between baseline and follow-up. Compared with controls, diet supplementation with orodispersible L-carnosine was associated with an improvement in peakVO2 (P < 0.0001), VO2 at anaerobic threshold, peak exercise workload, 6 MWT and quality-of life assessed by the EQ-5D test and the VAS score. CONCLUSION: This study suggests that L-carnosine, added to conventional therapy, has beneficial effects on exercise performance and quality of life in stable CHF. More data are necessary to evaluate its effects on left-ventricular ejection fraction and prognosis in CHF. PMID- 25287763 TI - Reaction of Np atom with H2O in the gas phase: reaction mechanisms and ab initio molecular dynamics study. AB - The gas-phase reaction of an Np atom with H2O was investigated using density functional theory and ab initio molecular dynamics. The reaction mechanisms and the corresponding potential energy profiles for different possible spin states were analyzed. Three reaction channels were found in the mechanism study: the isomerization channel, the H2 elimination channel, and the H atom elimination channel. The latter two were observed in the dynamics simulation. It was found that the branching ratio of the title reaction depends on the initial kinetic energy along the transition vector. Product energy distributions for the reaction were evaluated by performing direct classical trajectory calculations on the lowest sextet potential energy surface. The results indicate that most of the available energy appears as the translational energy of the products. The overall results indicate that the H2 elimination channel with low kinetic energy is thermodynamically favored but competes with the H atom elimination channel with higher kinetic energy. PMID- 25287764 TI - Density functional study of molecular nitrogen adsorption on gold-copper and gold silver binary clusters. AB - Density functional theory calculations were performed to investigate the adsorption behaviors of nitrogen molecule on small bimetallic AunCum and AunAgm clusters, with n + m <= 5. In all cases the N2 forms a linear or quasi-linear M-N N structure (M = Au, Cu or Ag). The adsorption energies of N2 on pure metal clusters follow the order CunN2 > AunN2 > AgnN2, which is due to the weaker orbital interaction between silver and N2. N2 prefers to bind to a copper atom in AunCumN2 complexes and prefers to bind to a silver atom in AunAgmN2 complexes. The combination of Cu atoms into Aun clusters makes the cluster more reactive toward N2 while the combination of Ag atoms into Aun clusters makes the cluster less reactive toward N2. The electrostatic interaction is strengthened while the back-donation from metal to N2 is reduced in bimetallic cluster nitrides, as compared to the mono cluster nitrides. The N-N stretching frequencies are all red shifted upon adsorption and the M-N stretching frequencies are highly correlated to the atoms to which the N is attached. PMID- 25287766 TI - Can media monitoring be a proxy for public opinion about technoscientific controversies? The case of the Italian public debate on nuclear power. AB - Is it possible to infer information about public opinion by looking at how the media discuss controversial technoscientific public issues? We conduct content analysis on media coverage of nuclear power in Italy in the years 1992-2012 and compare it with longitudinal public opinion surveys. By treating a large amount of textual data and applying an innovative methodology based on indicators of the presence of 'risky terms', that is, keywords referring to the issue of risk and danger, very high correlation has been found between media discourse on risk and opposition within public opinion. The analysis is conducted testing as a preliminary step Mazur's hypothesis on quantity of coverage and opposition towards controversial technoscience. Then, risk content measures are used in order to gain stronger correlations between media and public attitudes towards nuclear power. PMID- 25287765 TI - Molecular modeling and simulation of the human eNOS reductase domain, an enzyme involved in the release of vascular nitric oxide. AB - Homology modeling of the reductase domain of endothelial nitric oxide synthase (eNOS), which regulates the catalytic activity of eNOS, and molecular dynamics studies focusing especially on the serine residues S615, S633, and S1177 were performed. MD analysis of this structure revealed that S633 is highly flexible and accessible to solvent molecules, while S1177 becomes highly flexible when S633 is phosphorylated. The presence of intramolecular interactions between S1177 among the major serine residues underscores its structural importance to the efficient synthesis of nitric oxide in endothelium. In order to evaluate the appropriateness of phosphomimetic (for phosphorylation) and phosphomutant (for dephosphorylation) eNOSs for use as experimental model systems, the structural dynamics and conformational changes in phosphomimetic (S615D, S633D, S1177D) and phosphomutant (S615A, S633A, S1177A) eNOSs were investigated. Phosphomimetic and phosphomutant eNOSs portrayed S633 as a modulator of S1177, whereas such correlations could not be observed in native and phosphorylated eNOSs. Computational analysis of the docked complex revealed that phosphorylated pS1177 and pS615 have high affinity for Akt (one of the key kinases in the eNOS activation pathway), with a significant number of hydrogen bonds and salt bridges observed between these residues and Akt . This work therefore provides evidence of the subtle structural changes that occur within the reductase domain which contribute to the stability-flexibility-activity relationship of eNOS. Such subtle changes are of great importance in the context of regulated nitric oxide release by different phosphorylated forms of eNOS and the need to account for the existence of subtle differences between real proteins and experimental model systems. PMID- 25287768 TI - Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting about vorapaxar. PMID- 25287767 TI - Gender differences in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial. AB - BACKGROUND: Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is associated with high mortality. Previous studies regarding gender-specific differences in CS are conflicting and there are insufficient data for the presence of gender-associated differences in the contemporary percutaneous coronary intervention era. Aim of this study was therefore to investigate gender specific differences in a large cohort of AMI patients with CS undergoing contemporary treatment. METHODS: In the randomized Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, 600 patients with CS complicating AMI undergoing early revascularization were assigned to therapy with or without intra aortic balloon pump. We compared sex-specific differences in these patients with regard to baseline and procedural characteristics as well as short- and long-term clinical outcome. RESULTS: Of 600 patients 187 (31%) were female. Women were significantly older than men and had a significantly lower systolic and diastolic blood pressure at presentation (p < 0.05 for all). Diabetes mellitus and hypertension were more frequent in women, whereas smoking was more frequent in men (p < 0.05 for all). Women showed a higher mortality within the first day after randomization (p = 0.004). However, after multivariable adjustment this numerical difference was no longer statistically significant. No gender-related differences in clinical outcome were observed after 1, 6 and 12 months of follow up. CONCLUSION: In this large-scale multicenter study in patients with CS complicating AMI, women had a worse-risk profile in comparison to men. No significant gender-related differences in treatment as well as short- and long term outcome were observed. PMID- 25287769 TI - Pheochromocytoma: a devious opponent in a game of hide-and-seek. PMID- 25287770 TI - ECG Response: October 7, 2014. PMID- 25287771 TI - Inflammatory abdominal aortic aneurysm with retroperitoneal fibrosis. PMID- 25287772 TI - Epicardial coronary artery compression secondary to pericardial adhesions demonstrated by multi-modality imaging, and treated by coronary stenting. PMID- 25287773 TI - Letter by Gasparini regarding article, "syncope in high-risk cardiomyopathy patients with implantable defibrillators: frequency, risk factors, mechanisms, and association with mortality: results from the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) study". PMID- 25287774 TI - Response to letter regarding article, "syncope in high-risk cardiomyopathy patients with implantable defibrillators: frequency, risk factors, mechanisms, and association with mortality: results from the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) study". PMID- 25287775 TI - Letter by Covolo et al regarding article, "accurate assessment of aortic stenosis: a review of diagnostic modalities and hemodynamics". PMID- 25287776 TI - Response to letter regarding article, "accurate assessment of aortic stenosis: a review of diagnostic modalities and hemodynamics". PMID- 25287778 TI - Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-alpha pathways. AB - Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Ralpha expression, IL-2 production by CD3(+)CD56(+) lymphocytes, and tumor necrosis factor (TNF)-alpha production. In co-culture assays, TNF-alpha directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-alpha decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide. PMID- 25287780 TI - Primary Liver PEComa. PMID- 25287779 TI - GAME (Goals - Activity - Motor Enrichment): protocol of a single blind randomised controlled trial of motor training, parent education and environmental enrichment for infants at high risk of cerebral palsy. AB - BACKGROUND: Cerebral palsy is the most common physical disability of childhood and early detection is possible using evidence based assessments. Systematic reviews indicate early intervention trials rarely demonstrate efficacy for improving motor outcomes but environmental enrichment interventions appear promising. This study is built on a previous pilot study and has been designed to assess the effectiveness of a goal - oriented motor training and enrichment intervention programme, "GAME", on the motor outcomes of infants at very high risk of cerebral palsy (CP) compared with standard community based care. METHODS/DESIGN: A two group, single blind randomised controlled trial (n = 30) will be conducted. Eligible infants are those diagnosed with CP or designated "at high risk of CP" on the basis of the General Movements Assessment and/or abnormal neuroimaging. A physiotherapist and occupational therapist will deliver home based GAME intervention at least fortnightly until the infant's first birthday. The intervention aims to optimize motor function and engage parents in developmental activities aimed at enriching the home learning environment. Primary endpoint measures will be taken 16 weeks after intervention commences with the secondary endpoint at 12 months and 24 months corrected age. The primary outcome measure will be the Peabody Developmental Motor Scale second edition. Secondary outcomes measures include the Gross Motor Function Measure, Bayley Scales of Infant and Toddler Development, Affordances in the Home Environment for Motor Development - Infant Scale, and the Canadian Occupational Performance Measure. Parent well-being will be monitored using the Depression Anxiety and Stress Scale. DISCUSSION: This paper presents the background, design and intervention protocol of a randomised trial of a goal driven, motor learning approach with customised environmental interventions and parental education for young infants at high risk of cerebral palsy. TRIAL REGISTRATION: This trial is registered on the Australian New Zealand Clinical Trial register: ACTRN12611000572965. PMID- 25287781 TI - Post-cholecystectomy biliary fistula. PMID- 25287783 TI - Decade in review-kidney cancer: discoveries, therapies and opportunities. PMID- 25287784 TI - Prostate cancer: Analysis of circulating tumour DNA could guide therapy. PMID- 25287786 TI - Infection: blocking bacterial biofilms on urinary bladder catheters. PMID- 25287785 TI - Management of ureteropelvic junction obstruction in adults. AB - Ureteropelvic junction obstruction (UPJO) is characterized by impaired flow of urine from the renal pelvis to the ureter. Untreated disease can result in renal impairment making effective management crucial. A combination of CT imaging and diuretic renography is typically used for diagnosis. CT is the investigation of choice for obtaining anatomical information about UPJO and can help to identify potential causes. Diuretic renography is best for providing functional information about UPJO. A variety of open and minimally invasive surgical techniques are available for treatment of UPJO. Traditionally open pyeloplasty has been the standard of care but minimally invasive surgical techniques have become increasingly popular. Endopyelotomy has a lower success rate than other modalities (42-90% depending on the approach), but is associated with reduced pain and shorter convalescence. Laparoscopic pyeloplasty and robot-assisted pyeloplasty have similar success rates to open pyeloplasty (>90%), with the additional advantages of significantly reduced morbidity and shorter convalescence. More long-term outcome data for minimally invasive surgical techniques are awaited. PMID- 25287788 TI - Cascade multicomponent synthesis of indoles, pyrazoles, and pyridazinones by functionalization of alkenes. AB - The development of multicomponent reactions for indole synthesis is demanding and has hardly been explored. The present study describes the development of a novel multicomponent, cascade approach for indole synthesis. Various substituted indole derivatives were obtained from simple reagents, such as unfunctionalized alkenes, diazonium salts, and sodium triflinate, by using an established straightforward and regioselective method. The method is based on the radical trifluoromethylation of alkenes as an entry into Fischer indole synthesis. Besides indole synthesis, the application of the multicomponent cascade reaction to the synthesis of pyrazoles and pyridazinones is described. PMID- 25287787 TI - Dispositional mindfulness predicts attenuated waking salivary cortisol levels in cancer survivors: a latent growth curve analysis. AB - PURPOSE: Cancer survivors experience significant stress and diminished well-being long after treatment. Dispositional mindfulness is linked with salutary coping with stress and enhanced well-being, with potentially beneficial effects on stress-related hormones. In the present study, we evaluated dispositional mindfulness as a predictor of changes in waking salivary cortisol levels among a sample of cancer survivors. METHODS: Mindfulness, well-being, and saliva samples were collected at baseline and at 4- and 12-week follow-ups. Latent growth curve analysis was conducted to examine baseline dispositional mindfulness as a predictor of changes in waking salivary cortisol over time, and regression analyses examined associations between well-being and cortisol. RESULTS: Findings indicated that cancer survivors who reported lower baseline levels of dispositional mindfulness exhibited increases in waking cortisol over time, whereas those who reported higher baseline dispositional mindfulness showed comparatively stable waking cortisol over the study period. Furthermore, increases in waking cortisol were associated with decreased well-being over the study period. CONCLUSIONS: This study provides preliminary evidence that cancer survivors with higher levels of dispositional mindfulness may be buffered from deleterious changes in cortisol secretion. IMPLICATIONS FOR CANCER SURVIVORS: Enhanced dispositional mindfulness may promote salutary neuroendocrine function among cancer survivors and thereby improve well-being during the survivorship process. PMID- 25287789 TI - Evaluation of pituitary function after infectious meningitis in childhood. AB - BACKGROUND: A number of studies of adults have shown that pituitary deficiencies can develop in a considerable proportion of subjects during the acute phase of meningitis or years after the infection has disappeared. The results of the very few studies of the impact of pediatric meningitis on hypothalamic-pituitary function are conflicting. METHODS: In order to determine the incidence of pituitary dysfunction in children with central nervous system infection, we evaluated pituitary function and anthropometric parameters in 19 children with meningitis of different etiologies (15 males; mean age +/- standard deviation [SD] at pituitary evaluation, 5.9 +/- 4.0 years; mean time from the acute event +/- SD, 18 +/- 10 months). RESULTS: All of the subjects had a normal stature and growth velocity for their age and gender, and none of them was obese. On the basis of Tanner's reference charts, 17 subjects (13 boys and all four girls) were pre-pubertal; two boys were in Tanner stage 2. None of the subjects had central hypothyroidism. All of the patients had normal serum of insulin growth factor (IGF)-I and prolactin. Their sex steroid and gonadotropin levels were concordant with their age and pubertal status. Early morning urine osmolality and serum electrolyte levels showed no signs of diabetes insipidus. All of the patients had normal plasma adrenocorticotropic hormone (ACTH) levels. Peak cortisol responses to the standard dose Synacthen test (SDST) were normal in all cases. CONCLUSIONS: The results showed that hypopituitarism following infectious meningitis appears to be infrequent in childhood and children's pituitary glands seem to be less vulnerable to damage than those of adults. PMID- 25287790 TI - An assessment of suicide attempts by self-poisoning in the west of Iran. AB - Intentional self-poisoning that is widely used all over the world is one of the most common methods of suicide. This study aim was to determine the rate of attempted intentional self-poisoning and to identify high risk persons in the west of Iran (Kermanshah). A total of 3138 people (1279 M and 1859 F) studied. The average annual rate of suicide in Kermanshah was 153 persons per 100 000 people. The most number of attempted intentional self-poisoning (55.5%) were in the 20-29 year age group. The most popular toxic substances for self-poisoning were drugs (71%) and oil and fuels (15%), respectively. The most number of intentional self-poisoning suicides are attempted by drugs. By considering the high rate of intentional self-poisoning, low age of suicide attempts and also its high mortality rate in Kermanshah, it is necessary to stop the opportunity to buy over-the-counter (OTC) drugs, especially those being most misused. PMID- 25287791 TI - Suicides in adolescence: a twelve-year study from Eastern Turkey. AB - Suicide is a form of behavior brought about by a combination of biological, psychological, and social factors and the adverse effects of those factors on individuals, their surroundings, society, and subsequent generations. In this study, attention is focused on the increase in adolescent suicides in Elazig and the surrounding province. The probable suicide cases among adolescent deaths that occurred in Eastern Turkey between 2001 and 2012 were examined retrospectively. A total of 67 cases were evaluated in terms of age, sex, method of death, death location, and the time of the year at which death occurred. Of the 67 study cases, 40 were female (59.70%) and 27 were male (40.29%). When the methods of suicide were analyzed, it was found that hanging came in first place with 34 cases (50.74%), followed by death using a firearm with 27 cases (40.29%). Other types of death were self-poisoning in four cases (5.97%) and jumping from a height in two cases (2.98%). According to this study, there are common risk factors both for suicidal thoughts and suicide attempts. Defining the prevalence of suicidal thoughts leading to suicide attempts, determining the risk factors, and evaluating the relationship between those factors and mental disorders will enable society to develop new approaches to suicidal behavior. PMID- 25287792 TI - Injuries in the vulnerable road user fatalities; a study from Sri Lanka. AB - Vulnerable Road Users defined as people at risk in traffic due to absence of an outside protective shield to absorb energy during a collision are mainly pedestrians, bicycle riders and motor cyclists. In low income countries, deaths of VRUs outnumber vehicular drivers and occupants. A forensic pathologist not only reports the cause of death but also forms opinions on type of road user. We attempted to find whether pedestrians could be differentiated from other types of VRUs. A retrospective descriptive study, based on case records of VRUs fatalities from 2005 to 2012 referred to a tertiary care unit for post-mortem examination, was conducted. A pro-forma was developed to extract data from the post-mortem reports and toxicology reports. Data was analysed using SPSS version16. Out of the 328 cases 48% (n = 157) were pedestrians while 45% (n = 147) were riders/pillion riders of two wheeled vehicles and 5% (n = 16) were drivers/occupants of three-wheelers. The majority (87%) was males and 43% of pedestrians were elderly. 59% had 10-25 injuries and 87% had external injuries in the head, face and neck. The majority of skeletal injuries were in the skull followed by ribs. Analysis of different variables of pedestrians to other types of VRUs showed that the variables of, elderly male, road crosser, skull injuries, brain injuries, cause of death being head injuries and multiple injuries were significantly greater among pedestrian group (p: <0.001). The traffic hours (peak and off peak), number of injuries, rib injuries, limb injuries, crushed/run over injuries or lung and liver injuries had no significant association. Although some features helped in determining a pedestrian, many other factors were not associated to differentiate a pedestrian from other VRUs. Therefore, a forensic pathologist has to be cautious in expressing opinions when other corroborative evidence is lacking. PMID- 25287793 TI - Forensic experience of Saudi nurses; an emerging need for forensic qualifications. AB - Forensic nursing was recognized as a nursing subspecialty after the perceived need for forensic nurses to bring about their nursing duties while at the same time helping legal authorities to deliver justice. With the increased rate of cases that are presenting to the forensic centers in Saudi Arabia, there was a need for the presence of nurses to work side by side to physicians. This study was aimed at determining the forensic qualifications of nurses working in emergency departments in the area of Dammam and their knowledge about principles of forensic nursing. A self-administered questionnaire was distributed to registered nurses who are working in Emergency departments of secondary hospitals in the area of Dammam. Questions included knowledge, awareness and attitude toward forensic nursing. A total of 96 participants responded to the questionnaire with females representing 78% (n: 75). Diploma was the highest earned nursing degree in 95% (n: 91) of participants. Only 33% (n: 32) were aware of the term forensic nursing and the majority of the respondents gave invalid or didn't know the answers to knowledge questions. A total of 77% (n: 74) agreed that they are not adequately trained for handling forensic cases. Saudi nurses need forensic education. The presence of qualified forensic nurses would help delivering optimal forensic services and would assist in bringing justice. PMID- 25287794 TI - Gamma-hydroxybutyric acid endogenous production and post-mortem behaviour - the importance of different biological matrices, cut-off reference values, sample collection and storage conditions. AB - Gamma-Hydroxybutyric Acid (GHB) is an endogenous compound with a story of clinical use, since the 1960's. However, due to its secondary effects, it has become a controlled substance, entering the illicit market for recreational and "dance club scene" use, muscle enhancement purposes and drug-facilitated sexual assaults. Its endogenous context can bring some difficulties when interpreting, in a forensic context, the analytical values achieved in biological samples. This manuscript reviewed several crucial aspects related to GHB forensic toxicology evaluation, such as its post-mortem behaviour in biological samples; endogenous production values, whether in in vivo and in post-mortem samples; sampling and storage conditions (including stability tests); and cut-off reference values evaluation for different biological samples, such as whole blood, plasma, serum, urine, saliva, bile, vitreous humour and hair. This revision highlights the need of specific sampling care, storage conditions, and cut-off reference values interpretation in different biological samples, essential for proper practical application in forensic toxicology. PMID- 25287795 TI - A crisis worker's observations on the psychosocial support for victims and families following child sexual abuse; a case study. AB - The Lancashire Sexual Assault Forensic Examination (SAFE) centre in Preston saw 204 children aged 16 and under for examination following allegation of sexual assault in 2013. The psychological impact on the child is well known but not always addressed correctly or appropriately; the impact and resulting difficulties faced by the parent/carer of the child can also easily go un noticed. Mrs A attended the centre with her 2 year old daughter in 2013, where I was the crisis worker in the case. She was contacted five months later and the support they received after attending the centre discussed. Her experiences, along with my own anecdotal experiences are discussed. Independent Sexual Assault Advisors (ISVAs) offer support following attendance at the centre, and various charitable organisations offer counselling, emotional and practical support. Health visitors, paediatricians, school nurses and social workers also play a role in looking after children and families following allegations of assault. However, the organisations and agencies involved in psychological aftercare for victims and parents are hindered by strict referral criteria and lack of funding or appropriate specialist expertise. The psychological, educational and behavioural support for parents and children, and specifically pre-trial counselling for children need significant improvement if we are to offer the best support for victims. PMID- 25287796 TI - An empirical analysis of suicidal death trends in India: a 5 year retrospective study. AB - Suicide, a major problem worldwide, continues to be a criminal offence in most of the developing countries of the world, including India. This paper retrospectively examines the latest trends and the relevant determinants of the suicidal deaths in one of the most important city of central India- Nagpur of Maharashtra state, carried out for a period of 5 years i.e. 2009-2013. Total 2036 cases were analyzed. An alarmingly increasing trend in the rate of suicides has been observed in the region, which increased from 16% to 22.68% during the study period. The male to female suicide ratio was found to be 2.50:1. The rate of suicidal deaths ranged from 15.34 to 21.74 per 100,000 populations. Hanging was found to be the most preferred mean adopted for suicide by males (54.77%) and females (47.65%), while, Family problems was the most common cause of suicide among both male (38.25%) and female (52.65%). The Suicides were concentrated in the age group of 30-44 years for males (35.76%), while in the age group of 15-29 years for females (51.75%). The prevalence was higher among the people who were married, being as high as 1099 (66.73%) males and 372 (56.45%) females. Highest trend has been found among the people with matriculate/secondary education level. The males with job in private sector accounted for 1007 suicides (61.14%) and 434 (65.86%) females in the category of housewives (non-working, homemakers) committed the same. PMID- 25287797 TI - The relevance of the Goudge inquiry to the practice of child protection/forensic paediatrics. AB - In 2008 Ontario, Canada the Goudge Inquiry arose following increasing concerns about practices surrounding forensic pathology and the investigation of paediatric deaths. Some of the considerations and recommendations have relevance to child protection/forensic paediatricians, particularly in relation to their responsibilities in opinion formulation and as expert witnesses. By examining the Inquiry recommendations, this paper applies them in relation to child protection/forensic paediatrics by discussing forensic medicine and its legal context, how interpretation of published reports and data should be used in opinion formulation; issues of 'diagnosis' versus 'opinion'; issues specific to child protection paediatrics; quality control; aspects of report writing and terminological considerations. It concludes with an adaptation of key recommendations directly from those of Goudge, applied to the context of paediatric forensic medicine undertaken in child protection assessments. PMID- 25287798 TI - Cartilage: a new parameter for the determination of the postmortem interval? AB - The determination of the time of death or the postmortem interval (PMI) is one of the most important and frequently asked questions in forensic medicine. The methods used for PMI determination are based largely on early and late postmortem changes. The determination of the PMI during the late postmortem changes is based primarily on a subjective assessment and is less precise due to the lack of objective methods. Different studies have presented a gradual decrease in chondrocytes' viability but these researches did not answer the question whether we can use the decrease of chondrocytes' viability for an objective PMI determination. The structure and anatomical location of the cartilage together with its mechanical, physical and chemical properties enable chondrocytes to survive for several weeks after the individual's death, and give cartilage the attributes of a compartment. Therefore, cartilage could be a new parameter for PMI determination. This idea had been partially confirmed by a few in vitro studies. The next step in testing this idea should be an extensive in corpore study. PMID- 25287799 TI - Does beta-APP staining of the brain in infant bed-sharing deaths differentiate these cases from sudden infant death syndrome? AB - Archival cerebral tissue from infants whose deaths were attributed to sudden infant death syndrome (SIDS) from South Australia and Western Denmark were stained for beta-amyloid precursor protein (beta-APP) and graded according to a simple scoring chart. The resulting APP scores were correlated with sleeping situation (shared vs. alone) showing a significantly higher amount of beta-APP staining in the non-bed-sharing, than in the bed-sharing infants (Mann-Whitney, Australia: p = 0.0128, Denmark: p = 0.0014, Combined: p = 0.0031). There was also a marked but non-significant difference in sex distribution between bed-sharers and non-bed-sharers with a male to female ratio of 1:1 in the first group and 2:1 in the latter. Of 48 Australian and 76 Danish SIDS infants, beta-APP staining was present in 116 (94%) cases. The eight negative cases were all from the Danish cohort. This study has shown that the amount of beta-APP staining was significantly higher in infants who were sleeping alone compared to those who were bed-sharing with one or more adults, in both an Australian and Danish cohort of SIDS infants. Whether this results from differences in the speed with which these infants die, differences in lethal mechanisms involving possible accidental asphyxiation in shared sleepers, or differences in the number of previous hypoxic ischemic events, remains to be clarified. PMID- 25287800 TI - Clinical forensic sample collection techniques following consensual intercourse in volunteers - cervical canal brush compared to conventional swabs. AB - The purpose of the research was to evaluate gynecological evidence collection techniques; the benefit of cervical canal brush sample compared to vaginal fornix and cervical swab samples and the time frame for detecting Y-chromosomal material QiAmp DNA Mini Kit((r)) and Quantifiler Y Human Male DNA Quantification Kit((r)) in adult volunteers following consensual intercourse. Eighty-four adult female volunteers following consensual intercourse were recruited for the study. By combining all sample collecting techniques, 81.0% of the volunteers were Y-DNA positive. Up to 60 h the conventional swab sampling techniques detected more Y DNA positive samples when compared to the brush technique. However, after 60 h, the cervical canal brush sample technique showed its benefit by detecting 27.3% (6/22) of Y-DNA positive samples, which were Y-DNA negative in both conventional swab sampling techniques. By combining swab and brush techniques, 75% of the volunteers were still Y-DNA positive in 72-144 post-coital hours. The rate of measurable Y-DNA decreased approximately 3% per hour. Despite reported consensual intercourse, 6.8% (3/44) of volunteers were Y-DNA negative within 48 h. Y-DNA was not detected after 144 post-coital hours (6 days). In conclusion, the brush as a forensic evidence collection method may provide additional biological trace evidence from the cervical canal, although the best biological trace evidence collection can be obtained by combining all three sampling techniques. The time frame for gynecological forensic evidence sample collection should be considered to be at least a week if sexual violence is suspected. PMID- 25287801 TI - Violence against physicians in training. A Romanian perspective. AB - The main purpose of this study was to assess whether there are differences between perceived and actual aggressions directed towards medical trainees from different medical specialties and different stages of medical training, and to characterize various types of aggressions against physicians in training in Romania. A multi-institutional survey was conducted in order to assess the prevalence of perceived and actual violence during medical residents; it included a total number of 384 medical residents from various specialties. Thirty two cases declared perceived physical aggression, most often in psychiatry. Actual physical aggression was 48% higher compared to perceived physical aggression. A similar situation occurred for sexual harassment, with only 9 perceived and 65 actual cases (an increase of 722%). Psychological abuse was the easiest to identify by the physicians in training, as the difference between perceived and actual aggression was minimal (202 and 205 respectively). The degree of perceived violence against physicians in training was much lower than the actual prevalence of the phenomenon, especially for physical and sexual types. This decreased awareness may lead to a failure in taking necessary safety measures and may subsequently increase the severity and consequences of the violent acts directed towards them. PMID- 25287802 TI - Oesophageal and gastric obstruction in a cocaine body packer. AB - While the management of asymptomatic body packers is mainly conservative, few individuals will require surgery for acute toxicity related to packets rupture, intestinal obstruction or very slow progression of the packages. Obstruction of the lower oesophagus or stomach is not frequently reported. We report the case of a 49-year-old woman who had ingested 92 cocaine-containing packages. She was admitted to the hospital after opioid syndrome related to the intake of morphine and codeine to decrease intestinal transit. The presence of more than 80 packages was suspected in the stomach on the initial abdomen computed tomography. Due to the absence of progression of the packages after four days of well-conducted laxative therapy and to major gastric distension at abdomen tomography, surgery was decided and gastrotomy allowed the evacuation of 80 packages that were still present in the stomach or in the lower oesophagus. In addition, 12 other packages had been retrieved either after laxative therapy (9) or by evacuation via the anal canal (3) after palpation of the intestine during the surgical procedure. No complication was observed. PMID- 25287803 TI - Suicidal ideation among medical students of Pakistan: a cross-sectional study. AB - Few studies have investigated suicidal ideation among medical students in the developing world. We found only one report on suicidal ideation among medical students in Pakistan published in the year 2005. The present cross-sectional survey on suicidal ideation conducted in July 2013 involved 331 medical students of Dow University of Health Sciences, Karachi, Pakistan. In the past one year, suicidal ideation was found in 118 (35.6%) students. Forty-six (13.9%) of all the students had made a plan in their life time to commit suicide while 16 (4.8%) of the 331 students tried to commit suicide at some point of time in their life. More females than males pondered suicide while first year medical students formed the majority of those with suicidal ideation. The single greatest risk factor predisposing to suicidal ideation was substance abuse. This was followed jointly by parental neglect and previous psychiatric disorder. Campaigns against substance abuse and counseling of vulnerable students will help in eradicating suicidal intent. PMID- 25287804 TI - Health needs of detainees in police custody in England and Wales. Literature review. AB - The aim of this systematic is to review and analyse the literature concerned with the health needs of detainees in police custody in England and Wales. The healthcare of detainees in police custody is regulated by the England and Wales Police and Criminal Evidence Act 1984. The Faculty of Forensic and Legal Medicine of the Royal College of Physicians also sets quality standards for the provision of custodial healthcare. The provision of healthcare in custody presents a number of challenges including the patient group, the setting and the overlap between the legal and medical concerns that are addressed by the medical team. Currently, care to the detainees in custody is delivered by a mixture of private organisations, police-led forensic medical services and the NHS. A search of the PUBMED, EMBASE and PsycINFO databases undertaken using the search terms: (police custody) OR (detainees) OR (police detainees) yielded 830 publications. All of the titles were screened to identify potentially relevant publications concerned with the health needs of detainees in police custodies in England and Wales. There were no design specific criteria set for inclusion of the studies in this literature review. 77 articles were initially identified as relevant and obtained in full. After further analysis 28 publications were included in this literature review. A total sample of over 12,000 detainees was examined in this literature review. Approximately 20% of detainees seen by health care teams suffer from psychiatric conditions. On average, 50% of patients claim that they have problems with drugs and alcohol. Physical health conditions are also highly prevalent with up to 74% of detainees requiring regular medication. Forensic medical issues included the management of detainees who were restrained using handcuffs, irritant sprays and TASER. Detainees who are suspected of internal drug concealment also require intensive medical input. Injury documentation in custody is often requested for both the police officer and detainees. Current literature indicates that mental health problems including substance misuse and physical conditions are highly prevalent among the custody population and require both emergency and routine care. The current quality of the health-care services has been discussed and the need for improvement has been indicated by a number of agencies. Recent attempts have been made to incorporate the custodial services into the general structure of the NHS, aiming for more robust governance and standardization of services. Implementation of a routine health promotion service in custody has also been discussed which can be integrated into the general health care provision during detention. PMID- 25287805 TI - Analysis of 121 fatal passenger car-adult pedestrian accidents in China. AB - To study the characteristics of fatal vehicle-pedestrian accidents in China,a team was established and passenger car-pedestrian crash cases occurring between 2006 and 2011 in Beijing and Chongqing, China were collected. A total of 121 fatal passenger car-adult pedestrian collisions were sampled and analyzed. The pedestrian injuries were scored according to Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). The demographical distributions of fatal pedestrian accidents differed from other pedestrian accidents. Among the victims, no significant discrepancy in the distribution of ISS and AIS in head, thorax, abdomen, and extremities by pedestrian age was found, while pedestrian behaviors prior to the crashes may affect the ISS. The distributions of AIS in head, thorax, and abdomen among the fatalities did not show any association with impact speeds or vehicle types, whereas there was a strong relationship between the ISS and impact speeds. Whether pedestrians died in the accident field or not was not associated with the ISS or AIS. The present results may be useful for not only forensic experts but also vehicle safety researchers. More investigations regarding fatal pedestrian accidents need be conducted in great detail. PMID- 25287806 TI - Response to "Hemodynamic consequences of restraints in the prone position in excited delirium syndrome". PMID- 25287807 TI - Hemodynamic consequences of restraints in the prone position in excited delirium syndrome. PMID- 25287808 TI - Intuitive steering assistance in critical understeer situations. AB - OBJECTIVE: To develop and verify a driver assistance function, working on the electric power steering of passenger cars, to support the driver on handling critical understeer situations. The main objectives of the so-called understeer assistance are reinforcing the driver's awareness of the driving conditions and giving support to handle the situation correctly without inducing irritation by abnormal steering behavior. METHODS: The system was designed in consideration of psychological aspects of human decision making while operating a vehicle in unfamiliar understeer situations. Using a comparison of vehicle dynamics with a reference model computed in the car, the level of understeer is calculated. Depending on the understeer level, the steering wheel restoring torque is increased while a vibration is applied to the steering wheel at the same time. To verify the achievement of the objectives, the standard steering system is compared to the developed understeer assistance in an active driving study on a test track. Not only objective measurement data but also subjective ratings delivered by 63 unbiased participants were used. RESULTS: The subjects follow the offered steering recommendation by steering less when the assistance function is activated (Deltagammamax = 44.38 degrees , p = 2.5 degrees .10-3%). In the sequel, an enhanced vehicle reaction arises that is validated by analyzing the achieved maximum lateral offset (DeltaSy,res = 0.16m, p = 0.07%). In addition, the evaluation of subjective ratings clearly indicates a better awareness of the understeer situation with the assistance function (chi= +0.44, p = 0.89%). Furthermore the subjects rate the understeer assistance better than the standard steering system (chi= +0.43, p = 3.03%). CONCLUSIONS: By measuring vehicle data and eliciting subjective opinions of the participants, the effectiveness regarding an improved handling of an understeering vehicle as well as the acceptance of the understeer assistance by the driver is confirmed. Larger subject groups and more realistic boundary conditions should be considered for additional evaluations. The approach of using standard vehicle hardware to adapt the vehicle to specific driving situations under consideration of psychological aspects of human decision making should be investigated further. PMID- 25287809 TI - Fetal pulse oximetry for fetal assessment in labour. AB - BACKGROUND: The use of conventional cardiotocographic (CTG) monitoring of fetal well-being during labour is associated with an increased caesarean section rate, compared with intermittent auscultation of the fetal heart rate, resulting in a reduction in neonatal seizures, although no differences in other neonatal outcomes. To improve the sensitivity of this test and therefore reduce the number of caesarean sections performed for nonreassuring fetal status, several additional measures of evaluating fetal well-being have been considered. These have demonstrated some effect on reducing caesarean section rates, for example, fetal scalp blood sampling for pH estimation/lactate measurement. The adaptation of pulse oximetry for use in the unborn fetus could potentially contribute to improved evaluation during labour and therefore lead to a reduction in caesarean sections for nonreassuring fetal status, without any change in neonatal outcomes. OBJECTIVES: To compare the effectiveness and safety of fetal intrapartum pulse oximetry with other surveillance techniques. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2014), contacted experts in the field and searched reference lists of retrieved studies. In previous versions of this review, we performed additional searches of MEDLINE, Embase and Current Contents. These searches were discontinued for this review update, as they consistently failed to identify any trials that were not shown in the Cochrane Pregnancy and Childbirth Group's Trials Register. SELECTION CRITERIA: All published and unpublished randomised controlled trials that compared maternal and fetal outcomes when fetal pulse oximetry was used in labour, (i) with or without concurrent use of conventional fetal surveillance, that is, cardiotocography (CTG), compared with using CTG alone or (ii) with or without concurrent use of both CTG and other method(s) of fetal surveillance, such as fetal electrocardiography (ECG) plus CTG. DATA COLLECTION AND ANALYSIS: At least two independent review authors performed data extraction. We sought additional information from the investigators of three of the reported trials. MAIN RESULTS: We included seven published trials: six comparing fetal pulse oximetry and CTG with CTG alone (or when fetal pulse oximetry values were blinded) and one comparing fetal pulse oximetry plus CTG with fetal ECG plus CTG. The published trials, with some unpublished data, were at high risk of bias in terms of the impractical nature of blinding participants and clinicians, as well as high risk or unclear risk of bias for outcome assessor for all but one report. Selection bias, attrition bias, reporting bias and other sources of bias were of low or unclear risk. The trials reported on a total of 8013 pregnancies. Differing entry criteria necessitated separate analyses, rather than meta analysis of all trials.Systematic review of four trials from 34 weeks not requiring fetal blood sampling (FBS) prior to study entry showed no evidence of differences in the overall caesarean section rate between those monitored with fetal oximetry and those not monitored with fetal pulse oximetry or for whom the fetal pulse oximetry results were masked (average risk ratio (RR) 0.99 using random-effects, 95% confidence intervals (CI) 0.86 to 1.13, n = 4008, I2 = 45%). There was evidence of a higher risk of caesarean section in the group with fetal oximetry plus CTG than in the group with fetal ECG plus CTG (one study, n = 180, RR 1.56, 95% CI 1.06 to 2.29). Neonatal seizures and neonatal encephalopathy were rare in both groups. No studies reported details of long-term disability.There was evidence of a decrease in caesarean section for nonreassuring fetal status in the fetal pulse oximetry plus CTG group compared to the CTG group, gestation from 34 weeks (average RR (random-effects) 0.65, 95% CI 0.46 to 0.90, n = 4008, I2 = 63%). There was no evidence of differences between groups in caesarean section for dystocia, although the overall incidence rates varied between the trials. AUTHORS' CONCLUSIONS: The addition of fetal pulse oximetry does not reduce overall caesarean section rates. One study found a higher caesarean section rate in the group monitored with fetal pulse oximetry plus CTG, compared with fetal ECG plus CTG. The data provide limited support for the use of fetal pulse oximetry when used in the presence of a nonreassuring CTG, to reduce caesarean section for nonreassuring fetal status. A better method than pulse oximetry is required to enhance the overall evaluation of fetal well-being in labour. PMID- 25287810 TI - Montasio cheese liking as affected by information about cows breed and rearing system. AB - European consumers are more and more aware of the credence attributes of foods, particularly of those of animal origin. The aim of the paper was to assess whether the information about production system may modify the consumer liking of cheese. Montasio PDO cheese (MC), usually made by milk from indoor reared cows of different breeds, was processed from pure milk of Italian Simmental (IS) cows (ISMC) or of IS cows grazing on mountain pasture (ALP-ISMC). A consumer test was carried out in two sessions on 60-d ripened cheeses. In the first, both cheeses were tasted by Montasio consumers in blind condition (Perceived liking, PL). Then the respondents were asked to read information about the breed and the rearing system and to give their Expected liking (EL). Two weeks after, in the second session, the same consumers tasted the two cheeses with the linked information (Actual liking, AL). Despite the similar PL average score (ISMC: 21+/-2.3 vs. ALP ISMC: 23+/-2.2 points on Labelled Affective Magnitude scale, P>0.05), it was possible to identifying consumers' clusters with differential liking for the two types of Montasio PDO, that were characterised by different physico-chemical properties. Consumers express a high EL for ISMC (38+/-2.6 points) and even more for ALP-ISMC (61+/-2.5 points). The AL of ISMC (35+/-2.1 points) was similar and statistically not different from the EL (complete assimilation of information about breed). For ALP-ISMC the assimilation was complete for consumers (29%) who have expressed a positive PL for it, at least twice as much than ISMC. For the rest of consumers, both information and intrinsic properties play a significant role in the AL of the pasture-derived cheese. PMID- 25287811 TI - The faculty of pain medicine of the Australian and New Zealand college of anaesthetists - history and strategic plan. AB - Since its formation, the Faculty of Pain Medicine (FPM) has grown into an organization with 369 fellows. It has 29 accredited pain medicine training units in Australia, New Zealand, Hong Kong, and Singapore. This article reviews the history of its birth and subsequent growth. The FPM fellowship is widely recognized as a high-quality qualification, based on a sound curriculum, excellent clinical exposure, and robust continuing professional development. But how does the Faculty position itself for the future? The Faculty's 5-year Strategic Plan (from 2013 to 2017) sets out its vision "to reduce the burden of pain in society through education, advocacy, training and research." PMID- 25287812 TI - Serum interleukin 6 (IL-6) as a potential biomarker of disease progression in active pulmonary tuberculosis following anti-tuberculosis drug therapy. PMID- 25287813 TI - Foreign bodies in the heart. AB - BACKGROUND: Foreign bodies in the heart are rare, may reach the heart by different ways, and cause serious complications. X-ray, computerized tomography, and echocardiography are main diagnostic modalities. Foreign body can be removed surgically, percutaneously or can be managed conservatively. In this work, we analyzed 100 published cases of a foreign body in the heart and 4 cases that were identified in our hospital. METHODS: We searched the literature for foreign body in the heart and found 100 published previously cases. Additional 4 cases were identified in our echo laboratory. A total series of 104 patients with a foreign body in the heart were analyzed for the etiology, clinical presentation, symptoms, complications and management. RESULTS: Mean patients' age was 46, there were more men than woman 73 versus 31 [P < 0.00005]. The most common foreign bodies were parts of inferior vena cava filters and devices implanted for relieving hydrocephalus. Foreign bodies in the heart were symptomatic in 56% of patients. Right heart chambers were occupied more often. A total of 20% presented within the first 24 hours and 30% of patients presented years after the penetration of the foreign body. A majority of foreign bodies reached the heart by migration [88%]. Mortality was reported in 4 patients [3.8%]. Here 54% of the patients underwent surgical and 29% percutaneous removal of the foreign body, while 14% were followed conservatively. CONCLUSION: Foreign bodies in the heart may present with a wide variety of symptoms. Physicians should be aware of this rare and peculiar complications which may be fatal. Larger devices may result in more severe complications. PMID- 25287814 TI - High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched-chain fatty acids. AB - The hallmark of nonalcoholic fatty liver disease is steatosis of unknown etiology. To test how dietary protein decreases steatosis, we fed female C57BL/6 J mice low-fat (8 en%) or high-fat (42 en%) combined with low-protein (11 en%), high-protein (HP; 35 en%) or extra-high-protein (HPX; 58 en%) diets for 3 weeks. The 35 en% protein diets reduced hepatic triglyceride, free fatty acid, cholesterol and phospholipid contents to ~50% of that in 11 en% protein diets. Every additional 10 en% protein reduced hepatic fat content ~1.5 g%. HP diets had no effect on lipogenic or fatty acid-oxidizing genes except Ppargc1alpha (+30%), increased hepatic PCK1 content 3- to 5-fold, left plasma glucose and hepatic glycogen concentration unchanged, and decreased inflammation and cell stress (decreased Fgf21 and increased Gsta expression). The HP-mediated decrease in steatosis correlated inversely with plasma branched-chain amino-acid (BCAA) concentrations and hepatic content of BCAA-derived monomethyl branched-chain fatty acids (mmBCFAs) 14-methylpentadecanoic (14-MPDA; valine-derived) and, to a lesser extent, 14-methylhexadecanoic acid (isoleucine-derived). Liver lipid content was 1.6- to 1.8-fold higher in females than in males, but the anti steatotic effect of HP diets was equally strong. The strong up-regulation of PCK1 and literature data showing an increase in phosphoenolpyruvate and a decline in tricarboxylic acid cycle intermediates in liver reveal that an increased efflux of these intermediates from mitochondria represents an important effect of an HP diet. The HP diet-induced increase in 14-MPDA and the dietary response in gene expression were more pronounced in females than males. Our findings are compatible with a facilitating role of valine-derived mmBCFAs in the antisteatotic effect of HP diets. PMID- 25287816 TI - Isolation and characterization of a prokaryotic cell organelle from the anammox bacterium Kuenenia stuttgartiensis. AB - Anaerobic ammonium oxidizing (anammox) bacteria oxidize ammonium with nitrite to nitrogen gas in the absence of oxygen. These microorganisms form a significant sink for fixed nitrogen in the oceans and the anammox process is applied as a cost-effective and environment-friendly nitrogen removal system from wastewater. Anammox bacteria have a compartmentalized cell plan that consists of three separate compartments. Here we report the fractionation of the anammox bacterium Kuenenia stuttgartiensis in order to isolate and analyze the innermost cell compartment called the anammoxosome. The subcellular fractions were microscopically characterized and all membranes in the anammox cell were shown to contain ladderane lipids which are unique for anammox bacteria. Proteome analyses and activity assays with the isolated anammoxosomes showed that these organelles harbor the energy metabolism in anammox cells. Together the experimental data provide the first thorough characterization of a respiratory cell organelle from a bacterium and demonstrate the essential role of the anammoxosome in the production of a major portion of the nitrogen gas in our atmosphere. PMID- 25287815 TI - Preventive supplementation with fresh and preserved peach attenuates CCl4-induced oxidative stress, inflammation and tissue damage. AB - The present study was elaborated to comparatively evaluate the preventive effect of different peach-derived products obtained from preserved fruits (Syrup and Preserve Pulp Peach [PPP]) and from fresh peels and pulps (Peel and Fresh Pulp Peach [FPP]) in a model of liver/renal toxicity and inflammation induced by carbon tetrachloride (CCl4) in rats. Tissue damage (carbonyl, thiobarbituric acid reactive species and sulfhydril), antioxidant enzymes activity (catalase and superoxide dismutase) and inflammatory parameters [tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta levels, and receptor for advanced glycation end products (RAGE) and nuclear factor (NF)kappaB-p65 immunocontent] were investigated. Our findings demonstrated that Peel, PPP and FPP (200 or 400 mg/kg) daily administration by oral gavage for 30 days conferred a significant protection against CCl4-induced antioxidant enzymes activation and, most importantly, oxidative damage to lipids and proteins as well as blocked induction of inflammatory mediators such as TNF-alpha, IL-1beta, RAGE and NFkappaB. This antioxidant/anti-inflammatory effect seems to be associated with the abundance of carotenoids and polyphenols present in peach-derived products, which are enriched in fresh-fruit-derived preparations (Peel and FPP) but are also present in PPP. The Syrup - which was the least enriched in antioxidants - displayed no protective effect in our experiments. These effects cumulated in decreased levels of transaminases and lactate dehydrogenase leakage into serum and maintenance of organ architecture. Therefore, the herein presented results show evidence that supplementation with peach products may be protective against organ damage caused by oxidative stress, being interesting candidates for production of antioxidant enriched functional foods. PMID- 25287817 TI - Photodynamic therapy using nanoparticle loaded with indocyanine green for experimental peritoneal dissemination of gastric cancer. AB - Although there have been multiple advances in the development of novel anticancer agents and operative procedures, prognosis of patients with advanced gastric cancer remains poor, especially in patients with peritoneal metastasis. In this study, we established nanoparticles loaded with indocyanine green (ICG) derivatives: ICG loaded lactosomes (ICGm) and investigated the diagnostic and therapeutic value of photodynamic therapy (PDT) using ICGm for experimental peritoneal dissemination of gastric cancer. Experimental peritoneal disseminated xenografts of human gastric cancer were established in nude mice. Three weeks after intraperitoneal injection of the cancer cells, either ICGm (ICGm-treated mice) or ICG solution (ICG-treated mice) was injected through the tail vein. Forty-eight hours after injection of the photosensitizer, in vivo and ex vivo imaging was carried out. For PDT, 48 h after injection of the photosensitizer, other mice were irradiated through the abdominal wall, and the body weight and survival rate were monitored. In vivo imaging revealed that peritoneal tumors were visualized through the abdominal wall in ICGm-treated mice, whereas only non specific fluorescence was observed in ICG-treated mice. The PDT reduced the total weight of the disseminated nodules and significantly improved weight loss and survival rate in ICGm-treated mice. In conclusion, ICGm can be used as a novel diagnostic and therapeutic nanodevice in peritoneal dissemination of gastric cancer. PMID- 25287818 TI - [Influence of surgical technique on graft and endothelial survival in endothelial keratoplasty]. AB - PURPOSE: To report survival of the graft and its endothelium after Descemet Stripping Endothelial Keratoplasty (DSEK) in a series of consecutive cases with no exclusion of cases corresponding to the learning curve and to analyze the influence of surgical techniques on survival. PATIENTS AND METHODS: This prospective observational study includes 170 consecutive DSEK's performed between 2006 and 2013. The main outcome criteria were graft survival and survival of the donor corneal endothelium as assessed by specular microscopy. The following parameters were analyzed: preoperative diagnosis, lens status, surgical techniques, and graft thickness. RESULTS: Graft survival was 91.7% at 1 year and 71.5% at 3 years. Graft survival was significantly associated with surgical technique (P=0.04). The best graft survival was achieved with scleral incision combined with graft insertion with the Endosaver(r) device (dedicated DSEK injector). Graft survival decreased with graft thickness (P<0.001). One-year endothelial cell density was significantly associated with surgical technique (P=0.003). Early 1-year endothelial cell loss was 42.0% for the scleral incision/Endosaver(r) group, 48.7% for the corneal incision/Endosaver(r) group, 49.4% for the corneal incision/Busin guide group, 66.0% for the corneal incision/IOL injector group, and 66.7% for the scleral incision/forceps group (P=0.002). CONCLUSION: The success rate of DSEK is close to that of penetrating keratoplasty. The use of a DSEK-dedicated injector results in higher survival of the graft and its endothelium. The use of ultrathin grafts also appears to represent significant progress. PMID- 25287819 TI - Cystic meningioma showing peripheral rim enhancement without mural nodule. PMID- 25287820 TI - Not everything that worsens on standing is intracranial hypotension! PMID- 25287821 TI - Four-week prevalence of mental disorders in patients with cancer across major tumor entities. AB - PURPOSE: To provide the 4-week prevalence estimates of mental disorders in cancer populations. PATIENTS AND METHODS: We enrolled adult patients with cancer from in and outpatient care facilities, using a proportional stratified random sample based on the nationwide cancer incidence in Germany. Patients who scored 9 or above on the Patient Health Questionnaire (PHQ-9) were administered to the standardized computer-assisted Composite International Diagnostic Interview for mental disorders adapted for cancer patients (CIDI-O). A random sample of those with a PHQ-9 score that was less than 9 were selected for a CIDI-O. RESULTS: A total of 5,889 patients were identified, which led to 4,020 participants (a 68.3% response rate); of those, 2,141 patients were interviewed. The 4-week total prevalence for any mental disorder was 31.8% (95% CI, 29.8% to 33.8%); this included any anxiety disorder (11.5%; 95% CI, 10.2% to 12.9%), any adjustment disorder (11.1%; 95% CI, 9.7% to 12.4%), any mood disorder (6.5%; 95% CI, 5.5% to 7.5%), any somatoform/conversion disorder (5.3%; 95% CI, 4.3% to 6.2%), nicotine dependence (4.5%; 95% CI, 3.6% to 5.4%), alcohol abuse/dependence (0.3%; 95% CI, 0.1% to 0.6%), any mental disorder resulting from general medical condition (2.3%; 95% CI, 1.7% to 2.9%), and any eating disorder (0%). The highest prevalence for any mental disorder was found in patients with breast cancer (41.6%; 95% CI, 36.8% to 46.4%), followed by patients with head and neck cancer (40.8%; 95% CI, 28.5% to 53.0%). The lowest prevalence was found in patients with pancreatic cancer (20.3%; 95% CI, 8.9% to 31.6%) and stomach/esophagus cancers (21.2%; 95% CI, 12.8% to 29.6%). CONCLUSION: Our findings provide evidence for the strong need for psycho-oncological interventions. PMID- 25287822 TI - Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. AB - PURPOSE: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). PATIENTS AND METHODS: Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). RESULTS: In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. CONCLUSION: Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib. PMID- 25287824 TI - Cost effectiveness of molecular profiling for adjuvant decision making in patients with node-negative breast cancer. AB - PURPOSE: To conduct an economic evaluation of the 70-gene signature used to guide adjuvant chemotherapy decision making both in patients with node-negative breast cancer (NNBC) and in the subgroup of estrogen receptor (ER) -positive patients. PATIENTS AND METHODS: We used a mixed approach combining patient-level data from a multicenter validation study of the 70-gene signature (untreated patients) and secondary sources for chemotherapy efficacy, unit costs, and utility values. Three strategies on which to base the decision to administer adjuvant chemotherapy were compared: the 70-gene signature, Adjuvant! Online, and chemotherapy in all patients. In the base-case analysis, costs from the French National Insurance Scheme, life-years (LYs), and quality-adjusted life-years (QALYs) were computed for the three strategies over a 10-year period. Cost effectiveness acceptability curves using the net monetary benefit were computed, combining bootstrap and probabilistic sensitivity analyses. RESULTS: The mean differences in LYs and QALYs were similar between the three strategies. The 70 gene signature strategy was associated with a higher cost, with a mean difference of ?2,037 (range, ?1,472 to ?2,515) compared with Adjuvant! Online and of ?657 (95% CI, -?642 to ?3,130) compared with systematic chemotherapy. For a ?50,000 per QALY willingness-to-pay threshold, the probability of being the most cost effective strategy was 92% (76% in ER-positive patients) for the Adjuvant! Online strategy, 6% (4% in ER-positive patients) for the systematic chemotherapy strategy, and 2% (20% in ER-positive patients) for the 70-gene strategy. CONCLUSION: Optimizing adjuvant chemotherapy decision making based on the 70-gene signature is unlikely to be cost effective in patients with NNBC. PMID- 25287823 TI - Individual prediction of heart failure among childhood cancer survivors. AB - PURPOSE: To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer. PATIENTS AND METHODS: Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models. RESULTS: Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%). CONCLUSION: Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions. PMID- 25287825 TI - Postinduction minimal residual disease monitoring by polymerase chain reaction in children with acute lymphoblastic leukemia. AB - PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Monitoring minimal residual disease (MRD) by using real-time quantitative polymerase chain reaction (RQ-PCR) provides information for patient stratification and individual risk-directed treatment. Cooperative studies have documented that measurement of blast clearance from the bone marrow during and after induction therapy identifies patient populations with different risk of relapse. We explored the possible contribution of measurements of MRD during the course of treatment. PATIENTS AND METHODS: We used RQ-PCR to detect MRD in 110 unselected patients treated in Italy in the International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia (AIEOP BFM ALL 2000). The trial took place in AIEOP centers during postinduction chemotherapy. Results were categorized as negative, low positive (below the quantitative range [< 5 * 10(-4)]), or high positive (>= 5 * 10(-4)). Patients with at least one low-positive or high-positive result were assigned to the corresponding subgroup. RESULTS: Patients who tested high positive, low positive, or negative had significantly different cumulative incidences of leukemia relapse: 83.3%, 34.8%, and 8.6%, respectively (P < .001). Two thirds of positive cases were identified within 4 months after induction-consolidation therapy, suggesting that this time frame may be most suitable for cost-effective MRD monitoring, particularly in patients who did not clear their disease at the end of consolidation. CONCLUSION: These findings provide further insights into the dynamic of MRD and the ongoing effort to define molecular relapse in childhood ALL. PMID- 25287826 TI - Geographic variation in use of laparoscopic colectomy for colon cancer. AB - PURPOSE: Emerging evidence supporting the use of laparoscopic colectomy in patients with cancer has led to dramatic increases in utilization. Though certain patient and hospital characteristics may be associated with the use of laparoscopy, the influence of geography is poorly understood. METHODS: We used national Medicare claims data from 2009 and 2010 to examine geographic variation in utilization of laparoscopic colectomy for patients with colon cancer. Patients were assigned to hospital referral regions (HRRs) where they were treated. Multivariable logistic regression was used to generate age, sex, and race adjusted rates of laparoscopic colectomy for each HRR. Patient quintiles of adjusted HRR utilization were used to evaluate differences in patient and hospital characteristics across low and high-utilizing HRRs. RESULTS: A total of 93,786 patients underwent colon resections at 3,476 hospitals during the study period, of which 30,502 (32.5%) were performed laparoscopically. Differences in patient characteristics between the lowest and highest quintiles of HRR utilization were negligible, and there was no difference in the availability of laparoscopic technology. Yet adjusted rates of laparoscopic colectomy utilization varied from 0% to 66.8% across 306 HRRs in the United States. CONCLUSION: There is wide geographic variation in the utilization of laparoscopic colectomy for Medicare patients with colon cancer, suggesting treatment location may substantially influence a patient's options for surgical approach. Future efforts to reduce variation will require increased dissemination of training techniques, novel opportunities for learning among surgeons, and enhanced educational resources for patients. PMID- 25287827 TI - Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. AB - PURPOSE: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600) mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. PATIENTS AND METHODS: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). RESULTS: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease >= 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib >= 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). CONCLUSION: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy >= 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy. PMID- 25287829 TI - Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. AB - PURPOSE: Patterns of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) -negative, antihepatitis B core antigen antibody (anti-HBc) positive patients with lymphoma receiving rituximab-containing chemotherapy have not been well described. PATIENTS AND METHODS: HBsAg-negative, anti-HBc-positive Chinese patients with undetectable serum HBV DNA (< 10 IU/mL), diagnosed with hematologic malignancies and receiving rituximab-containing chemotherapy, were prospectively monitored every 4 weeks for up to 2 years. Entecavir was started when HBV reactivation (defined as detectable HBV DNA) was encountered. RESULTS: Among 260 patients receiving rituximab-containing chemotherapy, 63 patients (24.2%) who were HBsAg negative and anti-HBc positive underwent follow-up for a median of 70 weeks (range, 6 to 104 weeks). The 2-year cumulative rate of HBV reactivation was 41.5%, occurring at a median of 23 weeks (range, 4 to 100 weeks) after rituximab treatment. The median HBV DNA level at reactivation was 43 IU/mL (range, 14 to 920 IU/mL). A baseline undetectable antibody to HBsAg (anti-HBs; < 10 mIU/mL) was the only significant risk factor that was positively associated with HBV reactivation (hazard ratio, 3.51; 95% CI, 1.37 to 8.98; P = .009). Patients with negative baseline anti-HBs, compared with those with positive anti HBs, had a significantly higher 2-year cumulative rate of HBV reactivation (68.3% v 34.4%; P = .012). At HBV reactivation, all patients had normal ALT, and all patients but one were HBsAg negative. Entecavir successfully controlled HBV reactivation in all patients. CONCLUSION: A high rate of HBV reactivation was observed in HBsAg-negative, anti-HBc-positive patients undergoing rituximab containing chemotherapy, with the risk of reactivation significantly higher in anti-HBs-negative patients. Periodic HBV DNA monitoring was an effective strategy in preventing HBV-related complications. PMID- 25287828 TI - Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Federation Francophone de Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) study. AB - PURPOSE: To compare epirubicin, cisplatin, and capecitabine (ECX) with fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatments in patients with advanced gastric or esophagogastric junction (EGJ) adenocarcinoma. PATIENTS AND METHODS: This open, randomized, phase III study was carried out in 71 centers. Patients with locally advanced or metastatic gastric or EGJ cancer were randomly assigned to receive either ECX as first-line treatment (ECX arm) or FOLFIRI (FOLFIRI arm). Second-line treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). The primary criterion was time-to-treatment failure (TTF) of the first-line therapy. Secondary criteria were progression-free survival (PFS), overall survival (OS), toxicity, and quality of life. RESULTS: In all, 416 patients were included (median age, 61.4 years; 74% male). After a median follow-up of 31 months, median TTF was significantly longer with FOLFIRI than with ECX (5.1 v 4.2 months; P = .008). There was no significant difference between the two groups in median PFS (5.3 v 5.8 months; P = .96), median OS (9.5 v 9.7 months; P = .95), or response rate (39.2% v 37.8%). First-line FOLFIRI was better tolerated (overall rate of grade 3 to 4 toxicity, 69% v 84%; P < .001; hematologic adverse events [AEs], 38% v 64.5%; P < .001; nonhematologic AEs: 53% v 53.5%; P = .81). CONCLUSION: FOLFIRI as first-line treatment for advanced gastric and EGJ cancer demonstrated significantly better TTF than did ECX. Other outcome results indicate that FOLFIRI is an acceptable first-line regimen in this setting and should be explored as a backbone regimen for targeted agents. PMID- 25287830 TI - Patterns and predictors of unplanned hospitalization in a population-based cohort of elderly patients with GI cancer. AB - PURPOSE: Hospitalizations among patients with cancer are common and costly and, if unplanned, may interrupt oncologic treatment. The rate of unplanned hospitalizations in the population of elderly patients with cancer is unknown. We sought to describe and quantify patterns and risk factors for early unplanned hospitalization among elderly patients with GI cancer. PATIENTS AND METHODS: We conducted a retrospective cohort study using linked Texas Cancer Registry and Medicare claims data from 2001 to 2009. Texas residents age 66 years or older initially diagnosed with GI cancer between 2001 and 2007 were included in the study. The unplanned hospitalization rate was estimated, and reasons for unplanned hospitalization were evaluated. Risk factors were identified using adjusted Cox proportional hazards modeling. RESULTS: Thirty thousand one hundred ninety-nine patients were included in our study, 59% of whom had one or more unplanned hospitalizations. Of 60,837 inpatient claims, 58% were unplanned. The rate of unplanned hospitalization was 93 events per 100 person-years. The most common reasons for unplanned hospitalization were fluid and electrolyte disorders, intestinal obstruction, and pneumonia. Multivariable analysis showed that black race; residing in census tracts with poverty levels greater than 13.3%; esophageal, gastric, and pancreatic cancer; advanced disease stage; high Charlson comorbidity index score; and dual eligibility for Medicare and Medicaid increased the risk for unplanned hospitalization (all P values < .05). CONCLUSION: Unplanned hospitalizations among elderly patients with GI cancer are common. Some of the top reasons for unplanned hospitalization are potentially preventable, suggesting that comorbidity management and close coordination among involved health care providers should be promoted. PMID- 25287831 TI - End-of-life care for older patients with ovarian cancer is intensive despite high rates of hospice use. AB - PURPOSE: To date, few studies have examined end-of-life care for patients with ovarian cancer. One study documented increased hospice use among older patients with ovarian cancer from 2000 to 2005. We sought to determine whether increased hospice use was associated with less-intensive end-of-life medical care. PATIENTS AND METHODS: We identified 6,956 individuals age >= 66 years living in SEER areas who were enrolled in fee-for-service Medicare, diagnosed with epithelial ovarian cancer between 1997 and 2007, and died as a result of ovarian cancer by December 2007. We examined changes in medical care during patients' last month of life over time. RESULTS: Between 1997 and 2007, hospice use increased significantly, and terminal hospitalizations decreased (both P < .001). However, during this time, we also observed statistically significant increases in intensive care unit admissions, hospitalizations, repeated emergency department visits, and health care transitions (all P <= .01). In addition, the proportion of patients referred to hospice from inpatient settings rose over time (P = .001). Inpatients referred to hospice were more likely to enroll in hospice within 3 days of death than outpatients (adjusted odds ratio, 1.36; 95% CI, 1.12 to 1.66). CONCLUSION: Older women with ovarian cancer were more likely to receive hospice services near death and less likely to die in a hospital in 2007 compared with earlier years. Despite this, use of hospital-based services increased over time, and patients underwent more transitions among health care settings near death, suggesting that the increasing use of hospice did not offset intensive end-of-life care. PMID- 25287833 TI - Consciousness science: real progress and lingering misconceptions. PMID- 25287832 TI - DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores. AB - DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26-33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts. PMID- 25287834 TI - Retracing in correlative light electron microscopy: where is my object of interest? AB - Correlative light electron microscopy (CLEM) combines the strengths of light and electron microscopy in a single experiment. There are many ways to perform a CLEM experiment and a variety of microscopy modalities can be combined either on separate instruments or as completely integrated solutions. In general, however, a CLEM experiment can be divided into three parts: probes, processing, and analysis. Most of the existing technologies are focussed around the development and use of probes or describe processing methodologies that explain or circumvent some of the compromises that need to be made when performing both light and electron microscopy on the same sample. So far, relatively little attention has been paid to the analysis part of CLEM experiments. Although it is an essential part of each CLEM experiment, it is usually a cumbersome manual process. Here, we briefly discuss each of the three above-mentioned steps, with a focus on the analysis part. We will also introduce an automated registration algorithm that can be applied to the analysis stage to enable the accurate registration of LM and EM images. This facilitates tracing back the right cell/object seen in the light microscope in the EM. PMID- 25287835 TI - Fluorescing the electron: strategies in correlative experimental design. AB - Correlative light and electron microscopy (CLEM) encompasses a growing number of imaging techniques aiming to combine the benefits of light microscopy, which allows routine labeling of molecules and live-cell imaging of fluorescently tagged proteins with the resolution and ultrastructural detail provided by electron microscopy (EM). Here we review three different strategies that are commonly used in CLEM and we illustrate each approach with one detailed example of their application. The focus is on different options for sample preparation with their respective benefits as well as on the imaging workflows that can be used. The three strategies cover: (1) the combination of live-cell imaging with the high resolution of EM (time-resolved CLEM), (2) the need to identify a fluorescent cell of interest for further exploration by EM (cell sorting), and (3) the subcellular correlation of a fluorescent feature in a cell with its associated ultrastructural features (spatial CLEM). Finally, we discuss future directions for CLEM exploring the possibilities for combining super-resolution microscopy with EM. PMID- 25287836 TI - Metallothioneins for correlative light and electron microscopy. AB - Structural biologists have been working for decades on new strategies to identify proteins in cells unambiguously. We recently explored the possibilities of using the small metal-binding protein, metallothionein (MT), as a tag to detect proteins in transmission electron microscopy. It had been reported that, when fused with a protein of interest and treated in vitro with gold salts, a single MT tag will build an electron-dense gold cluster ~1 nm in diameter; we provided proof of this principle by demonstrating that MT can be used to detect intracellular proteins in bacteria and eukaryotic cells. The method, which is compatible with a variety of sample processing techniques, allows specific detection of proteins in cells with exceptional sensitivity. We illustrated the applicability of the technique in a series of studies to visualize the intracellular distribution of bacterial and viral proteins. Immunogold labeling was fundamental to confirm the specificity of the MT-gold method. When proteins were double-tagged with green fluorescent protein and MT, direct correlative light and electron microscopy allowed visualization of the same macromolecular complexes with different spatial resolutions. MT-gold tagging might also become a useful tool for mapping proteins into the 3D-density maps produced by (cryo) electron tomography. New protocols will be needed for double or multiple labeling of proteins, using different versions of MT with fluorophores of different colors. Further research is also necessary to render the MT-gold labeling procedure compatible with immunogold labeling on Tokuyasu cryosections and with cryo-electron microscopy of vitreous sections. PMID- 25287837 TI - Correlative light microscopy and electron tomography to study Von Willebrand factor exocytosis from vascular endothelial cells. AB - Revealing the ultrastructure and function of fluorescently labeled cellular components by correlative light and electron microscopy (CLEM) facilitates the study of structure-function relationships in complex biological processes. Given the diversity of available fluorescent tags, light microscopy is ideal for monitoring dynamic cellular processes, while electron microscopy reveals the morphological context of structures at high resolution. Endothelial cells lining the blood vessel wall contain storage organelles called Weibel-Palade bodies (WPBs), which contain tubules of densely packed helical spirals of the blood coagulation protein Von Willebrand factor (VWF). Exocytosis of WPBs is triggered upon vascular damage and results in the transformation of stored tubular VWF into secreted extracellular VWF. Upon exocytosis, VWF rearranges into long filamentous strings to recruit platelets from the blood. During this secretion process, large intracellular VWF exocytosis structures are formed called secretory pods. Here, we describe a CLEM method used to study the relationship between the secretory pod and secreted VWF where confocal microscopy on whole cells was combined with serial electron tomography on chemically fixed, plastic-embedded sections. We show that the combination of these two well-established microscopy modalities provides a robust and generic CLEM method suitable for the characterization of VWF secretion sites. PMID- 25287838 TI - A simple procedure to analyze positions of interest in infectious cell cultures by correlative light and electron microscopy. AB - Plastic cell culture dishes that contain a thin bottom of highest optical quality including an imprinted finder grid (MU-Dish Grid-500) are optimally suited for routine correlative light and electron microscopy using chemical fixation. Such dishes allow high-resolution fluorescence and bright-field imaging using fixed and living cells and are compatible with standard protocols for scanning and transmission electron microscopy. Ease of use during cell culture and imaging, as well as a tight cover render the dishes particularly suitable for working with infectious organisms up to the highest biosafety level. Detailed protocols are provided and demonstrated by showing two examples: monitoring the production of virus-like particles of the Human Endogenous Retrovirus HERV-K(HML-2) by HeLa cells and investigation of Rab11-positive membrane-compartments of HeLa cells after infection with Chlamydia trachomatis. PMID- 25287839 TI - Correlative light and electron microscopy for a free-floating spindle in Xenopus laevis egg extracts. AB - Cryoimmobilization is an optimal method of preserving sample ultrastructure in electron microscopy studies. However, cryoimmobilization is limited to thin samples and this limitation may necessitate the isolation of the structure of interest. For cellular structures that are found in low number, or only during certain phases of the cell cycle, an added benefit of isolation is the possibility to concentrate the structures. We developed a method to perform correlative light and electron microscopy on infrequent isolated subcellular structures. In this chapter, we will describe our protocol that uses a combination of existing techniques and new solutions for the isolation, identification, cryoimmobilization, targeted ultramicrotomy, and imaging of the free-floating meiotic spindles assembled in Xenopus laevis egg extract. PMID- 25287840 TI - Combining wide-field super-resolution microscopy and electron tomography: rendering nanoscopic correlative arrays on subcellular architecture. AB - In this chapter, the authors outline in full detail, an uncomplicated approach that enables the combination of wide-field fluorescence super-resolution microscopy with electron tomography, thereby providing an approach that affords the best possible confidence in the structures investigated. The methodical steps to obtain these high-throughput correlative nanoscopic arrays will be visually explored and outlined in detail. The authors will demonstrate the feasibility of the method on cultured Caco-2 colorectal cancer cells that are labeled for filamentous actin. The presented images, morphometric data, and generated models illustrate the strengths of our correlative approach for future advanced structural-biology-oriented questions. Correlative nanoscopy applications can be readily found in which there is a need to reveal biomolecular information at unprecedented resolution on subcellular behavior in various biological and pathobiological processes. PMID- 25287841 TI - Correlative cryo-fluorescence and cryo-soft X-ray tomography of adherent cells at European synchrotrons. AB - Cryo-soft X-ray tomography (cryo-SXT) is a synchrotron-hosted imaging technique used to analyze the ultrastructure of intact, cryo-prepared cells. Correlation of cryo-fluorescence microscopy and cryo-SXT can be used to localize fluorescent proteins to organelles preserved close to native state. Cryo-correlative light and X-ray microscopy (cryo-CLXM) is particularly useful for the study of organelles that are susceptible to chemical fixation artifacts during sample preparation for electron microscopy. In our recent work, we used cryo-CLXM to characterize GFP-LC3-positive early autophagosomes in nutrient-starved HEK293A cells (Duke et al., 2013). Cup-shaped omegasomes were found to form at "hot spots" on the endoplasmic reticulum. Furthermore, cryo-SXT image stacks revealed the presence of large complex networks of tubulated mitochondria in the starved cells, which would be challenging to model at this scale and resolution using light or electron microscopy. In this chapter, we detail the cryo-CLXM workflow that we developed and optimized for studying adherent mammalian cells. We show examples of data collected at the three European synchrotrons that currently host cryo-SXT microscopes, and describe how raw cryo-SXT datasets are processed into tomoX stacks, modeled, and correlated with cryo-fluorescence data to identify structures of interest. PMID- 25287842 TI - Critical step-by-step approaches toward correlative fluorescence/soft X-ray cryo microscopy of adherent mammalian cells. AB - Soft X-ray cryo-microscopy/tomography with its extraordinary capability to map vitreous cells with high absorption contrast in their full three-dimensional extent, and at a resolution exceeding super-resolution fluorescence microscopy, is a valuable tool for integrative structural cell biology. Focusing on cell biological applications, its ongoing methodological development gained momentum by combining it with fluorescence cryo-microscopy, thus correlating highly resolved structural and specific information in situ. In this chapter, we provide a basic description of the techniques, as well as an overview of equipment and methods available to carry out correlative soft X-ray cryo-tomography experiments on frozen-hydrated cells grown on a planar support. Our aim here is to suggest ways that biologically representative data can be recorded to the highest possible resolution, while also keeping in mind the limitations of the technique during data acquisition and analysis. We have written from our perspective as electron cryo-microscopists/structural cell biologists who have experience using correlative fluorescence/cryoXM/T at synchrotron beamlines presently available for external users in Europe (HZB TXM at U41-FSGM, BESSY II, Berlin/Germany; Carl Zeiss TXMs at MISTRAL, ALBA, Barcelona/Spain, and B24, DLS, Oxfordshire, UK). PMID- 25287843 TI - Correlative cryo-fluorescence light microscopy and cryo-electron tomography of Streptomyces. AB - Light microscopy and electron microscopy are complementary techniques that in a correlative approach enable identification and targeting of fluorescently labeled structures in situ for three-dimensional imaging at nanometer resolution. Correlative imaging allows electron microscopic images to be positioned in a broader temporal and spatial context. We employed cryo-correlative light and electron microscopy (cryo-CLEM), combining cryo-fluorescence light microscopy and cryo-electron tomography, on vitrified Streptomyces bacteria to study cell division. Streptomycetes are mycelial bacteria that grow as long hyphae and reproduce via sporulation. On solid media, Streptomyces subsequently form distinct aerial mycelia where cell division leads to the formation of unigenomic spores which separate and disperse to form new colonies. In liquid media, only vegetative hyphae are present divided by noncell separating crosswalls. Their multicellular life style makes them exciting model systems for the study of bacterial development and cell division. Complex intracellular structures have been visualized with transmission electron microscopy. Here, we describe the methods for cryo-CLEM that we applied for studying Streptomyces. These methods include cell growth, fluorescent labeling, cryo-fixation by vitrification, cryo light microscopy using a Linkam cryo-stage, image overlay and relocation, cryo electron tomography using a Titan Krios, and tomographic reconstruction. Additionally, methods for segmentation, volume rendering, and visualization of the correlative data are described. PMID- 25287844 TI - Immuno correlative light and electron microscopy on Tokuyasu cryosections. AB - Finding a rare structure by electron microscopy is the equivalent of finding a "needle in a haystack." Correlative light- and immunoelectron microscopy (CLEM) on Tokuyasu cryosections is a sophisticated technique to address this challenge. Hereby, fluorescently labeled structures of interest are identified in an overview image by light microscopy and subsequently traced in electron microscopy. While the direct transfer and imaging of the same sections from optical to electron microscopy enables straightforward correlation, the sample preparation is crucial and technically demanding. We provide a detailed guide outlining the critical steps for sample embedding, cryosectioning, immunolabeling, and imaging. In the example provided, we use CLEM to trace aggregates formed in a zebrafish myopathy model expressing enhanced green fluorescent protein (eGFP) tagged actin. In our case, only a few muscle fibers express eGFP-actin with a subset of fibers containing aggregates. By fluorescence microscopy, we are able to identify the aggregates in the zebrafish tissue, and we subsequently, use immunoelectron microscopy to image the same structures at high resolution. The CLEM method described here using Tokuyasu cryosections can be applied to a large range of samples including small organisms, tissue samples, and cells. PMID- 25287845 TI - Step by step manipulation of the CryoCapsule with HPM high pressure freezers. AB - The CryoCapsule is a tool dedicated to correlative light to electron microscopy experiments. Focused on simplifying the specimen manipulation throughout the entire workflow from live-cell imaging to freeze substitution following cryofixation by high pressure freezing, we introduce here a step by step procedure to use the CryoCapsule either with the high pressure freezing machines: HPM010 or the HPM100. PMID- 25287846 TI - Live-cell CLEM of subcellular targets: an optimized procedure for polymer-based imaging substrates. AB - Live-cell correlative light and electron microscopy permits the visualization of ultrastructure details associated with dynamic biological processes. On the optical level, fluorescence microscopy can be further combined with functional studies of intracellular processes and manipulation of biological samples using laser light. However, the major challenge is to relocate intracellular compartments in three dimensions after the sample has undergone an extensive EM sample preparation process. Here, we describe a detailed protocol for live-cell CLEM that provides easy guidance for 3D relocalization. Based on the use of the novel polymer film TOPAS as direct imaging substrate, we provide a setup that uses highly visible toner particles for tracking the region of interest in 2D and fiducial markers for the 3D relocation of intracellular structures. An example is given where a single mitochondria is targeted by laser microirradiation in live cell fluorescence microscopy. After relocating the same structure in 3D in serial EM sections, the changes to the mitochondrial ultrastructure are observed by TEM. The method is suitable for correlation of live-cell microscopy of cells and can be performed using any inverted optical microscope. PMID- 25287847 TI - Correlative fluorescence and scanning transmission electron microscopy of quantum dot-labeled proteins on whole cells in liquid. AB - Correlative fluorescence microscopy combined with scanning transmission electron microscopy (STEM) of cells fully immersed in liquid is a new methodology with many application areas. Proteins, in live cells immobilized on microchips, are labeled with fluorescent quantum dot nanoparticles. In this protocol, the epidermal growth factor receptor (EGFR) is labeled. The cells are fixed after a selected labeling time, for example, 5 min as needed to form EGFR dimers. The microchip with cells is then imaged with fluorescence microscopy. Thereafter, STEM can be accomplished in two ways. The microchip with the labeled cells and one microchip with a spacer are assembled into a special microfluidic device and imaged with dedicated high-voltage STEM. Alternatively, thin edges of cells can be studied with environmental scanning electron microscopy with a STEM detector, by placing a microchip with cells in a cooled wet environment. PMID- 25287848 TI - The use of a laser for correlating light and electron microscopic images in thick tissue specimens. AB - Correlating images between light and electron microscopy is difficult especially in tissue specimens with a substantial z-dimension. To facilitate correlated light and electron microscopy (CLEM) in thick tissue specimens, we describe a basic method of using a femto-pulsed near-infrared laser to burn precise three dimensional fiducial markers that circumscribe cells or regions of interest for easy identification between imaging methods. This rapid and reliable approach permits traditional fixation and avoids the use of electron-dense labeling methods that can obscure ultrastructural details. The versatility of the technique permits CLEM in a variety of tissue specimens to allow interpretation of highly resolved ultrastructural data in the more macroscopic and potentially dynamic context of light microscopy. PMID- 25287849 TI - Correlative in vivo 2-photon imaging and focused ion beam scanning electron microscopy: 3D analysis of neuronal ultrastructure. AB - This protocol describes how dendrites and axons, imaged in vivo, can subsequently be analyzed in 3D using focused ion beam scanning electron microscopy (FIBSEM). The fluorescent structures are identified after chemical fixation and their position highlighted using the 2-photon laser to burn fiducial marks around the region. Once the section has been stained and resin embedded, a small block is trimmed close to these marks. Serially aligned EM images are acquired through this region, using FIBSEM, and the neurites of interest then reconstructed semi automatically using the Ilastik software (ilastik.org). This fast and reliable imaging and reconstruction technique avoids the use of specific labels to identify the features of interest in the electron microscope and optimizes their preservation for high-quality imaging and 3D analysis. PMID- 25287850 TI - Integrated light and scanning electron microscopy of GFP-expressing cells. AB - Integration of light and electron microscopes provides imaging tools in which fluorescent proteins can be localized to cellular structures with a high level of precision. However, until recently, there were few methods that could deliver specimens with sufficient fluorescent signal and electron contrast for dual imaging without intermediate staining steps. Here, we report protocols that preserve green fluorescent protein (GFP) in whole cells and in ultrathin sections of resin-embedded cells, with membrane contrast for integrated imaging. Critically, GFP is maintained in a stable and active state within the vacuum of an integrated light and scanning electron microscope. For light microscopists, additional structural information gives context to fluorescent protein expression in whole cells, illustrated here by analysis of filopodia and focal adhesions in Madin Darby canine kidney cells expressing GFP-Paxillin. For electron microscopists, GFP highlights the proteins of interest within the architectural space of the cell, illustrated here by localization of the conical lipid diacylglycerol to cellular membranes. PMID- 25287851 TI - Correlation of the same fields imaged in the TEM, confocal, LM, and microCT by image registration: from specimen preparation to displaying a final composite image. AB - Correlated imaging is the process of imaging a specimen with two complementary modalities and then registering and overlaying the fields obtained in each modality to create a composite view. One of the images is made somewhat transparent, allowing detail in the underlying image to be visible and assisting in the registration of the two images. As an example, an image localizing a specific tissue component by fluorescence may be overlaid atop a TEM image of the same field. The resulting composite image would demonstrate specific ultrastructural features in the high-resolution TEM field, which are colorized in the overlay. Other examples include composites from MicroCT or soft X-ray images overlaid atop light microscopy or TEM images. Automated image registration may be facilitated by a variety of sophisticated computer programs utilized by high throughput laboratories. This chapter is meant for the more occasional user wishing to align images manually. ImageJ is a public domain, image processing program developed at the National Institutes of Health and is available to anyone as a free download. ImageJ performs marvelously well for the purpose of image registration; therefore, step-by-step instructions are included here. Specimen handling, including fixation and choice of embedding media, is not straightforward for correlative imaging. A step-by-step description of the protocols which work in our laboratory is included for simultaneous localization in LM, EM and micro-CT, as well as maintaining GFP emission in tissue embedded for TEM. PMID- 25287852 TI - Preface. Correlative light and electron microscopy II. PMID- 25287854 TI - Online discourse on fibromyalgia: text-mining to identify clinical distinction and patient concerns. AB - BACKGROUND: The purpose of this study was to evaluate the possibility of using text-mining to identify clinical distinctions and patient concerns in online memoires posted by patients with fibromyalgia (FM). MATERIAL AND METHODS: A total of 399 memoirs were collected from an FM group website. The unstructured data of memoirs associated with FM were collected through a crawling process and converted into structured data with a concordance, parts of speech tagging, and word frequency. We also conducted a lexical analysis and phrase pattern identification. After examining the data, a set of FM-related keywords were obtained and phrase net relationships were set through a web-based visualization tool. RESULTS: The clinical distinction of FM was verified. Pain is the biggest issue to the FM patients. The pains were affecting body parts including 'muscles,' 'leg,' 'neck,' 'back,' 'joints,' and 'shoulders' with accompanying symptoms such as 'spasms,' 'stiffness,' and 'aching,' and were described as 'sever,' 'chronic,' and 'constant.' This study also demonstrated that it was possible to understand the interests and concerns of FM patients through text mining. FM patients wanted to escape from the pain and symptoms, so they were interested in medical treatment and help. Also, they seemed to have interest in their work and occupation, and hope to continue to live life through the relationships with the people around them. CONCLUSIONS: This research shows the potential for extracting keywords to confirm the clinical distinction of a certain disease, and text-mining can help objectively understand the concerns of patients by generalizing their large number of subjective illness experiences. However, it is believed that there are limitations to the processes and methods for organizing and classifying large amounts of text, so these limits have to be considered when analyzing the results. The development of research methodology to overcome these limitations is greatly needed. PMID- 25287853 TI - Optimizing polypharmacy among elderly hospital patients with chronic diseases- study protocol of the cluster randomized controlled POLITE-RCT trial. AB - BACKGROUND: Treatment of patients with multimorbidity is challenging. A rational reduction of long-term drugs can lead to decreased mortality, less acute hospital treatment, and a reduction of costs. Simplification of drug treatment schemes is also related to higher levels of patient satisfaction and adherence. The POLITE RCT trial will test the effectiveness of an intervention aiming at reducing the number of prescribed long-term drugs among multimorbid and chronically ill patients. The intervention focuses on the interface between primary and secondary health care and includes a pharmacist-based, patient-centered medication review prior to the patient's discharge from hospital. METHODS: The POLITE-RCT trial is a cluster randomized controlled trial. Two major secondary health care providers of Mecklenburg-Western Pomerania, Germany, take part in the study. Clusters are wards of both medical centers. All wards where patients with chronic diseases and multimorbidity are regularly treated will be included. Patients aged 65+ years who take five or more prescribed long-term drugs and who are likely to spend at least 5 days in the participating hospitals will be recruited and included consecutively. Cluster-randomization takes place after a six-month baseline data collection period. Patients of the control group receive care as usual. The independent two main primary outcomes are (1) health-related quality of life (EQ 5D) and (2) the difference in the number of prescribed long-term pharmaceutical agents between intervention and control group. The secondary outcomes are appropriateness of prescribed medication (PRISCUS list, Beers Criteria, MAI), patient satisfaction (TSQM), patient empowerment (PEF-FB-9), patient autonomy (IADL), falls, re-hospitalization, and death. The points of measurement are at admission to (T0) and discharge from hospital (T1) as well as 6 and 12 months after discharge from the hospital (T2 and T3). In 42 wards, 1,626 patients will be recruited. DISCUSSION: In case of positive evaluation, the proposed study will provide evidence for a sustainable reduction of polypharmacy by enhancing patient centeredness and patient autonomy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42003273. PMID- 25287855 TI - High prevalence of Staphylococcus aureus and methicillin-resistant S. aureus colonization among healthy children attending public daycare centers in informal settlements in a large urban center in Brazil. AB - BACKGROUND: In the past decade methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly prevalent in community settings. Attending a daycare center (DCC) is a known risk factor for colonization with MRSA. Brazil operates free, public DCCs for low-income families, some of which are located in census tracts defined by the Brazilian Census Bureau as informal settlements (aglomerados subnormais, AGSN). Physical and demographic characteristics of AGSNs suggest that S. aureus colonization prevalence would be higher, but little is known about the prevalence of MRSA in these settings. METHODS: We conducted a cross-sectional study to assess risk factors for S. aureus and MRSA colonization among children attending DCCs located in AGSN vs non-AGSN. Nasal swabs were collected from children aged three months to six years in 23 public DCCs in Niteroi, Brazil between August 2011 and October 2012. RESULTS: Of 500 children enrolled in the study, 240 (48%) were colonized with S. aureus and 31 (6.2%) were colonized with MRSA. Children attending DCCs in AGSNs were 2.32 times more likely to be colonized with S. aureus (95% CI: 1.32, 4.08), and 3.27 times more likely to be colonized with MRSA than children attending non-AGSN DCCs (95% CI: 1.52, 7.01), adjusted for confounding variables. CONCLUSION: S. aureus and MRSA colonization prevalence among children attending DCCs in informal settlement census tracts was higher than previously reported in healthy pre-school children in Latin America. Our data suggest that transmission may occur more frequently in DCCs rather than at home, highlighting the importance of DCCs in AGSNs as potential MRSA reservoirs. This finding underscores the importance of local epidemiologic surveillance in vulnerable AGSN communities. PMID- 25287856 TI - The cotton driver: an alternative technique for removing fractured screw fragments. PMID- 25287857 TI - Discovery and structural characterization of an allosteric inhibitor of bacterial cis-prenyltransferase. AB - Undecaprenyl pyrophosphate synthase (UPPs) is an essential enzyme in a key bacterial cell wall synthesis pathway. It catalyzes the consecutive condensations of isopentenyl pyrophosphate (IPP) groups on to a trans-farnesyl pyrophosphate (FPP) to produce a C55 isoprenoid, undecaprenyl pyrophosphate (UPP). Here we report the discovery and co-crystal structures of a drug-like UPPs inhibitor in complex with Streptococcus pneumoniae UPPs, with and without substrate FPP, at resolutions of 2.2 and 2.1 A, respectively. The UPPs inhibitor has a low molecular weight (355 Da), but displays potent inhibition of UPP synthesis in vitro (IC50 50 nM) that translates into excellent whole cell antimicrobial activity against pathogenic strains of Streptococcal species (MIC90 0.4 ug mL(-1) ). Interestingly, the inhibitor does not compete with the substrates but rather binds at a site adjacent to the FPP binding site and interacts with the tail of the substrate. Based on the structures, an allosteric inhibition mechanism of UPPs is proposed for this inhibitor. This inhibition mechanism is supported by biochemical and biophysical experiments, and provides a basis for the development of novel antibiotics targeting Streptococcus pneumoniae. PMID- 25287860 TI - Astrocyte reactivity and reactive astrogliosis: costs and benefits. AB - Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions. During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling. Reactive gliosis or reactive astrogliosis is a term coined for the morphological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases. Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function. Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment strategies that will, in a context dependent manner and at appropriate time points, modulate reactive astrogliosis to promote brain repair and reduce the neurological impairment. PMID- 25287862 TI - Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. AB - Mineral and bone metabolism are regulated differently in utero compared with the adult. The fetal kidneys, intestines, and skeleton are not dominant sources of mineral supply for the fetus. Instead, the placenta meets the fetal need for mineral by actively transporting calcium, phosphorus, and magnesium from the maternal circulation. These minerals are maintained in the fetal circulation at higher concentrations than in the mother and normal adult, and such high levels appear necessary for the developing skeleton to accrete a normal amount of mineral by term. Parathyroid hormone (PTH) and calcitriol circulate at low concentrations in the fetal circulation. Fetal bone development and the regulation of serum minerals are critically dependent on PTH and PTH-related protein, but not vitamin D/calcitriol, fibroblast growth factor-23, calcitonin, or the sex steroids. After birth, the serum calcium falls and phosphorus rises before gradually reaching adult values over the subsequent 24-48 h. The intestines are the main source of mineral for the neonate, while the kidneys reabsorb mineral, and bone turnover contributes mineral to the circulation. This switch in the regulation of mineral homeostasis is triggered by loss of the placenta and a postnatal fall in serum calcium, and is followed in sequence by a rise in PTH and then an increase in calcitriol. Intestinal calcium absorption is initially a passive process facilitated by lactose, but later becomes active and calcitriol-dependent. However, calcitriol's role can be bypassed by increasing the calcium content of the diet, or by parenteral administration of calcium. PMID- 25287858 TI - Regulation and function of adult neurogenesis: from genes to cognition. AB - Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders. PMID- 25287863 TI - Dynamic shaping of cellular membranes by phospholipids and membrane-deforming proteins. AB - All cellular compartments are separated from the external environment by a membrane, which consists of a lipid bilayer. Subcellular structures, including clathrin-coated pits, caveolae, filopodia, lamellipodia, podosomes, and other intracellular membrane systems, are molded into their specific submicron-scale shapes through various mechanisms. Cells construct their micro-structures on plasma membrane and execute vital functions for life, such as cell migration, cell division, endocytosis, exocytosis, and cytoskeletal regulation. The plasma membrane, rich in anionic phospholipids, utilizes the electrostatic nature of the lipids, specifically the phosphoinositides, to form interactions with cytosolic proteins. These cytosolic proteins have three modes of interaction: 1) electrostatic interaction through unstructured polycationic regions, 2) through structured phosphoinositide-specific binding domains, and 3) through structured domains that bind the membrane without specificity for particular phospholipid. Among the structured domains, there are several that have membrane-deforming activity, which is essential for the formation of concave or convex membrane curvature. These domains include the amphipathic helix, which deforms the membrane by hemi-insertion of the helix with both hydrophobic and electrostatic interactions, and/or the BAR domain superfamily, known to use their positively charged, curved structural surface to deform membranes. Below the membrane, actin filaments support the micro-structures through interactions with several BAR proteins as well as other scaffold proteins, resulting in outward and inward membrane micro-structure formation. Here, we describe the characteristics of phospholipids, and the mechanisms utilized by phosphoinositides to regulate cellular events. We then summarize the precise mechanisms underlying the construction of membrane micro-structures and their involvements in physiological and pathological processes. PMID- 25287865 TI - The biology of YAP/TAZ: hippo signaling and beyond. AB - The transcriptional regulators YAP and TAZ are the focus of intense interest given their remarkable biological properties in development, tissue homeostasis and cancer. YAP and TAZ activity is key for the growth of whole organs, for amplification of tissue-specific progenitor cells during tissue renewal and regeneration, and for cell proliferation. In tumors, YAP/TAZ can reprogram cancer cells into cancer stem cells and incite tumor initiation, progression and metastasis. As such, YAP/TAZ are appealing therapeutic targets in cancer and regenerative medicine. Just like the function of YAP/TAZ offers a molecular entry point into the mysteries of tissue biology, their regulation by upstream cues is equally captivating. YAP/TAZ are well known for being the effectors of the Hippo signaling cascade, and mouse mutants in Hippo pathway components display remarkable phenotypes of organ overgrowth, enhanced stem cell content and reduced cellular differentiation. YAP/TAZ are primary sensors of the cell's physical nature, as defined by cell structure, shape and polarity. YAP/TAZ activation also reflects the cell "social" behavior, including cell adhesion and the mechanical signals that the cell receives from tissue architecture and surrounding extracellular matrix (ECM). At the same time, YAP/TAZ entertain relationships with morphogenetic signals, such as Wnt growth factors, and are also regulated by Rho, GPCRs and mevalonate metabolism. YAP/TAZ thus appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context. PMID- 25287867 TI - Systematic review of fall risk screening tools for older patients in acute hospitals. AB - AIMS: To determine the most accurate fall risk screening tools for predicting falls among patients aged 65 years or older admitted to acute care hospitals. BACKGROUND: Falls represent a serious problem in older inpatients due to the potential physical, social, psychological and economic consequences. Older inpatients present with risk factors associated with age-related physiological and psychological changes as well as multiple morbidities. Thus, fall risk screening tools for older adults should include these specific risk factors. There are no published recommendations addressing what tools are appropriate for older hospitalized adults. DESIGN: Systematic review. DATA SOURCES: MEDLINE, CINAHL and Cochrane electronic databases were searched between January 1981-April 2013. Only prospective validation studies reporting sensitivity and specificity values were included. REVIEW METHODS: Recommendations of the Cochrane Handbook of Diagnostic Test Accuracy Reviews have been followed. RESULTS: Three fall risk assessment tools were evaluated in seven articles. Due to the limited number of studies, meta-analysis was carried out only for the STRATIFY and Hendrich Fall Risk Model II. In the combined analysis, the Hendrich Fall Risk Model II demonstrated higher sensitivity than STRATIFY, while the STRATIFY showed higher specificity. In both tools, the Youden index showed low prognostic accuracy. CONCLUSION: The identified tools do not demonstrate predictive values as high as needed for identifying older inpatients at risk for falls. For this reason, no tool can be recommended for fall detection. More research is needed to evaluate fall risk screening tools for older inpatients. PMID- 25287868 TI - A multi-step transmission electron microscopy sample preparation technique for cracked, heavily damaged, brittle materials. AB - A new technique for the preparation of heavily cracked, heavily damaged, brittle materials for examination in a transmission electron microscope (TEM) is described in detail. In this study, cross-sectional TEM samples were prepared from indented silicon carbide (SiC) bulk ceramics, although this technique could also be applied to other brittle and/or multiphase materials. During TEM sample preparation, milling-induced damage must be minimized, since in studying deformation mechanisms, it would be difficult to distinguish deformation-induced cracking from cracking occurring due to the sample preparation. The samples were prepared using a site-specific, two-step ion milling sequence accompanied by epoxy vacuum infiltration into the cracks. This technique allows the heavily cracked, brittle ceramic material to stay intact during sample preparation and also helps preserve the true microstructure of the cracked area underneath the indent. Some preliminary TEM results are given and discussed in regards to deformation studies in ceramic materials. This sample preparation technique could be applied to other cracked and/or heavily damaged materials, including geological materials, archaeological materials, fatigued materials, and corrosion samples. PMID- 25287866 TI - Impact of ozone exposure on the response to glucocorticoid in a mouse model of asthma: involvements of p38 MAPK and MKP-1. AB - BACKGROUND: Molecular mechanisms involved in the oxidative stress induced glucocorticoids insensitivity remain elusive. The mitogen-activated protein kinase phosphatase (MKP) 1 mediates a part of glucocorticoids action and can be modified by exogenous oxidants. Whether oxidant ozone (O3) can affect the function of MKP-1 and hence blunt the response to corticotherapy is not clear. METHODS: Here we employed a murine model of asthma established with ovalbumin (OVA) sensitization and challenge to evaluate the influence of O3 on the inhibitory effect of dexamethasone on AHR and airway inflammation, and by administration of SB239063, a selective p38 MAPK inhibitor, to explore the underlying involvements of the activation of p38 MAPK and the expression of MKP 1. RESULTS: Ozone exposure not only aggravated the pulmonary inflammation and AHR, but also decreased the inhibitory effects of dexamethasone, accompanied by the elevated oxidative stress, airway neutrophilia, enhanced phosphorylation of p38 MAPK, and upregulated expression of IL-17. Administration of SB239063 caused significant inhibition of the p38 MAPK phosphorylation, alleviation of the airway neutrophilia, and decrement of the ozone-induced IL-17 expression, and partly restored the ozone-impaired effects of dexamethasone. Ozone exposure not only decreased the protein expression of MKP-1, but also diminished the dexamethasone mediated induction process of MKP-1 mRNA and protein expression. CONCLUSIONS: The glucocorticoids insensitivity elicited by ozone exposure on current asthma model may involve the enhanced phosphorylation of p38 MAPK and disturbed expression of MKP-1. PMID- 25287869 TI - Pharyngolaryngeal paralysis in a patient with pharyngeal tuberculosis. AB - Pharyngeal tuberculosis is a rare disease, and its commonly reported symptoms include sore throat, dysphagia, and throat discomfort. The dysphagia in pharyngeal tuberculosis cases is not due to pharyngolaryngeal paralysis but due to odynophagia. Herein, we describe the first case of dysphagia caused by pharyngolaryngeal paralysis secondary to pharyngeal tuberculosis. An irregular mass at the right nasopharynx was detected in a 57-year-old female patient, along with dysphagia and hoarseness. She had poor right soft palate elevation, inadequate right velopharyngeal closure, poor constrictor pharyngus muscle contraction, and an immobilized right vocal cord, which collectively indicate right pharyngolaryngeal paralysis. Pathological examination and culture testing revealed pharyngeal tuberculosis. She was diagnosed with pharyngolaryngeal paralysis secondary to pharyngeal tuberculosis. The pharyngolaryngeal paralysis resolved after beginning anti-tuberculous treatment. Right pharyngolaryngeal paralysis was attributed to glossopharyngeal and vagus nerve impairment in the parapharyngeal space. Prior reports indicate that peripheral nerve paralysis, including recurrent laryngeal nerve paralysis caused by tuberculous lymphadenitis, often recovers after anti-tuberculous treatment. Pharyngeal tuberculosis rarely causes dysphagia and hoarseness attributable to pharyngolaryngeal paralysis. The neuropathy may recover after anti-tuberculous treatment. Pharyngeal tuberculosis is a new potential differential diagnosis in pharyngolaryngeal paralysis. PMID- 25287870 TI - Decision to recommend drug to cut drink dependence proves controversial. PMID- 25287871 TI - Profiling spontaneous speech decline in Alzheimer's disease: a longitudinal study. AB - OBJECTIVE: This study aims to document the nature and progression of spontaneous speech impairment suffered by patients with Alzheimer's disease (AD) over a 12 month period, using both cross-sectional and prospective longitudinal design. METHODS: Thirty one mild-moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex oral description task at baseline. The AD patients then underwent follow-up assessments at 6 and 12 months. RESULTS: Cross-sectional comparisons indicated that mild-moderate AD patients produced more word-finding delays (WFDs) and empty and indefinite phrases, while producing fewer pictorial themes, repairing fewer errors, responding to fewer WFDs, produce shorter and less complex phrases and produce speech with less intonational contour than controls. However, the two groups could not be distinguished on the basis of phonological paraphasias. Longitudinal follow-up, however, suggested that phonological processing deteriorates over time, where the prevalence of phonological errors increased over 12 months. Discussion Consistent with findings from neuropsychological, neuropathological and neuroimaging studies, the language deterioration shown by the AD patients shows a pattern of impairment dominated by semantic errors, which is later joined by a disruption in the phonological aspects of speech. PMID- 25287859 TI - Early developmental conditioning of later health and disease: physiology or pathophysiology? AB - Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention. PMID- 25287872 TI - beta-Carboline harmine reverses the effects induced by stress on behaviour and citrate synthase activity in the rat prefrontal cortex. AB - OBJECTIVES: The present study was aimed at evaluating the effects of the administration of beta-carboline harmine on behaviour and citrate synthase activity in the brain of rats exposed to chronic mild stress (CMS) procedure. METHODS: To this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days, then memory, anhedonia and citrate synthase activity were assessed. Result Our findings demonstrated that stressed rats treated with saline increased the sucrose intake, and the stressed rats treated with harmine reversed this effect. Neither stress nor harmine treatment altered memory performance in rats. In addition, chronic stressful situations induced increase in citrate synthase activity in the prefrontal cortex, but not in the hippocampus and striatum. Treatment with harmine reversed the increase in citrate synthase activity in the prefrontal cortex. CONCLUSION: These findings support the hypothesis that harmine could be involved in controlling the energy metabolism. PMID- 25287861 TI - Calcitonin gene-related peptide: physiology and pathophysiology. AB - Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (alpha and beta). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule. PMID- 25287873 TI - A comparison of cognitive functioning in acute schizophrenia and depression. AB - OBJECTIVE: Even though cognitive deficits are well recognised in schizophrenia and depression, direct comparisons between the disorders are scarce in literature. This study aims to assess specificity and degree of cognitive deficits in inpatients with acute schizophrenia and unipolar major depression. METHODS: A neuropsychological test battery was administered to 76 schizophrenic patients, 102 patients with unipolar major depression and 85 healthy controls (HCs), assessing verbal learning [Rey Auditory Verbal Learning Test (RAVLT)], processing speed (Trail Making Test), verbal fluency and visual memory (Wechsler Memory Scale-Revised test). RESULTS: Both patient groups were significantly impaired compared with HCs with regard to all test outcomes. The schizophrenia group (SG) performed significantly worse in the Wechsler Memory Scale and verbal fluency than the depression group (DG). The DG reached significantly lower scores than the SG in the RAVLT delayed recall subtest. No significant group difference between SG and DG was found for the Trail Making Test and the RAVLT direct recall trails. CONCLUSION: Our results indicate that cognitive impairment is present in both disorders. Schizophrenic patients performed worse than patients with unipolar depression in only two of the administered tests. Differences in cognitive performance between the groups are not as general as often assumed. Therefore, during the acute phase of illness, a diagnostic classification on the grounds of the patients' neurocognitive performance has to be done with caution. PMID- 25287864 TI - Neuronal SUMOylation: mechanisms, physiology, and roles in neuronal dysfunction. AB - Protein SUMOylation is a critically important posttranslational protein modification that participates in nearly all aspects of cellular physiology. In the nearly 20 years since its discovery, SUMOylation has emerged as a major regulator of nuclear function, and more recently, it has become clear that SUMOylation has key roles in the regulation of protein trafficking and function outside of the nucleus. In neurons, SUMOylation participates in cellular processes ranging from neuronal differentiation and control of synapse formation to regulation of synaptic transmission and cell survival. It is a highly dynamic and usually transient modification that enhances or hinders interactions between proteins, and its consequences are extremely diverse. Hundreds of different proteins are SUMO substrates, and dysfunction of protein SUMOylation is implicated in a many different diseases. Here we briefly outline core aspects of the SUMO system and provide a detailed overview of the current understanding of the roles of SUMOylation in healthy and diseased neurons. PMID- 25287874 TI - Association of schizophrenia with T102C (rs6313) and 1438 A/G (rs6311) polymorphisms of HTR2A gene. AB - OBJECTIVE: The aim of this study is to investigate whether there were any associations between the T102C and 1438 A/G polymorphisms of the 5-HT2A receptor gene and schizophrenia. We conducted a case-control study of the T102C and 1438 A/G polymorphisms in Turkish patients. METHODS: We compared genotypes and allele frequencies of T102C and 1438 A/G polymorphisms of 5-HT2A receptor gene in 102 patients with schizophrenia diagnosed, according to DSM-IV, and 107 healthy controls. Genotyping was performed by real-time polymerase chain reaction. RESULTS: We found no significant association between schizophrenia and genotypic or allele frequencies of HTR2A gene 102T/C (rs6313) and 1438 A/G (6311) polymorphisms. However, comparison of HTR2A gene 102 T/C and 1438 A/G polymorphisms in terms of genotypic and allele frequencies between the two patient groups, with or without a family history of schizophrenia, shows that T- and A-allele frequencies were significantly higher (p < 0.05) in the case group that has a history of schizophrenia in their family. CONCLUSION: In conclusion, our results do not support the hypothesis that the T102C and 1438 A/G polymorphisms in the 5-HT2A receptor gene are associated with schizophrenia, but further studies in a larger sample are needed. PMID- 25287875 TI - A gender-specific association of interleukin 1 receptor antagonist polymorphism with schizophrenia susceptibility. AB - OBJECTIVE: Recent genetic studies have revealed that the interleukin (IL) 1 gene complex is associated with schizophrenia in the Caucasian population; however, data from the North African population are limited. To further assess the role of interleukin 1 receptor antagonist protein (IL1Ra) in schizophrenia, we examined a functional multiallelic polymorphism localised in intron 2 of this receptor gene associated with an altered level of IL1Ra. METHODS: In the present case-control study, we have analysed the (86 bp) n polymorphism of the interleukin 1 receptor antagonist (IL1RN) gene (RS 1794068) by polymerase chain reaction genotyping in 259 patients with schizophrenia and 178 healthy controls from the Tunisian population. RESULTS: We showed that the frequencies of the IL1RN*2/2 genotype and allele 2 were higher in the patient group compared with the control group, and the difference was statistically significant [13.5% vs. 5.6%, p = 10-3, odds ratio (OR) = 3.2% and 32.8% vs. 21.9%, p = 3 * 10-4, OR = 1.76, respectively). When we evaluated the association between this genetic polymorphism and the clinical variables of schizophrenia, we found that the frequencies of the 2/2 genotype and allele 2 were significantly higher in the male patient group (p = 10 4 and 10-5, respectively) compared with the male control group, indicating a substantially increased risk for sex-onset schizophrenia with inheritance of the IL1RN2 allele. When the association between the genotypes and outcome was evaluated by multiple logistic regression analysis, the adjusted OR for the IL1RN genotypes remained statistically significant [1.39; 95% confidence interval (CI) = 1.11-1.73; p = 0.003]. CONCLUSION: The intron 2 polymorphism in IL1RN or a genetic polymorphism at proximity seems to be associated specifically with schizophrenia in the Tunisian male population. PMID- 25287876 TI - Neurogenic locus notch homolog protein 4 and brain-derived neurotrophic factor variants combined effect on schizophrenia susceptibility. AB - OBJECTIVES: To investigate the relationships between single-nucleotide polymorphisms (SNPs) in NOTCH4 and brain-derived neurotrophic factor (BDNF) with schizophrenia among Han Chinese in Southern China. METHODS: Two NOTCH4 SNPs (rs520688 and rs415929) and two BDNF SNPs (rs2030324 and rs12273539) were examined in 464 schizophrenics and 464 healthy controls from Hunan province in South China, using the Sequenom MassARRAY(r) iPLEX System. RESULTS: In the study population, rs520688 and rs2030324 were significantly associated with schizophrenia. A decreased risk of schizophrenia was associated with the rs520688 GA genotype (p = 0.035), whereas an increased risk of schizophrenia was associated with the rs2030324 CC/CT genotype (p = 0.044). The genotype distributions of rs415929 in NOTCH4 and rs12273539 in BDNF did not differ significantly between the case and control groups. Although no allele-allele interactions were detected between rs520688 and rs2030324, recombination analysis revealed a combined effect of the two on the susceptibility to schizophrenia, with GA-TT decreasing and CT/CC-GG/GA increasing the risk of schizophrenia. CONCLUSION: In conclusion, rs520688 in NOTCH4 and rs2030324 in BDNF are significantly associated with schizophrenia among Han Chinese in Southern China. The two had a combined effect on the susceptibility to schizophrenia among Han Chinese in Southern China, but this may not be caused by an allele-allele interaction. PMID- 25287877 TI - Memantine may affect pseudobulbar affect in patients with Alzheimer's disease. AB - OBJECTIVE: Behavioural symptoms are common in moderate to severe Alzheimer's disease (AD) and are improved by memantine with the most pronounced effect on agitation/aggression. Dextromethorphan in combination with quinidine is the only drug approved by US Food and Drug Administration for the treatment of pseudobulbar affect (PBA) on the basis of efficacy in patients with multiple sclerosis or amyotrophic lateral sclerosis. The aim of our study was to evaluate the efficacy of memantine on PBA in patients with AD. METHODS: In a prospective, double-blind, case-control study to assess PBA with pathological laughter and crying scale patients were administered memantine (final dose of 20 mg daily) or citalopram (20 mg once daily), each for 10 weeks. The number of episodes of involuntary emotional expression, Neuropsychiatric Inventory (NPI) and Overt Aggression Scale-Modified (OAS-M) total scores were also recorded. Furthermore, the platelet serotonin (5-HT) concentration was measured. RESULTS: Although memantine had beneficial effects on PBA, it also had a crucial impact on behavioural symptoms, especially aggression and agitation (to an average of 3.5 times higher end-point scores on OAS-M and increase of NPI total scores for an average of 114% of initial value). Therefore, the study was prematurely stopped. In addition, we had evidenced a drop of platelet 5-HT concentration (to an average of 73% of initial value). CONCLUSION: Surprisingly, our research showed the opposite action of memantine on neuropsychiatric symptoms as expected. In a limited number of AD patients with PBA, memantine had a beneficial effect on involuntary emotional expression, but it potentiated agitation/aggression, irritability and caused a crucial drop of the platelet 5-HT concentration. PMID- 25287878 TI - A manic episode after bilateral subthalamic stimulation in a patient with advanced Parkinson's disease. AB - Deep brain stimulation (DBS) has proven to be an effective treatment for patients with refractory symptoms in the advanced stages of Parkinson's disease. However, different psychiatric and cognitive problems may occur after DBS. We report a case of a manic episode after DBS of the subthalamic nucleus in a patient with advanced Parkinson's disease. After slow and gradually restart of the neurostimulation using the lowest effective intensity, the motor symptoms remained sufficiently under control without causing any psychiatric problems. PMID- 25287879 TI - 3D printing: a valuable resource in human anatomy education. PMID- 25287881 TI - Electric control of spin in monolayer WSe2 field effect transistors. AB - We report first-principles theoretical investigations of quantum transport in a monolayer WSe2 field effect transistor (FET). Due to strong spin-orbit interaction (SOI) and the atomic structure of the two-dimensional lattice, monolayer WSe2 has an electronic structure that exhibits Zeeman-like up-down spin texture near the K and K' points of the Brillouin zone. In a FET, the gate electric field induces an extra, externally tunable SOI that re-orients the spins into a Rashba-like texture thereby realizing electric control of the spin. The conductance of FET is modulated by the spin texture, namely by if the spin orientation of the carrier after the gated channel region, matches or miss matches that of the FET drain electrode. The carrier current I(tau, s) in the FET is labelled by both the valley index and spin index, realizing valleytronics and spintronics in the same device. PMID- 25287880 TI - A novel one-pot green synthesis of selenium nanoparticles and evaluation of its toxicity in zebrafish embryos. AB - Over the last 50 years, compelling evidence has accumulated on the beneficial role of selenium in human health. In the present study, different proteins were evaluated as reducing agents for the eco-friendly synthesis of selenium nanoparticles from an aqueous solution of sodium selenite. This method is a simple, low cost green synthesis alternative to chemical synthesis. The high conversion of selenium ions to selenium nanoparticles (SeNPs) was achieved by a reaction mixture of 0.1 g bovine serum albumin and 0.1 g sodium selenite at a reaction temperature of 121 degrees C for 20 min duration. The selenium nanoparticles were characterized by fourier transform infrared (FTIR), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy. The FTIR spectral bands were sharp with strong absorption peaks at 1649 and 1551 cm(-1). SEM analysis of the synthesized selenium nanoparticles clearly showed the spherical shape with an average size ranging from 500 to 600 nm. The toxicity of SeNPs was evaluated using zebrafish embryos as a model system. SeNPs induced malformations in zebrafish embryos in a concentration-dependent manner. Selenium nanoparticles at 15-25 MUg/ml concentration caused pericardial edema, tail malformation and decrease in heart rate in zebrafish embryos. Treatments with lower concentrations did not alter the heart rate or display any heart abnormalities. This study underlines the importance of identifying optimal SeNP concentration that could have potential therapeutic applications. PMID- 25287882 TI - Laparoscopic left adrenalectomy for suspected adrenocortical carcinoma (with video). PMID- 25287884 TI - CE-MS for metabolomics: developments and applications in the period 2012-2014. AB - In the field of metabolomics, CE-MS is now regarded as a useful complementary analytical technique for the profiling of (highly) polar ionogenic metabolites in biological samples. Over the past few years, significant advancements have been made in CE-MS approaches for metabolic profiling studies. This paper, which is a follow-up of three previous review papers covering the years 2000-2012 [Electrophoresis 2009, 30, 276-291; Electrophoresis 2011, 32, 52-65; Electrophoresis 2013, 34, 86-98], provides an update of these developments covering the scientific literature from July 2012 to June 2014. Attention will be paid to novel interfacing techniques for coupling CE to MS and their implications for metabolomics studies. The potential of CEC-MS and MEKC-MS are also considered, and CE-MS systems for high-throughput metabolic profiling are discussed. The applicability of CE-MS for metabolomics studies is demonstrated by representative examples in the fields of biomedical, clinical, microbial, plant, environmental, and food metabolomics. An overview of recent CE-MS-based metabolomics studies is given in a table, which provides information on sample type and pretreatment, capillary coatings, and MS detection mode. Finally, general conclusions and perspectives are given. PMID- 25287883 TI - What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? AB - AIMS: To examine changes in the evidence on the adverse health effects of cannabis since 1993. METHODS: A comparison of the evidence in 1993 with the evidence and interpretation of the same health outcomes in 2013. RESULTS: Research in the past 20 years has shown that driving while cannabis-impaired approximately doubles car crash risk and that around one in 10 regular cannabis users develop dependence. Regular cannabis use in adolescence approximately doubles the risks of early school-leaving and of cognitive impairment and psychoses in adulthood. Regular cannabis use in adolescence is also associated strongly with the use of other illicit drugs. These associations persist after controlling for plausible confounding variables in longitudinal studies. This suggests that cannabis use is a contributory cause of these outcomes but some researchers still argue that these relationships are explained by shared causes or risk factors. Cannabis smoking probably increases cardiovascular disease risk in middle-aged adults but its effects on respiratory function and respiratory cancer remain unclear, because most cannabis smokers have smoked or still smoke tobacco. CONCLUSIONS: The epidemiological literature in the past 20 years shows that cannabis use increases the risk of accidents and can produce dependence, and that there are consistent associations between regular cannabis use and poor psychosocial outcomes and mental health in adulthood. PMID- 25287885 TI - N-heterocyclic carbene-phosphinidyne transition metal complexes. AB - The N-heterocyclic carbene-phosphinidene adduct IPr?PSiMe3 is introduced as a synthon for the preparation of terminal carbene-phosphinidyne transition metal complexes of the type [(IPr?P)MLn ] (MLn =(eta(6) -p-cymene)RuCl) and (eta(5) -C5 Me5 )RhCl). Their spectroscopic and structural characteristics, namely low-field (31) P NMR chemical shifts and short metal-phosphorus bonds, show their similarity with arylphosphinidene complexes. The formally mononegative IPr?P ligand is also capable of bridging two or three metal atoms as demonstrated by the preparation of bi- and trimetallic RuAu, RhAu, Rh2 , and Rh2 Au complexes. PMID- 25287886 TI - Sequencing and molecular characterization of CTNCEC25, a China fixed rabies virus vaccine strain CTN-1 adapted to primary chicken embryo cells. AB - BACKGROUND: Rabies virus is the main etiologic agent of the widespread neurological disease rabies. Recently, the China rabies virus vaccine strain CTN 1 adapted to chicken embryo cells, which has been designated as CTNCEC25, was obtained and demonstrated to have high immunogenicity. However, the full genome sequence of CTNCEC25 and its phylogenetic relationship with other rabies virus street and vaccine strains have not been characterized. RESULTS: The complete genome of CTNCEC25 was sequenced and analyzed. The length of CTNCEC25 genome is 11,924 nucleotides (nt), comprising a 3' leader sequence of 59 nt, nucleoprotein (N) gene of 1,425 nt, phosphoprotein (P) gene of 989 nt, matrix protein (M) gene of 803 nt, glycoprotein (G) gene of 2,067 nt, RNA-dependent RNA polymerase gene (L) of 6,474 nt and a 5' trailer region of 71 nt. A comparison of the entire genomes of CTN-1 and CTNCEC25 identified 16 nt substitutions and 1 deletion, resulting in 8 amino acid (aa) changes in the five structural proteins with one in L (aa 1602), two in M (aa 99 and 191) and six in mature G (aa 147, 333, 389, 421 and 485). The percentage homology of the CTNCEC25 genomic sequence with other fully sequenced rabies virus strains ranged from 81.4% to 99.9%. Phylogenetic analysis indicated that CTNCEC25 was more closely related with those recently isolated China street strains than other vaccine strains. Virus growth analysis showed that CTNCEC25 achieved high rate of propagation in cultured cells. CONCLUSIONS: In this study, the complete genome of CTNCEC25 was sequenced and characterized. Our results showed that CTNCEC25 was more closely related to wild street strains circulating in China than other vaccine strains. Sequence analysis showed that the G protein ectodomain amino acid sequence identity between CTNCEC25 and other rabies virus strains was at least 90% identical. Furthermore, CTNCEC25 achieved high virus titers in cultured cells. Given that CTNCEC25 has high immunogenicity and induced strong protective immune response in animals, these results collectively demonstrated that CTNCEC25 is an ideal vaccine strain candidate for producing human vaccine with high quality and safety in China. PMID- 25287888 TI - Acquired interstitial hernia. PMID- 25287887 TI - Augmentation and repair tissue formation of the nucleus pulposus after partial nucleotomy in a rabbit model. AB - Disc degeneration alters disc height and mechanics of the spinal column and is associated with lower back pain. In preclinical studies gel-like materials or resorbable polymer-based implants are frequently used to rebuild the nucleus pulposus, aiming at tissue regeneration and restoration of tissue function. To compare the outcome of tissue repair, freeze-dried resorbable polyglycolic acid hyaluronan (PGA/HA) implants without any bioactive components or bioactivated fibrin (fibrin-serum) was used in a degenerated disc disease model in New Zealand white rabbits. Animals with partial nucleotomy only served as controls. The T2 weighted/fat suppression sequence signal intensity in the nuclear region of operated discs as assessed by magnet resonance imaging was reduced in operated compared to healthy discs, indicating loss of water and did not change from week 1 to month 6 after surgery. Quantification of histological and immunohistochemical staining indicated that the implantation of PGA/HA leads to significantly more repair tissue compared to nucleotomy only. Type II collagen content of the repair tissue formed after PGA/HA or fibrin-serum treatment is significantly increased compared to controls with nucleotomy only. The data indicate that intervertebral disc augmentation after nucleotomy has a positive effect on repair tissue formation and type II collagen deposition as shown in the rabbit model. PMID- 25287894 TI - Screening the antifungal activity of essential oils against decay fungi from palmyrah leaf handicrafts. AB - BACKGROUND: The whitish tender leaves of Palmyrah are used for making handicrafts. The problem with these articles is discolouration with time and become more brittle due to fungal attack. This could be prevented by some protective coating. Instead of expensive and harmful chemicals we decided to test natural plant essential oils to control fungal attack. Palmyrah leaf article decay fungi were isolated from two different sites of Jaffna peninsula. In this investigation Antifungal Activity of different plant essential oils from neem (Azadirachta indica), castor (Ricinus communis), citronella (Cymbopogon sp) and camphor (Cinnamomum camphora) obtained from local market have been evaluated against isolated fungi. For screening of Antifungal activity, tests and controls were set to determine minimum inhibitory concentration (MIC) and Percentage of Growth Inhibition. RESULTS: Morphologically three different types of Palmyrah leaf decay fungi were isolated and characterized as Aspergillus niger, Aspergillus flavus and Penicillium sp. Neem and castor oils have recorded no significant (0.05 > P) antifungal activity while citronella and camphor oils showed significantly different antifungal activity compared with control. Camphor oil and Citronella oil showed 100, 58.13% of average growth inhibition for A. niger. 96.38, 51.32% for A.flavus and 84.99, 72.76% for Penicillium sp respectively. Camphor oil showed highest percentage of growth inhibition at lowest minimum inhibitory concentration compared with citronella oil. Camphor oil was found to be highly antifungal and most effective against A niger, and A. flavus, compared with Penicillium sp and gave 100 percentage of growth inhibitions at 5, 1 and 15 ml/dl minimum inhibitory concentration respectively. CONCLUSION: Significantly higher broad-spectrum of antifungal activity was observed in camphor oil than other tested oils because it showed highest percentage of growth inhibition at lowest inhibitory concentration. Therefore it could be used for the development of new environmental friendly antifungal agent for the preservation of leafy handicrafts. Further formulation, field experiments are necessary to achieve this target. PMID- 25287896 TI - All in a tangle: a mishap with an oesophagostomy tube in an intubated cat. PMID- 25287889 TI - Modification by covalent reaction or oxidation of cysteine residues in the tandem SH2 domains of ZAP-70 and Syk can block phosphopeptide binding. AB - Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase (Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell antigen receptor signalling respectively. They are recruited, via their tandem SH2 (Src-homology domain 2) domains, to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of immune antigen receptors. Because of their critical roles in immune signalling, ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases. We show that three thiol-reactive small molecules can prevent the tandem-SH2 domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a specific cysteine residue in the phosphotyrosine-binding pocket of each protein (Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive to the presence of H2O2 and these two cysteine residues are also necessary for inhibition by H2O2. Our findings suggest a mechanism by which the reactive oxygen species generated during responses to antigen could attenuate signalling through these kinases and may also inform the development of ZAP-70 and Syk inhibitors that bind covalently to their SH2 domains. PMID- 25287895 TI - Effect of Chronic Heart Rate Reduction by I(f) Current Inhibitor Ivabradine on Left Ventricular Remodeling and Systolic Performance in Middle-Aged Rats With Postmyocardial Infarction Heart Failure. AB - BACKGROUND: A large myocardial infarction (MI) initiates progressive cardiac remodeling that leads to systolic heart failure (HF). Long-term heart rate reduction (HRR) induced by the I f current inhibitor ivabradine (IVA) ameliorates left ventricular (LV) remodeling and improves systolic performance in young post MI rats. However, the beneficial effects of chronic IVA treatment in middle-aged rats remain to be determined. METHODS: A large MI was induced in 12-month-old rats by left coronary artery ligation. Rats were treated with IVA via osmotic pumps intraperitoneal in a dose of 10.5 mg/kg/d (MI + IVA) and compared with MI and sham-operated animals 12 weeks after MI. RESULTS: Heart rate in MI + IVA rats was on average 29% lower than that of rats in the MI group. Left ventricular remodeling was comparable between post-MI groups, although MI + IVA rats did not show the compensatory thickening of the noninfarcted myocardium. Chronic HRR had no effect on transverse cardiac myocyte size and capillary growth, but it reduced the collagen content in noninfarcted myocardium. Left ventricular systolic performance remained similarly impaired in MI and MI + IVA rats. Moreover, abrupt IVA withdrawal led to worsening HF and reduction of coronary reserve. CONCLUSION: Our data reveal that chronic IVA-induced HRR does not provide sustainable benefits for LV systolic performance in middle-aged rats with post-MI HF. PMID- 25287897 TI - Expression of classical components of the renin-angiotensin system in the human eye. AB - PURPOSE: The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the adult human eye. METHODS: We obtained 14 post-mortem enucleated human eyes from patients whom had no history of inflammatory ocular disease nor pre-mortem ocular infection. We determined the gene expression for prorenin, renin, prorenin receptor, angiotensin-converting enzyme, angiotensinogen and angiotensin II Type 1 receptor, on tissue sections and in cultured human primary retinal pigment epithelial and iris pigment epithelial (RPE/IPE) cell lines, using both qualitative and quantitative reverse transcription polymerase chain reaction (RT PCR). Protein expression was studied using indirect immunofluorescence (IF). RESULTS: Almost all components of the classical RAS were found at high levels, at both the transcript and protein level, in the eyes' uvea and retina; and at lower levels in the cornea, conjunctiva and sclera. There was a much lower level of expression in the reference cultured RPE/IPE cells lines. CONCLUSION: This study describes the distribution of RAS in the normal adult human eye and demonstrates the existence of an independent ocular RAS, with uveal and retinal tissues showing the highest expression of RAS components. These preliminary findings provide scope for examination of additional components of this system in the human eye, as well as possible differential expression under pathological conditions. PMID- 25287898 TI - Urinary angiotensin-converting enzyme 2 increases in diabetic nephropathy by angiotensin II type 1 receptor blocker olmesartan. AB - INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) is a member of the renin angiotensin system that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7). We evaluated the changes in urinary ACE2 levels in response to treatment with the angiotensin II type 1 receptor blocker olmesartan in diabetes patients with nephropathy. MATERIALS AND METHODS: This prospective, open-label, interventional study was conducted with 31 type 2 diabetes patients with nephropathy. After initial evaluation, patients received 20 mg/day olmesartan, which was increased to 40 mg/day over a 24-week period. RESULTS: In diabetes patients with chronic kidney disease, olmesartan significantly increased urinary ACE2 levels independently of blood pressure and plasma aldosterone levels and reduced albuminuria, urinary liver-type fatty acid binding protein (L-FABP), and plasma aldosterone levels. Multivariable regression analysis revealed that the change in urinary L-FABP levels was an independent predictor of increased urinary ACE2 levels. CONCLUSION: Olmesartan may have the unique effect of increasing urinary ACE2 levels. However, whether this contributes to olmesartan's renoprotective effect must be examined further. PMID- 25287899 TI - Differences in autism spectrum disorders incidence by sub-populations in Israel 1992-2009: a total population study. AB - We analyzed data from the Israeli National Insurance Institute (NII). Autism Spectrum Disorder (ASD) incidence was calculated for all children born in Israel 1992-2009, and by population groups. Overall, 9,109 ASD cases among 2,431,649 children were identified. ASD cumulative incidence by age 8 years increased 10 fold during 2000-2011, from 0.49% to 0.49%, while other child disabilities in NII increased only 1.65-fold. There was a consistent increase in ASD incidence with advancing birth cohorts born 1992-2004, stabilizing among those born 2005-2009. ASD rates among Israeli Arabs were substantially lower, and increased about 10 years later than the general population. The findings suggest a role for ASD awareness, accessing of the government benefit, or the way the concept of ASD is perceived. PMID- 25287901 TI - Molecular classes in 209 patients with Prader-Willi or Angelman syndromes: lessons for genetic counseling. PMID- 25287900 TI - Parenting stress, salivary biomarkers, and ambulatory blood pressure: a comparison between mothers and fathers of children with autism spectrum disorders. AB - Parents of children with autism spectrum disorders (ASD) may experience higher levels of stress and health problems than parents of children with typical development. However, most research has focused on mothers, with emphasis on parent-reported stress and wellbeing. This study compared parenting responsibility, distress, anxiety, depression, cortisol, alpha-amylase, and cardiovascular activity between 19 mother-father dyads of children with ASD. Mothers reported higher parenting responsibility, distress, anxiety, and depression than fathers, while fathers had higher blood pressure and heart rate variability. Mothers and fathers had lower than average morning cortisol levels, suggesting stress effects on the hypothalamic-pituitary-adrenal-axis. Parents of children with ASD may benefit from routine health screening (particularly adrenal and cardiovascular function) and referral for stress reduction interventions or supports. PMID- 25287902 TI - Effects of long-term land use change on dissolved carbon characteristics in the permafrost streams of northeast China. AB - Permafrost soils act as large sinks of organic carbon but are highly sensitive to interference such as changes in land use, which can greatly influence dissolved carbon loads in streams. This study examines the effects of long-term land reclamation on seasonal concentrations of dissolved carbons in the upper reaches of the Nenjiang River, northeast China. A comparison of streams in natural and agricultural systems shows that the dissolved organic carbon (DOC) concentration is much lower in the agricultural stream (AG) than in the two natural streams (WAF, wetland dominated; FR, forest dominated), suggesting that land use change is associated with reduced DOC exporting capacity. Moreover, the fluorescence indexes and the ratio of dissolved carbon to nitrogen also differ greatly between the natural and agricultural streams, indicating that the chemical characteristics and the origin of the DOC released from the whole reaches are also altered to some extent. Importantly, the exporting concentration of dissolved inorganic carbon (DIC) and its proportion of total dissolved carbon (TDC) substantially increase following land reclamation, which would largely alter the carbon cycling processes in the downstream fluvial system. Although the strong association between the stream discharge and the DOC concentration was unchanged, the reduction in total soil organic carbon following land reclamation led to remarkable decline of the total flux and exporting coefficient of the dissolved carbons. The results suggest that dissolved carbons in permafrost streams have been greatly affected by changes in land use since the 1970s, and the changes in the concentration and chemical characteristics of dissolved carbons will last until the alteration in both the traditional agriculture pattern and the persistent reclamation activities. PMID- 25287904 TI - Genome-wide miRNA profiling in myelodysplastic syndrome with del(5q) treated with lenalidomide. AB - OBJECTIVES: Lenalidomide is a potent drug with pleiotropic effects in patients with myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 [del(5q)]. We investigated its effect on regulation of microRNA (miRNA) expression profiles in del(5q) patients with MDS in vivo. METHODS: We used miRNA expression microarrays to study changes in miRNA levels in peripheral blood CD14+ monocytes collected from patients before and during lenalidomide treatment and compared them with those from healthy donors. RESULTS: Before treatment, we observed strong upregulation of pro-apoptotic miR-34a and miR-34a* that diminished during lenalidomide exposure. Upregulation of HOX-related miR-196b and erythroid-specific miR-451 seen in untreated patients remained unchanged after the treatment. At the time of hematologic response, expression of several miRNAs clustering to the 14q32 locus was reduced. Additionally, we focused more deeply on miRNAs from the 5q commonly deleted region and found that levels of miR-378 and miR-378* followed haploinsufficiency trend. CONCLUSIONS: This report describes changes in miRNA expression in del(5q) patients with MDS treated with lenalidomide, likely arising from deregulation of pathways implicated in lenalidomide action. PMID- 25287903 TI - Effects of partial inhibition of respiratory complex I on H2O 2 production by isolated brain mitochondria in different respiratory states. AB - The aim of this work was to characterize the effects of partial inhibition of respiratory complex I by rotenone on H2O2 production by isolated rat brain mitochondria in different respiratory states. Flow cytometric analysis of membrane potential in isolated mitochondria indicated that rotenone leads to uniform respiratory inhibition when added to a suspension of mitochondria. When mitochondria were incubated in the presence of a low concentration of rotenone (10 nm) and NADH-linked substrates, oxygen consumption was reduced from 45.9 +/- 1.0 to 26.4 +/- 2.6 nmol O2 mg(-1) min(-1) and from 7.8 +/- 0.3 to 6.3 +/- 0.3 nmol O2 mg(-1) min(-1) in respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration), respectively. Under these conditions, mitochondrial H2O2 production was stimulated from 12.2 +/- 1.1 to 21.0 +/- 1.2 pmol H2O2 mg(-1) min( 1) and 56.5 +/- 4.7 to 95.0 +/- 11.1 pmol H2O2 mg(-1) min(-1) in respiratory states 3 and 4, respectively. Similar results were observed when comparing mitochondrial preparations enriched with synaptic or nonsynaptic mitochondria or when 1-methyl-4-phenylpyridinium ion (MPP(+)) was used as a respiratory complex I inhibitor. Rotenone-stimulated H2O2 production in respiratory states 3 and 4 was associated with a high reduction state of endogenous nicotinamide nucleotides. In succinate-supported mitochondrial respiration, where most of the mitochondrial H2O2 production relies on electron backflow from complex II to complex I, low rotenone concentrations inhibited H2O2 production. Rotenone had no effect on mitochondrial elimination of micromolar concentrations of H2O2. The present results support the conclusion that partial complex I inhibition may result in mitochondrial energy crisis and oxidative stress, the former being predominant under oxidative phosphorylation and the latter under resting respiration conditions. PMID- 25287905 TI - Timing of feather molt related to date of spring migration in male white-throated sparrows, Zonotrichia albicollis. AB - In migratory birds, the ability to depart wintering grounds at the appropriate time is an important determinant of fitness. Understanding the regulation of this timing will be essential for predicting whether timing of bird migration keeps up with global climate change. We examined whether the timing of the late-winter molt, in which white-throated sparrows (Zonotrichia albicollis) replace head and body feathers in advance of mating, may constrain the timing of northward migratory departure. In an observational study, we found a significant correlation between timing of molt and the date on which free-living male white throated sparrows disappeared from our study site during migration. The following year, we tested whether experimentally manipulating molt date by advancing photoperiod during temporary captivity would subsequently advance disappearance date once the birds were released. Sparrows that were experimentally induced to molt early disappeared from the wintering site before controls. However, the captive control birds also molted and disappeared from the site earlier than free living controls, suggesting that the diet during captivity had played a role. In the third winter we completed the study by advancing or delaying molt using only dietary manipulation. Together, these results show that the ability to molt early in spring is related to early disappearance from the wintering site. Early molt likely has carry-over effects on reproduction and the requirements of molt may prevent populations from adjusting migration timing in response to global climate change. PMID- 25287906 TI - Factors related to clinical quality improvement for small practices using an EHR. AB - OBJECTIVE: To analyze the impact of three primary care practice transformation program models on performance: Meaningful Use (MU), Patient-Centered Medical Home (PCMH), and a pay-for-performance program (eHearts). DATA SOURCES/STUDY SETTING: Data for seven quality measures (QM) were retrospectively collected from 192 small primary care practices between October 2009 and October 2012; practice demographics and program participation status were extracted from in-house data. STUDY DESIGN: Bivariate analyses were conducted to measure the impact of individual programs, and a Generalized Estimating Equation model was built to test the impact of each program alongside the others. DATA COLLECTION/EXTRACTION METHODS: Monthly data were extracted via a structured query data network and were compared to program participation status, adjusting for variables including practice size and patient volume. Seven QMs were analyzed related to smoking prevention, blood pressure control, BMI, diabetes, and antithrombotic therapy. PRINCIPAL FINDINGS: In bivariate analysis, MU practices tended to perform better on process measures, PCMH practices on more complex process measures, and eHearts practices on measures for which they were incentivized; in multivariate analysis, PCMH recognition was associated with better performance on more QMs than any other program. CONCLUSIONS: Results suggest each of the programs can positively impact performance. In our data, PCMH appears to have the most positive impact. PMID- 25287908 TI - Diagnosis and treatment of intrahepatic biliary cystadenoma: experience with 14 cases in a single center. AB - Intrahepatic biliary cystadenoma (IHBCA) is a rare type of liver tumor. There are no specific diagnostic methods for IHBCA, so its preoperative diagnostic rate is still fairly low. The aims of this study were to evaluate the clinical manifestations, diagnosis, and treatment of IHBCA. We retrospectively analyzed data from 14 patients treated in our hospital from January 2004 to April 2014. Eleven patients (78.6 %) were female, and the average age was 48.0 years (range 16-77 years). The most common clinical symptoms were abdominal discomfort (i.e., abdominal pain), reported in seven cases (50 %), and fullness after eating, reported in two cases (14.3 %). Jaundice was a less common symptom reported in one case (7.1 %). Four patients (28.6 %) were asymptomatic. Enhanced computed tomography (CT) scan showed multilocular or internal septations in 11 cases (78.6 %) and papillary projections or mural nodules on the cyst wall in one case (7.1 %). After injection of a contrast agent, the cyst walls or septations were slightly enhanced in nine cases (64.3 %). All 14 patients underwent surgical resection. Only one case showed recurrence (2 years postoperatively); the remaining 13 patients were recurrence-free. Intrahepatic biliary cystadenoma often occurs in middle-aged women. The main clinical symptoms are abdominal fullness with a sense of pain and jaundice. Enhanced CT is the main preoperative diagnostic method. Radical resection is the best treatment for IHBCA and can effectively prevent recurrence. PMID- 25287909 TI - Small therapeutic window of warfarin in Japanese population. PMID- 25287907 TI - Minimal residual disease in acute lymphoblastic leukemia: optimal methods and clinical relevance, pitfalls and recent approaches. AB - After advances in experimental and clinical testing, minimal residual disease (MRD) assay results are considered a determining factor in treatment of acute lymphoblastic leukemia patients. According to MRD assay results, bone marrow (BM) leukemic burden and the rate of its decline after treatment can be directly evaluated. Detailed knowledge of the leukemic burden in BM can minimize toxicity and treatment complications in patients by tailoring the therapeutic dose based on patients' conditions. In addition, reduction of MRD before allo-HSCT is an important prerequisite for reception of transplant by the patient. In direct examination of MRD by morphological methods (even by a professional hematologist), leukemic cells can be under- or over-estimated due to similarity with hematopoietic precursor cells. As a result, considering the importance of MRD, it is necessary to use other methods including flow cytometry, polymerase chain reaction (PCR) amplification and RQ-PCR to detect MRD. Each of these methods has its own advantages and disadvantages in terms of accuracy and sensitivity. In this review article, different MRD assay methods and their sensitivity, correlation of MRD assay results with clinical symptoms of the patient as well as pitfalls in results of these methods are evaluated. In the final section, recent advances in MRD have been addressed. PMID- 25287910 TI - Evaluation of denitrification-nitrification biofilter systems in treating wastewater with low carbon: nitrogen ratios. AB - A two-stage biological aerated/anoxic filter (BAF) system for denitrification nitrification was developed to increase nitrogen removal in the treatment of municipal wastewater with low carbon:nitrogen (C/N) ratio [Formula: see text]. This system exhibited a high denitrification efficiency (67%), despite the low C/N ratio, and the ratio of reduced nitrate to consumed organic compounds was greater than the theoretical value due to the minimization of the conversion of organic carbon to biomass growth, the maintenance of low levels of dissolved oxygen in recycled water, and the maximization of use of organic carbon biosorbed inside biomass in the denitrification BAF. The maximum rate of nitrogen removal was achieved at a recycle ratio of 170%, and the headloss in two BAFs was maintained after a 24-h backwash. Biological nitrogen removal in a two-stage BAF system was possible in a short hydraulic retention time (1.2 h) because the maximum reaction rates of nitrifiers and denitrifiers in each column were achieved. PMID- 25287912 TI - Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues. AB - Metastases to the central nervous system (CNS) are common in several cancer types. For most primary tumors that commonly metastasize to the CNS, molecular biomarker analyses are recommended in the clinical setting for selection of appropriate targeted therapies. Therapeutic efficacy of some of these agents has been documented in patients with brain metastases, and molecular testing of CNS metastases should be considered in the clinical setting. Here, we summarize the clinically relevant biomarker tests that should be considered in neurosurgical specimens based on the current recommendations of the European Society of Medical Oncology (ESMO) or the National Comprehensive Cancer Network (NCCN) for the most relevant primary tumor types: lung cancer (EGFR mutations, ALK rearrangement, BRAF mutations), breast cancer (HER2 amplification, steroid receptor overexpression), melanoma (BRAF mutations), and colorectal cancer (RAS mutations). Furthermore, we discuss emerging therapeutic targets including novel oncogenic alterations (ROS1 rearrangements, FGFR1 amplifications, CMET amplifications, and others) and molecular features of the tumor microenvironment (including immune-checkpoint molecules such as CTLA4 and PD-1/PD-L1). We also discuss the potential role of advanced biomarker tests such as next-generation sequencing and "liquid biopsies" for patients with CNS metastases. PMID- 25287914 TI - Risk factors for malignancy in branched-type intraductal papillary mucinous neoplasms of the pancreas during the follow-up period. AB - BACKGROUND: The international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas were revised in 2012 Tanaka (Pancreatology 12(3):183-197, 2012), making the indications for operation less aggressive. Therefore, the number of branch duct-type IPMN (BD IPMN) patients requiring follow-up care is expected to increase in the future. METHODS: The aim of this study was to identify risk factors for malignancy in BD IPMN patients during the follow-up period. This study included 47 BD-IPMN patients without a mural nodule (MN) at the time of initial diagnosis and who subsequently underwent resection after a follow-up period of more than 3 months. Data for the patients were reviewed retrospectively, and the clinicopathological factors were investigated. RESULTS: In a univariate analysis, age (? 65 years), an increase in the main pancreatic duct (MPD) diameter, the MPD diameter at resection (? 5 mm), and the occurrence of MN were significantly associated with malignancy. The occurrence of MN was the only significant factor in a multivariate analysis. In addition, 7 of the 17 patients (41.2 %) who only exhibited an increase in the cyst diameter during the follow-up period were diagnosed as having malignancies. All 6 patients who exhibited an increase in the cyst diameter of 100 % or more were diagnosed as having carcinoma. CONCLUSIONS: During the follow-up period, the incidence of malignancy was higher among patients with BD-IPMNs and the occurrence of MN, an increase in the MPD diameter, or an increase ratio of 100 % or more in cyst diameter than the others; resection was recommended for these patients. PMID- 25287911 TI - The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. AB - The amyloid precursor protein (APP) has occupied a central position in Alzheimer's disease (AD) pathophysiology, in large part due to the seminal role of amyloid-beta peptide (Abeta), a proteolytic fragment derived from APP. Although the contribution of Abeta to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP's involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPalpha, sAPPbeta), various C- and N terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the -YENPTY- motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology. PMID- 25287913 TI - Thermal green protein, an extremely stable, nonaggregating fluorescent protein created by structure-guided surface engineering. AB - In this article, we describe the engineering and X-ray crystal structure of Thermal Green Protein (TGP), an extremely stable, highly soluble, non-aggregating green fluorescent protein. TGP is a soluble variant of the fluorescent protein eCGP123, which despite being highly stable, has proven to be aggregation-prone. The X-ray crystal structure of eCGP123, also determined within the context of this paper, was used to carry out rational surface engineering to improve its solubility, leading to TGP. The approach involved simultaneously eliminating crystal lattice contacts while increasing the overall negative charge of the protein. Despite intentional disruption of lattice contacts and introduction of high entropy glutamate side chains, TGP crystallized readily in a number of different conditions and the X-ray crystal structure of TGP was determined to 1.9 A resolution. The structural reasons for the enhanced stability of TGP and eCGP123 are discussed. We demonstrate the utility of using TGP as a fusion partner in various assays and significantly, in amyloid assays in which the standard fluorescent protein, EGFP, is undesirable because of aberrant oligomerization. PMID- 25287915 TI - Effects of postoperative morbidity on long-term outcome following surgery for colorectal liver metastases. AB - BACKGROUND: The impact of postoperative complications on long-term outcomes after surgery for colorectal liver metastases (CRLM) remains controversial. During the last decade, advances in surgical as well as non-surgical treatment have increased resectability and altered outcomes. We sought to determine the influence of postoperative morbidity on disease-free (DFS) and overall survival (OS). METHODS: All patients undergoing liver resection for CRLM for the first time between 2000 and 2011 were retrospectively identified from a prospective database. Postoperative morbidity was classified according to Dindo-Clavien grade. A Dindo-Clavien grade >= 3a was considered a major complication. Primary outcomes were DFS and OS depending on the presence or absence of postoperative morbidity. RESULTS: Of the 266 included patients, 97 patients (37 %) developed postoperative complications, of whom 61 (23 %) had major complications. Median DFS and OS (5-year) were 17 and 53 months (42 %). The occurrence of postoperative morbidity did not significantly shorten OS (p = 0.130) and DFS (p = 0.101). However, major morbidity reduced DFS significantly (p < 0.05). CONCLUSION: In the present study, the occurrence of major postoperative complications was associated with diminished DFS. However, the effect of (major) complications on OS did not reach statistical significance. PMID- 25287916 TI - The influence of histological differentiation grade on the outcome of liver resection for hepatocellular carcinomas 2 cm or smaller in size. AB - BACKGROUND: Small hepatocellular carcinomas (HCC) with poorly differentiated components (PDC) are reportedly at risk of dissemination and needle tract seeding after percutaneous radiofrequency ablation, although it is the preferred treatment for HCC <= 2 cm because of the low rate of vascular invasion. On the other hand, the clinical outcomes after hepatectomy for these tumors are still unclear because of their rarity. METHODS: A total of 233 cases of solitary HCC <= 2 cm were retrospectively reviewed and divided into two groups according to the presence of PDC: 199 without PDC (NP-HCCs) and 34 with PDC (P-HCCs). The clinicopathological characteristics and prognosis were compared. RESULTS: A comparison of clinicopathological characteristics showed that the elevation of the tumor markers alpha-fetoprotein (AFP) (>20 ng/mL) and des-gamma carboxyprothrombin (DCP) (>40 AU/L) was significantly frequent in P-HCCs. The 3- and 5-year recurrence-free survival rates for P-HCCS were 39 and 29 %, respectively, which were significantly worse than those for NP-HCCs (64 and 50 %, respectively) (p < 0.01). Initial recurrence of P-HCCs was significantly more frequent, as well as extrahepatic recurrence and advanced recurrence in the early period after the operation. Recurrences with tumor dissemination were observed in 15 % of P-HCCs and 4 % of NP-HCCs (p = 0.03). CONCLUSION: PDC is present in 15 % of HCC < 2 cm and should be suspected when the both tumor markers are elevated. Moreover, significantly worse post-hepatectomy outcomes such as early advanced recurrence or recurrence with dissemination should be taken into account if PDC is present even in HCCs <= 2 cm. PMID- 25287917 TI - Diagnostic and therapeutic strategies to manage post-pancreaticoduodenectomy hemorrhage. AB - OBJECTIVE: To explore the causes, diagnosis and treatment of post pancreaticoduodenectomy hemorrhages (PPHs). METHODS: A database of 703 pancreaticoduodenectomy patients in our institution (January 2008-July 2013) was analyzed retrospectively. RESULTS: PPHs occurred in 62 patients of which, 38 had clear causes and 15 died because of uncontrolled bleeding and multiple organ failure. Pancreatic fistula and abdominal infection rates were significantly higher in the PPH group compared to the group who did not experience hemorrhages (P < 0.05) but did not significantly increase the mortality of PPH patients. Hemostasis was attempted by endotherapy in 7 patients and was successful in 4 (57.1 %). Angioembolization was performed in 12 patients and was successful in 10 (83.3 %) and relaparotomy in 24 patients successful in 13 (54.2 %). All deceased patients belonged to International Study Group of Pancreatic Surgery clinical grade C and sentinel bleeding occurred in 60 % of PPH mortalities (9/15) (P = 0.005). CONCLUSION: Pancreatic fistulae and abdominal infections are associated with PPH. Control of early mild upper gastrointestinal hemorrhages could be attempted by endotherapy, but angiography with intervention or surgical treatments were always required for delayed bleeding. The mortality in cases with sentinel bleedings was obviously increased. PMID- 25287918 TI - Aeromonas salmonicida binds differentially to mucins isolated from skin and intestinal regions of Atlantic salmon in an N-acetylneuraminic acid-dependent manner. AB - Aeromonas salmonicida subsp. salmonicida infection, also known as furunculosis disease, is associated with high morbidity and mortality in salmonid aquaculture. The first line of defense the pathogen encounters is the mucus layer, which is predominantly comprised of secreted mucins. Here we isolated and characterized mucins from the skin and intestinal tract of healthy Atlantic salmon and studied how A. salmonicida bound to them. The mucins from the skin, pyloric ceca, and proximal and distal intestine mainly consisted of mucins soluble in chaotropic agents. The mucin density and mucin glycan chain length from the skin were lower than were seen with mucin from the intestinal tract. A. salmonicida bound to the mucins isolated from the intestinal tract to a greater extent than to the skin mucins. The mucins from the intestinal regions had higher levels of sialylation than the skin mucins. Desialylating intestinal mucins decreased A. salmonicida binding, whereas desialylation of skin mucins resulted in complete loss of binding. In line with this, A. salmonicida also bound better to mammalian mucins with high levels of sialylation, and N-acetylneuraminic acid appeared to be the sialic acid whose presence was imperative for binding. Thus, sialylated structures are important for A. salmonicida binding, suggesting a pivotal role for sialylation in mucosal defense. The marked differences in sialylation as well as A. salmonicida binding between the skin and intestinal tract suggest interorgan differences in the host-pathogen interaction and in the mucin defense against A. salmonicida. PMID- 25287920 TI - Anaplasma marginale superinfection attributable to pathogen strains with distinct genomic backgrounds. AB - Strain superinfection occurs when a second pathogen strain infects a host already infected with a primary strain. The selective pressures that drive strain divergence, which underlies superinfection, and allow penetration of a new strain into a host population are critical knowledge gaps relevant to shifts in infectious disease epidemiology. In regions of endemicity with a high prevalence of infection, broad population immunity develops against Anaplasma marginale, a highly antigenically variant rickettsial pathogen, and creates strong selective pressure for emergence of and superinfection with strains that differ in their Msp2 variant repertoires. The strains may emerge either by msp2 locus duplication and allelic divergence on an existing genomic background or by introduction of a strain with a different msp2 allelic repertoire on a distinct genomic background. To answer this question, we developed a multilocus typing assay based on high throughput sequencing of non-msp2 target loci to distinguish among strains with different genomic backgrounds. The technical error level was statistically defined based on the percentage of perfect sequence matches of clones of each target locus and validated using experimental single strains and strain pairs. Testing of A. marginale-positive samples from tropical regions where A. marginale infection is endemic identified individual infections that contained unique alleles for all five targeted loci. The data revealed a highly significant difference in the number of strains per animal in the tropical regions compared to infections in temperate regions and strongly supported the hypothesis that transmission of genomically distinct A. marginale strains predominates in high prevalence areas of endemicity. PMID- 25287919 TI - Intracellular trafficking of AIP56, an NF-kappaB-cleaving toxin from Photobacterium damselae subsp. piscicida. AB - AIP56 (apoptosis-inducing protein of 56 kDa) is a metalloprotease AB toxin secreted by Photobacterium damselae subsp. piscicida that acts by cleaving NF kappaB. During infection, AIP56 spreads systemically and depletes phagocytes by postapoptotic secondary necrosis, impairing the host phagocytic defense and contributing to the genesis of infection-associated necrotic lesions. Here we show that mouse bone marrow-derived macrophages (mBMDM) intoxicated by AIP56 undergo NF-kappaB p65 depletion and apoptosis. Similarly to what was reported for sea bass phagocytes, intoxication of mBMDM involves interaction of AIP56 C terminal region with cell surface components, suggesting the existence of a conserved receptor. Biochemical approaches and confocal microscopy revealed that AIP56 undergoes clathrin-dependent endocytosis, reaches early endosomes, and follows the recycling pathway. Translocation of AIP56 into the cytosol requires endosome acidification, and an acidic pulse triggers translocation of cell surface-bound AIP56 into the cytosol. Accordingly, at acidic pH, AIP56 becomes more hydrophobic, interacting with artificial lipid bilayer membranes. Altogether, these data indicate that AIP56 is a short-trip toxin that reaches the cytosol using an acidic-pH-dependent mechanism, probably from early endosomes. Usually, for short-trip AB toxins, a minor pool reaches the cytosol by translocating from endosomes, whereas the rest is routed to lysosomes for degradation. Here we demonstrate that part of endocytosed AIP56 is recycled back and released extracellularly through a mechanism requiring phosphoinositide 3 kinase (PI3K) activity but independent of endosome acidification. So far, we have been unable to detect biological activity of recycled AIP56, thereby bringing into question its biological relevance as well as the importance of the recycling pathway. PMID- 25287921 TI - Contribution of the interaction of Streptococcus mutans serotype k strains with fibrinogen to the pathogenicity of infective endocarditis. AB - Streptococcus mutans, a pathogen responsible for dental caries, is occasionally isolated from the blood of patients with bacteremia and infective endocarditis (IE). Our previous study demonstrated that serotype k-specific bacterial DNA is frequently detected in S. mutans-positive heart valve specimens extirpated from IE patients. However, the reason for this frequent detection remains unknown. In the present study, we analyzed the virulence of IE from S. mutans strains, focusing on the characterization of serotype k strains, most of which are positive for the 120-kDa cell surface collagen-binding protein Cbm and negative for the 190-kDa protein antigen (PA) known as SpaP, P1, antigen I/II, and other designations. Fibrinogen-binding assays were performed with 85 clinical strains classified by Cbm and PA expression levels. The Cbm(+)/PA(-) group strains had significantly higher fibrinogen-binding rates than the other groups. Analysis of platelet aggregation revealed that SA31, a Cbm(+)/PA(-) strain, induced an increased level of aggregation in the presence of fibrinogen, while negligible aggregation was induced by the Cbm-defective isogenic mutant SA31CBD. A rat IE model with an artificial impairment of the aortic valve created using a catheter showed that extirpated heart valves in the SA31 group displayed a prominent vegetation mass not seen in those in the SA31CBD group. These findings could explain why Cbm(+)/PA(-) strains are highly virulent and are related to the development of IE, and the findings could also explain the frequent detection of serotype k DNA in S. mutans-positive heart valve clinical specimens. PMID- 25287922 TI - Cyclic AMP-mediated suppression of neutrophil extracellular trap formation and apoptosis by the Bordetella pertussis adenylate cyclase toxin. AB - The adenylate cyclase toxin (ACT) of Bordetella pertussis intoxicates target cells by generating supraphysiologic levels of intracellular cyclic AMP (cAMP). Since ACT kills macrophages rapidly and potently, we asked whether ACT would also kill neutrophils. In fact, ACT prolongs the neutrophil life span by inhibiting constitutive apoptosis and preventing apoptosis induced by exposure to live B. pertussis. Imaging of B. pertussis-exposed neutrophils revealed that B. pertussis lacking ACT induces formation of neutrophil extracellular traps (NETs), whereas wild-type B. pertussis does not, suggesting that ACT suppresses NET formation. Indeed, ACT inhibits formation of NETs by generating cAMP and consequently inhibiting the oxidative burst. Convalescent-phase serum from humans following clinical pertussis blocks the ACT-mediated suppression of NET formation. These studies provide novel insight into the phagocyte impotence caused by ACT, which not only impairs neutrophil function but also inhibits death of neutrophils by apoptosis and NETosis. PMID- 25287923 TI - Simultaneous exposure to Escherichia coli heat-labile and heat-stable enterotoxins increases fluid secretion and alters cyclic nucleotide and cytokine production by intestinal epithelial cells. AB - Enterotoxigenic Escherichia coli (ETEC) is a significant cause of diarrheal disease and death, especially in children in developing countries. ETEC causes disease by colonizing the small intestine and producing heat-labile toxin (LT), heat-stable toxin (ST), or both LT and ST (LT+ST). The majority of ETEC strains produce both ST and LT. Despite the prevalence of LT+ST-producing organisms, few studies have examined the physiologic or immunologic consequences of simultaneous exposure to these two potent enterotoxins. In the current report, we demonstrate that when LT and ST are both present, they increase water movement into the intestinal lumen over and above the levels observed with either toxin alone. As expected, cultured intestinal epithelial cells increased their expression of intracellular cyclic GMP (cGMP) when treated with ST and their expression of intracellular cyclic AMP (cAMP) when treated with LT. When both toxins were present, cGMP levels but not cAMP levels were synergistically elevated compared with the levels of expression caused by the corresponding single-toxin treatment. Our data also demonstrate that the levels of inflammatory cytokines produced by intestinal epithelial cells in response to LT are significantly reduced in animals exposed to both enterotoxins. These findings suggest that there may be complex differences between the epithelial cell intoxication and, potentially, secretory outcomes induced by ETEC strains expressing LT+ST compared with strains that express LT or ST only. Our results also reveal a novel mechanism wherein ST production may reduce the hosts' ability to mount an effective innate or adaptive immune response to infecting organisms. PMID- 25287924 TI - Transcription of the Streptococcus pyogenes hyaluronic acid capsule biosynthesis operon is regulated by previously unknown upstream elements. AB - The important human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]) produces a hyaluronic acid (HA) capsule that plays critical roles in immune evasion. Previous studies showed that the hasABC operon encoding the capsule biosynthesis enzymes is under the control of a single promoter, P1, which is negatively regulated by the two-component regulatory system CovR/S. In this work, we characterize the sequence upstream of P1 and identify a novel regulatory region controlling transcription of the capsule biosynthesis operon in the M1 serotype strain MGAS2221. This region consists of a promoter, P2, which initiates transcription of a novel small RNA, HasS, an intrinsic transcriptional terminator that inefficiently terminates HasS, permitting read-through transcription of hasABC, and a putative promoter which lies upstream of P2. Electrophoretic mobility shift assays, quantitative reverse transcription-PCR, and transcriptional reporter data identified CovR as a negative regulator of P2. We found that the P1 and P2 promoters are completely repressed by CovR, and capsule expression is regulated by the putative promoter upstream of P2. Deletion of hasS or of the terminator eliminates CovR-binding sequences, relieving repression and increasing read-through, hasA transcription, and capsule production. Sequence analysis of 44 GAS genomes revealed a high level of polymorphism in the HasS sequence region. Most of the HasS variations were located in the terminator sequences, suggesting that this region is under strong selective pressure. We discovered that the terminator deletion mutant is highly resistant to neutrophil mediated killing and is significantly more virulent in a mouse model of GAS invasive disease than the wild-type strain. Together, these results are consistent with the naturally occurring mutations in this region modulating GAS virulence. PMID- 25287925 TI - Comparative evaluation of lesion development, tissue damage, and cytokine expression in golden hamsters (Mesocricetus auratus) infected by inocula with different Leishmania (Viannia) braziliensis concentrations. AB - The golden hamster (Mesocricetus auratus) is a susceptible model to Leishmania (Viannia) spp.; however, available studies employ different infection protocols, which account for clinical and pathological presentation differences. Herein, L. (V.) braziliensis preparations were standardized to contain 10(4), 10(5), or 10(6) parasites to determine an optimal inoculum that ensured cutaneous lesions without causing a disseminated infection in hamsters. Lesion development was followed for 105 days by size measurements, and skin, draining lymph node, spleen, and sera were investigated to check parasite load, spleen visceralization, cytokine expression, histopathological changes, and anti Leishmania IgG levels. The lesion emergence time was inversely proportional to the parasite concentration in the inocula. Animals infected by 10(4) parasites presented nodular lesions, while those infected with 10(6) parasites often exhibited ulcerated lesions. The differences in the final lesion sizes were observed between 10(4) and 10(5) inocula or 10(4) and 10(6) inocula. High IFNG expression, anti-Leishmania IgG levels, and parasite load occurred independently of the inoculum used. A mild inflammatory skin involvement was observed in animals infected with 10(4) parasites, while extensive tissue damage and parasite spleen visceralization occurred with 10(5) and 10(6) parasites. These results indicate that inocula with different concentrations of parasites generate differences in the time of lesion emergence, clinical presentation, and systemic commitment, despite high and similar IFNG expression and parasite load. This suggests that a modulation in the immune response to different parasite numbers occurs in an early phase of the infection, which could dictate the establishment and magnitude of the chronic phase of the disease. PMID- 25287926 TI - Mycobacterium tuberculosis strains lacking surface lipid phthiocerol dimycocerosate are susceptible to killing by an early innate host response. AB - The innate immune response plays an important but unknown role in host defense against Mycobacterium tuberculosis. To define the function of innate immunity during tuberculosis, we evaluated M. tuberculosis replication dynamics during murine infection. Our data show that the early pulmonary innate immune response limits M. tuberculosis replication in a MyD88-dependent manner. Strikingly, we found that little M. tuberculosis cell death occurs during the first 2 weeks of infection. In contrast, M. tuberculosis cells deficient in the surface lipid phthiocerol dimycocerosate (PDIM) exhibited significant death rates, and consequently, total bacterial numbers were reduced. Host restriction of PDIM deficient M. tuberculosis was not alleviated by the absence of interferon gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), or the phagocyte oxidase subunit p47. Taken together, these data indicate that PDIM protects M. tuberculosis from an early innate host response that is independent of IFN-gamma, reactive nitrogen intermediates, and reactive oxygen species. By employing a pathogen replication tracking tool to evaluate M. tuberculosis replication and death during infection, we identify both host and pathogen factors affecting the outcome of infection. PMID- 25287927 TI - Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. AB - Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways. PMID- 25287928 TI - Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses. AB - Mycobacteria, the etiological agents of tuberculosis and leprosy, have coevolved with mammals for millions of years and have numerous ways of suppressing their host's immune response. It has been suggested that mycobacteria may contain genes that reduce the host's ability to elicit CD8(+) T cell responses. We screened 3,290 mutant Mycobacterium bovis bacillus Calmette Guerin (BCG) strains to identify genes that decrease major histocompatibility complex (MHC) class I presentation of mycobacterium-encoded epitope peptides. Through our analysis, we identified 16 mutant BCG strains that generated increased transgene product specific CD8(+) T cell responses. The genes disrupted in these mutant strains had disparate predicted functions. Reconstruction of strains via targeted deletion of genes identified in the screen recapitulated the enhanced immunogenicity phenotype of the original mutant strains. When we introduced the simian immunodeficiency virus (SIV) gag gene into several of these novel BCG strains, we observed enhanced SIV Gag-specific CD8(+) T cell responses in vivo. This study demonstrates that mycobacteria carry numerous genes that act to dampen CD8(+) T cell responses and suggests that genetic modification of these genes may generate a novel group of recombinant BCG strains capable of serving as more effective and immunogenic vaccine vectors. PMID- 25287929 TI - Site-specific mutation of the sensor kinase GraS in Staphylococcus aureus alters the adaptive response to distinct cationic antimicrobial peptides. AB - The Staphylococcus aureus two-component regulatory system, GraRS, is involved in resistance to killing by distinct host defense cationic antimicrobial peptides (HD-CAPs). It is believed to regulate downstream target genes such as mprF and dltABCD to modify the S. aureus surface charge. However, the detailed mechanism(s) by which the histidine kinase, GraS, senses specific HD-CAPs is not well defined. Here, we studied a well-characterized clinical methicillin resistant S. aureus (MRSA) strain (MW2), its isogenic graS deletion mutant (DeltagraS strain), a nonameric extracellular loop mutant (DeltaEL strain), and four residue-specific DeltaEL mutants (D37A, P39A, P39S, and D35G D37G D41G strains). The DeltagraS and DeltaEL strains were unable to induce mprF and dltA expression and, in turn, demonstrated significantly increased susceptibilities to daptomycin, polymyxin B, and two prototypical HD-CAPs (hNP-1 and RP-1). Further, P39A, P39S, and D35G-D37G-D41G DeltaEL mutations correlated with moderate increases in HD-CAP susceptibility. Reductions of mprF and dltA induction by PMB were also found in the DeltaEL mutants, suggesting these residues are pivotal to appropriate activation of the GraS sensor kinase. Importantly, a synthetic exogenous soluble EL mimic of GraS protected the parental MW2 strain against hNP 1- and RP-1-mediated killing, suggesting a direct interaction of the EL with HD CAPs in GraS activation. In vivo, the DeltagraS and DeltaEL strains displayed dramatic reductions in achieved target tissue MRSA counts in an endocarditis model. Taken together, our results provide new insights into potential roles of GraS in S. aureus sensing of HD-CAPs to induce adaptive survival responses to these molecules. PMID- 25287930 TI - Plasmid-encoded Pgp3 is a major virulence factor for Chlamydia muridarum to induce hydrosalpinx in mice. AB - Hydrosalpinx induction in mice by Chlamydia muridarum infection, a model that has been used to study C. trachomatis pathogenesis in women, is known to depend on the cryptic plasmid that encodes eight genes designated pgp1 to pgp8. To identify the plasmid-encoded pathogenic determinants, we evaluated C. muridarum transformants deficient in the plasmid-borne gene pgp3, -4, or -7 for induction of hydrosalpinx. C. muridarum transformants with an in-frame deletion of either pgp3 or -4 but not -7 failed to induce hydrosalpinx. The deletion mutant phenotype was reproduced by using transformants with premature termination codon insertions in the corresponding pgp genes (to minimize polar effects inherent in the deletion mutants). Pgp4 is known to regulate pgp3 expression, while lack of Pgp3 does not significantly affect Pgp4 function. Thus, we conclude that Pgp3 is an effector virulence factor and that lack of Pgp3 may be responsible for the attenuation in C. muridarum pathogenicity described above. This attenuated pathogenicity was further correlated with a rapid decrease in chlamydial survival in the lower genital tract and reduced ascension to the upper genital tract in mice infected with C. muridarum deficient in Pgp3 but not Pgp7. The Pgp3 deficient C. muridarum organisms were also less invasive when delivered directly to the oviduct on day 7 after inoculation. These observations demonstrate that plasmid-encoded Pgp3 is required for C. muridarum survival in the mouse genital tract and represents a major virulence factor in C. muridarum pathogenesis in mice. PMID- 25287931 TI - The Tudor domain protein Tapas, a homolog of the vertebrate Tdrd7, functions in the piRNA pathway to regulate retrotransposons in germline of Drosophila melanogaster. AB - BACKGROUND: Piwi-interacting RNAs (piRNAs) are a special class of small RNAs that provide defense against transposable elements in animal germline cells. In Drosophila, germline piRNAs are thought to be processed at a unique perinuclear structure, the nuage, that houses piRNA pathway proteins including the Piwi clade of Argonaute family proteins, along with several Tudor domain proteins, RNA helicases and nucleases. We previously demonstrated that Tudor domain protein Tejas (Tej), an ortholog of vertebrate Tdrd5, is an important component of the piRNA pathway. RESULTS: In the current study, we identified the paralog of the Drosophila tej gene, tapas (tap), which is an ortholog of vertebrate Tdrd7. Like Tej, Tap is localized at the nuage. Alone, tap loss leads to a mild increase in transposon expression and decrease in piRNAs targeting transposons expressed in the germline. The tap gene genetically interacts with other piRNA pathway genes and we also show that Tap physically interacts with piRNA pathway components, such as Piwi family proteins Aubergine and Argonaute3 and the RNA helicases Spindle-E and Vasa. Together with tej, tap is required for survival of germline cells during early stages and for polarity formation. We further observed that loss of tej and tap together results in more severe defects in the piRNA pathway in germline cells compared to single mutants: the double-mutant ovaries exhibit mis-localization of piRNA pathway components and significantly greater reduction of piRNAs against transposons predominantly expressed in germline compared to single mutants. The single or double mutants did not have any reduction in piRNAs mapping to transposons predominantly expressed in gonadal somatic cells or those derived from unidirectional clusters such as flamenco. Consistently, the loss of both tej and tap function resulted in mis-localization of Piwi in germline cells, whereas Piwi remained localized to the nucleus in somatic cells. CONCLUSIONS: Our observations suggest that tej and tap work together for germline maintenance. tej and tap also function in a synergistic manner to maintain examined piRNA components at the perinuclear nuage and for piRNA production in Drosophila germline cells. PMID- 25287934 TI - Pharmacoeconomic study of chronic constipation in a secondary care centre. AB - OBJECTIVE: The aim of this study was to measure any incremental costs or savings within the health system associated with the introduction of the new technology, prucalopride, for the management of chronic constipation. METHODOLOGY: The study design was based on a budget impact analysis conducted by the National Institute of Clinical Excellence (NICE). To validate the findings of the NICE costing template, a case series audit capturing real world data was used to determine the financial impact of adopting prucalopride in 40 women suffering with chronic constipation. This facilitated the application of local unit costs to the resources used and determined whether the use of prucalopride, as an alternative treatment to laxatives, resulted in a reduction in the use of secondary care resources. RESULTS: Patients were treated with an average of 2.6 laxatives in the baseline (laxatives only) scenario. The total medication costs in the baseline (laxatives only) and the new treatment (prucalopride) scenario amounted to ?17,440.84 and ?18,417.62, respectively. There was a significant reduction in the number of investigations and procedures in the 12 months after commencing prucalopride, with cost savings of ?41,923.28 (?1,048.08 per patient per year) demonstrated. Input cost variables were adjusted as part of sensitivity analysis. CONCLUSION: This study validated the findings of the NICE costing template and suggests that the use of prucalopride for the treatment of chronic constipation in women refractory to laxatives has the potential to reduce secondary care resource use and hence led to cost savings. PMID- 25287936 TI - Enantio- and diastereoselective access to distant stereocenters embedded within tetrahydroxanthenes: utilizing ortho-quinone methides as reactive intermediates in asymmetric Bronsted acid catalysis. AB - A protocol for the highly enantioselective synthesis of 9-substituted tetrahydroxanthenones by means of asymmetric Bronsted acid catalysis has been developed. A chiral binol-based N-triflyphosphoramide was found to promote the in situ generation of ortho-quinone methides and their subsequent reaction with 1,3 cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio- and diastereoselective Bronsted acid catalyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl substrates with ortho-quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters. PMID- 25287935 TI - The implantation of cervical neoplasia at postpartum episiotomy scar: the clinical evidence. AB - BACKGROUND: Cervical cancer recurrence in episiotomy scars after vaginal deliveries is a rather rare event. AIM: We present a review of the current literature data on the field. METHODS: A systematic search was performed in PubMed and Scopus. RESULTS: 10 case reports and 3 case series with total 18 patients were included. The mean age of the patients was 33.3 years. One of them was diagnosed 1 year before her pregnancy, two of them were diagnosed during pregnancy, six of them during labor and eight patients at postpartum follow-up appointments from 1 week to 8 months postpartum. Twelve cases were squamous cell carcinoma, five cases adenocarcinoma and one case adenosquamous carcinoma with the majority of them staged as Ib1-2. The interval time from initial diagnosis to detection of recurrence had a wide range from 5 weeks to 5.5 years. The diameter of the recurrence was also ranging (5-60 mm). The management of such a recurrence included different extent of wide local excision or chemotherapy or radiotherapy or combinations of them. CONCLUSION: Clinicians should be aware about the importance of carefully examining not only the cervix at the time of labor, but also the episiotomy scar in women following a pregnancy complicated by cervical cancer. PMID- 25287938 TI - Head kinematics and shoulder biomechanics in shoulder impacts similar to pedestrian crashes--a THUMS study. AB - OBJECTIVE: Head injuries account for the largest percentage of fatalities among pedestrians in car crashes. To prevent or mitigate such injuries, safety systems that reduce head linear and rotational acceleration should be introduced. Human body models (HBMs) are valuable safety system evaluation tools for assessing both head injury risk and head kinematics prior to head contact. This article aims to evaluate the suitability of the Total Human Model for Safety (THUMS) version 4.0 for studying shoulder impacts, similar to pedestrian crashes, investigating head, spine, and shoulder kinematics as well as shoulder biomechanics. METHODS: Shoulder impact experiments including volunteers and postmortem human subjects (PMHSs) were simulated with THUMS. Head linear and angular and vertebral linear displacements of THUMS were compared with volunteers and shoulder deflections with both volunteers and PMHSs. A parameter variation study was conducted to assess head response to shoulder impacts, by varying shoulder posture and impact directions mimicking shoulder-to-vehicle contacts. Functional biomechanics literature was compared with THUMS responses in view of pedestrian-like shoulder impacts. RESULTS: THUMS head linear displacement compared better with tensed than with relaxed volunteers. Head lateral rotation was comparable with volunteer responses up to 120 ms; head twist was greater in THUMS than in the volunteers. The THUMS spine appeared to be stiffer than in the volunteers. Shoulder deflections were smaller than in the relaxed volunteers but matched the PMHSs. Raised shoulder postures decreased the THUMS shoulder deflections and increased head lateral displacements. When the impactor surface orientation or the impact velocity angle was changed from lateral to superolateral, THUMS head lateral displacement decreased. THUMS scapula and clavicle kinematics compared well with previous experimental studies. The shoulder impact conditions influenced the scapula motion over the thorax, which had considerable effect on upper torso and head kinematics. The clavicle primarily acted as a guide for the scapula. In the PMHS experiments, it took 20 ms from first impactor-to-shoulder contact to head response, indicating that shoulder impacts in pedestrian crashes may influence head kinematics during head impact. CONCLUSIONS: THUMS is generally suitable for studying head linear kinematics and head lateral rotation in shoulder impacts similar to pedestrian crashes and for studying shoulder girdle biomechanics. Head twist and spine stiffness were more pronounced than in the volunteers. The results have identified the need for additional volunteer shoulder impact testing, mimicking pedestrian crashes, as well as the need to address shoulder impacts in full-scale pedestrian experiments. PMID- 25287933 TI - Renal control of calcium, phosphate, and magnesium homeostasis. AB - Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys. PMID- 25287937 TI - Proteome profiling of lipopolysaccharide induced L6 rat skeletal muscle cells response to flavonoids from Scutellaria baicalensis Georgi. AB - BACKGROUND: Scutellaria baicalensis Georgi is a commonly used medicinal herb in several Asian countries like Korea, China and Japan for thousands of years. It has been reported to have various medicinal properties such as anti-microbial, anti-inflammatory and anti-cancer effects. However, the anti-inflammatory mechanism of S. baicalensis G at proteome level has not yet been reported. Hence, we performed a proteome analysis to study differentially expressed proteins and its anti-inflammatory role in lipopolysaccharide (LPS) stimulated L6 skeletal muscle cells response to flavonoids isolated from S. baicalensis G. METHODS: For that, 150 MUg of proteins from the L6 cells of the control (Vehicle only), LPS treated and flavonoid treated groups were separated using 18 cm, pH 4-7 IPG strips in the first dimension and resolved by 12% linear gradient SDS polyacrylamide gel electrophoresis (SDS-PAGE). The silver stained gels were analyzed by using progenesis SameSpots software and twenty six differentially expressed protein spots (>= 2 fold, p < 0.05) were selected for matrix assisted laser desorption ionization- time of flight mass spectroscopy/mass spectrometry (MALDI-TOF/MS) analysis. Also, the expression of COX-2, iNOS and Annexin A2 proteins were analyzed by western blot. RESULTS: Totally, 12 differentially expressed proteins were successfully identified by MALDI-TOF/MS and database searching, that's involved in inflammatory responses such vimentin, T-box transcription factor TBX3, annexin A1, annexin A2 and annexin A5. In addition, flavonoids inhibited the expression of COX-2, iNOS and Annexin A2 proteins in LPS stimulated L6 skeletal muscle cells. CONCLUSIONS: The findings revealed that the flavonoids from S. baicalensis G. directly protect the LPS stimulated inflammation process in L6 cells and, would be helpful to study further the muscle cell inflammatory mechanism. This is the first proteome study provide the anti-inflammatory mechanism of flavonoids from S. baicalensis G. in LPS stimulated L6 skeletal muscle cells. PMID- 25287939 TI - Dietary supplements for chronic gout. AB - BACKGROUND: Dietary supplements are frequently used for the treatment of several medical conditions, both prescribed by physicians or self administered. However, evidence of benefit and safety of these supplements is usually limited or absent. OBJECTIVES: To assess the efficacy and safety of dietary supplementation for people with chronic gout. SEARCH METHODS: We performed a search in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL on 6 June 2013. We applied no date or language restrictions. In addition, we performed a handsearch of the abstracts from the 2010 to 2013 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conferences, checked the references of all included studies and trial registries. SELECTION CRITERIA: We considered all published randomised controlled trials (RCTs) or quasi-RCTs that compared dietary supplements with no supplements, placebo, another supplement or pharmacological agents for adults with chronic gout for inclusion. Dietary supplements included, but were not limited to, amino acids, antioxidants, essential minerals, polyunsaturated fatty acids, prebiotic agents, probiotic agents and vitamins. The main outcomes were reduction in frequency of gouty attacks and trial participant withdrawal due to adverse events. We also considered pain reduction, health-related quality of life, serum uric acid (sUA) normalisation, function (i.e. activity limitation), tophus regression and the rate of serious adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified two RCTs (160 participants) that fulfilled our inclusion criteria. As these two trials evaluated different diet supplements (enriched skim milk powder (SMP) and vitamin C) with different outcomes (gout flare prevention for enriched SMP and sUA reduction for vitamin C), we reported the results separately.One trial including 120 participants, at moderate risk of bias, compared SMP enriched with glycomacropeptides (GMP) with unenriched SMP and with lactose over three months. Participants were predominantly men aged in their 50's who had severe gout. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the study period.The effects of enriched SMP (SMP/GMP/G600) compared with the combined control groups (SMP and lactose powder) at three months in terms of mean number of gout flares per month were uncertain (mean +/- standard deviation (SD) flares per month: 0.49 +/- 1.52 in SMP/GMP/G60 group versus 0.70 +/- 1.28 in control groups; mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34; low-quality evidence). The number of withdrawals due to adverse effects was similar in both groups although again the results were imprecise (7/40 in SMP/GMP/G600 group versus 11/80 in control groups; risk ratio (RR) 1.27, 95% CI 0.53 to 3.03; low quality evidence). The findings for adverse events were also uncertain (2/40 in SMP/GMP/G600 group versus 3/80 in control groups; RR 1.33, 95% CI 0.23 to 7.66; low-quality evidence). Gastrointestinal events were the most commonly reported adverse effects. Pain from self reported gout flares (measured on a 10-point Likert scale) improved slightly more in the SMP/GMP/G600 group compared with controls (mean +/- SD reduction -1.97 +/- 2.28 points in SMP/GMP/G600 group versus -0.94 +/- 2.25 in control groups; MD -1.03, 95% CI -1.96 to -0.10; low quality evidence). This was an absolute reduction of 10% (95% CI 20% to 1% reduction), which may not be of clinical relevance. Results were imprecise for the outcome improvement in physical function (mean +/- SD Health Assessment Questionnaire (HAQ)-II (scale 0 to 3, 0 = no disability): 0.08 +/- 0.23 in SMP/GMP/G60 group versus 0.11 +/- 0.31 in control groups; MD -0.03, 95% CI -0.14 to 0.08; low-quality evidence). Similarly, results for sUA reduction were imprecise (mean +/- SD reduction: -0.025 +/- 0.067 mmol/L in SMP/GMP/G60 group versus -0.010 +/- 0.069 in control groups; MD -0.01, 95% CI -0.04 to 0.01; low quality evidence). The study did not report tophus regression and health-related quality of life impact.One trial including 40 participants, at moderate to high risk of bias, compared vitamin C alone with allopurinol and with allopurinol plus vitamin C in a three-arm trial. We only compared vitamin C with allopurinol in this review. Participants were predominantly middle-aged men, and their severity of gout was representative of gout in general. The effect of vitamin C on the rate of gout attacks was not assessed. Vitamin C did not lower sUA as much as allopurinol (-0.014 mmol/L in vitamin C group versus -0.118 mmol/L in allopurinol group; MD 0.10, 95% CI 0.06 to 0.15; low-quality evidence). The study did not assess tophus regression, pain reduction or disability or health-related quality of life impact. The study reported no adverse events and no participant withdrawal due to adverse events. AUTHORS' CONCLUSIONS: While dietary supplements may be widely used for gout, this review has shown a paucity of high-quality evidence assessing dietary supplementation. PMID- 25287940 TI - Susceptibility of preparasitic stages of Chordodes nobilii (Gordiida, Nematomorpha) to the fungicide carbendazim. AB - We evaluated the effect of carbendazim on non-target organisms using the parasite Chordodes nobilii as a test organism. The Gordiida act as a link between freshwater and terrestrial ecosystems; and C. nobilii, a neotropical representative species of this group, has been shown to be sensitive to other contaminants even at environmentally acceptable concentrations. The taxa susceptible to carbendazim, however, may not be adequately represented among the standard aquatic test species used in ecotoxicological risk assessment. Moreover, the autochthonous organisms in this area that could be used as bioindicators still need to be found. The aim of the present work was therefore to assess the susceptibility of the preparasitic stages of C. nobilii to noxious effects by carbendazim. The assay protocol consisted in 96- and 48-h acute exposures of early embryonic stages and larvae, respectively, to concentrations ranging from 10 to 360 MUg/l. Embryonic development was not inhibited by carbendazim at any of the evaluated concentrations, but the infectivity of larvae emerging from the exposed eggs was significantly diminished. Larval survival rate was also affected at the lowest concentration assayed. Values of the mean inhibition concentration (IC50) were 7 and 11 MUg/l for embryos and larvae, respectively. Compared to other freshwater organisms, C. nobilii can be considered a species moderately to highly susceptible to carbendazim. As the expected environmental concentrations of carbendazim range from 6.25 to 41.3 MUg/l, C. nobilii could well be a species in danger when exposed to this fungicide. PMID- 25287941 TI - Sedation for diagnostic injections: prioritizing patient interests. PMID- 25287942 TI - Medical Marijuana programs: implications for cannabis control policy- observations from Canada. AB - While prohibition has been the dominant regime of cannabis control in most countries for decades, an increasing number of countries have been implementing cannabis control reforms recently, including decriminalization or even legalization frameworks. Canada has held out from this trend, although it has among the highest cannabis use rates in the world. Cannabis use is universally criminalized, and the current (conservative) federal government has vowed not to implement any softening reforms to cannabis control. As a result of several higher court decisions, the then federal government was forced to implement a 'medical marijuana access regulations' program in 2001 to allow severely ill patients therapeutic use and access to therapeutic cannabis while shielding them from prosecution. The program's regulations and approval processes were complex and subject to extensive criticism; initial uptake was low and most medical marijuana users continued their use and supply outside the program's auspices. This year, the government introduced new 'marijuana for medical purposes regulations', which allow physicians to 'authorize' medical marijuana use for virtually any health condition for which this is considered beneficial; supply is facilitated by licensed commercial producers. It is expected that some 500,000 users, and dozens of commercial producers will soon be approved under the program, arguably constituting - as with medical marijuana schemes elsewhere, e.g. in California--de facto 'legalization'. We discuss the question whether the evolving scope and realities of 'medical cannabis' provisions in Canada offer a 'sneaky side door' or a 'better third way' to cannabis control reform, and what the potential wider implications are of these developments. PMID- 25287943 TI - Tricuspid annular plane systolic excursion is reduced in infants with pulmonary hypertension. AB - BACKGROUND: Right ventricular (RV) function is reduced in infants with pulmonary hypertension (PH) but echocardiographic assessment can be challenging. We sought to determine the role of tricuspid annular plane systolic excursion (TAPSE) in infants with PH and compared it with other markers such as tricuspid annular S' and RV fractional area change (RVFAC). METHODS: Retrospective review of medical records of 30 infants treated for PH and 69 healthy controls from January 2012 to November 2012 was performed. Patients with significant congenital heart disease were excluded. Offline analysis of echocardiograms was performed to obtain TAPSE, tricuspid annular S', and RVFAC. TAPSE was indexed to body surface area (TAPSE/BSA). Logistic regression analysis was performed to evaluate the relation between echocardiographic markers and PH. RESULTS: TAPSE and TAPSE/BSA were significantly lower in PH patients. PH patients were younger than controls; however, TAPSE was significantly lower in PH patients after matching with controls by age. Tricuspid annular S' was decreased in PH patients, but RVFAC was similar. On multivariate analysis, tricuspid S' did not have a significant effect on the probability of PH (P = 0.067). The odds of PH significantly increased with each 1 mm decrease in TAPSE (OR 1.78, 95% CI 1.26-2.45). Inter-observer agreement for TAPSE showed concordance correlation coefficient of 0.89. CONCLUSIONS: TAPSE is a feasible and reproducible marker of RV systolic function in infants with PH and is superior to tricuspid annular S' and RVFAC. Longitudinal studies are needed to evaluate the role of TAPSE in serial evaluation of PH. PMID- 25287944 TI - Mycobacterium smegmatis BioQ defines a new regulatory network for biotin metabolism. AB - Biotin (vitamin H), the sulfur-containing enzyme cofactor, is an essential micronutrient for three domains of life. Given the fact that biotin is an energetically expensive molecule whose de novo biosynthesis demands 20 ATP equivalents each, it is reasonable that bacteria have evolved diversified mechanisms in various microorganisms to tightly control biotin metabolism. Unlike the Escherichia coli BirA, the prototypical bi-functional version of biotin protein ligase (BPL) in that it acts as a repressor for biotin biosynthesis pathway, the BirA protein of Mycobacterium smegmatis (M. smegmatis), a closely relative of the tuberculosis-causing pathogen, Mycobacterium tuberculosis, lacked the DNA-binding activity. It raised a possibility that an alternative new regulator might be present to compensate the loss of regulatory function. Here we report that this is the case. Genomic context analyses of M. smegmatis detected a newly identified BioQ homolog classified into the TetR family of transcription factor and its recognizable palindromes. The M. smegmatis BioQ protein was overexpressed and purified to homogeneity. Size-exclusion chromatography combined with chemical cross-linking studies demonstrated that the BioQ protein had a propensity to dimerize. The promoters of bioFD and bioQ/B were mapped using 5' RACE. Electrophoretic mobility shift assays revealed that BioQ binds specifically to the promoter regions of bioFD and bioQ/B. Further DNase I foot-printing elucidated the BioQ-binding palindromes. Site-directed mutagenesis suggested the important residues critical for BioQ/DNA binding. The isogenic mutant of bioQ (DeltabioQ) was generated using the approach of homologous recombination. The in vivo data from the real-time qPCR combined with the lacZ transcriptional fusion experiments proved that removal of bioQ gave significant increment with expression of bio operons. Also, expression of bio operons were repressed by exogenous addition of biotin, and this repression seemed to depend on the presence of BioQ protein. Thereby, we believed that M. smegmatis BioQ is not only a negative auto-regulator but also a repressor for bioFD and bioB operons involved in the biotin biosynthesis pathway. Collectively, this finding defined the two-protein paradigm of BirA and BioQ, representing a new mechanism for bacterial biotin metabolism. PMID- 25287945 TI - IGF antagonizes the Wnt/beta-Catenin pathway and promotes differentiation of extra-embryonic endoderm. AB - Mouse F9 teratocarcinoma cells are an established model for the differentiation of extra-embryonic endoderm (ExEn). Primitive endoderm, parietal and visceral endoderm can be generated by stimulation of F9 cells with retinoic acid and dibutyryl cyclic adenosine monophosphate. Here we show that Wnt/beta-Catenin signaling is down-regulated during ExEn differentiation in F9 cells and that the inhibition of the Wnt pathway promotes differentiation of the three extra embryonic endoderm lineages. Wnt inhibition is achieved through the IGF pathway, which is up-regulated during differentiation. IGF signaling antagonizes the Wnt pathway by stimulating transcription of axin2 and by stabilizing Axin1 protein. Both Axin1 and Axin2 are components of the beta-Catenin destruction complex and act as intra-cellular inhibitors of the Wnt/beta-Catenin pathway. The data presented reveal a mechanism which restricts pluripotency of undifferentiated cells and directs them toward extra-embryonic lineages. PMID- 25287946 TI - Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase dependent anti-apoptotic signaling. AB - Angiopoietin-like protein 2 (ANGPTL2) plays an important role in inflammatory carcinogenesis and tumor metastasis by activating tumor angiogenesis and tumor cell chemotaxis and invasiveness. However, it is unclear whether ANGPTL2 expression has an effect on tumor cell survival. Here, we explored that possibility by determining whether ANGPTL2 expression altered survival of human colorectal cancer cell lines treated with antineoplastic drugs. To do so, we generated SW480 cells expressing ANGPTL2 (SW480/ANGPTL2) and control (SW480/Ctrl) cells. Apoptosis induced by antineoplastic drug treatment was significantly decreased in SW480/ANGPTL2 compared to control cells. Expression of anti apoptotic BCL-2 family genes was upregulated in SW480/ANGPTL2 compared to SW480/Ctrl cells. To assess signaling downstream of ANGPTL2 underlying this effect, we carried out RNA sequencing analysis of SW480/ANGPTL2 and SW480/Ctrl cells. That analysis, combined with in vitro experiments, indicated that Syk-PI3K signaling induced expression of BCL-2 family genes in SW480/ANGPTL2 cells. Furthermore, ANGPTL2 increased its own expression in a feedback loop by activating the spleen tyrosine kinase-nuclear factor of activated T cells (Syk NFAT) pathway. Finally, we observed a correlation between higher ANGPTL2 expression in primary unresectable tumors from colorectal cancer patients who underwent chemotherapy with a lower objective response rate. These findings suggest that attenuating ANGPTL2 signaling in tumor cells may block tumor cell resistance to antineoplastic therapies. PMID- 25287947 TI - Antibacterial Treatment of Meticillin-Resistant Staphylococcus Aureus Complicated Skin and Soft Tissue Infections: a Cost and Budget Impact Analysis in Greek Hospitals. AB - INTRODUCTION: Meticillin-resistant staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant infections worldwide. Its prevalence remains high in the Greek hospital setting. Complicated skin and soft tissue infections (cSSTIs) due to MRSA are associated with prolonged hospitalization, additional healthcare costs and significant morbidity. The purpose of this study was to conduct a cost analysis and a budget impact analysis relative to different management scenarios for MRSA-cSSTIs from a hospital perspective. METHODS: Equal efficacy was assumed for the pharmacotherapies under evaluation and resource use was elicited via an expert panel of seven local infectious disease specialists. The model was based on a previously published economic model that was adapted for the Greek hospital setting and included a decision tree for the management of hospitalized patients with MRSA-cSSTIs, which simulated costs and outcomes for the duration of hospitalization according to the therapeutic scenario. Inpatient costs consisted of hospitalization, diagnostic/laboratory testing, physician visits and antibiotic treatment. RESULTS: Current economic impact of MRSA-cSSTIs for the inpatient setting in Greek hospitals was estimated at ?29,196,218. Total per patient cost according to first-line agent was ?2,457, ?2,762, ?2,850, ?3,494 and ?3,094 and mean length of stay was 9.2, 12.5, 10.3, 13.0 and 14.0 days for linezolid, vancomycin, daptomycin, tigecycline, and teicoplanin, respectively. An estimated 10,287 MRSA-cSSTI patients are treated annually in Greek hospitals. Thus, increasing the use of linezolid by 11% over a 3-year period (current use 19%; 3 year projection 30%), for the management of MRSA-cSSTIs, could result in 3 year savings of ?896,065. CONCLUSION: Management of MRSA-cSSTI requires intensive resource use; overall healthcare costs differ according to the chosen first-line treatment. In light of considerable budget constraints, development of hospital strategies which facilitate early discharge, such as the introduction of clinical criteria and guidelines for switching from intravenous to oral MRSA-cSSTI therapy, could result in substantial savings for the Greek hospital budget. PMID- 25287948 TI - A Bad Case of Good's Syndrome. AB - Good's syndrome is a relatively rare immunodeficiency condition that presents in the fourth or fifth decade of life and is defined by hypogammaglobulinemia in the setting of a thymoma. The humoral defect may be severe enough to cause an absence in B cells, with a consequent recurrence of sinopulmonary disease, chronic non infectious diarrhea and opportunistic infections. The prognosis in patients with Good's syndrome appears to be worse than in those with X-linked agammaglobulinemia (XLA) and common variable immune deficiency (CVID). There have only been three cases of Good's syndrome associated with mycobacterium, and only one case with a cavitary lesion in the lungs. We present here a unique case of Good's syndrome with a non-mycobacterial cavitary lesion. PMID- 25287949 TI - Routine stethoscope cleaning and seniority of clinician: time for guidelines? PMID- 25287950 TI - Infections and exposures: reported incidents associated with unsuccessful decontamination of reusable surgical instruments. AB - Reusable surgical instruments provide a potential route for the transmission of pathogenic agents between patients in healthcare facilities. As such, the decontamination process between uses is a vital component in the prevention of healthcare-associated infections. This article reviews reported outbreaks and incidents associated with inappropriate, inadequate, or unsuccessful decontamination of surgical instruments, indicating potential pitfalls of decontamination practices worldwide. To the author's knowledge, this is the first review of surgical instrument decontamination failures. Databases of medical literature, Medline and Embase, were searched systematically. Articles detailing incidents associated with unsuccessful decontamination of surgical instruments were identified. Twenty-one articles were identified reporting incidents associated with failures in decontamination. A large proportion of incidents involved the attempted disinfection, rather than sterilization, of surgical instruments (43% of articles), counter to a number of national guidelines. Instruments used in eye surgery were most frequently reported to be associated with decontamination failures (29% of articles). Of the few articles detailing potential or confirmed pathogenic transmission, Pseudomonas aeruginosa and Mycobacterium spp. were most represented. One incident of possible variant Creutzfeldt-Jakob disease transmission was also identified. Limitations of analysing only published incidents mean that the likelihood of under-reporting (including reluctance to publish failure) must be considered. Despite these limitations, the small number of articles identified suggests a relatively low risk of cross-infection through reusable surgical instruments when cleaning/sterilization procedures are adhered to. The diverse nature of reported incidents also suggests that failures are not systemic. PMID- 25287951 TI - Are multifaceted interventions more effective than single-component interventions in changing health-care professionals' behaviours? An overview of systematic reviews. AB - BACKGROUND: One of the greatest challenges in healthcare is how to best translate research evidence into clinical practice, which includes how to change health care professionals' behaviours. A commonly held view is that multifaceted interventions are more effective than single-component interventions. The purpose of this study was to conduct an overview of systematic reviews to evaluate the effectiveness of multifaceted interventions in comparison to single-component interventions in changing health-care professionals' behaviour in clinical settings. METHODS: The Rx for Change database, which consists of quality appraised systematic reviews of interventions to change health-care professional behaviour, was used to identify systematic reviews for the overview. Dual, independent screening and data extraction was conducted. Included reviews used three different approaches (of varying methodological robustness) to evaluate the effectiveness of multifaceted interventions: (1) effect size/dose-response statistical analyses, (2) direct (non-statistical) comparisons of multifaceted to single interventions and (3) indirect comparisons of multifaceted to single interventions. RESULTS: Twenty-five reviews were included in the overview. Three reviews provided effect size/dose-response statistical analyses of the effectiveness of multifaceted interventions; no statistical evidence of a relationship between the number of intervention components and the effect size was found. Eight reviews reported direct (non-statistical) comparisons of multifaceted to single-component interventions; four of these reviews found multifaceted interventions to be generally effective compared to single interventions, while the remaining four reviews found that multifaceted interventions had either mixed effects or were generally ineffective compared to single interventions. Twenty-three reviews indirectly compared the effectiveness of multifaceted to single interventions; nine of which also reported either a statistical (dose-response) analysis (N = 2) or a non-statistical direct comparison (N = 7). The majority (N = 15) of reviews reporting indirect comparisons of multifaceted to single interventions showed similar effectiveness for multifaceted and single interventions when compared to controls. Of the remaining eight reviews, six found single interventions to be generally effective while multifaceted had mixed effectiveness. CONCLUSION: This overview of systematic reviews offers no compelling evidence that multifaceted interventions are more effective than single-component interventions. PMID- 25287952 TI - Breakthrough reactions of iodinated and gadolinium contrast media after oral steroid premedication protocol. AB - BACKGROUND: Adverse reactions to iodinated and gadolinium contrast media are an important clinical issue. Although some guidelines have proposed oral steroid premedication protocols to prevent adverse reactions, some patients may have reactions to contrast media in spite of premedication (breakthrough reaction; BTR).The purpose of this study was to assess the frequency, type and severity of BTR when following an oral steroid premedication protocol. METHODS: All iodinated and gadolinium contrast-enhanced radiologic examinations between August 2011 and February 2013 for which the premedication protocol was applied in our institution were assessed for BTRs. RESULTS: The protocol was applied to a total of 252 examinations (153 patients, ages 15-87 years; 63 males, 90 females). Of these, 152 were for prior acute adverse reactions to contrast media, 85 were for a history of bronchial asthma, and 15 were for other reasons. There were 198 contrast enhanced CTs and 54 contrast enhanced MRIs. There were nine BTR (4.5%) for iodinated contrast media, and only one BTR (1.9%) for gadolinium contrast media: eight were mild and one was moderate. No patient who had a mild index reaction (IR) had a severe BTR. CONCLUSION: Incidence of BTRs when following the premedication protocol was low. This study by no means proves the efficacy of premedication, but provides some support for following a premedication protocol to improve safety of contrast-enhanced examinations when prior adverse reactions are mild, or when there is a history of asthma. PMID- 25287953 TI - Impact of cardiac rehabilitation on peripheral circulation as assessed by impedance plethysmography: a randomized clinical trial. AB - BACKGROUND: It's known, controlled physical exercise which is a part of cardiac rehabilitation lead to positive changes in coronary circulation and contributes to minimizing other risk factors, such as lipid concentration in the blood or body weight as well as decreases the risk of another acute coronary disease. Monitoring cardiovascular activity is a necessary element of supervising the patient during cardiac rehabilitation. This supervision is primarily concerned with coronary circulation, bypassing the peripheral circulation which may seem like an important part of properly reacts to physical activity. AIM: The aim of the study was to evaluate changes in the peripheral circulation in the calf, induced by controlled physical exercise performed within a standard rehabilitation procedure in patients with acute coronary disease, with the use of impedance plethysmography. DESIGN: Clinical trial (CT). MATERIALS SETTING: All the patients were referred to be cardiologically rehabilitated to the hospital in the Clinic of Internal Diseases and Cardiological Rehabilitation of the Medical University of Lodz not later than one month following the occurrence of acute coronary disease. POPULATION: Forty-seven patients with acute coronary disease were divided into two study groups. Group I (N.=23) participated in a two-week and Group II in a four-week cardiac rehabilitation. METHODS: Forty-seven patients participated in interval training on a cycle ergometer and exercise improving general physical state held five times a week. All the patients underwent impedance plethysmography test before and after the training session in order to evaluate peripheral circulation in lower limbs. RESULTS: The authors of the study observed changes in plethysmographic parameters. After two weeks of performing physical exercise Group I demonstrated an increase in the following parameters: PSlope by 3.8%, PAmpl by 1.7%, CT by 3.3% and PT by 1% (p>0.05). With regards to Group II, the parameters increased respectively by: 23.8% (PSlope), 20.4% (PAmpl), 11.6% (CT) and 6.8% (PT) (p<0.05). The authors also noted a complete correlation between the results of the plethysmographic parameters and cardiac stroke volume (Pearson=1). CONCLUSIONS: Findings of the studies confirm that cardiac rehabilitation improves blood flow in lower limbs vessels in patients with acute coronary disease. Impedance plethysmography allows for non-invasive monitoring of local blood flow and is a precise and repeated method of evaluating peripheral circulation in patients during cardiac rehabilitation. CLINICAL REHABILITATION IMPACT: The results indicate the role of the length of the training time, which has a beneficial effect on the peripheral circulation of the lower limbs. That could help change the rehabilitation program in other rehabilitation clinic. PMID- 25287954 TI - A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma. AB - Risk stratification in myeloma requires an accurate assessment of the presence of a range of molecular abnormalities including the differing IGH translocations and the recurrent copy number abnormalities that can impact clinical behavior. Currently, interphase fluorescence in situ hybridization is used to detect these abnormalities. High failure rates, slow turnaround, cost, and labor intensiveness make it difficult and expensive to use in routine clinical practice. Multiplex ligation-dependent probe amplification (MLPA), a molecular approach based on a multiplex polymerase chain reaction method, offers an alternative for the assessment of copy number changes present in the myeloma genome. Here, we provide evidence showing that MLPA is a powerful tool for the efficient detection of copy number abnormalities and when combined with expression assays, MLPA can detect all of the prognostically relevant molecular events which characterize presenting myeloma. This approach opens the way for a molecular diagnostic strategy that is efficient, high throughput, and cost effective. PMID- 25287955 TI - Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. AB - Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress. PMID- 25287956 TI - Furaldehyde substrate specificity and kinetics of Saccharomyces cerevisiae alcohol dehydrogenase 1 variants. AB - BACKGROUND: A previously discovered mutant of Saccharomyces cerevisiae alcohol dehydrogenase 1 (Adh1p) was shown to enable a unique NADH-dependent reduction of 5-hydroxymethylfurfural (HMF), a well-known inhibitor of yeast fermentation. In the present study, site-directed mutagenesis of both native and mutated ADH1 genes was performed in order to identify the key amino acids involved in this substrate shift, resulting in Adh1p-variants with different substrate specificities. RESULTS: In vitro activities of the Adh1p-variants using two furaldehydes, HMF and furfural, revealed that HMF reduction ability could be acquired after a single amino acid substitution (Y295C). The highest activity, however, was reached with the double mutation S110P Y295C. Kinetic characterization with both aldehydes and the in vivo primary substrate acetaldehyde also enabled to correlate the alterations in substrate affinity with the different amino acid substitutions. CONCLUSIONS: We demonstrated the key role of Y295C mutation in HMF reduction by Adh1p. We generated and kinetically characterized a group of protein variants using two furaldehyde compounds of industrial relevance. Also, we showed that there is a threshold after which higher in vitro HMF reduction activities do not correlate any more with faster in vivo rates of HMF conversion, indicating other cell limitations in the conversion of HMF. PMID- 25287957 TI - Identification and characterization of 2-keto-3-deoxygluconate kinase and 2-keto 3-deoxygalactonate kinase in the haloarchaeon Haloferax volcanii. AB - The halophilic archaeon Haloferax volcanii has been proposed to degrade glucose via the semi-phosphorylative Entner-Doudoroff pathway, involving 2-keto-3 deoxygluconate kinase (KDGK) as key enzyme. So far, neither the enzyme has been characterized nor the encoding gene has been identified. In the genome of H. volcanii, two genes, HVO_0549 (kdgK1) and HVO_A0328 (kdgK2), are annotated encoding putative KDGK-1 and KDGK-2. To identify the physiological role of both kinases, transcriptional regulation analyses of both genes and growth experiments of the respective deletion mutants were performed on different sugars. Further, recombinant KDGK-1 and KDGK-2 were characterized. Together, the data indicate that KDGK-1 represents the functional constitutively expressed KDG kinase in glucose degradation, whereas KDGK-2 is an inducible 2-keto-3-deoxygalactonate kinase likely involved in d-galactose catabolism. PMID- 25287958 TI - Beliefs about management of irritable bowel syndrome in primary care: cross sectional survey in one locality. AB - AIM: To examine beliefs about irritable bowel syndrome (IBS) management among primary care physicians. BACKGROUND: There have been considerable advances in evidence synthesis concerning management of IBS in the last five years, with guidelines for its management in primary care published by the National Institute for Health and Care Excellence (NICE). METHODS: This was a cross-sectional web based questionnaire survey of 275 primary care physicians. We emailed a link to a SurveyMonkey questionnaire, containing 18 items, to all eligible primary care physicians registered with three clinical commissioning groups in Leeds, UK. Participants were given one month to respond, with a reminder sent out after two weeks. FINDINGS: One-hundred and two (37.1%) primary care physicians responded. Among responders, 70% believed IBS was a diagnosis of exclusion, and >80% checked coeliac serology often or always in suspected IBS. Between >50% and >70% believed soluble fibre, antispasmodics, peppermint oil, and psychological therapies were potentially efficacious therapies. The respondents were less convinced that antidepressants or probiotics were effective. Despite perceived efficacy of psychological therapies, 80% stated these were not easily available. Levels of use of soluble fibre, antispasmodics, and peppermint oil were in the range of 40% to >50%. Most primary care physicians obtained up-to-date evidence about IBS management from NICE guidelines. Most primary care physicians still believe IBS is a diagnosis of exclusion, and many are reluctant to use antidepressants or probiotics to treat IBS. More research studies addressing diagnosis and treatment of IBS based in primary are required. PMID- 25287959 TI - Breast cancer leptomeningeal metastasis: the results of combined treatment and the comparison of methotrexate and liposomal cytarabine as intra-cerebrospinal fluid chemotherapy. AB - BACKGROUND: This was a prospective observational study to assess the results of the treatment of patients with breast cancer leptomeningeal metastasis (LM) and to compare the efficacy of methotrexate and liposomal cytarabine in patients treated intrathecally by lumbar puncture. PATIENTS AND METHODS: In this prospective observational study, 149 consecutive patients with breast cancer and LM treated between the years 1999 and 2011 were assessed. Multimodality treatment methods were used: systemic therapy in 77 patients, radiotherapy in 92 patients, intrathecal methotrexate in 81 patients, and intrathecal liposomal cytarabine in 15 patients. RESULTS: The median survival of all patients was 4.2 months. The median survival of patients in whom systemic intravenous/oral treatment was used was 6 months, in those who did not have systemic treatment, the median survival was 2 months (P < .001). The median survival of patients treated with intrathecal methotrexate was 4.2 months; in patients treated with intrathecal liposomal cytarabine, the median survival was 4.6 months, and in patients who did not receive intrathecal treatment, the median survival was 3.7 months (P = .717). Median survival after whole-brain radiotherapy was 4.6 months and with no radiotherapy, it was 3.2 months (P = .028). Multivariate analysis revealed a Karnofsky performance status (KPS) of > 70. Systemic intravenous/oral treatment and bone as a site of metastasis were factors prolonging survival from LM. CONCLUSION: Among treatment methods, only systemic therapy prolonged survival in patients with LM. Neither radiotherapy nor lumbar intrathecal therapy influenced survival in those patients; however, both methods alleviated signs and symptoms of LM. No difference in survival was observed in patients treated intrathecally with methotrexate and those treated with liposomal cytarabine. Treatment with both drugs was comparable. PMID- 25287960 TI - Age-related changes of the diffusion tensor imaging parameters of the normal cervical spinal cord. AB - BACKGROUND: The diffusion tensor imaging (DTI) parameters of the cervical spinal cord (CSC) changes with age. However, previous studies only examined specific CSC areas. OBJECTIVES: To analyze the DTI parameters in all intervertebral space levels of the whole normal CSC and to study the impact of age on these parameters in a Chinese population. METHODS: Thirty-six healthy subjects aged 20-77 years were recruited. DTI parameters were calculated for gray matter (GM) and white matter (WM) funiculi in all the CSC intervertebral spaces (C1/2-C6/7). Age related changes of DTI parameters were analyzed for the GM and WM funiculi. RESULTS: Fractional anisotropy (FA) and mean diffusivity (MD) were lower in GM than in WM. MD and FA values were lower in the WM in the lower CSC compared with the upper CSC (all P<0.05), but no difference was observed in GM. In ventral funiculi, MD increased with age, while FA decreased (all P<0.001). In lateral and dorsal funiculi, MD and FA decreased with age (all P<0.001). In GM, MD and FA decreased with age (all P<0.001). Significant age-related changes were observed in FA and MD from GM and WM funiculi. FA was correlated with age in all funiculi (ventral: r=-0.733; lateral: r=-0.468; dorsal: r=-0.607; GM: r=-0.724; all P<0.01). CONCLUSION: Important changes in MD and FA were observed with advancing age at all levels of CSC in Chinese patients. DTI parameters may be useful to assess CSC pathology, but the influence of age and segments need to be taken into account in diagnosis. PMID- 25287962 TI - The temporal relationship between early postoperative delirium and postoperative cognitive dysfunction in older patients: a prospective cohort study. AB - BACKGROUND: Postoperative delirium and cognitive dysfunction are frequent phenomena in older patients; however, few studies have examined the temporal relationship between these two conditions in the early postoperative period. Therefore, this study aimed to determine if postoperative delirium and postoperative cognitive dysfunction (POCD) coexist after major noncardiac surgery. METHODS: This was a prospective cohort study of patients who were >= 65 yr of age undergoing noncardiac surgery. Patients were evaluated preoperatively and for two days postoperatively for delirium and POCD. Delirium was determined using the Confusion Assessment Method, and POCD was measured by three cognitive tests addressing changes in executive function, memory, attention, and concentration. For each postoperative day, patients' neurologic status was categorized into three mutually exclusive categories: delirium, POCD, or neither condition. RESULTS: Four hundred sixty-one patients aged >= 65 yr of age were studied, and 421 patients with complete postoperative cognitive testing were reported. Eighty percent of patients experienced either delirium or POCD on the first day after surgery. Seventy percent of patients who had delirium on the first postoperative day also had delirium on the second postoperative day. Sixty three percent of patients who had POCD on postoperative day one continued to have POCD on the next day. Sixteen percent of patients with delirium on day one were non-delirious on day two but met criteria for POCD on day two. Conversely, 15% of patients with POCD on day one became delirious on day two. Only 13% of patients did not experience delirium or POCD on either day after surgery. CONCLUSIONS: Eighty percent of surgical patients experienced some form of cognitive dysfunction the day after surgery, and few recovered by the second day after surgery. PMID- 25287961 TI - Effects of adalimumab treatment on endothelial cell activation markers in the skeletal muscle of patients with rheumatoid arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA), particularly those with severe disease, have increased risk of cardiovascular disease (CVD). Previous studies suggest that endothelial cell activation may contribute to this co morbidity, and that treatment with tumour necrosis factor (TNF) inhibitors could reduce the risk of CVD in these patients. The aim of this study was to investigate endothelial cell activation markers in muscle tissue of patients after adalimumab treatment. METHODS: Patients with active RA who started treatment with adalimumab 40 mg every two weeks were included. Muscle biopsies taken before and 3 months after start of treatment were available from 11 patients (9 females, mean age 54.2 years, median disease duration 6.5 years, 91% anti-CCP positive, 7 on methotrexate [median dose 20 mg/week]). None of the patients had clinical signs of myopathy. IL-1alpha and HLA-DQ were investigated by immunohistochemistry. Quantification was performed by computer assisted image analysis. RESULTS: Disease activity, measured by DAS28 decreased (mean 5.5 vs. 4.1; p=0018). A good or moderate EULAR response was seen in 6/11 patients. HLA-DQ was mainly expressed in endothelial cells in capillaries, whereas IL-1alpha was mainly seen in larger vessels. HLA-DQ expression decreased significantly after treatment (p=0.041). There was a similar trend for IL-1alpha, in particlar in EULAR good/moderate responders. CONCLUSIONS: Adalimumab treatment was associated with decreased expression of endothelial markers previously associated with severe systemic inflammation in RA. Our findings indicate a reduced endothelial activation in patients treated with anti-TNF drugs, which might contribute to a lower risk of cardiovascular co-morbidity. PMID- 25287964 TI - Efficient white light emitting diodes based on Cu-doped ZnInS/ZnS core/shell quantum dots. AB - We report the fabrication of efficient white light-emitting diodes (WLEDs) based on Cu : ZnInS/ZnS core/shell quantum dots (QDs) with super large Stokes shifts. The composition-controllable Cu : ZnInS/ZnS QDs with a tunable emission from deep red to green were prepared by a one-pot noninjection synthetic approach. The high performance Cu : ZnInS QD-WLEDs with the colour rendering index up to 96, luminous efficacy of 70-78 lm W(-1), and colour temperature of 3800-5760 K were successfully fabricated by integration of red and green Cu-doped QDs. Negligible energy transfer between Cu-doped QDs was clearly found by measuring the photoluminescence lifetimes of the QDs, consistent with the small spectral overlap between QD emission and absorption. The experimental results indicated low toxic Cu : ZnInS/ZnS QDs could be suitable for solid state lighting. PMID- 25287963 TI - Investigating the capability to resolve complex white matter structures with high b-value diffusion magnetic resonance imaging on the MGH-USC Connectom scanner. AB - One of the major goals of the NIH Blueprint Human Connectome Project was to map and quantify the white matter connections in the brain using diffusion tractography. Given the prevalence of complex white matter structures, the capability of resolving local white matter geometries with multiple crossings in the diffusion magnetic resonance imaging (dMRI) data is critical. Increasing b value has been suggested for delineation of the finer details of the orientation distribution function (ODF). Although increased gradient strength and duration increase sensitivity to highly restricted intra-axonal water, gradient strength limitations require longer echo times (TE) to accommodate the increased diffusion encoding times needed to achieve a higher b-value, exponentially lowering the signal-to-noise ratio of the acquisition. To mitigate this effect, the MGH-USC Connectom scanner was built with 300 mT/m gradients, which can significantly reduce the TE of high b-value diffusion imaging. Here we report comparisons performed across b-values based on q-ball ODF metrics to investigate whether high b-value diffusion imaging on the Connectom scanner can improve resolving complex white matter structures. The q-ball ODF features became sharper as the b-value increased, with increased power fraction in higher order spherical harmonic series of the ODF and increased peak heights relative to the overall size of the ODF. Crossing structures were detected in an increasingly larger fraction of white matter voxels and the spatial distribution of two-way and three-way crossing structures was largely consistent with known anatomy. Results indicate that dMRI with high diffusion encoding on the Connectom system is a promising tool to better characterize, and ultimately understand, the underlying structural organization and motifs in the human brain. PMID- 25287965 TI - Differentiated thyroid cancer in patients over 60 years of age at presentation: a retrospective study of 438 patients. AB - OBJECTIVES: The aim of this study is to identify the prognostic factors predicting remission and subsequent disease relapse in patients with differentiated thyroid cancer (DTC) greater than 60years of age. MATERIALS AND METHODS: The institute thyroid cancer database had 4370 patients with DTC, of which 447 (10%) were aged>60. However, 9 patients were excluded due to follow-up less than 1year. The prognostic factors in the remaining 438 patients were studied. RESULTS: Among the 438 patients, 311 (71%) had only loco-regional disease (M0) and 127 (29%) had distant metastases (M1) at the time of initial presentation. The host factors predictive of distant metastases at presentation were female gender, primary tumor size (>4cm), follicular histology, and extra thyroidal extension. Among Mo patients, 195 (63%) achieved complete remission while only 12 (9%) M1 patients did so. Average number of radioactive iodine ((131)I) doses administered to achieve complete remission was 2.3 (range, 1-6) and the mean cumulative dose was 3404MBq (range, 925-46,250MBq). In multivariate logistic regression among M0 patients, follicular histology, nodal metastases, and surgical treatment lesser than total/near-total thyroidectomy and among M1 patients, site of distant metastases (skeletal and multiple sites) were independent factors predicting non-remission. Among the patients (both M0 and M1) who achieved remission, factors associated with disease recurrence were primary tumor size (>4cm), nodal metastases, pulmonary metastases, and non-remission after first dose of radioactive iodine and were associated with greater chances of disease relapse. CONCLUSION: This study highlights that DTC in older patients behaves more aggressively than in adults age<60years, and identifies several prognostic factors for remission and subsequent relapse. PMID- 25287966 TI - Current palliative chemotherapy trials in the elderly neglect patient-centred outcome measures. AB - BACKGROUND: The elderly comprise the majority of patients newly diagnosed with cancer. Despite this, little evidence-based data are available on the care of the growing number of older patients with cancer. The objective of the current study was to evaluate the characteristics and outcome measures of current clinical trials on palliative chemotherapy in elderly patients. METHODS: Fourteen international clinical trials registries were searched using the terms "cancer" and "elderly" to identify clinical palliative chemotherapy trials designed specifically for patients aged 70+ years. From the trial protocol, data were extracted on trial characteristics and outcome measures. RESULTS: Of 127 trials, 81% formulated one or more stringent criteria with respect to organ function; 32% excluded patients with WHO performance status (PS) 2 and 83% with PS3. Functional outcomes, health care utilisation, cognitive function after treatment, and quality of life were reported in 6%, 3%, 6%, and 31% of trials, respectively. In only 16% of trials on palliative cancer treatment, a geriatric assessment was performed at baseline. CONCLUSION: Although recent years have seen a growing evidence base regarding fit older patients, our study suggests a lack of representative cohorts of older patients and patient-centred outcome measures in current palliative treatment trials for the elderly. Research addressing alternative outcome measures, including quality of life and impact of therapy on general functioning, cognition, and preservation of independence, and incorporation of a geriatric assessment are needed to provide elderly patients with cancer and their treating physicians with realistic information about palliative chemotherapy. PMID- 25287968 TI - A general palladium-catalyzed method for alkylation of heteroarenes using secondary and tertiary alkyl halides. AB - A general alkylation of heterocycles using a simple palladium catalyst is reported. Most classes of heterocycles, including indoles and pyridines, efficiently coupled with unactivated secondary and tertiary alkyl halides. An alkyl radical addition to neutral heteroarenes is most likely involved. PMID- 25287970 TI - Out-of-hours services are mostly good but quality still varies, says regulator. PMID- 25287969 TI - Identification of an env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines. AB - BACKGROUND: Attempts to eradicate HIV from cellular reservoirs are vital but depend on a clear understanding of how viral variants are transmitted and survive in the different cell types that constitute such reservoirs. Mutations in the env gene of HIV may be able to exert a differential influence on viral transmission ability in regard to cell-free and cell-associated viral forms. METHODS: The ability of HIV containing an env G367R mutation in cell-free and cell-associated viruses to cause infection and to revert to wild-type was measured using several T cell lines. To determine factors that might potentially influence the reversion of G367R, we studied each of entry inhibitors, inhibitors of cellular endocytosis, and modulators of cell growth and activation. RESULTS: We demonstrate that an HIV-1 variant containing a G367R substitution within the CD4 binding site of gp120 was non-infectious as free virus in culture but was infectious when infected cells were co-cultured with certain T cell lines or when cells were transfected by a relevant proviral plasmid. Differences in viral infectivity by cell-associated G367R viruses were determined by the type of target cell employed, regardless which type of donor cell was used. Reversion was slowed or inhibited by entry inhibitors and by inhibitors of cellular endocytosis. Interleukin 2 was able to block G367R reversion in only one of the T cell lines studied but not in the other, while phorbol 12-myristate 13-acetate (PMA) inhibited G367R reversion in all the T cell lines. CONCLUSIONS: Env defective HIV may have a different phenotype as cell-free versus cell-associated virus. The persistence of defective forms can potentially lead to the emergence of virulent forms. The heterogeneity of cell types that constitute the HIV reservoir can contribute to viral variability, even among similar types of cells. This is the first demonstration of a mutation in the HIV envelope, i.e. G367R, that can compromise infection by cell-free virus but less severely by cell associated virus and that does so in a cell type-dependent manner. PMID- 25287967 TI - Liquid phase based separation systems for depletion, prefractionation, and enrichment of proteins in biological fluids and matrices for in-depth proteomics analysis-An update covering the period 2011-2014. AB - This review article expands on the previous one (S. Selvaraju and Z. El Rassi, Electrophoresis 2012, 33, 74-88) by reviewing pertinent literature in the period extending from early 2011 to present. As the previous review article, the present one is concerned with proteomic sample preparation (e.g., depletion of high abundance proteins, reduction of the protein dynamic concentration range, enrichment of a particular subproteome), and the subsequent chromatographic and/or electrophoretic prefractionation prior to peptide separation and identification by LC-MS/MS. This review article, however, is distinguished from its earlier version by expanding on capturing/enriching subphosphoproteomes by immobilized metal affinity chromatography and metal oxide affinity chromatography. Seventy-seven papers published in the period extending from mid 2011 to the present have been reviewed. By no means this review article is exhaustive, given the fact that its aim is to give a concise treatment of the latest developments in the field. PMID- 25287972 TI - The costs and benefits of perceived sexual agency for men and women. AB - Women are less likely than men to engage in sexually agentic behavior (e.g., initiating sexual encounters), despite the benefits associated with sexual agency (Kiefer & Sanchez, 2007). Two studies examined possible explanations, related to person perception, for gender differences in sexually agentic behavior. In Study 1, participants viewed the dating profiles of targets who were either high or low on sexual agency and rated sexually agentic targets as more desirable but also riskier sexual partners (i.e., having more previous sexual partners), as well as more selfish partners overall. Participants believed the agentic female targets to be the most desirable but also to have the highest number of previous sexual partners. In Study 2, female participants weighed the importance and consequences of sexual agency differently than male participants. Based on the two studies, we suggest that although men and women are judged similarly for sexual agency, women may refrain from sexual agency because they view the traits and characteristics that are perceived to go hand in hand with sexual agency more negatively. PMID- 25287973 TI - Dispersion of Lamb waves in a honeycomb composite sandwich panel. AB - Composite materials are increasingly being used in advanced aircraft and aerospace structures. Despite their many advantages, composites are often susceptible to hidden damages that may occur during manufacturing and/or service of the structure. Therefore, safe operation of composite structures requires careful monitoring of the initiation and growth of such defects. Ultrasonic methods using guided waves offer a reliable and cost effective method for defects monitoring in advanced structures due to their long propagation range and their sensitivity to defects in their propagation path. In this paper, some of the useful properties of guided Lamb type waves are investigated, using analytical, numerical and experimental methods, in an effort to provide the knowledge base required for the development of viable structural health monitoring systems for composite structures. The laboratory experiments involve a pitch-catch method in which a pair of movable transducers is placed on the outside surface of the structure for generating and recording the wave signals. The specific cases considered include an aluminum plate, a woven composite laminate and an aluminum honeycomb sandwich panel. The agreement between experimental, numerical and theoretical results are shown to be excellent in certain frequency ranges, providing a guidance for the design of effective inspection systems. PMID- 25287971 TI - "He enjoys giving her pleasure": diversity and complexity in young men's sexual scripts. AB - Research on heterosexual men's sexual expectations has focused on self-described personal traits and culturally dominant models of masculinity. In a pair of studies, we used a sexual scripts perspective to explore the range and diversity of young men's thoughts about sex and relationships with women and to develop measures for assessing these scripts. In the first study, we conducted semi structured interviews to elicit young men's accounts of their sexual relationships. We used these narratives to produce brief sexual script scenarios describing typical sexual situations, as well as conventional survey items assessing sexual behavior themes. In the second study, we administered the scenarios and theme items to an ethnically diverse, national sample of 648 heterosexually active young men in an online survey. Using exploratory factor analysis, we delineated sets of sexual scripts and sexual behavior themes. In the scenarios, we found both a traditional masculine "player" script and a script that emphasized mutual sexual pleasure. Analysis of theme items produced scales of Drinking and Courtship, Monogamy and Emotion, and Sexual Focus and Variety. We discuss the implications of these findings for understanding heterosexual men's thinking about sexuality and how cultural change in sexual thinking may arise. We also discuss the need for measures of sexual thinking that better integrate perceptions and expectations about the partner as well as the self in relation to the partner, rather than solely self-assessed traits. PMID- 25287974 TI - Use of ultrasonic back-reflection intensity for predicting the onset of crack growth due to low-cycle fatigue in stainless steel under block loading. AB - The present study proposes the use of ultrasonic back-reflected waves for evaluating low cycle fatigue crack growth from persistent slip bands (PSBs) of stainless steel under block loading. Fatigue under high-low block loading changes the back-reflected intensity of the ultrasonic wave that emanates from the surface. Measuring the change in ultrasonic intensity can predict the start of crack growth with reasonable accuracy. The present study also proposes a modified constant cumulative plastic strain method and a PSB damage evolution model to predict the onset of crack growth under block loads. PMID- 25287975 TI - A novel breast ultrasound system for providing coronal images: system development and feasibility study. AB - Breast ultrasound images along coronal plane contain important diagnosis information. However, conventional clinical 2D ultrasound cannot provide such images. In order to solve this problem, we developed a novel ultrasound system aimed at providing breast coronal images. In this system, a spatial sensor was fixed on an ultrasound probe to obtain the image spatial data. A narrow-band rendering method was used to form coronal images based on B-mode images and their corresponding spatial data. Software was developed for data acquisition, processing, rendering and visualization. In phantom experiments, 20 inclusions with different size (5-20 mm) were measured using this new system. The results obtained by the new method well correlated with those measured by a micrometer (y=1.0147x, R(2)=0.9927). The phantom tests also showed that this system had excellent intra- and inter-operator repeatability (ICC>0.995). Three subjects with breast lesions were scanned in vivo using this new system and a commercially available three-dimensional (3D) probe. The average scanning times for the two systems were 64 s and 74 s, respectively. The results revealed that this new method required shorter scanning time. The tumor sizes measured on the coronal plane provided by the new method were smaller by 5.6-11.9% in comparison with the results of the 3D probe. The phantom tests and preliminary subject tests indicated the feasibility of this system for clinical applications by providing additional information for clinical breast ultrasound diagnosis. PMID- 25287976 TI - Diffraction, attenuation, and source corrections for nonlinear Rayleigh wave ultrasonic measurements. AB - This research considers the effects of diffraction, attenuation, and the nonlinearity of generating sources on measurements of nonlinear ultrasonic Rayleigh wave propagation. A new theoretical framework for correcting measurements made with air-coupled and contact piezoelectric receivers for the aforementioned effects is provided based on analytical models and experimental considerations. A method for extracting the nonlinearity parameter beta11 is proposed based on a nonlinear least squares curve-fitting algorithm that is tailored for Rayleigh wave measurements. Quantitative experiments are conducted to confirm the predictions for the nonlinearity of the piezoelectric source and to demonstrate the effectiveness of the curve-fitting procedure. These experiments are conducted on aluminum 2024 and 7075 specimens and a beta11(7075)/beta11(2024) measure of 1.363 agrees well with previous literature and earlier work. The proposed work is also applied to a set of 2205 duplex stainless steel specimens that underwent various degrees of heat-treatment over 24h, and the results improve upon conclusions drawn from previous analysis. PMID- 25287977 TI - Catheter-related upper limb venous thrombosis in a tertiary hospital setting. AB - BACKGROUND: To determine the relative likelihood of upper limb venous thrombosis (ULVT) in patients with peripherally inserted central catheter (PICC) versus central venous catheter (CVC), compared with patients without a catheter, in a tertiary hospital setting. METHODS: Retrospective review of all upper limb venous duplex ultrasounds performed for the investigation of venous thrombosis from the Prince of Wales Hospital Vascular Diagnostic Laboratory between July 2009 and October 2012 was conducted. Multivariate logistic regression analysis was used to determine the association between risk factors and the presence of ULVT. The total number of lines inserted was determined from medical, electronic and departmental records. RESULTS: Eight hundred and seventy-six US scans in 637 patients were identified yielding 213 cases of ULVT. ULVT was found in 38/85 scans in patients with PICC, 36/103 scans in patients with CVC and 139/688 scans in patients without a catheter in situ. Compared with patients without catheters, the odds ratio (OR) for developing ULVT was 3.5 (P < 0.001) for PICC and 2.1 (P = 0.002) for CVC. Previous deep venous thrombosis (OR = 11.60; P < 0.001) and malignancy (OR = 2.10; P < 0.02) were additional risk factors. Median time from catheter insertion to diagnosis was 10 days for PICC and 19 days for CVC. The incidence of pulmonary embolism (PE) was 1.8%. The overall 6-month mortality for patients with PICC was 5.9% and CVC was 17.7%. A total of 1855 PICC and 2435 CVC were inserted. The incidence of ULVT was 2.05% per PICC and 1.48% per CVC inserted (P = 0.08). CONCLUSION: Catheters predispose to the formation of ULVT. PICCs are more likely to be associated with ULVT than CVC and have shorter time to symptomatic clot. PE from ULVT is uncommon. PMID- 25287978 TI - Identification and characterization of a novel HLA-B hybrid allele, B*08:132 with Next Generation Sequencing. AB - The new allele is a hybrid between B*08:01:01 and B*42:01:01. PMID- 25287979 TI - Antioxidant, antimicrobial, toxicity and analgesic properties of ethanol extract of Solena amplexicaulis root. AB - BACKGROUND: This study was subjected to investigate different pharmacological properties of ethanol extract of Solena amplexicaulis root. RESULTS: The extract contains flavonoid, alkaloid, saponin and steroid compounds. The extract exhibited excellent antioxidant activity in DPPH radical scavenging activity. The extract also showed potent activity in brine shrimp lethality bioassay. The LC50 value was found to 44.677 MUg/ml. The extract showed better anti-bacterial activity against gram-negative bacteria. In antifungal assay, the maximum 79.31% of anti-mycotic activity was observed against Aspergillus ochraceus while minimum 44.2% against Rhizopus oryzae. MIC value ranged between 1500-3000 MUg/ml. The extract was found moderately toxic with a 24-hr LD50 value of 81.47 mg/kg in Swiss albino mice. The degree of inhibition by the ethanolic extract of the root was found less than that of standard analgesic drug diclofenac sodium. The extract also showed moderate anti-inflammatory and antinociceptive activity and anti-diabetic property. Reducing power of the extract was comparable with standard ascorbic acid. Moderate in vitro thrombolytic activity, lipid peroxidation inhibition property, metal chelating ability and stress-protective activity was also observed. CONCLUSION: Ethanol extract of Solena amplexicaulis root can be valuable for treatment of different diseases. PMID- 25287980 TI - Comparison of epidural versus intrathecal anaesthesia in dogs undergoing pelvic limb orthopaedic surgery. AB - OBJECTIVE: To compare the procedural failure rate (PFR), intraoperative rescue analgesia (iRA) probability and postoperative duration of motor block after epidural and intrathecal anaesthesia in dogs undergoing pelvic limb orthopaedic surgery. STUDY DESIGN: Prospective, randomized clinical trial. ANIMALS: Ninety two client-owned dogs. METHODS: Dogs were assigned randomly to receive either lumbosacral epidural anaesthesia (EA) (bupivacaine 0.5% and morphine 1%) or intrathecal anaesthesia with the same drugs in a hyperbaric solution (HIA). Inaccurate positioning of the needle, assessed by radiographic imaging, and lack of cerebral spinal fluid outflow were considered procedural failures (PFs) of EA and HIA, respectively. Fentanyl (1 MUg kg(-1) IV) was provided for intraoperative rescue analgesia, when either the heart rate or the mean arterial pressure increased by 30% above the pre-stimulation value. Its use was recorded as a sign of intraoperative analgesic failure. The motor block resolution was evaluated postoperatively. Variables were compared using Fisher's exact test, the Mann Whitney U test and the Kaplan-Meier 'survival' analysis as relevant. RESULTS: The PFRs in the EA and HIA groups were 15/47 (32%) and 3/45 (7%), respectively (p = 0.003). Differences in iRA were analysed in 26 and 30 subjects in the EA and HIA groups respectively, using Kaplan-Meier survival analysis. The iRA probability within the first 80 minutes of needle injection (NI) was higher in the EA group (p = 0.045). The incidence of dogs walking within 3 hours of NI was significantly higher in the HIA group (8/20, 40%) than in the EA group (0/17) (p = 0.004). CONCLUSIONS AND CLINICAL RELEVANCE: HIA was found to have lower PF, lower intraoperative analgesic failure and faster motor block resolution. In this study HIA was shown to provide some advantages over EA in dogs undergoing commonly performed pelvic limb orthopaedic surgery in a day-hospital regime. PMID- 25287981 TI - Fishing on chips: up-and-coming technological advances in analysis of zebrafish and Xenopus embryos. AB - Biotests performed on small vertebrate model organisms provide significant investigative advantages as compared with bioassays that employ cell lines, isolated primary cells, or tissue samples. The main advantage offered by whole organism approaches is that the effects under study occur in the context of intact physiological milieu, with all its intercellular and multisystem interactions. The gap between the high-throughput cell-based in vitro assays and low-throughput, disproportionally expensive and ethically controversial mammal in vivo tests can be closed by small model organisms such as zebrafish or Xenopus. The optical transparency of their tissues, the ease of genetic manipulation and straightforward husbandry, explain the growing popularity of these model organisms. Nevertheless, despite the potential for miniaturization, automation and subsequent increase in throughput of experimental setups, the manipulation, dispensing and analysis of living fish and frog embryos remain labor-intensive. Recently, a new generation of miniaturized chip-based devices have been developed for zebrafish and Xenopus embryo on-chip culture and experimentation. In this work, we review the critical developments in the field of Lab-on-a-Chip devices designed to alleviate the limits of traditional platforms for studies on zebrafish and clawed frog embryo and larvae. (c) 2014 International Society for Advancement of Cytometry. PMID- 25287982 TI - Adolescent parenting in the neonatal intensive care unit. AB - This review presents data from studies that report on adolescent parents as part of larger neonatal intensive care unit (NICU) parent populations, as well as studies where adolescent parents are given central consideration. A systematic search for English publications from 1990 onward relevant to adolescent parenting in the NICU was conducted. Most studies reporting on adolescent parents focus on parental stress or parenting practices in the NICU. A few studies examine parent staff communication, parental needs, and parent intervention programs. One study presents a qualitative examination of teenage mothers' experiences in the NICU. Areas for further research include experiences of younger adolescent parents, adolescent fathers, and same-sex partners; issues unique to adolescent parents; and support programs for adolescent parents in the NICU. PMID- 25287983 TI - Shared longitudinal predictors of physical peer and dating violence. AB - PURPOSE: Peers and dates are common targets of adolescent violence. Prevention programs typically address either peer violence (PV) or dating violence (DV) but not both. However, if PV and DV share predictors, prevention strategies could target both behaviors, yielding economic and time efficiencies. Longitudinal data were examined to determine the extent to which physical PV and DV shared predictors. Guided by social learning and social control theories, both risk and protective factors were examined at multiple levels of the social ecology. METHODS: Adolescents in the eighth through 10th grades in three North Carolina counties completed self-administered questionnaires in school in the fall 2003 (Wave 1) and again in spring 2004 (Wave 2) (n = 4,227). The sample was 48% male; 55% white, 33% black, and 12% of other race/ethnicity. A generalized estimating equations approach used adjusted standard errors to account for the correlation between the two violence outcomes. RESULTS: For both boys and girls, anger, family conflict, and having models of deviant behavior in the school were shared risk factors, and holding prosocial beliefs was a shared protective factor. For girls, anxiety and having models of deviant behavior in the neighborhood were additional shared risk factors. For boys, heavy alcohol use was an additional shared risk factor and parental monitoring was an additional shared protective factor. CONCLUSIONS: Findings can inform the development of comprehensive cross cutting prevention strategies at multiple levels of the social ecology designed to prevent both types of violence. PMID- 25287984 TI - Pediatric to adult transition: a quality improvement model for primary care. AB - PURPOSE: To examine the relationship between quality improvement activities with pediatric and adult primary care practices and improvements in transition from pediatric to adult care. METHODS: This was a time-series comparative study of changes in pediatric and adult practices involving five large pediatric and adult academic health centers in the District of Columbia. Using the Health Care Transition Index (pediatric and adult versions), we examined improvements in specific indicators of transition performance, including development of an office transition policy, provider knowledge and skills related to transition, identification of transitioning youth, transition preparation of youth, transition planning, and transfer of care. RESULTS: Improvements took place in all six transition quality indicators in the pediatric and adult practices that participated in a 2-year learning collaborative to implement the "Six Core Elements of Health Care Transition," a quality improvement intervention modeled after the American Academy of Pediatrics/American Academy of Family Physicians/American College of Physicians Clinical Report on Transition. All sites established a practice-wide policy on transition and created an organized clinical process for tracking transition preparation. The pediatric sites conducted transition readiness assessments with 88% of eligible youth and prepared transition plans for 29% of this group. The adult sites conducted transition readiness assessments with 73% of eligible young adults and developed plans for 33%. A total of 50 were transferred in a systematic way to adult primary care practices. CONCLUSIONS: Quality improvement using the Six Core Elements of Health Care Transition resulted in the development of a systematic clinical transition process in pediatric and adult academic primary care practices. PMID- 25287985 TI - Blue blocker glasses as a countermeasure for alerting effects of evening light emitting diode screen exposure in male teenagers. AB - PURPOSE: Adolescents prefer sleep and wake times that are considerably delayed compared with younger children or adults. Concomitantly, multimedia use in the evening is prevalent among teenagers and involves light exposure, particularly in the blue-wavelength range to which the biological clock and its associated arousal promotion system is the most sensitive. We investigated whether the use of blue light-blocking glasses (BB) during the evening, while sitting in front of a light-emitting diode (LED) computer screen, favors sleep initiating mechanisms at the subjective, cognitive, and physiological level. METHODS: The ambulatory part of the study comprised 2 weeks during which the sleep-wake cycle, evening light exposure, and multimedia screen use were monitored in thirteen 15- to 17 year-old healthy male volunteers. BB or clear lenses as control glasses were worn in a counterbalanced crossover design for 1 week each, during the evening hours while using LED screens. Afterward, participants entered the laboratory and underwent an evening blue light-enriched LED screen exposure during which they wore the same glasses as during the preceding week. Salivary melatonin, subjective sleepiness, and vigilant attention were regularly assayed, and subsequent sleep was recorded by polysomnography. RESULTS: Compared with clear lenses, BB significantly attenuated LED-induced melatonin suppression in the evening and decreased vigilant attention and subjective alertness before bedtime. Visually scored sleep stages and behavioral measures collected the morning after were not modified. CONCLUSIONS: BB glasses may be useful in adolescents as a countermeasure for alerting effects induced by light exposure through LED screens and therefore potentially impede the negative effects modern lighting imposes on circadian physiology in the evening. PMID- 25287986 TI - The association of alcohol outlet density with illegal underage adolescent purchasing of alcohol. AB - PURPOSE: Although previous studies have suggested that greater community densities of alcohol sales outlets are associated with greater alcohol use and problems, the mechanisms are unclear. The present study examined whether density was associated with increased purchasing of alcohol by adolescents younger than the legal purchase age of 18 in Australia. METHODS: The number of alcohol outlets per 10,000 population was identified within geographic regions in Victoria, Australia. A state-representative student survey (N = 10,143) identified adolescent reports of purchasing alcohol, and multilevel modeling was then used to predict the effects for different densities of outlet types (packaged, club, on-premise, general, and overall). RESULTS: Each extra sales outlet per 10,000 population was associated with a significant increase in the risk of underage adolescent purchasing. The strongest effect was for club density (odds ratio = 1.22) and packaged (takeaway) outlet density (odds ratio = 1.12). Males, older children, smokers, and those with substance-using friends were more likely to purchase alcohol. CONCLUSIONS: One mechanism by which alcohol sales outlet density may influence population rates of alcohol use and related problems is through increasing the illegal underage purchasing of alcohol. PMID- 25287987 TI - Could sleep exert a relevant role on sexual problems in young men recruited to military service? PMID- 25287988 TI - Effective nonvaccine interventions to be considered alongside human papilloma virus vaccine delivery. AB - World Health Organization recommends that girls, ages 9-13 years, get the human papilloma virus (HPV) vaccine. Global Alliance for Vaccines Initiative, which provides low-cost vaccine to eligible countries, requires that an additional intervention to be offered alongside the vaccine. We systematically searched and assessed the published literature in lower- and middle-income countries to identify effective interventions. We conducted systematic searches of four databases: PubMed, EMBASE, Global Index Medicus Regional Databases, and Cochrane Reviews for effective adolescent health interventions that could be delivered with the HPV vaccine in the following areas: (1) iron and folic acid supplementation (iron alone or with folic acid); (2) voucher delivery and cash transfer programs; (3) hand washing and soap provision; (4) vision screening; (5) promotion of physical activity/exercise; (6) menstrual hygiene education; (7) sexual and reproductive health education; (8) human immunodeficiency virus prevention activities; and (9) condom promotion, condom use skill building, and demonstration. We found limited evidence of consistent positive impact. Iron supplementation reduced iron-deficiency anemia and raised serum ferritin levels. Promotion of physical activity lowered blood pressure and reduced weight gain. Sexual and reproductive health and human immunodeficiency virus interventions improved adolescent communication with adults but did not influence behavioral outcomes. Countries should consider locally relevant and proven interventions to be offered alongside the HPV vaccine. PMID- 25287990 TI - "We prefer greeting rather than eating:" life in an elder care center in Ethiopia. AB - In Ethiopia where family care is a centuries-long tradition, living in an elder care institution invariably brings social devaluation. Accordingly, this study explored the psychosocial needs of older adults in a residential elder care center in Ethiopia from the perspective of both staff and residents. Three focus group discussions of 24 residents and interviews with 5 staff persons revealed that elders were living a subsistence lifestyle, eating the same meal every day, mostly cutoff from the surrounding community, and lacking basic amenities. Despite the absence of basic amenities, residents yearned even more so for meaningful social interaction. Psychosocial support was both undervalued and underutilized by staff members, and thus, residents' psychosocial well-being appeared to be at risk. The addition of social workers in institutional care in Ethiopia may help to promote improved living standards. Advocacy is needed on behalf of residents to establish and implement guidelines on care and support of residents in old age homes. As elders in developing countries are living longer- a growing number with disabilities--at the same time that informal supports are waning, the need for developing long term care policies is becoming critical. PMID- 25287989 TI - Associations between menarche-related genetic variants and pubertal growth in male and female adolescents. AB - PURPOSE: Previous studies have identified novel genetic variants associated with age at menarche in females of European descent. The pubertal growth effects of these variants have not been carefully evaluated in non-European descent groups. We aimed to examine the effects of 31 newly identified menarche-related single nucleotide polymorphisms (SNPs) on growth outcomes in African-American (AA) and European-American (EA) children in a prospective cohort. METHODS: We analyzed longitudinal data collected from 263 AAs and 338 EAs enrolled between ages 5 and 17 years; the subjects were followed semiannually for an average of 6 years. The associations between the SNPs and growth-related outcomes, including weight, height, and body mass index (BMI), were examined using mixed-effect models. RESULTS: Longitudinal analyses revealed that 4 (near or in genes VGLL3, PEX2, CA10, and SKOR2) of the 14 menarche-only-related SNPs were associated with changes in weight and BMI in EA and AA (p <= .0032), but none of them was associated with changes in height. Of the eight menarche-timing and BMI-related SNPs, none was associated with changes in height, but three (in or near genes NEGR1, ETV5, and FTO) were associated with more rapid increases in weight and/or BMI in EA (p <= .0059). Among the nine menarche-timing and height-related SNPs, four (in or near genes ZBTB38, LOC728666, TBX2, and CABLES) were associated with changes in weight or height in EA and AA (p <= .0042). CONCLUSIONS: Genetic variants related to age at menarche were found to be associated with various growth parameters in healthy adolescents. The identified associations were often race and sex specific. PMID- 25287992 TI - Diet-induced obesity promotes a myeloma-like condition in vivo. PMID- 25287991 TI - Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. AB - In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials. PMID- 25287993 TI - Ventilator-associated pneumonia prevention: we still have a long way to go! PMID- 25287994 TI - Smoke and mirrors: the perils of water-pipe smoking and implications for Western countries. PMID- 25287995 TI - From the echo bed to the pulmonary vascular bed: dobutamine testing in the noninvasive laboratory. PMID- 25287996 TI - Treating the exercise problem in COPD. PMID- 25287997 TI - Ventilator-associated pneumonia prevention methods using topical antibiotics: herd protection or herd peril? AB - Ventilator-associated pneumonia (VAP) develops in approximately 20% of patients in the ICU receiving prolonged mechanical ventilation (MV). Among the range of methods for preventing VAP, the evidence base for topical antibiotics (TAs), including selective digestive decontamination, appears to be the most compelling. However, several observations are puzzling, and the contextual influence resulting from concurrent use of both topical placebo and TA within an ICU remains untested. As with herd protection conferred by vaccination, contextual influences resulting from a population-based intervention cannot be estimated at the level of a single trial. Estimating contextual effects requires multilevel random-effects methods. In this way the dispersion in VAP incidence across groups from 206 studies, as cited in various-source systematic reviews, was calibrated. The benchmark mean VAP incidence derived from 49 observational groups of patients receiving MV is 23.7% (95% CI, 20.6%-27.2%). In contrast, for 20 and 15 concurrent control groups from the TA evidence base that did vs did not receive topical placebo, respectively, this incidence is 38% (95% CI, 29%-48%) and 33% (95% CI, 20%-50%). This contextual influence remains significant in a meta regression model adjusted for group-level variables, such as within a trauma ICU context. The mean VAP incidence for five other categories of control groups from the broader evidence base is within four percentage points of the benchmark. The contextual effect of TA is paradoxic, peculiar, potent, perfidious, and potentially perilous. The TA evidence base requires reappraisal to consider this herd peril. PMID- 25287999 TI - Brain death and Islam: the interface of religion, culture, history, law, and modern medicine. AB - How one defines death may vary. It is important for clinicians to recognize those aspects of a patient's religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only. PMID- 25287998 TI - Matrix metalloproteinases and protein tyrosine kinases: potential novel targets in acute lung injury and ARDS. AB - Acute lung injury (ALI) and ARDS fall within a spectrum of pulmonary disease that is characterized by hypoxemia, noncardiogenic pulmonary edema, and dysregulated and excessive inflammation. While mortality rates have improved with the advent of specialized ICUs and lung protective mechanical ventilation strategies, few other therapies have proven effective in the management of ARDS, which remains a significant clinical problem. Further development of biomarkers of disease severity, response to therapy, and prognosis is urgently needed. Several novel pathways have been identified and studied with respect to the pathogenesis of ALI and ARDS that show promise in bridging some of these gaps. This review will focus on the roles of matrix metalloproteinases and protein tyrosine kinases in the pathobiology of ALI in humans, and in animal models and in vitro studies. These molecules can act independently, as well as coordinately, in a feed-forward manner via activation of tyrosine kinase-regulated pathways that are pivotal in the development of ARDS. Specific signaling events involving proteolytic processing by matrix metalloproteinases that contribute to ALI, including cytokine and chemokine activation and release, neutrophil recruitment, transmigration and activation, and disruption of the intact alveolar-capillary barrier, will be explored in the context of these novel molecular pathways. PMID- 25288001 TI - Sleep apnea and the kidney: is sleep apnea a risk factor for chronic kidney disease? AB - The prevalence of chronic kidney disease (CKD) is increasing, which presents challenges for both patients and health-care budgets. Although this phenomenon has been attributed to the growth in diabetes, hypertension, and obesity, sleep apnea and nocturnal hypoxemia may also contribute to the pathogenesis of CKD and its progression to kidney failure. Two pathophysiologic mechanisms responsible for CKD are glomerular hyperfiltration and chronic intrarenal hypoxia, resulting in tubulointerstitial injury, the final common pathway to end-stage kidney disease (ESKD). Multiple descriptive studies have demonstrated an association between CKD and sleep apnea. Although sleep apnea is common in patients with CKD and associated with significant nocturnal hypoxemia, it is often relatively free of sleep-related symptoms, making it difficult to detect without objective nocturnal monitoring. Nevertheless, sleep apnea and nocturnal hypoxemia have been associated with loss of kidney function and kidney injury, suggesting that they contribute to the pathogenesis of continued deterioration in kidney function. There are several pathways through which sleep apnea may achieve this, including a direct effect of intrarenal hypoxia and activation of the systemic and renal renin-angiotensin system. Further research is required to better understand these relationships and determine whether specific interventions in patients with sleep apnea have an impact on clinical outcomes, such as reducing the prevalence of CKD and delaying its progression to ESKD. PMID- 25288002 TI - Anthracycline-dependent cardiotoxicity and extracellular matrix remodeling. AB - The mechanisms of anthracycline-dependent cardiotoxicity have been studied widely, with the suggested principal mechanism of anthracycline damage being the generation of reactive oxygen species by iron-anthracycline complexes, leading to lipid peroxidation and membrane damage. An increasing number of researchers studying cardiovascular events associated with anthracycline-based chemotherapy are addressing cardiac extracellular matrix (ECM) remodeling. The heart is an efficient muscular pump, with the cardiomyocytes and intramural coronary vasculature of the heart tethered in an ECM consisting of a network of fibrillar, structural proteins, mostly collagens. Increasing evidence suggests that the ECM plays a complex and diverse role in the processes initiated by anthracycline class drugs that lead to cardiac damage. This review discusses adverse myocardial remodeling induced by anthracyclines and focuses on their mechanisms of action. PMID- 25288000 TI - Preventing ARDS: progress, promise, and pitfalls. AB - Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high. Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges. ARDS has not been validated as an end point for pivotal clinical trials, and caution is needed when testing toxic therapies that may prevent ARDS yet potentially increase mortality. PMID- 25288003 TI - Streptococcus anginosus infections: crossing tissue planes. AB - Streptococcus anginosus has long been recognized to cause invasive pyogenic infections. This holds true for thoracic infections where S. anginosus has a propensity for abscess and empyema formation. Early diagnosis is important given the significant morbidity and mortality associated with thoracic S. anginosus infections. Yet, distinguishing thoracic S. anginosus clinically is difficult. We present three cases of thoracic S. anginosus that demonstrated radiographic extension across tissue planes, including the interlobar fissure, diaphragm, and chest wall. Few infectious etiologies are known to cross tissue planes. Accordingly, we propose S. anginosus be considered among the differential diagnosis of potential infectious etiologies causing radiographic extension across tissue planes. PMID- 25288004 TI - Survival following investigational treatment of amanita mushroom poisoning: thistle or shamrock? AB - We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the ethical and decisional challenges of offering an investigational treatment of a rare disease. Acute liver failure due to ingestion of amatoxin containing mushrooms is a relatively rare entity. Once amatoxin poisoning is identified, there is no clearly effective treatment, leading to a broad range of theoretically beneficial, anecdotally successful, or investigational options. The evolution of hepatotoxicity led us to offer investigational treatment with silibinin, an extract of Mediterranean milk thistle. We explore the pitfalls in medical decision-making experienced by both the patient and the physician in the face of ambiguity. The patient did well following silibinin infusion, but we are left uncertain as to whether the patient truly responded to treatment or was simply destined to recover. PMID- 25288005 TI - A 72-year-old man presenting with melena and multiple falls becomes acutely decompensated. PMID- 25288006 TI - A 40-year-old woman with multilobar nodular densities and massive hemoptysis. PMID- 25288007 TI - A 60-year-old woman with PET scan-avid lung nodules and a history of a ruptured silicone breast implant. AB - A 60-year-old woman was referred to the pulmonary clinic for evaluation of lung nodules. Her medical history was notable for hypothyroidism, anxiety, and a ruptured breast implant for which incomplete surgical resection and evacuation had been performed 10 years previously. She was a lifelong nonsmoker and worked as a gym instructor. The patient denied occupational exposures and had not traveled recently. Medications included levothyroxine and alprazolam. Except for a 1-month history of occasional dry cough, the review of systems was negative. The patient's physician queried whether the previously ruptured silicone breast implant may have played a role in the genesis of the nodules and referred the patient to our institution for further management. The lack of systemic symptoms relative to the degree of lung involvement provided an early diagnostic clue. PMID- 25288008 TI - Systemic vascular resistance should be banned. PMID- 25288009 TI - Response. PMID- 25288010 TI - Aspiration following elective intubation. PMID- 25288011 TI - Ultrasound assessment of the diaphragm in patients with COPD. PMID- 25288012 TI - Response. PMID- 25288013 TI - Significantly decreased and more variable expression of major CYPs and UGTs in liver microsomes prepared from HBV-positive human hepatocellular carcinoma and matched pericarcinomatous tissues determined using an isotope label-free UPLC MS/MS method. AB - PURPOSE: To determine the liver expression of cytochrome P450 (CYPs) and uridine 5'-diphosphate-glucuronosyltransferases (UGTs), the major phase I and II metabolism enzymes responsible for clearance and detoxification of drugs, xenobiotic and endogenous substances. METHODS: A validated isotope label-free method was established for absolute and simultaneous quantification of 9 CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D, 2E1 and 3A4) and 5 UGTs (1A1, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes using LC-MS/MS. RESULTS: The LC-MS/MS method displayed excellent dynamic range (at least 250-fold) and high sensitivity for each of the signature peptides with acceptable recovery, accuracy and precision. The protein expression profile of CYP and UGT isoforms were then determined in match microsomes samples prepared from patients with HBV-positive human hepatocellular carcinoma (HCC). In the tumor microsomes, the average absolute amounts of 8 major CYP isoforms (except CYP2C19) and 3 UGT isoforms (UGT1A1, UGT1A4 and UGT2B7) were decreased significantly (p < 0.05), whereas UGT1A6 and UGT1A9 levels were unchanged (p > 0.05). In addition, among isoforms with altered expression, 6 of 8 CYP isoforms and all three UGT isoforms were much more variable in tumor microsomes. Lastly, the importance of CYP3A4 was greatly diminished whereas the importance of UGT1A6 was enhanced in tumor microsomes. CONCLUSION: The use of an isotope label-free absolute quantification method for the simultaneous determination of 9 CYPs and 5 UGTs in human liver microsomes reveals that expression levels of CYPs and UGTs in human liver are severely impact by HCC, which could impact drug metabolism, disposition and pharmacotherapy. PMID- 25288014 TI - pH-responsive nano carriers for doxorubicin delivery. AB - PURPOSE: The aim of this study was to design stimuli-responsive nanocarriers for anti-cancer drug delivery. For this purpose, doxorubicin (DOX)-loaded, polysebacic anhydride (PSA) based nanocapsules (NC) were combined with pH sensitive poly (L-histidine) (PLH). METHOD: PSA nano-carriers were first loaded with DOX and were coated with poly L-histidine to introduce pH sensitivity. The PLH-coated NCs were then covered with polyethylene glycol (PEG) to reduce macrophage uptake. The drug release profile from this system was examined in two different buffer solutions prepared as acidic (pH5) and physiological (pH 7.4) media. The physical and chemical properties of the nanocapsules were characterized by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), ultraviolet and visible absorption spectroscopy (UV-VIS), and scanning electron microscopy (SEM). In vitro studies of the prepared nanocapsules were conducted in MDA-MB-231 breast cancer cells. RESULTS: The results obtained by SEM and DLS revealed that nanocapsules have spherical morphology with an average size of 230 nm. Prepared pH sensitive nanocapsules exhibited pH-dependent drug release profile and promising intracellular release of drug. PEGylation of nanoparticles significantly prevented macrophage uptake compared to non-PEGylated particles. PMID- 25288016 TI - A multifunctional amphiphilic polymer as a platform for surface-functionalizing metallic and other inorganic nanostructures. AB - We designed a new set of polymer ligands that combine multiple metal-coordinating groups and short polyethylene glycol (PEG) moieties in the same structure. The ligand design relies on the controlled grafting of a large number of amine terminated histamines and PEG short chains onto a poly(isobutylene-alt-maleic anhydride) backbone, via a one-step nucleophilic addition reaction. This addition reaction is highly efficient, can be carried out in organic media and does not require additional reagents. We show that when imidazole groups are used the resulting polymer ligand can strongly ligate onto metal nanostructures such as nanoparticles (NPs) and nanorods (NRs) made of gold cores. The resulting polymer coated NPs and NRs exhibit good colloidal stability to pH changes and added electrolytes. This constitutes a departure from the use of thiol-based ligands to coordinate on Au surfaces. The present chemical approach also opens up additional opportunities for designing hydrophilic and reactive platforms where the polymer coating can be adjusted to various metal and metal oxide surfaces by simply modifying or combining the addition reaction with other metal coordinating groups. These could include iron oxide NPs and semiconductor QDs. These polymer capped NPs and NRs can be used to develop biologically-active platforms with potential use for drug delivery and sensing. PMID- 25288015 TI - Toward the establishment of standardized in vitro tests for lipid-based formulations. 5. Lipolysis of representative formulations by gastric lipase. AB - PURPOSE: Lipid-based formulations (LBF) are substrates for digestive lipases and digestion can significantly alter their properties and potential to support drug absorption. LBFs have been widely examined for their behaviour in the presence of pancreatic enzymes. Here, the impact of gastric lipase on the digestion of representative formulations from the Lipid Formulation Classification System has been investigated. METHODS: The pHstat technique was used to measure the lipolysis by recombinant dog gastric lipase (rDGL) of eight LBFs containing either medium (MC) or long (LC) chain triglycerides and a range of surfactants, at various pH values [1.5 to 7] representative of gastric and small intestine contents under both fasting and fed conditions. RESULTS: All LBFs were hydrolyzed by rDGL. The highest specific activities were measured at pH 4 with the type II and IIIA MC formulations that contained Tween(r)85 or Cremophor EL respectively. The maximum activity on LC formulations was recorded at pH 5 for the type IIIA-LC formulation. Direct measurement of LBF lipolysis using the pHstat, however, was limited by poor LC fatty acid ionization at low pH. CONCLUSIONS: Since gastric lipase initiates lipid digestion in the stomach, remains active in the intestine and acts on all representative LBFs, its implementation in future standardized in vitro assays may be beneficial. At this stage, however, routine use remains technically challenging. PMID- 25288017 TI - Enhanced photoproduction of hydrogen peroxide by humic substances in the presence of phenol electron donors. AB - Addition of a series of phenol electron donors to solutions of humic substances (HS) enhanced substantially the initial rates of hydrogen peroxide (H2O2) photoproduction (RH2O2), with enhancement factors (EF) ranging from a low of ~3 for 2,4,6-trimethylphenol (TMP) to a high of ~15 for 3,4-dimethoxyphenol (DMOP). The substantial inhibition of the enhanced RH2O2 following borohydride reduction of the HS, as well as the dependence of RH2O2 on phenol and dioxygen concentrations are consistent with a mechanism in which the phenols react with the triplet excited states of (aromatic) ketones within the HS to form initially a phenoxy and ketyl radical. The ketyl radical then reacts rapidly with dioxygen to regenerate the ketone and form superoxide (O2-), which subsequently dismutates to H2O2. However, as was previously noted for the photosensitized loss of TMP, the incomplete inhibition of the enhanced RH2O2 following borohydride reduction suggests that there may remain another pool of oxidizing triplets. The results demonstrate that H2O2 can be generated through an additional pathway in the presence of sufficiently high concentrations of appropriate electron donors through reaction with the excited triplet states of aromatic ketones and possibly of other species such as quinones. However, in some cases, the much lower ratio of H2O2 produced to phenol consumed suggests that secondary reactions could alter this ratio significantly. PMID- 25288018 TI - Weekly rituximab consolidation following four cycles of R-CHOP induction chemotherapy in very elderly patients with diffuse large B-cell lymphoma: Consortium for improving survival of lymphoma study (CISL). AB - This study aimed to determine the objective response, toxicity, and clinical outcome of weekly rituximab consolidation after four cycles of R-CHOP21 in very elderly patients with DLBCL. A prospective, multi-institutional phase II trial was conducted on patients with previously untreated CD20(+) DLBCL who were older than 70 yr. Patients were treated with four cycles of R-CHOP21 followed by weekly consolidation with rituximab (375 mg/m(2) , four times infusion) (NCT01181999). We also compared the clinical outcomes with an historical case-matched control group treated conventionally with six cycles of R-CHOP21. A total of 51 patients with newly diagnosed DLBCL were enrolled at 15 institutes between June 2010 and September 2013. The median age was 76 yr (range: 70-89). Forty-one of the 51 patients completed the planned rituximab consolidation (R-consolidation). The overall response rate was 78.4%, comprising 74.5% with a complete response and 3.9% with a partial response. After a median follow-up of 20.3 months, 2-yr progression-free survival and overall survival were 63.9% and 68.7%, respectively. No serious toxicities were reported during rituximab consolidation. Weekly rituximab consolidation following four cycles of R-CHOP21 resulted in an acceptable response with high tolerability and could be a good compromise between efficacy and safety for elderly patients with DLBCL. PMID- 25288019 TI - Deficits in cerebellar granule cell development and social interactions in CD47 knockout mice. AB - CD47 is involved in neurite differentiation in cultured neurons, but the function of CD47 in brain development is largely unknown. We determined that CD47 mRNA was robustly expressed in the developing cerebellum, especially in granule cells. CD47 protein was mainly expressed in the inner layer of the external granule layer (EGL), molecular layer, and internal granule layer (IGL), where granule cells individually become postmitotic and migrate, leading to neurite fasciculation. At postnatal day 8 (P8), CD47 knockout mice exhibited an increased number of proliferating granule cells in the EGL, whereas the CD47 agonist peptide 4N1K increased the number of postmitotic cells in primary granule cells. Knocking out the CD47 gene and anti-CD47 antibody impaired the radial migration of granule cells from the EGL to the IGL individually in mice and slice cultures. In primary granule cells, knocking out CD47 reduced the number of axonal collaterals and dendritic branches; by contrast, overexpressing CD47 or 4N1K treatment increased the axonal length and numbers of axonal collaterals and dendritic branches. Furthermore, the length of the fissure between Lobules VI and VII was decreased in CD47 knockout mice at P21 and at 14 wk after birth. Lastly, CD47 knockout mice exhibited increased social interaction at P21 and depressive like behaviors at 10 wk after birth. Our study revealed that the cell adhesion molecule CD47 participates in multiple phases of granule cell development, including proliferation, migration, and neurite differentiation implying that aberrations of CD47 are risk factors that cause abnormalities in cerebellar development and atypical behaviors. PMID- 25288020 TI - A study of the impact of the 21-gene breast cancer assay on the use of adjuvant chemotherapy in women with breast cancer in a Mexican public hospital. AB - BACKGROUND: The majority of breast cancer patients in Mexico are treated through the public health system and >80% receive adjuvant chemotherapy. The aim of this prospective study was to characterize the impact of the Oncotype DX assay on adjuvant therapy decision making and the confidence in those decisions amongst public sector physicians in Mexico. METHODS: Ninety-eight consecutive patients with ER+, HER2-, stage I-IIIa, N0/N1-3 node-positive breast cancer from the Instituto Nacional de Cancerologia were eligible for the study. The primary endpoint was the overall change in treatment recommendations after receiving the assay results. RESULTS: Of 96 patients, 48% received a chemohormonal therapy recommendation prior to testing. Following receipt of results, treatment decisions changed for 31/96 (32%) patients, including 17/62 (27%) node-negative patients and 14/34 (41%) node-positive patients. The proportion of patients with a chemotherapy-based recommendation decreased from 48% pre- to 34% post-assay (P=0.024). 92% of physicians agreed that they were more confident in their treatment recommendation after ordering the assay. CONCLUSIONS: These results suggest that use of the 21-gene assay in the Mexican public health system has a meaningful impact on adjuvant treatment recommendations that may reduce the overall use of chemotherapy. PMID- 25288021 TI - Competency frameworks for advanced practice nursing: a literature review. AB - AIM: This paper describes a literature review that identified common traits in advanced practice nursing that are specific to competency development worldwide. BACKGROUND: There is a lack of international agreement on the definition of advanced practice nursing and its core competencies. Despite the lack of consensus, there is an ongoing process worldwide to establish and outline the standards and competencies for advanced practice nursing roles. INTRODUCTION: International agencies, such as the International Council of Nurses, have provided general definitions for advanced practice nursing. Additionally, a set of competency standards for this aim has been developed. METHODS: A literature review and a directed search of institutional websites were performed to identify specific developments in advanced practice nursing competencies and standards of practice. To determine a competency map specific to international advanced practice nursing, key documents were analysed using a qualitative approach based on content analysis to identify common traits among documents and countries. RESULTS: The review process identified 119 relevant journal articles related to advanced practice nursing competencies. Additionally, 97 documents from grey literature that were related to advanced practice nursing competency mapping were identified. From the text analysis, 17 worldwide transversal competency domains emerged. CONCLUSIONS: Despite the variety of patterns in international advanced practice nursing development, essential competency domains can be found in most national frameworks for the role development of international advanced practice nursing. These 17 core competencies can be used to further develop instruments that assess the perceived competency of advanced practice nurses. IMPLICATIONS FOR NURSING AND HEALTH POLICY: The results of this review can help policy developers and researchers develop instruments to compare advanced practice nursing services in various contexts and to examine their association with related outcomes. PMID- 25288022 TI - A nonfusogenic antigen mimic of influenza hemagglutinin glycoproteins constituted with soluble full-length HA1 and truncated HA2 proteins expressed in E. coli. AB - A novel method is proposed to produce a soluble recombinant antigen mimic, constituted with full-length HA1 and truncated HA2 individually expressed in E. coli, instead of a precursor form of hemagglutinin protein, that is similar to the naturally processed and disulfide-linked HA1/HA2 on the envelope of the influenza A virus strain X-31 (H3N2). A truncated ectodomain of HA2 subunit, HA2(23-185)/C137S, lacked two membrane-interacting sequences, i.e., the N terminal fusion peptide as well as the transmembrane domain and short cytoplasmic segment at the C terminus. A recombinant HA1 (rHA1) subunit protein, HA1(1 328)/C14S/L157S, lacked the signal peptide. Mutations C137S and C14S in the HA2 and HA1 subunits, respectively, were introduced to prevent any possible disulfide linkage between the two subunit proteins. The rHA antigen mimic would be nonfusogenic mainly due to the absence of the N-terminal fusion peptide as well as the C-terminal transmembrane domain in the truncated HA2, and eventually less cytotoxic as well. Antibody responses induced by two soluble rHA antigens were evaluated by ELISA assays to detect rHA antigens injected and to validate both anti-HA1 and anti-HA2 antibodies produced in the mice sera. Antigenic rHA proteins also elicited neutralizing antibodies against homologous H3N2 influenza virus in the immunized mice, without severe body weight loss or any other adverse symptoms. PMID- 25288023 TI - Bone mineral density is not associated with musculoskeletal pain in postmenopausal Korean women aged >=50 years. AB - Although many studies reported improvement of back pain after osteoporosis treatment, there is insufficient evidence to determine whether osteoporosis is painful. We investigated whether bone mineral density correlated with musculoskeletal pain in postmenopausal Korean women aged >=50 years. Data for postmenopausal women aged >=50 years were obtained from the fifth Korea National Health and Nutrition Examination Survey database. Demographics, Kellgren-Lawrence grade, and numeric rating scale for pain in the hip and knee joints, presence of back pain, and activity level were analyzed. Only subjects with dual-energy X-ray absorptiometry scans and hip and knee radiographs were included. Those with malignancy, pain medication use, or a history of fragility fractures were excluded. After univariate analysis, multiple linear regression analysis was performed to examine the significant factors correlated with the degree of hip and knee pain. Binary logistic regression analysis was performed to identify factors significantly associated with the presence of back pain. In total, 387 women were included in the data analysis. Age (p = 0.005) was the only significant factor correlated with the intensity of hip pain, while Kellgren Lawrence grade (p < 0.001) was the only significant factor correlated with knee pain intensity in multiple regression analysis. Binary logistic regression analysis showed that age (p = 0.002) was the only significant factor associated with the presence of back pain. Musculoskeletal pain was not affected by or associated with the bone mineral density (BMD) of the affected body part in postmenopausal Korean women aged >=50 years after adjusting for the degree of osteoarthritis. PMID- 25288024 TI - Comparing written programs and self-reported respiratory protection practices in acute care hospitals. AB - Airborne biological hazards in hospitals require the use of respiratory protection. A well-implemented respiratory protection program can protect health care workers from these exposures. This study examines the relationship between written respiratory programs and reported practices in health care settings. Twenty-eight hospitals in Illinois and Minnesota were recruited to a study of respiratory protection programs and practices in acute care settings. Interviews were conducted with hospital managers, unit managers, and health care workers from departments where respirators are commonly required. Each hospital's written respiratory protection program was scored for the 11 elements required by the Occupational Safety and Health Administration (OSHA), using a standardized tool, for a maximum possible score of 22 (2 pts. per element). Twenty interview questions associated with program practices were also scored by percent correct responses. Written program scores ranged from 2-17 with an average of 9.2. Hospital and unit managers scored on average 82% and 81%, respectively, when compared to the OSHA standard; health care workers scored significantly lower, 71% (p < 0.001). Minnesota written program scores were not significantly higher than Illinois hospitals (p = 0.16), while all Illinois survey respondents scored higher than those in Minnesota (p < 0.001). There was no trend between written programs and interview responses. Written respiratory protection programs in the study sites did not provide the level of detail required OSHA. Interview responses representing hospital practices surrounding respiratory protection indicated that hospitals were aware of and following regulatory guidelines. PMID- 25288025 TI - Magnetic resonance volumetry of the hippocampus in familial spontaneous epileptic cats. AB - A strain of familial spontaneous epileptic cats (FSECs) with typical limbic seizures was identified in 2010. The electroencephalographic features suggested that an epileptogenic zone is present in the mesial temporal structures (i.e., amygdala and/or hippocampus). In this study, visual evaluations and quantitative analyses were performed by using 3D MR hippocampal volumetry in comparing FSECs with age-matched controls. Visual hippocampal asymmetries were seen in 8 of 14 (57.1%) FSECs. The FSEC group showed a significantly higher asymmetric ratio (4.15%) than the control group (0.99%). The smaller side of hippocampal volume (HV) (0.206 cm(3)) in FSECs was significantly smaller than the mean HV in controls (0.227 cm(3)). However, the means of left and right HVs and total HVs in FSECs showed no differences because the laterality of hippocampal atrophy was different in each individual. Therefore, since FSECs represent a true model of spontaneous epilepsy, hippocampal volumetry should be evaluated in each individual as well as in human patients. The significant asymmetry of HV suggests the potential for hippocampal atrophy in FSECs. PMID- 25288026 TI - Adverse events, placebo and nocebo effects in placebo-treated paediatric patients with refractory focal epilepsies. Analysis of double-blind studies. AB - BACKGROUND AND PURPOSE: Assessment of placebo and nocebo effects and evaluation of background incidence of some predefined adverse effects (AEs) of antiepileptic drugs (AEDs) in placebo-treated paediatric patients recruited in randomized controlled studies (RCTs) of refractory focal epilepsies. METHODS: We searched all add-on, double-blind, placebo-controlled trials investigating any AED in paediatric patients with focal epilepsies and extracted both for patients treated with placebo and for those treated with the active drug, number of patients, number of responders (>=50% reduction of seizure frequency) number of patients withdrawing because of AEs, number of patients with AEs, and number of patients with 11 predefined AEs. The association between placebo and active treatment AEs was also explored. RESULTS: Seven RCTs were included in our study with a total of 668 children treated with the experimental drug and 634 with placebo. In placebo treated patients, overall responder rate was 19.7% [(95% CI), (16.0, 23.4)], proportion of placebo-treated patients withdrawing because of AEs was 3.6% (2.1, 5.1%), and proportions of patients with any AE was 81.3% (68.5, 94.1%). The three most frequently reported AEs were headache (PR=11.4%, 6.4,16.3%) somnolence (PR=9.6%, 4.9, 14.3%), and ataxia (PR=4.6, -1.1, 10.2). A significant correlation between placebo-treated patients and those treated with the active drug was found for the outcome measure any AE and the AEs somnolence, headache and fatigue. CONCLUSIONS: Both placebo and nocebo effects assessed in this paediatric population did not differ from findings reported in adults. This is in partial contrast to what has been previously reported and with observations in other diseases. Also specific AEs, which are at least in part, caused by the background treatment, failed to show significant differences from what previously observed in adult RCTs. PMID- 25288027 TI - Comparison between autologous blood transfusion drainage and no drainage/closed suction drainage in primary total hip arthroplasty: a meta-analysis. AB - PURPOSE: Primary aim of this meta-analysis of randomized controlled trials (RCTs) was to compare blood loss, transfusion rate and postoperative hemoglobin levels at 24-48 h after primary total hip arthroplasty (THA) between autologous blood transfusion (ABT) drainage and no drainage/closed-suction drainage and to obtain a powerful conclusion which way of drainage had the best clinical efficacy. Secondary aim was to compare the postoperative complication rates during the first year to indentify which way of drainage was safest. METHODS: We searched the PubMed, Embase and Cochrane Central Register of Controlled Trials and identified 12 RCTs (including a total of 1,574 patients) for the meta-analysis. Methodological quality was assessed by the Physiotherapy Evidence Database scale. Two researchers extracted relevant data including study characteristics, blood loss, transfusion rate, hemoglobin levels, hospital stay and complications. After data extraction, we compared results using fixed-effects or random-effects models depending on the heterogeneity of the included studies. RESULTS: Autologous blood transfusion drainage had less total blood loss and lower superficial infection rate than no drainage/closed-suction drainage. While there were no statistical differences in postoperative pain, hematoma, hemoglobin levels, hospital stay and other complications between ABT drainage and no drainage/closed-suction drainage. CONCLUSIONS: Autologous blood transfusion drainage and no drainage/closed-suction drainage have similar clinical efficacy and safety in primary THA with regard to clinical outcomes and complication rates. PMID- 25288028 TI - Think twice before re-manipulating distal metaphyseal forearm fractures in children. AB - BACKGROUND: Treatment of displaced paediatric distal forearm fractures is not always successful. Re-occurrence of angular deformity is a frequent complication. No consensus exists when to perform secondary manipulations. The purpose of this study was to analyse the long-term outcome of re-angulated paediatric forearm fractures to determine if re-manipulations can be avoided. METHODS: Children who underwent closed reduction for distal forearm fractures and presented with re angulation at follow-up were included in this retrospective cohort study. We compared those that were re-manipulated to those managed conservatively. Re angulation was defined as >=15 degrees of angulation on either the AP or lateral view. Children were reviewed after 1-8 years post injury. Outcome measures were residual angulation on radiographs, active range of motion, grip strength, Visual Analogue Scales (satisfaction, cosmetics and pain) and the ABILHANDS-kids questionnaire. RESULTS: Sixty-six children (mean age of 9.6 years) were included. Twenty-four fractures were re-manipulated and 42 fractures had been left to heal in angulated position. At time of re-angulation, children <12 years in the conservative group had similar angulations to those re-manipulated. Children >=12 years in the re-manipulation group had significantly greater angulations than children in the conservative group. At final follow-up, after a mean of 4.0 years, near anatomical alignment was seen on radiographs in all patients. Functional outcome was predominantly excellent. There was no significant difference in functional, subjective or radiological outcomes between treatment groups. CONCLUSION: Re-manipulation of distal forearm fractures in children <12 years did not improve outcomes, deeming re-manipulations unnecessary. Children >=12 years in the conservative group achieved satisfactory outcomes despite re angulations exceeding current guidelines. Based on observed remodelling, we now accept up to 30 degrees angulation in children <9 years; 25 degrees angulation in children aged 9-<12; 20 degrees angulation in children >=12 years, when re angulation occurs. We conclude that clinicians should be more reluctant to perform re-manipulations. PMID- 25288029 TI - Midterm functional outcome after dorsal capsular imbrication for posttraumatic instability of the distal radioulnar joint. AB - INTRODUCTION: The dorsal capsular imbrication of the distal radioulnar joint (DRUJ) which was performed because of posttraumatic dorsal instability showed promising functional results after the first postoperative years. Therefore, we hypothesized that patients after capsular imbrication are characterized by good subjective and functional outcome measurements after a midterm period. MATERIALS AND METHODS: Eleven patients (range 21-50 years of age; median 35 years of age) were examined after capsular imbrication of the DRUJ because of posttraumatic instability with a mean follow-up time of 72 months (range 46-114 months; median 66 months). Examination parameters included the determination of range of motion (ROM), grip strength, pain and functional outcome scores (modified Mayo wrist score (MMWS); Disabilities of the Arm, Shoulder and Hand questionnaire (DASH score)). RESULTS: A mean DASH score of 6.7 (range 0-22.5) and mean MMWS of 91.8 (range 75-100) were measured. Grip strength reached 96.7 % of the contralateral hand. Range of motion reached at least 93.1 % of the contralateral hand. Eight of 11 patients regarded functional outcome and pain reduction as excellent. Six of 11 patients did not recognize a diagnosed instability of DRUJ as such. Ulnar sided wrist pain was the apparent symptom in these cases. CONCLUSIONS: Capsular imbrication of the DRUJ is a reliable and sufficient treatment option in case of posttraumatic dorsal instability. Since DRUJ instability is seldom recognized by the patients as such, a standardised diagnostic algorithm is mandatory to guarantee reliability and efficacy for identifying DRUJ instability. PMID- 25288030 TI - The national incidence and clinical picture of SLE in children in Australia - a report from the Australian Paediatric Surveillance Unit. AB - OBJECTIVES: The objectives of this paper are to prospectively determine the incidence of paediatric systemic lupus erythematosus (pSLE) in Australia as well as describe the demographics, clinical presentation and one-year outcome. STUDY DESIGN: Newly diagnosed cases of pSLE were ascertained prospectively from October 2009 to October 2011 through the Australian Paediatric Surveillance Unit (a national monthly surveillance scheme for notification of childhood rare diseases) as well as national subspecialty groups. Questionnaires were sent to notifying physicians at presentation and at one year. RESULTS: The annual incidence rate was 0.32 per 10(5) children aged less than 16 years. The incidence was significantly higher in children of Asian or Australian Aboriginal and Torres Strait Islander parents. Approximately one-third of children underwent a renal biopsy at presentation and 7% required dialysis initially although only one child had end-stage kidney disease (ESKD) at one-year follow-up. CONCLUSION: The incidence of pSLE in Australia is comparable to that worldwide with a significantly higher incidence seen in children of Asian and Australian Aboriginal and Torres Strait Islander backgrounds. Renal involvement is common but progression to ESKD, at least in the short term, is rare. PMID- 25288031 TI - Enantiomeric separations of ruthenium (II) polypyridyl complexes using HPLC with cyclofructan chiral stationary phases. AB - The enantiomeric separation of 21 ruthenium (II) polypyridyl complexes was achieved with a novel class of cyclofructan-based chiral stationary phases (CSPs) in the polar organic mode. Aromatic derivatives on the chiral selectors proved to be essential for enantioselectivity. The R-napthylethyl carbamate functionalized cyclofructan 6 (LARIHC CF6-RN) column proved to be the most effective overall, while the dimethylphenyl carbamate cyclofructan 7 (LARIHC CF7-DMP) showed complementary selectivity. A combination of acid and base additives was necessary for optimal separations. The retention factor vs. acetonitrile/methanol ratio plot showed a U-shaped retention curve, indicating that different interactions take place at different polar organic solvent compositions. The separation results indicated that pi-pi interactions, steric effects, and hydrogen bonding contribute to the enantiomeric separation of ruthenium (II) polypyridyl complexes with cyclofructan chiral stationary phases in the polar organic mode. PMID- 25288032 TI - Statement on surgical pre-residency preparatory courses. PMID- 25288034 TI - Impact of the federal contraceptive coverage guarantee on out-of-pocket payments for contraceptives: 2014 update. AB - BACKGROUND: The Affordable Care Act requires most private health plans to cover contraceptive methods, services and counseling, without any out-of-pocket costs to patients; that requirement took effect for millions of Americans in January 2013. STUDY DESIGN: Data for this study come from a subset of the 1842 women aged 18-39 years who responded to all four waves of a national longitudinal survey. This analysis focuses on the 892 women who had private health insurance and who used a prescription contraceptive method during any of the four study periods. Women were asked about the amount they paid out of pocket in an average month for their method of choice. RESULTS: Between fall 2012 and spring 2014, the proportion of privately insured women paying zero dollars out of pocket for oral contraceptives increased substantially, from 15% to 67%. Similar changes occurred among privately insured women using injectable contraception, the vaginal ring and the intrauterine device. CONCLUSIONS: The implementation of the federal contraceptive coverage requirement appears to have had a notable impact on the out-of-pocket costs paid by privately insured women, and that impact has increased over time. IMPLICATIONS: This study measures the out-of-pocket costs for women with private insurance prior to the federal contraceptive coverage requirement and after it took effect; in doing so, it highlights areas of progress in eliminating these costs. PMID- 25288035 TI - HIV status and postpartum contraceptive use in an antenatal population in Durban, South Africa. AB - OBJECTIVE: We examined contraceptive use and dual protection in the postpartum period in a Prevention of Mother to Child Transmission population and whether it varied by HIV status. STUDY DESIGN: Data are from a prospective study, the South Africa HIV Antenatal Post-test Support Study. Pregnant participants were recruited from a government clinic in an urban township, and the analytic sample was 821. Following enrollment, participants were tested for HIV and administered a questionnaire at baseline and 14 weeks postpartum. We used generalized linear regression models to examine HIV status and use of modern contraceptives at 14 weeks. RESULTS: The risk ratio of condom use at 14 weeks postpartum was 1.66 [95% confidence interval (CI): 1.36-2.02] for HIV-positive compared to HIV-negative women. The risk ratio for dual protection (use of a condom and a hormonal method) was 1.96 (95% CI: 1.39-2.79) at 14 weeks for HIV-positive compared to HIV negative women. CONCLUSIONS: HIV positive status may be a motivating factor for women to use condoms and dual protection. In this setting where HIV is highly prevalent, it is ever more important that women control the timing and limiting of births so as to preserve the health of the mother and child. IMPLICATION: HIV status may be an important motivating behavioral factor for women to use contraceptives and dual protection in the postpartum period. PMID- 25288036 TI - Syntactic and discourse skills in Chinese adolescent readers with dyslexia: a profiling study. AB - This study aims to investigate the relation of syntactic and discourse skills to morphological skills, rapid naming, and working memory in Chinese adolescent readers with dyslexia and to examine their cognitive-linguistic profiles. Fifty two dyslexic readers (mean age, 13;42) from grade 7 to 9 in Hong Kong high schools were compared with 52 typically developing readers of the same chronological age (mean age, 13;30) in the measures of word reading, 1-min word reading, reading comprehension, morpheme discrimination, morpheme production, morphosyntactic knowledge, sentence order knowledge, digit rapid naming, letter rapid naming, backward digit span, and non-word repetition. Results showed that dyslexic readers performed significantly worse than their peers on all the cognitive-linguistic tasks. Analyses of individual performance also revealed that over half of the dyslexic readers exhibited deficits in syntactic and discourse skills. Moreover, syntactic skills, morphological skills, and rapid naming best distinguished dyslexic from non-dyslexic readers. Findings underscore the significance of syntactic and discourse skills for understanding reading impairment in Chinese adolescent readers. PMID- 25288037 TI - Analysis of descriptive electrophysiological parameters in contralateral interlimb reflexes on tetraplegic patients. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: The present study aims to analyze and correlate the interlimb reflexes (ILRs), through a standard methodology, in tetraplegic and healthy subjects. The study of the connectivity between the injured spinal cord and the ILR transmission empowers new rehabilitation pathways for tetraplegic patients. SETTING: University Hospital UNICAMP, Campinas, Brazil. METHODS: A total of 15 chronic tetraplegic patients and 10 healthy subjects were analyzed with the same methodology. Two tests were performed: (i) In test 1, the stimulus was applied to the right-arm radial nerve and the electromyography (EMG) signal collected in contralateral left tibial muscle. (ii) In test 2, the stimulus was applied to the left-leg fibular nerve and EMG collected in contralateral limb biceps, exploring the opposite direction of the pathway. In both tests, the subjects were stimulated with intensities from 5 to 30 mA (5 mA step) and 40 * 500 MUs current modulated pulses. Reflexes were detected from the averaging of the 40 EMG sweeps. RESULTS: Each group was analyzed with regard to the reflexes' incidence, amplitude and latency. ILRs were found with similar prominence in both groups. A correlation between the ILR amplitude and the subject injury level was verified. Significant differences were found in the correlation of ILR latency with stimulation charge between healthy and tetraplegic subjects. CONCLUSION: The ILR transmission parameters of healthy and tetraplegic subjects were studied. The results obtained strongly suggest a different ILR transmission between healthy and tetraplegic subjects, reinforcing the hypothesis of nerve regeneration after injury. PMID- 25288038 TI - Effect of intermittent normobaric hyperoxia for treatment of neuropathic pain in Chinese patients with spinal cord injury. AB - Study design:Prospective, randomized and controlled study.Objectives:The aim of the study was to investigate the effect of intermittent normobaric hyperoxia (InHO) for treatment of neuropathic pain in patients with spinal cord injury (SCI).Setting:The First Affiliated Hospital of Nanhua University, Hengyang, Hunan Province, China.Methods:Patients with SCI from Hunan Province were recruited from the First Affiliated Hospital of Nanhua University. History, duration, localization and characteristics of pain were recorded. Visual analog scale (VAS), the Patient Global Impression of Change (PGIC) and Short Form-36 walk wheel (SF-36ww) was used to investigate the effect of InHO. Patients were randomly assigned to study and control groups. In study group, patients were exposed to pure oxygen via non-rebreathing reservoir mask, which increased the provided oxygen at a rate of 7 l min-1 for 1 or 4 h daily in 2 weeks. While in control group, patients breathed air via non-rebreathing reservoir mask at the same rate.Results:A total of 62 SCI patients with neuropathic pain were included in the study. The mean age of the patients was 36.85+/-10.71 years. Out of 62 patients, 21 were tetraplegic and 41 were paraplegic. Overall, 14 patients had complete SCI while 48 patients had incomplete injuries. Three groups were similar with respect to age, gender, duration, smoker or not, level and severity of injury. In the 4 h per day InHO groups, a statistically significant reduction of the VAS values was observed (P<0.05). Significant difference was also found in SF 36ww pain scores and PGIC (P<0.05). However, such an effect was not evident in the control group.Conclusion:This study revealed that in treatment of neuropathic pain of SCI patients, InHO may be effective.Perspective:This article presents InHO may effectively complement pharmacological treatment in patients with SCI and neuropathic pain.Spinal Cord advance online publication, 7 October 2014; doi:10.1038/sc.2014.161. PMID- 25288039 TI - Teaching seven principles for public health ethics: towards a curriculum for a short course on ethics in public health programmes. AB - BACKGROUND: Teaching ethics in public health programmes is not routine everywhere - at least not in most schools of public health in the European region. Yet empirical evidence shows that schools of public health are more and more interested in the integration of ethics in their curricula, since public health professionals often have to face difficult ethical decisions. DISCUSSION: The authors have developed and practiced an approach to how ethics can be taught even in crowded curricula, requiring five to eight hours of teaching and learning contact time. In this way, if programme curricula do not allow more time for ethics, students of public health can at least be sensitised to ethics and ethical argumentation. This approach - focusing on the application of seven mid level principles to cases (non-maleficence, beneficence, health maximisation, efficiency, respect for autonomy, justice, proportionality) - is presented in this paper. Easy to use 'tools' applying ethics to public health are presented. SUMMARY: The crowded nature of the public health curriculum, and the nature of students participating in it, required us to devise and develop a short course, and to use techniques that were likely to provide a relatively efficient introduction to the processes, content and methods involved in the field of ethics. PMID- 25288040 TI - Post and during event effect of cell phone talking and texting on driving performance--a driving simulator study. AB - OBJECTIVE: A number of studies have been done in the field of driver distraction, specifically on the use of cell phone for either conversation or texting while driving. Researchers have focused on the driving performance of drivers when they were actually engaged in the task; that is, during the texting or phone conversation event. However, it is still unknown whether the impact of cell phone usages ceases immediately after the end of task. The primary objective of this article is to analyze the post-event effect of cell phone usage (texting and conversation) in order to verify whether the distracting effect lingers after the actual event has ceased. METHODS: This study utilizes a driving simulator study of 36 participants to test whether a significant decrease in driver performance occurs during cell phone usage and after usage. Surrogate measures used to represent lateral and longitudinal control of the vehicle were standard deviation (SD) of lane position and mean velocity, respectively. RESULTS: RESULTS suggest that there was no significant decrease in driver performance (both lateral and longitudinal control) during and after the cell phone conversation. For the texting event, there were significant decreases in driver performance in both the longitudinal and lateral control of the vehicle during the actual texting task. The diminished longitudinal control ceased immediately after the texting event but the diminished lateral control lingered for an average of 3.38 s. The number of text messages exchanged did not affect the magnitude or duration of the diminished lateral control. CONCLUSION: The result indicates that the distraction and subsequent elevated crash risk of texting while driving linger even after the texting event has ceased. This finding has safety and policy implications in reducing distracted driving. PMID- 25288041 TI - Interventions to improve the appropriate use of polypharmacy for older people. AB - BACKGROUND: Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients, is growing. OBJECTIVES: This review sought to determine which interventions, alone or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people. SEARCH METHODS: In November 2013, for this first update, a range of literature databases including MEDLINE and EMBASE were searched, and handsearching of reference lists was performed. Search terms included 'polypharmacy', 'medication appropriateness' and 'inappropriate prescribing'. SELECTION CRITERIA: A range of study designs were eligible. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people 65 years of age and older in which a validated measure of appropriateness was used (e.g. Beers criteria, Medication Appropriateness Index (MAI)). DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. Study-specific estimates were pooled, and a random-effects model was used to yield summary estimates of effect and 95% confidence intervals (CIs). The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall quality of evidence for each pooled outcome. MAIN RESULTS: Two studies were added to this review to bring the total number of included studies to 12. One intervention consisted of computerised decision support; 11 complex, multi-faceted pharmaceutical approaches to interventions were provided in a variety of settings. Interventions were delivered by healthcare professionals, such as prescribers and pharmacists. Appropriateness of prescribing was measured using validated tools, including the MAI score post intervention (eight studies), Beers criteria (four studies), STOPP criteria (two studies) and START criteria (one study). Interventions included in this review resulted in a reduction in inappropriate medication usage. Based on the GRADE approach, the overall quality of evidence for all pooled outcomes ranged from very low to low. A greater reduction in MAI scores between baseline and follow-up was seen in the intervention group when compared with the control group (four studies; mean difference -6.78, 95% CI -12.34 to -1.22). Postintervention pooled data showed a lower summated MAI score (five studies; mean difference -3.88, 95% CI -5.40 to -2.35) and fewer Beers drugs per participant (two studies; mean difference -0.1, 95% CI -0.28 to 0.09) in the intervention group compared with the control group. Evidence of the effects of interventions on hospital admissions (five studies) and of medication-related problems (six studies) was conflicting. AUTHORS' CONCLUSIONS: It is unclear whether interventions to improve appropriate polypharmacy, such as pharmaceutical care, resulted in clinically significant improvement; however, they appear beneficial in terms of reducing inappropriate prescribing. PMID- 25288042 TI - Lithium-induced differential expression of SAT1 in suicide completers and controls is not correlated with polymorphisms in the promoter region of the gene. PMID- 25288043 TI - Subjective experience of emotions and emotional empathy in paranoid schizophrenia. AB - Unlike the cognitive dimensions, alterations of the affective components of empathy in schizophrenia are less well understood. This study explored cognitive and affective dimensions of empathy in the context of the subjective experience of aspects of emotion processing, including emotion regulation, emotional contagion, and interpersonal distress, in individuals with schizophrenia and healthy controls. In addition, the predictive value of these parameters on psychosocial function was investigated. Fifty-five patients with paranoid schizophrenia and 55 healthy controls were investigated using the Multifaceted Empathy Test and Interpersonal Reactivity Index, as well as the Subjective Experience of Emotions and Emotional Contagion Scales. Individuals with schizophrenia showed impairments of cognitive empathy, but maintained emotional empathy. They reported significantly more negative emotional contagion, overwhelming emotions, lack of emotions, and symbolization of emotions by imagination, but less self-control of emotional expression than healthy persons. Besides cognitive empathy, the experience of a higher extent of overwhelming emotions and of less interpersonal distress predicted psychosocial function in patients. People with schizophrenia and healthy controls showed diverging patterns of how cognitive and emotional empathy related to the subjective aspects of emotion processing. It can be assumed that variables of emotion processing are important moderators of empathic abilities in schizophrenia. PMID- 25288044 TI - A fluorescence resonance energy transfer (FRET) biosensor based on graphene quantum dots (GQDs) and gold nanoparticles (AuNPs) for the detection of mecA gene sequence of Staphylococcus aureus. AB - In this work, a novel fluorescence resonance energy transfer (FRET) biosensor based on graphene quantum dots (GQDs) and gold nanoparticles (AuNPs) pairs was developed for Staphylococcus aureus specific gene sequence detection. This FRET biosensor platform was realized by immobilization of capture probes on GQDs and conjugation of reporter probes on AuNPs. Target oligos then co-hybridized with capture probes and reporter probes to form a sandwich structure which brought GQDs and AuNPs to close proximity to trigger FRET effect. The fluorescence signals before and after addition of targets were measured and the fluorescence quenching efficiency could reach around 87% with 100 nM target oligo. The limit of detection (LOD) of this FRET biosensor was around 1 nM for S.aureus gene detection. Experiments with both single-base mismatched oligos and double-base mismatched oligos demonstrated the good sequence selectivity of this FRET biosensor. PMID- 25288045 TI - Cohen et al. Reach inappropriate conclusions on the effect of sedation on the accuracy and treatment outcomes for diagnostic injections. PMID- 25288046 TI - A residual intramyocardial cystic dissection after cardiac fibroma resection. PMID- 25288047 TI - Influence of a user-adaptive prosthetic knee on quality of life, balance confidence, and measures of mobility: a randomised cross-over trial. AB - OBJECTIVE: To study the influence of a transition from a non-microprocessor controlled to the Rheo Knee((r)) II on quality of life, balance confidence and measures of mobility. DESIGN: Randomised crossover trial. SETTING: Research department of a rehabilitation centre. SUBJECTS: Persons with a transfemoral amputation or knee disarticulation (n=10). INTERVENTIONS: Participants were assessed with their own non-microprocessor controlled knee and with the Rheo Knee((r)) II. The low-profile Vari-Flex with EVO foot was installed in both knee conditions, followed by eight weeks of acclimatisation. The order in which knees were tested was randomised. MAIN MEASURES: Prosthesis Evaluation Questionnaire with addendum, Activities-specific Balance Confidence scale, Timed "up & go" test, Timed up and down stairs test, Hill Assessment Index, Stairs Assessment Index, Standardized Walking Obstacle Course and One Leg Balance test. RESULTS: Significant higher scores were found for the Rheo Knee((r)) II on the Residual Limb Health subscale of the Prosthesis Evaluation Questionnaire when compared to the non-microprocessor controlled prosthetic knee (median [interquartile range] resp. 86.67 [62.21-93.08] and 68.71 [46.15-94.83]; P=0.047) In addition, participants needed significantly more steps to complete an obstacle course when walking with the Rheo Knee((r)) II compared to the non-microprocessor controlled prosthetic knee (median [interquartile range] resp. 23.50 [19.92-26.25] and 22.17 [19.50-25.75]; P=0.041). On other outcome measures, no significant differences were found. CONCLUSIONS: Transition towards the Rheo Knee((r)) II had little effect on the studied outcome measures. PMID- 25288048 TI - Twelve-year follow-up of a randomized controlled trial of comprehensive physiotherapy following disc herniation operation. AB - OBJECTIVE: To evaluate the long-term effects of postoperative comprehensive physiotherapy starting one week after lumbar disc surgery. DESIGN: Twelve-year follow-up of a three-armed, randomized, controlled, single-blinded clinical trial. SETTING: Department of Physical Medicine & Rehabilitation. PARTICIPANTS: Of 111 patients following first-time, uncomplicated lumbar disc surgery who participated in the original study and completed the treatment originally allocated, 74 ((67%; 29 (73%) physiotherapy, 22 (58%) sham therapy, 23 (68%) no therapy) completed a 12-year follow-up examination. INTERVENTIONS: In the original study, patients had been randomly assigned to comprehensive physiotherapy, sham intervention (neck massage), or no therapy. MEASURES: Low Back Pain Rating Scale; best score 0, worst score 130 points). RESULTS: At 12 years after surgery, the group participating in comprehensive physiotherapy had significantly better functional outcomes, as rated on the Low Back Pain Rating Score, than the untreated group (mean difference: -13.2 (95% CI: (-25.4; -1.0)). Equally, there was a clinically relevant, non-significant difference between the sham therapy and no therapy (mean difference: -12.5 (95%CI: -26.1; 1.1)). Consequently, the Low Back Pain Rating Score outcome did not differ between physiotherapy and sham therapy (mean difference: -0.7 (95%CI: -14.2; 12.8)). CONCLUSIONS: Participating in a comprehensive physiotherapy program following lumbar disc surgery may be associated with better long-term health benefits over no intervention, but may not be superior to sham therapy. PMID- 25288049 TI - Pick your poison: not all opioids are created equal in the eyes of dopamine (commentary on Vander Weele et al.). PMID- 25288050 TI - Field measurements for evaluating the RZWQM and PESTFADE models for the tropical zone of Thailand. AB - Evaluation of the field scale agricultural non-point source (NPS) simulation model against field experimental data is an important step that must be considered before a model can be used as a management tool. Therefore, the present study focuses on the testing of two NPS models known as the RZWQM (Root Zone Water Quality Model) and the PESTFADE (PESTicide Fate And Dynamics in the Environment). These models are used to predict the soil water content, metribuzin fate, and transport in a sprinkler-irrigated soybean field located at the experimental farm of the Asian Institute of Technology (AIT) in the Pathumthani Province, Thailand. Field soil water content and metribuzin residue adsorbed at soil profile depths of 0-10, 10-20, and 30-40 cm at different time periods were intensively measured by the gravimetric method and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), respectively. When comparing the field measured data, it was observed that the RZWQM performed better in simulating the soil water fcontent, whereas the performance of the PESTFADE model was better at simulating the metribuzin residue in the soil. Specifically, a reasonable agreement existed between the measured soil water content and that predicted by the RZWQM for 0-10 and 30-40 cm soil depths. The model slightly overpredicted the metribuzin residue at 0-10 cm soil depth one day after herbicide application, whereas the prediction of metribuzin residue at 10-20 and 30-40 cm soil depths was in accordance with the measured values. The PESTFADE model performed relatively well in simulating the soil water content at 10-20 cm and metribuzin residue concentration at 0-10 and 10-20 cm soil profile depths. However, the model performed relatively poorly at 30-40 cm soil profile depth. These results indicate that when properly calibrated, both the RZWQM and PESTFADE models can be used to predict the movement of water and metribuzin residue in the soil of tropical zones. PMID- 25288051 TI - Clinical course and management of acute and chronic viral hepatitis during pregnancy. AB - Pregnancy is a para-physiologic condition, which usually evolves without any complications in the majority of women, even if in some circumstances moderate or severe clinical problems can also occur. Among complications occurring during the second and the third trimester very important are those considered as concurrent to pregnancy such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, HELLP syndrome and acute fatty liver of pregnancy. The liver diseases concurrent to pregnancy typically occur at specific times during the gestation and they may lead to significant maternal and foetal morbidity and mortality. Commonly, delivery of the foetus, even preterm, usually terminates the progression of these disorders. All chronic liver diseases, such as chronic viral hepatitis, autoimmune hepatitis, Wilson's disease, and cirrhosis of different aetiologies may cause liver damage, independently from pregnancy. In this review we will also comment the clinical implications of pregnancies occurring in women who received a orthotopic liver transplantation (OLT) Therefore, the management of immunosuppressive therapy before and after the delivery in women who received liver transplant is becoming a relevant clinical issue. Finally, we will focus on acute and chronic viral hepatitis occurring during pregnancy, on management of advanced liver disease and we will review the literature on the challenging issue regarding pregnancy and OLT. PMID- 25288052 TI - Bridging the gap: exploring the barriers to using economic evidence in healthcare decision making and strategies for improving uptake. AB - Evidence from economic evaluations is often not used to inform healthcare policy despite being well regarded by policy makers and physicians. This article employs the accessibility and acceptability framework to review the barriers to using evidence from economic evaluation in healthcare policy and the strategies used to overcome these barriers. Economic evaluations are often inaccessible to policymakers due to the absence of relevant economic evaluations, the time and cost required to conduct and interpret economic evaluations, and lack of expertise to evaluate quality and interpret results. Consistently reported factors that limit the translation of findings from economic evaluations into healthcare policy include poor quality of research informing economic evaluations, assumptions used in economic modelling, conflicts of interest, difficulties in transferring resources between sectors, negative attitudes to healthcare rationing, and the absence of equity considerations. Strategies to overcome these barriers have been suggested in the literature, including training, structured abstract databases, rapid evaluation, reporting checklists for journals, and considering factors other than cost effectiveness in economic evaluations, such as equity or budget impact. The factors that prevent or encourage decision makers to use evidence from economic evaluations have been identified, but the relative importance of these factors to decision makers is uncertain. PMID- 25288053 TI - Associations between socioeconomic status, aging and functionality among older women. AB - To assess if there is an association between socioeconomic status and quality of life, functional status and markers of aging, we studied 86 women aged 73 +/- 7 years, who answered the WHO Qol Bref quality of life survey. Mini mental state examination, timed up and go test, 12 minutes' walk, hand grip and quadriceps strength, dual X-ray absorptiometry (DEXA), carotid intima-media thickness and telomere length in peripheral leukocytes were measured. Successful aging was defined as a walking speed, handgrip strength, appendicular lean body mass, timed up and go and minimental values above cutoff points for disability. Participants with successful aging had a higher quality of life score and were more likely to live in rich municipalities. There was a positive correlation between telomere length, right handgrip strength and total fat free mass. Therefore, there is an association between socioeconomic status, successful aging and quality of life. PMID- 25288054 TI - Nucleation, growth and characterization of semiorganic nonlinear optical crystal sodium acetate doped L-tyrosine. AB - Sodium acetate doped L-tyrosine single crystal with dimensions 47*15*8 mm(3) was grown by slow evaporation solution growth technique. Nucleation kinetics of the growth of the material was studied to optimize the growth conditions. The grown doped crystal was then characterized using single crystal XRD, UV-vis-NIR, FTIR, NMR, SEM-EDAX and NLO studies. XRD study reveals that the grown crystal belongs to monoclinic system with space group P21. Lattice parameters of the grown crystals are found to be a=5.096 A, b=8.966 A, c=11.088 A, alpha=beta=90 degrees and gamma=92.035 degrees . The transparent range of the grown crystal was measured as 260-1100 nm with 260 nm as lower cut off wavelength using UV-vis-NIR absorption spectrum and the optical band gap was evaluated as 3.24 eV from the Tauc's plot. The various functional groups were identified using FTIR spectral analysis. The thermal behavior of the title compound has been analyzed using TGA/DTA and DSC thermal curves. From the thermal study, the material is found to possess thermal stability up to 158 degrees C. The microstructure of the grown crystal and the presence of various elements in the crystal were analyzed using SEM and EDAX techniques. NMR spectral analysis confirms the molecular structure of the grown compound. The nonlinear optical property was tested using Kurtz Perry powder technique and SHG efficiency was measured nearly same as that of KDP. PMID- 25288055 TI - Cytotoxic effects of cobalt and nickel ions on osteocytes in vitro. AB - BACKGROUND: Metal-on-metal prostheses undergo wear and corrosion, releasing soluble ions and wear particles into the surrounding environment. Reports described early failures of the metal-on-metal prostheses, with histologic features similar to a Type IV immune response. Mechanisms by which metal wear products and metal ion causing this reaction are not completely understood, and the effects of metal ions on osteocytes, which represent more than 95% of all the bone cells, have not been also studied. We hypothesized that soluble metal ions released from the cobalt-chromium-molybdenum (Co-Cr-Mo) prosthesis may have cytotoxic effect on osteocytes. METHODS: MLO-Y4 osteocytes were treated with various metal ion solutions for 24 and 48 h. The effect of ion treatment on cytotoxicity was assessed by WST-1 reagents and cell death ELISA. Morphological changes were analyzed by a phase-contrast microscope or fluorescent microscope using Hoechst 33342 and propidium iodine staining. RESULTS: Cr and Mo ions did not cause cell death under 0.50 mM, highest concentration studied, whereas Co and Ni ions had significant cytotoxic effect on MLO-Y4 cells at concentrations grater than 0.10 mM and at 0.50 mM, respectively, in a dose-dependent manner. According to the ELISA data, osteocytes treated with Co ions were more susceptible to necrotic than apoptotic cell death, while Ni ions caused osteocyte apoptosis. The morphological assays show that cells treated with Co and Ni ions at high concentration were fewer in number and rounded. In addition, fluorescent images showed a marked reduction in live cells and an increase in dead osteocytes treated with Co and Ni ions at high concentration. CONCLUSIONS: Metal ions released from metal-on-metal bearing surfaces have potentially cytotoxic effects on MLO-Y4 osteocytes, in vitro. PMID- 25288056 TI - Does morphology predict trophic position and habitat use of ant species and assemblages? AB - A functional traits-based theory of organismal communities is critical for understanding the principles underlying community assembly, and predicting responses to environmental change. This is particularly true for terrestrial arthropods, of which only 20% are described. Using epigaeic ant assemblages, we asked: (1) can we use morphological variation among species to predict trophic position or preferred microhabitat; (2) does the strength of morphological associations suggest recent trait divergence; (3) do environmental variables at site scale predict trait sets for whole assemblages? We pitfall-trapped ants from a revegetation chronosequence and measured their morphology, trophic position [using C:N stoichiometry and stable isotope ratios (delta)] and characteristics of microhabitat and macrohabitat. We found strong associations between high trophic position (low C:N and high delta(15)N) in body tissue and morphological traits: predators were larger, had more laterally positioned eyes, more physical protection and tended to be monomorphic. In addition, morphological traits were associated with certain microhabitat features, e.g. smaller heads were associated with the bare ground microhabitat. Trait-microhabitat relationships were more pronounced when phylogenetic adjustments were used, indicating a strong influence of recent trait divergences. At the assemblage level, our fourth corner analysis revealed associations between the prevalence of traits and macrohabitat, although these associations were not the same as those based on microhabitat associations. This study shows direct links between species-level traits and both diet and habitat preference. Trait-based prediction of ecological roles and community structure is thus achievable when integrating stoichiometry, morphology and phylogeny, but scale is an important consideration in such predictions. PMID- 25288057 TI - Weaker resource diffusion effect at coarser spatial scales observed for egg distribution of cabbage white butterflies. AB - Mobile organisms frequently forage for patchy resources; e.g. herbivorous insects searching for host plants. The resource diffusion hypothesis predicts that insect herbivores, such as Pieris rapae butterflies, are disproportionally attracted to more isolated, or 'diffused', host plants. Surprisingly little is known about how this response to variation in resource density manifests itself at different spatial scales. We measured the outcome of oviposition by P. rapae butterflies foraging among groups of host plants, with plant density experimentally varied to achieve comparability between three nested scales: fine (1 * 1 m), medium (6 * 6 m), and coarse (36 * 36 m). Hierarchical linear models were used to measure density-dependent responses in the number of eggs laid per plant, with plant density measured at nested spatial scales. At a fine scale, isolated plants received significantly more eggs, while at medium and coarse scales the differences were less pronounced, and tended towards a neutral distribution of eggs across plants. Larger plants also tended to receive more eggs. Since multiple processes, acting at multiple scales, are likely to be the rule rather than the exception in ecology, methods for detecting and characterising multi scale responses are important to ensure a robust transfer of ecological models from one situation to another. PMID- 25288058 TI - [The ins and outs of evaluating lupus progression]. PMID- 25288059 TI - [Prevalence of cancer in the Afro-Caribbean population presenting dermatomyositis and anti-synthetase syndrome: a preliminary study conducted at Pointe-a-Pitre University Hospital, 2000-2012]. AB - BACKGROUND: An association with cancer is described in 17-32% of cases of dermatomyositis (DM) and in 5-16% of cases of anti-synthetase syndrome (ASS). The literature contains very few studies involving Afro-Caribbean patients with DM or ASS. The aim of our retrospective study was to determine the prevalence of cancer in a series of patients with DM or ASS at the University Hospital of Pointe-a Pitre between 1st January 2000 and 31st December 2012. The secondary objective was to review the clinical and laboratory features as well as the course of DM/ASS in these patients. PATIENTS AND METHODS: The inclusion criteria were as follows: Afro-Caribbean origin; age >15 years; patient living in Guadeloupe; screening for malignancy. RESULTS: Twenty-two patients were included (15 DM, 7 ASS). Only one case of cancer was diagnosed in the entire study population at a mean follow-up of 6 +/- 4 years (prevalence: 6.7%, CI95% [1.7-31.9]). Of the 15 patients presenting DM (sex ratio F/M: 4, mean age: 45 +/- 14 years), 6 (40%) had associated connective tissue disease. CONCLUSION: Our study suggests a weak association between DM and cancer in Afro-Caribbean patients. These results may be explained by the features of the disease seen in these patients (female gender, young age at onset, associated connective tissue disease) and the low prevalence in the Caribbean region of cancers typically associated with DM. PMID- 25288060 TI - [New pets, allergens and allergic dermatitis]. AB - The number of household pets increased greatly during the twentieth century, with the numbers of new pets (NP, i.e. any pet other than cats and dogs) rising especially sharply over the last decade. Contact with such animals, whose owners do not always know how to look after them properly, expose the population to new risks such as trauma, infection and allergy. While the most common allergies are respiratory, allergic skin reactions, both immediate and delayed, may also result from contact with these new allergens. The animal itself or its environment may be the cause. Herein, we review NPs and reports of allergic dermatitis associated with them. PMID- 25288061 TI - [Immunoallergic skin manifestations associated with new pets: three cases]. AB - BACKGROUND: The number of household pets increased greatly during the twentieth century, with numbers of new pets (NP, i.e. any pets other than cats and dogs) rising especially sharply over the last decade. PATIENTS AND METHODS: We first of all report the case of a female patient with eczema lesions on areas skin coming into contact with a ferret, with removal of the animal resulting in wound healing, followed by two patients presenting atypical polymorphous erythema reactions induced by dermatophytes present in their pet rat. DISCUSSION: While the most common allergies are respiratory, allergic skin reactions, both immediate and delayed, may also result from contact with these new allergens. The animal itself or its environment may be the cause. PMID- 25288062 TI - [Capecitabine-induced subacute cutaneous lupus: a case report]. AB - BACKGROUND: More than 100 drugs have been registered as inducing subacute cutaneous lupus erythematosus (SCLE). Recently, some types of chemotherapy have also been incriminated. If SCLE develops in a setting of neoplasia, two possibilities should be considered: it is either a paraneoplastic syndrome or it is caused by the chemotherapy, thus calling for important decisions on the benefit/risk of stopping potentially effective medication. We report a case of SCLE induced by Xeloda (capecitabine). PATIENTS AND METHODS: A 50-year-old female patient consulted with an annular erythematosquamous and pruriginous eruption, predominantly on areas of the body exposed to sunlight, occurring 4 months after the initiation of capecitabine for advanced colon cancer. She had presented systemic lupus erythematosus (SLE) for many years, which was not treated, was not progressive and had no cutaneous manifestations. The appearance of the cutaneous lesions, positivity for anti-SSA antibodies and the histological aspect led to diagnosis of SCLE. The lesions were resistant to treatment with hydroxychloroquine and systemic corticosteroids, but disappeared after discontinuation of capecitabine, suggesting chemotherapy-induced SCLE. DISCUSSION: Some types of chemotherapy such as capecitabine may reveal or induce SCLE lesions, whether or not there is a previous history of SLE. Cases of chemotherapy-induced cutaneous lupus reported to the French pharmacovigilance agency are rare, but this side effect must be recognised due to the constantly rising use of this type of anticancer agent. PMID- 25288063 TI - [Eosinophilic fasciitis, morphea and vitiligo in a single patient]. AB - BACKGROUND: Fasciitis with eosinophilia (FE), or Shulman syndrome, is a rare disease of unknown origin for which the nosological profile has not been clearly defined. It is clinically characterised by oedema and induration of the limbs with hypereosinophilia. It may be associated with morphea, in which case it carries a poor prognosis, or other diseases, particularly autoimmune conditions. Herein, we report a case of fasciitis associated with eosinophilia, morphea and vitiligo. PATIENT AND METHODS: A 45-year-old male patient followed up for vitiligo for 20 years had been presenting swelling and induration of the skin on all 4 limbs for the previous 7 months associated with morphea on the trunk. Treatment consisting of systemic corticosteroids and methotrexate was initiated and displayed a certain degree of efficacy. DISCUSSION: The association of morphea/fasciitis with eosinophilia is a classical finding; the presence of vitiligo raises the question of possible association between these different disorders. PMID- 25288064 TI - [Rheumatoid neutrophilic dermatitis]. AB - BACKGROUND: Rhumatoid arthritis (RA) is a chronic inflammatory joint disease. It appears to be caused by a combination of genetic and environmental factors. It may be accompanied by well-known extra-articular damage (e.g. lung, kidney, heart), while cutaneous involvement such as rheumatoid neutrophilic dermatitis (RND) is much less frequent. PATIENTS AND METHODS: A 64-year-old woman was referred by rheumatologists after she developed a cutaneous eruption on the forearms, elbows and scalp in a setting of progressive RA. A skin biopsy showed a dermal neutrophilic infiltrate throughout its entire thickness as well as leukocytoclasia, with fibrinoid material visible in certain areas. No vasculitis was observed. This histological examination led to a diagnosis of RND. The eruption was successfully treated with topical corticosteroids. COMMENTS: RND is a rare sign in RA that presents clinically as plaques, erythematous nodules or urticarial lesions. The lesions tend to disappear naturally or on treatment of RA. Topical corticosteroids or systemic therapy, in particular dapsone, may be suggested to treat cutaneous damage. PMID- 25288065 TI - [Solitary subungual glomangioma]. AB - BACKGROUND: Glomangiomas are benign vascular tumours. They are usually multiple, painless and extradigital. Herein we report a case of a solitary subungual glomangioma. PATIENTS AND METHODS: This 65-year-old woman presented with a history of bluish, asymptomatic, subungual lesions located in the lunula of her right thumb. Surgical exploration by a transungual approach showed a large bluish, well-circumscribed tumour, which was completely excised. Histological examination revealed numerous dilated blood vessels surrounded by aggregates of glomus cells, which was consistent with the diagnosis of glomangioma. DISCUSSION: Glomus tumours are benign tumours arising from glomus cells. Histopathologically, based on the predominant tissue type present, glomus tumours are classified as solid glomus tumours, glomangiomas or glomangiomyomas. The classical form usually consists of a painful erythematous nodule with exaggerated sensitivity to cold and pressure. The nails are frequently involved, with two sites of predilection: the matrix and the nail bed. Vascular forms of glomus tumours or glomangiomas have a different clinical presentation and are usually multifocal, bluish, painless and extradigital. Diagnosis is frequently based on histological examination. Our observation raises the question of differential diagnosis with regard to matrix melanocytic tumours (blue nevi or melanomas). CONCLUSION: We report the case of a solitary subungual glomangioma. Histological examination is necessary to rule out a clinically indistinguishable benign or malignant melanocytic tumour. PMID- 25288066 TI - [Yellow nail syndrome: two pediatric case reports]. AB - BACKGROUND: Yellow nail syndrome (YNS) is a combination of specific nail dystrophy (yellowish or green nails, transverse ridging, increased curvature with "a hump" and distal onycholysis), lymphoedema and respiratory tract involvement (mainly bronchial hyper-responsiveness, recurrent pneumonia, bronchiectasis and pleural effusion), with or without sinusitis. This rare condition is most often seen in middle age. We report two pediatric cases. PATIENTS: A 9-year-old boy had 20 yellow nails and lymphedema of the lower and upper left limbs. He was born at 32 weeks of gestation. At birth, he had fetal hydrops with bilateral chylothorax. Since then, he presented bronchopulmonary dysplasia. In his first year of life, he had recurrent nasopharyngitis and serosal otitis. Lymphoscintigraphy was not performed. A 14-year-old boy had 10 yellow toenails and 2 yellow fingernails. He was born at 36 weeks of gestation with fetal hydrops. He had recurrent serosal otitis and asthma attacks. Lymphoscintigraphy showed lymphatic hypoplasia, especially of the left limbs. DISCUSSION: These two children have the classic triad of YNS, including yellow nails, lymphedema and respiratory tract involvement. Thirteen cases have been reported in children from birth to 10 years of age, three of whom were siblings, thus suggesting genetic predisposition. In most cases lymphoscintigraphy showed hypoplasia and/or ectasia of lymphatic vessels. These lymphatic abnormalities may be responsible for nail changes as seen in Turner's syndrome. The prognosis of YNS in adults may be serious because of the pulmonary tract involvement. However, it is not known in children. CONCLUSION: Yellow dystrophic nails in children may be associated with lymphedema and respiratory tract involvement, as in adults, and this condition should therefore be investigated in cases of YNS. PMID- 25288067 TI - [Efficacy and safety of intravenous cidofovir in the treatment of giant molluscum contagiosum in an immunosuppressed patient]. PMID- 25288068 TI - [Beard and moustache dermatosis and alopecia]. PMID- 25288069 TI - [Shave biopsy for a digital onychomatricoma]. PMID- 25288070 TI - [Improving performance in clinical trials through harmonisation of evaluation criteria: the case of atopic dermatitis]. PMID- 25288071 TI - [Cutaneous metastases of melanoma]. PMID- 25288072 TI - [Contribution of reflectance confocal microscopy to the diagnosis of fibroepithelioma of Pinkus]. PMID- 25288073 TI - [Pemphigus herpetiformis]. PMID- 25288074 TI - [Of genes and hair]. PMID- 25288075 TI - Women's experiences of two different self-assessment methods for monitoring fetal movements in full-term pregnancy--a crossover trial. AB - BACKGROUND: Low maternal awareness of fetal movements is associated with negative birth outcomes. Knowledge regarding pregnant women's compliance with programs of systematic self-assessment of fetal movements is needed. The aim of this study was to investigate women's experiences using two different self-assessment methods for monitoring fetal movements and to determine if the women had a preference for one or the other method. METHODS: Data were collected by a crossover trial; 40 healthy women with an uncomplicated full-term pregnancy counted the fetal movements according to a Count-to-ten method and assessed the character of the movements according to the Mindfetalness method. Each self assessment was observed by a midwife and followed by a questionnaire. A total of 80 self-assessments was performed; 40 with each method. RESULTS: Of the 40 women, only one did not find at least one method suitable. Twenty of the total of 39 reported a preference, 15 for the Mindfetalness method and five for the Count-to ten method. All 39 said they felt calm, relaxed, mentally present and focused during the observations. Furthermore, the women described the observation of the movements as safe and reassuring and a moment for communication with their unborn baby. CONCLUSIONS: In the 80 assessments all but one of the women found one or both methods suitable for self-assessment of fetal movements and they felt comfortable during the assessments. More women preferred the Mindfetalness method compared to the count-to-ten method, than vice versa. PMID- 25288076 TI - In vitro activity of human-simulated epithelial lining fluid exposures of ceftaroline, ceftriaxone, and vancomycin against methicillin-susceptible and resistant Staphylococcus aureus. AB - Staphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ~ 10(6) CFU/ml. Time-kill curves were constructed, and microbiological response (change in log10 CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log10 CFU/ml was largest for ceftaroline q8h (reductions of >3 log10 CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log10 CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log10 CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log10 CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia. PMID- 25288077 TI - Antibacterial properties of magnesium in vitro and in an in vivo model of implant associated methicillin-resistant Staphylococcus aureus infection. AB - Periprosthetic infection remains a challenging clinical complication. We investigated the antibacterial properties of pure (99.9%) magnesium (Mg) in vitro and in an in vivo rat model of implant-related infection. Mg was highly effective against methicillin-resistant Staphylococcus aureus-induced osteomyelitis and improved new peri-implant bone formation. Bacterial icaA and agr RNAIII transcription levels were also assessed to characterize the mechanism underlying the antibacterial properties of the Mg implant. PMID- 25288078 TI - Within-population distribution of trimethoprim resistance in Escherichia coli before and after a community-wide intervention on trimethoprim use. AB - A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a health care region with 178,000 inhabitants. Here, we performed before-and-after analyses of the within-population distribution of trimethoprim resistance in Escherichia coli. Phylogenetic and population genetic methods were applied to multilocus sequence typing data of 548 consecutively collected E. coli isolates from clinical urinary specimens. Results were analyzed in relation to antibiotic susceptibility and the presence and genomic location of different trimethoprim resistance gene classes. A total of 163 E. coli sequence types (STs) were identified, of which 68 were previously undescribed. The isolates fell into one of three distinct genetic clusters designated BAPS 1 (E. coli phylogroup B2), BAPS 2 (phylogroup A and B1), and BAPS 3 (phylogroup D), each with a similar frequency before and after the intervention. BAPS 2 and BAPS 3 were positively and BAPS 1 was negatively associated with trimethoprim resistance (odds ratios of 1.97, 3.17, and 0.26, respectively). In before-and-after analyses, trimethoprim resistance frequency increased in BAPS 1 and decreased in BAPS 2. Resistance to antibiotics other than trimethoprim increased in BAPS 2. Analysis of the genomic location of different trimethoprim resistance genes in isolates of ST69, ST58, and ST73 identified multiple independent acquisition events in isolates of the same ST. The results show that despite a stable overall resistance frequency in E. coli before and after the intervention, marked within-population changes occurred. A decrease of resistance in one major genetic cluster was masked by a reciprocal increase in another major cluster. PMID- 25288079 TI - Phenobarbital induction and chemical synergism demonstrate the role of UDP glucuronosyltransferases in detoxification of naphthalophos by Haemonchus contortus larvae. AB - We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC50) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5 nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field. PMID- 25288080 TI - Metallo-beta-lactamase-producing bacteroides species can shield other members of the gut microbiota from antibiotics. AB - Antibiotics disrupt the intestinal microbiota, rendering patients vulnerable to colonization by exogenous pathogens. Intermicrobial interactions may attenuate this effect. Incubation with ceftriaxone-resistant, ccrA-positive, beta-lactamase producing Bacteroides strains raised the minimum bactericidal concentration of ceftriaxone required to kill a susceptible Escherichia coli strain (mean change, <0.25 to 29 mg/liter; P = 0.009); incubation with ceftriaxone-resistant but non beta-lactamase-producing Bacteroides strains had no effect. The production of beta-lactamase by common members of the intestinal microbiota (Bacteroides) can protect susceptible fellow commensals from beta-lactams. PMID- 25288081 TI - Abdominal candidiasis is a hidden reservoir of echinocandin resistance. AB - FKS mutant Candida isolates were recovered from 24% (6/25) of abdominal candidiasis patients exposed to echinocandin. Candida glabrata (29%) and Candida albicans (14%) mutants were identified. Multidrug-resistant bacteria were recovered from 83% of FKS mutant infections. Mutations were associated with prolonged echinocandin exposure (P = 0.01), breakthrough infections (P = 0.03), and therapeutic failures despite source control interventions (100%). Abdominal candidiasis is a hidden reservoir for the emergence of echinocandin-resistant Candida. PMID- 25288082 TI - Quinacrine inhibits Candida albicans growth and filamentation at neutral pH. AB - Candida albicans is a common cause of catheter-related bloodstream infections (CR BSI), in part due to its strong propensity to form biofilms. Drug repurposing is an approach that might identify agents that are able to overcome antifungal drug resistance within biofilms. Quinacrine (QNC) is clinically active against the eukaryotic protozoan parasites Plasmodium and Giardia. We sought to investigate the antifungal activity of QNC against C. albicans biofilms. C. albicans biofilms were incubated with QNC at serially increasing concentrations (4 to 2,048 MUg/ml) and assessed using a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide (XTT) assay in a static microplate model. Combinations of QNC and standard antifungals were assayed using biofilm checkerboard analyses. To define a mechanism of action, QNC was assessed for the inhibition of filamentation, effects on endocytosis, and pH-dependent activity. High-dose QNC was effective for the prevention and treatment of C. albicans biofilms in vitro. QNC with fluconazole had no interaction, while the combination of QNC and either caspofungin or amphotericin B demonstrated synergy. QNC was most active against planktonic growth at alkaline pH. QNC dramatically inhibited filamentation. QNC accumulated within vacuoles as expected and caused defects in endocytosis. A tetracycline-regulated VMA3 mutant lacking vacuolar ATPase (V-ATPase) function demonstrated increased susceptibility to QNC. These experiments indicate that QNC is active against C. albicans growth in a pH-dependent manner. Although QNC activity is not biofilm specific, QNC is effective in the prevention and treatment of biofilms. QNC antibiofilm activity likely occurs via several independent mechanisms: vacuolar alkalinization, inhibition of endocytosis, and impaired filamentation. Further investigation of QNC for the treatment and prevention of biofilm-related Candida CR-BSI is warranted. PMID- 25288083 TI - Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity. AB - Resistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the family Enterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, including Klebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains of K. pneumoniae, some with MIC values of 1 MUg/ml. In order to further the design of potent and selective antifolates against members of the Enterobacteriaceae, we determined the first crystal structures of K. pneumoniae DHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity. PMID- 25288084 TI - Pharmacokinetics, biodistribution, and toxicity of folic acid-coated antiretroviral nanoformulations. AB - The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r. PMID- 25288086 TI - In vitro activity of AZD0914, a novel DNA gyrase inhibitor, against Chlamydia trachomatis and Chlamydia pneumoniae. AB - The in vitro activities of AZD0914, levofloxacin, azithromycin, and doxycycline against 10 isolates each of Chlamydia trachomatis and Chlamydia pneumoniae were tested. For AZD0914, the MIC90s for C. trachomatis and C. pneumoniae were 0.25 MUg/ml (range, 0.06 to 0.5 MUg/ml) and 1 MUg/ml (range, 0.25 to 1 MUg/ml), respectively, and the minimal bactericidal concentrations at which 90% of the isolates were killed (MBC90s) were 0.5 MUg/ml for C. trachomatis (range, 0.125 to 1 MUg/ml) and 2 MUg/ml for C. pneumoniae (range, 0.5 to 2 MUg/ml). PMID- 25288085 TI - Propensity-based study of aminoglycoside nephrotoxicity in patients with severe sepsis or septic shock. AB - To assess the risk of acute kidney injury (AKI) attributable to aminoglycosides (AGs) in patients with severe sepsis or septic shock, we performed a retrospective cohort study in one medical intensive care unit (ICU) in France. Patients admitted for severe sepsis/septic shock between November 2008 and January 2010 were eligible. A propensity score for AG administration was built using day 1 demographic and clinical characteristics. Patients still on the ICU on day 3 were included. Patients with renal failure before day 3 or endocarditis were excluded. The time window for assessment of renal risk was day 3 to day 15, defined according to the RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification. The AKI risk was assessed by means of a propensity adjusted Cox proportional hazards regression analysis. Of 317 consecutive patients, 198 received AGs. The SAPS II (simplified acute physiology score II) score and nosocomial origin of infection favored the use of AGs, whereas a preexisting renal insufficiency and the neurological site of infection decreased the propensity for AG treatment. One hundred three patients with renal failure before day 3 were excluded. AGs were given once daily over 2.6 +/- 1.1 days. AKI occurred in 16.3% of patients in a median time of 6 (interquartile range, 5 to 10) days. After adjustment to the clinical course and exposure to other nephrotoxic agents between day 1 and day 3, a propensity-adjusted Cox proportional hazards regression analysis showed no increased risk of AKI in patients receiving AGs (adjusted relative risk = 0.75 [0.32 to 1.76]). In conclusion, in critically septic patients presenting without early renal failure, aminoglycoside therapy for less than 3 days was not associated with an increased risk of AKI. PMID- 25288087 TI - First report of NDM-1-producing Acinetobacter baumannii sequence type 25 in Brazil. AB - New Delhi metallo-beta-lactamase 1 (NDM-1) was first identified in Brazil in Enterobacter hormaechei and Providencia rettgeri in 2013. Here, we describe the first case of NDM-1-producing Acinetobacter baumannii sequence type 25 isolated from the urinary tract of a 71-year-old man who died of multiple complications, including A. baumannii infection. The NDM-1 gene was detected by quantitative PCR, and its sequence confirmed its presence in an ~ 100-kb plasmid. PMID- 25288088 TI - Assessment of the induction of dormant ring stages in Plasmodium falciparum parasites by artemisone and artemisone entrapped in Pheroid vesicles in vitro. AB - The in vitro antimalarial activities of artemisone and artemisone entrapped in Pheroid vesicles were compared, as was their ability to induce dormancy in Plasmodium falciparum. There was no increase in the activity of artemisone entrapped in Pheroid vesicles against multidrug-resistant P. falciparum lines. Artemisone induced the formation of dormant ring stages similar to dihydroartemisinin. Thus, the Pheroid delivery system neither improved the activity of artemisone nor prevented the induction of dormant rings. PMID- 25288089 TI - KPC-producing Klebsiella pneumoniae strains that harbor AAC(6')-Ib exhibit intermediate resistance to amikacin. AB - The aminoglycoside-modifying enzyme AAC(6')-Ib is common among carbapenem resistant Klebsiella pneumoniae (CR-Kp) strains. We investigated amikacin (AMK) activity against 20 AAC(6')-Ib-producing CR-Kp strains. MICs clustered at 16 to 32 MUg/ml. By the time-kill study, AMK (1* and 4* the MIC) was bactericidal against 30% and 85% of the strains, respectively. At achievable human serum concentrations, however, the majority of strains showed regrowth, suggesting that AAC(6')-Ib confers intermediate AMK resistance. AMK and trimethoprim sulfamethoxazole (TMP-SMX) were synergistic against 90% of the strains, indicating that the combination may overcome resistance. PMID- 25288090 TI - Triazole-based compound as a candidate to develop novel medicines to treat toxoplasmosis. AB - This article reports anti-Toxoplasma gondii activity of 3-(thiophen-2-yl)-1,2,4 triazole-5-thione. The compound displayed significant and reproducible antiparasitic effects at nontoxic concentrations for the host cells, with an experimentally determined 50% inhibitory concentration (IC50) at least 30 times better than that of the known chemotherapeutic agent sulfadiazine. Purine nucleoside phosphorylase was defined as the probable target for anti-Toxoplasma activity of the tested compound. These results provide the foundation for future work to develop a new class of medicines to better treat toxoplasmosis. PMID- 25288091 TI - Heterogeneity of mprF sequences in methicillin-resistant Staphylococcus aureus clinical isolates: role in cross-resistance between daptomycin and host defense antimicrobial peptides. AB - Over the past several years, single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) have been proposed to be associated with a gain-of function phenotype in terms of daptomycin (DAP) nonsusceptibility (referred to as daptomycin resistance [DAP-R] herein for ease of presentation) in Staphylococcus aureus. We investigated the frequencies of SNPs within the mprF ORF and the relationships of such SNPs to cross-resistance between DAP and cationic host defense peptides (HDPs). Thirty-five well-characterized, unique DAP-susceptible (DAP-S) and DAP-R methicillin-resistant S. aureus (MRSA) isolates of the clonal complex 5 genotype were used. In addition to mprF SNPs and DAP-HDP cross resistance, several other key genotypic and phenotypic metrics often associated with DAP-R were delineated, as follows: (i) mprF expression, (ii) membrane phospholipid content, (iii) positive surface charge, (iv) DAP binding, and (v) cell wall thickness profiles. A number of DAP-S strains (MICs of <= 1 MUg/ml) exhibited mprF SNPs, occasionally with high-level mprF sequence variation from the genotype reference strain. However, none of these SNPs were localized to well chronicled mprF hot spot locations associated with DAP-R in S. aureus. In contrast, all 8 DAP-R isolates demonstrated SNPs within such known mprF hot spots. Moreover, only the DAP-R strains showed MprF gain-of-function phenotypes, enhanced mprF expression, higher survival against two prototypical HDPs, and reduced DAP binding. Although a heterogenous array of mprF SNPs were often found in DAP-S strains, only selected hot spot SNPs, combined with concurrent mprF dysregulation, were associated with the DAP-R phenotype. PMID- 25288092 TI - Rifampin induces hydroxyl radical formation in Mycobacterium tuberculosis. AB - The antituberculosis (anti-TB) drug rifampin (RIF) binds to the beta subunit of the RNA polymerase (RpoB) of Mycobacterium tuberculosis, but the bactericidal responses triggered after target interaction are not known. To evaluate whether RIF induced an oxidative burst, lysates of RIF-treated M. tuberculosis were tested for determination of reactive oxygen species (ROS) by the electron paramagnetic resonance (EPR) technique using 1-hydroxy-3-carboxy-pyrrolidine (CPH) and 5,5-dimethyl-1-pyrrolidine-N-oxide (DMPO) as spin traps. M. tuberculosis killing by RIF stimulated an increase in the rate of formation of the CPH radical (CP.). Lysate pretreatment with the O2.(-) and .OH scavengers superoxide dismutase (SOD) and thiourea (THIO), respectively, or with the metal chelator diethylene triamine pentaacetic acid (DTPA) inhibited CP. formation, arguing in favor of a metal-catalyzed ROS response. Formation of CP. did not increase following treatment of RIF-resistant strains with RIF, indicating that the ROS were induced after RpoB binding. To identify the ROS formed, lysates of RIF-treated bacilli were incubated with DMPO, a spin trap specific for .OH and O2.(-), with or without pretreatment with SOD, catalase, THIO, or DTPA. Superoxide dismutase, catalase, and THIO decreased formation of the DMPO-OH adduct, and SOD plus DTPA completely suppressed it, suggesting that RIF activated metal-dependent O2.(-)-mediated mechanisms producing .OH inside tubercle bacilli. The finding that the metal chelator DTPA reduced the bactericidal activity of RIF supported the possibility that .OH was generated through these mechanisms and that it participated at least in part in M. tuberculosis killing by the drug. PMID- 25288094 TI - Oxytocin and vasopressin levels are decreased in the plasma of male schizophrenia patients. AB - OBJECTIVE: Impaired social functioning and autistic symptoms are characteristics of schizophrenia. The social hormones oxytocin (OT) and arginine-vasopressin (AVP) both modulate social interaction and therefore may be involved in the pathogenesis of schizophrenia. We investigated whether men with schizophrenia show altered OT and AVP levels compared with healthy controls (HC) and whether autism symptoms are associated with OT levels. METHODS: Forty-one men with non acute schizophrenia and 45 matched HC were enrolled. Schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). Blood samples were collected on 2 days, and plasma OT and AVP levels were measured by ELISA immunoassay. RESULTS: The schizophrenia patients had significantly lower plasma OT levels than the HC; a similar trend was found for AVP. Plasma OT levels were associated with severe life events, fewer important attached persons, and a higher score on the PANSS negative scale; the most dominant PANSS items were 'preoccupation', 'emotional withdrawal', and 'passive/apathetic social withdrawal'. CONCLUSION: These findings support an association between the social hormones OT and AVP and schizophrenia. We suggest that OT metabolism may be altered in schizophrenia, but other possible causes for decreased plasma OT levels in schizophrenia patients include decreased OT synthesis, mRNA expression, and translation. Especially the 'autistic' symptoms of schizophrenia seem to be closely linked to an altered metabolism of OT, the 'attachment' hormone. PMID- 25288093 TI - Oral administration of the broad-spectrum antibiofilm compound toremifene inhibits Candida albicans and Staphylococcus aureus biofilm formation in vivo. AB - We here report on the in vitro activity of toremifene to inhibit biofilm formation of different fungal and bacterial pathogens, including Candida albicans, Candida glabrata, Candida dubliniensis, Candida krusei, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. We validated the in vivo efficacy of orally administered toremifene against C. albicans and S. aureus biofilm formation in a rat subcutaneous catheter model. Combined, our results demonstrate the potential of toremifene as a broad-spectrum oral antibiofilm compound. PMID- 25288095 TI - Associations between insomnia, sleep duration and poor work ability. AB - OBJECTIVE: The aim of this study was to examine the independent and joint effect of insomnia and objective sleep duration on poor work ability. METHODS: In this cross-sectional study, a total of 2820 Chinese manufacturing workers were categorized as insomnia patients and individuals with normal sleeping pattern by interview according to DSM-IV criteria. Sleep duration was classified into four categories: >=7h, 6-7h, 5-6h, and <5h according to objective sleep duration of Watch-PAT-200 test. Work ability was assessed using the Chinese Work Ability Index (WAI) questionnaire. Regression analysis examined the independent and joint association of sleep duration and insomnia with poor work ability, after adjusting for various confounding factors. RESULTS: Insomnia and objective short sleep duration were both independently associated with poor work ability. Compared with the normal sleeping and >=7h sleep duration group, the highest risk of poor work ability was in the insomnia patients with <5h sleep duration [odds ratio (OR) 3.43, 95% confidence interval (CI) 1.87-5.23], followed by the individuals with insomnia who slept 5-6h (OR 2.03, 95% CI 1.42-2.67). CONCLUSIONS: Insomnia and sleep duration in workers are both separately and together associated with increased risk of poor work ability. Objective sleep duration should be taken into consideration when assessing the work ability of people with insomnia. PMID- 25288096 TI - The new combination of risk factors determining a high risk of gestational diabetes mellitus. AB - AIM: The aim of this study was to identify early markers of gestational diabetes mellitus (GDM) and to reveal the most significant of them. METHODS: A total of 548 pregnant women were screened for GDM between weeks 24 and 28 of gestation, as defined by International Association of Diabetes In Pregnancy Study Groups (IADPSG) criteria, in a retrospective case-control study. First trimester maternal fasting glucose, anthropometric parameters and blood pressure were obtained from medical records. Classification Tree Method was used to identify combination of early pregnancy risk factors that predict the highest risk of the development of GDM in later pregnancy. RESULTS: The combination of Body Mass Index (BMI) >38.6 kg/m2 with, abdominal circumference >91.5 cm and fasting glucose >4.5 mmol/L was associated with a 13-fold increased risk of GDM as compared to women who do not have this combination of symptoms (OR 13.2 95% CI: 2.7-63.3, P<0.001). In women with BMI less than 38,6 kg/m 2 the combination of fasting glucose >4.5 mmol/L, abdominal circumference >91.5 cm with the presence of polycystic ovary syndrome (PCOS) was associated with a 6-fold increased risk of GDM as compared with women who do not have this combination of symptoms (OR=7.6, 95% CI: 1.9-30.02, P=0.003). CONCLUSION: A higher BMI, abdominal circumference, fasting glycemia in the first trimester of pregnancy and the presence of PCOS predict increased GDM risk. Taking these combinations into consideration may facilitate identification of women at particular risk for GDM. PMID- 25288097 TI - Insulin resistance and androgen levels in eugonadic and hypogonadic women with prolactinoma. AB - BACKGROUND: Hyperprolactinemia is the most common endocrinologic disorder in causing menstrual irregularities. Although the correlation between hyperprolactinemia and menstrual dysfunction is widely known, the etiology of menstrual cycle disorders is not profoundly understood in patients with prolactinoma. We aimed to investigate the correlation between prolactin levels and insulin resistance and hyperandrogenism in patients with prolactinoma. METHODS: Sixty-four patients with microprolactinoma and 33 healthy women were enrolled. Thirty-six of these patients with prolactinoma (group 1) had an estradiol (E2) level under 30 pg/mL, and 28 (group 2) had an E2 level greater than 30 pg/mL. Blood samples were drawn to measure the levels of the following hormones: Follicle stimulating hormone (FSH), luteinizing hormone (LH), E2, prolactin (PRL), total testosterone (TT), androstenedione (AS) and dehydroepiandrostenedione sulphate (DHEAS). Body Mass Index (BMI of >=30 kg/m2) was excluded from the study. Insulin resistance (IR) was calculated by the HOMA IR. RESULTS: BMI was higher in patients with prolactinoma than the control group (P=0.02, P=0.025, respectively). IR and glucose intolerance existence were higher in patients with prolactinoma (P=0.007, P=0.097, respectively) than the healthy women, but these differences did not exist between eugonadic and hypogonadic women with prolactinoma (P=0.020, P=0.032, respectively, Bonferroni correction). TT and AS were higher in eugonadic women with prolactinoma than the control group (P=0.004, P=0.003, Bonferroni correction, respectively). CONCLUSIONS: Our study revealed that the relationship between hyperprolactinemia and IR/glucose intolerance is irrespective of gonadal status in women with prolactinoma. Also, the study concluded that hyperandrogenism may be a cause of menstrual dysfunction in eugonadic women with prolactinoma. PMID- 25288098 TI - Mullerian duct anomalies: embryological development, classification, and MRI assessment. AB - Mullerian duct anomalies (MDA) occur due to abnormal development of the uterus, cervix, and vagina, many times affecting a woman's ability to conceive and carry a pregnancy to term. The spectrum of possible abnormalities are related to the development of two separate Mullerian systems, which then fuse and subsequently undergo degeneration of the fused segments. This multiphasic development explains the multiple variations within the scheme of MDA classification. The purpose of this article is to review the embryologic development of the Mullerian ducts, relate the development to the most commonly used classification system, and review the magnetic resonance imaging (MRI) assessment of Mullerian duct anomalies. A brief review of the treatment options, as they relate to the imaging diagnosis, will be provided as well. PMID- 25288099 TI - Development of the Incontinence Utility Index: estimating population-based utilities associated with urinary problems from the Incontinence Quality of Life Questionnaire and Neurogenic Module. AB - BACKGROUND: Generic utility instruments may not fully capture the impact and consequences of urinary problems. Condition-specific preference-based measures, developed from previously validated disease-specific patient-reported outcomes instruments, may add relevant information for economic evaluations. The aim of this study was to develop a condition-specific preference-based measure, the Incontinence Utility Index (IUI), for valuing health states associated with urinary problems. METHODS: A two-step process was implemented. First, an abbreviated health state classification system was developed from the Incontinence Quality of Life Questionnaire (I-QOL) and Neurogenic Module by applying Rasch modelling, classical psychometrical testing and expert criteria to data from two pivotal trials comprised of neurogenic detrusor overactivity (NDO) patients. Criterion, convergent validity and concordance with the original instrument was assessed in the abbreviated version. Then, a multi-attribute utility function (MAUF) was estimated from a representative sample of the UK non institutionalized adult general population. Visual analogue and time-trade off (TTO) evaluations were applied in the elicitation process. Predictive validity of the MAUF was tested comparing estimated and direct utility scores. RESULTS: The abbreviated health state classification system generated from the NDO sample contained 5 attributes with 3 levels of response and had adequate psychometrical properties: significant differences in scores according to the reduction in the frequency of urinary incontinence episodes [UIE] (p < 0.001); Spearman correlation coefficient with number of daily UIE = -0.43; p < 0.01 and Intraclass Correlation Coefficient (ICC, 95% CI) with the original version = 0.90 (0.89 0.91; p < 0.001). Next, 442 participants were interviewed (398 cases were valid, generating 2,388 TTO evaluations) to estimate the social preferences for derived health states. Mean age was 44.75 years (interquartile range 33.5-55.5) and 60.1% were female. An overall algorithm for the IUI was estimated and transformed onto a dead = 0.00 and full health = 1.00 scale. Model fits were acceptable (R-squared = 0.923 and 0.978). Predictive validity was adequate: ICC (95% CI) = 0.928 (0.648 0.985) and Mean of Absolute Differences = 0.038. CONCLUSIONS: The newly developed IUI is a preference-based measure for urinary problems related to NDO that provides general population-based utility scores with adequate predictive validity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00461292, NCT00311376. PMID- 25288100 TI - [Lateral hinge fractures in open wedge high tibial osteotomy]. AB - BACKGROUND: Open wedge high tibial osteotomy (HTO) is an increasingly more common surgical method. A typical problem of this procedure is fracture of the lateral hinge. OBJECTIVES: The aims of this article are to present the special issue of fractures of the lateral hinge after HTO and to discuss surgical hints on how to prevent and treat this problem. METHODS: The results of recently published clinical studies are summarized and tips from own clinical experiences are given. RESULTS: Type II fractures of the lateral hinge are unstable and can create a major problem. Using short spacer plates results in a problem of stability for all types of fractures. CONCLUSION: The classification into Takeuchi grades I-III has been proven to be suitable for fractures of the lateral hinge. The TomoFix plate is a safe implant to stabilize the osteotomy in type I and III fractures with which healing can be achieved with no problems. Type II fractures can be stabilized with the TomoFix plate; however, an autologous bone graft has to be taken into consideration. For fractures of the lateral hinge short spacer plates are not recommended due to stability issues. PMID- 25288101 TI - A comparative study of video-assisted thoracoscopic resection versus thoracotomy for neurogenic tumours arising at the thoracic apex. AB - OBJECTIVES: The surgical outcome of neurogenic tumours arising at the thoracic apex remains largely undefined. In this retrospective study, we compared the efficacy and safety of thoracoscopic surgery and thoracotomy for neurogenic tumours at the thoracic apex in 63 patients who received surgical treatment between 1992 and 2012 at our medical centre. METHODS: Forty-four (69.8%) patients received thoracotomy (Group A) and 19 (30.2%) patients underwent video-assisted thoracoscopic surgery (Group B). Operative time, estimated blood loss (EBL), postoperative length of hospital stay and nervous system complications were recorded. RESULTS: The two groups of patients were comparable in demographic and baseline characteristics except that Group A patients had a significantly larger tumour size (mean, 4.9 +/- 1.0 cm) than Group B patients (mean, 4.1 +/- 1.2 cm; P = 0.01). The mean operative time was markedly greater for Group A (120.2 +/- 41.2 min) than Group B (93.2 +/- 34.5 min; P = 0.009). Group A had significantly greater EBL (245.23 +/- 197.78 ml) than Group B (117.4 +/- 138.2 ml; P < 0.001). Total tumour resection was achieved in all patients and all neurogenic tumours were benign. The mean length of postoperative hospital stay was markedly longer in Group A (7.0 +/- 2.1 days) than Group B (4.8 +/- 2.0; P < 0.001). Postoperatively, brachial plexus injury was found in 1 patient (2.3%) in Group A and 4 patients (21.1%) in Group B (P = 0.026). CONCLUSIONS: Though thoracoscopic surgery is associated with diminished blood loss, reduced operative time and shortened hospital stay, it has a markedly increased incidence of brachial plexus injury. PMID- 25288102 TI - Surgery for scimitar syndrome: the Melbourne experience. AB - OBJECTIVES: To evaluate the outcomes associated with surgical repair of scimitar syndrome. METHODS: From 1974 to 2012, 21 patients with scimitar syndrome underwent corrective surgery. Outcomes included mortality, reoperation rate, hospital length of stay and long-term functional status. RESULTS: The mean age of surgery was 5.4 years (2.5 months to 16.7 years). Sixteen (76.2%) patients were symptomatic at presentation. Fifteen (71.4%) patients presented with the infantile form and 6 (28.6%) with the adult form of scimitar syndrome. Operative techniques included baffle repair in 15 (71.4%) patients, reimplantation in 5 (23.8%) patients and pneumonectomy in 1 (4.8%) patient. Six (28.6%) patients were operated in infancy at a mean of 4 months (2.5-9.6 months) of age. There was 1 (4.8%) hospital death and 3 (15%) late deaths. The risk factors for mortality included preoperative pulmonary hypertension (P = 0.006) and surgery during infancy (P = 0.003). The incidence of postoperative pulmonary vein stenosis was 23.8% (n = 5). Three (14.3%) patients underwent reoperation for pulmonary vein stenosis. Neither baffle (P = 0.6) nor reimplantation (P = 0.55) surgical techniques influenced the rate of stenosis. The follow-up was complete in 15 (88%) survivors at a mean of 13.7 years (1.3-38.5 years). All surviving patients were asymptomatic and had a New York Heart Association functional status Class I. CONCLUSIONS: Mortality was highest in patients who had preoperative pulmonary hypertension and those who were operated on before 1 year of age. Surgical technique did not influence the occurrence of pulmonary vein stenosis. Survivors were asymptomatic at the long-term follow-up. PMID- 25288103 TI - Draft genome sequence of Sphingobium sp. strain ba1, resistant to kanamycin and nickel ions. AB - The genome sequence of a Sphingobium strain capable of tolerating high concentrations of Ni ions, and exhibiting natural kanamycin resistance, is presented. The presence of a transposon derived kanamycin resistance gene and several genes for efflux-mediated metal resistance may explain the observed characteristics of the new Sphingobium isolate. PMID- 25288105 TI - The patient with underlying disease must be excluded or analyzed separately. PMID- 25288104 TI - Differences between spent hens of different genotype in performance, meat yield and suitability of the meat for sausage production. AB - The valorization of spent hens via the food chain has some major limitations, which include low meat yield and tough meat. The latter issue can be overcome by producing convenience foods; the first may be alleviated by employing a genotype with higher meatiness. To quantitatively compare two common layer genotypes in production performance, meat yield and sausage quality, 2200 57 weeks old Institut de Selection Animale (ISA) Warren and Dekalb White hens each were investigated during the last 60 days of egg laying. The hens were housed in an aviary system in 2*10 compartments (10 compartments/each genotype). Measurements included feed intake, laying performance, egg weight and feed conversion ratio as measured per compartment. BW was determined twice on 10 animals per compartment. Finally, two sub-groups of five hens per compartment were slaughtered, meat yield was recorded and bratwurst-type sausages were produced (n=20 per genotype). Fat proportion, cooking loss, connective tissue properties and Kramer shear energy were measured. After 1, 4, 7 and 10 months of frozen storage, oxidative stability (thiobarbituric acid reactive substances (TBARS)) and microbiological status were determined as shelf-life related criteria. ANOVA was performed considering genotype as the main effect. The ISA Warren hens were inferior in laying performance (-11%) and feed conversion ratio (+10%) compared with Dekalb White, but had the same feed intake. The ISA Warren had higher BW and carcass weight than the Dekalb White. Carcass yield was higher by 5.9%. There were 80 g (23%) more meat available for sausage production from ISA Warren compared with Dekalb White. Sausages prepared from meat of ISA Warren hens contained less fat than those from Dekalb White, but showed the same cooking loss. Although the collagen proportion of the sausages produced from ISA Warren was lower than from Dekalb White, collagen solubility was lower and shear energy was higher. During the 10 months of frozen storage, TBARS increased continuously, but not to an extent that would prevent its use as food. The sausages from the ISA Warren genotype had marginally higher TBARS levels during storage. Total colony counts decreased with storage time, with slightly lower values found in the non-spiced sausage material from the ISA Warren hens. In conclusion, when intending to use spent hens as food, ISA Warren are clearly superior to Dekalb White in meat and sausage yield. When processing the meat to sausages, the higher shear energy is probably advantageous. PMID- 25288106 TI - Methemoglobinemia after local anesthesia with prilocaine: a case report. PMID- 25288107 TI - Melatonin antagonizes Mn-induced oxidative injury through the activation of keap1 Nrf2-ARE signaling pathway in the striatum of mice. AB - Excessive manganese (Mn) exposure can lead to oxidative injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) exerts an antioxidant response toward various environmental toxicants in the brain. However, the role of Nrf2 against Mn induced oxidative injury remains largely unexplored. This study investigated the role of melatonin (MLT), an agent that was recently shown to induce the activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2-antioxidant response elements (ARE) pathway against manganism. Mice were randomly divided into six groups, including control, 12.5, 25, 50 mg/kg MnCl2, MLT control, and MLT + 50 mg/kg MnCl2. The following were determined: behavioral activity; pathological changes; immunofluorescence staining of Neuronal Nuclei and glial fibrillary acidic protein; cell apoptosis; the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH); the immunohistochemical expression; and the protein levels of Nrf2, Keap1, and downstream enzymes. Mn induced motor disorders, pathological damage, neuron degeneration, astrocytes activation, apoptosis, ROS and MDA generation, and GSH depletion. Nrf2, keap1, heme oxygenase-1 and NAD(P)H dehydrogenase, and quinone 1 showed a biphasic expression trend, which was most evidenced in the 12.5 mg/kg MnCl2 group. Changes in gamma-glutamylcysteine synthetase, glutathione peroxidase 1, glutathionine S transferase, glutathione reductase, and superoxide dismutase decreased in a concentration-dependent manner as a result of Mn exposure. MLT antagonized oxidative injury through the activation of the Keap1-Nrf2-ARE signaling pathway. In conclusion, disturbance of the Keap1-Nrf2-ARE signaling pathway partly caused oxidative injury. MLT can activate Nrf2 and its downstream enzymes and reverse Mn induced oxidative injury. PMID- 25288109 TI - Shape elongation of Zn nanoparticles in silica irradiated with swift heavy ions of different species and energies: scaling law and some insights on the elongation mechanism. AB - Zinc nanoparticles (NPs) embedded in silica were irradiated with swift heavy ions (SHIs) of seven different combinations of species and energies. The shape elongation induced by the irradiations was evaluated by optical linear dichroism (OLD) spectroscopy, which is a sensitive tool for determining the change in the mean aspect ratio (AR) of NPs. Although the mean AR change indicated a linear fluence dependence in the low- and medium-fluence regions, it indicated a nonlinear dependence in the high-fluence region. The data reveal that the elongation efficiency of Zn is correlated with the electronic stopping power 'Se in silica' and is not correlated with either the 'Se in Zn' or the nuclear stopping power. The elongation efficiency plotted as a function of the 'Se in silica' revealed a linear relationship, with a threshold value of ~2 keV nm(-1), which is the same dependence exhibited by the ion-track formation in silica. The log-log plot showed that the elongation efficiency increased linearly with Se above a critical value of ~3 keV nm(-1) and steeply decreased with Se to the power of 5 below the critical Se. The steep decrease can be ascribed to the discontinuous nature of the ion tracks, which is expected at Se ~ 2-4 keV nm(-1) in silica. The fluence Phi dependences of AR - 1 under various irradiations are well-normalized with the electronic energy deposition of SHIs, i.e., the product of Se and Phi, with a Se greater than the same critical value of ~3 keV nm(-1). The normalized data above the critical value fell on a linear relation, AR(Phi) - 1 ? SePhi, for SePhi < 2 keV nm(-3) and a sublinear relation, AR(Phi) - 1 ? (SePhi)(1/2) for SePhi > 2 keV nm(-3). On the basis of these experimental results, we discuss some insights into the elongation mechanism. PMID- 25288108 TI - Correlation between attenuation of protein disulfide isomerase activity through S mercuration and neurotoxicity induced by methylmercury. AB - Methylmercury (MeHg), an environmental pollutant, causes neuronal death via endoplasmic reticulum (ER) stress; however, the precise mechanism is not fully understood. The aim of this study was to elucidate the possible mechanism of MeHg induced neurotoxicity. Treatment with MeHg resulted in a loss of cell viability in a concentration-dependent manner accompanying the expression of ER stress marker genes in human neuroblastoma SH-SY5Y cells. We next attempted to identify a target protein for MeHg in the ER. MeHg covalently modified protein disulfide isomerase (PDI), which is important for disulfide bond formation in nascent proteins in the ER lumen. S-Nitrosylation of the catalytic domains of PDI by nitric oxide was attenuated up to 50 % by a MeHg challenge in cells. The MeHg modified C-terminal catalytic domain in PDI was detected by MALDI-TOF/MS. Furthermore, treatment with MeHg significantly attenuated the enzymatic activity of PDI. Taken together, these observations suggest that MeHg results in ER stress and following the unfolded protein response pathway via ER dysfunction due to S mercuration of the C-terminus of PDI. PMID- 25288110 TI - Golimumab in uveitis previously treated with other anti-TNF-alpha drugs: a retrospective study of three cases from a single centre and literature review. AB - OBJECTIVES: The aim of this paper is to assess the clinical response to golimumab (GLM) in patients with non-infectious uveitis from a single centre that had previously been treated with other anti-TNF-alpha drugs. METHODS: A retrospective chart review was carried out of patients with immune-mediated uveitis refractory to standard synthetic immunosuppressive drugs who were treated with GLM at Hospital Universitario Marques de Valdecilla, Santander (Spain). Patients were included in this study if they had previously been treated with other anti-TNF alpha drugs. A literature review of patients with immune-mediated uveitis undergoing GLM therapy was conducted. RESULTS: Three patients (2 men and 1 woman) were included in this study. Two of them were refractory to other anti-TNF-alpha drugs. The median age of patients was 26 years (range 20-42). Uveitis was bilateral in two patients. The underlying diseases were uveitis associated with HLA-B27 and psoriasis in one case and sarcoidosis in the other two cases. Improvement of the main ocular parameters following GLM therapy was achieved in all cases. After a median follow-up of 3 (range 1-9) months using GLM therapy, none of the patients had experienced new relapses of uveitis. None of them had side effects during treatment with this drug. A literature review disclosed that our observations were in keeping with other reports that showed good response to GLM in 13 of 16 patients with immune-mediated uveitis refractory to other biologic agents. CONCLUSIONS: Although the follow-up was too short in our series, GLM could be an effective and safe therapy for the management of patients with uveitis previously treated with other anti-TNF-alpha drugs. PMID- 25288112 TI - Liquid-liquid phase separation in biology. AB - Cells organize many of their biochemical reactions in non-membrane compartments. Recent evidence has shown that many of these compartments are liquids that form by phase separation from the cytoplasm. Here we discuss the basic physical concepts necessary to understand the consequences of liquid-like states for biological functions. PMID- 25288111 TI - Twists and turns: a scientific journey. AB - In this perspective I look back on the twists and turns that influenced the direction of my scientific career over the past 40 years. From my early ambition to be a chemist to my training in Philadelphia and Bethesda as a molecular biologist, I benefited enormously from generous and valuable mentoring. In my independent career in Philadelphia and Princeton, I was motivated by a keen interest in the changes in gene expression that direct the development of the mammalian embryo and inspired by the creativity and energy of my students, fellows, and research staff. After twelve years as President of Princeton University, I have happily returned to the faculty of the Department of Molecular Biology. PMID- 25288113 TI - Intercellular protein movement: deciphering the language of development. AB - Development in multicellular organisms requires the coordinated production of a large number of specialized cell types through sophisticated signaling mechanisms. Non-cell-autonomous signals are one of the key mechanisms by which organisms coordinate development. In plants, intercellular movement of transcription factors and other mobile signals, such as hormones and peptides, is essential for normal development. Through a combination of different approaches, a large number of non-cell-autonomous signals that control plant development have been identified. We review some of the transcriptional regulators that traffic between cells, as well as how changes in symplasmic continuity affect and are affected by development. We also review current models for how mobile signals move via plasmodesmata and how movement is inhibited. Finally, we consider challenges in and new tools for studying protein movement. PMID- 25288114 TI - Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. AB - In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes. PMID- 25288115 TI - Determinants and functions of mitochondrial behavior. AB - Mitochondria are ancient organelles evolved from bacteria. Over the course of evolution, the behavior of mitochondria inside eukaryotic cells has changed dramatically, and the corresponding machineries that control it are in most cases new inventions. The evolution of mitochondrial behavior reflects the necessity to create a dynamic compartment to integrate the myriad mitochondrial functions with the status of other endomembrane compartments, such as the endoplasmic reticulum, and with signaling pathways that monitor cellular homeostasis and respond to stress. Here we review what has been discovered about the molecular machineries that work together to control the collective behavior of mitochondria in cells, as well as their physiological roles in healthy and disease states. PMID- 25288116 TI - Astrocyte regulation of synaptic behavior. AB - Astrocytes regulate multiple aspects of neuronal and synaptic function from development through to adulthood. Instead of addressing each function independently, this review provides a comprehensive overview of the different ways astrocytes modulate neuronal synaptic function throughout life, with a particular focus on recent findings in each area. It includes the emerging functions of astrocytes, such as a role in synapse formation, as well as more established roles, including the uptake and recycling of neurotransmitters. This broad approach covers the many ways astrocytes and neurons constantly interact to maintain the correct functioning of the brain. It is important to consider all of these diverse functions of astrocytes when investigating how astrocyte-neuron interactions regulate synaptic behavior to appreciate the complexity of these ongoing interactions. PMID- 25288117 TI - Myelination of the nervous system: mechanisms and functions. AB - Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology. However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions. In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath. In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors. The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models. Thus, myelinating cells serve a key role in preserving the connectivity and functions of a healthy nervous system. PMID- 25288118 TI - Histone H3 variants and their chaperones during development and disease: contributing to epigenetic control. AB - Within the nucleus, the interplay between lineage-specific transcription factors and chromatin dynamics defines cellular identity. Control of this interplay is necessary to properly balance stability and plasticity during the development and entire life span of multicellular organisms. Here, we present our current knowledge of the contribution of histone H3 variants to chromatin dynamics during development. We review the network of histone chaperones that governs their deposition timing and sites of incorporation and highlight how their distinct distribution impacts genome organization and function. We integrate the importance of H3 variants in the context of nuclear reprogramming and cell differentiation, and, using the centromere as a paradigm, we describe a case in which the identity of a given genomic locus is propagated across different cell types. Finally, we compare development to changes in stress and disease. Both physiological and pathological settings underline the importance of H3 dynamics for genome and chromatin integrity. PMID- 25288119 TI - The nature of embryonic stem cells. AB - Mouse embryonic stem (ES) cells perpetuate in vitro the broad developmental potential of naive founder cells in the preimplantation embryo. ES cells self renew relentlessly in culture but can reenter embryonic development seamlessly, differentiating on schedule to form all elements of the fetus. Here we review the properties of these remarkable cells. Arising from the stability, homogeneity, and equipotency of ES cells, we consider the concept of a pluripotent ground state. We evaluate the authenticity of ES cells in relation to cells in the embryo and examine their utility for dissecting mechanisms that confer pluripotency and that execute fate choice. We summarize current knowledge of the transcription factor circuitry that governs the ES cell state and discuss the opportunity to expose molecular logic further through iterative computational modeling and experimentation. Finally, we present a perspective on unresolved questions, including the challenge of deriving ground state pluripotent stem cells from non-rodent species. PMID- 25288120 TI - Haploid mouse embryonic stem cells: rapid genetic screening and germline transmission. AB - Most animal genomes are diploid, and mammalian development depends on specific adaptations that have evolved secondary to diploidy. Genomic imprinting and dosage compensation restrict haploid development to early embryos. Recently, haploid mammalian development has been reinvestigated since the establishment of haploid embryonic stem cells (ESCs) from mouse embryos. Haploid cells possess one copy of each gene, facilitating the generation of loss-of-function mutations in a single step. Recessive mutations can then be assessed in forward genetic screens. Applications of haploid mammalian cell systems in screens have been illustrated in several recent publications. Haploid ESCs are characterized by a wide developmental potential and can contribute to chimeric embryos and mice. Different strategies for introducing genetic modifications from haploid ESCs into the mouse germline have been further developed. Haploid ESCs therefore introduce new possibilities in mammalian genetics and could offer an unprecedented tool for genome exploration in the future. PMID- 25288121 TI - Epidemiology, prognosis and treatment of simultaneous squamous cell carcinomas of the oral cavity and hypopharynx. AB - OBJECTIVE: The study was designed to assess the prevalence, management and survival of patients with simultaneous squamous cell carcinomas of the oral cavity and hypopharynx (OC/HP). MATERIAL AND METHODS: A multicenter, retrospective study (2 university hospitals) was conducted between 2003 and 2007 on a series of 96 patients with simultaneous squamous cell cancers of the OC/HP. RESULTS: A total of 88 men and 8 women were included in the study: 81 patients presented double sites, 14 presented triple sites and one presented quadruple sites. The tumour sites most frequently observed were: hypopharynx in 61% of cases (involving the pyriform sinus in 42% of cases) and the oropharynx in 59% of cases (involving the palatine tonsil in 30% of cases). Upper aerodigestive tract endoscopy under general anaesthesia revealed a simultaneous lesion not suspected on clinical examination in 45% of patients: the site discovered on endoscopy was hypopharyngeal in 2 out of 3 cases; the tumour was classified T1 or T2 in 95.5% of cases. Patients treated simultaneously for all sites had a better prognosis than patients in whom each tumour was treated separately. The 5-year specific survival was 34% and the 5-year overall survival was 28%. CONCLUSION: The prevalence of simultaneous squamous cell carcinomas of the oral cavity and hypopharynx ranges between 1 to 7.4% in the literature and was 4.6% in the present series. A common treatment strategy for each of the patient's tumours appears to be superior to the current theoretical approach that consists of considering each tumour separately. PMID- 25288122 TI - Capacitance-to-digital: the upgrades of single chip detector. AB - The capacitance-to-digital single chip detector was upgraded. The paper discusses hardware issues and benefits of the designed/upgraded detector. The device can be operated from rechargeable lithium-ion battery as stand-alone, portable system and is capable of transmitting real-time data wirelessly. The detector and additional modules (battery, battery holder, microcontroller board, wireless module) weight is less than 85 g. Electrophoretic separation in low conductivity 20 mM MES/L-His buffer, pH 6.1, was performed in order to evaluate detection parameters. The system is capable of quantification of potassium ions down to 0.31 MUM. Investigation of differential signal acquisition configuration showed improved performance regarding external noise and temperature fluctuations. The system can be a solution for stand-alone, field-portable capillary format separation detector. PMID- 25288123 TI - Condition dependence of female choosiness in a field cricket. AB - Females generally choose mates that produce the loudest, brightest or most elaborate sexual displays, and these costly male displays are predicted to be condition dependent. However, mate choice itself is a costly behaviour also expected to be condition dependent. Male fall field crickets, Gryllus pennsylvanicus, produce a conspicuous long-distance calling song that attracts females and is condition dependent. In this study, we tested the condition dependence of female preferences (preference function and choosiness) for male calling effort in G. pennsylvanicus. We manipulated female condition by raising crickets from hatching on either a low- or high-quality diet. In a series of two speaker phonotaxis trials, both low- and high-condition females preferred playbacks reflecting greater calling effort. However, relative to low-condition females, high-condition females took significantly longer to make a choice, were more likely to fail to choose within the time allotted for a phonotaxis trial and significantly increased their latency to choose over the course of multiple trials. We discuss these results with respect to the possibility that female G. pennsylvanicus may be foraging for direct benefits when they choose their mates. PMID- 25288124 TI - Gram-scale enantioselective formal synthesis of morphine through an ortho-para oxidative phenolic coupling strategy. AB - A gram-scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho-para oxidative phenolic coupling and a highly diastereoselective "desymmetrization" of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives. PMID- 25288125 TI - Comparing the effectiveness of the 0.018-inch versus the 0.022-inch bracket slot system in orthodontic treatment: study protocol for a randomized controlled trial. AB - BACKGROUND: Edgewise fixed orthodontic appliances are available in two different bracket slot sizes (0.018 and 0.022 inch). Both systems are used by clinicians worldwide with some orthodontists claiming the superiority and clinical advantages of one system over the other. However, the scientific evidence supporting this area is scarce and weak. This leaves the clinician's choice of bracket slot system to clinical preference. We aim to compare the 0.018-inch and 0.022-inch pre-adjusted bracket slot systems in terms of the effectiveness of orthodontic treatment. METHODS/DESIGN: This is a prospective, multicenter, randomized clinical trial, undertaken in the secondary care hospital environment in the NHS Tayside region of Scotland (United Kingdom). A total of 216 orthodontic patients will be recruited in three centers in secondary care hospitals in NHS Tayside. The participants will be randomly allocated to treatment with either the 0.018-inch or 0.022-inch bracket slot systems (n = 108 for each group) using Victory seriesTM conventional pre-adjusted bracket systems (3 M Unitek, Monrovia, United States). Baseline records and outcome data collected during and at the end of orthodontic treatment will be assessed. The primary outcome measures will be the duration of orthodontic treatment in the maxillary and mandibular arches. The secondary outcome measures will be the number of scheduled appointments for orthodontic treatment in the maxillary and mandibular arches, treatment outcome using Peer Assessment Rating index (PAR), orthodontically induced inflammatory root resorption (as measured using periapical radiographs) and the patient's perception of wearing orthodontic appliances. DISCUSSION: The results from the current study will serve as evidence to guide the clinician in deciding whether the difference in bracket slot size has a significant impact on the effectiveness of orthodontic treatment. TRIAL REGISTRATION: Registered with ClinicalTrials.gov on 5 March 2014, registration number: NCT02080338. PMID- 25288126 TI - Disease severity and clinical outcome in phosphosglucomutase deficiency. PMID- 25288128 TI - Endoscopic self-expandable metallic stenting for palliation of malignant gastric outlet obstruction in Southeast Asia. AB - BACKGROUND: Malignant gastric outlet obstruction (GOO) is a pre-terminal event in the natural history of gastric and pancreaticobiliary cancers. The use of endoscopic placement of self-expandable metallic stents (SEMS) is a less invasive alternative palliative option for these patients. This is the first study in Southeast Asia to evaluate the clinical efficacy and safety of endoscopic SEMS placement in patients with malignant GOO. METHODS: A retrospective review of our department's database in endoscopic SEMS placement for the treatment of malignant GOO was performed. Twenty-four patients with advanced or metastatic malignancy that underwent placement of SEMS for treatment of malignant GOO between January 2003 and July 2013 were analysed. The GOO severity score was used as an objective means of assessing patients' oral intake. RESULTS: Technical success rate was 100%. All patients resumed oral intake of liquids within the same day of stent placement. Clinical success was achieved in 21 patients (87.5%). There was a significant improvement of GOO severity score from 0.62 +/- 1.0 (mean +/- standard deviation) before stent placement to 2.04 +/- 0.86 after stent placement (P < 0.001). Complication rate was 12.5%. Stent-related complications observed include stent migration (two patients) and tumour ingrowth (one patient). Serious complications such as gastrointestinal haemorrhage or perforation did not occur in any patients. The median survival after stent placement was 57 days (95% confidence interval, 12.2-101.8 days). None of the patients died from stent related complications. CONCLUSION: Endoscopic SEMS placement is a minimally invasive, safe and effective option for the palliation of malignant GOO. PMID- 25288127 TI - Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose 6-phosphate transporter complexes. AB - Disorders of the glucose-6-phosphatase (G6Pase)/glucose-6-phosphate transporter (G6PT) complexes consist of three subtypes: glycogen storage disease type Ia (GSD Ia), deficient in the liver/kidney/intestine-restricted G6Pase-alpha (or G6PC); GSD-Ib, deficient in a ubiquitously expressed G6PT (or SLC37A4); and G6Pase-beta deficiency or severe congenital neutropenia syndrome type 4 (SCN4), deficient in the ubiquitously expressed G6Pase-beta (or G6PC3). G6Pase-alpha and G6Pase-beta are glucose-6-phosphate (G6P) hydrolases with active sites lying inside the endoplasmic reticulum (ER) lumen and as such are dependent upon the G6PT to translocate G6P from the cytoplasm into the lumen. The tissue expression profiles of the G6Pase enzymes dictate the disease's phenotype. A functional G6Pase alpha/G6PT complex maintains interprandial glucose homeostasis, while a functional G6Pase-beta/G6PT complex maintains neutrophil/macrophage energy homeostasis and functionality. G6Pase-beta deficiency is not a glycogen storage disease but biochemically it is a GSD-I related syndrome (GSD-Irs). GSD-Ia and GSD-Ib patients manifest a common metabolic phenotype of impaired blood glucose homeostasis not shared by GSD-Irs. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and neutrophil/macrophage dysfunction not shared by GSD-Ia. While a disruption of the activity of the G6Pase-alpha/G6PT complex readily explains why GSD-Ia and GSD-Ib patients exhibit impaired glucose homeostasis, the basis for neutropenia and myeloid dysfunction in GSD-Ib and GSD Irs are only now starting to be understood. Animal models of all three disorders are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy. PMID- 25288129 TI - Induction of secondary metabolite production by UV-C radiation in Vitis vinifera L. Okuzgozu callus cultures. AB - BACKGROUND: The aim of the present work was to examine the role of UV-C irradiation on the production of secondary metabolites (total phenolic, total flavanols, total flavonols, catechin, ferulic acid and trans-resveratrol in phenolic compounds and alpha-, beta-, gamma- delta-tocopherols) in callus cultures. Studies on the effects of UV-C treatment on callus culture are seldom and generally focused on UV-B. However UV-C radiation play an important role in accumule secondary metabolites. RESULTS: In this study, callus cultures from Okuzgozu grape cultivar were initiated from leaf petiole explants. Calli formed after 6 weeks on the medium supplemented with 0.5 mg L-1 benzylaminopurine (BA), 0.5 mg L-1 indole acetic acid (IAA) on B5 media. Callus tissues were exposed to UV-C irradiation at 10, 20 and 30 cm distances from the UV source for 5 and 10 minutes and samples were collected at hours 0, 24 and 48. CONCLUSIONS: The greatest total phenolic content (155.14 mg 100 g-1) was detected in calli exposed to UV-C for 5 min from 30 cm distance and sampled after 24 h. 24 h and 48 h incubation times, 30 cm and 5 min were the most appropriate combination of UV-C application in total flavanol content. Maximum total flavonol content (7.12 mg 100 g-1) was obtained on 0 h, 5 min and 20 cm combination. The highest (+)- catechin accumulation (8.89 mg g-1) was found in calli with 10 min UV-C application from 30 cm distance and sampled after 48 h. Ferulic acid content increased 6 fold in Okuzgozu callus cultures (31.37 MUg g-1) compared to the control group. The greatest trans-resveratrol content (8.43 MUg g-1) was detected in calli exposed to UV-C for 5 min from 30 cm distance and sampled after 24 h. The highest alpha-tocopherol concentration was found in calli exposed to UV-C for 10 min from 30 cm distance and sampled after 24 h. As a conclusion, it was showed that UV-C radiation had remarkable promoting effects on the accumulation of secondary metabolites in the calli of Okuzgozu grape cultivar. PMID- 25288130 TI - The associations between fatigue, apathy, and depression in Parkinson's disease. AB - OBJECTIVES: Fatigue and apathy are two of the most common and most disabling non motor symptoms of Parkinson's disease (PD). They have a high coincidence and can often be confused; moreover, their relationship is not fully understood. The aim of our study was to describe the coincidence of apathy with different fatigue domains in the presence/absence of depression and to separately describe the associations of different aspects of primary and secondary fatigue with apathy and other clinical and disease-related factors. MATERIALS AND METHODS: A total of 151 non-demented patients with PD were examined using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Starkstein Apathy Scale, Multidimensional Fatigue Inventory (MFI), Beck Depression Inventory-II, and Epworth Sleepiness Scale. RESULTS: The prevalence and severity of fatigue and apathy were significantly higher in depressed PD patients. However, our results show that depression, fatigue, and apathy can be clearly distinguished in PD. Apathy was associated with the MFI's-reduced motivation domain in both depressed and non-depressed patients. However, apathy was associated with mental fatigue aspects only in non-depressed patients, and it was not related to the physical aspects of fatigue in any of the studied groups. CONCLUSIONS: Although the pathophysiology of fatigue and apathy in PD is clearly multifactorial, in a proportion of PD patients, these symptoms are associated with depression, dopaminergic depletion in the mesocorticolimbic structures, and disruption of the prefrontal cortex-basal ganglia axis. Therefore, in some PD patients, adequate management of depression and optimal dopaminergic medication may improve both fatigue and apathy. PMID- 25288131 TI - Subfertility/infertility and assisted reproductive conception are independent risk factors for pre-eclampsia. PMID- 25288132 TI - Novel microcalorimetric assay for antibacterial activity of implant coatings: The cases of silver-doped hydroxyapatite and calcium hydroxide. AB - Biomaterials with antimicrobial properties are now commonly used in different clinical specialties including orthopedics, endodontic, and traumatology. As a result, assessing the antimicrobial effect of coatings applied on implants is of critical importance. In this study, we demonstrate that isothermal microcalorimetry (IMC) can be used for monitoring bacterial growth and biofilm formation at the surface of such coatings and for determining their antimicrobial effects. The antibacterial effects of silver doped hydroxyapatite (HA) and calcium hydroxide coatings on Staphylococcus epidermidis were determined with a minimal workload. Using the Gompertz growth model we determined biofilm growth rates close to those values reported in the literature. Furthermore, we were able to estimate the reduction in the bacterial inocula originally applied at the surface of the coatings. Therefore, in addition to monitoring the antimicrobial effect of silver doped HA and calcium hydroxide coatings, we also demonstrate that IMC might be a valuable tool for assessing such antimicrobial properties of implant coatings at a minimal workload. PMID- 25288133 TI - How are epileptic events linked to obstructive sleep apneas in epilepsy? PMID- 25288134 TI - Non-equilibrium dynamics of stochastic gene regulation. AB - The process of gene regulation is comprised of intrinsically random events resulting in large cell-to-cell variability in mRNA and protein numbers. With gene expression being the central dogma of molecular biology, it is essential to understand the origin and role of these fluctuations. An intriguing observation is that the number of mRNA present in a cell are not only random and small but also that they are produced in bursts. The gene switches between an active and an inactive state, and the active gene transcribes mRNA in bursts. Transcriptional noise being bursty, so are the number of proteins and the subsequent gene expression levels. It is natural to ask the question: what is the reason for the bursty mRNA dynamics? And can the bursty dynamics be shown to be entropically favorable by studying the reaction kinetics underlying the gene regulation mechanism? The dynamics being an out-of-equilibrium process, the fluctuation theorem for entropy production in the reversible reaction channel is discussed. We compute the entropy production rate for varying degrees of burstiness. We find that the reaction parameters that maximize the burstiness simultaneously maximize the entropy production rate. PMID- 25288135 TI - Genomics of schizophrenia: time to consider the gut microbiome? AB - Research into the genomics of schizophrenia promises much, but so far is resplendent with failures to replicate, and has yielded little of therapeutic potential. Within our bodies resides a dynamic population of gut microbes forming a symbiotic superorganism comprising a myriad of bacteria of approximately 10(14) cells, containing 100 times the number of genes of the human genome and weighing approximately the same as the human brain. Recent preclinical investigations indicate that these microbes majorly impact on cognitive function and fundamental behavior patterns, such as social interaction and stress management. We are pivotally dependent on the neuroactive substances produced by such bacteria. The biological diversity of this ecosystem is established in the initial months of life and is highly impacted upon by environmental factors. To date, this vast quantity of DNA has been largely ignored in schizophrenia research. Perhaps it is time to reconsider this omission. PMID- 25288137 TI - Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. AB - PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD. PMID- 25288138 TI - APOE and BDNF polymorphisms moderate amyloid beta-related cognitive decline in preclinical Alzheimer's disease. AB - Accumulation of beta-amyloid (Abeta) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (E4 carrier[E4(+)], E4 non-carrier[E4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Abeta-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Abeta neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Abeta positron emission tomography neuroimaging was used to classify participants as Abeta(-) or Abeta(+). Relative to Abeta(-)E4(-), Abeta(+)E4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Abeta(+)E4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Abeta(-)E4(-) and Abeta(-)E4(+) groups. Among Abeta(+) individuals, E4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with E4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Abeta-related cognitive decline. Abeta(+)E4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Abeta(+)E4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Abeta(-) and Abeta(+) E4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials. PMID- 25288140 TI - Margaret McCartney: Have we given guidelines too much power? PMID- 25288139 TI - Epigenetic modulation of chronic anxiety and pain by histone deacetylation. AB - Prolonged exposure of the central amygdala (CeA) to elevated corticosteroids (CORT) facilitates long-term anxiety and pain through activation of glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF). However, the mechanisms maintaining these responses are unknown. Since chronic phenotypes can be sustained by epigenetic mechanisms, including histone modifications such as deacetylation, we tested the hypothesis that histone deacetylation contributes to the maintenance of chronic anxiety and pain induced by prolonged exposure of the CeA to CORT. We found that bilateral infusions of a histone deacetylase inhibitor into the CeA attenuated anxiety-like behavior as well as somatic and visceral hypersensitivity resulting from elevated CORT exposure. Moreover, we delineated a novel pathway through which histone deacetylation could contribute to CORT regulation of GR and subsequent CRF expression in the CeA. Specifically, deacetylation of histone 3 at lysine 9 (H3K9), through the coordinated action of the NAD+-dependent protein deacetylase sirtuin-6 (SIRT6) and nuclear factor kappa B (NFkappaB), sequesters GR expression leading to disinhibition of CRF. Our results indicate that epigenetic programming in the amygdala, specifically histone modifications, is important in the maintenance of chronic anxiety and pain. PMID- 25288142 TI - Influence of the American Society of Hematology guidelines on the management of newly diagnosed childhood immune thrombocytopenia. AB - IMPORTANCE: In 2011, the American Society of Hematology (ASH) published updated guidelines for the management of childhood immune thrombocytopenia (ITP) recommending management with observation alone when there are mild or no bleeding symptoms, regardless of platelet count. Little is known about practice patterns of newly diagnosed ITP in the United States. OBJECTIVE: To understand the impact of management recommendations on practice patterns. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review in the Children's Hospital of Philadelphia, a large, urban, pediatric tertiary care hospital in Philadelphia, Pennsylvania. The study involved 311 pediatric patients with newly diagnosed ITP managed between January 1, 2007, and December 31, 2012. MAIN OUTCOMES AND MEASURES: Management type (observation alone vs pharmacotherapy) was determined via medical record review and electronic pharmacy data at diagnosis and within 6 months after diagnosis. RESULTS: Overall, 44.7% of patients were managed with observation alone at diagnosis, with a significant increase from 34.9% in 2007 2010 to 49.2% in 2011 (P < .02) and 71.1% in 2012 (P < .001). Of those treated, 99% were treated with intravenous immunoglobulin. In multivariable logistic regression, younger age (odds ratio, 0.92; 95% CI, 0.87-0.99), lower platelet count (odds ratio, 0.86; 95% CI, 0.83-0.89), and earlier period (2007-2010) of diagnosis (odds ratio, 0.17; 95% CI, 0.09-0.34) were significantly associated with increased odds of pharmacologic management. During 2010-2012, 20.8% of patients were also treated within 6 months after diagnosis. There was no significant difference by year or initial management type in those who received this later pharmacotherapy. Additionally, 19.6% of patients had documented bleeding symptoms beyond cutaneous bruising or petechiae at diagnosis. Intracranial hemorrhage at diagnosis was rare (0.6%). CONCLUSIONS AND RELEVANCE: We demonstrated a significant practice change in the management of newly diagnosed ITP at a pediatric care tertiary care hospital in the United States surrounding revision of the ASH management guidelines for childhood ITP. Our experience supports adoption of observation alone for a proportion of patients with newly diagnosed childhood ITP. This form of management did not lead to an increase in later treatment or an increase in delayed bleeding symptoms. PMID- 25288141 TI - Prompting asthma intervention in Rochester-uniting parents and providers (PAIR UP): a randomized trial. AB - IMPORTANCE: A disproportionate number of impoverished and minority children have asthma and receive suboptimal preventive care. OBJECTIVE: To evaluate whether the Prompting Asthma Intervention in Rochester-Uniting Parents and Providers (PAIR UP) intervention, administered in primary care offices, improves the delivery of preventive care and reduces morbidity for urban children with asthma. DESIGN, SETTING, AND PARTICIPANTS: Cluster randomized trial in which 12 urban primary care practices were matched based on size and type and randomly allocated to the PAIR-UP intervention or usual care (UC). We enrolled 638 children aged 2 to 12 years with persistent or poorly controlled asthma in the waiting room prior to a visit with a clinician for any reason from October 2009 to January 2013. Blinded interviewers called caregivers within 2 weeks to inquire about preventive measures taken at the visit and called them 2 and 6 months later to assess symptoms. INTERVENTIONS: Children enrolled at PAIR-UP practices received prompts for the caregiver and clinician at the time of the visit that outlined the child's asthma severity or control as well as specific guideline-based recommendations to enhance preventive care. These practices also received educational resources and periodic feedback on their asthma care performance. The UC practices received copies of the asthma guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was symptom-free days (SFDs) per 2 weeks at the 2 month follow-up. RESULTS: We enrolled 638 children (participation rate of 80%; 36% were black, 36% were Hispanic, and 68% had Medicaid insurance). Groups were similar in demographic characteristics and asthma severity at baseline. At the index visit, more children in the PAIR-UP group received a preventive medication action (new medication, increased dose, recommendation to restart preventive medication) than in the UC group (58% vs 33%; odds ratio [OR] = 2.8; 95% CI, 1.9 to 3.9). More children in the PAIR-UP group than in the UC group received an asthma action plan (61% vs 23%; OR = 8.3; 95% CI, 3.7 to 18.7), discussions regarding asthma (93% vs 78%; OR = 4.5; 95% CI, 2.8 to 7.2), and secondhand smoke counseling (80% vs 63%; OR = 2.6; 95% CI, 1.2 to 5.5). At the 2-month follow-up, children in the PAIR-UP group had more SFDs per 2 weeks than those in the UC group (mean difference, 0.78 days; 95% CI, 0.29 to 1.27). At 6 months, the improvement in SFDs was no longer statistically significant (mean difference, 0.56; 95% CI, -0.14 to 1.25). CONCLUSIONS AND RELEVANCE: The PAIR-UP intervention improved the delivery of preventive asthma care and reduced asthma morbidity for high-risk urban children with persistent asthma at 2 months, but the improvement in SFDs was no longer significant at 6 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01105754. PMID- 25288143 TI - Disparities in cancer incidence and mortality by area-level socioeconomic status: a multilevel analysis. AB - BACKGROUND: Disparities in cancer incidence and mortality have been observed by measures of area-level socioeconomic status (SES); however, the extent to which these disparities are explained by individual SES is unclear. METHODS: Participants included 60 756 men and women in the VITamins And Lifestyle (VITAL) study cohort, aged 50-76 years at baseline (2000-2002) and followed through 2010. We constructed a block group SES index using the 2000 US Census and fit Cox proportional hazards models to estimate the association between area-level SES (by quintile) and total and site-specific cancer incidence and total cancer mortality, with and without household income and individual education in the models. RESULTS: Lower area-level SES was weakly associated with higher total cancer incidence and lower prostate cancer risk, but was not associated with risk of breast cancer. Compared with the highest-SES areas, living in the lowest-SES areas was associated with higher lung (HR: 2.21, 95% CI 1.69 to 2.90) and colorectal cancer incidence (HR: 1.52, 95% CI 1.11 to 2.09) and total cancer mortality (HR: 1.68, 95% CI 1.47 to 1.93). Controlling for individual education and household income weakened the observed associations, but did not eliminate them (lung cancer HR: 1.43, 95% CI 1.07 to 1.91; colorectal cancer HR: 1.35, 95% CI 0.97 to 1.88; cancer mortality HR: 1.28, 95% CI 1.11 to 1.48). CONCLUSIONS: Area-level socioeconomic disparities exist for several cancer outcomes. These differences are not fully explained by individual SES, suggesting area-level factors may play a role. PMID- 25288144 TI - Hospital pharmacists' roles and attitudes in providing information on the safety of non-steroidal anti-inflammatory drugs in Thailand. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for patients to manage pain and inflammation, especially in older adults. Failure to cope with some adverse drug reactions (ADRs) of NSAIDs could lead to more serious symptoms, therefore, providing useful information about medicine is an important step in protecting patients from developing serious ADRs. The pharmacy service should be a frequent source of medicine information for patients, however in Thailand, little is known about pharmacists' provision of safety information to patients for management and prevention of these ADRs. OBJECTIVE: Aims of this study were to determine Thai hospital pharmacists' roles in providing drug safety information and to assess their attitudes towards the importance of giving drug safety education to patients. SETTING: All government hospitals in north-eastern Thailand. METHODS: This study was a cross-sectional survey. A total of 761 pharmacists in 287 hospitals in north-eastern Thailand were selected by stratified random sampling. Self-administered questionnaires were sent by post, with two reminders. MAIN OUTCOME MEASURES: Proportion of hospital pharmacists providing ADR information on NSAIDs to patients, factors affecting this provision, and pharmacist attitudes towards drug safety education for patients. RESULTS: The response rate was 54.8% (N = 417), the majority of respondents worked in community hospitals (57.2%). A total of 347 pharmacists (83.6%) had informed patients about ADRs, although less than half had informed patients about ADR monitoring and management (36.6% and 44.1% respectively). The proportion of time spent in direct patient contact, type of hospital, and other routine work were associated with the frequency of drug safety information provision. Pharmacists had moderately good attitudinal scores towards drug safety education (62.2 +/- 5.4), with significantly higher scores found in those who provided most ADR information to patients (60.3 +/- 5.2 vs. 62.6 +/- 5.4, P = 0.002). The majority (82.2%) agreed that patient information leaflets should be provided. CONCLUSIONS: Thai hospital pharmacists' provision of ADR information for NSAIDs may occur less frequently than is desirable. However, their positive attitude towards provision of ADR information suggests that drug safety education by pharmacists should be routinely provided to patients, particularly patients at high risk of NSAID use. PMID- 25288145 TI - Paediatric adverse drug reactions following use of asthma medications in Europe from 2007 to 2011. AB - BACKGROUND: Information about safety issues from use of asthma medications in children is limited. Spontaneous adverse drug reaction (ADR) reports can provide information about serious and rarely occurring ADRs in children. OBJECTIVE: To characterize paediatric ADRs reported for asthma medications licensed for paediatric use. SETTING: Spontaneous ADR reports located in the European ADR database, EudraVigilance. METHOD: ADRs reported for asthma medications licensed for paediatric use from 2007 to 2011 were analysed. The included substances were beclometasone, budesonide, fenoterol, fluticasone, formoterol, mometasone, montelukast, salbutamol and terbutaline and the combinations of budesonide/formoterol, fenoterol/ipratropium and fluticasone/salmeterol. MAIN OUTCOME MEASURES: Reported ADRs were categorized with respect to distribution on age, sex, type and seriousness of reported ADRs, medications and type of reporter. The unit of analysis was one ADR. RESULTS: We located 326 spontaneous reports corresponding to 774 ADRs for the included asthma medications. Approximately 85% of reported ADRs were serious including six fatal cases. In total, 57% of ADRs were reported for boys. One quarter of all ADRs occurred in children up to 1 year of age. Physicians reported the majority of ADRs. Across medicines, the majority of reported ADRs were of the type "psychiatric disorders" (13% of total ADRs), followed by "respiratory, thoracic and mediastinal disorders" (10% of total ADRs) and "skin and subcutaneous disorders" (9% of total ADRs). The largest number of ADRs was reported for budesonide (21% of total ADRs), followed by salbutamol (20% of total ADRs) and fluticasone (19% of total ADRs). For salbutamol, the largest numbers of serious ADRs were "tachycardia", "accidental exposure/incorrect dose administered" and "respiratory failure". CONCLUSION: Only a few ADRs from use of asthma medications in children were identified in the EudraVigilance ADR database, but a large majority of these were serious including fatal cases. PMID- 25288146 TI - Persistent drug interaction between aprepitant and warfarin in patients receiving anticancer chemotherapy. AB - CASE: We describe two cases in which treatment with aprepitant persistently altered antithrombotic control in patients receiving warfarin. A 60-year-old man received 5 weekly cycles of chemotherapy. Aprepitant was administered as a 3-day regimen from the second cycle of chemotherapy. In each of the chemotherapy cycles that included aprepitant, the therapeutic international normalized ratio (INR) decreased markedly to <1.6, and slowly recovered over several weeks. A 47-year old woman was treated with 4 weekly cycles of chemotherapy. Aprepitant was administered as a 3-day regimen. On day 8 of the first cycle of chemotherapy, the patient's INR fell markedly to 1.1. Although warfarin dosage was steadily increased over the four subsequent cycles of chemotherapy, therapeutic target range was not recovered. INR gradually returned to normal during the 2 months after the final cycle of chemotherapy. CONCLUSION: To our knowledge, this is the first case report to document the effects of aprepitant in cancer patients receiving anticoagulation therapy. PMID- 25288136 TI - Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. AB - Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03 0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 * 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. PMID- 25288147 TI - Methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa for anemia in non-dialysis-dependent CKD: a systematic review. AB - BACKGROUND: Anemia management in non-dialysis-dependent chronic kidney disease (CKD) patients is associated with cardiovascular and cost benefits, slows decline in renal function, and prevents mortality. Different reviews have focused on evaluating the safety and efficacy of methoxy polyethylene glycol-epoetin beta (MPG-EPO), a continuous erythropoietin receptor activator, in CKD patients regardless of dialysis dependency and others have studied this novel agent exclusively in CKD patients receiving dialysis. AIM OF THE REVIEW: To evaluate the efficacy and tolerability of MPG-EPO compared with other erythropoiesis stimulating agents (in particular darbepoetin alfa) for the treatment of anemia in non-dialysis-dependent CKD patients. METHODS: A systematic review of original studies published mainly in MEDLINE, Cochrane Database, ScienceDirect, ProQuest, clinical trials registries, and Google Scholar was carried out to identify randomized controlled trials (RCTs) comparing MPG-EPO with other erythropoiesis stimulating agents or placebo among patients with anemia of CKD who were not yet receiving dialysis. Data were independently extracted by two reviewers using standardized data abstraction tool. RESULTS: Four trials involving 1,155 patients were included in the review. The changes in hemoglobin level from the baseline reported by the reviewed studies demonstrate that MPG-EPO was clinically non inferior to darbepoetin alfa. In addition, the studies documented that MPG-EPO treated patients experienced a lower rate of hemoglobin level above the target range of 12-13 g/dL than darbepoetin-treated patients. The proportion of patients requiring RBC transfusion was higher among patients who received darbepoetin alfa than those who received MPG-EPO. However, the time to hemoglobin response was longer with MPG-EPO than with darbepoetin. Finally, the incidences of serious adverse events were similar between the two therapeutic agents. CONCLUSION: There are currently only few well-designed head-to-head RCTs investigating the efficacy and safety of MPG-EPO compared with other ESAs in non-dialysis-dependent patients. MPG-EPO therapy compared with darbepoetin alfa has demonstrated favorable effects of increasing and maintaining hemoglobin concentrations to recommended target levels. This mini-review is not conclusive due to limited number of studies. Therefore, the beneficial effects and tolerability of MPG-EPO among non-dialysis-dependent CKD patients should be further investigated, given the economic and clinical benefits of managing anemia in this population. PMID- 25288149 TI - Pathophysiology and principles of management of the many faces of the acute vaso occlusive crisis in patients with sickle cell disease. AB - Effective management of sickle cell pain entails a thorough understanding of its pathophysiology and the pharmacogenomics of the opioids used to manage it. In recent years, there has been significant progress along these two lines. At the pathophysiologic level, there is evidence that the severity and frequency of painful stimuli modulate their transmission at the level of the dorsal horn of the spinal cord. This modulation is achieved via two channels: the alpha-Amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors. Initially, the AMPA channel controls the transmission of stimuli of mild-moderate severity. Once the AMPA channel reaches its limit of membrane depolarization, the NMDA channel is activated and facilitates the transmission of painful stimuli in a progressive fashion leading to central sensitization and glial activation. At the level of pharmacogenomics, the metabolism of each opioid is patient-specific. Glucuronidation is unique for the metabolism of morphine, hydromorphone, and oxymorphone. The metabolism of all other opioids requires specific Cytochrome P450 (CYP) isoenzymes. The activity of each isoenzyme and the activity of the metabolites of each opioid vary among patients depending on their genetic makeup and coexistent environmental factors such as the use of other medications that may enhance or inhibit the CYP isoenzyme activity. PMID- 25288148 TI - Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways. AB - Hericium erinaceus (Bull.: Fr.) Pers. is an edible and medicinal mushroom used traditionally to improve memory. In this study, we investigated the neuritogenic effects of hericenones isolated from H. erinaceus and the mechanisms of action involved. H. erinaceus was cultivated and the secondary metabolites were elucidated by high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). The secondary metabolites were tested for neurite outgrowth activity (if any). Rat pheochromocytoma (PC12) cells were employed and the nerve growth factor (NGF) level was also determined. The signaling pathways involved in the mushroom induced neuritogenesis were investigated using several pharmacological inhibitors. Hericenones B-E (1-4), erinacerin A (5) and isohericerin (6) were isolated from the basidiocarps of H. erinaceus. The hericenones did not promote neurite outgrowth but when induced with a low concentration of NGF (5 ng mL(-1)), the neuritogenic activity was comparable to that of the positive control (50 ng mL(-1) of NGF). Hericenone E was able to stimulate NGF secretion which was two fold higher than that of the positive control. The neuritogenesis process was partially blocked by the tyrosine kinase receptor (Trk) inhibitor, K252a, suggesting that the neuritogenic effect was not solely due to NGF. Hericenone E also increased the phosphorylation of extracellular-signal regulated kinases (ERKs) and protein kinase B (Akt). Taken together, this study suggests that hericenone E potentiated NGF-induced neuritogenesis in PC12 cells via the MEK/ERK and PI3K/Akt pathways. PMID- 25288150 TI - Flame retardant transfers from U.S. households (dust and laundry wastewater) to the aquatic environment. AB - Levels of flame retardants in house dust and a transport pathway from homes to the outdoor environment were investigated in communities near the Columbia River in Washington state (WA). Residential house dust and laundry wastewater were collected from 20 homes in Vancouver and Longview, WA and analyzed for a suite of flame retardants to test the hypothesis that dust collecting on clothing and transferring to laundry water is a source of flame retardants to wastewater treatment plants (WWTPs) and subsequently to waterways. Influent and effluent from two WWTPs servicing these communities were also analyzed for flame retardants. A total of 21 compounds were detected in house dust, including polybrominated diphenyl ethers (PBDEs), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB or EH-TBB), bis(2-ethylhexyl) 3,4,5,6-tetrabromophthalate (TBPH), 1,2 bis(2,4,6,-tribromophenoxy)ethane (BTBPE) and decabromodiphenylethane (DBDPE), hexabromocyclododecane (HBCD or HBCDD), tetrabromobisphenol A (TBBPA), and three chlorinated organophosphate flame retardants (ClOPFRs), tris(1,3-dichloro-2 propyl)phosphate (TDCPP or TDCIPP), tris(1-chloro-2-propyl)phosphate (TCPP or TCIPP), and tris(2-chloroethyl)phosphate (TCEP). Levels ranged from 3.6 to 82,700 ng g(-1) (dry weight). Of the 21 compounds detected in dust, 18 were also detected in laundry wastewater. Levels ranged from 47.1 to 561,000 ng L(-1). ClOPFRs were present at the highest concentrations in both dust and laundry wastewater, making up 72% of total flame retardant mass in dust and 92% in laundry wastewater. Comparison of flame retardant levels in WWTP influents to estimates based on laundry wastewater levels indicated that laundry wastewater may be the primary source to these WWTPs. Mass loadings to the Columbia River from each treatment plant were by far the highest for the ClOPFRs and ranged up to 114 kg/yr for TCPP. PMID- 25288151 TI - Calreticulin Regulates VEGF-A in Neuroblastoma Cells. AB - Calreticulin (CRT) has been previously correlated with the differentiation of neuroblastoma (NB), implying a favorable prognostic factor. Vascular endothelial growth factor (VEGF) has been reported to participate in the behavior of NB. This study investigated the association of CRT and VEGF-A in NB cells. The expressions of VEGF-A and HIF-1alpha, with overexpression or knockdown of CRT, were measured in three NB cells (SH-SY5Y, SK-N-DZ, and stNB-V1). An inducible CRT NB cell line and knockdown CRT stable cell lines were also established. The impacts of CRT overexpression on NB cell apoptosis, proliferation, and differentiation were also evaluated. We further examined the role of VEGF-A in the NB cell differentiation via VEGF receptor blockade. Constitutive overexpression of CRT led to NB cell differentiation without proliferation. Thus, an inducible CRT stNB-V1 cell line was generated by a tetracycline-regulated gene system. CRT overexpression increased VEGF-A and HIF-1alpha messenger RNA (mRNA) expressions in SH-SY5Y, SK-N DZ, and stNB-V1 cells. CRT overexpression also enhanced VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. Knockdown of CRT decreased VEGF-A and HIF-1alpha mRNA expressions and lowered VEGF-A protein expression and secretion level in conditioned media in different NB cell lines. We further demonstrated that NB cell apoptosis was not affected by CRT overexpression in stNB-V1 cells. Nevertheless, overexpression of CRT suppressed cell proliferation and enhanced cell differentiation in stNB-V1 cells, whereas blockage of VEGFR-1 markedly suppressed the expression of neuron-specific markers including GAP43, NSE2, and NFH, as well as TrkA, a molecular marker indicative of NB cell differentiation. Our findings suggest that VEGF-A is involved in CRT related neuronal differentiation in NB. Our work may provide important information for developing a new therapeutic strategy to improve the outcome of NB patients. PMID- 25288152 TI - Effect of Gestational Exposure of Cypermethrin on Postnatal Development of Brain Cytochrome P450 2D1 and 3A1 and Neurotransmitter Receptors. AB - Oral administration of low doses (1.25, 2.5, or 5 mg/kg) of cypermethrin to pregnant Wistar rats from gestation days 5 to 21 led to dose-dependent differences in the induction of cytochrome P450 2D1 (CYP2D1) and 3A1 messenger RNA (mRNA) and protein in brain regions isolated from the offsprings postnatally at 3 weeks that persisted up to adulthood (12 weeks). Similar alterations were observed in the expression of GABAergic, muscarinic, dopaminergic, and serotonergic neurotransmitter receptors in brain regions of rat offsprings. Rechallenge of the prenatally exposed offsprings at adulthood (12 weeks old) with cypermethrin (p.o., 10 mg/kg for 6 days) led to a greater magnitude of alterations in the expression of CYPs, neurotransmitter receptors, and neurotransmitter receptor binding in the brain regions when compared to the control offsprings treated at adulthood with cypermethrin or prenatally exposed offsprings. A greater magnitude of decrease was also observed in the spontaneous locomotor activity (SLA) in prenatally exposed offsprings rechallenged with cypermethrin. The present data indicating similarities in the alterations in the expression of CYPs (2D1 and 3A1) and neurotransmitter receptors in brain has led us to suggest that endogenous function regulating CYPs is possibly associated with neurotransmission processes. A greater magnitude of alterations in CYP2D1, 3A1, neurotransmitter receptors, and SLA in rechallenged animals has further provided evidence that alterations in CYPs are possibly linked with neurotransmission processes. PMID- 25288154 TI - Hypoxia/Reoxygenation-Preconditioned Human Bone Marrow-Derived Mesenchymal Stromal Cells Rescue Ischemic Rat Cortical Neurons by Enhancing Trophic Factor Release. AB - Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent a promising tool for stem cell-based therapies. However, the majority of MSCs fail to reach the injury site and have only minimal therapeutic effect. In this study, we assessed whether hypoxia/reoxygenation (H/R) preconditioning of human BM-MSCs could increase their functional capacity and beneficial effect on ischemic rat cortical neurons. Human BM-MSCs were cultured under hypoxia (1% O2) and with long term reoxygenation for various times to identify the optimal conditions for increasing their viability and proliferation. The effects of H/R preconditioning on the BM-MSCs were assessed by analyzing the expression of prosurvival genes, trophic factors, and cell migration assays. The functionally improved BM-MSCs were cocultured with ischemic rat cortical neurons to compare with normoxic cultured BM-MSCs. Although the cell viability and proliferation of BM-MSCs were reduced after 1 day of hypoxic culture (1% O2), when this was followed by 5-day reoxygenation, the BM-MSCs recovered and multiplied extensively. The immunophenotype and trilineage differentiation of BM-MSCs were also maintained under this H/R preconditioning. In addition, the preconditioning enhanced the expression of prosurvival genes, the messenger RNA (mRNA) levels of various trophic factors and migration capacity. Finally, coculture with the H/R preconditioned BM-MSCs promoted the survival of ischemic rat cortical neurons. H/R preconditioning of BM-MSCs increases prosurvival signals, trophic factor release, and cell migration and appears to increase their ability to rescue ischemic cortical neurons. This optimized H/R preconditioning procedure could provide the basis for a new strategy for stem cell therapy in ischemic stroke patients. PMID- 25288153 TI - Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells. AB - Dysfunctional Omi/HtrA2, a mitochondrial serine protease, has been implicated in various neurodegenerative disorders. Despite the wealth of evidence on the roles of Omi/HtrA2 in apoptosis, little is known about its cytosolic targets, the cleavage of which could account for the observed morphological changes such as cytoskeletal reorganizations in axons. By proteomic analysis, vimentin was identified as a substrate for Omi/HtrA2 and we have reported increased Omi/HtrA2 protease activity in Alzheimer disease (AD) brain. Here, we investigated a possible link between Omi/HtrA2 and vimentin cleavage, and consequence of this cleavage on mitochondrial distribution in neurons. In vitro protease assays showed vimentin to be cleaved by Omi/HtrA2 protease, and proximity ligation assay demonstrated an increased interaction between Omi/HtrA2 and vimentin in human primary neurons upon stress stimuli. Using differentiated neuroblastoma SH-SY5Y cells, we showed that Omi/HtrA2 under several different stress conditions induces cleavage of vimentin in wild-type as well as SH-SY5Y cells transfected with amyloid precursor protein with the Alzheimer disease-associated Swedish mutation. After stress treatment, inhibition of Omi/HtrA2 protease activity by the Omi/HtrA2 specific inhibitor, Ucf-101, reduced the cleavage of vimentin in wild type cells. Following altered vimentin filaments integrity by stress stimuli, mitochondria was redistributed in differentiated SH-SY5Y cells and human primary neurons. In summary, the findings outlined in this paper suggest a role of Omi/HtrA2 in modulation of vimentin filamentous structure in neurons. Our results provide important findings for understanding the biological role of Omi/HtrA2 activity during stress conditions, and give knowledge of interplay between Omi/HtrA2 and vimentin which might affect mitochondrial distribution in neurons. PMID- 25288155 TI - Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer's Disease. AB - The dentate gyrus (DG) of the hippocampus is known to be more resistant to the effects of various external factors than other hippocampal areas. This study investigated the neuroprotective effects of moderate treadmill exercise on early phase long-term potentiation (E-LTP) and its molecular signaling pathways in the DG of amyloid beta rat model of sporadic Alzheimer's disease (AD). Animals were preconditioned to run on treadmill for 4 weeks and concurrently received ICV infusion of Abeta1-42 peptides (250 pmol/day) during the third and fourth weeks of exercise training. We utilized in vivo electrophysiological recordings to assess the effect of exercise and/or AD pathology on basal synaptic transmission and E-LTP magnitude of the perforant pathway synapses in urethane-anesthetized rats. Immunoblotting analysis was used to quantify changes in the levels of learning and memory-related key signaling molecules. The AD-impaired basal synaptic transmission and suppression of E-LTP in the DG were prevented by prior moderate treadmill exercise. In addition, exercise normalized the basal levels of memory and E-LTP-related signaling molecules including Ca(2+)/calmodulin dependent protein kinase II (CaMKII), calcineurin (PP2B), and brain-derived neurotrophic factor (BDNF). Exercise also prevented the reduction of phosphorylated CaMKII and aberrant increase of PP2B seen after E-LTP induction in amyloid-infused rats. Our data suggests that by restoring the balance of kinase phosphatase, 4 weeks of moderate treadmill exercise prevents DG synaptic deficits and deleterious alterations in signaling pathways associated with AD. PMID- 25288156 TI - Mitochondria-Targeted Peptide Reverses Mitochondrial Dysfunction and Cognitive Deficits in Sepsis-Associated Encephalopathy. AB - Sepsis-associated encephalopathy (SAE) is associated with increased mortality, morbidity, and long-term cognitive impairments. Its pathophysiology remains to be determined and an effective pharmacologic treatment is lacking. The goal of this study was to investigate the effects of the mitochondria-targeted peptide SS-31 on mitochondrial function and cognitive deficits in SAE mice. C57BL/6 male mice were randomly divided into sham, sham + SS-31, cecal ligation and puncture (CLP), and CLP + SS-31 groups. Peptide SS-31 (5 mg/kg) was intraperitoneally administrated immediately after operation and afterwards once daily for six consecutive days. Surviving mice were subjected to behavioral tests and the hippocampus was collected for biochemical analysis 7 days after operation. The results showed that CLP resulted in high mortality rate and cognitive deficits, representative characteristics of SAE. A physiological mechanistic investigation revealed that mitochondrial function of hippocampus was severely impaired, coupled with reactive oxygen species (ROS) generation, triggering neuronal apoptosis and inflammation. Notably, administration of peptide SS-31 protected the integrity of mitochondria, reversed the mitochondrial dysfunction, inhibited the apoptosis resulting from the release of cytochrome c, diminished the response of inflammation, and ultimately reversed the behavior deficits in the SAE mice. In conclusion, our data demonstrate that daily treatment with mitochondria targeted peptide SS-31 reduces mortality rate and ameliorates cognitive deficits, which is possibly through a mechanism of reversing mitochondrial dysfunction and partial inhibition of neuronal apoptosis and inflammation in the hippocampus of the SAE mice. PMID- 25288157 TI - Nhej1 Deficiency Causes Abnormal Development of the Cerebral Cortex. AB - DNA double-strand breaks (DSBs) frequently occur in rapidly dividing cells such as proliferating progenitors during central nervous system development. If they cannot be repaired, these lesions will cause cell death. The non-homologous end joining (NHEJ) DNA repair pathway is the only pathway available to repair DSBs in post-mitotic neurons. The non-homologous end joining factor 1 (Nhej1) protein is a key component of the NHEJ pathway. Nhej1 interacts with Xrcc4 and Lig4 to repair DSBs. Loss of function of Xrcc4 or Lig4 is embryonic lethal in the mouse while the loss of Nhej1 is not. Surprisingly, the brains of Nhej1-deficient mice appear to be normal although NHEJ1 deficiency in humans causes severe neurological dysfunction and microcephaly. Here, we studied the consequences of Nhej1 dysfunction for the development of the cerebral cortex using in utero electroporation of inactivating small hairpin RNAs (shRNAs) in the developing rat brain. We found that decreasing Nhej1 expression during neuronal migration phases causes severe neuronal migration defects visualized at embryonic stages by an accumulation of heterotopic neurons in the intermediate zone. Knocked-down cells die by 7 days after birth and the brain regions where RNA interference was achieved are structurally abnormal, suffering from a reduction of the width of the external cortical layers. These results indicate that the Nhej1 protein is necessary for proper rat cortical development. Neurons unable to properly repair DNA DSBs are unable to reach their final destination during the development and undergo apoptosis, leading to an abnormal cortical development. PMID- 25288158 TI - Survey of American (USA) gasolines (2008). AB - The regulations for gasoline's content vary depending on the time of year and physical location within the United States while the refinery and distribution system mixes product batches; this results in variability of content. ASTM E1618 requires both the aromatic and alkane EIP patterns of gasoline to compare with references. A survey was conducted by collecting gasoline from Florida to Oregon, from 85 to 93 octane. Samples were analyzed in accordance with ASTM E1618 in various states of evaporation. The range of differences found in the 90% evaporated alkane EIPs is presented and showed a continuum of response when the n alkane response was compared with the branched alkane response. Similarly, the ratio of the alkane EIP to the aromatic EIP also showed a continuum of response at the 90% evaporated state. Gasoline samples with unusual characteristics are also discussed. PMID- 25288159 TI - The increase of carcinoembryonic antigen (CEA), high-sensitivity C-reactive protein, and neutrophil/lymphocyte ratio in Parkinson's disease. AB - The role of carcinoembryonic antigen (CEA) in Parkinson's disease (PD) has not been previously investigated. The aim of the present study was to evaluate the serum level of carcinoembryonic antigen, high-sensitivity C-reactive protein (hs CRP), and Neutrophil/lymphocyte ratio (NLR) among patients with Parkinson's disease and to examine the relationship between these inflammatory markers. The cross-sectional design includes 51 patients with Parkinson's disease and 50 age- and sex-matched healthy controls. We investigated the differences in hs-CRP, CEA, and NLR levels between these two groups. CEA was significantly higher in PD patients relative to the control group (mean 2.40 +/- 1.51 vs. 1.72 +/- 0.87 (ng/mL), respectively; p = 0.015). Mean NLR was significantly higher in PD patients relative to the control group (mean 3.1 +/- 1.3 vs. 2.1 +/- 0.32, respectively; p < 0.001). Serum level of hs-CRP was higher in PD patients than in control group (mean 1.04 +/- 0.62 and 0.54 +/- 0.31, respectively; p < 0.01). Correlation analysis revealed significant correlation between hs-CRP, CEA, and Neutrophil/lymphocyte ratio (p < 0.05). This study demonstrates for the first time the association between CEA, hs-CRP, NLR, and PD. We found CEA, hs-CRP, and NLR levels to be significantly higher in the PD patients than in the normal controls. PMID- 25288161 TI - Classical Statements: A new feature of Public Understanding of Science. PMID- 25288160 TI - Embolization treatment of cerebral arteriovenous malformations and amyotrophic lateral sclerosis. PMID- 25288162 TI - The magic of social thought. AB - Studying social thinking provides a promising field of investigation for the constitution of common knowledge in communication and action of historically and culturally situated groups. Its genealogy helps the understanding of the symbolic efficacy of social practices and their own operating collective logic. The English translation of a short version of Serge Moscovici's article on the new magical thinking allows a wider audience to gain access, for the first time, to a text that perfectly illustrates the currentness and relevance of the social psychology of knowledge. PMID- 25288163 TI - The new magical thinking. PMID- 25288164 TI - Novel missense mutations of ABCB6 in two chinese families with dyschromatosis universalis hereditaria. PMID- 25288165 TI - Adolescent gang involvement: The role of individual, family, peer, and school factors in a multilevel perspective. AB - Youth gang involvement is a serious public health challenge as adolescents involved in gangs are more likely than others to engage in violence and aggression. To better understand gang involvement, we examined the role of protective (empathy and parental support) and risk (peer deviance and lack of safety at school) factors, as well as their interactions, in predicting adolescent gang affiliation. The study involved a sample of 26,232 students (53.4% females; mean age = 14.62, SD = 1.69) participating in the California Healthy Kids Survey (CHKS), a survey investigating a wide range of youth health and risk behaviors administered in all California schools every 2 years. Using hierarchical linear modeling (HLM), findings indicated that high levels of empathy and parental support were associated with a lower likelihood of affiliating with a gang. Associating with deviant peers and perceiving the school as unsafe were positively correlated with gang membership. At the school level, lack of safety and type of school (special education, vocational, or alternative school vs. comprehensive schools) were associated with greater probability of gang membership. Empathy mitigated the association between deviant peers and gang membership. PMID- 25288166 TI - The significant role of autophagy in the granular layer in normal skin differentiation and hair growth. AB - As a major intracellular degradation system, autophagy contributes to the maintenance of skin keratinocyte homeostasis. However, the precise role of autophagy in skin differentiation has not been fully investigated. To clarify whether autophagy plays a role in skin differentiation and maturation, autophagy related gene 7 (Atg7)-deficient mice were generated. Atg7-deficient mice cannot survive for more than 24 h after birth. Therefore, the skins of Atg7-deficient mice and wild-type mice (as a control) were grafted onto severe combined immunodeficient mice. The resulting morphological and pathological changes were monitored for 28 days. Histopathological examination revealed acanthosis, hyperkeratosis, and abnormal hair growth in the skin grafts from the Atg7 deficient mice. Immune-density analysis of the skin grafts revealed reduced immunostaining of keratinization-related proteins, including loricrin, filaggrin, and involucrin, in the skin grafts from the Atg7-deficient mice. Furthermore, quantitative RT-PCR and Western blot analyses revealed the reduced expression of these three keratinization-related proteins in the skin grafts from the Atg7 deficient mice. Morphometric analysis using electron microscopy further revealed a reduction in the number and diameter of the keratohyalin and trichohyalin granules in these skin grafts. The differences were maintained for at least 1 month after transplantation. These results show that autophagy has a significant role in epidermal keratinization and hair growth until a certain stage of maturation. PMID- 25288170 TI - Frontispiece: asymmetric reduction of alpha-amino ketones with a KBH4 solution catalyzed by Chiral Lewis acids. AB - Asymmetric Alkali Metal Borohydride Reduction Alkali metal borohydrides are mild, inexpensive, highly selective, and environmentally friendly reducing agents in organic chemistry. In their Communication on page 13482 ff., X. Feng et al. demonstrate an efficient enantioselective reduction of both secondary and primary alpha-amino ketones with potassium borohydride solution catalyzed by chiral N,N' dioxide-metal complex catalysts. The catalytic system features a convenient operation and tolerance to water, without the need for basic additives. PMID- 25288173 TI - Percutaneous irreversible electroporation of locally advanced pancreatic carcinoma using the dorsal approach: a case report. AB - Irreversible electroporation (IRE) is a novel image-guided ablation technique that is increasingly used to treat locally advanced pancreatic carcinoma (LAPC). We describe a 67-year-old male patient with a 5 cm stage III pancreatic tumor who was referred for IRE. Because the ventral approach for electrode placement was considered dangerous due to vicinity of the tumor to collateral vessels and duodenum, the dorsal approach was chosen. Under CT-guidance, six electrodes were advanced in the tumor, approaching paravertebrally alongside the aorta and inferior vena cava. Ablation was performed without complications. This case describes that when ventral electrode placement for pancreatic IRE is impaired, the dorsal approach could be considered alternatively. PMID- 25288171 TI - Distinct iEEG activity patterns in temporal-limbic and prefrontal sites induced by emotional intentionality. AB - Our emotions tend to be directed towards someone or something. Such emotional intentionality calls for the integration between two streams of information; abstract hedonic value and its associated concrete content. In a previous functional magnetic resonance imaging (fMRI) study we found that the combination of these two streams, as modeled by short emotional music excerpts and neutral film clips, was associated with synergistic activation in both temporal-limbic (TL) and ventral-lateral PFC (vLPFC) regions. This additive effect implies the integration of domain-specific 'affective' and 'cognitive' processes. Yet, the low temporal resolution of the fMRI limits the characterization of such cross domain integration. To this end, we complemented the fMRI data with intracranial electroencephalogram (iEEG) recordings from twelve patients with intractable epilepsy. As expected, the additive fMRI activation in the amygdala and vLPFC was associated with distinct spatio-temporal iEEG patterns among electrodes situated within the vicinity of the fMRI activation foci. On the one hand, TL channels exhibited a transient (0-500 msec) increase in gamma power (61-69 Hz), possibly reflecting initial relevance detection or hedonic value tagging. On the other hand, vLPFC channels showed sustained (1-12 sec) suppression of low frequency power (2.3-24 Hz), possibly mediating changes in gating, enabling an on-going readiness for content-based processing of emotionally tagged signals. Moreover, an additive effect in delta-gamma phase-amplitude coupling (PAC) was found among the TL channels, possibly reflecting the integration between distinct domain specific processes. Together, this study provides a multi-faceted neurophysiological signature for computations that possibly underlie emotional intentionality in humans. PMID- 25288172 TI - Checkpoint-independent scaling of the Saccharomyces cerevisiae DNA replication program. AB - BACKGROUND: In budding yeast, perturbations that prolong S phase lead to a proportionate delay in the activation times of most origins. The DNA replication checkpoint was implicated in this scaling phenotype, as an intact checkpoint was shown to be required for the delayed activation of late origins in response to hydroxyurea treatment. In support of that, scaling is lost in cells deleted of mrc1, a mediator of the replication checkpoint signal. Mrc1p, however, also plays a role in normal replication. RESULTS: To examine whether the replication checkpoint is required for scaling the replication profile with S phase duration we measured the genome-wide replication profile of different MRC1 alleles that separate its checkpoint function from its role in normal replication, and further analyzed the replication profiles of S phase mutants that are checkpoint deficient. We found that the checkpoint is not required for scaling; rather the unique replication phenotype of mrc1 deleted cells is attributed to the role of Mrc1 in normal replication. This is further supported by the replication profiles of tof1Delta which functions together with Mrc1p in normal replication, and by the distinct replication profiles of specific POL2 alleles which differ in their interaction with Mrc1p. CONCLUSIONS: We suggest that the slow fork progression in mrc1 deleted cells reduces the likelihood of passive replication leading to the activation of origins that remain mostly dormant in wild-type cells. PMID- 25288174 TI - Stent-graft placement with early debridement and antibiotic treatment for femoral pseudoaneurysms in intravenous drug addicts. AB - PURPOSE: Explore the application of endovascular covered stent-graft (SG) placement in femoral pseudoaneurysms in intravenous drug addicts. MATERIALS AND METHODS: We evaluated a consecutive series of pseudoaneurysm in intravenous drug addicts treated with SGs from August 2010 to December 2013. RESULTS: 15 patients with 16 arterial pseudoaneurysms were enrolled in this study. All were males with a mean age of 36.9 years. Hemorrhage was the most common reason (93.8 %) for seeking medical care, and 3 of these patients were in hemorrhagic shock at admission. All patients received broad-spectrum antibiotics, and debridement and drainage were implemented after SG placement. 7 of the 13 cases which had microbiologic results showed mixed infections, while gram-negative bacteria were the major pathogens. Except for 2 patients, who were lost to follow-up, two new pseudoaneurysms formed due to delayed debridement, and one stent thrombosis occurred, none of the remaining cases had SG infection or developed claudication. CONCLUSIONS: SG placement controls massive hemorrhage rapidly, gives enough time for subsequent treatment for pseudoaneurysms due to intravenous drug abuse, and reduces the incidence of postoperative claudication. With appropriate broad spectrum antibiotics and early debridement, the incidence of SG infection is relatively low. It is an effective alternative especially as temporary bridge measure for critical patients. However, the high cost, uncertain long-term prospects, high demand for medical adherence, and the risk of using the conduits for re-puncture call for a cautious selection of patients. More evidence is required for the application of this treatment. PMID- 25288177 TI - Statins, glycemia, and diabetes mellitus: another point of view. AB - Glycemic effects of statins have recently become a topic of heated debate. On closer inspection, however, the prevailing opinion regarding this issue may prove to be unsubstantiated. We suggest that the harmful effect of statin-induced diabetes is likely overestimated, and the consequences of the glycemic effects of statins may, theoretically, apply to a greater number of patients beyond just those with statin-induced diabetes. Most notably, though, careful consideration of the issue suggests, albeit surprisingly, that the clinical implications of the glycemic effects of statins may actually be rather limited. PMID- 25288176 TI - Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. AB - Look AHEAD (Action for Health in Diabetes) was a randomized controlled trial that examined the impact of long-term participation in an intensive weight loss intervention on cardiovascular disease (CVD) morbidity and mortality in people with type 2 diabetes (T2D). The results from this trial suggest that intensive lifestyle interventions are effective in helping patients to achieve management of cardiovascular risk factors and reducing the need to initiate medication usage to manage these conditions, though the benefits in terms of the prevention of CVD morbidity and mortality beyond those achieved through aggressive medical management of hypertension and dyslipidemia is not clear. Additional benefits of participation in an intensive lifestyle intervention such as lowered chronic kidney disease risk, blood pressure, medication usage, improved sleep apnea, and partial remission of diabetes are discussed. PMID- 25288178 TI - The association between the rs6495309 polymorphism in CHRNA3 gene and lung cancer risk in Chinese: a meta-analysis. AB - The association between the rs6495309 polymorphism in CHRNA3 gene and lung cancer risk has been studied in Chinese by several number case-control control studies with small number of cases and controls, and these studies might be underpowered to reveal the true association. Thus we sought to investigate the association with the risk of lung cancer by performing a comprehensive meta-analysis on the polymorphism. Five case-control studies were extracted from 3 articles on the polymorphism involving 4608 lung cancer cases and 4617 controls. The results of meta-analysis showed that significant increased risk were found for the polymorphism with the risk of lung cancer in Chinese: OR = 1.47, 95%CI = 1.33 1.63, P < 0.00001 for CC + TC vs. TT; OR = 1.24, 95%CI = 1.07-1.44, P = 0.005 for CC vs. TT + TC; OR = 1.62, 95%CI = 1.32-2.00, P < 0.00001 for CC vs. TT; OR = 1.42, 95%CI = 1.26-1.61, P < 0.00001 for CT vs. TT; OR = 1.42, 95%CI = 1.26-1.61, P < 0.00001. No significant publication bias was found for the five genetic models. Our findings demonstrated that CHRNA3 gene rs6495309 polymorphism might be a risk factor for the development of lung cancer in Chinese. PMID- 25288180 TI - Dynamic photocontrol of the coffee-ring effect with optically tunable particle stickiness. AB - When a colloidal drop dries on a surface, most of the particles accumulate at the drop periphery, yielding a characteristic ring-shaped pattern. This so-called coffee-ring effect (CRE) is observed in any pinned evaporating drop containing non-volatile solutes. Here, the CRE is dynamically controlled for the first time by using light, and an unprecedented reconfigurability of the deposit profile is demonstrated. This is achieved through a new mechanism where particle stickiness is optically tuned on demand, thus offering reliable modulation of the deposition pattern. The system consists of anionic nanoparticles and photosensitive cationic surfactants dispersed in water. It is shown that light-dependent modulation of surfactant-particle interactions dictates particle attraction and trapping at the liquid-gas interface, which allows us to direct particle deposition into a wide range of patterns from rings to homogeneous disks. Patterning from single drops is photoreversible upon changing the wavelength whereas spatial control in multiple drop arrays is achieved using a photomask. PMID- 25288179 TI - Effects of patient health literacy, patient engagement and a system-level health literacy attribute on patient-reported outcomes: a representative statewide survey. AB - BACKGROUND: The effects of health literacy are thought to be based on interactions between patients' skill levels and health care system demands. Little health literacy research has focused on attributes of health care organizations. We examined whether the attribute of individuals' experiences with front desk staff, patient engagement through bringing questions to a doctor visit, and health literacy skills were related to two patient-reported outcomes. METHODS: We administered a telephone survey with two sampling frames (i.e., household landline, cell phone numbers) to a randomly selected statewide sample of 3358 English-speaking adult residents of Missouri. We examined two patient reported outcomes - whether or not respondents reported knowing more about their health and made better choices about their health following their last doctor visit. Multivariable logistic regression models were used to examine the independent contributions of predictor variables (i.e., front desk staff, bringing questions to a doctor visit, health literacy skills). RESULTS: Controlling for self-reported health, having a personal doctor, time since last visit, number of chronic conditions, health insurance, and sociodemographic characteristics, respondents who had a good front desk experience were 2.65 times as likely (95% confidence interval [CI]: 2.13, 3.30) and those who brought questions were 1.73 times as likely (95% CI: 1.32, 2.27) to report knowing more about their health after seeing a doctor. In a second model, respondents who had a good front desk experience were 1.57 times as likely (95% CI: 1.26, 1.95) and those who brought questions were 1.66 times as likely (95% CI: 1.29, 2.14) to report making better choices about their health after seeing a doctor. Patients' health literacy skills were not associated with either outcome. CONCLUSIONS: Results from this representative statewide survey may indicate that one attribute of a health care organization (i.e., having a respectful workforce) and patient engagement through question asking may be more important to patient knowledge and health behaviors than patients' health literacy skills. Findings support focused research to examine the effects of organizational attributes on patient health outcomes and system-level interventions that might enhance patient health. PMID- 25288181 TI - Progress in neuro-oncology: imaging in-phase! PMID- 25288182 TI - #CochraneTech: technology and the future of systematic reviews. PMID- 25288183 TI - Comparative efficacy of biological treatments for moderate-to-severe psoriasis: a network meta-analysis adjusting for cross-trial differences in reference arm response. AB - BACKGROUND: Multiple biological therapies are approved for the treatment of moderate-to-severe psoriasis. OBJECTIVES: To assess the short-term efficacy of biological treatments for moderate-to-severe psoriasis via a network meta analysis that adjusts for reference arm response rates. METHODS: Fifteen randomized trials of biological treatments for moderate-to-severe psoriasis were identified. Rates of response, assessed as 50%, 75% and 90% reductions in the Psoriasis Area and Severity Index (PASI), were compared using a network meta analysis. To account for variation across trials, the model was adjusted for placebo responses, the relevance of which was assessed by testing its statistical significance, impact on model fit, and extent to which lack of adjustment confounded the efficacy estimates for biologics. RESULTS: Psoriasis Area and Severity Index 75 response rates for placebo arms ranged from 1.8% to 18.9%. The probability of achieving a PASI 75 response was 80.5% [95% credible interval (CrI) 74.8-85.7] with infliximab 5 mg kg(-1) ; 72.5% (95% CI 66.1-78.3) with ustekinumab 90 mg; 67.5% (95% CI 60.7-73.9) with ustekinumab 45 mg; 66.2% (95% CI 57.3-73.3) with adalimumab 40 mg; 51.9% (95% CI 45.7-58.4) with etanercept 50 mg; and 38.0% (95% CI 31.6-45.1) with etanercept 25 mg. Infliximab had the highest PASI 75 response. Adalimumab and both ustekinumab doses had significantly higher PASI 75 responses than both etanercept doses. There were no significant differences among adalimumab and ustekinumab doses. CONCLUSIONS: A model adjusted for reference arm response rates was found to fit clinical trial data significantly better than unadjusted models. PMID- 25288184 TI - Discovery of substituted 4-aminoquinazolines as selective Toll-like receptor 4 ligands. AB - The Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-kappaB activation. A human cell-based high throughput screen (HTS) revealed substituted 4 aminoquinazolines to be small molecular weight activators of NF-kappaB. The most potent hit compound predominantly stimulated through the human TLR4/MD2 complex, and had less activity with the mouse TLR4/MD2. There was no activity with other TLRs and the TLR4 activation was MD-2 dependent and CD14 independent. Synthetic modifications of the quinazoline scaffold at the 2 and 4 positions revealed trends in structure-activity relationships with respect to TLR dependent production of the NF-kappaB associated cytokine IL-8 in human peripheral blood mononuclear cells, as well as IL-6 in mouse antigen presenting cells. Furthermore, the hit compound in this series also activated the interferon signaling pathway resulting in type I interferon production. Substitution at the O-phenyl moiety with groups such as bromine, chlorine and methyl resulted in enhanced immunological activity. Computational studies indicated that the 4 aminoquinazoline compounds bind primarily to human MD-2 in the TLR4/MD-2 complex. These small molecules, which preferentially stimulate human rather than mouse innate immune cells, may be useful as adjuvants or immunotherapeutic agents. PMID- 25288186 TI - An update on therapeutic opportunities offered by cancer glycolytic metabolism. AB - Almost all invasive cancers, regardless of tissue origin, are characterized by specific modifications of their cellular energy metabolism. In fact, a strong predominance of aerobic glycolysis over oxidative phosphorylation (Warburg effect) is usually associated with aggressive tumour phenotypes. This metabolic shift offers a survival advantage to cancer cells, since they may continue to produce energy and anabolites even when they are exposed to either transient or permanent hypoxic conditions. Moreover, it ensures a high production rate of glycolysis intermediates, useful as building blocks for fast cell proliferation of cancer cells. This peculiar metabolic profile may constitute an ideal target for therapeutic interventions that selectively hit cancer cells with minimal residual systemic toxicity. In this review we provide an update about some of the most recent advances in the discovery of new bioactive molecules that are able to interfere with cancer glycolysis. PMID- 25288185 TI - Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents. AB - Previous investigations identified 2'-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin. PMID- 25288187 TI - Bioavailable pyrrolo-benzo-1,4-diazines as Na(v)1.7 sodium channel blockers for the treatment of pain. AB - A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 MUM. PMID- 25288189 TI - Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. AB - BACKGROUND: Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, presenting significant challenges in its management. METHODS: A randomized, double-blind, placebo controlled study involving 15 relapsing-remitting MS patients with MS-induced NPP was conducted to evaluate nabilone combined with gabapentin (GBP). Eligible patients stabilized on GBP (>=1,800 mg/day) with inadequate pain relief were recruited. Nabilone or placebo was titrated over 4 weeks (0.5 mg/week increase) followed by 5-week maintenance of 1 mg oral nabilone (placebo) twice daily. Primary outcomes included two daily patient-reported measures using a 100-mm visual analog scale (VAS), pain intensity (VASpain), and impact of pain on daily activities (VASimpact). Hierarchical regression modeling was conducted on each outcome to determine if within-person pain trajectory differed across study groups, during 63-day follow-up. RESULTS: After adjustment for key patient-level covariates (e.g., age, sex, Expanded Disability Status Scale, duration of MS, baseline pain), a significant group * time(2) interaction term was reported for both the VASpain (P < 0.01) and VASimpact score (P < 0.01), demonstrating the adjusted rate of decrease for both outcomes was statistically greater in nabilone vs placebo study group. No significant difference in attrition rates was noted between treatments. Nabilone was well tolerated, with dizziness/drowsiness most frequently reported. CONCLUSION: Nabilone as an adjunctive to GBP is an effective, well-tolerated combination for MS-induced NPP. The results of this study identify a novel therapeutic combination for use in this population of patients predisposed to tolerability issues that may otherwise prevent effective pain management. PMID- 25288188 TI - 2-Guanidinoquinazolines as new inhibitors of the STAT3 pathway. AB - Synthesis and SAR investigation of 2-guanidinoquinazolines, initially identified in a high content screen for selective STAT3 pathway inhibitors, led to a more potent analog (11c) that demonstrated improved anti-proliferative activity against a panel of HNSCC cell lines. PMID- 25288190 TI - Associative plasticity in surround inhibition circuits in human motor cortex. AB - Surround inhibition is a physiological mechanism that is hypothesised to improve contrast between signals in the central nervous system. In the human motor system, motor surround inhibition (mSI) can be assessed using transcranial magnetic stimulation (TMS). We evaluated whether it is possible to modulate mSI, using a paradigm able to induce plastic effects in primary motor cortex (M1). Fifteen healthy volunteers participated in the experiments. To assess mSI, we delivered single pulses at rest and at the onset of a right thumb abduction. TMS pulses over abductor digiti minimi (ADM; surround muscle) hotspot were delivered when EMG activity in right abductor pollicis brevis (APB; active muscle) > 100 MUV was detected. Paired associative stimulation (PAS) was delivered using peripheral median nerve electric stimulation and TMS over APB M1 area at an interstimulus interval of 21.5 ms for the real PAS (PAS21.5) and 100 ms for the sham PAS (PAS100). To verify the effect of PAS21.5 on mSI we collected 20 MEPs from ADM at rest and during APB movements before (T0) and 5 (T1), 15 (T2) and 30 (T3) minutes after PAS21.5. mSI from APB to ADM was present at baseline. PAS21.5 increased the amount of mSI compared with baseline whereas there was no effect after PAS100. Our results suggest that mSI is an adaptable phenomenon depending on prior experience. PMID- 25288191 TI - Re: Cheryl T. Lee, Sam S. Chang, Ashish M. Kamat, et al. Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial. Eur urol 2014;66:265-72. PMID- 25288192 TI - Modeling factors explaining the acceptance, actual use and satisfaction of nurses using an Electronic Patient Record in acute care settings: an extension of the UTAUT. AB - BACKGROUND AND PURPOSE: End-user acceptance and satisfaction are considered critical factors for successful implementation of an Electronic Patient Record (EPR). The aim of this study was to explain the acceptance and actual use of an EPR and nurses' satisfaction by testing a theoretical model adapted from the Unified Theory of Acceptance and Use of Technology (UTAUT). METHODS: A multicenter cross-sectional study was conducted in the medical-surgical wards of four hospitals ranked at different EPR adoption stages. A randomized stratified sampling approach was used to recruit 616 nurses. Structural equation modeling techniques were applied. RESULTS: Support was found for 13 of the model's 20 research hypotheses. The strongest effects are those between performance expectancy and actual use of the EPR (r=0.55, p=0.006), facilitating conditions and effort expectancy (r=0.45, p=0.009), compatibility and performance expectancy (r=0.39, p=0.002). The variables explained 33.6% of the variance of actual use, 54.9% of nurses' satisfaction, 50.2% of performance expectancy and 52.9% of effort expectancy. CONCLUSIONS: Many results of this study support the conclusions of prior research, but some take exception, such as the non significant relationship between the effort expectancy construct and actual use of the EPR. The results highlight the importance of the mediating effects of the effort expectancy and performance expectancy constructs. Compatibility of the EPR with preferred work style, existing work practices and the values of nurses were the most important factors explaining nurses' satisfaction. The results reveal the complexity of this change and suggest several avenues for future research and for the implementation of IT in healthcare. PMID- 25288194 TI - Compensation for clinical trial-related injury and death in India: challenges and the way forward. AB - Clinical research, including clinical trials, is the bedrock of evidence-based medicine and is the most reliable method of generating credible data. Over the last decade, India has been one of the preferred destinations for clinical research activities. However, a couple of trials generated widespread media coverage due to alleged ethical transgressions, which generated debate among various stakeholders and dented the overall image of clinical research activities in the country. One of the major issues which has emerged is of compensation to research participants for clinical trial-related injury or death. To address this question, the Government of India has come up with regulations regarding compensation for research participants. While these rules provide a robust framework for compensation, some concerns have been raised regarding interpretation and implementation of these guidelines. In this article, we have tried to raise some debatable issues that need to be addressed to bring more clarity to this subject. These issues need to be handled in a balanced manner so that they are able to address the concerns of all stakeholders. It is envisaged that once clarity emerges, confidence in the clinical research process will be restored. PMID- 25288193 TI - HCV treatment rates and sustained viral response among people who inject drugs in seven UK sites: real world results and modelling of treatment impact. AB - Hepatitis C virus (HCV) antiviral treatment for people who inject drugs (PWID) could prevent onwards transmission and reduce chronic prevalence. We assessed current PWID treatment rates in seven UK settings and projected the potential impact of current and scaled-up treatment on HCV chronic prevalence. Data on number of PWID treated and sustained viral response rates (SVR) were collected from seven UK settings: Bristol (37-48% HCV chronic prevalence among PWID), East London (37-48%), Manchester (48-56%), Nottingham (37-44%), Plymouth (30-37%), Dundee (20-27%) and North Wales (27-33%). A model of HCV transmission among PWID projected the 10-year impact of (i) current treatment rates and SVR (ii) scale-up with interferon-free direct acting antivirals (IFN-free DAAs) with 90% SVR. Treatment rates varied from <5 to over 25 per 1000 PWID. Pooled intention-to treat SVR for PWID were 45% genotypes 1/4 [95%CI 33-57%] and 61% genotypes 2/3 [95%CI 47-76%]. Projections of chronic HCV prevalence among PWID after 10 years of current levels of treatment overlapped substantially with current HCV prevalence estimates. Scaling-up treatment to 26/1000 PWID annually (achieved already in two sites) with IFN-free DAAs could achieve an observable absolute reduction in HCV chronic prevalence of at least 15% among PWID in all sites and greater than a halving in chronic HCV in Plymouth, Dundee and North Wales within a decade. Current treatment rates among PWID are unlikely to achieve observable reductions in HCV chronic prevalence over the next 10 years. Achievable scale-up, however, could lead to substantial reductions in HCV chronic prevalence. PMID- 25288196 TI - Gene and protein expression and cellular localisation of cytochrome P450 enzymes of the 1A, 2A, 2C, 2D and 2E subfamilies in equine intestine and liver. AB - BACKGROUND: Among the cytochrome P450 enzymes (CYP), families 1-3 constitute almost half of total CYPs in mammals and play a central role in metabolism of a wide range of pharmaceuticals. This study investigated gene and protein expression and cellular localisation of CYP1A, CYP2A, CYP2C, CYP2D and CYP2E in equine intestine and liver. Real-time polymerase chain reaction (RT-PCR) was used to analyse gene expression, western blot to examine protein expression and immunohistochemical analyses to investigate cellular localisation. RESULTS: CYP1A and CYP2C were the CYPs with the highest gene expression in the intestine and also showed considerable gene expression in the liver. CYP2E and CYP2A showed the highest gene expression in the liver. CYP2E showed moderate intestinal gene expression, whereas that of CYP2A was very low or undetectable. For CYP2D, rather low gene expression levels were found in both intestine and the liver. In the intestine, CYP gene expression levels, except for CYP2E, exhibited patterns resembling those of the proteins, indicating that intestinal protein expression of these CYPs is regulated at the transcriptional level. For CYP2E, the results showed that the intestinal gene expression did not correlate to any visible protein expression, indicating that intestinal protein expression of this CYP is regulated at the post-transcriptional level. Immunostaining of intestine tissue samples showed preferential CYP staining in enterocytes at the tips of intestinal villi in the small intestine. In the liver, all CYPs showed preferential localisation in the centrilobular hepatocytes. CONCLUSIONS: Overall, different gene expression profiles were displayed by the CYPs examined in equine intestine and liver. The CYPs present in the intestine may act in concert with those in the liver to affect the oral bioavailability and therapeutic efficiency of substrate drugs. In addition, they may play a role in first-pass metabolism of feed constituents and of herbal supplements used in equine practice. PMID- 25288197 TI - The diagnosis of esophageal eosinophilia is not increased in the summer months. AB - Smaller studies have suggested seasonal variation of the diagnosis of eosinophilic esophagitis with more patients being diagnosed in the aeroallergen season. We evaluated a large group of adult patients for a seasonal variation of the diagnosis of symptomatic eosinophilic esophageal infiltration. We performed a retrospective review of adult patients from a large Eosinophilic esophagitis database at the Mayo Clinic Rochester. We only included patients from three states in the upper Midwest, who had 15 or more eosinophils per high-power field on esophageal biopsy, symptomatic dysphagia, and were seen, in our Gastroenterology Clinic between 2000 and 2008. Clinical data were abstracted and the month of diagnosis was determined. The Rayleigh circular test and the Chi square goodness-of-fit test were used to detect seasonality of symptomatic esophageal eosinophilia diagnosis and seasonality corrected for esophagogastroduodenoscopy monthly volume. The diagnosis of symptomatic eosinophilic esophageal infiltration was made in 372 patients. The mean number of eosinophils was 39.6 per high-power field. The December/January and May/June periods seem to have an increased presentation rate (p = 0.014). Of those tested, reactions to any aeroallergen was present in 69 % (48/70), reactions to >4 aeroallergens in 47 % (33/70) and reactions to any food allergen in 63 % (50/80) of patients. There was no evidence of monthly concentration of symptomatic esophageal eosinophilia diagnosis in the subgroups of patients with any positive aeroallergen, >4 positive aeroallergens, or history of atopy. The diagnosis of symptomatic esophageal eosinophilia is not made more frequently in the summer months. PMID- 25288199 TI - The death of Cajal and the end of scientific romanticism and individualism. PMID- 25288200 TI - To what extent psychiatric patients feel involved in decision making about their mental health care? Relationships with socio-demographic, clinical, and psychological variables. AB - BACKGROUND: Shared decision making (SDM) is an essential component of patient centered care, but there is little information about its use in the psychiatric care. OBJECTIVE: To measure to what extent psychiatric patients feel they were involved in the process and steps of decision making about treatment choice and to analyse the influence of socio-demographic, clinical, and psychological processes on this perception. METHODS: Cross-sectional survey involving 1100 consecutive psychiatric outpatients invited to complete the nine-item Shared Decision-Making Questionnaire (SDM-Q-9), health locus of control and control preferences, self-efficacy and drug attitude scales, as well as a questionnaire including socio-demographic and clinical variables. RESULTS: A high response rate of 77% was registered, resulting in a sample of 846 psychiatric outpatients. SDM Q-9 total score indicate a moderately low degree of perceived participation, with differing perceived implementation of the individual the SDM process steps. Patient diagnosis evidenced significant differences in SDM perception. Patients' perception of SDM was explained by four main variables: the older the patient, the lower self-reported SDM; having a diagnosis of schizophrenia increases the likelihood of lower SDM; a positive attitude towards psychiatric drugs favors greater SDM, as well as a higher level of self-efficacy. CONCLUSION: The result of this study suggests that SDM is currently not widely practiced in psychiatric care. Further research is needed to examine if the low level of participation self-reported is justified by psychiatric patients' decisional capacity. PMID- 25288198 TI - Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive(r)) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. AB - BACKGROUND: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1). METHODS/DESIGN: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments. DISCUSSION: RNActive self adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41. PMID- 25288201 TI - Differentiating autoimmune pancreatitis from pancreatic cancer. AB - Differential diagnosis between autoimmune pancreatitis (AIP) and pancreatic cancer can be very difficult. The main clinical symptoms in patients with autoimmune pancreatitis are jaundice, weight loss, abdominal pain and new onset of diabetes mellitus. Unfortunately, the same symptoms could be observed in patients with pancreatic carcinoma too. Imaging methods as computed tomography (CT) scan, magnetic resonance imaging (MRI) and endosonography (EUS); together with serological examination (IgG4 and Ca 19-9) play the important role in differentiation autoimmune pancreatitis from pancreatic cancer. Extrapancreatic findings are distinctive in patients with autoimmune pancreatitis. In some cases the pancreatic biopsy is indicated, mainly in patients with focal or multifocal form of autoimmune pancreatitis. Response to steroids (decreased pancreatic or extrapancreatic lesion or damage) is distinctive to AIP. In clinical practice, CT scan seems to be the most reasonable tool for examining the patients with obstructive jaundice with or without present pancreatic mass. Stratification the patients with possible AIP versus pancreatic cancer is important. In patients with AIP it may avoid pancreatic resection, as well as incorrect steroid treatment in patients with pancreatic carcinoma. PMID- 25288202 TI - Value of real-time gastric juice analysis in upper gastrointestinal endoscopy. AB - AIM: Esophagogastroduodenoscopy (EGDS) cannot identify microscopic lesions. We determined the contribution of real-time gastric juice analysis in detecting lesions non-detectable with the simple endoscopic inspection. METHODS: Endoscopy, histology and gastric juice analysis were performed in 216 patients. We assessed six diagnostic strategies: EGDS (strategy-1), EGDS with antral biopsies (hematoxylin-eosin staining) in hypochlorhydrics (strategy-2) or all patients (strategy-3), EGDS with antral and fundic biopsies (hematoxylin-eosin staining) in hypochlorhydrics (strategy-4) or all patients (strategy-5), EGDS with antral and fundic biopsies (hematoxylin-eosin + immunohistochemical staining) in hypochlorhydrics (strategy-6). Then, we determined how many of the pathological conditions identified by the complete histological evaluation would have been detected by each strategy. RESULTS: In total, 220 pathological conditions were identified. Hypochlorhydria was correlated (r=0.67; P<0.01) with histological lesions (85% lesions were detected in hypochlorhydrics) and high ammonium levels, with H.pylori infection (r=0.69; P<0.01). Strategy-1 identified only 5% conditions, while strategies 3 and 5 detected 68.6% and 83.2% conditions, respectively. Strategies 2, 4 and 6 (based on gastric juice analysis) yielded detection rates (61.4%, 75.5%, 90.9%) similar to or better than those of strategies 3 and 5. CONCLUSION: Real-time gastric juice analysis provided information about the presence of gastric lesions in an otherwise "normal" stomach at EGDS. It improved the diagnostic yield and optimized resource utilization without any additional effort by the endoscopist. PMID- 25288203 TI - Role of endoscopic ultrasound in pancreatic diseases: a systematic review. AB - AIM: Since its introduction, endoscopic ultrasonography (EUS) has been increasingly gaining more attention for diagnosing various gastrointestinal conditions. We aim to systematically review the literature and highlight the benefit of using EUS in different pancreatic diseases by primarily reviewing its importance in diagnosing, treating pancreatic pathologies, comparing its accuracy to other modalities and determining its limitations and complications. METHODS: Using defined (MeSH) terms and keywords; two reviewers conducted a MEDLINE search through August 2014, in addition to manually searching relevant bibliographies cited in the included studies. All case reports, case series, letters, non English and non-human articles were excluded. RESULTS: Total of (N.=2144) potentially relevant citations were identified and screened, of which (N.=525) fulfilled eligibility criteria and grouped into seven pancreatic disease categories: chronic pancreatitis (N.=72), acute pancreatitis (N.=75), autoimmune pancreatitis (N.=31), pancreatic cancer (N.=179), neuroendocrine pancreatic tumors (N.=48), pancreatic cysts (N.=111) and pancreatic divisum (N.=9). CONCLUSION: EUS sensitivity to diagnose chronic pancreatitis is greater than endoscopic retrograde cholangiopancreatography and CT, but using EUS-guided fine needle aspiration (EUS-FNA) is not diagnostic. In acute biliary pancreatitis, EUS is superior to CT and to magnetic resonance cholangiopancreatography (MRCP) for detection of microlithiasis. EUS-guided pseudocyst drainage is safe with a high success rate. Contrast-enhanced EUS is more valuable than EUS in autoimmune pancreatitis and EUS-FNA is not recommended. EUS is superior to MRCP and multiple detector CT in evaluating pancreatic divisum. Cystic carcinoembryonic antigen level obtained using EUS-FNA is the most accurate test to exclude malignant pancreatic cyst. PMID- 25288204 TI - The effect of levosimendan on lung damage after myocardial ischemia reperfusion in rats in which experimental diabetes was induced. AB - BACKGROUND: It is known that diabetic complications and lipid peroxidation are closely associated. During ischemia and reperfusion (IR), injury may occur in distant organs, as well as in tissues next to the region exposed to the ischemia, and the lungs can be one of the most affected of these organs. Therefore, this study investigated the effects of levosimendan on lung tissue and the oxidant antioxidant system in diabetic rats. MATERIALS AND METHODS: The study was conducted in 24 Wistar albino rats that were separated into four groups (C, control; DC, diabetic control; DIR, diabetic IR; and DIRL, diabetic IR levosimendan). Diabetes was induced in 18 rats using streptozotocin (55 mg/kg), and the animals were randomly separated into three groups after the effects of the diabetes became apparent. After a left thoracotomy, ischemia was performed on the myocardial muscle with the left main coronary artery (LAD) for 30 min in the DIR and DIRL groups. After ischemia, the LAD ligation was removed, and reperfusion was applied for 120 min. Single-dose intraperitoneal 12 MUg/kg levosimendan was administered to group DIRL before the ischemia. Group DC was evaluated as the diabetic control group, and six rats were considered to be the control group (group C), in which thoracotomy was performed and then closed with no induction of myocardial ischemia. We measured the levels of malondialdehyde, as a lipid peroxidation end product, as well as catalase and glutathione S transferase activities, as antioxidant enzymes in the lung tissue. Tissue samples were also examined histopathologically. RESULTS: Neutrophil infiltration or aggregation in lung tissue was significantly higher in the DIR group compared with the C, DC, and DIRL groups (P = 0.003, P = 0.026, and P = 0.026, respectively). Alveolar wall thickening in lung tissue was significantly higher in the DIR group compared with the C, DC, and DIRL groups (P = 0.002, P = 0.002, and P = 0.006, respectively). In addition, the lung tissue damage score was significantly higher in the DIR group compared with the C, DC, and DIRL groups (P = 0.001, P = 0.004, and P = 0.007, respectively). Finally, catalase and glutathione S-transferase activity levels were significantly higher in the DIR group compared with those observed in the C, DC, and DIRL groups. CONCLUSIONS: Although diabetes increases lipid peroxidation, it suppresses antioxidant activity. Our results showed that levosimendan had a protective effect against lung damage secondary to IR in the rats with induced diabetes. We recommend that experimental and clinical studies be conducted to examine the effects of levosimendan at different doses and different IR durations on various organs for clinical use. PMID- 25288206 TI - Echography is mandatory for the initial management of critically ill patients: we are not sure. PMID- 25288205 TI - A novel small-molecule MRCK inhibitor blocks cancer cell invasion. AB - BACKGROUND: The myotonic dystrophy kinase-related CDC42-binding kinases MRCKalpha and MRCKbeta regulate actin-myosin contractility and have been implicated in cancer metastasis. Along with the related ROCK1 and ROCK2 kinases, the MRCK proteins initiate signalling events that lead to contractile force generation which powers cancer cell motility and invasion. A potential strategy for cancer therapy is to reduce metastasis by blocking MRCK activity, either alone or in combination with ROCK inhibition. However, to date no potent small molecule inhibitors have been developed with selectivity towards MRCK. RESULTS: Screening a kinase-focused small molecule chemical library resulted in the identification of compounds with inhibitory activity towards MRCK. Medicinal chemistry combined with in vitro enzyme profiling led to the discovery of 4-chloro-1-(4-piperidyl)-N [5-(2-pyridyl)-1H-pyrazol-4-yl]pyrazole-3-carboxamide (BDP00005290; abbreviated as BDP5290) as a potent MRCK inhibitor. X-ray crystallography of the MRCKbeta kinase domain in complex with BDP5290 revealed how this ligand interacts with the nucleotide binding pocket. BDP5290 demonstrated marked selectivity for MRCKbeta over ROCK1 or ROCK2 for inhibition of myosin II light chain (MLC) phosphorylation in cells. While BDP5290 was able to block MLC phosphorylation at both cytoplasmic actin stress fibres and peripheral cortical actin bundles, the ROCK selective inhibitor Y27632 primarily reduced MLC phosphorylation on stress fibres. BDP5290 was also more effective at reducing MDA-MB-231 breast cancer cell invasion through Matrigel than Y27632. Finally, the ability of human SCC12 squamous cell carcinoma cells to invade a three-dimensional collagen matrix was strongly inhibited by 2 MUM BDP5290 but not the identical concentration of Y27632, despite equivalent inhibition of MLC phosphorylation. CONCLUSIONS: BDP5290 is a potent MRCK inhibitor with activity in cells, resulting in reduced MLC phosphorylation, cell motility and tumour cell invasion. The discovery of this compound will enable further investigations into the biological activities of MRCK proteins and their contributions to cancer progression. PMID- 25288207 TI - Echography is mandatory for the initial management of critically ill patients: yes. PMID- 25288208 TI - Echography is mandatory for the initial management of critically ill patients: no. PMID- 25288209 TI - Quality of dying in the intensive care unit: it's a matter of time. PMID- 25288212 TI - An uncommon cause of weaning failure from mechanical ventilation. PMID- 25288210 TI - Methicillin-resistant Staphylococcus aureus bloodstream infections are associated with a higher energy deficit than other ICU-acquired bacteremia. AB - PURPOSE: Caloric insufficiency during the first week of intensive care unit (ICU) stay was reported to be associated with increased infection rates, especially ICU acquired bloodstream infection (ICU-BSI). However, the predisposition to ICU-BSI by a given pathogen remains not well known. We aimed to determine the impact of early energy-calorie deficit on the pathogens responsible for ICU-BSI. DESIGN: Prospective, observational, cohort study in a 18-bed medical ICU of a tertiary care hospital. METHODS: Daily energy balance (energy-calorie intakes minus calculated energy-calorie expenditure) was compared according to the microbiological results of the blood cultures of 92 consecutive prolonged (at least 96 h) acute mechanically ventilated patients who developed a first episode of ICU-BSI. RESULTS: Among the 92 ICU-BSI, nine were due to methicillin-resistant Staphylococcus aureus (MRSA). The cumulated energy deficit of patients with MRSA ICU-BSI was greater than those with ICU-BSI caused by other pathogens (-1,348 +/- 260 vs -1,000 +/- 401 kcal/day from ICU admission to day of ICU-BSI, p = 0.008). ICU admission, risk factors for nosocomial infections, nutritional status, and conditions potentially limiting feeding did not differ significantly between the two groups. Patients with MRSA ICU-BSI had lower delivered energy and similar energy expenditure, causing higher energy deficits. More severe energy deficit and higher rate of MRSA blood cultures (p = 0.01 comparing quartiles) were observed. CONCLUSIONS: Early in-ICU energy deficit was associated with MRSA ICU BSI in prolonged acute mechanically ventilated patients. Results suggest that limiting the early energy deficit could be a way to optimize MRSA ICU-BSI prevention. PMID- 25288213 TI - Overoptimism in the interpretation of statistics: the ethical role of statistical reviewers in medical journals. PMID- 25288214 TI - Quality of dying in the ICU: understanding ways to make it better. PMID- 25288216 TI - Operationalizing public health skills to resource poor settings: is this the Achilles heel in the Ebola epidemic campaign? AB - Sustainable approaches to crises, especially non-trauma-related public health emergencies, are severely lacking. At present, the Ebola crisis is defining the operational public health skill sets for infectious disease epidemics that are not widely known or appreciated. Indigenous and foreign medical teams will need to adapt to build competency-based curriculum and standards of care for the future that concentrate on public health emergencies. Only by adjusting and adapting specific operational public health skill sets to resource poor environments will it be possible to provide sustainable prevention and preparedness initiatives that work well across cultures and borders. PMID- 25288215 TI - Structural and regulatory mutations in Vibrio parahaemolyticus type III secretion systems display variable effects on virulence. AB - The Gram-negative bacterium, Vibrio parahaemolyticus, is a major cause of seafood derived food poisoning throughout the world. The pathogenicity of V. parahaemolyticus is attributed to several virulence factors, including two type III secretion systems (T3SS), T3SS1 and T3SS2. Herein, we compare the virulence of V. parahaemolyticus POR strains, which harbor a mutation in the T3SS needle apparatus of either system, to V. parahaemolyticus CAB strains, which harbor mutations in positive transcriptional regulators of either system. These strains are derived from the clinical RIMD 2210633 strain. We demonstrate that each mutation affects the virulence of the bacterium in a different manner. POR and CAB strains exhibited similar levels of swarming motility and T3SS effector production and secretion, but the CAB3 and CAB4 strains, which harbor a mutation in the T3SS2 master regulator gene, formed reduced biofilm growth under T3SS2 inducing conditions. Additionally, while the cytotoxicity of the POR and CAB strains was similar, the CAB2 (T3SS1 regulatory mutant) strain was strikingly more invasive than the comparable POR2 (T3SS1 structural mutant) strain. In summary, creating structural or regulatory mutations in either T3SS1 or T3SS2 causes differential downstream effects on other virulence systems. Understanding the biological differences of strains created from a clinical isolate is critical for interpreting and understanding the pathogenic nature of V. parahaemolyticus. PMID- 25288217 TI - What factors are predictive of benefit finding in women treated for non metastatic breast cancer? A prospective study. AB - OBJECTIVE: Patients with breast cancer are able to gain psychological benefits from cancer diagnosis and treatment, such as a greater purpose of life and closer relationships, termed as 'benefit finding' (BF). The objective of this study was to determine the effects of sociodemographic, pathological, and psychological variables on BF in women with non-metastatic breast cancer. METHODS: A total of 404 patients with breast cancer were recruited to complete a demographic survey, a Chinese version of the Benefit Finding Scale, the Optimism-pessimism Scale, the Multidimensional Scale of Perceived Social Support, and the Cognitive Emotion Regulation Questionnaire during the first week after the confirmation of the diagnosis (T1). All participants finished the Chinese version of the Benefit Finding Scale again 6 weeks after diagnosis (T2). RESULTS: Age and education of patients, perceived social support from family, acceptance, positive reappraisal, and the baseline level of BF exhibited a positive prediction on BF. Education, pessimism, and perceived social support from family had a positive prediction and perceived social support from friends and refocus on planning had a negative prediction on the family relationship of BF. Education, perceived social support from family and friends, and the baseline level of BF had a positive prediction on the acceptance of BF. CONCLUSIONS: Perceived social support and cognitive emotion regulation strategies employed in response to breast cancer are important contributing factors to BF in women with breast cancer. In order to improve the longer-term adaptation of patients, benefit finding, either directly or via cognitive emotion regulation strategies, could be targeted for intervention. PMID- 25288218 TI - Working together, sharing resources: An interuniversity collaboration to advance anatomy education. PMID- 25288219 TI - Prolonged Acetaminophen-Protein Adduct Elimination During Renal Failure, Lack of Adduct Removal by Hemodiafiltration, and Urinary Adduct Concentrations After Acetaminophen Overdose. AB - Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 +/- 2.2 h versus 26.8 +/- 1.1 h [mean +/- SEM], respectively, p < 0.001). CVVHDF failed to remove detectable amounts of APAP-CYS in any of the nine subjects studied. Sixty-eight percent of 557 urine samples from 168 subjects contained no detectable APAP-CYS, despite levels in serum up to 16.99 MUM. Terminal elimination half-life of serum APAP-CYS was prolonged in patients with renal failure for reasons unrelated to renal urinary adduct elimination, and consideration of prolonged elimination needs to be considered if attempting back extrapolation of adduct concentrations. CVVHDF did not remove detectable APAP CYS, suggesting approximate APAP-protein adduct molecular weights >= 50,000 Da. The presence of urinary APAP-CYS in the minority of instances was most compatible with renal adduct production and protein shedding into urine rather than elimination of serum adducts. PMID- 25288220 TI - Targeting the P2X7 receptor in rheumatoid arthritis: biological rationale for P2X7 antagonism. AB - OBJECTIVES: This paper aims to explore the functional significance of the P2X7 receptor in preclinical models of rheumatoid arthritis. METHODS: Preclinical studies in vivo were performed using the rat streptococcal cell wall (SCW) arthritis model. Ex vivo cultures of lipopolysaccharide (LPS)/benzoylbenzoyl adenosine triphosphate (BzATP)-stimulated human monocytes were generated to test the activities of a novel, highly specific inhibitor of human P2X7, AZD9056, on interleukin (IL)-1 and IL-18 release. RESULTS: P2X7 receptor expression was detected in inflamed synovial tissue after onset of SCW-induced arthritis in rats. Inhibition of P2X7 therein led to reduced articular inflammation and erosive progression. No effect was noted on acute-phase responses. Ex vivo, AZD9056 inhibited IL-1 and IL-18 release to BzATP in LPS-primed human monocytes. CONCLUSIONS: P2X7 receptor inhibition could represent a novel approach to the treatment of inflammatory arthritis. However, confirmatory clinical studies are warranted to further explore this possibility. PMID- 25288221 TI - CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: the INTERGENE case-control study. AB - Alcohol consumption at moderate levels has been associated with decreased risk of coronary heart disease (CHD). However, the cardio-protective effect of alcohol may be restricted to subjects with a particular genotype of the cholesteryl ester transfer protein (CETP) polymorphism. There is evidence for this from one study in men, but the finding has not been confirmed since. The present study specifically re-examines the potential modification of the association between alcohol consumption and CHD by the CETP TaqIB (rs708272) polymorphism in a sample including both men and women. The INTERGENE case-control study consists of 618 patients with CHD and 2921 control subjects, of whom 19% were homozygous for the CETP TaqIB B2 allele. Alcohol consumption was categorized into sex-specific tertiles of ethanol intake, with non-drinkers constituting a separate category. Logistic regression was used to determine the association between CHD with genotype, ethanol intake, and their interaction. Participants with intermediate ethanol intake (2nd tertile) had lower risk of CHD than those with low ethanol intake (odds ratio [OR] = 0.65; 95% confidence interval [CI] 0.50-0.85). The strongest protective association was seen in the CETP TaqIB B2 homozygotes for intermediate vs. low ethanol intake (odds ratio OR = 0.21; 95% CI 0.10-0.44). The interaction between ethanol intake and genotype was statistically significant (p = 0.008), and of similar size in men and women though significant only in men (p = 0.01). The effect modification could not be explained by differences in lifestyle, socioeconomics, or alcohol-related biological variables such as HDL cholesterol. Our study is the first to replicate previous findings of an effect modification in men. It gives only suggestive results for women, possibly due to the small number of female cases (n = 165). The prevented fraction for the favorable combination of genotype and alcohol consumption is about 6%, a value suggesting that the cardio-protective effect of moderate alcohol consumption applies only to a small segment of the general population. PMID- 25288222 TI - Ethanol intake and ethanol-conditioned place preference are reduced in mice treated with the bioflavonoid agent naringin. AB - Recently, PPAR-gamma activation has emerged as a potential treatment for alcoholism. However, the adverse effects of synthetic PPAR-gamma activators, despite being effective drugs, prompted the need for novel PPAR-gamma agonists that retain efficacy and potency with a lower potential of side effects. Hence, naringin, a bioflavonoid isolated from citrus fruits and recently identified as a natural ligand of PPAR-gamma, has begun to be evaluated for treatment of alcoholism. It is well known to possess several therapeutic benefits in addition to its anti-anxiety and antidepressant properties. In the present study, we assessed whether naringin treatment possesses anti-ethanol reward properties in C57BL/6 mice. We used the two-bottle choice drinking paradigm and ethanol-induced conditioned place preference (CPP) to examine the effect of naringin treatment on ethanol drinking. Results have shown that, compared with vehicle, naringin (10 100 mg/kg) significantly and dose-dependently decreased voluntary ethanol intake and preference in a two-bottle choice drinking paradigm [3-15% (v/v) escalating over 2 weeks], with no significant effect observed on saccharin [0.02-0.08% (w/v)] or on quinine [15-60 MUM (w/v)] intake. In addition, there was no significant difference in blood ethanol concentration (BEC) between groups following naringin administration of 3 g of ethanol/kg body weight. Interestingly, when mice were treated with vehicle or naringin (30 mg/kg) before injection of ethanol (1.5 g/kg) during conditioning days, naringin inhibited the acquisition of ethanol-CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) antagonist, GW9662. Taken together, the present findings are the first to implicate naringin and PPAR-gamma receptors in the behavioral and reward-related effects of ethanol and raise the question of whether specific drugs that target PPAR-gamma receptors could potentially reduce excessive ethanol consumption and preference. PMID- 25288224 TI - VHF NEMS-CMOS piezoresistive resonators for advanced sensing applications. AB - This work reports on top-down nanoelectromechanical resonators, which are among the smallest resonators listed in the literature. To overcome the fact that their electromechanical transduction is intrinsically very challenging due to their very high frequency (100 MHz) and ultimate size (each resonator is a 1.2 MUm long, 100 nm wide, 20 nm thick silicon beam with 100 nm long and 30 nm wide piezoresistive lateral nanowire gauges), they have been monolithically integrated with an advanced fully depleted SOI CMOS technology. By advantageously combining the unique benefits of nanomechanics and nanoelectronics, this hybrid NEMS-CMOS device paves the way for novel breakthrough applications, such as NEMS-based mass spectrometry or hybrid NEMS/CMOS logic, which cannot be fully implemented without this association. PMID- 25288225 TI - Phenolic compounds and vitamins in wild and cultivated apricot (Prunus armeniaca L.) fruits grown in irrigated and dry farming conditions. AB - BACKGROUND: Turkey is the main apricot producer in the world and apricots have been produced under both dry and irrigated conditions in the country. In this study, phenolic compounds and vitamins in fruits of one wild (Zerdali) and three main apricot cultivars ('Cataloglu', 'Hacihaliloglu' and 'Kabaasi') grown in both dry and irrigated conditions in Malatya provinces in Turkey were investigated. RESULTS: The findings indicated that higher content of phenolic compounds and vitamins was found in apricot fruits grown in irrigated conditions. Among the cultivars, 'Cataloglu' had the highest rutin contents both in irrigated and dry farming conditions as 2855 MUg in irrigated and 6952 MUg per 100 g dried weight base in dry conditions and the highest chlorogenic acid content in irrigated and dry farming conditions were measured in fruits of 'Hacihaliloglu' cultivar as 7542 MUg and 15251 MUg per 100 g dried weight base. Vitamin C contents in homogenates of fruit flesh and skin was found to be higher than beta-caroten, retinol, vitamin E and lycopen contents in apricot fruits both in irrigated and dry farming conditions. CONCLUSION: The results suggested that apricot fruits grown in both dry and irrigated conditions had high health benefits phytochemicals and phytochemical content varied among cultivars and irrigation conditions as well. However, more detailed biological and pharmacological studies are needed for the demonstration and clarification of health benefits of apricot fruits. PMID- 25288226 TI - Ocular higher-order aberrations in a school children population. AB - PURPOSE: The primary objective of the study was to explore the statistics of ocular higher-order aberrations in a population of primary and secondary school children. METHODS: A sample of 557 children aged 10-15 years were selected from two primary and two secondary schools in Heraklion, Greece. Children were classified by age in three subgroups: group I (10.7+/-0.5 years), group II (12.4+/-0.5 years) and group III (14.5+/-0.5 years). Ocular aberrations were measured using a wavefront aberrometer (COAS, AMO Wavefront Sciences, USA) at mesopic light levels (illuminance at cornea was 4lux). Wavefront analysis was achieved for a 5mm pupil. Statistical analysis was carried out for the right eye only. RESULTS: The average coefficient of most high-order aberrations did not differ from zero with the exception of vertical (0.076MUm) and horizontal (0.018MUm) coma, oblique trefoil (-0.055MUm) and spherical aberration (0.018MUm). The most prominent change between the three groups was observed for the spherical aberration, which increased from 0.007MUm (SE 0.005) in group I to 0.011MUm (SE 0.004) in group II and 0.030MUm (SE 0.004) in group III. Significant differences were also found for the oblique astigmatism and the third-order coma aberrations. CONCLUSIONS: Differences in the low levels of ocular spherical aberration in young children possibly reflect differences in lenticular spherical aberration and relate to the gradient refractive index of the lens. The evaluation of spherical aberration at certain stages of eye growth may help to better understand the underlying mechanisms of myopia development. PMID- 25288227 TI - Fish odor syndrome (trimethylaminuria) supporting the possible FMO3 down expression in childhood: a case report. AB - INTRODUCTION: Trimethylaminuria is a rare inherited disorder due to decreased metabolism of dietary-derived trimethylamine by flavin-containing monooxygenase 3. Several single nucleotide polymorphisms of the flavin-containing monooxygenase 3 gene have been described and result in an enzyme with decreased or abolished functional activity for trimethylamine N-oxygenation thus leading to trimethylaminuria. CASE PRESENTATION: Here we investigated an Italian family in which the proband was a 7-year-old girl with suspected trimethylaminuria, by flavin-containing monooxygenase 3 gene direct sequencing and urinary determination of trimethylamine and trimethylamine N-oxide. Genetic analysis found that, as with her parents and one of her two brothers, the proband carried three polymorphisms: c.472 G>A p. E158K (rs 2266782) in exon 4, c.627+10 C>G (IVS5+10G>C) (rs 2066534) and c.485-21 G>A (IVS4-22G>A) (rs 1920149) in intronic regions. CONCLUSIONS: Despite the same genotypic condition only the girl had symptoms attributable to the trimethylaminuria. The suspicion is that she has transient childhood trimethylaminuria. Therefore, we bring attention to the importance of genetic testing and eventual determination of urinary trimethylamine and trimethylamine N-oxide as instruments to offer to clinicians in the management of these pediatric patients. PMID- 25288228 TI - The role of integrin antagonists in the treatment of inflammatory bowel disease. AB - INTRODUCTION: Ulcerative colitis (UC) and Crohn's disease are chronic inflammatory diseases of the bowel associated with complex inflammatory cascades within the mucosal lining of the gut. AREAS COVERED: INTEGRINS and their use as therapies in UC and Crohn's. EXPERT OPINION: The anti-adhesion molecules are a welcome addition to the armamentarium of medical therapies for inflammatory bowel disease. PMID- 25288229 TI - Remission of migraine after clipping of saccular intracranial aneurysms. AB - BACKGROUND: Unruptured saccular intracranial aneurysm (SIA) is associated with an increased prevalence of migraine, but it is unclear whether this is altered by clipping of the aneurysm. The aim of our study was to determine whether remission rate of migraine and other recurrent headaches was greater in patients with SIA after clipping than in controls. METHODS: We prospectively studied 87 SIA patients with migraine or other recurrent headaches. They were interviewed about headaches in the preceding year before and 1 year after clipping using a validated semi-structured neurologist conducted interview. The remission rates of migraine and tension-type headache (TTH) in these patients were compared to 92 patients from a headache center. Diagnoses were made according to the ICHD-2. RESULTS: During 1 year preceding rupture 51 patients with SIA had migraine. During the year after clipping, this was reduced by 74.5% (P < 0.0001). At first encounter, 47 control patients had migraine during the preceding year, and during 1 year of treatment, it was 41, a reduction 12.8% (P > 0.5). The decrease of migraine in SIA patients was significantly higher than in controls: 74.5% vs 12.8% (P < 0.001). A history of TTH was given by 33 patients with SIA during the year preceding rupture and by 44 during 1 year after clipping (P > 0.75). Forty one control patients had TTH, 27 after 1 year of treatment, a reduction 34.1% (P < 0.05). No factors except clipping of the aneurysm could explain the remission of migraine. CONCLUSIONS: Migraine prevalence in patients with SIA decreases significantly after clipping. Further comparative studies of migraine after coiling vs clipping in SIA patients are needed. PMID- 25288230 TI - Two-year serum metal ion levels in minimally invasive total conservative hip resurfacing: preliminary results of a prospective study. AB - BACKGROUND: Metal-on-metal (MoM) hip resurfacings have been associated with the potential development of metallic debris and its associated pathology. Serum cobalt and chromium levels are a reliable surrogate marker of wear rates in MoM bearings. The aim of the study was to examine the trend in serum metal ion levels in the initial 2-year post-operative period following implantation of the minimally invasive total conservative hip MoM hip resurfacing and to determine whether head size, acetabular component orientation, clinical outcome scores or post-operative range of movement would affect these levels. METHODS: In this prospective cohort study, serum cobalt and chromium ion levels were measured pre- and post-operatively in 25 patients who underwent minimally invasive total conservative hip MoM hip resurfacing. The results were correlated with acetabular component orientation, head size, outcome scores and post-operative range of movement. RESULTS: The mean serum cobalt and chromium levels at 2 years were 1.2 ppb (0.4-4.4 ppb) and 2.1 ppb (0.7-5.7 ppb). The mean cup inclination was 43 degrees (30 degrees -60 degrees ) and anteversion was 18 degrees (1 degrees -47 degrees ). There was no clear relationship between serum ions and acetabular component orientation, outcome scores or range of movement. Patients with a head size <=52 mm had significantly higher metal ion levels (cobalt P = 0.02, chromium P = 0.045). CONCLUSION: Our preliminary results show all patients had cobalt and chromium levels below those indicating a high-risk implant, suggesting successful early outcome from minimally invasive total conservative hip resurfacing surgery. PMID- 25288231 TI - Expression of regulators of mitotic fidelity are associated with intercellular heterogeneity and chromosomal instability in primary breast cancer. AB - Regulators of transition through mitosis such as SURVIVIN and Aurora kinase A (AURKA) have been previously implicated in the initiation of chromosomal instability (CIN), a driver of intratumour heterogeneity. We investigate the relationship between protein expression of these genes and directly quantified CIN, and their prognostic utility in breast cancer. The expression of SURVIVIN and AURKA was determined by immunohistochemistry in a cohort of 426 patients with primary breast cancer. The association between protein expression and histopathological characteristics, clinical outcome and CIN status, as determined by centromeric FISH and defined by modal centromere deviation, was analysed. Significantly poorer clinical outcome was observed in patients with high AURKA expression levels. Expression of SURVIVIN was elevated in ER-negative relative to ER-positive breast cancer. Both AURKA and SURVIVIN increased expression were significantly associated with breast cancer grade. There was a significant association between increased CIN and both increased AURKA and SURVIVIN expression. AURKA gene amplification was also associated with increased CIN. To our knowledge this is the largest study assessing CIN status in parallel with the expression of the mitotic regulators AURKA and SURVIVIN. These data suggest that elevated expression of AURKA and SURVIVIN, together with AURKA gene amplification, are associated with increased CIN in breast cancer, and may be used as a proxy for CIN in breast cancer samples in the absence of more advanced molecular measurements. PMID- 25288233 TI - GNAS mutation as an alternative mechanism of activation of the Wnt/beta-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type. AB - Gastric adenocarcinoma of the fundic gland type (GAFG) is a rare variant of gastric tumor. We have recently reported the frequent accumulation of beta catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in CTNNB1/AXINs/APC, leading to the constitutive activation of the Wnt/beta-catenin pathway. However, the mechanisms of Wnt signaling activation in the remaining cases are unknown. Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt/beta-catenin pathway or the ERK1/2 MAPK pathway. Therefore, we analyzed the mutations in GNAS (exons 8 and 9) and in KRAS (exon 2) in 26 GAFGs. Immunohistochemistry revealed nuclear beta-catenin expression in 22 of 26 GAFGs, and 10 (38.5%) of 26 cases harbored at least 1 mutation in CTNNB1/AXINs/APC. Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations. Activating mutations in KRAS were found in 2 (7.7%) of 26 GAFGs, and both of these also contained GNAS activating mutations. Four of 5 cases with GNAS mutation showed nuclear beta-catenin expression, and presence of GNAS mutation was associated with beta-catenin nuclear expression (P = .01). Furthermore, 3 of these 4 cases did not harbor mutations in CTNNB1, APC, or AXINs, suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively. These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt/beta catenin signaling pathway. PMID- 25288234 TI - Molecular characterization of a population-based series of endometrial stromal sarcomas in Kuwait. AB - Endometrial stromal sarcomas (ESSs) frequently harbor genetic fusions, including JAZF1-SUZ12 and equivalent fusions in low-grade ESS (LGESS) and YWHAE-NUTM2 in high-grade ESS (HGESS). This study aims to classify a population-based series of ESSs in Kuwait based on the 2014 World Health Organization classification system and to assess the diagnostic use of interferon-induced transmembrane protein 1 (IFITM1) immunomarker for ESSs. Twenty ESSs including 19 LGESSs and 1 HGESS treated during the period between 2002 and 2013 were identified, and the cases were reviewed and characterized using fluorescence in situ hybridization and immunohistochemical studies. Thirteen (81.3%) of 16 LGESSs with interpretable results showed JAZF1 and/or PHF1 genetic rearrangements by fluorescence in situ hybridization, and the only HGESS in the series showed YWHAE genetic rearrangement. All LGESSs with interpretable results showed positive immunostaining for CD10 compared with 11 (61%) of 18 that showed positive immunostaining for IFITM1; 4 of 7 IFITM1-negative LGESSs showed JAZF1 and/or PHF1 rearrangements. A series of uterine leiomyomas, leiomyosarcomas, adenosarcomas, and carcinosarcomas were included for comparison, and positive IFITM1 staining was found in 1 of 10 leiomyomas, 3 of 13 leiomyosarcomas, 3 of 4 adenosarcomas, and 3 of 8 carcinosarcomas, compared to 0 of 10 leiomyomas, 9 of 13 leiomyosarcomas, 3 of 4 adenosarcomas, and 5 of 8 carcinosarcomas that were positive for CD10. Our results demonstrated characteristic genetic rearrangements in a high percentage of LGESSs in this Middle Eastern population, and IFITM1 antibody appears to be less sensitive than CD10 for LGESS. PMID- 25288235 TI - Invasive Paget disease of the breast: 20 years of experience at a single institution. AB - Mammary Paget disease with dermal invasion (invMPD) is rare, and its prognosis remains largely unknown. We reviewed MPD cases diagnosed at our institution and analyzed the clinicopathological characteristics of invMPD and non-invMPD to compare their incidences and outcomes. We retrospectively reviewed 205 cases of women diagnosed as having MPD between 1994 and 2013. Sixteen of 205 MPD cases (7.8%) had dermal invasion. Twelve of 16 invMPD cases had separate, underlying invasive breast carcinoma, and 3 invMPD cases had ductal carcinoma in situ. To exclude the influence of underlying disease on prognosis, we compared prognosis of invMPD with matched non-invMPD. The mean depth and extent of Paget cell invasion in invMPD cases were 0.637 and 1.268 mm, respectively. The horizontal extent of MPD was significantly larger in invMPD versus non-invMPD (mean, 14.31 mm versus 7.35 mm; P = .002). Distant metastasis and disease-related death were observed in 12.6% (24/189) and 12.1% (23/189) of non-invMPD patients, respectively, compared with 6.3% (1/16) and 6.3% (1/16) of invMPD patients; this difference was not significant (P = .7 and P = .7). Clinical outcomes of the invMPD patients were also not significantly different from the matched non-invMPD patients. In this study, MPD extent significantly correlated with MPD invasion. However, other clinicopathological parameters were not associated with dermal MPD invasion. Dermal MPD invasion was rare and did not predict regional lymph node metastasis or poor prognosis. The prognosis is usually similar for invMPD and non invMPD, and MPD must be distinguished from locally advanced breast cancer presenting as satellite skin nodules. PMID- 25288236 TI - Molecular alterations in non-small cell lung carcinomas of the young. AB - Lung cancer is the leading cause of cancer death in the United States. Gene alterations are significant in lung tumorigenesis, with certain genes (Kristen rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], and B-Raf proto-oncogene, serine/threonine kinase (BRAF)) possessing alterations important in the prognosis and treatment of lung adenocarcinoma. Mutation frequencies are affected by different patient factors, such as smoking history, age, and race. Because most lung cancers occur in patients older than age of 50 years, few studies have examined molecular alterations present in these younger patients. The pathology database was searched for patients age of 50 years or younger with non-small cell lung carcinomas (NSCLCs) tested for EGFR, ALK, KRAS, and/or BRAF alterations. A total of 53 cases were identified. The mean patient age was 44.4 years old, and there were 19 men and 34 women. Of the tumors, 11.6% had ALK rearrangements, 25.5% had KRAS mutations, and 20.0% had EGFR mutations. No BRAF mutations were identified in the 28 cases tested. All but 1 (92% [12/13]) tumor with KRAS mutation were from women patients. A smoking history of greater than 5 pack-years was associated with KRAS mutations and negatively associated with EGFR mutations and ALK translocation. The frequencies of EGFR mutation and ALK translocation in the study cohort are greater than the reported frequencies among NSCLC from adults of all ages in the United States but less than the reported frequencies among NSCLC from East Asian young adults. The frequency of KRAS mutation is significantly greater than what was previously found in young Japanese patients. PMID- 25288237 TI - Synchronous adrenocortical neoplasms, paragangliomas, and pheochromocytomas: syndromic considerations regarding an unusual constellation of endocrine tumors. AB - The most common clinical syndromes presenting with paragangliomas and/or pheochromocytomas as their endocrine components are multiple endocrine neoplasia type 2, neurofibromatosis, Von Hippel-Lindau syndrome, Carney-Stratakis syndrome, Carney triad, and the recently described hereditary paraganglioma syndrome. Only Carney triad is known to also present with adrenocortical adenomas, currently representing the only described syndrome in which all 3 of the aforementioned tumors are found together. In most cases, prototypical lesions of the triad such as gastrointestinal stromal tumor and pulmonary chondromas are also seen. We present a case of a young woman with synchronous paragangliomas, adrenal/extra adrenal cortical neoplasms, and pheochromocytoma without genetic mutations for multiple endocrine neoplasia 2, Von Hippel-Lindau syndrome, neurofibromatosis, and succinate dehydrogenase. We speculate that this represents a previously undescribed presentation of Carney triad and, at the very least, indicates the need for monitoring for the development of other tumors of the triad. PMID- 25288238 TI - Sport and ethics. PMID- 25288239 TI - Health needs of regional Australian children in out-of-home care. AB - AIM: This study aims to identify the health needs of children placed in out-of home care in regional Queensland and to compare them with the needs of similar children in metropolitan Queensland. METHODS: Retrospective chart review and subsequent analysis of data from the first assessments of the children placed in care from January 2005 to April 2011. Health needs based on assessment recommendations were then compared with needs and recommendations from a similar clinic in metropolitan Brisbane. RESULTS: Two hundred thirty-nine first assessments were reviewed. The average number of health referrals arising out of each assessment was 2. 72% children were between 2 and 12 years of age and accounted for 76% of the health referrals made. The 10-13% of the children needed referrals for medical and surgical specialties, audiology, speech pathology, dental, and ophthalmology/optometry, each. A percentage of 30 needed ongoing paediatric care. The 15% needed immunisation catch up, 35% counselling and behaviour management, and 15% formal mental health referrals. These were comparable to the health needs identified in out-of-home care children residing in metropolitan Queensland. CONCLUSION: Children in care who live in a regional setting have similar health-care needs compared with urban children. Given restricted health services in regional settings, there is difficulty in accessing services to meet these needs. PMID- 25288244 TI - A glowing 23-week gestation infant: a novel use of a Wee Sight transilluminator. Tension pneumothorax. PMID- 25288245 TI - Chronic fatigue syndrome in adolescents: definition and epidemiological characteristics. PMID- 25288246 TI - Ten-year review of Henoch-Schonlein purpura in Campbelltown Hospital, south western Sydney. PMID- 25288247 TI - Newborn pulse oximetry screening. PMID- 25288248 TI - Echinacea-induced acute liver failure in a child. PMID- 25288250 TI - Hitchhiker's guide to the literature. Journal: Cell. PMID- 25288251 TI - Nutrition and metabolic support recommendations for the bariatric patient. AB - Managing the metabolic needs of the patient with obesity is a challenge unto itself without the added demands of accounting for an altered gastrointestinal tract. Nevertheless, with about 200,000 bariatric procedures being performed annually in the United States, clinicians must be prepared to manage the critically ill bariatric surgery patient. This article reviews the recent literature relating to nutrient needs and metabolic support for the bariatric patient. Bariatric patients are at risk for several micronutrient deficiencies, including vitamins D and B12, calcium, and iron; some bariatric procedures affect macronutrient needs as well. Literature on nutrition support guidelines for the bariatric population is limited. However, with an understanding of the anatomical and physiological effects of bariatric surgery, recent guidelines for critically ill patients with obesity can be applied to the bariatric surgery population. The unique needs of the bariatric population, such as susceptibility to micronutrient deficiencies and specialized access routes, must be considered to provide safe and efficacious nutrition support. Further research is necessary to develop specific nutrition support recommendations for the bariatric population. PMID- 25288252 TI - American society for parenteral and enteral nutrition (a.s.p.e.N.) standards of practice for nutrition support pharmacists. PMID- 25288253 TI - Nutrition and pancreatic enzyme intake in patients with cystic fibrosis with distal intestinal obstruction syndrome. AB - BACKGROUND: The etiology of distal intestinal obstruction syndrome (DIOS) remains unclear. Food intake and pancreatic enzyme replacement therapy (PERT) are often blamed for its occurrence. This study evaluates the nutrition intake and PERT of patients with cystic fibrosis (CF) at a first episode of DIOS. METHODS: All patients with CF perform annually a 3-day intake diary to evaluate their caloric, protein, fat, dietary fiber, liquid, and PERT intake. Patients diagnosed with a first episode of DIOS (n = 12) retrospectively completed an intake diary of the 3 days preceding the DIOS episode supervised by an expert dietitian. RESULTS were compared with those of 1 year before and also with 36 CF controls matched for age, sex, genotype, and disease severity. All were pancreatic insufficient. RESULTS: A first DIOS episode was diagnosed in 12 patients with CF. Only the absolute median fat intake (P = .015) and pancreatic enzyme intake (P = .035) were higher at the time of the DIOS attack in comparison to the preceding year. This could result from the difference in data collection or from the recommendations to increase fat intake and concomitant enzyme intake, since this trend was also found in the control group. The significant difference disappears when enzyme intake is expressed as units of lipase/g of fat. No other significant dietary differences were found. CONCLUSIONS: This study provides no indications for a potential role of nutrition factors or pancreatic enzymes in the first occurrence of DIOS. PMID- 25288255 TI - A randomised study of metformin versus insulin in gestational diabetes: early childhood outcomes. PMID- 25288254 TI - Pseudopheochromocytoma induced by anxiolytic withdrawal. AB - BACKGROUND: Symptomatic paroxysmal hypertension without significantly elevated catecholamine concentrations and with no evidence of an underlying adrenal tumor is known as pseudopheochromocytoma. METHODS: We describe the case of a female patient with paroxysmal hypertensive crises accompanied by headache, vertigo, tachycardia, nausea and altered mental status. Previously, she was treated for a longer period with alprazolam due to panic disorder. Causes of secondary hypertension were excluded. Neurological triggers (intracranial tumor, cerebral vascular lesions, hemorrhage, and epilepsy) could not be detected. RESULTS: Setting of the diagnosis of pseudopheochromocytoma treatment was initiated with alpha- and beta-blockers resulting in reduced frequency of symptoms. Alprazolam was restarted at a daily dose of 1 mg. The patient's clinical condition improved rapidly and the dosage of alpha- and beta-blockers could be decreased. CONCLUSIONS: We conclude that the withdrawal of an anxiolytic therapeutic regimen may generate sympathetic overdrive resulting in life-threatening paroxysmal malignant hypertension and secondary encephalopathy. We emphasize that pseudopheochromocytoma can be diagnosed only after exclusion of the secondary causes of hypertension. We highlight the importance of a psychopharmacological approach to this clinical entity. PMID- 25288256 TI - Biocompatibility of new nanostructural materials based on active silicate systems and hydroxyapatite: in vitro and in vivo study. AB - AIM: To evaluate in vitro cytotoxicity and in vivo inflammatory response to new nanostructural materials based on active calcium silicate systems (CS) and hydroxyapatite (HA-CS). METHODOLOGY: Cytotoxicity of eluates of new nanostructural noncommercial materials CS and HA-CS, and MTA (White MTA, Angelus((r)) Solucoes Odontologicas, Londrina, Brazil) as a control, were tested using the MTT assay on MRC-5 cells. Eluates of set materials were tested in 100% and 50% concentrations, 24 h, 7 days and 21 days post-elution. The pH values were determined for undiluted eluates of set materials. Polyethylene tubes containing the test materials (CS, HA-CS, MTA) were implanted in subcutaneous tissue of Wistar rats. Histopathological examinations were conducted at 7, 15, 30 and 60 days after the implantation. Data were statistically analyzed using three-way and one-way anova Tukey's post hoc test as well as Kruskall-Wallis test with Dunn's post hoc test at alpha = 0.05. RESULTS: All materials significantly reduced cell viability; especially when undiluted eluates were used (P < 0.001). After 24 h elution, cell viability was 10 +/- 1.8%, 49.5 +/- 4.2% and 61 +/- 7.4%, for MTA, and HA-CS, respectively. However, CS and HA-CS were significantly less toxic than the control material MTA (P < 0.05). Cytotoxicity could be at least partially attributed to pH kinetics over time. Dilution of eluates of all tested materials resulted in better cell survival. Histopathological examination indicated similar inflammatory reaction, vascular congestion and connective tissue integrity associated with CS, HA-CS and MTA at each observation period (P > 0.05). The only significant difference was found for capsule thickness, that is thicker capsule was associated with HA-CS compared to MTA at 60 days (P = 0.0039). HA-CS induced moderately thick capsules (median score 3, score range 2-3), whereas MTA resulted in thin capsule formation (median score 2, score range 1-3). CONCLUSIONS: Evaluation of cytotoxicity and inflammatory response indicated better biocompatibility of CS and HA-CS, in comparison with MTA (White MTA, Angelus((r)) Solucoes Odontologicas, Londrina, Brazil). PMID- 25288257 TI - Modeling and simulation for medical product development and evaluation: highlights from the FDA-C-Path-ISOP 2013 workshop. AB - Medical-product development has become increasingly challenging and resource intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA's 2011 Strategic Plan for Regulatory Science [Appendix]. In an effort to support and advance model-informed medical product development (MIMPD), the Critical Path Institute (C-Path) [www.c path.org], FDA, and International Society of Pharmacometrics [www.go-isop.org] co sponsored a workshop in Washington, D.C. on September 26, 2013, to examine integrated approaches to developing and applying model- MIMPD. The workshop brought together an international group of scientists from industry, academia, FDA, and the European Medicines Agency to discuss MIMPD strategies and their applications. A commentary on the proceedings of that workshop is presented here. PMID- 25288258 TI - New molecular insights into cognitive and autistic-like disabilities. PMID- 25288259 TI - [Differential aspects of treatment dropout risk in cocaine dependent patients with and without personality disorders]. AB - The aim of this study was to examine the link between psychosocial adjustment, impulsivity and comorbid Axis II psychopathology, and the risk of treatment dropout in cocaine dependent patients. The sample consisted of 95 cocaine dependent participants, 53.7% of whom had been diagnosed with Axis II personality disorders. We utilised a descriptive methodology, which allowed us to examine correlations between the different variables, group differences in these variables, and their ability to predict different dimensions associated with the risk of dropout. Results show that the risk of dropout during the first two months of treatment is not associated with the existence of comorbid personality disorders. With regard to the cognitive profiles of personality disorders, we show that the antisocial profile is associated with higher risk of dropout. The profile of patients at higher risk of treatment dropout is characterised by lower levels of perceived quality of life and elevated levels of impulsivity, especially the experience of strong impulses under positive affect. Therefore, the presence of psychological dimensions tightly associated with emotions, affects and subjective feelings are the more relevant to estimate the risk of treatment dropout in cocaine dependent patients. This study stresses the variables that need to be specifically addressed during early phases of cocaine addiction treatment, since they are associated with higher risk of treatment dropout. PMID- 25288260 TI - A loop unique to ferredoxin-dependent glutamate synthases is not absolutely essential for ferredoxin-dependent catalytic activity. AB - It had been proposed that a loop, typically containing 26 or 27 amino acids, which is only present in monomeric, ferredoxin-dependent, "plant-type" glutamate synthases and is absent from the catalytic alpha-subunits of both NADPH dependent, heterodimeric glutamate synthases found in non-photosynthetic bacteria and NADH-dependent heterodimeric cyanobacterial glutamate synthases, plays a key role in productive binding of ferredoxin to the plant-type enzymes. Site-directed mutagenesis has been used to delete the entire 27 amino acid-long loop in the ferredoxin-dependent glutamate synthase from the cyanobacterium Synechocystis sp. PCC 6803. The specific activity of the resulting loopless variant of this glutamate synthase, when reduced ferredoxin serves as the electron donor, is actually higher than that of the wild-type enzyme, suggesting that this loop is not absolutely essential for efficient electron transfer from reduced ferredoxin to the enzyme. These results are consistent with the results of an in-silico study that suggests that the loop is unlikely to interact directly with ferredoxin in the energetically most favorable model of a 1:1 complex of ferredoxin with the wild-type enzyme. PMID- 25288261 TI - Impartial institutions, pathogen stress and the expanding social network. AB - Anthropologists have documented substantial cross-society variation in people's willingness to treat strangers with impartial, universal norms versus favoring members of their local community. Researchers have proposed several adaptive accounts for these differences. One variant of the pathogen stress hypothesis predicts that people will be more likely to favor local in-group members when they are under greater infectious disease threat. The material security hypothesis instead proposes that institutions that permit people to meet their basic needs through impartial interactions with strangers reinforce a tendency toward impartiality, whereas people lacking such institutions must rely on local community members to meet their basic needs. Some studies have examined these hypotheses using self-reported preferences, but not with behavioral measures. We conducted behavioral experiments in eight diverse societies that measure individuals' willingness to favor in-group members by ignoring an impartial rule. Consistent with the material security hypothesis, members of societies enjoying better-quality government services and food security show a stronger preference for following an impartial rule over investing in their local in-group. Our data show no support for the pathogen stress hypothesis as applied to favoring in groups and instead suggest that favoring in-group members more closely reflects a general adaptive fit with social institutions that have arisen in each society. PMID- 25288262 TI - Safety and efficacy of 2,790-nm laser resurfacing for chest photoaging. AB - Chest photodamage is a common cosmetic complaint. Laser treatment of the chest may be higher risk than other areas. The objective of this study was to assess the safety and efficacy of 2,790-nm chest resurfacing for photodamage. Twelve patients with Fitzpatrick skin types I-III were enrolled in this university IRB approved study. Photo documentation was obtained at baseline and each visit. A test spot with the 2,790-nm resurfacing laser was performed on the chest. Patients who did not have adverse effects from the test spot went on to have a full chest resurfacing procedure. Patients were instructed on standardized aftercare, including sunscreen. A 5-point healing and photodamage improvement scale was used to rate improvement by both investigators and the patients and was obtained at 2 weeks, 1 month, 2 months, and 3 months. One pass chest treatment with the 2,790-nm resurfacing laser at fluences greater than or equal to 3.0 mJ with 10% overlap leads to unacceptable rates of hyperpigmentation. Double pass chest treatment at fluences less than or equal to 2.5 mJ with 10% overlap leads to mild improvement in chest photodamage parameters without significant or persistent adverse effects. Laser treatment of aging/photodamaged chest skin remains a challenge due to the delicacy of chest skin. Mild improvement may be obtained with double pass resurfacing with the 2,790-nm wavelength. PMID- 25288263 TI - Photodynamic effects of zinc phthalocyanines on intracellular amastigotes of Leishmania amazonensis and Leishmania braziliensis. AB - This study investigated the photoactivity of four zinc phthalocyanines (PcZns) on a murine macrophage cell line infected with Leishmania amazonensis or Leishmania braziliensis. Infected and uninfected cells were incubated with PcZns at different concentrations (1-10 MUM) for 3 h and then exposed to an LED device in continuous wave mode at 660 nm with a fluency of 50 J/cm(2) (25 mV). Enzymatic activity was determined by MTT assay 24 h after light treatment. The results demonstrated that all PcZns exhibited high photoactivity, particularly when used at 10 MUM. The photodynamic effects were different for uninfected cells versus parasite-infected cells and among the four PcZns. Uninfected cells were more sensitive to photoactivity than infected cells. Although PcZns photodynamic therapy provided promising results, further studies are necessary to better understand its mechanism of action in the treatment of leishmaniasis. PMID- 25288264 TI - Efficacy of LED versus KTP laser activation of photodynamic bleaching of tetracycline-stained dentine. AB - In some well-established laser applications where large spot sizes are used, an array of high-intensity light emitting diodes (LED) emitting at similar wavelength could potentially replace the laser. This situation applies for the photodynamic bleaching of stains in teeth. This study compared the relative efficacy of an array of visible green LED (535 nm +/- 15 nm) with a KTP laser in photodynamic bleaching of tetracycline-stained dentine in human tooth roots. After establishing consistent staining in 96 roots using a validated method, the roots were sectioned into 2-3-mm thick horizontal slices that were treated with gels containing rhodamine B (Smartbleach(r) or Smartbleach(r) 3LT). Colour changes were tracked up to 1 month after treatment. While both systems were effective in bleaching the tetracycline-stained dentine, KTP laser activation gave greater bleaching efficacy than LED activation, enhancing the action of the gel. Use of the KTP laser would be preferable over an LED system when confronted with tetracycline staining. Use of this photodynamic bleaching method offers valuable means to reduce the severity of tetracycline staining. PMID- 25288265 TI - Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis. AB - Multiple candidate biomarkers for amyotrophic lateral sclerosis (ALS) have emerged across a range of platforms. Replication of results, however, has been absent in all but a few cases, and the range of control samples has been limited. If progress toward clinical translation is to continue, the specific biomarker needs of ALS, which differ from those of other neurodegenerative disorders, as well as the challenges inherent to longitudinal ALS biomarker cohorts, must be understood. Appropriate application of multimodal approaches, international collaboration, presymptomatic studies, and biomarker integration into future therapeutic trials are among the essential priorities going forward. PMID- 25288266 TI - Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. AB - Serological, molecular and phylogenetic analyses of a recently imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) in Greece are reported. Although MERS-CoV remained detectable in the respiratory tract secretions of the patient until the fourth week of illness, viraemia was last detected 2 days after initiation of triple combination therapy with pegylated interferon, ribavirin and lopinavir/ritonavir, administered from Day 13 of illness. Phylogenetic analysis of the virus showed close similarity with other human MERS-CoVs from the recent Jeddah outbreak in Saudi Arabia. Immunoglobulin G (IgG) titres peaked 3 weeks after the onset of illness, whilst IgM levels remained constantly elevated during the follow-up period (second to fifth week of illness). Serological testing confirmed by virus neutralisation assay detected an additional case that was a close contact of the patient. PMID- 25288267 TI - The hidden curriculum of the medical care for elderly patients in medical education: a qualitative study. AB - Despite more attention being given to geriatrics in medical curricula, few new physicians are seeking training in this field. So far, there has been no exploration of factors in the hidden curriculum that could potentially influence the persisting lack of interest in this field of medicine. To study this hidden curriculum in medical education in relation to medical care of elderly patients, the authors used a qualitative research design including participant observations on two internal medicine wards in a teaching hospital and semistructured interviews. The results showed that elderly patients with multiple problems are seen as frustrating and not interesting. Medical students were not stimulated to go into the totality of medical problems of elderly patients. They picked up a lot of disparaging remarks about these patients. The mainly negative attitudes demonstrated by role models, in particular the residents, may potentially influence the development of future doctors and their choice of career. PMID- 25288268 TI - Accuracy of magnetic resonance in deeply infiltrating endometriosis: a systematic review and meta-analysis. AB - OBJECTIVE: To estimate the accuracy of pelvic magnetic resonance imaging (MRI) in the diagnosis of deeply infiltrating endometriosis (DIE). METHODS: A comprehensive search of the Medline, Pubmed, Lilacs, Scopus, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Biomed Central, and ISI Web of Science databases was conducted from January 1990 to December 2013. The medical subject headings (MeSHs) and text words "deep endometriosis", "deeply infiltrating endometriosis", "DIE", "magnetic resonance", and "MRI" were searched. Studies that compared the parameters of pelvic MRIs with those of paraffin-embedded sections for the diagnosis of DIE were included. RESULTS: Twenty studies were analyzed, which included 1,819 women. Pooled sensitivity and specificity were calculated across eight subgroups: for all sites, these were 0.83 and 0.90, respectively; for the bladder, 0.64 and 0.98, respectively; for the intestine, 0.84 and 0.97, respectively; for the pouch of Douglas, 0.89 and 0.94, respectively; for the rectosigmoid, 0.83 and 0.88, respectively; for the rectovaginal, 0.77 and 0.95, respectively; for the uterosacral ligaments, 0.85 and 0.80, respectively; and for the vagina and the posterior vaginal fornix, 0.82 and 0.82, respectively. CONCLUSION: In summary, pelvic MRI is a useful preoperative test for predicting the diagnosis of multiple sites of deep infiltrating endometriosis. PMID- 25288269 TI - Conservative management of placenta percreta: a stepwise approach. AB - PURPOSE: To describe a modified surgical approach in the form of stepwise cesarean section in placenta percreta. METHODS: We conducted a prospective observational study. A total of 71 patients with placenta percreta were subjected to the new stepwise surgical approach and uterine repair at the time of cesarean delivery. RESULTS: The procedure was successful in controlling the bleeding and preserving the patient's uterus in 65 (91.5%) women. Ten patients (14.1%) had urinary tract complications, nine (90%) were managed during cesarean section and one presented late in the form of vesicouterine fistula. CONCLUSIONS: A stepwise cesarean section is safe and effective procedure that can be applied in placenta percreta. PMID- 25288270 TI - Symbol "&" suture to control atonic postpartum hemorrhage with placenta previa accreta. AB - OBJECTIVE: To evaluate the efficacy and safety of a symbol "&" compression suture technique in controlling severe atonic postpartum hemorrhage with placenta previa accreta during cesarean delivery. METHODS: Nine women with heavy postpartum bleeding from uterine inertia and placenta previa percret, which did not react to conventional initial management protocols, were underwent the suture in the shape of symbol "&" in China Meitan General Hospital. The suture procedure was to staple the anterior and posterior walls (of the lower uterine segment as well as corpus uterus) together using number 1 chromic catgut, with a cross at about 2 cm above the upper boundary of lower uterine segment. RESULTS: Symbol "&" compression suture was capable of stanching the postpartum hemorrhage immediately in all nine women. None of these patients developed complications related to this method. Subsequent pregnancies after the suture were occurred in two women and delivered with repeat cesarean section. CONCLUSION: Symbol "&" compression suture is a simple, safe and highly effective technique to control the treatment resistant uterine atonic bleeding, particularly in previous cesarean scar at lower segment and placenta previa accreta. PMID- 25288271 TI - Idiopathic polyhydramnios and fetal gender. AB - OBJECTIVES: To determine the relationship between idiopathic polyhydramnios and fetal gender in the absence of fetal or maternal abnormalities. METHODS: This was a retrospective population-based register study. 295 women with singleton pregnancies complicated by idiopathic polyhydramnios (amniotic fluid index (AFI) higher than 24 cm) who were delivered at our institution from January 2002 till December 2012 were included. Only pregnancies with an uncomplicated outcome were accepted in this study. The incidence of the male to female fetuses was compared with the one in the general population. RESULTS: Among pregnancies complicated by idiopathic polyhydramnios, the following gender distribution was found: 72.9% male and 37.1% female. The distribution in the general population was 51.5% female and 48.5% male. The mean AFI was significantly increased in male fetuses (p < 0.001). The increased AFI did not correlate with gestation age, fetal head circumference or estimated fetal weight. CONCLUSIONS: Idiopathic polyhydramnios is more frequent in male normal fetuses than in female ones. PMID- 25288272 TI - Report shows causes of maternal deaths in India. PMID- 25288273 TI - Trifluoromethylation of tetraphenylborate counterions in cationic iridium(III) complexes: enhanced electrochemical stabilities, charge-transport abilities, and device performance. AB - Trifluoromethylation of tetraphenlyborate counterions was successfully used to improve the electrochemical stabilities and device performance of cationic iridium(III) complexes. Melioration of the thermal, photoluminescent, electrochemical, and electrophosphorescent characteristics was achieved. Interionic hydrogen bonds were first found between the aromatic hydrogen atoms in the ancillary ligands of cations and the fluorine atoms in the trifluoromethyl groups of the anions. The strong impact of the counterions on the charge transport in the devices was investigated. A compound with two trifluoromethyl groups in the tetraphenlyborate ion shows the highest photoluminescent efficiency, the best electrochemical stability, and the greatest performance in green-blue-emitting devices, with a high current efficiency of 12.4 cd A(-1) and an emission peak at lambda=480 nm. The efficiencies achieved are the highest reported for OLEDs with ionic complexes emitting in the blue-green region. PMID- 25288274 TI - Standard laboratory tests to identify older adults at increased risk of death. AB - BACKGROUND: Older adults are at an increased risk of death, but not all people of the same age have the same risk. Many methods identify frail people (that is, those at increased risk) but these often require time-consuming interactions with health care providers. We evaluated whether standard laboratory tests on their own, or added to a clinical frailty index (FI), could improve identification of older adults at increased risk of death. METHODS: This is a secondary analysis of a prospective cohort study, where community dwelling and institutionalized participants in the Canadian Study of Health and Aging who also volunteered for blood collection (n = 1,013) were followed for up to six years. A standard FI (FI CSHA) was constructed from data obtained during the clinical evaluation and a second, novel FI was constructed from laboratory data plus systolic and diastolic blood pressure measurements (FI-LAB). A combined FI included all items from each index. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves. RESULTS: Of 1,013 participants, 51.3% had died by six years. The mean baseline value of the FI-LAB was 0.27 (standard deviation 0.11; range 0.05 to 0.63), the FI-CSHA was 0.25 (0.11; 0.02 to 0.72), and the combined FI was 0.26 (0.09; 0.06 to 0.59). In an age- and sex-adjusted model, with each increment in the FI-LAB, the hazard ratios increased by 2.8% (95% confidence interval 1.02 to 1.04). The hazard ratios for the FI-CSHA and the combined FI were 1.02 (1.01 to 1.03) and 1.04 (1.03 to 1.05), respectively. The FI-LAB and FI-CSHA remained independently associated with death in the face of the other. The areas under the ROC curves were 0.72 for FI-LAB, 0.73 for FI-CSHA and 0.74 for the combined FI. CONCLUSIONS: An FI based on routine laboratory data can identify older adults at increased risk of death. Additional evaluation of this approach in clinical settings is warranted. PMID- 25288275 TI - A very original case of a mini accessory liver lobe with its own gallbladder. AB - PURPOSE: Anatomic variation of the hepatobiliary system is often related to the biliary tract and vascular supply of the liver. We present here one of the smallest accessory hepatobiliary system. METHODS: The case of a 30-year-old male who was a living liver donor is presented. RESULTS: During the dissection of the portal hilum, 1.5 cm of accessory liver (AL) tissue was noted below the left lobe of the liver. This AL tissue had a gallbladder of 1.5 cm and which had a cystic duct opening to the bile duct of the accessory liver. The AL bile duct opened to the left bile duct of the liver. The arterial and portal supply of the AL came from the left artery and left portal vein of the liver. The accessory gallbladder also had a cystic artery coming from the arterial branch of the AL. It was noted that the hepatic vein of the AL opened directly to left lobe tissue. CONCLUSIONS: The hepatobiliary system has many anatomic variations, but this case is rare and original in the literature in that it may be a cause of confusion and even a false diagnosis. PMID- 25288276 TI - Differential effects of ionic and non-ionic surfactants on lysozyme fibrillation. AB - Fibril formation is a common property of many proteins, though not all are associated with diseases. Protein surface charges and the added co-solvents play vital roles in determining fibrillation pathways and kinetics. In order to understand these phenomena, the effects of anionic, cationic and non-ionic surfactants on lysozyme fibrillation were studied. Lysozyme forms fibrils in 2 M and 4 M urea solutions following nucleation-dependent and nucleation-independent pathways, respectively, at neutral pH. Under these conditions, the effects of sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB), and triton X 100 (Tx) were investigated on the lysozyme structure and fibrillation. The results indicate that there are differential effects of ionic and non-ionic surfactants on fibrillation. In the presence of SDS and CTAB, above their critical micelle concentrations (CMC), lysozyme could not form fibrils. However, non-ionic Tx does not inhibit fibril formation at all concentrations. Note that the time for complete fibril formation is increased by Tx. All of the surfactants are found to increase the initial nucleation phase; however, the extent of increase is less at near the CMC of the ionic surfactants and at above the CMC of Tx. The rates of fibril elongation show varying effects in the presence of different surfactants. The results suggest that the nucleation phase of lysozyme fibrillation is primarily controlled by charge interactions and micellation of the surfactants, but multiple factors might influence the fibril elongation. Furthermore, the surfactants do not alter the fibrillation pathway from nucleation-dependent to nucleation-independent or vice versa in the studied conditions. PMID- 25288277 TI - Review of recent behavioral interventions targeting older adults living with HIV/AIDS. AB - Increasing attention has been paid to older adults living with HIV over the past few years given the increasing prevalence of HIV in this age group. Yet, despite numerous studies documenting psychosocial and behavioral differences between older and younger HIV-infected adults, few evidence-based behavioral interventions have been developed for this population. This review found only 12 manuscripts describing behavioral intervention studies in older HIV-positive adults published between 2011 and 2014, and they reported on a total of six interventions. Despite promising findings, there is a clear need for large-scale clinical trials to replicate these initial results and further develop additional interventions to address important clinical issues such as depression, sexual risk behaviors, cognition, and other significant issues affecting this cohort. This represents an exciting opportunity for behavioral scientists and HIV specialists to develop interventions that combine the psychological and behavioral with medical aspects of the disease. PMID- 25288278 TI - Thermococcus eurythermalis sp. nov., a conditional piezophilic, hyperthermophilic archaeon with a wide temperature range for growth, isolated from an oil-immersed chimney in the Guaymas Basin. AB - A conditional piezophilic, hyperthermophilic archaeon showing growth over a wide range of temperature, pH and pressure was isolated from an oil-immersed hydrothermal chimney at a depth of 2006.9 m in the Guaymas Basin. Enrichment and isolation of strain A501(T) were performed at 80 degrees C at 0.1 MPa. Cells of isolate A501(T) were irregular motile cocci with a polar tuft of flagella and generally 0.6-2.6 um in diameter. Growth was detected over the range 50-100 degrees C (optimal growth at 85 degrees C) at atmospheric pressure and was observed at 102 degrees C at a pressure of 10 MPa. At 85 degrees C, growth was observed at a pressure of 0.1-70 MPa (optimum pressure 0.1 MPa-30 MPa), while at 95 degrees C, the pressure allowing growth ranged from 0.1 MPa to 50 MPa (optimum pressure 10 MPa). Cells of strain A501(T) grew at pH 4-9 (optimum pH 7.0) and a NaCl concentration of 1.0-5.0 % (w/v) (optimum concentration 2.5 % NaCl). This isolate was an anaerobic chemo-organoheterotroph and was able to utilize yeast extract, peptone, tryptone and starch as the single carbon source for growth. Elemental sulfur and cysteine stimulated growth; however, these molecules were not necessary. The DNA G+C content of the complete genome was 53.47 mol%. The results of 16S rRNA gene sequence analysis indicated that strain A501(T) belongs to the genus Thermococcus. There was no significant similarity between strain A501(T) and the phylogenetically related species of the genus Thermococcus based on complete genome sequence alignments and calculation of the average nucleotide identity and the tetranucleotide signature frequency correlation coefficient. These results indicate that strain A501(T) represents a novel species, Thermococcus eurythermalis sp. nov. The type strain is A501(T) ( = CGMCC 7834(T) = JCM 30233(T)). PMID- 25288279 TI - Parasegetibacter terrae sp. nov., isolated from paddy soil and emended description of the genus Parasegetibacter. AB - A Gram-stain-negative, variably shaped, non-flagellated, yellow-pigmented, aerobic bacterium, designated strain SGM2-10(T), was isolated from a paddy soil sample from the Suwon region, South Korea. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate was related most closely to Parasegetibacter luojiensis RHYL-37(T). Strain SGM2-10(T) showed highest 16S rRNA gene sequence similarity to P. luojiensis RHYL-37(T) (95.1 %), Flavitalea populi HY-50R(T) (95.0 %) and Flavitalea gansuensis JCN-23(T) (94.4 %). No other species in the family Chitinophagaceae shared more than 94.1 % 16S rRNA gene sequence similarity with strain SGM2-10(T). The major fatty acids of strain SGM2-10(T) were iso-C15 : 0, iso-C15 : 1 G and iso-C17 : 0 3-OH. The only menaquinone was MK 7. The polar lipids comprised phosphatidylethanolamine, seven unknown lipids and ten unknown aminolipids. The G+C content of the DNA of strain SGM2-10(T) was 46.7 mol%. On the basis of the results of the polyphasic characterization presented in this study, it is concluded that strain SGM2-10(T) represents a novel species of the genus Parasegetibacter, for which the name Parasegetibacter terrae sp. nov. is proposed. The type strain is SGM2-10(T) ( = KACC 17341(T) = JCM 19942(T)). The description of the genus Parasegetibacter has also been emended. PMID- 25288280 TI - Paenibacillus lemnae sp. nov., an endophytic bacterium of duckweed (Lemna aequinoctialis). AB - A Gram-stain-variable, rod-shaped and endospore-forming bacterium, designated strain L7-75, was isolated from duckweed (Lemna aequinoctialis). Cells were motile with a monopolar flagellum. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain L7-75(T) belonged to the genus Paenibacillus, and the closest phylogenetically related species were Paenibacillus uliginis N3/975(T) (98.5% 16S rRNA gene sequence similarity), Paenibacillus purispatii ES_M17(T) (98.5%), Paenibacillus lactis MB 1871(T) (98.2%), Paenibacillus campinasensis 324(T) (97.7%), Paenibacillus glucanolyticus S93(T) (97.7%) and Paenibacillus lautus ATCC 43898(T) (97.4%). Growth of strain L7-75(T) was observed at pH 7-10 and at 20-40 degrees C, and NaCl concentrations up to 5% (w/v) were tolerated. Major cellular fatty acids included anteiso-C15 : 0, C16 : 0 and anteiso-C17:0 that were present at 36.0%, 14.2 % and 10.0% of the total cellular fatty acid profile, respectively. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidyl-N-methylethanolamine. MK-7 was the predominant menaquinone. The diamino acid found in the cell-wall peptidoglycan was meso-diaminopimelic acid. The DNA G+C content was 49.1 mol% (Tm). DNA-DNA relatedness values between strain L7-75(T) and its closest relatives ranged from 4.4 to 47.8%. These results indicate that strain L7-75(T) represents a novel species of the genus Paenibacillus, for which the name Paenibacillus lemnae sp. nov. is proposed. The type strain is L7-75(T) ( = BCC 67838(T) = NBRC 109972(T)). PMID- 25288281 TI - Influence of increasing combustion temperature on the AMS 14C dating of modern crop phytoliths. AB - Several attempts have been made to directly date phytoliths, but most (14)C results are not consistent with other independent chronologies. Due to the limited dataset, there is not a clear explanation for these discrepancies. Herein, we report the (14)C ages of phytolith-occluded carbon (PhytOC) from contemporary rice and millet crops that were combusted at different temperatures to investigate the relationship between the combustion temperature and resulting (14)C age. Our results show that the (14)C age of PhytOC increases directly with combustion temperature (up to 1100 degrees C) and results in age overestimations of hundreds of years. Considerably older ages are observed at higher temperatures, suggesting that it may be possible to distinguish between two fractions of organic carbon in phytoliths: labile and recalcitrant carbon. These findings challenge the assumption that PhytOC is homogeneous, an assumption made by those who have previously attempted to directly date phytoliths using (14)C. PMID- 25288283 TI - Auto-oxidative coupling of glycine derivatives. AB - The unprecedented title reaction between glycine derivatives and indoles, as well as the auto-oxidative Povarov/aromatization tandem reaction of glycine derivatives with olefins are described. The reactions were performed in the absence of redox-active catalysts and chemical oxidants under mild reaction conditions. Only simple organic solvents and air (or O2 ) were required. PMID- 25288282 TI - Quality improvement in practice: improving diabetes care and patient outcomes in Aboriginal Community Controlled Health Services. AB - BACKGROUND: Management of chronic disease, including diabetes, is a central focus of most Aboriginal Community Controlled Health Services (ACCHSs) in Australia. We have previously demonstrated that diabetes monitoring and outcomes can be improved and maintained over a 10-year period at Derby Aboriginal Health Service (DAHS). While continuous quality improvement (CQI) has been shown to improve service delivery rates and clinical outcome measures, the process of interpreting audit results and developing strategies for improvement is less well described. This paper describes the evaluation of care of patients with type 2 diabetes mellitus (T2DM) and features of effective CQI in ACCHSs in the remote Kimberley region of north Western Australia. METHODS: Retrospective audit of records for Aboriginal and Torres Strait Islander primary care patients aged >=15 years with a confirmed diagnosis of T2DM at four Kimberley ACCHSs from 1 July 2011 to 30 June 2012. Interviews with health service staff and focus group discussions with patients post audit. MAIN OUTCOME MEASURES: diabetes care related activities, clinical outcome measures and factors influencing good diabetes related care and effective CQI. RESULTS: A total of 348 patients from the four ACCHSs were included in the study. Clinical care activities were generally high across three of the four health services (at least 71% of patients had cholesterol recorded, 89% blood pressure, 84% HbA1c). Patients from DAHS had lower median cholesterol levels (4.4 mmol/L) and the highest proportion of patients meeting clinical targets for HbA1c (31% v 16% ACCHS-3; P = 0.02). Features that facilitated good care included clearly defined staff roles for diabetes management, support and involvement of Aboriginal Health Workers, efficient recall systems, and well coordinated allied health services. Effective CQI features included seamless and timely data collection, local ownership of the process, openness to admitting deficiencies and willingness to embrace change. CONCLUSIONS: Well-designed health care delivery and CQI systems, with a strong sense of ownership over diabetes management led to increased service delivery rates and improved clinical outcome measures in ACCHSs. Locally run CQI processes may be more responsive to individual health services and more sustainable than externally driven systems. PMID- 25288284 TI - Primary flexor tendon repair and early mobilization. PMID- 25288285 TI - Intra-operative correction of volar tilt of distal radius fractures using volar locking plate as reduction tool: review of 24 cases. AB - In surgical fixation of distal radius fractures with metaphyseal comminution, volar tilt can be restored using an anatomical volar locking plate as a reduction tool. The purpose of our study is to assess the degree of over or under correction of volar tilt that can result with our 'lift' technique and to determine the ratio between theoretical and actual angular correction. We retrospectively reviewed 24 patients who underwent distal radius fracture fixation using this technique and assessed intra-operative radiographs for parameters including pre-'lift' and post-'lift' volar tilt and pre-'lift' plate shaft angles. The ratio between actual angular correction and theoretical angular correction was calculated. The 'lift' technique is found to be reliable in restoring volar tilt in most fractures. Over- or under-correction does occur due to errors in visual estimation and actual angular correction is generally less than the theoretical angular correction. PMID- 25288286 TI - Lytic lesions of distal radius in children: a rare tubercular presentation. AB - INTRODUCTION: We report the presentation, management, and outcome in five children with osteoarticular tuberculosis of distal radius. PATIENTS: PATIENTS were recruited in a prospective study. All patients underwent an open biopsy, curettage and diagnosis confirmed by histopathological/microbiological examination. In cavitary lytic lesions, bone grafting was also undertaken. The multidrug anti-tubercular chemotherapy was given for one year. OBSERVATIONS: Five patients were included in the study. The average follow-up post-completion chemotherapy was 34.8 months. Bony lesions presented as a poorly defined radiolucent lytic area in metaphysis, cavitary lytic lesions with or without sequestrum or spanned the physeal plate. At final follow-up, except for one case, a full pain free range of movements was achieved in all cases. Fibular graft was used in two cases with cavitary lesions and incorporated well in both cases. CONCLUSIONS: Tuberculosis can involve the adjacent physis and can be multifocal. The presentation is usually lytic with minimal sclerosis. For smaller ill defined lesions, curettage and multidrug anti-tubercular chemotherapy results in excellent outcome. Cavitary lytic lesions should be bone grafted as there is a risk of pathological fractures. PMID- 25288287 TI - New technique for reducing fibrosis in recurrent cases of carpal tunnel syndrome. AB - PURPOSE: Synthetic bio-degradable materials have been used as an artificial barrier in prophylaxis of adhesions. We report on the use of lactid caprolacton film (Mesofol) in recurrent carpal tunnel syndrome. We hypothesise that its use will give favourable results regarding the functional outcome and the recurrence rate. PATIENTS AND METHODS: Fourteen patients were prospectively reviewed following neurolysis and application of Mesofol film. Average age was 48 years. Outcome assessment measures included; two-point discrimination, verbal rating scale, and Boston Questionnaire. RESULTS: Follow-up period averaged 25.5 months. Post-operative two-point discrimination improved to an average of 4.57 mm. The post-operative average verbal rating scale was 1.5. The mean symptom severity score improved to 1.88 and the mean functional score improved to 1.69 post operatively. CONCLUSION: In cases of recurrent carpal tunnel syndrome, the use of mesofol barrier yields good functional results at the short term follow-up. The technique is simple. No patients needed further surgeries. PMID- 25288288 TI - Prospective study on the management of trigger finger. AB - Trigger finger is one of the very common conditions encountered in hand surgery. Currently, the treatment modes we offer in our clinics are combination therapy of topical NSAIDS, occupational therapy and splinting or invasive modes involving corticosteroid injections and trigger finger release. This is a prospective review looking at the outcomes of the various initial treatment modules currently used for treating trigger fingers and the rate of surgery following non-surgical treatment. From our study we have noted that 26% of the digits which were subjected to combination therapy eventually underwent surgery whereas 60% of digits which received corticosteroid injections underwent surgery. Even though our results comparing operation rates are not statistically significant, they appear to show that combination therapy was more effective in avoiding surgery than corticosteroid injection in lower grades of trigger. PMID- 25288289 TI - Treatment of chronic mallet fractures using extension-block Kirschner wire. AB - Eleven patients with chronic mallet fractures that were seen later than four weeks after injury were treated by extension-block Kirschner wire technique. The average duration from injury to operative treatment was 56 days (range, 28-111). The follow-up evaluations took place after a mean of eight months. The radiographic bone union was obtained in all patients. The average extension loss of the DIP joint was 4 degree (range, 0-15) and the average flexion was 68 degree (range, 43-90). The results according to Crawford's criteria were six excellent, two good, two fair, and one poor. We would say that the technique we treated is effective method of treatment for younger patients with chronic mallet fractures. PMID- 25288290 TI - Tardy posterior interosseous nerve palsy following total elbow arthroplasty: report of a case, literature review and a classification system. AB - We present an unusual case of tardy posterior interosseous nerve palsy in a female patient following total elbow arthroplasty for rheumatoid arthritis. The patient was neurologically intact immediately following surgery but developed loss of active finger and thumb extension within 12 hours following surgery. Expectant management was adapted. The palsy recovered fully without the need of surgical intervention. A literature review is presented and a classification system proposed. PMID- 25288291 TI - A rare combination: locked volar distal radio-ulnar joint dislocation with isolated volar capsule rupture. AB - Distal Radioulnar Joint (DRUJ) dislocation is a commonly missed injury. A high clinical suspicion is required as the dislocation may not be obvious in the conventional views of radiographs. Volar DRUJ dislocations are far less common than the dorsal ones. Since triangular fibrocartilage complex (TFCC) is the major stabilizer of DRUJ, it is common that the irreducible DRUJ dislocation is associated with TFCC tear. We report a patient who had irreducible volar DRUJ dislocation blocked by the volar lip of sigmoid notch, with only isolated volar capsule rupture. PMID- 25288292 TI - Is Masson's tumour only a slow-growing benign neoplasm? A case report. AB - Masson's tumour is a rare benign neoplasm of vascular origin characterized histologically by papillary endothelial hyperplasia. Unlike previous scientific articles we report a case of a "rapid growing" lesion in a 73-year-old man underlining the clinical features to distinguish this uncommon lesion from other neoplasms of vascular origin. PMID- 25288293 TI - An adjustable Kirchner wire frame traction method for the treatment of dorsal fracture-dislocation of the distal interphalangeal joint. AB - We applied an adjustable traction method which enables early range of motion exercise for the dorsal fracture-dislocation of the distal interphalangeal joint, and obtained satisfactory results. The reduction of comminuted fragments or depression of the joint is unnecessary using the traction method, because early exercise accelerates the remodelling of the injured soft tissue, followed by the development of joint stability. This traction mechanism is independent of the vector force of the traction applied due to the frame-structure construction. Our method makes it easy to adjust the traction force in millimetre increments of the glove-finger length, and has broad range of traction force. In cases where the dislocation is persistent even after strengthening the traction force, a transverse-transfixing Kirschner wire (K-wire) can be inserted to hold the reduction securely against subluxation. PMID- 25288294 TI - Minimally invasive surgery for radial neck fractures using bone paste. AB - We treat radial neck fractures by a minimally invasive technique using bone paste. The indication of this technique is radial neck fractures in which the continuity with the radius shaft is retained. We have treated 13 patients using this technique. As a result, the average range of motion of the elbow was 90 degrees for supination and 92 degrees for pronation, +5 degrees for extension, and 141 degrees for flexion. The reduced position at surgery was kept unchanged until bone union. None of the patients complained of pain. The surgical scar was unnoticeable. This technique is recommended surgery for the radial neck fractures when the indication is appropriate. PMID- 25288295 TI - A systematic review of complications and recurrence rate of arthroscopic resection of volar wrist ganglion. AB - The purpose of this systematic review is to determine the incidence of complications and the recurrence rate of a volar wrist ganglion following arthroscopic resection. We performed a systematic review of English and non English articles using Google Scholar, Medline, and Web of Knowledge. Articles were screened for study inclusion by three independent reviewers using the terms "arthroscopic treatment of volar wrist ganglion" and "arthroscopic resection of volar wrist ganglion". INCLUSION CRITERIA: (1) level I-V evidence, (2) documentation of the number of wrists subjected to surgery, (3) documentation of surgical techniques used on wrists, and (4) documentation of surgical or post surgical complications and recurrence rate of a volar wrist ganglion after arthroscopic resection. A complication was defined as an adverse outcome that was directly related to the operative procedure. Between 2001 and 2012, 13 articles met the inclusion criteria. Two articles were excluded and 11 were reviewed. A total of 232 wrists underwent arthroscopic surgery with 14 recurrences. The recurrence rate ranged from 0 to 20%, with mean of 6.03%. There were 16 (6.89%) complications. There was no connection with the ganglion in six wrists, three haematomas, three cases of neuropraxia of the dorsal radial nerve, two partial lesions of the median nerve, and two lesions of a branch of the radial artery. Patients did not have a decrease in the arc range of motion. Treatment of volar ganglia of the midcarpal joint was technically difficult and associated with a higher number of complications. In general, arthroscopic resection results in fewer complications and lower recurrence rates than an open surgical approach, but there is no clear evidence of such an advantage for arthroscopic resection of a volar wrist ganglion. Additional prospective, controlled clinical trials will be essential to address this important issue. PMID- 25288296 TI - Dupuytren's contracture: emerging insight into a Viking disease. AB - Dupuytren's disease is a fibroproliferative condition of the palm, with a predilection for men, which has affected Northern Europeans since the Viking conquests. Although strongly heritable, clear evidence exists for environmental factors that modify the underlying genetic risk, such as diabetes, heavy drinking, and smoking. Evidence also exists for epilepsy (probably due to treatment with certain anti-epileptic drugs), and Human Immunodeficiency Virus infection. Recent large studies have shown no relationship with manual labour or vibrating tools. Two theories have emerged regarding the pathogenic mechanism: the first attributes the aberrant healing process that characterises Dupuytren's to free radicals, generated as a result of microangiopathy, whereas the second cites a genetic tendency toward apoptosis-resistant myofibroblasts. Despite only one study demonstrating linkage, emerging data from genome-wide association studies highlight a series of single nucleotide polymorphisms near members of the Wnt signalling pathway, and transcriptional profiling studies have consistently identified certain components of the extracellular matrix. PMID- 25288297 TI - Might needless post-operative hand elevation do more harm than good? PMID- 25288300 TI - RORgammat, but not T-bet, overexpression exacerbates an autoimmune model for multiple sclerosis. AB - Th17 cells play an important role in multiple sclerosis (MS) and its autoimmune model, experimental autoimmune encephalomyelitis (EAE). However, studies have not addressed how enhanced Th17 immune responses can affect demyelinating diseases. We induced EAE with MOG in RORgammat transgenic C57BL/6 mice that overexpress a Th17 inducing transcription factor. RORgammat transgenic mice developed more severe EAE than wild-type mice with more robust anti-MOG Th17 immune responses. In contrast, mice overexpressing T-bet, a Th1-inducing transcription factor, were resistant to EAE. Therefore, a genetic bias toward Th17 immune responses could contribute to CNS immunopathology. PMID- 25288301 TI - Effects of ouabain on cytokine/chemokine levels in an animal model of mania. AB - Bipolar disorder (BD) is a chronic and severe psychiatric disorder and despite its importance, little is known about the precise pathophysiology of this disorder. Several studies have reported that inflammation plays a role in the pathogenesis of BD and that cytokines are altered in these patients. Intracerebroventricular (ICV) injection of ouabain (a potent Na(+)/K(+)-ATPase inhibitor) in rats resulted in manic-like effects and it has been widely used as an animal model of bipolar mania. In this study, we assessed the cytokine levels (IL-1beta, IL-6, IL-10, TNF-alpha, CINC-1) in the brain structures (hippocampus, striatum, frontal cortex, amygdala), serum and cerebrospinal fluid (CSF) of rats submitted to an animal model of mania induced by ouabain. Our findings demonstrated that ouabain induced hyperlocomotion in rats. However, the only cytokine that showed alteration was IL-6, which was decreased in the striatum after ouabain administration. In conclusion, despite the ouabain administration in rats be a valid model to study the physiopathology of bipolar mania, it seems that this model was not able to mimic the changes in cytokines observed in bipolar patients. PMID- 25288302 TI - Analysis of polymorphisms in RIG-I-like receptor genes in German multiple sclerosis patients. AB - Variation in genes encoding retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs) has been implicated in the pathogenesis of autoimmune disorders. We investigated if polymorphisms in the IFIH1, RIG-I, LGP2 and VISA genes influence the risk for multiple sclerosis (MS) in a German case-control cohort comprising 716 patients and 706 controls. Evaluation of 18 single nucleotide polymorphisms (SNPs) in the four genes did not reveal significant single-SNP associations with MS risk, but two VISA polymorphisms were modestly associated with age of onset. Further, we provide initial evidence for combinatorial effects of polymorphic variants in the RIG-I, LGP2 and IFIH1 genes on MS risk. PMID- 25288304 TI - No benefit of routine surveillance imaging in Hodgkin lymphoma. PMID- 25288303 TI - Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE. AB - Evidence from experimental autoimmune encephalomyelitis (EAE) suggests that CNS infiltrating dendritic cells (DCs) are crucial for restimulation of coinfiltrating T cells. Here we systematically quantified and visualized the distribution and interaction of CNS DCs and T cells during EAE. We report marked periventricular accumulation of DCs and myelin-specific T cells during EAE disease onset prior to accumulation in the spinal cord, indicating that the choroid plexus-CSF axis is a CNS entry portal. Moreover, despite emphasis on spinal cord inflammation in EAE and in correspondence with MS pathology, inflammatory lesions containing interacting DCs and T cells are present in specific brain regions. PMID- 25288305 TI - Transforaminal vs interlaminar epidural steroid injections: differences in the surgical rates and safety concerns. PMID- 25288306 TI - Brd4 is on the move during inflammation. AB - Enhancer landscapes are shaped by the integrated functions of lineage-specific and signal-dependent transcription factors. A new study by Brown et al. suggests that the signal-dependent transcription factor NF-kB can modulate global enhancer activities by altering the occupancy of Brd4, a BET bromodomain coactivator protein, across the genome. This work reveals new principles of enhancer dynamics and insights into the therapeutic modulation of enhancer function with BET bromodomain inhibitors. PMID- 25288307 TI - Beta2 oscillations (23-30 Hz) in the mouse hippocampus during novel object recognition. AB - The oscillatory activity of hippocampal neuronal networks is believed to play a role in memory acquisition and consolidation. Particular focus has been given to characterising theta (4-12 Hz), gamma (40-100 Hz) and ripple (150-250 Hz) oscillations. Beyond these well-described network states, few studies have investigated hippocampal beta2 (23-30 Hz) activity in vivo and its link to behaviour. A previous sudy showed that the exploration of novel environments may lead to the appearance of beta2 oscillations in the mouse hippocampus. In the present study we characterised hippocampal beta2 oscillations in mice during an object recognition task. We found prominent bursts of beta2 oscillations in the beginning of novel exploration sessions (four new objects), which could be readily observed by spectral analysis and visual inspection of local field potentials. Beta2 modulated hippocampal but not neocortical neurons and its power decreased along the session. We also found increased beta2 power in the beginning of a second exploration session performed 24 h later in a slightly modified environment (two new, two familiar objects), but to a lesser extent than in the first session. However, the increase in beta2 power in the second exploration session became similar to the first session when we pharmacologically impaired object recognition in a new set of experiments performed 1 week later. Our results suggest that hippocampal beta2 activity is associated with a dynamic network state tuned for novelty detection and which may allow new learning to occur. PMID- 25288308 TI - Effect of pre-cardiac and adult stages of Dirofilaria immitis in pulmonary disease of cats: CBC, bronchial lavage cytology, serology, radiographs, CT images, bronchial reactivity, and histopathology. AB - A controlled, blind study was conducted to define the initial inflammatory response and lung damage associated with the death of precardiac stages of Dirofilaria immitis in cats as compared to adult heartworm infections and normal cats. Three groups of six cats each were used: UU: uninfected untreated controls; PreS I: infected with 100 D. immitis L3 by subcutaneous injection and treated topically with selamectin 32 and 2 days pre-infection and once monthly for 8 months); IU: infected with 100 D. immitis L3 and left untreated. Peripheral blood, serum, bronchial lavage, and thoracic radiographic images were collected from all cats on Days 0, 70, 110, 168, and 240. CT images were acquired on Days 0, 110, and 240. Cats were euthanized, and necropsies were conducted on Day 240 to determine the presence of heartworms. Bronchial rings were collected for in vitro reactivity. Lung, heart, brain, kidney, and liver tissues were collected for histopathology. Results were compared for changes within each group. Pearson and Spearman correlations were performed for association between histologic, radiographic, serologic, hematologic and bronchoalveolar lavage (BAL) results. Infected cats treated with selamectin did not develop radiographically evident changes throughout the study, were heartworm antibody negative, and were free of adult heartworms and worm fragments at necropsy. Histologic lung scores and CT analysis were not significantly different between PreS I cats and UU controls. Subtle alveolar myofibrosis was noted in isolated areas of several PreS I cats and an eosinophilic BAL cytology was noted on Days 75 and 120. Bronchial ring reactivity was blunted in IU cats but was normal in PreS I and UU cats. The IU cats became antibody positive, and five cats developed adult heartworms. All cats with heartworms were antigen positive at one time point; but one cat was antibody positive, antigen negative, with viable adult females at necropsy. The CT revealed early involvement of all pulmonary arteries and a random pattern of parenchymal disease with severe lesions immediately adjacent to normal areas. Analysis of CT 3D reconstruction and Hounsfield units demonstrated lung disease consistent with restrictive pulmonary fibrosis with an interstitial infiltrate, absence of air trapping, and decrease in total lung volume in Group IU as compared to Groups UU and PreS I. The clinical implications of this study are that cats pretreated with selamectin 1 month before D. immitis L3 infection did not become serologically positive and did not develop pulmonary arterial hypertrophy and myofibrosis. PMID- 25288309 TI - [A brief history of the anatomy and physiology of a mysterious and hidden gland called the pancreas]. AB - Because of its retrogastric location and appearance, which is similar to mesenteric fat, for centuries the pancreas has been a mysterious, hidden organ that has received little attention. However, its importance was intuited and described by Herophilus, Ruphos of Ephesus and Galen. This gland began to appearin distinct medical treatises from the 16th century. There are two important scientists in the history of the pancreas. The fist, Johann Georg Wirsung, described the main pancreatic duct in 1642, a date considered by many to be the start of Pancreatology. The second, Claude Bernard, described pancreatic exocrine function between 1849 and 1856 and is considered the father of pancreatic physiology. Besides these two outstanding figures, there is a constellation of personalities who contributed to improving knowledge of this enigmatic gland with the results of their studies. The aim of this article is to call attention to some of the most notable findings that have enhanced knowledge of this gland over the years. PMID- 25288310 TI - Differential clinical symptoms among acute phase Indian patients revealed significant association with dengue viral load and serum IFN-gamma level. AB - BACKGROUND: During last three decades, dengue (DF), an arthropod-borne viral disease is increasingly prevalent worldwide including India, resulting in serious public health problems. OBJECTIVE: This study was carried out during 2012-2013 to evaluate the association of WHO-classified dengue disease symptoms with viral load (VL) and serum IFN-gamma levels in dengue patients from India. STUDY DESIGN: Blood samples were collected from dengue symptomatic febrile patients (n=127). DEN-VL was determined by quantitative real-time RT-PCR using RNA, extracted from plasma and anti-DENV-IgM was detected by ELISA. Serum IFN-gamma level was detected by ELISA among DENV infected and age-matched control individuals. Association between DEN-VL and IFN-gamma level in patient's sera with WHO classified disease symptoms was statistically analyzed. RESULTS: DENV RNA and anti-DENV-IgM was detected among 94% (n=73) and 36% (n=28) of dengue infected patients (n=78) respectively. Fever, nausea, rash, aches & pains, leucopenia and persistent vomiting were significantly correlated with DENV infection (P value<0.05). Only patients with high-VL exhibited leucopenia, persistent vomiting, abdominal pain and clinical fluid accumulation, which were warning signs of dengue infection according to revised WHO-criteria (P-value<0.05). Clinical symptoms of DENV infected patients, viz. leucopenia, abdominal pain and persistent vomiting were significantly correlated to each other (P-value<0.05). Increased serum IFN-gamma level was detected among dengue patients compared to control individuals. DEN-VL and symptoms like nausea, leucopenia, persistent vomiting and abdominal pain were significantly negatively correlated with serum IFN-gamma level (P-value<0.05). CONCLUSION: Serum IFN-gamma level and dengue viremia among acute stage patients might be used as early prognostic marker for disease severity prediction. PMID- 25288311 TI - The management of opioid dependence during pregnancy in rural and remote settings. PMID- 25288312 TI - Shale gas development in Canada: what are the potential health effects? PMID- 25288313 TI - 10 health stories that mattered: Sept. 27-Oct. 3. PMID- 25288314 TI - A 42-year-old man with elevated ferritin. PMID- 25288315 TI - The periodic health examination in adults. PMID- 25288317 TI - Physician pushes for improved Ebola care. PMID- 25288318 TI - Ebola research fueled by bioterrorism threat. PMID- 25288319 TI - Provinces press for e-cigarette crackdown. PMID- 25288320 TI - Frustrated expected reward induces differential transcriptional changes in the mouse brain. AB - Frustration represents a particular aspect of the addictive process that is related to loss of control when the expected reward is not obtained. We aim to study the consequences of frustrated expected reward on gene expression in the mouse brain. For this purpose, we used an operant model of frustration using palatable food as reward combined with microarrays. Transcriptomic profiles of frontal cortex, ventral striatum and hippocampus were analysed in five groups of mice: (1) positive control receiving palatable food and the cue light as conditioned stimulus; (2) frustrated group only receiving the cue light; (3) extinction learning group that did not receive palatable food nor the light; (4) negative control that never received the reinforcer nor the light during the whole experiment; and (5) yoked that received palatable food passively. Gene expression changes produced by frustration were revealed in the frontal cortex and ventral striatum, but not in the hippocampus. Most of the changes, such as the modification of the dopamine-DARPP-32 signalling pathway, were common in both areas and estimated to have neuronal origin. Extinction learning induced transcriptional changes only in the ventral striatum, with most genes showing down-regulation and without alteration in the dopamine-DARPP-32 signalling pathway. Active palatable food-seeking behaviour induced changes in gene expression in ventral striatum mainly affecting cell communication. In conclusion, frustration behaviour-induced changes in frontal cortex and ventral striatum mainly related to dopamine-DARPP-32 signalling that could play an important role in the loss of behavioural control during the addictive processes. PMID- 25288321 TI - Statins: do they have a potential role in cancer prevention and modifying cancer related outcomes? AB - 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are currently among the most commonly prescribed pharmaceutical agents worldwide. Apart from their well-established therapeutic value in cardiovascular disease, there is a long-standing debate on their potential association with cancer. To obtain and discuss the existing clinical evidence, an overview of meta-analysis articles addressing this issue was carried out. As of today, the accumulated evidence does not support the hypothesis that statins affect the risk of developing cancer, when they are taken at low doses for managing hypercholesterolaemia. However, current data cannot exclude an increased cancer risk in elderly patients associated with hydrophilic statin use, or decreases in the risks of certain cancers, such as gastric, oesophageal, liver, colorectal and advanced/aggressive prostate cancer. On the other hand, some recent observational studies have provided evidence that statins might be useful in modifying the prognosis of patients diagnosed with malignancy. Until a definitive benefit is demonstrated in randomized controlled trials, statins cannot be recommended either for cancer prevention or for modifying cancer-related outcomes. Further research is warranted to clarify the potential role(s) of statins in the prevention and treatment of cancer. PMID- 25288323 TI - In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila. AB - Mutations of VPS35, a component of the retromer complex have been associated with late onset familial Parkinson's disease. The D620N mutation in VPS35 appears to be most prevalent, however, P316S was found in two cases within the same family and a control, whereas L774M was identified in 6 cases and 1 control. In vivo evidence of their pathogenicity is lacking. Here we investigated the in vivo effects of P316S, D620N and L774M using Drosophila as a model. We generated transgenic human VPS35-expressing mutations and demonstrated that VPS35 D620N transgenic flies led to late-onset loss of TH-positive DA neurons, poor mobility, shortened lifespans and increased sensitivity to rotenone, a PD-linked environmental toxin, with some of these phenotypes observed for P316S but not in L774M transgenic flies. We conclude that D620N and to a smaller extent P316S are associated with pathogenicity in PD. PMID- 25288325 TI - Effects of 4 month exercise on left ventricular remodeling and autonomic nervous system in hypertensive patients. AB - BACKGROUND: We sought to investigate effects of supervised exercise training on left ventricular remodeling, left ventricular function and autonomic nervous system of hypertensive patients without medication. METHODS: Fifty borderline and mildly hypertensive patients were enrolled and randomly divided into 2 groups (25 in each). Exercise group received a 4 months' exercise program, prescribed according to their first cardiopulmonary exercise tests, while the control group received routine dietary recommendation. All patients underwent noradrenalin assay, cardiopulmonary exercise tests and echocardiographic studies at enrollment and 4 month follow-up. RESULTS: At baseline no statistically difference between the two groups were observed in clinical characteristics, echographic variants or cardiopulmonary test index. Four months later, exercise group showed higher values of VO2peak, Powermax (max workload), AT (anaerobic threshold), VO2AT (VO2 at anaerobic threshold), tAT (time from beginning to anaerobic threshold) and heart rate recovery compared to the control group (P<0.05). Additionally, systolic/diastolic blood pressure decreased significantly in the exercise group compared to the control group (P<0.05). Moreover, there was significant reduction in left ventricular mass index in the exercise group (P<0.01), and there was also an inverse correlation between changes in left ventricular mass index and heart rate recovery (r=-0.52, P<0.01). CONCLUSIONS: Four-month exercise training in borderline and mildly hypertensive patients not only decreased their blood pressure levels, but also induced an improvement of exercise capability, left ventricular remodeling and heart rate recovery. Heart rate recovery improvement was significantly associated with decrease of left ventricular mass index, which indicated that favorable adjustment in autonomic nervous system of exercise training might be an important pathway to reverse left ventricular remodeling. PMID- 25288326 TI - Hormone replacement therapy: consensus and controversies. AB - While the use of menopausal hormone therapy [MHT] when initiated in women younger than 60 years is generally considered to have a good safety profile and to be associated with important treatment and prevention benefits, the length of therapy and the long-term risk benefit profile remains highly controversial. PMID- 25288324 TI - ERbeta1: characterization, prognosis, and evaluation of treatment strategies in ERalpha-positive and -negative breast cancer. AB - BACKGROUND: The role and clinical value of ERbeta1 expression is controversial and recent data demonstrates that many ERbeta antibodies are insensitive and/or non-specific. Therefore, we sought to comprehensively characterize ERbeta1 expression across all sub-types of breast cancer using a validated antibody and determine the roles of this receptor in mediating response to multiple forms of endocrine therapy both in the presence and absence of ERalpha expression. METHODS: Nuclear and cytoplasmic expression patterns of ERbeta1 were analyzed in three patient cohorts, including a retrospective analysis of a prospective adjuvant tamoxifen study and a triple negative breast cancer cohort. To investigate the utility of therapeutically targeting ERbeta1, we generated multiple ERbeta1 expressing cell model systems and determined their proliferative responses following anti-estrogenic or ERbeta-specific agonist exposure. RESULTS: Nuclear ERbeta1 was shown to be expressed across all major sub-types of breast cancer, including 25% of triple negative breast cancers and 33% of ER-positive tumors, and was associated with significantly improved outcomes in ERalpha positive tamoxifen-treated patients. In agreement with these observations, ERbeta1 expression sensitized ERalpha-positive breast cancer cells to the anti cancer effects of selective estrogen receptor modulators (SERMs). However, in the absence of ERalpha expression, ERbeta-specific agonists potently inhibited cell proliferation rates while anti-estrogenic therapies were ineffective. CONCLUSIONS: Using a validated antibody, we have confirmed that nuclear ERbeta1 expression is commonly present in breast cancer and is prognostic in tamoxifen treated patients. Using multiple breast cancer cell lines, ERbeta appears to be a novel therapeutic target. However, the efficacy of SERMs and ERbeta-specific agonists differ as a function of ERalpha expression. PMID- 25288328 TI - Laboratory diagnosis of Lyme neuroborreliosis is influenced by the test used: comparison of two ELISAs, immunoblot and CXCL13 testing. AB - PURPOSE: To compare Borrelia-specific intrathecal antibodies by two different ELISAs, an immunoblot (IB) and CXCL13. METHODS: Twenty-seven adults and 23 children with clinical symptoms compatible with NB were tested for Borrelia specific intrathecal antibodies by flagellum ELISA-AI (flELISA), a recombinant ELISA-AI (rELISA) and by IB. Patients were classified according to the European Federation of Neurological Societies (EFNS) criteria as definite NB, possible NB, or non-NB. CSF CXCL13 levels were measured by ELISA. RESULTS: Among 50 patients, definite NB was diagnosed with the rELISA-AI in 29 (58%) patients, confirmed by IB in 19/29 patients, with flELISA-AI in 17 (34%) patients, confirmed by IB in 15/17 patients, and with IB in 20 (40%) patients. CXCL13 was positive in 22 (44%) patients. In 4 of 8 patients with negative AI, IB showed many detectable bands both in the CSF and serum. CONCLUSIONS: The diagnosis of NB strongly relies on the used test method. The rELISA-AI test appears to be the most sensitive while the flELISA-AI is the least sensitive. However when the ELISA-AIs were confirmed by IB, different patients were identified as NB, while only 26% were identified by all performed test methods. There is a demand for standardized test methods with well-defined sensitivity and specificity to establish validated diagnostic criteria for NB including the use of the IB assay and CXCL13 as an additional non Borrelia specific determinant in early NB. PMID- 25288329 TI - Exposure via sequential release of the metatarsophalangeal joint for plantar plate repair through a dorsal approach without an intraarticular osteotomy. AB - BACKGROUND: Traditionally, plantar plate repairs have been performed from either a direct plantar approach or through a dorsal approach utilizing an intraarticular metatarsal osteotomy. It is unknown if a plantar plate repair can be reliably performed through a dorsal approach without an osteotomy. METHODS: The second through fourth metatarsal phalangeal (MTP) joints of 4 fresh frozen cadavers were sequentially dissected and the exposure of the plantar plate was quantified with a digital micrometer. A suture passer was then utilized to pass a suture through the released plantar plate without a metatarsal osteotomy. RESULTS: The mean plantar plate exposure after capsulotomy was 1.1 mm, after capsulotomy and release of the collateral ligaments exposure was 2.5 mm, after the addition of a release of plantar structures with a McGlamry elevator exposure was 4.1 mm, and after the addition of a plantar plate takedown the exposure was 5.3 mm. Every specimen had a minimum of 4 mm of exposure. Two sutures were successfully passed through every plantar plate with the exposure obtained. CONCLUSION: Significant improvement in exposure of the plantar plate was achieved with each successive structure released . CLINICAL RELEVANCE: Successful plantar plate repair can be reliably performed through a dorsal approach without a metatarsal osteotomy in a cadaveric model. PMID- 25288330 TI - Natural history of nonoperatively treated osteochondral lesions of the talus. AB - BACKGROUND: We hypothesized that patients undergoing nonoperative treatment for asymptomatic or minimally symptomatic osteochondral lesions of the talus (OLTs) would not deteriorate clinically or radiologically over time. METHODS: Forty eight patients (mean age = 48 years; range, 13-78 years) with an OLT confirmed by magnetic resonance imaging (MRI) who had not undergone ankle joint surgery were retrospectively reviewed. All patients were evaluated after a minimum follow-up of 2 years (mean = 52 months; range, 27-124 months). All patients filled out an individual questionnaire and underwent a physical and radiographic assessment (radiograph and hindfoot MRI). RESULTS: At final follow-up, 43 ankles (86%) in 41 patients were pain-free (visual analogue scale [VAS] 0, n = 12) or less painful (VAS 1-3, n = 31). Radiographically, osteoarthritis was absent in 47%, and grade 1 and 2 osteoarthritis each were found in 27% (van Dijk classification). Magnetic resonance imaging revealed no substantial progression in staging or lesion size. Pain at time of follow-up correlated with the depth of the lesion at initial MRI (P < .05) and with subchondral cyst formation and presence or change of bone marrow edema at follow-up MRI (P < .05). CONCLUSION: Minimally symptomatic OLTs did not appear to progress or worsen over time when treated nonoperatively. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25288327 TI - A clinical research integration special program (CRISP) for young women with primary ovarian insufficiency. AB - Large-scale medical sequencing provides a focal point around which to reorganize health care and health care research. Mobile health (mHealth) is also currently undergoing explosive growth and could be another innovation that will change the face of future health care. We are employing primary ovarian insufficiency (POI) as a model rare condition to explore the intersection of these potentials. As both sequencing capabilities and our ability to intepret this information improve, sequencing for medical purposes will play an increasing role in health care beyond basic research: it will help guide the delivery of care to patients. POI is a serious chronic disorder and syndrome characterized by hypergonadotrophic hypogonadism before the age of 40 years and most commonly presents with amenorrhea. It may have adverse health effects that become fully evident years after the initial diagnosis. The condition is most commonly viewed as one of infertility, however, it may also be associated with adverse long-term outcomes related to inadequate bone mineral density, increased risk of cardiovascular disease, adrenal insufficiency, hypothyroidism and, if pregnancy ensues, having a child with Fragile X Syndrome. There may also be adverse outcomes related to increased rates of anxiety and depression. POI is also a rare disease, and accordingly, presents special challenges. Too often advances in research are not effectively integrated into community care at the point of service for those with rare diseases. There is a need to connect community health providers in real time with investigators who have the requisite knowledge and expertise to help manage the rare disease and to conduct ongoing research. Here we review the pathophysiology and management of POI and propose the development of an international Clinical Research Integration Special Program (CRISP) for the condition. PMID- 25288331 TI - Postoperative pain and preemptive local anesthetic infiltration in hallux valgus surgery. AB - BACKGROUND: Several techniques of anesthesia are used in foot surgery. Preemptive analgesia helps to prevent the development of hypersensitivity in the perioperative period. The aim of our study was to assess the role of preemptive local anesthetic infiltration and postoperative pain after hallux valgus surgery. METHODS: We evaluated 118 patients who underwent modified chevron and mini invasive Mitchell-Kramer bunionectomy of the first distal metatarsal. After spinal anesthesia each patient randomly received an infiltration of local anesthetic or the same amount of normal saline 10 minutes before the skin incision. We measured the intensity of pain 4, 8, 12, 16, 24, and 72 hours after the release of the tourniquet using a visual analogue scale (VAS). Rescue analgesia and all other side effects were noted. RESULTS: Preemptive analgesia resulted in less pain during the first 24 hours after surgery. The decrease of VAS score was significantly lower in the study group during all the short postoperative periods measured. The rescue analgesia was administered in 11.9% of patients in the injected group and 42.4% in the placebo group (P < .05). In the injected group we did not observe significant difference in VAS score between patients post-chevron and miniinvasive Mitchell-Kramer osteotomy of the first distal metatarsal. No systemic adverse effects were noted. One persistent injury of dorsomedial cutaneous nerve was observed. CONCLUSION: Preemptive local anesthetic infiltration was an efficient and safe method to reduce postoperative pain after hallux valgus surgery. The analgesic effect was satisfactory in both traditional and minimally invasive techniques. PMID- 25288332 TI - Dorsal wedge phalangeal osteotomy for grade II-III hallux rigidus in active adult patients. AB - BACKGROUND: The purpose of this study was to evaluate prospectively the results of the dorsal wedge phalangeal osteotomy for treating moderate hallux rigidus. METHODS: The prospective study included 42 consecutive feet in 40 active patients, with an average age of 55.1 (range, 41-65) years. Clinical evaluation included American Orthopaedic Foot and Ankle Society (AOFAS) score, pain visual analog scale, range of motion, and subjective patient satisfaction. Radiographic evaluation was performed, including linear and angular measurements. The average follow-up was 2.7 (range, 2-3.8) years. RESULTS: The preoperative and postoperative mean AOFAS scores were 51.7 and 88.8, respectively (P = .001), and for pain VAS were 7.6 and 1.9, respectively (P = .001). Good and excellent results at final follow-up were seen in 34 feet. All patients returned to their previous activities. Satisfaction with surgery was good or excellent in 39 patients. The average passive metatarsophalangeal (MTP) dorsiflexion improved from 20.3 to 55.7 degrees (P = .001). The average MTP joint space improved from 2.2 to 2.3 degrees (P = .001). The radiographic measurements were unchanged, except anatomic angles related to phalangeal dorsiflexion. The average width of the bone wedge was 3.5 (range, 2.2-5.0) mm, and significant correlation was found with final AOFAS score (P = .006) and pain VAS (P = .001). There were 2 revisions for screw irritation. CONCLUSION: Phalangeal osteotomy was a reliable and reproducible treatment for moderate hallux rigidus in active patients, with substantial improvement in AOFAS score and MTP dorsiflexion and decreased pain. LEVEL OF EVIDENCE: Level IV, prospective case series. PMID- 25288333 TI - Intraoperative and perioperative complications during revision arthroplasty for salvage of a failed total ankle arthroplasty. AB - BACKGROUND: Revision of a failed total ankle arthroplasty (TAA) remains a challenge. Advances in total ankle implant design have renewed interest in revision TAA as an alternative to ankle arthrodesis or amputation in the management of a failed TAA. The purpose of our study was to review a series of failed Agility TAA revised to INBONE II TAA and identify reasons for revision as well as perioperative complications. METHODS: A retrospective review of 35 cases of failed Agility TAA revised to an INBONE II TAA was performed at 1 institution. Patient demographics, indications for revision, radiographs, and complications were reviewed. The average follow-up was 9.1 months (range, 0-28 months). All revisions were performed by 1 of 2 foot and ankle surgeons familiar with both prostheses. RESULTS: The Agility TAA lasted a mean of 6.7 years prior to revision to an INBONE II TAA. Revision TAA was indicated due to mechanical loosening, osteolysis, periprosthetic fracture, and a dislocated prosthesis. Adjunctive procedures were performed in 31 of 35 cases. There were 6 intraoperative and 5 acute postoperative complications, leading to an overall 31.4% complication rate. There was 1 patient with continued pain postoperatively who underwent a second revision of the INBONE II 20 months postoperatively. CONCLUSION: Revision TAA was a viable treatment option for failed TAA. A high risk of perioperative complications remains, and physicians should be aware of the challenges that occur during these procedures in order to plan for them preoperatively. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25288335 TI - Art and science a unique world. PMID- 25288336 TI - Changes in patellofemoral alignment do not cause clinical impact after open-wedge high tibial osteotomy. AB - PURPOSE: The objectives of this study were (1) to evaluate the clinical and radiologic outcomes of open-wedge high tibial osteotomy focusing on patellofemoral alignment and (2) to search for correlation between variables and patellofemoral malalignment. METHODS: A total of 46 knees (46 patients) from 32 females and 14 males who underwent open-wedge high tibial osteotomy were included in this retrospective case series. Outcomes were evaluated using clinical scales and radiologic parameters at the last follow-up. Pre-operative and final follow up values were compared for the outcome analysis. For the focused analysis of the patellofemoral joint, correlation analyses between patellofemoral variables and pre- and post-operative weight-bearing line (WBL), clinical score, posterior slope, Blackburn Peel ratio, lateral patellar tilt, lateral patellar shift, and congruence angle were performed. RESULTS: The minimum follow-up period was 2 years and median follow-up period was 44 months (range 24-88 months). The percentage of weight-bearing line was shifted from 17.2 +/- 11.1 to 56.7 +/- 12.7%, and it was statistically significant (p < 0.01). Regarding the clinical results, statistical significance was observed using all scores (p < 0.01). In the radiologic evaluation, patellar descent was observed with statistical significance (p < 0.01). Last follow-up lateral patellar tilt was decreased with statistical significance (p < 0.01). In correlation analysis between variables of patellofemoral malalignment, the pre-operative weight-bearing line showed an association with the change in lateral patellar tilt and lateral patellar shift (correlation coefficient: 0.3). CONCLUSION: After open-wedge high tibial osteotomy, clinical results showed improvement, compared to pre-operative values. The patellar tilt and lateral patellar shift were not changed; however, descent of the patella was observed. Therefore, mild patellofemoral problems should not be a contraindication of the open-wedge high tibial osteotomy. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 25288334 TI - let-7b/g silencing activates AKT signaling to promote gastric carcinogenesis. AB - BACKGROUND: Aberrant AKT activation contributes to gastric cancer cell survival and chemotherapy resistance, however its regulation is poorly understood. microRNAs have been established to be important regulators in gastric carcinogenesis. Here, we showed the functional role and putative target of let-7b and let-7g (let-7b/g) in gastric carcinogenesis. METHODS: The expression of let 7b/g in gastric cancer cell lines and primary tumors were evaluated by miRNA qRT PCR. The putative target gene of let-7b/g was explored by TargetScan followed by further validation. Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches. RESULTS: let-7b/g was found down regulated in gastric cancer and its downregulation was associated with poor survival and correlated with lymph node metastasis. let-7b/g inhibited AKT2 expression by directly binding to its 3'UTR, reduced p-AKT (S473) activation and suppressed expression of the downstream effector pS6. AKT2 mRNA expression showed negative correlation with the expression of let-7b/g in primary tumors. Short interfering RNA (siRNA) mediated knockdown of AKT2 phenocopied the tumor suppressive effects of let-7b/g. Moreover, AKT2 re-expression partly abrogated the growth-inhibitory effect of let-7b/g. CONCLUSION: In conclusion, our findings reveal decreased let-7b/g contributes to aberrant AKT activation in gastric tumorigenesis and provide a potential therapeutic strategy for gastric cancer. PMID- 25288337 TI - Magnetic resonance angiography evaluation of the bone tunnel and graft following ACL reconstruction with a hamstring tendon autograft. AB - PURPOSE: In this study, magnetic resonance angiography (MRA) was performed in the early phase after anterior cruciate ligament (ACL) reconstruction to analyse the changes in nutrient blood vessels and blood flow to the femoral and tibial tunnels and the intraosseous tendon grafts. METHODS: The subjects were 30 patients who underwent single-bundle ACL reconstruction with an autogenous hamstring tendon. MRA was performed at 2, 3, and 6 months postoperatively (n = 10 at each time point). The mean overall signal-to-noise ratios (SNRs) in the tunnel regions and in the region of the tendon graft were compared in each femur and tibia. RESULTS: Blood vessels from arteries reached the femoral and tibial tunnels 2 months postoperatively. The tunnel walls showed high signal intensity, while the intraosseous tendon grafts had lower intensity. SNRs showed significant differences between the femoral and tibial tunnels overall and the intraosseous tendon grafts. At 3 and 6 months postoperatively, the signal intensity of the tunnel walls was decreased significantly, while that of the intraosseous tendon grafts was also decreased, but not significantly. At these times, the SNRs of the femoral and tibial tunnels did not differ significantly, both overall and in the region of the intraosseous tendon grafts. CONCLUSION: Revascularization around the femoral and tibial tunnels occurred at 2 months postoperatively, with blood flow subsequently decreasing over time until 6 months. This revascularization may be involved in bone tendon healing and maturation of the tendon graft within the bone tunnels. Evaluations of revascularization by MRA may show the maturation stage of the graft and guide medical rehabilitation. LEVEL OF EVIDENCE: IV. PMID- 25288338 TI - The pie-crusting technique using a blade knife for medial collateral ligament release is unreliable in varus total knee arthroplasty. AB - PURPOSE: Despite the documented clinical efficacy of the pie-crusting technique for medial collateral ligament (MCL) release in varus total knee arthroplasty, its quantitative effects on medial gaps and safety remain unclear. This study was undertaken to determine the efficacy (quantitative effect and consistency of the number of punctures) and the safety (frequency of early over-release) of the pie crusting technique for MCL release. METHODS: From ten pairs of cadaveric knees, one knee from each pair was randomly assigned to undergo pie crusting in extension (group E) or in flexion (group F). Pie crusting was performed in the superficial MCL using a blade until over-release occurred. After every puncture, the incremental medial gap increase was recorded, and the number of punctures required for 2- or 4-mm gap increases was assessed. RESULTS: In group E, the extension gap increased from 0.8 to 5.0 mm and the flexion gap increased from 0.8 to 3.0 mm. In group F, the extension gap increased from 1.0 to 3.0 mm and the flexion gap increased from 2.6 to 6.0 mm. However, the gap increments were inconsistent with those that followed the preceding blade punctures, and the number of punctures required to increase the gaps by 2 or 4 mm was variable. The number of punctures leading to over-release in group E and group F was 6 +/- 1 and 3 +/- 1 punctures, respectively. Overall, 70% of over-release occurred earlier than the average number of punctures leading to over-release. CONCLUSIONS: Pie crusting led to unpredictable gap increments and to frequent early over-release. Surgeons should decide carefully before using the pie crusting technique for MCL release and should be cautious of performing throughout the procedure, especially when performing in a flexed knee. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 25288339 TI - Tunnel collision during simultaneous anterior cruciate ligament and posterolateral corner reconstruction. AB - PURPOSE: To verify the safest angle to drill femoral tunnels in simultaneous anterior cruciate ligament (ACL) and posterolateral corner (PLC) reconstructions to minimize the risk of tunnel collision and to examine the relationship between lateral femoral condyle (LFC) width and tunnel collision occurrence. METHODS: Ten fresh-frozen cadaveric knees were used. In each knee, anatomical single-bundle ACL femoral tunnels were arthroscopically drilled at 120 and 140 degrees of flexion, and tunnels for popliteus tendon (PLT) and fibular collateral ligament (FCL) were drilled at 20 degrees axial/20 degrees coronal angulations and 10 degrees axial/30 degrees coronal angulations. Three-dimensional computed tomography exams of the knees were performed. The presence of tunnel collision was evaluated, and the minimal distance between tunnels and the LFC width was measured. RESULTS: Risk of tunnel collision was significantly increased if FCL and PLT tunnels were drilled at 10 degrees axial/30 degrees coronal angulation (P < 0.05). Tunnel collision was noted in only one knee when FCL and PLT tunnels were drilled at 20 degrees axial/20 degrees coronal angulations. Knees with smaller LFC width had significantly higher risk for tunnel collision (P < 0.05). CONCLUSION: Drilling PLT and FCL femoral tunnels at 20 degrees axial/20 degrees coronal angulation is a safe positioning for simultaneous ACL and PLC reconstructions. However, in smaller knees, the risk for tunnel collision could be greater. Surgeons should consider the possibility of tunnel collision when performing simultaneous ACL and PLC anatomical reconstruction, especially in knees with a small LFC width where the risk for tunnel collision could be greater. PMID- 25288341 TI - Implementation of external cephalic version in the Netherlands: a retrospective cohort study. AB - BACKGROUND: External cephalic version (ECV) reduces the rate of elective cesarean sections as a result of breech presentation. Several studies have shown that not all eligible women undergo an ECV attempt. The aim of this study was to evaluate the implementation of ECV in the Netherlands and to explain variation in implementation rates with hospital characteristics and individual factors. METHODS: We invited 40 hospitals to participate in this retrospective cohort study. We reviewed hospital charts for all singleton breech deliveries from 36 weeks' gestation and onwards between January 2008 and December 2009. We documented whether an ECV attempt was performed, reasons for not performing an attempt, mode of delivery, and hospital characteristics. RESULTS: We included 4,770 women from 36 hospitals. ECV was performed in 2,443 women (62.2% of eligible women, range 8.2-83.6% in different hospitals). Implementation rates were higher in teaching hospitals, hospitals with special office hours for ECV, larger obstetric units, and hospitals located in larger cities. Suboptimal implementation was mainly caused by health care providers who did not offer ECV. CONCLUSION: ECV implementation rates vary widely among hospitals. Suboptimal implementation is mostly caused by the care provider not offering the treatment and secondly due to women not opting for the offered attempt. A prerequisite for designing a proper implementation strategy is a detailed understanding of the exact reasons for not offering and not opting for ECV. PMID- 25288340 TI - Which analgesic mixture is appropriate for periarticular injection after total knee arthroplasty? Prospective, randomized, double-blind study. AB - PURPOSE: Although the analgesic effect of periarticular injection after total knee arthroplasty (TKA) has been well documented, the gold standard for drug combination has not yet been established. In this study, the analgesic effects of six different drug combinations were compared. METHODS: A total of 256 patients undergoing TKA for primary osteoarthritis were randomized into one of six groups: a control group (saline solution, epinephrine, and cefazolin, n = 42), Group 1 (ropivacaine, n = 43), Group 2 (ropivacaine + morphine, n = 43), Group 3 (ropivacaine + ketorolac, n = 42), Group 4 (ropivacaine + morphine + ketorolac, n = 43), and Group 5 (ropivacaine + morphine + ketorolac + methylprednisolone, n = 43). Pain level assessed by visual analogue scale (VAS) and opioid consumption were primary outcomes. The incidence of complications, range of motion (ROM), C reactive protein (CRP) value, and the amount of post-operative blood drainage were also compared. RESULTS: Patients in Groups 4 and 5 complained less pain than the control group for the first 12 h after surgery, and the patients in the other groups showed less pain only during the initial 6 h after surgery. Groups 4 and 5 also showed less opioid consumption than the control group during the 24 h period after surgery. Patients in Group 5 showed no significant difference in VAS score and opioid consumption compared with Group 4, but they had lower CRP value and greater ROM than any other groups at post-operative day 2 and day 4. CONCLUSION: The combination of ropivacaine, morphine, and ketorolac showed a significantly stronger and sufficiently synergistic analgesic effect without adding methylprednisolone in periarticular injection after TKA. The clinical relevance of the study is that the combination of ropivacaine, morphine, and ketorolac can be a good option for periarticular injection following TKA in terms of synergistic analgesic effect and efficiency of drug combination. PMID- 25288342 TI - The Ebola epidemic and translational public health. PMID- 25288343 TI - Investigating the use of quick response codes in the gross anatomy laboratory. AB - The use of quick response (QR) codes within undergraduate university courses is on the rise, yet literature concerning their use in medical education is scant. This study examined student perceptions on the usefulness of QR codes as learning aids in a medical gross anatomy course, statistically analyzed whether this learning aid impacted student performance, and evaluated whether performance could be explained by the frequency of QR code usage. Question prompts and QR codes tagged on cadaveric specimens and models were available for four weeks as learning aids to medical (n = 155) and doctor of physical therapy (n = 39) students. Each QR code provided answers to posed questions in the form of embedded text or hyperlinked web pages. Students' perceptions were gathered using a formative questionnaire and practical examination scores were used to assess potential gains in student achievement. Overall, students responded positively to the use of QR codes in the gross anatomy laboratory as 89% (57/64) agreed the codes augmented their learning of anatomy. The users' most noticeable objection to using QR codes was the reluctance to bring their smartphones into the gross anatomy laboratory. A comparison between the performance of QR code users and non users was found to be nonsignificant (P = 0.113), and no significant gains in performance (P = 0.302) were observed after the intervention. Learners welcomed the implementation of QR code technology in the gross anatomy laboratory, yet this intervention had no apparent effect on practical examination performance. PMID- 25288344 TI - Patient cues and symptoms of psychosocial distress: what predicts assessment and treatment of distress by oncology clinicians? AB - OBJECTIVE: Psychosocial concerns arise after a cancer diagnosis and during treatment requiring oncology clinicians to initiate discussions to identify distress. This study examined patient-clinician communication about psychosocial concerns and predictors of assessment and treatment/referral for distress. METHODS: Secondary analysis of existing dataset coded to explore patient clinician communication during ambulatory visits in two comprehensive cancer centers was carried out. Sample included adult patients with various cancers and stages. Dataset included audio-recordings and symptom/QOL reports 4-6 weeks after starting treatment from all distressed patients (n = 66) in parent study and random sample of nondistressed patients (n = 23). Distressed patients had moderate-to-severe depression (Patient Health Questionnaire-9 scores >=10) and/or poor emotional functioning (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire emotional function scores <50). Audio recordings were coded to describe patient-clinician communication about psychosocial concerns using the coding scheme from the parent study plus Medical Interview Aural Rating System. RESULTS: The remaining patients gave 222 cues of psychosocial concerns: 183 from 46 distressed patients and 39 from nine nondistressed patients. Distressed patients were younger, were female, had higher symptom burden, and/or gave more cues. Significantly, more distressed patients had at least one cue/visit. Clinicians initiated 62% of discussions overall with no statistical difference between distressed and nondistressed groups. More explicit cues and more than four cues predicted treatment/referral for distress. CONCLUSIONS: Distressed patients were younger, were female, had higher symptom burden, and/or gave more verbal cues. Clinicians responded to explicit and more frequent cues by providing treatment and/or referrals for distress. Further exploration is needed regarding clinician factors related to assessment of psychosocial concerns. PMID- 25288345 TI - Comment on: can bariatric surgery improve cardiovascular risk factors in the metabolically healthy but morbidly obese patient? PMID- 25288346 TI - New Biogeographic insight into Bauhinia s.l. (Leguminosae): integration from fossil records and molecular analyses. AB - BACKGROUND: Given that most species that have ever existed on earth are extinct, it stands to reason that the evolutionary history can be better understood with fossil taxa. Bauhinia is a typical genus of pantropical intercontinental disjunction among the Asian, African, and American continents. Geographic distribution patterns are better recognized when fossil records and molecular sequences are combined in the analyses. Here, we describe a new macrofossil species of Bauhinia from the Upper Miocene Xiaolongtan Formation in Wenshan County, Southeast Yunnan, China, and elucidate the biogeographic significance through the analyses of molecules and fossils. RESULTS: Morphometric analysis demonstrates that the leaf shapes of B. acuminata, B. championii, B. chalcophylla, B. purpurea, and B. podopetala closely resemble the leaf shapes of the new finding fossil. Phylogenetic relationships among the Bauhinia species were reconstructed using maximum parsimony and Bayesian inference, which inferred that species in Bauhinia species are well-resolved into three main groups. Divergence times were estimated by the Bayesian Markov chain Monte Carlo (MCMC) method under a relaxed clock, and inferred that the stem diversification time of Bauhinia was ca. 62.7 Ma. The Asian lineage first diverged at ca. 59.8 Ma, followed by divergence of the Africa lineage starting during the late Eocene, whereas that of the neotropical lineage starting during the middle Miocene. CONCLUSIONS: Hypotheses relying on vicariance or continental history to explain pantropical disjunct distributions are dismissed because they require mostly Palaeogene and older tectonic events. We suggest that Bauhinia originated in the middle Paleocene in Laurasia, probably in Asia, implying a possible Tethys Seaway origin or an "Out of Tropical Asia", and dispersal of legumes. Its present pantropical disjunction resulted from disruption of the boreotropical flora by climatic cooling after the Paleocene-Eocene Thermal Maximum (PETM). North Atlantic land bridges (NALB) seem the most plausible route for migration of Bauhinia from Asia to America; and additional aspects of the Bauhinia species distribution are explained by migration and long distance dispersal (LDD) from Eurasia to the African and American continents. PMID- 25288347 TI - Feasibility Study of Engaging Barbershops for Prostate Cancer Education in Rural African-American Communities. AB - The barbershop is a promising setting where African-American men might receive information and education about prostate cancer. In this study, we assessed the feasibility of engaging rural barbershops as venues for barbers to deliver a prostate cancer education intervention to increase informed decision-making for prostate cancer screening among customers. Twelve barbershops were recruited from two separate micropolitan areas in Georgia as intervention and control sites. Structured interviews were conducted with 11 barbers in both sites about customer characteristics as well as their willingness to participate in the study. The interviews were audio recorded and transcribed for analysis. In the intervention site, six barbers completed a survey and a pre-/posttest prostate cancer knowledge instrument following training classes. Barbers reported a wide average range of customers served per week (50 to 300). African-American men made up an average of 87% of customers. Barbers thought prostate cancer was an important discussion topic, felt they would be comfortable discussing it, and supported the participation of their barbershop in the study. For intervention group barbers, there was a statistically significant difference between the average pretest knowledge score of 72% (mean 12.2, SD=3.2) and the posttest knowledge score of 89% (mean 15.2, SD=1.1) (P=0.03) on the 17-item prostate cancer knowledge instrument. Based on the multiple interactions with the barbers, there was high receptivity to the topic and consensus about the importance of addressing prostate cancer with their customers. Rural barbershops represent feasible venues for delivering a prostate cancer education intervention. PMID- 25288348 TI - Are ultrasonographic signs of inflammation predictors for response to intra articular glucocorticoids in knee osteoarthritis? AB - OBJECTIVES: To investigate the predictive value of ultrasound (US) characteristics for the effect of intra-articular glucocorticoids in knee osteoarthritis (OA). METHODS: In this prospective cohort study, 62 patients with symptomatic knee OA (clinical knee OA criteria, pain>4 on a Numerical Rating Scale (NRS; 0-10)) received an intra-articular glucocorticoid injection (40 mg triamcinolone acetonide). Patients with NRS pain <=4 at 4 weeks were defined as responders. On inclusion, demographics, clinical data (body mass index, local swelling) knee x-rays and knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire were collected. Six US features were assessed including: effusion, synovial hypertrophy, Baker's cyst, infrapatellar bursitis, meniscal protrusion and cartilage thickness. Stepwise multiple logistic regression analyses with forward selection were conducted to identify possible predictors. RESULTS: At 4 weeks, 42% of the study participants reached a NRS <=4; an effect comparable to existing literature. Regression analyses showed that patients who used analgesics at baseline were less likely to have a good response. The small proportion of patients with infrapatellar bursitis was more likely to respond to the injection. CONCLUSIONS: No patient, disease or US characteristic of inflammation, turned out to be a reliable and clinically meaningful predictor for the effect of intra articular glucocorticoids after four weeks in knee OA. PMID- 25288350 TI - Benefits and shortcomings of superselective transarterial embolization of renal tumors before zero ischemia laparoscopic partial nephrectomy. AB - AIMS: To report feasibility, safety and effectiveness of "zero-ischemia" laparoscopic partial nephrectomy (LPN) following preoperative superselective transarterial embolization (STE) for clinical T1 renal tumors. METHODS: We retrospectively reviewed perioperative data of 23 consecutive patients, who underwent STE prior LPN between March 2010 and November 2012 for incidental clinical T1 renal mass. STE was performed by two experienced radiologists the day before surgery. Surgical procedures were performed in extended flank position, transperitoneally, by a single surgeon. RESULTS: Mean patients age was 68 years (range 56-74), mean tumor size was 3.5 cm (range 2.2-6.3 cm). STE was successfully completed in 16 patients 12-15 h before surgery. In 4 cases STE failed to provide a complete occlusion of all feeding arteries, while in 3 cases the ischemic area was larger than expected. LPN was successfully completed in all patients but one where open conversion was necessary; a "zero-ischemia" approach was performed in 19/23 patients (82.6%) while hilar clamp was necessary in 4 cases, with a mean warm-ischemia time of 14.8 min (range 5-22). Mean operative time was 123 min (range 115-130) and mean intraoperative blood loss was 250 mL (range 20-450). No patient experienced postoperative acute renal failure and no patient developed new onset IV stage chronic kidney disease at 1-yr follow-up. CONCLUSIONS: STE is a viable option to perform "zero-ischemia" LPN at beginning of learning curve; however, hilar clamp was necessary to achieve a relatively blood-less field in 17.4% of cases. PMID- 25288351 TI - Study of thermal stability of (3-aminopropyl)trimethoxy silane-grafted titanate nanotubes for application as nanofillers in polymers. AB - Protonated titanate nanotubes (TiNT-H) were surface-modified with (3 aminopropyl)trimethoxy silane (APTMS) by a novel method suitable for the syntheses of large amounts of materials at a low cost. The usage of prepared nanotubes for polymer reinforcement was studied. Since the thermal stability of the nanofiller was important to preserve its functional properties, its stability was studied by in situ high-temperature measurements. The most thermally stable nanotubes were silanized for 20 min and used for the preparation of epoxy-based nanocomposites. The nanofiller formed smaller (a few hundred nm) and larger (a few MUm) aggregates in the polymer matrix, and the amount of aggregates increased as the nanofiller content increased. The APTMS-modified titanate nanotubes bonded well with the epoxy matrix since amine groups on the TiNT's surface can react with an epoxy group to form covalent bonds between the matrix and the nanofiller. A very small addition (0.19-1.52 wt%) of the nanotubes significantly increased the glass transition temperature and the modulus in the rubbery state of the epoxy-based polymer. Smaller nanofiller content leads to a larger increase in these parameters and therefore better dynamic mechanical properties due to the smaller amount of large aggregates. APTMS-modified titanate nanotubes have proven to be a promising nanofiller in epoxy-based nanocomposites. PMID- 25288353 TI - Reprint of "Learning to breathe? Feedforward regulation of the inspiratory motor drive". AB - Claims have been made that breathing is in part controlled by feedforward regulation. In a classical conditioning paradigm, we investigated anticipatory increases in the inspiratory motor drive as measured by inspiratory occlusion pressure (P100). In an acquisition phase, an experimental group (N = 13) received a low-intensity resistive load (5 cmH2O/l/s) for three consecutive inspirations as Conditioned Stimulus (CS), preceding a load of a stronger intensity (20 cmH2O/l/s) for three subsequent inspirations as unconditioned stimulus (US). The control group (N = 11) received the low-intensity load for six consecutive inspirations. In a post-acquisition phase both groups received the low-intensity load for six consecutive inspirations. Responses to the CS-load only differed between groups during the first acquisition trials and a strong increase in P100 during the US-loads was observed, which habituated across the experiment. Our results suggest that the disruption caused by adding low to moderate resistive loads to three consecutive inspirations results in a short-lasting anticipatory increase in inspiratory motor drive. PMID- 25288352 TI - The effects of cadmium chloride on secondary metabolite production in Vitis vinifera cv. cell suspension cultures. AB - BACKGROUND: Plant secondary metabolites are possess several biological activities such as anti-mutagenic, anti-carcinogenic, anti-aging, etc. Cell suspension culture is one of the most effective systems to produce secondary metabolites. It is possible to increase the phenolic compounds and tocopherols by using cell suspensions. Studies on tocopherols production by cell suspension cultures are seldom and generally focused on seed oil plants. Although fresh grape, grape seed, pomace and grape seed oil had tocopherols, with our best knowledge, there is no research on tocopherol accumulation in the grape cell suspension cultures. In this study, it was aimed to determine the effects of cadmium chloride treatments on secondary metabolite production in cell suspension cultures of grapevine. Cell suspensions initiated from callus belonging to petiole tissue was used as a plant material. Cadmium chloride was applied to cell suspension cultures in different concentration (1.0 mM and 1.5 mM) to enhance secondary metabolite (total phenolics, total flavanols, total flavonols, trans-resveratrol, and alpha-, beta-, gamma- delta-tocopherols) production. Cells were harvested at two days intervals until the 6th day of cultures. Amounts of total phenolics, total flavanols and total flavonols; trans-resveratrol and tocopherols (alpha-, beta-, gamma- and delta-tocopherols) and dry cell weights were determined in the harvested cells. RESULTS: Phenolic contents were significantly affected by the sampling time and cadmium concentrations. The highest values of total phenolic (168.82 mg/100 g), total flavanol (15.94 mg/100 g), total flavonol (14.73 mg/100 g) and trans-resveratrol (490.76 MUg/100 g) were found in cells treated with 1.0 mM CdCl2 and harvested at day 2. Contents of tocopherols in the cells cultured in the presence of 1.0 mM CdCl2 gradually increased during the culture period and the highest values of alpha, beta and gamma tocopherols (145.61, 25.52 and 18.56 MUg/100 g) were detected in the cell cultures collected at day 6. CONCLUSIONS: As a conclusion, secondary metabolite contents were increased by cadmium chloride application and sampling time, while dry cell weights was reduced by cadmium chloride treatments. PMID- 25288354 TI - Impact of direct drug delivery via gastric access devices. AB - INTRODUCTION: Gastric access devices such as nasogastric tubes and gastrostomy tubes are increasingly being used in clinical practice to provide both short- and long-term nutrition support therapy. Increasingly these devices are being utilized to help deliver oral medications, where swallowing is impaired. This concomitant administration of medications and enteral formulas could derive potential benefits in regard to time and cost; however, uncertainty exists regarding potential drug and nutrient interactions and the influence this may have on both safety and efficacy. AREAS COVERED: This article provides an overview of the differing gastric access devices used in clinical practice and evaluates the evidence base for using oral medications via these routes. Alternative methods of drug administration are discussed, alongside common drug nutrient interactions and potential complications. EXPERT OPINION: Delivering medications via gastric access devices can be performed safely; however, careful consideration needs to be made regarding tube and patient influences, alongside drug-nutrient interactions. Improving practice in this area in the future necessitates enhancement of an evidence base to substantiate the safety of drug delivery via gastric access devices and improvement in education among healthcare professionals about the potential problems. PMID- 25288355 TI - Improving care for patients with oesophageal and gastric cancer: impact of a statewide multidisciplinary team. AB - BACKGROUND: To standardize management of upper gastrointestinal (GI) cancer in South Australia, a statewide video linked multidisciplinary team (MDT) meeting was established in late 2009. Although cancer MDTs are recognized as a standard of care, it is important to audit their impact. METHODS: A retrospective audit of MDT outcomes and recommendations for patients reviewed by the upper GI MDT between 1 January 2010 and 31 December 2011 was undertaken. The proportion of patients with new upper GI malignancies reviewed and the proportion reviewed within 2 weeks of diagnosis were determined. Recommendations from the MDT meetings regarding treatment intent, management, investigations and trial participation were audited. RESULTS: From 2010 to 2011, the proportion of newly diagnosed upper GI malignancies in South Australia reviewed by the MDT increased from 43.2% to 54.3%. More oesophageal than gastric cancer cases were reviewed by the MDT. The proportion of patients reviewed within 2 weeks of diagnosis increased from 20% to 50%. The proportion of patients referred for neoadjuvant or definitive chemoradiotherapy increased from 2010 to 2011. Fifty per cent of all patients reviewed were recommended to have further investigations. Recommendations for clinical trial participation increased from 0% in 2010 to 11% in 2011. CONCLUSION: A statewide upper GI cancer MDT is feasible. Implementation of the MDT was followed by an increase in the number of patients reviewed and the proportion reviewed within 2 weeks of diagnosis. Greater awareness of the MDT and access to it may be required to continue to increase the proportion of cancers reviewed. PMID- 25288356 TI - Assessing time to treatment and patient inflow in a Danish emergency department: a cohort study using data from electronic emergency screen boards. AB - BACKGROUND: The purpose of this study was to assess and describe the patient inflow during a 1-month period in a Danish emergency department and to evaluate if the intended times to treatment (TTT) related to category of triage were met. METHODS: Data from electronic emergency screen boards were extracted from the 1st to the 30th of April 2013. 2000 patients were enrolled of which 1011 were eligible for inclusion in the study of TTT. Patient inflow was described according to hours of the day and days of the week. Patients were divided into groups of triage and TTT was assessed in the different groups. Adjusted odds ratios of not being seen on time were calculated between triage groups and time of the day/week. RESULTS: The pattern of inflow differed between weekdays and weekends. On weekdays it peaked around midday and on weekends it peaked during the late afternoon/evening. The distributions of the different triage categories between days were similar. Monday had the most patient contacts while Saturday showed the least. Category II (orange) patients were the most prone to exceed the intended TTT. The risk of not being seen on time when compared to daytime, was on evenings OR 2.3 [1.1;4.9] and on nights OR 2.0 [1.2;3.9]. On weekends the odds ratio was OR 1.9 [0.8;4.7] compared to weekdays. CONCLUSION: The results demonstrated varying patterns of patient inflow between weekdays and weekends. There was a significantly increased risk of being attended late when arriving on evenings and nights. Likewise higher acuity was associated with exceeded TTT. PMID- 25288357 TI - Determination of culprit coronary artery branches using hemodynamic indices from angiographic images. AB - A recently reported angiographic technique for hemodynamic indices based on first pass distribution analysis (FPA) could potentially be helpful for determining the culprit artery responsible for myocardial ischemia. The purpose of this study was to determinate the culprit coronary arterial branches based on coronary flow reserve (CFR) and fractional flow reserve (FFR) using only angiographic images. The study was performed in 14 anesthetized swine. Microspheres were injected into coronary arterial branches to create microvascular disruption. Stenosis was also created by inserting plastic tubings in LAD and LCX arterial branches. Adenosine was used to produce maximum hyperemia. Angiographic CFR (CFRa), relative angiographic CFR (rCFRa), and angiographic FFR (FFRa) were calculated by FPA. The diagnostic abilities of CFRa, rCFRa, and FFRa were compared in three models: (1) epicardial stenosis model (S), (2) microcirculation disruption model (M), and (3) combined(S + M) model by using the area under the ROC curve (AUC). The mean differences between FFRa and the pressure-derived FFR (FFRp) measurements were 0.01 +/- 0.21 in S model (N = 37) and 0.01 +/- 0.18 in M model (N = 53). From 225 measurements in S model, the AUCs for CFRa and FFRa were 0.720 and 0.918, respectively. From 262 measurements in M model and 238 measurements in (S + M) model, the AUCs for CFRa, rCFRa, FFRa were 0.744, 0.715, 0.959 and 0.806, 0.738, 0.995, respectively. The hemodynamic indices of the small branches (down to ~0.7 mm) could be measured using only angiographic image data. The application of FFRa could potentially provide a useful method to assess the severity of disease in coronary arterial branches. PMID- 25288358 TI - Uric acid relates to dopamine transporter availability in Parkinson's disease. AB - BACKGROUND: Diagnosing Parkinson's disease (PD) and tracking its progression may require the combination of reliable biomarkers. Among them, both serum uric acid (UA) and dopamine transporter (DaT) binding deserve more investigations. AIMS OF THE STUDY: We aimed to investigate the relationship between serum UA levels and DaT availability in newly diagnosed, drug-naive PD patients, by means of semiquantitative [(123) I]FP-CIT-SPECT. METHODS: We recruited 52 newly diagnosed, drug-naive PD patients, and performed serum UA dosage and [(123) I]FP-CIT-SPECT. RESULTS: Pearson's correlation analysis showed that UA levels were significantly higher in patients with higher averaged, ipsilateral and contralateral DaT binding in caudate, putamen, and striatum. CONCLUSIONS: We showed, for the first time, by regional semiquantitative analysis of DaT binding in PD patients that UA levels significantly correlates with the severity of dopaminergic impairment in caudate, putamen, and striatum. This study broadens our knowledge on the importance of UA as a biomarker of PD. PMID- 25288359 TI - Comment on "Emergence and fate of cyclic volatile polydimethylsiloxanes (D4, D5) in municipal waste streams: release mechanisms, partitioning and persistence in air, water, soil and sediments". AB - The review article "Emergence and fate of cyclic volatile polydimethylsiloxanes (D4, D5) in municipal waste streams: Release mechanisms, partitioning and persistence in air, water, soil and sediments" by Surita and Tansel covers a relevant topic, but there are several serious issues with this paper. The inappropriate handling of data gathered from various sources has resulted in a flawed dataset. In addition, the authors performed several erroneous or meaningless calculations with the data. Their dataset leads to incorrect and misleading interpretations and should not be used. PMID- 25288360 TI - In vivo study of cerebral white matter in the dog using diffusion tensor tractography. AB - Conventional magnetic resonance imaging (MRI) allows investigators and clinicians to observe the anatomy and injuries of the cerebral white matter (CWM) in dogs. However, dynamic images based on the diffusion tensor (DT) technique are required to assess fiber tract integrity of the CWM. Diffusion tensor tractography (DTT) produces a three-dimensional representation in which data are displayed on a colored map obtained from the anisotropy of water molecules in the CWM tracts. Fractional anisotropy (FA) is a value that measures changes in water diffusion, which can occur if the CWM tracts are displaced, disrupted, or infiltrated. The goal of this study was to determine the feasibility of DTT for in vivo examination of the normal appearance of CWM in dogs through visual and quantitative analysis of the most representative CWM tracts. Nine tractographies were performed on healthy dogs using a 3T MRI scanner. T1- and T2-weighted images and DTI were acquired at different planes. Using DTT, three-dimensional reconstructions were obtained. Fractional ansisotropy and apparent diffusion coefficient (ADC) values of the right and left corticospinal tracts, corpus callosum, cingulum, and right and left fronto-occipital fasciculus were determined. Tract reconstructions were similar in 8/9 healthy dogs. Values for FA and ADC were similar in all the dogs. In one dog, tract reconstructions were inhomogeneous; these were displaced because it had larger lateral ventricles. Findings indicated that DTT is a feasible technique for in vivo study of CWM in dogs and that it complements information from conventional MRI. PMID- 25288361 TI - Limited risks of major congenital anomalies in children of mothers with coeliac disease: a population-based cohort study. AB - OBJECTIVE: To examine major congenital anomaly (CA) risks in children of mothers with coeliac disease (CD) compared with mothers without CD. DESIGN: Population based cohort study. SETTING: Linked maternal-child medical records from a large primary care database from the UK. POPULATION: A total of 562,332 live singletons of mothers with and without CD in 1990-2013. METHODS: We calculated the absolute major CA risks in children whose mothers had CD, and whether this was diagnosed or undiagnosed before childbirth. Logistic regression with a generalised estimating equation was used to estimate adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) for CAs associated with CD. MAIN OUTCOME MEASURES: Fourteen system-specific major CA groups classified according to the European Surveillance of Congenital Anomalies and neural tube defects (NTDs). RESULTS: Major CA risk in 1880 children of mothers with CD was 293 per 10,000 liveborn singletons, similar to the risk in those without CD (282; aOR 0.98, 95% CI 0.74 1.30). The risk was slightly higher in 971 children, whose mothers were undiagnosed (350; aOR 1.14, 95% CI 0.79-1.64), than in 909 children whose mothers were diagnosed (231; aOR 0.80, 95% CI 0.52-1.24). There was a three-fold increase in nervous system anomalies in the children of mothers with undiagnosed CD (aOR 2.98, 95% CI 1.06-8.33, based on five exposed cases and one had an NTD), and these women were all diagnosed with CD at least 4 years after their children were born. CONCLUSIONS: There was no statistically significant increase in risk of major CAs in children of mothers with coeliac disease overall, compared with the general population. PMID- 25288362 TI - Knock-down of p300 decreases the proliferation and odontogenic differentiation potentiality of HDPCs. AB - AIM: To investigate the role of p300 in the regulation of proliferation and odontogenic differentiation of human dental pulp cells (HDPCs). METHODOLOGY: The recombinant lentiviral vector pshRNA-copGFP was used to knock-down p300 expression in HDPCs. Protein level of acetylated H3 was detected. The proliferation of HDPCs was measured using the CCK8 assay. The cell cycle and apoptosis were analysed using flow cytometry and TUNEL staining, respectively. The expression levels of Cdc25A, p21(waf1) and the cleaved products of caspase 3 and caspase 7 were determined utilizing real-time quantitative polymerase chain reaction and Western blotting analysis. The alkaline phosphatase (ALP) activity was measured, and the formation of mineralized nodules was assessed using alizarin red staining after the induction of odontogenic differentiation of HDPCs. The expression levels of the odontogenic differentiation markers DMP-1, DSPP and DSP were detected utilizing real-time quantitative polymerase chain reaction and Western blotting analysis. RESULTS: After p300 was knocked down in HDPCs, p300 was significantly down-regulated at both the mRNA and protein levels, and histone H3 acetylation was reduced. The proliferation capacity of HDPCs was suppressed in p300 knock-down groups. The cells were arrested in the G0/G1 phase of the cell cycle, and cell apoptosis was triggered. ALP activity, the formation of mineralized nodules and the expression levels of DMP-1, DSPP and DSP were all decreased in p300-knock-down HDPCs undergoing odontogenic differentiation. CONCLUSION: Knocking down p300 restrains the proliferation and odontogenic differentiation potentiality of HDPCs. PMID- 25288364 TI - Colloidal pen lithography. AB - Colloidal pen lithography, a low-cost, high-throughput scanning probe contact printing method, has been developed, which is based on self-assembled colloidal arrays embedded in a soft elastomeric stamp. Patterned protein arrays are demonstrated using this method, with a feature size ranging from 100 nm to several micrometers. A brief study into the specificity reorganization of protein gives evidence for the feasibility of this method for writing protein chips. PMID- 25288365 TI - Erythema elevatum diutinum: a review of presentation and treatment. AB - Erythema elevatum diutinum (EED) is a rare, chronic and treatable skin condition. It has many histological mimics and is often associated with a variety of underlying systemic diseases, when these are present the management and prognosis dictates the course of the EED. This review aims to highlight the differential diagnosis, clinical manifestations of EED and the possible underlying systemic disease. It is important for clinicians to be aware that EED may predate underlying conditions and the presence of lesions may indicate underlying disease activity. In some cases one may need 'search' for underlying disease. Treatment of these lesions is notoriously difficult. Dapsone is used as the mainstay of treatment, however other options exist. We have highlighted different treatment options and suggested a treatment algorithm. In some cases, treatment may need to be targeted at underlying disease. PMID- 25288366 TI - Trapping particles using waveguide-coupled gold bowtie plasmonic tweezers. AB - We propose and demonstrate a trapping configuration integrating coupled waveguides and gold bowtie structures to form near-field plasmonic tweezers. Compared with excitation from the top, waves coupled through the waveguide can excite specific bowties on the waveguide and trap particles precisely. Thus this scheme is more efficient and compact, and will assist the circuit design on a chip. With lightning rod and gap effects, the gold bowtie structures can generate highly concentrated resonant fields and induce trapping forces as strong as 652 pN W(-1) on particles with diameters as small as 20 nm. This trapping capability is investigated numerically and verified experimentally with observations of the transport, trapping, and release of particles in the system. PMID- 25288368 TI - Differential predictors of acute post-surgical pain intensity after abdominal hysterectomy and major joint arthroplasty. AB - BACKGROUND: Psychological factors have a significant role in post-surgical pain, and their study can inform pain management. PURPOSE: The aims of this study are to identify psychological predictors of post-surgical pain following abdominal hysterectomy (AH) and major joint arthroplasty (MJA) and to investigate differential predictors by type of surgery. METHOD: One hundred forty-two women undergoing AH and 110 patients undergoing MJA were assessed 24 h before (T1) and 48 h after (T2) surgery. RESULTS: A predictive post-surgical pain model was found for AH and MJA yielding pre-surgical pain experience and pain catastrophizing as significant predictors and a significant interaction of pre-surgical optimism and surgery type. Separate regression models by surgery type showed that pre-surgical optimism was the best predictor of post-surgical pain after MJA, but not after AH. CONCLUSIONS: Findings highlight the relevance of psychological predictors for both surgeries and the value of targeting specific psychological factors by surgery type in order to effectively manage acute post-surgical pain. PMID- 25288369 TI - Exclusive selectivity in the one-pot formation of C-C and C-Se bonds involving Ni catalyzed alkyne hydroselenation: optimization of the synthetic procedure and a mechanistic study. AB - A unique Ni-catalyzed transformation is reported for the one-pot highly selective synthesis of previously unknown monoseleno-substituted 1,3-dienes starting from easily available terminal alkynes and benzeneselenol. The combination of a readily available catalyst precursor, Ni(acac)2, and an appropriately tuned phosphine ligand, PPh2Cy, resulted in the exclusive assembly of the s-gauche diene skeleton via the selective formation of C-C and C-Se bonds. The unusual diene products were stable under regular experimental conditions, and the products maintained the s-gauche geometry both in the solid state and in solution, as confirmed by X-ray analysis and NMR spectroscopy. Thorough mechanistic studies using ESI-MS revealed the key Ni-containing species involved in the reaction. PMID- 25288371 TI - Paraproteinemic neuropathies. AB - The paraproteinemias are a heterogeneous group of disorders in which monoclonal plasma cells cause the proliferation of monoclonal proteins. They are of importance to clinicians because they often occur in association with neuropathies. Neurologists play a particularly important role when the neuropathy is the presenting feature, in which case they may uncover clinical, laboratory, radiologic, electrodiagnostic, or biopsy findings that lead to identification of the underlying paraproteinemia. The frequency of neuropathies in these patients, and the extent to which such neuropathies dominate the clinical picture, varies significantly between the different paraproteinemias. Treatments may be aimed specifically at the neuropathy, or against the underlying hematologic disorder. In all patients with paraproteinemias, the neurologist can work collaboratively with the hematologist to formulate therapeutic plans and goals and can provide follow-up and monitoring to determine the response of the neuropathy to treatment. PMID- 25288367 TI - The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis. AB - Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-kappaB and expression of proinflammatory cytokines including TNF-alpha, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation. PMID- 25288370 TI - An AAVS1-targeted minigene platform for correction of iPSCs from all five types of chronic granulomatous disease. AB - There are five genetic forms of chronic granulomatous disease (CGD), resulting from mutations in any of five subunits of phagocyte oxidase, an enzyme complex in neutrophils, monocytes, and macrophages that produces microbicidal reactive oxygen species. We generated induced pluripotent stem cells (iPSCs) from peripheral blood CD34(+) hematopoietic stem cells of patients with each of five CGD genotypes. We used zinc finger nuclease (ZFN) targeting the AAVS1 safe harbor site together with CGD genotype-specific minigene plasmids with flanking AAVS1 sequence to target correction of iPSC representing each form of CGD. We achieved targeted insertion with constitutive expression of desired oxidase subunit in 70 80% of selected iPSC clones. Neutrophils and macrophages differentiated from corrected CGD iPSCs demonstrated restored oxidase activity and antimicrobial function against CGD bacterial pathogens Staphylococcus aureus and Granulibacter bethesdensis. Using a standard platform that combines iPSC generation from peripheral blood CD34(+) cells and ZFN mediated AAVS1 safe harbor minigene targeting, we demonstrate efficient generation of genetically corrected iPSCs using an identical approach for all five genetic forms of CGD. This safe harbor minigene targeting platform is broadly applicable to a wide range of inherited single gene metabolic disorders. PMID- 25288373 TI - A patient safety and transitions of care curriculum for third-year medical students. AB - The elderly are the most vulnerable to adverse events during and after hospitalization. This study sought to evaluate the effectiveness of a curriculum on patient safety and transitions of care for medical students during an Internal Medicine-Geriatrics Clerkship on students' knowledge, skills, and attitudes. The curriculum included didactics on patient safety, health literacy, discharge planning and transitions of care, and postdischarge visits to patients. Analysis of pre- and postassessments showed afterwards students were significantly more comfortable assessing a patient's health literacy and confident performing a medication reconciliation, providing education regarding medications, and identifying barriers during transitions. More students were able to identify the most common source of adverse events after discharge (86% vs. 62% before), risk factors for low health literacy (28% vs. 14%), and ways to assess a patient's health literacy (14% vs. 2%). It was feasible to implement a postdischarge visit assignment in an urban tertiary care setting and only required on average of approximately an one and one half hours for students to complete. PMID- 25288372 TI - Vestibular evoked myogenic potential responses in obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome (OSAS) provokes oxidative stress and ischemia, which affects the central nervous system. The degeneration of neurons in the brainstem due to periodic hypoxia can be evaluated by vestibular and audiologic tests. The objective of this study is to determine brainstem damage in severe OSAS patients with the help of vestibular evoked myogenic potential (VEMP) responses. Prospective, randomize, double-blind. Research-training hospital. We compared cervical vestibular evoked myogenic potential (cVEMP) responses between severe OSAS patients and a control group. 54 patients were included and divided into the OSAS group, with severe OSAS (apnea-hypopnea index, AHI >70), and a control group with snoring without OSAS (AHI <5). Both groups underwent cVEMP. Bilateral recordings with simultaneous binaural logon stimulations were used during VEMP recordings. The existing p1n1 and n2p2 responses, p1, n1, n2, and p2 latencies and amplitudes, and p1n1 and n2p2 intervals were measured. Statistically significant differences were revealed between patients and controls for the response rate of the p1n1, n2p2 and p1n1, n2p2 amplitudes. There were no significant differences between the two groups with respect to the latencies of p1, n1, n2 and p2, or the p1n1 and n2p2 intervals. The VEMP response rate was lower in severe OSAS patients, and all amplitudes were shorter than in healthy subjects. VEMP recordings in severe OSAS subjects demonstrates abnormalities in brainstem pathways. It appears that brainstem damage in severe OSAS can be detected by cVEMP recordings. PMID- 25288374 TI - Double-addition reaction of aryl methyl sulfones with N-tert-butylsulfinyl imines: diastereoselective and concise synthesis of 2-sulfonylated 1,3-diamines. AB - We report a double-addition reaction of methyl phenyl sulfone and methyl 2 pyridyl sulfone with N-tert-butylsulfinyl imines. This method provides concise access to 2-sulfonylated 1,3-anti diamines with good to excellent diastereoselectivities. This protocol has the benefit of using readily accessible starting materials and is operationally simple. PMID- 25288376 TI - Multiple myeloma. PMID- 25288375 TI - Association of behaviour change techniques with effectiveness of dietary interventions among adults of retirement age: a systematic review and meta analysis of randomised controlled trials. AB - BACKGROUND: There is a need for development of more effective interventions to achieve healthy eating, enhance healthy ageing, and to reduce the risk of age related diseases. The aim of this study was to identify the behaviour change techniques (BCTs) used in complex dietary behaviour change interventions and to explore the association between BCTs utilised and intervention effectiveness. METHODS: We undertook a secondary analysis of data from a previous systematic review with meta-analysis of the effectiveness of dietary interventions among people of retirement age. BCTs were identified using the reliable CALO-RE taxonomy in studies reporting fruit and vegetable (F and V) consumption as outcomes. The mean difference in F and V intake between active and control arms was compared between studies in which the BCTs were identified versus those not using the BCTs. Random-effects meta-regression models were used to assess the association of interventions BCTs with F and V intakes. RESULTS: Twenty-eight of the 40 BCTs listed in the CALO-RE taxonomy were identified in the 22 papers reviewed. Studies using the techniques 'barrier identification/problem solving' (93 g, 95% confidence interval (CI) 48 to 137 greater F and V intake), 'plan social support/social change' (78 g, 95%CI 24 to 132 greater F and V intake), 'goal setting (outcome)' (55 g 95%CI 7 to 103 greater F and V intake), 'use of follow-up prompts' (66 g, 95%CI 10 to 123 greater F and V intake) and 'provide feedback on performance' (39 g, 95%CI -2 to 81 greater F and V intake) were associated with greater effects of interventions on F and V consumption compared with studies not using these BCTs. The number of BCTs per study ranged from 2 to 16 (median = 6). Meta-regression showed that one additional BCT led to 8.3 g (95%CI 0.006 to 16.6 g) increase in F and V intake. CONCLUSIONS: Overall, this study has identified BCTs associated with effectiveness suggesting that these might be active ingredients of dietary interventions which will be effective in increasing F and V intake in older adults. For interventions targeting those in the peri-retirement age group, 'barrier identification/problem solving' and 'plan for social support/social change' may be particularly useful in increasing the effectiveness of dietary interventions. PMID- 25288377 TI - Outcomes of platelet transfusion in patients with thrombotic thrombocytopenic purpura: a retrospective case series study. AB - Current guidelines advise against the transfusion of platelets in patients with thrombotic thrombocytopenic purpura (TTP) except in cases of life-threatening hemorrhage. We conducted a retrospective medical chart review to examine the outcomes of patients with TTP who received platelet transfusion at our institution from September 2002 to September 2012. A search for "thrombotic thrombocytopenic purpura" in the discharge summary identified 233 patients, out of which only 15 patients had TTP and received platelet transfusion. Primary outcomes were death due to any cause, myocardial infarction, ischemic stroke, coma, seizure, or worsening neurologic status within 24 h of platelet transfusion. Secondary outcomes included bleeding and worsening thrombocytopenia. No adverse outcomes occurred within 24 h of platelet transfusion. Two patients experienced bleeding following renal biopsy despite having platelet counts of greater than 50,000/MUl and receiving one pack of pooled platelets prior to the procedures. The response to transfusion was variable. In general, platelet transfusion was not detrimental in this population; however, the efficacy is uncertain. PMID- 25288378 TI - Unilateral hearing loss due to lymphocytosis and a contralateral putamen lesion. PMID- 25288379 TI - FFLO superfluids in 2D spin-orbit coupled Fermi gases. AB - We show that the combination of spin-orbit coupling and in-plane Zeeman field in a two-dimensional degenerate Fermi gas can lead to a larger parameter region for Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phases than that using spin-imbalanced Fermi gases. The resulting FFLO superfluids are also more stable due to the enhanced energy difference between FFLO and conventional Bardeen-Cooper Schrieffer (BCS) excited states. We clarify the crucial role of the symmetry of Fermi surface on the formation of finite momentum pairing. The phase diagram for FFLO superfluids is obtained in the BCS-BEC crossover region and possible experimental observations of FFLO phases are discussed. PMID- 25288380 TI - Plasmodium prevalence and artemisinin-resistant falciparum malaria in Preah Vihear Province, Cambodia: a cross-sectional population-based study. AB - BACKGROUND: Intensified efforts are urgently needed to contain and eliminate artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion. Medecins Sans Frontieres plans to support the Ministry of Health in eliminating P. falciparum in an area with artemisinin resistance in the north-east of Cambodia. As a first step, the prevalence of Plasmodium spp. and the presence of mutations associated with artemisinin resistance were evaluated in two districts of Preah Vihear Province. METHODS: A cross-sectional population-based study using a two-stage cluster sampling was conducted in the rural districts of Chhaeb and Chey Saen, from September to October 2013. In each district, 30 clusters of 10 households were randomly selected. In total, blood samples were collected for 1,275 participants in Chhaeb and 1,224 in Chey Saen. Prevalence of Plasmodium spp. was assessed by PCR on dried blood spots. Plasmodium falciparum positive samples were screened for mutations in the K13-propeller domain gene (PF3D7_1343700). RESULT: The prevalence of Plasmodium spp. was estimated at 1.49% (95% CI 0.71-3.11%) in Chhaeb and 2.61% (95% CI 1.45-4.66%) in Chey Saen. Twenty seven samples were positive for P. falciparum, giving a prevalence of 0.16% (95% CI 0.04-0.65) in Chhaeb and 2.04% (95% CI 1.04-3.99%) in Chey Saen. Only 4.0% of the participants testing positive presented with fever or history of fever. K13 propeller domain mutant type alleles (C580Y and Y493H) were found, only in Chey Saen district, in seven out of 11 P. falciparum positive samples with enough genetic material to allow testing. CONCLUSION: The overall prevalence of P. falciparum was low in both districts but parasites presenting mutations in the K13-propeller domain gene, strongly associated with artemisinin-resistance, are circulating in Chey Saen.The prevalence might be underestimated because of the absentees - mainly forest workers - and the workers of private companies who were not included in the study. These results confirm the need to urgently develop and implement targeted interventions to contain and eliminate P. falciparum malaria in this district before it spreads to other areas. PMID- 25288381 TI - Sc(OTf)3-catalyzed bicyclization of o-alkynylanilines with aldehydes: ring-fused 1,2-dihydroquinolines. AB - A Sc(OTf)3 -catalyzed cascade Prins-type cyclization reaction of o alkynylanilines, bearing a hydroxy or amine functionality, with aldehydes affords 1,2-dihydroquinoline derivatives having an extra fused ring efficiently under mild reaction conditions. It is interesting to observe the reversed reactivity in the highly selective formation of 1,2-dihydroquinoline derivatives instead of the formation of the usually favored indole derivatives. PMID- 25288382 TI - Comparison of the FilmArray assay and in-house real-time PCR for detection of respiratory infection. AB - Recently, molecular methods capable of detecting almost all microbial agents that may cause acute respiratory infection have been introduced. The FilmArray Respiratory Panel assay, which integrates nucleic acid extraction, nested amplification and detection in a reaction pouch preloaded with all reagents required for detection of 17 viruses and 3 bacteria, was compared with an in house real-time PCR that detects these agents in 8 parallel amplifications. When 128 clinical samples representing 18 of these agents were analysed by both assays the agreement was excellent, with kappa values ranging between 0.54 and 1.0. Discordances were mainly observed for adenovirus, but not when version 1.7 of FilmArray was used. The results show that these assays detect a wide range of pathogens with similar performance. FilmArray provides results after approximately 1 h, including ~ 5 min hands-on time, and does not require advanced equipment or expertise in molecular diagnostics, making it a useful point-of-care test for acute respiratory infections. PMID- 25288383 TI - Positive tip culture with Candida and negative blood culture: to treat or not to treat? A systematic review with meta-analysis. AB - BACKGROUND: Invasive candidiasis is a major invasive fungal infection. It has high lethality, and even higher if not treated early. There is no consensus on antifungal treatment in patients with positive catheter tip culture for Candida spp. The objective of this study was to evaluate the impact of antifungal therapy and mortality of patients with positive culture for Candida spp. in catheter tip that have negative blood culture. METHODS: The PubMed database was searched to identify articles related to Candida and catheter. Articles with adequate data were included. RESULTS: Of 1208 studies initially screened, 5 met the selection criteria. All were retrospective studies. In all, 265 patients were evaluated for outcomes 'candidemia' and 'invasive candidiasis' and 158 for the outcome 'mortality.' Antifungal therapy had no impact on the development of invasive fungal disease (Odds ratio (OR) = 1.41; 95% confidence interval (CI) = 0.56 3.52). Also there was no benefit of therapy on mortality (OR = 1.02; 95% CI = 0.54-1.95). CONCLUSION: Due to the poor quality of the studies no conclusion can be made. Randomized prospective studies are needed to better evaluate this therapeutic strategy. PMID- 25288384 TI - Sputum bacteriology and antibiotic sensitivity patterns of community-acquired pneumonia in hospitalized adult patients in Nigeria: a 5-year multicentre retrospective study. AB - BACKGROUND: A clear knowledge of the pathogens responsible for community-acquired pneumonia (CAP) in a given region and their antibiotic sensitivity patterns is necessary for optimal treatment. We determined the common bacterial pathogens causing CAP in Nigeria and further reviewed their antibiotic senstivity patterns with a view to providing recommendations to improve antibiotic management of CAP. METHODS: Case notes of all adult patients who were 18 years or more admitted to four major tertiary hospitals in South East Nigeria with a diagnosis of CAP between 2008 and 2012 were retrospectively studied. To be eligible, patients were required to have sputum culture and sensitivity results available. Socio demographic, clinical, pre-admission and in-hospital treatment data were also obtained. RESULTS: Of 400 patients with a radiologically confirmed diagnosis of CAP, 232 fulfilled the study criteria; 122 (52.6%) were women and the mean age was 50.6 +/- 18.8 years. Aetiological agents were identified from sputum in 189 (81.5%) patients. Streptococcus pneumoniae (n = 90, 47.6%) was the most frequent isolate followed by Klebsiella pneumoniae (n = 62, 32.8%), Staphylococcus aureus (n = 24, 12.7%) and Streptococcus pyogenes (n = 13, 6.9%). The pathogens were most sensitive to levofloxacin (77%), ceftazidime (75.5%) and ofloxacin (55.8%). The susceptibility of the isolates to antibiotics most frequently presecribed for empirical therapy was low (co-amoxiclav, 47.6%; ciprofloxacin, 45.9% and ceftriaxone, 47.6%) and this was associated with higher mortality and/or longer duration of hospital stay in survivors. CONCLUSION: Strep. pneumoniae and K. pneumoniae were the most common causes of CAP. The pathogens were most sensitive to levofloxacin and ceftazidime. We suggest that these antibiotics should increasingly be considered as superior options for empirical treatment of CAP in Nigeria. PMID- 25288385 TI - Hard and soft colloids at fluid interfaces: Adsorption, interactions, assembly & rheology. AB - Soft microgel particles inherently possess qualities of both polymers as well as particles. We review the similarities and differences between soft microgel particles and stiff colloids at fluid-fluid interfaces. We compare two fundamental aspects of particle-laden interfaces namely the adsorption kinetics and the interactions between adsorbed particles. Although it is well established that the transport of both hard particles and microgels to the interface is driven by diffusion, the analysis of the adsorption kinetics needs reconsideration and a proper equation of state relating the surface pressure to the adsorbed mass should be used. We review the theoretical and experimental investigations into the interactions of particles at the interface. The rheology of the interfacial layers is intimately related to the interactions, and the differences between hard particles and microgels become pronounced. The assembly of particles into the layer is another distinguishing factor that separates hard particles from soft microgel particles. Microgels deform substantially upon adsorption and the stability of a microgel-stabilized emulsion depends on the conformational changes triggered by external stimuli. PMID- 25288386 TI - GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. AB - OBJECTIVES: Mutations in the DFNB1 locus are the most common cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) worldwide. The aim of this study was to identify the most frequent mutations in patients with ARNSHL who reside in Northeastern Mexico. METHODS: We determined the nucleotide sequence the coding region of GJB2 of 78 patients with ARNSHL. Polymerase chain reaction assays were used to detect the GJB2 IVS1+1G>A mutation and deletions within GJB6. RESULTS: GJB2 mutations were detected in 9.6% of the alleles, and c.35delG was the most frequent. Six other less-frequent mutations were detected, including an extremely rare variant (c.645_648delTAGA), a novel mutation (c.35G>A), and one of possible Mexican origin (c.34G>T). GJB6 deletions and GJB2 IVS1+1G>A were not detected. CONCLUSIONS: These data suggest that mutations in the DFNB1 locus are a rare cause of ARNSHL among the population of Northeastern Mexico. This confirms the genetic heterogeneity of this condition and indicates that further research is required to determine the other mechanisms of pathogenesis of ARNSHL in Mexicans. PMID- 25288388 TI - Tobacco companies protest about federal court ruling on corrective statements. PMID- 25288387 TI - Perception of 'mothers of beneficiaries' regarding a rural community based hearing screening service. AB - A rural community-based hearing screening project was established in villages in a rural district of Tamil Nadu in South India. The goal of this project was to address early detection of hearing loss among infants and young children. Village health workers (VHW) were trained to conduct hearing screenings using an Oto Acoustic Emissions (OAE) equipment. They were also trained to provide information about ear and hearing health, and to facilitate follow up visits for diagnostic testing when required. OBJECTIVES: The purpose of this study was to review the project by examining the caregiver perception from the mothers of children who have undergone hearing screening regarding the service provided. METHODS: Focus group discussions (FGDs), were conducted in nine villages of the district to obtain information and perceptions from mothers. In all, 70 mothers with children less than 2 years of age, and 13 mothers with children greater than 2 years of age, participated in the FGDs. RESULTS: Responses obtained from mothers indicated that door to door health services are rare and are primarily related to sensitizing the community regarding health camps and preventive measures for widespread diseases (like dengue fever). Door to door screening for hearing among children is unique in these villages. Mothers were familiar with the NGO which coordinated the hearing screening program. Local pre-school (Balwadi) teachers were informed about the hearing screening program and its significance. From the responses of the participants it was clear that the sensitization carried out through them in all villages was successful. It was noteworthy that mothers mentioned the result of screening as "pass/refer" as instead of "pass/fail". This outcome suggests that health workers have used appropriate terminology to convey screening results. Mothers reported test conditions to be present and therefore confirmed that valid testing was conducted by VHWs. CONCLUSIONS: Mothers in the community accepted hearing screening services delivered by health workers. The health workers were effective in delivering the services. Pre-school teachers seemed to have played a pivotal role in communicating about the hearing screening program to the mothers. Ultimately, collaborating with local NGO facilitated acceptance and compliance due to the NGOs strong presence in the community. PMID- 25288389 TI - Imaging of the axilla before preoperative chemotherapy: implications for postmastectomy radiation. AB - Postmastectomy radiation therapy (PMRT) improves breast cancer survival in many women with lymph node-positive disease who undergo surgery followed by adjuvant chemotherapy. The role of PMRT after women receive neoadjuvant chemotherapy (NAC) is less clear. The available data suggest that clinical extent of disease at presentation before NAC, pathologic residual disease (especially pathologically involved lymph nodes) after NAC, and response to NAC are key prognostic factors for locoregional recurrence. Therefore, accurate axillary staging before the initiation of NAC and assessment of response to chemotherapy are critically important. Here, the authors review the literature addressing the radiotherapy management of patients with breast cancer who received NAC and underwent mastectomy with a special focus on the imaging modalities used to assess axillary lymph node status. PMID- 25288390 TI - Microdiscectomy with and without insertion of interspinous device for herniated disc at the L5-S1 level. AB - The role of interspinous devices (ISD) after lumbar herniated disc surgery for the prevention of postoperative back pain is controversial. The aim of this comparative prospective study was to determine outcomes in a selective cohort with L5-S1 disc herniation and degenerative disc changes after microdiscectomy with or without insertion of an ISD. One hundred and two consecutive patients underwent an L5-S1 microdiscectomy with or without implantation of an ISD. Group 1 consisted of 47 patients, with mild (n=22), moderate (n=14) or severe (n=11) degenerative disc changes who had microdiscectomy alone. Group 2 comprised 45 patients with similar types of disc changes who underwent microdiscectomy with an ISD implant. The Visual Analogue Scale (VAS) was used to grade low-back pain and postoperative clinical status was rated according to the modified MacNab criteria. Mean VAS score for low-back pain improved significantly at 1 year follow-up from 7.3 at baseline to 2.75 (p<0.001) in Group 1 and from 6.7 to 1.5 (p=0.001) in Group 2. VAS score at 1 year showed significant improvements in 21 Group 1 patients versus 30 Group 2 patients (p=0.001). Forty four percent of Group 1 patients and 80% of Group 2 patients showed improvement using the modified MacNab criteria. Patients in both groups reported significant improvement in sciatic pain and disability after microdiscectomy with or without an ISD implant. Patients with mild degenerative disc changes were more likely to achieve improvement of their low-back pain when treated with both microdiscectomy and ISD insertion. PMID- 25288391 TI - Prediction of postoperative pain intensity after lumbar spinal surgery using pain sensitivity and preoperative back pain severity. AB - OBJECTIVES: To investigate the role of preoperative pain sensitivity and preoperative symptom severity for prediction of postoperative pain intensity after lumbar spine surgery. METHODS: This study consisted of two groups who underwent decompression surgery alone (62 patients) or decompression with fusion surgery (37 patients) for lumbar spinal stenosis (LSS). Pain Sensitivity Questionnaire (PSQ) and visual analog pain scale (VAS) for back pain and leg pain were collected preoperatively with detailed medical history. The assessment was performed immediately after surgery when the patients had completely recovered and regained their complete consciousness from general anesthesia (H0) and subsequently 4, 8, 18, 30, 48, and 72 hours (H4, H8, H18, H30, H48, and H72) thereafter as they recovered. RESULTS: Both groups showed a decrease in back pain and leg pain with the time postoperatively. In fusion group, preoperative VAS for back pain was significantly correlated with postoperative VAS for back pain at H0, H4, H8, and H18, and PSQ minor/total PSQ also showed a significant correlation with postoperative back pain at H48 and H72. In contrast, only total PSQ and PSQ minors were significantly correlated with postoperative back pain at H18 and H30 in decompression group. Hierarchical regression analysis finally showed that each preoperative back pain and PSQ minor was predictive of immediate postoperative back pain (from H0 to H18) in fusion group and delayed postoperative back pain (H18, H30) in decompression group. CONCLUSIONS: The study highlights that each preoperative back pain and individual pain sensitivity could predict the different aspects of postoperative pain after lumbar surgery. PMID- 25288392 TI - Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology. AB - We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication. PMID- 25288393 TI - The effects of transcranial direct current stimulation on conscious perception of sensory inputs from hand palm and dorsum. AB - Conscious perception of sensory signals depends in part on stimulus salience, relevance and topography. Letting aside differences at skin receptor level and afferent fibres, it is the CNS that makes a contextual selection of relevant sensory inputs. We hypothesized that subjective awareness (AW) of the time at which a sensory stimulus is perceived, a cortical function, may be differently modified by cortical stimulation, according to site and type of the stimulus. In 24 healthy volunteers, we examined the effects of transcranial direct current stimulation (tDCS) on the assessment of AW to heat pain or weak electrical stimuli applied to either the hand palm or dorsum. We also recorded the vertex evoked potentials to the same stimuli. The assessment was done before, during and after cathodal or anodal tDCS over the parietal cortex contralateral to the hand receiving the stimuli. At baseline, AW to thermal stimuli was significantly longer for palm than for dorsum (P < 0.01), while no differences between stimulation sites were observed for the electrical stimuli. Both cathodal and anodal tDCS caused a significant shortening of AW to thermal stimuli in the palm but not in the dorsum, and no effects on AW to electrical stimuli. Longer AW in the palm than in the dorsum may be attributable to differences in skin thickness. However, the selectivity of the effects of tDCS on AW to thermal stimulation of the glabrous skin reflects the specificity of CNS processing for site and type of sensory inputs. PMID- 25288394 TI - Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. AB - Genetic studies have shown that the tuberous sclerosis complex (TSC) 1-TSC2 mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity. PMID- 25288395 TI - Spt5 accumulation at variable genes distinguishes somatic hypermutation in germinal center B cells from ex vivo-activated cells. AB - Variable (V) genes of immunoglobulins undergo somatic hypermutation by activation induced deaminase (AID) to generate amino acid substitutions that encode antibodies with increased affinity for antigen. Hypermutation is restricted to germinal center B cells and cannot be recapitulated in ex vivo-activated splenic cells, even though the latter express high levels of AID. This suggests that there is a specific feature of antigen activation in germinal centers that recruits AID to V genes which is absent in mitogen-activated cultured cells. Using two Igh knock-in mouse models, we found that RNA polymerase II accumulates in V regions in B cells after both types of stimulation for an extended distance of 1.2 kb from the TATA box. The paused polymerases generate abundant single strand DNA targets for AID. However, there is a distinct accumulation of the initiating form of polymerase, along with the transcription cofactor Spt5 and AID, in the V region from germinal center cells, which is totally absent in cultured cells. These data support a model where mutations are prevalent in germinal center cells, but not in ex vivo cells, because the initiating form of polymerase is retained, which affects Spt5 and AID recruitment. PMID- 25288396 TI - Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F. AB - The majority of patients with myeloproliferative neoplasms (MPNs) carry a somatic JAK2-V617F mutation. Because additional mutations can precede JAK2-V617F, it is questioned whether JAK2-V617F alone can initiate MPN. Several mouse models have demonstrated that JAK2-V617F can cause MPN; however, in all these models disease was polyclonal. Conversely, cancer initiates at the single cell level, but attempts to recapitulate single-cell disease initiation in mice have thus far failed. We demonstrate by limiting dilution and single-cell transplantations that MPN disease, manifesting either as erythrocytosis or thrombocytosis, can be initiated clonally from a single cell carrying JAK2-V617F. However, only a subset of mice reconstituted from single hematopoietic stem cells (HSCs) displayed MPN phenotype. Expression of JAK2-V617F in HSCs promoted cell division and increased DNA damage. Higher JAK2-V617F expression correlated with a short-term HSC signature and increased myeloid bias in single-cell gene expression analyses. Lower JAK2-V617F expression in progenitor and stem cells was associated with the capacity to stably engraft in secondary recipients. Furthermore, long-term repopulating capacity was also present in a compartment with intermediate expression levels of lineage markers. Our studies demonstrate that MPN can be initiated from a single HSC and illustrate that JAK2-V617F has complex effects on HSC biology. PMID- 25288397 TI - The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells. AB - The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell-specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression. PMID- 25288398 TI - The miR-155-PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation. AB - A single microRNA (miRNA) can regulate the expression of many genes, though the level of repression imparted on any given target is generally low. How then is the selective pressure for a single miRNA/target interaction maintained across long evolutionary distances? We addressed this problem by disrupting in vivo the interaction between miR-155 and PU.1 in mice. Remarkably, this interaction proved to be key to promoting optimal T cell-dependent B cell responses, a previously unrecognized role for PU.1. Mechanistically, miR-155 inhibits PU.1 expression, leading to Pax5 down-regulation and the initiation of the plasma cell differentiation pathway. Additional PU.1 targets include a network of genes whose products are involved in adhesion, with direct links to B-T cell interactions. We conclude that the evolutionary adaptive selection of the miR-155-PU.1 interaction is exercised through the effectiveness of terminal B cell differentiation. PMID- 25288400 TI - [Microbiology of pressure and vascular ulcer infections]. AB - INTRODUCTION: Pressure ulcer (PU) infection is a significant clinical problem in many elderly patients. MATERIAL AND METHODS: To determine the microbiology of PU and vascular ulcer (VU) infections by conducting a cross-sectional study of outpatients treated in a chronic wounds unit over an 18 month period. RESULTS: Sixty six patients with PU infection and 159 patients with an infected VU were identified. The PUs were located below the knee in 36 patients (52%). Patients with pressure ulcers had a higher proportion of institutionalization, cognitive impairment, inability to walk, and sphincter incontinence. There was a greater number of infections caused by Enterobacteriaceae (52%, P=.002) and fewer S. aureus infections (24%, P<.001) in patients with a PU compared to those with those with a VU. Forty-one percent of S. aureus strains isolated in all the patients were resistant to methicillin (MRSA). The proportion of Enterobacteriaceae infections was similar in patients with infection of pelvic girdle PU and in those located below the knee. CONCLUSIONS: PU patients suffer a higher rate of infection by enterobacteria. The most common pathogen in UV infections is S. aureus. The proportion of MRSA infection in patients with chronic wounds is high. The microbiology of the infection in the pelvic girdle PU is similar to those located below the knee. PMID- 25288399 TI - The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. AB - Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell-promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1-IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration dependent competition between these factors controls B cell terminal differentiation. PMID- 25288401 TI - ClpB chaperone passively threads soluble denatured proteins through its central pore. AB - ClpB disaggregase forms a ring-shaped hexamer that threads substrate proteins through the central pore using energy from ATP. The ClpB protomer consists of an N-terminal domain, a middle domain, and two AAA+ modules. These two AAA+ modules bind and hydrolyze ATP and construct the core of the hexameric ring. Here, we investigated the roles of the two AAA+ modules in substrate threading. BAP is an engineered ClpB that can bind ClpP proteolytic chamber; substrates threaded by BAP are degraded by ClpP. We combined BAP with conserved motif mutations in two AAA+ modules and measured the steady-state rates of threading of soluble denatured proteins by these mutants over a range of substrate concentrations. By fitting the data to the Michaelis-Menten equation, k(cat) and K(m) values were determined. We found that the kinetic parameters of the substrate threading correlate with the type of mutation introduced rather than the ATPase activity of the mutant. Moreover, some mutants having no or marginal ATPase activity could thread denatured proteins significantly. These results indicate that ClpB can passively thread soluble denatured proteins. PMID- 25288402 TI - Congenital long QT syndromes: prevalence, pathophysiology and management. AB - Long QT syndrome is a genetic disorder associated with life threatening ventricular arrhythmias and sudden death. This inherited arrhythmic disorder exhibits genetic heterogeneity, incomplete penetrance, and variable expressivity. During the past two decades there have been major advancements in understanding the genotype-phenotype correlations in LQTS. This genotype-phenotype relationship can lead to improved management of LQTS. However, development of genotype specific or mutation-specific management strategies is very challenging. This review describes the pathophysiology of LQTS, genotype-phenotype correlations, and focuses on the management of LQTS. In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. We further summarize current data on the efficacy of pharmacological treatment options for the three most prevalent LQTS variants including beta-blockers in LQT1, LQT2 and LQT3, sodium channel blockers and ranolazine for LQT3, potassium supplementation and spironolactone for LQT2, and possibly sex hormone-based therapy for LQT2. PMID- 25288404 TI - Experiences of cancer caregiving in socioeconomically deprived areas of Attica, Greece. AB - The shift of the majority of cancer care from inpatient to outpatient settings has given rise to a number of issues that have not yet been adequately addressed. This is especially true in countries undergoing rapid and profound socioeconomic changes that have substantially affected the health care sector. We conducted 12 in-depth interviews with family cancer caregivers residing in socioeconomically deprived areas of Attica, Greece. Using an inductive thematic approach, we identified three major themes: (a) the truth within boundaries, focusing on the flow of information in the triad doctor-caregiver-patient; (b) the evil called "cancer," reflecting caregivers' perceptions of the illness; and (c) being left "high and dry," reflecting participant experiences of home-based care. Against a background of financial crisis, this study underlines the need for safeguarding the rights of chronically ill patients and ensuring that informal cancer care, apart from a cost-effective solution, will also be an efficient one. PMID- 25288403 TI - Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities. AB - The pentacyclic acridinium salt RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate, compound 1) is one of the most interesting DNA G-quadruplex binding molecules due to its high efficacy in tumor cell growth inhibition both in in vitro models and in vivo against human tumor xenografts in combination with conventional chemotherapeutics. Despite compound 1 having desirable chemical and pharmaceutical properties, its potential as a therapeutic agent is compromised by off-target effects on cardiovascular physiology. In this paper we report a new series of structurally-related compounds which were developed in an attempt to minimize its off-target profile, but maintaining the same favorable chemical and pharmacological features of the lead compound. By performing a comparative analysis it was possible to identify which derivatives had the following properties: (i) to show a reduced capacity in respect to compound 1 to inhibit the hERG tail current tested in a patch clamp assay and/or to interact with the human recombinant beta2 receptor; (ii) to maintain both a good G4-binding affinity and cancer cell selectivity; and (iii) to trigger DNA damage with specific telomere uncapping. These studies allowed us to identify a novel G4-stabilizing molecule, compound 8, being characterized by reduced off target effects and potent telomere on-target properties compared to the prototypic compound 1. Moreover, compound 8 shares with compound 1 the same molecular mode of action and an anti-tumour activity specifically restricted to replicating cells, as evident with its particularly efficient activity in combination therapy with a topoisomerase I inhibitor. In conclusion, we have identified a new pentacyclic derivative 8 having suitable properties to be the focus of further investigations as a clinical candidate for cancer therapy. PMID- 25288405 TI - The evolution of case management for service members injured in Iraq and Afghanistan. AB - In this article we describe the nursing care needs of wounded service members (WSMs) from the wars in Iraq and Afghanistan and the evolving role of the nurse case manager (CM). New types of injuries, in-field treatment, immediate transport to multiple care centers, and new technologies have created a new patient population of WSMs that requires new types of nursing care and knowledge. We interviewed 235 nurses, including CMs from nine military treatment facilities (MTFs) and the Veterans Administration (VA), on actual patient care experiences and new knowledge development, and 67 WSMs about their experiences of care. New military and VA nurse case management roles are essential for the effective functioning of the evolving, highly specialized, and transport-based health care system. Working effectively with WSMs required that the CM role be expanded beyond health care management to include family support, re-entry, and life coaching for the extremely altered life circumstances of WSMs. PMID- 25288406 TI - Clinical Positioning Space: Residents' Clinical Experiences in the Outpatient Oncology Clinic. AB - In this article, we present a case study of residents' clinical experiences and communication in outpatient oncology consultations. We apply positioning theory, a dynamic alternative to role theory, to investigate how oncology residents and patients situate themselves as persons with rights and duties. Drawing from seven qualitative interviews and six days of observation, we investigate the residents' social positioning and their conversations with patients or supervisors. Our focus is on how (a) relational shifts in authority depend on each situation and its participants; (b) storylines establish acts and positions and narratively frame what participants can expect from a medical consultation viewed as a social episode; and (c) the positioning of rights and duties can lead to misunderstandings and frustrations. We conclude that residents and patients locate themselves in outpatient conversations as participants who jointly produce and are produced by patients' and nurses' storylines about who should take responsibility for treatment. PMID- 25288407 TI - Examining the interplay among family, culture, and latina teen suicidal behavior. AB - In this article, we explore the relationships among culture, family, and attempted suicide by U.S. Latinas. We analyzed qualitative interviews conducted with Latina teen suicide attempters (n = 10) and their parents. We also incorporated data collected from adolescents with no reported history of self harm (n = 10) and their parents to examine why some individuals turned to suicide under similar experiences of cultural conflict. Our results reveal that Latina teens who attempted suicide lacked the resources to forge meaningful social ties. Without the tools to bridge experiences of cultural contradiction, the girls in our study described feeling isolated and alone. Under such conditions, adolescents turned to behaviors aimed at self-destruction. Unlike their peers who attempted suicide, adolescent Latinas with no lifetime history of attempted suicide were able to mobilize resources in ways that balanced experiences of acculturative tension by creating supportive relationships with other individuals. PMID- 25288408 TI - African American Women's Breastfeeding Experiences: Cultural, Personal, and Political Voices. AB - The low rate of breastfeeding among African American women in the United States is a poorly understood, persistent disparity. Our purpose in this study was to gain an understanding of how African American women experience breastfeeding in the context of their day-to-day lives. The Sequential-Consensual Qualitative Design (SCQD), a 3-stage qualitative methodology aimed at exploring the cultural, personal, and political context of phenomena, was used to explore the experiences of African American women who felt successful with breastfeeding. An integration of qualitative content analysis and Black feminist theory was used to analyze the data. Themes that emerged from Stage-2 data analysis included self-determination, spirituality and breastfeeding, and empowerment. In Stage 3 of the study, participant recommendations regarding breastfeeding promotion and support initiatives for African American breastfeeding were categorized into three themes, including engaging spheres of influence, sparking breastfeeding activism, and addressing images of the sexual breast vs. the nurturing breast. PMID- 25288409 TI - From patient to therapatient: social work students coping with mental illness. AB - We explored the experiences of social work students with psychiatric difficulties and focused on their challenges as they went through the different stages of development as health care professionals. We interviewed 12 social work students with psychiatric difficulties and analyzed the data using the immersion/crystallization method. The findings reveal the developmental process they underwent from being patients to being "therapatients" (therapists who are also patients; here, therapists coping with psychiatric difficulties). This process included four stages: an initial exploration of the health care world; questioning the possibility of a patient being a therapist and feeling incompetent; identifying their ability to be professionals; and integrating between their patient and therapist parts to become a therapatient. Understanding this process and finding ways to help students through it is crucial to allowing the patient and therapist parts to "live" together and enrich each other, and to allowing integration of professional knowledge and personal experience. PMID- 25288410 TI - Erratum to: Mass in failed renal allograft: Question. PMID- 25288412 TI - The promise of specialty pharmaceuticals. PMID- 25288411 TI - Extrarenal nephroblastomatosis in children: a report of two cases. AB - BACKGROUND: Extrarenal nephroblastomatosis is a rare entity which occurs in retroperitoneum and inguinal region predominantly. Here we report two cases of primary extrarenal nephroblastomatosis of Han Chinese in Asian in unusual locations, one is located in testis and paratestis, and the other is paraspinal cord. CASE PRESENTATION: Patient 1 was a 19-month-old boy with a hard and nodular mass adherent to the left testis in inguinal region. Patient 2 was a 9-month-old boy with a 1 * 0.7 * 0.4 cm mass in spinal canal at the midline thoracolumbar region. Histological examinations of the two patients after operations revealed extrarenall nephroblastomatosis with multiple nephrogenic foci, composed of immature glomeruli, tubules and blastemal cells.Then the patients were closely monitored without adjuvant chemotherapy, and has been alive and well without any recurrence for >6 months. CONCLUSIONS: Most nephrogenic rests remain subclinical, and thus, complete excision of the lesion with conservative treatment is recommended. Otherwise, nephrogenic rests are close associated with Wilms tumor and regular follow-up is required to ensure early detection of malignant transformation. PMID- 25288413 TI - New players join the drug development game. AB - In the hope of speeding new treatments to market, nonprofits are making targeted investments in translational research. PMID- 25288414 TI - The impact of specialty pharmaceuticals as drivers of health care costs. AB - The pharmaceutical industry is shifting its focus from blockbuster small molecules to specialty pharmaceuticals. Specialty pharmaceuticals are novel drugs and biologic agents that require special handling and ongoing monitoring, are administered by injection or infusion, and are sold in the marketplace by a small number of distributors. They are frequently identified by having a cost to payers and patients of $600 or more per treatment. The total costs of the new agents are likely to have a substantial impact on overall health care costs and on patients during the next decade, unless steps are taken to align competing interests. We examine the economic and policy issues related to specialty pharmaceuticals, taking care to consider the impact on patients. We assess the role of cost sharing provisions, legislation that is promoting realignment within the market, the role of biosimilars in price competition, and the potential for novel drug development paradigms to help bend the cost curve. The economic aspects of this analysis highlight the need for a far-reaching discussion of potential novel approaches to innovation pathways in our quest for both affordability and new technology. PMID- 25288415 TI - National trends in spending on and use of oral oncologics, first quarter 2006 through third quarter 2011. AB - Oral prescription drugs are an increasingly important treatment option for cancer. Yet contemporaneous US trends in spending on anticancer drugs known as oral oncologics have not been described. Using nationally representative data, we describe trends in national spending on and use of forty-seven oral oncologics between the first quarter of 2006 and the third quarter of 2011. Average quarterly national spending on oral oncologics increased 37 percent, from $940.3 million to $1.4 billion in 2012 dollars, a significant change. Average quarterly use of oral oncologics in the same time period measured in extended units increased at a significant pace but more slowly than spending (10 percent). Within this broader trend, differences in spending among categories of oral oncologics were observed. High levels of and increases in both spending and use were concentrated among new brand-name and patent-protected oral oncologics, including second-generation tyrosine kinase inhibitors used to treat chronic myelogenous leukemia. Decreased spending but increased use was observed among oral oncologics that lost patent protection during the study period and were available in generic form, including hormonal therapies used to treat breast and prostate cancers. Spending on new and patent-protected oral oncologics and associated price increases are significant drivers of increased spending. PMID- 25288416 TI - Hospitalizations and costs associated with hepatitis C and advanced liver disease continue to increase. AB - Disease burden models have predicted worsening morbidity of liver disease caused by hepatitis C in the United States. The aim of this study was to determine the trend in hospitalizations caused by hepatitis C and advanced liver disease. We analyzed data for the period 2004-11 from the Nationwide Inpatient Sample, the largest nationwide all-payer hospital inpatient care database. Hospitalization rates for hepatitis C per 100,000 people increased significantly from 4.76 in 2004-05 to 13.81 in 2010-11-an increase of 190 percent. Hospitalization rates for advanced liver disease also increased, particularly for hepatorenal syndrome (93 percent) and portal hypertension (62 percent). Hepatitis C was the principal diagnosis for 64,867 hospitalizations in 2010-11, resulting in a total charge of $3.5 billion. We found nationwide trends in increasing morbidity and medical costs for advanced liver disease associated with hepatitis C. Our findings suggest that hepatitis C is a public health problem and has been growing in magnitude in recent years. Stakeholders and policy makers should implement both recommended screenings for people born in the period 1945-65 and more effective treatment for hepatitis C, which have the potential to reverse the rising morbidity and costs of hepatitis C. PMID- 25288417 TI - Specialty medications: traditional and novel tools can address rising spending on these costly drugs. AB - Spending on specialty medications, which represented a small proportion of US pharmacy spending at the beginning of this decade, is growing by more than 15 percent annually. It is expected to account for approximately half ($235 billion) of total annual pharmacy spending by 2018. Among the numerous reasons for the high cost of this heterogeneous group of medications are the increasing size of target patient populations, the high cost of drug development, and a complex and uncoordinated delivery system. In this article we describe the evolution of the specialty market, characterize the current state of specialty medication use, and articulate key challenges and potential solutions. Fully realizing the potential value of the expanding universe of specialty medications will require collaborative efforts to reduce waste and promote value. Those who prescribe, dispense, deliver, and pay for specialty medications will need to employ a combination of traditional and novel management approaches, such as prior authorization, step therapy, tiered formularies, administration at lower-cost sites, and the unique tools being developed for cancer medications. PMID- 25288418 TI - Specialty pharmaceuticals: policy initiatives to improve assessment, pricing, prescription, and use. AB - The value of "specialty pharmaceuticals" for cancer and other complex conditions depends not merely on their molecular structures but also on the manner in which the drugs are assessed, insured, priced, prescribed, and used. This article analyzes the five principal stages through which a specialty drug must pass on its journey from the laboratory to the bedside. These include regulatory approval by the Food and Drug Administration for market access, insurance coverage, pricing and payment, physician prescription, and patient engagement. If structured appropriately, each stage improves performance and supports continued research and development. If structured inappropriately, however, each stage adds to administrative burdens, distorts clinical decision making, and weakens incentives for innovation. Cautious optimism is in order, but neither the continued development of breakthrough products nor their use according to evidence-based guidelines can be taken for granted. PMID- 25288419 TI - Despite high costs, specialty drugs may offer value for money comparable to that of traditional drugs. AB - Specialty drugs are often many times more expensive than traditional drugs, which raises questions of affordability and value. We compared the value of specialty and traditional drugs approved by the Food and Drug Administration (FDA) in the period 1999-2011. To do this, we identified published estimates of additional health gains (measured in quality-adjusted life-years, or QALYs) and increased costs of drug and health care resource use that were associated with fifty-eight specialty drugs and forty-four traditional drugs, compared to preexisting care. We found that specialty drugs offered greater QALY gains (0.183 versus 0.002 QALYs) but were associated with greater additional costs ($12,238 versus $784), compared to traditional drugs. The two types of drugs had comparable cost effectiveness. However, the distributions across the two types differed, with 26 percent of specialty drugs--but only 9 percent of traditional drugs--associated with incremental cost-effectiveness ratios of greater than $150,000 per QALY. Our study suggests that although specialty drugs often have higher costs than traditional drugs, they also tend to confer greater benefits and hence may still offer reasonable value for money. PMID- 25288420 TI - Specialty drug coupons lower out-of-pocket costs and may improve adherence at the risk of increasing premiums. AB - Expenditures for specialty drugs account for more than 25 percent of total US drug spending and have been increasing at more than 13 percent annually. We examined insurers' role in maintaining the affordability and accessibility of specialty drugs while maximizing their value. We conducted two analyses: one using an administrative claims database with information on more than ten million commercially insured patients and another using the same database combined with the drug prescription records from a specialty pharmacy. First, we examined the prevalence of specialty drug coupons and the degree to which these reduced patients' out-of-pocket costs, focusing on 264,801 prescriptions. Second, we quantified the association between the magnitude of out-of-pocket costs for specialty drugs and patients' abandonment of their new or restarted therapy, focusing on a group of nearly 16,000 patients. We found that drug coupons accounted for $21.2 million of patients' $35.3 million annual out-of-pocket costs. In the vast majority of cases, coupons reduced monthly cost sharing to less than $250, a point at which patients were far less likely to abandon therapy with biologic anti-inflammatory drugs or with drugs for multiple sclerosis. However, by reducing cost sharing, coupons may also circumvent efforts to encourage patients to use the most cost-effective drugs. PMID- 25288421 TI - Existing FDA pathways have potential to ensure early access to, and appropriate use of, specialty drugs. AB - Specialty drugs are notable among prescription drugs in that they offer the possibility of substantial clinical improvement, come with important risks of adverse events and mortality, can be complex to manufacture or administer, and are usually extremely costly. The Food and Drug Administration (FDA) plays a critical role in ensuring that patients who could benefit from specialty drugs have access to them in a timely fashion. In this article we review the different strategies that the FDA can use to approve and influence the post-approval prescribing of specialty drugs. When specialty drugs show promise in early clinical trials, the FDA can expedite the drugs' availability to patients through expanded access programs and expedited approval pathways that speed regulatory authorization. After approval, to ensure that specialty drugs are directed to the patients who are most likely to benefit from them, the FDA can limit the scope of the drugs' indications, encourage the development of companion diagnostic tests to indicate which patients should receive the drugs, or require that manufacturers subject them to Risk Evaluation and Mitigation Strategies to ensure that their use is appropriately limited to a restricted population that is aware of the drugs' risks and benefits. Implementing these existing regulatory approaches can promote timely patient access to specialty drugs while preventing expensive and potentially inappropriate overuse. PMID- 25288422 TI - The ethics of 'fail first': guidelines and practical scenarios for step therapy coverage policies. AB - In an effort to control health costs, payers are increasingly turning to step therapy (or "fail first") policies in pharmacy benefit design. These policies restrict coverage of expensive therapies unless patients have already failed treatment with a lower-cost alternative. More than other utilization management tools such as formulary tiering, step therapy raises important ethical concerns regarding the proper balance between cost control and the ability of patients and clinicians to tailor care to the needs of the individual patient. This article provides eight design criteria to guide the ethical development and evaluation of step therapy policies and describes six clinical scenarios in which step therapy may be appropriate. The ethical criteria and scenarios are intended to provide guidance and transparency for insurers, patients, clinicians, and policy makers in choosing and paying for the appropriate therapies. PMID- 25288423 TI - The 340B drug discount program: hospitals generate profits by expanding to reach more affluent communities. AB - The federal 340B program gives participating hospitals and other medical providers deep discounts on outpatient drugs. Named for a section of the Veterans Health Care Act of 1992, the program's original intent was to help low-income and uninsured patients. But the program has come under scrutiny by critics who contend that some hospitals exploit the drug discounts to generate profits instead of either investing in programs for the poor or passing the discounts along to patients and insurers. We examined whether the program is expanding in ways that could maximize hospitals' ability to generate profits from the 340B drug discounts. We matched data for 960 hospitals and 3,964 affiliated clinics registered with the 340B program in 2012 with the socioeconomic characteristics of their communities from the US Census Bureau's American Community Survey. We found that hospital-affiliated clinics that registered for the 340B program in 2004 or later served communities that were wealthier and had higher rates of health insurance compared to communities served by hospitals and clinics that registered for the program before 2004. Our findings support the criticism that the 340B program is being converted from one that serves vulnerable patient populations to one that enriches hospitals and their affiliated clinics. PMID- 25288425 TI - Five myths about cancer care in America. AB - In this commentary we debunk a number of the most common misconceptions about cancer treatment, such as claims that the war on cancer has been a failure and that treatment costs are unsustainable. In addition, there is good evidence that patients value these treatments more highly than traditional cost-effectiveness analysis would indicate. We argue that coverage policies placing undue burden on patients are socially wasteful and will likely discourage further innovation. PMID- 25288424 TI - Acute hospital care is the chief driver of regional spending variation in Medicare patients with advanced cancer. AB - The root causes of regional variation in medical spending are poorly understood and vary by clinical condition. To identify drivers of regional spending variation for Medicare patients with advanced cancer, we used linked Surveillance, Epidemiology, and End Results program (SEER)-Medicare data from the period 2004-10. We broke down Medicare spending into thirteen cancer-relevant service categories. We then calculated the contribution of each category to spending and regional spending variation. Acute hospital care was the largest component of spending and the chief driver of regional spending variation, accounting for 48 percent of spending and 67 percent of variation. In contrast, chemotherapy accounted for 16 percent of spending and 10 percent of variation. Hospice care constituted 5 percent of spending. However, variation in hospice spending was fully offset by opposing variation in other categories. Our analysis suggests that the strategy with the greatest potential to improve the value of care for patients with advanced cancer is to reduce reliance on acute hospital care for this patient population. PMID- 25288426 TI - Myths and realities in cancer care: another point of view. AB - Cancer care is advancing, and the cancer community is right to celebrate that progress. Simultaneously, however, the cost of cancer therapy is rising along with all medical costs. In a matter of just a few years, the cost of health coverage is projected to reach heights that are simply unsustainable for most American families, overshadowing every other daily expense. Such an overwhelming burden will continue to undermine the progress made in developing new, more effective treatment and care for cancer patients. There cannot be a celebration of discoveries if there is no way to pay for them. It is from that perspective that I react and respond here to the commentary of Dana Goldman and Tomas Philipson, who debunk five myths in cancer care. I concur with the authors' assessment of the value and impact of progress in cancer care. However, I also argue that researchers and policy makers must pay more attention to the impact of cost on patients' adherence and experience and the speed with which new treatment and care are being developed. PMID- 25288427 TI - Few ACOs pursue innovative models that integrate care for mental illness and substance abuse with primary care. AB - Accountable care organizations (ACOs) may be well positioned to increase the focus on managing behavioral health conditions (mental health and substance abuse) through the integration of behavioral health treatment and primary care. We used a mixed-methods research design to examine the extent to which ACOs are clinically, organizationally, and financially integrating behavioral health care and primary care. We used data from 257 respondents to the National Survey of Accountable Care Organizations, a nationally representative survey of ACOs. The data were supplemented with semistructured, in-depth interviews with clinical leaders at sixteen ACOs purposively sampled to represent the spectrum of behavioral health integration. We found that most ACOs hold responsibility for some behavioral health care costs, and 42 percent include behavioral health specialists among their providers. However, integration of behavioral health care and primary care remains low, with most ACOs pursuing traditional fragmented approaches to physical and behavioral health care and only a minority implementing innovative models. Contract design and contextual factors appear to influence the extent to which ACOs integrate behavioral health care. Nevertheless, the ACO model has the potential to create opportunities for improving behavioral health care and integrating it with primary care. PMID- 25288428 TI - Patient-to-physician messaging: volume nearly tripled as more patients joined system, but per capita rate plateaued. AB - Patients want to be able to communicate with their physicians by e-mail. However, physicians are often concerned about the impact that such communications will have on their time, productivity, and reimbursement. Typically, physicians are not reimbursed for time spent communicating with patients electronically. But under federal meaningful-use criteria for information technology, physicians can receive a modest incentive for such communications. Little is known about trends in secure e-mail messaging between physicians and patients. To understand these trends, we analyzed the volume of messages in a large academic health system's patient portal in the period 2001-10. At the end of 2010, 49,778 patients (22.7 percent of all patients seen within the system) had enrolled in the portal, and 36.9 percent of enrolled patients (8.4 percent of all patients) had sent at least one message to a physician. Physicians in the aggregate saw a near tripling of e mail messages during the study period. However, the number of messages per hundred patients per month stabilized between 2005 and 2010, at an average of 18.9 messages. As physician reimbursement moves toward global payments, physicians' and patients' participation in secure messaging will likely increase, and electronic communication should be considered part of physicians' job descriptions. PMID- 25288429 TI - Patient-centered medical home initiatives expanded in 2009-13: providers, patients, and payment incentives increased. AB - Patient-centered medical home initiatives are central to many efforts to reform the US health care delivery system. To better understand the extent and nature of these initiatives, in 2013 we performed a nationwide cross-sectional survey of initiatives that included payment reform incentives in their models, and we compared the results to those of a similar survey we conducted in 2009. We found that the number of initiatives featuring payment reform incentives had increased from 26 in 2009 to 114 in 2013. The number of patients covered by these initiatives had increased from nearly five million to almost twenty-one million. We also found that the proportion of time-limited initiatives--those with a planned end date--was 20 percent in 2013, a decrease from 77 percent in 2009. Finally, we found that the dominant payment model for patient-centered medical homes remained fee-for-service payments augmented by per member per month payments and pay-for-performance bonuses. However, those payments and bonuses were higher in 2013 than they were in 2009, and the use of shared-savings models was greater. The patient-centered medical home model is likely to continue both to become more common and to play an important role in delivery system reform. PMID- 25288430 TI - Exposing physicians to reduced residency work hours did not adversely affect patient outcomes after residency. AB - In 2003, work hours for physicians-in-training (residents) were capped by regulation at eighty hours per week, leading to the hotly debated but unexplored issue of whether physicians today are less well trained as a result of these work hour reforms. Using a unique database of nearly all hospitalizations in Florida during 2000-09 that were linked to detailed information on the medical training history of the physician of record for each hospitalization, we studied whether hospital mortality and patients' length-of-stay varied according to the number of years a physician was exposed to the 2003 duty-hour regulations during his or her residency. We examined this database of practicing Florida physicians, using a difference-in-differences analysis that compared trends in outcomes of junior physicians (those with one-year post-residency experience) pre- and post-2003 to a control group of senior physicians (those with ten or more years of post residency experience) who were not exposed to these reforms during their residency. We found that the duty-hour reforms did not adversely affect hospital mortality and length-of-stay of patients cared for by new attending physicians who were partly or fully exposed to reduced duty hours during their own residency. However, assessment of the impact of the duty-hour reforms on other clinical outcomes is needed. PMID- 25288431 TI - A simple case of chest pain: sensitizing doctors to patients with disabilities. AB - A doctor who stutters confronts the stigma against patients-and providers-with disabilities. PMID- 25288434 TI - Fraud and electronic health records. PMID- 25288435 TI - Electronic health records: the authors reply. PMID- 25288436 TI - Big data related to physicians. PMID- 25288437 TI - Medicare spending per beneficiary. PMID- 25288439 TI - The role of the globular heads of the C1q receptor in HPV-16 E2-induced human cervical squamous carcinoma cell apoptosis via a mitochondria-dependent pathway. AB - BACKGROUND: Human papillomavirus type-16 (HPV-16) E2 protein acts as a transcriptional modulator and plays a key role in regulating many biological responses. The purpose of this study was to investigate the relationship between HPV-16 E2, the receptor for the globular heads of human C1q (gC1qR) gene expression, mitochondrial dysfunction and apoptosis regulation in human cervical squamous carcinoma cells (C33a and SiHa). METHODS: HPV-16 E2 and gC1qR expression was examined using real-time PCR and western blot analysis. Apoptosis in C33a and SiHa cells was assessed by flow cytometry. Mitochondrial function was detected via ROS generation, the amount of cytosolic Ca2+, and changes in the mitochondrial membrane potential (Deltapsim). RESULTS: The expression of the HPV 16 E2 and gC1qR gene significantly decreased in human cervical squamous carcinoma samples relative to the non-cancerous cervix samples. C33a and SiHa cells that were transfected with a vector encoding HPV-16 E2 displayed significantly increased gC1qR gene expression and mitochondrial dysfunction as well as an up regulation of cellular apoptosis, which was abrogated by the addition of gC1qR small-interfering RNA (siRNA). CONCLUSIONS: These data support a mechanism whereby gC1qR plays an important role in HPV-16 E2-induced human cervical squamous carcinoma cell apoptosis via a mitochondria-dependent pathway. PMID- 25288440 TI - Autism research funding allocation: can economics tell us if we have got it right? AB - There is a concern that the allocation of autism spectrum disorder (ASD) research funding may be misallocating resources, overemphasizing basic science at the expense of translational and clinical research. Anthony Bailey has proposed that an economic evaluation of autism research funding allocations could be beneficial for funding agencies by identifying under- or overfunded areas of research. In response to Bailey, we illustrate why economics cannot provide an objective, technical solution for identifying the "best" allocation of research resources. Economic evaluation has its greatest power as a late-stage research tool for interventions with identified objectives, outcomes, and data. This is not the case for evaluating whether research areas are over- or underfunded. Without an understanding of how research funding influences the likelihood and value of a discovery, or without a statement of the societal objectives for ASD research and level of risk aversion, economic analysis cannot provide a useful normative evaluation of ASD research. PMID- 25288441 TI - Professional occupation and the number of teeth retained among older adults aged 50 and above. AB - OBJECTIVE: To examine the association between occupational characteristics and number of natural teeth retained among older adults aged 50 and above. BACKGROUND: Despite the integral part of the professional occupation of a person's time, few studies have examined the effect of the occupational environment on one's oral health. MATERIAL AND METHODS: Self-administered questionnaires were randomly distributed among 280 participants, who had at least one professional occupation over a period of 10 years or more. Data from the questionnaire were collected concerning variables related to professional occupation and the self-reported number of natural teeth retained. The data were analysed using a logistic regression analysis with stepwise-backward selection. RESULTS: Significant risk factors for the number of natural teeth being <=25 were age (p < 0.001), years of education (p = 0.019) and a hospital/commercial environment of work (p = 0.021). The odds ratio for the number of natural teeth <=25 increased with each year by 1.109, decreased with each additional year of education by 0.881, and was 2.693 folds higher for individuals working in a hospital/commercial environment compared to those in an office environment. CONCLUSIONS: These findings suggest the importance of operating community-based oral health programmes for these occupational risk groups. The results from this study also implicate the need for further studies of this subject to find the underlying reasons for these occupational environmental risks. PMID- 25288442 TI - An evaluation of clinical risk factors for estimating fracture risk in postmenopausal osteoporosis using an electronic medical record database. AB - SUMMARY: Many of the clinical risk factors used in fracture risk assessment (FRAX) calculator are available in electronic medical record (EMR) databases and are good sources of osteoporosis risk factor information. The EPIC EMR database showed a lower prevalence of FRAX risk factors and, consequently, proportion of patients who would be deemed "high risk." INTRODUCTION: The FRAX tool is underutilized for osteoporosis screening. Many of the clinical risk factors for FRAX may be available in EMR databases and may enable health systems to perform fracture risk assessments. We intended to identify variables in an EMR database for calculating FRAX score in a cohort of postmenopausal women, to estimate absolute fracture risk, and to determine the proportions of women whose absolute fracture risks exceed the National Osteoporosis Foundation (NOF) thresholds. METHODS: Our cohort was selected using an EMR database with demographic, inpatient, outpatient, and clinical information for female patients age>=50 in a family practice, internal medicine, or obstetrics/gynecology clinic in 2007-2008. The latest physician encounter was the index date. Variables, problem and medication lists, diagnosis codes, and histories from the EMR were used to populate the 11 clinical risk factor variables used in the FRAX. These risk factor prevalence and treatment-eligible proportions were compared to those of published epidemiology studies. RESULTS: The study included 345 patients. Mean (SD) 10-year risk for any major fracture was 11.1% (6.8) when bone mineral density (BMD) was used and 11.2% (6.5) when BMI was used. About 10.1% of the cohort exceeded the NOF's 20% major fracture risk threshold and 32.5% exceeded the NOF's 3% hip fracture risk threshold when BMD was used. Overall, the number of treatment-eligible patients was slightly lower when FRAX was calculated using BMD versus BMI (13.6 and 36.8%). CONCLUSION: Our cohort using EMR data most likely underestimated the mean 10-year probability of any major fracture compared to other cohorts in published literature. The difference may be in the nature of EMRs for supporting only passive data collection of risk factor information. PMID- 25288443 TI - Artificially low cortical bone mineral density in Turner syndrome is due to the partial volume effect. AB - We aimed to show that the decrease in the cortical bone mineral density (BMD) in the radius in Turner syndrome (TS) is artificially caused by the partial volume effect. We confirmed that the partial volume effect-corrected cortical BMD is not decreased in TS compared to in the healthy controls. Other factors are responsible for the increased fracture rate in TS. INTRODUCTION: Decreased cortical bone mineral density (BMD) has been reported in Turner syndrome (TS), using peripheral quantitative computerised tomography, and it is perceived as one of the major factors leading to increased fracture risk. We tested the hypothesis that low cortical BMD in the radius is caused artificially by the partial volume effect. METHODS: A cross-sectional study was conducted at the university hospital referral centre between March and October 2013. Thirty-two participants with TS who consented to the study were included (mean age 15.3 +/- 3.2 years). We assessed the cortical BMD in the radius as well as the tibia, where the cortex is thicker compared with the radius. RESULTS: Whereas the cortical BMD was decreased in the radius (mean +/- SD Z-score -0.6 +/- 1.5, p = 0.037), it was increased in the tibia (mean Z-score 0.83 +/- 1.0, p < 0.001). After correcting the cortical BMD for the partial volume effect, the mean Z-score was normal in the radius in TS (0.4 +/- 1.3, p = 0.064). The corrected cortical BMD values were similar in the radius and tibia (1108 +/- 52 vs. 1104 +/- 48, group difference p = 0.75). CONCLUSIONS: The cortical BMD is not decreased in TS. The partial volume effect is responsible for previous findings of decreased cortical BMD in the radius. Altered bone geometry or other factors rather than low cortical BMD likely play a role in the increased fracture risk in TS. PMID- 25288444 TI - Peak-bone-mass development in young adults: effects of study program related levels of occupational and leisure time physical activity and exercise. A prospective 5-year study. AB - SUMMARY: Young adulthood is characterized by profound life-style changes. This study suggests that reduction of sport or exercise, induced by alteration of the occupational situation, negatively impacts generation/maintenance of peak bone mass. In order to compensate occupational-related reductions of physical activity, workplace exercise programs will be helpful. INTRODUCTION: Only few studies have determined the effect of physical activity or physical exercise on bone mineral density (BMD) in the period of late skeletal maturation, i.e. around peak bone mass. The aim of this article was to determine the long-term effect of different levels of physical activity and exercise directly and indirectly derived by occupation during young adulthood. METHODS: Sixty-one male and female dental students (DES) and 53 male and female sport students (SPS) 21+/-2 years old were accompanied over the course (4.8+/-0.5 years) of their study program. BMD at the lumbar spine (LS), hip, and whole body (WB) were determined using dual energy X-ray absorptiometry. RESULTS: Parameters of physical activity increased non-significantly in both groups with no relevant differences between the groups. Indices of exercise, however, increased significantly in the SPS group while a significant decrease was assessed for the DES group. Independent of gender, BMD of the SPS increased significantly (p<=0.007) at all skeletal sites (LS, 2.4+/ 3.9%; hip, 1.6+/-3.5%; WB, 1.8+/-2.8%) while BMD of the DES remained unchanged at LS (-0.6+/-4.4%, p=0.432) and WB (0.5+/-1.9%, p=0.092) but decreased significantly at the hip (-1.9+/-4.3%, p=0.010). BMD-changes at LS, hip, and WB differ significantly between SPS and DES (p<=0.017). Results remained unchanged after adjusting for baseline BMD-values that differed (p=0.030 to p=0.082) in favor of the SPS group. CONCLUSION: Changes of exercise levels directly or indirectly caused by occupational factors during young adulthood significantly affected generation and/or maintenance of peak bone mass. Compensatory exercise is thus highly relevant for bone health of young adults. PMID- 25288445 TI - Osteoporosis therapy: a novel insight from natural homeostatic system in the skeleton. AB - The skeleton normally responds to mechanical environment to maintain the resulting elastic deformation (strain) of bone, while increased bone strength by an osteoporosis drug results in decreased bone strain. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by natural homeostatic system in the skeleton. This logic is consistent with the fact that there exists a powerful effect that returns bone mass to its pre-treatment level after the withdrawal of treatment with osteoporosis agents. The present hypothesis provides a new significant insight into the mechanisms by which osteoporosis drugs improve bone fragility. Here we briefly discuss the effects of teriparatide, romosozumab, and odanacatib on bones in animals and humans. PMID- 25288447 TI - Family caregivers' involvement in caring for a hospitalized patient with cancer and their quality of life in a country with strong family bonds. AB - BACKGROUND: Being involved in caring for family members during illness is part of the Indonesian culture, even during hospitalization. It is unknown which factors influence the quality of life (QoL) of family members taking care of their loved ones. The present study aims to identify factors influencing the QoL of family caregivers of hospitalized patients with cancer in Indonesia. METHODS: A cross sectional survey was performed. Data were collected in a general hospital in Yogyakarta from September to December 2011. Family caregivers of patients with cancer were invited to participate. Regression analysis was used to determine which aspects of caring and which demographic characteristics influenced their QoL. The Caregiver QoL Index-Cancer questionnaire was used to measure the QoL. RESULTS: One hundred of 120 invited caregivers (83%) completed the questionnaire. Being involved in psychological issues in caring (beta = 0.374; p = 0.000), younger age (beta = -0.282; p = 0.003), no previous caring experience (beta = 0.301; p = 0.001), and not being the spouse (beta = -0.228; p = 0.015) negatively influenced the QoL and explained 31% of the variation (adjusted R(2) = 0.312; F = 12.24; p = 0.000). Gender, education level, and time spent on caring did not influence the QoL of family caregivers. CONCLUSIONS: Our findings identified modifiable factors such as dealing with psychological issues and lack of experience in caring that negatively influenced the QoL of family caregivers. These factors are potential targets for intervention strategies. Education and intervention programs focusing on dealing with psychological problems in cancer care might improve the QoL of both patients and their families. PMID- 25288449 TI - Modeling of magnetoelastic nanostructures with a fully coupled mechanical micromagnetic model. AB - Micromagnetic simulations of magnetoelastic nanostructures traditionally rely on either the Stoner-Wohlfarth model or the Landau-Lifshitz-Gilbert (LLG) model, assuming uniform strain (and/or assuming uniform magnetization). While the uniform strain assumption is reasonable when modeling magnetoelastic thin films, this constant strain approach becomes increasingly inaccurate for smaller in plane nanoscale structures. This paper presents analytical work intended to significantly improve the simulation of finite structures by fully coupling the LLG model with elastodynamics, i.e., the partial differential equations are intrinsically coupled. The coupled equations developed in this manuscript, along with the Stoner-Wohlfarth model and the LLG (constant strain) model are compared to experimental data on nickel nanostructures. The nickel nanostructures are 100 * 300 * 35 nm single domain elements that are fabricated on a Si/SiO2 substrate; these nanostructures are mechanically strained when they experience an applied magnetic field, which is used to generate M vs H curves. Results reveal that this paper's fully-coupled approach corresponds the best with the experimental data on coercive field changes. This more sophisticated modeling technique is critical for guiding the design process of future nanoscale strain-mediated multiferroic elements, such as those needed in memory systems. PMID- 25288448 TI - Medication oversupply in patients with diabetes. AB - BACKGROUND: Studies in integrated health systems suggest that patients often accumulate oversupplies of prescribed medications, which is associated with higher costs and hospitalization risk. However, predictors of oversupply are poorly understood, with no studies in Medicare Part D. OBJECTIVE: The aim of this study was to describe prevalence and predictors of oversupply of antidiabetic, antihypertensive, and antihyperlipidemic medications in adults with diabetes managed by a large, multidisciplinary, academic physician group and enrolled in Medicare Part D or a local private health plan. METHODS: This was a retrospective cohort study. Electronic health record data were linked to medical and pharmacy claims and enrollment data from Medicare and a local private payer for 2006-2008 to construct a patient-quarter dataset for patients managed by the physician group. Patients' quarterly refill adherence was calculated using ReComp, a continuous, multiple-interval measure of medication acquisition (CMA), and categorized as <0.80 = Undersupply, 0.80-1.20 = Appropriate Supply, >1.20 = Oversupply. We examined associations of baseline and time-varying predisposing, enabling, and medical need factors to quarterly supply using multinomial logistic regression. RESULTS: The sample included 2519 adults with diabetes. Relative to patients with private insurance, higher odds of oversupply were observed in patients aged <65 in Medicare (OR = 3.36, 95% CI = 1.61-6.99), patients 65+ in Medicare (OR = 2.51, 95% CI = 1.37-4.60), patients <65 in Medicare/Medicaid (OR = 4.55, 95% CI = 2.33-8.92), and patients 65+ in Medicare/Medicaid (OR = 5.73, 95% CI = 2.89-11.33). Other factors associated with higher odds of oversupply included any 90-day refills during the quarter, psychotic disorder diagnosis, and moderate versus tight glycemic control. CONCLUSIONS: Oversupply was less prevalent than in previous studies of integrated systems, but Medicare Part D enrollees had greater odds of oversupply than privately insured individuals. Future research should examine utilization management practices of Part D versus private health plans that may affect oversupply. PMID- 25288450 TI - The complete mitochondrial genome of Scutopus ventrolineatus (Mollusca: Chaetodermomorpha) supports the Aculifera hypothesis. AB - BACKGROUND: With more than 100000 living species, mollusks are the second most diverse metazoan phylum. The current taxonomic classification of mollusks recognizes eight classes (Neomeniomorpha, Chaetodermomorpha, Polyplacophora, Monoplacophora, Cephalopoda, Gastropoda, Bivalvia, and Scaphopoda) that exhibit very distinct body plans. In the past, phylogenetic relationships among mollusk classes have been contentious due to the lack of indisputable morphological synapomorphies. Fortunately, recent phylogenetic analyses based on multi-gene data sets are rendering promising results. In this regard, mitochondrial genomes have been widely used to reconstruct deep phylogenies. For mollusks, complete mitochondrial genomes are mostly available for gastropods, bivalves, and cephalopods, whereas other less-diverse lineages have few or none reported. RESULTS: The complete DNA sequence (14662 bp) of the mitochondrial genome of the chaetodermomorph Scutopus ventrolineatus Salvini-Plawen, 1968 was determined. Compared with other mollusks, the relative position of protein-coding genes in the mitochondrial genome of S. ventrolineatus is very similar to those reported for Polyplacophora, Cephalopoda and early-diverging lineages of Bivalvia and Gastropoda (Vetigastropoda and Neritimorpha; but not Patellogastropoda). The reconstructed phylogenetic tree based on combined mitochondrial and nuclear sequence data recovered monophyletic Aplacophora, Aculifera, and Conchifera. Within the latter, Cephalopoda was the sister group of Gastropoda and Bivalvia + Scaphopoda. CONCLUSIONS: Phylogenetic analyses of mitochondrial sequences showed strong among-lineage rate heterogeneity that produced long-branch attraction biases. Removal of long branches (namely those of bivalves and patellogastropods) ameliorated but not fully resolved the problem. Best results in terms of statistical support were achieved when mitochondrial and nuclear sequence data were concatenated. PMID- 25288451 TI - Intrinsic disorder within the erythrocyte binding-like proteins from Plasmodium falciparum. AB - The ability of the malaria parasite, Plasmodium falciparum, to proliferate within the human host depends on its invasion of erythrocytes. Erythrocyte binding-like (EBL) proteins play crucial roles in the attachment of merozoites to human erythrocytes by binding to specific receptors on the cell surface. In this study, we have carried out a bioinformatics analysis of the three EBL proteins EBA-140, EBA-175 and EBA-181 and show that they contain a large amount of intrinsic disorder in particular within the RIII-V domains. The functional role of these domains has so far not been identified, although antibodies raised against these regions were shown to inhibit parasite invasion. Here, we obtain a more complete structural and dynamic view of the EBL proteins by focusing on the biophysical characterization of a smaller construct of the RIII-V regions of EBA-181 (EBA 181945-1097). We show using a number of techniques that EBA-181945-1097 is intrinsically disordered, and we obtain a detailed structural and dynamic characterization of the protein at atomic resolution using nuclear magnetic resonance (NMR) spectroscopy. Our results show that EBA-181945-1097 is essentially a statistical coil with the presence of several turn motifs and does not possess transiently populated secondary structures as is common for many intrinsically disordered proteins that fold via specific, pre-formed molecular recognition elements. PMID- 25288452 TI - Wavefunction in density functional theory embedding for excited states: which wavefunctions, which densities? AB - We present a detailed analysis of our recently proposed wavefunction in density functional theory method to include differential polarization effects through state-specific embedding potentials. We study methylenecyclopropene and acrolein in water by using several wavefunction approaches to validate the supermolecular reference and to assess their response to embedding. We find that quantum Monte Carlo, complete-active space second-order perturbation theory, and coupled cluster methods give very consistent solvatochromic shifts and a similar response to embedding. Our scheme corrects the excitation energies produced with a frozen environment, but the values are often overshot. To ameliorate the problem, one needs to use wavefunction densities to polarize the environment. The choice of the exchange-correlation functional in the construction of the potential has little effect on the excitation, whereas the approximate kinetic-energy functional appears to be the largest source of error. PMID- 25288455 TI - SOX11 target genes: implications for neurogenesis and neuropsychiatric illness. PMID- 25288453 TI - Complete radiological response of an initially locally advanced unresectable pancreatic cancer to chemoradiotherapy using FOLFIRINOX regimen: report of a case. PMID- 25288456 TI - Excessive activation of the loop between the NR2B subunit of the N-methyl-d aspartate receptor and glycogen synthase kinase-3beta in the hippocampi of patients with major depressive disorder. PMID- 25288457 TI - Increased white matter integrity of posterior cingulate gyrus in the evolution of post-traumatic stress disorder. PMID- 25288458 TI - Construct validity and factor structure of Tamil version of Beck Cognitive Insight Scale to assess cognitive insight of patients with schizophrenia. PMID- 25288459 TI - Visually evoked potentials, NMDA receptors and the magnocellular system in schizophrenia. PMID- 25288460 TI - Can mobile skin conductance assessments be helpful in signalling imminent inpatient aggression?. PMID- 25288461 TI - Planting a misdiagnosis of Alzheimer's disease in a person's mind. PMID- 25288462 TI - [Are antimitochondrial antibodies the invariable hallmark of primary biliary cirrhosis?]. PMID- 25288463 TI - Preparing surgeons for rural Australia: the RACS Rural Surgical Training Program. AB - BACKGROUND: The Royal Australasian College of Surgeons' Rural Surgical Training Program (RSTP) ran from 1996 to 2007. As a formal review of the RSTP had never occurred, it remained unknown whether the RSTP had achieved its objectives of training surgeons for and retaining them in practice in rural Australia. METHODS: Sixty-six RSTP fellows and 67 general surgery fellows were asked to complete a survey evaluating factors influencing the decision to pursue a rural surgical career, the influence of the RSTP on subsequent career pathways and the adequacy of the RSTP in preparing its trainees for rural work. RESULTS: Fifty-one out of 66 RSTP fellows were noted to be in practice in metropolitan Australia, with only 15 in rural Australia. Responses obtained revealed rural surgical rotations during training as a major influence in the decision to perform rural work. Thirty out of 35 RSTP participants stated that the RSTP did not influence their subsequent careers. Six out of 15 RSTP respondents responded positively when asked about the adequacy of the RSTP in preparing its trainees for rural work. CONCLUSION: The RSTP largely succeeded in preparing its trainees for rural work, but did not succeed in retaining the majority of its trainees in practice in rural Australia. It appears that targeting doctors at the point of admission to surgical training, in the hope that this would translate into more rural surgeons, did not result in improved retention in rural areas. PMID- 25288464 TI - Characterization of nucleic acids by tandem mass spectrometry - The second decade (2004-2013): From DNA to RNA and modified sequences. AB - Nucleic acids play key roles in the storage and processing of genetic information, as well as in the regulation of cellular processes. Consequently, they represent attractive targets for drugs against gene-related diseases. On the other hand, synthetic oligonucleotide analogues have found application as chemotherapeutic agents targeting cellular DNA and RNA. The development of effective nucleic acid-based chemotherapeutic strategies requires adequate analytical techniques capable of providing detailed information about the nucleotide sequences, the presence of structural modifications, the formation of higher-order structures, as well as the interaction of nucleic acids with other cellular components and chemotherapeutic agents. Due to the impressive technical and methodological developments of the past years, tandem mass spectrometry has evolved to one of the most powerful tools supporting research related to nucleic acids. This review covers the literature of the past decade devoted to the tandem mass spectrometric investigation of nucleic acids, with the main focus on the fundamental mechanistic aspects governing the gas-phase dissociation of DNA, RNA, modified oligonucleotide analogues, and their adducts with metal ions. Additionally, recent findings on the elucidation of nucleic acid higher-order structures by tandem mass spectrometry are reviewed. (c) 2014 Wiley Periodicals, Inc., Mass Spec Rev 35:483-523, 2016. PMID- 25288465 TI - A novel polymorphism in the PAI-1 gene promoter enhances gene expression. A novel pro-thrombotic risk factor? AB - INTRODUCTION: Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of tissue-type plasminogen activator in plasma and the most important regulator of the fibrinolytic pathway. The 4G/5G polymorphism (rs1799889) in the PAI-1 promoter is associated with altered PAI-1 transcription. We have identified a new 4G/5G allele, in which a T is inserted near the 4G tract or replaces a G in the 5G tract, forming a T plus 4G (T4G) region. MATERIALS AND METHODS: This new variant was first identified in two women, one had experienced juvenile myocardial infarction, the other repeated miscarriage; both had increased PAI-1 plasma activity. In view of the important influence of this promoter region on PAI-1 protein plasma level, we performed in vitro evaluation of the effects of the T4G variant on the transcription activity of the PAI-1 gene promoter. RESULTS AND CONCLUSIONS: In silico prediction analysis showed that presence of the T4G allele disrupts the E-Box region upstream of the T4G variant, altering the affinity of the target sequence for E-Box binding factors like upstream stimulatory factor-1 (USF-1). Basal T4G promoter activity was 50% higher compared to 4G and 5G variants, but it was less stimulated by USF-1 overexpression. We also analyzed the effects of IL-1beta and IL-6 on the PAI-1 promoter activity of our three constructs and showed that the T4G variant was less affected by IL-1beta than the other variants. These findings indicate that the T4G variant may be a novel risk factor for thrombotic events. PMID- 25288466 TI - Anti-apoptotic role of sonic hedgehog on blood platelets. AB - Sonic hedgehog (Shh) is an essential morphogen involved in vertebrate organogenesis. Perturbation of Hh signaling is associated with pathological consequences like tumor formation and chronic lung fibrosis. Platelets are highly sensitive circulating blood cells responsible for hemostasis, while hyperactivity of these cells lead to morbidities like ischemic heart diseases and stroke. Despite being terminally differentiated cells with life span of 10-12 days, platelets have recently been shown to respond to Wnt ligand, another developmental signal similar to Shh. In this study, we demonstrate that components of Shh signaling, Patched and Gli3, are expressed in human platelets consistent with existence of functional Hedgehog signaling in these cells. Shh had potent inhibitory effect on platelet apoptosis induced by ABT-737 or thrombin through attenuation of caspase-3 activity. The Shh-mediated pathway may thus represent a novel endogenous mechanism for regulating platelet activity and life span. PMID- 25288467 TI - Increased factor XIa levels in patients with a first acute myocardial infarction: the introduction of a new thrombin generation based factor XIa assay. AB - OBJECTIVE: One of the contributing mechanisms in acute myocardial infarction (AMI) is plasma hypercoagulability. Recently, it was suggested that factor XI activation might play a role in atherothrombosis. To quantify factor XIa plasma levels, we developed a new thrombin generation based assay and hypothesized that in AMI patients factor XIa levels are increased during the acute thrombotic event. METHODS: A prospective cohort study was performed including 56 patients with first AMI. Blood was collected upon admission and after 6 months. Reference blood samples were obtained from 30 apparently healthy control subjects. Plasma samples were diluted (1:5) in factor XI deficient plasma and factor XIa plasma levels were established using a reference curve (0-12.5 pM factor XIa) and an inhibitory anti-factor XIa antibody. The established FXIa concentrations were related to the 1-year outcome. RESULTS: Factor XIa plasma concentrations were significantly increased in AMI patients on admission compared to 6 months after the event (3.7 pM [2.7-5.5] vs. 2.8 [1.9-4.3], median +/- IQR; P=0.001) and compared to healthy controls (3.7 pM [2.7-5.5] vs. 2.7 [1.6-4.2], median +/- IQR; P=0.004). However, a high factor FXIa level at baseline was not significantly associated with a recurrent cardiovascular event (OR 1.26, 95%CI 0.33-4.7). CONCLUSIONS: This study presents the first application of a new thrombin generation based factor XIa assay, showing significantly increased factor XIa levels in AMI patients on admission compared to 6 months after the event and compared to healthy controls. The factor XIa concentration was not associated with the risk of recurrence. PMID- 25288468 TI - Screening high-risk cancer patients for VTE: a prospective observational study. AB - BACKGROUND: The utility of screening for venous thromboembolism (VTE) in cancer patients is unknown. We evaluated this in a prospective cohort study of cancer patients initiating a new chemotherapy regimen and deemed high-risk (score >=3) based on a validated Risk Score. METHODS: Patients were evaluated with baseline and Q4 (+/-1) week serial ultrasonography for up to 16 weeks; additionally, computed tomography scans for restaging were also evaluated for VTE. RESULTS: The study population comprised 35 patients. Pancreatic and gastro-esophageal cancers were the most common diagnoses. Of these, 8 (23%) developed a VTE. This included 5 patients with DVT alone (14%), 1 patient with PE alone (3%) and 2 (6%) with both. Ultrasound examinations identified asymptomatic DVT in 9.3% of patients at baseline; 0% at weeks 4 and 8 and 5.6% at week 12. Restaging CT scans identified asymptomatic PE in one patient at week 6 and in one patient at week 9 with subsequent DVT at week 10. CONCLUSIONS: Screening for asymptomatic VTE has not been previously used as a clinical strategy in ambulatory cancer patients. We report that one-tenth of patients at baseline had occult DVT and in this high risk population, screening at baseline may be of value. PMID- 25288469 TI - Echocardiographic evolution of pulmonary artery pressure after acute pulmonary embolism. Results from IPER registry. AB - AIMS: The aim of the study is to describe the course of the echocardiographically measured pulmonary artery systolic pressure (PAsP) in a series of patients included in the Italian Pulmonary Embolism Registry (IPER). METHODS: Patients with confirmed PE received an echo-Doppler evaluation within 24 hours from hospital admission and after one year. Pulmonary hypertension (PH) was considered "likely" , "possible" or "unlikely" with a right ventricular-right atrial (RV-RA) pressure gradient>45 mm Hg, between 32 and 45 mm Hg and <=31 mm Hg and no additional echocardiographic variables suggestive of PH, respectively. RESULTS: We studied 286 patients (169 females and 117 males, mean age 67 +/- 15; mean follow-up 387 +/- 45 days): 240 had a baseline tricuspid regurgitation (TR) and a RV-RA gradient of variable degree. PH was considered likely, unlikely and possible in 97, 93 and 50 patients respectively. At FU echocardiography, 6 patients (2.1%) had a likely PH and all of them were part of the group of 97 patients with a baseline likely PH; 24 patients (8.4%) had a possible PH, and 67% of them had an initial likely PH. No patients with a baseline unlikely PH or without TR developed a follow-up PH (both likely or possible). The probability to show a likely PH at FU echocardiography for patients with a baseline RV-RA gradient>45 mm Hg was 6.2%, while the probability not to have a likely PH for patients with a baseline RV-RA gradient <= 45 mm Hg was 100%. CONCLUSION: In our study population of patients with acute PE, we observed that those presenting with a baseline echocardiographic RV-RA pressure gradient <= 45 mm Hg were completely free from a likely PH after 1-year. PMID- 25288470 TI - Cross-sectional serosurvey and associated factors of bluetongue virus antibodies presence in small ruminants of Nepal. AB - BACKGROUND: Bluetongue (BT) is an infectious, insect-borne viral disease primarily affecting sheep and occasionally cattle and goats. In Nepal, BT is an emerging disease of economic importance. The objective of this study was to estimate the seroprevalence of BT virus (BTV) in small ruminants of two eco-zones of Nepal, Hills and Terai, and to identify the factors associated with virus exposure. We conducted a cross-sectional serosurvey from March 2012 through February 2013 by sampling 318 small ruminants (184 sheep and 134 goats) from seven clusters (villages) of selected vulnerable communities of Chitwan (Terai) and Lamjung (Hills) Districts of Nepal. RESULTS: Of the 318 serum sample tested, 27.9% [95% confidence interval (CI): 23.1- 33.2] were positive for BTV antibodies (25.0% sheep and 31.3% goats). Bivariate analysis indicated a positive association between seroconversion to BTV and flock size, eco-zone, breed, and contact history with cattle. Additionally, in female sheep and goats, a history of abortion was positively associated with seropositivity to BTV. However, the final multivariable model, after controlling for clustering of animals within the villages, identified only history of abortion and breed as the factors significantly associated with BT seropositivity in female sheep and goats. Based on this model, female small ruminants having a history of abortion were more likely to be seropositive compared to those without such history [Odds Ratio (OR) = 46.14 (95% CI: 11.66- 182.5)]. Exotic breeds were more likely to be seropositive compared to indigenous breeds [OR = 9.04 (95% CI: 3.08- 24.46)] while the risk for BTV seropositivity was not significantly different between indigenous and cross breeds. CONCLUSIONS: Our results showed that nearly a quarter of small ruminants in two regions of Nepal were seropositive for BTV, indicating wide exposure of small ruminants to this pathogen. We identified history of abortion and breed as factors significantly associated with the seropositivity of BTV. We recommend that surveillance for BTV infection in Nepal be strengthened and that it would be valuable to enhance the education of farmers about the possible impacts of this disease. PMID- 25288471 TI - Iron allocation in leaves of Fe-deficient cucumber plants fed with natural Fe complexes. AB - Iron (Fe) sources available for plants in the rhizospheric solution are mainly a mixture of complexes between Fe and organic ligands, including phytosiderophores (PS) and water-extractable humic substances (WEHS). In comparison with the other Fe sources, Fe-WEHS are more efficiently used by plants, and experimental evidences show that Fe translocation contributes to this better response. On the other hand, very little is known on the mechanisms involved in Fe allocation in leaves. In this work, physiological and molecular processes involved in Fe distribution in leaves of Fe-deficient Cucumis sativus supplied with Fe-PS or Fe WEHS up to 5 days were studied combining different techniques, such as radiochemical experiments, synchrotron micro X-ray fluorescence, real-time reverse transcription polymerase chain reaction and in situ hybridization. In Fe WEHS-fed plants, Fe was rapidly (1 day) allocated into the leaf veins, and after 5 days, Fe was completely transferred into interveinal cells; moreover, the amount of accumulated Fe was much higher than with Fe-PS. This redistribution in Fe-WEHS plants was associated with an upregulation of genes encoding a ferric(III) -chelate reductase (FRO), a Fe(2+) transporter (IRT1) and a natural resistance-associated macrophage protein (NRAMP). The localization of FRO and IRT1 transcripts next to the midveins, beside that of NRAMP in the interveinal area, may suggest a rapid and efficient response induced by the presence of Fe WEHS in the extra-radical solution for the allocation in leaves of high amounts of Fe. In conclusion, Fe is more efficiently used when chelated to WEHS than PS and seems to involve Fe distribution and gene regulation of Fe acquisition mechanisms operating in leaves. PMID- 25288472 TI - Contact sensitization in patients with suspected cosmetic intolerance: results of the IVDK 2006-2011. AB - BACKGROUND: Ingredients of leave-on cosmetics and body care products may sensitize. However, not every case of cosmetic intolerance is due to contact sensitization. OBJECTIVE: To describe the frequency of contact sensitization due to cosmetics in a large clinic population, and a possible particular allergen pattern. METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology, 2006-2011. RESULTS: Of 69 487 patients tested, 'cosmetics, creams, sunscreens' was the only suspected allergen source category in 10 124 patients (14.6%). A final diagnosis 'allergic contact dermatitis' was stated in 2658 of these patients (26.3%).Compared to a control group, there were significantly more reactions to fragrance mixes I and II, balsam of Peru, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and lanolin alcohols. No special pattern of fragrance sensitization could be identified. Among the preservatives, MI was by far the leading allergen, while sensitization to other widely used compounds like parabens or phenoxyethanol was rare. CONCLUSIONS: True allergic reactions to cosmetic ingredients are rarer than generally assumed. Limitation of exposure to MI in leave-on cosmetics and body care products is urgently needed. PMID- 25288473 TI - A randomized controlled trial of gonadotropin-releasing hormone agonist versus gonadotropin-releasing hormone antagonist in Iranian infertile couples: oocyte gene expression. AB - BACKGROUND: The main objective of the present work was to compare the effects of the gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH ant) on the gene expression profiles of oocytes obtained from Iranian infertile couples undergoing in vitro fertilization (IVF). METHODS: Fifty infertile couples who underwent IVF between June 2012 and November 2013 at the Infertility Center of Tehran Women General Hospital, Tehran University of Medical Sciences, were included in this study. We included women that had undergone IVF treatment because of male factor, tubal factor, or unexplained infertility. The women randomly underwent controlled ovarian stimulation (COS) with either the GnRH-a (n = 26) or the GnRH-ant (n = 24). We obtained 50 germinal vesicle (GV) oocytes donated by women in each group. After the sampling, pool of 50 GV oocytes for each group was separately analyzed by quantitative polymerase chain reaction (qPCR). RESULT: The expression levels of Adenosine triphosphatase 6 (ATPase 6), Bone morphogenetic protein 15 (BMP15), and Neuronal apoptosis inhibitory protein (NAIP) genes were significantly upregulated in the GnRH-ant group compared to the GnRH-a group, with the fold change of 3.990 (SD +/- 1.325), 6.274 (SD +/- 1.542), and 2.156 (SD +/- 1.443), respectively, (P < 0.001). Growth differentiation factor 9 (GDF9) mRNA did not have any expression in the GnRH-a group; however, GDF9 mRNA was expressed in the GnRH-ant group. Finally, it was found that the genes involved in the DNA repairing and cell cycle checkpoint did not have any expression in either group. CONCLUSION: The present study showed, for the first time, the expression levels of genes involved in the cytoplasmic maturity (BMP15, GDF9), adenosine triphosphate production (ATPase 6), and antiapoptotic process (NAIP), in human GV oocytes were significantly higher in the GnRH-anta group than in the GnRH-a group in COS. Higher expression level of these genes when GnRH-ant protocol is applied, this protocol seems to be a more appropriate choice for women with poly cystic ovarian syndrome, because it can probably improve the expression of the aforementioned genes. TRIAL REGISTRATION: Current Controlled Trials: IRCT 2014031112307 N3. PMID- 25288475 TI - Synthesis, microwave spectrum, quantum chemical calculations, and conformational composition of the novel compound cyclopropylethylidynephosphine (C3H5CH2C=P). AB - The synthesis of the novel compound cyclopropylethylidynephosphine (C3H5CH2C=P) and its microwave spectrum are reported together with quantum chemical calculations. The spectrum, which reveals the existence of two conformers, has been recorded in the 38-109 GHz spectral range at room temperature. The H-C-CH2-C chain of atoms is synclinal in one rotamer denoted sc, and antiperiplanar in the second conformer called ap. The spectra of the ground vibrational state and two vibrationally excited states were assigned for each rotamer. The vibrational frequencies of these excited states were determined by relative intensity measurements. Relative intensity measurements were also conducted to determine the energy difference between ap and sc. The latter conformer was found to be the lower-energy form and E(ap) - E(sc) was determined to be 0.9(4) kJ/mol. The microwave study has been augmented by quantum chemical calculations at the CCSD/cc-pVQZ and MP2/cc-pVTZ levels of theory. The CCSD predictions were generally in good agreement with experiment, while somewhat mixed results were obtained in the MP2 calculations. PMID- 25288474 TI - Combinations of obesity prevention strategies in US elementary schools: a critical review. AB - The prevalence of obesity among children has roughly tripled in the past 30 years. Given the numerous health risks associated with obesity, elementary schools have implemented a variety of prevention programs targeting this problem. This review examines recent studies of combinations of obesity prevention programs in US elementary schools and offers recommendations about effective strategies. We found 12 studies that met selection criteria and reviewed their findings related to obesity-related outcomes. Among the single intervention strategies, neither physical activity nor education alone demonstrated efficacy in reducing objective measures of obesity. Most studies of programs with two or three components (i.e., physical activity plus nutrition, physical activity plus both education and nutrition) reported statistically significant improvements in objective obesity-related outcomes. Studies evaluating programs with community and parental involvement suggest that these components may increase effectiveness. However, studies assessing outcomes following the cessation of the program showed a reversal of positive effects, suggesting that long-term implementation of programs is important for sustained gains. Results suggest that combinations of obesity prevention programs sustained over time are most likely to be effective. PMID- 25288476 TI - Air filtration in the free molecular flow regime: a review of high-efficiency particulate air filters based on carbon nanotubes. AB - Air filtration in the free molecular flow (FMF) regime is important and challenging because a higher filtration efficiency and lower pressure drop are obtained when the fiber diameter is smaller than the gas mean free path in the FMF regime. In previous studies, FMF conditions have been obtained by increasing the gas mean free path through reducing the pressure and increasing the temperature. In the case of carbon nanotubes (CNTs) with nanoscale diameters, it is possible to filtrate in the FMF regime under normal conditions. This paper reviews recent progress in theoretical and experimental studies of air filtration in the FMF regime. Typical structure models of high-efficiency particulate (HEPA) air filters based on CNTs are introduced. The pressure drop in air filters operated in the FMF regime is less than that predicted by the conventional air filtration theory. The thinnest HEPA filters fabricated from single-walled CNT films have an extremely low pressure drop. CNT air filters with a gradient nanostructure are shown to give a much better filtration performance in dynamic filtration. CNT air filters with a hierarchical structure and an agglomerated CNT fluidized bed air filter are also introduced. Finally, the challenges and opportunities for the application of CNTs in air filtration are discussed. PMID- 25288478 TI - Distinct structural neural patterns of trait physical and social anhedonia: evidence from cortical thickness, subcortical volumes and inter-regional correlations. AB - Anhedonia is an enduring trait accounting for the reduced capacity to experience pleasure. Few studies have investigated the brain structural features associated with trait anhedonia. In this study, the relationships between cortical thickness, volume of subcortical structures and scores on the Chapman physical and social anhedonia scales were examined in a non-clinical sample (n=72, 35 males). FreeSurfer was used to examine the cortical thickness and the volume of six identified subcortical structures related to trait anhedonia. We found that the cortical thickness of the superior frontal gyrus and the volume of the pallidum in the left hemisphere were correlated with anhedonia scores in both physical and social aspects. Specifically, positive correlations were found between levels of social anhedonia and the thickness of the postcentral and the inferior parietal gyri. Cortico-subcortical inter-correlations between these clusters were also observed. Our findings revealed distinct correlation patterns of neural substrates with trait physical and social anhedonia in a non-clinical sample. These findings contribute to the understanding of the pathologies underlying the anhedonia phenotype in schizophrenia and other psychiatric disorders. PMID- 25288479 TI - A hybrid approach to the computational aeroacoustics of human voice production. AB - The aeroacoustic mechanisms in human voice production are complex coupled processes that are still not fully understood. In this article, a hybrid numerical approach to analyzing sound generation in human voice production is presented. First, the fluid flow problem is solved using a parallel finite-volume computational fluid dynamics (CFD) solver on a fine computational mesh covering the larynx. The CFD simulations are run for four geometrical configurations: both with and without false vocal folds, and with fixed convergent or convergent divergent motion of the medial vocal fold surface. Then the aeroacoustic sources and propagation of sound waves are calculated using Lighthill's analogy or acoustic perturbation equations on a coarse mesh covering the larynx, vocal tract, and radiation region near the mouth. Aeroacoustic sound sources are investigated in the time and frequency domains to determine their precise origin and correlation with the flow field. The problem of acoustic wave propagation from the larynx and vocal tract into the free field is solved using the finite element method. Two different vocal-tract shapes are considered and modeled according to MRI vocal-tract data of the vowels /i/ and /u/. The spectra of the radiated sound evaluated from acoustic simulations show good agreement with formant frequencies known from human subjects. PMID- 25288477 TI - CMV-encoded Fcgamma receptors: modulators at the interface of innate and adaptive immunity. AB - The constant region of IgG antibodies mediates antiviral activities upon engaging host Fcgamma receptors (FcgammaRs) expressed by a variety of immune cells, such as antibody-dependent cellullar cytotoxcity (ADCC) executed by natural killer (NK)cells. Human cytomegalovirus (HCMV) is unique among viruses by encoding also an array of several Fcgamma-binding glycoproteins with cell surface disposition and concomitant incorporation into the virion. Evidence is increasing that the virus-encoded Fcgamma receptors differ in their Fcgamma binding mode but effectively operate as adversaries of host FcgammaRs since they are able to prevent IgG-mediated triggering of activating host FcgammaRs, i.e., FcgammaRI, FcgammaRIIA, and FcgammaRIIIA. Here we discuss virus-encoded FcgammaRs as the first known HCMV inhibitors of IgG-mediated immunity which could account for the limited efficacy of HCMV hyperimmune globulin in clinical settings. A better understanding of their molecular mode of action opens up new perspectives for improving IgG therapies against HCMV disease. PMID- 25288480 TI - A nano-sized supramolecule beyond the fullerene topology. AB - The reaction of [Cp(Bn) Fe(eta(5) -P5 )] (1) (Cp(Bn) =eta(5) -C5 (CH2 Ph)5 ) with CuI selectively yields a novel spherical supramolecule (CH2 Cl2 )3.4 @[(Cp(Bn) FeP5 )12 {CuI}54 (MeCN)1.46 ] (2) showing a linkage of the scaffold atoms which is beyond the Fullerene topology. Its extended CuI framework reveals an outer diameter of 3.7 nm-a size that has not been reached before using five-fold symmetric building blocks. Furthermore, 2 shows a remarkable solubility in CH2 Cl2 , and NMR spectroscopy reveals that the scaffold of the supramolecule remains intact in solution. In addition, a novel 2D polymer [{Cp(Bn) Fe(eta(5) -P5 )}2 {Cu6 (MU-I)2 (MU3 -I)4 }]n (3) with an uncommon structural motif was isolated. Its formation can be avoided by using a large excess of CuI in the reaction with 1. PMID- 25288481 TI - Fibular nerve damage in knee dislocation: Spectrum of ultrasound patterns. AB - INTRODUCTION: At least 25% of knee dislocations are associated with common fibular nerve injury. Diagnosis is usually based on clinical and neurophysiological findings. We assessed the role of nerve ultrasound in common fibular nerve injury. METHODS: Eight consecutive patients (6 men and 2 women, mean age 34 years) with knee luxation referred to our laboratory underwent clinical, neurophysiological, and ultrasound examination. RESULTS: In all patients we observed a similar pattern: severe weakness (plegia or severe paresis); neurophysiological involvement of both fibular nerve branches; and ultrasound evidence of increased fibular nerve area with hypoechogenicity. On follow-up evaluation, 6 patients remained stable, and 2 patients improved. The greater the ultrasound fibular nerve enlargement, the worse the recovery. CONCLUSIONS: Nerve ultrasound was confirmed to be a useful diagnostic/prognostic tool in traumatic nerve lesions. A prompt ultrasound examination of the fibular nerve should be considered after any case of knee dislocation. PMID- 25288483 TI - Synthesis and microwave absorption characterization of SiO2 coated Fe3O4-MWCNT composites. AB - This study investigated the microwave absorption properties of core-shell composites containing; iron oxide decorated carbon nanotubes (CNTs) and silica (SiO2@Fe3O4-MWCNTs) with various thicknesses of silica shells (7, 20 and 50 nm). Transmission electron microscopy (TEM) and X-ray diffraction results confirmed the formation of these core-shell structures. Microwave absorption characterization of the samples at the ranging band under consideration (the X band) showed increased absorption and shifting of the peaks to lower frequencies compared to the uncoated sample (Fe3O4-MWCNTs). The minimum reflection loss decreased with increasing SiO2 thickness. The minimum reflection loss of the composite with an optimized thickness of the silica shell (7 nm) exceeded -41 dB at 8.7-9 GHz. PMID- 25288482 TI - Transcriptomic and proteomic analysis reveals mechanisms of embryo abortion during chrysanthemum cross breeding. AB - Embryo abortion is the main cause of failure in chrysanthemum cross breeding, and the genes and proteins associated with embryo abortion are poorly understood. Here, we applied RNA sequencing and isobaric tags for relative and absolute quantitation (iTRAQ) to analyse transcriptomic and proteomic profiles of normal and abortive embryos. More than 68,000 annotated unigenes and 700 proteins were obtained from normal and abortive embryos. Functional analysis showed that 140 differentially expressed genes (DEGs) and 41 differentially expressed proteins (DEPs) were involved in embryo abortion. Most DEGs and DEPs associated with cell death, protein degradation, reactive oxygen species scavenging, and stress response transcriptional factors were significantly up-regulated in abortive embryos relative to normal embryos. In contrast, most genes and proteins related to cell division and expansion, the cytoskeleton, protein synthesis and energy metabolism were significantly down-regulated in abortive embryos. Furthermore, abortive embryos had the highest activity of three executioner caspase-like enzymes. These results indicate that embryo abortion may be related to programmed cell death and the senescence- or death-associated genes or proteins contribute to embryo abortion. This adds to our understanding of embryo abortion and will aid in the cross breeding of chrysanthemum and other crops in the future. PMID- 25288484 TI - Using cluster analysis to identify phenotypes and validation of mortality in men with COPD. AB - PURPOSE: Cluster analysis has been proposed to examine phenotypic heterogeneity in chronic obstructive pulmonary disease (COPD). The aim of this study was to use cluster analysis to define COPD phenotypes and validate them by assessing their relationship with mortality. METHODS: Male subjects with COPD were recruited to identify and validate COPD phenotypes. Seven variables were assessed for their relevance to COPD, age, FEV(1) % predicted, BMI, history of severe exacerbations, mMRC, SpO(2), and Charlson index. COPD groups were identified by cluster analysis and validated prospectively against mortality during a 4-year follow-up. RESULTS: Analysis of 332 COPD subjects identified five clusters from cluster A to cluster E. Assessment of the predictive validity of these clusters of COPD showed that cluster E patients had higher all cause mortality (HR 18.3, p < 0.0001), and respiratory cause mortality (HR 21.5, p < 0.0001) than those in the other four groups. Cluster E patients also had higher all cause mortality (HR 14.3, p = 0.0002) and respiratory cause mortality (HR 10.1, p = 0.0013) than patients in cluster D alone. CONCLUSION: COPD patient with severe airflow limitation, many symptoms, and a history of frequent severe exacerbations was a novel and distinct clinical phenotype predicting mortality in men with COPD. PMID- 25288486 TI - Group-based differences in anti-aging bias among medical students. AB - Medical students (MS) may develop ageist attitudes early in their training that may predict their future avoidance of caring for the elderly. This study sought to determine MS' patterns of explicit and implicit anti-aging bias, intent to practice with older people and using the quad model, the role of gender, race, and motivation-based differences. One hundred and three MS completed an online survey that included explicit and implicit measures. Explicit measures revealed a moderately positive perception of older people. Female medical students and those high in internal motivation showed lower anti-aging bias, and both were more likely to intend to practice with older people. Although the implicit measure revealed more negativity toward the elderly than the explicit measures, there were no group differences. However, using the quad model the authors identified gender, race, and motivation-based differences in controlled and automatic processes involved in anti-aging bias. PMID- 25288485 TI - Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. AB - Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5 HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders. PMID- 25288487 TI - Fishing with bed nets on Lake Tanganyika: a randomized survey. AB - BACKGROUND: Malaria is among the most common causes of death along Lake Tanganyika, a problem which many aid organizations have attempted to combat through the distribution of free mosquito bed nets to high-risk communities. The Lake Tanganyika Floating Health Clinic (LTFHC), a health-based non-governmental organization (NGO), has observed residents of the Lake Tanganyika basin using bed nets to fish small fry near the shoreline, despite a series of laws that prohibit bed net use and other fine-gauge nets for fishing, implemented to protect the near-shore fish ecology. The LTFHC sought to quantify the sources of bed nets and whether they were being used for fishing. METHODS: The LTFHC conducted a survey of seven lakeside villages in Lagosa Ward, Tanzania. The government has divided each village into two to six pre-existing geographic sub-villages depending on population size. Seven households per sub-village were chosen at random for survey administration. The survey consisted of 23 questions regarding mosquito bed net practices, including the use of bed nets for fishing, as well as questions pertaining to any perceived changes to the fish supply. RESULTS: A total of 196 surveys were administered over a four-week period with a 100% response rate. Over 87% of households surveyed have used a mosquito bed net for fishing at some point. The majority of respondents reported receiving their bed net for free (96.4%), observing "many" residents of their village using bed nets for fishing (97.4%), and noticing a subjective decrease in the fish supply over time (64.9%). CONCLUSIONS: The findings of this study raise concerns that the use of free malaria bed nets for fishing is widespread along Lake Tanganyika, and that this dynamic will have an adverse effect on fish ecology. Further studies are indicated to fully define the scope of bed net misuse and the effects of alternative vector control strategies in water-based communities. PMID- 25288488 TI - Outcome of a food observational study among low-income preschool children participating in a family-style meal setting. AB - INTRODUCTION: In the United States, one out of every seven low-income children between the ages of 2 and 5 years is at risk for overweight and obesity. Formative research was conducted to determine if preschool children participating in family-style meals consumed the minimum food servings according to U.S. Department of Agriculture dietary guidelines. METHOD: Participants were 135 low income children aged 3 to 4 years who attended an urban child care center. Participant's parents completed a Family Demographic Questionnaire to provide information on race/ethnicity, parent's level of education, and household income. Direct observation of children's food and beverage consumption during school breakfast and lunch was collected over 3 consecutive days. Dietary data were assessed using the Nutrition Data System for Research software. Height and weight measurements were obtained to determine risk for obesity. Descriptive statistics were reported by using the Statistical Package for the Social Sciences Version 16. RESULTS: Among 135 participants, 98% identified as Mexican American, 75% lived at or below poverty level, and 24% reported a family history of diabetes. Children consumed less than half of the calories provided between breakfast and lunch and did not consume the minimum recommended dietary food servings. Despite the poor dietary intake, physical measurement findings showed 25% obesity prevalence among study participants. CONCLUSIONS: Findings support the need for evidenced-based early childhood obesity prevention programs that provide behavior change opportunities for children, their families, teachers, and menu planners. Family-style meal settings are ideal opportunities for implementing nutrition education strategies to prevent early childhood obesity. PMID- 25288489 TI - Dissecting an online intervention for cancer survivors: four exploratory analyses of internet engagement and its effects on health status and health behaviors. AB - The Internet has been used extensively to offer health education content and also for social support. More recently, we have seen the advent of Internet-based health education interventions that combine content with structured social networking. In many ways this is the Internet equivalent to small group interventions. While we have some knowledge about the efficacy of these interventions, few studies have examined how participants engage with programs and how that might affect outcomes. This study seeks to explore (a) the content of posts and (b) the nature of participant engagement with an online, 6-week workshop for cancer survivors and how such engagement may affect health outcomes. Using methodologies related to computational linguistics (latent Dirichlet allocation) and more standard statistical approaches, we identified (a) discussion board themes; (b) the relationship between reading and posting messages and outcomes; (c) how making, completing, or not completing action plans is related to outcome; and (d) how self-tailoring relates to outcomes. When considering all posts, emotional support is a key theme. However, different sets of themes are expressed in the first workshop post where participants are asked to express their primary concern. Writing posts was related to improved outcomes, but reading posts was less important. Completing, but not merely making, action plans and self-tailoring are statistically associated with future positive health outcomes. The findings from these exploratory studies can be considered when shaping future electronically mediated social networking interventions. In addition, the methods used here can be used in analyzing other large electronically mediated social-networking interventions. PMID- 25288490 TI - Revisiting the importance of knowledge: from Namibia, a case for promoting knowledge by campaigns to reduce stigma. AB - Reducing stigma against people living with HIV is key to encouraging HIV testing, which in turn is an important component in the treatment-as-prevention approach. We analyzed nationally representative survey data of participants aged 15 years and older in Namibia (N = 4,300) to determine whether knowledge about HIV and self-efficacy to protect against sexually transmitted HIV would be independently and jointly associated with stigma against people living with HIV, after controlling for demographics. Findings indicated that having less knowledge and feeling less self-efficacy were associated with greater stigma. Our key interaction hypothesis was also supported: stigma among those with lower self efficacy to reduce risk of sexually transmitted HIV infection was particularly sensitive to the effects of increased knowledge about HIV. Results highlight the importance of enriching knowledge about HIV transmission modes, prevention strategies, and support services among those with low self-efficacy in order to reduce stigma against people living with HIV, and has useful implications for designing anti-stigma campaigns. PMID- 25288491 TI - Prognostic implications of CD30 expression in extranodal natural killer/T-cell lymphoma according to treatment modalities. AB - Extranodal natural killer/T-cell lymphoma (NKTCL) has aggressive behaviors and poor clinical outcomes. A monomethyl auristatin E-conjugated anti-CD30 antibody (brentuximab vedotin) was recently introduced to treat CD30-positive lymphomas. Thus we investigated the clinicopathological features and prognostic implications of CD30 expression in 72 patients with NKTCL. CD30-positive cases, defined as cases with CD30 expression in more than 1%, 5% and 25% of tumor cells as cut-off values (COVs), accounted for 40 (56%), 27 (38%) and 16 (22%) cases of NKTCL, respectively. CD30 expression was significantly higher in large/anaplastic cell predominant NKTCL than in small/medium cell-predominant cases. CD30-positive NKTCL showed better responses to non-anthracycline-based therapy. CD30-positive NKTCL with COV of 25% showed a lower rate of relapse. Moreover, in patients treated with non-anthracycline-based chemotherapy, CD30 positivity with COV of 5% was significantly and independently associated with longer overall survival. CD30 may be useful as a prognostic factor and therapeutic target in NKTCL. PMID- 25288492 TI - Spectrotemporal dynamics of the EEG during working memory encoding and maintenance predicts individual behavioral capacity. AB - We investigated the effect of memory load on encoding and maintenance of information in working memory. Electroencephalography (EEG) signals were recorded while participants performed a modified Sternberg visual memory task. Independent component analysis (ICA) was used to factorise the EEG signals into distinct temporal activations to perform spectrotemporal analysis and localisation of source activities. We found 'encoding' and 'maintenance' operations were correlated with negative and positive changes in alpha-band power, respectively. Transient activities were observed during encoding of information in the bilateral cuneus, precuneus, inferior parietal gyrus and fusiform gyrus, and a sustained activity in the inferior frontal gyrus. Strong correlations were also observed between changes in alpha-power and behavioral performance during both encoding and maintenance. Furthermore, it was also found that individuals with higher working memory capacity experienced stronger neural oscillatory responses during the encoding of visual objects into working memory. Our results suggest an interplay between two distinct neural pathways and different spatiotemporal operations during the encoding and maintenance of information which predict individual differences in working memory capacity observed at the behavioral level. PMID- 25288493 TI - Human alpha1-adrenoceptor subtype selectivity of substituted homobivalent 4 aminoquinolines. AB - A series of ring-substituted ethyl- and heptyl-linked 4-aminoquinoline dimers were synthesized and evaluated for their affinities at the 3 human alpha(1) adrenoceptor (alpha(1)-AR) subtypes and the human serotonin 5-HT(1A)-receptor (5 HT(1A)-R). We find that the structure-specificity profiles are different for the two series at the alpha(1)-AR subtypes, which suggests that homobivalent 4 aminoquinolines can be developed with alpha(1)-AR subtype selectivity. The 8 methyl (8-Me) ethyl-linked analogue has the highest affinity for the alpha(1A) AR, 7 nM, and the greatest capacity for discriminating between alpha(1A)-AR and alpha(1B)-AR (6-fold), alpha(1D)-AR (68-fold), and the 5-HT(1A)-R (168-fold). alpha(1B)-AR selectivity was observed with the 6-methyl (6-Me) derivative of the ethyl- and heptyl-linked 4-aminoquinoline dimers and the 7-methoxy (7-OMe) derivative of the heptyl-linked analogue. These substitutions result in 4- to 80 fold selectivity for alpha(1B)-AR over alpha(1A)-AR, alpha(1D)-AR, and 5-HT(1A) R. In contrast, 4-aminoquinoline dimers with selectivity for alpha(1D)-AR are more elusive, since none studied to date has greater affinity for the alpha(1D) AR over the other two alpha(1)-ARs. The selectivity of the 8-Me ethyl-linked 4 aminoquinoline dimer for the alpha(1A)-AR, and 6-Me ethyl-linked, and the 6-Me and 7-OMe heptyl-linked 4-aminoquinoline dimers for the alpha(1B)-AR, makes them promising leads for drug development of alpha(1A)-AR or alpha(1B)-AR subtype selective ligands with reduced 5-HT(1A)-R affinity. PMID- 25288494 TI - Structure-activity relationships of the thujaplicins for inhibition of human tyrosinase. AB - Tyrosinase inhibitors have become increasingly critical agents in cosmetic, agricultural, and medicinal products. Although a large number of tyrosinase inhibitors have been reported, almost all the inhibitors were unfortunately evaluated by using commercial available mushroom tyrosinase. Here, we examined the inhibitory effects of three isomers of thujaplicin (alpha, beta, and gamma) on human tyrosinase and analyzed their binding modes using homology model and docking studies. As the results, gamma-thujaplicin was found to strongly inhibit human tyrosinase with the IC50 of 1.15 MUM, extremely superior to a well-known tyrosinase inhibitor kojic acid (IC50 = 571.17 MUM). MM-GB/SA binding free energy decomposition analyses suggested that the potent inhibitory activity of gamma thujaplicin may be due to the interactions with His367, Ile368, and Val377 (hot spot amino acid residues) in human tyrosinase. Furthermore, the binding mode of alpha-thujaplicin indicated that Val377 and Ser380 may cause van der Waals clashes with the isopropyl group of alpha-thujaplicin. These results provide a novel structural insight into the hot spot of human tyrosinase for the specific binding of gamma-thujaplicin and a way to optimize not only thujaplicins but also other lead compounds as specific inhibitors for human tyrosinase in a rational manner. PMID- 25288495 TI - Peptidomimetics of Arg-Phe-NH2 as small molecule agonists of Mas-related gene C (MrgC) receptors. AB - A series of Arg-Phe-NH2 peptidomimetics containing an Arg mimetic were synthesized and tested as agonists of human MrgX1, rat MrgC, and mouse MrgC11 receptors. As predicted from the previously established species specificity, these peptidomimetics were found to be devoid of MrgX1 agonist activity. In contrast, these compounds acted as agonists of MrgC and/or MrgC11 with varying degrees of potency. These new peptidomimetics should complement the existing small molecule human MrgX1 agonists and enhance our ability to assess the therapeutic utility of targeting Mrg receptors in rodent models. PMID- 25288496 TI - Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus. AB - The gyraseB subunit of Staphylococcus aureus DNA gyrase is a well-established and validated target though less explored for the development of novel antimicrobial agents. Starting from the available structural information in PDB (3TTZ), we identified a novel series of benzimidazole used as inhibitors of DNA gyraseB with low micromolar inhibitory activity by employing structure-based drug design strategy. Subsequently, this chemical class of DNA gyrase inhibitors was extensively investigated biologically through in vitro assays, biofilm inhibition assays, cytotoxicity, and in vivo studies. The binding affinity of the most potent inhibitor 10 was further ascertained biophysically through differential scanning fluorimetry. Further, the most potent analogues did not show any signs of cardiotoxicity in Zebra fish ether-a-go-go-related gene (zERG), a major breakthrough among the previously reported cardiotoxic gyraseB inhibitors. PMID- 25288497 TI - Infectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: a systematic review and meta-analysis. AB - BACKGROUND: Clinical trials have reported a substantial variation in the risk of infection related to anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab. We performed a systematic review and meta-analysis to assess the infection risk in cancer patients treated with anti-EGFR mAbs. PATIENTS AND METHODS: We searched PubMed and the ASCO online database of meeting abstracts up to January 2014 for relevant clinical trials. Eligible studies included randomized controlled trials (RCTs) of cetuximab and panitumumab that reported adequate safety data for grade 3-4 infection or febrile neutropenia (FN). The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 14,957 patients from 28 trials were included. Treatment with anti-EGFR mAbs was associated with an increased risk of high-grade infection (RR, 1.49; 95% CI, 1.33-1.66; P<0.001) and FN (RR, 1.27; 95% CI, 1.09 1.48; P=0.002). The incidence of high-grade infection and FN due to anti-EGFR mAbs was 9.3% (95% CI, 7.2-12.0%) and 5.3% (95% CI, 3.3-8.3%), respectively. A significantly increased risk of high-grade infection was observed in all subgroups analyses (type of anti-EGFR mAb, therapy of control arm and duration of treatment) except for tumor type (only colorectal cancer and non-small cell lung cancer (NSCLC) groups had the increased risk). Subgroup analyses revealed a significantly increased risk of FN in the following subgroups: cetuximab, NSCLC and treatment duration longer than the median of all trials (3.1months). CONCLUSIONS: The use of anti-EGFR mAbs is associated with a significantly higher risk of high-grade infection and febrile neutropenia. PMID- 25288498 TI - [Consensus document for the detection and management of chronic kidney disease]. AB - Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations. PMID- 25288499 TI - Effect of low serum total bilirubin levels (<=0.32 mg/dl) on risk of coronary artery disease in patients with metabolic syndrome. AB - The objective of this study was to investigate the effects of low serum bilirubin levels on the risk for future coronary artery disease (CAD) in a prospective cohort. CAD events were examined according to baseline serum bilirubin levels in a prospective large-scale, community-based Korean cohort in 2 subsequent prospective biennial surveys. A total of 8,593 subjects were included, 0.9% of whom reported newly developed CAD events during the 4 years of follow-up. Cox regression analyses showed that the lowest serum total bilirubin level category (bilirubin <=0.32 mg/dl) was an independent risk factor for future CAD events (adjusted hazard ratio [HR] 1.890, 95% confidence interval [CI] 1.088 to 3.284; p = 0.024). Subjects with metabolic syndrome had a higher risk for future CAD events than those without metabolic syndrome (HR 3.366, 95% CI 2.079 to 5.448, p <0.001). Low bilirubin levels increased the CAD risk in subjects with metabolic syndrome further (HR 2.016, 95% CI 1.069 to 3.800; p = 0.030), with these subjects showing a >6 times higher risk for CAD than subjects with bilirubin levels >0.32 mg/dl and no metabolic syndrome (HR 6.228, 95% CI 3.118 to 12.437; p <0.001). In conclusion, the addition of low serum bilirubin levels to the traditional risk factors for CAD, such as metabolic syndrome, may yield an improvement of risk prediction. PMID- 25288500 TI - Incremental value of diagonal earlobe crease to the Diamond-Forrester classification in estimating the probability of significant coronary artery disease determined by computed tomographic angiography. AB - The Diamond-Forrester (DF) algorithm overestimates the likelihood of significant coronary artery disease (>=50% stenosis, CAD50). The aim of the present study was to evaluate whether the addition of a diagonal earlobe crease (DELC) enhances the predictive ability of DF to detect CAD50 by coronary computed tomographic angiography (CTA). We evaluated 430 patients referred for CTA for symptoms, cardiovascular risk factors, and CAD50 likelihood using DF. Observers blinded to CTA findings evaluated the presence of DELC. The diagnostic accuracy and relation of DF, DELC, and DF + DELC for predicting CAD50 in patients with chest pain were evaluated using receiver operating characteristics curve (area under curve) analyses and multivariate logistic regression analyses. In 199 patients with chest pain, the sensitivity and specificity for CAD50 were 96% and 20% for DF (AUC 0.59, p = 0.59), 91% and 32% for DELC (AUC 0.62, p = 0.03), and 91% and 41% for DF + DELC (AUC 0.66, p = 0.004). On multivariate analyses DELC was the only independent predictor of CAD50 (odds ratio 3.6, 95% confidence interval 1 to 12.9, p = 0.048). DF + DELC increased the predictive ability to detect CAD50 above cardiovascular risk factors (odds ratio 5.6, 95% confidence interval 1.6 to 19.8, p = 0.007). In patients with chest pain, the presence of DELC is related to CAD50 beyond DF. A combined variable of DF + DELC provides superior discriminatory ability for detecting CAD50 than either method alone. PMID- 25288501 TI - Relation of perinatal risk and early parenting to executive control at the transition to school. AB - Executive control (EC) develops rapidly during the preschool years and is central to academic achievement and functional outcome. Although children with perinatal adversity are at known risk for EC impairments, little is known about the underlying nature of these impairments or the mechanisms that contribute to their development over time. Drawing on a cohort of 110 high-risk children born very preterm (VPT; < 33 weeks / < 1500 g) and 113 healthy full-term children, this study examined the implications of perinatal adversity and early parenting for children's EC as they transitioned to formal schooling. Parent supportive presence, intrusiveness, and parent-child synchrony were observed during a series of problem-solving tasks at ages 2 and 4 years. At age 6, children completed a comprehensive battery of EC tasks. Academic outcomes were assessed at age 9. The VPT group showed global EC impairments at age 6, although the unitary factor that best characterized the structure of EC was the same in both groups. High-risk dyads were characterized by more intrusive and less synchronous parent-child interactions in early childhood, which in turn predicted poorer child EC at age 6. EC partially mediated the relation of risk status to poorer academic achievement at age 9. Findings demonstrate the cumulative effects of perinatal adversity on children's EC in the crucial transition to schooling. They also highlight the importance of the parent-child relationship as a target for intervention efforts to help mitigate these effects. PMID- 25288502 TI - Transcranial direct current stimulation (tDCS) and the cardiovascular responses to acute pain in humans. AB - OBJECTIVE: To determine if transcranial direct current stimulation (tDCS) reduces both acute pain perception and the resultant cardiovascular responses. METHODS: Data were acquired on 15 healthy subjects at rest and in response to three cold pressor tests: 0, 7, and 14 degrees C. Subsequently, single sessions of sham and active anodal tDCS (2.0 mA for 40 min) were delivered to the left primary motor cortex (M1). RESULTS: Perceived pain was reduced only after active tDCS with the 14 degrees C cold pressor test. This was accompanied by tendency for lesser increases in heart rate (~2 beats/min, p=0.09) and blood pressure (~3 mmHg, p=0.06). The effect size of tDCS on peak heart rate and blood pressure responses at 14 degrees C was 0.47 and 0.54, respectively. On the other hand, baseline heart rate, blood pressure, leg blood flow, and leg vascular resistance were unaffected by tDCS. No other responses were affected. CONCLUSIONS: Our results demonstrate that M1 anodal tDCS has no effect on basal hemodynamics or cardiovascular autonomic outflow and has only modest effects on the responses to acute pain in healthy humans. SIGNIFICANCE: Application of tDCS shifts the pain perception threshold in healthy individuals but does not significantly modulate efferent cardiovascular control at rest or in response to pain. PMID- 25288504 TI - Texas court dismisses defamation case brought by Andrew Wakefield against The BMJ. PMID- 25288503 TI - A four-long non-coding RNA signature in predicting breast cancer survival. AB - BACKGROUND: Many long non-coding RNAs(lncRNAs) have been found to be a good marker for several tumors. Using lncRNA-mining approach, we aimed to identify lncRNA expression signature that can predict breast cancer patient survival. METHODS: We performed LncRNA expression profiling in 887 breast cancer patients from Gene Expression Omnibus (GEO) datasets. The association between lncRNA signature and clinical survival was analyzed using the training set(n = 327, from GSE 20685). The validation for the association was performed in another three independent testing sets(252 from GSE21653, 204 from GSE12276, and 104 from GSE42568). RESULTS: A set of four lncRNA genes (U79277, AK024118, BC040204, AK000974) have been identified by the random survival forest algorithm. Using a risk score based on the expression signature of these lncRNAs, we separated the patients into low-risk and high-risk groups with significantly different survival times in the training set. This signature was validated in the other three cohorts. Further study revealed that the four-lncRNA expression signature was independent of age and subtype. Gene Set Enrichment Analysis (GSEA) suggested that gene sets were involved in several cancer metastasis related pathways. CONCLUSIONS: These findings indicate that lncRNAs may be implicated in breast cancer pathogenesis. The four-lncRNA signature may have clinical implications in the selection of high-risk patients for adjuvant therapy. PMID- 25288505 TI - Perioperative anesthetic implications of epilepsy surgery: a retrospective analysis. AB - PURPOSE: Drug-resistant epilepsy (DRE) occurs in about 30 % of individuals with epilepsy. For seizure control, a wide range of surgical procedures are performed, depending on the underlying pathology. To address the anesthetic and perioperative concerns in these patients, we analyzed the data of persons with DRE who underwent epilepsy surgery at our institute. METHODS: A retrospective analysis of patients who underwent epilepsy surgery from 2005-2010 was performed. For data collection and analysis, patients were divided into three groups: Group I (temporal lobe epilepsy), Group II (extratemporal lobe epilepsy), and Group III (multilobar epilepsy and others). RESULTS: A total of 241 surgical procedures were performed on 235 persons with DRE. The procedures included temporal (149) and extratemporal (47) lobe resection, hemispherotomy (31), corpus callosotomy (5), vagus nerve stimulation (3), and implantation of invasive cerebral electrodes (6). General anesthesia was the more common anesthetic technique; awake craniotomy was performed in only five cases. Intraoperative neuromonitoring was used most frequently in Group II. Patients in Group III had the longest intraoperative course and the greatest blood loss. The overall incidence of postoperative mechanical ventilation was 17.84 %, with 53.84 % of patients in Group III alone. At one-year follow-up, a good outcome was seen in 78 % of temporal lobe resection, 55 % of extratemporal cortical resection, 82 % of hemispherotomy, and 80 % of corpus callosotomy procedures. CONCLUSIONS: Careful preoperative selection and meticulous perioperative management are the most significant factors for success of epilepsy surgery. Although temporal and extratemporal lobe surgeries have a fairly stable perioperative course, multilobar epilepsy requiring disconnective surgery poses a greater challenge. PMID- 25288506 TI - A pilot study to assess adductor canal catheter tip migration in a cadaver model. AB - An adductor canal catheter may facilitate early ambulation after total knee arthroplasty, but there is concern over preoperative placement since intraoperative migration of catheters may occur from surgical manipulation and result in ineffective analgesia. We hypothesized that catheter type and subcutaneous tunneling may influence tip migration for preoperatively inserted adductor canal catheters. In a male unembalmed human cadaver, 20 catheter insertion trials were divided randomly into one of four groups: flexible epidural catheter either tunneled or not tunneled; or rigid stimulating catheter either tunneled or not tunneled. Intraoperative patient manipulation was simulated by five range-of-motion exercises of the knee. Distance and length measurements were performed by a blinded regional anesthesiologist. Changes in catheter tip to nerve distance (p = 0.225) and length of catheter within the adductor canal (p = 0.467) were not different between the four groups. Two of five non-tunneled stimulating catheters (40 %) were dislodged compared to 0/5 in all other groups (p = 0.187). A cadaver model may be useful for assessing migration of regional anesthesia catheters; catheter type and subcutaneous tunneling may not affect migration of adductor canal catheters based on this preliminary study. However, future studies involving a larger sample size, actual patients, and other catheter types are warranted. PMID- 25288507 TI - Emergence of contact injuries in invasion team sports: an ecological dynamics rationale. AB - The incidence of contact injuries in team sports is considerable, and injury mechanisms need to be comprehensively understood to facilitate the adoption of preventive measures. In Association Football, evidence shows that the highest prevalence of contact injuries emerges in one-on-one interactions. However, previous studies have tended to operationally report injury mechanisms in isolation, failing to provide a theoretical rationale to explain how injuries might emerge from interactions between opposing players. In this position paper, we propose an ecological dynamics framework to enhance current understanding of behavioural processes leading to contact injuries in team sports. Based on previous research highlighting the dynamics of performer-environment interactions, contact injuries are proposed to emerge from symmetry-breaking processes during on-field interpersonal interactions among competing players and the ball. Central to this approach is consideration of candidate control parameters that may provide insights on the information sources used by players to reduce risk of contact injuries during performance. Clinically, an ecological dynamics analysis could allow sport practitioners to design training sessions based on selected parameter threshold values as primary and/or secondary preventing measures during training and rehabilitation sessions. PMID- 25288508 TI - Dr. Boullosa's forgotten pieces don't fit the puzzle: a response to Dr. Buchheit and Dr. Laursen. PMID- 25288509 TI - Quantitative expression of bone-related cytokines induced by mechanical tension stress during distraction osteogenesis in a rabbit mandible. AB - AIM: The aim of the present study was to investigate the temporal and spatial gene expression of bone morphogenetic proteins (BMP)-2, -4, and -7, and transforming growth factor-beta (TGF-beta), during the distraction process of the rabbit mandible. METHODS: Twenty rabbits each had an osteotomy on the left mandibular body, and distraction devices were fixed. After a delay of 3 days, distraction was started at a rate of 0.5 mm/12 h for 10 days, followed by a 3 week consolidation phase. Four rabbits were killed 5 and 10 days of distraction, and 1, 2, and 3 weeks after the completion of distraction. The clinical, histological, and radiographic appearances were evaluated and analyzed with the concomitant BMP expression pattern at each interval. RESULTS: After the distraction was started, the fibrous interzone developed between the osteotomy fragments, where intramembranous ossification was noted. The quantitative expression of BMP-2, -4, and -7, and TGF-beta, were increased immediately after active distraction before a gradual decline to normal levels after the third week of consolidation. CONCLUSION: These results suggest that BMP and TGF-beta play an important role in the induction of bone formation during distraction osteogenesis. The selective expression of each bone-related cytokine could provide useful insight into accelerated bone maturation and the treatment of poorly-healing fractures in clinical cases. PMID- 25288510 TI - Exact one-sided confidence limits for Cohen's kappa as a measurement of agreement. AB - Cohen's kappa coefficient, kappa, is a statistical measure of inter-rater agreement or inter-annotator agreement for qualitative items. In this paper, we focus on interval estimation of kappa in the case of two raters and binary items. So far, only asymptotic and bootstrap intervals are available for kappa due to its complexity. However, there is no guarantee that such intervals will capture kappa with the desired nominal level 1- alpha. In other words, the statistical inferences based on these intervals are not reliable. We apply the Buehler method to obtain exact confidence intervals based on four widely used asymptotic intervals, three Wald-type confidence intervals and one interval constructed from a profile variance. These exact intervals are compared with regard to coverage probability and length for small to medium sample sizes. The exact intervals based on the Garner interval and the Lee and Tu interval are generally recommended for use in practice due to good performance in both coverage probability and length. PMID- 25288511 TI - Strategies for handling ethical problems in end of life care: obstacles and possibilities. AB - BACKGROUND: In end of life care, ethical problems often come to the fore. Little research is performed on ways or strategies for handling those problems and even less on obstacles to and possibilities of using such strategies. A previous study illuminated stroke team members' experiences of ethical problems and how the teams managed the situation when caring for patients faced with sudden and unexpected death from stroke. These findings have been further explored in this study. OBJECTIVE: The aim of the study was to illuminate obstacles and possibilities perceived by stroke team members in using strategies for handling ethical problems when caring for patients afflicted by sudden and unexpected death caused by stroke. RESEARCH DESIGN: A qualitative method with combined deductive and inductive content analysis was utilized. PARTICIPANTS AND RESEARCH CONTEXT: Data were collected through individual interviews with 15 stroke team members working in stroke units of two associated county hospitals in western Sweden. ETHICAL CONSIDERATIONS: The study was approved by the Regional Ethics Review Board, Gothenburg, Sweden. Permission was also obtained from the director of each stroke unit. FINDINGS: All the studied strategies for handling of ethical problems were found to have both obstacles and possibilities. Uncertainty is shown as a major obstacle and unanimity as a possibility in the use of the strategies. The findings also illuminate the value of the concept "the patient's best interests" as a starting point for the carers' ethical reasoning. CONCLUSION: The concept "the patient's best interests" used as a starting point for ethical reasoning among the carers is not explicitly defined yet, which might make this value difficult to use both as a universal concept and as an argument for decisions. Carers therefore need to strengthen their argumentation and reflect on and use ethically grounded arguments and defined ethical values like dignity in their clinical work and decisions. PMID- 25288512 TI - Cannabis and creativity: highly potent cannabis impairs divergent thinking in regular cannabis users. AB - RATIONALE: Cannabis users often claim that cannabis has the potential to enhance their creativity. Research suggests that aspects of creative performance might be improved when intoxicated with cannabis; however, the evidence is not conclusive. OBJECTIVE: The aim of this study was to investigate the acute effects of cannabis on creativity. METHODS: We examined the effects of administering a low (5.5 mg delta-9-tetrahydrocannabinol [THC]) or high (22 mg THC) dose of vaporized cannabis vs. placebo on creativity tasks tapping into divergent (Alternate Uses Task) and convergent (Remote Associates Task) thinking, in a population of regular cannabis users. The study used a randomized, double-blind, between-groups design. RESULTS: Participants in the high-dose group (n = 18) displayed significantly worse performance on the divergent thinking task, compared to individuals in both the low-dose (n = 18) and placebo (n = 18) groups. CONCLUSIONS: The findings suggest that cannabis with low potency does not have any impact on creativity, while highly potent cannabis actually impairs divergent thinking. PMID- 25288513 TI - Glucose administration and cognitive function: differential effects of age and effort during a dual task paradigm in younger and older adults. AB - RATIONALE: Current research suggests that glucose facilitates performance on cognitive tasks which possess an episodic memory component and a relatively high level of cognitive demand. However, the extent to which this glucose facilitation effect is uniform across the lifespan is uncertain. METHODS: This study was a repeated measures, randomised, placebo-controlled, cross-over trial designed to assess the cognitive effects of glucose in younger and older adults under single and dual task conditions. Participants were 24 healthy younger (average age 20.6 years) and 24 healthy older adults (average age 72.5 years). They completed a recognition memory task after consuming drinks containing 25 g glucose and a placebo drink, both in the presence and absence of a secondary tracking task. RESULTS AND CONCLUSIONS: Glucose enhanced recognition memory response time and tracking precision during the secondary task, in older adults only. These findings do not support preferential targeting of hippocampal function by glucose, rather they suggest that glucose administration differentially increases the availability of attentional resources in older individuals. PMID- 25288514 TI - Effects of central activation of serotonin 5-HT2A/2C or dopamine D 2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test. AB - RATIONALE: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. OBJECTIVE: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. METHODS: 2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested. RESULTS: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) MUg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 MUg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. CONCLUSIONS: Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC. PMID- 25288516 TI - Genome-wide association study for somatic cell score in Valdostana Red Pied cattle breed using pooled DNA. AB - BACKGROUND: Mastitis is a major disease of dairy cattle occurring in response to environmental exposure to infective agents with a great economic impact on dairy industry. Somatic cell count (SCC) and its log transformation in somatic cell score (SCS) are traits that have been used as indirect measures of resistance to mastitis for decades in selective breeding. A selective DNA pooling (SDP) approach was applied to identify Quantitative Trait Loci (QTL) for SCS in Valdostana Red Pied cattle using the Illumina Bovine HD BeadChip. RESULTS: A total of 171 SNPs reached the genome-wide significance for association with SCS. Fifty-two SNPs were annotated within genes, some of those involved in the immune response to mastitis. On BTAs 1, 2, 3, 4, 9, 13, 15, 17, 21 and 22 the largest number of markers in association to the trait was found. These regions identified novel genomic regions related to mastitis (1-Mb SNP windows) and confirmed those already mapped. The largest number of significant SNPs exceeding the threshold for genome-wide significant signal was found on BTA 15, located at 50.43-51.63 Mb. CONCLUSIONS: The genomic regions identified in this study contribute to a better understanding of the genetic control of the mastitis immune response in cattle and may allow the inclusion of more detailed QTL information in selection programs. PMID- 25288515 TI - Food sovereignty, food security and health equity: a meta-narrative mapping exercise. AB - There has been growing policy interest in social justice issues related to both health and food. We sought to understand the state of knowledge on relationships between health equity--i.e. health inequalities that are socially produced--and food systems, where the concepts of 'food security' and 'food sovereignty' are prominent. We undertook exploratory scoping and mapping stages of a 'meta narrative synthesis' on pathways from global food systems to health equity outcomes. The review was oriented by a conceptual framework delineating eight pathways to health (in)equity through the food system: 1--Multi-Scalar Environmental, Social Context; 2--Occupational Exposures; 3--Environmental Change; 4--Traditional Livelihoods, Cultural Continuity; 5--Intake of Contaminants; 6--Nutrition; 7--Social Determinants of Health and 8--Political, Economic and Regulatory context. The terms 'food security' and 'food sovereignty' were, respectively, paired with a series of health equity-related terms. Combinations of health equity and food security (1414 citations) greatly outnumbered pairings with food sovereignty (18 citations). Prominent crosscutting themes that were observed included climate change, biotechnology, gender, racialization, indigeneity, poverty, citizenship and HIV as well as institutional barriers to reducing health inequities in the food system. The literature indicates that food sovereignty-based approaches to health in specific contexts, such as advancing healthy school food systems, promoting soil fertility, gender equity and nutrition, and addressing structural racism, can complement the longer term socio-political restructuring processes that health equity requires. Our conceptual model offers a useful starting point for identifying interventions with strong potential to promote health equity. A research agenda to explore project-based interventions in the food system along these pathways can support the identification of ways to strengthen both food sovereignty and health equity. PMID- 25288517 TI - Clinical profile and impact of family history of premature coronary artery disease on clinical outcomes of patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction: analysis from the HORIZONS AMI Trial. AB - BACKGROUND/PURPOSE: Family history of coronary artery disease (CAD) is a well established risk factor of future cardiovascular events. The authors sought to examine the relationship between family history of CAD and clinical profile and prognosis of patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). MATERIALS/METHODS: Baseline features and clinical outcomes at 30 days and at 3 years from 3601 patients with STEMI enrolled in the HORIZONS-AMI trial were compared in patients with and without family history of premature CAD, which was present in 1059 patients (29.4%). RESULTS: These patients were younger (median 56.7 vs. 62.1years, P<0.0001) and more often current smokers (52.4% vs. 43.5%, P<0.0001), had more dyslipidemia (47.7% vs. 41.1%, P=0.0003), less diabetes mellitus (14.1% vs. 17.5%, P=0.01) and had shorter symptom onset to balloon times (median 213 vs. 225 min, P=0.02). Patients with a family history of premature CAD had higher rates of final TIMI 3 flow (93.8% vs. 90.6%, P=0.002), and myocardial blush grade 2 or 3 (83.2% vs. 78.0% P=0.0008), and fewer procedural complications. Although the unadjusted 30-day and 3-year mortality rates were lower in patients with a family history of premature CAD (1.8% vs. 3.0%, P=0.046 and 4.8% vs. 7.7%, P=0.002, respectively), by multivariable analysis the presence of a family history of premature CAD was not an independent predictor of death at 3 years (HR [95%CI]=1.00 [0.70, 1.44], P=0.98). CONCLUSIONS: A family history of premature CAD is not an independent predictor of higher mortality. PMID- 25288518 TI - Balancing the stability and drug release of polymer micelles by the coordination of dual-sensitive cleavable bonds in cross-linked core. AB - The optimal structure design of nanocarriers to inhibit premature release of anticancer drugs from nanocarriers during blood circulation and improve drug release inside tumor cells is still a significant issue for polymer micelles applied to antitumor drug delivery. Herein, in order to balance the contradiction between polymer micellar stability and drug release, dual-sensitive cleavable cross-linkages of benzoic imine conjugated disulfide bonds were introduced into the core of the amphiphilic copolymer micelles to form core-cross-linked micelles. First, biodegradable poly(ethylene glycol)-b-(polycaprolactone-g poly(methacrylic acid-p-hydroxy benzaldehyde-cystamine)), i.e. mPEG-b-(PCL-g P(MAA-Hy-Cys)) (PECMHC) copolymers were synthesized and assembled into PECMHC micelles (PECMHC Ms). Then, simply by introducing H2O2 to the PECMHC Ms dispersions to oxidate the thiol groups of cystamine moieties in the core, core cross-linked PECMHC micelles (cc-PECMHC Ms) ~100 nm in size were readily obtained in water. In vitro studies of doxorubicin (DOX)-loaded cc-PECMHC Ms show that the cross-linked core impeded the drug release in the physical conditions, owing to the high stability of the micelles against both extensive dilution and salt concentration, while it greatly accelerated DOX release in mildly acidic (pH ~5.0 6.0) medium with glutathione, owing to the coordination of the pH-sensitive cleaving of benzoic imine bonds and the reduction-sensitive cleaving of disulfide bonds. The in vivo tissue distribution and tumor accumulation of the DOX-loaded cc-PECMHC Ms were monitored via fluorescence images of DOX. DOX-loaded cc-PECMHC Ms exhibited enhanced tumor accumulation because of their high stability in blood circulation and less DOX premature release. Therefore, the cc-PECMHC Ms with dual sensitive cleavable bonds in the cross-linked core were of excellent biocompatibility, high extracellular stability and had intelligent intracellular drug release properties, indicating promise as candidates for anticancer drug delivery. PMID- 25288520 TI - Patterns of alcohol consumption in the older population of Spain, 2008-2010. AB - BACKGROUND: Older adults are a growing segment of the European population and alcohol is an important cause of disease burden; thus, it is noteworthy that little information is available on alcohol intake among older adults in Europe. OBJECTIVE: The aim of this study was to examine alcohol consumption patterns and their association with demographic and clinical variables in the older population of Spain. DESIGN: This was a cross-sectional study. PARTICIPANTS/SETTING: The sample included 3,058 individuals, representative of the Spanish population aged >=60 years during 2008-2010. MAIN OUTCOME MEASURE: Regular alcohol consumption was measured with a validated diet history questionnaire. The threshold between moderate and heavy drinking was >=40 g alcohol/day in men (>=24 g in women). Binge drinking was defined as intake of >=80 g alcohol in men (>=60 g in women) during any drinking occasion in the previous month, and problem drinking by a CAGE score >=2. STATISTICAL ANALYSIS PERFORMED: The prevalence and 95% CI of the drinking patterns were calculated after accounting for sampling design. RESULTS: The prevalence of moderate drinking was 44.3% (95% CI 42.0% to 46.6%) and of heavy drinking was 7.8% (95% CI 6.7% to 8.9%). In total, 68.4% (95% CI 65.7% to 71.2%) of individuals obtained >80% of alcohol from wine and 61.8% (95% CI 58.9% to 64.6%) drank only with meals. Furthermore, 1% (95% CI 0.6% to 1.4%) showed binge drinking and 3.1% (95% CI 2.3% to 3.8%) showed problem drinking. Heavy alcohol consumption was significantly more frequent in men. Moderate alcohol consumption was significantly less frequent among women, persons who were not married, living alone, with a diagnosis of diabetes, receiving treatment for diabetes, and with suboptimal self-rated health. About 5% to 10% of individuals with diagnosed hypertension, diabetes, or cardiovascular disease showed heavy drinking. Among those taking sleeping pills or antidiabetes or antithrombotic treatment, 37% to 46% had moderate alcohol intake and 5% to 8% had heavy intake. CONCLUSIONS: Alcohol consumption among older adults in Spain is frequent and mostly consistent with the traditional Mediterranean drinking pattern. However, a proportion of individuals were heavy drinkers and used medication that may interact with alcohol. PMID- 25288519 TI - A hypothesis-driven parametric study of effects of polymeric scaffold properties on tissue engineered neovessel formation. AB - Continued advances in the tissue engineering of vascular grafts have enabled a paradigm shift from the desire to design for adequate suture retention, burst pressure and thrombo-resistance to the goal of achieving grafts having near native properties, including growth potential. Achieving this far more ambitious outcome will require the identification of optimal, not just adequate, scaffold structure and material properties. Given the myriad possible combinations of scaffold parameters, there is a need for a new strategy for reducing the experimental search space. Toward this end, we present a new modeling framework for in vivo neovessel development that allows one to begin to assess in silico the potential consequences of different combinations of scaffold structure and material properties. To restrict the number of parameters considered, we also utilize a non-dimensionalization to identify key properties of interest. Using illustrative constitutive relations for both the evolving fibrous scaffold and the neotissue that develops in response to inflammatory and mechanobiological cues, we show that this combined non-dimensionalization computational approach predicts salient aspects of neotissue development that depend directly on two key scaffold parameters, porosity and fiber diameter. We suggest, therefore, that hypothesis-driven computational models should continue to be pursued given their potential to identify preferred combinations of scaffold parameters that have the promise of improving neovessel outcome. In this way, we can begin to move beyond a purely empirical trial-and-error search for optimal combinations of parameters and instead focus our experimental resources on those combinations that are predicted to have the most promise. PMID- 25288521 TI - Sleep Onset and Night Waking Insomnias in Preschoolers with Psychiatric Disorders. AB - This study examined the nature and prevalence of diagnostically defined sleep disorders, including Sleep Onset Insomnia (SOI) and Night Waking Insomnia (NWI), in a sample of 183 young children admitted to an early childhood psychiatric day treatment program. A semi-structured diagnostic interview, the Diagnostic Infant and Preschool Assessment, was used to assess for sleep and other psychiatric disorders. Daily sleep diaries and the Child Behavior Checklist were also examined. 41 % of children met criteria for a sleep disorder; 23 % met diagnostic criteria for SOI and 4 % met criteria for NWI, with an additional 14 % meeting criteria for both (SOI + NWI). Sleep-disordered children demonstrated longer latency to sleep onset, longer and more frequent night awakenings, less total sleep, and lower sleep efficiency than non-sleep disordered participants. Diagnosable sleep disorders, particularly SOI, were quite common in this acute clinical sample, exceeding previous estimates obtained in community and pediatric practice samples. PMID- 25288522 TI - Mother-Reported and Children's Perceived Social and Academic Competence in Clinic Referred Youth: Unique Relations to Depression and/or Social Anxiety and the Role of Self-perceptions. AB - Depression and social anxiety symptoms and disorders are highly comorbid, and are associated with low social acceptance and academic competence. Theoretical models of both depression and social anxiety highlight the saliency of negative self perceptions. We examined whether children's self-perceptions of social acceptance and mother-reported youth social acceptance are independently and uniquely related to children's depression and social anxiety, both before and after controlling for comorbid symptoms. Similar questions were examined regarding academic competence. The sample was 110 clinic-referred youth aged 8-16 years (65 boys, 45 girls; M age = 11.15, SD = 2.57). In the social acceptance area, both youth self-perceptions and mother-perceptions had independent and unique relations to depression and social anxiety, before and after controlling for comorbid symptoms. In the academic domain, both youth self-perceptions and mother perceptions had independent and unique relations to depression, before and after controlling for social anxiety; yet only youth self-perceptions were related to social anxiety, before, but not after controlling for depression. For depression, larger effect sizes were observed for children's perceived, versus mother reported, social acceptance and academic competence. Bootstrapping and Sobel tests found youth self-perceptions of social acceptance mediated the relation between mothers' perceptions and each of youth depression and social anxiety; and perceived academic competence mediated the relation between mothers' perceptions and youth depression, both before and after controlling for social anxiety. We found similarities and differences in findings for depression and social anxiety. Theoretical and treatment implications are highlighted, and future research directions are discussed. PMID- 25288523 TI - Factor Structure of the Screen for Child Anxiety-Related Emotional Disorders (SCARED) in a Community Sample of Hong Kong Chinese Adolescents. AB - The current study tested the factor structure of the 41-item SCARED in assessing anxiety in a sample of Hong Kong adolescents. Data were collected from 5,226 youths (54.5 % boys) aged 12-18. Results showed that the scale and the five subscales had high internal consistency. However, confirmatory factor analyses showed that the original five-factor model did not fit the data collected in this sample. Instead, the results revealed a seven-factor model consisting of one second-order factor of anxiety and seven first-order factors: the four original factors of General Anxiety, Panic/Somatic Syndromes, Social Anxiety, and School Phobia and three new factors representing different aspects of Separation Anxiety. Group invariance in the Boys and Girls models was found. It is recommended that the three new factors (Fear of Loneliness, Separation Fear, Worry about Harm) be further developed by adding new items so as to enhance the content and construct validities of the SCARED when used with Hong Kong adolescents. PMID- 25288524 TI - Biomechanical validation of medial pie-crusting for soft-tissue balancing in knee arthroplasty. AB - Balancing a varus knee is traditionally accomplished by releasing the medial soft tissue sleeve off the tibia. Recently, "pie-crusting" (PC) medial structures has been described. In a biomechanical cadaver study we compared PC to traditional release (TR) to determine their effects on flexion and extension gaps. PC was done in five specimens along the anterior half of the medial soft-tissue sleeve and five along the posterior half, followed by a traditional release. In 90 degrees flexion, valgus laxity after TR was significantly greater than after PC alone. PC of the anterior or posterior aspect of the medial soft-tissue sleeve can effect changes more in flexion than in extension, respectively. Complete TR did not provide more gap opening than PC in extension, but produced more effect in flexion. PMID- 25288525 TI - Linburg-Comstock anomaly of the flexor tendons of hand. PMID- 25288526 TI - Factors affecting total dissolved solids concentration of gamma-ray-irradiated aqueous hexamethylenetetramine solution: a dosimetric study. AB - A new gamma-ray-radiation dosimetric system (TDS-HMTA), comprising a 'total dissolved solids (TDS)' meter and 0.02 M aqueous hexamethylenetetramine (HMTA) solution, is introduced for medical and biological applications. Gamma-ray radiolysis of aqueous HTMA solutions increases the concentrations (ppm) of TDS, which is measured by the TDS meter. The effects of HMTA concentration, absorbed radiation dose, absorbed dose rate, and storage time on the TDS concentration of irradiated HMTA solutions were studied. It was found that 0.02 M aqueous HMTA solution yields the highest sensitivity to gamma-ray-radiation according to TDS concentration measurements. The effect of absorbed radiation dose was studied in the range 1.64-435.5 kGy. The TDS concentration increases linearly up to the maximum of the studied absorbed radiation dose range (R(2) = 0.9965). The overall coefficient of variation (CV %) associated with TDS concentration measurements of 0.02 M HMTA solution as a function of absorbed dose was found to be 0.732%. The effect of dose rate on the TDS concentration was studied in the range 0.33-3.31 kGy/h. It was found, also, that the TDS concentration is relatively stable over a storage period of 144 h after irradiation with different doses. The tissue equivalency of 0.02 M aqueous HMTA solutions allow it to be used for radiation dose measurement during sterilization in human tissue banks. Therefore, this system (TDS-HMTA) could be considered as a promising candidate for gamma-ray radiation dosimetry in technical, medical and research fields. PMID- 25288527 TI - Generating and using patient-specific whole-body models for organ dose estimates in CT with increased accuracy: feasibility and validation. AB - The estimation of patient dose using Monte Carlo (MC) simulations based on the available patient CT images is limited to the length of the scan. Software tools for dose estimation based on standard computational phantoms overcome this problem; however, they are limited with respect to taking individual patient anatomy into account. The purpose of this study was to generate whole-body patient models in order to take scattered radiation and over-scanning effects into account. Thorax examinations were performed on three physical anthropomorphic phantoms at tube voltages of 80 kV and 120 kV; absorbed dose was measured using thermoluminescence dosimeters (TLD). Whole-body voxel models were built as a combination of the acquired CT images appended by data taken from widely used anthropomorphic voxel phantoms. MC simulations were performed both for the CT image volumes alone and for the whole-body models. Measured and calculated dose distributions were compared for each TLD chip position; additionally, organ doses were determined. MC simulations based only on CT data underestimated dose by 8%-15% on average depending on patient size with highest underestimation values of 37% for the adult phantom at the caudal border of the image volume. The use of whole-body models substantially reduced these errors; measured and simulated results consistently agreed to better than 10%. This study demonstrates that combined whole-body models can provide three-dimensional dose distributions with improved accuracy. Using the presented concept should be of high interest for research studies which demand high accuracy, e.g. for dose optimization efforts. PMID- 25288528 TI - Structural insights into RNA recognition properties of glyceraldehyde-3-phosphate dehydrogenase 3 from Saccharomyces cerevisiae. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC: 1.2.1.12) is an essential enzyme in the glycolytic pathway. However, recent evidence demonstrates that GAPDH displays a range of new functions unrelated to its glycolytic function. GAPDH has long been known as a 3' AU-rich element-binding protein; however, its RNA recognition mechanism is still not well understood. Here, we present the first crystal structure of GAPDH3 from Saccharomyces cerevisiae and identify its RNA-binding specificity and propose an RNA recognition model based on structural and biochemical studies. This study sheds light on the RNA-binding mechanism of GAPDH3 and contributes to a better understanding of the molecular mechanisms of its RNA-related functions. PMID- 25288529 TI - Post-treatment MRI aspects of photodynamic therapy for prostate cancer. AB - OBJECTIVES: Photodynamic therapy is a new focal therapy for prostate cancer. METHODS: In this technique, a photosensitising agent is introduced intravenously, then activated by local laser illumination to induce tumour necrosis. Treatment efficacy is assessed by magnetic resonance imaging (MRI). RESULTS AND CONCLUSIONS: We illustrate specific post-treatment MRI aspects at early and late follow-up with pathological correlations. TEACHING POINTS: * Dynamic phototherapy is a new and promising focal therapy for prostate cancer. * One-week MRI shows increased volume of the treated lobe and large, homogeneous necrosis area. * Six month MRI shows significant changes of the prostate shape and signal. * Six-month MRI becomes "base line" appearance for further follow-up or monitoring. PMID- 25288530 TI - Status of oral anticoagulant treatment in patients with nonvalvular atrial fibrillation in Spain. REACT-AF Study. AB - BACKGROUND AND OBJECTIVES: Oral anticoagulant therapy is complex due to the need for control and the hemorrhagic risk the therapy entails. This study aims to determine the standard clinical practice in the treatment for preventing stroke in patients with nonvalvular atrial fibrillation (NVAF) in Spain. PATIENTS AND METHOD: The Real Evidence of Anti Coagulation Treatment in AF is a European, multicenter, multinational, observational, retrospectively monitored cohort of patients with NVAF. This study included patients recruited in Spain with at least one visit during the period of inclusion (May 2010/April 2012). The study evaluated the following: a) persistence of oral anticoagulant treatment (time to discontinuation); b) persistence rate (% of patients in treatment) at 6, 12 and 24 months and at 5 years; c) therapeutic compliance (medication possession ratio); d) the correlation between the treatment followed and that recommended by the European Society of Cardiology; and the incidence of stroke and hemorrhagic events. RESULTS: The patients treated with oral anticoagulants (n=7,526) had a median time to discontinuation of treatment of 1.99 years and a persistence rate at 5 years of 26% (discontinuation >=3 months). The compliance (mean MPR) was 0.54+/-0.36. The incidence of stroke was 0.3/100 person-years, and the incidence of hemorrhagic events was 2.4/100 person-years. Fifty-eight percent of the patients with NVAF (n=12,514) followed the recommendations of the European Society of Cardiology. CONCLUSION: Forty-two percent of the patients with NVAF did not follow the recommendations of the European Society of Cardiology. We detected low persistence and treatment compliance rates for oral anticoagulants. PMID- 25288531 TI - Interactions of skin with gold nanoparticles of different surface charge, shape, and functionality. AB - The interactions between skin and colloidal gold nanoparticles of different physicochemical characteristics are investigated. By systematically varying the charge, shape, and functionality of gold nanoparticles, the nanoparticle penetration through the different skin layers is assessed. The penetration is evaluated both qualitatively and quantitatively using a variety of complementary techniques. Inductively coupled plasma optical emission spectrometry (ICP-OES) is used to quantify the total number of particles which penetrate the skin structure. Transmission electron microscopy (TEM) and two photon photoluminescence microscopy (TPPL) on skin cross sections provide a direct visualization of nanoparticle migration within the different skin substructures. These studies reveal that gold nanoparticles functionalized with cell penetrating peptides (CPPs) TAT and R7 are found in the skin in larger quantities than polyethylene glycol-functionalized nanoparticles, and are able to enter deep into the skin structure. The systematic studies presented in this work may be of strong interest for developments in transdermal administration of drugs and therapy. PMID- 25288532 TI - Fabrication of monodisperse liposomes-in-microgel hybrid microparticles in capillary-based microfluidic devices. AB - This study introduces a drop-based microfluidic approach to physically immobilize liposomes in microgel (liposomes-in-microgel) particles. For this, we generate a uniform liposomes-in-water-in-oil emulsion in a capillary-based microfluidic device. Basically, we have investigated how the flow rate and flow composition affect generation of emulsion precursor drops in micro-channels. Then, the precursor emulsion drops are solidified by photo-polymerization. From characterization of hydrogel mesh sizes, we have figured out that the mesh size of the liposomes-in-microgel particles is bigger than that of bare microgel particles, since liposomes take space in the hydrogel phase. In our further study on drug releasing, we have observed that immobilization of liposomes in the microgel particles can not only remarkably retard drug releasing, but also enables a sustained release, which stems from the enhanced matrix viscosity of the surrounding hydrogel phase. PMID- 25288533 TI - Polydopamine-based superparamagnetic molecularly imprinted polymer nanospheres for efficient protein recognition. AB - A new strategy for synthesis of superparamagnetic molecularly imprinted polymer nanospheres (MIPNSs) for efficient protein recognition is described here. Homogeneous hydroxyl group functionalized Fe3O4/polymethyl methacrylate (PMMA) composite nanospheres were prepared using improved miniemulsion polymerization. Uniform superparamagnetic MIPNSs were obtained via self-polymerization of dopamine (DA) on the surface of Fe3O4/PMMA composite nanospheres in the presence of lysozyme (lyz) template. The as-synthesized Fe3O4/PMMA/PDA MIPNSs had average diameters of 180 nm, high saturation magnetization and a good magnetic response. The lyz-imprinted Fe3O4/PMMA/PDA MIPNSs exhibited specific recognition and efficient adsorption capacity toward lyz template. The amount of lyz adsorbed onto the lyz-imprinted Fe3O4/PMMA/PDA MIPNSs was about 4 times greater than that of the Fe3O4/PMMA/PDA non-imprinted polymer nanospheres (NIPNSs) and about 14, 5, and 5 times greater than that of BSA, BHb, and cyt C, respectively. PMID- 25288534 TI - The involvement of selected membrane transport mechanisms in the cellular uptake of (177)Lu-labeled bombesin, somatostatin and gastrin analogues. AB - INTRODUCTION: Radiolabeled receptor-targeting peptides are a useful tool for the diagnostic imaging and radiotherapy of some malignancies. However, the retention of radioactivity in the kidney may result in renal radiotoxic injury. This study seeks to evaluate the role of endocytic receptor megalin, renal SLC influx transporters and fluid phase endocytosis (FPE) in the cellular accumulation of radiolabeled peptides. METHODS: In vitro transport cellular studies using megalin ligands (RAP, albumin), fluid phase endocytosis (FPE) inhibitor rottlerin and low temperature were employed to evaluate the transport mechanisms of the peptides. Cells transfected with hOAT1 or hOCT2 were used to analyze the role of these SLC transporters. Somatostatin ((177)Lu-DOTA-[Tyr(3)]octreotate, (177)Lu-DOTA-[1 Nal(3)]octreotide), gastrin ((177)Lu-DOTA-sargastrin) and bombesin ((177)Lu-DOTA [Pro(1),Tyr(4)]bombesin, (177)Lu-DOTA-[Lys(3)]bombesin, (177)Lu-PCTA [Lys(3)]bombesin) analogues were involved in the study. RESULTS: RAP, albumin and low temperature decreased the accumulation of all the studied peptides significantly. With one exception, rottlerin caused the concentration dependent inhibition of the cellular accumulation of the radiopeptides. No significant differences in the uptake of the peptides between the control cells and those transfected with hOAT1 or hOCT2 were observed. CONCLUSION: The study showed that active transport mechanisms are decisive for the cellular accumulation in all tested (177)Lu-labeled somatostatin, gastrin and bombesin analogues. Besides receptor-mediated endocytosis by megalin, FPE participates significantly in the uptake. The tested types of renal SLC transporters are not involved in this process. PMID- 25288535 TI - Ability of procalcitonin to predict bacterial meningitis in the emergency department. AB - INTRODUCTION: The aim of this study was to analyse and compare procalcitonin (PCT) and C-reactive protein (CRP) as tools for detecting bacterial meningitis and predicting bacteraemia. METHODS: Prospective, observational, and descriptive analytical study of 98 consecutive patients aged >=15 years and diagnosed with acute meningitis in an emergency department between August 2009 and July 2013. RESULTS: We analysed 98 patients with AM (66 males [67%]); mean age was 44+/-21 years. The diagnosis was bacterial meningitis in 38 patients (20 with bacteraemia); viral meningitis in 33; probable viral meningitis in 15; and presumptively diagnosed partially treated acute meningitis in 12. PCT had the highest area under the ROC curve (AUC) (0.996; 95% CI, 0.987-1; p<0.001). With a cutoff of >= 0.74 ng/ml, PCT achieved 94.7% sensitivity, 100% specificity, negative predictive value (NPV) of 93.9%, and positive predictive value (PPV) of 100%. The mean levels for PCT were11.47+/-7.76 ng/ml in bacterial meningitis vs. 0.10+/-0.15 ng/ml in viral meningitis (p <0.001). The AUC for CRP was 0.916 and a cutoff of >= 90 mg/L achieved 67.5% sensitivity, 86.3% specificity, PPV of 89.2%, and NPV of 90.4%. As a predictor of bacteraemia in bacterial meningitis, only PCT delivered a significant difference (14.7+/-7.1 ng/mL vs. 4.68+/-3.54 ng/mL, p<0.001). A cutoff of >= 1.1 ng/mL achieved 94.6% sensitivity, 72.4% specificity, NPV of 95.4%, and PPV of 69.2%; the AUC was 0.965 (95% CI, 0.921-1; p<0.001). CONCLUSIONS: PCT has a high diagnostic power for acute meningitis in emergency department patients. PCT outperforms CRP in the detection of bacterial aetiology and is a good predictor of bacteraemia in bacterial meningitis. PMID- 25288536 TI - Electroencephalography as a post-stroke assessment method: An updated review. AB - Given that stroke is currently a serious problem in the population, employing more reliable and objective techniques for determining diagnosis and prognosis is necessary in order to enable effective clinical decision-making. EEG is a simple, low-cost, non-invasive tool that can provide information about the changes occurring in the cerebral cortex during the recovery process after stroke. EEG provides data on the evolution of cortical activation patterns which can be used to establish a prognosis geared toward harnessing each patient's full potential. This strategy can be used to prevent compensation and maladaptive plasticity, redirect treatments, and develop new interventions that will let stroke patients reach their new maximum motor levels. PMID- 25288537 TI - Model-based hypothesis of gut microbe populations and gut/brain barrier permeabilities in the development of regressive autism. AB - Regressive autism is a devastating disorder affecting children between the ages of 15-30 months. The disorder is characterized by the loss of social interaction and communication ability following otherwise healthy development. In spite of rising autism prevalence, current detection methods and treatment options for this disease are lacking. Therefore, this study introduces a systems-level model, which suggests that gut microbes and intestinal inflammation influence the onset of regressive autism through increasing gut permeability. This computational model provides a framework for quantitative understanding of how imbalances in populations of gut microbes alters the whole-body and brain distributions of neurotoxins produced by GI tract bacteria. Our results indicate that increased levels of the bacteria Bacteroides vulgatus lead to increased brain levels of propionic acid, a neurotoxin which has been known to cause symptoms characteristic of autism when injected into the brain of rats. Our results further indicate that immune response to virulence factors produced by bacteria in the gut leads to increased systemic levels of inflammatory cytokines, such as IL-1beta, which significantly alter the permeability of the gut epithelial layer and the blood-brain barrier. Due to the large size of cytokines, however, we predict the time required for concentrations in the brain to stabilize to be on the order of years. This suggests that treatments preventing autism development could be administered after identifying microbial biomarkers of disease but before debilitating brain inflammation leads to regressive autism progression. Future research extending this work could provide new treatment options and diagnostic techniques to help combat regressive autism. PMID- 25288538 TI - A toxicity-based method for evaluating safety of reclaimed water for environmental reuses. AB - A large quantity of toxic chemical pollutants possibly remains in reclaimed water due to the limited removal efficiency in traditional reclamation processes. It is not enough to guarantee the safety of reclaimed water using conventional water quality criteria. An integrated assessment method based on toxicity test is necessary to vividly depict the safety of reclaimed water for reuse. A toxicity test battery consisting of lethality, genotoxicity and endocrine disrupting effect was designed to screen the multiple biological effects of residual toxic chemicals in reclaimed water. The toxicity results of reclaimed water were converted into the equivalent concentrations of the corresponding positive reference substances (EQC). Simultaneously, the predicted no-effect concentration (PNEC) of each positive reference substance was obtained by analyzing the species sensitivity distribution (SSD) of toxicity data. An index "toxicity score" was proposed and valued as 1, 2, 3, or 4 depending on the ratio of the corresponding EQC to PNEC. For vividly ranking the safety of reclaimed water, an integrated assessment index "toxicity rank" was proposed, which was classified into A, B, C, or D rank with A being the safest. The proposed method was proved to be effective in evaluating reclaimed water samples in case studies. PMID- 25288539 TI - Enhanced anaerobic fermentation with azo dye as electron acceptor: simultaneous acceleration of organics decomposition and azo decolorization. AB - Accumulation of hydrogen during anaerobic processes usually results in low decomposition of volatile organic acids (VFAs). On the other hand, hydrogen is a good electron donor for dye reduction, which would help the acetogenic conversion in keeping low hydrogen concentration. The main objective of the study was to accelerate VFA composition through using azo dye as electron acceptor. The results indicated that the azo dye serving as an electron acceptor could avoid H2 accumulation and accelerate anaerobic digestion of VFAs. After adding the azo dye, propionate decreased from 2400.0 to 689.5mg/L and acetate production increased from 180.0 to 519.5mg/L. It meant that the conversion of propionate into acetate was enhanced. Fluorescence in situ hybridization analysis showed that the abundance of propionate-utilizing acetogens with the presence of azo dye was greater than that in a reference without azo dye. The experiments via using glucose as the substrate further demonstrated that the VFA decomposition and the chemical oxygen demand (COD) removal increased by 319.7mg/L and 23.3% respectively after adding the azo dye. Therefore, adding moderate azo dye might be a way to recover anaerobic system from deterioration due to the accumulation of H2 or VFAs. PMID- 25288540 TI - Arsenic fractionation and contamination assessment in sediments of thirteen lakes from the East Plain and Yungui Plateau Ecoregions, China. AB - Arsenic (As) fractions in the sediments of seven lakes from East Plain Ecoregion and six lakes from Yungui Plateau Ecoregion, China, were investigated. Results indicated that the total As concentrations in sediment samples of lakes of the East Plain Lake Ecoregion are higher than those of Yungui Plateau Lake Ecoregion. Residual As is the main fraction in sediment samples of lakes from both ecoregions, followed by reducible As and soluble or oxidizable As. The total As is correlated to oxidizable As and residual As in sediment samples from both lake ecoregions. As distribution in sediment samples of lakes of the East Plain Ecoregion appears to be affected by human activity, while the As origin mainly comes from natural sources in sediment samples of lakes in the Yungui Plateau Ecoregion. The potential ecological risk index and geoaccumulation index values suggest "low to moderate" risk degree and "unpolluted to moderately polluted" for As in the studied lake sediments. PMID- 25288541 TI - Changes in the quality of river water before, during and after a major flood event associated with a La Nina cycle and treatment for drinking purposes. AB - The treatment of organics present in the lower reaches of a major river system (the Murray-Darling Basin, Australia) before (March-July 2010), during (December 2010-May 2011) and after (April-December 2012) a major flood period was investigated. The flood period (over 6months) occurred during an intense La Nina cycle, leading to rapid and high increases in river flows and organic loads in the river water. Dissolved organic carbon (DOC) increased (2-3 times) to high concentrations (up to 16mg/L) and was found to correlate with river flow rates. The treatability of organics was studied using conventional jar tests with alum and an enhanced coagulation model (mEnCo(c)). Predicted mean alum dose rates (per mg DOC) were higher before (9.1mg alum/mg DOC) and after (8.5mg alum/mg DOC) than during the flood event (8.0mg alum/mg DOC), indicating differences in the character of the organics in raw waters. To assess the character of natural organic matter present in raw and treated waters, high performance size exclusion chromatography with UV and fluorescence detectors were used. During the flood period, high molecular weight UV absorbing compounds (>2kDa) were mostly detected in waters collected, but were not evident in waters collected before and afterwards. The relative abundances of humic-like and protein-like compounds during and following the flood period were also investigated and found to be of a higher molecular weight during the flood period. The treatability of the organics was found to vary over the three climate conditions investigated. PMID- 25288542 TI - Experimental study using the dilution incubation method to assess water biostability. AB - Water biostability is of particular concern to water supply as a major limiting factor for heterotrophic bacterial growth in water distribution systems. This study focused on bacterial growth dynamics in the series dilution of water samples with TOC (total organic carbon) values determined beforehand. The results showed that the specific growth rate of Pseudomonas fluorescens P17 varied dramatically and irregularly with TOC value when TOC concentrations were low enough during the initial periods of incubation under given conditions. According to this relationship between bacterial growth rate and TOC, a dilution incubation method was designed for the study of water biostability. With the method under a given condition, a turning-point TOC value was found at a relatively fixed point in the curve between bacterial growth rate and TOC of water sample, and the variation of growth rate had different characteristics below the turning-point TOC value relative to that over this value. A turning-point TOC value similarly existed in all experiments not only with tap water, but also with acetate and mixed solutions. And in the dilution incubation method study, the affections were analyzed by condition factors such as inoculum amount, incubation time and nature of the organic carbon source. In very low organic carbon water environments, the variation characteristics of bacterial growth rate will be useful to further understand the meaning of water biostability. PMID- 25288543 TI - Effect of the chlortetracycline addition method on methane production from the anaerobic digestion of swine wastewater. AB - Effects of antibiotic residues on methane production in anaerobic digestion are commonly studied using the following two antibiotic addition methods: (1) adding manure from animals that consume a diet containing antibiotics, and (2) adding antibiotic-free animal manure spiked with antibiotics. This study used chlortetracycline (CTC) as a model antibiotic to examine the effects of the antibiotic addition method on methane production in anaerobic digestion under two different swine wastewater concentrations (0.55 and 0.22mg CTC/g dry manure). The results showed that CTC degradation rate in which manure was directly added at 0.55mg CTC/g (HSPIKE treatment) was lower than the control values and the rest of the treatment groups. Methane production from the HSPIKE treatment was reduced (p<0.05) by 12% during the whole experimental period and 15% during the first 7days. The treatments had no significant effect on the pH and chemical oxygen demand value of the digesters, and the total nitrogen of the 0.55mg CTC/kg manure collected from mediated swine was significantly higher than the other values. Therefore, different methane production under different antibiotic addition methods might be explained by the microbial activity and the concentrations of antibiotic intermediate products and metabolites. Because the primary entry route of veterinary antibiotics into an anaerobic digester is by contaminated animal manure, the most appropriate method for studying antibiotic residue effects on methane production may be using manure from animals that are given a particular antibiotic, rather than adding the antibiotic directly to the anaerobic digester. PMID- 25288544 TI - Peroxyacetyl nitrate observed in Beijing in August from 2005 to 2009. AB - Measurements of peroxyacetyl nitrate (PAN) were made at a Beijing urban site each August from 2005 to 2009. Over this 5-year period, the average PAN concentration for August in each year increased from 3 (2005) to 11.7MUg/m(3) (2007); however, it decreased rapidly in 2008 (4.1MUg/m(3)). Generally, the variation over the 5 years showed a rise in the first part of the study period, followed by a decline. We considered two categories of local and regional air masses in this study, which revealed that the PAN concentration in Beijing was affected mainly by southeastern air masses. The August PAN variation was influenced predominantly by local air masses in 2005, but by 2009 regional air masses had become more important. This study showed the level and variation of PAN in the month of August in 5 consecutive years for the first time, and proved that control measures are useful in decreasing photochemical pollution; hence, these measures are probably feasible for other megacities too. Furthermore, this method of analyzing regional and local impacts might be useful for other studies as well. PMID- 25288545 TI - PM2.5, PM10 and health risk assessment of heavy metals in a typical printed circuit noards manufacturing workshop. AB - A typical Printed Circuit Board (PCB) manufacturer was chosen as the object of this study. During PCB processing, fine particulate matter and heavy metals (Cu, Zn, Pb, Cr, Cd and Ni) will be released into the air and dust, which then impact workers' health and the environment. The concentrations of total suspended particle (TSP), PM10 and PM2.5 in the off-site were 106.3, 90.0 and 50.2MUg/m(3), respectively, while the concentrations of TSP, PM10 and PM2.5 in the workshops ranged from 36.1 to 365.3, from 27.1 to 289.8 and from 22.1 to 212.3MUg/m(3), respectively. Almost all six of the heavy metals were detected in all of the particle samples except Cd. For each workshop, it was obvious that Zn was the most enriched metal in TSP, followed by Cu>Pb (Cr)>Ni>Cd, and the same trend was found for PM10 and PM2.5. In the dust samples, Cu (which ranged from 4.02 to 56.31mg/g) was the most enriched metal, followed by Zn, Cr, Pb, Ni and Cd, and the corresponding concentrations ranged from 0.77 to 4.47, 0.37 to 1.59, 0.26 to 0.84, 0.13 to 0.44 and nd to 0.078mg/g, respectively. The health risk assessment showed that noncancerous effects are unlikely for Zn, Pb, Cr, Cu, Cd and Ni. The carcinogenic risks for Cd and Ni were all lower than 10(-6), except for Cr. This result indicates that carcinogenic risks for workers are relatively possible in the workshops. These findings suggest that this technology is advanced from the perspective of environmental protection in the waste PCB's recycling industry. PMID- 25288546 TI - Unregulated emissions from diesel engine with particulate filter using Fe-based fuel borne catalyst. AB - The alteration and formation of toxic compounds and potential changes in the toxicity of emissions when using after-treatment technologies have gained wide attention. Volatile organic compound (VOC), carbonyl compound and particle-phase polycyclic aromatic hydrocarbon (PAH) emissions were tested at European Steady State Cycle (ESC) to study unregulated emissions from a diesel engine with a fuel borne catalyst and diesel particulate filter (FBC-DPF). An Fe-based fuel-borne catalyst was used for this study. According to the results, brake specific emissions of total VOCs without and with DPF were 4.7 and 4.9mg/kWh, respectively, showing a 4.3% increase. Benzene and n-undecane emissions increased and toluene emission decreased, while other individual VOC emissions basically had no change. When retrofitted with the FBC-DPF, total carbonyl compound emission decreased 15.7%, from 25.8 to 21.8mg/kWh. The two highest carbonyls, formaldehyde and acetaldehyde, were reduced from 20.0 and 3.7 to 16.5 and 3.3mg/kWh respectively. The specific reactivity (SR) with DPF was reduced from 6.68 to 6.64mg/kWh. Total particle-phase PAH emissions decreased 66.4% with DPF compared to that without DPF. However, the Benzo[a]pyrene equivalent (BaPeq) with DPF had increased from 0.016 to 0.030mg/kWh. Fluoranthene and Pyrene had the greatest decrease, 91.1% and 88.4% respectively. The increase of two- and three ring PAHs with DPF indicates that the fuel-borne catalyst caused some gas-phase PAHs to adsorb on particles. The results of this study expand the knowledge of the effects of using a particulate filter and a Fe-based fuel-borne catalyst on diesel engine unregulated emissions. PMID- 25288547 TI - Arbuscular mycorrhizal fungal phylogenetic groups differ in affecting host plants along heavy metal levels. AB - Arbuscular mycorrhizal fungi (AMF) are important components of soil microbial communities, and play important role in plant growth. However, the effects of AMF phylogenetic groups (Glomeraceae and non-Glomeraceae) on host plant under various heavy metal levels are not clear. Here we conducted a meta-analysis to compare symbiotic relationship between AMF phylogenetic groups (Glomeraceae and non Glomeraceae) and host plant functional groups (herbs vs. trees, and non-legumes vs. legumes) at three heavy metal levels. In the meta-analysis, we calculate the effect size (ln(RR)) by taking the natural logarithm of the response ratio of inoculated to non-inoculated shoot biomass from each study. We found that the effect size of Glomeraceae increased, but the effect size of non-Glomeraceae decreased under high level of heavy metal compared to low level. According to the effect size, both Glomeraceae and non-Glomeraceae promoted host plant growth, but had different effects under various heavy metal levels. Glomeraceae provided more benefit to host plants than non-Glomeraceae did under heavy metal condition, while non-Glomeraceae provided more benefit to host plants than Glomeraceae did under no heavy metal. AMF phylogenetic groups also differed in promoting plant functional groups under various heavy metal levels. Interacting with Glomeraceae, herbs and legumes grew better than trees and non-legumes did under high heavy metal level, while trees and legumes grew better than herbs and non-legumes did under medium heavy metal level. Interacting with non-Glomeraceae, herbs and legumes grew better than trees and non-legumes did under no heavy metal. We suggested that the combination of legume with Glomeraceae could be a useful way in the remediation of heavy metal polluted environment. PMID- 25288548 TI - Polychlorinated dibenzo-p-dioxins and dibenzofurans and polychlorinated biphenyls in surface soil from the Tibetan Plateau. AB - Concentrations of Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in soil samples from Tibetan Plateau were determined. The average concentration of total 2,3,7,8-PCDD/Fs was (2.30+/-1.02) pg/g, and World Health Organization Toxicity Equivalency (WHO-TEQ) average concentration was (0.013+/-0.010) pgWHO-TEQ/g. The average concentration of ?PCBs (7 indicator PCB and 12 dioxin like-PCB congeners) was (16.2+/-9.25) pg/g, and WHO-TEQ average concentration was 0.043+/-0.049pgWHO-TEQ/g. Comparing to previous studies in similar environmental conditions, PCDD/Fs and PCBs in this study showed a relatively lower concentration. The altitude dependences of PCDD/Fs and PCBs were also studied. Total organic carbon (TOC) normalized concentrations presented a quadratic relation with the altitudes, and an inflection could be found on the parabola of the total concentrations and some congeners of high concentration. The concentrations decreased with altitudes below about 4500m above sea level (a.s.l.), while they increased with altitudes above it. These phenomena indicate that cold condensation of PCDD/Fs and PCBs would happen above 4500m a.s.l, on the Tibetan Plateau. PMID- 25288549 TI - Cadmium accumulation and tolerance of two castor cultivars in relation to antioxidant systems. AB - To investigate the effects of Cd on tolerance and antioxidant activities of castor, two different castor (Ricinus communis L.) cultivars (Zibo No. 5 and Zibo No. 8) were used for a hydroponic experiment (0, 1 and 2mg/L Cd) and a pot experiment using Cd-contaminated soil (34mg/kg) with the addition of ethylenedinitrilotetraacetic acid (EDTA). The results indicated that there were significant differences between the two cultivars with respect to Cd uptake in shoots (113-248mg/kg for Zibo No. 5 and 130-288mg/kg Zibo No. 8), biomass tolerance indexes (64.9%-74.6% for Zibo No. 5 and 80.1%-90.9% for Zibo No. 8) in the hydroponic experiment and survival rates (0% for Zibo No. 5 and 100% for Zibo No. 8) determined by the addition of EDTA in the pot experiment, suggesting that Zibo No. 8 has higher tolerance than Zibo No. 5. Moreover, the castor cultivars have low bioconcentration factors (4.80% for Zibo No. 5 and 5.43% for Zibo No. 8) and low translocation factors (<1%). Consequently, Zibo No. 8 can participate in Cd phytostabilization in highly Cd-polluted areas. The results indicated that glutathione (GSH) as a non-enzymatic antioxidant, and antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and guaiacol peroxidase (GPX), were cultivar- and dose-dependent. The higher tolerance of Zibo No. 8 compared with Zibo No. 5 can be attributed to the higher GSH levels in the root and higher GPX activity in the leaf. PMID- 25288550 TI - Biosorption mechanisms involved in immobilization of soil Pb by Bacillus subtilis DBM in a multi-metal-contaminated soil. AB - Mechanisms of soil Pb immobilization by Bacillus subtilis DBM, a bacterial strain isolated from a heavy-metal-contaminated soil, were investigated. Adsorption and desorption experiments with living bacterial cells as well as dead cells revealed that both extracellular adsorption and intracellular accumulation were involved in the Pb(2+) removal from the liquid phase. Of the sequestered Pb(II), 8.5% was held by physical entrapment within the cell wall, 43.3% was held by ion-exchange, 9.7% was complexed with cell surface functional groups or precipitated on the cell surface, and 38.5% was intracellularly accumulated. Complexation of Pb(2+) with carboxyl, hydroxyl, carbonyl, amido, and phosphate groups was demonstrated by Fourier transform infrared spectroscopic analysis. Precipitates of Pb5(PO4)3OH, Pb5(PO4)3Cl and Pb10(PO4)6(OH)2 that formed on the cell surface during the biosorption process were identified by X-ray diffraction analysis. Transmission electron microscopy-energy dispersive spectroscopic analysis confirmed the presence of the Pb(II) precipitates and that Pb(II) could be sequestered both extracellularly and intracellularly. Incubation with B. subtilis DBM significantly decreased the amount of the weak-acid-soluble Pb fraction in a heavy-metal-contaminated soil, resulting in a reduction in Pb bioavailability, but increased the amount of its organic-matter-bound fraction by 71%. The ability of B. subtilis DBM to reduce the bioavailability of soil Pb makes it potentially useful for bacteria-assisted phytostabilization of multi-heavy-metal-contaminated soil. PMID- 25288551 TI - Physiological cellular responses and adaptations of Rhodococcus erythropolis IBBPo1 to toxic organic solvents. AB - A new Gram-positive bacterium, Rhodococcus erythropolis IBBPo1 (KF059972.1) was isolated from a crude oil-contaminated soil sample by enrichment culture method. R. erythropolis IBBPo1 was able to tolerate a wide range of toxic compounds, such as antibiotics (800-1000MUg/mL), synthetic surfactants (50-200MUg/mL), and organic solvents (40%-100%). R. erythropolis IBBPo1 showed good tolerance to both alkanes (cyclohexane, n-hexane, n-decane) and aromatics (toluene, styrene, ethylbenzene) with logPOW (logarithm of the partition coefficient of the solvent in octanol-water mixture) values between 2.64 and 5.98. However, alkanes were less toxic for R. erythropolis IBBPo1 cells, compared with aromatics. The high organic solvent tolerance of R. erythropolis IBBPo1 could be due to the presence in their large genome of some catabolic (alkB, alkB1, todC1, todM, xylM), transporter (HAE1) and trehalose-6-phosphate synthase (otsA1, KF059973.1) genes. Numerous and complex physiological cellular responses and adaptations involved in organic solvent tolerance were revealed in R. erythropolis IBBPo1 cells exposed 1 and 24hr to 1% organic solvents. R. erythropolis IBBPo1 cells adapt to 1% organic solvents by changing surface hydrophobicity, morphology and their metabolic fingerprinting. Considerable modifications in otsA1 gene sequence were also observed in cells exposed to organic solvents (except ethylbenzene). PMID- 25288552 TI - Optimized production of a novel bioflocculant M-C11 by Klebsiella sp. and its application in sludge dewatering. AB - The optimized production of a novel bioflocculant M-C11 produced by Klebsiella sp. and its application in sludge dewatering were investigated. The optimal medium carbon source, nitrogen source, metal ion, initial pH and culture temperature for the bioflocculant production were glucose, NaNO3, MgSO4, and pH7.0 and 25 degrees C, respectively. A compositional analysis indicated that the purified M-C11 consisted of 91.2% sugar, 4.6% protein and 3.9% nucleic acids (m/m). A Fourier transform infrared spectrum confirmed the presence of carboxyl, hydroxyl, methoxyl and amino groups. The microbial flocculant exhibited excellent pH and thermal stability in a kaolin suspension over a pH range of 4.0 to 8.0 and a temperature range of 20 to 60 degrees C. The optimum bioflocculating activity was observed as 92.37% for 2.56mL M-C11 and 0.37g/L CaCl2 dosages using response surface methodology. The sludge resistance in filtration (SRF) decreased from 11.6*10(12) to 4.7*10(12)m/kg, which indicated that the sludge dewaterability was remarkably enhanced by the bioflocculant conditioning. The sludge dewatering performance conditioned by M-C11 was more efficient than that of inorganic flocculating reagents, such as aluminum sulfate and polymeric aluminum chloride. The bioflocculant has advantages over traditional sludge conditioners due to its lower cost, benign biodegradability and negligible secondary pollution. In addition, the bioflocculant was favorably adapted to the specific sludge pH and salinity. PMID- 25288553 TI - Molecular characterization and developmental expression patterns of thyroid hormone receptors (TRs) and their responsiveness to TR agonist and antagonist in Rana nigromaculata. AB - Considering some advantages of Rana nigromaculata as an experimental species, we propose that this species, like Xenopus laevis, could be used to assay thyroid hormone (TH) signaling disrupting actions. To validate the utilizability of R. nigromaculata, we investigated the responsiveness of R. nigromaculata to a TH receptor (TR) agonist (T3) and antagonist (amiodarone) by analyzing expression, based on characterizing TR cDNA and developmental expression patterns. With high levels of identity with the corresponding genes in X. laevis, both TRalpha and TRbeta in R. nigromaculata exhibited roughly similar developmental expression patterns to those of X. laevis, in spite of some species-specific differences. Both TRalpha and TRbeta expression had greater changes in the liver and intestine than in the tail and brain during metamorphosis. T3 exposure for 2days induced more dramatic increases of TRbeta expression in stage 27 than in stage 34 tadpoles but not in stage 42 tadpoles, showing that the responsiveness of R. nigromaculata to TH decreased with development and disappeared at the onset of metamorphic climax. Corresponding to greater changes of TRbeta expression in the liver and intestine than in the tail and brain during metamorphosis, the liver and intestine had higher responsiveness to exogenous T3 than the tail and brain. Amiodarone inhibited T3-induced TRbeta expression. Our results show that R. nigromaculata can be used as a model species for assaying TH signaling disrupting actions by analyzing TRbeta expression, and intestine tissues at stage 27 are ideal test materials due to high responsiveness and easy accessibility. PMID- 25288554 TI - Activated carbon enhanced ozonation of oxalate attributed to HO oxidation in bulk solution and surface oxidation: effect of activated carbon dosage and pH. AB - Ozonation of oxalate in aqueous phase was performed with a commercial activated carbon (AC) in this work. The effect of AC dosage and solution pH on the contribution of hydroxyl radicals (HO) in bulk solution and oxidation on the AC surface to the removal of oxalate was studied. We found that the removal of oxalate was reduced by tert-butyl alcohol (tBA) with low dosages of AC, while it was hardly affected by tBA when the AC dosage was greater than 0.3g/L. tBA also inhibited ozone decomposition when the AC dosage was no more than 0.05g/L, but it did not work when the AC dosage was no less than 0.1g/L. These observations indicate that HO in bulk solution and oxidation on the AC surface both contribute to the removal of oxalate. HO oxidation in bulk solution is significant when the dosage of AC is low, whereas surface oxidation is dominant when the dosage of AC is high. The oxalate removal decreased with increasing pH of the solution with an AC dosage of 0.5g/L. The degradation of oxalate occurs mainly through surface oxidation in acid and neutral solution, but through HO oxidation in basic bulk solution. A mechanism involving both HO oxidation in bulk solution and surface oxidation was proposed for AC enhanced ozonation of oxalate. PMID- 25288555 TI - Effect of Ce doping of TiO2 support on NH3-SCR activity over V2O5-WO3/CeO2-TiO2 catalyst. AB - CeO2-TiO2 composite supports with different Ce/Ti molar ratios were prepared by a homogeneous precipitation method, and V2O5-WO3/CeO2-TiO2 catalysts for the selective catalytic reduction (SCR) of NOx with NH3 were prepared by an incipient wetness impregnation method. These catalysts were characterized by means of BET, XRD, UV-Vis, Raman and XPS techniques. The results showed that the catalytic activity of V2O5-WO3/TiO2 was greatly enhanced by Ce doping (molar ratio of Ce/Ti=1/10) in the TiO2 support. The catalysts that were predominantly anatase TiO2 showed better catalytic performance than the catalysts that were predominantly fluorite CeO2. The Ce additive could enhance the surface adsorbed oxygen and accelerate the SCR reaction. The effects of O2 concentration, ratio of NH3/NO, space velocity and SO2 on the catalytic activity were also investigated. The presence of oxygen played an important role in NO reduction. The optimal ratio of NH3/NO was 1/1 and the catalyst had good resistance to SO2 poisoning. PMID- 25288556 TI - Graphene TiO2 nanocomposites with high photocatalytic activity for the degradation of sodium pentachlorophenol. AB - A series of graphene-TiO2 photocatalysts was synthesized by doping TiO2 with graphene oxide via hydrothermal treatment. The photocatalytic capability of the catalysts under ultraviolet irradiation was evaluated in terms of sodium pentachlorophenol (PCP-Na) decomposition and mineralization. The structural and physicochemical properties of these nanocomposites were characterized by X-ray diffraction, N2 adsorption-desorption, transmission electron microscopy, scanning electron microscopy, Ultraviolet-visible diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, electron paramagnetic resonance spectra, and Fourier transform infrared spectroscopy. The graphene-TiO2 nanocomposites exhibited higher photocatalytic efficiency than commercial P25 for the degradation of PCP Na, and 63.4% to 82.9% of the total organic carbon was fully mineralized. The improved photocatalytic activity may be attributed to the accelerated interfacial electron-transfer process and the significantly prolonged lifetime of electron hole pairs imparted by graphene sheets in the nanocomposites. However, excessive graphene and the inhomogeneous aggregation of TiO2 nanoparticles may decrease photodegradation efficiency. PMID- 25288557 TI - Mechanism of Cu(II) adsorption inhibition on biochar by its aging process. AB - Biochar exposed in the environment may experience a series of surface changes, which is called biochar aging. In order to study the effects of biochar aging on Cu(II) adsorption, we analyzed the surface properties before and after biochar aging with scanning electron microscopy (SEM) coupled to an energy-dispersive X ray spectrometer (EDX) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and then explored the influence of the aging process on Cu(II) adsorption by batch experiments. After the aging process, the oxygen concentration, phenolic hydroxyl groups, aromatic ethers and other oxygen containing functional groups on the biochar surface increased, while carboxyl groups slightly decreased. Thus, over a range of pH, the cation exchange capacity (CEC) and adsorption capacity of Cu(II) on the aged biochar were smaller than those of new biochar, indicating that when biochar is incubated at constant temperature and water holding capacity in the dark, the aging process may inhibit Cu(II) adsorption. Meanwhile, the dissociation characteristics of oxygen containing functional groups changed through the aging process, which may be the mechanism by which the biochar aging process inhibits the Cu(II) adsorption. Carboxyl groups became more easily dissociated at low pH (3.3-5.0), and the variation of maximum adsorption capability (qm) of Cu(II) on the old biochar was enlarged. Phenolic hydroxyl groups increased after the aging, making them and carboxyl groups more difficult to dissociate at high pH (5.0-6.8), and the variation of qm of Cu(II) on the aged biochar was reduced. PMID- 25288559 TI - AANPCP announces changes in the certification program. PMID- 25288558 TI - Assessment of estrogen disrupting potency in animal foodstuffs of China by combined biological and chemical analyses. AB - Food has been documented as one of major routes for human exposure to environmental estrogens (EEs), but information on the occurrence of EEs in animal foodstuffs is still scarce. This study analyzed estrogenic activity in 16 types of animal foodstuffs (n=142) collected from four cities (Wuhan, Guangzhou, Wenzhou and Yantai) of China by combined yeast estrogen screen (YES) bioassay and chemical analysis. By bioassay, all samples' extracts were found to induce estrogenic activities and the bioassay-derived 17beta-estradiol equivalent (EEQbio) ranged from 8.29 to 118.32ng/g. In addition, the samples were analyzed by liquid chromatography coupled to tandem mass spectrometry for further chemical analysis. 17beta-Estradiol was found in all samples in this survey at levels of 0.44 to 15.04ng/g. All samples had 33.1% detection rate of 17alpha ethinylestradiol (EE2), and the maximum concentration was 2.80ng/g. Bisphenol A and 4-nonylphenols were detected in 83.8% and 83.1% of samples, with concentrations up to 12.56ng/g and 35.76ng/g, respectively. However, the concentrations of estrone, diethylstilbestrol and 4-t-octylphenol were found to be below the limit of detection. A comparison of EEQbio measured from the YES assay and EEQchem calculated from chemical analysis showed good correlation (R(2)=0.84). Based on the results, the YES assay can be used as a rapid pre screening method for monitoring the levels of estrogenic activity in large numbers of animal foodstuffs, and chemical analysis used in combination can be used for the identification of specific EEs. PMID- 25288560 TI - Dogs, physical activity, and walking (dogs PAW): acceptability and feasibility of a pilot physical activity intervention. AB - BACKGROUND: The aims of this study were to describe the development of and investigate the feasibility and acceptability of a pilot randomized controlled physical activity intervention based on social cognitive theory that used a dog walking strategy. METHOD: Participants (n = 49) were randomized into an intervention or control group. Overall, participants were middle-aged (M = 45.7 +/- 13.4 years), Caucasian, and on average considered obese with a mean body mass index of 30.0 +/- 5.5. Descriptive statistics were used to summarize participant characteristics and analyze the feasibility and acceptability data. Regression models were used to (a) examine significant differences between intervention and control groups across time (baseline to post-intervention) and (b) examine if changes in theoretical constructs from baseline to post-intervention resulted in changes in dog walking in both the intervention and control group. RESULTS: Participants agreed that the intervention e-mails were easy to read and understand (M = 4.3 +/- 0.7). Participants reported that the frequency of e-mails was adequate (M = 4.3 +/- 0.8), but there was lower agreement that the e-mails encouraged an increase in dog walking (M = 3.6 +/- 1.2). Post-intervention, the control group increased weekly dog walking to 19.4 +/- 4.9 minutes, whereas the intervention group increased it to 79.3 +/- 11.2 minutes. CONCLUSIONS: Preliminary results suggest that this pilot intervention is an acceptable and feasible strategy for promoting dog walking among dog owners. PMID- 25288562 TI - Uncorrected refractive error and education. PMID- 25288561 TI - RAD51AP1-deficiency in vertebrate cells impairs DNA replication. AB - RAD51-associated protein 1 (RAD51AP1) is critical for homologous recombination (HR) by interacting with and stimulating the activities of the RAD51 and DMC1 recombinases. In human somatic cells, knockdown of RAD51AP1 results in increased sensitivity to DNA damaging agents and to impaired HR, but the formation of DNA damage-induced RAD51 foci is unaffected. Here, we generated a genetic model system, based on chicken DT40 cells, to assess the phenotype of fully inactivated RAD51AP1 in vertebrate cells. Targeted inactivation of both RAD51AP1 alleles has no effect on either viability or doubling-time in undamaged cells, but leads to increased levels of cytotoxicity after exposure to cisplatin or to ionizing radiation. Interestingly, ectopic expression of GgRAD51AP1, but not of HsRAD51AP1 is able to fully complement in cell survival assays. Notably, in RAD51AP1 deficient DT40 cells the resolution of DNA damage-induced RAD51 foci is greatly slowed down, while their formation is not impaired. We also identify, for the first time, an important role for RAD51AP1 in counteracting both spontaneous and DNA damage-induced replication stress. In human and in chicken cells, RAD51AP1 is required to maintain wild type speed of replication fork progression, and both RAD51AP1-depleted human cells and RAD51AP1-deficient DT40 cells respond to replication stress by a slow-down of replication fork elongation rates. However, increased firing of replication origins occurs in RAD51AP1-/- DT40 cells, likely to ensure the timely duplication of the entire genome. Taken together, our results may explain why RAD51AP1 commonly is overexpressed in tumor cells and tissues, and we speculate that the disruption of RAD51AP1 function could be a promising approach in targeted tumor therapy. PMID- 25288563 TI - A Support Program for English as an Additional Language Nursing Students. AB - Canada is among the most diverse countries in the world. To provide meaningful health care, the Canadian health care system requires nursing health care teams reflecting this diversity. Meeting this demand should be a specific goal of Canadian nursing schools. Nursing students with English as an Additional Language (EALs) are graduating and passing national licencing exams at a lower rate than nursing students whose first language is English. It is the premise of the article that EALs require both academic and nonacademic forms of support during their years of nursing education. A literature review reveals that EALs facing academic crisis benefit from individual and group English language support, aimed at improving their understanding and use of English in an academic environment. Studies also suggest that group sessions help improve EALs' psychosocial functioning. This article provides an overview of the establishment and implementation of a proactive nursing support program, purposely designed to address the challenges faced by EALs. PMID- 25288564 TI - [Life satisfaction and related socio-demographic factors during female midlife]. AB - OBJECTIVE: To assess life satisfaction and related factors in middle-aged Spanish women. METHOD: This was a cross-sectional study including 235 women aged 40 to 65, living in Granada (Spain), healthy companions of patients visiting the obstetrics and gynecology clinics. They completed the Diener Satisfaction with Life Scale, the Menopause Rating Scale, the Perceived Stress Scale, the Insomnia Severity Index and a sociodemographic questionnaire containing personal and partner data. Internal consistency of each tool was also calculated. RESULTS: Almost two-thirds (61.3%) of the women were postmenopausal, and 43.8% had abdominal obesity, 36.6% had insomnia, 18.7% had poor menopause-related quality of life, 31.9% performed regular exercise, and 5.1% had severe financial problems. Life satisfaction showed significant positive correlations (Spearman's test) with female and male age, and inverse correlations with menopause-related quality of life, perceived stress and insomnia. In the multiple linear regression analysis, high life satisfaction is positively correlated with having a partner who performed exercise, and inversely with having work problems, perceived stress and the suspicion of partner infidelity. These factors explained 40% of the variance of the multiple regression analysis for life satisfaction in middle-aged women. CONCLUSION: Life satisfaction is a construct related to perceived stress, work problems, and having a partner, while aspects of menopause and general health had no significant influence. PMID- 25288565 TI - A systematic review with meta-analysis of survival, quality of life and cost effectiveness of home parenteral nutrition in patients with inoperable malignant bowel obstruction. AB - BACKGROUND AND AIMS: Inoperable bowel obstruction is the most common and judicious indication for long term parenteral nutrition in patients with palliative malignancy. Considerable uncertainty exists about the survival length, quality of life (QOL) and associated health economics of home parenteral nutrition (HPN) for this patient group. METHODS: A systematic review was carried out for survival length and QOL of adult patients treated with HPN due to malignancy causing inoperable bowel obstruction in the palliative phase. Whenever possible, individual patient data were extracted to allow meta-analyses. Health economic evaluation was undertaken to calculate cost and incremental cost effectiveness ratio (ICER). RESULTS: Twelve studies involving 437 patients, met the inclusion criteria. Meta-analyses of extracted survival length data, representing the largest published cohort of HPN patients with palliative malignancy and inoperable bowel obstruction (n = 244 patients), revealed a mean survival of 116 days, median 83 days, with 45% and 24% still alive at 3 and 6 months, and only 2% survival at one year. Limited evidence suggests QOL deteriorated before death in a highly symptomatic group. The ICER is L176,587 per quality adjusted life year. CONCLUSIONS: This is the first health economic evaluation and systematic review of survival and QOL for patients with inoperable bowel obstruction receiving HPN during the palliative phase of malignancy. Meta analyses reveal a short survival and health economic analysis demonstrates high associated costs. This information can be used by clinicians to inform and guide selection of patients in this cohort for HPN treatment. PMID- 25288566 TI - Mediterranean diet reduces thromboxane A2 production in atrial fibrillation patients. AB - BACKGROUND & AIMS: Platelet activation plays a major role in cardiovascular events (CVEs). Mediterranean diet (Med-Diet) reduces the incidence of stroke and myocardial infarction but it is still unclear if it affects platelet activation. Aim of the study was to evaluate the effect of Med-Diet on the urinary excretion of 11-dehydro-thromboxane (Tx) B2, a marker of in vivo platelet activation, in patients with atrial fibrillation (AF). METHODS: Prospective observational cohort study including 801 non-valvular AF patients on chronic treatment with warfarin/acenocumarol referring to I Medical Clinic - Atherothrombosis Center of Sapienza University of Rome, Italy, from February 2008 to December 2013. Adherence to Med-Diet was evaluated by a short nine-items dietary questionnaire. Urinary excretion of 11-dehydro-TxB2 was measured in all patients. RESULTS: Mean follow-up was 33.9 (+/-19.8) months, yielding 2223 patient/year of observation. Mean age of patients was 73.3 (+/-8.9) years, 43.7% were female. Median value of urinary TxB2 was 105.5 [60.0-190.0] ng/mg creatinine. We found a significant inverse correlation between total Med-Diet score and 11-dehydro-TxB2 values (Rs: 0.356, p < 0.001). In a multivariable stepwise linear regression analysis, history of stroke/TIA (beta = 0.146, p = 0.003), olive oil (beta = -0.130, p = 0.007), wine (beta = -0.102, p = 0.036) and antiplatelet drugs (beta = -0.098, p = 0.045) were independently associated to 11-dehydro-TxB2. We found no differences in the rate of ischemic or bleeding events across tertiles of Med Diet score during follow-up. CONCLUSIONS: Med-Diet adherence is inversely associated to urinary excretion of 11-dehydro-TxB2, suggesting that Med-Diet may favorably affect platelet function in AF patients. Clinical Trial Registration: ClinicalTrials.gov NCT01882114. PMID- 25288567 TI - Coordinated regulation of NK receptor expression in the maturing human immune system. AB - NK cells are responsible for recognizing and killing transformed, stressed, and infected cells. They recognize a set of non-Ag-specific features termed "altered self" through combinatorial signals from activating and inhibitory receptors. These NKRs are also expressed on CD4(+) and CD8(+) T cells, B cells, and monocytes, although a comprehensive inventory of NKR expression patterns across leukocyte lineages has never been performed. Using mass cytometry, we found that NKR expression patterns distinguish cell lineages in human peripheral blood. In individuals with high levels of CD57, indicative of a mature immune repertoire, NKRs are more likely to be expressed on non-NK cells, especially CD8(+) T cells. Mature NK and CD8(+) T cell populations show increased diversity of NKR surface expression patterns, but with distinct determinants: mature NK cells acquire primarily inhibitory receptors, whereas CD8(+) T cells attain a specific subset of both activating and inhibitory receptors, potentially imbuing them with a distinct functional role. Concurrently, monocytes show decreased expression of the generalized inhibitory receptor leukocyte Ig-like receptor subfamily b member 1, consistent with an increased activation threshold. Therefore, NKR expression is coordinately regulated as the immune system matures, resulting in the transfer of "altered self" recognition potential among leukocyte lineages. This likely reduces Ag specificity in the mature human immune system, and implies that vaccines and therapeutics that engage both its innate and adaptive branches may be more effective in the settings of aging and chronic infection. PMID- 25288568 TI - Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D/RAE-1 and release of IFN-gamma in experimental dry eye. AB - The Th1-associated chemokines CXCL9, CXCL10, and CXCL11 coordinate migration of CXCR3(+) Th1 cells. The objective of this study was to evaluate the role of the innate immune system in stimulating chemokine expression in an experimental model of dry eye and bridge the gap between innate and adaptive immunity. Desiccating stress (DS) induced very early (6 h) expression and production of Th1-associated chemokines in cornea and conjunctiva of C57BL/6 and RAG1 knockout (KO) mice, demonstrating that chemokine expression does not require innate T cells. We then demonstrated that activating the innate immune system prior to adoptive transfer of T cells to RAG1KO mice increased disease severity. Interestingly, lack of induction of chemokines CXCL9, CXCL10, and CXCL11 in IFN-gammaKO mice provided evidence that their expression requires IFN-gamma for induction. Treatment of RAG1KO mice with anti-NK1.1 prevented the increase of CXCL9, CXCL10, and CXCL11 in response to DS, compared with isotype controls. Additionally, DS increased the expression of NKG2D in the conjunctiva. The expression of the NKG2D ligand, retinoic acid early inducible gene 1, also increased at the ocular surface at both the protein and gene levels. Neutralization of NKG2D at the ocular surface decreased the expression of CXCL9, CXCL10, CXCL11, and IFN-gamma. In summary, upregulation of CXCL9, CXCL10, and CXCL11 expression in experimental dry eye is T cell-independent, requiring IFN-gamma-producing NKG2D(+) NK cells that are activated in response to DS-induced stress signals. This study provides insight into the events that trigger the initial immune response in dry eye pathology. PMID- 25288569 TI - Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. AB - Heterozygous gain-of-function (GOF) mutations of STAT1 are responsible for chronic mucocutaneous candidiasis disease (CMCD), one of the primary immunodeficiency diseases characterized by susceptibility to mucocutaneous Candida infection. To date, 30 aa changes have been reported: 21 in the coiled coil domain and 9 in the DNA-binding domain. In this study, we report two novel STAT1 GOF mutations of p.K278E in coiled-coil domain and p.G384D in DNA-binding domain in Japanese CMCD patients. Ectopic expression of these STAT1 mutants in HeLa cells was associated with increased phosphorylation of the mutant and the endogenous wild-type STAT1 due to impaired dephosphorylation, indicating heterodimers of the wild-type and mutant STAT1 cause impaired dephosphorylation, as did homodimers of the mutants. Because IL-17A production was not significantly reduced at least in one of the patients following PMA plus ionomycin stimulation, we further studied Th17-associated cytokines IL-17A, IL-17F, and IL-22 in response to more physiologically relevant stimulations. IL-17A and IL-22 production from PBMCs and CD4(+) cells was significantly reduced in four patients with STAT1 GOF mutations, including the previously reported R274Q in response to anti-CD3 plus anti-CD28 Abs or Candida stimulations. In contrast, IL-17F production was comparable to healthy controls in response to anti-CD3 plus anti CD28 Abs stimulation. These results indicate impaired production of IL-17A and IL 22 rather than IL-17F was associated with the development of CMCD in these patients. Additionally, only the anti-IL-17F autoantibody was detected in sera from 11 of 17 patients with STAT1 GOF mutations, which may be useful as a marker for this disease. PMID- 25288570 TI - Dendritic cell maturation and survival are differentially regulated by TNFR1 and TNFR2. AB - The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF is a well-known maturation and survival factor for DC, the role of the two TNFR, TNFR1 and TNFR2, in mediating these effects is poorly understood. By using unique TNF variants that selectively signal through TNFR1 and/or TNFR2, we demonstrate differential functions of TNFR in human monocyte-derived and blood CD1c(+) DC. Activation of TNFR1, but not TNFR2, efficiently induced DC maturation, as defined by enhanced expression of cell surface maturation markers (CD83, CD86, and HLA-DR) as well as enhanced T cell stimulatory capacity. In contrast, both TNFR1 and TNFR2 significantly protected DC against cell death, indicating that innate signals can promote DC survival in the absence of DC maturation. We further show differential activation of NF-kappaB signaling pathways by the TNFR: TNFR1 activated both the p65 and p52 pathways, whereas TNFR2 triggered p52, but not p65, activation. Accordingly, the p65 NF-kappaB pathway only played a role in the prosurvival effect of TNFR1. However, cell death protection through both TNFR was mediated through the Bcl-2/Bcl-xL pathway. Taken together, our data show that TNFR1, but not TNFR2, signaling induces DC maturation, whereas DC survival can be mediated independently through both TNFR. These data indicate differential but partly overlapping responses through TNFR1 and TNFR2 in both inflammatory and conventional DC, and they demonstrate that DC maturation and DC survival can be regulated through independent signaling pathways. PMID- 25288571 TI - Antigen-specific immunotherapeutic vaccine for experimental autoimmune myasthenia gravis. AB - Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused by Ab-mediated autoimmune responses to muscle nicotinic acetylcholine receptors (AChRs) that impair neuromuscular transmission, thereby causing muscle weakness. Previously, we discovered that i.p. injection of a therapeutic vaccine consisting of bacterially expressed cytoplasmic domains of human AChR subunits reduced the development of chronic EAMG in rats. In this article, we show that immunization with the therapeutic vaccine in adjuvants does not induce EAMG and, thus, is safe. The potency and efficacy of the therapeutic vaccine were greatly increased by s.c. administration of repeated low doses in IFA. Onset of chronic EAMG could be prevented. Established chronic EAMG could be rapidly reversed, modeling therapy of chronic MG. Therapy reduced pathological Abs assayed by immune precipitation of a main immunogenic region chimera. Successfully treated rats exhibited long-term resistance to reinduction of EAMG, suggesting a lasting cure of MG. A long-term effect of therapy was to change the isotype of the pathogenic Ab response from IgG2b, which fixes complement, to IgG1, which does not. Prevention and reversal of chronic EAMG was not caused by the isotype switch, but the isotype switch may contribute to resistance to reinduction of EAMG. Immunization with AChR cytoplasmic domains in adjuvant is promising as a safe, Ag-specific, potent, effective, rapidly acting, and long-lasting therapeutic approach to MG. PMID- 25288572 TI - The presence of high-grade prostatic intraepithelial neoplasia or atypia on prostate biopsy does not adversely affect prostatectomy outcomes for patients otherwise eligible for active surveillance. AB - OBJECTIVE: To investigate if the presence of concomitant high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) on biopsy increases the risk of occult adverse pathology in patients otherwise suitable for active surveillance (AS). METHODS: Patients with D'Amico low-risk prostate cancer on >= 10-core biopsy who underwent radical prostatectomy at our academic center were evaluated for eligibility for AS by either Epstein criteria or Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Prostatectomy specimens of patients eligible for AS were compared to determine if the presence of clinical HGPIN or ASAP affected the primary outcomes of pathologic upstaging and Gleason score upgrading. RESULTS: Of 553 patients with low-risk prostate cancer, 400 patients (72.3%) met the MSKCC criteria, whereas only 170 patients (30.7%) met the Epstein criteria. HGPIN was present in approximately 32%, and ASAP in approximately 12%, of each AS cohort. On univariate and multivariate analyses, HGPIN and ASAP had no impact on the rate of upgrading and upstaging in either Epstein or MSKCC AS-eligible patients. Furthermore, the presence of HGPIN and ASAP had no impact on the 5-year biochemical recurrence-free survival. CONCLUSION: The presence of HGPIN or ASAP does not increase the risk of upgrading, upstaging, or adverse pathology at the time of prostatectomy for patients who meet the AS criteria. If otherwise suitable, HGPIN and ASAP should not impact the decision to choose AS. However, analysis of prospective AS trials is required to determine if HGPIN or ASAP impacts tumor progression once on AS. PMID- 25288573 TI - Comparison of perioperative outcomes of retroperitoneal and transperitoneal minimally invasive partial nephrectomy after adjusting for tumor complexity. AB - OBJECTIVE: To evaluate and compare perioperative outcomes of transperitoneal and retroperitoneal (RP) laparoscopic and robotic partial nephrectomies (LPNs) while adjusting for tumor complexity. MATERIALS AND METHODS: Retrospective review was conducted of 191 patients who underwent transperitoneal (n = 116) or RP (n = 75) LPN. To adjust for tumor complexity, individual components of the radius, exophytic or endophytic properties, nearness to the collecting system or sinus, anterior or posterior location, and location in reference to polar lines (R.E.N.A.L.) nephrometry score were used in multivariate linear and logistic regression models to compare perioperative outcomes between the 2 groups. A propensity approach was also used to adjust for multiple covariates. Investigated outcomes included estimated blood loss (EBL), ischemia and operative times, length of hospital stay, margin status, opioid use, postoperative estimated glomerular filtration rate, complications within 30 days, and readmission rates. RESULTS: Tumors resected by RPLPN were more likely to have lower complexity score by nephrometry (P = .04). Four of the 5 components of the R.E.N.A.L. nephrometry score were significantly different between the groups. After adjustment for these factors, a lower EBL was noted in the RP group (beta, -97; 95% confidence interval, -156 to -39; P = .001). Risk of readmission for the RP group was significantly lower (odds ratio, 0.15; P = .024) using propensity analysis. CONCLUSION: Using adjustment for tumor complexity, RPLPN was associated with lower EBL and readmission rates supporting the potential clinical advantage for this approach when feasible. PMID- 25288574 TI - Flexible ureterorenoscopy for the treatment of kidney stone within pelvic ectopic kidney. AB - OBJECTIVE: To present the outcomes of flexible ureterorenoscopy (F-URS) and laser lithotripsy for the treatment of calculi within pelvic ectopic kidney (PEK). PATIENTS AND METHODS: We retrospectively reviewed the medical records of 26 patients with calculi in PEK treated with F-URS in 5 referral hospitals between 2010 and 2013. Patient demographics and stone characteristics (age, sex, body mass index, stone size, location, history of shock wave lithotripsy or kidney surgery), and perioperative measures (duration of operation, fluoroscopic imaging, and hospitalization and success and complication rates) were reviewed. RESULTS: A total of 26 patients with mean age of 41.1 +/- 15.8 years (7-72 years) were included in the study. The mean stone size was 17.0 +/- 5.1 mm (10-28 mm). The mean procedure and fluoroscopy times were calculated as 52.1 +/- 27.7 minutes (30-120 minutes) and 54.8 +/- 48.9 seconds (10-180 seconds), respectively. The mean length of hospital stay was 2.7 +/- 1.8 days (1-9 days). Treatment was deemed successful in 22 patients (84.6%). Ureteroscopy failed in 4 patients (15.4%) due to impaired passage of fragments (n = 3) or inability to reach the stone secondary to the location in an isolated lower calyx (n = 1). Minor postoperative complications were observed in 5 patients (19.2%; persistent hematuria [n = 1], fever [n = 1], renal colic [n = 2], and urinary tract infection [n = 1]). No severe complications or mortality occurred. CONCLUSION: Our results suggest that F-URS is a safe and effective minimally invasive treatment modality for small- and medium-sized stones in PEK. PMID- 25288576 TI - Editorial comment. PMID- 25288575 TI - Clinical predictors and recommendations for staging computed tomography scan among men with prostate cancer. AB - OBJECTIVE: To identify clinical variables associated with a positive computed tomography (CT) scan and estimate the performance of imaging recommendations in patients from a diverse sample of urology practices. MATERIALS AND METHODS: This study comprised 2380 men with newly diagnosed prostate cancer seen at 28 practices in the Michigan Urological Surgery Improvement Collaborative from March 2012 through September 2013. Data included age, prostate-specific antigen (PSA) level, Gleason score (GS), clinical T stage, total number of positive biopsy cores, whether or not the patient received a staging abdominal and/or pelvic CT scan, and CT scan result. We fit a multivariate logistic regression model to identify clinical variables associated with metastases detected by CT scan. We estimated the sensitivity and specificity of existing imaging recommendations. RESULTS: Among 643 men (27.4%) who underwent a staging CT scan, 62 men (9.6%) had a positive study. In the multivariate analysis, PSA, GS, and clinical T stage were independently associated with the occurrence of a positive CT scan (all P values <.05). The American Urological Association's Best Practice Statements' recommendations for imaging when PSA level >20 ng/mL or GS >= 8 or locally advanced cancer had a sensitivity of 87.3% and specificity of 82.6%. Compared with current practice, implementing this recommendation in the Michigan Urological Surgery Improvement Collaborative population was estimated to result in approximately 0.5% of positive study results being missed, and 26.1% of fewer study results overall. CONCLUSION: Successful implementation of CT imaging criterion of PSA level >20, GS >= 8, or clinical stage >= T3 would ensure that CT scans are performed for almost all men who would have positive study results while reducing the number of negative study results. PMID- 25288577 TI - Hypogonadal symptoms are associated with different serum testosterone thresholds in middle-aged and elderly men. AB - OBJECTIVE: To determine the association between hypogonadal symptoms and total serum testosterone levels in middle-aged and elderly men (aged > 40 years), and to identify whether there exists a clear-cut discriminatory threshold of total testosterone below which the probability of hypogonadal symptoms increases. METHODS: We retrospectively reviewed the charts of 360 men who presented to an outpatient men's health clinic with a chief complaint of low testosterone. Sexual, psychological, and physical symptoms were evaluated using the androgen deficiency in the aging male (ADAM) questionnaire. Serum levels of total testosterone were collected on the same day on which men completed their ADAM questionnaires. We performed the univariate (t test, chi-square, and binary logistic regression) and multivariate analyses (binary logistic regression) to evaluate the total testosterone threshold and the symptoms that predicted a low testosterone level. RESULTS: A cluster of symptoms: 1 sexual (decreased libido), 1 psychological (decreased energy), and 3 physical (decreased strength or endurance, decreased ability to play sports, and falling asleep after dinner) were most associated with total serum testosterone levels of <= 300 ng/dL. The threshold testosterone serum levels that were associated with an increased prevalence of these hypogonadal symptoms ranged from 320 to 375 ng/dL. On multivariate analysis, age, but not symptoms on the ADAM questionnaire, predicted a total testosterone level of < 300 ng/dL. CONCLUSION: A distinct constellation of hypogonadal symptoms exists at various serum testosterone levels. Consequently, identification of the thresholds for specific symptom management will be critical in establishing patient-centered treatment algorithms. PMID- 25288578 TI - Serum osmolarity and haematocrit do not modify the association between the impedance index (Ht(2)/Z) and total body water in the very old: the Newcastle 85+ study. AB - PURPOSE OF THE RESEARCH: Bioelectrical impedance is a non-invasive technique for the assessment of body composition; however, information on its accuracy in the very old (80+years) is limited. We investigated whether the association between the impedance index and total body water (TBW) was modified by hydration status as assessed by haematocrit and serum osmolarity. MATERIALS AND METHODS: This was a cross-sectional analysis of baseline data from the Newcastle 85+Cohort Study. Anthropometric measurements [weight, height (Ht)] were taken and body mass index (BMI) calculated. Leg-to-leg bioimpedance was used to measure the impedance value (Z) and to estimate fat mass, fat free mass and TBW. The impedance index (Ht2/Z) was calculated. Blood haematocrit, haemoglobin, glucose, sodium, potassium, urea and creatinine concentrations were measured. Serum osmolarity was calculated using a validated prediction equation. PRINCIPAL RESULTS: 677 men and women aged 85 years were included. The average BMI of the population was 24.3+/-4.2kg/m2 and the prevalence of overweight and obesity was 32.6% and 9.5%, respectively. The impedance index was significantly associated with TBW in both men (n=274, r=0.76, p<0.001) and women (n=403, r=0.96, p<0.001); in regression models, the impedance index remained associated with TBW after adjustment for height, weight and gender, and further adjustment for serum osmolarity and haematocrit. The impedance index values increased with BMI and the relationship was not modified by hydration status in women (p=0.69) and only marginally in men (p=0.02). MAJOR CONCLUSIONS: The association between the impedance index and TBW was not modified by hydration status, which may support the utilisation of leg-to-leg bioimpedance for the assessment of body composition in the very old. PMID- 25288579 TI - Do diabetic foot infections with methicillin-resistant Staphylococcus aureus differ from those with other pathogens? AB - There is controversy as to whether or not diabetic foot infections (DFIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) are associated with worse outcomes than DFIs caused by other pathogens. To address this issue we performed a nonsystematic literature search of published articles in English language journals seeking studies reporting on the outcomes of DFIs related to their microbiology. We retrieved 48 articles published from 1999 to 2013 that described a total of 7771 cases of DFI. The overall proportion of DFIs with an isolate of S aureus was about 30%; just over one third of these (11% of all cases) were MRSA strains. Among the DFI cases caused by MRSA 1543 were episodes of soft tissue infections and 113 of osteomyelitis, while non-MRSA organisms caused 5761 soft tissue infections and 354 cases of osteomyelitis. Only 5 of the included articles attempted a comparison between DFI caused by MRSA and those caused by other pathogens, with no clear differences noted. The median total duration of antibiotic therapy for DFI caused by MRSA was 26 days, of which a median of 10 days was given intravenously. Only a few articles reported the proportion of patients with a recurrence, but they often did not differentiate between MRSA and non-MRSA cases. Four publications reported a worse functional or microbiological outcome in MRSA, compared to non-MRSA, cases, but the findings were variable and differences did not seem to be significant. Many trials failed to adjust for case mix or to definitively demonstrate a relationship between microbiology and outcomes. Few of the articles specifically commented on whether the MRSA isolates were health care- or community-acquired strains. Notwithstanding the substantial limitations of the available literature, there does not appear to be a need for any special treatment for DFI caused by MRSA. The current guidelines for treating according to established international recommendations seem appropriate. PMID- 25288580 TI - Diagnosis and management of subclinical hypothyroidism in pregnancy. AB - In prospective studies, the prevalence of undiagnosed subclinical hypothyroidism in pregnant women ranges from 3% to 15%. Subclinical hypothyroidism is associated with multiple adverse outcomes in the mother and fetus, including spontaneous abortion, pre-eclampsia, gestational hypertension, gestational diabetes, preterm delivery, and decreased IQ in the offspring. Only two prospective studies have evaluated the impact of levothyroxine therapy in pregnant women with subclinical hypothyroidism, and the results were mixed. Subclinical hypothyroidism is defined as raised thyrotropin combined with a normal serum free thyroxine level. The normal range of thyrotropin varies according to geographic region and ethnic background. In the absence of local normative data, the recommended upper limit of thyrotropin in the first trimester of pregnancy is 2.5 mIU/L, and 3.0 mIU/L in the second and third trimester. The thyroid gland needs to produce 50% more thyroid hormone during pregnancy to maintain a euthyroid state. Consequently, most women on levothyroxine therapy before pregnancy require an increase in dose when pregnant to maintain euthyroidism. Ongoing prospective trials that are evaluating the impact of levothyroxine therapy on adverse outcomes in the mother and fetus in women with subclinical hypothyroidism will provide crucial data on the role of thyroid hormone replacement in pregnancy. PMID- 25288582 TI - Reduced Dual-Task Performance in MS Patients Is Further Decreased by Muscle Fatigue. AB - BACKGROUND: Multiple sclerosis (MS) can be accompanied by motor, cognitive, and sensory impairments. Additionally, MS patients often report fatigue as one of their most debilitating symptoms. It is, therefore, expected that MS patients will have difficulties in performing cognitive-motor dual tasks (DTs), especially in a fatiguing condition. OBJECTIVE: To determine whether MS patients are more challenged by a DT than controls in a fatiguing and less-fatiguing condition and whether DT performance is associated with perceived fatigue. METHODS: A group of 19 MS patients and 19 age-, sex-, and education-matched controls performed a cognitive task (2-choice reaction time task) separately or concurrent with a low force or a high-force motor task (index finger abduction at 10% or 30% maximal voluntary contraction). RESULTS: MS patients performed less well on a cognitive task than controls. Cognitive task performance under DT conditions decreased more for MS patients. Moreover, under high-force DT conditions, cognitive performance declined in both groups but to a larger degree for MS patients. Besides a decline in cognitive task performance, MS patients also showed a stronger decrease in motor performance under high-force DT conditions. DT costs were positively related to perceived fatigue as measured by questionnaires. CONCLUSIONS: Compared with controls, MS patients performed less well on DTs as demonstrated by a reduction in both cognitive and motor performances. This performance decrease was stronger under fatiguing conditions and was related to the sense of fatigue of MS patients. These data illustrate problems that MS patients may encounter in daily life because of their fatigue. PMID- 25288583 TI - Novartis must face kickback lawsuit over "sham" speaker events. PMID- 25288581 TI - Walking speed and step length asymmetry modify the energy cost of walking after stroke. AB - BACKGROUND: A higher energy cost of walking poststroke has been linked to reduced walking performance and reduced participation in the community. OBJECTIVE: To determine the contribution of postintervention improvements in walking speed and spatiotemporal gait asymmetry to the reduction in the energy cost of walking after stroke. METHODS: In all, 42 individuals with chronic hemiparesis (>6 months poststroke) were recruited to participate in 12 weeks of walking rehabilitation. The energy cost of walking, walking speed, and step length, swing time, and stance time asymmetries were calculated pretraining and posttraining. Sequential regression analyses tested the cross-sectional (ie, pretraining) and longitudinal (ie, posttraining changes) relationships between the energy cost of walking versus speed and each measure of asymmetry. RESULTS: Pretraining walking speed (beta = -.506) and swing time asymmetry (beta = .403) predicted pretraining energy costs: (adj)R(2) = 0.713; F(3, 37) = 34.05; P < .001. In contrast, change in walking speed (beta = .340) and change in step length asymmetry (beta = .934) predicted change in energy costs with a significant interaction between these independent predictors: (adj)R(2) = 0.699; F(4, 31) = 21.326; P < .001. Moderation by the direction or the magnitude of pretraining asymmetry was not found. CONCLUSIONS: For persons in the chronic phase of stroke recovery, faster and more symmetric walking after intervention appears to be more energetically advantageous than merely walking faster or more symmetrically. This finding has important functional implications, given the relationship between the energy cost of walking and community walking participation. PMID- 25288584 TI - [First case of complete genomic sequencing in prostate cancer]. PMID- 25288585 TI - [Obstructive pyelonephritis caused by ureteral orifice catheterization with a bladder catheter]. AB - This article reports a rare case of acute pyelonephritis secondary to left ureteral obstruction by a bladder catheter. The patient was 93years old man hospitalized in the hospital emergency department with a 39 degrees C fever and pyuria from an indwelling catheter. Blood test found hyperleukocytosis, inflammatory syndrome and acute renal failure. Diagnosis was confirmed by non contrast abdominal CT scan showing distal part of the catheter inside left ureteral orifice with ureterohydronephrosis. Treatment consisted in replacing the catheter by a three-way catheter for irrigation and parenteral antibiotics therapy. Clinico-biological evolution was successful and a urinary tract CT scan could be realized at day 9. The left upper urinary tract function was recovered. With a short review of the literature we propose to describe the different procedures to manage those obstructions. PMID- 25288586 TI - The impact of a multiple intelligences teaching approach drug education programme on drug refusal skills of Nigerian pupils. AB - The rising incidence of drug abuse among youths in Nigeria is a source of concern for health educators. This study was carried out on primary six pupils to determine the effect of a Multiple Intelligences Teaching Approach Drug Education Programme (MITA-DEP) on pupils' acquisition of drug refusal skills. A programme of drug education based on the Multiple Intelligences Teaching Approach (MITA) was developed. An experimental group was taught using this programme while a control group was taught using the same programme but developed based on the Traditional Teaching Approach. Pupils taught with the MITA acquired more drug refusal skills than those taught with the Traditional Teaching Approach. Urban pupils taught with the MITA acquired more skills than rural pupils. There was no statistically significant difference in the mean refusal skills of male and female pupils taught with the MITA. PMID- 25288587 TI - A longitudinal examination of social participation, loneliness, and use of physician and hospital services. AB - OBJECTIVE: This study examined whether social participation and loneliness predicted health care service use (physician visits, hospitalizations, length of stay in hospital). METHOD: Participants' (N = 954; 54% female; aged 45+ years) health data were tracked over 2.5 years following in-person interviews. RESULTS: Being lonely was associated with greater number of physician visits, though this relationship was mediated by health. Neither loneliness nor social participation was associated with admission to hospital. However, for those who were hospitalized at least once over 2.5 years, being lonely was associated with a higher odds of being re-hospitalized; furthermore, greater social participation was associated with a lower odds of being in the hospital for an extended duration. These relationships held even when controlling for initial health. DISCUSSION: Results provide evidence, using objective health care data, of the potential importance of social factors in predicting adults' physician visits, re hospitalization, and length of stay in hospital. PMID- 25288589 TI - Identifying the Barriers and Enablers to Nutrition Care in Head and Neck and Esophageal Cancers: An International Qualitative Study. AB - BACKGROUND: The goal of this work was to identify barriers and enablers to the implementation of nutrition care in head and neck and esophageal (HNE) cancers and to prioritize barriers to help improve the nutrition care process. MATERIALS AND METHODS: This study used a multimethod qualitative study design (including semistructured interviews, focus group). Interviews (n = 29) were conducted at 5 European sites providing care and treatment to patients with HNE cancers. A focus group (n = 21) reviewed and corroborated interview findings and identified priorities for nutrition care. Participants were healthcare providers and researchers with direct experience in the field of HNE cancer. RESULTS: Five themes with accompanying barriers and enablers were identified related to nutrition care: (1) evidence for the benefit of nutrition interventions, (2) implementation of nutrition care processes (assessment, intervention, and follow up), (3) characteristics of healthcare providers, (4) site factors, and (5) patient characteristics. Focus group discussions identified 2 priorities that must be acted on to improve nutrition care: (1) improve the evidence base and (2) develop standardized nutrition care pathways. CONCLUSION: Themes related to nutrition care in HNE cancers were similar between sites, but barriers and enablers differed. Interview and focus group participants agreed the following actions will result in improvements in nutrition care: (1) enhance the evidence base to test the benefit of nutrition interventions, with a focus on resolving specific controversies regarding nutrition therapy, and (2) establish a minimum data set with a goal to create standardized nutrition care pathways where roles and responsibilities for care are clearly defined. PMID- 25288588 TI - Chronic obstructive pulmonary disease, hospital visits, and comorbidities: National Survey of Residential Care Facilities, 2010. AB - OBJECTIVE: To characterize the prevalence of chronic obstructive pulmonary disease (COPD) among residential care facility (RCF) residents in the United States, and to compare patterns of hospital visits and comorbidities with residents without COPD. METHOD: Resident data from the 2010 National Survey of Residential Care Facilities were analyzed. Medical history and information on past-year hospital visits for 8,089 adult residents were obtained from interviews with RCF staff. RESULTS: COPD prevalence was 12.4%. Compared with residents without COPD, emergency department visits or overnight hospital stays in the previous year were more prevalent (p < .05) among residents with COPD. Less than 3% of residents with COPD had no comorbidities. Arthritis, depression, congestive heart failure (CHF), diabetes, coronary heart disease, and asthma were more common (p < .05) among residents with COPD than those without COPD, but Alzheimer's disease was less common. DISCUSSION: COPD is associated with more emergency department visits, hospital stays, and comorbidities among RCF residents. PMID- 25288590 TI - Modified Tessari Tourbillon technique for making foam sclerotherapy with silicone free syringes. AB - The longevity of foam made using sodium tetradecyl sulphate and gas (air or a CO2:O2 mixture) is increased significantly if silicone-free syringes are used over the normal syringes containing silicone oil lubrication. However, the plungers in silicone-free syringes start sticking after several passages when making foam for sclerotherapy, preventing the smooth injection of the resulting foam. We describe a three syringe technique which allows foam to be made using the Tessari Tourbillon 'three-way stopcock' principle between two syringes, but with the foam ending up in a third syringe which has not undergone multiple passages of the plunger. This allows a smoother injection of the resultant foam, which is particularly useful when injecting small diameter veins under ultrasound control. PMID- 25288591 TI - Interaction of electrons with light metal hydrides in the transmission electron microscope. AB - Transmission electron microscope (TEM) observation of light metal hydrides is complicated by the instability of these materials under electron irradiation. In this study, the electron kinetic energy dependences of the interactions of incident electrons with lithium, sodium and magnesium hydrides, as well as the constituting element effect on the interactions, were theoretically discussed, and electron irradiation damage to these hydrides was examined using in situ TEM. The results indicate that high incident electron kinetic energy helps alleviate the irradiation damage resulting from inelastic or elastic scattering of the incident electrons in the TEM. Therefore, observations and characterizations of these materials would benefit from increased, instead decreased, TEM operating voltage. PMID- 25288592 TI - Early onset of prosthesis failure after aortic valve replacement. AB - We report an unusual case of a 78-year-old male who underwent an aortic valve replacement with a 21 mm Labcor tissue porcine aortic valve due to symptomatic aortic stenosis of his native valve. Only 3 months after an uncomplicated postoperative course, on a routine follow-up, transthoracic echo showed restrictive motion of the non-coronary cusp, incomplete closure of the coaptation line and severe aortic regurgitation. The patient was scheduled for a new operation during which the previous prosthetic valve was explanted and a different model was used. PMID- 25288593 TI - Sexual harassment victimization and perpetration among high school students. AB - This large, population-based study is one of the few to examine prevalence rates of sexual harassment occurring during the past 12 months by victimization and perpetration among adolescents. In this large, cross-sectional survey of students attending 26 high schools, sexual harassment was defined using three questions from the Sexual Experiences Questionnaire. Among 18,090 students completing the survey, 30% disclosed sexual harassment victimization (37% of females, 21% of males) and 8.5% reported perpetration (5% of females, 12% of males). Sexual harassment perpetration was highly correlated with male sex, minority race/ethnicity, same-sex attraction, bullying, alcohol binge drinking, and intraparental partner violence. PMID- 25288594 TI - The association of mental health conditions with employment, interpersonal, and subjective functioning after intimate partner violence. AB - This study explored the associations of posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and depressive symptoms with employment, social support, and subjective functioning in 100 women who were seeking mental health assistance after intimate partner violence. Depressive disorders showed significant associations with low levels of social support, diminished self esteem, reduced quality of life, and elevated negative social problem-solving orientation. PTSD severity was significantly associated with low self-esteem and elevated negative problem orientation, while severity of GAD was only associated with negative problem orientation. Results are discussed in light of current service models for women who have experienced intimate partner violence. PMID- 25288596 TI - The role of sexual violence in creating and maintaining economic insecurity among asset-poor women of color. AB - This article argues that economic instability and sexual violence reinforce each other in two ways. First, the devastating psychological consequences of sexual assault can diminish work performance and disrupt income, creating economic instability, particularly for the asset-poor. Latina and African American women face particular risk due to barriers to appropriate post-assault resources and low rates of asset ownership. Second, income- and asset poverty increase women's risk for sexual violence and complicate recovery. Women with financial and social resources can leverage these assets to both avoid and recover from sexual assault, whereas women without such resources lack these options. Policy solutions are proposed. PMID- 25288595 TI - Relationship type and sexual precedence: their associations with characteristics of sexual assault perpetrators and incidents. AB - Although most sexual assaults are committed by men who know their victims, few researchers have considered how characteristics of perpetrators and incidents differ depending on the victim-perpetrator relationship. This study addresses this gap with a community sample of 204 men who reported committing a sexually aggressive act in an audio computer-assisted self-interview. 2 (Relationship Type: Committed vs. Casual) * 2 (Sexual Precedence: Yes vs. No) ANOVAs revealed significant main effects of relationship type and sexual precedence associated with individual difference and incident characteristics. These findings demonstrate the importance of developing theories and prevention programs tailored for different relationship contexts. PMID- 25288598 TI - Introduction to the special issue. PMID- 25288597 TI - Non-partner violence against women who use drugs in San Francisco. AB - This article examines non-partner violence among women who use methamphetamine (N = 322), recruited in an inner-city neighborhood of San Francisco. The combined prevalence of non-partner physical or sexual violence in the past 6 months was 28%, roughly equal to the prevalence of partner violence (26%). In multivariate analysis, factors associated with non-partner violence included frequent subsistence difficulty (adjusted odds ratio [AOR] = 2.43, 95% confidence interval [CI] = [1.3, 4.6]) and sex trade (AOR = 2.27, 95% CI = [1.4, 4.1]). Having a steady male partner was not protective against non-partner violence. Violence perpetrated by non-partners should be considered when assessing social and structural factors that influence women's health. PMID- 25288599 TI - Stalking and psychosocial distress following the termination of an abusive dating relationship: a prospective analysis. AB - The purpose of the current study was to utilize a prospective methodology to better understand the extent to which women report stalking behaviors perpetrated by their abusive ex-partners and how these stalking experiences affect women's psychological adjustment. Participants included 56 college women who completed measures of partner abuse and psychological adjustment prior to and after terminating an abusive dating relationship. A little over half of the women (51.8%) reported some type of stalking victimization following the termination of the abusive relationship. After controlling for baseline levels of psychological distress and partner abuse variables, experiences of post-relationship stalking victimization predicted greater levels of posttraumatic stress symptomatology and interpersonal sensitivity, whereas post-relationship stalking victimization was unrelated to depression and personal empowerment. PMID- 25288600 TI - A pilot randomized control trial: testing a transitional care model for acute psychiatric conditions. AB - OBJECTIVE: People with multiple and persistent mental and physical health problems have high rates of transition failures when transferring from a hospital level of care to home. The transitional care model (TCM) is evidence-based and demonstrated to improve posthospital outcomes for elderly with physical health conditions, but it has not been studied in the population with serious mental illness. METHOD: Using a randomized controlled design, 40 inpatients from two general hospital psychiatric units were recruited and randomly assigned to an intervention group (n = 20) that received the TCM intervention that was delivered by a psychiatric nurse practitioner for 90 days posthospitalization, or a control group (n = 20) that received usual care. Outcomes were as follows: service utilization, health-related quality of life, and continuity of care. RESULTS: The intervention group showed higher medical and psychiatric rehospitalization than the control group (p = .054). Emergency room use was lower for intervention group but not statistically significant. Continuity of care with primary care appointments were significantly higher for the intervention group (p = .023). The intervention group's general health improved but was not statistically significant compared with controls. CONCLUSIONS: A transitional care intervention is recommended; however, the model needs to be modified from a single nurse to a multidisciplinary team with expertise from a psychiatric nurse practitioner, a social worker, and a peer support specialist. A team approach can best manage the complex physical/mental health conditions and complicated social needs of the population with serious mental illness. PMID- 25288602 TI - Psychiatric nursing researchers: canaries in the gold mine? PMID- 25288601 TI - A qualitative understanding of patient falls in inpatient mental health units. AB - BACKGROUND: Falls are the leading cause of injury-related deaths among people age 65 and older, and fractures are the major category of serious injuries produced by falls. OBJECTIVE: Determine market segment-specific recommendations for "selling" falls prevention in acute inpatient psychiatry. DESIGN: Descriptive using focus groups. SETTING: One inpatient unit at a Veterans' hospital in the Southeastern United States and one national conference of psychiatric and mental health nurses. PATIENTS: A convenience sample of 22 registered nurses and advanced practice nurses, one physical therapist and two physicians participated in one of six focus groups. INTERVENTION: None. MEASUREMENTS: Focus groups were conducted by expert facilitators using a semistructured interview guide. Focus groups were recorded and transcribed. Content analysis was used to organize findings. RESULTS: Findings were grouped into fall risk assessment, clinical fall risk precautions, programmatic fall prevention, and "selling" fall prevention in psychiatry. Participants focused on falls prevention instead of fall injury prevention, were committed to reducing risk, and were receptive to learning how to improve safety. Participants recognized unique features of their patients and care settings that defined risk, and were highly motivated to work with other disciplines to keep patients safe. CONCLUSIONS: Selling fall injury prevention to staff in psychiatric settings is similar to selling fall injury prevention to staff in other health care settings. Appealing to the larger construct of patient safety will motivate staff in psychiatric settings to implement best practices and customize these to account for unique population needs characteristics. PMID- 25288603 TI - Harnessing mobile health technology to digitally engage mental health consumers in recovery. PMID- 25288604 TI - The dominant humoral epitope in phospholipase A2 receptor-1: presentation matters when serving up a slice of pi. PMID- 25288605 TI - Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. AB - Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides from the ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of this major epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies. PMID- 25288606 TI - A pilot study on the protein composition of induced nonpuerperal human milk. AB - BACKGROUND: Our understanding of the components of human puerperal milk is extensive and increasing, yet the literature on nonpuerperal human milk has been limited to studies that measure the success of induced lactation. OBJECTIVE: This study aimed to describe the composition of total protein and key bioactive proteins when lactation is induced in nonpuerperal women. METHODS: Two women who induced lactation in the absence of pregnancy provided weekly milk samples over a 2-month period for analysis of total protein, secretory immunoglobulin A (sIgA), lysozyme, and lactoferrin. Composition was compared to the mature milk of 3 puerperal control subjects who were 11 months postpartum. RESULTS: Median total protein for subject A was 2.30 g/dL (interquartile range [IQR] = 0.46) and showed a significant downward trend over time (P < .0001), whereas the median total protein for subject B was 2.21 g/dL (IQR = 0.18) and showed a nonsignificant decline (P = .232). Total protein in both nonpuerperal subjects was elevated compared to control subjects. Secretory IgA activity declined for both nonpuerperal subjects over time, whereas lysozyme concentrations increased over time. Both sIgA and lysozyme approached the levels seen in the puerperal controls. Lactoferrin levels remained stable for both nonpuerperal subjects and were elevated compared to puerperal milk samples. CONCLUSION: This pilot study suggests that nonpuerperal milk has similar or higher levels of total protein, sIgA, lactoferrin, and lysozyme compared to puerperal, mature milk at 11 months postpartum, which warrants more attention as adoptive mothers increasingly choose to induce lactation. PMID- 25288607 TI - Eradicating reliance on free artificial milk. AB - Hospitals that set forth to obtain Baby-Friendly Hospital designation often face considerable challenges in implementing the purchase of formula and supplies at a fair market rate as outlined in the International Code of Marketing of Breast milk Substitutes. Some of the challenges include difficulty tracking products in use and volumes used and obtaining pricing information from manufacturers of artificial milk. We report on our experience with assessing these factors, with an example of calculations used to arrive at fair market pricing, which might benefit other institutions seeking Baby-Friendly Hospital designation. PMID- 25288609 TI - TRPV1, CGRP and SP in scalp arteries of patients suffering from chronic migraine. Some like it hot! Chronic migraine increases TRPV1 receptors in the scalp. PMID- 25288608 TI - TRPV1, CGRP and SP in scalp arteries of patients suffering from chronic migraine. AB - OBJECTIVE: The transient receptor potential vanilloid type-1 receptor (TRPV1) and the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) appear to be differently involved in migraine pain. A role of neurovascular scalp structures is also suggested by several data. We performed a quantitative study of TRPV1-like immunoreactive (LI), CGRP-LI and SP-LI innervation of scalp arterial samples from patients affected with chronic migraine (CM). METHODS: Short segments of scalp arteries were collected from 17 participants undergoing vascular surgery for treatment-resistant CM and from 6 controls who underwent neurosurgery for various indications. The immunoreactivity of the arterial innervation to TRPV1, CGRP, SP and to the pan-neuronal marker protein gene product 9.5 (PGP9.5) was examined. Immunoreactive nerve fibres in vessel cross sections were quantified by computerised image analysis. RESULTS: A significant increase of TRPV1-LI nerve fibres was found in the arterial wall from CM compared with control patients (p<0.05), while no significant difference was found for CGRP and SP. CONCLUSIONS: This study yields the first evidence for the existence of a TRPV1-LI innervation in human scalp arteries and provides the first quantitative assessment of the TRPV1-LI, CGRP-LI and SP-LI innervation of those vessels. The increase of TRPV1-LI periarterial nociceptive fibres of scalp arteries may represent, at least in some participants, a structural condition favouring CM (and possibly migraine), for example, by causing a higher sensitivity to algogenic agents. PMID- 25288610 TI - Maternal Experiences of Their Unborn Child's Spiritual Care: Patterns of Abstinence in Iran. AB - Preparing for pregnancy and childbirth has significant association with spirituality. Review of the literature shows that the spirituality of the "unborn child" has not yet attracted much critical attention. This study was conducted with the aim of exploration of maternal behaviors associated with the spiritual health of the unborn child. A qualitative approach was used to investigate the research question. Twenty-seven in-depth unstructured interviews were conducted with 22 Iranian mothers in Tehran city (Iran) who were pregnant or had experienced pregnancy in 2012-2013. Data analysis was carried out using a conventional content analysis approach. "Refusing to eat forbidden food," "Overcoming mental adversity," "Regulating one's social interactions," "Preventing the effects of harmful environments on the senses," "Avoidance of using insulting and abusive language," "Keeping one's mind and spirit free from evil traits," and "Refraining from damaging behaviors" were important experiences that the mothers used for "Holistic Abstinence." The results provide new information about the subjective experiences of Iranian women on the patterns of abstinence for the midwives, research community, policy makers, and planners of maternal and child health care services in order to contribute to holistic, culturally, and religiously competent prenatal care for Muslim pregnant women throughout the world. PMID- 25288614 TI - Importance of coronary artery disease in sudden cardiac death. PMID- 25288613 TI - Ischemic heart disease diagnosed before sudden cardiac arrest is independently associated with improved survival. AB - BACKGROUND: Sudden cardiac arrest (SCA) is a significant public health problem, and rates of survival after resuscitation remain well below 10%. While several resuscitation-related factors are consistently associated with survival from SCA, the impact of specific comorbid conditions has not been assessed. METHODS AND RESULTS: The Oregon Sudden Unexpected Study is an ongoing, multisource, community based study in Portland, Oregon. Patients with SCA who underwent attempted resuscitation between 2002 and 2012 were included in this analysis if there were both arrest and prearrest medical records available. Information from the emergency medical services system, medical examiner, public health division, hospitals, and clinics was used to adjudicate SCA, evaluate comorbidities, and identify medical treatments. Univariate and multivariate analyses were performed to investigate the influence of prearrest comorbidities on survival to hospital discharge. Among 1466 included patients, established resuscitation-related predictors (Utstein factors) were associated with survival, consistent with prior reports. When a panel of prearrest comorbidities was evaluated along with Utstein factors, recognized coronary artery disease was significantly associated and predicted higher odds of survival (unadjusted odds ratio 1.5, P<0.001; adjusted odds ratio 1.5, P=0.02). In multivariable logistic models, prearrest coronary artery disease modified the survival effects of bystander cardiopulmonary resuscitation, but did not modify other Utstein factors. CONCLUSIONS: An established diagnosis of coronary artery disease was associated with 50% higher odds of survival from resuscitated SCA after adjustment for all arrest-related predictors. These findings raise novel potential mechanistic insights into survival after SCA, while highlighting the importance of early recognition and treatment of coronary artery disease. PMID- 25288615 TI - Alcohol drinking and pro-drinking practices in parents of Hong Kong adolescents. AB - AIMS: We investigated the prevalence of various parental pro-drinking practices and its association with parental drinking status. METHODS: A school-based survey was completed by 2200 students (mean age 14.8, SD 2.0; boys 51.4%) from 4 randomly selected secondary schools in Hong Kong. Students reported whether they had ever experienced each of nine parental pro-drinking practices (PPDPs). RESULTS: Overall, 67.5% of students reported at least one PPDP, but the prevalence was much higher if both parents were drinkers (89.0%) compared with non-drinkers (38.8%). The adjusted odds ratio (AOR) (95% CI) of experiencing at least one PPDP was 6.79 (4.98, 9.26) if either parent drank and 15.71 (10.50, 23.50) if both drank compared with none (P for trend <0.001). Compared with non drinking, the AORs (95% CI) of experiencing at least one PPDP for occasional drinking and frequent drinking were 6.72 (5.03, 8.98) and 18.11 (9.88, 33.18) in fathers (P for trend <0.001), and 7.33 (5.15, 10.44) and 5.33 (1.98, 14.45) in mothers. CONCLUSION: The prevalence of PPDPs was generally low in non-drinking parents, but increased dramatically with the number of drinking parents and the frequency of paternal drinking. PMID- 25288616 TI - Looking beyond skin color: addressing heterogeneity in health disparities research. PMID- 25288617 TI - A quantitative description of uncertainty with mild cognitive impairment. PMID- 25288618 TI - Internet health information seeking (IHIS): an integrative review of the literature. PMID- 25288619 TI - Self-concepts of exercise in frail older adults with heart failure: a literature review. PMID- 25288620 TI - State of the science on potentially inappropriate medications in community dwelling older adults. PMID- 25288621 TI - Urinary tract infections in long-term care: an implementation project to reduce inappropriate antibiotic treatment. PMID- 25288622 TI - Shared mental models of patients, oncology providers, and primary care providers regarding roles in cancer survivorship care. PMID- 25288623 TI - The use of stress-reducing techniques in nursing education. PMID- 25288624 TI - Transtibial versus tibial inlay techniques for posterior cruciate ligament reconstruction: long-term follow-up study. AB - BACKGROUND: The most common technique for posterior cruciate ligament (PCL) reconstruction is transtibial or tibial inlay. However, few studies have reported long-term outcome comparisons between the 2 techniques. HYPOTHESIS: Tibial inlay PCL reconstruction with patellar tendon autograft will exhibit better clinical and radiographic outcomes than transtibial PCL reconstruction with hamstring autograft. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 66 patients (66 knees) treated with PCL reconstruction for chronic injuries constituted the study cohort. Patients were divided into 2 groups: transtibial with hamstring (36 patients) and tibial inlay with patellar tendon (30 patients). The mean time from injury to reconstruction was 12.2 months (range, 2-60 months), and the mean follow-up was 148 months (range, 98-196 months). Outcomes were measured by use of Lysholm knee scores, Tegner activity scores, return to preinjury sports activity, posterior drawer test, laxity test with a Telos device, and development of osteoarthritis. RESULTS: The preoperative mean Lysholm knee score was 59.9 (range, 37-70) in the transtibial group and 54.5 (range, 22 76) in the tibial inlay group, improving postoperatively to 89.9 (range, 74-100) and 92.1 (range, 80-100), respectively. The mean Tegner activity scores increased from 2.5 (range, 2-5) to 5.9 (range, 4-7) in the transtibial group and 2.3 (range, 2-4) to 6.0 (range, 3-8) in the tibial inlay group. Twenty-one patients (58.3%) in the transtibial group and 19 patients (63.3%) in the tibial inlay group were able to return to preinjury sports activity. In the posterior drawer test, 6 patients in the transtibial group and 4 patients in the tibial inlay group showed grade II laxity. The mean side-to-side difference was 10.1 mm (range, 7-12 mm) in the transtibial group and 10.4 mm (range, 9-13 mm) in the tibial inlay group, improving postoperatively to 4.1 mm (range, 0-8 mm) and 4.2 mm (range, 1-8 mm), respectively. There was significant improvement between preoperative and final follow-up values. However, there were no significant differences between the 2 groups in final follow-up outcomes. Final follow-up radiographs showed that 6 patients (16.7%) in the transtibial group and 3 patients (10.0%) in the tibial inlay group were rated grade C according to International Knee Documentation Committee guidelines. CONCLUSION: Clinical and radiographic outcomes between the 2 PCL reconstruction techniques were comparable. Osteoarthritis was observed in patients, with a significant proportion presenting loss of joint space. Examined factors, excluding meniscectomy, were not correlated with the development of osteoarthritis. PMID- 25288625 TI - The multiligament quality of life questionnaire: development and evaluation of test-retest reliability and validity in patients with multiligament knee injuries. AB - BACKGROUND: Existing knee joint-specific outcome questionnaires lack content pertinent to patients with multiligament knee injuries. PURPOSE: To develop and test the reliability and validity of a novel disease-specific quality of life questionnaire for patients with multiligament knee injuries. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Participants in this study included patients with multiligament knee injuries and clinician experts. Inclusion criteria were (1) patients with multiligament knee injury (age, 18-60 years), (2) >=6 months after injury, and (3) operative or nonoperative treatment. Exclusion criteria were (1) preexisting osteoarthritis or inflammatory arthritis and (2) intracerebral/spinal cord injury. In phase I of the study, 85 eligible patients were mailed a questionnaire composed of 132 items from 11 existing knee questionnaires. Items were rated with regard to importance and frequency on a 5 point Likert scale. Criteria for inclusion in the first draft of the Multiligament Quality of Life (MLQOL) questionnaire included mean importance rating >=3.5 and frequency <30% for the response "never experienced." In phase II, patient focus groups and expert interviews were conducted until no further new content was generated for the MLQOL, and in phase III, 99 eligible patients across 2 centers were mailed a preliminary MLQOL questionnaire along with the Tegner activity scale, Short Form (SF)-36, and anchor questions. Interitem and item-to-total correlations were used to perform item reduction to generate a final MLQOL instrument, which was tested for internal consistency (Cronbach alpha), test-retest reliability (interclass correlation coefficient [ICC]), and construct validity. RESULTS: At the end of phase III, a final MLQOL instrument was developed that was composed of 4 domains (physical impairments [PI], emotional impairments [EI], activity limitations [AL], and societal involvement [SI]) with 52 items in total. The MLQOL had adequate content validity, as none of the domains had any floor or ceiling effects. The Cronbach alpha was .94 (PI), .93 (EI), .94 (AL), and .91 (SI); ICC values were .89 (PI), .86 (EI), .91 (AL), and .88 (SI). Seven of 8 a priori hypotheses were satisfied, indicating good construct validity. CONCLUSION: The MLQOL instrument is a novel disease-specific quality of life tool that has demonstrated excellent content validity, reliability, and construct validity. PMID- 25288626 TI - Contamination of SVG p12 cells with BK polyomavirus occurred after deposit in the American Type Culture Collection. PMID- 25288627 TI - Reply to "Contamination of SVG p12 cells with BK polyomavirus occurred after deposit in the American type culture collection". PMID- 25288631 TI - Using euhalophytes to understand salt tolerance and to develop saline agriculture: Suaeda salsa as a promising model. AB - BACKGROUND: As important components in saline agriculture, halophytes can help to provide food for a growing world population. In addition to being potential crops in their own right, halophytes are also potential sources of salt-resistance genes that might help plant breeders and molecular biologists increase the salt tolerance of conventional crop plants. One especially promising halophyte is Suaeda salsa, a euhalophytic herb that occurs both on inland saline soils and in the intertidal zone. The species produces dimorphic seeds: black seeds are sensitive to salinity and remain dormant in light under high salt concentrations, while brown seeds can germinate under high salinity (e.g. 600 mm NaCl) regardless of light. Consequently, the species is useful for studying the mechanisms by which dimorphic seeds are adapted to saline environments. S. salsa has succulent leaves and is highly salt tolerant (e.g. its optimal NaCl concentration for growth is 200 mm). A series of S. salsa genes related to salt tolerance have been cloned and their functions tested: these include SsNHX1, SsHKT1, SsAPX, SsCAT1, SsP5CS and SsBADH. The species is economically important because its fresh branches have high value as a vegetable, and its seed oil is edible and rich in unsaturated fatty acids. Because it can remove salts and heavy metals from saline soils, S. salsa can also be used in the restoration of salinized or contaminated saline land. SCOPE: Because of its economic and ecological value in saline agriculture, S. salsa is one of the most important halophytes in China. In this review, the value of S. salsa as a source of food, medicine and forage is discussed. Its uses in the restoration of salinized or contaminated land and as a source of salt-resistance genes are also considered. PMID- 25288634 TI - The effects of rheumatoid factor and anticitrullinated peptide antibodies on bone erosions in rheumatoid arthritis. PMID- 25288633 TI - ULTRAPETALA1 and LEAFY pathways function independently in specifying identity and determinacy at the Arabidopsis floral meristem. AB - BACKGROUND AND AIMS: The morphological variability of the flower in angiosperms, combined with its relatively simple structure, makes it an excellent model to study cell specification and the establishment of morphogenetic patterns. Flowers are the products of floral meristems, which are determinate structures that generate four different types of floral organs before terminating. The precise organization of the flower in whorls, each defined by the identity and number of organs it contains, is controlled by a multi-layered network involving numerous transcriptional regulators. In particular, the AGAMOUS (AG) MADS domain containing transcription factor plays a major role in controlling floral determinacy in Arabidopsis thaliana in addition to specifying reproductive organ identity. This study aims to characterize the genetic interactions between the ULTRAPETALA1 (ULT1) and LEAFY (LFY) transcriptional regulators during flower morphogenesis, with a focus on AG regulation. METHODS: Genetic and molecular approaches were used to address the question of redundancy and reciprocal interdependency for the establishment of flower meristem initiation, identity and termination. In particular, the effects of loss of both ULT1 and LFY function were determined by analysing flower developmental phenotypes of double-mutant plants. The dependency of each factor on the other for activating developmental genes was also investigated in gain-of-function experiments. KEY RESULTS: The ULT1 and LFY pathways, while both activating AG expression in the centre of the flower meristem, functioned independently in floral meristem determinacy. Ectopic transcriptional activation by ULT1 of AG and AP3, another gene encoding a MADS domain-containing flower architect, did not depend on LFY function. Similarly, LFY did not require ULT1 function to ectopically determine floral fate. CONCLUSIONS: The results indicate that the ULT1 and LFY pathways act separately in regulating identity and determinacy at the floral meristem. In particular, they independently induce AG expression in the centre of the flower to terminate meristem activity. A model is proposed whereby these independent contributions bring about a switch at the AG locus from an inactive to an active transcriptional state at the correct time and place during flower development. PMID- 25288632 TI - Flowers under pressure: ins and outs of turgor regulation in development. AB - BACKGROUND: Turgor pressure is an essential feature of plants; however, whereas its physiological importance is unequivocally recognized, its relevance to development is often reduced to a role in cell elongation. SCOPE: This review surveys the roles of turgor in development, the molecular mechanisms of turgor regulation and the methods used to measure turgor and related quantities, while also covering the basic concepts associated with water potential and water flow in plants. Three key processes in flower development are then considered more specifically: flower opening, anther dehiscence and pollen tube growth. CONCLUSIONS: Many molecular determinants of turgor and its regulation have been characterized, while a number of methods are now available to quantify water potential, turgor and hydraulic conductivity. Data on flower opening, anther dehiscence and lateral root emergence suggest that turgor needs to be finely tuned during development, both spatially and temporally. It is anticipated that a combination of biological experiments and physical measurements will reinforce the existing data and reveal unexpected roles of turgor in development. PMID- 25288635 TI - Focus on roots. PMID- 25288636 TI - Glycosylphosphatidylinositol anchoring: control through modification. PMID- 25288637 TI - Nicotianamine secretion for zinc excess tolerance. PMID- 25288638 TI - Structural and functional characterization of ybr137wp implicates its involvement in the targeting of tail-anchored proteins to membranes. AB - Nearly 5% of membrane proteins are guided to nuclear, endoplasmic reticulum (ER), mitochondrial, Golgi, or peroxisome membranes by their C-terminal transmembrane domain and are classified as tail-anchored (TA) membrane proteins. In Saccharomyces cerevisiae, the guided entry of TA protein (GET) pathway has been shown to function in the delivery of TA proteins to the ER. The sorting complex for this pathway is comprised of Sgt2, Get4, and Get5 and facilitates the loading of nascent tail-anchored proteins onto the Get3 ATPase. Multiple pulldown assays also indicated that Ybr137wp associates with this complex in vivo. Here, we report a 2.8-A-resolution crystal structure for Ybr137wp from Saccharomyces cerevisiae. The protein is a decamer in the crystal and also in solution, as observed by size exclusion chromatography and analytical ultracentrifugation. In addition, isothermal titration calorimetry indicated that the C-terminal acidic motif of Ybr137wp interacts with the tetratricopeptide repeat (TPR) domain of Sgt2. Moreover, an in vivo study demonstrated that Ybr137wp is induced in yeast exiting the log phase and ameliorates the defect of TA protein delivery and cell viability derived by the impaired GET system under starvation conditions. Therefore, this study suggests a possible role for Ybr137wp related to targeting of tail-anchored proteins. PMID- 25288639 TI - Tropomyosin Tm5NM1 spatially restricts src kinase activity through perturbation of Rab11 vesicle trafficking. AB - In order for cells to stop moving, they must synchronously stabilize actin filaments and their associated focal adhesions. How these two structures are coordinated in time and space is not known. We show here that the actin association protein Tm5NM1, which induces stable actin filaments, concurrently suppresses the trafficking of focal-adhesion-regulatory molecules. Using combinations of fluorescent biosensors and fluorescence recovery after photobleaching (FRAP), we demonstrate that Tm5NM1 reduces the level of delivery of Src kinase to focal adhesions, resulting in reduced phosphorylation of adhesion-resident Src substrates. Live imaging of Rab11-positive recycling endosomes that carry Src to focal adhesions reveals disruption of this pathway. We propose that tropomyosin synchronizes adhesion dynamics with the cytoskeleton by regulating actin-dependent trafficking of essential focal-adhesion molecules. PMID- 25288641 TI - mTOR signaling regulates nucleolar targeting of the SUMO-specific isopeptidase SENP3. AB - Ribosome biogenesis is a multistep cellular pathway that involves more than 200 regulatory components to ultimately generate translation-competent 80S ribosomes. The initial steps of this process, particularly rRNA processing, take place in the nucleolus, while later stages occur in the nucleoplasm and cytoplasm. One critical factor of 28S rRNA maturation is the SUMO-isopeptidase SENP3. SENP3 tightly interacts with the nucleolar scaffold protein NPM1 and is associated with nucleolar 60S preribosomes. A central question is how changes in energy supply feed into the regulation of ribosome maturation. Here, we show that the nutrient sensing mTOR kinase pathway controls the nucleolar targeting of SENP3 by regulating its interaction with NPM1. We define an N-terminal domain in SENP3 as the critical NPM1 binding region and provide evidence that mTOR-mediated phosphorylation of serine/threonine residues within this region fosters the interaction of SENP3 with NPM1. The inhibition of mTOR triggers the nucleolar release of SENP3, thereby likely compromising its activity in rRNA processing. Since mTOR activity is tightly coupled to nutrient availability, we propose that this pathway contributes to the adaptation of ribosome maturation in response to the cellular energy status. PMID- 25288640 TI - Genetic dissection of the vav2-rac1 signaling axis in vascular smooth muscle cells. AB - Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them. PMID- 25288642 TI - In vivo role of phosphorylation of cryptochrome 2 in the mouse circadian clock. AB - The circadian clock is finely regulated by posttranslational modifications of clock components. Mouse CRY2, a critical player in the mammalian clock, is phosphorylated at Ser557 for proteasome-mediated degradation, but its in vivo role in circadian organization was not revealed. Here, we generated CRY2(S557A) mutant mice, in which Ser557 phosphorylation is specifically abolished. The mutation lengthened free-running periods of the behavioral rhythms and PER2::LUC bioluminescence rhythms of cultured liver. In livers from mutant mice, the nuclear CRY2 level was elevated, with enhanced PER2 nuclear occupancy and suppression of E-box-regulated genes. Thus, Ser557 phosphorylation-dependent regulation of CRY2 is essential for proper clock oscillation in vivo. PMID- 25288643 TI - Whole glucan particles as a vaccine against murine aspergillosis. AB - Vaccination with heat-killed Saccharomyces cerevisiae (HKY) protects against experimental infection by pathogenic fungi of five genera. Here we tested whether purified Saccharomyces cell wall beta-glucan could induce protection against systemic aspergillosis. CD-1 mice were given three weekly vaccine doses subcutaneously prior to intravenous infection with Aspergillus fumigatus. Mice received PBS, 2.5 mg HKY, whole glucan particles (WGP), WGP conjugated to BSA (0.06 to 12 mg per dose), a soluble medium molecular mass (MMW) beta-glucan alone or MMW-BSA (<=24 mg per dose). Survival and c.f.u. were determined, and cytokine induction and anti-beta-glucan antibodies were assessed in vaccinated mice. Neither soluble MMW glucan, nor MMW-BSA was effective. HKY protected in two studies (survival and c.f.u. were reduced in brain and kidney organs, P<0.004). Six or 12 mg WGP or WGP-BSA prolonged survival (P<=0.004) and reduced c.f.u. in each organ (P<=0.015) in both experiments; 0.6 mg WGP or WGP-BSA prolonged survival (P<=0.015) and reduced c.f.u. (P<=0.015) in one experiment. Cytokine profiles in serum and bronchoalveolar lavage from uninfected vaccinated mice showed an innate and adaptive immune profile (i.e. upregulation of colony stimulating factors, interferons, TNF-alpha, chemokines such as MCP-1, MIP 1alpha, RANTES and KC, and Th17-activating cytokines such as IL-6, IL-1beta, IL 17). No anti-beta-glucan antibodies were in the sera, suggesting an adaptive T cell-mediated, not a B cell-mediated, protective response. Vaccination with WGP or WGP-BSA proved protective against systemic aspergillosis, equivalent to that of HKY, supporting the potential of particulate beta-glucans, alone or conjugated, as vaccines against aspergillosis. PMID- 25288644 TI - Cross-protective effect of a novel multi-antigen-chimeric vaccine against Streptococcus and Staphylococcus aureus infection in mice. AB - Staphylococcal and streptococcal species are the most common pathogens that cause bovine mastitis. Induction of a broad-spectrum protective immunity against staphylococci and streptococci by combining multiple antigens into a single vaccine is highlighted. To develop a universal vaccine candidate, a GapC1-tIsdB TRAP (GIT) construct was generated. The GIT contained the truncated GapC from Streptococcus dysgalactiae, and truncated IsdB and full-length TRAP from Staphylococcus aureus. The humoral and cellular immune responses elicited by GIT were evaluated in mice. Antibody levels against GIT displayed a consistent tendency with antibody levels against GapC, IsdB and TRAP. The level of IFN-gamma was higher in the GIT group than in the IsdB group (P<0.05), and the level of IL 4 was higher in the GIT group than in the GapC or TRAP groups (P<0.05). The GIT group showed an improved protection against Streptococcus in comparison with GapC group. A significant difference in S. aureus challenge test was detected between the GIT group and the IsdB or TRAP groups (P<0.05) in per cent survival of mice, and a synergistic immunoprotection against S. aureus or S. dysgalactiae was produced in the GIT group. These results suggested that the GIT would be a promising common vaccine candidate against S. aureus and Streptococcus. PMID- 25288645 TI - Poly-gamma-glutamic acid: production, properties and applications. AB - Poly-gamma-glutamic acid (gamma-PGA) is a naturally occurring biopolymer made up of repeating units of l-glutamic acid, d-glutamic acid or both. gamma-PGA can exhibit different properties (conformational states, enantiomeric properties and molecular mass). Owing to its biodegradable, non-toxic and non-immunogenic properties, it has been used successfully in the food, medical and wastewater industries. Amongst other novel applications, it has the potential to be used for protein crystallization, as a soft tissue adhesive and a non-viral vector for safe gene delivery. This review focuses on the production, properties and applications of gamma-PGA. Each application of gamma-PGA utilizes specific properties attributed to various forms of gamma-PGA. As a result of its growing applications, more strains of bacteria need to be investigated for gamma-PGA production to obtain high yields of gamma-PGA with different properties. Many medical applications (especially drug delivery) have exploited alpha-PGA. As gamma-PGA is essentially different from alpha-PGA (i.e. it does not involve a chemical modification step and is not susceptible to proteases), it could be better utilized for such medical applications. Optimization of gamma-PGA with respect to cost of production, molecular mass and conformational/enantiomeric properties is a major step in making its application practical. Analyses of gamma PGA production and knowledge of the enzymes and genes involved in gamma-PGA production will not only help increase productivity whilst reducing the cost of production, but also help to understand the mechanism by which gamma-PGA is effective in numerous applications. PMID- 25288646 TI - Tyrosine phosphorylation enhances activity of pneumococcal autolysin LytA. AB - Tyrosine phosphorylation has long been recognized as a crucial post-translational regulatory mechanism in eukaryotes. However, only in the past decade has recognition been given to the crucial importance of bacterial tyrosine phosphorylation as an important regulatory feature of pathogenesis. This study describes the effect of tyrosine phosphorylation on the activity of a major virulence factor of the pneumococcus, the autolysin LytA, and a possible connection to the Streptococcus pneumoniae capsule synthesis regulatory proteins (CpsB, CpsC and CpsD). We show that in vitro pneumococcal tyrosine kinase, CpsD, and the protein tyrosine phosphatase, CpsB, act to phosphorylate and dephosphorylate LytA. Furthermore, this modulates LytA function in vitro with phosphorylated LytA binding more strongly to the choline analogue DEAE. A phospho mimetic (Y264E) mutation of the LytA phosphorylation site displayed similar phenotypes as well as an enhanced dimerization capacity. Similarly, tyrosine phosphorylation increased LytA amidase activity, as evidenced by a turbidometric amidase activity assay. Similarly, when the phospho-mimetic mutation was introduced in the chromosomal lytA of S. pneumoniae, autolysis occurred earlier and at an enhanced rate. This study thus describes, to our knowledge, the first functional regulatory effect of tyrosine phosphorylation on a non-capsule-related protein in the pneumococcus, and suggests a link between the regulation of LytA dependent autolysis of the cell and the biosynthesis of capsular polysaccharide. PMID- 25288647 TI - Localization and expression of the Bacillus subtilis DL-endopeptidase LytF are influenced by mutations in LTA synthases and glycolipid anchor synthetic enzymes. AB - Bacillus subtilis LytF plays a principal role in cell separation through its localization at the septa and poles on the vegetative cell surface. In this study, we found that a mutation in a major lipoteichoic acid (LTA) synthase gene- ltaS--results in a considerable reduction in the sigma(D)-dependent transcription of lytF. The lytF transcription was also reduced in mutants that affected glycolipid anchor biosynthesis. Immunofluorescence microscopy revealed that both the numbers of cells expressing LytF and the LytF foci in these mutants were decreased. In addition, the transcriptional activity of lytF was almost abolished in the double (ltaS yfnI), triple (ltaS yfnI yqgS), and quadruple (ltaS yfnI yqgS yvgJ) mutants during vegetative growth. Cell separation defects in these mutants were partially restored with artificial expression of LytF. Interestingly, when lytF transcription was induced in the ltaS single or multiple mutants, LytF was localized not only at the septum, but also along the sidewall. The amounts of LytF bound to cell wall in the single (ltaS) and double (ltaS yfnI) mutants gradually increased as compared with that in the WT strain, and those in the triple (ltaS yfnI yqgS) and quadruple mutants were almost similar to that in the double mutant. Moreover, reduction of the lytF transcription and chained cell morphology in the ltaS mutant were completely restored with artificial induction of the yqgS gene. These results strongly suggest that LTA influences the temporal, sigma(D)-dependent transcription of lytF and is an additional inhibitory component to the vegetative cell separation enzyme LytF. PMID- 25288648 TI - Why do Canadians use so much plasma? PMID- 25288650 TI - Physical inactivity in developing countries. PMID- 25288651 TI - Not all patients are the same. PMID- 25288652 TI - Efficacy of caspofungin, a 1,3-beta-D-glucan synthase inhibitor, on Pneumocystis carinii pneumonia in rats. AB - Pneumocystis carinii pneumonia (PcP) is a common and potentially fatal opportunistic infection in immunosuppressed patients, and the standard trimethoprim-sulfamethoxazole (TMP-SMZ) treatment has serious side effects. The cell wall of the causative fungal pathogen is enriched in 1-3-beta-D-glucan, providing an alternative therapeutic target. We directly compared the efficacy of the 1,3-beta-D-glucan synthase inhibitor caspofungin to TMP-SMZ for promoting survival and reducing lung cyst number during the early phase of treatment in a rat model of PcP. Rats were immunosuppressed using dexamethasone for 8 weeks and PcP infection confirmed in test animals by lung print smear. The remaining rats were randomly divided into three control groups, a baseline group and two observed for 7 or 14 days, two caspofungin groups treated intravenously for 7 or 14 days (1 mg/kg/d), and 2 TMP-SMZ positive control groups treated by oral gavage for 7 or 14 days (300 mg/kg/d). Mortality was markedly reduced by both caspofungin and TMP-SMZ after 14 days (caspofungin: 20.0%, TMP-SMZ: 13.3%, Control: 40.0%). Body weight gain in caspofungin-treated rats after 7 (3.04 +/- 3.54%) and 14 (4.27 +/- 2.79%) days was similar to that in TMP-SMZ-treated rats (3.35 +/- 1.88% and 5.85 +/- 2.78%, respectively), whereas untreated controls showed weight loss. Lung weight to body weight ratio, and mean cyst number per 50 microscopic fields were significantly lower (all P < 0.05) in caspofungin-treated rats than untreated controls at both 7 and 14 days, and similar to those in the TMP-SMZ-treated rats (all P > 0.05 vs. caspofungin). Caspofungin exhibited similar efficacy to TMP-SMZ for enhancing survival and reducing lung edema and cyst load in a rat model of PcP, suggesting potential clinical utility against PcP. PMID- 25288653 TI - High prevalence of Pneumocystis jirovecii colonization among HIV-positive patients in southern Brazil. AB - A high prevalence of Pneumocystis jirovecii colonization was observed in patients positive for the human immunodeficiency virus (HIV) admitted to a tertiary hospital in southern Brazil between August 2012 and December 2012. Amplification of the mitochondrial large subunit ribosomal RNA gene in oropharyngeal samples through nested polymerase chain reaction identified P. jirovecii colonization in 26 of 58 (44.8%) HIV-positive patients admitted for causes other than Pneumocystis pneumonia. Colonization was more frequent among patients with an absolute CD4 count <=200 cells/MUl. These findings suggest that the HIV-infected population is a major reservoir and source of P. jirovecii infection and that identification of such individuals may contribute to future strategies for improving management of HIV-infected patients. PMID- 25288654 TI - Cutaneous mucormycosis and motor vehicle accidents: Findings from an Australian case series. AB - Cutaneous disease is the third most frequent manifestation of mucormycosis. The clinical manifestations of and subsequent mortality due to cutaneous mucormycosis are dependent on the mode of acquisition and the host immune status. Here, we describe the epidemiology, clinical presentation, microbiology, and outcomes of 16 cutaneous mucormycosis infections managed in an Australian tertiary hospital over a 15-year period. The proportion with localized (56%), deep (38%), and disseminated (6%) cutaneous disease as well as the overall mortality (25%) were consistent with findings reported in the published literature. Two novel forms of hospital-acquired infection were reported following a sacral pressure sore and insertion of a foreign body during a bone graft procedure. The majority of patients were immunocompetent (75%) and/or suffered trauma (56%) with associated environmental contamination. A novel finding was that motor vehicle accidents (MVAs) accounted for 78% of all trauma-related cases, suggesting MVAs should receive greater recognition as a potential precipitant of cutaneous mucormycosis. Aggressive decontamination and debridement of devitalized tissue following trauma is therefore likely to play an important role in the prevention of this rare but potentially devastating infection. PMID- 25288655 TI - MetaProx: the database of metagenomic proximons. AB - MetaProx is the database of metagenomic proximons: a searchable repository of proximon objects conceived with two specific goals. The first objective is to accelerate research involving metagenomic functional interactions by providing a database of metagenomic operon candidates. Proximons represent a special subset of directons (series of contiguous co-directional genes) where each member gene is in close proximity to its neighbours with respect to intergenic distance. As a result, proximons represent significant operon candidates where some subset of proximons is the set of true metagenomic operons. Proximons are well suited for the inference of metagenomic functional networks because predicted functional linkages do not rely on homology-dependent information that is frequently unavailable in metagenomic scenarios. The second objective is to explore representations for semistructured biological data that can offer an alternative to the traditional relational database approach. In particular, we use a serialized object implementation and advocate a Data as Data policy where the same serialized objects can be used at all levels (database, search tool and saved user file) without conversion or the use of human-readable markups. MetaProx currently includes 4,210,818 proximons consisting of 8 ?,926,993 total member genes. Database URL: http://metaprox.uwaterloo.ca. PMID- 25288658 TI - The status of the name Lactobacillus rogosae Holdeman and Moore 1974. Opinion 88. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that the COMBINATION: Lactobacillus rogosae Holdeman and Moore 1974 represented by the type strain ATCC 27753 listed on the Approved Lists of Bacterial Names does not appear to be currently represented by an extant type strain. Further work is needed to determine whether a derivative of the original type can be found or whether a neotype can be designated. PMID- 25288656 TI - miRIAD-integrating microRNA inter- and intragenic data. AB - MicroRNAs (miRNAs) are a class of small (~22 nucleotides) non-coding RNAs that post-transcriptionally regulate gene expression by interacting with target mRNAs. A majority of miRNAs is located within intronic or exonic regions of protein coding genes (host genes), and increasing evidence suggests a functional relationship between these miRNAs and their host genes. Here, we introduce miRIAD, a web-service to facilitate the analysis of genomic and structural features of intragenic miRNAs and their host genes for five species (human, rhesus monkey, mouse, chicken and opossum). miRIAD contains the genomic classification of all miRNAs (inter- and intragenic), as well as classification of all protein-coding genes into host or non-host genes (depending on whether they contain an intragenic miRNA or not). We collected and processed public data from several sources to provide a clear visualization of relevant knowledge related to intragenic miRNAs, such as host gene function, genomic context, names of and references to intragenic miRNAs, miRNA binding sites, clusters of intragenic miRNAs, miRNA and host gene expression across different tissues and expression correlation for intragenic miRNAs and their host genes. Protein protein interaction data are also presented for functional network analysis of host genes. In summary, miRIAD was designed to help the research community to explore, in a user-friendly environment, intragenic miRNAs, their host genes and functional annotations with minimal effort, facilitating hypothesis generation and in-silico validations. Database URL: http://www.miriad-database.org. PMID- 25288659 TI - The epithet aurantiaca in Micromonospora aurantiaca Sveshnikova et al. 1969 (Approved Lists 1980) is illegitimate and requires a replacement epithet. Opinion 89. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that the combination Micromonospora aurantiaca Sveshnikova et al. 1969 (Approved Lists 1980) may not serve as the correct name of the taxon because Rule 12b states that no specific or Subspecific epithets within the same genus may be the same if based on different types and the specific epithet aurantiaca in Micromonospora aurantiaca Sveshnikova et al. 1969 (Approved Lists 1980) is the same as the subspecific epithet aurantiaca in Micromonospora carbonacea subsp. aurantiaca Luedemann and Brodsky 1964 (Approved Lists 1980) and the latter has priority. According to Rule 53, the duplication of the same specific or subspecific epithet based on different types creates an illegitimate epithet with the principle of priority determining which is to be replaced as specified in Rule 54. The replacement of the specific epithet aurantiaca in Micromonospora aurantiaca Sveshnikova et al. 1969 (Approved Lists 1980) also requires that the authorship of the original authors is retained. However, action of this nature requires that the original epithet is maintained in the original combination. There currently appears to be no mechanisms where such action can be taken. PMID- 25288660 TI - The combination Enterobacter agglomerans is to be cited as Enterobacter agglomerans (Beijerinck 1888) Ewing and Fife 1972 and the combination Pantoea agglomerans is to be cited as Pantoea agglomerans (Beijerinck 1888) Gavini et al. 1989. Opinion 90. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that, according to information presented to it, the combination Enterobacter agglomerans is to be cited as Enterobacter agglomerans (Beijerinck 1888) Ewing and Fife 1972 and the combination Pantoea agglomerans is to be cited as Pantoea agglomerans (Beijerinck 1888) Gavini et al. 1989. PMID- 25288661 TI - ATCC 43642 replaces ATCC 23581 as the type strain of Leptospira interrogans (Stimson 1907) Wenyon 1926. Opinion 91. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that, according to information presented to it, the type strain of Leptospira interrogans (Stimson 1907) Wenyon 1926 designated on the Approved Lists of Bacterial Names (ATCC 23581) has been shown not to represent an authentic culture of strain RGA (a member of the serovar Icterohaemorrhagiae) and ATCC 43642, derived from an authentic strain of strain RGA, a member of the serovar Icterohaemorrhagiae, is designated the type strain of Leptospira interrogans (Stimson 1907) Wenyon 1926. PMID- 25288662 TI - The Request for an Opinion that the current use of the genus name Mycoplasma be maintained and Mycoplasma coccoides be considered a legitimate name is denied. Opinion 92. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that the request that the current use of the genus name Mycoplasma be maintained and Mycoplasma coccoides be considered a legitimate name is denied. PMID- 25288663 TI - The designated type strain of Pseudomonas halophila Fendrich 1989 is DSM 3051, the designated type strain of Halovibrio variabilis Fendrich 1989 is DSM 3050, the new name Halomonas utahensis (Fendrich 1989) Sorokin and Tindall 2006 is created for the species represented by DSM 3051 when treated as a member of the genus Halomonas, the combination Halomonas variabilis (Fendrich 1989) Dobson and Franzmann 1996 is rejected, and the combination Halovibrio denitrificans Sorokin et al. 2006 is validly published with an emendation of the description of the genus Halovibrio Fendrich 1989 emend. Sorokin et al. 2006. Opinion 93. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that, according to information presented to it, the designated type strain of Pseudomonas halophila Fendrich 1989 is DSM 3051 (replacing DSM 3050) and the designated type strain of Halovibrio variabilis Fendrich 1989 is DSM 3050 (replacing DSM 3051). A new name, Halomonas utahensis (Fendrich 1989) Sorokin and Tindall 2006 nom. nov., is created for the species represented by DSM 3051 when treated as a member of the genus Halomonas, because the combination Halomonas halophila (Quesada et al. 1984) Dobson and Franzmann 1996 has priority based on the fact that the epithet halophila in the combination Halomonas halophila (Quesada et al. 1984) Dobson and Franzmann 1996 ( BASOYNM: Deleya halophila Quesada et al. 1984) has priority over the epithet halophila should the taxon Pseudomonas halophila Fendrich 1989 be treated as a member of the genus Halomonas. The combination Halomonas variabilis (Fendrich 1989) Dobson and Franzmann 1996 is rejected. The combination Halovibrio denitrificans Sorokin et al. 2006 is validly published with an emendation of the description of the genus Halovibrio Fendrich 1989 emend. Sorokin et al. 2006. PMID- 25288664 TI - Agrobacterium radiobacter (Beijerinck and van Delden 1902) Conn 1942 has priority over Agrobacterium tumefaciens (Smith and Townsend 1907) Conn 1942 when the two are treated as members of the same species based on the principle of priority and Rule 23a, Note 1 as applied to the corresponding specific epithets. Opinion 94. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that, according to the Rules of the International Code of Nomenclature of Bacteria (including changes made to the wording), the combination Agrobacterium radiobacter (Beijerinck and van Delden 1902) Conn 1942 has priority over the combination Agrobacterium tumefaciens (Smith and Townsend 1907) Conn 1942 when the two are treated as members of the same species based on the principle of priority as applied to the corresponding specific epithets. The type species of the genus is Agrobacterium tumefaciens (Smith and Townsend 1907) Conn 1942, even if treated as a later heterotypic synonym of Agrobacterium radiobacter (Beijerinck and van Delden 1902) Conn 1942. Agrobacterium tumefaciens (Smith and Townsend 1907) Conn 1942 is typified by the strain defined on the Approved Lists of Bacterial Names and by strains known to be derived from the nomenclatural type. PMID- 25288665 TI - The properties given at the time of publication for the designated type strain of Leifsonia rubra Reddy et al. 2003, CMS 76r, do not correspond with those of MTCC 4210, DSM 15304, CIP 107783 and JCM 12471 that are deposited as representing the type strain: Opinion 96. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that, according to information presented to it, the type strain of Leifsonia rubra Reddy et al. 2003 designated in the original publication as strain CMS 76r and deposited as MTCC 4210, DSM 15304, CIP 107783 and JCM 12471 does not have properties corresponding with those of the strains held in those collections under those accession numbers. The species Leifsonia rubra Reddy et al. 2003 was not represented by an authentic deposit of a type strain at the time of effective publication in the pages of the International Journal of Systematic and Evolutionary Microbiology. PMID- 25288666 TI - The subgenus names Moraxella and Branhamella (in the genus Moraxella) are not in accordance with the International Code of Nomenclature of Bacteria and are therefore not validly published: Supplementary information to Opinion 83. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The publication of Opinion 83, which dealt with the valid publication of the subgenus names Moraxella and Branhamella (in the genus Moraxella), has highlighted a problem relating to the absence of descriptions associated with these names at the time they were effectively published. This calls into question whether the ruling outlined in Opinion 83, that these names should have qualified for inclusion on the Approved Lists of Bacterial Names, and their inclusion on Validation List 15 are not in accordance with Rule 27 of the International Code of Nomenclature of Bacteria governing the valid publication of a name. The subgenus names Moraxella and Branhamella (in the genus Moraxella) are not to be considered to be included on the Approved Lists of Bacterial Names, nor are they to be considered to be validly published by inclusion on Validation List 15. PMID- 25288667 TI - The genus name Methanothrix Huser et al. 1983 and the species combination Methanothrix soehngenii Huser et al. 1983 do not contravene Rule 31a and are not to be considered as rejected names, the genus name Methanosaeta Patel and Sprott 1990 refers to the same taxon as Methanothrix soehngenii Huser et al. 1983 and the species combination Methanothrix thermophila Kamagata et al. 1992 is rejected: Supplementary information to Opinion 75. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The Judicial Commission affirms that the genus name Methanothrix Huser et al. 1983 and the species combination Methanothrix soehngenii Huser et al. 1983 do not contravene Rule 31a and are not to be considered as rejected names. The genus name Methanosaeta Patel and Sprott 1990 applies to the same taxon as Methanothrix Huser et al. 1983 and is therefore a later heterotypic synonym. The combinations Methanothrix thermoacetophila corrig. Nozhevnikova and Chudina 1988 and Methanothrix thermophila Kamagata et al. 1992 are considered to refer to the same taxon, a consequence of which is that Methanothrix thermophila Kamagata et al. 1992 contravenes Rule 51b and is placed on the List of Rejected Names. PMID- 25288668 TI - Names at the rank of class, subclass and order, their typification and current status: Supplementary information to Opinion 79. Judicial Commission of the International Committee on Systematics of Prokaryotes. AB - The attention of the Judicial Commission was drawn to issues relating to the use of names at the rank of class, subclass and order and the nomenclatural type of names at the rank of class and subclass that were not covered by Opinion 79. The Judicial Commission ruled that names at the rank of class and order proposed by Cavalier-Smith (Int. J. Syst. Evol. Microbiol., 52, 7-76, 2002) are to be placed on the List of Rejected Names (nomina rejicienda) and the use of names proposed in that publication above the rank of class is to be actively discouraged. In addition a list of names at the rank of class, subclass and order is given where the nomenclatural type, description or circumscription is unclear or where they otherwise appear to be not in accordance with the Rules of the International Code of Nomenclature of Bacteria. PMID- 25288669 TI - DNA double-strand breaks by Cr(VI) are targeted to euchromatin and cause ATR dependent phosphorylation of histone H2AX and its ubiquitination. AB - Hexavalent chromium is a human respiratory carcinogen that undergoes intracellular activation in vivo primarily via reduction with ascorbate. Replication of Cr-adducted DNA triggers mismatch repair that generates toxic DNA double-strand breaks (DSBs) as secondary lesions. Here, we examined the intranuclear distribution of chromate-induced breaks and a central DSB signaling branch targeting histone H2AX. Using ascorbate-restored cells (H460 human lung epithelial cells, normal human lung and normal mouse embryonic fibroblasts (MEFs)), we found that Cr(VI) produced a typical DSB-associated spectrum of H2AX modifications, including its Ser139-phosphorylated (known as gammaH2AX) and mono- and diubiquitinated forms. However, whereas canonical DSB signaling relies on ATM, the formation of gammaH2AX and its ubiquitinated products by Cr(VI) was dependent on ATR kinase. Based on the established mode of ATR activation, this suggests that Cr-induced DSB are not blunt-ended and likely contain single stranded tails. Confocal imaging with markers of active and inactive chromatin revealed a selective formation of Cr-induced DSB in euchromatin of mouse and human cells. In contrast to DSB, Cr-DNA adducts were produced in both types of chromatin. The euchromatin targeting of Cr-induced DSB makes these lesions particularly dangerous by increasing the probability of deleting active tumor suppressors and producing oncogenic translocations. Accumulation of transcription inhibiting ubiquitinated forms of gammaH2AX in euchromatin is expected to contribute to the ability of Cr(VI) to suppress upregulation of inducible genes. PMID- 25288670 TI - Exposure to As-, Cd-, and Pb-mixture induces Abeta, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats. AB - Environmental pollutants act as risk factors for Alzheimer's disease (AD), mainly affecting the aging population. We investigated early manifestations of AD-like pathology by a mixture of arsenic (As), cadmium (Cd), and lead (Pb), reported to impair neurodevelopment. We treated rats with As+Cd+Pb at their concentrations detected in groundwater of India, ie, 0.38, 0.098, and 0.22 ppm or 10 times of each, respectively, from gestation-05 to postnatal day-180. We identified dose dependent increase in amyloid-beta (Abeta) in frontal cortex and hippocampus as early as post-weaning. The effect was strongly significant during early adulthood, reaching levels comparable to an Abeta-infused AD-like rat model. The metals activated the proamyloidogenic pathway, mediated by increase in amyloid precursor protein (APP), and subsequent beta secretase (BACE) and presenilin (PS) mediated APP-processing. Investigating the mechanism of Abeta-induction revealed an augmentation in oxidative stress-dependent neuroinflammation that stimulated APP expression through interleukin-responsive-APP-mRNA 5'-untranslated region. We then examined the effects of individual metals and binary mixtures in comparison with the tertiary. Among individual metals, Pb triggered maximum induction of Abeta, whereas individual As or Cd had a relatively non-significant effect on Abeta despite enhanced APP, owing to reduced induction of BACE and PS. Interestingly, when combined the metals demonstrated synergism, with a major contribution by As. The synergistic effect was significant and consistent in tertiary mixture, resulting in the augmentation of Abeta. Eventually, increase in Abeta culminated in cognitive impairments in the young rats. Together, our data demonstrate that exposure to As+Cd+Pb induces premature manifestation of AD-like pathology that is synergistic, and oxidative stress and inflammation dependent. PMID- 25288671 TI - Diabetic microangiopathy: impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice. AB - Diabetes increases the risk of stroke by three, increases related mortality, and delays recovery. We aimed to characterize functional and structural alterations in cerebral microvasculature before and after experimental cerebral ischemia in a mouse model of type 1 diabetes. We hypothesized that preexisting brain microvascular disease in patients with diabetes might partly explain increased stroke severity and impact on outcome. Diabetes was induced in 4-week-old C57Bl/6J mice by intraperitoneal injections of streptozotocin (60 mg/kg). After 8 weeks of diabetes, the vasoreactivity of the neurovascular network to CO2 was abolished and was not reversed by nitric oxide (NO) donor administration; endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) mRNA, phospho-eNOS protein, nNOS, and phospho-nNOS protein were significantly decreased; angiogenic and vessel maturation factors (vascular endothelial growth factor a [VEGFa], angiopoietin 1 (Ang1), Ang2, transforming growth factor-beta [TGF-beta], and platelet-derived growth factor-beta [PDGF-beta]) and blood-brain barrier (BBB) occludin and zona occludens 1 (ZO-1) expression were significantly decreased; and microvessel density was increased without changes in ultrastructural imaging. After permanent focal cerebral ischemia induction, infarct volume and neurological deficit were significantly increased at D1 and D7, and neuronal death (TUNEL+ / NeuN+ cells) and BBB permeability (extravasation of Evans blue) at D1. At D7, CD31+ / Ki67+ double-immunolabeled cells and VEGFa and Ang2 expression were significantly increased, indicating delayed angiogenesis. We show that cerebral microangiopathy thus partly explains stroke severity in diabetes. PMID- 25288674 TI - Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. AB - Intranasal insulin (INI) has been shown to modulate food intake and food-related activity in the central nervous system in humans. Because INI increases insulin concentration in the cerebrospinal fluid, these effects have been postulated to be mediated via insulin action in the brain, although peripheral effects of insulin cannot be excluded. INI has been shown to lower plasma glucose in some studies, but whether it regulates endogenous glucose production (EGP) is not known. To assess the role of INI in the regulation of EGP, eight healthy men were studied in a single-blind, crossover study with two randomized visits (one with 40 IU INI and the other with intranasal placebo [INP] administration) 4 weeks apart. EGP was assessed under conditions of an arterial pancreatic clamp, with a primed, constant infusion of deuterated glucose and infusion of 20% dextrose as required to maintain euglycemia. Between 180 and 360 min after administration, INI significantly suppressed EGP by 35.6% compared with INP, despite similar venous insulin concentrations. In conclusion, INI lowers EGP in humans compared with INP, despite similar venous insulin concentrations. INI may therefore be of value in treating excess liver glucose production in diabetes. PMID- 25288672 TI - Loss of NADPH oxidase-derived superoxide skews macrophage phenotypes to delay type 1 diabetes. AB - Macrophages are early islet-infiltrating cells seen in type 1 diabetes (T1D). While proinflammatory M1 macrophages induce T1D, M2 macrophages have been shown to delay this autoimmune disease in nonobese diabetic (NOD) mice, but the environmental cues that govern macrophage polarization and differentiation remain unresolved. We previously demonstrated the importance of reactive oxygen species (ROS) in T1D, as NOD mice deficient in NADPH oxidase (NOX)-derived superoxide (Ncf1(m1J)) were protected against T1D partly because of blunted Toll-like receptor-dependent macrophage responses. We provide evidence that NOX-derived ROS contribute to macrophage differentiation in T1D. During spontaneous diabetes progression, T1D-resistant NOD.Ncf1(m1J) islet-resident macrophages displayed a dampened M1 and increased M2 phenotype. The transfer of diabetogenic T cells into NOX-deficient NOD.Rag.Ncf1(m1J) recipients resulted in decreased TNF-alpha(+) and IL-1beta(+) islet-infiltrating M1 macrophages and a concomitant enhancement in arginase-1(+) M2 macrophages. Mechanistic analysis of superoxide-deficient bone marrow-derived macrophages revealed a marked diminution in a proinflammatory M1 phenotype due to decreased P-STAT1 (Y701) and interferon regulatory factor 5 compared with NOD mice. We have therefore defined a novel mechanistic link between NOX-derived ROS and macrophage phenotypes, and implicated superoxide as an important factor in macrophage differentiation. Thus, targeting macrophage redox status may represent a promising therapy in halting human T1D. PMID- 25288673 TI - Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production. AB - The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes. Remarkably, mice genetically deficient in the glucagon receptor (Gcgr) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr-null mice is the high circulating concentrations of GLP-1. Hence, the objective of this report was to investigate potential noninsulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic beta-cells were chemically destroyed by streptozotocin (STZ) in Gcgr(-/-):Glp-1r( /-) mice and in Glp-1r(-/-) animals that were subsequently treated with a high affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened nonfasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ treated Gcgr(-/-) mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non-beta-cell actions of GLP-1 analogs may improve metabolic control in patients with insulinopenic diabetes. PMID- 25288675 TI - The influence of new European Union driver's license legislation on reporting of severe hypoglycemia by patients with type 1 diabetes. AB - OBJECTIVE: We test the hypotheses that the implementation in Denmark of new, stricter European Union (EU) legislation on driver's licensing, with the purpose to improve traffic safety in January 2012, has reduced the self-reported rate of severe hypoglycemia in a routine clinical setting and that anonymous reporting results in higher event rates. RESEARCH DESIGN AND METHODS: A cohort of 309 patients with type 1 diabetes was recruited in the outpatient clinic at Nordsjaellands University Hospital Hillerod, Denmark. Yearly numbers of severe hypoglycemic events defined by need for treatment assistance from another person were retrieved from medical records in the years 2010 to 2012 and retrospectively reported in an anonymous questionnaire. Data from medical records in 2012 were compared with those from 2010 and 2011 and with data from the questionnaire. RESULTS: Reported rates of severe hypoglycemia in the medical records were reduced by 55% in 2012 compared with the prior years (P = 0.034). The proportion of subjects reporting recurrent episodes was grossly reduced from 5.6 to 1.5% (P = 0.014). Compared with anonymous reporting in the questionnaire, the rate of severe hypoglycemia in 2012 was 70% lower (P < 0.001). CONCLUSIONS: Reporting of severe hypoglycemia by patients with type 1 diabetes is significantly reduced following implementation of EU driver's licensing legislation that implies withdrawal of driver's licensing in case of recurrent episodes within 1 year. The resulting burden of concealed severe hypoglycemia may impair the safety of affected patients and unintentionally paradoxically reduce the general traffic safety. PMID- 25288676 TI - Optic neuropathy secondary to spontaneous intracranial hypotension (SIH) as related to experimental primate model. PMID- 25288677 TI - Author response: Optic neuropathy secondary to spontaneous intracranial hypotension (SIH) as related to experimental primate model. PMID- 25288678 TI - Expression of homologous RND efflux pump genes is dependent upon AcrB expression: implications for efflux and virulence inhibitor design. AB - OBJECTIVES: Enterobacteriaceae have multiple efflux pumps that confer intrinsic resistance to antibiotics. AcrB mediates clinically relevant multidrug resistance and is required for virulence and biofilm formation, making it an attractive target for the design of inhibitors. The aim of this study was to assess the viability of single transporters as a target for efflux inhibition using Salmonella Typhimurium as the model pathogen. METHODS: The expression of resistance-nodulation-division (RND) efflux pump genes in response to the inactivation of single or multiple homologues was measured using real-time RT PCR. Phenotypes of mutants were characterized by measuring antimicrobial susceptibility, dye accumulation and the ability to cause infection in vitro. RESULTS: The expression of all RND efflux pump genes was increased when single or multiple acr genes were inactivated, suggesting a feedback mechanism that activates the transcription of homologous efflux pump genes. When two or three acr genes were inactivated, the mutants had further reduced efflux, altered susceptibility to antimicrobials (including increased susceptibility to some, but conversely and counterintuitively, decreased susceptibility to some others) and were more attenuated in the tissue culture model than mutants lacking single pumps were. CONCLUSIONS: These data indicate that it is critical to understand which pumps an inhibitor is active against and the effect of this on the expression of homologous systems. For some antimicrobials, an inhibitor with activity against multiple pumps will have a greater impact on susceptibility, but an unintended consequence of this may be decreased susceptibility to other drugs, such as aminoglycosides. PMID- 25288680 TI - Initiation and termination of antibiotic regimens in Veterans Affairs hospitals. AB - OBJECTIVES: To assess rates of starting or stopping antibiotics across different hospitals. METHODS: We used barcode medication administration data to measure antibiotic use on acute-care wards in 128 Veterans Affairs medical centres (VAMCs) in 2010. A treatment day (TD) was defined as the administration of any antibiotic on a given day. A treatment period (TP) was defined as an interval of inpatient antimicrobial therapy with gaps of <=1 day in TDs. The rate of starting antibiotics was calculated for inpatients who had not yet started antibiotics, as the number of start events divided by the 'person-time at risk'. The rate of stopping antibiotics was calculated analogously for inpatients that were on antibiotics. Once individuals had stopped antibiotics they were removed from further analysis. Per-day start and stop rates were also calculated for each day of hospitalization. RESULTS: The hospital mean rate of starting the first TP was 18.1 start events/100 days at risk (range 8.4-25.6/100 days at risk). The mean hospital stopping rate was 21.1 stop events/100 days at risk (range 13.3-29.5/100 days at risk). The ratio of a facility's starting and stopping rates was highly correlated with overall antibiotic use in TDs/1000 patient-days (rs=0.92, P<0.001), while starting and stopping rates individually were only moderately correlated (rs=0.39, P<0.001). CONCLUSIONS: VAMCs with similar antibiotic use showed marked differences in their starting and stopping rates of antibiotics. It may be useful to target empirical therapy when starting rates are high and definitive therapy when stopping rates are low. PMID- 25288679 TI - In vitro interactions between farnesol and fluconazole, amphotericin B or micafungin against Candida albicans biofilms. AB - OBJECTIVES: Biofilm formation by Candida albicans poses an important therapeutic challenge in human diseases. Typically, conventional antifungal agents encounter difficulty in treating and fully eradicating biofilm-related infections. Novel therapeutic approaches are needed to treat recalcitrant Candida biofilms. Farnesol is a quorum-sensing molecule, which induces apoptosis, inhibits Ras protein pathways and profoundly affects the morphogenesis of C. albicans. We therefore investigated the interactions between farnesol and different classes of antifungal agents. METHODS: The combined antifungal effects of triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (micafungin) with farnesol against C. albicans biofilms were assessed in vitro. Antifungal activity was determined by the XTT metabolic assay and confocal microscopy. The nature and the intensity of the interactions were assessed using the Loewe additivity model [fractional inhibitory concentration (FIC) index] and the Bliss independence (BI) model. RESULTS: Significant synergy was found between each of the three antifungal agents and farnesol, while antagonism was not observed for any of the combinations tested. The greatest synergistic effect was found with the farnesol/micafungin combination, for which the BI-based model showed the observed effects as being 39%-52% higher than expected if the drugs had been acting independently. The FIC indices ranged from 0.49 to 0.79, indicating synergism for farnesol/micafungin and farnesol/fluconazole and no interaction for farnesol/amphotericin B. Structural changes in the biofilm correlated well with the efficacies of these combinations. The maximum combined effect was dependent on the farnesol concentration for micafungin and amphotericin B. CONCLUSIONS: Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study. PMID- 25288681 TI - Loss of Tropomodulin4 in the zebrafish mutant trage causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy. AB - Nemaline myopathy is an inherited muscle disease that is mainly diagnosed by the presence of nemaline rods in muscle biopsies. Of the nine genes associated with the disease, five encode components of striated muscle sarcomeres. In a genetic zebrafish screen, the mutant trage (trg) was isolated based on its reduction in muscle birefringence, indicating muscle damage. Myofibres in trg appeared disorganised and showed inhomogeneous cytoplasmic eosin staining alongside malformed nuclei. Linkage analysis of trg combined with sequencing identified a nonsense mutation in tropomodulin4 (tmod4), a regulator of thin filament length and stability. Accordingly, although actin monomers polymerize to form thin filaments in the skeletal muscle of tmod4(trg) mutants, thin filaments often appeared to be dispersed throughout myofibres. Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion and early death. Myofibrils of tmod4(trg) mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones and electron dense aggregations of various shapes and sizes. Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods, together with the reactivity of rods with phalloidin and an antibody against actinin, is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4(trg) mutants. Although Tropomodulin4 has not been associated with myopathy, the results presented here implicateTMOD4 as a novel candidate for unresolved nemaline myopathies and suggest that the tmod4(trg) mutant will be a valuable tool to study human muscle disorders. PMID- 25288682 TI - An in vitro model of human neocortical development using pluripotent stem cells: cocaine-induced cytoarchitectural alterations. AB - Neocortical development involves ordered specification of forebrain cortical progenitors to various neuronal subtypes, ultimately forming the layered cortical structure. Modeling of this process using human pluripotent stem cells (hPSCs) would enable mechanistic studies of human neocortical development, while providing new avenues for exploration of developmental neocortical abnormalities. Here, we show that preserving hPSCs aggregates - allowing embryoid body formation - while adding basic fibroblast growth factor (bFGF) during neuroepithelial development generates neural rosettes showing dorsal forebrain identity, including Mash1(+) dorsal telencephalic GABAergic progenitors. Structures that mirrored the organization of the cerebral cortex formed after rosettes were seeded and cultured for 3 weeks in the presence of FGF18, BDNF and NT3. Neurons migrated along radial glia scaffolding, with deep-layer CTIP2(+) cortical neurons appearing after 1 week and upper-layer SATB2(+) cortical neurons forming during the second and third weeks. At the end of differentiation, these structures contained both glutamatergic and GABAergic neurons, with glutamatergic neurons being most abundant. Thus, this differentiation protocol generated an hPSC-based model that exhibits temporal patterning and a neuronal subtype ratio similar to that of the developing human neocortex. This model was used to examine the effects of cocaine during neocorticogenesis. Cocaine caused premature neuronal differentiation and enhanced neurogenesis of various cortical neuronal subtypes. These cocaine-induced changes were inhibited by the cytochrome P450 inhibitor cimetidine. This in vitro model enables mechanistic studies of neocorticogenesis, and can be used to examine the mechanisms through which cocaine alters the development of the human neocortex. PMID- 25288685 TI - A hands-on practical tutorial on performing meta-analysis with Stata. AB - Statistical synthesis of research findings via meta-analysis is widely used to assess the relative effectiveness of competing interventions. A series of three papers aimed at familiarising mental health scientists with the key statistical concepts and problems in meta-analysis was recently published in this journal. One paper focused on the selection and interpretation of the appropriate model to synthesise results (fixed effect or random effects model) whereas the other two papers focused on two major threats that compromise the validity of meta-analysis results, namely publication bias and missing outcome data. In this paper we provide guidance on how to undertake meta-analysis using Stata, one of the most commonly used software packages for meta-analysis. We address the three topics covered in the previous issues of the journal, focusing on their implementation in Stata using a working example from mental health research. PMID- 25288683 TI - The utility of Apc-mutant rats in modeling human colon cancer. AB - Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer. PMID- 25288686 TI - Study presents limited assessment of pharmacotherapy for alcohol use disorders. PMID- 25288684 TI - Novel ethyl methanesulfonate (EMS)-induced null alleles of the Drosophila homolog of LRRK2 reveal a crucial role in endolysosomal functions and autophagy in vivo. AB - Mutations in LRRK2 cause a dominantly inherited form of Parkinson's disease (PD) and are the most common known genetic determinant of PD. Inhibitor-based therapies targeting LRRK2 have emerged as a key therapeutic strategy in PD; thus, understanding the consequences of inhibiting the normal cellular functions of this protein is vital. Despite much interest, the physiological functions of LRRK2 remain unclear. Several recent studies have linked the toxicity caused by overexpression of pathogenic mutant forms of LRRK2 to defects in the endolysosomal and autophagy pathways, raising the question of whether endogenous LRRK2 might play a role in these processes. Here, we report the characterization of multiple novel ethyl methanesulfonate (EMS)-induced nonsense alleles in the Drosophila LRRK2 homolog, lrrk. Using these alleles, we show that lrrk loss-of function causes striking defects in the endolysosomal and autophagy pathways, including the accumulation of markedly enlarged lysosomes that are laden with undigested contents, consistent with a defect in lysosomal degradation. lrrk loss of-function also results in the accumulation of autophagosomes, as well as the presence of enlarged early endosomes laden with mono-ubiquitylated cargo proteins, suggesting an additional defect in lysosomal substrate delivery. Interestingly, the lysosomal abnormalities in these lrrk mutants can be suppressed by a constitutively active form of the small GTPase rab9, which promotes retromer-dependent recycling from late endosomes to the Golgi. Collectively, our data provides compelling evidence of a vital role for lrrk in lysosomal function and endolysosomal membrane transport in vivo, and suggests a link between lrrk and retromer-mediated endosomal recycling. PMID- 25288687 TI - The impact of obesity on the development and progression of rheumatoid arthritis. PMID- 25288688 TI - Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study. AB - OBJECTIVES: We evaluated clinical features, treatment practices and early outcome in a multicentre cohort of children with cerebral sinovenous thrombosis (CSVT). METHODS: Children with CSVT from 10 countries were enrolled from January 2003 to July 2007 in the International Paediatric Stroke Study. We analysed clinical symptoms, underlying conditions, antithrombotic treatment and neurological outcome at hospital discharge in 170 children. RESULTS: Of 170 children enrolled, 60% were male; median age 7.2 years (IQR 2.9-12.4). Headache, altered consciousness, focal deficits and seizures were common presenting clinical features. Infarction affected 37% and intracranial haemorrhage 31%. Risk factors included chronic disease in 50%; acute systemic illness or head/neck disorders 41%; prothrombotic state 20% and other haematological abnormality 19%. Discharge neurological status was normal in 48%, abnormal in 43% and unknown in 5%. Antithrombotic therapy was common, most often low molecular weight heparin was common, with significant regional variation in treatment practices. Mortality was low (4%) and was associated with no anticoagulation but not underlying chronic disease, anatomic extent of thrombosis or intracranial haemorrhage. Abnormal neurological status at discharge or death was associated with decreased level of consciousness at presentation and the presence of an identified prothrombotic state. CONCLUSIONS: Our study extends the observations of previously published smaller studies in children with CSVT that this is a morbid disease with diverse underlying causes and risk factors. Divergent treatment practices among highly specialised centres as well as limited data on treatment efficacy and safety suggest that further study of this condition is warranted. PMID- 25288689 TI - Just what do physicians do? Unexpected continuities from sixteenth-century Padua. PMID- 25288693 TI - Extensive expertise in endocrinology. Adrenal crisis. AB - Adrenal crisis is a life-threatening emergency contributing to the excess mortality of patients with adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5-10 adrenal crises/100 patient years and suggested a mortality rate from adrenal crisis of 0.5/100 patient years. Patients with adrenal crisis typically present with profoundly impaired well-being, hypotension, nausea and vomiting, and fever responding well to parenteral hydrocortisone administration. Infections are the major precipitating causes of adrenal crisis. Lack of increased cortisol concentrations during infection enhances pro-inflammatory cytokine release and sensitivity to the toxic effects of these cytokines (e.g. tumour necrosis factor alpha). Furthermore, pro-inflammatory cytokines may impair glucocorticoid receptor function aggravating glucocorticoid deficiency. Treatment of adrenal crisis is simple and highly effective consisting of i.v. hydrocortisone (initial bolus of 100 mg followed by 200 mg over 24 h as continuous infusion) and 0.9% saline (1000 ml within the first hour). Prevention of adrenal crisis requires appropriate hydrocortisone dose adjustments to stressful medical procedures (e.g. major surgery) and other stressful events (e.g. infection). Patient education is a key for such dose adjustments but current education concepts are not sufficiently effective. Thus, improved education strategies are needed. Every patient should carry an emergency card and should be provided with an emergency kit for parenteral hydrocortisone self-administration. A hydrocortisone pen would hold a great potential to lower the current barriers to hydrocortisone self injection. Improved patient education and measures to facilitate parenteral hydrocortisone self-administration in impending crisis are expected to significantly reduce morbidity and mortality from adrenal crisis. PMID- 25288694 TI - Unfolding humility. PMID- 25288696 TI - Clinical and ethical judgment: a profound dilemma. PMID- 25288697 TI - Comment: Autonomy vs beneficence. PMID- 25288698 TI - Memantine-induced myoclonus. PMID- 25288699 TI - Reforms in academic neurology: needs of a rapidly changing India. PMID- 25288700 TI - Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine. PMID- 25288701 TI - Pearls & Oy-sters: A cause of intractable vomiting. PMID- 25288702 TI - Pearls & Oy-sters: CSF analysis and the therapeutic paradox in tuberculous meningitis. PMID- 25288703 TI - Teaching NeuroImages: Ulnar neuropathy related to a contraceptive subdermal implant. PMID- 25288704 TI - Study examining fullerene toxicity raises questions as to the purity of the nanomaterials and erroneous experimental conclusions. PMID- 25288705 TI - Improving osteopathic medical training in providing health care to lesbian, gay, bisexual, and transgender patients. PMID- 25288706 TI - Gray zone: why a delayed acceptance of osteopathic medicine persists in the international community. PMID- 25288707 TI - Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-I. PMID- 25288708 TI - Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-II. PMID- 25288709 TI - Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-III. PMID- 25288710 TI - Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-IV. PMID- 25288711 TI - Response. PMID- 25288712 TI - Changes in rat spinal cord gene expression after inflammatory hyperalgesia of the joint and manual therapy. AB - CONTEXT: Mobilization of a joint affects local tissue directly but may also have other effects that are mediated through the central nervous system. OBJECTIVE: To identify differential gene expression in the spinal cords of rats with or without inflammatory joint injury after manual therapy or no treatment. METHODS: Rats were randomly assigned to 1 of 4 treatment groups: no injury and no touch (NI/NT), injury and no touch (I/NT), no injury and manual therapy (NI/MT), and injury and manual therapy (I/MT). We induced acute inflammatory joint injury in the rats by injecting carrageenan into an ankle. Rats in the no-injury groups did not receive carrageenan injection. One day after injury, rats received manual therapy to the knee of the injured limb. Rats in the no-touch groups were anesthetized without receiving manual therapy. Spinal cords were harvested 30 minutes after therapy or no touch, and spinal cord gene expression was analyzed by microarray for 3 comparisons: NI/NT vs I/NT, I/MT vs I/NT, and NI/NT vs NI/MT. RESULTS: Three rats were assigned to each group. Of 38,875 expressed sequence tags, 755 were differentially expressed in the NI/NT vs I/NT comparison. For the other comparisons, no expressed sequence tags were differentially expressed. Cluster analysis revealed that the differentially expressed sequence tags were over-represented in several categories, including ion homeostasis (enrichment score, 2.29), transmembrane (enrichment score, 1.55), and disulfide bond (enrichment score, 2.04). CONCLUSIONS: An inflammatory injury to the ankle of rats caused differential expression of genes in the spinal cord. Consistent with other studies, genes involved in ion transport were among those affected. However, manual therapy to the knees of injured limbs or to rats without injury did not alter gene expression in the spinal cord. Thus, evidence for central nervous system mediation of manual therapy was not observed. PMID- 25288713 TI - Deformations experienced in the human skin, adipose tissue, and fascia in osteopathic manipulative medicine. AB - CONTEXT: Osteopathic manipulative medicine techniques involve compressive and tangential forces to target the fascia. These forces are transmitted to the skin and adipose tissue before the fascia is encountered. Knowing the extent of deformation of these 2 tissue layers relative to the fascia will assist osteopathic physicians in evaluating techniques for manual therapies and adjusting these therapies to reduce patient discomfort and improve results. OBJECTIVE: To determine the magnitude of the forces transmitted to the skin, adipose tissue, and fascia, and to determine the magnitude of deformation produced in the skin and adipose tissue relative to the fascia using a mathematical model. METHODS: The large deformation theory of elasticity, valid for 3-dimensional deformations, was used to evaluate the forces that need to be applied such that a specified deformation is produced in any region of the skin, adipose tissue, or fascia layers. Similarly, if the forces are specified, then the deformation produced can be determined. RESULTS: The normal and tangential forces required to produce a deformation of 9% compression and 4% shear for the skin were 50 N and 11 N, respectively. Normal and tangential forces of about 100 N and 22 N were found for a similar deformation of fascia. For adipose tissue, these forces were 36 N and 8 N, respectively. In addition, the skin experienced more compression and shear-about 1.5 times as much as the fascia, and the adipose tissue experienced about 2.5 to 3.5 times the deformation of the fascia and 50% more than the skin when a given force was applied to the skin. CONCLUSION: The forces applied to the surface of the skin were transmitted through this layer and the adipose layer entirely to the fascia. Therefore, the skin and adipose tissue experienced the same magnitude of force as the fascia. However, the skin and adipose tissue experienced more compression and shear than the fascia. PMID- 25288714 TI - Acceptance of lesbian, gay, bisexual, and transgender patients, attitudes about their treatment, and related medical knowledge among osteopathic medical students. AB - CONTEXT: Limited research exists on the health issues faced by lesbian, gay, bisexual, and transgender (LGBT) patients, as viewed in the context of osteopathic medical education. A full understanding of current medical students' acceptance of, attitudes toward, and knowledge of these issues could lead to the development and incorporation of curricula focusing on the care of LGBT patients into colleges of osteopathic medicine (COMs). OBJECTIVE: To determine among osteopathic medical students the levels of acceptance of LGBT patients, attitudes toward treating this population, and medically relevant knowledge about their distinct health-related issues. METHODS: In August 2012, students at 6 COMs were sent an e-mail invitation that contained basic information about the study and a link providing access to an anonymous Web-based survey. Standard scales used in previous studies were compiled and individualized into 130 items for the purposes of the present study. RESULTS: Of the 4112 osteopathic medical students contacted, 1698 (41.3%) entered the survey and 1335 (32.5%) completed it. Two hundred respondents (15%) self-identified as having a sexual orientation on the lesbian, gay, or bisexual (LGB) spectrum. Although respondents generally had favorable levels of acceptance of LGBT patients and positive attitudes toward treatment of this population, self-identified LGB students had even greater acceptance of LGBT patients (P<.001) and more positive attitudes toward their treatment (P<.001). When medically relevant knowledge of issues related to the health of LGBT patients was assessed, 125 respondents (12.9%) obtained a passing score of 7 or higher, with LGB students scoring significantly higher than students whose self-identified sexual orientation was heterosexual only (P=.01). Differences in the levels of acceptance of (P=.008), treatment attitudes toward (P=.001), and relevant medical knowledge (P=.05) pertaining to LGBT patients were noted between respondents from the 6 COMs. CONCLUSION: The results suggest that even though osteopathic medical students had mostly positive personal attitudes and treatment attitudes toward LGBT patients, some disparities were still present. Also, students lacked adequate knowledge of the unique medical issues faced by the LGBT population. In the future, students should be given more training to effectively treat LGBT patients and their health-related issues. PMID- 25288715 TI - A call to include medical humanities in the curriculum of colleges of osteopathic medicine and in applicant selection. AB - Medicine stands at a crossroad. Disruptive physician behavior has increased, and patient satisfaction has decreased. A growing body of knowledge demonstrates that the medical humanities assist in the creation of compassionate, resilient physicians. Incorporating medical humanities into the medical school curriculum promotes the development of compassionate, culturally sensitive physicians, and also encourages the development of resilience in health care professionals at a time when internal and external pressures on physicians are increasing. PMID- 25288716 TI - Secondary pseudoainhum in a patient with Turner syndrome. AB - Secondary pseudoainhum is an autoamputation that develops in individuals aged approximately 20 to 50 years and is caused by diseases such as keratodermas, trauma, or congenital factors. The authors report a novel case of secondary pseudoainhum in a patient with Turner syndrome (45,X) who presented with bandlike constrictions in the toes bilaterally. To the authors' knowledge, secondary pseudoainhum has not been reported to be associated with Turner syndrome. However, physicians should be aware of this potentially deforming disease in patients with Turner syndrome. PMID- 25288717 TI - Hidradenitis suppurativa. PMID- 25288719 TI - Response to urine drug testing for oxycodone and its metabolites as a tool for drug-drug interactions. PMID- 25288720 TI - Sensitivity of an opiate immunoassay for detecting hydrocodone and hydromorphone in urine from a clinical population: analysis of subthreshold results. AB - Urine drug testing (UDT) is an emerging standard of care in the evaluation and treatment of chronic non-cancer pain patients with opioid analgesics. UDT may be used both to verify adherence with the opioid analgesic regimen and to monitor abstinence from non-prescribed or illicit controlled substances. In the former scenario, it is vital to determine whether the drug is present in the urine, even at low concentrations, because failure to detect the drug may lead to accusations of opioid abuse or diversion. Opiate immunoassays typically are developed to detect morphine and are most sensitive to morphine and codeine. Although many opiate immunoassays also detect hydrocodone (HC) and/or hydromorphone (HM), sensitivities for these analytes are often much lower, increasing the possibility of negative screening results when the drug is present in the urine. We selected 112 urine specimens from patients who had been prescribed HC or hydromorphone but were presumptive negative by the Roche Online DAT Opiate IITM urine drug screening assay, which is calibrated to 300 ng/mL morphine. Using a GC/MS confirmatory method with a detection limit of 50 ng/mL both for HC and for HM, one or both of these opiates were detected in 81 (72.3%) of the urine specimens. Examination of the raw data from these presumptive negative opiate screens revealed that, in many cases, the turbidity signal was greater than the signal obtained for the negative control, but less than the signal for the 300 ng/mL (morphine) threshold calibrator. A receiver operating characteristic curve generated for the reciprocal of the ratio of turbidity measurements in the patient specimens and negative (drug-free) controls, against the presence or absence of HC and/or HM by confirmatory analyses, produced an area under the curve of 0.910. We conclude that this opiate immunoassay has sufficient sensitivity to detect HC and/or HM in some urine specimens that screen presumptive negative for these commonly prescribed opiates at the established threshold. PMID- 25288721 TI - Urine drug testing for oxycodone and its metabolites as a tool for drug-drug interactions? PMID- 25288722 TI - Hopping and the Stokes-Einstein relation breakdown in simple glass formers. AB - One of the most actively debated issues in the study of the glass transition is whether a mean-field description is a reasonable starting point for understanding experimental glass formers. Although the mean-field theory of the glass transition--like that of other statistical systems--is exact when the spatial dimension d -> infinity, the evolution of systems properties with d may not be smooth. Finite-dimensional effects could dramatically change what happens in physical dimensions,d = 2, 3. For standard phase transitions finite-dimensional effects are typically captured by renormalization group methods, but for glasses the corrections are much more subtle and only partially understood. Here, we investigate hopping between localized cages formed by neighboring particles in a model that allows to cleanly isolate that effect. By bringing together results from replica theory, cavity reconstruction, void percolation, and molecular dynamics, we obtain insights into how hopping induces a breakdown of the Stokes Einstein relation and modifies the mean-field scenario in experimental systems. Although hopping is found to supersede the dynamical glass transition, it nonetheless leaves a sizable part of the critical regime untouched. By providing a constructive framework for identifying and quantifying the role of hopping, we thus take an important step toward describing dynamic facilitation in the framework of the mean-field theory of glasses. PMID- 25288723 TI - Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. AB - Inherited predisposition to breast cancer is known to be caused by loss-of function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26 2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC. PMID- 25288724 TI - Intrinsic disorder as a generalizable strategy for the rational design of highly responsive, allosterically cooperative receptors. AB - Control over the sensitivity with which biomolecular receptors respond to small changes in the concentration of their target ligand is critical for the proper function of many cellular processes. Such control could likewise be of utility in artificial biotechnologies, such as biosensors, genetic logic gates, and "smart" materials, in which highly responsive behavior is of value. In nature, the control of molecular responsiveness is often achieved using "Hill-type" cooperativity, a mechanism in which sequential binding events on a multivalent receptor are coupled such that the first enhances the affinity of the next, producing a steep, higher-order dependence on target concentration. Here, we use an intrinsic-disorder-based mechanism that can be implemented without requiring detailed structural knowledge to rationally introduce this potentially useful property into several normally noncooperative biomolecules. To do so, we fabricate a tandem repeat of the receptor that is destabilized (unfolded) via the introduction of a long, unstructured loop. The first binding event requires the energetically unfavorable closing of this loop, reducing its affinity relative to that of the second binding event, which, in contrast occurs at a preformed site. Using this approach, we have rationally introduced cooperativity into three unrelated DNA aptamers, achieving in the best of these a Hill coefficient experimentally indistinguishable from the theoretically expected maximum. The extent of cooperativity and thus the steepness of the binding transition are, moreover, well modeled as simple functions of the energetic cost of binding induced folding, speaking to the quantitative nature of this design strategy. PMID- 25288725 TI - Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress. AB - Plant cells have developed specific protective molecular machinery against environmental stresses. The family of CBL-interacting protein kinases (CIPK) and their interacting activators, the calcium sensors calcineurin B-like (CBLs), work together to decode calcium signals elicited by stress situations. The molecular basis of biological activation of CIPKs relies on the calcium-dependent interaction of a self-inhibitory NAF motif with a particular CBL, the phosphorylation of the activation loop by upstream kinases, and the subsequent phosphorylation of the CBL by the CIPK. We present the crystal structures of the NAF-truncated and pseudophosphorylated kinase domains of CIPK23 and CIPK24/SOS2. In addition, we provide biochemical data showing that although CIPK23 is intrinsically inactive and requires an external stimulation, CIPK24/SOS2 displays basal activity. This data correlates well with the observed conformation of the respective activation loops: Although the loop of CIPK23 is folded into a well ordered structure that blocks the active site access to substrates, the loop of CIPK24/SOS2 protrudes out of the active site and allows catalysis. These structures together with biochemical and biophysical data show that CIPK kinase activity necessarily requires the coordinated releases of the activation loop from the active site and of the NAF motif from the nucleotide-binding site. Taken all together, we postulate the basis for a conserved calcium-dependent NAF mediated regulation of CIPKs and a variable regulation by upstream kinases. PMID- 25288726 TI - Single-molecule packaging initiation in real time by a viral DNA packaging machine from bacteriophage T4. AB - Viral DNA packaging motors are among the most powerful molecular motors known. A variety of structural, biochemical, and single-molecule biophysical approaches have been used to understand their mechanochemistry. However, packaging initiation has been difficult to analyze because of its transient and highly dynamic nature. Here, we developed a single-molecule fluorescence assay that allowed visualization of packaging initiation and reinitiation in real time and quantification of motor assembly and initiation kinetics. We observed that a single bacteriophage T4 packaging machine can package multiple DNA molecules in bursts of activity separated by long pauses, suggesting that it switches between active and quiescent states. Multiple initiation pathways were discovered including, unexpectedly, direct DNA binding to the capsid portal followed by recruitment of motor subunits. Rapid succession of ATP hydrolysis was essential for efficient initiation. These observations have implications for the evolution of icosahedral viruses and regulation of virus assembly. PMID- 25288727 TI - Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers. AB - Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses. PMID- 25288728 TI - The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. AB - Because educational achievement at the end of compulsory schooling represents a major tipping point in life, understanding its causes and correlates is important for individual children, their families, and society. Here we identify the general ingredients of educational achievement using a multivariate design that goes beyond intelligence to consider a wide range of predictors, such as self efficacy, personality, and behavior problems, to assess their independent and joint contributions to educational achievement. We use a genetically sensitive design to address the question of why educational achievement is so highly heritable. We focus on the results of a United Kingdom-wide examination, the General Certificate of Secondary Education (GCSE), which is administered at the end of compulsory education at age 16. GCSE scores were obtained for 13,306 twins at age 16, whom we also assessed contemporaneously on 83 scales that were condensed to nine broad psychological domains, including intelligence, self efficacy, personality, well-being, and behavior problems. The mean of GCSE core subjects (English, mathematics, science) is more heritable (62%) than the nine predictor domains (35-58%). Each of the domains correlates significantly with GCSE results, and these correlations are largely mediated genetically. The main finding is that, although intelligence accounts for more of the heritability of GCSE than any other single domain, the other domains collectively account for about as much GCSE heritability as intelligence. Together with intelligence, these domains account for 75% of the heritability of GCSE. We conclude that the high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. PMID- 25288729 TI - Cross-modal effects of value on perceptual acuity and stimulus encoding. AB - Cross-modal interactions are very common in perception. An important feature of many perceptual stimuli is their reward-predicting properties, the utilization of which is essential for adaptive behavior. What is unknown is whether reward associations in one sensory modality influence perception of stimuli in another modality. Here we show that auditory stimuli with high-reward associations increase the sensitivity of visual perception, even when sounds and reward associations are both irrelevant for the visual task. This increased sensitivity correlates with a change in stimulus representation in the visual cortex, indexed by increased multivariate decoding accuracy in simultaneously acquired functional MRI data. Univariate analysis showed that reward associations modulated responses in regions associated with multisensory processing in which the strength of modulation was a better predictor of the magnitude of the behavioral effect than the modulation in classical reward regions. Our findings demonstrate a value driven cross-modal interaction that affects perception and stimulus encoding, with a resemblance to well-described modulatory effects of attention. We suggest that multisensory processing areas may mediate the transfer of value signals across senses. PMID- 25288730 TI - Bioinspired micrograting arrays mimicking the reverse color diffraction elements evolved by the butterfly Pierella luna. AB - Recently, diffraction elements that reverse the color sequence normally observed in planar diffraction gratings have been found in the wing scales of the butterfly Pierella luna. Here, we describe the creation of an artificial photonic material mimicking this reverse color-order diffraction effect. The bioinspired system consists of ordered arrays of vertically oriented microdiffraction gratings. We present a detailed analysis and modeling of the coupling of diffraction resulting from individual structural components and demonstrate its strong dependence on the orientation of the individual miniature gratings. This photonic material could provide a basis for novel developments in biosensing, anticounterfeiting, and efficient light management in photovoltaic systems and light-emitting diodes. PMID- 25288731 TI - Role of Erbin in ErbB2-dependent breast tumor growth. AB - ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression. PMID- 25288732 TI - Estrogen-related receptor alpha decreases RHOA stability to induce orientated cell migration. AB - Several physiopathological processes require orientated cellular migration. This phenomenon highly depends on members of the RHO family of GTPases. Both excessive and deficient RHO activity impair directional migration. A tight control is thus exerted on these proteins through the regulation of their activation and of their stability. Here we show that the estrogen-related receptor alpha (ERRalpha) directly activates the expression of TNFAIP1, the product of which [BTB/POZ domain-containing adapter for Cullin3-mediated RhoA degradation 2 (BACURD2)] regulates RHOA protein turnover. Inactivation of the receptor leads to enhanced RHOA stability and activation. This results in cell disorientation, increased actin network, and inability to form a lamellipodium at the migration edge. As a consequence, directional migration, but not cell motility per se, is impaired in the absence of the receptor, under pathological as well as physiological conditions. Altogether, our results show that the control exerted by ERRalpha on RHOA stability is required for directional migration. PMID- 25288733 TI - Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly identified betacoronavirus causing high morbidity and mortality in humans. The coronavirus spike (S) protein is the main determinant of viral entry, and although it was previously shown that MERS-CoV S can be activated by various proteases, the details of the mechanisms of proteolytic activation of fusion are still incompletely characterized. Here, we have uncovered distinctive characteristics of MERS-CoV S. We identify, by bioinformatics and peptide cleavage assays, two cleavage sites for furin, a ubiquitously expressed protease, which are located at the S1/S2 interface and at the S2' position of the S protein. We show that although the S1/S2 site is proteolytically processed by furin during protein biosynthesis, the S2' site is cleaved upon viral entry. MERS-CoV pseudovirion infection was shown to be enhanced by elevated levels of furin expression, and entry could be decreased by furin siRNA silencing. Enhanced furin activity appeared to partially override the low pH-dependent nature of MERS-CoV entry. Inhibition of furin activity was shown to decrease MERS-CoV S-mediated entry, as well as infection by the virus. Overall, we show that MERS-CoV has evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population. The ability of MERS-CoV to use furin in this manner, along with other proteases, may explain the polytropic nature of the virus. PMID- 25288734 TI - Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. AB - Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS. PMID- 25288736 TI - Fluid-induced organic synthesis in the solar nebula recorded in extraterrestrial dust from meteorites. AB - Isotopically anomalous carbonaceous grains in extraterrestrial samples represent the most pristine organics that were delivered to the early Earth. Here we report on gentle aberration-corrected scanning transmission electron microscopy investigations of eight (15)N-rich or D-rich organic grains within two carbonaceous Renazzo-type (CR) chondrites and two interplanetary dust particles (IDPs) originating from comets. Organic matter in the IDP samples is less aromatic than that in the CR chondrites, and its functional group chemistry is mainly characterized by C-O bonding and aliphatic C. Organic grains in CR chondrites are associated with carbonates and elemental Ca, which originate either from aqueous fluids or possibly an indigenous organic source. One distinct grain from the CR chondrite NWA 852 exhibits a rim structure only visible in chemical maps. The outer part is nanoglobular in shape, highly aromatic, and enriched in anomalous nitrogen. Functional group chemistry of the inner part is similar to spectra from IDP organic grains and less aromatic with nitrogen below the detection limit. The boundary between these two areas is very sharp. The direct association of both IDP-like organic matter with dominant C-O bonding environments and nanoglobular organics with dominant aromatic and C-N functionality within one unique grain provides for the first time to our knowledge strong evidence for organic synthesis in the early solar system activated by an anomalous nitrogen-containing parent body fluid. PMID- 25288735 TI - Quantitation of interactions between two DNA loops demonstrates loop domain insulation in E. coli cells. AB - Eukaryotic gene regulation involves complex patterns of long-range DNA-looping interactions between enhancers and promoters, but how these specific interactions are achieved is poorly understood. Models that posit other DNA loops--that aid or inhibit enhancer-promoter contact--are difficult to test or quantitate rigorously in eukaryotic cells. Here, we use the well-characterized DNA-looping proteins Lac repressor and phage lambda CI to measure interactions between pairs of long DNA loops in E. coli cells in the three possible topological arrangements. We find that side-by-side loops do not affect each other. Nested loops assist each other's formation consistent with their distance-shortening effect. In contrast, alternating loops, where one looping element is placed within the other DNA loop, inhibit each other's formation, thus providing clear support for the loop domain model for insulation. Modeling shows that combining loop assistance and loop interference can provide strong specificity in long-range interactions. PMID- 25288737 TI - Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion. AB - Axon branching is remodeled by sensory-evoked and spontaneous neuronal activity. However, the underlying molecular mechanism is largely unknown. Here, we demonstrate that the netrin family member netrin-4 (NTN4) contributes to activity dependent thalamocortical (TC) axon branching. In the postnatal developmental stages of rodents, ntn4 expression was abundant in and around the TC recipient layers of sensory cortices. Neuronal activity dramatically altered the ntn4 expression level in the cortex in vitro and in vivo. TC axon branching was promoted by exogenous NTN4 and suppressed by depletion of the endogenous protein. Moreover, unc-5 homolog B (Unc5B), which strongly bound to NTN4, was expressed in the sensory thalamus, and knockdown of Unc5B in thalamic cells markedly reduced TC axon branching. These results suggest that NTN4 acts as a positive regulator for TC axon branching through activity-dependent expression. PMID- 25288738 TI - Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. AB - Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions- phenotypically and genetically--although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases. PMID- 25288740 TI - Public awareness, concerns, and priorities about anthropogenic impacts on marine environments. AB - Numerous international bodies have advocated the development of strategies to achieve the sustainability of marine environments. Typically, such strategies are based on information from expert groups about causes of degradation and policy options to address them, but these strategies rarely take into account assessed information about public awareness, concerns, and priorities. Here we report the results of a pan-European survey of public perceptions about marine environmental impacts as a way to inform the formation of science and policy priorities. On the basis of 10,106 responses to an online survey from people in 10 European nations, spanning a diversity of socioeconomic and geographical areas, we examine the public's informedness and concern regarding marine impacts, trust in different information sources, and priorities for policy and funding. Results show that the level of concern regarding marine impacts is closely associated with the level of informedness and that pollution and overfishing are two areas prioritized by the public for policy development. The level of trust varies greatly among different information sources and is highest for academics and scholarly publications but lower for government or industry scientists. Results suggest that the public perceives the immediacy of marine anthropogenic impacts and is highly concerned about ocean pollution, overfishing, and ocean acidification. Eliciting public awareness, concerns, and priorities can enable scientists and funders to understand how the public relates to marine environments, frame impacts, and align managerial and policy priorities with public demand. PMID- 25288739 TI - Role for LSM genes in the regulation of circadian rhythms. AB - Growing evidence suggests that core spliceosomal components differentially affect RNA processing of specific genes; however, whether changes in the levels or activities of these factors control specific signaling pathways is largely unknown. Here we show that some SM-like (LSM) genes, which encode core components of the spliceosomal U6 small nuclear ribonucleoprotein complex, regulate circadian rhythms in plants and mammals. We found that the circadian clock regulates the expression of LSM5 in Arabidopsis plants and several LSM genes in mouse suprachiasmatic nucleus. Further, mutations in LSM5 or LSM4 in Arabidopsis, or down-regulation of LSM3, LSM5, or LSM7 expression in human cells, lengthens the circadian period. Although we identified changes in the expression and alternative splicing of some core clock genes in Arabidopsis lsm5 mutants, the precise molecular mechanism causing period lengthening remains to be identified. Genome-wide expression analysis of either a weak lsm5 or a strong lsm4 mutant allele in Arabidopsis revealed larger effects on alternative splicing than on constitutive splicing. Remarkably, large splicing defects were not observed in most of the introns evaluated using RNA-seq in the strong lsm4 mutant allele used in this study. These findings support the idea that some LSM genes play both regulatory and constitutive roles in RNA processing, contributing to the fine tuning of specific signaling pathways. PMID- 25288741 TI - Integrated life-cycle assessment of electricity-supply scenarios confirms global environmental benefit of low-carbon technologies. AB - Decarbonization of electricity generation can support climate-change mitigation and presents an opportunity to address pollution resulting from fossil-fuel combustion. Generally, renewable technologies require higher initial investments in infrastructure than fossil-based power systems. To assess the tradeoffs of increased up-front emissions and reduced operational emissions, we present, to our knowledge, the first global, integrated life-cycle assessment (LCA) of long term, wide-scale implementation of electricity generation from renewable sources (i.e., photovoltaic and solar thermal, wind, and hydropower) and of carbon dioxide capture and storage for fossil power generation. We compare emissions causing particulate matter exposure, freshwater ecotoxicity, freshwater eutrophication, and climate change for the climate-change-mitigation (BLUE Map) and business-as-usual (Baseline) scenarios of the International Energy Agency up to 2050. We use a vintage stock model to conduct an LCA of newly installed capacity year-by-year for each region, thus accounting for changes in the energy mix used to manufacture future power plants. Under the Baseline scenario, emissions of air and water pollutants more than double whereas the low-carbon technologies introduced in the BLUE Map scenario allow a doubling of electricity supply while stabilizing or even reducing pollution. Material requirements per unit generation for low-carbon technologies can be higher than for conventional fossil generation: 11-40 times more copper for photovoltaic systems and 6-14 times more iron for wind power plants. However, only two years of current global copper and one year of iron production will suffice to build a low-carbon energy system capable of supplying the world's electricity needs in 2050. PMID- 25288742 TI - PGC-1beta promotes enterocyte lifespan and tumorigenesis in the intestine. AB - The mucosa of the small intestine is renewed completely every 3-5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1beta gain and loss of function in the gut, we generated both intestinal-specific PGC 1beta transgenic and PGC-1beta knockout mice. Mice overexpressing PGC-1beta present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1beta knockout mice are protected from carcinogenesis. We show that PGC-1beta triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1beta in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production. PMID- 25288743 TI - Enhancement of anammox by the excretion of diel vertical migrators. AB - Measurements show that anaerobic ammonium oxidation with nitrite (anammox) is a major pathway of fixed nitrogen removal in the anoxic zones of the open ocean. Anammox requires a source of ammonium, which under anoxic conditions could be supplied by the breakdown of sinking organic matter via heterotrophic denitrification. However, at many locations where anammox is measured, denitrification rates are small or undetectable. Alternative sources of ammonium have been proposed to explain this paradox, for example through dissimilatory reduction of nitrate to ammonium and transport from anoxic sediments. However, the relevance of these sources in open-ocean anoxic zones is debated. Here, we bring to attention an additional source of ammonium, namely, the daytime excretion by zooplankton and micronekton migrating from the surface to anoxic waters. We use a synthesis of acoustic data to show that, where anoxic waters occur within the water column, most migrators spend the daytime within them. Although migrators export only a small fraction of primary production from the surface, they focus excretion within a confined depth range of anoxic water where particle input is small. Using a simple biogeochemical model, we suggest that, at those depths, the source of ammonium from organisms undergoing diel vertical migrations could exceed the release from particle remineralization, enhancing in situ anammox rates. The contribution of this previously overlooked process, and the numerous uncertainties surrounding it, call for further efforts to evaluate the role of animals in oxygen minimum zone biogeochemistry. PMID- 25288744 TI - Ultraefficient homogeneous catalyst for the CO2-to-CO electrochemical conversion. AB - A very efficient electrogenerated Fe(0) porphyrin catalyst was obtained by substituting in tetraphenylporphyrin two of the opposite phenyl rings by ortho-, ortho'-phenol groups while the other two are perfluorinated. It proves to be an excellent catalyst of the CO2-to-CO conversion as to selectivity (the CO faradaic yield is nearly quantitative), overpotential, and turnover frequency. Benchmarking with other catalysts, through catalytic Tafel plots, shows that it is the most efficient, to the best of our knowledge, homogeneous molecular catalyst of the CO2-to-CO conversion at present. Comparison with another Fe(0) tetraphenylporphyrin bearing eight ortho-, ortho'-phenol functionalities launches a general strategy where changes in substituents will be designed so as to optimize the operational combination of all catalyst elements of merit. PMID- 25288745 TI - Human TLR10 is an anti-inflammatory pattern-recognition receptor. AB - Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1beta, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 +/- 106 pg/mL IL-1beta (mean +/- SEM) in comparison with 1,043 +/- 51 pg/mL IL-1beta after addition of nonspecific IgG antibodies. Several mechanisms mediate the modulatory effects of TLR10: on the one hand, cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2; on the other hand, cross-linking experiments showed specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra, 16 +/- 1.7 ng/mL, mean +/- SEM). After cross-linking anti-TLR10 antibody, no production of IL-1beta and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1beta, TNF-alpha, and IL-6 upon ligation of TLR2, in a gene-dose-dependent manner. The modulatory effects of TLR10 are complex, involving at least several mechanisms: there is competition for ligands or for the formation of heterodimer receptors with TLR2, as well as PI3K/Akt-mediated induction of the anti-inflammatory cytokine IL-1Ra. Finally, transgenic mice expressing human TLR10 produced fewer cytokines when challenged with a TLR2 agonist. In conclusion, to our knowledge we demonstrate for the first time that TLR10 is a modulatory pattern-recognition receptor with mainly inhibitory properties. PMID- 25288746 TI - A receptor-like protein mediates the response to pectin modification by activating brassinosteroid signaling. AB - The brassinosteroid (BR) signaling module is a central regulator of plant morphogenesis, as indicated by the large number of BR-responsive cell wall related genes and the severe growth defects of BR mutants. Despite a detailed knowledge of the signaling components, the logic of this auto-/paracrine signaling module in growth control remains poorly understood. Recently, extensive cross-talk with other signaling pathways has been shown, suggesting that the outputs of BR signaling, such as gene-expression changes, are subject to complex control mechanisms. We previously provided evidence for a role of BR signaling in a feedback loop controlling the integrity of the cell wall. Here, we identify the first dedicated component of this feedback loop: a receptor-like protein (RLP44), which is essential for the compensatory triggering of BR signaling upon inhibition of pectin de-methylesterification in the cell wall. RLP44 is required for normal growth and stress responses and connects with the BR signaling pathway, presumably through a direct interaction with the regulatory receptor like kinase BAK1. These findings corroborate a role for BR in controlling the sensitivity of a feedback signaling module involved in maintaining the physico chemical homeostasis of the cell wall during cell expansion. PMID- 25288747 TI - KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. AB - An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells. PMID- 25288748 TI - Allopolyploidy, diversification, and the Miocene grassland expansion. AB - The role of polyploidy, particularly allopolyploidy, in plant diversification is a subject of debate. Whole-genome duplications precede the origins of many major clades (e.g., angiosperms, Brassicaceae, Poaceae), suggesting that polyploidy drives diversification. However, theoretical arguments and empirical studies suggest that polyploid lineages may actually have lower speciation rates and higher extinction rates than diploid lineages. We focus here on the grass tribe Andropogoneae, an economically and ecologically important group of C4 species with a high frequency of polyploids. A phylogeny was constructed for ca. 10% of the species of the clade, based on sequences of four concatenated low-copy nuclear loci. Genetic allopolyploidy was documented using the characteristic pattern of double-labeled gene trees. At least 32% of the species sampled are the result of genetic allopolyploidy and result from 28 distinct tetraploidy events plus an additional six hexaploidy events. This number is a minimum, and the actual frequency could be considerably higher. The parental genomes of most Andropogoneae polyploids diverged in the Late Miocene coincident with the expansion of the major C4 grasslands that dominate the earth today. The well documented whole-genome duplication in Zea mays ssp. mays occurred after the divergence of Zea and Sorghum. We find no evidence that polyploidization is followed by an increase in net diversification rate; nonetheless, allopolyploidy itself is a major mode of speciation. PMID- 25288749 TI - Visualization and quantification of nascent RAD51 filament formation at single monomer resolution. AB - During recombinational repair of double-stranded DNA breaks, RAD51 recombinase assembles as a nucleoprotein filament around single-stranded DNA to form a catalytically proficient structure able to promote homology recognition and strand exchange. Mediators and accessory factors guide the action and control the dynamics of RAD51 filaments. Elucidation of these control mechanisms necessitates development of approaches to quantitatively probe transient aspects of RAD51 filament dynamics. Here, we combine fluorescence microscopy, optical tweezers, and microfluidics to visualize the assembly of RAD51 filaments on bare single stranded DNA and quantify the process with single-monomer sensitivity. We show that filaments are seeded from RAD51 nuclei that are heterogeneous in size. This heterogeneity appears to arise from the energetic balance between RAD51 self assembly in solution and the size-dependent interaction time of the nuclei with DNA. We show that nucleation intrinsically is substrate selective, strongly favoring filament formation on bare single-stranded DNA. Furthermore, we devised a single-molecule fluorescence recovery after photobleaching assay to independently observe filament nucleation and growth, permitting direct measurement of their contributions to filament formation. Our findings yield a comprehensive, quantitative understanding of RAD51 filament formation on bare single-stranded DNA that will serve as a basis to elucidate how mediators help RAD51 filament assembly and accessory factors control filament dynamics. PMID- 25288750 TI - Structural studies on the authentic mumps virus nucleocapsid showing uncoiling by the phosphoprotein. AB - Mumps virus (MuV) is a highly contagious pathogen, and despite extensive vaccination campaigns, outbreaks continue to occur worldwide. The virus has a negative-sense, single-stranded RNA genome that is encapsidated by the nucleocapsid protein (N) to form the nucleocapsid (NC). NC serves as the template for both transcription and replication. In this paper we solved an 18-A resolution structure of the authentic MuV NC using cryo-electron microscopy. We also observed the effects of phosphoprotein (P) binding on the MuV NC structure. The N-terminal domain of P (PNTD) has been shown to bind NC and appeared to induce uncoiling of the helical NC. Additionally, we solved a 25-A-resolution structure of the authentic MuV NC bound with the C-terminal domain of P (PCTD). The location of the encapsidated viral genomic RNA was defined by modeling crystal structures of homologous negative strand RNA virus Ns in NC. Both the N terminal and C-terminal domains of MuV P bind NC to participate in access to the genomic RNA by the viral RNA-dependent-RNA polymerase. These results provide critical insights on the structure-function of the MuV NC and the structural alterations that occur through its interactions with P. PMID- 25288751 TI - Part-crystalline part-liquid state and rattling-like thermal damping in materials with chemical-bond hierarchy. AB - Understanding thermal and phonon transport in solids has been of great importance in many disciplines such as thermoelectric materials, which usually requires an extremely low lattice thermal conductivity (LTC). By analyzing the finite temperature structural and vibrational characteristics of typical thermoelectric compounds such as filled skutterudites and Cu3SbSe3, we demonstrate a concept of part-crystalline part-liquid state in the compounds with chemical-bond hierarchy, in which certain constituent species weakly bond to other part of the crystal. Such a material could intrinsically manifest the coexistence of rigid crystalline sublattices and other fluctuating noncrystalline sublattices with thermally induced large-amplitude vibrations and even flow of the group of species atoms, leading to atomic-level heterogeneity, mixed part-crystalline part-liquid structure, and thus rattling-like thermal damping due to the collective soft-mode vibrations similar to the Boson peak in amorphous materials. The observed abnormal LTC close to the amorphous limit in these materials can only be described by an effective approach that approximately treats the rattling-like damping as a "resonant" phonon scattering. PMID- 25288752 TI - Following movement of domain IV of elongation factor G during ribosomal translocation. AB - Translocation of mRNA and tRNAs through the ribosome is catalyzed by a universally conserved elongation factor (EF-G in prokaryotes and EF-2 in eukaryotes). Previous studies have suggested that ribosome-bound EF-G undergoes significant structural rearrangements. Here, we follow the movement of domain IV of EF-G, which is critical for the catalysis of translocation, relative to protein S12 of the small ribosomal subunit using single-molecule FRET. We show that ribosome-bound EF-G adopts distinct conformations corresponding to the pre- and posttranslocation states of the ribosome. Our results suggest that, upon ribosomal translocation, domain IV of EF-G moves toward the A site of the small ribosomal subunit and facilitates the movement of peptidyl-tRNA from the A to the P site. We found no evidence of direct coupling between the observed movement of domain IV of EF-G and GTP hydrolysis. In addition, our results suggest that the pretranslocation conformation of the EF-G-ribosome complex is significantly less stable than the posttranslocation conformation. Hence, the structural rearrangement of EF-G makes a considerable energetic contribution to promoting tRNA translocation. PMID- 25288753 TI - Cold and hunger induce diurnality in a nocturnal mammal. AB - The mammalian circadian system synchronizes daily timing of activity and rest with the environmental light-dark cycle. Although the underlying molecular oscillatory mechanism is well studied, factors that influence phenotypic plasticity in daily activity patterns (temporal niche switching, chronotype) are presently unknown. Molecular evidence suggests that metabolism may influence the circadian molecular clock, but evidence at the level of the organism is lacking. Here we show that a metabolic challenge by cold and hunger induces diurnality in otherwise nocturnal mice. Lowering ambient temperature changes the phase of circadian light-dark entrainment in mice by increasing daytime and decreasing nighttime activity. This effect is further enhanced by simulated food shortage, which identifies metabolic balance as the underlying common factor influencing circadian organization. Clock gene expression analysis shows that the underlying neuronal mechanism is downstream from or parallel to the main circadian pacemaker (the hypothalamic suprachiasmatic nucleus) and that the behavioral phenotype is accompanied by phase adjustment of peripheral tissues. These findings indicate that nocturnal mammals can display considerable plasticity in circadian organization and may adopt a diurnal phenotype when energetically challenged. Our previously defined circadian thermoenergetics hypothesis proposes that such circadian plasticity, which naturally occurs in nocturnal mammals, reflects adaptive maintenance of energy balance. Quantification of energy expenditure shows that diurnality under natural conditions reduces thermoregulatory costs in small burrowing mammals like mice. Metabolic feedback on circadian organization thus provides functional benefits by reducing energy expenditure. Our findings may help to clarify relationships between sleep-wake patterns and metabolic phenotypes in humans. PMID- 25288755 TI - Impact of heterogeneity and socioeconomic factors on individual behavior in decentralized sharing ecosystems. AB - Tens of millions of individuals around the world use decentralized content distribution systems, a fact of growing social, economic, and technological importance. These sharing systems are poorly understood because, unlike in other technosocial systems, it is difficult to gather large-scale data about user behavior. Here, we investigate user activity patterns and the socioeconomic factors that could explain the behavior. Our analysis reveals that (i) the ecosystem is heterogeneous at several levels: content types are heterogeneous, users specialize in a few content types, and countries are heterogeneous in user profiles; and (ii) there is a strong correlation between socioeconomic indicators of a country and users behavior. Our findings open a research area on the dynamics of decentralized sharing ecosystems and the socioeconomic factors affecting them, and may have implications for the design of algorithms and for policymaking. PMID- 25288754 TI - Nitrate foraging by Arabidopsis roots is mediated by the transcription factor TCP20 through the systemic signaling pathway. AB - To compete for nutrients in diverse soil microenvironments, plants proliferate lateral roots preferentially in nutrient-rich zones. For nitrate, root foraging involves local and systemic signaling; however, little is known about the genes that function in the systemic signaling pathway. By using nitrate enhancer DNA to screen a library of Arabidopsis transcription factors in the yeast one-hybrid system, the transcription factor gene TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1-20 (TCP20) was identified. TCP20, which belongs to an ancient, plant specific gene family that regulates shoot, flower, and embryo development, was implicated in nitrate signaling by its ability to bind DNA in more than 100 nitrate-regulated genes. Analysis of insertion mutants of TCP20 showed that they had normal primary and lateral root growth on homogenous nitrate media but were impaired in preferential lateral root growth (root foraging) on heterogeneous media in split-root plates. Inhibition of preferential lateral root growth was still evident in the mutants even when ammonium was uniformly present in the media, indicating that the TCP20 response was to nitrate. Comparison of tcp20 mutants with those of nlp7 mutants, which are defective in local control of root growth but not in the root-foraging response, indicated that TCP20 function is independent of and distinct from NLP7 function. Further analysis showed that tcp20 mutants lack systemic control of root growth regardless of the local nitrate concentrations. These results indicate that TCP20 plays a key role in the systemic signaling pathway that directs nitrate foraging by Arabidopsis roots. PMID- 25288756 TI - Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway. AB - The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/p21 Cdk interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N- and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras independent mechanism. PMID- 25288757 TI - Label-free electrochemical detection of human methyltransferase from tumors. AB - The role of abnormal DNA methyltransferase activity in the development and progression of cancer is an essential and rapidly growing area of research, both for improved diagnosis and treatment. However, current technologies for the assessment of methyltransferase activity, particularly from crude tumor samples, limit this work because they rely on radioactivity or fluorescence and require bulky instrumentation. Here, we report an electrochemical platform that overcomes these limitations for the label-free detection of human DNA(cytosine-5) methyltransferase1 (DNMT1) methyltransferase activity, enabling measurements from crude cultured colorectal cancer cell lysates (HCT116) and biopsied tumor tissues. Our multiplexed detection system involving patterning and detection from a secondary electrode array combines low-density DNA monolayer patterning and electrocatalytically amplified DNA charge transport chemistry to measure selectively and sensitively DNMT1 activity within these complex and congested cellular samples. Based on differences in DNMT1 activity measured with this assay, we distinguish colorectal tumor tissue from healthy adjacent tissue, illustrating the effectiveness of this two-electrode platform for clinical applications. PMID- 25288758 TI - The negligible chondritic contribution in the lunar soils water. AB - Recent data from Apollo samples demonstrate the presence of water in the lunar interior and at the surface, challenging previous assumption that the Moon was free of water. However, the source(s) of this water remains enigmatic. The external flux of particles and solid materials that reach the surface of the airless Moon constitute a hydrogen (H) surface reservoir that can be converted to water (or OH) during proton implantation in rocks or remobilization during magmatic events. Our original goal was thus to quantify the relative contributions to this H surface reservoir. To this end, we report NanoSIMS measurements of D/H and (7)Li/(6)Li ratios on agglutinates, volcanic glasses, and plagioclase grains from the Apollo sample collection. Clear correlations emerge between cosmogenic D and (6)Li revealing that almost all D is produced by spallation reactions both on the surface and in the interior of the grains. In grain interiors, no evidence of chondritic water has been found. This observation allows us to constrain the H isotopic ratio of hypothetical juvenile lunar water to deltaD <= -5500/00. On the grain surface, the hydroxyl concentrations are significant and the D/H ratios indicate that they originate from solar wind implantation. The scattering distribution of the data around the theoretical D vs. (6)Li spallation correlation is compatible with a chondritic contribution <15%. In conclusion, (i) solar wind implantation is the major mechanism responsible for hydroxyls on the lunar surface, and (ii) the postulated chondritic lunar water is not retained in the regolith. PMID- 25288759 TI - Bloom of resident antibiotic-resistant bacteria in soil following manure fertilization. AB - The increasing prevalence of antibiotic-resistant bacteria is a global threat to public health. Agricultural use of antibiotics is believed to contribute to the spread of antibiotic resistance, but the mechanisms by which many agricultural practices influence resistance remain obscure. Although manure from dairy farms is a common soil amendment in crop production, its impact on the soil microbiome and resistome is not known. To gain insight into this impact, we cultured bacteria from soil before and at 10 time points after application of manure from cows that had not received antibiotic treatment. Soil treated with manure contained a higher abundance of beta-lactam-resistant bacteria than soil treated with inorganic fertilizer. Functional metagenomics identified beta-lactam resistance genes in treated and untreated soil, and indicated that the higher frequency of resistant bacteria in manure-amended soil was attributable to enrichment of resident soil bacteria that harbor beta-lactamases. Quantitative PCR indicated that manure treatment enriched the blaCEP-04 gene, which is highly similar (96%) to a gene found previously in a Pseudomonas sp. Analysis of 16S rRNA genes indicated that the abundance of Pseudomonas spp. increased in manure amended soil. Populations of other soil bacteria that commonly harbor beta lactamases, including Janthinobacterium sp. and Psychrobacter pulmonis, also increased in response to manure treatment. These results indicate that manure amendment induced a bloom of certain antibiotic-resistant bacteria in soil that was independent of antibiotic exposure of the cows from which the manure was derived. Our data illustrate the unintended consequences that can result from agricultural practices, and demonstrate the need for empirical analysis of the agroecosystem. PMID- 25288760 TI - Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. AB - Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence. PMID- 25288761 TI - Neutral molecular cluster formation of sulfuric acid-dimethylamine observed in real time under atmospheric conditions. AB - For atmospheric sulfuric acid (SA) concentrations the presence of dimethylamine (DMA) at mixing ratios of several parts per trillion by volume can explain observed boundary layer new particle formation rates. However, the concentration and molecular composition of the neutral (uncharged) clusters have not been reported so far due to the lack of suitable instrumentation. Here we report on experiments from the Cosmics Leaving Outdoor Droplets chamber at the European Organization for Nuclear Research revealing the formation of neutral particles containing up to 14 SA and 16 DMA molecules, corresponding to a mobility diameter of about 2 nm, under atmospherically relevant conditions. These measurements bridge the gap between the molecular and particle perspectives of nucleation, revealing the fundamental processes involved in particle formation and growth. The neutral clusters are found to form at or close to the kinetic limit where particle formation is limited only by the collision rate of SA molecules. Even though the neutral particles are stable against evaporation from the SA dimer onward, the formation rates of particles at 1.7-nm size, which contain about 10 SA molecules, are up to 4 orders of magnitude smaller compared with those of the dimer due to coagulation and wall loss of particles before they reach 1.7 nm in diameter. This demonstrates that neither the atmospheric particle formation rate nor its dependence on SA can simply be interpreted in terms of cluster evaporation or the molecular composition of a critical nucleus. PMID- 25288762 TI - Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. AB - Necroptosis is considered to be complementary to the classical caspase-dependent programmed cell death pathway, apoptosis. The pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) is an essential effector protein in the necroptotic cell death pathway downstream of the protein kinase Receptor Interacting Protein Kinase-3 (RIPK3). How MLKL causes cell death is unclear, however RIPK3-mediated phosphorylation of the activation loop in MLKL trips a molecular switch to induce necroptotic cell death. Here, we show that the MLKL pseudokinase domain acts as a latch to restrain the N-terminal four-helix bundle (4HB) domain and that unleashing this domain results in formation of a high-molecular-weight, membrane localized complex and cell death. Using alanine-scanning mutagenesis, we identified two clusters of residues on opposing faces of the 4HB domain that were required for the 4HB domain to kill cells. The integrity of one cluster was essential for membrane localization, whereas MLKL mutations in the other cluster did not prevent membrane translocation but prevented killing; this demonstrates that membrane localization is necessary, but insufficient, to induce cell death. Finally, we identified a small molecule that binds the nucleotide binding site within the MLKL pseudokinase domain and retards MLKL translocation to membranes, thereby preventing necroptosis. This inhibitor provides a novel tool to investigate necroptosis and demonstrates the feasibility of using small molecules to target the nucleotide binding site of pseudokinases to modulate signal transduction. PMID- 25288763 TI - Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging. AB - Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca(2+) transients, decreased intracellular Ca(2+) leak and increased sarcoplasmic reticulum (SR) Ca(2+) load compared with age-matched wild type (WT) littermates. Furthermore, ryanodine receptor 1 (the sarcoplasmic reticulum Ca(2+) release channel required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of the channel stabilizing subunit, calstabin1, and displayed increased single channel open probability (Po). Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca(2+) leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders. PMID- 25288764 TI - Defects in T-tubular electrical activity underlie local alterations of calcium release in heart failure. AB - Action potentials (APs), via the transverse axial tubular system (TATS), synchronously trigger uniform Ca(2+) release throughout the cardiomyocyte. In heart failure (HF), TATS structural remodeling occurs, leading to asynchronous Ca(2+) release across the myocyte and contributing to contractile dysfunction. In cardiomyocytes from failing rat hearts, we previously documented the presence of TATS elements which failed to propagate AP and displayed spontaneous electrical activity; the consequence for Ca(2+) release remained, however, unsolved. Here, we develop an imaging method to simultaneously assess TATS electrical activity and local Ca(2+) release. In HF cardiomyocytes, sites where T-tubules fail to conduct AP show a slower and reduced local Ca(2+) transient compared with regions with electrically coupled elements. It is concluded that TATS electrical remodeling is a major determinant of altered kinetics, amplitude, and homogeneity of Ca(2+) release in HF. Moreover, spontaneous depolarization events occurring in failing T-tubules can trigger local Ca(2+) release, resulting in Ca(2+) sparks. The occurrence of tubule-driven depolarizations and Ca(2+) sparks may contribute to the arrhythmic burden in heart failure. PMID- 25288765 TI - Autism as a disorder of prediction. AB - A rich collection of empirical findings accumulated over the past three decades attests to the diversity of traits that constitute the autism phenotypes. It is unclear whether subsets of these traits share any underlying causality. This lack of a cohesive conceptualization of the disorder has complicated the search for broadly effective therapies, diagnostic markers, and neural/genetic correlates. In this paper, we describe how theoretical considerations and a review of empirical data lead to the hypothesis that some salient aspects of the autism phenotype may be manifestations of an underlying impairment in predictive abilities. With compromised prediction skills, an individual with autism inhabits a seemingly "magical" world wherein events occur unexpectedly and without cause. Immersion in such a capricious environment can prove overwhelming and compromise one's ability to effectively interact with it. If validated, this hypothesis has the potential of providing unifying insights into multiple aspects of autism, with attendant benefits for improving diagnosis and therapy. PMID- 25288766 TI - LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity. AB - LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders. PMID- 25288767 TI - Gene coexpression measures in large heterogeneous samples using count statistics. AB - With the advent of high-throughput technologies making large-scale gene expression data readily available, developing appropriate computational tools to process these data and distill insights into systems biology has been an important part of the "big data" challenge. Gene coexpression is one of the earliest techniques developed that is still widely in use for functional annotation, pathway analysis, and, most importantly, the reconstruction of gene regulatory networks, based on gene expression data. However, most coexpression measures do not specifically account for local features in expression profiles. For example, it is very likely that the patterns of gene association may change or only exist in a subset of the samples, especially when the samples are pooled from a range of experiments. We propose two new gene coexpression statistics based on counting local patterns of gene expression ranks to take into account the potentially diverse nature of gene interactions. In particular, one of our statistics is designed for time-course data with local dependence structures, such as time series coupled over a subregion of the time domain. We provide asymptotic analysis of their distributions and power, and evaluate their performance against a wide range of existing coexpression measures on simulated and real data. Our new statistics are fast to compute, robust against outliers, and show comparable and often better general performance. PMID- 25288768 TI - Computational design of a self-assembling symmetrical beta-propeller protein. AB - The modular structure of many protein families, such as beta-propeller proteins, strongly implies that duplication played an important role in their evolution, leading to highly symmetrical intermediate forms. Previous attempts to create perfectly symmetrical propeller proteins have failed, however. We have therefore developed a new and rapid computational approach to design such proteins. As a test case, we have created a sixfold symmetrical beta-propeller protein and experimentally validated the structure using X-ray crystallography. Each blade consists of 42 residues. Proteins carrying 2-10 identical blades were also expressed and purified. Two or three tandem blades assemble to recreate the highly stable sixfold symmetrical architecture, consistent with the duplication and fusion theory. The other proteins produce different monodisperse complexes, up to 42 blades (180 kDa) in size, which self-assemble according to simple symmetry rules. Our procedure is suitable for creating nano-building blocks from different protein templates of desired symmetry. PMID- 25288769 TI - GABAB(1) receptor subunit isoforms differentially regulate stress resilience. AB - Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression. PMID- 25288770 TI - Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle income countries. AB - To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middle-income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies. PMID- 25288771 TI - The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1. AB - The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF 1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As. PMID- 25288772 TI - Conformational coupling between the active site and residues within the K(C) channel of the Vibrio cholerae cbb3-type (C-family) oxygen reductase. AB - The respiratory chains of nearly all aerobic organisms are terminated by proton pumping heme-copper oxygen reductases (HCOs). Previous studies have established that C-family HCOs contain a single channel for uptake from the bacterial cytoplasm of all chemical and pumped protons, and that the entrance of the K(C) channel is a conserved glutamate in subunit III. However, the majority of the K(C)-channel is within subunit I, and the pathway from this conserved glutamate to subunit I is not evident. In the present study, molecular dynamics simulations were used to characterize a chain of water molecules leading from the cytoplasmic solution, passing the conserved glutamate in subunit III and extending into subunit I. Formation of the water chain, which controls the delivery of protons to the K(C)-channel, was found to depend on the conformation of Y241(Vc), located in subunit I at the interface with subunit III. Mutations of Y241(Vc) (to A/F/H/S) in the Vibrio cholerae cbb3 eliminate catalytic activity, but also cause perturbations that propagate over a 28-A distance to the active site heme b3. The data suggest a linkage between residues lining the K(C)-channel and the active site of the enzyme, possibly mediated by transmembrane helix alpha7, which contains both Y241(Vc) and the active site cross-linked Y255(Vc), as well as two CuB histidine ligands. Other mutations of residues within or near helix alpha7 also perturb the active site, indicating that this helix is involved in modulation of the active site of the enzyme. PMID- 25288774 TI - Reputation and impact in academic careers. AB - Reputation is an important social construct in science, which enables informed quality assessments of both publications and careers of scientists in the absence of complete systemic information. However, the relation between reputation and career growth of an individual remains poorly understood, despite recent proliferation of quantitative research evaluation methods. Here, we develop an original framework for measuring how a publication's citation rate Deltac depends on the reputation of its central author i, in addition to its net citation count c. To estimate the strength of the reputation effect, we perform a longitudinal analysis on the careers of 450 highly cited scientists, using the total citations Ci of each scientist as his/her reputation measure. We find a citation crossover c*, which distinguishes the strength of the reputation effect. For publications with c < c*, the author's reputation is found to dominate the annual citation rate. Hence, a new publication may gain a significant early advantage corresponding to roughly a 66% increase in the citation rate for each tenfold increase in Ci. However, the reputation effect becomes negligible for highly cited publications meaning that, for c >= c*, the citation rate measures scientific impact more transparently. In addition, we have developed a stochastic reputation model, which is found to reproduce numerous statistical observations for real careers, thus providing insight into the microscopic mechanisms underlying cumulative advantage in science. PMID- 25288773 TI - Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. AB - Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-kappaB to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5. PMID- 25288777 TI - The 'V' sign of endomyocardial fibrosis. PMID- 25288775 TI - Structure of the ArgRS-GlnRS-AIMP1 complex and its implications for mammalian translation. AB - In higher eukaryotes, one of the two arginyl-tRNA synthetases (ArgRSs) has evolved to have an extended N-terminal domain that plays a crucial role in protein synthesis and cell growth and in integration into the multisynthetase complex (MSC). Here, we report a crystal structure of the MSC subcomplex comprising ArgRS, glutaminyl-tRNA synthetase (GlnRS), and the auxiliary factor aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)/p43. In this complex, the N-terminal domain of ArgRS forms a long coiled coil structure with the N-terminal helix of AIMP1 and anchors the C-terminal core of GlnRS, thereby playing a central role in assembly of the three components. Mutation of AIMP1 destabilized the N-terminal helix of ArgRS and abrogated its catalytic activity. Mutation of the N-terminal helix of ArgRS liberated GlnRS, which is known to control cell death. This ternary complex was further anchored to AIMP2/p38 through interaction with AIMP1. These findings demonstrate the importance of interactions between the N-terminal domains of ArgRS and AIMP1 for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex. PMID- 25288778 TI - Aortic regurgitation in Takayasu's arteritis. PMID- 25288779 TI - IL-17-producing CD4+ T cells are increased in early, active axial spondyloarthritis including patients without imaging abnormalities. AB - OBJECTIVE: Increased numbers of IL-17-producing CD4(+) T cells have been observed in AS. However, it is not known whether these CD4(+) T cells are already present in early disease or if this is a late disease phenomenon only. Therefore we aimed to investigate whether IL-17-producing CD4(+) T cells are involved in early active axial SpA, including patients without imaging abnormalities, by determining the frequency and phenotype of IL-17-producing CD4(+) T cells in these patients. METHODS: Flow cytometry was used to analyse cytokine production and surface marker expression of peripheral blood mononuclear cells from 31 patients suffering from early active HLA-B27-positive axial SpA fulfilling the Assessment of SpondyloArthritis International Society criteria with or without MRI abnormalities and 21 healthy controls. RESULTS: Patients with early active axial SpA showed an increased percentage of IL-17-producing CD4(+) T cells compared with healthy controls (mean 1.1% vs 0.4%, respectively; P = 0.013). The percentage of IL-17-producing CD4(+) T cells was equally increased in patients with and without MRI abnormalities (1.2% vs 1.1%, respectively; P = 0.81). These IL-17-producing CD4(+)T cells expressed the alphabeta T cell receptor but not the gammadelta T cell receptor, exhibited a memory phenotype and expressed CD161, but only sporadically expressed killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2). CONCLUSION: IL-17-producing CD4(+) T cells are increased in patients with early active axial SpA both with and without MRI abnormalities. This finding shows that the frequency of IL-17-producing CD4(+) T cells is enhanced in the early stages of disease. PMID- 25288776 TI - JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response. AB - Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of exogenous JAK2V617F impairs replication fork progression and is associated with activation of the intra-S checkpoint, with both effects mediated by phosphatidylinositide 3-kinase (PI3K) signaling. Analysis of clonally derived JAK2V617F-positive erythroblasts from MPN patients also demonstrated impaired replication fork progression accompanied by increased levels of replication protein A (RPA)-containing foci. However, the associated intra-S checkpoint response was impaired in erythroblasts from polycythemia vera (PV) patients, but not in those from essential thrombocythemia (ET) patients. Moreover, inhibition of p53 in PV erythroblasts resulted in more gamma-H2Ax (gamma-H2Ax)-marked double-stranded breaks compared with in like-treated ET erythroblasts, suggesting the defective intra-S checkpoint function seen in PV increases DNA damage in the context of attenuated p53 signaling. These results demonstrate oncogene-induced impairment of replication fork progression in primary cells from MPN patients, reveal unexpected disease-restricted differences in activation of the intra-S checkpoint, and have potential implications for the clonal evolution of malignancies. PMID- 25288780 TI - Prevalence and risk factors of arthritis in a middle-aged and older Chinese population: the China health and retirement longitudinal study. AB - OBJECTIVES: The aims of this study were to estimate the prevalence of arthritis and to identify risk factors of arthritis in a middle-aged and older Chinese adult population. METHODS: The China Health and Retirement Longitudinal Study (CHARLS) national survey data were used to estimate overall arthritis prevalence and prevalence by age and gender groups taking into account the complex survey design and response rate. The PROC SURVEYLOGISTIC procedure (SAS 9.3; SAS Institute, Cary, NC, USA) was applied to identify factors associated with arthritis using the CHARLS national survey data. Significant factors were further evaluated in the longitudinal CHARLS pilot study. RESULTS: The overall prevalence of arthritis among middle-aged and older Chinese adults was 31.4% (95% CI 30.3, 32.4). Prevalence increased with age. Females had a higher prevalence of arthritis than males in each age group. In the cross-sectional analysis, age, gender, education, BMI, sleep duration, vigorous physical activity and self reported doctor-diagnosed chronic lung disease, hypertension, chronic liver disease, cardiovascular disease, stroke, chronic kidney disease and chronic digestive disease were associated with arthritis. Age, gender, vigorous physical activity and cardiovascular disease were confirmed to be risk factors of arthritis in the longitudinal analysis. Participants with cardiovascular disease were 1.67 times (95% CI 1.02, 2.74) more likely to have self-reported arthritis in a 4-year period of follow-up in the CHARLS pilot study. CONCLUSION: Middle aged and older Chinese adults had a high prevalence of arthritis. Cardiovascular disease is a novel risk factor for arthritis in this population. PMID- 25288782 TI - Salivary gland ultrasound to diagnose Sjogren's syndrome: a claim to standardize the procedure. PMID- 25288781 TI - The Canadian systemic sclerosis oral health study II: the relationship between oral and global health-related quality of life in systemic sclerosis. AB - OBJECTIVE: Both oral and global health-related quality of life (HRQoL) are markedly impaired in SSc. In this study we aimed to determine the degree of association between oral HRQoL and global HRQoL in SSc. METHODS: Subjects were recruited from the Canadian Scleroderma Research Group registry. Global HRQoL was measured using the Medical Outcomes Trust 36-item Short Form Health Survey (SF 36) and oral HRQoL with the Oral Health Impact Profile (OHIP). The Medsger Disease Severity Score was used to determine organ involvement. Multivariate regression models determined the independent association of the OHIP with the SF 36 after adjusting for confounders. RESULTS: This study included 156 SSc subjects. The majority (90%) were women, with a mean age of 56 years, mean disease duration 13.8 years (s.d. 8.5) and 29% of the subjects had dcSSc. Mean total OHIP score was 40.8 (s.d. 32.4). Mean SF-36 mental component summary (MCS) score was 49.7 (s.d. 11.1) and physical component summary (PCS) score was 37.0 (s.d. 10.7). In adjusted analyses, the total OHIP score was significantly associated with the SF-36 MCS and PCS, accounting for 9.7% and 5.6% of their respective variances. Measures of disease severity were not related to OHIP score. CONCLUSION: Oral HRQoL in SSc is independently associated with global HRQoL. Oral HRQoL, however, is not related to physician-assessed disease severity. This suggests that physicians may be disregarding issues related to oral health. HRQoL is an additional dimension of HRQoL not captured by generic instruments such as the SF-36. PMID- 25288784 TI - Psychological profiles in patients with Sjogren's syndrome related to fatigue: a cluster analysis. AB - OBJECTIVE: Fatigue is a highly prevalent and debilitating symptom in the autoimmune disease SS. Although the disease process plays a role in fatigue, psychological factors may influence fatigue and the ability to deal with its consequences. Profiles of co-occurring psychological factors may suggest potential targets for the treatment of fatigue. The aim of this study was to identify psychological profiles in patients with SS and the accompanying levels of fatigue. METHODS: Three hundred patients with primary SS (mean age 57 years, 93% female) completed questionnaires on fatigue (multidimensional fatigue inventory), physical activity cognitions (TAMPA-SK), illness cognitions, cognitive regulation, emotion processing and regulation [Toronto Alexithymia Scale 20, Emotion Regulation Questionnaire (ERQ), Berkeley Expressivity Questionnaire], coping strategies (Brief COPE) and social support. RESULTS: Principal axis factor analysis (oblimin rotation) yielded six psychological factors: social support, negative thinking, positive thinking, emotional expressivity, avoidance and alexithymia (i.e. the inability to differentiate emotions). Using cluster analyses, these factors were grouped in four psychological profiles: functional (39%), alexithymic (27%), self-reliant (23%) and dysfunctional (11%). Irrespective of the psychological profile, the level of fatigue was substantially higher in patients than in the general population. Patients with a dysfunctional or an alexithymic profile reported more fatigue than those with a self-reliant profile. CONCLUSION: Our study in SS yielded four psychological profiles that were differentially associated with fatigue. These profiles can be used to examine determinants and prognosis of fatigue as well as the possibility of customizing cognitive behavioural interventions for chronic fatigue. PMID- 25288783 TI - Clinical and laboratory features of fatal rapidly progressive interstitial lung disease associated with juvenile dermatomyositis. AB - OBJECTIVE: Rapidly progressive interstitial lung disease (RP-ILD) is a rare but potentially fatal complication of JDM. The aim of this study was to establish markers for the prediction and early diagnosis of RP-ILD associated with JDM. METHODS: The clinical records of 54 patients with JDM were retrospectively reviewed: 10 had RP-ILD (7 died, 3 survived), 19 had chronic ILD and 24 were without ILD. Routine tests included a high-resolution CT (HRCT) scan of the chest and measurement of serum levels of creatine phosphokinase, ferritin and Krebs von den Lungen-6 (KL-6). Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies and IL-18 levels were measured by ELISA. RESULTS: No differences were found in the ratio of juvenile clinically amyopathic DM between the three groups. Initial chest HRCT scan findings were variable and could not distinguish between RP-ILD and chronic ILD. Anti-MDA5 antibodies were positive in all 8 patients with RP-ILD and 10 of 14 with chronic ILD, but none of the patients without ILD. Serum levels of anti-MDA5 antibody, ferritin, KL-6 and IL-18 were significantly higher in the RP-ILD group than in the chronic ILD and non-ILD groups. Serum levels of IL-18 positively correlated with serum KL-6 (R = 0.66, P < 0.001). CONCLUSION: High serum levels of IL-18, KL-6, ferritin and anti-MDA5 antibodies (e.g. >200 units by ELISA) are associated with RP-ILD. These can be used as an indication for early intensive treatment. Both alveolar macrophages and autoimmunity to MDA5 are possibly involved in the development of RP-ILD associated with JDM. PMID- 25288785 TI - Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis. AB - Mesenchymal stem cells (MSCs) are multipotent cells with the capacity to undergo chondrogenic differentiation. Systemically administered MSCs have been shown to preferentially accumulate at sites of tissue damage and inflammation, thus MSC based therapy holds great promise for the treatment of inflammatory diseases such as RA. Modulation of MSC homing may allow targeted delivery of systemically administered MSCs to damaged articular cartilage, where they can suppress immune mediated cartilage destruction and contribute to cartilage repair via a combination of chondrogenic differentiation and paracrine stimulation of intrinsic residual repair. To harness the potential of MSC homing, a thorough understanding of the mechanism is key. This review discusses current knowledge of the mechanism of MSC homing to injured/inflamed tissue and its implications for targeted MSC-based therapy in arthritis. PMID- 25288786 TI - Quality of life and unmet needs in patients with inflammatory arthropathies: results from the multicentre, observational RAPSODIA study. AB - OBJECTIVE: The observational RAPSODIA (RA, PsA and spondylitis including AS) study was planned to assess, in patients with RA, AS and PsA, their involvement in medical decisions, quality of life and unmet needs 15 years after the introduction of biologic therapies in Italy. METHODS: Patients completed a questionnaire during their scheduled rheumatology consultation. They rated their satisfaction with disease knowledge on a 5-point scale (1 = not at all satisfied, 5 = totally satisfied). Self-efficacy, defined as judgement of one's own ability to achieve given levels of performance and exercise control over events, was measured using the pain subscale of the Arthritis Self-Efficacy Scale. Patients' global assessments of pain, fatigue and disease activity were recorded on 100 mm visual analogue scales (0 = best status, 100 = worse status). Disease activity status was assessed using standard tools. Health status was measured using the 36 item Short Form Health Survey and the Italian version of the HAQ. RESULTS: Ninety eight per cent of patients reported that their health care practitioner used understandable terms to explain their condition. Joint issues and general symptoms (e.g. fatigue and malaise) were common. All measures of disease activity and self-efficacy scores were markedly better in patients receiving biologic vs conventional therapy. Biologic therapy recipients were more productive at work. CONCLUSION: These results confirm that some patients with rheumatic diseases are not satisfied with the level of information they receive about their treatments. Biologic therapy appears to be an important advance, with patients receiving this form of treatment having improved symptoms and productivity. However, patients still report unmet needs. Thus further research, and perhaps new and more effective therapies, along with better education and multidisciplinary collaboration, are required to improve outcomes. PMID- 25288787 TI - Successful treatment of warm-type haemolytic anaemia with bortezomib in a rituximab-failed systemic lupus erythematosus patient. PMID- 25288788 TI - High glucose forces a positive feedback loop connecting Akt kinase and FoxO1 transcription factor to activate mTORC1 kinase for mesangial cell hypertrophy and matrix protein expression. AB - High glucose-induced Akt acts as a signaling hub for mesangial cell hypertrophy and matrix expansion, which are recognized as cardinal signatures for the development of diabetic nephropathy. How mesangial cells sustain the activated state of Akt is not clearly understood. Here we show Akt-dependent phosphorylation of the transcription factor FoxO1 by high glucose. Phosphorylation-deficient, constitutively active FoxO1 inhibited the high glucose induced phosphorylation of Akt to suppress the phosphorylation/inactivation of PRAS40 and mTORC1 activity. In contrast, dominant negative FoxO1 increased the phosphorylation of Akt, resulting in increased mTORC1 activity similar to high glucose treatment. Notably, FoxO1 regulates high glucose-induced protein synthesis, hypertrophy, and expression of fibronectin and PAI-1. High glucose paves the way for complications of diabetic nephropathy through the production of reactive oxygen species (ROS). We considered whether the FoxO1 target antioxidant enzyme catalase contributes to sustained activation of Akt. High glucose inactivated FoxO1 decreases the expression of catalase to increase the production of ROS. Moreover, we show that catalase blocks high glucose-stimulated Akt phosphorylation to attenuate the inactivation of FoxO1 and PRAS40, resulting in the inhibition of mTORC1 and mesangial cell hypertrophy and fibronectin and PAI-1 expression. Finally, using kidney cortices from type 1 diabetic OVE26 mice, we show that increased FoxO1 phosphorylation is associated with decreased catalase expression and increased fibronectin and PAI-1 expression. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of Akt involving inactivated FoxO1 and a decrease in catalase expression, leading to increased ROS and mesangial cell hypertrophy and matrix protein expression. PMID- 25288790 TI - Interaction between the pentose phosphate pathway and gluconeogenesis from glycerol in the liver. AB - After exposure to [U-(13)C3]glycerol, the liver produces primarily [1,2,3-(13)C3] and [4,5,6-(13)C3]glucose in equal proportions through gluconeogenesis from the level of trioses. Other (13)C-labeling patterns occur as a consequence of alternative pathways for glucose production. The pentose phosphate pathway (PPP), metabolism in the citric acid cycle, incomplete equilibration by triose phosphate isomerase, or the transaldolase reaction all interact to produce complex (13)C labeling patterns in exported glucose. Here, we investigated (13)C labeling in plasma glucose in rats given [U-(13)C3]glycerol under various nutritional conditions. Blood was drawn at multiple time points to extract glucose for NMR analysis. Because the transaldolase reaction and incomplete equilibrium by triose phosphate isomerase cannot break a (13)C-(13)C bond within the trioses contributing to glucose, the appearance of [1,2-(13)C2]-, [2,3-(13)C2]-, [5,6 (13)C2]-, and [4,5-(13)C2]glucose provides direct evidence for metabolism of glycerol in the citric acid cycle or the PPP but not an influence of either triose phosphate isomerase or the transaldolase reaction. In all animals, [1,2 (13)C2]glucose/[2,3-(13)C2]glucose was significantly greater than [5,6 (13)C2]glucose/[4,5-(13)C2]glucose, a relationship that can only arise from gluconeogenesis followed by passage of substrates through the PPP. In summary, the hepatic PPP in vivo can be detected by (13)C distribution in blood glucose after [U-(13)C3]glycerol administration. PMID- 25288789 TI - Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages. AB - Cholesterol-loaded foam cell macrophages are prominent in atherosclerotic lesions and play complex roles in both inflammatory signaling and lipid metabolism, which are underpinned by large scale reprogramming of gene expression. We performed a microarray study of primary human macrophages that showed that transcription of the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene is up-regulated after cholesterol loading. SMPDL3A protein expression in and secretion from primary macrophages are stimulated by cholesterol loading, liver X receptor ligands, and cyclic AMP, and N-glycosylated SMPDL3A protein is detectable in circulating blood. We demonstrate for the first time that SMPDL3A is a functional phosphodiesterase with an acidic pH optimum. We provide evidence that SMPDL3A is not an acid sphingomyelinase but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH. SMPDL3A is a major source of nucleotide phosphodiesterase activity secreted by liver X receptor-stimulated human macrophages. Extracellular nucleotides such as ATP may activate pro-inflammatory responses in immune cells. Increased expression and secretion of SMPDL3A by cholesterol-loaded macrophage foam cells in lesions may decrease local concentrations of pro-inflammatory nucleotides and potentially represent a novel anti-inflammatory axis linking lipid metabolism with purinergic signaling in atherosclerosis. PMID- 25288791 TI - Gluconeogenesis in Leishmania mexicana: contribution of glycerol kinase, phosphoenolpyruvate carboxykinase, and pyruvate phosphate dikinase. AB - Gluconeogenesis is an active pathway in Leishmania amastigotes and is essential for their survival within the mammalian cells. However, our knowledge about this pathway in trypanosomatids is very limited. We investigated the role of glycerol kinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate phosphate dikinase (PPDK) in gluconeogenesis by generating the respective Leishmania mexicana Deltagk, Deltapepck, and Deltappdk null mutants. Our results demonstrated that indeed GK, PEPCK, and PPDK are key players in the gluconeogenesis pathway in Leishmania, although stage-specific differences in their contribution to this pathway were found. GK participates in the entry of glycerol in promastigotes and amastigotes; PEPCK participates in the entry of aspartate in promastigotes, and PPDK is involved in the entry of alanine in amastigotes. Furthermore, the majority of alanine enters into the pathway via decarboxylation of pyruvate in promastigotes, whereas pathway redundancy is suggested for the entry of aspartate in amastigotes. Interestingly, we also found that l-lactate, an abundant glucogenic precursor in mammals, was used by Leishmania amastigotes to synthesize mannogen, entering the pathway through PPDK. On the basis of these new results, we propose a revision in the current model of gluconeogenesis in Leishmania, emphasizing the differences between amastigotes and promastigotes. This work underlines the importance of studying the trypanosomatid intracellular life cycle stages to gain a better understanding of the pathologies caused in humans. PMID- 25288792 TI - Changes in signal transducer and activator of transcription 3 (STAT3) dynamics induced by complexation with pharmacological inhibitors of Src homology 2 (SH2) domain dimerization. AB - The activity of the transcription factor signal transducer and activator of transcription 3 (STAT3) is dysregulated in a number of hematological and solid malignancies. Development of pharmacological STAT3 Src homology 2 (SH2) domain interaction inhibitors holds great promise for cancer therapy, and a novel class of salicylic acid-based STAT3 dimerization inhibitors that includes orally bioavailable drug candidates has been recently developed. The compounds SF-1-066 and BP-1-102 are predicted to bind to the STAT3 SH2 domain. However, given the highly unstructured and dynamic nature of the SH2 domain, experimental confirmation of this prediction was elusive. We have interrogated the protein ligand interaction of STAT3 with these small molecule inhibitors by means of time resolved electrospray ionization hydrogen-deuterium exchange mass spectrometry. Analysis of site-specific evolution of deuterium uptake induced by the complexation of STAT3 with SF-1-066 or BP-1-102 under physiological conditions enabled the mapping of the in silico predicted inhibitor binding site to the STAT3 SH2 domain. The binding of both inhibitors to the SH2 domain resulted in significant local decreases in dynamics, consistent with solvent exclusion at the inhibitor binding site and increased rigidity of the inhibitor-complexed SH2 domain. Interestingly, inhibitor binding induced hot spots of allosteric perturbations outside of the SH2 domain, manifesting mainly as increased deuterium uptake, in regions of STAT3 important for DNA binding and nuclear localization. PMID- 25288793 TI - Biochemical characterization of pathogenic mutations in human mitochondrial methionyl-tRNA formyltransferase. AB - N-Formylation of initiator methionyl-tRNA (Met-tRNA(Met)) by methionyl-tRNA formyltransferase (MTF) is important for translation initiation in bacteria, mitochondria, and chloroplasts. Unlike all other translation systems, the metazoan mitochondrial system is unique in using a single methionine tRNA (tRNA(Met)) for both initiation and elongation. A portion of Met-tRNA(Met) is formylated for initiation, whereas the remainder is used for elongation. Recently, we showed that compound heterozygous mutations within the nuclear gene encoding human mitochondrial MTF (mt-MTF) significantly reduced mitochondrial translation efficiency, leading to combined oxidative phosphorylation deficiency and Leigh syndrome in two unrelated patients. Patient P1 has a stop codon mutation in one of the MTF genes and an S209L mutation in the other MTF gene. P2 has a S125L mutation in one of the MTF genes and the same S209L mutation as P1 in the other MTF gene. Here, we have investigated the effect of mutations at Ser-125 and Ser-209 on activities of human mt-MTF and of the corresponding mutations, Ala 89 or Ala-172, respectively, on activities of Escherichia coli MTF. The S125L mutant has 653-fold lower activity, whereas the S209L mutant has 36-fold lower activity. Thus, both patients depend upon residual activity of the S209L mutant to support low levels of mitochondrial protein synthesis. We discuss the implications of these and other results for whether the effect of the S209L mutation on mitochondrial translational efficiency is due to reduced activity of the mutant mt-MTF and/or reduced levels of the mutant mt-MTF. PMID- 25288794 TI - Structural basis of allosteric activation of sterile alpha motif and histidine aspartate domain-containing protein 1 (SAMHD1) by nucleoside triphosphates. AB - Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) plays a critical role in inhibiting HIV infection, curtailing the pool of dNTPs available for reverse transcription of the viral genome. Recent structural data suggested a compelling mechanism for the regulation of SAMHD1 enzymatic activity and revealed dGTP-induced association of two inactive dimers into an active tetrameric enzyme. Here, we present the crystal structures of SAMHD1 catalytic core (residues 113-626) tetramers, complexed with mixtures of nucleotides, including dGTP/dATP, dGTP/dCTP, dGTP/dTTP, and dGTP/dUTP. The combined structural and biochemical data provide insight into dNTP promiscuity at the secondary allosteric site and how enzymatic activity is modulated. In addition, we present biochemical analyses of GTP-induced SAMHD1 full-length tetramerization and the structure of SAMHD1 catalytic core tetramer in complex with GTP/dATP, revealing the structural basis of GTP-mediated SAMHD1 activation. Altogether, the data presented here advance our understanding of SAMHD1 function during cellular homeostasis. PMID- 25288795 TI - Conversion of a chaperonin GroEL-independent protein into an obligate substrate. AB - Chaperones assist protein folding by preventing unproductive protein aggregation in the cell. In Escherichia coli, chaperonin GroEL/GroES (GroE) is the only indispensable chaperone and is absolutely required for the de novo folding of at least ~60 proteins. We previously found that several orthologs of the obligate GroE substrates in Ureaplasma urealyticum, which lacks the groE gene in the genome, are E. coli GroE-independent folders, despite their significant sequence identities. Here, we investigated the key features that define the GroE dependence. Chimera or random mutagenesis analyses revealed that independent multiple point mutations, and even single mutations, were sufficient to confer GroE dependence on the Ureaplasma MetK. Strikingly, the GroE dependence was well correlated with the propensity to form protein aggregates during folding. The results reveal the delicate balance between GroE dependence and independence. The function of GroE to buffering the aggregation-prone mutations plays a role in maintaining higher genetic diversity of proteins. PMID- 25288796 TI - An alternative mechanism for the methylation of phosphoethanolamine catalyzed by Plasmodium falciparum phosphoethanolamine methyltransferase. AB - The phosphobase methylation pathway catalyzed by the phosphoethanolamine methyltransferase in Plasmodium falciparum (PfPMT), the malaria parasite, offers an attractive target for anti-parasitic drug development. PfPMT methylates phosphoethanolamine (pEA) to phosphocholine for use in membrane biogenesis. Quantum mechanics and molecular mechanics (QM/MM) calculations tested the proposed reaction mechanism for methylation of pEA involving the previously identified Tyr-19-His-132 dyad, which indicated an energetically unfavorable mechanism. Instead, the QM/MM calculations suggested an alternative mechanism involving Asp-128. The reaction coordinate involves the stepwise transfer of a proton to Asp-128 via a bridging water molecule followed by a typical Sn2-type methyl transfer from S-adenosylmethionine to pEA. Functional analysis of the D128A, D128E, D128Q, and D128N PfPMT mutants shows a loss of activity with pEA but not with the final substrate of the methylation pathway. X-ray crystal structures of the PfPMT-D128A mutant in complex with S-adenosylhomocysteine and either pEA or phosphocholine reveal how mutation of Asp-128 disrupts a hydrogen bond network in the active site. The combined QM/MM, biochemical, and structural studies identify a key role for Asp-128 in the initial step of the phosphobase methylation pathway in Plasmodium and provide molecular insight on the evolution of multiple activities in the active site of the PMT. PMID- 25288797 TI - Integration and oligomerization of Bax protein in lipid bilayers characterized by single molecule fluorescence study. AB - Bax is a pro-apoptotic Bcl-2 family protein. The activated Bax translocates to mitochondria, where it forms pore and permeabilizes the mitochondrial outer membrane. This process requires the BH3-only activator protein (i.e. tBid) and can be inhibited by anti-apoptotic Bcl-2 family proteins such as Bcl-xL. Here by using single molecule fluorescence techniques, we studied the integration and oligomerization of Bax in lipid bilayers. Our study revealed that Bax can bind to lipid membrane spontaneously in the absence of tBid. The Bax pore formation undergoes at least two steps: pre-pore formation and membrane insertion. The activated Bax triggered by tBid or BH3 domain peptide integrates on bilayers and tends to form tetramers, which are termed as pre-pore. Subsequent insertion of the pre-pore into membrane is highly dependent on the composition of cardiolipin in lipid bilayers. Bcl-xL can translocate Bax from membrane to solution and inhibit the pore formation. The study of Bax integration and oligomerization at the single molecule level provides new evidences that may help elucidate the pore formation of Bax and its regulatory mechanism in apoptosis. PMID- 25288798 TI - Residue Leu940 has a crucial role in the linkage and reaction specificity of the glucansucrase GTF180 of the probiotic bacterium Lactobacillus reuteri 180. AB - Highly conserved glycoside hydrolase family 70 glucansucrases are able to catalyze the synthesis of alpha-glucans with different structure from sucrose. The structural determinants of glucansucrase specificity have remained unclear. Residue Leu(940) in domain B of GTF180, the glucansucrase of the probiotic bacterium Lactobacillus reuteri 180, was shown to vary in different glucansucrases and is close to the +1 glucosyl unit in the crystal structure of GTF180-DeltaN in complex with maltose. Herein, we show that mutations in Leu(940) of wild-type GTF180-DeltaN all caused an increased percentage of (alpha1->6) linkages and a decreased percentage of (alpha1->3) linkages in the products. alpha-Glucans with potential different physicochemical properties (containing 67 100% of (alpha1->6) linkages) were produced by GTF180 and its Leu(940) mutants. Mutant L940W was unable to form (alpha1->3) linkages and synthesized a smaller and linear glucan polysaccharide with only (alpha1->6) linkages. Docking studies revealed that the introduction of the large aromatic amino acid residue tryptophan at position 940 partially blocked the binding groove, preventing the isomalto-oligosaccharide acceptor to bind in an favorable orientation for the formation of (alpha1->3) linkages. Our data showed that the reaction specificity of GTF180 mutant was shifted either to increased polysaccharide synthesis (L940A, L940S, L940E, and L940F) or increased oligosaccharide synthesis (L940W). The L940W mutant is capable of producing a large amount of isomalto-oligosaccharides using released glucose from sucrose as acceptors. Thus, residue Leu(940) in domain B is crucial for linkage and reaction specificity of GTF180. This study provides clear and novel insights into the structure-function relationships of glucansucrase enzymes. PMID- 25288799 TI - New selective peptidyl di(chlorophenyl) phosphonate esters for visualizing and blocking neutrophil proteinase 3 in human diseases. AB - The function of neutrophil protease 3 (PR3) is poorly understood despite of its role in autoimmune vasculitides and its possible involvement in cell apoptosis. This makes it different from its structural homologue neutrophil elastase (HNE). Endogenous inhibitors of human neutrophil serine proteases preferentially inhibit HNE and to a lesser extent, PR3. We constructed a single-residue mutant PR3 (I217R) to investigate the S4 subsite preferences of PR3 and HNE and used the best peptide substrate sequences to develop selective phosphonate inhibitors with the structure Ac-peptidyl(P)(O-C6H4-4-Cl)2. The combination of a prolyl residue at P4 and an aspartyl residue at P2 was totally selective for PR3. We then synthesized N-terminally biotinylated peptidyl phosphonates to identify the PR3 in complex biological samples. These inhibitors resisted proteolytic degradation and rapidly inactivated PR3 in biological fluids such as inflammatory lung secretions and the urine of patients with bladder cancer. One of these inhibitors revealed intracellular PR3 in permeabilized neutrophils and on the surface of activated cells. They hardly inhibited PR3 bound to the surface of stimulated neutrophils despite their low molecular mass, suggesting that the conformation and reactivity of membrane-bound PR3 is altered. This finding is relevant for autoantibody binding and the subsequent activation of neutrophils in granulomatosis with polyangiitis (formerly Wegener disease). These are the first inhibitors that can be used as probes to monitor, detect, and control PR3 activity in a variety of inflammatory diseases. PMID- 25288801 TI - The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. AB - Lysosome rupture triggers NLRP3 inflammasome activation in macrophages. However, the underlying mechanism is not fully understood. Here we showed that the TAK1 JNK pathway, a MAPK signaling pathway, is activated through lysosome rupture and that this activation is necessary for the complete activation of the NLRP3 inflammasome through the oligomerization of an adapter protein, apoptosis associated speck-like protein containing a caspase recruitment domain (ASC). We also revealed that the activation of the TAK1-JNK pathway is sustained through Ca(2+) ions and that calcium/calmodulin-dependent protein kinase type II functions upstream of the TAK1-JNK pathway and specifically regulates lysosome rupture-induced NLRP3 inflammasome activation. These data suggest a novel role for the TAK1-JNK pathway as a critical regulator of NLRP3 inflammasome activation. PMID- 25288802 TI - Compromised catalysis and potential folding defects in in vitro studies of missense mutants associated with hereditary phosphoglucomutase 1 deficiency. AB - Recent studies have identified phosphoglucomutase 1 (PGM1) deficiency as an inherited metabolic disorder in humans. Affected patients show multiple disease phenotypes, including dilated cardiomyopathy, exercise intolerance, and hepatopathy, reflecting the central role of the enzyme in glucose metabolism. We present here the first in vitro biochemical characterization of 13 missense mutations involved in PGM1 deficiency. The biochemical phenotypes of the PGM1 mutants cluster into two groups: those with compromised catalysis and those with possible folding defects. Relative to the recombinant wild-type enzyme, certain missense mutants show greatly decreased expression of soluble protein and/or increased aggregation. In contrast, other missense variants are well behaved in solution, but show dramatic reductions in enzyme activity, with kcat/Km often <1.5% of wild-type. Modest changes in protein conformation and flexibility are also apparent in some of the catalytically impaired variants. In the case of the G291R mutant, severely compromised activity is linked to the inability of a key active site serine to be phosphorylated, a prerequisite for catalysis. Our results complement previous in vivo studies, which suggest that both protein misfolding and catalytic impairment may play a role in PGM1 deficiency. PMID- 25288800 TI - Kruppel-like factor-9 (KLF9) inhibits glioblastoma stemness through global transcription repression and integrin alpha6 inhibition. AB - It is increasingly important to understand the molecular basis for the plasticity of neoplastic cells and their capacity to transition between differentiated and stemlike phenotypes. Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation, and neural development; however, the molecular basis for the diverse contextual functions of KLF9 remains unclear. This study focused on the functions of KLF9 in human glioblastoma stemlike cells. We established for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stemlike cells and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, showed that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation and identify KLF9-regulated molecular targets applicable to cancer therapeutics. PMID- 25288803 TI - Inhibition of ubiquitin proteasome system rescues the defective sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1) protein causing Chianina cattle pseudomyotonia. AB - A missense mutation in ATP2A1 gene, encoding sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA1) protein, causes Chianina cattle congenital pseudomyotonia, an exercise-induced impairment of muscle relaxation. Skeletal muscles of affected cattle are characterized by a selective reduction of SERCA1 in sarcoplasmic reticulum membranes. In this study, we provide evidence that the ubiquitin proteasome system is involved in the reduced density of mutated SERCA1. The treatment with MG132, an inhibitor of ubiquitin proteasome system, rescues the expression level and membrane localization of the SERCA1 mutant in a heterologous cellular model. Cells co-transfected with the Ca(2+)-sensitive probe aequorin show that the rescued SERCA1 mutant exhibits the same ability of wild type to maintain Ca(2+) homeostasis within cells. These data have been confirmed by those obtained ex vivo on adult skeletal muscle fibers from a biopsy from a pseudomyotonia-affected subject. Our data show that the mutation generates a protein most likely corrupted in proper folding but not in catalytic activity. Rescue of mutated SERCA1 to sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca(2+) concentration and prevent the appearance of pathological signs of cattle pseudomyotonia. PMID- 25288804 TI - Structure-based conversion of the coenzyme requirement of a short-chain dehydrogenase/reductase involved in bacterial alginate metabolism. AB - The alginate-assimilating bacterium, Sphingomonas sp. strain A1, degrades the polysaccharides to monosaccharides through four alginate lyase reactions. The resultant monosaccharide, which is nonenzymatically converted to 4-deoxy-L erythro-5-hexoseulose uronate (DEH), is further metabolized to 2-keto-3-deoxy-D gluconate by NADPH-dependent reductase A1-R in the short-chain dehydrogenase/reductase (SDR) family. A1-R-deficient cells produced another DEH reductase, designated A1-R', with a preference for NADH. Here, we show the identification of a novel NADH-dependent DEH reductase A1-R' in strain A1, structural determination of A1-R' by x-ray crystallography, and structure-based conversion of a coenzyme requirement in SDR enzymes, A1-R and A1-R'. A1-R' was purified from strain A1 cells and enzymatically characterized. Except for the coenzyme requirement, there was no significant difference in enzyme characteristics between A1-R and A1-R'. Crystal structures of A1-R' and A1 R'.NAD(+) complex were determined at 1.8 and 2.7 A resolutions, respectively. Because of a 64% sequence identity, overall structures of A1-R' and A1-R were similar, although a difference in the coenzyme-binding site (particularly the nucleoside ribose 2' region) was observed. Distinct from A1-R, A1-R' included a negatively charged, shallower binding site. These differences were caused by amino acid residues on the two loops around the site. The A1-R' mutant with the two A1-R-typed loops maintained potent enzyme activity with specificity for NADPH rather than NADH, demonstrating that the two loops determine the coenzyme requirement, and loop exchange is a promising method for conversion of coenzyme requirement in the SDR family. PMID- 25288805 TI - Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling. AB - Neuronal protein-tyrosine phosphatase 1B (PTP1B) deficiency in mice results in enhanced leptin signaling and protection from diet-induced obesity; however, whether additional signaling pathways in the brain contribute to the metabolic effects of PTP1B deficiency remains unclear. Here, we show that the tropomyosin receptor kinase B (TrkB) receptor is a direct PTP1B substrate and implicate PTP1B in the regulation of the central brain-derived neurotrophic factor (BDNF) signaling. PTP1B interacts with activated TrkB receptor in mouse brain and human SH-SY5Y neuroblastoma cells. PTP1B overexpression reduces TrkB phosphorylation and activation of downstream signaling pathways, whereas PTP1B inhibition augments TrkB signaling. Notably, brains of Ptpn1(-/-) mice exhibit enhanced TrkB phosphorylation, and Ptpn1(-/-) mice are hypersensitive to central BDNF-induced increase in core temperature. Taken together, our findings demonstrate that PTP1B is a novel physiological regulator of TrkB and that enhanced BDNF/TrkB signaling may contribute to the beneficial metabolic effects of PTP1B deficiency. PMID- 25288806 TI - Insulin secretion induced by glucose-dependent insulinotropic polypeptide requires phosphatidylinositol 3-kinase gamma in rodent and human beta-cells. AB - PI3Kgamma, a G-protein-coupled type 1B phosphoinositol 3-kinase, exhibits a basal glucose-independent activity in beta-cells and can be activated by the glucose dependent insulinotropic polypeptide (GIP). We therefore investigated the role of the PI3Kgamma catalytic subunit (p110gamma) in insulin secretion and beta-cell exocytosis stimulated by GIP. We inhibited p110gamma with AS604850 (1 MUmol/liter) or knocked it down using an shRNA adenovirus or siRNA duplex in mouse and human islets and beta-cells. Inhibition of PI3Kgamma blunted the exocytotic and insulinotropic response to GIP receptor activation, whereas responses to the glucagon-like peptide-1 or the glucagon-like peptide-1 receptor agonist exendin-4 were unchanged. Downstream, we find that GIP, much like glucose stimulation, activates the small GTPase protein Rac1 to induce actin remodeling. Inhibition of PI3Kgamma blocked these effects of GIP. Although exendin-4 could also stimulate actin remodeling, this was not prevented by p110gamma inhibition. Finally, forced actin depolymerization with latrunculin B restored the exocytotic and secretory responses to GIP during PI3Kgamma inhibition, demonstrating that the loss of GIP-induced actin depolymerization was indeed limiting insulin exocytosis. PMID- 25288808 TI - Evolution of wealth in a non-conservative economy driven by local Nash equilibria. AB - We develop a model for the evolution of wealth in a non-conservative economic environment, extending a theory developed in Degond et al. (2014 J. Stat. Phys. 154, 751-780 (doi:10.1007/s10955-013-0888-4)). The model considers a system of rational agents interacting in a game-theoretical framework. This evolution drives the dynamics of the agents in both wealth and economic configuration variables. The cost function is chosen to represent a risk-averse strategy of each agent. That is, the agent is more likely to interact with the market, the more predictable the market, and therefore the smaller its individual risk. This yields a kinetic equation for an effective single particle agent density with a Nash equilibrium serving as the local thermodynamic equilibrium. We consider a regime of scale separation where the large-scale dynamics is given by a hydrodynamic closure with this local equilibrium. A class of generalized collision invariants is developed to overcome the difficulty of the non conservative property in the hydrodynamic closure derivation of the large-scale dynamics for the evolution of wealth distribution. The result is a system of gas dynamics-type equations for the density and average wealth of the agents on large scales. We recover the inverse Gamma distribution, which has been previously considered in the literature, as a local equilibrium for particular choices of the cost function. PMID- 25288809 TI - From Nash to Cournot-Nash equilibria via the Monge-Kantorovich problem. AB - The notion of Nash equilibria plays a key role in the analysis of strategic interactions in the framework of N player games. Analysis of Nash equilibria is however a complex issue when the number of players is large. In this article, we emphasize the role of optimal transport theory in (i) the passage from Nash to Cournot-Nash equilibria as the number of players tends to infinity and (ii) the analysis of Cournot-Nash equilibria. PMID- 25288810 TI - On global minimizers of repulsive-attractive power-law interaction energies. AB - We consider the minimization of the repulsive-attractive power-law interaction energies that occur in many biological and physical situations. We show the existence of global minimizers in the discrete setting and obtain bounds for their supports independently of the number of Dirac deltas in a certain range of exponents. These global discrete minimizers correspond to the stable spatial profiles of flock patterns in swarming models. Global minimizers of the continuum problem are obtained by compactness. We also illustrate our results through numerical simulations. PMID- 25288807 TI - A role for stefin B (cystatin B) in inflammation and endotoxemia. AB - Stefin B (cystatin B) is an endogenous cysteine cathepsin inhibitor, and the loss of-function mutations in the stefin B gene were reported in patients with Unverricht-Lundborg disease (EPM1). In this study we demonstrated that stefin B deficient (StB KO) mice were significantly more sensitive to the lethal LPS induced sepsis and secreted higher amounts of pro-inflammatory cytokines IL-1beta and IL-18 in the serum. We further showed that increased caspase-11 gene expression and better pro-inflammatory caspase-1 and -11 activation determined in StB KO bone marrow-derived macrophages resulted in enhanced IL-1beta processing. Pretreatment of macrophages with the cathepsin inhibitor E-64d did not affect secretion of IL-1beta, suggesting that the increased cathepsin activity determined in StB KO bone marrow-derived macrophages is not essential for inflammasome activation. Upon LPS stimulation, stefin B was targeted into the mitochondria, and the lack of stefin B resulted in the increased destabilization of mitochondrial membrane potential and mitochondrial superoxide generation. Collectively, our study demonstrates that the LPS-induced sepsis in StB KO mice is dependent on caspase-11 and mitochondrial reactive oxygen species but is not associated with the lysosomal destabilization and increased cathepsin activity in the cytosol. PMID- 25288811 TI - Partial differential equation models in macroeconomics. AB - The purpose of this article is to get mathematicians interested in studying a number of partial differential equations (PDEs) that naturally arise in macroeconomics. These PDEs come from models designed to study some of the most important questions in economics. At the same time, they are highly interesting for mathematicians because their structure is often quite difficult. We present a number of examples of such PDEs, discuss what is known about their properties, and list some open questions for future research. PMID- 25288812 TI - Wealth distribution and collective knowledge: a Boltzmann approach. AB - We introduce and discuss a nonlinear kinetic equation of Boltzmann type that describes the influence of knowledge in the evolution of wealth in a system of agents that interact through the binary trades, an equation first introduced by Cordier et al. (2005 J. Stat. Phys. 120, 253-277 (doi:10.1007/S10955-005-5456 0)). The trades, which include both saving propensity and the risks of the market, are here modified in the risk and saving parameters, which now are assumed to depend on the personal degree of knowledge. The numerical simulations show that the presence of knowledge has the potential to produce a class of wealthy agents and to account for a larger proportion of wealth inequality. PMID- 25288813 TI - Critical thresholds in flocking hydrodynamics with non-local alignment. AB - We study the large-time behaviour of Eulerian systems augmented with non-local alignment. Such systems arise as hydrodynamic descriptions of agent-based models for self-organized dynamics, e.g. Cucker & Smale (2007 IEEE Trans. Autom. Control 52, 852-862. (doi:10.1109/TAC.2007.895842)) and Motsch & Tadmor (2011 J. Stat. Phys. 144, 923-947. (doi:10.1007/s10955-011-0285-9)) models. We prove that, in analogy with the agent-based models, the presence of non-local alignment enforces strong solutions to self-organize into a macroscopic flock. This then raises the question of existence of such strong solutions. We address this question in one- and two-dimensional set-ups, proving global regularity for subcritical initial data. Indeed, we show that there exist critical thresholds in the phase space of the initial configuration which dictate the global regularity versus a finite time blow-up. In particular, we explore the regularity of non-local alignment in the presence of vacuum. PMID- 25288814 TI - Partial differential equation models in the socio-economic sciences. AB - Mathematical models based on partial differential equations (PDEs) have become an integral part of quantitative analysis in most branches of science and engineering, recently expanding also towards biomedicine and socio-economic sciences. The application of PDEs in the latter is a promising field, but widely quite open and leading to a variety of novel mathematical challenges. In this introductory article of the Theme Issue, we will provide an overview of the field and its recent boosting topics. Moreover, we will put the contributions to the Theme Issue in an appropriate perspective. PMID- 25288815 TI - A non-local free boundary problem arising in a theory of financial bubbles. AB - We consider an evolution non-local free boundary problem that arises in the modelling of speculative bubbles. The solution of the model is the speculative component in the price of an asset. In the framework of viscosity solutions, we show the existence and uniqueness of the solution. We also show that the solution is convex in space, and establish several monotonicity properties of the solution and of the free boundary with respect to parameters of the problem. To study the free boundary, we use, in particular, the fact that the odd part of the solution solves a more standard obstacle problem. We show that the free boundary is [Formula: see text] and describe the asymptotics of the free boundary as c, the cost of transacting the asset, goes to zero. PMID- 25288816 TI - Socio-economic applications of finite state mean field games. AB - In this paper, we present different applications of finite state mean field games to socio-economic sciences. Examples include paradigm shifts in the scientific community or consumer choice behaviour in the free market. The corresponding finite state mean field game models are hyperbolic systems of partial differential equations, for which we present and validate different numerical methods. We illustrate the behaviour of solutions with various numerical experiments, which show interesting phenomena such as shock formation. Hence, we conclude with an investigation of the shock structure in the case of two-state problems. PMID- 25288817 TI - Non-local crime density estimation incorporating housing information. AB - Given a discrete sample of event locations, we wish to produce a probability density that models the relative probability of events occurring in a spatial domain. Standard density estimation techniques do not incorporate priors informed by spatial data. Such methods can result in assigning significant positive probability to locations where events cannot realistically occur. In particular, when modelling residential burglaries, standard density estimation can predict residential burglaries occurring where there are no residences. Incorporating the spatial data can inform the valid region for the density. When modelling very few events, additional priors can help to correctly fill in the gaps. Learning and enforcing correlation between spatial data and event data can yield better estimates from fewer events. We propose a non-local version of maximum penalized likelihood estimation based on the H(1) Sobolev seminorm regularizer that computes non-local weights from spatial data to obtain more spatially accurate density estimates. We evaluate this method in application to a residential burglary dataset from San Fernando Valley with the non-local weights informed by housing data or a satellite image. PMID- 25288818 TI - Mean-field sparse optimal control. AB - We introduce the rigorous limit process connecting finite dimensional sparse optimal control problems with ODE constraints, modelling parsimonious interventions on the dynamics of a moving population divided into leaders and followers, to an infinite dimensional optimal control problem with a constraint given by a system of ODE for the leaders coupled with a PDE of Vlasov-type, governing the dynamics of the probability distribution of the followers. In the classical mean-field theory, one studies the behaviour of a large number of small individuals freely interacting with each other, by simplifying the effect of all the other individuals on any given individual by a single averaged effect. In this paper, we address instead the situation where the leaders are actually influenced also by an external policy maker, and we propagate its effect for the number N of followers going to infinity. The technical derivation of the sparse mean-field optimal control is realized by the simultaneous development of the mean-field limit of the equations governing the followers dynamics together with the Gamma-limit of the finite dimensional sparse optimal control problems. PMID- 25288819 TI - Inverse problems in geographical economics: parameter identification in the spatial Solow model. AB - The identification of production functions from data is an important task in the modelling of economic growth. In this paper, we consider a non-parametric approach to this identification problem in the context of the spatial Solow model which allows for rather general production functions, in particular convex concave ones that have recently been proposed as reasonable shapes. We formulate the inverse problem and apply Tikhonov regularization. The inverse problem is discretized by finite elements and solved iteratively via a preconditioned gradient descent approach. Numerical results for the reconstruction of the production function are given and analysed at the end of this paper. PMID- 25288820 TI - Boltzmann-type control of opinion consensus through leaders. AB - The study of formations and dynamics of opinions leading to the so-called opinion consensus is one of the most important areas in mathematical modelling of social sciences. Following the Boltzmann-type control approach recently introduced by the first two authors, we consider a group of opinion leaders who modify their strategy accordingly to an objective functional with the aim of achieving opinion consensus. The main feature of the Boltzmann-type control is that, owing to an instantaneous binary control formulation, it permits the minimization of the cost functional to be embedded into the microscopic leaders' interactions of the corresponding Boltzmann equation. The related Fokker-Planck asymptotic limits are also derived, which allow one to give explicit expressions of stationary solutions. The results demonstrate the validity of the Boltzmann-type control approach and the capability of the leaders' control to strategically lead the followers' opinion. PMID- 25288821 TI - Regulating the path from legacy recognition, through recovery to release from regulatory control. AB - Past development of processes and technologies using radioactive material led to construction of many facilities worldwide. Some of these facilities were built and operated before the regulatory infrastructure was in place to ensure adequate control of radioactive material during operation and decommissioning. In other cases, controls were in place but did not meet modern standards, leading to what is now considered to have been inadequate control. Accidents and other events have occurred resulting in loss of control of radioactive material and unplanned releases to the environment. The legacy from these circumstances is that many countries have areas or facilities at which abnormal radiation conditions exist at levels that give rise to concerns about environmental and human health of potential interest to regulatory authorities. Regulation of these legacy situations is complex. This paper examines the regulatory challenges associated with such legacy management and brings forward suggestions for finding the path from: legacy recognition; implementation, as necessary, of urgent mitigation measures; development of a longer-term management strategy, through to release from regulatory control. PMID- 25288822 TI - Achievement of therapeutic anti-Xa levels in a proven heparin-resistant patient through the use of nontraditional high-dose enoxaparin. AB - OBJECTIVE: To describe the successful use of high-dose enoxaparin therapy (1.5 mg/kg subcutaneously twice daily) to attain a therapeutic anti-factor Xa (anti Xa) level in a cancer patient with heparin resistance. CASE SUMMARY: A proven heparin-resistant patient with venous thromboembolism (VTE) and lung cancer who required approximately 66 000 units of unfractionated heparin daily was successfully transitioned to an off-label high-dose enoxaparin (OLHDE) 1.5 mg/kg subcutaneously twice daily. The patient was maintained on this same dose, and therapeutic levels were confirmed via use of the anti-Xa monitoring test. The patient was able to be discharged from the medical floor on this same dose with no further complications of VTE noted. No adverse events from this dosing were observed during the duration of therapy. DISCUSSION: Options for overcoming heparin resistance are limited to case reports and small studies. The best course of treatment in the cancer patient is unclear. OLHDE allowed for the transition from intravenous to subcutaneous medication and transition off the medical floor. This case supports the use of OLHDE as a therapeutic option in heparin-resistant patients with cancer. Further study is needed to confirm the efficacy of OLHDE in this patient population. CONCLUSION: High-dose enoxaparin may be an option to treat cancer patients with confirmed heparin resistance and venous thromboembolism. PMID- 25288823 TI - Evaluation of aspirin use in patients with diabetes receiving care in community health. AB - BACKGROUND: The American Diabetes Association (ADA) recommends low-dose aspirin therapy as a primary prevention strategy in patients with type 1 or type 2 diabetes mellitus (DM) at increased cardiovascular risk. However, not all patients who are indicated are taking aspirin therapy, and it is not routinely documented in the electronic health record (EHR). OBJECTIVE: To determine frequencies of appropriate aspirin use and documentation in the EHR in adult patients with DM. METHODS: Adult patients with DM were randomized and contacted for participation in a telephonic survey between January and October 2013. Patients who consented were administered a standardized oral telephone survey regarding aspirin use. Patient demographics, current medications, allergies, past medical history, and pertinent laboratory values were collected. Patients were then stratified by the ADA-defined indication for aspirin. The primary outcomes were rates of appropriate aspirin use and documentation of aspirin therapy in the EHR. RESULTS: Investigators contacted 276 patients for inclusion. Of the 81 patients surveyed, 74% were indicated for aspirin therapy. Nearly all (92.3%) patients reporting aspirin use were indicated for aspirin therapy compared with only 57.1% of patients who did not report aspirin but were indicated (P = 0.0003). Alternatively, 96.7% of patients with aspirin use documented in their EHR were indicated for aspirin therapy compared with only 60.8% of patients who did not have aspirin use documented in the EHR but had an indication (P = 0.0002). Approximately 20% of the patients indicated for and reporting aspirin use did not have aspirin documented in their EHR. CONCLUSIONS: Aspirin use in patients with DM who are indicated for therapy is significantly underutilized and underdocumented. PMID- 25288824 TI - A brief retrospective method for identifying longitudinal trajectories of adjustment following acute stress. AB - Research increasingly indicates that prototypical trajectories of resilience, recovery, delayed, and chronic distress characterize reactions to acute adversity. However, trajectory research has been limited by the practical and methodological difficulties of obtaining pre-event and longitudinal data. In two studies, we employed a novel method in which trained interviewers provided a graphical depiction of prototypical stress trajectories to participants and asked them to select the one that best described their experience. In Study 1, self identified trajectories from 21 high-exposure survivors of the September 11th World Trade Center attacks distinguished variation in posttraumatic stress disorder and depression symptoms at 7 and 18 months, and were consistent with trajectories based on longitudinal outcomes and friend/relative ratings. In Study 2, we examined self-identified trajectories from 115 bereaved spouses at 1.5 to 3 years. Persons who identified a resilient trajectory, compared with recovery and chronic distress trajectories, had fewer interviewer-rated symptoms of grief, depression, and posttraumatic stress disorder were rated as functioning more effectively by friends, reported higher life satisfaction, and had fewer somatic complaints. The present results provide initial evidence for the construct validity of a cross-sectional and less demanding method for identifying acute stress trajectories. PMID- 25288826 TI - Is the Sky Falling? Grade Inflation and the Signaling Power of Grades. AB - Grades are the fundamental currency of our educational system; they signal academic achievement and non-cognitive skills to parents, employers, postsecondary gatekeepers, and students themselves. Grade inflation compromises the signaling value of grades, undermining their capacity to achieve the functions for which they are intended. We challenge the 'increases in grade point average' definition of grade inflation and argue that grade inflation must be understood in terms of the signaling power of grades. Analyzing data from four nationally representative samples, we find that in the decades following 1972: (a) grades have risen at high schools and dropped at four-year colleges, in general, and selective four-year institutions, in particular; and (b) the signaling power of grades has attenuated little, if at all. PMID- 25288825 TI - Epigenome variation in severe asthma. AB - BACKGROUND: Asthma is a complex heterogeneous disease process with mild, moderate, and severe classifications. Although the science of genomics has opened our understanding of the molecular underpinnings of asthma, epigenetics is emerging as a mechanism whereby the expression of disease-risk genes may be influenced by environmental exposure. OBJECTIVES: The purpose of this article is to discuss the methodology of data collection and evaluation involved in genome wide methylation profiling (epigenomic) through presentation of data generated for a population presenting with severe asthma. METHOD: Over 14,000 gene promoter sites were analyzed for methylation status among six subjects with severe asthma and four normal controls in this pilot study. Two duplicate samples were used as technical replicates. Nonsmoking case/control subjects were chosen based on similar gender and age. Blood samples were used for DNA extraction, and methylation data were collected utilizing the Illumina Infinium HumanMethylation27BeadChip platform. RESULTS: Technical replicates were highly concordant, and statistically significant differences were found in methylation profiles between subjects with severe asthma and normal controls (p < 10(-8)), some previously reported with pulmonary function and others never before reported. After correction for multiple testing, three gene promoter regions remained statistically different: FAM181A, ZNF718, and MRI1. DISCUSSION: This research supports the internal validity of the Illumina platform in methylation analysis of DNA from stored blood samples. Although significant differences in methylation were noted between subjects with severe asthma and controls, the small sample size warrants further investigation into these results. PMID- 25288827 TI - ANISOTROPIC FUNCTION ESTIMATION USING MULTI-BANDWIDTH GAUSSIAN PROCESSES. AB - In nonparametric regression problems involving multiple predictors, there is typically interest in estimating an anisotropic multivariate regression surface in the important predictors while discarding the unimportant ones. Our focus is on defining a Bayesian procedure that leads to the minimax optimal rate of posterior contraction (up to a log factor) adapting to the unknown dimension and anisotropic smoothness of the true surface. We propose such an approach based on a Gaussian process prior with dimension-specific scalings, which are assigned carefully-chosen hyperpriors. We additionally show that using a homogenous Gaussian process with a single bandwidth leads to a sub-optimal rate in anisotropic cases. PMID- 25288828 TI - Aging in Place in a Retirement Community: 90+ Year Olds. AB - Aging in place, an image of growing old in one's home and maintaining one's daily routine, is desired by most older adults. To identify variables promoting such independent living in the oldest-old, we examined the association between living situation of a population-based cohort of 90+ year olds with health and lifestyle variables. Of 1485 participants, 53% still lived in their home at a retirement community designed to foster wellness. Those living at home tended to be healthier, with smaller proportions having chronic diseases or hospitalizations in the preceding year and a greater proportion having normal functional ability. Dementia was the chronic disease most significantly related to living situation. In addition to not having dementia, not using a wheelchair or bath aid, receiving meals on wheels, and being married were jointly related to living at home. With the help of family and friends and with a medical and social support system, many 90+ year olds can age in place. This is often because they have a caregiving spouse or paid caregiver. PMID- 25288830 TI - Lightning medicine in rural practice. PMID- 25288829 TI - Investigating the importance of sediment resuspension in Alexandrium fundyense cyst population dynamics in the Gulf of Maine. AB - Cysts of Alexandrium fundyense, a dinoflagellate that causes toxic algal blooms in the Gulf of Maine, spend the winter as dormant cells in the upper layer of bottom sediment or the bottom nepheloid layer and germinate in spring to initiate new blooms. Erosion measurements were made on sediment cores collected at seven stations in the Gulf of Maine in the autumn of 2011 to explore if resuspension (by waves and currents) could change the distribution of over-wintering cysts from patterns observed in the previous autumn; or if resuspension could contribute cysts to the water column during spring when cysts are viable. The mass of sediment eroded from the core surface at 0.4 Pa ranged from 0.05 kg m-2 near Grand Manan Island, to 0.35 kg m-2 in northern Wilkinson Basin. The depth of sediment eroded ranged from about 0.05 mm at a station with sandy sediment at 70 m water depth on the western Maine shelf, to about 1.2 mm in clayey-silt sediment at 250 m water depth in northern Wilkinson Basin. The sediment erodibility measurements were used in a sediment-transport model forced with modeled waves and currents for the period October 1, 2010 to May 31, 2011 to predict resuspension and bed erosion. The simulated spatial distribution and variation of bottom shear stress was controlled by the strength of the semi-diurnal tidal currents, which decrease from east to west along the Maine coast, and oscillatory wave-induced currents, which are strongest in shallow water. Simulations showed occasional sediment resuspension along the central and western Maine coast associated with storms, steady resuspension on the eastern Maine shelf and in the Bay of Fundy associated with tidal currents, no resuspension in northern Wilkinson Basin, and very small resuspension in western Jordan Basin. The sediment response in the model depended primarily on the profile of sediment erodibility, strength and time history of bottom stress, consolidation time scale, and the current in the water column. Based on analysis of wave data from offshore buoys from 1996 to 2012, the number of wave events inducing a bottom shear stress large enough to resuspend sediment at 80 m ranged from 0 to 2 in spring (April and May) and 0 to 10 in winter (October through March). Wave induced resuspension is unlikely in water greater than about 100 m deep. The observations and model results suggest that a millimeter or so of sediment and associated cysts may be mobilized in both winter and spring, and that the frequency of resuspension will vary interannually. Depending on cyst concentration in the sediment and the vertical distribution in the water column, these events could result in a concentration in the water column of at least 104 cysts m-3. In some years, resuspension events could episodically introduce cysts into the water column in spring, where germination is likely to be facilitated at the time of bloom formation. An assessment of the quantitative effects of cyst resuspension on bloom dynamics in any particular year requires more detailed investigation. PMID- 25288831 TI - Intracranial hypertension: Is it primary, secondary, or idiopathic? PMID- 25288832 TI - Atypical presentations of chronic subdural hematomas. PMID- 25288833 TI - Accuracy of clinical stroke scores for distinguishing stroke subtypes in resource poor settings: A systematic review of diagnostic test accuracy. AB - BACKGROUND: Stroke is the second leading cause of death globally. Computerized tomography is used to distinguish between ischemic and hemorrhagic subtypes, but it is expensive and unavailable in low and middle income countries. Clinical stroke scores are proposed to differentiate between stroke subtypes but their reliability is unknown. MATERIALS AND METHODS: We searched online databases for studies written in English and identified articles using predefined criteria. We considered studies in which the Siriraj, Guy's Hospital, Besson and Greek stroke scores were compared to computerized tomography as the reference standard. We calculated the pooled sensitivity and specificity of the clinical stroke scores using a bivariate mixed effects binomial regression model. RESULTS: In meta analysis, sensitivity and specificity for the Siriraj stroke score, were 0.69 (95% CI 0.62-0.75) and 0.83 (95% CI 0.75-0.88) for ischemic stroke and 0.65 (95% CI 0.56-0.73) and 0.88 (95% CI 0.83-0.91) for hemorrhagic stroke. For the Guy's hospital stroke score overall sensitivity and specificity were 0.70 (95% CI 0.53 0.83) and 0.79 (95% CI 0.68-0.87) for ischemic stroke and 0.54 (95% CI 0.42-0.66) and 0.89 (95% CI 0.83-0.94) for hemorrhagic stroke. CONCLUSIONS: Clinical stroke scores are not accurate enough for use in clinical or epidemiological settings. Computerized tomography is recommended for differentiating stroke subtypes. Larger studies using different patient populations are required for validation of clinical stroke scores. PMID- 25288834 TI - Neurogenic vision loss: Causes and outcome. An experience from a tertiary center in Northern India. AB - INTRODUCTION: Vision loss can be a consequence of numerous disorders of eye and neural pathway conveying visual input to brain. A variety of conditions can affect visual pathway producing neurogenic vision loss. The presentation and course of vision loss depends on the site of involvement and underlying etiology. We conducted this unprecedented study to evaluate the characteristics and outcome of various diseases of the visual pathway. MATERIALS AND METHODS: In this prospective cohort study, we evaluated 64 patients with neurogenic visual impairment. Ophthalmological causes were excluded in all of them. Their presentation, ophthalmological characteristics and investigation findings were recorded. These patients were followed up till 6 months. RESULTS: Out of 69 patients evaluated, 5 were excluded as they had ophthalmological abnormalities. The remaining 64 cases (113 eyes) were enrolled. 54 cases were due to diseases of anterior visual pathway and rest 10 had cortical vision loss. The etiologic distribution is as follows: Isolated optic neuritis- 12 (19%), multiple sclerosis 4 (6.3%), neuromyelitis optica- 5 (7.9%), tubercular meningitis- 15 (23.8%), non arteritic ischemic optic neuropathy, ischemic optic neuropathy complicating cavernous sinus thrombosis, cryptococcal meningitis, malignant infiltration of optic nerve, Crouzon's syndrome, calvarial thickening and traumatic occipital gliosis- 1 (1.6%) case each, idiopathic intracranial hypertension, pituitary adenoma, acute disseminated encephalomyelitis, posterior reversible leukoencephalopathy- 3 (4.8%) cases each, cortical venous thrombosis 5 (7.9%), subacute scleroing panencephalitis- 4 (6.3%) cases. CONCLUSIONS: The diseases of anterior visual pathway were much more common than cortical vision loss. A majority of our patients had severe impairment of vision at presentation. PMID- 25288835 TI - Novel free-hand T1 pedicle screw method: Review of 44 consecutive cases. AB - SUMMARY OF BACKGROUND DATA: Multilevel posterior cervical instrumented fusions are becoming more prevalent in current practice. Biomechanical characteristics of the cervicothoracic junction may necessitate extending the construct to upper thoracic segments. However, fixation in upper thoracic spine can be technically demanding owing to transitional anatomy while suboptimal placement facilitates vascular and neurologic complications. Thoracic instrumentation methods include free-hand, fluoroscopic guidance, and CT-based image guidance. However, fluoroscopy of upper thoracic spine is challenging secondary to vertebral geometry and patient positioning, while image-guided systems present substantial financial commitment and are not readily available at most centers. Additionally, imaging modalities increase radiation exposure to the patient and surgeon while potentially lengthening surgical time. MATERIALS AND METHODS: Retrospective review of 44 consecutive patients undergoing a cervicothoracic fusion by a single surgeon using the novel free-hand T1 pedicle screw technique between June 2009 and November 2012. A starting point medial and cephalad to classic entry as well as new trajectory were utilized. No imaging modalities were employed during screw insertion. Postoperative CT scans were obtained on day 1. Screw accuracy was independently evaluated according to the Heary classification. RESULTS: In total, 87 pedicle screws placed were at T1. Grade 1 placement occurred in 72 (82.8%) screws, Grade 2 in 4 (4.6%) screws and Grade 3 in 9 (10.3%) screws. All Grade 2 and 3 breaches were <2 mm except one Grade 3 screw breaching 2-4 mm laterally. Only two screws (2.3%) were noted to be Grade 4, both breaching medially by less than 2 mm. No new neurological deficits or returns to operating room took place postoperatively. CONCLUSIONS: This modification of the traditional starting point and trajectory at T1 is safe and effective. It attenuates additional bone removal or imaging modalities while maintaining a high rate of successful screw placement compared to historical controls. PMID- 25288836 TI - Infantile subdural empyema: The role of brain sonography and percutaneous subdural tapping in a resource-challenged region. AB - BACKGROUND: This study explored the outcome of children with patent anterior fontanelles who were treated with trans-fontanelle ultrasound scan (TFUSS), which is more affordable and available than CT scan and MRI in the diagnosis of childhood intracranial pathologies and treatment of subdural empyema, in developing countries. PATIENTS AND METHODS: Seventeen infants with post meningitic subdural empyema, diagnosed using trans-fontanelle ultrasound alone and treated with subdural tapping over a 31-months period, were studied. RESULTS: Eleven patients presented with grades II and III Bannister and William grading for level of consciousness in intracranial subdural empyema. Aspirate from 7 (41.2%) patients were sterile. The most common organisms isolated were Streptococcus faecalis 3 (17.6%), Haemophilus Influenza 2 (11.8) and Staphylococcus aureus 2 (11.8), multiple organisms were isolated in three of the patients. Ninety-four percent (94%) of the patients had good outcome. Five subjects developed hydrocephalus, one patient had a recurrence of subdural empyema, four patients had residual hemiparesis, two of the four patients had speech difficulties, while one patient (~6%) died. CONCLUSION: While CT and MRI remain the gold standard for investigating intracranial lesions, transfontanelle ultrasonography is adequate for diagnosis of infantile subdural empyema in resource-challenged areas. Percutaneous subdural tap is an affordable and effective therapy in such patients with financial challenges. PMID- 25288837 TI - Level of literacy and dementia: A secondary post-hoc analysis from North-West India. AB - INTRODUCTION: A relation between literacy and dementia has been studied in past and an association has been documented. This is in spite of some studies pointing to the contrary. The current study was aimed at investigating the influence of level of literacy on dementia in a sample stratified by geography (Migrant, Urban, Rural and Tribal areas of sub-Himalayan state of Himachal Pradesh, India). MATERIALS AND METHODS: The study was based on post-hoc analysis of data obtained from a study conducted on elderly population (60 years and above) from selected geographical areas (Migrant, Urban, Rural and Tribal) of Himachal Pradesh state in North-west India. RESULTS: Analysis of variance revealed an effect of education on cognitive scores [F = 2.823, P =0.01], however, post-hoc Tukey's HSD test did not reveal any significant pairwise comparisons. DISCUSSION: The possibility that education effects dementia needs further evaluation, more so in Indian context. PMID- 25288838 TI - Quality of life and health of opioid-dependent subjects in India. AB - BACKGROUND AND OBJECTIVES: The quality of life (QoL) of substance abusers is known to be severely impaired. This study was carried out to assess the impact of opioid dependence on the QoL of subjects and compared it with the normal subjects. MATERIALS AND METHODS: Based on specified inclusion criteria a total of 47 subjects were recruited from a tertiary care center from India. The WHOQoL BREF scale domain scores obtained at baseline were compared to that of normal subjects. An assessment of dysfunction and reasons for continuing and other parameters were assessed. RESULTS: WHOQoL-BREF domains (Physical, Psychological, Social relationships and Environment) showed significantly lower scores and the difference was statistically significant. INTERPRETATION AND CONCLUSIONS: The results showed that QoL is an important parameter in assessment of substance abusers and can be used for long-term prognosis of these individuals. PMID- 25288839 TI - Study of cluster headache: A hospital-based study. AB - INTRODUCTION: Cluster headache (CH) is uncommon and most painful of all primary headaches, and continues to be managed suboptimally because of wrong diagnosis. It needs to be diagnosed correctly and specifically treated. There are few studies and none from this region on CH. MATERIALS AND METHODS: To study the detailed clinical profile of CH patients and to compare them among both the genders. Study was conducted at Mahatma Gandhi hospital, Jodhpur (from January 2011to December 2013). Study comprises 30 CH patients diagnosed according to International Headache Society guidelines (ICHD-II). Routine investigations and MRI brain was done in all patients. All measurements were reported as mean +/- SD. Categorical variables were compared using the Chi-square test, and continuous variables were compared using Student's t-test. SPSS for Windows, Version 16.0, was used for statistical analyses with the significance level set at P = 0.05. RESULTS: M: F ratio was 9:1. Age at presentation was from 22-60 years (mean - 38 years). Latency before diagnosis was 3 months-12 years (mean - 3.5 years). All suffered from episodic CH and aura was found in none. Pain was strictly unilateral (right-19, left-11), predominantly over temporal region-18 (60%). Pain intensity was severe in 27 (90%) and moderate in 3 (10%). Pain quality was throbbing in 12 (40%). Peak intensity was reached in 5 minutes-30 minutes and attack duration varied from 30 minutes to 3 hours (mean - 2.45 hours). Among autonomic features, conjunctival injection-23 (76.6%) and lacrimation-25 (83.3%) were most common. Restlessness during episode was found in 80%. CH duration varied from 10 days to 12 weeks. Circadian periodicity for attacks was noted in 24 (80%). CONCLUSION: Results are consistent with other studies on many accounts, but is different from Western studies with respect to low frequency of family history, chronic CH, restlessness and aura preceeding the attack. Detailed elicitation of history is paramount as misdiagnosis is common. PMID- 25288840 TI - Attitudes toward psychotropic medications among patients with chronic psychiatric disorders and their family caregivers. AB - AIM: To examine attitudes towards psychotropic medications among patients with chronic psychiatric disorders as well as their family caregivers by using factor analysis. MATERIALS AND METHODS: The study included 200 patients and their family caregivers with chronic psychiatric disorders who are attending the psychiatry outpatient services. A self-designed 18-item self-rated questionnaire was used to evaluate the attitude toward psychotropics and factor analysis was done to study the different models of attitudes. RESULTS: In general both patients and caregivers had positive attitude toward the psychotropic medications and there was no significant difference between the patients and caregivers on the various items of the questionnaire assessing the attitude. Factor analysis of the questionnaire indicated that either two-factor or four-factor models explained the attitude of the patients and caregivers. In the two-factor model there was one positive and one negative attitude factor, whereas the four-factor model comprised of two positive and two negative attitude factors. The four-factor model of attitudes provided a more comprehensive solution to how attitudes might be formed among patients and their family caregivers. Factors one and four in the four-factor solution still reflected positive attitudes, but appeared to portray a risk-benefit approach, in which benefits such as the efficacy of psychotropic medications in treating mental illnesses and preventing relapse, and medications being better than other options were being contrasted with the risks of side effects and permanent damage or harm. CONCLUSION: Attitudes of patients with chronic psychiatric disorders and their caregivers toward psychotropic medications appear to be shaped by factors such as perceived efficacy or benefit from medicines, the necessity for taking treatment and concerns such as side effects, harm or expense. PMID- 25288841 TI - Over-the-counter self-medication leading to intracranial hypertension in a young lady. AB - Intracranial hypertension (idiopathic-IIH and secondary) is a potentially treatable condition. Although various factors such as female gender and obesity, certain drugs have been implicated as risk factors for IIH, there remains a lack of clarity in the exact causal-effect relationship. In India, self-medication by obtaining drugs over the counter due to lack of adequate drug regulation and ignorance of the public is a very common practice with a potential for severe adverse effects. We present a case of a young lady who has developed intracranial hypertension possibly due to self-medication with steroids and cyproheptadine, obtained over the counter. PMID- 25288842 TI - Commentary. PMID- 25288843 TI - Iniencephaly: Radiological and pathological features of a series of three cases. AB - Iniencephaly is a rare form of neural tube defect with an incidence of 0.1-10 in 10,000 pregnancies. It is characterized by the presence of occipital bone defects at foramen magnum, fixed retroflexion of head, spinal dysmorphism, and lordosis of cervicothoracic vertebrae. It is usually associated with central nervous system, gastrointestinal, and cardiovascular anomalies. We present radiological and autopsy findings in a series of 3 cases of iniencephaly (gestational ages 29.3, 23, and 24 weeks) first fetus in addition showed omphalocele, pulmonary hypoplasia, two lobes in right lung, accessory spleen, atrial septal defect, bilateral clubfoot, ambiguous genitalia, and single umbilical artery. Second fetus was a classical case of iniencephaly apertus with spina bifida. Third fetus had colpocephaly and bifid spine. PMID- 25288844 TI - A case of Ross syndrome presented with Horner and chronic cough. AB - Ross syndrome is a rare sweating disorder associated with Adie's tonic pupil, decreased or diminished tendon reflex and unknown etiology. Although autonomic disturbances affecting sudomotor and vasomotor functions are seen commonly, they are rarely symptomatic. While Ross syndrome is typically characterized with dilated tonic pupil, it may be rarely manifested with miotic pupils (little old Adie's pupil), which can make diagnosis difficult. In this article, we aim to specify the atypical clinical manifestations of syndrome by means of Ross syndrome manifested by autonomic symptoms, Horner syndrome, chronic cough together with bilateral little old Adie's pupil. PMID- 25288845 TI - Commentary. PMID- 25288846 TI - Lightning strike-induced brachial plexopathy. AB - We describe a patient who presented with a history of lightning strike injury. Following the injury, he sustained acute right upper limb weakness with pain. Clinically, the lesion was located to the upper and middle trunk of the right brachial plexus, and the same confirmed with electrophysiological studies. Nerve damage due to lightning injuries is considered very rare, and a plexus damage has been described infrequently, if ever. Thus, the proposed hypothesis that lightning rarely causes neuropathy, as against high-voltage electric current, due to its shorter duration of exposure not causing severe burns which lead to nerve damage, needs to be reconsidered. PMID- 25288847 TI - Commentary. PMID- 25288848 TI - M5 segment aneurysm presenting as "pure acute SDH". AB - Spontaneous "pure acute subdural hematoma (SDH)" is arguably a rare condition. We report on a pregnant female patient presenting as spontaneous acute SDH without subarachnoid hemorrhage (SAH) due to rupture of distal (M5 segment) middle cerebral artery aneurysm. We hereby discuss the diagnostic dilemma of this rare condition, along with the need for watchful evaluation of acute SDH without preceding head injury presenting in emergency outpatient departments, especially when it is first encountered by a trainee resident. PMID- 25288849 TI - Head banging persisting during adolescence: A case with polysomnographic findings. AB - Head banging is a sleep-related rhythmic movement disorder of unknown etiology. It is common during infancy; however, available literature suggests that prevalence decreases dramatically after childhood. We report the case of a 16 year-old male who presented with head banging. The symptoms were interfering with his functioning and he had been injured because of the same in the past. We are presenting the video-polysomnographic data of the case. Possible differential diagnoses, etiology, and treatment modalities are discussed. The boy was prescribed clonazepam and followed up for 3 months. Parents did not report any episode afterward. PMID- 25288850 TI - Giant cell arteritis or tension-type headache?: A differential diagnostic dilemma. AB - Giant cell arteritis (GCA) or Temporal arteritis (TA) is an autoimmune disease and the most common type of vasculitis in the elderly. It causes inflammation of the medium and large arteries in the upper part of the body. GCA is an under recognized cause of head aches in the elderly, especially when it presents itself with atypical features, resulting in delayed or incorrect diagnosis. Since GCA is a treatable condition, an accurate diagnosis is crucial to prevent the most serious complication of CGA, permanent vision loss. The diagnosis can be further complicated as GCA may present with features of other painful neurological conditions. The present case is an 81-year-old woman diagnosed with GCA, who initially presented with features similar to tension-type headache. Due to overlapping features of these conditions, the diagnosis of GCA was delayed, resulting in irreversible vision loss. Although previous research highlights diagnostic dilemmas featuring GCA and other disease states, this case is exclusive in describing a unique dilemma where tension-type headache mimics GCA. PMID- 25288851 TI - Commentary. PMID- 25288852 TI - Commentary. PMID- 25288853 TI - Extensive long-segment cervicothoracic traumatic spinal epidural hematoma with avulsion of C7, C8, and T1 nerve roots. AB - Traumatic spinal epidural hematoma (TSEH) is of rare clinical occurrence. We report a case of a young man with posttraumatic long-segment spinal epidural hematoma. Evacuation of the hematoma led to complete neurologic recovery in our patient. Our case highlights the importance of early diagnosis and prompt surgical intervention for the evacuation of hematoma in preservation or maximum recovery of neurologic function. Imaging findings, management options, and the relevant literature are reviewed. PMID- 25288854 TI - Ischemic stroke following abuse of Marijuana in a Nigerian adult male. AB - Cannabis is the most widely used illicit drug among adolescents and young adults. Despite its widespread use, only a few reports exist on the association of cannabis use and stroke. A 26-year-old Nigerian male, developed right-sided ischemic stroke few hours after smoking three wraps of cannabis. He had smoked cannabis consistently for the past 4 years prior to the development of the stroke. Known stroke etiology and abuse of other illicit drugs were ruled out from history and investigations. Neuroimaging studies of the brain revealed infarcts in basal ganglia secondary to occlusion of blood flow in the left anterior and middle cerebral arteries. The mechanism of stroke in this patient was thought to be a cannabis-induced vasculopathy. Many cases of stroke in the young are increasingly being seen in hospitals in resource scarce countries. There seems to be a predilection for the basal ganglia in ischemic stroke following cannabis abuse. Therefore, cannabis abuse should be considered in young adults with basal ganglia infarcts, after excluding other known etiologies. PMID- 25288855 TI - Psychiatric disorders revealing multiple sclerosis after 20 years of evolvement. AB - Previous research indicates that the onset of psychiatric disorders is sometimes associated with multiple sclerosis (MS) evolving several years later. However, information on why this might occur, and on the outcomes of such patients, is still lacking. We aim to discuss these limitations with the current paper. We describe a 51-year-old female who demonstrated severe anxiety disorder and depression years before developing MS neurological symptoms. The patient was treated for these psychiatric disorders over 20 years. In the last 3 years of her treatment, the patient demonstrated a choreic-type of movement disorder in all her limbs. This disorder is consistent with relapsing-remitting MS. Clinical and magnetic resonance imaging (MRI) examinations demonstrated aspects of MS, without MS being diagnosed conclusively. The visual evoked potential indicated a diagnosis of conduction abnormalities. The established diagnosis was slow relapsing MS. The patient underwent methylprednisolone bolus (1 g/day). This case study suggests that health professionals should conduct a full neurological assessment when they find atypical psychiatric symptoms in a patient. This would make sure that patients receive a better standard of care, and thus experience a better quality of life. PMID- 25288856 TI - Malignant nodular hidradenoma of scalp. AB - Malignant nodular hidradenoma (MNH) is a rare tumor of sweat gland known by many names in the literature. Scalp is a known and yet uncommon site of occurrence. We describe two patients with scalp MNH with brain parenchymal invasion. Both tumors recurred in spite of total excision and radiotherapy. PMID- 25288857 TI - Commentary. PMID- 25288858 TI - Psychiatry in 21(st) century: The road ahead. AB - In spite of becoming more humane in its approach with improvements in understanding of mental illnesses over last century, psychiatry still has a long way to go. At this point in time, on one hand the world faces issues like terrorism, wars and global warming; while on the other it is witnessing economic and gender empowerment like never before. With technology providing us with immense opportunities to advance care for the mentally ill, we are closer than ever to finding the holy-grail of psychiatry, and overcoming daunting challenges. PMID- 25288860 TI - "White cerebellum" sign - A dark prognosticator. PMID- 25288859 TI - Strengthening molecular genetics and training in craniosynostosis: The need of the hour. AB - Craniosynostosis (CS) is premature fusion of skull. It is divided into two groups: Syndromic craniosynostosis (SCS) and non-syndromic craniosynostosis (NSC). Its incidence in Indian population is 1:1000 live births where as in the USA it is 1:2500 live births. Its incidence varies from country to country. Molecular genetics having great interest and relevance in medical students, faculty, scientist, pediatric neurosurgeon and staff nurses, our objective was to educate the medical students, residents, researchers, clinicians, pediatric neurosurgeon, anesthetists, pediatricians, staff nurses and paramedics. We summarized here including with diagnosis, investigations, surgical therapy, induction therapy, and molecular therapy. Molecular genetics training is needed to know the information regarding development of skull, cranial connective tissue, craniofacial dysplasia, frame work, network of receptors and its etiopathogenesis. The important part is clinically with molecular therapy (MT) how to manage CS in rural sector and metropolitan cities need a special attention. PMID- 25288861 TI - Arterial infarct following surgery for pituitary adenoma. PMID- 25288862 TI - Partially thrombosed distal orbitofrontal artery aneurysm mimicking an A1 segment aneurysm. PMID- 25288863 TI - Is staged surgery for giant vestibular schwannomas always better in improving outcome: Needs socioeconomic consideration? PMID- 25288864 TI - Isolated hemimegalencephaly in an adult. PMID- 25288865 TI - Stereotactic procedures using the BRA_K (FN) system: An experience with the first 100 cases. PMID- 25288866 TI - High intradural lumbar disk herniation: Known result of an unknown cause. PMID- 25288867 TI - Dissecting aneurysm of the posterior cerebral artery: Defining the role of deliberate surgical proximal artery occlusion. PMID- 25288868 TI - Chronic subdural hematoma presenting as diplegia-A rare presentation. PMID- 25288869 TI - Hoffman's syndrome - A rare facet of hypothyroid myopathy. PMID- 25288870 TI - Benefits of self-superparasitism in a polyembryonic parasitoid. AB - Macrocentrus grandii is a polyembryonic parasitoid, with embryos that divide asexually within the host (European corn borer, Ostrinia nubilalis) to produce broods of clonal offspring. From a biological control standpoint, polyembryony seems advantageous because each parasitized host yields multiple parasitoids with minimal time and egg investment. When we observed M. grandii in the field, however, we found that the parasitoid virtually always invested additional time and, if possible, stings into hosts that it had already stung, apparently reducing some of the advantages of polyembryony. We therefore investigated and found support for two potential benefits that can be gained by self superparasitism in this system. First, multiple stings allowed production of mixed-sex broods: 27% of multiply-stung versus 0% of singly-stung hosts produced mixed-sex broods. Second, multiple stings increased mean parasitoid progeny produced per host, primarily by reducing the chance of complete brood failure. Our results indicate substantial benefit for a second sting, but little benefit for three or more stings, even though M. grandii was sometimes observed to invest more than two stings within a single host. However, we also found that within host larval competition is prevalent, suggesting that supernumerary stings may pay off in competition against conspecific larvae. Such additional investment within a single host would be particularly beneficial when hosts, rather than eggs, are limiting, but would decrease the overall efficacy of M. grandii as a biological control agent. PMID- 25288871 TI - Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C-H Functionalization Sequences. AB - A Rh-catalyzed C-H bond activation/alkenylation/electrocyclization cascade reaction provides diverse 1,2-dihydropyridines from simple and readily available precursors. The reaction can be carried out at low (<1%) Rh-catalyst loadings, and the use of the robust, air-stable Rh precatalyst, [RhCl(cod)]2, enables the cascade reaction to be easily performed on the benchtop. The 1,2-dihydropyridine products serve as extremely versatile synthetic intermediates for further elaboration often without isolation. The addition of electrophiles under kinetic or thermodynamic conditions provides a wide range of iminiums. Subsequent addition of a nucleophile then generates a diverse array of differently substituted piperidine products. Additionally, [3 + 2] and [4 + 2] cycloadditions of the 1,2-dihydropyridine intermediate provides access to bridged bicyclic structures such as tropanes and isoquinuclidines. These concise reaction sequences enable the formation of highly substituted piperidines in synthetically useful yields with excellent diastereoselectivity. PMID- 25288872 TI - Preparative Synthesis of Highly Substituted Tetrahydropyridines via a Rh(I) Catalyzed C-H Functionalization Sequence. AB - We report a Rh(I)-catalyzed C-H activation/alkenylation/electrocyclization cascade and subsequent reduction for the synthesis of highly substituted tetrahydropyridines. These products can be accessed on a gram scale with low catalyst loadings and at high reaction concentrations. Additionally, a modified Rh-catalyst, prepared from [RhCl(cod)]2 as a robust bench-stable precatalyst was developed to enable straightforward reaction set up without the use of a glovebox. To demonstrate the practicality of this reaction, a >100 mmol scale Rh catalyzed cascade reaction sequence utilizing the air-stable precatalyst [RhCl(cod)]2 was performed on the bench to furnish the pure tetrahydropyridine product in 93% yield. PMID- 25288873 TI - Revising the Dust Bowl: High Above the Kansas Grasslands. AB - This article reconstructs land cover patterns in Depressionera Kansas from historical aerial photos and compares the locations of crop fields to areas of submarginal land identified in modern digital soil survey maps. The analysis argues that New Deal land retirement programs overestimated the degree of bad land use because they lacked the basic science to make comprehensive assessments. The findings demonstrate that the misuse of land unfit for cultivation was relatively rare across the central plains but especially in the Dust Bowl region. PMID- 25288874 TI - Classification, predictive modelling, and statistical analysis of cancer data (a). PMID- 25288877 TI - A bayesian integrative model for genetical genomics with spatially informed variable selection. AB - We consider a Bayesian hierarchical model for the integration of gene expression levels with comparative genomic hybridization (CGH) array measurements collected on the same subjects. The approach defines a measurement error model that relates the gene expression levels to latent copy number states. In turn, the latent states are related to the observed surrogate CGH measurements via a hidden Markov model. The model further incorporates variable selection with a spatial prior based on a probit link that exploits dependencies across adjacent DNA segments. Posterior inference is carried out via Markov chain Monte Carlo stochastic search techniques. We study the performance of the model in simulations and show better results than those achieved with recently proposed alternative priors. We also show an application to data from a genomic study on lung squamous cell carcinoma, where we identify potential candidates of associations between copy number variants and the transcriptional activity of target genes. Gene ontology (GO) analyses of our findings reveal enrichments in genes that code for proteins involved in cancer. Our model also identifies a number of potential candidate biomarkers for further experimental validation. PMID- 25288878 TI - Integrative bayesian network analysis of genomic data. AB - Rapid development of genome-wide profiling technologies has made it possible to conduct integrative analysis on genomic data from multiple platforms. In this study, we develop a novel integrative Bayesian network approach to investigate the relationships between genetic and epigenetic alterations as well as how these mutations affect a patient's clinical outcome. We take a Bayesian network approach that admits a convenient decomposition of the joint distribution into local distributions. Exploiting the prior biological knowledge about regulatory mechanisms, we model each local distribution as linear regressions. This allows us to analyze multi-platform genome-wide data in a computationally efficient manner. We illustrate the performance of our approach through simulation studies. Our methods are motivated by and applied to a multi-platform glioblastoma dataset, from which we reveal several biologically relevant relationships that have been validated in the literature as well as new genes that could potentially be novel biomarkers for cancer progression. PMID- 25288875 TI - Functional annotation of putative regulatory elements at cancer susceptibility Loci. AB - Most cancer-associated genetic variants identified from genome-wide association studies (GWAS) do not obviously change protein structure, leading to the hypothesis that the associations are attributable to regulatory polymorphisms. Translating genetic associations into mechanistic insights can be facilitated by knowledge of the causal regulatory variant (or variants) responsible for the statistical signal. Experimental validation of candidate functional variants is onerous, making bioinformatic approaches necessary to prioritize candidates for laboratory analysis. Thus, a systematic approach for recognizing functional (and, therefore, likely causal) variants in noncoding regions is an important step toward interpreting cancer risk loci. This review provides a detailed introduction to current regulatory variant annotations, followed by an overview of how to leverage these resources to prioritize candidate functional polymorphisms in regulatory regions. PMID- 25288876 TI - A review of cancer risk prediction models with genetic variants. AB - Cancer risk prediction models are important in identifying individuals at high risk of developing cancer, which could result in targeted screening and interventions to maximize the treatment benefit and minimize the burden of cancer. The cancer-associated genetic variants identified in genome-wide or candidate gene association studies have been shown to collectively enhance cancer risk prediction, improve our understanding of carcinogenesis, and possibly result in the development of targeted treatments for patients. In this article, we review the cancer risk prediction models that have been developed for popular cancers and assess their applicability, strengths, and weaknesses. We also discuss the factors to be considered for future development and improvement of models for cancer risk prediction. PMID- 25288879 TI - Integrated analysis of whole-genome paired-end and mate-pair sequencing data for identifying genomic structural variations in multiple myeloma. AB - We present a pipeline to perform integrative analysis of mate-pair (MP) and paired-end (PE) genomic DNA sequencing data. Our pipeline detects structural variations (SVs) by taking aligned sequencing read pairs as input and classifying these reads into properly paired and discordantly paired categories based on their orientation and inferred insert sizes. Recurrent SV was identified from the discordant read pairs. Our pipeline takes into account genomic annotation and genome repetitive element information to increase detection specificity. Application of our pipeline to whole-genome MP and PE sequencing data from three multiple myeloma cell lines (KMS11, MM.1S, and RPMI8226) recovered known SVs, such as heterozygous TRAF3 deletion, as well as a novel experimentally validated SPI1 - ZNF287 inter-chromosomal rearrangement in the RPMI8226 cell line. PMID- 25288880 TI - Comparative study of computational methods for reconstructing genetic networks of cancer-related pathways. AB - Network reconstruction is an important yet challenging task in systems biology. While many methods have been recently proposed for reconstructing biological networks from diverse data types, properties of estimated networks and differences between reconstruction methods are not well understood. In this paper, we conduct a comprehensive empirical evaluation of seven existing network reconstruction methods, by comparing the estimated networks with different sparsity levels for both normal and tumor samples. The results suggest substantial heterogeneity in networks reconstructed using different reconstruction methods. Our findings also provide evidence for significant differences between networks of normal and tumor samples, even after accounting for the considerable variability in structures of networks estimated using different reconstruction methods. These differences can offer new insight into changes in mechanisms of genetic interaction associated with cancer initiation and progression. PMID- 25288882 TI - Preclinical evaluation of recombinant human IFNalpha2b-containing magnetoliposomes for treating hepatocellular carcinoma. AB - Magnetoliposomes are phospholipid vesicles encapsulating magnetic nanoparticles that can be used to encapsulate therapeutic drugs for delivery into specific organs. Herein, we developed magnetoliposomes containing recombinant human IFNalpha2b, designated as MIL, and evaluated this combination's biological safety and therapeutic effect on both cellular and animal hepatocellular carcinoma models. Our data showed that MIL neither hemolyzed erythrocytes nor affected platelet-aggregation rates in blood. Nitroblue tetrazolium-reducing testing showed that MIL did not change the absolute numbers or phagocytic activities of leukocytes. Acute-toxicity testing also showed that MIL had no devastating effect on mice behaviors. All the results indicated that the nanoparticles could be a safe biomaterial. Pharmacokinetic analysis and tissue-distribution studies showed that MIL maintained stable and sustained drug concentrations in target organs under a magnetic field, helped to increase bioavailability, and reduced administration time. MIL also dramatically inhibited the growth of hepatoma cells. Targeting of MIL in the livers of nude mice bearing human hepatocellular carcinoma showed that MIL significantly reduced the tumor size to 38% of that of the control group. Further studies proved that growth inhibition of cells or tumors was due to apoptosis-signaling pathway activation by human IFNalpha2b. PMID- 25288883 TI - Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model. AB - Exogenous administration of growth factors has potential benefits in wound healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulation composed of highly skin-permeable multimeric nanocomplex of growth factors. In the present study, we fused low-molecular-weight protamine (LMWP) with epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-I), and platelet-derived growth factor A ligand (PDGF-A) (producing recombinant [r]LMWP-EGF, rLMWP-IGF-I, and rLMWP-PDGF-A, respectively) via genetic modification. Then, we used in vitro cell proliferation studies to assess the biological activity and the benefits of the combination. The LMWP-conjugated growth factors were complexed with low-molecular weight heparin (LMWH) and formulated with Poloxamer 188 as a delivery vehicle. After confirming the enhanced skin permeability, in vivo studies were performed to assess whether the LMWP-conjugated growth factor nanocomplex formulations accelerated the healing of full-thickness wounds in mice. The LMWP-conjugated growth factors were biologically equivalent to their native forms, and their combination induced greater fibroblast proliferation. rLMWP-EGF showed significantly enhanced permeability and cumulative permeation, and the rates for rLMWP-IGF-I and rLMWP-PDGF-A, across excised mouse skin, were 124% and 164% higher, respectively, than for the native forms. The LMWP-fused growth factors resulted in formation of nanocomplexes (23.51+/-1.12 nm in diameter) in combination with LMWH. Topical delivery of growth factors fused with LMWP accelerated wound re-epithelialization significantly, accompanied by the formation of healthy granulation tissue within 9 days compared with a free-growth factor complex or vehicle. Thus, the LMWP-conjugated growth factor nanocomplex can induce rapid, comprehensive healing and may be a candidate wound-healing therapeutic. PMID- 25288884 TI - Sleep Disturbances in Individuals with Alcohol-Related Disorders: A Review of Cognitive-Behavioral Therapy for Insomnia (CBT-I) and Associated Non Pharmacological Therapies. AB - Sleep disturbances are common among alcohol-dependent individuals and are often associated with relapse. The utility of behavioral therapies for sleep disturbances, including cognitive-behavioral therapy for insomnia (CBT-I), among those with alcohol-related disorders is not well understood. This review systematically evaluates the evidence of CBT-I and related behavioral therapies applied to those with alcohol-related disorders and accompanying sleep disturbances. A search of four research databases (PubMed, PsycINFO, Embase, and CINAHL Plus) yielded six studies that met selection criteria. Articles were reviewed using Cochrane's Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) scoring system. A majority of the studies demonstrated significant improvements in sleep efficiency among behavioral therapy treatment group(s), including but not limited to CBT-I. While behavioral sleep interventions have been successful in varied populations, they may not be utilized to their full potential among those with alcohol-related disorders as evidenced by the low number of studies found. These findings suggest a need for mixed-methods research on individuals' sleep experience to inform interventions that are acceptable to the target population. PMID- 25288881 TI - Review of current methods, applications, and data management for the bioinformatics analysis of whole exome sequencing. AB - The advent of next-generation sequencing technologies has greatly promoted advances in the study of human diseases at the genomic, transcriptomic, and epigenetic levels. Exome sequencing, where the coding region of the genome is captured and sequenced at a deep level, has proven to be a cost-effective method to detect disease-causing variants and discover gene targets. In this review, we outline the general framework of whole exome sequence data analysis. We focus on established bioinformatics tools and applications that support five analytical steps: raw data quality assessment, pre-processing, alignment, post-processing, and variant analysis (detection, annotation, and prioritization). We evaluate the performance of open-source alignment programs and variant calling tools using simulated and benchmark datasets, and highlight the challenges posed by the lack of concordance among variant detection tools. Based on these results, we recommend adopting multiple tools and resources to reduce false positives and increase the sensitivity of variant calling. In addition, we briefly discuss the current status and solutions for big data management, analysis, and summarization in the field of bioinformatics. PMID- 25288885 TI - Limitations of Using Propidium Monoazide with qPCR to Discriminate between Live and Dead Legionella in Biofilm Samples. AB - Accurately quantifying Legionella for regulatory purposes to protect public health is essential. Real-time PCR (qPCR) has been proposed as a better method for detecting and enumerating Legionella in samples than conventional culture method. However, since qPCR amplifies any target DNA in the sample, the technique's inability to discriminate between live and dead cells means that counts are generally significantly overestimated. Propidium monoazide (PMA) has been used successfully in qPCR to aid live/dead discrimination. We tested PMA use as a method to count only live Legionella cells in samples collected from a modified chemostat that generates environmentally comparable samples. Counts from PMA-treated samples that were pretreated with either heat or three types of disinfectants (to kill the cells) were highly variable, with the only consistent trend being the relationship between biofilm mass and numbers of Legionella cells. Two possibilities explain this result: 1. PMA treatment worked and the subsequent muted response of Legionella to disinfection treatment is a factor of biofilm/microbiological effects; although this does not account for the relationship between the amount of biofilm sampled and the viable Legionella count as determined by PMA-qPCR; or 2. PMA treatment did not work, and any measured decrease or increase in detectable Legionella is because of other factors affecting the method. This is the most likely explanation for our results, suggesting that higher concentrations of PMA might be needed to compensate for the presence of other compounds in an environmental sample or that lower amounts of biofilm need to be sampled. As PMA becomes increasingly toxic at higher concentrations and is very expensive, augmenting the method to include higher PMA concentrations is both counterproductive and cost prohibitive. Conversely, if smaller volumes of biofilm are used, the reproducibility of the method is reduced. Our results suggest that using PMA is not an appropriate method for discriminating between live and dead cells to enumerate Legionella for regulatory purposes. PMID- 25288886 TI - A survey of membrane proteins in human serum. AB - Serum and membrane proteins are two of the most attractive targets for proteomic analysis. Previous membrane protein studies tend to focus on tissue sample, while membrane protein studies in serum are still limited. In this study, an analysis of membrane proteins in normal human serum was carried out. Nano-liquid chromatography-electrospray ionization mass spectrometry (NanoLC-ESI-MS/MS) and bioinformatics tools were used to identify membrane proteins. Two hundred and seventeen membrane proteins were detected in the human serum, of which 129 membrane proteins have at least one transmembrane domain (TMD). Further characterizations of identified membrane proteins including their subcellular distributions, molecular weights, post translational modifications, transmembrane domains and average of hydrophobicity, were also implemented. Our results showed the potential of membrane proteins in serum for diagnosis and treatment of diseases. PMID- 25288887 TI - Mutational effect of structural parameters on coiled-coil stability of proteins. AB - Understanding the parameters that influence the melting temperature of coiled coils (CC) and their stability is very important. We have analyzed 45 CC mutants of DNA binding protein, electron transport protein, hydrolase, oxidoreductase, and transcription factors. Many mutants have been observed at Tm = 40 degrees C 60 degrees C with DeltaS = 9-11 kcal/ degrees C mol, DeltaG = -400 to -450 kcal/mol, and Keq = 0.98-1.03. The multiple regression analysis of Tm reveals that influences of thermodynamic parameters are strong (R = 0.97); chemical parameters are moderate (R = 0.63); and the geometrical parameters are negligible (R = 0.19). The combination of all these three parameters exhibits a little higher influence on Tm (R = 0.98). From the analysis, it has been concluded that the thermodynamic parameters alone are very important in stability studies on protein coil mutants. Besides, the derived regression model would have been useful for the reliable prediction of the melting temperature of coil mutants. PMID- 25288888 TI - Proteomic Analysis of Soybean [Glycine max (L.) Merrill] Roots Inoculated with Bradyrhizobium japonicum Strain CPAC 15. AB - This research intended to analyze the expression pattern of proteins in roots of the Brazilian soybean cultivar Conquista when inoculated with Bradyrhizobium japonicum CPAC 15, a strain broadly used in commercial inoculants in Brazil. At ten days after bacterial inoculation, whole-cell proteins were extracted from roots and separated by 2-D gel electrophoresis. Comparative analysis revealed significant changes in the intensity of 37 spots due to the inoculation (17 up regulated and 20 down-regulated proteins), identified by MALDI-TOF/TOF-TOF. Identified proteins were associated with COG functional categories of information storage and processing, cellular processes and signaling, metabolism, and also in the "poorly characterized" and "not in COG" categories. Among the up-regulated proteins, we identified sucrose synthase (nodulin-100), beta-tubulin, rubisco activase, glutathione-S-transferase, a putative heat-shock 70-kDa protein, pyridine nucleotide-disulphideoxidoreductase and a putative transposase. Proteomic analysis allowed for the identification of some putative symbiotic functions and confirmed the main biological processes triggered in the nitrogen fixing symbiosis with soybean. PMID- 25288890 TI - Hemophilia A in Brazil - epidemiology and treatment developments. AB - Hemophilia A is an inherited disorder characterized by deficiency of coagulation factor VIII, which predisposes patients to bleeding events. Treatment is based on replacement of the deficient factor, in a therapeutic or prophylactic manner. Brazil is the country with the third largest population of people with hemophilia, for which the public health system provides free comprehensive care. Maintaining an updated registry of patients, documenting the prevalence of complications, and assessing the effectiveness of resource use are indispensable elements in the design of a well-coordinated national program. According to sociodemographic, clinical, and laboratory data collected by the computerized Brazilian system on coagulopathies, in June 2013, there were 9,122 registered patients with hemophilia A in Brazil, of which 36.1% had a severe form of the disease. Clotting factor inhibitors were present in 7.5%, but 25.7% of records did not provide this type of data. Around 70% of the patients belonged to the economically active population, being between 15 and 59 years old. Infection by the human immunodeficiency virus was present in 23.4% of the patients tested and infection by hepatitis C virus antibodies in 59.3%. Infection by the hepatitis B virus and human T-lymphotropic virus was also reported. The high percentage of incomplete records regarding serological data shows the fragility of the information system to date. There was also no information available on the prevalence of permanent or disabling joint damage. Although few hemophiliacs receive adequate care in developing countries, and despite Brazil exhibiting great social inequalities, the Ministry of Health has made significant advances in the treatment of hemophilia A. The gradual increase in importation of factor VIII concentrate enabled the implementation of primary and secondary modalities of prophylaxis, in addition to the induction of immune tolerance. There are also plans to set up a factory in the country, to ensure Brazilian self-sufficiency in the production of blood products. PMID- 25288889 TI - Imbalanced kynurenine pathway in schizophrenia. AB - Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 +/- 1.5 nM vs. 18.2 +/- 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls (P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia. PMID- 25288891 TI - Impact of treatment time on the survival of patients suffering from invasive fungal rhinosinusitis. AB - BACKGROUND: Invasive fungal rhinosinusitis is an uncommon disease with high mortality rates. There is currently no consensus on the best treatment timing. We studied the impact of the treatment timing on the survival of patients experiencing invasive fungal rhinosinusitis. METHODS: We conducted a retrospective study of patients suffering from invasive fungal rhinosinusitis. The duration of symptoms, clinical presentations, clinical signs, diagnoses, treatments, and outcomes were collected. RESULTS: It was observed that more than 70% of the mortalities occurred within the subgroup of patients who exhibited symptoms of the disease within 14 days before admission. After adjusting for the confounders, the time taken to treat the patients was the most statistically significant predictor for mortality (P = 0.045). We found no significant relationships between mortality and its significant covariates, which included the underlying diseases (P = 0.91) or complications (P = 0.55). CONCLUSIONS: Our study demonstrates that the time taken to treat the patients is an important determinant for the survival of patients who are afflicted with invasive fungal rhinosinusitis. The appropriate treatments should be administered within 14 days from the time the symptoms begin to manifest. PMID- 25288892 TI - A clinical perspective of canagliflozin in the management of type 2 diabetes mellitus. AB - OBJECTIVE: To assess the real-world efficacy and safety of the first sodium glucose cotransporter-2 inhibitor, canagliflozin, in the treatment of patients with type 2 diabetes mellitus (T2DM). METHODS: This observational study assessed the efficacy and tolerability of canagliflozin in T2DM patients. Primary study outcomes were changes in HbA1C and weight, and percentage of patients reporting adverse effects of therapy. RESULTS: The study criteria were met by 111 patient records. Baseline patient characteristics were: average age, 59 +/- 9 years; mean duration of T2DM, 11.9 +/- 7.3 years; 57.6% of patients were male; 92.8% were Caucasian; baseline BMI, 38.9 +/- 11 kg/m(2); and mean baseline HbA1C, 7.53 (58.8 mmol/mol) +/- 1.08%. HbA1C and weight were significantly reduced by 0.37% and 4.4 kg, respectively. Adverse effects were reported by 21 patients, and 17 (15.3%) discontinued canagliflozin because of adverse reactions. CONCLUSION: Canagliflozin was generally well tolerated and significantly reduced HbA1C levels and body weight in patients with T2DM when added to a regimen of other anti hyperglycemic agents. PMID- 25288893 TI - Human papilloma virus and squamous cell carcinoma of the anus. AB - The incidence of anal cancer is increasing. In the UK, the incidence is estimated at approximately 1.5 per 100,000. Most of this increase is attributed to certain at-risk populations. Persons who are human immunodeficiency virus (HIV)-positive and men who have sex with men (MSM), Organ transplant recipients, women with a history of cervical cancer, human papilloma virus (HPV), or cervical intraepithelial neoplasia (CIN) are known to have a greater risk for anal cancer. This paper will focus on HPV as a risk factor for anal intraepithelial neoplasia (AIN) and discusses the etiology, anatomy, pathogenesis, management of squamous cell carcinoma (SCC) of the anus. PMID- 25288894 TI - Chronic Lymphocytic Leukemia with t(14;18)(q32;q21) As a Sole Cytogenetic Abnormality. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The chromosomal abnormality t(14;18)(q32;q21) is most commonly associated with neoplasms of a follicular center cell origin. However, t(14;18) has also been reported in rare cases of CLL. OBJECTIVE: We describe the clinicopathologic, immunophenotypic, conventional, and molecular cytogenetic features of two rare cases proven to be CLL morphologically and immunologically in which t(14;18) was found as the sole cytogenetic abnormality. METHODS: Morphologic, flow cytometric analysis and molecular cytogenetic of peripheral blood and/or bone marrow samples were analyzed. RESULTS: Cytomorphologically, the cells were small mature lymphocytes without any findings that had characteristics of follicular lymphoma (FL) such as indented or clefted nuclei. Immunologic findings were characteristic of typical CLL without expression of CD10. A cytogenetic study revealed the two cases of CLL carrying t(14;18)(q32;q21). CONCLUSION: We concluded that CLL with t(14;18) is rare and should be differentiated from FL as the therapy is highly diverse between both diseases. Using immunoglobulin heavy chain gene (IGH) probes are important in the workup of patients with suspected CLL and suggest that the IGH probe should be used routinely in all CLL fluorescence in situ hybridization (FISH) panels. PMID- 25288895 TI - Distal Deletion of Chromosome 11q Encompassing Jacobsen Syndrome without Platelet Abnormality. AB - Terminal 11q deletion, known as Jacobsen syndrome (JBS), is a rare genetic disorder associated with numerous dysmorphic features. We studied two cases with multiple congenital anomalies that were cytogenetically detected with deletions on 11q encompassing JBS region: 46,XX,der(11) del(11)(q24). Array comparative genomic hybridization (aCGH) analysis confirmed partial deletion of 11.8-11.9 Mb at 11q24.1q25 (case 1) and 13.9-14 Mb deletion at 11q23.3q25 together with 7.3 7.6 Mb duplication at 12q24.32q24.33 (case 2). Dysmorphism because of the partial duplication of 12q was not overtly decipherable over the Jacobsen phenotype except for a triangular facial profile. Aberrant chromosome 11 was inherited from phenotypically normal father, carrier of balanced translocation 46,XY,t(11;12)(q23.3; q24.32). In the present study, both cases had phenotypes that were milder than the ones described in literature despite having large deletion size. Most prominent features in classical JBS is thrombocytopenia, which was absent in both these cases. Therefore, detailed functional analysis of terminal 11q region is warranted to elucidate etiology of JBS and their clinical presentation. PMID- 25288896 TI - A Comparative Approach to Hand Force Estimation using Artificial Neural Networks. AB - In many applications that include direct human involvement such as control of prosthetic arms, athletic training, and studying muscle physiology, hand force is needed for control, modeling and monitoring purposes. The use of inexpensive and easily portable active electromyography (EMG) electrodes and position sensors would be advantageous in these applications compared to the use of force sensors which are often very expensive and require bulky frames. Among non-model-based estimation methods, Multilayer Perceptron Artificial Neural Networks (MLPANN) has widely been used to estimate muscle force or joint torque from different anatomical features in humans or animals. This paper investigates the use of Radial Basis Function (RBF) ANN and MLPANN for force estimation and experimentally compares the performance of the two methodologies for the same human anatomy, ie, hand force estimation, under an ensemble of operational conditions. In this unified study, the EMG signal readings from upper-arm muscles involved in elbow joint movement and elbow angular position and velocity are utilized as inputs to the ANNs. In addition, the use of the elbow angular acceleration signal as an input for the ANNs is also investigated. PMID- 25288897 TI - Application of a Bioinformatics-Based Approach to Identify Novel Putative in vivo BACE1 Substrates. AB - BACE1, a membrane-bound aspartyl protease that is implicated in Alzheimer's disease, is the first protease to cut the amyloid precursor protein resulting in the generation of amyloid-beta and its aggregation to form senile plaques, a hallmark feature of the disease. Few other native BACE1 substrates have been identified despite its relatively loose substrate specificity. We report a bioinformatics approach identifying several putative BACE1 substrates. Using our algorithm, we successfully predicted the cleavage sites for 70% of known BACE1 substrates and further validated our algorithm output against substrates identified in a recent BACE1 proteomics study that also showed a 70% success rate. Having validated our approach with known substrates, we report putative cleavage recognition sequences within 962 proteins, which can be explored using in vivo methods. Approximately 900 of these proteins have not been identified or implicated as BACE1 substrates. Gene ontology cluster analysis of the putative substrates identified enrichment in proteins involved in immune system processes and in cell surface protein-protein interactions. PMID- 25288898 TI - Some perspectives on network modeling in therapeutic target prediction. AB - Drug target identification is of significant commercial interest to pharmaceutical companies, and there is a vast amount of research done related to the topic of therapeutic target identification. Interdisciplinary research in this area involves both the biological network community and the graph algorithms community. Key steps of a typical therapeutic target identification problem include synthesizing or inferring the complex network of interactions relevant to the disease, connecting this network to the disease-specific behavior, and predicting which components are key mediators of the behavior. All of these steps involve graph theoretical or graph algorithmic aspects. In this perspective, we provide modelling and algorithmic perspectives for therapeutic target identification and highlight a number of algorithmic advances, which have gotten relatively little attention so far, with the hope of strengthening the ties between these two research communities. PMID- 25288899 TI - Current status of endovascular devices to treat abdominal aortic aneurysms. AB - The introduction of endovascular abdominal aortic aneurysm (AAA) repair has revolutionized the therapeutic approach to patients with AAA. Due to an on-going and prolific collaboration between vascular interventionalists and biomedical engineers, the devices used to perform endovascular AAA repair have also changed dramatically. The purpose of this publication is to provide an overview of the currently available and upcoming options for endovascular AAA repair. PMID- 25288900 TI - An Empirical Muscle Intracellular Action Potential Model with Multiple Erlang Probability Density Functions based on a Modified Newton Method. AB - The convolution of the transmembrane current of an excitable cell and a weighting function generates a single fiber action potential (SFAP) model by using the volume conductor theory. Here, we propose an empirical muscle IAP model with multiple Erlang probability density functions (PDFs) based on a modified Newton method. In addition, we generate SFAPs based on our IAP model and referent sources, and use the peak-to-peak ratios (PPRs) of SFAPs for model verification. Through this verification, we find that the relation between an IAP profile and the PPR of its SFAP is consistent with some previous studies, and our IAP model shows close profiles to the referent sources. Moreover, we simulate and discuss some possible ionic activities by using the Erlang PDFs in our IAP model, which might present the underlying activities of ions or their channels during an IAP. PMID- 25288901 TI - Sequencing and computational approaches to identification and characterization of microbial organisms. AB - The recent advances in sequencing technologies and computational approaches are propelling scientists ever closer towards complete understanding of human microbial interactions. The powerful sequencing platforms are rapidly producing huge amounts of nucleotide sequence data which are compiled into huge databases. This sequence data can be retrieved, assembled, and analyzed for identification of microbial pathogens and diagnosis of diseases. In this article, we present a commentary on how the metagenomics incorporated with microarray and new sequencing techniques are helping microbial detection and characterization. PMID- 25288902 TI - Neurotrauma and Repair Research: Traumatic Brain Injury (TBI) and its Treatments. AB - Traumatic brain injury (TBI) affects a growing portion of the population and continues to take national spotlight with advances in imaging technology and understanding of long-term effects. However, there is large variance in TBI treatment protocols due to injury variability and lack of both mechanistic understanding and strong treatment recommendations. Recent practice suggests three disparate treatment approaches, all which aim at promoting neuroprotection after TBI, show promise: immediate hypothermia, hyperbaric oxygen, and progesterone supplementation. The research is controversial at times, yet there are abundant opportunities to develop the technology behind hypothermia and hyperbaric oxygen treatments which would surely aid in aligning the current data. Additionally, while progesterone has already been packaged in nanoparticle form it may benefit from continued formulation and administration research. The treatments and the avenues for improvement are reviewed in the present paper. PMID- 25288903 TI - Automated Identification of Fiducial Points on 3D Torso Images. AB - Breast reconstruction is an important part of the breast cancer treatment process for many women. Recently, 2D and 3D images have been used by plastic surgeons for evaluating surgical outcomes. Distances between different fiducial points are frequently used as quantitative measures for characterizing breast morphology. Fiducial points can be directly marked on subjects for direct anthropometry, or can be manually marked on images. This paper introduces novel algorithms to automate the identification of fiducial points in 3D images. Automating the process will make measurements of breast morphology more reliable, reducing the inter- and intra-observer bias. Algorithms to identify three fiducial points, the nipples, sternal notch, and umbilicus, are described. The algorithms used for localization of these fiducial points are formulated using a combination of surface curvature and 2D color information. Comparison of the 3D co-ordinates of automatically detected fiducial points and those identified manually, and geodesic distances between the fiducial points are used to validate algorithm performance. The algorithms reliably identified the location of all three of the fiducial points. We dedicate this article to our late colleague and friend, Dr. Elisabeth K. Beahm. Elisabeth was both a talented plastic surgeon and physician scientist; we deeply miss her insight and her fellowship. PMID- 25288904 TI - Cardiac electrophysiological dynamics from the cellular level to the organ level. AB - Cardiac alternans describes contraction of the ventricles in a strong-weak-strong weak sequence at a constant pacing frequency. Clinically, alternans manifests as alternation of the T-wave on the ECG and predisposes individuals to arrhythmia and sudden cardiac death. In this review, we focus on the fundamental dynamical mechanisms of alternans and show how alternans at the cellular level underlies alternans in the tissue and on the ECG. A clear picture of dynamical mechanisms underlying alternans is important to allow development of effective anti arrhythmic strategies. PMID- 25288905 TI - Study of Stress Induced Failure of the Blood-gas Barrier and the Epithelial epithelial Cells Connections of the Lung of the Domestic Fowl, Gallus gallus Variant Domesticus after Vascular Perfusion. AB - Complete blood-gas barrier breaks (BGBBs) and epithelial-epithelial cells connections breaks (E-ECCBs) were enumerated in the lungs of free range chickens, Gallus gallus variant domesticus after vascular perfusion at different pressures. The E-ECCBs surpassed the BGBBs by a factor of ~2. This showed that the former parts of the gas exchange tissue were structurally weaker or more vulnerable to failure than the latter. The differences in the numbers of BGBBs and E-ECCBs in the different regions of the lung supplied with blood by the 4 main branches of the pulmonary artery (PA) corresponded with the diameters of the blood vessels, the angles at which they bifurcated from the PA, and the positions along the PA where they branched off. Most of the BGBBs and the E-ECCBs occurred in the regions supplied by the accessory- and the caudomedial branches: the former is the narrowest branch and the first blood vessel to separate from the PA while the latter is the most direct extension of the PA and is the widest. The E-ECCBs appeared to separate and fail from tensing of the blood capillary walls, as the perfusion- and intramural pressures increased. Compared to the mammalian lungs on which data are available, i.e., those of the rabbit, the dog, and the horse, the blood-gas barrier of the lung of free range chickens appears to be substantially stronger for its thinness. PMID- 25288906 TI - Quality and safety of minimally invasive surgery: past, present, and future. AB - Adverse events because of medical errors are a leading cause of death in the United States (US) exceeding the mortality rates of motor vehicle accidents, breast cancer, and AIDS. Improvements can and should be made to reduce the rates of preventable surgical errors because they account for nearly half of all adverse events within hospitals. Although minimally invasive surgery (MIS) has proven patient benefits such as reduced postoperative pain and hospital stay, its operative environment imposes substantial physical and cognitive strain on the surgeon increasing the risk of error. To mitigate errors and protect patients, a multidisciplinary approach is needed to improve MIS. Clinical human factors, and biomedical engineering principles and methodologies can be used to develop and assess laparoscopic surgery instrumentation, practices, and procedures. First, the foundational understanding and the imperative to transform health care into a high-quality and safe system is discussed. Next, a generalized perspective is presented on the impact of the design and redesign of surgical technologies and processes on human performance. Finally, the future of this field and the research needed to further improve the quality and safety of MIS is discussed. PMID- 25288907 TI - Design strategies of biodegradable scaffolds for tissue regeneration. AB - There are numerous available biodegradable materials that can be used as scaffolds in regenerative medicine. Currently, there is a huge emphasis on the designing phase of the scaffolds. Materials can be designed to have different properties in order to match the specific application. Modifying scaffolds enhances their bioactivity and improves the regeneration capacity. Modifications of the scaffolds can be later characterized using several tissue engineering tools. In addition to the material, cell source is an important component of the regeneration process. Modified materials must be able to support survival and growth of different cell types. Together, cells and modified biomaterials contribute to the remodeling of the engineered tissue, which affects its performance. This review focuses on the recent advancements in the designs of the scaffolds including the physical and chemical modifications. The last part of this review also discusses designing processes that involve viability of cells. PMID- 25288908 TI - Liraglutide Versus Sitagliptin in a 24-week, Multicenter, Open-label, Randomized, Parallel-group Study in Japanese Type 2 Diabetes Mellitus Patients Responding Inadequately to a Sulfonylurea and/or One or Two Other Oral Antidiabetic Drugs (JDDM 33). AB - OBJECTIVE: Liraglutide (glucagon-like peptide-1 [GLP-1] receptor agonist) and sitagliptin (dipeptidyl peptidase-4 inhibitor) are approved in Japan for treating type 2 diabetes mellitus (T2DM). We compared the efficacy and safety of adding liraglutide or sitagliptin to a sulfonylurea in Japanese T2DM patients. METHODS: Patients aged 18 to <80 years with hemoglobin A1c (HbA1c; National Glycohemoglobin Standardization Program [NGSP]) of 6.9-9.4%, body mass index <=35 kg/m(2), and treatment with a sulfonylurea and/or one or two non-sulfonylurea oral antidiabetic drugs for greater than or equal to eight weeks before enrollment were eligible. Patients were randomized in an open-label manner to either 0.9 mg/day liraglutide (n = 50) or 50-100 mg/day sitagliptin (n = 49) and were treated for 24 weeks. Non-sulfonylureas were discontinued before randomization. Patients using other oral antidiabetic drugs started sulfonylurea treatment. The primary endpoint was the change in HbA1c from baseline to Week 24. RESULTS: HbA1c decreased in both groups, and the reduction was significantly greater throughout in the liraglutide group except for Week 24 (0.59 +/- 0.80 vs. 0.24 +/- 0.94%; P = 0.0525). Fasting plasma glucose (FPG) decreased significantly in the liraglutide group compared with the sitagliptin group (-21.15 +/- 31.22 vs. +0.46 +/- 39.39 mg/dL; P = 0.0014). Homeostasis model assessment of beta cell function and C-peptide increased significantly in the liraglutide group but not in the sitagliptin group. Hypoglycemic symptoms and adverse events occurred in four and nine patients, respectively, in the liraglutide group, and in two and five patients, respectively, in the sitagliptin group. CONCLUSION: Treatment with liraglutide or sitagliptin together with a sulfonylurea improved HbA1c in Japanese T2DM patients in primary care. Both drugs were associated with low rates of adverse events and hypoglycemia. The improvement in beta cell function probably contributed to the improvement in glycemic control in the liraglutide group. PMID- 25288909 TI - Nanoparticles prepared from porous silicon nanowires for bio-imaging and sonodynamic therapy. AB - Evaluation of cytotoxicity, photoluminescence, bio-imaging, and sonosensitizing properties of silicon nanoparticles (SiNPs) prepared by ultrasound grinding of porous silicon nanowires (SiNWs) have been investigated. SiNWs were formed by metal (silver)-assisted wet chemical etching of heavily boron-doped (100) oriented single crystalline silicon wafers. The prepared SiNWs and aqueous suspensions of SiNPs exhibit efficient room temperature photoluminescence (PL) in the spectral region of 600 to 1,000 nm that is explained by the radiative recombination of excitons confined in small silicon nanocrystals, from which SiNWs and SiNPs consist of. On the one hand, in vitro studies have demonstrated low cytotoxicity of SiNPs and possibilities of their bio-imaging applications. On the other hand, it has been found that SiNPs can act as efficient sensitizers of ultrasound-induced suppression of the viability of Hep-2 cancer cells. PMID- 25288910 TI - Synthesis and characterization of electrically conductive polyethylene-supported graphene films. AB - We describe a simple mechanical approach for low-density polyethylene film coating by multilayer graphene. The technique is based on the exfoliation of nanocrystalline graphite (few-layer graphene) by application of shear stress and allows to obtain thin graphene layers on the plastic substrate. We report on the temperature dependence of electrical resistance behaviors in films of different thickness. The experimental results suggest that the semiconducting behavior observed at low temperature can be described in the framework of the Efros Shklovskii variable-range-hopping model. The obtained films exhibit good electrical conductivity and transparency in the visible spectral region. PACS: 72.80.Vp; 78.67.Wj; 78.66.Qn; 85.40.Hp. PMID- 25288911 TI - Investigation of extended-gate field-effect transistor pH sensors based on different-temperature-annealed bi-layer MWCNTs-In2O3 films. AB - In this paper, indium (In) films were deposited on glass substrates using DC sputtering method. Multiwalled carbon nanotubes (MWCNTs) and dispersant were dissolved in alcohol, and the mixed solution was deposited on the In films using the spray method. The bi-layer MWCNTs-In2O3 films were annealed at different temperatures (from room temperature to 500 degrees C) in O2 atmosphere. The influences of annealing temperature on the characteristics of the bi-layer MWCNTs In2O3 films were investigated by scanning electron microscopy, X-ray diffraction pattern, Fourier transform infrared (FT-IR) spectroscopy, and Raman spectroscopy. A separative extended-gate field-effect transistor (EGFET) device combined with a bi-layer MWCNTs-In2O3 film was constructed as a pH sensor. The influences of different annealing temperatures on the performances of the EGFET-based pH sensors were investigated. We would show that the pH sensitivity was dependent on the thermal oxygenation temperature of the bi-layer MWCNTs-In2O3 films. PMID- 25288912 TI - Electronic properties of core-shell nanowire resonant tunneling diodes. AB - The electronic sub-band structure of InAs/InP/InAs/InP/InAs core-shell nanowire resonant tunneling diodes has been investigated in the effective mass approximation by varying the core radius and the thickness of the InP barriers and InAs shells. A top-hat, double-barrier potential profile and optimal energy configuration are obtained for core radii and surface shells >10 nm, InAs middle shells <10 nm, and 5 nm InP barriers. In this case, two sub-bands exist above the Fermi level in the InAs middle shell which belongs to the m = 0 and m = 1 ladder of states that have similar wave functions and energies. On the other hand, the lowest m = 0 sub-band in the core falls below the Fermi level but the m = 1 states do not contribute to the current transport since they reside energetically well above the Fermi level. We compare the case of GaAs/AlGaAs/GaAs/AlGaAs/GaAs which may conduct current with smaller applied voltages due to the larger effective mass of electrons in GaAs and discuss the need for doping. PMID- 25288913 TI - The effects of the size of nanocrystalline materials on their thermodynamic and mechanical properties. AB - This work has considered the intrinsic influence of bond energy on the macroscopic, thermodynamic, and mechanical properties of crystalline materials. A general criterion is proposed to evaluate the properties of nanocrystalline materials. The interrelation between the thermodynamic and mechanical properties of nanomaterials is presented and the relationship between the variation of these properties and the size of the nanomaterials is explained. The results of our work agree well with thermodynamics, molecular dynamics simulations, and experimental results. This method is of significance in investigating the size effects of nanomaterials and provides a new approach for studying their thermodynamic and mechanical properties. PMID- 25288914 TI - Self-assembly behaviors of thermal- and pH- sensitive magnetic nanocarriers for stimuli-triggered release. AB - In the present work, we prepare thermo- and pH-sensitive polymer-based nanoparticles incorporating with magnetic iron oxide as the remote-controlled, stimuli-response nanocarriers. Well-defined, dual functional tri-block copolymer poly[(acrylic acid)-block-(N-isopropylacrylamide)-block-(acrylic acid)], was synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization with S,S'-bis(alpha,alpha'-dimethyl-alpha"-acetic acid)trithiocarbonate (CMP) as a chain transfer agent (CTA). With the aid of using 3-aminopropyltriethoxysilane, the surface-modified iron oxides, Fe3O4-NH2, was then attached on the surface of self-assembled tri-block copolymer micelles via 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride/N hydroxysuccinamide (EDC/NHS) crosslinking method in order to furnish not only the magnetic resources for remote control but also the structure maintenance for spherical morphology of our nanocarriers. The nanocarrier was characterized by transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR), and ultraviolet-visible (UV/Vis) spectral analysis. Rhodamine 6G (R6G), as the modeling drugs, was encapsulated into the magnetic nanocarriers by a simple swelling method for fluorescence-labeling and controlled release monitoring. Biocompatibility of the nanocarriers was studied via 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed that neither the pristine nanocarrier nor the R6G-loaded nanocarriers were cytotoxic to the normal fibroblast cells (L-929 cells). The in vitro stimuli triggered release measurement showed that the intelligent nanocarriers were highly sensitive to the change of pH value and temperature rising by the high frequency magnetic field (HFMF) treatment, which provided the significant potential to apply this technology to biomedical therapy by stimuli-responsive controlled release. PMID- 25288915 TI - Mechanical and electrical properties of electrospun PVDF/MWCNT ultrafine fibers using rotating collector. AB - Poly(vinylidene fluoride) (PVDF) ultrafine fibers with different proportions of multi-walled carbon nanotube (MWCNT) embedded have been fabricated using a modified electrospinning device with a rotating collector. With the increasing of MWCNT content, the beta phase was noticeable enhanced, and the fibers became more elastic, which was manifested by Young's modulus decreased drastically. Furthermore, with adding the amounts of MWCNTs, the density of carbon nanotube (CNT)-CNT junctions among the fibers increased accordingly. When the MWCNT content was of 1.2 wt.%, a stable three-dimensional conducting network was formed. After this percolation threshold, the density of CNT-CNT junctions among the fibers tended to be a constant quantity, leading to a stabilized conductivity consequently. It is hoped that our results can be helpful for the fabrication of flexible devices, piezoelectric devices, force transducer, and so on. PACS: 81.05.Qk; 81.16.-c. PMID- 25288916 TI - Paclitaxel-incorporated nanoparticles using block copolymers composed of poly(ethylene glycol)/poly(3-hydroxyoctanoate). AB - Block copolymers composed of poly(3-hydroxyoctanoate) (PHO) and methoxy poly(ethylene glycol) (PEG) were synthesized to prepare paclitaxel-incorporated nanoparticle for antitumor drug delivery. In a (1)H-NMR study, chemical structures of PHO/PEG block copolymers were confirmed and their molecular weight (M.W.) was analyzed with gel permeation chromatography (GPC). Paclitaxel as a model anticancer drug was incorporated into the nanoparticles of PHO/PEG block copolymer. They have spherical shapes and their particle sizes were less than 100 nm. In a (1)H-NMR study in D2O, specific peaks of PEG solely appeared while peaks of PHO disappeared, indicating that nanoparticles have core-shell structures. The higher M.W. of PEG decreased loading efficiency and particle size. The higher drug feeding increased drug contents and average size of nanoparticles. In the drug release study, the higher M.W. of PEG block induced the acceleration of drug release rate. The increase in drug contents induced the slow release rate of drug. In an antitumor activity study in vitro, paclitaxel nanoparticles have practically similar anti-proliferation activity against HCT116 human colon carcinoma cells. In an in vivo animal study using HCT116 colon carcinoma cell bearing mice, paclitaxel nanoparticles have enhanced antitumor activity compared to paclitaxel itself. Therefore, paclitaxel-incorporated nanoparticles of PHO/PEG block copolymer are a promising vehicle for antitumor drug delivery. PMID- 25288917 TI - SERS active silver nanoparticles synthesized by inkjet printing on mesoporous silicon. AB - Inkjet printing technique is exploited for the synthesis of Ag nanoparticles (NPs) patterned on electrochemically etched silicon-based substrates. The nanostructure morphology, here analyzed by scanning electron microscopy, is dictated by the ink composition and the printing parameters. Under suitable excitation conditions, resonant surface-enhanced Raman scattering (SERS) performed on such metal-dielectric nanostructures can approach single-molecule detection as recently demonstrated on silvered porous silicon synthesized by immersion plating. PACS: 78.67.Bf; 78.30.-j. PMID- 25288918 TI - Polyethylene glycol-modified dendrimer-entrapped gold nanoparticles enhance CT imaging of blood pool in atherosclerotic mice. AB - We report a new use of dendrimer-entrapped gold nanoparticles (Au DENPs) modified by polyethylene glycol (PEG) with good biocompatibility for in vitro and in vivo imaging of atherosclerotic mice by computed tomography (CT). In this study, Au DENPs were synthesized using poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5.NH2) modified by PEG monomethyl ether (G5.NH2-mPEG20) as templates. In vitro cytotoxicity and flow cytometry assays show that the formed PEGylated Au DENPs have good biocompatibility and are non-cytotoxic at the Au concentration up to 300 MUM. Silver staining and transmission electron microscopy (TEM) further confirm that the Au DENPs are able to be uptaken by macrophages and are located dominantly in the lysosomes of the cells. Importantly, the formed PEGylated Au DENPs are able to be used for CT imaging of murine macrophages in vitro and macrophages in atherosclerotic mice in vivo using apolipoprotein-E-gene-deficient mice as a model. These findings suggest that the formed PEGylated Au DENPs are a promising contrast agent for CT imaging of atherosclerosis. PMID- 25288919 TI - Intestinal absorption and biological effects of orally administered amorphous silica particles. AB - Although amorphous silica nanoparticles are widely used in the production of food products (e.g., as anticaking agents), there is little information available about their absorption and biological effects after oral exposure. Here, we examined the in vitro intestinal absorption and in vivo biological effects in mice of orally administered amorphous silica particles with diameters of 70, 300, and 1,000 nm (nSP70, mSP300, and mSP1000, respectively) and of nSP70 that had been surface-modified with carboxyl or amine groups (nSP70-C and nSP70-N, respectively). Analysis of intestinal absorption by means of the everted gut sac method combined with an inductively coupled plasma optical emission spectrometer showed that the intestinal absorption of nSP70-C was significantly greater than that of nSP70. The absorption of nSP70-N tended to be greater than that of nSP70; however, the results were not statistically significant. Our results indicate that silica nanoparticles can be absorbed through the intestine and that particle diameter and surface properties are major determinants of the degree of absorption. We also examined the biological effects of the silica particles after 28-day oral exposure in mice. Hematological, histopathological, and biochemical analyses showed no significant differences between control mice and mice treated with the silica particles, suggesting that the silica nanoparticles evaluated in this study are safe for use in food production. PMID- 25288920 TI - Cross-sectional analysis of W-cored Ni nanoparticle via focused ion beam milling with impregnation. AB - Tungsten and nickel bimetallic nanoparticle is synthesized by radio frequency thermal plasma process which belongs to the vapor phase condensation technology. The morphology and chemical composition of the synthesized particle were investigated using the conventional nanoparticle transmission electron microscopy (TEM) sample. A few part of them looked like core/shell structured particle, but ambiguities were caused by either TEM sample preparation or TEM analysis. In order to clarify whether a core/shell structure is developed for the particle, various methodologies were tried to prepare a cross-sectional TEM sample. Focused ion beam (FIB) milling was conducted for cold-compacted particles, dispersed particles on silicon wafer, and impregnated particles with epoxy which is compatible with electron beam. A sound cross-sectional sample was just obtained from cyanoacrylate impregnation and FIB milling procedure. A tungsten-cored nickel shell structure was precisely confirmed with aid of cross-sectional sample preparation method. PMID- 25288921 TI - Potential applications of magnetic particles to detect and treat Alzheimer's disease. AB - Nanotechnology is an exciting and promising scientific discipline. At the nanoscale, a material displays novel physical properties that offer many new and beneficial products and applications. In particular, magnetic nanoparticles - a core/shell nanoparticle - present considerable diagnostic and therapeutic potentials, and superparamagnetic iron oxide nanoparticles (SPIONs) are considered promising theranostic tools. Alzheimer's disease (AD) is a neurodegenerative disorder that predominantly affects people over 65 years of age. The disease is characterized by the presence of extracellular plaques in the brain which are formed by interwoven fibrils composed of variants of the beta amyloid peptide. Medication can temporarily retard worsening of symptoms, but only in the first stages of the disease; early detection is thus of crucial importance. This minireview covers the progress made in research on the use of magnetic nanoparticles for ex vivo and/or in vivo detection and diagnosis of AD by means of magnetic resonance imaging (MRI), or to label peptides and fibrils. Of particular importance is the use of these nanoparticles to detect AD biomarkers in biological fluids. A description is given of the bio-barcode amplification assay using functionalized magnetic particles, as well as the use of such nanoparticles as a system for inhibiting or delaying the assembly of peptide monomers into oligomers and fibrils. Lastly, a brief overview is given of possible future lines of research in this. PMID- 25288923 TI - Recent trends in studies on botanical fungicides in agriculture. AB - Plants are attacked by various phytopathogenic fungi. For many years, synthetic fungicides have been used to control plant diseases. Although synthetic fungicides are highly effective, their repeated use has led to problems such as environmental pollution, development of resistance, and residual toxicity. This has prompted intensive research on the development of biopesticides, including botanical fungicides. To date, relatively few botanical fungicides have been registered and commercialized. However, many scientists have reported isolation and characterization of a variety of antifungal plant derivatives. Here, we present a survey of a wide range of reported plant-derived antifungal metabolites. PMID- 25288924 TI - Neofusicoccum ribis Associated with Leaf Blight on Rubber (Hevea brasiliensis) in Peninsular Malaysia. AB - Hevea brasiliensis is a natural source of rubber and an important plantation tree species in Malaysia. Leaf blight disease caused by Fusicoccum substantially reduces the growth and performance of H. brasiliensis. The aim of this study was to use a combination of both morphological characteristics and molecular data to clarify the taxonomic position of the fungus associated with leaf blight disease. Fusicoccum species were isolated from infected leaves collected from plantations at 3 widely separated locations - Selangor, Perak, and Johor states - in Peninsular Malaysia in 2010. All the isolates were identified according to their conidial patterns and DNA sequences generated from internal transcribed spacers (ITS1 and ITS2), the 5.8S rRNA, and an unknown locus (BotF15) containing microsatellite repeats. Based on taxonomic and sequence data, Neofusicoccum ribis was identified as the main cause of leaf blight disease in H. brasiliensis in commercial plantations in Malaysia. A pathogenicity trial on detached leaves further confirmed that N. ribis causes leaf blight disease. N. ribis is an important leaf pathogen, and its detection in Malaysia has important implications for future planting of H. brasiliensis. PMID- 25288922 TI - NKT Cell Subsets Can Exert Opposing Effects in Autoimmunity, Tumor Surveillance and Inflammation. AB - The innate-like natural killer T (NKT) cells are essential regulators of immunity. These cells comprise at least two distinct subsets and recognize different lipid antigens presented by the MHC class I like molecules CD1d. The CD1d-dependent recognition pathway of NKT cells is highly conserved from mouse to humans. While most type I NKT cells can recognize alphaGalCer and express a semi invariant T cell receptor (TCR), a major population of type II NKT cells reactive to sulfatide utilizes an oligoclonal TCR. Furthermore TCR recognition features of NKT subsets are also distinctive with almost parallel as opposed to perpendicular footprints on the CD1d molecules for the type I and type II NKT cells respectively. Here we present a view based upon the recent studies in different clinical and experimental settings that while type I NKT cells are more often pathogenic, they may also be regulatory. On the other hand, sulfatide-reactive type II NKT cells mostly play an inhibitory role in the control of autoimmune and inflammatory diseases. Since the activity and cytokine secretion profiles of NKT cell subsets can be modulated differently by lipid ligands or their analogs, novel immunotherapeutic strategies are being developed for their differential activation for potential intervention in inflammatory diseases. PMID- 25288925 TI - Actin Cytoskeleton and Golgi Involvement in Barley stripe mosaic virus Movement and Cell Wall Localization of Triple Gene Block Proteins. AB - Barley stripe mosaic virus (BSMV) induces massive actin filament thickening at the infection front of infected Nicotiana benthamiana leaves. To determine the mechanisms leading to actin remodeling, fluorescent protein fusions of the BSMV triple gene block (TGB) proteins were coexpressed in cells with the actin marker DsRed: Talin. TGB ectopic expression experiments revealed that TGB3 is a major elicitor of filament thickening, that TGB2 resulted in formation of intermediate DsRed:Talin filaments, and that TGB1 alone had no obvious effects on actin filament structure. Latrunculin B (LatB) treatments retarded BSMV cell-to-cell movement, disrupted actin filament organization, and dramatically decreased the proportion of paired TGB3 foci appearing at the cell wall (CW). BSMV infection of transgenic plants tagged with GFP-KDEL exhibited membrane proliferation and vesicle formation that were especially evident around the nucleus. Similar membrane proliferation occurred in plants expressing TGB2 and/or TGB3, and DsRed: Talin fluorescence in these plants colocalized with the ER vesicles. TGB3 also associated with the Golgi apparatus and overlapped with cortical vesicles appearing at the cell periphery. Brefeldin A treatments disrupted Golgi and also altered vesicles at the CW, but failed to interfere with TGB CW localization. Our results indicate that actin cytoskeleton interactions are important in BSMV cell to-cell movement and for CW localization of TGB3. PMID- 25288926 TI - The First Identified Citrus tristeza virus Isolate of Turkey Contains a Mixture of Mild and Severe Strains. AB - The presence of Citrus tristeza virus (CTV) has previously been reported in citrus growing regions of Turkey. All serologically and biologically characterized isolates including Igdir, which was the first identified CTV isolates from Turkey, were considered mild isolates. In this study, molecular characteristics of the Igdir isolate were determined by different methods. Analysis of the Igdir isolate by western blot and BD-RT-PCR assays showed the presence of MCA13 epitope, predominantly found in severe isolates, in the Igdir isolate revealing that it contains a severe component. For further characterization, the coat protein (CP) and the RNA-dependent RNA polymerase (RdRp) genes representing the 3' and 5' half of CTV genome, respectively, were amplified from dsRNA by RT-PCR. Both genes were cloned separately and two clones for each gene were sequenced. Comparisons of nucleotide and deduced amino acid sequences showed that while two CP gene sequences were identical, two RdRp clones showed only 90% and 91% sequence identity in their nucleotide and amino acid sequences, respectively, suggesting a mixed infection with different strains. Phylogenetic analyses of the CP and RdRp genes of Igdir isolate with previously characterized CTV isolates from different citrus growing regions showed that the CP gene was clustered with NZRB-TH30, a resistance breaking isolate from New Zealand, clearly showing the presence of severe component. Furthermore, two different clones of the RdRp gene were clustered separately with different CTV isolates with a diverse biological activity. While the RdRp-1 was clustered with T30 and T385, two well-characterized mild isolates from Florida and Spain, respectively, the RdRp-2 was most closely related to NZRB-G90 and NZRB-TH30, two well-characterized resistance breaking and stem pitting (SP) isolates from New Zealand confirming the mixed infection. These results clearly demonstrated that the Igdir isolate, which was previously described as biologically a mild isolate, actually contains a mixture of mild and severe strains. PMID- 25288927 TI - Biocontrol Characteristics of Bacillus Species in Suppressing Stem Rot of Grafted Cactus Caused by Bipolaris cactivora. AB - One of the most important limiting factors for the production of the grafted cactus in Korea is the qualitative and quantitative yield loss derived from stem rots especially caused by Bipolaris cactivora. This study is aimed to develop microbial control agents useful for the control of the bipolaris stem rot. Two bacteria (GA1-23 and GA4-4) selected out of 943 microbial isolates because of their strong antibiotic activity against B. cactivora were identified as Bacillus subtilis and B. amyloliquefaciens, respectively, by the cultural characteristics, Biolog program and 16S rRNA sequencing analyses. Both bacterial isolates significantly inhibited the conidial germination and mycelial growth of the pathogen with no significant difference between the two, of which the inhibitory efficacies varied depending on the cultural conditions such as temperature, nutritional compositions and concentrations. Light and electron microscopy of the pathogen treated with the bacterial isolates showed the inhibition of spore germination with initial malformation of germ tubes and later formation of circle like vesicles with no hyphal growth and hyphal disruption sometimes accompanied by hyphal swellings and shrinkages adjacent to the bacteria, suggesting their antibiotic mode of antagonistic activity. Control efficacy of B. subtilis GA1-23 and B. amyloliquefaciens GA4-4 on the cactus stem rot were not as high as but comparable to that of fungicide difenoconazole when they were treated simultaneously at the time of pathogen inoculation. All of these results suggest the two bacterial isolates have a good potential to be developed as biocontrol agents for the bipolaris stem rot of the grafted cactus. PMID- 25288928 TI - Biological Efficacy of Streptomyces sp. Strain BN1 against the Cereal Head Blight Pathogen Fusarium graminearum. AB - Fusarium head blight (FHB) caused by the filamentous fungus Fusarium graminearum is one of the most severe diseases threatening the production of small grains. Infected grains are often contaminated with mycotoxins such as zearalenone and trichothecences. During survey of contamination by FHB in rice grains, we found a bacterial isolate, designated as BN1, antagonistic to F. graminearum. The strain BN1 had branching vegetative hyphae and spores, and its aerial hyphae often had long, straight filaments bearing spores. The 16S rRNA gene of BN1 had 100% sequence identity with those found in several Streptomyces species. Phylogenetic analysis of ITS regions showed that BN1 grouped with S. sampsonii with 77% bootstrap value, suggesting that BN1 was not a known Streptomyces species. In addition, the efficacy of the BN1 strain against F. graminearum strains was tested both in vitro and in vivo. Wheat seedling length was significantly decreased by F. graminearum infection. However, this effect was mitigated when wheat seeds were treated with BN1 spore suspension prior to F. graminearum infection. BN1 also significantly decreased FHB severity when it was sprayed onto wheat heads, whereas BN1 was not effective when wheat heads were point inoculated. These results suggest that spraying of BN1 spores onto wheat heads during the wheat flowering season can be efficient for plant protection. Mechanistic studies on the antagonistic effect of BN1 against F. graminearum remain to be analyzed. PMID- 25288929 TI - Bacterial Traits Involved in Colonization of Arabidopsis thaliana Roots by Bacillus amyloliquefaciens FZB42. AB - Colonization studies previously performed with a green-fluorescent-protein, GFP, labeled derivative of Bacillus amyloliquefaciens FZB42 revealed that the bacterium behaved different in colonizing surfaces of plant roots of different species (Fan et al., 2012). In order to extend these studies and to elucidate which genes are crucial for root colonization, we applied targeted mutant strains to Arabidopsis seedlings. The fates of root colonization in mutant strains impaired in synthesis of alternative sigma factors, non-ribosomal synthesis of lipopeptides and polyketides, biofilm formation, swarming motility, and plant growth promoting activity were analyzed by confocal laser scanning microscopy. Whilst the wild-type strain heavily colonized surfaces of root tips and lateral roots, the mutant strains were impaired in their ability to colonize root tips and most of them were unable to colonize lateral roots. Ability to colonize plant roots is not only dependent on the ability to form biofilms or swarming motility. Six mutants, deficient in abrB-, sigH-, sigD-, nrfA-, yusV and RBAM017410, but not affected in biofilm formation, displayed significantly reduced root colonization. The nrfA- and yusV-mutant strains colonized border cells and, partly, root surfaces but did not colonize root tips or lateral roots. PMID- 25288930 TI - Biocontrol of Late Blight (Phytophthora capsici) Disease and Growth Promotion of Pepper by Burkholderia cepacia MPC-7. AB - A chitinolytic bacterial strain having strong antifungal activity was isolated and identified as Burkholderia cepacia MPC-7 based on 16S rRNA gene analysis. MPC 7 solubilized insoluble phosphorous in hydroxyapatite agar media. It produced gluconic acid and 2-ketogluconic acid related to the decrease in pH of broth culture. The antagonist produced benzoic acid (BA) and phenylacetic acid (PA). The authentic compounds, BA and PA, showed a broad spectrum of antimicrobial activity against yeast, several bacterial and fungal pathogens in vitro. To demonstrate the biocontrol efficiency of MPC-7 on late blight disease caused by Phytophthora capsici, pepper plants in pot trials were treated with modified medium only (M), M plus zoospore inoculation (MP), MPC-7 cultured broth (B) and B plus zoospore inoculation (BP). With the sudden increase in root mortality, plants in MP wilted as early as five days after pathogen inoculation. However, plant in BP did not show any symptom of wilting until five days. Root mortality in BP was markedly reduced for as much as 50%. Plants in B had higher dry weight, P concentration in root, and larger leaf area compared to those in M and MP. These results suggested that B. cepacia MPC-7 should be considered as a candidate for the biological fertilizer as well as antimicrobial agent for pepper plants. PMID- 25288931 TI - Phyllosticta musarum Infection-Induced Defences Suppress Anthracnose Disease Caused by Colletotrichum musae in Banana Fruits cv 'Embul'. AB - Anthracnose development by Colletotrichum musae was observed to be significantly less in the fruits of the banana cultivar 'Embul' (Mysore, AAB) infected with Phyllosticta musarum than in fruits without such infections. Anthracnose disease originates from quiescent C. musae infections in the immature fruit. P. musarum incites minute, scattered spots, referred to as freckles, in the superficial tissues of immature banana peel which do not expand during maturation or ripening. P. musarum does not appear to have a direct suppressive effect on C. musae as conidia of C. musae germinate on both freckled and non-freckled fruit forming quiescent infections. Our investigations have shown that P. musarum infection induced several defence responses in fruit including the accumulation of five phytoalexins, upregulation of chitinase and beta-1,3-glucanase, phenylalanine ammonia lyase (PAL) activity and cell wall lignification. (1)H and (13)C NMR spectral data of one purified phytoalexin compared closely with 4' hydroxyanigorufone. Some of the P. musarum-induced defences that retained during ripening, restrict C. musae development at the ripe stage. This paper examines the potential of P. musarum-induced defences, in the control of anthracnose, the most destructive postharvest disease in banana. PMID- 25288932 TI - Evaluation of Watermelon Germplasm for Resistance to Phytophthora Blight Caused by Phytophthora capsici. AB - This study was conducted to determine the Phytophthora rot resistance of 514 accessions of watermelon germplasm, Citrullus lanatus var lanatus. About 46% of the 514 accessions tested were collections from Uzbekistan, Turkey, China, U.S.A., and Ukraine. Phytophthora capsici was inoculated to 45-day-old watermelon seedlings by drenching with 5 ml of sporangial suspension (10(6) sporangia/ml). At 7 days after inoculation, 21 accessions showed no disease symptoms while 291 accessions of susceptible watermelon germplasm showed more than 60.1% disease severity. A total of 510 accessions of watermelon germplasm showed significant disease symptoms and were rated as susceptible to highly susceptible 35 days after inoculation. The highly susceptible watermelon germplasm exhibited white fungal hyphae on the lesion or damping off with water-soaked and browning symptoms. One accession (IT032840) showed moderate resistance and two accessions (IT185446 and IT187904) were resistant to P. capsici. Results suggest that these two resistant germplasm can be used as a rootstock and as a source of resistance in breeding resistant watermelon varieties against Phytophthora. PMID- 25288933 TI - Virulence of Xanthomonas translucens pv. poae Isolated from Poa annua. AB - Bacterial wilt is a vascular wilt disease caused by Xanthomonas translucens pv. poae that infects Poa annua, a grass that is commonly found on golf course greens throughout the world. Bacterial wilt causes symptoms of etiolation, wilting, and foliar necrosis. The damage is most prevalent during the summer and the pathogen can kill turf under conditions optimal for disease development. Fifteen isolates of X. translucens pv. poae were collected from northern regions in the United States and tested for virulence against P. annua. All 15 isolates were pathogenic on P. annua, but demonstrated variable levels of virulence when inoculated onto P. annua under greenhouse conditions. The isolates were divided into two virulence groups. The first group containing four isolates generally resulted in less than 40% mortality following inoculation. The second group, containing the other eleven isolates, produced between 90 and 100% mortality following inoculation. These results suggest that differences in the virulence of bacterial populations present on a golf course may result in more or less severe amounts of observed disease. PMID- 25288934 TI - Highly Specific Detection of Five Exotic Quarantine Plant Viruses using RT-PCR. AB - To detect five plant viruses (Beet black scorch virus, Beet necrotic yellow vein virus, Eggplant mottled dwarf virus, Pelargonium zonate spot virus, and Rice yellow mottle virus) for quarantine purposes, we designed 15 RT-PCR primer sets. Primer design was based on the nucleotide sequence of the coat protein gene, which is highly conserved within species. All but one primer set successfully amplified the targets, and gradient PCRs indicated that the optimal temperature for the 14 useful primer sets was 51.9 degrees C. Some primer sets worked well regardless of annealing temperature while others required a very specific annealing temperature. A primer specificity test using plant total RNAs and cDNAs of other plant virus-infected samples demonstrated that the designed primer sets were highly specific and generated reproducible results. The newly developed RT PCR primer sets would be useful for quarantine inspections aimed at preventing the entry of exotic plant viruses into Korea. PMID- 25288935 TI - Feasibility Study for Detection of Turnip yellow mosaic virus (TYMV) Infection of Chinese Cabbage Plants Using Raman Spectroscopy. AB - Raman spectroscopy provides many advantages compared to other common analytical techniques due to its ability of rapid and accurate identification of unknown specimens as well as simple sample preparation. Here, we described potential of Raman spectroscopic technique as an efficient and high throughput method to detect plants infected by economically important viruses. To enhance the detection sensitivity of Raman measurement, surface enhanced Raman scattering (SERS) was employed. Spectra of extracts from healthy and Turnip yellow mosaic virus (TYMV) infected Chinese cabbage leaves were collected by mixing with gold (Au) nanoparticles. Our result showed that TYMV infected plants could be discriminated from non-infected healthy plants, suggesting the current method described here would be an alternative potential tool to screen virus-infection of plants in fields although it needs more studies to generalize the technique. PMID- 25288936 TI - Theobroxide Treatment Inhibits Wild Fire Disease Occurrence in Nicotiana benthamiana by the Overexpression of Defense-related Genes. AB - Theobroxide, a novel compound isolated from a fungus Lasiodiplodia theobromae, stimulates potato tuber formation and induces flowering of morning glory by initiating the jasmonic acid synthesis pathway. To elucidate the effect of theobroxide on pathogen resistance in plants, Nicotiana benthamiana plants treated with theobroxide were immediately infiltrated with Pseudomonas syringae pv. tabaci. Exogenous application of theobroxide inhibited development of lesion symptoms, and growth of the bacterial cells was significantly retarded. Semi quantitative RT-PCRs using the primers of 18 defense-related genes were performed to investigate the molecular mechanisms of resistance. Among the genes, the theobroxide treatment increased the expression of pathogenesis-related protein 1a (PR1a), pathogenesis-related protein 1b (PR1b), glutathione S-transferase (GST), allen oxide cyclase (AOC), and lipoxyganase (LOX). All these data strongly indicate that theobroxide treatment inhibits disease development by faster induction of defense responses, which can be possible by the induction of defense related genes including PR1a, PR1b, and GST triggered by the elevated jasmonic acid. PMID- 25288937 TI - Migrations and Multiplications of Bursaphelenchus xylophilus and B. mucronatus in Pinus thumbergii in Relation to Their Pathogenicity. AB - To evaluate the mechanisms of pathogenicity and non-pathogenicity of Bursaphelenchus xylophilus and B. mucronatus isolated in South Korea, we used 4 year-old P. thunbergii seedlings and 20-cm long one-year-old stem cuttings of 5 year-old Pinus thunbergii, and studied distributions and multiplications of pine wood nematodes after inoculation. The distributions of B. xylophilus in the 20-cm pine stem cuttings were not significantly different from that of B. mucronatus. Conversely, the proliferation rate of B. xylophilus on mycelial mats of Botrytis cinerea was significantly different from that of B. mucronatus. The study using 4 year-old P. thunbergii seedlings also showed that B. mucronatus can migrate to distal portions of the pine seedlings the same as B. xylophilus, but the populations of B. xylophilus remaining in the pine seedlings were relatively larger than those of B. mucronatus. Therefore, we concluded that the pathogenicity of B. xylophilus could be strongly influenced by its ability to multiply. PMID- 25288938 TI - Promoting plant protection by root-associated microbes. PMID- 25288939 TI - Take-all of Wheat and Natural Disease Suppression: A Review. AB - In agro-ecosystems worldwide, some of the most important and devastating diseases are caused by soil-borne necrotrophic fungal pathogens, against which crop plants generally lack genetic resistance. However, plants have evolved approaches to protect themselves against pathogens by stimulating and supporting specific groups of beneficial microorganisms that have the ability to protect either by direct inhibition of the pathogen or by inducing resistance mechanisms in the plant. One of the best examples of protection of plant roots by antagonistic microbes occurs in soils that are suppressive to take-all disease of wheat. Take all, caused by Gaeumannomyces graminis var. tritici, is the most economically important root disease of wheat worldwide. Take-all decline (TAD) is the spontaneous decline in incidence and severity of disease after a severe outbreak of take-all during continuous wheat or barley monoculture. TAD occurs worldwide, and in the United States and The Netherlands it results from a build-up of populations of 2,4-diacetylphloroglucinol (2,4-DAPG)-producing fluorescent Pseudomonas spp. during wheat monoculture. The antibiotic 2,4-DAPG has a broad spectrum of activity and is especially active against the take-all pathogen. Based on genotype analysis by repetitive sequence-based-PCR analysis and restriction fragment length polymorphism of phlD, a key 2,4-DAPG biosynthesis gene, at least 22 genotypes of 2,4-DAPG producing fluorescent Pseudomonas spp. have been described worldwide. In this review, we provide an overview of G. graminis var. tritici, the take-all disease, Pseudomonas biocontrol agents, and mechanism of disease suppression. PMID- 25288940 TI - Induced systemic resistance and the rhizosphere microbiome. AB - Microbial communities that are associated with plant roots are highly diverse and harbor tens of thousands of species. This so-called microbiome controls plant health through several mechanisms including the suppression of infectious diseases, which is especially prominent in disease suppressive soils. The mechanisms implicated in disease suppression include competition for nutrients, antibiosis, and induced systemic resistance (ISR). For many biological control agents ISR has been recognized as the mechanism that at least partly explains disease suppression. Implications of ISR on recruitment and functioning of the rhizosphere microbiome are discussed. PMID- 25288941 TI - Sampling and Selection Factors that Enhance the Diversity of Microbial Collections: Application to Biopesticide Development. AB - Diverse bacteria are known to colonize plants. However, only a small fraction of that diversity has been evaluated for their biopesticide potential. To date, the criteria for sampling and selection in such bioprospecting endeavors have not been systematically evaluated in terms of the relative amount of diversity they provide for analysis. The present study aimed to enhance the success of bio prospecting efforts by increasing the diversity while removing the genotypic redundancy often present in large collections of bacteria. We developed a multivariate sampling and marker-based selection strategy that significantly increase the diversity of bacteria recovered from plants. In doing so, we quantified the effects of varying sampling intensity, media composition, incubation conditions, plant species, and soil source on the diversity of recovered isolates. Subsequent sequencing and high-throughput phenotypic analyses of a small fraction of the collected isolates revealed that this approach led to the recovery of over a dozen rare and, to date, poorly characterized genera of plant-associated bacteria with significant biopesticide activities. Overall, the sampling and selection approach described led to an approximately 5-fold improvement in efficiency and the recovery of several novel strains of bacteria with significant biopesticide potential. PMID- 25288942 TI - Biocontrol of Phytophthora Blight and Anthracnose in Pepper by Sequentially Selected Antagonistic Rhizobacteria against Phytophthora capsici. AB - We previously developed a sequential screening procedure to select antagonistic bacterial strains against Phytophthora capsici in pepper plants. In this study, we used a modified screening procedure to select effective biocontrol strains against P. capsici; we evaluated the effect of selected strains on Phytophthora blight and anthracnose occurrence and fruit yield in pepper plants under field and plastic house conditions from 2007 to 2009. We selected four potential biocontrol strains (Pseudomonas otitidis YJR27, P. putida YJR92, Tsukamurella tyrosinosolvens YJR102, and Novosphingobium capsulatum YJR107) among 239 bacterial strains. In the 3-year field tests, all the selected strains significantly (P < 0.05) reduced Phytophthora blight without influencing rhizosphere microbial populations; they showed similar or better levels of disease suppressions than in metalaxyl treatment in the 2007 and 2009 tests, but not in the 2008 test. In the 2-year plastic house tests, all the selected strains significantly (P < 0.05) reduced anthracnose incidence in at least one of the test years, but their biocontrol activities were variable. In addition, strains YJR27, YJR92, and YJR102, in certain harvests, increased pepper fruit numbers in field tests and red fruit weights in plastic house tests. Taken together, these results indicate that the screening procedure is rapid and reliable for the selection of potential biocontrol strains against P. capsici in pepper plants. In addition, these selected strains exhibited biocontrol activities against anthracnose, and some of the strains showed plant growth-promotion activities on pepper fruit. PMID- 25288943 TI - Biological Control of Apple Ring Rot on Fruit by Bacillus amyloliquefaciens 9001. AB - Apple ring rot disease, caused by Botryosphaeria dothidea (Moug. ex. Fr) Ces. et de Not., is one of the most important diseases on apple fruits. In this study, strain 9001 isolated from healthy apple fruits from an infested orchard was evaluated for its biocontrol activity against apple ring rot in vitro and in vivo. Strain 9001 showed obvious antagonistic activity to B. dothidea YL-1 when plated on potato dextrose agar. Soaking healthy apples in the bacterial suspensions of strain 9001 prior to artificial inoculation of fungal pathogen resulted in a dramatic decrease in disease incidence when compared to the control. Moreover, either field application in the growth season or postharvest treatment of apples from infected orchards with bacterial suspensions of strain 9001 resulted in significantly reduced disease incidence within the storage period for 4 months at room temperature. Based on the phylogenetic analysis of 16S rRNA and the gyrA gene, strain 9001 was identified as Bacillus amyloliquefaciens. These results indicated that B. amyloliquefaciens 9001 could be a promising agent in biocontrol of apple ring rot on fruit, which might help to minimize the yield loss of apple fruit during the long postharvest period. PMID- 25288944 TI - Determinants of Plant Growth-promoting Ochrobactrum lupini KUDC1013 Involved in Induction of Systemic Resistance against Pectobacterium carotovorum subsp. carotovorum in Tobacco Leaves. AB - The plant growth-promoting rhizobacterium Ochrobactrum lupini KUDC1013 elicited induced systemic resistance (ISR) in tobacco against soft rot disease caused by Pectobacterium carotovorum subsp. carotovorum. We investigated of its factors involved in ISR elicitation. To characterize the ISR determinants, KUDC1013 cell suspension, heat-treated cells, supernatant from a culture medium, crude bacterial lipopolysaccharide (LPS) and flagella were tested for their ISR activities. Both LPS and flagella from KUDC1013 were effective in ISR elicitation. Crude cell free supernatant elicited ISR and factors with the highest ISR activity were retained in the n-butanol fraction. Analysis of the ISR active fraction revealed the metabolites, phenylacetic acid (PAA), 1-hexadecene and linoleic acid (LA), as elicitors of ISR. Treatment of tobacco with these compounds significantly decreased the soft rot disease symptoms. This is the first report on the ISR determinants by plant growth-promoting rhizobacteria (PGPR) KUDC1013 and identifying PAA, 1-hexadecene and LA as ISR-related compounds. This study shows that KUDC1013 has a great potential as biological control agent because of its multiple factors involved in induction of systemic resistance against phytopathogens. PMID- 25288945 TI - Modulation of Quorum Sensing in Acylhomoserine Lactone-Producing or -Degrading Tobacco Plants Leads to Alteration of Induced Systemic Resistance Elicited by the Rhizobacterium Serratia marcescens 90-166. AB - Numerous root-associated bacteria (rhizobacteria) are known to elicit induced systemic resistance (ISR) in plants. Bacterial cell-density-dependent quorum sensing (QS) is thought to be important for ISR. Here, we investigated the role of QS in the ISR elicited by the rhizobacterium, Serratia marcescens strain 90 166, in tobacco. Since S. marcescens 90-166 produces at least three QS signals, QS-mediated ISR in strain 90-166 has been difficult to understand. Therefore, we investigated the ISR capacity of two transgenic tobacco (Nicotiana tabacum) plants that contained either bacterial acylhomoserine lactone-producing (AHL) or degrading (AiiA) genes in conjunction with S. marcescens 90-166 to induce resistance against bacterial and viral pathogens. Root application of S. marcescens 90-166 increased ISR to the bacterial pathogens, Pectobacterium carotovorum subsp. carotovorum and Pseudomonas syringae pv. tabaci, in AHL plants and decreased ISR in AiiA plants. In contrast, ISR to Cucumber mosaic virus was reduced in AHL plants treated with S. marcescens 90-166 but enhanced in AiiA plants. Taken together, these data indicate that QS-dependent ISR is elicited by S. marcescens 90-166 in a pathogen-dependent manner. This study provides insight into QS-dependent ISR in tobacco elicited by S. marcescens 90-166. PMID- 25288946 TI - Induction of Systemic Resistance against Cucumber mosaic virus in Arabidopsis thaliana by Trichoderma asperellum SKT-1. AB - Trichoderma asperellum SKT-1 is a microbial pesticide that is very effective against various diseases. Our study was undertaken to evaluate T. asperellum SKT 1 for induction of resistance against yellow strain of Cucumber mosaic virus (CMV Y) in Arabidopsis plants. Disease severity was rated at 2 weeks post inoculation (WPI). CMV titre in Arabidopsis leaves was determined by indirect enzyme-linked immunosorbent assay (ELISA) at 2 WPI. Our results demonstrated that among all Arabidopsis plants treated with barley grain inoculum (BGI) of SKT-1 NahG and npr1 plants showed no significant reduction in disease severity and CMV titre as compared with control plants. In contrast, disease severity and CMV titre were significantly reduced in all Arabidopsis plants treated with culture filtrate (CF) of SKT-1 as compared with control plants. RT-PCR results showed increased expression levels of SA-inducible genes, but not JA/ET-inducible genes, in leaves of BGI treated plants. Moreover, expression levels of SA- and JA/ET-inducible genes were increased in leaves of CF treated plants. In conclusion, BGI treatment induced systemic resistance against CMV through SA signaling cascade in Arabidopsis plants. While, treatment with CF of SKT-1 mediated the expression of a majority of the various pathogen related genes, which led to the increased defense mechanism against CMV infection. PMID- 25288947 TI - Induction of Drought Stress Resistance by Multi-Functional PGPR Bacillus licheniformis K11 in Pepper. AB - Drought stress is one of the major yield affecting factor for pepper plant. The effects of PGPRs were analyzed in relation with drought resistance. The PGPRs inoculated pepper plants tolerate the drought stress and survived as compared to non-inoculated pepper plants that died after 15 days of drought stress. Variations in protein and RNA accumulation patterns of inoculated and non inoculated pepper plants subjected to drought conditions for 10 days were confirmed by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and differential display PCR (DD-PCR), respectively. A total of six differentially expressed stress proteins were identified in the treated pepper plants by 2D PAGE. Among the stress proteins, specific genes of Cadhn, VA, sHSP and CaPR-10 showed more than a 1.5-fold expressed in amount in B. licheniformis K11-treated drought pepper compared to untreated drought pepper. The changes in proteins and gene expression patterns were attributed to the B. licheniformis K11. Accordingly, auxin and ACC deaminase producing PGPR B. licheniformis K11 could reduce drought stress in drought affected regions without the need for overusing agrochemicals and chemical fertilizer. These results will contribute to the development of a microbial agent for organic farming by PGPR. PMID- 25288948 TI - Transcriptome Analysis of Induced Systemic Drought Tolerance Elicited by Pseudomonas chlororaphis O6 in Arabidopsis thaliana. AB - Root colonization by Pseudomonas chlororaphis O6 induces systemic drought tolerance in Arabidopsis thaliana. Microarray analysis was performed using the 22,800-gene Affymetrix GeneChips to identify differentially-expressed genes from plants colonized with or without P. chlororaphis O6 under drought stressed conditions or normal growth conditions. Root colonization in plants grown under regular irrigation condition increased transcript accumulation from genes associated with defense, response to reactive oxygen species, and auxin- and jasmonic acid-responsive genes, but decreased transcription factors associated with ethylene and abscisic acid signaling. The cluster of genes involved in plant disease resistance were up-regulated, but the set of drought signaling response genes were down-regulated in the P. chlororaphis O6-colonized under drought stress plants compared to those of the drought stressed plants without bacterial treatment. Transcripts of the jasmonic acid-marker genes, VSP1 and pdf-1.2, the salicylic acid regulated gene, PR-1, and the ethylene-response gene, HEL, also were up-regulated in plants colonized by P. chlororaphis O6, but differed in their responsiveness to drought stress. These data show how gene expression in plants lacking adequate water can be remarkably influenced by microbial colonization leading to plant protection, and the activation of the plant defense signal pathway induced by root colonization of P. chlororaphis O6 might be a key element for induced systemic tolerance by microbes. PMID- 25288949 TI - Current Insights into Research on Rice stripe virus. AB - Rice stripe virus (RSV) is one of the most destructive viruses of rice, and greatly reduces rice production in China, Japan, and Korea, where mostly japonica cultivars of rice are grown. RSV is transmitted by the small brown plant-hopper (SBPH) in a persistent and circulative-propagative manner. Several methods have been developed for detection of RSV, which is composed of four single-stranded RNAs that encode seven proteins. Genome sequence data and comparative phylogenetic analysis have been used to identify the origin and diversity of RSV isolates. Several rice varieties resistant to RSV have been selected and QTL analysis and fine mapping have been intensively performed to map RSV resistance loci or genes. RSV genes have been used to generate several genetically modified transgenic rice plants with RSV resistance. Recently, genome-wide transcriptome analyses and deep sequencing have been used to identify mRNAs and small RNAs involved in RSV infection; several rice host factors that interact with RSV proteins have also been identified. In this article, we review the current statues of RSV research and propose integrated approaches for the study of interactions among RSV, rice, and the SBPH. PMID- 25288950 TI - Phylogenetics and Gene Structure Dynamics of Polygalacturonase Genes in Aspergillus and Neurospora crassa. AB - Polygalacturonase (PG) gene is a typical gene family present in eukaryotes. Forty nine PGs were mined from the genomes of Neurospora crassa and five Aspergillus species. The PGs were classified into 3 clades such as clade 1 for rhamno-PGs, clade 2 for exo-PGs and clade 3 for exo- and endo-PGs, which were further grouped into 13 sub-clades based on the polypeptide sequence similarity. In gene structure analysis, a total of 124 introns were present in 44 genes and five genes lacked introns to give an average of 2.5 introns per gene. Intron phase distribution was 64.5% for phase 0, 21.8% for phase 1, and 13.7% for phase 2, respectively. The introns varied in their sequences and their lengths ranged from 20 bp to 424 bp with an average of 65.9 bp, which is approximately half the size of introns in other fungal genes. There were 29 homologous intron blocks and 26 of those were sub-clade specific. Intron losses were counted in 18 introns in which no obvious phase preference for intron loss was observed. Eighteen introns were placed at novel positions, which is considerably higher than those of plant PGs. In an evolutionary sense both intron loss and gain must have taken place for shaping the current PGs in these fungi. Together with the small intron size, low conservation of homologous intron blocks and higher number of novel introns, PGs of fungal species seem to have recently undergone highly dynamic evolution. PMID- 25288951 TI - Responses of Guava Plants to Inoculation with Arbuscular Mycorrhizal Fungi in Soil Infested with Meloidogyne enterolobii. AB - In the Northeast of Brazil, expansion of guava crops has been impaired by Meloidogyne enterolobii that causes root galls, leaf fall and plant death. Considering the fact that arbuscular mycorrhizal Fungi (AMF) improve plant growth giving protection against damages by plant pathogens, this work was carried out to select AMF efficient to increase production of guava seedlings and their tolerance to M. enterolobii. Seedlings of guava were inoculated with 200 spores of Gigaspora albida, Glomus etunicatum or Acaulospora longula and 55 days later with 4,000 eggs of M. enterolobii. The interactions between the AMF and M. enterolobii were assessed by measuring leaf number, aerial dry biomass, CO2 evolution and arbuscular and total mycorrhizal colonization. In general, plant growth was improved by the treatments with A. longula or with G. albida. The presence of the nematode decreased arbuscular colonization and increased general enzymatic activity. Higher dehydrogenase activity occurred with the A. longula treatment and CO2 evolution was higher in the control with the nematode. More spores and higher production of glomalin-related soil proteins were observed in the treatment with G. albida. The numbers of galls, egg masses and eggs were reduced in the presence of A. longula. Inoculation with this fungus benefitted plant growth and decreased nematode reproduction. PMID- 25288952 TI - RNAseq-based Transcriptome Analysis of Burkholderia glumae Quorum Sensing. AB - Burkholderia glumae causes rice grain rot and sheath rot by producing toxoflavin, the expression of which is regulated by quorum sensing (QS). The QS systems of B. glumae rely on N-octanoyl homoserine lactone, synthesized by TofI and its cognate receptor TofR, to activate the genes for toxoflavin biosynthesis and an IclR-type transcriptional regulator gene, qsmR. To understand genome-wide transcriptional profiling of QS signaling, we employed RNAseq of the wild-type B. glumae BGR1 with QS-defective mutant, BGS2 (BGR1 tofI::Omega) and QS-dependent transcriptional regulator mutant, BGS9 (BGR1 qsmR::Omega). A comparison of gene expression profiling among the wild-type BGR1 and the two mutants before and after QS onset as well as gene ontology (GO) enrichment analysis from differential expressed genes (DEGs) revealed that genes involved in motility were highly enriched in TofI-dependent DEGs, whereas genes for transport and DNA polymerase were highly enriched in QsmR-dependent DEGs. Further, a combination of pathways with these DEGs and phenotype analysis of mutants pointed to a couple of metabolic processes, which are dependent on QS in B. glumae, that were directly or indirectly related with bacterial motility. The consistency of observed bacterial phenotypes with GOs or metabolic pathways in QS-regulated genes implied that integration RNAseq with GO enrichment or pathways would be useful to study bacterial physiology and phenotypes. PMID- 25288953 TI - Prevalence of Tobacco mosaic virus in Iran and Evolutionary Analyses of the Coat Protein Gene. AB - The incidence and distribution of Tobacco mosaic virus (TMV) and related tobamoviruses was determined using an enzyme-linked immunosorbent assay on 1,926 symptomatic horticultural crops and 107 asymptomatic weed samples collected from 78 highly infected fields in the major horticultural crop-producing areas in 17 provinces throughout Iran. The results were confirmed by host range studies and reverse transcription-polymerase chain reaction. The overall incidence of infection by these viruses in symptomatic plants was 11.3%. The coat protein (CP) gene sequences of a number of isolates were determined and disclosed to be a high identity (up to 100%) among the Iranian isolates. Phylogenetic analysis of all known TMV CP genes showed three clades on the basis of nucleotide sequences with all Iranian isolates distinctly clustered in clade II. Analysis using the complete CP amino acid sequence showed one clade with two subgroups, IA and IB, with Iranian isolates in both subgroups. The nucleotide diversity within each sub group was very low, but higher between the two clades. No correlation was found between genetic distance and geographical origin or host species of isolation. Statistical analyses suggested a negative selection and demonstrated the occurrence of gene flow from the isolates in other clades to the Iranian population. PMID- 25288954 TI - Genetic Compositions of Broad bean wilt virus 2 Infecting Red Pepper in Korea. AB - The incidence of Broad bean wilt virus 2 (BBWV2) on red pepper was investigated using the samples obtained from 24 areas of 8 provinces in Korea. Two hundred and five samples (79%) out of 260 collected samples were found to be infected with BBWV2. While the single infection rate of BBWV2 was 21.5%, the co-infection rate of BBWV2 with Cucumber mosaic virus, Pepper mottle virus, Pepper mild mottle virus and/or Potato virus Y was 78.5%. To characterize the genetic diversity of BBWV2 Korean isolates, 7 isolates were fully sequenced and analyzed. Phylogenetic analyses revealed that BBWV2 isolates could be divided largely into two groups as Group I and Group II. Based on the partial sequence analyses, 153 selected BBWV2 isolates were subgrouped into GS-I (21.6%), GS-II (3.9%) and GS-III (56.9%). BBWV2 GS-III, which was predominant in Korea, appears to be a new combination between Group I RNA-1 and Group II RNA-2. Viral disease incidence of BBWV2 on red pepper was under 2% before 2004. However, the incidence was increased abruptly to 41.3% in 2005, 58.2% in 2006 and 79% in 2007. These rapid increases might be related with the emergence of new combinations between BBWV2 groups. PMID- 25288955 TI - Occurrence of Squash yellow mild mottle virus and Pepper golden mosaic virus in Potential New Hosts in Costa Rica. AB - Leaf samples of Solanum lycopersicum, Capsicum annuum, Cucurbita moschata, Cucurbita pepo, Sechium edule and Erythrina spp. were collected. All samples were positive for begomoviruses using polymerase chain reaction and degenerate primers. A sequence of ~1,100 bp was obtained from the genomic component DNA-A of 14 samples. In addition, one sequence of ~580 bp corresponding to the coat protein (AV1) was obtained from a chayote (S. edule) leaf sample. The presence of Squash yellow mild mottle virus (SYMMoV) and Pepper golden mosaic virus (PepGMV) were confirmed. The host range reported for SYMMoV includes species of the Cucurbitaceae, Caricaceae and Fabaceae families. This report extends the host range of SYMMoV to include the Solanaceae family, and extends the host range of PepGMV to include C. moschata, C. pepo and the Fabaceae Erythrina spp. This is the first report of a begomovirus (PepGMV) infecting chayote in the Western Hemisphere. PMID- 25288956 TI - A three-year field validation study to improve the integrated pest management of hot pepper. AB - To improve the integrated pest management (IPM) of hot pepper, field study was conducted in Hwasung from 2010 to 2012 and an IPM system was developed to help growers decide when to apply pesticides to control anthracnose, tobacco budworm, Phytophthora blight, bacterial wilt, and bacterial leaf spot. The three field treatments consisted of IPM sprays following the forecast model advisory, a periodic spray at 7-to-10-day intervals, and no spray (control). The number of annual pesticide applications for the IPM treatment ranged from six to eight, whereas the plots subjected to the periodic treatment received pesticide 11 or 12 times annually for three years. Compared to the former strategy, our improved IPM strategy features more intense pest management, with frequent spraying for anthracnose and mixed spraying for tobacco budworm or Phytophthora blight. The incidences for no pesticide control in 2010, 2011, and 2012 were 91, 97.6, and 41.4%, respectively. Conversely, the incidences for the IPM treatment for those years were 7.6, 62.6, and 2%, and the yields from IPM-treated plots were 48.6 kg, 12.1 kg, and 48.8 kg. The incidence and yield in the IPM-treated plots were almost the same as those of the periodic treatment except in 2011, in which no unnecessary sprays were given, meaning that the IPM control was quite successful. From reviewing eight years of field work, sophisticated forecasts that optimize pesticide spray timing reveal that reliance on pesticides can be reduced without compromising yield. Eco-friendly strategies can be implemented in the pest management of hot pepper. PMID- 25288958 TI - Taxonomic Re-evaluation of Colletotrichum gloeosporioides Isolated from Strawberry in Korea. AB - For the past two decades, the causal agent of anthracnose occurring on strawberry in Korea was considered Colletotrichum gloeosporioides. However, the recent molecular analysis has shown that the genus Colletotrichum has undergone many taxonomic changes with introduction of several new species. As a result, it revealed that C. gloeosporioides indeed consisted of more than 20 distinct species. Therefore, the Korean pathogen isolated from strawberry should be reclassified. The shape and size of the conidia of the pathogen were not distinctly different from those of C. gloeosporioides and C. fructicola, but it differed in shape of the appressoria. A combined sequence analysis of partial actin, glycer-aldehydes-3-phosphate dehydrogenase genes, and the internal transcribed spacer regions showed that the strawberry isolates formed a monophyletic group with authentic strains of C. fructicola. On the basis of these results, the anthracnose fungi of the domestic strawberry in Korea were identified as C. fructicola and distinguished from C. gloeosporioides. PMID- 25288957 TI - beta-Amino-n-butyric Acid Regulates Seedling Growth and Disease Resistance of Kimchi Cabbage. AB - Non-protein amino acid, beta-amino-n-butyric acid (BABA), has been involved in diverse physiological processes including seedling growth, stress tolerance and disease resistance of many plant species. In the current study, treatment of kimchi cabbage seedlings with BABA significantly reduced primary root elongation and cotyledon development in a dose-dependent manner, which adverse effects were similar to the plant response to exogenous abscisic acid (ABA) application. BABA was synergistically contributing ABA-induced growth arrest during the early seedling development. Kimchi cabbage leaves were highly damaged and seedling growth was delayed by foliar spraying with high concentrations of BABA (10 to 20 mM). BABA played roles differentially in in vitro fungal conidial germination, mycelial growth and conidation of necrotroph Alternaria brassicicola causing black spot disease and hemibiotroph Colletotrichum higginsianum causing anthracnose. Pretreatment with BABA conferred induced resistance of the kimchi cabbage against challenges by the two different classes of fungal pathogens in a dose-dependent manner. These results suggest that BABA is involved in plant development, fungal development as well as induced fungal disease resistance of kimchi cabbage plant. PMID- 25288959 TI - The RpoS Sigma Factor Negatively Regulates Production of IAA and Siderophore in a Biocontrol Rhizobacterium, Pseudomonas chlororaphis O6. AB - The stationary-phase sigma factor, RpoS, influences the expression of factors important in survival of Pseudomonas chlororaphis O6 in the rhizosphere. A partial proteomic profile of a rpoS mutant in P. chlororaphis O6 was conducted to identify proteins under RpoS regulation. Five of 14 differentially regulated proteins had unknown roles. Changes in levels of proteins in P. chlororaphis O6 rpoS mutant were associated with iron metabolism, and protection against oxidative stress. The P. chlororaphis O6 rpoS mutant showed increased production of a pyoverdine-like siderophore, indole acetic acid, and altered isozyme patterns for peroxidase, catalase and superoxide dismutase. Consequently, sensitivity to hydrogen peroxide exposure increased in the P. chlororaphis O6 rpoS mutant, compared with the wild type. Taken together, RpoS exerted regulatory control over factors important for the habitat of P. chlororaphis O6 in soil and on root surfaces. The properties of several of the proteins in the RpoS regulon are currently unknown. PMID- 25288960 TI - Transcriptome Analysis of the Small Brown Planthopper, Laodelphax striatellus Carrying Rice stripe virus. AB - Rice stripe virus (RSV), the type member of the genus Tenuivirus, transmits by the feeding behavior of small brown planthopper (SBPH), Laodelphax striatellus. To investigate the interactions between the virus and vector insect, total RNA was extracted from RSV-viruliferous SBPH (RVLS) and non-viruliferous SBPH (NVLS) adults to construct expressed sequence tag databases for comparative transcriptome analysis. Over 30 million bases were sequenced by 454 pyrosequencing to construct 1,538 and 953 of isotigs from the mRNA of RVLS and NVLS, respectively. The gene ontology (GO) analysis demonstrated that both libraries have similar GO structures, however, the gene expression pattern analysis revealed that 17.8% and 16.8% of isotigs were up- and down-regulated significantly in the RVLS, respectively. These RSV-dependently regulated genes possibly have important roles in the physiology of SBPH, transmission of RSV, and RSV and SBPH interaction. PMID- 25288961 TI - Reverse Transcription Polymerase Chain Reaction-based System for Simultaneous Detection of Multiple Lily-infecting Viruses. AB - A detection system based on a multiplex reverse transcription (RT) polymerase chain reaction (PCR) was developed to simultaneously identify multiple viruses in the lily plant. The most common viruses infecting lily plants are the cucumber mosaic virus (CMV), lily mottle virus (LMoV), lily symptomless virus (LSV). Leaf samples were collected at lily-cultivation facilities located in the Kangwon province of Korea and used to evaluate the detection system. Simplex and multiplex RT-PCR were performed using virus-specific primers to detect single-or mixed viral infections in lily plants. Our results demonstrate the selective detection of 3 different viruses (CMV, LMoV and LSV) by using specific primers as well as the potential of simultaneously detecting 2 or 3 different viruses in lily plants with mixed infections. Three sets of primers for each target virus, and one set of internal control primers were used to evaluate the detection system for efficiency, reliability, and reproducibility. PMID- 25288962 TI - Morphometric Variation in Pine Wood Nematodes, Bursaphelenchus xylophilus and B. mucronatus, Isolated from Multiple Locations in South Korea. AB - Intraspecific variation in morphometry of pine wood nematodes Bursaphelenchus xylophilus and B. mucronatus in relation to geographical locations in South Korea was investigated using morphometric characters (body length, a, b and c ratio, stylet length, and spicule length for a male nematode and V (%) value for a female nematode). B. xylophilus was isolated from Pinus thunbergii in Jinju (1998), Ulsan (2000), Yangsan (2000), Mokpo (2001) and Jeju (2004), and from P. densiflora in Gumi (2001). B. mucronatus was isolated from P. thunbergii in Jinju (1991) and from P. densiflora in Milyang (2001). The body length of male and female B. xylophilus had the highest coefficient of variability and showed significant differences among geographical locations. The V (%) value for female B. xylophilus showed the lowest coefficient of variability, changing little with geographical area and host plant. All morphometric characters in B. mucronatus except for stylet length and female body length showed no significant differences between locations or hosts, suggesting they may not be affected by geographical area or host plant. PMID- 25288963 TI - Systemic Induction of the Small Antibacterial Compound in the Leaf Exudate During Benzothiadiazole-elicited Systemic Acquired Resistance in Pepper. AB - Plants protect themselves from diverse potential pathogens by induction of the immune systems such as systemic acquired resistance (SAR). Most bacterial plant pathogens thrive in the intercellular space (apoplast) of plant tissues and cause symptoms. The apoplastic leaf exudate (LE) is believed to contain nutrients to provide food resource for phytopathogenic bacteria to survive and to bring harmful phytocompounds to protect plants against bacterial pathogens. In this study, we employed the pepper-Xanthomonas axonopodis system to assess whether apoplastic fluid from LE in pepper affects the fitness of X. axonopodis during the induction of SAR. The LE was extracted from pepper leaves 7 days after soil drench-application of a chemical trigger, benzothiadiazole (BTH). Elicitation of plant immunity was confirmed by significant up-regulation of four genes, CaPR1, CaPR4, CaPR9, and CaCHI2, by BTH treatment. Bacterial fitness was evaluated by measuring growth rate during cultivation with LE from BTH- or water-treated leaves. LE from BTH-treatment significantly inhibited bacterial growth when compared to that from the water-treated control. The antibacterial activity of LE from BTH-treated samples was not affected by heating at 100 degrees C for 30 min. Although the antibacterial molecules were not precisely identified, the data suggest that small (less than 5 kDa), heat-stable compound(s) that are present in BTH-induced LE directly attenuate bacterial growth during the elicitation of plant immunity. PMID- 25288964 TI - Specific and Sensitive Detection of Venturia nashicola, the Scab Fungus of Asian Pears, by Nested PCR. AB - The fungus Venturia nashicola is the causal agent of scab on Asian pears. For the rapid and reliable identification as well as sensitive detection of V. nashicola, a PCR-based technique was developed. DNA fingerprints of three closely related species, V. nashicola, V. pirina, and V. inaequalis, were obtained by random amplified polymorphic DNA (RAPD) analysis. Two RAPD markers specific to V. nashicola were identified by PCR, after which two pairs of sequence characterized amplified region (SCAR) primers were designed from the nucleotide sequences of the markers. The SCAR primer pairs, designated as D12F/D12R and E11F/E11R, amplified 535-bp and 525-bp DNA fragments, respectively, only from genomic DNA of V. nashicola. The specificity of the primer sets was tested on strains representing three species of Venturia and 20 fungal plant pathogens. The nested PCR primer pair specific to V. nashicola was developed based on the sequence of the species-specific 525-bp DNA fragment amplified by primer set E11F/E11R. The internal primer pair Na11F/Na11R amplified a 235-bp fragment from V. nashicola, but not from any other fungal species tested. The nested PCR assay was sensitive enough to detect the specific fragment in 50 fg of V. nashicola DNA. PMID- 25288965 TI - Xanthomonas oryzae pv. oryzae RpfE Regulates Virulence and Carbon Source Utilization without Change of the DSF Production. AB - It has been known that most regulation of pathogenicity factor (rpf) genes in xanthomonads regulates virulence in response to the diffusible signal factor, DSF. Although many rpf genes have been functionally characterized, the function of rpfE is still unknown. We cloned the rpfE gene from a Xanthomonas oryzae pv. oryzae (Xoo) Korean race KACC10859 and generated mutant strains to elucidate the role of RpfE with respect to the rpf system. Through experiments using the rpfE deficient mutant strain, we found that mutation in rpfE gene in Xoo reduced virulence, swarm motility, and production of virulence factors such as cellulase and extracellular polysaccharide. Disease progress by the rpfE-deficient mutant strain was significantly slowed compared to disease progress by the wild type and the number of the rpfE-deficient mutant strain was lower than that of the wild type in the early phase of infection in the inoculated rice leaf. The rpfE mutant strain was unable to utilize sucrose or xylose as carbon sources efficiently in culture. The mutation in rpfE, however, did not affect DSF synthesis. Our results suggest that the rpfE gene regulates the virulence of Xoo under different nutrient conditions without change of DSF production. PMID- 25288966 TI - Altered Gene Expression and Intracellular Changes of the Viable But Nonculturable State in Ralstonia solanacearum by Copper Treatment. AB - Environmental stresses induce several plant pathogenic bacteria into a viable but nonculturable (VBNC) state, but the basis for VBNC is largely uncharacterized. We investigated the physiology and morphology ofthe copper-induced VBNC state in the plant pathogen Ralstonia solanacearum in liquid microcosm. Supplementation of 200 MUM copper sulfate to the liquid microcosm completely suppressed bacterial colony formation on culture media; however, LIVE/DEAD BacLight bacterial viability staining showed that the bacterial cells maintained viability, and that the viable cells contain higher level of DNA. Based on electron microscopic observations, the bacterial cells in the VBNC state were unchanged in size, but heavily aggregated and surrounded by an unknown extracellular material. Cellular ribosome contents, however, were less, resulting in a reduction of the total RNA in VBNC cells. Proteome comparison and reverse transcription PCR analysis showed that the Dps protein production was up-regulated at the transcriptional level and that 2 catalases/peroxidases were present at lower level in VBNC cells. Cell aggregation and elevated levels of Dps protein are typical oxidative stress responses. H2O2 levels also increased in VBNC cells, which could result if catalase/peroxidase levels are reduced. Some of phenotypic changes in VBNC cells of R. solanacearum could be an oxidative stress response due to H2O2 accumulation. This report is the first of the distinct phenotypic changes in cells of R. solanacearum in the VBNC state. PMID- 25288967 TI - Hydrogen Peroxide- and Nitric Oxide-mediated Disease Control of Bacterial Wilt in Tomato Plants. AB - Reactive oxygen species (ROS) generation in tomato plants by Ralstonia solanacearum infection and the role of hydrogen peroxide (H2O2) and nitric oxide in tomato bacterial wilt control were demonstrated. During disease development of tomato bacterial wilt, accumulation of superoxide anion (O2 (-)) and H2O2 was observed and lipid peroxidation also occurred in the tomato leaf tissues. High doses of H2O2and sodium nitroprusside (SNP) nitric oxide donor showed phytotoxicity to detached tomato leaves 1 day after petiole feeding showing reduced fresh weight. Both H2O2and SNP have in vitro antibacterial activities against R. solanacearum in a dose-dependent manner, as well as plant protection in detached tomato leaves against bacterial wilt by 10(6) and 10(7) cfu/ml of R. solanacearum. H2O2- and SNP-mediated protection was also evaluated in pots using soil-drench treatment with the bacterial inoculation, and relative 'area under the disease progressive curve (AUDPC)' was calculated to compare disease protection by H2O2 and/or SNP with untreated control. Neither H2O2 nor SNP protect the tomato seedlings from the bacterial wilt, but H2O2+ SNP mixture significantly decreased disease severity with reduced relative AUDPC. These results suggest that H2O2 and SNP could be used together to control bacterial wilt in tomato plants as bactericidal agents. PMID- 25288968 TI - Molecular Characterization and Variation of the Broad bean wilt virus 2 Isolates Based on Analyses of Complete Genome Sequences. AB - The full-genome sequences of fourteen isolates of Broad bean wilt virus 2 (BBWV2), collected from broad bean, pea, spinach, bell pepper and paprika plants in Korea during the years 2006-2012, were determined and analyzed comparatively along with fifteen previously reported BBWV2 genome sequences. Sequence analyses showed that RNA-1 and RNA-2 sequences of BBWV2 Korean isolates consisted of 5950 5956 and 3568-3604 nucleotides, respectively. Full-length genome sequence-based phylogenetic analyses revealed that the BBWV2 Korean isolates could be divided into three major groups comprising GS-I (isolates BB2 and RP7) along with isolate IP, GS-II (isolates BB5, P2, P3 and RP3) along with isolate B935, and GS-III including 16 BBWV2 Korean isolates. Interestingly, GS-III appears to be newly emerged and predominant in Korea. Recombination analyses identified two recombination events in the analyzed BBWV2 population: one in the RNA-1 of isolate K and another one in the RNA-2 of isolate XJ14-3. However, no recombination events were detected in the other 21 Korean isolates. On the other hand, out of 29 BBWV2 isolates, 16 isolates were found to be reassortants, of which each RNA segment (i.e. RNA1 and RNA2) was originated from different parental isolates. Our findings suggested that reassortment rather than recombination is a major evolutionary force in the genetic diversification of BBWV population in Korea. PMID- 25288969 TI - Biological and Molecular Variability of Alfalfa mosaic virus Affecting Alfalfa Crop in Riyadh Region. AB - In 2011-2012, sixty nine samples were collected from alfalfa plants showing viral infection symptoms in Riyadh region. Mechanical inoculation with sap prepared from two collected samples out of twenty five possitive for Alfalfa mosaic virus (AMV) by ELISA were produced systemic mosaic on Vigna unguiculata and Nicotiana tabacum, local lesion on Chenopodium amaranticolor and C. quinoa. Vicia faba indicator plants that induce mosaic and mottle with AMV-Sagir isolate and no infection with AMV-Wadi aldawasser isolate. Approximately 700-bp was formed by RT PCR using AMV coat protein specific primer. Samples from infected alfalfa gave positive results, while healthy plant gave negative result using dot blot hybridization assay. The nucleotide sequences of the Saudi isolates were compared with corresponding viral nucleotide sequences reported in GenBank. The obtained results showed that the AMV from Australia, Brazil, Puglia and China had the highest similarity with AMV-Sajer isolate. While, the AMV from Spain and New Zealaland had the lowest similarity with AMV-Sajer and Wadi aldawasser isolates. The data obtained in this study has been deposited in the GenBank under the accession numbers KC434083 and KC434084 for AMV-Sajer and AMV- Wadialdawasser respectively. This is the first report regarding the gnetic make up of AMV in Saudi Arabia. PMID- 25288970 TI - Enhanced biological control of phytophthora blight of pepper by biosurfactant producing pseudomonas. AB - Pseudomonas isolates from different crop plants were screened for in vitro growth inhibition of Phytophthora capsici and production of biosurfactant. Two in vivo experiments were performed to determine the efficacy of selected Pseudomonas strains against Phytophthora blight of pepper by comparing two fungicide treatments [acibenzolar-S-methyl (ASM) and ASM + mefenoxam]. Bacterial isolates were applied by soil drenching (1 * 10(9) cells/ml), ASM (0.1 MUg a.i./ml) and ASM + mefenoxam (0.2 mg product/ml) were applied by foliar spraying, and P. capsici inoculum was incorporated into the pot soil three days after treatments. In the first experiment, four Pseudomonas strains resulted in significant reduction from 48.4 to 61.3% in Phytophthora blight severity. In the second experiment, bacterial treatments combining with olive oil (5 mL per plant) significantly enhanced biological control activity, resulting in a reduction of disease level ranging from 56.8 to 81.1%. ASM + mefenoxam was the most effective treatment while ASM alone was less effective in both bioassays. These results indicate that our Pseudomonas fluorescens strains (6L10, 6ba6 and 3ss9) that have biosurfactant-producing abilities are effective against P. capsici on pepper, and enhanced disease suppression could be achieved when they were used in combination with olive oil. PMID- 25288971 TI - Nitric Oxide and Hydrogen Peroxide Production are Involved in Systemic Drought Tolerance Induced by 2R,3R-Butanediol in Arabidopsis thaliana. AB - 2R,3R-Butanediol, a volatile compound produced by certain rhizobacteria, is involved in induced drought tolerance in Arabidopsis thaliana through mechanisms involving stomatal closure. In this study, we examined the involvement of nitric oxide and hydrogen peroxide in induced drought tolerance, because these are signaling agents in drought stress responses mediated by abscisic acid (ABA). Fluorescence-based assays showed that systemic nitric oxide and hydrogen peroxide production was induced by 2R,3R-butanediol and correlated with expression of genes encoding nitrate reductase and nitric oxide synthase. Co-treatment of 2R,3R butanediol with an inhibitor of nitrate reductase or an inhibitor of nitric oxide synthase lowered nitric oxide production and lessened induced drought tolerance. Increases in hydrogen peroxide were negated by co-treatment of 2R,3R-butanediol with inhibitors of NADPH oxidase, or peroxidase. These findings support the volatile 2R,3R-butanediol synthesized by certain rhizobacteria is an active player in induction of drought tolerance through mechanisms involving nitric oxide and hydrogen peroxide production. PMID- 25288972 TI - Comparative Analysis of the Korean Population of Magnaporthe oryzae by Multilocus Microsatellite Typing. AB - Rice blast fungus, Magnaporthe oryzae, inflicts serious damage to global rice production. Due to high variability of this fungal pathogen, resistance of newly released rice cultivars is easily broken down. To understand the population structure of M. oryzae, we analyzed the genetic diversity of the Korean population using multilocus microsatellite typing. Eleven microsatellite markers were applied to the population of 190 rice isolates which had been collected in Korea for two decades since the 1980's. Average values of gene diversity and allele frequency were 0.412 and 6.5, respectively. Comparative analysis of the digitized allele information revealed that the Korean population exhibited a similar level of allele diversity to the integrated diversity of the world populations, suggesting a particularly high diversity of the Korean population. Therefore, these microsatellite markers and the comprehensive collection of field isolates will be useful genetic resources to identify the genetic diversity of M. oryzae population. PMID- 25288973 TI - Root Rot of Balloon Flower (Platycodon grandiflorum) Caused by Fusarium solani and Fusarium oxysporum. AB - Balloon flower (Platycodon grandiflorum) is a kind of mountain herbs whose roots have restorative properties and the cultivating acreage of balloon flower has been steadily increasing in Korea. More frequent rain and high amount of rainfalls as a result of climate changes predisposed balloon flower to the outbreaks of root rot at high-density cultivation area in recent years. Root crowns were usually discolored into brown to blackish brown at first and the infected plants showed slight wilting symptom at early infection stage. Severely infected roots were entirely rotted and whole plants eventually died at late infection stage. The overall disease severities of root rot of balloon flower were quite variable according to the surveyed fields in Jeonnam, Gyeongnam and Jeju Provinces, which ranged from 0.1% to 40%. The root rot occurred more severely at the paddy or clay soils than the sandy soils and their severities were much higher at lowland than upland in the same localty. The disease increased with aging of the balloon flower. The causal fungi were identified as Fusarium solani and F. oxysporum on the basis of their mycological characteristics. The optimum temperature ranges of their mycelial growths was found to be 24 degrees C. The pathogenic characters of F. solani and F. oxysporum treated by artificial wounding inoculation on healthy roots of balloon flower revealed that F. solani was more virulent than F. oxysporum. This study identified the causal agents of root rot of balloon flower as Fusarium solani and F. oxysporum, probably for the first time. PMID- 25288974 TI - Development of a Selective Medium for the Fungal Pathogen Fusarium graminearum Using Toxoflavin Produced by the Bacterial Pathogen Burkholderia glumae. AB - The ascomycete fungus Fusarium graminearum is a major causal agent for Fusarium head blight in cereals and produces mycotoxins such as trichothecenes and zearalenone. Isolation of the fungal strains from air or cereals can be hampered by various other airborne fungal pathogens and saprophytic fungi. In this study, we developed a selective medium specific to F. graminearum using toxoflavin produced by the bacterial pathogen Burkholderia glumae. F. graminearum was resistant to toxoflavin, while other fungi were sensitive to this toxin. Supplementing toxoflavin into medium enhanced the isolation of F. graminearum from rice grains by suppressing the growth of saprophytic fungal species. In addition, a medium with or without toxoflavin exposed to wheat fields for 1 h had 84% or 25%, respectively, of colonies identified as F. graminearum. This selection medium provides an efficient tool for isolating F. graminearum, and can be adopted by research groups working on genetics and disease forecasting. PMID- 25288975 TI - A simple method for assessing severity of common root rot on barley. AB - Common root rot caused by Cochliobolus sativus is a serious disease of barley. A simple and reliable method for assessing this disease would enhance our capacity in identifying resistance sources and developing resistant barley cultivars. In searching for such a method, a conidial suspension of C. sativus was dropped onto sterilized elongated subcrown internodes and incubated in sandwich filter paper using polyethylene transparent envelopes. Initial disease symptoms were easily detected after 48h of inoculation. Highly significant correlation coefficients were found in each experiment (A, B and C) between sandwich filter paper and seedling assays, indicating that this testing procedure was reliable. The method presented facilitates a rapid pre-selection under uniform conditions which is of importance from a breeder's point of view. PMID- 25288976 TI - AltMV TGB1 Nucleolar Localization Requires Homologous Interaction and Correlates with Cell Wall Localization Associated with Cell-to-Cell Movement. AB - The Potexvirus Alternanthera mosaic virus (AltMV) has multifunctional triple gene block (TGB) proteins, among which our studies have focused on the properties of the TGB1 protein. The TGB1 of AltMV has functions including RNA binding, RNA silencing suppression, and cell-to-cell movement, and is known to form homologous interactions. The helicase domains of AltMV TGB1 were separately mutated to identify which regions are involved in homologous TGB1 interactions. The yeast two hybrid system and Bimolecular Fluorescence Complementation (BiFC) in planta were utilized to examine homologous interactions of the mutants. Helicase motif I of AltMV TGB1 was found to be critical to maintain homologous interactions. Mutations in the remaining helicase motifs did not inhibit TGB1 homologous interactions. In the absence of homologous interaction of TGB1, subcellular localization of helicase domain I mutants showed distinctively different patterns from that of WT TGB1. These results provide important information to study viral movement and replication of AltMV. PMID- 25288977 TI - Occurrence of dsRNA Mycovirus (LeV-FMRI0339) in the Edible Mushroom Lentinula edodes and Meiotic Stability of LeV-FMRI0339 among Monokaryotic Progeny. AB - dsRNA was found in malformed cultures of Lentinula edodes strain FMRI0339, one of the three most popular sawdust cultivated commercial strains of shiitake, and was also found in healthy-looking fruiting bodies and actively growing mycelia. Cloning of the partial genome of the dsRNA revealed the presence of the RdRp sequence of a novel L. edodes mycovirus (LeV), and sequence comparison of the cloned amplicon showed identical sequences sequence to known RNA-dependent RNA polymerase genes of LeV found in strain HKA. The meiotic stability of dsRNA was examined by measuring the ratio of the presence of dsRNA among sexual monokaryotic progeny. More than 40% of the monokaryotic progeny still contained the dsRNA, indicating the persistence of dsRNA during sexual reproduction. Comparing the mycelia growth of monokaryotic progeny suggested that there appeared to be a tendency toward a lower frequency of virus incidence in actively growing progeny. PMID- 25288978 TI - Occurrence of Stolbur Phytoplasma Disease in Spreading Type Petunia hybrida Cultivars in Korea. AB - In January 2012, spreading type petunia cv. Wave Pink plants showing an abnormal growth habit of sprouting unusual multiple plantlets from the lateral buds were collected from a greenhouse in Gwacheon, Gyeonggi Province, Korea. The presence of phytoplasma was investigated using PCR with the primer pairs P1/P6, and R16F1/R1 for nested-PCR. In the nested PCR, 1,096 bp PCR products were obtained, and through sequencing 12 Pet-Stol isolates were identified. Comparison of the nucleotide sequences of 16S rRNA gene of the 12 Pet-Stol isolates with other phytoplasmas belonging to aster yellows or Stolbur showed that Pet-Stol isolates were members of Stolbur. The presence of phytoplasma in petunia was also confirmed by microscopic observation of the pathogens. In this study, Stolbur phytoplasma was identified from spreading type petunia cultivars by sequence analysis of 16S rRNA gene of phytoplasma and microscopic observation of phytoplasma bodies. This is the first report of Stolbur phytoplasma in commercial Petunia hybrida cultivars. PMID- 25288979 TI - Arabidopsis PYL8 Plays an Important Role for ABA Signaling and Drought Stress Responses. AB - Plants are frequently exposed to numerous environmental stresses such as dehydration and high salinity, and have developed elaborate mechanisms to counteract the deleterious effects of stress. The phytohormone abscisic acid (ABA) plays a critical role as an integrator of plant responses to water-limited condition to activate ABA signal transduction pathway. Although perception of ABA has been suggested to be important, the function of each ABA receptor remains elusive in dehydration condition. Here, we show that ABA receptor, pyrabactin resistance-like protein 8 (PYL8), functions in dehydration conditions. Transgenic plants overexpressing PYL8 exhibited hypersensitive phenotype to ABA in seed germination, seedling growth and establishment. We found that hypersensitivity to ABA of transgenic plants results in high degrees of stomatal closure in response to ABA leading to low transpiration rates and ultimately more vulnerable to drought than the wild-type plants. In addition, high expression of ABA maker genes also contributes to altered drought tolerance phenotype. Overall, this work emphasizes the importance of ABA signaling by ABA receptor in stomata during defense response to drought stress. PMID- 25288981 TI - Genetic Diversity and Differentiation of Colletotrichum spp. Isolates Associated with Leguminosae Using Multigene Loci, RAPD and ISSR. AB - Genetic diversity and differentiation of 50 Colletotrichum spp. isolates from legume crops studied through multigene loci, RAPD and ISSR analysis. DNA sequence comparisons by six genes (ITS, ACT, Tub2, CHS-1, GAPDH, and HIS3) verified species identity of C. truncatum, C. dematium and C. gloeosporiodes and identity C. capsici as a synonym of C. truncatum. Based on the matrix distance analysis of multigene sequences, the Colletotrichum species showed diverse degrees of intera and interspecific divergence (0.0 to 1.4%) and (15.5-19.9), respectively. A multilocus molecular phylogenetic analysis clustered Colletotrichum spp. isolates into 3 well-defined clades, representing three distinct species; C. truncatum, C. dematium and C. gloeosporioides. The ISSR and RAPD and cluster analysis exhibited a high degree of variability among different isolates and permitted the grouping of isolates of Colletotrichum spp. into three distinct clusters. Distinct populations of Colletotrichum spp. isolates were genetically in accordance with host specificity and inconsistent with geographical origins. The large population of C. truncatum showed greater amounts of genetic diversity than smaller populations of C. dematium and C. gloeosporioides species. Results of ISSR and RAPD markers were congruent, but the effective maker ratio and the number of private alleles were greater in ISSR markers. PMID- 25288980 TI - Histone acetylation in fungal pathogens of plants. AB - Acetylation of histone lysine residues occurs in different organisms ranging from yeast to plants and mammals for the regulation of diverse cellular processes. With the identification of enzymes that create or reverse this modification, our understanding on histone acetylation has expanded at an amazing pace during the last two decades. In fungal pathogens of plants, however, the importance of such modification has only just begun to be appreciated in the recent years and there is a dearth of information on how histone acetylation is implicated in fungal pathogenesis. This review covers the current status of research related to histone acetylation in plant pathogenic fungi and considers relevant findings in the interaction between fungal pathogens and host plants. We first describe the families of histone acetyltransferases and deacetylases. Then we provide the cases where histone acetylation was investigated in the context of fungal pathogenesis. Finally, future directions and perspectives in epigenetics of fungal pathogenesis are discussed. PMID- 25288982 TI - A Simple Method for the Assessment of Fusarium Head Blight Resistance in Korean Wheat Seedlings Inoculated with Fusarium graminearum. AB - Fusarium head blight (FHB; scab) caused mainly by Fusarium graminearum is a devastating disease of wheat and barley around the world. FHB causes yield reductions and contamination of grain with trichothecene mycotoxins such as deoxynivalenol (DON) which are a major health concern for humans and animals. The objective of this research was to develop an easy seed or seedling inoculation assay, and to compare these assays with whole plant resistance of twenty-nine Korean winter wheat cultivars to FHB. The clip-dipping assay consists of cutting off the coleoptiles apex, dipping the coleoptiles apex in conidial suspension, covering in plastic bag for 3 days, and measuring the lengths of lesions 7 days after inoculation. There were significant cultivar differences after inoculation with F. graminearum in seedling relative to the controls. Correlation coefficients between the lesion lengths of clip-dipping inoculation and FHB Type II resistance from adult plants were significant (r=0.45; P<0.05). Results from two other seedling inoculation methods, spraying and pin-point inoculation, were not correlated with adult FHB resistance. Single linear correlation was not significant between seed germination assays (soaking and soak-dry) and FHB resistance (Type I and Type II), respectively. These results showed that clip dipping inoculation method using F. graminearum may offer a real possibility of simple, rapid, and reliable for the early screening of FHB resistance in wheat. PMID- 25288983 TI - Comparison of Trichothecene Biosynthetic Gene Expression between Fusarium graminearum and Fusarium asiaticum. AB - Nivalenol (NIV) and deoxynivalenol (DON) are predominant Fusarium-producing mycotoxins found in grains, which are mainly produced by Fusarium asiaticum and F. graminearum. NIV is found in most of cereals grown in Korea, but the genetic basis for NIV production by F. asiaticum has not been extensively explored. In this study, 12 genes belonging to the trichothecene biosynthetic gene cluster were compared at the transcriptional level between two NIV-producing F. asiaticum and four DON-producing F. graminearum strains. Chemical analysis revealed that time-course toxin production patterns over 14 days did not differ between NIV and DON strains, excluding F. asiaticum R308, which was a low NIV producer. Both quantitative real-time polymerase chain reaction and Northern analysis revealed that the majority of TRI gene transcripts peaked at day 2 in both NIV and DON producers, which is 2 days earlier than trichothecene accumulation in liquid medium. Comparison of the gene expression profiles identified an NIV-specific pattern in two transcription factor-encoding TRI genes (TRI6 and TRI10) and TRI101, which showed two gene expression peaks during both the early and late incubation periods. In addition, the amount of trichothecenes produced by both DON and NIV producers were correlated with the expression levels of TRI genes, regardless of the trichothecene chemotypes. Therefore, the reduced production of NIV by R308 compared to NIV or DON by the other strains may be attributable to the significantly lower expression levels of the TRI genes, which showed early expression patterns. PMID- 25288984 TI - Oak tree canker disease supports arthropod diversity in a natural ecosystem. AB - Microorganisms have many roles in nature. They may act as decomposers that obtain nutrients from dead materials, while some are pathogens that cause diseases in animals, insects, and plants. Some are symbionts that enhance plant growth, such as arbuscular mycorrhizae and nitrogen fixation bacteria. However, roles of plant pathogens and diseases in natural ecosystems are still poorly understood. Thus, the current study addressed this deficiency by investigating possible roles of plant diseases in natural ecosystems, particularly, their positive effects on arthropod diversity. In this study, the model system was the oak tree (Quercus spp.) and the canker disease caused by Annulohypoxylon truncatum, and its effects on arthropod diversity. The oak tree site contained 44 oak trees; 31 had canker disease symptoms while 13 were disease-free. A total of 370 individual arthropods were detected at the site during the survey period. The arthropods belonged to 25 species, 17 families, and seven orders. Interestingly, the cankered trees had significantly higher biodiversity and richness compared with the canker-free trees. This study clearly demonstrated that arthropod diversity was supported by the oak tree canker disease. PMID- 25288985 TI - Development of the large-scale oligonucleotide chip for the diagnosis of plant viruses and its practical use. AB - A large-scale oligonucleotide (LSON) chip was developed for the detection of the plant viruses with known genetic information. The LSON chip contains two sets of 3,978 probes for 538 species of targets including plant viruses, satellite RNAs and viroids. A hundred forty thousand probes, consisting of isolate-, species- and genus-specific probes respectively, are designed from 20,000 of independent nucleotide sequence of plant viruses. Based on the economic importance, the amount of genome information, and the number of strains and/or isolates, one to fifty-one probes for each target virus are selected and spotted on the chip. The standard and field samples for the analysis of the LSON chip have been prepared and tested by RT-PCR. The probe's specific and/or nonspecific reaction patterns by LSON chip allow us to diagnose the unidentified viruses. Thus, the LSON chip in this study could be highly useful for the detection of unexpected plant viruses, the monitoring of emerging viruses and the fluctuation of the population of major viruses in each plant. PMID- 25288986 TI - Selective Interaction Between Chloroplast beta-ATPase and TGB1L88 Retards Severe Symptoms Caused by Alternanthera mosaic virus Infection. AB - The multifunctional triple gene block protein 1 (TGB1) of the Potexvirus Alternanthera mosaic virus (AltMV) has been reported to have silencing suppressor, cell-to-cell movement, and helicase functions. Yeast two hybrid screening using an Arabidopsis thaliana cDNA library with TGB1 as bait, and co purification with TGB1 inclusion bodies identified several host proteins which interact with AltMV TGB1. Host protein interactions with TGB1 were confirmed by biomolecular fluorescence complementation, which showed positive TGB1 interaction with mitochondrial ATP synthase delta' chain subunit (ATP synthase delta'), light harvesting chlorophyll-protein complex I subunit A4 (LHCA4), chlorophyll a/b binding protein 1 (LHB1B2), chloroplast-localized IscA-like protein (ATCPISCA), and chloroplast beta-ATPase. However, chloroplast beta-ATPase interacts only with TGB1L88, and not with weak silencing suppressor TGB1P88. This selective interaction indicates that chloroplast beta-ATPase is not required for AltMV movement and replication; however, TRV silencing of chloroplast beta-ATPase in Nicotiana benthamiana induced severe tissue necrosis when plants were infected by AltMV TGB1L88 but not AltMV TGB1P88, suggesting that beta-ATPase selectively responded to TGB1L88 to induce defense responses. PMID- 25288987 TI - Construction of Infectious cDNA Clone of a Chrysanthemum stunt viroid Korean Isolate. AB - Chrysanthemum stunt viroid (CSVd), a noncoding infectious RNA molecule, causes seriously economic losses of chrysanthemum for 3 or 4 years after its first infection. Monomeric cDNA clones of CSVd isolate SK1 (CSVd-SK1) were constructed in the plasmids pGEM-T easy vector and pUC19 vector. Linear positive-sense transcripts synthesized in vitro from the full-length monomeric cDNA clones of CSVd-SK1 could infect systemically tomato seedlings and chrysanthemum plants, suggesting that the linear CSVd RNA transcribed from the cDNA clones could be replicated as efficiently as circular CSVd in host species. However, direct inoculation of plasmid cDNA clones containing full-length monomeric cDNA of CSVd SK1 failed to infect tomato and chrysanthemum and linear negative-sense transcripts from the plasmid DNAs were not infectious in the two plant species. The cDNA sequences of progeny viroid in systemically infected tomato and chrysanthemum showed a few substitutions at a specific nucleotide position, but there were no deletions and insertions in the sequences of the CSVd progeny from tomato and chrysanthemum plants. PMID- 25288988 TI - Screening and Histopathological Characterization of Korean Carrot Lines for Resistance to the Root-Knot Nematode Meloidogyne incognita. AB - In total, 170 carrot lines developed in Korea were screened for resistance to Meloidogyne incognita race 1 to select parental genetic resources useful for the development of nematode-resistant carrot cultivars. Using the gall index (GI), gall formation was examined on carrot roots inoculated with approximately 1,000 second-stage juveniles of the nematode 7 weeks after inoculation. Sixty-one carrot lines were resistant (GI <= 1.0), while the other 109 were susceptible (GI > 1.0) with coefficient of variance (CV) of GI for total carrot lines 0.68, indicating low-variation of GI within the lines examined. The histopathological responses of two carrot plants from resistant and susceptible lines were examined after nematode infection. In susceptible carrots, giant cells formed with no discernible necrosis around the infecting nematodes. In the resistant carrot line, however, no giant cells formed, although modified cells were observed with extensive formation of necrotic layers through their middle lamella and around the infecting nematodes. This suggested that these structural modifications were related to hypersensitive responses governed by the expression of true resistance genes. Therefore, the Korean carrot lines resistant to the nematode infection are potential genetic resources for the development of quality carrot cultivars resistant to M. incognita race 1. PMID- 25288989 TI - Fungicide Sensitivity and Characterization of Cobweb Disease on a Pleurotus eryngii Mushroom Crop Caused by Cladobotryum mycophilum. AB - In 2009-2010, unusual symptoms were observed on Pleurotus eryngii grown in mushroom farms in Gyeongnam Province, Republic of Korea. One of the main symptoms was a cobweb-like growth of fungal mycelia over the surface of the mushroom. The colonies on the surface rapidly overwhelmed the mushrooms and developed several spores within 3-4 days. The colonized surface turned pale brown or yellow. The fruit body eventually turned dark brown and became rancid. Koch's postulates were completed by spraying and spotting using isolated strains. The phylogenetic tree obtained from the internal transcribed spacer sequence analysis showed that the isolated fungal pathogen corresponded to Cladobotryum mycophilum (99.5%). In the fungicide sensitivity tests, the ED50 values for the isolate with respect to benomyl and carbendazim were from 0.29 to 0.31 ppm. Benzimidazole fungicides were most effective against C. mycophilum, a causal agent of cobweb disease in P. eryngii. PMID- 25288990 TI - Evaluation of lettuce germplasm resistance to gray mold disease for organic cultivations. AB - This study was conducted to evaluate the resistance of 212 accessions of lettuce germplasm to gray mold disease caused by Botrytis cinerea. The lettuce germplasm were composed of five species: Lactuca sativa (193 accessions), L. sativa var. longifolia (2 accessions), L. sativa var. crispa (2 accessions), L. saligna (2 accessions), and L. serriola (1 accession); majority of these originated from Korea, Netherlands, USA, Russia, and Bulgaria. After 35 days of spray inoculation with conidial suspension (3*10(7) conidia/ml) of B. cinerea on the surface of lettuce leaves, tested lettuce germplasm showed severe symptoms of gray mold disease. There were 208 susceptible accessions to B. cinerea counted with 100% of disease incidence and four resistant accessions, IT908801, K000598, K000599, and K021055. Two moderately resistant accessions of L. sativa, K021055 and IT908801, showed 20% of disease incidence of gray mold disease at 45 days after inoculation; and two accessions of L. saligna, K000598 and K000599, which are wild relatives of lettuce germplasm with loose-leaf type, showed complete resistance to B. cinerea. These four accessions are candidates for breeding lettuce cultivars resistant to gray mold disease. PMID- 25288991 TI - Molecular Characteristics of Pseudomonas syringae pv. actinidiae Strains Isolated in Korea and a Multiplex PCR Assay for Haplotype Differentiation. AB - The molecular features of Pseudomonas syringae pv. actinidiae strains isolated in Korea were compared with strains isolated in Japan and Italy. Sequencing of eight P. syringae pv. actinidiae and three P. syringae pv. theae strains revealed a total of 44 single nucleotide polymorphisms across 4,818 bp of the concatenated alignment of nine genes. A multiplex PCR assay was developed for the detection of P. syringae pv. actinidiae and for the specific detection of recent haplotype strains other than strains isolated since the 1980s in Korea. The primer pair, designated as TacF and TacR, specifically amplified a 545-bp fragment with the genomic DNA of new haplotype of P. syringae pv. actinidiae strains. A multiplex PCR conducted with the TacF/TacR primer pair and the universal primer pair for all P. syringae pv. actinidiae strains can be simultaneously applied for the detection of P. syringae pv. actinidiae and for the differentiation of new haplotype strains. PMID- 25288992 TI - Antifungal Activity of Paenibacillus kribbensis Strain T-9 Isolated from Soils against Several Plant Pathogenic Fungi. AB - The bacterial strain T-9, which shows strong antifungal activity, is isolated from the soils of Samcheok, Gangwondo and identified as Paenibacillus kribbensis according to morphological and taxonomic characteristics and 16S rRNA gene sequence analysis. The P. kribbensis strain T-9 strongly inhibits the growth of various phytopathogenic fungi including Botrytis cinerea, Colletotricum acutatum, Fusarium oxysporum f. sp. radicis-lycopersici, Magnaporthe oryzae, Phytophthora capsici, Rhizoctonia solani, and Sclerotium cepivorum in vitro. Also, the P. kribbensis strain T-9 exhibited similar or better control effects to plant diseases than in fungicide treatment through in vivo assays. In the 2-year greenhouse experiments, P. kribbensis strain T-9 was highly effective against clubroot. In the 2-year field trials, the P. kribbensis strain T-9 was less effective than the fungicide, but reduced clubroot on Chinese cabbage when compared to the control. The above-described results indicate that the strain T-9 may have the potential as an antagonist to control various phytopathogenic fungi. PMID- 25288993 TI - The interaction of human enteric pathogens with plants. AB - There are an increasing number of outbreaks of human pathogens related to fresh produce. Thus, the growth of human pathogens on plants should be explored. Human pathogens can survive under the harsh environments in plants, and can adhere and actively invade plants. Plant-associated microbiota or insects contribute to the survival and transmission of enteric pathogens in plants. Human enteric pathogens also trigger plant innate immunity, but some pathogens-such as Salmonella-can overcome this defense mechanism. PMID- 25288994 TI - Genetic Diversity of Pectobacterium carotovorum subsp. brasiliensis Isolated in Korea. AB - The plant pathogenic bacterial genus Pectobacteirum consists of heterogeneous strains. The P. carotovorum species is a complex strain showing divergent characteristics, and a new subspecies named P. carotovorum subsp. brasiliensis has been identified recently. In this paper, we re-identified the P. carotovorum subsp. brasiliensis isolates from those classified under the subspecies carotovorum and newly isolated P. carotovorum subsp. brasiliensis strains. All isolates were able to produce plant cell-wall degrading enzymes such as pectate lyase, polygalacturonase, cellulase and protease. We used genetic and biochemical methods to examine the diversity of P. carotovorum subsp. brasiliensis isolates, and found genetic diversity within the brasiliensis subsp. isolates in Korea. The restriction fragment length polymorphism analysis based on the recA gene revealed a unique pattern for the brasiliensis subspecies. The Korean brasiliensis subsp. isolates were divided into four clades based on pulsed-field gel electrophoresis. However, correlations between clades and isolated hosts or year could not be found, suggesting that diverse brasiliensis subsp. isolates existed. PMID- 25288995 TI - Development of a Model to Predict the Primary Infection Date of Bacterial Spot (Xanthomonas campestris pv. vesicatoria) on Hot Pepper. AB - A population model of bacterial spot caused by Xanthomonas campestris pv. vesicatoria on hot pepper was developed to predict the primary disease infection date. The model estimated the pathogen population on the surface and within the leaf of the host based on the wetness period and temperature. For successful infection, at least 5,000 cells/ml of the bacterial population were required. Also, wind and rain were necessary according to regression analyses of the monitored data. Bacterial spot on the model is initiated when the pathogen population exceeds 10(15) cells/g within the leaf. The developed model was validated using 94 assessed samples from 2000 to 2007 obtained from monitored fields. Based on the validation study, the predicted initial infection dates varied based on the year rather than the location. Differences in initial infection dates between the model predictions and the monitored data in the field were minimal. For example, predicted infection dates for 7 locations were within the same month as the actual infection dates, 11 locations were within 1 month of the actual infection, and only 3 locations were more than 2 months apart from the actual infection. The predicted infection dates were mapped from 2009 to 2012; 2011 was the most severe year. Although the model was not sensitive enough to predict disease severity of less than 0.1% in the field, our model predicted bacterial spot severity of 1% or more. Therefore, this model can be applied in the field to determine when bacterial spot control is required. PMID- 25288996 TI - Roles of Forkhead-box Transcription Factors in Controlling Development, Pathogenicity, and Stress Response in Magnaporthe oryzae. AB - Although multiple transcription factors (TFs) have been characterized via mutagenesis to understand their roles in controlling pathogenicity and infection related development in Magnaporthe oryzae, the causal agent of rice blast, if and how forkhead-box (FOX) TFs contribute to these processes remain to be characterized. Four putative FOX TF genes were identified in the genome of M. oryzae, and phylogenetic analysis suggested that two of them (MoFKH1 and MoHCM1) correspond to Ascomycota-specific members of the FOX TF family while the others (MoFOX1 and MoFOX2) are Pezizomycotina-specific members. Deletion of MoFKH1 (DeltaMofkh1) resulted in reduced mycelial growth and conidial germination, abnormal septation and stress response, and reduced virulence. Similarly, DeltaMohcm1 exhibited reduced mycelial growth and conidial germination. Conidia of DeltaMofkh1 and DeltaMohcm1 were more sensitive to one or both of the cell cycle inhibitors hydroxyurea and benomyl, suggesting their role in cell cycle control. On the other hand, loss of MoFOX1 (DeltaMofox1) did not show any noticeable changes in development, pathogenicity, and stress response. Deletion of MoFOX2 was not successful even after repeated attempts. Taken together, these results suggested that MoFKH1 and Mo-HCM1 are important in fungal development and that MoFKH1 is further implicated in pathogenicity and stress response in M. oryzae. PMID- 25288997 TI - Molecular Characterization of a Novel Putative Partitivirus Infecting Cytospora sacchari, a Plant Pathogenic Fungus. AB - Three double-stranded RNAs (dsRNAs), approximately 1.85, 1.65 and 1.27 kb in size, were detected in an isolate of Cytospora sacchari from Iran. Partial nucleotide sequence revealed a 1,284 bp segment containing one ORF that potentially encodes a 405 aa protein. This protein contains conserved motifs related to RNA dependent RNA polymerases (RdRp) that showed similarity to RdRps of partitiviruses. The results indicate that these dsRNAs represent a novel Partitivirus that we tentatively designate Cytospora sacchari partitivirus (CsPV). Treatment of the fungal strain by cyclohexamide and also hyphal tip culture had no effect on removing the putative virus. Phylogenetic analysis of putative RdRp of CsPV and other partitiviruses places CsPV as a member of the genus Partitivirus in the family Partitiviridae, and clustering with Aspergillus ochraceous virus 1. PMID- 25288998 TI - Molecular and Biological Characterization of an Isolate of Cucumber mosaic virus from Glycine soja by Generating its Infectious Full-genome cDNA Clones. AB - Molecular and biological characteristics of an isolate of Cucumber mosaic virus (CMV) from Glycine soja (wild soybean), named as CMV-209, was examined in this study. Comparison of nucleotide sequences and phylogenetic analyses of CMV-209 with the other CMV strains revealed that CMV-209 belonged to CMV subgroup I. However, CMV-209 showed some genetic distance from the CMV strains assigned to subgroup IA or subgroup IB. Infectious full-genome cDNA clones of CMV-209 were generated under the control of the Cauliflower mosaic virus 35S promoter. Infectivity of the CMV-209 clones was evaluated in Nicotiana benthamiana and various legume species. Our assays revealed that CMV-209 could systemically infect Glycine soja (wild soybean) and Pisum sativum (pea) as well as N. benthamiana, but not the other legume species. PMID- 25288999 TI - Involvement of the OsMKK4-OsMPK1 Cascade and its Downstream Transcription Factor OsWRKY53 in the Wounding Response in Rice. AB - Plant has possessed diverse stress signals from outside and maintained its fitness. Out of such plant responses, it is well known that mitogen-activated protein kinase (MAPK) cascade plays important role in wounding and pathogen attack in most dicot plants. However, little is understood about its role in wounding response for the economically important monocot rice plant. In this study, therefore, the involvement of MAPK was investigated to understand the wounding signaling pathway in rice. The OsMPK1 was rapidly activated by wounding within 10 min, and OsMPK1 was also activated by challenge of rice blast fungus. Further analysis revealed that OsMKK4, the upstream kinase of OsMPK1, phosphorylated OsMPK1 by wounding in vivo. Furthermore, OsMPK1 directly interacted with a rice defense-related transcription factor OsWRKY53. To understand a functional link between MAPK and its target transcription factor, we showed that OsMPK1 activated by the constitutively active mutant OsMKK4(DD) phosphorylated OsWRKY53 in vitro. Taken together, components involving in the wounding signaling pathway, OsMKK4-OsMPK1-OsWRKY53, can be important players in regulating crosstalk between abiotic stress and biotic stress. PMID- 25289000 TI - Development and Practical Use of RT-PCR for Seed-transmitted Prune dwarf virus in Quarantine. AB - Among imported plants, seeds are the items that have many latent pathogens and are difficult to inspect. Also, they are the import and export items whose market is expected to expand. The biggest problem with seeds is viruses. Prune dwarf virus (PDV) is the virus that is commonly inspected in Prunus cerasifera, P. persica, P. armeniaca, P. mandshurica, P. cerasus, P. avium or P. serotina seeds. In this study, two RT-PCR primer sets, which can promptly and specifically diagnose plant quarantine seed-transmitted PDV, were developed; and nested PCR primers, where products amplify 739 and 673 nucleotides (nt), and an nested PCR product, 305 nt, can be obtained as these products are amplified again, were developed. Also, a modified-positive control plasmid was developed, where the restriction enzyme XhoI, which can identify the contamination of samples from the control, was inserted. The method developed in this study has detected PDV in 18 cases since 2007, and is expected to continuously contribute to the plant quarantine in Korea. PMID- 25289001 TI - Characteristics of a Lettuce mosaic virus Isolate Infecting Lettuce in Korea. AB - Lettuce mosaic virus (LMV) causes disease of plants in the family Asteraceae, especially lettuce crops. LMV isolates have previously been clustered in three main groups, LMV-Yar, LMV-Greek and LMVRoW. The first two groups, LMV-Yar and LMV Greek, have similar characteristics such as no seed-borne transmission and non resistance-breaking. The latter one, LMV-RoW, comprising a large percentage of the LMV isolates contains two large subgroups, LMV-Common and LMV-Most. To date, however, no Korean LMV isolate has been classified and characterized. In this study, LMV-Muju, the Korean LMV isolate, was isolated from lettuce showing pale green and mottle symptoms, and its complete genome sequence was determined. Classification method of LMV isolates based on nucleotide sequence divergence of the NIb-CP junction showed that LMV-Muju was categorized as LMV-Common. LMV-Muju was more similar to LMV-O (LMV-Common subgroup) than to LMV-E (LMV-RoW group but not LMV-Common subgroup) even in the amino acid domains of HC-Pro associated with pathogenicity, and in the CI and VPg regions related to ability to overcome resistance. Taken together, LMV-Muju belongs to the LMV-Common subgroup, and is expected to be a seed-borne, non-resistance-breaking isolate. According to our analysis, all other LMV isolates not previously assigned to a subgroup were also included in the LMV-RoW group. PMID- 25289002 TI - Inheritance of pigeonpea sterility mosaic disease resistance in pigeonpea. AB - A comprehensive study was conducted using PPSMV resistant (BSMR 736) and susceptible (ICP 8863) genotypes to develop a segregating population and understand the inheritance of PPSMV resistance. The observed segregation was comparable to 13 (susceptible): 3 (resistant). Hence, the inheritance was controlled by two genes, SV1 and SV2, with inhibitory gene interaction. PMID- 25289003 TI - Genetic Diversity of a Natural Population of Apple stem pitting virus Isolated from Apple in Korea. AB - Apple stem pitting virus (ASPV), of the Foveavirus genus in the family Betaflexiviridae, is one of the most common viruses of apple and pear trees. To examine variability of the coat protein (CP) gene from ASPV, eight isolates originating from 251 apple trees, which were collected from 22 apple orchards located in intensive apple growing areas of the North Gyeongsang and North Jeolla Provinces in Korea, were sequenced and compared. The nucleotide sequence identity of the CP gene of eight ASPV isolates ranged from 77.0 to 97.0%, while the amino acid sequence identity ranged from 87.7 to 98.5%. The N-terminal region of the viral CP gene was highly variable, whereas the C-terminal region was conserved. Genetic algorithm recombination detection (GARD) and single breakpoint recombination (SBP) analyses identified base substitutions between eight ASPV isolates at positions 54 and 57 and position 771, respectively. GABranch analysis was used to determine whether the eight isolates evolved due to positive selection. All values in the GABranch analysis showed a ratio of substitution rates at non-synonymous and synonymous sites (dNS/dS) below 1, suggestive of strong negative selection forces during ASPV CP history. Although negative selection dominated CP evolution in the eight ASPV isolates, SLAC and FEL tests identified four possible positive selection sites at codons 10, 22, 102, and 158. This is the first study of the ASPV genome in Korea. PMID- 25289004 TI - First Report of Cucumber mosaic virus Isolated from Wild Vigna angularis var. nipponensis in Korea. AB - A viral disease causing severe mosaic, necrotic, and yellow symptoms on Vigna angularis var. nipponensis was prevalent around Suwon area in Korea. The causal virus was characterized as Cucumber mosaic virus (CMV) on the basis of biological and nucleotide sequence properties of RNAs 1, 2 and 3 and named as CMV-wVa. CMV wVa isolate caused mosaic symptoms on indicator plants, Nicotiana tabacum cv. Xanthi-nc, Petunia hybrida, and Cucumis sativus. Strikingly, CMV-wVa induced severe mosaic and malformation on Cucurbita pepo, and Solanum lycopersicum. Moreover, it caused necrotic or mosaic symptoms on V. angularis and V. radiate of Fabaceae. Symptoms of necrotic local or pin point were observed on inoculated leaves of V. unguiculata, Vicia fava, Pisum sativum and Phaseolus vulgaris. However, CMV-wVa isolate failed to infect in Glycine max cvs. 'Sorok', 'Sodam' and 'Somyeong'. To assess genetic variation between CMV-wVa and the other known CMV isolates, phylogenetic analysis using 16 complete nucleotide sequences of CMV RNA1, RNA2, and RNA3 including CMV-wVa was performed. CMV-wVa was more closely related to CMV isolates belonging to CMV subgroup I showing about 85.1-100% nucleotide sequences identity to those of subgroup I isolates. This is the first report of CMV as the causal virus infecting wild Vigna angularis var. nipponensis in Korea. PMID- 25289005 TI - An Acidic PATHOGENESIS-RELATED1 Gene of Oryza grandiglumis is Involved in Disease Resistance Response Against Bacterial Infection. AB - Wild rice, Oryza grandiglumis shows hyper-resistance response to pathogen infection. In order to identify genes necessary for defense response in plants, we have carried out a subtractive hybridization coupled with a cDNA macroarray. An acidic PATHOGENESIS-RELATED1 (PR1) gene of the wild rice is highly identical to the acidic PR1 genes of different plant species. The OgPR1a cDNA has an apparent single open reading frame with a predicted molecular mass 40,621 Da and an isoelectic point of 5.14. Both in silico analysis and a transient expression assay in onion epidermal cells revealed that the OgPR1a protein could be localized in intercellular space in plants. The OgPR1a mRNA was strongly transcribed by the exogenous treatment with ethylene and jasmonic acid as well as protein phosphatase inhibitors. Additionally, ectopic expression of the OgPR1a conferred disease resistance on Arabidopsis to the bacterial and fungal infections. PMID- 25289006 TI - The Sensor Kinase GacS Negatively Regulates Flagellar Formation and Motility in a Biocontrol Bacterium, Pseudomonas chlororaphis O6. AB - The GacS/GacA two component system regulates various traits related to the biocontrol potential of plant-associated pseudomonads. The role of the sensor kinase, GacS, differs between strains in regulation of motility. In this study, we determined how a gacS mutation changed cell morphology and motility in Pseudomonas chlororaphis O6. The gacS mutant cells were elongated in stationary phase compared to the wild type and the complemented gacS mutant, but cells did not differ in length in logarithmic phase. The gacS mutant had a two-fold increase in the number of flagella compared with the wild type strain; flagella number was restored to that of the wild type in the complemented gacS mutant. The more highly flagellated gacS mutant cells had greater swimming motilities than that of the wild type strain. Enhanced flagella formation in the gacS mutant correlated with increased expression of three genes, fleQ, fliQ and flhF, involved in flagellar formation. Expression of these genes in the complemented gacS mutant was similar to that of the wild type. These findings show that this root-colonizing pseudomonad adjusts flagella formation and cell morphology in stationary-phase using GacS as a major regulator. PMID- 25289007 TI - Proteomic Analysis of a Global Regulator GacS Sensor Kinase in the Rhizobacterium, Pseudomonas chlororaphis O6. AB - The GacS/GacA system in the root colonizer Pseudomonas chlororaphis O6 is a key regulator of many traits relevant to the biocontrol function of this bacterium. Proteomic analysis revealed 12 proteins were down-regulated in a gacS mutant of P. chlororaphis O6. These GacS-regulated proteins functioned in combating oxidative stress, cell signaling, biosynthesis of secondary metabolism, and secretion. The extent of regulation was shown by real-time RT-PCR to vary between the genes. Mutants of P. chlororaphis O6 were generated in two GacS-regulated genes, trpE, encoding a protein involved in tryptophan synthesis, and prnA, required for conversion of tryptophan to the antimicrobial compound, pyrrolitrin. Failure of the trpE mutant to induce systemic resistance in tobacco against a foliar pathogen causing soft rot, Pectobacterium carotovorum SCCI, correlated with reduced colonization of root surfaces implying an inadequate supply of tryptophan to support growth. Although colonization was not affected by mutation in the prnA gene, induction of systemic resistance was reduced, suggesting that pyrrolnitrin was an activator of plant resistance as well as an antifungal agent. Study of mutants in the other GacS-regulated proteins will indicate further the features required for biocontrol-activity in this rhizobacterium. PMID- 25289008 TI - Pear Skin Stain Caused by Mycosphaerella graminicola on Niitaka Pear (Pyrus pyrifolia Nakai). AB - Pear skin stains on 'Niitaka' pears, which occur from the growing stage to the cold storage stage, reportedly negatively influence the marketing of pears. These stains on fruit skin are likely due to a pathogenic fungus that resides on the skin and is characterized by dark stains; however, the mycelium of this fungus does not penetrate into the sarcocarp and is only present on the cuticle layer of fruit skin. A pathogenic fungus was isolated from the skin lesions of infected fruits, and its pathogenicity was subsequently tested. According to the pathogenicity test, Mycosphaerella sp. was strongly pathogenic, while Penicillium spp. and Alternaria spp. showed modest pathogenicity. In this present study, we isolated the pathogenic fungus responsible for the symptoms of pears (i.e., dark brown-colored specks) and identified it as Mycosphaerella graminicola based on its morphological characteristics and the nucleotide sequence of the beta-tubulin gene. M. graminicola was pathogenic to the skin of 'Niitaka' pears, which are one of the most widely growing varieties of pears in South Korea. PMID- 25289009 TI - A Putative Transcription Factor pcs1 Positively Regulates Both Conidiation and Sexual Reproduction in the Cereal Pathogen Fusarium graminearum. AB - The plant pathogen Fusarium graminearum causes Fusarium head blight in cereal crops and produces mycotoxins that are harmful to animals and humans. For the initiation and spread of disease, asexual and sexual reproduction is required. Therefore, studies on fungal reproduction contribute to the development of new methods to control and maintain the fungal population. Screening a previously generated transcription factor mutant collection, we identified one putative C2H2 zinc-finger transcription factor, pcs1, which is required for both sexual and asexual reproduction. Deleting pcs1 in F. graminearum resulted in a dramatic reduction in conidial production and a complete loss of sexual reproduction. The pathways and gene ontology of pcs1-dependent genes from microarray experiments showed that several G-protein related pathways, oxidase activity, ribosome biogenesis, and RNA binding and processing were highly enriched, suggesting that pcs1 is involved in several different biological processes. Further, overexpression of pcs1 increased conidial production and resulted in earlier maturation of ascospores compared to the wild-type strain. Additionally, the vegetative growth of the overexpression mutants was decreased in nutrient-rich conditions but was not different from the wild-type strain in nutrient-poor conditions. Overall, we discovered that the pcs1 transcription factor positively regulates both conidiation and sexual reproduction and confers nutrient condition dependent vegetative growth. PMID- 25289010 TI - Antimicrobial Effects of a Hexapetide KCM21 against Pseudomonas syringae pv. tomato DC3000 and Clavibacter michiganensis subsp. michiganensis. AB - Antimicrobial peptides (AMPs) are small but effective cationic peptides with variable length. In previous study, four hexapeptides were identified that showed antimicrobial activities against various phytopathogenic bacteria. KCM21, the most effective antimicrobial peptide, was selected for further analysis to understand its modes of action by monitoring inhibitory effects of various cations, time-dependent antimicrobial kinetics, and observing cell disruption by electron microscopy. The effects of KCM21 on Gram-negative strain, Pseudomonas syringae pv. tomato DC3000 and Gram-positive strain, Clavibacter michiganensis subsp. michiganensis were compared. Treatment with divalent cations such as Ca(2+) and Mg(2+) inhibited the bactericidal activities of KCM21 significantly against P. syringae pv. tomato DC3000. The bactericidal kinetic study showed that KCM21 killed both bacteria rapidly and the process was faster against C. michiganensis subsp. michiganensis. The electron microscopic analysis revealed that KCM21 induced the formation of micelles and blebs on the surface of P. syringae pv. tomato DC3000 cells, while it caused cell rupture against C. michiganensis subsp. michiganensis cells. The outer membrane alteration and higher sensitivity to Ca(2+) suggest that KCM21 interact with the outer membrane of P. syringae pv. tomato DC3000 cells during the process of killing, but not with C. michiganensis subsp. michiganensis cells that lack outer membrane. Considering that both strains had similar sensitivity to KCM21 in LB medium, outer membrane could not be the main target of KCM21, instead common compartments such as cytoplasmic membrane or internal macromolecules might be a possible target(s) of KCM21. PMID- 25289011 TI - Rpi-blb2-Mediated Hypersensitive Cell Death Caused by Phytophthora infestans AVRblb2 Requires SGT1, but not EDS1, NDR1, Salicylic Acid-, Jasmonic Acid-, or Ethylene-Mediated Signaling. AB - Potato Rpi-blb2 encodes a protein with a coiled-coil-nucleotide binding site and leucine-rich repeat (CC-NBS-LRR) motif that recognizes the Phytophthora infestans AVRblb2 effector and triggers hypersensitive cell death (HCD). To better understand the components required for Rpi-blb2-mediated HCD in plants, we used virus-induced gene silencing to repress candidate genes in Rpi-blb2-transgenic Nicotiana benthamiana plants and assayed the plants for AVRblb2 effector. Rpi blb2 triggers HCD through NbSGT1-mediated pathways, but not NbEDS1- or NbNDR1 mediated pathways. In addition, the role of salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) in Rpi-blb2-mediated HCD were analyzed by monitoring of the responses of NbICS1-, NbCOI1-, or NbEIN2-silenced or Rpi-blb2::NahG transgenic plants. Rpi-blb2-mediated HCD in response to AVRblb2 was not associated with SA accumulation. Thus, SA affects Rpi-blb2-mediated resistance against P. infestans, but not Rpi-blb2-mediated HCD in response to AVRblb2. Additionally, JA and ET signaling were not required for Rpi-blb2-mediated HCD in N. benthamiana. Taken together, these findings suggest that NbSGT1 is a unique positive regulator of Rpi-blb2-mediated HCD in response to AVRblb2, but EDS1, NDR1, SA, JA, and ET are not required. PMID- 25289012 TI - Evaluation of mungbean genotypes based on yield stability and reaction to mungbean yellow mosaic virus disease. AB - This work was conducted to identify mungbean genotypes showing yield stability and resistance to mungbean yellow mosaic virus (MYMV) disease. Sixteen genotypes were evaluated in a randomized complete block design with two replications for two years (2011 and 2012) at three locations (Gazipur, Ishurdi and Madaripur) of the Bangladesh Agricultural Research Institute. An analysis of variance exhibited significant effects of genotype (G), environment (E), and genotype * environment (G*E) on grain yield. Among eight agronomic characters, the principal component 1 (PC1) was always higher than the PC2. Considering G*E interaction, BM6 was the best genotype at all three locations in both years. Based on grain yield and stability performance, BM6 ranked first while the worst performing genotypes were BM1 and G10. Based on discrimination and representation, Gazipur was identified as an ideal environment for these mungbeans. Relationship between soil-plant analysis developments (SPAD) value was positive with yield but negative with MYMV severity. BM6, G1 and G2 were considered as promising sources of resistance for low disease score and stable response across the environments. The environment proved to have an influence on MYMV infection under natural infestation. A positive correlation was observed between disease score and the temperature under natural growing condition. PMID- 25289014 TI - Selection and a 3-Year Field Trial of Sorangium cellulosum KYC 3262 Against Anthracnose in Hot Pepper. AB - KYC 3262 was selected as a biocontrol agent against anthracnose on hot pepper from 813 extracts of myxobacterial isolates. Dual culture with Colletotrichum acutatum and 813 myxobacterial extracts was conducted, and 19 extracts were selected that inhibited germination and mycelial growth of C. acutatum. All selections were Sorangium cellulosum, which are cellulolytic myxobacteria from soil. With the infection bioassay on detached fruits in airtight containers, KYC 3262, KYC 3512, KYC 3279, and KYC 3584 were selected. The listed four myxobacteria were cultured in CSG/1 liquid media, and harvested filtrates were sprayed on the infected fruits. KYC 3262 was selected from the studies of attached fruit in a greenhouse study. KYC 3262 filtrate was applied for 3 years (from 2011 to 2013) in a field study in Asan, Republic of Korea. Control values of the KYC 3262 in the field were 31%, 89%, and 82% in 2011, 2012, and 2013, whereas values of the fungicide spray treatment were 19%, 97%, and 91%, respectively. Yields (kg/20 plants) of the KYC 3262 were 2.66 kg and 18.6 kg in 2011 and 2013, respectively, and those of the fungicide treatment were 2.0 kg and 20.2 kg, in 2011 and 2013, respectively. PMID- 25289013 TI - Arabidopsis thaliana Remorins Interact with SnRK1 and Play a Role in Susceptibility to Beet Curly Top Virus and Beet Severe Curly Top Virus. AB - Remorins, a family of plant-specific proteins containing a variable N-terminal region and conserved C-terminal domain, play a role in various biotic and abiotic stresses, including host-microbe interactions. However, their functions remain to be completely elucidated, especially for the Arabidopsis thaliana remorin group 4 (AtREM4). To elucidate the role of remorins in Arabidopsis, we first showed that AtREM4s have typical molecular characteristics of the remorins, such as induction by various types of biotic and abiotic stresses, localization in plasma membrane and homo- and hetero-oligomeric interaction. Next, we showed that their loss-of function mutants displayed reduced susceptibility to geminiviruses, Beet Curly Top Virus and Beet Severe Curly Top Virus, while overexpressors enhanced susceptibility. Moreover, we found that they interacted with SnRK1, which phosphorylated AtREM4.1, and were degraded by the 26S proteasome pathway. These results suggest that AtREM4s may be involved in the SnRK1-mediated signaling pathway and play a role as positive regulators of the cell cycle during geminivirus infection. PMID- 25289015 TI - Biological Control of Meloidogyne hapla Using an Antagonistic Bacterium. AB - We examined the efficacy of a bacterium for biocontrol of the root-knot nematode (RKN) Meloidogyne hapla in carrot (Daucus carota subsp. sativus) and tomato (Solanum lycopersicum). Among 542 bacterial isolates from various soils and plants, the highest nematode mortality was observed for treatments with isolate C1-7, which was identified as Bacillus cereus based on cultural and morphological characteristics, the Biolog program, and 16S rRNA sequencing analyses. The population density and the nematicidal activity of B. cereus C1-7 remained high until the end of culture in brain heart infusion broth, suggesting that it may have sustainable biocontrol potential. In pot experiments, the biocontrol efficacy of B. cereus C1-7 was high, showing complete inhibition of root gall or egg mass formation by RKN in carrot and tomato plants, and subsequently reducing RKN damage and suppressing nematode population growth, respectively. Light microscopy of RKN-infected carrot root tissues treated with C1-7 showed reduced formation of gall cells and fully developed giant cells, while extensive gall cells and fully mature giant cells with prominent cell wall ingrowths formed in the untreated control plants infected with RKNs. These histopathological characteristics may be the result of residual or systemic biocontrol activity of the bacterium, which may coincide with the biocontrol efficacies of nematodes in pots. These results suggest that B. cereus C1-7 can be used as a biocontrol agent for M. hapla. PMID- 25289016 TI - First Report of Bacterial Wilt Caused by Ralstonia solanacearum Biovar 2 Race 1 on Tomato in Egypt. AB - This study aims to isolate and identify the causal pathogen of tomato bacterial wilt in Egypt. In 2008, tomato plants showing typical symptoms of bacterial wilt disease with no foliar yellowing were observed in Minia, Assiut and Sohag governorates, Egypt. When cut stems of symptomatic plants were submerged in water, whitish ooze was evident and longitudinal sections showed a brown discoloration in the vascular tissues. Bacteria were isolated on triphenyl tetrazolium chloride medium and fifteen isolates shown typical morphological and cultural characteristics were confirmed as Ralstonia solanacearum biovar 2 race 1. Pathogenicity tests showed that all isolates proved to be pathogenic to tomato plants, varied from 52 to 97% wilting. This is the first report of R. solanacearum biovar 2 race 1 causing bacterial wilt in tomato crop in Egypt. PMID- 25289017 TI - Expression of colSR Genes Increased in the rpf Mutants of Xanthomonas oryzae pv. oryzae KACC10859. AB - The rpf genes and colS XOO1207/colR XOO1208 were known to require for virulence of Xanthomonas oryzae pv. oryzae (Xoo). In Xoo KACC10331 genome, two more colS/colR genes, colS XOO3534 (raxH)/colR XOO3535 (raxR) and colS XOO3762/colR XOO3763 were annotated. The colS XOO3534/colR XOO3535 were known to control AvrXa21 activity and functions of colS XOO3762/colR XOO3763 were unknown in Xoo. To characterize the relationship between rpf and colS/colR genes, expression of colS/colR genes in Rpf mutants of Xoo were analyzed with quantitative reverse transcription PCR (qRT-PCR). Expressions of all three colS/colR genes increased in the rpfF mutant in which DSF synthesis is defective. Expression of colS XOO1207/colR XOO1208, colS XOO3534/colR XOO3535 and colS XOO3762/colR XOO3763 increased 2, 2-7, 3-13 folds respectively. Expression of colS XOO3534 and colS XOO3762 also increased 2-4 folds in the rpfG mutant in which the signal from DSF is no longer transferred to down-stream. Expression of the other colS/colR genes was not significantly changed in the rpfG mutant compared to the wild type. Since RpfF and RpfG are responsible for DSF synthesis and signal transfer from DSF to down-stream to regulate virulence gene expression, these results suggest that the DSF and DSF-mediated signal regulate negatively three colS/colR genes in Xoo. PMID- 25289018 TI - A Rapid and Efficient Method for Construction of an Infectious Clone of Tomato yellow leaf curl virus. AB - Tomato yellow leaf curl virus (TYLCV), a member of the genus Begomovirus, is responsible for one of the most devastating viral diseases in tomato-growing countries and is becoming a serious problem in many subtropical and tropical countries. The climate in Korea is getting warmer and developing subtropical features in response to global warming. These changes are being accompanied by TYLCV, which is now becoming a large problem in the Korean tomato industry. The most effective way to reduce damage caused by TYLCV is to breed resistant varieties of tomatoes. To accomplish this, it is necessary to establish a simple inoculation technique for the efficient evaluation of resistance to TYLCV. Here, we present the rolling circle amplification (RCA) method, which employs a bacteriophage using phi-29 DNA polymerase for construction of infectious TYLCV clones. The RCA method is simple, does not require sequence information for cloning, and is less expensive and time consuming than conventional PCR based methods. Furthermore, RCA-based construction of an infectious clone can be very useful to other emerging and unknown geminiviruses in Korea. PMID- 25289019 TI - Pseudorecombination between Two Distinct Strains of Cucumber mosaic virus Results in Enhancement of Symptom Severity. AB - Recently, a Cucumber mosaic virus (CMV) strain, named as CMV-209, was isolated from Glycine soja. In this study, symptom expression of CMV-209 was analyzed in detail in Nicotiana benthamiana by comparing with that of CMV-Fny, which is a representative strain of CMV. Using infectious cDNA clones of CMV strains 209 and Fny, symptom expression of various pseudorecombinants between these two strains were examined in the early and late infection stages. In the early infection stage, the pseudorecombinants containing Fny-RNA2 induced stunting and leaf distortion on the newly emerged leaves whereas the pseudorecombinants containing 209-RNA2 caused no obvious symptoms. In the late infection stage, the pseudorecombinants containing 209-RNA1 and Fny-RNA2 induced severe leaf distortion and stunting, while CMV-209 induced mild symptom and CMV-Fny caused typical mosaic, general stunting, and leaf distortion symptoms, indicating that RNA 2 encodes a symptom determinant(s) of CMV, which is capable of enhancing symptoms. Furthermore, our results support the possibility that natural recombination between compatible viruses can result in emergence of novel viruses causing severe damages in crop fields. PMID- 25289020 TI - Altered cultivar resistance of kimchi cabbage seedlings mediated by salicylic Acid, jasmonic Acid and ethylene. AB - Two cultivars Buram-3-ho (susceptible) and CR-Hagwang (moderate resistant) of kimchi cabbage seedlings showed differential defense responses to anthracnose (Colletotrichum higginsianum), black spot (Alternaria brassicicola) and black rot (Xanthomonas campestris pv. campestris, Xcc) diseases in our previous study. Defense-related hormones salicylic acid (SA), jasmonic acid (JA) and ethylene led to different transcriptional regulation of pathogenesis-related (PR) gene expression in both cultivars. In this study, exogenous application of SA suppressed basal defenses to C. higginsianum in the 1st leaves of the susceptible cultivar and cultivar resistance of the 2nd leaves of the resistant cultivar. SA also enhanced susceptibility of the susceptible cultivar to A. brassicicola. By contrast, SA elevated disease resistance to Xcc in the resistant cultivar, but not in the susceptible cultivar. Methyl jasmonate (MJ) treatment did not affect the disease resistance to C. higginsianum and Xcc in either cultivar, but it compromised the disease resistance to A. brassicicola in the resistant cultivar. Treatment with 1-aminocyclopropane-1-carboxylic acid (ACC) ethylene precursor did not change resistance of the either cultivar to C. higginsianum and Xcc. Effect of ACC pretreatment on the resistance to A. brassicicola was not distinguished between susceptible and resistant cultivars, because cultivar resistance of the resistant cultivar was lost by prolonged moist dark conditions. Taken together, exogenously applied SA, JA and ethylene altered defense signaling crosstalk to three diseases of anthracnose, black spot and black rot in a cultivar-dependent manner. PMID- 25289021 TI - Engineered yeast for enhanced CO2 mineralization. AB - In this work, a biologically catalyzed CO2 mineralization process for the capture of CO2 from point sources was designed, constructed at a laboratory scale, and, using standard chemical process scale-up protocols, was modeled and evaluated at an industrial scale. A yeast display system in Saccharomyces cerevisae was used to screen several carbonic anhydrase isoforms and mineralization peptides for their impact on CO2 hydration, CaCO3 mineralization, and particle settling rate. Enhanced rates for each of these steps in the CaCO3 mineralization process were confirmed using quantitative techniques in lab-scale measurements. The effect of these enhanced rates on the CO2 capture cost in an industrial scale CO2 mineralization process using coal fly ash as the CaO source was evaluated. The model predicts a process using bCA2- yeast and fly ash is ~10% more cost effective per ton of CO2 captured than a process with no biological molecules, a savings not realized by wild-type yeast and high-temperature stable recombinant CA2 alone or in combination. The levelized cost of electricity for a power plant using this process was calculated and scenarios in which this process compares favorably to CO2 capture by MEA absorption process are presented. PMID- 25289022 TI - Conditional and inducible transgene expression in endothelial and hematopoietic cells using Cre/loxP and tetracycline-off systems. AB - In the present study, the tetracycline-off and Cre/loxP systems were combined to gain temporal and spatial control of transgene expression. Mice were generated that carried three transgenes: Tie2-tTA, tet-O-Cre and either the ZEG or ZAP reporter. Tie2-tTA directs expression of tetracycline-controlled transactivator (tTA) in endothelial and hematopoietic cells under the control of the Tie2 promoter. Tet-O-Cre produces Cre recombinase from a minimal promoter containing the tet-operator (tetO). ZEG or ZAP contains a strong promoter and a loxP-flanked stop sequence, followed by an enhanced green fluorescence protein (EGFP) or human placental alkaline phosphatase (hPLAP) reporter. In the presence of tetracycline, the tTA transactivator produced by Tie-2-tTA is disabled and Cre is not expressed. In the absence of tetracycline, the tTA binds tet-O-Cre to drive the expression of Cre, which recombines the loxP sites of the ZEG or ZAP transgene and results in reporter gene expression. In the present study, the expression of the ZEG or ZAP reporter genes in embryos and adult animals with and without tetracycline treatment was examined. In the presence of tetracycline, no reporter gene expression was observed. When tetracycline was withdrawn, Cre excision was activated and the reporter genes were detected in endothelial and hematopoietic cells. These results demonstrate that this system may be used to bypass embryonic lethality and access adult phenotypes. PMID- 25289023 TI - Expression of matrix metalloproteinases-8 and -9 and their tissue inhibitor in the condyles of diabetic rats with mandibular advancement. AB - The present study aimed to evaluate the effects of type 1 diabetes mellitus on the condylar response during treatment with a functional appliance. Sprague Dawley rats were divided into 3 groups, normal (NG), diabetes (DG) and diabetes with insulin-treatment (TG). Bite-jumping appliances were fitted to the rats in the experimental groups. At 7, 14, 21 and 28 days following fitting, animals were sacrificed and condyles were excised and processed using routine histological techniques. The expression of matrix metalloproteinase (MMP)-8, MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) was detected using immunohistochemical analysis. Mandibular advancement increased the expression levels of MMP-8 (peaked on day 28), MMP-9 (peaked on day 21), TIMP-1 (peaked on days 21 and 28) and the ratio of MMP-8 to TIMP-1 and MMP-9 to TIMP-1. In the DG, diabetes decreased the expression levels of MMP-8 and MMP-9 induced by mandibular advancement and increased the expression levels of TIMP-1 compared with that of the NG. The ratio of MMP-8 to TIMP-1 and MMP-9 to TIMP-1 also showed a significant decrease in the DG compared with that of the NG. A recovery of these parameters was observed in the TG. Diabetes significantly altered the condylar response, which was triggered by mandibular advancement, and weakened subsequent bone deposition. The results from the TG were not significantly different from that of the NG. PMID- 25289024 TI - Clinical classification and treatment of cubital tunnel syndrome. AB - The aim of the present study was to investigate a new clinical classification of cubital tunnel syndrome that provides an improved basis for the clinical diagnosis and treatment of the disease. Retrospective analysis was performed on 341 patients with cubital tunnel syndrome. Based on the etiology, signs and symptoms, neurophysiological tests and computed tomography (CT) imaging, a new clinical classification was proposed. The patients enrolled in the study were treated according to the new classification. According to the new classification, cubital tunnel syndrome cases were divided into types I-IV. Treatment for patients with type I consisted of rest, immobilization or physiotherapy, while patients with type II received simple ulnar neurolysis. Type III patients underwent ulnar neurolysis with expansion of the ulnar nerve sulcus or ulnar nerve anterior transposition surgery. Type IV patients represented a subgroup of cubital tunnel syndrome cases caused by factors other than degenerative joint diseases, including cysts, tumors, traumatic fracture, deformity and elbow deformity. Patients of this type received appropriate surgical treatment according to the specific etiology. Based on previous classifications that relied on sensation and strength symptoms, a new clinical classification of elbow tunnel syndrome has been established in the present study that adopts a CT imaging evaluation index. The new classification is reasonable, simple and practical, and therapies based on this classification are more targeted than those based on previous classifications. PMID- 25289025 TI - Effect of Hyssopus officinalis L. on inhibiting airway inflammation and immune regulation in a chronic asthmatic mouse model. AB - The Uygur herb, Hyssopus officinalis L., has been demonstrated to affect the levels of a number of cytokines in asthmatic mice, including interleukin-4, -6 and -17 and interferon-gamma. In the present study, the effect of Hyssopus officinalis L. on airway immune regulation and airway inflammation was investigated in a mouse model of chronic asthma. A total of 32 BALB/c mice were randomly divided into four groups, which included the normal, chronic asthmatic, dexamethasone treatment and Hyssopus officinalis L.treatment groups. Mice were sensitized and challenged with ovalbumin to establish an asthma model and the ratio of eosinophils (EOS) in the bronchoalveolar lavage fluid (BALF) was determined. In addition, the levels of immunoglobulin (Ig)E and IgG were detected using an enzyme-linked immunosorbent assay. The degree of airway mucus secretion was observed using the periodic acid-Schiff stain method. The results demonstrated that the ratio of EOS in the BALF and the level of serum IgE in the chronic asthmatic and dexamethasone treatment groups increased, while the level of serum IgG decreased, when compared with the normal group. In addition, excessive secretion of airway mucus was observed in these two groups. However, the EOS ratio in the BALF and the levels of serum IgE and IgG in the Hyssopus officinalis L. treatment group were similar to the results observed in the normal group. In conclusion, Hyssopus officinalis L. not only plays an anti-inflammatory role by inhibiting the invasion of EOS and decreasing the levels of IgE, but also affects immune regulation. PMID- 25289026 TI - Fluorescence resonance energy transfer detection methods: Sensitized emission and acceptor bleaching. AB - The present study compared the advantages and disadvantages of fluorescence resonance energy transfer (FRET) determination technologies, namely, sensitized emission (SE) and acceptor bleaching (AB), in order to analyze the applicability of SE and AB for studies investigating particularly interesting new cysteine histidine-rich protein 1 (PINCH1)/integrin-linked kinase (ILK) interaction. HeLa cells were transfected with cyan fluorescent protein (CFP)-PINCH1 and yellow fluorescent protein (YFP)-ILK to establish a PINCH1/ILK interaction examination model. PINCH1/ILK interactions in different parts of the cells were also examined by SE and AB. The FRET determination technologies SE and AB were able to examine PINCH1/ILK interaction. SE was more sensitive for FRET determination and thus had greater reliability. Therefore, SE is highly commended for membrane protein protein interaction studies. PMID- 25289027 TI - In vivo ossification of a scaffold combining beta-tricalcium phosphate and platelet-rich plasma. AB - Tricalcium phosphate (TCP) and platelet-rich plasma (PRP) are commonly used in bone tissue engineering. The aim of the present study was to investigate a composite that combined TCP with PRP and assess its effectiveness in the treatment of bone defects. Cavity-shaped bone defects were established on the tibiae of 27 beagle dogs, and were repaired by pure beta-TCP with bone marrow stromal cells (BMSCs), beta-TCP/PRP with BMSCs and autogenic ilium. The samples were harvested at 4, 8 and 12 weeks, and bone regeneration was evaluated using X ray radiography, immunocytochemical staining of osteocalcin (OCN), hematoxylin and eosin staining and reverse transcription-polymerase chain reaction analyses. Biomechanical tests of the scaffolds were performed at the 12th week after scaffold implantation. When using pure beta-TCP as a scaffold, the scaffold-bone interface was clear and no material adsorption and bone healing was observed. Substantial bone regeneration was observed when the tibial defects were restored using beta-TCP/PRP and autogenic ilium. Furthermore, the mRNA expression levels of OCN, alkaline phosphatase and collagen type I alpha1 were significantly higher in the animals with beta-TCP/PRP scaffolds at 8 and 12 weeks following implantation compared with those in the animals with the pure beta-TCP scaffolds. The maximum load and compressive strength of the beta-TCP/PRP scaffolds were similar to those of the autogenic ilium; however, they were significantly higher than those of the pure beta-TCP scaffold. Thus, the beta-TCP/PRP composite may be used as a potential scaffold to carry in vitro cultured BMSCs to treat bone defects. PMID- 25289028 TI - Roles of the co-culture of human umbilical cord Wharton's jelly-derived mesenchymal stem cells with rat pancreatic cells in the treatment of rats with diabetes mellitus. AB - The aim of the present study was to investigate the roles of the co-culture of human umbilical cord Wharton's jelly-derived mesenchymal stem cells (hUC-MSCs) with rat pancreatic cells in the treatment of rats with diabetes mellitus. hUC MSCs were isolated and passaged, followed by Transwell co-culture with rat pancreatic cells. The induced islet-like cell clusters were transplanted into the renal capsule in rats with streptozotocin (STZ)-induced diabetes mellitus. The effects of co-culture on blood glucose levels in rats were observed. The isolated hUC-MSCs expressed the specific surface markers, including cluster of differentiation 44 (CD44) (91.4%), CD29 (91.3%) and CD105 (99.2%). Following co culture with hUC-MSCs for 7 and 10 days, the rat pancreatic cells were strongly stained by pancreatic and duodenal homeobox-1 and human insulin. The insulin and C-peptide concentrations were increased significantly compared to the pure culture group. One week following the transplantation of induced islet-like cells into the renal capsule, the blood glucose level of rats in the STZ experimental group was significantly lower than that of the STZ control group. There were notable 5-bromo-2'-deoxyuridine-positive nuclei and insulin-positive cytoplasm in the renal capsule following cell transplantation. Therefore, co-culture of hUC MSCs with rat pancreatic cells can lower the blood glucose levels in rats with diabetes mellitus. PMID- 25289029 TI - Pure sensory Guillain-Barre syndrome: A case report and review of the literature. AB - Sensory Guillain-Barre syndrome (GBS) is an acute demyelinating neuropathy that presents clinically with involvement of the sensory peripheral nerve only. To date, <10 cases of pure sensory GBS have been reported; thus, the clinical and pathological features of sensory variant GBS are yet to be well characterized. The current study reports the case of a 43-year-old female that presented with acute, symmetric and monophasic sensory neuropathy, without motor weakness. Patient history, clinical examination, routine nerve conduction studies and sural nerve biopsy were reviewed. All the observations were consistent with a diagnosis of pure sensory GBS. In particular, the pathological features of the sural nerve biopsy revealed that the form of regenerated nerve fibers have complete structure of myelinated nerve fascicles, and these myelinated nerve fibers are thicker than other parts of the biopsy. The patient received small-dose (20 mg/day) prednisone initially, but without any benefit. Satisfactory improvements were observed with one course of intravenous immunoglobulin. PMID- 25289030 TI - Lung dendritic cells undergo maturation and polarization towards a T helper type 2-stimulating phenotype in a mouse model of asthma: Role of nerve growth factor. AB - Nerve growth factor (NGF) and dendritic cells (DCs) have been hypothesized to modulate T cell responses in a mouse model of asthma. However, whether NGF plays a role in regulating the maturation and polarization of lung DCs remains unclear. In the present study, the effect of NGF inhibition on the maturation and phenotype of lung DCs was investigated in a mouse model of asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and subsequently received anti-NGF treatment. At 24 h following the last challenge, airway responsiveness and inflammation were examined. The concentrations of NGF, interferon (IFN)-gamma and interleukin (IL)-4 were analyzed. In addition, maturation and CD103 expression in the lung DCs were investigated. Anti-NGF treatment was found to significantly reduce airway hyperreactivity and inflammation in asthmatic mice. In addition, a subdued T helper 2 (Th2) response was observed, characterized by the downregulation of IL-4 and the upregulation of IFN-gamma. Furthermore, the expression of the DC surface molecules, CD80, CD86 and major histocompatibility complex class II, as well as the proportion of lung CD103+ DCs, decreased in the OVA-sensitized and challenged mice. The proportion of lung CD103+ DCs also exhibited a positive correlation with the levels of plasma NGF in the mice. These results may provide an explanation for the role of NGF in amplifying the Th2 response in allergic diseases. Therefore, NGF may promote the maturation and polarization towards a Th2-stimulating phenotype of activated DCs, contributing to an amplification of the Th2 response in asthma. PMID- 25289031 TI - Endovascular interventional therapy and classification of vertebral artery dissecting aneurysms. AB - The current study aimed to summarise the clinical features and classifications of vertebral artery dissecting aneurysms (VADAs) to optimise strategies for endovascular interventional therapy. The clinical features and results of 31 inpatients with VADA were retrospectively analysed. The aneurysms were classified according to their location and association between the aneurysm and posterior inferior cerebellar artery (PICA), and into subtypes according to the developmental state of the contralateral vertebral artery. Different endovascular interventional therapy strategies were selected for each classification. Three types of aneurysm with two subtypes each were identified. An aneurysm located distally to the PICA was termed type I (10/31 patients). Aneurysms with a contralateral vertebral artery were denoted as subtype a (type Ia, 6/31 patients) and aneurysms with hypoplasia of the contralateral vertebral artery were denoted as subtype b (type Ib, 4/31 patients). An aneurysm located at the origin of the PICA was termed type II (13/31 patients), with seven cases classified as IIa and six cases as IIb. An aneurysm located proximally to the PICA was termed type III (8/31 patients), with five cases classified as IIIa and three cases as IIIb. Among the 31 patients, 18 received stent-assisted coiling, two received coiling, 10 received coiling with parent artery occlusion and one patient received conservative treatment. Among the 31 patients with VADA, 21 were occluded completely, nine were partially occluded and one was not occluded. One patient developed a coma following coiling; however, the other 30 patients recovered well. Thus, the classification of an aneurysm based on its location and the developmental state of the contralateral vertebral arteries appears to be an effective and safe approach for the selection of appropriate endovascular interventional therapy strategies. PMID- 25289033 TI - Efficacy and safety of ozonated autohemotherapy in patients with hyperuricemia and gout: A phase I pilot study. AB - Gout is a common form of arthritis; however, there are currently no effective therapies available. Ozonated autohemotherapy (O3-AHT) is a controversial, but successful method of treatment for a number of diseases. The present study is the first pilot study investigating the application of O3-AHT in patients with hyperuricemia and gout. In total, 10 patients diagnosed with gout were recruited and subjected to O3-AHT. Self-reported pain visual analog scale (VAS) scores and creatinine clearance values were evaluated prior to (T0), during (after the fifth session of O3-AHT treatment; 1-4 weeks; T1) and following the treatment course (5 28 weeks; T2). At T1, the creatinine clearance rate of the patients significantly increased from 105.14+/-35.33 (T0) to 121.45+/-44.52 ml/min (t=2.165, P=0.062), while the pain VAS score decreased from 5.35+/-2.78 (T0) to 3.30+/-2.21 (t=2.004, P=0.076). However, at T2, the creatinine clearance rate decreased slightly to 111.15+/-36.52 ml/min, and no statistically significant difference was observed from the value at T0 (t=1.723, P=0.123). The pain VAS score further decreased to 2.30+/-2.66 (t=2.628, P=0.027). In conclusion, O3-AHT decreased the creatinine clearance rate and the pain VAS scores of patients with hyperuricemia and gout; thus, may be a potential effective therapeutic approach. PMID- 25289032 TI - Clinical significance of mismatch repair gene expression in sporadic colorectal cancer. AB - Mismatch repair (MMR) genes play an important role in the occurrence and development of sporadic colorectal cancer; however, the effect of MMR genes on clinicopathological features and prognosis remains unclear. The aim of the present study was to observe the clinical significance of MMR gene expression in sporadic colorectal cancer. Clinicopathological data and postoperative samples from 404 patients with sporadic colorectal cancer were obtained from the Affiliated Tumor Hospital of Xinjiang Medical University. The immunohistochemistry PV-9000 two-step method was performed to measure the protein expression of human mutL homolog 1 (hMLH1), human mutS homolog (hMSH) 2, human postmeiotic segregation increased 2 (hPSM2) and hMSH6. Differences in clinicopathological features, family history and survival time subsequent to surgery between groups with normal and aberrant MMR protein (MMRP) expression were compared. A total of 27.23% of all patients showed aberrant nuclear staining of MMRP. Among the patients with aberrant MMRP expression, a higher proportion of patients showed aberrant expression of more than one type of MMRP than aberrant expression of only one type of MMRP. Aberrant expression of hMLH1/hPSM2 was most commonly observed (29/404). In addition, aberrant MMRP expression in colorectal cancer was indicated predominantly in the right hemicolon. Histological type primarily showed mucinous adenocarcinoma. In addition, with increasing body mass index (BMI), the MMRP deficiency rate was also shown to increase gradually. There was a close association between MMRP expression deficiency and family history of cancer (P<0.05). For TNM stage III patients, the Kaplan-Meier survival curve showed that the aberrant MMRP expression group had a three-year disease-free survival (DFS) rate of 66.67%, which was longer than the DFS rate of the normal group (55.41%), with no statistical difference (P>0.05). In conclusion, the immunohistochemistry PV-9000 two-step method can be used to measure MMRP expression in colorectal cancer. Aberrant MMRP expression is closely correlated with tumor location, histological type, BMI and tumor family history in sporadic colorectal cancer. Aberrant MMRP expression may have an effect on the prognosis of stage III patients. PMID- 25289034 TI - Effects of dual arterial blood supply on liver regeneration in the graft and the host following heterotopic auxiliary liver transplantation. AB - This study aimed to investigate the effect of the dual arterial blood supply method used in auxiliary liver transplantation on the regeneration of grafted and host liver. A total of 72 male Sprague-Dawley rats were randomly assigned to three experimental groups, namely the 68% hepatectomy group (group A), the 68% hepatectomy with dual arterial blood supply group (group B) and the auxiliary liver transplantation with dual arterial blood supply group (group C). Group C was further divided into the host liver subgroup (group Ca) and the transplanted liver subgroup (group Cb). Six animals from each group were sacrificed at 1, 2 and 7 days after surgery. The calculation of the liver regeneration rate (LRR) was based on measuring liver weight. Liver function was assessed by measuring serum alanine aminotransferase (ALT) levels. Immunohistochemistry was employed to detect the expression of proliferating cell nuclear antigen (PCNA). Apoptotic changes in the grafts and host livers were evaluated using TUNEL staining. The LRR in each group exhibited a tendency to increase over time. At each time point, the LRR of transplanted livers in group C exhibited no significant difference from that of host livers in group C (P>0.05). The ALT levels for each group exhibited a time-dependent decreasing tendency. The ALT level in group C was significantly higher compared to that in groups A and B at each time point (P<0.05). The expression of PCNA in transplanted and host livers in group C was significantly lower compared to that in groups A and B at the same time point (P<0.001). Although the number of apoptotic cells in each group varied at different time points, there was no statistically significant difference (P>0.05). In auxiliary liver transplantation with the dual arterial blood supply method, the capacity of the liver regeneration in the grafts was similar to that of the host livers. Therefore, this technique may reduce the potential risk of graft liver atrophy caused by functional competition. PMID- 25289035 TI - Protein tyrosine phosphatase PTPN22 +1858C/T polymorphism is associated with active vitiligo. AB - Vitiligo is characterized by a skin depigmentation disorder resulting from an autoimmune response targeting melanocytes. Within the genetic factors involved in the development of the vitiligo immune response, various genes in the major histocompatibility complex (MHC) and non-MHC loci have been considered to be risk factors. The PTPN22 gene encodes for a lymphoid protein tyrosine phosphatase, a regulator of the activation and development of T-cells. The +1858C/T polymorphism has been associated to autoimmune disease susceptibility in different populations and could be implicated in the onset of vitiligo. To assess the possible association between the presence of PTPN22 +1858C/T and vitiligo, 187 patients with vitiligo and 223 control subjects were analyzed in the study. Genomic DNA was isolated using the salting-out method and samples were subjected to polymerase chain reaction-restriction fragment length polymorphism in order to detect the PTPN22 +1858C/T polymorphism. Causal associations were determined by chi2 test and their respective odds ratio (OR) was assessed in a 2*2 contingency table. The results showed an association between active vitiligo and the allele T load [P=0.0418; OR, 2.5706; 95% confidence interval (CI), 1.0040-6.5816], and active vitiligo-CT genotype (P=0.0389, OR, 2.6548; 95% CI, 1.0191-6.9156). In conclusion, the present data indicates a possible association between the PTPN22 +1858C/T genotype and a significant susceptibility of developing an active form of vitiligo. PMID- 25289036 TI - Impact of oxidative stress on the cytoskeleton of pancreatic epithelial cells. AB - In the present study the effect of reactive oxygen species on the morphological changes of pancreatic epithelial cells in a three-dimensional culture system was investigated. In addition, the expression of signaling molecules during this process was determined. MatrigelTM was used to construct a three-dimensional culture model of pancreatic epithelial and cancer cells. The cultured cells were stimulated with 1 or 200 MUmol/l H2O2 (a typical reactive oxygen species), and the morphological changes were then evaluated after 15 min, 1 h and 4 h. The cytoskeleton of the cells was observed using laser scanning confocal microscopy with immunofluorescence staining. In addition, the nuclear content of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) was detected using ELISA. The results demonstrated that treatment with 200 MUmol/l H2O2 induced cell contraction after 15 min, and cell morphology recovered after 1 h; however, cell size was reduced after 4 h. Consequently, intracellular actin and microtubules were rapidly lost following H2O2 treatment, and the cytoskeleton became indistinct and eventually disintegrated after 4 h. Similar observations were noted for the normal pancreatic epithelial and cancer cells. By contrast, treatment with 1 MUmol/l H2O2 did not affect the morphology and cytoskeleton of pancreatic epithelial cells. In addition, 200 MUmol/l H2O2 treatment increased the activity of NF-kappaB gradually, while 1 MUmol/l H2O2 treatment was found to have little impact on the activity of NF-kappaB. Therefore, it was demonstrated that oxidative stress can induce the early onset of reversible cell contraction and cytoskeleton depolarization in pancreatic epithelial cells, and can increase NF-kappaB expression. PMID- 25289037 TI - Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation. AB - Acute lung injury, a critical illness characterized by acute respiratory failure with bilateral pulmonary infiltrates, remains unresponsive to current treatments. The condition involves injury to the alveolar capillary barrier, neutrophil accumulation and the induction of proinflammatory cytokines followed by lung fibrosis. In the present study, a rabbit model of bleomycin-induced acute lung injury was established to examine the effects of asialoerythropoietin (AEP), an agent with tissue-protective activities, on pulmonary inflammation. Six Japanese white rabbits were randomly divided into two equal groups. Acute lung injury was induced in all rabbits by intratracheally injecting bleomycin. The control group was injected with bleomycin only; the experimental (AEP) group was injected intravenously with AEP (80 MUg/kg) prior to the bleomycin injection. Computed tomography (CT) studies were performed seven days later. The CT inflammatory scores of areas exhibiting abnormal density and the pathological inflammatory scores were recorded as a ratio on a 7*7 mm grid. The CT and pathological inflammatory scores were significantly different between the control and AEP groups [122+/-10 and 16.3+/-1.5 (controls) vs. 71+/-8.5 and 9.7+/-1.4 (AEP), respectively; P<0.01]. Thus, the present study revealed that AEP prevents bleomycin-induced acute lung injury in rabbits. PMID- 25289038 TI - Risk of node metastasis of sentinel lymph nodes detected in level II/III of the axilla by single-photon emission computed tomography/computed tomography. AB - In breast cancer, single-photon emission computed tomography/computed tomography (SPECT/CT) shows the exact anatomical location of sentinel nodes (SN). SPECT/CT mainly exposes axilla and partly exposes atypical sites of extra-axillary lymphatic drainage. The mechanism of how the atypical hot nodes are involved in lymphatic metastasis was retrospectively investigated in the present study, particularly at the level II/III region. SPECT/CT was performed in 92 clinical stage 0-IIA breast cancer patients. Sentinel lymph nodes are depicted as hot nodes in SPECT/CT. Patients were divided into two groups: With or without hot node in level II/III on SPECT/CT. The existence of metastasis in level II/III was investigated and the risk factors were identified. A total of 12 patients were sentinel lymph node biopsy metastasis positive and axillary lymph node dissection (ALND) was performed. These patients were divided into two groups: With and without SN in level II/III, and nodes in level II/III were pathologically proven. In 11 of the 92 patients, hot nodes were detected in level II/III. There was a significant difference in node metastasis depending on whether there were hot nodes in level II/III (P=0.0319). Multivariate analysis indicated that the hot nodes in level II/III and lymphatic invasion were independent factors associated with node metastasis. There were 12 SN-positive patients followed by ALND. In four of the 12 patients, hot nodes were observed in level II/III. Two of the four patients with hot nodes depicted by SPECT/CT and metastatic nodes were pathologically evident in the same lesion. Therefore, the present study indicated that the hot node in level II/III as depicted by SPECT/CT may be a risk of SN metastasis, including deeper nodes. PMID- 25289039 TI - Overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in sacral giant cell tumors and the correlation with tumor microvessel density. AB - Although classified as benign, giant cell tumors of the bone (GCTB) may be aggressive, recur and even metastasize to the lungs. In addition, the pathogenesis and histogenesis remain unclear; thus, the driving factors behind the strong tumor growth capacity of GCTB require investigation. In the present study, the expression levels of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF), which are promoted by hypoxic conditions, were determined in 22 sacral GCTB samples using immunohistochemistry and western blot analysis. Furthermore, CD34 expression was analyzed using these methods. The correlation between HIF-1alpha or VEGF expression and the tumor microvessel density (MVD) was then determined. The results demonstrated that HIF 1alpha, VEGF and CD34 were overexpressed in the 22 sacral GCTB specimens, and overexpression of HIF-1alpha and VEGF correlated with the tumor MVD. Thus, the present study has provided novel indicators for the tumor growth capacity of GCTBs. PMID- 25289040 TI - Acute paraquat poisoning with sinus bradycardia: A case report. AB - Paraquat (PQ) is a highly toxic herbicide, which not only leads to acute organ damage, but also to a variety of complications. Patients with severe PQ-induced poisoning may succumb to multiple organ failure involving the circulatory and respiratory systems. Although numerous studies have been performed investigating PQ poisoning, cases of extreme bradycardia caused by acute PQ-induced poisoning are rare. In the present case report, a 59-year-old male who ingested PQ was admitted to the Department of Poisoning and Occupational Disease at Qilu Hospital of Shandong University (Jinan, China) after three days. The patient received treatment known as the 'Qilu scheme', which was established in the Department of Poisoning and Occupational Disease. However, the heart rate of the patient remained low following the administration of conventional medicines, until thyroid tablets were administered. To the best of our knowledge, cases of bradycardia following PQ poisoning are rare. PMID- 25289041 TI - Ameloblastic fibrosarcoma of the mandible: A case report and mini review. AB - Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic neoplasm of the jaw. AFS is characteristically composed of a benign odontogenic epithelium and a malignant mesenchymal component. The posterior region of the mandible is the predominantly occupied site. In the present report, a new case of AFS in a 22 year-old male that originated from ameloblastic fibroma was described. Histologically, the tumor showed biphasic components: Benign epithelium and a malignant mesenchymal component. Immunochemical findings revealed that the tumor cells were positive for cluster of differentiation (CD) 34, vimentin, Ki-67 and p53, but negative for smooth muscle actin, S-100, CD68 and desmin. The clinical presentation, radiographic appearances and treatment measures were additionally described and reviewed. PMID- 25289042 TI - Evaluation of blood-brain barrier permeability in tryptophan hydroxylase 2 knockout mice. AB - The blood-brain barrier (BBB) is critical to the health of the central nervous system (CNS). The possibility that 5-hydroxytryptamine (5-HT) participates in the alteration of the BBB has been previously demonstrated. Tryptophan hydroxylase 2 (TPH2) is a unique genetic enzyme isoform that catalyzes the rate-limiting step in the biosynthesis of 5-HT in the CNS; however, its role in the permeability changes of the BBB remains unclear. In the present study, TPH2-knockout mice were utilized in the assessment of BBB disruption, as measured by the Evans Blue (EB) extravasation or fluorescein isothiocyanate-albumin leakage assay in the brain. EB was not found to be retained in the brain in the TPH2-knockout mice or the wild-type controls. The results of the study demonstrate that TPH2 knockout has no effect on BBB permeability, indicating that TPH2 and the 5-HT system in the CNS are not sufficient to influence the BBB leakage. PMID- 25289043 TI - Intracranial pure yolk sac tumor in the anterior third ventricle of an adult: A case report. AB - A 45-year-old female patient presented with symptoms of polydipsia and polyuria, menopause, headache, gait disturbance and deteriorated mental state. Brain magnetic resonance imaging (MRI) showed an irregular mass in the anterior third ventricle. The tumor was excised using a transfrontal approach from the anterior section of the third ventricle. The histological diagnosis was of an intracranial pure yolk sac tumor. The patient underwent radiotherapy and suffered no tumor recurrence one year after the surgery. Overall, when heterogeneous enhancement and an irregular mass with surrounding invasion and ventricular dilation are observed in the anterior third ventricle of an adult, a yolk sac tumor should be considered, and MRI may aid the differential diagnosis. A combination of surgical resection and radiotherapy is recommended for the yolk sac tumor. PMID- 25289044 TI - Azurocidin-induced inhibition of oxygen metabolism in mitochondria is antagonized by heparin. AB - Heparin is a potent blood anticoagulant that has been demonstrated to attenuate inflammatory responses in sepsis. Sepsis is considered to be a microcirculation mitochondrial distress syndrome. Azurocidin (AZU), a protein with strong heparin binding potential that induces inflammatory responses and apoptosis, has been shown to increase the permeability of endothelial cells and induce the prognosis of sepsis. However, the function of AZU in mitochondrial oxygen metabolism has yet to be reported. The aim of the present study was to investigate whether heparin exhibits an antagonistic effect on AZU-induced mitochondrial dysfunction in human umbilical vein endothelial cells (HUVECs) and to further investigate the possible underlying mechanisms. HUVECs were randomly assigned into blank control, AZU, heparin plus AZU and heparin groups. The blank control group were incubated with phosphate-buffered saline for 12 h, while the AZU group were incubated with 1 MUg/ml AZU for 12 h. The heparin plus AZU group were incubated with 100 MUg/ml heparin for 2 h, followed by the addition of 1 MUg/ml AZU and incubation for 12 h. The heparin group were incubated with 100 MUg/ml heparin for 12 h. Flow cytometry was used to determine the mitochondrial membrane potential, while electron microscopy was used to determine the mitochondrial morphology. Western blotting and quantitative polymerase chain reaction were used to determine the protein and mRNA expression levels of Cox II in the mitochondria, respectively. Western blotting was also used to evaluate the concentration of AZU in cytoplasm, along with immunofluorescence analysis. AZU was revealed to decrease the mitochondrial membrane potential, reduce cytochrome c oxidase subunit II expression and destroy the morphology of the mitochondria. Heparin exhibited an antagonistic function on these processes and inhibited the endocytosis of AZU by HUVECs. In conclusion, the results indicated that AZU inhibited the oxygen metabolic function in mitochondria, and this function was effectively antagonized by heparin via the inhibition of AZU endocytosis by HUVECs. Therefore, heparin may be a potential therapeutic agent for treating mitochondrial dysfunction in the future. PMID- 25289045 TI - Antioxidant and anti-inflammatory effects of Schisandra and Paeonia extracts in the treatment of asthma. AB - The aim of the present study was to investigate the antioxidant and anti inflammatory effects of Paeonia and Schisandra extracts in asthmatic rats. An ethanol extraction method was used to prepare the Schisandra and Paeonia extracts, and the levels of hydroxyl radical, total antioxidant activity and total phenolic content were detected. The rats were divided into three groups: Treatment (group A), model (group B) and control (group C). The treatment group received traditional Chinese antiasthmatic medicine (mixed extract, 2 ml/day) for 10 days. Levels of malondialdehyde (MDA), Cu-Zn-superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were detected in the serum, while interleukin (IL)-4, IL-6, interferon (IFN)-gamma, IL-13 and IL-22 levels were analyzed in the serum, bronchoalveolar lavage fluid and lung tissue homogenates of the three groups. In addition, pathological changes of the tracheal tissues were observed via biopsies and the NF-kappaB p65 level was measured in the lung tissue using immunohistochemistry. Total antioxidant activity, hydroxyl radical levels and total phenolic content in the mixed herbal extracts were higher than those in the single herbal extracts. At day 5 following the treatment, the number of eosinophils was significantly reduced in the tracheal tissues. At day 10 following the treatment, the mucosa was significantly repaired. In vivo antioxidant levels revealed that the serum and erythrocyte SOD activity and GSH Px were higher in group A as compared with group B, while the level of MDA in group A was lower than that in group B (P<0.05). The levels of serum and erythrocyte SOD activity and GSH-Px in group B were lower than those in group C, while the level of MDA in group B was higher than that in group C (P<0.05). IL-4, IL-6 and IL-13 levels in the serum, bronchoalveolar lavage fluid and lung tissue in group A were not significantly different from those in group B (P>0.05). However, IFN-gamma levels in group A significantly increased as compared with the level in group B, while IL-22 levels decreased significantly in group A as compared with group B (P<0.05). IL-4, IL-6, IL-13 and IL-22 levels in the lung tissue, bronchoalveolar lavage fluid and serum in group B were significantly higher than those in group C. In addition, the IFN-gamma level decreased significantly in group B as compared with the level in group C (P<0.05). Immunohistochemical analysis revealed that the protein expression of NF-kappaB p65 in group A was significantly lower compared with group B (P<0.05). Therefore, Paeonia and Schisandra extracts may be used to treat asthma through their in vivo antioxidant and anti-inflammatory effects. PMID- 25289046 TI - Effect of ECRG2 in combination with cisplatin on the proliferation and apoptosis of EC9706 cells. AB - The aim of the present study was to explore the effect of esophageal cancer related gene 2 (ECRG2) protein in combination with cisplatin (DDP) on the proliferation and apoptosis of esophageal cancer cells. A 3-(4, 5-dimethylthiazol 2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay was used to examine the effects of ECRG2 alone and ECRG2 in combination with DDP on the proliferation of EC9706 esophageal cancer cells. Hoechst 33258 staining was performed to analyze the effects of ECRG2 alone and ECRG2 in combination with DDP on apoptosis in the EC9706 cells. The expression levels of Bcl-2-associated X protein (Bax) mRNA and protein were determined by reverse transcription polymerase chain reaction (RT PCR) and western blot analysis, respectively. The results from the MTT assay revealed that ECRG2 inhibited the proliferation of EC9706 cells and that ECRG2 in combination with DDP had a greater inhibitory effect on cell proliferation. The antiproliferative effects were time- and concentration-dependent, within a certain range of concentrations. The Hoechst 33258 staining results demonstrated that the number of apoptotic cells following treatment with ECRG2 in combination with DDP for 24 h was higher than that following treatment with ECRG2 alone for the same duration. Western blot analysis and RT-PCR results revealed that the expression levels of Bax mRNA and protein were upregulated in cells treated with ECRG2 in combination with DDP compared with those in cells treated with ECRG2 alone. Thus, ECRG2 in combination with DDP had an enhanced inhibitory effect on EC9706 cell proliferation compared with that of ECRG2 alone, and an increased inductive effect on EC9706 cell apoptosis, possibly due to the upregulation of the expression of Bax. PMID- 25289047 TI - Expression levels of TWIST1 are associated with the clinicopathological stage of B-cell non-Hodgkin lymphoma. AB - The aim of the present study was to investigate the expression level of TWIST1 in B-cell non-Hodgkin lymphoma (BNHL) and its association with the clinicopathological characteristics of BNHL. Expression levels of TWIST1 were analyzed in patients with BNHL (n=45) and lymphadenosis (n=21) using immunohistochemical staining and western blot analysis. In addition, the mRNA expression levels of TWIST1 in the peripheral blood were detected by fluorescent quantitative polymerase chain reaction. The positive rate of TWIST1 expression in the BNHL tissue was 82.2%, which was significantly higher compared with the lymphadenosis tissue (5%; P<0.05). In addition, the protein expression level of TWIST1 in the BNHL tissue was higher compared with the lymphadenosis tissue. TWIST1 expression was also higher in stage III/IV BNHL tissues than in stage I/II tissues (P<0.05). The tissues were staged following the Ann Arbor system. Furthermore, the mRNA expression level of TWIST1 in the peripheral blood of the BNHL tissue (3.03+/-0.03) was higher compared with the lymphadenosis tissue, and the mRNA expression level of TWIST1 was higher in stage III/IV (4.41+/-0.12) tissues than in stage I/II BNHL (2.03+/-0.08) tissues. In conclusion, TWIST1 expression was higher in the tissue and peripheral blood of patients with BNHL when compared with those with lymphadenosis. Thus, TWIST1 expression was associated with the clinicopathological stage of BNHL. PMID- 25289048 TI - Activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway is involved in the casticin-induced apoptosis of colon cancer cells. AB - Casticin is one of the main components of the fruits of Vitex rotundifolia L. Studies have shown that casticin inhibits the growth of various cancer cells, including colon cancer. In the present study, the anti-carcinogenic effects of casticin on human colon cancer and the underlying mechanisms were investigated. The results revealed that casticin significantly induced apoptosis of HT-29, HCT 116, SW480 and Caco-2 cells, induced the accumulation of reactive oxygen species (ROS) and increased the protein levels of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and B-cell lymphoma 2-interacting mediator of cell death (Bim) in HT-29 cells. Pretreatment with N-acetylcysteine, an antioxidant chemical compound, inhibited the activation of ASK1, JNK and Bim, as well as the apoptosis induced by casticin. Small interfering RNA targeting ASK1 significantly attenuated the induction of JNK and Bim activation and apoptotic cell death by casticin treatment. SP600125, a specific JNK inhibitor, attenuated Bim activation and apoptosis, but did not alter ASK1 phosphorylation levels. In addition, casticin treatment resulted in apoptosis by the same mechanism in HCT 116, SW480 and Caco-2 cells. These results suggest that casticin significantly induced apoptosis by the activation of the ASK1-JNK-Bim signaling cascade and the accumulation of ROS in colon cancer cells. PMID- 25289049 TI - Detection of Her-2/neu expression in gastric cancer: Quantitative PCR versus immunohistochemistry. AB - The aim of this study was to compare quantitative polymerase chain reaction (qPCR) with immunohistochemistry (IHC) for the detection of Her-2 in gastric cancer, and to investigate the correlation between the expression levels of human epidermal growth factor receptor 2 (Her-2) and clinical features. Clinical data from 426 cases of gastric cancer were collected. Her-2 expression levels in cancerous tissue were detected using IHC, and the Her-2/neu gene expression levels were determined by qPCR. The correlation between the expression level of Her-2 and clinical features was investigated. The positive expression rate of Her 2 in cancerous tissue detected using qPCR and IHC was 11.17% (46/412) and 13.38% (57/426), respectively. The positive expression of the Her-2 protein/gene was significantly correlated with the depth of invasion and lymphatic metastasis, as well as the TNM stage (P<0.05). No significant correlation was identified between positive expression of the Her-2 protein/gene and tumor location, age, gender, differentiation degree and Lauren classification (P>0.05). The diagnostic consistency was good between the two methods (kappa=0.828). The results indicate that the expression of Her-2/neu is closely associated with the development of gastric cancer. qPCR is a convenient, objective and efficient method, which may be used as an alternative to IHC or fluorescence in situ hybridization for the detection of Her-2/neu gene. PMID- 25289050 TI - Karyotype stability of human umbilical cord-derived mesenchymal stem cells during in vitro culture. AB - The aim of this study was to investigate whether the chromosomes of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) change following in vitro culture for several generations. In the present study, umbilical cords from two healthy infants following cesarean delivery were collected aseptically and hUCMSCs were isolated by digestion with collagenase and trypsin, and then cultured in vitro. hUCMSCs with fibroblastic morphology were presented from the human umbilical cord tissue after 7 days of adherent culture. When cultured for 6 passages in vitro, the hUCMSCs maintained a stable spindle-shaped morphology. Cells reached the logarithmic growth phase after 3-4 days of culture. In addition, CD13, CD29, CD44, CD90 and CD105 were highly expressed in generations P3-P6. The expression of CD31, CD34, CD45 and HLA-DR was negative. Furthermore, karyotype analysis revealed a normal diploid karyotype with 46 chromosomes and no abnormal changes were found in chromosome structure. These findings suggest that when cultured for 6 passages in vitro, hUCMSCs maintain a stable immunophenotype and chromosome structure, which provides an experimental basis for the safety of hUCMSC cytotherapy. PMID- 25289051 TI - Overexpression of CyclinA2 ameliorates hypoxia-impaired proliferation of cardiomyocytes. AB - Hypoxia is a primary mediator for cell survival, and has been reported to inhibit cardiomyocyte proliferation in fetal and neonatal hearts. CyclinA2 is a key regulator of cell proliferation. Whether CyclinA2 affects cardiomyocyte proliferation in hypoxic conditions remains unexamined. This study was designed to investigate the roles of CyclinA2 expression on hypoxia-impaired cardiomyocyte proliferation. Cardiomyocytes were isolated from neonatal rats and randomly separated into six groups: Control, hypoxia, enhanced green fluorescent protein (EGFP)-Adv, EGFP-Ccna2, EGFP-Adv + hypoxia and EGFP-Ccna2 + hypoxia. The cells in the control group were cultured in a general cell incubator; the cells in the hypoxia group were placed in a hypoxic chamber for 12 h; the cells in the EGFP Adv and EGFP-Ccna2 groups were separately transfected with EGFP-adenovirus capsids or EGFP-adenovirus capsids with CyclinA2 cDNA for 18 h, and then placed in a general incubator for an additional 12 h; the cells in the EGFP-Adv + hypoxia and EGFP-Ccna2 + hypoxia groups were separately transfected with EGFP adenovirus capsids or EGFP-adenovirus capsids with CyclinA2 cDNA for 18 h, and then placed in a hypoxia chamber for an additional 12 h. CyclinA2 expression was measured using immunochemical staining and western blot analysis, and cardiomyocyte proliferation was measured using the cell counting kit 8. GFP fluorescence indicated a high transfection efficiency (>80%), and immunochemical staining showed that CyclinA2 was mainly distributed in the nucleus. CyclinA2 expression was downregulated following exposure to hypoxia for 12 h. Cardiomyocyte proliferation was also significantly decreased following exposure to hypoxia for 12 h. However, compared with the EGFP-Adv group, CyclinA2 expression and cardiomyocyte proliferation was markedly increased in the EGFP Ccna2 group. Furthermore, compared with the EGFP-Adv + hypoxia group, CyclinA2 expression and cell proliferation were markedly increased in the EGFP-Ccna2 + hypoxia group. These findings indicate that CyclinA2 upregulation improves cardiomyocyte proliferation in hypoxic conditions. PMID- 25289052 TI - Cellular and molecular mechanism study of declined intestinal transit function in the cholesterol gallstone formation process of the guinea pig. AB - The aim of this study was to investigate the cellular and molecular mechanisms of declined intestinal transit (IT) function in the cholesterol gallstone (CG) formation process. Forty guinea pigs were divided into an experimental group (EG) and a control group (CoG), and the reverse transcription-polymerase chain reaction (RT-PCR) was performed for the analysis of c-kit and stem cell factor (scf) mRNA expression in the small bowel. In addition, immunofluorescence staining and confocal laser microscopy were performed for the observation of the changes in the number of interstitial cells of Cajal (ICCs) in the terminal ileum of each group. RT-PCR showed that, compared with the CoG, the intestinal c-kit and scf mRNA expression levels in the EG were significantly decreased; the average positive area of ICCs in the ileum in the EG was also significantly reduced. During the diet-induced CG formation procedure, the c-kit and scf mRNA expression levels in the small intestine decreased and the number of ICCs decreased. Inhibition of the c-kit/scf pathway may be involved in the declined IT function during the CG formation process. PMID- 25289053 TI - Levels of microRNA-181b and plasminogen activator inhibitor-1 are associated with hypertensive disorders complicating pregnancy. AB - The aim of the present study was to explore the association between the expression of microRNA (miRNA)-181b and plasminogen activator inhibitor-1 (PAI-1) in the placental tissue of pregnant females with a hypertensive disorder complicating pregnancy (HDCP). Placental tissue samples were obtained from 48 patients with HDCP and 40 females with a normal pregnancy. The levels of miRNA 181b and PAI-1 mRNA were determined by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of PAI-1 protein was analyzed by western blotting. Vascular smooth muscle cells (VSMCs) were transfected with the pEGP-miRNA-181b plasmid using Lipofectamine(r) 2000. Transfection efficiency was confirmed by immunohistochemical analysis. The levels of miRNA-181b in the placental tissue of patients with HDCP were lower than those in the control group, whereas the levels of PAI-1 mRNA in the placental tissue of patients with HDCP were higher than those in the control group. The expression of the PAI-1 protein in the HDCP group was higher than that in the control group. Following transfection of VSMCs with plasmid pGCMV/EGFP/miRNA-181b, the levels of PAI-1 mRNA were reduced while the levels of miRNA-181 were upregulated. Furthermore, the expression levels of PAI-1 protein were lower than those in the control group. The levels of miRNA-181b and PAI-1 mRNA were strongly associated with HDCP. Thus, miRNA-181b may play an important role in the regulation of PAI-1. PAI 1 and miRNA-181b may be novel biomarkers to be used in HDCP therapy. PMID- 25289054 TI - Icariin promotes directed chondrogenic differentiation of bone marrow mesenchymal stem cells but not hypertrophy in vitro. AB - Icariin (ICA), a Traditional Chinese Medicine, has been demonstrated to be a promoting compound for extracellular matrix synthesis and gene expression of chondrocytes. However, whether ICA can act as a substitute for or cooperate with growth factors to directly promote stable chondrogenesis of bone marrow mesenchymal stem cells (BMSCs) remains unknown. In the present study, rat BMSCs were cultivated in monolayer cultures with a chondrogenic medium containing transforming growth factor-beta3 for 14 days; ICA was added to the same chondrogenic medium throughout the culture period at a concentration of 1*10-6 M. Cell morphology was observed using an inverted microscope, and chondrogenic differentiation markers, including collagen II, aggrecan and SRY (sex determining region Y)-box 9 (SOX9), were detected by immunofluorescence, reverse transcription-quantitative polymerase chain reaction and western blot analysis. Hypertrophic differentiation was also analyzed using collagen I gene expression and alkaline phosphatase (ALP) activity. The results revealed that ICA was effective at forming an increased number of and larger aggregates, and significantly upregulated the mRNA expression levels and protein synthesis of collagen II, aggrecan and SOX9. Furthermore, the chondrogenic medium alone caused hypertrophic differentiation through the upregulation of collagen I gene expression and ALP activity, which was not potentiated by the presence of ICA. Thus, ICA promoted directed chondrogenic differentiation of BMSCs, but had no effect on hypertrophic differentiation. The present results also suggested that ICA may be an effective accelerant of growth factors for cartilage tissue engineering by promoting their chondrogenic differentiating effects but reducing the effect of hypertrophic differentiation. PMID- 25289055 TI - Epithelial ovarian cancer: A case report. AB - An 82-year-old female was diagnosed with ovarian cancer in May 2004. Following gynecological surgery, pathological evaluation showed stage IIIC epithelial ovarian cancer. From June 2004 to January 2005, the patient received six cycles of conventional treatment combined with intravenous paclitaxel (Taxol(r)) and cisplatin. The patient developed abdominal distension and experienced a gradual deterioration in health during 2007, with admission to The First Affiliated Hospital in May 2007. The patient presented with severe abdominal distension and breathing difficulty on May 15 and appeared to be in critical condition. Ultrasound examination revealed massive ascites and left-side pleural effusion. Thoracentesis and abdominocentesis were performed, and 300 mg carboplatin was administered intraperitoneally on May 19, followed by a second abdominocentesis on May 21. However, these treatments did not alleviate the symptoms, and 200 mg bevacizumab was administered by intravenous infusion on May 27. The condition of the patient gradually improved and 400 mg bevacizumab was administered by intravenous infusion every two weeks from June 9. From December, the dosage of bevacizumab was reduced to 200 mg every two weeks. In addition, 300 mg carboplatin was administered intraperitoneally on November 4 and intraperitoneal carboplatin chemotherapy was repeated thereafter. The patient exhibited disease free survival until July 2009, at which time disease progression was observed and the cancer recurred in August 2009. The patient died of multiple organ failure in September 2009. Bevacizumab rapidly eliminated the patient's massive ascites and pleural effusion, and achieved an effect that was not possible with other treatments. Therefore, bevacizumab is an effective therapy for late-stage relapse and refractory ovarian cancer. PMID- 25289056 TI - Complications analysis of posterior vertebral column resection in 40 patients with spinal tumors. AB - The aim of the present study was to summarize and analyze the complications of posterior vertebral column resection in patients with spinal tumors. The complications of 40 patients following surgery were recorded, and surgery-related parameters including segments, bleeding volume and surgical duration were recorded and analyzed. SPSS 12.0 software was used to analyze the correlation between the complications and these parameters retrospectively. A total of 36 complications were reported. The median follow-up duration of the patients was 14 months (range, 4-78 months). Transient late tracheal extubation was associated with higher intraoperative bleeding volume, lower preoperative forced vital capacity and forced expiratory volume in 1 sec. Replaced spinal segment subsidence was associated with increased duration of surgery, higher intraoperative bleeding volume and higher total blood transfusion volume. Thrombocytopenia was associated with increased duration of surgery and higher total blood transfusion volume. The majority of the complications were minor and did not affect the recovery of the patients. Active prevention is necessary to reduce the incidence of complications, in particular, major ones. PMID- 25289057 TI - Neferine inhibits angiotensin II-induced rat aortic smooth muscle cell proliferation predominantly by downregulating fractalkine gene expression. AB - Neferine inhibits the angiotensin II (AngII)-induced proliferation of vascular smooth muscle cells (SMCs), but the underlying mechanism is unclear. The aim of this study was to explore the mechanism underlying the effect of neferine on the proliferation of vascular SMCs. Rat aortic SMCs (RASMCs) were used and fractalkine (Fkn) gene expression was measured by quantitative polymerase chain reaction and western blot analysis. The proliferation of RASMCs was analyzed by MTT assay and flow cytometry. It was revealed that AngII induced Fkn expression in a dose- and time-dependent manner. Fkn-knockdown with small interfering RNA attenuated the AngII-induced RASMC proliferation. Furthermore, neferine inhibited Fkn expression and attenuated the AngII-induced RASMC proliferation. These findings suggest that the Fkn gene may play an important role in AngII-induced RASMC proliferation and that neferine acts to attenuate AngII-induced RASMC proliferation by inhibiting Fkn expression. PMID- 25289058 TI - Heparin modulation on hepatic nitric oxide synthase in experimental steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome, and has been etiologically associated with insulin resistance (IR). The histopathology of NAFLD ranges between simple steatosis and nonalcoholic steatohepatitis (NASH), with or without fibrosis. The aim of the present study was to examine the effect of heparin on steatohepatitis and hepatic-induced nitric oxide synthase (iNOS) expression in mice. Male mice were divided into four groups, which included the normal basal diet (control), high fat (HF) diet, HF diet + heparin (treatment group) and heparin control groups. After eight weeks from the initiation of the experiment, blood was collected and livers were harvested for biochemical analysis and histological studies. Serum levels of aspartate aminotransferase, alanine aminotransferase, hepatic triglyceride (TG) and hydroxyproline, as well as the IR, superoxide anion generation and mRNA expression of the hepatic iNOS enzyme were evaluated. Liver specimens were processed for histopathological and immunohistopathological evaluation. Heparin administration decreased the levels of the liver enzymes, IR, superoxide generation, hepatic TG, hydroxyproline and iNOS expression when compared with the HF diet group. These changes were associated with an improvement in inflammation and fibrosis observed via histopathological examination. Therefore, heparin treatment attenuates hepatic injury in steatohepatitis. PMID- 25289059 TI - Effect of a heat shock protein 90-specific inhibitor on the proliferation and apoptosis induced by VEGF-C in cervical cancer cells. AB - The aim of the present study was to investigate the effect of heat shock protein 90 (Hsp90)-specific inhibitor geldanamycin (GA) on the proliferation and apoptosis induced by vascular endothelial growth factor-C (VEGF-C) in cervical cancer cells. HeLa cells (1*106/ml) in the logarithmic growth phase were incubated without serum for 24 h. The cells were pretreated with kinase insert domain receptor antibody (KDR)-Ab (20 MUg/ml), phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (3 MUmol/l), mitogen-activated protein kinase (MAPK) inhibitor PD98059 (30 MUmol/l) or Hsp90-specific inhibitor GA (10 MUmol/l) for 30 min, and then treated with VEGF-C (50 ng/MUl) for a further 24 h. The cells were harvested for MTT analysis, annexin V-FITC/propidium iodide double staining for early apoptosis and SDS-PAGE and western blot analysis in order to determine Hsp90, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and cyclin D1 expression. Treatment with VEGF-C alone induced Hsp90 protein expression in HeLa cells at all time-points. Hsp90 expression was increased 3.31-fold in VEGF-C treated HeLa cells, and this increase was attenuated in the treatment groups (2.17-, 1.69-, 1.82-fold in VEGF-C + KDR-Ab, VEGF-C + PD98059 and VEGF-C + LY294002, respectively). The proliferation of the VEGF-C-treated HeLa cells was increased ~2.13-fold, while that of the VEGF-C + GA-treated HeLa cells decreased 0.87-fold (P<0.05). Even low concentrations of GA (0.02 MUmol/l) were found to inhibit the Bcl-2 and cyclin D1 protein expression induced by VEGF-C. Therefore, the results indicate that the Hsp90-specific inhibitor GA has a critical role in the proliferation and apoptosis induced by VEGF-C in cervical cancer cells. PMID- 25289060 TI - DC-CIK biotherapy for a recurrent benign lymphoepithelial lesion of the salivary gland: A case report and literature review. AB - A benign lymphoepithelial lesion (BLEL) is an idiopathic inflammation of the parotid gland, characterized by hyperplasia, lymphocyte infiltration and the formation of epimyoepithelial islands, as well as atrophy of the gland parenchyma. Common treatment methods include immunosuppression and glucocorticoid therapies, in addition to surgical dissections. Cytokine-induced killer (CIK) cells sensitized to specific antigens by dendritic cells (DCs) are used in DC-CIK biotherapy. The present study reports the case of a 22-year-old female suffering from a postoperative recurrent BLEL on the left parotid gland, which was gradually increasing. Following initial unsuccessful conservative treatment attempts, a 10-day course of DC-CIK therapy was initiated, after which the lesion in the gland area was reduced in size and local infection and skin ulcerations were improved. DC-CIK biotherapy was continued for three months (four sessions of 10-day treatments with a 10-day break in between) until the lesion disappeared and the skin ulceration was healed. Computerized tomography scans of the parotid gland revealed complete remission of the primary lesion and recovery of the bone destruction. The patient was discharged and remained stable with no sign of recurrence during a 10-month follow-up period. In the present case report, a successful DC-CIK adoptive cellular immunotherapy treatment for a BLEL was described for the first time. PMID- 25289061 TI - Functional classification and mutation analysis of a synpolydactyly kindred. AB - The aim of the present study was to analyze a congenital syndactyly/polydactyly kindred and propose a new functional classification method of clinical significance. The modes of inheritance and mutational mechanisms were also determined using genetic analyses. Hand and foot anatomy and functions were measured using photographic images, X-ray imaging and grip ability tests. Genetic analysis comprised the genotyping of polymorphic microsatellite markers at known polydactyly-associated loci and the sequencing of the candidate gene. A functional classification system was devised to divide the clinical features into three types, which included mild, moderate or severe deformity. The family was concluded to have syndactyly type II with autosomal dominant inheritance. The microsatellites, D2S2310 and D2S2314, at the 2q31-32 chromosome, which have previously been associated with synpolydactyly type I, were found to be associated with the disorder in the current family. A 27-bp insertion mutation was identified in the affected individuals in the HOXD13 gene at this locus. The insertion added a further nine alanine residues to the polyalanine stretch within the encoded protein. In conclusion, the functional classification method described in the present study may be used to guide surgical approaches to treatment. A family was identified in whom expansion of the polyalanine tract in the HOXD13 gene causes autosomal dominant hereditary synpolydactyly. PMID- 25289062 TI - miR-155 inhibitor reduces the proliferation and migration in osteosarcoma MG-63 cells. AB - As the most common malignant primary bone tumor in childhood, osteosarcoma (OS) maintains a high recurrence, despite the significant improvements in the overall survival rate of high-grade OS patients during the recent decades. Therefore, a novel therapy strategy is required for OS treatment. Recently, various microRNAs (miRNAs or miRs) have been confirmed as deregulated in OS, and the miR-155 dysregulation in OS has been discovered by the microarray analysis. In the present study, the regulation of miR-155 on the OS cell proliferation, migration and invasion on the MG-63 cells was explored in vitro. The miR-155 mimics were found to promote cell proliferation, colony formation, migration and invasion significantly, compared to the control miRNA. An miR-155 inhibitor was also used to evaluate whether miR-155 served as a therapeutic target for OS. The results demonstrated that the miR-155 inhibitor significantly reduced the proliferation, colony formation, migration and invasion of the MG-63 OS cells. Thus, the study confirmed the oncogenic regulation on the OS progression of miR-155, which could serve as a therapeutic target with an miR-155 inhibitor. PMID- 25289063 TI - Hypoglycemic coma due to insulin autoimmune syndrome induced by methimazole: A rare case report. AB - Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin-binding autoantibodies and fasting or late postprandial hypoglycemia. The number of reports on the association of human leukocyte antigen (HLA) genotype with this disease in adolescents in China is limited. This is the case report of a 17-year-old female patient with Graves' disease who was treated with methimazole (MTZ). After 4 weeks of continuous MTZ treatment, the patient suffered an episode of unconsciousness during the late postprandial phase and was admitted to the hospital, where the blood glucose level was found to be 2.88 mmol/l. The symptoms were relieved following intravenous glucose administration. Imaging studies of the pancreas were unremarkable, but the laboratory investigations on admission revealed high serum levels of total insulin, associated with relatively low levels of free insulin and markedly elevated insulin autoantibody (IAB) levels. HLA testing revealed DRB1*0406/0901 and the patient discontinued MTZ and was prescribed propylthiouracil. During the long-term follow-up, the total insulin and IAB levels gradually declined. There was no other episode of hypoglycemia. Therefore, in adolescents with Graves' disease receiving antithyroid treatment with MTZ who experience hypoglycemia, the IAB levels should be assessed to exclude or confirm IAS as the underlying cause. PMID- 25289064 TI - Etanercept in the treatment of ankylosing spondylitis: A systematic review and meta-analysis. AB - Etanercept (ETN) has been widely applied in the treatment of ankylosing spondylitis (AS). As the use of ETN has increased, associated adverse effects have been reported frequently. Previous meta-analyses have focused on comparing the differences in clinical outcomes between ETN and placebo (PBO). The present meta-analysis evaluated randomised controlled trials (RCTs) to compare the effects of ETN and a PBO or sulfasalazine (SSZ) in patients with AS. The study population characteristics and the main results, including the Assessment in AS 20% response (ASAS 20), the Bath AS Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI), were extracted. The pooled odds ratios (ORs) or weighted mean differences (MDs) were calculated using a fixed or random effects model. Fifteen randomised controlled trials (RCTs) involving 2,194 subjects were included. Compared with a PBO, ETN significantly improved the ASAS 20 [P<0.00001; OR, 8.25; 95% confidence interval (CI), 5.92-11.50], BASDAI (P<0.00001; MD, 18.81; 95% CI, -24.47 to -13.15) and BASFI (P<0.00001; standard MD, -0.68; 95% CI, -0.85 to -0.50). In comparison with SSZ, ETN significantly decreased the BASDAI (P<0.00001; MD, -2.40; 95% CI, -2.89 to -1.90) and C-reactive protein (CRP) levels (P<0.0001; MD, -8.01; 95% CI, -11.73 to -4.29). The most common adverse effect of ETN was an injection site reaction. This meta-analysis shows that ETN monotherapy is effective in improving physical function and reducing disease activity in patients with AS. Compared with SSZ, ETN markedly decreased the BASDAI and CRP levels. However, the efficacy of ETN in treating AS requires further evaluation by more RCTs in a larger population of patients prior to recommending ETN as a substitute for synthetic disease-modifying antirheumatic drug (DMARD) monotherapy, or combinations of synthetic DMARDs. PMID- 25289065 TI - Xuebijing injection improves the respiratory function in rabbits with oleic acid induced acute lung injury by inhibiting IL-6 expression and promoting IL-10 expression at the protein and mRNA levels. AB - Xuebijing injection is a complex herbal medicine, and clinical and experimental studies have shown that it has a significant effect on acute respiratory distress syndrome and multiple organ dysfunction syndrome. However, the majority of studies regarding Xuebijing injection have focused on serum inflammatory factors, and few studies have been carried out from the perspective of the protein and mRNA expression of inflammatory cytokines. In this study, 60 healthy rabbits of mixed gender were randomly assigned to a normal control group (CG), oleic acid group (model group; MG) and oleic acid + Xuebijing injection group (treatment group; TG). Rabbits of the CG were treated with normal saline through the ear vein, rabbits of the MG were injected with oleic acid (0.4 ml/kg) and rabbits of the TG received 0.4 ml/kg oleic acid + 10 ml/kg Xuebijing injection. Blood samples were collected from the common carotid artery of all rabbits of all groups 1 h after the ear vein was injected with the corresponding reagent, and was used to measure the arterial partial pressure of oxygen (PaO2) and of carbon dioxide (PaCO2). The activity of myeloperoxidase (MPO) was tested, and the protein and mRNA expression levels of interleukin (IL)-6 and IL-10 were determined. Rabbits of the MG exhibited evident respiratory dysfunction (PaO2 and PaCO2 were low), histopathological lung damage and overactive inflammatory responses (the expression of the proinflammatory cytokine IL-6 and the anti inflammatory cytokine IL-10 was increased at the protein and mRNA levels). Following the administration of the Xuebijing injection, the inflammatory response of the rabbits was significantly reduced. Xuebijing injection raised PaO2 and PaCO2, weakened the activity of MPO in the lung tissue, downregulated the expression of the proinflammatory cytokine IL-6 and further increased the expression of the anti-inflammatory cytokine IL-10. These results demonstrated that Xuebijing injection improved the respiratory function of rabbits with acute oleic acid-induced lung injury by inhibiting IL-6 expression and promoting IL-10 expression. PMID- 25289066 TI - Establishment of an animal model of vascular dementia. AB - The aim of this study was to establish a mouse model of vascular dementia (VaD) in order to overcome the shortcomings of rat models of VaD, which include high production costs, difficult surgery, surgical trauma and high mortality. In this study, repeated ischemia-reperfusion of the total bilateral carotid artery in mice, combined with a reduction of blood pressure, was used to establish an animal model of VaD. A total of 40 Kunming mice (clean grade) were randomly divided into a sham group and a model group. Behavioral tests were performed for each group following the surgery, and the morphology of the hippocampus was analyzed. The results of the step-down avoidance test, water maze test and microscopy examinations confirmed that following surgery, learning and memory dysfunction was significantly increased in the model group. The results of the morphological observations showed that the number of hippocampal CA1 neurons was significantly decreased in the model group compared with that in the sham surgery group (P<0.01). In the present study, a mouse model of VaD was successfully established, which was simple, effective and reliable, and may be used in the future to investigate VaD. PMID- 25289067 TI - Levels of CD105+ cells increase and cell proliferation decreases during S-phase arrest of amniotic fluid cells in long-term culture. AB - The present study aimed to improve the characterization of amniotic fluid cells (AFCs) in order to optimize their use in chromosomal prenatal diagnosis and as seed or stem cells for tissue engineering. The AFCs used in the current study were obtained from three females in their second trimester of pregnancy. The cells were cultured independently and characterized by cell morphology, cell markers, cell cycle distribution and chromosome Giemsa banding in an early- and late-passage. The AFCs remained homogeneous in culture and expressed mesenchymal markers, but not endothelial markers along the culture process. In addition, compared with the early-passage cells, the late-passage cells exhibit an increase in CD105 expression, a decrease in cell division and a delay in the cell cycle, and a number of cells underwent cell cycle arrest. However, the cells retained a normal karyotype. Therefore, the current study characterized AFCs in a clinical culture and confirmed that AFCs are mesenchymal precursors. The results obtained may be useful for the application of AFCs in prenatal diagnosis. PMID- 25289068 TI - Germacrone reverses Adriamycin resistance through cell apoptosis in multidrug resistant breast cancer cells. AB - Multidrug resistance (MDR) is a major obstacle to the chemotherapeutic treatment of breast cancer. Germacrone, the main component of Rhizoma Curcuma, has been shown to possess antitumor, anti-inflammatory and immunomodulatory properties. The aim of the present study was to investigate the effect of germacrone on MCF 7/Adriamycin (ADR) multidrug-resistant human breast cancer cells. The treatment of MCF-7/ADR cells with a combination of germacrone and ADR resulted in an increase in cytotoxicity compared with that of ADR alone, as determined using an MTT assay. Flow cytometric analysis revealed that germacrone promoted cell apoptosis in a dose-dependent manner, whilst treatment with germacrone plus ADR enhanced the apoptotic effect synergistically. Furthermore, the results from the western blot analysis demonstrated that augmenting ADR treatment with germacrone resulted in a reduction of anti-apoptotic protein expression levels (bcl-2) and enhancement of pro-apoptotic protein expression levels (p53 and bax) in MCF-7/ADR cells compared with the levels achieved by treatment with ADR alone. In addition, germacrone significantly reduced the expression of P-glycoprotein via the inhibition of the multidrug resistance 1 (MDR1) gene promoter. These findings demonstrate that germacrone has a critical role against MDR and may be a novel MDR reversal agent for breast cancer chemotherapy. PMID- 25289069 TI - Protective effect of tanshinone IIA on the brain and its therapeutic time window in rat models of cerebral ischemia-reperfusion. AB - The aims of the present study were to investigate the protective effect of tanshinone IIA on the brain and its therapeutic time window in a rat model of cerebral ischemia-reperfusion. The rat model of cerebral ischemia-reperfusion was established by suture occlusion. In an initial experiment, male Sprague-Dawley (SD) rats were randomly divided into control cerebral ischemia-reperfusion rat model, tanshinone IIA1 (TSA1), tanshinone IIA4 (TSA4), tanshinone IIA6 (TSA6) and tanshinone IIA12 (TSA12) groups (n=8 per group). The rats in the control group were given 4 ml phosphate-buffered saline (PBS) intraperitoneally following suture occlusion. The other groups were respectively treated with 25 mg/kg tanshinone IIA intraperitoneally at 1, 4, 6 and 12 h following the initiation of reperfusion and once a day for a total of three days. The grades of neurologic impairment and volume of cerebral infarction of each group were measured 72 h after suture occlusion. In another experiment, 16 male SD rats were randomly divided into a 6 h reperfusion group and a 24 h reperfusion group following drug administration. The rats in each group were further divided into a control subgroup (4 ml PBS) and a tanshinone IIA subgroup (25 mg/kg). The rats were immediately administered their respective treatments following the establishment of the model. The rats were decapitated 6 and 24 h after the initiation of reperfusion. The expression levels of cytoplasmic thioredoxin (Trx-1) and mitochondrial thioredoxin (Trx-2) in the ischemic penumbra were determined by western blot analysis. The nitric oxide (NO) levels, and total NO synthase (tNOS) and inducible NO synthase (iNOS) activities in the rat blood were measured using a reagent kit. The changes in cerebral blood flow were evaluated by Doppler imaging. The grade of neurological impairment of the TSA1 group was statistically lower than that of the other groups (P<0.05). The cerebral infarction volume results showed that the volumes of infarction in the TSA1 and TSA4 groups were lower than those in the other groups (P<0.05). Tanshinone IIA significantly increased cerebral blood flow compared with that of the control group (P<0.05). Moreover, tanshinone IIA significantly increased the expression levels of Trx-1 and Trx-2 compared with those in the control group (P<0.05). Tanshinone IIA significantly decreased the NO levels and iNOS and tNOS activities compared with those of the control group (P<0.05). However, the iNOS activity in the rats in the 6 h reperfusion group was not statistically significantly different from that of the respective control group (P>0.05). Tanshinone IIA has a protective effect on the cranial nerves when administered during the initial stages of cerebral ischemia. This protective effect is associated with an improvement of cerebral blood flow as well as an increase in anti-oxygen radical and anti-inflammatory activities. PMID- 25289070 TI - Histological aspects of the small intestine under variable feed restriction: The effects of short and intense restriction on a growing rabbit model. AB - The objective of this study was to investigate the effect of seven days of feed restriction (between days 42 and 49) on the morphology of the small intestine in experimental rabbit models. Sixty weaned Hyplus rabbits (35 days old) were included in the experiment and split into three groups of 20 rabbits. The first control group (n=20) received feed ad libitum (ADL group), the second (R1) experimental group (n=20) was fed 50 g feed per rabbit per day and the third (R2) experimental group (n=20) received 65 g feed per rabbit per day. Duodenal samples were collected when the rabbits were aged 49, 56, 63 and 70 days. The mean villus height, crypt depth and small intestine length were measured. Significant interactions (P<0.001) between group and age were identified in the villi height and crypt depths. The maximum mean villus height was found in the R2 group in 56 day-old rabbits (643.14 MUm), while the minimum was found in the ADL group in 49 day-old rabbits (460.29 MUm). The longest (P<0.001) small intestine was measured in the R1 group in 63-day-old rabbits (347.60 cm), while the shortest was measured in the ADL group in 49-day-old rabbits (263.60 cm). The models show that villus height, crypt depth and the length of the small intestine change with the intensity of feed restriction and age. PMID- 25289071 TI - A novel combination of the Arndt endobronchial blocker and the laryngeal mask airway ProSealTM provides one-lung ventilation for thoracic surgery. AB - In this study, the feasibility and performance of the combination of the Arndt endobronchial blocker and the laryngeal mask airway (LMA) ProSealTM in airway establishment, ventilation, oxygenation and lung isolation was evaluated. Fifty five patients undergoing general anesthesia for elective thoracic surgeries were randomly allocated to group Arndt (n=26) or group double-lumen tube (DLT; n=29). Data concerning post-operative airway morbidity, ease of insertion, hemodynamics, lung collapse, ventilators, oxygenation and ventilation were collected for analysis. Compared with group DLT, group Arndt showed a significantly attenuated hemodynamic response to intubation (blood pressure, 149+/-31 vs. 115+/-16 mmHg; heart rate, 86+/-15 vs. 68+/-15 bpm), less severe injuries to the bronchus (injury score, 1.4+/-0.2 vs. 0.4+/-0.1) and vocal cords (injury score, 1.3+/-0.2 vs. 0.6+/-0.1), and lower incidences of post-operative sore throat and hoarseness. Furthermore, the novel combination of the Arndt and the LMA ProSeal showed similar ease of airway establishment, comparable ventilation and oxygenation performance, and an analogous lung isolation effect to DLT. The novel combined use of the Arndt endobronchial blocker and the LMA ProSeal can serve as a promising alternative for thoracic procedures requiring one-lung ventilation. The less traumatic properties and equally ideal lung isolation are likely to promote its use in rapidly spreading minimally invasive thoracic surgeries. PMID- 25289072 TI - Association between the transcriptional levels of Htr-1a and tryptophan hydroxylase-1 in the hippocampus and the antifatigue effects of leucine on rats with postoperative fatigue. AB - Leucine (Leu), a branched-chain amino acid (BCAA), is widely used in clinical practice following severe burns, gastrointestinal surgery, trauma and sepsis. In the present study, the antifatigue effects of BCAAs on a postoperative fatigue (POF) rat model, induced by 70% intestinal resection, were investigated. Leu (16.5 g/l) was administered intraperitoneally at a dose of 18 ml/kg/day. The fatigue level and antifatigue effects of Leu were evaluated by open-field testing on day 1, 3, 5 and 7 after surgery. In addition, mRNA specimens were extracted and measured using a quantitative polymerase chain reaction method. The open field test results indicated that Leu exhibited a significant antifatigue effect. The total distance travelled and the number of times the rats passed from the outermost grids of an open-top case were greatly improved in the Leu treatment group when compared with the POF model group. With the exception of the normal group, the mRNA expression levels of Htr-1a exhibited a similar trend in all other groups, reaching a climax on day 3 and 5, while being restored to a normal level on day 7. With regard to the Leu intervention group, the mRNA expression level of Htr-1a decreased significantly on day 3 and 5 following surgery. The mRNA expression levels of tryptophan hydroxylase-1 were unchanged in this short time period; however, the levels were increased gradually in the Leu treatment group. Therefore, Leu exhibited an apparent antifatigue effect on various 5 hydroxytryptamine-associated genes. PMID- 25289073 TI - Protective effect of Asarum extract in rats with adjuvant arthritis. AB - The aim of the present study was to investigate the protective effect of Asarum extract on rats with adjuvant arthritis (AA) and to determine the underlying mechanism. An AA model was established by injecting Freund's complete adjuvant into the rats. The degree of toe swelling, arthritis index, spleen index, and the expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 were measured. In addition, the underlying molecular mechanism was investigated using murine macrophage-derived RAW 264.7 cells. Asarum extract was found to significantly reduce the severity of arthritis by decreasing hind paw swelling, the arthritis index, the spleen index, and TNF-alpha, IL-1beta and IL-6 expression levels in plasma. In vitro, Asarum extract inhibited the nuclear factor (NF)-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways. These results indicate that Asarum extract may be a therapeutic agent for AA and may exert an anti-inflammatory effect by mediating the NF-kappaB and MAPK signaling pathways. PMID- 25289074 TI - Upregulated expression level of the growth factor, progranulin, is associated with the development of primary Sjogren's syndrome. AB - The aim of the present study was to investigate the expression and effect of progranulin (PGRN) in patients with primary Sjogren's syndrome (pSS). In total, 26 newly diagnosed pSS patients and 26 healthy subjects were enrolled in this study. The serum levels of PGRN and the inflammatory factor, interleukin-6 (IL 6), were detected using ELISA. In addition, the mRNA expression levels of these molecules were detected by quantitative polymerase chain reaction. The serum levels of PGRN and IL-6 in the pSS patients increased significantly compared with the healthy controls (P<0.05). During the remission stages, the levels of PGRN and IL-6 were comparable to those of the healthy controls. The serum level of PGRN in the pSS patients was shown to correlate with that of IL-6 in the pre treatment and post-treatment stages. PGRN was upregulated in the pSS patients, indicating a possible role of PGRN in the pathogenesis and development of pSS. PMID- 25289075 TI - NR4A1 is associated with chronic low-grade inflammation in patients with type 2 diabetes. AB - Type 2 diabetes (T2D) is a common disorder characterized by chronic low-grade inflammation. In the present study, the expression levels of nuclear receptor subfamily 4 group A member 1 (NR4A1) and the correlation with inflammatory cytokine production and free fatty acids (FFAs) in patients with T2D and healthy participants were investigated. NR4A1 expression levels in peripheral blood mononuclear cells (PBMCs) from patients with T2D (n=30) and healthy controls (n=34) were analyzed. In addition, the levels of fasting blood glucose (FBG), fasting plasma insulin (FIN), FFAs, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were analyzed, and the homeostasis model assessment (HOMA) was used to estimate the insulin resistance (IR). Additionally, PBMCs from healthy subjects were cultured with or without 250 MUM palmitic acid (PA). Levels of NR4A1, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the PBMCs were also analyzed. The basal expression levels of NR4A1, TNF-alpha and IL 6 were higher in the T2D patients when compared with the controls. In addition, the levels of FFAs, TG and LDL-C, as well as the HOMA-IR, were higher in T2D patients. Furthermore, NR4A1 expression was demonstrated to positively correlate with the HOMA-IR and the levels of FFAs, TNF-alpha, IL-6, FIN and FBG. Furthermore, 250 MUM PA stimulation was shown to increase NR4A1 expression and the secretion of inflammatory cytokines in the cultured PBMCs. Therefore, increased NR4A1 expression levels are correlated with a chronic low-grade inflammatory state and the disorder of lipid metabolism in patients with T2D. PMID- 25289076 TI - Correlation between mutation of MDR3 gene exon 6 and parenteral nutrition associated cholestasis of preterm infants. AB - The aim of this study was to investigate the association between the mutation of multidrug resistance 3 (MDR3) exon 6 and parenteral nutrition-associated cholestasis (PNAC) in preterm infants. A total of 41 preterm infants with PNAC formed the experimental group, and 56 preterm infants receiving total parenteral nutrition (TPN) for >14 days but without cholestasis formed the control group. Genomic DNA was extracted from peripheral venous blood leukocytes. Polymerase chain reaction was used to amplify exon 6 of the MDR3 gene. The target band of MDR3 gene exon 6 was identified in all blood samples from all cases. We identified five cases with C. 504 C>T heterozygous mutations of exon 6 of the MDR3 gene and 14 cases with C. 504 C>T homozygous mutations in the experimental group. In the control group, we identified seven cases with the C. 504 C>T homozygous mutation and six cases with the C. 504 C>T heterozygous mutation. The distribution of the T/C allele frequency of C. 504 in exon 6 of the MDR3 gene between the experimental group and control group was statistically significant (P<0.05). Further analysis revealed the odds ratio of the T/C allele frequency of the C. 504 mutation in exon 6 of the MDR3 gene between the experimental group and control group to be 0.316. Point mutation C. 485 T>A was detected in one case in the experimental group. The C. 504 C>T and C. 485 T>A MDR3 mutations in exon 6 are possibly responsible for the development of PNAC in infants. C. 504 C>T may not be the only risk factor of neonatal PNAC. In order to further confirm the association between exon 6 of the MDR3 gene and PNAC, a large-sample multicenter study should be carried out. PMID- 25289077 TI - Cardiovascular effects of resveratrol and atorvastatin treatments in an H2O2 induced stress model. AB - Oxidative stress has been implicated in the pathophysiology of several types of cardiovascular disease (CVD). Statins are widely used to inhibit the progression of atherosclerosis and reduce the incidence of CVD. Certain over-the-counter products, including resveratrol, show similar effects to statins and may thus be used in conjunction with statins for the treatment of the majority of patients with CVD. The aim of the present study was to evaluate the effects of atorvastatin, resveratrol and resveratrol + atorvastatin (R+A) pretreatment on myocardial contractions and vascular endothelial functions in the presence of H2O2 as an experimental model of oxidative stress in rats. Four groups were established and referred to as the control, atorvastatin, resveratrol and R+A groups. Atorvastatin (40 mg/kg, per oral) and/or resveratrol (30 mg/kg, intraperitoneal) treatments were administered for 14 days. On the 15th day, the thoracic aortas and hearts of the rats were dissected and placed into isolated organ baths. Vascular responses to cumulative doses of H2O2 (1*10-8-1*10-4 M H2O2) with and without N (G)-nitro-L-arginine methyl ester (L-NAME) incubation were measured. In addition, myocardial electrical stimulation (ES) responses to various H2O2 concentrations (1*10-7-1*10-5 M H2O2) were evaluated. In the control and atorvastatin groups, H2O2 application caused a significant dose-dependent decrease in the ES-induced contractions in the myocardial tissue of rats. In the resveratrol and R+A groups, H2O2 application did not significantly affect myocardial contraction at any dose. In all groups, incubation with L-NAME caused a significant augmentation in the H2O2 response, revealing that this effect was mediated via the vascular endothelium. In conclusion, pretreatment with R+A for CVD appears to be superior to pretreatment with either agent alone. PMID- 25289078 TI - The role of the RhoA/Rho kinase pathway in angiogenesis and its potential value in prostate cancer (Review). AB - Prostate cancer (PCa) remains a major cause of mortality among males in western countries, with little change in mortality rates observed over the past 25 years. Despite recent advances in therapy, treatment options for metastatic castration resistant disease remain limited. In terms of chemotherapy, only the combination of docetaxel and prednisone has been shown to improve survival in these patients, but duration of response to therapy is short. There is a continuing unmet need for new systemic interventions that act either alone or synergistically with chemotherapy in patients with progressive PCa. Angiogenesis plays a critical role in tumor growth and metastasis in PCa. Several strategies have been used to target angiogenesis; however, it is becoming increasingly apparent that current anti-angiogenic therapies frequently achieve only modest effects in clinical settings. The RhoA/Rho kinase (ROCK) pathway plays a crucial role in the process of angiogenesis in PCa, and studies have demonstrated that ROCK inhibitors decrease VEGF-induced angiogenesis and tumor cell growth. However, further research is required to fully elucidate the molecular mechanisms involved in this pathway, and the potential value of modulating these mechanisms in the treatment of PCa. This study reviews the current understanding of the role of the RhoA/ROCK pathway in the process of angiogenesis in PCa, and the potential of this pathway as a therapeutic target in the future. PMID- 25289079 TI - Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. AB - Recurrent respiratory papillomatosis (RRP) is a primary benign disease, which is characterized by papillomatous growth in the respiratory tract. Malignant transformation occurs in only 3-5% of cases, however, local growth of the benign papillomas is interpreted as clinically malignant in a markedly higher proportion of patients. Local surgical or endoscopic interventional debulking or excision is currently the commonly selected treatment method and antiviral therapy is a potential adjuvant approach. However, the long-term management of RRP patients, who commonly require multiple procedures over numerous years, is challenging and the overall therapeutic armamentarium remains unsatisfactory. The administration of systemic bevacizumab treatment in a series of five patients with long histories of RRP, who required repeated local interventions to control papilloma growth is evaluated. Treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was administered at a dose of 5 mg/kg (n=1), 10 mg/kg (n=3) or 15 mg/kg (n=1) intravenously to the five RRP patients, who were clinically classified as exhibiting progressive disease. Endoscopic evaluations were performed prior to the first infusion of bevacizumab and intermittently at variable time points during the course of therapy. Histopathological analyses were performed using pre- and post-treatment papilloma biopsies, including immunohistochemical analyses of VEGF and phosphorylated VEGF receptor (VEGFR)-2 expression. The patients received between three and 16 courses of bevacizumab (median, six courses). The first course was initiated when progression following the previous intervention was observed. An immediate response to bevacizumab treatment was demonstrated in all five RRP patients. While the cumulative number of interventions in the five patients was 18 throughout the 12 months prior to the initiation of bevacizumab treatment, only one patient required interventional treatment due to a malignant transformation during the 12 months following treatment with bevacizumab (18 vs. 1 interventions, P=0.042). Histopathological analyses revealed regressive perivascular edema and normalization of the vascular structure, however, immunohistochemical analyses of the VEGF and phosphorylated VEGFR-2 expression did not demonstrate any changes following therapy. Due to the limited number of alternative treatments, VEGF-targeted therapies may represent a promising novel strategy in the treatment of RRP, which may have the potential to modify the current treatment standards, particularly in patients with poorly accessible papilloma lesions, however, this requires further investigation in clinical trials. PMID- 25289080 TI - Priapism as the initial symptom of primary penile lymphoma: A case report. AB - Primary penile lymphoma presenting with priapism as the initial symptom is extremely rare. In total, <10 cases have been previously reported. The diagnosis can be difficult and patients often develop metastasis. The current study reports the case of a 48-year-old male, who presented with a one-month history of painless priapism. On admission to Yantai Yuhuangding Hospital Affiliated to Qingdao University (Yantai, China), examination revealed an erect penis, enlarged lymph nodes in the bilateral inguinal and swelling in the thighs. A biopsy was taken from the right inguinal lymph node and the pathological diagnosis confirmed a diffuse large B-cell type of non-Hodgkin's lymphoma, while an enhanced computed tomography scan of the chest revealed evidence of the invasion of malignant lymphoma cells. Priapism disappeared two days following the completion of the first cycle of chemotherapy with the E-CHOP regimen (cyclophosphamide, vincristine, prednisone, epirubicin and etoposide); however, evidence of brain metastases was observed one month later, which was confirmed by magnetic resonance imaging. The patient received cranial radiotheraphy and systemic treatment for cerebral edema. The patient did not respond well to treatment and succumbed to the disease three months following the initial diagnosis of lymphoma. Lymphoma may be difficult to diagnose, depending on the initial symptoms; therefore, the patient history must be carefully assessed so as to determine an early diagnosis and prevent metastasis, thus improving the prognostic outcome. PMID- 25289081 TI - A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps. AB - A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP status was classified according to the number of methylated genes and was correlated with the clinicopathological features, including the concomitant polyps in and around the tumors. The frequency of aberrant methylation in each CRC showed a bimodal pattern, and the CRCs were classified as CIMP-high (CIMP-H), CIMP-low (CIMP-L) and CIMP-negative (CIMP-N). CIMP-H was associated with aberrant methylation of MLH1 (P=0.005) and with an improved recurrence-free survival (RFS) rate following curative resection compared with CIMP-L/N (five-year RFS rate, 93.8 vs. 67.1%; P=0.044), while CIMP N tumors were associated with frequent distant metastases at diagnosis (P=0.023). No concomitant serrated lesions were present in the tumors, whereas conventional adenoma was contiguous with 11 (10.6%) of 104 CRCs, including four CIMP-H CRCs. CIMP-H was classified in CRCs by a novel CIMP marker panel and the presence of concomitant tumors revealed that certain CIMP-H CRCs may have arisen from conventional adenomas. PMID- 25289082 TI - BRAF-activated long non-coding RNA contributes to cell proliferation and activates autophagy in papillary thyroid carcinoma. AB - Long non-coding RNAs (lncRNAs) are novel regulators in cancer biology. BRAF activated lncRNA (BANCR) is overexpressed in melanoma and has a potential functional role in melanoma cell migration. However, little is known about the role of BANCR in the development of papillary thyroid carcinoma (PTC). In the present study, BANCR expression was examined in six pairs of PTC and matched adjacent normal tissues. The results revealed that BANCR levels were significantly higher in the PTC tissues and PTC IHH-4 cells compared with the normal controls. Knockdown of BANCR in the IHH-4 cells inhibited proliferation and increased apoptosis of the cells in vitro. Further investigation of the underlying mechanisms revealed that BANCR markedly activated autophagy. Overexpression of BANCR inhibited apoptosis in the IHH-4 cells, whereas inhibition of autophagy stimulated apoptosis in the BANCR-overexpressed cells. BANCR overexpression also increased cell proliferation and the inhibition of autophagy abrogated BANCR overexpression-induced cell proliferation. In addition, the overexpression of BANCR resulted in an increase in the ratio of LC3-II/LC3-I, a marker for autophagy, while the knockdown of BANCR decreased the ratio of LC3 II/LC3-I. These results revealed that BANCR expression levels are upregulated in PTC. Additionally, BANCR increases PTC cell proliferation, which could activate autophagy. PMID- 25289083 TI - PKM2 regulates Gli1 expression in hepatocellular carcinoma. AB - Hedgehog (Hh) signaling and the pyruvate kinase isoenzyme M2 (PKM2 or M2-PK) are often involved in tumorigenesis and growth. Aberrant activation of Hh signaling is found in a variety of malignancies. In tumor cells, PKM2 determines whether glucose is used for the synthesis of cellular building blocks or the production of lactate for energy regeneration; it associated with the Warburg effect. Gli1 is a downstream molecule of the Hh signaling pathway; however, the association between Hh signaling and PKM2 is not well understood. In the present study, it was identified that PKM2 and Gli1 expression levels were significantly elevated in hepatocellular carcinoma (HCC) compared with para-carcinoma. In vitro study revealed that overexpression of PKM2 in HepG2 cells upregulated the transcription of Gli1, while the ablation of PKM2 by shRNA caused the downregulation of Gli1 gene expression. Gli1 transcription could be rescued by PKM2. Overall, these findings suggest that PKM2 is a regulator of Gli1 gene expression in HCC, and may contribute to tumorigenesis through Gli1. PMID- 25289084 TI - Paraneoplastic secondary hypertension due to a renin-secreting desmoplastic small round cell tumor: A case report. AB - Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy with a poor outcome that occurs in adolescents and young adults; <200 cases of DSRCT have been reported. Renin-producing tumors are also rare and cases of extrarenal renin-producing tumors are even rarer. The present study describes the case of a 20-year-old male that was diagnosed with DSRCT and presented with severe hypertension and hypokalemia, as well as metabolic alkalosis. The plasma renin activity (PRA) level was identified to be markedly elevated (normal range in standing and supine positions, 1.3-4.0 ng/ml/h and 0.15-2.33 ng/ml/h, respectively) and the plasma aldosterone level was also increased (normal range in standing and supine positions, 4.0-31.0 ng/dl and 1.0-1.6 ng/dl, respectively). The symptoms of the patient were consistent with the renin secreting tumor triad, which comprises hypertension, hypokalemia and elevated PRA. Paraneoplastic syndromes must always be considered in cancer patients exhibiting unusual clinical findings, despite their rarity. The current patient was diagnosed with paraneoplastic secondary hypertension due to the presence of disseminated renin-secreting DSRCT. The patient was treated with the VAC/IE regimen (vincristine, adriamycin, cyclophosphamide, ifosfamide and etoposide) for six cycles. Following this treatment, the serum renin and aldosterone levels fell to within the normal range and the patient's blood pressure was normalized without antihypertensive medication. Although an immunohistochemical evaluation of renin was not conducted as the sample size was inadequate, the present study demonstrated that the tumor had produced renin. The biosynthesis of renin was identified by the presence of mRNA that coded for the renin precursor, which was observed in the ascites of the patient. The current study describes, to the best of our knowledge, the first reported case of paraneoplastic secondary hypertension in a patient presenting with a renin-producing DSRCT. PMID- 25289085 TI - Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells. AB - Obesity, diabetes and insulin resistance are marked risk factors that promote the development of type I endometrial cancer. Previous studies have demonstrated that insulin-like growth factor 1 (IGF-1) and IGF-2 promote cell proliferation in endometrial cancer cells, while metformin reverses this effect and inhibits cell proliferation. However, the effects of metformin on the regulation of the IGF signaling pathway are unclear. The aim of this study was to investigate the regulation of IGF signaling by metformin in endometrial cancer cells, and to determine the effects of metformin combined with IGF-1 receptor (IGF-1R) inhibitor on cell proliferation and apoptosis. Cell proliferation was assessed following exposure of Ishikawa and HEC-1B endometrial cancer cell lines to metformin and/or the IGF-1R inhibitor, PPP. Apoptosis was assessed by TdT mediated dUTP nick end labeling assay. Metformin was observed to downregulate IGF 1R and upregulate IGF binding protein-1 (IGFBP-1) mRNA and protein expression, while compound C, an adenosine monophosphate protein kinase inhibitor, reversed this effect. Metformin administered with PPP inhibited endometrial cancer cell proliferation to a greater degree than treatment with either agent alone. At high concentrations (1 or 2 mM), metformin induced apoptosis in endometrial cancer cells. Metformin combined with IGF-1R axis inhibitors may act synergistically to kill tumor cells, as metformin was shown to delay and prevent IGF-1R feedback. In conclusion, this study supported the results of animal studies and subclinical studies, demonstrating the feasibility of metformin combined with IGF-1R axis inhibitors in the treatment of endometrial cancer. PMID- 25289086 TI - A dual-targeting liposome conjugated with transferrin and arginine-glycine aspartic acid peptide for glioma-targeting therapy. AB - The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy. PMID- 25289088 TI - Picropodophyllin and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells. AB - Resistance is one limitation of sorafenib in the treatment of hepatocellular carcinoma (HCC). Insulin-like growth factor-1 receptor (IGF-1R) is involved in cancer cell proliferation. To assess the potential synergistic antitumor effects of picropodophyllin (PPP), an IGF-1R inhibitor, HLF and PLC/PRL/5, HCC cells were treated with PPP alone or PPP in combination with sorafenib, a multikinase inhibitor. Normal human umbilical vein endothelial cells (HUVECs) were also used to analyze the antiangiogenic effects of the drugs. HCC cells and HUVECs were cultured on 96-well plates, and then treated with PPP, with and without the addition of sorafenib. A 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) 2-(4-sulfophenyl)-2H-tetrazolium inner salt assay and hematoxylin and eosin staining were then performed 48 h later. The HCC cells were also analyzed using scratch assays and hematoxylin and eosin staining after 48 h. The proliferation of HLF, PLC/PRF/5 and HUVEC cells was suppressed by the combination of 0.2 MUM PPP and 3 MUM sorafenib more effectively than by 10 MUM sorafenib alone. The motility of HLF and PLC/PRF/5 cells was also suppressed to a greater extent with the combination of PPP at 0.2 MUM and sorafenib at 3 MUM than with sorafenib at 10 MUM alone. The cells that had been treated with 0.2 MUM PPP and 3 MUM sorafenib also exhibited pyknotic nuclei, which is characteristic of apoptosis. In conclusion, PPP enhanced sorafenib-mediated suppression of proliferation and motility in HCC cells. Therefore, the combination of PPP and sorafenib may exert antitumor and antiangiogenic effects. PMID- 25289087 TI - Evaluating the various phases of cisplatin-induced emesis in rats. AB - Use of cisplatin as a chemotherapeutic agent causes acute and delayed emesis. Kaolin, saccharin solution and normal feed consumption have been evaluated as an index of cisplatin-induced emesis in rats; however, the most preferable of these methods for evaluating the various phases of emesis remains unclear. In the current study, kaolin, saccharin solution and normal feed consumption following cisplatin administration (6 mg/kg intraperitoneally) were simultaneously investigated in rats. Kaolin consumption increased significantly following cisplatin administration and was attenuated by granisetron administration 0-24 h following the injection. Saccharin solution consumption, however, decreased significantly 0-48 h following cisplatin administration, however, was attenuated by administration of granisetron within 0-24 h only. A reduced intake of normal feed was observed in the control group and was reversed by granisetron within the 0-72 h period. The present study indicates that kaolin consumption may be evaluated as an index of cisplatin-induced acute emesis and saccharin solution consumption may be evaluated as an index of delayed emesis, while normal feed consumption as an indicator of anorexia nervosa may be suitable to evaluate all phases of emesis and serve as an indicator of quality of life. PMID- 25289089 TI - Laparoscopic heminephrectomy of a horseshoe kidney with giant renal cell carcinoma: A case report. AB - A 72-year-old male was diagnosed incidentally with a 7-cm renal tumor in the right moiety of a horseshoe kidney during a routine physical examination, and was treated with laparoscopic radical heminephrectomy. The surgical time was 153 min and the estimated blood loss was 150 ml. The patient was discharged on post operative day eight with no complications. Computed tomography angiography is desirable prior to surgery for the evaluation of the anatomical variations of horseshoe kidneys, and a pre-operative understanding is necessary for achieving reliable vascular control. In conclusion, the present technique is safe and effective for this complex clinical condition. PMID- 25289090 TI - Improved ataxia telangiectasia mutated kinase inhibitor KU60019 provides a promising treatment strategy for non-invasive breast cancer. AB - It has previously been reported that KU60019, as a highly effective radiosensitizer, inhibits the DNA damage response and blocks radiation-induced phosphorylation of key ataxia telangiectasia mutated targets in human glioma cells. The present study investigated whether KU60019 affects cell physiological activities and strengthens the efficacy of doxorubicin-induced DNA damage. It was demonstrated that the compound suppressed the proliferation of MCF-7 cells and significantly increased chemosensitization. In addition, KU60019 (without doxorubicin) inhibited MCF-7 cell motility and invasion, potentially by acting on the phosphorylated-Akt and E-cadherin signaling pathways. Although the majority of MCF-7 cells were arrested at the G1/S phase following treatment with KU60019, the combination of the two compounds did not result in such a marked effect on the cell cycle. In conclusion, KU60019 is a potent chemosensitizer in combination with doxorubicin, therefore, it may provide a promising strategy for non-invasive breast cancer. PMID- 25289092 TI - Electron microscopic analysis of an angiosarcoma of the thyroid from a non-Alpine endemic goiter region: A case report and brief review of the literature. AB - Angiomatoid tumors of the thyroid gland are rare endocrine neoplasms, which exhibit an aggressive behavior. Angiosarcomas of the thyroid are generally reported from the European Alpine region and have a histogenesis that has been under debate for a number of years. The current study presents a rare case of angiosarcoma of the thyroid in a 62-year-old Turkish female. The patient had a 10 year history of goiter and was from the Black Sea region, an endemic goiter region of Turkey. The patient was not taking any medication at the time of admission and swelling had been observed on the right side of the neck throughout the previous few months. Thyroid function tests, which analyzed the levels of thyroid-stimulating hormone, thyroxine and triiodothyronine, were within the normal limits, however, the histopathological findings were consistent with an angiosarcoma of the thyroid. The patient rejected the complementary surgery and chemotherapy options, and is currently disease-free (as per the 15-month follow up). The current study describes a case of angiosarcoma that was characterized by Weibel-Palade bodies, and light microscopy and immunohistochemical findings, as well as an endothelial origin, which was demonstrated via electron microscopy. To the best of our knowledge, this is the first reported case of angiosarcoma of the thyroid in a patient from Turkey to be validated by electron microscopy. Furthermore, this case is one of the few reported thyroid angiosarcoma cases in a non-Alpine region. PMID- 25289091 TI - Knockdown of phosphodiesterase 4D inhibits nasopharyngeal carcinoma proliferation via the epidermal growth factor receptor signaling pathway. AB - Phosphodiesterase 4D (PDE4D) is a subtype of metallohydrolases, and it has been reported that PDE4D functions as a proliferation promoting factor in certain types of cancer, including head and neck cancer. The present study first investigated the function of PDE4D in nasopharyngeal carcinoma (NPC). Western blot analysis was applied to detect PDE4D expression in NPC samples and cells. A lentiviral infection technique was used to stabilize the knockdown of PDE4D, which was subsequently examined in vitro and in vivo. The results showed that PDE4D was overexpressed in the NPC tissues and cells. Knockdown of PDE4D inhibited the growth of CNE2 and 5-8F, inducing cell cycle arrest in the G0/G1 phase in CNE2. These effects could be reversed by epidermal growth factor (EGF) stimulation. Furthermore, knockdown of PDE4D significantly inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and AKT. The results were further validated in an NPC xenograft in nude mice. In conclusion, this study demonstrated that PDE4D may function as a proliferation promoting factor in NPC, by affecting the EGFR/PI3K/AKT signaling pathway. Therefore, the targeting of PDE4D may be a rational strategy in the treatment of NPC. PMID- 25289093 TI - Primary squamous cell carcinoma of the stomach: A case report. AB - Pure squamous cell carcinoma (SCC) of the stomach is rare and resembles SCC arising elsewhere in the body. The pathogenesis of SCC remains unclear and controversial. At present, <100 cases of primary SCC of the stomach have been reported. The current study presents a case of SCC of the stomach in a 61-year old male. Total gastrectomy was performed and a 7.0*6.7*4.5-cm tumor with a superiorly located ulcer was identified in the cardia. Upon histological examination, a moderately-differentiated SCC was observed. Tumor cells extended to the serosa, and the perigastric regional lymph node was also involved. No evidence of human papillomavirus (HPV) or Epstein-Barr virus (EBV) infection was identified using a DNA microarray and in situ hybridization, respectively. A post operative computed tomography scan four months after the gastrectomy revealed tumor recurrence and dissemination of the tumor to the jejunum and pancreas. The patient succumbed to the disease six months later despite the administration of low-dose adjuvant 5-fluorouracil/cisplatin chemotherapy. PMID- 25289094 TI - Knockdown of DNA methyltransferase-1 inhibits proliferation and derepresses tumor suppressor genes in myeloma cells. AB - DNA methyltransferases (including DNMT1, DNMT3A and DNMT3B), catalyze the transfer of methyl groups from S-adenosyl-l-methionine to cytosine position 5; this methylation in promoter regions silences gene expression. In addition, DNMT1 plays a critical role in the maintenance of genomic DNA methylation during DNA replication. In the present study, silencing of DNMT1 with siRNA was performed in RPMI-8226 human multiple myeloma (MM) cells, and the impact on gene methylation status and proliferation of the cells was analyzed. Upon DNMT1 downregulation, proliferation decreased significantly compared with that in the control, non transfected cells. The expression of B-cell lymphoma 2 and nuclear factor kappaB proteins was also significantly reduced. Furthermore, nested methylation-specific polymerase chain reaction revealed that methylation of the tumor suppressor genes, suppressor of cytokine signaling 1 and p16, was significantly reduced upon DNMT1 knockdown. Our results suggest that DNMT1 silencing may be a promising strategy to consider during development of novel MM treatment strategies. PMID- 25289095 TI - Magnetic resonance imaging of intracranial hemangiopericytoma and correlation with pathological findings. AB - The present study aimed to evaluate the radiological and pathological features of intracranial hemangiopericytoma, and improve the understanding of this tumor. A retrospective analysis of radiological and pathological features of five cases of intracranial hemangiopericytoma was conducted between 2006 and 2012 in the Second Xiangya Hospital of Central South University. A total of five cases (three males and two females; aged 37-60 years) were enrolled. Magnetic resonance imaging revealed that the lesions were lobulated with iso-intensity T1-weighted image signals and slightly long T2-weighted image signals. Cystic degeneration, necrosis and flow void were observed. The case with the lesion located under the tentorium cerebelli exhibited compression of the fourth ventricle with lateral ventricle dilatation hydrocephalus. In all cases, the solid section of the lesion was markedly enhanced following injection of the contrast agent, and intratumoral vessels were observed. No case exhibited the dural tail sign. Immunohistochemical examination revealed positive expression of cluster of differentiation 34(CD34), vimentin and CD99, and negative expression of epithelial membrane antigen, S100 and glial fibrillary acidic protein. Proliferating cell nuclear antigen Ki-67 immunohistochemical staining revealed that <5% of cells expressed Ki-67 in two cases and 5-10% of cells expressed Ki-67 in three cases. In conclusion, intracranial hemangiopericytoma exhibits certain distinctive characteristics in radiological examination, allowing for improved diagnosis. However, pathological examination is required for confirmation. PMID- 25289096 TI - Stanniocalcin 2 expression predicts poor prognosis of hepatocellular carcinoma. AB - Previous studies have shown that the expression level of stanniocalcin 2 (STC2) is associated with tumor progression. However, to date, the association between STC2 and clinicopathological factors in hepatocellular carcinoma (HCC) has not been investigated. The clinical significance of STC2 was investigated in 30 fresh HCC samples using western blot analysis and in 240 HCC tissues using immunohistochemical analysis. The level of STC2 in cancerous tissue was higher than in the matched non-cancerous tissues. Using immunohistochemistry, the STC2 positive group exhibited a higher incidence of lymph node metastasis and venous invasion compared with the STC2-negative group. Kaplan-Meier survival analysis revealed that the positive expression of STC2 correlated with poor overall survival (OS) and disease-free survival of HCC patients (P<0.01). STC2 expression was observed to be an independent prognostic factor for OS in HCC patients by multivariate analysis (hazard ratio, 2.39; 95% confidence interval, 1.04-5.89; P=0.013). These data suggest that STC2 expression may be a useful indicator of poor prognosis in HCC patients. PMID- 25289097 TI - Rapidly growing and ulcerating metastatic renal cell carcinoma of the lower lip: A case report and review of the literature. AB - Renal cell carcinomas (RCCs) have a tendency to metastasize at an early stage, therefore, the patients frequently exhibit metastatic disease at the time of diagnosis. Common locations for the metastases are adjacent organs and abdominal lymph nodes; however, occasionally metastasis to the peripheral organs may be the initial clinical symptom. The 71-year-old male patient in the current case suffered from radioresistant and aggressively behaving RCC metastasis in the mandible and lower lip, which was successfully managed by surgical resection. RCC metastasis to the facial area is considered to be uncommon based on a review of the existing literature. RCC are somewhat radioresistant and therefore, palliative surgery must be considered when treating patients with this metastatic disease. PMID- 25289098 TI - Late relapse of non-seminomatous testicular cancer during treatment of multiple sclerosis with interferon beta-1a: A case report. AB - Germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes. The present study reports a patient diagnosed with non-seminomatous testicular cancer, stage IB, with a good risk prediction according to the International Germ Cell Cancer Collaborative Group classification. The patient received chemotherapy with bleomycin, etoposide and cisplatin, and achieved complete remission. Eleven years later, while receiving treatment with interferon beta-1a for multiple sclerosis, the patient developed a relapse of the original cancer in the lungs and lymph nodes. The majority of GCTs relapse within the first two years of treatment, while 2-4% of patients can present with late relapses. There is no clear established association between multiple sclerosis and testicular cancer; we present the hypothesis that the inmunosupressor treatment that was administered for the multiple sclerosis promoted the cancer relapse. PMID- 25289099 TI - MicroRNA-7 sensitizes non-small cell lung cancer cells to paclitaxel. AB - Paclitaxel (PTX) is the front-line chemotherapeutic agent against human non-small cell lung cancer (NSCLC). However, its therapeutic efficacy is restricted by the increasing frequency of chemotherapeutic resistance in NSCLC. Accumulating evidence has shown the potential role of microRNAs (miRNAs) in the chemotherapeutic sensitivity of cancer cells. Previously it was reported that microRNA-7 (miR-7) acts as an important tumor suppressor in NSCLC. Therefore, the present study was conducted to determine the regulatory role of miR-7 in PTX chemotherapy for NSCLC. Four NSCLC cell lines were used to analyze the correlation of the PTX-sensitivity and endogenoaus miR-7 expression. miR-7 expression was up- and downregulated using miR-7 mimics and inhibitors respectively, and the role of miR-7 in sensitizing NSCLC cells to PTX was assessed by cell viability and apoptosis assays. The molecular mechanism of PTX sensitivity was determined by quantitative polymerase chain reaction and western blotting. It was found that the sensitivity of NSCLC cells to PTX was dependent on endogenous miR-7. Upregulation of miR-7 enhanced the PTX-sensitivity of NSCLC cells by suppressing cell proliferation and promoting cell apoptosis, while the inhibition of miR-7 abrogated the antiproliferative proapoptotic effects of PTX. Pretreatment of miR-7 mimics enhanced the PTX-mediated downregulation of epidermal growth factor receptor (EGFR) in NSCLC cells. These results have identified miR-7 as a potential EGFR-targeting sensitizer in PTX therapy. These data may facilitate the development of novel chemotherapeutic approaches for NSCLC. PMID- 25289100 TI - Colon cancer metastasis to mediastinal lymph nodes without liver or lung involvement: A case report. AB - Colon cancer is the second most common type of cancer in females and the third in males, worldwide. The most common sites of colon cancer metastasis are the regional lymph nodes, liver, lung, bone and brain. In this study, an extremely rare case of colon adenocarcinoma with extensive metastasis to the mediastinal lymph nodes without any other organ involvement is presented. A 44-year-old Caucasian male presented with abdominal pain, a change in bowel habits, melena and weight loss. Colonoscopy revealed a large friable, ulcerated, circumferential mass in the ascending colon. Biopsies were consistent with the diagnosis of invasive moderately differentiated adenocarcinoma. Subsequently, right colon resection was performed, and pathological analysis revealed moderately differentiated adenocarcinoma of the right colon with extensive regional lymph node involvement. Computed tomography (CT) scans of the chest, abdomen and pelvis were performed preoperatively as part of routine staging for colon cancer. No liver or lung pathology was identified; however, multiple pathologically enlarged mediastinal lymph nodes were observed. Endoscopic ultrasound with fine needle aspiration of the largest mediastinal lymph node, which measured 5.2*3.5 cm on CT scans, was performed. The pathology was again consistent with the diagnosis of metastatic colorectal primary adenocarcinoma. At present, no optimum treatment has been identified for metastatic colon cancer to the mediastinal lymph nodes. The patient in the current case received chemotherapy with folinic acid, fluorouracil and oxaliplatin (FOLFOX), as well as with bevacizumab. Initial follow-up CT scans of the chest revealed a positive response to treatment. Physicians, in particular, radiologists, must consider the mediastinum during the first evaluation and further follow-up of patients with colorectal carcinoma even in the absence of metastasis. PMID- 25289101 TI - MicroRNA and gene networks in human diffuse large B-cell lymphoma. AB - Molecular biologists have collected considerable data regarding the involvement of genes and microRNAs (miRNAs) in cancer. However the underlying mechanisms of cancer with regard to genes and miRNAs remain unclear. The aim of the present study was to evaluate diffuse large B-cell lymphoma (DLBCL) and construct regulatory networks of genes and miRNAs to gradually reveal the underlying mechanisms of DLBCL development. The first differential expression network that is presented is an experimentally validated network of miRNAs and genes. This network presents known biological regulatory associations among miRNAs and genes in the human body. The second network is a DLBCL differential expression network. Differentially expressed gene and miRNA data regarding DLBCL were collected and, based on the first network and the differentially expressed data, the second network was inferred, which demonstrates the irregular regulatory associations that may lead to the occurrence of DLBCL. The third network is a DLBCL-associated network. This network is comprised of non-differentially expressed genes and miRNAs that contribute to numerous DLBCL processes. The similarities and differences among the three networks were extracted and compared to distinguish key regulatory associations; furthermore, important signaling pathways in DLBCL were identified. The present study partially clarified the pathogenesis of DLBCL and provided an improved understanding of the underlying molecular mechanisms, as well as a potential treatment for DLBCL. PMID- 25289103 TI - Comparison of pemetrexed plus cisplatin with gemcitabine plus docetaxel in refractory/metastatic osteosarcoma: Clinical outcomes from a retrospective database monitored in a single institute. AB - The prognosis for patients with relapsed/metastatic osteosarcoma is poor and the optimal treatment strategy remains to be refined. Whilst gemcitabine plus docetaxel combination treatment has already been demonstrated to have certain promising results in the treatment of osteosarcoma, the use of pemetrexed, a multi-targeted antifolate, remains controversial. In the present study, a retrospective investigation was conducted to evaluate the toxicity and efficacy of the pemetrexed plus cisplatin combination in relapsed/metastatic osteosarcoma. Comparison of this treatment with that of the gemcitabine plus docetaxel combination was also conducted. Clinical data from 39 patients suffering from refractory/metastatic osteosarcoma between January 2005 and May 2011 were reviewed retrospectively. Of these patients, 21 were administered the gemcitabine plus docetaxel combination, and 18 were provided the pemetrexed plus cisplatin combination. Treatment was continued until the occurrence of disease progression or unacceptable toxicity. In the gemcitabine plus docetaxel group, the overall response rate and disease control rate were found to be 9.5 and 28.5% respectively, compared with 5.5 and 33.3% respectively in the pemetrexed plus cisplatin group. The median progression-free survival (PFS) time was found to be 1.8 months for both the gemcitabine plus docetaxel and pemetrexed plus cisplatin groups. The median overall survival (OS) time was 6 months in the gemcitabine plus docetaxel group and 7 months in the pemetrexed plus cisplatin group. No statistically significant differences were recognized between the overall response rates, disease control rates, PFS times and OS times in the two groups. The two combinations appeared to be well tolerated. However, the incidence of grade 3/4 thrombocytopenia and leucopenia was higher in the gemcitabine plus docetaxel group than in the pemetrexed plus cisplatin group. The present study clearly demonstrated that both chemo-combinations were well-tolerated and exerted antitumor activity in patients with refractory/metastatic osteosarcoma. However, with regard to grade 3/4 toxicity, the pemetrexed plus cisplatin chemotherapy appears to be better tolerated. PMID- 25289102 TI - A rare case of primary chondrosarcoma arising from the sternum: A case report. AB - The current study reports a case of an extremely rare tumor that presented in an uncommon location, which was successfully treated via radical resection and reconstruction. A 37-year-old female, with no notable medical history, with the exception of a cesarean delivery, was admitted to The First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) due to pain and a lump of the anterior chest wall. The mass was identified on the manubrium sterni and was not tender on palpation. A chest computed tomography (CT) scan reconstruction identified the abnormal mass on the manubrium sterni (size, 5*4 cm in diameter) and positron emission tomography-CT interpretation strongly indicated a type of well-differentiated malignant tumor, such as a giant cell tumor. An aspiration needle biopsy was not conducted, however, the patient underwent tumor radical resection and sternal reconstruction using steel wire and titanium mesh. Histopathological examination of the surgical specimen determined the diagnosis of chondrosarcoma. A postoperative chest X-ray revealed that the sternal defect had repaired well, therefore, this procedure may be highly beneficial in future for repairing defects in the sternum. PMID- 25289104 TI - Elucidating the correlation between treatment with tyrosine kinase inhibitors and mean platelet volume in patients with metastatic renal cell cancer. AB - Patients with cancer are at increased risk of thrombosis. Additionally, an increased mean platelet volume (MPV) has been demonstrated to be associated with thromboembolism. Tyrosine kinase inhibitors (TKIs) may modulate the activation of systemic coagulation in cancer patients, rendering them more susceptible to thromboembolism. The aim of the current study was to investigate the association between antiangiogenic TKIs and MPV. A total of 45 patients with metastatic renal cell carcinoma (RCC), who were treated with TKIs and were patients at the Akdeniz University Hospital and Afyon Kocatepe University Ahmet Necdet Sezer Research and Practice Hospital, were retrospectively reviewed. The results prior to treatment and after three months for the MPV values and platelet levels were evaluated. The MPV values increased following the treatment with TKIs; however, no statistically significant difference was observed between the baseline and three month values (P=0.286). Conversely, a significant decrease was observed in the platelet levels following treatment (P=0.005). Treatment with TKIs in patients with metastatic RCC caused a modest increase in MPV, which is an indicator of thrombocytic reactivity; however, further studies are required to validate these results. PMID- 25289105 TI - Extranodal natural killer/T-cell lymphoma, nasal type, involving the skin, misdiagnosed as nasosinusitis and a fungal infection: A case report and literature review. AB - The present study reports a case of extranodal natural killer (NK)/T-cell lymphoma, nasal type, involving the skin. The clinical manifestations, pathological characteristics, treatment and prognosis of the case were analyzed to improve the clinical diagnosis and treatment for this disease. The patient was a 56-year-old male, presenting with dark red nodules and plaques that had been visible on the nose for half a year. Based on the skin lesions and histopathological and immunohistochemical examination results, the patient was diagnosed with extranodal NK/T-cell lymphoma, nasal type. This disease has unique histopathological and immunohistochemical features and a high malignancy. The condition tends to be misdiagnosed and has a poor prognosis, but seldom involves the skin. In the present case, only radiotherapy was performed, with no relapse occurring within 6 months. PMID- 25289106 TI - Transarterial chemoembolization combined with sorafenib for advanced hepatocellular carcinoma. AB - Sorafenib has been demonstrated to improve survival rate in patients with advanced hepatocellular carcinoma (HCC); however, the survival benefit remains modest and the response rates remain poor. Transarterial chemoembolization (TACE) may be used for the treatment of advanced HCC with well-preserved liver function and has a high local tumor control rate. We hypothesized that patients with advanced HCC may benefit from the combination of sorafenib with TACE. A retrospective study was conducted involving patients with advanced HCC, who had received at least one TACE session. Patients subsequently received 400 mg sorafenib twice per day and were monitored monthly. A dose reduction from 400 to 200 mg of sorafenib twice per day was permitted. The overall survival and side effects were subsequently followed up. In total, 38 patients were included from April 1st, 2009 to March 31st, 2012. All patients were treated with sorafenib after TACE was performed. As of March 31st, 2013, seven patients remained on sorafenib, and were censored at that time point. The median overall survival time was 12 months (95% confidence interval, 6.3-17.7 months). The sorafenib dose was reduced temporarily in 32 patients (84.2%). The most common toxicities were dermatological adverse effects (94.7%), diarrhea (63.2%) and alopecia (26.3%). The survival benefit of sorafenib combined with TACE for advanced HCC is promising, with no intolerable adverse events, provided that dose adjustment is permitted. PMID- 25289107 TI - Serum and salivary macrophage migration inhibitory factor in patients with oral squamous cell carcinoma. AB - The overexpression of macrophage migration inhibitory factor (MIF) has been identified in a variety of tumors and the investigation of its molecular mechanisms in tumor progression is a key topic of research. The present study aimed to investigate MIF as a potential marker for disease control or recurrence, and to assess the association between serum and salivary MIF and the clinicopathological characteristics of patients with oral squamous cell carcinoma (OSCC). Serum and salivary samples were collected prior to and following the surgical treatment of 50 patients with OSCC. MIF concentrations were assessed by enzyme-linked immunosorbent assay and the adopted level of statistical significance was P<0.05. The results revealed that serum MIF concentrations were significantly reduced following tumor resection in OSCC patients. Furthermore, higher preoperative salivary MIF concentrations were observed in patients with larger tumors and in those who succumbed to the disease. In conclusion, high salivary and serological MIF concentrations were identified in patients with OSCC. Nevertheless, only serological MIF concentrations may be considered as a potential marker for the early detection of OSCC recurrence once the salivary levels, prior and following treatment, do not show any significant differences. PMID- 25289108 TI - Clinicopathological analysis of CD8-positive lymphocytes in the tumor parenchyma and stroma of hepatocellular carcinoma. AB - Tumor-infiltrating lymphocytes may be a manifestation of antitumor immunity. In the present study, hepatocellular carcinoma (HCC) and pericancerous non-tumor liver tissues samples were obtained from 86 surgical patients who had not received preoperative treatment. The cellular expression levels of CD4 and CD8 were immunohistochemically examined in the two tissue groups using tissue microarrays, to evaluate their clinicopathological relevance. Immunohistochemically, CD4 and CD8 T cells were observed in the tumor parenchyma and tumor stroma, and the intensity of CD4 and CD8 immunoreactivity was homogeneous in all HCC samples examined. Morphometrically, the average numbers of CD4- and CD8-positive T cells were significantly increased in the tumor stroma, compared with those in the tumor parenchyma (tumor stroma versus tumor parenchyma: 22+/-3.6 versus 7.4+/-0.9 in CD4, 32.8+/-4.2 versus 16+/-2.5 in CD8; both P<0.01). Furthermore, the average numbers of CD8-positive T cells in the tumor parenchyma and stroma were significantly increased, compared with the average numbers of CD4-positive cells (P<0.05). In addition, in the tumor parenchyma and stroma, the average numbers of CD8 T cells were significantly higher in patients with tumor diameters <=5 cm compared with those in patients with tumor diameters >5 cm (diameter <=5 cm versus diameter >5 cm: 18.1+/-3.3 versus 12.2+/-3.8 in tumor parenchyma, 36.5+/-4.8 versus 21.9+/-8.9 in tumor stroma; both P<0.05). In addition, CD8 expression was significantly enhanced in patients with chronic hepatitis and cirrhosis, compared with paired tumor parenchymal tissues (P<0.01). Furthermore, a significant positive correlation was observed between CD4 and CD8 expression in the tumor parenchyma and stroma (both P<0.001). These observations suggest that tumor parenchyma- or stroma infiltrating CD8 T cells may be involved in HCC tumor diameter control. PMID- 25289109 TI - Prognostic value of serum gamma-glutamyl transferase in unresectable hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization combined with conformal radiotherapy. AB - The detection of gamma-glutamyl transferase (GGT) has previously been reported to be useful in the diagnosis in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the baseline serum GGT levels in patients with intermediate HCC (Barcelona Clinic Liver Cancer stage B) following treatment with transcatheter arterial chemoembolization (TACE) combined with three-dimensional conformal radiotherapy (3DCRT). A total of 154 intermediate HCC patients with Child-Pugh grade A were retrospectively investigated. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold for the GGT serum levels, and univariate and multivariate analyses were used to establish the prognostic factors. The median overall survival (OS) time was 24.3 months. The optimal threshold for GGT was 85 U/L (sensitivity, 75.13%; specificity, 69.81%; and area under the ROC curve, 0.763). The one-, three- and five-year OS rates were 79.9, 49.7 and 17.2%, respectively, for patients with low GGT levels (<=85 U/l) and 52.3, 22.1 and 8.5%, respectively, for patients with high GGT levels (>85 U/l) (P=0.007). The results indicated that the serum GGT level was an independent prognostic factor (hazard ratio=2.32; P=0.007) for OS. Furthermore, in subgroups stratified according to serum alpha-fetoprotein, gross tumor volume and radiation dose, serum GGT was also found to correlate with OS (P<0.05). Therefore, the baseline GGT level may be a significant prognostic factor for intermediate HCC patients with Child-Pugh grade A following TACE combined with 3DCRT. PMID- 25289110 TI - Superficial-type endobronchial metastases from colon cancer: A case report. AB - Certain internal malignancies, including colon cancer, can develop endobronchial metastasis. The present study reports a case of colon cancer with superficial type endobronchial metastases in a 76-year-old male. Chest computed tomography revealed small masses and infiltrates in each lung, with bilateral hilar lymph node swelling. Superficial endobronchial tumors in each of the bronchi were unexpectedly found by bronchoscopic examination. A biopsy specimen obtained from the endobronchial tumor was diagnosed as colon cancer. Superficial-type endobronchial metastasis from colon cancer is extremely rare, however, such metastasis should be considered for patients who have a history of colon cancer. There should be no hesitation in performing a bronchoscopic biopsy as an additional examination. PMID- 25289111 TI - ANXA9 gene expression in colorectal cancer: A novel marker for prognosis. AB - Annexin A9 (ANXA9) is involved with the interaction with membrane phospholipids in a Ca2+-dependent manner. A previous study has shown that ANXA9 expression is associated with bone metastasis in breast cancer, whereas its significance in colorectal cancer (CRC) is unknown. The present study was comprised of 100 patients who underwent surgery for CRC. The correlation between gene expression and the clinical parameters of the patients was assessed. Patients with high ANXA9 expression were statistically susceptible to a relatively worse prognosis, and those with low ANXA9 expression showed improved overall survival compared with those with high expression. In conclusion, the present data suggests that ANXA9 expression is a prognostic factor in CRC patients. PMID- 25289112 TI - Assessment of Radiation doses to Paediatric Patients in Computed Tomography Procedures. AB - BACKGROUND: The use of pediatric CT that had recently emerged as a valuable imaging tool has increased rapidly with an annual growth estimated at about 10% per year. Worldwide, there is a remarkable increase in the number of CT examinations performed. The purposes of this study are to: (i) to measure the radiation dose and estimate the effective doses to pediatric patients during CT for chest, abdomen and brain. MATERIAL/METHODS: A total of 182 patients were investigated. CT scanners that participated in this study are helical CT scanners (64 slices, 16 slices and dual slices). Organ and surface dose to specific radiosensitive organs were estimated by using software from National Radiological Protection Board (NRPB). RESULTS: For all patients, the age was ranged between 1.12 month-10.0 years while the weight was ranged between 5.0 kg to 29.0 kg. The DLP was 320.58 mGy.cm, 79.93 mGy.cm, 66.63 mGy.cm for brain, abdomen and chest respectively. The effective dose was, 2.05, 1.8, 1.08 mSv for brain, abdomen and chest respectively. CONCLUSIONS: The patient dose is independent of CT modality and depends on operator experience and CT protocol. The study has shown a great need for referring criteria, continuous training of staff in radiation protection concepts. Further studies are required in order to establish a reference level in Sudan. PMID- 25289113 TI - Efficient Blockwise Permutation Tests Preserving Exchangeability. AB - In this paper, we present a new blockwise permutation test approach based on the moments of the test statistic. The method is of importance to neuroimaging studies. In order to preserve the exchangeability condition required in permutation tests, we divide the entire set of data into certain exchangeability blocks. In addition, computationally efficient moments-based permutation tests are performed by approximating the permutation distribution of the test statistic with the Pearson distribution series. This involves the calculation of the first four moments of the permutation distribution within each block and then over the entire set of data. The accuracy and efficiency of the proposed method are demonstrated through simulated experiment on the magnetic resonance imaging (MRI) brain data, specifically the multi-site voxel-based morphometry analysis from structural MRI (sMRI). PMID- 25289114 TI - Synergistic Behavior of Tubes, Junctions, and Sheets Imparts Mechano-Mutable Functionality in 3D Porous Boron Nitride Nanostructures. AB - One-dimensional (1D) boron nitride nanotube (BNNT) and 2D hexagonal BN (h-BN) are attractive for demonstrating fundamental physics and promising applications in nano-/microscale devices. However, there is a high anisotropy associated with these BN allotropes as their excellent properties are either along the tube axis or in-plane directions, posing an obstacle in their widespread use in technological and industrial applications. Herein, we report a series of 3D BN prototypes, namely, pillared boron nitride (PBN), by fusing single-wall BNNT and monolayer h-BN aimed at filling this gap. We use density functional theory and molecular dynamics simulations to probe the diverse mechano-mutable properties of PBN prototypes. Our results demonstrate that the synergistic effect of the tubes, junctions, and sheets imparts cooperative deformation mechanisms, which overcome the intrinsic limitations of the PBN constituents and provide a number of superior characteristics including 3D balance of strength and toughness, emergence of negative Poisson's ratio, and elimination of strain softening along the armchair orientation. These features, combined with the ultrahigh surface area and lightweight structure, render PBN as a 3D multifunctional template for applications in graphene-based nanoelectronics, optoelectronics, gas storage, and functional composites with fascinating in-plane and out-of-plane tailorable properties. PMID- 25289115 TI - In vitro degradation behavior of chitosan based hybrid microparticles. AB - The degradation properties of the MPs is important to the long-term benefits of the use of the chitosan (CS) based hybrid MPs in bone tissue-engineering, because the degradation kinetics could affect a multitude of processes within the cell, such as cell growth, tissue regeneration, and host response. The aim of this study was to investigate the degradation of solid, hybrid CS microparticles (MPs), CS-10% calcium phosphate (CaHPO4, w/w), and CS-10% calcium carbonate (CaCO3, w/w) MPs in phosphate buffered solution (PBS) over a 30-week period. The hybrid MPs were synthesized by emulsification technique, cross-linked with 64% sodium tripolyphosphate (TPP), purified and air dried overnight. Each sample had 30 mg of MPs was placed in a glass vial with 9 ml of PBS added and then the vial was closed to prevent evaporation. Every week 4 ml of the incubated solution was removed for sample measurement and all samples were replaced with an equivalent amount of fresh medium. The samples were maintained at 37 degrees C under continuous shaking. The hybrid MPs were measured for pH and calcium release, every week in triplicate. At 0, 5, 10, 15, 20, 25, and 30 weeks, surface and bulk morphology were analyzed with a scanning electron microscope (SEM). The degradation data suggested that the hybrid MPs were stable at least up to 25 week and maintain the physiologically relevant pH. Therefore, we can use these hybrid MPs to apply in the bone tissue engineering applications since they do not degrade within a short period. PMID- 25289116 TI - Hamiltonian Mapping Revisited: Calibrating Minimalist Models to Capture Molecular Recognition by Intrinsically Disordered Proteins. AB - Molecular recognition by intrinsically disordered proteins (IDPs) plays a central role in many critical cellular processes. Toward achieving detailed mechanistic understanding of IDP-target interactions, here we employ the "Hamiltonian mapping" methodology, which is rooted in the weighted histogram analysis method (WHAM), for the fast and efficient calibration of structure-based models in studies of IDPs. By performing reference simulations on a given Hamiltonian, we illustrate for two model IDPs how this method can extrapolate thermodynamic behavior under a range of modified Hamiltonians, in this case representing changes in the binding affinity (Kd) of the system. Given sufficient conformational sampling in a single trajectory, Hamiltonian mapping accurately reproduces Kd values from direct simulation. This method may be generally applied to systems beyond IDPs in force field optimization and in describing changes in thermodynamic behavior as a function of external conditions for connection with experiment. PMID- 25289117 TI - Curcumin Stimulates Proliferation of Spinal Cord Neural Progenitor Cells via a Mitogen-Activated Protein Kinase Signaling Pathway. AB - OBJECTIVE: The aims of our study are to evaluate the effect of curcumin on spinal cord neural progenitor cell (SC-NPC) proliferation and to clarify the mechanisms of mitogen-activated protein (MAP) kinase signaling pathways in SC-NPCs. METHODS: We established cultures of SC-NPCs, extracted from the spinal cord of Sprague Dawley rats weighing 250 g to 350 g. We measured proliferation rates of SC-NPCs after curcumin treatment at different dosage. The immuno-blotting method was used to evaluate the MAP kinase signaling protein that contains extracellular signal regulated kinases (ERKs), p38, c-Jun NH2-terminal kinases (JNKs) and beta-actin as the control group. RESULTS: Curcumin has a biphasic effect on SC-NPC proliferation. Lower dosage (0.1, 0.5, 1 uM) of curcumin increased SC-NPC proliferation. However, higher dosage decreased SC-NPC proliferation. Also, curcumin stimulates proliferation of SC-NPCs via the MAP kinase signaling pathway, especially involving the p-ERK and p-38 protein. The p-ERK protein and p38 protein levels varied depending on curcumin dosage (0.5 and 1 uM, p<0.05). CONCLUSION: Curcumin can stimulate proliferation of SC-NPCs via ERKs and the p38 signaling pathway in low concentrations. PMID- 25289118 TI - Feasibility of bilateral crossing c7 intralaminar screws: a cadaveric study. AB - OBJECTIVE: When the pedicle screw insertion technique is failed or not applicable, C7 intralaminar screw insertion method has been used as an alternative or salvage fixation method recently. However, profound understanding of anatomy is required for safe application of the bilaterally crossing laminar screw at C7 in clinic. In this cadaveric study, we evaluated the anatomic feasibility of the bilateral crossing intralaminar screw insertion and especially focused on determination of proper screw entry point. METHODS: The C7 vertebrae from 18 adult specimens were studied. Morphometric measurements of the mid laminar height, the minimum laminar thickness, the maximal screw length, and spino-laminar angle were performed and cross-sectioned vertically at the screw entry point (spino-laminar junction). The sectioned surface was equally divided into 3 parts and maximal thickness and surface area of the parts were measured. All measurements were obtained bilaterally. RESULTS: The mean mid-laminar height was 13.7 mm, mean minimal laminar thickness was 6.6 mm, mean maximal screw length was 24.6 mm, and mean spinolaminar angle was 50.8+/-4.7 degrees . Based on the measured laminar thickness, the feasibility of 3.5 mm diameter intralaminar screw application was 83.3% (30 sides laminae out of total 36) when assuming a tolerance of 1 mm on each side. Cross-sectional measurement results showed that the mean maximal thickness of upper, middle, and lower thirds was 5.0 mm, 7.5 mm, and 7.3 mm, respectively, and mean surface area for each part was 21.2 mm(2), 46.8 mm(2), and 34.7 mm(2), respectively. Fourteen (38.9%) sides of laminae would be feasible for 3.5 mm intralaminar screw insertion when upper thirds of C7 spino laminar junction is the screw entry point. In case of middle and lower thirds of C7 spino-laminar junction, 32 (88.9%) and 28 (77.8%) sides of laminae were feasible for 3.5 mm screw insertion, respectively. CONCLUSION: The vertical cross sectioned area of middle thirds at C7 spinolaminar junction was the largest area and 3.5 mm screw can be accommodated with 77.8% of feasibility when lower thirds were the screw entry point. Thus, selection of middle and lower thirds for each side of screw entry point in spino-laminar junction would be the safest way to place bilateral crossing laminar screw within the entire lamina. This anatomic study result will help surgeons to place the screw safely and accurately. PMID- 25289119 TI - Preoperative identification of facial nerve in vestibular schwannomas surgery using diffusion tensor tractography. AB - OBJECTIVE: Facial nerve palsy is a common complication of treatment for vestibular schwannoma (VS), so preserving facial nerve function is important. The preoperative visualization of the course of facial nerve in relation to VS could help prevent injury to the nerve during the surgery. In this study, we evaluate the accuracy of diffusion tensor tractography (DTT) for preoperative identification of facial nerve. METHODS: We prospectively collected data from 11 patients with VS, who underwent preoperative DTT for facial nerve. Imaging results were correlated with intraoperative findings. Postoperative DTT was performed at postoperative 3 month. Facial nerve function was clinically evaluated according to the House-Brackmann (HB) facial nerve grading system. RESULTS: Facial nerve courses on preoperative tractography were entirely correlated with intraoperative findings in all patients. Facial nerve was located on the anterior of the tumor surface in 5 cases, on anteroinferior in 3 cases, on anterosuperior in 2 cases, and on posteroinferior in 1 case. In postoperative facial nerve tractography, preservation of facial nerve was confirmed in all patients. No patient had severe facial paralysis at postoperative one year. CONCLUSION: This study shows that DTT for preoperative identification of facial nerve in VS surgery could be a very accurate and useful radiological method and could help to improve facial nerve preservation. PMID- 25289120 TI - Accuracy of pedicle screw insertion using fluoroscopy-based navigation-assisted surgery : computed tomography postoperative assessment in 96 consecutive patients. AB - OBJECTIVE: Two-dimensional fluoroscopy-based computerized navigation for the placement of pedicle screws offers the advantage of using stored patient-specific imaging data in providing real-time guidance during screw placement. The study aimed to describe the accuracy and reliability of a fluoroscopy-based navigation system for pedicle screw insertion. METHODS: A total of 477 pedicle screws were inserted in the lower back of 96 consecutive patients between October 2007 and June 2012 using fluoroscopy-based computer-assisted surgery. The accuracy of screw placement was evaluated using a sophisticated computed tomography protocol. RESULTS: Of the 477 pedicle screws, 461 (96.7%) were judged to be inserted correctly. Frank screw misplacement [16 screws (3.3%)] was observed in 15 patients. Of these, 8 were classified as minimally misplaced (<=2 mm); 3, as moderately misplaced (2.1-4 mm); and 5, as severely misplaced (>4 mm). No complications, including nerve root injury, cerebrospinal fluid leakage, or internal organ injury, were observed in any of the patients. CONCLUSION: The accuracy of pedicle screw placement using a fluoroscopy-based computer navigation system was observed to be superior to that obtained with conventional techniques. PMID- 25289121 TI - Microbiology and epidemiology of infectious spinal disease. AB - OBJECTIVE: Infectious spinal disease is regarded as an infection by a specific organism that affects the vertebral body, intervertebral disc and adjacent perivertebral soft tissue. Its incidence seems to be increasing as a result of larger proportion of the older patients with chronic debilitating disease, the rise of intravenous drug abuser, and the increase in spinal procedure and surgery. In Korea, studies assessing infectious spinal disease are rare and have not been addressed in recent times. The objectives of this study are to describe the epidemiology of all kind of spinal infectious disease and their clinical and microbiological characteristics as well as to assess the diagnostic methodology and the parameters related to the outcomes. METHODS: A retrospective study was performed in all infectious spinal disease cases presenting from January 2005 to April 2010 to three tertiary teaching hospitals within a city of 1.5 million in Korea. Patient demographics, risk factors, clinical features, and outcomes were assessed. Risk factors entailed the presence of diabetes, chronic renal failure, liver cirrhosis, immunosuppressants, remote infection, underlying malignancy and previous spinal surgery or procedure. We comparatively analyzed the results between the groups of pyogenic and tuberculous spinal infection. SPSS version 14 statistical software was used to perform the analyses of the data. The threshold for statistical significance was established at p<0.05. RESULTS: Ninety-two cases fulfilled the inclusion criteria and were reviewed. Overall, patients of tuberculous spinal infection (TSI) and pyogenic spinal infection (PSI) entailed 20 (21.7%) and 72 (78.3%) cases, respectively. A previous spinal surgery or procedure was the most commonly noted risk factor (39.1%), followed by diabetes (15.2%). The occurrence of both pyogenic and tuberculous spondylitis was predominant in the lumbar spine. Discs are more easily invaded in PSI. At initial presentation, white cell blood count and C-reactive protein levels were higher in PSI compared to TSI (p<0.05). Etiological agents were identified in 53.3%, and the most effective method for identification of etiological agents was tissue culture (50.0%). Staphyococcus aureus was the most commonly isolated infective agent associated with pyogenic spondylitis, followed by E. coli. Surgical treatment was performed in 31.5% of pyogenic spondylitis and in 35.0% of tuberculous spondylitis cases. CONCLUSION: Many previous studies in Korea usually reported that tuberculous spondylitis is the predominant infection. However, in our study, the number of pyogenic infection was 3 times greater than that of tuberculous spinal disease. Etiological agents were identified in a half of all infectious spinal disease. For better outcomes, we should try to identify the causative microorganism before antibiotic therapy and make every effort to improve the result of culture and biopsy. PMID- 25289122 TI - Risk factors for delirium after spine surgery in elderly patients. AB - OBJECTIVE: Postoperative delirium is a common complication in the elderly after surgery but few papers have reported after spinal surgery. We analyzed various risk factors for postoperative delirium after spine surgery. METHODS: Between May 2012 and September 2013, 70 patients over 60 years of age were examined. The patients were divided into two groups : Group A with delirium and Group B without delirium. Cognitive function was examined with the Mini-Mental State Examination Korea (MMSE-K), Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS). Information was also obtained on the patients' education level, underlying diseases, duration of hospital stay and laboratory findings. Intraoperative assessment included Bispectral index (BIS), type of surgery or anesthesia, blood pressure, fluid balance, estimated blood loss and duration of surgery. RESULTS: Postoperative delirium developed in 17 patients. The preoperative scores for the MMSE, CDR, and GDS in Group A were 19.1+/-5.4, 0.9+/-0.6, and 3.3+/-1.1. These were significantly lower than those of Group B (25.6+/-3.4, 0.5+/-0.2, and 2.1+/ 0.7) (p<0.05). BIS was lower in Group A (30.2+/-6.8 compared to 35.4+/-5.6 in group B) (p<0.05). The number of BIS <40 were 5.1+/-3.1 times in Group A, 2.5+/ 2.2 times in Group B (p<0.01). In addition, longer operation time and longer hospital stay were risk factors. CONCLUSION: Precise analysis of risk factors for postoperative delirium seems to be more important in spinal surgery because the surgery is not usually expected to have an effect on brain function. Although no risk factors specific to spinal surgery were identified, the BIS may represent a valuable new intraoperative predictor of the risk of delirium. PMID- 25289123 TI - Risk factors associated with poor outcomes in patients with brain abscesses. AB - OBJECTIVE: The purpose of this study was to describe the clinical characteristics, treatment outcomes, and prognostic factors in patients with brain abscesses treated in a single institute during a recent 10-year period. METHODS: Fifty-one patients with brain abscesses who underwent navigation assisted abscess aspiration with antibiotic treatment were included in this study. Variable parameters were collected from the patients' medical records and radiological data. A comparison was made between patients with favorable [Glasgow Outcome Scale (GOS) >=4] and unfavorable (GOS <4) outcomes at discharge. Additionally, we investigated the factors influencing the duration of antibiotic administration. RESULTS: The study included 41 male and 10 female patients with a mean age of 53 years. At admission, 42 patients (82%) showed either clear or mildly disturbed consciousness (GCS >=13) and 24 patients (47%) had predisposing factors. The offending microorganisms were identified in 25 patients (49%), and Streptococcus species were the most commonly isolated bacteria (27%). The mean duration of antibiotic administration was 42 days. At discharge, 41 patients had a favorable outcome and 10 had an unfavorable outcome including 8 deaths. The decreased level of consciousness (GCS <13) on admission was likely associated with an unfavorable outcome (p=0.052), and initial hyperglycemia (>=140 mg/dL) was an independent risk factor for prolonged antibiotic therapy (p=0.032). CONCLUSION: We found that the level of consciousness at admission was associated with treatment outcomes in patients with brain abscesses. Furthermore, initial hyperglycemia was closely related to the long-term use of antibiotic agents. PMID- 25289124 TI - The Effectiveness Evaluation of Helicopter Ambulance Transport among Neurotrauma Patients in Korea. AB - OBJECTIVE: Helicopter ambulance transport (HAT) is a highly resource-intensive facility that is a well-established part of the trauma transport system in many developed countries. Here, we review the benefit of HAT for neurosurgical patients in Korea. METHODS: This retrospective study followed neurotrauma patients who were transferred by HAT to a single emergency trauma center over a period of 2 years. The clinical benefits of HAT were measured according to the necessity of emergency surgical intervention and the differences in the time taken to transport patients by ground ambulance transport (GAT) and HAT. RESULTS: Ninety-nine patients were transferred to a single university hospital using HAT, of whom 32 were taken to the neurosurgery department. Of these 32 patients, 10 (31.3%) needed neurosurgical intervention, 14 (43.8%) needed non-neurosurgical intervention, 3 (9.4%) required both, and 11 (34.4%) did not require any intervention. The transfer time was faster using HAT than the estimated time needed for GAT, although for a relatively close distance (<50 km) without ground obstacles (mountain or sea) HAT did not improve transfer time. The cost comparison showed that HAT was more expensive than GAT (3,292,000 vs. 84,000 KRW, p<0.001). CONCLUSION: In this Korean-based study, we found that HAT has a clinical benefit for neurotrauma cases involving a transfer from a distant site or an isolated area. A more precise triage for using HAT should be considered to prevent overuse of this expensive transport method. PMID- 25289125 TI - Asymptomatic penetration of the oculomotor nerve by a de novo aneurysm associated with severe atherosclerotic stenosis of the supraclinoid internal carotid artery. AB - A 70-year-old woman presented with headaches and recurrent stroke symptoms. During five years, the patient has been treated for cerebral infarction associated with severe atherosclerotic stenosis of the internal carotid artery. Three-year follow-up magnetic resonance angiography showed a tiny de novo aneurysm arising from the distal part of atherosclerotic internal carotid artery. And 5-year follow-up three-dimensional CT angiogram demonstrated a definite aneurysm enlargement as large as requiring treatment. During dissection of aneurysm, the oculomotor nerve was found to be penetrated with the growing de novo aneurysm. The authors report a case of a de novo aneurysm, which resulted from atherosclerotic stenosis of the internal carotid artery at the supraclinoid portion, that was found to be penetrating the oculomotor nerve with no ocular palsy. PMID- 25289126 TI - Leptomeningeal carcinomatosis of gastric cancer misdiagnosed as vestibular schwannoma. AB - Gastric cancer is one of the most common causes of cancer-related death in Asian countries, including Korea. We experienced a case of leptomeningeal carcinomatosis (LC) from gastric cancer that was originally misdiagnosed as vestibular schwannoma based on the similar radiological characteristics. To our knowledge, LC from gastric cancer is very rare. In conclusion, our experience with this case suggests that clinicians should consider the possibility of delayed leptomeningeal metastasis when treating patients with gastric cancer. PMID- 25289127 TI - Acute myelopathy caused by a cervical synovial cyst. AB - Synovial cysts of the cervical spine, although they occur infrequently, may cause acute radiculopathy or myelopathy. Here, we report a case of a cervical synovial cyst presenting as acute myelopathy after manual stretching. A 68-year-old man presented with gait disturbance, decreased touch senses, and increased sensitivity to pain below T12 level. These symptoms developed after manual stretching 3 days prior. Computed tomography scanning and magnetic resonance imaging revealed a 1-cm, small multilocular cystic lesion in the spinal canal with cord compression at the C7-T1 level. We performed a left partial laminectomy of C7 and T1 using a posterior approach and completely removed the cystic mass. Histological examination of the resected mass revealed fibrous tissue fragments with amorphous materials and granulation tissue compatible with a synovial cyst. The patient's symptoms resolved after surgery. We describe a case of acute myelopathy caused by a cervical synovial cyst that was treated by surgical excision. Although cervical synovial cysts are often associated with degenerative facet joints, clinicians should be aware of the possibility that these cysts can cause acute neurologic symptoms. PMID- 25289128 TI - Non-dural-based spinal meningioma : the first case report of a fibrous subtype and a review of the literature. AB - Spinal meningiomas typically adhere to the dura matter. Non-dural based spinal meningiomas are rare and most are clear cell meningiomas. We report here the first case of a fibrous meningioma with non-dural attachment. The patient was a 49-year-old female, who complained of numbness in the legs and a gait disturbance. Magnetic resonance imaging revealed a 1.7*1.4-cm mass in the C7-T1 intra-dural extramedullary space, showing peripheral gadolinium enhancement without a "dural tail sign". A complete microsurgical resection was performed. The mass was covered with a white membrane but was not adhered to the dura, and its appearance was consistent with a neurilemmoma. The histopathological diagnosis was fibrous-type meningioma. The recovery of the patient was uneventful. No surgical complications and no recurrence of the tumor had occurred at the 6-month follow-up. PMID- 25289129 TI - Neurocutaneous melanosis in association with dandy-walker complex with extensive intracerebral and spinal cord involvement. AB - Neurocutaneous melanosis (NCM) is a rare congenital syndrome consisting of benign or malignant melanotic tumors of the central nervous system with large or numerous cutaneous melanocytic nevi. The Dandy-Walker complex (DWC) is characterized by an enlarged posterior fossa with high insertion of the tentorium, hypoplasia or aplasia of the cerebellar vermis, and cystic dilatation of the fourth ventricle. These each two conditions are rare, but NCM associated with DWC is even more rare. Most patients of NCM with DWC present neurological symptoms early in life such as intracranial hemorrhage, hydrocephalus, and malignant transformation of the melanocytes. We report a 14-year-old male patient who was finally diagnosed as NCM in association with DWC with extensive intracerebral and spinal cord involvement. PMID- 25289130 TI - Successful treatment of severe sympathetically maintained pain following anterior spine surgery. AB - Sympathetic dysfunction is one of the possible complications of anterior spine surgery; however, it has been underestimated as a cause of complications. We report two successful experiences of treating severe dysesthetic pain occurring after anterior spine surgery, by performing a sympathetic block. The first patient experienced a burning and stabbing pain in the contralateral upper extremity of approach side used in anterior cervical discectomy and fusion, and underwent a stellate ganglion block with a significant relief of his pain. The second patient complained of a cold sensation and severe unexpected pain in the lower extremity of the contralateral side after anterior lumbar interbody fusion and was treated with lumbar sympathetic block. We aimed to describe sympathetically maintained pain as one of the important causes of early postoperative pain and the treatment option chosen for these cases in detail. PMID- 25289131 TI - Stereotactic mesencephalotomy for cancer - related facial pain. AB - Cancer-related facial pain refractory to pharmacologic management or nondestructive means is a major indication for destructive pain surgery. Stereotactic mesencephalotomy can be a valuable procedure in the management of cancer pain involving the upper extremities or the face, with the assistance of magnetic resonance imaging (MRI) and electrophysiologic mapping. A 72-year-old man presented with a 3-year history of intractable left-sided facial pain. When pharmacologic and nondestructive measures failed to provide pain alleviation, he was reexamined and diagnosed with inoperable hard palate cancer with intracranial extension. During the concurrent chemoradiation treatment, his cancer-related facial pain was aggravated and became medically intractable. After careful consideration, MRI-based stereotactic mesencephalotomy was performed at a point 5 mm behind the posterior commissure, 6 mm lateral to and 5 mm below the intercommissural plane using a 2-mm electrode, with the temperature of the electrode raised to 80C for 60 seconds. Up until now, the pain has been relatively well-controlled by intermittent intraventricular morphine injection and oral opioids, with the pain level remaining at visual analogue scale 4 or 5. Stereotactic mesencephalotomy with the use of high-resolution MRI and electrophysiologic localization is a valuable procedure in patients with cancer related facial pain. PMID- 25289132 TI - Type 1 diabetes mellitus and gluten induced disorders. AB - Over the last five decades the association between coeliac disease and other autoimmune disorders such as autoimmune thyroid disease or diabetes mellitus type 1 has been well established through many studies and to this day is subject to on going clinical and scientific investigation worldwide. While no link has been established between celiac disease and type-2 diabetes mellitus, coeliac disease is common in patients with type 1 diabetes. The improvement of symptoms in patients with both conditions through dietary intervention, in the form of a gluten free diet, has been widely described within the literature. Our objectives were to review and synthesise the current knowledge on the nutritional treatment for patients with both conditions. PMID- 25289133 TI - Polymorphism of SMAD7 gene (rs2337104) and risk of colorectal cancer in an Iranian population: a case-control study. AB - AIM: The purpose of this study was to evaluate the influence of intronic polymorphism of the SMAD7 (Mothers Against Decantaplegic Homolog 7) gene (rs2337104) on the risk of colorectal cancer (CRC) and clinicopathological features in an Iranian population. BACKGROUND: SMAD7 has been identified as an antagonist of transforming growth factor beta (TGF-b)-mediating fibrosis, carcinogenesis, and inflammation. Regarding to the recent genome-wide scan, a risk locus for colorectal cancer at 18q21 has been found, which maps to the SMAD7 gene. PATIENTS AND METHODS: This case-control study was performed on 109 CRC patients and 109 healthy controls recruited in Taleghani Hospital. The genotyping of all samples were done by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) with DNA from peripheral blood. The association of this polymorphism with the risk of CRC and clinicopathological features was investigated. RESULTS: Our results indicated that there were no significant association between genotypic and allelic frequencies of SMAD7 polymorphism (rs2337104) and CRC risk in our population. Although the T allele is the most frequent one in this population and its frequency was 86.7% in patients compared with 91.7% in controls (OR=1.705, 95% CI= 0.916-3.172). Also, the SMAD7 genotypes were not associated with any clinicopathological characteristics in CRC patients (P>0.05). CONCLUSION: For the first time, this study results revealed that this SMAD7 polymorphism couldn't be a potential risk factor for CRC or a prognostic biomarker for prediction of clinicopathological features in an Iranian population. A large-scale case-control study is needed to validate our results. PMID- 25289134 TI - Familial adenomatous polyposis: ileo-anal pouch versus ileo-rectal anastomosis. AB - AIM: In this study we describe the presentation, treatment, and complications of 27 FAP patients. BACKGROUND: Treatment of Familial adenomatous polyposis (FAP) is centered on early recognition and curative surgery with either restorative proctocolectomy with ileal-pouch-anal-anastomosis (IPAA) or colectomy with ileo rectal anastomosis (IRA). PATIENTS AND METHODS: All patients diagnosed with FAP at our center from 2008 to 2012 were included in this case series. Either IPAA or IRA was used for treatment. Complications were recorded for 12 months after the procedure. RESULTS: Overall 27 patients were included, 12 (44.44%) index patients, and 15 (55.55%) relatives diagnosed by screening. Eight Index patients presented with rectal bleeding, two with occult fecal blood and two with abdominal masses found to be desmoid tumors. Nineteen patients were treated by IPAA, 6 with IRA, and 2 were inoperable due to diffuse desmoid tumors. Daytime stool frequency was the most common side effect (70.37%), followed by bowel discomfort episodes (55.56%), requiring dietary restrictions (37.4%), passive incontinence (25.93%), soiling (22.22%), nighttime stool frequency (18.52%), flatus incontinence (16.0%), and anastomosis leakage (3.70%). On average patients treated by IPAA experienced less complication than those treated by IRA. CONCLUSION: compared with previous reports, this series had older age of diagnosis, higher rate of adenocarcinoma at diagnosis, and fewer side effects after IPAA than IRA. The latter may reflect technique improvement with experience, and if supported by future studies, will cement IPAA as the treatment of choice in FAP. PMID- 25289135 TI - Survival of patients with stomach adenocarcinoma in North of Iran. AB - AIM: This study was proposed for estimation of survival time in patients with stomach adenocarcinoma. BACKGROUND: North of Iran has a high mortality rate of stomach adenocarcinoma. PATIENTS AND METHODS: The study was historical cohort. The samples were the patients with stomach adenocarcinoma referred to Tooba Clinic between three years (2007-2010). Survival estimates were calculated using the Kaplan-Meier method the effects of covariates on survival time were assessed by, using survival parametric regression model with gamma frailty. RESULTS: The survival probability of more than two years of patients was calculated 27.7% by using Kaplan Mayer method. The stage, metastasis, surgery, and age were the variables which affect the survival probability of patients, by using survival parametric regression model with gamma frailty and hazard ratio of patients with three treatment protocol was 0.43 times of others (P<0.01) and increasing of patients ages decrease life time of them significantly as per year increasing patient age, risk of death increased by 4% (P<0.04) and patients with staging disease lower 4 had hazard ratio lower than 0.46 times of stage 4 (P<0.01). CONCLUSION: The survival time of our patients is much lower than the developed countries, which are related to latency in diagnosis and therapeutic limitations. PMID- 25289136 TI - Isolation and antibiotic susceptibility of Shigella species from stool samples among hospitalized children in Abadan, Iran. AB - AIM: The aim of this study was to determine the incidence of Shigella species and their antimicrobial susceptibility patterns in hospitalized children with Shigellosis in Abadan, Iran. BACKGROUND: Shigellosis is caused by different species of Shigella and one of the most common causes of diarrhea in children. This disease is endemic in many developing countries including Iran. PATIENTS AND METHODS: This prospective cross sectional study was conducted in a teaching hospital in Abadan, Iran during June 2011 to May 2013. Stool specimens were collected from pediatric age group. All isolates were confirmed as Shigella species by biochemical and serologic tests. Antibiotic sensitivity pattern of these isolates was studied by disk diffusion Method. RESULTS: Among all 705 stool samples, 36 (5.1%) yielded Shigella. Of cases, 392 (55.6%) were girl and 313 (44.4%) were boy. The most common Shigella isolates were S. flexneri (n=19, 52.7%) followed by S. sonnei (n=11, 30.5%), S. boydii (n=4, 11.1%) and S. dysenteriae 2(5.5%). Of the Shigella isolates, 47.2% showed resistance to two or more antimicrobial agents. Resistance pattern against various antimicrobials were as follows: trimethoprim-sulphamethoxazole (80.5%), ampicillin (63.8%), tetracycline (58.3%), chloramphenicol (33.3%), nalidixic acid (27.7%), and cefixime (16.6%). There was no resistance against ciprofloxacin and ceftriaxone. CONCLUSION: The most common isolates were S. flexneri followed by S. Sonnei. There was no antibiotic resistance against ciprofloxacin and ceftriaxone. TMP-SMZ showed highest resistance pattern. PMID- 25289137 TI - Bacteriologic study of cirrhotic patients with non-neutrocytic ascites. AB - AIM: We aimed for detection of bacterial DNA (bactDNA) in spontaneous bacterial peritonitis (SBP) by polymerase chain reaction (PCR) and its prognostic relevance in cirrhotic patients with culture-negative non-neutrocytic ascites (CNNNA). BACKGROUND: approximately 60% of patients with spontaneous bacterial peritonitis (SBP) are ascites culture negative. PATIENTS AND METHODS: Of each 77 patients with cirrhosis and ascites, two samples including blood and ascitic fluid (AF) were taken. Blood samples were obtained for routine biochemical study and PMN count. AF samples were used for biochemical analysis and aerobic and anaerobic culture. BactDNA was detected by polymerase chain reaction (PCR) using bacterial universal 16srRNA gene primer. RESULTS: Of all AF samples, 3 (3.9%) were positive for bacterial culture (one streptococcus alpha hemolytic and two E.coli). The mean number of PMN in AF was 63. BactDNA was detected in 33 (42.9%) of 77 of samples (group A) and bactDNA was absent in 41 (53.2%) of samples (group B). Blood WBC, prothrombin time, LDH, serum total protein, AF WBC, serum albumin, AF albumin, AF total protein, serum total bilirubin, AST, ALT and BUN were not statically different among group A and B. Hepatitis B, 41(45%), was the most frequent cause of cirrhosis. CONCLUSION: Hepatitis B is the common cause of cirrhosis in Iranian cirrhotic patients. Also, current study showed that high number of Iranian cirrhotic patients with CNNNA carries bactDNA in their AF. The clinical findings as well as clinical laboratory data in patients with CNNNA are independent to bactDNA status in their ascitic fluid. PMID- 25289139 TI - Recent advances in gastric cancer. PMID- 25289138 TI - Primary esophageal Burkitt's lymphoma: a rare case report and review of literature. AB - Esophageal lymphoma is a rare condition, accounting for less than 1% of all gastrointestinal lymphomas. Primary extra nodal esophageal lymphoma constitutes less than 0.2% cases of the total esophageal lymphomas. The definition of primary GI lymphoma has differed among authors. The etiology of the disease is unknown, with the role of Epstein-Barr virus being controversial. The common symptoms of patients with esophageal lymphoma include dysphasia, odynophagia, weight loss, chest pain or present as a result of complications. Burkitt's lymphoma is one of the fastest growing human malignancies, with a 100% replication rate. Endemic, sporadic (non-endemic) and immunodeficient variants have been recognized. The diagnosis of Burkitt's lymphoma relies on morphologic findings, immunophenotyping results, and cytogenetic features. Burkitt's lymphoma is usually treated with LMB 96 protocol depending on the risk stratification. We present a case of primary esophageal Burkitt's lymphoma, which has been successfully treated with LMB-96 protocol. An extensive review of literature did not reveal a single case of esophageal Burkitt's lymphoma. To the best of our knowledge this is the first case report in the world literature with diagnosis of primary esophageal Burkitt's lymphoma. PMID- 25289140 TI - Multiple or metastatic clear cell chondrosarcoma: a case report. AB - We report multiple synchronous clear-cell chondrosarcomas in a 43-year-old patient. The patient had a lesion in the right proximal humerus and in the left femoral condyle. Bone scintigraphy revealed increased uptake in both foci. Pathological analysis confirmed the diagnosis in both locations. In the proximal humerus, wide resection of the tumour was performed with allograft reconstruction of the joint with osteosynthesis. The femoral condyle was treated with curettage, phenolization, and cementation. Over a follow-up of 10 years no recurrence or metastasis was observed. PMID- 25289141 TI - A cohort study of duplex Doppler examinations of the carotid artery in primary open angle glaucoma. AB - OBJECTIVES: To explore the possibility of pathological change in the common carotid artery at the bifurcation and in the internal carotid artery beyond the bifurcation which could contribute to a reduced diastolic pressure as observed in primary open angle glaucoma. DESIGN: Duplex ultrasonic examinations of carotid bifurcations were conducted on 80 patients. Carotid artery defects were allocated into three types: no demonstrable flow defects, internal carotid artery abnormalities and disease in the carotid bulb. SETTING: Bristol Royal Infirmary Vascular Laboratory. PARTICIPANTS: Eighty patients (mean age 69.6 years) providing a total of 160 sides to the analysis. MAIN OUTCOME MEASURES: An estimated central retinal artery pressure, intraocular pressure and field loss were recorded for each side measured. RESULTS: Doppler investigations revealed significant levels of pathological change in the internal carotid distinct from changes at the carotid bulb. The disease revealed in the internal carotid artery was significantly associated with intraocular pressure (p = 0.032), with an effect small to medium in magnitude. The Q2 measure, derived from mean arterial pressure and intraocular pressure, was also substantively associated with disease in the internal carotid artery. Both intraocular pressure and the Q2 measure effectively discriminated between groups, with field loss providing rather less discriminating capability. There was a strong trend towards a higher intraocular pressures and a greater visual field loss with internal carotid artery disease. CONCLUSIONS: Pathological changes in the extra cranial carotid artery in primary open angle glaucoma exceed those in the arteries classified as normal. The presence of disease specifically in the internal carotid artery emphasised the need for a mechanism for the evaluation of the internal carotid apart from the carotid bulb. A basis for clarifying the presence of an ischaemic zone is proposed. PMID- 25289142 TI - Therapeutic drug monitoring in a developing nation: a clinical guide. AB - Therapeutic drug monitoring is aimed at using drug concentration measurements to manage a patient's medication requirement and optimise clinical outcome, particularly in respect of drugs with narrow therapeutic index. Typically, immunoassay methods of various techniques are employed with the advantage of rapid turnaround time and ease of operation. The chromatographic methods are specific and cost effective, though more demanding and require technical expertise. The most crucial aspect of any therapeutic drug monitoring service is the expert clinical interpretation of drug concentration measurements taking into consideration individual pharmacokinetic variability in drug disposition across different populations. The setting up of a therapeutic drug monitoring service requires enormous resources, both in terms of equipment and trained personnel. This poses considerable constraints in developing countries due to limited scarce resources, coupled with ignorance among health practitioners on the relevance of therapeutic drug monitoring in clinical practice. Consequently, the need for advocacy, training and encouragement of health practitioners on the usefulness of therapeutic drug monitoring in enhancing patient care and overall clinical outcome in a developing country such as Nigeria can never be over-emphasised. PMID- 25289143 TI - Sequential strokes in a hyperacute stroke unit. AB - Vasculitis is a rare, but treatable condition that can present to hyperacute stroke units. Thrombolysis does not treat the underlying pathology, and a rapidly evolving clinical picture drives clinical decision often before all the investigation results are available. PMID- 25289144 TI - Witnessing images of extreme violence: a psychological study of journalists in the newsroom. AB - OBJECTIVE: User Generated Content - photos and videos submitted to newsrooms by the public - has become a prominent source of information for news organisations. Journalists working with uncensored material can frequently witness disturbing images for prolonged periods. How this might affect their psychological health is not known and it is the focus of this study. DESIGN: Descriptive, exploratory. SETTING: The newsrooms of three international news organisations. PARTICIPANTS: One hundred and sixteen journalists working with User Generated Content material. MAIN OUTCOME MEASURES: Psychometric data included the re-experiencing, avoidance and autonomic arousal indices of posttraumatic stress disorder (Impact of Event Scale-revised), depression (Beck Depression Inventory-II; BDI-II), a measure of psychological distress (GHQ-28), the latter comprising four subscales measuring somatisation, anxiety, social dysfunction and depression, and mean weekly alcohol consumption divided according to gender. RESULTS: Regression analyses revealed that frequent (i.e. daily) exposure to violent images independently predicted higher scores on all indices of the Impact of Event Scale-revised, the BDI-II and the somatic and anxiety subscales of the GHQ-28. Exposure per shift only predicted scores on the intrusion subscale of the Impact of Event Scale-revised. CONCLUSIONS: The present study, the first of its kind, suggests that frequency rather than duration of exposure to images of graphic violence is more emotionally distressing to journalists working with User Generated Content material. Given that good journalism depends on healthy journalists, news organisations will need to look anew at what can be done to offset the risks inherent in viewing User Generated Content material. Our findings, in need of replication, suggest that reducing the frequency of exposure may be one way to go. PMID- 25289145 TI - Is mortality a good indicator of the clinical quality of National Health Service hospitals? A cross-sectional study of outlier trusts for mortality indices using quality dashboards. AB - OBJECTIVES: This study assessed whether the 14 National Health Service (NHS) acute trusts reviewed by Sir Bruce Keogh in July 2013 were performance outliers on the Acute Trust Quality Dashboard (ATQD) and examined whether high mortality indices results are associated with increased numbers of quality risk alerts and alarms. DESIGN: The proportion of dashboard indicators rated amber or red in the Keogh Review trust group was compared with that for all trusts. Quality performance at primary care level was assessed for lead Clinical Commissioning Groups (CCG) of Keogh Review trusts through the national General Practice High Level Indicators. SETTING: England. PARTICIPANTS: The study examined the performance of all acute NHS trusts in England and the performance of the lead CCGs for all acute NHS trusts included in the Keogh Review. MAIN OUTCOME MEASURE: The primary outcome was the proportion of alerts and alarms identified in the summer 2013 ATQD. RESULTS: The mean proportion of indicators scored as alert or alarm across all trusts was 14.1% (13.5-14.7%). For Keogh Review trusts, the mean was 14.5% (12.6-16.4%). There was no significant difference between Keogh Review trusts and all acute trusts in numbers of alerts or alarms or for lead CCG quality performance. CONCLUSION: This study finds no evidence to suggest the trusts reviewed by Sir Bruce Keogh in spring 2013 were outliers for overall quality of care as defined by the ATQD. The use of mortality indices alone to identify potential quality outliers in secondary care may not be sufficient. PMID- 25289146 TI - Alcohol-related mortality following self-harm: a multicentre cohort study. AB - OBJECTIVES: To assess alcohol-related premature death in people who self-harm compared to the general population, including variation by socioeconomic deprivation. DESIGN: A retrospective longitudinal cohort analysis from the Multicentre Study of self-harm in England, 1 January 2000 to 31 December 2010, with cause-specific mortality follow-up through to 31 December 2012. SETTING: Six emergency departments in Oxford, Manchester and Derby. PARTICIPANTS: All individuals aged 15 years or more who presented with self-harm (n = 39,014) to general hospital emergency departments, together with follow-up mortality information from the Data Linkage Service of the Health and Social Care Information Centre. MAIN OUTCOME MEASURES: STANDARDISED MORTALITY RATIOS (OBSERVED/EXPECTED NUMBER OF DEATHS: SMRs) and mean number of years of life lost (YLL) were estimated for alcohol-related mortality. Patients' characteristics and clinical management following self-harm were also examined. RESULTS: After 7.5 years' (median) follow-up, 2695 individuals (6.9%) had died, significantly more males (9.5%) than females (5.0%), including 307 (11.4%) from alcohol-related causes. Alcohol-related death was more frequent than expected in both males (SMR 8.5, 95% CI 7.3 to 9.8) and females (11.6, 9.8 to 13.7), equating to 33.7 YLL (95% CI 32.4 to 35.0) in males and 38.1 YLL (36.6 to 39.6) in females. It was not associated with area-level socioeconomic deprivation. Alcohol-related death was associated with unemployed/sick/disabled status, alcohol use during self-harm, referral to drug/alcohol services and lack of psychosocial assessment following self-harm. CONCLUSIONS: Hospital-presenting self-harm patients should receive assessment following self-ham according to national guidance to enable early identification and treatment of alcohol problems. PMID- 25289147 TI - Adolescent prediabetes in a high-risk Middle East country: a cross-sectional study. AB - OBJECTIVE: To estimate the prevalence of prediabetes in adolescents living in a high-risk country and to detect risk factors associated with this disorder. DESIGN: Survey questionnaire combined with physical measurements and blood sugar determination. SETTING: Doha, capital city of Qatar. PARTICIPANTS: A total of 1694 male and female students aged 11-18 years without previously diagnosed diabetes enrolled in four schools. MAIN OUTCOME MEASURE: Blood sugar measurements. Other measured variables included gender, height, weight, abdominal circumference, country of origin, family history of diabetes and frequency of exercise. RESULTS: Using a random blood sugar >=7.8 mmol/L or a fasting blood sugar >=5.5 mmol/L as cutpoints, we identified 4.2% of students (56 boys, 15 girls) as probable prediabetics. In a multivariate model, being boys (OR 3.2, 95% CI 1.7-6.2), having a diabetic parent (OR 1.9, 95% CI 1.1-3.2) or having a waist to-height ratio >0.5 (OR 1.8, 95% CI 1.1-3.0) were significantly associated with being a prediabetic. The parental origin of diabetes had a differential effect upon blood sugar. The mean random blood sugar in students with a maternal inheritance pattern of diabetes was 5.61 mmol/L +/- 1.0, compared to 5.39 mmol/L +/- 0.89 in students with a paternal inheritance pattern (p = 0.02). CONCLUSIONS: In a country with a high risk of adult diabetes, we identified 4.2% of students aged 11-18 as being prediabetic. Risk factors associated with prediabetes included male gender, family history of diabetes and waist-to-height ratio >0.5. PMID- 25289148 TI - Totally extradural spinal en plaque meningiomas - Diagnostic dilemmas and treatment strategies. AB - BACKGROUND: Meningiomas are the second most common intraspinal tumors, constituting ~25% of all intraspinal tumors; however, in the context of extradural spinal lesions, the diagnosis of meningioma is an uncommon one. Purely extradural spinal meningiomas, especially of the en plaque variety, frequently mimic metastatic disease and may result in inadequate therapy. CASE DESCRIPTION: We report two cases of totally extradural en-plaque meningiomas of the spine, one each in the cervical and dorsal spine. We present the significant diagnostic dilemmas posed by these cases and discuss the pathogenesis, treatment strategies, and long-term behavior of these uncommon lesions. CONCLUSION: Attention needs to be drawn to this dangerous preoperative and intraoperative misinterpretation. Intraoperative histopathology support for correct identification, gross total resection at surgery, inclusion of a durotomy to rule out intradural extension, and long-term follow-up are cornerstones for successful management of totally extradural en plaque spinal meningiomas. PMID- 25289149 TI - Multidisciplinary in-hospital teams improve patient outcomes: A review. AB - BACKGROUND: The use of multidisciplinary in-hospital teams limits adverse events (AE), improves outcomes, and adds to patient and employee satisfaction. METHODS: Acting like "well-oiled machines," multidisciplinary in-hospital teams include "staff" from different levels of the treatment pyramid (e.g. staff including nurses' aids, surgical technicians, nurses, anesthesiologists, attending physicians, and others). Their enhanced teamwork counters the "silo effect" by enhancing communication between the different levels of healthcare workers and thus reduces AE (e.g. morbidity/mortality) while improving patient and healthcare worker satisfaction. RESULTS: Multiple articles across diverse disciplines incorporate a variety of concepts of "teamwork" for staff covering emergency rooms (ERs), hospital wards, intensive care units (ICUs), and most critically, operating rooms (ORs). Cohesive teamwork improved communication between different levels of healthcare workers, and limited adverse events, improved outcomes, decreased the length of stay (LOS), and yielded greater patient "staff" satisfaction. CONCLUSION: Within hospitals, delivering the best medical/surgical care is a "team sport." The goals include: Maximizing patient safety (e.g. limiting AE) and satisfaction, decreasing the LOS, and increasing the quality of outcomes. Added benefits include optimizing healthcare workers' performance, reducing hospital costs/complications, and increasing job satisfaction. This review should remind hospital administrators of the critical need to keep multidisciplinary teams together, so that they can continue to operate their "well-oiled machines" enhancing the quality/safety of patient care, while enabling "staff" to optimize their performance and enhance their job satisfaction. PMID- 25289151 TI - History of myelography with pantopaque contributing to arachnoiditis. PMID- 25289150 TI - Hemostasis and other benefits of fibrin sealants/glues in spine surgery beyond cerebrospinal fluid leak repairs. AB - BACKGROUND: Fibrin sealants (FS)/glues (FG) are primarily utilized in spinal surgery to either strengthen repairs of elective (e.g., intradural tumors/pathology) or traumatic cerebrospinal fluid (CSF) fistulas. Here, additional roles/benefits of FS/FG in spine surgery are explored; these include increased hemostasis, reduction of scar, reduction of the risk of infection if impregnated with antibiotics, and its application to restrict diffusion and limit some of the major complications attributed to the controversial "off-label" use of bone morphogeneitc protein (rhBMP-2/INFUSE). METHODS: We reviewed multiple studies, focusing not just on the utility of FS/FG in the treatment of CSF fistulas, but on its other applications. RESULTS: FS/FG have been primarily used to supplement elective/traumatic dural closure in spinal surgery. However, FS/FG also contribute to; hemostasis, reducing intraoperative/postoperative bleeding/transfusion requirements, length of stay (LOS)/costs, reduced postoperative scar/radiculitis, and infection when impregnated with antibiotics. Nevertheless, one should seriously question whether FS/FG should be applied to prevent diffusion and limit major complications attributed to the "off-label" use of BMP/INFUSE (e.g., limit/prevent heterotopic ossification, dysphagia/respiratory decompensation, and new neurological deficits). CONCLUSIONS: FS/FG successfully supplement watertight dural closure following elective (e.g., intradural tumor) or traumatic CSF fistulas occurring during spinal surgery. Additional benefits include: intraoperative hemostasis with reduced postoperative drainage, reduced transfusion requirements, reduced LOS, cost, scar, and prophylaxis against infection (e.g., impregnated with antibiotics). However, one should seriously question whether FS/FG should be used to contain the diffusion of BMP/INFUSE and limit its complications when utilized "off-label". PMID- 25289152 TI - Bilateral neurological deficits following unilateral minimally invasive TLIF: A review of four patients. AB - BACKGROUND: Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is commonly used for the treatment of degenerative lumbar spinal disorders. The rate of postoperative neurological deficits is traditionally low. New neurological postoperative complications may be underreported. We report our infrequent rate of MI-TLIF procedures complicated by postoperative weakness. METHODS: A database of 340 patients was evaluated, all of whom underwent MI-TLIF procedures performed between January 2002 and June 2012 by the senior author. We identified four cases (1.2%) whose postoperative course was complicated with bilateral lower extremity weakness. We retrospectively reviewed their past medical history, operative time, estimated blood loss, length of hospital stay, changes in intraoperative neurophysiological monitoring, and pre- and postoperative neurological exams. RESULTS: The average age of the four patients was 65.5 years(range: 62-75 years), average body mass index (BMI) was 25.1 (range: 24.1-26.6), and there were three females and one male. All patients had preoperative degenerative spondylolisthesis (either grade I or grade II). All patients were placed on a Wilson frame during surgery and underwent unilateral left-sided MI-TLIF. Three out of the four patients had a past medical history significant for abdominal or pelvic surgery and one patient had factor V Leiden deficiency syndrome. CONCLUSIONS: The rate of new neurological deficits following an MI-TLIF procedure is low, as documented in this study where the rate was 1.2%. Nonetheless, acknowledgement and open discussion of this serious complication is important for surgeon education. Of interest, the specific etiology or pathophysiology behind these complications remains relatively unknown (e.g. direct neural injury, traction injury, hypoperfusion, positioning complication, and others) despite there being some similarities between the patients and their perioperative courses. PMID- 25289153 TI - Commentary: Unnecessary preoperative epidural steroid injections lead to cerebrospinal fluid leaks confirmed during spinal stenosis surgery. AB - BACKGROUND: Increasingly, older patients with severe spinal stenosis/instability undergo multiple unnecessary preoperative epidural spinal injections (ESI), despite their risks and lack of long-term benefits. Here we add to the list of risks by showing how often preoperative ESI lead to punctate cerebrospinal fluid (CSF) fistulas documented during subsequent surgery (e.g. multilevel laminectomies with non-instrumented fusions). METHODS: A series of 39 patients with spinal stenosis/instability prospectively underwent multilevel laminectomy/non-instrumented fusion utilizing lamina autograft and NanOss Bioactive. We asked how often preoperative ESI were performed in this population and how frequently they contributed to operatively confirmed punctate cerebrospinal fluid (CSF) fistulas. Notably, CSF leaks were clearly attributed to ESI, as they were located centrally/paracentrally at the L4-L5 level, just below hypertrophied/ossified yellow ligament (OYL), and were the exact size of a Tuohy needle with clean edges. RESULTS: An average of 4.1 (range 2-12) preoperative ESI were performed in 33 of 39 patients undergoing average 4.3 level laminectomies and 1.3 level non-instrumented fusions; 6 (18.2%) patients exhibited operatively confirmed, punctate CSF fistulas attributed to these ESI. The most recent injections were administered between 2 and 5 weeks prior to surgery (average 3.9 weeks). Fistulas were primarily repaired with 7-0 GORE-TEX sutures and fibrin Sealant (Tisseel). CONCLUSIONS: Of 33 patients undergoing multilevel laminectomies with non-instrumented fusions receiving preoperative ESI, 6 (18.2%) had operatively confirmed punctate CSF fistulas due to preoperative ESI performed an average of 4.1 times per patient. PMID- 25289154 TI - Neurological outcome in a series of 58 patients operated for traumatic thoracolumbar spinal cord injuries. AB - BACKGROUND: Traumatic thoracolumbar spinal fractures represent approximately 65% of all traumatic spinal fractures and are frequently associated to permanent disability with significant social and economic impact. These injuries create severe physical limitations depending on neurological status, level of fracture, severity of injury, patient age and comorbidities. Predicting neurological improvement in patients with traumatic spinal cord injuries (SCIs) is very difficult because it is related to different preoperative prognostic factors. We evaluated the neurological improvement related to the preoperative neurological conditions and the anatomic level of spinal cord injury. METHODS: From January 2004 to June 2010, we operated 207 patients for unstable thoracolumbar spinal fractures. We carried out a retrospective analysis of 69 patients with traumatic SCIs operated on by a posterior fixation performed within 24 hours from the trauma. The preoperative neurological conditions (ASIA grade), the type of the fracture, the anatomic level of spinal cord injury and the postoperative neurological improvement were evaluated for each patient. RESULTS: The ASIA grade at admission (P = 0,0005), the fracture type according to the AO spine classification (P = 0,0002), and the anatomic location of the injury (P = 0,0213) represented predictive factors of neurological improvement at univariate analysis. The preoperative neurological status (P = 0,0491) and the fracture type (P = 0,049) confirmed a positive predictive value also in the multivariate analysis. CONCLUSIONS: Our study confirms that the preoperative neurological status, the fracture type and the anatomic location of the fracture are predictive factors of the neurological outcome in patients with spinal cord injury. PMID- 25289155 TI - Surgical management of spinal meningiomas: A retrospective case analysis based on preoperative surgical grade. AB - BACKGROUND: Although spinal meningiomas respond favorably to surgical excision, their surgical management is impacted by several factors. This study utilized a surgery-based grading system to discuss the optimal surgical strategy. METHODS: Twenty-three consecutive patients who underwent surgery for spinal meningiomas were included in this retrospective study. The patients' neurological condition was assessed using the modified McCormick functional schema (mMFS) and sensory pain scale (SPS), and tumor removal was assessed using Simpson grade. Major factors contributing to surgical difficulty included; tumor size, extent/severity of cord compression, location of tumor attachment, spinal level, and anatomical relationships plus tumor extending in a dumbbell shape and local postoperative recurrence. RESULTS: Fifteen cases were classified as ventral attachment (65.2%). There were two dumbbell-shaped tumors and three local recurrences at the primary site. Simpson grade 1 or 2 resections were performed in 18 of 20 cases (90%) with preoperative surgical grades 0 to 3. Simpson grade 4 resections were achieved in all three cases with preoperative surgical grades 4 to 5. Overall neurological assessment after surgery revealed the satisfactory or acceptable recovery on mMFS and SPS analysis. CONCLUSIONS: Lower preoperative grade yielded better results, while the higher the preoperative grade, the more likely tumor was insufficiently removed. A preoperative surgical grading system appeared to be helpful when considering the surgical strategy. Ventral meningiomas could be safely resected via the posterolateral or lateral approach using technical modifications. Recurrent tumors, especially with ventral attachment, were hard to resolve, and primary surgery appears to be important. PMID- 25289156 TI - Effects of teriparatide on lung function and pain relief in women with multiple osteoporotic vertebral compression fractures. AB - BACKGROUND: Osteoporosis is predominantly a condition of the elderly. In this study, we evaluated the effects of teriparatide on lung function and pain relief in elderly women with multiple osteoporotic vertebral compression fractures. METHODS: A total of 37 patients who received teriparatide treatment during the period January 2010 to December 2011 were enrolled. Dual-energy X-ray absorptiometry scans were used to measure bone mineral density (BMD) and lung function was measured using a MasterScreen Body Jaeger spirometer. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values were recorded. The Oswestry Disability Index (ODI) and the Visual Analog Scale (VAS) for pain were used to evaluate physical health and pain intensity, respectively, at baseline and after 6 months of teriparatide treatment. RESULTS: Mean BMD at the lumbar spine increased from 0.716 g/cm(2) at baseline to 0.829 g/cm(2) after 6 months of treatment. In addition, both mean FVC and FEV1 values after 6 months of treatment were significantly higher than baseline values (99.01% and 100.06% vs. 87.62% and 90.62%, respectively). Teriparatide treatment also resulted in a significant reduction in self-reported pain intensity and a significant improvement in physical health as measured by VAS and ODI scores, respectively. CONCLUSIONS: In addition to increasing BMD, teriparatide treatment improves the lung function and results in diminished pain intensity in women with multiple osteoporotic vertebral compression fractures. PMID- 25289157 TI - Biomechanical impact of C2 pedicle screw length in an atlantoaxial fusion construct. AB - BACKGROUND: Posterior, atlantoaxial (AA) fusions of the cervical spine may include either standard (26 mm) or short (16 mm) C2 pedicle screws. This manuscript focused on an in vitro biomechanical comparison of standard versus short C2 pedicle screws to perform posterior C1-C2 AA fusions. METHODS: Twelve human cadaveric spines underwent C1 lateral mass screw and standard C2 pedicle screw (n = 6) versus short C2 pedicle screw (n = 6) fixation. Six additional controls were not instrumented. The peak torque, peak rotational interval, and peak stiffness of the constructs were analyzed to failure levels. RESULTS: The peak torque to construct failure was not statistically significantly different among the control spine (12.2 Nm), short pedicle fixation (15.5 Nm), or the standard pedicle fixation (11.6 Nm), P = 0.79. While the angle at the peak rotation statistically significantly differed between the control specimens (47.7 degrees of relative motion) and the overall instrumented specimens (P < 0.001), the 20.7 degrees of relative rotation in the short C2 pedicle screw specimens was not statistically significantly higher than the 13.7 degrees of relative rotation in the standard C2 pedicle screw specimens (P = 0.39). Similarly, although the average stiffness was statistically significantly lower in control group (0.026 Nm/degree) versus the overall instrumented specimens (P = 0.001), the standard C2 pedicle screws (2.54 Nm/degree) did not differ from the short C2 pedicle screws. CONCLUSIONS: Both standard and short C2 pedicle screws allow for equally rigid fixation of C1 lateral mass-C2 AA fusions. Usage of a short C2 pedicle screw may be an acceptable method of stabilization in carefully selected patient populations. PMID- 25289158 TI - Commentary on NIH Guidelines for research on chronic low back pain. PMID- 25289159 TI - Cystic spinal schwannomas: A short series of six cases. Can we predict them preoperatively? AB - BACKGROUND: Spinal schwannomas are benign tumors arising from the spinal nerve root sheaths and are the commonest intradural extramedullary spinal tumors. Though cystic changes in schwannomas are well described, predominantly cystic schwannomas are uncommon lesions and form a different spectrum of conditions as compared with the commonly seen intradural extramedullary solid lesions. CASE DESCRIPTION: We present a case series of six patients with spinal intradural extramedullary cystic schwannomas. Two patients had uniloculated cystic schwannomas, two patients had multi-loculated cystic lesions with thick walls and intralesional septations, and two patients had giant cystic schwannomas, one of which had an extradural extension. We report two cases in which preoperative radiological dilemma was encountered and discuss the differential diagnoses of this uncommon entity. CONCLUSION: Cystic spinal schwannomas may be confused with other cystic lesions in the spine, differentiating them preoperatively is important and in this regard, contrast-enhanced magnetic resonance imaging plays a vital role. Frozen section histopathology should be used to identify them at surgery. It is important to detect these lesions at surgery, as total excision is possible and almost always results in good long-term neurological outcome. PMID- 25289160 TI - Tisseel utilized as hemostatic in spine surgery impacts time to drain removal and length of stay. AB - BACKGROUND: Although fibrin sealants (FSs) and fibrin glues (FGs) are predominantly utilized to strengthen repairs of cerebrospinal fluid (CSF) fistulas (deliberate/traumatic) during spinal surgery, they are also increasingly utilized to achieve hemostasis. Here, we investigated whether adding Tisseel (Baxter International Inc., Westlake Village, CA, USA), utilized to address increased bleeding during multilevel lumbar laminectomies with non-instrumented fusions, would reduce or equalize the time to drain removal and length of stay (LOS) without contributing to infections or prolonging time to fusion. METHODS: Prospectively, 39 patients underwent multilevel laminectomies and 1-2 level non instrumented (in situ) fusions to address stenosis/olisthesis; 22 who demonstrated increased intraoperative bleeding received Tisseel, while 17 without such bleeding did not. RESULTS: The 22 receiving versus 17 not receiving Tisseel, with similar clinical parameters, underwent comparable average multilevel laminectomies (4.36 and 4.25) and 1-2 level fusions (1.4 vs. 1.29 levels). As anticipated, for those receiving Tisseel, the average intraoperative estimated blood loss (EBL), total postoperative blood loss, and total perioperative transfusion requirements [red blood cells (RBC), fresh frozen plasma (FFP), platelets] were higher. However, Tisseel had the added benefit of equalizing the time to postoperative drain removal [e.g. 3.41 days (with) vs. 3.38 days (without)] and LOS [e.g. 5.86 days (with) vs. 5.82 days (without)] without increasing the infection rates (e.g. one superficial infection per group) or average times to fusion (e.g. 5.9 vs. 5.5 months). CONCLUSIONS: Adding Tisseel for increased bleeding during multilevel laminectomies/in situ fusions contributed to hemostasis by equalizing the average times to drain removal/LOS compared to patients without increased bleeding and not requiring Tisseel. PMID- 25289162 TI - Complications corner: Quadriplegia after a minor hyperextension injury with severe OPLL teaching case and illustrative images. AB - BACKGROUND: A previously healthy and asymptomatic male surviving well into his ninth decade (86 years of age) was rendered immediately and completely quadriplegic after a minor fall associated with cervical hyperextension. METHODS: Since he was unable to undergo a magnetic resonance (MR) scan due to the presence of a cardiac pacemaker, a non-contrast computed tomography (CT) was performed. This study demonstrated extremely severe cervical spinal canal stenosis secondary to previously undiagnosed ossification of the posterior longitudinal ligament (OPLL) resulting in marked spinal cord compression between C5 and C6. RESULTS: Secondary to his severe and irreversible quadriplegia, the patient elected not to undergo any intervention; he expired 4 days later. Had his deficit not been so severe, and had he been diagnosed earlier and undergone prophylactic/preventive posterior decompression (e.g. laminectomy C4-C7) sufficient to allow his cord to migrate dorsally, his irreversible quadriplegic deficit might have been avoided. CONCLUSIONS: Older patients with symptoms of progressive myelopathy should undergo early cervical MR (or CT if they have a pacemaker) screening looking for "silent" cord compression due to stenosis, spondyloarthrosis, and/or OPLL. This case highlights the devastating consequences of even a mild hyperextension injury in a patient harboring extremely severe but previously undiagnosed OPLL. Devastating life-threatening or life-ending injuries may be avoided by maintaining a low threshold for performing screening" cervical studies in elderly patients with vague complaints that might signal the onset of myelopathy. PMID- 25289161 TI - Prospective validation of a blood ordering protocol for elective spine arthrodesis and its impact on cost reduction. AB - BACKGROUND: On the basis of an institutional audit, the authors published an individual patient-based protocol for preoperative arrangement of blood products in patients undergoing elective spine arthrodesis. The present study was conducted for the prospective validation of the proposed protocol in reducing cross match to transfusion ratio, and its implications on overall cost. METHODS: This cross-sectional study was conducted over 1 year (2012). All adult patients who underwent elective spinal arthrodesis were included and prospectively observed. The actual transfusion index was calculated for individual patients with the formula C1/T, where C1 is the number of units of packed RBCs cross matched and T is the number of actual transfusions. C1/T was then compared with a theoretical transfusion index C2/T for the same group of patients, C2 being the number derived from calculating the number of units of packed RBCs that would have been ordered for individual patient according to the protocol. The cost difference between C1/T and C2/T was analyzed. RESULTS: A total of 125 patients were included. A total of 435 units of packed RBCs were ordered (C1), out of which only 108 units were transfused (T), yielding a C1/T of 4.02. The C2 for the same group of patients was 188 units of packed RBCs and the C2/T was thus calculated to be 1.74. Implementation of the protocol would reduce per patient cost from Pakistani Rupees (PKR) 6676.8 +/- 4125.8 to 4700.8 +/- 1712.86, with a P < 0.001 and an overall reduction of 30%. CONCLUSION: Cross match to transfusion ratio and blood ordering related cost are both significantly reduced with the application of institutional cross-match protocol. PMID- 25289163 TI - Acute spontaneous cervical disc herniation causing rapidly progressive myelopathy in a patient with comorbid ossified posterior longitudinal ligament: Case report and literature review. AB - BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) and cervical disc herniation are commonly encountered neurosurgical conditions. Here we present an unusual case of nontraumatic rapidly progressive myelopathy due to cervical disc herniation with comorbid OPLL and conduct a literature review focusing on the frequency and management of disc herniations with OPLL. CASE DESCRIPTION: A 52-year-old healthy female presented with a 72-h history of rapid progression of dense quadriparesis with sensory deficits, with a precedent 4-week history of nontraumatic midline neck pain. Clinical examination revealed profound motor deficits below the C5 myotome. Spinal neuroimaging revealed OPLL (computed tomography [CT]) and a cervical disc herniation spanning from C4/5 to C5/6 with significant retrovertebral disease (magnetic resonance imaging [MRI]). Operative management involved an anterior cervical corpectomy and instrumented fusion, with removal of both the sequestered disc material and the locally compressive OPLL. The patient recovered full motor function and independent ambulation with no residual signs or symptoms of myelopathy at the time of discharge. CONCLUSION: This unique case of a spontaneous cervical disc herniation in the context of OPLL causing rapidly progressive myelopathy illustrates the complementarity of CT and MRI in diagnosing the underlying cause of a rapidly progressive neurologic deficit in the absence of antecedent trauma. Though the optimal surgical management of such pathology remains uncertain; in this case, the anterior approach was motivated by the significant retrovertebral ventrally compressive sequestrum, and provided for excellent neurologic outcome. This article also reviews the occurrence/management of such acute cervical discs with OPLL. PMID- 25289164 TI - Primary Extradural Tumors of the Spine - Case Review with Evidence-guided Management. AB - BACKGROUND: Primary extradural tumors of the spine comprise only a small percentage of all spinal tumors. However, given their relative radioresistance and their typical malignant, invasive nature, surgery may be associated with fairly high morbidity and mortality rates. Furthermore, it may be especially difficult to achieve gross total resections with tumor-free margins. CASE DESCRIPTIONS: We present two cases and review the literature regarding the presentation, diagnosis, and evidence-based guidance/treatment of primary extradural spinal tumors. The first patient with an L1 chordoma presented with cauda equina syndrome. Following surgery, the second patient, with a giant cell tumor of the cervicothoracic junction, responded well to the novel drug denosumab, a monoclonal antibody to the RANK ligand. CONCLUSION: Primary extradural spine tumors pose significant challenges to surgeons as the aim is to achieve satisfactory surgical outcomes with clean tumor margins (e.g, thus avoid recurrence) while minimizing morbidity. Improvements in radiotherapy, chemotherapy, and novel molecular drugs may increase survival rates and improve overall outcomes. PMID- 25289165 TI - Continuation of medically necessary platelet aggregation inhibitors - acetylsalicylic acid and clopidogrel - during surgery for spinal degenerative disorders: Results in 100 patients. AB - BACKGROUND: Patients undergoing spinal surgery while under anticoagulation therapy are at risk of developing bleeding complications, even though lower incidences have been reported for joint arthroplasty surgery. There is a gap in the medical literature examining the incidence of postoperative spinal bleeding in patients who were under anticoagulation medication at the time of surgery. METHODS: We prospectively followed a consecutive cohort of 100 patients (58 male, 42 female) undergoing spinal surgery. The average patient age was 48.7 years and the minimum follow up time was 12 months. Diagnosis was lumbar spinal stenosis in 20, herniated lumbar discs in 63, degenerative cervical disc disease in 3, and cervical disc herniation in 14 cases. In our study, platelet aggregation inhibitors (clopidogrel and/or acetylsalicylic acid) were given for the treatment of cardiovascular and cerebrovascular thrombotic events, to reduce risk of stroke in patients who have had transient ischemia of the brain or acute coronary syndrome, and as secondary prevention of atherosclerotic events (fatal or nonfatal myocardial infarction (MI). A cessation of anticoagulants (acetylsalicylic acid or clopidogrel) in our patients in the peri- and postoperative period was contraindicated. RESULTS: Sixty-three patients were on both clopidogrel and acetylsalicylic acid and 37 on acetylsalicylic acid only. None of the patients suffered any postoperative bleeding complication. Three patients suffered postoperative wound dehiscence and one patient had an infection that required reoperation. CONCLUSION: The question of whether preoperative platelet aggregation inhibitors must be stopped before elective spinal surgery has never been answered in the literature. In our prospective series, we have found no increase in the risk of postoperative spinal bleeding with the use of clopidogrel or acetylsalicylic acid. This finding suggests that spine surgery can be done without stopping anticoagulation. Lacking specific guidelines, each patient should be treated on an individual basis, and the potential benefits of anticoagulation should be compared with the potential risks (risk-benefit ratio). PMID- 25289166 TI - A computed tomography morphometric study of occipital bone and C2 pedicle anatomy for occipital-cervical fusion. AB - BACKGROUND: Occipital-cervical fusion (OCF) has been used to treat instability of the occipito-cervical junction and to provide biomechanical stability after decompressive surgery. The specific areas that require detailed morphologic knowledge to prevent technical failures are the thickness of the occipital bone and diameter of the C2 pedicle, as the occipital midline bone and the C2 pedicle have structurally the strongest bone to provide the biomechanical purchase for cranio-cervical instrumentation. The aim of this study was to perform a quantitative morphometric analysis using computed tomography (CT) to determine the variability of the occipital bone thickness and C2 pedicle thickness to optimize screw placement for OCF in a South East Asian population. METHODS: Thirty patients undergoing cranio-cervical junction instrumentation during the period 2008-2010 were included. The thickness of the occipital bone and the length and diameter of the C2 pedicle were measured based on CT. RESULTS: The thickest point on the occipital bone was in the midline with a maximum thickness below the external occipital protuberance of 16.2 mm (+/-3.0 mm), which was thicker than in the Western population. The average C2 pedicle diameter was 5.3 mm (+/-2.0 mm). This was smaller than Western population pedicle diameters. The average length of the both pedicles to the midpoint of the C2 vertebral body was 23.5 mm (+/-3.3 mm on the left and +/-2.3 mm on the right). CONCLUSIONS: The results of this first study in the South East Asian population should help guide and improve the safety in occipito-cervical region instrumentation. Thus reducing the risk of technical failures and neuro-vascular injury. PMID- 25289167 TI - Alzheimer's disease: The role for neurosurgery. AB - Dementia, most commonly caused by Alzheimer's disease (AD), affects approximately 35 million people worldwide, with the incidence expected to increase as the population ages. After decades of investigation, AD is now understood to be a complex disease that affects behavior and cognition through several mechanisms: Disrupted neuronal communication, abnormal regional tissue metabolism, and impaired cellular repair. Existing therapies have demonstrated limited efficacy, which has spurred the search for specific disease markers and predictors as well as innovative therapeutic options. Deep brain stimulation (DBS) of the memory circuits is one such option, with early studies suggesting that modulation of neural activity in these networks may improve cognitive function. Encapsulated cell biodelivery (ECB) is a device that delivers nerve growth factor to the cholinergic basal forebrain to potentially improve cognitive decline in AD patients. This review discusses the pathogenesis of AD, novel neuroimaging and biochemical markers, and the emerging role for neurosurgical applications such as DBS and ECB. PMID- 25289168 TI - Gamma Knife radiosurgery for intracranial meningiomas: Do we need to treat the dural tail? A single-center retrospective analysis and an overview of the literature. AB - BACKGROUND: The dural tail (DT) has been described as a common feature in meningiomas. There is a great variation of tumor invasion and extent of tumor cells in the DT. Therefore, the necessity to include the whole DT in Gamma Knife radiosurgery is not clear, since inclusion increases the target volume and therefore increases the risk of complications. In this analysis, we evaluated whether the complete tail should be included as part of the target in Gamma Knife radiosurgery for meningiomas. METHODS: Between June 2002 and December 2010, Gamma Knife radiosurgery was performed in 160 patients with 203 meningiomas with a DT. In 105 tumors, the diagnosis was based on magnetic resonance imaging (MRI) characteristics, and in 98 tumors, the diagnosis was confirmed by histopathologic examination after surgery. The median volume of the tumors was 3.55 cc. All tumors were treated with Gamma Knife radiosurgery with a median prescribed dose of 13 Gy (range 11-15), resulting in a median marginal dose of 11 Gy (range 10 15). Only the part of the DT closely related to the tumor mass was included in the target. The median follow-up period was 41 months (range 12-123). RESULTS: In image-based meningiomas, the overall local control rate was 96.2% with 2- and 5 year control rates of 98.0% and 95.1%, respectively. In WHO grade I tumors, the overall local control rate was 85.9% with 2- and 5-year control rates of 94.5% and 88.0%, respectively. The overall local control rate in World Health Organization (WHO) grade II tumors was 70.6% with control rates of 83.4% and 64.4% after 2 and 5 years, respectively. The growth of all new tumors was found in the radiation target area. No tumor growth was observed in the part of the DT that had been excluded from the target volume. CONCLUSION: We found in this study that routinely excluding the DT from the target does not lead to out-of-field tumor progression. Given the possibility that the DT is infiltrated with tumor cells, regular follow-up is needed. PMID- 25289169 TI - Long-term outcome of gamma knife radiosurgery for metastatic brain tumors originating from lung cancer. AB - BACKGROUND: Gamma knife radiosurgery (GKRS) has emerged as an important treatment option for metastasis brain tumors (MBTs). However, the long-term outcome of GKRS on MBTs originating from lung carcinoma is not well understood. The treatment of MBTs derived from lung cancer with GKRS at our institution is reviewed. METHODS: We performed a retrospective review (2000-2013) of 173 patients with MBTs from lung cancer who received GKRS. Out of 173 patients, 38 patients had recurrent tumors after microsurgical resection and whole brain radiotherapy (WBT). RESULTS: GKRS in MBTs metastasized from lung carcinoma showed significant variations in tumor growth control (decreased in 79 [45.7%] patients, arrested growth in 54 [31.2%] patients, and increased tumor size in 40 [23.1%] patients). The median survival in the study population was 14 months. Overall survival after 3 years was 25%, whereas progression-free survival after 3 years was 45%. The predictive factors for improving survival in the patients with MBTs were recursive partitioning analysis (RPA) class I (P = 0.005), absence of hydrocephalus (P = 0.001), Karnofsky performance scale (KPS) >70 (P = 0.007), age <=65 (P = 0.041), tumor size <=3 cm (P = 0.023), controlled primary tumor (P = 0.049), and single number of MBTS (P = 0.044). CONCLUSION: Long-term follow-up revealed that GKRS offers a high rate of tumor control and good overall survival period in both new and recurrent patients with MBTs originating from lung carcinoma. Thus, GKRS is an effective treatment option for new patients with MBTs from lung cancer, as well as an adjuvant therapy in patients with recurrent MBTs derived from lung cancer. PMID- 25289170 TI - Evaluation of Thiel cadaveric model for MRI-guided stereotactic procedures in neurosurgery. AB - BACKGROUND: Magnetic resonance imaging (MRI)-guided deep brain stimulation (DBS) and high frequency focused ultrasound (FUS) is an emerging modality to treat several neurological disorders of the brain. Developing reliable models to train and assess future neurosurgeons is paramount to ensure safety and adequate training of neurosurgeons of the future. METHODS: We evaluated the use of Thiel cadaveric model to practice MRI-guided DBS implantation and high frequency MRI guided FUS in the human brain. We performed three training sessions for DBS and five sonications using high frequency MRI-guided FUS in five consecutive cadavers to assess the suitability of this model to use in training for stereotactic functional procedures. RESULTS: We found the brains of these cadavers preserved in an excellent anatomical condition up to 15 months after embalmment and they were excellent model to use, MRI-guided DBS implantation and FUS produced the desired lesions accurately and precisely in these cadaveric brains. CONCLUSION: Thiel cadavers provided a very good model to perform these procedures and a potential model to train and assess neurosurgeons of the future. PMID- 25289171 TI - Twiddler (or Not) Syndrome: Questioning etiology for an uncommon form of hardware malfunction in deep brain stimulation. AB - BACKGROUND: Hardware failure or malfunction after deep brain stimulation is an infrequent but costly occurrence with currently available systems. CASE DESCRIPTION: The authors present the case of a 65-year-old female patient with predominantly tremoric Parkinson's disease who, 4 months after bilateral subthalamic nucleus stimulation with very good clinical results, began to display signs of recurrent disease and an increasingly smaller response to stimulation. Radiological studies, changes in electrode impedance and surgical findings and results established the diagnosis of Twiddler syndrome. Close patient follow-up, lack of a psychiatric history and physical examination findings were, however, contrary to the previously described causative mechanism. CONCLUSION: The clinical and radiological setup of Twiddler syndrome must be readily recognized. Its causative mechanism should remain under discussion, and intraoperative technical details may help to explain its occurrence. PMID- 25289172 TI - Holmes tremor in a patient with progressive multifocal leukoencephalopathy. AB - BACKGROUND: Progressive multifocal leukencephalopathy (PML) is a rare, sometimes fatal viral disease in patients with primary or secondary immunosuppression. CASE DESCRIPTION: A 57-year-old immunocompetent female with intractable Holmes tremor and elongated unique brainstem lesion reported to our hospital. The cerebrospinal fluid (CSF) screening for John Cunningham virus was negative and the diagnosis was established by brain biopsy. The course was rapidly fatal. CONCLUSION: This atypical presentation of PML in an immunocompetent patient illustrates that diagnosis can be missed without brain biopsy. PMID- 25289173 TI - Long-term follow-up of deep brain stimulation of peduncolopontine nucleus in progressive supranuclear palsy: Report of three cases. AB - BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disease due to mitochondrial dysfunction. The PSP syndrome presents generally with gait disorder, Parkinsonism, ophthalmoparesis and cognitive alteration. Few reports exist on deep brain stimulation (DBS) in patients with atypical Parkinsonism. The aim of our study was to evaluate further the potential role of DBS in PSP. CASE DESCRIPTION: We report three patients with PSP with long-term follow up undergoing DBS. Two patients had right peripedunculopontine nucleus (PPN) stimulation and one patient had simultaneous right PPN and bilateral globus pallidus internus DBS. DBS of the PPN alone or combined with globus pallidus internus (GPi) determined an improvement in gait and a reduction in falls sustained over time. Combined target stimulation (GPi-PPN) was correlated with better clinical outcome than single target (PPN) DBS for PSP. CONCLUSIONS: Although few data on DBS for PSP exist, reported clinical results are encouraging. DBS might be considered as an alternative therapeutic option for patients with PSP presenting with relevant gait imbalance and frequent falls, who fail to respond to pharmacological treatment. Larger cohorts with longer follow ups are needed to evaluate more exhaustively the efficacy of DBS in PSP. PMID- 25289174 TI - Diagnostic yield and morbidity by neuronavigation-guided frameless stereotactic biopsy using magnetic resonance imaging and by frame-based computed tomography guided stereotactic biopsy. AB - BACKGROUND: We compared the diagnostic yield and morbidity by frame-based computed tomography-guided stereotactic biopsy (CTSTB) with Brown-Roberts-Wells (BRW) unit and by neuronavigation-guided frameless stereotactic biopsy (NSTB) using magnetic resonance imaging (MRI). METHODS: The subjects' age range was 15 83 years. CTSTB with BRW unit was performed for 59 tumors (58 cases, 1988-2007). NSTB was performed for 38 tumors (35 cases, 2007-2013) with the needle sheath attached to the head holder. By NSTB, target locations of sampling points and trajectories were confirmed by using MRI. Diffusion tensor imaging-based fiber tractography was used to achieve safe trajectories. STB by using BRW did not visualize the trajectory virtually; however, the planning images for NSTB were able to show the trajectory virtually before the procedure. RESULTS: Histological diagnoses were established for 93 tumors at the first biopsy. The diagnostic yield was 94.9% by CTSTB and 97.4% by NSTB (P = 0.944). The morbidity rate was 5.1% by CTSTB and 0% by NSTB (P = 0.417). The absolute risk reduction was 23.1% by NSTB when the targets were basal ganglia (putamen, globus pallidus) or thalamus. In the cases of glioma for which the targets were basal ganglia (putamen, globus pallidus) or thalamus, the absolute risk reduction by NSTB was 30%. CONCLUSIONS: There was no significant difference between CTSTB and NSTB concerning the diagnostic yield and morbidity. However, when the target is the basal ganglia (putamen, globus pallidus) or thalamus and glioma is suspected, NSTB by using MRI with virtual trajectory is preferable to CTSTB concerning morbidity. PMID- 25289175 TI - Unfolding Physiological State: Mortality Modelling in Intensive Care Units. AB - Accurate knowledge of a patient's disease state and trajectory is critical in a clinical setting. Modern electronic healthcare records contain an increasingly large amount of data, and the ability to automatically identify the factors that influence patient outcomes stand to greatly improve the efficiency and quality of care. We examined the use of latent variable models (viz. Latent Dirichlet Allocation) to decompose free-text hospital notes into meaningful features, and the predictive power of these features for patient mortality. We considered three prediction regimes: (1) baseline prediction, (2) dynamic (time-varying) outcome prediction, and (3) retrospective outcome prediction. In each, our prediction task differs from the familiar time-varying situation whereby data accumulates; since fewer patients have long ICU stays, as we move forward in time fewer patients are available and the prediction task becomes increasingly difficult. We found that latent topic-derived features were effective in determining patient mortality under three timelines: inhospital, 30 day post-discharge, and 1 year post-discharge mortality. Our results demonstrated that the latent topic features important in predicting hospital mortality are very different from those that are important in post-discharge mortality. In general, latent topic features were more predictive than structured features, and a combination of the two performed best. The time-varying models that combined latent topic features and baseline features had AUCs that reached 0.85, 0.80, and 0.77 for in-hospital, 30 day post discharge and 1 year post-discharge mortality respectively. Our results agreed with other work suggesting that the first 24 hours of patient information are often the most predictive of hospital mortality. Retrospective models that used a combination of latent topic features and structured features achieved AUCs of 0.96, 0.82, and 0.81 for in-hospital, 30 day, and 1-year mortality prediction. Our work focuses on the dynamic (time-varying) setting because models from this regime could facilitate an on-going severity stratification system that helps direct care-staff resources and inform treatment strategies. PMID- 25289176 TI - Species and size diversity in protective services offered by coral guard-crabs. AB - Coral guard-crabs in the genus Trapezia are well-documented defenders of their pocilloporid coral hosts against coral predators such as the Crown-of-Thorns seastar (Acanthaster planci complex). The objectives of this study were to examine the protective services of six species of Trapezia against corallivory, and the extent of functional diversity among these Trapezia species. Studies conducted in Mo'orea, French Polynesia showed the Trapezia-coral mutualism protected the host corals from multiple predators through functional diversity in the assemblage of crab symbionts. Species differed in their defensive efficacy, but species within similar size classes shared similar abilities. Smaller-size Trapezia species, which were previously thought to be ineffective guards, play important defensive roles against small corallivores. We also measured the benefits of this mutualism to corals in the midst of an Acanthaster outbreak that reduced the live coral cover on the fore reef to less than 4%. The mutualism may positively affect the reef coral demography and potential for recovery during adverse predation events through shelter of multiple species of small corals near the host coral. Our results show that while functional diversity is supported within the genus, some Trapezia species may be functionally equivalent within the same size class, decreasing the threat of gaps in coral protection caused by absence or replacement of any single Trapezia species. PMID- 25289177 TI - Factors associated with leisure time physical inactivity in black individuals: hierarchical model. AB - Background. A number of studies have shown that the black population exhibits higher levels of leisure-time physical inactivity (LTPI), but few have investigated the factors associated with this behavior. Objective. The aim of this study was to analyze associated factors and the explanatory model proposed for LTPI in black adults. Methods. The design was cross-sectional with a sample of 2,305 adults from 20-96 years of age, 902 (39.1%) men, living in the city of Salvador, Brazil. LTPI was analyzed using the International Physical Activity Questionnaire (IPAQ). A hierarchical model was built with the possible factors associated with LTPI, distributed in distal (age and sex), intermediate 1 (socioeconomic status, educational level and marital status), intermediate 2 (perception of safety/violence in the neighborhood, racial discrimination in private settings and physical activity at work) and proximal blocks (smoking and participation in Carnival block rehearsals). We estimated crude and adjusted odds ratio (OR) using logistic regression. Results. The variables inversely associated with LTPI were male gender, socioeconomic status and secondary/university education, although the proposed model explains only 4.2% of LTPI. Conclusions. We conclude that male gender, higher education and socioeconomic status can reduce LTPI in black adults. PMID- 25289179 TI - Case based rubella surveillance in Abia State, South East Nigeria, 2007-2011. AB - Introduction. Rubella infection has the potential of causing severe fetal birth defects collectively called congenital rubella syndrome (CRS) if the mother is infected early in pregnancy. However, little is known about rubella and CRS epidemiology in Nigeria and rubella vaccines are still not part of routine childhood immunization in Nigeria. Methods. Analysis of confirmed cases of rubella in Abia State, Nigeria from 2007 to 2011 detected through Abia State Integrated Disease Surveillance and Response system. Results. Of the 757 febrile rash cases, 81(10.7%) tested positive for rubella immunoglobulin M (IgM). New rubella infection decreased from 6.81/1,000,000 population in 2007 to 2.28/1,000,000 in 2009 and increased to 6.34/1,000,000 in 2011. The relative risk of rubella was 1.5 (CI [0.98-2.28]) times as high in females compared to males and 1.6 times (CI [0.90-2.91]) as high in rural areas compared to urban areas. Eighty six percent of rubella infections occurred in children less than 15 years with a high proportion of cases occurring between 5 and 14 years. Conclusion. Rubella infection in Abia State, Nigeria is predominantly in those who are younger than 15 years old. It is also more prevalent in females and in those living in rural areas of the state. Unfortunately, there is no surveillance of CRS in Nigeria and so the public health impact of rubella infection in the state is not known. Efforts should be made to expand the rubella surveillance in Nigeria to incorporate surveillance for CRS. PMID- 25289178 TI - A candidate multimodal functional genetic network for thermal adaptation. AB - Vertebrate ectotherms such as reptiles provide ideal organisms for the study of adaptation to environmental thermal change. Comparative genomic and exomic studies can recover markers that diverge between warm and cold adapted lineages, but the genes that are functionally related to thermal adaptation may be difficult to identify. We here used a bioinformatics genome-mining approach to predict and identify functions for suitable candidate markers for thermal adaptation in the chicken. We first established a framework of candidate functions for such markers, and then compiled the literature on genes known to adapt to the thermal environment in different lineages of vertebrates. We then identified them in the genomes of human, chicken, and the lizard Anolis carolinensis, and established a functional genetic interaction network in the chicken. Surprisingly, markers initially identified from diverse lineages of vertebrates such as human and fish were all in close functional relationship with each other and more associated than expected by chance. This indicates that the general genetic functional network for thermoregulation and/or thermal adaptation to the environment might be regulated via similar evolutionarily conserved pathways in different vertebrate lineages. We were able to identify seven functions that were statistically overrepresented in this network, corresponding to four of our originally predicted functions plus three unpredicted functions. We describe this network as multimodal: central regulator genes with the function of relaying thermal signal (1), affect genes with different cellular functions, namely (2) lipoprotein metabolism, (3) membrane channels, (4) stress response, (5) response to oxidative stress, (6) muscle contraction and relaxation, and (7) vasodilation, vasoconstriction and regulation of blood pressure. This network constitutes a novel resource for the study of thermal adaptation in the closely related nonavian reptiles and other vertebrate ectotherms. PMID- 25289180 TI - Fibrochondrogenic potential of synoviocytes from osteoarthritic and normal joints cultured as tensioned bioscaffolds for meniscal tissue engineering in dogs. AB - Meniscal tears are a common cause of stifle lameness in dogs. Use of autologous synoviocytes from the affected stifle is an attractive cell source for tissue engineering replacement fibrocartilage. However, the diseased state of these cells may impede in vitro fibrocartilage formation. Synoviocytes from 12 osteoarthritic ("oaTSB") and 6 normal joints ("nTSB") were cultured as tensioned bioscaffolds and compared for their ability to synthesize fibrocartilage sheets. Gene expression of collagens type I and II were higher and expression of interleukin-6 was lower in oaTSB versus nTSB. Compared with nTSB, oaTSB had more glycosaminoglycan and alpha smooth muscle staining and less collagen I and II staining on histologic analysis, whereas collagen and glycosaminoglycan quantities were similar. In conclusion, osteoarthritic joint-origin synoviocytes can produce extracellular matrix components of meniscal fibrocartilage at similar levels to normal joint-origin synoviocytes, which makes them a potential cell source for canine meniscal tissue engineering. PMID- 25289181 TI - Spatial genetic structure across a hybrid zone between European rabbit subspecies. AB - The Iberian Peninsula is the only region in the world where the two existing subspecies of the European rabbit (Oryctolagus cuniculus) naturally occur and hybridize. In this study we explore the relative roles of historical and contemporary processes in shaping the spatial genetic structure of the rabbit across its native distribution range, and how they differently affect each subspecies and the hybrid zone. For that purpose we obtained multilocus genotypes and mitochondrial DNA data from 771 rabbits across most of the distribution range of the European rabbit in Spain. Based on the nuclear markers we observed a hierarchical genetic structure firstly comprised by two genetic groups, largely congruent with the mitochondrial lineages and subspecies distributions (O. c. algirus and O. c. cuniculus), which were subsequently subdivided into seven genetic groups. Geographic distance alone emerged as an important factor explaining genetic differentiation across the whole range, without the need to invoke for the effect for geographical barriers. Additionally, the significantly positive spatial correlation up to a distance of only 100 km supported the idea that differentiation at a local level is of greater importance when considering the species overall genetic structure. When looking at the subspecies, northern populations of O. c. cuniculus showed more spatial genetic structure and differentiation than O. c. algirus. This could be due to local geographic barriers, limited resources, soil type and/or social behavior limiting dispersal. The hybrid zone showed similar genetic structure to the southern populations but a larger introgression from the northern lineage genome. These differences have been attributed to selection against the hybrids rather than to behavioral differences between subspecies. Ultimately, the genetic structure of the rabbit in its native distribution range is the result of an ensemble of factors, from geographical and ecological, to behavioral and molecular, that hierarchically interact through time and space. PMID- 25289182 TI - One pair of hands is not like another: caudate BOLD response in dogs depends on signal source and canine temperament. AB - Having previously used functional MRI to map the response to a reward signal in the ventral caudate in awake unrestrained dogs, here we examined the importance of signal source to canine caudate activation. Hand signals representing either incipient reward or no reward were presented by a familiar human (each dog's respective handler), an unfamiliar human, and via illustrated images of hands on a computer screen to 13 dogs undergoing voluntary fMRI. All dogs had received extensive training with the reward and no-reward signals from their handlers and with the computer images and had minimal exposure to the signals from strangers. All dogs showed differentially higher BOLD response in the ventral caudate to the reward versus no reward signals, and there was a robust effect at the group level. Further, differential response to the signal source had a highly significant interaction with a dog's general aggressivity as measured by the C BARQ canine personality assessment. Dogs with greater aggressivity showed a higher differential response to the reward signal versus no-reward signal presented by the unfamiliar human and computer, while dogs with lower aggressivity showed a higher differential response to the reward signal versus no reward signal from their handler. This suggests that specific facets of canine temperament bear more strongly on the perceived reward value of relevant communication signals than does reinforcement history, as each of the dogs were reinforced similarly for each signal, regardless of the source (familiar human, unfamiliar human, or computer). A group-level psychophysiological interaction (PPI) connectivity analysis showed increased functional coupling between the caudate and a region of cortex associated with visual discrimination and learning on reward versus no-reward trials. Our findings emphasize the sensitivity of the domestic dog to human social interaction, and may have other implications and applications pertinent to the training and assessment of working and pet dogs. PMID- 25289183 TI - Induced sensitivity of Bacillus subtilis colony morphology to mechanical media compression. AB - Bacteria from several taxa, including Kurthia zopfii, Myxococcus xanthus, and Bacillus mycoides, have been reported to align growth of their colonies to small features on the surface of solid media, including anisotropies created by compression. While the function of this phenomenon is unclear, it may help organisms navigate on solid phases, such as soil. The origin of this behavior is also unknown: it may be biological (that is, dependent on components that sense the environment and regulate growth accordingly) or merely physical. Here we show that B. subtilis, an organism that typically does not respond to media compression, can be induced to do so with two simple and synergistic perturbations: a mutation that maintains cells in the swarming (chained) state, and the addition of EDTA to the growth media, which further increases chain length. EDTA apparently increases chain length by inducing defects in cell separation, as the treatment has only marginal effects on the length of individual cells. These results lead us to three conclusions. First, the wealth of genetic tools available to B. subtilis will provide a new, tractable chassis for engineering compression sensitive organisms. Second, the sensitivity of colony morphology to media compression in Bacillus can be modulated by altering a simple physical property of rod-shaped cells. And third, colony morphology under compression holds promise as a rapid, simple, and low-cost way to screen for changes in the length of rod-shaped cells or chains thereof. PMID- 25289184 TI - Multi-decade biomass dynamics in an old-growth hemlock-northern hardwood forest, Michigan, USA. AB - Trends in living aboveground biomass and inputs to the pool of coarse woody debris (CWD) in an undisturbed, old-growth hemlock-northern hardwood forest in northern MI were estimated from multi-decade observations of permanent plots. Growth and demographic data from seven plot censuses over 47 years (1962-2009), combined with one-time measurement of CWD pools, help assess biomass/carbon status of this landscape. Are trends consistent with traditional notions of late successional forests as equilibrial ecosystems? Specifically, do biomass pools and CWD inputs show consistent long-term trends and relationships, and can living and dead biomass pools and trends be related to forest composition and history? Aboveground living biomass densities, estimated using standard allometric relationships, range from 360-450 Mg/ha among sampled stands and types; these values are among the highest recorded for northeastern North American forests. Biomass densities showed significant decade-scale variation, but no consistent trends over the full study period (one stand, originating following an 1830 fire, showed an aggrading trend during the first 25 years of the study). Even though total above-ground biomass pools are neither increasing nor decreasing, they have been increasingly dominated, over the full study period, by very large (>70 cm dbh) stems and by the most shade-tolerant species (Acer saccharum and Tsuga canadensis). CWD pools measured in 2007 averaged 151 m(3)/ha, with highest values in Acer-dominated stands. Snag densities averaged 27/ha, but varied nearly ten fold with canopy composition (highest in Tsuga-dominated stands, lowest in Acer dominated); snags constituted 10-50% of CWD biomass. Annualized CWD inputs from tree mortality over the full study period averaged 1.9-3.2 Mg/ha/yr, depending on stand and species composition. CWD input rates tended to increase over the course of the study. Input rates may be expected to increase over longer-term observations because, (a) living biomass is increasingly dominated by very large trees whose dead trunks have longer residence time in the CWD pool, and (b) infrequent major disturbances, thought to be important in the dynamics of these forests, have not occurred during the study period but would be expected to produce major, episodic pulses in CWD input. Few fragments of old-growth cool temperate forests remain, but such forests can constitute a very large carbon pool on a per-area basis. The carbon sink/source status of these forests remains unclear. While aboveground living biomass at this study site shows no strong aggrading or declining trend over the last half-century, this remains a modest span in the innate time-scale of late-successional forest. The effects of rare disturbances, long-term shifts in composition and size structure, and changes in soil carbon and CWD pools may all influence long-term carbon status. PMID- 25289186 TI - Nest-building behavior of Monk Parakeets and insights into potential mechanisms for reducing damage to utility poles. AB - The Monk Parakeet (Myiopsitta monachus) commonly uses utility poles as a substrate for building large, bulky nests. These nests often cause fires and electric power outages, creating public safety risks and increasing liability and maintenance costs for electric companies. Previous research has focused on lethal methods and chemical contraception to prevent nesting on utility poles and electrical substations. However, implementation of lethal methods has led to public protests and lawsuits, while chemical contraception may affect other than the targeted species, and must be continually reapplied for effectiveness. One non-lethal alternative, nest removal, is costly and may not be a sustainable measure if Monk Parakeet populations continue to grow. In order to identify cost effective non-lethal solutions to problems caused by Monk Parakeet nesting, we studied their behavior as they built nests on utility poles. Monk Parakeets initiate nests by attaching sticks at the intersection of the pole and electric lines. We found that parakeets use the electric lines exclusively to gain access to the intersection of lines and pole during nest initiation, and continue to use the lines intensively throughout construction. Monk Parakeets also have more difficulty attaching sticks during the early stages of nest construction than when the nest is nearing completion. These findings suggest that intervention during the earlier stages of nest building, by excluding Monk Parakeets from electric lines adjacent to poles, may be an effective, non-lethal method of reducing or eliminating parakeets nesting on, and damaging, utility poles. PMID- 25289185 TI - Detailed comparison of two popular variant calling packages for exome and targeted exon studies. AB - The Genome Analysis Toolkit (GATK) is commonly used for variant calling of single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) from short-read sequencing data aligned against a reference genome. There have been a number of variant calling comparisons against GATK, but an equally comprehensive comparison for VarScan not yet been performed. More specifically, we compare (1) the effects of different pre-processing steps prior to variant calling with both GATK and VarScan, (2) VarScan variants called with increasingly conservative parameters, and (3) filtered and unfiltered GATK variant calls (for both the UnifiedGenotyper and the HaplotypeCaller). Variant calling was performed on three datasets (1 targeted exon dataset and 2 exome datasets), each with approximately a dozen subjects. In most cases, pre-processing steps (e.g., indel realignment and quality score base recalibration using GATK) had only a modest impact on the variant calls, but the importance of the pre-processing steps varied between datasets and variant callers. Based upon concordance statistics presented in this study, we recommend GATK users focus on "high-quality" GATK variants by filtering out variants flagged as low-quality. We also found that running VarScan with a conservative set of parameters (referred to as "VarScan-Cons") resulted in a reproducible list of variants, with high concordance (>97%) to high-quality variants called by the GATK UnifiedGenotyper and HaplotypeCaller. These conservative parameters result in decreased sensitivity, but the VarScan-Cons variant list could still recover 84-88% of the high-quality GATK SNPs in the exome datasets. This study also provides limited evidence that VarScan-Cons has a decreased false positive rate among novel variants (relative to high-quality GATK SNPs) and that the GATK HaplotypeCaller has an increased false positive rate for indels (relative to VarScan-Cons and high-quality GATK UnifiedGenotyper indels). More broadly, we believe the metrics used for comparison in this study can be useful in assessing the quality of variant calls in the context of a specific experimental design. As an example, a limited number of variant calling comparisons are also performed on two additional variant callers. PMID- 25289187 TI - Eutrophication and the dietary promotion of sea turtle tumors. AB - The tumor-forming disease fibropapillomatosis (FP) has afflicted sea turtle populations for decades with no clear cause. A lineage of alpha-herpesviruses associated with these tumors has existed for millennia, suggesting environmental factors are responsible for its recent epidemiology. In previous work, we described how herpesviruses could cause FP tumors through a metabolic influx of arginine. We demonstrated the disease prevails in chronically eutrophied coastal waters, and that turtles foraging in these sites might consume arginine-enriched macroalgae. Here, we test the idea using High-Performance Liquid Chromatography (HPLC) to describe the amino acid profiles of green turtle (Chelonia mydas) tumors and five common forage species of macroalgae from a range of eutrophic states. Tumors were notably elevated in glycine, proline, alanine, arginine, and serine and depleted in lysine when compared to baseline samples. All macroalgae from eutrophic locations had elevated arginine, and all species preferentially stored environmental nitrogen as arginine even at oligotrophic sites. From these results, we estimate adult turtles foraging at eutrophied sites increase their arginine intake 17-26 g daily, up to 14 times the background level. Arginine nitrogen increased with total macroalgae nitrogen and watershed nitrogen, and the invasive rhodophyte Hypnea musciformis significantly outperformed all other species in this respect. Our results confirm that eutrophication substantially increases the arginine content of macroalgae, which may metabolically promote latent herpesviruses and cause FP tumors in green turtles. PMID- 25289188 TI - GroopM: an automated tool for the recovery of population genomes from related metagenomes. AB - Metagenomic binning methods that leverage differential population abundances in microbial communities (differential coverage) are emerging as a complementary approach to conventional composition-based binning. Here we introduce GroopM, an automated binning tool that primarily uses differential coverage to obtain high fidelity population genomes from related metagenomes. We demonstrate the effectiveness of GroopM using synthetic and real-world metagenomes, and show that GroopM produces results comparable with more time consuming, labor-intensive methods. PMID- 25289189 TI - Bumblebee size polymorphism and worker response to queen pheromone. AB - Queen pheromones are chemical signals produced by reproductive individuals in social insect colonies. In many species they are key to the maintenance of reproductive division of labor, with workers beginning to reproduce individually once the queen pheromone disappears. Recently, a queen pheromone that negatively affects worker fecundity was discovered in the bumblebee Bombus terrestris, presenting an exciting opportunity for comparisons with analogous queen pheromones in independently-evolved eusocial lineages such as honey bees, ants, wasps and termites. I set out to replicate this discovery and verify its reproducibility. Using blind, controlled experiments, I found that n-pentacosane (C25) does indeed negatively affect worker ovary development. Moreover, the pheromone affects both large and small workers, and applies to workers from large, mature colonies as well as young colonies. Given that C25 is readily available and that bumblebees are popular study organisms, I hope that this replication will encourage other researchers to tackle the many research questions enabled by the discovery of a queen pheromone. PMID- 25289190 TI - Effect of obesity and exercise on the expression of the novel myokines, Myonectin and Fibronectin type III domain containing 5. AB - Metabolic dysfunction in skeletal muscle is a major contributor to the development of type 2 diabetes. Endurance exercise training has long been established as an effective means to directly restore skeletal muscle glucose and lipid uptake and metabolism. However, in addition to the direct effects of skeletal muscle on glucose and lipids, there is renewed interest in the ability of skeletal muscle to coordinate metabolic activity of other tissues, such as adipose tissue and liver. The purpose of this study was to examine the effects of endurance exercise on the expression level of two novel muscle-derived secreted factors, or myokines, Myonectin and Fibronectin type III domain containing 5 (FNDC5), the precursor for Irisin. Methods. We performed immunoblot analysis and quantitative real-time PCR analysis of Myonectin and FNDC5 in the diaphragm muscles of obese Zucker rat (OZR) and lean Zucker rat (LZR) with 9 weeks of aerobic training on a motorized treadmill. Results. We show that myonectin gene expression is increased in the OZR model of obesity and decreases with exercise in both lean and obese Zucker rats. Conversely, myonectin protein concentration was elevated with exercise. Similarly, FNDC5 mRNA levels are significantly higher in the OZR, however exercise training had no effect on the expression level of FNDC5 in either the LZR or OZR. We did not observe any difference in muscle protein content of Irisin with obesity or exercise. Conclusion. Our data shows that exercise training does not increase either FNDC5 or myonectin gene expression, indicating that increased transcriptional regulation of these myokines is not induced by exercise. However, our data also indicates a yet to be explored disconnect between myonectin gene expression and protein content. Further, this report highlights the importance of verifying reference genes when completing gene expression analysis. We found that many commonly used reference genes varied significantly by obesity and/or exercise and would have skewed the results of this study if used to normalize gene expression data. The unstable reference genes include: beta-Actin, beta-2-microglobulin, Non-POU domain containing, octamer-binding, Peptidylprolyl isomerase H, 18S ribosomal RNA, TATA box binding protein and Transferrin receptor. PMID- 25289191 TI - Massively parallel read mapping on GPUs with the q-group index and PEANUT. AB - We present the q-group index, a novel data structure for read mapping tailored towards graphics processing units (GPUs) with a small memory footprint and efficient parallel algorithms for querying and building. On top of the q-group index we introduce PEANUT, a highly parallel GPU-based read mapper. PEANUT provides the possibility to output both the best hits or all hits of a read. Our benchmarks show that PEANUT outperforms other state-of-the-art read mappers in terms of speed while maintaining or slightly increasing precision, recall and sensitivity. PMID- 25289192 TI - The cranial osteology of Tyrannoneustes lythrodectikos (Crocodylomorpha: Metriorhynchidae) from the Middle Jurassic of Europe. AB - Tyrannoneustes lythrodectikos is one of numerous metriorhynchid crocodylomorph species known from the Oxford Clay Formation of England (Callovian-Oxfordian; Middle-Late Jurassic). This taxon is of evolutionary importance, as it is the oldest and most basal known macrophagous metriorhynchid. It has a mosaic of plesiomorphic and derived feeding related characteristics, including: teeth with microscopic, poorly formed and non-contiguous denticles; increased tooth apicobasal length; ventrally displaced dentary tooth row (increased gape); reduced dentary tooth count; and a proportionally long mandibular symphysis. However the type specimen, and current referred specimens, all lack a preserved cranium. As such, the craniofacial morphology of this taxon, and its potential feeding ecology, remains poorly understood. Here we describe two skulls and two lower jaws which we refer to T. lythrodectikos. Previously these specimens were referred to 'Metriorhynchus' brachyrhynchus. They share with the T. lythrodectikos holotype: the in-line reception pits on the dentary, dorsal margin of the surangular is strongly concave in lateral view, and the most of the angular ventral margin is strongly convex. Based on our description of these specimens, the skull of T. lythrodectikos has three autapomorphies: very long posterior processes of the premaxilla terminating in line with the 4th or 5th maxillary alveoli, deep lateral notches on the lateral surface of the maxillary with reception pits for dentary teeth, and the premaxilla forms the anterior margin of the first maxillary alveoli. Our description of the cranial anatomy of Tyrannoneustes lythrodectikos confirms that some macrophagous characteristics evolved during the Middle Jurassic, and were not exclusive to the clade Geosaurini. Moreover, the skulls further highlight the mosaic nature of Tyrannoneustes lythrodectikos and wide-gape macrophagous evolution in Geosaurinae. PMID- 25289193 TI - A cross-sectional study of self-reported general health, lifestyle factors, and disease: the Hordaland Health Study. AB - Background. Information on self-reported health is important for health professionals, and the aim of this study was to examine associations between lifestyle factors and self-reported health and the mediating effect of disease in a Norwegian population. Methods and Materials. The data collection was conducted as part of the Hordaland Health Study (HUSK) 1997-99, which was a cross-sectional epidemiological study. All individuals in Hordaland county born in 1953-1957 were invited to participate (aged 40-44 years). Complete information for the present study was obtained from 12,883 individuals (44% response rate). Height and weight were measured at a physical examination. Information on lifestyle factors, self reported health, disease (heart attack, apoplexy, angina pectoris, and diabetes), and socio-demographic variables was obtained from a self-administered questionnaire. Self-reported health was measured with a one-item question. Odds ratios for fair or poor self-reported health were calculated using multiple logistic regression analyses adjusted for disease and socio-demographic variables. Results. Respondents reporting adverse lifestyle behaviours (obesity (odds ratio (OR) 1.7, p < 0.001), smoking (OR 1.2, p < 0.001), or excessive intake of alcohol (OR 3.3, p < 0.001)) showed an increased risk of poor self reported health. Furthermore, a moderate intake of wine (OR 0.6, p < 0.001) or strenuous physical activity (OR 0.5, p < 0.001) decreased the risk of poor health. Disease did not mediate the effect. Conclusion. A one-item question measuring self-reported health may be a suitable measure for health professionals to identify levels of subjective health and reveal a need to target lifestyle factors in relatively young individuals with or without disease. PMID- 25289195 TI - Use of Hyperbaric Oxygen as Adjunct in Salvage of Near-complete Ear Amputation. AB - SUMMARY: There have been several cases of microvascular repair of traumatically avulsed or amputated ears in the literature. It seems that, if possible at the time of operation, microsurgical techniques yield the best results. However, because of the nature, complexity, and acuity of traumatic injuries, this option is not always feasible. Although the possibility of microsurgical repair exists, the small size of these vessels is often prohibitive, even for a skilled microsurgeon. Here, we present the case of a 4-year-old boy with almost complete amputation of the left ear attached by an inferior narrow skin pedicle after a dog bite. He was treated with primary repair and postoperative hyperbaric oxygen therapy (HBOT) with good results. This case is another example that even a narrow skin pedicle can contain artery and vein that can supply a large segment of the auricle, making primary repair feasible because of the vascular anatomy and communicating helical arcade. Also, this case demonstrates the successful use of HBOT with a pediatric patient as an adjuvant postoperative therapy. PMID- 25289194 TI - Computed tomography analysis of guinea pig bone: architecture, bone thickness and dimensions throughout development. AB - The domestic guinea pig, Cavia aperea f. porcellus, belongs to the Caviidae family of rodents. It is an important species as a pet, a source of food and in medical research. Adult weight is achieved at 8-12 months and life expectancy is ~5-6 years. Our aim was to map bone local thickness, structure and dimensions across developmental stages in the normal animal. Guinea pigs (n = 23) that had died of natural causes were collected and the bones manually extracted and cleaned. Institutional ethical permission was given under the UK Home Office guidelines and the Veterinary Surgeons Act. X-ray Micro Computed Tomography (microCT) was undertaken on the left and right scapula, humerus and femur from each animal to ascertain bone local thickness. Images were also used to undertake manual and automated bone measurements, volumes and surface areas, identify and describe nutrient, supratrochlear and supracondylar foramina. Statistical analysis between groups was carried out using ANOVA with post-hoc testing. Our data mapped a number of dimensions, and mean and maximum bone thickness of the scapula, humerus and femur in guinea pigs aged 0-1 month, 1-3 months, 3-6 months, 6 months-1 year and 1-4 years. Bone dimensions, growth rates and local bone thicknesses differed between ages and between the scapula, humerus and femur. The microCT and imaging software technology showed very distinct differences between the relative local bone thickness across the structure of the bones. Only one bone showed a singular nutrient foramen, every other bone had between 2 and 5, and every nutrient canal ran in an oblique direction. In contrast to other species, a supratrochlear foramen was observed in every humerus whereas the supracondylar foramen was always absent. Our data showed the bone local thickness, bone structure and measurements of guinea pig bones from birth to 4 years old. Importantly it showed that bone development continued after 1 year, the point at which most guinea pigs have reached full weight. This study is the first to show the high abundance (100% in this study) of the supratrochlear foramen within the guinea pig humerus and the complete absence of a supracondylar foramen, which is different to many other species and may also affect potential fracture points and frequencies. Understanding bone morphology and growth is essential in not only understanding the requirements of the healthy guinea pig, but also necessary in order to investigate disease states. PMID- 25289196 TI - Large axillary defect after lymph node dissection directly closed by suturing the pectoralis major to the latissimus dorsi. AB - SUMMARY: In 2009, the Union for International Cancer Control defined lymph node (LN) metastasis >=6 cm in diameter as stage 4 in squamous cell carcinoma of the skin. Lesions from such LNs become ulcerated and infected and bleed without treatment. A 67-year-old man suffered from skin cancer on his right back and a 7 cm-diameter LN metastasis. After axillary LN dissection, a large skin and soft tissue defect was apparent. To rectify the defect, we simply sutured the pectoralis major muscle to the latissimus dorsi muscle and covered the suture with a split-skin mesh graft. After the surgery, the range of motion of the upper limb on the side where surgery was performed remained in good condition. PMID- 25289197 TI - Suspension of Leg via a Single Tibial Pin Provides Postoperative Elevation and Pressure Off-loading for Lower Extremity Free Flaps. PMID- 25289198 TI - Semipermanent volumization by an absorbable filler: onlay injection technique to the bone. AB - BACKGROUND: Hyaluronic acid (HA) fillers have become the most popular tool for wrinkle treatment and volumization, although HA is generally absorbed within 6-12 months and requires repeated treatments to maintain the effects. METHODS: HA was injected onto the bone for volumization with a small 30-gauge needle to examine the long-lasting effects. Of the 63 Japanese patients with 97 treated sites followed up more than 12 months, 51 had HA injections for cosmetic purposes and 12 were treated for reconstructive volumization of facial deformity such as localized scleroderma and postsurgical bony deformity. Treated sites included the forehead, temple, nasal root, mentum, tear trough, and infraorbital sulcus. RESULTS: After long-term follow-up (12-93 months, mean = 21.6), persistent volumizing effects were observed in most patients. In fact, 86.6% of the treated sites showed >50% volume retention and 49.5% showed >75% retention. Magnetic resonance imaging analyses revealed that the injected space was well maintained, capsulated, and filled with heterogeneous content. Magnetic resonance imaging quantitative T2 maps indicated that much of the injected HA was replaced with other materials. Together with clinical inspection, these findings suggest that onlay injection of HA on the bone induced formation of capsule, fibrosis, and/or calcification/ossification, which contributed to persistent volumization. CONCLUSIONS: Semipermanent volumizing effects can be achieved by HA injection if the target area has an underlying bony floor. Periosteal stem cells may be activated by HA injection and may contribute to persistent volumizing effects. This treatment may be a much less invasive alternative to fat or bone grafting. PMID- 25289199 TI - Plastic and reconstructive surgery-global open: the beginning of a new era in plastic and reconstructive surgery publishing. PMID- 25289200 TI - Early Venous Occlusion Detection in a Free Flap Using Real-time Laser Doppler Imaging. AB - SUMMARY: Early detection of venous occlusion in free flaps is particularly difficult to identify, and its duration is known to be directly proportional to flap mortality. Here, we report a case of deep inferior epigastric perforator based breast reconstruction in which the intraoperative use of a perfusion camera enabled identifying a venous occlusion based on microcirculatory pulsation dynamics in real time. The sensitivity of our proposed method suggests that in certain cases in which the onset of venous occlusion begins in the operating room we can detect and treat occlusion before sending the patient to recovery. Further development of this technique will allow for earlier and more objective decision making with regard to venous occlusion detection in free tissue transfer. PMID- 25289201 TI - Minimally invasive fascia lata harvest: a new method. PMID- 25289202 TI - The Science and Theory behind Facial Aging. AB - SUMMARY: The etiology of age-related facial changes has many layers. Multiple theories have been presented over the past 50-100 years with an evolution of understanding regarding facial changes related to skin, soft tissue, muscle, and bone. This special topic will provide an overview of the current literature and evidence and theories of facial changes of the skeleton, soft tissues, and skin over time. PMID- 25289203 TI - How many work hours are requisite to publish a manuscript? PMID- 25289205 TI - High-grade Angiosarcoma Associated with Ruptured Breast Implants. AB - SUMMARY: Since the serendipitous discovery that implanted polymers cause sarcomas in rats, much research has been conducted to prove or disprove a link between silicone breast implants and/or polymer-based materials and breast cancer. In light of an initial report that 35% of rats implanted with a variety of polymers developed fibrosarcomas, we report a case of primary angiosarcoma found in a patient presenting with bilateral rupture of gel-filled breast implants. PMID- 25289204 TI - The role of wound healing and its everyday application in plastic surgery: a practical perspective and systematic review. AB - BACKGROUND: After surgery it is often recommended that patients should refrain from strenuous physical activity for 4-6 weeks. This recommendation is based on the time course of wound healing. Here, we present an overview of incisional wound healing with a focus on 2 principles that guide our postoperative recommendations: the gain of tensile strength of a wound over time and the effect of mechanical stress on wound healing. METHODS: A systematic search of the English literature was conducted using OVID, Cochrane databases, and PubMed. Inclusion criteria consisted of articles discussing the dynamics of incisional wound healing, and exclusion criteria consisted of articles discussing nonincisional wounds. RESULTS: Experiments as early as 1929 laid the groundwork for our postoperative activity recommendations. Research using animal models has shown that the gain in tensile strength of a surgical wound is sigmoidal in trajectory, reaching maximal strength approximately 6 weeks postoperatively. Although human and clinical data are limited, the principles gained from laboratory investigation have provided important insights into the relationship among mechanical stress, collagen dynamics, and the time course of wound healing. CONCLUSION: Our postoperative activity recommendations are based on a series of animal studies. Clinical research supporting these recommendations is minimal, with the most relevant clinical data stemming from early motion protocols in the orthopedic literature. We must seek to establish clinical data to support our postoperative activity recommendations so that we can maximize the physiologic relationships between wound healing and mechanical stress. PMID- 25289206 TI - Lymphatic vessel function and lymphatic growth factor secretion after microvascular lymph node transfer in lymphedema patients. AB - BACKGROUND: Recent reports have shown that microvascular lymph node transfer may improve lymphatic drainage in lymphedema patients. Lymphatic anastomoses are expected to form spontaneously in response to lymphatic growth factor [vascular endothelial growth factor C (VEGF-C)] secreted by the transferred lymph nodes. METHODS: We have analyzed the results of 19 lymph node transfer patients operated on 2007-2012. Postoperat ive lymphatic function of the affected arm was evaluated using semiquantitative lymphoscintigraphy (transport index) and limb circumference measurements. To investigate the postoperative VEGF-C secretion, we examined axillary seroma fluid samples after different surgical operations, including lymph node transfer. RESULTS: The transport index was improved postoperatively in 7 of 19 patients. Ten of the 19 patients were able to reduce or even discontinue using compression garments. Arm circumferences were reduced in 12 of 19 patients. Six of the 7 patients with preoperative erysipelas infections have not had infectious episodes postoperatively during 15-67 months follow-up. Neuropathic pain was relieved in 5 of 5 patients. VEGF-C protein was detected in the axillary seroma fluid both after lymph node transfer and normal breast reconstruction. CONCLUSIONS: Reconstructing the lymphatic anatomy of the axilla with a lymph node flap may offer possibilities that other reconstructive options are lacking. However, we will need further reports and comparative studies about the clinical efficacy of this new promising technique. In addition to the transferred lymph nodes, lymphatic growth factor production may also be induced by other factors related to microvascular breast reconstruction. PMID- 25289207 TI - Double-eyelid surgery using septoaponeurosis junctional thickening results in dynamic fold in asians. AB - BACKGROUND: To avoid a static double-eyelid fold characterized by nonmobile overdepression of the fold, we propose a new surgical approach of using septoaponeurosis junctional thickening (SAJT) to create a dynamic fold. METHODS: Six hundred eighty patients underwent double-eyelid surgery using the SAJT fixation technique. The orbital septum was exposed and transversely opened superior to the incision margin. The lower septal stump was trimmed to expose the SAJT. The dermis and orbicularis oculi muscle of the lower flap of the upper eyelid were attached to the SAJT. Patients were followed for 2-8 years (mean, 3.6 y). Anatomic study with 28 upper eyelids from 28 Korean adult cadavers was performed to confirm the histological structure of the SAJT. RESULTS: This technique created a dynamic fold. When the eyes were open, the fold depth was moderate. When the eyes were closed, the fold site was smooth and not depressed. The surgery had a 95% patient satisfaction rate (365 responded as satisfied and 236 responded as very satisfied). Postoperative complications included partial or complete loss of the double-eyelid line in 14 and 4 cases, respectively, hypertrophic scar formation in 7 cases, and asymmetric fold in 8 cases. CONCLUSIONS: The authors introduce a double-eyelid surgery technique using the SAJT. This SAJT fixation technique creates a dynamic double-eyelid fold. Our study showed a high patient satisfaction rate and that the resulting fold mimics the movement of the congenital supratarsal fold in Asians. PMID- 25289208 TI - Treatment of localized involutional lipoatrophy after local injection of corticosteroids into a keloidal scar with fat injection. PMID- 25289209 TI - Unilateral and Bilateral Breast Reconstruction with Pedicled TRAM Flaps: An Outcomes Analysis of 188 Consecutive Patients. AB - BACKGROUND: The abdomen remains a popular donor site for autologous tissue breast reconstruction. Recently, however, some authors have questioned whether the pedicled transverse rectus abdominis myocutaneous (TRAM) flap should remain a first-line reconstruction option. METHODS: Between 1998 and 2009, 188 women underwent breast reconstruction with pedicled TRAM flaps by the senior author (J.A.A.). All TRAM flaps involved reinforcement of the abdominal wall repair with polypropylene mesh. Reconstruction was unilateral in 164 patients and bilateral in 24 patients, yielding a total of 212 flaps. RESULTS: The mean follow-up period was 36 months. There were no complete flap losses. Overall hernia rate for the series was 1.6%, and overall abdominal bulge rate was 0.5%. When combining all types of morbidity, 38 unilateral (23.2%) and zero bilateral TRAM flap patients experienced flap site complications (P = 0.005), and 16 unilateral (9.8%) and 5 bilateral patients (20.8%) experienced donor site complications (P = 0.155). For morbidity that required a return to the operating room, the overall rate was 4.3% for unilateral TRAM flap patients and 4.2% for bilateral TRAM flap patients. Flap site morbidity was significantly associated with obesity, former or active smoking, and receiving 2 or more adjuvant therapies. Donor site morbidity was significantly associated with obesity. CONCLUSIONS: The pedicled TRAM flap continues to be an excellent option for breast reconstruction. Complication rates for both unilateral and bilateral TRAM flaps were low in this series, with no complete flap losses and just 4.3% of patients requiring a return to the operating room secondary to morbidity. PMID- 25289210 TI - Regenerative Surgery for the Definitive Repair of a Vasculitic Nonhealing Ulcer Using Platelet-derived Growth Factors and Noncultured Autologous Cell Suspension. AB - SUMMARY: Vasculitic ulcers are caused by numerous disorders and may be chronic if not well treated. Various modalities of treatment, both medical and surgical, are available. We describe the case of a 63-year-old patient with a vasculitic ulcer treated with platelet-derived growth factors and noncultured autologous cell suspension collected by an innovative single-use device (ReCell). PMID- 25289211 TI - Long-term Follow-up with AlloDerm in Breast Reconstruction. AB - SUMMARY: Little is known about the long-term fate of acellular dermal matrices in breast implant surgery. A 12-year follow-up case with tissue analysis of AlloDerm in revision breast reconstruction reveals retention of graft volume and integration with an organized collagen structure, minimal capsule formation, and little or no indication of inflammation. PMID- 25289212 TI - Increased Flap Weight and Decreased Perforator Number Predict Fat Necrosis in DIEP Breast Reconstruction. AB - BACKGROUND: Compromised perfusion in autologous breast reconstruction results in fat necrosis and flap loss. Increased flap weight with fewer perforator vessels may exacerbate imbalances in flap perfusion. We studied deep inferior epigastric perforator (DIEP) and muscle-sparing transverse rectus abdominis myocutaneous (MS TRAM) flaps to assess this concept. METHODS: Data from patients who underwent reconstruction with DIEP and/or MS-TRAM flaps between January 1, 2010 and December 31, 2011 (n = 123) were retrospectively reviewed. Patient demographics, comorbidities, intraoperative parameters, and postoperative outcomes were collected, including flap fat necrosis and donor/recipient site complications. Logistic regression analysis was used to examine effects of flap weight and perforator number on breast flap fat necrosis. RESULTS: One hundred twenty-three patients who underwent 179 total flap reconstructions (166 DIEP, 13 MS-TRAM) were included. Mean flap weight was 658 +/- 289 g; 132 (73.7%) were single perforator flaps. Thirteen flaps (7.5%) developed fat necrosis. African American patients had increased odds of fat necrosis (odds ratio, 11.58; P < 0.001). Odds of developing fat necrosis significantly increased with flap weight (odds ratio, 1.5 per 100 g increase; P < 0.001). In single perforator flaps weighing more than 1000 g, six (42.9%) developed fat necrosis, compared to 14.3% of large multiple perforator flaps. CONCLUSIONS: Flaps with increasing weight have increased risk of fat necrosis. These data suggest that inclusion of more than 1 perforator may decrease odds of fat necrosis in large flaps. Perforator flap breast reconstruction can be performed safely; however, considerations concerning race, body mass index, staging with tissue expanders, perforator number, and flap weight may optimize outcomes. PMID- 25289213 TI - Transcutaneous PCO2 Measurement at Low Temperature for Reliable and Continuous Free Flap Monitoring: Experimental and Clinical Study. AB - BACKGROUND: Measurement of transcutaneous oxygen pressure (TcPO2) and transcutaneous carbon dioxide pressure (TcPCO2) has been used for free flap monitoring. Because these values are obtained with sensor probes heated to 44 degrees C, there is potential for low-temperature burns on skin flaps. We measured TcPO2 and TcPCO2 at 37 degrees C in both animals and humans to determine the feasibility and safety of the procedure as a postoperative flap monitoring method. METHODS: Twelve epigastric island flaps were elevated in rabbits, and TcPO2 and TcPCO2 were measured at 37 degrees C before and after ligation of the pedicles. In addition, TcPO2 and TcPCO2 at 37 degrees C were measured in healthy men. Subsequently, the method was applied to postoperative monitoring of free flaps in 49 clinical cases. RESULTS: TcPO2 and TcPCO2 values were significantly affected by the experimental flap elevation. A rapid increase in TcPCO2 was observed with both arterial and venous occlusion. In the healthy men, TcPO2 and TcPCO2 were measurable at all skin surface sites. In the clinical cases of free flap transfer, TcPO2 values remained very low for at least 72 hours. TcPCO2 values ranged from 40 to 70 mm Hg for 72 hours in more than 80% of cases. In 2 cases, TcPCO2 values increased to more than 90 mm Hg, and exploration surgery was performed. These compromised flaps were saved by reanastomosis of the veins. CONCLUSIONS: Continuous monitoring of TcPCO2 at 37 degrees C can provide objective information and alert doctors and nurses to the need for checking the free flap. PMID- 25289214 TI - Anatomical Research of the Three-dimensional Route of the Thoracodorsal Nerve, Artery, and Veins in Latissimus Dorsi Muscle. AB - BACKGROUND: The latissimus dorsi (LD) muscle flap has been widely used in facial reanimation surgery. However, there are no standards to what degree the muscle flap may be safely thinned because the three-dimensional positional relationship of thoracodorsal artery, vein, and nerve inside the LD muscle is poorly understood. METHODS: From 18 formalin-fixed cadavers, we made 36 transparent specimens of LD muscles using a newly developed decoloration technique. In 26 specimens, nerve staining (Sihler's staining method) and silicone rubber (Microfil) injection to the thoracodorsal artery were performed, and the relationship of the artery and the vein was examined in 10 specimens. RESULTS: The thoracodorsal artery and vein always ran parallel in a deeper layer compared to the nerve. The thoracodorsal nerve constantly existed in a deeper layer than half (50%) of the muscle in the range of use of the muscle flap in facial reanimation surgery. CONCLUSIONS: The thoracodorsal nerves ran in a shallower layer, and the depth to the nerve in the muscle flap in actual facial reanimation surgery is safe enough to avoid damage to the nerves. The LD muscle may be thinned to half its original thickness safely. PMID- 25289215 TI - A case of microstomia subsequent to toxic epidermal necrolysis surgically treated by simple technique. AB - SUMMARY: Toxic epidermal necrolysis (TEN) is a rare but severe adverse dermatitis that is an autoimmune reaction to drugs such as nonsteroidal anti-inflammatory drugs. TEN most severely affects the mucous membranes including the mouth and could develop into microstomia; however, microstomia in relation to TEN has rarely been reported in the literature. We describe an adult female patient who developed microstomia due to scar contracture of the bilateral oral commissures subsequent to TEN and was successfully treated by a simple surgical technique consisting solely of transverse incision of the commissure and longitudinal closure. PMID- 25289216 TI - Differentiated Adipose-derived Stem Cells Promote Reinnervation of Rat Skin Flaps. AB - BACKGROUND: Sensory recovery of skin flaps is generally poor unless they are elevated as an innervated flap. The aim of this study was to elucidate if Schwann cell (SC)-like cells differentiated from adipose-derived stem cells (ASCs) could improve the cutaneous nerve regeneration in skin flaps. METHODS: Microvascular island groin flaps were elevated bilaterally in 32 Lewis rats. On the right flap, the epigastric nerve was resected and ligated (noninnervated flap), and on the left flap, the nerve was crushed (innervated flap). ASCs, SC-like cells differentiated from ASCs (dASCs), SCs, or vehicle were simultaneously injected to the dermal and hypodermal layers of flap. After 20 weeks, the reinnervation pattern of flap was assessed immunohistochemically using a neuronal marker, PGP9.5. RESULTS: dASC cultures produced significantly higher amount of nerve growth factor and brain-derived neurotrophic factor compared with ASC cultures (P < 0.01), and the level was comparable to that of SC cultures. Although a long term survival of the transplanted cells was not found, dASCs and SCs significantly increased reinnervation density in the periphery of both types of flaps (P < 0.05), and this effect was more pronounced in noninnervated flaps. On the other hand, ASC transplantation showed no statistically significant effect on the peripheral reinnervation (P > 0.05). In the center of flap, there was no statistically significant increase in reinnervation density in all groups irrespective of flap innervation (P > 0.05). CONCLUSIONS: dASCs could improve flap reinnervation by 2 mechanisms: First, neurotrophic factors produced by dASCs facilitated regrowth of cutaneous axons from the surroundings of flap. Second, nerve growth factor released by dASCs induced the collateral sprouting of undamaged axons in adjacent tissues. In addition to the use of innervated flaps, dASC transplantation therapy could be a new approach to improve the sensory recovery of skin flaps. PMID- 25289217 TI - Chemoprophylaxis for venous thromboembolism prevention: concerns regarding efficacy and ethics. AB - SUMMARY: Chemoprophylaxis has been recommended for plastic surgery patients judged to be at increased risk for venous thromboembolism. Several investigators have encountered this complication in patients despite anticoagulation therapy. An increased rate of complications related to postoperative bleeding has been reported. This article examines the efficacy and safety of this intervention, along with ethical considerations, in an attempt to determine whether any benefits of chemoprophylaxis justify the additional risks. The statistical methods and conclusion of the Venous Thromboembolism Prevention Study are challenged. Other preventative measures that do not cause negative side effects are discussed as safer alternatives. PMID- 25289218 TI - The Positive Effect of Neurolysis on Diabetic Patients with Compressed Nerves of the Lower Extremities: A Systematic Review and Meta-analysis. AB - BACKGROUND: Despite proven benefits of upper extremity nerve decompression in diabetics, neurolysis for diabetic patients with lower extremity (LE) nerve compression remains controversial. METHODS: A search of ClinicalTrials.gov and Cochrane clinical trials registries, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, CINAHL, SCOPUS, and Google Scholar from 1962 to 2012, yielded 1956 citations. Any potential randomized or quasi-randomized controlled trials and observational cohort studies of diabetics with neurolysis of the common peroneal nerve, deep peroneal nerve, or tibial nerve were assessed. We included articles in any language that 1) provided information about diabetic patients who had neurolysis for symptomatic nerve compression diagnosed by (+) Tinel sign or electrodiagnostic study, and 2) quantified outcomes for pain, sensibility, or ulcerations/amputations. Case reports, review articles, animal or cadaver studies, and studies with <10 patients were excluded. We assessed pain relief, recovery of sensibility, and postoperative incidence of ulcerations/amputations at follow-up >3 months. A meta-analysis of descriptive statistics was performed. RESULTS: Ten clinical series with a mean clinical relevance score of 70% and a mean methodologic quality score of 50% met inclusion criteria. We included 875 diabetic patients and 1053 LEs. Pain relief >3 points on visual analog scale occurred in 91% of patients; sensibility improved in 69%. Postoperative ulceration/amputation incidence was significantly reduced compared to preoperative incidence (odds ratio = 0.066, 95% confidence interval = 0.026 0.164, P < 0.0001). CONCLUSIONS: Observational data suggest that neurolysis significantly improves outcomes for diabetic patients with compressed nerves of the LE. No randomized controlled trials have been published. PMID- 25289220 TI - An extraoral nasoalveolar molding technique in complete unilateral cleft lip and palate. AB - SUMMARY: Although nasoalveolar molding is commonly performed before cleft lip surgery, customized palatal plate availability is limited for patients far from a hospital. This case report describes a preformed extraoral nasoalveolar molding (PENAM) appliance and treatment approach for presurgical nasoalveolar molding in newborns with complete unilateral cleft lip and palate. A 12-day-old boy presented with complete unilateral cleft lip and palate. The PENAM device was supported by an adhesive-taped upper lip, which consisted of a lip nasal stent made from a 0.5-mm stainless steel wire. The spring was activated monthly. The shape of the cartilaginous septum, alar cartilage tip, medial crus, lateral crus, and alveolar segments was molded to resemble the normal shape of these structures. The 9.3-mm alveolar gaps were reduced and approximated. The approximation mostly came from the major alveolus segment with approximately 6.4 mm movement. Cleft side nostril height increased 5.5 mm and deviation of the columella was corrected by 42 degrees . PENAM can be helpful in infants with unilateral cleft lip and palate because it has benefits for long-term forced delivery, requires less frequent activations, and is suitable for patients who live far from a hospital. PMID- 25289219 TI - Keloids and hypertrophic scars: update and future directions. AB - SUMMARY: The development of cutaneous pathological scars, namely, hypertrophic scars (HSs) and keloids, involves complex pathways, and the exact mechanisms by which they are initiated, evolved, and regulated remain to be fully elucidated. The generally held concepts that keloids and HSs represent "aberrant wound healing" or that they are "characterized by hyalinized collagen bundles" have done little to promote their accurate clinicopathological classification or to stimulate research into the specific causes of these scars and effective preventative therapies. To overcome this barrier, we review here the most recent findings regarding the pathology and pathogenesis of keloids and HSs. The aberrations of HSs and keloids in terms of the inflammation, proliferation, and remodeling phases of the wound healing process are described. In particular, the significant roles that the extracellular matrix and the epidermal and dermal layers of skin play in scar pathogenesis are examined. Finally, the current hypotheses of pathological scar etiology that should be tested by basic and clinical investigators are detailed. Therapies that have been found to be effective are described, including several that evolved directly from the aforementioned etiology hypotheses. A better understanding of pathological scar etiology and manifestations will improve the clinical and histopathological classification and treatment of these important lesions. PMID- 25289221 TI - My first 100 consecutive microvascular free flaps: pearls and lessons learned in first year of practice. AB - BACKGROUND: Microvascular reconstruction for oncologic defects is a challenging and rewarding endeavor, and successful outcomes are dependent on a multitude of factors. This study represents lessons learned from a personal prospective experience with 100 consecutive free flaps. METHODS: All patients' medical records were reviewed for demographics, operative notes, and complications. RESULTS: Overall 100 flaps were performed in 84 consecutive patients for reconstruction of breast, head and neck, trunk, and extremity defects. Nineteen patients underwent free flap breast reconstruction with 10 patients undergoing bilateral reconstruction and 2 patients receiving a bipedicle flap for reconstruction of a unilateral breast defect. Sixty-five free flaps were performed in 61 patients with 3 patients receiving 2 free flaps for reconstruction of extensive head and neck defects and 1 patient who required a second flap for partial flap loss. Trunk and extremity reconstruction was less common with 2 free flaps performed in each group. Overall, 19 patients (22.6%) developed complications and 14 required a return to the operating room. There were no flap losses in this cohort. Thorough preoperative evaluation and workup, meticulous surgical technique and intraoperative planning, and diligent postoperative monitoring and prompt intervention are critical for flap success. CONCLUSIONS: As a young plastic surgeon embarking in reconstructive plastic surgery at an academic institution, the challenges and dilemmas presented in the first year of practice have been daunting but also represent opportunities for learning and improvement. Skills and knowledge acquired from time, experience, and mentors are invaluable in optimizing outcomes in microvascular free flap reconstruction. PMID- 25289222 TI - Polydactylous subungual squamous cell carcinoma caused by chemical contact. AB - SUMMARY: Polydactylous squamous cell carcinoma (SCC) is rare and has been associated with human papillomavirus (HPV). Our recent case was HPV negative and provides greater evidence for chemical irritants being an alternative cause of subungual SCC. Our patient had spent a number of years with her hands in direct contact with undiluted cleaning chemicals including one containing ethanolamine. Ethanolamine has been shown to have carcinogen sensitizing role. Although HPV has a strong association with subungual SCCs, the accumulation and concentration of noxious substances around and under the nails must also be considered as a potential cause. PMID- 25289223 TI - Bilateral poly implant prothese implant rupture: an uncommon presentation. AB - SUMMARY: A woman in her 50s underwent delayed bilateral Poly Implant Prothese implant reconstruction following mastectomy for breast cancer. Symptoms of implant rupture developed 43 months after surgery with an erythematous rash on her trunk. The rash then spread to her reconstructed breast mounds. Initial ultrasound scan and magnetic resonance imaging were normal; however, subsequent magnetic resonance imaging demonstrated left implant rupture only. In theater, following removal of both implants, both were found to be ruptured. The rash on her trunk resolved within 3 weeks in the postoperative period. Chemical analyses of silicone in both implants confirmed a nonauthorized silicone source; in addition, the chemical structure was significantly different between the left and right implant, perhaps explaining the variation in presentation. PMID- 25289224 TI - Preoperative Anemia and Postoperative Outcomes in Immediate Breast Reconstructive Surgery: A Critical Analysis of 10,958 Patients from the ACS-NSQIP Database. AB - BACKGROUND: Preoperative anemia is independently associated with adverse outcomes after general and cardiac surgery. Outcomes after breast reconstruction are not established. We assessed the effect of preoperative anemia on 30-day postoperative morbidity and length of hospital stay (LOS) in patients undergoing immediate breast reconstruction. METHODS: We identified patients undergoing immediate breast reconstruction from 2008 to 2010 from the American College of Surgeons' National Surgical Quality Improvement Program database (a prospective outcomes-based registry from hospitals worldwide). De-identified data were obtained for demographics, preoperative risk factors, 30-day morbidity, and LOS. Morbidity variables included flap/graft/prosthesis, cardiac, respiratory, neurological, urinary, wound, and venous thromboembolism outcomes. Logistic regression assessed the crude and adjusted effect of anemia (hematocrit <36%) on postoperative 30-day morbidity. Measures of central tendency of LOS were compared across increasing severities of anemia in patients developing adverse events versus controls. RESULTS: The study population included 10,958 patients; 1556 (16.74%) had preoperative anemia. Crude odds ratio for 30-day morbidity was significantly higher in anemic patients, unadjusted odds ratio = 1.33 (P < 0.008). This prevailed after extensive adjustment for confounding, yielding an adjusted odds ratio = 1.38 (P < 0.03). Patients who experienced adverse effects had protracted LOS, and the presence of anemia significantly amplified this effect. CONCLUSIONS: These data provide new insight into the effect of anemia in immediate breast reconstruction, demonstrating an independent association between preoperative anemia and 30-day morbidity. These findings suggest treating anemia when possible; however, prospective studies should explore the efficacy, safety, and cost-effectiveness of such treatments. PMID- 25289225 TI - Patient-Reported Assessment of Functional Gait Outcomes following Superior Gluteal Artery Perforator Reconstruction. AB - BACKGROUND: Harvesting the superior gluteal artery perforator (SGAP) flap involves dissection of vessels through the gluteal muscle, potentially compromising gait and ambulation. We compared patient-reported gait and ambulation problems between SGAP flap and deep inferior epigastric perforator (DIEP) flap reconstructions. METHODS: Forty-three patients who underwent bilateral free flap breast reconstruction (17 SGAP, 26 DIEP) participated in the study. The Lower Extremity Functional Score (LEFS) was administered with a supplementary section evaluating gait, balance, fatigue, and pain. Patients evaluated how they felt 2 months postoperatively and at time of survey administration. Multivariate regressions were fit to assess association between type of reconstruction and self-reported lower extremity function controlling for potential confounding factors. RESULTS: Although there was no significant difference in overall LEFS between the cohorts on the date of survey, the SGAP patients reported greater difficulty performing the following activities after surgery (P < 0.05): work, usual hobbies, squatting, walking a mile, walking up stairs, sitting for an hour, running, turning, and hopping. The SGAP patients also reported easier fatigue (P < 0.01) both during the early postoperative period and on the date of survey. CONCLUSIONS: SGAP flap surgery causes no statistically significant differences in overall LEFS. However, SGAP patients did report donor-site morbidity with decreased ability to perform certain activities and increased fatigue and pain in the longer follow-up period. We feel that patients should be educated regarding gait issues and undergo physical therapy during the early postoperative period. PMID- 25289226 TI - Prospective clinical study of 551 cases of liposuction and abdominoplasty performed individually and in combination. AB - BACKGROUND: Despite the popularity of these procedures, there are limited published prospective studies evaluating liposuction and abdominoplasty. Lipoabdominoplasty is a subject of recent attention. Several investigators have recommended alternative techniques that preserve the Scarpa fascia in an effort to reduce complications, particularly the risk of seromas. METHODS: Over a 5-year period, 551 consecutive patients were treated with ultrasonic liposuction alone (n = 384), liposuction/abdominoplasty (n = 150), or abdominoplasty alone (n = 17). In lipoabdominoplasties, the abdomen and flanks were first treated with liposuction. A traditional flap dissection was used for all abdominoplasties. Scalpel dissection was used rather than electrodissection. A supine "jackknife" position was used in surgery to provide maximum hip flexion, allowing a secure deep fascial repair. RESULTS: The complication rate after liposuction was 4.2% vs 50% for patients treated with an abdominoplasty. Approximately half of the abdominoplasty complications were minor scar deformities, including widened umbilical scars (17.3%) that were revised. The seroma rate after abdominoplasties was 5.4%; there were no seromas after liposuction alone. CONCLUSIONS: Lipoabdominoplasty may be performed safely, so that patients may benefit from both modalities. The seroma rate is reduced by avoiding electrodissection, making Scarpa fascia preservation a moot point. A deep fascial repair keeps the abdominoplasty scar within the bikini line. Deep venous thrombosis and other complications may be minimized with precautions that do not include anticoagulation. PMID- 25289227 TI - Generation Y and the Integrated Plastic Surgery Residency Match: A Cross sectional Study of the 2011 Match Outcomes. AB - BACKGROUND: Plastic surgery is the most competitive specialty in medicine. We sought to identify factors associated with the successful match of generation Y applicants into integrated plastic surgery residency. METHODS: We utilized the most recent data from the Charting Outcomes in the Match published by the National Resident Matching Program in 2011. We had data on US senior or independent applicant status, Alpha Omega Alpha (AOA) status, attendance of top 40 medical schools, advanced degree status, and number of contiguous ranks within plastic surgery. Our main outcome measure was match status. RESULTS: A total of 81 out of 197 applicants (41.1%) successfully matched into integrated plastic surgery in the 2011 main match. US seniors matched at a significantly higher rate compared to independent applicants (44.0% vs 24.1%, P = 0.044). Matched US seniors were more likely to have AOA membership compared to unmatched US seniors (45.9% vs 27.7%, P = 0.014) and attend a top 40 medical school (52.7% vs 35.1%, P = 0.022). There were no differences in terms of advanced degrees between matched and unmatched US seniors. Unmatched US seniors were more likely to have 3 or fewer contiguous ranks of plastic surgery residency programs than matched US seniors (86.2% vs 68.9%, P = 0.007). CONCLUSIONS: US senior status, AOA membership, and attendance at a top 40 medical school are predictors of matching into integrated plastic surgery. Program directors need to be aware of the background of the millennial applicants to recruit and maintain top residents. PMID- 25289228 TI - Revascularization of Arterialized Venous Flaps through a Total Retrograde Reverse Blood Flow: Randomized Experimental Trial of Viability. AB - BACKGROUND: Arterialized venous flaps (AVFs) have been used for reconstruction of soft tissue defects throughout the body. Several different revascularization models have been performed, but venous drainage through the arterial system has not been studied. In our total retrograde reverse blood flow (TRRBF) perfusion model, the arterial blood flow enters through the venous system and venous drainage exits through the arterial system. METHODS: We developed a novel experimental model in rabbit ears to evaluate the capacity of TRRBF perfusion pattern to allow AVF viability. The ears were assigned to 3 groups: group 1, total devascularization without revascularization (n = 3); group 2, TRRBF (n = 12); and group 3, conventional AVF (n = 12). The ears were observed during a 30 day follow-up period, and clinical serial assessment of edema, cyanosis, and necrosis was performed. Tissue oxygenation was determined at the beginning and end of the follow-up. Histological analysis was performed. RESULTS: Necrosis was found in 3/3 (100%) ears in group 1, 3/12 (25%) in group 2, and 0/12 (0%) in group 3 (95% CI, 0.505-0.994; P = 0.0001). In group 2, edema was higher (5/12, 41.66%) than in group 3 (0/12, 0%) (95% CI, 0.0135-0.65; P = 0.041). Cyanosis and venous congestion was of greater intensity and duration in group 2 than in group 3 (10.33 +/- 4.51 vs 4.5 +/- 2.06 d). CONCLUSIONS: Although evolution is torpid and prolonged in ears with TRRBF, 9/12 (75%) survived, suggesting that TRRBF can be used as a rescue method. PMID- 25289229 TI - Calf contouring with endoscopic fascial release, calf implant, and structural fat grafting. AB - BACKGROUND: Curved lower legs cause psychological stress for women. In evaluating the shape, if thickness is the main contributing factor of leg aesthetic, then lipoplasty or calf reducing procedures will be the option. If the legs are slender and have no muscle hypertrophy but still have some indentation or bulges on both sides and lack an aesthetic shape what will be the options? The answer to the question is discussed in detail in this article. METHODS: Twenty-two patients, operated over a period of 5 years from 2007 to 2012, were included in the study. A novel technique has been introduced. This method requires release of fascia covering muscles of the inner leg bulge via endoscopic approach and simultaneous calf augmentation with calf implant, liposuction, and structural fat grafting to optimize the results. RESULTS: Patients were followed on a regular basis with a mean follow-up of 31 months. The procedure was well tolerated with minimal discomfort during the postoperative period. Increase in diameter of proximal and distal lower legs was measured at least 6 months after surgery. Mean diameter change of proximal lower legs was 2.16 cm and 1.77 cm in distal lower legs. CONCLUSIONS: A novel endoscopic approach for lower leg contouring is discussed. Endoscopic fasciotomy technique with calf implant and structural fat grafting for improved lower leg aesthetics is a simple, effective, reliable, and predictable technique for calf contouring. PMID- 25289230 TI - Free Radial Forearm "Bunting" Flap for Reconstructing Soft-tissue Defects Involving Multiple Fingers. AB - SUMMARY: Reconstruction of soft-tissue defects on multiple fingers is challenging because the number of recipient vessels for free flaps is limited. We report the use of a free radial forearm flap with multiple perforator-based skin islands for the reconstruction of complex soft-tissue defects involving multiple fingers. The injuries were caused by a heat press. The flap was transferred, like "bunting," to the injured hand with an exteriorized pedicle. The technique presented here is advantageous because it simultaneously covers multiple defects and allows immediate hand therapy after the operation. PMID- 25289231 TI - Radiofrequency-assisted Liposuction for Arm Contouring: Technique under Local Anesthesia. AB - BACKGROUND: Contouring of the arms that does not involve skin excision remains a difficult challenge due to the dependent nature and quality of the skin. Although brachioplasty remains effective, it requires a lengthy incision. Radiofrequency assisted liposuction (RFAL) may improve skin retraction with a satisfactory aesthetic result without skin resection and the resultant scar. The purpose of this study is to present our experience of RFAL arm contouring under local anesthesia, detailing safety guidelines, the marking technique, operative technique, complications, third-party surgeon appraisal, and patient satisfaction survey. METHODS: Forty patients underwent RFAL under local tumescent anesthesia for aesthetic arm contouring. Postoperative patient satisfaction surveys were conducted and independent third-party surgeons were surveyed to assess improvements in contour and skin quality with preoperative and postoperative photographs. RESULTS: Complications included 1 burn near the elbow treated successfully with local wound care and 1 seroma that resolved with aspiration. The patient survey indicated that most patients had minimal or no discomfort with the injection of local anesthesia, application of radiofrequency energy, or aspiration of fat. The majority of patients were satisfied with their contouring result and degree of skin tightening. Third-party plastic surgeons found the improvement in contouring and degree of skin tightening good to excellent. CONCLUSIONS: In appropriately selected patients, RFAL arm contouring under local anesthesia represents an alternative procedure with acceptably low morbidity and high patient satisfaction. To achieve consistent results while minimizing complications, consideration to anatomic details, infiltration of the local anesthetic, and application of the radiofrequency energy must be given. PMID- 25289232 TI - Posterior Scar Brachioplasty with Fascial Suspension: A Long-term Follow-up of a Modified Technique. AB - BACKGROUND: The traditional long medial arm incision with its resultant scar is not acceptable. The author presents his long-term experience in performing the posterior scar brachioplasty with fascial suspension. The technique is a modification described by other authors. The aim of the author is to demonstrate the reasons for the choice of the posterior scar technique with fascial suspension. METHODS: Between 1999 and 2012, the posterior scar technique with fascial suspension was used to treat 205 patients with brachial deformities. Age at operation ranged between 21 and 66 years. All patients were examined, and the author reviewed their medical charts during the follow-up period (29-98 mo). A Likert scale and an evaluation questionnaire were used to assess the aesthetic outcome of the posterior scar brachioplasty technique. RESULTS: All patients who underwent the posterior scar technique were free of postoperative contour deformities. Postoperatively, the scar was completely invisible when viewed from patient's front and patient's lateral but was partially visible when viewed from patient's back. And 88.8% of patients tolerated the scar with high satisfaction. CONCLUSIONS: The current posterior scar maneuver with fascial suspension prevented the tension on the suture line and consequently prevented the widening of the scar and facilitated the modeling procedure by removing the appropriate amount of skin and subcutaneous tissues. It creates a low-lying, posterior, well hidden scar when viewed from the patient's front or patient's lateral. The scar is partially (upper third) visible when viewed from patient's back. The technique is avoiding injury to the sensory and motor nerves of the arm and decreases the insult to the lymphatic. PMID- 25289233 TI - The Role of the Very Long Posterior Tibial Artery Flap following Severe Lower Limb Trauma: Case Series and Literature Review. AB - SUMMARY: With advancing techniques, knowledge, and training, the decision to salvage a lower limb following severe trauma is becoming ever more popular and successful. However, in cases where amputation is inevitable due to extensive injury or infection, we encourage the use of the very long posterior tibial artery (VLPTA) flap when the sole of the foot and posterior tibial neurovasculature are intact. We report 3 patients who underwent below-knee amputation and reconstruction using the VLPTA flap. A literature review was also performed to identify the outcomes and any complications associated with VLPTA flap. PMID- 25289234 TI - The fate of nonvascularized fat grafts: histological and bioluminescent study. AB - BACKGROUND: Nonvascularized fat grafting has become one of the most popular options for breast contouring. However, the survival process of the grafts remains to be elucidated. In this study, we tracked the fate of nonvascularized fat grafts with in vivo bioluminescence and immunohistochemistry. METHODS: Nonvascularized fat grafts or vascularized adiposal flaps from luciferase transgenic rats were transplanted to Lewis rats. The bioluminescent signals from the grafts were monitored longitudinally. In addition, nonvascularized fat grafts from Lewis rats were engrafted to Lewis rats and the viability of the adipocytes in the grafts was evaluated with immunohistochemical staining for perilipin at postoperative week 1, 2, 3, 4, and 6. RESULTS: The bioluminescent signals from the nonvascularized fat grafts increased drastically from postoperative day 3 to 7, stayed flat from day 7 to 12, and declined from day 12 to 17, whereas those from the vascularized fat flaps remained throughout the entire postoperative period. Immunohistochemistry revealed that the survival zones with large adipocytes were decreased within 2 weeks and the regenerating zones with small adipocytes appeared after 3 weeks. CONCLUSIONS: Our study showed the process of survival and regeneration of nonvascularized fat grafts and suggested that graft derived stromal cells proliferated within 7 days after transplantation and differentiated into adipocytes after postoperative week 3. PMID- 25289235 TI - Histological and Ultrastructural Effects of Ultrasound-induced Cavitation on Human Skin Adipose Tissue. AB - BACKGROUND: In aesthetic medicine, the most promising techniques for noninvasive body sculpturing purposes are based on ultrasound-induced fat cavitation. Liporeductive ultrasound devices afford clinically relevant subcutaneous fat pad reduction without significant adverse reactions. This study aims at evaluating the histological and ultrastructural changes induced by ultrasound cavitation on the different cell components of human skin. METHODS: Control and ultrasound treated ex vivo abdominal full-thickness skin samples and skin biopsies from patients pretreated with or without ultrasound cavitation were studied histologically, morphometrically, and ultrastructurally to evaluate possible changes in adipocyte size and morphology. Adipocyte apoptosis and triglyceride release were also assayed. Clinical evaluation of the effects of 4 weekly ultrasound vs sham treatments was performed by plicometry. RESULTS: Compared with the sham-treated control samples, ultrasound cavitation induced a statistically significant reduction in the size of the adipocytes (P < 0.001), the appearance of micropores and triglyceride leakage and release in the conditioned medium (P < 0.05 at 15 min), or adipose tissue interstitium, without appreciable changes in microvascular, stromal, and epidermal components and in the number of apoptotic adipocytes. Clinically, the ultrasound treatment caused a significant reduction of abdominal fat. CONCLUSIONS: This study further strengthens the current notion that noninvasive transcutaneous ultrasound cavitation is a promising and safe technology for localized reduction of fat and provides experimental evidence for its specific mechanism of action on the adipocytes. PMID- 25289236 TI - Usefulness of Irradiated Polyglactin 910 (Vicryl Rapide) for Skin Suturing during Surgery for Lateral Ray Polydactyly of the Toes in Children. AB - BACKGROUND: This study describes the use of a bioabsorbable suture for skin suturing during surgery for lateral ray polydactyly followed by favorable postoperative outcome without the need for postoperative suture removal. METHODS: A 5-0 Vicryl Rapide suture was used for skin suturing during surgery for lateral ray polydactyly in 9 children (mean age, 12.4 mo). Children were allowed to walk and bathe 2 weeks after surgery when over-the-suture taping therapy was started. RESULTS: In all cases, the Vicryl Rapide suture disappeared completely within 3 weeks of surgery, and no removal of residual suture was required. No postoperative complications, such as suture abscess, wound dehiscence, or ulcer, were observed. During a mean 24-month postoperative follow-up, no elevation of the interdigital space due to hypertrophic scarring or scar contracture was observed, and no revision surgery was required. CONCLUSIONS: Although the breaking strength of Vicryl Rapide declines within the first 10 days after surgery, this property will unlikely lead to postoperative wound dehiscence due to a relatively light load being applied to the lateral toes. The use of a bioabsorbable suture for skin suturing during surgery for lateral lay polydactyly is highly beneficial as it eliminates pain caused by suture removal and the risk of tissue damage while reducing the burden on medical staff. PMID- 25289237 TI - Silicone breast implants are thicker than water. PMID- 25289239 TI - Correction of asian short nose with lower lateral cartilage repositioning and ear cartilage grafting. AB - BACKGROUND: Asians with short nose lack the cartilage needed to extend the length of the nose. A rhinoplasty technique using lower lateral cartilage (LLC) repositioning and ear cartilage grafting allows for sufficient nasal lengthening and nasal tip mobility in the correction of short nose in Asians. METHODS: Short nose was classified into 3 subtypes: type I, II, or III. During LLC repositioning, the LLC was separated from surrounding retaining structures, except at the footplate. The LLC was approximated medially and advanced with a Medpor strut. A silicone dorsal implant was inserted to suit the newly projected nasal tip. An ear cartilage onlay graft or ear cartilage extension graft was applied to further project and enhance the nasal tip and columella. RESULTS: Of the 854 primary rhinoplasty procedures performed on Asian patients between January 2008 and December 2011, 295 were performed on patients with short nose. LLC repositioning and ear cartilage onlay grafting were performed on 228 patients. LLC repositioning and ear cartilage extension grafting with or without ear cartilage onlay grafting were performed on 67 patients. Short nasal tip, alar retraction, and columellar retraction were corrected. Wound dehiscence with marginal necrosis occurred in 7 patients. One patient developed nasal infection. CONCLUSIONS: LLC repositioning and ear cartilage grafting aid in the correction of short nose in Asians. With LLC repositioning and ear cartilage grafting, the nasal tip can be positioned in accordance with the patient's anatomic limits. The entire nasal tip and columella can be lengthened, while the tip maintains its mobility. PMID- 25289238 TI - The Effect of Control-released Basic Fibroblast Growth Factor in Wound Healing: Histological Analyses and Clinical Application. AB - BACKGROUND: Basic fibroblast growth factors (bFGFs) play a crucial role in wound healing by promoting fibroblast proliferation and neovascularization. However, drawback of bFGF is short half-life in free form. Gelatin has a capability of sustaining growth factors, which are gradually released while degradation. The purpose of this study is to see whether bFGF-impregnated gelatin sheet is effective in a murine model and whether it could also be available for patients in a safe manner. METHODS: Full-thickness skin defect was created on C57BL/6J mice and covered with bFGF with gelatin sheet (group A), bFGF without gelatin sheet (group B), phosphate buffer saline (PBS) with gelatin sheet (group C), and only PBS (group D). Wound healing was evaluated in terms of percent wound closure, granulation thickness, wound maturity, and vascular density. Clinical trial was conducted for patients who received either acute or chronic ulcers. The sheets were put onto the wounds and covered by hydrocolloid dressing, which was changed weekly. RESULTS: Groups A and B exhibited better wound healing than groups C and D in all aspects. Moreover, group A showed better results than group B at day 7 in terms of wound closure, collagen maturity, and vascularity. Efficacy without any adverse events was found in the clinical series. CONCLUSIONS: These findings suggest that control-released bFGF using gelatin sheet is effective for promoting wound healing. Such therapeutic strategy was considered to offer several clinical advantages including rapid healing and reduction of the dressing change with less patient discomfort. PMID- 25289240 TI - The "posterior cervical lift": a new approach to pterygium colli management. AB - BACKGROUND: The prevalence of pterygium colli ("webbed neck") is 75% in patients with Turner syndrome. This congenital deformity manifests as a bilateral cervical skin fold stretching from the mastoid to the acromion. Although the visibility of this skin fold varies among patients, it frequently has negative social effects. The surgical management of this malformation remains challenging as it requires the achievement of a harmonious neck profile and natural hairline implantation. METHODS: We describe a series of 5 girls with Turner syndrome who were managed in our department at the University Hospital Center of Toulouse-Rangueil, France. All patients benefited from a surgical approach based on a new posterior technique, including half-moon resection of the skin fold with an inferior back cut and suturing of the superficial lamina of the cervical fascia. To ensure solidity, the fascia was fastened to the nuchal ligament. RESULTS: Patients' mean age at surgery was 10 years (range, 6-13 y). The mean duration of follow-up was 13.7 years (range, 2-20 y). No scar enlargement or recurrence was remotely authenticated. The patients were satisfied with the cosmetic results, including an esthetic neck profile and recovery of hairline implantation. CONCLUSION: The "posterior cervical lift," an innovative surgical technique for the management of pterygium colli, achieved satisfying cosmetic outcomes and stability over time. PMID- 25289241 TI - Fractional Skin Harvesting: Autologous Skin Grafting without Donor-site Morbidity. AB - BACKGROUND: Conventional autologous skin grafts are associated with significant donor-site morbidity. This study was conducted to determine feasibility, safety, and efficacy of a new strategy for skin grafting based on harvesting small columns of full-thickness skin with minimal donor-site morbidity. METHODS: The swine model was used for this study. Hundreds of full-thickness columns of skin tissue (~700 um diameter) were harvested using a custom-made harvesting device, and then applied directly to excisional skin wounds. Healing in donor and graft sites was evaluated over 3 months by digital photographic measurement of wound size and blinded, computer-aided evaluation of histological features and compared with control wounds that healed by secondary intention or with conventional split thickness skin grafts (STSG). RESULTS: After harvesting hundreds of skin columns, the donor sites healed rapidly without scarring. These sites reepithelialized within days and were grossly and histologically indistinguishable from normal skin within 7 weeks. By contrast, STSG donor sites required 2 weeks for reepithelialization and retained scar-like characteristics in epidermal and dermal architecture throughout the experiment. Wounds grafted with skin columns resulted in accelerated reepithelialization compared with ungrafted wounds while avoiding the "fish-net" patterning caused by STSG. CONCLUSION: Full-thickness columns of skin can be harvested in large quantities with negligible long-term donor-site morbidity, and these columns can be applied directly to skin wounds to enhance wound healing. PMID- 25289242 TI - Reconstruction of upper and lower eyelids with auricular, postauricular, and retroauricular scalping flap with cartilage flap. PMID- 25289244 TI - Curvature index of pincer nail. AB - SUMMARY: Pincer nails are a common problem, and various treatments have been reported. However, there is no simple assessment of severity. We designed a curvature index for the nail plate to assess the severity of pincer nail. Measurement of the curvature index was as follows. The apparent width of the nail tip was defined as A, and the traced length of the nail tip was defined as B. The curvature index was defined as B divided by A (B/A). With this curvature index, it is easy to describe the severity of the pincer nail and to compare the improvement before and after treatment. PMID- 25289243 TI - Impact of diabetes and peripheral arterial occlusive disease on the functional microcirculation at the plantar foot. AB - BACKGROUND: Plastic and reconstructive surgeons are commonly faced with chronic ulcerations and consecutive wound infections of the feet as complications in patients with diabetes and/or peripheral arterial occlusive disease (PAOD). Microcirculatory changes seem to play an important role. However, the evaluation of functional changes in the soft tissue microcirculation at the plantar foot using combined Laser-Doppler and Photospectrometry System has not yet been performed in patients with DM or PAOD. METHODS: A prospective, controlled cohort study was designed consisting of a total of 107 subjects allocated to 1 of 3 groups-group A: healthy subjects (57% males, 63.3 y); group B: patients with diabetes mellitus (DM) (53% males, 59.4 y); and group C: patients with PAOD (81% males, 66.1 y). Microcirculatory data were assessed using a combined Laser Doppler and Photospectrometry System. RESULTS: Global cutaneous oxygen saturation microcirculation at the plantar foot of healthy individuals was 8.4% higher than in patients with DM and 8.1% higher than in patients with PAOD (both P = 0.033). Patients with diabetes did not show significant differences in global cutaneous blood flow when compared with either healthy subjects or patients suffering from PAOD. CONCLUSIONS: Functional microcirculation at the plantar foot differs between healthy subjects and patients suffering from diabetes or PAOD of the same age. Patients with either diabetes or PAOD demonstrate deteriorated cutaneous oxygen saturation with equivalent blood perfusion at the plantar foot. More clinical studies have to be conducted to evaluate therapeutical methods that might ameliorate cutaneous oxygen saturation within diabetic foot disease and PAOD. PMID- 25289245 TI - Mycobacterium fortuitum Infection following Reconstructive Breast Surgery: Differentiation from Classically Described Red Breast Syndrome. AB - BACKGROUND: Red breast syndrome (RBS) has been described as an erythema that may be associated with 2-stage prosthetic reconstructive breast surgery using biologic mesh. RBS is differentiated from infectious cellulitis through absence of fever and laboratory abnormalities and usually has a self-limiting course. There have been no clinical reports on etiology, risk factors, or management of RBS. This report describes patient data that raise the need to rule out mycobacterial infection when RBS is being considered as a diagnosis. METHODS: We present 6 cases of Mycobacterium fortuitum infection occurring after prosthetic breast reconstruction performed with a human-derived acellular dermal matrix, including the timing and course of erythema, laboratory results, treatments used, and long-term outcomes. We also describe the differential diagnoses of RBS in the context of these cases, including emergence of acid-fast bacilli and diagnostic and treatment considerations. Exact two-tailed 95% confidence intervals based on the F-distribution are provided with estimates of the incidence rates of infection. RESULTS: The 6 cases presented here do not fit the typical description of RBS and were caused by mycobacterium infection. Statistical evaluation of the estimated incidence rate of M. fortuitum infection in a patient thought to have RBS, which occurred 100% of the time in this series, revealed a 95% confidence interval of 54.1-100%. CONCLUSIONS: When presented with possible RBS, surgeons must rule out cellulitis, culture for acid-fast bacilli such as mycobacterium species, and then determine the best course of treatment. Patient counseling regarding potential household sources of infection is warranted to minimize postoperative infection risk. PMID- 25289246 TI - A method for direct fabrication of a lingual splint for management of pediatric mandibular fractures. AB - SUMMARY: Pediatric mandibular fractures have successfully been managed in various ways. The use of a lingual splint is one such option. The typical indirect method for acrylic lingual splint fabrication involves obtaining dental impressions. Dental models are produced from those impressions so that model surgery may be performed. The splint is then made on those models using resin powder and liquid monomer in a wet laboratory and transferred to the patient. Obvious limitations to this technique exist for both patient and operator. We present a technique for direct, intraoperative, fabrication of a splint using commercially available light-cured material that avoids some of the shortcomings of the indirect method. Recommendations are made based on available material safety information. PMID- 25289248 TI - Preconstruction of the Pars Pendulans Urethrae for Phalloplasty with Digestive Mucosa Using a Prefabricated Anterolateral Thigh Flap in a One-arm Patient. AB - SUMMARY: We herein report a successful preconstruction of the pars pendulans urethrae with the ileum mucosa for phalloplasty in a one-arm patient using a prefabricated anterolateral thigh flap. After a 2-stage operation and an 18-month follow-up, the patient achieved a good postoperative appearance and an excellent function of neophallus. We believe the use of digestive mucosa for urethral reconstruction enlightens us and deserves further comprehensive clinical studies. PMID- 25289247 TI - Salvage of intraoperative deep inferior epigastric perforator flap venous congestion with augmentation of venous outflow: flap morbidity and review of the literature. AB - BACKGROUND: Breast reconstruction with deep inferior epigastric perforator (DIEP) flaps has gained considerable popularity due to reduced donor-site morbidity. Previous studies have identified the superficial venous system as the dominant outflow to DIEP flaps. DIEP flap venous congestion occurs if superficial venous outflow via the deep venous system is insufficient for effective flap drainage. Although augmentation of venous outflow through a second venous anastomosis may relieve venous congestion, effects on flap morbidity remain ill defined. METHODS: A retrospective analysis of 1616 patients who underwent 2618 DIEP flap breast reconstructions between March 2005 and January 2012 was performed. Patients with intraoperative venous congestion underwent a second venous anastomosis. Preoperative demographic data and methods used to relieve venous congestion were recorded. Incidence of flap morbidity was calculated and compared with a group of 418 controls having 639 DIEP flap breast reconstructions with no venous congestion. RESULTS: Venous augmentation was required to relieve venous congestion in 87 (3.3%) DIEP flaps on 81 patients. The superficial inferior epigastric vein or accompanying deep inferior epigastric venae comitantes was used to augment venous outflow. Preoperative comorbidities were similar between both groups. Patients requiring a second venous anastomosis had a longer operative time and length of hospital stay. Overall, flap morbidity, delayed wound healing, fat necrosis, and flap loss were similar to controls. CONCLUSIONS: Arterial and venous anatomies play unique roles in flap reliability. DIEP flap venous congestion must be treated expeditiously with venous augmentation to relieve venous congestion and mitigate flap morbidity. PMID- 25289249 TI - Systemic nicardipine as an adjunct to combat vasospasm after prior flap failure. AB - SUMMARY: Unrecognized or untreated vasospasm in microsurgery can lead to flap hypoperfusion and failure. Numerous strategies have been explored for their efficacy in potentiating vasodilation. We present a case of unrecognized vasospasm leading to flap failure followed by a second free flap reconstruction in which severe vasospasm was treated with systemic nicardipine used as an adjunct to other more commonly employed antispasmodics. Although the literature investigating the use of systemic calcium channel blockade in microsurgery is limited, it should be considered an alternative when addressing arterial vasospasm. PMID- 25289250 TI - Revisiting Triple Antibiotic Irrigation of Breast Implant Pockets: A Placebo controlled Single Practice Cohort Study. AB - BACKGROUND: Capsular contracture is the most common complication following primary augmentation mammoplasty. It remains poorly understood but is attributed to subclinical infection, immunologic response to breast implants, and chronic inflammatory changes caused by the presence of the implants. The infectious theory of contracture has lead to the practice of irrigating implant pockets with a triple antibiotic solution. The purpose of this study was to determine if antibiotic irrigation reduced the incidence and severity of capsular contracture compared with saline irrigation. METHODS: A cohort study enrolling all patients having undergone primary augmentation mammoplasty performed by surgeon A and surgeon B between 2011 and 2012 for all women satisfying inclusion and exclusion criteria was conducted. The only difference in surgical technique was the use of antibiotic irrigation by surgeon B. A chi-square test and analysis of variance with predetermined 95% confidence intervals were performed. RESULTS: Fifty-five patients were operated on. Twenty-eight of surgeon A's patients were included, ranging in age from 22 to 50 with a mean follow-up time of 1.8 years. Twenty seven of surgeon B's patients were included, ranging in age from 22 to 56 with a mean follow-up time of 1.6 years. Rate of capsular contracture was 3.6% (surgeon A) and 3.7% (surgeon B). Chi-square statistic was found to be 0.0014 (P = 0.97) and analysis of variance F value was 1 (P = 0.39). CONCLUSIONS: Triple antibiotic breast irrigation is not associated with a significant reduction in the incidence or severity of capsular contracture compared with sterile saline when high quality surgical technique is used. PMID- 25289251 TI - Mechanical Leeching with Venocutaneous Fistula and Monitoring with Near-infrared Spectroscopy. AB - SUMMARY: The report herein describes the use of a venocutaneous fistula with angiocatheter attachment and near-infrared spectroscopy device to correct venous congestion of a vertical upper gracilis free flap used for breast reconstruction. This method of mechanical leeching was precisely controlled through monitoring trends in the tissue oxygen saturation levels of the flap, allowing venous congestion to be relieved before it became clinically apparent. PMID- 25289253 TI - Serratus branch as recipient vessel for microvascular tissue transfer in breast reconstruction. PMID- 25289252 TI - Complication rate of autologous cartilage microtia reconstruction: a systematic review. AB - BACKGROUND: Autologous cartilage has been widely accepted as the frame material of ear reconstruction for patients with microtia. Although rare, there are multiple complications related with the surgical reconstruction techniques. The authors performed a systematic review of the English literature of microtia reconstruction to determine significant surgical factors that are predictors of postoperative complications. METHODS: A PubMed search using the terms "ear reconstruction" and "microtia" was conducted. Articles were screened using predetermined inclusion and exclusion criteria. Data collected included patient characteristics, surgical techniques, the incidence of all kinds of complications, and the specific postoperative morbidity. Patient cohorts were pooled, and the incidence of complications was calculated. Significant predictors such as the use of tissue expander, simultaneously mid-ear reconstruction, with/without skin graft, and different fascia coverage were analyzed by chi square test. RESULT: Of 320 articles found, 60 met the inclusion criteria. Totally 9415 patients with microtia were analyzed in this review with 1525 cases with complications. The overall complication incidence is 16.2% in average with a range of 0-72.9%. There was no significant difference when comparing the overall complication rate between with/without preexpansion 2-stage and multiple-stage techniques or with/without mid-ear reconstruction simultaneously. CONCLUSION: Although there is little agreement in literature regarding risk factors for complications, the authors were able to demonstrate several significant predictors by systematically analyzing 60 articles. Improved knowledge of the incidence of different complications related with various surgical methods can help surgeons provide improved preoperative counseling and take measures to minimize the risk. PMID- 25289254 TI - Obesity-induced Upper Extremity Lymphedema. AB - SUMMARY: Obesity increases the risk of upper extremity lymphedema following treatment for breast cancer and can cause lower extremity lymphatic dysfunction in extremely obese individuals. We report the first patient with obesity-induced upper extremity lymphedema. A 62-year-old man with a previous body mass index (BMI) of 105.6, presented with a BMI 60.3 following weight loss. He complained of lymphedema of all 4 extremities, which was confirmed by lymphoscintigraphy. Because the upper limbs are more resistant to lymphedema than the lower extremities, a higher BMI threshold may be necessary to cause upper extremity lymphatic dysfunction. PMID- 25289255 TI - HSL Attenuates the Follicular Oxidative Stress and Enhances the Hair Growth in ob/ob Mice. AB - SUMMARY: We demonstrated enhanced hair regeneration following topical administration of N-(3-oxododecanoyl)-l-homoserine lactone (HSL) in ob/ob mice. The ob/ob mice showed delayed hair regeneration (more than 6 wk) after depilation, which rapidly induced transition to anagen in the hair cycle in wild type mice. Vehicle and HSL solutions were applied to the depilated dorsal skin of ob/ob mice. The depilated skin of the HSL-treated mice was fully covered with hair, whereas no macroscopic alteration was observed in vehicle-treated group by the fourth week after depilation. Oxidative stress was drastically decreased and the expression of the antioxidative enzymes PON1 and PON3 was increased in the HSL-treated skin with highly proliferative anagen follicles. These results suggest that HSL is a candidate therapeutic agent for alopecia in metabolic syndrome. PMID- 25289256 TI - Objective integrated assessment of functional outcomes in reduction mammaplasty. AB - BACKGROUND: The aim of our study was an objective integrated assessment of the functional outcomes of reduction mammaplasty. METHODS: The study involved 17 women undergoing reduction mammaplasty from March 2009 to June 2011. Each patient was assessed before surgery and 2 months postoperatively with the original association of 4 subjective and objective assessment methods: a physiatric clinical examination, the Roland Morris Disability Questionnaire, the Berg Balance Scale, and a static force platform analysis. RESULTS: All of the tests proved multiple statistically significant associated outcomes demonstrating a significant improvement in the functional status following reduction mammaplasty. Surgical correction of breast hypertrophy could achieve both spinal pain relief and recovery of performance status in everyday life tasks, owing to a muscular postural functional rearrangement with a consistent antigravity muscle activity sparing. Pain reduction in turn could reduce the antalgic stiffness and improved the spinal range of motion. In our sample, the improvement of the spinal range of motion in flexion matched a similar improvement in extension. Recovery of a more favorable postural pattern with reduction of the anterior imbalance was demonstrated by the static force stabilometry. Therefore, postoperatively, all of our patients narrowed the gap between the actual body barycenter and the ideal one. The static force platform assessment also consistently confirmed the effectiveness of an accurate clinical examination of functional impairment from breast hypertrophy. CONCLUSIONS: The static force platform assessment might help the clinician to support the diagnosis of functional impairment from a breast hypertrophy with objectively based data. PMID- 25289258 TI - Impact of medical tourism on cosmetic surgery in the United States. AB - SUMMARY: Developing countries have been attracting more international patients by building state-of-the-art facilities and offering sought-after healthcare services at a fraction of the cost of the US healthcare system. These price differentials matter most for elective procedures, including cosmetic surgeries, which are paid for out of pocket. It is unclear how this rise in medical tourism will affect the practice of plastic surgery, which encompasses a uniquely large number of elective procedures. By examining trends in the globalization of the cosmetic surgery market, we can better understand the current situation and what plastic surgeons in the United States can expect. In this article, we explore both domestic and foreign factors that affect surgical tourism and the current state of this industry. We also discuss how it may affect the practice of cosmetic surgery within the United States. PMID- 25289257 TI - Clinical characteristics and surgical decision making for infants with metopic craniosynostosis in conjunction with other congenital anomalies. AB - BACKGROUND: Metopic craniosynostosis can occur in isolation or in conjunction with other congenital anomalies. The surgical decision making and outcomes between these 2 groups are analyzed. METHODS: A retrospective review of all children evaluated in the craniofacial clinic at Seattle Children's Hospital for metopic craniosynostosis between 2004 and 2009 was performed. Physical examination and CT scan characteristics were analyzed as were the treatment decisions and surgical outcomes. RESULTS: From 2004 to 2009, 282 patients were evaluated and 100 were determined to have metopic craniosynostosis. Of these, 19 patients were found to have additional congenital anomalies. Review of these patients' CT scans revealed 13 with classic trigonencephaly, 3 with microcephaly, and 3 with narrow frontal bones, abnormal orbits, and small anterior fossa. Patients (90%) with isolated metopic craniosynostosis underwent cranial vault expansion, whereas only 63% of the complex group did so. The complex metopic group had a longer hospital stay (5 d vs 3.4 d), more intraoperative complications, and required more repeat surgery. CONCLUSION: Patients with metopic craniosynostosis and additional anomalies require special consideration when deciding upon surgical intervention and should be cared for by a multidisciplinary team to address their additional needs. PMID- 25289259 TI - Cause of androgenic alopecia: crux of the matter. AB - SUMMARY: What is wrong with the current understanding of etiopatho genesis of androgenic alopecia (AGA)? What is the most important question to ask to understand AGA? Why is that question skimped? Which findings are interpreted incorrectly? Is there anything that has not been discerned about AGA until today? What are the deceptive factors for investigators? Is it possible to snap the whole view uninterruptedly in one clear picture? Answers and an overview with fresh perspectives are provided. PMID- 25289260 TI - Preserving the posttrapeziectomy space with a human acellular dermal matrix spacer: a pilot case series of patients with thumb carpometacarpal joint arthritis. AB - BACKGROUND: Advanced thumb carpometacarpal arthritis is widely treated with trapeziectomy and tendon interposition despite donor-site morbidities. Trapeziectomy alone leaves a postresection space, leading to proximal metacarpal migration and scaphoid/trapezoid impingement. Prosthetic implants have been unsuccessful due to particulate debris, silicone synovitis, osteolysis, and migration. Recent studies have shown successful use of allograft for interposition material in the posttrapeziectomy space both in animal and human models. To obviate the need for autologous tissue, maintain thumb length, and reduce the risk of scaphoid impingement, the senior author developed an interposition arthroplasty technique using a spacer constructed from human acellular dermal matrix (HADM). METHODS: Sixteen patients with Eaton stage III-IV thumb carpometacarpal osteoarthritis received the above procedure from the 2 senior authors. HADM was imbricated to fill the posttrapeziectomy space and secured to the volar capsule and metacarpal base. Pre- and postoperative trapezial space on radiograph, pain scores, and grip strength were recorded. RESULTS: Six months postoperatively, radiographs showed an average joint space loss of 11%. Heights postoperatively were not significantly different from immediate postoperative heights (P >= 0.01). At 6 months, patients had improved pain and grip strength (P <= 0.01). No infections, foreign body reactions, or other complications occurred. CONCLUSIONS: HADM has been used extensively in other forms of reconstruction and has been shown to incorporate into surrounding tissues through neovascularization. Our early results illustrate that HADM can safely fill the dead space left by trapeziectomy. PMID- 25289262 TI - Beware the masquerading malignancy. PMID- 25289263 TI - Latissimus dorsi flap invasion by ductal breast carcinoma after lipofilling. AB - SUMMARY: Autologous fat grafting is commonly performed in reconstructive breast surgery but also increasingly in breast augmentation surgery. On the international level, we are witnessing an important increased confidence for this procedure. Nevertheless, it continues to raise questions on the risks of cancer. A 66-year-old patient benefited from a lipofilling to improve a latissimus dorsi flap breast reconstruction, 7 years after initial cancer management. Two years later, constant pain in the flap leads to reoperation. The flap showed a major retraction with histologically massive infiltration of the muscle by an undifferentiated carcinoma of breast origin. The tumor cells were displayed directly in contact with lipofilling inside the muscle. Without establishing any causal link between these 2 events, this case raises the question once more of the risks of breast cancer and encourages us to continue being careful. PMID- 25289261 TI - Levels of Evidence in Cosmetic Surgery: Analysis and Recommendations Using a New CLEAR Classification. AB - BACKGROUND: The Level of Evidence rating was introduced in 2011 to grade the quality of publications. This system evaluates study design but does not assess several other quality indicators. This study introduces a new "Cosmetic Level of Evidence And Recommendation" (CLEAR) classification that includes additional methodological criteria and compares this new classification with the existing system. METHODS: All rated publications in the Cosmetic Section of Plastic and Reconstructive Surgery, July 2011 through June 2013, were evaluated. The published Level of Evidence rating (1-5) and criteria relevant to study design and methodology for each study were tabulated. A new CLEAR rating was assigned to each article, including a recommendation grade (A-D). The published Level of Evidence rating (1-5) was compared with the recommendation grade determined using the CLEAR classification. RESULTS: Among the 87 cosmetic articles, 48 studies (55%) were designated as level 4. Three articles were assigned a level 1, but they contained deficiencies sufficient to undermine the conclusions. The correlation between the published Level of Evidence classification (1-5) and CLEAR Grade (A-D) was weak (rho = 0.11, not significant). Only 41 studies (48%) evaluated consecutive patients or consecutive patients meeting inclusion criteria. CONCLUSIONS: The CLEAR classification considers methodological factors in evaluating study reliability. A prospective study among consecutive patients meeting eligibility criteria, with a reported inclusion rate, the use of contemporaneous controls when indicated, and consideration of confounders is a realistic goal. Such measures are likely to improve study quality. PMID- 25289264 TI - Free nipple graft technique to correct nipple and areola malposition after breast procedures. AB - SUMMARY: Secondary correction of nipple areola complex (NAC) malposition represents a major concern after breast reconstructive procedures. It is frequently requested by patients complaining about asymmetric areolas impairing the whole reconstructive procedure and asking for improved cosmetic outcomes. Several methods have been described to achieve a good symmetry between the 2 areolas, either natural or reconstructed. We describe our correction technique with free NAC graft. A total of 16 patients were treated with free NAC grafts between April 2010 and April 2013 at the European Institute of Oncology, Milan, Italy. This series focused on the surgical technique and its postoperative outcomes. Three cases of partial graft loss (18%) were observed in the postoperative period. No total NAC necrosis occurred. No infection was observed. All the complications were managed with a conservative treatment, not requiring any further surgery. NAC malposition following breast reconstructive procedures can be corrected using the technique of free NAC graft with reliable and satisfactory results. PMID- 25289265 TI - Muscle is a target for preservation in a rat limb replantation model. AB - BACKGROUND: Ischemia exceeding 6 hours makes clinical limb replantation difficult and places the patient at risk of functional deficit or limb loss. We investigated the preservation of muscle function and morphology with solutions in rat hindlimb in vivo and in vitro. METHODS: Quadriceps femoris muscles from luciferase transgenic rats were preserved for 24 hours at 4 degrees C in extracellular-type trehalose containing Kyoto (ETK), University of Wisconsin (UW), or lactated Ringer's (LR) solution (control). Muscle luminescence was measured with a bioimaging system. Amputated limbs of Lewis rats preserved with ETK, UW, or LR for 6 or 24 hours at 4 degrees C were transplanted orthotopically. At week 8, terminal latency and amplitude were measured in the tibialis anterior muscle. The muscles were also analyzed histologically. RESULTS: Isolated muscles preserved in ETK or UW had significantly higher luminescence than did muscles immersed in LR (P < 0.05). In the 6-hour-preserved limb transplantation model, although the 3 groups had almost the same terminal latency, electrical amplitude was significantly lower in the LR group. Histologically, muscles preserved with LR showed the most atrophic changes. In the 24-hour-preserved model, the survival rate of the LR group was 37.5% in contrast to 80% in the ETK and UW groups. Electrical signals were not detected in the LR group owing to severe muscle atrophy and fibrosis. The ETK and UW groups showed good muscle function electrophysiologically. CONCLUSIONS: Preservation solutions can protect muscle function and morphology in ischemia-reperfusion limbs and improve recipient survival rates after transplantation of long-term-preserved limbs. PMID- 25289266 TI - Breast Reconstruction after a Bilateral Mastectomy Using the BRAVA Expansion System and Fat Grafting. AB - SUMMARY: Fat graft breast reconstruction following a mastectomy is always limited by the size of the skin envelope, which affects the amount of graft that can be injected in 1 session. Because the fat graft naturally resorbs in all patients, several sessions of fat grafting are necessary. BRAVA's negative pressure causes a "reverse" expansion of the skin envelope, thus permitting more space for the fat graft. This allows decreasing number of required procedures for an adequate breast reconstruction. We operated on a 38-year-old patient 4 years after bilateral mastectomy without irradiation for breast cancer. Before the procedure, the patient was instructed to wear the BRAVA system for 12 hours daily for 2 months before the first session, at all times between the sessions and for 1 month following the last fat grafting session. We performed 3 fat grafting sessions, as planned. Altogether, we injected 840 cm(3) of fat on the right side and 790 cm(3) of fat on the left side. Four months after the last operation, the patient was very satisfied with her new breasts. The breasts were soft, with good sensation and a natural feel. Using the BRAVA external expansion system for the enhancement of fat grafting is a suitable technique for breast reconstruction after a mastectomy. This technique produces soft and natural feeling breasts in fewer operative sessions, with a minimal risk of complications. Patient compliance, however, is greatly needed to achieve the desired results. PMID- 25289267 TI - Breast Reinnervation: DIEP Neurotization Using the Third Anterior Intercostal Nerve. AB - BACKGROUND: The purpose of this article is to evaluate a new method of DIEP flap neurotization using a reliably located recipient nerve. We hypothesize that neurotization by this method (with either nerve conduit or direct nerve coaptation) will have a positive effect on sensory recovery. METHODS: Fifty-seven deep inferior epigastric perforator (DIEP) flaps were performed on 35 patients. Neurotizations were performed to the third anterior intercostal nerve by directly coapting the flap donor nerve or coapting with a nerve conduit. Nine nonneurotized DIEP flaps served as controls and received no attempted neurotization. All patients were tested for breast sensibility in 9 areas of the flap skin-island and adjacent postmastectomy skin. Testing occurred at an average of 111 weeks (23-309) postoperatively. RESULTS: At a mean of 111 weeks after breast reconstruction, neurotization of the DIEP flap resulted in recovery of sensibility that was statistically significantly better (lower threshold) in the flap skin (P < 0.01) and statistically significantly better than in the native mastectomy skin into which the DIEP flap was inserted (P < 0.01). Sensibility recovered in DIEP flaps neurotized using the nerve conduit was significantly better (lower threshold) than that in the corresponding areas of the DIEP flaps neurotized by direct coaptation (P < 0.01). CONCLUSION: DIEP flap neurotization using the third anterior intercostal nerve is an effective technique to provide a significant increase in sensory recovery for breast reconstruction patients, while adding minimal surgical time. Additionally, the use of a nerve conduit produces increased sensory recovery when compared direct coaptation. PMID- 25289268 TI - Morcellized Omental Transfer for Severe HIV Facial Wasting. AB - BACKGROUND: A novel surgical technique to reconstruct facial wasting was developed for patients with severe human immunodeficiency virus lipoatrophy and no source of subcutaneous fat for donor material. Fourteen patients underwent endoscopic harvest of omentum, extracorporeal morcellation, and autologous transfer to the face. METHODS: Omental fat was harvested using a standard 3-port laparoscopic technique. A mechanical tissue processor created morsels suitable for transfer. Gold-plated, multi-holed catheters delivered living particulate fat to the subcutaneous planes of the buccal, malar, lateral cheek, and temporal regions. Results were evaluated using standardized pre- and postoperative photographs for specific anatomic criteria found along the typical progression of the disease process. RESULTS: Electron microscopy confirmed that morcellized fat retained intact cell walls and was appropriate for autologous transfer. Complications were minor and transient. Patients were discharged home within 24 hours. No patient required open laparotomy. Survival of the adipose grafts was deemed good to excellent in 13 of the 14 cases. CONCLUSIONS: Mechanically morcellized omental fat transfer provides a safe option to restore facial volume in those unusual patients with severe wasting and no available subcutaneous tissue for transfer. Consistent anatomic progression of facial wasting permits preoperative classification, counseling of patients, and postoperative evaluation of surgical improvement. PMID- 25289269 TI - Isolated malignant melanoma metastasis to the pancreas. AB - SUMMARY: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field. PMID- 25289270 TI - Advances in liposuction: five key principles with emphasis on patient safety and outcomes. AB - SUMMARY: Since Illouz's presentation of a technique for lipoplasty at the 1982 Annual Meeting of the American Society of Plastic and Reconstructive Surgeons, liposuction has become one of the most commonly performed aesthetic surgery procedures. The evolution of liposuction has seen refinements in technique and improvement of patient safety-related standards of care. Based on long-term experience with body contouring surgery, 5 principles of advanced liposuction are presented: preoperative evaluation and planning, intraoperative monitoring-safety measures, the role of wetting solutions and fluid resuscitation, circumferential contouring and complication prevention, and outcomes measurement. PMID- 25289271 TI - Use of nasal septal bone for septal extension graft after jaw surgery. AB - BACKGROUND: After jaw surgery, there is often posterior caudal septal defect with dislocation of caudal septum from anterior nasal spine. In such patients, reconstruction of caudal septum is required during rhinoplasty. The authors used septal bone for nasal tip surgery reconstructing caudal septum in patients who have no desire to use autologous or homologous costal cartilage or foreign material. METHODS: This study included 50 patients who underwent rhinoplasty using septal bone from November 2009 to September 2012. The subjective satisfaction of patients was evaluated 6 to 12 months after rhinoplasty with a questionnaire. RESULTS: Mean follow-up was 9 months. Forty-three patients (86%) answered the questionnaire after the operation. Postoperative subjective satisfaction was excellent in 28 cases (65%), good in 9 cases (21%), fair in 4 cases (9%), no change in 1 case (2%), and poor or worse in 1 case (2%). CONCLUSIONS: Use of septal bone for septal extension graft may serve as a valuable option in septal cartilage-depleted patients. It gives a strong construct for tip surgery with patient satisfaction. PMID- 25289272 TI - Porcine acellular dermis-assisted breast reconstruction: influence of adjuvant radiotherapy on complications and outcomes. AB - BACKGROUND: Implant-based reconstruction is the most frequently performed breast reconstruction procedure. A persistent issue with this approach is optimizing outcomes in the setting of radiotherapy. Experimental evidence suggests that acellular dermal matrix use may provide a protective benefit, but clinical evidence is lacking. The purpose of this study was to assess postoperative complications and the effect of radiotherapy on complications and outcomes in women who underwent immediate, porcine acellular dermal matrix (PADM, Strattice) assisted, implant-based breast reconstruction postmastectomy. METHODS: Patients with at least 1 year of follow-up were included in this retrospective study. Patient charts were reviewed for demographic data, adjunctive therapy use, duration of follow-up, and type and incidence of complications during follow-up. RESULTS: A total of 158 reconstructions were performed in 103 patients. Adjuvant therapy included chemotherapy in 51% of patients and radiotherapy in 25% of breasts. Mean follow-up was 36.2 months. Complications occurred in 17 breasts (10.8%): implant/expander loss (8.2%); infection (5.7%); dehiscence (3.8%); eschar (1.9%); and ischemia, hematoma, and seroma (0.6% each). Nine breasts with complications had been irradiated; all were irradiated prereconstruction. Rate of total complications, implant/expander loss, and dehiscence was significantly higher in irradiated breasts. Breasts irradiated postreconstruction had no complications. CONCLUSIONS: Addition of PADM to implant-based reconstruction is associated with acceptable complication rates comparable to those observed with standard submuscular reconstructions. Complications are increased in the setting of radiotherapy; but PADM use may protect against the adverse effects of postreconstruction radiotherapy. PMID- 25289273 TI - Are We Killing Our Fat Cells before Grafting Them? PMID- 25289274 TI - Application of transverse titanium plate refixation in deep sternal wound infection: a retrospective analysis. PMID- 25289275 TI - Trans-vastus Intermedius Transfer of the Pedicled Anterolateral Thigh Flap for Posterior Thigh Reconstruction. AB - SUMMARY: Proximal, posterior thigh wounds from oncologic or traumatic defects can be difficult wounds to reconstruct if local flap options have been sacrificed during the trauma or oncologic resection. Free flap options to cover these defects are also difficult because of the lack of convenient recipient vessels in the region. The authors present 2 cases (oncologic and traumatic) wherein a myocutaneous anterolateral thigh (ALT) flap was harvested and tunneled from the anterior muscle compartment to the posterior muscle compartment of the thigh through a medially based transmuscular tunnel, decreasing the required pedicle distance to the wound. This technique of transmuscular tunneling of the ALT flap expands the indications and utility of the ALT flap to cover posterior thigh wounds. PMID- 25289276 TI - Skin lesions after prophylactic mastectomy and immediate reconstruction. AB - SUMMARY: Metastatic breast carcinoma can mimic benign cutaneous lesions. Breast surgeons should be aware of skin manifestations to be able to distinguish them and set a proper therapeutic strategy. A clinical case of cutaneous lesion after breast cancer is presented. A 41-year-old woman with a history of left breast cancer underwent a prophylactic right nipple-sparing mastectomy with immediate breast implant reconstruction. After surgery, she attended our service due to a right periareolar rash resistant to medical treatment, accompanied by cutaneous induration and fixed axillary adenopathy. A differential diagnosis of skin metastases was considered. Cutaneous metastases should be the first diagnosis of skin lesions in oncological patients due to the implications in terms of treatment and prognosis. However, differential diagnoses have to be discussed. PMID- 25289277 TI - Metastasis of hepatocellular and renal cell carcinoma to the hand. AB - SUMMARY: Malignant carcinoma metastasis to the skeleton is the third most common site of metastasis after lung and liver, usually involving the axial skeleton and the proximal ends of long bones, ribs, and vertebrae. Acrometastasis, metastasis to hands or feet, comprises only 0.1% of all metastases. Here, we present 2 cases of acrometastasis, one from hepatocellular carcinoma and the other from renal cell carcinoma. We describe the presentation, radiographs, surgical treatment, and outcomes for each patient. Patients presented with swelling and pain at the tumor sites and were treated with amputations. The second patient's disease progressed resulting in death shortly after amputation indicating acrometastasis may be a poor prognostic indicator of survival. We review the literature and discuss the importance of disease process recognition and prognosis. PMID- 25289278 TI - Evaluation of Six Split-thickness Skin Graft Donor-site Dressing Materials in a Swine Model. AB - BACKGROUND: Numerous dressings for split-thickness skin graft donor sites are commercially available with no conclusive evidence-based consensus regarding the optimal dressing choice. This study was conducted to identify which of 5 commonly used materials promotes wound healing most effectively for use on split-thickness donor sites in comparison with our standard dressing, Xeroform (petrolatum gauze). METHODS: Twenty-four partial-thickness wounds were created on the backs of 4 pigs using a dermatome. Wounds (n = 4 per dressing type per pig) were treated with Xeroform, Opsite (polyurethane film), Kaltostat ( calcium sodium alginate), DuoDERM (hydrocolloid), Aquacel (hydrofiber), and Mepilex (silicone foam). Full-thickness skin samples were excised at 3 or 5 days and evaluated histologically for reepithelialization and inflammation. Comparisons also included incidence of infection, ease of use, and cost analyses. RESULTS: DuoDERM elicited the greatest percent reepithelialization (81%) and Mepilex the lowest (33%) after 3 days (P = 0.004). All dressings demonstrated complete reepithelialization except Mepilex (85%) at 5 days. There were no infections and inflammation was mild among all treatments. Mepilex was easiest to use, whereas Aquacel, Kaltostat, and Opsite were most difficult (P = 0.03). Xeroform was most cost-effective and Aquacel most expensive. Combined scoring revealed DuoDERM = Xeroform > Opsite = Mepilex > Kaltostat > Aquacel. CONCLUSIONS: DuoDERM and Xeroform were most effective overall. DuoDERM tended to outperform all dressings in reepithelialization at 3 days, while Xeroform was least expensive, easy to use, and demonstrated rapid reepithelialization. These findings suggest that Xeroform may be preferred for use on large donor-site areas. DuoDERM may be more appropriate for small donor sites when healing time is a priority. PMID- 25289279 TI - Utility of the method using the tsukisui device to control intraoperative bleeding applied to neurofibroma resection. AB - SUMMARY: The resection of neurofibromas in Von Recklinghausen's disease [neurofibromatosis type 1 (NF-1)] is frequently complicated due to size, location, hypervascularity, and tissue friability. A repeat resection, however, is necessary for patients with functional problems such as unexpected tumor bleeding or with changes in esthetic appearance. This report describes application of the method using the Tsukisui device to resecting NF-1 tumors while minimizing blood loss. The method using the Tsukisui device was applied for the resection of 8 NF-1 tumors (5 patients), and intraoperative blood loss, operative time, and postoperative complications were recorded. In all cases employing this method, intraoperative blood loss was <360 ml (10-360 ml), and none of the patients developed postoperative hematoma or other notable bleeding complications. The method using the Tsukisui device, which provided excellent hemostasis and was associated with few complications, shows promise for application to neurofibroma resection. PMID- 25289280 TI - Use of SERI Surgical Scaffold for Soft-tissue Support in a Massive Weight Loss Patient. AB - SUMMARY: Patients with a history of massive weight loss have compromised and poor quality skin and fascia. Various body contouring surgeries aim to improve appearance and shape of the trunk and restore fascial integrity. These patients may be at increased risk of recurrent fascial laxity or bulges after conventional techniques. Here, the author presents a case where a silk-based bioresorbable scaffold was used prophylactically in a massive weight loss patient undergoing a circumferential body lift. PMID- 25289281 TI - No Residual Basal Cell Carcinoma after Excision for Biopsy-proven Tumor: Clinical and Medicolegal Implications. AB - SUMMARY: Our analysis of 127 head and neck region basal cell carcinomas (BCCs) showed that there was no evidence of residual BCC in 15% of patients, one of which is presented in this report. These patients received some type of reconstructive surgery after excision of lesions with negative tumor. Thus, there is a chance that any reexcision after a shave biopsy which is positive for BCC may be negative for tumor. This finding substantiates our realization that sometimes what some would call unnecessary surgery is a common reality. The surgeon's goal is tumor eradication, and therefore, watchful waiting is usually not a legitimate clinical implication. This report has value in letting our esteemed legal colleagues know what we do not know, which still remains within the standard of appropriate care. However, the finding of no residual tumor in the current report may change our practice habits. Watchful waiting may be an option, particularly in the elderly and fragile patients. Also, one may opt to decrease the safety margins during excision when treating patients with biopsy proven BCC. However, reconstructive procedures may still be required in the case of nonpersistent tumor. Therefore, it is extremely important that the informed consent should include statements regarding possible reconstructive procedures to avoid medicolegal implications. PMID- 25289282 TI - Reverse Anterolateral Thigh Flap to Revise a Below-knee Amputation Stump at the Mid-tibial Level. AB - SUMMARY: The reconstruction of defects around the knee often poses a challenge due to the limited availability of local soft tissues. Indeed, this same problem is encountered when attempting to revise a below-knee amputation stump. Moreover, due to a paucity of recipient vessels in those who have undergone previous amputation secondary to trauma, free-flap reconstruction is often challenging and not always successful. We report a case of a reverse anterolateral thigh (ALT) flap used to revise a long below-knee amputation stump. Previous reports in the literature attest to the versatility of the reverse ALT to cover defects around the knee and proximal tibia, but to our knowledge, this is the first report of a reverse ALT reaching to the mid-tibial level. PMID- 25289283 TI - Comparison of vertical and inverted-T mammaplasties using photographic measurements. AB - BACKGROUND: Surgeons have long debated the relative merits of vertical and inverted-T mammaplasties. These debates have centered on surgeons' opinions. Without measurements, this controversy is unlikely to be resolved. This study compares these common techniques using a recently published measurement system. Such a study using measurements on photographs matched for size and orientation has not been previously published. METHODS: A prospective group of women undergoing primary vertical mastopexies, augmentation/mastopexies, and reductions (n = 78) was compared with a retrospective group of women treated with inverted-T mastopexies, augmentation/mastopexies, and reductions (n = 35). Consecutive patients with photographs at least 3 months after surgery and no subsequent procedures were evaluated. RESULTS: All patient groups demonstrated a significant elevation (P < 0.001) of the breast mound. Vertical mastopexy, but not inverted-T mastopexy, increased breast projection and upper pole projection (P < 0.008). Neither vertical nor inverted-T breast reduction significantly increased breast projection. Vertical breast reduction better preserved breast projection (P < 0.017) than the inverted-T technique. Vertical reduction significantly increased upper pole projection (P < 0.008), but inverted-T reduction did not. The inverted T breast reduction caused greater breast constriction (reduced lower pole distance) than the vertical technique. Lower pole ratios were significantly higher for inverted-T patients (P < 0.01), indicating boxier lower poles. CONCLUSIONS: Photographic measurements of relevant breast parameters favor the vertical technique over the inverted-T technique and are consistent with anatomical considerations and clinical experience. PMID- 25289284 TI - The influence of preservation solution on the viability of grafts in hair transplantation surgery. AB - SUMMARY: Hair transplantation techniques have changed in the last decades. Partial longitudinal follicular unit transplantation is a new hair transplantation technique, which differs from all other hair transplantation techniques by the size of the graft and therefore much more vulnerable grafts compared to the conventional hair transplantation grafts. In this study, we reveal the influence of the preservation solution on the viability of the grafts. We have extracted 15 hair transplantation grafts of 0.6 mm and 15 hair transplantation grafts of 0.7 mm from 3 different patients and investigated the influence of 2 commercially available preservation media, saline solution (Braun, Melsungen, Germany) and Ringer's lactate (Braun), on the viability of grafts and compared these solutions with the preservation solution developed by Hair Science Institute with trypan blue. The grafts stored in the preservation solution developed by Hair Science Institute showed a significant better viability compared with the 2 commercially available preservation media saline solution and Ringer's lactate. This study shows that a preservation solution could influence the viability of the grafts which could be essential for hair transplantations with small grafts such as in partial longitudinal follicular unit transplantation. PMID- 25289285 TI - Bioprosthetic tissue matrices in complex abdominal wall reconstruction. AB - BACKGROUND: Complex abdominal defects are difficult problems encountered by surgeons in multiple specialties. Although current evidence supports the primary repair of these defects with mesh reinforcement, it is unclear which mesh is superior for any given clinical scenario. The purpose of this review was to explore the characteristics of and clinical relevance behind bioprosthetic tissue matrices in an effort to better clarify their role in abdominal wall reconstruction. METHODS: We reviewed the peer-reviewed literature on the use of bioprosthetic mesh in human subjects. Basic science articles and large retrospective and prospective reviews were included in author's analysis. The clinical performance and characteristics of 13 bioprosthetic tissue matrices were evaluated. RESULTS: The majority of the products evaluated perform well in contaminated fields, where the risk of wound-healing difficulties is high. Clinical outcomes, which included infection, reherniation, and bulge formation, were variable, and the majority of the studies had a mean follow-up of less than 24 months. CONCLUSIONS: Although bioprosthetic matrix has a multitude of indications within the growing field of abdominal wall reconstruction, the functionality, regenerative capacity, and long-term fate of these products have yet to be fully established. Furthermore, the clinical performance, indications, and contraindications for each type of matrix need to be fully evaluated in long term outcome studies. PMID- 25289286 TI - The clinical importance of the fat compartments in midfacial aging. AB - SUMMARY: The recent identification of the facial fat compartments has greatly affected our understanding of midfacial aging. This article chronicles the discovery of these fat compartments including the shift of attention from a purely gravitational to a volumetric approach to facial aging and the series of methodologies attempted to ultimately define the anatomy of these compartments. The revived interest in volumetric facial rejuvenation including compartment guided augmentation techniques is discussed. Lastly, the article discusses interesting distributional patterns noted in these fat compartments likely related to the different mechanical and biologic environments of the deep and superficial facial fat pads. PMID- 25289287 TI - Utilization of Near-infrared Indocyanine Green Angiography for Immediate and Delayed Venous Outflow Assessment in Breast Reconstruction: A Case Report. AB - Supplemental Digital Content is available in the text. PMID- 25289288 TI - Klotho mice: a novel wound model of aged skin. AB - BACKGROUND: As the elderly population continues to expand, it becomes increasingly important to develop treatments to improve wound healing in the elderly. One problem limiting the research is the lack of appropriate animal models for wound healing in elderly patients. We hypothesized that the Klotho mouse of premature aging is a suitable animal model to shed light on many of the biological processes involved in aging skin. METHODS: Klotho mice (kl/kl), Klotho heterozygous mice (kl/+), and wild-type mice (+/+) were wounded, and the area of the wound was measured every 3 days until the wound was healed. To compare the klotho phenotype with wild-type mice, wounds were also harvested at 4 and 7 days after wounding. For histological examination, paraffin-embedded sections were stained with hematoxylin and eosin and Masson trichrome. Collagen expression in the wound was also studied by analyzing messenger RNA using real-time polymerase chain reaction. RESULTS: Klotho mice showed a significantly slower rate of wound closure compared with Klotho-heterozygous mice and wild-type mice. Histology showed substantial less healing and collagen deposition in the wounds of the Klotho mice. The expression of collagen messenger RNA in Klotho mice was also less than that in heterozygous and wild-type mice. The Klotho mice exhibited significant phenotypic similarities with aged skin, such as atrophy and delayed wound healing. CONCLUSION: These preliminary data suggest that the Klotho mouse may be a model to further investigate wound healing in the elderly. PMID- 25289289 TI - Usefulness of Omega-shaped Incision in Skin Tumor Excision. AB - SUMMARY: We devised the Omega-shaped incision as a technique for skin tumor resection on the areas of skin with an arc-shaped fold. With this technique, the dog-ear that is formed during 6 wound closure can be resected within the range of the first skin incision. We report this technique after performing it on the face or trunk of 18 patients and confirmed its usefulness. PMID- 25289290 TI - Reusing of the failing free flap "nutrient flap" as salvage procedure. AB - SUMMARY: A 26-year-old woman sustained a traffic accident injury to her left medial malleolus. A soft-tissue defect 15 * 7 cm with exposure of bone was found and underwent free anterolateral thigh flap to cover it. On the second postoperative day, venous congestion occurred and re-exploration was performed. Re-anastomosis of the vein was done after the thrombectomy; unfortunately, the flap did not recover. We found there was a good granulation bed under the failing flap and thinned the failing flap and used it as a full-thickness skin graft. The graft survived completely; 9 months later, the graft site was softer and of good texture. The patient can wear the same size shoes without a debulking procedure. The free flap provided nutrients to the raw surface and nurtured a good granulation bed while it survived for 50 hours; as a result, it was used as "the nutrient flap." Reuse of the failing free flap as "the nutrient flap" is useful as an alternative backup procedure. PMID- 25289291 TI - A Pilot Assessment of Ethnic Differences in Cosmetic Outcomes following Breast Conservation Therapy. AB - BACKGROUND: One of the primary benefits of breast conserving therapy (BCT) is the potential ability to preserve the aesthetic appearance of the breast. However, current literature and clinical experience suggest that the aesthetic benefits of BCT may not be equally shared among ethnic groups. This is a pilot study that uses novel techniques to evaluate the cosmetic outcomes of African American and white women following BCT. METHODS: A total of 21 participants (10 African American and 11 white) completed the study. Cosmetic outcomes following BCT were evaluated by a multidisciplinary team using both quantitative and qualitative measures, including 3-dimensional photographic analysis and a pilot questionnaire. Preliminary measures were taken to evaluate the validity of the questionnaire. RESULTS: There were no statistically significant differences in objective measures of breast symmetry between African American patients and white patients (P > 0.05 in all cases). However, all raters reported the African American patients to have worse breast symmetry and appearance when compared with white patients. Interrater reliability was found to be fair with regard to the nipple complex questions [intraclass correlation (ICC), 0.56], good with regard to the breast mound questions (ICC, 0.66), and poor with regard to the scar appearance questions (ICC = 0.32). CONCLUSIONS: Although generalizing the results of this study is limited by the small sample size, it seems that there is a difference in the perception of cosmetic outcomes between white and African American patients. The novel techniques of cosmetic evaluation used in this study show promise toward identifying variables that can affect cosmetic outcome following BCT. PMID- 25289292 TI - Cystic eccrine spiradenoma of the finger mimicking a ganglion. AB - SUMMARY: We report a rare case of cystic eccrine spiradenoma in the finger. A 46 year-old man presented with a cystic mass in his left index finger. Clinical assessment along with the investigation pointed toward a diagnosis of a ganglion. However, excisional biopsy of the mass revealed histopathological findings of cystic eccrine spiradenoma. Very few cases of eccrine spiradenoma have been reported in the hand and none of them were cystic in consistency. We believe that this case will draw the surgeon's attention to the possibility of unusual differential diagnoses in the evaluation and treatment of cystic lumps in the hand. PMID- 25289293 TI - Reconstruction of Wide-apart Double Defect Using a Branch-based Chimeric Anterolateral Thigh Flap. AB - SUMMARY: Wide-apart double defect in head and neck region is rare and difficult to reconstruct at one time. Double free flaps are normally used for this scenario and often tedious and technically complicated. This study presented a technique using branch-based anterolateral thigh free flap to simultaneously reconstruct the 2 defects separated wide apart. The concept, indications, surgical technique, and anatomical variations are discussed. Branch-based anterolateral thigh flap is a safe technique and the dissection will be easy when the oblique branch is present. PMID- 25289294 TI - Infraorbital nerve block for isolated orbital floor fractures repair: review of 135 consecutive cases. AB - BACKGROUND: Orbital blowout fractures can be managed by several surgical specialties including plastic and maxillofacial surgery, otolaryngology, and ophthalmology. Recommendations for surgical fracture repair depend on a combination of clinical and imaging studies to evaluate muscle/nerve entrapment and periorbital tissue herniation. METHODS: The aim of this study was to verify the applicability of regional anesthesia when repairing orbital floor fractures. A retrospective chart review was performed for isolated orbital floor fractures treated at the Department of Maxillofacial Surgery in Florence between May 2011 and July 2012. The study included 135 patients who met the inclusion criteria: 96 subjects were male (71%) and 39 were female (29%). The mean age was 45.3 years, ranging from 16 to 77 years. RESULTS: The results revealed that isolated anterior orbital floor fractures can be safely repaired under regional and local anesthesia. Regional and local anesthesia should be combined with intravenous sedation when the fracture involves the posterior floor. The surgical outcome was comparable to the outcome achieved under general anesthesia. There was a lower rate of surgical revisions due to concealed malposition or entrapment of the inferior rectus muscle (19% vs 22%). However, this result was not statistically significant (P > 0.05). CONCLUSIONS: THERE ARE SEVERAL ADVANTAGES TO SURGICALLY REPAIRING ISOLATED ORBITAL FLOOR FRACTURES UNDER REGIONAL AND LOCAL ANESTHESIA THAT INCLUDE THE FOLLOWING: surgeons can check the surgical outcome (enophthalmos and extrinsic ocular muscles function) intraoperatively, thereby reducing the reoperation rate; patient discomfort due to general anesthesia is eliminated; and the hospital stay is reduced, thus decreasing overall healthcare costs. PMID- 25289295 TI - The Molecular and Cellular Events That Take Place during Craniofacial Distraction Osteogenesis. AB - SUMMARY: Gradual bone lengthening using distraction osteogenesis principles is the gold standard for the treatment of hypoplastic facial bones. However, the long treatment time is a major disadvantage of the lengthening procedures. The aim of this study is to review the current literature and summarize the cellular and molecular events occurring during membranous craniofacial distraction osteogenesis. Mechanical stimulation by distraction induces biological responses of skeletal regeneration that is accomplished by a cascade of biological processes that may include differentiation of pluripotential tissue, angiogenesis, osteogenesis, mineralization, and remodeling. There are complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly vascular endothelial cells that may be pivotal members of a complex interactive communication network in bone. Studies have implicated number of cytokines that are intimately involved in the regulation of bone synthesis and turnover. The gene regulation of numerous cytokines (transforming growth factor-beta, bone morphogenetic proteins, insulin like growth factor-1, and fibroblast growth factor-2) and extracellular matrix proteins (osteonectin, osteopontin) during distraction osteogenesis has been best characterized and discussed. Understanding the biomolecular mechanisms that mediate membranous distraction osteogenesis may guide the development of targeted strategies designed to improve distraction osteogenesis and accelerate bone regeneration that may lead to shorten the treatment duration. PMID- 25289297 TI - Mechanically powered negative pressure wound therapy as a bolster for skin grafting. AB - SUMMARY: The use of negative pressure wound therapy (NPWT) as a bolster for split thickness skin grafts has been well documented in the literature. It facilitates the removal of transudate, which can result in the formation of seroma, and mitigates shear stress, which can detach the graft from the underlying wound bed. Its widespread use may be limited by factors such as increased cost and length of hospitalization. Recently, mechanically powered devices (Smart Negative Pressure; Spiracur, Inc., Sunnyvale, Calif.) have been reported as showing promise in healing wounds with outcomes surprisingly comparable to standard NPWT in the populations studied. We are unaware of any reports in the literature that have detailed the use of a mechanically powered NPWT device as a postoperative bolster for split-thickness skin grafts. PMID- 25289296 TI - Nipple sparing mastectomy: does breast morphological factor related to necrotic complications? AB - BACKGROUND: Nipple sparing mastectomy (NSM) can be performed for prophylactic mastectomy and the treatment of selected breast cancer with oncologic safety. The risk of skin and nipple necrosis is a frequent complication of NSM procedure, and it is usually related to surgical technique. However, the role of the breast morphology should be also investigated. METHOD: We prospectively performed an analysis of 124 NSM from September 2012 to January 2013 at the European Institute of Oncology, Milan, Italy, focusing on necrotic complications. We analyzed the association between the risks of skin necrosis and the breast morphology of the patients. RESULTS: Among 124 NSM in 113 patients, NSM procedures were associated with necrosis in 22 mastectomies (17.7%) among which included partial necrosis of nipple-areolar complex (NAC) in 15 of 124 NSM (12.1%) and total necrosis in 4 cases (3.5%). The NAC was removed in 5 NSM cases (4%). The volume of breast removed was the only significant factor increasing the risk of skin necrosis. The degree of ptosis was not significantly related to the necrosis risk. CONCLUSIONS: Large glandular specimen increases the risk of NAC necrosis. The degree of ptosis and the distance between the sternal notch and the NAC have no significant impact on necrotic complications in NSM. To reduce the necrotic complications in large breast after NSM, reconstruction should better be performed with autologous flap or slow skin expansion using the expander technique. PMID- 25289298 TI - Conchal Cartilage Graft for Correction of Bilateral Cleft Lip Nasal Deformities during Childhood. AB - BACKGROUND: Various methods for primary repair of bilateral cleft lip have been developed, but they often produce inadequate results, such as an upturned nose or a short columella. We perform primary lip repair with muscle reconstruction to correct depression of the nasal floor and inferoposterior displacement of the alar base. Then, open rhinoplasty to project the nasal tip is performed during childhood. This article describes the methods and results of open rhinoplasty for bilateral cleft lip patients. METHODS: Open rhinoplasty with a modified forked flap is performed. The harvested conchal cartilage is grafted as a strut to strengthen and extend the septum. The lower lateral cartilages are sutured to the grafted cartilage and fixed in the correct position. Before skin closure, the tips of the 2 V flaps of the forked flap and the reverse V-flap between the forked flap are trimmed. Three trapezoidal flaps are sutured to the base of the columella. Thirty patients with bilateral cleft lip nasal deformities have undergone surgery. The operative results of 15 of 30 patients were evaluated photogrammetrically. RESULTS: The nose was refined and more projected. The nasolabial angle and the nasal tip projection were improved. The reformed configuration was well maintained for many years. Photogrammetric analysis demonstrated increases in both the nasal height-to-width ratio and the nostril height-to-width ratio and a decrease in the nasolabial angle. CONCLUSIONS: Open rhinoplasty during childhood using 3 trapezoidal flaps and conchal cartilage graft improves bilateral cleft lip nasal deformities effectively. PMID- 25289299 TI - Mirror, mirror on the wall, which breast is bigger of them all. AB - SUMMARY: Symmetry is a topic of utmost importance when interviewing a patient who comes asking for cosmetic surgery. We must warn that asymmetry is "the normal." There is no perfect symmetry in the human body, and this overstated search can be sign of psychological and psychiatric disorders. Sometimes multiple procedures are needed to improve a breast's symmetry and appearance. To give an extra intraoperative view, the authors have developed a new instrument to be used during the mammoplasty (reduction or augmentation) surgery. PMID- 25289300 TI - Ultrasound elastography to evaluate keloids. PMID- 25289301 TI - Successful reconstruction of complex pediatric nasal lesions: improving outcomes using dermal regenerative templates. AB - BACKGROUND: Dermal regenerate templates are currently widely used in both adult and pediatric burn reconstruction. Despite this, the safety and efficacy of regenerate templates combined with full-thickness skin grafts for the reconstruction of pediatric facial defects traditionally treated with local flaps is not widely published. The aim of this study is to report the safety and efficacy of pediatric nasal defect reconstruction using regenerative templates/full-thickness skin grafts. METHODS: A retrospective review of one institution's experience with pediatric nasal defects treated with regenerative templates was performed. All patients (n = 4) were treated with a multistage protocol. Two reviewers independently assigned Visual Analogue Cosmetic Scale (VACS) scores: 1 surgeon and 1 nonsurgical researcher not involved in patient care. Standardized photographs (anteroposterior, oblique, lateral, and worm's eye view) were assigned VACS scores according to a 100-point scale: "abhorrent," 0 24; "poor," 25-49; "moderate," 50-74; and "excellent," 75-100. Statistical analysis was performed using Mann-Whitney U and Wilcoxon paired signed-rank tests. RESULTS: Four patients (2 boys and 2 girls, average age 6.8 yr) who met the inclusion criteria were identified. A total of 5 nasal lesions (2 spitz nevi, 1 vascular lesion, and 2 congenital nevi) were removed. The preoperative VACS score was 45.2 (range, 5-70), compared with 84.5 (range, 45-100) postoperatively (P <0.000). There was no significant difference between raters (preoperative, P = 0.346; postoperative, P = 0.678). CONCLUSIONS: The reconstruction of complex pediatric nasal lesions using dermal regenerative templates and full-thickness postauricular skin grafts is safe and effective, and associated with low morbidity and significant improvement in VACS scores. PMID- 25289302 TI - Plotting dermal sutures: an easy dermal suture technique. PMID- 25289303 TI - Symptomatic elbow ganglion causing pronator syndrome. AB - SUMMARY: Descriptions of ganglion cysts date back to 400 BC. Ganglions causing peripheral nerve compression have been described most notably at the wrist. Ganglion compression of the median nerve at the elbow is rare. We report a case of a palmar elbow ganglion causing median nerve compression and the clinical presentation of pronator syndrome. After removal of the ganglion and median nerve decompression, the patient's symptoms fully resolved. PMID- 25289304 TI - Variant anterior digastric muscle transfer for marginal mandibular branch of facial nerve palsy. AB - SUMMARY: Marginal mandibular branch of facial nerve (MMBFN) palsy is a common consequence of head and neck surgeries. MMBFN palsy results in paralysis of muscles which depress the inferior lip. Current management of MMBFN palsy involves ruination of normal neuromuscular anatomy and physiology to restore symmetry to the mouth. The article outlines the possibility to transfer variant anterior digastric musculature to accomplish reanimation of the mouth without adversely affecting normal nonvariant anatomy. The procedure may have the additional cosmetic benefit of correcting asymmetrical muscular bulk in the submental region. PMID- 25289305 TI - Extended Hair-bearing Lateral Orbital Flap for Simultaneous Reconstruction of Eyebrow and Eyelid. AB - BACKGROUND: When a tumor in the lateral eyebrow region is resected, reconstruction of the eyebrow and upper eyelid defects is necessary. We perform simultaneous reconstruction of such defects; sideburn hair is included on an extended lateral orbital flap. We describe our method and results of a retrospective evaluation. METHODS: We treated 6 patients with partial eyebrow and upper eyelid defects. An extended lateral orbital flap was designed on the lateral region of the lateral canthus including sideburn hair and was elevated with a pedicle of the orbicularis oculi muscle. Flap size, surgical outcomes, and reconstructed eyebrow morphology were evaluated. RESULTS: Mean flap size was 2.7 * 4.1 cm, with a maximum width and length of 3.5 and 5.1 cm, respectively. The mean hair-bearing region was 1.4 * 0.9 cm, with a maximum width and length of 1.8 and 1.3 cm, respectively. Total flap survival and hair growth were confirmed in all patients. The reconstructed eyebrow and eyelid were aesthetically satisfactory. The new eyebrow hair grew long and was directed upward but considered acceptable. No additional surgery was performed for any patient. The donor site scar was acceptable because it followed the wrinkles of the lateral eyelid. No paralysis of the temporal branch of the facial nerve resulted. CONCLUSIONS: The procedure for raising an extended hair-bearing lateral orbital flap is relatively easy, although attention must be paid to the temporal facial nerve. This flap is useful for simultaneously reconstructing defects of the upper eyelid and lateral eyebrow. PMID- 25289306 TI - The folded buccal musculomucosal flap for large palatal fistulae in cleft palate. AB - BACKGROUND: A palatal fistula is a common complication of cleft palate repair. Although a buccal musculomucosal flap (BMMF) is effective for fistula repair, it does have the following problems: a second operation may be required to release the pedicle on the oral side and unilateral BMMF cannot close mucosal defects of both the nasal and oral sides. A novel fistula closure method using the folded BMMF (f-BMMF) invented by the authors is presented. CASE: A 8-year-old-boy with bilateral cleft lip and palate with anencephaly. A fistula in the hard palate occurred after palatoplasty by the Furlow method, and an f-BMMF was planned. The mucosal defects of the nasal and oral sides were covered by 2 separate islands of mucosal epithelium. Finally, no reoperation was needed to remove the pedicle of the f-BMMF. CONCLUSION: The f-BMMF is able to cover both sides without a raw surface and a mucosal graft even in cases of large fistula closure, although BMMF cannot usually cover both oral and nasal sides of a fistula. The advantages of this procedure are that it does not require second surgery to release the pedicle and that its distal island mucosa can be used to monitor engraftment. This proposed method seems to be an appealing alternative. PMID- 25289307 TI - A osteogenesis distraction device enabling control of vertical direction for syndromic craniosynostosis. AB - BACKGROUND: We have developed a hybrid facial osteogenesis distraction system that combines the advantages of external and internal distraction devices to enable control of both the distraction distance and vector. However, when the advanced maxilla has excessive clockwise rotation and shifts more downward vertically than planned, it might be impossible to pull it up to correct it. We invented devices attached to external distraction systems that can control the vertical vector of distraction to resolve this problem. The purpose of this article is to describe the result of utilizing the distraction system for syndromic craniosynostosis. METHODS: In addition to a previously reported hybrid facial distraction system, the devices for controlling the vertical direction of the advanced maxilla were attached to the external distraction device. The vertical direction of the advanced maxilla can be controlled by adjustment of the spindle units. This system was used for 2 patients with Crouzon and Apert syndrome. RESULTS: The system enabled control of the vertical distance, with no complications during the procedures. As a result, the maxilla could be advanced into the planned position including overcorrection without excessive clockwise rotation of distraction. CONCLUSION: Our system can alter the cases and bring them into the planned position, by controlling the vertical vector of distraction. We believe that this system might be effective in infants with syndromic craniosynostosis as it involves 2 osteotomies and horizontal and vertical direction of elongation can be controlled. PMID- 25289308 TI - Squamous-cell Carcinoma Arises in Red Parts of Multicolored Tattoo within Months. AB - SUMMARY: Skin cancer formation is on the rise. Only a few case reports, which focus on skin cancer being caused by tattoos, have been published so far. Our aim is to determine whether skin cancer occurrence can be triggered by tattoos. In our presented case, a squamous-cell carcinoma developed inside of the red areas of a multicolored tattoo within months. Furthermore, surgical removal of the cancerously mutated skin area without mutilating the design of the tattoo was challenging. Due to widespread skin alterations in other red areas of the tattoo, those affected skin regions were surgically removed and split-skin grafting was performed. After 1-year follow-up period, the patient has been tumor free. Squamous-cell carcinoma is an unusual reaction that can occur in tattoos. Nevertheless, this skin cancer should be included in the list of cutaneous complications related to tattooing. PMID- 25289309 TI - Clinical Evidence for the Relationship between Nail Configuration and Mechanical Forces. AB - SUMMARY: Mechanobiology is an emerging field of science that focuses on the way physical forces and changes in cell or tissue mechanics contribute to development, physiology, and disease. As nails are always exposed to physical stimulation, mechanical forces may have a particularly pronounced effect on nail configuration and could be involved in the development of nail deformities. However, the role of mechanobiology in nail configuration and deformities has rarely been assessed. This review describes what is currently understood regarding the effect of mechanical force on nail configuration and deformities. On the basis of these observations, we hypothesize that nails have an automatic curvature function that allows them to adapt to the daily upward mechanical forces. Under normal conditions, the upward daily mechanical force and the automatic curvature force are well balanced. However, an imbalance between these 2 forces may cause nail deformation. For example, pincer nails may be caused by the absence of upward mechanical forces or a genetic propensity increase in the automatic curvature force, whereas koilonychias may occur when the upward mechanical force exceeds the automatic curvature force, thereby causing the nail to curve outward. This hypothesis is a new concept that could aid the development of innovative methods to prevent and treat nail deformities. PMID- 25289310 TI - Shaped versus Round Implants for Breast Reconstruction: Indications and Outcomes. AB - BACKGROUND: With the reintroduction of shaped silicone gel implants in the United States, questions regarding indications and outcomes for each are likely. The purpose of this article is to review the author's early experience using shaped and round implants for breast reconstruction over a 14-month consecutive interval. METHODS: Breast reconstruction using shaped or round implants was performed on 69 women that included shaped silicone gel devices in 49 and round devices in 20. Patients were evaluated based on nipple-sparing vs skin-sparing mastectomy, 1-stage vs 2-stage, radiation therapy, unilateral vs bilateral, occurrence of complications, and follow-up. RESULTS: Of the 49 patients (78 breasts) who had shaped implants, reoperation was necessary in 6 patients (12.2%) and in 7 breasts (9%). This was secondary to infection in 2 breasts, capsular contracture in 2 breasts, incisional dehiscence in 1 breast, asymmetry in 1 breast, and exposure in 1 breast. Of the 20 patients (28 breasts) who had round implants, reoperation was necessary in 2 patients (10%) and 2 breasts (7.1%) and included the removal of the device secondary to a late infection in 1 patient and the correction of a malposition (double bubble deformity) in 1 patient. There were no malpositions involving the shaped silicone gel implants. CONCLUSIONS: Both shaped and round silicone gel devices can result in natural aesthetic outcomes. Shaped devices are preferred for contouring the upper pole and for optimizing breast projection. Round devices are preferred when the upper pole is not deficient and the patient desires softer breasts. Longer follow-up studies will be necessary. PMID- 25289311 TI - Correction of Postoperative Nipple/Areola Malposition without Nipple Grafting. PMID- 25289312 TI - A retrospective analysis on the proper size of tissue expanders to treat scalp lesions. AB - BACKGROUND: Tissue expanders have become established instruments for scalp reconstruction. However, selection of the size of the expander has not been investigated systematically, and it generally depends on the experience of the surgeon. METHODS: We retrospectively analyzed 21 patients who had undergone treatment for scalp lesions using tissue expanders without any complications and measured 2 variables: the volume of the expanders per area of the excised lesions and the hypothetical stretched functional skin width relative to the width of the excised lesions. We also sought to evaluate the relationship between these 2 variables and the need for revision surgery during the postoperative course. RESULTS: The need for revision surgery was statistically higher in patients with a volume of 7 ml/cm(2) lesion or less and width of functional skin of less than 2.5 cm/cm lesion (P < 0.05). For scar repairs, the required size and volume of the expanders tended to be larger than those required for any other lesions. CONCLUSIONS: Expanders that generate functional skin at least more than 2.5 times the width of the lesion and have a volume more than 7 ml/cm(2) lesion are necessary to cover scalp lesions without complications. PMID- 25289313 TI - Comparison between Freeze-dried and Ready-to-use AlloDerm in Alloplastic Breast Reconstruction. AB - BACKGROUND: AlloDerm, a brand of acellular dermal matrix, is commonly used as an internal hammock to support the tissue expander or permanent implant in breast reconstruction. The aim of our study is to evaluate the complication rates associated with the freeze-dried (FD) AlloDerm and the ready-to-use (RTU) AlloDerm. METHODS: This institutional review board-approved retrospective study involved 103 patients who underwent immediate postmastectomy breast reconstructions from June 2011 to August 2012. The first 51 patients underwent 96 immediate breast reconstructions with FD AlloDerm. The subsequent 52 patients underwent 100 immediate breast reconstructions with RTU AlloDerm. Patient demographics, postoperative complication rates in study cohort, and complication rates stratified by body mass index (BMI) were analyzed. RESULTS: Multiple patient demographics in the 2 cohorts are closely matched (P > 0.05). RTU AlloDerm was associated with higher rates of seroma and cellulitis compared with FD AlloDerm (22.0% vs 18.8%, P = 0.599 and 21.0% vs 12.5%, P = 0.129, respectively). Significantly higher rates of seroma and cellulitis were found in patients with BMI >= 30 compared with BMI < 30 (34.5% vs 9.2%, P < 0.001 and 29.9% vs 6.4%, P < 0.001, respectively). A generalized linear mixed model shows that obesity and RTU AlloDerm are statistically significant predictors of cellulitis (adjusted odds ratio = 10.413, P < 0.001 and adjusted odds ratio = 3.712, P = 0.011, respectively). CONCLUSIONS: Our study demonstrates a clinically higher postoperative complication rate in immediate breast reconstruction with RTU AlloDerm compared with FD AlloDerm and highlights the unfavorable risk factor correlation with significant obesity. PMID- 25289314 TI - Neglected giant scalp Basal cell carcinoma. AB - SUMMARY: Rarely, basal cell carcinoma grows to a giant size, invading the underlying deep tissue and complicating the treatment and reconstruction modalities. A giant basal cell carcinoma on the scalp is in some cases treated with a combination of surgery and radiation therapy, resulting in local control, a satisfactory long-term cosmetic and functional result. We present a case with a neglected basal cell scalp carcinoma, treated with wide excision and postoperative radiotherapy, reconstructed with a free latissimus dorsi flap. The cosmetic result is acceptable and there is no sign of recurrence 1 year postoperatively. PMID- 25289315 TI - Developing a Lower Limb Lymphedema Animal Model with Combined Lymphadenectomy and Low-dose Radiation. AB - BACKGROUND: This study was aimed to establish a consistent lower limb lymphedema animal model for further investigation of the mechanism and treatment of lymphedema. METHODS: Lymphedema in the lower extremity was created by removing unilateral inguinal lymph nodes followed by 20, 30, and 40 Gy (groups IA, IB, and IC, respectively) radiation or by removing both inguinal lymph nodes and popliteal lymph nodes followed by 20 Gy (group II) radiation in Sprague-Dawley rats (350-400 g). Tc(99) lymphoscintigraphy was used to monitor lymphatic flow patterns. Volume differentiation was assessed by microcomputed tomography and defined as the percentage change of the lesioned limb compared to the healthy limb. RESULTS: At 4 weeks postoperatively, 0% in group IA (n = 3), 37.5% in group IB (n = 16), and 50% in group IC (n = 26) developed lymphedema in the lower limb with total mortality and morbidity rate of 0%, 56.3%, and 50%, respectively. As a result of the high morbidity and mortality rates, 20 Gy was selected, and the success rate for development of lymphedema in the lower limb in group II was 81.5% (n = 27). The mean volume differentiation of the lymphedematous limb compared to the health limb was 7.76% +/- 1.94% in group II, which was statistically significant compared to group I (P < 0.01). CONCLUSIONS: Removal of both inguinal and popliteal lymph nodes followed by radiation of 20 Gy can successfully develop lymphedema in the lower limb with minimal morbidity in 4 months. PMID- 25289316 TI - Immediate Single-stage Endoscopic Latissimus Dorsi Breast and Nipple Reconstruction. AB - SUMMARY: Immediate breast reconstruction usually is a multistep surgical treatment. We introduce a new technique with positive results that reduces the reconstruction to 1 single step. This new technique promises to reduce patient consequences from multistaged procedures while reducing the costs. A retrospective review of 7 patients is presented. PMID- 25289317 TI - Autologous Fat Grafting as a Novel Approach to Parastomal Soft-tissue Volume Deficiencies. AB - SUMMARY: The aim of this study is to describe a novel approach to revise maladaptive soft-tissue contour around an ileostomy. A patient with permanent ileostomy suffered from significant defects in soft-tissue contour due to scarring and wound contraction. He underwent autologous fat grafting to achieve sealing of his stoma appliance and improve cosmesis. Due to numerous surgeries, the stoma appliance would not seal and required daily appliance changes. The patient received autologous fat grafting to augment the contour around stoma. A complete fitting of stoma was achieved. The patient is satisfied with stoma sealing and is changing his stoma appliance every 5-7 days without skin excoriation. Autologous fat transfer is an effective approach to treat a subset of stoma patients with complex subcutaneous defects. PMID- 25289318 TI - Autologous fat grafting for whole breast reconstruction. AB - SUMMARY: This is the first reported case of a patient who had a single-stage large-volume breast reconstruction with autologous fat grafting, following rotation flap approach (RoFA) mastectomy. The purpose of this case study was to evaluate the viability of reconstruction of the breast by autologous fat grafting alone, in the context of RoFA mastectomy. The hypothesis was that there would be minimal interval loss of autologous fat on the whole breast reconstruction side. Right RoFA mastectomy was used for resection of an invasive primary breast cancer and resulted in the right breast skin envelope. Eleven months later, the patient underwent grafting of 400 ml of autologous fat into the skin envelope and underlying pectoralis major muscle. Outcome was assessed by using a validated 3D laser scan technique for quantitative breast volume measurement. Other outcome measures included the BREAST-Q questionnaire and 2D clinical photography. At 12 month follow-up, the patient was observed to have maintenance of volume of the reconstructed breast. Her BREAST-Q scores were markedly improved compared with before fat grafting, and there was observable improvement in shape, contour, and symmetry on 2D clinical photography. The 2 new techniques, RoFA mastectomy and large-volume single-stage autologous fat grafting, were used in combination to achieve a satisfactory postmastectomy breast reconstruction. Novel tools for measurement of outcome were the 3D whole-body laser scanner and BREAST-Q questionnaire. This case demonstrates the potential for the use of fat grafting for reconstruction. Outcomes in a larger patient populations are needed to confirm these findings. PMID- 25289319 TI - Effect of Control-released Basic Fibroblast Growth Factor Incorporated in beta Tricalcium Phosphate for Murine Cranial Model. AB - BACKGROUND: beta-Tricalcium phosphate (beta-TCP) is used clinically as a bone substitute, but complete osteoinduction is slow. Basic fibroblast growth factor (bFGF) is important in bone regeneration, but the biological effects are very limited because of the short half-life of the free form. Incorporation in gelatin allows slow release of growth factors during degradation. The present study evaluated whether control-released bFGF incorporated in beta-TCP can promote bone regeneration in a murine cranial defect model. METHODS: Bilateral cranial defects of 4 mm in diameter were made in 10-week-old male Sprague-Dawley rats treated as follows: group 1, 20 MUl saline as control; group 2, beta-TCP disk in 20 MUl saline; group 3, beta-TCP disk in 50 MUg bFGF solution; and group 4, beta-TCP disk in 50 MUg bFGF-containing gelatin hydrogel (n = 6 each). Histological and imaging analyses were performed at 1, 2, and 4 weeks after surgery. RESULTS: The computed tomography value was lower in groups 3 and 4, whereas the rate of osteogenesis was higher histologically in group 4 than in the other groups. The appearance of tartrate-resistant acid phosphate-positive cells and osteocalcin positive cells and disappearance of osteopontin-positive cells occurred earlier in group 4 than in the other groups. CONCLUSIONS: These findings suggest that control-released bFGF incorporated in beta-TCP can accelerate bone regeneration in the murine cranial defect model and may be promising for the clinical treatment of cranial defects. PMID- 25289320 TI - Early Mobilization after Free-flap Transfer to the Lower Extremities: Preferential Use of Flow-through Anastomosis. AB - BACKGROUND: Prolonged bed rest and elevation have traditionally been considered necessary after free-flap transfer to the lower extremities. In this retrospective study, we tried to mobilize patients early after free-flap transfer to the lower extremity by means of flow-through anastomosis for both arteries and veins. METHODS: This study included 13 consecutive patients who underwent immediate free-flap transfer after wide resection of soft-tissue tumors of the lower extremity from March 2012 through July 2013. The defects were above the knee in 5 patients and below the knee in 8 patients. In all patients, flow through anastomosis was used for both arteries and veins. The patients were mobilized starting on the first postoperative day, and their activities of daily life were gradually expanded, depending on the wound conditions. Postoperative complications and the progression of their activities of daily life were investigated retrospectively. RESULTS: No anastomotic failure or take back occurred. Partial flap necrosis occurred in 1 patient because of a poor perforator but was unrelated to early mobilization. All patients could move to wheelchairs on the first postoperative day. Within 1 week, 12 of 13 patients could start dangling and 10 of 13 patients could start ambulating. CONCLUSIONS: This study demonstrates that early mobilization after free-flap transfer to the lower extremity is made possible by flow-through anastomosis for both arteries and veins. Flow-through flaps have stable circulation from the acute phase and can tolerate early dangling and ambulation. PMID- 25289321 TI - Management of vascular malformations. AB - BACKGROUND: Even though vascular malformations are well categorized, further details are relatively unknown. Of treated patients regarding the frequency, demographic distributions, and other related factors by multivariate regression analyses in proportion to total vascular malformations, methods of treatment and how to manage them have not been elucidated thoroughly. METHODS: From January 2006 to March 2012, consecutively treated patients with vascular anomalies were included in this investigation at least 1-year follow-up. RESULTS: Of the total of 123 cases, 86 females and 37 males, the mean follow-up was 3.5 +/- 1.68 years, and the frequency of treatment was 1-8 times (1.8 +/- 1.30). Surgery was performed for 22 cases (17.9%) of venous malformations and arteriovenous malformations. In multivariate regression, the frequency of treatment was significantly correlated with the length of follow-up (P < 0.001), age (P < 0.05), and type of malformations (P < 0.05) (R (2) = 0.18). Need for surgery was significantly increased with age at odds ratio (OR) of 1.06 [95% confidence interval (CI), 1.03-1.80] (P < 0.001), and head/face/neck, and upper limb are more performed at OR of 0.24 (95% CI, 0.07-0.85) (P < 0.05). The satisfaction score varied from 1 to 5 (3.9 +/- 0.68). Complications occurred in 3 cases (2.4%). In logistic regression of complications, the OR of the satisfaction score was 0.13 (95% CI, 0.02-0.80) (P < 0.05). CONCLUSIONS: Treatment of vascular malformations is an integral part of multidisciplinary approaches. Venous malformations are more frequent in combination surgery, and if there are fewer complications, the patients' satisfaction increases. PMID- 25289322 TI - T-shaped Pectoralis Major Musculocutaneous Flap for Reconstruction of an Extensive Circumferential Pharyngeal Defect. AB - SUMMARY: In the era of free-flap transfer, the pectoralis major musculocutaneous flap still plays a unique role in head and neck reconstruction. We report on a patient with a recurrent hypopharyngeal carcinoma after total pharyngolaryngectomy and adjuvant chemoradiotherapy in whom defects included a circumferential defect of the oropharynx and the entire tongue. The defects were successfully reconstructed with a T-shaped pectoralis major musculocutaneous flap whose skin island included multiple intercostal perforators from the internal mammary vessels. This flap design is effective for reconstructing circumferential pharyngeal defects in vessel-depleted neck. PMID- 25289324 TI - A simple technique to deflate a tissue expander. AB - SUMMARY: Removal of an intact, inflated tissue expander can result in uncontrolled spillage of expander contents on the drapes, surgeons, staff, or patient. The technique described has been used for the past 4 years to eliminate these spillage concerns. It is simple and inexpensive using common disposable supplies found in any operating room. An irrigating syringe is modified by cutting away its 2 flanges. The bulb is removed and suction is applied to the syringe tip. The expander is punctured with a scalpel while the puncture hole is covered by the syringe opening. The applied suction aspirates the contents thereby deflating the expander. Uncontrolled content spillage and spray are eliminated. PMID- 25289323 TI - Variation in the Use of Therapy following Distal Radius Fractures in the United States. AB - BACKGROUND: Distal radius fractures (DRFs) are one of the most common injuries among the elderly, resulting in significant expense and disability. The specific aims of this study are (1) to examine rates of therapy following DRFs and (2) to identify those factors that influence utilization of therapy and time span between DRF treatment and therapy among a national cohort of elderly patients. METHODS: We examined national use of physical and occupational therapy among all Medicare beneficiaries who suffered DRFs between January 1, 2007, and October 1, 2007, and assessed the effect of treatment, patient-related, and surgeon-related factors on utilization of therapy. RESULTS: Overall, 20.6% of patients received either physical or occupational therapy following DRF. Use of therapy varied by DRF treatment, and patients who underwent open reduction and internal fixation were more likely to receive therapy compared with patients who received closed reduction. Patients who received open reduction and internal fixation were also referred to therapy earlier compared with patients who received external fixation, percutaneous pinning, and closed reduction. Surgeon specialization is associated with greater use of postoperative therapy. Patient predictors of therapy use include younger age, female sex, higher socioeconomic status, and fewer comorbidity conditions. CONCLUSION: Use of therapy following DRF varies significantly by both patient- and surgeon-related factors. Identifying patients who benefit from postinjury therapy can allow for better resource utilization following these common injuries. PMID- 25289325 TI - Overexpressed HIF-2alpha in Endothelial Cells Promotes Vascularization and Improves Random Pattern Skin Flap Survival. AB - BACKGROUND: The local skin flap procedure is very useful for reconstruction. However, flap necrosis caused by circulatory failure can occur at its distal portion. Hypoxia-inducible factors (HIFs) in endothelial cells (ECs) help to maintain ECs and promote vascularization, and HIF-2alpha is abundantly expressed in ECs. However, the mechanisms of action of HIF-2alpha in ECs are not yet fully understood. The aim of this study was to evaluate the in vivo effects of overexpression of HIF-2alpha in ECs on skin flap survival. METHODS: A random pattern skin flap (1.0 * 3.0 cm) was elevated on the dorsum of transgenic mice (Tg mice) with EC-specific HIF-2alpha conditional overexpression and wild-type littermate control mice (n = 6). Flap survival was evaluated on postoperative day 7. Tissue samples from the skin flaps were harvested and analyzed using Western blotting, quantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry. RESULTS: The HIF-2alpha mRNA and protein levels were significantly increased in the Tg mice when compared with control mice. Tg mice had significantly increased skin flap survival areas (72.0% +/- 2.7%) when compared with wild-type mice (45.7% +/- 1.1%). Moreover, histological examination revealed an increase in the subcutaneous blood vessel counts in the Tg mice. CONCLUSIONS: Specific overexpression of HIF-2alpha in ECs promoted vascularization and enhanced skin flap survival in vivo in a mouse model. PMID- 25289326 TI - Current update in asian rhinoplasty. AB - SUMMARY: There has been a tremendous growth of cosmetic surgery among Asians worldwide. Rhinoplasty is second only to blepharoplasty in terms of popularity among Asians regarding cosmetic surgical procedures. Most Asians seek to improve their appearance while maintaining the essential features of their ethnicity. There are considerable ethnic nasal and facial variations in this population alone. Successful rhinoplasty in Asians must take into account underlying anatomic differences between Asians and whites. Due to ethnic variations, cultural differences, and occasional language barriers, careful preoperative counseling is necessary to align the patient's expectations with the limitations of the procedure. This article will review the many facets of Asian rhinoplasty as it is practiced today. PMID- 25289327 TI - Cranial Reconstruction following the Removal of an Infected Synthetic Dura Mater Substitute. AB - BACKGROUND: The objective of this study was to describe the outcomes of an algorithmic approach to cranial reconstruction following the removal of an infected synthetic dura mater substitute due to postcraniotomy infection. METHODS: A retrospective review was conducted of the cases of 12 patients who underwent cranial reconstruction from 2006 to 2013 after the removal of an infected expanded polytetrafluoroethylene sheet (a synthetic dura mater substitute) due to postcraniotomy infection. RESULTS: Average patient age was 46 years (range, 19-70 years). Follow-up was 4.6 years. The expanded polytetrafluoroethylene sheets were implanted after decompressive craniectomy or after combined resection of the dura mater and a tumor. Epidural, but not subdural, abscesses were found in 6 patients, in whom a sufficient capsule developed underneath the synthetic dura mater. Both epidural and subdural abscesses were found in the remaining 6 patients, and the capsule remained intact after debridement of the subdural abscesses in half of them. Secondary cranial reconstruction was safely performed by leaving the capsule intact in the 9 cases in which no additional dural reconstruction was performed. In the remaining 3 patients, in whom no capsule remained after debridement, secondary cranial reconstruction was carried out by leaving the pericranium over the brain surface. None of the patients developed postoperative complications in follow-up periods. CONCLUSIONS: Staged cranial reconstruction after the removal of an infected synthetic dura mater substitute using an algorithmic approach is feasible and safe, produces satisfactory cosmetic results, and is not associated with any complications. PMID- 25289328 TI - Supercharging and augmenting venous drainage of an anterolateral thigh free flap: options and indications. AB - SUMMARY: This study introduces the options for supercharging and augmenting venous drainage of an anterolateral thigh free flap. Clinical indications and options for additional microvascular anastomoses are reviewed in 5 consecutive patients. The indications were simultaneous mucosal and cutaneous defects, divergent mucosal defects, and extensively wide and long cutaneous defects. Three additional vascular pedicles were anastomosed: the transverse branch of the lateral circumflex (n = 3), a perforator coming directly off the superficial femoral artery (n = 1), and a posterior perforator from the profundus femoral artery (n = 1). The anastomosis of a separate pedicle from the superior, medial, and/or posterior-lateral thigh may be a useful technique when confronted with an extensive defect that may not reliably be reconstructed with a routine anterolateral thigh flap based on a single perforator. PMID- 25289329 TI - A new rat model for orthotopic abdominal wall allotransplantation. AB - BACKGROUND: Abdominal wall, one of the most commonly transplanted composite tissues, is less researched and lacking animal models. Its clinical necessities were emphasized in multiple case series to reconstruct large abdominal defects. Previous animal models have only studied components of the abdominal wall transplant. We describe findings from a new model that more likely reflect clinical transplantation. METHODS: Full-thickness hemiabdominal wall flap was procured from Brown Norway (BN) rats and transplanted to an orthotopic defect on Lewis rats. Three groups were studied: group 1: Lewis to Lewis syngeneic; group 2: BN to Lewis control; and group 3: BN to Lewis with postoperative cyclosporine. Vascular imaging and cross vessel section were performed along with full thickness abdominal wall. Immune cell profiling with flow cytometry at different time points was studied in all groups. RESULTS: Syngeneic group had no rejection. Control group consistently showed rejection around postoperative day 6. With cyclosporine treatment, however, transplant and recipient tissue integration was observed. Flow cytometry revealed that innate immunity is responsible for the initial inflammatory events following abdominal wall engraftment. Adaptive immunity cells, specifically interferon-gamma-producing T helper (Th) 1 and interleukin-17-producing Th17 cells, dramatically and positively correlate with rejection progression of abdominal wall transplants. CONCLUSIONS: Technical, histological, and immunological aspects of a new rat model are described. These results give clues to what occurs in human abdominal wall transplantation. In addition, Th1, a proinflammatory cell, was found to be a potential biomarker for allograft rejection. PMID- 25289330 TI - The Running Barbed Tie-over Dressing. AB - SUMMARY: Barbed suture technology is becoming increasingly popular in plastic surgery and is now being used in body contouring surgery and facial rejuvenation. We describe the novel application of a barbed suture as a running tie-over dressing for skin grafts. The barbs act as anchors in the skin, so constant tensioning of the suture is not required. The bidirectional nature of the suture prevents any slippage, and the barbs even act as a grip on the underlying wool dressing. Furthermore, the method described is both quick and simple to learn and would be useful for the sole operator. PMID- 25289331 TI - Five-year Safety Data for Eurosilicone's Round and Anatomical Silicone Gel Breast Implants. AB - BACKGROUND: Multicenter prospective studies assessing the safety and efficacy of silicone gel breast implants are relatively rare. Eurosilicone S.A.S. present their safety and efficacy data herein for the largest European silicone gel breast implant study published to date. METHODS: One thousand and ten of Eurosilicone's textured cohesive Cristalline Paragel range of mammary implants was implanted in women undergoing augmentation and reconstructive surgery at 17 centers throughout France. Physical examinations and complications were recorded by physicians at 3 months and annually thereafter until 10 years postimplantation. Descriptive statistics were used and key complications were analyzed using the Kaplan-Meier analysis method. RESULTS: Two ruptures were observed within 5 years postimplantation, one of which was subject to mechanical trauma during reoperation and the other was identified during routine screening. Capsular contracture, one of the most common complications associated with breast implants, was reported in 6.6% implants across all indications through 5 years. The Kaplan-Meier risk of capsular contracture (Baker III/IV) was 10.7% (95% confidence interval, 7.2-14.2%) and 17.2% (95% confidence interval, 5.4-29%) in the primary augmentation and primary reconstruction patient cohorts, respectively. Implant removal (explantation/exchange) was 8.5% and 16.5% for primary augmentation and primary reconstruction cohorts, respectively. Rates of local complications including infection and seroma were low with risk rates of 0.6% and 0.2% by subject. CONCLUSIONS: Eurosilicone S.A.S. prospective study involving 1010 Eurosilicone silicone gel breast implants in both round and shaped profiles demonstrated a low rupture rate and an excellent safety profile through 5 years. PMID- 25289332 TI - Incidence of Complications Associated with Mandibuloplasty: A Review of 588 Cases over 5 Years. AB - BACKGROUND: The number of patients undergoing mandibuloplasty in East Asia has increased in recent years. Angle resection, corticectomy, and tubercle excisions are the most commonly used methods of mandibuloplasty. However, no data are available on complications following mandibuloplasty. This study aimed to determine the prevalence and significance of intra- and postoperative complications associated with mandibuloplasty. METHODS: A total of 588 Korean patients (99 men, 489 women; age range, 19-62 years) who underwent mandibuloplasty (performed by a single surgeon in the same clinic) were divided into 4 groups: group I, angle resection (190); group II, angle resection and genioplasty, including tubercle excision (130); group III, angle resection and zygoma reduction (114); and group IV, angle resection, genioplasty, and zygoma reduction (154). The average follow-up period was 14 weeks. RESULTS: The most common complication was numbness. Of 38 patients (6.46%) with sensory deficits, 16 (2.72%), 11 (1.87%), and 11 (1.87%) patients reported these changes around the chin, lower lip, and intraoral incision areas at postoperative 6 months and 3, 1, and 5 patients reported these changes at postoperative 1 year, respectively. Infection occurred in 19 patients (3.23%) within 2 weeks and was resolved with IV antibiotics in 1-2 weeks in 17 patients but was unresolved in 2 after 3 months. Hemifacial palsy, intraoperative bleeding requiring transfusion, and hardness and burning sensation were also noted in 1 patient. CONCLUSIONS: Surgeons must be aware of the complications of mandibuloplasty and their occurrence rates. PMID- 25289333 TI - Use of thoracodorsal artery perforator flaps to enhance outcomes in alloplastic breast reconstruction. AB - BACKGROUND: Use of the thoracodorsal artery perforator (TDAP) flap in combination with alloplastic devices has been proven to be a safe method of breast reconstruction. However, preoperative irradiation increases the complication rate and thus some consider preoperative radiotherapy a relative contraindication to alloplastic alone reconstruction. We evaluated the long-term outcomes of patients with preoperative radiotherapy who had delayed alloplastic reconstruction with a TDAP flap. METHODS: A retrospective analysis of a prospectively maintained database was performed to identify patients who had received a Latissimus Dorsi (LD), a Muscle Sparing Latissimus Dorsi (MSLD), or a TDAP flap plus a tissue expander or implant between 2005 and 2012. Information regarding patients' primary diagnosis, radiation history, prior breast reconstructions, and complications was collected and analyzed. RESULTS: Sixteen patients who had a total of 16 breast reconstructions with an LD (6) or TDAP/MSLD1 flap (10). Demographic data, device type, co-morbidities and complications were analyzed. The rate of capsular contracture and size asymmetry were higher in the LD group, but there was no difference noted for major complications. Minor complications were also similar between the 2 groups. CONCLUSIONS: Patients who underwent irradiation before TDAP flap did not have a higher complication rate when compared with patients who had a full LD flap following radiation. By integrating well-vascularized, nonradiated tissue of a TDAP flap in reconstruction, overall complication rate may be minimized and the results are comparable to the generally accepted method of utilizing the entire latissimus dorsi muscle. PMID- 25289334 TI - Cephalic Vein Transposition versus Vein Grafts for Venous Outflow in Free-flap Breast Reconstruction. AB - INTRODUCTION: When recipient veins for free-flap breast reconstruction are unavailable or inadequate, vein grafts or cephalic vein transposition (CVT) an option to provide alternate venous outflow. There are no comparative data to elucidate the indications and outcomes for each. We hypothesize that the CVT is as reliable as vein grafts when indicated. METHODS: All consecutive cases where a CVT or venous vein grafts were used for free-flap breast reconstruction between 2000 and 2012 were reviewed. Patient demographics, operative notes, indications, and flap survival were compared between the 2 groups. RESULTS: Ten patients underwent a CVT and 38 patients received a vein graft for insufficient venous outflow. There were no differences in average age, body mass index, or comorbid conditions between the groups. Similarly, there was no difference in previous radiotherapy, timing of reconstruction, or side of reconstruction. A CVT was used for salvage following venous thrombosis in 7 patients (70.0%) and for primary venous outflow in the remaining patients due to inability to use the internal mammary vein. Vein grafts were performed primarily in 31 patients, 22 for augmenting venous drainage (supercharge), 9 for the dominant venous outflow, and 7 for salvage of a thrombosis. One patient in each group suffered a complete loss of the free flap (cephalic: 10.0% vs vein graft: 14.3%, P = 0.36). CONCLUSIONS: The CVT is a reliable alternate venous outflow that can be used as a primary recipient vein or as a salvage option following venous thrombosis. Surgeons should consider a CVT when primary recipient veins are compromised or unavailable. PMID- 25289335 TI - The internal pudendal artery perforator thigh flap: a new freestyle pedicle flap for the ischial region. AB - BACKGROUND: Recurrence and complication rates of pressure sores are highest in the ischial region, and other donor sites are needed for recurrent pressure sores. The potential of a new freestyle pedicle flap for ischial lesions, an internal pudendal artery perforator (iPap) thigh flap, was examined through anatomical and theoretical analyses and a case series using computed tomography angiography. METHODS: The skin flap was designed in the thigh region based on an iPap. The skin perforators were marked with a Doppler probe. One patient underwent computed tomography angiography with fistulography to identify the damage to or effects on the pedicle vessels of the flap. Debridement of ischial lesions and flap elevation were performed in the jackknife position. RESULTS: The iPap thigh flaps were performed in 5 patients, 4 with ischial pressure sores and 1 with calcinosis cutis of the ischial region. The width and length of the flaps ranged from 5 to 8 cm (mean, 6.6 cm) and 10 to 17 cm (mean, 12.6 cm), respectively. Three patients underwent partial osteotomy of the ischial bone. No complications, including flap necrosis or wound dehiscence of the donor and reconstructed sites, were observed. CONCLUSIONS: The perforator vessels of the internal pudendal artery are very close to the ischial tuberosity. Blood flow to the flap is reliable when careful debridement of the pressure sore is performed. The iPap thigh flap is a new option for soft-tissue defects in the ischial region, including ischial pressure sores. PMID- 25289336 TI - Local anesthesia for surgical procedures of the upper eyelid using filling cannula: our technique. AB - SUMMARY: Sometimes, after local anesthetic injection for surgical procedures of the upper eyelid, it is possible to observe superficial preseptal hematomas or excessive lid swelling that may distort the tissues and obscure surgical landmarks. We present a technique to perform local anesthesia of the upper eyelids, using a 27-gauge needle and a 26-gauge filling cannula, that may decrease the incidence of hematomas and bruising. PMID- 25289337 TI - Trans-scaphoid Trans-lunotriquetral Perilunate Dislocation in a Patient with a Carpal Coalition. AB - SUMMARY: Congenital carpal coalitions are rare conditions that arise from a failure or an incomplete cavitation of a common cartilaginous precursor of the carpal bones between the fourth and eighth week of intrauterine life. The incidence of coalitions has been estimated to occur in about 0.1% of the population and up to 1.6% in people of African descent. This study reports a case of trans-scaphoid trans-lunotriquetral perilunate dislocation with a lunotriquetral coalition and successful management with closed reduction, percutaneous fixation, and a thumb spica cast. PMID- 25289338 TI - A method for reconstruction of vermilion tubercle. AB - BACKGROUND: This article reports on the bilateral lip mucosa flaps (BLMFs) for reconstruction of the vermilion tubercle of the corrected cleft lip deformity. METHODS: From 2005 to 2013, the bilateral mucosa flaps procedures were performed on 34 secondary cleft lip patients (bilateral, n = 25; unilateral, n = 9). We retrospectively reviewed the pre-, intra-, and postoperative data of these 34 cases receiving BLMFs. RESULTS: Satisfactory results were obtained, both cosmetically and functionally, in all 34 patients. Lateral projection measurements of the reconstructive vermilion tubercle showed a mean increase of 151%. There were minimal perioperative complications. The color and texture matched well with the surrounding tissue. The postoperative scars are not remarkable at all. CONCLUSIONS: The technique is relatively simple. The BLMFs provided a versatile and reliable option for the reconstruction of the vermilion tubercle from secondary cleft lip deformities. PMID- 25289339 TI - Could "Teardrop"-shaped Anterolateral Thigh Flaps Facilitate Primary Closure of the Donor Site? PMID- 25289340 TI - The scarless latissimus dorsi flap provides effective lower pole prosthetic coverage in breast reconstruction. AB - BACKGROUND: The evolution of surgical breast cancer treatment has led to the oncologically safe preservation of greater amounts of native skin, yet we are still often using flaps with large skin paddles, thereby resulting in significant donor-site scars. This explains the increasing appeal of acellular dermal matrix reconstructions. Acellular dermal matrices can, however, have significant problems, particularly if there is any vascular compromise of the mastectomy skin flaps. We have developed a method of raising the latissimus dorsi flap through the anterior mastectomy incisions without requiring special instruments or repositioning. This can provide autologous vascularized cover of the prosthesis. METHODS: A clear surgical description of the scarless latissimus dorsi flap harvest is provided, and our results of a retrospective cohort review of 20 consecutive patients with 27 traditional latissimus dorsi breast reconstructions were compared with those of 20 consecutive patients with 30 scarless latissimus dorsi breast reconstructions. RESULTS: Operative time, length of stay, and complication rates were reduced in the scarless group. Patients Breast-Q scores were equivalent in each group. The aesthetic assessment was good/excellent in 77% of both groups; however, subscale assessment was better in the scarless group. This was statistically significant (P = 0.0). CONCLUSIONS: Breast reconstruction using the scarless latissimus dorsi flap is time effective, requires no patient repositioning, and uses standard breast instrumentation. It is safe and versatile while reducing the risk of exposed prosthesis if native skin necrosis occurs. It is a vascularized alternative to acellular dermal matrices. PMID- 25289341 TI - Aesthetic subunit reconstruction facilitated with v-y island advancement flaps on the face: a case report. AB - SUMMARY: The reconstruction of complex facial soft-tissue defects is a challenge that is often encountered by the plastic surgeon. Careful planning and knowledge of the aesthetic subunits that border the defect are paramount to achieve optimal results. We present a case of a 56-year-old woman who underwent excision of a large disfiguring chronic xanthelasma that extended from canthus to canthus across the nasal bridge. An aesthetic outcome was achieved by use of bilateral V Y nasolabial flaps combined with a V-Y glabella advancement, which allowed for a tension-free like-for-like subunit reconstruction. PMID- 25289342 TI - Three-dimensional Reconstruction of Scar Contracture-bearing Axilla and Digital Webs Using the Square Flap Method. AB - BACKGROUND: Joint scar contractures are characterized by tight bands of soft tissue that bridge the 2 ends of the joint like a web. Classical treatment methods such as Z-plasties are mainly based on 2-dimensional designs. Our square flap method is an alternative surgical method that restores the span of the web in a stereometric fashion, thereby reconstructing joint function. METHODS: In total, 20 Japanese patients with joint scar contractures on the axillary (n = 10) or first digital web (n = 10) underwent square flap surgery. The maximum range of motion and commissure length were measured before and after surgery. A theoretical stereometric geometrical model of the square flap was established to compare it to the classical single (60 degree), 4-flap (45 degree), and 5-flap (60 degree) Z-plasties in terms of theoretical web reconstruction efficacy. RESULTS: All cases achieved 100% contracture release. The maximum range of motion and web space improved after square flap surgery (P = 0.001). Stereometric geometrical modeling revealed that the standard square flap (alpha = 45 degree; beta = 90 degree) yields a larger flap area, length/width ratio, and postsurgical commissure length than the Z-plasties. It can also be adapted by varying angles alpha and beta, although certain angle thresholds must be met to obtain the stereometric advantages of this method. CONCLUSIONS: When used to treat joint scar contractures, the square flap method can fully span the web space in a stereometric manner, thus yielding a close-to-original shape and function. Compared with the classical Z-plasties, it also provides sufficient anatomical blood supply while imposing the least physiological tension on the adjacent skin. PMID- 25289344 TI - Paralytic ectropion treatment with lateral periosteal flap canthoplasty and introduction of the ectropion severity score. AB - BACKGROUND: Paralytic ectropion patients suffer from impairment of function and appearance of the lower eyelid and are at high risk of developing an exposure keratitis. A canthoplasty procedure can reduce the horizontal eyelid laxity and elevate the lower eyelid. We used a periosteal flap from the outer orbit to create a new canthal ligament. This study investigates the long-term outcomes of this technique. METHODS: Cross-sectional outcome study in which 30 cases of paralytic ectropion are treated with a lateral periosteal flap canthoplasty after adequate eyelid shortening. At the desired canthal height, a periosteal flap from the outer temporal orbital rim is mobilized around the rim and sutured in a double-breasted fashion to a tarsal strip. Effect of the operation is measured by comparing preoperative and postoperative photographs for signs of ectropion. For this purpose, a new photograph-based scoring method [the Ectropion Severity Score (ESS)] was developed and evaluated. RESULTS: The ESS proved to be reliable and sensitive to the presence of ectropion. Significant improvement of the ectropion sequelae was measured after a mean follow-up period of 2 years. In 3 cases (13%), a revision procedure was necessary because of relapse of lower eyelid sagging after a mean time of 1.9 years. In these cases, the periosteal flap could be reused. CONCLUSIONS: The ESS is a useful instrument to score the severity of paralytic ectropion. The periosteal flap canthoplasty is an effective procedure, with durable results in paralytic ectropion patients. The same periosteal flap can be used in a revision procedure. PMID- 25289343 TI - Update/Review: changing of use of local anesthesia in the hand. AB - SUMMARY: Among the many advances in local anesthesia of the hand, some of the most significant changes in the last 5 years have been the following: (1) the acceptance of safety of locally infiltrated epinephrine with lidocaine for hemostasis, which has removed the need for sedation, brachial plexus blocks, and general anesthesia for most common hand surgery operations and minor hand trauma. (2) The elimination of the 2 injection finger block technique in favor of the single injection palmar block. (3) Local anesthesia can now be consistently injected in the hand with minimal pain. (4) Liposomal release of local anesthetic after injection into the surgical site can provide pain control up to 3 days. This article reviews the impact and best evidence related to these changes. PMID- 25289345 TI - Application of normobaric hyperoxygenation to an ischemic flap and a composite skin graft. AB - BACKGROUND: Hyperbaric oxygenation has been used for various purposes, but its clinical application is limited due to its pulmonary toxicity. We evaluated the therapeutic value of normobaric hyperoxygenation (NBO) for vascularized and nonvascularized tissue transplantation. METHODS: Tissue oxygen partial pressure (PtO2) was measured for various organs in mice under inspiratory oxygen of 20%, 60%, or 100%. A rectangular skin flap (1 * 4 cm) or a composite skin graft (2 * 2 cm) was made on the back of mice, which were housed under 20% or 60% oxygen for the first 3 days after surgery. Cell survival was also examined in organ culture skin samples. RESULTS: PtO2 varied among tissues/organs, but increased depending on inspiratory oxygen concentration in all tissues/organs. Although NBO with 100% O2 was toxic, NBO with 60% O2 was safe even when used continuously for a long period. NBO did not significantly improve survival of the rectangular skin flap. On the other hand, in the composite skin graft model, the engraftment area increased significantly (52 +/- 10 at 20% vs 68 +/- 5.1 at 60%) and contraction decreased significantly (42 +/- 8.0 at 20% vs 27 +/- 5.7 at 60%). Organ culture of a composite skin sample showed significant cell death under lower oxygen concentrations, supporting the data in vivo. CONCLUSIONS: The composite graft was maintained until revascularization by plasmatic diffusion from surrounding tissues, in which PtO2 was improved by NBO. NBO may be an effective adjunct therapy that can be performed readily after nonvascularized tissue grafting. PMID- 25289346 TI - Five-year Experience with Perma Facial Implant. AB - SUMMARY: Augmentation cheiloplasty is becoming an increasingly popular aesthetic procedure despite current methodologies having met with disappointment among surgeons and patients. The goal of this study was to examine the benefits and drawbacks of 1 device in particular-Perma Facial Implant (PFI). The senior authors (P.R. and S.W.H.) performed 832 consecutive PFI lip augmentations with excellent results based on photographic documentation, patient satisfaction surveys, unbiased surgeon ratings, and low complication rates. In addition to augmenting thin lips, PFIs hide excess dentition and improve vermilion rhytids and pout. Contrary to alternatives, they are both permanent and reversible. However, they do not level out asymmetries or benefit razor-thin lips without prior lifting or mucosal advancement. PMID- 25289347 TI - Successful treatment of lower eyelid melanoma in situ. AB - SUMMARY: We present a brief literature review of the topical immune-modulating medication Imiquimod. The treatment of periorbital melanoma in situ typically requires surgical resection. Here we discuss a case of lower eyelid melanoma in situ successfully treated non-operatively with Imiquimod. PMID- 25289348 TI - Bovine versus Porcine Acellular Dermal Matrix: A Comparison of Mechanical Properties. AB - BACKGROUND: Porcine and bovine acellular dermal matrices (PADM and BADM, respectively) are the most commonly used biologic meshes for ventral hernia repair. A previous study suggests a higher rate of intraoperative device failures using PADM than BADM. We hypothesize that this difference is, in part, related to intrinsic mechanical properties of the matrix substrate and source material. The following study directly compares these 2 matrices to identify any potential differences in mechanical properties that may relate to clinical outcomes. METHODS: Sections of PADM (Strattice; Lifecell, Branchburg, N.J.) and BADM (SurgiMend; TEI Biosciences, Boston, Mass.) were subjected to a series of biomechanical tests, including suture retention, tear strength, and uniaxial tensile strength. Results were collected and compared statistically. RESULTS: In all parameters, BADM exhibited a superior mechanical strength profile compared with PADM of similar thickness. Increased BADM thickness correlated with increased mechanical strength. In suture tear-through testing with steel wire, failure of the steel wire occurred in the 4-mm-thick BADM, whereas the matrix material failed in all other thicknesses of BADM and PADM. CONCLUSIONS: Before implantation, BADM is inherently stronger than PADM at equivalent thicknesses and considerably stronger at increased thicknesses. These results corroborate clinical data from a previous study in which PADM was associated with a higher intraoperative device failure rate. Although numerous properties of acellular dermal matrix contribute to clinical outcomes, surgeons should consider initial mechanical strength properties when choosing acellular dermal matrices for load bearing applications such as hernia repair. PMID- 25289349 TI - A Cluster of Surgical Site Infections following Breast Augmentation and Face Lift Surgery. PMID- 25289350 TI - Skirt flap for nasal alar reconstruction. PMID- 25289351 TI - A comparative analysis of 2 national breast reconstruction surveys: concerns regarding autologous and microsurgical breast reconstruction. AB - BACKGROUND: Pertinent findings of two national breast reconstruction (BR) surveys from two different institutions at two separate times (2012 vs 2010) were analyzed for comparison. METHODS: An appraisal of sampling methodology, sample demographics, years of practice, practice affiliation, BR type, and annual volume between the two studies was conducted using statistical analysis. RESULTS: Proper sampling technique and adequate sample size were used in both surveys to represent the typical population of general US plastic surgeons practicing BR. There were no differences in mean age or years of practice between the sample population in both studies. The percentage of plastic surgeons with academic affiliation was higher in the 2012 survey compared to the 2010 survey (28% vs 18%, P<0.05). Implant-based BR was the predominant method among surveyed plastic surgeons in both surveys. There was a substantial decrease in the proportion of plastic surgeons performing >20 cases per year in the 2012 survey compared to the 2010 survey (P<0.05). A high volume of BR, defined as >60 cases per year in the 2010 survey and >20 cases per year in the 2012 survey, correlated significantly with academic practice and multidisciplinary cancer centers, respectively (P<0.05). There was a significant decline in the percentage of plastic surgeons performing microsurgical BR from 2010 to 2012 (35% vs 25%, P<0.05). CONCLUSIONS: Comparative data suggest that there are fewer high volume BR cases being performed by US plastic surgeons and that there has been a reduction among plastic surgeons in the use of microsurgical BR from 2010 to 2012. We believe that these findings may indicate early signs of the changes in BR trends in the US. PMID- 25289352 TI - Discomfort during Periorbital and Lateral Temporal Laser Vein Treatment: A Double blind Randomized Controlled Trial. AB - BACKGROUND: Treatments for cosmetically unpleasing periocular and lateral temporal veins are limited. The purpose of this study was to test the hypothesis that the application of topical lidocaine before the cosmetic treatment of periorbital and lateral temporal veins with a neodymium-doped yttrium aluminum garnet (ND:YAG) laser will result in a significant reduction in subjective pain compared with placebo as assessed using a visual analogue scale. METHODS: Twenty patients who required bilateral treatment of facial veins were randomly assigned to receive either placebo or 30% lidocaine gel applied topically over the veins, a split-body design. Both the investigator and the patient were blinded to the treatment. An ND:YAG laser was used to treat the veins. Patients completed a visual analogue scale to assess the pain on each side of the face. Data were analyzed using nonparametric data testing. RESULTS: There was a 64.0% reduction in pain on the treatment side compared with the placebo side (P < 0.001). There was no significant difference in patient-assessed subjective efficacy between sides (P = 0.2). Complications were minimal and mild. CONCLUSIONS: Patients undergoing periorbital and temporal vein ablation using ND:YAG laser should be offered topical lidocaine as the pain levels are moderate. The use of topical 30% lidocaine results in a significant reduction in pain levels. PMID- 25289353 TI - The Case against Chemoprophylaxis for Venous Thromboembolism Prevention and the Rationale for SAFE Anesthesia. AB - SUMMARY: The Venous Thromboembolism Prevention study concludes that anticoagulation is effective in reducing the risk of thromboembolism in patients who are identified as higher risk by Caprini scores. This report critically assesses the statistics used in the Venous Thromboembolism Prevention study, its method of data presentation, and its conclusions. The usefulness of risk stratification and the value of anticoagulation-both prevailing concepts in risk reduction today-are challenged. Actual data show that chemoprophylaxis has no proven benefit in plastic surgery. Complications of anticoagulation predictably include excessive bleeding and hematomas, which may be serious and life threatening. Several large published series of patients undergoing elective plastic surgery under total intravenous anesthesia have shown a much reduced risk of thromboembolism. A SAFE (Spontaneous breathing, Avoid gas, Face up, Extremities mobile) anesthesia method is discussed as a safer and more effective alternative to traditional general endotracheal anesthesia and anticoagulation. The choice for plastic surgeons is not between a venous thromboembolism and a hematoma. The choice is between a thromboembolism and adjusting our anesthesia and surgery habits to reduce the risk to a baseline level. PMID- 25289354 TI - Validity, reliability, and the questionable role of psychometrics in plastic surgery. AB - SUMMARY: This report examines the meaning of validity and reliability and the role of psychometrics in plastic surgery. Study titles increasingly include the word "valid" to support the authors' claims. Studies by other investigators may be labeled "not validated." Validity simply refers to the ability of a device to measure what it intends to measure. Validity is not an intrinsic test property. It is a relative term most credibly assigned by the independent user. Similarly, the word "reliable" is subject to interpretation. In psychometrics, its meaning is synonymous with "reproducible." The definitions of valid and reliable are analogous to accuracy and precision. Reliability (both the reliability of the data and the consistency of measurements) is a prerequisite for validity. Outcome measures in plastic surgery are intended to be surveys, not tests. The role of psychometric modeling in plastic surgery is unclear, and this discipline introduces difficult jargon that can discourage investigators. Standard statistical tests suffice. The unambiguous term "reproducible" is preferred when discussing data consistency. Study design and methodology are essential considerations when assessing a study's validity. PMID- 25289355 TI - A New Economic Method for Preparing Platelet-rich Plasma. AB - BACKGROUND: Although platelet-rich plasma (PRP) is nowadays a common method in various medical fields, including cosmetic surgery or dermatology, the expensiveness of the kit for processing is still a hurdle. METHODS: A new unique economic method for preparing PRP was reported. The method consists in a simple modification of a disposable 5-mL syringe that allows insertion into a common centrifuge and positioning of the syringe on the centrifuge so the PRP separates next to the tip of the syringe. Platelet-derived growth factor BB in PRP was measured under anticoagulant dextrose solution A (ACD-A) or heparin as anticoagulant and with or without prostaglandin E1 (PGE1) as a platelet aggregation suppressant. RESULTS: The new method successfully created PRP with high platelet-derived growth factor BB in all conditions, and the highest value was obtained by using ACD-A and PGE1. CONCLUSIONS: The new method is useful, and the use of ACD-A and PGE1 is the most recommended. PMID- 25289356 TI - Long-term Survival after Metastatic Childhood Melanoma. AB - SUMMARY: Malignant melanoma in children is very rare and accounts for only 1-3% of all melanomas. A congenital melanocytic nevus depending on the size of the lesion is one of the risk factors for developing childhood melanoma because of the possible malignant transformation. Childhood malignant melanoma is a potentially fatal disease. Surgical excision is the primary treatment of choice for malignant melanoma. Clinicians need to be aware of the possible malignant transformation in children with congenital melanocytic nevus because early diagnosis and treatment improves prognosis. The suspicion of malign melanoma must be in mind when evaluating a pigmented lesion in a pediatric patient. We present a case of a patient born with a congenital nevus diagnosed with metastatic childhood malignant scalp melanoma at the age of 6 years. The patient underwent surgical ablation and reconstruction and has survived 26 years without recurrence, thus representing an uplifting case of long-term survival of childhood melanoma. PMID- 25289357 TI - Sites of Basal cell carcinomas and head and neck congenital clefts: topographic correlation. AB - BACKGROUND: The embryologic fusion planes might be related with the sites of onset of basal cell carcinoma (BCC), thus supporting an embryologic role for its pathogenesis. METHODS: A study involving 495 patients with 627 BCCs of the head and neck was carried out over a period of 5 years by correlating the distribution of all BCCs with the sites of congenital clefts of the head and neck using (1) the original anatomic diagram of the Tessier classification of craniofacial clefts, (2) the anatomic diagram by Moore et al featuring the paths of the "hairline indicators" of craniofacial clefts that represent the cranial extensions of the Tessier classification, and (3) an anatomical diagram featuring the sites of congenital clefts of the neck. RESULTS: The proportion of BCCs localized within a cleft site was significantly higher than those in the noncleft sites. The age of patients with BCCs localized within the Tessier cleft number 3 was the lowest among all cleft regions. CONCLUSIONS: A topographic correspondence between the sites of BCCs and the sites of congenital clefts was demonstrated in the head and neck. This evidence would support the hypothesis of an embryologic role for the pathogenesis of BCC. The existence of clusters of embryological stem cells in the sites of fusion and/or merging of embryonic processes might therefore be proposed. There may be special biology/physiology along these cleft lines that predispose BCC formation. PMID- 25289358 TI - Does a Nebulized Heparin/N-acetylcysteine Protocol Improve Outcomes in Adult Smoke Inhalation? AB - BACKGROUND: Smoke inhalation is a major source of morbidity and mortality. Heparin and N-acetylcysteine treatment has potential efficacy in inhalation injury. We investigated the impact of a heparin/N-acetylcysteine/albuterol nebulization protocol in adult patients with inhalation injury. METHODS: A retrospective review was performed of adult inhalation injury patients, admitted to a regional burn center between January 2011 and July 2012, who underwent a protocol of alternating treatments of heparin and N-acetylcysteine/albuterol nebulization every 4 hours. The study cohort was matched 1:1 by age, sex, and burn size to a control cohort admitted within 5 years before protocol implementation. RESULTS: The study (n = 20) and control cohorts (n = 20) were well matched, with nearly identical age (50 vs 49 years), sex distribution (70% male), burn size (total body surface area, 22% vs 21%), and inhalation injury, except grade I injuries (79% vs 47%, P = 0.01). The protocol did not change mortality (30% vs 25%, P = 0.72) or duration of mechanical ventilation (8.5 vs 8.8 days, P = 0.9). There was no difference in development of sepsis (40% vs 33%, P = 0.7) or acute respiratory distress syndrome (15% vs 10%, P = 1); however, those who received the protocol were more likely to develop pneumonia (45% vs 11%, P = 0.03). CONCLUSIONS: The implementation of a heparin/N acetylcysteine/albuterol protocol did not reduce mortality or duration of mechanical ventilation in this cohort of adults with inhalation injury and resulted in a significant increase in pneumonia rates. Larger prospective studies are necessary, with close attention paid to minimizing the infection risk incurred from frequent administration of nebulized medications. PMID- 25289359 TI - Untreatable surgical site infection: consider pyoderma gangrenosum. AB - SUMMARY: Pyoderma gangrenosum (PG) is an inflammatory disease characterized by sterile infiltration of the skin by neutrophils. We describe a case of a 63-year old woman who developed PG following an abdominal wall reconstruction. Her initial presentation was thought to be consistent with a surgical site infection. Antibiotic therapy was initiated, and the patient was taken for multiple irrigation/lavage of her abdomen and debridement of necrotic tissue. Wound cultures remained negative, and maximal antibiotic coverage did not halt tissue breakdown. A trial of steroids was initiated, and the patient's condition subsequently improved. Tissue biopsy results were compatible with the diagnosis of PG. PMID- 25289360 TI - Vascularized lymph node flap transfer and lymphovenous anastomosis for klippel trenaunay syndrome with congenital lymphedema. AB - SUMMARY: A female patient with Klippel-Trenaunay syndrome, including hypertrophic bone and soft tissue in the forelimbs, bilateral lower limbs lymphedema, port wine stains, and superficial veins of Servelle, was presented. The diagnosis of lymphedema was confirmed by lymphoscintigraphy and indocyanine green lymphography. The novel treatments consisted of vascularized lymph node transplantation to the left lymphedematous extremity and lymphovenous anastomosis to the right lymphedematous extremity. Significant improvements in subjective and objective clinical outcome were observed early in the postoperative period with continued improvements during the follow-up period. PMID- 25289361 TI - Soccer-related Facial Trauma: Multicenter Experience in 2 Brazilian University Hospitals. AB - BACKGROUND: Soccer is the most popular sport in Brazil and a high incidence of related trauma is reported. Maxillofacial trauma can be quite common, sometimes requiring prolonged hospitalization and invasive procedures. To characterize soccer-related facial fractures needing surgery in 2 major Brazilian Centers. METHODS: A retrospective review of trauma medical records from the Plastic Surgery Divisions at the Universidade Federal de Sao Paulo-Escola Paulista de Medicina and the Hospital das Clinicas-Universidade de Sao Paulo was carried out to identify patients who underwent invasive surgical procedures due to acute soccer-related facial fractures. Data points reviewed included gender, date of injury, type of fracture, date of surgery, and procedure performed. RESULTS: A total of 45 patients (31 from Escola Paulista de Medicina and 14 from Universidade de Sao Paulo) underwent surgical procedures to address facial fractures between March 2000 and September 2013. Forty-four patients were men, and mean age was 28 years. The fracture patterns seen were nasal bones (16 patients, 35%), orbitozygomatic (16 patients, 35%), mandibular (7 patients, 16%), orbital (6 patients, 13%), frontal (1 patient, 2%), and naso-orbito-ethmoid (1 patient, 2%). Mechanisms of injury included collisions with another player (n = 39) and being struck by the ball (n = 6). CONCLUSIONS: Although it is less common than orthopedic injuries, soccer players do sustain maxillofacial trauma. Knowledge of its frequency is important to first responders, nurses, and physicians who have initial contact with patients. Missed diagnosis or delayed treatment can lead to facial deformities and functional problems in the physiological actions of breathing, vision, and chewing. PMID- 25289362 TI - Silicone breast implants can save lives. AB - SUMMARY: The authors present a case in which a patient sustained 2 shotgun wounds at close range, resulting in a ruptured silicone breast implant and no other injuries. PMID- 25289363 TI - Coverage of Deep Cutaneous Wounds Using Dermal Template in Combination with Negative-pressure Therapy and Subsequent Skin Graft. AB - BACKGROUND: We consider the use of dermal matrix associated with a skin graft to cover deep wounds in the extremities when tendon and bone are exposed. The objective of this article was to evaluate the efficacy of covering acute deep wounds through the use of a dermal regeneration template (Integra) associated with vacuum therapy and subsequent skin grafting. METHODS: Twenty patients were evaluated prospectively. All of them had acute (up to 3 weeks) deep wounds in the limbs. We consider a deep wound to be that with exposure of bone, tendon, or joint. RESULTS: The average area of integration of the dermal regeneration template was 86.5%. There was complete integration of the skin graft over the dermal matrix in 14 patients (70%), partial integration in 5 patients (25%), and total loss in 1 case (5%). The wound has completely closed in 95% of patients. CONCLUSIONS: The use of Integra dermal template associated with negative-pressure therapy and skin grafting showed an adequate rate of resolution of deep wounds with low morbidity. PMID- 25289364 TI - Minimally painful local anesthetic injection for cleft lip/nasal repair in grown patients. AB - INTRODUCTION: There has been a recent interest in injecting large body and face areas with local anesthetic in a minimally painful manner. The method includes adherence to minimal pain injection details as well feedback from the patient who counts the number of times he feels pain during the injection process. This article describes the successes and limitations of this technique as applied to primary cleft lip/nasal repair in grown patients. METHODS: Thirty-two primary cleft lip patients were injected with local anesthesia by 3 surgeons and then underwent surgical correction of their deformity. At the beginning of the injection of the local anesthetic, patients were instructed to clearly inform the injector each and every time they felt pain during the entire injection process. RESULTS: The average patient felt pain only 1.6 times during the injection process. This included the first sting of the first 27-gauge needle poke. The only pain that 51% of the patients felt was that first poke of the first needle; 24% of the patients only felt pain twice during the whole injection process. The worst pain score occurred in a patient who felt pain 6 times during the injection process. Ninety-one percent of the patients felt no pain at all after the injection of the local anesthetic and did not require a top-up. CONCLUSION: It is possible to successfully and reliably inject local anesthesia in a minimally painful manner for cleft lip and nasal repair in the fully grown cleft patient. PMID- 25289365 TI - Effective Use of a Silicone-induced Capsular Flap in Secondary Asian Rhinoplasty. AB - SUMMARY: Performing secondary rhinoplasty in patients who underwent primary rhinoplasty using a silicone implant is difficult due to thinning of nasal skin and formation of a capsule. Excess capsule formation can cause capsular contracture, resulting in short nose deformity or implant deviation, migration, or implant demarcation. Revision rhinoplasty using a capsular flap, dorsal silicone implant, and tip plasty was performed in 95 Korean patients (91 women and 4 men; mean age, 27 years) who previously underwent primary augmentation rhinoplasty using silicone implants. The capsular flap was composed by creating a dual plane above the anterior capsule and below the posterior capsule. The existing silicone implant was removed, and a new silicone implant was placed under the posterior capsule. The patients were followed up for 6 months to 4 years (mean, 31.7 months). Of the 95 patients who underwent secondary augmentation rhinoplasty using a capsular flap, 88 patients (92.6%) showed satisfactory results. There was no hematoma or nasal skin vascular compromise. There was no visible or palpable capsule resorption or recurrent capsular contracture. Early implant malpositioning (within 30 days postoperatively) was observed in 4 patients, and tip shape dissatisfaction (within 60 days postoperatively) was reported by 3 patients. Four patients underwent revision surgery and had successful outcomes. Nasal augmentation using a silicone implant and capsular flap in secondary rhinoplasty avoids complications caused by removal of the capsule. Recurrent capsule formation or clinically noticeable resorption of the capsular flap was not observed in this study. PMID- 25289366 TI - Quantitative magnetic resonance imaging volumetry of facial muscles in healthy patients with facial palsy. AB - BACKGROUND: Magnetic resonance imaging (MRI) has not yet been established systematically to detect structural muscular changes after facial nerve lesion. The purpose of this pilot study was to investigate quantitative assessment of MRI muscle volume data for facial muscles. METHODS: Ten healthy subjects and 5 patients with facial palsy were recruited. Using manual or semiautomatic segmentation of 3T MRI, volume measurements were performed for the frontal, procerus, risorius, corrugator supercilii, orbicularis oculi, nasalis, zygomaticus major, zygomaticus minor, levator labii superioris, orbicularis oris, depressor anguli oris, depressor labii inferioris, and mentalis, as well as for the masseter and temporalis as masticatory muscles for control. RESULTS: All muscles except the frontal (identification in 4/10 volunteers), procerus (4/10), risorius (6/10), and zygomaticus minor (8/10) were identified in all volunteers. Sex or age effects were not seen (all P > 0.05). There was no facial asymmetry with exception of the zygomaticus major (larger on the left side; P = 0.012). The exploratory examination of 5 patients revealed considerably smaller muscle volumes on the palsy side 2 months after facial injury. One patient with chronic palsy showed substantial muscle volume decrease, which also occurred in another patient with incomplete chronic palsy restricted to the involved facial area. Facial nerve reconstruction led to mixed results of decreased but also increased muscle volumes on the palsy side compared with the healthy side. CONCLUSIONS: First systematic quantitative MRI volume measures of 5 different clinical presentations of facial paralysis are provided. PMID- 25289367 TI - Successful bilateral composite ear reattachment. AB - SUMMARY: A successful bilateral ear composite graft nonmicrosurgical reattachment is presented. In cases where suitable vessels are unavailable for microsurgical revascularization, the reconstructive challenge can be formidable for salvaging the unique anatomic and aesthetic structure of the ear. The case is presented of an 18-year-old woman who was a victim of an assault wherein both of her ears were intentionally amputated by her attacker. She underwent successful surgical reattachment followed by a postoperative regimen of hyperbaric oxygen, cooling, and meticulous wound care. The patient achieved 100% survival of her left ear graft and 95% survival of her right ear graft. Clinical photographs at 18 months are presented, along with a discussion of the possible implications for other reconstructive applications. PMID- 25289368 TI - Severe, Steroid-responsive, Myositis Mimicking Necrotizing Fasciitis following Orthopedic Surgery: A Pyoderma Variant with Myonecrosis. AB - SUMMARY: Postoperative pyoderma gangrenosum is a rare neutrophilic dermatosis that may be confused for necrotizing fasciitis. The inflammatory response is triggered by the trauma of surgery and thus must be managed nonsurgically. Clinical and pathological findings in the 2 diseases can be identical, leading to misdiagnosis and massive surgical defects from the ensuing surgery. This report documents a severe case of postsurgical pyoderma following an elective rotator cuff repair presenting with myositis and myonecrosis. The patient was initially treated as having an infection, which resulted in multiple aggressive surgical debridements. Despite this, the patient continued to deteriorate and was in a critical and hemodynamically unstable condition. Following administration of high dose intravenous corticosteroids, the patient made a dramatic recovery and went on to have internal fixation of the shoulder and closure of the wound with a combination of a free flap and a rotational flap. Extensive myositis, as seen in this case, has not been previously reported in postoperative pyoderma gangrenosum variants. Clinicians should be aware that the presence of myositis and myonecrosis should not preclude this diagnosis. PMID- 25289369 TI - Microtia Reconstruction and Postsurgical Grisel's Syndrome: A Rare Cause of Torticollis in a Child. AB - SUMMARY: Grisel's syndrome is an unusual but important cause of torticollis which may be encountered in a pediatric plastic surgery practice, where craniofacial and oropharyngeal surgeries are commonly performed. Grisel's syndrome is characterized by painful torticollis and limited cervical rotation, and the diagnosis is confirmed via radiologic imaging. Initial management of Grisel's syndrome is with anti-inflammatories and in some cases antibiotics. In unresolving or recurrent cases, more invasive treatments, such as cervical collar, halo, or surgical arthrodesis, may be considered. PMID- 25289370 TI - New Developments in Understanding and Treating Adolescent Marijuana Dependence. AB - BACKGROUND: Marijuana is the most commonly used illicit substance in the United States and worldwide. Marijuana use is a problem of increasing magnitude among adolescents. Use typically begins in adolescence and is associated with a variety of adverse outcomes. METHOD: This article will present an overview of trends in marijuana use, and will review the endocannabinoid system and marijuana. It will discuss recent policy developments in US and their implications, especially for adolescents. Existing treatments will be reviewed, including findings from a recent randomized double-blind trial of N-acetylcysteine, a compound that reverses the dysregulation of the glutamate system that occurs in substance dependence. CONCLUSIONS: The core treatment approaches include psychosocial interventions, sometimes in combination with each other. While a reduction in days of use is often achieved with most of these approaches, abstinence is a much more elusive goal. The evidence base for effective treatments remains inadequate especially with regard to adolescents, and there is an urgent need for more research in this area. Promising new treatments include N-acetylcysteine in conjunction with contingency management. PMID- 25289371 TI - Inhalation anesthesia in a patient with xeroderma pigmentosum: a case report. AB - INTRODUCTION: Xeroderma Pigmentosum (XP) is a rare autosomal recessive disease, which is defined by extreme sensitivity to sunlight and UV radiation and characterized by skin lesions and neuromuscular abnormalities. It is caused by a molecular defect in nucleotide excision repair genes. It has been reported that volatile anesthetics may cause genotoxic side effects or aggravation of the neurological signs. We report an XP patient with difficult intubation whose airway was controlled with Laryngeal Mask Airway (LMA) and was anesthetized with sevoflurane. CASE PRESENTATION: A 23-year-old woman, who had been a known case of XP since her childhood, was admitted to our hospital for excision of face mass (SCC) and skin graft surgery. Her airway examination revealed some anatomical and pathological abnormalities, including limitation of mouth opening, jaw protrusion, head extension, and class 4 of mallampati, all predicting difficult intubation. We chose general anesthesia with inhalation induction, LMA insertion and maintenance with sevoflurane without muscle relaxant. The surgery was completed uneventfully and the patient left the hospital the day after the surgery without any new complaint. CONCLUSIONS: We suggest that for XP patients with compromised air-way, sevoflurane (not all volatiles) may be preferred. PMID- 25289372 TI - Comparing the prevalence of chronic pain after sternotomy in patients undergoing coronary artery bypass grafting using the internal mammary artery and other open heart surgeries. AB - BACKGROUND: The prevalence of chronic postoperative pain after cardiac surgery has been reported from 17% to 56%. OBJECTIVES: We aimed to compare the prevalence of postoperative pain between patients who had undergone CABG using the internal mammary artery (IMA) and those who had undergone other cardiac surgeries including CABG using the saphenous vein or cardiac valvular surgeries. PATIENTS AND METHODS: In this cohort study, medical records of 188 patients were evaluated and divided into two equal groups (94 in each group); patients who had undergone CABG using the IMA (IMA group) and those who had undergone other cardiac surgeries using the saphenous vein or other cardiac valvular surgeries (non-IMA group). The patients' data were recorded in a self-structured questionnaire and then phone interviews were performed 3 months after the operations regarding the rate of postoperative pain. The severity of chronic pain was rated based on the numerical rating pain scale. RESULTS: The two groups differed significantly regarding the prevalence of pain (P = 0.023). In the IMA group, 83 (88.3%) patients experienced pain lasting for more than three months compared to 71 (75.5%) patients in non-IMA group. The two groups differed significantly with respect to the severity of chronic pain after cardiac surgery via sternotomy (P = 0.001). The groups did not differ significantly regarding the effects of chronic pain on their sleep, referral to a physician, and drug consumption to alleviate their pain. The IMA group experienced more complications at work and during their occupational activity. CONCLUSIONS: The rate and severity of chronic pain after cardiac surgery via sternotomy was higher in patients undergoing CABG with separation of IMA for revascularization. PMID- 25289373 TI - Reducing postoperative opioid consumption by adding an ultrasound-guided rectus sheath block to multimodal analgesia for abdominal cancer surgery with midline incision. AB - BACKGROUND: Many multimodal analgesia techniques have been tried to provide adequate analgesia for midline incisions extending above and below the umbilicus aiming at limiting the perioperative use of morphine thus limiting side effects. Ultrasound (US) guidance made the anesthesiologist reconsider old techniques for wider clinical use. The rectus sheath block (RSB) is a useful technique under utilized in the adult population. OBJECTIVES: Our study examined the efficacy of a preemptive single-injection rectus sheath block in providing better early postoperative pain scores compared to general anesthesia alone. PATIENTS AND METHODS: Sixty patients were recruited in this randomized controlled trial. These patients were divided into two groups: RSB group had an RSB after induction of anesthesia and before surgical incision, and GA (general anesthesia) group had general anesthesia alone. Both groups were compared for verbal analogue scale (VAS) score, opioid consumption and hemodynamic variables in the post-anesthesia care unit (PACU). Analgesic requirements in surgical wards were recorded in postoperative days (POD) 0, 1 and 2. RESULTS: The median VAS score was significantly lower in RSB group compared with GA group in all 5 time points in the PACU (P ? 0.05). Also PACU morphine consumption was lower in RSB group than GA group patients (95% confidence interval [CI] of the difference in means between groups, -4.59 to -2.23 mg). Morphine consumption was also less in the first 2 postoperative days (POD0 and POD1). CONCLUSIONS: Ultrasound-guided rectus sheath block is an easy technique to learn. This technique, when it is used with general anesthesia, will be more effective in reducing pain scores and opioid consumption compared with general anesthesia alone. PMID- 25289375 TI - Ascorbic Acid interaction with analgesic effect of morphine and tramadol in mice. AB - BACKGROUND: Combining different analgesic drugs for improvement of drug efficacy is a recommended strategy intended to achieve the optimal therapeutic effects. OBJECTIVES: The purpose of the present study was to assess the nature of the interaction between ascorbic acid and two analgesic drugs, morphine and tramadol. MATERIALS AND METHODS: The analgesic activity was assessed by the acetic acid writhing test in male Naval Medical Research Institute (NMRI) mice. The results were obtained using four to six animals in each group. All the drugs were injected intraperitoneally. The effective doses (ED) that produced 20%, 50%, and 65% antinociception (ED20, ED50 and ED65) were calculated from the dose-response curve of each drug alone as well as co-administration of ascorbic acid and tramadol or morphine. The interaction index was calculated as experimental ED/theoretical ED. For each drug combination, ED50, ED20 and ED65 were determined by linear regression analysis of the dose-response curve, and they were compared to theoretical ED50, ED20 and ED65 using t-test. RESULTS: The antinociceptive effects of all drugs were dose-dependent (ED50was 206.1 mg/kg for ascorbic acid, 8.33 mg/kg for tramadol, and 0.79 mg/kg for morphine). The interaction index demonstrated additive effects at ED50 and ED65 for co-administration of ascorbic acid and tramadol or morphine. However, at ED20, combination of ascorbic acid and tramadol or morphine showed synergic effects. The interaction index values of the combinations demonstrated the potency ratio of ascorbic acid/morphine to be lower than ascorbic acid/tramadol. CONCLUSIONS: This study demonstrated the results of interactions between ascorbic acid and tramadol or morphine. The results showed that the interaction effects on antinociception may be synergistic or additive, depending on the level of effect. PMID- 25289374 TI - Lumbar plexus block for management of hip surgeries. AB - BACKGROUND: Lumbar plexus block (LPB) is one of the anesthetic options in the elderly patients undergoing hip surgeries. LPB could be safe because it targets somatic nerve in psoas region. Effectiveness of LPB is attributed to the sufficient analgesia provided intraoperatively as well as postoperatively. Adequate muscle relaxation and immobility during surgery refers to its acceptability. OBJECTIVES: In this study, LPB was used as the anesthetic method to manage the elderly patients subjected to hip surgery. PATIENTS AND METHODS: A total of 50 patients aged 51 to 100 years were enrolled in this study. LPB was accomplished after a mild sedation and with a modified method using patient's fingertip width (FTW) as the distance unit to determine needle entry point under electrical nerve stimulation assistance. After targeted injection, procedure time, establishment time, block duration, surgery time, hemodynamic variables, and surgeon satisfaction score were documented and analyzed. Propofol in trivial doses was infused intraoperatively to provide clinical sedation. RESULTS: Mean patient's age was 73 +/- 12 years with ASA II/III. Procedure time was 5.65 +/- 1.24 minutes, establishment time was 130 +/- 36 seconds, block duration was 13.1 +/- 8 hours, surgery time was 149.7 +/- 32.2 minutes, and surgeon satisfaction score was 9.8 +/- 0.1. There was no complication and no failure. Hemodynamic stability was pleasantly achieved. CONCLUSIONS: By preserving hemodynamic stability, LPB in conjunction with a light sedation could be considered as a reliable prudent satisfying anesthetic option in management of hip fractures in the elderly patients with three beneficial characteristics of safety, effectiveness, and acceptability. PMID- 25289376 TI - Comparison of the incidence of sore throat after rapid sequence intubation with succinylcholine and cisatracurium. AB - BACKGROUND: Postoperative sore throat is a common complication of endotracheal intubation and can lead to dissatisfaction after surgery. Airway management has the strongest influence on the incidence of sore throat and improving endotracheal intubating conditions can reduce this complaint. Type of induction agent used during anesthesia can contribute to variances in the degree of post operative sore throat. OBJECTIVES: We aimed to compare the incidence of postoperative sore throat after rapid sequence induction with Succinylcholine and high dose Cisatracurium. PATIENTS AND METHODS: The study was carried out on patients admitted to Shohada-e-Tajrish hospital for emergent abdominal surgery. Of the 80 patients who were enrolled in the study, 40 were randomly assigned to receive Succinylcholine while the remaining patients received Cistracurium during induction. Sore throat, muscle ache, hoarseness, dry throat and pain were assessed in each patient at baseline in recovery and at 2, 4, 12 and 24 hours post-operation. RESULTS: Number of patients who developed sore throat was significantly higher in the Succinylcholine group (75%) compared to Cisatracurium group (27.5%) at the time of entrance to the recovery room (P = 0.001). These numbers decreased at 2 hours post-operation (42% versus 17.5%) but the difference was still statistically significant (P < 0.05). At 12 (P = 0.062) and 24 (P = 0.14) hours post operation, the difference was no longer significant. CONCLUSIONS: Use of high dose Cisatracurium for induction during rapid sequence intubation carries a lower chance of developing sore throat compared to Succinylcholine. Studies comparing other adverse effects of these two agents are required to guide physician's choice of induction agent. PMID- 25289377 TI - Significance of preoperative total lymphocyte count as a prognostic criterion in adult cardiac surgery. AB - BACKGROUND: Evaluation of operational risk is a consequential goal in perioperative management of patients in cardiac surgery. Preoperative total lymphocyte count (PTLC) is a prognostic criterion of adverse major cardiovascular outcomes. OBJECTIVES: The purpose of this study was to investigate the prognostic value of PTLC as an independent predictor of postoperative morbidity and mortality in cardiac surgery. PATIENTS AND METHODS: Of 1604 patients scheduled for cardiac surgery between September, 2012 and March, 2013, a total of 1171 consecutive patients underwent elective primary valvular heart surgery and coronary artery bypass grafting. The patients were divided to three groups according to their PTLCs. The baseline characteristics and postoperative mortality and morbidity of the patients as well as the intensive care unit (ICU) stay according to the PTLCs were recorded and analyzed. The only inclusion criterion was a preoperative complete blood count. Exclusion criteria included: ages under 18 or over 80 years old, emergency surgery, adult patients with congenital heart disease and previous open heart surgery, and patients with any bacterial or viral infection during two weeks before the surgery. Protocol of anesthetic medications was used in all the patients similarly and according to standard. All the patients were admitted to the ICU after the surgery. RESULTS: A PTLC < 1500 cells/uL was associated with significantly high mortality and morbidity (P = 0.0001). In-hospital mortality and major composite morbidity were 9.65% and 28.4%, respectively. Low PTLC was associated with more frequent need for inotropic and intra-aortic balloon pump (IABP) support (P < 0.001), dialysis dependent acute renal failure (P = 0.0001), postoperative superficial wound infections (P = 0.0001) and prolong ICU stay (P = 0.0001). CONCLUSIONS: Our study results showed that low PTLC was an independent, valuable prognostic criterion, with high sensitivity and specificity for evaluation of postoperative morbidity and mortality in cardiac surgery. PMID- 25289378 TI - Comparison of surgical stress responses during spinal and general anesthesia in curettage surgery. AB - BACKGROUND: Response to the surgical stress is an involuntary response to metabolic, autonomic as well as hormonal changes that leads to heart rate and blood pressure fluctuations. OBJECTIVES: This study aimed to investigate the effect of general versus spinal anesthesia on blood sugar level and hemodynamic changes in patients undergoing curettage surgery. PATIENTS AND METHODS: In this randomized clinical trial, 50 patients who were candidate for elective curettage surgery were divided into two groups of general (n = 25) and spinal (n = 25) anesthesia. In both groups, blood glucose level was evaluated 10 minutes before, 20 and 60 minutes after initiation of anesthesia. Also, heart rate and mean arterial blood pressure were evaluated at 10 minutes before, 10, 20, 30, 40, 50 and 60 minutes after intiation of anesthesia. RESULTS: There was not significantly difference between blood glucose level of both groups during 10 minutes before, 20 and 60 minutes after the intiation of anesthesia. Heart rate changes in the general and spinal groups compared to the baseline level were decreased up to maximum12.5% and 14.5%, respectively. The mean arterial pressure changes in the general and spinal groups compared to the baseline level were decreased up to maximum 5.4% and 8%, respectively. CONCLUSIONS: Blood glucose and hemodynamic changes caused by surgical stress were not significantly different between two groups. PMID- 25289379 TI - Hospital-acquired pneumonia in patients undergoing coronary artery bypass graft; comparison of the center for disease control clinical criteria with physicians' judgment. AB - BACKGROUND: Following coronary artery bypass graft (CABG), patients are at high risk (3.2%-8.3%) for developing hospital-acquired pneumonia (HAP) with mortality rate of 24% to 50%. Some of routine features in patients undergoing CABG are similar to clinical criteria of Center of Disease Control (CDC) for diagnosis of pneumonia. This may lead to over-diagnosis of pneumonia in these patients. OBJECTIVES: This study aimed to assess the frequency of CDC criteria for diagnosis of pneumonia in patients undergoing CABG. PATIENTS AND METHODS: This study was performed on CABG candidates admitted to post cardiac surgery Intensive Care Unit (ICU) in a six-month period. Patient's records, Chest-X-Ray, and Laboratory tests were assessed for PNU1-CDC criteria for HAP diagnosis. At the same time, a physician who was unaware of the study protocol assessed the clinical diagnosis. Then the results were compared with CDC criteria-based diagnosis. RESULTS: Of total 300 patients, 9 (3%) met CDC criteria for diagnosis of pneumonia while none of the cases were diagnosed as HAP according to the physicians' clinical diagnosis. All nine patients were discharged with proper general condition and no need of antibiotic therapy. This study showed that loss of consciousness, tachypnea, dyspnea, PaO2 < 60 mm Hg, PaO2/FiO2 < 240, and local infiltration in 24 hours of operation were misleading features of CDC criteria, which were not considered in physicians' clinical judgment to establish the diagnosis. CONCLUSIONS: Our findings suggest that in Post-CABG patients, physicians could judge the occurrence of HAP more accurately in comparison to making the diagnosis based on CDC criteria alone. Expert physician may intentionally do not take some of these criteria into account according the patients' course of disease. Therefore, it is suggested that the value of these criteria in special group of patients like those undergoing CABG should be re evaluated. PMID- 25289380 TI - Anesthetic management in a child with citrullinemia: a case report. AB - INTRODUCTION: Citrullinemia is a defect in the urea cycle that causes ammonia to accumulate in the blood. We describe the anesthetic management of a patient with citrullinemia, who experienced an unexpected 10 day hospital admission. CASE PRESENTATION: We anesthetized a 3.5 year-old boy with citrullinemia who was scheduled for a dentistry procedure. Perioperative precautions included minimizing fasting period, hypothermia prevention, relieving anxiety and pain, perioperative infusion of D10W and benzoate sodium, as well as a pediatric endocrinology consultation. The operation lasted 4 hours and its course was uneventful. He had a delayed recovery from anesthesia and was discharged from hospital after 10 days. CONCLUSIONS: General anesthesia and surgery can be a risk factor for exacerbating the course of the disease in patients with citrullinemia. It appears that administering short acting sedatives and analgesics in these patients would be of more benefit. Further studies are required to identify a safe method for anesthesia in citrullinemia. PMID- 25289381 TI - "The perfect smile". PMID- 25289382 TI - Full-mouth esthetic rehabilitation with acellular dermal matrix. AB - Treatment of multiple recession defects with the adjunct use of a connective tissue graft (CTG) represents a challenge when diagnosed in several teeth of the mouth. The amount of CTG harvested from the palate may not be adequate to address this condition. In such scenarios, alternative sources such as acellular dermal matrix (ADM) are preferred due to the unlimited availability. A case report is presented, dealing with the treatment of multiple gingival recessions affecting the majority of dentition using ADM, with a 6-month follow-up. PMID- 25289383 TI - Purpose of esthetic risk assessment in prosthetic rehabilitations with gingiva shade ceramics. AB - Esthetic predictability and the possibility to reduce the need for more aggressive surgical interventions have been two strong reasons for the growing acceptance of gingiva shade ceramics in dental treatments. However this type of rehabilitation also has several esthetic constraints. The aim of this paper is to present an assessment system that may serve as a clinician's guideline to clearly identify the risk factors influencing the esthetic result of gum-shade ceramics and, in the end, to grade these clinical situations as high, medium or low esthetic risk. Over several years of clinical experience, the authors have identified different factors that influence the achievement of satisfactory esthetic results using gumshade ceramics: smile line, extension of the prosthetic rehabilitation, anatomical area, vertical and horizontal transition between the prosthesis and the natural gingiva, contact surface, framework material, and color. In conclusion, despite the great applicability of gingiva-shade ceramics in the resolution of clinical cases involving complex architecture of the hard and soft tissues, this procedure should not be considered one free of esthetic risk. There are different factors that should be evaluated when considering the esthetic results with gingiva-shade ceramics. PMID- 25289384 TI - A novel approach to implant screw-retained restorations: adhesive combination between zirconia frameworks and monolithic lithium disilicate. AB - The use of zirconia is an esthetic alternative to metal for implant-supported frameworks, and it has increased primarily for its high biocompatibility, low bacterial surface adhesion, high flexural strength and high mechanical features. The zirconia frameworks in fixed prosthetic restorations that are supported by implants is commonly covered with hand-layered overlay porcelain. This technical procedure is highly esthetic but it can cause some complications, such as porcelain fractures. The purpose of this article is to introduce an innovative approach to create an esthetic fixed ceramic implant restoration to minimize and facilitate the repair of the mechanical complications, by combining the adhesive cementation of lithium disilicate full coverage restorations on implant screw retained zirconia frameworks. PMID- 25289385 TI - Treatment planning and dental rehabilitation of periodontally compromised partially edentulous patient: a case report - part II. AB - When planning a prosthetic rehabilitation of a periodontally compromised case, the clinician is often confronted with difficulties and dilemmas related to selecting the appropriate treatment that would provide long-term successful outcomes in function and esthetics. In such cases, a correct diagnosis and prognosis of the intraoral situation supported by evidence-based dentistry is the basis for the establishment of a proper treatment strategy. In this second part of a two-part treatment planning series, a systematic approach of patient examination and prognosis of each tooth is presented. Furthermore, different removable and fixed treatment possibilities are described and the rationale governing the decision-making process is revealed. The execution of the final treatment plan as specified by the concept of comprehensive dental care is outlined, and the final outcome is discussed according to the literature. PMID- 25289386 TI - Vestibular unit transplantation in the coverage of gingival recession: a microsurgical approach. AB - The palate, maxillary tuberosity and edentulous ridges are generally used as the donor sites for connective tissue grafts. This article shows the use of vestibular soft tissue of a tooth in the coverage of localized gingival recession. The vestibular unit was harvested during crown lengthening procedures, sutured over the denuded root surface, and covered with a coronally advanced flap without vertical incisions. The healing was uneventful with complete coverage of the recession up to 18 months. The vestibular unit of a tooth can serve as the donor area for a connective tissue graft in the coverage of gingival recessions, resulting in stable outcomes. PMID- 25289387 TI - Integrating techniques to re-establish dentogingival esthetics. AB - The aim of this article was to report the clinical case of a male patient of 20 years with hyperpigmented gingiva and moderate fluorosis, whose smile was reestablished by the use of a laser assisted depigmentation procedure, an enamel microabrasion technique, followed by at-home bleaching and subsequent remineralization therapy. The association of these techniques presented excellent results and the patient was satisfied. All techniques are painless, fast and easy to perform, in addition to preserving the hard and soft dental structure. Treatment showed immediate and permanent results; these techniques must be divulged among professionals and their patients. PMID- 25289388 TI - Interfacial characterization of ceramic core materials with veneering porcelain for all-ceramic bi-layered restorative systems. AB - OBJECTIVE: The aim of the study was to characterize the elemental distribution at the interface between all-ceramic core and veneering porcelain materials. MATERIALS AND METHODS: Three groups of all-ceramic cores were selected: A) Glass ceramics (Cergo, IPS Empress, IPS Empress 2, e-max Press, Finesse); B) Glass infiltrated ceramics (Celay Alumina, Celay Zirconia) and C) Densely sintered ceramics (Cercon, Procera Alumina, ZirCAD, Noritake Zirconia). The cores were combined with compatible veneering porcelains and three flat square test specimens were produced for each system. The core-veneer interfaces were examined by scanning electron microscopy and energy dispersive x-ray microanalysis. RESULTS: The glass-ceramic systems showed interfacial zones reach in Si and O, with the presence of K, Ca, Al in core and Ca, Ce, Na, Mg or Al in veneer material, depending on the system tested. IPS Empress and IPS Empress 2 demonstrated distinct transitional phases at the core-veneer interface. In the glassinfiltrated systems, intermixing of core (Ce, La) with veneer (Na, Si) elements occurred, whereas an abrupt drop of the core-veneer elemental concentration was documented at the interfaces of all densely sintered ceramics. SIGNIFICANCE: The results of the study provided no evidence of elemental interdiffusion at the core-veneer interfaces in densely sintered ceramics, which implies lack of primary chemical bonding. For the glass-containing systems (glassceramics and glass-infiltrated ceramics) interdiffusion of the glass-phase seems to play a critical role in establishing a primary bonding condition between ceramic core and veneering porcelain. PMID- 25289389 TI - Sustainable production of food and renewable energy resources. Preface. PMID- 25289391 TI - Intracardiac 'leadless' pacemakers are going in all over Europe! PMID- 25289392 TI - PREvention of late Stent Thrombosis by an Interdisciplinary Global European effort: PRESTIGE. PMID- 25289390 TI - Regulation of rat hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase, a key enzyme in the tryptophan- NAD pathway, by dietary cholesterol and sterol regulatory element-binding protein-2. AB - PURPOSE: Nicotinic acid is one of the older drugs used to treat hyperlipidemia, the greatest risk factor of coronary heart disease. Nicotinic acid is also a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD). In mammals, alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) plays a key role in NAD biosynthesis from tryptophan. However, the relationship between ACMSD and cholesterol metabolism has not been clarified enough yet. The present study was performed to make clear the relationship between ACMSD and cholesterol metabolism using hypercholesterolemic rats and rat primary hepatocytes. METHODS: Male Sprague-Dawley rats were fed a diet containing cholesterol for 10 days to induce hypercholesterolemia. The NAD levels in the plasma and liver and hepatic ACMSD activity were determined. In vitro study, the expression of ACMSD and the transcriptional factors that regulate cholesterol metabolism were determined using rat primary hepatocytes treated with cholesterol and 25-hydroxycholesterol or simvastatin, a statin medication, by quantitative real-time PCR analysis and Western blotting analysis. RESULTS: The hepatic NAD level of the hypercholesterolemic group was significantly higher than the control, and the hepatic ACMSD activity of this group was significantly suppressed. There was a significant negative correlation between the hepatic ACMSD activity and liver cholesterol levels. Additionally, in primary rat hepatocytes treated with cholesterol and 25-hydroxycholesterol or simvastatin, ACMSD gene and protein expression was subjected to sterol-dependent regulation. This gene expression changed in parallel to sterol regulatory element-binding protein (SREBP)-2 expression. CONCLUSION: These results provide the first evidence that ACMSD is associated with cholesterol metabolism, and ACMSD gene expression may be upregulated by SREBP-2. PMID- 25289393 TI - 9Be and 31P NMR analyses on the influence of imino groups on Be2+ complex stabilities of a series of cyclo-MU-imido triphosphate anions. AB - The complexation behaviors of Be2+ with cyclo-MU-imido triphosphate anions, cP3O9 n(NH)n(3-)n= 1, 2),have been investigated by both 9Be and 31P NMR techniques at 2.3 degrees C in order to clarify the coordination structures of the complexes. The spectra showed that cP3O9n(NH)n (n = 1, 2) ligands form ML, ML2, and M2L complexes with Be2+ ions, and the formation of complexes coordinating with nitrogen atoms of the cyclic framework in the ligand molecule has been excluded. These complexation trends are very similar to those of Be2+-cP3O6(NH)-33system, which has been reported by us. The peak deconvolution of 9BeNMR spectra made these beryllium complexes amenable to stability constant determinations. The stability constants of the complexes increase with an increase in the protonation constants of the ligands as the number of imino groups, which constitute the ligand molecules, is ascended. This increase is primarily attributable to the lower electronegativity of nitrogen atoms than oxygen atoms, which are directly bonded to central phosphorus atoms; moreover, tautomerism equilibrium in the entire of the imidopolyphosphate molecule is also responsible to the higher basicity. 31P NMR spectra measured concurrently have verified the formation of the complexes estimated by the 9Be NMR measurement. Intrinsic 31P NMR chemical shift values of the phosphorus atoms belonging to ligand molecules complexed with Be2+ cations have been determined. Not only the protonation constants but also the stability constants of all Be2+ complexes increase approximately linearly with an increase in the number of imino groups. PMID- 25289394 TI - The European Society of Cardiology Young Community Groups. PMID- 25289395 TI - The Kyrgyz Society of Cardiology of Kyrgyzstan. PMID- 25289396 TI - Landmarks in the history of cardiology IV. PMID- 25289397 TI - [Microbial identification and susceptibility testing with endophthalmitis]. PMID- 25289398 TI - [Integrity of the anterior capsulotomy after femtosecond laser-assisted cataract surgery]. PMID- 25289399 TI - [Increase in gray matter in the visual cortex after unilateral cataract surgery]. PMID- 25289401 TI - Preface. Cytotoxic T-cells. PMID- 25289400 TI - Preface. Basophils and mast cells. PMID- 25289402 TI - Typhoid fever surveillance and vaccine use, South-East Asia and Western Pacific Regions, 2009-2013. PMID- 25289403 TI - Trametenolic acid B reverses multidrug resistance in breast cancer cells through regulating the expression level of P-glycoprotein. AB - Trametenolic acid B (TAB) is the main active composition of Trametes lactinea (Berk.) Pat which possesses antitumor activities. There was no report its antitumor effect through regulating P-glycoprotein (P-gp) so far, due toP-gp over expression is one of the most important mechanisms contributing to the multiple drug resistance phenotype. The present aim was to investigate the effects of TAB on P-gp in multidrug-resistant cells;Paclitaxel-resistant cell line MDA-MB 231/Taxol was established by stepwise exposure for 10 months.MDA-MB-231 cells and MDA-MB-231/Taxol cells were treated with TAB, and their growth was evaluated using MTT assays. Paclitaxel accumulation in the cells was analyzed by high performance liquid chromatogram(HPLC). The activity of P-gp was detected by intracellular accumulation of rhodamine 123 (Rho123), and the protein expression of P-gp was evaluated using western blot. Results indicated that the IC50 of MDA MB-231/Taxol to paclitaxel (Taxol) was 33 times higher than that of nature MDA-MB 231. TAB increased the intracellular concentration of Taxol and inhibited the activity of P-gp and suppressed the expression of P-gp in MDA-MB-231/Taxol cells. Our present results showed that TAB could reverse Taxol resistance in MDA-MB 231/Taxol cells,mainly inhibiting the activity of P-gp and down-regulating the expression level of P-gp, and then enhancing the accumulation of chemotherapy agents. PMID- 25289404 TI - For Cohn, relevance of AVMA and profession is front-and-center. PMID- 25289405 TI - Helping to prepare for the worst. PMID- 25289406 TI - A new perspective from APHIS' Clifford. PMID- 25289407 TI - FDA issues guidance on regulation of cell-based products in animals. PMID- 25289408 TI - Surveillance, diagnostics unaffected by lab closures. PMID- 25289409 TI - Growing a green practice. PMID- 25289410 TI - If an animal looks obese, precise estimation of body composition is of limited clinical value. PMID- 25289411 TI - Recognizing good work. PMID- 25289412 TI - T cells of patients with myelodysplastic syndrome are frequently derived from the malignant clone. PMID- 25289413 TI - [andomized MRC RT01 trial of 64 Gy vs. 74 Gy in localized primary prostate cancer: Significant improvement in biochemical control, but still no significant improvement in long-term survival]. PMID- 25289414 TI - [Comparison of different radio-chemotherapy-based treatments of primary nonresectable glioblastomas]. PMID- 25289415 TI - At the bench: The right mix. PMID- 25289416 TI - Pharmacogenomics in drug discovery and development. Preface. PMID- 25289417 TI - Colombian physician Rodrigo Guerrero wins first Roux Prize. PMID- 25289418 TI - Rare enterovirus continues to circulate in North America. PMID- 25289419 TI - T-helper cells: methods and protocols. Preface. PMID- 25289420 TI - Flood waters cripple health facilities in Kashmir. PMID- 25289421 TI - Fighting restricts access to health care in South Sudan. PMID- 25289422 TI - Seen but not heard: children and epistemic injustice. PMID- 25289424 TI - New sentinel event alert targets tubing misconnections. PMID- 25289423 TI - Jesse Steinfeld. PMID- 25289425 TI - IPPS puts quality at payment's center in 2015. PMID- 25289426 TI - Appropriate is the new byword in hospitals. PMID- 25289427 TI - Gainsharing program alters physician behavior. PMID- 25289428 TI - Sepsis gets its measure taken. PMID- 25289429 TI - Nurses and midwives commence industrial action over wage freeze. PMID- 25289430 TI - Funding for dementia research but cuts to dementia care? PMID- 25289431 TI - Union aid providing better lives globally. PMID- 25289432 TI - Nurse informatics expert recognised. PMID- 25289433 TI - An app driven by midwives. PMID- 25289434 TI - Nurse involvement in IT systems equals better outcomes. PMID- 25289435 TI - Scholarship honours WW1 nurse and midwife midwife. PMID- 25289436 TI - Follow-up care for Indigenous remains poor. PMID- 25289437 TI - Birthweight improves for Indigenous babies. PMID- 25289438 TI - New health service for the Northern Territory. PMID- 25289439 TI - Women economic empowerment and leadership boosted in Asia. PMID- 25289440 TI - Nurses staying in the workforce longer. PMID- 25289441 TI - Industrial action over a 0.7% payrise. PMID- 25289442 TI - Planned registration fee hike comes under fire. PMID- 25289443 TI - BiPAP/CPAP. PMID- 25289444 TI - Flawed recruitment and retention. PMID- 25289445 TI - Sports concussion headache. AB - BACKGROUND: Sports concussion headache (SCH) is common; yet poorly researched and understood. Somatic complaints including headache are frequently reported by both amateur and professional athletes. Although the literature is replete with reports of a high incidence of headache following sports concussive injuries, there is a dearth of evidence-based medicine to provide practitioners with an understanding of sports concussion headache risk factors, epidemiology, biomechanical risk factors and/or injury thresholds, aetiology, assessment, treatment or prognosis. REVIEW: This article will provide readers with an overview of SCH based on the available literature (which as noted is limited); and, where evidence is lacking, information will be provided from the more general post-traumatic headache (PTHA) literature, the author's extensive clinical experience and literature from parallel primary headache disorders. Incidence, pathoanatomy, neurobiology, classification, natural history and prognosis of sports concussion headache will be reviewed. Common, as well as less common, sports concussion headache sub-types will be discussed. General approaches to evaluation (including history taking and physical examination), as well as treatment approaches will also be addressed for specific headache subtypes. Lastly, directions for future research will be explored. PMID- 25289446 TI - Body image flexibility moderates the association between disordered eating cognition and disordered eating behavior in a non-clinical sample of women: a cross-sectional investigation. AB - Body image flexibility, a regulation process of openly and freely experiencing disordered eating thoughts and body dissatisfaction, has been found to be a buffering factor against disordered eating symptomatology. The present cross sectional study investigates whether body image flexibility accounts for disordered eating behavior above and beyond disordered eating cognition, mindfulness, and psychological inflexibility in a sample of nonclinical women, and whether body image flexibility moderates the associations between these correlates and disordered eating behavior. Participants were 421 women, age 21+/ 5.3 years old on average, who completed a web-based survey that included the self report measures of interest. Results demonstrate the incremental effects of body image flexibility on disordered eating behavior above and beyond disordered eating cognition, mindfulness, and psychological inflexibility. Women with greater body image flexibility endorse disordered eating behavior less so than those with lower body image flexibility. Body image flexibility moderates the association between disordered eating cognition and disordered eating behavior; for women with greater body image flexibility, disordered eating cognition is not positively associated with disordered eating behavior. PMID- 25289447 TI - A comparative study of short chain and long chain mercapto acids used in biosensor fabrication: A VEGF-R1-based immunosensor as a model system. AB - A novel impedimetric biosensor utilizing a biological receptor, vascular endothelial growth factor receptor-1 (VEGF-R1), was developed for the determination of vascular endothelial growth factor (VEGF). VEGF-R1 was covalently immobilized by coupling with 11-mercaptoundecanoic acid, which formed a self-assembled monolayer on gold electrodes. Cyclic voltammetry and electrochemical impedance spectroscopy techniques were employed to characterize the immobilization process and to detect VEGF. To successfully construct the biosensor current, the experimental parameters were optimized. A Kramers-Kronig transform was performed on the experimental impedance data. The results obtained provided a linear response range from 1 to 6 ng/mL human VEGF. The applicability of the biosensor developed to determine VEGF in a spiked artificial human serum sample was tested. The important parameters related with the biosensors fabricated by using two different mercapto acids were compared in terms of the self-assembly processes, the activation conditions of -COOH ends, linear ranges obtained for VEGF, repeatabilities and reproducibilities, and cleaning procedures. The results of this study revealed that the length of the mercapto acids used for biosensor fabrication considerably affected the analytical performance and the practicability of the preparation of the biosensor. PMID- 25289449 TI - Immunodiagnostics in birmingham. AB - Anxieties that commercial interests might compromise academics and their research have always been the subject of lively debate but the shouting has been particularly loud recently with the growth of the new biomedical technologies and the pressures that it has brought upon academics with something relevant and important to sell. Such easily acquired money is bound to disturb the academic milieu in times that are hard for universities. In this invited article university-based immunologists discuss their experience of direct links with industry in the supply of immunodiagnostics. This experience, predating the 'biotechnology gold rush' of the last three years (The Economist, June 13) is set in the context of U.K. science but the issues raised are relevant to developments now taking place in North America, several European countries and Australia. PMID- 25289448 TI - Methylprednisolone acetate-Eudragit(r) RS100 electrospuns: Preparation and physicochemical characterization. AB - The aim of the present study was to formulate methylprednisolone acetate Eudragit((r)) RS100 nanofibers and nanobeads by the electrospinning method. The physicochemical characteristics of the prepared electrospuns were assessed as well. The particle size and morphology were evaluated using scanning electron microscopy. The crystallinity of the drug in the nanofibers and nanobeads obtained was also studied by X-ray crystallography and differential scanning calorimetry (DSC) thermograms. In addition, FT-IR spectroscopy was applied to investigate any possible chemical interaction between the drug and carrier during the preparation process. The drug release kinetics were considered, to predict the release mechanism. Increasing the concentration of the injected solution resulted in the production of more nanofibers and less nanobeads, with the particle size ranging from 100 to 500 nm. The drug crystallinity was decreased during the electrospinning process; however, no interaction between drug and polymer was observed. The electrospuns showed faster drug release pattern compared to the pure drug. The release data were best fitted to the Weibull model, in which the corresponding shape factor values of the model were less than 0.75 indicating the diffusion mechanism of drug release. In conclusion, electrospinning could be considered as a simple and cost effective method for fabricating the drug: polymer nanofibers and nanobeads. PMID- 25289450 TI - A new beginning in autoimmunity? PMID- 25289451 TI - Is idiotypic regulation the real thing? PMID- 25289452 TI - Antibodies to sperm as a causative factor in human infertility. PMID- 25289453 TI - The immunobiology of Langerhans cells. AB - Interest in the biology of Langerhans cells has recently been stimulated by observations, reviewed here by Peter Friedmann, that they are active members o f the immune system. PMID- 25289454 TI - Complement activation. AB - When activated, the system of serum proteins known as complement is involved in a wide variety of responses to inflammatory and noxious stimuli. In this article Eric Brown and Michael Frank review the activation of complement by the classical and alternative pathways and discuss some of its biological effects. PMID- 25289455 TI - The biolgoical significance of antibody affinity. PMID- 25289456 TI - Hybridoma antibodies in immunodiagnosis of parasitic infection. PMID- 25289458 TI - Interaction of adenanthin with glutathione and thiol enzymes: selectivity for thioredoxin reductase and inhibition of peroxiredoxin recycling. AB - The diterpenoid, adenanthin, represses tumor growth and prolongs survival in mouse promyelocytic leukemia models (Liu et al., Nat. Chem. Biol. 8, 486, 2012). It was proposed that this was done by inactivating peroxiredoxins (Prxs) 1 and 2 through the formation of an adduct specifically on the resolving Cys residue. We confirmed that adenanthin underwent Michael addition to isolated Prx2, thereby inhibiting oxidation to a disulfide-linked dimer. However, contrary to the original report, both the peroxidatic and the resolving Cys residues could be derivatized. Glutathione also formed an adenanthin adduct, reacting with a second order rate constant of 25+/-5 M(-1) s(-1). With 50 uM adenanthin, the peroxidatic and resolving Cys of Prx2 reacted with half-times of 7 and 40 min, respectively, compared with 10 min for GSH. When erythrocytes or Jurkat T cells were treated with adenanthin, we saw no evidence for a reaction with Prxs 1 or 2. Instead, adenanthin caused time- and concentration-dependent loss of GSH followed by dimerization of the Prxs. Prxs undergo continuous oxidation in cells and are normally recycled by thioredoxin reductase and thioredoxin. Our results indicate that Prx reduction was inhibited. We observed rapid inhibition of purified thioredoxin reductase (half-time 5 min with 2 uM adenanthin) and in cells, thioredoxin reductase was much more sensitive than GSH and loss of both preceded accumulation of oxidized Prxs. Thus, adenanthin is not a specific Prx inhibitor, and its reported antitumor and anti-inflammatory effects are more likely to involve more general inhibition of thioredoxin and/or glutathione redox pathways. PMID- 25289459 TI - Water-driven micromotors for rapid photocatalytic degradation of biological and chemical warfare agents. AB - Threats of chemical and biological warfare agents (CBWA) represent a serious global concern and require rapid and efficient neutralization methods. We present a highly effective micromotor strategy for photocatalytic degradation of CBWA based on light-activated TiO2/Au/Mg microspheres that propel autonomously in natural water and obviate the need for external fuel, decontaminating reagent, or mechanical agitation. The activated TiO2/Au/Mg micromotors generate highly reactive oxygen species responsible for the efficient destruction of the cell membranes of the anthrax simulant Bacillus globigii spore, as well as rapid and complete in situ mineralization of the highly persistent organophosphate nerve agents into nonharmful products. The water-driven propulsion of the TiO2/Au/Mg micromotors facilitates efficient fluid transport and dispersion of the photogenerated reactive oxidative species and their interaction with the CBWA. Coupling of the photocatalytic surface of the micromotors and their autonomous water-driven propulsion thus leads to a reagent-free operation which holds a considerable promise for diverse "green" defense and environmental applications. PMID- 25289460 TI - Clozapine administration and the risk of drug-related pure red cell aplasia: a novel case report. PMID- 25289457 TI - Redox regulation of Rac1 by thiol oxidation. AB - The Rac1 GTPase is an essential and ubiquitous protein that signals through numerous pathways to control critical cellular processes, including cell growth, morphology, and motility. Rac1 deletion is embryonic lethal, and its dysregulation or mutation can promote cancer, arthritis, cardiovascular disease, and neurological disorders. Rac1 activity is highly regulated by modulatory proteins and posttranslational modifications. Whereas much attention has been devoted to guanine nucleotide exchange factors that act on Rac1 to promote GTP loading and Rac1 activation, cellular oxidants may also regulate Rac1 activation by promoting guanine nucleotide exchange. Herein, we show that Rac1 contains a redox-sensitive cysteine (Cys(18)) that can be selectively oxidized at physiological pH because of its lowered pKa. Consistent with these observations, we show that Rac1 is glutathiolated in primary chondrocytes. Oxidation of Cys(18) by glutathione greatly perturbs Rac1 guanine nucleotide binding and promotes nucleotide exchange. As aspartate substitutions have been previously used to mimic cysteine oxidation, we characterized the biochemical properties of Rac1(C18D). We also evaluated Rac1(C18S) as a redox-insensitive variant and found that it retains structural and biochemical properties similar to those of Rac1(WT) but is resistant to thiol oxidation. In addition, Rac1(C18D), but not Rac1(C18S), shows greatly enhanced nucleotide exchange, similar to that observed for Rac1 oxidation by glutathione. We employed Rac1(C18D) in cell-based studies to assess whether this fast-cycling variant, which mimics Rac1 oxidation by glutathione, affects Rac1 activity and function. Expression of Rac1(C18D) in Swiss 3T3 cells showed greatly enhanced GTP-bound Rac1 relative to Rac1(WT) and the redox-insensitive Rac1(C18S) variant. Moreover, expression of Rac1(C18D) in HEK-293T cells greatly promoted lamellipodia formation. Our results suggest that Rac1 oxidation at Cys(18) is a novel posttranslational modification that upregulates Rac1 activity. PMID- 25289461 TI - Reduced dielectric screening and enhanced energy transfer in single- and few layer MoS2. AB - We report highly efficient nonradiative energy transfer from cadmium selenide (CdSe) quantum dots to monolayer and few-layer molybdenum disulfide (MoS2). The quenching of the donor quantum dot photoluminescence increases as the MoS2 flake thickness decreases with the highest efficiency (>95%) observed for monolayer MoS2. This counterintuitive result arises from reduced dielectric screening in thin layer semiconductors having unusually large permittivity and a strong in plane transition dipole moment, as found in MoS2. Excitonic energy transfer between a zero-dimensional emitter and a two-dimensional absorber is fundamentally interesting and enables a wide range of applications including broadband optical down-conversion, optical detection, photovoltaic sensitization, and color shifting in light-emitting devices. PMID- 25289462 TI - Study of transitions between wetting states on microcavity arrays by optical transmission microscopy. AB - In this article, we present a simple and fast optical method based on transmission microscopy to study the stochastic wetting transitions on micro- and nanostructured polymer surfaces immersed in water. We analyze the influence of immersion time and the liquid pressure on the degree of water intrusion in individual microcavities on these surfaces as well as the lifespan of their superhydrophobicity. We show that transitions among the three wetting states (Cassie, Cassie-impregnating, and Wenzel) occur with a certain pressure threshold (300 mbar for a microcavity diameter of 7.5 MUm). Below this threshold, the transitions between the Cassie and the Cassie-impregnating states are reversible, whereas above this threshold, irreversible transitions to the Wenzel state start to occur. The transitions between the different wetting states can be explained by taking into account both the Young-Laplace equation for the water menisci in the cavities and the diffusion of dissolved gas molecules in the water. In addition, the wetting transitions had a stochastic nature, which resulted from the short diffusion distance for dissolved gas molecules in the water between neighboring cavities. Furthermore, we compared the contact angle properties of two polymeric materials (COC and PP) with moderate hydrophobicity. We attributed the difference in the water repellency of the two materials to a difference in the wetting of their nanostructures. Our experimental observations thus indicate that both the diffusion of gas molecules in water and the wetting properties of nanostructures are important for understanding the sustainability of superhydrophobicity of surfaces under water and for improving the structural design of superhydrophobic surfaces. PMID- 25289464 TI - Antigen recognition by T lymphocytes. AB - Many questions remain about the mechanisms of antigen recognition by T cells. Is antigen processing an absolute requirement for recognition by helper T cells? Does processing affect those areas of the antigen which associate with class II major histocompatibility complex (MHC) molecules (la antigens) or those which associate with T cell receptors or both? Where in the antigen-presenting cell (APC) does processing occur, and where does processed antigen associate with la? These questions were posed and discussed at a recent meeting on the immunology of proteins and peptides. PMID- 25289463 TI - Tweet content related to sexually transmitted diseases: no joking matter. AB - BACKGROUND: Online social media, such as the microblogging site Twitter, have become a space for speedy exchange of information regarding sexually transmitted diseases (STDs), presenting a potential risk environment for how STDs are portrayed. Examining the types of "tweeters" (users who post messages on Twitter) and the nature of "tweet" messages is important for identifying how information related to STDs is posted in online social media. OBJECTIVE: The intent of the study was to describe the types of message emitters on Twitter in relation to two different STDs-chlamydia and human immunodeficiency virus (HIV)-as well as the nature of content tweeted, including how seriously the topic was treated. METHODS: We used the Twitter search engine to look for tweets posted worldwide from August 1-7, 2013, and from September 1-7, 2013, containing the words "chlamydia" or "HIV", and the hashtags "#chlamydia" or "#HIV". Tweeters were classified by two independent reviewers according to the type of avatar of the user (human, logo, or fantasy), the identification of the emitter (identifiable, semi-identifiable, or non-identifiable), and the source (private company, general media, scientific media, non-governmental, individual account, academic institution, government department, or undefined). Tweet messages were also independently classified according to their nature (serious or jokes/funny), and whether their main message was factual or of a personal nature/experience. RESULTS: A total of 694 tweets were posted by 426 different users during the first 7 days of August and September, containing the hashtags and/or simple words "chlamydia" and/or "HIV". Jokes or funny tweets were more frequently posted by individual users (89%, 66/74), with a human avatar (81%, 60/74), from a non identifiable user (72%, 53/74), and they were most frequently related to chlamydia (76%, 56/74). Serious tweets were most frequently posted by the general media (20.6%, 128/620), using a logo avatar (66.9%, 415/620), and with identifiable accounts (85.2%, 528/620). No government departments, non governmental organizations, scientific media, or academic institutions posted a joke on STDs. A total of 104 of these analyzed tweets were re-tweeted messages, belonging to 68 unique tweets. The content was serious (99%, 67/68), factual (90%, 52/58), and about HIV (85%, 58/68). CONCLUSIONS: Social media such as Twitter may be an important source of information regarding STDs provided that the topic is presented appropriately. Reassuringly, the study showed that almost 9/10 of tweets on STDs (chlamydia and HIV) were of serious content, and many of the tweets that were re-tweeted were facts. The jokes that were tweeted were mainly about chlamydia, and posted by non-identifiable emitters. We believe social media should be used to an even larger extent to disseminate correct information about STDs. PMID- 25289465 TI - Proposed classification of leukocyte- associated cytolytic molecules. AB - The continuous discovery of leukocyte- associated cytolytic factors and the lack of a nomenclature system to accommodate them prompted the nomendlature committee of the Reticuloendothelial Society (RES) to sponsor a recent dry workshop on the topic, which was attended by about 100, mainly American, scientist. PMID- 25289466 TI - Experimental autoimmune thyroiditis induced by recombinant interferon-gamma. PMID- 25289467 TI - Do natural autoantibodies prevent autoimmune disease? PMID- 25289468 TI - Anti-DNA antibodies by ELISA. PMID- 25289469 TI - Cross-reactivity of anti-dsDNA antibodies. PMID- 25289470 TI - Immunoregulation by Fc signals A mechanism for self-nonself discrimination. AB - B-cell activation is regulated by several means, among them the feedback effect of secreted antibody, which binds to antigen on antigen receptors and to the B cells' Fc receptors. In the view of N. R. Sinclair and A. Panoskaltsis, outlined here, this repressive influence is exerted early in an immune response but can be relieved by various T-cell factors. These include rheumatoid factors which, by binding specific antigen as well as blocking repressive Fc signals, may permit immune responses to proceed. Aberrant production of rheumatoid factor may deregulate suppressed self-reactive B cells, triggering autoimmune responses. PMID- 25289471 TI - T cells recognize antigen alone and not MHC molecules. AB - It is a central dogma of contemporary immunology that T cells engaged in immune responses to foreign antigens or cells recognize determinants on major histocompatibility complex (MHC) molecules. Here Ole Werdelin argues that this dogma is false. Taking the case of T-cell responses which are controlled by MHC class II molecules, he suggests that la molecules serve to bind antigen fragments and stabilize them in the membrane of presenting cells, shielding them from proteolytic degradation and permitting T cells to bind the epitopes so displayed. PMID- 25289472 TI - Interferon beta2 as a promoter of growth and differentiation of B cells. PMID- 25289473 TI - Total lymphoid irradiation. AB - The delivery of ionizing radiation to lymph nodes, thymus and spleen while non lymphoid organs are shielded has profoundly immunosuppressive effects that may have value in transplantation and the treatment of autoimmune disorders. Here Shimon Slavin reviews what is known of the cellular consequences of total lymphoid irradiation in animals and discusses the results of its use in various clinical immunosuppressive treatment regimens. PMID- 25289474 TI - The regulation of immune responses to dietary protein antigens. AB - Hypersensitivity reactions to food proteins are rare, probably because the intestinal immune system has evolved efficient means of preventing such responses. In this article Allan Mowat reviews the mechanisms underlying the induction of immunological tolerance after feeding proteins and suggests how a breakdown in oral tolerance may lead to potentially harmful hypersensitivity in the intestine. PMID- 25289477 TI - Interleukin 17A polymorphism elevates gene expression and is associated with increased risk of nonsmall cell lung cancer. AB - Interleukin 17 (IL-17), also known as IL-17A, is a proinflammatory cytokine and plays critical roles in tumor immunity. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancers. The aim of this study was to investigate the correlation between IL-17A genetic polymorphisms and susceptibility to NSCLC. Two single nucleotide polymorphisms (SNPs) in IL-17A gene, rs3819024A/G and rs8193037G/A, were detected in 322 NSCLC patients and 366 healthy donors. Data revealed that prevalence of IL-17A rs8193037GA and AA genotypes were significantly higher in the patients than in controls (odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.53-3.16, p<0.001; and OR: 3.19, 95% CI: 1.42-7.15, p=0.003). Stratification analyses showed that rs8193037A allele had significantly higher percentage in adenocarcinoma than in squamous cell carcinoma (OR: 1.72, 95% CI: 1.12-2.64, p=0.013). When examining the possible function of the SNPs, we found that in vitro stimulated peripheral blood mononuclear cells from subjects possessing rs8193037A allele produced significantly more IL-17 than those with the GG genotype, and this phenomenon could be observed in both controls and the NSCLC patients. These data indicate IL-17A polymorphism is associated with increased risk of NSCLC probably by elevating gene expression. PMID- 25289478 TI - Hypoglycemic effects of glycosaminoglycan from Urechis unicinctus in diabetic mice. AB - To further utilize glycosaminoglycan from Urechis unicinctus, the hypoglycemic effect and possible mechanism of glycosaminoglycan on diabetic mice were evaluated. Diabetes was induced in mice by intraperitoneal injections of streptozotocin for 3 consecutive days and fed with high-sugar and high-lipid fodder. After diabetes was confirmed, the hypoglycemic effect of glycosaminoglycan from U. unicinctus was investigated in the diabetic mice. Results demonstrated that glycosaminoglycan could significantly decrease blood glucose concentrations, HOMA-IR, AUG, and liver MDA content in diabetic mice. In addition, it significantly enhanced liver SOD and GSH-Px activity, as well as liver GCK activity and hepatic glycogen levels. Glycosaminoglycan from U. unicinctus exhibited efficacy against diabetes, suggesting its potential use as a natural intervention against diabetes. PMID- 25289479 TI - Transcranial Doppler Sonography: Atypical Dicrotic Pulse Waveforms in a Man with HIV Infection and Severe Cardiomyopathy. AB - A 27-year-old human immunodeficiency virus--positive man presented with abdominal pain. Computed tomography of the abdomen revealed large right pleural effusion, pericardial effusion and marked ascites with diffuse intra- and extraperitoneal lymphadenopathy. Echocardiography showed severely reduced left ventricular systolic function. After drainage of pleural and pericardial fluid, the patient developed severe hypotension and hypoxic respiratory failure. Extra- and intracranial neurovascular sonography demonstrated low carotid artery flow volume and dicrotic pulse waveforms in all vessels insonated bilaterally. This case report demonstrates an atypical dicrotic waveform pattern of transcranial Doppler in advanced ventricular dysfunction with shock. PMID- 25289480 TI - Advanced fibrosis: Correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver. AB - PURPOSE: To compare the value of enhancement and pharmacokinetic parameters measured at dynamic gadoxetate-enhanced magnetic resonance (MR) imaging in determining hepatic organic anion transporter expression in control rats and rats with advanced liver fibrosis. MATERIALS AND METHODS: Institutional animal review board approval was received before the study began. Advanced liver fibrosis was created in rats by means of carbon tetrachloride injections over an 8-week period. In 17 rats with liver fibrosis and eight control rats, dynamic gadoxetate enhanced MR images of the liver were obtained during 1 hour after injection of 0.025 mmol gadoxetate per kilogram of body weight. Enhancement parameters (maximum enhancement [Emax], time to peak [Tmax], and elimination half-life) were measured on enhancement-versus-time curves, and pharmacokinetic parameters (hepatic extraction fraction [HEF] and mean residence time [MRT]) were obtained by means of deconvolution analysis of the concentration-versus-time curves in the liver and the portal vein. The parameters were correlated at simple and multiple regression analysis with the expression of the hepatic anion uptake transporter organic anion-transporting polypeptide 1A1 (Oatp1a1), the hepatobiliary transporter multidrug resistance-associated protein 2 (Mrp2), and the backflux transporter Mrp4, as determined with reverse transcription polymerase chain reaction. RESULTS: In rats with advanced liver fibrosis, the Emax, Tmax, HEF, and MRT decreased significantly relative to those in control rats, whereas the elimination half-life increased significantly. The enhancement and pharmacokinetic parameters correlated significantly with the expression of the transporters at simple regression analysis. At multiple regression analysis, HEF was the only parameter that was significantly associated with the expression of Oatp1a1 and Mrp2 (P < .001, r = 0.74 and P < .001, r = 0.70, respectively). CONCLUSION: The pharmacokinetic parameter HEF at dynamic gadoxetate-enhanced MR imaging is independently correlated with hepatic organic anion transporter expression. PMID- 25289481 TI - De novo reciprocal translocation t(5;11)(q22;p15) associated with hydrops fetalis (reciprocal translocation and hydrops fetalis). AB - OBJECTIVE: This is a case of a prenatally diagnosed non-immune hydrops fetalis (NIHF) associated with translocation t(5;11)(q22;p15). An association between NIHF and this translocation has not been reported previously. CASE REPORT: The patient was referred to the perinatology clinic with hydrops fetalis diagnosis at 23 weeks' gestation. We noted that the fetus had bilateral pleural effusion, ascites, widespread subcutaneous edema, membranous ventricular septal defect, hypoplastic fifth finger middle phalanx, clinodactyly, single umbilical artery. We performed cordocentesis. Chromosomal analysis on blood showed a balanced translocation between the long arm of chromosome 5 and the short arm of chromosome 11 with karyotype of 46,XX,t(5;11)(q22;p15). CONCLUSION: We present prenatal diagnosis of a de novo translocation (5;11) in a hydropic fetus with ultrason abnormalities. In our case, karyotype analysis of the fetus, mother and father provided evidence of a de novo translocation, that might explain the NIHF. PMID- 25289482 TI - Diagnosis of fetal osteogenesis imperfecta by multidisciplinary assessment: a retrospective study of 10 cases. AB - OBJECTIVE: To describe our 2 year experience in diagnosing prenatal-onset osteogenesis imperfecta (OI) by multidisciplinary assessment. METHODS: We retrospectively analyzed 10 cases of fetal OI by using prenatal ultrasound evaluation, postnatal radiographic diagnosis, and molecular genetic testing of COL1A1/2. RESULTS: By postnatal radiographic examination, five patients were diagnosed with type II OI and five were diagnosed with type III OI. A causative variant in the COL1A1 gene was found in four cases of type II and one case of type III OI; a causative variant in the COL1A2 gene was found in two cases of type III OI. CONCLUSION: The definitive diagnosis of fetal OI should be accomplished using a multidisciplinary assessment, which is paramount for proper genetic counseling. With the discovery of COL1A1/2 gene variants as a cause of OI, sequence analysis of these genes will add to the diagnostic process. PMID- 25289483 TI - Combining ligand- and structure-based approaches for the discovery of new inhibitors of the EPHA2-ephrin-A1 interaction. AB - The EPH receptor A2 (EPHA2) represents an attractive anticancer target. With the aim to identify novel EPHA2 receptor antagonists, a virtual screening campaign, combining shape-similarity and docking calculations, was conducted on a set of commercially available compounds. A combined score, taking into account both ligand- and structure-based results, was then used to identify the most promising candidates. Two compounds, selected among the best-ranked ones, were identified as EPHA2 receptor antagonists with micromolar affinity. PMID- 25289484 TI - Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. AB - BACKGROUND: Neonatal exposure to general anesthetics may pose significant neurocognitive risk. Human epidemiological studies demonstrate higher rates of learning disability among children with multiple, but not single, exposures to anesthesia. The authors employ a rat model to provide a histological correlate for these population-based observations. The authors examined long-term differences in hippocampal synaptic density, mitochondrial density, and dendritic spine morphology. METHODS: Twenty male rat pups (n = 5/condition) were exposed to 2.5% sevoflurane under one of four conditions: single 2-h exposure on postnatal day 7 (P7); single 6-h exposure on P7; repeated 2-h exposures on P7, P10, and P13 for a cumulative 6 h of general anesthetics; or control exposure to 30% oxygen on P7, P10, and P13. RESULTS: Repeated exposure to general anesthetics resulted in greater synaptic loss relative to a single 2-h exposure (P < 0.001). The magnitude of synaptic loss induced by three 2-h exposures (1.977 +/- 0.040 MUm [mean +/- SEM]) was more profound than that of a single 6-h exposure (2.280 +/- 0.045 MUm, P = 0.022). Repeated exposures did not alter the distribution of postsynaptic density length, indicating a uniform pattern of loss across spine types. In contrast, mitochondrial toxicity was best predicted by the cumulative duration of exposure. Relative to control (0.595 +/- 0.017), both repeated 2-h exposures (0.479 +/- 0.015) and a single 6-h exposure (0.488 +/- 0.013) were associated with equivalent reductions in the fraction of presynaptic terminals containing mitochondria (P < 0.001). CONCLUSION: This suggests a "threshold effect" for general anesthetic-induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss. PMID- 25289486 TI - Bronchiectasis. PMID- 25289485 TI - Prick testing with chemicals in the diagnosis of occupational contact urticaria and respiratory diseases. AB - BACKGROUND: Little is known about the use of prick tests with chemicals in diagnosing occupational diseases. OBJECTIVE: To evaluate the use of prick tests in the diagnosis of occupational contact urticaria, asthma and rhinitis caused by chemicals (undertaken at the Finnish Institute of Occupational Health). MATERIAL AND METHODS: We retrospectively reviewed the patient and test files for the period 1 January 1991 to 31 May 2011. Prick tests were performed with chemical solutions and human serum albumin (HSA)-chemical conjugates. RESULTS: Positive prick test reactions to isocyanate-HSA conjugates were associated with isocyanate specific IgE in all 20 patients, and 17 patients had a relevant occupational disease. Positive reactions to chloramine-T-HSA conjugates in 10 patients also indicated the presence of specific IgE, although occupational diseases were not always diagnosed. Eleven of 17 patients with positive reactions to persulfate solutions were diagnosed with an occupational disease. Methacrylates, colophonium related substances, amine hardeners, ethanolamines, glutaraldehyde, glyoxal, pyrocatechol and ammonium thioglycolate did not elicit any relevant prick test reactions. No generalized reactions were detected. CONCLUSION: Prick tests can be safely used for diagnosing contact urticaria, asthma and rhinitis caused by isocyanates, chloramine-T, persulfates, and chlorhexidine, but the results should be carefully interpreted and related to clinical symptoms and other diagnostic tests. PMID- 25289487 TI - Autoimmune haemolytic anaemia for the non-specialist. PMID- 25289488 TI - How to make the most of your study budget at conferences. PMID- 25289489 TI - Long-term betamethasone 21-phosphate disodium treatment has distinct effects in CD1 and DBA/2 mice on animal behavior accompanied by opposite effects on neurogenesis. AB - One of the most peculiar characteristics of the stress response is the pronounced inter-individual and inter-strain variability both in behavioral and neurochemical outcomes. Several studies confirm that rodents belonging to the same or different strain and/or gender, when exposed to a stressor, may show behavioral and cognitive differences. We compared the effects of long-term betamethasone 21-phosphate disodium (BTM), a widely clinically used corticosteroid, on animal behavior and neurogenesis in CD1 and DBA/2 mice. BTM treatment, in CD1 mice, increased body weight gain and anxiety parameters while having pro-depressant effects. Furthermore, BTM significantly reduced neurogenesis in the dentate gyrus of the hippocampus. Finally, BTM treatment induced a significant impairment in memory and learning performance in the Morris water maze. At odds, BTM administration, in DBA/2 mice, caused a significant reduction in the body weight while not modifying anxiety parameters. In addition, both an increased synaptogenesis and neurogenesis were found. Similarly to CD1 mice, also in DBA/2 mice, memory and learning were impaired. Our data confirm that long-term exposure to corticosteroids can generate or aggravate psychiatric/neurologic disorders such as depression, anxiety, memory and learning. Our study did not reveal significant differences between corticosterone and BTM treatment in CD1 mice. In contrast, BTM treatment in mice with an anxious phenotype (DBA/2 mice) revealed some contrasting results indicating that genetic factors can influence corticosteroids dependent effects. Finally, our data further underline the need for a re-evaluation of neurogenesis role; the increased neurogenesis observed in DBA/2 mice and behavioral effects might be distinguished phenomena. PMID- 25289491 TI - The immune system: our mobile brain? AB - In a recent commentary (Nature 309, 400; 1984) John Maddox suggested that the study of psychological effects on immunologic functions - 'psychoimmunology' - was somewhat premature. Specifically, he argued that while the concept of a link between the central nervous system and the immune system was easily accepted, there was a paucity of data of a mechanistic nature to explain the evidence that the 'mind' can control immune responses. He doubted, therefore, whether enough is known to sustain the hope that psychoimmunology was explainable. Much evidence to the contrary was apparent in the proceedings of three recent meetings on the subject which has been variously termed neuroimmunomodulation, psychoimmunology and neuroimmunoendocrinology. PMID- 25289490 TI - Do you like Arcimboldo's? Esthetic appreciation modulates brain activity in solving perceptual ambiguity. AB - Esthetic experience is a unique, affectively colored, self-transcending subject object relationship in which cognitive processing is felt to flow differently than during everyday experiences. Notwithstanding previous multidisciplinary investigations, how esthetic experience modulates perception is still obscure. We used Arcimboldo's ambiguous portraits to assess how the esthetic context organizes ambiguous percepts. The study was carried out using functional magnetic resonance imaging (fMRI) in healthy young volunteers (mean age 25.45; S.D. 4.51; 9 females), during both an explicit esthetic judgment task and an artwork/non artwork classification task. We show that a distinct neural mechanism in the fusiform gyrus contributes to the esthetic experience of ambiguous portraits, according to the valence of the esthetic experience. Ambiguous artworks eliciting a negative esthetic experience lead to more pronounced activation of the fusiform face areas than ambiguous artworks eliciting a positive esthetic experience. We also found an interaction between task and ambiguity in the right superior parietal lobule. Taken together, our results demonstrate that a neural mechanism in the content-dependent brain regions of face processing underlies the esthetic experience of ambiguous portraits. Furthermore, they suggest that esthetic experience interacts with perceptual qualities of stimuli in the right superior parietal lobe, supporting the idea that esthetic experience arises from the interaction between top-down orienting of attention and bottom-up perceptual facilitation. PMID- 25289492 TI - Complement receptor structure and function. AB - Membrane complement receptors (CRs) are now recognized as important cell-bound components of the complement system and research into the structure and function of complement receptors is one of the main thrusts of current complement research. PMID- 25289493 TI - Life span of MRL/lpr/lpr mice. PMID- 25289494 TI - [Not Available]. PMID- 25289495 TI - Forbidden clones et al. PMID- 25289496 TI - Retroviral infection of accessory cells and the immunological paradox in AIDS. PMID- 25289497 TI - Cross-reactions of anti-DNA antibodies and the central dogma of lupus nephritis. AB - DNA-anti-DNA immune complexes have been implicated in the path1ogenesis of systemic lupus erythematosus (SLE) despite the absence of convincing evidence for the presence of DNA antigen in patients' blood or tissues. Several cross reactions of anti-DNA antibodies have been described in recentyears. Some of these reactions provide new insights into the mechanisms of tissue injury in SLE. Here Dan Eilat suggests that the target antigen for anti-DNA antibodies may be other than DNA. PMID- 25289498 TI - D-J joining and D-J proteins in B cells and T cells. PMID- 25289499 TI - Leukocyte activation and the asthmatic response. PMID- 25289500 TI - Immune interferon: a pleiotropic lymphokine with multiple effects. AB - Immune (gamma) interferon (IFN-gamma) is produced during an immune response by antigen-specific T cells and probably also by natural killer (NK) cells recruited by the T cell-product interleukin 2 (IL-2). IFN-gamma was discovered and originally measured on the basis of its anti-viral activity, but its complex anti cellular activities probably reflect its biological role more clearly. In this review, Giorgio Trinchieri and Bice Perussia discuss some aspects of the biology of IFN-gamma, its pleiomorphic anti-cellular effects and its ability to modulate cellular responses to other regulatory factors. PMID- 25289501 TI - The role of arginase in the immune response. AB - Arginase activity - mainly known for its involvement in urea formation in the liver - inhibits DNA synthesis in cultured mammalian cells(1). Arginase is synthesised and released by activated macrophages mediating immunosuppression during mixed leucocyte culture(2) and may be implicated in macrophage cytotoxicity during the anti-tumor(3), anti-parasite(4) and anti-viral(5) responses. Here Elke Schneider and Michel Dy discuss these aspects of arginase activity as well as more recent indications that arginase may be involved in the cell differentiation and/or proliferation taking place during the immune responses(6,7). A lymphokine with arginase-enhancing activity has been identified. By producing ornithine, arginase provides the unique precursor of polyamines which are essential for DNA synthesis(8). PMID- 25289505 TI - Self-analysis of coherent oscillations in time-resolved optical signals. AB - The specific origin of oscillations in time-resolved optical signals, in particular, for complex systems with nontrivial interstate couplings and nonseparable electron-nuclear motion, is often difficult to assign. Here, we show that coherent oscillations in two-dimensional photon-echo are capable of self analysis; their beating maps provide a tool to tell apart ground-state bleach (GSB), stimulated emission (SE), and excited-state absorption (ESA) contributions to the oscillatory signal component. Because GSB carries information on ground state coherence while SE and ESA reflect the excited-state coherence, the observed oscillations can be unambiguously assigned to ground-state or excited state coherent motion. The findings prove especially advantageous for systems with dense detectable manifolds of states pertaining to each electronic state. An analogous analysis for frequency-resolved (dispersed) pump-probe spectroscopy is discussed briefly. PMID- 25289506 TI - Chemotactic function and disease. PMID- 25289507 TI - Lymphocyte migration into lymph nodes. PMID- 25289508 TI - A lymphokine in liposomes. PMID- 25289509 TI - The role of monoclonal antibody technology in immunoparasitology. PMID- 25289510 TI - How do immune response genes work? AB - Ir genes could operate either by controlling T-cell receptor repertoires, or by controlling antigen presentation to T cells. The idea thatIr genes are a germline set ofV genes for T-cell receptors for foreign antigens can be excluded. Models involving indirect control of the T-cell receptor repertoire during somatic generation of diversity are still possible, though evidence fromH-2 mutations suggests that the probability of their being correct is low. The idea thatIr genes control cell-surfaceMHC antigens that must associate closely with foreign antigens in the surface of antigen-presenting cells to cause T-cell activation is compatible with most, if not all of the available data. PMID- 25289511 TI - The mechanism of T-cell-mediated lysis. PMID- 25289512 TI - Autoimmunity and the diverse pathways to B-cell unresponsiveness. AB - In many chronic diseases there is some degree of disturbance of the immunological self/non-self discriminatory mechanism. Before a rational approach to therapy can be made, it is necessary to know what factors are involved in the pathogenesis of these diseases and thus what requires manipulation. This is the prime reason for trying to understand why an animal does not normally make deleterious immune responses to its own antigens. Many possible mechanisms have come to light from studies of unresponsiveness induced by foreign antigens. In such slates animals may fail to make an antibody response because either their T cells or B cells are unavailable or because the activity of these cells is suppressed. There is controversy over which of these mechanisms contributes to self-unresponsiveness. In this article Chris Elson reviews their importance in the prevention or control of harmful autoantibody responses. PMID- 25289513 TI - Surface carbohydrates and lectins in cellular recognition. PMID- 25289514 TI - Separation of peripheral blood lymphocytes from an individual mouse for functional studies. PMID- 25289516 TI - A direct heating model to overcome the edge effect in microplates. AB - Array-based tests in a microplate format are complicated by the regional variation in results of the outer against the inner wells of the plate. Analysis of the evaporation mechanics of sessile drops showed that evaporation rate increase with temperature was due to changes in the heat of vaporization, density and diffusion coefficient. In simulations of direct bottom heating of standard microplates, considerable heat transfer via conduction from the side walls was found to be responsible for lower temperatures in the liquid in wells close to the edge. Applying a two temperature heating mode, 304 K at the side compared to 310 K at the bottom, allowed for a more uniform temperature distribution. Transparency microplates were found to inherently possess immunity to the edge effect problem due to the presence of air between the liquid and solid wall. PMID- 25289517 TI - In situ determination of colloidal gold concentrations with UV-vis spectroscopy: limitations and perspectives. AB - This paper studies the UV-vis absorbance of colloidal gold nanoparticles at 400 nm and validates it as a method to determine Au(0) concentrations in colloidal gold solutions. The method is shown to be valid with restrictions depending on the investigated system. The uncertainty of the determined Au(0) concentration can be up to 30%. This deviation is the result of the combined influence of parameters such as particle size, surface modification, or oxidation state. However, quantifying the influence of these parameters enables a much more precise Au(0) determination for specific systems. As an example, the reduction process of the well-known Turkevich method was monitored and the Au(0) concentration was determined with a deviation of less than 5%. Hence, a simple, fast, easy, and cheap in situ method for Au(0) determination is demonstrated that has in the presence of other gold species such as Au(III) an unprecedented accuracy. PMID- 25289518 TI - Role of Fe-responsive genes in bioreduction and transport of ionic gold to roots of Arabidopsis thaliana during synthesis of gold nanoparticles. AB - Several studies have shown potassium chloroaurate (KAuCl4)-mediated synthesis of gold nanoparticles (AuNPs) by using extracts of different parts of diverse plant species. However, the mechanism underlying the formation of AuNPs in planta has far from being elucidated. Here, we report the molecular evidence towards the role of genes involved in iron (Fe) homeostasis during in planta synthesis of AuNPs in roots of Arabidopsis thaliana. Firstly, we examined the dosage-dependent effects of KAuCl4 treatment on primary root length (PRL), and meristematic activity of roots in transgenic CycB1;1::uidA. Compared to control seedling (0 ppm KAuCl4), PRL and meristematic activity of primary and lateral roots showed progressive attenuation in seedlings treated with higher concentrations of KAuCl4 (25 ppm or above). Therefore, subsequent studies on in planta synthesis of AuNPs, and molecular responses were carried out in roots of the seedlings treated with 10 ppm KAuCl4 for 7 d. TEM of KAuCl4-treated seedlings showed the presence of monodisperse AuNPs of different shapes and sizes in root biomatrix. There was a significant induction of FRO2 in KAuCl4-treated roots, and therefore its likely involvement in bioreduction of Au(3)(+) could be assumed. Elevated expression levels of Fe transporters IRT1 and IRT2 further suggested their potential role in transport of bioreduced Au(3+) across root membrane. Expression levels of other genes involved in Fe homeostasis, and also different members of zinc (Zn), phosphate (Pi), and potassium (K) transporter families remained unaffected by KAuCl4 treatment. An increased Au content in Fe-deprived roots further provided evidence towards the specific role of a subset of Fe-responsive genes during in planta synthesis of AuNPs. PMID- 25289519 TI - Endogenous hormones response to cytokinins with regard to organogenesis in explants of peach (Prunus persica L. Batsch) cultivars and rootstocks (P. persica * Prunus dulcis). AB - Organogenesis in peach (Prunus persica L. Batsch) and peach rootstocks (P. persica * Prunus dulcis) has been achieved and the action of the regeneration medium on 7 phytohormones, zeatin (Z), zeatin riboside (ZR), indole-3-acetic acid (IAA), abscisic acid (ABA), ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC), salicylic acid (SA), and jasmonic acid (JA), has been studied using High performance liquid chromatography - mass spectrometry (HPLC-MS/MS). Three scion peach cultivars, 'UFO-3', 'Flariba' and 'Alice Bigi', and the peach * almond rootstocks 'Garnem' and 'GF677' were cultured in two different media, Murashige and Skoog supplemented with plant growth regulators (PGRs) (regeneration medium) and without PGRs (control medium), in order to study the effects of the media and/or genotypes in the endogenous hormones content and their role in organogenesis. The highest regeneration rate was obtained with the peach * almond rootstocks and showed a lower content of Z, IAA, ABA, ACC and JA. Only Z, ZR and IAA were affected by the action of the culture media. This study shows which hormones are external PGRs-dependent and what is the weight of the genotype and hormones in peach organogenesis that provide an avenue to manipulate in vitro organogenesis in peach. PMID- 25289520 TI - Involvement of ethylene-responsive microRNAs and their targets in increased latex yield in the rubber tree in response to ethylene treatment. AB - The rubber tree is an economically important plant that produces natural rubber for various industrial uses. The application of ethylene contributes to increased latex production in rubber trees; however, the molecular biology behind the effects of ethylene on latex yield remains to be elucidated. Recently, the intersection between microRNA (miRNA) regulation and phytohormone responses has been revealed. Insight into the regulation of miRNAs and their target genes should help to determine the functional importance of miRNAs as well as the role of miRNAs in signaling under ethylene stimulation in the rubber tree. In this study, hbr-miR159 and hbr-miR166 were down-regulated in bark under ethylene treatment. The ethylene also down-regulated ATHB15-like (Class III Homeodomain Leucine Zipper, HD-ZIP III) which have been extensively implicated in the regulation of primary and secondary vascular tissue pattern formation. The strong negative-regulation of ARF6/ARF8 caused by hbr-miR167 involved in an attenuation of vascular development and may gradually lead to bark dryness syndrome in the long term ethylene treatment. The negative correlation of hbr-miR172 and its target REF3 in the inner soft bark under ethylene treatment results in dramatic increases in latex yield in the ethylene-sensitive clone of the rubber tree. The overall results suggested that the differential expression of HD-ZIP III, miR167/ARF6, ARF8, and miR172/REF3 and related genes may play possible roles in the response to ethylene treatment, resulting in longer latex flow and increased latex yield. PMID- 25289521 TI - A modular approach to adaptive structures. AB - A remarkable property of nastic, shape changing plants is their complete fusion between actuators and structure. This is achieved by combining a large number of cells whose geometry, internal pressures and material properties are optimized for a given set of target shapes and stiffness requirements. An advantage of such a fusion is that cell walls are prestressed by cell pressures which increases, decreases the overall structural stiffness, weight. Inspired by the nastic movement of plants, Pagitz et al (2012 Bioinspir. Biomim. 7) published a novel concept for pressure actuated cellular structures. This article extends previous work by introducing a modular approach to adaptive structures. An algorithm that breaks down any continuous target shapes into a small number of standardized modules is presented. Furthermore it is shown how cytoskeletons within each cell enhance the properties of adaptive modules. An adaptive passenger seat and an aircrafts leading, trailing edge is used to demonstrate the potential of a modular approach. PMID- 25289522 TI - Pharmacokinetics and safety of oseltamivir in patients with end-stage renal disease treated with automated peritoneal dialysis. AB - AIMS: Patients with end-stage renal disease (ESRD) are at increased risk of developing complications associated with influenza infection. Oseltamivir is indicated for influenza treatment in ESRD patients, but the disposition is poorly understood in this patient population. This study aimed to characterize the pharmacokinetics and tolerability of oseltamivir in automated peritoneal dialysis (APD) and construct a pharmacokinetic model to assist with optimized dosing. METHODS: Ten adults with ESRD were prescribed an aggressive APD regimen consisting of three continuous cycler-assisted peritoneal dialysis (CCPD) sessions during the day and two continuous ambulatory (CAPD) sessions overnight. Oseltamivir was administered as a single 75 mg dose, immediately before APD treatment. RESULTS: Oseltamivir was rapidly eliminated via first-pass metabolism, with most of the dose (Fraction metabolized = 0.964) reaching the circulation as the active metabolite, oseltamivir carboxylate. This metabolite was cleared slowly and was quantifiable throughout the sampling interval. The disposition of oseltamivir and oseltamivir carboxylate was described by a two- and a one compartment model, respectively. Metabolite clearance by CCPD [0.32 l h(-1) (70 kg)(-1) ] was 1.9-fold faster than via CAPD [0.17 l h(-1) (70 kg)(-1) ], with renal elimination being dominant in patients with residual urine production. Model simulations showed that a single 75 mg dose attained target exposures in patients with negligible or low urine clearance. However, higher doses are recommended for further investigation in patients with high residual renal function. In all patients, oseltamivir was well tolerated. CONCLUSIONS: In APD patients with anuria or low residual renal elimination, a single 75 mg dose of oseltamivir produced exposures at the upper end of the safety margin. PMID- 25289524 TI - Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines. AB - CONTEXT: Parthenolide (a sesquiterpene lactone), a bioactive compound of Tanacetum parthenium (L.) Schultz Bip. (Asteraceae) herb, has been reported for antioxidant and anticancer activities. OBJECTIVE: The present study evaluated the effect of parthenolide on growth and apoptosis-regulatory genes of human cervical cancer (SiHa) and breast cancer (MCF-7) cell lines. MATERIALS AND METHODS: The cytotoxic activity of parthenolide (3.5-21 uM) was examined by MTT and LDH assays at 24 and 48 h time intervals. Apoptotic activity was evaluated by expression analysis of multiple apoptosis-regulatory genes (i.e., p53, Bcl-2, Bax, caspase 3, -6, and -9) by reverse transcriptase-PCR and DNA fragmentation assay. RESULTS: Parthenolide inhibited the growth of SiHa and MCF-7 cell lines in a concentration dependent manner at 24 and 48 h time intervals (p < 0.001). The IC50 value of parthenolide against SiHa and MCF-7 cells were 8.42 +/- 0.76 and 9.54 +/- 0.82 MUM, respectively. Parthenolide-treated cells showed up-regulation of p53, Bax, caspase-3, -6, and -3 genes and down-regulation of Bcl-2 gene (p <= 0.008). At IC50, the p53 gene was up-regulated by 9.67- and 3.15-fold in SiHa and MCF-7 cells, respectively. The Bax to Bcl-2 ratio was 3.4 and 2.3 for SiHa and MCF-7 cells, respectively. Also, the fragmented genomic DNA in parthenolide-treated cells showed the signs of apoptosis. CONCLUSION: Our study endorsed the biological activity of parthenolide and demonstrated the parthenolide-induced growth inhibition and apoptosis in SiHa and MCF-7 cells by modulating the expression of apoptosis-regulatory genes. PMID- 25289523 TI - Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts. AB - Highly pathogenic avian H5N1 influenza viruses have sporadically transmitted to humans causing high mortality. The mechanistic basis for adaptation is still poorly understood, although several residues in viral protein PB2 are known to be important for this event. Here, we demonstrate that three residues, 147T, 339T and 588T, in PB2 play critical roles in the virulence of avian H5N1 influenza viruses in a mammalian host in vitro and in vivo and, together, result in a phenotype comparable to that conferred by the previously known PB2-627K mutation with respect to virus polymerase activity. A virus with the three residues and 627K in PB2, as has been isolated from a lethal human case, is more pathogenic than viruses with only the three residues or 627K in PB2. Importantly, H5N1 viruses bearing the former three PB2 residues have circulated widely in recent years in avian species in nature. PMID- 25289525 TI - Ameliorative effect of propolis against cyclophosphamide-induced toxicity in mice. AB - CONTEXT: Cyclophosphamide (CTX) is a common anticancer agent used for the treatment of several malignancies. However, upon treatment, it induces severe toxicity due to its oxidative stress capability. Propolis, a natural product collected by honey bees, has shown several biological activities, such as free radical scavenging and antioxidant agent. OBJECTIVE: This study elucidates the protective effects of propolis against CTX-induced changes in mice. MATERIALS AND METHODS: Forty-eight male Swiss albino mice were divided into four groups; group 1 was intraperitoneally (i.p.) injected with 200 uL of phosphate buffer saline (PBS), group 2 was injected with 100 mg/kg/d propolis, group 3 was injected with a single dose of CTX (200 mg/kg), and group 4 was injected with a single dose of CTX (200 mg/kg) followed by propolis (100 mg/kg) for 7 consecutive days. After 12 d, mice were bled and then sacrificed to analyze the hematological, biochemical, and histological parameters. RESULTS: The results indicated that CTX-injected mice showed an increase in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine and a decrease in the total number of white blood cells (WBCs) and platelets. Moreover, dramatically changes in the histological architectures of the liver and kidney were observed. The mice that were injected with CTX/propolis showed an improvement in the levels of ALT, AST, urea, creatinine, WBCs, and platelets. Moreover, the histological picture of the liver and kidney was significantly improved. CONCLUSIONS: In conclusion, propolis might be considered an effective agent in ameliorating the toxicity resulted from CTX treatment. PMID- 25289526 TI - Bioassay guided fractionation and identification of active anti-inflammatory constituent from Delonix elata flowers using RAW 264.7 cells. AB - CONTEXT: Delonix elata (L.) Gamble (Fabaceae) has been used in the Indian traditional medicine system to treat rheumatism and inflammation. AIM: To assess the anti-inflammatory effect of Delonix elata flowers and to isolate the active principle. MATERIALS AND METHODS: The prompt anti-inflammatory constituent was isolated from Delonix elata flower extracts using bioassay guided fractionation in liposaccharide (LPS) stimulated RAW 264.7 macrophage cell line. The anti inflammatory activity of extracts/fractions/sub-fractions/compounds (10, 25, and 50 ug/ml) was evaluated by estimating the levels of nitric oxide (NO), TNF-alpha, and IL-1beta after 24 h of LPS induction (1 MUg/ml). The isolated active compound was subjected to NMR, IR, and UV analyses for structure determination. RESULTS: In an attempt to search for anti-inflammatory constituents, the active pure principle was isolated and crystallized as a white compound from Delonix elata flowers methanol extract. This active compound (50 ug/ml) decreased the release of inflammatory mediators levels such as NO (0.263 +/- 0.03 uM), TNFalpha (160.20 +/- 17.57 pg/ml), and IL-1beta (285.79 +/- 15.16 pg/ml) significantly (p < 0.05); when compared to the levels of NO (0.774 +/- 0.08 uM), TNFalpha (501.71 +/- 25.14 pg/ml), and IL-1beta (712.68 +/- 52.25 pg/ml) from LPS-stimulated macrophage cells. The active compound was confirmed as hesperidin with NMR, IR, and UV spectroscopy data. This is the first report of this compound from Delonix elata flowers. CONCLUSION: The findings of the study support the traditional use of Delonix elata flowers to treat inflammation. PMID- 25289527 TI - Chemical identification and evaluation of the antimicrobial activity of fixed oil extracted from Rhinella jimi. AB - CONTEXT: The toad Rhinella jimi (Stevaux, 2002) (Bufonidae) is used in traditional medicine to treat a number of illnesses (inflammation, infections, and wounds) in humans as well as animals. OBJECTIVES: The present work examined the antimicrobial actions of the extracted oils from the body fat of R. jimi (ORJ) against fungi and standard and multi-resistant lines of bacteria, as well as their effects when combined with aminoglycosides. MATERIALS AND METHODS: The toads were collected in the municipality of Exu in Pernambuco State, Brazil, and their body fat oils extracted in a Soxhlet apparatus using hexane. A gas chromatograph coupled to a mass spectrometer was used to identify the fatty acids, based on their methyl esters. The antimicrobial activities of the oil were analyzed against standard and multi-resistant lines of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, as well as against fungal lines of Candida albicans and Candida krusei using the broth micro-dilution method. RESULTS: The minimum inhibitory concentrations (MIC) of ORJ were 512 ug/mL for Candida krusei and >=1024 ug/mL for the other microorganisms. When associated with amikacin, ORJ demonstrated an increase in its ability to inhibit E. coli growth (from 156.25 to 39.06 ug/mL), indicating synergistic interaction. In the same way, when allied with amikacin, gentamicin, and neomycin, the ORJ reduced the MICs meaningly, against P. aeruginosa. CONCLUSIONS: These data will enable searches to be made to obtain new products in combination with antibiotics, enhancing the efficacy of these drugs against drug-resistant microorganisms. PMID- 25289528 TI - Lipidomics investigation of reversal effect of glycyrrhizin (GL) towards lithocholic acid (LCA)-induced alteration of phospholipid profiles. AB - CONTEXT: Glycyrrhizin (GL), the major ingredient isolated from licorice, exerts multiple pharmacological activities. OBJECTIVE: To elucidate the protective mechanism of GL towards lithocholic acid (LCA)-induced liver toxicity using lipidomics. MATERIALS AND METHODS: GL (200 mg/kg) dissolved in corn oil was treated intraperitoneally for 7 d. On the 4th day, 200 mg/kg LCA was used to treat mice (i.p., twice daily) for another 4 d. The protective role of GL towards LCA-induced liver toxicity was investigated through evaluating the liver histology and the activity of alanine transaminase (ALT). The complete lipid profile was employed using UFLC-Triple TOF MS-based lipidomics. RESULTS: Intraperitoneal (i.p.) administration of 200 mg/kg GL can significantly protect LCA-induced liver damage, indicated by alleviated histology alteration and prevention of the ALT elevation. Lipidomics analysis can well separate the control group from LCA-treated group, and three lipid components were major contributors, including LPC 16:0, LPC 18:0, and LPC 18:2. GL treatment can significantly prevent LCA-induced reduction of these three lipid compounds, providing a new explanation for GL's protection mechanism towards LCA-induced liver toxicity. DISCUSSION AND CONCLUSION: The recent study highlights the importance of lipidomics in elucidating the therapeutic mechanism of herbs. PMID- 25289529 TI - Heparin fails to inhibit the leukocyte recruitment for an extended time following inflammatory stimulus. AB - CONTEXT: Several studies have shown that heparin is able to inhibit leukocyte recruitment during an early acute inflammatory response. However, considering the pharmacokinetic aspects of heparin and the dynamics of inflammation our objective was to determine if heparin is able to retain its antimigratory property during a prolonged inflammatory response. OBJECTIVE: Compare the effect of heparin on leukocyte recruitment to the peritoneal cavity during early acute inflammatory response and for a longer time post-inflammatory stimulus. MATERIALS AND METHODS: Wistar rats pre-treated with subcutaneous heparin in doses of 1, 5, and 15 ug/kg were challenged with 2 mL intraperitoneal thioglycollate. After 3 or 8 h, the animals were killed. The cells in the peritoneal cavity were collected and counted. For differential counting, cells from peritoneal lavage and from blood were distended over a glass slide, stained, and counted. RESULTS: After 3 h, heparin inhibited cell influx to the injury site at all tested dosages. The largest effect was achieved at a 5 ug/kg dose (83% of reduction, p < 0.001). After 8 h, heparin at a 1 ug/kg dose reduced 63% of cellular infiltration (p < 0.001); the group treated with a 15 ug/kg dose presented an pro-inflammatory effect observed by the higher proportions, when compared with the thioglycollate group, of neutrophils on whole blood (60.9%, p < 0.001) and peritoneal fluid (27.3%, p < 0.05), and whole blood monocytes (117.8%, p < 0.01). CONCLUSION: These findings show that the heparin effect on leukocyte recruitment varies depending on its dosage and the duration of the inflammation. PMID- 25289530 TI - Flavonoid rich fraction of Punica granatum improves early diabetic nephropathy by ameliorating proteinuria and disturbed glucose homeostasis in experimental animals. AB - CONTEXT: Different parts of Punica granatum Linn. (Punicaceae) are traditionally used as renal protective agents in the Indian system of medicine. However, there is paucity of information regarding its role in diabetic nephropathy. OBJECTIVE: The present study investigates the nephroprotective potential of flavonoid-rich fraction of P. granatum leaves in streptozotocin (STZ)-induced early diabetic nephropathy in experimental animals. MATERIALS AND METHODS: Experimental diabetic nephropathy was induced in Wistar rats by single intraperitonial injection of STZ (65 mg/kg) dissolved in ice cold citrophosphate buffer (pH 4.3). After induction rats were divided into five groups (6 normal; 24 diabetic) and administered with glibenclamide (5 mg/kg) and three dose levels of flavonoid-rich fraction of P. granatum leaves (PGFF), i.e. 50, 100, and 200 mg/kg body weight/day for 28 d. Fasting blood glucose, lipid profile, serum albumin, serum total protein, serum creatinine, blood urea nitrogen (BUN) glycosylated hemoglobin, and biomarkers of kidney oxidative stress were assessed at the end of the treatment period. Urine was analyzed for the measurement of total protein, albumin, and creatinine clearance. Kidney sections were subjected to histopathological study. RESULTS: Daily oral administration of variable dose levels of PGFF for 28 d normalized various biochemical, metabolic, and histopathological changes in the diabetic rats. PGFF significantly (p < 0.01 and p < 0.05) improved the glycemic status and renal function in diabetic rats as compared with diabetic control rats. DISCUSSION AND CONCLUSION: The results of our study thus prove the protective effect of PGFF in early diabetic nephropathy by ameliorating proteinuria and disturbed glucose homeostasis in experimental animals. PMID- 25289531 TI - The anti-inflammatory effect of triphala in arthritic-induced rats. AB - CONTEXT: Triphala, an Indian Ayurvedic herbal formulation which contains Terminalia chebula Retz. (Combretaceae), Terminalia bellerica (Gaertn.) Roxb. (Combretaceae) and Emblica officinalis L. (Phyllanthaceae), is used for treating bowel-related complications, inflammatory disorders, and gastritis. OBJECTIVE: To determine the anti-arthritic effect of triphala in arthritis-induced rats. For comparison purpose, the non-steroidal anti-inflammatory drug indomethacin was used. MATERIALS AND METHODS: Arthritis was induced in Wistar albino rats by intradermal injection of complete Freund's adjuvant (0.1 ml) into the foot pad of right hind paw. Triphala (100 mg/kg b wt, i.p.) was administered from day 11 to 18 after the administration of complete Freund's adjuvant. The activities/levels of lysosomal enzymes, glycoproteins, antioxidant status, and lipid peroxidation were determined in the paw tissues of arthritic rats. In addition, the inflammatory mediators were also measured in both the serum and the paw tissue of arthritic rats. RESULTS: The levels/activities of lipid peroxidation (~41.5%), glycoproteins (hexose ~43.3%, hexosamine ~36.5%, and sialic acid ~33.7%), lysosomal enzymes (acid phosphatase ~52.4%, beta-galactosidase ~22.9%, N-acetyl beta-glucosaminidase ~22.1%, and cathepsin-D ~27.7%) were found to be decreased and the antioxidant status (SOD ~75.6%, CAT ~62.7%, GPx ~55.8%, GST ~82.1%, and GSH ~72.7%) was increased in the paw tissues of triphala-treated arthritic rats. In addition, the inflammatory mediator levels in serum (TNF-alpha ~75.5%, IL 1beta ~99%, VEGF ~75.2%, MCP-1 ~76.4%, and PGE2 ~69.9%) and in paw tissues (TNF alpha ~71.6%, IL-1beta ~75.5%, VEGF ~55.1%, MCP-1 ~69.1%, and PGE2 ~66.8%) were found to be suppressed. CONCLUSION: Triphala has a promising anti-inflammatory effect in the inflamed paw of arthritis-induced rats. PMID- 25289532 TI - Bengt Saltin. "Don't be sad it is over - be glad that it happened". PMID- 25289533 TI - Chimeras - no longer a myth. AB - Since its first successful application less than 15 years ago, allogeneic marrow transplantation has been used with continuously improving results for the treatment of severe aplastic anemia, leukemia and congenital immunodeficiency syndromes. With this background, a recent meeting(*) provided an excellent opportunity to critically review problems and achievements of marrow transplant and non-transplant approaches to the treatment of malignant and nonmalignant lymphohemopoietic disorders. PMID- 25289534 TI - Is controversy about 'transfer factor therapy' nearing an end? AB - Nearly 30-years after Lawrencefirst described 'transfer factor' the therapeutic value of dialysable leukocyte extracts is now being examined in adequately designed trials. The evidence of its efficacy in certain patients in certain circumstances is unmistakable. PMID- 25289535 TI - Receptors for lymphokines. PMID- 25289536 TI - Immunotherapeutic potential of idiotype/anti-idiotype regulation of the IgE response. AB - Studies of the induction of suppressor cells by soluble factors and anti idiotypic antibody in mice have progressed to the point where it now seems likely that patients' allergic responses to grass pollen can be reduced by manipulation through the idiotype-anti-idiotype network. PMID- 25289537 TI - Molecular mechanisms in tumor-cell killing by activated macrophages. AB - Macrophages kill tumor cells with and without the aid of antibody and evidence suggests that secreted cytotoxic substances are at work in each system. Here Dolph Adams and Carl Nathan discuss the likely involvement in both pathways of several such substances including cytolytic protease and hydrogen peroxide. PMID- 25289538 TI - Mechanisms of autoimmunity: a role for cross-reactive idiotypes. AB - Ehrlich was rarely given to trivial pronouncements and his recognition of the central importance of the distinction between self and non-self by the immune system, embodied in his concept of 'horror autotoxicus'(1), is no exception. This is despite the apparent paradox of the idiotype network in which antibodies recognize self-epitopes on other antibody molecules or antigen receptors as part of the normal process of immune regulation. In this review Anne Cooke and her colleagues examine the possible factors which may contribute to the breakdown of self-tolerance and the establishment of autoimmune states. PMID- 25289545 TI - Mechanism and selectivity of methyl and phenyl migrations in hypervalent silylated iminoquinones. AB - Chlorosilanes R(X)(Y)SiCl (R = Me, Ph; X, Y = Me, Ph, Cl) have been reported to react with Pb(ONO(Q))2 (ONO(Q) = 3,5-di-tert-butyl-1,2-quinone-(3,5-di-tert-butyl 2-oxy-1-phenyl)imine) to give five-coordinate (X)(Y)Si(ON[R]O), in which the R group has migrated from silicon to nitrogen. This migration is intramolecular, as confirmed by the lack of crossover between (CH3)3SiCl and (CD3)3SiCl in their reaction with Pb(ONO(Q))2. Reaction of PhSiMeCl2 takes place with high kinetic stereoselectivity to produce isomer Ph(Cl)Si(ON[Me]O) in which the phenyl is axial in the trigonal bipyramid, which subsequently isomerizes to the thermodynamic isomer with axial chlorine. This indicates that migration takes place preferentially from the stereoisomer of the octahedral intermediate, kappa(3)-Ph(CH3)(Cl)Si(ONO(Q)), in which the phenyl and methyl groups are mutually trans, indicating that the observed complete selectivity for methyl over phenyl migration is due to intrinsic differences in migratory aptitude. DFT calculations suggest that migration takes place from this isomer not because it undergoes migration faster than other possible stereoisomers, but because it is formed most rapidly, and migration occurs faster than isomerization. PMID- 25289542 TI - Reproductive outcomes and nononcologic complications after radioactive iodine ablation for well-differentiated thyroid cancer. AB - BACKGROUND: Radioactive iodine (RAI) ablation is frequently performed after initial surgery for well-differentiated thyroid cancer (WDTC). We examined the frequency and timing of childbirth as well as nononcologic complications after RAI ablation for WDTC on a population level. METHODS: A retrospective cohort study of 25,333 patients (18,850 women) with WDTC was performed using the California Cancer Registry and California Office of Statewide Health Planning and Development database, 1999-2008. The primary outcomes were birthrate and median time to first live birth among women of childbearing age. Secondary outcomes were nononcologic diagnoses occurring outside the acute setting (>30 days) after ablation. RESULTS: RAI ablation did not affect birthrate among women in the full dataset. However, in subgroup analyses, birthrate among women age 35-39 was significantly decreased in those who received RAI versus those who did not (11.5 versus 16.3 births per 1000 woman-years, p<0.001). Median time to first live birth after diagnosis of WDTC was prolonged among women who received RAI compared to those who did not (34.5 versus 26.1 months; p<0.0001). When 5-year age groups were examined individually, delay to first live birth was observed in women age 20-39 (p<0.05). This remained significant after adjustment for tumor characteristics, socioeconomic status, and marital status. The only nononcologic, nonreproductive adverse effect associated with RAI ablation was an increased rate of nasolacrimal stenosis (RR 3.44, p<0.0001). CONCLUSIONS: RAI ablation is associated with delayed childbearing in women across most of the reproductive lifespan, and with decreased birthrate in the late reproductive years. The underlying mechanism likely involves physician recommendation to delay pregnancy, as well as a potential impact of RAI on both reproductive choice and reproductive health. Further investigation is merited. PMID- 25289546 TI - Ab initio metadynamics study on hydronium ion dynamics at acid-functionalized interfaces: effect of surface group density. AB - This article presents an ab initio metadynamics study of elementary hydronium ion transitions at dense arrays of surface groups with sulfonic acid head groups. Calculations simulate minimally hydrated conditions of the interfacial ionic system. The specific focus is on the influence of the surface group density on hydronium ion transport. Results reveal a high sensitivity of the activation free energy of hydronium translocations to the surface group density. A spontaneous concerted transition with low activation barrier is found at a surface group separation of 6.8 A. When hydroniums translocate concertedly, the activation barrier of the transition drops by more than a factor of two to the value of 0.25 eV. An approach is presented to determine interaction constants of hydronium ions and anionic surface groups as well as the surface group flexibility from the analysis of frequency spectra. These properties are discussed in the context of a recently developed soliton theory of interfacial proton transport. PMID- 25289547 TI - Immune dysfunction is one of many defects. AB - Ataxia-telangiectasea (AT), a progressive and uniformly fatal inherited neuroimmunological disorder, affects approximately 1 in 40 000 children. Patients are born to normal parents and appear to develop normally for about two years. They then begin to stagger (ataxia) and show signs of degenerating cerebellar function; by five years of age, they have dilated blood vessels (telangiectases) over the exposed bulbar conjunctiva and skin of the ear. By 10 years of age, they are usually confined to a wheel-chair. Most AT patients have IgA and IgG2 deficiency as well as various T cell-associated immune dysfunctions. Because one of every five patients develops cancer, usually lymphoid, during their shortened life-span, it is believed that unravelling the pathogenesis of AT will also shed light upon the genetics of cancer susceptibility and upon the relationship of immunodeficiency to oncogenesis. A recent conference(*) focused on four areas of this complex disorder: DNA repair/replication, genetics, neuropathology and immunopathology. PMID- 25289548 TI - Agreement now the norm. AB - Many immunologists hold that complement is baffling or irrelevant or, most conveniently, both but a recent meeting(*) emphasized that complement is interesting and that it may be important, even if only as an elegant model system. Moreover agreement is now the norm. The biochemistry has now advanced to the point where the outlines of the reaction mechanisms are agreed and work is under way with detailed analysis and model building. PMID- 25289549 TI - Anti-Ia-like antibodies: preliminary use in rheumatoid arthritis. PMID- 25289550 TI - Anti-Ia antibodies in therapy. PMID- 25289551 TI - More pitfalls in the use of monoclonal antibodies. PMID- 25289552 TI - The avidin-biotin system. PMID- 25289553 TI - Helper T cells and isotype expression. PMID- 25289554 TI - High determinant density may explain the phenomenon of alloreactivity. AB - When two members of the same species differfrom each other in their MHC-encoded antigens, mixing their lymphocytes leads to a vigorous T-cell response. This is the phenomenon of alloreactivity, exempl here as a mixed lymphocyte response. In this article Michael Bevan presents a hypothesis to account for alloreactivity, based on the notion that the alloreactive target determinant is a sequence or conformational determinant contributed entirely by the foreign MHC molecule in isolation, which is expressed at high density on the antigen-presenting cell. PMID- 25289555 TI - Possible target antigens in autoimmune endocrine disease. AB - Insulin is most familiar in its circulatingform, binding to appropriately equipped target cells which are remote from the site of insulin synthesis, the pancreatic islet cells. Here David Kaplan describes recent observations that insulin and perhaps other hormones are also detectable as surface membrane antigens on the cells that secrete them, and discusses the implications of these findings for the study of autoimmune disease. PMID- 25289556 TI - Antigen presentation - a transformed approach. PMID- 25289557 TI - Probing the boundaries of the extended immunoglobulin family of recognition molecules: jumping domains, convergence and minigenes. AB - Structural studies on proteins have placed certain molecules with related functions in extended families with a possible common ancestor. The immunoglobulin family is one such grouping: among its putative members are Thy-1, C-reactive protein, beta2-microglobulin, and MHC class-I and class-II products. Here John Marchalonis and his colleagues discuss new computer analyses of sequence data and serological studies which argue against the inclusion of Thy-1 and C-reactive protein in the immunoglobulin family. The sequence data suggest, however, that domains may be shared by recognition molecules with different evolutionary histories and that immunoglobulin and non-immunoglobulin molecules may cross-react serologically because they have 'minigenes' in common. PMID- 25289558 TI - Surface carbohydrates and surface lectins are recognition determinants in phagocytosis. AB - Phagocytic cells constantly come into contact with various cells and particulate materials, yet in the absence of antibody they attach to and ingest only some of them. The molecular basis for this selective recognition, discussed here by Nathan Sharon, seems on recent evidence to lie in interactions between lectins and sugars on the surface of the phagocytes and the particles they engulf. PMID- 25289559 TI - An Fc receptor-bearing, third population of human mononuclear cells with cytotoxic and regulatory function. AB - In 1973 Froland and Natvig reported that 14.5% of human blood lymphocytes expressed distinctive Fc receptors for IgG (FcR) and that this subset lacked surface receptors believed to be characteristic for T and B cells. They named this subset 'third population' cells. Although these cells have been extensively studied since that time, whether they are a single unique population or immatureforms of other mononuclear populations is controversial. Their lineage is unknown. They have morphologic featur s that distinguish them from other mononuclear cells, but studies with monoclonal antibodies have revealed that they share surface markers andfunctions with T cells, monocytes and even granulocytes. Subsets of these cells are the effectors of natural and antibody-dependent cell killing, regulators of T-cell proliferation and suppressors of immunoglobulin synthesis. Here, David Horwitz and Antony Bakke discuss the present understanding of these cells, which they call 'L cells' because of the characteristic temperature-labile attachment of IgG molecules to their Fc receptors. PMID- 25289563 TI - Core-shell nanoparticles based on pullulan and poly(beta-amino) ester for hepatoma-targeted codelivery of gene and chemotherapy agent. AB - This study designs a novel nanoparticle system with core-shell structure based on pullulan and poly(beta-amino) ester (PBAE) for the hepatoma-targeted codelivery of gene and chemotherapy agent. Plasmid DNA expressing green fluorescent protein (pEGFP), as a model gene, was fully condensed with cationic PBAE to form the inner core of PBAE/pEGFP polycomplex. Methotrexate (MTX), as a model chemotherapy agent, was conjugated to pullulan by ester bond to synthesize polymeric prodrug of MTX-PL. MTX-PL was then adsorbed on the surface of PBAE/pEGFP polycomplex to form MTX-PL/PBAE/pEGFP nanoparticles with a classic core-shell structure. MTX-PL was also used as a hepatoma targeting moiety, because of its specific binding affinity for asialoglycoprotein receptor (ASGPR) overexpressed by human hepatoma HepG2 cells. MTX-PL/PBAE/pEGFP nanoparticles realized the efficient transfection of pEGFP in HepG2 cells and exhibited significant inhibitory effect on the cell proliferation. In HepG2 tumor-bearing nude mice, MTX-PL/PBAE/pEGFP nanoparticles were mainly distributed in the tumor after 24 h postintravenous injection. Altogether, this novel codelivery system with a strong hepatoma-targeting property achieved simultaneous delivery of gene and chemotherapy agent into tumor at both cellular and animal levels. PMID- 25289564 TI - Thin-film versus slurry-phase carbonation of steel slag: CO2 uptake and effects on mineralogy. AB - The results of direct aqueous accelerated carbonation of three types of steel manufacturing residues, including an electric arc furnace (EAF) slag and two basic oxygen furnace (BOF) slags, are reported. Batch accelerated carbonation tests were conducted at different temperatures and CO2 pressures applying the thin-film route (liquid to solid, L/S, ratio=0.3L/kg) or the slurry-phase route (L/S ratio=5L/kg). The CO2 uptake strongly depended on both the slag characteristics and the process route; maximum yields of 280 (EAF), 325 (BOF1) and 403 (BOF2) gCO2/kg slag were achieved in slurry phase at T=100 degrees C and pCO2=10 bar. Differently from previous studies, additional carbonates (other than Ca-based phases) were retrieved in the carbonated BOF slags, indicating that also Mg-, Fe- and Mn-containing phases partially reacted with CO2 under the tested conditions. The results hence show that the effects of accelerated carbonation in terms of CO2 uptake capacity, yield of mineral conversion into carbonates and mineralogy of the treated product, strongly rely on several factors. These include, above all, the mineralogy of the original material and the operating conditions adopted, which thus need specific case-by-case optimization to maximize the CO2 sequestration yield. PMID- 25289565 TI - Apoptosis, necrosis, and autophagy in mouse intestinal damage after 15-Gy whole body irradiation. AB - Enterocytes die during high-dose radiation exposure in radiation accidents. The modality of cell death has a profound effect on the therapeutic response. The ilea from mice with 15 Gy total body irradiation (TBI) were drawn, morphological features observed by hematoxylin and eosin staining and transmission electron micrographs. The biochemical features of mouse ileum presented with the structure were cleaved Caspase-3 (apoptosis marker), Light Chain 3 (LC3)-I's conversion to LC3-II (autophagy marker) and high mobility group box chromosomal protein 1's secretion (necrosis marker). Then, the autophagy inhibitor (3-methyladenine), caspase inhibitor (Z-VAD-FMK) or necrosis inhibitor (necrostatin) was used to prevent death. Apoptosis, autophagy and necrosis were all appeared in the ileum, but necrosis had the biggest size; the use of 3-methyladenine and Z-VAD-FMK prolong one day's life of the mice after 15 Gy TBI, necrostatin significantly extended the lifespan of 15 Gy irradiated mice (p < 0.05). The results suggest that the death of enterocytes could not be classified into one type of cell death but rather as 'mixed death.' PMID- 25289566 TI - Method validation for preparing urine samples for downstream proteomic and metabolomic applications. AB - BACKGROUND: Formal validation of methods for biospecimen processing in the context of accreditation in laboratories and biobanks is lacking. A protocol for processing of a biospecimen (urine) was validated for fitness-for-purpose in terms of key downstream endpoints. METHODS: Urine processing was optimized for centrifugation conditions on the basis of microparticle counts at room temperature (RT) and at 4 degrees C. The optimal protocol was validated for performance (microparticle counts), and for reproducibility and robustness for centrifugation temperature (4 degrees C vs. RT) and brake speed (soft, medium, hard). Acceptance criteria were based on microparticle counts, cystatin C and creatinine concentrations, and the metabolomic profile. RESULTS: The optimal protocol was a 20-min, 12,000 g centrifugation at 4 degrees C, and was validated for urine collection in terms of microparticle counts. All reproducibility acceptance criteria were met. The protocol was robust for centrifugation at 4 degrees C versus RT for all parameters. The protocol was considered robust overall in terms of brake speeds, although a hard brake gave significantly fewer microparticles than a soft brake. CONCLUSIONS: We validated a urine processing method suitable for downstream proteomic and metabolomic applications. Temperature and brake speed can influence analytic results, with 4 degrees C and high brake speed considered optimal. Laboratories and biobanks should ensure these conditions are systematically recorded in the scope of accreditation. PMID- 25289567 TI - Enhanced cellular uptake of antisecretory peptide AF-16 through proteoglycan binding. AB - Peptide AF-16, which includes the active site of Antisecretory Factor protein, has antisecretory and anti-inflammatory properties, making it a potent drug candidate for treatment of secretory and inflammatory diseases such as diarrhea, inflammatory bowel diseases, and intracranial hypertension. Despite remarkable physiological effects and great pharmaceutical need for drug discovery, very little is yet understood about AF-16 mechanism of action. In order to address interaction mechanisms, we investigated the binding of AF-16 to sulfated glycosaminoglycan, heparin, with focus on the effect of pH and ionic strength, and studied the influence of cell-surface proteoglycans on cellular uptake efficiency. Confocal laser scanning microscopy and flow cytometry experiments on wild type and proteoglycan-deficient Chinese hamster ovary cells reveal an endocytotic nature of AF-16 cellular uptake that is, however, less efficient for the cells lacking cell-surface proteoglycans. Isothermal titration calorimetry provides quantitative thermodynamic data and evidence for that the peptide affinity to heparin increases at lower pH and ionic strength. Experimental data, supported by theoretical modeling, of peptide-glycosaminoglycan interaction indicate that it has a large electrostatic contribution, which will be enhanced in diseases accompanied by decreased pH and ionic strength. These observations show that cell-surface proteoglycans are of general and crucial importance for the antisecretory and anti-inflammatory activities of AF-16. PMID- 25289568 TI - The structural basis for mTOR function. AB - The phosphoinositide 3-kinase (PI3K) related protein kinases (PIKKs) are a family of protein kinases with a diverse range of vital cellular functions. Recent high resolution crystal structures of the protein kinase mTOR suggest general architectural principles that are likely to be common to all of the PIKKs. Furthermore, the structures make clear the close relationship of the PIKKs to the PI3Ks. However, the structures also make clear the unique features of mTOR that enable its substrate specificity. The active site is deeply recessed and flanked by structural elements unique to the PIKKs, namely, the FRB domain, the LST8 binding element, and a C-terminal stretch of helices known as the FATC domain. The FRB has a conserved element in it that is part of a bipartite substrate recognition mechanism that is probably characteristic of all of the PIKKs. The FRB also binds the mTOR inhibitor rapamycin that has been referred to as an allosteric inhibitor, implying that this inhibitor is actually a competitive inhibitor of the protein substrate. This bipartite substrate-binding site also helps clarify how rapamycin can result in substrate-specific inhibition. PMID- 25289570 TI - Factor-induced differentiation and activation of macrophages. AB - The cells of the mononuclear phagocyte lineage, namely monocytes and macrophages secrete over 50 proteins. This impressive versatility is regulated both internally, during the cells' maturation, and by events in the extracellular environment which activate the cells. Differentiation and activation are profoundly influenced by a variety of cytokines and these interactions were among the themes of a recently reported meeting. PMID- 25289569 TI - mTOR signalling, embryogenesis and the control of lung development. AB - The existence of a nutrient sensitive "autocatakinetic" regulator of embryonic tissue growth has been hypothesised since the early 20th century, beginning with pioneering work on the determinants of foetal size by the Australian physiologist, Thorburn Brailsford-Robertson. We now know that the mammalian target of rapamycin complexes (mTORC1 and 2) perform this essential function in all eukaryotic tissues by balancing nutrient and energy supply during the first stages of embryonic cleavage, the formation of embryonic stem cell layers and niches, the highly specified programmes of tissue growth during organogenesis and, at birth, paving the way for the first few breaths of life. This review provides a synopsis of the role of the mTOR complexes in each of these events, culminating in an analysis of lung branching morphogenesis as a way of demonstrating the central role mTOR in defining organ structural complexity. We conclude that the mTOR complexes satisfy the key requirements of a nutrient sensitive growth controller and can therefore be considered as Brailsford Robertson's autocatakinetic centre that drives tissue growth programmes during foetal development. PMID- 25289572 TI - There is, regrettably, more than one interleukin 4. PMID- 25289571 TI - Advances in ELISA and other solid-phase immunoassays. AB - Increased sensitivity and ease of performance have made solid-phase immunoassays increasingly popular. Freedom from the hazards of radioisotopes and the expensive equipment needed to measure them have helped to make the enzyme-linked immunosorbent assay (ELISA) one of the fastest growing immunological tests used today. ELISA possesses equal and sometimes greater sensitivity than the solid phase immunoradiometric assay (SPIRMA), but many of the rules that govern SPIRMA do not apply to ELISA and where they do they are often ignored. Papers from a meeting on developments in these techniques have just been published. PMID- 25289573 TI - Are inflammatory phagocytes responsible for resistance to facultative intracellular bacteria? AB - At least 38 deaths from listeriosis in the United States in recent months have drawn attention to how little we know about resistance to facultative intracellular bacteria. Much more is known about resistance to obligate intracellular parasites. Macrophages, activated by T cell-derived macrophage activating factors (MAF), are able to kill obligate intracellular parasites and tumor cells(1-10) including Leishmania, certain trypanosomes, Toxoplasma, the obligate intracellular bacterium Rickettsia, and perhaps bacteria such as mycobacteria and Legionella. However, macrophages, stimulated by MAF, may not be the only host cells which can defend against infection by facultative intracellular bacteria such as Salmonella typhimurium or Listeria monocytogenes. Six different observations made by Priscilla Campbell and colleagues, and by others, suggest that it is not the so-called 'activated' macrophage which is primarily responsible for resistance against facultative intracellular bacteria. Rather, she proposes that an early inflammatory cell recently recruited in response to an inflammatory stimulus - a cell whose presence seems to be under the control of immunologically-specific T cells - plays a critical role in resistance to infection by these organisms. PMID- 25289574 TI - T-cell ontogeny: the role of a stimulator - suppressor cell. AB - The thymus presents two major problems in cellular differentiation. How is self non-self discrimination achieved in developing thymocytes? What determines the development of T-cell classes? In this discussion, Alan Herbert and James Watson propose a mechanism for regulating T-cell differentiation which involves the alternative pathway of T-cell activation. They postulate that T cells with a stimulator-suppressor phenotype stimulate resting helper T cells (Th) to produce interleukin 2 (IL-2) and suppress T cells which have bound antigen through antigen-specific receptors by preventing induction of IL-2 receptors. Stimulator suppressor T cells therefore suppress the clonal expansion of T cells in an antigen-specific manner, yet promote their own clonal expansion in a manner independent of antigen. They further suggest that the molecule responsible for suppression is the product of the gamma genes known to rearrange in gamma cells. PMID- 25289575 TI - Is tolerance of minor transplantation antigens MHC restricted? PMID- 25289576 TI - The evolution of MHC class II genes. PMID- 25289577 TI - Contrasuppression in the mouse. PMID- 25289578 TI - Antigen presenting, contrasuppressor human T cells. PMID- 25289579 TI - The computer and the reprint file. AB - A collection of reprints or references is often difficult and tedious to use and maintain. Here John Weiler reviews BIBLIOFILE and REFERENCE MANAGER, two sophisticated software packages which help the user to manage a reprint file. BIBLIOFILE is command oriented (you have to know the commands to run the program) and REFERENCE MANAGER is menu oriented (choices are presented on the screen). PMID- 25289580 TI - 'And next, just for your enjoyment!': sex, technology and the constitution of desire. AB - In the 1976 sci-fi film Logan's Run, actor Michael York, relaxing in a fetching caftan after a day hunting 'Runners', logs-in to the 'Circuit', a de- and re materialisation technology that allows those seeking sex to select partners. Logan's first candidate, a young man, is passed over with a smile. The second is co-star Jenny Agutter; she is accepted and we join a sexual ride in the future. Online dating sites such as Gaydar(r) and RSVP(r) would seem to have a long way to go to achieve that, and MicrosoftTM needs some fast apps development to get us there. Against this background, this paper examines some starting points in our fascination with technosex, long before the Internet, in books and magazines, the creative arts and other media and cultural forms. It focuses upon gay men's contribution to this fascination, and looks at the queering of heterosexuality and the part technology has played in that process. Online technologies are examined, particularly in relation to the 'publicisation' of sexual life and to shifts in sexual identity and practice related to changing processes of sexual objectification, self-objectification and subjectification. Finally, the transformation of sex into health and healthy sex is discussed. PMID- 25289582 TI - Dynamic modeling and simulation of rough cylindrical micro/nanoparticle manipulation with atomic force microscopy. AB - In this paper, the process of pushing rough cylindrical micro/nanoparticles on a surface with an atomic force microscope (AFM) probe is investigated. For this purpose, the mechanics of contact involving adhesion are studied first. Then, a method is presented for estimating the real area of contact between a rough cylindrical particle (whose surface roughness is described by the Rumpf and Rabinovich models) and a smooth surface. A dynamic model is then obtained for the pushing of rough cylindrical particles on a surface with an AFM probe. Afterwards, the process is simulated for different particle sizes and various roughness dimensions. Finally, by reducing the length of the cylindrical particle, the simulation condition is brought closer to the manipulation condition of a smooth spherical particle on a rough substrate, and the simulation results of the two cases are compared. Based on the simulation results, the critical force and time of manipulation diminish for rough particles relative to smooth ones. Reduction in the aspect ratio at a constant cross-section radius and the radius of asperities (height of asperities based on the Rabinovich model) results in an increase in critical force and time of manipulation. PMID- 25289581 TI - Excess non-psychiatric hospitalizations among employees with mental disorders: a 10-year prospective study of the GAZEL cohort. AB - OBJECTIVE: To examine whether non-psychiatric hospitalizations rates were higher in those with mental disorders. METHOD: In a cohort of 15,811 employees, aged 35 50 years in 1989, mental disorder status was defined from 1989 to 2000. Hospitalizations for all-causes, myocardial infarction (MI), stroke, and cancer, were recorded yearly from 2001 to 2011. Negative binomial regression models were used to estimate hospitalization rates over the follow-up. RESULTS: After controlling for baseline sociodemographic factors, health-related behaviors, self rated health, and self-reported medical conditions, participants with a mental disorder had significantly higher rates of all-cause hospitalization [incidence rate ratio, IRR=1.20 (95%, 1.14-1.26)], as well as hospitalization due to MI [IRR=1.44 (95%, 1.12-1.85)]. For stroke, the IRR did not reach statistical significance [IRR=1.37 (95%, 0.95-1.99)] and there was no association with cancer [IRR=1.01 (95%, 0.86-1.19)]. A similar trend was observed when mental disorders groups were considered (no mental disorder, depressive disorder, mental disorders due to psychoactive substance use, other mental disorders, mixed mental disorders, and severe mental disorder). CONCLUSION: In this prospective cohort of employees with stable employment as well as universal access to healthcare, we found participants with mental disorders to have higher rates of non-psychiatric hospitalizations. PMID- 25289583 TI - Integrated signaling pathway and gene expression regulatory model to dissect dynamics of Escherichia coli challenged mammary epithelial cells. AB - Cells transform external stimuli, through the activation of signaling pathways, which in turn activate gene regulatory networks, in gene expression. As more omics data are generated from experiments, eliciting the integrated relationship between the external stimuli, the signaling process in the cell and the subsequent gene expression is a major challenge in systems biology. The complex system of non-linear dynamic protein interactions in signaling pathways and gene networks regulates gene expression. The complexity and non-linear aspects have resulted in the study of the signaling pathway or the gene network regulation in isolation. However, this limits the analysis of the interaction between the two components and the identification of the source of the mechanism differentiating the gene expression profiles. Here, we present a study of a model of the combined signaling pathway and gene network to highlight the importance of integrated modeling. Based on the experimental findings we developed a compartmental model and conducted several simulation experiments. The model simulates the mRNA expression of three different cytokines (RANTES, IL8 and TNFalpha) regulated by the transcription factor NFkappaB in mammary epithelial cells challenged with E. coli. The analysis of the gene network regulation identifies a lack of robustness and therefore sensitivity for the transcription factor regulation. However, analysis of the integrated signaling and gene network regulation model reveals distinctly different underlying mechanisms in the signaling pathway responsible for the variation between the three cytokine's mRNA expression levels. Our key findings reveal the importance of integrating the signaling pathway and gene expression dynamics in modeling. Modeling infers valid research questions which need to be verified experimentally and can assist in the design of future biological experiments. PMID- 25289584 TI - Two new steroidal glycosides from Cynanchum otophyllum Schneid. AB - Two new C21 steroidal glycosides were isolated from Cynanchum otophyllum Schneid. Their structures were elucidated as qinyangshengenin-3-O-beta-d digitoxopyranoside (1) and rostratamine-3-O-beta-d-cymaropyranosyl-(1 -> 4)-beta d-digitoxopyranoside (2) on the basis of chemical and spectroscopic methods, including 1D and 2D NMR experiments. PMID- 25289587 TI - Fate of microplastics in the marine isopod Idotea emarginata. AB - Plastic pollution is an emerging global threat for marine wildlife. Many species of birds, reptiles, and fishes are directly impaired by plastics as they can get entangled in ropes and drown or they can ingest plastic fragments which, in turn, may clog their stomachs and guts. Microplastics of less than 1 mm can be ingested by small invertebrates, but their fate in the digestive organs and their effects on the animals are yet not well understood. We embedded fluorescent microplastics in artificial agarose-based food and offered the food to marine isopods, Idotea emarginata. The isopods did not distinguish between food with and food without microplastics. Upon ingestion, the microplastics were present in the stomach and in the gut but not in the tubules of the midgut gland which is the principal organ of enzyme-secretion and nutrient resorption. The feces contained the same concentration of microplastics as the food which indicates that no accumulation of microplastics happens during the gut passage. Long-term bioassays of 6 weeks showed no distinct effects of continuous microplastic consumption on mortality, growth, and intermolt duration. I. emarginata are able to prevent intrusion of particles even smaller than 1 MUm into the midgut gland which is facilitated by the complex structure of the stomach including a fine filter system. It separates the midgut gland tubules from the stomach and allows only the passage of fluids and chyme. Our results indicate that microplastics, as administered in the experiments, do not clog the digestive organs of isopods and do not have adverse effects on their life history parameters. PMID- 25289588 TI - Proteomic analysis of responsive stem proteins of resistant and susceptible cashew plants after Lasiodiplodia theobromae infection. AB - Gummosis is an aggressive disease caused by the necrotrophic fungus Lasiodiplodia theobromae (Pat.) Griffon & Maubl that threatens commercial cashew orchads in Brazil. To study the molecular mechanisms involved in the cashew response to L. theobromae, a proteomic analysis of stems from the commercial cashew clone BRS 226 (resistant) was conducted at early times post-artificial infection. In addition, changes in the stem proteome profiles of gummosis resistant and susceptible cashew plants grown under field condition and naturally exposed to pathogen were also compared. After two-dimensional gel electrophoresis (2D-PAGE), 73 proteins showed statistically significant differences in spot abundance. Of these, 31 spots were identified in BRS 226 stems compared with mock-inoculated controls and 32 in stems collected from field-grown resistant and susceptible cashew plants. L. theobromae-responsive proteins were mainly involved in energy metabolism pathways, stress and defense, cell signaling and protein metabolism indicating modulation of various cellular functions upon fungal infection. As stress-inducing factors seem to be important for susceptibility to disease, the change in the abundance relative these proteins may possibly indicate an attempt to maintain cellular homeostasis, as resistance determinant factor, related with a possible role in the regulation of oxidative burst. These findings provide the first information about the cellular mechanisms acting in the Anacardium occidentale genotypes associated with the pathophysiological state of infection with L. theobromae. BIOLOGICAL SIGNIFICANCE: Gummosis caused by Lasiodiplodia theobromae, a necrotrophic fungus, is the major disease of cashew plants in the semi-arid conditions of northeastern Brazil. Although various studies were carried out on this pathosystem, there is no information available on the molecular mechanisms of plant defense related to the incompatible interaction of cashew with L. theobromae. Therefore, this original study comprises a differential proteomic analysis of cashew stems from: (i) resistant dwarf clone BRS 226 mock-inoculated (control) and artificially inoculated with L. theobromae; and (ii) cashew plants bearing resistant and susceptible traits to gummosis, originated from open pollination of BRS 226 in a commercial orchard with high disease incidence. The contribution of the reprogrammed proteins to molecular events triggered in cashew plants challenged by L. theobromae has a great relevance in the identification of the host candidate proteins linked to biological pathways that respond to L. theobromae infection. Furthermore this study may contribute to improve breeding programs aimed at selecting resistant/tolerant cashew clones toward this pathogen. PMID- 25289586 TI - Cerebellar learning mechanisms. AB - The mechanisms underlying cerebellar learning are reviewed with an emphasis on old arguments and new perspectives on eyeblink conditioning. Eyeblink conditioning has been used for decades a model system for elucidating cerebellar learning mechanisms. The standard model of the mechanisms underlying eyeblink conditioning is that there two synaptic plasticity processes within the cerebellum that are necessary for acquisition of the conditioned response: (1) long-term depression (LTD) at parallel fiber-Purkinje cell synapses and (2) long term potentiation (LTP) at mossy fiber-interpositus nucleus synapses. Additional Purkinje cell plasticity mechanisms may also contribute to eyeblink conditioning including LTP, excitability, and entrainment of deep nucleus activity. Recent analyses of the sensory input pathways necessary for eyeblink conditioning indicate that the cerebellum regulates its inputs to facilitate learning and maintain plasticity. Cerebellar learning during eyeblink conditioning is therefore a dynamic interactive process which maximizes responding to significant stimuli and suppresses responding to irrelevant or redundant stimuli. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25289589 TI - Investigation of minor species Candida africana, Candida stellatoidea and Candida dubliniensis in the Candida albicans complex among Yaounde (Cameroon) HIV infected patients. AB - Minor species of the Candida albicans complex may cause overestimation of the epidemiology of C. albicans, and misidentifications could mask their implication in human pathology. Authors determined the occurrence of minor species of the C. albicans complex (C. africana, C. dubliniensis and C. stellatoidea) among Yaounde HIV-infected patients, Cameroon. Stool, vaginal discharge, urine and oropharyngeal samples were analysed by mycological diagnosis. Isolates were identified by conventional methods and mass spectrometry (MS; carried out by the matrix-assisted laser desorption-ionisation time-of-flight MS protocol). Candida albicans isolates were thereafter submitted to the PCR amplification of the Hwp1 gene. The susceptibility of isolates to antifungal drugs was tested using the Clinical and Laboratory Standards Institute M27-A3 protocol. From 115 C. albicans obtained isolates, neither C. dubliniensis nor C. stellatoidea was observed; two strains of C. africana (422PV and 448PV) were identified by PCR electrophoretic profiles at 700 bp. These two C. africana strains were vaginal isolates. The isolate 448PV was resistant to ketoconazole at the minimal inhibitory concentration of 2 MUg ml(-1), and showed reduced susceptibility to amphotericin B at 1 MUg ml(-1). This first report on C. africana occurrence in Cameroon brings clues for the understanding of the global epidemiology of this yeast as well as that of minor species of the C. albicans complex. PMID- 25289592 TI - Receptors, antibodies and disease. PMID- 25289591 TI - The timing is right. PMID- 25289593 TI - Applied wisdom. PMID- 25289590 TI - A 3D cellular context for the macromolecular world. PMID- 25289585 TI - A fruitful endeavor: modeling ALS in the fruit fly. AB - For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research. This article is part of a Special Issue entitled ALS complex pathogenesis. PMID- 25289594 TI - Interleukins: a rose is a rose .... PMID- 25289595 TI - Is sperm immunosuppressive in male homosexuals and vasectomized men? PMID- 25289597 TI - Complement and solubilization of immune complexes. PMID- 25289596 TI - The vulnerability of skin grafts to allo- and xeno-antibodies: a conundrum resolved? PMID- 25289598 TI - Monoclonal antibodies - tools to dissect the nervous system. AB - With monoclonal antibodies it is now possible to describe the morphological features and physiological events of the nervous system in molecular terms. PMID- 25289599 TI - The three-dimensional structure of antibodies. PMID- 25289600 TI - The mammary gland as an immunological organ. AB - It has been known for decades that milk contains antibodies but because they were not resorbed by the breast-fed infant they were long regarded to be of no biological significance. However, with the discovery that the dominant milk immunoglobulin was secretory IgA - the first description of this class of antibody - came the realization that breast milk was potentially important for the infant's anti-microbial defense. In this review Lars Hanson discusses the protective capacity of milk and the role of milk IgA in the mucosal defense system. PMID- 25289603 TI - Bringing Reactivity to the Aggregation-Volume-Bias Monte Carlo Based Simulation Framework: Water Nucleation Induced by a Reactive Proton. AB - The development of the aggregation-volume-bias Monte Carlo based simulation technique has led to recent success in studying rare nucleation events, but thus far, this simulation method has been limited to nonreactive systems. This work presents the first application of this technique to study a reactive system of relevance to atmospheric chemistry, i.e., formation of water droplets in the presence of a reactive proton, by combining this approach with a multistate empirical valence bond (MSEVB) description of the excess proton (or the hydronium). It was shown that the ability for the hydronium to share its charge with adjacent water molecules changes dramatically with the cluster size, especially when clusters are small and the distribution of the charge is affected by the presence of an interface, emphasizing the need to use this more sophisticated MSEVB model for such a reactive system. In addition, the simulation results obtained from this system are compared to those with nonreactive hard sphere ions of different sizes. Overall, the presence of a hydronium or ions appeared to dramatically change the free energy landscape of nucleation compared to the pure water system, leading to the formation of a stable precritical cluster. Although the free energy change due to the addition of the first few water molecules was shown to be very sensitive to the ionic details, the later portion of the free energy profile was found to be nearly independent of the nature of the ion. PMID- 25289605 TI - Closure of uterus and the risk of uterine rupture. PMID- 25289604 TI - Pedicled parathyroid gland autotransposition in secondary and tertiary hyperparathyroidism. PMID- 25289606 TI - Lessons from changing times. AB - It will not have escaped your notice that it is the centenary of the outbreak of the first world war. In nursing, the event has prompted the profession to look back on how society has changed but, as this month's issue shows, there are age old public health challenges that have yet to be combated and new ones arising, to boot. PMID- 25289607 TI - Data reveals gaps in dedicated paediatric continence provision. AB - CLINICAL COMMISSIONING groups (CCGs) are failing to drive improvements in children's continence care, according to the Paediatric Continence Forum (PCF). PMID- 25289608 TI - Urgent action needed to tackle growing childhood obesity. AB - NURSES, MIDWIVES and GPs are calling for a national emergency taskforce to tackle childhood obesity in England. PMID- 25289609 TI - Wales and Scotland see fall in number of children's nurses. AB - WHILE THERE has been an increase in commissioned children's nursing training places across the UK since 2013/14, the number of children's nurses in Wales and Scotland has fallen, government figures show. PMID- 25289610 TI - Consultation seeks views on new criteria for heart services. AB - FRESH PROPOSALS for reorganising children's heart surgery have been published for consultation just over a year after the government described the proposed reforms arising from a previous review as 'flawed'. PMID- 25289611 TI - Better engagement with South Asian communities will improve asthma care. AB - TAILORED TREATMENT PLANS should be developed with families to help children with asthma from South Asian backgrounds in the UK, a study has concluded. PMID- 25289613 TI - Call for more specialisation in children's care. AB - RECOGNITION THAT the health outcomes for children and young people in the UK lag behind comparable countries has prompted the government to respond by calling for services to be redesigned. PMID- 25289614 TI - Study shows ongoing benefits of cooling therapy for neonates. AB - OXYGEN DEPRIVATION at birth - perinatal asphyxia - is a well-known risk to children's health and development, resulting in permanent neurological damage that can include cerebral palsy and/or learning disability. PMID- 25289620 TI - Research and commentary: Giving feedback on weight to parents following the National Child Measurement Programme. PMID- 25289619 TI - Research essentials: How to find funds to support projects. AB - IF YOU HAVE an idea for a research project, whether it is an investigation or a literature review, it can be difficult to know where to start looking for financial support. Finding colleagues to work with will provide you with a sounding board for your idea, as well as support and encouragement. PMID- 25289621 TI - Promoting healthy lifestyle changes to families is a challenge. AB - Nearly 30% of UK children aged 2-15 years are overweight or obese ( Department of Health 2013), with Lepkowska (2014) highlighting the rise in the number of children admitted to hospital with obesity-related problems. PMID- 25289622 TI - How do you give information? AB - BEING A PATIENT in the NHS is like being a stranger in a foreign country. It has its own food, language and customs, clans and chiefs. It can be frightening, confusing and alienating for adults, let alone children visiting a hospital or GP's surgery. PMID- 25289625 TI - Student voice - Questioning others as a child's advocate. AB - RECENTLY I WAS involved in a situation in which I was asked to assist two staff nurses in an invasive procedure with a young child. Initially, I held the child down as instructed to do by the staff nurses. The child became distressed, so I asked the nurses to stop the procedure and to give the child a break. PMID- 25289627 TI - Evaluating a specialist nurse's role in a general paediatric surgical team. AB - A surgical care practitioner (SCP) is a registered nurse or allied health professional who, following specific education and competency training, carries out pre- and post-operative treatment and some surgical interventions under the supervision of a consultant surgeon, contributing to the maintenance of surgical services and the enhancement of patient care. With a cohesive approach, the SCP can do much to ensure continuity of care and mutual understanding and concordance between staff, child and family. Costs can be reduced and the surgical training of junior doctors supported. The results of this audit show that, with the inclusion of an SCP, higher quality general children's surgery can be provided at a medium-sized district general hospital, so that patients can be seen locally. PMID- 25289628 TI - Understanding the effect of miliary tuberculosis through the experience of one young person. AB - In the UK, tuberculosis (TB) is on the increase. Miliary TB affects the lungs and can leave lasting damage, and affect a person's quality of life adversely. Healthcare professionals need to co-ordinate services efficiently, to ensure a smooth transition from hospital to home, and ensure there is appropriate support in the community for as long as necessary. In this article, a boy describes his journey through the illness: the associated bewilderment, deterioration, pain, fear and isolation; the emergencies; the prolonged but effective treatment; the care he received; and the support of his family. On discharge, he was still breathless and found it difficult to adapt to home life but, with thorough planning of his support with healthcare professionals, parents and relevant agencies, he was able to get back to school and continue his education. PMID- 25289629 TI - Health visiting and its role in addressing the nutritional needs of children in the first world war. AB - The first known UK health visitor post was established in 1862, in response to the living conditions of the poor. Before the first world war, local government boards advised district councils generally to employ health visitors: breastfeeding and child nutrition needed particular attention. In 1910, Hucknall District Council in Nottinghamshire, England, appointed nurse Ellen Woodcock to advise mothers and caregivers on looking after their children and themselves. Focusing on the welfare of women and children, health visitors could not fail to reach everyone in the community. This historical perspective shows that many of the initiatives and policies of today mirror those of a century ago. PMID- 25289631 TI - A clear view in area of risk and complexity. PMID- 25289630 TI - Fundamentals of chronic pain in children and young people. Part 1. AB - Persistent and recurrent pain is a common condition in childhood. Chronic pain can have a negative effect on all aspects of quality of life, including physical, emotional, social and role functioning. A small percentage of these children and young people (5-8%) will experience significant impairments due to their pain condition. Most chronic pain requires a holistic multidisciplinary approach to treatment--pharmacological, physical and psychological strategies. Nurses are key members of the health care team in terms of helping children, young people and their families to manage the negative consequences of chronic pain. This article will review the prevalence, pathophysiology, contributing factors, consequences. Part two, to be published next month, will cover multimodal treatment of chronic pain in children and young people. PMID- 25289632 TI - PET-CT derived Artificial Neural Network can predict mediastinal lymph nodes metastases in Non-Small Cell Lung Cancer patients. Preliminary report and scoring model. AB - AIM: Mediastinal lymph nodes staging in NSCLC (non small cell lung cancer) is of undisputable importance. Although relatively precise, diagnostic modalities, mediastinoscopy and EBUS/EUS - TBNA (endobronchial/endoscopic ultrasound guided- transbronchial needle aspiration) still employ certain level of invasiveness. Artificial Neural Network (ANN) is an established predictor tool which, due to underlying distribution and relationship among the given variables, allow for construction of multidimensional models trained in prognosis of given outcome. Their performance in mediastinal staging based on radiological data only, remains limited to single studies. METHODS: We obtained 467 groups of lymph nodes from 160 patients with primary NSCLC by means of EBUS--TBNA, mediastinoscopy or lymphadenectomy during thoracotomy and analyzed them microscopically. ANN models were created and prospectively validated on unmatched cohort of 50 consecutive patients (158 groups of lymph nodes). To identify factors correlated with nodal involvement single factor tests and logistic regression analyzes were performed. Additionally, logistic regression analysis allowed for construction of scoring model with certain parameters corresponding to risk thresholds of metastatic disease. RESULTS: Size and standard uptake value (SUV) of the node along with primary tumour T characteristics were identified as the most sensitive variables regardless of the analysis conducted. Two ANN models predicted metastatic involvement with 89% and 92% accuracy. Single factor tests maintained high accuracy only for 2 out of 4 most sensitive variables (SUV >2.8 and length >15mm) in prospective validation. CONCLUSIONS: ANN is a repeatable and accurate diagnostic tool in mediastinal staging in NSCLC patients. Before its role in clinical practice will be established in large multi--centre study, findings of this preliminary report should be considered as exploratory only. PMID- 25289633 TI - Stable metabolic disease on FDG-PET provides information on response to endocrine therapy for breast cancer. AB - BACKGROUND: The aim of this study was to assess whether outcome in advanced breast cancer patients is related to metabolic response to endocrine therapy determined by fluorodeoxyglucose positron-emission tomography (FDG-PET). METHODS: We retrospectively identified 21 consecutive breast cancer patients receiving endocrine therapy for metastatic disease (mean number of previous therapies 3.6+/ 3.5). All patients had been evaluated with at least 2 FDG-PETs. The first scan was performed by initiation of endocrine therapy. The second scan was performed after a mean of 3.8+/-1.14 months. Seventy-two FDG-avid lesions were identified and followed. The mean change in SUVmax (DeltaSUVmax) was calculated per patient. RESULTS: DeltaSUVmax dichotomized using the group median as cut-off (8.6%) was predictive of progression-free survival (PFS). The median PFS for the response group (N.=10, median DeltaSUVmax -20.9%) was 10.1 months. The median PFS for the progressive disease-group (N.=11, median DeltaSUVmax 40.6%) was 6.7 months (log rank testing P=0.033). CONCLUSIONS: Our data suggest that breast cancer patients under hormonal therapy with stable disease on FDG-PET have a longer PFS when compared to non-responders. This finding is new, supporting the value of endocrine therapy among patients with advanced breast cancer. PMID- 25289634 TI - Human neural stem cell transplantation provides long-term restoration of neuronal plasticity in the irradiated hippocampus. AB - For the majority of CNS malignancies, radiotherapy provides the best option for forestalling tumor growth, but is frequently associated with debilitating and progressive cognitive dysfunction. Despite the recognition of this serious side effect, satisfactory long-term solutions are not currently available and have prompted our efforts to explore the potential therapeutic efficacy of cranial stem cell transplants. We have demonstrated that intrahippocampal transplantation of human neural stem cells (hNSCs) can provide long-lasting cognitive benefits using an athymic rat model subjected to cranial irradiation. To explore the possible mechanisms underlying the capability of engrafted cells to ameliorate radiation-induced cognitive dysfunction we analyzed the expression patterns of the behaviorally induced activity-regulated cytoskeleton-associated protein (Arc) in the hippocampus at 1 and 8 months postgrafting. While immunohistochemical analyses revealed a small fraction (4.5%) of surviving hNSCs in the irradiated brain that did not express neuronal or astroglial makers, hNSC transplantation impacted the irradiated microenvironment of the host brain by promoting the expression of Arc at both time points. Arc is known to play key roles in the neuronal mechanisms underlying long-term synaptic plasticity and memory and provides a reliable marker for detecting neurons that are actively engaged in spatial and contextual information processing associated with memory consolidation. Cranial irradiation significantly reduced the number of pyramidal (CA1) and granule neurons (DG) expressing behaviorally induced Arc at 1 and 8 months postirradiation. Transplantation of hNSCs restored the expression of plasticity-related Arc in the host brain to control levels. These findings suggest that hNSC transplantation promotes the long-term recovery of host hippocampal neurons and indicates that one mechanism promoting the preservation of cognition after irradiation involves trophic support from engrafted cells. PMID- 25289635 TI - Measuring soluble ICAM-1 in African populations. AB - The level of plasma soluble ICAM-1 (sICAM-1) has been associated with the pathogenesis of several diseases. Previously, a commercial antibody was reported not to recognize an ICAM-1 allele known as ICAM-1kilifi prevalent among African populations. However, that study was based on 19 samples from African Americans of whom 13 had the wild type allele, five heterozygotes and one homozygote. Here, we compare plasma sICAM-1 measures using three different commercial antibodies in samples from Kenyan children genotyped for ICAM-1kilifi allele. We show that two of these antibodies have some degree of deficiency in detecting the ICAM-1kilifi allele. Consideration of the antibody used to measure sICAM-1 is important as up to 30% of the populations in Africa harbour this allele. PMID- 25289636 TI - Validation of housekeeping genes in the brains of rats submitted to chronic intermittent hypoxia, a sleep apnea model. AB - Obstructive sleep apnea (OSA) is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH), which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3 phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses. PMID- 25289637 TI - Dynamic epigenetic control of highly conserved noncoding elements. AB - BACKGROUND: Many noncoding genomic loci have remained constant over long evolutionary periods, suggesting that they are exposed to strong selective pressures. The molecular functions of these elements have been partially elucidated, but the fundamental reason for their extreme conservation is still unknown. RESULTS: To gain new insights into the extreme selection of highly conserved noncoding elements (HCNEs), we used a systematic analysis of multi-omic data to study the epigenetic regulation of such elements during the development of Drosophila melanogaster. At the sequence level, HCNEs are GC-rich and have a characteristic oligomeric composition. They have higher levels of stable nucleosome occupancy than their flanking regions, and lower levels of mononucleosomes and H3.3, suggesting that these regions reside in compact chromatin. Furthermore, these regions showed remarkable modulations in histone modification and the expression levels of adjacent genes during development. Although HCNEs are primarily initiated late in replication, about 10% were related to early replication origins. Finally, HCNEs showed strong enrichment within lamina-associated domains. CONCLUSION: HCNEs have distinct and protective sequence properties, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. These observations indicate that such elements are likely to have essential cellular functions, and offer insights into their epigenetic properties. PMID- 25289638 TI - Temperature effects on bacterial phytochrome. AB - Bacteriophytochromes (BphPs) are light-sensing regulatory proteins encoded in photosynthetic and non-photosynthetic bacteria. This protein class incorporate bilin as their chromophore, with majority of them bearing a light- regulated His kinase or His kinase related module in the C-terminal. We studied the His kinase actives in the temperature range of 5 degrees C to 40 degrees C on two BphPs, Agp1 from Agrobacterium tumefaciens and Cph1 from cyanobacterium Synechocystis PCC 6803. As reported, the phosphorylation activities of the far red (FR) irradiated form of the holoprotein is stronger than that of the red (R) irradiated form in both phytochromes. We observed for the apoprotein and FR irradiated holoprotein of Agp1 an increase in the phosphorylation activities from 5 degrees C to 25 degrees C and a decrease from 25 degrees C to 40 degrees C. At 5 degrees C the activities of the apoprotein were significantly lower than those of the FR irradiated holoprotein, which was opposite at 40 degrees C. A similar temperature pattern was observed for Cph1, but the maximum of the apoprotein was at 20 degrees C while the maximum of the FR irradiated holoprotein was at 10 degrees C. At 40 degrees C, prolonged R irradiation leads to an irreversible bleaching of Cph1, an effect which depends on the C-terminal His kinase module. A more prominent and reversible temperature effect on spectral properties of Agp1, mediated by the His kinase, has been reported before. His kinases in phytochromes could therefore share similar temperature characteristics. We also found that phytochrome B mutants of Arabidopsis have reduced hypocotyl growth at 37 degrees C in darkness, suggesting that this phytochrome senses the temperature or mediates signal transduction of temperature effects. PMID- 25289639 TI - Phylogenetic analysis of the spider mite sub-family Tetranychinae (Acari: Tetranychidae) based on the mitochondrial COI gene and the 18S and the 5' end of the 28S rRNA genes indicates that several genera are polyphyletic. AB - The spider mite sub-family Tetranychinae includes many agricultural pests. The internal transcribed spacer (ITS) region of nuclear ribosomal RNA genes and the cytochrome c oxidase subunit I (COI) gene of mitochondrial DNA have been used for species identification and phylogenetic reconstruction within the sub-family Tetranychinae, although they have not always been successful. The 18S and 28S rRNA genes should be more suitable for resolving higher levels of phylogeny, such as tribes or genera of Tetranychinae because these genes evolve more slowly and are made up of conserved regions and divergent domains. Therefore, we used both the 18S (1,825-1,901 bp) and 28S (the 5' end of 646-743 bp) rRNA genes to infer phylogenetic relationships within the sub-family Tetranychinae with a focus on the tribe Tetranychini. Then, we compared the phylogenetic tree of the 18S and 28S genes with that of the mitochondrial COI gene (618 bp). As observed in previous studies, our phylogeny based on the COI gene was not resolved because of the low bootstrap values for most nodes of the tree. On the other hand, our phylogenetic tree of the 18S and 28S genes revealed several well-supported clades within the sub-family Tetranychinae. The 18S and 28S phylogenetic trees suggest that the tribes Bryobiini, Petrobiini and Eurytetranychini are monophyletic and that the tribe Tetranychini is polyphyletic. At the genus level, six genera for which more than two species were sampled appear to be monophyletic, while four genera (Oligonychus, Tetranychus, Schizotetranychus and Eotetranychus) appear to be polyphyletic. The topology presented here does not fully agree with the current morphology-based taxonomy, so that the diagnostic morphological characters of Tetranychinae need to be reconsidered. PMID- 25289642 TI - Cellular senescence in biliary pathology. Special emphasis on expression of a polycomb group protein EZH2 and a senescent marker p16INK4a in bile ductular tumors and lesions. AB - A subgroup of intrahepatic cholangiocarcinoma and combined hepatocellular- cholangiocarcinoma contain a component of cholangiolocellular carcinoma, which is composed of small bile ductular cells. Ductular reaction, a reactive lesion at the portal tract interface comprising increased bile ductules, is frequently seen in chronic advanced liver diseases. Bile duct adenoma, a benign tumor/tumorous lesion is also composed of bile ductular cells. Differential diagnosis among these bile ductular tumors/lesions is sometimes difficult. Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile ductular tumors/lesions. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, while it was not observed in bile duct adenomas or ductular reactions. In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas. A borderline between cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a. In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile ductular tumors/lesions. PMID- 25289641 TI - Cell turnover and detritus production in marine sponges from tropical and temperate benthic ecosystems. AB - This study describes in vivo cell turnover (the balance between cell proliferation and cell loss) in eight marine sponge species from tropical coral reef, mangrove and temperate Mediterranean reef ecosystems. Cell proliferation was determined through the incorporation of 5-bromo-2'-deoxyuridine (BrdU) and measuring the percentage of BrdU-positive cells after 6 h of continuous labeling (10 h for Chondrosia reniformis). Apoptosis was identified using an antibody against active caspase-3. Cell loss through shedding was studied quantitatively by collecting and weighing sponge-expelled detritus and qualitatively by light microscopy of sponge tissue and detritus. All species investigated displayed substantial cell proliferation, predominantly in the choanoderm, but also in the mesohyl. The majority of coral reef species (five) showed between 16.1+/-15.9% and 19.0+/-2.0% choanocyte proliferation (mean+/-SD) after 6 h and the Mediterranean species, C. reniformis, showed 16.6+/-3.2% after 10 h BrdU labeling. Monanchora arbuscula showed lower choanocyte proliferation (8.1+/ 3.7%), whereas the mangrove species Mycale microsigmatosa showed relatively higher levels of choanocyte proliferation (70.5+/-6.6%). Choanocyte proliferation in Haliclona vansoesti was variable (2.8-73.1%). Apoptosis was negligible and not the primary mechanism of cell loss involved in cell turnover. All species investigated produced significant amounts of detritus (2.5-18% detritus bodyweight(-1).d(-1)) and cell shedding was observed in seven out of eight species. The amount of shed cells observed in histological sections may be related to differences in residence time of detritus within canals. Detritus production could not be directly linked to cell shedding due to the degraded nature of expelled cellular debris. We have demonstrated that under steady-state conditions, cell turnover through cell proliferation and cell shedding are common processes to maintain tissue homeostasis in a variety of sponge species from different ecosystems. Cell turnover is hypothesized to be the main underlying mechanism producing sponge-derived detritus, a major trophic resource transferred through sponges in benthic ecosystems, such as coral reefs. PMID- 25289643 TI - Netrin-1 and semaphorin 3A predict the development of acute kidney injury in liver transplant patients. AB - Acute kidney injury (AKI) is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients' samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8 +/- 112.4 pg/mg creatinine), semaphorin 3A (847.9 +/- 93.3 pg/mg creatinine) and NGAL (2172.2 +/- 378.1 ng/mg creatinine) levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732) only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364). These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation. PMID- 25289644 TI - A Compound fault diagnosis for rolling bearings method based on blind source separation and ensemble empirical mode decomposition. AB - A Compound fault signal usually contains multiple characteristic signals and strong confusion noise, which makes it difficult to separate week fault signals from them through conventional ways, such as FFT-based envelope detection, wavelet transform or empirical mode decomposition individually. In order to improve the compound faults diagnose of rolling bearings via signals' separation, the present paper proposes a new method to identify compound faults from measured mixed-signals, which is based on ensemble empirical mode decomposition (EEMD) method and independent component analysis (ICA) technique. With the approach, a vibration signal is firstly decomposed into intrinsic mode functions (IMF) by EEMD method to obtain multichannel signals. Then, according to a cross correlation criterion, the corresponding IMF is selected as the input matrix of ICA. Finally, the compound faults can be separated effectively by executing ICA method, which makes the fault features more easily extracted and more clearly identified. Experimental results validate the effectiveness of the proposed method in compound fault separating, which works not only for the outer race defect, but also for the rollers defect and the unbalance fault of the experimental system. PMID- 25289640 TI - Prevalence and correlates of bacterial vaginosis in different sub-populations of women in sub-Saharan Africa: a cross-sectional study. AB - BACKGROUND: Clinical development of vaginally applied products aimed at reducing the transmission of HIV and other sexually transmitted infections, has highlighted the need for a better characterisation of the vaginal environment. We set out to characterise the vaginal environment in women in different settings in sub-Saharan Africa. METHODS: A longitudinal study was conducted in Kenya, Rwanda and South-Africa. Women were recruited into pre-defined study groups including adult, non-pregnant, HIV-negative women; pregnant women; adolescent girls; HIV negative women engaging in vaginal practices; female sex workers; and HIV positive women. Consenting women were interviewed and underwent a pelvic exam. Samples of vaginal fluid and a blood sample were taken and tested for bacterial vaginosis (BV), HIV and other reproductive tract infections (RTIs). This paper presents the cross-sectional analyses of BV Nugent scores and RTI prevalence and correlates at the screening and the enrolment visit. RESULTS: At the screening visit 38% of women had BV defined as a Nugent score of 7-10, and 64% had more than one RTI (N. gonorrhoea, C. trachomatis, T. vaginalis, syphilis) and/or Candida. At screening the likelihood of BV was lower in women using progestin only contraception and higher in women with more than one RTI. At enrolment, BV scores were significantly associated with the presence of prostate specific antigen (PSA) in the vaginal fluid and with being a self-acknowledged sex worker. Further, sex workers were more likely to have incident BV by Nugent score at enrolment. CONCLUSIONS: Our study confirmed some of the correlates of BV that have been previously reported but the most salient finding was the association between BV and the presence of PSA in the vaginal fluid which is suggestive of recent unprotected sexual intercourse. PMID- 25289645 TI - Hemoglobin A1c Levels and risk of severe hypoglycemia in children and young adults with type 1 diabetes from Germany and Austria: a trend analysis in a cohort of 37,539 patients between 1995 and 2012. AB - BACKGROUND: Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years. METHODS AND FINDINGS: We analyzed data of 37,539 patients with type 1 diabetes (mean age +/- standard deviation 14.4 +/- 3.8 y, range 1-20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19-1.37) to 1.05 (1.00-1.09) and from 1.39 (1.23 1.56) to 1.01 (0.93-1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6-1.7, p<0.001) and 1.9% (0.8-2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%-6.9% (RR 0.96 and 0.90 each year) and 7.0% 7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study. CONCLUSIONS: The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near normal glycemic control in these patients. Please see later in the article for the Editors' Summary. PMID- 25289648 TI - HAX-1: a novel p-body protein. AB - HAX-1, a multifunctional protein involved in the regulation of apoptosis, cell migration, and calcium homeostasis, binds the 3' untranslated region motifs of specific transcripts. This suggests that HAX-1 plays a role in post transcriptional regulation, at the level of mRNA stability/transport or translation. In this study, we analyze in detail HAX-1 colocalization with processing bodies (P-bodies) and its dependence on mRNA availability. Endogenous P-body markers DCP1 and Rck/p54 were shown to colocalize with endogenous HAX-1, but in case of the overexpressed proteins, only DCP1 displayed unperturbed colocalization with HAX-1. HAX-1 colocalization with DCP1 was observed in most of the cell lines studied, but its presence was not required for P-body formation, and its silencing caused an increase in P-body number. Preliminary mapping suggested that HAX-1 has more than one short P-body-targeting sequence. The pools of P-body-localized HAX-1 and cytosolic HAX-1 were demonstrated to dynamically exchange, suggesting steady flow of the protein. Active transcription was shown to be a factor in the localization of HAX-1 to P-bodies. Also, it was observed that HAX-1 localizes to some unidentified foci, which do not contain DCP1. In addition, it was demonstrated that HAX-1 status influences vimentin expression levels. Overall, HAX-1 was shown to colocalize with P-body markers and influence P-body number per cell in a manner dependent on mRNA availability. Presented data support the hypothesis that HAX-1 is involved in mRNA processing as an element of P-body interaction network. PMID- 25289646 TI - Induction of oligodendrocyte differentiation and in vitro myelination by inhibition of rho-associated kinase. AB - In inflammatory demyelinating diseases such as multiple sclerosis (MS), myelin degradation results in loss of axonal function and eventual axonal degeneration. Differentiation of resident oligodendrocyte precursor cells (OPCs) leading to remyelination of denuded axons occurs regularly in early stages of MS but halts as the pathology transitions into progressive MS. Pharmacological potentiation of endogenous OPC maturation and remyelination is now recognized as a promising therapeutic approach for MS. In this study, we analyzed the effects of modulating the Rho-A/Rho-associated kinase (ROCK) signaling pathway, by the use of selective inhibitors of ROCK, on the transformation of OPCs into mature, myelinating oligodendrocytes. Here we demonstrate, with the use of cellular cultures from rodent and human origin, that ROCK inhibition in OPCs results in a significant generation of branches and cell processes in early differentiation stages, followed by accelerated production of myelin protein as an indication of advanced maturation. Furthermore, inhibition of ROCK enhanced myelin formation in cocultures of human OPCs and neurons and remyelination in rat cerebellar tissue explants previously demyelinated with lysolecithin. Our findings indicate that by direct inhibition of this signaling molecule, the OPC differentiation program is activated resulting in morphological and functional cell maturation, myelin formation, and regeneration. Altogether, we show evidence of modulation of the Rho-A/ROCK signaling pathway as a viable target for the induction of remyelination in demyelinating pathologies. PMID- 25289649 TI - A VLU complicated by severe group a streptococcal infection resulting in necrotising fasciitis and septic shock: a case report. AB - This case study outlines the management of a patient with a venous leg ulcer whose swabs cultured Staphylococcus aureus and beta-haemolytic streptococcus group A while in hospital with cellulitis, which was treated with antibiotics as per sensitivities. However, the patient presented at the emergency department five weeks later with a diagnosis of invasive group A streptococcal disease resulting in necrotising fasciitis and streptococcal toxic shock syndrome. This paper describes the holistic care and wound management that the patient received. PMID- 25289650 TI - Role of hyperbaric medicine for intractable leg ulcers: a case report. AB - We present a case report of intractable multifactorial leg ulcer that was treated successfully with multiple approaches including hyperbaric oxygen treatment (HBOT) to prepare for skin grafting. A 66-year-old female with a history of rheumatoid arthritis and Felty's syndrome presented with a non-healing ulcer on her left leg that was caused by a trauma. She failed multiple treatment options including debridement, different wound dressings, antibiotics, anti inflammatories and vein closure procedure. She finally healed with skin graft following HBOT that prepared the wound bed before the procedure. PMID- 25289651 TI - Foreword. PMID- 25289647 TI - Functions of FUS/TLS from DNA repair to stress response: implications for ALS. AB - Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional DNA-/RNA-binding protein that is involved in a variety of cellular functions including transcription, protein translation, RNA splicing, and transport. FUS was initially identified as a fusion oncoprotein, and thus, the early literature focused on the role of FUS in cancer. With the recent discoveries revealing the role of FUS in neurodegenerative diseases, namely amyotrophic lateral sclerosis and frontotemporal lobar degeneration, there has been a renewed interest in elucidating the normal functions of FUS. It is not clear which, if any, endogenous functions of FUS are involved in disease pathogenesis. Here, we review what is currently known regarding the normal functions of FUS with an emphasis on DNA damage repair, RNA processing, and cellular stress response. Further, we discuss how ALS-causing mutations can potentially alter the role of FUS in these pathways, thereby contributing to disease pathogenesis. PMID- 25289652 TI - Treatment of a paediatric patient with a distal lower extremity traumatic wound using a dermal regeneration template and NPWT. AB - Degloving injuries are common in trauma and represent a spectrum of complex wounds, the management of which may be highly challenging especially in the paediatric population. In severe injuries leading to wounds reaching tendon and bone, vascularity is compromised precluding traditional wound management, and sometimes necessitating amputation. This report highlights the use of a dermal regeneration template combined with vacuum-assisted closure (VAC) in the treatment of complex traumatic degloving wounds. Here, we present a case of a five-year-old boy who sustained a high-energy shear injury to his lower extremity that resulted in an extensive degloving wound involving the distal third of his leg and the dorsum of his foot. After debridement, the patient underwent VAC combined with a dermal skin substitute placement, followed by split-thickness skin grafting. The extremity healed with no complications and without the need for amputation or flap reconstruction, achieving satisfactory recovery of range of motion and favourable cosmetic results. PMID- 25289653 TI - Successful use of a gastrocnemius flap for an exposed PTFE femorodistal graft: a case report. AB - Peripheral vascular disease (PVD) is a condition requiring aggressive management to minimise the associated increased morbidity and mortality. Femoro-distal bypass grafting is used in patients with extensive occlusion affecting the crural arteries and poor limb function, but is associated with infection, wound dehiscence and graft exposure. We report a case of a 73-year-old male with history of PVD and occluded ipsilateral femoro-distal bypass graft who underwent limb salvage surgery with a left 6 mm heparin-bonded polytetrafluoroethylene femoro-distal bypass graft in September 2011. He later presented with exposure of the graft over the lateral aspect of the knee following wound dehiscence. During surgery, the exposed portion of the graft was covered by a lateral gastrocnemius muscle flap with an overlying split thickness skin graft. Minor donor site healing problems were noted, but he otherwise made an excellent recovery. While gastrocnemius muscle flaps have been used to cover soft tissue tibial defects secondary to sarcoma and exposed knee joint prostheses, our case adds to the limited literature demonstrating successful salvage of an exposed synthetic graft as a viable alternative to amputation. We therefore recommend prompt referral to plastic services for the management of these complex wounds. PMID- 25289654 TI - Periodontal health of anterior teeth with two types of fixed retainers. AB - OBJECTIVE: To compare the periodontal health of maxillary and mandibular anterior teeth retained with two types of fixed retainers. MATERIALS AND METHODS: A fixed straight retainer (SR) group had 39 subjects, and a fixed wave retainer (WR) group had 35 subjects. Subjects were between the ages of 13 and 22 years and had been in fixed retention for 2 to 4 years. Pocket probing depths, bleeding on probing, plaque index, calculus index, recession, and gingival crevicular fluid volume were compared between the two retainer groups. A four-question oral hygiene survey was given to each subject. The Mann-Whitney U-test and Fisher exact test was used to analyze the data. RESULTS: There was no clinically significant difference between the retainer groups regarding plaque index, gingival crevicular fluid volume, calculus index, recession, bleeding on probing, and pocket probing depths. A statistically significant increase in the reported frequency of flossing (P = .006) and ease of flossing (P < .001) was associated with the WR group. There was no significant difference between the groups in reported frequency of brushing and comfort of the retainer. CONCLUSIONS: Under the conditions of this study, no clinical difference was found in the periodontal health of anterior teeth retained with a SR or WR for a period of 2 to 4 years. Subjects in the WR group reported an increase in frequency and ease of flossing. PMID- 25289656 TI - The rational imperative to aim high. PMID- 25289655 TI - Effects of laser vs ultrasound on bone healing after distraction osteogenesis: A histomorphometric analysis. AB - OBJECTIVE: To assess the effects of low-level laser irradiation vs ultrasound irradiation on bone healing after distraction osteogenesis. MATERIALS AND METHODS: Distraction osteogenesis was performed with rapid maxillary expansion devices (Hyrax-Morelli, Sorocaba, Sao Paulo Brazil) in 24 rabbits (Oryctolagus cuniculus). After a 2-day latency period, the distraction devices were activated for 10 days at a rate of 1 mm/d. Four groups of six animals were treated as follows: (1) control, (2) laser irradiation on the right side, (3) ultrasound irradiation on the right side, and (4) laser irradiation on the right side and ultrasound on the left side. Histomorphometric analysis was used to assess the bone healing area. Analysis of variance was used to perform the statistical analyses. RESULTS: The influence of low-intensity laser associated with ultrasound irradiation on bone healing was statistically significant. The analyses showed the greatest amount of bone healing in the jaws of animals in group 4, which received treatment with both ultrasound and laser. CONCLUSION: This study concluded that bone healing is accelerated with the application of laser irradiation. The greatest effects were observed with combined ultrasound and laser treatment. PMID- 25289657 TI - Associations of inflammatory cytokines with choroidal neovascularization in highly myopic eyes. AB - PURPOSE: To determine the relationships between the levels of intraocular inflammatory cytokines and the clinical characteristics of myopic choroidal neovascularization (mCNV) in eyes with myopic maculopathy. METHODS: One hundred eyes of 100 cases, including 51 mCNV eyes, 14 highly myopic eyes without choroidal neovascularization, and 35 normal subjects, were studied. The intraocular levels of choroidal neovascularization-related cytokines, like vascular endothelial growth factor, MCP-1, IL-8, IL-10, and IL-23, were determined. RESULTS: The levels of vascular endothelial growth factor and IL-8 were significantly higher in eyes with mCNV than in high myopia eyes without mCNV with significant odds ratio of 2.00 and 2.25 per quartile, respectively (P < 0.05). When myopic lesions of patients with mCNV were classified into 3 categories based on the severity, IL-8 and MCP-1 were significantly elevated depending on the presence of maculopathy (P < 0.05). Vascular endothelial growth factor was significantly elevated in eyes of Category 2. An advancement of the maculopathy category was significantly associated with the need for multiple treatment of intravitreal bevacizumab (P < 0.05). In 12 eyes that required multiple intravitreal bevacizumab, the MCP-1 level was significantly elevated. CONCLUSION: The significant associations of mCNV in highly myopic eyes with elevated levels of vascular endothelial growth factor or inflammatory cytokines and maculopathy lesions strongly suggest an involvement of inflammation in the etiology of mCNVs. PMID- 25289659 TI - Thyroid nodule morphology affects the efficacy of ultrasound-guided interstitial laser ablation: a nested case-control study. AB - PURPOSE: The literature reports a wide range of percentages of ablation in the treatment of thyroid nodules. The aim of this nested case-control study was to evaluate whether the different morphological (well-defined vs. agglomerate) characteristics of nodules affect the success rate. MATERIALS AND METHODS: We selected 20 patients with a single and /or dominant well-defined nodule (group 1) and 20 with a nodular formation resulting from the fusion of multiple nodules (group 2). All the nodules were treated by the laser method receiving the same energy. RESULTS: At 6 months, patients in group 1 showed a greater decrease in volume than those in group 2. These differences were more evident after 12 months. CONCLUSIONS: Our study demonstrates that the efficacy of laser treatment can be predicted by nodule morphology and contributes to explaining the wide differences in the percentages of ablation reported in literature. PMID- 25289658 TI - Locomotion of inchworm-inspired robot made of smart soft composite (SSC). AB - A soft-bodied robot made of smart soft composite with inchworm-inspired locomotion capable of both two-way linear and turning movement has been proposed, developed, and tested. The robot was divided into three functional parts based on the different functions of the inchworm: the body, the back foot, and the front foot. Shape memory alloy wires were embedded longitudinally in a soft polymer to imitate the longitudinal muscle fibers that control the abdominal contractions of the inchworm during locomotion. Each foot of the robot has three segments with different friction coefficients to implement the anchor and sliding movement. Then, utilizing actuation patterns between the body and feet based on the looping gait, the robot achieves a biomimetic inchworm gait. Experiments were conducted to evaluate the robot's locomotive performance for both linear locomotion and turning movement. Results show that the proposed robot's stride length was nearly one third of its body length, with a maximum linear speed of 3.6 mm s(-1), a linear locomotion efficiency of 96.4%, a maximum turning capability of 4.3 degrees per stride, and a turning locomotion efficiency of 39.7%. PMID- 25289661 TI - The effectiveness of suggestive techniques in reducing postoperative side effects: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Suggestive interventions such as hypnosis and therapeutic suggestions are frequently used to alleviate surgical side effects; however, the effectiveness of therapeutic suggestion intervention has not yet been systematically evaluated. In the present study, we tested the hypotheses that (1) suggestive interventions are useful for reducing postoperative side effects; (2) therapeutic suggestions are comparable in effectiveness to hypnosis; (3) live presentation is more effective than recordings; and (4) suggestive interventions would be equally effective used in minor and major surgeries. METHODS: We performed random effect meta-analysis with meta-regression and sensitivity analysis by moderating factors on a pool of 26 studies meeting the inclusion criteria (N = 1890). Outcome variables were postoperative anxiety, pain intensity, pain medication requirement, and nausea. RESULTS: Suggestive interventions reduced postoperative anxiety (g = 0.40; 99% confidence interval [CI] = 0.13-0.66; P < 0.001) and pain intensity (g = 0.25; 99% CI = 0.00-0.50; P = 0.010), but did not significantly affect postoperative analgesic drug consumption (g = 0.16; 99% CI = -0.16 to 0.47; P = 0.202) and nausea (g = 0.38; 99% CI = -0.06 to 0.81; P = 0.026). No significant differences were found for intervention type, presentation method, and severity of surgery; however, sensitivity analysis only supported the effectiveness of hypnosis (g = 0.62; 99% CI = 0.31-0.92; P < 0.001) and live presentation (g = 0.55; 99% CI = 0.23-0.88; P < 0.001) for decreasing postoperative anxiety, and that of live presentation for alleviating postoperative pain (g = 0.44; 99% CI = 0.07-0.82; P = 0.002). Sensitivity analyses also suggested that suggestive interventions are only effective for decreasing pain intensity during minor surgical procedures (g = 0.39; 99% CI = 0.00-0.78; P = 0.009). CONCLUSIONS: Suggestive techniques might be useful tools to alleviate postoperative anxiety and pain; however, strength of the evidence is weak because of possible bias in the reviewed articles. The lack of access to within-subjects data and the overlap between moderator conditions also limit the scope of the analysis. More methodologically correct studies are required with sensitivity to moderating factors and to within-subjects changes. For clinical purposes, we advise the use of hypnosis with live presentation to reduce postoperative anxiety and pain, until convincing evidence is uncovered for the effectiveness of therapeutic suggestions and recorded presentation. Pain management with adjunct suggestive interventions is mostly encouraged in minor rather than major surgeries. PMID- 25289662 TI - The effect of the presence and characteristics of an outlying group on exposure outcome associations. AB - OBJECTIVES: Physical exposures (eg, lifting or bending) are believed to be risk factors for low-back pain (LBP), but the literature is inconsistent. Exposure and LBP prevalence differ considerably between occupations, and exposure-outcome associations could be severely modified by the presence of particular occupational groups. We aimed to investigate the influence of such outlying groups on the properties of associations between exposure and LBP. METHODS: Lifting and trunk flexion were observed for 371 of 1131 workers within 19 groups. LBP was obtained from all workers during three follow-up years. Both exposure variables were associated with LBP (P<0.01) in this parent dataset. By removing the 19 groups one-by-one and performing logistic regressions analysis on the 18 remaining groups, we demonstrated that one group, mainly road workers, with outlying exposures and LBP prevalence substantially affected the exposure-outcome association in the total population. In order to further examine this phenomenon, we assessed, by simulation, the influence of realistic sizes (n=4, 8, 16, 32, 64, 128), mean exposures (e=2000, 3000, 4000 lifts and e=30, 40, 50% trunk flexion time) and LBP prevalences (p=70, 80, 90, 100%) of the outlying group on the strength and certainty of the eventual relationship between exposure and LBP. For each combination of n, e and p, 3000 virtual studies were constructed, including the simulated group together with the other 18 original groups from the parent data-set. Average odds ratios (OR), 95% confidence limits, and power (P<0.05) were calculated across these 3000 studies as measures of the properties of each virtual study design. RESULTS: OR were attenuated more towards 1 and power decreased with smaller values of n, e, and p in the outlying group. Changes in group size and prevalence had a larger influence on OR and power than changes in mean exposure. CONCLUSIONS: The size and characteristics of a single group with high exposure and outcome prevalence can strongly influence both the OR point estimate and the likelihood of obtaining significant exposure-outcome associations in studies of large populations. These findings can guide interpretations of prior epidemiological studies and support informed design of future studies. PMID- 25289663 TI - Can genetic variability in alpha-tocopherol bioavailability explain the heterogeneous response to alpha-tocopherol supplements? AB - Both vitamin E (VE) consumption and blood VE status have been negatively associated with the incidence of degenerative diseases and some cancers. However, the response to VE supplementation is very variable among individuals. This could be due to interindividual variability in VE bioavailability, due, at least partly, to genetic variations in genes involved in VE metabolism. Thus, the main objective was to identify single nucleotide polymorphisms (SNPs) that may be involved in the interindividual variability in alpha-tocopherol (TOL) bioavailability. The postprandial chylomicron (CM) TOL response (area under the curve of the postprandial CM TOL concentration) to a TOL-rich meal was highly variable (coefficient of variation=81%; n=38). This response was positively correlated with the fasting plasma TOL concentration (r=0.5, p=0.004). A significant (p=1.8*10(-8)) partial least-squares regression model, which included 28 SNPs in 11 genes, explained 82% of this response. First evidence that the interindividual variability in TOL bioavailability is, at least partly, modulated by a combination of SNPs. TOL bioavailability is, at least partly, modulated by genetic variations that can affect long-term TOL status. This allows us to propose a new hypothesis that links the biological response to VE supplementation with one's individual genetic characteristics. PMID- 25289664 TI - Magnetic nanoparticles from Magnetospirillum gryphiswaldense increase the efficacy of thermotherapy in a model of colon carcinoma. AB - Magnetic nanoparticles (MNPs) are capable of generate heating power under the influence of alternating magnetic fields (AMF); this behaviour recently opened new scenarios for advanced biomedical applications, mainly as new promising tumor therapies. In this paper we have tested magnetic nanoparticles called magnetosomes (MNs): a class of MNPs naturally produced by magnetotactic bacteria. We extracted MNs from Magnetospirillum gryphiswaldense strain MSR-1 and tested the interaction with cellular elements and anti-neoplastic activity both in vitro and in vivo, with the aim of developing new therapeutic approaches for neoplastic diseases. In vitro experiments performed on Human Colon Carcinoma HT-29 cell cultures demonstrated a strong uptake of MNs with no evident signs of cytotoxicity and revealed three phases in the interaction: adherence, transport and accumulation in Golgi vesicles. In vivo studies were performed on subcutaneous tumors in mice; in this model MNs are administered by direct injection in the tumor volume, then a protocol consisting of three exposures to an AMF rated at 187 kHz and 23kA/m is carried out on alternate days, over a week. Tumors were monitored by Magnetic Resonance Imaging (MRI) to obtain information about MNs distribution and possible tissue modifications induced by hyperthermia. Histological analysis showed fibrous and necrotic areas close to MNs injection sites in mice subjected to a complete thermotherapy protocol. These results, although concerning a specific tumor model, could be useful to further investigate the feasibility and efficacy of protocols based on MFH. Magnetic nanoparticles naturally produced and extracted from bacteria seem to be promising candidates for theranostic applications in cancer therapy. PMID- 25289665 TI - Non-invasive prenatal chromosomal aneuploidy testing--clinical experience: 100,000 clinical samples. AB - OBJECTIVE: As the first laboratory to offer massively parallel sequencing-based noninvasive prenatal testing (NIPT) for fetal aneuploidies, Sequenom Laboratories has been able to collect the largest clinical population experience data to date, including >100,000 clinical samples from all 50 U.S. states and 13 other countries. The objective of this study is to give a robust clinical picture of the current laboratory performance of the MaterniT21 PLUS LDT. STUDY DESIGN: The study includes plasma samples collected from patients with high-risk pregnancies in our CLIA-licensed, CAP-accredited laboratory between August 2012 to June 2013. Samples were assessed for trisomies 13, 18, 21 and for the presence of chromosome Y-specific DNA. Sample data and ad hoc outcome information provided by the clinician was compiled and reviewed to determine the characteristics of this patient population, as well as estimate the assay performance in a clinical setting. RESULTS: NIPT patients most commonly undergo testing at an average of 15 weeks, 3 days gestation; and average 35.1 years of age. The average turnaround time is 4.54 business days and an overall 1.3% not reportable rate. The positivity rate for Trisomy 21 was 1.51%, followed by 0.45% and 0.21% rate for Trisomies 18 and 13, respectively. NIPT positivity rates are similar to previous large clinical studies of aneuploidy in women of maternal age >= 35 undergoing amniocentesis. In this population 3519 patients had multifetal gestations (3.5%) with 2.61% yielding a positive NIPT result. CONCLUSION: NIPT has been commercially offered for just over 2 years and the clinical use by patients and clinicians has increased significantly. The risks associated with invasive testing have been substantially reduced by providing another assessment of aneuploidy status in high-risk patients. The accuracy and NIPT assay positivity rate are as predicted by clinical validations and the test demonstrates improvement in the current standard of care. PMID- 25289666 TI - Simulation studies as designed experiments: the comparison of penalized regression models in the "large p, small n" setting. AB - New algorithms are continuously proposed in computational biology. Performance evaluation of novel methods is important in practice. Nonetheless, the field experiences a lack of rigorous methodology aimed to systematically and objectively evaluate competing approaches. Simulation studies are frequently used to show that a particular method outperforms another. Often times, however, simulation studies are not well designed, and it is hard to characterize the particular conditions under which different methods perform better. In this paper we propose the adoption of well established techniques in the design of computer and physical experiments for developing effective simulation studies. By following best practices in planning of experiments we are better able to understand the strengths and weaknesses of competing algorithms leading to more informed decisions about which method to use for a particular task. We illustrate the application of our proposed simulation framework with a detailed comparison of the ridge-regression, lasso and elastic-net algorithms in a large scale study investigating the effects on predictive performance of sample size, number of features, true model sparsity, signal-to-noise ratio, and feature correlation, in situations where the number of covariates is usually much larger than sample size. Analysis of data sets containing tens of thousands of features but only a few hundred samples is nowadays routine in computational biology, where "omics" features such as gene expression, copy number variation and sequence data are frequently used in the predictive modeling of complex phenotypes such as anticancer drug response. The penalized regression approaches investigated in this study are popular choices in this setting and our simulations corroborate well established results concerning the conditions under which each one of these methods is expected to perform best while providing several novel insights. PMID- 25289667 TI - Kernel density surface modelling as a means to identify significant concentrations of vulnerable marine ecosystem indicators. AB - The United Nations General Assembly Resolution 61/105, concerning sustainable fisheries in the marine ecosystem, calls for the protection of vulnerable marine ecosystems (VME) from destructive fishing practices. Subsequently, the Food and Agriculture Organization (FAO) produced guidelines for identification of VME indicator species/taxa to assist in the implementation of the resolution, but recommended the development of case-specific operational definitions for their application. We applied kernel density estimation (KDE) to research vessel trawl survey data from inside the fishing footprint of the Northwest Atlantic Fisheries Organization (NAFO) Regulatory Area in the high seas of the northwest Atlantic to create biomass density surfaces for four VME indicator taxa: large-sized sponges, sea pens, small and large gorgonian corals. These VME indicator taxa were identified previously by NAFO using the fragility, life history characteristics and structural complexity criteria presented by FAO, along with an evaluation of their recovery trajectories. KDE, a non-parametric neighbour-based smoothing function, has been used previously in ecology to identify hotspots, that is, areas of relatively high biomass/abundance. We present a novel approach of examining relative changes in area under polygons created from encircling successive biomass categories on the KDE surface to identify "significant concentrations" of biomass, which we equate to VMEs. This allows identification of the VMEs from the broader distribution of the species in the study area. We provide independent assessments of the VMEs so identified using underwater images, benthic sampling with other gear types (dredges, cores), and/or published species distribution models of probability of occurrence, as available. For each VME indicator taxon we provide a brief review of their ecological function which will be important in future assessments of significant adverse impact on these habitats here and elsewhere. PMID- 25289668 TI - Angiopoietin-like 4 is over-expressed in rheumatoid arthritis patients: association with pathological bone resorption. AB - INTRODUCTION: Osteoclasts are responsible for the bone loss associated with rheumatoid arthritis (RA). The secreted adipokine angiopoietin-like 4 (ANGPTL4) specifically increases osteoclast-mediated bone resorption. We have investigated expression of ANGPTL4 and its regulatory transcription factor, hypoxia-inducible factor-1 alpha (HIF-1alpha), in osteoclasts and other cells within rheumatoid synovium. We have also examined whether circulating levels of ANGPTL4 differ in RA patients compared with that in normal controls or patients with osteoarthritis (OA). RESULTS: Immunohistochemical analysis revealed that bone-apposing osteoclasts within the rheumatoid synovium express both ANGPTL4 and HIF-1alpha. ANGPTL4 was also strongly expressed in synovial lining cells, endothelial cells, stromal cells, CD68+ macrophages and plasma cells within RA synovium. Little ANGPTL4 was evident in normal synovial tissue. This reflected the over-expression of HIF-1alpha in rheumatoid versus normal synovial tissue. The concentration of ANGPTL4 was higher in both the serum and the synovial fluid of RA patients than in patients with OA or normal controls. High serum ANGPTL4 associated with elevated levels of the serum marker of bone resorption, receptor activator for nuclear factor kappaB ligand (RANKL). CONCLUSIONS: Over-expression of ANGPTL4 in multiple cell types within the rheumatoid synovium potentially provides a local pool of ANGPTL4 to stimulate osteoclast-mediated bone resorption in RA. Additionally, correlation of high serum ANGPTL4 with circulating RANKL suggests that ANGPTL4 may represent a novel marker for bone destruction in RA. PMID- 25289669 TI - Quantifying forearm muscle activity during wrist and finger movements by means of multi-channel electromyography. AB - The study of hand and finger movement is an important topic with applications in prosthetics, rehabilitation, and ergonomics. Surface electromyography (sEMG) is the gold standard for the analysis of muscle activation. Previous studies investigated the optimal electrode number and positioning on the forearm to obtain information representative of muscle activation and robust to movements. However, the sEMG spatial distribution on the forearm during hand and finger movements and its changes due to different hand positions has never been quantified. The aim of this work is to quantify 1) the spatial localization of surface EMG activity of distinct forearm muscles during dynamic free movements of wrist and single fingers and 2) the effect of hand position on sEMG activity distribution. The subjects performed cyclic dynamic tasks involving the wrist and the fingers. The wrist tasks and the hand opening/closing task were performed with the hand in prone and neutral positions. A sensorized glove was used for kinematics recording. sEMG signals were acquired from the forearm muscles using a grid of 112 electrodes integrated into a stretchable textile sleeve. The areas of sEMG activity have been identified by a segmentation technique after a data dimensionality reduction step based on Non Negative Matrix Factorization applied to the EMG envelopes. The results show that 1) it is possible to identify distinct areas of sEMG activity on the forearm for different fingers; 2) hand position influences sEMG activity level and spatial distribution. This work gives new quantitative information about sEMG activity distribution on the forearm in healthy subjects and provides a basis for future works on the identification of optimal electrode configuration for sEMG based control of prostheses, exoskeletons, or orthoses. An example of use of this information for the optimization of the detection system for the estimation of joint kinematics from sEMG is reported. PMID- 25289670 TI - Leukemogenic Ptpn11 allele causes defective erythropoiesis in mice. AB - Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by PTPN11, regulates signaling networks and cell fate in many tissues. Expression of oncogenic PTPN11 in the hematopoietic compartment causes myeloproliferative neoplasm (MPN) in humans and mice. However, the stage-specific effect(s) of mutant Ptpn11 on erythroid development have remained unknown. We found that expression of an activated, leukemogenic Ptpn11 allele, Ptpn11D61Y, specifically in the erythroid lineage causes dyserythropoiesis in mice. Ptpn11D61Y progenitors produce excess cKIT+ CD71+ Ter119- cells and aberrant numbers of cKITl degrees CD71+ erythroblasts. Mutant erythroblasts show elevated activation of ERK, AKT and STAT3 in response to EPO stimulation, and MEK inhibitor treatment blocks Ptpn11D61Y-evoked erythroid hyperproliferation in vitro. Thus, the expression of oncogenic Ptpn11 causes dyserythropoiesis in a cell-autonomous manner in vivo. PMID- 25289671 TI - Early treatment response in non-small cell lung cancer patients using diffusion weighted imaging and functional diffusion maps--a feasibility study. AB - OBJECTIVE: The aim of this study was to prospectively evaluate the feasibility of monitoring treatment response to chemotherapy in patients with non-small cell lung carcinoma using functional diffusion maps (fDMs). MATERIALS AND METHODS: This study was approved by the Cantonal Research Ethics Committee and informed written consent was obtained from all patients. Nine patients (mean age = 66 years; range = 53-76 years, 5 females, 4 males) with overall 13 lesions were included. Imaging was performed within two weeks before initiation of chemotherapy and at one, two, and six weeks after initiation of chemotherapy. Imaging included a respiratory-triggered diffusion-weighted sequence including three b-factors (100, 600, and 800 s/mm2). Treatment response was defined by change in tumor diameter on computed tomography (CT) after two cycles of chemotherapy. Changes in the apparent diffusion coefficient (ADC) on a per-lesion basis and the percentages of voxel with significantly increased or decreased ADCs on fDMs were analyzed using repeated measures analysis of variance (ANOVA). Changes in tumor size were used as covariate to examine the ability of ADCs and fDM parameters to predict treatment response. RESULTS: Repeated measures ANOVA revealed that the percentage of voxels with increased ADCs on fDMs (p = 0.002) as well as the mean ADC increase (p = 0.011) were significantly higher in good responders with a large reduction in tumor size on CT. CONCLUSION: Our results indicate that the percentage of voxels with significantly increased ADCs on fDMs seems to be a promising biomarker for early prediction of treatment response in patients with non-small cell lung carcinoma. Contrary to averaged values, this approach allows the spatial heterogeneity of treatment response to be resolved. PMID- 25289672 TI - Whole-exome sequencing to decipher the genetic heterogeneity of hearing loss in a Chinese family with deaf by deaf mating. AB - Inherited deafness has been shown to have high genetic heterogeneity. For many decades, linkage analysis and candidate gene approaches have been the main tools to elucidate the genetics of hearing loss. However, this associated study design is costly, time-consuming, and unsuitable for small families. This is mainly due to the inadequate numbers of available affected individuals, locus heterogeneity, and assortative mating. Exome sequencing has now become technically feasible and a cost-effective method for detection of disease variants underlying Mendelian disorders due to the recent advances in next-generation sequencing (NGS) technologies. In the present study, we have combined both the Deafness Gene Mutation Detection Array and exome sequencing to identify deafness causative variants in a large Chinese composite family with deaf by deaf mating. The simultaneous screening of the 9 common deafness mutations using the allele specific PCR based universal array, resulted in the identification of the 1555A>G in the mitochondrial DNA (mtDNA) 12S rRNA in affected individuals in one branch of the family. We then subjected the mutation-negative cases to exome sequencing and identified novel causative variants in the MYH14 and WFS1 genes. This report confirms the effective use of a NGS technique to detect pathogenic mutations in affected individuals who were not candidates for classical genetic studies. PMID- 25289673 TI - Expression of protease-activated receptor 1 and 2 and anti-tubulogenic activity of protease-activated receptor 1 in human endothelial colony-forming cells. AB - Endothelial colony-forming cells (ECFCs) are obtained from the culture of human peripheral blood mononuclear cell (hPBMNC) fractions and are characterised by high proliferative and pro-vasculogenic potential, which makes them of great interest for cell therapy. Here, we describe the detection of protease-activated receptor (PAR) 1 and 2 amongst the surface proteins expressed in ECFCs. Both receptors are functionally coupled to extracellular signal-regulated kinase (ERK) 1 and 2, which become activated and phosphorylated in response to selective PAR1- or PAR2-activating peptides. Specific stimulation of PAR1, but not PAR2, significantly inhibits capillary-like tube formation by ECFCs in vitro, suggesting that tubulogenesis is negatively regulated by proteases able to stimulate PAR1 (e.g. thrombin). The activation of ERKs is not involved in the regulation of tubulogenesis in vitro, as suggested by use of the MEK inhibitor PD98059 and by the fact that PAR2 stimulation activates ERKs without affecting capillary tube formation. Both qPCR and immunoblotting showed a significant downregulation of vascular endothelial growth factor 2 (VEGFR2) in response to PAR1 stimulation. Moreover, the addition of VEGF (50-100 ng/ml) but not basic Fibroblast Growth Factor (FGF) (25-100 ng/ml) rescued tube formation by ECFCs treated with PAR1-activating peptide. Therefore, we propose that reduction of VEGF responsiveness resulting from down-regulation of VEGFR2 is underlying the anti-tubulogenic effect of PAR1 activation. Although the role of PAR2 remains elusive, this study sheds new light on the regulation of the vasculogenic activity of ECFCs and suggests a potential link between adult vasculogenesis and the coagulation cascade. PMID- 25289674 TI - Is the effect of aerobic exercise on cognition a placebo effect? AB - A number of studies and meta-analyses conclude that aerobic fitness (walking) interventions improve cognition. Such interventions typically compare improvements from these interventions to an active control group in which participants engage in non-aerobic activities (typically stretching and toning) for an equivalent amount of time. However, in the absence of a double-blind design, the presence of an active control group does not necessarily control for placebo effects; participants might expect different amounts of improvement for the treatment and control interventions. We conducted a large survey to explore whether people expect greater cognitive benefits from an aerobic exercise intervention compared to a control intervention. If participants expect greater improvement following aerobic exercise, then the benefits of such interventions might be due in part to a placebo effect. In general, expectations did not differ between aerobic and non-aerobic interventions. If anything, some of the results suggest the opposite (e.g., respondents expected the control, non-aerobic intervention to yield bigger memory gains). These results provide the first evidence that cognitive improvements following aerobic fitness training are not due to differential expectations. PMID- 25289675 TI - Deep sequencing reveals low incidence of endogenous LINE-1 retrotransposition in human induced pluripotent stem cells. AB - Long interspersed element-1 (LINE-1 or L1) retrotransposition induces insertional mutations that can result in diseases. It was recently shown that the copy number of L1 and other retroelements is stable in induced pluripotent stem cells (iPSCs). However, by using an engineered reporter construct over-expressing L1, another study suggests that reprogramming activates L1 mobility in iPSCs. Given the potential of human iPSCs in therapeutic applications, it is important to clarify whether these cells harbor somatic insertions resulting from endogenous L1 retrotransposition. Here, we verified L1 expression during and after reprogramming as well as potential somatic insertions driven by the most active human endogenous L1 subfamily (L1Hs). Our results indicate that L1 over expression is initiated during the reprogramming process and is subsequently sustained in isolated clones. To detect potential somatic insertions in iPSCs caused by L1Hs retotransposition, we used a novel sequencing strategy. As opposed to conventional sequencing direction, we sequenced from the 3' end of L1Hs to the genomic DNA, thus enabling the direct detection of the polyA tail signature of retrotransposition for verification of true insertions. Deep coverage sequencing thus allowed us to detect seven potential somatic insertions with low read counts from two iPSC clones. Negative PCR amplification in parental cells, presence of a polyA tail and absence from seven L1 germline insertion databases highly suggested true somatic insertions in iPSCs. Furthermore, these insertions could not be detected in iPSCs by PCR, likely due to low abundance. We conclude that L1Hs retrotransposes at low levels in iPSCs and therefore warrants careful analyses for genotoxic effects. PMID- 25289677 TI - Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus leukemia effect. AB - We have recently reported that interferon gamma receptor deficient (IFNgammaR-/-) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNgammaR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNgammaR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNgammaR-/- T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases. PMID- 25289679 TI - Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex. AB - Hedgehog (Hh) signalling is crucial for developmental patterning and tissue homeostasis. In Drosophila, Hh signalling is mediated by a bifunctional transcriptional mediator, called Cubitus interruptus (Ci). Protein Kinase A (PKA) dependent phosphorylation of the serpentine protein Smoothened (Smo) leads to Ci activation, whereas PKA-dependent phosphorylation of Ci leads to the formation of Ci repressor form. The mechanism that switches PKA from an activator to a repressor is not known. Here we show that Hh signalling activation causes PKA to switch its substrates from Ci to Smo within the Hh signalling complex (HSC). In particular, Hh signalling increases the level of Smo, which then outcompetes Ci for association with PKA and causes a switch in PKA substrate recognition. We propose a new model in which the PKA is constitutively present and active within the HSC, and in which the relative levels of Ci and Smo within the HSC determine differential activation and cellular response to Hh signalling. PMID- 25289678 TI - Giardia duodenalis infection reduces granulocyte infiltration in an in vivo model of bacterial toxin-induced colitis and attenuates inflammation in human intestinal tissue. AB - Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a predominant cause of waterborne diarrheal disease that may lead to post-infectious functional gastrointestinal disorders. Although Giardia-infected individuals could carry as much as 106 trophozoites per centimetre of gut, their intestinal mucosa is devoid of overt signs of inflammation. Recent studies have shown that in endemic countries where bacterial infectious diseases are common, Giardia infections can protect against the development of diarrheal disease and fever. Conversely, separate observations have indicated Giardia infections may enhance the severity of diarrheal disease from a co-infecting pathogen. Polymorphonuclear leukocytes or neutrophils (PMNs) are granulocytic, innate immune cells characteristic of acute intestinal inflammatory responses against bacterial pathogens that contribute to the development of diarrheal disease following recruitment into intestinal tissues. Giardia cathepsin B cysteine proteases have been shown to attenuate PMN chemotaxis towards IL-8/CXCL8, suggesting Giardia targets PMN accumulation. However, the ability of Giardia infections to attenuate PMN accumulation in vivo and how in turn this effect may alter the host inflammatory response in the intestine has yet to be demonstrated. Herein, we report that Giardia infection attenuates granulocyte tissue infiltration induced by intra rectal instillation of Clostridium difficile toxin A and B in an isolate dependent manner. This attenuation of granulocyte infiltration into colonic tissues paralled decreased expression of several cytokines associated with the recruitment of PMNs. Giardia trophozoite isolates that attenuated granulocyte infiltration in vivo also decreased protein expression of cytokines released from inflamed mucosal biopsy tissues collected from patients with active Crohn's disease, including several cytokines associated with PMN recruitment. These results demonstrate for the first time that certain Giardia infections may attenuate PMN accumulation by decreasing the expression of the mediators responsible for their recruitment. PMID- 25289680 TI - BFMP: a method for discretizing and visualizing pyranose conformations. AB - We report a new classification method for pyranose ring conformations called Best fit, Four-Membered Plane (BFMP), which describes pyranose ring conformations based on reference planes defined by four atoms. The method is able to characterize all asymmetrical and symmetrical shapes of a pyran ring, is readily automated, easy to interpret, and maps trivially to IUPAC definitions. It also provides a qualitative measurement of the distortion of the ring. Example applications include the analysis of data from crystal structures and molecular dynamics simulations. PMID- 25289681 TI - Physiological reactivity during autobiographical narratives in older adults: the roles of depression and anxiety. AB - OBJECTIVES: Physiological reactivity (PR) describes the change in physiological functioning (e.g., heart rate, blood pressure, pulse pressure) that occurs after the induction of a stressful task. This study aims to understand the influence of mental health symptoms on patterns of PR during autobiographical narratives in an older adult sample. METHOD: Eighty older adults completed self-report measures regarding their symptoms of depression and anxiety. Next, their blood pressure was recorded while they completed two verbal autobiographical narratives. RESULTS: During the positive narrative, anxiety was positively associated with increased PR while depression was negatively associated with PR. During the negative narrative, a significant interaction occurred whereby anxiety was significantly positively associated with PR for those participants low in depression. DISCUSSION: The above results are explained in the context of the Tripartite Model of Depression and Anxiety, which predicts different patterns of PR as a function of mental health symptoms. Limitations and future directions are also discussed. PMID- 25289682 TI - The Millennium child with autism: early childhood trajectories for health, education and economic wellbeing. AB - OBJECTIVE: Most of what we know about children with autism spectrum disorder (ASD) is based on post-diagnostic, retrospective, self-select studies. Oftentimes, there is no direct comparison between trajectories of children with ASD and children without ASD. METHODS: To circumvent both of these problems, the present secondary data analysis utilised a large-scale longitudinal general population survey of children born in the year 2000 (i.e. the Millennium Cohort Study; MCS; n = 18,522). Bi-annual MCS data were available from five data sweeps (children aged 9 months to 11 years of age). RESULTS: Pre-diagnostic data showed early health problems differentiated children later diagnosed with autism from non-diagnosed peers. Prevalence was much higher than previously estimated (3.5% for 11-year olds). Post-diagnosis, trajectories deteriorated significantly for the children with ASD and their families in relation to education, health and economic wellbeing. CONCLUSION: These findings raise many issues for service delivery and the rights of persons with disabilities and their families. PMID- 25289683 TI - The X-C...pi (X = F, Cl, Br, CN) carbon bond. AB - High-level ab initio calculations have been used to study the interactions between the CH3 group of CH3X (X = F, Cl, Br, CN) molecules and pi-electrons. These interactions are important because of the abundance of both the CH3 groups and pi-electrons in biological systems. Complexes between C2H4/C2H2 and CH3X molecules have been used as model systems. Various theoretical methods such as atoms in molecules theory, reduced density gradient analysis, and natural bond orbital analysis have been used to discern these interactions. These analyses show that the interaction of the pi-electrons with the CH3X molecules leads to the formation of X-C...pi carbon bonds. Similar complexes with other tetrel molecules, SiH3X and GeH3X, have also been considered. PMID- 25289684 TI - Analysis of web height ratios according to age and sex. AB - Each component of the web space, a three-dimensional structure, should be carefully created during reconstruction of web space loss. One of these web space components is the web height. In this study, the dorsal view of subjects' hands was analyzed to determine the web height ratios. The web height ratios were then compared with respect to age and sex. The second and third web height ratios differed between adult men and women and between children and adults. However, no differences were observed among children. This study is unique because it focuses on the web height ratios of all web spaces according to age and sex and provides a very easy-to-use scale that may help surgeons to perform web space reconstruction. Moreover, the present study adds to the literature by providing information on the first web height ratios of the hand. PMID- 25289685 TI - Complications in skin grafts when continuing antithrombotic therapy prior to cutaneous surgery requiring skin grafting: A systematic review. AB - The risk of postoperative bleeding and wound healing complications in skin grafts among anticoagulated patients undergoing cutaneous surgery has not been firmly established. The objective was to examine the literature and assess the risk of postoperative bleeding or wound healing complications in skin grafts among anticoagulated patients, compared with patients who discontinue or patients who are not receiving antithrombotic therapy prior to cutaneous surgery requiring skin grafting. A systematic review examining the effect of antithrombotic therapy on cutaneous surgery was performed according to the PRISMA-guidelines. PubMed and Embase databases were primarily searched for relevant literature in the period from the start date of each database to 2014. A total of eight studies representing 443 patients met criteria for inclusion. No randomised controlled trials were found; the included studies were of prospective and retrospective design. Most of the reviewed studies suggest that the use of antithrombotic therapy can increase the risk of bleeding complications in skin grafts. These complications are only wound threatening and not life threatening. Therefore, this is of concern mostly in terms of hemostasis by the surgeon and good pressure dressings. Care should be taken when operating on anticoagulated patients undergoing cutaneous surgery requiring skin grafting. However, graft failure is rare and, given the risk of thrombotic events, the reviewed studies recommend continuing all medically necessary antithrombotic therapy. The limitations of this study are the small sample sizes and the level of evidence; hence, more research is needed to substantiate these preliminary findings. PMID- 25289686 TI - Electronic structure of cesium butyratouranylate(VI) as derived from DFT-assisted powder X-ray diffraction data. AB - Investigation of chemical bonding and electronic structure of coordination polymers that do not form high-quality single crystals requires special techniques. Here, we report the molecular and electronic structure of the first cesium butyratouranylate, Cs[UO(2)(n-C(3)H(7)COO)(3)][UO(2)(n C(3)H(7)COO)(OH)(H2O)], as obtained from DFT-assisted powder X-ray diffraction data because of the low quality of crystalline sample. The topological analysis of the charge distribution within the quantum theory of atoms-in-molecules (QTAIM) space partitioning and the distribution of electron localization function (ELF) is reported. The constancy of atomic domain of the uranium(VI) atom at different coordination numbers (7 and 8) and the presence of three ELF maxima in equatorial plane of an uranyl cation attributed to the 6s and 6p electrons were demonstrated for the first time. Details of methodologies applied for additional verification of the correctness of powder XRD refinement (Voronoi atomic descriptors and the Morse restraints) are discussed. PMID- 25289688 TI - The self-expanding Symetis Acurate does not increase cerebral microembolic load when compared to the balloon-expandable Edwards Sapien prosthesis: a transcranial Doppler study in patients undergoing transapical aortic valve implantation. AB - OBJECTIVES: The aim of this study was to quantify potential differences in count, frequency and pattern of high-intensity transient signals (HITS) during transapical transcatheter aortic valve implantation (TA-TAVI), by comparing the Symetis Acurate TA (SA) with the balloon-expandable Edwards Sapien XT (ES) system. BACKGROUND: Recently, the Symetis Acurate TA revalving system has been introduced for TA-TAVI. The Symetis Acurate TA aortic bioprosthesis is self expanding and is deployed by a specific two-step implantation technique. Whether this novel method increases the load of intraprocedural emboli, detected by transcranial Doppler ultrasound (TCD) as HITS, or not is not clear. METHODS: Twenty-two patients (n = 11 in each study arm, median logistic EuroScore 20%, median STS score 7%) displayed continuous TCD signals of good quality throughout the entire TA-TAVI procedure and were included in the final analysis. Data are presented as median with interquartile ranges. RESULTS: No significant differences were detected in total procedural or interval-related HITS load (SA: 303 [200; 594], ES: 499 [285; 941]; p = 0.16). With both devices, HITS peaked during prosthesis deployment (PD), whereas significantly fewer HITS occurred during instrumentation (SA: p = 0.002; ES: < 0.001) or post-implantation PI (SA: p = 0.007; ES: < 0.001). PD-associated HITS amounted to almost half of the total HITS load. One patient suffered new disabling stroke at 30 days. Thirty-day mortality amounted to 13.6% (3 of 22 patients). CONCLUSIONS: Simplified transapical delivery using the self-expanding SA device does not increase HITS, despite of a two-step deployment technique with more interactions with the native aortic valve, when compared to the balloon-expandable ES valve. The similarity in HITS count, frequency and pattern with the two systems suggests a common mechanism for the release of cerebral microemboli. PMID- 25289687 TI - Human adenovirus-specific gamma/delta and CD8+ T cells generated by T-cell receptor transfection to treat adenovirus infection after allogeneic stem cell transplantation. AB - Human adenovirus infection is life threatening after allogeneic haematopoietic stem cell transplantation (HSCT). Immunotherapy with donor-derived adenovirus specific T cells is promising; however, 20% of all donors lack adenovirus specific T cells. To overcome this, we transfected alpha/beta T cells with mRNA encoding a T-cell receptor (TCR) specific for the HLA-A*0101-restricted peptide LTDLGQNLLY from the adenovirus hexon protein. Furthermore, since allo-reactive endogenous TCR of donor T lymphocytes would induce graft-versus-host disease (GvHD) in a mismatched patient, we transferred the TCR into gamma/delta T cells, which are not allo-reactive. TCR-transfected gamma/delta T cells secreted low quantities of cytokines after antigen-specific stimulation, which were increased dramatically after co-transfection of CD8alpha-encoding mRNA. In direct comparison with TCR-transfected alpha/beta T cells, TCR-CD8alpha-co-transfected gamma/delta T cells produced more tumor necrosis factor (TNF), and lysed peptide loaded target cells as efficiently. Most importantly, TCR-transfected alpha/beta T cells and TCR-CD8alpha-co-transfected gamma/delta T cells efficiently lysed adenovirus-infected target cells. We show here, for the first time, that not only alpha/beta T cells but also gamma/delta T cells can be equipped with an adenovirus specificity by TCR-RNA electroporation. Thus, our strategy offers a new means for the immunotherapy of adenovirus infection after allogeneic HSCT. PMID- 25289690 TI - Synthesis of phosphoramidates: a facile approach based on the C-N bond formation via Ir-catalyzed direct C-H amidation. AB - A new synthetic route to phosphoramidates by intermolecular C-H amidation is presented. Substrates with assorted directing groups were activated by an iridium based catalyst system and reacted with a number of phosphoryl azides, executing efficient phosphoramidate synthesis via C-N bond formations. PMID- 25289689 TI - A biomarker panel (Bioscore) incorporating monocytic surface and soluble TREM-1 has high discriminative value for ventilator-associated pneumonia: a prospective observational study. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) increases mortality in critical illness. However, clinical diagnostic uncertainty persists. We hypothesised that measuring cell-surface and soluble inflammatory markers, incorporating Triggering Receptor Expressed by Myeloid cells (TREM)-1, would improve diagnostic accuracy. METHODS: A single centre prospective observational study, set in a University Hospital medical-surgical intensive Care unit, recruited 91 patients into 3 groups: 27 patients with VAP, 33 ventilated controls without evidence of pulmonary sepsis (non-VAP), and 31 non-ventilated controls (NVC), without clinical infection, attending for bronchoscopy. Paired samples of Bronchiolo-alveolar lavage fluid (BALF) and blood from each subject were analysed for putative biomarkers of infection: Cellular (TREM-1, CD11b and CD62L) and soluble (IL-1beta, IL-6, IL-8, sTREM-1, Procalcitonin). Expression of cellular markers on monocytes and neutrophils were measured by flow cytometry. Soluble inflammatory markers were determined by ELISA. A biomarker panel ('Bioscore'), was constructed, tested and validated, using Fisher's discriminant function analysis, to assess its value in distinguishing VAP from non VAP. RESULTS: The expression of TREM-1 on monocytes (mTREM-1) and neutrophils (nTREM-1) and concentrations of IL-1beta, IL-8, and sTREM-1 in BALF were significantly higher in VAP compared with non-VAP and NVC (p<0.001). The BALF/blood mTREM-1 was significantly higher in VAP patients compared to non-VAP and NVC (0.8 v 0.4 v 0.3 p<0.001). A seven marker Bioscore (BALF/blood ratio mTREM-1 and mCD11b, BALF sTREM-1, IL-8 and IL-1beta, and serum CRP and IL-6) correctly identified 88.9% of VAP cases and 100% of non-VAP cases. CONCLUSION: A 7-marker bioscore, incorporating cellular and soluble TREM-1, accurately discriminates VAP from non pulmonary infection. PMID- 25289691 TI - Molecular beam and ab initio studies of photoactive yellow protein chromophores: influence of the thioester functionality and single bond rotation. AB - We report on experimental high-resolution spectroscopic studies in combination with ab initio computational studies that investigate the excited-state dynamics of methyl-4-hydroxycinnamate thioester and (5-hydroxyindan-(1E)-ylidene)acetic acid, derivatives of the photoactive yellow protein (PYP) chromophore. These studies aim to elucidate (a) how the thioester moiety influences the photophysics and photochemistry of the p-coumaric acid chromophore and (b) to what extent rotation of the single bond adjacent to the phenyl ring is involved in the decay dynamics of the electronically excited states. The experimental studies show that sulfur substitution leads to broad, unstructured excitation spectra that contrast sharply with the well-resolved spectra of compounds with an oxygen-based ester. Furthermore, internal conversion to the lower-lying npi* state is absent. The absence of this decay channel is rationalized by quantum-chemical calculations that reveal that in the npi* state of the thio compounds the molecule exhibits a large out-of-plane "kink" at the sulfur atom. Franck-Condon simulations of the excitation spectra of the V(pipi*) state highlight the activity of various vibrational modes in the neutral chromophore and indicate that upon sulfur substitution internal conversion to the ground state occurs at a significantly higher rate. The similarities observed in the excitation spectra and decay dynamics of the locked and unlocked compounds suggest that in the present experiments single-bond torsion does not show up prominently. The conclusion that for the isolated molecule double-bond torsion is dominating the excited-state dynamics is tentatively confirmed by the quantum-chemical calculations. PMID- 25289692 TI - Digital, ultrasensitive, end-point protein measurements with large dynamic range via Brownian trapping with drift. AB - This communication shows that the concept of Brownian trapping with drift can be applied to improve quantitative molecular measurements. It has the potential to combine the robustness of end-point spatially resolved readouts, the ultrasensitivity of digital single-molecule measurements, and the large dynamic range of qPCR; furthermore, at low concentrations of analytes, it can provide a direct comparison of the signals arising from the analyte and from the background. It relies on the finding that molecules simultaneously diffusing, drifting (via slow flow), and binding to an array of nonsaturable surface traps have an exponentially decreasing probability of escaping the traps over time and therefore give rise to an exponentially decaying distribution of trapped molecules in space. This concept was tested with enzyme and protein measurements in a microfluidic device. PMID- 25289693 TI - Evidence of common cadmium and copper uptake routes in zebrafish Danio rerio. AB - Cadmium and copper accumulations in gills of zebrafish were measured during a 48 h exposure to 0.025 MUM 106Cd and 0.05 or 0.5 MUM 65Cu as a single metal or their mixtures. The gill transcript levels of genes involved in the transport of Cu (CTR1 and ATP7A), Na (NHE-2), Ca (ECaC), divalent metals (DMT1), and Zn (ZIP8) were also compared between treatments at 24 and 48 h. Cd uptake was significantly suppressed in the presence of Cu, indicating interaction between Cu and Cd at uptake sites, but Cu uptake was unaffected by Cd. The decrease in Cd accumulation rates in the presence of Cu was associated with an increase in transcript abundance of ECaC at 24 h and DMT1 at 48 h and a decrease in Zip8 transcript levels, all known as routes for Cd uptake. Fish exposed to 0.5 MUM 65Cu show an increase in gill ATP7a transcript abundance, suggesting that Cu is removed from the gill and is transferred to other organs for detoxification. A reduction in gill CTR1 transcript abundance was observed during the Cu-Cd exposure; this may be a regulatory mechanism to reduce Cu loading if Cu is entering the gills by other uptake routes, such as ECaC and DMT1. PMID- 25289694 TI - Fractionation of fulvic acid by iron and aluminum oxides--influence on copper toxicity to Ceriodaphnia dubia. AB - This study examines the effect on aquatic copper toxicity of the chemical fractionation of fulvic acid (FA) that results from its association with iron and aluminum oxyhydroxide precipitates. Fractionated and unfractionated FAs obtained from streamwater and suspended sediment were utilized in acute Cu toxicity tests on Ceriodaphnia dubia. Toxicity test results with equal FA concentrations (6 mg FA/L) show that the fractionated dissolved FA was 3 times less effective at reducing Cu toxicity (EC50 13 +/- 0.6 MUg Cu/L) than were the unfractionated dissolved FAs (EC50 39 +/- 0.4 and 41 +/- 1.2 MUg Cu/L). The fractionation is a consequence of preferential sorption of molecules having strong metal-binding (more aromatic) moieties to precipitating Fe- and Al-rich oxyhydroxides, causing the remaining dissolved FA to be depleted in these functional groups. As a result, there is more bioavailable dissolved Cu in the water and hence greater potential for Cu toxicity to aquatic organisms. In predicting Cu toxicity, biotic ligand models (BLMs) take into account dissolved organic carbon (DOC) concentration; however, unless DOC characteristics are accounted for, model predictions can underestimate acute Cu toxicity for water containing fractionated dissolved FA. This may have implications for water-quality criteria in systems containing Fe- and Al-rich sediment, and in mined and mineralized areas in particular. Optical measurements, such as specific ultraviolet absorbance at 254 nm (SUVA254), show promise for use as spectral indicators of DOC chemical fractionation and inferred increased Cu toxicity. PMID- 25289696 TI - Two new dendrocandins with neurite outgrowth-promoting activity from Dendrobium officinale. AB - Two new bibenzyl derivatives, dendrocandin T (1) and dendrocandin U (2), together with eight known bibenzyls, were isolated from the stems of Dendrobium officinale. Those compounds were sent for the first time for central nervous system-related bioassay and the results indicated that compounds 3, 4, and 5 have a certain degree of neurite outgrowth-promoting activity, and compounds 1, 2, 6, and 7 also have weak activity. The results indicated that D. officinale used as health food and traditional Chinese medicine "Tiepi Shihu" has a health function of neurotrophic effects. PMID- 25289697 TI - Influence of molecular dipole orientations on long-range exponential interaction forces at hydrophobic contacts in aqueous solutions. AB - Strong and particularly long ranged (>100 nm) interaction forces between apposing hydrophobic lipid monolayers are now well understood in terms of a partial turnover of mobile lipid patches, giving rise to a correlated long-range electrostatic attraction. Here we describe similarly strong long-ranged attractive forces between self-assembled monolayers of carboranethiols, with dipole moments aligned either parallel or perpendicular to the surface, and hydrophobic lipid monolayers deposited on mica. We compare the interaction forces measured at very different length scales using atomic force microscope and surface forces apparatus measurements. Both systems gave a long-ranged exponential attraction with a decay length of 2.0 +/- 0.2 nm for dipole alignments perpendicular to the surface. The effect of dipole alignment parallel to the surface is larger than for perpendicular dipoles, likely due to greater lateral correlation of in-plane surface dipoles. The magnitudes and range of the measured interaction forces also depend on the surface area of the probe used: At extended surfaces, dipole alignment parallel to the surface leads to a stronger attraction due to electrostatic correlations of freely rotating surface dipoles and charge patches on the apposing surfaces. In contrast, perpendicular dipoles at extended surfaces, where molecular rotation cannot lead to large dipole correlations, do not depend on the scale of the probe used. Our results may be important to a range of scale-dependent interaction phenomena related to solvent/water structuring on dipolar and hydrophobic surfaces at interfaces. PMID- 25289695 TI - Regulation of the tyrosine phosphorylation of Phospholipid Scramblase 1 in mast cells that are stimulated through the high-affinity IgE receptor. AB - Engagement of high-affinity immunoglobulin E receptors (FcepsilonRI) activates two signaling pathways in mast cells. The Lyn pathway leads to recruitment of Syk and to calcium mobilization whereas the Fyn pathway leads to phosphatidylinositol 3-kinase recruitment. Mapping the connections between both pathways remains an important task to be completed. We previously reported that Phospholipid Scramblase 1 (PLSCR1) is phosphorylated on tyrosine after cross-linking FcepsilonRI on RBL-2H3 rat mast cells, amplifies mast cell degranulation, and is associated with both Lyn and Syk tyrosine kinases. Here, analysis of the pathway leading to PLSCR1 tyrosine phosphorylation reveals that it depends on the FcRgamma chain. FcepsilonRI aggregation in Fyn-deficient mouse bone marrow derived mast cells (BMMC) induced a more robust increase in FcepsilonRI-dependent tyrosine phosphorylation of PLSCR1 compared to wild-type cells, whereas PLSCR1 phosphorylation was abolished in Lyn-deficient BMMC. Lyn association with PLSCR1 was not altered in Fyn-deficient BMMC. PLSCR1 phosphorylation was also dependent on the kinase Syk and significantly, but partially, dependent on detectable calcium mobilization. Thus, the Lyn/Syk/calcium axis promotes PLSCR1 phosphorylation in multiple ways. Conversely, the Fyn-dependent pathway negatively regulates it. This study reveals a complex regulation for PLSCR1 tyrosine phosphorylation in FcepsilonRI-activated mast cells and that PLSCR1 sits at a crossroads between Lyn and Fyn pathways. PMID- 25289698 TI - Streamflow impacts of biofuel policy-driven landscape change. AB - Likely changes in precipitation (P) and potential evapotranspiration (PET) resulting from policy-driven expansion of bioenergy crops in the United States are shown to create significant changes in streamflow volumes and increase water stress in the High Plains. Regional climate simulations for current and biofuel cropping system scenarios are evaluated using the same atmospheric forcing data over the period 1979-2004 using the Weather Research Forecast (WRF) model coupled to the NOAH land surface model. PET is projected to increase under the biofuel crop production scenario. The magnitude of the mean annual increase in PET is larger than the inter-annual variability of change in PET, indicating that PET increase is a forced response to the biofuel cropping system land use. Across the conterminous U.S., the change in mean streamflow volume under the biofuel scenario is estimated to range from negative 56% to positive 20% relative to a business-as-usual baseline scenario. In Kansas and Oklahoma, annual streamflow volume is reduced by an average of 20%, and this reduction in streamflow volume is due primarily to increased PET. Predicted increase in mean annual P under the biofuel crop production scenario is lower than its inter-annual variability, indicating that additional simulations would be necessary to determine conclusively whether predicted change in P is a response to biofuel crop production. Although estimated changes in streamflow volume include the influence of P change, sensitivity results show that PET change is the significantly dominant factor causing streamflow change. Higher PET and lower streamflow due to biofuel feedstock production are likely to increase water stress in the High Plains. When pursuing sustainable biofuels policy, decision-makers should consider the impacts of feedstock production on water scarcity. PMID- 25289699 TI - Indexes of large genome collections on a PC. AB - The availability of thousands of individual genomes of one species should boost rapid progress in personalized medicine or understanding of the interaction between genotype and phenotype, to name a few applications. A key operation useful in such analyses is aligning sequencing reads against a collection of genomes, which is costly with the use of existing algorithms due to their large memory requirements. We present MuGI, Multiple Genome Index, which reports all occurrences of a given pattern, in exact and approximate matching model, against a collection of thousand(s) genomes. Its unique feature is the small index size, which is customisable. It fits in a standard computer with 16-32 GB, or even 8 GB, of RAM, for the 1000GP collection of 1092 diploid human genomes. The solution is also fast. For example, the exact matching queries (of average length 150 bp) are handled in average time of 39 us and with up to 3 mismatches in 373 us on the test PC with the index size of 13.4 GB. For a smaller index, occupying 7.4 GB in memory, the respective times grow to 76 us and 917 us. Software is available at http://sun.aei.polsl.pl/mugi under a free license. Data S1 is available at PLOS One online. PMID- 25289700 TI - Analysis of gene expression and proteomic profiles of clonal genotypes from Theobroma cacao subjected to soil flooding. AB - Soil flooding causes changes in gene transcription, synthesis and degradation of proteins and cell metabolism. The main objective of this study was to understand the biological events of Theobroma cacao during soil flooding-induced stress, using the analyses of gene expression and activity of key enzymes involved in fermentation, as well as the identification of differentially expressed proteins by mass spectrometry in two contrasting genotypes for flooding tolerance (tolerant - TSA-792 and susceptible - TSH-774). Soil anoxia caused by flooding has led to changes in the expression pattern of genes associated with the biosynthesis of alcohol dehydrogenase (ADH), pyruvate decarboxylase (PDC) and lactate dehydrogenase (LDH) in leaves and roots of the two evaluated genotypes. Significant differences were observed between the enzyme activities of the two genotypes. Leaves and roots of the TSA-792 genotype showed higher ADH activity as compared to the TSH-774 genotype, whereas the activities of PDC and LDH have varied over the 96 h of soil flooding, being higher for TSA-792 genotype, at the initial stage, and TSH-774 genotype, at the final stage. Some of the identified proteins are those typical of the anaerobic metabolism-involved in glycolysis and alcoholic fermentation-and different proteins associated with photosynthesis, protein metabolism and oxidative stress. The ability to maintain glycolysis and induce fermentation was observed to play an important role in anoxia tolerance in cacao and may also serve to distinguish tolerant and susceptible genotypes in relation to this stressor. PMID- 25289702 TI - Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy. AB - BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency- (MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein- and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once. METHODS: We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (~ 3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging. RESULTS: During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay. CONCLUSION: NaHB is a highly effective and safe treatment that needs further controlled studies. PMID- 25289701 TI - Effect of swimming on the production of aldosterone in rats. AB - It has been demonstrated that exercise is one of the stresses known to increase the aldosterone secretion. Both potassium and angiotensin II (Ang II) levels are shown to be correlated with aldosterone production during exercise, but the mechanism is still unclear. In an in vivo study, male rats were catheterized via right jugular vein (RJV), and divided into four groups namely water immersion, swimming, lactate infusion (13 mg/kg/min) and pyruvate infusion (13 mg/kg/min) groups. Each group was treated for 10 min. Blood samples were collected at 0, 10, 15, 30, 60 and 120 min from RJV after administration. In an in vitro study, rat zona glomerulosa (ZG) cells were challenged by lactate (1-10 mM) in the presence or absence of Ang II (10(-8) M) for 60 min. The levels of aldosterone in plasma and medium were measured by radioimmunoassay. Cell lysates were analyzed by immunoblotting assay. After exercise and lactate infusion, plasma levels of aldosterone and lactate were significantly higher than those in the control group. Swimming for 10 min significantly increased the plasma Ang II levels in male rats. Administration of lactate plus Ang II significantly increased aldosterone production and enhanced protein expression of steroidogenic acute regulatory protein (StAR) in ZG cells. These results demonstrated that acute exercise led to the increase of both aldosterone and Ang II secretion, which is associated with lactate action on ZG cells and might be dependent on the activity of renin-angiotensin system. PMID- 25289703 TI - Spatial variation in carbon and nitrogen in cultivated soils in Henan Province, China: potential effect on crop yield. AB - Improved management of soil carbon (C) and nitrogen (N) storage in agro ecosystems represents an important strategy for ensuring food security and sustainable agricultural development in China. Accurate estimates of the distribution of soil C and N stores and their relationship to crop yield are crucial to developing appropriate cropland management policies. The current study examined the spatial variation of soil organic C (SOC), total soil N (TSN), and associated variables in the surface layer (0-40 cm) of soils from intensive agricultural systems in 19 counties within Henan Province, China, and compared these patterns with crop yield. Mean soil C and N concentrations were 14.9 g kg( 1) and 1.37 g kg(-1), respectively, whereas soil C and N stores were 4.1 kg m(-2) and 0.4 kg m(-2), respectively. Total crop production of each county was significantly, positively related to SOC, TSN, soil C and N store, and soil C and N stock. Soil C and N were positively correlated with soil bulk density but negatively correlated with soil porosity. These results indicate that variations in soil C could regulate crop yield in intensive agricultural systems, and that spatial patterns of C and N levels in soils may be regulated by both climatic factors and agro-ecosystem management. When developing suitable management programs, the importance of soil C and N stores and their effects on crop yield should be considered. PMID- 25289704 TI - Musical training, bilingualism, and executive function: a closer look at task switching and dual-task performance. AB - This study investigated whether musical training and bilingualism are associated with enhancements in specific components of executive function, namely, task switching and dual-task performance. Participants (n = 153) belonging to one of four groups (monolingual musician, bilingual musician, bilingual non-musician, or monolingual non-musician) were matched on age and socioeconomic status and administered task switching and dual-task paradigms. Results demonstrated reduced global and local switch costs in musicians compared with non-musicians, suggesting that musical training can contribute to increased efficiency in the ability to shift flexibly between mental sets. On dual-task performance, musicians also outperformed non-musicians. There was neither a cognitive advantage for bilinguals relative to monolinguals, nor an interaction between music and language to suggest additive effects of both types of experience. These findings demonstrate that long-term musical training is associated with improvements in task switching and dual-task performance. PMID- 25289705 TI - Tranexamic acid to reduce postpartum hemorrhage: A MANDATE systematic review and analyses of impact on maternal mortality. AB - OBJECTIVE: Postpartum hemorrhage (PPH) is a major cause of maternal mortality, with almost 300,000 cases and ~72,000 PPH deaths annually in sub-Saharan Africa. Novel prevention methods practical in community settings are required. Tranexamic acid, a drug to reduce bleeding during surgical cases including postpartum bleeding, is potentially suitable for community settings. Thus, we sought to determine the impact of tranexamic acid on PPH-related maternal mortality in sub Saharan Africa. STUDY DESIGN: We created a mathematical model to determine the impact of interventions on PPH-related maternal mortality. The model was populated with baseline birth rates and mortality estimates based on a review of current interventions for PPH in sub-Saharan Africa. Based on a systematic review of literature on tranexamic acid, we assumed 30% efficacy of tranexamic acid to reduce PPH; the model assessed prophylactic and treatment tranexamic acid use, for deliveries at homes, clinics, and hospitals. RESULTS: With tranexamic acid only in the hospitals, less than 2% of the PPH mortality would be reduced. However, if tranexamic acid were available in the home and clinic settings for PPH prophylaxis and treatment, a nearly 30% reduction (nearly 22,000 deaths per year) in PPH mortality is possible. CONCLUSION: These analyses point to the importance of preventive and treatment interventions compatible with home and clinic use, especially for sub-Saharan Africa, where the majority of births occur at home or community health clinics. Given its feasibility to be given in the home, tranexamic acid has potential to save many lives. PMID- 25289706 TI - Health behavior change in pregnant women: a two-phase study. AB - BACKGROUND: Maternal health behaviors during pregnancy/infancy can have a significant impact on maternal and child health. Many women engage in health risk behaviors during pregnancy. Multiple health behavior change (MHBC) interventions provide support to change health behaviors, but further information is needed on potential targets for such an intervention, as well as on the feasibility of technology use and e-health with this population. MATERIALS AND METHODS: Two studies were completed as part of this project. First, a survey to examine views regarding health behaviors, desires to change health behaviors, and use of technology was completed by 68 pregnant women presenting for routine care. Based on survey findings, a brief MHBC e-health educational intervention related to breastfeeding, healthy nutrition/lifestyle, and stress management, using iPad((r)) (Apple, Cupertino, CA) and text-messaging media, was then developed and piloted in the home with five pregnant women. RESULTS: In the survey, the majority of participants reported interest in receiving help to improve health behaviors, including losing weight or eating a healthier diet, breastfeeding, smoking cessation, and help with depression. The majority of women reported access to a computer with Internet, a phone, and frequent use of text messaging. In the second phase, results suggest that the home-based intervention was feasible and that the technology was convenient and user-friendly. CONCLUSIONS: Pregnant women are interested in improving health behaviors and found a brief technology-based e-health intervention feasible, convenient, and user-friendly. In-home technology appears to be a feasible and convenient approach to addressing the multiple health behavior change needs of pregnant women. PMID- 25289707 TI - Recrystallization of highly-mismatched Be(x)Zn(1-x)O alloys: formation of a degenerate interface. AB - We investigate the effect of thermally induced phase transformations on a metastable oxide alloy film, a multiphase Be(x)Zn(1-x)O (BZO), grown on Al2O3(0001) substrate for annealing temperatures in the range of 600-950 degrees C. A pronounced structural transition is shown together with strain relaxation and atomic redistribution in the annealed films. Increasing annealing temperature initiates out-diffusion and segregation of Be and subsequent nucleation of nanoparticles at the surface, corresponding to a monotonic decrease in the lattice phonon energies and band gap energy of the films. Infrared reflectance simulations identify a highly conductive ZnO interface layer (thicknesses in the range of ~ 10-29 nm for annealing temperatures >= 800 degrees C). The highly degenerate interface layers with temperature-independent carrier concentration and mobility significantly influence the electronic and optical properties of the BZO films. A parallel conduction model is employed to determine the carrier concentration and conductivity of the bulk and interface regions. The density-of states-averaged effective mass of the conduction electrons for the interfaces is calculated to be in the range of 0.31 m0 and 0.67 m0. A conductivity as high as 1.4 * 10(3) S . cm(-1) is attained, corresponding to the carrier concentration n(Int) = 2.16 * 10(20) cm(-3) at the interface layers, and comparable to the highest conductivities achieved in highly doped ZnO. The origin of such a nanoscale degenerate interface layer is attributed to the counter-diffusion of Be and Zn, rendering a high accumulation of Zn interstitials and a giant reduction of charge-compensating defects. These observations provide a broad understanding of the thermodynamics and phase transformations in Be(x)Zn(1-x)O alloys for the application of highly conductive and transparent oxide-based devices and fabrication of their alloy nanostructures. PMID- 25289708 TI - A quantitative assessment of circulating progenitor cells in competitive athletes and in sedentary subjects. AB - AIM: Hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs) are known to play a role in the vascular responses and adaptations to exercise. We performed a quantitative assessment of HSCs and EPCs in adolescents in order to investigate whether resting levels of circulating HSCs and EPCs are comparable between elite athletes and sedentary healthy subjects. METHODS: HSCs and EPCs levels were measured in adolescent competitive football players and in age- and sex-matched sedentary controls. A laboratory testing was also performed to determine the white blood cells count and the lipid profile. All athletes were evaluated at the same stage of their training program, after 6 months of training. Controls were not engaged in any kind of routine training program. RESULTS: Twenty male competitive athletes (18.4 +/- 0.5 years) and 9 sedentary controls (18.7 +/- 0.4 years) participated in the study. As expected, HDL cholesterol was higher in athletes as compared with controls (P<0.05). No significant differences in the other laboratory parameters were observed among groups. Circulating levels of HSCs were significantly lower in athletes in comparison with sedentary controls (P<0.05). Conversely, EPCs and KDR+ cell subpopulations did not substantially differ between athletes and controls. CONCLUSION: Adolescent athletes exhibit lower levels of circulating HSCs but not of EPCs compared to sedentary controls. The process of tissue repair associated with intensive training can contribute to this difference, acting as a stimulus for mobilization and homing of HSCs in the site of injuries. PMID- 25289709 TI - Combined swimming and soybean intake reduce early atherosclerotic lesions and serum oxidative stress in mice. AB - AIM: Physical exercise and soybean intake reduced oxidative stress and atherosclerosis. However, the associated effects of both interventions have not been yet investigated. Thus, we aimed to evaluate the combined effects of swimming and soybean intake on lipid profile, oxidative stress and atherogenesis. METHODS: Ten-week-old male Low-Density Lipoprotein Receptor Knockout mice were divided into 4 groups (N.=8 for each group): control diet without swimming; control diet with swimming; soybean rich diet without swimming and soybean rich diet with swimming. Diets were based on American Institute of Nutrition 93 Growth. The diet of soybean groups was made by soybean extract contained isoflavones. The animals in the exercise groups underwent a 6-week swimming program five times per week. Plasma lipid profile was determined using enzymatic kits. Oxidative stress was measured by thiobarbituric acid reactive substances, hydroperoxide and the lipid oxidation resistance determinations. Atherosclerotic lesions were calculated by morphometry. RESULTS: Soybean intake increased high density lipoprotein cholesterol. Moreover, soybean and exercise individually reduced hepatic oxidative stress and atherogenesis in aortic valve. No additional effect was seen in soybean+exercise group. However, the association of soybean and exercise reduced the percentage of lesion area in arch, thoracic and abdominal aorta and increased serum antioxidant potential. CONCLUSION: Soybean intake and swimming are beneficial in reducing atherosclerosis besides improving lipid profile and reducing lipid peroxidation. The association of soybean and swimming aggregates beneficial effects in serum antioxidant potential and in aorta lesion. PMID- 25289710 TI - The effects of one-week training camp on motor skills in Karate kids. AB - AIM: The purpose of this study was to evaluate the effects of short-term increased hours of specific high-intensity karate training on motor skills in young karate athletes aged between 8 and 12 years. METHODS: Seventy-three children, who regularly trained three karate sessions per-week were divided in two groups: high-intensity karate group (HG=53) and low-intensity karate group (LG=20). HG trained for 7 days: with two sessions per-day (one hour per-session) including specific karate techniques as well as coordination, balance, and flexibility exercises. LG, however, followed the same number of karate training sessions as before the beginning of the study (i.e., three sessions per-week with one hour per-session). Participants performed a battery of tests, 24 hours pre- and one week post-training: a medicine ball throw (MBT), standing long jump (SLJ), active joint flexibility (JM) and lateral/frontal jumps (JLT). RESULTS: Significant differences between results of pre and post karate training (ANOVA with repeated measures) included: MBT (P<0.05), SLJ (P<0.0001), JM (P<0.0001), JLT (P<0.0001); whilst the interaction training * time was: MBT (P=0.145), SLJ (P<0.0001), JM (P<0.0001), JLT (P< 0.0001). The HG significantly improved their performance on MBT by 3.23% (P<0.05), SLJ by 5.09% (P<0.001), JM by 1.51% (P<0.001), and JLT by 21.36% (P<0.001). For LG group, there were no significant differences between pre and post-testing in all fitness tests. CONCLUSION: Muscular power, flexibility and coordination represent the basics of karate fitness component. In this regard, short term high-intensity karate training represents an effective method for enhancing muscular power and range of motion (i.e. flexibility) in young karate athletes aged between 8 and 12 years. Further studies are needed to support these findings with deeper data. PMID- 25289711 TI - Effects of acute L-carnitine supplementation on nitric oxide production and oxidative stress after exhaustive exercise in young soccer players. AB - AIM: The aim of this study was to investigate the effect of acute L-carnitine supplementation at two different doses on nitric oxide (NO) production and oxidative stress after exhaustive exercise. METHODS: The subjects were 26 healthy males aged 17-19 years. Subjects were randomly divided into two groups of 13 each and received 3 or 4 g L-carnitine via a glass of fruit juice. After 1 h, the treadmill test was started at a speed of 8 km/h, afterwards increasing the speed 1 km/h every 3 min with a 1 min rest before every speed increase until exhaustion. Venous blood samples were collected again within 5 min following the exercise test. One week later, the test was repeated on the same athletes with placebo fluids. All subjects received a placebo via a glass of fruit juice. 1 h after the same exercise protocol mentioned above was performed and blood samples were drawn immediately. These plasma samples were used for measurement of nitrate nitrite (NOx), which are known to be the stable end products of NO, TBARs as a lipid peroxidation indicator and an antioxidant glutathione (GSH) levels. RESULTS AND CONCLUSION: The results of this study have shown that L-carnitine applied at a 3 g dose provides strong antioxidant action by increasing the GSH and NOx level and decreasing the TBARs level. PMID- 25289712 TI - Analysis of session-RPE and profile of mood states during a triathlon training camp. AB - AIM: The aim of the present study was to monitor the internal training load and profile of mood states (POMS) during a training camp in junior-elite triathletes. METHODS: Sixteen (10 male and 6 female) young triathlon athletes (junior-elite: 18+/-1 yrs) were included in this study. All triathletes had been training for 7+/-3 years, and regularly trained 4 times a week 3h per session, throughout the year. The training camp (5 days) included two daily supervised training sessions. The CR-10RPE scale was used 30 minutes after every training session to evaluate session-RPE. POMS was administered 3 times during the training camp: at the beginning, on the 3rd day, and at the end of training camp. RESULTS: Session-RPE throughout the different training days showed significant differences (P<0.001). POMS scores showed a significant increase (P<0.001) in fatigue from the first (7.8+/-1.4), to the third (10.5+/-2.2) and to the last day of training (14.2+/ 3.4). At the end of the camp, lower (P<0.01) vigour values (12.7+/-2.8) emerged with respect to the first day (15.8+/-3.0), whereas anger decreased (P=0.015) the last day (8.6+/-2.2) with respect to the intermediate evaluation (9.6+/-2.7). CONCLUSION: The 45% increase in fatigue, the 24% decrease in vigour, and the intraindividual variability in session RPE that emerged, indicates that young triathletes need to be monitored closely during training camps in order to individualize training to avoid training maladaptation such as non-functional overreaching. PMID- 25289713 TI - Peripheral neuromuscular fatigue induced by repeated-sprint exercise: cycling vs. running. AB - BACKGROUND: Peripheral fatigue in knee extensor (KE) and plantar flexor (PF) muscles were investigated following repeated-sprint ability (RSA) cycling and running tests. METHODS: Both RSA tests involved 5x6 s sprints and peripheral fatigue was quantified using diverse electrical stimulations (1Hz, 10Hz, 20Hz, 50Hz and 100Hz). RESULTS: RSA cycling induced higher KE decrements in peak torque (PT), maximal rate of torque development and relaxation (PT decrements at different stimulation frequencies: from -39% to -53% cycling vs. -16% to -39% running, P<0.049). The PT ratios of the KE did not highlight differences in low frequency fatigue. No major differences were noted in PT decrements of PF (P>0.231); however, greater reductions in some PT ratios (10/100 Hz, 20/50 Hz and 20/100 Hz) confirmed the presence of low-frequency fatigue in PF following RSA cycling. Subjects reported significantly higher RPE leg values following RSA cycling (8.2 vs 7.3 respectively, P=0.018) despite no differences in blood lactate, hydrogen ions and bicarbonates (P>0.467). CONCLUSIONS: Higher levels of peripheral fatigue induced by RSA cycling may be partially related to longer fractional duration of muscle contraction phases that can limit local blood flow. The discrepancies in neuromuscular fatigue between KE and PF can be explained by differences in muscle fibre composition or muscle contributions during RSA tests. PMID- 25289714 TI - Determination the validity of the new developed Sport Experts(r) hand grip dynamometer, measuring continuity of force, and comparison with current Takei and Baseline(r) dynamometers. AB - AIM: In this study the Sport Experts TM brand of hand grip dynamometer, measuring the continuity of force with the new developed load cell technology, was compared with Takei and Baseline(r) dynamometers, the current in use. It was tried to determine the correlation between them. In a study with provides use of clinical, orthopedic and rehabilitative purposes in the athletes and patient populations, this developed dynamometer can provide useful data by observing the continuity of force. METHODS: The sample of the study included 60 badminton players in 2010 2011; consisting of Turkish Junior National male players (N.=16, age: 16.8+/ 1.5), Junior National female players (N.=14, age: 16.9+/-1.6), amateur level male players (N.=15, age: 16.3+/-0.8) and amateur level female players (N.=15, age: 16.1+/-0.6). ANOVA was used in the statistical methods in order to compare the hand grip strength made by different brands; Pearson's correlation coefficient was used to determine the relationship level between dynamometers. Furthermore, test-retest reliability analysis was completed the new developed expert dynamometer. RESULTS: There was no statistically significant difference in the comparison of the dynamometers (P>0.05). Besides, a highly significant relationship (r=0.95 to 0.96) was found among all three dynamometers. However, the reliability coefficient was found (Chronbachs alpha: 0.989, ICC:0.97, r=0.97), (P<0.01) for the new developed expert dynamometer. CONCLUSION: Comparison between the dynamometers and the statistical results obtained from the correlation relationships shows interchangeability of dynamometers. As a result, our observation of force continuity (progression) of the athlete and patient populations is thought to be important. PMID- 25289715 TI - The effects of beta alanine plus creatine administration on performance during repeated bouts of supramaximal exercise in sedentary men. AB - AIM: The aim of this study was to investigate the effects of beta alanine and/or creatine supplementation on performance during repeated bouts of supramaximal exercise in sedentary men. METHODS: Forty-four untrained healthy men (aged 20-22 years, weight: 68-72 kg, height: 174-178 cm) participated in the present study. After performing the Wingate Test (WAnT) for three times in the baseline exercise session, the subjects were assigned to one of four treatment groups randomly: 1) placebo (P; 10 g maltodextrose); 2) creatine (Cr; 5 g creatine plus 5 g maltodextrose); 3) beta-alanine (beta-ALA; 1,6 g beta alanine plus 8,4 g maltodextrose); and 4) beta-alanine plus creatine (beta-ALA+Cr; 1,6 g beta alanine plus 5 g creatine plus 3,4 g maltodextrose). Participants were given the supplements orally twice a day for 22 consecutive days, then four times a day for the following 6 days. After 28 days, the second exercise session was applied during which peak power (PP) and mean power (MP) were measured and fatigue index (FI) was calculated. RESULTS: PP and MP decreased and FI increased in all groups during exercise before and after the treatment. During the postsupplementation session PP2 and PP3 increased in creatine supplemented group (from 642.7+/-148.6 to 825.1+/-205.2 in PP2 and from 522.9+/-117.5 to 683.0+/-148.0 in PP3, respectively). However, MP increased in beta-ALA+Cr during the postsupplementation compared to presupplementation in all exercise sessions (from 586.2+/-55.4 to 620.6+/-49.6 in MP1, from 418.1+/-37.2 to 478.3+/-30.3 in MP2 and from 362.0+/-41.3 to 399.1+/-3 in MP3, respectively). FI did not change with beta alanine and beta alanine plus creatine supplementation during the postsupplementation exercise session. CONCLUSION: Beta-alanine and beta alanine plus creatine supplementations have strong performance enhancing effect by increasing mean power and delaying fatigue Index during the repeated WAnT. PMID- 25289716 TI - Mortality in international professional football (soccer): a descriptive study. AB - The objective of this study was to describe the characteristics of mortalities from 2007 to 2013 in active (during career) and recently retired (post career) professional footballers. An observational prospective study was conducted. From 2007, the World Footballers' Union (FIFPro) and its related national footballers' unions (more than 70 countries distributed across all continents) collected descriptive data (football-related, cause, etc.) on mortality of active (during career) and recently retired (postcareer before reaching 45 years of age) professional footballers by means of several official sources. A total of 214 deaths were recorded among active and recently retired professional footballers, leading to an overall mortality rate of 0.47 per 1000 footballers per year. Of the 214 deaths, 183 were recorded among active players and 31 among recently retired players. Among the active players, 17% of the fatalities were related to football participation. Disease was the leading cause of death among professional footballers (55%), of which up to 33% accounted for suspected cardiac pathology. Accidents accounted for 25% of the overall deaths, and suicide for 11%. From 2007 to 2013, 214 deaths were recorded among active (during career) and recently retired (post career) professional footballers. Leading cause of death was disease (55%), one third of which were accounted for by suspected cardiac pathology, while accidents accounted for 25% of all deaths, and suicide for 11%. Attention to the predictive validity and application of heart-related precompetition medical assessment should be given, and mental health support should be developed and implemented both during and after a professional football career to prevent potential suicidal behaviors. PMID- 25289717 TI - Match-play activity profile in professional soccer players during official games and the relationship between external and internal load. AB - AIM: The aim was to quantify for the first time the physical and physiological profile of professional soccer players in official games using GPS and heart rate (HR) response. METHODS: Thirty professional soccer players were investigated during a half in competitive club level matches (N.=348) using GPS devices. RESULTS: The relative total distance was 118.9+/-10.7 m?min(-1) and player's Work To-Rest Ratio was 2.1:1. Defenders covered the lowest total distance, while Second-Strikers (2(nd)S) and Wide-Midfielders (W-MD) traveled the greatest total distance. Defenders presented the lowest Work-To-Rest Ratio values. Playing position also impacted on all sprinting performance results, except in average sprint distance and time of sprint. The number of sprints and repeated-sprint sequences recorded by the W-MD and Strikers (S) were significantly greater than any other group. The average HR recorded was 87.1%HRmax and the relationship between the external and internal load value (Effindex) was 1.4 with significant differences in both between playing positions. W-MD recorded a significantly smaller average HR than any other group and Centre-Backs showed a significantly smaller Effindex value than any other group. Conversely, W-MD showed a significantly greater Effindex value than any other group, except the 2(nd)S. CONCLUSION: This study has verified a number of statistically significant differences between the different playing positions. Coaches should be focused on the specific physical and physiological requirements of the playing positions to optimize the training prescription in soccer. The relationships between external and internal load measures among position-specific indicates that players with less overall running performance during match-play were the worst in Effindex. PMID- 25289718 TI - "Another stimulating meeting on basic and clinical corneal research," 19th Annual Meeting of the Kyoto Cornea Club, November 29-30, 2013. PMID- 25289719 TI - Functional visual acuity assessment of severe atopic keratoconjunctivitis. AB - PURPOSE: To evaluate changes in functional visual acuity (FVA) measurements before and after treatment with 0.1% cyclosporine ophthalmic solution for 3 months in patients with severe atopic keratoconjunctivitis (AKC). METHODS: Pairs of eyes were analyzed from 3 boys (mean age 9 +/- 3.6 years) who complained of having severe AKC and were recruited for the study. Conventional Landolt visual acuity, FVA, and visual maintenance ratio (VMR) measurements were conducted before and after 3 months of 0.1% cyclosporine eye drop treatment. Tear film lipid layer interferometry, tear film break-up time, fluorescein and rose bengal vital stainings, and the Schirmer test were also performed before and after treatment. RESULTS: Eye drop treatment was associated not only with improvement of tear function and ocular surface status but also with better quality of visual function. The mean logarithm of the minimum angle of resolution FVA and Landolt visual acuity values improved from 0.45 +/- 0.26 and 0.13 +/- 0.17 before treatment to 0.16 +/- 0.03 and -0.06 +/- 0.05 after treatment, respectively. Similarly, the mean VMR values were markedly improved from 0.88 +/- 0.06 to 0.95 +/- 0.03 after treatment. CONCLUSIONS: FVA and VMR are promising parameters in the assessment of dynamic visual acuity changes in AKC-affected patients and evaluation of treatment outcome. PMID- 25289720 TI - Histological analysis of a cornea following experimental femtosecond laser ablation. AB - Corneal photorefractive surgery is currently performed by ablation of corneal stroma under the stromal flap. A stromal flap is created using a femtosecond (FS) laser or mechanical microkeratome, although the FS laser procedure is considered safer and more accurate. This review assesses and compares the use of FS laser versus mechanical microkeratome ablation for corneal stromal characteristics mainly examined by histology and cellular biological responses. Supporting data from our studies, using corneas of enucleated porcine eye globes, are included in this review. Histological analysis and experimental studies of cellular/tissue responses to FS laser irradiation should be further investigated, and the equipment used to perform these techniques should be improved. PMID- 25289721 TI - New therapeutic modality for corneal endothelial disease using Rho-associated kinase inhibitor eye drops. AB - Corneal endothelial dysfunction accompanied by visual disturbance is a primary indication for corneal endothelial transplantation. However, despite the value and potential of endothelial graft surgery, a strictly pharmacological approach for treating corneal endothelial dysfunction remains an attractive proposition. Previously, we reported that the selective Rho-associated kinase (ROCK) inhibitor Y-27632 promotes cell adhesion and proliferation, and inhibits the apoptosis of primate corneal endothelial cells in culture. These findings have led us to develop a novel medical treatment for the early phase of corneal endothelial disease using ROCK inhibitor eye drops. In rabbit and monkey models of partial endothelial dysfunction, we showed that corneal endothelial wound healing was accelerated via the topical application of ROCK inhibitor to the ocular surface, resulting in the regeneration of a corneal endothelial monolayer with a high endothelial cell density. Based on these animal studies, we are now attempting to advance the clinical application of ROCK inhibitor eye drops for patients with corneal endothelial dysfunction. A pilot clinical study was performed at the Kyoto Prefectural University of Medicine, and the effects of Y-27632 eye drops after transcorneal freezing were evaluated in 8 patients with corneal endothelial dysfunction. We observed a positive effect of ROCK inhibitor eye drops in treating patients with central edema caused by Fuchs corneal endothelial dystrophy. We believe that our new findings will contribute to the establishment of a new approach for the treatment of corneal endothelial dysfunction. PMID- 25289722 TI - Oral immunotherapy for allergic conjunctivitis. AB - Antigen-specific immunotherapy is expected to be a desirable treatment for allergic diseases. Currently, antigen-specific immunotherapy is performed by administering disease-causing antigens subcutaneously or sublingually. These approaches induce long-term remission in patients with allergic rhinitis or asthma. The oral route is an alternative to subcutaneous and sublingual routes, and can also induce long-term remission, a phenomenon known as "oral tolerance." The effectiveness of oral tolerance has been reported in the context of autoimmune diseases, food allergies, asthma, atopic dermatitis, and allergic rhinitis in both human patients and animal models. However, few studies have examined its efficacy in animal models of allergic conjunctivitis. Previously, we showed that ovalbumin feeding suppressed ovalbumin-induced experimental allergic conjunctivitis, indicating the induction of oral tolerance is effective in treating experimental allergic conjunctivitis. In recent years, transgenic rice has been developed that can induce oral tolerance and reduce the severity of anaphylaxis. The major Japanese cedar pollen antigens in transgenic rice, Cryptomeria japonica 1 and C. japonica 2, were deconstructed by molecular shuffling, fragmentation, and changes in the oligomeric structure. Thus, transgenic rice may be an effective treatment for allergic conjunctivitis. PMID- 25289723 TI - Ocular surface reconstruction by cultivated epithelial sheet transplantation. AB - Recent advances in ocular surface reconstruction for patients with severe ocular surface diseases have significantly improved the prognosis of patients with vision-impairing corneal abnormalities. The history of cultivated epithelial sheet transplantation is short, and debate on the current approaches for these procedures is continuing. Limbal stem cell transplantation, including conjunctivolimbal autograft and keratolimbal allograft, has brought opportunities for vision improvement. In addition, the use of cultivated limbal epithelial transplantation from both allogeneic and autologous sources has provided further options for immediate postoperative epithelialization of the corneal surface. Finally, cultivated oral mucosal epithelial transplantation, which allows autologous transplantation for patients with bilateral limbal stem cell deficiency, has provided the best overall midterm and long-term results. Its biggest advantages are the absence of rejection reactions and the reduction of postoperative complications associated with steroid therapy. However, a solitary surgical approach is not sufficient for obtaining a good clinical outcome. To maximize the possibility of success using these procedures, it is important to preoperatively enhance aggressive treatment of the ocular surface, especially with factors that facilitate moisture retention. In this review article, we also discuss our clinical experience in relation to these surgical procedures. PMID- 25289724 TI - Translational research on ocular surface reconstruction using oral mucosal epithelial cell sheets. AB - Ocular surface reconstruction using autologous oral mucosal epithelial cell sheets has drastically changed the treatment of limbal stem-cell deficiency. The morphological and functional characteristics of oral mucosal epithelial cell sheets are similar to those of normal corneal epithelium. Ocular surface reconstruction can prevent potential problems associated with limbal transplantation, including immune rejection and donor tissue shortages. Thus far, ocular reconstruction using epithelial cell sheets has been limited to clinical research. Although the effectiveness and safety of this surgical approach have been confirmed to some extent, efforts to make its use more widespread are required. "Translational research" refers to the process of developing a new treatment based on basic research findings with useful practical applications in the field of health care. Medical centers for translational research are required to promote translational research in academic institutes. The Pharmaceutical Affairs Law was revised to promote technologies in the field of regenerative medicine in Japan. This article reviews translational research of ocular surface reconstruction using oral mucosal epithelial cell sheets. PMID- 25289725 TI - A novel approach for coronoid fractures. AB - The coronoid process serves as an important constraint that provides ulnohumeral joint stability. We describe a novel approach to coronoid fractures that minimizes surgical dissection, without compromising fracture visualization. We present the case of a 65-year-old woman who sustained an anteromedial facet fracture of the coronoid process. The elbow demonstrated intractable posteromedial instability and the inability to maintain reduction even up to 90 degrees. This report describes a surgical approach to the coronoid process that minimizes extensive soft tissue dissection. It is a variation of the previously described approach by Taylor and Scham, although it can achieve a similar exposure without elevation of the entirety of the flexor-pronator mass. Our approach involves a limited skin incision, followed by elevation of enough of the flexor-pronator mass such that adequate visualization of the posterior medial collateral ligament (which was repaired), anteromedial facet, and the fractured fragment of coronoid were achieved. Moreover, this approach enables the course of the ulnar nerve to remain unaltered. PMID- 25289726 TI - Technique of harvest of the free vascularized fibula. AB - Vascularized free fibula transfer is an attractive option for the treatment of segmental bone defects because of faster union rates, fewer fatigue fractures, rapid hypertrophy, and less resorption compared with nonvascularized bone transfer. It is classically indicated for those patients with segmental bone defects >6 to 8 cm. The presence of several peroneal artery fasciocutaneous perforators also makes the inclusion of a skin paddle possible. Although rare, the surgeon must be aware of possible complications associated with this procedure. A careful operative technique is necessary for obtaining excellent surgical outcomes. PMID- 25289727 TI - Photo-cross-linked poly(thioether-co-carbonate) networks derived from the natural product quinic acid. AB - Polycarbonate networks derived from the natural product quinic acid that can potentially return to their natural building blocks upon hydrolytic degradation are described herein. Solvent-free thiol-ene chemistry was utilized in the copolymerization of tris(alloc)quinic acid and a variety of multifunctional thiol monomers to obtain poly(thioether-co-carbonate) networks with a wide range of achievable thermomechanical properties including glass transition temperatures from -18 to +65 degrees C and rubbery moduli from 3.8 to 20 MPa. The network containing 1,2-ethanedithiol expressed an average toughness at 25 and 63 degrees C of 1.08 and 2.35 MJ/m(3), respectively, and an order-of-magnitude increase in the average toughness at 37 degrees C of 15.56 MJ/m(3). PMID- 25289728 TI - Single hair analysis of small molecules using MALDI-triple quadrupole MS imaging and LC-MS/MS: investigations on opportunities and pitfalls. AB - Single hair analysis normally requires extensive sample preparation microscale protocols including time-consuming steps like segmentation and extraction. Matrix assisted laser desorption and ionization mass spectrometric imaging (MALDI-MSI) was shown to be an alternative tool in single hair analysis, but still, questions remain. Therefore, an investigation of MALDI-MSI in single hair analysis concerning the extraction process, usage of internal standard (IS), and influences on the ionization processes were systematically investigated to enable the reliable application to hair analysis. Furthermore, single dose detection, quantitative correlation to a single hair, and hair strand LC-MS/MS results were performed, and the performance was compared to LC-MS/MS single hair monitoring. The MALDI process was shown to be independent from natural hair color and not influenced by the presence of melanin. Ionization was shown to be reproducible along and in between different hair samples. MALDI image intensities in single hair and hair snippets showed good semiquantitative correlation to zolpidem hair concentrations obtained from validated routine LC-MS/MS methods. MALDI-MSI is superior to LC-MS/MS analysis when a fast, easy, and cheap sample preparation is necessary, whereas LC-MS/MS showed higher sensitivity with the ability of single dose detection for zolpidem. MALDI-MSI and LC-MS/MS segmental single hair analysis showed good correlation, and both are suitable for consumption monitoring of drugs of abuse with a high time resolution. PMID- 25289729 TI - Carbon nanotubes size classification, characterization and nasal airway deposition. AB - Workers and researchers in the carbon nanotubes (CNT)-related industries and laboratories might be exposed to CNT aerosols while generating and handling CNT materials. From the viewpoint of occupational health, it is essential to study the deposition of CNT aerosol in the human respiratory tract to investigate the potential adverse health effects. In this study, a human nasal airway replica and two types of CNT materials were employed to conduct CNT nasal airway deposition studies. The two CNT materials were aerosolized by a nebulizer-based wet generation method, with size classified by three designated classification diameters (51, 101 and 215 nm), and then characterized individually in terms of their morphology and aerodynamic diameter. The nasal deposition experiments were carried out by delivering the size classified CNTs into the nasal airway replica in three different inspiratory flow rates. From the characterization study, it showed that the morphology of the size classified CNTs could be in a variety of complex shapes with their physical dimension much larger than their classification diameter. In addition, it was found that the aerodynamic diameters of the classified CNTs were slightly smaller than their classification diameter. The nasal deposition data acquired in this study showed that the deposition efficiency of CNTs in the nasal airway were generally less than 0.1, which implies that the majority of the CNTs inhaled into the nose could easily penetrate through the entire nasal airway and transit further down to the lower airways, possibly causing adverse health effects. PMID- 25289730 TI - The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next? AB - Postpartum haemorrhage (PPH) remains a major cause of maternal deaths worldwide, and is estimated to cause the death of a woman every 10 minutes. This review presents the latest clinical advice, including new evidence on controlled cord traction, misoprostol, and oxytocin. The controversy around the diagnosis of PPH, the limitations of universal prophylaxis, and novel ways to provide obstetric first aid are also presented. It ends with a call to develop high-quality front line obstetric services that can deal rapidly with unexpected haemorrhages as well as minimising blood loss at critical times: major abruption, placenta praevia, and caesarean for prolonged labour. PMID- 25289731 TI - Functional polymorphisms in monocyte chemoattractant protein-1 are associated with increased susceptibility to ovarian cancer. AB - Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Monocyte chemoattractant protein-1 (MCP-1) is highly expressed in various malignancies and promotes carcinogenesis. The aim of the study was to investigate the association between MCP-1 genetic polymorphisms and the susceptibility to ovarian cancer. MCP 1 rs1024611A/G and rs3760396C/G polymorphisms were examined in 257 ovarian cancer patients and 273 healthy controls. We found that distributions of rs1024611GG genotype and rs3760396GG genotype were clearly increased in ovarian cancer cases compared to healthy donors (odds ratio [OR]=1.93, 95% confidence interval [CI]: 1.13-3.29, p=0.015; OR=3.89, 95% CI: 1.63-9.33, p=0.001). Stratification analyses revealed that patients with serous papillary type had further increased percentage of rs3760396GG genotype than those with other types (OR=3.89, 95% CI: 1.11-13.66, p=0.024). In addition, we evaluated the possible effect of MCP-1 polymorphisms on gene expression by examining the serum level of MCP-1 in patients and controls. Data revealed that subjects carrying rs1024611AG and GG genotypes had a significantly higher serum level of MCP-1 than those with AA genotype. These data suggest that MCP-1 rs1024611A/G and rs3760396C/G polymorphisms are associated with increased susceptibility to ovarian cancer, in which rs1024611A/G may increase serum level of MCP-1 in the Chinese population. PMID- 25289732 TI - Endoscopic, transoral, reduction of epiglottic entrapment via wire snare technique. AB - OBJECTIVE: To describe the use of a wire snare technique for epiglottic entrapment. STUDY DESIGN: Case series. ANIMALS: Eight adult horses. METHODS: Under general anesthesia, a modified mouth gag was placed in the oropharynx. An endoscope was passed through the gag until there was adequate visualization of the entrapped epiglottis. The entrapping mucosa was grasped with bronchoesophageal forceps and pulled rostrally, releasing the epiglottis. A custom snare was passed down the bronchoesophageal forceps to encircle the redundant subepiglottic mucosa. Tension was applied to the entrapping mucosa via the forceps as the obstetric wire was tightened at the base and the redundant mucosa (aryepiglottic fold) was excised. RESULTS: The procedure was performed on 8 adult thoroughbred horses. Re-evaluation by endoscopy did not show entrapment in any horse and no horse developed complications or has had problems with performance. CONCLUSIONS: This technique is a minimally invasive, competitively priced and straightforward method for resection of entrapping subepiglottic mucosa in adult horses. PMID- 25289733 TI - Bedside nursing handover: patients' opinions. AB - Within the context of contemporary nursing practice, bedside handover has been advocated as a potentially more suitable mode for achieving patient-centred care. Given that patients can play an important role in the process, better understanding of patients' perspectives of bedside handover could be a critical determinate for successful implementation of the practice. Using a phenomenological approach, this study attempted to explore patients' perceptions of bedside nursing handover. Four key themes emerged from the patient interviews: 'a more effective and personalised approach', 'being empowered and contributing to error minimization', 'privacy, confidentiality and sensitive topics', and 'training need and avoidance of using technical jargon'. Patients welcome bedside handover as they can be empowered through participation in the process. Nevertheless, attention is needed to ensure that adequate training is provided to nurses and to minimize the use of technical jargon so that handover is delivered with a professional and consistent approach. PMID- 25289734 TI - Nursing students' expectations regarding effective clinical education: a qualitative study. AB - This study aimed to describe the expectations of Bachelor of Science nursing students regarding what constitutes an effective clinical education. In this study, a semistructured interview process was utilized with 17 nursing students studying in sophomore, junior and senior years in training units of hospitals affiliated with Tehran University of Medical Sciences. Content analysis was employed to analyse the data. Data analysis led to identification of three main themes: (i) appropriate communication and interaction between instructors and students; (ii) incorporation of both theory and practice in clinical education, with two subthemes, one being the presence of the instructor as a factor for reducing the gap between theory and practice and the other being evaluation based on appropriate criteria; and (iii) having specialized instructors, with a specific emphasis on the instructor's knowledge and motivation as important factors in learning. The findings reveal the significant role of mentors in providing effective educational and clinical experiences. Therefore, mentors must strive to develop their knowledge and clinical behaviours according to students' needs in clinical settings. PMID- 25289735 TI - Effect on pain intensity of injection sites and speed of injection associated with intramuscular penicillin. AB - The aim of this one-group, quasi-experimental study was to examine the effect of choice of injection site and injection duration on the intensity of pain associated with intramuscular penicillin injection. Injections containing the same dose of drug were administered 12 hours apart for each patient over 5 s/mL and 10 s/mL durations in the dorsogluteal and ventrogluteal sites. Sixty patients who had a medical order for intramuscular penicillin at least twice in a day and for two successive days at the same dose were included in the study. No difference in pain was perceived by participants between the two injection durations at either the dorsogluteal or the ventrogluteal site. This study showed that intramuscular penicillin can be administered to either site over 5 s/mL or 10 s/mL durations. There is a need for further research with a randomized controlled design in different settings and in a larger sample on the impact of choice of injection site and injection duration on pain intensity. PMID- 25289737 TI - Differentiation human leukocyte antigens: a proposed nomenclature. PMID- 25289736 TI - The complex mediators of cell growth and differentiation. PMID- 25289738 TI - T-cell regulation of IgA responses. PMID- 25289739 TI - Mechanisms in chronic inflammation. PMID- 25289740 TI - Suppressor cells in immunological maturation. PMID- 25289741 TI - A continuum of cells leading to an in-vivo humoral response. AB - A fortuitous series of observations reported in 1955-56 allowed the first demonstration that a lymphoid structure, the bursa of Fabricius, exerts a profound influence on humoral immunity. These and later studies contributed to our understanding of the role of the cell in immunology and, in particular, to the T- and B-cell concept. The bursa gained acceptance as an exporter of specialized lymphocytes following the demonstration of certain bursa-dependent cell populations in specific regions of peripheral lymphoid tissue such as thegerminal centre. Here Bruce Glick and Imre Olah discuss a newly identified family of cells which they believe may influence B-cell differentiation. PMID- 25289742 TI - What is tumour necrosis factor really for? PMID- 25289743 TI - Tumor-associated transplantation antigens of chemically-induced tumors: new complexities. PMID- 25289744 TI - Hormones, handedness, and autoimmunity. PMID- 25289745 TI - Prostaglandins and immunity. AB - The prostaglandins are a family of biologically active compounds generated from unsaturated fatty acids. They are produced and found in every tissue of the body and their diverse biological activities and possible role in human disease processes are receiving much attention. There is increasing evidence that these compounds are a vital component of the balance achieved by normal immunoregulatory mechanisms. How this balance is achieved, the cells involved, and the consequence of an imbalance in prostaglandin production or consumption are the subject of the articles which follow. PMID- 25289746 TI - Prostaglandins in inflammation and disease. PMID- 25289747 TI - Prostaglandin regulation of B-lymphocyte function. AB - The local production of prostaglandins (PGs) in tissues by monocytes, po lymorphonuclear leucocytes, endothelial cells and platelets, and their rapid degradation, gives PGs an ideal opportunity for the selective regulation of inflammatory and immune responses. Much is known about the PG regulation of monocyte and T-cell function(1-3) but our knowledge of PG-mediated regulation of B-lymphocytefunction is still very poor, with many apparent contradictions in the literature. Here Nigel Staite and Gabriel Panayi discuss the indirect and direct effects of PGs on B-lymphocyte function with particular emphasis on the regulation of human lymphocytes, acknowledging that most of what is known was learned from animal studies. PMID- 25289748 TI - Retinoids and in vivo immunity to transplantable tumours: a terra relatively incognita. AB - Miroslav Malkovsky and Peter Medawar discuss here the role of retinoids in anti tumour immunity in vivo with the intention of provoking a reassessment of the current status and potential of this topic. Their selection of results discussed is influenced by the belief that they may form a basis for a renaissance in the study of the biological functions of vitamin A. PMID- 25289754 TI - Single particle tracking with sterol modulation reveals the cholesterol-mediated diffusion properties of integrin receptors. AB - A combination of sterol modulation with cyclodextrins plus fluorescence microscopy revealed a biophysical mechanism behind cholesterol's influence on the diffusion of a ubiquitous class of receptors called integrins. The heterogeneous diffusion of integrins bound to ligand-coated quantum dots was measured using single particle tracking (SPT), and the ensemble changes in integrin diffusion were measured by fluorescence recovery after photobleaching (FRAP). A 25 +/- 1% reduction of membrane cholesterol resulted in three significant changes to the diffusion of ligand-bound alphaPS2CbetaPS integrins as measured by SPT. There was a 23% increase in ligand-bound mobile integrins; there was a statistically significant increase in the average diffusion coefficient inside zones of confined diffusion, and histograms of confined integrin trajectories showed an increased frequency in the range of 0.1-1 MUm(2) s(-1) and a decreased frequency in the 0.001-0.1 MUm(2) s(-1) range. No statistical change was measured in the duration of confinement nor the size of confined zones. Restoring the cholesterol depleted cells with exogenous cholesterol or exogenous epicholesterol resulted in similar diffusion properties. Epicholesterol differs from cholesterol in the orientation of a single hydroxyl group. The ability of epicholesterol to substitute for cholesterol suggests a biophysical mechanism for cholesterol's effect on integrin diffusion. Influences of bilayer thickness, viscosity and organization are discussed as possible explanations for the measured changes in integrin diffusion when the membrane cholesterol concentration is reduced. PMID- 25289755 TI - Rings, igloos, and pebbles of salt formed by drying saline drops. AB - It is well-known that evaporation of sessile drops with suspended particles like colloids and coffee powders can yield a variety of two-dimensional patterns depending on the particle shapes and internal flow patterns. Here we show that ordered three-dimensional structures can be built via evaporation of saline drops on highly hydrophobic substrates like pristine PP (polypropylene) with micropores and nanostructured low-surface-energy PP. On pristine PP having a high contact angle but a large contact angle hysteresis (CAH) with water, either rings or igloos of salt are formed depending on the salt concentration and evaporation rate. On nanostructured low-surface-energy PP having extreme water repellency with a very low CAH, pebbles of salt are formed regardless of salt concentration and evaporation rate. These observations lead us to conclude that combined effects of solubility, evaporation rate, and mobility of the contact line determine the final three-dimensional shape of the salt precipitate. PMID- 25289756 TI - A new method for morphometric analysis of opal phytoliths from plants. AB - Micro-morphometry has substantially gained ground in the field of phytolith analysis, but the comparability of results is limited due to the use of different methods. This paper presents a new, user-friendly method based on open-source software (FIJI) that is proposed as a step towards the introduction of a standard method. After obtaining a mask of a phytolith by making a digital drawing, 27 commonly used variables of size and shape are measured automatically. This method is not only useful for phytolith analysis, but may also be used for other fields of morphometric research. Users can furthermore customize the software tool when additional variables are required. PMID- 25289757 TI - N-linked Glycosylation on the N-terminus of the dopamine D2 and D3 receptors determines receptor association with specific microdomains in the plasma membrane. AB - Numerous G protein-coupled receptors (GPCRs) are glycosylated at extracellular regions. The regulatory roles of glycosylation on receptor function vary across receptor types. In this study, we used the dopamine D2and D3receptors as an experimental model to understand the underlying principles governing the functional roles of glycosylation. We used the pharmacological inhibitor, tunicamycin, to inhibit glycosylation, generated chimeric D2and D3receptors by swapping their respective N-termini, and produced the glycosylation site mutant D2and D3receptors to study the roles of glycosylation on receptor functions, including cell surface expression, signaling, and internalization through specific microdomains. Our results demonstrate that glycosylation on the N terminus of the D3 receptor is involved in the development of desensitization and proper cell surface expression. In addition, glycosylation on the N-terminus mediates the internalization of D2and D3receptors within the caveolae and clathrin-coated pit microdomains of the plasma membrane, respectively, by regulating receptor interactions with caveolin-1 and clathrin. In conclusion, this study shows for the first time that glycosylation on the N-terminus of GPCRs is involved in endocytic pathway selection through specific microdomains. These data suggest that changes in the cellular environment that influence posttranslational modification could be an important determinant of intracellular GPCR trafficking. PMID- 25289760 TI - Another disease caused by autoantibodies to receptors? PMID- 25289759 TI - Inhibitory effects of capsaicin on hepatic stellate cells and liver fibrosis. AB - Hepatic stellate cells (HSCs) play an important role in the process of liver fibrosis. In this study, we investigated the inhibitory effects of capsaicin on HSCs and liver fibrosis. Cultured HSCs were incubated with various concentrations of capsaicin. Cell proliferation was examined using a cell counting kit. Production of hydrogen peroxide was determined using a 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay. The mRNA and protein expression of target genes was analyzed by reverse transcription PCR and Western blot analysis, respectively. Cell apoptosis was evaluated by annexin V-FITC and propidium iodide (PI) costaining followed by flow cytometric analysis. A CCl4 rat liver fibrosis model was used to assess in vivo effects of capsaicin by histological examination and measurement of liver fibrosis markers, including hydroxyproline content, serum type III collagen, and hyaluronic acid (HA) levels. Our results show that capsaicin dose-dependently inhibited cell proliferation, suppressed cell activation, and decreased hydrogen peroxide production in cultured HSCs. Capsaicin reduced the mRNA levels of tissue inhibitors of metalloproteinase 1 (TIMP-1) and transforming growth factor-beta1 (TGF-beta1) in HSCs. Moreover, capsaicin-induced cell apoptosis was associated with increased expression of Bax, cytochrome c (cyt c), and caspase-3, but reduced levels of Bcl-2. The animal studies further revealed that capsaicin efficiently reduced the extent of liver fibrosis, inhibited HSC proliferation, and promoted cell apoptosis. Our findings suggest that capsaicin might inhibit fibrogenesis by inhibiting the activities of HSCs. PMID- 25289761 TI - Recent developments in the study of immunoregulatory lymphokines. PMID- 25289758 TI - A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer. AB - PURPOSE: Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity. EXPERIMENTAL DESIGN: In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0. RESULTS: Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1alpha and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1beta, TIMP-1 and TNF-alpha were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity. CONCLUSIONS: Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies. PMID- 25289762 TI - Phagocyte function in pregnancy. PMID- 25289763 TI - Clinical applications of monoclonal antibodies. AB - Monoclonal antibodies offer many distinct advantages over conventional antisera, the most obvious being their precise specificity for a single epitope on a single antigen and their potentially unlimited supply. The quantity and purity of available antibodies facilitates antigen purification by affinity chromatography. Monoclonal antibodies can also be used to characterize different parts of a macromolecule with regard to antigenicity, functional activity or genetic variability. Here Andrew McMichael and Judy Bastin concentrate on the potential value of monoclonal antibodies in clinical medicine, surveying papers published up to June 1980, and a number of preprints and personal communications, kindly made available to them by colleagues. PMID- 25289764 TI - Mouse T-lymphocyte subpopulations: relationships between function and Lyt antigen phenotype. AB - The study of cell-surface markers has permitted the dissection of lymphocyte populations into subsets and made possible many of the current ideas about how cells interact to produce an immune response. In particular, the Lyt molecules of the mouse, originally described by Boyse and his colleagues, have been of great importance in defining functionally distinct subsets of T cells and examining the interactions among them (reviewed in Ref. 2). A major question raised by these studies concerns the nature of the relationship between Lyt phenotype and the function of the T-cell subset so defined. Are such associations fortuitous, are they indirect manifestations of some other factor(s), or do they indicate that the molecules themselves have a functional role? In this article, Susan Swain and Richard Dutton discuss what is known about Lyt antigens, how their expression correlates with function of T cells and with the recognition of major histocompatibility complex (MHC) subregion antigens by T cells, and what role(s) such molecules may have in T-cell activities. PMID- 25289765 TI - Prostaglandins: fine tuning the immune system? AB - Like the catecholamines, kinins and corticosteroids the prostaglandins are a major class of intercellular messenger and so may be important in maintaining many 'physiological balances'. In this article Michael Bray discusses evidence that the prostaglandins derived from immuno-derived from immuno-inflammatory cell populations influence a range of immunological responses. He proposes that such small molecular weight mediators provide a mechanism for the local homeostatic regulation of immune cell function and that the mechanism's breakdown contributed to the pathology of diseases in which immunological dysfunction plays a part. PMID- 25289766 TI - Are there Fc receptors on non-lymphoreticular tumor cells? AB - The distribution of Fc receptors is not restricted to lymphoid cells - indeed, they were first discovered on macrophages and subsequently on a range of other leukocytes and granulocytes. It should not come as a surprise, therefore, to discover that solid, non-lymphoid tumors are generally filled to varying degrees with cells that have Fc receptor. After all, it has been known for over a century that such tumors can become infiltrated with all kinds of lymphoreticular host cells, an observation which has been claimed by some to be good morphologicalin vivo evidence for the body's anti-cancer immune surveillance system. What did come as a surprise, then, was the claim that a considerable proportion - perhaps the vast majority - of such Fc-receptor-positive cells were tumorous, regardless of the nature or origin of the malignant tumor. R. S. Kerbel wrote in 1974 that the importance of lymphocyte-associated receptors could be 'eclipsed in terms of biological significance by the finding that an astonishing array of non-lymphoid and non-reticuliondothelial tumors appear to possess Fc types of receptors'. How does that statement hold up today? In this review, R. S. Kerbel and J. W. Dennis attempt to answer this question and summarize the current state of affairs. PMID- 25289767 TI - Translational research-focusing on overweight and obesity in childhood and adolescence to improve health. PMID- 25289768 TI - Special issue on childhood overweight and obesity. PMID- 25289769 TI - Risk factors associated with hospital readmission in pediatric asthma. AB - Asthma is a leading cause of hospitalization among children, and about 15-50% of pediatric patients are readmitted after an index admission. The purpose of this integrative review is to explore contemporary scientific findings on the association between pediatric asthma readmission and various demographic, environmental, psychosocial and clinical risk factors. An electronic database search resulted in a sample of 29 studies. African American, public or no insurers, previous admission and complex chronic comorbidity were identified as risk factors associated with pediatric asthma readmission. However, more interdisciplinary and well-designed investigations are warranted to further explicate the spectrum of environmental and psychosocial correlates. PMID- 25289770 TI - Protective roles of aldo-keto reductase 1B10 and autophagy against toxicity induced by p-quinone metabolites of tert-butylhydroquinone in lung cancer A549 cells. AB - tert-Butylhydroquinone (BHQ), an antioxidant used as a food additive, exhibits an anticancer effect at low doses, but is carcinogenic in rodents at high doses. BHQ is metabolized into cytotoxic tert-butylquinone (TBQ), which is further converted to 6-tert-butyl-2,3-epoxy-4-hydroxy-5-cyclohexen-1-one (TBEH) through 6-tert butyl-2,3-epoxy-4-benzoquinone (TBE). Both TBQ and TBE are cytotoxic, but their toxic mechanisms have not been fully characterized. In this study, we have investigated the toxic mechanisms of TBQ and TBE, and the defense system against the two p-quinones using lung cancer A549 cells. TBQ and TBE, but not BHQ and TBEH, showed cytotoxicity to A549 cells. Neither caspase-3 activation nor an increase in the expression of endoplasmic reticulum stress-associating target genes was observed. TBQ and TBE reacted with reduced glutathione, and significantly decreased the glutathione level in A549 cells, suggesting that the cytotoxicity of the p-quinones is caused by their high electrophilicity reacting with biomolecules. The A549 cells treated with the p-quinones also showed increased levels of autophagic vacuoles and LC3-II protein, which are specific autophagy markers. An autophagy inhibitor, 3-methyladenine (3MA), decreased the LC3-II production by the p-quinones, but enhanced the cytotoxicity induced by TBQ and TBE, suggesting that autophagy contributes to alleviating the p-quinone triggered cytotoxicity. In addition, the TBE-induced cytotoxicity and autophagy activation in the cells were significantly suppressed by overexpression of aldo keto reductase (AKR)1B10 that efficiently reduces TBE into TBEH, and were augmented by pretreatment with a potent AKR1B10 inhibitor, C1. The effects of 3MA and C1 on the TBE-induced cytotoxicity were additive. The data provides evidence for the first time that autophagy and AKR1B10 contribute to the defense system against the cytotoxicity caused by the electrophilic p-quinone metabolites of BHQ. PMID- 25289771 TI - Gastroprotective effect of nymphayol isolated from Nymphaea stellata (Willd.) flowers: contribution of antioxidant, anti-inflammatory and anti-apoptotic activities. AB - Gastric ulcer is an illness that affects a great number of people worldwide. The goal of the present research was to assess the anti-ulcerogenic activity of nymphayol (NYM), isolated from Nymphaea stellata, against an ethanol-induced ulcer model in rats. Administration of ethanol elevates the levels of the ulcer index (UI) along with causing tremendous increases in lipid peroxidation and myeloperoxidase (MPO) and significant decreases in gastric mucus, catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and prostaglandin E2 (PGE2). However, the NYM- (45 mg/kg) pretreated animals showed considerable increases in antioxidants, gastric mucus, and PGE2 level and significant decreases in UI, lipid peroxidation, and MPO level. Pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were increased and the level of interleukin-10 (IL-10), an anti-inflammatory cytokine, was decreased in ethanol-induced ulcerated animals, and these inequalities were amended by NYM pretreatment. Pro-apoptotic markers including caspase-8, caspase 9, and caspase-3 were decreased and Bcl-2, an anti-apoptotic marker, was increased through NYM pretreatment, as compared with the ethanol-induced ulcer group. Pretreatment with indomethacin, SC560, rofecoxib, and Nomega-Nitro-L arginine methyl ester (L-NAME) considerably prevented the ulcer protective activity of NYM (45 mg/kg), indicating the involvement of cyclooxygenase (COX) and nitric oxide synthase (NOS) in NYM-mediated gastroprotection against ethanol induced ulcer. These outcomes suggest that the gastroprotective effect of NYM might be mediated by adjustment of inflammatory mediators and apoptotic markers and increasing antioxidants. PMID- 25289772 TI - A flavonoid isolated from Streptomyces sp. (ERINLG-4) induces apoptosis in human lung cancer A549 cells through p53 and cytochrome c release caspase dependant pathway. AB - The aim of this study was to investigate the anticancer activity of a flavonoid type of compound isolated from soil derived filamentous bacterium Streptomyces sp. (ERINLG-4) and to explore the molecular mechanisms of action. Cytotoxic properties of ethyl acetate extract was carried out against A549 lung cancer cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cytotoxic properties of isolated compound were investigated in A549 lung cancer cell line, COLO320DM cancer cell line and Vero cells. The compound showed potent cytotoxic properties against A549 lung cancer cell line and moderate cytotoxic properties against COLO320DM cancer cell line. Isolated compound showed no toxicity up to 2000 MUg/mL in Vero cells. So we have chosen the A549 lung cancer cell line for further anticancer studies. Intracellular visualization was done by using a laser scanning confocal microscope. Apoptosis was measured using DNA fragmentation technique. Treatment of the A549 cancer cells with isolated compound significantly reduced cell proliferation, increased formation of fragmented DNA and apoptotic body. Activation of caspase-9 and caspase-3 indicated that compound may be inducing intrinsic and extrinsic apoptosis pathways. Bcl-2, p53, pro-caspases, caspase-3, caspase-9 and cytochrome c release were detected by western blotting analysis after compound treatment (123 and 164 MUM). The activities of pro-caspases-3, caspase-9 cleaved to caspase 3 and caspase-9 gradually increased after the addition of isolated compound. But Bcl-2 protein was down regulated after treatment with isolated compound. Molecular docking studies showed that the compound bound stably to the active sites of caspase-3 and caspase-9. These results strongly suggest that the isolated compound induces apoptosis in A549 cancer cells via caspase activation through cytochrome c release from mitochondria. The present results might provide helpful suggestions for the design of antitumor drugs toward lung cancer treatment. PMID- 25289773 TI - Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin. AB - The carcinogenicity potential of canagliflozin, an inhibitor of SGLT2, was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Systemic exposure multiples at the highest dose relative to the maximum clinical dose were 12- to 21-fold. Pheochromocytomas and renal tubular tumors were noted in both sexes at 100 mg/kg. Leydig cell tumors were observed in males in all dose groups and were associated with increased luteinizing hormone levels. Hyperplasia was increased in the adrenal medulla at 100 mg/kg, but only a limited increase in simple tubular hyperplasia was observed in the kidney of males at 100 mg/kg. Hyperostosis occurred and was accompanied by substantial effects on calcium metabolism, including increased urinary calcium excretion and decreased levels of calcium regulating hormones (1,25-dihydroxyvitamin D and parathyroid hormone). A separate study with radiolabeled calcium confirmed that increased urinary calcium excretion was mediated via increased calcium absorption from the gastrointestinal tract. It was hypothesized that, at high doses, canagliflozin might have inhibited glucose absorption in the intestine via SGLT1 inhibition that resulted in glucose malabsorption, which increased calcium absorption by stimulating colonic glucose fermentation and reducing intestinal pH. Pheochromocytomas and adrenal medullary hyperplasia were attributed to altered calcium homeostasis, which have a known relationship in the rat. In conclusion, Leydig cell tumors were associated with increased luteinizing hormone levels and pheochromocytomas were most likely related to glucose malabsorption and altered calcium homeostasis. Renal tubular tumors may also have been linked to glucose malabsorption. PMID- 25289775 TI - Cells and antigens at the materno-fetal interface. PMID- 25289776 TI - Tumor-infiltrating leukocytes. AB - Leukocytes are often found in neoplastic tissues. Morphological, histochemical and monoclonal antibody-defined markers are now available with which these cells can be separated in vitro or identified in situ. The tumor-host relationship can therefore be analysed at its interface. Current research in this area was discussed at a recent workshop(*). PMID- 25289774 TI - Autophagic cell death of human hepatoma G2 cells mediated by procyanidins from Castanea mollissima Bl. Shell-induced reactive oxygen species generation. AB - The autophagy of human hepatoma G2 (HepG2) cells induced by procyanidins from chestnut (Castanea mollissima Bl.) shell (CSPCs) was investigated, and the inherent relationship between autophagic levels and reactive oxygen species (ROS) generation was studied. The results showed that CSPCs induced HepG2 cell death in a time- and concentration-dependent manner, increased the accumulation of autophagolysosomes and microtubule-associated proteins light chain 3-II (LC3-II, a marker of autophagy). However, these phenomena were not observed in the group pretreated with the autophagy inhibitor 3-MA, suggesting that CSPCs induced HepG2 cell autophagy. Furthermore, we found that CSPCs triggered ROS generation in cells, while the levels of ROS decreased in the N-acetylcysteine (Nac) co treatment, revealing that CSPCs-mediated autophagy was partly blocked by Nac. In addition, treatment with CSPCs decreased the mitochondrial membrane potential of HepG2 cells. These results suggested CSPCs could trigger autophagy via ROS generation, which may be associated with the mitochondria-dependent signaling way. PMID- 25289777 TI - Cryopreservation of CTLL, a murine IL2-dependent cell line. PMID- 25289778 TI - The advantage of being a low responder. AB - Immune response genes determine the magnitude of many immune responses. A low response is often ascribed to a genetic defect. Here Irun Cohen argues that a poor response instead reflects a heightened sensitivity to the conditions in which antigen is encountered. When these are optimal the response is normal. Poor responders thus have the advantage of a greater fexibility of response over individuals who respond strongly regardless of prevailing circumstances. PMID- 25289779 TI - The study of circulating lymphocytes in vivo: a personal view of artifice and artifact. PMID- 25289780 TI - Pathogenesis of milk hypersensitivity. PMID- 25289781 TI - Activated suppressor T cells and the role of interferon in aplastic anaemia. PMID- 25289782 TI - Lymphotoxin redux. AB - Lymphotoxin, (LT), a ymphokine released by activated lymphocytes, kills bystander cells such as fibroblasts and lymphocytes. Its production by mouse T cells is antigen-specific and restricted by MHC genes. It is also produced by human T4(+) and T8(+) cells and some B lymphoblastoid lines. Its action has been difficult to distinguish from that of other lymphokines, particularly the interferons, but its individuality has been emphasized by the recent cloning of the human LT gene. Here Nancy Ruddle discusses new insights into the nature of LT, its mechanism of action and its possible role in several kinds of tissue-damaging response. PMID- 25289783 TI - Cellular immune abnormalities and autoreactive T lymphocytes in insulin-dependent diabetes mellitus in rats. PMID- 25289784 TI - Limiting factors in the localization of tumours with radiolabelled antibodies. AB - The use of radiolabelled antibodies in tumour detection is being intensely studied. Here A. R. Bradwell and colleagues discuss the use of radioimmunolocation and conclude that although many different tumour types can be localized, results at present are no better than with otherscanning techniques. Dramatic improvements will depend upon afuller understanding of tumour cell biology and the optimization of all the parameters that contribute to successful scans. PMID- 25289788 TI - Photoelectron-photofragment coincidence studies of the tert-butoxide anion (CH3)3CO((-)), the carbanion isomer (CH3)2CH2COH((-)), and corresponding radicals. AB - A study of the photodetachment and dissociative photodetachment (DPD) of the C(4)H(9)O(-) isomers tert-butoxide, (CH(3))(3)CO(-), and the alpha-hydroxy carbanion (CH(3))(2)C(CH(2))OH(-) is reported. Photoelectron-photofragment coincidence spectroscopy was used to study these anions at 387, 537, and 600 nm. Supported by CBS-QB3 ab initio calculations, the product mass and translational energy distributions were found to be consistent with dissociation of either highly excited (CH3)(3)CO radicals or (CH(3))(2)C(CH2)OH alkylhydroxy radicals. Vibrationally resolved photoelectron spectra of stable radicals at 537 and 600 nm in conjunction with Franck-Condon simulations were used to assign the dominant channel to tert-butoxide ((CH(3)3)CO(-)) anions thermalized to a vibrational temperature of 550 K. DPD is assigned to highly vibrationally excited radicals produced by photodetachment of unrelaxed tert-butoxide products formed at an effective source temperature of 1400 K. The higher energy carbanion was found to be a minor channel and was not observed to dissociate. Calculated energetics for photodetachment and DPD of (CH(3))(3)CO(-) and (CH(3))(2)C(CH(2))OH(-) are discussed and compared with the experimental results. PMID- 25289789 TI - Simultaneous determination of scutellarin and tetrahydropalmatine of Deng-yan granule in rat plasma by UFLC-MS/MS and its application to a pharmacokinetic study. AB - Deng-yan granule, consisting of Herba Erigerontis Breviscapi, Rhizoma Corydalis Yanhusuo and Radix Astragali Mongolici, is a widely used Traditional Chinese Medicine preparation for treatment of coronary heart disease. Scutellarin and tetrahydropalmatine are main active constituents in Herba Erigerontis Breviscapi and Rhizoma Corydalis Yanhusuo, and have been used as marker components for quality control of Deng-yan preparations. In order to make good and rational use of Deng-yan granule in the future, a rapid, sensitive and high throughput ultra fast liquid chromatography with tandem mass spectrometry (UFLC-MS/MS) method was developed for the simultaneous determination of scutellarin and tetrahydropalmatine in rat plasma using rutin as internal standard (IS). The plasma samples were extracted by liquid-liquid extraction with ethyl acetate after acidification and separated on a Shim-pack XR-ODS C18 column (75mm*3.0mm, 2.2MUm) with a mobile phase consisting of methanol-0.1% formic acid water (50:50, v/v) at a flow rate of 0.4mL/min. Mass spectrometric detection was conducted on an API 3200 QTRAP mass spectrometry equipped with electrospray ionization source in positive ionization mode. Quantification was performed using multiple reaction monitoring (MRM) by monitoring the fragmentation of m/z 463.2->287.1 for scutellarin, m/z 356.1->192.1 for tetrahydropalmatine and m/z 611.2->303.2 for IS, respectively. The linear range was 10-5000ng/mL for both scutellarin and tetrahydropalmatine with lower limit of quantitation (LLOQ) of 10ng/mL. The intra and inter-day precisions were below 12.2% for scutellarin and below 9.7% for tetrahydropalmatine in terms of relative standard deviation (RSD), and the accuracy was within +/-9.1% for scutellarin and within +/-11.2% for tetrahydropalmatine in terms of relative error (RE). Extraction recovery, matrix effect and stability were satisfactory in rat plasma. The validated method was successfully applied to a pharmacokinetic study of scutellarin and tetrahydropalmatine after oral administration of Deng-yan granule to rats. PMID- 25289790 TI - Chiral liquid chromatography-tandem mass spectrometry assay to determine that dexpramipexole is not converted to pramipexole in vivo after administered in humans. AB - Dexpramipexole (DEX) was being investigated in clinical studies for the treatment of amyotrophic lateral sclerosis (ALS). To monitor the potential chiral interconversion of dexpramipexole to pramipexole (PPX) in vivo, a highly sensitive and selective chiral LC-MS/MS assay was developed and qualified for the detection of pramipexole in the presence of dexpramipexole in human plasma. In this assay, plasma samples were extracted by protein precipitation coupled with solid phase extraction (SPE). The analyte PPX was separated from its enantiomer DEX using a chiral HPLC method. The assay was qualified with a dynamic range of 0.150-1.00ng/mL. The lower limit of quantitation (LLOQ) for PPX was 0.150ng/mL in the presence of up to 1000ng/mL of DEX. The qualified method was used to analyze plasma samples from a DEX clinical study. No PPX was detected in humans at pharmacologically significant levels after administration of dexpramipexole at single doses up to 600mg per day. PMID- 25289791 TI - Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage. AB - We compared blood component requirements during major obstetric haemorrhage, following the introduction of fibrinogen concentrate. A prospective study of transfusion requirements and patient outcomes was performed for 12 months to evaluate the major obstetric haemorrhage pathway using shock packs (Shock Pack phase). The study was repeated after the pathway was amended to include fibrinogen concentrate (Fibrinogen phase). The median (IQR [range]) number of blood components given was 8.0 (3.0-14.5 [0-32]) during the Shock Pack phase, and 3.0 (2.0-5.0 [0-26]) during the Fibrinogen phase (p = 0.0004). The median (IQR [range]) quantity of fibrinogen administered was significantly greater in the Shock Pack phase, 3.2 (0-7.1 [0-20.4]) g, than in the Fibrinogen phase, 0 (0-3.0 [0-12.4]) g, p = 0.0005. Four (9.5%) of 42 patients in the Shock Pack phase developed transfusion associated circulatory overload compared with none of 51 patients in the Fibrinogen phase (p = 0.038). Fibrinogen concentrate allows prompt correction of coagulation deficits associated with major obstetric haemorrhage, reducing the requirement for blood component therapy and the attendant risks of complications. PMID- 25289794 TI - Diagnosis and therapy with labeled antibodies. AB - Both polyclonal antibodies and monoclonal antibodies can be conjugated to enzymes or fluorescent molecules, or be synthesized with radioactive amino acid residues. The specificity of such labeled antibodies allows the localization of cell or tissue components, including transplantation antigens, and - when the conjugate is a drug or toxin - the treatment of tumors. Applications of labeled antibodies and systems for the production of antibodies, such as virus-transformed B-cell lines, were discussed at a recent conference. PMID- 25289793 TI - Acute whole body UVA irradiation combined with nitrate ingestion enhances time trial performance in trained cyclists. AB - Dietary nitrate supplementation has been shown to increase nitric oxide (NO) metabolites, reduce blood pressure (BP) and enhance exercise performance. Acute exposure to ultraviolet (UV)-A light also increases NO bioavailability and reduces BP. We conducted a randomized, counterbalanced placebo-controlled trial to determine the effects of UV-A light alone and in combination with nitrate on the responses to sub-maximal steady-state exercise and time trial (TT) performance. Nine cyclists (VO2max 53.1 +/- 4.4 ml/kg/min) completed five performance trials comprising 10 min submaximal steady-state cycling followed by a 16.1 km TT. Following a familiarization the final four trials were preceded, in random order, by either (1) Nitrate gels (NIT) + UV-A, (2) Placebo (PLA) + UV-A, (3) NIT + Sham light (SHAM) and (4) PLA + SHAM (control). The NIT gels (2 * 60 ml gels, ~8.1 mmol nitrate) or a low-nitrate PLA were ingested 2.5 h prior to the trial. The light exposure consisted of 20 J/cm(2) whole body irradiation with either UV-A or SHAM light. Plasma nitrite was measured pre- and post-irradiation and VO2 was measured continuously during steady-state exercise. Plasma nitrite was higher for NIT + SHAM (geometric mean (95% CI), 332 (292-377) nM; P = 0.029) and NIT + UV-A (456 (312-666) nM; P = 0.014) compared to PLA + SHAM (215 (167 277) nM). Differences between PLA + SHAM and PLA + UV-A (282 (248-356) nM) were small and non-significant. During steady-state exercise VO2 was reduced following NIT + UVA (P = 0.034) and tended to be lower in NIT + SHAM (P = 0.086) but not PLA + UV-A (P = 0.381) compared to PLA + SHAM. Performance in the TT was significantly faster following NIT + UV-A (mean +/- SD 1447 +/- 41 s P = 0.005; d = 0.47), but not PLA + UV-A (1450 +/- 40 s; d = 0.41) or NIT + SHAM (1455 +/- 47 s; d = 0.28) compared to PLA + SHAM (1469 +/- 52 s). These findings demonstrate that exposure to UV-A light alone does not alter the physiological responses to exercise or improve performance in a laboratory setting. A combination of UV-A and NIT, however, does improve cycling TT performance in this environment, which may be due to a larger increase in NO availability. PMID- 25289795 TI - B-cell lymphokines and activation of the immune system by internal structures. PMID- 25289796 TI - Cigarette smoking and the antibody response to inhaled antigens. PMID- 25289797 TI - Induction of transplantation tolerance. PMID- 25289798 TI - The 'complete' idiotype network is an absurd immune system. AB - Idiotypic networks have attained the status of unavoidable necessities in the regulation of immune responses. In this article Rod Langman and Mel Cohn contend that the conceptual foundations for such idiotypic networks are formal absurdities. PMID- 25289799 TI - Does cyclosporine act in vivo as it does in vitro? AB - Cyclosporine aborts the activation of lymphocytes in vitro before DNA synthesis begins, yet there is also compelling evidence that lymphocytes can become primed, i.e. presumably proliferate in vivo, under the cover of immunosuppressive levels of the drug. Here, Gerry Klaus and Patricia Chisholm discuss the possibility that cyclosporine has a different mode of action in vivo and in vitro. PMID- 25289800 TI - Growth, receptors and interleukin 3. PMID- 25289801 TI - Transfer and expression of MHC genes. AB - Monoclonal antibodies have extended our knowledge of the numerous cell-surface molecules which participate in T lymphocyte functions. However, how these molecules interact and function collectively is largely unknown. The histocompatibility antigens were the first of this set of molecules to be fully characterized at the DNA level. With DNA manipulation it is possible to alter a cloned gene in vitro so as to change any specific base in the sequence to any other base, to delete a given segment of the gene or to insert a new segment. Transfection into cells of normal or genetically engineered genes allows the relationships between the structure and the function of the protein products of these genes to be investigated. In this article, Bernard Malissen summarizes recent advances in the use of gene transfer and in-vitro directed mutagenesis techniques to dissect the behaviour of immunologically relevant molecules such as histocompatibility antigens. PMID- 25289802 TI - The veto phenomenon and T-cell regulation. AB - Lymphocytes bearing anti-self receptors are produced during ontogeny, yet normally the immune system does not actively react against self components. Instead, it is thought that selfreactive cells are either deleted or, failing this, suppressed by regulatory networks similar to those limiting the immune response against non-self determinants. Recognition events between T cells play a central role in both mechanisms. Here Rick Miller describes 'veto cells' which can inactive (apparently permanently) T cells which recognize them. Some T cells can themselves serve as veto cells. The veto mechanism has been shown capable of eliminating T cells reactive against self class I major histocompatibility complex (MHC) antigens and against antigen in association with either class I or class II MHC products. PMID- 25289803 TI - Death and the cell. AB - Cell death is an important component of many - perhaps all - immunological reactions. Target cells die after attack by complement, cytotoxic T lymphocytes, K cells, NK cells or lymphotoxins. In lymphoid cells themselves death occurs in parallel with proliferation in the normal thymus and in the periphery during immune responses. Cell death, therefore, is sometimes a pathological event and sometimes a physiological process, apparently as tightly regulated as cell proliferation. In this article Edward Duvall and Andrew Wyllie develop the theme that the internal organization and metabolism of nucleated cells determines their mode of death by one or other of two relatively stereotyped patterns, necrosis or apoptosis. They discuss the general mechanisms involved in each pattern, their relevance to immunology, and their biological significance. PMID- 25289805 TI - Prevalence and disability of comorbid social phobia and obsessive-compulsive disorder in patients with panic disorder and generalized anxiety disorder. AB - OBJECTIVE: Generalized anxiety disorder (GAD) and panic disorder (PD) are disabling conditions, often comorbid with other anxiety disorders. The present study was aimed to assess prevalence and related disability of comorbid social phobia (SP) and obsessive-compulsive disorder (OCD) in 115 patients with GAD (57) or PD (58). METHODS: Patients were classified as having threshold, subthreshold, or no comorbidity, and related prevalence rates, as well as disability (Sheehan Disability Scale, SDS), were compared across diagnostic subgroups. RESULTS: SP and OCD comorbidities were present in 30.4% of the sample, with subthreshold comorbidities present at twice the rate of threshold ones (22.6% vs. 11.3%). Compared with GAD patients, PD patients showed significantly higher subthreshold and threshold comorbidity rates (27.6% and 13.8% vs. 17.5% and 8.8%, respectively). Comorbid PD patients had higher SDS scores than the comorbid and non-comorbid GAD subjects. The presence of threshold SP comorbidity was associated with the highest SDS scores. CONCLUSIONS: SP and OCD comorbidities were found to be prevalent and disabling among GAD and PD patients, with higher subthreshold than threshold rates, and a negative impact on quality of life. Present findings stress the importance of a dimensional approach to anxiety disorders, the presence of threshold and subthreshold comorbidity being the rule rather than the exception. PMID- 25289808 TI - Immunological intervention with monoclonal antibodies. AB - A recent workshop held in the Bavarian alps considered the possibilities for immunological intervention with monoclonal antibodies. While at present the benefits of most attempts to use monoclonal antibodies in vivo in man are uncertain, in-vitro and animal experiments have yielded enough positive results to encourage further efforts. Immediate dramatic effects are not to be expected because as one participant noted, we are still at an early stage in the use of monoclonal antibodies as therapeutic agents. PMID- 25289807 TI - Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators. AB - It is well established that pubertal activation of the reproductive axis and maintenance of fertility are critically dependent on the magnitude of body energy reserves and the metabolic state of the organism. Hence, conditions of impaired energy homeostasis often result in deregulation of puberty and reproduction, whereas gonadal dysfunction can be associated with the worsening of the metabolic profile and, eventually, changes in body weight. While much progress has taken place in our knowledge about the neuroendocrine mechanisms linking metabolism and reproduction, our understanding of how such dynamic interplay happens is still incomplete. As paradigmatic example, much has been learned in the last two decades on the reproductive roles of key metabolic hormones (such as leptin, insulin and ghrelin), their brain targets and the major transmitters and neuropeptides involved. Yet, the molecular mechanisms whereby metabolic information is translated and engages into the reproductive circuits remain largely unsolved. In this work, we will summarize recent developments in the characterization of the putative central roles of key cellular energy sensors, such as mTOR, in this phenomenon, and will relate these with other molecular mechanisms likely contributing to the brain coupling of energy balance and fertility. In doing so, we aim to provide an updated view of an area that, despite still underdeveloped, may be critically important to fully understand how reproduction and metabolism are tightly connected in health and disease. PMID- 25289809 TI - Immunotoxicology and the new biotechnology. AB - The use of recombinant DNA techniques, cell fusion and novel bioprocessing in the pharmaceutical industry has assisted the development of many kinds of diagnostic and therapeutic products. Some directly affect the immune system (e.g. interleukins, interferons, tumour necrosis factor, and colony stimulating factors). Others (e.g. peptides, cytokines, growth factors, H2-receptor antagonists, non-steroidal anti-inflammatory drugs and neurohormonal agents) have immunological reactivity even though they are not designed to be immune modulators. The need to define the immunotoxicological potential of these products during preclinical safety evaluation was among the topics discussed at a recent meeting. PMID- 25289806 TI - Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret. AB - Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT PCR, in situ hybridization, and immunohistochemistry. Microarray expression profiling of whole adrenal mRNA from ovariectomized vs. intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX induced adrenocortical tumors of the mouse. A complementary candidate gene approach identified Foxl2 as another gonadal-like marker expressed in GDX-induced neoplasms of the mouse and ferret. That both "male-specific" (Spinlw1) and "female-specific" (Foxl2) markers were identified is noteworthy and implies that the neoplasms exhibit mixed characteristics of male and female gonadal somatic cells. Genome-wide methylation analysis showed that two genes with hypomethylated promoters, Igfbp6 and Foxs1, are upregulated in GDX-induced adrenocortical neoplasms. These new genetic and epigenetic markers may prove useful for studies of steroidogenic cell development and for diagnostic testing. PMID- 25289810 TI - Is tolerance the result of engaging surface Ig of B cells in cycle? AB - B-cell lymphomas, neonatal B cells and recently stimulated memory precursor B cells are all susceptible to tolerance induction. A property common to these cells is that they are all cycling. In this article, David Scott and Norman Klinman propose that tolerance is induced by the binding of a B cell's slg at a critical point in early G1 phase of the cell cycle. They make predictions from their hypothesis and invite suggestions for testing it. PMID- 25289811 TI - A functional model of the human C1 complex Emergence of a functional model. AB - Precise structural data on C1s-C1r-C1r-C1s, the catalytic subunit of C1 (the first component of the classical pathway of human complement), led to the emergence of a structural and functional model of this complex protease. Now with new structural information on the amino acid sequence of the protease responsible for C1 activation (C1r), Gerard Arlaud and his colleagues propose a refinement of their original C1 model, and an overall scheme of the intramolecular events associated with the activation and control of C1. PMID- 25289813 TI - Characterization of human leukocyte differentiation antigens Stephen Shaw (1987) Immunol. Today 8, 1-3. PMID- 25289814 TI - Inappropriate rearrangement of immunoglobulin and T-cell receptor genes. PMID- 25289812 TI - The role of immunoglobulin heavy chain binding protein in immunoglobulin transport. AB - More than ten years ago a heavy chain binding protein (BiP) was described which is associated with immunoglobulin heavy chains (HC) within the endoplasmic reticulum (ER) [which is the site of Immunoglobulin (Ig) assembly]. Recently, Linda Hendershot and her collegues suggested that BiP might combine with nascent HC as they enter the ER and hold them there until assembly with light chain (LC) occurs. In the absence of LC synthesis or assembly, the HC would remain associated with BiP and would eventually be degraded internally. They now propose a means for BiP to block the transport of unassembled Ig molecules. Transport of protein from ER to the Golgi apparatus seems to be mediated by transport signals inherent to the protein molecule itself. Ig transport signals have been thought to be on the LC because LC can be secreted alone while HC cannot under normal circumstances. When BiP is displaced by LC, completed Ig molecules are transported. They use this model to explain regulated transport of Ig molecules during B-cell development, and suggest that BiP may be post-translationally associated with the nascent chains of other membrane and secretory proteins before folding or subunit assembly. PMID- 25289815 TI - Some new perspectives on transplantation immunity and tolerance. AB - To provoke a rejection response, an allograft's antigens must be presented to the host by accessory cells of the graft's MHC genotype. Tolerance induction, too, in neonatal rodents is an MHC-restricted response: third party grafts on tolerant animals survive longer if they are MHC-compatible with the tolerizing cells, rather than the host. In this article, Willys Silvers and his colleagues review the evidence for these observations and discuss their implications. PMID- 25289816 TI - The regulation of antibody class expression. AB - The regulation of antibody class expression has been an active and controversial area of research for many years. Although it is well established that T cells influence which antibody isotypes are produced during an immune response, their exact mode of action has not been delineated. In this review Judy Teale and Kristin Abraham briefly summarize current understanding of isotype regulation and describe the T cells and/or their factors which may provide the biological signals that induce the immunoglobulin class switch. PMID- 25289819 TI - One from column A, one from column B. AB - Idiotypes on immunoglobulin molecules have been used for years as serological markers of variable regions but nearly two decades after their discovery, precise structural correlates for these antigenic determinants are still exceedingly difficult to provide. At a recent conference several experts attempted to bring further structural definition to the idiotypic determinants. PMID- 25289820 TI - A clinician and a scientist look at acquired a validation of immunology's theoretical foundation. PMID- 25289821 TI - Immune-deficiency syndrome (AIDS) A consequence of allogeneic Ia-antigen recognition. PMID- 25289822 TI - C-type viral particles in hybridomas. PMID- 25289824 TI - T cells specific for IgA switching and for IgA B-cell differentiation. PMID- 25289823 TI - An ordered sequence of expression of human MHC class-II antigens during B-cell maturation? AB - Studies with monoclonal antibodies confirm that human MHC class-II antigens are encoded by at least three pairs of loci. Here Keith Guy and Veronica van Heyningen suggest that as B cells mature theproducts of these loci are expressed in the sequence SB -> DR -> DC antigens - a sequence which parallels the order of the genes on chromosome 6. PMID- 25289825 TI - Synthetic peptides and their impact on immunology. PMID- 25289826 TI - Isotype-specific regulation of the IgE response by IgE-binding factors. AB - The IgE response is regulated by antigen-speck helper and suppressor T cells. Here Kimishige Ishizaka and his colleagues discuss recent work which indicates that soluble IgE-binding T-cell factors provide an additional, isotypespecific level of control on the antibody response. PMID- 25289827 TI - The single-cell assay in cell-mediated cytotoxicity. AB - Studies on the humoral antibody response were greatly advanced by the introduction in 1963 of the Jerne plaque assay which permitted direct enumeration of individual antibody-producing plasma cells(1). Studies of cellular cytotoxicity were limited until recently to the examination of whole populations of effector cells(2). Here, Benjamin Bonavida and his colleagues describe an assay in agarose which allows the study of single cytotoxic cells(3-5). PMID- 25289828 TI - The restless tide: The persistent challenge of the microbial world by Richard M. Krause, National Foundation for Infectious Diseases, 1981. $16. 00 (i + 152 pages) Library of Congress No. 82-116089. PMID- 25289837 TI - Electric Field Effect on Phospholipid Monolayers at an Aqueous-Organic Liquid Liquid Interface. AB - The electric potential difference across cell membranes, known as the membrane potential, plays an important role in the activation of many biological processes. To investigate the effect of the membrane potential on the molecular ordering of lipids within a biomimetic membrane, a self-assembled monolayer of 1 stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) lipids at an electrified 1,2 dichloroethane/water interface is studied with X-ray reflectivity and interfacial tension. Measurements over a range of electric potential differences, -150 to +130 mV, that encompass the range of typical biomembrane potentials demonstrate a nearly constant and stable structure whose lipid interfacial density is comparable to that found in other biomimetic membrane systems. Measurements at higher positive potentials, up to 330 mV, illustrate a monotonic decrease in the lipid interfacial density and accompanying variations in the interfacial configuration of the lipid. Molecular dynamics simulations, designed to mimic the experimental conditions, show that the measured changes in lipid configuration are due primarily to the variation in area per lipid with increasing applied electric field. Rotation of the SOPC dipole moment by the torque from the applied electric field appears to be negligible, except at the highest measured potentials. The simulations confirm in atomistic detail the measured potential dependent characteristics of SOPC monolayers. Our hybrid study sheds light on phospholipid monolayer stability under different membrane potentials, which is important for understanding membrane processes. This study also illustrates the use of X-ray surface scattering to probe the ordering of surfactant monolayers at an electrified aqueous-organic liquid-liquid interface. PMID- 25289838 TI - Ultrasonography of subcoracoid bursal impingement syndrome. AB - Subcoracoid impingement syndrome with bursitis is an underrecognized cause of anterior shoulder pain. It usually presents with pain around the coracoid process and a positive impingement test with shoulder adduction, forward flexion, and internal rotation. The pain is mediated by impingement of soft tissues such as the subcoracoid bursa or subscapularis tendon between the coracoid process and humerus. Ultrasonography (US) can be useful in the evaluation of subcoracoid bursal impingement syndrome because of its high resolution capacity and the use of dynamic maneuvers. In this case series, we present 3 patients with subcoracoid impingement syndrome with bursitis diagnosed with in-office US. This case series illustrates the application of US in the evaluation of anterior shoulder pain with subcoracoid bursal impingement syndrome. PMID- 25289839 TI - Improved functional capacity evaluation performance predicts successful return to work one year after completing a functional restoration rehabilitation program. AB - OBJECTIVE: To evaluate whether functional capacity evaluation (FCE) scores are responsive to functional restoration treatment, and to assess the ability of FCEs at program discharge to predict work outcomes. DESIGN: An interdisciplinary cohort study of prospectively collected data. SETTING: A functional restoration center. PATIENTS: A consecutive sample of 354 patients with chronic disabling occupational musculoskeletal disorders (CDOMDs) completed a functional restoration program consisting of quantitatively directed exercise progression and multi-modal disability management with interdisciplinary medical supervision. METHODS: Each patient participated in an FCE at admission and discharge from treatment. The results of each FCE yielded the physical demand level (PDL) at which patients were functioning. Patients were initially divided into 5 PDL groups, based on job-of-injury lifting, carrying, and pushing/pulling requirements, for the pre- to posttreatment responsiveness analyses. Patients were subsequently divided into 5 PDL groups, based on their performance on the FCE upon program completion. MAIN OUTCOME MEASURES: Outcome measures included admission-to-discharge changes in PDLs and 2 specific FCE lifting tasks: isokinetic lifting; and the Progressive Isoinertial Lifting Evaluation (PILE). Socioeconomic outcomes were also evaluated, including post-discharge work return and work retention 1-year after treatment completion. RESULTS: Overall, 96% of the patients demonstrated improvement in their PDLs from admission to discharge. A majority of patients (56%) were able to achieve a discharge PDL that was comparable to their estimated job-of-injury lifting requirement or higher (P < .001). Lifting ability improved from admission to discharge by approximately 50% (all P < .001). Discharge PDLs predicted both work return (P < .001) and work retention (P < .001) 1 year later. CONCLUSIONS: FCE scores were responsive to functional restoration treatment, and the associated discharge PDLs predicted work return after treatment completion and work retention 1 year later. PMID- 25289841 TI - Content analysis of CMS Healthcare Innovation Awards from a physiatric perspective. AB - On June 15, 2012, the Centers for Medicare and Medicaid Services (CMS) announced the 107 recipients of the Healthcare Innovation Awards (HCIA). The 107 awardees received a total of $874,074,900 in funding, with a projected 3-year savings of $1,863,119,104. A word frequency calculator was used to perform a content analysis on the document that announced the projects receiving funding in the 2012 HCIA program. Results were tabulated and categorized to look for prevailing themes and trends. The words generated by the word frequency calculator were grouped into common roots and tabulated to better understand how CMS was rewarding value. Some of the most common words were "manage," "community," "coordinate," "team," "system" and "integrate." Additionally, the job positions that the projects propose to create were tabulated and grouped into categories. Physicians, including physiatrists, were not often mentioned, whereas nursing and nonclinical positions were frequently listed. This content analysis showed that the concepts emphasized in the HCIA projects parallel fundamental physiatric principles. The findings may help physiatrists understand how reform is unfolding, prepare for the evolving health care landscape, and recognize future opportunities. PMID- 25289840 TI - Efficacy of blood flow-restricted, low-load resistance training in women with risk factors for symptomatic knee osteoarthritis. AB - OBJECTIVE: To assess whether concurrent blood flow restriction (BFR) during low load resistance training is an efficacious and tolerable means of improving quadriceps strength and volume in women with risk factors for symptomatic knee osteoarthritis (OA). DESIGN: Randomized, double-blinded, controlled trial. SETTING: Exercise training clinical research laboratory. PARTICIPANTS: Women over age 45 years with risk factors for symptomatic knee OA. METHODS: Participants were randomized to either low-load resistance training (30% 1RM) alone (control) or with concurrent BFR and completed 4 weeks of 3 times per week leg-press resistance training. Those randomized to BFR wore a cuff that progressively restricted femoral blood flow over the weeks of training. Intergroup differences in outcome measures were compared using regression methods, while adjusting for BMI. MAIN OUTCOME MEASURES: Isotonic bilateral leg press strength, isokinetic knee extensor strength, and quadriceps volume by magnetic resonance imaging were assessed before and after participation. Secondary measures included lower limb muscle power (leg press and stair climb). Knee pain was assessed to determine tolerance. RESULTS: Of 45 women who consented to study participation, 40 completed the program. There were no significant intergroup differences in baseline characteristics except that body mass index was lower in the BFR group (P = .0223). Isotonic 1RM improved significantly more in the BFR group (28.3 +/- 4.8 kg) than in the control group (15.6 +/- 4.5 kg) (P = .0385). Isokinetic knee extensor strength scaled to body mass increased significantly more in the BFR group (0.07 +/- 0.03 nm/kg) than in the control group (-0.05 +/- 0.03 nm/kg) (P = .0048). Changes in quadriceps volume, leg press power, and knee-related pain did not significantly differ between groups. CONCLUSIONS: Addition of BFR to a 30% 1RM resistance training program was effective in increasing leg press and knee extensor strength in women at risk for knee OA, in comparison with the same program without BFR. PMID- 25289842 TI - Primary subcutaneous hydatid cyst presenting with low back pain. PMID- 25289844 TI - A truly specific tumour marker? PMID- 25289843 TI - Generalized pruritus as an unusual side effect after epidural injection with dexamethasone. AB - A 51-year-old man with lumbar radiculopathy underwent a right L5 transforaminal epidural steroid injection with dexamethasone. One minute after the injection, the patient experienced severe pruritus and burning, which began in the groin and then spread throughout his body. The symptoms resolved completely after 1 minute, and the patient was discharged without any complications. Although there are a small number of publications reporting perineal pruritus after intravenous administration of dexamethasone, to our knowledge there is no report of a generalized reaction to an epidural dexamethasone injection such as the one described here. PMID- 25289845 TI - HLA-DR: more than three loci? PMID- 25289846 TI - Agreeing terms. PMID- 25289847 TI - Challenges to nature's transplant. PMID- 25289848 TI - Can cytotoxic T cells recognize self determinants on molecules lacking polymorphic MHC self determinants. PMID- 25289849 TI - T-cell hybridomas: sources of specific mediators in the immune system. PMID- 25289850 TI - Interleukin 3 - a new lymphokine? PMID- 25289851 TI - How pure are inbred strains of mice? AB - As useful as immunologists find the inbred mouse, they cannot help but become disenchanted when they encounter genetically disparate mice in a purportedly inbred strain. Genetic impurity (allogenicity) can arise from a number of sources: incomplete inbreeding, mutation, inadvertent outcrossing, mislabeling, and epislatic and heterozygote selection. In this article D. W. Bailey discusses these vitiating sources and the appropriate precautions against there. PMID- 25289852 TI - The molecular mechanisms of the immunoglobulin class switch. PMID- 25289853 TI - Thymus-independent antigens: complexity of B-lymphocyte activation revealed. PMID- 25289858 TI - Long-term carbon loss in fragmented Neotropical forests. AB - Tropical forests play an important role in the global carbon cycle, as they store a large amount of carbon (C). Tropical forest deforestation has been identified as a major source of CO2 emissions, though biomass loss due to fragmentation--the creation of additional forest edges--has been largely overlooked as an additional CO2 source. Here, through the combination of remote sensing and knowledge on ecological processes, we present long-term carbon loss estimates due to fragmentation of Neotropical forests: within 10 years the Brazilian Atlantic Forest has lost 69 (+/-14) Tg C, and the Amazon 599 (+/-120) Tg C due to fragmentation alone. For all tropical forests, we estimate emissions up to 0.2 Pg C y(-1) or 9 to 24% of the annual global C loss due to deforestation. In conclusion, tropical forest fragmentation increases carbon loss and should be accounted for when attempting to understand the role of vegetation in the global carbon balance. PMID- 25289860 TI - RGS2 and RGS4 proteins: New modulators of the kappa-opioid receptor signaling. AB - Previous studies have shown that RGS4 associates with the C-termini of MU- and delta-opioid receptors in living cells and plays a key role in Gi/Go protein coupling selectivity and signalling of these receptors [12,20]. To deduce whether similar effects also occur for the kappa-opioid receptor (kappa-OmicronR) and define the ability of members of the Regulators of G protein Signaling (RGS) of the B/R4 subfamily to interact with kappa-OmicronR subdomains we generated glutathione S-transferase fusion peptides encompassing the carboxyl-termini of kappa-OR (kappa-CT). Results from pull down experiments indicated that RGS2 and RGS4 directly interact within different domains of the kappa-CT. Co-precipitation studies in living cells indicated that RGS2 and RGS4 associate with kappa OmicronR constitutively and upon receptor activation and confer selectivity for coupling with a specific subset of G proteins. Expression of both members, RGS2 and/or RGS4, in 293F cells attenuated kappa-agonist mediated-adenylyl cyclase inhibition and extracellular signal regulated kinase (ERK1,2) phosphorylation with a different amplitude in their modulatory effect in kappa-OmicronR signaling. Our findings demonstrate that RGS2 and RGS4 are new interacting partners that play key roles in G protein coupling to negatively regulate kappa OmicronR signaling. PMID- 25289863 TI - Interactions of complement components with antibody - antigen aggregates and cell surfaces. PMID- 25289859 TI - Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling. AB - Signaling through the G protein-coupled kinin receptors B1 (kB1R) and B2 (kB2R) plays a critical role in inflammatory responses mediated by activation of the kallikrein-kinin system. The kB2R is constitutively expressed and rapidly desensitized in response to agonist whereas kB1R expression is upregulated by inflammatory stimuli and it is resistant to internalization and desensitization. Here we show that the kB1R heterodimerizes with kB2Rs in co-transfected HEK293 cells and natively expressing endothelial cells, resulting in significant internalization and desensitization of the kB1R response in cells pre-treated with kB2R agonist. However, pre-treatment of cells with kB1R agonist did not affect subsequent kB2R responses. Agonists of other G protein-coupled receptors (thrombin, lysophosphatidic acid) had no effect on a subsequent kB1R response. The loss of kB1R response after pretreatment with kB2R agonist was partially reversed with kB2R mutant Y129S, which blocks kB2R signaling without affecting endocytosis, or T342A, which signals like wild type but is not endocytosed. Co endocytosis of the kB1R with kB2R was dependent on beta-arrestin and clathrin coated pits but not caveolae. The sorting pathway of kB1R and kB2R after endocytosis differed as recycling of kB1R to the cell surface was much slower than that of kB2R. In cytokine-treated human lung microvascular endothelial cells, pre-treatment with kB2R agonist inhibited kB1R-mediated increase in transendothelial electrical resistance (TER) caused by kB1R stimulation (to generate nitric oxide) and blocked the profound drop in TER caused by kB1R activation in the presence of pyrogallol (a superoxide generator). Thus, kB1R function can be downregulated by kB2R co-endocytosis and signaling, suggesting new approaches to control kB1R signaling in pathological conditions. PMID- 25289861 TI - The involvement of nuclear factor-kappaappaB in the nuclear targeting and cyclin E1 upregulating activities of hepatoma upregulated protein. AB - Hepatoma upregulated protein (HURP) is originally isolated during the search for the genes associated with hepatoma. HURP is upregulated in many human cancers. Culture cells exhibit transformed and invasive phenotype when ectopic HURP is introduced, revealing HURP as an oncogene candidate. Our previous studies demonstrated that Aurora-A regulated the cell transforming activities of HURP by phosphorylating HURP at four serines. To unravel how the Aurora-A/HURP cascade contributes to cell transformation, we firstly noticed that HURP shuttled between cytoplasm and nucleus. The nuclear localization activity of HURP was promoted or abolished by overexpression or knockdown of Aurora-A. Similarly, the HURP phosphorylation mimicking mutant 4E had higher nuclear targeting activity than the phosphorylation deficient mutant 4A. The HURP 4E accelerated G1 progression and upregulated cyclin E1, and the cyclin E1 upregulating and cell transforming activities of HURP were diminished when the nuclear localization signal (NLS) was removed from HURP. Furthermore, HURP employed p38/nuclear factor-kappaB (NF kappaB) cascade to stimulate cell growth. Interestingly, NF-kappaB trapped HURP in nucleus by interacting with HURP 4E. At last, the HURP/NF-kappaB complex activated the cyclin E1 promoter. Collectively, Aurora-A/HURP relays cell transforming signal to NF-kappaB, and the HURP/NF-kappaB complex is engaged in the regulation of cyclin E1 expression. PMID- 25289862 TI - A high-efficiency induction of dopaminergic cells from human umbilical mesenchymal stem cells for the treatment of hemiparkinsonian rats. AB - The success rate in previous attempts at transforming human umbilical mesenchymal stem cells (HUMSCs) isolated from Wharton's jelly of the umbilical cord into dopaminergic cells was a mere 12.7%. The present study was therefore initiated to establish a more effective procedure for better yield of dopaminergic cells in such transformation for more effective HUMSC-based therapy for parkinsonism. To examine, in vitro, the effects of enhanced Nurr1 expression in HUMSCs on their differentiation, cells were processed through the three-stage differentiation protocol. The capacity of such cells to synthesize and release dopamine was measured by HPLC. The therapeutic effects of Nurr1-overexppressed HUMSCs were examined in 6-hydroxydopamine-lesioned rats by quantification of rotations in response to amphetamine. Enhanced Nurr1 expression in HUMSCs promoted the transformation into dopaminergic cells in vitro through stepwise culturing in sonic hedgehog, fibroblast growth factor-8, and neuron-conditioned medium. The success rate was about 71%, as determined by immunostaining for tyrosine hydroxylase and around 94 nM dopamine synthesis (intracellular and released into the culture medium), as measured by HPLC. Additionally, transplantation of such cells into the striatum of hemiparkinsonian rats resulted in improvement of their behavioral deficits, as indicated by amphetamine-evoked rotation scores. Viability of the transplanted cells lasted for at least 3 months as verified by positive staining for tyrosine hydroxylase. Nurr1, FGF8, Shh, and NCM can synergistically enhance the differentiation of HUMSCs into dopaminergic cells and may pave the way for HUMSC-based treatments for Parkinson's disease. PMID- 25289864 TI - Studies with monoclonal antibodies to complement components. PMID- 25289865 TI - Murine systemic lupus erythematosus. PMID- 25289866 TI - Mast-cell secretion and structure-functional relationships of granule constituents and leukotrienes. PMID- 25289867 TI - From synthetic antigens to synthetic vaccines. PMID- 25289868 TI - The genetic control of immune responses. PMID- 25289869 TI - Cell interactions in specific immune suppression. PMID- 25289870 TI - Antigen transport in the spleen. PMID- 25289871 TI - Selective effects of cyclosporin A on B-cell subpopulations in the mouse. PMID- 25289872 TI - T-cell recognition of influenza-infected cells. PMID- 25289873 TI - Clonal deletion in self-tolerance. PMID- 25289874 TI - Forbidden clones. PMID- 25289875 TI - Emphysema, smoking and the alveolar macrophage. PMID- 25289876 TI - The regulation of gastrointestinal immune responses. PMID- 25289877 TI - The delayed hypersensitivity T cell and its interaction with other T cells. AB - In this review Tony Nash and Philip Gell consider mainly recent work on the delayed hypersensitivity (DH) T cell (TDH) in mice, using viruses as infectious agents to probe the nature of DH and its relationship to protection. PMID- 25289878 TI - Over-commitment of EMS personnel in North Carolina with implications for disaster planning. AB - BACKGROUND: While large-scale disasters are uncommon, our society relies on emergency personnel to be available to respond and act. Faith in their availability may lead to a false sense of security. Many emergency personnel obligate themselves to more than one agency and so may be overcommitted, leaving agencies with unfilled positions in a disaster. We sought to describe the frequency of overcommitment of emergency medical services (EMS) personnel in North Carolina. METHODS: We conducted a cross-sectional study utilizing the Credentialing Information System (CIS) of the North Carolina Office of EMS. The CIS database manages demographic and certification information for all EMS personnel in North Carolina. The state is divided into 100 EMS systems based on county boundaries. Utilizing de-identified provider data from the CIS, we collected system(s) affiliation(s) and level of certification. To calculate an overcommitment rate per system, we divided the number of personnel with more than one system affiliation by total number of system roster personnel. To compare urbanicity and certification level with overcommitment, analysis of variance and the chi-square test were used, respectively. RESULTS: North Carolina credentials 14,717 EMS providers (8,346 EMT, 1,709 EMT-intermediate (EMT-I), 4,662 EMT paramedic (EMT-P)). Of these, 10,928 (74%) are affiliated with a single system. Of the 3,789 committed to more than one system, 3,020 (21%) were committed to two systems, 571 (4%) to three, 138 (1%) to four, and 60 (<1%) to five or more. EMT Is and EMT-Ps were more likely to be overcommitted when compared to EMTs (37, 32, 20% respectively, p < 0.0001). Statewide, the median overcommitment rate for EMS systems was 24% (IQR 16-37%). Personnel working in systems servicing less densely populated areas were more likely to be overcommitted: 33% wilderness, 29% rural, 20% suburban and 11% urban (p < 0.0001). Additionally, 40% wilderness, 23% rural, 4% suburban, and 0% urban systems had >37% of their personnel engaged in 9-1-1 response in more than one system. CONCLUSION: Many EMS personnel have multiple EMS commitments. Disaster planners and emergency managers should consider overcommitment of emergency responders when calculating the work force on which they can rely. PMID- 25289879 TI - Driving force analysis of the agricultural water footprint in China based on the LMDI method. AB - China's water scarcity problems have become more severe because of the unprecedented economic development and population explosion. Considering agriculture's large share of water consumption, obtaining a clear understanding of Chinese agricultural consumptive water use plays a key role in addressing China's water resource stress and providing appropriate water mitigation policies. We account for the Chinese agricultural water footprint from 1990 to 2009 based on bottom up approach. Then, the underlying driving forces are decomposed into diet structure effect, efficiency effect, economic activity effect, and population effect, and analyzed by applying a log-mean Divisia index (LMDI) model. The results reveal that the Chinese agricultural water footprint has risen from the 94.1 Gm3 in 1990 to 141 Gm3 in 2009. The economic activity effect is the largest positive contributor to promoting the water footprint growth, followed by the population effect and diet structure effect. Although water efficiency improvement as a significant negative effect has reduced overall water footprint, the water footprint decline from water efficiency improvement cannot compensate for the huge increase from the three positive driving factors. The combination of water efficiency improvement and dietary structure adjustment is the most effective approach for controlling the Chinese agricultural water footprint's further growth. PMID- 25289880 TI - Smad-induced alterations of matrix metabolism by a myristoyl tetra peptide. AB - Regulation of extracellular matrix (ECM) components is essential for tissue homeostasis and function. We screened a small peptide that induces ECM protein synthesis for its usefulness in protecting keratinocytes. In this report, we demonstrate that myristoyl tetrapeptide Ala-Ala-Pro-Val (mAAPV) stimulates the expression of ECM proteins and inhibits the expression of metalloproteinases (MMPs) that degrade ECM proteins in Hs68 human fibroblast cells. In order to elucidate the underlying molecular mechanisms for the effects of mAAVP, we investigated the changes in gene expression in the presence of mAAPV using a cDNA microarray. Treatment with mAAPV resulted in decreased expression of MMP-related genes such as MMP1, MMP3, TIMP1 and TIMP3 and increased expression of collagen genes, including COL1A1, COL1A2, COL3A1, COL5A1 and COL6A3. The pattern of gene expression regulated by mAAPV was very similar to that of gene expression induced by transforming growth factor (TGF)-beta, indicating that the TGF-beta signaling pathway is crucial for simultaneous activation of several ECM-related genes by mAAPV. We examined whether the activation of SMAD, a downstream protein of TGF beta receptor, is involved in the signal transduction pathway induced by mAAPV. The results demonstrate that mAAVP directly activates SMAD2 and induces SMAD3 to bind to DNA. In conclusion, our results demonstrate that mAAPV both enhances the expression of collagen and inhibits its degradation via production of protease inhibitors that prevent enzymatic breakdown of the ECM. The results suggest that mAAPV would be a useful ECM-protecting agent. PMID- 25289881 TI - Etiology and management of recurrent parotid pleomorphic adenoma. AB - The objective of this review study was to encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem. The source of the data was Ovid MEDLINE from 1946 to 2014. Review methods consisted of articles with clinical correlates. The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of pleomorphic adenoma tissue, and satellite pleomorphic beyond the pseudocapsule are also likely linked to recurrent pleomorphic adenoma. Most recurrent pleomorphic adenoma are multinodular. Magnetic resonance imaging is the imaging study of choice for recurrent pleomorphic adenoma. Nerve integrity monitoring may reduce morbidity for recurrent pleomorphic adenoma. Treatment of recurrent pleomorphic adenoma must be individualized. Total parotidectomy, given the multicentricity of recurrent pleomorphic adenoma, is appropriate in many patients, but may be inadequate to control recurrent pleomorphic. There is accumulating evidence from retrospective series that postoperative radiation therapy results in significantly better local control. PMID- 25289882 TI - Lanthanide-based heteroepitaxial core-shell nanostructures: compressive versus tensile strain asymmetry. AB - Heteroepitaxial core-shell nanostructures have been proven advantageous in a wide variety of applications, ranging from luminescence enhancement, band gap engineering, multimodal theranostics, to catalysis. However, precisely tailoring the epitaxial growth is challenging, and a general understanding of the parameters that impact epitaxial growth remains unclear. Here we demonstrate the critical role of the sign of the lattice mismatch of the shell relative to the core (compressed/tensile) in generating lanthanide-based core-shell structures, a parameter conventionally not considered in heteroepitaxial design. We took advantage of the very gradual contraction of lanthanide ions along the series to control precisely both the magnitude and the sign of lattice mismatch and investigated multiple sodium lanthanide fluoride (NaLnF4) core-shell heterostructures of variable composition and size. We discovered that the tensile strained shells adapt to the core crystallite shape (i.e., conformal) and lattice structure (i.e., coherent), while under identical magnitude of mismatch, the compressively strained shells are neither conformal nor coherent to the core. This striking asymmetry between the tensile and compressively strained epitaxial growth arises from the fundamental anharmonicity of the interatomic interactions between the attractive and repulsive pairs. From a broader perspective, our findings redefine the a priori design consideration and provide a fundamental insight on the necessity to include the sign of lattice mismatch and not just its magnitude in designing heteroepitaxial core-shell nanostructures. PMID- 25289883 TI - Three new limonoids from Azadirachta indica. AB - Three new limonoids, azadiraindins E-G (1-3, respectively), together with six known analogs, were isolated from the fresh fruit coats of Azadirachta indica. The structures of these compounds were elucidated by spectroscopic methods (IR, MS, HR-ESI-MS, 1D NMR, and 2D NMR). PMID- 25289884 TI - Development of a colorimetric sensor array for the discrimination of Chinese liquors based on selected volatile markers determined by GC-MS. AB - A new colorimetric sensor array was developed for the discrimination of 12 high alcoholic Chinese base liquors from Luzhou Co., Ltd., and 15 commercial Chinese liquor of different brands as well as flavor types. Seventeen volatile compounds within four chemical groups were determined as markers in the base liquor by GC MS analysis and factor analysis method (FAM). A specialized colorimetric sensor array composed of 20 sensitive dots was fabricated accordingly to obtain sensitive interaction with different types of volatile markers. Discrimination of the liquor samples was subsequently performed using chemometric and statistical methods, including principal component analysis (PCA) and hierarchical clustering analysis (HCA). The results suggested that facile identification of either base liquors with high-alcoholic volume or commercial liquors of the same flavor types could be achieved by analysis of the color change profiles. The response of the sensor improved significantly in comparison with those that rely on nonspecific interactions, and no misclassification was observed for both liquor samples using two chemometric methods. Besides, it was also found that the discrimination is closely related to the characteristic flavor compounds (esters, aldehydes, and acids) and alcoholic strength in liquors, and its performance was even comparable with that of GC-MS. PMID- 25289885 TI - Effect of time of day on performance, hormonal and metabolic response during a 1000-M cycling time trial. AB - The aim of this study was to determine the effect of time of day on performance, pacing, and hormonal and metabolic responses during a 1000-m cycling time-trial. Nine male, recreational cyclists visited the laboratory four times. During the 1st visit the participants performed an incremental test and during the 2nd visit they performed a 1000-m cycling familiarization trial. On the 3rd and 4th visits, the participants performed a 1000-m TT at either 8 am or 6 pm, in randomized, repeated-measures, crossover design. The time to complete the time trial was lower in the evening than in the morning (88.2+/-8.7 versus 94.7+/-10.9 s, respectively, p<0.05), but there was no significant different in pacing. However, oxygen uptake and aerobic mechanical power output at 600 and 1000 m tended to be higher in the evening (p<0.07 and 0.09, respectively). There was also a main effect of time of day for insulin, cortisol, and total and free testosterone concentration, which were all higher in the morning (+60%, +26%, +31% and +22%, respectively, p<0.05). The growth hormone, was twofold higher in the evening (p<0.05). The plasma glucose was ~11% lower in the morning (p<0.05). Glucagon, norepinephrine, epinephrine and lactate were similar for the morning and evening trials (p>0.05), but the norepinephrine response to the exercise was increased in the morning (+46%, p<0.05), and it was accompanied by a 5-fold increase in the response of glucose. Muscle recruitment, as measured by electromyography, was similar between morning and evening trials (p>0.05). Our findings suggest that performance was improved in the evening, and it was accompanied by an improved hormonal and metabolic milieu. PMID- 25289886 TI - Ultra high content image analysis and phenotype profiling of 3D cultured micro tissues. AB - In many situations, 3D cell cultures mimic the natural organization of tissues more closely than 2D cultures. Conventional methods for phenotyping such 3D cultures use either single or multiple simple parameters based on morphology and fluorescence staining intensity. However, due to their simplicity many details are not taken into account which limits system-level study of phenotype characteristics. Here, we have developed a new image analysis platform to automatically profile 3D cell phenotypes with 598 parameters including morphology, topology, and texture parameters such as wavelet and image moments. As proof of concept, we analyzed mouse breast cancer cells (4T1 cells) in a 384 well plate format following exposure to a diverse set of compounds at different concentrations. The result showed concentration dependent phenotypic trajectories for different biologically active compounds that could be used to classify compounds based on their biological target. To demonstrate the wider applicability of our method, we analyzed the phenotypes of a collection of 44 human breast cancer cell lines cultured in 3D and showed that our method correctly distinguished basal-A, basal-B, luminal and ERBB2+ cell lines in a supervised nearest neighbor classification method. PMID- 25289888 TI - Ebola vaccine--an urgent international priority. PMID- 25289887 TI - MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis. AB - Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors. PMID- 25289890 TI - Alterations in tight junction protein and IgG permeability accompany leukocyte extravasation across the choroid plexus during neuroinflammation. AB - The choroid plexus (CP) is considered to be a point of leukocyte entry into the CNS during normal immune surveillance and in neuroinflammatory diseases. The structural and functional alterations within the CP that support this migration are not understood. We used quantitative, high-resolution, 3-dimensional (3-D) fluorescence imaging to analyze CP alterations associated with inflammatory responses in C57/Bl6 mice after the induction of experimental autoimmune encephalomyelitis by immunization with myelin oligodendrocyte glycoprotein (MOG) and complete Freund adjuvant/pertussis toxin (MOG-CFA/PTX) or adjuvants alone (CFA-PTX). The MOG-CFA/PTX and CFA/PTX produced similar effects, although those caused by the former were consistently more marked. Both treatments resulted in the accumulation of serum immunoglobulin G and leukocytes in the CP stroma, consistent with elevated stromal capillary permeability. They also provoked distortions and diminished immunostaining patterns of the tight junction adaptor protein ZO-1 in the choroidal epithelium but no obvious change in the patterns of the tight junction associated protein claudin-2. Only MOG-CFA/PTX triggered visible extravasation of immunoglobulin G and leukocytes across the choroidal epithelium. Our results suggest that CFA/PTX primes the CP for neuroinflammation by inducing structural changes that are exacerbated when there is an immune response to MOG and reinforce the CP as a gateway for leukocytes to enter the CNS by accessing the CSF and leptomeninges. PMID- 25289889 TI - Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades. AB - Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes xenograft growth. In vitro, tamoxifen inhibits MPNST proliferation and survival in an estrogen receptor-independent manner; these effects are phenocopied by the calmodulin inhibitor trifluoperazine. The present study was performed to establish the mechanism of action of tamoxifen in vivo and optimize its therapeutic effectiveness. To determine if tamoxifen has estrogen receptor dependent effects in vivo, we grafted MPNST cells in castrated and ovariectomized mice; xenograft growth was unaffected by reductions in sex hormones. To establish whether tamoxifen and trifluoperazine additively or synergistically impede MPNST growth, mice xenografted with neurofibromatosis type 1-associated or sporadic MPNST cells were treated with tamoxifen, trifluoperazine, or both drugs for 30 days. Both monotherapies inhibited graft growth by 50%, whereas combinatorial treatment maximally reduced graft mass by 90% and enhanced decreases in proliferation and survival. Kinomic analyses showed that tamoxifen and trifluoperazine have both shared and distinct targets in MPNSTs. In addition, trifluoperazine prevented tamoxifen-induced increases in serum/glucocorticoid regulated kinase 1, a protein linked to tamoxifen resistance. These findings suggest that combinatorial therapy with tamoxifen and trifluoperazine is effective against MPNSTs because these agents target complementary pathways that are essential for MPNST pathogenesis. PMID- 25289891 TI - Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex. AB - A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas. PMID- 25289892 TI - How stemlike are sphere cultures from long-term cancer cell lines? Lessons from mouse glioma models. AB - Cancer stem cells may mediate therapy resistance and recurrence in various types of cancer, including glioblastoma. Cancer stemlike cells can be isolated from long-term cancer cell lines, including glioma lines. Using sphere formation as a model for cancer cell stemness in vitro, we derived sphere cultures from SMA-497, SMA-540, SMA-560, and GL-261 glioma cells. Gene expression and proteomics profiling demonstrated that sphere cultures uniformly showed an elevated expression of stemness-associated genes, notably including CD44. Differences in neural lineage marker expression between nonsphere and sphere cultures were heterogeneous except for a uniform reduction of beta-III-tubulin in sphere cultures. All sphere cultures showed slower growth. Self-renewal capacity was influenced by medium conditions but not nonsphere versus sphere culture phenotype. Sphere cultures were more resistant to irradiation, whereas both nonsphere and sphere cultures were highly resistant to temozolomide. Nonsphere cells formed more aggressive tumors in syngeneic mice than sphere cells in all models except SMA-560. There were no major differences in vascularization or infiltration by T cells or microglia/macrophages between nonsphere and sphere cell-derived tumors implanted in syngeneic hosts. Together, these data indicate that mouse glioma cell lines may be induced in vitro to form spheres that acquire features of stemness, but they do not exhibit a uniform biologic phenotype, thereby challenging the view that they represent a superior model system. PMID- 25289894 TI - Enterovirus 71 can directly infect the brainstem via cranial nerves and infection can be ameliorated by passive immunization. AB - Enterovirus 71 (EV71)-associated hand, foot, and mouth disease may be complicated by encephalomyelitis. We investigated EV71 brainstem infection and whether this infection could be ameliorated by passive immunization in a mouse model. Enterovirus 71 was injected into unilateral jaw/facial muscles of 2-week-old mice, and hyperimmune sera were given before or after infection. Harvested tissues were studied by light microscopy, immunohistochemistry, in situ hybridization, and viral titration. In unimmunized mice, viral antigen and RNA were detected within 24 hours after infection only in ipsilateral cranial nerves, motor trigeminal nucleus, reticular formation, and facial nucleus; viral titers were significantly higher in the brainstem than in the spinal cord samples. Mice given preinfection hyperimmune serum showed a marked reduction of ipsilateral viral antigen/RNA and viral titers in the brainstem in a dose-dependent manner. With optimum hyperimmune serum given after infection, brainstem infection was significantly reduced in a time-dependent manner. A delay in disease onset and a reduction of disease severity and mortality were also observed. Thus, EV71 can directly infect the brainstem, including the medulla, via cranial nerves, most likely by retrograde axonal transport. This may explain the sudden cardiorespiratory collapse in human patients with fatal encephalomyelitis. Moreover, our results suggest that passive immunization may still benefit EV71 infected patients who have neurologic complications. PMID- 25289895 TI - Neuropathologic features of pontocerebellar hypoplasia type 6. AB - Pontocerebellar hypoplasia is a group of severe developmental disorders with prenatal onset affecting the growth and function of the brainstem and cerebellum. The rarity and genetic heterogeneity of this group of disorders can make molecular diagnosis challenging. We report 3 siblings who were born to nonconsanguineous parents, were hypotonic at birth, developed seizures, had repeated apneic spells, and died within 2 months of life. Neuroimaging showed that all had profound cerebellar hypoplasia and simplified cortical gyration. Genetic analysis by whole-exome sequencing demonstrated compound heterozygous mutations in the mitochondrial arginyl transfer RNA synthetase gene RARS2, indicating that the children had pontocerebellar hypoplasia type 6. Autopsies on the younger twin siblings revealed small and immature cerebella at an approximate developmental age of less than 18 weeks. The basis pontis showed regressive changes, and the medulla had marked inferior olivary hypoplasia. The brains of both twins were microencephalic and had simplified gyri; cortices were immature, and deep white matter had extensive astrocytosis. The findings suggest a near normal embryologic period followed by midgestation developmental slowing or cessation and later regression in select anatomic regions. This is the first detailed description of neuropathologic findings associated with pontocerebellar hypoplasia type 6 and demonstrates the profound effects of RARS2 disruption during early neurodevelopment. PMID- 25289893 TI - Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people. AB - The blood-brain barrier protects brain tissue from potentially harmful plasma components. Small vessel disease (SVD; also termed arteriolosclerosis) is common in the brains of older people and is associated with lacunar infarcts, leukoaraiosis, and vascular dementia. To determine whether plasma extravasation is associated with SVD, we immunolabeled the plasma proteins fibrinogen and immunoglobulin G, which are assumed to reflect blood-brain barrier dysfunction, in deep gray matter (DGM; anterior caudate-putamen) and deep subcortical white matter (DWM) in the brains of a well-characterized cohort of donated brains with minimal Alzheimer disease pathology (Braak Stages 0-II) (n = 84; aged 65 years or older). Morphometric measures of fibrinogen labeling were compared between people with neuropathologically defined SVD and aged control subjects. Parenchymal cellular labeling with fibrinogen and immunoglobulin G was detectable in DGM and DWM in many subjects (>70%). Quantitative measures of fibrinogen were not associated with SVD in DGM or DWM; SVD severity was correlated between DGM and DWM (p < 0.0001). Fibrinogen in DGM showed a modest association with a history of hypertension; DWM fibrinogen was associated with dementia and cerebral amyloid angiopathy (all p < 0.05). In DWM, SVD was associated with leukoaraiosis identified in life (p < 0.05), but fibrinogen was not. Our data suggest that, in aged brains, plasma extravasation and hence local blood-brain barrier dysfunction are common but do not support an association with SVD. PMID- 25289896 TI - Cytomegalovirus and glioblastoma: a review of evidence for their association and indications for testing and treatment. AB - Glioblastoma is the most common and most fatal primary malignant brain tumor in adults. Despite progress in characterizing the genetic and molecular mechanisms of glioblastomas, advances in treatment that translate into substantial improvement in prognosis have yet to be realized. A role for cytomegalovirus in glioblastoma pathogenesis was proposed more than a decade ago and has generated considerable debate as a possible therapeutic target. Independent groups have had variable success in detecting cytomegalovirus infection in tumor cells; the overall consensus is that very low levels of viral proteins and nucleic acids can be observed. Although cytomegalovirus has not been found to be oncogenic in this context, a possible oncomodulatory role has been suggested. A recent clinical trial evaluating valganciclovir as an adjuvant therapy for the treatment of glioblastoma did not demonstrate a beneficial effect on tumor growth or overall survival, although retrospective analysis subsequently indicted a significant survival benefit. In light of the publicity of that report, patients and neuro oncologists are requesting cytomegalovirus testing to justify antiviral treatment. Based on questions on the significance of cytomegalovirus infection in glioblastomas and the lack of a clear clinical benefit of valganciclovir, we reviewed this topic and conclude that, at this time, there is insufficient evidence to recommend routine testing and treatment. PMID- 25289897 TI - Semiconducting polymer encapsulated mesoporous silica particles with conjugated Europium complexes: toward enhanced luminescence under aqueous conditions. AB - Immobilization of lanthanide organic complexes in meso-organized hybrid materials for luminescence applications have attracted immense interest due to the possibility of controlled segregation at the nanoscopic level for novel optical properties. Aimed at enhancing the luminescence intensity and stability of the hybrid materials in aqueous media, we developed polyvinylpyrrolidone (PVP) stabilized, semiconducting polymer (poly(9-vinylcarbazole), PVK) encapsulated mesoporous silica hybrid particles grafted with Europium(III) complexes. Monosilylated beta-diketonate ligands (1-(2-naphthoyl)-3,3,3-trifluoroacetonate, NTA) were first co-condensed in the mesoporous silica particles as pendent groups for bridging and anchoring the lanthanide complexes, resulting in particles with an mean diameter of ~ 450 nm and a bimodal pore size distribution centered at 3.5 and 5.3 nm. PVK was encapsulated on the resulted particles by a solvent-induced surface precipitation process, in order to seal the mesopores and protect Europium ions from luminescence quenching by producing a hydrophobic environment. The obtained polymer encapsulated MSN-EuLC@PVK-PVP particles exhibit significantly higher intrinsic quantum yield (Phi(Ln) = 39%) and longer lifetime (tau(obs) = 0.51 ms), as compared with those without polymer encapsulation. Most importantly, a high luminescence stability was realized when MSN-EuLC@PVK-PVP particles were dispersed in various aqueous media, showing no noticeable quenching effect. The beneficial features and positive attributes of both mesoporous silica and semiconducting polymers as lanthanide-complex host were merged in a single hybrid carrier, opening up the possibility of using these hybrid luminescent materials under complex aqueous conditions such as biological/physiological environments. PMID- 25289899 TI - Esophagus. PMID- 25289900 TI - Small intestine/unclassified. PMID- 25289901 TI - Liver. PMID- 25289902 TI - Colon. PMID- 25289903 TI - Clinical vignettes/case reports - esophagus. PMID- 25289898 TI - Prostaglandin E2 stimulates beta1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-kappaB pathway. AB - Prostaglandin E2 (PGE2) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased beta1-integrin expression and cell migration; however, the mechanism remains unclear. PGE2 exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1-4). The present study investigated the effect of EP1 receptor activation on beta1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT PGE2 (EP1 agonist), which was suppressed by pretreatment with a beta1-integrin polyclonal antibody. PGE2 increased beta1-integrin expression by approximately 2 fold. EP1 receptor transfection or treatment with 17-PT-PGE2 mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated beta1-integrin expression. 17 PT-PGE2 treatment induced PKC and NF-kappaB activation; PKC and NF-kappaB inhibitors suppressed 17-PT-PGE2-mediated beta1-integrin expression. FoxC2, a beta1-integrin transcription factor, was also upregulated by 17-PT-PGE2. NF kappaB inhibitor suppressed 17-PT-PGE2-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and beta1-integrin were all highly expressed in the HCC cases. This study suggested that PGE2 upregulates beta1-integrin expression and cell migration in HCC cells by activating the PKC/NF-kappaB signaling pathway. Targeting PGE2/EP1/PKC/NF-kappaB/FoxC2/beta1 integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer. PMID- 25289904 TI - Stomach. PMID- 25289905 TI - Endoscopy. PMID- 25289906 TI - Inflammatory bowel disease. PMID- 25289907 TI - Functional bowel disorders. PMID- 25289908 TI - Pancreatic/Biliary. PMID- 25289909 TI - Pediatrics. PMID- 25289910 TI - Colorectal cancer prevention. PMID- 25289911 TI - Endoscopy video forum. PMID- 25289912 TI - Outcomes research. PMID- 25289915 TI - Alopecia areata. How not to miss Satoyoshi syndrome? AB - Satoyoshi syndrome is a multisystem disorder of suspected autoimmune etiology, characterized predominantly by alopecia, muscle spasms and diarrhea. Antinuclear antibodies are present in 60% of patients. The syndrome primarily affects girls and young women. Trichoscopy shows regularly distributed yellow dots, indistinguishable from typical alopecia areata. The condition may be easily misdiagnosed and treated as alopecia areata. On the basis of an in-depth analysis of all published cases we developed diagnostic criteria for Satoyoshi syndrome. We also suggest that two subtypes of the disorder should be distinguished, the ANA-positive Satoyoshi syndrome with generally good response to systemic glucocorticosteroid therapy and the ANA-negative Satoyoshi with less favorable prognosis. In our opinion all patients will alopecia areata (in particular alopecia totalis) should be inquired about muscle spasms and diarrhea and tested for antinuclear antibodies to decrease the risk of missing Satoyoshi syndrome. PMID- 25289916 TI - Gut microbial community structure and complications after kidney transplantation: a pilot study. AB - BACKGROUND: The gut microbiome plays a role in the regulation of the immune system. METHODS: We prospectively enrolled 26 kidney transplant recipients and collected serial fecal specimens (N=85) during the first three months of transplantation. We characterized bacterial composition by polymerase chain reaction amplification of the 16S rRNA V4-V5 variable region and deep sequencing using the Illumina MiSeq platform. RESULTS: An increase in the relative abundance of Proteobacteria was observed in the posttransplantation specimens compared to pretransplantation specimens (P=0.04, Wilcoxon signed-rank test). In patients with posttransplant diarrhea, the mean(+/-standard deviation [SD]) Shannon diversity index was lower in those with diarrhea (N=6) than those without diarrhea (N=9) (2.5+/-0.3 vs. 3.4+/-0.8; P = 0.02, Wilcoxon rank-sum test). Principal coordinate analysis showed clear separation between the two groups, and linear discriminant analysis effect size (LEfSe) method revealed that Bacteroides, Ruminococcus, Coprococcus, and Dorea were significantly lower in the patients with diarrhea. Principal coordinate analysis also showed clear separation between the acute rejection (AR) group (N=3) and the no AR group (N=23) and the LEfSe method revealed significant differences between the two groups. Fecal abundance of Enterococcus was associated with Enterococcus urinary tract infection (UTI). The median Enterococcus fecal abundance was 24% (range, 8% 95%) in the three patients with Enterococcus UTI compared to 0% in the 23 patients without Enterococcus UTI (interquartile range, 0.00%-0.08%) (P=0.005, Wilcoxon rank-sum test). CONCLUSION: Our pilot study identified significant alterations in the gut microbiota after kidney transplantation. Moreover, distinct microbiota structures were observed in allograft recipients with posttransplant diarrhea, AR, and Enterococcus UTI. PMID- 25289917 TI - Denatured class I human leukocyte antigen antibodies in sensitized kidney recipients: prevalence, relevance, and impact on organ allocation. AB - BACKGROUND: Single antigen flow beads assays may overestimate sensitization because of the detection of supposedly irrelevant antibodies recognizing denatured class I human leukocyte antigens (HLAs). METHODS: Sera of 323 HLA sensitized kidney transplant candidates positive with a class I HLA single antigen flow beads assay were retested after acid treatment of the beads. Denatured HLA antibodies were identified according to ratio between the measured fluorescence intensity for treated and nontreated beads. T-lymphocyte flow cytometry crossmatches were performed to characterize the ability of these antibodies to recognize HLA on normal cells as a surrogate of their potential clinical relevance. Their impact on organ allocation was evaluated through a calculated panel reactive antibody. The utility of single antigen flow beads largely devoid of denatured HLA (iBeads) was also evaluated. RESULTS: Denatured HLA antibodies were detected in 39% of the patients. They provided much less positive flow cytometry crossmatches than anti-native HLA antibodies (16% vs. 83%, P<0.0001). Removing the HLA-A and HLA-B antigens targeted by denatured HLA antibodies from unacceptable antigens lowered the calculated panel reactive antibody for 90 patients, sometimes dramatically. The iBeads assay demonstrated nearly the same ability to predict crossmatch results than the acid treatment assay. CONCLUSION: Denatured class I HLA antibodies are common, but the antigens they target should not be considered as unacceptable in most cases, because they negatively impact access to a transplant while predominantly providing negative sensitive crossmatches. The iBeads assay seems to be a valuable alternative to better define unacceptable antigens. PMID- 25289918 TI - [How soon can patients be operated after suffering from a stroke? Interdisciplinary perioperative management is more important than ever before]. PMID- 25289919 TI - [GLP-1 analogues in treatment of type 1 diabetes mellitus]. AB - INTRODUCTION: The insulin replacement is essential in the treatment of type 1 diabetes. Insulin therapy has been coupled with relevant side effects such as hypoglycemia and weight gain. Glucagon-like Peptide 1(GLP-1) analogues (liraglutide) and incretin mimetics (exenatide) are approved only for the treatment of type 2 diabetes mellitus. This review aims to answer the question of what effects exercise GLP-1 analogues on glucose metabolism in people with type 1 diabetes mellitus. METHODS: A systematic literature search. We included studies in people with diabetes mellitus type 1 and GLP-1 analogues intervention. The report quality, the methodological quality of the studies and reviews was based on CONSORT and PRISMA assessed. RESULTS: A total of 19 potentially relevant publications 219 hits were identified. Included were four randomized-controlled trials, two non-randomized-controlled trials and five reviews. The studies and reviews have shown a different methodological quality. There were significant changes in insulin dose (p <= 0.01) reduced Hyperglykamierate detected (p <= 0.01) reduction of blood glucose variations (p <= 0.01) and a reduction in glucagon (p <= 0.05). CONCLUSION: The delayed gastric emptying and reduction of glucagon is the main mechanism of the improved glycemic control in the glucose metabolism of type 1 diabetes. The present literature shows promising results for the additional substitution of GLP-1 analogues in the treatment of type 1 diabetes mellitus. Based on the current data, there is a need to carry out large randomized-controlled trials. PMID- 25289920 TI - [Episodic breathlessness: translation and consenting of the international definition using the Delphi method]. AB - BACKGROUND: Similar to pain, refractory breathlessness can occur episodically. Episodic Breathlessness is a distressing symptom in patients with advanced life limiting disease. The lack of a universal definition impedes symptom understanding in clinical practice and effective management, respectively. The aim of the study was to formally consent a German translation of the English definition and terminology of episodic breathlessness. METHODS: A web-based Delphi survey was conducted with German breathlessness experts (breathlessness working group of Germany's National Guideline (S3) for Palliative Care). Drafts of German-language definitions und terminology were assessed using structured questionnaires by binary rating or rankings, respectively. Optional comments were analysed by content analysis. Consensus was defined by >= 70% agreement among participants. RESULTS: In two resulting Delphi-rounds 8/16 (50%) und 11/16 (69%) experts, 30-59 years of age, 50%/55% female, participated. After the second round, consensus was reached for the symptom's description "Atemnotattacke" (73%) and a German-language definition (90%). The terms "vorhersehbar" vs. "unvorhersehbar" were directly consented for the categorization (88%). CONCLUSION: The formally consented German definition and terminology of episodic breathlessness enable clearer symptom understanding and provide a precise basis for education and research on the symptom and its management also in Germany. Effective management options are warranted to improve quality of life of suffering patients and their relatives. PMID- 25289921 TI - [Splenic cysts as an incidental finding--what's next?]. AB - HISTORY AND ADMISSION FINDINGS: A 55-year-old woman presented comfortable and well-nourished for a check up. The physical examination remained without pathological results. However lipase parameter in serum was conspicuously elevated we performed an ultrasound examination. EXAMINATIONS: An abdomen sonography revealed besides regular pancreas morphology a hypoechoic lesion of 11 * 10 mm in the liver and multiple hypoechoic inhomgeneous lesions in the spleen. Because of the inhomogeneous results and septa we decided to arrange an abdomen computer tomography (CT) in which the complex of cysts was stated with a size of 59 * 44 mm. As the differential diagnosis of the cysts could be an echinococcosis or amoebic infection we performed a serological analysis at the first appointment and 4 weeks later. Both test results were negative. TREATMENT AND COURSE: Eight years later we indicated a magnetic resonance tomography (MRI with MRCP) to exclude a compression of the pancreatic duct by the splenic or liver cysts because the lipase und C-reactive protein (CRP) in serum was rising up again . The MRI scan showed a progression of the splenic cysts complex to 88 * 69 mm and the liver cyst to 25 * 20 mm without signs for compression or a malignant process. A correlation between elevated lipase and splenic cysts was not evident. Despite progression of the splenic cysts we decided in view of the comfortable condition of the patient and negative serological analysis for a conservative proceeding in terms of regular check ups. CONCLUSION: From our point of view also in extended non-parasitic splenic cysts it is reasonable to follow a nonoperative regime as long as clinical complaints, parasitic genesis and malignant process can be excluded. PMID- 25289922 TI - [Rare cause of severely impaired left and right ventricular function--case 7/2014]. AB - HISTORY AND ADMISSION FINDINGS: We report on a case of a 31-year-old patient who was admitted to hospital with acute cardiac failure. At physical examination we found peripheral edema and wet rales. INVESTIGATIONS: Cardiac ultrasound revealed severely impaired left and right ventricular function and prominent trabeculation in the right ventricle, but also in the apex of the left ventricle. This was confirmed by cardiac magnetic resonance imaging. Both pulmonary embolism and coronary heart disease were excluded by thoracic computed tomography and coronary angiography. DIAGNOSIS, TREATMENT AND COURSE: These findings were in line with the diagnosis of non-compaction cardiomyopathy resulting in cardiac failure. We introduced diuretic therapy which leads to weight loss and release of dyspnoea. Due to prevention of embolic events an anticoagulative therapy was started. In light of rhythmogenic vulnerability, a subcutaneous implantable cardioverter defibrillator (ICD) system was implanted. Afterwards the patient was discharged in good general health. CONCLUSION: Non-compaction cardiomyopathy (NCCM) is a hereditary non-ischaemic cardiac disease which occurs due to the failure of myocardial compaction during embryogenesis. Common manifestation is the triad of heart failure, rhythmogenic vulnerability and systemic embolic events. First-line imaging technique for diagnosing NCCM is cardiac ultrasound. The prognosis depends on severity of heart failure, ventricular arrhythmia and the incidence of embolic events. PMID- 25289923 TI - [56-year-old man with incidental finding before kidney transplantation]. PMID- 25289924 TI - [Multimodal treatment of esophageal carcinoma]. AB - Despite major progress in clinical diagnostics and therapy, esophageal carcinoma represents a tumor entity with limited prognosis. In case of carcinoma restricted to mucosa endoscopic resection has developed into an important therapeutic method. Surgical resection represents the standard procedure for patients with locally limited (cT1/T2, N0) and advanced carcinoma (cT3, T4, Nx). In multimodal therapy neoadjuvant treatment concepts with chemotherapy or radiochemotherapy for patients with locally advanced tumors are well established. In case of metastatic disease palliative radio- and chemotherapy represent a treatment concept, however therapy efficiency is very limited. This review reflects the current status of multimodal therapy. PMID- 25289925 TI - [Thyroid dysfunction in pregnancy]. AB - Thyroid dysfunction may impair fertility, course of pregnancy and fetal development. Physiological alterations of thyroid function parameters, that occur during pregnancy need to be distinguished from pathophysiological states of hypo- and hyperthyroidism. We performed a literature search (PubMed 1990-2013) and review relevant publications as well as consensus and practice guidelines of international thyroid/endocrine societies. Interpretation of thyroid function values in pregnancy must be based on trimester-specific TSH and T4 ranges. Alterations in thyroid function are present in up to 15% of pregnancies (0.4% overt hypothyroidism, 0.1-0.4% hyperthyroidism) and may lead to preventable complications in the pregnant woman and the fetus. Hypothyroidism is associated with an increased risk for abortion, premature delivery and stillbirth, besides impairment of neurocognitive development. The latter has also been shown in situations of grave iodine deficiency. In addition to new-born screening directed at early recognition of congenital hypothyroidism (incidence 0.03%), universal screening of all pregnant women should be implemented in health care guidelines. Newly diagnosed overt hypothyroidism in a pregnant woman requires immediate levothyroxine substitution at adequate doses. In subclinical hypothyroidism thyroid hormone replacement should be considered. Iodine supplementation is strongly recommended in all pregnant and breast-feeding women. Pregnancy causes a number of, that need to be of thyroid dysfunction. Both hypothyroidism and thyrotoxicosis may impair the course of pregnancy and may negatively affect the fetus. In particular, maternal hypothyroidism may lead to irreparable and detrimental deficits in the neurocognitive development of the fetus. Autoimmune thyroid disease is the most common cause of thyroid dysfunction in pregnancy. Hashimoto's thyroiditis is associated with impaired fertility and miscarriage, and may first manifest in pregnancy due to the increased thyroid hormone requirement. Graves' disease often shows a characteristic course in pregnancy with amelioration of thyrotoxicosis in the second half of pregnancy and exacerbation after delivery. In addition transplacental passage of maternal TSH receptor antibodies may lead to thyrotoxicosis in the fetus and/or newborn. PMID- 25289926 TI - [Suprapubic catheter insertion]. PMID- 25289927 TI - [Closed-Loop at night for the treatment of type 1 diabetes]. AB - This mini-review describes the latest efforts, challenges, and experience of using automated insulin delivery systems at outpatient settings and home studies. Predictive low glucose management (PLGM) may help prevent hypoglycemia by stopping insulin pump delivery based on predicted sensor glucose values. In silico modeling and early feasibility data demonstrate that PLGM may further reduce the severity of hypoglycemia beyond that already established for algorithms that use a threshold-based suspension. Recent studies have shown that an closed-loop system can improve glucose control and reduce nocturnal hypoglycemia. In the multinational, multicenter DREAM project patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. Studies using closed-loop systems at patients' home are currently being carried out. The preliminary results of these experiments are encouraging and enhance our confidence in this tool as suitable for use in clinical daily practice. PMID- 25289929 TI - Caregivers of people at the end of life: emerging evidence. AB - PURPOSE OF REVIEW: This review aims to identify and highlight recent evidence from studies that aim to improve outcomes for caregivers of patients living with life-limiting progressive conditions. It appears that although the volume and quality of studies reporting outcomes for this population is increasing, there is still a paucity of evidence that has reliable quality and can inform policy and practice. RECENT FINDINGS: One trial has been reported, which found that a one-to one psychoeducational intervention found no change in distress at 1 week after intervention but found improvements in preparedness and competence. Follow-up data at 8 weeks found that distress worsened significantly less for those with one home visit but surprisingly not for those who received two visits (in this three-arm trial) compared with controls. SUMMARY: Although the evidence of outcome studies is small, the research agenda is broadening to include nontraditional families and caregivers in low-and middle-income countries.The recent trial of psychoeducational interventions suggests that longer-term benefits are present. PMID- 25289928 TI - Role of osteocytes in multiple myeloma bone disease. AB - PURPOSE OF REVIEW: Despite the increased knowledge of osteocyte biology, the contribution of this most abundant bone cell to the development and progression of multiple myeloma in bone is practically unexplored. RECENT FINDINGS: Multiple myeloma bone disease is characterized by exacerbated bone resorption and the presence of osteolytic lesions that do not heal because of a concomitant reduction in bone formation. Osteocytes produce molecules that regulate both bone formation and resorption. Recent findings suggest that the life span of osteocytes is compromised in multiple myeloma patients with bone lesions. In addition, multiple myeloma cells affect the transcriptional profile of osteocytes by upregulating the production of pro-osteoclastogenic cytokines, stimulating osteoclast formation and activity. Further, patients with active multiple myeloma have elevated circulating levels of sclerostin, a potent inhibitor of bone formation which is specifically expressed by osteocytes in bone. SUMMARY: Understanding the contribution of osteocytes to the mechanisms underlying the skeletal consequences of multiple myeloma bone disease has the potential to provide important new therapeutic strategies that specifically target multiple myeloma-osteocyte interactions. PMID- 25289930 TI - Hydrocortisone prevents immunosuppression by interleukin-10+ natural killer cells after trauma-hemorrhage. AB - OBJECTIVE: Trauma induces a state of immunosuppression, which is responsible for the development of nosocomial infections. Hydrocortisone reduces the rate of pneumonia in patients with trauma. Because alterations of dendritic cells and natural killer cells play a central role in trauma-induced immunosuppression, we investigated whether hydrocortisone modulates the dendritic cell/natural killer cell cross talk in the context of posttraumatic pneumonia. DESIGN: Experimental study. SETTINGS: Research laboratory from an university hospital. SUBJECTS: Bagg Albino/cJ mice (weight, 20-24 g). INTERVENTIONS: First, in an a priori substudy of a multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone (200 mg/d for 7 d) in patients with severe trauma, we have measured the blood levels of five cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10, interleukin-12, interleukin-17) at day 1 and day 8. In a second step, the effects of hydrocortisone on dendritic cell/natural killer cell cross talk were studied in a mouse model of posttraumatic pneumonia. Hydrocortisone (0.6 mg/mice i.p.) was administered immediately after hemorrhage. Twenty-four hours later, the mice were challenged with Staphylococcus aureus (7 * 10 colony-forming units). MEASUREMENTS AND MAIN RESULTS: Using sera collected during a multicenter study in patients with trauma, we found that hydrocortisone decreased the blood level of interleukin-10, a cytokine centrally involved in the regulation of dendritic cell/natural killer cell cluster. In a mouse model of trauma-hemorrhage-induced immunosuppression, splenic natural killer cells induced an interleukin-10-dependent elimination of splenic dendritic cell. Hydrocortisone treatment reduced this suppressive function of natural killer cells and increased survival of mice with posthemorrhage pneumonia. The reduction of the interleukin 10 level in natural killer cells by hydrocortisone was partially dependent on the up-regulation of glucocorticoid-induced tumor necrosis factor receptor-ligand (TNFsf18) on dendritic cell. CONCLUSIONS: These data demonstrate that trauma induced immunosuppression is characterized by an interleukin-10-dependent elimination of dendritic cell by natural killer cells and that hydrocortisone improves outcome by limiting this immunosuppressive feedback loop. PMID- 25289931 TI - The relationship among obesity, nutritional status, and mortality in the critically ill. AB - INTRODUCTION: The association between obesity and mortality in critically ill patients is unclear based on the current literature. To clarify this relationship, we analyzed the association between obesity and mortality in a large population of critically ill patients and hypothesized that mortality would be impacted by nutritional status. METHODS: We performed a single-center observational study of 6,518 adult patients treated in medical and surgical ICUs between 2004 and 2011. All patients received a formal, in-person, and standardized evaluation by a registered dietitian. Body mass index was determined at the time of dietitian consultation from the estimated dry weight or hospital admission weight and categorized a priori as less than 18.5 kg/m (underweight), 18.5-24.9 kg/m (normal/referent), 25-29.9 kg/m (overweight), 30-39.9 kg/m (obesity class I and II), and more than or equal to 40.0 kg/m (obesity class III). Malnutrition diagnoses were categorized as nonspecific malnutrition, protein-energy malnutrition, or well nourished. The primary outcome was all-cause 30-day mortality determined by the Social Security Death Master File. Associations between body mass index groups and mortality were estimated by bivariable and multivariable logistic regression models. Adjusted odds ratios were estimated with inclusion of covariate terms thought to plausibly interact with both body mass index and mortality. We utilized propensity score matching on baseline characteristics and nutrition status to reduce residual confounding of the body mass index category assignment. RESULTS: In the cohort, 5% were underweight, 36% were normal weight, 31% were overweight, 23% had class I/II obesity, and 5% had class III obesity. Nonspecific malnutrition was present in 56%, protein-energy malnutrition was present in 12%, and 32% were well nourished. The 30-day and 90-day mortality rate for the cohort was 19.1 and 26.6%, respectively. Obesity is a significant predictor of improved 30-day mortality following adjustment for age, gender, race, medical versus surgical patient type, Deyo-Charlson index, acute organ failure, vasopressor use, and sepsis: underweight odds ratio 30-day mortality is 1.09 (95% CI, 0.80-1.48), overweight 30-day mortality odds ratio is 0.93 (95% CI, 0.80-1.09), class I/II obesity 30 day mortality odds ratio is 0.80 (95% CI, 0.67-0.96), and class III obesity 30 day mortality odds ratio is 0.69 (95% CI, 0.49-0.97), all relative to patients with body mass index 18.5-24.9 kg/m. Importantly, there is confounding of the obesity-mortality association on the basis of malnutrition. Adjustment for only nutrition status attenuates the obesity-30-day mortality association: underweight odds ratio is 0.74 (95% CI, 0.54-1.00), overweight odds ratio is 1.05 (95% CI, 0.90-1.23), class I/II obesity odds ratio is 0.96 (95% CI, 0.81-1.15), and class III obesity odds ratio is 0.81 (95% CI, 0.59-1.12), all relative to patients with body mass index 18.5-24.9 kg/m. In a subset of patients with body mass index more than or equal to 30.0 kg/m (n = 1,799), those with either nonspecific or protein energy malnutrition have increased mortality relative to well-nourished patients with body mass index more than or equal to 30.0 kg/m: odds ratio of 90-day mortality is 1.67 (95% CI, 1.29-2.15; p < 0.0001), fully adjusted. In a cohort of propensity score matched patients (n = 3,554), the body mass index-mortality association was not statistically significant, likely from matching on nutrition status. CONCLUSIONS: In a large population of critically ill adults, the association between improved mortality and obesity is confounded by malnutrition status. Critically ill obese patients with malnutrition have worse outcomes than obese patients without malnutrition. PMID- 25289932 TI - Pharmacologic agents for the prevention and treatment of delirium in patients undergoing cardiac surgery: systematic review and metaanalysis. AB - OBJECTIVES: Postcardiac surgery delirium is associated with increased risks of morbidity, cognitive decline, poor health-related quality of life and mortality, and higher healthcare costs. We performed a systematic review of randomized controlled trials to examine the effect of pharmacologic agents for the prevention and the treatment of delirium after cardiac surgery. DATA SOURCES: Electronic search on PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, ISI Web of Science, and CINAHL up to December 2013. STUDY SELECTION: Randomized controlled trials of pharmacologic agents used for the prevention and the treatment of delirium after emergency or elective cardiac surgery in adults. DATA EXTRACTION: We extracted data on patient population, pharmacologic agents, delirium characteristics, rescue treatment, length of stays in the ICU and hospital, and mortality. For each trial, we assessed the risk of bias domains and rated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Of the 13 studies (10 prevention and three treatment) involving 5,848 patients, one multicentered randomized controlled trial on prophylactic dexamethasone made up 77% of the total sample size. The use of pharmacologic agents (dexamethasone, rivastigmine, risperidone, ketamine, dexmedetomidine, propofol, and clonidine) reduced the risk of delirium (relative risk, 0.57; 95% CI, 0.40-0.80) with quality of evidence rated as moderate. There was high quality of evidence for no increased risk of mortality (relative risk, 0.89; 95% CI, 0.57-1.38) associated with the use of prophylactic pharmacologic agents. Metaanalysis of treatment trials was not undertaken because of high heterogeneity. In two small trials (total number of patients = 133), haloperidol did not appear to be effective in treating delirium. CONCLUSIONS: Moderate to high-quality evidence supports the use of pharmacologic agents for the prevention of delirium, but results are based largely on one randomized controlled trial. The evidence for treating postcardiac surgery delirium with pharmacologic agents is inconclusive. PMID- 25289933 TI - Critical cerebral perfusion pressure at high intracranial pressure measured by induced cerebrovascular and intracranial pressure reactivity. AB - OBJECTIVES: The lower limit of cerebral blood flow autoregulation is the critical cerebral perfusion pressure at which cerebral blood flow begins to fall. It is important that cerebral perfusion pressure be maintained above this level to ensure adequate cerebral blood flow, especially in patients with high intracranial pressure. However, the critical cerebral perfusion pressure of 50 mm Hg, obtained by decreasing mean arterial pressure, differs from the value of 30 mm Hg, obtained by increasing intracranial pressure, which we previously showed was due to microvascular shunt flow maintenance of a falsely high cerebral blood flow. The present study shows that the critical cerebral perfusion pressure, measured by increasing intracranial pressure to decrease cerebral perfusion pressure, is inaccurate but accurately determined by dopamine-induced dynamic intracranial pressure reactivity and cerebrovascular reactivity. DESIGN: Cerebral perfusion pressure was decreased either by increasing intracranial pressure or decreasing mean arterial pressure and the critical cerebral perfusion pressure by both methods compared. Cortical Doppler flux, intracranial pressure, and mean arterial pressure were monitored throughout the study. At each cerebral perfusion pressure, we measured microvascular RBC flow velocity, blood-brain barrier integrity (transcapillary dye extravasation), and tissue oxygenation (reduced nicotinamide adenine dinucleotide) in the cerebral cortex of rats using in vivo two-photon laser scanning microscopy. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: At each cerebral perfusion pressure, dopamine-induced arterial pressure transients (~10 mm Hg, ~45 s duration) were used to measure induced intracranial pressure reactivity (Delta intracranial pressure/Delta mean arterial pressure) and induced cerebrovascular reactivity (Delta cerebral blood flow/Delta mean arterial pressure). MEASUREMENTS AND MAIN RESULTS: At a normal cerebral perfusion pressure of 70 mm Hg, 10 mm Hg mean arterial pressure pulses had no effect on intracranial pressure or cerebral blood flow (induced intracranial pressure reactivity = -0.03 +/- 0.07 and induced cerebrovascular reactivity = -0.02 +/- 0.09), reflecting intact autoregulation. Decreasing cerebral perfusion pressure to 50 mm Hg by increasing intracranial pressure increased induced intracranial pressure reactivity and induced cerebrovascular reactivity to 0.24 +/- 0.09 and 0.31 +/- 0.13, respectively, reflecting impaired autoregulation (p < 0.05). By static cerebral blood flow, the first significant decrease in cerebral blood flow occurred at a cerebral perfusion pressure of 30 mm Hg (0.71 +/- 0.08, p < 0.05). CONCLUSIONS: Critical cerebral perfusion pressure of 50 mm Hg was accurately determined by induced intracranial pressure reactivity and induced cerebrovascular reactivity, whereas the static method failed. PMID- 25289934 TI - Preventing the contamination of hospital personnel by cytotoxic agents: evaluation and training of the para-professional healthcare workers in oncology units. AB - This study was specifically focused on para-professional healthcare workers (PHCWs) who handle cytotoxic drugs and contaminated wastes at the Public Teaching Hospitals of Marseille (AP-HM), France. It first aimed at evaluating the knowledge and professional practice of the PHCWs who belong to a personnel category among the less informed and protected in hospitals. In a second time, this study also proposed to raise awareness, educate and train the staff on protective measures to minimise the exposure of the PHCWs to the potential toxicity of anticancer chemotherapy agents (or metabolites) when cleaning and handling both cytotoxic drugs and wastes. Among the 11 oncology units evaluated, 82% completed an assessment survey, 63% of which were PHCWs. Out of nine oncology units assessed, 89% reported limited knowledge of the general risk and of the safe handling of cytotoxic drugs, 89% reported using vinyl gloves which are the less protective ones. Forty-four per cent of the units used wet sweeping techniques for cleaning the floors, and 11% of the units did not have specific procedures for cleaning the equipments used for collecting contaminated excreta. Protective outer apparel was not always worn and chemotherapy wastes were not managed consistently between all units. Standardized procedures and guidelines to prevent occupational exposure were not used by PHCWs. More education and training are needed to improve safety. PMID- 25289935 TI - Distributional vowel training is less effective for adults than for infants. A study using the mismatch response. AB - Distributional learning of speech sounds (i.e., learning from simple exposure to frequency distributions of speech sounds in the environment) has been observed in the lab repeatedly in both infants and adults. The current study is the first attempt to examine whether the capacity for using the mechanism is different in adults than in infants. To this end, a previous event-related potential study that had shown distributional learning of the English vowel contrast /ae/~/epsilon/ in 2-to-3-month old Dutch infants was repeated with Dutch adults. Specifically, the adults were exposed to either a bimodal distribution that suggested the existence of the two vowels (as appropriate in English), or to a unimodal distribution that did not (as appropriate in Dutch). After exposure the participants were tested on their discrimination of a representative [ae] and a representative [epsilon], in an oddball paradigm for measuring mismatch responses (MMRs). Bimodally trained adults did not have a significantly larger MMR amplitude, and hence did not show significantly better neural discrimination of the test vowels, than unimodally trained adults. A direct comparison between the normalized MMR amplitudes of the adults with those of the previously tested infants showed that within a reasonable range of normalization parameters, the bimodal advantage is reliably smaller in adults than in infants, indicating that distributional learning is a weaker mechanism for learning speech sounds in adults (if it exists in that group at all) than in infants. PMID- 25289936 TI - MicroRNA-217 regulates WASF3 expression and suppresses tumor growth and metastasis in osteosarcoma. AB - Osteosarcoma is the most common type of primary tumor of bone which mainly affects adolescents and young adults. Osteosarcoma causes large number of deaths because of its complex pathogenesis and resistance to conventional treatment. MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs, causing translational repression or degradation. In this study, we showed that miR-217 was down-regulated in osteosarcoma cell lines and tissues in comparison to that in normal bone cells or tissues. Meanwhile, the lower level of miR-217 was associated with metastasis in clinical osteosarcoma patients. Furthermore, we found that overexpession of miR 217 markedly suppressed cell proliferation, migration, and invasion of osteosarcoma cells. Conversely, the inhibition of miR-217 expression significantly accelerated the cell proliferation, migration, and invasion. Moreover, we identified WASF3 as a novel functional downstream target of miR-217. The ectopic expression of WASF3 can partially reverse the inhibition of cell proliferation and invasion caused by miR-217. Take together, our results demonstrate that miR-217 functions as a tumor-suppressive miRNA and inhibits the osteosarcoma tumorigenesis through targeting WASF3. PMID- 25289937 TI - Comparing bacterial community composition of healthy and dark spot-affected Siderastrea siderea in Florida and the Caribbean. AB - Coral disease is one of the major causes of reef degradation. Dark Spot Syndrome (DSS) was described in the early 1990's as brown or purple amorphous areas of tissue on a coral and has since become one of the most prevalent diseases reported on Caribbean reefs. It has been identified in a number of coral species, but there is debate as to whether it is in fact the same disease in different corals. Further, it is questioned whether these macroscopic signs are in fact diagnostic of an infectious disease at all. The most commonly affected species in the Caribbean is the massive starlet coral Siderastrea siderea. We sampled this species in two locations, Dry Tortugas National Park and Virgin Islands National Park. Tissue biopsies were collected from both healthy colonies and those with dark spot lesions. Microbial-community DNA was extracted from coral samples (mucus, tissue, and skeleton), amplified using bacterial-specific primers, and applied to PhyloChip G3 microarrays to examine the bacterial diversity associated with this coral. Samples were also screened for the presence of a fungal ribotype that has recently been implicated as a causative agent of DSS in another coral species, but the amplifications were unsuccessful. S. siderea samples did not cluster consistently based on health state (i.e., normal versus dark spot). Various bacteria, including Cyanobacteria and Vibrios, were observed to have increased relative abundance in the discolored tissue, but the patterns were not consistent across all DSS samples. Overall, our findings do not support the hypothesis that DSS in S. siderea is linked to a bacterial pathogen or pathogens. This dataset provides the most comprehensive overview to date of the bacterial community associated with the scleractinian coral S. siderea. PMID- 25289938 TI - Ecosystem scale acoustic sensing reveals humpback whale behavior synchronous with herring spawning processes and re-evaluation finds no effect of sonar on humpback song occurrence in the Gulf of Maine in fall 2006. AB - We show that humpback-whale vocalization behavior is synchronous with peak annual Atlantic herring spawning processes in the Gulf of Maine. With a passive, wide aperture, densely-sampled, coherent hydrophone array towed north of Georges Bank in a Fall 2006 Ocean Acoustic Waveguide Remote Sensing (OAWRS) experiment, vocalizing whales could be instantaneously detected and localized over most of the Gulf of Maine ecosystem in a roughly 400-km diameter area by introducing array gain, of 18 dB, orders of magnitude higher than previously available in acoustic whale sensing. With humpback-whale vocalizations consistently recorded at roughly 2000/day, we show that vocalizing humpbacks (i) were overwhelmingly distributed along the northern flank of Georges Bank, coinciding with the peak spawning time and location of Atlantic herring, and (ii) their overall vocalization behavior was strongly diurnal, synchronous with the formation of large nocturnal herring shoals, with a call rate roughly ten-times higher at night than during the day. Humpback-whale vocalizations were comprised of (1) highly diurnal non-song calls, suited to hunting and feeding behavior, and (2) songs, which had constant occurrence rate over a diurnal cycle, invariant to diurnal herring shoaling. Before and during OAWRS survey transmissions: (a) no vocalizing whales were found at Stellwagen Bank, which had negligible herring populations, and (b) a constant humpback-whale song occurrence rate indicates the transmissions had no effect on humpback song. These measurements contradict the conclusions of Risch et al. Our analysis indicates that (a) the song occurrence variation reported in Risch et al. is consistent with natural causes other than sonar, (b) the reducing change in song reported in Risch et al. occurred days before the sonar survey began, and (c) the Risch et al. method lacks the statistical significance to draw the conclusions of Risch et al. because it has a 98-100% false-positive rate and lacks any true-positive confirmation. PMID- 25289939 TI - Testing different versions of the Affective Neuroscience Personality Scales in a clinical sample. AB - BACKGROUND: As a tool to investigate the experiences of six primary emotions, Davis, Panksepp, and Normansell developed the Affective Neuroscience Personality Scales (ANPS). However, the psychometric properties of the ANPS have been questioned, and in particular the factor structure. This study replicates earlier psychometric studies on ANPS in a sample of (546) personality disordered patients, and also includes ANPS-S, a recent short version of ANPS by Pingault and colleagues, and a truncated version of BANPS by Barrett and colleagues. METHODOLOGY/PRINCIPAL FINDINGS: The study of the full ANPS revealed acceptable internal consistencies of the primary emotion subscales, ranging from 0.74-0.87. However, factor analyses revealed poor to mediocre fit for a six factor solution. Correlational analyses, in addition, revealed too high correlations between PLAY and SEEK, and between SADNESS and FEAR. The two short versions displayed better psychometric properties. The range of internal consistency was 0.61-0.80 for the BANPS scales and 0.65-84 for the ANPS-S. Backward Cronbach Alpha Curves indicated potentials for improvement on all three versions of the questionnaire. Items retained in the short versions did not systematically cover the full theoretical content of the long scales, in particular for CARE and SADNESS in the BANPS. The major problems seem to reside in the operationalization of the CARE and SADNESS subscales of ANPS. CONCLUSIONS/SIGNIFICANCE: Further work needs to be done in order to realize a psychometrically sound instrument for the assessment of primary emotional experiences. PMID- 25289941 TI - Clarifying when to recommend progesterone to prevent preterm birth: clear as mud. PMID- 25289940 TI - The order of exercise during concurrent training for rehabilitation does not alter acute genetic expression, mitochondrial enzyme activity or improvements in muscle function. AB - Concurrent exercise combines different modes of exercise (e.g., aerobic and resistance) into one training protocol, providing stimuli meant to increase muscle strength, aerobic capacity and mass. As disuse is associated with decrements in strength, aerobic capacity and muscle size concurrent training is an attractive modality for rehabilitation. However, interference between the signaling pathways may result in preferential improvements for one of the exercise modes. We recruited 18 young adults (10 ?, 8 ?) to determine if order of exercise mode during concurrent training would differentially affect gene expression, protein content and measures of strength and aerobic capacity after 2 weeks of knee-brace induced disuse. Concurrent exercise sessions were performed 3x/week for 6 weeks at gradually increasing intensities either with endurance exercise preceding (END>RES) or following (RES>END) resistance exercise. Biopsies were collected from the vastus lateralis before, 3 h after the first exercise bout and 48 h after the end of training. Concurrent exercise altered the expression of genes involved in mitochondrial biogenesis (PGC-1alpha, PRC, PPARgamma), hypertrophy (PGC-1alpha4, REDD2, Rheb) and atrophy (MuRF-1, Runx1), increased electron transport chain complex protein content, citrate synthase and mitochondrial cytochrome c oxidase enzyme activity, muscle mass, maximum isometric strength and VO 2peak. However, the order in which exercise was completed (END>RES or RES>END) only affected the protein content of mitochondrial complex II subunit. In conclusion, concurrent exercise training is an effective modality for the rehabilitation of the loss of skeletal muscle mass, maximum strength, and peak aerobic capacity resulting from disuse, regardless of the order in which the modes of exercise are performed. PMID- 25289942 TI - Effects of tiotropium on hyperinflation and treadmill exercise tolerance in mild to moderate chronic obstructive pulmonary disease. AB - RATIONALE: Bronchodilator therapy represents a potentially valuable therapeutic option to increase exercise tolerance and enhance lung function in mild to moderate chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine effects of tiotropium on pulmonary hyperinflation and exercise tolerance in patients with symptomatic Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and 2 COPD who experienced inspiratory capacity decrease greater than or equal to 100 ml during incremental and constant work rate treadmill exercise. METHODS: This 22-week, randomized, double-blind, two-period crossover study evaluated the efficacy of once-daily tiotropium bromide (18 MUg) versus placebo in patients with GOLD 1 and 2 COPD. Primary endpoint was between-group (tiotropium vs. placebo) difference in inspiratory capacity at isotime (i.e., at the time the shortest test ended) during constant work rate treadmill exercise from baseline to the end of a 6-week treatment period. Key secondary endpoints included differences in exercise duration and exertional dyspnea. Safety was assessed by recording adverse events. MEASUREMENTS AND MAIN RESULTS: Study population comprised 48 patients with GOLD 1 COPD and 78 patients with GOLD 2 COPD. Resting inspiratory capacity significantly improved with tiotropium versus placebo in the overall (P < 0.0001), GOLD 1 (P = 0.0183), and GOLD 2 (P < 0.0001) groups. Isotime inspiratory capacity was significantly enhanced during exercise in the overall (P = 0.0087) and GOLD 2 (P = 0.0494) groups after tiotropium versus placebo. Tiotropium versus placebo significantly enhanced exercise duration in the GOLD 2 group (P = 0.0070) but not in the GOLD 1 or overall patient groups. In the overall group, increase in exercise duration seen with tiotropium was well correlated with the increase in isotime inspiratory capacity (r = 0.463, P < 0.0001). CONCLUSIONS: Resting and exercise hyperinflation were ameliorated by bronchodilator therapy with tiotropium in the overall GOLD 1 plus 2 COPD group. Exercise tolerance was enhanced in GOLD 2, but not GOLD 1, COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01072396). PMID- 25289943 TI - Client-centred coaching in the paediatric health professions: a critical scoping review. AB - PURPOSE: Coaching is mainstream in business and is expanding into paediatric health care. With the focus on evidence-informed health practice, it is imperative to identify the key active components of interventions. Coaching is by definition a complex intervention with numerous components. The purpose of this critical review is to determine how coaching is currently defined, its prevalence in paediatric health care services and the frequency of the active components of coaching and to consider the findings of research to date. METHOD: A critical review of the literature was conducted. Inclusion/exclusion criteria were based on the International Coach Federation, which stipulates that coaching is a collaborative process that involves client-centred goal setting, facilitation, self-discovery and capacity building. Seventeen studies were selected for thorough review. RESULTS: Throughout the literature, there was inconsistency in how coaching was defined. Studies included various components, but overall the literature lacked cohesion. CONCLUSION: To advance the field, a list of components that foster client engagement was developed along with a comprehensive definition of coaching involving affective, behavioural and cognitive components and a path of research necessary to evaluate this complex intervention. Implications for Rehabilitation A comprehensive approach to coaching involves consideration of multiple components. A coaching approach can enhance engagement in rehabilitation interventions. The operationalization of holistic ABC coaching that encapsulates the important components, which are affective, behavioural and cognitive in nature. PMID- 25289944 TI - Short-term complications after colic surgery in geriatric versus mature non geriatric horses. AB - OBJECTIVE: To compare in geriatric and mature horses the occurrence of short-term complications and short-term outcome associated with complications after colic surgery. STUDY DESIGN: Retrospective case-control study. SAMPLE POPULATION: Horses aged >=20 years (geriatric, n = 78) and 4-15 years (mature non-geriatric, n = 156) that had exploratory celiotomy for colic and survived recovery from general anesthesia. METHODS: Medical records (2000-2010) of horses that recovered from general anesthesia after colic surgery were reviewed. Postoperative complications evaluated included postoperative reflux (POR), diarrhea, inappetence, fever, leukopenia, incisional infection, incisional dehiscence, thrombophlebitis, colic, repeat celiotomy, pneumonia, and laminitis. Short-term outcome (alive vs. dead at hospital discharge) of geriatric and mature horses with these complications were compared. Data were analyzed using a chi(2) or Fisher's exact test or an ANOVA. Level of significance P < .05. RESULTS: Geriatric horses had higher odds of having a small intestinal strangulating lesion than mature horses. A higher proportion of geriatric horses had POR and inappetence; however, there was no difference in the proportion of geriatric and mature horses with small intestinal strangulating lesions having POR. Short-term outcome with and without complications was similar between the 2 age groups. CONCLUSION: Geriatric and mature horses have similar occurrences of short-term complications and short-term outcomes associated with complications after colic surgery. PMID- 25289946 TI - Immunity and graft rejection in the ear. AB - Immunological activity in the ear and nose is often overlooked but can cause disease. Some examples were discussed at a recent conference*. Also considered was one of the most successful applications of tissue transplantation, middle ear reconstruction. PMID- 25289945 TI - Clinical characteristics of pulmonary arteriovenous malformations in Koreans. AB - BACKGROUND AND OBJECTIVE: Although pulmonary arteriovenous malformations (PAVMs) are rare, they are important in clinical practice because they are associated with life-threatening complications such as brain abscess, stroke and lung haemorrhage. The aims of the present study were to characterize PAVMs in a Korean population and to examine the incidence and factors associated with cerebral complications, which are a major cause of mortality. METHODS: The medical records of patients with PAVMs between 2000 and 2013 were retrospectively reviewed. PAVMs were confirmed by enhanced chest computed tomography or by pulmonary angiography. RESULTS: Ninety patients (median age, 47.5 years; 81.8% female) with PAVMs were included. Twelve patients (13.3%) were clinically diagnosed with hereditary haemorrhagic telangiectasia (HHT) according to the Curacao criteria. Sixty-three patients underwent transcatheter embolization with no severe adverse events. Three patients required retreatment during a mean follow-up period of 3.3 years. Six and 14 patients suffered brain abscess or stroke, respectively, as a complication of PAVMs. These complications were not associated with the diameter of the arteries feeding the PAVMs (odds ratio, 1.106; 95% confidence interval, 0.895-1.366; P = 0.352) CONCLUSIONS: PAVMs are less associated with HHT in Koreans than in Western populations. Transcatheter embolization of PAVMs is safe and effective, and physicians need to consider treating the small arteries feeding PAVMs to prevent cerebral complications. PMID- 25289947 TI - Viral hepatitis: diagnosis, treatment and prevention. PMID- 25289948 TI - Paradigm regained. PMID- 25289949 TI - Hormones, handedness and immunity. PMID- 25289950 TI - [Not Available]. PMID- 25289951 TI - Self-Ia reactive T cells in autoimmunity. PMID- 25289952 TI - A stylistically Shaw touch. PMID- 25289953 TI - Do natural killer cells regulate B-cell activity? AB - For the past ten years or so the natural killer (NW) cell has masqueraded as the cell par excellence in immunosurveillance(1). In this article Keith James and Alistair Ritchie discuss the evidence (both direct and indirect) for NK cells' influence on the differentiation, proliferation and activity of B cells. PMID- 25289954 TI - The origin and significance of class discrimination in immunity. AB - In this purely speculative article, Rod Langman develops the theme that a decision-making process requires information which distinguishes the choices and an interpretive mechanism which links a choice with an appropriate consequence. PMID- 25289955 TI - The probable cause of AIDS. PMID- 25289956 TI - Immunoregulation in leprosy. PMID- 25289957 TI - The 20 faces of the fourth component of complement. PMID- 25289958 TI - Interleukin 2: the molecule and its function. AB - IL2 plays an essential role in triggering proliferation of activated T cells, a response mediated by interaction of the factor with a high-affinity membrane receptor. IL2 also influences a number of other cellular responses, including natural killer cell activity and antibody secretion. Thus, directly or indirectly, IL2 has the properties of both a growth factor and a differentiation signal. Both IL2 and its receptor have been purified to homogeneity and extensively characterized at the molecular level. In this review, Richard Robb discusses the current biochemical understanding of IL2 and its receptor and new information relating to its role in cellular responses. PMID- 25289959 TI - Advances in immunoassay -five books evaluated. PMID- 25289960 TI - Antibiotic prophylaxis for third- and fourth-degree perineal tear during vaginal birth. AB - BACKGROUND: One to eight per cent of women suffer third-degree perineal tear (anal sphincter injury) and fourth-degree perineal tear (rectal mucosa injury) during vaginal birth, and these tears are more common after forceps delivery (28%) and midline episiotomies. Third- and fourth-degree tears can become contaminated with bacteria from the rectum and this significantly increases in the chance of perineal wound infection. Prophylactic antibiotics might have a role in preventing this infection. OBJECTIVES: To assess the effectiveness of antibiotic prophylaxis for reducing maternal morbidity and side effects in third- and fourth-degree perineal tear during vaginal birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2014) and the reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials comparing outcomes of prophylactic antibiotics versus placebo or no antibiotics in third- and fourth-degree perineal tear during vaginal birth. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the trial reports for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We identified and included one trial (147 women from a pre-planned sample size of 310 women) that compared the effect of prophylactic antibiotic (single-dose, second-generation cephalosporin - cefotetan or cefoxitin, 1 g intravenously) on postpartum perineal wound complications in third or fourth-degree perineal tears compared with placebo. Perineal wound complications (wound disruption and purulent discharge) at the two-week postpartum check up were 8.20% and 24.10% in the treatment and the control groups respectively (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.12 to 0.96). However, the high failed-appointment rate may limit the generalisability of the results. The overall risk of bias was low except for incomplete outcome data. The quality of the evidence using GRADE was moderate for infection rate at two weeks' postpartum, and low for infection rate at six weeks' postpartum. AUTHORS' CONCLUSIONS: Although the data suggest that prophylactic antibiotics help to prevent perineal wound complications following third- or fourth-degree perineal tear, loss to follow-up was very high. The results should be interpreted with caution as they are based on one small trial. PMID- 25289961 TI - Sub-10 nm monoclinic Gd2O3:Eu3+ nanoparticles as dual-modal nanoprobes for magnetic resonance and fluorescence imaging. AB - Monoclinic Gd2O3:Eu(3+) nanoparticles (NPs) possess favorable magnetic and optical properties for biomedical application. However, how to obtain small enough NPs still remains a challenge. Here we combined the standard solid-state reaction with the laser ablation in liquids (LAL) technique to fabricate sub-10 nm monoclinic Gd2O3:Eu(3+) NPs and explained their formation mechanism. The obtained Gd2O3:Eu(3+) NPs exhibit bright red fluorescence emission and can be successfully used as fluorescence probe for cells imaging. In vitro and in vivo magnetic resonance imaging (MRI) studies show that the product can also serve as MRI good contrast agent. Then, we systematically investigated the nanotoxicity including cell viability, apoptosis in vitro, as well as the immunotoxicity and pharmacokinetics assays in vivo. This investigation provides a platform for the fabrication of ultrafine monoclinic Gd2O3:Eu(3+) NPs and evaluation of their efficiency and safety in preclinical application. PMID- 25289962 TI - Evolutionary, epidemiological, demographical, and geographical dissection of porcine bocavirus in China and America. AB - Porcine bocavirus was first discovered in Swedish pigs with post-weaning multisystemic wasting syndrome (PMWS) in 2009. Many efforts have been implemented to investigate the porcine bocavirus, but it remains enigmatic. In the current study, we utilized data from both China and the USA. The China-derived data included 403 pig samples collected from five provinces, 122 gene sequences from the GenBank database, and 637 old porcine bocavirus (PBoV) cases. The USA-derived data comprised 181 pig samples from 18 states, 39 new gene sequences, and 85 new emerging cases. First, we executed a comprehensive analysis of the disease's prevalence, phylogenetics, evolutionary distances, mutation network, geographical distribution, occurrence frequency, and phylogeographical estimation in both China and the USA. The results showed that the positive rates of PBoV (42.0%, 76/181) in American samples were significantly higher than those (11.4%, 46/403) in the Chinese samples. All PBoV cases from these countries can be divided into six groups: PBoV1 (group 1), PBoV2 (group 2), PBoV3C (group 3), PBoV5 (group 4), PBoV3/4 (group 5), and PBoV6V7V (group 6). PBoV1 and PBoV2 were epidemic strains from 2006 to 2011 in China, whereas the PBoV3 subtypes were epidemic from 2010 to 2012 in China and the USA. At present, PBoV3C (group 3), PBoV5 (group 4), and PBoV3/4 (group 5) are epidemic viruses and co-exist in China and the USA. The geographical distribution of PBoV mainly lies in the east and south coastal areas of China and the central states of the USA. Jiangsu Province and the state of Minnesota were the centers of high occurrence frequency of PBoV with six outbreaks. The old PBoV cases involved 14 provinces and regions of China and North Carolina in the USA, whereas the new emerging cases involved five provinces in China and 13 states in the USA, of which two provinces and 12 states reported for the first time that piglets were infected by PBoV. Hong Kong, Hebei, and Jiangsu Provinces and the states of Minnesota and North Carolina were possibly geographical origins of PBoV in China and America, respectively. These data can help us systematically understand porcine bocavirus in China and America and find effective strategies for its treatment. PMID- 25289963 TI - The influence of host species and location in the host detection ability of tiphiid (Hymenoptera: Tiphiidae) parasitoids. AB - Tiphia vernalis Rohwer and Tiphia popilliavora Rohwer are ectoparasitoids of root feeding larvae of the Japanese beetle, Popillia japonica Newman, and oriental beetles, Anomala orientalis Waterhouse (Coleoptera: Scarabaeidae). Little is known about the influence of host species and location in the host detection ability of tiphiid wasps. In this study, we examined the response of female T. popilliavora wasps, an understudied Tiphia species, to potential host stimuli using dual choice tests in an observation chamber filled with soil. T. popilliavora wasps were able to successfully discriminate the trails containing body odor or frass of P. japonica grubs from trails without cues. Frass trails of P. japonica grubs elicited stronger responses than body odor trails. We also examined the preference of host cues by tiphiid wasps using dual choice behavioral assays. Both T. vernalis and T. popilliavora wasps did not show preference toward trails that either contained P. japonica or A. orientalis cues. In addition, we also determined the detection of host cues by tiphiid wasps in a dual-choice test for cues presented at varying soil depths. Wasps were able to successfully discriminate between the Y-tube arms with and without cues when the cues of P. japonica were buried at a depth of 2 cm. In contrast, both Tiphia species were unable to distinguish between the Y-tube arms with and without cues when the cues were buried at a depth of 5 cm. Thus, our findings suggest that once Tiphia wasps land on the ground, they can detect the presence of their specific hosts, just below the soil surface by exploiting the kairomones present in grub body odor trails and frass and once the wasps are in the soil, they use the same cues to direct themselves to the host grubs. PMID- 25289964 TI - Catalysis for production of renewable energy. PMID- 25289965 TI - Should topical antibiotics be routinely used following sinus surgery? PMID- 25289966 TI - Moringa oleifera leaf extract ameliorates alloxan-induced diabetes in rats by regeneration of beta cells and reduction of pyruvate carboxylase expression. AB - Moringa oleifera Lam. contains many active ingredients with nutritional and medicinal values. It is commonly used in folk medicine as an antidiabetic agent. The present study was designed to investigate how an aqueous extract from the leaves of M. oleifera reveals hypoglycemia in diabetic rats. M. oleifera leaf extract counteracted the alloxan-induced diabetic effects in rats as it normalized the elevated serum levels of glucose, triglycerides, cholesterol, and malondialdehyde, and normalized mRNA expression of the gluconeogenic enzyme pyruvate carboxylase in hepatic tissues. It also increased live body weight gain and normalized the reduced mRNA expression of fatty acid synthase in the liver of diabetic rats. Moreover, it restored the normal histological structure of the liver and pancreas damaged by alloxan in diabetic rats. This study revealed that the aqueous extract of M. oleifera leaves possesses potent hypoglycemic effects through the normalization of elevated hepatic pyruvate carboxylase enzyme and regeneration of damaged hepatocytes and pancreatic beta cells via its antioxidant properties. PMID- 25289967 TI - Immunoregulatory networks. PMID- 25289968 TI - Antigen specificity in food allergies. PMID- 25289969 TI - Mother/child mixed lymphocyte reaction: is it depressed? AB - Several alternative reasons have been offered for the immunological inertia between the pregnant mother and her fetus. None of these alone has proved correct and sufficient. In this review Paavo Toivanen and Christer Granberg look at one interesting mechanism - the inhibition of maternal lymphocyte reactivity by fetal suppressor cells observedin vitro when untreated populations of maternal and neonatal lymphocytes are cultured together. PMID- 25289970 TI - Macrophage handling of soluble immune complexes. AB - Twoin-vivo observations underline the importance of studying macrophage interactions with soluble immune complexes. The first is the clearance of soluble complexes from the circulation after experimental administration of free or complexed antigen, during an acute infection, or even after a heavy meal. Clearance is mediated by the mononuclear phagocyte system, particularly by the Kupffer cells of the liver, and its rate is dependent on both the macrophage binding activity of the complexed antibodies and complex size. The second is the association of circulating immune complexes with diseases such as rheumatoid arthritis and systemic lupus erythematosus, where damage to specific organs and tissues is thought to be caused by complexes deposited at these sites. The basis of the persistence of soluble complexes in the blood, and the part played by the circulating, as opposed to the deposited, complexes in pathogenesis are aspects of these diseases in which the activity and responsiveness of mononuclear phagocytes may be extremely important. Studiesin vitro provide a valuable background for investigating the activitiesin vivo of soluble complexes by defining (i) the way in which macrophages recognize cytophilic antibodies and the basis of binding enhancement which follows antibody combination with antigen, (ii) the kinetics of complex uptake and destruction by phagocytes and the biochemical mechanisms involved; and (iii) the regulatory effect that soluble immune complexes may have on macrophage activities such as oxidative metabolism and lysosomal enzyme release. In this review, Graham Leslie outlines the progress that has been made in characterizing these events. PMID- 25289971 TI - The cytochemistry of human lymphoreticular subpopulations. AB - For more than twenty years, haemotologists have used cytochemical stains as an aid to the identification and classification of cell types. This approach was particularly useful in distinguishing lymphoid from myeloid cells, and has been developed as a means of performing automated differential cell counts. More recently cytochemical methods have proved capable of identifying lymphoid subpopulations. Here John Cawley and Gordon Burns discuss why these techniques have become of general interest to immunologists. PMID- 25289972 TI - Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC-MS/MS method. AB - OBJECTIVE: Clozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP-TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography-tandem mass spectrometric method (UHPLC-MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples. DESIGN AND METHODS: Serum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid-liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC-MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP-TDM guidelines. RESULTS: For clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350-600 ng/mL, while 67.9% of the concentrations were below 350 ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100-600 ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range. CONCLUSION: This retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations. PMID- 25289973 TI - Combined effects of Fenton peroxidation and CaO conditioning on sewage sludge thermal drying. AB - Joint application of Fenton's reagent and CaO can dramatically enhance sludge dewaterability, thus are also likely to affect subsequent thermal drying process. This study investigated the synergistic effects of the two conditioners on the thermal drying behavior of sewage sludge and the emission characteristics of main sulfur-/nitrogen-containing gases. According to the results, Fenton peroxidation combined with CaO conditioning efficiently promoted sludge heat transfer, reduced the amounts of both free and bound water, and created porous structure in solids to provide evaporation channels, thus producing significant positive effects on sludge drying performance. In this case, the required time for drying was shortened to one-third. Additionally, joint usage of Fenton's reagent and CaO did not increase the losses of organic matter during sludge drying process. Meanwhile, they facilitated the formation of sulfate and sulfonic acid/sulfone, leading to sulfur retention in dried sludge. Both of Fenton peroxidation and CaO conditioning promoted the oxidation, decomposition, and/or dissolution of protein and inorganic nitrogen in sludge pre-treatment. As a consequence, the emissions of sulfurous and nitrogenous gases from dewatered sludge drying were greatly suppressed. These indicate that combining Fenton peroxidation with CaO conditioning is a promising strategy to improve drying efficiency of sewage sludge and to control sulfur and nitrogen contaminants during sludge thermal drying process. PMID- 25289974 TI - Correlates of treatment outcomes and drug resistance among pulmonary tuberculosis patients attending tertiary care hospitals of Kolkata, India. AB - BACKGROUND: Worldwide highest number of new pulmonary tuberculosis (PTB) cases, was reported from India in 2012. Adverse treatment outcomes and emergence of drug resistance further complicated the prevailing scenario owing to increased duration, cost and toxicity associated with the treatment of drug-resistant cases. Hence to reinforce India's fight against TB, identification of the correlates of adverse treatment outcomes and drug resistance, seemed critical. METHODS: To estimate the associations between diagnostic findings, patient types (based on treatment outcomes), drug resistance and socio-demographic characteristics of PTB patients, a cross-sectional study was conducted in two tertiary-care hospitals in Kolkata between April 2010 and March 2013. Altogether, 350 consenting Mycobacterium tuberculosis sputum-culture positive PTB patients were interviewed about their socio-demographic background, evaluated regarding their X-ray findings (minimal/moderately advanced/far advanced/cavities), sputum smear positivity, and treatment history/outcomes (new/defaulter/relapse/treatment failure cases). Multiple-allele-specific polymerase chain reaction (MAS-PCR) was conducted to diagnose drug resistance. RESULTS: Among all participants, 31.43% were newly diagnosed, while 44%, 15.43% and 9.14% patients fell into the categories of relapsed, defaulters and treatment-failures, respectively. 12.29% were multi-drug-resistant (MDR: resistant to at least isoniazid and rifampicin), 57.71% had non-MDR two-drug resistance and 12% had single-drug resistance. Subjects with higher BMI had lower odds of being a relapse/defaulter/treatment failure case while females were more likely to be defaulters and older age-groups had more relapse. Elderly, females, unmarried, those with low BMI and higher grade of sputum-smear positivity were more likely to have advanced X-ray features. Higher grade of sputum-smear positivity and advanced chest X-ray findings were associated with relapse/treatment-failures. Elderly, unmarried, relapse/defaulter/treatment-failure cases had higher odds and those with higher BMI and moderately/far advanced X-ray findings had lower odds of having MDR/non MDR two-drug resistant PTB. CONCLUSION: Targeted intervention and appropriate counseling are needed urgently to prevent adverse treatment outcomes and development of drug resistance among PTB patients in Kolkata. PMID- 25289975 TI - Clickable protein nanocapsules for targeted delivery of recombinant p53 protein. AB - Encapsulating anticancer protein therapeutics in nanocarriers is an attractive option to minimize active drug destruction, increase local accumulation at the disease site, and decrease side effects to other tissues. Tumor-specific ligands can further facilitate targeting the nanocarriers to tumor cells and reduce nonspecific cellular internalization. Rationally designed non-covalent protein nanocapsules incorporating copper-free "click chemistry" moieties, polyethylene glycol (PEG) units, redox-sensitive cross-linker, and tumor-specific targeting ligands were synthesized to selectively deliver intracellular protein therapeutics into tumor cells via receptor-mediated endocytosis. These nanocapsules can be conjugated to different targeting ligands of choice, such as anti-Her2 antibody single-chain variable fragment (scFv) and luteinizing hormone releasing hormone (LHRH) peptide, resulting in specific and efficient accumulation within tumor cells overexpressing corresponding receptors. LHRH conjugated nanocapsules selectively delivered recombinant human tumor suppressor protein p53 and its tumor-selective supervariant into targeted tumor cells, which led to reactivation of p53-mediated apoptosis. Our results validate a general approach for targeted protein delivery into tumor cells using cellular-responsive nanocarriers, opening up new opportunities for the development of intracellular protein-based anticancer treatment. PMID- 25289976 TI - Monitoring change in renal function. PMID- 25289977 TI - Are lysosornes involved in antigen processing? PMID- 25289978 TI - Somatic diversification of B cells: a role for autoreactive T lymphocytes. AB - Although the immune system discriminates self from non-self, and autoreactivity has pathologic consequences, lymphocytes do recognize self antigens. Self recognition involves immunoglobulin variable (Ig V) regions and major histocompatibility complex (MHC)-encoded molecules. Jerne postulated that recognition of self-idiotypes within an immune system was a necessary homeostatic mechanism, important in the regulation of the immune system both in the presence and absence of perturbation by exogenous antigen'. Support for this hypothesis has accumulated from a variety of experimental systems but the significance of autoreactive T lymphocytes which recognize MHC-encoded class II (Ia) molecules(2 5) remains unknown. Rosenberg et al. s have proposed that autoreactive T cells are involved in mediating autoimmunity when the mechanisms controlling theirfunction degenerate. Here Ronald Corley suggests that autoreactive T lymphocytes are responsible for the expansion and somatic diversification of the B-cell compartment from germ-line encoded V genes. Furthermore, he proposes that autoreactive T cells do not function autonomously but that B-cell activation follows occupation of the two relevant triggering molecules on the B-cell membrane, namely Ia molecules by the autoreactive T cells and surface immunoglobulin by internally complementary idiotypes. PMID- 25289979 TI - The role of carbohydrate in lymphoid cell traffic. PMID- 25289980 TI - Trancriptional regulation of IgM and Ig. PMID- 25289981 TI - Complex aggregation: a critical event in macrophage handling of soluble immune complexes. AB - IgG-containing soluble immune complexes are bound by macrophages and trigger activities, such as lysosomal enzyme release and the synthesis of reactive oxygen metabolites, which are involved in the phagocyte's attack on target organisms(1). Complexes are ingested at a rate four fold faster than the rate of membrane internalization associated with fluid phase pinocytosis(2,3) (a constitutive activity of macrophages) and the rate of ingestion is independent of complex size(2). One explanation offered for these observations is that complex endocytosis is preceded by rapid reorganization of the small membrane-bound complexes into large aggregates which may either initiate the ingestion process or congregate selectivity at the sites of forming pinosomes(2). Complex aggregation was viewed as occurring by a mechanism analogous to that of the patch formation induced by cross-linking native-bound IgG, on macrophages, with F(ab(1))2 fragments of anti-Ig antibodies(4). Here Graham Leslie discusses recent studies of complex re-arrangement at the macrophage surface that have provided a detailed theoretical framework to account for the phenomenon and have established the critical importance of this event in the efficient ingestion of membrane bound complexes and soluble complex clearance from the circulation. PMID- 25289982 TI - Human C3b- and C4b-regulatory proteins: a new multi-gene family. AB - The complement cascade is regulated to prevent inappropriate activation. This regulation is targeted not only at the initiation of the cascade but also at the amplification andjunctional (C3) steps. Five glycoproteins with both complement regulatory activity and binding affinity for C3b/C4b have been characterized. In plasma these molecules are factor H(H) and C4-binding protein (C4-bp) and, on cells, they are the C3b/C4b receptor (CR1), decay-accelerating factor (DAF), and gp45-70. Here Michael Holers and his colleagues review structural, functional and genetic studies of these proteins and discuss the evidence for a new multi-gene family with a common ancestral protein. PMID- 25289983 TI - Mast cells, T cells and abnormal fibrosis. AB - Inflamed, fibrotic lesions containing mast cells are characteristic of several clinical disorders and have been noted in graft versus host disease. Here Henry Claman reviews recent insights into the interactions between mast cells, T lymphocytes and fibroblasts which may account for abnormal collagen deposition. PMID- 25289985 TI - Density functional theory calculations of pressure effects on the structure and vibrations of 1,1-diamino-2,2-dinitroethene (FOX-7). AB - Pressure effects on the Raman vibrations of an energetic crystal FOX-7 (1, 1 diamino-2, 2-dinitroethene) were examined using density functional theory (DFT) calculations. High accuracy calculations were performed with a periodic plane wave DFT method using norm-conserving pseudopotentials. Different exchange correlation functionals were examined for their applicability in describing the structural and vibrational experimental data. It is shown that the PBE functional with an empirical dispersion correction by Grimme, PBE-D method, reproduces best the molecular geometry, unit cell parameters, and vibrational frequencies. Assignments of intramolecular Raman active vibrations are provided. The calculated pressure dependence of Raman shifts for the intramolecular and lattice modes were found to be in good agreement with the experimental data; in particular, the calculations predicted correctly a decrease of frequencies for the NH2 stretching modes with pressure. Also, in accord with experiments, the calculations indicated some instances of modes mixing/coupling with increasing pressure. This work demonstrates that the dispersion-corrected PBE functional can account for the structural and vibrational properties of FOX-7 crystal at ambient and high pressures. PMID- 25289986 TI - An aid to drug dosing safety in obese children: development of a new nomogram and comparison with existing methods for estimation of ideal body weight and lean body mass. AB - The risk of accidental over-dosing of obese children poses challenges to anaesthetists during dose calculations for drugs with serious side-effects, such as analgesics. For many drugs, dosing scalars such as ideal body weight and lean body mass are recommended instead of total body weight during weight-based dose calculations. However, the complex current methods of obtaining these dosing scalars are impractical in the peri-operative setting. Arbitrary dose adjustments and guesswork are, unfortunately, tempting solutions for the time-pressured anaesthetist. The study's aim was to develop and validate an accurate, convenient alternative. A nomogram was created and its performance compared with the standard calculation method by volunteers using measurements from 108 obese children. The nomogram was as accurate (bias 0.12 kg vs -0.41 kg, respectively, p = 0.4), faster (mean (SD) time taken 2.8 (1.0) min (vs 3.3 (0.9) min respectively, p = 0.003) and less likely to result in mistakes (significant errors 3% vs 19%, respectively, p = 0.001). We present a system that simplifies estimation of ideal body weight and lean body mass in obese children, providing foundations for safer drug dose calculation. PMID- 25289987 TI - 75 years of the AAI. PMID- 25289988 TI - Annual conferences for San Marino. PMID- 25289989 TI - Errata. PMID- 25289990 TI - Interleukin 4A. PMID- 25289993 TI - Huddling reduces evaporative water loss in torpid Natterer's bats, Myotis nattereri. AB - Periodic arousals during hibernation consume most of the winter energy budget for hibernating mammals. Evaporative water loss (EWL) is thought to affect the frequency of arousals and thus energy balance, and might have dramatic implications for over-winter survival and fitness. We hypothesized that huddling affects EWL and energy expenditure in torpid mammals. We tested this hypothesis using bats as a model and predicted that, during torpor, EWL and energy expenditure of huddling individuals would be lower than in individuals that are not in a huddle. We measured EWL and metabolic rate of torpid Myotis nattereri (Kuhl, 1817) huddling in groups or roosting individually. Evaporative water loss in huddling individual bats was almost 30% lower than in solitary animals (P=0.03), even after correcting for the effects of metabolic rate. Our results suggest that conservation of water is a substantial benefit underlying huddling by bats during hibernation. Ultimately, huddling could reduce the total cost of hibernation by reducing the number of expensive periodic arousals from torpor caused by the need to supplement water. PMID- 25289994 TI - Detection of long-term influence of prenatal temperature stimulation on hypothalamic type-II iodothyronine deiodinase in juvenile female broiler chickens using a novel immunohistochemical amplification protocol. AB - It has been clearly shown that early environmental stimulation may have long lasting influence on body functions. Because of the strong relationship between thermoregulation and other homeostatic linked physiological parameters, perinatal thermal manipulation will also have an impact on other body functions like reproduction. As a maturation stimulant for later reproductive performance, hypothalamic type-2 iodothyronine deiodinase (Dio2) expression was investigated in 35day old immature female broilers with and without embryonic temperature stimulation. For the first time, human-specific Dio2 primary antibodies combined with additional amplification enabled the immunohistochemical detection of hypothalamic Dio2 protein in birds. The novel protocol includes an additional amplification step involving swine-anti-rabbit/mouse/goat antibodies against both goat anti-Dio2 primary and rabbit anti-goat biotinylated secondary commercial antibodies in the standard diaminobenzidine protocol. However, significant Dio2 expression was exclusively found in perinatally short-term temperature stimulated hens. Caudal but not rostral hypothalamic slices revealed that elevating incubation temperature by 1 degrees C for 2h daily, from day 18 of embryonic development until hatching, induced a statistical significant expression of Dio2 within the subcommisural organ and the median eminence. This ample expression of Dio2 protein within caudal but not rostral hypothalamic slices of embryonic temperature stimulated chickens, leads to the assumption of a novel physiological prospective for embryonic thermal manipulation involving the suppression of thyroid hormone and the boosting of hypothalamic Dio2-induced FSH secretion to considerably advance the age of photoinduced egg production. It could be also of practicable relevance for broiler breeder females, and needs further investigations. PMID- 25289996 TI - Genetic and molecular aspects of demyelination. AB - Three groups of investigators came together to learn from each other in a workshop: neurologists and neuropathologists interested in the pathogenesis of multiple sclerosis (MS) and other demyelinative diseases of man and similar autoimmune and virus-induced model diseases in animals; immunologists and virologists concerned with the genetic controls found to play a role in these diseases; and geneticists and molecular biologists investigating specific gene products and their role in recognition function and cell interactions in model immunological systems. PMID- 25289995 TI - Short-term effects of cortisol implantation on blood biochemistry and thyroid hormones in previtellogenic great sturgeon Huso huso. AB - This study examined the effects of implanted cortisol on various aspects of intermediary metabolism of great sturgeon, Huso huso. Prior to experimentation all fish were examined using an endoscope to observe the stage of ovarian development. Subsequently, the 3-year-old female fish in the previtellogenic stage (mean body weight of 6759+/-53.2g) were intraperitoneally implanted with cocoa butter pellets containing cortisol to mimic the effects of chronic stress. The implant doses were 0 (C0; as control), 5 (C5) and 50 (C50) mg cortisol/kg body weight. Blood samples were taken every seven days during the four weeks of the experiment and analyzed for cortisol, glucose, adrenocorticotropic hormone (ACTH), total protein, total lipid, triiodothyronine (T3), thyroxine (T4), cholesterol and triglyceride content. Growth was reduced in all experimental groups and was not affected by cortisol treatment. Surprisingly, serum cortisol levels were higher in the C5 group than in the C50 throughout the experiment. A significant increase in glucose levels was observed in the cortisol-implanted fish from day 14 onwards. The high dose of cortisol elicited a significant increase in serum T3 and T4 levels. Fish implanted with the high cortisol dose also showed increases in serum ACTH, total lipid and cholesterol levels throughout a 28-day experimental period. The present study reveals that the negative effects of endoscopic surgery remain for at least four weeks and that a sustained-release implant of cortisol to mimic the effects of chronic stress affects metabolic responses. Since the adverse effects of endoscopic surgery on sturgeon welfare can be amplified by cortisol, special attention should be paid to the potential effects of chronic stress on sturgeon in culture. PMID- 25289997 TI - Interleukin 1 production for detection of bacterial polysaccharide in fetal calf sera and other solutions. PMID- 25289998 TI - The introversion of the immune response. PMID- 25289999 TI - 'Immune surveillance' without immunogenicity. AB - The hypothesis of immune surveillance against cancer is based on two premises; (1) that transformed and normal cells generally have different antigenic qualities, and (2) that the immune system responds to the antigenically modified cells in essentially the same way as it responds to invasive microorganisms. Both premises have been questioned. Here, Zvi Grossman and Ronald Herberman suggest that lymphoid cells not only mediate immune responses but also assist in regulating the differentiation of a variety of normal cells. They do so by recognizing self rather than foreign antigens. By forcing and steering the turnover of tissue cells, lymphoid cells prevent the accumulation of small irregular phenotypic and karyotypic changes in the tissue. Tumor escape from surveillance may therefore be described as escape from regulatory differentiation pressures. PMID- 25290000 TI - Evidence for three types of human cytotoxic lymphocyte. AB - Natural killer (NK) cells lyse a broad spectrum of tumor-cell lines and virus infected cells, they are MHC unrestricted and they are detectable in unimmunized subjects: cytotoxic T cells (CTL) have fine antigen specificity, are MHC restricted and are usually detectable only after they multiply on exposure to antigen. Here Lewis Lanier and Joseph Phillips argue that these functional criteria do not adequately distinguish types of cytotoxic cell. They propose a classification based on recognition structure, which identifies three distinct effector cells. PMID- 25290001 TI - Proteoglycans in secretory granules of NK cells. PMID- 25290002 TI - A function for IgD? PMID- 25290003 TI - Transgenic mice: 'new wave' immunogenetics. AB - It is now possible to investigate the function of cloned genes in vivo by injecting the genes into mouse embryos and tracing the pattern of expression of the genes' products. In this review Christophe Benoist and his colleagues discuss the technique of gene transfer, its power and limitations, and its particular application in the study of immune function. PMID- 25290004 TI - The T4 molecule: function and structure. AB - T4 antigen bearing T lymphocytes are central immunoregulatory cells which display helperlinducer functions, proliferate in response to antigen, control suppression and release lymphokines. In this review, Angus Dalgleish describes growing evidence that these different functions are carried out by phenotypically different subpopulations of T4-positive T cells, and discusses T4 as a putative receptor for class II MHC molecules and HTLV-III. PMID- 25290005 TI - Is spondylitis caused by Klebsiella? AB - The aetiology of ankylosing spondylitis involves some genetic predisposition: the disease occurs mainly in males, and many spondylitics have the HLA-827 antigen. However, the correlation with known genetic factors is not absolute. For example, not all identical twin siblings of spondylitics develop the disease. In this review Andrew Keat discusses the genetic and environmental factors which may contribute to the development of spondylitis. PMID- 25290006 TI - The computer and the reprint file (3). AB - This month two more software packages designed to manage bibliographic reference databases are reviewed. DG Systems' REF-11 is designed specifically for reprint files but has some limitations and a very poor manual. Eagle's CITATION is an all purpose professional database, program designed for many applications with a very good manual but with some major limitations. PMID- 25290007 TI - Intimate partner violence during pregnancy and adverse neonatal outcomes in low income women. AB - BACKGROUND: Intimate partner violence (IPV) affects an estimated 1.5 million U.S. women annually. IPV impacts maternal and neonatal health with higher rates of depression and low birth weight (LBW). Less studied is experiencing IPV and delivering a small for gestational age (SGA) baby. SGA neonates are at increased risk of developmental and behavioral problems. The negative sequelae persist into adulthood with increased rates of diabetes mellitus and coronary heart disease. METHODS: In a sample of 239 pregnant women experiencing IPV, in urban and rural settings, we examined cross-sectional associations of severity of IPV and neonatal outcomes (i.e., birth weight and gestational age). Severity of IPV was measured by the Conflict Tactics Scale 2 and neonatal outcomes were collected at the time of delivery. RESULTS: Outcomes were collected on 194 neonates; 14.9% (n=29) were classified as LBW, 19.1% (n=37) classified as SGA, and 9.8% (n=19) as LBW and SGA. Women reporting higher severity of IPV during pregnancy had a greater likelihood of delivering an SGA neonate (odds ratio [OR] 4.81; 95% confidence interval [95% CI] 1.86-12.47), and LBW neonate (OR 4.20; 95% CI 1.46 12.10). CONCLUSIONS: In a sample of pregnant women experiencing perinatal IPV, women experiencing greater severities of IPV were more likely to deliver a neonate with an adverse outcome. Early recognition and intervention of IPV is essential to reduce disparities in birth outcomes and long-term health outcomes for these neonates. PMID- 25290008 TI - Cholestasis induced antinociception and decreased gene expression of MOR1 in rat brain. AB - We examined antinociception and gene expression of mu-opioid receptor 1 (MOR1) in some brain areas of cholestatic rats, 21 days after common bile duct ligation (BDL). Cholestasis was induced in male Wistar rats during laparotomy and common BDL. Pain behavior was assessed on days 7, 14 or 21 of BDL using a hotplate test in control, sham and cholestatic groups. On day 21 of BDL, other groups of rats were sacrificed, whole brains were extracted, and the hypothalamus, prefrontal cortex (PFC), hippocampus and striatum in control, sham and cholestatic rats were dissected. We used a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method for evaluating MOR1 gene expression. The results revealed that cholestatic rats showed significant antinociception on days 14 and 21 of ligation with the most significant effect on day 21, which was prevented by naloxone (1 mg/kg). On the other hand, the expression of MOR1 gene compared to the sham group was decreased by 42% in the hypothalamus, 41% in the PFC, and 67% in the hippocampus after 21 days of BDL, while no significant change in its expression in the striatum was observed. It can be concluded that a change in endogenous opioid levels and its subsequent influence on the gene expression of MOR in some areas of the rat brain may underlie the altered nociception and other possible pathological changes such as pruritus after induction of cholestasis. PMID- 25290009 TI - Temporal and anatomic patterns of immediate-early gene expression in the forebrain of C57BL/6 and DBA/2 mice after morphine administration. AB - Although morphine was previously reported to produce an instant induction of c fos in the striatum, our recent studies have demonstrated that the expression of numerous immediate early genes (IEGs) is significantly elevated at delayed time points (several hours) after morphine administration. To better dissect the time course of opioid-produced IEG induction, we used in situ hybridization to examine the expression of the IEGs c-fos, zif268 and arc in the mouse forebrain at several time-points after acute morphine injection. To link drug-produced behavioral changes with the activity of specific neuronal complexes, this study was performed comparatively in the C57BL/6 and DBA/2 mouse strains, which differ markedly in their locomotor responses to opioids and opioid reward. Our study demonstrates that morphine produces two episodes of IEG induction, which are separate in time (30 min vs. 4-6 h) and which have different neuroanatomic distribution. At 30 min, one or more IEGs were induced in circumscribed subregions of the dorsal striatum (dStr) and of the nucleus accumbens (NAc) shell, as well as in the lateral septum. The observed inter-strain differences in IEG expression at 30 min support earlier proposals that activation of the dorsomedial striatum may mediate morphine-elicited locomotor stimulation (both effects were present only in the C57BL/6 strain). In contrast, NAc shell activation does not appear to be linked to morphine-elicited changes in locomotor behavior. The second IEG induction (of arc and of zif268) was more widespread, involving most of the dStr and the cortex. The second IEG induction peaked earlier in the DBA/2 mice than in the C57BL/6 mice (4 h compared with 6 h) and displayed no apparent relation to locomotor behavior. This delayed episode of IEG activation, which has largely been overlooked thus far, may contribute to the development of long-term effects of opioids such as tolerance, dependence and/or addiction. PMID- 25290010 TI - beta-Catenin is required for maintaining hippocampal morphology during the perinatal period. AB - In mice, the compact hippocampal primordium is formed during the prenatal stage by early-generated neurons that migrate from the lateral ventricular zone. However, despite much being understood about the formation of the hippocampus, the molecular mechanisms that maintain the morphology of the hippocampal primordium after its formation remain to be characterized. beta-Catenin is a key factor of canonical Wnt signaling and also a component of adherens junctions. Previous embryonic deletion studies have demonstrated that beta-catenin is required for early development and generation of granule cells. However, whether beta-catenin is involved in the morphological maintenance of the hippocampus as a cell adhesion molecule is still unknown. Here, we report that perinatal deletion of beta-catenin in postmitotic neurons and some radial glial cells of hippocampus using CamKIIalpha-iCre; beta-cateninflox/flox conditional knockout mice, leads to disorganization of the radial glial scaffold and consequentially severe defects in hippocampal morphology. We demonstrate that beta-catenin is required for maintaining radial glial scaffold possibly via its well-known role in cell adhesion during the perinatal period. These findings provide essential advances into our understanding of the maintenance of the hippocampal primordium during the perinatal period. PMID- 25290011 TI - Taurine attenuates hippocampal and corpus callosum damage, and enhances neurological recovery after closed head injury in rats. AB - The protective effects of taurine against closed head injury (CHI) have been reported. This study was designed to investigate whether taurine reduced white matter damage and hippocampal neuronal death through suppressing calpain activation after CHI in rats. Taurine (50 mg/kg) was administered intravenously 30 min and 4 h again after CHI. It was found that taurine lessened the corpus callosum damage, attenuated the neuronal cell death in hippocampal CA1 and CA3 subfields and improved the neurological functions 7 days after CHI. Moreover, it suppressed the over-activation of calpain, enhanced the levels of calpastatin, and reduced the degradation of neurofilament heavy protein, myelin basic protein and alphaII-spectrin in traumatic tissue 24 h after CHI. These data confirm the protective effects of taurine against gray and white matter damage due to CHI, and suggest that down-regulating calpain activation could be one of the protective mechanisms of taurine against CHI. PMID- 25290012 TI - Axonal regeneration through the fibrous scar in lesioned goldfish spinal cord. AB - Spontaneous nerve regeneration beyond the scar frequently occurs in fish after spinal cord lesions, in contrast to mammals. Here we examined the spatiotemporal relationship between the fibrous scar and axonal regeneration in the goldfish. Within 1 week after hemisection of the spinal cord, the open wound was closed by a fibrous scar that was demarcated from the surrounding nervous tissue by the glia limitans, which was immunoreactive for laminin. Within 1 week after hemisection, regenerating axons entered the fibrous scar, and were surrounded by laminin-coated tubular structures continuous with the glia limitans. Regenerating axons that initially entered the fibrous scar were usually accompanied by glial processes. Within 2-3 weeks after hemisection, the tubular structures became enlarged, and the regenerating axons increased in number, fasciculating in the tubules. Glial processes immunoreactive for glial fibrillary acid protein and 5 hydroxytryptamine neurons then entered the tubular structures to associate with the regenerating axons. The tubular structures developed further, creating tunnels that penetrated the fibrous scar, through which the regenerating axons passed. At 6-12 weeks after hemisection, the fibrous scar was smaller and the enlarged tunnels contained many glial processes and several axons. The findings of present study demonstrated that, following spinal lesions in goldfish, regenerating axons enter and pass the scar tissue. The regenerating axons first enter the fibrous scar with glial elements and then grow through laminin-coated tubular structures within the fibrous scar. Invasion by glial processes and neuronal elements into the tubular structures reduces the fibrous scar area and allows for more regenerating axons to pass beyond the fibrous scar. PMID- 25290013 TI - Jaw movement-related primary somatosensory cortical area in the rat. AB - It has anatomically been revealed that the rostral part of the rat primary somatosensory cortex (S1) directly projects to the dorsal part of the trigeminal oral subnucleus (dorVo) and the dorsal part of juxtatrigeminal region (dorVjuxt), and that the dorVo and dorVjuxt contain premotoneurons projecting directly to the jaw-opening or jaw-closing motoneurons in the trigeminal motor nucleus (Vmo). However, little is known about how the rostral S1 regulates jaw movements in relation to its corticofugal projections. To address this issue, we performed intracortical microstimulation of the rat rostral S1 by monitoring jaw movements and electromyographic (EMG) activities. We for the first time found that low frequency long-train stimulation of the rostral S1 induced single sustained opening of the jaw with elevated EMG activities of the anterior digastric muscles (jaw-opener). The effective sites for the low-frequency long-train stimulation overlapped the S1 sites where traditional high-frequency short-train stimulation was effective to induce single twitch-like jaw movement. We also found that the effective sites for the two kinds of train stimuli were included in the rostral S1 area, which has previously been identified to send direct projections to the dorVo or the dorVjuxt. Specifically, the most effective stimulation sites for the two kinds of train stimuli were located in the rostralmost part of S1 which has been reported to emanate strong direct projections to the dorVjuxt but less to the dorVo. Therefore, the present study suggests that the rat rostral S1, especially its rostralmost part, plays an important role in controlling jaw movements by activation of direct descending projections from the rostral S1 to the trigeminal premotoneuron pools, especially to the dorVjuxt. PMID- 25290014 TI - Pregabalin alleviates the nitroglycerin-induced hyperalgesia in rats. AB - The association between the clinical use of nitroglycerin (NTG) and migraine suggests NTG as an animal model trigger for migraine. NTG-induced hyperalgesia in rats has been extensively used as a migraine model for pre-clinical research. Pregabalin is an anti-epileptic drug and may play a role in the preventive treatment of migraine; however, the mechanism of this action remains to be clarified. Herein, we performed the present study to investigate the effect of pregabalin on the NTG-induced hyperalgesia in rats. Sixty male Sprague-Dawley rats were divided equally into six groups. Thirty minutes before NTG injection, the rats were pretreated with pregabalin. von Frey hair testing was employed to evaluate tactile sensitivity. Enzyme-linked immunosorbent assay was used to analyze plasma calcitonin gene-related peptide (CGRP) levels in the jugular vein. Immunohistochemistry was applied to detect c-Fos-immunoreactive neurons and western blot was performed to detect c-Fos protein expression in trigeminal nucleus caudalis (TNC). We found that pregabalin pretreatment alleviated the NTG induced hyperalgesia. Moreover, pregabalin suppressed peripheral CGRP release, c Fos-immunoreactive neurons and the protein expression of c-Fos in TNC as well. These data suggest that pregabalin could alleviate the NTG-induced hyperalgesia. Further studies are required to determine the mechanisms of action for this effect. PMID- 25290015 TI - Contribution of hyperpolarization-activated channels to heat hypersensitivity and ongoing activity in the neuritis model. AB - Neuritis can cause pain hypersensitivities in the absence of axonal degeneration. Such hypersensitivities are reputed to be maintained by ongoing activity into the spinal cord, which, in the neuritis model, is mainly generated from intact C fiber neurons. The hyperpolarization-activated cyclic nucleotide-gated (HCN) family of ion channels has been implicated in nerve injury-induced pain hypersensitivities. The present study has examined the role of these channels in the development of heat and mechanical hypersensitivities in the neuritis model. The systemic administration of the HCN-specific blocker ZD7288 produced a reversal of heat but not mechanical hypersensitivity within one hour post administration. Recordings from C-fiber neurons were performed to determine whether ZD7288 acts by inhibiting ongoing activity. ZD7288 (0.5mM) caused a 44.1% decrease in the ongoing activity rate following its application to the neuritis site. Immunohistochemical examination of the HCN2 channel subtype within the L5 dorsal root ganglia revealed an increase in expression in neuronal cell bodies of all sizes post-neuritis. In conclusion, HCN channels contribute to the development of neuritis-induced heat hypersensitivity and ongoing activity. Drugs that target HCN channels may be beneficial in the treatment of neuropathic pain in patients with nerve inflammation. PMID- 25290017 TI - A common functional neural network for overt production of speech and gesture. AB - The perception of co-speech gestures, i.e., hand movements that co-occur with speech, has been investigated by several studies. The results show that the perception of co-speech gestures engages a core set of frontal, temporal, and parietal areas. However, no study has yet investigated the neural processes underlying the production of co-speech gestures. Specifically, it remains an open question whether Broca's area is central to the coordination of speech and gestures as has been suggested previously. The objective of this study was to use functional magnetic resonance imaging to (i) investigate the regional activations underlying overt production of speech, gestures, and co-speech gestures, and (ii) examine functional connectivity with Broca's area. We hypothesized that co-speech gesture production would activate frontal, temporal, and parietal regions that are similar to areas previously found during co-speech gesture perception and that both speech and gesture as well as co-speech gesture production would engage a neural network connected to Broca's area. Whole-brain analysis confirmed our hypothesis and showed that co-speech gesturing did engage brain areas that form part of networks known to subserve language and gesture. Functional connectivity analysis further revealed a functional network connected to Broca's area that is common to speech, gesture, and co-speech gesture production. This network consists of brain areas that play essential roles in motor control, suggesting that the coordination of speech and gesture is mediated by a shared motor control network. Our findings thus lend support to the idea that speech can influence co speech gesture production on a motoric level. PMID- 25290016 TI - Epileptiform synchronization and high-frequency oscillations in brain slices comprising piriform and entorhinal cortices. AB - We employed field potential recordings in extended in vitro brain slices form Sprague-Dawley rats containing the piriform and entorhinal cortices (PC and EC, respectively) to identify the characteristics of epileptiform discharges and concomitant high-frequency oscillations (HFOs, ripples: 80-200Hz, fast ripples: 250-500Hz) during bath application of 4-aminopyridine (4AP, 50MUM). Ictal-like discharges occurred in PC and EC either synchronously or independently of each other; synchronous ictal discharges always emerged from a synchronous "fast" interictal background whereas asynchronous ictal discharges were preceded by a "slow" interictal event. In addition, asynchronous ictal discharges had longer duration and interval of occurrence than synchronous ictal discharges, and contained a higher proportion of ripples and fast ripples. Cutting the connections between PC and EC made synchronicity disappear and increased ictal discharges duration in the EC but failed in changing HFO occurrence in both areas. Finally, antagonizing ionotropic glutamatergic receptors abolished ictal activity in all experiments, increased the duration and rate of occurrence of interictal discharges occurring in PC-EC interconnected slices while it did not influence the slow asynchronous interictal discharges in both areas. Our results identify some novel in vitro interactions between olfactory (PC) and limbic (EC) structures that presumably contribute to in vivo ictogenesis as well. PMID- 25290018 TI - Differential contribution of the hippocampus in two different demanding tasks at early stages of hepatic encephalopathy. AB - The hippocampus has been established as a site of plasticity during the acquisition of spatial memory. The memory for spatial locations is impaired in patients who develop hepatic encephalopathy (HE). We wondered how the hippocampus can manage different hippocampal-dependent tasks in a type B model of the early evolutive phases of HE induced by triple portal vein ligation. We used a one trial object-place recognition task that involves making judgements about whether a stimulus was encountered before in that location and a reversal learning task performed in the Morris water maze that involves reward-guided behavior and decision making. Our behavioral results showed impairments in the acquisition of both tasks by the portal hypertension group compared with the sham-operated group. To label brain areas related to these tasks, we marked the expression of the c-Fos protein and revealed high c-Fos immunoreactivity in cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and entorhinal (Ent) cortex of the PH group compared with the SHAM group in the object-place recognition task and a decrease in c-Fos positive cells in the reversal task in the CA1, CA3, dentate gyrus (DG), cingulate (CG), prelimbic (PL), and infralimbic (IL) cortices in the PH group compared with the SHAM group. In conclusion, the study corroborated the pivotal role of the hippocampus in spatial memory deficits found in the early stages of type B HE and noted its differential contribution in each of the tasks. PMID- 25290019 TI - Polyion complex micelle based on albumin-polymer conjugates: multifunctional oligonucleotide transfection vectors for anticancer chemotherapeutics. AB - Novel biocompatible polyion complex micelles, containing bovine serum albumin (BSA), polymer, and oligonucleotide, were synthesized as a generation of vectors for the gene transfection. Maleimide-terminated poly((N,N-dimethyl amino) ethyl methacrylate) (PDMAEMA) was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequently deprotected. Precise one to one albumin-PDMAEMA bioconjugates have been achieved via 1,4-addition with the free thiol group on Cys34 on the BSA protein. SDS-PAGE and GPC (water) confirmed and quantified the successful conjugation. The conjugation efficiency was found to be independent of the molecular weight of PDMAEMA. After careful pH adjustment, the conjugate could efficiently condense anticancer oligonucleotide, ISIS 5132, which resulted in particles of 15-35 nm with a negative zeta-potential. The size was easily controlled by the polymer chain length. The albumin corona provides complete protection of the cationic polymer and genetic drug, which gave rise to lower potential toxicity from the polymer and higher gene transfection efficiency. Although a control experiment with a traditional PEG-based polyion complex micelle could deliver the drug just as effectively, if not more so, to the ovarian cancer cell line OVCAR-3, this carrier had no selectivity toward cancerous cells and proved just as toxic to HS27 (fibroblast) cell line. In contrast, the albumin-coated particles demonstrated desirable selectivity toward cancerous cells and have been shown to have outstanding performance in the cytotoxicity tests of several carcinoma monolayer cell models. In addition, the complex micelles were able to destroy pancreatic multicellular tumor spheroids, while free ISIS 5132 could not penetrate the spheroid at all. Hence, albumin coated/oligonucleotide complex micelles are far more promising than the most classical gene delivery vectors. PMID- 25290021 TI - Some new perspectives on transplantation immunity and tolerance. PMID- 25290020 TI - n-Alkylboronic acid inhibitors reveal determinants of ligand specificity in the quorum-quenching and siderophore biosynthetic enzyme PvdQ. AB - The enzyme PvdQ (E.C. 3.5.1.97) from Pseudomonas aeruginosa is an N-terminal nucleophile hydrolase that catalyzes the removal of an N-myristyl substituent from a biosynthetic precursor of the iron-chelating siderophore pyoverdine. Inhibitors of pyoverdine biosynthesis are potential antibiotics since iron is essential for growth and scarce in most infections. PvdQ also catalyzes hydrolytic amide bond cleavage of selected N-acyl-l-homoserine lactone quorum sensing signals used by some Gram-negative pathogens to coordinate the transcription of virulence factors. The resulting quorum-quenching activity of PvdQ has potential applications in antivirulence therapies. To inform both inhibitor design and enzyme engineering efforts, a series of n-alkylboronic acid inhibitors of PvdQ was characterized to reveal determinants of ligand selectivity. A simple homologation series results in compounds with Ki values that span from 4.7 mM to 190 pM, with a dependence of DeltaGbind values on chain length of -1.0 kcal/mol/CH2. X-ray crystal structures are determined for the PvdQ complexes with 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octylboronic acids at 1.6, 1.8, 2.0, and 2.1 A resolution, respectively. The 1-hexyl- and 1-octylboronic acids form tetrahedral adducts with the active-site N-terminal Ser217 in the beta subunit of PvdQ, and the n-alkyl substituents are bound in the acyl-group binding site. The 1-ethyl- and 1-butylboronic acids also form adducts with Ser217 but instead form trigonal planar adducts and extend their n-alkyl substituents into an alternative binding site. These results are interpreted to propose a ligand discrimination model for PvdQ that informs the development of PvdQ-related tools and therapeutics. PMID- 25290022 TI - Letters Natural autoantibodies might prevent autoimmune disease. PMID- 25290023 TI - Letters. PMID- 25290024 TI - Why do hemopoietic growth factor receptors interact with each other? AB - Hemopoietic growth factors (colony-stimulating factors, CSFs) interact with distinct cellular receptors that recognize only their cognate ligand. Yet, like other growth factor/receptor systems, the binding of one type of CSF to its receptor can 'down-modulate' the availability of a different tyoe of CSF receptor. In this article Nicos Nicola discusses the distinctive pattern of] CSF receptor modulations and suggests a novel interpretation of such modulations as a means of coupling receptor-derived signals which is consistent with the known biology of the system. PMID- 25290025 TI - Are proteinases functional molecules of T lymphocytes? AB - Recent studies have shown that activated T cells possess cytoplasmic granules containing a serine proteinase. In this article Michael Kramer and Markus Simon suggest that the regulated release of this enzyme has an important part to play in the activities of T cells, such as B-cell regulation, cytolysis and migration. PMID- 25290026 TI - Microenvironments for B-cell production and stimulation. PMID- 25290027 TI - The T-cell antigen receptor gamma chain and its accomplices. PMID- 25290028 TI - Macroglia: neural cells responsive to lymphokines and growth factors. PMID- 25290029 TI - Molecular mechanisms of signal transduction in macrophages. AB - The mechanisms by which extracellular signals are received and transduced across the cell membrane are being illuminated by studies in macrophages. In this review Tom Hamilton and Dolph Adams discuss mechanisms of signal transduction which either initiate rapid execution of function in macrophages or alter the cells' potential for taking such action. PMID- 25290035 TI - High-precision temperature determination of evaporating light-absorbing and non light-absorbing droplets. AB - Models describing evaporation or condensation of a droplet have existed for over a century, and the temporal evolutions of droplet radius and temperature could be predicted. However, the accuracy of results was questionable, since the models contain free parameters and the means of accurate calibration were not available. In previous work (Holyst et al. Soft Matter 2013, 9, 7766), a model with an efficacious parametrization in terms of the mean free path was proposed and calibrated with molecular dynamics numerical experiment. It was shown that it is essentially possible to determine reliably the temperature of a steadily evaporating/condensing homogeneous droplet relative to ambient temperature when the evolution of the droplet radius is known. The accuracy of such measurement can reach fractions of mK. In the case of an evaporating droplet of pure liquid, the (droplet) temperature is constant during the stationary stage of evaporation. In this paper, we show that, in many cases, it is also possible to determine the temporal evolution of droplet temperature from the evolution of the droplet radius if the droplet (initial) composition is known. We found the droplet radius evolution with high accuracy and obtained the evolution of droplet temperature (and composition) for droplets of (i) a two-component mixture of pure liquids; (ii) solutions of solid in liquid, one that is non-surface-active and another that is; and (iii) suspensions of non-light-absorbing and light-absorbing particles. PMID- 25290036 TI - Adult headform impact tests of three Japanese child bicycle helmets into a vehicle. AB - The head is the body region that most frequently incurs fatal and serious injuries of cyclists in collisions against vehicles. Many research studies investigated helmet effectiveness in preventing head injuries using accident data. In this study, the impact attenuation characteristics of three Japanese child bicycle helmets were examined experimentally in impact tests into a concrete surface and a vehicle. A pedestrian adult headform with and without a Japanese child bicycle helmet was dropped onto a concrete surface and then propelled into a vehicle at 35 km/h in various locations such as the bonnet, roof header, windshield and A-pillar. Accelerations were measured and head injury criterion (HIC) calculated. In the drop tests using the adult headform onto a concrete surface from the height of 1.5m, the HIC for a headform without a child helmet was 6325, and was reduced by around 80% when a child helmet was fitted to the headform. In the impact tests, where the headform was fired into the vehicle at 35 km/h at various locations on a car, the computed acceleration based HIC varied depending on the vehicle impact locations. The HIC was reduced by 10-38% for impacts headforms with a child helmet when the impact was onto a bonnet-top and roof header although the HIC was already less than 1000 in impacts with the headform without a child helmet. Similarly, for impacts into the windshield (where a cyclist's head is most frequently impacted), the HIC using the adult headform without a child helmet was 122; whereas when the adult headform was used with a child helmet, a higher HIC value of more than 850 was recorded. But again, the HIC values are below 1000. In impacts into the A-pillar, the HIC was 4816 for a headform without a child helmet and was reduced by 18-38% for a headform with a child helmet depending on the type of Japanese child helmet used. The tests demonstrated that Japanese child helmets are effective in reducing accelerations and HIC in a drop test using an adult headform onto a relatively rigid hard surface, i.e., simulating a road surface or concrete path. However, when the impact tests are into softer surfaces, the child helmet's capacity to decrease accelerations is accordingly reduced. Impacts into the windshield, while below the critical HIC value of 1000, indicated higher HIC values for a headform with a child helmet compared to an adult headform without a child helmet. The unpredictable nature of the results indicates further research work is required to assess how representative the stiffness of an adult headform is when compared to an actual head. PMID- 25290037 TI - Do different circadian typology measures modulate their relationship with personality? A test using the Alternative Five Factor Model. AB - The relationship between personality and circadian typology shows some inconsistent results and it has been hypothesized that the model used to measure personality might have a moderating effect on this relationship. However, it has never been explored if this inconsistency was dependent on the questionnaire used to measure differences in circadian rhythms as well. We explored this issue in a sample of 564 university students (32% men; 19-40 years) using the Zuckerman Kuhlman Personality Questionnaire, which is based on an evolutionary-biological approach, in combination with the Composite Scale of Morningness (CSM) and the reduced Morningness-Eveningness Questionnaire (rMEQ). Both questionnaires detected differences between circadian typologies in Sociability (highest in evening types; ET) and Impulsive Sensation-Seeking scales (highest in ET), while the CSM also detected differences in Activity (lowest in ET) and Aggression Hostility (highest in ET). Further, both questionnaires detected differences between circadian typologies in the subscales General Activity (morning types [MT] higher than ET), Impulsivity (ET highest) and Sensation-Seeking (highest in ET). Differences between circadian typologies/groups in the subscales Parties (highest in ET) and Isolation Intolerance (lowest in MT) were only detected by the rMEQ. The CSM clearly separated evening types from neither and morning types while the rMEQ showed that neither types are not intermediate but closer to evening types in General Activity and Isolation Intolerance, and closer to morning types in Impulsive Sensation-Seeking, Parties, Impulsivity and Sensation Seeking. The obtained results indicate that the relationship between circadian typology and personality may be dependent on the instrument used to assess circadian typology. This fact may help to explain some of the conflicting data available on the relationship between these two concepts. PMID- 25290038 TI - Shift work and diabetes--a systematic review. AB - Diabetes mellitus is a chronic disease, which has an increasing trend all over the world. Type 2 diabetes constitutes 90% of all diabetes. It is associated with weight gain and insulin resistance. Research during recent years has suggested that shift work could be a risk factor of type 2 diabetes. Since shift work is becoming more common, it could contribute to the increasing trend of diabetes. In this systematic review, we have studied the potential association between shift work and type 2 diabetes. We have also reviewed studies on control of diabetes in relation to shift work. PMID- 25290039 TI - Weekend work and depressive symptoms among Korean employees. AB - The purpose of this study was to quantify the association between weekend work and depressive symptoms in a representative sample of Korean employees. Subjects were 29 171 employees of companies in Korea. Data were obtained as part of the 2011 Korean Working Conditions Survey. Depressive symptoms were measured as a score of <=7 on the World Health Organization Well-being Index. The association between weekend work and depressive symptoms was quantified using logistic regression, controlling for sociodemographic and work-related factors including the number of hours worked per week and stratified by gender. The prevalence of depressive symptoms was higher in employees who reported working at least one weekend day in the past month than in employees who reported working no weekend days in the past month. After controlling for confounders, including the number of hours worked per week, 1-4 days of weekend work in the past month (odds ratio [95% confidence interval] of 1.36 [1.18-1.57] in males and 1.32 [1.12-1.58] in females) and >4 days of weekend work in the past month (odds ratio [95% confidence interval] of 1.45 [1.19-1.78] in males and 1.36 [1.07-1.73] in females) were significantly associated with depressive symptoms. Weekend work was related with a significant increase in the prevalence of depressive symptoms in Korean workers. PMID- 25290040 TI - Estimating photoreceptor excitations from spectral outputs of a personal light exposure measurement device. AB - The intrinsic circadian clock requires photoentrainment to synchronize the 24 hour solar day. Therefore, light stimulation is an important component of chronobiological research. Currently, the chronobiological research field overwhelmingly uses photopic illuminance that is based on the luminous efficiency function, V(lambda), to quantify light levels. However, recent discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are activated by self-contained melanopsin photopigment and also by inputs from rods and cones, makes light specification using a one-dimensional unit inadequate. Since the current understanding of how different photoreceptor inputs contribute to the circadian system through ipRGCs is limited, it is recommended to specify light in terms of the excitations of five photoreceptors (S-, M-, L-cones, rods and ipRGCs; Lucas et al., 2014). In the current study, we assessed whether the spectral outputs from a commercially available spectral watch (i.e. Actiwatch Spectrum) could be used to estimate photoreceptor excitations. Based on the color sensor spectral sensitivity functions from a previously published work, as well as from our measurements, we computed spectral outputs in the long-wavelength range (R), middle-wavelength range (G), short-wavelength range (B) and broadband range (W) under 52 CIE illuminants (25 daylight illuminants, 27 fluorescent lights). We also computed the photoreceptor excitations for each illuminant using human photoreceptor spectral sensitivity functions. Linear regression analyses indicated that the Actiwatch spectral outputs could predict photoreceptor excitations reliably, under the assumption of linear responses of the Actiwatch color sensors. In addition, R, G, B outputs could classify illuminant types (fluorescent versus daylight illuminants) satisfactorily. However, the assessment of actual Actiwatch recording under several testing light sources showed that the spectral outputs were subject to great non-linearity, leading to less accurate estimation of photoreceptor excitations. Based on our analyses, we recommend that each spectral watch should be calibrated to measure spectral sensitivity functions and linearization characteristics for each sensor to have an accurate estimation of photoreceptor excitations. The method we provided to estimate photoreceptor excitations from the outputs of spectral watches could be used for chronobiological studies that can tolerate an error in the range of 0.2-0.5 log units. Our method can be easily expanded to incorporate linearization functions to have more accurate estimations. PMID- 25290043 TI - The role and spectrum of SLC26A4 mutations in Iranian patients with autosomal recessive hereditary deafness. AB - OBJECTIVE: To determine the prevalence and types of SLC26A4 mutations and the relevant phenotypes in a series of Iranian deaf patients. DESIGN: A descriptive laboratory study. STUDY SAMPLE: One hundred and twenty-one families including 60 unrelated patients and 61 unrelated multiplex families with autosomal recessive deafness were included. In the 61 multiplex families, linkage was conducted for short tandem repeats (STRs) of the DFNB4. Selected individuals from the linked families and all of the 60 deaf individuals were subjected to sequencing of SLC26A4. RESULTS: Seven out of the 61 (11.5%) families were linked to the locus which upon further inquiry led to identification of eight different mutations. Also, five out of the 60 (8.3%) patients were positive for the mutations. The SLC26A4 mutations clarified in 9.1% (12 families) of total investigated alleles included: c.2106delG, c.65-66insT, c.881-882delAC, c.863-864insT, c.1226G> A, c.1238A> G, c.1334T> G, c.1790T> C, c.1489G> A, c.919-2A> G (IVS7-2A> G), c.1412delT, and c.1197delT. Six out of 12 (50%) families with mutations were confirmed to be Pendred syndrome (PS). CONCLUSIONS: The results probably suggest a high prevalence and specificity of SLC26A4 mutations among Iranian deaf patients. Molecular study of SLC26A4 may lead to elucidation of the population specific mutation profile which is of importance in diagnostics of deafness. PMID- 25290041 TI - Circadian rest/activity rhythms in knee osteoarthritis with insomnia: a study of osteoarthritis patients and pain-free controls with insomnia or normal sleep. AB - Aberrant circadian rest/activity rhythms (RARs) may promote poor aging-related health outcomes. Osteoarthritis and chronic insomnia are common age-related conditions, but the circadian RARs of each group have not been well characterized or compared. We evaluated actigraphic RARs in individuals with: (1) knee osteoarthritis (KOA) only; (2) chronic insomnia only; (3) KOA + insomnia; and (4) pain-free good sleepers. Compared to participants with KOA only, those with KOA + insomnia had less robust RARs. There were no differences between other groups. Further research is needed to evaluate whether aberrant RARs contribute to arthritis symptoms and insomnia in KOA, and whether strengthening RARs ameliorates arthritis symptoms. PMID- 25290045 TI - Fetal antigens, cancer and the wooden spoon. PMID- 25290044 TI - Racial/ethnic and gender differences in severity of diabetes-related complications, health care resource use, and costs in a Medicare population. AB - This retrospective cohort study evaluated associations of race/ethnicity and gender with outcomes of diabetes complications severity, health care resource utilization (HRU), and costs among Medicare Advantage health plan members with type 2 diabetes (T2DM). Medical and pharmacy claims were evaluated for 333,576 members continuously enrolled from January 1, 2010, to December 31, 2011, aged 18 89 years, with >=1 primary diagnosis medical claim, or >=2 claims with a secondary diagnosis of T2DM (International Classification of Diseases, Ninth Revision, Clinical Modification code 250.x0 or 250.x2). Complications severity assessment by Diabetes Complications Severity Index ranged from 0 (no complications) to 5+. Mean (SD) all-cause medical, pharmacy, and total costs were reported alongside all-cause HRU by place of service (outpatient, inpatient, emergency room [ER]) and number of visits. Multivariate regression showed being Hispanic, black, or male was associated with higher prevalence of more severe complications. This racial/ethnic disparity was more pronounced among females, among whom odds of having more severe complications were higher for Hispanic and black as compared to white females [(Hispanic vs. white odds ratio [OR], 1.40; 95% confidence interval [CI], 1.32-1.48), and (black vs. white OR, 1.22; 95% CI, 1.19-1.25)]. Regardless of gender, blacks had more ER visits than whites. White females incurred the highest total health care costs (mean annual costs: $13,086; 95% CI, $12,935-$13,240, vs. Hispanic females: $10,732; 95% CI, $10,406-$11,067). These effects held regardless of other demographic and clinical attributes. These findings suggest racial/ethnic and gender differences exist in certain T2DM clinical and economic outcomes. PMID- 25290042 TI - Exploration of stimulus-frequency otoacoustic emission suppression tuning in hearing-impaired listeners. AB - OBJECTIVE: Otoacoustic emissions (OAEs) can provide useful measures of tuning of auditory filters. We previously established that stimulus-frequency (SF) OAE suppression tuning curves (STCs) reflect major features of behavioral tuning (psychophysical tuning curves, PTCs) in normally-hearing listeners. Here, we aim to evaluate whether SFOAE STCs reflect changes in PTC tuning in cases of abnormal hearing. DESIGN: PTCs and SFOAE STCs were obtained at 1 kHz and/or 4 kHz probe frequencies. For exploratory purposes, we collected SFOAEs measured across a wide frequency range and contrasted them to commonly measured distortion product (DP) OAEs. STUDY SAMPLE: Thirteen listeners with varying degrees of sensorineural hearing loss. RESULTS: Except for a few listeners with the most hearing loss, the listeners had normal/nearly normal PTCs. However, attempts to record SFOAE STCs in hearing-impaired listeners were challenging and sometimes unsuccessful due to the high level of noise at the SFOAE frequency, which is not a factor for DPOAEs. In cases of successful measurements of SFOAE STCs there was a large variability in agreement between SFOAE STC and PTC tuning. CONCLUSIONS: These results indicate that SFOAE STCs cannot substitute for PTCs in cases of abnormal hearing, at least with the paradigm adopted in this study. PMID- 25290046 TI - Type I diabetes - an autoimmune disease? PMID- 25290047 TI - Cyclosporin A in human transplantation. PMID- 25290048 TI - Cyclosporin A in human transplantation. PMID- 25290049 TI - The vulnerability of skin grafts to allo- and xeno-antibodies. PMID- 25290050 TI - Regulatory idiotopes and immune networks: a hypothesis. PMID- 25290051 TI - Lyt antigens as markers for functional T-cell subpopulations. PMID- 25290052 TI - Further intricacy of HLA-DR antigens. PMID- 25290053 TI - Complement fragments suppress lymphocyte immune responses. AB - There has been controversy as to whether complement augments immune responses or inhibits them. In this article John Weiler and his colleagues discuss recent evidence that complement fragments can inhibit immune responses that depend upon cellular proliferation. PMID- 25290054 TI - 'Background' immunoglobulin production: measurement, biological significance and regulation. AB - Every individual produces immunoglobulins, even under germfree conditions. This article discusses the measurement, biological significance and regulation of this 'spontaneous' ('background') immunoglobulin production. The authors relate this phenomenon to the original suggestions of Niels Kaj Jerne, in 1955, about the role of 'natural' circulating antibodies in antibody formation and the completeness of the repertoire of antigen-binding specificities as represented among the natural antibodies. PMID- 25290055 TI - T-cell recruitment: a tool for specific immunosuppression. PMID- 25290057 TI - Realist review to inform development of the electronic advance care plan for the personally controlled electronic health record in Australia. AB - INTRODUCTION: Australia has invested heavily to introduce an opt-in personally controlled electronic healthcare record (PCEHR), which incorporates an element of advance care planning (ACP). A further investment of $10 million AUD has been made to increase capability to a fully integrated electronic ACP (eACP). Australia has an aging population, the majority of whom will live, be cared for, and die in the community. ACP in the community setting can support older people to navigate their illness trajectories and health decision-making. Sharing this information with care providers across different healthcare settings is crucial. MATERIALS AND METHODS: The eACPs was conceptualized as a complex social intervention. We conducted a realist review of the literature to explore evidenced-based models of eACP for community-dwelling older people, with chronic, life-limiting illness. A scoping search identified gray literature; a systematic search for empirical evidence was conducted of eight databases, including PubMed and Google Scholar. RESULTS: Seventeen articles were included, along with 71 other documents. Realist synthesis based on data collected using original abstraction forms was used to develop a model to explain what worked for whom and in what circumstances. Electronic physician reminders and information to patients increased ACP completions. However, there were no precedents for transferring ACPs into a national PCEHR. CONCLUSIONS: We developed a model informed by six core themes from the literature: information sharing, process, initiating conversations, dignity of life (individualized approach), education (individual and community), and collaborative practice (engagement). End-of-life care that is consistent with older people's values and preferences requires robust care processes and efficient information sharing across the healthcare continuum. PMID- 25290059 TI - Antibiotic resistance, virulence factors and genetics of Clostridium sordellii. AB - Clostridium sordellii is gram positive bacterial pathogen of humans and animals. While the incidence of human-related C. sordellii infection is low, the mortality rate associated with infection is high. Of particular concern are C. sordellii infections after child-birth or medical abortion, which have an almost 100% mortality rate. Recent genetic and epidemiological work has increased our understanding of how this pathogen has evolved and how it causes disease. This review will summarise studies involving the genetics of C. sordellii, including an antibiotic resistance profile, the genetic determinants of virulence and mutagenesis of C. sordellii. PMID- 25290058 TI - NAD+ protects against EAE by regulating CD4+ T-cell differentiation. AB - CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNgamma(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD(+), the frequency of T-bet(-/-) CD4(+)IFNgamma(+) T cells was twofold higher than wild-type CD4(+) T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4(+) T-cell differentiation and demonstrate that NAD(+) may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases. PMID- 25290061 TI - Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia. AB - Exogenous ketone bodies (KBs), acetoacetate (AA), and beta-hydroxybutyrate (BHB) act as alternative energy substrates in neural cells under starvation. The present study examined the endogenous ketogenic capacity of astroglia under hypoxia with/without glucose and the possible roles of KBs in neuronal energy metabolism. Cultured neurons and astroglia were prepared from Sprague-Dawley rats. Palmitic acid (PAL) and l-carnitine (LC) were added to the assay medium. The 4- to 24-hr production of AA and BHB was measured using the cyclic thio-NADH method. (14)C-labeled acid-soluble products (KBs) and (14)CO2 produced from [1 (14)C]PAL were also measured. l-[U-(14)C]lactic acid ([(14)C]LAC), [1 (14)C]pyruvic acid ([(14)C]PYR), or beta-[1-(14)C]hydroxybutyric acid ([(14)C]BHB) was used to compare the oxidative metabolism of the glycolysis end products with that of the KBs. Some cells were placed in a hypoxic chamber (1% O2). PAL and LC induced a higher production of KBs in astroglia than in neurons, while the CO2 production from PAL was less than 5% of the KB production in both astroglia and neurons. KB production in astroglia was augmented by the AMP activated protein kinase activators, AICAR and metformin, as well as hypoxia with/without glucose. Neuronal KB production increased under hypoxia in the absence of PAL and LC. In neurons, [(14)C]LAC and [(14)C]PYR oxidation decreased after 24 hr of hypoxia, while [(14)C]BHB oxidation was preserved. Astroglia responds to ischemia in vitro by enhancing KB production, and astroglia-produced KBs derived from fatty acid might serve as a neuronal energy substrate for the tricarboxylic acid cycle instead of lactate, as pyruvate dehydrogenase is susceptible to ischemia. PMID- 25290060 TI - MAL overexpression leads to disturbed expression of genes that influence cytoskeletal organization and differentiation of Schwann cells. AB - In the developing peripheral nervous system, a coordinated reciprocal signaling between Schwann cells and axons is crucial for accurate myelination. The myelin and lymphocyte protein MAL is a component of lipid rafts that is important for targeting proteins and lipids to distinct domains. MAL overexpression impedes peripheral myelinogenesis, which is evident by a delayed onset of myelination and reduced expression of the myelin protein zero (Mpz/P0) and the low-affinity neurotrophin receptor p75(NTR). This study shows that MAL overexpression leads to a significant reduction of Mpz and p75(NTR) expression in primary mouse Schwann cell cultures, which was already evident before differentiation, implicating an effect of MAL in early Schwann cell development. Their transcription was robustly reduced, despite normal expression of essential transcription factors and receptors. Further, the cAMP response element-binding protein (CREB) and phosphoinositide 3-kinase signaling pathways important for Schwann cell differentiation were correctly induced, highlighting that other so far unknown rate limiting factors do exist. We identified novel genes expressed by Schwann cells in a MAL-dependent manner in vivo and in vitro. A number of those, including S100a4, RhoU and Krt23, are implicated in cytoskeletal organization and plasma membrane dynamics. We showed that S100a4 is predominantly expressed by nonmyelinating Schwann cells, whereas RhoU was localized within myelin membranes, and Krt23 was detected in nonmyelinating as well as in myelinating Schwann cells. Their differential expression during early peripheral nerve development further underlines their possible role in influencing Schwann cell differentiation and myelination. PMID- 25290062 TI - Comparison of cortical and white matter traumatic brain injury models reveals differential effects in the subventricular zone and divergent Sonic hedgehog signaling pathways in neuroblasts and oligodendrocyte progenitors. AB - The regenerative capacity of the central nervous system must be optimized to promote repair following traumatic brain injury (TBI) and may differ with the site and form of damage. Sonic hedgehog (Shh) maintains neural stem cells and promotes oligodendrogenesis. We examined whether Shh signaling contributes to neuroblast (doublecortin) or oligodendrocyte progenitor (neural/glial antigen 2 [NG2]) responses in two distinct TBI models. Shh-responsive cells were heritably labeled in vivo using Gli1-CreER(T2);R26-YFP bitransgenic mice with tamoxifen administration on Days 2 and 3 post-TBI. Injury to the cerebral cortex was produced with mild controlled cortical impact. Yellow fluorescent protein (YFP) cells decreased in cortical lesions. Total YFP cells increased in the subventricular zone (SVZ), indicating Shh pathway activation in SVZ cells, including doublecortin-labeled neuroblasts. The alternate TBI model produced traumatic axonal injury in the corpus callosum. YFP cells decreased within the SVZ and were rarely double labeled as NG2 progenitors. NG2 progenitors increased in the cortex, with a similar pattern in the corpus callosum. To further test the potential of NG2 progenitors to respond through Shh signaling, Smoothened agonist was microinjected into the corpus callosum to activate Shh signaling. YFP cells and NG2 progenitors increased in the SVZ but were not double labeled. This result indicates that either direct Smoothened activation in NG2 progenitors does not signal through Gli1 or that Smoothened agonist acts indirectly to increase NG2 progenitors. Therefore, in all conditions, neuroblasts exhibited differential Shh pathway utilization compared with oligodendrocyte progenitors. Notably, cortical versus white matter damage from TBI produced opposite responses of Shh-activated cells within the SVZ. PMID- 25290063 TI - A new model of cuprizone-mediated demyelination/remyelination. AB - In the central nervous system, demyelinating diseases, such as multiple sclerosis, result in devastating long-term neurologic damage, in part because of the lack of effective remyelination in the adult human brain. One model used to understand the mechanisms regulating remyelination is cuprizone-induced demyelination, which allows investigation of remyelination mechanisms in adult animals following toxin-induced demyelination. Unfortunately, the degree of demyelination in the cuprizone model can vary, which complicates understanding the process of remyelination. Previous work in our laboratory demonstrated that the Akt/mTOR pathway regulates active myelination. When given to young postnatal mice, the mTOR inhibitor, rapamycin, inhibits active myelination. In the current study, the cuprizone model was modified by the addition of rapamycin during cuprizone exposure. When administered together, cuprizone and rapamycin produced more complete demyelination and provided a longer time frame over which to investigate remyelination than treatment with cuprizone alone. The consistency in demyelination will allow a better understanding of the mechanisms initiating remyelination. Furthermore, the slower rate of remyelination provides a longer window of time in which to investigate the diverse contributing factors that regulate remyelination. This new model of cuprizone-induced demyelination could potentially aid in identification of new therapeutic targets to enhance remyelination in demyelinating diseases. PMID- 25290064 TI - Cerebral protein synthesis in a knockin mouse model of the fragile X premutation. AB - The (CGG)n-repeat in the 5'-untranslated region of the fragile X mental retardation gene (FMR1) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMR1 and absence of its protein product, fragile X mental retardation protein (FMRP). CGG repeat lengths between 55 and 200 occur in fragile X premutation (FXPM) carriers and have a high risk of expansion to a full mutation on maternal transmission. FXPM carriers have an increased risk for developing progressive neurodegenerative syndromes and neuropsychological symptoms. FMR1 mRNA levels are elevated in FXPM, and it is thought that clinical symptoms might be caused by a toxic gain of function due to elevated FMR1 mRNA. Paradoxically, FMRP levels decrease moderately with increasing CGG repeat length in FXPM. Lowered FMRP levels may also contribute to the appearance of clinical problems. We previously reported increases in regional rates of cerebral protein synthesis (rCPS) in the absence of FMRP in an Fmr1 knockout mouse model and in a FXPM knockin (KI) mouse model with 120 to 140 CGG repeats in which FMRP levels are profoundly reduced (80%-90%). To explore whether the concentration of FMRP contributes to the rCPS changes, we measured rCPS in another FXPM KI model with a similar CGG repeat length and a 50% reduction in FMRP. In all 24 brain regions examined, rCPS were unaffected. These results suggest that even with 50% reductions in FMRP, normal protein synthesis rates are maintained. PMID- 25290067 TI - A call for a rational nomenclature. PMID- 25290066 TI - Pd-catalyzed intramolecular aerobic oxidative C-H amination of 2-aryl-3 (arylamino)quinazolinones: synthesis of fluorescent indazolo[3,2 b]quinazolinones. AB - A palladium-catalyzed intramolecular aerobic oxidative C-H amination of 2-aryl-3 (arylamino)quinazolinones has been developed, providing a variety of substituted indazolo[3,2-b]quinazolinone derivatives in moderate to excellent yields. Preliminary mechanistic studies suggested that a palladacycle dimer could be the key intermediate, which underwent a cascade "rollover" cyclometalation and C-H amination sequence. Furthermore, the potential utility of these products has been demonstrated as a new class of blue fluorophores for fluorescent materials. PMID- 25290068 TI - The case for a functional nomenclature. PMID- 25290069 TI - T cells, mast cells and IgE. PMID- 25290065 TI - p75NTR, but not proNGF, is upregulated following status epilepticus in mice. AB - ProNGF and p75(NTR) are upregulated and induce cell death following status epilepticus (SE) in rats. However, less is known about the proneurotrophin response to SE in mice, a more genetically tractable species where mechanisms can be more readily dissected. We evaluated the temporal- and cell-specific induction of the proneurotrophins and their receptors, including p75(NTR), sortilin, and sorCS2, following mild SE induced with kainic acid (KA) or severe SE induced by pilocarpine. We found that mature NGF, p75(NTR), and proBDNF were upregulated following SE, while proNGF was not altered, indicating potential mechanistic differences between rats and mice. ProBDNF was localized to mossy fibers and microglia following SE. p75(NTR) was transiently induced primarily in axons and axon terminals following SE, as well as in neuron and astrocyte cell bodies. ProBDNF and p75(NTR) increased independently of cell death and their localization was different depending on the severity of SE. We also examined the expression of proneurotrophin co-receptors, sortilin and sorCS2. Following severe SE, sorCS2, but not sortilin, was elevated in neurons and astrocytes. These data indicate that important differences exist between rat and mouse in the proneurotrophin response following SE. Moreover, the proBDNF and p75(NTR) increase after seizures in the absence of significant cell death suggests that proneurotrophin signaling may play other roles following SE. PMID- 25290070 TI - A common evolutionary origin for class I molecules of the MHC and T1 a region. PMID- 25290071 TI - IgG heavy chain (Gm) allotypes in diabetes. PMID- 25290072 TI - Presence of receptors for self MHC antigens on non-T cells. AB - It is generally accepted that the major hislocompatibility complex (MHC) plays a key role in the recognition of foreign antigens by T lymphocytes. However, recent studies indicate that a range of non-T cells can also recognize sell MHCstructures. This review discusses these recent findings and suggests that the MHC plays a fundamental role in cell-cell communication and differentialion of both lymphoid and non-lymphoid cells. PMID- 25290073 TI - Self and non-self in the brain. PMID- 25290074 TI - B lymphocyte activation. AB - A review focussing on the lessons learned from polyclonal activation of B cells. PMID- 25290075 TI - Description of the 2012 NEMSIS public-release research dataset. AB - BACKGROUND: The National Emergency Medical Services Information System (NEMSIS) is a federally funded project designed to standardize emergency medical services (EMS) patient care reporting and facilitate state and national data repositories for the assessment of EMS systems of care. The purpose of this assessment is to characterize the annual NEMSIS 2012 Public-Release Research Dataset, detailing the strengths and limitations associated with use of these data for EMS quality assurance and/or research purposes. METHODOLOGY: Using descriptive statistics, we evaluated the dataset completeness (i.e., presence of missing/null values) and dataset content. To assess data generalizability, we compared age distributions to the 2010 National Hospital Ambulatory Medical Care Survey (NHAMCS). Subanalyses were conducted for cardiac arrest- and trauma-related EMS activations to describe their characteristics, treatments, and dispositions. The analysis focuses primarily on 9-1-1 EMS activations resulting in the treatment and transport of a patient, excepting the analysis conducted for out-of-hospital cardiac arrests (OHCA), which includes scene deaths. RESULTS: In 2012, 19,831,189 EMS activations were reported to NEMSIS by 8,439 agencies located in 42 states and territories. Of the 10,733,925 9-1-1 EMS activations reportedly treating and transporting a patient, the majority were attended by a paid EMT-paramedic (82%) employed by a fire-based EMS agency (25%) working in an urban area (53%). 9-1-1 call centers most likely dispatched EMS for a "sick person" (14%), while providers most likely reported pain (26%) as the patient's primary symptom and "traumatic injury" (13%) as the likely cause. NEMSIS data adequately characterize specific patient populations and demonstrate significant similarity to independent distributions of EMS patients (i.e., NHAMCS), yet missing data and use of null values remain prevalent. CONCLUSIONS: The annual NEMSIS Public Release Research Dataset is a valuable resource for evaluating the U.S. EMS activation population and can be used to conduct in-depth descriptions of the care of specific populations. However, the utility of the data are limited until the number of null values can be diminished and reporting becomes universal. PMID- 25290076 TI - Synergistic Effects of a Calcium Phosphate/Fibronectin Coating on the Adhesion of Periodontal Ligament Stem Cells Onto Decellularized Dental Root Surfaces. AB - This study aimed to enhance the attachment of periodontal ligament stem cells (PDLSCs) onto the decellularized dental root surface using surface coating with fibronectin and/or calcium phosphate (CaP) and to evaluate the activity of PDLSCs attached to a coated dental root surface following tooth replantation. PDLSCs were isolated from five dogs, and the other dental roots were used as a scaffold for carrying PDLSCs and then assigned to one of four groups according to whether their surface was coated with CaP, fibronectin, CaP/fibronectin, or left uncoated (control). Fibronectin increased the adhesion of PDLSCs onto dental root surfaces compared to both the control and CaP-coated groups, and simultaneous surface coating with CaP and fibronectin significantly accelerated and increased PDLSC adhesion compared to the fibronectin-only group. On in vivo tooth replantation, functionally oriented periodontal new attachment was observed on the CaP/fibronectin-coated dental roots to which autologous PDLSCs had adhered, while in the control condition, dental root replantation was associated only with root resorption and ankylosis along the entire root length. CaP and fibronectin synergistically enhanced the attachment of PDLSCs onto dental root surfaces, and autologous PDLSCs could produce de novo periodontal new attachment in an experimental in vivo model. PMID- 25290077 TI - Exploring the triplet excited state potential energy surfaces of a cyclometalated Pt(II) complex: is there non-Kasha emissive behavior? AB - In this Article, we address the complexity of the emissive processes of a square planar heteroleptic Pt(II) complex bearing 2-phenylpyridine (ppy) as cyclometalated ligand and an acetylacetonate derivative (dbm) as ancillary ligand. The origins of emission were identified with the help of density functional theory (DFT) and quadratic response (QR) time-dependent (TD)-DFT calculations including spin-orbit coupling (SOC). To unveil the photodeactivation mechanisms, we explored the triplet potential energy surfaces and computed the SOCs and the radiative decay rates (kr) from possible emissive states. We find that emission likely originates from a higher-lying (3)MLCT/(3)LLCT state and not from the Kasha-like (3)MLCT/(3)LCdbm state. The temperature-dependent nonradiative deactivation mechanisms were also elucidated. The active role of metal-centered ((3)MC) triplet excited states is confirmed for these deactivation pathways. PMID- 25290079 TI - Tubeless tracheotomy for survival airway surgery in the leporine model. AB - OBJECTIVES/HYPOTHESIS: The ideal animal experimental tracheostomy technique is one that is 1) safe and easy to perform, 2) requires no tracheostomy tube, and 3) requires minimal cleaning or suctioning to maintain patency. The leporine model for airway injury has been well established and offers an inexpensive and practical animal model for experimental evaluation. However, previous research has demonstrated a high mortality rate with survival airway surgery in rabbits. This study demonstrates the feasibility of airway management in the leporine model using a simple maturing suture tracheostomy that avoids a tracheostomy tube. STUDY DESIGN: Tracheostomy was performed in six New Zealand white rabbits in the setting of survival surgery over a 2-week study period. METHODS: A vertical tracheal incision was made from the second to the sixth tracheal ring. The anterior portion of the tracheal rings was removed and the skin surrounding the stoma was sutured down to the tracheal wall. The lateral tracheal wall was then suspended to the soft tissue in the lateral neck. RESULTS: All six rabbits survived the study period with minimal care and maintained stoma patency until sacrifice. Granulation tissue and edema were noted during the first week and largely resolved by the second week. An average of 5-mm-diameter stoma was measured 14 days after surgery without intraluminal stenosis or laryngeal edema. CONCLUSIONS: This method meets the defined criteria for the ideal experimental tracheostomy, demonstrating potential benefit in a laryngotracheal stenosis model and a rabbit model of evoked phonation. PMID- 25290080 TI - Sulfur-graphene nanostructured cathodes via ball-milling for high-performance lithium-sulfur batteries. AB - Although much progress has been made to develop high-performance lithium-sulfur batteries (LSBs), the reported physical or chemical routes to sulfur cathode materials are often multistep/complex and even involve environmentally hazardous reagents, and hence are infeasible for mass production. Here, we report a simple ball-milling technique to combine both the physical and chemical routes into a one-step process for low-cost, scalable, and eco-friendly production of graphene nanoplatelets (GnPs) edge-functionalized with sulfur (S-GnPs) as highly efficient LSB cathode materials of practical significance. LSBs based on the S-GnP cathode materials, produced by ball-milling 70 wt % sulfur and 30 wt % graphite, delivered a high initial reversible capacity of 1265.3 mAh g(-1) at 0.1 C in the voltage range of 1.5-3.0 V with an excellent rate capability, followed by a high reversible capacity of 966.1 mAh g(-1) at 2 C with a low capacity decay rate of 0.099% per cycle over 500 cycles, outperformed the current state-of-the-art cathode materials for LSBs. The observed excellent electrochemical performance can be attributed to a 3D "sandwich-like" structure of S-GnPs with an enhanced ionic conductivity and lithium insertion/extraction capacity during the discharge charge process. Furthermore, a low-cost porous carbon paper pyrolyzed from common filter paper was inserted between the 0.7S-0.3GnP electrode and porous polypropylene film separator to reduce/eliminate the dissolution of physically adsorbed polysulfide into the electrolyte and subsequent cross-deposition on the anode, leading to further improved capacity and cycling stability. PMID- 25290078 TI - Cloning of a functional 25-hydroxyvitamin D-1alpha-hydroxylase in zebrafish (Danio rerio). AB - Activation of precursor 25-hydroxyvitamin D3 (25D) to hormonal 1,25 dihydroxyvitamin D3 (1,25D) is a pivotal step in vitamin D physiology, catalysed by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase). To establish new models for assessing the physiological importance of the 1alpha hydroxylase-25D-axis, we used Danio rerio (zebrafish) to characterize expression and biological activity of the gene for 1alpha-hydroxylase (cyp27b1). Treatment of day 5 zebrafish larvae with inactive 25D (5-150 nM) or active 1,25D (0.1-10 nM) induced dose responsive expression (15-95-fold) of the vitamin D-target gene cyp24a1 relative to larvae treated with vehicle, suggesting the presence of Cyp27b1 activity. A full-length zebrafish cyp27b1 cDNA was then generated using RACE and RT-PCR methods. Sequencing of the resulting clone revealed an open reading frame encoding a protein of 505 amino acids with 54% identity to human CYP27B1. Transfection of a cyp27b1 expression vector into HKC-8, a human kidney proximal tubular epithelial cell line, enhanced intracrine metabolism of 25D to 1,25D resulting in greater than twofold induction of CYP24A1 mRNA expression and a 25-fold increase in 1,25D production compared to empty vector. These data indicate that we have cloned a functional zebrafish CYP27B1, representing a phylogenetically distant branch from mammals of this key enzyme in vitamin D metabolism. Further analysis of cyp27b1 expression and activity in zebrafish may provide new perspectives on the biological importance of 25D metabolism. PMID- 25290081 TI - Synthesis, antifungal activity, and QSAR study of novel trichodermin derivatives. AB - In an attempt to discover more potential antifungal agents, in this study, 21 novel trichodermin derivatives containing conjugated oxime ester (5a-5u) were designed and synthesized and were screened for in vitro antifungal activity. The bioassay tests showed that some of them exhibited good inhibitory activity against the tested pathogenic fungi. Compound 5a exhibited better activity against Pyricularia oryzae and Sclerotonia sclerotiorum than trichodermin, and compound 5j showed particular activity against P.oryzae and Botrytis cinerea. The quantitative structure-activity relationship (QSAR) indicated that log P and hardness were two critical parameters for the biological activities. The result suggested that these would be potential lead compounds for the development of fungicides with further structure modification. PMID- 25290082 TI - Development of a microsphere-based fluorescence immunochromatographic assay for monitoring lincomycin in milk, honey, beef, and swine urine. AB - The residue of lincomycin (LIN) in edible animal foodstuffs caused by the widespread use of veterinary drugs is in need of rapid, simple, and sensitive detection methods. The present work introduces a fluorescent microsphere immunoassay (FMIA) for detecting LIN in different samples based on the competitive immunoreaction on the chromatography test strip. The residues of LIN in different samples compete with bovine serum albumin (BSA) labeled LIN conjugates on the T-line to bind to the anti-LIN monoclonal antibody labeled fluorescent microspheres (FM-mAbs). Captured FM-mAbs on the T-line represent the fluorescent intensity, which is detected under UV light and quantified by a fluorescent reader. Under optimized conditions, the dynamic range is from 1.35 to 3.57 ng/mL, and the 50% inhibition concentration (IC50) is 2.20 ng/mL. This method has 4.4% cross-reactivity with clindamycin and negligible cross-reactivity (<0.1%) with other analogues. To reduce the matrix effects, a dilution method is used to pretreat the samples, and the recoveries range from 73.92 to 120.50% with coefficient of variations <21.76%. In comparison with the results of ELISA and colloidal gold immunoassay, FMIA has obvious advantages such as easy operation, time savings, high sensitivity and specificity, and broader prospect. PMID- 25290083 TI - Cerebrospinal fluid biomarkers for neuropsychological symptoms in early stage of late-onset Alzheimer's disease. AB - PURPOSE: In addition to testing blood, cerebrospinal fluid (CSF) has been analyzed in the search for biomarkers. The aim of this study was to identify biomarkers in CSF for neuropsychological symptoms in early-stage late-onset Alzheimer's disease (LOAD). METHODS: CSF levels of beta-amyloid 1-42 (Abeta42), F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NPs) were assayed in nine patients with mild Alzheimer's disease (AD), nine patients with amnestic mild cognitive impairment (a-MCI) and nine individuals with normal mental function. The three groups underwent neuropsychological testing. RESULTS: CSF levels of F2 IsoPs and F4-NPs did not significantly differ among the three groups. Abeta42 in CSF was significantly higher in the control group compared with the mild AD group (p < 0.001) and a-MCI group (p = 0.03). There was a significant positive correlation between the level of F2-IsoPs and Abeta42 in the a-MCI group and between the level of F2-IsoPs and F4-NPs in the mild AD group. In comparisons between the mild AD group and a-MCI group combined, the cognitive impairment (CI) group, with the control group, the median levels of F2-IsoPs and F4-NPs were significantly higher in the CI group and median level of Abeta42 was significantly lower in the CI group. Both the levels of F2-IsoPs and Abeta42 were significantly negatively correlated with paranoid and delusional ideation and total score for the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE AD). CONCLUSIONS: The findings suggest CSF levels of Abeta42 and F2-IsoPs are associated with the severity of neuropsychological symptoms. PMID- 25290084 TI - From Bad to Worse: Anemia on Admission and Hospital-Acquired Anemia. AB - BACKGROUND: Anemia at hospitalization is often treated as an accompaniment to an underlying illness, without active investigation, despite its association with morbidity. Development of hospital-acquired anemia (HAA) has also been associated with increased risk for poor outcomes. Together, they may further heighten morbidity risk from bad to worse. OBJECTIVES: The aims of this study were to (1) examine mortality, length of stay, and total charges in patients with present-on admission (POA) anemia and (2) determine whether these are exacerbated by development of HAA. DESIGN/SETTING/PATIENTS: In this cohort investigation, from January 1, 2009, to August 31, 2011, a total of 44,483 patients with POA anemia were admitted to a single health system compared with a reference group of 48,640 without POA anemia or HAA. MEASUREMENTS: Data sources included the University HealthSystem Consortium database and electronic medical records. Risk-adjustment methods included logistic and linear regression models for mortality, length of stay, and total charges. Present-on-admission anemia was defined by administrative coding. Hospital-acquired anemia was determined by changes in hemoglobin values from the electronic medical record. RESULTS: Approximately one half of the patients experienced worsening of anemia with development of HAA. Risk for death and resource use increased with increasing severity of HAA. Those who developed severe HAA had 2-fold greater odds for death; that is, mild POA anemia with development of severe HAA resulted in greater mortality (odds ratio, 2.57; 95% confidence interval, 2.08-3.18; P < 0.001), increased length of stay (2.23; 2.16-2.31; P < 0.001), and higher charges (2.09; 2.03-2.15; P < 0.001). CONCLUSIONS: Present-on-admission anemia is associated with increased mortality and resource use. This risk is further increased from bad to worse when patients develop HAA. Efforts to address POA anemia and HAA deserve attention. PMID- 25290085 TI - Design of Au@ZnO yolk-shell nanospheres with enhanced gas sensing properties. AB - The Au@ZnO yolk-shell nanospheres with a distinctive core@void@shell configuration have been successfully synthesized by deposition of ZnO on Au@carbon nanospheres. Various techniques were employed for the characterization of the structure and morphology of as-obtained hybrid nanostructures. The results indicated that the Au@ZnO yolk-shell nanospheres have an average diameter of about 280 nm and the average thickness of the ZnO shell is ca. 40 nm. To demonstrate how such a unique structure might bring about more excellent gas sensing property, we carried out a comparison of the sensing performances of ZnO nanospheres with different inner structures. It was found that Au@ZnO yolk-shell nanospheres exhibited an obvious improvement in response to acetone compared with the pure ZnO nanospheres with hollow and solid inner structures. For instance, the response of the Au@ZnO nanospheres to 100 ppm acetone was about 37, which was about 2 (3) times higher than that of ZnO hollow (solid) nanostructures. The enhanced sensing properties were attributed to their unique microstructures (porous shell and internal voids) and the catalytic effect of the encapsulated Au nanoparticles. PMID- 25290086 TI - Breast cancer incidence and mortality in a transitioning Chinese population: current and future trends. AB - BACKGROUND: Projections of future trends in cancer incidence and mortality are important for public health planning. METHODS: By using 1976-2010 data in Hong Kong, we fitted Poisson age-period-cohort models and made projections for future breast cancer incidence and mortality to 2025. RESULTS: Age-standardised breast cancer incidence (/mortality) is projected to increase (/decline) from 56.7 (/9.3) in 2011-2015 to 62.5 (/8.6) per 100,000 women in 2021-2025. CONCLUSIONS: The incidence pattern may relate to Hong Kong's socio-economic developmental history, while falling mortality trends are, most likely, due to improvements in survival from treatment advancement and improved health service delivery. PMID- 25290087 TI - Statin use and risk of nonmelanoma skin cancer: a nationwide study in Denmark. AB - BACKGROUND: Evidence is conflicting regarding statin use and risk of basal cell (BCC) and squamous cell skin cancer (SCC). METHODS: Using Danish nationwide registries, we identified all patients with incident BCC/SCC during 2005-2009 and matched them to population controls. We computed odds ratios (ORs) for BCC and SCC associated with statin use. RESULTS: We identified 38,484 cases of BCC and 3724 cases of SCC. Statin ever use was associated with ORs of 1.09 (CI: 1.06 1.13) for BCC and 1.01 (CI: 0.91-1.11) for SCC. CONCLUSIONS: Statin use was not associated with risk of SCC. Residual confounding plausibly explains the marginally increased risk of BCC. PMID- 25290088 TI - Childhood leukaemia and nuclear installations: the long and winding road. PMID- 25290089 TI - IRAK signalling in cancer. AB - Innate immune signalling has an essential role in inflammation, and the dysregulation of signalling components of this pathway is increasingly being recognised as an important mediator in cancer initiation and progression. In some malignancies, dysregulation of inflammatory toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signalling is typified by increased NF-kappaB activity, and it occurs through somatic mutations, chromosomal deletions, and/or transcriptional deregulation. Interleukin-1 receptor-associated kinase (IRAK) family members are mediators of TLR/IL1R superfamily signalling, and mounting evidence implicates these kinases as viable cancer targets. Although there have been previous efforts aimed at the development of IRAK kinase inhibitors, this is currently an area of renewed interest for cancer drug development. PMID- 25290090 TI - Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study. AB - BACKGROUND: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. METHODS: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an 'up-down' design to determine the toxicity contour of the combination. RESULTS: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m(-2) twice daily) experienced dose limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. CONCLUSIONS: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed. PMID- 25290092 TI - Seasonal variation in the month of birth in patients with skin cancer. AB - BACKGROUND: Month of birth influences the risk of developing several diseases. We investigated the influence of date of birth on melanoma skin cancer (MSC) and non melanoma skin cancer (NMSC) incidence. METHODS: Enhanced cancer registry data were analysed including 1751 MSC and 15 200 NMSC. RESULTS: People born in February to April showed significantly elevated risks of NMSC compared with those born in summertime. CONCLUSIONS: We demonstrated seasonality by date of birth for skin cancer incidence. Neonatal UV exposure may explain this finding. PMID- 25290091 TI - A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. AB - BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK 2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK 2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK 0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed. PMID- 25290093 TI - Prevalence, location and symmetry of noncatastrophic ligamentous suspensory apparatus lesions in California Thoroughbred racehorses, and association of these lesions with catastrophic injuries. AB - REASONS FOR PERFORMING STUDY: Knowledge of the site distribution of ligamentous injuries facilitates clinical diagnosis of suspensory apparatus conditions. OBJECTIVES: To determine if lesions within the suspensory ligament (SL) and distal ligaments of the proximal sesamoid bones (DSLs) were associated with suspensory apparatus failure or metacarpal lateral condylar fracture in California Thoroughbred racehorses. STUDY DESIGN: Cross-sectional study. METHODS: Suspensory apparatus specimens from 327 deceased Thoroughbred racehorses were sectioned within the SL body and branches, and oblique and straight DSLs. Purple lesions >=2 mm in width were categorised as moderate and paler or smaller lesions as mild. Associations between moderate lesions and age, sex, racetrack and cause of death were evaluated using multivariable logistic regression. RESULTS: Moderate lesions were evident in 16% and milder lesions in 77% of racehorses. Moderate lesions occurred with similar frequency in SL branches and oblique DSLs. Moderate lesions were more likely to occur in horses that died as a result of suspensory apparatus failure (odds ratio [OR] = 4.60; 95% confidence interval [CI] 1.61-13.13; and P = 0.004) or metacarpal lateral condylar fracture (OR = 5.05; 95% CI 1.42-17.93; and P = 0.012) compared with horses that died from nonmusculoskeletal causes, and in horses aged >=7 years horses compared with 2 year-old horses (OR = 5.33; 95% CI 1.44-19.75; and P = 0.012). CONCLUSIONS: Moderate lesions are common in the SL branches and oblique DSLs of racehorses, and may be associated with risk for suspensory apparatus failure and metacarpal condylar fracture. Monitoring health of the suspensory apparatus ligamentous structures may be a simple means of assessing fatigue in, and preventing more extensive injuries to, the forelimb suspensory apparatus and metacarpal condyles. PMID- 25290094 TI - The effect of sample storage on the Peroxidation of Leukocytes Index Ratio (PLIR) measure. AB - Delays in processing are frequent because of problems associated with transporting the samples to the laboratory. Thus, we aimed to evaluate the effect of sample storage on the Peroxidation of Leukocytes Index Ratio (PLIR). Differences between PLIR values of lymphocytes (PLIR-L), monocytes (PLIR-M) and granulocytes (PLIR-G) were observed in fresh samples. Sample storage affected the evaluation of PLIR. In particular, PLIR-L was lower in stored samples compared to fresh samples. In conclusion, our results suggest that fresh samples are recommended for assessing the PLIR. PMID- 25290096 TI - Utility of double-balloon enteroscopy in patients with left ventricular assist devices and obscure overt gastrointestinal bleeding. AB - Obscure overt gastrointestinal bleeding (OGIB) is a challenge in patients with left ventricular assist devices (LVADs). We evaluated the utility and safety of double-balloon enteroscopy (DBE) in patients with LVADs in an observational consecutive-patient cohort from a single tertiary referral center. Ten patients with LVADs underwent thirteen DBEs for obscure OGIB. The first OGIB event necessitating DBE occurred after a mean of 512 +/- 363 days of LVAD support. All patients underwent DBE, eleven anterograde and two retrograde, with a mean insertion depth 176 +/- 85 cm. Diagnostic yield was 69 % with the primary bleeding lesion most frequently found in the mid-bowel. The most common lesions were arteriovenous malformations. Therapeutic yield with argon plasma coagulation (APC), epinephrine injection, and/or hemoclip placement was 89 %. There were no procedure-related complications. DBE in patients with LVADs has good diagnostic yield and high therapeutic yield for obscure OGIB and is safe and well tolerated. PMID- 25290095 TI - Down-regulation by resveratrol of basic fibroblast growth factor-stimulated osteoprotegerin synthesis through suppression of Akt in osteoblasts. AB - It is firmly established that resveratrol, a natural food compound abundantly found in grape skins and red wine, has beneficial properties for human health. In the present study, we investigated the effect of basic fibroblast growth factor (FGF-2) on osteoprotegerin (OPG) synthesis in osteoblast-like MC3T3-E1 cells and whether resveratrol affects the OPG synthesis. FGF-2 stimulated both the OPG release and the expression of OPG mRNA. Resveratrol significantly suppressed the FGF-2-stimulated OPG release and the mRNA levels of OPG. SRT1720, an activator of SIRT1, reduced the FGF-2-induced OPG release and the OPG mRNA expression. PD98059, an inhibitor of upstream kinase activating p44/p42 mitogen-activated protein (MAP) kinase, had little effect on the FGF-2-stimulated OPG release. On the other hand, SB203580, an inhibitor of p38 MAP kinase, SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and Akt inhibitor suppressed the OPG release induced by FGF-2. Resveratrol failed to affect the FGF-2-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase or SAPK/JNK. The phosphorylation of Akt induced by FGF-2 was significantly suppressed by resveratrol or SRT1720. These findings strongly suggest that resveratrol down-regulates FGF-2-stimulated OPG synthesis through the suppression of the Akt pathway in osteoblasts and that the inhibitory effect of resveratrol is mediated at least in part by SIRT1 activation. PMID- 25290097 TI - Radiofrequency ablation for the treatment of radiation proctitis. AB - BACKGROUND AND STUDY AIMS: The main endoscopic therapy for radiation proctitis is argon plasma coagulation (APC); however treatment is not always successful. Radiofrequency ablation (RFA) is a possible treatment for radiation proctitis but data are scarce. The aim of this study was to report on the safety and efficacy of RFA in the treatment of radiation proctitis. PATIENTS AND METHODS: This study was an open-label, retrospective, multicenter study of patients with chronic hemorrhagic radiation proctitis who were treated with RFA. Data included a three item symptom score, the number of packed red blood cell transfusions, the lowest hemoglobin concentration, and complications, during the 6 months prior to and after RFA. Clinical success was defined as a decrease in the symptom score. Biological success was defined as an increase in the hemoglobin rate with equal or decreased number of transfusions required. RESULTS: A total of 17 patients underwent a median of 2 RFA sessions (range 1 - 4), without perioperative complications. Symptom scores decreased in 16 patients (clinical success 94 %), from a mean score of 3.6 (median 4) to 1.4 (median 1) (P < 0.01). Two patients developed rectal ulceration, with no local symptoms. During the 6 months after RFA, hemoglobin concentration increased in all 17 patients (from mean 8.3 +/- 2.8 g/dL [median 7.5] to 11.3 +/- 2.2 g/dL [median 11.0]; P < 0.01). Among 13 patients who were transfusion dependent prior to RFA (mean 7.2 +/- 7.7 transfusions [median 4]), 9 patients (69 %) were weaned off transfusions after RFA. A significant increase in the hemoglobin level was observed in this subgroup of patients (from mean 7.2 +/- 1.4 g/dL [median 7.3] to 10.7 +/- 1.5 g/dL [median 10.5]; P < 0.001). Biological success was 100 %. CONCLUSIONS: RFA seems to significantly decrease clinical symptoms and increase the hemoglobin concentration, thus reducing the need for transfusions. PMID- 25290098 TI - What has finite element analysis taught us about diabetic foot disease and its management? A systematic review. AB - BACKGROUND: Over the past two decades finite element (FE) analysis has become a popular tool for researchers seeking to simulate the biomechanics of the healthy and diabetic foot. The primary aims of these simulations have been to improve our understanding of the foot's complicated mechanical loading in health and disease and to inform interventions designed to prevent plantar ulceration, a major complication of diabetes. This article provides a systematic review and summary of the findings from FE analysis-based computational simulations of the diabetic foot. METHODS: A systematic literature search was carried out and 31 relevant articles were identified covering three primary themes: methodological aspects relevant to modelling the diabetic foot; investigations of the pathomechanics of the diabetic foot; and simulation-based design of interventions to reduce ulceration risk. RESULTS: Methodological studies illustrated appropriate use of FE analysis for simulation of foot mechanics, incorporating nonlinear tissue mechanics, contact and rigid body movements. FE studies of pathomechanics have provided estimates of internal soft tissue stresses, and suggest that such stresses may often be considerably larger than those measured at the plantar surface and are proportionally greater in the diabetic foot compared to controls. FE analysis allowed evaluation of insole performance and development of new insole designs, footwear and corrective surgery to effectively provide intervention strategies. The technique also presents the opportunity to simulate the effect of changes associated with the diabetic foot on non-mechanical factors such as blood supply to local tissues. DISCUSSION: While significant advancement in diabetic foot research has been made possible by the use of FE analysis, translational utility of this powerful tool for routine clinical care at the patient level requires adoption of cost-effective (both in terms of labour and computation) and reliable approaches with clear clinical validity for decision making. PMID- 25290101 TI - Transposition of the vertebral artery after a unilateral c1 lateral mass fracture: a case report and review of the literature. AB - In any cervical spine trauma involving dislocation of the facet joints or transverse foramen, a concomitant injury of the vertebral arteries must be excluded. Early diagnosis of an arterial occlusion is important because therapeutic intervention can prevent further complications, such as irreversible vertebrobasilar ischemia. Conservative and surgical treatment strategies are chosen depending on patient symptoms, fracture morphology, and grade of vascular injury. The benefit of anticoagulant medication after blunt injuries of the vertebral arteries in preventing thromboembolic events remains a matter of debate in the current literature. We present a case report of a professional biathlete with a unilateral vertebral artery injury. Adequate interpretation of both initial clinical and radiological findings is essential to detect this injury and to determine appropriate therapeutic intervention to optimize clinical outcome. PMID- 25290100 TI - A thermostable Salmonella phage endolysin, Lys68, with broad bactericidal properties against gram-negative pathogens in presence of weak acids. AB - Resistance rates are increasing among several problematic Gram-negative pathogens, a fact that has encouraged the development of new antimicrobial agents. This paper characterizes a Salmonella phage endolysin (Lys68) and demonstrates its potential antimicrobial effectiveness when combined with organic acids towards Gram-negative pathogens. Biochemical characterization reveals that Lys68 is more active at pH 7.0, maintaining 76.7% of its activity when stored at 4 degrees C for two months. Thermostability tests showed that Lys68 is only completely inactivated upon exposure to 100 degrees C for 30 min, and circular dichroism analysis demonstrated the ability to refold into its original conformation upon thermal denaturation. It was shown that Lys68 is able to lyse a wide panel of Gram-negative bacteria (13 different species) in combination with the outer membrane permeabilizers EDTA, citric and malic acid. While the EDTA/Lys68 combination only inactivated Pseudomonas strains, the use of citric or malic acid broadened Lys68 antibacterial effect to other Gram-negative pathogens (lytic activity against 9 and 11 species, respectively). Particularly against Salmonella Typhimurium LT2, the combinatory effect of malic or citric acid with Lys68 led to approximately 3 to 5 log reductions in bacterial load/CFUs after 2 hours, respectively, and was also able to reduce stationary-phase cells and bacterial biofilms by approximately 1 log. The broad killing capacity of malic/citric acid-Lys68 is explained by the destabilization and major disruptions of the cell outer membrane integrity due to the acidity caused by the organic acids and a relatively high muralytic activity of Lys68 at low pH. Lys68 demonstrates good (thermo)stability properties that combined with different outer membrane permeabilizers, could become useful to combat Gram-negative pathogens in agricultural, food and medical industry. PMID- 25290099 TI - Proteomic profiles in acute respiratory distress syndrome differentiates survivors from non-survivors. AB - Acute Respiratory Distress Syndrome (ARDS) continues to have a high mortality. Currently, there are no biomarkers that provide reliable prognostic information to guide clinical management or stratify risk among clinical trial participants. The objective of this study was to probe the bronchoalveolar lavage fluid (BALF) proteome to identify proteins that differentiate survivors from non-survivors of ARDS. Patients were divided into early-phase (1 to 7 days) and late-phase (8 to 35 days) groups based on time after initiation of mechanical ventilation for ARDS (Day 1). Isobaric tags for absolute and relative quantitation (iTRAQ) with LC MS/MS was performed on pooled BALF enriched for medium and low abundance proteins from early-phase survivors (n = 7), early-phase non-survivors (n = 8), and late phase survivors (n = 7). Of the 724 proteins identified at a global false discovery rate of 1%, quantitative information was available for 499. In early phase ARDS, proteins more abundant in survivors mapped to ontologies indicating a coordinated compensatory response to injury and stress. These included coagulation and fibrinolysis; immune system activation; and cation and iron homeostasis. Proteins more abundant in early-phase non-survivors participate in carbohydrate catabolism and collagen synthesis, with no activation of compensatory responses. The compensatory immune activation and ion homeostatic response seen in early-phase survivors transitioned to cell migration and actin filament based processes in late-phase survivors, revealing dynamic changes in the BALF proteome as the lung heals. Early phase proteins differentiating survivors from non-survivors are candidate biomarkers for predicting survival in ARDS. PMID- 25290102 TI - Predictors of Frontal Plane Knee Moments During Side-Step Cutting to 45 and 110 Degrees in Men and Women: Implications for Anterior Cruciate Ligament Injury. AB - OBJECTIVE: To compare frontal plane knee moments, and kinematics and kinetics associated with knee valgus moments between cutting to 45 and 110 degrees, and to determine the predictive value of kinematics and ground reaction forces (GRFs) on knee valgus moments when cutting to these angles. Also, to determine whether sex differences exist in kinematics and kinetics when cutting to 45 and 110 degrees. DESIGN: Cross-sectional study. SETTING: Laboratory setting. PARTICIPANTS: Forty five (20 females) healthy young adult soccer athletes aged 16 to 23 years. ASSESSMENT OF RISK FACTORS: Kinematic and kinetic variables were compared between randomly cued side-step cutting maneuvers to 45 and 110 degrees. Predictors of knee valgus moment were determined for each task. MAIN OUTCOME MEASURES: Kinematic variables: knee valgus angle, hip abduction, and internal rotation angles. Kinetic variables: vertical, posterior, and lateral GRFs, and knee valgus moment. RESULTS: Knee valgus moments were greater when cutting to 110 degrees compared with 45 degrees, and females exhibited greater moments than males. Vertical and lateral GRFs, hip internal rotation angle, and knee valgus angle explained 63% of the variance in knee valgus moment during cutting to 45 degrees. During cutting to 110 degrees, posterior GRF, hip internal rotation angle, and knee valgus angle explained 41% of the variance in knee valgus moment. CONCLUSIONS: Cutting tasks with larger redirection demands result in greater knee valgus moments. Similar factors, including shear GRFs, hip internal rotation, and knee valgus position contribute to knee valgus loading during cuts performed to smaller (45 degrees) and larger (110 degrees) angles. CLINICAL RELEVANCE: Reducing vertical and shear GRFs during cutting maneuvers may reduce knee valgus moments and thereby potentially reduce risk for anterior cruciate ligament injury. PMID- 25290103 TI - Lateral Pectoral Nerve Injury Mimicking Cervical Radiculopathy. AB - The lateral pectoral nerve (LPN) is commonly injured along with the brachial plexus, but its isolated lesions are rare. Here, we present a case of an isolated LPN lesion confused with cervical radiculopathy. A 41-year-old man was admitted to our clinic because of weakness in his right arm. Previous magnetic resonance imaging (MRI) examination revealed right posterolateral protrusion at the C6-7 level. At the initial assessment, atrophy of the right pectoralis major muscle was evident, and mild weakness of the right shoulder adductor, internal rotator, and flexor muscles was observed. Therefore, electrodiagnostic evaluation was performed, and a diagnosis of isolated LPN injury was made. Nerve injury was thought to have been caused by weightlifting exercises and traction injury. Lateral pectoral nerve injury can mimic cervical radiculopathy, and MRI examination alone may lead to misdiagnosis. Repeated physical examinations during the evaluation and treatment phase will identify the muscle atrophy that occurs 1 or more months after the injury. PMID- 25290104 TI - Vibration Therapy Is No More Effective Than the Standard Practice of Massage and Stretching for Promoting Recovery From Muscle Damage After Eccentric Exercise. AB - OBJECTIVE: The purpose of this study was to determine if vibration therapy is more effective than the standard treatment of stretching and massage for improving recovery of muscle strength and reducing muscle soreness after muscle damage induced by eccentric exercise. DESIGN: A randomized, single-blinded parallel intervention trial design was used. SETTING: Research laboratory. PARTICIPANTS: Fifty untrained men aged 18 to 30 years completed the study. INTERVENTIONS: Participants performed 100 maximal eccentric muscle actions (ECCmax) of the right knee extensor muscles. For the next 7 days, 25 participants applied cycloidal vibration therapy to the knee extensors twice daily and 25 participants performed stretching and sports massage (SSM) twice daily. MAIN OUTCOME MEASURES: Changes in markers of muscle damage [peak isometric torque (PIT), serum creatine kinase (CK), and serum myoglobin (Mb)], muscle soreness (visual analog scale), and inflammation [serum C-reactive protein (CRP)] were assessed. RESULTS: After ECCmax, there was no difference in recovery of PIT and muscle soreness or serum CK, Mb, and CRP levels between vibration and SSM groups (P > 0.28). CONCLUSIONS: Cycloidal vibration therapy is no more effective than the standard practice of stretching and massage to promote muscle recovery after the performance of muscle-damaging exercise. CLINICAL RELEVANCE: Prescription of vibration therapy after maximal exercise involving eccentric muscle damage did not alleviate signs and symptoms of muscle damage faster than the standard prescription of stretching and massage. PMID- 25290105 TI - Pressurized Intravenous Fluid Administration in the Professional Football Player: A Unique Setting for Venous Air Embolism. AB - Venous air embolism (VAE) is a potentially life-threatening event that is most commonly associated with certain surgical procedures, although this theoretical complication of pressurized rapid infusion of intravenous (IV) fluids has been described. This series of cases describes 4 athletes who presented with continuous coughing and other chest complaints after peripheral IV infusion of normal saline through manual pressurized infusion. Symptoms resolved within 20 minutes, and these incidences did not interfere with resuming athletic competition with no recurrence of symptoms or complications. These cases are most consistent with varying degrees of VAE and reveal the risk of VAE associated with pressurized peripheral IV fluid administration along with the unique clinical presentation of more modest forms of VAE in an awake patient. Becoming more knowledgeable about IV infusion technique and understanding potential pitfalls can be helpful in reducing future incidences of VAE. PMID- 25290106 TI - Impact of Total Shoulder Arthroplasty on Golfing Activity. AB - OBJECTIVE: Golf is a widely popular sport in the United States with 29 million Americans participating in the game. With an aging population and increased incidence of glenohumeral degenerative arthritis, the number of active golfers requiring total shoulder replacement is on the rise. This study aims to evaluate the effect of total shoulder replacement on golfing activity. DESIGN: Retrospective; questionnaire. SETTING: Survey. PARTICIPANTS: Three hundred sixty seven patients were identified based on Current Procedural Terminology codes who underwent total shoulder arthroplasty (TSA) between January 2004 and January 2013. INTERVENTIONS: A voluntary anonymous questionnaire was sent to patients by mail including both objective and subjective questions about their level of golf activity and ability both before and after the surgery. MAIN OUTCOME MEASURES: Two hundred sixty-eight (73%) patients responded with 35 (34 right-handed and 1 left-handed patients) golfers completing the questionnaire. Results including visual analog pain scores, handicap change, and driving distance were evaluated statistically using the Student t test. RESULTS: Thirty-five golfers at an average time of 3.2 years after TSA completed the questionnaire with 31/35 being able to return to the sport at an average time of 8.4 months postoperatively. Thirty of 31 patients reported improvement in their pain level during and after golfing activity by an average of 4.3 (P < 0.05) on a visual analog scale (VAS) for pain. On average, driving distances increased by 12.5 yd (P = 0.0012) and handicap improved by 1.4 strokes (P = 0.03). CONCLUSIONS: Patients who undergo TSA for primary glenohumeral arthritis can safely return to golfing activity with a significant decrease in their perceived pain level as per VAS scores. Statistically significant findings included an increase in driving distance by 12.5 yd and an improvement in handicap by 1.4. CLINICAL RELEVANCE: In counseling patients, it is the authors' opinion that based on our experience with golfers undergoing TSA, patients can safely return to sport at an average of 8.4 months. The likelihood of return to play was quite high, but not 100%, and as such no guarantee should be provided to patients. Outcomes of patients with TSA desiring a return to golf are positive, and possible benefits include improvement of pain and possible improvements in driving distance and handicap. LEVEL OF EVIDENCE: IV. PMID- 25290107 TI - Molecular-clock methods for estimating evolutionary rates and timescales. AB - The molecular clock presents a means of estimating evolutionary rates and timescales using genetic data. These estimates can lead to important insights into evolutionary processes and mechanisms, as well as providing a framework for further biological analyses. To deal with rate variation among genes and among lineages, a diverse range of molecular-clock methods have been developed. These methods have been implemented in various software packages and differ in their statistical properties, ability to handle different models of rate variation, capacity to incorporate various forms of calibrating information and tractability for analysing large data sets. Choosing a suitable molecular-clock model can be a challenging exercise, but a number of model-selection techniques are available. In this review, we describe the different forms of evolutionary rate heterogeneity and explain how they can be accommodated in molecular-clock analyses. We provide an outline of the various clock methods and models that are available, including the strict clock, local clocks, discrete clocks and relaxed clocks. Techniques for calibration and clock-model selection are also described, along with methods for handling multilocus data sets. We conclude our review with some comments about the future of molecular clocks. PMID- 25290108 TI - Oncogenes and B-lymphocyte neoplasia. AB - Genetic alterations associated with B-lymphocyte neoplasias were the focus of a workshop organized at the Basel Institute for Immunology on 15-17 March 1983 by Fritz Melchers, Michael Potter and Martin Weigert. The role of viruses, chromosomal abnormalities and cellular one genes in the oncogenic process was discussed in relationship to the normal pathway of B-cell development. PMID- 25290109 TI - A case for immune response genes? AB - Diabetes is not a single disease. Some patients develop insulin deficiency fairly rapidly and these are usually young, have lymphocytic infiltration of their pancreatic islets, possess circulating islet-cell antibody, and show a strong association with certain HLA phenotypes. This form of the disease is designated type I (juvenile onset or insulin-dependent diabetes mellitus, IDDM). The key factors involved in its pathogenesis were recently reviewed at the fourth of a series of international meetings on the immunology of diabetes'. This meeting was held in memory of Andrew Cudworth whose standing was pre-eminent in the immunogenetics of diabetes and whose untimely death is keenly felt. PMID- 25290110 TI - The value of theoretical models in immunological research. AB - With the increase in understanding of immunological phenomena has come an increase in availability of mathematical models which describe them. Here Judith Rae Lumb argues that theoretical models should be more widely appreciated and used, especially since helpful computer programs are now becoming available. PMID- 25290111 TI - Interferon, beta-2-microglobulin and immunoselection in the pathway to malignancy A blinkered view from Nag's Head Yard. AB - Recent clinical studies suggest that benign tumour cells express MHC class-I antigens while malignant cells with the same tissue origin do not. Interferons induce normal cells to increase the expression of class-I antigens but Arnold Sanderson and Peter Beverley argue here that malignant cells may not respond in this way. As a result, they may lack the antigens that would make them vulnerable to immune mechanisms dependent on T cells which recognize class-I self-MHC antigens. PMID- 25290112 TI - Phase variation in the modulation of the human immune response. PMID- 25290113 TI - Does breast-feeding prevent the development of allergy? PMID- 25290114 TI - The abolition of infection: hope or illusion? PMID- 25290115 TI - The human MHC : evidence for multiple HLA-D-region genes. AB - The human major histocompatibiliy complex regulates immune responsiveness through a complex series of HLA-D-region-controlled molecules. The use of monoclonal antibodies to dissect this expanding array of molecules has allowed the structural characterization of several of these molecular species. Here biochemical studies are discussed which, coupled with classic serological techniques, have been used to construct a model of the genetic organization of the human HLA-D region. PMID- 25290116 TI - Vaccination against autoimmune disease with lines of autoimmune T lymphocytes. AB - The etiological agents of auto' mmune diseases are endogenous lymphocytes which attack apparently normal constituents of the individual, while in infectious disease the individual is attacked by an exogenous microbial agent. Nevertheless, the clinical expression of autoimmunity and infection may result from similar pathological processes of edema, cellular infiltration, phagocytosis, cytotoxicity, fibrosis, calcification, etc. And as Irun Cohen and colleagues show here both types of illness can be studied to advantage by the basic strategy of isolating in pure culture the etiological agent of disease. PMID- 25290117 TI - Somatic cell genetics, immunogenetics and gene mapping. AB - The use of immunological techniques to study genetics and the reciprocal use of genetic analysis to study immunology has proved to be a very powerful combination resulting in the definition of many systems including the major histocompatibility complex. The production of monoclonal antibodies by somatic cell hybrids (usually known as 'hybridomas') provides a more recent example of the exploitation of a genetic techniquefor the benefit of immunology. The reciprocal to the hybridoma technique is to use antibodies to analyse somatic cell hybrids. In this review Alan Tunnaclie and colleagues describe the analysis of the human cell surface using somatic cell genetics in conjunction with monoclonal antibodies, and suggest that this is a powerful approach which should be applied more specifically to cells of the lymphoid system. PMID- 25290118 TI - Immunoregulatory T-cell defects. AB - In normal circumstances homeostatic balance is maintained between T-cell help and suppression. In this review Raif Geha and Fred Rosen discuss examples of human diseases which involve excess or deficiency of T-cell help or T-cell suppression diseases which have contributed greatly to an understanding of how T cells regulate the human immune response. PMID- 25290119 TI - Cell-cell adhesion in the immune system. AB - Interactions between cells are essential for function and regulation of the immune system. Some of these interactions are mediated by soluble factors such as immunoglobulins or interleukins, which can serve as chemical messengers that transmit information between widely separated cells. In other cases interaction requires physical contact between the cells and cell-cell adhesion. In this review George Bell emphasizes adhesion mediated by specific cell-surface receptors and/or ligands, including instances in which the receptors have not been identified and are inferred from specificity of interaction rather than biochemical characterization. PMID- 25290122 TI - Use of a commercial HIV co-receptor tropism assay in clinical practice. PMID- 25290123 TI - Potpourri (revisited). PMID- 25290124 TI - An 8-day-old boy with abdominal distention after oral feeding. PMID- 25290125 TI - Managing cervical lymphadenitis--a total pain in the neck! AB - Patients presenting with cervical lymphadenitis are a complex and common occurrence in a general pediatric practice. Although Staphylococcus aureus (often methicillin-resistant S. aureus [MRSA]) and Streptococcus pyogenes predominate as causative pathogens, the next most common pathogens, Bartonella, atypical mycobacterium, and mononucleosis, also must be considered early on. The best way to diagnose and manage these cases initially is to proceed methodically, with detailed history and physical examination, initial streptococcal mono rapid tests, serial office visits, and complete blood counts. In nonviral cases, an empiric oral antibiotic trial is usually prescribed as early as possible to cover for MRSA or Bartonella. Very tender or reddened lymph nodes larger than 5 cm that are unresponsive and worsening may likely require inpatient parenteral antibiotics and sometimes surgical removal. The practitioner must also realize that submandibular and supraclavicular node locations are highly suggestive of atypical mycombacterium and cancer, respectively. PMID- 25290126 TI - A 6-year-old girl with painful rash on her left lower extremity. PMID- 25290128 TI - Adolescent substance use. PMID- 25290127 TI - A persistently febrile adolescent with headache and vision changes. PMID- 25290129 TI - The role of the parent in adolescent substance use. AB - The overall goal of adolescent development is personal emancipation through individuation. The parent is considered an adolescent's most powerful formative influence and role model regarding health attitudes, behavioral norms, and social boundaries. For adolescents, engaging in risk-taking behaviors can be a normal maturational "rewarding" response or a strategy to cope with perceived stress and express emotions. Effective stress management is an important skill set for the developing adolescent who may experiment with a range of unhealthy strategies for coping or personal expression despite their high potential for hazardous consequences. Parenting the adolescent poses the immense challenge of promoting the adolescent's development of life skills while enabling stimulating healthy opportunities during a time of increased access and vulnerability to risky choices, including substance use. Effective parenting includes consistency, communication, respect and safety-based boundaries as well as monitoring the adolescents' friends and activities, particularly media use. Not only are parents important in deterring, suspecting, and at times detecting their adolescents' substance use, they can facilitate the evaluation or interventions that may be needed to stop substance use, start recovery, and sustain it. The role of parents is to guide adolescents in developing strengths and resilience, and fulfilling their fullest life potential. PMID- 25290130 TI - Averting the perfect storm: addressing youth substance use risk from social media use. AB - Adolescents are developmentally sensitive to pathways that influence alcohol and other drug (AOD) use. In the absence of guidance, their routine engagement with social media may add a further layer of risk. There are several potential mechanisms for social media use to influence AOD risk, including exposure to peer portrayals of AOD use, socially amplified advertising, misinformation, and predatory marketing against a backdrop of lax regulatory systems and privacy controls. Here the authors summarize the influences of the social media world and suggest how pediatricians in everyday practice can alert youth and their parents to these risks to foster conversation, awareness, and harm reduction. PMID- 25290131 TI - Substance abuse screening and brief intervention for adolescents in primary care. AB - Adolescent substance use is common and is associated with serious mental, physical, and social risks, warranting systematic screening in the primary care setting. It is important for clinicians to become familiar with Screening, Brief Intervention, and Referral to Treatment (SBIRT), including administration of validated screening tools to identify level of risk associated with substance use and application of appropriate brief interventions. Positive reinforcement and brief advice is indicated for those adolescents with no or minimal risk for a substance use disorder. Providing a brief intervention using motivational interviewing strategies with subsequent close clinical follow-up is warranted when an adolescent meets criteria for a mild to moderate substance use disorder. Referral to treatment is recommended in cases of severe substance use. Immediate action, including breaking confidentiality, may be necessary when an adolescent's behavior raises acute safety concerns. Making time to interview adolescents alone is essential. It is also important to review the limitations of confidentiality with patients and parents/guardians and offer them strategies to discuss sensitive issues with their adolescents. Available resources for adolescents, parents/guardians, and clinicians regarding the risks of adolescent substance use and evidence-based treatment options can be used to support implementation of SBIRT in adolescent primary care. PMID- 25290132 TI - Erythrocyte sedimentation rate and C-reactive protein: how best to use them in clinical practice. AB - Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are markers of inflammatory conditions and have been used extensively by clinicians both in outpatient and inpatient settings. It is important to understand the physiologic principles behind these two tests so clinicians may use them appropriately. For example, fibrinogen (for which ESR is an indirect measure) has a much longer half life than CRP, making ESR helpful in monitoring chronic inflammatory conditions, whereas CRP is more useful in diagnosis as well as in monitoring responses to therapy in acute inflammatory conditions, such as acute infections. Many factors can result in falsely high or low ESR and CRP levels, and it is important to take note of these. Therefore, if used wisely, ESR and CRP can be complementary to good history taking and physical examination in the diagnosis and monitoring of inflammatory conditions. PMID- 25290133 TI - Ultrasound guided transarterial coil placement in the internal and external carotid artery in horses. AB - OBJECTIVES: To assess ultrasound guided transarterial coil placement (UGTACP) for occlusion of the internal carotid artery (ICA) and external carotid artery (ECA) in horses. STUDY DESIGN: Cadaveric and in vivo study. ANIMALS: Cadaveric horses (n = 10), healthy horses (3), and 1 clinical case. METHODS: Cadaveric and in vivo (healthy horses): UGTACP was performed in the caudal part of the ICA and ECA. Coil placement in the rostral part of the ICA was performed blindly and controlled by conventional radiography. No coils were placed in the rostral part of the ECA. CLINICAL CASE: UGTACP of the ICA was in a horse with guttural pouch mycosis of the left guttural pouch. RESULTS: Accurate ultrasound-guided catheterization of the ICA and ECA was performed in all specimens. Ultrasound guided coil placement was successfully performed in all cases except 1. No complications occurred in the in vivo study. The clinical case fully recovered and returned to its intended use. CONCLUSIONS: Based on our study, UGTACP of the ICA and ECA caudal part is a feasible alternative to fluoroscopy. An advantage of this technique is the accuracy with which you can catheterize both ICA and ECA and the ability to identify unusual branching at the origin of the ICA. Regarding the rostral part of the ICA, angiographic catheter guidance in this region is probably more precise using fluoroscopy as it is performed blindly. In a clinical situation, combination of US and fluoroscopy guidance can result in reduction of radiation exposure time. PMID- 25290135 TI - Mechanisms in B-cell neoplasia. PMID- 25290134 TI - Influence of acetate and propionate on sulphate-reducing bacteria activity. AB - AIMS: Sulphate-reducing bacteria (SRB) activity is generally considered as inconvenience in domestic wastewater treatment plants (WWTP), but could also be applied beneficially. The competition between SRB and methanogens is a point of concern for stable process design. As limited attention was given to the effect of varying acetate and propionate concentrations on SRB activity, this study focused specially on these substrates. METHODS AND RESULTS: The research was performed in sequencing batch reactors operated at 20 degrees C and an SRT of 15 days. In the acetate-fed reactor, methanogens became dominant, while in the propionate reactor, SRB were the dominant population. In the mixed-substrate-fed reactor, both substrates were converted by SRB. The dominant SRB population in the mixed-substrate-fed reactor was different from the propionate-fed reactor, but all operational characteristics such as the substrate consumption rate, yield and growth rate were similar. The sludge adapted to propionate could easily switch to an acetate feed procedure. CONCLUSIONS: These results indicate that under wastewater temperature of 20 degrees C, the SRB are likely to outcompete methanogens more easily as inferred from pure substrate studies on acetate solely. SIGNIFICANCE AND IMPACT OF THE STUDY: The present results show that the natural presence of propionate in wastewater allows stable sulphate reduction, which decreases the biogas production, but provides an opportunity for using SRB beneficially in wastewater treatment. PMID- 25290136 TI - Brain neocortex and the immune system. PMID- 25290137 TI - 'Mucosal' mast cells. PMID- 25290138 TI - Molecules in the immunoglobulin superfamily. PMID- 25290139 TI - Further comments on the molecular members of extended immunoglobulin family. PMID- 25290140 TI - Host-protective immunity and its suppression in a parasitic disease: murine cutaneous leishmaniasis. AB - The accumulation of knowledge on the cellular immunology of host parasite relationships can be very rapid when infection of mice with a human parasite causes a disease resembling that seen in man. This is so of Old World cutaneous leishmaniasis ('oriental sore'). As must be the case in all chronic infectious diseases, manifestations of the clinical disease spectrum in cutaneous leishmaniosis reflect both host and parasite factors. In this article Graham Mitchell describes how this spectrum can be exploited in inbred mice injected with isolates of Leishmania trop ica major (L. major) for detailed analysis of interactions between host and parasite. PMID- 25290141 TI - The elimination of allogeneic lymphocytes: a useful model of natural killer cell activity in vivo? PMID- 25290142 TI - Idiotypic regulation of self-reactive and allo-reactive T cells in autoimmunity and graft-versus-host disease. PMID- 25290143 TI - Hypotheses on genetic contributions to the aetiology of diabetes mellitus. PMID- 25290144 TI - Ion channels in lymphocytes. PMID- 25290145 TI - Tissue-specific and tissue-restricted histocompatibility antigens. AB - Strictly defined, tissue-specific antigens are antigens characteristic of one particular tissue or cell. They are usually associated with autoimmunity and are remarkably homologous between species. In contrast, histocompatibility (H) antigens reflect polymorphism within species - they are alloantigens - and class I major H complex (MHC) antigens - at least mouse H-2D and H-2 K and human HLA-A and -B, the commonest targets of acute allograft rejection - are widely distributed in the body; class-II MHC antigens - mouse Ia and human DR - have a much more limited distribution, being expressed primarily on B lymphocytes and on macrophages and other cells involved in antigen presentation and immune activation. This review is devoted to H antigens other than class-IIMHC antigens with limited if not highly specific, tissue distribution. Some of these antigens are classic tissue-specific antigens, others are alloantigens with limited tissue expression. Much of the evidence that they evoke immune responses that damage or destroy transplanted tissue is incomplete or circumstantial, but some is convincing and includes the immunogenetic characterization of new antigen systems that may have to be reckoned with clinically, especially when dealing with HLA matched transplants. PMID- 25290146 TI - Immunosuppressive activity of the retroviral envelope protein P 15E and its possible relationship to neoplasia. AB - Type C retroviral infections can cause profound immunosuppression as well as neoplasms. The retroviral envelope protein p15E has both immunosuppressive and anti-inflammatory activities which may contribute to the pathogenicity of retroviruses. Murine and human neoplastic cells, not infected with retroviruses, have recently been found to contain p15E like antigens. In this article Ralph Snyderman and George Cianciolo discuss the potential relationship between p15E production, immunosuppression and neoplasia. PMID- 25290147 TI - The gene for staphylococcal protein A. AB - Protein A from Staphylococcus aureus has become an important tool in immunology and molecular biology due to its specific binding to the constant region of immunoglobulins (Igs) from most mammalian species(1). Many qualitative and quantitative techniques have been developed which take advantage of this 'pseudo immune' reaction(2). In addition, solid state protein A has recently been introduced in medical therapy to decrease the amount of circulating immune complexes in sera(3). In this article Mathias Uhlen, Martin Lindberg and Lennart Philipson describe the structure of the protein A molecule and its gene. They also discuss the possibilities for fusing the protein A gene to other genes. PMID- 25290151 TI - A capsaicin (8%) patch in the treatment of severe persistent inguinal postherniorrhaphy pain: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Persistent pain after inguinal herniorrhaphy is a disabling condition with a lack of evidence-based pharmacological treatment options. This randomized placebo-controlled trial investigated the efficacy of a capsaicin 8% cutaneous patch in the treatment of severe persistent inguinal postherniorrhaphy pain. METHODS: Forty-six patients with persistent inguinal postherniorrhaphy pain were randomized to receive either a capsaicin 8% patch or a placebo patch. Pain intensity (Numerical Rating Scale [NRS 0-10]) was evaluated under standardized conditions (at rest, during movement, and during pressure) at baseline and at 1, 2 and 3 months after patch application. Skin punch biopsies for intraepidermal nerve fiber density (IENFD) measurements were taken at baseline and 1 month after patch application. Quantitative sensory testing was performed at baseline and at 1, 2, and 3 months after patch application. The primary outcome was comparisons of summed pain intensity differences (SPIDs) between capsaicin and placebo treatments at 1, 2 and 3 months after patch application (significance level P < 0.01). RESULTS: The maximum difference in SPID, between capsaicin and placebo treatments, was observed at 1 month after patch application, but the pain reduction was not significant (NRS, mean difference [95% CI]: 5.0 [0.09 to 9.9]; P = 0.046). No differences in SPID between treatments were observed at 2 and 3 months after patch application. Changes in IENFD on the pain side, from baseline to 1 month after patch application, did not differ between capsaicin and placebo treatment: 1.9 [-0.1 to 3.9] and 0.6 [-1.2 to 2.5] fibers/mm, respectively (P = 0.32). No significant changes in sensory function, sleep quality or psychological factors were associated with capsaicin patch treatment. CONCLUSIONS: The study did not demonstrate significant differences in pain relief between capsaicin and placebo treatment, although a trend toward pain improvement in capsaicin treated patients was observed 1 month after patch application. TRIAL REGISTRATION: Clinicaltrialsregister.eu 2012-001540-22 ClinicalTrials.gov NCT01699854. PMID- 25290150 TI - Involvement of YAP, TAZ and HSP90 in contact guidance and intercellular junction formation in corneal epithelial cells. AB - The extracellular environment possesses a rich milieu of biophysical and biochemical signaling cues that are simultaneously integrated by cells and influence cellular phenotype. Yes-associated protein (YAP) and transcriptional co activator with PDZ-binding motif (WWTR1; TAZ), two important signaling molecules of the Hippo pathway, have been recently implicated as nuclear relays of cytoskeletal changes mediated by substratum rigidity and topography. These proteins intersect with other important intracellular signaling pathways (e.g. Wnt and TGFbeta). In the cornea, epithelial cells adhere to the stroma through a 3-dimensional topography-rich basement membrane, with features in the nano submicron size-scale that are capable of profoundly modulating a wide range of fundamental cell behaviors. The influences of substratum-topography, YAP/TAZ knockdown, and HSP90 inhibition on cell morphology, YAP/TAZ localization, and the expression of TGFbeta2 and CTGF, were investigated. The results demonstrate (a) that knockdown of TAZ enhances contact guidance in a YAP dependent manner, (b) that CTGF is predominantly regulated by YAP and not TAZ, and (c) that TGFbeta2 is regulated by both YAP and TAZ in these cells. Additionally, inhibition of HSP90 resulted in nuclear localization and subsequent transcriptional-activation of YAP, formation of cell-cell junctions and co-localization of E-cadherin and beta catenin at adherens junctions. Results presented in this study reflect the complexities underlying the molecular relationships between the cytoskeleton, growth factors, heat shock proteins, and co-activators of transcription that impact mechanotransduction. The data reveal the importance of YAP/TAZ on the cell behaviors, and gene and protein expression. PMID- 25290153 TI - Development and validation of an Haemophilus influenzae supragenome hybridization (SGH) array for transcriptomic analyses. AB - We previously carried out the design and testing of a custom-built Haemophilus influenzae supragenome hybridization (SGH) array that contains probe sequences to 2,890 gene clusters identified by whole genome sequencing of 24 strains of H. influenzae. The array was originally designed as a tool to interrogate the gene content of large numbers of clinical isolates without the need for sequencing, however, the data obtained is quantitative and is thus suitable for transcriptomic analyses. In the current study RNA was extracted from H. influenzae strain CZ4126/02 (which was not included in the design of the array) converted to cDNA, and labelled and hybridized to the SGH arrays to assess the quality and reproducibility of data obtained from these custom-designed chips to serve as a tool for transcriptomics. Three types of experimental replicates were analyzed with all showing very high degrees of correlation, thus validating both the array and the methods used for RNA profiling. A custom filtering pipeline for two-condition unpaired data using five metrics was developed to minimize variability within replicates and to maximize the identification of the most significant true transcriptional differences between two samples. These methods can be extended to transcriptional analysis of other bacterial species utilizing supragenome-based arrays. PMID- 25290152 TI - 21-Benzylidene digoxin: a proapoptotic cardenolide of cancer cells that up regulates Na,K-ATPase and epithelial tight junctions. AB - Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high uM amounts inhibits the activity of Na,K-ATPase alpha1, but not alpha2 and alpha3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low uM concentrations, 21 BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions. PMID- 25290154 TI - The rose (Rosa hybrida) NAC transcription factor 3 gene, RhNAC3, involved in ABA signaling pathway both in rose and Arabidopsis. AB - Plant transcription factors involved in stress responses are generally classified by their involvement in either the abscisic acid (ABA)-dependent or the ABA independent regulatory pathways. A stress-associated NAC gene from rose (Rosa hybrida), RhNAC3, was previously found to increase dehydration tolerance in both rose and Arabidopsis. However, the regulatory mechanism involved in RhNAC3 action is still not fully understood. In this study, we isolated and analyzed the upstream regulatory sequence of RhNAC3 and found many stress-related cis-elements to be present in the promoter, with five ABA-responsive element (ABRE) motifs being of particular interest. Characterization of Arabidopsis thaliana plants transformed with the putative RhNAC3 promoter sequence fused to the beta glucuronidase (GUS) reporter gene revealed that RhNAC3 is expressed at high basal levels in leaf guard cells and in vascular tissues. Moreover, the ABRE motifs in the RhNAC3 promoter were observed to have a cumulative effect on the transcriptional activity of this gene both in the presence and absence of exogenous ABA. Overexpression of RhNAC3 in A. thaliana resulted in ABA hypersensitivity during seed germination and promoted leaf closure after ABA or drought treatments. Additionally, the expression of 11 ABA-responsive genes was induced to a greater degree by dehydration in the transgenic plants overexpressing RhNAC3 than control lines transformed with the vector alone. Further analysis revealed that all these genes contain NAC binding cis-elements in their promoter regions, and RhNAC3 was found to partially bind to these putative NAC recognition sites. We further found that of 219 A. thaliana genes previously shown by microarray analysis to be regulated by heterologous overexpression RhNAC3, 85 are responsive to ABA. In rose, the expression of genes downstream of the ABA-signaling pathways was also repressed in RhNAC3-silenced petals. Taken together, we propose that the rose RhNAC3 protein could mediate ABA signaling both in rose and in A. thaliana. PMID- 25290156 TI - The role of phospholipid headgroup composition and trehalose in the desiccation tolerance of Caenorhabditis elegans. AB - Anhydrobiotic organisms have the remarkable ability to lose extensive amounts of body water and survive in an ametabolic state. Distributed to various taxa of life, these organisms have developed strategies to efficiently protect their cell membranes and proteins against extreme water loss. Recently, we showed that the dauer larva of the nematode Caenorhabditis elegans is anhydrobiotic and accumulates high amounts of trehalose during preparation to harsh desiccation (preconditioning). Here, we have used this genetic model to study the biophysical manifestations of anhydrobiosis and show that, in addition to trehalose accumulation, dauer larvae dramatically reduce their phosphatidylcholine (PC) content. The chemical composition of the phospholipids (PLs) has key consequences not only for their interaction with trehalose, as we demonstrate with Langmuir Blodgett monolayers, but also, the kinetic response of PLs to hydration transients is strongly influenced as evidenced by time-resolved FTIR spectroscopy. PLs from preconditioned larvae with reduced PC content exhibit a higher trehalose affinity, a stronger hydration-induced gain in acyl chain free volume, and a wider spread of structural relaxation rates of their lyotropic transitions and sub-headgroup H-bond interactions. The different hydration properties of PC and phosphatidylethanolamine (PE) headgroups are crucial for the hydration-dependent rearrangement of the trehalose-mediated H-bond network. As a consequence, the compressibility modulus of PLs from preconditioned larvae is about 2.6-fold smaller than that from non-preconditioned ones. Thus, the biological relevance of reducing the PC:PE ratio by PL headgroup adaptation should be the preservation of plasma membrane integrity by relieving mechanical strain from desiccated trehalose-containing cells during fast rehydration. PMID- 25290155 TI - Novel respiratory syncytial virus (RSV) genotype ON1 predominates in Germany during winter season 2012-13. AB - Respiratory syncytial virus (RSV) is the leading cause of hospitalization especially in young children with respiratory tract infections (RTI). Patterns of circulating RSV genotypes can provide a better understanding of the molecular epidemiology of RSV infection. We retrospectively analyzed the genetic diversity of RSV infection in hospitalized children with acute RTI admitted to University Hospital Heidelberg/Germany between October 2012 and April 2013. Nasopharyngeal aspirates (NPA) were routinely obtained in 240 children younger than 2 years of age who presented with clinical symptoms of upper or lower RTI. We analyzed NPAs via PCR and sequence analysis of the second variable region of the RSV G gene coding for the attachment glycoprotein. We obtained medical records reviewing routine clinical data. RSV was detected in 134/240 children. In RSV-positive patients the most common diagnosis was bronchitis/bronchiolitis (75.4%). The mean duration of hospitalization was longer in RSV-positive compared to RSV-negative patients (3.5 vs. 5.1 days; p<0.01). RSV-A was detected in 82.1%, RSV-B in 17.9% of all samples. Phylogenetic analysis of 112 isolates revealed that the majority of RSV-A strains (65%) belonged to the novel ON1 genotype containing a 72 nucleotide duplication. However, genotype ON1 was not associated with a more severe course of illness when taking basic clinical/laboratory parameters into account. Molecular characterization of RSV confirms the co-circulation of multiple genotypes of subtype RSV-A and RSV-B. The duplication in the G gene of genotype ON1 might have an effect on the rapid spread of this emerging RSV strain. PMID- 25290157 TI - Perphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia. AB - BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects. OBJECTIVES: To review the effects of high-potency, first-generation perphenazine compared with low-potency, first-generation antipsychotic drugs for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (October 2010). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing perphenazine with first-generation, low-potency antipsychotic drugs for people with schizophrenia or schizophrenia like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis and using a random-effects model. MAIN RESULTS: The review currently includes four relevant randomised trials with 365 participants. The size of the included studies was between 42 and 158 participants with a study length between one and four months. Overall, the methods of sequence generation and allocation concealment were poorly reported. Most studies were rated as low risk of bias in terms of blinding. Overall, attrition bias in the studies was high.The effects of perphenazine and low potency antipsychotic drugs seemed to be similar in terms of the primary outcome response to treatment (perphenazine 58%, low-potency antipsychotics 59%, 2 RCTs, n = 138, RR 0.97 CI 0.74 to 1.26 - moderate quality of evidence). There was also no clear evidence of a difference in acceptability of treatment with the number of participants leaving the studies early due to any reason, however results were imprecise (perphenazine 30%, low-potency antipsychotics 28%, 3 RCTs, n = 323, RR 0.78 CI 0.35 to 1.76, very low quality of evidence).There were low numbers of studies available for the outcomes experiencing at least one adverse effect (perphenazine 33%, low-potency antipsychotics 47%, 2 RCTs, n = 165, RR 0.83 CI 0.36 to 1.95, low quality evidence) and experiencing at least one movement disorder (perphenazine 22%, low-potency first-generation antipsychotics 0%, 1 RCT, n = 69, RR 15.62 CI 0.94 to 260.49, low quality evidence), and the confidence intervals for the estimated effects did not exclude important differences. Akathisia was more frequent in the perphenazine group (perphenazine 25%, low-potency antipsychotics 22%, 2 RCTs, n = 227, RR 9.45 CI 1.69 to 52.88), whereas severe toxicity was less so (perphenazine 42%, low-potency antipsychotics 69%, 1 RCT, n = 96, RR 0.61 CI 0.41 to 0.89).There were three deaths in the low potency group by four months but the difference between groups was not significant (perphenazine 0%, low-potency antipsychotics 2%, 1 RCT, n = 96, RR 0.14 CI 0.01 to 2.69, moderate quality evidence). No data were available for our prespecified outcomes of interest sedation or quality of life. Data were not available for other outcomes such as relapse, service use, costs and satisfaction with care.The event rates reported quote simple aggregates and are not based on the RRs. AUTHORS' CONCLUSIONS: The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made. PMID- 25290158 TI - Peptides derived from central turn motifs within integrin alphaIIb and alphaV cytoplasmic tails inhibit integrin activation. AB - We previously found that peptides derived from the full length of integrin alphaIIb and alphaV cytoplasmic tails inhibited their parent integrin activation, respectively. Here we showed that the cell-permeable peptides corresponding to the conserved central turn motif within alphaIIb and alphaV cytoplasmic tails, myr-KRNRPPLEED (alphaIIb peptide) and myr-KRVRPPQEEQ (alphaV peptide), similarly inhibited both alphaIIb and alphaV integrin activation. Pre-treatment with alphaIIb or alphaV peptides inhibited Mn(2+)-activated alphaIIbbeta3 binding to soluble fibrinogen as well as the binding of alphaIIbbeta3-expressing Chinese Hamster Ovary cells to immobilized fibrinogen. Our turn peptides also inhibited adhesion of two breast cancer cell lines (MDA-MB-435 and MCF7) to alphaV ligand vitronectin. These results suggest that alphaIIb and alphaV peptides share a same mechanism in regulating integrin function. Using alphaIIb peptide as a model, we found that replacement of RPP with AAA significantly attenuated the inhibitory activity of alphaIIb peptide. Furthermore, we found that alphaIIb peptide specifically bound to beta-tubulin in cells. Our work suggests that the central motif of alpha tails is an anchoring point for cytoskeletons during integrin activation and integrin-mediated cell adhesion, and its function depends on the turn structure at RPP. However, post-treatment of peptides derived from the full length tail or from the turn motif did not reverse alphaIIb and alphaV integrin activation. PMID- 25290159 TI - Low-dose adrenomedullin-2/intermedin(8-47) reduces pulmonary ischemia/reperfusion injury. AB - Adrenomedullin-2/intermedin stabilizes the pulmonary microvascular barrier challenged by application of thrombin ex vivo and by experimental ventilation in vivo. Here, we test the hypothesis that adrenomedullin-2/intermedin(8-47) protects mouse lungs from ischemia/reperfusion injury in vivo. C57BL/6 mice were anesthetized, intubated, ventilated, and heparinized. Blood vessels and the main bronchus of the left lung were clamped for 90min. Thereafter, lungs were reperfused for 120min. Five min before clamping and before reperfusion, mice obtained intravenous injections of adrenomedullin-2/intermedin(8-47). After reperfusion, mice were sacrificed and bronchoalveolar lavage of the left and the right lung was performed separately. The integrity of the blood-air barrier was investigated by electron microscopy using stereological methods. In response to ischemia/reperfusion injury, intraalveolar leukocytes accumulated in the ischemic lung. Two applications of 10ng/kg body weight adrenomedullin-2/intermedin(8-47) dramatically reduced leukocyte infiltration to about 15% (p<=0.001). Also the proportion of the subpopulation of neutrophil granulocytes decreased (12% vs 5%, p=0.013). Electron microscopy revealed a protection of the blood-air barrier by adrenomedullin-2/intermedin(8-47). Adrenomedullin-2/intermedin(8-47) ameliorates early ischemia/reperfusion injury in mouse lungs by protecting the integrity of the blood-air barrier and by potently reducing leukocyte influx into the alveolar space. Adrenomedullin-2/intermedin(8-47) might be of therapeutic interest in lung transplantation and cardiopulmonary bypass. PMID- 25290161 TI - Comment on "Analysis of CF . . . FC interactions on cyclohexane and naphthalene frameworks". PMID- 25290160 TI - Imaging molecular structure through femtosecond photoelectron diffraction on aligned and oriented gas-phase molecules. AB - This paper gives an account of our progress towards performing femtosecond time resolved photoelectron diffraction on gas-phase molecules in a pump-probe setup combining optical lasers and an X-ray free-electron laser. We present results of two experiments aimed at measuring photoelectron angular distributions of laser aligned 1-ethynyl-4-fluorobenzene (C(8)H(5)F) and dissociating, laser-aligned 1,4 dibromobenzene (C(6)H(4)Br(2)) molecules and discuss them in the larger context of photoelectron diffraction on gas-phase molecules. We also show how the strong nanosecond laser pulse used for adiabatically laser-aligning the molecules influences the measured electron and ion spectra and angular distributions, and discuss how this may affect the outcome of future time-resolved photoelectron diffraction experiments. PMID- 25290163 TI - El Nino-Southern Oscillation (ENSO) effects on Hessian fly (Diptera: Cecidomyiidae) infestation in the southeastern United States. AB - Climate variability is expected to have an influence on the population of Hessian fly, Mayetiola destructor Say (Diptera: Cecidomyiidae), a serious insect pest of winter wheat in the southeastern United States. This study had two objectives: 1) to examine the effects of El Nino-Southern Oscillation (ENSO) on Hessian fly infestation and 2) to develop a weather-based Hessian fly infestation model for wheat yield loss prediction. At least 20 years of Hessian fly infestation and wheat yield records from two locations in South Georgia were used for this study. The yearly values of infestation were separated by ENSO phase and tested to assess the infestation differences across ENSO phases. Each year, yield losses from infestation were calculated by subtracting the yields of resistant varieties from those of susceptible ones. The yield losses were then separated by ENSO phase and tested. Multiple regression analyses were conducted to identify the contribution of monthly weather variables and changes in wheat acreage to Hessian fly infestation. Results showed that Hessian fly infestation and yield losses were greatest during the La Nina and least during the El Nino phase. The weather conditions that significantly increased the risk for infestation were those of the August-February period. The risk of infestation was higher during August September under wetter, cooler conditions and during October-February under drier, warmer conditions. These findings could help wheat growers reduce the risk of infestation in the years that are expected to have more infestation through the adoption of necessary mitigation measures before the crop season. PMID- 25290164 TI - The major histocompatibility complex: the modern synthesis. PMID- 25290162 TI - Breastfeeding practices in a hospital-based study of Vietnamese women. AB - BACKGROUND: The benefits of breastfeeding to both maternal and infant health are vast and widely known. The aim of this study was to elicit the rates of exclusive breastfeeding, early initiation of breastfeeding, and colostrum feeding and to determine the attitudes, knowledge, and influences around breastfeeding in postpartum Vietnamese women. MATERIALS AND METHODS: A cross-sectional study was conducted at the Hung Vuong Hospital in Ho Chi Minh City, Viet Nam, between December 2010 and January 2011. Postpartum women were randomly selected and interviewed within 48 hours of delivery. RESULTS: Of the 223 women interviewed, 86% had initiated breastfeeding at the time of the interview. Modes of feeding included exclusive breastfeeding (7%), mixed feeding (79%), which included breastmilk and formula or water, and exclusive formula feeding (14%). Of the breastfeeding women, 14% had initiated breastfeeding within 60 minutes of delivery, 92% had initiated within 24 hours, and 8% had initiated after 24 hours of delivery. Of women who had initiated breastfeeding, 37% had discarded their colostrum. Factors that positively influenced breastfeeding were knowledge that breastfeeding is good for the infant, advice obtained from "public information," and the influence of health professionals and family on the decision to breastfeed. Factors that influenced the decision not to initiate breastfeeding included pain or fever after cesarean section and perceived lack of breastmilk after delivery. CONCLUSIONS: The rate of exclusive breastfeeding at Hung Vuong Hospital in this study was lower than the national average of 17%. Specific interventions targeting this must be formulated to increase these rates. PMID- 25290165 TI - Cellular aspects of polyclonal activation of B lymphocytes. AB - The responses of B lymphocytes to exogenous stimulation can be antigen-specific or non-specific. Non-specific stimulation by a single agent activates a multitude of clones of B cells, each secreting antibody of pre-programmed specificity. In this review Michael Goodman examines how polyclonal activation of B cells can be achieved, and the relationship between such stimulation and DNA synthesis, considers the evidence for and against the existence of B-cell subpopulations responsive to different polyclonal activators, and looks at the ways in which polyclonal activation is regulated. PMID- 25290166 TI - Do NK cells play a role in anti-tumor surveillance? AB - A class of lymphocytes found in several mammalian species including man will kill cells of many tumor lines invitro(1-4). There is growing evidence, derived mainly from the work of Kiessling and co-workers, that these natural killer (NK) cells play a role in surveillance against tumor developmentin vivo. In this article John Roder and Tina Haliotis discuss a hypothesis for anti-tumor surveillance which integrates all of the potentially important immunological systems in the host and gives to NK cells the role of foremost barrier against developing tumors. PMID- 25290167 TI - Biliglobulin: a new look at IgA. AB - The teaching of Hippocrates and Galen ensured that physicians have always had a lively appreciation of the importance of bile, but somehow immunologists never got the message and hitherto they have paid it scant attention. Here Joe Hall and Liz Andrew discuss recent discoveries in Belgium and Britain which have shown that bile is a rich source of the secretory immunoglobulin IgA because the hepatocytes rapidly and actively transport this immunoglobulin from blood to bile. Not only are these findings important for understanding diseases involving the liver, the gut, immune complexes and tolerance to dietary antigens, but, in addition, they have provided research workers with an easy way of investigating secretory antibodies in small laboratory animals. PMID- 25290168 TI - Assessment of cell-mediated cytotoxicity. AB - Several different techniques are used to assess the expression of cellular immunity (reviewed in Ref. 1). In this article Benjamin Bonavida and Thomas Bradley discuss ways of measuring one aspect of cellular immunity-the activity of cytotoxic cells on target cells. PMID- 25290170 TI - Gas/particle partitioning of PCDD/F compounds in the atmosphere of Istanbul. AB - Gas/particle partitioning of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) compounds in the ambient atmosphere were investigated at three different sites (urban-industrial, urban and sub-urban) in Istanbul. Average gas and particle phase concentrations were measured as 133fgm( 3) and 1605fgm(-3), respectively. Gas phase concentrations of polychlorinated dibenzo-p-dioxin/furan (PCDD/F) compounds were determined to be 128fgm(-3), 50fgm(-3), 153fgm(-3) during summer season and 204fgm(-3), 164fgm(-3), 154fgm(-3) during winter season for the respective three sampling sites. Particle phase concentrations were determined to be 287fgm(-3), 176fgm(-3), 160fgm(-3) during summer and 6586fgm(-3), 2570fgm(-3) and 1861fgm(-3) during winter season for those three sampling sites. Chlorination level and molecular weight of congeners affected gas/particle partitioning of PCDD/F compounds. Gas phase percentages of 2,3,7,8-TCDD and OCDD concentrations were determined to be 47% and 1% respectively. A relatively high correlation was found between total particle matter (TPM) and particle phase PCDD/F concentration during winter season. PMID- 25290169 TI - Mallory-Denk Body (MDB) formation modulates Ufmylation expression epigenetically in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH). AB - Promoter CpG island hypermethylation is an important mechanism for inactivating key cellular enzymes that mediate epigenetic processes in hepatitis-related hepatocellular carcinoma (HCC). The ubiquitin-fold modifier 1 (Ufm1) conjugation pathway (Ufmylation) plays an essential role in protein degradation, protein quality control and signal transduction. Previous studies showed that the Ufmylation pathway was downregulated in alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH) and in mice fed DDC, resulting in the formation of Mallory Denk Bodies (MDBs). In this study, we further discovered that betaine, a methyl donor, fed together with DDC significantly prevents the increased expression of Ufmylation in drug-primed mice fed DDC. Betaine significantly prevented transcript silencing of Ufm1, Uba5 and UfSP1 where MDBs developed and also prevented the increased expression of FAT10 and LMP7 caused by DDC re-fed mice. Similar downregulation of Ufmylation was observed in multiple AH and NASH biopsies which had formed MDBs. The DNA methylation levels of Ufm1, Ufc1 and UfSP1 in the promoter CpG region were significantly increased both in AH and NASH patients compared to normal subjects. DNA (cytosine-5-)-methyltransferase 1 (DNMT1) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) mRNA levels were markedly upregulated in AH and NASH patients, implying that the maintenance of Ufmylation methylation might be mediated by DNMT1 and DNMT3B together. These data show that MDB formation results from Ufmylation expression epigenetically in AH and NASH patients. Promoter CpG methylation may be a major mechanism silencing Ufmylation expression. PMID- 25290171 TI - Changes of polybrominated diphenyl ether concentrations in ducks with background exposure level and time. AB - To reveal what degree bioaccumulation of polybrominated diphenyl ethers (PBDEs) depends on exposure time and other factors, we conducted a semi-field experiment for a year (June 2008-June 2009) in a village in an e-waste recycling site in Taizhou, China. Approximately one hundred of juvenile ducks (Anas domestica Linnaeus) were entrusted to a villager. The ducks lived and forged in a PBDE polluted pond from the late March to the end of November. Fish and mudsnails that were heavily polluted by PBDEs were main food. In cold days (from December to the middle March), the ducks lived in the villager' house, and mainly fed on paddy, which contained lower concentrations of PBDEs than fish and mudsnails. The female ducks were sampled for PBDE analysis every three months. We found that the ?PBDE concentrations in duck liver, muscle, lung and brain fluctuated greatly with the changes of exposure levels that were determined by the environment and diets, but the ?PBDE concentrations in fat tissue increased successively with time. Congener analysis demonstrated that the successive increase in the ?PBDE concentrations with time in fat tissue was due to the successive increase in BDE-209, -183 and 153 concentrations, with large fluctuations of low brominated congeners. The results show that PBDE concentrations in liver, muscle, lung and brain tissues heavily depends on exposure levels rather than exposure time. In fat tissue, by contrast, PBDE concentrations (mainly high brominated congeners) slightly depends on exposure levels but heavily depend on time relative to other tissues, implying that high brominated congeners seem to have longer half-lives than low brominated congeners in fat tissue. PMID- 25290174 TI - Human T-cell clones find ever wider application. AB - With clones of human T lymphocytes and the means of propagating them for prolonged periods in vitro, several kinds of investigation are possible: the physiological role of cell surface molecules; T-cell heterogeneity and functional repertoires with regard to immunoregulatory and effector activities; the pathophysiology of disorders related to abnormal immune responses; and screening for potential vaccines. To best exploit this technology, collaborations among investigators in cell and molecular biology, immunochemistry and clinical medicine are required. A recent workshop(*) brought together such specialists. PMID- 25290175 TI - Notes. PMID- 25290172 TI - Long-range distance measurements in proteins at physiological temperatures using saturation recovery EPR spectroscopy. AB - Site-directed spin labeling in combination with EPR is a powerful method for providing distances on the nm scale in biological systems. The most popular strategy, double electron-electron resonance (DEER), is carried out at cryogenic temperatures (50-80 K) to increase the short spin-spin relaxation time (T2) upon which the technique relies. A challenge is to measure long-range distances (20-60 A) in proteins near physiological temperatures. Toward this goal we are investigating an alternative approach based on the distance-dependent enhancement of spin-lattice relaxation rate (T1(-1)) of a nitroxide spin label by a paramagnetic metal. With a commonly used nitroxide side chain (R1) and Cu(2+), it has been found that interspin distances <=25 A can be determined in this way (Jun et al. Biochemistry 2006, 45, 11666). Here, the upper limit of the accessible distance is extended to ~40 A using spin labels with long T1, a high-affinity 5 residue Cu(2+) binding loop inserted into the protein sequence, and pulsed saturation recovery to measure relaxation enhancement. Time-domain Cu(2+) electron paramagnetic resonance, quantum mechanical calculations, and molecular dynamics simulations provide information on the structure and geometry of the Cu(2+) loop and indicate that the metal ion is well-localized in the protein. An important aspect of these studies is that both Cu(2+)/nitroxide DEER at cryogenic temperatures and T1 relaxation measurements at room temperature can be carried out on the same sample, allowing both validation of the relaxation method and assessment of the effect of freezing on protein structure. PMID- 25290176 TI - Are kappa and lambda light-chain-bearing B cells functionally distinct? PMID- 25290173 TI - Distinct dendritic cell subsets actively induce Th2 polarization. AB - The mechanisms by which dendritic cells induce Th2 polarization (DC(Th2) cells) have been controversial. Many have argued that DC(Th2) cells are not a distinct functional DC subset, but rather, DC-induced polarization of Th2 cells is a default pathway that occurs in the absence of inflammatory signals leading to DC induced polarization of Th1/Th17 cells. However, recent studies demonstrate that distinct subsets of tissue DCs actively polarize Th2 cells after stimulation with type-2 inducing stimuli. DC(Th2) cells development is marked by the upregulation of specific transcription factors, cell surface molecules, and cytokines. These findings counter previous hypotheses that Th2 skewing by DCs is a passive response and support a model in which DCs are actively programmed to induce Th2 differentiation. PMID- 25290177 TI - Immunosuppression by seminal plasma. PMID- 25290178 TI - Alien MHC expression and high alloreactivity: gene conversion or Qa/Tla antigen expression? PMID- 25290180 TI - Does the immunopathology induced by schistosome eggs potentiate parasite survival? AB - Infection with schistosomes is accompanied by inflammatory lesions resembling delayed hypersensitivity reactions, that are induced by eggs in host tissues. Here Michael Doenhoff and his colleagues demonstrate that T-cell-deprived mice excrete much fewer eggs than do intact control animals. From the results of serum and cell transfer experiments, they conclude that immune processes assist egg expulsion and thus contribute to the parasite's success. PMID- 25290179 TI - Serologically detectable H-Y ('male') antigen: Mr or myth? AB - The rejection by inbred female mice of skin from syngeneic males is provoked by the male-specific transplantation antigen H- Y. Here D. N. Crichton and C. M. Steel discuss conflicting claims surrounding the detection of H-Y antigen with polyclonal and monoclonal antibodies. PMID- 25290181 TI - New directions in research Ultraviolet light and skin cancer. PMID- 25290182 TI - Myc/Ig juxtaposition by chromosomal translocations: some new insights, puzzles and paradoxes. AB - Human Burkitt's lymphoma and murine plasmacytoma cells contain characteristic chromosomal translocations that show the following common features: ,juxtaposition of the c-myc oncogene to one of the three immunoglobulin loci(2 4); wide variability of the translocation breakpoint in and outside the oncogene, but with rigorous avoidance of any damage to the two coding exons(5-21); high expression of the Ig juxtaposed c-myc gene with concomitant shutdown of the normal, non-translocatedallele(4,7,11,14,15,18). The latter fact suggests that the translocation has removed the oncogene from its normal regulatory circuit andplaced it under the constitutively activating influence of an Ig-locus. This is believed to play an essential role in the malignant transformation(23). Numerous papers have dealt with the possible role of the translocations in tumorigenesis. less attention has been given to their implications with regard to the normal DNA rearrangement process that takes place during B-cell differentiation. In this article, George and Eva Klein consider both areas and their interrelations. PMID- 25290183 TI - Allostimulation-induced tumor cytotoxic cells: from mouse to man. AB - Experimental tumors may express cell surface antigens which cross-react with alloantigens of normal allogeneic tissues(1). These may be H-2 or non-H-2 histocompatibility antigens and differentiation antigens(1-3). Because of this cross-reactivity animals immunized with allogeneic normal tissues bearing determinants shared by a syngeneic transplantable tumor acquire resistance to the tumor in vivo and lymphocytes specifically cytotoxic to syngeneic tumor cells in vitro. However, in similar experiments tumor cells which did not express detectable amounts of cross-reacting antigens were also rejected in syngeneic animals (mouse and rat) immunized with normal allogeneic tissues(4,5). In this instance the mechanism of antitumor rejection could not be clearly established(5). In other investigations allostimulation of the mouse lymphocytes in vitro generated cells cytotoxic against syngeneic tumor cells and allostimulation of human lymphocytes generated cells which killed autologous tumor cells(6-10). The mechanisms underlying these phenomena differ in detail but in each case the end result is the production of tumor-restricted cytotoxic cells. Here Giorgio Parmiani and his colleagues review these investigations and discuss the possible clinical utility of cytotoxic cells generated in this way. PMID- 25290184 TI - The biochemical basis of transmembrane signalling by B lymphocyte surface immunoglobulin. AB - The specificity of humoral immune responses is determined primarily at the level of antigen interaction with B lymphocytes which express antigen-specific receptor immunoglobulin. When receptor immunoglobulin is crosslinked by antigen or anti receptor antibodies there isgeneration and transduction of signals which result in new membrane Ia antigen expression and, in some instances, entry of cells into cycle. Until recently, the molecular basis of signal transduction across membrane immunoglobulins has remained enigmatic. Here John Cambier and colleagues discuss studies which indicate that membrane appears similar to thrombin receptors, muscarinic receptors, al adrenergic receptors and many others in transducing signals via initiation of phosphoinositide hydrolysis, yielding diacylglycerol and inositol phosphates which in turn appear to activate protein kinase and calcium mobilization, respectively. PMID- 25290185 TI - The ontogeny and cloning of B cells in the bursa of Fabricius. AB - A pluripotent or multipotent stem cell must undergo two major changes on the way to becoming an immunoglobulin (Ig) secreting B lymphocyte. Thefirst is the commitment to the lineage of a B cell rather than a T lymphocyte or other cell type. The second is a commitment to the production of antibody with a particular specificity. The latter involves selection of germ-line Ig variable region genes and the somatic rearrangements required for their expression (reviewed in detail elsewhere(1-4)). Since the selection of variable region genes for both Ig heavy and light chains (VH and VL) precedes the expression of Ig on the surface of the B cell(3), a sIgM(+) cell is committed both to the B-cell lineage and to the use of a particular combination of germ-line VH and VL genes. The chicken is one of the most convenient species with which to study lymphoid ontogeny. In this review Michael Ratcliffe examines recent evidence about the commitment of avian lymphoid cells as they progress from immature precursors to mature antibody producing cells. PMID- 25290187 TI - Assignment of the terahertz spectra of crystalline copper sulfate and its hydrates via solid-state density functional theory. AB - Terahertz (THz) vibrational spectroscopy is a promising tool for the nondestructive and potentially noninvasive characterization of historical objects, which can provide information on the materials used for their production as well as identify and monitor their chemical degradation. Copper sulfate (CuSO4) has drawn interest due to its inclusion in the preparation of iron gall inks found in historical artwork and documents. Copper sulfate rapidly forms hydrates which contribute to the formulation of these ink species and may influence their corrosive nature. In this study, copper sulfate has been studied using a combination of THz time-domain spectroscopy, powder X-ray diffraction (PXRD), and solid-state density functional theory (DFT) in order to better understand the spectral absorbances in the THz region. The results have revealed that the THz spectrum of commercially available "anhydrous" copper sulfate results from the presence of not only the anhydrous form but also the monohydrate (CuSO4.H2O) and trihydrate (CuSO4.3H2O) forms. Complete assignment of the experimental spectrum was achieved through a comparison of density functionals and extensive investigation of the influence of basis set polarization functions on the bonding interactions, lattice parameters, and low-frequency motions in these crystalline solids. PMID- 25290188 TI - Tripartite interactions between Wnt signaling, Notch and Myb for stem/progenitor cell functions during intestinal tumorigenesis. AB - Deletion studies confirm Wnt, Notch and Myb transcriptional pathway engagement in intestinal tumorigenesis. Nevertheless, their contrasting and combined roles when activated have not been elucidated. This is important as these pathways are not ablated but rather are aberrantly activated during carcinogenesis. Using ApcMin/+ mice as a source of organoids we documented their transition, on a clone-by-clone basis, to cyst-like spheres with constitutively activated Wnt pathway, increased self-renewal and growth and reduced differentiation. We then looked at this transition when Myb and/or Notch1 are activated. Activated Notch promoted cyst like organoids. Conversely growth and propagation of cyst-like, but not normal organoids were Notch-independent. Activated Myb promoted normal, but not cyst like organoids. Interestingly the Wnt, Notch and Myb pathways were all involved in regulating the expression of the intestinal stem cell (ISC) gene Lgr5 in organoids, while ISC gene and Notch target Olfm4 was dominantly repressed by Wnt. These findings parallel mouse intestinal adenoma formation where Notch promoted the initiation, but not growth, of Wnt-driven Olfm4-repressed colon tumors. Also Myb was essential for colon tumor initiation and collateral mouse pathologies. These data reveal the complex interplay and hierarchy of transcriptional networks that operate in ISCs and uncover a shift in pathway-dependencies during tumor initiation. PMID- 25290190 TI - The effect of needle dimensions and infusion rates on injection pressures in regional anaesthesia needles: a bench-top study. AB - Animal studies have shown that injection pressures > 75 kPa indicate probable intrafascicular needle tip position. This study describes the flow/pressure characteristics of seven common needle systems. A syringe pump delivered flow rates of 5, 6.67, 10, 13.3, 15 and 20 ml.min(-1) through these needle systems, while keeping the needle tips open to atmosphere. A pressure transducer connected between the syringe and needle provided a real-time graphical display for analysis. Mean plateau pressures increased linearly with flow and with decreasing needle diameter (2.7-92 kPa). Flow rates > 17 ml.min(-1) and needle sizes 22 G and smaller produced mean plateau pressures > 75 kPa. Pressure monitors upstream from the needle may produce false-positive alarms at high flow rates due to needle resistance, and unreliable readings due to non-laminar flow. We recommend injection rates <= 15 ml.min(-1) (0.25 ml.s(-1) ) to reduce the effect of factors upstream from the needle tip as a cause of high pressure readings. PMID- 25290189 TI - Adipose tissue-derived stromal cells acquire endothelial-like features upon reprogramming with SOX18. AB - Adipose tissue-derived stromal cells (ASC) form a rich source of autologous cells for use in regenerative medicine. In vitro induction of an endothelial phenotype may improve performance of ASCs in cardiovascular repair. Here, we report on an in vitro strategy using direct reprogramming of ASCs by means of ectopic expression of the endothelial-specific transcription factor SRY (sex determining region Y)-box18 (SOX18). SOX18 induces ASCs to express a set of genes involved in vascular patterning: MMP7, KDR, EFNB2, SEMA3G and CXCR4. Accordingly, SOX18 transduced ASCs reorganize under conditions of shear stress, display VEGF-induced chemotaxis and form tubular structures in 3D matrices in an MMP7-dependent manner. These in vitro findings provide insight into molecular and cellular processes downstream of SOX18 and show that reprogramming using SOX18 is sufficient to induce several endothelial-like features in ASCs. PMID- 25290191 TI - Reply. PMID- 25290196 TI - Virus-induced cytotoxic factor in AIDS and dengue. PMID- 25290195 TI - Female and male moths display different reproductive behavior when facing new versus previous mates. AB - Multiple mating allows females to obtain material (more sperm and nutrient) and/or genetic benefits. The genetic benefit models require sperm from different males to fertilize eggs competitively or the offspring be fathered by multiple males. To maximize genetic benefits from multiple mating, females have evolved strategies to prefer novel versus previous mates in their subsequent matings. However, the reproductive behavior during mate encounter, mate choice and egg laying in relation to discrimination and preference between sexes has been largely neglected. In the present study, we used novel and previous mate treatments and studied male and female behavior and reproductive output in Spodoptera litura. The results of this study do not support the sperm and nutrient replenishment hypotheses because neither the number of mates nor the number of copulations achieved by females significantly increased female fecundity, fertility and longevity. However, females showed different oviposition patterns when facing new versus previous mates by slowing down oviposition, which allows the last male has opportunities to fertilize her eggs and the female to promote offspring diversity. Moreover, females that have novel males present called earlier and more than females that have their previous mates present, whereas no significant differences were found on male courtship between treatments. These results suggest that S. litura females can distinguish novel from previous mates and prefer the former, whereas males generally remate regardless of whether the female is a previous mate or not. In S. litura, eggs are laid in large clusters and offspring competition, inbreeding and disease transfer risks are thus increased. Therefore, offspring diversity should be valuable for S. litura, and genetic benefits should be the main force behind the evolution of female behavioral strategies found in the present study. PMID- 25290197 TI - Codon usage in the immune system. PMID- 25290198 TI - The introversion of the immune response. PMID- 25290199 TI - A re-evaluation of the role of C3 in B-cell activation. AB - There is considerable evidence that, in vivo, C3 is required for the induction and maintenance of memory cells of the B-cell lineage. Recent data from in-vitro systems indicate that ligation of C3 receptors on B cells can activate these cells, and that appropriately presented C3 split products can act as B-cell growth factors. Here, Gerry Klaus and John Humphrey propose that in vivo these growth-promoting effects of C3 may operate within the microenvironment of germinal centres, where B cells encounter antigen-antibody-C3 complexes on the surfaces of follicular dendritic cells. PMID- 25290201 TI - Alternative processing of RNA in lymphoid cells. PMID- 25290200 TI - Is IgM-like dislocation a common feature of antibody function? PMID- 25290202 TI - Immunoglobulin flexibility in complement activation. AB - Next to antigen-binding, the interaction between antibody and complement is among the most familiar and well-studied of all immunological events. Now that many of the molecular details are known, antibody-mediated complement activation provides a fascinating example of the subtle relationship between protein structure and function. In this discussion, Arnold Feinstein and his colleagues are concerned with the initial step in the classical pathway of complement activation, namely the activation of the first complement component (C1) after it has bound to a site on the Fc portion of an antibody molecule, and in particular with the problem of how the site is made available in different antibody classes. PMID- 25290203 TI - Computer models of the human immunoglobulins shape and segmental flexibility. AB - At present there is interest in the design and deployment of engineered biosensor molecules. Antibodies are the most versatile of the naturally occurring biosensors and it is important to understand their mechanical properties and the ways in which they can interact with their natural ligands. Two dimensional representations are clearly inadequate, and three dimensional representations are too complicated to manipulate except as numerical abstractions in computers. Recent improvements in computer graphics allow these coordinate matrices to be seen and more easily comprehended, and interactive programs permit the modification and reassembly of molecular fragments. The models which result have distinct advantages both over those of lower resolution, and those showing every atom, which are limited to the few fragments(2-5) or mutant molecules for which the X-ray crystallographic coordinates are known. In this review Richard Pumphrey describes the shape and flexibility of immunoglobulin molecules in relation to the three dimensional structure. PMID- 25290204 TI - The influence of B-cell idiotypes on the repertoire of suppressor T cells. AB - The idiotypes expressed by T cells involved in responses to a particular antigen are very similar to those on immunoglobulin (Ig) molecules specific for the same antigen. However, the T-cell antigen receptors do not use the same variable region genes as the Ig heavy chain molecules. Here, Kent HayGlass and his colleagues review the evidence for this interesting puzzle and suggest that the idiotypes expressed by 8 cells to which maturing T cells are exposed determine the final T-cell idiotype repertoire. PMID- 25290207 TI - Dorsomedial hypothalamus serotonin 1A receptors mediate a panic-related response in the elevated T-maze. AB - The dorsomedial hypothalamus (DMH) has long been associated with the regulation of escape, a panic-related defensive response. Previous evidence has shown that the activation of serotonin (5-HT) 1A and 2A receptors impairs escape behavior induced by the electrical stimulation of the same region. In this study we further explore the relationship of the DMH with defense by investigating the effects of 5-HT1A activation on escape behavior generated in male Wistar rats by an ethologically based aversive stimuli, exposure to one of the open arms of the elevated T-maze (ETM). Aside from escape, the ETM also allows the measurement of inhibitory avoidance, a defensive response associated with generalized anxiety disorder. To evaluate locomotor activity, after ETM measurements animals were submitted to an open field. Results showed that intra-DMH administration of the 5 HT1A receptor agonist 8-OH-DPAT inhibited escape expression. Local administration of the 5-HT1A antagonist WAY-100635 by its own was ineffective, but blocked the panicolytic-like effect of 8-OH-DPAT. Chronic (21 days) systemic treatment with imipramine potentiated the anti-escape effect of 8-OH-DPAT. No significant effects of treatment with 8-OH-DPAT or imipramine on avoidance latencies or the number of lines crossed in the open field were found. These results indicate that 5-HT1A receptors within the DMH may play a phasic inhibitory role on ETM escape expression. As previously proposed, facilitation of 5-HT1A-mediated neurotransmission in the DMH may be involved in the mechanism of action of anti panic compounds. PMID- 25290208 TI - Protective effects of perindopril on d-galactose and aluminum trichloride induced neurotoxicity via the apoptosis of mitochondria-mediated intrinsic pathway in the hippocampus of mice. AB - Perindopril, an angiotensin converting enzyme inhibitor, has been reported to improve learning and memory in a mouse or rat model of Alzheimer's disease (AD) induced by injection of beta-amyloid protein. However, the exact mechanism of perindopril on the cognitive deficits is not fully understood. Our previous data have indicated that perindopril improves learning and memory in a mouse model of AD induced by D-galactose (D-gal) and aluminum trichloride (AlCl3) via inhibition of acetylcholinesterase activity and oxidative stress. Whether perindopril also inhibit apoptosis to prevent cognitive decline remains unknown in mice. Therefore, the present study explored the protective effects of perindopril in the hippocampus of mice further. Perindopril (0.5 mg/kg/day) was administered intragastrically for 60 days after the mice were given a D-gal (150 mg/kg/day) and AlCl3 (10 mg/kg/day) intraperitoneally for 90 days. Then the expression of Bcl-2, Bax, Fas, FasL, caspase-3, caspase-8 and caspase-9 were analyzed by RT-PCR and western blotting in the hippocampus. Perindopril significantly decreased caspase-3 and caspase-9 activities, and elevated Bcl-2/Bax ratio in the hippocampus. However, the expression of Fas, FasL and caspase-8 did not change in the hippocampus whether treatment with d-gal and AlCl3 or perindopril. Taken together, the above findings indicated that perindopril inhibited apoptosis in the hippocampus may be another mechanism by which perindopril improves learning and memory functions in d-gal and AlCl3 treated mice. PMID- 25290209 TI - Thermoresponsive nanostructured surfaces generated by the Langmuir-Schaefer method are suitable for cell sheet fabrication. AB - Thermoresponsive poly(N-isopropylacrylamide) (PIPAAm)-immobilized surfaces for controlling cell adhesion and detachment were fabricated by the Langmuir-Schaefer method. Block copolymers composed of polystyrene and PIPAAm (St-IPAAms) having various chain lengths and compositions were synthesized by reversible addition fragmentation chain transfer radical polymerization. The St-IPAAm Langmuir film at an air-water interface was horizontally transferred onto a hydrophobically modified glass substrate while regulating its density. Atomic force microscopy images clearly visualized nanoscaled sea-island structures on the surface. By adjusting both the composition of St-IPAAms and the density of immobilized PIPAAms, a series of thermoresponsive surfaces was prepared to control the strength, rate, and quality of cell adhesion and detachment through changes in temperature across the lower critical solution temperature range of PIPAAm molecules. In addition, a two-dimensional cell structure (cell sheet) was more rapidly recovered on the optimized surfaces than on conventional PIPAAm surfaces. These unique PIPAAm surfaces are suggested to be useful for controlling the strength of cell adhesion and detachment. PMID- 25290211 TI - Transmission of AIDS. PMID- 25290210 TI - Hydrogen-deuterium exchange and mass spectrometry reveal the pH-dependent conformational changes of diphtheria toxin T domain. AB - The translocation (T) domain of diphtheria toxin plays a critical role in moving the catalytic domain across the endosomal membrane. Translocation/insertion is triggered by a decrease in pH in the endosome where conformational changes of T domain occur through several kinetic intermediates to yield a final trans membrane form. High-resolution structural studies are only applicable to the static T-domain structure at physiological pH, and studies of the T-domain translocation pathway are hindered by the simultaneous presence of multiple conformations. Here, we report the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) for the study of the pH-dependent conformational changes of the T domain in solution. Effects of pH on intrinsic HDX rates were deconvolved by converting the on-exchange times at low pH into times under our "standard condition" (pH 7.5). pH-Dependent HDX kinetic analysis of T domain clearly reveals the conformational transition from the native state (W-state) to a membrane-competent state (W(+)-state). The initial transition occurs at pH 6 and includes the destabilization of N-terminal helices accompanied by the separation between N- and C-terminal segments. The structural rearrangements accompanying the formation of the membrane-competent state expose a hydrophobic hairpin (TH8-9) to solvent, prepare it to insert into the membrane. At pH 5.5, the transition is complete, and the protein further unfolds, resulting in the exposure of its C-terminal hydrophobic TH8-9, leading to subsequent aggregation in the absence of membranes. This solution-based study complements high resolution crystal structures and provides a detailed understanding of the pH dependent structural rearrangement and acid-induced oligomerization of T domain. PMID- 25290212 TI - CD nomenclature for mouse antigens? PMID- 25290213 TI - Is there a role for MHC class I antigens in the elimination of somatic mutants? PMID- 25290214 TI - Natural killer activity: the definition of a function rather than a cell type. PMID- 25290215 TI - Activation of a gene activator. PMID- 25290216 TI - Non-H-2 histocompatibility antigens: can they be retroviral products? PMID- 25290217 TI - Lymphokine-activated killer cell activity Characteristics of effector cells and their progenitors in blood and spleen. AB - Leukocytes in blood and spleen can be activated by interleukin 2 (IL-2) to become cytotoxic to certain tumor cell lines in vitro. Recent evidence suggests that such lymphokine-activated killer (LAK) cells can bring about the regression of solid tumors in animals and patients, under certain circumstances. Here, Ronald Herberman and colleagues from eight international laboratories, review what is known of the characteristics of LAK cell activity and conclude that most of it can be attributed to natural killer cells stimulated by IL-2. PMID- 25290218 TI - Carbohydrate antigens as possible parasite vaccines A case for the Leishmania glycolipid. AB - Vaccination is one of the most cost-effective means of controlling and eradicating infectious disease but at present there is no vaccine against any human parasitic disease. Developments in gene cloning have focused attention on protein antigen vaccines and have opened the way for their large-scale production. There is, however, another class of non-clonable, biologically important molecules, the complex carbohydrates. In this review Emanuela Handman and her colleagues examine the structure and function of carbohydrate antigens of Leishmania, and their possible role in the search for a vaccine against this organism. PMID- 25290219 TI - Some new perspectives on transplantation immunity and tolerance. PMID- 25290220 TI - Transcriptome analysis of Escherichia coli O157:H7 grown in vitro in the sterile filtrated cecal content of human gut microbiota associated rats reveals an adaptive expression of metabolic and virulence genes. AB - In developed countries, enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a leading cause of bloody diarrhea and renal failures in human. Understanding strategies employed by EHEC to colonize the intestine is of major importance since to date no cure exists to eradicate the pathogen. In this study, the adaptive response of EHEC to the intestinal milieu conditioned by a human microbiota was examined. A transcriptomic analysis was performed on the EHEC strain EDL933 incubated in vitro in the sterile-filtrated cecal content of human microbiota-associated rats (HMC) compared with EDL933 incubated in the sterile filtrated cecal content of germ-free rat (GFC). EDL933 switches from a glycolytic metabolic profile in the GFC to an anaplerotic metabolic profile in HMC. The expression of several catabolism genes was strongly affected such as those involved in the utilization of sugars, glycerol, N-acetylneuraminic acid, amino acids and secondary metabolites. Interestingly, expression level of critical EHEC O157:H7 virulence genes including genes from the locus of enterocyte effacement was reduced in HMC. Altogether, these results contribute to the understanding of EHEC adaptive response to a digestive content and highlight the ability of the microbiota to repress EHEC virulence gene expression. PMID- 25290222 TI - Statement of Retraction: Mullie P, Clarys P, Deriemaeker P, Hebbelinck M. "Estimation of daily human intake of food flavonoids". PMID- 25290221 TI - Sex-steroid imbalance in females and dry eye. AB - Dry eye (DE) is a multifactorial disorder of the ocular surface unit that results in eye discomfort, visual disturbance and ocular surface damage. It is one of the most common complaints in daily ophthalmic practice. The risk of DE increases with age in both sexes, while its incidence is higher among females. In addition, the condition of menopause in aging women may also contribute to DE onset or worsening as a consequence of an overall hormonal imbalance. Sex hormones play a key role in ocular surface physiology and they impact differently on ocular surface tissues. Reduced estrogen levels were historically thought to be responsible in age-related DE onset but more recent investigations have reconsidered the role of androgens that are present and exert a protective function on the ocular surface. Hormone levels themselves, withdrawal changes in hormone levels, and the changes in hormone-receptor responsiveness are all important factors but it remains to be fully elucidated how estrogen or androgen insufficiency act alone or together in a combined imbalance or interplay to raise the risk of disease. The purpose of this review is to briefly outline current scientific evidence on the influence of androgens and estrogens, on the Lachrymal and Meibomian glands and on ocular surface epithelia including conjunctival goblet cells during reproductive and menopausal periods. The role of sex steroids is also discussed in relation to the pathogenesis of different forms of DE and Sjogren's syndrome (SS). The impact of systemic hormone therapy (HT) in DE post menopausal women still appears as a controversial issue, despite the many clinical studies. Finally, the outcomes of topical applications of steroid-based products are summarized, underlying the need for potential (tear) biomarker(s) in the rationale of DE-targeted therapy. PMID- 25290223 TI - Exploring electronic health records as a population health surveillance tool of cardiovascular disease risk factors. AB - The objective of this study was to examine the utility of using electronic health record (EHR) data for periodic community health surveillance of cardiovascular disease (CVD) risk factors through 2 research questions. First, how many years of EHR data are needed to produce reliable estimates of key population-level CVD health indicators for a community? Second, how comparable are the EHR estimates relative to those from community screenings? The study takes place in the context of the Heart of New Ulm Project, a 10-year population health initiative designed to reduce myocardial infarctions and CVD risk factor burden in a rural community. The community is served by 1 medical center that includes a clinic and hospital. The project screened adult residents of New Ulm for CVD risk factors in 2009. EHR data for 3 years prior to the heart health screenings were extracted for patients from the community. Single- and multiple-year EHR prevalence estimates were compared for individuals ages 40-79 years (N=5918). EHR estimates also were compared to screening estimates (N=3123). Single-year compared with multiyear EHR data prevalence estimates were sufficiently precise for this rural community. EHR and screening prevalence estimates differed significantly-systolic blood pressure (BP) (124.0 vs. 128.9), diastolic BP (73.3 vs. 79.2), total cholesterol (186.0 vs. 201.0), body mass index (30.2 vs. 29.5), and smoking (16.6% vs. 8.2%) suggesting some selection bias depending on the method used. Despite differences between data sources, EHR data may be a useful source of population health surveillance to inform and evaluate local population health initiatives. PMID- 25290225 TI - Collaborative study of monoclonal antibodies to human IgG subclasses and allotypes. PMID- 25290224 TI - B-cell or T-cell immunity? AB - The influenza virus behaves unpredictably and can cause devastating pandemics. Nearly 50 years after its first isolation it is probably the most infectious agent known that we cannot yet control. Why? The answer lies in the virus's unique capacity to alter antigenically and in the inability of the host's immune system to respond satisfactorily to the vaccines currently available. What follows is a record, prepared exclusively for Immunology Today, of a conference held in Oxford on March 21-24 this year, to discuss problems relating to protection against influenza. PMID- 25290226 TI - The selection of self-MHC recognizing T lymphocytes: a role for idiotypes? PMID- 25290227 TI - The characterization of cell receptors for IgG. PMID- 25290228 TI - The symbiosis of immunocompetent and endothelial cells. PMID- 25290229 TI - Cell-mediated immune deficiency in Hodgkin's disease. AB - Disturbances of the immune system frequently accompany the development of lymphomas in man. In the early stages of non-Hodgkin's lymphomas, abnormalities of immunological function are usually minimal, but impairment of both antibody- and cell-mediated immunity is often noted in advanced disease. In contrast, while antibody-mediated immune responses in patients with Hodgkin's disease usually remain intact until late in the course of the illness, cell-mediated immune dysfunction is an early and consistent feature. Here Rakesh Kumar and Ronald Penny discuss the abnormalities of cell-mediated immunity in Hodgkin's disease. PMID- 25290230 TI - Cellular interactions in thymus-dependent antibody responses. PMID- 25290231 TI - The immunology of methanogens: a new development in microbial biotechnology. AB - The immunology of methanogens is an important area of research into biotechnology bioengineering involving these bacteria. Here, recent findings regarding the antigenic characteristics of methanogens are discussed, emphasizing the present availability of antibody probes and immunological methods for their identification, classification, and structural analysis. PMID- 25290233 TI - Patient evaluation of an acute care pediatric telemedicine service in urban neighborhoods. AB - BACKGROUND: Telemedicine has enhanced care for children with illness in Rochester, NY, since May 2001, enabling 13,568 acute illness visits through December 2013. Prior findings included high parent satisfaction with childcare- and school-based telemedicine ("school telemedicine") and potential to replace 85% of office visits for illness. Urban neighborhood telemedicine ("neighborhood telemedicine") was designed to offer convenient care for illness episodes that school telemedicine often cannot serve because illness arises when children are at home or symptoms preclude attendance. This study was designed to characterize health problems prompting neighborhood telemedicine use and to assess parent perceptions of its value. MATERIALS AND METHODS: A parent satisfaction instrument was developed with input from parents and providers. Neighborhood telemedicine was initiated in January 2009 and totaled 1,362 visits through November 2013. During a 29-month survey period through January 2012, 3,871 acute illness telemedicine visits were completed, 908 (23.5%) of them via neighborhood telemedicine. Instruments were completed for 392 (43.2%) of the 908 visits. RESULTS: Neighborhood telemedicine comprised 27% of all telemedicine visits during the year of peak neighborhood activity. Almost all survey respondents were satisfied or highly satisfied with neighborhood visits (97.6%) and endorsed greater convenience than alternatives (94.5%). CONCLUSIONS: Family preferences and the high value placed on neighborhood telemedicine suggest such service is important, especially in health systems driven by patient values. Service provided by neighborhood telemedicine holds potential to meet a large demand for care of acute childhood illness. Financing reform to support patient-centered care (e.g., bundled payments) should encompass sustainable business models for this service. PMID- 25290234 TI - Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity. AB - Young cystic fibrosis (CF) patients' airways are mainly colonized by Staphylococcus aureus, while Pseudomonas aeruginosa predominates in adults. However, the mechanisms behind this infection switch are unclear. Here, we show that levels of type-IIA-secreted phospholipase A2 (sPLA2-IIA, a host enzyme with bactericidal activity) increase in expectorations of CF patients in an age dependent manner. These levels are sufficient to kill S. aureus, with marginal effects on P. aeruginosa strains. P. aeruginosa laboratory strains and isolates from CF patients induce sPLA2-IIA expression in bronchial epithelial cells from CF patients (these cells are a major source of the enzyme). In an animal model of lung infection, P. aeruginosa induces sPLA2-IIA production that favours S. aureus killing. We suggest that sPLA2-IIA induction by P. aeruginosa contributes to S. aureus eradication in CF airways. Our results indicate that a bacterium can eradicate another bacterium by manipulating the host immunity. PMID- 25290235 TI - Spatial and temporal events in tooth development of Astyanax mexicanus. AB - The Mexican tetra (Astyanax mexicanus), a freshwater teleost fish, is an excellent vertebrate model organism to study tooth development, specifically the spatiotemporal events related to the development of the oral and pharyngeal dentitions. In contrast to the coordinated early tooth development in the premaxilla and mandible, the maxillary teeth develop much later in life at 60 dpf. By analysing a growth series of bone and cartilage stained tetra and histological sectioning of the tooth bearing bones, we track the developmental events of tooth development over ontogeny of this animal. Whole mount in situ hybridisation with bone morphogenetic proteins and their inhibitor Noggin was conducted to track the late tooth development events. Our data show that the first generation teeth are small and unicuspid irrespective of their location. Oral jaw teeth become multicuspid and large over ontogeny while the pharyngeal dentition remains unicuspid and disorganised. Tooth eruption occurs late in the maxillary bone. The distinct expression pattern of the BMP antagonist, Noggin, suggests that Noggin plays an inhibitory role by preventing early tooth development in the maxillary bone. These data further support and highlight the use of the Mexican tetra in understanding the spatio-temporal differences in tooth development in vertebrate jaws. PMID- 25290237 TI - Catalytic enantioselective desymmetrization of 1,3-diazido-2-propanol via intramolecular interception of alkyl azides with diazo(aryl)acetates. AB - The first catalytic enantioselective desymmetrization of 1,3-diazido-2-propanol via an intramolecular interception of alkyl azides by Cu-carbenoids has been realized. A wide range of 1,3-diazidoisopropyl diazo(aryl)acetates were converted to cyclic alpha-imino esters in the presence of bisoxazoline ligand (S,S)-Ph-Box with good to excellent yields, and the enantiomeric excess was up to 97%. PMID- 25290236 TI - The Bernstein prize. PMID- 25290238 TI - Primary structures of transplantation antigens. PMID- 25290239 TI - Relations between Waldeyer's ring and upper respiratory tract infections. PMID- 25290240 TI - Co-operative T-T interactions in the human T suppressor cell circuit. PMID- 25290241 TI - Immunogenetics of graft-versus-host reactions to minor histocompatibility antigens. PMID- 25290242 TI - The avian immune system. AB - Some of the most pioneering discoveries in immunology, e.g. the dichotomy of the lymphoid system and the extrinsic origin of stem cells in primary lymphoid organs, have been made using the avian immune system. A considerable amount of information has been accumulated but the immune system in birds is still poorly understood compared with the murine or human immune systems, and experimental studies have been confined almost exclusively to chickens. This review discusses some of the major findings concerning the avian immune system. PMID- 25290243 TI - Rosette tests for T and B lymphocyte immunoglobulin. AB - B lymphocytes synthesize and then express in their surface membranes immunoglobulin (Ig) molecules which serve as antigen receptors. Although controversy surrounds the precise nature of antigen receptors in T lymphocytes, these receptor molecules react with certain anti-Ig reagents and are considered to be Ig-related. Antiglobulin rosette tests and in particular the mixed antiglobulin rosetting reaction (MARR) and the direct antiglobulin rosetting reaction (DARR) have special merit in demonstration of lymphocyte Ig and Ig related surface determinants; these lest systems are reviewed and compared with more conventional direct binding methodology which uses free anti-Ig molecules to sensitize lymphocytess. PMID- 25290244 TI - The effects of ice slurry ingestion before exertion in Wildland firefighting gear. AB - PURPOSE: To investigate the effect of ice slurry ingestion precooling on body core temperature (Tc) during exertion in wildland firefighting garments in uncompensable heat stress. METHODS: On two separate trials, 10 males ingested 7.5 g.kg(-1) of either an ice slurry (0.1 degrees C) or control beverage (20 degrees C) during seated rest for 30 minutes prior to simulating the U.S. Forest Service Pack Test on a treadmill in wildland firefighting garments in a hot environment (38.8 +/- 1.2 degrees C, 17.5 +/- 1.4% relative humidity). Deep gastric temperature, mean skin temperature (Tsk), and heart rate (HR) were recorded. Ratings of perceived exertion, thermal sensation, comfort, and sweating were assessed. RESULTS: Compared with ingestion of a temperate beverage, precooling with ice slurry before exertion in a hot environment reduced Tc during the first 30 minutes of the exercise bout. Exercise time and distance completed were not different between treatments. Skin temperature, heart rate, and perceptual responses rose in both conditions during exercise but did not differ by condition. CONCLUSION: Pretreatment with ice slurry prior to exertion in wildland firefighting garments results in a modest reduction in Tc during the first 30 minutes of exercise when compared to pretreatment with control beverage but the ice slurry precooling advantage did not persist throughout the 45-minute exercise protocol. PMID- 25290245 TI - Inhibitory act of selenoprotein P on Cu(+)/Cu(2+)-induced tau aggregation and neurotoxicity. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by peptide and protein misfolding and aggregation, in part due to the presence of excess metal ions such as copper. Aggregation and cytotoxicity of amyloid-beta (Abeta) peptide with copper ion have been investigated extensively; however, the effects of metalation on tau are less known. Here, we presented the effects of Cu(+) and Cu(2+) on aggregation and neurotoxicity of the second repeat unit of the microtubule-binding domain of tau (tau-R2). Tau-R2 was demonstrated to bind 0.44 Cu(2+) and 0.34 Cu(+) per monomer with dissociation constants of 1.1 nM and 0.2 pM, respectively. Copper in both oxidation states stimulated the aggregation, ROS production, and neuronal cytotoxicity of tau-R2. We showed that copper associated tau-R2 aggregates, decreased protein levels of microtubule-associated protein 2 (MAP-2), and synaptophysin in the primarily cultured cortical neurons, reduced mitochondrial density and mobility in the axon and, as a consequence, impaired the growth and probably also the function of neurons. Previously, we reported that the His-rich domain of selenoprotein P (SelP-H) inhibited metal induced aggregation and toxicity of Abeta, due to its metal chelation ability. Here we demonstrated that SelP-H not only inhibited copper-mediated tau aggregation but also interfered with the ongoing aggregation and reversed the already formed aggregates. More intriguing, SelP-H significantly attenuated Cu(2+)/Cu(+)-tau-R2-induced intracellular ROS production and the impairments of synapse and mitochondrial movement in neurons. This work implies that the surface exposed His-rich domain of SelP makes it capable of modulating Cu(+)/Cu(2+) mediated aggregation and neurotoxicity of both Abeta and tau and may play important roles in the prevention of AD progression. PMID- 25290246 TI - DNA microarray and signal transduction analysis in pulmonary artery smooth muscle cells from heritable and idiopathic pulmonary arterial hypertension subjects. AB - Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular smooth muscle contraction and proliferation. Here, we analyze genome wide mRNA expression in human pulmonary arterial smooth muscle cells (HPASMC) isolated from three control, three hereditary (HPAH), and three idiopathic PAH (IPAH) subjects using the Affymetrix Human Gene ST 1.0 chip. The microarray analysis reveals the expression of 537 genes in HPAH and 1024 genes in IPAH changed compared with control HPASMC. Among those genes, 227 genes show similar directionality of expression in both HPAH and IPAH HPASMC. IngenuityTM Pathway Analysis (IPA) suggests that many of those genes are involved in cellular growth/proliferation and cell cycle regulation and that signaling pathways such as the mitotic activators, polo-like kinases, ATM signaling are activated under PAH conditions. Furthermore, the analysis demonstrates downregulated mRNA expression of certain vasoactive receptors such as bradykinin receptor B2 (BKB2R). Using real time PCR, we verified the downregulated BKB2R expression in the PAH cells. Bradykinin-stimulated calcium influx is also decreased in PAH PASMC. IPA also identified transcriptional factors such p53 and Rb as downregulated, and FoxM1 and Myc as upregulated in both HPAH and IPAH HPASMC. The decreased level of phospho-p53 in PAH cells was confirmed with a phospho-protein array; and we experimentally show a dysregulated proliferation of both HPAH and IPAH PASMC. Together, the microarray experiments and bioinformatics analysis highlight an aberrant proliferation and cell cycle regulation in HPASMC from PAH subjects. These newly identified pathways may provide new targets for the treatment of both hereditary and idiopathic PAH. PMID- 25290247 TI - Positive allostery in metal ion binding by a cooperatively folded beta-peptide bundle. AB - Metal ion binding is exploited by proteins in nature to catalyze reactions, bind molecules, and favor discrete structures, but it has not been demonstrated in beta-peptides or their assemblies. Here we report the design, synthesis, and characterization of a beta-peptide bundle that uniquely binds two Cd(II) ions in a distinct bicoordinate array. The two Cd(II) ions bind with positive allosteric cooperativity and increase the thermodynamic stability of the bundle by more than 50 degrees C. This system provides a unique, synthetic context to explore allosteric regulation and should pave the way to sophisticated molecular assemblies with catalytic and substrate-sensing functions that have historically not been available to de novo designed synthetic proteomimetics in water. PMID- 25290248 TI - Optimizing temperature threshold testing in small-fiber neuropathy. AB - INTRODUCTION: We examined optimization of a temperature threshold testing (TTT) protocol for patients with suspected small-fiber neuropathy (SFN) to lessen the burden for both patients and technicians, without sacrificing accuracy. METHODS: Data from 81 patients with SFN (skin biopsy and TTT abnormal) and 81 without SFN (skin biopsy and TTT normal) were used. Warm, cold, and heat pain sensation thresholds were determined bilaterally on the thenar eminence and foot dorsum by methods of limits and levels. Diagnostic accuracy was determined for various sensory modality combinations through comparative corresponding area under the receiver-operator characteristic curves. RESULTS: Assessment of warm and cold thresholds in all extremities by the method of levels showed the best discriminatory ability (area under the curve 0.95, sensitivity 84.2%, specificity 93.8%). CONCLUSIONS: These assessments are suggested for TTT examination in possible SFN patients. By applying this combination, the time needed for TTT can be reduced, maintaining diagnostic accuracy. PMID- 25290250 TI - Electron transfer kinetics on mono- and multilayer graphene. AB - Understanding of the electrochemical properties of graphene, especially the electron transfer kinetics of a redox reaction between the graphene surface and a molecule, in comparison to graphite or other carbon-based materials, is essential for its potential in energy conversion and storage to be realized. Here we use voltammetric determination of the electron transfer rate for three redox mediators, ferricyanide, hexaammineruthenium, and hexachloroiridate (Fe(CN)(6)(3 ), Ru(NH3)(6)(3+), and IrCl(6)(2-), respectively), to measure the reactivity of graphene samples prepared by mechanical exfoliation of natural graphite. Electron transfer rates are measured for varied number of graphene layers (1 to ca. 1000 layers) using microscopic droplets. The basal planes of mono- and multilayer graphene, supported on an insulating Si/SiO(2) substrate, exhibit significant electron transfer activity and changes in kinetics are observed for all three mediators. No significant trend in kinetics with flake thickness is discernible for each mediator; however, a large variation in kinetics is observed across the basal plane of the same flakes, indicating that local surface conditions affect the electrochemical performance. This is confirmed by in situ graphite exfoliation, which reveals significant deterioration of initially, near reversible kinetics for Ru(NH3)(6)(3+) when comparing the atmosphere-aged and freshly exfoliated graphite surfaces. PMID- 25290251 TI - Two new compounds from the plant endophytic fungus Pestalotiopsis versicolor. AB - A new coumarin, 4,6-dihydroxy-7-formyl-3-methylcoumarin (1), and an alpha-pyrone derivative, 6-[(7S,8R)-8-propyloxiran-1-yl]-4-methoxy-pyran-2-one (2), together with four known alpha-pyrone derivatives (3-6), were isolated from the broth extract of the plant endophytic fungus Pestalotiopsis versicolor. Their structures were elucidated by extensive spectroscopic analysis and by comparison of the chemical shift values with those of related known compounds. PMID- 25290249 TI - Mesenchymal Stromal Cells Improve Renovascular Function in Polycystic Kidney Disease. AB - Polycystic kidney disease (PKD) is a common cause of end-stage renal failure, for which there is no accepted treatment. Progenitor and stem cells have been shown to restore renal function in a model of renovascular disease, a disease that shares many features with PKD. The objective of this study was to examine the potential of adult stem cells to restore renal structure and function in PKD. Bone marrow-derived mesenchymal stromal cells (MSCs, 2.5 * 10(5)) were intrarenally infused in 6-week-old PCK rats. At 10 weeks of age, PCK rats had an increase in systolic blood pressure (SBP) versus controls (126.22 +/- 2.74 vs. 116.45 +/- 3.53 mmHg, p < 0.05) and decreased creatinine clearance (3.76 +/- 0.31 vs. 6.10 +/- 0.48 ul/min/g, p < 0.01), which were improved in PKD animals that received MSCs (SBP: 114.67 +/- 1.34 mmHg, and creatinine clearance: 4.82 +/- 0.24 ul/min/g, p = 0.001 and p = 0.003 vs. PKD, respectively). MSCs preserved vascular density and glomeruli diameter, measured using microcomputed tomography. PCK animals had increased urine osmolality (843.9 +/- 54.95 vs. 605.6 +/- 45.34 mOsm, p < 0.01 vs. control), which was improved after MSC infusion and not different from control (723.75 +/- 56.6 mOsm, p = 0.13 vs. control). Furthermore, MSCs reduced fibrosis and preserved the expression of proangiogenic molecules, while cyst size and number were unaltered by MSCs. Delivery of exogenous MSCs improved vascular density and renal function in PCK animals, and the benefit was observed up to 4 weeks after a single infusion. Cell-based therapy constitutes a novel approach in PKD. PMID- 25290252 TI - Plasma cholesterol-lowering activity of gingerol- and shogaol-enriched extract is mediated by increasing sterol excretion. AB - The present study investigated the cholesterol-lowering activity of gingerol- and shogaol-enriched ginger extract (GSE). Thirty hamsters were divided into three groups and fed the control diet or one of the two experimental diets containing 0.5 and 1.0% GSE. Plasma total cholesterol, liver cholesterol, and aorta atherosclerotic plaque were dose-dependently decreased with increasing amounts of GSE added into diets. The fecal sterol analysis showed dietary GSE increased the excretion of both neutral and acidic sterols in a dose-dependent manner. GSE down regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5), whereas it up-regulated hepatic cholesterol-7alpha-hydroxylase (CYP7A1). It was concluded that beneficial modification of the lipoprotein profile by dietary GSE was mediated by enhancing excretion of fecal cholesterol and bile acids via up regulation of hepatic CYP7A1 and down-regulation of mRNA of intestinal NPC1L1, ACAT2, and MTP. PMID- 25290254 TI - Prevalence of Bilateral JOCD of the Knee and Associated Risk Factors. AB - PURPOSE: Juvenile osteochondritis dissecans (JOCD) of the knee affects cartilage and subchondral bone surface. Multifocal JOCD is described as multiple lesions within the knee or presence of lesions in other joints. The true prevalence of bilaterality of JOCD is unknown. The purpose of this study is to determine the prevalence of bilateral JOCD and to identify potential risk factors for bilateral disease. METHODS: We evaluated 108 consecutive patients presenting for JOCD at a single pediatric hospital system. If an OCD lesion of the knee was found, contralateral knee x-rays were performed. Lesion location was documented according to Cahill and Berg, magnetic resonance imaging (MRI) grading documented according to Dipaola, and if surgical treatment was undertaken, intraoperative grading performed according to Guhl. Patients with unilateral JOCD were compared with those with bilateral disease. Statistical analysis of categorical data was performed utilizing likelihood ratio chi test or Fisher exact test and continuous data compared using nonparametric Wilcoxon 2-sample test. RESULTS: There were 85 male (79%) and 23 females (21%) with an average age of 12.3 years (range, 6 to 18 y). Sixty-three percent of lesions were located on the medial femoral condyle and 33% on the lateral femoral condyle. Ninety percent of all lesions were considered weight-bearing lesions. Eighty percent were considered stable on MRI evaluation. Of those lesions that underwent surgical intervention, 61% were either grade I or II lesions. Seventy-three of 108 patients (68%) underwent some form of surgical intervention. Thirty-one patients (29%) were found to have contralateral JOCD lesions. Thirty-nine percent of contralateral lesions found on contralateral radiographs were asymptomatic at presentation and nearly all of those evaluated with MRI (16 of 18) were stable. Sixty-nine percent of contralateral lesions were located on the medial femoral condyle, 27% on the lateral femoral condyle, and 94% were considered weight-bearing lesions. Twelve of 31 contralateral lesions (39%) underwent surgical intervention. Comparing patients with unilateral and bilateral disease, female patients (P<0.05) and younger age at presentation (P<0.009) were risk factors for bilateral JOCD. No statistical difference among other variables was seen with regard to location, MRI or operative stability of lesion, or presence of symptoms. CONCLUSIONS: In our consecutive series of 108 patients with JOCD, we found a 29% incidence of bilateral disease. Almost 40% of contralateral lesions were asymptomatic upon presentation. Female sex and younger age at presentation were significant risk factors for bilateral disease. Lesion location, stability, and pain were not statistically significant variables. The authors recommend bilateral radiographic knee evaluation for all patients found to have JOCD. LEVEL OF EVIDENCE: Level IV-retrospective case series. PMID- 25290255 TI - What's New in Idiopathic Clubfoot? AB - This update summarizes selected research highlights pertaining to idiopathic clubfoot deformity that were published in peer-reviewed journals between January 2010 and December 2013. PMID- 25290256 TI - Optically active microspheres constructed by helical substituted polyacetylene and used for adsorption of organic compounds in aqueous systems. AB - This article reports optically active microspheres consisting of chiral helical substituted polyacetylene and beta-cyclodextrin-derivative (beta-CD-A). The microspheres showed remarkable adsorption toward various organic compounds in water. To prepare the microspheres, an acetylenic-derived helical macro-monomer was synthesized and then underwent aqueous suspension copolymerization with octadecyl acrylate and butyl acrylate by using azobis(isobutyronitrile) as initiator and beta-CD-A simultaneously as comonomer and cross-linking agent. The helical macro-monomer chains enabled the microspheres to exhibit desirable enantio-differentiating adsorption capacity toward chiral compounds respectively dissolved in organic solvent, dispersed in water, and dissolved in water. The saturated absorbency toward (R)-(+)- and (S)-(-)-1-phenylethylamine was 29 and 12 mg . g(-1), respectively. The microspheres also showed large oil absorbency (e.g., 22 g . g(-1) CCl4) and a large adsorption toward methyl red (as a model for organic dyes) dispersed in water. The presence of beta-CD-A moieties improved the adsorption performance of the microspheres. The present optically active microspheres open a new approach for preparing adsorbents particularly chiral adsorbents with potentials for wastewater treatment. PMID- 25290253 TI - Endogenous neural stem/progenitor cells stabilize the cortical microenvironment after traumatic brain injury. AB - Although a myriad of pathological responses contribute to traumatic brain injury (TBI), cerebral dysfunction has been closely linked to cell death mechanisms. A number of therapeutic strategies have been studied in an attempt to minimize or ameliorate tissue damage; however, few studies have evaluated the inherent protective capacity of the brain. Endogenous neural stem/progenitor cells (NSPCs) reside in distinct brain regions and have been shown to respond to tissue damage by migrating to regions of injury. Until now, it remained unknown whether these cells have the capacity to promote endogenous repair. We ablated NSPCs in the subventricular zone to examine their contribution to the injury microenvironment after controlled cortical impact (CCI) injury. Studies were performed in transgenic mice expressing the herpes simplex virus thymidine kinase gene under the control of the nestin(delta) promoter exposed to CCI injury. Two weeks after CCI injury, mice deficient in NSPCs had reduced neuronal survival in the perilesional cortex and fewer Iba-1-positive and glial fibrillary acidic protein positive glial cells but increased glial hypertrophy at the injury site. These findings suggest that the presence of NSPCs play a supportive role in the cortex to promote neuronal survival and glial cell expansion after TBI injury, which corresponds with improvements in motor function. We conclude that enhancing this endogenous response may have acute protective roles after TBI. PMID- 25290259 TI - Interpreting noninvasive prenatal paternity tests. PMID- 25290260 TI - Response to Drabek and Cereda. PMID- 25290261 TI - Genetic counseling for women referred for advanced maternal age: a telegenetic approach. PMID- 25290262 TI - Exercise-induced pulmonary haemorrhage impairs racing performance in Thoroughbred racehorses. AB - REASONS FOR PERFORMING STUDY: Exercise-induced pulmonary haemorrhage (EIPH) occurs commonly in Thoroughbred racehorses worldwide. While EIPH is believed to be an important cause of impaired performance in these horses, there is limited evidence from sufficiently powered studies to evaluate this association. OBJECTIVES: To evaluate whether EIPH is associated with finishing position, distance finished behind race winners and differences in race earning among Thoroughbred horses racing in South Africa. STUDY DESIGN: Prospective cross sectional study. METHODS: One thousand Thoroughbred horses racing in South Africa were enrolled prior to a single race and underwent tracheobronchoscopic examination within 2 h of racing. Three observers, blinded to the horses' identity and race performance, independently evaluated EIPH occurrence and severity using video recordings of the examination. Data were analysed using multivariable logistic and linear regression while controlling for important horse and race factors as potential confounding variables. RESULTS: Overall, 68% of horses had evidence of EIPH (grade >=1). Horses without evidence of EIPH (severity grade 0), when compared with horses with any evidence of EIPH (grade >=1), were >2 times more likely to win races (odds ratio = 2.3; 95% confidence interval 1.4-3.7; P = 0.001), finished an average of one length ahead of horses with EIPH (P = 0.03), and were 2.5 times more likely to be in the highest decile in race earnings (odds ratio = 2.5, 95% CI 1.5-4.1, P<0.001). However, no association was identified regarding finishing in the top 3 positions or earning money when analysed as a continuous variable or analysed as any winnings vs. none. CONCLUSIONS: Exercise-induced pulmonary haemorrhage was associated with impaired performance in Thoroughbred racehorses not medicated with furosemide and not using nasal dilator strips. These findings provide strong corroboration of previous research indicating that the occurrence of EIPH has a major impact on the ability of Thoroughbred racehorses to compete successfully as elite athletes. PMID- 25290263 TI - Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate. AB - Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 * 10(-5)). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow. PMID- 25290264 TI - alphaCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans. AB - Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca(2+)/calmodulin-dependent protein kinase-II (alphaCaMKII) is a key mediator of learning and memory also involved in drug related plasticity. The autophosphorylation of alphaCaMKII was shown to accelerate learning. Thus, we investigated the role of alphaCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that alphaCaMKII autophosphorylation-deficient alphaCaMKII(T286A) mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg(-1), intraperitoneal). In vivo microdialysis revealed that alphaCaMKII(T286A) mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg(-1), intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in alphaCaMKII(T286A) mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that alphaCaMKII controls the speed for the establishment of cocaine's reinforcing effects. PMID- 25290265 TI - Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide alpha-MSH, at the origin of eating disorders. AB - The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies (auto-Abs) reactive with alpha-melanocyte-stimulating hormone (alpha-MSH) are involved in regulation of feeding and emotion; however, the origin of such auto Abs is unknown. Here, using proteomics, we identified ClpB heat-shock disaggregation chaperone protein of commensal gut bacteria Escherichia coli as a conformational antigen mimetic of alpha-MSH. We show that ClpB-immunized mice produce anti-ClpB IgG crossreactive with alpha-MSH, influencing food intake, body weight, anxiety and melanocortin receptor 4 signaling. Furthermore, chronic intragastric delivery of E. coli in mice decreased food intake and stimulated formation of ClpB- and alpha-MSH-reactive antibodies, while ClpB-deficient E. coli did not affect food intake or antibody levels. Finally, we show that plasma levels of anti-ClpB IgG crossreactive with alpha-MSH are increased in patients with AN, bulimia and BED, and that the ED Inventory-2 scores in ED patients correlate with anti-ClpB IgG and IgM, which is similar to our previous findings for alpha-MSH auto-Abs. In conclusion, this work shows that the bacterial ClpB protein, which is present in several commensal and pathogenic microorganisms, can be responsible for the production of auto-Abs crossreactive with alpha-MSH, associated with altered feeding and emotion in humans with ED. Our data suggest that ClpB-expressing gut microorganisms might be involved in the etiology of EDs. PMID- 25290267 TI - Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. AB - Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription factor, previously implicated in autism, is essential for normal cerebellar patterning and development. We previously reported EN-2 overexpression associated with promoter DNA hypermethylation in the autism cerebellum but because traditional DNA methylation methodology cannot distinguish 5-methylcytosine (5 mC) from 5-hmC, we now extend our investigation by quantifying global and gene specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the autism cerebellum and accompanied by increases in the expression of de novo methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3, and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage. Within the EN-2 promoter, there was a significant positive correlation between 5 hmC content and EN-2 gene expression. Based on reports of reduced MeCP2 affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a significant decrease in repressive MeCP2 binding that may contribute to the aberrant overexpression of EN-2. Because normal cerebellar development depends on perinatal EN-2 downregulation, the sustained postnatal overexpression suggests that a critical window of cerebellar development may have been missed in some individuals with autism with downstream developmental consequences. Epigenetic regulation of the programmed on-off switches in gene expression that occur at birth and during early brain development warrants further investigation. PMID- 25290269 TI - [Arthroscopically assisted osteosynthesis of dorsally tilted intraarticular distal radius fractures--technique and results]. AB - The present paper describes the indication and application of an arthroscopically assisted osteosynthesis for distal radius fractures. Visualisation of articular incongruency is emphasised with special regard to articular fracture fragment reduction. In addition to that, classification of soft tissue injuries and treatment options are discussed. The final clinical and radiological results of 17 patients are presented: DASH and PRWE averaged 4.9 and 6.0 respectively. Active range of motion measured 123 degrees for flexion/extension, 51 degrees for radial and ulnar deviation and 163 degrees for pronosupination, which is 87%, 98% and 97%, respectively, compared with the opposite wrist. Radial inclination at final follow-up was 23 degrees , palmar tilt measured 6 degrees and ulnar variance averaged -1.2 mm. The scapholunate gap at follow-up was 1.6 mm, and the scapholunate angle measured 57 degrees . PMID- 25290268 TI - CACNA1C risk variant affects reward responsiveness in healthy individuals. AB - The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this risk variant affects reward responsiveness because reward processing is one of the central cognitive motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders. PMID- 25290270 TI - Plate presetting and arthroscopic reduction technique (PART) for treatment of distal radius fractures. AB - BACKGROUND: Arthroscopy has been reported to be an efficient adjunct for the surgical treatment for distal radius fractures (DRF). However, performing wrist arthroscopy during palmar locking plate fixation seems to be troublesome. We have developed a surgical technique involving presetting of a palmar locking plate and an arthroscopic reduction technique (PART) of the fracture that can facilitate the procedure. This study is aimed to investigate the effectiveness of our technique in the treatment of DRF. PATIENTS AND METHODS: 249 fractures of the distal radius were treated by PART. 205 fractures in 200 patients were followed up on average for 15 (12-60) months. There were 46 men and 154 women with an average age of 62 (16-85) years. According to the AO/ASIF fracture classification system there were 51 extra-articular fractures, and 154 intra-articular fractures. Scapholunate interosseous ligament injuries were classified according to Geissler and tears of the triangular fibrocartilage complex according to Abe. On arthroscopic inspection, residual intra-articular fragment dislocation after reduction under fluoroscopy was evaluated. Final evaluation included a radiological examination, measurements of wrist and forearm motion, grip strength, the Mayo modified wrist score (MMWS), and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. RESULTS: On arthroscopic inspection, intraarticular dislocations were found to be residual in 22.7%, even if reduction seemed to have been achieved when viewed by fluoroscopy. Scapholunate interosseous ligament tears were recognized in 29.8%, and triangular fibrocartilage complex tears in 62.4%. The mean palmar tilt was 5.7 (-10 to 16) degrees , radial inclination 26.0 (18-31) degrees , and ulnar variance 0.1 (-2 to 5) mm. The mean extension of the wrist was 71 (50-85) degrees , and the mean flexion was 62 (40-79) degrees . The mean pronation of the forearm was 87.5 (70 90) degrees , and the mean supination was 89.1 (75-95) degrees . The mean grip strength was 90.0% (31-133%) of the opposite side. According to the MMWS there were 156 excellent, 47 good, and 2 fair results. The mean DASH score was 3.9. CONCLUSIONS: The palmar locking plate in combination with arthroscopic reduction technique (PART) leads to good and excellent results. It can be recommended for all fractures of the distal radius needing operative treatment. Arthroscopic reduction of intra-articular fragments is superior to reduction under fluoroscopy. PART allows also the detection of intra-articular soft tissue lesions such as scapholunate ligament tears and injuries of the triangular fibrocartilage complex. PMID- 25290266 TI - A meta-analysis of gene expression quantitative trait loci in brain. AB - Current catalogs of brain expression quantitative trait loci (eQTL) are incomplete and the findings do not replicate well across studies. All existing cortical eQTL studies are small and emphasize the need for a meta-analysis. We performed a meta-analysis of 424 brain samples across five studies to identify regulatory variants influencing gene expression in human cortex. We identified 3584 genes in autosomes and chromosome X with false discovery rate q<0.05 whose expression was significantly associated with DNA sequence variation. Consistent with previous eQTL studies, local regulatory variants tended to occur symmetrically around transcription start sites and the effect was more evident in studies with large sample sizes. In contrast to random SNPs, we observed that significant eQTLs were more likely to be near 5'-untranslated regions and intersect with regulatory features. Permutation-based enrichment analysis revealed that SNPs associated with schizophrenia and bipolar disorder were enriched among brain eQTLs. Genes with significant eQTL evidence were also strongly associated with diseases from OMIM (Online Mendelian Inheritance in Man) and the NHGRI (National Human Genome Research Institute) genome-wide association study catalog. Surprisingly, we found that a large proportion (28%) of ~1000 autosomal genes encoding proteins needed for mitochondrial structure or function were eQTLs (enrichment P-value=1.3 * 10(-9)), suggesting a potential role for common genetic variation influencing the robustness of energy supply in brain and a possible role in the etiology of some psychiatric disorders. These systematically generated eQTL information should be a valuable resource in determining the functional mechanisms of brain gene expression and the underlying biology of associations with psychiatric disorders. PMID- 25290271 TI - [Arthroscopic procedures at the wrist]. PMID- 25290272 TI - [Arthroscopic repair for ulnar-sided tears of the TFCC]. AB - Accurately performed anatomic and biomechanical studies as well as clinical experience during the last years have widened our knowledge about function and pathology of the distal radioulnar joint (DRUJ) making a differentiated treatment possible. In cases of trauma a rupture of the ulnar part of the triangular fibrocartilaginous complex (TFCC) frequently occurs. An overview is given on the development of different arthroscopic techniques for repair and the state of the art is presented. The ulnar part of the TFCC is constituted of the superficial part which is less important for stability and the deep part which is anchored to the fovea of the ulnar head. This deep part is the most important stabiliser of the DRUJ. Each of these parts may rupture separately or both of them may rupture at the same time. Keystones for diagnosis are clinical examination and arthroscopy. On clinical examination instability of the DRUJ is to be evaluated by comparing it to the contralateral side. Furthermore, the degree of instability should be estimated. Extraarticular associated lesions must also be assessed clinically. On arthroscopy the TFCC may be evaluated from the radiocarpal joint as well as from its undersurface, from the DRUJ. In cases of avulsion from the fovea, an anatomic reconstruction with reinsertion of the deep part to the bone is indicated and may be performed successfully according to the published studies and our own experience. If a severe instability is found on clinical examination it is to be supposed that more stabilising structures - then only the radioulnar ligaments - are affected and reinsertion of the deep fibres to the fovea may not be sufficient. PMID- 25290273 TI - [Arthroscopic resection of dorsal wrist ganglia]. AB - In arthroscopic wrist surgery, the resection of dorsal wrist ganglia has become a well accepted practice. As advantages for the minimally invasive procedure the low complication rate and low postoperative morbidity, less postoperative pain and faster recovery over open techniques are discussed. The possibility to assess accompanying joint pathology is considered as another advantage. The importance of identifying a so-called ganglion cyst stalk seems to have been overstated. Regarding the technique, the main discussion points are the size and localisation of the capsular window and the necessity of additional midcarpal arthroscopy. The possibility and results of treatment of recurrent ganglion cysts are still controversial. Our own experience and that of some authors are positive. Hardly mentioned in the literature is the treatment of occult dorsal wrist ganglia and its results, which is considered as very successful by the authors. PMID- 25290274 TI - Arthroscopy of the distal radioulnar joint. AB - Wrist arthroscopy is now widely indicated for diagnosis and treatment of acute or chronic wrist pain, especially for triangular fibrocartilage complex (TFCC) lesions, as a gold standard. In most cases radiocarpal and midcarpal arthroscopy was performed, while DRUJ arthroscopy has been rarely performed because of its difficulties. Recent anatomic and biomechanical studies demonstrated that the radioulnar ligament (RUL), which is the proximal component of the TFCC facing to the DRUJ, is the primary stabilizer of the distal radioulnar joint (DRUJ). Rupture of the radioulnar ligament (RUL) at the fovea area, where it is the main attaching portion to the ulna and is the isometric point during forearm rotation as the rotation axis passes, is responsible for DRUJ instability. Although physical examination and imaging diagnosis may indicate a foveal detachment of the TFCC, DRUJ arthroscopy is potential for visualizing the RUL at the fovea. Role of DRUJ arthroscopy should be more important not only for diagnosis of rupture of the RUL but also for decision making of treatment option for RUL tear. DRUJ arthroscopy also demonstrates the joint surface of both the sigmoid notch and ulnar head, and the proximal surface of the TFCC. PMID- 25290275 TI - (Dry) arthroscopic partial wrist arthrodesis: tips and tricks. AB - One of the options for performing a partial wrist arthrodesis is the arthroscopic technique. As a first advantage arthroscopy allows us to directly assess the state of the articular surface of the carpal bones and define the best surgical option during the salvage operation. Furthermore, it allows performance of the procedure with minimal ligament damage and minimal interference with the blood supply of the carpals. These will (presumably) entail less capsular scarring and more rapid healing. Lastly, there is cosmetic benefit by reducing the amount of external scarring. The procedure has a steep learning curve even for accomplished arthroscopists but can be performed in a competitive manner to the open procedure if the dry technique is used. The aim of this paper is to present the technical details, tricks and tips to make the procedure accessible to all hand specialists with an arthroscopic interest. As it is paramount that the surgeon is acquainted with the "dry" technique, some technical details about it will also be presented. PMID- 25290276 TI - [Arthroscopy of the metacarpophalangeal joints]. AB - With the advancements in arthroscopic technique, arthroscopy has become feasible in most human joints, even those as small as the finger joints. The metacarpophalangeal joints are very well suited for arthroscopy and arthroscopic therapy. Good results have been reported on arthroscopic synovectomy of the metacarpophalangeal joints in rheumatoid arthritis. Osteochondral lesions in degenerative arthritis, loose bodies and foreign bodies can well be treated. Arthroscopic arthrolysis for capsular contracture and treatment of post-traumatic lesions have been performed successfully. The arthroscopic assistance in the treatment of intraarticular fractures and the capsular shrinkage for instability have been described. However, metacarpophalangeal joint arthroscopy has not been popularised up to now and its role in clinical practice remains to be established. Existing indications will be discussed with respect to our own experience. PMID- 25290277 TI - Radiolucent inflammatory implant periapical lesions: a review of the literature. AB - PURPOSE: To discuss the terminology, etiopathogenesis, and treatment of radiolucent inflammatory implant periapical lesions. MATERIALS AND METHODS: An electronic search for relevant articles published in the English literature in the PubMed database. RESULTS: Bacterial contamination of the apical portion of the implant either from a preexisting dental periapical infection or from a periapical lesion of endodontic origin of an adjacent tooth is the probable causative factor. Aseptic bone necrosis owing to overheating of the bone during preparation of osteotomies, or compression of the bone at the apex of the implant owing to excessive tightening, may also play a role. The histopathological features are of a mixed inflammatory cell infiltrate on a background of granulation tissue consistent with either a granuloma or an abscess as may be found at the apex of a nonvital tooth. Treatment consists of immediate and aggressive surgical debridement, chemical detoxification of the apical portion of the exposed implant surface, and systemic antibiotics with or without a bone regenerative procedure. CONCLUSION: A radiolucent inflammatory implant periapical lesion is analogous to either a granuloma or an abscess as may be found at the apex of a nonvital tooth. PMID- 25290278 TI - Do dual-thread orthodontic mini-implants improve bone/tissue mechanical retention? AB - PURPOSE: The aim of this study was to understand whether the pitch relationship between micro and macro thread designs with a parametrical relationship in a dual thread mini-implant can improve primary stability. MATERIALS AND METHODS: Three types of mini-implants consisting of single-thread (ST) (0.75 mm pitch in whole length), dual-thread A (DTA) with double-start 0.375 mm pitch, and dual-thread B (DTB) with single-start 0.2 mm pitch in upper 2-mm micro thread region for performing insertion and pull-out testing. Histomorphometric analysis was performed in these specimens in evaluating peri-implant bone defects using a non contact vision measuring system. RESULTS: The maximum inserted torque (Tmax) in type DTA was found to be the smallest significantly, but corresponding values found no significant difference between ST and DTB. The largest pull-out strength (Fmax) in the DTA mini-implant was found significantly greater than that for the ST mini-implant regardless of implant insertion orientation. Mini-implant engaged the cortical bone well as observed in ST and DTA types. CONCLUSION: Dual-thread mini-implant with correct micro thread pitch (parametrical relationship with macro thread pitch) in the cortical bone region can improve primary stability and enhanced mechanical retention. PMID- 25290279 TI - Evaluation of an endosseous oral implant system according to UNI EN ISO 14801 fatigue test protocol. AB - PURPOSE: The aim of this in vitro study was to evaluate the maximum fracture load and the mechanical performance to cyclic fatigue stress of a dental implant system. METHODS: An experimental study according to the international standards (UNI EN ISO 14801: 2008) was carried out using 15 implants (3.80 mm of diameter and 13 mm of length) with applied straight titanium abutment tightened to 30 N. Five samples were subjected to compression stress at break. Based on the mean fracture load value obtained in this test, the levels of dynamic loading range were set that were carried on at a frequency of 15 Hz for 5 * 10 cycles. RESULTS: The compression stress at break mean value of the tested implants was 499.40 N (SD +/-50.1 N). In the mechanical fatigue stress test, the fatigue limit for 5 * 10 load cycles for all tested samples was 250 N. CONCLUSIONS: The evaluated implant system proved to withstand considerable mechanical loads under the "worst case" loading situation performed according to UNI EN ISO 14801 standard. The reliability of this test protocol makes it suitable to be accomplished for understanding and comparing mechanical properties of other implant systems. PMID- 25290280 TI - Investigation of influence of different implant size and placement on stress distribution with 3-dimensional finite element analysis. AB - PURPOSE: The purpose of this study was to analyze the biomechanical behavior of implants with varying number, inclination, and size, using 3-dimensional finite element (FE) analysis. MATERIAL AND METHODS: A total of 10 FE models were constructed to simulate 5 implant placement configurations: 4 and 5 axial implants, 4 implants inclined with 17.5 degrees mesial and 35 degrees distal, and 2 axial and 2 distal implants inclined with 17.5 and 35 degrees, using implants of 3.5 and 5.5 mm diameters. A vertical load of 300 N was applied to the distal portion of a standardized size metal framework. RESULTS: Increasing the number of implants decreased the stress in the bone for axially placed implant models. The short implants with a large diameter resulted in lower stress values in the bone, but higher stresses in the implant/abutment assembly than the long implants with a small diameter. Increasing diameter of implants decreased high stress concentration in the cortical bone, resulting from increasing cantilever length. CONCLUSIONS: Decreasing cantilever length with distal implant inclination decreases the stress values in the implant, cortical bone, and framework. PMID- 25290281 TI - Significance of osteogenic surface coatings on implants to enhance osseointegration under osteoporotic-like conditions. AB - PURPOSE: The aim was to assess the significance of osteogenic surface coatings on implants to enhance osseointegration under osteoporotic-like (OP-like) conditions. METHODS: To address the focused question "Do osteogenic surface coatings on implants enhance osseointegration under OP-like conditions?" PubMed/MEDLINE and Google-Scholar databases were searched from 1995 up to and including February 2014 using various keywords. Unpublished data, letters to the editor, review articles, and articles published in languages other than English were excluded. RESULTS: Of the 28 studies identified, 11 experimental studies were included. These studies were performed on bilaterally ovariectomized animals. In all studies, implant surface roughness was increased by various osteogenetic surface coatings including alumina, hydroxyapatite, calcium phosphate, and zoledronic acid. Nine studies reported that compared with non coated surfaces, osteogenic coatings on implant surfaces increases bone volume and bone-to-implant contact (BIC) under OP-like conditions. In 2 studies, there was no difference in BIC around hydroxyapatite-coated implants placed in animals with and without OP-like conditions. CONCLUSION: Osteogenic coatings on implant surfaces enhanced osseointegration in animals with OP-like conditions. However, additional clinical studies are warranted to assess the role of osteogenic coatings in increasing osseointegration in patients with osteoporosis. PMID- 25290282 TI - Soft tissue biological response to zirconia and metal implant abutments compared with natural tooth: microcirculation monitoring as a novel bioindicator. AB - INTRODUCTION: Zirconia is often used for implant abutments for esthetics. The aim of this clinical study was to compare the effects of zirconia and metal abutments on periimplant soft tissue. MATERIALS AND METHODS: Ten maxillary anterior implant patients, 5 with metal abutments and 5 with zirconia abutments, were enrolled in this trial. The soft tissue around the implant abutments was evaluated by 2 dimensional laser speckle imaging and thermography. The blood flow in soft tissue around natural teeth was also measured to correct for differences among the subjects. RESULTS: Significantly greater blood flow was detected in the zirconia abutment group (95.64 +/- 5.17%) relative to the metal abutment group (82.25 +/- 8.92%) in free gingiva (P = 0.0317). Reduced blood flow (by almost 18%) was detected in the tissue surrounding metal abutments compared with the tissue surrounding natural teeth. The surface temperature showed no significant difference for all measurements. CONCLUSIONS: These results suggest that blood flow in tissue surrounding zirconia abutments is similar to that in soft tissue around natural teeth. Moreover, zirconia abutments could be advantageous for the maintenance of immune function by improving blood circulation. PMID- 25290283 TI - Guided "sandwich" technique: a novel surgical approach for safe osteotomies in the treatment of vertical bone defects in the posterior atrophic mandible: a case report. AB - PURPOSE: A novel technique to perform safe osteotomies during inlay block regenerative procedures in the posterior atrophic mandible is described. MATERIAL AND METHODS: A 52-year-old male patient with vertical atrophy of the left posterior mandible was treated adopting an inlay block "sandwich" technique using an allogenic cancelous block and a mixture of mineralized and demineralized human bone allograft in putty form as graft. The horizontal osteotomy for the lifting of the osteotomized bone segment was performed using a template prepared from a virtual anatomical replica of the patient's mandible obtained from cone beam computed tomography data. In the second surgical phase, 3 months after the augmentation, 2 implants were easily placed. RESULTS: The horizontal osteotomy was carried out, with no risk, very close to the nerve structures after the precise osteotomy line established preoperatively on the three-dimensional computed tomography (3D-CT) virtual reconstruction. No neurological complications were observed in the first days after the procedure, and no subsequent problems were recorded during the 3-month healing period. CONCLUSION: Radiographic evaluations and complication-free clinical healing demonstrate the effectiveness of this technique to obtain safe and precise osteotomies. PMID- 25290284 TI - Influence of implant diameter in the displacement of dental implants in trabecular bovine bone under a static lateral load: experimental results and computational modeling. AB - PURPOSE: Primary stability and micromovement of dental implants depend on structural properties of the surrounding bone and on implant dimension and design. The purpose of this study was to provide objective data for the influence of implant diameter on the displacement of titanium screw implants. MATERIALS AND METHODS: Ninety Semados implants (length 15 mm, diameter 3.25, 3.75, and 4.5 mm; Bego, Bremen, Germany) were inserted in trabecular bone specimens. All implants were inserted with a torque up to 30 N.cm and loaded horizontally with 10, 20, and 30 N for 2 seconds. RESULTS: All implants showed primary stability. With increasing force, a gradual increase of micromovement was observed (Kruskal Wallis test, P = 0.000). No significant differences were found (Kruskal-Wallis test, P = 0.148) comparing different diameters for every force. CONCLUSIONS: Variation of the diameter of standard implants between 3.25 and 4.5 mm does not seem to influence the primary stability in trabecular bone specimen. Differences between experimental and computational results may be due to the simplification used when modeling. PMID- 25290285 TI - Photoelastic stress analysis of mandibular fixed prostheses supported by 3 dental implants. AB - PURPOSE: To observe the photoelastic stress patterns generated around implants in relation to variations in the diameter and total number of implants supporting fixed complete-arch mandibular frameworks. MATERIALS AND METHODS: Three different implant configurations were analyzed (n = 3): 5 standard implants with diameters of 3.75 mm (C), 3 standard implants with diameters of 3.75 mm (3S), and 3 wide implants with diameters of 5.0 mm (3W). The samples were subjected to a vertical compressive load (1.33 kgf) applied at the end of the distal cantilever of the framework. The shear stresses were calculated around the implants, and the data were analyzed using one-way analysis of variance. RESULTS: The implants nearest to the loading showed higher stress values regardless of the group. The C group showed lower shear stress when compared with the other groups (P = 0.001). No significant difference was observed between the 3W and 3S groups (P = 0.785). CONCLUSION: A reduction in the number of implants, regardless of the implant diameter, showed higher stress concentration around the implants. Five-implant configuration showed lower stress concentration and seems to be more biomechanically predictable. PMID- 25290286 TI - Retrospective long-term evaluation of dental implants in totally and partially edentulous patients. Part I: survival and marginal bone loss. AB - PURPOSE: This retrospective longitudinal study aims to assess long-term outcomes of osseointegrated dental implants in partially and totally edentulous patients. MATERIALS AND METHODS: Patients willing to sign the informed consent and attend a check-up were included. Implant failures were recorded, and marginal bone level and bone loss were evaluated on intraoral radiographs. Univariate and multivariate statistical analyses were conducted to determine the influence of various factors. Complications and patient satisfaction were recorded. RESULTS: One hundred five patients who received 342 implants were included. Mean follow-up was 13.19 +/- 3.70 years. 9.4% of implants were lost, and 78.1% of patients retained all implants placed. Mean marginal bone loss was 0.77 +/- 1.10 mm, being greater than 3 mm in 2.5% of analyzed implants. Factors with possible influence on implant survival and marginal bone loss were smoking, osteopenia or osteoporosis, check-up frequency, implant surface, length and position, and type of prosthesis. 24.8% of patients remained free of complications. Patient satisfaction was high. CONCLUSIONS: In our sample, which included both totally and partially edentulous patients, long-term implant survival was more than 90% with a mean marginal bone loss of 0.77 mm and an implant survival at patient level of 78%; patient satisfaction was high despite the fact that complications were frequent. PMID- 25290287 TI - Force sensor characterization under sinusoidal excitations. AB - The aim in the current work is the development of a method to characterize force sensors under sinusoidal excitations using a primary standard as the source of traceability. During this work the influence factors have been studied and a method to minimise their contributions, as well as the corrections to be performed under dynamic conditions have been established. These results will allow the realization of an adequate characterization of force sensors under sinusoidal excitations, which will be essential for its further proper use under dynamic conditions. The traceability of the sensor characterization is based in the direct definition of force as mass multiplied by acceleration. To do so, the sensor is loaded with different calibrated loads and is maintained under different sinusoidal accelerations by means of a vibration shaker system that is able to generate accelerations up to 100 m/s2 with frequencies from 5 Hz up to 2400 Hz. The acceleration is measured by means of a laser vibrometer with traceability to the units of time and length. A multiple channel data acquisition system is also required to simultaneously acquire the electrical output signals of the involved instrument in real time. PMID- 25290288 TI - Bone scan alterations in aromatase inhibitor-treated patients. AB - We report bone scan changes in 3 patients receiving aromatase inhibitors as adjuvant treatment for postmenopausal hormone receptor-positive breast cancer. Compared with bone scans before treatment, repeated scans after at least 10 months of aromatase inhibitor treatment showed increased activity in the peripheral skeleton and the skull. In 2 patients, these alterations could be correlated with increased markers of bone turnover. They probably result from high bone turnover induced by estrogen depletion caused by aromatase inhibitors. This effect should be taken into account in the differential diagnosis of a bone scan pattern suggestive of hyperparathyroidism, which was ruled out. PMID- 25290290 TI - Primary Rosai-Dorfman disease of the bone in a patient with history of breast cancer: appearance on 99mTc-MDP scintigraphy, CT, and X-ray. AB - A 49-year-old woman with history of breast cancer presented with pain at the level of the left anterior proximal tibia. An x-ray of the tibia demonstrated a lytic cortical lesion that prompted a whole-body 99mTc-MDP bone scan. The bone scan revealed intense bone remodeling at the level of the tibial lytic lesion and in the cervical spine. CT demonstrated an expansile lesion eroding the vertebral bodies of C6 and C7 with a large soft tissue component. A biopsy of the cervical spine mass demonstrated features diagnostic of Rosai-Dorfman disease without evidence of neoplastic cells. PMID- 25290289 TI - Performance of 18F-fluoride PET or PET/CT for the detection of bone metastases: a meta-analysis. AB - PURPOSE: This study aimed to evaluate the diagnostic accuracy of F-fluoride PET or PET/CT compared with Tc-MDP bone scintigraphy and F-FDG PET/CT in the detection of bone metastases. PATIENTS AND METHODS: An electronic search was conducted using PubMed/MEDLINE and EMBASE. The methodological quality of the included studies was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. All analyses were performed on Stata version 12.0 and Meta-DiSc version 1.4. RESULTS: Twenty articles containing 1170 patients were identified. On a patient basis, the pooled sensitivity, specificity, and the area under the summary receiver operating characteristic curve of F-fluoride PET or PET/CT were 92% (95% confidence interval [CI], 89%-95%), 93% (95% CI, 91%-95%), and 0.985, respectively. On a lesion basis, the pooled sensitivity, specificity, and area under the summary receiver operating characteristic curve of F-fluoride PET or PET/CT were 87% (95% CI, 85%-88%), 95% (95% CI, 94%-96%), and 0.979, respectively. When compared with Tc-MDP bone scintigraphy, F-fluoride PET or PET/CT showed both higher sensitivity (96% vs. 88%, P = 0.002) and specificity (91% vs. 80%, P = 0.001). When compared with F-FDG PET/CT, F-fluoride PET/CT showed higher sensitivity (94% vs. 73%, P = 0.003), whereas no significant difference was observed in specificity (88% vs. 98%, P = 0.06). CONCLUSIONS: F fluoride PET or PET/CT has an excellent diagnostic capacity for the detection of bone metastases and shows advantages when compared with Tc-MDP bone scintigraphy and F-FDG PET/CT. PMID- 25290291 TI - Ipilimumab-induced hepatitis on 18F-FDG PET/CT in a patient with malignant melanoma. AB - A 78-year-old man with metastatic malignant melanoma underwent a restaging 18F FDG PET/CT after initiation of ipilimumab therapy, a Food and Drug Administration approved human monoclonal antibody targeting CTLA-4. PET/CT demonstrated intense FDG uptake fusing to poorly circumscribed hypodensities throughout the liver. Patient was experiencing high-grade fever, chills, and generalized fatigue at the time of imaging, as well as mildly elevated liver function tests. Patient was subsequently treated with corticosteroids for suspected ipilimumab-induced hepatitis, and the patient rapidly improved clinically. Follow-up PET/CT 2 months later revealed complete resolution of abnormal FDG uptake in the liver, confirming the diagnosis of ipilimumab-induced hepatitis. PMID- 25290292 TI - Localization of parathyroid adenoma by 11C-choline PET/CT: preliminary results. AB - PURPOSE: This prospective pilot study was aimed to evaluate 11C-choline PET/CT (choline) as a tool for localization of parathyroid adenoma (PTA). METHODS: Forty patients with biochemical hyperparathyroidism underwent choline and 99mTc-MIBI imaging within a median interval of 56 days. Choline and MIBI images were analyzed and correlated with each other, with additional modalities such as ultrasound, CT, MRI, and with surgical findings, when available. RESULTS: Thirty seven of forty cases were choline-positive, and 3 were choline-negative. Choline uptake on PET was identified with corresponding nodules on CT of the PET/CT, yielding precise localization. Twenty of thirty-seven foci were located in typical sites in the neck, and 17 were ectopic. Clear visualization of PTA was achieved in 33 of 37, whereas findings in 4 cases were suspicious for PTA. MIBI was positive in 33 of 40 cases (22 clearly positive, 11 suspicious). In 29 of 40 cases, choline and MIBI were concordant, but choline findings were clearer in 9 of these 29 studies.At the time of writing, 27 patients had undergone surgery. In 24 cases, there was complete matching of choline with surgical findings of PTA. Overall in 23 cases, both choline and MIBI matched surgical findings of PTA. In 1 case, PTA was correctly localized on choline but not on MIBI, and in 2 cases, neither choline nor MIBI corresponded to the surgical findings. CONCLUSIONS: These preliminary results indicate that the combined functional and anatomical modality of choline PET/CT is a promising tool for PTA localization, providing clearer images than MIBI, equal or better accuracy, and quicker and easier acquisition. PMID- 25290293 TI - FDG uptake in liposclerosing myxofibrous tumor causes upstaging of Hodgkin lymphoma. AB - A 22-year-old woman with Hodgkin lymphoma underwent a staging 18F-FDG PET/CT scan, which showed an intense uptake in the right proximal femur, in addition to FDG-avid mediastinal and cervical lymph nodes. The patient thus was diagnosed with stage IV lymphoma with bone marrow involvement. Postchemotherapy restaging scan showed complete resolution of nodal uptake but persistent activity in the right femur. Radiography and biopsy confirmed liposclerosing myxofibrous tumor. PMID- 25290294 TI - Correlation between 123I-FP-CIT brain SPECT and parkinsonism in dementia with Lewy bodies: caveat for clinical use. AB - INTRODUCTION: Although parkinsonism is considered a core feature of dementia with Lewy bodies (DLB), it is occasionally mild or even absent. I-FP-CIT SPECT has been accepted as a diagnostic support tool in this context, given that low striatal uptake is associated with neuronal loss. The aim of this retrospective study was to look for correlations between I-FP-CIT uptake in the striatum and clinical extrapyramidal signs (EPSs) in patients with a diagnosis of probable DLB to clarify the extent to which the supporting role of I-FP-CIT is related to motor impairment. METHODS: Semiquantitative I-FP-CIT uptake was analyzed and correlated with Unified Parkinson Disease Rating Scale Part III scores in a sample of 22 patients with a diagnosis of probable DLB and a wide range of EPSs. RESULTS: A significant negative linear correlation between I-FP-CIT uptake and Unified Parkinson Disease Rating Scale Part III score was found both in the caudate and the putamen (r = -0.69 and -0.72, respectively, P < 0.001). Striatal uptake in patients with no or questionable EPS was comparable to that recorded in normal age-matched subjects (99% [22%] in the putamen) but significantly reduced in those with mild and severe EPS (43% [35%] and 30% [17%], respectively, P < 0.0001, but P = nonsignificant between mild and severe EPS). CONCLUSIONS: SPECT may be redundant when there are no doubts about the parkinsonism (ie, when it is absent or unequivocally present), but it may be helpful in identifying presynaptic nigrostriatal degeneration in patients with mild EPSs. PMID- 25290295 TI - Tips for a physician in getting the right job, part XVIII: rejections and offers. AB - If the candidate for a job is rejected, the individual should not necessarily be discouraged. It may be that the position was particularly competitive or that there were factors beyond the control of the applicant. However, it is important that the candidate carefully considers all aspects of the application and interview process for that position to see if anything could be learned from the process. If the applicant is not successful in being given a job offer for multiple positions, then there must be a careful analysis of the reasons. It could be caused by training, communication issues, a competitive job market especially in that location, a problematic job record, and so on. If the job seeker is given an offer of employment, it is important to carefully consider all aspects of the offer and consider respectful, professional negotiations on some items. PMID- 25290296 TI - Female mate choice predicts paternity success in the absence of additive genetic variance for other female paternity bias mechanisms in Drosophila serrata. AB - After choosing a first mate, polyandrous females have access to a range of opportunities to bias paternity, such as repeating matings with the preferred male, facilitating fertilization from the best sperm or differentially investing in offspring according to their sire. Female ability to bias paternity after a first mating has been demonstrated in a few species, but unambiguous evidence remains limited by the access to complex behaviours, sperm storage organs and fertilization processes within females. Even when found at the phenotypic level, the potential evolution of any mechanism allowing females to bias paternity other than mate choice remains little explored. Using a large population of pedigreed females, we developed a simple test to determine whether there is additive genetic variation in female ability to bias paternity after a first, chosen, mating. We applied this method in the highly polyandrous Drosophila serrata, giving females the opportunity to successively mate with two males ad libitum. We found that despite high levels of polyandry (females mated more than once per day), the first mate choice was a significant predictor of male total reproductive success. Importantly, there was no detectable genetic variance in female ability to bias paternity beyond mate choice. Therefore, whether or not females can bias paternity before or after copulation, their role on the evolution of sexual male traits is likely to be limited to their first mate choice in D. serrata. PMID- 25290297 TI - Lymphopoiesis and lymphokines. PMID- 25290298 TI - On getting a T-cell clone and being assured you have one. AB - Cellular immunology has for years been plagued by the heterogeneity in function and specificity of antigen recognition present within the populations of lymphocytes available for study. The ability to clone single T cells from those populations is therefore a most useful technology because the progeny in any one clone will be of a single functional subtype and, at the very least, will have the great specificity associated with monoclonality. Cloning is being widely used to push forward our understanding of both the antigens that elicit response and the cells that respond. My purpose here, however, is not to review those very exciting applications but rather to address the sometimes thorny issues of the definition of clonality, how it is achieved, and the circumstances in which 'proof' of clonality is or is not essential to the interpretation of data. PMID- 25290299 TI - Richard keeve gershon (1932-1983). PMID- 25290300 TI - On the necessity of the idiotype network: studies with nude mice. AB - jerne suggested that a quintessentialfeature of the immune system was the recognition of self-idiotypes(1,2). Despite intense interest and investigation, the concept remains a hypothesis. Here the authors discuss data which place in question the necessity of an idiotype network. PMID- 25290301 TI - Dietary regulation of the autoimmune process in murine lupus. PMID- 25290302 TI - The efficiency of complement activation in MHC-linked diseases. PMID- 25290303 TI - Suppressor B lymphocytes. AB - B cells can influence an immune response in an antigen-specific manner by generating antibody which shuts down the response through negativefeedback. But there is growing evidence that B cells can also act upon antibody production as non-specific suppressor cells. Kathleen Gilbert and Michael Hoffnann here review this often overlooked aspect of immunoregulation. PMID- 25290304 TI - Cell-surface molecules involved in T-cell functions. AB - A complete understanding of immune response mechanisms requires both identification of the cellular subpopulations participating in a given response and elucidation of the antigen-specific receptors employed by these cells. A great deal of recent study has been directed at the characterization of T-cell subpopulations and the receptor structures expressed by these cells. Perhaps the most powerful tools so far employed have been the serological reagents which distinguish cell-surface molecules on lymphoid populations. In this review, Jeffrey Bluestone and Richard Hodes summarize our understanding of the surface molecules expressed on functionally distinct T-cell subpopulations, and the role of these molecules in antigen-specific T-cell activation. PMID- 25290305 TI - Delayed-type hypersensitivity: activation of mast cells by antigen-specific T cell factors initiates the cascade of cellular interactions. AB - In delayed-type hypersensitivity reactions sensitized T cells orchestrate a cascade of cellular interactions. Initiation of these responses depends on a newly recognized event, namely the release of vasoactive mediators fiom mast cells that are activated by antigen-specific T-cell-derivedfactors. Here Philip Askenase and Henk Van Loveren discuss how this event initiates a sequence of steps that lead to T-cell recruitment of effector cells; and how this event differs from activation of mast cells by IgE antibody. They also suggest that the conventional time-based separation of immediate and delayed hypersensitivity should be replaced by a classcation based on the type of antigen-specific lymphocyte - B or T-responsible for the effects of hypersensitivity. PMID- 25290312 TI - Genome-wide identification and tissue-specific expression analysis of UDP glycosyltransferases genes confirm their abundance in Cicer arietinum (Chickpea) genome. AB - UDP-glycosyltransferases (EC 2.4.1.x; UGTs) are enzymes coded by an important gene family of higher plants. They are involved in the modification of secondary metabolites, phytohormones, and xenobiotics by transfer of sugar moieties from an activated nucleotide molecule to a wide range of acceptors. This modification regulates various functions like detoxification of xenobiotics, hormone homeostasis, and biosynthesis of secondary metabolites. Here, we describe the identification of 96 UGT genes in Cicer arietinum (CaUGT) and report their tissue specific differential expression based on publically available RNA-seq and expressed sequence tag data. This analysis has established medium to high expression of 84 CaUGTs and low expression of 12 CaUGTs. We identified several closely related orthologs of CaUGTs in other genomes and compared their exon intron arrangement. An attempt was made to assign functional specificity to chickpea UGTs by comparing substrate binding sites with experimentally determined specificity. These findings will assist in precise selection of candidate genes for various applications and understanding functional genomics of chickpea. PMID- 25290311 TI - Nucleolin down-regulation is involved in ADP-induced cell cycle arrest in S phase and cell apoptosis in vascular endothelial cells. AB - High concentration of extracellular ADP has been reported to induce cell apoptosis, but the molecular mechanisms remain not fully elucidated. In this study, we found by serendipity that ADP treatment of human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC) down regulated the protein level of nucleolin in a dose- and time-dependent manner. ADP treatment did not decrease the transcript level of nucloelin, suggesting that ADP might induce nucleolin protein degradation. HUVEC and HAEC expressed ADP receptor P2Y13 receptor, but did not express P2Y1 or P2Y12 receptors. However, P2Y1, 12, 13 receptor antagonists MRS2179, PSB0739, MRS2211 did not inhibit ADP induced down-regulation of nucleolin. Moreover, MRS2211 itself down-regulated nucleolin protein level. In addition, 2-MeSADP, an agonist for P2Y1, 12 and 13 receptors, did not down-regulate nucleolin protein. These results suggested that ADP-induced nucleolin down-regulation was not due to the activation of P2Y1, 12, or 13 receptors. We also found that ADP treatment induced cell cycle arrest in S phase, cell apoptosis and cell proliferation inhibition via nucleolin down regulation. The over-expression of nucleolin by gene transfer partly reversed ADP induced cell cycle arrest, cell apoptosis and cell proliferation inhibition. Furthermore, ADP sensitized HUVEC to cisplatin-induced cell death by the down regulation of Bcl-2 expression. Taken together, we found, for the first time to our knowledge, a novel mechanism by which ADP regulates cell proliferation by induction of cell cycle arrest and cell apoptosis via targeting nucelolin. PMID- 25290313 TI - Association between the PNPLA3 I148M polymorphism and non-alcoholic fatty liver disease in the Uygur and Han ethnic groups of northwestern China. AB - OBJECTIVE: Multiple common gene variants play a role in non-alcoholic fatty liver disease (NAFLD) susceptibility. Our goal was to investigate the association between variants polymorphisms and NAFLD in the Uygur and Han from Northwestern China. METHODS: Eight tag single nucleotide polymorphisms (tSNPs) previously reported to be associated with NAFLD were characterized in 396 NAFLD individuals and 399 controls. The association of variants with NAFLD in the Uygur and Han was assessed using the chi-squared (chi2) test in different gene models. Unconditional logistic regression analysis was performed to obtain the odds ratios (ORs) for risk of NAFLD and their 95% confidence intervals (CI), adjusted for confounding factors. Finally, stratified analysis was used to explore the potential gene-environment interactions on the risk of NAFLD. RESULTS: In a recessive model, we found a potential association between rs738409 and NAFLD in both ethnic groups: Chinese Han (OR = 1.84, 95% CI: 1.03-3.27, p = 0.036), Uygur (OR = 2.25, 95% CI: 1.23-4.09, p = 0.006). The multiple logistic regression revealed that PNPLA3 rs738409 GG genotype may increase the risk of NAFLD by adjusting some confounding factors: Han (OR = 5.22, 95% CI: 1.94-14.04, p = 0.001), Uygur (OR = 4.29, 95% CI: 1.60-11.48, p = 0.004). Stratified analysis found that rs738409 polymorphism appeared to have interaction with sex, smoking status in Uygur, and have interaction with sex, age, BMI stage, lifestyle in Han. CONCLUSION: Our data suggest the PNPLA3 I148M polymorphism influences susceptibility to NAFLD in the Han and Uygur of Northwestern China. PMID- 25290314 TI - Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients. AB - BACKGROUND & AIMS: The BCLC-staging system is used to facilitate treatment decisions in patients with hepatocellular carcinoma (HCC). Owing to the observed clinical heterogeneity of the intermediate stage BCLC-B, a subclassification was proposed taking Child-Pugh score and extended criteria for transplantation into account. Analysis of the prognostic significance of a proposed subclassification of the BCLC-B score in a European cohort of HCC patients. METHODS: Eight hundred and eighty four consecutive HCC patients were retrospectively analysed. Patients with stage BCLC-B were grouped according to the proposed subclassification. Baseline patient and tumour characteristics, therapy and overall survival were analysed. RESULTS: Two hundred and fifty four patients with stage BCLC-B were classified as B1/B2/B3 and B4 in 16.1/56.7/7.9 and 19.3%. OS compared between adjacent subgroups (B1 vs. B2, B2 vs. B3, B3 vs. B4) did not reach statistical significance. Groupwise comparison showed significant differences between B1 vs. B3 (P = 0.035), B1 vs. B4 (P = 0.006) and B2 vs. B4 (P < 0.0001). OS was significantly improved in patients undergoing OLT (P < 0.0001). Cox regression showed no significant influence of the BCLC-B substage on survival. CONCLUSIONS: No significant survival differences between subgroups were found in the retrospective analysis. We could not confirm the BCLC-B subclassification to be prognostically meaningful in our cohort. As liver function and therapy influenced survival in this study, a more refined BCLC-B subclassification has the potential to be a useful tool to better stratify treatment decisions. Further studies in larger collectives with homogenous staging and treatment strategies are warranted to confirm the prognostic significance of the proposed subclassifications. PMID- 25290315 TI - Aspirin desensitization as a treatment for aspirin-sensitive chronic spontaneous urticaria. PMID- 25290318 TI - Histocompatibility 1984. AB - It is twenty years and nine workshops on from the first international gathering of tissue typers in Durham, North Carolina. The size and range of the series of meetings centred on this year's workshop show the success achieved by the unique collaboration of workers in the HLA field. The main workshop meeting in Munich, organized by Ekkehard Albert and Wolfgang Mayr, was preceded by the third H-2 and HLA cloning meeting, organized by Jean Dausset in Strasbourg and by a biochemistry workshop in Munich organized by Julia and Walter Bodmer and Michael Crumpton. The workshop was then followed by a conference in Vienna which demonstrated, by the selection of papers presented, the increasing importance of molecular and biochemical studies in the understanding of the HLA region of chromosome 6, its function and relationship to disease. PMID- 25290317 TI - The role of social support among people living with HIV in rural Mozambique. AB - A Positive Health, Dignity, and Prevention framework is being implemented in Mozambique to maintain the health of persons living with HIV (PLHIV) and prevent onward HIV transmission. An important intervention component is psycho-social support. However, coordinating support services has been challenging. Seventy in depth individual interviews were conducted with PLHIV between January and June 2010 in three rural provinces to clarify the receipt and provision of support by PLHIV. Thematic coding and analysis were conducted to identify salient responses. PLHIV reported that the majority of social support received was instrumental, followed by emotional and informational support. Instrumental support included material, medical, and financial assistance. Emotional support was mentioned less frequently and was supplied most by family and friends. PLHIV also received informational support from a variety of sources, the most common being family members. Informational support from health providers was rarely mentioned, but this advice was valued and used to educate others. Although most participants described receiving social support from many sources, there were consistently identified needs. This study revealed that social support is central in the lives of PLHIV and identified areas where social support can be improved to better respond to the needs of PLHIV in the Mozambican context. PMID- 25290319 TI - Lytic granules, adhesion molecules, and other recent insights. AB - Probably the most exciting of the insights into the mechanism of cell-mediated lysis reported at a recent workshop was the cytolytic activity detected in granule preparations from large granular lymphocytes with natural killer activity, tumor cells and cloned lines of cytotoxic lymphocytes (TC). For the first time, several labs agree on the existence of cell-free mediators with properties which make them attractive candidates for the lytic effector molecules employed by TC as well as NK cells. Such results were reported by Pierre Henkart (NIH, Bethesda), Eckhard Podack (New York Medical College, Valhalla), and john Ding-E Young (Rockefeller Univ., New York). At sufficient concentrations, these granule preparations can effect complete lysis of P815 or EL4 tumor cell populations within minutes. PMID- 25290320 TI - Sponsoring science - successfully? PMID- 25290321 TI - Repulsive MHC restriction. PMID- 25290322 TI - The basis of autoimmunity in MRL-lpr/lpr mice and man. PMID- 25290323 TI - T-cell suppression of human antibody responses: specific or non-specific? AB - Although 'disorders of immunoregulation' are thought to be characteristic of a variety of human diseases, Robin Callard argues here that this conclusion is too often readily drawn from investigations which measured non-specific rather than antigen-induced, antigen-speck suppression. PMID- 25290324 TI - The effect of gamma-interferon on MHC antigens. PMID- 25290325 TI - Major histocompatibility complex molecules as virus receptors. PMID- 25290326 TI - Limiting dilution analysis of the cells of immune system I. The clonal basis of the immune response. PMID- 25290327 TI - Infectious disease, fever, and the immune response. AB - Fever is a characteristic response to infection in almost all vertebrates. Its function appears to be the restriction of infectious agents' replication and the enhancement of host resistance. Here Bob Ashman and Arno Mullbacher discuss fever and examine the effects of raised temperature on aspects of the immune response. PMID- 25290328 TI - Immunologic surveillance and human papillomaviruses. AB - Papillomaviruses, the cause of warts, are the oldest known human tumor viruses. Here Holger Kirchner reviews the evidence for immunosurveillance against human papillomaviruses and concludes that surveillance mechanisms may also operate against the tumors that these viruses induce. PMID- 25290331 TI - Impact of psychoendocrine systems in cancer and immunity edited by Bernard H. Fox and Benjamin H. Newberry, C f. Hogrefe Inc., 1984. US $36. 00(xi +314pages)ISBN0889370052. PMID- 25290334 TI - Conversion of phenyl methyl ethers by Desulfitobacterium spp. and screening for the genes involved. AB - Microbial growth coupled to O-demethylation of phenyl methyl ethers, which are lignin decomposition products, was described for acetogenic bacteria and recently also for two species belonging to the nonacetogenic genus Desulfitobacterium. To elucidate the potential role of desulfitobacteria in the O-demethylation of phenyl methyl ethers in the environment, we cultivated Desulfitobacterium chlororespirans, D. dehalogenans, D. metallireducens, and different strains of D. hafniense with phenyl methyl ethers as sole electron donors. With the exception of D. metallireducens, all species and strains tested were able to demethylate at least three of the four phenyl methyl ethers applied with fumarate, nitrate, or thiosulfate as electron acceptor. Furthermore, a high number of operons putatively encoding demethylase systems were identified in the genomes of Desulfitobacterium spp., although discrimination between O-, S-, N- and, Cl demethylases was not possible. These findings provide evidence for the importance of the methylotrophic metabolism for desulfitobacteria and point to their involvement in the O-demethylation of phenyl methyl ethers in the environment. PMID- 25290335 TI - Structure of adsorption layer of silver nanoparticles in sodium bis(2-ethylhexyl) sulfosuccinate solutions in n-decane as observed by photon-correlation spectroscopy and nonaqueous electrophoresis. AB - Photon correlation spectroscopy, nonaqueous electrophoresis, and transmission electron microscopy were used to study the structure of silver nanoparticles (NPs) in n-decane, as a dependence of the concentration of sodium bis(2 ethylhexyl) sulfosuccinate (AOT) and temperature. If the concentration of AOT is lower than the critical micelle concentration (CMC), a silver NP is covered with a monolayer of AOT and reveals no electrophoretic mobility. At average concentrations (from CMC to 0.1 M) the hydrodynamic diameter of a NP does not change, but the zeta-potential increases from 0 to 110 mV. When the concentration of AOT increases from 0.1 to 1 M, zeta potential drops to 13 mV, and the hydrodynamic diameter increases to 90 nm. An increase in temperature to 70 degrees C leads to a reversible decrease in diameter to 40 nm. The hypothesis of clustering (polylayer adsorption) of "empty" micelles on silver NPs is proposed for the qualitative interpretation of the experimental data. PMID- 25290336 TI - Alzheimer's disease and epigenetic diet. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease. Many efforts have been directed to prevent AD due to its rising prevalence and the lack of an effective curative treatment. Various epigenetic mechanisms are linked to pathogenesis of AD. Epigenetic alterations may occur through external factors and are known for their reversibility. Dietary factors can influence epigenetic mechanisms. Several neuroprotective nutrients have been shown to enhance cognition, memory and other impaired functions seen in AD. Within recent years neuroprotective nutrients have gained more attention in the field of epigenetic. A growing body of evidence suggest that epigenetic changes triggered by dietary nutrients have an important role in health and in prevention of some diseases, especially neurodegenerative disorders. Several studies have shown that folic acid, vitamin B12, choline, zinc, selenium, dietary polyphenols are capable of interacting with epigenetic mechanisms and ultimately gene expression. Epigenetic mechanisms resulting in neuronal dysfunction may be modified by diet. Therefore manipulation of epigenetic mechanisms via dietary nutrients may affect influence the vulnerability of neurons to degeneration which is seen in AD. The aim of this article is to provide a brief overview about the recent findings related to epigenetic alterations that are linked to AD pathogenesis, and to discuss the bioactive nutrients which can affect these epigenetic mechanisms. PMID- 25290337 TI - Advanced visualization and visual analytics: general discussion. PMID- 25290338 TI - Surgical decompression of painful diabetic peripheral neuropathy: the role of pain distribution. AB - OBJECTIVE: To investigate the effect of surgical decompression on painful diabetic peripheral neuropathy (DPN) patients and discuss the role which pain distribution and characterization play in the management of painful DPN as well as the underlying mechanism involved. METHODS: A total of 306 patients with painful diabetic lower-extremity neuropathy were treated with Dellon surgical nerve decompression in our department. Clinical evaluation including Visual analogue scale (VAS), Brief Pain Inventory Short Form for diabetic peripheral neuropathy (BPI-DPN) questionnaire, two-point discrimination (2-PD), nerve conduction velocity (NCV) and high-resolution ultrasonography (cross-sectional area, CSA) were performed in all cases preoperatively, and at 6 month intervals for 2 years post-decompression. The patients who underwent surgery were retrospectively assigned into two subgroups (focal and diffuse pain) according to the distribution of the diabetic neuropathic pain. The control group included 92 painful DPN patients without surgery. RESULTS: The levels of VAS, scores in BPI DPN, 2-PD, NCV results and CSA were all improved in surgical group when compared to the control group (P<0.05). More improvement of VAS, scores in BPI-DPN and CSA was observed in focal pain group than that in diffuse group (P<0.05). CONCLUSIONS: Efficacy of decompression of multiple lower-extremity peripheral nerves in patients with painful diabetic neuropathy was confirmed in this study. While both focal and diffuse group could benefit from surgical decompression, pain relief and morphological restoration could be better achieved in focal group. PMID- 25290339 TI - Case based measles surveillance in Pune: evidence to guide current and future measles control and elimination efforts in India. AB - BACKGROUND: According to WHO estimates, 35% of global measles deaths in 2011 occurred in India. In 2013, India committed to a goal of measles elimination by 2020. Laboratory supported case based measles surveillance is an essential component of measles elimination strategies. Results from a case-based measles surveillance system in Pune district (November 2009 through December 2011) are reported here with wider implications for measles elimination efforts in India. METHODS: Standard protocols were followed for case identification, investigation and classification. Suspected measles cases were confirmed through serology (IgM) or epidemiological linkage or clinical presentation. Data regarding age, sex, vaccination status were collected and annualized incidence rates for measles and rubella cases calculated. RESULTS: Of the 1011 suspected measles cases reported to the surveillance system, 76% were confirmed measles, 6% were confirmed rubella, and 17% were non-measles, non-rubella cases. Of the confirmed measles cases, 95% were less than 15 years of age. Annual measles incidence rate was more than 250 per million persons and nearly half were associated with outbreaks. Thirty-nine per cent of the confirmed measles cases were vaccinated with one dose of measles vaccine (MCV1). CONCLUSION: Surveillance demonstrated high measles incidence and frequent outbreaks in Pune where MCV1 coverage in infants was above 90%. Results indicate that even high coverage with a single dose of measles vaccine was insufficient to provide population protection and prevent measles outbreaks. An effective measles and rubella surveillance system provides essential information to plan, implement and evaluate measles immunization strategies and monitor progress towards measles elimination. PMID- 25290340 TI - Cost-effectiveness of HIV drug resistance testing to inform switching to second line antiretroviral therapy in low income settings. AB - BACKGROUND: To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations being identified. METHODS: An individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa. Underlying monitoring strategies considered were based on clinical disease, CD4 count or viral load. Within each we considered a strategy in which no further measures are performed, one with a viral load measure to confirm failure, and one with both a viral load measure and a resistance test. Predicted outcomes were assessed over 2015-2025 in terms of viral suppression, first line failure, switching to second line regimen, death, HIV incidence, disability-adjusted-life-years averted and costs. Potential future low costs of resistance tests ($30) were used. RESULTS: The most effective strategy, in terms of DALYs averted, was one using viral load monitoring without confirmation. The incremental cost-effectiveness ratio for this strategy was $2113 (the same as that for viral load monitoring with confirmation). ART monitoring strategies which involved resistance testing did not emerge as being more effective or cost effective than strategies not using it. The slightly reduced ART costs resulting from use of resistance testing, due to less use of second line regimens, was of similar magnitude to the costs of resistance tests. CONCLUSION: Use of resistance testing at the time of first line failure as part of the decision whether to switch to second line therapy was not cost-effective, even though the test was assumed to be very inexpensive. PMID- 25290341 TI - Phenology and productivity of C3 and C4 grasslands in Hawaii. AB - Grasslands account for a large proportion of global terrestrial productivity and play a critical role in carbon and water cycling. Within grasslands, photosynthetic pathway is an important functional trait yielding different rates of productivity along environmental gradients. Recently, C3-C4 sorting along spatial environmental gradients has been reassessed by controlling for confounding traits in phylogenetically structured comparisons. C3 and C4 grasses should sort along temporal environmental gradients as well, resulting in differing phenologies and growing season lengths. Here we use 10 years of satellite data (NDVI) to examine the phenology and greenness (as a proxy for productivity) of C3 and C4 grass habitats, which reflect differences in both environment and plant physiology. We perform phylogenetically structured comparisons based on 3,595 digitized herbarium collections of 152 grass species across the Hawaiian Islands. Our results show that the clade identity of grasses captures differences in their habitats better than photosynthetic pathway. Growing season length (GSL) and associated productivity (GSP) were not significantly different when considering photosynthetic type alone, but were indeed different when considering photosynthetic type nested within clade. The relationship between GSL and GSP differed most strongly between C3 clade habitats, and not between C3-C4 habitats. Our results suggest that accounting for the interaction between phylogeny and photosynthetic pathway can help improve predictions of productivity, as commonly used C3-C4 classifications are very broad and appear to mask important diversity in grassland ecosystem functions. PMID- 25290342 TI - Optimizing hill seeding density for high-yielding hybrid rice in a single rice cropping system in South China. AB - Mechanical hill direct seeding of hybrid rice could be the way to solve the problems of high seeding rates and uneven plant establishment now faced in direct seeded rice; however, it is not clear what the optimum hill seeding density should be for high-yielding hybrid rice in the single-season rice production system. Experiments were conducted in 2010 and 2011 to determine the effects of hill seeding density (25 cm*15 cm, 25 cm*17 cm, 25 cm*19 cm, 25 cm*21 cm, and 25 cm*23 cm; three to five seeds per hill) on plant growth and grain yield of a hybrid variety, Nei2you6, in two fields with different fertility (soil fertility 1 and 2). In addition, in 2012 and 2013, comparisons among mechanical hill seeding, broadcasting, and transplanting were conducted with three hybrid varieties to evaluate the optimum seeding density. With increases in seeding spacing from 25 cm*15 cm to 25 cm*23 cm, productive tillers per hill increased by 34.2% and 50.0% in soil fertility 1 and 2. Panicles per m2 declined with increases in seeding spacing in soil fertility 1. In soil fertility 2, no difference in panicles per m2 was found at spacing ranging from 25 cm*17 cm to 25 cm*23 cm, while decreases in the area of the top three leaves and aboveground dry weight per shoot at flowering were observed. Grain yield was the maximum at 25 cm*17 cm spacing in both soil fertility fields. Our results suggest that a seeding density of 25 cm*17 cm was suitable for high-yielding hybrid rice. These results were verified through on-farm demonstration experiments, in which mechanical hill-seeded rice at this density had equal or higher grain yield than transplanted rice. PMID- 25290343 TI - Maternal oral mutans streptococci (MS) status, not breastfeeding, predicts predentate infant oral MS status. AB - The purpose of this study was to investigate infant oral mutans streptococci (MS) by feeding method and by the mother's oral MS status. For this cross-sectional data collection, full-term infants at 4-6 weeks of age and their mothers were tested for oral MS using the Dentocult((r)) SM chairside test (Orion Diagnostica, Espoo, Finland). For the 104 mother-infant pairs (68 breastfed, 36 formula-fed), the two groups differed by mother's race/ethnicity (p=0.006) but not by delivery mode, level of care at birth, or MS in the mothers or the infants. Thirty-one percent of mothers and 12% of infants were MS positive. Infant MS was not predicted by mother's race/ethnicity, delivery mode, feeding method, or MS status. When stratified by feeding method, the mother's MS status did significantly predict the infant's MS status in the breastfed group (odds ratio=5.97; 95% confidence interval, 1.06-33.7; p=0.043). In conclusion, oral MS at >10(4) colony-forming units/mL were detected in 12% of the 4-6-week-old infants, and the effect of the mothers' oral MS status was modified by the feeding method. Future research is needed to clarify the modifiable perinatal and maternal risks associated with the development of the infant's predentate oral microbial environment, before the introduction of the first tooth. PMID- 25290344 TI - Formal comment to Gong et al.: Ecosystem scale acoustic sensing reveals humpback whale behavior synchronous with herring spawning processes and re-evaluation finds no effect of sonar on humpback song occurrence in the Gulf of Maine in fall 2006. PMID- 25290346 TI - Leptin: A hormone linking activation of neuroendocrine axes with neuropathology. AB - Leptin, a peptide hormone secreted by adipocytes, plays a central role in controlling appetite and weight in both rodents and humans. Basic science and clinical research suggest that this hormone not only affects the regulation of the neuroendocrine axes, but also exerts effects on the central nervous system with subsequent alterations in psychological functions. For instance, leptin suppresses cortisol secretion during stress-related activation of the adrenal axis. As psychiatric disorders like depression are associated with hypercortisolism, leptin is proposed to exert anti-depressant-like effects due to its inhibition of chronically overactive hypothalamo-pituitary-adrenal axis function. Moreover, leptin status of depressed patients could serve as a prognostic marker for therapy response. Besides its influence on neuroendocrine pathways leptin seems to have direct central effects on brain development and neuroplasticity. Low leptin levels have been shown to be associated with increased risk of developing dementia, supporting the idea of a pro-cognitive effect of leptin. These areas may have direct clinical implications and deserve to be studied further in the future. PMID- 25290345 TI - An experimental study of the job demand-control model with measures of heart rate variability and salivary alpha-amylase: Evidence of increased stress responses to increased break autonomy. AB - We assessed in an experimental design whether the stress response towards a work task was moderated by the autonomy to choose a break during the assigned time to complete the task. This setting is defined in accordance with the theoretical framework of the job-demand-control (JDC) model of work related stress. The findings from naturalistic investigations of a stress-buffering effect of autonomy (or 'buffer hypothesis') are equivocal and the experimental evidence is limited, especially with relation to physiological indices of stress. Our objective was to investigate if increased autonomy in a particular domain (break time control) was related with adaptive physiology using objective physiological markers of stress; heart rate variability (HRV) and salivary alpha amylase (sAA). We used a within-subject design and the 60 female participants were randomly assigned to an autonomy (free timing of break) and standard conditions (fixed timing of break) of a word processing task in a simulated office environment in a random order. Participants reported increased perceptions of autonomy, no difference in demand and performed worse in the task in the break-time autonomy versus the standard condition. The results revealed support for the manipulation of increased autonomy, but in the opposing direction. Increased autonomy was related with dysregulated physiological reactivity, synonymous with typical increased stress responses. Potentially, our findings may indicate that autonomy is not necessary a resource but could become an additional stressor when it adds additional complexity while the amount of work (demands) remains unchanged. Further, our findings underscore the need to collect objective physiological evidence of stress to supplement self-reported information. Self-report biases may partially explain the inconsistent findings with the buffer hypothesis. PMID- 25290347 TI - Blunted endocrine and cardiovascular reactivity in young healthy women reporting a history of childhood adversity. AB - BACKGROUND: Chronic or prolonged stress exposure in childhood can alter structural and functional brain development, leading to mental and physical illness and alterations of psychobiological stress systems in adulthood. Recently, attenuation in stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and cardiovascular system have been related to the number of adverse childhood experiences (ACEs). We set out to investigate the association of ACE duration and age of ACE occurrence on stress reactivity. METHODS: 104 women in the age range 18-25 years (mean=21.7) free of mental and physical illness underwent psychosocial stress testing with the Montreal Imaging Stress Task (MIST). Free saliva cortisol and heart rate were assessed repeatedly before and after the MIST. RESULTS: Number of ACEs was associated with attenuated cortisol and heart rate responses to stress in a dose-response relationship. Whereas overall duration of ACEs was significantly associated with an attenuated cortisol response, the specific age of first ACE occurrence did not contribute further to the dampened stress response. CONCLUSIONS: ACEs are associated with blunted endocrine and cardiovascular stress reactivity in young and healthy women. Adverse life events in childhood, particularly if they occur repeatedly and chronically, show a strong association with alterations in stress reactivity in adulthood, potentially predisposing for later mental or physical disorders. PMID- 25290348 TI - Psychobiological stress response to a simulated school shooting in police officers. AB - INTRODUCTION: Police work is one of the most demanding professions with various sources of high occupational stress. Among the most demanding tasks are amok situations, such as school shootings. Hardly anything is known about endocrine and cardiovascular markers in safety professionals during emergency situations in real life and how this relates to stress perception and management. This study will therefore explore police officers' stress responses to a reality-based school shooting simulation assessing neuroendocrine, cardiovascular, and psychological stress markers. METHODS: A convenience sample of 50 police officers (39.5 +/- 8.7 yrs, 9 women) participating in a basic or refresher amok training session for the German uniformed and criminal police were recruited. Saliva samples were collected shortly before the simulation task (school shooting), immediately after, 20 and 45 min after finishing the task for the assessment of cortisol and alpha-amylase (sAA), as markers of the hypothalamic-pituitary adrenal axis and the autonomic nervous system, respectively. Heart rate (variability) was assessed continuously. Officers rated their actual mood right before and 10 min after the simulation. Subjective experience of task stressfulness was assessed minutes after finishing the simulation. RESULTS: Overall, the simulated school shooting did not result in changes of mood, tiredness, or calmness but higher restlessness was experienced during the basic training, which was also experienced as more controllable. Female officers reported to experience more strain and anxiety. Cortisol showed highest levels at the beginning of the training and steadily decreasing values thereafter. In contrast, sAA increased substantially right after the simulation with officers on the front position showing most pronounced changes. Cardiovascular reactivity was highest in officers acting on the side positions while advancing to find the suspect. Furthermore higher self-efficacy as well as, by trend, controllability and relevance of results correlated with cardiovascular measures. DISCUSSION: Autonomic but not endocrine stress markers increased to a simulated school shooting, which were further related to the subjective experience of the simulation. Our results provide a more in-depth picture of stress responses in such situations, which will in the long run raise the possibility to refine training programs, design more effective stress-management strategies for these critical incidents, and improve performance but also coping with work-related stress. PMID- 25290350 TI - HLA A, B, DR and endothelial-specific antigens in kidney-graft rejection. PMID- 25290349 TI - Eustachian tube and internal carotid artery in skull base surgery: an anatomical study. AB - OBJECTIVES/HYPOTHESIS: The eustachian tube (ET) is an important landmark in skull base surgery, which has a close relationship with the petrous segment of the internal carotid artery (ICA). The goal of the current study was to establish the detailed anatomic relationship of the ET and petrous segment of the ICA. STUDY DESIGN: Anatomical study. METHODS: Six silicon-injected adult cadaveric heads (12 sides) were dissected using a lateral infratemporal fossa approach (type C) and endoscopic endonasal approach. The ET and ICA were exposed; their detailed relationships were demonstrated. High-quality pictures were obtained. RESULTS: In the anterior genu/foramen lacerum segment of the ICA, the vidian nerve was an important landmark. The cartilaginous ET was divided into four segments, from anterior to posterior: nasopharyngeal, pterygoid, lacerum, and petrosal segment. The anterior and inferior wall of the carotid canal was consistently between the horizontal ICA and petrous segment of the cartilaginous ET. In the posterior genu of the ICA, the bony part of the ET, and the tendon of the tensor tympani muscle were paramount landmarks. The posterior genu of the ICA was imbedded in the carotid canal. The landmarks of the junction of the cartilaginous ET and bony ET were the sphenoid spine and foramen spinosum. CONCLUSIONS: The anatomical segmentation of the ET provides the basis for safe and effective transection of the ET in skull base surgery. An understanding of the complex relationships of the ET and petrous segment of the ICA is paramount for surgically dealing with disease located within the region of the ET and petrous segment of the ICA. LEVEL OF EVIDENCE: NA PMID- 25290351 TI - Auto-oxidation and neutrophil function. PMID- 25290352 TI - Circulating immune complexes in infectious tropical diseases. PMID- 25290353 TI - T-cell growth factors: interleukin 2. AB - One of the key aspects of immunoregulation is the ability of T-cell subpopulations to help or suppress the expression of antigen-sensitive lymphocytes. The cloning of lymphoid cells - usually neoplastic cells - has long been a basic approach to the analysis of cellular function within the immune system but in the investigation of how T-cells act, T-cell lymphoma lines have been of limited value because the antigen specificity of their effector functions could not be detected. Now, however, lymphokines have been isolated which permit the growth of continuous lines of human and mouse T-cells with known specificity for antigen(2-8). In this review, James Watson and his colleagues discuss these lymphokines and some of the outstanding questions about their nature and function. PMID- 25290354 TI - Biochemistry of major human histocompatibility antigens. AB - The major histocompatibility region, designated HLA in man and H-2 in the mouse, controls the expression of at least three groups of gene product - serum complement components and two sets of highly polymorphic cell-surface antigens, the so called histocompatibility antigens. In this review Michael Owen and Michael Crumpton describe some recent insights into the biochemical structure of HLA antigens. PMID- 25290355 TI - New methods of analysing for antigens and glycoproteins in complex mixtures. AB - The analysis of complex mixtures of proteins and particularly those which make up macromolecular assemblies including membranes, received a major fillip in the late 1960s with the introduction of sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The resolving power of electrophoresis in polyacrylamide gels is considerably superior to that achieved with any other support medium including agar, the immunochemist's standby. The essential physical property which makes polyacrylamide the medium of choice is the limiting pore size of the gel: its sieving effect on the movement of macromolecules and the reduction of diffusion together result in increased sharpness of bands. On the other hand, in all the standard immunochemical techniques such as immunodiffusion, immunoelectrophoresis, and rockets, free diffusion of protein molecules in the support medium is essential and agar or agarose satisfy this requirement. There has therefore been a search for ways in which polycrylamide gel electrophoresis, particularly SDS-gel electrophoresis of aggregates of proteins (as in membranes, viruses, the cellular cytoskeleton), can be adapted to immunochemical analysis of their constituent antigens. Here Brian Anderton and Robin Thorpe discuss several of the methods now in use. PMID- 25290356 TI - Characterization of the pattern of ribosomal protein L19 production during the lifecycle of Leishmania spp. AB - Leishmania is a genus of protozoan parasites causing a wide clinical spectrum of diseases in humans. Analysis of a region of chromosome 6 from Leishmania major (Iribar et al.) showed that the transcript of a putative L19 ribosomal protein (RPL19) was most abundant at the amastigote stage. We therefore decided to characterize L19 protein abundance throughout the lifecycle of Leishmania. Differential expression of the L19 gene during development has been observed for all Leishmania species studied to date (L. major, L. braziliensis, L. donovani, and L. amazonensis). Immunoblotting with polyclonal antibodies against L. major RPL19 revealed that changes to L19 protein abundance follow a similar pattern in various species. The amount of L19 protein was higher in exponentially growing promastigotes than in stationary phase promastigotes. The L19 protein was barely detectable in amastigotes, despite the abundance of L19 transcripts observed in L. major at this stage. Immunofluorescence assays showed a granular, dispersed distribution of RPL19 throughout the cytoplasm. Subcellular fractionation confirmed the presence of the protein in the ribosomal fraction, but not in the cytosol of L. major. We generated a L. major transfectant bearing a plasmid-borne L19 gene. Overproduction of the L19 transcript and protein resulted in impaired growth of the transfectants in association with high polysome peaks. We also showed by metabolic labeling that L19 overexpressing clones display low rates of translation. These data suggest that L19 overexpression affects negatively translation elongation or termination. The lack of correlation between L19 transcript and protein abundances suggest that the translation of L19 is differentially controlled during development in the various species investigated. PMID- 25290357 TI - Inhibitory effects of antibiotic combinations on syntrophic bacteria, homoacetogens and methanogens. AB - Antibiotics have the potential to adversely affect the microbial community that is present in biological wastewater treatment processes. The antibiotics that exist in waste streams directly inhibit substrate degradation and also have an influence on the composition of the microbial community. The aim of this study was to evaluate the short-term inhibition impact that various antibiotic combinations had on the syntrophic bacteria, homoacetogenic and methanogenic activities of a microbial community that had been fed with propionate and butyrate as the sole carbon source and VFA mixture (acetate, propionate and butyrate). Acute tests were constructed using on a two way-factorial design, where one factor was the composition of antibiotic mixture and another was the concentration of antibiotics added. In addition, the inhibitory effect of antibiotics was evaluated by monitoring biogas production and the accumulation of individual volatile fatty acids. Specific methanogenic activity batch tests showed a significant (p<0.05) decrease in the maximum methane production rate in the presence of 1 mg L(-1) of antibiotics for the substrate in a VFA mixture and propionate; 1 mg L(-1) of ETS, 25 mg L(-1) of ET, 10 mg L(-1) of ST and ES combination for substrates butyrate. The addition of antibiotics to the batch tests affected the utilization of acetate, propionate and butyrate. This study indicated that antibiotic mixtures have an effect on homoacetogenic bacteria and methanogens, which may exert inhibitory effects on propionate and butyrate oxidizing syntrophic bacteria, resulting in unfavorable effects on methanogenesis. PMID- 25290358 TI - Enhanced photocatalytic performance of N-nitrosodimethylamine on TiO2 nanotube based on the role of singlet oxygen. AB - N-nitrosodimethylamine (NDMA) photocatalytic degradation performance and mechanism were investigated on the TiO2 nanotube prepared from anatase TiO2 nanopowder in terms of the production of reactive oxygen species including hydroxyl radical, singlet oxygen and superoxide radical. Significantly higher NDMA degradation efficiency was obtained on anatase TiO2 nanotube rather than anatase TiO2 nanopowder. The tubular morphology may be responsible for almost 100% NDMA removal on TiO2 nanotube, presumably due to its confinement effect leading to NDMA molecules within the nanotube being attacked by reactive oxygen species such as hydroxyl radical and singlet oxygen, and initiating reaction inside the nanotube. In particular, the ability of the nanotubular structure of TiO2 nanotube to promote a singlet oxygen oxidation pathway contributes much to the enhanced NDMA degradation efficiency and favors the formation of dimethylamine and NO3(-). Such function originating from nanotube morphology could bring new insights for the photocatalytic degradation of organic pollutants. PMID- 25290361 TI - The immune destruction of pancreatic beta cells. PMID- 25290360 TI - Thermodynamically driven one-dimensional evolution of anatase TiO2 nanorods: one step hydrothermal synthesis for emerging intrinsic superiority of dimensionality. AB - In photoelectrochemical cells, there exists a competition between transport of electrons through the porous semiconductor electrode toward the conducting substrate and back-reaction of electrons to recombine with oxidized species on the semiconductor-electrolyte interface, which determines the charge collection efficiency and is strongly influenced by the density and distribution of electronic states in band gap and architectures of the semiconductor electrodes. One-dimensional (1D) anatase TiO2 nanostructures are promising to improve charge transport in photoelectrochemical devices. However, the conventional preparation of 1D anatase nanostructures usually steps via a titanic acid intermediate (e.g., H2Ti3O7), which unavoidably introduces electronic defects into the host lattice, resulting in undesired shielding of the intrinsic role of dimensionality. Here, we manage to promote the 1D growth of anatase TiO2 nanostructures by adjusting the growth kinetics, which allows us to grow single-crystalline anatase TiO2 nanorods through a one-step hydrothermal reaction. The synthesized anatase nanorods possess a lower density of trap states and thus can simultaneously facilitate the diffusion-driven charge transport and suppress the electron recombination. Moreover, the electronically boundary free nanostructures significantly enhance the trap-free charge diffusion coefficient of the anatase nanorods, which enables the emergence of the intrinsic superiority of dimensionality. By virtue of these merits, the anatase nanorods synthesized in this work take obvious advantages over the conventional anatase counterparts in photoelectrochemical systems (e.g., dye-sensitized solar cells) by showing more efficient charge transport and collection and higher energy conversion efficiency. PMID- 25290362 TI - Achievements and prospects. AB - New applications which are areas of potential growth for the science of flow microfluorimetry (FMF) and represent a major shift in direction away from its principal current use by cellular immunologists were highlighted at a recent meeting. Its intention was to inform flow microfluorimetrists of current trends in machine and dye technology and new applications in particular chromosome analysis and the analysis of cells isolated from solid tissue. PMID- 25290359 TI - Proteomic and biomarker studies and neurological complications of pediatric sickle cell disease. AB - Biomarker analysis and proteomic discovery in pediatric sickle cell disease has the potential to lead to important discoveries and improve care. The aim of this review article is to describe proteomic and biomarker articles involving neurological and developmental complications in this population. A systematic review was conducted to identify relevant research publications. Articles were selected for children under the age of 21 years with the most common subtypes of sickle cell disease. Included articles focused on growth factors (platelet derived growth factor), intra and extracellular brain proteins (glial fibrillary acidic protein, brain-derived neurotrophic factor), and inflammatory and coagulation markers (interleukin-1beta, l-selectin, thrombospondin-1, erythrocyte, and platelet-derived microparticles). Positive findings include increases in plasma brain-derived neurotrophic factor and platelet-derived growth factor with elevated transcranial Dopplers velocities, increases in platelet derived growth factor isoform AA with overt stroke, and increases in glial fibrillary acidic protein with acute brain injury. These promising potential neuro-biomarkers provide insight into pathophysiologic processes and clinical events, but their clinical utility is yet to be established. Additional proteomics research is needed, including broad-based proteomic discovery of plasma constituents and blood cell proteins, as well as urine and cerebrospinal fluid components, before, during and after neurological and developmental complications. PMID- 25290363 TI - Tolerance and interleukin 2 deficiency. PMID- 25290364 TI - Activity and chronopharmacology of very low doses of physiological immune inducers. PMID- 25290365 TI - Interleukin 1: amino acid sequencing reveals microheterogeneity and relationship with an interferon-inducing monokine. PMID- 25290366 TI - Virus-specific MHC-restricted T lymphocytes may initiate allograft rejection. PMID- 25290367 TI - Thymic lymphomas in the mouse. AB - Although they are major tools for immunological and oncological research, basic information about T-cell lymphomas is still incomplete. Are we dealing with a single disease or with a spectrum of related diseases or, to phrase the same question in other terms, could all T-cell tumours result from the transformation of only one cell type, with differentiation proceeding in any direction after transformation? Alternatively, are T cells at various stages of differentiation all susceptible to transformation? Which cells are the targets for neoplastic transformation and what are the normal counterparts of the tumour cells? These questions are important if murine lymphoma is to be taken as a model for human disease(1). They are also relevant to immunologists who choose to study thymic lymphopoiesis and T-cell differentiation using tumours as models(2-10). In this review, R. Hooghe and J Boniver discuss the tumour cell, the elusive target cell for neoplastic transformation and the results of recent studies in molecular biology. PMID- 25290368 TI - Vaccinia virus expression vector: a new tool for immunologists. AB - Advances in genetic engineering have made it possible to use animal viruses as vectors for expression of unrelatedgenes(1). Small DNA viruses, such as SV40 and adenovirus, provide powerful tools for molecular biologists interested in studying the regulation of gene expression in eukaryotic cells. The more recent development of large DNA viruses, such as vaccinia virus(2-4) and herpes simplex virus(5), as vectors may prove equally valuablefor immunological studies. These large viruses can express one or many foreign genes while retaining infectivity for animals as well as cultured cells. Moreover, the proteins appear to undergo appropriate processing steps including glycosylation and membrane transport. Here Bernard Moss reviews initial studies indicating that both humoral(6,7) and cell mediated(8) immune responses are made to the expressed protein and that the recombinant viruses have potential as live vaccines(9,10). PMID- 25290369 TI - Regulation of immune response by antibodies: the importance of antibody and monocyte Fc receptor interaction in T-cell activation. AB - The interaction between the Fc portions of antibodies and Fc receptors (FcR) on monocytes and macrophages is well known for such immune effector functions as the phagocytosis of antibody-coated bacterial and viral particles. Two additional functions of this Fc-FcR interaction have been described recently and both relate to the regulatory aspects of immune responses. These interactions, discussed here by Tse Wen Chang, are involved in antigen presentation, T cell activation and proliferation, and antibody production. PMID- 25290370 TI - Improving area-selective molecular layer deposition by selective SAM removal. AB - Area selective molecular layer deposition (MLD) is a promising technique for achieving micro- or nanoscale patterned organic structures. However, this technique still faces challenges in attaining high selectivity, especially at large MLD cycle numbers. Here, we illustrate a new strategy for achieving high quality patterns in selective film deposition on patterned Cu/Si substrates. We employed the intrinsically selective adsorption of an octadecylphosphonic acid self-assembled monolayer (SAM) on Cu over Si surfaces to selectively create a resist layer only on Cu. MLD was then performed on the patterns to deposit organic films predominantly on the Si surface, with only small amounts growing on the Cu regions. A negative potential bias was subsequently applied to the pattern to selectively desorb the layer of SAMs electrochemically from the Cu surface while preserving the MLD films on Si. Selectivity could be enhanced up to 30-fold after this treatment. PMID- 25290375 TI - Stink bug species composition and relative abundance of the redbanded stink bug (Hemiptera: Pentatomidae) in soybean in the upper gulf coast Texas. AB - Stink bugs are the primary arthropod soybean pests in the southern United States. Historically, important stink bug species damaging soybeans in the southern United States included the southern green stink bug Nezara viridula (L.), the green stink bug Chinavia hilaris (Say), and the brown stink bug Euschistus servus (Say) (Hemiptera: Pentatomidae). The redbanded stink bug, Piezodorus guildinii (Westwood), has recently become an economic pest of soybean in the southern region of the United States, especially in Louisiana and Texas. Little is known about current stink bug species composition and relative abundance in Texan soybean agro-ecosystems. To fill this gap, commercial soybean fields in the Upper Gulf Coast of Texas were sampled weekly during the growing season using a sweep net throughout R2 (full flowering) to R7 (beginning maturity) from 2011 to 2013. Adults and nymphs (third, fourth, and fifth instars) of redbanded stink bug, southern green stink bug, green stink bug, and brown stink bug were counted per 25 sweeps. The relative abundance of redbanded stink bug was significantly higher than any other stink bug species throughout 2011-2013. Over 65% of the total population of major stink bugs collected during this period were redbanded stink bugs and ?19% were southern green stink bugs. The highest redbanded stink bug densities and the highest ratio of redbanded stink bug nymphs to adults were recorded at R7. Results from this study show that redbanded stink bug has become the predominant stink bug species in soybean in the Upper Gulf Coast of Texas. PMID- 25290376 TI - Reconciling structural and thermodynamic predictions using all-atom and coarse grain force fields: the case of charged oligo-arginine translocation into DMPC bilayers. AB - Using the translocation of short, charged cationic oligo-arginine peptides (mono , di-, and triarginine) from bulk aqueous solution into model DMPC bilayers, we explore the question of the similarity of thermodynamic and structural predictions obtained from molecular dynamics simulations using all-atom and Martini coarse-grain force fields. Specifically, we estimate potentials of mean force associated with translocation using standard all-atom (CHARMM36 lipid) and polarizable and nonpolarizable Martini force fields, as well as a series of modified Martini-based parameter sets. We find that we are able to reproduce qualitative features of potentials of mean force of single amino acid side chain analogues into model bilayers. In particular, modifications of peptide-water and peptide-membrane interactions allow prediction of free energy minima at the bilayer-water interface as obtained with all-atom force fields. In the case of oligo-arginine peptides, the modified parameter sets predict interfacial free energy minima as well as free energy barriers in almost quantitative agreement with all-atom force field based simulations. Interfacial free energy minima predicted by a modified coarse-grained parameter set are -2.51, -4.28, and -5.42 for mono-, di-, and triarginine; corresponding values from all-atom simulations are -0.83, -3.33, and -3.29, respectively, all in units of kcal/mol. We found that a stronger interaction between oligo-arginine and the membrane components and a weaker interaction between oligo-arginine and water are crucial for producing such minima in PMFs using the polarizable CG model. The difference between bulk aqueous and bilayer center states predicted by the modified coarse grain force field are 11.71, 14.14, and 16.53 kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80 kcal/mol; those are of almost the same order of magnitude. Our simulations also demonstrate a remarkable similarity in the structural aspects of the ensemble of configurations generated using the all-atom and coarse-grain force fields. Both resolutions show that oligo-arginine peptides adopt preferential orientations as they translocate into the bilayer. The guiding theme centers on charged groups maintaining coordination with polar and charged bilayer components as well as local water. We also observe similar behaviors related with membrane deformations. PMID- 25290378 TI - Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. AB - BACKGROUND: The aetiology of insulin resistance (IR) in naturally occurring canine hypothyroidism is poorly understood and likely multifactorial. Excess secretion of growth hormone (GH) by transdifferentiated pituitary cells may contribute to IR in some hypothyroid dogs, but although this has been demonstrated in experimental studies, it has not yet been documented in clinical cases. CASE REPORT: A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics and glucocorticoid therapy. The dog also exhibited exercise intolerance and polydipsia of 12 and 2 months duration, respectively. On physical examination, obesity, poor coat condition, widened interdental spaces and mild respiratory stridor were noted. Initial laboratory test results revealed concurrent hypothyroidism and diabetes mellitus (DM). Further investigations showed IR, GH excess and a paradoxical increase of GH following stimulation with thyrotropin-releasing hormone. CONCLUSIONS: To the authors' knowledge, this is the first reported case that suggests that GH alterations may have clinical significance in naturally occurring hypothyroidism. Among other factors, hypothyroidism-induced GH excess should be considered as a possible cause of IR in patients suffering from hypothyroidism and concurrent DM. In such cases, DM may reverse with treatment of hypothyroidism, as was documented in this case. PMID- 25290379 TI - Evolution of minimally invasive techniques within an academic surgical practice at a single institution. AB - AIM: We aimed to understand how changes in surgical techniques are transferred into surgical practice. We hypothesized that the integration of minimally invasive surgery (MIS) techniques into a pediatric surgical practice is dependent on the hiring of junior partners who can transfer their MIS knowledge to senior surgeons. MATERIALS AND METHODS: We reviewed the operative approach to six different general pediatric surgical procedures from 2000 to 2012, including appendectomy, fundoplication, gastrostomy tube placement, pyloromyotomy, colectomy, and lobectomy (lung). The percentage of MIS cases was calculated for each procedure annually. Each year six to nine fellowship-trained pediatric surgeons operated at our institution. Three surgeons completed training in the era of MIS (hired in 2001, 2007, and 2009) and remained on staff for at least 3 years. RESULTS: In 2000, 49% of procedures were performed with MIS. This increased to 98% in 2013 (P<.0001). Appendectomy, pyloromyotomy, and fundoplication demonstrated early adoption and uniform use of laparoscopy (>85%) by 2007. Gastrostomy tube placement reached 90% laparoscopy utilization in 2009. Lobectomy (lung) and colectomy also reached >80% MIS use in 2009 and 2010, respectively. The same trends were seen when looking only at senior surgeons who completed training prior to 2000. CONCLUSIONS: The hiring of junior surgeons with MIS training was associated with an increase in adoption of MIS techniques by the entire group. Procedures that were introduced early in the MIS era demonstrated a gradual rise toward uniform adoption of MIS techniques. More advanced and recently adopted MIS techniques demonstrated a rapid rise to uniform adoption. PMID- 25290377 TI - Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. AB - Methamphetamine (MA) is a potent psychostimulant with a high addictive capacity, which induces many deleterious effects on the brain. Chronic MA abuse leads to cognitive dysfunction and motor impairment. MA affects many cells in the brain, but the effects on astrocytes of repeated MA exposure is not well understood. In this report, we used Gene chip array to analyze the changes in the gene expression profile of primary human astrocytes treated with MA for 3 days. Range of genes were found to be differentially regulated, with a large number of genes significantly downregulated, including NEK2, TTK, TOP2A, and CCNE2. Gene ontology and pathway analysis showed a highly significant clustering of genes involved in cell cycle progression and DNA replication. Further pathway analysis showed that the genes downregulated by multiple MA treatment were critical for G2/M phase progression and G1/S transition. Cell cycle analysis of SVG astrocytes showed a significant reduction in the percentage of cell in the G2/M phase with a concomitant increase in G1 percentage. This was consistent with the gene array and validation data, which showed that repeated MA treatment downregulated the genes associated with cell cycle regulation. This is a novel finding, which explains the effect of MA treatment on astrocytes and has clear implication in neuroinflammation among the drug abusers. PMID- 25290380 TI - Management of a Peripheral Giant Cell Granuloma in the esthetic area of upper jaw: A case report. AB - INTRODUCTION: Peripheral Giant Cell Granuloma (PGCG) is the most common giant cell lesion found in the jaws; it originates from the connective tissue of the periosteum or from the periodontal ligament in response to local chronic irritation. Early and accurate diagnosis of these lesions allows for conservative management without compromising adjacent teeth or tissues. PRESENTATION OF CASE: This paper presents a case of PGCG in the esthetic zone of the upper jaw in a 23 year-old female patient. The treatment offered consisted of an excisional biopsy with immediate soft tissue grafting to prevent esthetic complications. The growing lesion has caused an interproximal spacing between the central and lateral incisors. The spacing spontaneously closed during the next six weeks after excision and no relapse occurred during postoperative follow-up. DISCUSSION: Proper management of a PGCG lesion requires excluding other pathologies prior to planning for surgery. Correct diagnosis of such lesions is essential to optimize the treatment and prevent recurrence. Clinical examination alone may not give a correct picture, thereby requiring histopathological confirmation. CONCLUSION: Immediate soft tissue augmentation using a connective tissue graft has been suggested as a surgical solution after removal of PGCG to minimize patient discomfort and the loss of precious tissues. PMID- 25290381 TI - The dilemma of denosumab: Salvage of a femoral head giant cell tumour. AB - INTRODUCTION: Denosumab is a monoclonal RANKL antibody which has been shown to be highly effective in treating giant cell tumour (GCT) of bone. We report on its use as a neo-adjuvant agent to avoid morbid surgery for an adolescent. PRESENTATION OF CASE: We report a case of a15-year old female with a Campanacci 3 GCT involving the femoral head and neck. DISCUSSION: To preserve bone stock and avoid an outright hip replacement, the patient was given denosumab pre operatively to consolidate the tumour. After receiving 6 months of treatment, a rim of cortical bone had developed to allow an extended curettage of the tumour to be performed without fear of collapse of the articular surface. CONCLUSION: This is the first reported case of the use of denosumab in GCT of the femoral head and neck. We describe our experience in the neo-adjuvant use of denosumab and offer suggestions for future use. Further studies will be needed to see if denosumab has a role in conventional GCT and whether it can lead to a lowering of local recurrence rates. PMID- 25290383 TI - Management of the hemophilic pseudotumor of the abdomen: A rare pathological entity. AB - INTRODUCTION: Hemophilic pseudotumor is a rare complication that occurs in patients with severe hemophilia. Results from multiple episodes of bleeding into the bones and soft tissues. PRESENTATION OF CASE: A 31 years old male patient, with severe hemophilia A. Diagnosed with an abdominal tumor 10 years ago during routine screening, that progressively grew to encompass the entire abdominal area, with symptoms of intestinal obstruction. DISCUSSION: Hemophilic pseudotumor appears as a painless tumor of slow growth that can compress vital organs producing bone destruction, muscle and skin necrosis. The tumor may have fistulas or break spontaneously. CONCLUSION: The abdominal hemophilic pseudotumor is a rare pathological entity, with few reports worldwide, but must be considered in hemophilic patients with a well documented abdominal tumor. PMID- 25290382 TI - Unusual gestational choriocarcinoma arising in an interstitial pregnancy. AB - INTRODUCTION: Choriocarcinoma is a highly malignant trophoblastic neoplasm. Its association with ectopic pregnancy is very rare and usually with aggressive behavior. PRESENTATION OF CASE: We report a new case arising in an interstitial pregnancy occurring in a 46-year-old woman. The patient was admitted for severe pelvic pain and abundant metrorrhagia. One month ago, she had had a laparoscopic resection of an interstitial pregnancy subsequent to failure of chemotherapy by methotrexate. The raise of serum betahCG level and the hyperechoic intrauterine mass were in favor of gestational trophoblastic disease. Urgent laparotomy was performed for circulatory collapse. Hysterectomy was done. Histological examination revealed a choriocarcinoma. The patient underwent chemotherapy. Two years later, neither metastasis nor recurrence was detected. DISCUSSION: Clinical diagnosis of primary interstitial choriocarcinoma is difficult, since it is rare and manifesting by non-specific abnormal vaginal bleeding. Imaging findings are also not helpful in ectopic location. The frequency of metastasis is related to the delayed diagnosis. Serial measurement of betahCG level was the most useful marker of diagnosis and follow up. Histopathological examination remains the only tool of the precise diagnosis. Choriocarcinoma has a very good prognosis even in advanced stages, since it is very chemosensitive. CONCLUSION: The current trend of the treatment of ectopic pregnancy by conservative surgery requires adequate monitoring of betahCG and careful examination of pathologic specimens to avoid misdiagnosis of ectopic gestational trophoblastic disease. PMID- 25290384 TI - Malignant peripheral nerve sheath tumor of the vulva, an unusual differential diagnosis for vulvar mass. AB - INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, up to one half of the MPNSTs occur in patients with neurofibromatosis type-1 (NF-1), while the rest are sporadic. Here, we present a 52-year-old woman with MPNST of the vulva without NF-1. We will discuss basics of the disease, treatment options and follow-up strategies. PRESENTATION OF CASE: 52-year-old female admitted to our hospital with complaint of abnormal uterine bleeding and rapidly growing vulvar mass. Excisional biopsy of the mass showed MPNST of the vulva. Afterwards, the patient underwent radical vulvectomy with inguinofemoral lymph node dissection. Short after the surgery, multiple lung metastasis were shown and responded to chemotherapy, but rapid local recurrence occurred short after the completion of the chemotherapy. DISCUSSION: The primary treatment option in MPNSTs is surgical excision with or without adjuvant therapy. There is not enough data about the role of systemic chemotherapy in the management of MPNSTs and it still remains controversial. CONCLUSION: In general, radiation therapy has not been demonstrated to improve overall survival. Complete surgical resection of the primary tumor is the mainstay of the treatment. PMID- 25290385 TI - Operative management of idiophatic myositis ossificans of lateral pterygoid muscle. AB - INTRODUCTION: Myositis ossificans (MO) is characterized as heterotopic bone formation within muscle. MO rarely occurs in the head and neck region. Excision of the heterotopic bone is the standard treatment. This report summarizes a case of a 12-year old female with MO involving the lateral pterygoid muscle. The heterotopic bone was excised using an intraoral incision. Despite intensive physical therapy, the operation failed as evidenced by new bone formation in the area within three weeks of the operation. PRESENTATION OF CASE: A twelve years old female patient presenting with mouth opening of 10 mm, no facial asymmetry, and no jaw joint pain or other symptoms. Computer tomography (CT) exam was requested and revealed calcification of the left lateral pterygoid muscle. No other masticatory or head muscles showed any signs of calcification. The calcified muscle was completely removed beyond the ossified segment and a 35 mm mouth opening was achieved immediately after the procedure. One month after total bone structure removal (first surgery) the patient could not open her mouth anymore due to a significant calcified mass. DISCUSSION: The surgical technique used in this case avoided invasive gap arthroplasty to access lateral pterygoid muscle and anaesthetic scarring formation, by using an intraorally incision accessing the muscle directly. The authors of these study did not see any relation with the condylar dislocation that the patient had five years prior to the pathology, and they could not find any real cause for the myositis ossificans of lateral pterygoid muscle. CONCLUSION: The outcome of the surgical procedure was not successful, perhaps due to the expression of the disease, indicating the need to further physiologic and genetic studies to elucidate the aetiology of MO as well as to provide directions to an adequate treatment choice for such cases. PMID- 25290386 TI - Nuclear envelope and striated muscle diseases. AB - The nuclear lamina is a mesh-like network of intermediate filaments localized mainly at the inner surface of the inner nuclear membrane and is composed of proteins called lamins. Many inherited diseases are linked with mutations in nuclear lamins and integral proteins of the inner nuclear membrane. In this article, we summarize basic aspects of the nuclear envelope architecture and provide some remarkable findings of the involvement of lamins in striated muscle disorders. PMID- 25290387 TI - Nanowire electrodes for electrochemical energy storage devices. PMID- 25290388 TI - Lymphokines and monokines in the clinic. AB - There has been a remarkable increase in understanding of the control of immune reactions and hemopoietic stem cell proliferation by cytokines. At a recent meeting(*) investigators engaged in basic research, clinicians, and representatives of bioengineering and pharmaceutical companies gathered to discuss the present state and future potential of clinical application of natural and recombinant lymphokines and cytokines. PMID- 25290390 TI - Interleukin 2 and B cells. PMID- 25290389 TI - Leucocytes at a molecular level. AB - Molecular biologists have left their imprint on almost every aspect of immunology investigation; one notable exception is the study of macrophage differentiation and activation. Few cells have as many interesting responses as the monocyte; and as most of the differentiation-activation responses occur without cellular proliferation, mononuclear phagocytes are excellent subjects in which to study environmental responses at the molecular level. Participants in a recent meeting(*) considered how the techniques of molecular biology, often focused on problems of nerve-cell differentiation and fibroblast growth responses, could be used to address what many perceive to be the central question of macrophage biology: how are the many and diverse differentiation pathways regulated and can differentiation be described in distinct molecular terms from the state of activation? PMID- 25290391 TI - Anergy induced by cyclosporin and C. parvum. PMID- 25290392 TI - Immunosuppression mediated by seminal plasma - fact or artefact? PMID- 25290393 TI - NK cell lineage and target specificity: a unifying concept. PMID- 25290394 TI - NK cell lineage and target specificity: a unifying concept. PMID- 25290395 TI - Is there a single differentiation pathway for all antibody-forming cells in the spleen? AB - By incubating tissue sections with antigen (or hapten)-enzyme conjugates, followed by enzyme cytochemistry(1-4), N. van Rooijen and his colleagues have been able to study the development and localization of specific antibody producing cells in the spleen of animals after a single intravenous antigen injection. Variations in this method(5-11) allowed them to compare the localization patterns of cells producing different antibodies and to determine simultaneously their Ig isotype. Studies on primary and secondary immune responses against thymus-dependent and thymus-independent antigens lead them to postulate that there is one 'differentiation pathway' for antibody-forming cells in the spleen, independent of the antigen and the type of immune response. PMID- 25290396 TI - The immunological meaning of Thy-1-negative NK cells. AB - In this article Donald Rowley and Prakash Shah propose that Thy-1(-) natural killer (NK) cells activated during the course of immune reactions suppress or eliminate dendritic cells (DC) which have interacted with antigen and are required to stimulate lymphocyte proliferation. They review the experimental basis for this concept of immune regulation and emphasize that nearly homogeneous populations of well-characterized NK cells are required to define the functions of NK cells. PMID- 25290397 TI - Is autoimmunity a side-effect of interleukin 2 production? AB - Because it has a role in lymphocyte activation, interleukin 2 (IL-2) has been tried as a therapeutic agent in several types of immune dysfunction in animals and man. Here, Georg Wick and his colleagues discuss the possibility that IL-2 production initiates and perpetuates autoimmune disease, and express caution about the clinical use of IL-2. PMID- 25290398 TI - Induction of interferon by lentiviruses. PMID- 25290399 TI - Strategies for cell-mediated immunotherapy of cancer: killing or help? PMID- 25290400 TI - The many facets of thymic involution. PMID- 25290401 TI - Computer models of the human immunoglobulins Binding sites and molecular interactions. AB - In last month's issue(1) Richard Pumphrey showed how low resolution computer models could be used to investigate the shape and segmental flexibility of human immunoglobulin molecules. In this article, he extends the use of these models to the study of interactions between immunoglobulins and other molecules, such as their receptors, J chain, secretory component and complement fragments. Although precise studies of molecular interaction require computation in atomic detail, there is still much to be learnt from low resolution modelling, in which atomic details are glossed over but general principles become more obvious. PMID- 25290402 TI - Cell-mediated immune responses of cattle to Theileria parva. AB - Theileria parva is a protozoan parasite that infects lymphocytes of cattle and African buffalo. As is the case with certain viruses, the parasite causes antigenic changes on the cell surface against which the host mounts cytotoxic T cell. Precise definition of the cells participating in these response and their specificity has been facilitated by the recent identification of markers for bovine T-cell subpopulations and functional analyses of bovine lymphocytes at the clonal level. In this paper Ivan Morrison and his colleagues discuss current information on the parasite specificity and MHC restriction of anti-Theileria cytotoxic T cell, in relation to their role in protective immunity. PMID- 25290403 TI - Multispecific monoclonal antibodies. AB - Monoclonal antibodies are frequently shown to participate in unexpected cross reactions involving two apparently dissimilar antigens. This can be attributed either to partial epitope identity or to irrelevant interactions involving additional binding capacity of the antibody. The majority of such interactions appear to fall into the latter category. Such cross reactions are most commonly detected when one of the antigens has a high epitope density and the antibody is multivalent so that a spurious interaction of low intrinsic affinity is amplified by local concentration effects. In this review Souravi Ghosh and Ailsa Campbell discuss the selection of a monoclonal antibody for maximum affinity for the antigens it is designed to study and minimum cross-reactivity. PMID- 25290404 TI - The non-MHC transplantation antigens: neither weak nor minor. AB - The existence of minor histocompatibility (mH) antigens is implied by the very naming of the major histocompatibility antigens. Grafts exchanged between individuals matched at the major histocompatibility complex (MHC) (which encodes the antigens that produce rapid graft rejection) are rejected, albeit at a somewhat slower pace than MHC grafts. There are multiple mH antigen differences between MHC (HLA) matched humans and between MHC (H-2) identical mouse strains. Using mH congenic mouse strains, however, individual mH antigens can be studied, and these provide a basis for interpretation of immune responses to multiple mH antigens in HLA matched human grafts. In this article Bruce Loveland and Elizabeth Simpson discuss four aspects of mH antigens: their immunogenicity; immune response (Ir) gene regulation; mH antigens in man; and recent models which might lead to their molecular identity. PMID- 25290405 TI - Complement system proteins which interact with C3b or C4b A superfamily of structurally related proteins. AB - Recent cDNA sequencing data has allowed the prediction of the entire amino acid sequences of complement components factor B and C2, the complement control proteins factor H and C4b-binding protein and a partial sequence for the Cab/C4b receptor CR1. These proteins all contain internal repeating units of approximately 60 amino acids, each repeating unit having a characteristic framework of highly conserved residues. The N-terminal Ba and CA portions of factor B and C2 both contain 3 repeating units and the chains of C4b-binding protein and factor H contain 8 and 20 repeating units, respectively, while the precise number of units in CR1 is not known yet. These structurally homologous complement proteins are also functionally related as they all interact with C3b and C4b during activation of the cascade. The repeating units also occur in the functionally unrelated proteins subcomponent C1r, beta2-glycoprotein 1, blood clotting factor XIII and interleukin-2 receptor. In this review Ken Reid and his colleagues propose that this could be a general feature of a superfamily of structurally related proteins. PMID- 25290406 TI - The skin immune system Its cellular constituents and their interactions. AB - The term immunodermatology describes the systematic investigation of the complex mechanisms of the 'skin immune system' in health and disease. In this review Jan Bos and Martien Kapsenberg discuss the skin's vascular and lymphatic systems and the various cells which participate in the immune response. These include Langerhans' cells, indeterminate cells, veiled cells, endothelial cells, mast cells, tissue macrophages and 'homing' T lymphocytes, which are all present in skin under physiological conditions. PMID- 25290407 TI - Use of anti-receptor antibodies to focus T-cell activity. AB - The T-cell receptor dictates that T cells recognize foreign antigen in the context of self major histocompatibility complex (MHC) encoded molecules. Cells which are recognized as foreign by the T-cell system are efficiently rejected by direct cytolysis or in a lymphokine-mediated way. Meanwhile, antibodies recognize native antigen and can be made available reproducibly and in quantity. Here, Uwe Staerz and Michael Bevan discuss the use of hybrid antibodies, composed of anti receptor/anti-X, to confer the specificity of antibody to a T-cell response. PMID- 25290410 TI - The computer and the reprint file (4). AB - This month Barry Ginsberg reviews Bookends Extended, for the APPLE ] series of computers, and reports that it is an excellent program to manage a reference library or to create a bibliography for manuscripts. He concludes that Bookends is simple to learn and powerful, particularly in its ability to input data directly from MEDLINE searches. PMID- 25290411 TI - Can early anti-TNF-alpha treatment be an effective therapeutic strategy in children with Crohn's disease? PMID- 25290412 TI - Investigating the positive relationship between tumor-infiltrating lymphocytes and trastuzumab therapy. PMID- 25290414 TI - Role of subcutaneous formulation of trastuzumab in the treatment of patients with HER2-positive breast cancer. AB - Tumors in about 15% of patients with breast cancer overexpress HER2. Trastuzumab (Herceptin((r)); F. Hoffmann-La Roche, Basel, Switzerland) is a humanized monoclonal antibody against HER2. While the introduction of trastuzumab has changed the natural course of HER2-positive breast cancer, the need for repeated administration of the drug over a prolonged period of time represents a challenge. Similarly to other chronic disorders, subcutaneous administration of monoclonal antibodies may be of advantage in this setting. The results of a prospective randomized Phase III study have demonstrated that subcutaneous trastuzumab is noninferior compared with the intravenous administration of the drug in terms of efficacy (assessed as pathological complete response rate) as well as in pharmacokinetic parameters. Moreover, another prospective randomized study showed that an overwhelming majority of patients prefer subcutaneous over intravenous trastuzumab. The advent of subcutaneous trastuzumab represents an important progress in the concept of cancer management that is based also on patient choice and preferences. PMID- 25290415 TI - Immunotherapeutic targeting of established sarcoma in Swiss mice by tumor-derived antigen-pulsed NLGP matured dendritic cells is CD8+ T-cell dependent. AB - AIM: Neem leaf glycoprotein (NLGP) matures human myeloid and mouse bone marrow derived dendritic cells (DCs). (NLGP) also therapeutically restricts the mouse established sarcoma growth by activating CD8(+) T cells along with increased proportion of tumor residing CD11c(+) DCs. Here, we intended to find out whether CD8(+) T cells become cytotoxic to sarcoma cells after presentation of sarcoma antigen by NLGP-matured DCs to restrict murine sarcoma growth. MATERIALS & METHODS: NLGP was prepared from matured neem(Azadirachta indica) leaves. Solid sarcoma tumor in Swiss mice was developed by subcutaneous inoculation of sarcoma cells. GMCSF-IL-4 generated DCs were matured with NLGP and pulsed with sarcoma antigen for immunotherapy. Status of CD8+CD69+T cells was studied by flow cytometry and secretion of cytokines was measured by ELISA. RT-PCR was used to monitor the status of perforin, granzyme B. RESULTS: NLGP-matured sarcoma antigen pulsed DCs (DCNLGPTAg) inhibit mouse sarcoma growth. DCNLGPTAg immunization enhances CD8(+) T-cell number within tumor-infiltrating lymphocytes and tumor draining lymph nodes along with increased perforin and granzyme B expression. Antigen-specific T-cell proliferation and IFN-gamma secretion were significantly higher in DCNLGP- and DCNLGPTAg-immunized mice groups. In vivo CD8(+) T-cell depletion abrogated the DCNLGPTAg-mediated tumor growth restriction. CONCLUSION: DCNLGPTAg restricts CD8(+) T-cell-dependent mouse established sarcoma growth, related to the optimum antigen presentation by DCs to CD8(+) T cells. PMID- 25290417 TI - Immunoglobulin replacement therapy for primary immunodeficiencies. AB - Exogenous antibody therapy to protect patients against infections and toxins is over 100 years old, yet progress continues to be made in the manufacture, administration and application of this type of immunotherapy, known as therapeutic human immunoglobulin. For the majority of patients with primary immunodeficiencies, immunoglobulin replacement is the only life-saving therapy and treatment is life-long, since the vast majority of primary immunodeficiency patients have primary antibody failure. Successful treatment depends on multiple factors: the availability of products, the type of immunodeficiency and any comorbidities of the individual patient. Essential components include long-term follow-up, regular monitoring and a close relationship between the patient and the multidisciplinary clinical immunology team. In this article, we describe the current immunoglobulin products and the types of adverse reactions. We provide evidence for clinical decision-making regarding dosing, route of administration and location of therapy, highlighting current 'best practice' recommendations. PMID- 25290419 TI - Nanoparticle based-immunotherapy against allergy. AB - Allergic diseases are one of the most prevalent diseases, reaching epidemic proportions in developed countries. An allergic reaction occurs after contact with an environmental protein, such as inhalants allergens (pollen, animal dander, house dust mites), or food proteins. This response is known as part of the type 2 immunity that is counterbalanced by Type 1 immunity and Tregs. Widely used allergen-specific immunotherapy (IT) is a long term treatment to induce such switch from Th2 to Th1 response. However, conventional IT requires multiple allergen injections over a long period of time and is not free of risk of producing allergic reactions. As a consequence, new safer and faster immunotherapeutic methods are required. This review deals with allergen IT using nanoparticles as allergen delivery system that will allow a different way of administration, reduce dose and diminish allergen exposure to IgE bound to mast cells or basophils. PMID- 25290420 TI - Bone marrow stromal cells and their factors regulate B-cell differentiation. AB - The bone marrow is the only tissue in which myeloid cells and B lymphocytes normally differentiate during postnatal life. This suggests that influences essential to the process of differentiation operate in the medullary cavity. It is now accepted that a population of bone marrow stromal cells provides the necessary environment for hemopoiesis and there is much interest in their regulatory effects- studies which have been assisted by methods of analysing stromal cell biology in vitro. Considerable recent progress has been made in understanding how stromal cells regulate B lymphopoiesis, a subject discussed at a recent conference. PMID- 25290418 TI - Selection of patients for sublingual versus subcutaneous immunotherapy. AB - Allergen immunotherapy is the sole treatment for IgE-mediated allergic diseases directed at the underlying mechanism. The two widely accepted administration routes are sublingual (SLIT) and subcutaneous (SCIT). We reviewed how patients should best be selected for immunotherapy and how the optimal administration route can be defined. Before deciding SCIT or SLIT, appropriate selection of patients for allergen immunotherapy (AIT) is mandatory. To be eligible for AIT, subjects must have a clear medical history of allergic disease, with exacerbation of symptoms on exposure to one or more allergens and a corresponding positive skin or in vitro test. Then the route of administration should be based on: published evidence of clinical and immunologic efficacy (which varies per allergic disease and per allergen); mono- or multi-allergen immunotherapy, for SLIT multi-allergen immunotherapy was not effective; safety: adverse events with SLIT are more frequent, but less severe; and, costs and patient preferences, closely related to adherence issues. All these are discussed in the article. PMID- 25290421 TI - Towards an AIDS vaccine: challenges and prospects. AB - Since the human immunodeficiency virus (HIV) started its spread through the human population, the AIDS epidemic has steadily increased on all continents unchecked by any therapeutic or preventive intervention, except for education. The search for an AIDS cure is facing great difficulties as HIV, a human retrovirus, is able to integrate and remain latent in the human genome for years. An effective vaccine thus remains the only foreseeable way to control and eventually eradicate AIDS. The unique pathogenicity and variability of HIV have raised new challenges in vaccine design, testing and evaluation. The status of the intense research efforts undertaken to solve these problems were assessed at a recent workshop on the AIDS vaccines. PMID- 25290416 TI - Targeting CD8+ T-cell tolerance for cancer immunotherapy. AB - In the final issue of Science in 2013, the American Association of Science recognized progress in the field of cancer immunotherapy as the 'Breakthrough of the Year.' The achievements were actually twofold, owing to the early success of genetically engineered chimeric antigen receptors (CAR) and to the mounting clinical triumphs achieved with checkpoint blockade antibodies. While fundamentally very different, the common thread of these independent strategies is the ability to prevent or overcome mechanisms of CD8(+) T-cell tolerance for improved tumor immunity. Here we discuss how circumventing T-cell tolerance has provided experimental insights that have guided the field of clinical cancer immunotherapy to a place where real breakthroughs can finally be claimed. PMID- 25290423 TI - Erratum. PMID- 25290422 TI - The effects of space flight on immunocompetence. AB - The National Aeronautics and Space Administration (NASA) conducts a research program in the biological and medical aspects of space flight and funds research proposals submitted by interested scientists. Changes that could influence immune status and possibly impair host resistance to infections have been noted and are summarized in a report prepared by the Life Sciences Research Office of the Federation of American Societies for Experimental Biology and a working group of eminent scientists. PMID- 25290424 TI - T cells recognize antigen alone and not MHC molecules. PMID- 25290425 TI - T cells recognize antigen alone and not MHC molecules. PMID- 25290426 TI - Cytokines in autoimmunity. PMID- 25290427 TI - The CD4 molecule, the human immunodeficiency virus and anti-idiotypic antibodies. AB - The CD4 molecule is the cellular receptor for human immunodeficiency viruses (HIV). Administration of antibodies to the equivalent molecule in mice (L3T4) induces unresponsiveness to antigens given to or around the same time. Here Paolo del Guercio and Maurizio Zanetti suggest that in AIDS patients anti-idiotypic antibodies elicited to anti-HIV antibodies may bind to CD4 molecules, inducing unresponsiveness to viral and other antigens as anti-L3T4 antibodies do in mice. This possibility may hinder attempts to establish anti-HIV immunity by vaccination. PMID- 25290428 TI - Is allograft rejection a clue to the mechanism promoting MHC polymorphism? AB - Extreme polymorphism at MHC loci is generally thought to be maintained by natural selection at a population level. Because allelic MHC molecules differ in their influence on the immune response, polymorphism ensures that the response repertoire is broad and that the group survives microbial challenge. Here Leif Anderson and his colleagues propose a different view, based on the observation that certain pathogens passively acquire MHC antigens from their primary host and carry these antigens into subsequent hosts. An immune response to the pathogen may depend on recognition of the non-self MHC antigens. PMID- 25290429 TI - The multifactorial etiology of graft-versus-host disease. AB - Graft-versus-host disease (GVHD), a major complication of bone marrow transplantation, often occurs despite genotypic HLA identity between patient and donor. Here, Gijsbert de Gast and his colleagues suggest that pretransplant cytoreductive therapy reactives latent virus and protozoan infections and promotes the invasion of bacteria and fungi through damaged mucosal membranes. Mature donor T cells sensitized to microbial antigens produce gamma interferon that induces the expression of HLA class II antigens. Non-HLA antigens are presented in conjunction with HLA class II antigens and stimulate graft-versus host reactions against non-HLA antigens expressed on the target cells. PMID- 25290430 TI - Separation of self from non-self in the complement system. AB - The alternative complement pathway is a self-contained and independent recognition and effector pathway that evolved to protect the host from microbes. As such, it must separate self from non-self. Via low grade continuous turnover (tickover) of the pivotal C3 component, the alternative complement pathway is always on guard to defend the host. Activated C3 binds continuously to self tissue and to foreign tissue, if present. There is no apparent discrimination at this initiation step. However, the amplification of C3 deposition on self (but not foreign) tissue, a necessity in establishing the effector functions of this pathway, is inhibited by a series of functionally, structurally and genetically related plasma and membrane glycoproteins which down-regulate complement activation. These regulatory molecules are widely distributed on human tissue. The plasma proteins are preferentially active on fluid-phase components while membrane-bound forms act on cell-bound components. Here, John Atkinson and Timothy Farries discuss these inhibitors of complement activation and suggest that their action explains the ability of the alternative pathway to amplify on foreign tissue but be down-regulated on autologous tissue. PMID- 25290431 TI - The 65kDa antigen of mycobacteria-a common bacterial protein? AB - The 65 kilodalton antigen of Mycobacterium tuberculosis and M. leprae is a well characterized, strongly immunogenic protein eliciting antibody and T-cell responses in infected patients. Recent studies have disclosed regions of cross reactivity between the 65kDa antigen and proteins in many other bacterial species. These include the product of the ams gene in E. coli which is involved in the processing of RNA. Here Douglas Young and his colleagues discuss these observations, the significance of the 65kDa antigen and its possible role in the pathogenesis of mycobacterial and other diseases. PMID- 25290432 TI - Antibody-mediated graft versus host reactions in renal transplantation. PMID- 25290433 TI - Soluble class I antigens: a conundrum with no solution? PMID- 25290434 TI - Two types of mouse helper T-cell clone Implications for immune regulation. AB - Lymphocytes mediate many important functions of the immune system, such as antibody production, cytotoxicity, and immediate and delayed type hypersensitivity (DTH). In 1968, two major divisions of lymphocytes were recognized: B cells (derived from bone marrow) that produce antibody, and T cells (thymus-dependent) responsible for DTH, cytotoxicity, and regulation of many B- and T-cell functions. The discovery of subset-specific cell surface antigens subsequently allowed division of T cells into two classes: mainly responsible for helper and DTH functions, T cells bearing Lyt-1 and L3T4 antigens, and T cells bearing the Lyt-2 antigen responsible for the majority of cytotoxic and suppressor functions. Evidence from studies with normal cell populations and T cell clones has since suggested that the Lyt-1(+)L3T4(+)Lyt-2(-) helper T cell population can be divided into at least two types. In this article, Tim Mosmann and Robert Coffman review evidence for this subdivision obtained with T-cell clones grown in vitro and discuss the implications of differences in function and lymphokine synthesis between the two types of cloned helper T cell. PMID- 25290435 TI - Immune regulation in schistosomiasis japonica. AB - In schistosomiasis caused by the blood fluke, Schistosoma japonicum, the major lesion responsible for clinical disease is the granuloma formed in the liver as an immune response to the eggs deposited there. In this review Abram Stavitsky discusses the most recent evidence for the mechanisms involved in the formation and spontaneous regression of the granulomas and presents a working hypothesis to guide future research. PMID- 25290436 TI - 'Nonspecific' MHC-unrestricted killer cells and their receptors. AB - The receptors involved in apparently nonspecific, MHC- unrestricted effector cell target cell interaction and lysis continue to raise controversy. They bind to distinct ligands on their target cells and activate diverse cellular functions such as gene expression, lymphokine production, proliferation and/or cytolytic activity by the effector cells. Several distinct receptors may mediate MHC unrestricted cytotoxicity. Here, Peter Hersey and Reinder Bolhuis review evidence that the four main receptors involved in triggering this form of lytic activity are the CD2 molecule (the sheep red cell receptor), CD3-associated alphabeta chain T-cell receptor (TCR), the gammadelta chain TCR-CD3 complex and the CD16 molecule (the IgG0Fc receptor). The apparent non-specificity specificity of killing is a reflection of the widespread expression of natural ligands for these receptors on target cells. PMID- 25290437 TI - The recognition of influenza A virus- infected cells by cytotoxic T lymphocytes. AB - Cytotoxic T cells (Tc) are important in the immune destruction of virus-infected cells. Recent studies, reviewed here by David Wraith, have disclosed much about the proteins of inlfuenza virus that are recognized by Tc and the nature of the recognition process. These findings have implications for an understanding of antigen presentation and the design of influenza vaccines. PMID- 25290438 TI - The immunobiology of Chlamydia. AB - Bacteria of the genus Chlamydia cause a wide variety of disorders in animals and people worldwide. The immune response to chlamydiae is poorly understood and, as Daniel Levitt shows here, there is recent evidence that these organisms induce perturbations in immune function that may assist their own survival in infected hosts and that of co-infecting microbes. PMID- 25290440 TI - Integration of multiple memories in sensory preconditioning. AB - The present study demonstrates that humans' response to a single stimulus (S1) is determined by what follows S1's associates. The experiment used a sensory preconditioning (SPC) design where S1 was associated with both S2 and S3 on separate trials before establishing relationships between these latter stimuli with an outcome or its absence in a second phase. When S2 and S3 were associated with the same consequence, either an outcome or its absence, strong consequence based responding to S1 was observed in a reaction time test. Participants responded quickly to indicate that the outcome was, or was not, predicted by S1. When S2 predicted the outcome and S3 did not, SPC was weaker although participants were not slower to respond to S1. Implications on the understanding of the mechanisms that allow for the response to S1 to emerge are discussed. PMID- 25290442 TI - Salivary antibody response to streptococci in preterm and fullterm children: a prospective study. AB - OBJECTIVES: Secretory immunoglobulins present in mucosa surfaces represent the first line of defense of the adaptive immune system against infectious challenges. Preterm (PT) neonates' humoral immunity is diminished compared to full-term (FT) newborns. The identification of important antigens (Ags) of virulence of oral species may help in the investigation of the mechanisms of antigenic stimulation and the development of the mucosal immune response. In the present study, we measured saliva levels of immunoglobulins A (IgA) and M (IgM) and characterized the specificity of IgA against Ags of several streptococcal species found early in life. METHODS: This was a prospective observational study. Salivary IgA (sIgA) antibody responses to bacterial species that are prototypes of pioneer (Streptococcus mitis, S. sanguinis, S. gordonii) and pathogenic (Streptococcus mutans) microorganisms of the oral cavity were studied in FT and PT children in two visits: at birth (T0) and at 3 months of age (T3). Salivas from 123 infants (72 FT and 51 PT) were collected during the first 10h after birth (T0) and again at 3 months of age (T3). Salivary levels of IgA and IgM antibodies were analysed by enzyme-linked immunosorbent assay (ELISA). A subgroup of 26 FT and 24 PT children were compared with respect to patterns of antibody specificities against different streptococci Ags using Western blot assays. RESULTS: No significant differences (P>0.05) in salivary levels of IgA and IgM between FT and PT babies were found at birth. At T3, mean sIgA values were similar between groups and sIgM levels were significantly higher in PT than FT (P<0.05). Western blot assays identified positive IgA response to streptococci in the majority of children, especially in the FT group. There were some differences between groups in relation to the frequency of children with positive response to Ags and intensity of IgA response. In general, oral streptococci Ags were more frequently detected and bands were more intense in FT than in PT, especially in T3. Prospective analysis of patterns of sIgA against Ags of different streptococcal species revealed an increase in complexity of the sIgA antibody response from the first day of birth (T0) to T3 in PT and FT. CONCLUSION: The patterns of sIgA response to streptococci Ags appear to be influenced by the gestational age, which might reflect the level of immunological maturity of the mucosal immune system. PMID- 25290443 TI - Are telehealth technologies for hypertension care and self-management effective or simply risky and costly? AB - Hypertension is a prevalent chronic disease that requires ongoing management and self-care. The disease affects 31% of American adults and contributed to or caused the deaths of 348,000 Americans in 2008, fewer than 50% of whom effectively self-managed the disease. However, self-management is complex, with patients requiring ongoing support and easy access to care. Telehealth may help foster the knowledge and skills necessary for those with hypertension to engage in successful self-management. This paper considers the applicability, efficacy, associated risks, and cost-effectiveness of telehealth for individuals and populations with hypertension. Telehealth is a broad term, encompassing telemedicine and mobile health that is used for physician-patient interactions, diagnostics, care delivery, education, information sharing, monitoring, and reminders. Telemedicine may have considerable utility for people diagnosed with hypertension who have poor access or social barriers that constrain access, but potential risks exist. Telehealth technology is evolving rapidly, even in the absence of fully proven cost-effectiveness and efficacy. Considering the cost of inpatient and emergency department care for patients with hypertension, telehealth is a highly attractive alternative, but there are risks to consider. Incorporating telehealth, which is increasingly characterized by mobile health, can increase both the capacity of health care providers and the reach of patient support, clinical management, and self-care. Telehealth studies need improvement; long-term outcome data on cardiovascular events must be obtained, and robust risk analyses and economic studies are needed to prospectively evaluate the safety and cost savings for hypertension self-management. PMID- 25290444 TI - Infants learn what they want to learn: responding to infant pointing leads to superior learning. AB - The majority of current developmental models prioritise a pedagogical approach to knowledge acquisition in infancy, in which infants play a relatively passive role as recipients of information. In view of recent evidence, demonstrating that infants use pointing to express interest and solicit information from adults, we set out to test whether giving the child the leading role in deciding what information to receive leads to better learning. Sixteen-month-olds were introduced to pairs of novel objects and, once they had pointed to an object, were shown a function for either the object they had chosen, or the object they had ignored. Ten minutes later, infants replicated the functions of chosen objects significantly more than those of un-chosen objects, despite having been equally visually attentive during demonstrations on both types of objects. These results show that offering information in response to infants' communicative gestures leads to superior learning (Experiment 1) and that this difference in performance is due to learning being facilitated when infants' pointing was responded to, not hindered when their pointing was ignored (Experiment 2), highlighting the importance of infants' own active engagement in acquiring information. PMID- 25290445 TI - Locational diversity of alpha satellite DNA and intergeneric hybridization aspects in the Nomascus and Hylobates genera of small apes. AB - Recently, we discovered that alpha satellite DNA has unique and genus-specific localizations on the chromosomes of small apes. This study describes the details of alpha satellite localization in the genera Nomascus and Hylobates and explores their usefulness in distinguishing parental genome sets in hybrids between these genera. Fluorescence in situ hybridization was used to establish diagnostic criteria of alpha satellite DNA markers in discriminating small ape genomes. In particular we established the genus specificity of alpha satellite distribution in three species of light-cheeked gibbons (Nomascus leucogenys, N. siki, and N. gabriellae) in comparison to that of Hylobates lar. Then we determined the localization of alpha satellite DNA in a hybrid individual which resulted from a cross between these two genera. In Nomascus the alpha satellite DNA blocks were located at the centromere, telomere, and four interstitial regions. In Hylobates detectable amounts of alpha satellite DNA were seen only at centromeric regions. The differences in alpha satellite DNA locations between Nomascus and Hylobates allowed us to easily distinguish the parental chromosomal sets in the genome of intergeneric hybrid individuals found in Thai and Japanese zoos. Our study illustrates how molecular cytogenetic markers can serve as diagnostic tools to identify the origin of individuals. These molecular tools can aid zoos, captive breeding programs and conservation efforts in managing small apes species. Discovering more information on alpha satellite distribution is also an opportunity to examine phylogenetic and evolutionary questions that are still controversial in small apes. PMID- 25290446 TI - Cerebellar and cortical abnormalities in paediatric opsoclonus-myoclonus syndrome. AB - AIM: Paediatric opsoclonus-myoclonus syndrome (OMS) is a poorly understood condition with long-term cognitive, behavioural, and motor sequelae. Neuroimaging has indicated cerebellar atrophy in the chronic phase, but this alone may not explain the cognitive sequelae seen in many children with OMS. This study aimed to determine the extent of structural change throughout the brain that may underpin the range of clinical outcomes. METHOD: Nine participants with OMS (one male, eight females; mean age [SD] 14y, [6y 5mo], range 12-30y) and 10 comparison individuals (three males, seven females; mean age 12y 6mo, [4y 9mo], range 10 23y) underwent magnetic resonance imaging to acquire T1-weighted structural images, diffusion-weighted images, and magnetic resonance spectroscopy scans. Neuroblastoma had been present in four participants with OMS. Voxel-based morphometry was used to determine changes in grey matter volume, tract-based spatial statistics to analyze white matter integrity, and Freesurfer to analyze cortical thickness across visual and motor cortices. RESULTS: Whole-brain analysis indicated that cerebellar grey matter was significantly reduced in the patients with OMS, particularly in the vermis and flocculonodular lobe. A region of-interest analysis indicated significantly lower cerebellar grey matter volume, particularly in patients with the greatest OMS scores. Diffusion-weighted images did not show effects at a whole brain level, but all major cerebellar tracts showed increased mean diffusivity when analysis was restricted to the cerebellum. Cortical thickness was reduced across the motor and visual areas in the OMS group, indicating involvement beyond the cerebellum. INTERPRETATION: Across individuals with OMS, there is considerable cerebellar atrophy, particularly in the vermis and flocculonodular lobes with atrophy severity associated with persistent symptomatology. Differences in cerebral cortical thickness indicate disease effects beyond the cerebellum. PMID- 25290447 TI - Circulating interleukin-18 as a biomarker of total-body radiation exposure in mice, minipigs, and nonhuman primates (NHP). AB - We aim to develop a rapid, easy-to-use, inexpensive and accurate radiation dose assessment assay that tests easily obtained samples (e.g., blood) to triage and track radiological casualties, and to evaluate the radioprotective and therapeutic effects of radiation countermeasures. In the present study, we evaluated the interleukin (IL)-1 family of cytokines, IL-1beta, IL-18 and IL-33, as well as their secondary cytokines' expression and secretion in CD2F1 mouse bone marrow (BM), spleen, thymus and serum in response to gamma-radiation from sublethal to lethal doses (5, 7, 8, 9, 10, or 12 Gy) at different time points using the enzyme-linked immune sorbent assay (ELISA), immunoblotting, and cytokine antibody array. Our data identified increases of IL-1beta, IL-18, and/or IL-33 in mouse thymus, spleen and BM cells after total-body irradiation (TBI). However, levels of these cytokines varied in different tissues. Interestingly, IL 18 but not IL-1beta or IL-33 increased significantly (2.5-24 fold) and stably in mouse serum from day 1 after TBI up to 13 days in a radiation dose-dependent manner. We further confirmed our finding in total-body gamma-irradiated nonhuman primates (NHPs) and minipigs, and demonstrated that radiation significantly enhanced IL-18 in serum from NHPs 2-4 days post-irradiation and in minipig plasma 1-3 days post-irradiation. Finally, we compared circulating IL-18 with the well known hematological radiation biomarkers lymphocyte and neutrophil counts in blood of mouse, minipigs and NHPs and demonstrated close correlations between these biomarkers in response to radiation. Our results suggest that the elevated levels of circulating IL-18 after radiation proportionally reflect radiation dose and severity of radiation injury and may be used both as a potential biomarker for triage and also to track casualties after radiological accidents as well as for therapeutic radiation exposure. PMID- 25290449 TI - Redescription and phylogenetic analysis of the mandible of an enigmatic Pennsylvanian (Late Carboniferous) tetrapod from Nova Scotia, and the lability of Meckelian jaw ossification. AB - The lower jaw of an unidentified Pennsylvanian (Late Carboniferous) tetrapod from Nova Scotia--the "Parrsboro jaw"--is redescribed in the light of recent tetrapod discoveries and work on evolution of tetrapod mandibular morphology and placed for the first time in a numerical cladistics analysis. All phylogenetic analyses place the jaw in a crownward polytomy of baphetids, temnospondyls, and embolomeres. Several features resemble baphetids and temnospondyls including dermal ornamentation, absence of coronoid teeth, and presence of coronoid shagreen. Dentary dentition is most similar to Baphetes. An adsymphysial toothplate may not preclude temnospondyl affinity. An apparent large exomeckelian fenestra, with the dorsal foraminal margins formed by an unossified element, echoes the morphology of the stem tetrapod Sigournea and is unusually primitive given the other features of the jaw. The jaw may thus provide an example of an intermediate stage in Meckelian element evolution. PMID- 25290448 TI - Host genetic variants and gene expression patterns associated with Epstein-Barr virus copy number in lymphoblastoid cell lines. AB - Lymphoblastoid cell lines (LCLs) are commonly used in molecular genetics, supplying DNA for the HapMap and 1000 Genomes Projects, used to test chemotherapeutic agents, and informing the basis of a number of population genetics studies of gene expression. The process of transforming human B cells into LCLs requires the presence of Epstein-Barr virus (EBV), a double-stranded DNA virus which through B-cell immortalisation maintains an episomal virus genome in every cell of an LCL at variable copy numbers. Previous studies have reported that EBV alters host-gene expression and EBV copy number may be under host genetic control. We performed a genome-wide association study of EBV genome copy number in LCLs and found the phenotype to be highly heritable, although no individual SNPs achieved a significant association with EBV copy number. The expression of two host genes (CXCL16 and AGL) was positively correlated and expression of ADARB2 was negatively correlated with EBV copy number in a genotype independent manner. This study shows an association between EBV copy number and the gene expression profile of LCLs, and suggests that EBV copy number should be considered as a covariate in future studies of host gene expression in LCLs. PMID- 25290451 TI - NK cells, anti-tumor surveillance and interleukins. PMID- 25290452 TI - Anti-MHC antibody idiotypes as important elements in immunoregulation. PMID- 25290450 TI - A transcriptome for the study of early processes of retinal regeneration in the adult newt, Cynops pyrrhogaster. AB - Retinal regeneration in the adult newt is a useful system to uncover essential mechanisms underlying the regeneration of body parts of this animal as well as to find clues to treat retinal disorders such as proliferative vitreoretinopathy. Here, to facilitate the study of early processes of retinal regeneration, we provide a de novo assembly transcriptome and inferred proteome of the Japanese fire bellied newt (Cynops pyrrhogaster), which was obtained from eyeball samples of day 0-14 after surgical removal of the lens and neural retina. This transcriptome (237,120 in silico transcripts) contains most information of cDNAs/ESTs which has been reported in newts (C. pyrrhogaster, Pleurodeles waltl and Notophthalmus viridescence) thus far. On the other hand, de novo assembly transcriptomes reported lately for N. viridescence only covered 16-31% of this transcriptome, suggesting that most constituents of this transcriptome are specific to the regenerating eye tissues of C. pyrrhogaster. A total of 87,102 in silico transcripts of this transcriptome were functionally annotated. Coding sequence prediction in combination with functional annotation revealed that 76,968 in silico transcripts encode protein/peptides recorded in public databases so far, whereas 17,316 might be unique. qPCR and Sanger sequencing demonstrated that this transcriptome contains much information pertaining to genes that are regulated in association with cell reprogramming, cell-cycle re entry/proliferation, and tissue patterning in an early phase of retinal regeneration. This data also provides important insight for further investigations addressing cellular mechanisms and molecular networks underlying retinal regeneration as well as differences between retinal regeneration and disorders. This transcriptome can be applied to ensuing comprehensive gene screening steps, providing candidate genes, regardless of whether annotated or unique, to uncover essential mechanisms underlying early processes of retinal regeneration. PMID- 25290454 TI - Antibody diversification by somatic mutation. PMID- 25290453 TI - Do cytotoxic T-lymphocytes cause transplant rejection? PMID- 25290455 TI - B-cell development. AB - The B cell population represents an extremely complex set of cells with respect to the existence of funclional and developmental cell subpopulations and their extremely diverse repertoire of antibody specificities. This article summarizes the key features of the ontogeny and developmental stages of murine B cells, the subjects of a recent extensive review(1), and considers several crucial unresolved issues central to the ultimate understanding of B cell function and expression. PMID- 25290456 TI - Thymic education. AB - T lymphocytes use major histocompatibility antigens as cell markers. During T cell induction by antigen from a resting state and during performance of effector, function, the self histocompatibility molecules must be recognized along with foreign antigen. The same markers expressed in the thymus are responsible, for selecting The T-cell receptor repertoire. In this review Michael Becan discusses the involvement of histocompatibility antigens in T-cell ontogeny. PMID- 25290457 TI - Controlling influenza epidemics. AB - Vaccination in most countries against influenza virus epidemics is by administration of either inactivated (non-infectious) whole virus preparations or a preparation which contains isolated viral antigens. There is considerable evidence to indicate that natural infection of humans by influenza virus confers more complete and long-lasting protection against subsequent outbreaks than does vaccination with inactivated whole virus and, presumably, subunit vaccines. This article summarizes recent evidence supporting these epidemiological observations. PMID- 25290458 TI - The multi-faceted zinc dependency of the immune system. AB - Zinc is an essential element in The development and function of the immune system. This article reviews some of the newest data on its role in immunity. PMID- 25290459 TI - The prevention and treatment effects of tanshinone IIA on oestrogen/androgen induced benign prostatic hyperplasia in rats. AB - Benign prostatic hyperplasia (BPH) is one of the major diseases of the urinary system in elderly men. Tanshinone IIA (Tan IIA) is the active ingredient extracted from the traditional Chinese medicine Salvia, and it has effects of anti-oxidation, anti-inflammation, vascular smooth muscle relaxation and tumour growth inhibition. The present study aimed to investigate the therapeutic potential of Tan IIA in the prevention and treatment of BPH. In a rat model of oestradiol/testosterone-induced BPH, Tan IIA inhibited the increase in the thickness of the peri-glandular smooth muscle layer, suppressed the expression of proliferating cell nuclear antigen (PCNA) in both prostate epithelial cells and stromal cells, downregulated the expression of androgen receptor (AR), oestrogen receptor alpha (ERalpha), cyclin B1 (CCNB1) and cyclin D1 (CCND1), and effectively prevented the development of the disorder. In vitro, Tan IIA inhibited the proliferation of human prostate stromal cell line WPMY-1 and epithelial cell line RWPE-1 in a dose- and time-dependent manner. In WPMY-1 cells, Tan IIA treatment arrested the cell cycle at the G2/M phase and downregulated the expression of CCNB1. However, in RWPE-1 cells, Tan IIA treatment arrested cell cycle at the G0/G1 phase and reduced the expression of CCND1. Tan IIA also reduced the expression of ERalpha and AR in WPMY-1 and RWPE-1 cells. These results suggest that Tan IIA can inhibit the growth of prostate stromal and epithelial cells both in vivo and in vitro by a mechanism that may involve arresting the cell cycle and downregulating ERalpha and AR expression. PMID- 25290460 TI - Aggregation of whey protein hydrolysate using Alcalase 2.4 L. AB - Here, we describe peptide aggregation, which is also known as enzymatic protein resynthesis. Whey protein hydrolysate (WPH) is the starting material for assembling peptides. Analyses of the involved amino acids, intrinsic fluorescence, fluorescence phase diagram, secondary structure, turbidity, and surface hydrophobicity were performed to investigate the reaction process. The aggregation mechanism consists of two parts: 1) formation and 2) aggregation of the building blocks that form the ordered secondary beta-sheet structure. Constructing the building blocks requires at least one intermediate state, which is formed after 0.5 hours. Non-synergistic changes in the secondary and tertiary structures then allow the intermediate state to emerge. PMID- 25290462 TI - Gambogic acid-loaded electrosprayed particles for site-specific treatment of hepatocellular carcinoma. AB - This study aims to assess the targeted effect and antitumor efficacy of Gambogic acid-loaded particles (GA-Ps). GA-Ps with uniform particle sizes of 69.8 +/- 17.8 nm (GA-P1), 185.6 +/- 33.8 nm (GA-P2), 357.8 +/- 81.5 nm (GA-P3), and 7.56 +/- 0.95 MUm (GA-P4) were prepared using an electrospray technique and exhibited extremely high entrapment efficiency. As the particle size increased from the nano- to microscale, the in vitro GA release rate sharply decreased. After tail vein injection in mice, GA-P samples GA-P1, GA-P2, GA-P3, and GA-P4 improved the uptake of GA 1.67-times in the liver, 1.78-times in the liver, 2.18-times in the spleen, and 2.35-times in the lung, respectively, compared with GA solution (GA S). The antitumor efficacy of GA-P2, with an 82.51% targeting efficiency (Te) for the liver, was examined in hepatocellular carcinoma (HCC) model mice. After 2 weeks of administration, HCC mice in the GA-P2 group exhibited a lower degree of tumor invasion and cell lesions in hepatic tissue, recovered liver function, and significantly prolonged survival time, compared with mice in the model, GA-S, and normal saline (NS) groups. Pharmacokinetic studies indicated that the superior antitumor efficacy of GA-P2 was attributed not only to tissue targeting but also to low clearance, extended retention, high bioavailability in plasma, and increased GA stability. PMID- 25290461 TI - Peyer's patches and mesenteric lymph nodes cooperatively promote enteropathy in a mouse model of food allergy. AB - BACKGROUND AND OBJECTIVE: To improve the efficacy and safety of tolerance induction for food allergies, identifying the tissues responsible for inducing intestinal inflammation and subsequent oral tolerance is important. We used OVA23 3 mice, which express an ovalbumin-specific T-cell receptor, to elucidate the roles of local and systemic immune tissues in intestinal inflammation. METHODS AND RESULTS: OVA23-3 mice developed marked enteropathy after consuming a diet containing egg white (EW diet) for 10 days but overcame the enteropathy (despite continued moderate inflammation) after receiving EW diet for a total of 28 days. Injecting mice with anti-IL-4 antibody or cyclosporine A confirmed the involvement of Th2 cells in the development of the enteropathy. To assess the individual contributions of Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and the spleen to the generation of effector CD4+ T-cells, we analyzed the IL-4 production, proliferation in response to ovalbumin, and CD4+ T-cell numbers of these tissues. EW feeding for 10 days induced significant IL-4 production in PPs, the infiltration of numerous CD4+ T-cells into MLNs, and a decrease in CD4+ T cell numbers in spleen. On day 28, CD4+ T-cells from all tissues had attenuated responses to ovalbumin, suggesting tolerance acquisition, although MLN CD4+ T cells still maintained IL-4 production with proliferation. In addition, removal of MLNs but not the spleen decreased the severity of enteropathy and PP-disrupted mice showed delayed onset of EW-induced inflammatory responses. Disruption of peripheral lymphoid tissues or of both PPs and MLNs almost completely prevented the enteropathy. CONCLUSIONS: PPs and MLNs coordinately promote enteropathy by generating effector T-cells during the initial and exacerbated phases, respectively; the spleen is dispensable for enteropathy and shows tolerogenic responses throughout EW-feeding. The regulation of PPs may suppress the initiation of intestinal inflammation, subsequently restricting MLNs and inhibiting the progression of food-allergic enteropathy. PMID- 25290464 TI - Effectiveness of permethrin-treated clothing to prevent tick exposure in foresters in the central Appalachian region of the USA. AB - Outdoor workers are at risk from mosquito and tick bites and the extent to which exposures are linked to vector-borne disease is not understood. This pilot study characterizes for ester exposure to mosquitoes and ticks, and assesses effectiveness of permethrin-treated clothing for prevention of tick bites. Foresters (N = 34) from Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia were placed into treatment (permethrin-treated clothing) or control (untreated clothing) groups. Foresters completed questionnaires about work related tick/mosquito exposure and 454 ticks were collected/identified from May to June 2013. A time-weighted analysis based on information submitted by foresters about time working outdoors showed that control participants received a lower rate of tick exposure (0.15 tick bites/hour; 13 bites/person) compared to treatment participants (0.27 bites/hour; 21 bites/person). However, more control participants (85 %) received at least one tick bite compared to treatment participants (52 %). Outdoor workers should be aware of available protective measures, such as permethrin-treated clothing, that may mitigate occupational risks. PMID- 25290465 TI - Determining the threshold of time-delay for teleoperation accuracy and efficiency in relation to telesurgery. AB - BACKGROUND: Advances in robotics have made teleoperated surgical procedures a feasible means of treating patients in remote locations. In this study a suite of experiments was performed to investigate the influence of time-delay on teleoperation accuracy and efficiency during a path-following task. MATERIALS AND METHODS: Subjects used a Phantom Omni 6-degrees of freedom (dof) input device (Sensable, Triangle Park, NC) to move the end-effector of a Mitsubishi (Tokyo, Japan) PA-10 7-dof robotic manipulator along a prescribed path. End-effector motion was recorded using a video motion capture system. Time-delays ranging from 0 to 2.5 s were artificially imposed. Performance was quantified by time to complete the task, path length, and square root-mean-square (RMS) error. Randomization of time-delay order and allowance for practice runs reduced the learning effect. An imposed time limit and pacing were used to negate the move and-pause strategy that emerged in early trials. RESULTS: Time to complete the task and RMS error generally increased with increasing time-delay. Path length also generally increased, but not as consistently. With imposed pacing, RMS error continued to increase beyond 1.5 s, and some subjects were not able to complete the task in the allotted 90 s. CONCLUSIONS: The results suggest a threshold of time-delay in the range of 1.5-2.0 s. Beyond 1.5 s, subjects adopted a move-and pause strategy that increased completion time to preserve path-tracking accuracy. If paced, tracking accuracy tended to degrade substantially beyond 1.5 s. A strong learning effect was evident, and experienced teleoperators performed substantially better than novices. PMID- 25290466 TI - Molecules, membranes and macrophage activation. PMID- 25290463 TI - Cognitive control network function in alcohol use disorder before and during treatment with lorazepam. AB - Individuals with alcohol use disorders (AUDs) have deficits in cognitive control, but how they change with treatment is unclear. Seven patients with AUD and anxiety from an open-label trial of disulfiram plus lorazepam performed a multisensory Stroop task during fMRI (both pre and post initiation of treatment), and were compared to nine healthy controls (HCs) (n = 16; Albuquerque, NM; years 2009-2012). Evoked BOLD signal and resting state functional connectivity were compared (HC vs. AUD; Scan 1 vs. Scan 2). AUD demonstrated hyperactivity and altered connectivity in the cognitive control network compared to HC, but treatment did not normalize function. PMID- 25290467 TI - The central nervous system and learning: a strategy for immune regulation. PMID- 25290468 TI - Hybridomas produce viruses as well as antibodies. PMID- 25290469 TI - Where do autoantibodies come from? PMID- 25290470 TI - Cellular interactions involved in T-dependent B-cell activation. AB - in this article, Michael Julius provides a framework within which to consider the activation requirements of B cells limited by T-helper cell activation and recognitive properties associated with effeclor function, focusing mainly on the requirement for an MHC-restricted T-B interaction. PMID- 25290471 TI - Cyclic nucleotides in mitogen-induced lymphocyte proliferation. PMID- 25290472 TI - The lymphocytes of splenic marginal zones: a distinct B-cell lineage. AB - In a recent article on B-cell development Klinman and his colleagues asked the question 'Do B cells exist as separate lineages?'. Studies of B cells in rat spleen support on affirmative answer to this question. Here Ian MacLennan and his colleagues discuss the nature, function and origins of a mayor population of B cells in human and rat spleens which populate the marginal zones, comparing them with recirculating lymphocytes found in the follicles of all secondary lymphoid tissue. PMID- 25290473 TI - Humoral immune response to liposomes. PMID- 25290486 TI - Three-dimensional macromolecules Obtainable from Carolina Biological Supply Company, Burlington, NC 27215, U.S.A. $17.95 (incl. booklet and 5 viewers). PMID- 25290492 TI - New Zealand health professional organisations' joint call for action on climate change and health. PMID- 25290491 TI - 3',4'-Dihydroxyflavonol attenuates spatial learning and memory impairments in global cerebral ischemia. AB - OBJECTIVES: In the present study, effects of 3',4'-dihydroxyflavonol (DiOHF) on anxiety-like behavior, and learning and memory were investigated in a model of transient global cerebral ischemia and reperfusion. METHODS: The animals were assigned to sham-operated, ischemia, and two DiOHF-treated (10 mg/kg i.p.) groups. DiOHF was administered at 1 hour before and immediately after the ischemia. Male rats were subjected to bilateral common carotid artery occlusion to induce acute cerebral ischemia for 20 minutes, followed by reperfusion for 7 days. The openfield, elevated plus maze (EPM), and Morris water maze tests were used to evaluate the effects of DiOHF treatment on ischemia-induced locomotor activity, anxiety-like behavior, and spatial and recognition memory impairments, respectively. RESULTS: In the open field test, locomotor activity in the ischemic rats was not altered 6 days after the ischemia, nor was anxiety-like behavior, which was evaluated with the EPM (P > 0.05). In the water-maze test, cerebral ischemia significantly decreased the exploration time in the target quadrant, and the platform crossing counts were lower (P < 0.05) in the probe trial test; this memory impairment was significantly improved by DiOHF applied 1 hour before and immediately after ischemia (P < 0.05). DISCUSSION: All together, these findings suggest that DiOHF reverses spatial learning and memory deficits resulting from transient global ischemia but has no significant effect on anxiety-like behavior. PMID- 25290493 TI - Medical careers--nature or nurture? PMID- 25290494 TI - Influence of rural background and rural medical training on postgraduate medical training and location in New Zealand. AB - AIMS: To evaluate the influence of the Otago Medical Programme's rural entry pathway and rural immersion programme on postgraduate medical training and location. METHODS: Retrospective cohort study of 2008-2011 medical school graduates. Rural background/training included students gaining preferential entry to medical training based on rural residence or schooling, and/or those who spent a year training in a rural setting. Postgraduate medical training and location were obtained from the NZ Medical Register in December 2013. RESULTS: 112/733 students (15.3%) had rural background/training. Significantly more students with rural background/training were training in rural hospital medicine or general practice after graduation. Multiple logistic regression identified both variables (rural background and rural training) as independently statistically significant (Odds Ratios (95%CI); rural background OR 2.1, 95%CI 1.2-3.6; rural training OR 2.5, 95%CI 1.4-4.5; p=0.002). Almost twice as many students with rural background/training were working in non-Major Urban Centres. CONCLUSIONS: These findings are similar to international reports on the influence of medical schools' rural initiatives on postgraduate training choices and practice location. University policies aimed at increasing the proportion of medical graduates practising in rural areas appear to be working as intended. PMID- 25290495 TI - Poisoning following exposure to chemicals stored in mislabelled or unlabelled containers: a recipe for potential disaster. AB - AIM: To investigate poisoning exposures to chemicals that were unlabelled, mislabelled or not in their original containers in New Zealand over the last 10 years, based on calls to the New Zealand National Poisons Centre (NZNPC). METHODS: Call data from the NZNPC between 2003 and 2012 were analysed retrospectively. Parameters reviewed included patient age, route and site of exposure, product classification and recommended intervention. RESULTS: Of the 324,411 calls received between 2003 and 2012, 100,465 calls were associated with acute human exposure to chemicals. There were 757 inquiries related to human exposure to mislabelled or unlabelled chemicals consisting of 0.75% of chemical exposures. Adults were involved in 51% of incidents, children, <5 years 32%, 5-10 years 10%, and adolescents 5%. Child exploratory behaviour was responsible for 38% of calls and adult unintentional exposures 61%. Medical attention was advised in 26% of calls. CONCLUSION: Inadvertent exposure to toxic products stored in unlabelled or mislabelled containers is a problem for all age groups. Although it represents a small proportion of total calls to the NZNPC it remains a potential risk for serious poisoning. It is important that chemicals are stored securely, in their original containers, and never stored in drinking vessels. PMID- 25290496 TI - Local impact of 'Antenatal Screening for Down syndrome and other conditions' on diagnosis and outcomes in a fetal medicine centre in New Zealand. AB - AIM: In 2010, the National Screening Unit of the Ministry of Health launched 'Antenatal Screening for Down syndrome and other conditions'. Our aim was to assess the local impact of the new screening process on the number and outcomes of women attending a south island Fetal Medicine Centre. METHODS: Retrospective audit; two time periods (T1 and T2) were reviewed. Data was prospectively collected in a viewpoint database and combined with data from other hospital databases and laboratories. Outcome measures included invasive procedures done and results and MSS1 results. Statistical analysis was done using Open Epi software. RESULTS: 51% of women who were pregnant in T2 underwent MSS1 screening. There was a statistically significant decrease in the number of invasive procedures carried out 2.9% (175) vs. 4.1% (253), p0.0003 in T2. The proportion of procedures undertaken by Chorionic Villus Sampling and amniocentesis did not change. In both time periods no babies with Down syndrome were born following pregnancies where screening was undertaken and was low risk. CONCLUSIONS: The implementation of the new antenatal screening process in Canterbury has so far proved to be successful in maintaining detection rates of genetic anomalies whilst decreasing the numbers of invasive diagnostic procedures being done. PMID- 25290497 TI - Warfarin reversal: an audit of prescribing practices at Capital and Coast District Health Board. AB - AIMS: In March 2013 the Australasian Society of Thrombosis and Haemostasis published an update of the Consensus Guidelines for Warfarin Reversal.3 We reviewed the prescribing practices at Capital and Coast District Health Board (CCDHB), following publication of the updated guidelines. METHODS: Patients were identified through multiple sources. CCDHB Medical Records identified admissions coded as "Haemorrhagic disorder due to circulating anticoagulants" or "Anticoagulants causing adverse effects in therapeutic use". CCDHB Haematology Laboratory identified International Normalised Ratio (INR) results greater than or equal to 4.5. Wellington Hospital Pharmacy identified patients dispensed vitamin K. New Zealand Blood Service identified recipients of Prothrombinex VF(reg.) and Fresh Frozen Plasma (FFP). RESULTS: The management of patients with elevated INR results or bleeding on warfarin therapy was consistent with the updated guidelines in 81/149 episodes. Thirty one patients received FFP unnecessarily and 24 patients did not receive Prothrombinex-VF when indicated. The greatest variability in management occurred in patients with bleeding complications and in patients requiring urgent warfarin reversal to allow acute surgery to proceed with only 5/31 patients and 5/21 patients having warfarin reversed as recommended. In some episodes more than one error was identified. CONCLUSIONS: The audit identified the suboptimal use of Prothrombinex-VF and the unnecessary use of FFP in the management of warfarin reversal. PMID- 25290498 TI - The changing landscape of antimicrobial resistance in New Zealand. AB - Antimicrobial resistance is one of the biggest health threats of the modern age, threatening the routine treatment of many common infectious diseases. Resistance to many common antimicrobials is now endemic in New Zealand, in both community and healthcare settings. Over the past two decades, the landscape of antimicrobial resistance has changed considerably in New Zealand, with the emergence and spread of pathogens such as community-associated methicillin resistant Staphylococcus aureus, extended-spectrum beta-lactamase-producing Enterobacteriaceae and multi- resistant Neisseria gonorrhoeae. Factors contributing to the emergence and spread of antimicrobial-resistant pathogens in New Zealand include the use and overuse of antimicrobials, transmission of resistant organisms in community and healthcare settings, and importation of resistant pathogens from areas where multi-resistant pathogens are endemic. In this review, we provide a summary of major antimicrobial-resistant bacteria in New Zealand, with a specific focus on those pathogens that pose major threats to human health. PMID- 25290499 TI - New Zealand's mental health legislation needs reform to avoid discrimination. AB - New Zealand's Mental Health (Compulsory Assessment and Treatment) Act (the Act) is now over 20 years old. As has occurred historically our conceptualisation of humane treatment of people with mental illness has altered significantly over the period in which the Act has been in force. The emergence of the philosophy of recovery, and its subsequent policy endorsement, has seen a significant shift in mental health service delivery towards a greater emphasis on autonomy. Human rights developments such as New Zealand's ratification of the 2006 United Nations Convention on the Rights of Persons with Disabilities have resulted in compulsory treatment, where it is justified in whole or part by a person's mental illness, now being considered antithetical to best practice, and discriminatory. However the number of people subject to the Act is increasing, especially in community settings, and it is questionable how effective the mechanisms for challenging compulsion are in practice. Moreover, monitoring of the situation at the systemic level lacks critical analysis. Complacency, including no indication that review and reform of this now antiquated legislation is nigh, continues a pattern of old where the situation of people with experience of mental illness is largely ignored and neglected. PMID- 25290500 TI - DTCA in New Zealand, finding a healthy balance. PMID- 25290501 TI - Potential for electronic household food purchase data to enhance population nutrition monitoring. PMID- 25290503 TI - Macrocyclic peptides self-assemble into robust vesicles with molecular recognition capabilities. AB - In this study, we developed macrocyclic peptide building blocks that formed self assembled peptide vesicles with molecular recognition capabilities. Macrocyclic peptides were significantly different from conventional amphiphiles, in that they could self-assemble into vesicles at very high hydrophilic-to-total mass ratios. The flexibility of the hydrophobic self-assembly segment was critical for vesicle formation. The unique features of this peptide vesicle system include a homogeneous size distribution, unusually small size, and robust structural and thermal stability. The peptide vesicles successfully entrapped a hydrophilic model drug, released the payload very slowly, and were internalized by cells in a highly efficient manner. Moreover, the peptide vesicles exhibited molecular recognition capabilities, in that they selectively bound to target RNA through surface-displayed peptides. This study demonstrates that self-assembled peptide vesicles can be used as strong intracellular delivery vehicles that recognize specific biomacromolecular targets. PMID- 25290504 TI - Fast 3D gradient shimming by only 2*2 pixels in XY plane for NMR-solution samples. AB - Shimming is an essential process for most NMR experiments, and time saving in this process is desired. Here we propose a fast 3D gradient shimming with a low resolution of only 2*2 pixels in the XY plane, and the number of pixels in the Z direction remains unchanged. The proposed pulse sequences employ the selective excitation and the convection compensation. Consequently, the fast 3D gradient shimming adapts to a wide range of samples on regular NMR spectrometers. PMID- 25290505 TI - Adhesion as a weapon in microbial competition. AB - Microbes attach to surfaces and form dense communities known as biofilms, which are central to how microbes live and influence humans. The key defining feature of biofilms is adhesion, whereby cells attach to one another and to surfaces, via attachment factors and extracellular polymers. While adhesion is known to be important for the initial stages of biofilm formation, its function within biofilm communities has not been studied. Here we utilise an individual-based model of microbial groups to study the evolution of adhesion. While adhering to a surface can enable cells to remain in a biofilm, consideration of within-biofilm competition reveals a potential cost to adhesion: immobility. Highly adhesive cells that are resistant to movement face being buried and starved at the base of the biofilm. However, we find that when growth occurs at the base of a biofilm, adhesion allows cells to capture substratum territory and force less adhesive, competing cells out of the system. This process may be particularly important when cells grow on a host epithelial surface. We test the predictions of our model using the enteric pathogen Vibrio cholerae, which produces an extracellular matrix important for biofilm formation. Flow cell experiments indicate that matrix-secreting cells are highly adhesive and form expanding clusters that remove non-secreting cells from the population, as predicted by our simulations. Our study shows how simple physical properties, such as adhesion, can be critical to understanding evolution and competition within microbial communities. PMID- 25290506 TI - Global abundance of planktonic heterotrophic protists in the deep ocean. AB - The dark ocean is one of the largest biomes on Earth, with critical roles in organic matter remineralization and global carbon sequestration. Despite its recognized importance, little is known about some key microbial players, such as the community of heterotrophic protists (HP), which are likely the main consumers of prokaryotic biomass. To investigate this microbial component at a global scale, we determined their abundance and biomass in deepwater column samples from the Malaspina 2010 circumnavigation using a combination of epifluorescence microscopy and flow cytometry. HP were ubiquitously found at all depths investigated down to 4000 m. HP abundances decreased with depth, from an average of 72+/-19 cells ml(-1) in mesopelagic waters down to 11+/-1 cells ml(-1) in bathypelagic waters, whereas their total biomass decreased from 280+/-46 to 50+/ 14 pg C ml(-1). The parameters that better explained the variance of HP abundance were depth and prokaryote abundance, and to lesser extent oxygen concentration. The generally good correlation with prokaryotic abundance suggested active grazing of HP on prokaryotes. On a finer scale, the prokaryote:HP abundance ratio varied at a regional scale, and sites with the highest ratios exhibited a larger contribution of fungi molecular signal. Our study is a step forward towards determining the relationship between HP and their environment, unveiling their importance as players in the dark ocean's microbial food web. PMID- 25290508 TI - MHC antigens and non-immune functions. AB - Thirty years of study of the major histocompatibility complex (MHC) have resulted in a satisfying picture of this complex in two species, mice and humans. Drawn by immunologists, it shows us a multigene complex whose main function is recognition in immune responses. The picture is only sketched in many places, but it fills its canvas. It is vivid and aesthetically pleasing and in many places details have been added to the bare outlines. But this is not the only picture extant of MHC function. PMID- 25290507 TI - Impact of lifestyle on the gut microbiota of healthy infants and their mothers the ALADDIN birth cohort. AB - An anthroposophic lifestyle, which has been associated with reduced allergy risk in children, has several characteristics that could influence gut microbiota. This study aimed to investigate the impact of anthroposophic lifestyle as well as specific early life exposures on the gut microbiota. In total, 665 stool samples from 128 mother-infant pairs from the ALADDIN birth cohort study were included. Samples collected from infants at ages 6 days, 3 weeks, 2 months and 6 months, and from their mothers before and after delivery, respectively, were analyzed using 454-pyrosequencing. Information regarding lifestyle exposures was collected prospectively through interviews and questionnaires. Six-month-old infants in anthroposophic families had a significantly higher abundance of Bifidobacterium and lower abundances of Bacteroides and Veillonella. Caesarean section and breastfeeding had a significant impact on the microbiota: caesarean section was primarily associated with delayed colonization of Bifidobacterium and Bacteroides, whereas breastfed children had a higher relative abundance of Bifidobacterium and a lower abundance of Clostridiales. However, despite large differences in lifestyle exposures, we determined no significant differences in the gut microbiota between the anthroposophic and non-anthroposophic mothers or their infants' before 6 months of age. PMID- 25290509 TI - One man's answer to immunological information overload: microcomputer management of the personal reprint collection. AB - The subject of information overload in immunology has been addressed recently by Waksman, who proposed some innovative solutions for the afferent pathways(1,2), (see also reactions by Sanderson(3), Turk(4) and Franklin(5)). Here Eric Martz describes his solution for efferent overload. PMID- 25290510 TI - When does an autoimmune disease start? PMID- 25290511 TI - More on rat monoclonal antibodies. PMID- 25290512 TI - Human T-cell clones with multiple and changing functions: indications of unexpected flexibility in immune response networks? AB - T-cell cloning' seems greatly to assist the reductionist approach to the dissection of cellular immune response networks. Each of the cell types involved can apparently be cloned, studied in isolation, and then recombined. The success of this approach depends, however, on the ability to maintain functionally active cells long enough to obtain sufficient working material; and the assumption that a T cell is committed irrevocably to a particular defined function, so that its properties do not change during clonal expansion. In this article Graham Pawelec and his colleagues discuss a restriction on the maintenance of clones and question the notion that a clone's function is rigidly fixed. PMID- 25290513 TI - Interleukin 3 and colony-stimulating factors. PMID- 25290514 TI - alpha1-Anti-trypsin and macrophages in immunity. PMID- 25290515 TI - Intrathymic events in the differentiation of T lymphocytes: a continuing enigma. AB - The thymus plays an important role in the differentiation of T lymphocytes, but the exact nature of this role remains unclear. As Roland Scollay shows here, a careful analysis of available data shows how poorly we understand the role of the thymic cortex and medulla and how little we know of the exact processes which give rise to thymus-dependent peripheral T cells. PMID- 25290516 TI - B-cell hyperactivity in murine lupus I. Immunological abnormalities in lupus prone strains and the activation of normal B cells. AB - B-cell hyperactivity is the general and cardinal feature of murine and human systemic lupus erythematosus (SLE), the prototype organ-non-specific autoimmune disease. The defect(s) responsible could be intrinsic to B cells, secondary to T cell or macrophage abnormalities resulting in excessive help or deficient suppression, or could stem f rom qualitative/quantitative abnormalities of autoantigens. Here Argyrios Theofilopoulos and his colleagues review the immunopathological and cellular abnormalities observed in murine lupus and the factors currently thought to play a role in normal B-cell proliferation, differentiation and Ig class switching. Next month, in a second article, they discuss abnormalities in B-cell response to and/or overproduction of T-cell derived accessory signals which may explain the generalized B-cell hyperactivity associated with mouse and human lupus. PMID- 25290517 TI - Immunopathology of X-linked lymphoproliferative syndrome. AB - Certain rare clinical disorders provide unusual opportunities to test concepts of immunoregulation derived from purely experimental studies. X-linked lymphoproliferative syndrome (XLP) is one such disorder, as David Purtilo here describes. PMID- 25290524 TI - Milk thistle extract and silymarin inhibit lipopolysaccharide induced lamellar separation of hoof explants in vitro. AB - The pathogenesis of laminitis is not completely identified and the role of endotoxins (lipopolysaccharides, LPS) in this process remains unclear. Phytogenic substances, like milk thistle (MT) and silymarin, are known for their anti inflammatory and antioxidant properties and might therefore have the potential to counteract endotoxin induced effects on the hoof lamellar tissue. The aim of our study was to investigate the influence of endotoxins on lamellar tissue integrity and to test if MT and silymarin are capable of inhibiting LPS-induced effects in an in vitro/ex vivo model. In preliminary tests, LPS neutralization efficiency of these phytogenics was determined in an in vitro neutralization assay. Furthermore, tissue explants gained from hooves of slaughter horses were tested for lamellar separation after incubation with different concentrations of LPS. By combined incubation of explants with LPS and either Polymyxin B (PMB; positive control), MT or silymarin, the influence of these substances on LPS-induced effects was assessed. In the in vitro neutralization assay, MT and silymarin reduced LPS concentrations by 64% and 75%, respectively, in comparison PMB reduced 98% of the LPS concentration. In hoof explants, LPS led to a concentration dependent separation. Accordantly, separation force was significantly decreased by 10 ug/mL LPS. PMB, MT and silymarin could significantly improve tissue integrity of explants incubated with 10 ug/mL LPS. This study showed that LPS had a negative influence on the structure of hoof explants in vitro. MT and silymarin reduced endotoxin activity and inhibited LPS induced effects on the lamellar tissue. Hence, MT and silymarin might be used to support the prevention of laminitis and should be further evaluated for this application. PMID- 25290525 TI - Experiences of Patients With Advanced Lung Cancer: Being Resigned to Sleep-Wake Disturbances While Maintaining Hope for Optimal Treatment Outcomes. AB - BACKGROUND: Sleep-wake disturbances are prevalent in patients with lung cancer yet are infrequently studied over time. This article reports on the qualitative results of a mixed-methods study of newly diagnosed patients' narratives over 6 months. OBJECTIVE: The objective of this study was to gain an understanding of the treatment and illness trajectory related to sleep-wake disturbances as well as the beliefs and practices of patients while seeking optimal treatment outcomes. METHODS: Longitudinal interview narratives of 26 patients' experiences with advanced lung cancer diagnosis (at baseline, pre-second and third treatment, and 6 months) were obtained from participants recruited from Veterans Administration Hospital Center and a Comprehensive Cancer Center in Northeast United States. Analysis of illness narratives used interpretive phenomenology based on Heideggarian hermeneutic traditions. RESULTS: At diagnosis, participants described poor sleep such as trouble falling asleep and frequent awakenings. Over time, as the treatment worsened their sleep symptoms, these participants still maintained hope for more time with treatment. This focus enabled them to tolerate the sleep-wake disturbances and treatment adverse effects. As the treatment effectiveness declined, their focus changed to spiritual meanings for the future and to keep living life with a purpose. CONCLUSIONS: By explicating lung cancer patients' experiences with sleep-wake disturbances, nurses will gain insight into potential interventions to improve sleep and support effective outcomes as well as open a dialogue about hope. IMPLICATIONS FOR PRACTICE: Findings offer insight for oncology nurses to provide opportunities for dialogue about treatment options and techniques to improve sleep, which will facilitate patients living their lives. PMID- 25290526 TI - General and smoking cessation weight concern in a Hispanic sample of light and intermittent smokers. AB - This study assessed general and cessation related weight concerns in a Hispanic sample of light (<=10 cigarettes per day) and intermittent (non-daily smoking) smokers (LITS) participating in a brief smoking cessation intervention. Three hundred and fifty-four Hispanic LITS (Mage=34.2, SD=14; 51.1% male; 57.9% Mexican American; 59.0% daily light, 41.0% intermittent) completed baseline measures assessing demographics, tobacco use/history, stage of change (SOC), general weight concern, and cessation related weight concern. Three multiple logistic regression models examined potential predictors (i.e., age, gender, SOC, cigarettes per month, smoking status [daily vs non-daily], weight, cessation related weight concern, general weight concern) of general weight concern, cessation related weight concern, and past 30day abstinence (controlling for the intervention). Study results indicated that a majority of participants reported general weight concern (59.6%), and slightly more than a third (35.6%) reported post cessation weight gain concern (mean and median weight tolerated before relapse were within the 10-12lb range). Lower weight and endorsing general weight concern were associated with cessation related weight concern. Female gender, higher weight, and endorsing cessation related weight concern were associated with general weight concern. Monthly cigarette use was associated with smoking cessation at the three-month follow-up. The results indicate a substantial prevalence of general weight concern and non-trivial rates of cessation related weight concern in Hispanic LITS attempting to quit, and greater success in quitting among those who reported lower rates of cigarettes smoked per month. PMID- 25290527 TI - Do aggressive signals evolve towards higher reliability or lower costs of assessment? AB - It has been suggested that the evolution of signals must be a wasteful process for the signaller, aimed at the maximization of signal honesty. However, the reliability of communication depends not only on the costs paid by signallers but also on the costs paid by receivers during assessment, and less attention has been given to the interaction between these two types of costs during the evolution of signalling systems. A signaller and receiver may accept some level of signal dishonesty by choosing signals that are cheaper in terms of assessment but that are stabilized with less reliable mechanisms. I studied the potential trade-off between signal reliability and the costs of signal assessment in the corncrake (Crex crex). I found that the birds prefer signals that are less costly regarding assessment rather than more reliable. Despite the fact that the fundamental frequency of calls was a strong predictor of male size, it was ignored by receivers unless they could directly compare signal variants. My data revealed a response advantage of costly signals when comparison between calls differing with fundamental frequencies is fast and straightforward, whereas cheap signalling is preferred in natural conditions. These data might improve our understanding of the influence of receivers on signal design because they support the hypothesis that fully honest signalling systems may be prone to dishonesty based on the effects of receiver costs and be replaced by signals that are cheaper in production and reception but more susceptible to cheating. PMID- 25290528 TI - Organocatalytic route to dihydrocoumarins and dihydroquinolinones in all stereochemical configurations. AB - A straightforward stereodivergent route to dihydrocoumarins and dihydroquinolinones based on cinchona alkaloid catalyzed addition reactions of monothiomalonates (MTMs) to functionalized nitroolefins followed by deprotection and chemoselective cyclization has been developed. The synthesis proceeds under mild conditions and yields heterocycles with adjacent quaternary and tertiary stereogenic centers in very high yields and stereoselectivities. Moreover, full control over the relative and absolute configuration is achieved by the use of (pseudo)enantiomeric catalysts and the difference in reactivity of thioester versus oxoester moieties. PMID- 25290531 TI - Microvascular coupler-induced intimal crimping causing venous thrombosis. PMID- 25290529 TI - A consensus-based gold standard for the evaluation of mass casualty triage systems. AB - INTRODUCTION: Accuracy and effectiveness analyses of mass casualty triage systems are limited because there are no gold standard definitions for each of the triage categories. Until there is agreement on which patients should be identified by each triage category, it will be impossible to calculate sensitivity and specificity or to compare accuracy between triage systems. OBJECTIVE: To develop a consensus-based, functional gold standard definition for each mass casualty triage category. METHODS: National experts were recruited through the lead investigators' contacts and their suggested contacts. Key informant interviews were conducted to develop a list of potential criteria for defining each triage category. Panelists were interviewed in order of their availability until redundancy of themes was achieved. Panelists were blinded to each other's responses during the interviews. A modified Delphi survey was developed with the potential criteria identified during the interview and delivered to all recruited experts. In the early rounds, panelists could add, remove, or modify criteria. In the final rounds edits were made to the criteria until at least 80% agreement was achieved. RESULTS: Thirteen national and local experts were recruited to participate in the project. Six interviews were conducted. Three rounds of voting were performed, with 12 panelists participating in the first round, 12 in the second round, and 13 in the third round. After the first two rounds, the criteria were modified according to respondent suggestions. In the final round, over 90% agreement was achieved for all but one criterion. A single e-mail vote was conducted on edits to the final criterion and consensus was achieved. CONCLUSION: A consensus-based, functional gold standard definition for each mass casualty triage category was developed. These gold standard definitions can be used to evaluate the accuracy of mass casualty triage systems after an actual incident, during training, or for research. PMID- 25290532 TI - Single-stage, double-conduit microvascular pharyngotracheal reconstruction. PMID- 25290533 TI - Lubiprostone Is Effective in Treating Functional Bowel Disease With Constipation. PMID- 25290535 TI - Metal-ligand cooperation in H2 activation with iron complexes bearing hemilabile bis(diphenylphosphino)amine ligands. AB - The octahedral transition-metal complex [(dppa)Fe(Ph2P-N-PPh2)2] (1) [dppa = bis(diphenylphosphino)amine] with homofunctional bidentate ligands is described. The ligand exhibits hemilability due to its small bite angle and the steric repulsion of the coordinated donor groups. As the {Ph2P-N-PPh2}(-) ligand can act as an internal base, heterolytic cleavage of dihydrogen by complex 1 leads to the formation of the hydride complex [(dppa)(Ph2P-N-PPh2)Fe(H)(kappa(1)-Ph2P-NH PPh2)2] (2), representing an example of cooperative bond activation with a homofunctional hemilabile ligand. This study demonstrates that hemilability of homofunctionalized ligands can be affected by careful adjustment of geometric parameters. PMID- 25290534 TI - Safety and efficacy of endoscopic ultrasound-guided drainage of pancreatic fluid collections with lumen-apposing covered self-expanding metal stents. AB - BACKGROUND & AIMS: Plastic stents, placed via endoscopy to drain pancreatic fluid collections (PFCs), require repeat access. Covered metal stents are larger in diameter and can be inserted in a single step, but can migrate. We evaluated the safety and efficacy of a lumen-apposing, covered, self-expanding metal stent (LACSEMS) for PFC drainage. METHODS: We performed a prospective study of the outcomes of stent placement in 33 patients (18 men; age, 53 +/- 14 y; 28 with chronic pancreatitis) with symptomatic pancreatic pseudocysts and walled-off necrosis (>= 6 cm with >= 70% fluid content). Subjects were enrolled at 7 tertiary care centers (6 in the United States and 1 in Europe) from October 2011 through August 2013. Cystenterostomies were created based on endoscopist preference. Safety outcomes included infection, bleeding, perforation, tissue injury, and stent migration. Efficacy end points included LACSEMS placement, patency, and removal, as well as 50% or more reduction in PFCs. RESULTS: The mean size of the patients' PFCs was 9 +/- 3.3 cm. LACSEMSs were placed successfully via endoscopic ultrasound guidance in 30 patients (91%); the remaining 3 patients received 2 double-pigtail stents. One subject could not be evaluated because of a pseudoaneurysm. In the patients receiving LACSEMS, PFCs resolved in 27 of 29 (93%). Overall, PFCs resolved in 30 of 33 patients (91%). Endoscopic debridement through the LACSEMS was conducted in 11 subjects. Complications (15%) included abdominal pain (n = 3), spontaneous stent migration, back pain (n = 1), access site infection, and stent dislodgement (n = 1). CONCLUSIONS: LACSEMS were placed successfully in 91% of subjects with PFCs. Overall, 93% had PFC resolution. Advantages of LACSEMSs over other stents include single-step deployment and the ability to perform endoscopic debridement with minimal stent migration. Clinicaltrials.gov: NCT01419769. PMID- 25290537 TI - Chinese obstetrician-gynecologists still need more education in menopausal hormone therapy. PMID- 25290536 TI - Association of menopause age and N-terminal pro brain natriuretic peptide: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: Menopause age can affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before age 45 y) and menopause age with N-terminal pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure. METHODS: Our cross-sectional study included 2,275 postmenopausal women, aged 45 to 85 years and without clinical CVD (2000-2002), from the Multi Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis. RESULTS: Five hundred sixty-one women had early menopause. The median (25th-75th percentiles) NT-proBNP value was 79.0 (41.1 151.6) pg/mL for all participants, 83.4 (41.4-164.9) pg/mL for women with early menopause, and 78.0 (40.8-148.3) pg/mL for women without early menopause. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause, respectively. No significant interactions between menopause age and ethnicity were observed. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP levels, whereas each 1-year increase in menopause age was associated with a 0.7% decrease in NT-proBNP levels. CONCLUSIONS: Early menopause is associated with greater NT-proBNP levels, whereas each 1-year increase in menopause age is associated with lower NT-proBNP levels, in postmenopausal women. PMID- 25290538 TI - Effects of vitamin D and calcium supplementation on hypercalcemia and hypercalciuria. PMID- 25290541 TI - More pieces of the jigsaw puzzle. PMID- 25290540 TI - The regulation of the immune system. AB - Fundamental questions about the processes of immune recognition are now being asked with the powerful techniques of molecular biology and biochemistry. The extent to which these disciplines have converged with cellular immunology was particularly striking at a recent meeting on the regulation of the immune response. PMID- 25290539 TI - Use and perceived efficacy of complementary and alternative medicines after discontinuation of hormone therapy: a nested United Kingdom Collaborative Trial of Ovarian Cancer Screening cohort study. AB - OBJECTIVE: Given that the Women's Health Initiative reported in 2002 increased risks of breast cancer and cardiovascular events with hormone therapy (HT) use and many women discontinued use, we assessed the use and perceived efficacy of complementary and alternative medicines (CAMs) for menopausal symptom relief after discontinuation of HT. METHODS: Postmenopausal women aged 50 to 65 years within the United Kingdom Collaborative Trial of Ovarian Cancer Screening who were willing to take part in a secondary study were mailed a survey to evaluate menopausal symptom management. Use and perceived efficacy of CAMs for relief of vasomotor symptoms (VMS) upon discontinuation of HT were examined. RESULTS: The survey was sent to 15,000 women between July 2 and July 9, 2008. Seventy-one percent (10,662 of 15,000) responded, and 10,607 women with complete data were included. Ever use of HT was reported by 60.2% (6,383 of 10,607). At survey completion, 79.3% (5,060 of 6,383) had discontinued HT, with 89.7% (4,540 of 5,060) of the latter reporting using one or more CAMs for VMS relief. About 70.4% (3,561 of 5,060) used herbal remedies, with evening primrose oil (48.6%; 2,205 of 4,540) and black cohosh (30.3%;1,377 of 4,540) being most commonly used. Exercise was used by 68.2% (3,098 of 4,540), whereas other behavioral/lifestyle approaches were less frequently reported (13.9%; 629 of 4,540). Contrarily, more women (57% 72%) rated behavioral/lifestyle approaches as effective compared with herbal remedies (28%-46%; rating >=4 on a "helpfulness" scale from 1-10). Among medical treatments, selective serotonin reuptake inhibitors were used by 10% and rated effective by 72.1%. CONCLUSIONS: Although more women use over-the-counter medicines, behavioral/lifestyle approaches seem to provide better relief of VMS. There is a pressing need for better evidence-based lay information to support decision-making on CAM use for relief of VMS. PMID- 25290543 TI - The T-cell antigen receptor: paradigm recalled. PMID- 25290542 TI - Surface carbohydrate recognition determinants for phagocytosis. PMID- 25290544 TI - B cells in the pathogenesis of AIDS. AB - In this article, Susan Zolla-Pazner argues that the etiologic agent of the acquired immune deficiency syndrome may infect both B cells and T cells. An infection which activates B cells could alter immunological homeostasis, inducing the activation of suppressor T lymphocytes which impair helper T-cell activity. If the same lymphotrophic agent that infects B cells also destroys helper T cells, the abnormalities of both these sub-populations which are observed in AIDS are readily explained. PMID- 25290545 TI - Depressed immunity and skin cancer. PMID- 25290546 TI - AIDS in Africa. PMID- 25290547 TI - Limiting dilution analysis of cells of the immune system II: What can be learnt? AB - Last month (p. 265) Herman Waldmann and Ivan Lefkovits described the principles underlying limiting dilution analysis. In this article they review some experimental approaches which have been useful in resolving some of the complexities of lymphocyte interactions. PMID- 25290548 TI - Hybrid hybridomas and the production of bi-specific monoclonal antibodies. AB - Cell fusion techniques can now be used to generate antibodies with two different specificities. Here Cesar Milstein and A. C. Cuello discuss the theoretical basis of the method they have devised and its first applications in histochemistry and immunoassay. PMID- 25290551 TI - Characterization of lignin extracted from birch wood by a modified hydrotropic process. AB - In this work an environmentally friendly hydrotropic process was used to extract lignin from industrial birch wood chips. Two hydrotropic treatments were performed, a conventional and a modified process. The lignins were characterized using FTIR, pyrolysis-gas chromatography-mass spectrometry (pyrolysis-GC-MS), (31)P and (1)H-(13)C HSQC NMR, and size exclusion chromatography (SEC). The chemical (carbohydrates, extractives, etc.) and elemental compositions of the lignins were also determined. The yields of both lignins were 16.1% (dry wood basis), and the obtained lignins had very low contents of non-lignin compounds. The treatments resulted in significant changes of the structure of the lignins, a decrease in aliphatic hydroxyls and an increase in phenolic ones. The lignin isolated by the modified treatment underwent more substantial change than the reference one. It is believed that the data presented will facilitate utilization of hydrotropic lignin and promote the adoption of the hydrotropic process in the pulp and biorefinery industry. PMID- 25290552 TI - Multifunctional rare-Earth vanadate nanoparticles: luminescent labels, oxidant sensors, and MRI contrast agents. AB - Collecting information on multiple pathophysiological parameters is essential for understanding complex pathologies, especially given the large interindividual variability. We report here multifunctional nanoparticles which are luminescent probes, oxidant sensors, and contrast agents in magnetic resonance imaging (MRI). Eu(3+) ions in an yttrium vanadate matrix have been demonstrated to emit strong, nonblinking, and stable luminescence. Time- and space-resolved optical oxidant detection is feasible after reversible photoreduction of Eu(3+) to Eu(2+) and reoxidation by oxidants, such as H2O2, leading to a modulation of the luminescence emission. The incorporation of paramagnetic Gd(3+) confers in addition proton relaxation enhancing properties to the system. We synthesized and characterized nanoparticles of either 5 or 30 nm diameter with compositions of GdVO4 and Gd0.6Eu0.4VO4. These particles retain the luminescence and oxidant detection properties of YVO4:Eu. Moreover, the proton relaxivity of GdVO4 and Gd0.6Eu0.4VO4 nanoparticles of 5 nm diameter is higher than that of the commercial Gd(3+) chelate compound Dotarem at 20 MHz. Nuclear magnetic resonance dispersion spectroscopy showed a relaxivity increase above 10 MHz. Complexometric titration indicated that rare-earth leaching is negligible. The 5 nm nanoparticles injected in mice were observed with MRI to concentrate in the liver and the bladder after 30 min. Thus, these multifunctional rare-earth vanadate nanoparticles pave the way for simultaneous optical and magnetic resonance detection, in particular, for in vivo localization evolution and reactive oxygen species detection in a broad range of physiological and pathophysiological conditions. PMID- 25290553 TI - Modulation of direct pathway striatal projection neurons by muscarinic M4-type receptors. AB - Models of basal ganglia (BG) function posit a dynamic balance between two classes of striatal projection neurons (SPNs): direct pathway neurons (dSPNs) that facilitate movements, and indirect pathway neurons (iSPNs) that repress movement execution. Two main modulatory transmitters regulate the output of these neurons: dopamine (DA) and acetylcholine (ACh). dSPNs express D1-type DA, M1-and M4-type ACh receptors, while iSPNs express D2-type DA and M1-type ACh receptors. Actions of M1-, D1-, and D2-receptors have been extensively reported, but we still ignore most actions of muscarinic M4-type receptors. Here, we used whole-cell recordings in acutely dissociated neurons, pharmacological tools such as mamba-toxins, and BAC D(1 or 2)-eGFP transgenic mice to show that activation of M4-type receptors with bath applied muscarine enhances Ca(2+)-currents through CaV1-channels in dSPNs and not in iSPNs. This action increases excitability of dSPNs after both direct current injection and synaptically driven stimulation. The increases in Ca(2+)-current and excitability were blocked specifically by mamba toxin-3, suggesting mediation via M4-type receptors. M4-receptor activation also increased network activity of dSPNs but not of iSPNs as seen with calcium-imaging techniques. Moreover, actions of D1-type and M4-type receptors may add to produce a larger enhancement of excitability of dSPNs or, paradoxically, oppose each other depending on the order of their activation. Possible implications of these findings are discussed. PMID- 25290554 TI - Induction of VEGF expression by alpha-tocopherol and alpha-tocopheryl phosphate via PI3Kgamma/PKB and hTAP1/SEC14L2-mediated lipid exchange. AB - In several studies, vitamin E has been observed to influence angiogenesis and vasculogenesis. We recently showed that the phosphorylated form of alpha tocopherol (alphaT), alpha-tocopheryl phosphate (alphaTP), increases the expression of the vascular endothelial growth factor (VEGF). Thus, alphaTP may act as an active lipid mediator increasing VEGF expression, angiogenesis, and vasculogenesis. Here, we investigated the molecular signaling mechanisms by which alphaTP induces VEGF expression using cultured HEK293 cells as model system. alphaT and more so alphaTP increased VEGF-promoter activity in a phosphatidylinositol-3-kinase gamma (PI3Kgamma)-dependent manner. In contrast, after overexpression of PI3Kgamma and/or protein kinase B (PKB), VEGF promoter activity was inhibited by alphaT and more so by alphaTP. Inhibition by alphaT and alphaTP was dependent on the lipid kinase activity of PI3Kgamma, whereas an induction was seen with the protein kinase activity, consistent with a model in which PKB inhibition by alphaT or alphaTP occurs only when activated at the plasma membrane and possibly involves a phosphatase such as PHLPP1. PI3Kgamma induced VEGF expression was reduced when the human tocopherol-associated protein 1 (hTAP1/SEC14L2) was overexpressed suggesting formation of an inactive PI3Kgamma/hTAP1 heterodimer, that could be reactivated by alphaT and more so by alphaTP. We suggest a novel signaling mechanism by which alphaTP stimulates PI3Kgamma activity by stimulating hTAP-mediated phosphatidylinositol exchange and presentation to the enzyme and/or dissociation of an inactive heterodimer. At cellular level, hTAP may act as sensor for intracellular lipid information (location, type, and amount of lipid) and translate it into responses of PI3K mediated signaling and gene expression. PMID- 25290555 TI - Comparison of whole-body vibration exposures in buses: effects and interactions of bus and seat design. AB - Bus and seat design may be important for the drivers' whole-body vibration (WBV). WBV exposures in buses during actual operation were assessed. WBV attenuation performance between an air-suspension seat and a static pedestal seat in low floor buses was compared; there were no differences in WBV attenuation between the seats. Air-suspension seat performance in a high-floor and low-floor bus was compared. Relative to the pedestal seat with its relatively static, limited travel seat suspension, the air-suspension seat with its dynamic, longer travel suspension provided little additional benefit. Relative to the measurement collected at the bus floor, the air-suspension seat amplified the WBV exposures in the high-floor bus. All WBV exposures were below European Union (EU) daily exposure action values. The EU Vibration Directive only allows the predominant axis of vibration exposure to be evaluated but a tri-axial vector sum exposure may be more representative of the actual health risks. PRACTITIONER SUMMARY: Low back pain is common in bus drivers and studies have shown a relationship with whole body vibration. Relative to a pedestal seat with its limited travel seat suspension, the air-suspension seat with its longer travel suspension provided little additional benefit. Exposures were below European Union daily exposure action values. PMID- 25290556 TI - Effect of a smartphone application incorporating personalized health-related imagery on adherence to antiretroviral therapy: a randomized clinical trial. AB - Poor adherence to combination antiretroviral therapy (ART) is a major global challenge. In this study we examined the efficacy of a smartphone application incorporating personalized health-related visual imagery that provided real-time information about the level of medication and the patient's level of immunoprotection, in order to improve adherence to ART. We randomized 28 people on ART to either a standard or augmented version of the smartphone application. The augmented version contained components that illustrated participants' current estimated plasma concentrations of antiretroviral drugs and the immune protection provided by ART. Adherence to ART was assessed at baseline and at 3 months using self-reported adherence, pharmacy dispensing records, and HIV viral load. Information was also collected on illness and medication beliefs and use of the application. Participants who received the augmented application showed a significantly higher level of self-reported adherence to ART at 3 months (p=0.03) and decreased viral load (p=0.023) as compared to individuals using the standard version. Greater usage of the extra components of the augmented application was associated with greater perceived understanding of HIV infection and increased perceived necessity for ART. Smartphone applications that incorporate personalized health-related visual imagery may have potential to improve adherence to ART. PMID- 25290557 TI - Longitudinal variations of laryngeal overpressure and voice-related quality of life in spasmodic dysphonia. AB - OBJECTIVES/HYPOTHESIS: Adductor spasmodic dysphonia (AdSD) is a voice disorder characterized by variable symptom severity and voice disability. Those with the disorder experience a wide spectrum of symptom severity over time, resulting in varied degrees of perceived voice disability. This study investigated the longitudinal variability of AdSD, with a focus on auditory-perceptual judgments of a dimension termed laryngeal overpressure (LO) and patient self-assessments of voice-related quality of life (V-RQOL). STUDY DESIGN: Longitudinal, correlational study. METHODS: Ten adults with AdSD were followed over three time periods. At each, both voice samples and self-ratings of V-RQOL were gathered prior to their scheduled Botox injection. Voice recordings subsequently were perceptually evaluated by eight listeners for LO using a visual analog scale. RESULTS: LO ratings for all-voiced and Rainbow Passage sentence stimuli were found to be highly correlated. However, only the LO ratings obtained from judgments of AV stimuli were found to correlate moderately with self-ratings of voice disability for both the physical functioning and social-emotional subscores, as well as the total V-RQOL score. Based on perceptual judgments, LO appears to provide a reliable means of quantifying the severity of voice abnormalities in AdSD. CONCLUSIONS: Variability in self-ratings of the V-RQOL suggest that perceived disability related to AdSD should be actively monitored. Further, auditory perceptual judgments may provide an accurate index of the potential impact of the disorder on the speaker. Similarly, LO was supported as a simple clinical measure that serves as a reliable index of voice change over time. PMID- 25290559 TI - Approaches to the study of human immunoregulation. AB - The specificity of the immune response appears to have originated at the cellular and clonal level through the evolution and development of separate T- and B-cell function. With the introduction of molecular techniques, it has become possible to examine the basis of these differences at the level of gene expression. Since less than 2 % of mRNA is different in T and B cells and there appear to be about 200 cell-specific genes, it has seemed increasingly likely that regulation of gene expression and signal transmission effectively forms a third component of the immune system. This was the theme of a recent meeting. Studies on the normal development of the immune system, focusing on key points of transition, and studies on primary and acquired immunodeficiency, focusing on molecularly defined alterations, suggest new approaches to human immunoregulation. PMID- 25290558 TI - Effect of fibroblast growth factor and enamel matrix derivative treatment on root resorption after delayed replantation. AB - BACKGROUND: Periodontal ligament (PDL) healing and long term prognosis of replanted avulsed teeth should rely on several factors including length of extra oral dry time and type of the storage medium. The status of periodontal ligament is critical for the healing of replanted teeth. Different substances have been used for root surface treatment to promote formation of PDL and increase the survival of avulsed teeth submitted to replantation. AIM: The purpose of this study was to assess the effect of recombinant basic fibroblast growth factor 2 (bFGF) and enamel matrix derivative (EMD) on root resorption after delayed replantation. DESIGN: 18 freshly extracted single-rooted incisor and premolar teeth were extracted from the beagle dogs and immersed in whole bovine milk for 45 and 60 min (n = 3 each). Following storage period, sockets washed and teeth were treated with bFGF and EMD and replanted into the sockets. After 8 weeks, dogs were sacrificed, specimens processed to 4-MUm thick serial sections for histopathologic examination and morphometric assessments. Thus, the proportions of the roots that exhibited signs of surface resorption, inflammatory resorption, and replacement resorption, that is, ankylosis and normal PDL were noted. RESULTS: The percentage of root resorption was in the following order: EMD>milk>bFGF for 45 min and milk>EMD>bFGF for 60 min. For all groups, teeth stored 60 min showed significantly higher incidence of PDL resorption than those stored for 45 min (P < 0.01). The highest incidence of replacement resorption was observed in teeth treated with EMD for 60 min. After 8 weeks, the least resorption was found in bFGF-treated group (P < 0.01). CONCLUSIONS: The findings of this study suggest that use of bFGF favored the formation of new periodontal ligament; prevent ankylosis and resorption process following delayed replantation of teeth while EMD shows replacement resorption, which may turn to ankylosis. PMID- 25290560 TI - Making the immune system work. AB - There have been recent new insights into antigen presentation and the response of the immune system to antigenic fragments, as well as progress in the development of adjuvants and their delivery systems. These developments and their implications for the production of new and improved vaccines were discussed at a recent meeting. PMID- 25290561 TI - Do we need suppressor cells to explain tolerance of self? PMID- 25290562 TI - Lymph nodes, accessory cells and the staging of AIDS. PMID- 25290563 TI - T-cell regulation of human B-cell activation. A reappraisal of the role of interleukin 2. AB - The polyclonal activator pokeweed mitogen (PWM) has been widely used to study regulatory mechanisms in the differentiation of human B cells into immunoglobulin (Ig) secreting plasma cells (for review see Ref. 1). PWM-induced proliferation and differentiation of human B cells is strictly T-cell dependent and may provide a means to study the immunoregulatory activities of T-cell subsets(1-3). Furthermore, several antigen-non-specific T-cell derived factors have been shown toregulate B-cell activation(4,5). One class ofsolublefactors, designatedB cellgrowthfactors(BCGF), supports growth of human B cells, when pre-activated by anti-Ig antibody or Staphylococcus aureus Cowan strain I(SAC)(4,5). A second class offactors, B-cell differentiation factors (BCDF) induces terminal differentiation of activated B cells into Ig secretingplasma cells(5). Here Frank Miedema and Cornelius Melief examine the claims and counterclaims concerning the influence of interleukin 2, a T-cell growth factor, on B cells and conclude that interleukin 2 has a pivotal role in the humoral immune response. The role of Interleukin-2 (IL-2) in B-cell activation is still controversial. Although a direct effect of IL-2 on resting murine B cells has been suggested by some investigators(6,7), others claim that IL-2 did not act on resting murine B cells(8-10). PMID- 25290564 TI - Evolution of the immunoglobulin superfamily by duplication of complementarity. PMID- 25290565 TI - Is beta2-microglobulin required for MHC class I heavy chain expression? PMID- 25290566 TI - Anti-idiotypes as surrogate antigens: structural considerations. AB - The immune response generates antibodies with combining sites complementary to the antigen. These molecules carry antigenic determinants which together define the idioype (Id) of that antibody. An anti-Id response generates some antibodies which complements the antigen-binding surface of the first population of antibodies, and thus represent, in Jerne's words(1), an 'internal image' of the antigen. In this journal recently, Erlanger(2) discussed the difficulties in accepting this concept caused by the persistent notion of the antibody combining site as a groove or cleft. Here Ivan Roitt and his colleagues return to this discussion and define three distinct sets of structural circumstances in which an anti-Id may substitute for an antigen. PMID- 25290567 TI - Nucleic acid hybridization-an alternative tool in diagnostic microbiology. AB - The use of radioimmunoossays (RIAs) and enzyme-linked immunosorbent assays (ELISAs) has revolutionized diagnostic microbiology. Their high specificity and sensitivity make them versatile, they are simple to carry out either for direct detection of microorganisms in specimens or for serological diagnosis, and they can easily and reliably be standardized. Monoclonal antibodies have further improved these immunoassays. However, the development of simple and highly sensitive detection methods for nucleic acids has nevertheless promoted an interest also in diagnostic methods based on nucleic acid hybridization. Here Ulf Pettersson and Timo Hyypia discuss methods which are likely to become a useful complement to the immunoassays in the near future. PMID- 25290568 TI - Random locomotion; chemotaxis and chemokinesis. A guide to terms defining cell locomotion. AB - There is still confusion about what is meant by widely used terms for cellular locomotion such as chemokinesis and random locomotion and how these are distinguished from chemotaxis. Also, most work on leukocyte locomotion up till now has been done with neutrophils, whose locomotion is easy to study in vitro, and is directed towards thefairly straightforward end ofaccumulation at sites of infection and tissue injury in vivo. In this article, Peter Wilkinson gives an outline of the classification of locomotor behaviour of cells(1) and of the end results expectedfrom each form of behaviour. PMID- 25290572 TI - GreenLight laser vs diode laser vaporization of the prostate: 3-year results of a prospective nonrandomized study. AB - BACKGROUND AND OBJECTIVE: Laser vaporization of the prostate is one of the alternatives to transurethral resection of the prostate. Short-term studies report a comparable outcome after laser vaporization with the 532 nm 120-W GreenLight high-performance system (HPS) laser and the 980 nm 200 W high intensity diode (diode) laser. In this study, we analyzed the intermediate-term results of both techniques. MATERIALS AND METHODS: From January 2007 to January 2008, 112 consecutive patients with symptomatic benign prostate enlargement were nonrandomly assigned to treatment with the GreenLight laser or the diode laser. Perioperative parameters, postoperative functional outcome, complications, and the reoperation rate at 3 years were analyzed. RESULTS: Improvement of voiding symptoms (International Prostate Symptom Score, quality-of-life) and micturition parameters (maximum flow rate, postvoid residual volume) showed no significant difference between the HPS group and the diode group. A significantly higher reoperation rate was observed in the diode group in comparison to the HPS group (37.5% vs 8.9%, p=0.0003) due to obstructive necrotic tissue (16.1% vs 0%, p=0.0018), bladder neck stricture (16.1% vs 1.8%, p=0.008), and persisting or recurrent adenoma (5.4% vs 7.1%, p=0.70), respectively. CONCLUSIONS: Both lasers lead to comparable improvement of voiding parameters and micturition symptoms. Treatment with the 200 W diode laser led to a significantly higher reoperation rate, which might be attributed to a higher degree of coagulation necrosis. Thus, a careful clinical application of this diode laser type is warranted. PMID- 25290573 TI - A commercially available immunoglobulin E-based test for food allergy gives inconsistent results in healthy ponies. AB - REASONS FOR PERFORMING STUDY: Commercial immunoglobulin E (IgE)-based tests are available for diagnosis of food allergies and are commonly used in equine practice. However, these tests have been proven unreliable as a screening method in man and other species, but not critically evaluated in equids. Therefore, a commercially available IgE-based test for horses was evaluated. OBJECTIVES: To evaluate the consistency of the results obtained with a commercially available IgE-based test for food allergy diagnosis in ponies (Phase I) and to subject ponies to a provocation trial with the presumed allergens (Phase II). STUDY DESIGN: Allergen screening followed by experimental food provocation trials in healthy ponies. METHODS: Blood samples of 17 healthy Shetland ponies were taken at 2 different time points, sent blinded to a commercial laboratory for screening of common food allergens and the results were evaluated for consistency (Phase I). Ponies that were positive for food allergens were consecutively challenged orally with each allergen separately for 14 days (Phase II). A washout period of one week was applied in ponies with multiple positive results. Clinical parameters and serum amyloid A were monitored during the provocation trial. RESULTS: Only 7/17 ponies were negative on the IgE-based test at the 2 time points, 3 had positive results twice but only one tested positive twice for the same food allergen. No abnormalities were noted during the provocation trials. CONCLUSIONS: This study demonstrated that this IgE-based test is not a reliable screening tool for food allergy in healthy equids. PMID- 25290574 TI - Bicontinuous zeolitic imidazolate framework ZIF-8@GO membrane with enhanced hydrogen selectivity. AB - Through layer-by-layer (LBL) deposition of a graphene oxide (GO) suspension on a semicontinuous ZIF-8 layer, we have developed a novel bicontinuous ZIF-8@GO membrane. Since only the gaps between the ZIF-8 crystals are sealed by the GO layer due to capillary forces and covalent bonds, the gas molecules can only permeate through the ZIF-8 micropore system (0.34 nm). Therefore, the ZIF-8@GO membranes show high hydrogen selectivity. At 250 degrees C and 1 bar, the mixture separation factors of H2/CO2, H2/N2, H2/CH4, and H2/C3H8 are 14.9, 90.5, 139.1, and 3816.6, with H2 permeances of about 1.3 * 10(-7) mol.m(-2).s(-1).Pa( 1), which is promising for hydrogen separation and purification by molecular sieving. PMID- 25290575 TI - Reply to Koppe and Ten Tusscher's letter to the Editor concerning the use of human peripheral blood lymphocytes to determine relative effect potencies for dioxin like compounds. PMID- 25290576 TI - Toxicological aspects of trans fat consumption over two sequential generations of rats: Oxidative damage and preference for amphetamine. AB - Chronic consumption of processed food causes structural changes in membrane phospholipids, affecting brain neurotransmission. Here we evaluated noxious influences of dietary fats over two generations of rats on amphetamine (AMPH) conditioned place preference (CPP). Female rats received soybean oil (SO, rich in n-6 fatty acids (FA)), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans fatty acids (TFA)) for two successive generations. Male pups from the 2nd generation were maintained on the same supplementation until 41 days of age, when they were conditioned with AMPH in CPP. While the FO group showed higher incorporation of n-3 polyunsaturated-FA (PUFA) in cortex/hippocampus, the HVF group showed TFA incorporation in these same brain areas. The SO and HVF groups showed AMPH-preference and anxiety-like symptoms during abstinence. Higher levels of protein carbonyl (PC) and lower levels of non protein thiols (NPSH) were observed in cortex/hippocampus of the HVF group, indicating antioxidant defense system impairment. In contrast, the FO group showed no drug-preference and lower PC levels in cortex. Cortical PC was positively correlated with n-6/n-3 PUFA ratio, locomotion and anxiety-like behavior, and hippocampal PC was positively correlated with AMPH-preference, reinforcing connections between oxidative damage and AMPH-induced preference/abstinence behaviors. As brain incorporation of trans and n-6 PUFA modifies its physiological functions, it may facilitate drug addiction. PMID- 25290577 TI - Metallothionein isoform 3 expression in human skin, related cancers and human skin derived cell cultures. AB - Human skin is a well known target site of inorganic arsenic with effects ranging from hyperkeratosis to dermal malignancies. The current study characterizes the expression of a protein known to bind inorganic, As(3+), metallothionein 3 (MT 3). Expression of this protein was assessed immunohistochemically with a specific MT-3 antibody on human formalin-fixed, paraffin-embedded biopsy specimens in normal skin, squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. Assessment in normal skin using nine normal specimens showed moderate to intense MT-3 staining in epidermal karatinocytes with staining extending into the basal cells and moderate to intense staining in melanocytes of nevi. MT-3 immunoexpression was shown to be moderate to intense in 12 of 13 of SCC, low to moderate in 8 of 10 BCC, and moderate to intense in 12 melanoma samples. MT-3 expression in cell culture models (normal human epidermal keratinocytes, normal human melanocytes, and HaCaT cells) showed only trace expression of MT-3, while exposures to the histone deacytalase inhibitor, MS-275, partially restored expression levels. These results indicate that the epidermis of human skin and resulting malignancies express high level of MT-3 and potentially impact on the known association of arsenic exposure and the development of skin disorders and related cancers. PMID- 25290578 TI - Human biomonitoring after chemical incidents and during short-term maintenance work as a tool for exposure analysis and assessment. AB - Human biomonitoring (HBM) is frequently used for the analysis and assessment of exposure to chemicals under routine working conditions. In recent years, HBM has also been applied to monitor the exposure of the general population, and of emergency responders in the aftermath of chemical incidents. Two examples of targeted HBM programs in the chemical industry are described and discussed in this paper: (1) analysis and assessment of the exposure of firefighters and chemical workers after the spill of p-chloroaniline from a burning chemical barrel, and (2) biomonitoring of maintenance workers potentially exposed to benzene during regular turnarounds. The results of these investigations underline that human biomonitoring contributes substantially to comprehensive exposure analyses, human health risk assessments and communication. In addition, regular HBM surveillance and feedback can assist in the continuous improvement of workplace safety measures and exposure control. In conclusion, data on accidental or short-term exposure to hazardous chemicals are an important source of information for the further development of limit and assessment values, the validation of biomarkers and of targeted HBM programs for both routine monitoring and disaster management. PMID- 25290579 TI - Fluorinated aromatic amino acids are sensitive 19F NMR probes for bromodomain ligand interactions. AB - We describe a (19)F NMR method for detecting bromodomain-ligand interactions using fluorine-labeled aromatic amino acids due to the conservation of aromatic residues in the bromodomain binding site. We test the sensitivity, accuracy, and speed of this method with small molecule ligands (+)-JQ1, BI2536, Dinaciclib, TG101348, and acetaminophen using three bromodomains Brd4, BrdT, and BPTF. Simplified (19)F NMR spectra allowed for simultaneous testing of multiple bromodomains to assess selectivity and identification of a new BPTF ligand. Fluorine labeling only modestly affected the Brd4 structure and function assessed by isothermal titration calorimetry, circular dichroism, and X-ray crystallography. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands. PMID- 25290581 TI - Enterococcus--virulence and susceptibility to photodynamic therapy of clinical isolates from Lower Silesia, Poland. AB - BACKGROUND: A collection of 400 enterococcal isolates from clinical samples of hospitalized patients were studied for their virulence traits according to the isolation site. Formation of biofilm and production of DNase, hemolysin, lipase, and gelatinase were characterized. Biofilms of selected strains were examined for their susceptibility to antimicrobial photodynamic therapy (aPDT). METHODS: All strains were tested for biofilm production by microtiter method and the activity of hemolysin, gelatinase, lipase, and DNase by plate method with an adequate substrate. Photodynamic therapy with Photolon and red laser light was performed towards 48 h biofilms of eight representative strains. The viability of biofilms was tested by the BactLight assay and visualized under a fluorescent microscope. RESULTS: Among the 400 isolates, 69.8% strains of Enterococcus faecalis, 30% of Enterococcus faecium, and 0.2% of Enterococcus casseliflavus were identified. In vitro, production of biofilm was found in 65.7% of enterococci. Biofilm-positive strains were isolated from urinary tract infections (81%), wound infections (71%), respiratory tract infections (62%), and gastrointestinal tract (47%) (colonization). Hemolysin activity was observed in 28.5%, gelatinase in 24.5%, lipase in 23%, and DNase in 3.5% of all, mostly biofilm-positive, isolates. Photodynamic therapy with Photolon efficiently reduced the enterococcal biofilms. CONCLUSIONS: The study demonstrated the high prevalence of biofilm-producing clinical enterococci, their virulence potential being higher than for biofilm negative strains, and the susceptibility to aPDT of mature biofilms produced by strains, regardless of their species and site of isolation. PMID- 25290580 TI - Blood culture-positive infections in patients with alcoholic hepatitis. AB - Acute alcoholic hepatitis (AH) is a life-threatening disease and its course is often determined by infections. However, the pattern of pathogens has not been studied. We examined the microbiological pathogens that caused blood-borne infection in patients with AH. We included 32 AH patients without infection at inclusion. Patients were followed for 1 month and their infection status was recorded based on clinical records, radiologic exams and cultures of different secreta. Nine patients (28%) developed blood culture-positive infections. The agents were of heterogeneous aetiology and came from various sites of infection. Candida species accounted for three of these infections (33%). Five patients (16%) died, two of which had positive blood cultures. A high fraction was invasively infected by a heterogeneous spectrum of microbes including yeasts and commensal bacteria. This may reflect the severe immune impairment of AH and suggests thorough infection screening and an immediate broad-spectrum antibiotic approach if infection is suspected. PMID- 25290582 TI - Septic internal jugular vein thrombosis caused by Fusobacterium necrophorum and mediated by a broken needle. AB - The injection of drugs into the neck is unusual and thrombosis of the internal jugular vein can be a rare clinical presentation with a high risk for severe complications. We report a case of a 31-year-old male intravenous drug user presenting with fever, shortness of breath and right neck oedema. Laboratory studies revealed elevated inflammation parameters. X-ray imaging revealed a broken syringe needle inside the soft tissues of the neck. Computed tomography (CT) scans of the thorax and brain were unremarkable, while cervical CT showed a fully thrombosed, right internal jugular vein. Intravenous antibiotics were initiated, and modified after identification of an anaerobic Gram-negative oropharynx-derived pathogen (Fusobacterium necrophorum). The patient was discharged after resolution of symptoms under treatment. Septic internal jugular vein thrombosis should always be included in the differential diagnosis of local neck inflammation and systemic sepsis in intravenous drug users. Prompt and aggressive antibiotic treatment is vital, whereas the role of anticoagulation therapy is not definitely known. PMID- 25290583 TI - Tuberculosis outbreak in an immigrant reception center in Israel: a clinical and epidemiologic perspective. AB - Tuberculosis (TB) outbreaks in congregate settings pose a public health concern and a clinical challenge. We report a TB outbreak involving 6 cases of active TB among 28 recent Ethiopian immigrants (EIs) in an immigrant reception center in Israel. The outbreak erupted several weeks after a meticulous pre-immigration TB screening of this group. All five culture-positive TB patients were infected with the CAS1_DELHI family, SIT 25 strain. Pulmonary involvement manifested as only a persistent cough without systemic symptoms. This outbreak occurred because of miscommunication among healthcare staff and between healthcare staff and the EI index case. It was fuelled by the staff ignorance of the social bonds within the group, and the sluggish once-monthly schedule of the on-site TB clinic operated at the reception center, which further lacked radiography facilities. This outbreak highlights the challenges of screening for active TB among immigrants and hard to reach groups. PMID- 25290585 TI - The role of thoracoscopic surgery in pediatric oncology. AB - The application of thoracoscopic surgical techniques to pediatric solid tumors represents an important adjunctive tool for the surgical management of childhood cancer. Nearly four decades has passed since the introduction of minimally invasive chest surgery in children, and although the adoption of minimally invasive surgery in general pediatric surgical practice is better recognized, its role in pediatric oncology is still considered a developing field. As no consensus exists regarding the use of thoracoscopy for pediatric thoracic solid tumors, the purpose of this article is to review the current literature surrounding the use of thoracoscopic interventions in pediatric oncology and examine established indications, procedures, and technologic advances. PMID- 25290584 TI - Delayed HIV diagnosis common in Sweden, 2003-2010. AB - BACKGROUND: Early diagnosis of HIV is important for the prognosis of individual patients, because antiretroviral treatment can be started at the appropriate time, and for public health, because transmission can be prevented. METHODS: Data were collected from 767 HIV patients who were diagnosed in Sweden during 2003 2010 and were infected in Sweden or born in Sweden and infected abroad. A recent infection testing algorithm (RITA) was applied to BED-EIA test results (OD-n < 0.8), CD4 counts (>= 200 cells/MUl), and clinical information. A recent infection classification was used as indicator for early diagnosis. Time trends in early diagnosis were investigated to detect population changes in HIV testing behavior. Patients with early diagnosis were compared to patients with delayed diagnosis with respect to age, gender, transmission route, and country of infection (Sweden or abroad). RESULTS: Early diagnosis was observed in 271 patients (35%). There was no statistically significant time trend in the yearly percentage of patients with early diagnosis in the entire study group (p = 0.836) or in subgroups. Early diagnosis was significantly more common in men who have sex men (MSM) (45%) than in heterosexuals (21%) and injecting drug users (27%) (p < 0.001 and p = 0.001, respectively) in both univariate and multivariable analyses. The only other factor that remained associated with early diagnosis in multivariable analysis was young age group. CONCLUSION: Approximately one-third of the study patients were diagnosed early with no significant change over time. Delayed HIV diagnosis is a considerable problem in Sweden, which does not appear to diminish. PMID- 25290586 TI - Development of peptidyl lysine dendrons: 1,3-dipolar cycloaddition for peptide coupling and antibody recognition. AB - A straightforward synthesis strategy to multimerize a peptide mimotopes for antibody B13-DE1 recognition is described based on lysine dendrons as multivalent scaffolds. Lysine dendrons that possess N-terminal alkyne residues at the periphery were quantitative functionalized with azido peptides using click chemistry. The solid-phase peptide synthesis (SPPS) allows preparing the peptide dendron in high purity and establishing the possibility of automation. The presented peptide dendron is a promising candidate as multivalent ligand and was used for antibody B13-DE1 recognition. The binding affinity increases with higher dendron generation without loss of specificity. The analysis of biospecific interaction between the synthesized peptide dendron and the antibody was done via surface plasmon resonance (SPR) technique. The presented results show a promising tool for investigations of antigen-antibody reactions. PMID- 25290588 TI - Theoretical study of plutonium(IV) complexes formed within the PUREX process: a proposal of a plutonium surrogate in fire conditions. AB - We present a relativistic quantum chemical study to determine the best surrogate for plutonium(IV) to be used in experimental investigations of the behavior of plutonium-nitrate-TBP in fire conditions that might occur in the nuclear fuel refining process known as PUREX. In this study geometries and stabilities of Pu(NO3)6(2-) and Pu(NO3)4(TBP)2 complexes were compared to that of equivalent complexes of selected elements from the lanthanide and actinide series (Ce, Th, U) chosen on the basis of similar ionic radii and stability as tetravalent species. PBE and PBE0 DFT functionals have proven to be sufficient and affordable for qualitative studies, performing as good as the wave function based correlated method MP2. On the basis of our results, cerium(IV) appears to be a good surrogate for plutonium(IV). PMID- 25290587 TI - Witnessing the formation and relaxation of dressed quasi-particles in a strongly correlated electron system. AB - The non-equilibrium approach to correlated electron systems is often based on the paradigm that different degrees of freedom interact on different timescales. In this context, photo-excitation is treated as an impulsive injection of electronic energy that is transferred to other degrees of freedom only at later times. Here, by studying the ultrafast dynamics of quasi-particles in an archetypal strongly correlated charge-transfer insulator (La2CuO(4+delta)), we show that the interaction between electrons and bosons manifests itself directly in the photo excitation processes of a correlated material. With the aid of a general theoretical framework (Hubbard-Holstein Hamiltonian), we reveal that sub-gap excitation pilots the formation of itinerant quasi-particles, which are suddenly dressed by an ultrafast reaction of the bosonic field. PMID- 25290589 TI - Characterisation of agricultural waste-derived biochars and their sorption potential for sulfamethoxazole in pasture soil: a spectroscopic investigation. AB - We investigated the effects of feedstock type and pyrolysis temperatures on the sorptive potential of a model pastoral soil amended with biochars for sulfamethoxazole (SMO), using laboratory batch sorption studies. The results indicated that high temperature chars exhibited enhanced adsorptive potential, compared to low temperature chars. Pine sawdust (PSD) biochar produced at 700 degrees C using the steam gasification process exhibited the highest sorptive capacity (2-fold greater than the control treatment) for SMO among the three biochars used. Soils amended with green waste (GW) biochars produced at three different pyrolysis temperatures showed a small increase in SMO sorption with the increases in temperature. The NMR spectra, the elemental molar ratios (H/C, O/C) and polarity index (O+N)/C of the biochars revealed that PSD biochar possessed the highest degree of aromatic condensation compared to CC and GW chars. These results correlated well with the sorption affinity of each biochar, with effective distribution coefficient (Kd(eff)) being highest for PSD and lowest for GW biochars. X-ray photoelectron spectroscopy results for the biochars showed a relatively large difference in oxygen containing surface functional groups amongst the GW biochars. However, they exhibited nearly identical sorption affinity to SMO, indicating negligible role of oxygen containing surface functional groups on SMO sorption. These observations provide important information on the use of biochars as engineered sorbents for environmental applications, such as reducing the bioavailability of antibiotics and/or predicting the fate of sulfonamides in biochar-amended soils. PMID- 25290590 TI - Suspended sediment regimes in contrasting reference-condition freshwater ecosystems: implications for water quality guidelines and management. AB - Suspended sediment (SS), ranging from nano-scale particles to sand-sized sediments, is one of the most common contributors to water quality impairment globally. However, there is currently little scientific evidence as to what should be regarded as an appropriate SS regime for different freshwater ecosystems. In this article, we compare the SS regimes of ten systematically selected contrasting reference-condition temperate river ecosystems that were observed through high-resolution monitoring between 2011 and 2013. The results indicate that mean SS concentrations vary spatially, between 3 and 29 mg L(-1). The observed mean SS concentrations were compared to predicted mean SS concentrations based on a model developed by Bilotta et al. (2012). Predictions were in the form of probability of membership to one of the five SS concentration ranges, predicted as a function of a number of the natural environmental characteristics associated with each river's catchment. This model predicted the correct or next closest SS range for all of the sites. Mean annual SS concentrations varied temporally in each river, by up to three-fold between a relatively dry year (2011-2012) and a relatively wet year (2012-2013). This inter annual variability could be predicted reasonably well for all the sites except the River Rother, using the model described above, but with modified input data to take into account the mean annual temperature ( degrees C) and total annual precipitation (mm) in the year for which the mean SS prediction is to be made. The findings highlight the need for water quality guidelines for SS to recognise natural spatial and temporal variations in SS within rivers. The findings also demonstrate the importance of the temporal resolution of SS sampling in determining assessments of compliance against water quality guidelines. PMID- 25290591 TI - Three year study of tropospheric ozone with back trajectories at a metropolitan and a medium scale urban area in Greece. AB - Three years of hourly O3 concentration measurements from a metropolitan and a medium scale urban area in Greece: Athens and Ioannina respectively, were analyzed in conjunction with hourly wind speed/direction data and air mass trajectories, aiming to reveal local and regional contributions respectively. Conditional Probability Function was used to indicate associations among distinct wind directions and extreme O3 episodes. Backward trajectory clusters were elaborated by Potential Source Contribution Function on a grid of a 0.5 degrees *0.5 degrees resolution, in order to localize potential exogenous sources of O3 and its precursors. In Athens, an increased likelihood of extreme O3 events at the Northern suburbs was associated with the influence of SSW-SW sea breeze from Saronikos Gulf, due to O3 transportation from the city center. In Ioannina, the impacts of O3 conveyance from the city center to the suburban monitoring site were weaker. Potential O3 transboundary sources for Athens were mainly localized over Balkan Peninsula, Greece and the Aegean Sea. Potential Source Contribution Function hotspots were isolated over the industrialized area of Ptolemaida basin and above the region of Thessaloniki. Potential regional O3 sources for Ioannina were indicated across northern Greece and Balkan Peninsula, whereas peak Potential Source Contribution Function values were particularly observed over the urban area of Sofia in Bulgaria. The implemented methods, revealed local and potential transboundary source areas of O3, influencing Athens and Ioannina. Differences among the two cities were highlighted and the role of topography was emerged. These findings can be used in order to reduce the emission of O3 precursors. PMID- 25290592 TI - Development of the intoxicated personality scale. AB - OBJECTIVE: To develop the Intoxicated Personality Scale (IPS). METHODS: Data were collected from 436 college students via an online survey. Through an iterative measurement development process, the resulting IPS was created. RESULTS: The 5 subscales (Good Time, Risky Choices, Risky Sex, Emotional, and Introvert) of the IPS positively related to alcohol consumption, alcohol problems, drinking motives, alcohol expectancies, and personality. CONCLUSIONS: The results suggest that the Intoxicated Personality Scale may be a useful tool for predicting problematic alcohol consumption, alcohol expectancies, and drinking motives. PMID- 25290593 TI - Subjective sleep inadequacy and self-rated health among homeless adults. AB - OBJECTIVE: To examine the association between subjective sleep inadequacy and self-rated health in a sample of 244 homeless adults. METHODS: Logistic regression analyses were conducted to assess associations among 4 sleep inadequacy items (days of inadequate rest or sleep, hours of sleep, days unintentionally falling asleep during daytime, and snoring) and self-rated health in analyses adjusted for age, sex, race, education, lifetime homelessness, lifetime serious mental illness, and current depression. RESULTS: Days of inadequate rest or sleep, fewer hours of sleep, and days unintentionally falling asleep were each significantly associated with higher odds of poor/fair self rated health. CONCLUSION: Because both inadequate sleep and poor self-rated health independently predict mortality, interventions targeting sleep quality among homeless adults are needed. PMID- 25290594 TI - Barriers to help-seeking in men diagnosed with benign colorectal diseases. AB - OBJECTIVE: To explore the help-seeking pathway for lower bowel symptoms in men diagnosed with benign bowel diseases. METHODS: Semi-structured interviews were conducted. The data were analyzed thematically using Andersen's Model of Patient Delay as the theoretical framework. RESULTS: The major delaying factors were attribution of symptoms to self-limiting conditions, failure to make time to visit a GP, low expectation of help from the GP, fear of cancer diagnosis and embarrassment. CONCLUSION: The major causes of delay in help-seeking were related to the participants, whereas factors associated with treatment delay were less prominent in diagnostic delay. PMID- 25290595 TI - Weight loss attitudes and social forces in urban poor Black and White women. AB - OBJECTIVE: To explore differences between Blacks and Whites in perceived influences on weight-related behaviors among obese urban poor women. METHODS: Participants (N = 27) received physician referrals to a weight loss program located in Federally Qualified Health Centers and either never attended or stopped attending. We conducted in-depth, in home interviews using a script informed by focus groups, pilot discussions, and the theory of planned behavior (TPB) to learn about participants' weight loss attitudes, social forces and perceived behavioral control. RESULTS: White women reported having more social support and social pressure for weight management activities. Black women reported eating for positive reasons whereas white women associated eating with negative emotions. CONCLUSION: Social networks and emotions may be critical factors in weight management and lifestyle program participation. PMID- 25290596 TI - Positivity and indicators of health among African Americans with diabetes. AB - OBJECTIVES: To examine the utility of the positivity ratio to distinguish differences in psychological and physiological health in African Americans with type 2 diabetes. METHODS: Study participants (N = 93) were recruited through radio and church announcements and grouped by their positivity ratio. RESULTS: Multivariate analyses showed flourishing individuals had the highest resilience and lowest depressive symptoms and HbA1c (A1C), whereas depressed individuals recorded the lowest resilience and highest depressive symptoms and A1C. Small to large effect sizes were reported. CONCLUSIONS: Further support for the utility and generalizability of the positivity ratio was provided. Cultivating positive emotions may improve the health of individuals with type 2 diabetes. PMID- 25290597 TI - Social cognitive mediators of dietary behavior change in adolescent girls. AB - OBJECTIVES: To examine potential mediators of adolescent girls' dietary behavior change in the Nutrition and Enjoyable Activity for Teen Girls (NEAT Girls) intervention for obesity prevention. METHODS: Participants were 294 adolescent girls attending 12 secondary schools located in low-income communities of New South Wales, Australia. Hypothesized social cognitive mediators of dietary behavior change were assessed using valid and reliable scales. RESULTS: The intervention effects on dietary outcomes and hypothesized mediators were not statistically significant. However, changes in hypothesized mediators were associated with changes in key dietary behaviors. CONCLUSIONS: Continued research is needed to examine effective strategies for improving dietary outcomes in youth, and to explore alternative theoretical mechanisms of dietary behavior change. PMID- 25290598 TI - Associations of overall sedentary time and screen time with sleep outcomes. AB - OBJECTIVE: To examine associations of accelerometer-assessed sedentary time and self-reported screen time with sleep outcomes. METHODS: Cross-sectional study of 1674 adults from the 2005-2006 US National Health and Nutrition Examination Survey. Accelerometers were used to assess sedentary time. Screen time and sleep metrics were assessed via self-report. RESULTS: Accelerometer-assessed sedentary time was not associated with sleep outcomes. Compared to participants with the least screen time (<2h/ day), participants with the most screen time (>6h/day) were more likely to report trouble falling asleep (OR = 2.78, 95% CI: 1.21, 6.40) and wake during the night (OR = 2.55, 95% CI: 1.17, 5.52). CONCLUSIONS: With respect to sleep outcomes, context-specific sedentary behaviors may be more important than overall sedentary time. PMID- 25290600 TI - Predicting depressive symptoms and self-care in patients with heart failure. AB - OBJECTIVE: To examine relationships among heart failure (HF) physical symptoms, social support, social problem-solving, depressive symptoms, and self-care behaviors in outpatients with HF. METHODS: Cross-sectional data were collected from 201 outpatients. Structural equation modeling was used in this preliminary analysis to examine the relationships among the study variables. RESULTS: HF physical symptoms and social support were predictors of depressive symptoms and self-care behaviors. Social problem-solving also predicted self-care behaviors. Social support mediated the relationship between HF physical symptoms and depressive symptoms. CONCLUSIONS: Social support may influence depressive symptoms and self-care behaviors, whereas social problem-solving may impact self care behaviors. Future research should examine causality and sub-components of social problem-solving on these outcome variables. PMID- 25290599 TI - Psychosocial factors and theory in physical activity studies in minorities. AB - OBJECTIVES: To summarize the effectiveness of interventions targeting psychosocial factors to increase physical activity (PA) among ethnic minority adults and explore theory use in PA interventions. METHODS: Studies (N = 11) were identified through a systematic review and targeted African American/Hispanic adults, specific psychosocial factors, and PA. Data were extracted using a standard code sheet and the Theory Coding Scheme. RESULTS: Social support was the most common psychosocial factor reported, followed by motivational readiness, and self-efficacy, as being associated with increased PA. Only 7 studies explicitly reported using a theoretical framework. CONCLUSIONS: Future efforts should explore theory use in PA interventions and how integration of theoretical constructs, including psychosocial factors, increases PA. PMID- 25290602 TI - Correlates of weapon carrying in school among adolescents in three countries. AB - OBJECTIVES: To determine the factors associated with weapon carrying in school among Czech, Russian, and US adolescents. METHODS: Logistic regression was used to analyze data drawn from the Social and Health Assessment (SAHA). RESULTS: Violent behavior (perpetration / victimization) was linked to adolescent weapon carrying in all countries. Substance use was associated with weapon carrying among boys in all countries. Greater parental warmth reduced the odds for weapon carrying among Czech and Russian adolescents. Associating with delinquent peers was important for weapon carrying only among US adolescents. CONCLUSIONS: Factors associated with weapon carrying in school vary among countries although violent behavior and substance use may be associated with weapon carrying across countries. PMID- 25290601 TI - Housing characteristics in relation to exhaled nitric oxide in China. AB - OBJECTIVE: To investigate indoor factors affecting fractional exhaled nitric oxide (FeNO) in community residents. METHODS: A total of 2404 adults (865 men, 1539 women, mean age 51.7 +/- 13.3 years) were recruited to the study. Factors affecting FeNO were analyzed by multiple linear regression analysis. RESULTS: Participants without a kitchen exhaust fan/hood had higher FeNO (GM: 10.21%, 95% CI: 4.18%-16.59%). Participants engaged in home cooking who used only liquefied petroleum gas had higher FeNO (GM: 5.75%, 95% CI: 0.10%-11.73%) compared to those using natural gas for residential (home) cooking. CONCLUSION: Nonuse of a kitchen exhaust fan/hood and use of liquefied petroleum gas among persons engaged in home cooking were associated with higher FeNO levels. PMID- 25290603 TI - Zumba(r) dance improves health in overweight/obese or type 2 diabetic women. AB - OBJECTIVE: To evaluate the feasibility and health improvements from a Zumba(r) intervention in overweight/obese women. METHODS: Twenty-eight (14 type 2 diabetic and 14 non-diabetic) over-weight/obese women (BMI: 37.3+/-1.5 kg/m(2)) 50.8+/-1.8 y of age, completed a 16-week intervention attending Zumba(r) dance classes 3 days/week, 60 minutes/class. We measured aerobic fitness, body weight, body fat %, and motivation to exercise before and after the study. RESULTS: Intrinsic motivation to exercise (p < .05) and aerobic fitness (1.01 +/- 0.40 mL/kg/min, p < .05) improved, and the participants lost body weight (-1.05 +/- 0.55kg, p < .05) and body fat% (-1.2 +/- 0.6%, p < .01). CONCLUSION: The Zumba(r) intervention improved health and physical fitness in women. PMID- 25290605 TI - Race, health-related quality of life and colorectal cancer screening rates in the National Health Interview Survey. AB - OBJECTIVES: To examine the association between colorectal cancer (CRC) screening rates and health-related quality of life (HRQOL). METHODS: Data were derived from a sample of 26,704 persons aged 50 to 75 years from the National Health Interview Survey (NHIS) 2010. The HRQOL factor and CRC screenings factor were developed in the NHIS cancer file. By using the Andersen model, confirmatory factor analysis with a multiple indicators, multiple causes model comprised data analysis. RESULTS: CRC screening rates were negatively associated with HRQOL. Identifying oneself as an African American was associated with better HRQOL but lower cancer screening rates. CONCLUSIONS: HRQOL may capture several confounding factors. Thus, CRC screening rates alone may not be a strong predictor of HRQOL in population-based studies. PMID- 25290604 TI - Receptivity to e-cigarette marketing, harm perceptions, and e-cigarette use. AB - OBJECTIVE: To test whether exposure and receptivity to e-cigarette marketing are associated with recent e-cigarette use among young adults through increased beliefs that e-cigarettes are less harmful than cigarettes. METHODS: Data were collected from 307 multiethnic 4- and 2-year college students; approximately equal proportions of current, never, and former cigarette smokers [mean age = 23.5 (SD = 5.5); 65% female]. RESULTS: Higher receptivity to e-cigarette marketing was associated with perceptions that e-cigarettes are less harmful than cigarettes, which in turn, were associated with higher recent e-cigarette use. CONCLUSIONS: The findings provide preliminary support to the proposition that marketing of e-cigarettes as safer alternatives to cigarettes or cessation aids is associated with increased e-cigarette use among young adults. The findings have implications for development of e-cigarette regulations. PMID- 25290606 TI - Can personality bridge the intention-behavior gap to predict who will exercise? AB - OBJECTIVES: To explore whether HEXACO personality domains could incrementally increase the prediction of exercise behavior above Theory of Planned Behavior (TPB) variables, and whether personality moderated the intention-behavior gap. METHODS: US College students (N = 1017) completed demographic, TPB, HEXACO domain and exercise behavior measures. RESULTS: The TPB predicted physical activity, accounting for 45% and 39% of variance in intention and behavior, respectively. Regarding personality domains, lower emotionality significantly predicted intention, and lower honesty-humility significantly predicted behavior, but these were small effects. Personality did not moderate the intention-behavior gap. CONCLUSIONS: Personality has a limited direct role in predicting exercise intention and behavior beyond the TPB. The prediction of exercise behavior from honesty-humility highlights the importance of considering the HEXACO personality model. PMID- 25290607 TI - Determinants of social status among homeless adults. AB - OBJECTIVES: To examine determinants of subjective social status (SSS) among 394 sheltered homeless adults. METHODS: Demographics, socioeconomic status, homelessness, and other life factors were examined as potential determinants of US and Community SSS using parametric tests. RESULTS: Higher income, African American/other race, having health insurance, being employed, having longer duration of homelessness, having children, and being of non-veteran status were each significantly associated with higher SSS-US. African-American/ other race and having health insurance were significantly associated with higher community SSS. Variables maintained significance in multivariate models except homelessness duration (for SSS-US). CONCLUSIONS: Given known relations of SSS and negative health behaviors and outcomes, understanding the correlates of SSS among homeless adults may facilitate targeted interventions. PMID- 25290609 TI - The safety of maternal elimination diets in breastfeeding mothers with food allergic infants. PMID- 25290608 TI - Survival advantage of cyromazine-resistant sheep blowfly larvae on dicyclanil- and cyromazine-treated Merinos. AB - OBJECTIVE: To determine whether a cyromazine-resistant strain of Lucilia cuprina was able to establish strikes sooner than a susceptible strain on cyromazine- or dicyclanil-treated sheep. METHODS: Groups of 7 sheep were treated with cyromazine or dicyclanil in accordance with label directions. Beginning 5 weeks after treatment, 5 sheep from each group were challenged by implantation of neonate larvae belonging to the cyromazine-resistant strain 'Nimmitabel-selected' and the susceptible blowfly strain 'Field 2011' according to standard larval implant technique. The implant sites were alternated between the shoulder, mid-back and rump within the treatment zone. Similarly, implants of the resistant and susceptible strain larvae were alternated at each challenge such that the strain implanted on the left side of the sheep at one challenge was implanted on the right side at the next. Challenges were conducted at 3-weekly intervals until the susceptible larvae formed strikes on at least 2 of the 5 sheep in a treatment group or until 29 weeks after treatment. RESULTS: Sheep treated with cyromazine or dicyclanil were protected from flystrike by the cyromazine-susceptible strain for periods consistent with, or longer than, the registered product label claims. The cyromazine-resistant strain created strikes several weeks sooner after treatment than did the susceptible strain. Accordingly, the protection periods provided by cyromazine and dicyclanil against the resistant strain were reduced from 14 and 18-24 weeks to <8 weeks and <11 weeks, respectively. CONCLUSION: Resistance, even in the pure-breeding resistant strain, was not so severe as to cause treatment failure with cyromazine or dicyclanil, but was sufficient to reduce the protection period provided. It is recommended that producers adopt management practices that minimise the development of resistance to these and other compounds. PMID- 25290610 TI - Reply. PMID- 25290611 TI - Errata. PMID- 25290615 TI - Prepare for the Great American Smokeout with Smokefree.gov apps, texts, and social media tools. PMID- 25290617 TI - Healthy lifestyle behaviors: the importance of individual and population approaches. PMID- 25290618 TI - 20 things you didn't know about the human gut microbiome. PMID- 25290621 TI - Bone marrow purging. AB - Bone marrow transplantation (BMT) is undertaken in a heroic attempt to increase the cute rate in malignancy and to treat deadly metabollic disorders. After ablative therapy, patients are transfused with their own or with HLA matched or haploidentical bone marrow. The inoculum cells or mature T cells which cause graft versus host disease. Meetings such as the recent First International Workshop on Bone Marrow are important as a forum for a review of current developments, advice about the selection of techniques - many of them exquisitely ingenious and efficient - and for a discussion of the exact role of bone marrow purging in the complex process of patient management. PMID- 25290620 TI - Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. AB - MicroRNAs (miRNAs) are aberrant in many human tumors which can be transferred to immune cells by tumor-derived exosomes. Dendritic cells (DCs) play an important role in activation of immune response. However, the effect of tumor-derived exosomes on toll-like receptor (TLR) in DCs remains unclear. We investigated the influence of pancreatic cancer derived exosomes on TLR4, and downstream cytokines via miR-203. Our results showed that miR-203 expressed in panc-1 cells and exosomes, and upregulated in exosomes-treated DCs. TLR4 decreased after treatment of exosomes and miR-203 mimics, while increased in exosomes-treated DCs by miR 203 inhibitors. But the mRNA level of TLR4 was not significantly different between DCs and exosomes-treated DCs. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12) also decreased under treatment of exosomes and miR-203 mimics, both of which increased in exosomes-treated DCs by miR-203 inhibitors. Collectively, pancreatic cancer derived exosomes downregulate TLR4 and downstream cytokines in DCs via miR-203. PMID- 25290622 TI - Nanotubes self-assembled from amphiphilic molecules via helical intermediates. PMID- 25290619 TI - Discovery of serum biomarkers of ovarian cancer using complementary proteomic profiling strategies. AB - PURPOSE: Ovarian cancer is a devastating disease and biomarkers for its early diagnosis are urgently required. Serum may be a valuable source of biomarkers that may be revealed by proteomic profiling. Herein, complementary serum protein profiling strategies were employed for discovery of biomarkers that could discriminate cases of malignant and benign ovarian cancer. EXPERIMENTAL DESIGN: Identically collected and processed serum samples from 22 cases of invasive epithelial ovarian cancer, 45 benign ovarian neoplasms, and 64 healthy volunteers were subjected to immunodepletion and protein equalization coupled to 2D-DIGE/MS and multidimensional fractionation coupled to SELDI-TOF profiling with MS/MS for protein identification. Selected candidates were verified by ELISA in samples from malignant (n = 70) and benign (n = 89) cases and combined marker panels tested against serum CA125. RESULTS: Both profiling platforms were complementary in identifying biomarker candidates, four of which (A1AT, SLPI, APOA4, VDBP) significantly discriminated malignant from benign cases. However, no combination of markers was as good as CA125 for diagnostic accuracy. SLPI was further tested as an early marker using prediagnosis serum samples. While it rose in cases toward diagnosis, it did not discriminate prediagnosis cases from controls. CONCLUSIONS AND CLINICAL RELEVANCE: The candidate biomarkers warrant further validation in independent sample sets. PMID- 25290623 TI - Mechanisms in B-cell neoplasia. PMID- 25290624 TI - Bacterial 'cross-reacting' determinants in ankylosing spondylitis. PMID- 25290625 TI - AIDS and the thymus. PMID- 25290626 TI - Contrasuppressor cells in mucosal immunity. PMID- 25290627 TI - Psoriasis: a disease of abnormal Keratinocyte proliferation induced by T lymphocytes. AB - Psoriasis affects 2% of the population in Western countries. Its aetiology and pathogenesis remain unknown but suggestions include abnormalities of blood vessels, neural components, epidermal cell cycle time or maturation of keratinocytes. More recently autoimmune reactions have been implicated involving stratum corneum antibodies(1) and antibodies to nuclei of basal epidermal cells(2). However, there is no convincing evidence that any of these abnormalities are of primary nature. In this article, Helgi Valdimarsson and his colleagues propose that the process leading to psoriatic lesions is triggered by T lymphocytes within the epidermal compartment. They envisage that psoratic lesions erupt where epidermal influx of antigen-carrying Langerhans cells and helper T lymphocytes overrides the normal epidermal suppressor mechanism. PMID- 25290628 TI - Processing of viral antigens and presentation to class II-restricted T cells. AB - Some antigens require intracellular processing by antigen presenting cells before being presented to T cells in conjunction with surface major histocompatibility complex antigens. The whole mechanism of these processing events is not known and in this article, Kingston Mills puts forward arguments for alternative routes of antigen processing, with particular reference to recognition of viral proteins by class II-restricted T-cell clones. PMID- 25290629 TI - Human leukocyte IgG Fc receptors. PMID- 25290630 TI - Amplification of the immune response by agonistic antibodies. AB - During the last seven years, more than 1000 munine monoclonal antibodies (mAb) have been made which react with human leucocyte differentiation antigens. International workshops have extensively evaluated these mAb; over 25 differentiation antigens have been identified and included in an international WHO-approved nomenclature(1-3), called clusters of differentiation (CD). These are identified by both serological and biochemical analyses. In this article Ed Clark and Jeff Ledbetter summarize a subset of these mAb specific for differentiation antigens that, as agonists, induce activation, growth, or differentiation of lymphocytes. PMID- 25290631 TI - Signal transduction and intracellular events in T-lymphocyte activation. AB - The important role of a novel signal transduction pathway has recently been established in the cellular activation and proliferation of many cell types. The key event in this pathway is the hydrolysis of a distinct membrane-associated inositol phospholipid and the resulting generation of two defined products that act as second messengers in cell activation. Sufficient evidence has accumulated to indicate that this signal transduction pathway plays an important role in T cell activation. In this article, Noah Isakov and his colleagues review briefly the general characteristics of this pathway and describe in more detail experimental evidence that establishes its critical role in T-cell activation. PMID- 25290632 TI - Interaction of amphiphilic aggregates with cells of the immune system. AB - The cell membrane - its composition, integrity, and function - is central to many biological processes, ranging from cell adherence and contact inhibition, to the cell-cell interactions involved in many immunological responses. While great progress has been made in understanding the biological and biochemical mechanisms responsible for cellular functions and interactions, similar strides have been taken in dissecting and quantifying the chemical and physical forces that govern the shape and structure of membranes(1). Here, Robert Ashman and his colleagues discuss principles derived from theory and experimentation in colloid and surface chemistry, the insights they may provide into the mechanisms of membrane function, and the means by which these membrane functions may be modified. PMID- 25290633 TI - Graphic software for the research laboratory. AB - This month two software packages designed to display graphic data from the research laboratory are reviewed. interactive Microware's CURVE FITTER-PC and SCIENTIFIC PLOTTER-PC are written in Basic and allow data to be entered from the keyboard. landel Corporation's DIGITAL PAINTBRUSH uses a digitizing pen to enter data and allows for computerized measurement of lines, curves and areas. PMID- 25290634 TI - Documentation of sexual partner gender is low in electronic health records: observations, predictors, and recommendations to improve population health management in primary care. AB - The 2011 Institute of Medicine report on LGBT health recommended that sexual orientation and gender identity (SO/GI) be documented in electronic health records (EHRs). Most EHRs cannot document all aspects of SO/GI, but some can record gender of sexual partners. This study sought to determine the proportion of patients who have the gender of sexual partners recorded in the EHR and to identify factors associated with documentation. A retrospective analysis was done of EHR data for 40 family medicine (FM) and general internal medicine (IM) practices, comprising 170,570 adult patients seen in 2012. The primary outcome was EHR documentation of sexual partner gender. Multivariate logistic regression assessed the impact of patient, provider, and practice factors on documentation. In all, 76,767 patients (45%) had the gender of sexual partners recorded, 4.3% of whom had same-gender partners (3.5% of females, 5.6% of males). Likelihood of documentation was independently higher for women; blacks; those with a preventive visit; those with a physician assistant, nurse practitioner, or resident primary care provider (vs. attending); those at urban practices; those at smaller practices; and those at a residency FM practice. Older age and Medicare insurance were associated with lower documentation. Sexual partner gender documentation is important to identify patients for targeted prevention and support, and holds great potential for population health management, yet documentation in the EHR currently is low. Primary care practices should routinely record the gender of sexual partners, and additional work is needed to identify best practices for collecting and using SO/GI data in this setting. PMID- 25290635 TI - Eliminating the roughness in cholesterol's beta-face: does it matter? AB - One of the long-standing issues surrounding cholesterol (Chol) relates to its two faced character. In particular, the consequences of its having a rough beta-face and a smooth alpha-face on its structural influence in cell membranes has remained elusive. In this study, direct comparisons have been made between cholesterol and a "smoothened" analog, DChol (i.e., 18,19-dinorcholesterol) using model membranes and a combination of nearest-neighbor recognition, differential scanning calorimetry, fluorescence, and monolayer measurements. Taken together, these results indicate that subtle differences exist between the interaction of these two sterols with the different states of 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC). Chol has a greater condensing power than DChol, but only slightly so, i.e., on the order of a few tens of calories per mole. PMID- 25290636 TI - Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium. AB - BACKGROUND: Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6 weeks of lithium monotherapy and matched with healthy controls. METHODS: Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21 item Hamilton Depression Rating Scale score >=18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and endpoint using ELISA method. RESULTS: Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p=0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p=0.032 and 0.034, respectively). CONCLUSION: Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT 3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD. PMID- 25290637 TI - Acute and chronic ethanol exposure differentially alters alcohol dehydrogenase and aldehyde dehydrogenase activity in the zebrafish liver. AB - Chronic ethanol exposure paradigms have been successfully used in the past to induce behavioral and central nervous system related changes in zebrafish. However, it is currently unknown whether chronic ethanol exposure alters ethanol metabolism in adult zebrafish. In the current study we examine the effect of acute ethanol exposure on adult zebrafish behavioral responses, as well as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activity in the liver. We then examine how two different chronic ethanol exposure paradigms (continuous and repeated ethanol exposure) alter behavioral responses and liver enzyme activity during a subsequent acute ethanol challenge. Acute ethanol exposure increased locomotor activity in a dose-dependent manner. ADH activity was shown to exhibit an inverted U-shaped curve and ALDH activity was decreased by ethanol exposure at all doses. During the acute ethanol challenge, animals that were continuously housed in ethanol exhibited a significantly reduced locomotor response and increased ADH activity, however, ALDH activity did not change. Zebrafish that were repeatedly exposed to ethanol demonstrated a small but significant attenuation of the locomotor response during the acute ethanol challenge but ADH and ALDH activity was similar to controls. Overall, we identified two different chronic ethanol exposure paradigms that differentially alter behavioral and physiological responses in zebrafish. We speculate that these two paradigms may allow dissociation of central nervous system-related and liver enzyme-dependent ethanol induced changes in zebrafish. PMID- 25290640 TI - T-cell growth factor (interleukin 2). PMID- 25290639 TI - Prominent reducing gas-sensing performances of n-SnO2 nanowires by local creation of p-n heterojunctions by functionalization with p-Cr2O3 nanoparticles. AB - A novel approach to improving the reducing gas-sensing properties of n-type nanowires (NWs), by locally creating p-n heterojunctions with p-type nanoparticles (NPs), is proposed. As a model system, this work investigates the sensing behaviors of n-SnO2 NWs functionalized with p-Cr2O3 NPs. Herein, n-SnO2 NWs demonstrate greatly improved reducing gas-sensing performance when functionalized with p-Cr2O3 NPs. Conversely, such functionalization deteriorates the oxidizing gas-sensing properties of n-SnO2 NWs. These phenomena are closely related to the local suppression of the conduction channel of n-type NWs, in the radial direction, beneath the p-n heterojunction by the flow of charge carriers. The approach used in this work can be used to fabricate sensitive reducing-gas sensors based on n-type NWs. PMID- 25290641 TI - Slow-reacting substances and leukotrienes. PMID- 25290638 TI - Zinc deficiency in rats is associated with up-regulation of hippocampal NMDA receptor. AB - RATIONALE: Data indicated that zinc deficiency may contribute to the development of depression; however changes induced by zinc deficiency are not fully described. OBJECTIVES: In the present paper we tested whether the dietary zinc restriction in rats causes alterations in N-methyl-D-aspartate receptor (NMDAR) subunits in brain regions that are relevant to depression. METHODS: Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50 mg Zn/kg) or a zinc deficient diet (ZnD, 3 mg Zn/kg) for 4 or 6weeks. Then, the behavior of the rats was examined in the forced swim test, sucrose intake test and social interaction test. Western blot assays were used to study the alterations in NMDAR subunits GluN2A and GluN2B and proteins associated with NMDAR signaling in the hippocampus (Hp) and prefrontal cortex (PFC). RESULTS: Following 4 or 6 weeks of zinc restriction, behavioral despair, anhedonia and a reduction of social behavior occurred in rats with concomitant increased expression of GluN2A and GluN2B and decreased expression of the PSD-95, p-CREB and BDNF protein levels in the Hp. The up-regulation of GluN2A protein was also found in the PFC, but only after prolonged (6 weeks) zinc deprivation. CONCLUSIONS: The procedure of zinc restriction in rats causes behavioral changes that share some similarities to the pathophysiology of depression. Obtained data indicated that depressive-like behavior induced by zinc deficiency is associated with the changes in NMDAR signaling pathway. PMID- 25290642 TI - Stem cell differentiation in the bone-marrow. AB - Even in the absence of antigenic challenge, the adult immune system is in a state of constant flux and each day receives large numbers of newly formed lymphocytes. The bone-marrow is vital to this continuous renewal, both in its regulation and because it is the direct source of B cells in normal animals and the indirect source of T cells, which are derived ultimately from stem cells that flow from the bone-marrow to the thymus. In this article, John Schrader outlines stem-cell differentiation in the bone-marrow from the viewpoint of an immunologist, dealing mainly with lymphopoiesis, but also with the role of lymphocytes in the regulation of the bone-marrow. PMID- 25290643 TI - The radioallergosorbent test (RAST). PMID- 25290644 TI - Health Care Utilization among Children Enrolled in Medicaid and CHIP via Express Lane Eligibility. AB - OBJECTIVE: To assess health care utilization among children enrolled in Medicaid and CHIP via Express Lane Eligibility (ELE). DATA SOURCES/STUDY SETTING: Enrollment, claims, and encounter data for children enrolled in Medicaid or CHIP in Alabama, Iowa, Louisiana, and New Jersey during 2009-2012. STUDY DESIGN: We compared health care utilization among children enrolled via ELE and nondisabled children who enrolled through standard pathways in each state. We used a two-step estimation approach, examining the likelihood of utilization and then the volume and cost of services among users. Regression adjustment corrected for demographic differences. PRINCIPAL FINDINGS: Most ELE and comparison group children used services within a year of enrollment and accessed a variety of services, including outpatient care, prescription drugs, and dental and vision care. ELE enrollees were somewhat less likely to use each service type, and those who used services often did so less intensively compared to other enrollees in their state. CONCLUSIONS: Health care use patterns suggest that ELE enrollees are aware of their coverage; enrollees accessed and repeatedly used services covered by public health insurance. However, states considering this policy may expect that remaining eligible but uninsured children may be less expensive to cover than existing beneficiaries. PMID- 25290646 TI - Macrophage or T cell - that is the question. PMID- 25290645 TI - Electrochemical aptasensor for mucin 1 based on dual signal amplification of poly(o-phenylenediamine) carrier and functionalized carbon nanotubes tracing tag. AB - Mucin 1 (MUC 1), as a most studied mucin, has become a useful marker for identifying breast cancer in the early stages. In this work, a novel method for the determination of MUC 1 in serum was developed based on a sandwich-type electrochemical aptasensor, which combined a dual signal amplification strategy of poly(o-phenylenediamine)-Au nanoparticles (PoPD-AuNPs) hybrid film as carrier and AuNPs functionalized silica/multiwalled carbon nanotubes core-shell nanocomposites (AuNPs/SiO2@MWCNTs) as tracing tag. The PoPD-AuNPs film provides a suitable microenvironment for stabilizing the primary aptamer (Apt) assembly, and the AuNPs/SiO2@MWCNTs enhances the surface area for immobilizing abundant secondary Apts as well as load large amounts of electrochemical probe thionine (Thi). In the presence of MUC 1, the sandwich-type recognition reacted on the aptasensor surface, and the Thi-AuNPs/SiO2@MWCNTs nanoprobes were captured onto the electrode surface to form biocomplex. AuNPs and MWCNTs could facilitate the electron transfer from Thi to the electrode, thus amplifying the detection response. Under the optimized experimental conditions, the proposed sensing strategy provided a wider linear dynamic range over three orders of magnitude with the detection limit down to 1 pM. Moreover, the aptasensor demonstrated good precision, acceptable stability and reproducibility. PMID- 25290647 TI - Heavy chain synthesis in pre-B cells. PMID- 25290648 TI - T-B co-operation examined by 'counterfeit' systems using cell surface antigens. PMID- 25290649 TI - What do B lymphocytes and nasopharyngeal epithelium have in common? PMID- 25290650 TI - Lymphocyte dysfunction caused by deficiencies in purine metabolism. AB - Two inborn errors of purine metabolism have been associated with autosomally inherited human immunodeficiency diseases. A lack of adenosine deaminase (ADA) produces severe lymphopenia and a combined immunodeficiency syndrome. A deficiency of purine nucleoside phosphorylase (PNP) is associated with a selective cellular immune depth. This article discusses the probable biochemical basis for lymphocyte-specific toxicity in these disorders. PMID- 25290651 TI - Use of radiolabelled monoclonal anti-CEA antibodies for the detection of human carcinomas by external photoscanning and tomoscintigraphy. AB - Paul Ehrlich's inspired concept of 'magic bullets' for the cure of diseases has been revitalized by recent advances in immunology(1). In particular, the development of cell fusion technology allowing the production of monoclonal antibodies (Mabs) with exquisite specificities(2) triggered new hopes that we may now have the perfect carrier molecules with which to deliver cytotoxic drugs(3) or toxins(4) to the hidden cancer cells. This article reviews data on one aspect of the magic bullet concept, the use of radiolabelled antibodies as tracers for tumour localization. It will also discuss the very recent clinical use of (131)I labelled Mabs against carcinoembryonic antigen (CEA)(5) to detect carcinoma either by conventional external photoscanning or by single photon emission computerized tomography (SPELT). This alliance of the most modern tools from immunology (Mabs) and nuclear medicine (SPELT) appears promising as a way to improve the sensitivity of 'immunoscintigraphy'. However, this approach is not yet ready, for widespread clinical use. PMID- 25290653 TI - Parasitization of commercially available parasitoid species against the lettuce aphid, Nasonovia ribisnigri (Hemiptera: Aphididae). AB - The lettuce aphid, Nasonovia ribisnigri (Mosley), is an economically important pest of lettuce worldwide. Little documentation exists for the control efficacy of aphid parasitoids against N. ribisnigri. This laboratory study evaluated three commercially available parasitoid species: Aphidius colemani (Viereck), Lysiphlebus testaceipes (Cresson), and Aphelinus abdominalis (Dalman) for their mortality impact on N. ribisnigri. The green peach aphid Myzus persicae (Sulzer) was included as a reference aphid. The study showed that A. abdominalis successfully parasitized 39 and 13% of the offered N. ribisnigri and M. persicae, respectively, within a 24-h exposure period. In contrast, none of the lettuce aphids exposed to Ap. colemani or L. testaceipes were successfully parasitized, whereas 60 and 3.5% of M. persicae, respectively, were successfully parasitized within a 6-h exposure period. Lettuce aphid mortality due to incomplete parasitization was 26 and 31% when exposed to Ap. colemani and L. testaceipes, respectively, with corresponding values for M. persicae being 5 and 10%, respectively. Mortality as a result of incomplete parasitization when aphids were exposed to A. abdominalis was low for both aphid species. The total mortality inflicted by A. abdominalis within a 24-h exposure period was 51% for the lettuce aphids and significantly less (19%) for green peach aphids. In contrast, Ap. colemani inflicted a higher mortality in M. persicae (65%) compared with N. ribisnigri (26%) within a 6-h exposure period. L. testaceipes caused a greater mortality in N. ribisnigri as compared with M. persicae. This study concludes that A. abdominalis has the potential to be used against N. ribisnigri in inoculative biocontrol programs as compared with the other parasitoid species based on successful parasitization. PMID- 25290655 TI - Human Vaccines & Immunotherapeutics. Letter from the editor. PMID- 25290654 TI - Association between TLR4 (+896A/G and +1196C/T) polymorphisms and gastric cancer risk: an updated meta-analysis. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is a receptor of lipopolysaccharide in the signaling transduction of gastric epithelial cell. It plays a pivotal role in activation of innate immunity and pathogen recognition and thus acts as a modulator in the development and progression of gastric cancer. Growing studies explored the association of polymorphisms in TLR4 with susceptibility to gastric cancer, but the results have remained controversial and conflicting. To investigate the effect of two selected TLR4 (+896A/G and +1196C/T) polymorphisms on gastric cancer, we performed a meta-analysis. METHODS: A comprehensive search was conducted to identify all eligible case-control publications investigating the association between TLR4 polymorphisms and gastric cancer risk. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to assess such association. RESULTS: Up to March 26 2014, 10 published case-control studies from PubMed and EMBase were available, involving a total of 1888 gastric cancer patients and 3433 control subjects. In the overall meta-analyses, a significantly increased gastric cancer risk was detected in TLR4 +896A/G polymorphism (heterozygous model, AG vs. AA: OR = 1.67, 95% CI, 1.39-2.01; additive model, G vs. A: OR = 1.64, 95% CI, 1.37-1.95) and TLR4 +1196C/T polymorphism (heterozygous model, CT vs. CC: OR = 1.42, 95% CI, 1.11-1.81; additive model, T vs. C: OR = 1.36, 95% CI, 1.08-1.72), similar results were obtained in the subgroup analyses of Caucasian, whereas no associations were detected in any genetic models of non Caucasian. CONCLUSIONS: The overall results suggest that TLR4 polymorphisms (+896A/G and +1196C/T) may be associated with a significantly increased gastric cancer risk in Caucasian. PMID- 25290656 TI - Human vaccines & immunotherapeutics: News. PMID- 25290657 TI - Novel vaccine technology and the future of vaccine science. PMID- 25290659 TI - Competitive sport involvement and substance use among adolescents: a nationwide study. AB - BACKGROUND: The empirical research examining the impact of sports participation on alcohol and other drug use has produced mixed results. Part of this problem may be the result of how different types of sports participation create different experiences that shape certain types of behaviors that either facilitate or deter substance use. OBJECTIVES: We examined the association between different types of competitive sports participation and substance use among a nationally representative sample of adolescents. METHODS: Two recent cross-sections from the Monitoring the Future were merged to capture a large subsection of adolescents who participate in either high-contact sports (football, wrestling, hockey, and lacrosse), semicontact sports (baseball, basketball, field hockey, and soccer), and noncontact sports (cross-country, gymnastics, swimming, tennis, track, and volleyball). RESULTS: Multivariate analyses revealed that adolescents who participated in high-contact sports had higher odds of using substances during the past 30 days and initiating substance use at early ages. Further, adolescents who participated in noncontact sports had lower odds to indicate smoking cigarettes and marijuana during the past 30 days. CONCLUSIONS: Parents, educators, and policy makers need to consider that some sporting contexts may be a catalyst to engage in risky behaviors like substance use. PMID- 25290658 TI - Chronic physical health problems moderate changes in depression and substance use among dual diagnosed individuals during and after treatment. AB - BACKGROUND: Physical illnesses frequently co-occur with depression and substance use disorders and may impact their improvement. Physical illness symptoms may overlap with or exacerbate somatic symptoms of depression. Individuals may use substances to cope with symptoms of physical illness. OBJECTIVES: We examined whether chronic physical health problems moderated changes in depression and substance use among dual diagnosed individuals during and in the year following treatment. METHODS: Participants were recruited from a Veterans Affairs dual diagnosis outpatient program between March 2000 and November 2007 and were randomized to either Integrated Cognitive-Behavioral Therapy or Twelve-Step Facilitation Therapy. A total of 214 veterans with assessment data for the variables of interest were included in analyses. Participants completed quarterly depression, substance use, and health assessments over an 18 month period. We used linear-mixed effects models to analyze patterns of change for depression and substance use. RESULTS: Individuals with severe chronic health problems and higher intake depression showed slower improvements in both nonsomatic and somatic depression symptoms. Individuals with severe chronic health problems and higher midtreatment substance use showed less improvement in substance use. CONCLUSIONS: Assessing and addressing physical health issues during depression and substance use disorder treatment may improve outcomes. PMID- 25290660 TI - Modeling the impact of place on individual methadone treatment outcomes in a national longitudinal cohort study. AB - BACKGROUND: Little has been published on the effect of geography on methadone treatment outcomes. OBJECTIVE: To measure the effect of place on longitudinal outcomes Methods: From 2003 to 2006, 215 clients were recruited to a cohort study of methadone treatment. Participants had their address and clinic geocoded. Treatment outcomes were measured at intake, at one and three years posttreatment using the Maudsley Addiction Profile instrument. Spider diagrams and buffer rings were used to visually map clinics and clients. Regression models were used to measure the effect of place. RESULTS: Client's accommodation and social and criminal problems in the region had a medium to large effect on heroin use. Analysis of buffer rings revealed that clients located within a 10-km radius of a major clinic demonstrated poorer outcomes in terms of heroin use. Conclusion/Importance: Findings illustrated the relevance of geography on drug treatment outcomes and the planning of services. PMID- 25290661 TI - Smoking is unrelated to female sexual function. AB - BACKGROUND: Previous research shows that smoking status is unrelated to female sexual difficulties. However, degree of nicotine dependence has not been measured, and the assessment of sexual functioning has not specified penile vaginal intercourse (henceforth, intercourse), which is more clearly impaired by sexual difficulties than other sexual behaviors. OBJECTIVES: To test if smoking status is associated with poorer female sexual function during intercourse, and if nicotine dependence rather than smoking status is related to poorer female sexual function. METHODS: During 2012, 129 Portuguese community women reported their smoking status, and completed the Fagerstrom Test for Nicotine Dependence, the Female Sexual Function Index (FSFI), and an adaptation of the FSFI to assess sexual functioning specifically during intercourse, as well as the desire thereof. RESULTS: Smokers reported higher desire for intercourse and were more likely to have actually engaged in it in the past 4 weeks. Among the coitally active women in the preceding 4 weeks, nicotine dependence correlated with lower desire for intercourse. Smoking status and nicotine dependence were unrelated to arousal, lubrication, orgasm, satisfaction, pain. CONCLUSIONS: The findings are consistent with many studies that fail to demonstrate an increased risk of sexual difficulties among female smokers. However, nicotine dependence, rather than smoking status per se, might be associated with lower libido. The results suggest the possibility of an inverse U-shaped relationship between smoking and libido with a moderate use of tobacco being associated with higher sexual desire. PMID- 25290662 TI - Changes in alcohol use among first year university students in Mexico. AB - BACKGROUND: Alcohol use and misuse is widespread among university students in many countries. Specific cultural factors may impact alcohol use after entering university. OBJECTIVE: This paper considers changes in alcohol use among first year university students in Mexico. METHODS: A qualitative study using ethnographic interviews with 57 female and 60 male student drinkers in Mexico City from March to June 2011. Each interview was evaluated by a set of thematic codes developed inductively from the interviews. Findings from excessive, heavy, regular, occasional drinkers, abstainers, and non-drinkers were analyzed to explore whether or not linkages existed between and/or among particular themes. RESULTS: Students reported factors associated with changes in role and status, friendships, and increased autonomy as reasons for increasing or decreasing their alcohol use after entering university. CONCLUSIONS/IMPORTANCE: Understanding the influence of Mexican cultural norms on alcohol use among Mexican and Mexican Americans can be helpful in informing studies and preventive efforts among both Mexican and Mexican American young people. PMID- 25290663 TI - Patterns of substance use, delinquency, and risk factors among adolescent inhalant users. AB - BACKGROUND: Despite insidious effects, use of inhalant substances by adolescents remains an understudied phenomenon. OBJECTIVE: This research was designed to identify patterns of past year substance use and delinquency among adolescent inhalant users. METHOD: The study used a sample of adolescent inhalant users (ages ranged from 12-17 years, n = 7,476) taken from a pooled sample of the 2002 through 2012 National Survey of Drug Use and Health (NSDUH). Three-step latent class analyses were conducted with past year substance use and delinquency behaviors as class indicators. Demographic and social covariates were included in the analyses. RESULTS: Analyses yielded a six-class solution comprised of classes of users characterized by low substance use/low delinquency, high substance use/low delinquency, low substance use/fighting, cigarettes/alcohol/marijuana, high substance use/high delinquency, and cigarettes/alcohol/ marijuana/opioids/moderate delinquency. CONCLUSIONS: Findings provide insight into the taxonomy of adolescent inhalant user heterogeneity, and may inform future efforts at detection and prevention of inhalant use by suggesting warning signs of co-occurring externalizing behaviors and possible indications of underlying internalized issues. PMID- 25290664 TI - Interaction of motivation and psychiatric symptoms on substance abuse outcomes in sober living houses. AB - BACKGROUND: Studies show residents of sober living recovery houses (SLHs) make improvements in a variety of areas including alcohol and drug use, arrests, and employment. Longitudinal measures of motivation (assessed as costs and benefits of continuing sobriety) have been shown to be associated with alcohol and drug outcomes in SLHs. However, how motivation interacts with other potentially important factors, such as psychiatric severity, is unclear. OBJECTIVE: The present study aimed to assess how perceived costs and benefits of sobriety among residents of SLHs differed by psychiatric severity. The study also aimed to assess how costs and benefits interacted with psychiatric severity to influence outcome. METHODS: Two hundred forty-five residents of SLHs were assessed at baseline and 6, 12, and 18 months. RESULTS: High psychiatric severity was associated with higher severity of alcohol and drug problems and higher perceived costs of sobriety at all data collection time points. Perceived costs and benefits of sobriety were strong predictors of alcohol and drug problems for participants with low psychiatric severity. Perceived costs, but not perceived benefits, predicted outcomes for residents with high psychiatric severity. CONCLUSIONS/IMPORTANCE: High psychiatric severity is a serious impediment for some residents in SLHs. These individuals perceive sobriety as difficult and that perception is associated with worse outcome. Finding ways to decrease perceived costs and challenges to sustained sobriety among these individuals is essential as is collaboration with local mental health services. SLHs should consider whether additional onsite services or modifications of SLH operations might help this population. PMID- 25290665 TI - Lidocaine patch for acute pain management: a meta-analysis of prospective controlled trials. AB - BACKGROUND: Local anesthetic is one of the cornerstones of multimodal analgesia. We investigated the efficacy of the lidocaine patch for acute pain management. METHODS: We searched MEDLINE, CINAHL, Scopus, and the Cochrane Controlled Trials Register for published prospective controlled clinical trials that evaluated the analgesic effect of the lidocaine patch for acute or postoperative pain management (1966--2014). The outcomes were postoperative opioid consumption, pain intensity and length of hospital stay. RESULTS: Five trials comparing the lidocaine patch with control (no treatment/placebo) for acute or postoperative pain treatment/management were included in this meta-analysis. Data was analyzed on 251 patients. Between the lidocaine patch group and the control group, no significant difference was found for all three outcomes (all p > 0.05). For postoperative opioid consumption, mean difference (MD) was -8.2 mg morphine equivalent (95% CI -28.68, 12.24). For postoperative pain intensity, MD was -9.1 mm visual analog scale or equivalent (95% CI -23.31, 5.20). For length of hospital stay, MD was -0.2 days (95% CI -0.80, 0.43). CONCLUSION: Application of a lidocaine patch may not be an effective adjunct for acute and postoperative pain management, in terms of pain intensity, opioid consumption and length of hospital stay. LIMITATIONS: The limitations were a small number of included studies, potential biases from some unblinded studies, clinical heterogeneity between studies, and incomplete reported data for adjunct analgesics. PMID- 25290666 TI - A RING finger protein 114 (RNF114) homolog from Chinese sturgeon (Acipenser sinensis) possesses immune-regulation properties via modulating RIG-I signaling pathway-mediated interferon expression. AB - Ubiquitin ligases play important roles in immune regulation. The human RNF114 (RING finger protein 114), an ubiquitin ligase, was recently reported to be involved in immune response to double-stranded RNA in disease pathogenesis. Here, we identified a RNF114 homolog in Chinese sturgeon (Acipenser sinensis) and investigated its potential role in immune response. The full-length cDNA of Chinese sturgeon RNF114 (csRNF114) contains an open reading frame (ORF) of 681 nucleotides coding a protein of 227 amino acids. csRNF114 shares the highest identity of 76% at amino acid level to other RNF114 homologs, clustering with bony fish RNF114s based on phylogenetic analysis. The main structural features of csRNF114, including a C3HC4 (Cys3-His-Cys4) RING domain, a C2HC (Cys2-His-Cys) type zinc finger motif, a C2H2 (Cys2-His2)-type zinc finger motif, and a UIM (ubiquitin-interacting motif), take csRNF114 as an ubiquitin ligase. csRNF114 mRNA was widely expressed in various tissues and significantly up-regulated in poly(I:C)-treated Chinese sturgeon. Over-expression of csRNF114 in HEK293T cells significantly promoted both basal and poly(I:C)-induced activation of interferon regulatory transcription factor 3 (IRF3) and nuclear factor-kappaB (NF-kappaB) downstream retinoic acid inducible gene I (RIG-I) signaling pathway and expression of target genes type I interferon (IFN), which was nearly abolished by knockdown of RIG-I with specific human siRNA and by mutation of the C3HC4 RING domain (C28A/C31A) in csRNF114 as well. Furthermore, csRNF114 associated with ubiquitinated proteins in HEK293T cells, for which the C3HC4 RING domain was essential. These data suggested that an ubiquitin ligase RNF114 homolog with a potential role in antiviral response possibly through modulating RIG-I signaling pathway was cloned from Chinese sturgeon, which might contribute to our understanding of the immune biology of Chinese sturgeon. PMID- 25290667 TI - Integration of tablet technologies in the e-laboratory of cytology: a health technology assessment. AB - INTRODUCTION: Although tablet systems are becoming a powerful technology, particularly useful in every application of medical imaging, to date no one has investigated the acceptance and performance of this technology in digital cytology. The specific aims of the work were (1) to design a health technology assessment (HTA) tool to assess, in terms of performance and acceptance, the introduction of tablet technologies (wearable, portable, and non portable) in the e-laboratories of cytology and (2) to test the tool in a first significant application of digital cytology. MATERIALS AND METHODS: An HTA tool was proposed operating on a domain of five dimensions of investigation comprising the basic information of the product of digital cytology, the perceived subjective quality of images, the assessment of the virtual navigation on the e-slide, the assessment of the information and communication technologies features, and the diagnostic power. Six e-slides regarding studies of cervicovaginal cytology digitalized by means of an Aperio ( www.aperio.com ) scanner and uploaded onto the www.digitalslide.it Web site were used for testing the methodology on three different network connections. RESULTS: Three experts of cytology successfully tested the methodology on seven tablets found suitable for the study in their own standard configuration. Specific indexes furnished by the tool indicated both a high degree of performance and subjective acceptance of the investigated technology. CONCLUSIONS: The HTA tool thus could be useful to investigate new tablet technologies in digital cytology and furnish stakeholders with useful information that may help them make decisions involving the healthcare system. From a global point of view the study demonstrates the feasibility of using the tablet technology in digital cytology. PMID- 25290668 TI - A health recreation program for u-healthcare clients: effects on mental health. AB - INTRODUCTION: In this study, a health recreation program was implemented with elderly patients (60 years of age or older) who were receiving ubiquitous healthcare (u-healthcare) services. Furthermore, we examined the effects of health recreation on perceived stress, anxiety, and depression, by comparing survey results before and after the recreation program was conducted. Thus, the aim of this study was to develop an offline service with the ability to promote the impact of the u-healthcare service on mental healthcare. MATERIALS AND METHODS: A health recreation program, consisting of a variety of weekly games, songs, and minilectures about mental health over a 10-week period, was offered at a senior citizens center in K-Gu, Seoul, Korea. This program targeted 18 elderly people currently receiving u-healthcare services. Data on the impact of the program on the mental health of the elderly were collected through surveys administered before and after the recreation program, and the results were compared with those of a control group. The control group consisted of 18 elderly people who were receiving u-healthcare services from the same district. RESULTS: The perceived stress and anxiety of the experimental group decreased significantly compared with those of the control group. However, the program did not result in a significant reduction in depression. CONCLUSIONS: This offline health recreation program offered to elderly u-healthcare service clients contributed to the promotion of their mental health. Further studies will be required to better incorporate the offline mental healthcare program into their daily lives within the u-healthcare service. PMID- 25290670 TI - Advanced fault diagnosis methods in molecular networks. AB - Analysis of the failure of cell signaling networks is an important topic in systems biology and has applications in target discovery and drug development. In this paper, some advanced methods for fault diagnosis in signaling networks are developed and then applied to a caspase network and an SHP2 network. The goal is to understand how, and to what extent, the dysfunction of molecules in a network contributes to the failure of the entire network. Network dysfunction (failure) is defined as failure to produce the expected outputs in response to the input signals. Vulnerability level of a molecule is defined as the probability of the network failure, when the molecule is dysfunctional. In this study, a method to calculate the vulnerability level of single molecules for different combinations of input signals is developed. Furthermore, a more complex yet biologically meaningful method for calculating the multi-fault vulnerability levels is suggested, in which two or more molecules are simultaneously dysfunctional. Finally, a method is developed for fault diagnosis of networks based on a ternary logic model, which considers three activity levels for a molecule instead of the previously published binary logic model, and provides equations for the vulnerabilities of molecules in a ternary framework. Multi-fault analysis shows that the pairs of molecules with high vulnerability typically include a highly vulnerable molecule identified by the single fault analysis. The ternary fault analysis for the caspase network shows that predictions obtained using the more complex ternary model are about the same as the predictions of the simpler binary approach. This study suggests that by increasing the number of activity levels the complexity of the model grows; however, the predictive power of the ternary model does not appear to be increased proportionally. PMID- 25290671 TI - Altered immune function in demyelinative disease. AB - Experimentally induced demyelination has an autoimmune origin in some mouse models and is somehow virally induced in others. In June, invited participants in a Kroc Foundation workshop discussed the damaging mechanisms involved and their relevance to an understanding of multiple sclerosis and human encephalomyelitis. PMID- 25290672 TI - Antibodies begin to count in the neurology clinic. PMID- 25290673 TI - Autoimmune diseases: defects in immune specificity rather than a loss of suppressor cells. AB - An argument that autoimmune responses arise not because immunoregulation is faulty but because somatic mutation in lymphocytes generates clones with autoreactive potential. PMID- 25290675 TI - The organization of B and T lymphocytes in lymph nodes. PMID- 25290674 TI - The construction and immunocompetence of totally allogeneic mouse radiation chimeras. PMID- 25290676 TI - The cross-reactive idiotype of A-strain mice Serological and structural analyses. AB - Idiolypes have been implicated in the induction and regulation of complex humoral and cell-mediated immune phenomena. Now, with the development of hybridoma technology, the enigma of the molecular basis of idiotypy is succumbing to systematic serological and structural analyses. Here Don Capra and his colleagues describe recent studies on one of the best known idiotype .systems, in the antibody response to arsonate. PMID- 25290677 TI - Ia antigens on non-lymphoid tissues their origins and functions. AB - Ia molecules are encoded in the 1 region of the mouse major histocompatibility complex (MIX) and expressed as surface antigens on certain immunologically active cells (reviewed in Ref. 1). B cells, subsets of T helper and T suppressor cells and accessory, antigen-presenting cells are Ia-positive (Ia+) while T killer cells and natural killer cells are not. This article discusses the nature and function of Ia+ cells found in non-lymphoid tissues, some of which are immunologically involved while others are not obviously so. PMID- 25290678 TI - Chronic lymphocytic leukaemia and its relationship to normal B lymphopoiesis. AB - The leukaemic cells from patients with chronic lymphocytic leukaemia have long been thought to represent circulating virgin B lymphocytes. In this article Alan Johnstone discusses the accumulated data from structural and functional analyses which place the leukaemic cells at a stage intermediate between the pre-B cell and mature B lymphocyte, a stage not normally found in the circulation. PMID- 25290679 TI - The immunological role of antigen-binding cells. AB - A well characterized antigen-binding cell population can yield important insights into antigen-induced activation events. But data interpretation must take into account the heterogeneity of these populations. The maturity of ABC and the proportion belonging to the various T and B-cell subsets depends on the source and on the conditions of the antigen-binding cell assay. There are a variety of useful methods for isolating highly purified populations of B-ABC, but the highest purity is achieved only by sacrificing yield and skewing the composition of the population. The direct demonstration that virtually every LPS-stimulatable precursor of IgM or IgG secreting cells in the SRC-ABC population is a precursor for specific antibody producing cells establishes the commitment of SRC-ABC to the SRC response. Although the majority of spleen B-ABC respond to immunization in vivo by switching surface isotypes and accelerating receptor turnover, the more stringent requirements for further differentiation to antibody production are still under active investigation(27). By investigating the biochemical events that take place in ABC during immune responses in vivo and in vitro, and pursuing parallel studies of cloned functional cell lines responding to antigen through surface receptors, wer may eventually understand the classical interactions of cellular immunology in terms of physiological changes in the antigen-reactive cells. PMID- 25290682 TI - Safety of unsedated PEG placement using transoral ultrathin endoscopy in patients with amyotrophic lateral sclerosis. AB - BACKGROUND AND AIMS: In patients with amyotrophic lateral sclerosis (ALS), percutaneous endoscopic gastrostomy (PEG) placement under sedation often causes apnea or hypoventilation. The aim of the present study was to assess whether unsedated PEG placement in ALS patients using ultrathin endoscopy (UTE) via the transoral route can improve safety. METHODS: Between 2003 and 2013, PEG placement was identified and reviewed in 45 patients with ALS. PEG was performed in 14 patients using transoral UTE without sedation (UTE group), 17 patients using conventional normal-diameter esophagogastroduodenoscopy (C-EGD) without sedation (unsedated C-EGD group) and 14 patients using C-EGD with sedation (sedated C-EGD group). We compared the clinical features, cardiopulmonary data before and during PEG placement, and complications related to PEG placement among the three groups. RESULTS: There were no significant differences in age, male/female ratio, forced vital capacity, blood pressure, oxygen saturation before and during PEG, or major complications among the three groups. No minor complications were observed in the UTE group, whereas apnea and/or hypoventilation were observed in the sedated C EGD group and aspiration pneumonia was observed in the unsedated C-EGD group. CONCLUSIONS: Unsedated PEG placement using transoral UTE in ALS patients is a safe method. PMID- 25290683 TI - Design, synthesis and evaluation of multifunctional salphen derivatives for the treatment of Alzheimer's disease. AB - A series of salphen derivatives (1-26) have been designed, synthesized, and evaluated as chemical reagents that target and modulate multiple facets of Alzheimer's disease. Most of the compounds exhibit a significant ability to inhibit self-induced and Cu(2+)-induced beta-amyloid (Abeta1-42) aggregation, and to function as potential antioxidants and biometal chelators. In particular, the antioxidant activity of compound 2 is 2.6-fold of the trolox value by using the ABTS radical scavenging method, and it also shows a significant ability to inhibit self-induced and Cu(2+)-induced beta-amyloid (Abeta1-42) aggregation (70.3%, 20 MUM and 85.7%, 50 MUM, respectively). Moreover, it is capable of decreasing reactive oxygen species (ROS) induced by Cu(2+)-Abeta, shows a good neuroprotective effect in human SH-SY5Y neuroblastoma cells and can cross the blood-brain barrier. In addition, compound 2 retains the activities of antioxidant, anti Abeta aggregation and neuroprotection after capturing the metal ions Cu(2+), Fe(3+) and Zn(2+) (its metal complexes 18, 22 and 23). Taken together, these results suggest that compound 2 might be a promising lead compound for AD treatment. PMID- 25290684 TI - Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype. AB - Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur deficient hair with alternating dark and light "tiger tail" banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. Although most of the TTD patients are photosensitive, patients with TTDN1 mutations were reported to be nonphotosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe five patients from four families with defects in the TTDN1 gene: four had no photosensitivity, and one patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (P=0.009 and P=0.024, respectively), whereas some characteristic TTD clinical, laboratory, and imaging findings were absent. The three oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120 kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease. PMID- 25290686 TI - Obesity and risks for malignant melanoma and non-melanoma skin cancer: results from a large Danish prospective cohort study. PMID- 25290685 TI - Expert advice provided through telemedicine improves healing of chronic wounds: prospective cluster controlled study. AB - Telemedicine is widely considered as an efficient approach to manage the growing problem of chronic wounds. However, to date, there is no convincing evidence to support the clinical efficacy of telemedicine in wound management. In this prospective cluster controlled study, we tested the hypothesis that advice on wound management provided by a team of wound-care specialists through telemedicine would significantly improve the likelihood of wound healing compared with the best available conventional practice. A total of 90 chronic wound patients in home care met all study criteria and were included: 50 in the telemedicine group and 40 in the conventional group. Patients with pressure ulcers, surgical wounds, and cancer wounds were excluded. During the 1-year follow-up, complete wound healing was achieved in 35 patients (70%) in the telemedicine group compared with 18 patients (45%) in the conventional group. After adjusting for important covariates, offering advice on wound management through telemedicine was associated with significantly increased healing compared with the best available conventional practice (telemedicine vs. conventional practice: adjusted hazard ratio 2.19; 95% confidence interval: 1.15-4.17; P=0.017). This study strongly supports the use of telemedicine to connect home care nurses to a team of wound experts in order to improve the management of chronic wounds. PMID- 25290687 TI - Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes. AB - Autophagy is the central cellular mechanism for delivering organelles and cytoplasm to lysosomes for degradation and recycling of their molecular components. To determine the contribution of autophagy to melanocyte (MC) biology, we inactivated the essential autophagy gene Atg7 specifically in MCs using the Cre-loxP system. This gene deletion efficiently suppressed a key step in autophagy, lipidation of microtubule-associated protein 1 light chain 3 beta (LC3), in MCs and induced slight hypopigmentation of the epidermis in mice. The melanin content of hair was decreased by 10-15% in mice with autophagy-deficient MC as compared with control animals. When cultured in vitro, MCs from mutant and control mice produced equal amounts of melanin per cell. However, Atg7-deficient MCs entered into premature growth arrest and accumulated reactive oxygen species (ROS) damage, ubiquitinated proteins, and the multi-functional adapter protein SQSTM1/p62. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) dependent expression of NAD(P)H dehydrogenase, quinone 1, and glutathione S transferase Mu 1 was increased, indicating a contribution of autophagy to redox homeostasis in MCs. In summary, the results of our study suggest that Atg7 dependent autophagy is dispensable for melanogenesis but necessary for achieving the full proliferative capacity of MCs. PMID- 25290688 TI - Synergism between basic Asp49 and Lys49 phospholipase A2 myotoxins of viperid snake venom in vitro and in vivo. AB - Two subtypes of phospholipases A2 (PLA2s) with the ability to induce myonecrosis, 'Asp49' and 'Lys49' myotoxins, often coexist in viperid snake venoms. Since the latter lack catalytic activity, two different mechanisms are involved in their myotoxicity. A synergism between Asp49 and Lys49 myotoxins from Bothrops asper was previously observed in vitro, enhancing Ca2+ entry and cell death when acting together upon C2C12 myotubes. These observations are extended for the first time in vivo, by demonstrating a clear enhancement of myonecrosis by the combined action of these two toxins in mice. In addition, novel aspects of their synergism were revealed using myotubes. Proportions of Asp49 myotoxin as low as 0.1% of the Lys49 myotoxin are sufficient to enhance cytotoxicity of the latter, but not the opposite. Sublytic amounts of Asp49 myotoxin also enhanced cytotoxicity of a synthetic peptide encompassing the toxic region of Lys49 myotoxin. Asp49 myotoxin rendered myotubes more susceptible to osmotic lysis, whereas Lys49 myotoxin did not. In contrast to myotoxic Asp49 PLA2, an acidic non-toxic PLA2 from the same venom did not markedly synergize with Lys49 myotoxin, revealing a functional difference between basic and acidic PLA2 enzymes. It is suggested that Asp49 myotoxins synergize with Lys49 myotoxins by virtue of their PLA2 activity. In addition to the membrane-destabilizing effect of this activity, Asp49 myotoxins may generate anionic patches of hydrolytic reaction products, facilitating electrostatic interactions with Lys49 myotoxins. These data provide new evidence for the evolutionary adaptive value of the two subtypes of PLA2 myotoxins acting synergistically in viperid venoms. PMID- 25290689 TI - Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury. AB - Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury. PMID- 25290690 TI - Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia. AB - The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI) is considered a primary contributor to the pathophysiology of schizophrenia (SZ), but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model. PMID- 25290691 TI - Break CDK2/Cyclin E1 interface allosterically with small peptides. AB - Most inhibitors of Cyclin-dependent kinase 2 (CDK2) target its ATP-binding pocket. It is difficult, however, to use this pocket to design very specific inhibitors because this catalytic pocket is highly conserved in the protein family of CDKs. Here we report some short peptides targeting a noncatalytic pocket near the interface of the CDK2/Cyclin complex. Docking and molecular dynamics simulations were used to select the peptides, and detailed dynamical network analysis revealed that these peptides weaken the complex formation via allosteric interactions. Our experiments showed that upon binding to the noncatalytic pocket, these peptides break the CDK2/Cyclin complex partially and diminish its kinase activity in vitro. The binding affinity of these peptides measured by Surface Plasmon Resonance can reach as low as 0.5 uM. PMID- 25290692 TI - Correlation between long-term aspirin use and F-fluorodeoxyglucose uptake in colorectal cancer measured by PET/CT. AB - PURPOSE: The aim of this study was to evaluate the relationship between long-term aspirin use with pretreatment 18 Fluorodeoxyglucose (FDG) uptake of primary lesions of Colorectal cancer (CRC) and evaluate their clinical significance. MATERIALS AND METHODS: We enrolled 84 patients with CRC who underwent 18F-FDG PET/CT scanning before surgery between 1st July 2008 and 1st March 2013 and followed up until 1st March 2014. Maximum standardized uptake value (SUVmax) of the primary tumor was measured by 18F-FDG PET/CT. The history of aspirin taken and other clinicopathogical factors were also obtained and their relationships were examined by Mann-Whitney or chi2 tests. Progression-free survival (PFS) was determined by standard Kaplan-Meier survival analysis. Cox proportional hazards regression was performed to determine whether history of aspirin taken, pretreatment SUVmax, age, gender, TNM stage, tumor sizes and differentiation influenced outcomes. RESULTS: CRC Patients with long-term history of aspirin use had lower SUVmax of primary lesions than control group (9.74+/-2.62 vs. 13.91+/ 6.18) and showed a trend towards improved PFS after curative surgery. However, pretreatment of SUVmax showed no prognostic value in patients with CRC. CONCLUSIONS: Long-term aspirin use is associated with lower pretreatment SUVmax of CRC and is a promising prognostic factor for predicting PFS in patients with CRC. PMID- 25290693 TI - Pyrophosphate-mediated iron acquisition from transferrin in Neisseria meningitidis does not require TonB activity. AB - The ability to acquire iron from various sources has been demonstrated to be a major determinant in the pathogenesis of Neisseria meningitidis. Outside the cells, iron is bound to transferrin in serum, or to lactoferrin in mucosal secretions. Meningococci can extract iron from iron-loaded human transferrin by the TbpA/TbpB outer membrane complex. Moreover, N. meningitidis expresses the LbpA/LbpB outer membrane complex, which can extract iron from iron-loaded human lactoferrin. Iron transport through the outer membrane requires energy provided by the ExbB-ExbD-TonB complex. After transportation through the outer membrane, iron is bound by periplasmic protein FbpA and is addressed to the FbpBC inner membrane transporter. Iron-complexing compounds like citrate and pyrophosphate have been shown to support meningococcal growth ex vivo. The use of iron pyrophosphate as an iron source by N. meningitidis was previously described, but has not been investigated. Pyrophosphate was shown to participate in iron transfer from transferrin to ferritin. In this report, we investigated the use of ferric pyrophosphate as an iron source by N. meningitidis both ex vivo and in a mouse model. We showed that pyrophosphate was able to sustain N. meningitidis growth when desferal was used as an iron chelator. Addition of a pyrophosphate analogue to bacterial suspension at millimolar concentrations supported N. meningitidis survival in the mouse model. Finally, we show that pyrophosphate enabled TonB-independent ex vivo use of iron-loaded human or bovine transferrin as an iron source by N. meningitidis. Our data suggest that, in addition to acquiring iron through sophisticated systems, N. meningitidis is able to use simple strategies to acquire iron from a wide range of sources so as to sustain bacterial survival. PMID- 25290695 TI - Bodipy-labeled nucleoside triphosphates for polymerase synthesis of fluorescent DNA. AB - New fluorescent nucleosides and nucleoside triphosphate (dNTPs) analogs bearing the F-Bodipy fluorophore linked through a short, flexible nonconjugate tether were synthesized. The Bodipy-labeled dNTPs were substrates for several DNA polymerases which incorporated them into DNA in primer extension, nicking enzyme amplification reaction, and polymerase chain reaction. The fluorescence of F Bodipy is not quenched upon incorporation in DNA and can be detected both in solutions and on gels. PMID- 25290694 TI - Expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in the rat dental pulp and trigeminal ganglion following inflammation. AB - BACKGROUND: There is increasing evidence that peripheral glutamate signaling mechanism is involved in the nociceptive transmission during pathological conditions. However, little is known about the glutamate signaling mechanism and related specific type of vesicular glutamate transporter (VGLUT) in the dental pulp following inflammation. To address this issue, we investigated expression and protein levels of VGLUT1 and VGLUT2 in the dental pulp and trigeminal ganglion (TG) following complete Freund's adjuvant (CFA) application to the rat dental pulp by light microscopic immunohistochemistry and Western blot analysis. RESULTS: The density of VGLUT2- immunopositive (+) axons in the dental pulp and the number of VGLUT2+ soma in the TG increased significantly in the CFA-treated group, compared to control group. The protein levels of VGLUT2 in the dental pulp and TG were also significantly higher in the CFA-treated group than control group by Western blot analysis. The density of VGLUT1+ axons in the dental pulp and soma in the TG remained unchanged in the CFA-treated group. CONCLUSIONS: These findings suggest that glutamate signaling that is mediated by VGLUT2 in the pulpal axons may be enhanced in the inflamed dental pulp, which may contribute to pulpal axon sensitization leading to hyperalgesia following inflammation. PMID- 25290696 TI - Familial thoracic aortic aneurysms. AB - PURPOSE OF REVIEW: A lot of new data have been obtained in familial thoracic aortic aneurysms, including description of new entities and better understanding of pathophysiology. The aim of this review is to put them in perspective. RECENT FINDINGS: The new data have been collected, put together, and allowed a new classification scheme to be proposed by the Montalcino Aortic Consortium on the basis of the role of proteins coded by the culprit gene (either protein of the extracellular matrix or protein of the transforming growth factor-beta pathway, or protein of the contractile apparatus of the smooth muscle cell). These groups of diseases include aortic aneurysm, but the extent of extra-aortic vascular risk and the presence of extra-aortic (skeletal, ophthalmologic, neurological, or immunological) features vary according to the gene involved. This understanding also sheds light on the therapeutic benefits that can be foreseen for new molecules, or old molecules used in a newer way. SUMMARY: Classification of familial forms of thoracic aortic aneurysm should allow a better understanding of these diseases and therefore standardization of initial evaluation of the patients (vascular evaluation limited or not to the aorta, and extravascular evaluation, including or not skeleton, eyes, neurology, digestive tract, and immunological diseases) and individualization of therapy (adapted to both the genotype and the phenotype). PMID- 25290698 TI - Bursts of transposable elements as an evolutionary driving force. AB - A burst of transposable elements (TEs) is a massive outbreak that may cause radical genomic rebuilding. This phenomenon has been reported in connection with the formation of taxonomic groups and species and has therefore been associated with major evolutionary events in the past. Over the past few years, several research groups have discovered recent stress-induced bursts of different TEs. The events for which bursts of TEs have been recorded include domestication, polyploidy, changes in mating systems, interspecific and intergeneric hybridization and abiotic stress. Cases involving abiotic stress, particularly bursts of TEs in natural populations driven by environmental change, are of special interest because this phenomenon may underlie micro- and macro evolutionary events and ultimately support the maintenance and generation of biological diversity. This study reviews the known cases of bursts of TEs and their possible consequences, with particular emphasis on the speciation process. PMID- 25290700 TI - Promising clues to reception genes and molecules. PMID- 25290697 TI - Centromere-independent accumulation of cohesin at ectopic heterochromatin sites induces chromosome stretching during anaphase. AB - Pericentric heterochromatin, while often considered as "junk" DNA, plays important functions in chromosome biology. It contributes to sister chromatid cohesion, a process mediated by the cohesin complex that ensures proper genome segregation during nuclear division. Long stretches of heterochromatin are almost exclusively placed at centromere-proximal regions but it remains unclear if there is functional (or mechanistic) importance in linking the sites of sister chromatid cohesion to the chromosomal regions that mediate spindle attachment (the centromere). Using engineered chromosomes in Drosophila melanogaster, we demonstrate that cohesin enrichment is dictated by the presence of heterochromatin rather than centromere proximity. This preferential accumulation is caused by an enrichment of the cohesin-loading factor (Nipped-B/NIPBL/Scc2) at dense heterochromatic regions. As a result, chromosome translocations containing ectopic pericentric heterochromatin embedded in euchromatin display additional cohesin-dependent constrictions. These ectopic cohesion sites, placed away from the centromere, disjoin abnormally during anaphase and chromosomes exhibit a significant increase in length during anaphase (termed chromatin stretching). These results provide evidence that long stretches of heterochromatin distant from the centromere, as often found in many cancers, are sufficient to induce abnormal accumulation of cohesin at these sites and thereby compromise the fidelity of chromosome segregation. PMID- 25290699 TI - Integrated 'omics analysis for studying the microbial community response to a pH perturbation of a cellulose-degrading bioreactor culture. AB - Integrated 'omics have been used on pure cultures and co-cultures, yet they have not been applied to complex microbial communities to examine questions of perturbation response. In this study, we used integrated 'omics to measure the perturbation response of a cellulose-degrading bioreactor community fed with microcrystalline cellulose (Avicel). We predicted that a pH decrease by addition of a pulse of acid would reduce microbial community diversity and temporarily reduce reactor function in terms of cellulose degradation. However, 16S rDNA gene pyrosequencing results revealed increased alpha diversity in the microbial community after the perturbation, and a persistence of the dominant community members over the duration of the experiment. Proteomics results showed a decrease in activity of proteins associated with Fibrobacter succinogenes 2 days after the perturbation followed by increased protein abundances 6 days after the perturbation. The decrease in cellulolytic activity suggested by the proteomics was confirmed by the accumulation of Avicel in the reactor. Metabolomics showed a pattern similar to that of the proteome, with amino acid production decreasing 2 days after the perturbation and increasing after 6 days. This study demonstrated that community 'omics data provide valuable information about the interactions and function of anaerobic cellulolytic community members after a perturbation. PMID- 25290701 TI - Unresolved matters of birth and descent. PMID- 25290702 TI - Questions of intrathymic ancestry. PMID- 25290703 TI - Presentation, regulation and cellular assassination. PMID- 25290704 TI - Immunological manoevres should not be dismissed. PMID- 25290705 TI - T-cell balance in organ targets. PMID- 25290706 TI - Insights into mast-cell biology and IgE production. PMID- 25290707 TI - AIDS-specific screening and therapy still elusive. PMID- 25290708 TI - NK cells take the centre stage. PMID- 25290709 TI - The many means of host protection. PMID- 25290710 TI - Cellular traffic cues in vivo. PMID- 25290711 TI - Regulatory influences on the fetal allograft. PMID- 25290712 TI - Antigens yield to new technology. PMID- 25290713 TI - Allograft response dissected. PMID- 25290714 TI - Power of molecular genetics amply confirmed. PMID- 25290715 TI - Enhancement, translocation and the behaviour of V genes. PMID- 25290716 TI - B-cell hyperactivity in murine lupus II. Defects in response to and production of accessory signals in lupus-prone mice. AB - The first part of this discussion, published in last month's issue (p. 287), reviewed the immunological abnormalities observed in murine lupus. The current theories on the signal requirements for B cell activation, proliferation, and differentiation were also described. This month, the authors discuss recent experiments which suggest that the B cell hyperactivity associated with lupus may be the result of abnormal responses to and/or production of T-cell-derived B-cell activating factors. PMID- 25290717 TI - T lymphocytes in viral clearance. PMID- 25290719 TI - Trace elements and immune responses. AB - The common association of malnutrition and infection has led to many studies that have examined the effects of nutritional status on immunocompetence. Children with the syndromes of marasmus and kwaskiorkor show marked impairment of cell mediated immunity (CMI), complement system, microbicidal function of polymorphonuclear leukocytes (PMN), and secretory IgA antibody response. The extensive literature on this burgeoning field has been summarized(1-5,40) Clinical malnutrition, however, is a complex combination of the deficiencies of many nutrients, including proteins, lipids, carbohydrates, vitamins, macrominerals and trace elements. Thus it is of fundamental importance to examine the influence of individual dietary factors on immune responses and disease (Fig. 1). Here Ranjit Chandra discusses the role of trace elements in host resistance to infection and other pathological diseases. PMID- 25290718 TI - Polymorphism and monomorphism in class-I MHC antigens. PMID- 25290720 TI - The use of myeloma cells to study immunoregulatory mechanisms. AB - A number of recent observations have established that murine myeloma cells are capable of responding to the same kinds of immunoregulatioy signals that so precisely govern the expansion and differentiation of non-neoplastic B-cell clones. However, myeloma cells have the distinct advantage of being a monoclonal and homogeneous source of target cells with which to investigate the cellular and molecular details of B-cell immunoregulation. In this review Richard Lynch and Gary Milburn summarize their results using the murine myeloma MOPC-315 to study immunoregulation. PMID- 25290722 TI - Epilepsy and autoimmunity in pediatric patients. AB - Our aim was to determine the presence and possible role of autoantibodies in epileptic patients with an undetermined etiology. Eighty epilepsy patients, who were referred to the Pediatric Neurology Department at Ankara University between November 2011 and April 2012, were enrolled in the study. Antinuclear antibodies (ANA), anticardiolipin IgG, antiphospholipid, antithyroid peroxidase, paraneoplastic, glutamic acid decarboxylase (GAD), and N-methyl-d-aspartate (NMDA) receptor antibodies were studied in our university laboratory. In addition, NMDA receptor (NMDAR), voltage-gated potassium channel (VGKC)-complex, leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) antibodies were studied at the Oxford University Immunology Laboratory. The study included 35 girls (44%) and 45 boys (56%) with a mean symptom age of 8.6 +/- 4.53 years. ANA was detected in 15 (18.8%), antiphospholipid Ab in 3 (3.75%), anticardiolipin Ab in 1 (1.25%), and antithyroid peroxidase in 3 (3.75%) epileptic patients. In addition, anti-GAD Ab was detected in 7 (8.75%), anti-Yo Ab in 3 (3.75%), and anti-Ma2 in 3 (3.75%) epileptic patients. Anti-VGKC was positive in 13 (16.25%) epileptic patients. We performed a pioneer study to investigate the association between autoimmunity and pediatric epilepsy and we conclude that autoimmunity should be considered in epileptic patients with an undetermined etiology. PMID- 25290723 TI - Brain magnetic resonance imaging in acute phase of pandemic influenza A (H1N1) 2009--associated encephalopathy in children. AB - Pandemic influenza A (H1N1) 2009 has been shown to be associated more with neurological complications than the seasonal influenza virus. In this study, we focused on the clinical usefulness of magnetic resonance imaging (MRI) in the acute phase of influenza A (H1N1) 2009-associated encephalopathy. A questionnaire was distributed to pediatric and general hospitals in Japan that treat children with encephalopathy. We conducted a questionnaire-based study involving the collection of information regarding 207 patients with encephalopathy. Brain MRI was performed in 97 of these 207 patients in the age group of 9 months to 15 years (mean, 7.5 years) within 48 hours after the development of encephalopathy symptoms. Sixty-six patients (68%) showed normal imaging. Diffuse brain edema was visible in five patients and an abnormal signal in the deep gray matter in two patients which is consistent with acute necrotizing encephalopathy. Abnormal signals of the splenial lesion, subcortical white matter (bright tree appearance), and cortical area were observed in 15, 1, and 8 patients, respectively. From our findings based on the questionnaire results, we suggest that MRI is useful for determining fatal cases of pandemic influenza A (H1N1) 2009 infection when performed in the acute phase. However, MRI is not useful in predicting the development of sequelae. PMID- 25290724 TI - Continuous myocloni and tonic spasms in a 2-month-old infant with enterovirus 71 brain stem encephalitis. AB - Brain stem encephalitis is a cardinal presentation of central nervous system involvement in enterovirus 71 infection, and manifests as myoclonus, ataxia, tremor, and autonomic dysfunction. A 2-month-old infant with enterovirus 71 brain stem encephalitis demonstrated continuous myocloni and tonic spasms. On admission, the patient's myoclonus, which mainly involved the shoulders and the arms, was considerably worse during wakefulness and occurred once or twice a minute. Several hours after admission, the myoclonic jerks steadily worsened, appeared ceaselessly every 1 to 2 seconds, and were intermixed with tonic spasms of all four extremities accompanied by crying. Video electroencephalography revealed a normal background without epileptiform discharges and no ictal electroencephalographic changes during the myoclonic jerks and tonic spasms. Complete remission was achieved without complications after completion of a 3-day immunoglobulin therapy. This case suggests that the brain stem may be a major origin site for not only myoclonus but also tonic spasm. PMID- 25290725 TI - Utilization of galectin-3 in case management across the spectrum of heart failure. AB - In patients with heart failure as a result of mechanical and neurohormonal derangements, macrophages secrete galectin-3, which is a paracrine and endocrine factor that stimulates additional macrophages, pericytes, myofibroblasts, and fibroblasts to proliferate and secrete procollagen I, which is irreversibly crosslinked to form fibrotic collagen. Normal plasma concentrations of galectin-3 are < 11.0 ng/mL. Galectin-3 measured in blood has been shown to predict the development of all-cause mortality and heart failure in the general population, identify increased risk for de novo heart failure and progressive loss of renal filtration function in healthy middle-aged adults, predict cardiac failure in patients after acute coronary syndromes, help establish the diagnosis of heart failure with preserved ejection fraction in patients presenting with effort intolerance, and aid in the prognosis of both systolic and nonsystolic heart failure for the outcomes of hospitalization and death. This article presents case discussions of these applications to highlight the importance of galectin-3 measurement across the spectrum of patients at risk for cardiorenal disease. PMID- 25290726 TI - Guiding the management of ventricular arrhythmias in patients with left ventricular noncompaction cardiomyopathy: a knowledge gap. AB - Left ventricular noncompaction (LVNC) is a cardiomyopathy that occurs due to an arrest of myocardial maturation during embryogenesis. The diagnostic echocardiographic features in individuals with LVNC include a thick, bilayered myocardium, prominent ventricular trabeculations, and deep intertrabecular recesses. Clinical features associated with LVNC vary in asymptomatic and symptomatic patients, and include the potential for heart failure, conduction defects (eg, left bundle branch block), supraventricular and ventricular arrhythmias, thromboembolic events, and sudden cardiac death. The authors report five cases that emphasize asymptomatic and apparently benign symptoms in patients with LVNC; despite normal physical examination and 12-lead electrocardiogram results, all of these cases unveiled potentially serious clinical consequences. These cases highlight the concern that LVNC patients with mild to moderate left ventricular systolic dysfunction, particularly in the presence of ventricular arrhythmias or a family history of sudden cardiac death, may need consideration for an implantable cardioverter defibrillator (ICD). All potential benefits of an ICD need to be balanced by the risk of device infection, lead and device malfunction, and potential for inappropriate shocks. PMID- 25290727 TI - Nutrigenetic associations with cardiovascular disease. AB - It is becoming increasingly evident that not all people respond equally to diet. Nutrigenetics and nutrigenomics is the study of how genes affect dietary response or how nutrients affect gene expression. Understanding gene-nutrient interactions has become essential in many areas of study to account for variation in results. Identifying subgroups or individuals who might benefit from more targeted recommendations has also been a result of studying these interactions. This review summarizes findings from genetic polymorphisms in apolipoprotein E, fatty acid desaturase, lipoxygenase-5, peroxisome proliferator-activated receptors, apolipoprotein A1, apolipoprotein A2, apolipoprotein A5, and methylenetetrahydrofolate reductase associated with cardiovascular disease. PMID- 25290728 TI - Worsening thoracic impedance as a ventricular tachyarrhythmia risk. AB - The use of heart failure classification to identify patients with systolic dysfunction who are at risk for ventricular tachyarrhythmias (VAs), sudden cardiac death, and shocks from implantable cardioverter defibrillators (ICDs) is limited by its subjectivity. Measurement of thoracic impedance offers a more objective tool for assessing worsening of heart failure. We sought to look at the correlation between ventricular arrhythmia and heart failure as assessed objectively by thoracic impedance. We reviewed device interrogation data on thoracic impedance from ICD with Medtronic's OptiVol(r) feature (Medtronic Inc., Minneapolis, MN) at two medical centers. Data from the last two interrogations of the same device separated by at least 2 months were included. An OptiVol fluid index threshold of 60 represented early heart failure prior to appearance of symptoms. VAs included were ventricular fibrillation and/or ventricular tachycardia lasting more than 16 beats. Chi square distribution test was used in statistical data analysis. There were 24 VAs identified among the 322 interrogations reviewed (7.5%). Elevated OptiVol fluid index was seen in 71% (17/24), whereas normal OptiVol index was seen in the remaining 29% (7/24) of these interrogations with VA (P < .05). Our review shows that heart failure patients who have VA are approximately 2.5 times as likely to have worsening thoracic impedance as assessed objectively by the OptiVol fluid index. Careful monitoring of the OptiVol fluid index may identify a population at high risk of VA that merits more intense attention. PMID- 25290729 TI - Cardiovascular complications of radiation exposure. AB - The cardiovascular sequelae of radiation exposure are an important cause of morbidity and mortality following radiation therapy for cancer, as well as after exposure to radiation after atomic bombs or nuclear accidents. In the United States, most of the data on radiation-induced heart disease (RIHD) come from patients treated with radiation therapy for Hodgkin disease and breast cancer. Additionally, people exposed to radiation from the atomic bombs in Hiroshima and Nagasaki, Japan, and the Chernobyl, Ukraine, nuclear accident have an increased risk of cardiovascular disease. The total dose of radiation, as well as the fractionation of the dose, plays an important role in the development of RIHD. All parts of the heart are affected, including the pericardium, vasculature, myocardium, valves, and conduction system. The mechanism of injury is complex, but one major mechanism is injury to endothelium in both the microvasculature and coronary arteries. This likely also contributes to damage and fibrosis within the myocardium. Additionally, various inflammatory and profibrotic cytokines contribute to injury. Diagnosis and treatment are not significantly different from those for conventional cardiovascular disease; however, screening for heart disease and lifelong cardiology follow-up is essential in patients with past radiation exposure. PMID- 25290730 TI - The use of micropuncture technique for vascular or body cavity access. AB - More than 1 million cardiac catheterizations are performed every year in the United States, and incur substantial risk of access site bleeding. Furthermore, insertion of central venous catheters and performance of pericardio- or pleurocentesis are common practice, also with substantial risk of vascular or organ injury. One of the major risks for access site bleeding is multiple or posterior arterial puncture with a large needle. Using a very small needle to obtain initial access to vessels or organ cavities has the potential to reduce the risk of bleeding or organ injury. Multiple unsuccessful attempts to achieve vascular access are more forgiving, and accidental organ injury during pericardio or pleurocentesis is less traumatic when using a small micropuncture needle. This article reviews the use of micropuncture technique for vascular or organ cavity access, a technique that has the potential to decrease vascular access site complications and organ injury. PMID- 25290731 TI - An innovative, multidisciplinary, process-driven approach to acute stroke in a community health system network. AB - Stroke is one of the major causes of death and disability in the United States, yet it is undertreated by many major medical centers across the country. Timely recognition and treatment of acute ischemic stroke remains a challenge due to confusing clinical presentations, hospital logistics, communication barriers among providers, and lack of standardized treatment algorithms. By creating a system-wide Code Stroke protocol, St. John Providence Health System improved documentation, increased intravenous tissue plasminogen activator delivery, reduced specialist call-back times, improved door-to-computer tomography scan and door-to-needle time, and identified appropriate patients for endovascular therapy. PMID- 25290732 TI - California cardiovascular legislation 2014. PMID- 25290733 TI - Intracardiac atypical leiomyoma involving all four cardiac chambers and the aorta. AB - Intravenous leiomyomatosis is a rare gynecologic disease that can be complicated with intracardiac involvement. All reported cases with cardiac extension involved the right cardiac chambers. Intracardiac leiomyoma may present with dyspnea, chest pain, palpitations, lower extremity swelling, or syncope. This is a unique case of a 40-year-old asymptomatic woman with incidental finding of a cardiac murmur. Echocardiography showed an echodensity in all cardiac chambers. Urgent cardiac surgery revealed an intracardiac leiomyoma, extending from the inferior vena cava and involving all four cardiac chambers and the aortic root. PMID- 25290734 TI - Undiagnosed Ebstein's Anomaly in a Pregnant Woman. AB - Ebstein's anomaly is an uncommon congenital heart defect characterized by an abnormal tricuspid valve. Pregnancy can be well tolerated, although cyanosis, arrhythmias, and cardiomegaly are associated with poor prognosis. An 18-year-old woman with a history of congenital cardiomyopathy presented at 37 weeks of gestation with hypoxia, dyspnea, central cyanosis, and uterine contractions. The patient underwent emergent cesarean delivery. Echocardiography revealed Ebstein's anomaly with patent foramen ovale and right-to-left shunting. Tricuspid valvuloplasty with primary closure of patent foramen ovale was performed. This case is presented, accompanied by a review of the literature. PMID- 25290735 TI - Correction to "lomitapide for the management of homozygous familial hypercholesterolemia". PMID- 25290736 TI - A clean and selective radical homocoupling employing carboxylic acids with titania photoredox catalysis. AB - A titania photoredox catalysis protocol was developed for the homocoupling of C centered radicals derived from carboxylic acids. Intermolecular reactions were generally efficient and selective, furnishing the desired dimers in good yields under mild neutral conditions. Selective cross-coupling with two acids proved unsuccessful. An intramolecular adaptation enabled macrocycles to be prepared, albeit in modest yields. PMID- 25290737 TI - Translation of EMS: clinical practice and system oversight from core content study guide to best practices implementation in an Urban EMS system. AB - Since 2009, the seminal text in emergency medical services (EMS) medicine has been used to guide the academic development of the new subspecialty but direct application of the material into EMS oversight has not been previously described. The EMS/Disaster Medicine fellowship program at our institution scheduled a monthly meeting to systematically review the text and develop a study guide to assist the fellow and affiliated faculty in preparation for the board examination. In addition to the summary of chapter content, the review included an assessment of areas from each chapter subject where our EMS system did not exhibit recommended characteristics. A matrix was developed in the form of a gap analysis to include specific recommendations based on each perceived gap. Initial review and completion dates for each identified gap enable tracking and a responsible party. This matrix assisted the fellow with development of projects for EMS system improvement in addition to focusing and prioritizing the work of other interested physicians working in the system. By discussing expert recommendations in the setting of an actual EMS system, the faculty can teach the fellow how to approach system improvements based on prior experiences and current stakeholders. This collaborative environment facilitates system-based practice and practice-based learning, aligning with ACGME core competencies. Our educational model has demonstrated the success of translating the text into action items for EMS systems. This model may be useful in other systems and could contribute to the development of EMS system standards nationwide. PMID- 25290738 TI - Gastrokine-2 is transiently expressed in the endodermal and endothelial cells of the maturing mouse yolk sac. AB - The yolk sac (YS) is a thin, bi-layered membrane encompassing the developing mammalian embryo in utero. The outer layer of the YS is composed of visceral endodermal cells derived from the primitive endoderm. The inner mesenchymal layer is highly vascularised and the first source of haematopoietic cells. YS haematopoiesis takes place from shortly after gastrulation (E7.5) until after midgestation (~E12.5) when the placenta and sites within the embryo proper predominate as sites of blood cell production. Here, we have assessed gene expression in the developing YS to determine what factors are associated with the end of haematopoietic cell production in this extra-embryonic tissue. We have observed that transcripts encoding gastrokine-2 (Gkn2) are up-regulated in the YS at E11.5, peak at E12.5 and are then reduced. Low levels of Gkn2 transcript were detected in purified YS endothelial cells. Gastrokine-2 protein was detected in the EpCAM-expressing visceral endodermal layer. Gastrokine-2 protein predominantly clustered at the basal side of the visceral endodermal cells facing the endothelial cell layer though did not appear to be strongly associated with secretory lysosomes. Gastrokine-1 protein binds F-actin. In contrast, gastrokine 2 in the YS is predominantly expressed at the basal side of the visceral endodermal cells, whereas F-actin in the YS is mostly found in the inner leaf of the luminal side of visceral endoderm. We have therefore identified expression of Gkn2 transcript and protein in the visceral endodermal layer and at lower levels in YS endothelial cells. This previously unreported expression of a "stomach specific" secreted protein may be linked to the changes in the YS niche coinciding with the shift of haematopoiesis away from the YS into the embryo. PMID- 25290739 TI - Neuronal maturation and laminar formation in the chicken optic tectum are accompanied by the transition of phosphorylated cofilin from cytoplasm to nucleus. AB - Laminar formation in the chicken optic tectum requires processes that coordinate proliferation, migration and differentiation of neurons, in which the dynamics of actin filaments are crucial. Cofilin plays pivotal roles in regulating actin arrangement via its phosphorylation on Ser3. Given poor studies on the profile of phosphorylated cofilin (p-cofilin) in the developing tectum, we investigated its expression pattern. As determined by immunofluorescence histochemistry and western blotting, p-cofilin could be detected in most tectal layers except for the neural epithelium. In addition, we found p-cofilin was expressed both in the cytoplasm and the nucleus. During development, the expression of the cytoplasmic p-cofilin was decreasing and the nuclear p-cofilin was gradually increasing, but the total level of p-cofilin was down regulated. Double-labeling experiments revealed that the nuclear p-cofilin could be labeled in mature neurons but undetected in immature neurons. Furthermore, the number of cells co-stained with nuclear p-cofilin and NeuN was up-regulated during lamination and 60% cells were detected to be mature neurons that can express nuclear p-cofilin just at the first appearance of completed laminae. Our results demonstrate that the maturation of neurons is accompanied by this cytoplasm-to-nucleus transition of p cofilin, and the nuclear p-cofilin can work effectively as a marker in the laminar formation of the chicken optic tectum. PMID- 25290740 TI - Structure-property relationships of symmetrical and asymmetrical azobenzene derivatives as gelators and their self-assemblies. AB - Two different series of symmetrical and asymmetrical azobenzenes containing terminal cholesteryl/adamantyl derivatives (SAC/SAA and AAC) with varying spacer lengths (alkyl chains) have been developed. The gelation and aggregation of these derivatives were studied relative to structural motifs, spacer lengths, solvent affinity, temperatures and light conditions. Among these derivatives, the cholesteryl derivatives that have short alkyl chains (<3) act as efficient gelators in a variety of solvents. However, the cholesteryl derivatives with longer alkyl chains (11 spacer) and adamantyl derivatives did not possess this ability. Self-assembled fibrous structures were constructed by gelators with short alkyl chains (<3), while flower-like structures were constructed by gelators with moderately longer alkyl chains (3-6) at their respective critical gelation concentrations (CGCs) according to SEM (Scanning Electron Microscopy) and TEM (Transmission Electron Microscopy) analyses. In some cases, a partial/weak gel was observed in different solvents, which exhibited uniform spherical nanoparticles at CGCs. These nanoparticles were further entangled to form interconnected fibrous structures when the concentration was increased above the CGC (according to the SEM and TEM analyses). Secondary forces (van der Waals/H-bonding) and pi-pi stacking played important roles in the aggregation of both series in the solvents according to variable temperature (1)H-NMR analysis. The reversibility of sol-gel transitions by light was studied with respect to solvent affinity. This study revealed that reversible transitions were only observed in the non-polar solvents, as supported by the FTIR analysis of the gelators in the various solvents. The thermal and mesomorphic behaviors of the gelators by DSC (Differential Scanning Calorimetry) and POM (Polarized Optical Microscopy) analyses revealed that the chiral nematic (N*) and cholesteric mesophase (Ch*) were exhibited by only the short and longer alkyl chain cholesteryl derivatives, respectively. However, the cholesteryl derivative without a spacer (AAC0) did not exhibit any liquid crystalline phase but acted as an efficient gelator relative to the other gelators in this study. PMID- 25290741 TI - Warm skin alters cardiovascular responses to cycling after preheating and precooling. AB - PURPOSE: Exercise in hot conditions increases core (TC) and skin temperature (TSK) and can lead to a progressive rise in HR and decline in stroke volume (SV) during prolonged exercise. Thermoregulatory-driven elevations in skin blood flow (SkBF) adds complexity to cardiovascular regulation during exercise in these conditions. Presently, the dominant, although debated, view is that raising TSK increases SkBF and reduces SV through diminished venous return; however, this scenario has not been rigorously investigated across core and skin temperatures. We tested the hypothesis that high TSK would raise HR and reduce SV during exercise after precooling (cold water bath) and preheating (hot water bath) and that no relationship would exist between SkBF and SV during exercise. METHODS: Non-endurance-trained individuals cycled for 20 min at 69% +/- 1% VO2peak on four occasions: cool skin-cool core (SkCCC), warm skin-cool core (SkWCC), cool skin warm core (SkCCW), and warm skin-warm core (SkWCW) on separate days. RESULTS: After precooling of TC, the rise in HR was greater in SkWCC than in SkCCC (P < 0.001), yet SV was similar (P = 0.26), which resulted in higher QC at min 20 in SkWCC (P < 0.01). Throughout exercise after preheating of TC, HR was higher (P < 0.001), SV was reduced (P < 0.01), and QC was similar (P = 0.40) in SkWCW versus SkCCW. When all trials were compared, there was no relationship between SkBF and SV (r = -0.08, P = 0.70); however, there was an inverse relationship between HR and SV (r = -0.75, P < 0.001). CONCLUSIONS: These data suggest that when TSK is elevated during exercise, HR and TC will rise but SV will only be reduced when TC is also elevated above 38 degrees C. Furthermore, changes in SV are not related to changes in SkBF. PMID- 25290742 TI - Botulinum toxin as a treatment for functional popliteal artery entrapment syndrome. AB - PURPOSE: Functional popliteal artery entrapment syndrome is responsible for exercise-induced muscle leg pain. This syndrome is caused, in most of the cases, by the excessive size of the gastrocnemius muscles. Currently, its treatment is based only on surgery with variable results. METHODS: We report the case of a young professional soldier in a combat unit with bilateral functional popliteal artery entrapment syndrome that was confirmed by dynamic arteriography, magnetic resonance angiography, and ultrasonography and did not improve after bilateral popliteal arteriolysis without resection of the gastrocnemius medial head. Treatment by injecting botulinum toxin in the proximal part of the gastrocnemius muscles was proposed and carried out. RESULTS: Regular follow-up (from 1 month to 3 yr after botulinum toxin treatment) showed the disappearance of exercise induced pain and the improvement of the patient's physical and sports performance. Results of follow-up ultrasonography during dynamic maneuvers at 2.5 months and 2 yr after botulinum toxin injection were normal. Neither adverse effects nor motor deficit of the gastrocnemius muscles was reported. CONCLUSIONS: This case report suggests that botulinum toxin treatment could be an alternative to surgery for patients with functional popliteal artery entrapment syndrome. Botulinum toxin could reduce functional compression and, consequently, exercise induced pain by decreasing the volume of the gastrocnemius muscle. PMID- 25290743 TI - Acceptance and commitment therapy improves exercise tolerance in sedentary women. AB - PURPOSE: To test the efficacy of an acute intervention derived from acceptance and commitment therapy (ACT) for increasing high-intensity constant work rate (CWR) cycle exercise tolerance in a group of low-active women age 18-45 yr. The secondary goals were to examine whether ACT would reduce perceived effort and improve in-task affect during exercise and increase postexercise enjoyment. METHODS: In a randomized controlled trial, 39 women were randomized to either the experimental (using ACT-based cognitive techniques and listening to music during the CWR exercise tests) or a control group (listening to music during the CWR exercise tests). Before (CWR-1) and after the intervention (CWR-2), participants completed a CWR cycle exercise test at 80% of maximal incremental work rate (Wmax) until volitional exhaustion. RESULTS: On average, ACT (n = 18) and control (n = 21) groups were matched for age, body mass index, weekly leisure activity scores, and Wmax (all P > 0.05). Exercise tolerance time (ETT) increased by 15% from CWR-1 to CWR-2 for the ACT group (392.05 +/- 146.4 vs 459.39 +/- 209.3 s; mean +/- SD) and decreased by 8% (384.71 +/- 120.1 vs 353.86 +/- 127.9 s) for the control group (P = 0.008). RPE were lower (e.g., by 1.5 Borg 6-20 scale units at 55% of ETT, P <= 0.01) during CWR-2 in the ACT versus that in the control group. By contrast, ACT had no effect on in-task affect. Exercise enjoyment was higher after CWR-2 in the ACT group versus that in the control group (P < 0.001). CONCLUSIONS: An acute ACT intervention increased high-intensity ETT and postexercise enjoyment and reduced perceived effort in low-active women. Further investigations of ACT as an effective intervention for enhancing the established health benefits of high-intensity exercise need to be provided. PMID- 25290744 TI - Older firefighters are susceptible to age-related impairments in heat dissipation. AB - PURPOSE: The aging-induced reduction in whole-body heat loss (HL) capacity generates concerns regarding the continued participation of older workers in occupations such as firefighting. We compared HL and change in body heat storage (S) during intermittent exercise in warm/dry and warm/humid conditions among older male firefighters (OLDER, n = 9, age = 54.7 +/- 2.1 yr), older (age matched) nonfirefighters (NON-FF, n = 9, age = 52.8 +/- 1.2 yr), and young firefighters (YOUNG, n = 6, age = 26.7 +/- 0.8 yr). METHODS: We measured evaporative heat loss and dry heat exchange via the Snellen whole-body direct calorimeter while participants performed four 15-min bouts of cycling at 400 W of metabolic heat production separated by 15-min recovery periods in warm/dry (35 degrees C, 20% relative humidity) and warm/humid (35 degrees C, 60% relative humidity) conditions. RESULTS: We found no differences (P > 0.05) in HL or cumulative S (DeltaS) between OLDER and NON-FF in the warm/dry (DeltaS: OLDER = 233 +/- 26 kJ, NON-FF = 270 +/- 29 kJ) or warm/humid (DeltaS: OLDER = 548 +/- 24 kJ, NON-FF = 504 +/- 47 kJ) conditions. The OLDER and NON-FF had lower HL than the YOUNG during exercise in both environmental conditions (P < 0.05). The OLDER stored 40% (P > 0.05) and 46% (P = 0.004) more heat than YOUNG in the warm/dry and warm/humid conditions, respectively. The NON-FF stored 63% (P = 0.016) and 34% (P = 0.025) more heat than the YOUNG in the dry and humid conditions, respectively. CONCLUSIONS: Older firefighters and age-matched nonfirefighters demonstrate similar HL and S during work in the heat. Moreover, HL is significantly reduced in older compared to younger firefighters during exercise in both warm/dry and warm/humid conditions. Consequently, older firefighters may be more susceptible to thermal injury while on duty than their younger counterparts. PMID- 25290745 TI - Neutron diffraction studies of a four-coordinated hydride in near square-planar geometry. AB - The structure of a nanospheric polyhydrido copper cluster, [Cu20(H)11{S2P(O(i)Pr)2}9], was determined by single-crystal neutron diffraction. The Cu20 cluster consists of an elongated triangular orthobicupola constructed from 18 Cu atoms that encapsulate a [Cu2H5](3-) ion with an exceptionally short Cu-Cu distance. The 11 hydrides in the cluster display three different coordination modes to the Cu atoms: six MU3-hydrides in a pyramidal geometry, two MU4-hydrides in a tetrahedral cavity, and three MU4-hydrides in an unprecedented near square-planar geometry. The neutron data set was collected for 7 days on a small crystal with dimensions of 0.20 mm * 0.50 mm * 0.65 mm using the Spallation Neutron Source TOPAZ single-crystal time-of-flight Laue diffractometer at Oak Ridge National Laboratory. The final R-factor was 8.63% for 16,014 reflections. PMID- 25290746 TI - New concepts in immunotherapy. PMID- 25290747 TI - IUIS council meets. PMID- 25290748 TI - The immunodeficiency-cancer registry is renewed. PMID- 25290749 TI - Tumour-association transplantation antigens. PMID- 25290750 TI - Androgens, thymus weight and immune responsiveness. PMID- 25290751 TI - Anti-HLA-DR autoantibodies in AIDS? PMID- 25290753 TI - May T3 protect us all. PMID- 25290752 TI - The role of the T3 molecular complex in antigen recognition and subsequent activation events. AB - Monoclonal antibodies raised against human T lymphocytes have identified several cell surface structures that are intimately involved in T-cell function. Perhaps the most familiar is the structure labelled T3. First identified as an antigen five years ago, it is now known to be a complex of at least three molecular species that is found on all T lymphocytes. There seems little doubt that T3 is closely associated with the antigen receptor on these cells, but how? A new (and different) answer is proposed in each of the following articles. PMID- 25290754 TI - B cells and the development of the T-cell repertoire. PMID- 25290755 TI - Leucocyte therapy for recurrent spontaneous abortion. PMID- 25290756 TI - Inductive and differentiative signals delivered by C8-substituted guanine ribonucleosides. AB - The C8-substituted guanine ribonucleosides area recently described class of immunomodulator which among a variety of pleiotropic effects have T-cell replacing activity in vitro and immunopotentiating activity in immunocompromised hosts. In this article Michael Goodman discusses the mechanism of nucleoside transport, the immunobiologic activities of these compounds, and the nature of the cellular interactions involved. PMID- 25290757 TI - Graft-versus-host reactions: clues to the etiopathology of a spectrum of immunological diseases. AB - Parental strain T lymphocytes injected into adult F, mice respond to allogeneic MHC antigens and so induce the symptoms of systemic graft v. host disease (GVHD). GVHD has two forms, stimulatory and suppressive, and in each there are pathological changes which resemble those seen in a variety of human disorders of immune regulation. In this article Ernst Gleichmann and his colleagues review the pathogenesis of these disorders and their induction by GVH reactions. PMID- 25290758 TI - The computer and the reprint file. AB - A reprintfile may ultimately grow so large that it it difficult to use and maintain. Here John Weiler reviews two computer software packages designed to help in this chore. One, called PAPERBASE, is simple, inexpensive and written in BASIC so that it can be modified by the experienced user to run on almost any computer. The other, called REFED, is more sophisticated, has more features and some defects. PMID- 25290759 TI - Fatty acid profile, carcass and quality traits of meat from Nellore young bulls on pasture supplemented with crude glycerin. AB - The aim of this study was to evaluate the carcass traits and meat quality of Nellore bulls (279.5+/-16.3 initial body weight) raised on pasture supplemented with crude glycerin at 0%, 7%, 14%, 21% or 28% (DM basis). The diets were similar in energy and protein levels, and the glycerin replaced corn in the supplement. After slaughter, the carcass characteristics were measured, and the longissimus muscle was collected to determine the meat quality. The inclusion of crude glycerin in the supplement did not change (P>0.05) any of the carcass characteristics and meat quality assessed; however, the pH decreased linearly (P=0.03), and margaric acid (17:0) increased (P=0.02) in the longissimus muscle with the addition of glycerin in the diet. Our conclusion is that the inclusion of crude glycerin up to the level of 28% of dry matter in the supplement does not alter the carcass characteristics or the meat quality from animals raised on pasture. PMID- 25290760 TI - Impact of steam explosion on the wheat straw lignin structure studied by solution state nuclear magnetic resonance and density functional methods. AB - Chemical changes of lignin induced by the steam explosion (SE) process were elucidated. Wheat straw was studied as the raw material, and lignins were isolated by the enzymatic mild acidolysis lignin (EMAL) procedure before and after the SE treatment for analyses mainly by two-dimensional (2D) [heteronuclear single-quantum coherence (HSQC) and heteronuclear multiple-bond correlation (HMBC)] and (31)P nuclear magnetic resonance (NMR). The beta-O-4 structures were found to be homolytically cleaved, followed by recoupling to beta-5 linkages. The homolytic cleavage/recoupling reactions were also studied by computational methods, which verified their thermodynamic feasibility. The presence of the tricin bound to wheat straw lignin was confirmed, and it was shown to participate in lignin reactions during the SE treatment. The preferred homolytic beta-O-4 cleavage reaction was calculated to follow bond dissociation energies: G-O-G (guaiacyl) (69.7 kcal/mol) > G-O-S (syringyl) (68.4 kcal/mol) > G-O-T (tricin) (67.0 kcal/mol). PMID- 25290761 TI - Plasma-assisted interface engineering of boron nitride nanostructure films. AB - Today many aspects of science and technology are progressing into the nanoscale realm where surfaces and interfaces are intrinsically important in determining properties and performances of materials and devices. One familiar phenomenon in which interfacial interactions play a major role is the wetting of solids. In this work we use a facile one-step plasma method to control the wettability of boron nitride (BN) nanostructure films via covalent chemical functionalization, while their surface morphology remains intact. By tailoring the concentration of grafted hydroxyl groups, superhydrophilic, hydrophilic, and hydrophobic patterns are created on the initially superhydrophobic BN nanosheet and nanotube films. Moreover, by introducing a gradient of the functional groups, directional liquid spreading toward increasing [OH] content is achieved on the films. The resulting insights are meant to illustrate great potentials of this method to tailor wettability of ceramic films, control liquid flow patterns for engineering applications such as microfluidics and biosensing, and improve the interfacial contact and adhesion in nanocomposite materials. PMID- 25290762 TI - Channeling satiation: a primer on the role of TRP channels in the control of glutamate release from vagal afferent neurons. AB - Obesity results from the chronic imbalance between food intake and energy expenditure. To maintain homeostasis, the brainstem nucleus of the solitary tract (NTS) integrates peripheral information from visceral organs and initiates reflex pathways that control food intake and other autonomic functions. This peripheral to-central neural communication occurs through activation of vagal afferent neurons which converge to form the solitary tract (ST) and synapse with strong glutamatergic contacts onto NTS neurons. Vagal afferents release glutamate containing vesicles via three distinct pathways (synchronous, asynchronous, and spontaneous) providing multiple levels of control through fast synaptic neurotransmission at ST-NTS synapses. While temperature at the NTS is relatively constant, vagal afferent neurons express an array of thermosensitive ion channels named transient receptor potential (TRP) channels. Here we review the evidence that TRP channels pre-synaptically control quantal glutamate release and examine the potential roles of TRP channels in vagally mediated satiety signaling. We summarize the current literature that TRP channels contribute to asynchronous and spontaneous release of glutamate which can distinctly influence the transfer of information across the ST-NTS synapse. In other words, multiple glutamate vesicle release pathways, guided by afferent TRP channels, provide for robust while adaptive neurotransmission and expand our understanding of vagal afferent signaling. PMID- 25290763 TI - A novel role of annexin A2 in human type I collagen gene expression. AB - The fibrillar collagen scaffold of the extracellular matrix provides a structural framework for cells in tissues and regulates intercellular communication; its disregulation has been associated with tumour development and progression. Previous work has shown that expression of type I collagen, the most abundant mammalian extracellular matrix protein, is decreased in chemically or virally transformed cells. This negative regulation could be mapped to a proximal COL1A2 promoter element spanning a CME (Collagen Modulating Element) site in SV40 transformed human fibroblasts (SV-WI38) that binds an unknown repressing protein. By magnetic bead pull-down, we observed a multi-protein complex bound to the CME with preference for single-stranded over conventional double-stranded DNA. MALDI TOF mass spectrometry of the CME-binding protein complex revealed involvement of nuclear annexin A2 (AnxA2) which was increased in SV40-transformed cells. Further EMSA analysis demonstrated that AnxA2 did not directly bind to the DNA but stabilised the complex and led to an increase in protein binding to the CME in SV WI38 but not untransformed WI38 cells. Knockdown of AnxA2 by siRNA increased type I collagen production in both WI38 and SV-WI38 cells; however, these effects were not mediated at the transcriptional level. Rather, our data indicate a novel functional role of AnxA2 in the negative post-transcriptional regulation of type I collagen synthesis in human fibroblasts. In SV40-transformed cells, AnxA2 is accumulated at the proximal COL1A2 promoter region, suggesting close association with the transcriptional machinery that possibly facilitates binding to the emerging mRNA, eventually contributing to overall repression of type I collagen protein synthesis. PMID- 25290764 TI - Measures of internal lumbar load in professional drivers - the use of a whole body finite-element model for the evaluation of adverse health effects of multi axis vibration. AB - The present study aimed to (1) employ the method for evaluation of vibration containing multiple shocks according to ISO/CD 2631-5:2014 (Model 1) and DIN SPEC 45697:2012 in a cohort of 537 professional drivers, (2) deliver the results for a re-analysis of epidemiological data obtained in the VIBRISKS study, (3) clarify the extent to which vibration acceleration and individual variables influence risk values, such as the daily compressive dose S(ed) and the risk factor R, and (4) compare the results with in vivo measurements and those obtained in previous studies with similar models. The risk factor R was influenced by the acceleration, lifetime exposure duration, sitting posture, age at the start of exposure and body mass/body mass index in order of decreasing effect. Age and annual and daily exposure duration had only a marginal effect. The daily compressive dose S(ed) and the risk factor R showed weak linear association with the daily vibration exposure A(8) and the vibration dose value VDV. The study revealed high shear forces in the lumbar spine. PRACTITIONER SUMMARY: In a re analysis of an epidemiological study of professional drivers, a software tool available with standards DIN SPEC 45697:2012 and ISO/CD 2631-5:2014 Model 1 was used to calculate the risk to the lumbar spine in terms of daily compressive dose S(ed) and risk factor R. The tool was found to be suitable for risk assessment in a large cohort. PMID- 25290765 TI - Providers caring for adolescents with perinatally-acquired HIV: Current practices and barriers to communication about sexual and reproductive health. AB - The population of adolescents and young adults (AYA) with perinatally-acquired HIV (PHIV) present challenges to HIV healthcare providers (HHCPs). Originally not expected to survive childhood, they are now living well into young adulthood. Little is known about the type of sexual and reproductive (SRH) information/services offered to AYA with PHIV by HHCPs. HHCPs (n=67) were recruited using snowball sampling, and completed an online survey. Providers' most frequently endorsed SRH topics discussed with both male and female patients included condom use (77.3%), STD prevention (73.1%), and screening (62.1%). Providers' reports indicated that females received significantly more education about SRH topics overall. The most frequently noted barriers to SRH communication included more pressing health concerns (53.0%), parent/guardian not receptive (43.9%), and lack of time during appointment (43.9%). Provider-reported SRH conversations with HHCPs were highly focused on horizontal transmission and pregnancy prevention. Salient social aspects of SRH promotion for AYAs with PHIV (e.g., managing disclosure and romantic relationships) were less commonly discussed, though such conversations may serve to reduce secondary transmission and enhance the overall well-being of AYA with PHIV. Findings indicated that further work must be done to identify strategies to address unmet SRH needs of the aging population of AYA with PHIV. PMID- 25290766 TI - Patterns in the evaluation of hoarseness: time to presentation, laryngeal visualization, and diagnostic accuracy. AB - OBJECTIVES/HYPOTHESIS: Controversial recommendations regarding the evaluation of dysphonia have been made in the absence of evidence related to clinical practice. This study aims to describe existing patterns of care for dysphonia to generate data for potential systemic improvement and provide a baseline for dysphonia recommendations. STUDY DESIGN: Retrospective review. METHODS: Information regarding the current complaint, including duration of hoarseness; inciting factors; number and type of previous physicians seen; Voice Handicap Index-10; and details of prior evaluation, diagnosis, and treatment was collected from patient records. RESULTS: A total of 259 patients complaining of hoarseness were evaluated. Of those, 35.1% presented directly to subspecialty care, whereas 61% were previously evaluated by another otolaryngologist. Median times (in months) from symptom onset to evaluation were as follows: initial evaluation, 3.0; laryngoscopy, 3.0; stroboscopic exam, 5.8; subspecialty evaluation, 6.6. A total of 64.5% of patients had at least one incoming diagnosis; 45% of all incoming diagnoses were revised on re-evaluation. Diagnoses most commonly revised included "no abnormality," edema or laryngopharyngeal reflux disease (LPR), infection or allergy, and muscle tension dysphonia (MTD) or behavioral disorders. Final diagnoses that most frequently differed from incoming diagnoses were paresis; MTD or behavioral disorders; malignancy; and sulcus, atrophy, or scar. CONCLUSIONS: Patients received prompt laryngeal visualization. However, we observed high rates of diagnostic error. Initial diagnoses of LPR, edema, infection, and allergy appear to be particularly likely to be revised on further evaluation; and scar, sulcus, atrophy, and paresis are likely to be overlooked. PMID- 25290767 TI - Structural and functional analysis of the fibronectin-binding protein FNE from Streptococcus equi spp. equi. AB - Streptococcus equi is a horse pathogen belonging to Lancefield group C. Infection by S. equi ssp. equi causes strangles, a serious and highly contagious disease of the upper respiratory tract. S. equi ssp. equi secretes a fibronectin (Fn) binding protein, FNE, that does not contain cell wall-anchoring motifs. FNE binds to the gelatin-binding domain (GBD) of Fn, composed of the motifs (6) FI (12) FII (789) FI . FNE lacks the canonical Fn-binding peptide repeats observed in many microbial surface components recognizing adhesive matrix molecules. We found that the interaction between FNE and the human GBD is mediated by the binding of the disordered C-terminal region (residues 208-262) of FNE to the (789) FI GBD subfragment. The crystal structure of FNE showed that it is similar to the minor pilus protein Spy0125 of Streptococcus pyogenes, found at the end of pilus polymers and responsible for adhesion. FNE and Spy0125 both have a superimposable internal thioester bond between highly conserved Cys and Gln residues. Small angle X-ray scattering of the FNE-(789) FI complex provided a model that aligns the C-terminal peptide of FNE with the E-strands of the FI domains, adopting the beta-zipper extension model observed in previous structures of microbial surface components recognizing adhesive matrix molecule adhesion peptides bound to FI domains. PMID- 25290768 TI - Mast cell differentiation and heterogeneity. AB - Major differences between mast cells from different tissues and species have been known for at least 20 years but have been rigorously studied only recently. A recent meeting focused on the ontogeny and differentiation of mast cells, their functional characteristics and the clinical and biological significance of their heterogeneity. PMID- 25290769 TI - Genes, structures and function of T lymphocyte antigen receptors. AB - Our knowledge of the genes encoding the T-cell antigen receptors has expanded dramatically in the last year. Much of the new data was presented at a recent EMBO workshop. The participants attempted to integrate the structural and genetic information with some of the immunological properties of T lymphocytes. PMID- 25290770 TI - Influences on life-span of NZB/W mice. PMID- 25290771 TI - More about NK cells and regulation of B cell activity. PMID- 25290772 TI - Therapy for AIDS. PMID- 25290773 TI - Modulation of immunity by drugs. PMID- 25290775 TI - [Not Available]. PMID- 25290774 TI - Lymphocytes handled in vitro do recirculate from blood to lymph. PMID- 25290776 TI - Rodney Robert Porter FRS, CH. PMID- 25290777 TI - Enteric infections and other cofactors in AIDS. AB - It is generally accepted that human T-cell lymphotropic virus type III (HTL VIII) is the causative agent of acquired immunodeficiency syndrome (AIDS), but, asyet, there are no clear reasons for the different clinical manifestations of AIDS among individuals. In this article Douglas Archer and Walter Glinsmann discuss the history of AIDS and propose a link between HTLV-III infection and gastrointestinal disease processes with attendant malabsorption. They further propose that maximizing the nutritional status and minimizing the incidence of gastrointestinal infection of individuals infected with HTLV-III may prevent development of the full-blown AIDS. PMID- 25290778 TI - Cloning and expression of mycobacterial genes in E. coli. PMID- 25290779 TI - Immunoregulation of MHC antigen expression. PMID- 25290780 TI - The idiotype network in autoimmune processes. AB - At the turning point of the mid-80s much experimental work stands as evidence that Jerne's original network hypothesis may be correct. However, much of the available information stems from studies on regulation of idiotypes on antibodies/lymphocytes which recognize exogenous or synthetic antigens. By comparison, much less is known about regulation of autoimmunity through the idiotype of antibodies or receptors directed against self components. A distinction between antigens of external and internal origin is probably not just a problem of semantics; self antigens may be regulated in a slightly different mode than are their non-self counterparts. Here Maurizio Zanetti discusses the need to analyse the immune response to self antigens independently. PMID- 25290781 TI - Immunoregulation by leukotrienes and other lipoxygenase metabolites. AB - The leukotrienes are a group of biologically active molecules derived from the oxidative metabolism of unsaturated fatty acids via the 5-lipoxygenase pathway. They are readily synthesized by leukocytes and probably by other cell types following immune or nonimmune stimulation. In addition to their initially described myotropic activities, they very strongly affect several leukocyte functions. Here Marek Rola-Pleszczynski suggests that leukotrienes may play an important role in immunoregulation during inflammatory processes. PMID- 25290782 TI - Tum variants: immunogenic variants obtained by mutagen treatment of tumor cells. AB - Mutagen treatment of mouse tumor cells produces at high frequency stable tumor cell variants that are rejected by syngeneic mice. As Thierry Boon discusses here, these 'tum-' variants express new surface antigens that can be recognized by cytolytic T lymphocytes. Tum- variants derived from spontaneous mouse tumors for which no immunogenicity had hitherto been demonstrated induce an immune protection against the parental tumor. Finally, he poses some interesting questions for future investigations. PMID- 25290785 TI - Detection of early osteoarthritis in the centrodistal joints of Icelandic horses: Evaluation of radiography and low-field magnetic resonance imaging. AB - REASONS FOR PERFORMING STUDY: Validated noninvasive detection methods for early osteoarthritis (OA) are required for OA prevention and early intervention treatment strategies. OBJECTIVES: To evaluate radiography and low-field magnetic resonance imaging (MRI) for the detection of early stage OA osteochondral lesions in equine centrodistal joints using microscopy as the reference standard. STUDY DESIGN: Prospective imaging of live horses and imaging and microscopy of cadaver tarsal joints. METHODS: Centrodistal (distal intertarsal) joints of 38 Icelandic research horses aged 27-29 months were radiographed. Horses were subjected to euthanasia approximately 2 months later and cadaver joints examined with low field MRI. Osteochondral joint specimens were classified as negative or positive for OA using light microscopy histology or scanning electron microscopy. Radiographs and MRIs were evaluated for osteochondral lesions and results compared with microscopy. RESULTS: Forty-two joints were classified OA positive with microscopy. Associations were detected between microscopic OA and the radiography lesion categories; mineralisation front defect (P<0.0001), joint margin lesion (P<0.0001), central osteophyte (P = 0.03) and the low-field MRI lesion categories; mineralisation front defect (P = 0.01), joint margin lesion (P = 0.02) and articular cartilage lesion (P = 0.0003). The most frequent lesion category detected in microscopic OA positive joints was the mineralisation front defect in radiographs (28/42 OA positive joints, specificity 97%, sensitivity 67%). No significant differences were detected between the sensitivity and specificity of radiography and low-field MRI pooled lesion categories, but radiography was often superior when individual lesion categories were compared. CONCLUSIONS: Early stage centrodistal joint OA changes may be detected with radiography and low-field MRI. Detection of mineralisation front defects in radiographs may be a useful screening method for detection of early OA in centrodistal joints of young Icelandic horses. PMID- 25290786 TI - Impact of angiosome-oriented revascularization on clinical outcomes in critical limb ischemia patients without concurrent wound infection and diabetes. AB - PURPOSE: To investigate the impact of angiosome-oriented revascularization on clinical outcomes in critical limb ischemia (CLI) patients excluding those with both diabetes and wound infection. METHODS: Using a retrospective multicenter database, a propensity score matching analysis was performed of 539 consecutive CLI patients (375 men; mean age 71+/-11 years) without concurrent wound infection and diabetes who underwent balloon angioplasty of isolated infrapopliteal lesions. Propensity score matching produced 2 groups of 182 patients each who underwent angiosome-oriented direct revascularization (123 men; mean age 72+/-11 years) or indirect revascularization (125 men; mean age 72+/-11 years). The groups were compared for wound healing rate, freedom from major adverse limb events (MALE), and amputation-free survival (AFS). RESULTS: In the overall population, indirect revascularization was performed in 36.6% (n=197). In the propensity matching analysis, the complete wound healing rate at 12 months was higher in the direct group than the indirect revascularization patients (75% vs. 64%, p=0.01), while freedom from MALE (p=0.99) and AFS (p=0.17) were not significantly different at up to 24 months. In multivariate analysis, indirect revascularization had an independent negative impact on wound healing (adjusted hazard ratio 0.7, p=0.008). CONCLUSION: After propensity matching analysis for CLI patients other than those with both diabetes and wound infection, the wound healing rate was higher after direct revascularization than after indirect revascularization, whereas MALE and AFS were not significantly different. PMID- 25290787 TI - Commentary: myths and proofs of angiosome applications in CLI: where do we stand? PMID- 25290788 TI - Diagnostic value of peripheral fractional flow reserve in isolated iliac artery stenosis: a comparison with the post-exercise ankle-brachial index. AB - PURPOSE: To examine in claudicant patients with aortoiliac lesions the relationship between the post-exercise ankle-brachial index (ABI) and the peripheral fractional flow reserve (p-FFR), a physiological test that has heretofore been used to assess coronary and renal artery stenosis. METHODS: Sixteen male patients (mean age 68.1+/-7.5 years) with isolated iliac artery lesions detected by ultrasound in 17 limbs were enrolled in this study. Resting ABI was measured and a treadmill test was administered to measure the post exercise ABI. During angiography, the p-FFR was measured using a pressure guidewire after administration of papaverine to induce hyperemia. Changes in the ABI during exercise and p-FFR at hyperemia were calculated. RESULTS: The mean resting ABI and post-exercise ABI were 0.87+/-0.12 and 0.65+/-0.24, respectively. There was no complication during the measurement of p-FFR. The mean p-FFR at hyperemia was 0.71+/-0.14. A significant linear correlation was observed between post-exercise ABI and p-FFR at hyperemia (r=0.857, p<0.001), which was stronger than the correlation between post-exercise ABI and peak-to-peak pressure gradient at hyperemia (r= -0.626, p=0.013). CONCLUSIONS: Measuring p-FFR appears to be a feasible and safe procedure, and there is a significant linear correlation between post-exercise ABI and p-FFR in aortoiliac lesions. The p-FFR was more accurate than a peak-to-peak pressure gradient in assessing the physiological significance of a stenosis. Though larger studies are required, p-FFR might be used to physiologically assess stenosis in PAD patients with isolated aortoiliac lesions. PMID- 25290789 TI - Commentary: endovascular hemodynamic pressure wire assessment in lower extremities: has the time come? PMID- 25290790 TI - Tailored use of transradial access for above-the-knee angioplasty. AB - PURPOSE: To report the results and complications of a single-center experience of above-the-knee angioplasty via transradial access (TRA). METHODS: In a prospective study, 110 consecutive patients (88 men; mean age 72 years, range 37 90) referred for critical limb ischemia (26, 24%) or claudication were eligible for lower limb angioplasty via TRA (patients with TASC D lesions of the superficial femoral artery and below-the-knee lesions were excluded). RESULTS: The majority of patients (84, 76%) were treated via a left TRA. A total of 170 lesions were addressed, of which 38 (22%) were occlusions; 113 stents were positioned in 82 patients. The overall technical success rate was 91%, with a 63% success rate in occlusions and a 98% success rate in stenoses; by location, the success rates were 91% in suprainguinal lesions and 90% in infrainguinal lesions. No hemorrhagic or local complications requiring surgery were observed. At 1-month follow-up, 101 patients had a downward shift of at least one category in the Rutherford classification of symptoms (clinical success rate 92%); 18 (16%) patients had occlusion of their access radial artery, but none had symptoms or discomfort. CONCLUSION: The present study demonstrates that TRA is a safe and effective approach for lower extremity arterial revascularization, at least for interventionists with longstanding experience in TRA and in selected anatomical subsets. PMID- 25290791 TI - Commentary: transradial access: an alternative or a standard of care for selected peripheral procedures? PMID- 25290792 TI - Two-year analysis of the Japanese cohort from the Zilver PTX randomized controlled trial supports the validity of multinational clinical trials. AB - PURPOSE: To report a subgroup analysis comparing safety and effectiveness outcomes in Japanese and non-Japanese patients as part of a prospective, multinational, randomized controlled trial (ClinicalTrials.gov identifier NCT00120406) evaluating a paclitaxel-coated drug-eluting stent (DES) compared to percutaneous transluminal angioplasty (PTA) for treating peripheral artery disease. METHODS: Patients were randomly assigned to primary DES or PTA. In the Japanese cohort, 27 patients (21 men; mean age 71.2+/-9.6 years) were randomized to PTA and 25 patients (19 men; mean age 69.8+/-10.2 years) to primary DES. In the non-Japanese cohort, 211 patients (131 men; mean age 67.3+/-10.6 years) were randomized to PTA and 211 patients (136 men; mean age 67.6+/-9.5 years) to primary DES. Outcome measures included event-free survival (EFS), freedom from target lesion revascularization (TLR), patency, stent fracture, and sustained clinical benefit through 2 years. RESULTS: Safety and effectiveness outcomes were similar in the Japanese and non-Japanese cohorts, although the outcomes in the Japanese cohort treated with primary DES were numerically better. In the DES group, the 2-year EFS was 92.0% vs. 85.0% (p=0.61), freedom from TLR was 96.0% vs. 85.5% (p=0.55), primary patency was 80.0% vs. 74.3% (p=0.61), and clinical benefit was sustained in 88.5% vs. 80.5% of patients (p=0.31) in the Japanese and non-Japanese cohorts, respectively. Stent fractures were seen in 4 of 457 stents at 12 months: 3 in the Japanese cohort and 1 in the non-Japanese cohort. CONCLUSION: The subgroup analysis comparing Japanese and non-Japanese patients supports the safety and effectiveness of the paclitaxel-coated DES in Japanese patients with stenotic lesions in the femoropopliteal arteries. The lack of major differences associated with ethnicity in these 2-year outcomes supports the validity and value of multinational clinical trials. PMID- 25290793 TI - Vascular elastography: a novel method to characterize occluded lower limb arteries prior to endovascular therapy. AB - PURPOSE: To examine the effectiveness of vascular elastography (VE) for the assessment of totally occluded lower limb arteries prior to endovascular treatment (EVT). METHODS: Of 812 consecutive patients who underwent EVT between April 2010 and April 2012, VE was used to evaluate the hardness of chronic total occlusions of the femoropopliteal segment prior to EVT in 65 consecutive patients (48 men; mean 73.9 years, range 63-86). Elastograms of the CTOs proximally and distally were scored using a 5-point scale, and outcomes in limbs with hard lesions (VE score 0-2) were compared to those with soft lesions (VE score 3-4) according to lesion length. The interventionists who performed the endovascular procedures were not informed of the VE score results. RESULTS: CTO characteristics could be evaluated in all cases. A VE score <=2 was found in 14 of the 23 lesions <150 mm in length. A flexible guidewire was sufficient for recanalization in more of the soft lesions than in the hard lesions [6/9 vs. 2/14, respectively]. In 39 lesions >150 mm, a VE score of 3 was recorded in most lesions proximally, while lesions distally were hard in many cases (VE score 1 or 2). A flexible guidewire alone was sufficient in many soft CTOs (8/13, p<0.01). In 16 cases, hard calcified plaque was indicated by difficulty in penetrating the lesion even with a stiff guidewire; all these cases had a VE score of 1 or 2. A retrograde approach was required only in hard CTOs (p<0.01). The procedure time was significantly longer for the hard lesion group (152.9+/-63.2 vs. 87.0+/-29.8 minutes, p=0.001). In 11 in-stent occlusions, only VE scores of 3 (n=4) or 4 (n=7) were recorded, indicating soft thrombus, which was aspirated under distal protection in 7 cases. CONCLUSION: VE may be a useful method for determining the hardness of CTO lesions noninvasively before endovascular therapy, providing information that can help plan the procedure. PMID- 25290794 TI - Predictive value of skin perfusion pressure after endovascular therapy for wound healing in critical limb ischemia. AB - PURPOSE: To determine the predictive value of skin perfusion pressure (SPP) for wound healing after endovascular therapy (EVT). METHODS: Between May 2004 and March 2011, 113 consecutive patients (84 men; mean age 71.5+/-12.5 years) with CLI (123 limbs) underwent successful balloon angioplasty +/- stenting (flow from >1 vessel to the foot without bypass) and were physically able to undergo SPP measurement before and within 48 hours after EVT. The status of wound healing was recorded over a mean follow-up of 17.4+/-12.4 months. RESULTS: The wound healing rate was 78.9% (97 limbs of 89 patients). SPP values after EVT were significantly higher in these patients than in the 24 patients (26 limbs) without wound healing (44.2+/-15.6 mmHg vs. 27.5+/-10.4 mmHg, p<0.001). Receiver operating characteristics analysis of SPP after EVT to predict wound healing had an area under the curve of 0.81 (95% CI 0.723 to 0.899, p<0.001). The optimal cutoff for predicting wound healing was 30 mmHg, with a sensitivity of 81.4% and a specificity of 69.2%. Binary logistic regression analysis demonstrated SPP after EVT to be an independent predictor of wound healing (p<0.001). The probability of wound healing with SPP values >30 mmHg, 40 mmHg, and 50 mmHg were 69.8%, 86.3%, and 94.5%, respectively. CONCLUSION: SPP after EVT is an independent predictor of wound healing in patients with CLI. In our study, an SPP value of 30 mmHg was shown to be the best cutoff for prediction of wound healing after EVT. PMID- 25290795 TI - Long-term results of drug-eluting balloon angioplasty for treatment of refractory recurrent carotid in-stent restenosis. AB - PURPOSE: To evaluate the potential role, safety, and efficacy of paclitaxel eluting balloon angioplasty for treatment of recurrent carotid in-stent restenosis (ISR). METHODS: Among 856 consecutive patients who underwent carotid artery stenting from May 2002 to January 2008, 41 patients had a significant ISR (>80% stenosis). Of these, 9 patients (7 women; mean age 78.1+/-5.6 years) had recurrent ISR despite multiple endovascular treatments (3.4+/-0.9 interventions) within a short period of time (2-5 months). These patients were treated with drug eluting balloon (DEB) angioplasty for neointimal hyperplasia. Imaging (ultrasound or computed tomographic angiography) was performed at 1, 3, and 6 months and yearly thereafter. RESULTS: Technical success was obtained in 100% of cases, with angiographic stenosis decreasing from 87%+/-4% to 6%+/-4% post treatment. Peak systolic velocity decreased significantly from 4.7+/-1.5 m/s to 0.6.+/-0.3 m/s after the procedure. Over a mean follow-up of 36.6+/-2.7 months, ultrasound imaging indicated recurrent ISR in only 3 patients at 18, 25, and 32 months after DEB angioplasty, respectively. The target vessel revascularization rate was 33.3% at 36 months. No neurological or myocardial events were recorded during follow up. One patient died at 3 months. CONCLUSION: DEB may have a potential role improving outcomes of those patients treated for early recurrent carotid ISR. PMID- 25290796 TI - Commentary: drug-coated balloons for treatment of carotid in-stent restenosis: did we find the ace of hearts? PMID- 25290797 TI - Bare metal vs. drug-eluting stents for extracranial vertebral artery disease: a meta-analysis of nonrandomized comparative studies. AB - PURPOSE: To compare through meta-analysis the use of drug-eluting stents (DES) vs. bare metal stents (BMS) in the treatment of extracranial vertebral artery (EVA) disease. METHODS: A literature search of the PubMed database was conducted to identify English-language articles in which both BMS and DES stenting were performed for EVA stenosis by the same investigator(s). Further, eligible studies had to provide data on in-stent restenosis during follow-up. The search identified 9 nonrandomized studies that met the inclusion criteria. The random effects model was employed to pool data. Meta-regression analyses were performed to evaluate the relationships between risk of restenosis and the age of patients, the length of follow-up, or the percentage of male patients. RESULTS: Reported technical success was high (range 99.2%-100%) and comparable for BMS [100% (276/276)] and DES [99.4% (166/167)]. The use of DES was associated with significantly lower (p<0.0001) overall restenosis rates [8.2% (14/170) over follow-up periods averaging 16 to 43 months] compared to BMS [23.7% (68/287) over mean follow-up periods of 19 to 46 months]. Moreover, DES showed significantly lower symptomatic restenosis rates as compared to BMS [4.7% (8/169) for DES vs. 11.6% (32/275) for BMS; p=0.005]. There was no change in the risk of restenosis for any factor explored in the meta-regression analysis. CONCLUSION: This meta analysis demonstrates that the use of DES for extracranial vertebral artery stenting significantly reduces both the rate of restenosis and recurrence of symptoms as compared to BMS. In future, randomized trials are needed to support these findings. PMID- 25290798 TI - Commentary: observations, trials, and meta-analyses: the life cycle of evidence based endovascular therapy. PMID- 25290799 TI - Large false lumen area is a predictor of failed false lumen volume reduction after stent-graft repair in type B aortic dissection. AB - PURPOSE: To investigate the predictors of failed false lumen (FL) volume reduction at 12 months after stent-graft implantation in patients with type B aortic dissection. METHODS: The retrospective analysis comprised 38 patients (25 men; mean age 60+/-12 years) with double-barrel type B aortic dissection (9 acute) treated with thoracic endovascular aortic repair (TEVAR) and evaluated with serial computed tomography (CT) scans up to 12 months. Aortic volume changes were determined. Based on FL volume change at 1 year after stent-graft implantation, patients were dichotomized according to the presence or absence of FL volume reduction. Clinical and CT variables were compared between groups to determine risk factors of failed FL volume reduction. A major adverse event (MAE) was defined as death or reintervention. RESULTS: Patients were followed for 4.2+/ 2.8 years. FL volume reduction (+FLVR) occurred in 27 (71%) patients, whereas 11 (29%) patients had no FL volume reduction (-FLVR). The MAE-free survival rate was significantly higher in the +FLVR patients than in the -FLVR group (88.9% vs. 27.3%, respectively; p=0.001). Chronicity of dissection, location of tear site, or the maximum total aortic lumen area was not associated with failure to achieve FL volume reduction. However, the maximum preprocedure FL area was significantly lower in the +FLVR group than in the -FLVR group (12.6+/-6.6 vs. 21.0+/-11.4 cm(2), respectively; p=0.041) and was an independent predictor for failed FL volume reduction (odds ratio 1.3, 95% confidence interval 1.02 to 1.70, p=0.031). CONCLUSION: Failed FL volume reduction after TEVAR was associated with a significantly increased rate of mortality or reintervention during follow-up. A larger preprocedure maximum FL area was a predictor of failed FL volume reduction after TEVAR in type B dissection. PMID- 25290801 TI - Treatment of type II endoleak after endovascular aneurysm repair: the role of selective vs. nonselective transcaval embolization. AB - PURPOSE: To assess the technical and midterm results in the treatment of type II endoleaks comparing nonselective (nTCE) vs. selective (sTCE) transcaval embolization. METHODS: During a 4-year period, 26 patients (18 men; median age 73 years, range 68-78) underwent direct transcaval aneurysm puncture followed by embolization of the sac (nTCE, n=9) or of the feeding vessels (sTCE, n=17). Intrasac pressure was recorded immediately after aneurysm sac puncture and at the end of the procedure. Technical success was defined as successful deployment of embolization material in the sac or in the feeding vessel. Clinical success was defined as absence of endoleak with stabilization of the sac on follow-up CTA. RESULTS: Technical success was 100% in the 9 patients treated with nTCE. Mean intrasac pressures before and after nTCE were 58.6+/-18.4 (range 51-105) and 6.5+/-1.2 mmHg (range 4-9), respectively. Over a mean 25.9+/-11.0 months of follow-up, 4 patients developed recurrent endoleak at a mean 9.7+/-3.9 months. Three patients were subsequently treated with sTCE, while the last patient underwent emergency surgery for aneurysm rupture due to an enlarging sac 5 months after nTCE. The 20 patients in the sTCE group had a successful procedure with no recurrence in a follow-up of 24.1+/-7.2 months. Mean intrasac pressure was reduced after sTCE from 63.6+/-15.2 mmHg (range 43-120) to 7.8+/-2.3 mmHg (range 5-12). CONCLUSION: The selective TCE approach appears to be a feasible and effective primary therapeutic option for treating type II endoleak. PMID- 25290800 TI - Computed tomography-based study exploring the feasibility of endovascular treatment of type A aortic dissection in the Chinese population. AB - PURPOSE: To characterize type A aortic dissection (TAAD) in the Chinese population using high-resolution computed tomography (CT) and explore potential candidacy for endovascular repair of TAAD. METHODS: The imaging studies and medical records of all 302 patients presenting with TAAD at two Chinese hospitals from 2010 to 2013 were reviewed. Of these, 221 patients were excluded because of missing/inadequate preoperative CT scans. The remaining 91 patients (64 men; mean age 51.1+/-7.5 years) had CT data adequate to assess anatomical suitability for endovascular treatment. Entry tears were identified using multiplanar reconstructions, while morphological measurements were based on a centerline of flow (CLF) technique. Suitability for endovascular treatment was based on a proximal landing zone >=20 mm long, a true lumen aortic diameter <=38 mm, and a total aortic diameter <=46 mm; no coronary bypass grafts originating from the ascending aorta; no malfunctioning aortic valve; and good cerebral and cardiac perfusion. RESULTS: In the 91 patients, the precise location of the primary proximal entry tear could be identified in only 34 (37.4%) patients; in these patients, the identifiable intimal tears were located 36.4+/-41.0 mm distal to the closest coronary artery. The CLF was successfully generated in the CT scans of all patients; the mean lumen and total aortic lumen diameters at the entry tear level were 37.6+/-6.3 and 44.3+/-13.3 mm, respectively. Based on the CT measurements, stent-graft repair would have been anatomically feasible in 35 (38.5%) patients. No proximal landing zone (n=23), large aortic diameter (n=15), abnormal aortic valve (n=10), previous coronary bypass graft surgery (n=5), and poor cerebral and cardiac perfusion (n=3) were obstacles that affected the suitability for this treatment. CONCLUSION: Based on high-resolution CT scans, our pilot study suggested that 38% of Chinese patients with TAAD could potentially be treated by stent-grafting based on the anatomical characteristics of the proximal dissection. PMID- 25290802 TI - Type IIIb endoleak is an important cause of failure following endovascular aneurysm repair. AB - PURPOSE: To present confirmed cases of type IIIb endoleak in second and third generation stent-grafts used for endovascular aneurysm repair (EVAR). CASE REPORTS: Four patients developed type IIIb endoleak caused by fabric tears between 4 and 13 years following their initial EVAR. Three patients presented with rupture and one with aneurysm expansion of unknown cause. In each case, the type IIIb endoleak was confirmed at open surgery after imaging proved non diagnostic. Only one patient survived. Had the cause for the expansion or ruptures been found prior to open reintervention, relining of the stent-graft may have been possible. CONCLUSION: Type IIIb endoleak remains difficult to diagnose. Avoidance of the high mortality associated with open secondary intervention requires a high degree of suspicion and it should be considered in any post-EVAR aneurysm expansion without an obvious cause. PMID- 25290803 TI - Endograft conformability and aortoiliac tortuosity in endovascular abdominal aortic aneurysm repair. AB - PURPOSE: To determine conformability of stent-grafts in endovascular aneurysm repair (EVAR) using centerline of flow measurements and to compare conformability in patients with severe aortoiliac tortuosity. METHODS: From 2012 to 2013, 111 consecutive patients (98 men; mean age 75.4+/-7.7 years) underwent endovascular aneurysm repair with Endurant I and II and Zenith Flex, LP, and Spiral Z stent grafts; their pre- and post-EVAR computed tomography (CT) studies were retrospectively analyzed using quantitative 3-dimensional imaging software. The length between the lowest renal artery and the iliac bifurcation was measured using centerline of flow and was defined as the treatment length (TL). The difference in TLs pre and post EVAR were compared as a surrogate to evaluate endograft conformability. RESULTS: A total of 203 pre and post EVAR aortoiliac TLs were measured (99 Endurant I, 20 Endurant II, 32 Flex, 6 LP, and 42 Spiral Z). Overall, there was a mean difference of 5.0+/-7.3 mm or 2.6%+/-3.9% between the pre- and post-EVAR TLs (p<0.001). No statistically significant difference in TLs was observed among the various stent-grafts (p=0.115). In 40 patients with severe aortoiliac tortuosity, the post-EVAR TL was 16.2+/-5.5 mm or 8.0%+/-2.7% shorter than the pre-EVAR TL (p<0.001); again, there was no difference in TLs among the various devices implanted (p=0.737). CONCLUSION: Overall, there was no difference in treatment lengths before and after EVAR among different stent grafts, suggesting similar conformability. Interestingly, patients with severe aortoiliac tortuosity were found to have significantly shorter post-EVAR treatment lengths compared to before EVAR, which should be considered when planning EVAR. PMID- 25290805 TI - First-in-man experience with the ReVive PV peripheral thrombectomy device for the revascularization of below-the-knee embolic occlusions. AB - PURPOSE: To report the initial use of a novel thrombectomy device for revascularization of below-the-knee thromboembolic occlusions encountered during proximal revascularization procedures. CASE REPORTS: The ReVive PV Peripheral Thrombectomy Device is a non-detachable, self-expanding stent-like device recently approved for peripheral thrombectomy. Four patients (3 women; mean age 68.8 years) undergoing proximal revascularization procedures experienced embolic occlusions of all 3 trifurcation vessels in 1 patient, the tibioperoneal trunk alone in 2 cases, and the peroneal artery alone in the last patient. In all cases, the involved arteries represented the primary or sole vessel(s) providing outflow to the lower extremity. In each case, the ReVive PV device was used to successfully extract the thrombus and restore flow to the distal extremity. No complications were encountered during any of the procedures. CONCLUSION: The ReVive PV peripheral thrombectomy device may facilitate the safe and efficient revascularization of distal arterial embolic occlusions. PMID- 25290804 TI - Fatigue and in vivo validation of a peritoneum-lined self-expanding nitinol stent graft. AB - PURPOSE: To assess the fatigue and in vivo performance of a new stent-graft incorporating bovine peritoneum lining that is designed for application in peripheral vascular occlusive disease. METHODS: Bovine peritoneum-lined stent grafts were subjected to accelerated in vitro pulsatile fatigue and axial/torsional fatigue testing designed to simulate 10 years of physiological strain on the devices. At specified times the devices were evaluated for stent fracture, suture failure, or tissue tearing. Seven dogs underwent bilateral common iliac artery (CIA) balloon angioplasty injury with unilateral placement of the peritoneum-lined stent-graft. Angiography and intravascular ultrasound were performed prior to treatment, after treatment, and prior to sacrifice at 30 days. Vessels were perfusion fixed and histologically evaluated at 5 regions: above stent, proximal stent, mid stent, distal stent, and below stent. RESULTS: No evidence of stent, suture, or tissue failure was present during or after pulsatile and axial/torsional fatigue testing. At 30+/-0.3 days after implantation, all vessels were patent. The average lumen area at explantation across stented vessels was 25.45 mm(2). Lumen areas tended to be reduced above (23.57 mm(2)) and below (24.17 mm(2)) the stent. Lumen areas were consistent across stented regions at explantation (proximal stent 27.80 mm(2), mid stent 25.88 mm(2), and distal stent 25.81 mm(2)). The mean neointimal area in peritoneum-lined stents was 2.02+/-1.52 mm(2), with a neointima:media ratio of 1.03+/-0.50. These values were significantly lower in the above and below stent areas than in the stented regions, but there was no difference in either measure within the proximal, mid, or distal stent. CONCLUSION: The custom-designed peritoneum-lined stent-graft is promising for clinical peripheral applications due to its ability to resist relevant long-term physiological stresses and outstanding short-term patency rates in canine implantations. PMID- 25290806 TI - Aspirex S catheter malfunction during arteriovenous fistula thrombectomy secondary to a jammed helix-guidewire complex. AB - PURPOSE: To report a potential complication when using the Aspirex S rotational thrombectomy catheter. CASE REPORT: A 76-year-old woman with end-stage renal failure presented with left brachiocephalic arteriovenous fistula (BCAVF) dysfunction and subsequently underwent percutaneous thrombectomy using the Aspirex S catheter. During the course of the thrombectomy, device malfunction ultimately resulted in complete thrombosis of the cephalic outflow tract; eventually, a new right BCAVF had to be created. CONCLUSION: There are possible complications when using the Aspirex S catheter in thrombectomy of dialysis accesses, and further experience with this thrombectomy device is needed to fully understand its potential and limitations. PMID- 25290807 TI - Use of a 3D printed hollow aortic model to assist EVAR planning in a case with complex neck anatomy: potential of 3D printing to improve patient outcome. PMID- 25290808 TI - Re: "technical challenges encountered during deployment of the ovation abdominal aortic stent-graft system". PMID- 25290809 TI - Regulation of the hydrolytic activity of Mg2+-dependent phosphatase models by intramolecular NH...O hydrogen bonds. AB - Magnesium-dependent phosphatase models containing intramolecular NH...O hydrogen bonds were synthesized and structurally characterized by X-ray analysis. The Mg-O bond distances varied with the mode of the hydrogen bonds. (1)H NMR spectra in nonpolar solvents revealed that the acidity of the coordinated water molecule was regulated by the hydrogen bonds. Further, stoichiometric hydrolysis of phosphoric ester significantly depended on the hydrogen bonds. Zinc analogues showed similar but smaller dependencies, which suggest the indispensable role of Mg(2+) ion in the activation of the enzymes. PMID- 25290810 TI - Development of artemether-loaded nanostructured lipid carrier (NLC) formulation for topical application. AB - NLC topical formulation as an alternative to oral and parenteral (IM) delivery of artemether (ART), a poorly water-soluble drug was designed. A Phospholipon 85G modified Gelucire 43/01 based NLC formulation containing 75% Transcutol was chosen from DSC studies and loaded with gradient concentration of ART (100-750 mg). ART-loaded NLCs were stable (-22 to -40 mV), polydispersed (0.4-0.7) with d90 size distribution range of 247-530 nm without microparticles up to one month of storage. The encapsulation efficiency (EE%) for ART in the NLC was concentration independent as 250 mg of ART loading achieved ~61%. DSC confirmed molecular dispersion of ART due to low matrix crystallinity (0.028J/g). Ex vivo study showed detectable ART amounts after 20h which gradually increased over 48h achieving ~26% cumulative amount permeated irrespective of the applied dose. This proves that ART permeates excised human epidermis, where the current formulation served as a reservoir to gradually control drug release over an extended period of time. Full thickness skin study therefore may confirm if this is a positive signal to hope for a topical delivery system of ART. PMID- 25290811 TI - Gastroretentive inorganic-organic hybrids to improve class IV drug absorption. AB - Therapeutic efficacy of some orally administered molecules is often conditioned by their solubility in physiological fluids as well as their absorption. The last aspect becomes more limitative and conditioning drug plasmatic profiles when the active ingredient is preferentially absorbed in a specific region of the gastrointestinal tract. A case is represented by furosemide (FURO) preferentially absorbed in the stomach, site in which, because of its acidic nature, is poorly soluble. To solve this problem new oral solid formulations have been developed. The inorganic-organic hybrid MgAl-HTlc-FURO has been formulated in tablet in which floating and mucoadhesion properties have been combined. Swellable (Methocel K4, Methocel K15, Methocel K100 M, hydroxypropyl methyl cellulose) or swellable/erodible polymers (Methocel E50 LV, Methocel K100 LV), used to obtain the floating, were combined to Carbopol((r)) (971P or 974P) to confer mucoadhesion capacity. Prepared tablets were deeply characterized in terms of hydration capacity, erosion %, buoyancy lag time/floating time and mucoadhesion. The most suitable tablets selected from these preliminary tests, submitted to in vitro release studies, showed a sustained release of FURO. This is useful to maintain the therapeutic concentrations for a long time, in comparison to conventional dosage forms, thanking to the enhancement of formulation residence time in the stomach. PMID- 25290812 TI - Sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA could effectively deliver siRNA to the liver. AB - In this study, we developed novel siRNA transfer method to the liver by sequential intravenous injection of anionic polymer and cationic liposome/cholesterol-modified siRNA complex (cationic lipoplex). When cationic lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when cationic lipoplex was intravenously injected at 1 min after intravenous injection of poly-L-glutamic acid (PGA) or chondroitin sulfate C (CS), siRNA was accumulated in the liver. In terms of suppression of gene expression in vivo, apolipoprotein B (ApoB) mRNA in the liver and low-density-lipoprotein (LDL) and very low-density-lipoprotein (VLDL) cholesterol level in serum were reduced at 48 h after single sequential injection of PGA or CS plus cationic lipoplex of cholesterol-modified ApoB siRNA. Furthermore, sequential injections of PGA plus cationic lipoplex of cholesterol modified luciferase siRNA could reduce luciferase activity in tumor xenografts bearing liver metastasis of human breast tumor MCF-7-Luc. From these findings, sequential injection of anionic polymer and cationic lipoplex of siRNA might produce a systemic vector of siRNA to the liver. PMID- 25290813 TI - Optimization of long circulating mixed polymeric micelles containing vinpocetine using simple lattice mixture design, in vitro and in vivo characterization. AB - The aim of this study was to increase the in vivo mean residence time of vinpocetine after IV injection utilizing long circulating mixed micellar systems. Mixed micelles were prepared using Pluronics L121, P123 and F127. The systems were characterized by testing their entrapment efficiency, particle size, polydispersity index, zeta potential, transmission electron microscopy and in vitro drug release. Simple lattice mixture design was planned for the optimization using Design-Expert((r)) software. The optimized formula was lyophilized, sterilized and imaged by scanning electron microscope. Moreover, the in vivo behavior of the optimized formula was evaluated after IV injection in rabbits. The optimized formula, containing 68% w/w Pluronic L121 and 32% w/w Pluronic F127, had the highest desirability value (0.621). Entrapment efficiency, particle size, polydispersity index and zeta potential of the optimized formula were 50.74 +/- 3.26%, 161.50 +/- 7.39 nm, 0.21 +/- 0.03 and -22.42 +/- 1.72 mV, respectively. Lyophilization and sterilization did not affect the characteristics of the optimized formula. Upon in vivo investigation in rabbits, the optimized formula showed a significantly higher elimination half-life and mean residence time than the market product. Finally, mixed micelles could be considered as a promising long circulating nanocarrier for lipophilic drugs. PMID- 25290814 TI - Insights into the mechanisms of chitosan-anionic polymers-based matrix tablets for extended drug release. AB - The aim of this study was to investigate drug release mechanisms from physical mixtures of chitosan-anionic polymers-based matrix tablets and to obtain a comprehensive understanding about release characteristics. Six types of anionic polymers (i.e., Eudragit((r)) L100, sodium alginate, carrageenan, carboxymethylcellulose sodium, carbomer and xanthan gum) and two model drugs (i.e., theophylline and metoprolol succinate) with varied solubility were chosen. Texture analyzer, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were applied to better understand drug release mechanisms. In vitro release experiments were conducted in a pH-changing medium to simulate the physiological condition of the gastrointestinal tract. Interestingly, a common phenomenon was observed in all the CS-anionic polymers based matrix tablets investigated here, that is, the inner layer of the swollen tablets was coated by CS-anionic polymer polyelectrolyte complexes (PEC)-based film formed by self-assembly. Formation of the in situ self-assembled film was further confirmed by texture analysis, DSC, and FTIR. It was further identified that properties of the film were influenced by the characteristics of anionic polymers and the physiological conditions of the gastrointestinal tract. Moreover, this novel structure could alter swelling and erosion-based release mechanisms of the tablets. In addition, drug release characteristics from CS anionic polymer systems depended on the properties of anionic polymers and the drug solubility. In conclusion, our studies may broaden current views on cationic polymer-anionic polymer-based oral matrix tablets for extended release. PMID- 25290815 TI - The use of a work-related asthma screening questionnaire in a primary care asthma program: an intervention trial. AB - OBJECTIVES: The work-related asthma screening questionnaire (long-version) (WRASQ(L)) is a 14-item tool designed to increase the recognition of work-related asthma (WRA) in primary care. The purpose of this study was to assess whether the WRASQ(L) provided additional information about a patient's likelihood of WRA, beyond what was collected in standard care, and to assess the use of the WRASQ(L) in the primary care setting. METHODS: This was an intervention study involving two Ontario primary care sites. Standard care for asthma patients in these sites involved completing the Asthma Care Map (ACM), a template for asthma management that includes seven WRA screening items. Participation in this study involved completing an electronic WRASQ(L) at each visit for participants and prompted care providers to record details related to WRA investigations. Ethics approval was obtained from an Institutional Review Board. RESULTS: The study sample (N = 37) was predominantly female (73.0%), with a mean age of 46.3 years (SD, 10.9). The use of WRASQ(L) identified additional work-related symptoms in 38% and exposures in 60% of participants over and above those identified by the ACM. Two participants were newly suspected of WRA during the study period. CONCLUSIONS: The WRASQ(L) provided added information about possible WRA over standard care. The use of the questionnaire's results by care providers was limited due to barriers encountered in incorporating the use of electronic version of the WRASQ(L) into clinical practice. Once validated and implemented in practice, the WRASQ(L) has the potential to increase the recognition of WRA. PMID- 25290816 TI - The impact of combat deployment on asthma diagnosis and severity. AB - OBJECTIVES: Environmental exposures during military deployments to Iraq and Afghanistan may lead to higher rates of respiratory complaints and diagnoses. This study investigates whether there is a relationship between rates of asthma diagnosis and severity associated with military deployment. METHODS: Retrospective review of active duty Army personnel underwent fitness for duty evaluation (Medical Evaluation Board) for asthma. The electronic medical record was reviewed for onset of diagnosis (pre- or post-deployment), disease severity, screening spirometry, bronchodilator response and bronchoprovocation testing. We compared patients with and without a history of combat deployment to Operations Iraqi Freedom/Enduring Freedom. RESULTS: Four hundred consecutive Army personnel with a clinical diagnosis of asthma were evaluated. Equal numbers of patients had deployed (48.5%) versus never deployed (51.5%). Of those who deployed, 98 (24.5%) were diagnosed post-deployment. The diagnosis of asthma was objectively confirmed in 74.8% of patients by obstructive screening spirometry, bronchodilator response, and/or methacholine challenge testing. There were no significant differences in spirometry between deployers and non-deployers or based on pre- and post-deployment diagnosis. Similarly, asthma severity classification did not differ between deployed and non-deployed service members, or by pre- and post deployment diagnosis status. CONCLUSIONS: Among active duty military personnel with career limiting asthma, there is no significant relationship between rates of diagnosis or severity based on history of deployment to Southwest Asia. PMID- 25290817 TI - Transumbilical laparoendoscopic single-site surgery with conventional instruments for choledochal cyst in children: early results of 86 cases. AB - INTRODUCTION: The aim of this study is to present our techniques and early results of transumbilical laparoendoscopic single-site surgery (TULESS) for childhood choledochal cyst (ChC). MATERIALS AND METHODS: Medical records of all children undergoing TULESS for ChC at our center from September 2012 to December 2013 were reviewed. Our TULESS operations started with a Z-shaped umbilical skin incision and placement of three 3-5-mm ports at separate points in the same incision site. The Roux-en-Y loop was created extracorporeally through the umbilical incision. Excision of the ChC and hepaticointestinal anastomosis were performed using conventional laparoscopic instruments. RESULTS: Eighty-six patients were identified with a median age of 24.5 months. The ChC was successfully excised by TULESS in all cases. Hepaticojejunostomy was performed in 84 cases, versus hepaticoduodenostomy in 2 cases. Additional trocars were needed in just 1.2%. There was no conversion to open surgery. The median operative time was 195 minutes. No drain was used in 90.7% of cases. There was no anastomotic leakage. Mild umbilical infection was noted in 2.3%. The median postoperative hospital stay was 5 days. At follow-up of 4-18 months, 1 patient needed a redo surgery for anastomotic stenosis; all other patients were in good health. The postoperative cosmesis was excellent as all TULESS patients were virtually scarless. CONCLUSIONS: TULESS with conventional laparoscopic instruments for ChC in children is feasible, with excellent postoperative cosmesis. The early outcome is promising, and TULESS can be a viable option for scarless surgical management of childhood ChC at experienced centers. PMID- 25290818 TI - Different effects of fenofibrate on metabolic and cardiovascular risk factors in mixed dyslipidemic women with normal thyroid function and subclinical hypothyroidism. AB - AIMS: Subclinical hypothyroidism is suggested to increase cardiovascular risk. No previous study compared the effect of any fibrate on plasma levels of lipids and other cardiovascular risk factors in patients with different thyroid function status. METHODS: The study included three age-, weight- and lipid-matched groups of women with mixed dyslipidemia in different thyroid function status: patients with untreated subclinical hypothyroidism (group 1, n = 18), women with treated hypothyroidism (group 2, n = 15), and subjects without thyroid disorders (group 3, n = 19). Plasma lipids, glucose homeostasis markers, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were determined before and after 12 weeks of fenofibrate therapy. RESULTS: Despite similar plasma lipid levels, mixed dyslipidemic patients with untreated hypothyroidism had decreased insulin sensitivity, as well as higher circulating levels of uric acid, hsCRP, homocysteine, and fibrinogen in comparison with the other groups. The effect of fenofibrate on plasma lipids and, with the exception of homocysteine, on circulating levels of all investigated risk factors was stronger in patients from groups 2 and 3 than in patients from group 1. CONCLUSIONS: The obtained results indicate that the effect of fenofibrate on plasma lipids and circulating levels of cardiovascular risk factors is partially related to thyroid function. They also suggest that to improve the strength of fibrate action in dyslipidemic patients with subclinical hypothyroidism, they should be administered together with L-thyroxine. PMID- 25290823 TI - Biomechanical evaluation of double Krackow sutures versus the three-loop pulley suture in a canine gastrocnemius tendon avulsion model. AB - OBJECTIVE: To compare two Krackow sutures with a three-loop pulley suture for the reattachment of canine gastrocnemius tendons, using a tendon avulsion model. STUDY DESIGN: In vitro biomechanical study. METHODS: Ten paired gastrocnemius tendons were severed at their insertions on the calcaneal tuberosity and repaired with either two modified Krackow sutures or a modified three-loop pulley suture. Sutures were placed in the tendon ends and through diverging bone tunnels in the medial and lateral processes of the calcaneal tuberosity. Tensile loads required to (a) create a 3-mm gap and (b) induce construct failure were measured. RESULTS: The mean load to achieve a 3-mm gap was 77.22 +/- 9.72 and 55.85 +/- 9.91 N, and to result in construct failure was 106.88 +/- 12.74 and 80.86 +/- 12.23 N for the Krackow and three-loop pulley suture patterns, respectively. These differences were statistically significant (P < 0.001 and P = 0.001, respectively). CONCLUSION AND CLINICAL RELEVANCE: Two Krackow sutures were superior to the three loop pulley pattern in both resistance to 3-mm gap formation and load to failure in a canine gastrocnemius avulsion model. The prevention of gap formation is critical for the success of tenorrhaphy. These results indicate that a suture pattern using two Krackow sutures may be clinically superior to the three-loop pulley suture pattern in the repair of canine gastrocnemius avulsion. Further work is required to determine if this superiority is mirrored in the repair of other tendon avulsion or laceration scenarios. PMID- 25290825 TI - Reply. PMID- 25290819 TI - Proof of dual-topology architecture of Fluc F- channels with monobody blockers. AB - Fluc-type F(-) channels--used by microorganisms for resisting fluoride toxicity- are unusual in their quaternary architecture: they are thought to associate as dimers with the two subunits in antiparallel transmembrane orientation. Here, we subject this unusual structural feature to a direct test. Single purified Fluc channels recorded in planar lipid bilayers are constitutively open, with rare, short-lived closings. Using combinatorial libraries, we generated synthetic binding proteins, 'monobodies,' that specifically bind to Fluc homologues with nanomolar affinity. Reversible binding of monobodies to two different Fluc channel homologues is seen in single-channel recordings as long-lived nonconducting events that follow bimolecular kinetics. By applying monobodies sequentially to the two sides of the bilayer in a double-sided perfusion manoeuvre, we show that Fluc channels present monobody-binding epitopes to both sides of the membrane. The result establishes that Fluc subunits are arranged in dimeric antiparallel orientation. PMID- 25290824 TI - Tongue-tie and breastfeeding in newborns-mothers' perspective. AB - OBJECTIVE: This study explored clinical implications of tongue-tie (TT) on breastfeeding from the mothers' perspective and evaluated the assistance provided. MATERIALS AND METHODS: This was a single-center observational study using a structured survey. All newborns with TT born in 2005-2010 were identified; two controls without TT were assigned for each. Mothers were interviewed using a uniform structured questionnaire regarding breastfeeding experience, challenges, lactation consultation, and frenotomy, if performed. RESULTS: One hundred eighty-three TT mothers and 314 controls were interviewed. Although the overall rates of breastfeeding problems in the first month were similar (59% vs. 52%, respectively), TT mothers reported significantly more problems with latching, prolonged breastfeeding, and infant's exhaustion during feedings, but not pain or sore nipples. Breastfeeding rates at 6 months were similar. TT mothers more frequently used pumped breastmilk to supplement breastfeeding. Significantly more TT mothers sought consultation after discharge, and a significantly greater proportion of them felt that lactation consultation helped. Eighty-seven percent of the mothers were aware of their children's TT, yet only 50% associated it with breastfeeding problems. Of the TT infants at 2 years of age or older, 11.9% were reported to have speech problems. The possibility of frenotomy was mentioned to 69% of mothers, and it was performed in 35% of cases. Procedure satisfaction was generally poor, except for when done to solve breastfeeding problems. CONCLUSIONS: TT infants had significantly more breastfeeding problems in the first month, but similar rates and durations of breastfeeding. Early diagnosis and lactation consultation may assist mother infant dyads substantially. Mothers whose infants underwent frenotomies for breastfeeding more frequently found the procedure alleviated breastfeeding problems. PMID- 25290828 TI - Challenges of Huntington's disease and quest for therapeutic biomarkers. AB - Huntington's disease (HD) is the most common inherited neurodegenerative disorder among polyglutamine (polyQ) diseases caused by cytosine-adenine-guanine repeat expansion in exon 1 of the huntingtin gene whose translation results in polyQ stretch in the N-terminus of the huntingtin protein (HD protein). This mutation significantly affects huntingtin conformation, proteolysis, PTMs, as well as its ability to bind interacting proteins. As a consequence, a variety of cellular mechanisms such as transcription, mitochondrial energy metabolism, axonal transport, neuronal vulnerability to oxidative stress, neurotransmission, and immune response are altered and involved in the pathogenesis of HD. Promising candidate molecular biomarkers of HD have emerged from proteomic studies. Recent analyses focused on HD protein itself, its PTM, and interacting proteins, which are of great importance for disease course. Furthermore, brain, body fluids, and immune system are intensively studied in order to search for additional proteins with a view to their use as a biomarker(s) or set of biomarkers in clinical trials in HD translational research. PMID- 25290830 TI - Metchnikoff, Bordet, Oudin and immunology today: the Pasteur Institute's first 100 years. PMID- 25290831 TI - Functional characteristics of cells infiltrating rejected allografts. PMID- 25290832 TI - A model for the transcriptional regulation of MHC class II genes. AB - The analysis of la antigens has focused primarily on their structure and function. However, the quantitative differences in immune response gene expression are equally important, since variation of cell surface la influences immunoregulation and the expression of immunologically mediated disease. Here, Kate Sullivan and her colleagues review the current knowledge of and propose a model for the transcriptional regulation of immune response gene expression. PMID- 25290833 TI - The T-cell antigen receptor gamma gene: rearrangement and cell lineages. AB - Most adult T cells have a T-cell antigen receptor composed of alphabeta heterodimers in a complex with the CD3 antigen. Immature thymocytes, however, can express CD3-associated heterodimers of a gamma chain and another poorly characterized chain ('delta'). Here James Allison and Lewis Lanier suggest that thymocytes can develop along two mutually exclusive ontological pathways, giving rise to T cells that express either alphabeta or gammadelta heterodimers, but not both or any other heterodimeric combination. PMID- 25290834 TI - The treatment of adenosine deaminase deficiency. PMID- 25290835 TI - A year in the life of the immunoglobulin superfamily. AB - The superfamily of molecules with immunoglobulin-like domains has recently been gaining new members-largely on the basis of sequence homology. Here Alan Williams reviews this new work and reveals how the comparison of sequence patterns enables decisions on membership to be made. Accommodation of the new structures demands the provision of new categories, and forces the abandonment of the conserved disulphide bond as the last invariant characteristic of an immunoglobulin-type domain. They may, however, provide more dues to the origins and evolution of the immunoglobulin superfamily. PMID- 25290836 TI - Regulatory structures on the V and C regions of immunoglobulin molecules. AB - As well as antibody-combining sites, an immunoglobulin (lg) molecule has several other structural features which permit it to bind to lymphoid cells, certain of their factors and other lg molecules. Here, Paolo del Guercio reviews these interactions and suggests that they help to regulate the production of lg molecules to extrinsic antigens and internal self structures. PMID- 25290837 TI - The surface antigens of human B lymphocytes. AB - During the past few years identification and characterization of the surface antigens of B lymphocytes using monoclonal antibodies has continued apace. International Workshops on Leucocyte Differentiation Antigens have categorized many antibodies using the cluster of differentiation (CD) system. Here Heddy Zola reviews the recent advances in antigen identification - including those defined by unclustered antibodies as well as CD antigens - and indicates that the bulk of future work will revolve around attempts to place them within a functional framework. PMID- 25290840 TI - Idiotypes and diseases. AB - Two of the founders of modern immunology, Henry G. Kunkel and Jacques Oudin, died recently. Since they were responsible for the discovery and naming of immunoglobulin idiotypes it was appropriate at a recent meeting to consider our present understanding of the role of idiotypes in the immune system. PMID- 25290841 TI - Clinical immunology in Venezuela. PMID- 25290842 TI - MHC class II nomenclature in the rat. PMID- 25290843 TI - Specific and stable CTL tolerance induced by veto mechanism. PMID- 25290844 TI - Properties of antigens that determine processing. PMID- 25290845 TI - HIV infection: facts and hypotheses. AB - The etiological agent of the acquired immunodeficiency syndrome (AIDS) was first isolated in 1983 and called lymphadenopathy associated virus (LAV). Other isolates of similar viruses have been named HTLV-III or ARV. Numerous studies of their biological and molecular characteristics have confirmed that they are all different isolates of the same virus for which the name human immunodeficiency virus (HIV) has recently been proposed by an international committee. The current understanding of HIV's biological properties, supported by epidemiological and clinical observations, enables David Klatzmann and John Gluckman to propose a general model for its pathogenicity: a complex pathway of interaction between host and virus properties controls the stepwise evolution from primary infection to disease. PMID- 25290847 TI - How significant are 'autoreactive' T cells? PMID- 25290846 TI - Polymorphisms of the HLA-DQ subregion. AB - The HLA-D region (analogous to the I region of the mouse H-2 complex gene) is now known to contain three subregions, one of which is HLA-DQ. The products of the HLA-DQ subregion are important in T-cell recognition. Three DQ specificities have been recognized by the International Histocompatibility Workshop but additional polymorphisms of DQ gene products have also been described. In this article, Massimo Trucco and Rene Duquesnoy discuss the relationship between serologically, cellularly and molecularly defined polymorphisms of HLA-DQ. PMID- 25290848 TI - Regulation of fibroblast proliferation and collagen synthesis by cytokines. AB - Fibroblasts are ubiquitous mesenchymal cells which synthesize collagen and other matrix macromolecules for the structural support of connective tissues. They are important in wound repair but also contribute connective tissue proteins to areas of chronic inflammation. In pathological processes such as hepatic cirrhosis, this may become deleterious to the host. Certain fibrotic diseases such as scleroderma and some forms of interstitial pneumonitis and interstitial nephritis are characterized by the presence of prominent mononuclear cell infiltrates. Studies in several laboratories have recently established that mononuclear cells produce soluble mediators capable of regulating several fibroblast functions including migration, proliferation and collagen synthesis. However, many of the studies on the immunoregulation of fibroblasts appear to present contradictory or mutually exclusive data. In this review Bruce Freundlich and his colleagues discuss the difficulties in identifying the factors that regulate fibroblast proliferation and collagen synthesis. PMID- 25290849 TI - The role of T-cell receptor alpha and beta genes in MHC-restricted antigen recognition. AB - T cells use alpha- and beta-chain genes, which are organized and diversified by somatic DNA rearrangements much like the immunoglobulin genes, to encode clonally distributed receptor molecules which confer specificity for MHC and antigen. Here Zlatko Dembic and his colleagues summarize recent mutagenesis and gene transfection experiments indicating that alpha- and beta-chain genes are necessary and sufficient for T-cell specificity. PMID- 25290850 TI - Natural suppressor (NS) cells members of the LGL regulatory family. AB - Natural suppressor (NS) activity is defined as the ability of unprimed 'null' cells to suppress the response of lymphocytes to immunogenic and mitogenic stimuli. Cells with this ability have been studied for a number of years(1-16). In this review, Tom Maier and his colleagues examine some aspects of non-specific suppression and relate them to NS activity. They also consider NS cells as part of a 'natural' non-specific suppressor-cell family along with natural killer and natural cytotoxic cells. This family has the large granular lymphocyte (LGL) phenotype. PMID- 25290852 TI - Is diabetes color-blind? Growth of prevalence of diagnosed diabetes in children through 2030. AB - Diabetes knows no age and affects millions of individuals. Preventing diabetes in children is increasingly becoming a major health policy concern and focus. The objective of this study is to project the number of children, aged 0-17 years, with diagnosed diabetes in the United States through 2030, accounting for changing demography, and diabetes and obesity prevalence rates. The study team combined historic diabetes and obesity prevalence data with US child population estimates and projections. A times-series regression model was used to forecast future diabetes prevalence and to account for the relationship between the forecasted diabetes prevalence and the lagged prevalence of childhood obesity. Overall, the prevalence of diagnosed diabetes is projected to increase 67% from 0.22% in 2010 to 0.36% in 2030. Lagged obesity prevalence in Hispanic boys and non-Hispanic black girls was significantly associated with increasing future diabetes prevalence. The study results showed that a 1% increase in obesity prevalence among Hispanic boys from the previous year was significantly associated with a 0.005% increase in future prevalence of diagnosed diabetes in children (P <= 0.01). Likewise, a unit increase in obesity prevalence among non Hispanic black girls was associated with a 0.003% increase in future diabetes prevalence (P < 0.05). Obesity rates for other race/ethnicity combinations were not associated with increasing future diabetes prevalence. To mitigate the continued threat posed by diabetes, serious discussions need to focus on the pediatric population, particularly non-Hispanic black girls and Hispanic boys whose obesity trends show the strongest associations with future diabetes prevalence in children. PMID- 25290853 TI - Assessing the blinking state of fluorescent quantum dots in free solution by combining fluorescence correlation spectroscopy with ensemble spectroscopic methods. AB - The current method for investigating the blinking behavior is to immobilize quantum dots (QDs) in the matrix and then apply a fluorescent technique to monitor the fluorescent trajectories of individual QDs. So far, no method can be used to directly assess the blinking state of ensemble QDs in free solution. In this study, a new method was described to characterize the blinking state of the QDs in free solution by combining single molecule fluorescence correlation spectroscopy (FCS) with ensemble spectroscopic methods. Its principle is based on the observation that the apparent concentration of bright QDs obtained by FCS is less than its actual concentration measured by ensemble spectroscopic method due to the QDs blinking. We proposed a blinking index (Kblink) for characterizing the blinking state of QDs, and Kblink is defined as the ratio of the actual concentration (Cb,actual) measured by the ensemble spectroscopic method to the apparent concentration (Cb,app) of QDs obtained by FCS. The effects of certain factors such as laser intensity, growth process, and ligands on blinking of QDs were investigated. The Kblink data of QDs obtained were successfully used to characterize the blinking state of QDs and explain certain experimental results. PMID- 25290854 TI - Characterizing the immunological effects of oral healthcare ingredients using an in vitro reconstructed human epithelial model. AB - Oral healthcare products are well tolerated and while adverse occurrences are rare there is still a need to explore the interaction between these products and the oral mucosa. This study assessed the effects of oral healthcare ingredients: sodium lauryl sulphate (SLS), a detergent; cinnamic aldehyde (CA), a flavouring agent; and cetylpyridinium chloride (CPC), an antiseptic, using a reconstructed human oral mucosal model (OMM). Differential release of inflammatory cytokines IL 1alpha, IL-8 and cytotoxicity was compared with other known irritants and sensitizers to identify a signature response profile that could be associated with oral mucosal irritation. Response profiles differed with irritants being more cytotoxic. CA and control sensitizers nickel sulphate (NiSO4) and 1-chloro 2,4-dinitrochlorobenzene (DNCB) released lower levels of IL-1alpha than CPC and control irritant benzalkonium chloride (BC), whereas the opposite was observed for IL-8. Significant levels of IL-8 and IL-1alpha were released with 5-15 mg/ml (0.5-1.5% w/v) SLS. Quantitative PCR indicated that cytokine release at lower SLS concentrations is not entirely due to cell necrosis but in part due to de novo synthesis. These findings suggest that the OMM can be used to predict oral irritation thus making it a potentially valuable model for screening new oral healthcare ingredients prior to clinical release. PMID- 25290855 TI - Dietary patterns and pulmonary function in Korean women: findings from the Korea National Health and Nutrition Examination Survey 2007-2011. AB - In the present study, we evaluated the association between dietary patterns and pulmonary functions in Korean women older than 40 years. This study analyzed the data from the Korea National Health and Nutrition Examination Survey IV and V (2007-2010). In total, 7615 women were included in the analysis. Using principal component analysis, two dietary patterns were identified, namely a balanced diet pattern (vegetables, fish, meat, seaweed, and mushrooms) and a refined diet (snacks, bread, milk, dairy products, and fast food). The refined diet pattern was positively associated with energy from fat but negatively associated with vitamin A, beta-carotene, niacin, and fiber. After adjusting for potential confounders, the refined diet pattern was negatively associated with levels of predicted forced vital capacity (odds ratio (OR): 0.84, 95% confidence intervals (CIs): 0.70, 0.99) and predicted forced expiratory volume in 1 second (OR: 0.79, 95% CIs: 0.66, 0.93). In conclusion, the refined diet pattern was associated with decreased pulmonary function in Korean women. This information may be useful toward the development of nutritional guidelines for improving pulmonary function in Korean women. PMID- 25290856 TI - An in silico skin absorption model for fragrance materials. AB - Fragrance materials are widely used in cosmetics and other consumer products. The Research Institute for Fragrance Materials (RIFM) evaluates the safety of these ingredients and skin absorption is an important parameter in refining systemic exposure. Currently, RIFM's safety assessment process assumes 100% skin absorption when experimental data are lacking. This 100% absorption default is not supportable and alternate default values were proposed. This study aims to develop and validate a practical skin absorption model (SAM) specific for fragrance material. It estimates skin absorption based on the methodology proposed by Kroes et al. SAM uses three default absorption values based on the maximum flux (J(max)) - namely, 10%, 40%, and 80%. J(max) may be calculated by using QSAR models that determine octanol/water partition coefficient (K(ow)), water solubility (S) and permeability coefficient (K(p)). Each of these QSAR models was refined and a semi-quantitative mechanistic model workflow is presented. SAM was validated with a large fragrance-focused data set containing 131 materials. All resulted in predicted values fitting the three-tiered absorption scenario based on Jmax ranges. This conservative SAM may be applied when fragrance material lack skin absorption data. PMID- 25290857 TI - Antibody and latent herpes simplex virus infections. PMID- 25290858 TI - Suppressor cells and treatment of multiple sclerosis. PMID- 25290859 TI - Antigens and embryos. PMID- 25290860 TI - The I-J subregion and surveillance. AB - A discussion of the control exerted by the I-J subregion of the H-2 complex over suppression, tolerance and self/non-self discrimination, and its implications in the study of tumour immunity and autoimmunity. PMID- 25290861 TI - The effect of HLA matching on kidney-graft survival. AB - All human skin grafts, even those perfectly matched for HLA antigens, are eventually rejected, some acutely, while over half the completely mismatched transplanted kidneys survive for more than a year. There is no doubt that the HLA system is the major human histocompatibility complex but, as Alan Ting shows in this article, the assessment of its influence on graft outcome is complex. PMID- 25290862 TI - Antigen uptake in the gut: immunologic implications. AB - Since the principal function of the gastrointestinal tract is that of digestion and absorption of nutrients, it is often assumed that intraluminal protein antigens are completely digested and thus are not transported in appreciable quantity across the epithelium into the lamina propria or systemic circulation. There is now, however, increasing experimental and clinical evidence to suggest that large antigenic molecules can penetrate the intestinal epithelial surface in quantities of no nutritional importance, but possibly immunological significance(1-3). In this review Allan Walker discusses our current understanding of small intestinal permeability to antigens and the potential importance of excessive absorption of macromolecules in mechanisms of immunologically mediated clinical disease. PMID- 25290863 TI - Desensitization treatment for hay fever. AB - In this review T. A. E. Platts-Mills discusses the history behind desensitization treatment for hay fever, theories about how it works and its usefulness in the light of recent pharmacological advances. PMID- 25290864 TI - Human monoclonal antibodies produced by immortalization with Epstein-Barr virus. PMID- 25290867 TI - From clones to clinic. PMID- 25290868 TI - Protection and prevention. PMID- 25290866 TI - Modeling hospital-acquired pressure ulcer prevalence on medical-surgical units: nurse workload, expertise, and clinical processes of care. AB - OBJECTIVE: This study modeled the predictive power of unit/patient characteristics, nurse workload, nurse expertise, and hospital-acquired pressure ulcer (HAPU) preventive clinical processes of care on unit-level prevalence of HAPUs. DATA SOURCES: Seven hundred and eighty-nine medical-surgical units (215 hospitals) in 2009. STUDY DESIGN: Using unit-level data, HAPUs were modeled with Poisson regression with zero-inflation (due to low prevalence of HAPUs) with significant covariates as predictors. DATA COLLECTION/EXTRACTION METHODS: Hospitals submitted data on NQF endorsed ongoing performance measures to CALNOC registry. PRINCIPAL FINDINGS: Fewer HAPUs were predicted by a combination of unit/patient characteristics (shorter length of stay, fewer patients at-risk, fewer male patients), RN workload (more hours of care, greater patient [bed] turnover), RN expertise (more years of experience, fewer contract staff hours), and processes of care (more risk assessment completed). CONCLUSIONS: Unit/patient characteristics were potent HAPU predictors yet generally are not modifiable. RN workload, nurse expertise, and processes of care (risk assessment/interventions) are significant predictors that can be addressed to reduce HAPU. Support strategies may be needed for units where experienced full-time nurses are not available for HAPU prevention. Further research is warranted to test these finding in the context of higher HAPU prevalence. PMID- 25290865 TI - The international society for developmental psychobiology Sackler symposium: early adversity and the maturation of emotion circuits--a cross-species analysis. AB - Early-life caregiving shapes the architecture and function of the developing brain. The fact that the infant-caregiver relationship is critically important for infant functioning across all altricial species, and that the anatomical circuits supporting emotional functioning are highly preserved across different species, suggests that the results of studies examining the role of early adversity and emotional functioning should be translatable across species. Here we present findings from four different research laboratories, using three different species, which have converged on a similar finding: adversity accelerates the developmental trajectory of amygdala-prefrontal cortex (PFC) development and modifies emotional behaviors. First, a rodent model of attachment learning associated with adversity is presented showing precocial disruption of attachment learning and emergence of heightened fear learning and emotionality. Second, a model of infant-mother separation is presented in which early adversity is shown to accelerate the developmental emergence of adult-like fear retention and extinction. Third, a model of early life adversity in Rhesus monkeys is presented in which a naturally occurring variation in maternal-care (abuse) is shown to alter the functioning of emotion circuits. Finally, a human model of maternal deprivation is presented in which children born into orphanages and then adopted abroad exhibit aberrant development of emotion circuits. The convergence of these cross-species studies on early life adversity suggests that adversity targets the amygdala and PFC and has immediate impact on infant behavior with the caregiver, and emotional reactions to the world. These results provide insight into mechanisms responsible for caregiver induced mental health trajectory alterations. PMID- 25290869 TI - The state of transfer factor. PMID- 25290870 TI - Binding of peanut lectin to lymphocytes: a marker of immaturity? PMID- 25290871 TI - Tumour-induced specific suppression: a limitation to immunotherapy. PMID- 25290872 TI - T-cell recognition of epitopes on MHC encoded molecules. PMID- 25290873 TI - The T-cell antigen receptor: the minimal hypothesis revisited. AB - A review in which J. J. Marchalonis discusses what has been learnt about the T cell receptor for antigen through the search for immunoglobulin-related recognition structures on antigen-specific T cells. PMID- 25290874 TI - Regulation of delayed-type hypersensitivity to pathogens and alloantigens. AB - Recent studies reinforce the notion that delayed-type hypersensitivity plays a key role in the host defence against microbial and intracellular parasitic infection, and in the rejection of skin allografts. F. Y. Liew reviews these studies and discusses the observation that this T-cell mediated immunity is profoundly regulated by antigen-specific suppressor T cells, some of which are restricted by products of the I-J subregion of the MHC. PMID- 25290882 TI - Tracking targeted bimodal nanovaccines: immune responses and routing in cells, tissue, and whole organism. AB - Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and currently exploited for antitumor immunotherapies. An optimized noninvasive imaging modality capable of determining and quantifying DC-targeted nanoparticle (NP) trajectories could provide valuable information regarding therapeutic vaccine outcome. Here, targeted poly(d,l lactide-co-glycolide) nanoparticles (PLGA NPs) recognizing DC receptors were equipped with superparamagnetic iron oxide particles (SPIO) or gold nanoparticles with fluorescently labeled antigen. The fluorescent label allowed for rapid analysis and quantification of DC-specific uptake of targeted PLGA NPs in comparison to uptake by other cells. Transmission electron microscopy (TEM) showed that a fraction of the encapsulated antigen reached the lysosomal compartment of DCs, where SPIO and gold were already partially released. However, part of the PLGA NPs localized within the cytoplasm, as confirmed by confocal microscopy. DCs targeted with NPs carrying SPIO or fluorescent antigen were detected within lymph nodes as early as 1 h after injection by magnetic resonance imaging (MRI). Despite the fact that targeting did not markedly affect PLGA NP biodistribution on organism and tissue level, it increased delivery of NPs to DCs residing in peripheral lymph nodes and resulted in enhanced T cell proliferation. In conclusion, two imaging agents within a single carrier allows tracking of targeted PLGA NPs at the subcellular, cellular, and organismal levels, thereby facilitating the rational design of in vivo targeted vaccination strategies. PMID- 25290881 TI - Neurobiology of dyslexia. AB - Dyslexia is one of the most common learning disabilities, yet its brain basis and core causes are not yet fully understood. Neuroimaging methods, including structural and functional magnetic resonance imaging, diffusion tensor imaging, and electrophysiology, have significantly contributed to knowledge about the neurobiology of dyslexia. Recent studies have discovered brain differences before formal instruction that likely encourage or discourage learning to read effectively, distinguished between brain differences that likely reflect the etiology of dyslexia versus brain differences that are the consequences of variation in reading experience, and identified distinct neural networks associated with specific psychological factors that are associated with dyslexia. PMID- 25290883 TI - Substitution of the Lys linker with the beta-Ala linker dramatically decreased the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated alpha-melanocyte stimulating hormone peptides. AB - The purpose of this study was to examine whether the substitution of the Lys linker with the beta-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X Asp-conjugated and X-Ala-Asp-conjugated alpha-melanocyte stimulating hormone (alpha-MSH) peptides. RSD-beta-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp] beta-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-beta-Ala (Arg(11))CCMSH (2), RVD-beta-Ala-(Arg(11))CCMSH (3), RAD-beta-Ala-(Arg(11))CCMSH (4), NAD-beta-Ala-(Arg(11))CCMSH (5), and EAD-beta-Ala-(Arg(11))CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their (99m)Tc conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with beta-Ala linker dramatically reduced the renal uptake of all six (99m)Tc-peptides. (99m)Tc-4 exhibited the highest melanoma uptake (15.66 +/- 6.19% ID/g) and the lowest kidney uptake (20.18 +/- 3.86% ID/g) among these (99m)Tc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using (99m)Tc-4 as an imaging probe. PMID- 25290884 TI - Biodegradable lysine-derived polyurethane scaffolds promote healing in a porcine full-thickness excisional wound model. AB - Lysine-derived polyurethane scaffolds (LTI-PUR) support cutaneous wound healing in loose-skinned small animal models. Due to the physiological and anatomical similarities of human and pig skin, we investigated the capacity of LTI-PUR scaffolds to support wound healing in a porcine excisional wound model. Modifications to scaffold design included the addition of carboxymethylcellulose (CMC) as a porogen to increase interconnectivity and an additional plasma treatment (Plasma) to decrease surface hydrophobicity. All LTI-PUR scaffold and formulations supported cellular infiltration and were biodegradable. At 15 days, CMC and plasma scaffolds simulated increased macrophages more so than LTI PUR or no treatment. This response was consistent with macrophage-mediated oxidative degradation of the lysine component of the scaffolds. Cell proliferation was similar in control and scaffold-treated wounds at 8 and 15 days. Neither apoptosis nor blood vessel area density showed significant differences in the presence of any of the scaffold variations compared with untreated wounds, providing further evidence that these synthetic biomaterials had no adverse effects on those pivotal wound healing processes. During the critical phase of granulation tissue formation in full thickness porcine excisional wounds, LTI-PUR scaffolds supported tissue infiltration, while undergoing biodegradation. Modifications to scaffold fabrication modify the reparative process. This study emphasizes the biocompatibility and favorable cellular responses of PUR scaffolding formulations in a clinically relevant animal model. PMID- 25290885 TI - Serum levels of caspase-cleaved cytokeratin-18 and mortality are associated in severe septic patients: pilot study. AB - OBJECTIVE: Apoptosis is increased in sepsis. Cytokeratin 18 (CK-18), a protein of the intermediate filament group present in most epithelial and parenchymal cells, is cleaved by the action of caspases and released into the blood as caspase cleaved CK (CCCK)-18 during apoptosis. Circulating levels of CCCK-18 have scarcely been explored in septic patients. In one study with 101 severe septic patients, the authors reported higher serum CCCK-18 levels in non-survivors than in survivors; however, the sample size was too small to demonstrate an association between serum CCCK-18 levels and early mortality and whether they could be used as a biomarker to predict outcomes in septic patients. Thus, these were the objectives of this study with a large series of patients. METHODS: We performed a prospective, multicenter, observational study in six Spanish Intensive Care Units with 224 severe septic patients. Blood samples were collected at the time that severe sepsis was diagnosed to determine serum levels of CCCK-18, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10. The end point was 30-day mortality. RESULTS: Non-surviving patients (n = 80) showed higher serum CCCK-18 levels (P<0.001) than survivors (n = 144). Multiple logistic regression analysis showed that serum CCCK-18 levels>391 u/L were associated with 30-day survival (Odds ratio = 2.687; 95% confidence interval = 1.449-4.983; P = 0.002), controlling for SOFA score, serum lactic acid levels and age. Kaplan Meier survival analysis showed that the risk of death in septic patients with serum CCCK-18 levels >391 u/L was higher than in patients with lower values (Hazard Ratio = 3.1; 95% CI = 1.96-4.84; P<0.001). Serum CCCK-18 levels were positively associated with serum levels of IL-6 and lactic acid, and with SOFA and APACHE scores. CONCLUSIONS: The major novel finding of our study, the largest cohort of septic patients providing data on circulating CCCK-18 levels, was that serum CCCK-18 levels are associated with mortality in severe septic patients. PMID- 25290886 TI - Decreased centrality of subcortical regions during the transition to adolescence: a functional connectivity study. AB - Investigations of brain maturation processes are a key step to understand the cognitive and emotional changes of adolescence. Although structural imaging findings have delineated clear brain developmental trajectories for typically developing individuals, less is known about the functional changes of this sensitive development period. Developmental changes, such as abstract thought, complex reasoning, and emotional and inhibitory control, have been associated with more prominent cortical control. The aim of this study is to assess brain networks connectivity changes in a large sample of 7- to 15-year-old subjects, testing the hypothesis that cortical regions will present an increasing relevance in commanding the global network. Functional magnetic resonance imaging (fMRI) data were collected in a sample of 447 typically developing children from a Brazilian community sample who were submitted to a resting state acquisition protocol. The fMRI data were used to build a functional weighted graph from which eigenvector centrality (EVC) was extracted. For each brain region (a node of the graph), the age-dependent effect on EVC was statistically tested and the developmental trajectories were estimated using polynomial functions. Our findings show that angular gyrus become more central during this maturation period, while the caudate; cerebellar tonsils, pyramis, thalamus; fusiform, parahippocampal and inferior semilunar lobe become less central. In conclusion, we report a novel finding of an increasing centrality of the angular gyrus during the transition to adolescence, with a decreasing centrality of many subcortical and cerebellar regions. PMID- 25290887 TI - MEG source reconstruction based on identification of directed source interactions on whole-brain anatomical networks. AB - We present an MEG source reconstruction method that simultaneously reconstructs source amplitudes and identifies source interactions across the whole brain. In the proposed method, a full multivariate autoregressive (MAR) model formulates directed interactions (i.e., effective connectivity) between sources. The MAR coefficients (the entries of the MAR matrix) are constrained by the prior knowledge of whole-brain anatomical networks inferred from diffusion MRI. Moreover, to increase the accuracy and robustness of our method, we apply an fMRI prior on the spatial activity patterns and a sparse prior on the MAR coefficients. The observation process of MEG data, the source dynamics, and a series of the priors are combined into a Bayesian framework using a state-space representation. The parameters, such as the source amplitudes and the MAR coefficients, are jointly estimated from a variational Bayesian learning algorithm. By formulating the source dynamics in the context of MEG source reconstruction, and unifying the estimations of source amplitudes and interactions, we can identify the effective connectivity without requiring the selection of regions of interest. Our method is quantitatively and qualitatively evaluated on simulated and experimental data, respectively. Compared with non dynamic methods, in which the interactions are estimated after source reconstruction with no dynamic constraints, the proposed dynamic method improves most of the performance measures in simulations, and provides better physiological interpretation and inter-subject consistency in real data applications. PMID- 25290889 TI - Immunotoxicity Undesirable effects of inappropriate responses. PMID- 25290888 TI - Overweight and obesity may lead to under-diagnosis of airflow limitation: findings from the Copenhagen City Heart Study. AB - BACKGROUND: The prevalence of obesity has increased during the last decades and varies from 10-20% in most European countries to approximately 32% in the United States. However, data on how obesity affects the presence of airflow limitation (AFL) defined as a reduced ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) are scarce. METHODS: Data was derived from the third examination of the Copenhagen City Heart Study from 1991 until 1994 (n = 10,135). We examine the impact of different adiposity markers (weight, body mass index (BMI), waist circumference, waist-hip ratio, and abdominal height) on AFL. AFL was defined in four ways: FEV1/FVC ratio < 0.70, FEV1/FVC ratio < lower limit of normal (LLN), FEV1/FVC ratio <0.70 including at least one respiratory symptom, and FEV1/FVC ratio < LLN and FEV1% of predicted < LLN. RESULTS: All adiposity markers were positively and significantly associated with FEV1/FVC independent of age, sex, height, smoking status, and cumulative tobacco consumption. Among all adiposity markers, BMI was the strongest predictor of FEV1/FVC. FEV1/FVC increased with 0.04 in men and 0.03 in women, as BMI increased with 10 units (kg . m-2). Consequently, diagnosis of AFL was significantly less likely in subjects with BMI >= 25 kg . m-2 with odds ratios 0.63 or less compared to subjects with BMI between 18.5-24.9 kg . m-2 when AFL was defined as FEV1/FVC < 0.70. CONCLUSION: High BMI reduces the probability of AFL. Ultimately, this may result in under-diagnosis and under-treatment of COPD among individuals with overweight and obesity. PMID- 25290890 TI - Ir genes New tests of familiar arguments. PMID- 25290891 TI - The delineation of antigen receptors on human T lymphocytes. AB - Monoclonal antibodies have identified several surface molecules involved in target cell recognition by cytotoxic human T cells. In this article it is proposed that T cells have two recognition units: a complex composed of the T3 molecule and a clonally unique glycoprotein which binds antigen associated with polymorphic MHC gene product; and the T4 or T8 molecule which binds to a constant region of an MHC gene product. PMID- 25290892 TI - DNA strand breaks and differentiation. PMID- 25290893 TI - Monoclonal antibodies to B cells. AB - Monoclonal antibodies (Mab) have defined functional T lymphocyte subsets in mouse and man: Ly-1/OKT4 positive helper T cells, Ly-123/OKT8 positive killer T cells and Ly-23/OKT8 positive suppressor T cells. An equivalent array of useful reagents for B-cell subsets is not yet available-although many laboratories are trying to produce them. In this review Ian Mckenzie and Heddy Zola summarize the Mob which are available and which detect polymorphic or monomorphic determinants on the B-cell surface in both man and mouse. PMID- 25290894 TI - Thymic hormones: inducers and. AB - The first evidence of the thymus's pivotal role in immune, function was gathered by experiment and clinical observation more than 20 years ago. Nathan Trainin and his colleagues have helped to establish the link between the endocrine mechanism of the thymus gland and its immunological function. Here they describe the chemistry, biochemistry, and biological effects o f hormones isolated from or originating in the thymus(1-3). PMID- 25290895 TI - Receptor-cytoskeleton interactions in the lymphocyte. AB - Plasma membrane receptors are essential for lymphocytes, providing the specificity through which the cells interact with antigens and regulatory molecules, and initiating the events which alter the lymphocytes' activity and state of differentiation. Here, Jonathan Braun discusses the lymphocyte contractile system and how it influences these membrane receptors. PMID- 25290901 TI - Bilateral Posterior Scleritis Presenting as the First Manifestation of Immunoglobulin A Nephropathy: Case Report and Review of the Literature. AB - PURPOSE: We describe a case of posterior scleritis presenting as the first manifestation in a Chinese patient with immunoglobin A nephropathy (IgAN). METHODS: Retrospective review of our patient and review of the published case reports from PubMed search. RESULTS: A 43-year-old woman developed bilateral posterior scleritis. Microscopic hematuria and proteinuria was found by urinalysis, and a kidney biopsy revealed IgAN. The posterior scleritis was resolved with oral prednisolone. For the review, 12 cases of episcleritis (70.6%), 4 cases of scleritis (23.5%), and 1 case of posterior scleritis (5.9%) associated with IgAN were analyzed. Five patients (29.4%) had scleritis or episcleritis as the first presenting manifestation. CONCLUSIONS: Posterior scleritis may be the first manifestation of IgAN in a patient. For any adult patient with scleral/episcleral inflammation, urinalysis should be done to rule out IgAN. PMID- 25290903 TI - Intraplant movement of generalist slug caterpillars (Limacodidae: Lepidoptera): effects of host plant and light environment. AB - Insect herbivores frequently move about on their host plants to obtain food, avoid enemies and competitors, and cope with changing environmental conditions. Although numerous plant traits influence the movement of specialist herbivores, few studies have examined movement responses of generalist herbivores to the variable ecological conditions associated with feeding and living on an array of host plants. We tested whether the movement patterns of two generalist caterpillars (Euclea delphinii Boisduval and Acharia stimulea Clemens, Limacodidae) differed on six different host tree species over 10 d. Because these tree species vary in the range of light environments in which they commonly grow, we also compared the movement responses of E. delphinii caterpillars to two contrasting light environments, sun and shade. For both caterpillar species, multiple measures of movement varied significantly among host tree species. In early censuses, movement rates and distances were highest on red oak and black cherry and lowest on white oak. Site fidelity was greatest on white oak and lowest on black cherry. Movement of both caterpillar species varied inversely with mean predator density on five of the six host trees. Other ecological predictors (e.g., leaf size and the density of other herbivores) were unrelated to movement. Light environment altered behavior such that caterpillars in the shade moved and fed more often, and moved greater distances, than caterpillars in the sun. Although the mechanism(s) promoting or inhibiting movement under these different conditions requires further study, the consequences of increased movement for caterpillar development and mortality from natural enemies are discussed. PMID- 25290902 TI - Epidemiology and control of Mycobacterium bovis infection in brushtail possums (Trichosurus vulpecula), the primary wildlife host of bovine tuberculosis in New Zealand. AB - The introduced Australian brushtail possum (Trichosurus vulpecula) is a maintenance host for bovine tuberculosis (TB) in New Zealand and plays a central role in the TB problem in this country. The TB-possum problem emerged in the late 1960s, and intensive lethal control of possums is now used to reduce densities to low levels over 8 million ha of the country. This review summarises what is currently known about the pathogenesis and epidemiology of TB in possums, and how the disease responds to possum control. TB in possums is a highly lethal disease, with most possums likely to die within 6 months of becoming infected. The mechanisms of transmission between possums remain unclear, but appear to require some form of close contact or proximity. At large geographic scales, TB prevalence in possum populations is usually low (1-5%), but local prevalence can sometimes reach 60%. Intensive, systematic and uniform population control has been highly effective in breaking the TB cycle in possum populations, and where that control has been sustained for many years the prevalence of TB is now zero or near zero. Although some uncertainties remain, local eradication of TB from possums appears to be straightforward, given that TB managers now have the ability to reduce possum numbers to near zero levels and to maintain them at those levels for extended periods where required. We conclude that, although far from complete, the current understanding of TB-possum epidemiology, and the current management strategies and tactics, are sufficient to achieve local, regional, and even national disease eradication from possums in New Zealand. PMID- 25290907 TI - Organophosphorus flame retardants and plasticizers: sources, occurrence, toxicity and human exposure. AB - Due to the restricted use and ban of brominated flame retardants, organophosphorus compounds (OPs), extensively used as flame retardants and plasticizers, are ubiquitous in various environmental compartments worldwide. The present study shows that the release of OPs from a wide variety of commercial products and wastewater discharge might be considered as primary emission sources and that high potential of long-range atmospheric transport and persistence of OPs would be responsible for their presence in various matrices on a global scale. The occurrence and environmental behaviors of OPs in diverse matrices (e.g., dust, air, water, sediment, soil and biota) are reviewed. Human exposures to OPs via dermal contact, dust ingestion, inhalation and dietary intake are comprehensively evaluated. Finally, this study identifies gaps in the existing issues and generates a future agenda for the emerging contaminants OPs. PMID- 25290910 TI - Three-Dimensional Microgel Platform for the Production of Cell Factories Tailored for the Nucleus Pulposus. AB - Intradiscal injection of growth factors or cells has been shown to attenuate symptoms of intervertebral disc degeneration. However, different approaches are needed to overcome limitations such as short-term efficacy and leakage of the injected solutions. The current study aims at creating a platform for the realization of functional cell factories by using in parallel cell delivery and gene therapy approaches. Superfect, a transfecting agent, was used as nonviral gene vector because of its ability to form complexes with plasmid DNA (polyplexes). Polyplexes were loaded into collagen hollow microsphere reservoirs, and their ability to transfect cells was ascertained in vitro. Adipose-derived stem cells were then embedded in three-dimensional (3D) microgels composed of type II collagen/hyaluronan, which mimics the environmental cues typical of the healthy nucleus pulposus. These were functionalized with polyplex-loaded collagen hollow spheres and the secretion of the target protein was assessed quantitatively. Delivery of polyplexes from a reservoir system lowered their toxicity significantly while maintaining high levels of transfection in a monolayer culture. In 3D microgels, lower levels of transfection were observed, however; increasing levels of luciferase were secreted from the microgels over 7 days of culture. These results indicate that 3D microgels, functionalized with polyplex-loaded reservoirs offer a reliable platform for the production of cell factories that are able to manufacture targeted therapeutic proteins for regenerative therapies that have applications in nucleus pulposus repair. PMID- 25290911 TI - Recent developments in the assessment of the multiply injured trauma patient. AB - PURPOSE OF REVIEW: To provide an update on the recent developments and controversies in the assessment of the traumatically injured patient. RECENT FINDINGS: Recent literature suggests that: whole-body computed tomography (CT) is an effective strategy in more severely injured blunt trauma patients; 64-slice CT scanning now provides an effective noninvasive screening method for blunt cerebrovascular injury; the need for MRI imaging, in addition to CT, for the diagnosis of occult ligamentous injury of the cervical spine remains an unresolved controversy; point-of-care testing has made significant improvements in our ability to predict which patients will need a massive transfusion; and thromboelastography has enhanced our ability to tailor a hemostatic resuscitation more accurately. SUMMARY: The recent advances in the assessment of the multiply injured patient allow clinicians to more efficiently diagnose a patient's injuries and implement treatment in a more timely manner. PMID- 25290912 TI - Joint hypermobility syndrome: a review for clinicians. AB - The term 'joint hypermobility' describes synovial joints that move beyond a normal range of motion. 'Joint hypermobilty syndrome' may also be associated with significant symptoms and impaired quality of life. The purpose of this review is to help the generalist to recognise the condition, exclude significant alternative diagnoses and understand the multidisciplinary approach to management. PMID- 25290909 TI - Ultrastructural analysis of Candida albicans when exposed to silver nanoparticles. AB - Candida albicans is the most common fungal pathogen in humans, and recently some studies have reported the antifungal activity of silver nanoparticles (AgNPs) against some Candida species. However, ultrastructural analyses on the interaction of AgNPs with these microorganisms have not been reported. In this work we evaluated the effect of AgNPs on C. albicans, and the minimum inhibitory concentration (MIC) was found to have a fungicidal effect. The IC50 was also determined, and the use of AgNPs with fluconazole (FLC), a fungistatic drug, reduced cell proliferation. In order to understand how AgNPs interact with living cells, the ultrastructural distribution of AgNPs in this fungus was determined. Transmission electron microscopy (TEM) analysis revealed a high accumulation of AgNPs outside the cells but also smaller nanoparticles (NPs) localized throughout the cytoplasm. Energy dispersive spectroscopy (EDS) analysis confirmed the presence of intracellular silver. From our results it is assumed that AgNPs used in this study do not penetrate the cell, but instead release silver ions that infiltrate into the cell leading to the formation of NPs through reduction by organic compounds present in the cell wall and cytoplasm. PMID- 25290913 TI - Impact of periodontal maintenance on tooth survival in patients with removable partial dentures. AB - AIM: Removable partial dentures (RPDs) may have a negative impact on oral health and have the potential to cause further tooth loss, especially of abutment teeth. However, no evidence indicates the effective interval of regular periodontal maintenance after RPD provision. This practice-based cohort study aimed to examine the impact of regular periodontal maintenance visits on survival of RPD abutment teeth. MATERIALS AND METHODS: One hundred and ninety-two patients had been previously provided with 304 new clasp-retained RPDs at Osaka University Dental Hospital, Japan. Using the Kaplan-Meier method and log-rank test, 1094 abutments were analysed to illustrate survival curves and to compare each curve. According to the frequency of periodontal maintenance, study samples were divided into three groups; every 3-6 months (3-6M) group, 1-year (1Y) group and no maintenance (NM) group. RESULTS: Seven-year cumulative survival rates were 83.7% (3-6M), 75.5% (1Y) and 71.9% (NM) respectively. Survival of abutment teeth in the 3-6M group was significantly better than both 1Y (p = 0.005) and NM (p < 0.001) groups. CONCLUSION: These longitudinal clinical data indicates that periodontal maintenance at least once in 6 months had the most favourable outcome. Frequent periodontal maintenance after RPD provision could be effective in preventing further tooth loss. PMID- 25290914 TI - Biochemical and pharmacological characterization of the human lymphocyte antigen B-associated transcript 5 (BAT5/ABHD16A). AB - BACKGROUND: Human lymphocyte antigen B-associated transcript 5 (BAT5, also known as ABHD16A) is a poorly characterized 63 kDa protein belonging to the alpha/beta hydrolase domain (ABHD) containing family of metabolic serine hydrolases. Its natural substrates and biochemical properties are unknown. METHODOLOGY/PRINCIPAL FINDINGS: Amino acid sequence comparison between seven mammalian BAT5 orthologs revealed that the overall primary structure was highly (>=95%) conserved. Activity-based protein profiling (ABPP) confirmed successful generation of catalytically active human (h) and mouse (m) BAT5 in HEK293 cells, enabling further biochemical characterization. A sensitive fluorescent glycerol assay reported hBAT5-mediated hydrolysis of medium-chain saturated (C14:0), long-chain unsaturated (C18:1, C18:2, C20:4) monoacylglycerols (MAGs) and 15-deoxy Delta12,14-prostaglandin J2-2-glycerol ester (15d-PGJ2-G). In contrast, hBAT5 possessed only marginal diacylglycerol (DAG), triacylglycerol (TAG), or lysophospholipase activity. The best MAG substrates were 1-linoleylglycerol (1 LG) and 15d-PGJ2-G, both exhibiting low-micromolar Km values. BAT5 had a neutral pH optimum and showed preference for the 1(3)- vs. 2-isomers of MAGs C18:1, C18:2 and C20:4. Inhibitor profiling revealed that beta-lactone-based lipase inhibitors were nanomolar inhibitors of hBAT5 activity (palmostatin B > tetrahydrolipstatin > ebelactone A). Moreover, the hormone-sensitive lipase inhibitor C7600 (5 methoxy-3-(4-phenoxyphenyl)-3H-[1], [3], [4]oxadiazol-2-one) was identified as a highly potent inhibitor (IC50 8.3 nM). Phenyl and benzyl substituted analogs of C7600 with increased BAT5 selectivity were synthesized and a preliminary SAR analysis was conducted to obtain initial insights into the active site dimensions. CONCLUSIONS/SIGNIFICANCE: This study provides an initial characterization of BAT5 activity, unveiling the biochemical and pharmacological properties with in vitro substrate preferences and inhibitor profiles. Utilization of glycerolipid substrates and sensitivity to lipase inhibitors suggest that BAT5 is a genuine lipase with preference for long-chain unsaturated MAGs and could in this capacity regulate glycerolipid metabolism in vivo as well. This preliminary SAR data should pave the way towards increasingly potent and BAT5-selective inhibitors. PMID- 25290915 TI - The concordance of care for age related macular degeneration with the chronic care model: a multi-centered cross-sectional study. AB - AIMS: The aim of the study was to assess the concordance of care for age related macular degeneration with the evidence-based framework for care for chronic medical conditions known as the chronic care model. Furthermore we aimed to identify factors associated with the concordance of care with the chronic care model. METHODS: Multi-centered cross-sectional study. 169 patients beginning medical treatment for age related macular degeneration were recruited and analyzed. Patients completed the Patient Assessment of Chronic Illness Care (PACIC) questionnaire, reflecting accordance to the chronic care model from a patient's perspective, the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) and Patient Health Questionnaire (PHQ-9). Visual acuity and chronic medical conditions were assessed. Nonparametric tests and correlation analyses were performed, also multivariable regression analysis. RESULTS: The median PACIC summary score was 2.4 (interquartile range 1.75 to 3.25), the lowest PACIC subscale score was "follow-up/coordination" with a median of 1.8 (interquartile range 1.00 to 2.60). In multivariable regression analysis the presence of diabetes type 2 was strongly associated with low PACIC scores (coefficient = -0.85, p = 0.007). CONCLUSION: Generally, care for patients with age related macular degeneration by ophthalmologists is in moderate concordance with the chronic care model. Concerning follow-up and coordination of health service, large improvements are possible. Future research should answer the question how healthcare delivery can be improved effecting relevant benefits to patients with AMD. PMID- 25290916 TI - Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: comparison with human bone marrow and adipose-derived mesenchymal stem cells. AB - We have investigated and compared the neurotrophic activity of human dental pulp stem cells (hDPSC), human bone marrow-derived mesenchymal stem cells (hBMSC) and human adipose-derived stem cells (hAMSC) on axotomised adult rat retinal ganglion cells (RGC) in vitro in order to evaluate their therapeutic potential for neurodegenerative conditions of RGC. Using the transwell system, RGC survival and length/number of neurites were quantified in coculture with stem cells in the presence or absence of specific Fc-receptor inhibitors to determine the role of NGF, BDNF, NT-3, VEGF, GDNF, PDGF-AA and PDGF-AB/BB in stem cell-mediated RGC neuroprotection and neuritogenesis. Conditioned media, collected from cultured hDPSC/hBMSC/hAMSC, were assayed for the secreted growth factors detailed above using ELISA. PCR array determined the hDPSC, hBMSC and hAMSC expression of genes encoding 84 growth factors and receptors. The results demonstrated that hDPSC promoted significantly more neuroprotection and neuritogenesis of axotomised RGC than either hBMSC or hAMSC, an effect that was neutralized after the addition of specific Fc-receptor inhibitors. hDPSC secreted greater levels of various growth factors including NGF, BDNF and VEGF compared with hBMSC/hAMSC. The PCR array confirmed these findings and identified VGF as a novel potentially therapeutic hDPSC-derived neurotrophic factor (NTF) with significant RGC neuroprotective properties after coculture with axotomised RGC. In conclusion, hDPSC promoted significant multi-factorial paracrine-mediated RGC survival and neurite outgrowth and may be considered a potent and advantageous cell therapy for retinal nerve repair. PMID- 25290917 TI - Synthetic aptamer-polymer hybrid constructs for programmed drug delivery into specific target cells. AB - Viruses have evolved specialized mechanisms to efficiently transport nucleic acids and other biomolecules into specific host cells. They achieve this by performing a coordinated series of complex functions, resulting in delivery that is far more efficient than existing synthetic delivery mechanisms. Inspired by these natural systems, we describe a process for synthesizing chemically defined molecular constructs that likewise achieve targeted delivery through a series of coordinated functions. We employ an efficient "click chemistry" technique to synthesize aptamer-polymer hybrids (APHs), coupling cell-targeting aptamers to block copolymers that secure a therapeutic payload in an inactive state. Upon recognizing the targeted cell-surface marker, the APH enters the host cell via endocytosis, at which point the payload is triggered to be released into the cytoplasm. After visualizing this process with coumarin dye, we demonstrate targeted killing of tumor cells with doxorubicin. Importantly, this process can be generalized to yield APHs that specifically target different surface markers. PMID- 25290919 TI - [Vaccinations in pneumology]. AB - The best measure to prevent infections of the respiratory tract is the use of vaccines against important respiratory tract pathogens. The Standing Vaccination Committee at the Robert Koch Institute recommends not only children but also adult vaccination against pneumococci, influenza A/B and Bordetella pertussis, because of a high disease burden. In the present review the clinical significance and safety of those vaccinations as well as advantages and disadvantages of the currently available vaccines are discussed. PMID- 25290918 TI - The C-terminal domain of Nrf1 negatively regulates the full-length CNC-bZIP factor and its shorter isoform LCR-F1/Nrf1beta; both are also inhibited by the small dominant-negative Nrf1gamma/delta isoforms that down-regulate ARE-battery gene expression. AB - The C-terminal domain (CTD, aa 686-741) of nuclear factor-erythroid 2 p45-related factor 1 (Nrf1) shares 53% amino acid sequence identity with the equivalent Neh3 domain of Nrf2, a homologous transcription factor. The Neh3 positively regulates Nrf2, but whether the Neh3-like (Neh3L) CTD of Nrf1 has a similar role in regulating Nrf1-target gene expression is unknown. Herein, we report that CTD negatively regulates the full-length Nrf1 (i.e. 120-kDa glycoprotein and 95-kDa deglycoprotein) and its shorter isoform LCR-F1/Nrf1beta (55-kDa). Attachment of its CTD-adjoining 112-aa to the C-terminus of Nrf2 yields the chimaeric Nrf2 C112Nrf1 factor with a markedly decreased activity. Live-cell imaging of GFP-CTD reveals that the extra-nuclear portion of the fusion protein is allowed to associate with the endoplasmic reticulum (ER) membrane through the amphipathic Neh3L region of Nrf1 and its basic c-tail. Thus removal of either the entire CTD or the essential Neh3L portion within CTD from Nrf1, LCR-F1/Nrf1beta and Nrf2 C112Nrf1, results in an increase in their transcriptional ability to regulate antioxidant response element (ARE)-driven reporter genes. Further examinations unravel that two smaller isoforms, 36-kDa Nrf1gamma and 25-kDa Nrf1delta, act as dominant-negative inhibitors to compete against Nrf1, LCR-F1/Nrf1beta and Nrf2. Relative to Nrf1, LCR-F1/Nrf1beta is a weak activator, that is positively regulated by its Asn/Ser/Thr-rich (NST) domain and acidic domain 2 (AD2). Like AD1 of Nrf1, both AD2 and NST domain of LCR-F1/Nrf1beta fused within two different chimaeric contexts to yield Gal4D:Nrf1beta607 and Nrf1beta:C270Nrf2, positively regulate their transactivation activity of cognate Gal4- and Nrf2 target reporter genes. More importantly, differential expression of endogenous ARE-battery genes is attributable to up-regulation by Nrf1 and LCR-F1/Nrf1beta and down-regulation by Nrf1gamma and Nrf1delta. PMID- 25290920 TI - [Update pneumococcal infections]. AB - Pneumococci remain the most important cause for community-acquired pneumonia. The colonization of the nasopharynx is prerequisite for their transmission and the colonization of toddlers are an important reservoir also for infections in the elderly. Since pneumococcal conjugate vaccines reduce the colonization rate of children its widespread use has also resulted in a reduction of invasive pneumococcal disease in adults. Advanced age and comorbidity are the most important risk factors for pneumococcal pneumonia and the mortality in this risk group is still very high. The strongest risk factor for invasive pneumococcal infections, however, is HIV/AIDS and solid or hematologic malignancies. A more rapid identification could aid de-escalation of empiric antibiotic therapy. The pneumococcal urinary antigen test, however lacks sensitivity for this purpose. In contrast, the direct identification of pathogens from positive blood culture bottles by MALDI-TOF is a very encouraging development in diagnostic microbiology. In several cohort studies patients treated with a combination of a betalactam plus macrolide had a lower mortality than patients treated with betalactam monotherapy. If these observations reflect a truly beneficial effect of combination therapy or rather confounding of the studies remains unclear and evidence from interventional studies is needed. PMID- 25290921 TI - [Update on the epidemiology, diagnosis and therapy of tuberculosis in HIV infected patients]. AB - Globally, the diagnosis and treatment of tuberculosis (TB) in HIV-co-infection has improved dramatically over the last 10 years. Nonetheless, the mortality of co-infected patients remains elevated. In European countries, the proportion of HIV-infected patients amongst all TB cases varies greatly; in Germany it is about 4 - 5%. HIV-infection changes the molecular epidemiology of TB and the drug resistance situation. In endemic areas, HIV-infected patients are often re infected after completion of treatment for active TB. HIV has a profound influence on the anti-TB-immune response and antiretroviral therapy (ART) cannot completely restore normal immune function. The clinical presentation in advanced HIV-infection is atypical and disseminated disease is common. New "Point-of-Care" test methods are poised to improve the diagnoses of TB in HIV-infection; however, further research is required. The treatment of co-infection is complicated by drug interactions and the immune reconstitution syndrome (IRIS). New concepts and treatment regimens for chemoprevention of TB are necessary, especially for HIV infected persons. PMID- 25290922 TI - [Antibiotics for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA)]. AB - Over the last 50 years methicillin-resistant S. aureus (MRSA) spread globally. Vancomycin is still the most recommended antibiotic for MRSA-infections. Teicoplanin is an alternative glycopeptide with longer elimination half-life. Telavancin is a more recently developed derivative of vancomycin with similar clinical efficacy as vancomycin. It is not recommended for treatment of patients with renal insufficiency. Nephrotoxicity limits the therapeutic use of glycopeptide antibiotics. The oxazolidinone linezolid exhibits similar to superior therapeutic efficacy. Hematologic controls are necessary during treatment with this antibacterial agent. Neurotoxic effects have been observed mainly in patients who received prolonged linezolid treatment. Attention must be paid to possible interactions with concomitantly given drugs acting on the serotonergic system. New therapeutic options arise with ceftaroline, the first beta-lactam antibiotic with activity against MRSA. However, controlled clinical trials with pulmonary MRSA infections have not been conducted with ceftaroline. Daptomycin, a lipopeptide, and tigecycline, a glycylcyclin are active in vitro against MRSA as well, but are also not indicated in pulmonary MRSA infections. These antibiotics show in an exemplary manner that antibacterial activity in vitro is an important prerequisite, but relevant data for a therapeutic decision should be derived from randomized controlled clinical double-blind trials. PMID- 25290923 TI - [Travel-associated pneumonias]. AB - Respiratory infections are responsible for up to 11% of febrile infections in travellers or immigrants from tropical and subtropical regions. The main pathogens are the same as in temperate climate zones: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, influenza viruses, Legionella pneumophila. However, some pulmonary diseases can be attributed to bacterial, parasitic, viral or fungal pathogens that are endemic in tropical and subtropical regions. The most commonly imported infections are malaria, dengue, and tuberculosis. Pulmonary symptoms and eosinophilia in returning travellers and migrants may be caused by several parasitic infections such as Katayama syndrome, Loeffler syndrome, tropical pulmonary eosinophilia, amebiasis, paragonimiasis, echinococcosis, and toxocariasis. In Asia, Tsutsugamushi fever is transmitted by chiggers, spotted fever rickettsiae are transmitted by ticks. Transmission of zoonotic diseases occurs mainly via contact with infected animals or their excretions, human-to-human transmission is generally rare: MERS-CoA (dromedary camels), pulmonary hantavirus infection (rodents), tularemia (rabbits and hares), leptospirosis (rats), Q-fever (sheep and goats), very rarely anthrax (hides of ruminants) and pest (infected rats and wildlife). Inhalation of contaminated dust can cause infections with dimorphic fungi: histoplasmosis (bat guano) and coccidioidomycosis in America and parts of Africa, blastomycosis in America. Some infections can cause symptoms years after a stay in tropical or subtropical regions (melioidosis, tuberculosis, histoplasmosis, schistosomiasis-associated pulmonary hypertension). Noninfectious respiratory diseases caused by inhalation of high amounts of air pollution or toxic dusts may also be considered. PMID- 25290924 TI - [Niels Ryberg Finsen]. PMID- 25290925 TI - Humoral or cellular effector mechanisms? AB - Human autoimmune diseases have long been regarded as the sole consequence of autoantibody production, often with concomitant immune complex formation. More recent evidence indicates that T lymphocytes and macrophages may play an important role in damaging target tissues. In july, invited participants discussed in the Diisseldorf Autoimmunity Workshop 1983(*) the evidence for the dominance of Immoral or cellular effector mechanisms in the various human autoimmune diseases. PMID- 25290926 TI - Immunoepidemiology helps to unravel the mysteries of dengue haemorrhagic fever. AB - It is now nearly 20 years since a strong correlation was noted in Thailand between secondary immune responses and severe dengue syndromes. It is currently thought that 'enhancing' antibodies, in an individual undergoing a second infection with a different serotype of dengue virus, promotes viral replication in monocytes which then become the targets of an immune elimination response (possibly T-cell mediated). The monocytes then release various chemical mediators which produce the symptoms of shock and haemorrhage seen in dengue haemorrhagic fever (DHF). Much new knowledge has been gained in recent years especially from immunoepidemiological and immunological studies, and these were discussed at a recent meeting. PMID- 25290927 TI - Proposed nomenclature for B-cell stimulating factors. PMID- 25290928 TI - T-cell regulation of IgA responses. PMID- 25290929 TI - [Not Available]. PMID- 25290930 TI - The value of theoretical immunology. PMID- 25290931 TI - Ordered sequence of expression of class-II antigens and cell-surface immunoglobulin. PMID- 25290933 TI - Natural autoantibodies to the fore - forbidden clones to the rear? PMID- 25290932 TI - Autoantibodies and the physiological role of immunoglobulins. AB - In this article Pierre Grabar returns to the proposal he first made 30 years ago that alloreactive and autoreactive antibodies represent a physiological system for disposing of the products of metabolism and catabolism. PMID- 25290934 TI - What do the immune system and the brain know about each other? AB - The immune system is generally viewed as being regulated by a variety of mechanisms 'from within'. This internal regulation is conceived to be mediated by different subsets of T cells, by antibodies including their idiotypic determinants, monokines, yphokines, etc., which appear in a given sequence and quantity. This autoregulation confers a high degree of autonomy on the immune system. However, processes essentialfor thefunctioning of immunological cells, such as metabolism, transport of substances, allosteric changes in membranes, lymphoid cell proliferation and transformation, and lymphokine synthesis (for bibliography, see Ref. 1), are affected by several hormones and neurotransmitters. These facts constitute by themselves good arguments for another kind of regulation, one 'from without' (a term used by Medawar in 1973) which is, as Hugo Besedovsky, Adriana del Rey and Ernst Sorkin have proposed, superimposed upon and interwoven with autoregulation. This postulate requires the existence of information channels between the immune system and the central nervous system, i. e. that they should know about each other. The apparently lofty title of this presentation raises a number of critical questions about the workings of the immune system in its natural environment. Here the authors discuss these questions: What do immune cells know about the brain? What does the brain know about the immune system? How do the brain and the immune system communicate with each other? Are brain-immune system interactions linked in regulatory feedback circuits? PMID- 25290935 TI - The role of iron and transferrin in lymphocyte transformation. AB - It has recently become apparent that many types of transformed cells possess membrane receptors for the plasma iron-binding protein transferrin. In this review Jeremy Brock and Tryfonia Mainou-Fowler discuss these observations in relation to transferrin's properties as an iron-transport protein, and the relative importance of iron and transferrin in lymphocyte transformation. PMID- 25290938 TI - Genetically engineered Lactococcus lactis protect against house dust mite allergy in a BALB/c mouse model. AB - BACKGROUND: Mucosal vaccine based on lactic acid bacteria is an attractive concept for the prevention and treatment of allergic diseases, but their mechanisms of action in vivo are poorly understood. Therefore, we sought to investigate how recombinant major dust mite allergen Der p2-expressing Lactococcus lactis as a mucosal vaccine induced the immune tolerance against house dust mite allergy in a mouse model. METHODS: Three strains of recombinant L. lactis producing Der p2 in different cell components (extracellular, intracellular and cell wall) were firstly constructed. Their prophylactic potential was evaluated in a Der p2-sensitised mouse model, and immunomodulation properties at the cellular level were determined by measuring cytokine production in vitro. RESULTS: Der p2 expressed in the different recombinant L. lactis strains was recognized by a polyclonal anti-Der p2 antibody. Oral treatment with the recombinant L. lactis prior sensitization significantly prevented the development of airway inflammation in the Der p2-sensitized mice, as determined by the attenuation of inflammatory cells infiltration in the lung tissues and decrease of Th2 cytokines IL-4 and IL-5 levels in bronchoalveolar lavage. In addition, the serum allergen-specific IgE levels were significantly reduced, and the levels of IL-4 in the spleen and mesenteric lymph nodes cell cultures were also markedly decreased upon allergen stimulation in the mice fed with the recombinant L. lactis strains. These protective effects correlated with a significant up-regulation of regulatory T cells in the mesenteric lymph nodes. CONCLUSION: Oral pretreatment with live recombinant L. lactis prevented the development of allergen-induced airway inflammation primarily by the induction of specific mucosal immune tolerance. PMID- 25290939 TI - Modeling the cost effectiveness of malaria control interventions in the highlands of western Kenya. AB - INTRODUCTION: Tools that allow for in silico optimization of available malaria control strategies can assist the decision-making process for prioritizing interventions. The OpenMalaria stochastic simulation modeling platform can be applied to simulate the impact of interventions singly and in combination as implemented in Rachuonyo South District, western Kenya, to support this goal. METHODS: Combinations of malaria interventions were simulated using a previously published, validated model of malaria epidemiology and control in the study area. An economic model of the costs of case management and malaria control interventions in Kenya was applied to simulation results and cost-effectiveness of each intervention combination compared to the corresponding simulated outputs of a scenario without interventions. Uncertainty was evaluated by varying health system and intervention delivery parameters. RESULTS: The intervention strategy with the greatest simulated health impact employed long lasting insecticide treated net (LLIN) use by 80% of the population, 90% of households covered by indoor residual spraying (IRS) with deployment starting in April, and intermittent screen and treat (IST) of school children using Artemether lumefantrine (AL) with 80% coverage twice per term. However, the current malaria control strategy in the study area including LLIN use of 56% and IRS coverage of 70% was the most cost effective at reducing disability-adjusted life years (DALYs) over a five year period. CONCLUSIONS: All the simulated intervention combinations can be considered cost effective in the context of available resources for health in Kenya. Increasing coverage of vector control interventions has a larger simulated impact compared to adding IST to the current implementation strategy, suggesting that transmission in the study area is not at a level to warrant replacing vector control to a school-based screen and treat program. These results have the potential to assist malaria control program managers in the study area in adding new or changing implementation of current interventions. PMID- 25290942 TI - Openness on animal research: the gauntlet has been thrown down. PMID- 25290941 TI - Urinary iodine as an iodine deficiency test in lung transplant recipients in order to prevent iodine deficiency disorders. AB - BACKGROUND: In Poland, lung transplantation (LTx) as a routine method began in 2004, and since then, the Silesian Center for Heart Disease in Zabrze 85 LTx has performed (54 single-lung transplantations, 30 double-lung transplantations, and 1 heart-lung) transplantation. The recommendation to take vitamin supplements (without specific indication of the iodine content) does not apply to another iodine prophylaxis in patients after lung transplantation, excluding patients with known thyroid disease. The aim of this study was to assess thyroid gland function based on hormones and urinary iodine (UI) concentration in patients after LTx. MATERIAL AND METHODS: UI analysis was performed in 19 lung recipients (12 men and 7 women; mean age: 46.2 +/- 12.47 years, BMI: 21 +/- 2.25) and compared to TSH, free T3, and free T4. RESULTS: Sufficient UI was observed only in 2 (9%) samples. In 12 samples (54.5%), mild iodine deficiency was recorded, in 4 samples (18.2%) moderate iodine deficiency was noted, and in 3 (13.6%) severe iodine deficiency was found. No correlation between BMI and UI, as well as hormones concentration, was observed. No correlation was revealed when analyzed samples were divided by patient sex. CONCLUSIONS: Although thyroid gland hormones were in the normal range, we found moderate, mild, and severe iodine deficiency in the majority of analyzed samples. Measurements of urinary iodine in lung transplant recipients should accompany thyroid hormone measurements as an iodine deficiency test and in order to prevent iodine deficiency disorders. PMID- 25290940 TI - Risk of primary liver cancer associated with gallstones and cholecystectomy: a meta-analysis. AB - BACKGROUND: Recent epidemiological evidence points to an association between gallstones or cholecystectomy and the incidence risk of liver cancer, but the results are inconsistent. We present a meta-analysis of observational studies to explore this association. METHODS: We identified studies by a literature search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and relevant conference proceedings up to March 2014. A random-effects model was used to generate pooled multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Between-study heterogeneity was assessed using Cochran's Q statistic and the I2. RESULTS: Fifteen studies (five case-control and 10 cohort studies) were included in this analysis. There were 4,487,662 subjects in total, 17,945 diagnoses of liver cancer, 328,420 exposed to gallstones, and 884,507 exposed to cholecystectomy. Pooled results indicated a significant increased risk of liver cancer in patients with a history of gallstones (OR = 2.54; 95% CI, 1.71 3.79; n = 11 studies), as well as cholecystectomy (OR = 1.62; 95% CI, 1.29-2.02; n = 12 studies), but there was considerable heterogeneity among these studies. The effects estimates did not vary markedly when stratified by gender, study design, study region, and study quality. The multivariate meta-regression analysis suggested that study region and study quality appeared to explain the heterogeneity observed in the cholecystectomy analysis. CONCLUSIONS: Our results suggest that individuals with a history of gallstones and cholecystectomy may have an increased risk of liver cancer. PMID- 25290943 TI - Student perspectives on the use of alternative methods for teaching in veterinary faculties. AB - The use of alternative methods for teaching purposes is gradually increasing in higher education. In order to evaluate the usefulness of non-animal based practical classes in veterinary science, and to inform on possible benefits and limitations of these teaching tools, a questionnaire was designed and distributed to students. Although there was no complete agreement among the student responses, it was apparent that the majority of the students would like traditional training methods to be paired with alternative approaches, and expressed their desire to be exposed to as many humane modes of learning as possible. In addition, the students agreed that alternative teaching methods for training in veterinary science can reinforce existing knowledge that is required at the clinical stage, and that they can be effective supplements to traditional training methods. It was also concluded from the study that the use of new alternative approaches is very much appreciated by the students, whereas the validity and effectiveness of these methods are debatable, suggesting that further optimisation, proper application and evaluation of these alternative methods is required. PMID- 25290944 TI - Lung fibrosis: drug screening and disease biomarker identification with a lung slice culture model and subtracted cDNA Library. AB - Pulmonary fibrosis is a progressive and irreversible disorder with no appropriate cure. A practical and effective experimental model that recapitulates the disease will greatly benefit the research community and, ultimately, patients. In this study, we tested the lung slice culture (LSC) system for its potential use in drug screening and disease biomarker identification. Fibrosis was induced by treating rat lung slices with 1ng/ml TGF-beta1 and 2.5MUM CdCl2, quantified by measuring the content of hydroxyproline, and confirmed by detecting the expression of collagen type III alpha 1 (Col3alpha1) and connective tissue growth factor (CTGF) genes. The anti-fibrotic effects of pirfenidone, spironolactone and eplerenone were assessed by their capability to reduce hydroxyproline content. A subtractive hybridisation technique was used to create two cDNA libraries (subtracted and unsubtracted) from lung slices. The housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was employed to assess the subtraction efficiency of the subtracted cDNA library. Clones from the two libraries were sequenced and the genes were identified by performing a BLAST search on the NCBI GenBank database. Furthermore, the relevance of the genes to fibrosis formation was verified. The results presented here show that fibrosis was effectively induced in cultured lung slices, which exhibited significantly elevated levels of hydroxyproline and Col3alpha1/CTGF gene expression. Several inhibitors have demonstrated their anti-fibrotic effects by significantly reducing hydroxyproline content. The subtracted cDNA library, which was enriched for differentially expressed genes, was used to successfully identify genes associated with fibrosis. Collectively, the results indicate that our LSC system is an effective model for the screening of drug candidates and for disease biomarker identification. PMID- 25290945 TI - The Three Rs--opportunities for improving animal welfare and the quality of scientific research. AB - In 2013, an undercover investigation by the BUAV raised serious concerns about the use, treatment and care of laboratory animals involved in regulated procedures at Imperial College, London. This led to an inquiry, set up by the college, which found deficiencies in the local ethical review process and a general lack of focus on the implementation of the Three Rs (Replacement, Refinement and Reduction). The Three Rs concept is the foundation of UK and EU legislation, but surveys of the published literature show that lack of its adoption is widespread. In spite of numerous guidelines, publications and publicity material extolling the benefits of the Three Rs to both animals and science, as well as substantial advances in the development, validation, and deployment of mechanistically-based non-animal methods, many scientists prefer to use traditional animal-based approaches. In addition, such scientists tend to pay less attention than they should to strategic planning, experimental design and the choice of appropriate statistical procedures. They are often unaware of the existence of replacement test methods to address all or some of their objectives, and are reluctant to develop and use new replacement methods. We explore some possible reasons for these shortcomings. We summarise the welfare and scientific effects of each of the Three Rs, and argue that: a) there is an urgent need for evidence to be made readily accessible to prospective licensees, which directly demonstrates the beneficial effects on animal welfare of the implementation of the Three Rs, separately and in combination, and the direct link this has with the quality of the scientific data obtained; b) a detailed systematic review of this evidence should be undertaken to augment the inadequate content of the prescribed Module 5 licensee training offered currently in the UK; c) such training (including that suggested in new EU-wide proposals) should be much more comprehensive, with stronger emphasis on the Three Rs, all parts of the syllabus should be fully examined, and there should be no exemptions from Module 5 training; and d) as the responsible Government department in the UK, the Home Office should take measures to tighten up its guidance for local ethical review, and its system of inspection of designated establishments, to obviate the justification for future undercover investigations. PMID- 25290946 TI - Statistics of Scientific Procedures on Living Animals 2013: Experimentation continues to rise--the reliance on genetically-altered animals must be addressed. AB - The 2013 Statistics of Scientific Procedures on Living Animals reveal that the level of animal experimentation in Great Britain continues to rise, with 4.12 million procedures being conducted. The figures indicate that this is almost exclusively a result of the breeding and use of genetically-altered (GA) animals (i.e. genetically-modified animals, plus those with harmful genetic defects). The breeding of GA animals increased to over half (51%) of all the procedures, and GA animals were involved in 61% of all the procedures. Indeed, if these animals were removed from the statistics, the number of procedures would actually have declined by 4%. It is argued that the Coalition Government has failed to address this issue, and, as a consequence, will not be able to deliver its pledge to reduce animal use in science. Recent publications supporting the need to reassess the dominance of genetic alteration are also discussed, as well as the need to move away from the use of dogs as the default second species in safety testing. The general trends in the species used, and the numbers and types of procedures, are also reviewed. Finally, forthcoming changes to the statistics are discussed. PMID- 25290947 TI - A 'road map' toward ending severe suffering of animals used in research and testing. AB - Ending severe suffering is desirable and achievable. In this article we have outlined a 'road map', or series of steps, that can be used to evaluate the extent to which severe suffering occurs within establishments, and some practical principles that can be employed in order to work toward ending it. We urge researchers to act upon these principles, and to begin a journey toward a future where causing severe suffering to animals used in scientific research is a thing of the past. PMID- 25290948 TI - Personal reflections on veterinary science training and the Three Rs. PMID- 25290949 TI - Lost in translation: the need for better tools. PMID- 25290951 TI - Genetic and antigenic typing of Clostridium perfringens isolates from ostriches. PMID- 25290954 TI - The "balance of nature"-evolution of a Panchreston. AB - The earliest concept of a balance of nature in Western thought saw it as being provided by gods but requiring human aid or encouragement for its maintenance. With the rise of Greek natural philosophy, emphasis shifted to traits gods endowed species with at the outset, rather than human actions, as key to maintaining the balance. The dominance of a constantly intervening God in the Middle Ages lessened interest in the inherent features of nature that would contribute to balance, but the Reformation led to renewed focus on such features, particularly traits of species that would maintain all of them but permit none to dominate nature. Darwin conceived of nature in balance, and his emphasis on competition and frequent tales of felicitous species interactions supported the idea of a balance of nature. But Darwin radically changed its underlying basis, from God to natural selection. Wallace was perhaps the first to challenge the very notion of a balance of nature as an undefined entity whose accuracy could not be tested. His skepticism was taken up again in the 20th century, culminating in a widespread rejection of the idea of a balance of nature by academic ecologists, who focus rather on a dynamic, often chaotic nature buffeted by constant disturbances. The balance-of-nature metaphor, however, lives on in large segments of the public, representing a fragile aspect of nature and biodiversity that it is our duty to protect. PMID- 25290952 TI - Prevalence, distribution, and sequence diversity of hmwA among commensal and otitis media non-typeable Haemophilus influenzae. AB - Nontypeable Haemophilus influenzae (NTHi) are Gram-negative coccobacilli that colonize the human pharynx, their only known natural reservoir. Adherence to the host epithelium facilitates NTHi colonization and marks one of the first steps in NTHi pathogenesis. Epithelial cell attachment is mediated, in part, by a pair of high molecular weight (HMW) adhesins that are highly immunogenic, antigenically diverse, and display a wide range of amino acid diversity both within and between isolates. In this study, the prevalence of hmwA, which encodes the HMW adhesin, was determined for a collection of 170 NTHi isolates recovered from the middle ears of children with otitis media (OM isolates) or throats or nasopharynges of healthy children (commensal isolates) from Finland, Israel, and the U.S. Overall, hmwA was detected in 61% of NTHi isolates and was significantly more prevalent (P=0.004) among OM isolates than among commensal isolates; the prevalence ratio comparing hmwA prevalence among ear isolates with that of commensal isolates was 1.47 (95% CI (1.12, 1.92)). Ninety-five percent (98/103) of the hmwA-positive NTHi isolates possessed two hmw loci. To advance our understanding of hmwA binding sequence diversity, we determined the DNA sequence of the hmwA binding region of 33 isolates from this collection. The average amino acid identity across all hmwA sequences was 62%. Phylogenetic analyses of the hmwA binding revealed four distinct sequence clusters, and the majority of hmwA sequences (83%) belonged to one of two dominant sequence clusters. hmwA sequences did not cluster by chromosomal location, geographic region, or disease status. PMID- 25290955 TI - [Health promotion: a component for business competitiveness]. PMID- 25290953 TI - Identification of a neurologic scale that optimizes EMS detection of older adult traumatic brain injury patients who require transport to a trauma center. AB - OBJECTIVE: We sought to identify a scale or components of a scale that optimize detection of older adult traumatic brain injury (TBI) patients who require transport to a trauma center, regardless of mechanism. METHODS: We assembled a consensus panel consisting of nine experts in geriatric emergency medicine, prehospital medicine, trauma surgery, geriatric medicine, and TBI, as well as prehospital providers, to evaluate the existing scales used to identify TBI. We reviewed the relevant literature and solicited group feedback to create a list of candidate scales and criteria for evaluation. Using the nominal group technique, scales were evaluated by the expert panel through an iterative process until consensus was achieved. RESULTS: We identified 15 scales for evaluation. The panel's criteria for rating the scales included ease of administration, prehospital familiarity with scale components, feasibility of use with older adults, time to administer, and strength of evidence for their performance in the prehospital setting. After review and discussion of aggregated ratings, the panel identified the Simplified Motor Scale, GCS-Motor Component, and AVPU (alert, voice, pain, unresponsive) as the strongest scales, but determined that none meet all EMS provider and patient needs due to poor usability and lack of supportive evidence. The panel proposed that a dichotomized decision scheme that includes domains of the top-rated scales -level of alertness (alert vs. not alert) and motor function (obeys commands vs. does not obey) -may be more effective in identifying older adult TBI patients who require transport to a trauma center in the prehospital setting. CONCLUSIONS: Existing scales to identify TBI are inadequate to detect older adult TBI patients who require transport to a trauma center. A new algorithm, derived from elements of previously established scales, has the potential to guide prehospital providers in improving the triage of older adult TBI patients, but needs further evaluation prior to use. PMID- 25290956 TI - [Archivos goes paperless: welcome to a new only-digital journal]. PMID- 25290957 TI - [Manual tool grip span and grip force during flower cutting]. AB - OBJECTIVE: To analyze the association between grip span of a manual flower cutting tool and maximum peak force exerted by each finger in the operating hand during apprehension. METHODS: An experiment was conducted in which 11 women performed the stem cut of a flower. These women did not suffer from carpal tunnel syndrome. Grip span was calculated when they exerted the maximum peak force with each finger. RESULTS: The main finding of the study reveals that fingers exert the maximum peak force when the grip span values are the same for everyone. However, due to the shape of the tool commonly used in the Colombian flower industry (first order level), each finger reaches its maximum peak force at different times, bypassing the full capacity of each finger's grip force. CONCLUSION: These findings could be used to improve the mechanical advantage of manual cutting tools to reduce risk factors for carpal tunnel syndrome due to overexertion. PMID- 25290958 TI - [Use of data display screens and ocular hypertension in local public sector workers]. AB - OBJECTIVE: The main objective of this study is to examine the association between work with data display screens (DDS) and ocular hypertension (OHT). METHODS: A cross-sectional study among local public sector workers (Diputacion Provincial de Valencia). Data from 620 people were collected over 25 months, from periodic medical examinations performed at an occupational health unit. Intraocular pressure (IOP) was obtained with a portable puff tonometer validated for screening, establishing the cut-off point for OHT at 22 mmHg. Both biological characteristics and other work-related variables were taken into account as covariates. Descriptive statistics of the data were obtained, together with nonparametric tests with a level of significance of 95% and logistic regression with p <0.1 as the level of significance of the likelihood test. RESULTS: The average age of the study population is 52.8 years. The prevalence of OHT was 3.5% (5.1% among men and 1.2% among women; p=0.012). No significant associations were found between hours of DDS-related work and OHT were found (p=0.395). Logistic regression corroborated the association between gender and OHT, with women less affected (OR = 0.234; 95%CI: 0.068 - 0.799; p=0.020). CONCLUSIONS: In our study, no associations were found between time of exposure to data display screens and ocular hypertension. Logistic regression points to a certain association between ocular hypertension and gender, with men being more predisposed. PMID- 25290959 TI - [300 years without Bernardino Rammazzini (1633-1714)]. PMID- 25290960 TI - Osmium(III) analogues of KP1019: electrochemical and chemical synthesis, spectroscopic characterization, X-ray crystallography, hydrolytic stability, and antiproliferative activity. AB - A one-electron reduction of osmium(IV) complexes trans-[Os(IV)Cl4(Hazole)2], where Hazole = 1H-pyrazole ([1](0)), 2H-indazole ([2](0)), 1H-imidazole ([3](0)), and 1H-benzimidazole ([4](0)), afforded a series of eight new complexes as osmium analogues of KP1019, a lead anticancer drug in clinical trials, with the general formula (cation)[trans-Os(III)Cl4(Hazole)2], where cation = H2pz(+) (H2pz[1]), H2ind(+) (H2ind[2]), H2im(+) (H2im[3]), Ph4P(+) (Ph4P[3]), nBu4N(+) (nBu4N[3]), H2bzim(+) (H2bzim[4]), Ph4P(+) (Ph4P[4]), and nBu4N(+) (nBu4N[4]). All complexes were characterized by elemental analysis, (1)H NMR spectroscopy, electrospray ionization mass spectrometry, UV-vis spectroscopy, cyclic voltammetry, while H2pz[1], H2ind[2], and nBu4[3], in addition, by X-ray diffraction. The reduced species [1](-) and [4](-) are stable in aqueous media in the absence of air oxygen and do not react with small biomolecules such as amino acids and the nucleotide 5'-dGMP. Cell culture experiments in five different human cancer cell lines (HeLa, A549, FemX, MDA-MB-453, and LS-174) and one noncancerous cell line (MRC-5) were performed, and the results were discussed and compared to those for KP1019 and cisplatin. Benzannulation in complexes with similar structure enhances antitumor activity by several orders of magnitude, implicating different mechanisms of action of the tested compounds. In particular, complexes H2ind[2] and H2bzim[4] exhibited significant antiproliferative activity in vitro when compared to H2pz[1] and H2im[3]. PMID- 25290961 TI - Using an eye tracker during medication administration to identify gaps in nursing students' contextual knowledge: an observational study. AB - In this clinical simulation study using an eye-tracking device, 40% of senior nursing students administered a contraindicated medication to a patient. Our findings suggest that the participants who did not identify the error did not know that amoxicillin is a type of penicillin. Eye-tracking devices may be valuable for determining whether nursing students are making rule- or knowledge based errors, a distinction not easily captured via observations and interviews. PMID- 25290962 TI - Should we prelab? A student-centered look at the time-honored tradition of prelab in clinical nursing education. AB - This study explores clinical preparation (prelab) in nursing education from the student's perspective. More than half of the students surveyed (n = 296) believed prelab learning activities were important; however, they reported that prelab increases stress and decreases sleep quantity. Timing, stress, and anxiety were factors affecting student perception of prelab. The findings suggest that students receive diminishing returns on the time spent on prelab; nevertheless, prelab may enhance their learning and patient safety. PMID- 25290963 TI - Improving self-directed learning/intercultural competencies: breaking the silence. AB - Nurse educators need to develop innovative, technological curricula that foster intercultural competencies as essential components of a university education and break the silence with respect to lesbian, gay, bisexual, transgender, and queer (LGBTQ) health. Goals are to foster using these competencies to make LGBTQ content explicit in nursing curricula and in their professional organizations to promote equality and lessen disparities in this group. PMID- 25290965 TI - Digital storytelling: an innovative technological approach to nursing education. AB - This study investigated the impact of using digital stories in promoting deeper understanding in nursing students about palliative care concepts. Students (N = 134) created a 5-minute narrated digital story utilizing VoiceThread technology that synthesized and applied knowledge that had been presented in class and course readings. Postsurvey and focus group evaluation data revealed that through the writing and sharing of digital stories, students embraced the personal and complex nature of palliative care. PMID- 25290964 TI - Becoming a nurse: role formation among accelerated baccalaureate students. AB - To understand nursing role formation for students enrolled in an accelerated baccalaureate nursing program, end-of-term narrative reflections from 34 students were analyzed over the course of the 15-month program. Using thematic analysis, 4 major themes were identified: evolving role perception, extending nursing student patient interaction, engaging with health care team and systems of care, and expanding clinical thinking. PMID- 25290966 TI - The flipped classroom: strategies for an undergraduate nursing course. AB - This article presents the authors' experience with flipping a fundamental concepts of nursing course for students in an undergraduate baccalaureate program. Authors describe implementing a flipped class, practical strategies to transform students' learning experience, and lessons learned. This article serves as a guide to faculty and programs seeking to develop and implement the flipped class model in nursing education. PMID- 25290967 TI - Comparative proteomic analysis of Aureobasidium pullulans in the presence of high and low levels of nitrogen source. AB - Pullulan, produced by Aureobasidium pullulans strain, has been broadly used in the food and medical industries. However, relatively little is known concerning the molecular basis of pullulan biosynthesis of this strain. In this paper, the effect of different concentrations of (NH4)2SO4 on pullulan fermentation was studied. Proteomics containing two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF MS) were used to analyze the protein with different expressions of A. pullulans cells between the nitrogen limitation and nitrogen repletion. Maximum pullulan production reached 37.72 g/L when 0.6 g/L of initial (NH4)2SO4 was added. Excess nitrogen source would impel carbon flux flow toward biomass production, but decreased the pullulan production. Nitrogen limitation in A. pullulans seemed to influence the flux change of carbon flux flow toward exopolysaccharide accumulation. The findings indicated that 12 identified protein spots were involved in energy-generating enzymes, antioxidant-related enzymes, amino acid biosynthesis, glycogen biosynthesis, glycolysis, protein transport, and transcriptional regulation. These results presented more evidence of pullulan biosynthesis under nitrogen-limited environment, which would provide a molecular understanding of the physiological response of A. pullulans for optimizing the performance of industrial pullulan fermentation. PMID- 25290968 TI - Forbidden clones. PMID- 25290969 TI - Possible target antigens in autoimmune endocrine disease. PMID- 25290970 TI - What is S3? PMID- 25290971 TI - The murine IL-2-dependent cytotoxic T-cell line CTLL can be preserved by freezing. PMID- 25290972 TI - Is tumor necrosis factor a physiological mediator? PMID- 25290973 TI - [Not Available]. PMID- 25290974 TI - Autoimmune induction by epithelial cells bearing class II MHC antigens. PMID- 25290975 TI - Is immunological tolerance (non-responsiveness) a consequence of interleukin 2 deficit during the recognition of antigen? AB - There have been recent demonstrations that immunological tolerance can be MHC restricted. The same antigen, therefore, can be recognized in the context of an appropriate MHC molecule both as an antigen andas a tolerogen. Here Miroslav Malkovsky and Peter Medawar propose that the outcome of the encounter is determined by the availability or effectiveness of interleukin 2. If there is a deficit of the hormone, unresponsiveness is promoted in the T cells which recognize the antigen. PMID- 25290976 TI - Gene conversion may be responsible for the generation of the alloreactive repertoire. AB - Meiotic gene conversion in the major histocompatibility complex (MHC) appears to be involved in the generation of MHC polymorphism. Here the authors suggest that mitotic gene conversion of MHC may generate somatic variants which sensitize the immune system. This could lead to an MHC-skewed repertoire with a high background alloreactive potential crossreacting with foreign antigens in the context of self MHC. Allodeterminant-bearing autologous cells may be deleted by the immune cells, thereby maintaining the observed genotype/phenotype correlation. PMID- 25290977 TI - The pathogenetic significance of cross reactions in autoimmune disease of the nervous system. PMID- 25290978 TI - High connectivity within the network? PMID- 25290979 TI - The intracellular traffic of immunologically active molecules. AB - An immune response is the result of a series of molecular and cellular interactions. The molecules involved include secreted proteins such as lymphokines and immunoglobulins and cell surface proteins such as histocompatibility antigens, Fc and lymphokine receptors and the T-cell receptor. Molecular immunologists initially focused on the structure and function of these molecules in extracellular space or on the cell surface but the control of their expression at the chromosomal level is now being studied. These investigations still leave an enormous gap in understanding the life-cycle and behavior of immunological molecules - a gap, literally, extending from the nuclear membrane to the plasma membrane. In this article Frances Brodsky discusses recent studies on molecular events in this region of the cell. PMID- 25290980 TI - Immunosuppression by seminal plasma and its possible clinical significance. AB - Several components of semen have immunomodulatory effects; these include spermatozoa(1-3) and a variety of seminal plasma factors. In addition semen may contain a small number of immunocompetent cells(4). In this review Keith James and Timothy Hargreave discuss the immunological effects of human seminal plasma, including its suppressive effect on in vitro and in vivo immune responses, the nature and action of the factors involved and their possible clinical relevance. PMID- 25290981 TI - Fc receptor-mediated transport of immunoglobulin across the intestinal epithelium of the neonatal rodent. AB - In mammals the transmission of maternal immunoglobulin across the foetal and neonatal tissues permits the developing animal to acquire passive immunity while its own immune systems are maturing. In the small intestine of neonatal rodents, immunoglobulin transport is specificfor IgG and there is even discrimination between subclasses of IgG. Here Neill Mackenzie reviews current ideas about the cellular basis for this discrimination. PMID- 25290984 TI - Poly (lactic acid)/chitosan fiber mats: investigation of effects of the support on lipase immobilization. AB - The greatest challenge for biotechnological processes is to have immobilized enzymes acting as good green catalysts with high reusability rates. In this work, we have produced electrospun fibers from poly (lactic acid)/chitosan blends. Further, we evaluated the influence of these materials as support for lipase immobilization. The PLA/chitosan fiber mats were composed by non-woven nanofibers, with diameters ranging from 200 nm to 1.3 MUm. The solvent (TFA) as well as the chitosan addition influenced morphology, hydrophobicity and mechanical properties of PLA nanofibers. It was observed that even for lower concentration of lipase (5 U) higher enzyme activity retention was detected in the PLA/chitosan blends. In addition, a remarkable improvement of lipase activity on pure PLA fiber mat was verified, indicating that most of the enzymes were probably in their active form. PMID- 25290985 TI - Comparison of chitin structures isolated from seven Orthoptera species. AB - Differences in the physichochemical properties of the chitin structure of the exoskeleton of seven species from four genera were investigated in this study. The same method was used to isolate the chitin structure of the seven species. The physicochemical properties of the isolated chitins were revealed by ESEM, FTIR, TGA and XRD analyses. The FTIR, TGA and XRD results from the chitin samples were similar. The surface morphologies of the chitins were investigated by ESEM and interesting results were noted. While the surface morphologies of the chitins isolated from two species within the same genus were quite different, the surface morphologies of chitins isolated from species belonging to different genera showed similarity. It was determined that the dry weight chitin contents of the grasshopper species varied between 5.3% and 8.9%. The results of molecular analysis showed that the chitins from seven Orthoptera species (between 5.2 and 6.8 kDa) have low molecular weights. Considering that these invasive and harmful species are killed with insecticides and go to waste in large amounts, this study suggests that they should be collected and evaluated as an alternative chitin source. PMID- 25290986 TI - Epigenetic pathways and glioblastoma treatment: insights from signaling cascades. AB - There is an urgent need to identify novel therapies for glioblastoma (GBM) as most therapies are ineffective. A first step in this process is to identify and validate targets for therapeutic intervention. Epigenetic modulators have emerged as attractive drug targets in several cancers including GBM. These epigenetic regulators affect gene expression without changing the DNA sequence. Recent studies suggest that epigenetic regulators interact with drivers of GBM cell and stem-like cell proliferation. These drivers include components of the Notch, Hedgehog, and Wingless (WNT) pathways. We highlight recent studies connecting epigenetic and signaling pathways in GBM. We also review systems and big data approaches for identifying patient specific therapies in GBM. Collectively, these studies will identify drug combinations that may be effective in GBM and other cancers. PMID- 25290987 TI - Causes and consequences of adult laryngotracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: Laryngotracheal stenosis (LTS) is largely considered a structural entity, defined on anatomic terms (i.e., percent stenosis, distance from vocal folds, overall length). This has significant implications for identifying at-risk populations, devising systems-based preventive strategies, and promoting patient-centered treatment. The present study was undertaken to test the hypothesis that LTS is heterogeneous with regard to etiology, natural history, and clinical outcome. STUDY DESIGN: Retrospective cohort study of consecutive adult tracheal stenosis patients from 1998 to 2013. METHODS: Subjects diagnosed with laryngotracheal stenosis (ICD-9: 478.74, 519.19) between January 1, 1998, and January 1, 2013, were identified. Patient characteristics (age, gender, race, follow-up duration) and comorbidities were extracted. Records were reviewed for etiology of stenosis, treatment approach, and surgical dates. Stenosis morphology was derived from intraoperative measurements. The presence of tracheostomy at last follow-up was recorded. RESULTS: One hundred and fifty patients met inclusion criteria. A total of 54.7% had an iatrogenic etiology, followed by idiopathic (18.5%), autoimmune (18.5%), and traumatic (8%). Tracheostomy dependence differed based on etiology (P < 0.001). Significantly more patients with iatrogenic (66%) and autoimmune (54%) etiologies remained tracheostomy-dependent compared to traumatic (33%) or idiopathic (0%) groups. On multivariate regression analysis, each additional point on Charlson Comorbidity Index was associated with a 67% increased odds of tracheostomy dependence (odds ratio 1.67; 95% confidence interval 1.04-2.69; P = 0.04). CONCLUSIONS: Laryngotracheal stenosis is not a homogeneous clinical entity. It has multiple distinct etiologies that demonstrate disparate rates of long-term tracheostomy dependence. Understanding the mechanism of injury and contribution of comorbid illnesses is critical to systems-based preventive strategies and patient-centered treatment. LEVEL OF EVIDENCE: 4. PMID- 25290988 TI - Is CD4 monitoring needed among ugandan clients achieving a virologic and immunologic response to treatment? AB - It is unclear whether ongoing CD4 monitoring is needed following immunologic and virologic response to antiretroviral therapy (ART). We investigated the proportion of clients who achieved a virologic and immunologic response and then had a subsequent CD4 count <200 cells/MUL despite continued virologic suppression. Included in this analysis were clients receiving ART through the Rakai Health Sciences Program between June 2004-May 2013 who achieved a CD4 >=200 cells/MUL and VL <=400 copies/mL and who had three sets of CD4 and VL measurements (defined as a sequence) within a 390 day period. A CD4 decline was defined as any drop in CD4 count to <200 cells/MUL during a period of viral suppression. A total of 1553 clients were included, 68% females, mean age of 35.5 years (SD 8.3), median baseline CD4 count 183 cells/MUL (IQR 106-224). 43 (2.8%) clients developed CD4 declines, the majority, 32/43 (74%), among individuals whose initial CD4 was <300 cells/MUL. Of the 43 clients with CD4 declines, 24 had an additional CD4 measurement and 20/24 (83%) achieved a CD4 >=200 cell/MUL on their next measurement (median 285 cells/MUL; IQR 220-365). CD4 declines were significantly greater among those with lower CD4 at sequence initiation [adjusted hazard ratio (AHR) 4.3 (95% CI 2.1, 9.0) CD4 200-249 versus >=350 cells/MUL]. Clients who achieved an immunologic and virologic response to ART were unlikely to experience a subsequent CD4 count decline to <200 cells/MUL, and among those experiencing a decline, the majority were transient in nature. Thus, ongoing CD4 monitoring could be omitted. PMID- 25290989 TI - Osteopontin expression in healing wounds of horses and in human keloids. AB - REASONS FOR PERFORMING STUDY: Convincing evidence shows that persistent or excessive expression of osteopontin (OPN) is linked to fibroproliferation of various organs in laboratory animals and in man, such that its downregulation is a logical therapeutic objective. OBJECTIVES: To investigate OPN expression in an equine model of wound healing and in clinical specimens of equine exuberant granulation tissue and human keloids in an effort to better understand the contribution of this protein to inflammation-associated skin fibrosis. STUDY DESIGN: Description of gene and protein expression in an experimental equine model of wound healing and clinical specimens in horse and man. METHODS: Osteopontin gene expression was evaluated by quantitative PCR, while protein expression was investigated by means of immunohistochemical staining. RESULTS: Quantitative PCR showed that the OPN gene is expressed in normal intact skin of horses and continues to be expressed during the wound-healing process. An increase in gene expression was observed throughout the phases of wound healing, with a final decrease at wound closure. The protein was not detected in normal skin. Keratinocytes in wound-edge samples did not express the protein, whereas dermal immunoreactivity was confined to inflammatory cells. Healed wounds were devoid of staining. Equine exuberant granulation tissue showed immunoreactivity of the surrounding epidermis, infiltrating neutrophils, mononuclear cells, endothelial cells and fibroblasts. Human keloids showed OPN immunoreactivity throughout the epidermis as well as in mononuclear cells and scattered fibroblasts. CONCLUSIONS: Immunohistochemical data show a different pattern of expression between normally healing and fibrotic wounds (exuberant granulation tissue and keloids), thus suggesting a role in fibroproliferation in horses and man. PMID- 25290990 TI - Water availability and calcium propionate affect fungal population and aflatoxins production in broiler finisher feed during storage. AB - The aim of this study was to investigate the effects of calcium propionate, water activity (aw) and incubation time on the total fungal count and aflatoxins B1 (AFB1), B2 (AFB2), G1 (AFG1) and G2 (AFG2) production in the broiler finisher feed. The feed was added with calcium propionate (5 g kg(-1)), adjusted to 0.85, 0.90 and 0.95 aw and stored for 28 days at 25 degrees C, analysing for mould growth and aflatoxins production every 7 days. Analysis of variance indicated that all the factors (preservative, aw and storage time) alone and in combination significantly (p < 0.001) affected the total fungal count and aflatoxins production in the feed. Minimum total fungal counts (1.99 * 10(2) CFU g(-1)) were observed in calcium propionate feed at 0.85 aw on day 1 and the highest (4.36 * 10(9) CFUs g(-1)) in control sample at 0.95 aw on day 28 of storage. During the storage period, AFB1 content in control samples increased from 11.35 to 73.44, from 11.58 to 81.81 and from 11.54 to 102.68 ng g(-1), whereas in preserved feed the content of B1 increased from 11.47 to 37.83, from 11.54 to 49.07 and from 11.20 to 53.14 ng g(-1) at 0.85, 0.90 and 0.95 aw, respectively. Similar patterns were noted for AFB2, AFG1 and AFG2 contents. All the aflatoxins readily increased over storage time; however, the increase was much slower in preserved feed that contained a lower amount of available water. This study reveals that calcium propionate addition to poultry litter along with water activity amelioration is an effective tool for controlling mould incidence and aflatoxin production in poultry feed. PMID- 25290991 TI - Immunity in the respiratory tract. AB - The mucosal surfaces of the gut and respiratory tract are often considered as equivalent from an immunological point of view, a tendency encouraged by the fact that far more is known about gut immunity. But there are profound differences in the defence mechanisms at each type of surface and some of these were discussed at a recent meeting. PMID- 25290992 TI - Autoantibodies and nuclear antigens. AB - Autoantibodies against nuclear antigens are common in the systemic rheumatic diseases. About sixteen such antigens have been characterized and they have been located in all the nuclear compartments. Little is known about the biological roles of these antigens but the significance and function of autoantibodies to them was one of the themes of a recent meeting. PMID- 25290993 TI - Mathematical analysis of the cellular immune reaction against tumour cells. PMID- 25290994 TI - Mast cells in fibrosis. PMID- 25290995 TI - Infectious disease, fever and the immune response. PMID- 25290996 TI - Regulation of lymphoid cell traffic. PMID- 25290997 TI - [Not Available]. PMID- 25290998 TI - [Not Available]. PMID- 25290999 TI - The immune profile of human seminal plasma. PMID- 25291000 TI - Allele-specific alien-driven diversity, immune responsiveness and MHC restriction. AB - Synthetic and environmental antigens are presented to T cells in the context of MHC determinants but, for certain antigens, some determinants are more effective than others(1-3), perhaps because they make an optimal or more immunogenic physical association with the antigen(2,3). Here, Randy Mandell and Paul Sondel use the concepts of immune crossreactivity and 'alien' MHC antigens to propose an alternative explanation for allele-specific MHC-restriction of T-cell responses to certain antigens. Such allele-specific, alien-driven diversity may also be relevant to the relationship between MHC determinants and immune response genes. PMID- 25291001 TI - Reading of D genes in variable frames as a source of antibody diversity. PMID- 25291002 TI - Phagocytes and carcinogenesis. PMID- 25291003 TI - Transmembrane signalling by the T3-antigen receptor complex. AB - Monoclonal antibodies to the T-cell antigen receptor can mimic the effects of antigen and induce cellular activation. In this article john Imboden and his colleagues report on the use of these antibodies as probes to study the mechanism by which the antigen receptor initiates activation. They also describe the critical role of cytoplasmic free calcium in transmembrane signal transduction by the T-cell antigen receptor. PMID- 25291004 TI - Synthesis and secretion of eosinophil granule substances. AB - There has been a rapid growth in knowledge about eosinophils during the past 2 3years. This recent work defined the way in which eosinophil production is regulated; their capacity to make a range of biologically important molecules; the nature of the constituents stored within them; the ways in which they are induced to synthesize and release these products; and, perhaps most important, the effects of these products on parasites, cells and tissues. In this article Christopher Spry reviews several aspects of this recent research. PMID- 25291005 TI - Transplantation tolerance and immunosuppression following liver grafting in rats. AB - Liver grafts between certain inbred rat strains seem to contradict the normal rules of transplantation by surviving and inducing tolerance in animals which would rapidly reject grafts of other organs from the liver donor. A liver graft also has remarkable powers of immunosuppression and can reverse rejection reactions in progress in distant sites. In this review, Naoshi Kamada discusses cellular and molecular mechanisms associated with liver-induced unresponsiveness. PMID- 25291007 TI - Bringing surgeons together across the world: diagnosis and management of acute appendicitis. AB - INTRODUCTION: Despite appendicitis being one of the most common surgical emergencies in the pediatric population, there is still a great deal of debate among pediatric surgeons regarding the workup and treatment. MATERIALS AND METHODS: In an interactive Web symposium consisting of 130 pediatric surgeons from various regions of the world, questions about diagnosis and management of appendicitis were displayed on the screen. The audience was asked to respond to the poll questions. The questions asked to the participants pertained to an example case of a 12-year-old boy presenting to the emergency department with the classic history and exam for appendicitis. RESULTS: The total number of respondents varied between 30 and 37, giving response rates of 23%-28%. Sixty-six percent of respondents would not order imaging. Thirty-one percent said that they would order ultrasound. No participant would order a computed tomography scan, whereas 5% would order some other form. Ninety-five percent of respondents said that they would treat the patient operatively. The majority (89%) of the participants felt comfortable waiting until morning to operate on the patient if the patient arrived at 11 p.m. Fifty-seven percent stated that they would use a three-port laparoscopic approach, and 38% would use a single port, whereas 5% would use an open surgical approach. The majority (34%) reported being able to visualize the appendix as the greatest benefit to using laparoscopy. Fifty-seven percent would give the patient one additional dose of antibiotics and then discharge him 24 hours later following treatment for acute, nonperforated appendicitis. Twenty percent of respondents would give no further antibiotics and would discharge the patient from the recovery room or soon after. Sixteen percent would not give any additional antibiotics and would discharge him 24 hours postoperatively, whereas 6% would give one additional dose of antibiotics and discharge him soon after. CONCLUSIONS: The use of virtual broadcasts affords a unique opportunity to surgeons around the world to share and learn from each other. PMID- 25291008 TI - In vitro neuroprotective activity of sesquiterpenoids from the flower buds of Tussilago farfara. AB - We have isolated four sesquiterpenoids from Tussilago farfara, a traditional herbal medicine in Korea and China, and investigated the protective effects on LPS-induced neuronal cell death. Four sesquiterpenoids inhibited the production of nitric oxide, prostaglandin E2 and tumor necrosis factor-alpha in LPS-treated BV-2 cells through the inhibition of NF-kappaB pathway. These sesquiterpenoids also inhibited reactive oxygen species (ROS) generation in LPS-treated BV-2 cells. Furthermore, they inhibited LPS-induced neuronal cell death in co-culture system through the inhibition of NF-kappaB pathway and scavenging of ROS. These results indicated that sesquiterpenoids from Tussilago farfara may have beneficial therapeutic potential for the treatment of neurodegenerative diseases through inhibition of microglial activation. PMID- 25291009 TI - C-glycosides incorporating the 6-methoxy-2-naphthyl moiety are selective inhibitors of fungal and bacterial carbonic anhydrases. AB - A small series of C-glycosides containing the methoxyaryl moieties was tested for the inhibition of the beta-class carbonic anhydrases (CAs, EC 4.2.1.1) from Cryptococcus neoformans and Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. The deprotected glycosides incorporating the 6-methoxy-2 naphthyl moiety showed the best inhibition profile and therefore represent leads for the development of novel anti-infectives with a new mechanism of action. PMID- 25291010 TI - Indian freshwater edible snail Bellamya bengalensis lipid extract prevents T cell mediated hypersensitivity and inhibits LPS induced macrophage activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Soup prepared from the foot of fresh water edible snail, Bellamya bengalensis, is traditionally consumed by the tribes of Jharkhand against rheumatism like bone and joint inflammation. As rheumatism has underlying involvement of cell mediated hypersensitivity, in vivo delayed-type hypersensitivity (DTH) model and in vitro LPS-induced macrophage signaling were studied to delineate the mechanism by which Bellamya bengalensis exerts its ethnomedicinal function. Since the whole meat is consumed, the lipid of Bellamya bengalensis (BBL) was hypothesized to be the active part. METHODS AND MATERIALS: BBL isolated from the foot part of this species, was characterized and given by gavage daily (10mg BBL/kg; 20mg BBL/kg) to mice for 3 weeks prior to initiating development of DTH. Effects of DTH induced changes in paw diameter, serum nitric oxide (NO), serum tumor necrosis factor (TNF)-alpha level, CINC1 level, splenic CD4(+)/CD8(+) cell ratios, and level of splenic Treg cells were then compared with values in untreated control mice. In vitro effect of BBL on LPS-stimulated macrophage, the immune cell that is active in DTH, was assessed by NF-kB p65 nuclear translocation, reactive oxygen species (ROS), TNFalpha, and NO production. RESULTS: BBL was characterized, and its supplementation in situ led to significant decrease in paw edema, tissue myeloperoxidase activity, NO level, serum TNFalpha level and CINC 1 level as well as decrease in splenic CD4(+)/CD8(+) ratios and increase in level of Treg cells. BBL was shown to inhibit ROS, NO, and TNFalpha production along with NF-kB p65 nuclear translocation in LPS stimulated macrophage. CONCLUSION: Bellamya bengalensis, traditionally used against diseases with underlying etiology of cell mediated immunity as in rheumatism, which acts through inhibition of overexpressed cell mediated immunity. The factor exerting this activity probably is the oleic acid and cyclopropane fatty acid rich lipid, isolated after the ethnomedicinal clue, from the foot of this species. PMID- 25291011 TI - Protective activity of medicinal plants and their isolated compounds against the toxic effects from the venom of Naja (cobra) species. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Various medicinal plants have protective properties against the toxicities of the venom of cobra snake (Naja species). They may be used as local first aid for the treatment of snakebite victims, and can significantly inhibit lethality, cardio-, neuro-, nephro- and myotoxicity, hemorrhage, and respiratory paralysis induced by the cobra snake venom. The plants or their extracts may also complement the benefits of conventional anti serum treatment. AIM OF THE REVIEW: This review provides information on the protective, anti-venom, properties of medicinal plants against snakebites from cobras. In addition, it identifies knowledge gaps and suggests further research opportunities. METHODS: The literature was searched using databases including Google Scholar, PubMed, ScienceDirect, Scopus and Web of Science. The searches were limited to peer-reviewed journals written in English with the exception of some books and a few articles in foreign languages. RESULTS: The plants possess neutralization properties against different cobra venom enzymes, such as hyaluronidase, acetylcholinesterase, phospholipase A2 and plasma proteases. Different active constituents that show promising activity against the effects of cobra venom include lupeol acetate, beta-sitosterol, stigmasterol, rediocides A and G, quercertin, aristolochic acid, and curcumin, as well as the broad chemical groups of tannins, glycoproteins, and flavones. The medicinal plants can increase snakebite victim survival time, decrease the severity of toxic signs, enhance diaphragm muscle contraction, block antibody attachment to venom, and inhibit protein destruction. In particular, the cardiovascular system is protected, with inhibition of blood pressure decline and depressed atrial contractility and rate, and prevention of damage to heart and vessels. The designs of experimental studies that show benefits, or otherwise, of use of medicinal plants have some limitations: deficiency in identification and isolation of active constituents responsible for therapeutic activity; lack of comparison with reference drugs; and little investigation of the mechanism of anti-venom activity. CONCLUSION: Despite some current deficiencies in experimental or clinical analysis, medicinal plants with anti-venom characteristics are effective and so are candidates for future therapeutic agents. We suggest that emphasis on identification and testing of active ingredients in research in the future will assist better understanding of their anti-venom activity. PMID- 25291012 TI - Bioelectrical impedance as a measure of change in body composition in young children. AB - BACKGROUND AND OBJECTIVES: The ability of bioelectrical impedance (BIA) to measure change in body composition in children has rarely been examined. METHODS: Body composition was estimated by BIA (Tanita BC-418) and dual-energy x-ray absorptiometry (DXA) in 187 children aged 4-8 years at baseline and at 12 months. Change in body composition was compared between the two methods using mixed models. RESULTS: Estimates of change in fat mass did not differ between BIA and DXA for overweight girls (mean difference between methods, 95% confidence interval: 0.04 kg, -0.19 to 0.28) or boys (0.07 kg, -0.14 to 0.27). BIA was also able to accurately detect change in fat-free mass, with no significant differences between methods (-0.14 kg, -0.10 to 0.38 in girls and -0.07 kg, -0.35 to -0.20 in boys). Change in percentage fat produced similar estimates in both genders (0.18%, -0.82 to 0.46 in girls and 0.38%, -0.37 to 1.13 in boys). BIA/DXA comparisons in normal weight children were also not significantly different, with the exception of percentage fat in girls, where BIA slightly underestimated change compared with DXA (0.7%, 0.02-0.37). CONCLUSION: BIA performed well as a measure of change in body composition, providing confidence for its use as an outcome measure in children. PMID- 25291013 TI - Why do brains need tau (MAPT)? PMID- 25291015 TI - Bond angles around a tetravalent atom. AB - Relationships among the six bond angles about a central tetravalent atom depend on symmetry, ranging from the most symmetrical Td point group to the least symmetrical C1 point group having only the identity element. Exact relationships are derived here in two ways: (1) a purely algebraic treatment of the general mathematical conditions among the bond angles, followed by factorizations that arise from various symmetry constraints and (2) a reverse approach based on geometric analysis, starting with the most symmetrical Td case and relaxing constraints stepwise to lower point groups. The mathematical formulas show systematically how the degrees of freedom among the bond angles increase from zero to a maximum of five as the symmetry is relaxed from the Td symmetry. PMID- 25291017 TI - C-reactive protein and the acute phase response. PMID- 25291016 TI - Health-related quality of life and depression in a sample of Latin American adults with rheumatoid arthritis. AB - OBJECTIVE: To compare the health related quality of life (HRQoL) and depression of individuals with rheumatoid arthritis (RA) to healthy controls in Colombia, as well as to examine the connections between these two variables in individuals with RA. METHOD: One hundred and three individuals with RA were recruited from ambulatory centers in Colombia. Seventy-three control participants were recruited from the local community. Both groups differed with respect to age, gender and marital status (P < 0.001), while education and socio-economic levels were similar. HRQoL was assessed using the Short Form-36 (SF-36) and depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: A multivariate analysis of covariance found that RA patients reported substantially higher depressive symptoms and lower HRQoL than healthy controls (P < 0.01 and P < 0.05, respectively). The effect sizes of the differences between patients and controls in HRQoL and depressive symptoms were all large. All SF-36 HRQoL variables were significantly correlated with depressive symptoms in patients and controls (P < 0.05). Social functioning and vitality were uniquely associated with depressive symptoms in the RA group (P < 0.01 and P < 0.05, respectively), whereas education and social functioning were uniquely associated with depressive symptoms in controls (P < 0.05 and P < 0.005, respectively). CONCLUSIONS: Research indicates that individuals with RA have deteriorated HRQoL, and this study extends these findings to a Colombian sample and highlights the importance of the independent relationship between depressive symptoms and vitality in this group of Colombians with RA. PMID- 25291018 TI - Judging the state of the art. PMID- 25291019 TI - Assays for sperm antibodies. PMID- 25291014 TI - Detection of lipid-linked peptidoglycan precursors by exploiting an unexpected transpeptidase reaction. AB - Penicillin-binding proteins (PBPs) are involved in the synthesis and remodeling of bacterial peptidoglycan (PG). Staphylococcus aureus expresses four PBPs. Genetic studies in S. aureus have implicated PBP4 in the formation of highly cross-linked PG, but biochemical studies have not reached a consensus on its primary enzymatic activity. Using synthetic Lipid II, we show here that PBP4 preferentially acts as a transpeptidase (TP) in vitro. Moreover, it is the PBP primarily responsible for incorporating exogenous d-amino acids into cellular PG, implying that it also has TP activity in vivo. Notably, PBP4 efficiently exchanges d-amino acids not only into PG polymers but also into the PG monomers Lipid I and Lipid II. This is the first demonstration that any TP domain of a PBP can activate the PG monomer building blocks. Exploiting the promiscuous TP activity of PBP4, we developed a simple, highly sensitive assay to detect cellular pools of lipid-linked PG precursors, which are of notoriously low abundance. This method, which addresses a longstanding problem, is useful for assessing how genetic and pharmacological perturbations affect precursor levels, and may facilitate studies to elucidate antibiotic mechanism of action. PMID- 25291020 TI - Is determinant selection dead? PMID- 25291021 TI - Determinant selection and macrophage function. PMID- 25291022 TI - Heritable alterations in tumor-cell immunogenicity. PMID- 25291023 TI - Accessory cells unrelated to mononuclear phagocytes and not of bone marrow origin. AB - The induction and regulation of immune responses require the participation of cells which maintain lymphocyte viability, promote necessary cellular interactions, secrete immunoregulatory molecules and present antigen. These are accessory cells, and their function is not antigen-specific. Classically, cells of the mononuclear phagocyte lineage have been considered to be the major accessory cell population in most immune responses. More recently, other cell types, such as Langerhans cells of the skin and dendritic cells of the lymphoid organs, have also been shown to be effective. This article reviews the evidence that additional cell types, such as endothelial cells or fibroblasts, serve an accessory role in immune responses. PMID- 25291024 TI - The cloning of T lymphocytes. AB - A new era of cellular immunology is clearly at hand. It is now possible, with a little bit of effort, to isolate monoclonal populations of T cells specific for any given antigen. The implications o f this technological advance are enormous in terms of applications to basic research and clinical medicine. In this article the two basic approaches that have been used to clone T lymphocytes are outlined, the pros and cons of each technique discussed and examples are given of recent experiments which have exploited this technology to gain new insights into T-cell specificity. PMID- 25291025 TI - Regulation of antibody responses by antibody towards the immunogen. PMID- 25291032 TI - Rural Aboriginal health. PMID- 25291034 TI - President's message. Still competent? PMID- 25291031 TI - Delta(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARalpha in MDA-MB-231 breast cancer cells. AB - We recently reported that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB 231 cells. Peroxisome proliferator-activated receptor alpha (PPARalpha) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Delta(9)-THC-treated samples and showed the selective up-regulation of the PPARalpha isoform coupled with the induction of FA2H over the other isoforms (beta and gamma). Delta(9)-THC itself had no binding/activation potential to/on PPARalpha, and palmitic acid (PA), a PPARalpha ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARalpha induced were involved in the Delta(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Delta(9)-THC activated the basal transcriptional activity of PPARalpha in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARalpha/FA2H was caused by Delta(9)-THC, (iii) PA could activate PPARalpha after the PPARalpha expression plasmid was introduced, and (iv) the Delta(9)-THC induced up-regulation of FA2H was further stimulated by the co-treatment with L 663,536 (a known PPARalpha inducer). Taken together, these results support the concept that the induced levels of PPARalpha may be involved in the Delta(9)-THC up-regulation of FA2H in MDA-MB-231 cells. PMID- 25291037 TI - Understanding healthy pregnancies: the perspective of Inuit midwives in northwestern Quebec. AB - INTRODUCTION: For 25 years, Inuit midwives have provided perinatal and newborn care for about 90% of the pregnancies in northwestern Quebec. Patients in this region continue to have high rates of preventable nutritional deficiencies. The objective of this study was to explore the perceptions of professional midwives and students about what makes a healthy pregnancy and a healthy newborn. METHODS: We convened, via teleconference, a semistructured focus group with the local midwives and students. The conversation focused on local understanding of a healthy pregnancy and a healthy newborn, and the role of midwives in the communities. RESULTS: Four midwives and 6 students took part in the focus group, representing 80% of local midwives and students. All of the participants were women, and their professional experience ranged from 3 to 25 years. Through inductive thematic analysis, it became apparent that personal experiences and professional training were important determinants of opinions. Midwives believed that the health of women and infants could be improved through better food selection, particularly reliance on traditional nutrient-rich food. They were aware that iron deficiency was a problem and that infants required vitamin D; however, they reported that supplement uptake was poor. CONCLUSION: Concern was expressed about a decline in traditional beliefs and about unhealthy behaviours. Participants advanced strategies to promote knowledge locally (e.g., visual aids, local radio) to attempt to reduce rates of nutritional deficiencies. PMID- 25291038 TI - Hospital admission for community-acquired pneumonia in a First Nations population. AB - INTRODUCTION: Northwestern Ontario is a large rural area with a high concentration of remote First Nations communities. In Ontario, the highest hospital admission rates for pneumonia are reported from northern and rural regions. However, data are lacking on the epidemiology of community-acquired pneumonia in northwestern Ontario. We sought to characterize cases of community acquired pneumonia requiring admission at the Sioux Lookout Meno Ya Win Health Centre, which serves a primarily First Nations population of 28,000. METHODS: We undertook a 3-year review of cases of community-acquired pneumonia requiring hospital admission at the centre. We used multivariable logistic regression to identify independent variables predictive of adverse outcomes. RESULTS: The annual incidence of hospital admissions related to community-acquired pneumonia was 3.42 per 1000 population. Of the 287 patients, 87% were First Nations and 52% were female. There was a high prevalence of diabetes, and chronic cardiovascular, renal and pulmonary diseases. Hospital admissions for community-acquired pneumonia were most prevalent among young children and older adults; both age groups had low coverage with recommended pneumococcal vaccines. Adverse outcomes included 10 deaths (3%) and 35 transfers to an intensive care facility (12%). Chronic renal disease and nonreceipt of azithromycin at initial presentation were identified as 2 independent predictors of an adverse outcome; there was a trend toward an increased risk of an adverse outcome in individuals with chronic obstructive pulmonary disease. CONCLUSION: Our findings emphasize the importance of preventing pneumonia in First Nations communities in northwestern Ontario. Research focusing on the distinct epidemiology of community-acquired pneumonia in this population is needed. PMID- 25291039 TI - From the community to the classroom: the Aboriginal health curriculum at the Northern Ontario School of Medicine. AB - More undergraduate medical education programs are including curricula concerning the health, culture and history of Aboriginal people. This is in response to growing international recognition of the large divide in health status between Aboriginal and non-Aboriginal people, and the role medical education may play in achieving health equity. In this paper, we describe the development and delivery of the Aboriginal health curriculum at the Northern Ontario School of Medicine (NOSM). We describe a process for curriculum development and delivery, which includes ongoing engagement with Aboriginal communities as well as faculty expertise. Aboriginal health is delivered as a core curriculum, and learning is evaluated in summative assessments. Aboriginal health objectives are present in 4 of 5 required courses, primarily in years 1 and 2. Students attend a required 4 week Aboriginal cultural immersion placement at the end of year 1. Resources of Aboriginal knowledge are integrated into learning. In this paper, we reflect on the key challenges encountered in the development and delivery of the Aboriginal health curriculum. These include differences in Aboriginal and non-Aboriginal knowledge; risk of reinforcing stereotypes in case presentations; negotiation of curricular time; and faculty readiness and development. An organizational commitment to social accountability and the resulting community engagement model have been instrumental in creating a robust, sustainable program in Aboriginal health at NOSM. PMID- 25291040 TI - Country cardiograms case 52. PMID- 25291041 TI - The occasional greater occipital nerve block. PMID- 25291043 TI - The evolving nature of narcotic use in northwestern Ontario. PMID- 25291044 TI - Epidemiology of Strongyloides stercoralis on Mekong islands in southern Laos. AB - Strongyloides stercoralis is a neglected helminth infection potentially that can lead to systemic infection in immunocompromised individuals. In Lao People's Democratic Republic (Lao PDR, Laos), information on S. stercoralis infection is scarce. We assessed S. stercoralis infection and associated risk factors and symptoms on the Mekong islands in Southern Laos. Baermann and Kato-Katz techniques were performed on two stool samples from each individual to detect S. stercoralis larvae and concomitant helminth infections. Among 729 individuals, 41.0% were infected with S. stercoralis. Men were at higher risk than women (OR 1.97, 95% CI 1.45-2.67). Urticaria and body itching was associated with S. stercoralis infection (OR 2.4, 95% CI 1.42-4.05). Infection with Opisthorchis viverrini (72.2%), Schistosoma mekongi (12.8%), and hookworm (56.1%) were very common. Few infections with Trichuris trichiura (3.3%), Ascaris lumbricoides (0.3%) and Taenia spp. (0.3%) were detected. The majority of helminth infections were of light intensity, with prevalences of 80.4%, 92.9%, 64.5%, 100% and 100%, for O. viverrini, hookworm, S. mekongi, T. trichiura and A. lumbricoides, respectively. Nevertheless, heavy infection intensities were observed for O. viverrini (1.0%), S. mekongi (14.0%) and hookworm (2.9%). S. stercoralis is highly endemic on the islands of Khong district, Champasack province, Southern Laos. The national helminth control programme should take action to control this helminth infection. PMID- 25291045 TI - Spotlight on the in vitro effect of artemisinin-naphthoquine phosphate on Schistosoma mansoni and its snail host Biomphalaria alexandrina. AB - Malaria and schistosomiasis are the two most important parasitic diseases in the tropics and sub-tropics with geographic overlap. Efforts have been made for developing new schistosomicidal drugs, or testing existing drugs originally used for non-related diseases. The antimalarial artemisinin-naphthoquine phosphate combination (CO-ArNp) was recently reported to be a promising novel antischistosomal therapy with potent in vivo activity against Schistosoma mansoni. In this work, we report the in vitro dose- and time-response effect of CO-ArNp against the Egyptian strain of S. mansoni, and its snail host, Biomphalaria alexandrina. Incubation of adult S. mansoni with CO-ArNp at 40 or 20 MUg/ml for 48 or 72 h killed all worms. Exposure of S. mansoni miracidia and cercariae to the molluscicidal LC50 of CO-ArNp (16.8 MUg/ml) resulted in 100% mortality of the free larval stages within 90 and 15 min, respectively. Moreover, incubation of adult B. alexandrina snails with this drug combination killed all snails at 40 MUg/ml within 24h. Scanning electron microscope revealed marked morphological and tegumental alterations on the different stages of the parasite and its snail soft tissue. Our study highlights the schistosomicidal and molluscicidal effects of artemisinin-naphthoquine phosphate. No doubt more studies are needed to clarify its potential value to control schistosomiasis. PMID- 25291046 TI - Multiparasitism and intensity of helminth infections in relation to symptoms and nutritional status among children: a cross-sectional study in southern Lao People's Democratic Republic. AB - The occurrence and spatial distribution of intestinal helminth infection in children is fairly well understood. However, knowledge on how helminth infections govern intestinal morbidity is scarce. We conducted a cross-sectional study to assess and quantify the relationship between single and multiple species helminth infection with clinical and self-reported morbidity indicators and nutritional status in Champasack province, southern Lao People's Democratic Republic (Lao PDR). A random sample of 1313 children, aged 6 months to 12 years, from villages in nine rural districts were enrolled and examined for helminth infection using duplicate Kato-Katz thick smears. Morbidity was assessed by self-reported symptoms, coupled with clinical examination and appraisal of nutritional status and anaemia. Bivariate and multivariate logistic regression was employed to study associations between helminth infection and morbidity indicators and anaemia. We found considerable morbidity among the surveyed children, including hepatomegaly (13.7%), pale conjunctiva (13.2%) and abdominal pain (10.4%). Anaemia was recorded in 60.4% of the children, whilst signs of stunting and low body mass index (BMI) were observed in 49.8% and 33.3% of the surveyed children, respectively. Hookworm and Opisthorchis viverrini were the predominant helminth species with prevalences of 51.0% and 43.3%, respectively. The prevalence of Schistosoma mekongi in the surveyed children was 5.6%. Multiple species helminth infections were recorded in 40.4% of the study cohort. Morbidity was associated with specific helminth species infection (e.g. S. mekongi with hepatomegaly; adjusted odds ratio (aOR): 9.49, 95% confidence interval (CI): 2.07-43.51) and multiparasitism (e.g. two or more helminth species with abdominal pain; aOR: 2.40, 95% CI: 1.46-3.93). Anaemia was associated with hookworm infection (aOR: 1.64, 95% CI: 1.16-2.34) and multiparasitism (aOR: 1.64, 95% CI: 1.18-2.29). Low BMI was associated with O. viverrini infection (aOR: 1.68, 95% CI: 1.14-2.49) and multiparasitism (aOR: 1.42, 95% CI: 1.01-2.00). The multiple strong associations reported here between helminth infections (single or multiple species) and intestinal morbidity among children in rural parts of southern Lao PDR call for concerted efforts to control helminth infections, which in turn might improve children's health and development. PMID- 25291047 TI - Dissociation of rapid response learning and facilitation in perceptual and conceptual networks of person recognition. AB - Repetition priming is a prominent example of non-declarative memory, and it increases the accuracy and speed of responses to repeatedly processed stimuli. Major long-hold memory theories posit that repetition priming results from facilitation within perceptual and conceptual networks for stimulus recognition and categorization. Stimuli can also be bound to particular responses, and it has recently been suggested that this rapid response learning, not network facilitation, provides a sound theory of priming of object recognition. Here, we addressed the relevance of network facilitation and rapid response learning for priming of person recognition with a view to advance general theories of priming. In four experiments, participants performed conceptual decisions like occupation or nationality judgments for famous faces. The magnitude of rapid response learning varied across experiments, and rapid response learning co-occurred and interacted with facilitation in perceptual and conceptual networks. These findings indicate that rapid response learning and facilitation in perceptual and conceptual networks are complementary rather than competing theories of priming. Thus, future memory theories need to incorporate both rapid response learning and network facilitation as individual facets of priming. PMID- 25291048 TI - Efficient gene delivery and multimodal imaging by lanthanide-based upconversion nanoparticles. AB - Nanoparticles have been explored as nonviral gene carriers for years because of the simplicity of surface modification and lack of immune response. Lanthanide based upconversion nanoparticles (UCNPs) are becoming attractive candidates for biomedical applications in virtue of their unique optical properties and multimodality imaging ability. Here, we report a UCNPs-based structure with polyethylenimine coating for both efficient gene transfection and trimodality imaging. Cytotoxicity tests demonstrated that the nanoparticles exhibited significantly decreased cytotoxicity compared to polyethylenimine polymer. Further, in vitro studies revealed that the gene carriers are able to transfer the enhanced green fluorescence protein (EGFP) plasmid DNA into Hela cells in higher transfection efficiency than PEI. Gene silencing was also examined by delivering bcl-2 siRNA into Hela cells, resulting in significant downregulation of target bcl-2 mRNA. More importantly, we demonstrated the feasibility of upconversion gene carriers to serve as effective contrast agents for MRI/CT/UCL trimodality imaging both in vitro and in vivo. The facile fabrication process, great biocompatibility, enhanced gene transfection efficiency, and great bioimaging ability can make it promising for application in gene therapy. PMID- 25291049 TI - Protective effects of grape seed extract fractions with different degrees of polymerisation on blood glucose, lipids and hepatic oxidative stress in diabetic rats. AB - The purpose of this study was to evaluate the effect of grape seed procyanidin (GSPE) fractions with different degrees of polymerisation (DPs) on blood glucose, lipids and hepatic oxidative stress in diabetic rats. Diabetic rats received a daily oral supplement of GSPE with different DPs for 6 weeks. During this period, blood glucose, body weight and food intake were assessed weekly. At the end of the experiment, serum lipid and hepatic oxidative stress were assessed compared with those of rats that did not receive GSPE. GSPE significantly decreased blood glucose, serum lipids and hepatic oxidative stress. Moreover, these effects were significantly better in the groups administered the oligomeric rather than the polymeric forms. These results demonstrate that GSPE has a positive effect on diabetes in rats, and the oligomeric form of GSPE may be more protective than other forms. PMID- 25291051 TI - Fifty years of H-2 research. PMID- 25291050 TI - Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. AB - CONTEXT: Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH secreting tumors are discussed. SETTING: A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009-2014. PATIENTS: Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1-21), and 3 are female. MEASUREMENTS: Clinical, biochemical, radiological features, treatment, and histological findings are described. RESULTS: Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). PATIENTS underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor. CONCLUSIONS: Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary. PMID- 25291052 TI - Mapping the autoimmunizing epitopes on acetylcholine receptors. AB - In the autoimmune disease myasthenia gravis (MG), patients experience muscle weakness and fatiguability owing to loss of functional acetylcholine receptors (AChR) at the neuromuscular junction. The loss may be caused by modulation of the receptors by anti-AChR autoantibody and/or by complement-mediated focal lysis at the post-synaptic membrane. The structure of the AChR has been studied primarily because of its function as a neurotransmitter receptor. The benefit of these studies to immunologists investigating MG was illustrated at a recent meeting in which the use of the products of DNA technology to study the immunological mechanisms of MG was among the topics discussed. PMID- 25291053 TI - MHC class I antigens and somatic mutants. PMID- 25291054 TI - How antibodies recognize virus proteins. AB - Numerous studies have addressed the nature of antibody-antigen interaction, but only recently have three-dimensional structures of complexes of antibodies with protein antigens been reported, one with lysozyme and one with the influenza virus antigen neuraminidase. Both structures show that there are epitopes involving about 16 amino acids on surface loops of the antigen. In the lysozyme complex the interaction of the components is rigid, but there is a degree of structural flexibility in the formation of the complex with neuraminidase. In this article, Peter Colman, Graeme Laver and their colleagues discuss some speculative implications of the results currently available. PMID- 25291055 TI - Self-tolerance for erythrocytes is not maintained by clonal deletion of T helper cells. AB - Recent findings suggest that T helper cells specific for autologous erythrocytes are not deleted from the repertoire of the normal animal. Here, Craig Hooper proposes that tolerance of normal erythrocytes is achieved partly by conventional immunoregulation and partly by a novel process which normally prevents priming with autoantigens in vivo. The nature of the initial contact with antigen may determine which mechanism has the primary role. PMID- 25291056 TI - Interleukin 1 and T-cell activation. PMID- 25291057 TI - Is cataract formation an autoimmune phenomenon? PMID- 25291058 TI - The ISCOM: an immunostimulating complex. AB - Vaccine development is based largely upon the use of killed or live attenuated organisms. But most of the components of an organism are irrelevant to the generation of an immune response and some may be positively harmful. Vaccines based on protective antigens have also had a chequered history, largely because of poor antigen immunogenicity and the obligatory use of damaging quantities of adjuvant. Here Bror Morein and colleagues report on an alernative vaccine vehicle -the immunostimulating complex (ISCOM). Composed of the adjuvant Quil A and immunizing peptides, ISCOM particles contain low concentrations of adjuvant and can significantly enhance immunogenicity. If early successes are confirmed, ISCOMs may be significant part of the future vaccine programmes. PMID- 25291059 TI - The molecules controlling B lymphocytes. AB - The need to activate B lymphocytes on antigen challenge is tempered by the requirement that the response is terminated when the challenge has been negotiated. Regulation is probably mediated via the interaction of soluble factors with surface receptors. Here, John Gordon and Graeme Guy review recent work that has focused on the actions of the soluble regulatory mediators and on the surface molecules they may interact with - emphasizing the growing importance of the CD23 antigen. PMID- 25291060 TI - Platelet-activating factor and cellular immune responses. AB - Platelet-activating factor is a phospholipid mediator of the allergic reaction that is a potent stimulator of acute inflammatory processes. It is produced by various inflammatory cells upon activation by immune or nonimmune stimuli. As Pierre Braquet and Marek Rola-Pleszcynski review here, evidence is now accumulating that platelet-activating factor is a component in the regulation of cellular immune responses. PMID- 25291061 TI - Synthesis and biological evaluation of novel peptide BF2 as an antibacterial agent against clinical isolates of vancomycin-resistant enterococci. AB - Enterococci are the leading cause of nosocomial infections worldwide and acquired resistance to a variety of antibiotics. Antimicrobial peptides represent a promising molecule against the antibiotic resistance in bacteria and an indispensable component of the innate immune system. The aim of the study was to develop an antimicrobial peptide against vancomycin-resistant enterococci (VRE). We have designed a series of peptides based on Sapecin B as template. An in vitro antibacterial study of synthetic peptide BF2 against the clinical isolates of vancomycin-resistant and control strains of enterococci showed rapid killing effect on enterococci by killing 99.9% of bacterial cells in 60 min and susceptibility at minimum inhibitory concentration (MIC) range of 6.25-12.5 MUg/mL. Synergy of BF2 was observed in combination with vancomycin and teicoplanin. The peptide was bactericidal and nontoxic to mammalian cells. An in vivo study also revealed the antibacterial activity against enterococci-infected Wistar albino rats. BF2 may be used synergistically with antibiotics. PMID- 25291062 TI - The inherence heuristic across development: systematic differences between children's and adults' explanations for everyday facts. AB - The inherence heuristic is a basic cognitive process that supplies quick-and-easy answers to what are, in reality, incredibly complex questions about why the broad patterns of the world are as they are (Cimpian & Salomon, 2014-a, 2014-b). This explanatory heuristic satisfies the human need to understand, but it is also a source of bias because the heuristic relies too often on the (easily accessible) inherent features of the entities in the patterns being explained. Here, we investigated the developmental trajectory of this heuristic. Given that the cognitive resources that help override the typical output of the inherence heuristic are scarce in childhood, we hypothesized that the heuristic's output would be more broadly endorsed by children than by adults. Five experiments involving young children and adults (N=480) provided consistent support for this hypothesis. The first three experiments (Part I) investigated participants' explanations for broad patterns (e.g., fire trucks are red) and suggested that, consistent with our predictions, children were particularly likely to endorse inherence-based explanations. The last two experiments (Part II) investigated two intuitions that accompany the output of the inherence heuristic: namely, that the patterns being explained cannot be changed and are temporally stable. As predicted, participants' judgments on these dimensions showed the same developmental differences as the explanations investigated in Part I, with children being particularly likely to see patterns as inalterable and temporally stable. The developmental differences found across these five experiments suggest that children start out with a broad reliance on the explanatory output of the inherence heuristic, a reliance that narrows in scope to some extent as children develop. PMID- 25291064 TI - HLA-DR bouillabaisse. PMID- 25291063 TI - The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue. AB - Intestinal invasion by the protozoan parasite Entamoeba histolytica is characterized by remodelling of the extracellular matrix (ECM). The parasite cysteine proteinase A5 (CP-A5) is thought to cooperate with human matrix metalloproteinases (MMPs) involved in ECM degradation. Here, we investigate the role CP-A5 plays in the regulation of MMPs upon mucosal invasion. We use human colon explants to determine whether CP-A5 activates human MMPs. Inhibition of the MMPs' proteolytic activities abolishes remodelling of the fibrillar collagen structure and prevents trophozoite invasion of the mucosa. In the presence of trophozoites, MMPs-1 and -3 are overexpressed and are associated with fibrillar collagen remodelling. In vitro, CP-A5 performs the catalytic cleavage needed to activate pro-MMP-3, which in turn activates pro-MMP-1. Ex vivo, incubation with recombinant CP-A5 was enough to rescue CP-A5-defective trophozoites. Our results suggest that MMP-3 and/or CP-A5 inhibitors may be of value in further studies aiming to treat intestinal amoebiasis. PMID- 25291065 TI - T-cell receptors: on the track of Tau? AB - Although the structure of the T cell's receptor for antigen is still a puzzle, antigen-binding material can be isolated from T cells. Now several different kinds of independently isolated 'T-cell product' have been found to have antigens in common. Are these determinants of a constant region on an elusive 'IgT'? PMID- 25291066 TI - The influence of T lymphocytes on antibody-induced B-cell suppression. AB - IgG antibody complexxd with antigen can inhibit the B lymphocytes which produced the antibody. Helper T cells make factors which interfere with this feedback loop. Could the reversal by T-cell factors of the repressed stale induced in B cells by immune complexes be a physiological trigger of immunoglobulin production? PMID- 25291067 TI - B-lymphocyte subpopulations. AB - B lymphocytes are exceptionally diverse, partly because different clones have membrane receptors with specificities for different antigens and partly because the cells exist in a series of distinct differentiation states and may constitute more than a single cellular lineage. In this article John Kung and William Pail discuss heterogeneity with particular reference to the subpopulations of immunoglobidin-bearing B lymphocytes and their distinctive properties. PMID- 25291068 TI - Thymus in vitro. PMID- 25291069 TI - The immunopathogenesis of dengue haemorrhagic fever. AB - Over the past 20 years, dengue haemorrhagic fever (DHF) has been the subject of intensive epidemiological, clinical, virological and immunological investigations. Considerable debate and controversy have surrounded its causation and the probable role of immunological mechanisms in its pathogenesis. The exact cause of DHF is still uncertain and this article reviews current thinking about the problem. PMID- 25291070 TI - B-lymphocyte function in immunodeficiency disease. AB - While B lymphocytes were originally named after their developmental site in the bursa of, Fabricius of chickens, it is currently accepted that bone marrow is the primary site of early events in the differentiation of postnatal B lymphocytes in humans and other mammals(1). B cells subsequently become widely dispersed in the circulation and peripheral lymphoid tissues. This review summarizes defects in the early and late stages of differentiation of B lymphocytes which contribute to immunologic dysfunction in the naturally occurring immunodeficiency diseases. PMID- 25291073 TI - Cryptic speciation in the white-shouldered antshrike (Thamnophilus aethiops, Aves - Thamnophilidae): the tale of a transcontinental radiation across rivers in lowland Amazonia and the northeastern Atlantic Forest. AB - The growing knowledge on paleogeography and the recent applications of molecular biology and phylogeography to the study of the Amazonian biota have provided a framework for testing competing hypotheses of biotic diversification in this region. Here, we reconstruct the spatio-temporal context of diversification of a widespread understory polytypic Amazonian bird species (Thamnophilus aethiops) and contrast it with different hypotheses of diversification and the taxonomy currently practiced in the group. Sequences of mtDNA (cytochrome b and ND2) and nuclear (beta-fibrinogen introns 5 and 7 and the Z-liked Musk4) genes, adding up to 4093bp of 89 individuals covering the Amazonian, Andean, and Atlantic Forest populations of T. aethiops were analyzed. Phylogenetic and population genetics analyses revealed ten reciprocally monophyletic and genetically isolated or nearly-isolated lineages in T. aethiops, highlighting several inconsistencies between taxonomy and evolutionary history in this group. Our data suggest that the diversification of T. aethiops started in the Andean highlands, and then proceeded into the Amazonian lowlands probably after the consolidation of the modern Amazonian drainage. The main cladogenetic events in T. aethiops may be related to the formation and structuring of large Amazonian rivers during the Late Miocene-Early Pleistocene, coinciding with the dates proposed for other lineages of Amazonian organisms. Population genetics data do not support climatic fluctuations as a major source of diversification in T. aethiops. Even though not entirely concordant with paleobiogeographic models derived from phylogenies of other vertebrate lineages, our results support a prominent role for rivers as major drivers of diversification in Amazonia, while underscoring that different diversification scenarios are probably related to the distinct evolutionary origins of groups being compared. PMID- 25291074 TI - Phylogeography and species boundaries of Leptopelis (Anura: Arthroleptidae) from the Albertine Rift. AB - The genus Leptopelis occurs in multiple habitats throughout sub-Saharan Africa, and it includes several species that have highly variable color patterns, which makes taxonomic studies challenging. In this study, we examined multiple populations of Leptopelis from the Albertine Rift (AR), a region known for its high levels of endemism and biodiversity. Currently, five species are recognized from the AR: L. anebos, L. fiziensis, L. karissimbensis, L. kivuensis, and L. mtoewaate, most of which are found in and around the Itombwe Plateau in Democratic Republic of the Congo (DRC). We sampled 90 individuals of Leptopelis from multiple localities in DRC, Uganda, Rwanda and Burundi. We employed concatenated gene-tree analyses, coalescent species-tree analyses, and divergence dating approaches to infer phylogenies and biogeographic patterns with a multi locus data set consisting of two mitochondrial (16S and cyt b) and one nuclear gene (RAG1). All analyses revealed several cryptic lineages within the genus, suggesting that a revision of AR Leptopelis taxonomy is needed. PMID- 25291075 TI - Multidisciplinary team conferences promote treatment according to guidelines in rectal cancer. AB - BACKGROUND: Multidisciplinary team (MDT) conferences have been introduced into standard cancer care, though evidence that it benefits the patient is weak. We used the national Swedish Rectal Cancer Register to evaluate predictors for case discussion at a MDT conference and its impact on treatment. MATERIAL AND METHODS: Of the 6760 patients diagnosed with rectal cancer in Sweden between 2007 and 2010, 78% were evaluated at a MDT. Factors that influenced whether a patient was discussed at a preoperative MDT conference were evaluated in 4883 patients, and the impact of MDT evaluation on the implementation of preoperative radiotherapy was evaluated in 1043 patients with pT3c-pT4 M0 tumours, and in 1991 patients with pN+ M0 tumours. RESULTS: Hospital volume, i.e. the number of rectal cancer surgical procedures performed per year, was the major predictor for MDT evaluation. Patients treated at hospitals with < 29 procedures per year had an odds ratio (OR) for MDT evaluation of 0.15. Age and tumour stage also influenced the chance of MDT evaluation. MDT evaluation significantly predicted the likelihood of being treated with preoperative radiotherapy in patients with pT3c pT4 M0 tumours (OR 5.06, 95% CI 3.08-8.34), and pN+ M0 (OR 3.55, 95% CI 2.60 4.85), even when corrected for co-morbidity and age. CONCLUSION: Patients with rectal cancer treated at high-volume hospitals are more likely to be discussed at a MDT conference, and that is an independent predictor of the use of adjuvant radiotherapy. These results indirectly support the introduction into clinical practice of discussing all rectal cancer patients at MDT conferences, not least those being treated at low-volume hospitals. PMID- 25291076 TI - High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors. AB - BACKGROUND: Evidence has suggested that radiation therapy with a lower dose per fraction may be a reasonable option for the treatment of centrally located non small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of two proton beam therapy (PBT) protocols for stage I NSCLC and to determine prognostic factors. MATERIAL AND METHODS: This study included patients clinically diagnosed with stage I NSCLC. Based on the location of the tumor, one of the two PBT protocols was administered. Patients with peripherally located tumors were given 66 Gy relative biological dose effectiveness (RBE) over 10 fractions (Protocol A) while patients with centrally located tumors were given 80 Gy (RBE) over 25 fractions (Protocol B). RESULTS: Between January 2009 and May 2012, 56 eligible patients were enrolled (protocol A: 32 patients; protocol B: 24 patients). The three-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 81.3% [95% confidence interval (CI) 75.9 86.7%], 73.4% (95% CI 67.2-79.6%), and 96.0% (95% CI 93.2-98.8%), respectively. There were no significant differences in outcomes between the two protocols. Late grade 2 and 3 pulmonary toxicities were observed in nine patients (13.4%) and one patient (1.5%), respectively; no grade 4 or 5 toxicities were observed. Sex, age, performance status, T-stage, operability, and tumor pathology were not associated with OS and PFS. Only maximum standardized uptake value (SUVmax; <5 vs. >=5) was identified as a significant prognostic factor for OS and PFS. CONCLUSION: Both high-dose PBT protocols achieved high LC rates with tolerable toxicities in stage I NSCLC patients, and SUVmax was a significant prognostic factor. PMID- 25291077 TI - Age dependent prognosis in concurrent chemo-radiation of locally advanced NSCLC. AB - BACKGROUND: Clinical trials indicate that the benefit of adding concurrent chemotherapy to radiotherapy of locally advanced non-small cell lung cancer (NSCLC) for fit elderly is similar to the benefit for younger patients. However, since elderly patients are under-represented in most trials, the results might be due to selection bias, thus reports from a cohort of consecutively treated patients are warranted. The current single institution study reports on the influence of age on survival of locally advanced NSCLC patients treated with radiotherapy combined with or without concurrent chemotherapy. MATERIAL AND METHODS: Altogether, 478 patients completed radical radiotherapy in doses of 60 66 Gy/30-33 fractions from 1995 to June 2012; 137 of the patients had concurrent chemotherapy. The data was analyzed in age groups<60, 60-69, and >=70 years. RESULTS: In the analyses of overall and lung cancer specific survival the hazard ratio was related to the use of concurrent chemotherapy was 0.49 (95% CI 0.29; 0.82), 0.68 (95% CI 0.48; 0.98) and 1.01 (95% CI 0.67; 1.51) for the age groups<60, 60-69, and >=70, respectively. CONCLUSION: Use of concurrent chemotherapy to radiotherapy of locally advanced NSCLC was associated with a survival benefit in patient younger than 70 years which was not the case for patients older than 70 years, indicating the need to be careful when selecting elderly patients for concurrent chemo-radiation. PMID- 25291078 TI - Acute aortic dissection in a patient with metastatic renal cell carcinoma treated with axitinib. PMID- 25291079 TI - A prospective analysis on fatigue and experienced burden in informal caregivers of cancer patients during cancer treatment in the palliative phase. AB - BACKGROUND: Although fatigue is the most frequently occurring symptom in patients with cancer, hardly anything is known about fatigue of their informal caregivers and the impact fatigue might have on perceived burden with providing care. We investigated the presence of fatigue in caregivers, its course and the relation of fatigue severity between caregivers and patients. Furthermore, we explored in caregivers whether fatigue severity was correlated to experienced burden. MATERIAL AND METHODS: Informal caregivers and patients on cancer treatment in the palliative phase completed questionnaires at baseline and follow-up (6 months later). To measure fatigue severity, both groups completed the Checklist Individual Strength. Additionally, caregivers completed the Caregivers Strain Index to assess experienced burden with providing care. Descriptive analyses, paired t-tests, chi(2)-tests, Pearson's correlations and regression analysis were performed. RESULTS: At baseline 111 couples (patients and caregivers) participated, at follow-up 75 couples. At both time points 23% of caregivers were severely fatigued. There was no significant correlation between patients and caregivers on fatigue. Higher fatigue in both patients and caregivers was correlated with higher burden in caregivers and over 30% of burden could be explained by fatigue. CONCLUSION: Almost a quarter of caregivers of patients on active palliative treatment were severely fatigued, which figure remained stable over time. Fatigue in both patients and caregivers was related to caregivers' burden. This observation should be taken into account with the growing demand on caregivers and the increase in cancer treatment options in the palliative setting. PMID- 25291081 TI - Working together to support breastfeeding. PMID- 25291085 TI - Health and economic burden of obesity in elderly individuals with asthma in the United States. AB - The health and economic burden of obesity among elderly individuals with asthma has not been adequately studied. This study assessed the association between obesity and asthma among the elderly and examined the impact of obesity on asthma related and total health care costs among elderly individuals with asthma. This was a retrospective analysis of the 2006-2010 Medical Expenditure Panel Survey (MEPS) data. Individuals aged 65 years or older were included in the study. Individuals with asthma were identified by an International Classification of Diseases, Ninth Revision code of 493 or a Clinical Classification Code of 128. Individuals with a self-reported body mass index >= 30 kg/m(2) were considered to be obese. Logistic regression was used to assess the relationship between obesity and asthma. Generalized linear models with gamma distribution and log link were used to assess the relationship between obesity and asthma-related and total direct medical costs. All analyses were conducted while accounting for the complex survey design of MEPS. In all, 675 elderly individuals were identified as having asthma, 292 of whom were obese. Obese elderly individuals were more likely to suffer from asthma as compared to the nonobese (odds ratio, 1.71; 95% confidence interval [CI],1.37-2.12). Obesity was a significant predictor of asthma-related costs (beta: 0.537; 95% CI: 0.18-0.89; P= 0.003) and total health care costs (beta: 0.154; 95% CI: 0.08-0.23; P = 0.001) among elderly individuals with asthma after controlling for sociodemographics and comorbidities. Appropriate weight management measures should be recommended to obese elderly individuals with asthma to improve asthma control and reduce health care costs. PMID- 25291080 TI - Looking for the roots of cortical sensory computation in three-layered cortices. AB - Despite considerable effort over a century and the benefit of remarkable technical advances in the past few decades, we are still far from understanding mammalian cerebral neocortex. With its six layers, modular architecture, canonical circuits, innumerable cell types, and computational complexity, isocortex remains a challenging mystery. In this review, we argue that identifying the structural and functional similarities between mammalian piriform cortex and reptilian dorsal cortex could help reveal common organizational and computational principles and by extension, some of the most primordial computations carried out in cortical networks. PMID- 25291087 TI - Emotional reactions to crime across cultures. AB - Information about the emotions experienced by observers when they witness crimes would have important theoretical and practical implications, but to date no study has broadly assessed such emotional reactions. This study addressed this gap in the literature. Observers in seven countries viewed seven videos portraying actual crimes and rated their emotional reactions to each using 14 emotion scales. Observers reported significantly high levels of negative emotions including anger, contempt, disgust, fear and sadness-related emotions, and anger, contempt and disgust were the most salient emotions experienced by viewers across all countries. Witnesses also reported significantly high levels of positive emotions as well (compared to not feeling the emotion at all), which was unexpected. Country moderated the emotion ratings; post-hoc analyses indicated that masculine-oriented cultures reported less nervousness, surprise, excitement, fear and embarrassment than feminine cultures. PMID- 25291086 TI - Unlocking a caged lysosomal protein from a polymeric nanogel with a pH trigger. AB - A polymeric nanogel has been used to sequester and turn off a lysosomal protein, acid alpha-glucosidase (GAA). The nanogel contains a beta-thiopropionate cross linker, which endows the nanogel with pH-sensitivity. While encapsulation of the enzyme fully turns off its activity, approximately 75% of the activity is recovered upon reducing the pH to 5.0. The recovered activity is ascribed to pH induced degradation of the beta-thiopropionate cross-linker causing the swelling of the nanogel and ultimately causing the release of the enzyme. We envision that strategies for sequestering protein molecules and releasing them at lysosomal pH might open up new directions for therapeutic treatment of lysosomal storage diseases. PMID- 25291088 TI - Rare Disease: Lobar Holoprosencephaly With a Median Cleft Lip-Case Report. AB - Holoprosencephaly is a complex malformation of the brain associated with the median facial defects. Variability of the clinical picture is the characteristic of this anomaly. In most cases, the degree of severity of the facial anomaly correlates with the degree of damage to the brain. This article aims to present a rare case of child with a milder form of brain anomaly combined with a severe form of facial anomaly. The article also presents the application of a feeding stimulator to improve the child's quality of life. The anomaly was diagnosed by postnatal sonography of the brain, magnetic resonance imaging of the endocranium, and three-dimensional computed tomography of the craniofacial skeleton. PMID- 25291089 TI - A Diagnostic Conundrum: Ectopic Nasal Ossification, Submucosal Alveolar Cleft, Absent Posterior Atlantal Arch, and Corpus Callosum Lipoma. AB - A 19-year-old woman was referred for nasal breathing and aesthetic concerns regarding her nose. A computed tomography scan revealed a massive osseous shield anterior to the piriform aperture. Furthermore, there was a submucosal median alveolar cleft, and the posterior arch of C1 was missing. The magnetic resonance imaging brain scan revealed a curvilinear lipoma of corpus callosum. The ectopic nasal bone was removed by open rhinoplast,y and nasal function and aesthetics were restored. The described features defy conventional clinical diagnosis and severity classifications and present a diagnostic conundrum somewhere between a mild form of frontonasal dysplasia, oculoauriculofrontonasal syndrome, and Pai syndrome. PMID- 25291090 TI - Antigen recognition by T cells. PMID- 25291091 TI - Cytokines and their receptors. PMID- 25291094 TI - Primary and acquired immunodeficiency disorders. PMID- 25291093 TI - B-cell differentiation. PMID- 25291092 TI - Draft proposals for interleukin nomenclature. PMID- 25291095 TI - Autoimmune disorders. PMID- 25291096 TI - Reproductive immunology. PMID- 25291098 TI - Immunoparasitology. PMID- 25291097 TI - The regulation of the IgE response. PMID- 25291100 TI - Notes. PMID- 25291099 TI - Lymphocyte migration. PMID- 25291101 TI - The selection of the alpha,beta heterodimeric T-cell receptor for antigen. AB - T cells express alpha,beta heterodimeric receptor proteins which are involved in the MHC-restricted binding of antigen (1,2). The nucleotide sequences of T-cell receptor genes(3-6) have not provided an obvious explanation for the 'MHC-ness' of T-cell specificity or the different specificity of T-cell subsets. The binding of alpha,beta heterodimeric T-cell receptors has not yet been studied in solution so it is possible that T cells express additional molecules that are involved in antigen binding. Recent experimental data(7), reviewed in our last issue (Immunol. Today 1986, 7, 308-311) indicate that the alpha,beta heterodimer alone is responsible for the MHC-restricted specificity of T cells. Here, Harald von Boehmer discusses the implications of these data and presents a model for the selection of alpha,beta heterodimeric T-cell receptors during T-cell differentiation in the thymus. PMID- 25291102 TI - How do T cells mediate autoimmune thyroiditis? AB - Susceptibility to experimental autoimmune thyroiditis (EAT) is linked to the mouse H-2 complex(1). Initiation of the condition by the thyroid antigen, thyroglobulin (Tg), requires T cells from susceptible mice(2). These T cells are autoreactive in that they recognize Tg and proliferate in vitro in response to it(3). The 1980s have brought forth confirmatory data from several laboratories on T-cell autoreactivity to mouse Tg both in vivo(4,5) and in vitro(6-13), and its correlation with EAT susceptibility. T cells from patients with Hashimoto's thyroiditis (HT), may proliferate in response to stimulation in vitro with human Tg(14-16). The capacity of murine T cells to expand and differentiate in vitro(17,18) and to serve as effector cells causing thyroiditis in vivo(7,8, 11,12) is strongly indicative of their pathogenic role. We are now in a position to discuss not only if T cells mediate autoimmune thyroiditis, but how they might contribute to the pathogenic process. At least two antigen-activated T-cell subsets seem to participate in initiating and perpetuating thyroid destruction. In this article, Yi-chi Kong and her colleagues present a synopsis of the supporting data from the mouse model and parallel findings from HT patients. PMID- 25291103 TI - Protein kinase C in T-cell regulation. AB - Protein kinase C (PKC) is activated when a T cell is stimulated by antigen or mitogen: the binding of receptor and ligand induces hydrolysis of phosphatidylinositol phosphates and production of the PKC activating substance diacylglycerol. However, the biochemical consequences of PKC activation are complex. Here, Wulf Drdge discusses the various positive and negative effects of PKC activation on cell proliferation and on the functional activation of helper and cytotoxic T cells. PMID- 25291104 TI - The production of more useful monoclonal antibodies I. Modifications of the basic technology. AB - Hybridoma technology has greatly expanded the usefulness and application of immunoassays and created the potential for in-vivo immunodiagnosis and therapy. While the basic technique has not changed appreciably, a number of modifications have been introduced which make it possible to obtain more useful monoclonal antibodies and to generate monoclonals against weakly immunogenic substances. In this first part of a two-part review, Matthew Scharff and his colleagues review the most useful of these modifications in the production of animal monoclonal antibodies, paying particular attention to the problem of raising antibodies against small amounts of weak immunogens. PMID- 25291105 TI - A better screening tool for HIV-associated neurocognitive disorders: is it what clinicians need? AB - OBJECTIVE: Existing screening tools for HIV-Associated Neurocognitive Disorders (HAND) may lack the accuracy required for clinical use. We hypothesized that the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) as a screening tool for HAND might be improved with a stronger scoring methodology. DESIGN: Two hundred HIV-positive participants aged 18-65 years completed the MoCA and a battery of neuropsychological tests. METHODS: HAND diagnosis was established according to the Frascati criteria, and an NPZ-8 score was also calculated. Rasch analysis was applied to the MoCA items to create a quantitative score. RESULTS: The optimal cut-off on the quantitative MoCA for detecting impairment as per Frascati criteria yielded a sensitivity of 0.74 and a specificity of 0.68. Overall accuracy was 0.79 (95% CI: 0.73-0.85), an improvement over standard scoring methods. However, whether cognition was quantified with the quantitative MoCA or with NPZ-8, there was substantial overlap between diagnostic categories; several individuals categorized as impaired had better overall cognitive function as assessed by NPZ-8 or quantitative MoCA than those classified as normal using standard criteria. CONCLUSION: Quantifying performance on MoCA items through Rasch analysis improves its accuracy as a screening tool for HAND, and demonstrates that cognition can be measured as a unidimensional construct in HIV, at least at the level of precision of bedside testing. However, the current categorical diagnostic approach to HAND is poorly aligned with summary measures of cognitive ability. Measuring cognition as a quasi-continuous construct may be more relevant than conventional HAND diagnostic categories for many clinical purposes. PMID- 25291107 TI - Carrier-specific induction of hapten-specific suppression. PMID- 25291106 TI - Improvement of dual-leached polycaprolactone porous scaffolds by incorporating with hydroxyapatite for bone tissue regeneration. AB - Polycaprolactone (PCL)/hydroxyapatite (HA) composite scaffolds were prepared by combining solvent casting and salt particulate leaching with a polymer leaching technique. The hydrophilicity of the dual-leached scaffold was improved by alkaline (NaOH) treatment. Well-defined interconnected pores were detected by scanning electron microscopy. The water absorption capacity of the NaOH-treated PCL/HA dual-leached scaffold increased greatly, confirming that the hydrophilicity of the scaffold was improved by NaOH treatment. The compressive modulus of the PCL/HA dual-leached scaffold was greatly increased by the addition of HA particles. An indirect evaluation of the cytotoxicity of all PCL dual leached scaffolds with mouse fibroblastic cells (L929) and mouse calvaria-derived pre-osteoblastic cells (MC3T3-E1) indicated that the PCL dual-leached scaffolds are non-toxic to cells. The ability of the scaffolds to support mouse calvaria derived pre-osteoblastic cell (MC3T3-E1) attachment, proliferation, differentiation, and mineralization was also evaluated. Although the viability of cells was lower on the PCL/HA dual-leached scaffold than on the tissue-culture polystyrene plates (TCPS) and on the other substrates at early time points, both the PCL and NaOH-treated PCL/HA dual-leached scaffolds supported the attachment of MC3T3-E1 at significantly higher levels than TCPS. During the proliferation period (days 1-3), all of the PCL dual-leached scaffolds were able to support the proliferation of MC3T3-E1 at higher levels than the TCPS; in addition, the cells grown on NaOH-treated PCL/HA dual-leached scaffolds proliferated more rapidly. The cells cultured on the surfaces of NaOH-treated PCL/HA dual-leached scaffolds had the highest rate of mineral deposition. PMID- 25291108 TI - Eosinophil effector functions. PMID- 25291109 TI - T-cell-mediated suppression of hemopoiesis. PMID- 25291110 TI - Prospects for vaccinating against pregnancy. PMID- 25291111 TI - The cellular basis of allograft rejection. PMID- 25291112 TI - Role of polyclonal B-cell activation in self/non-self discrimination. PMID- 25291114 TI - Prebiotics and probiotics and the specialized UN agencies. PMID- 25291115 TI - Can Lactobacillus fermentum LF10 and Lactobacillus acidophilus LA02 in a slow release vaginal product be useful for prevention of recurrent vulvovaginal candidiasis?: A clinical study. AB - OBJECTIVE: To assess the effectiveness of the association of 2 specific strains, Lactobacillus fermentum LF10 (DSM 19187) and Lactobacillus acidophilus LA02 (DSM 21717), specifically formulated in slow-release effervescent tablets, in patients with recurrent vulvovaginal candidiasis. STUDY DESIGN: The study was a clinical trial of 58 women diagnosed with recurrent VVC (>=4 culture-confirmed episodes in a 12-mo period). All patients were given 200 mg of fluconazole orally as an induction dose for 3 alternate days during the first treatment week. Afterward, the patients were given a new product formulated in slow-release vaginal tablets containing at least 0.4 billion live cells of each of lactobacillus L. fermentum LF10 and L. acidophilus LA02 (first phase of the prophylactic period), on alternate days for 10 consecutive nights. Patients who were still free of symptoms were given 1 vaginal tablet every week for the next 10 weeks (second phase of the prophylactic period). Patients asymptomatic after the total duration of the observation phase (7 mo) were considered as responders. RESULTS: During the second 10-week prophylactic phase, 49 of 57 (86.0%) patients remained free of clinical recurrence, whereas symptomatic VVC occurred in 8 patients (14.0%). During the 7-month follow-up, 42 patients of 49 (85.7%) were symptom free at the end of the protocol, whereas clinical recurrences occurred in 7 women (14.3%). Overall, 42 of 58 women enrolled in the study (72.4%) experienced no clinical recurrence throughout the 7-month observation phase (responders). CONCLUSIONS: This study strengthens the evidence supporting the use of specific lactobacilli with well-demonstrated activities associated with the creation and maintenance of a vaginal biofilm that hinders the persistence of an infection caused by Candida. PMID- 25291116 TI - Effectiveness of the two microorganisms Lactobacillus fermentum LF15 and Lactobacillus plantarum LP01, formulated in slow-release vaginal tablets, in women affected by bacterial vaginosis: a pilot study. AB - BACKGROUND: Bacterial vaginosis (BV) is the most common reason for abnormal vaginal discharge in reproductive-age women and one of its most important causative agents is the gram-variable bacterium Gardnerella vaginalis. BV is not accompanied by significant local inflammation, whereas the "fishy odor" test is always positive. In contrast, aerobic vaginitis (AV) is predominantly associated with Escherichia coli, but Streptococcus agalactiae and Staphylococcus aureus are also involved. Standard treatment of BV consists of oral or intravaginal antibiotics, although these are unable to spontaneously restore normal flora characterized by a high concentration of lactobacilli. The main limitation is the inability to offer a long-term defensive barrier, thus facilitating relapses and recurrences. This study was undertaken firstly to assess the ability of selected lactobacilli to in vitro antagonize G. vaginalis to determine an association with a strain able to inhibit E. coli, thus identifying a possible use in AV. The second step of the study was to conduct a human pilot trial in women affected by BV using an association of the most promising and active bacteria. MATERIALS AND METHODS: For this purpose, neutralized supernatants of individual lactobacilli were tested at percentages ranging from 0.5% to 4% to determine their ability to hinder the growth of G. vaginalis American Type Culture Collection 10231. The bacterium that was able to exert the strongest inhibition was subsequently tested with Lactobacillus plantarum LP01 in a human intervention, placebo-controlled, pilot trial involving 34 female subjects (aged between 18 and 50, mean 34.7+/ 8.9, no menopausal women) diagnosed with BV. The 2 microorganisms Lactobacillus fermentum LF15 (DSM 26955) and L. plantarum LP01 (LMG P-21021) were delivered to the vagina by means of slow-release vaginal tablets, also containing 50 mg of tara gum. The amount of each strain was 400 million live cells per dose. The women were instructed to apply a vaginal tablet once a day for 7 consecutive nights, followed by 1 tablet every 3 nights for a further 3-week application (acute phase) and, finally, 1 tablet per week to maintain a long-term vaginal colonization against possible recurrences. A clinical examination was performed and the Nugent score was quantified for each patient at enrollment (d0), after 28 days (d28), and at the end of the second month of relapse prevention (d56). A statistical comparison was made between d28, or d56, and d0, and between d56 and d28 to quantify the efficacy against possible recurrences. RESULTS: L. fermentum LF15 showed the strongest in vitro inhibitory activity towards G. vaginalis American Type Culture Collection (ATCC) 10231 after both 24 and 48 hours. In the human trial, the 2 lactobacilli selected, namely L. fermentum LF15 and L. plantarum LP01, significantly reduced the Nugent score below the threshold of 7 after 28 days in 22 patients of 24 in the active group (91.7%, P<0.001). Eight women (33.3%) recorded a Nugent score between 4 and 6, evidence of an intermediate situation, whereas the remaining 14 (58.3%) showed a score <4, therefore suggesting the restoration of physiological vaginal microbiota. At the end of the second month, only 4 women registered a Nugent score >7, definable as BV (16.7%, P=0.065 compared with d28). In the placebo group, no significant differences were recorded at any time. CONCLUSIONS: BV, also known as vaginal bacteriosis is the most common cause of vaginal infection in women of childbearing age. Furthermore, BV is often asymptomatic as about 50% of women with this condition have no symptoms at all and the prevalence rate in apparently healthy women is around 10%. This study suggests the ability of the 2 strains L. fermentum LF15 and L. plantarum LP01 to counteract acute Gardnerella infections effectively and significantly improve the related uncomfortable symptoms in a very high percentage of women. This could be partially attributed to the presence of tara gum, which is able to create a mechanical barrier against Gardnerella on the surface of vaginal mucosa as a primary mechanism. Furthermore, long-term physiological protection seems to be established, thanks to the integration of the 2 lactobacilli into the vaginal microbiota and to their adhesion to the epithelial cells of the mucosa. In the light of the additional in vitro inhibitory activity against E. coli, their prospective use in AV could also prove interesting. PMID- 25291117 TI - Protective effects of lactococci strains delivering either IL-10 protein or cDNA in a TNBS-induced chronic colitis model. AB - BACKGROUND: Oral treatment with Lactococcus lactis strains secreting the anti inflammatory cytokine interleukin (IL)-10 has previously shown success as a therapy for inflammatory bowel diseases (IBD). GOALS: Our aim was to compare the protective effects of IL-10, delivered by recombinant lactoccoci using 2 novel expression systems, in a murine colitis model mimicking the relapsing nature of IBD. The first system is based on a Stress-Inducible Controlled Expression system for the production and delivery of heterologous proteins at mucosal surfaces and the second allows the delivery to the host cells of an il-10 cDNA cassette, harbored in a eukaryotic DNA expression vector (pValac). STUDY: Colitis was induced in female BALB/c mice by intrarectal injection of 2,4,6 trinitrobenzenesulphonic acid (TNBS). Mice that recovered received one of the bacteria treatments or saline solution orally during 14 days. Colitis was reactivated 25 days after the first TNBS injection with a second TNBS challenge. Three days after colitis reactivation, cytokine profiles and inflammation in colon samples were evaluated. RESULTS: Animals (N=9) receiving L. lactis strains secreting IL-10 using Stress-Inducible Controlled Expression system or delivering pValac:il-10 plasmid showed lower weight loss (P<0.005), lower damage scores (P<0.005), and immune activation in their large intestines compared with inflamed nontreated mice. CONCLUSIONS: Our results confirm the protective effect of IL-10 delivered either as a protein or as a cDNA in a colitis model mimicking the relapsing nature of IBD and provides a step further in the "proof-of-concept" of genetically engineered bacteria as a valid system to deliver therapeutic molecules at mucosal level. PMID- 25291118 TI - Postbiotic activities of lactobacilli-derived factors. AB - Probiotics are alive nonpathogenic microorganisms present in the gut microbiota that confer benefits to the host for his health. They act through molecular and cellular mechanisms that contrast pathogen bacteria adhesion, enhance innate immunity, decrease pathogen-induced inflammation, and promote intestinal epithelial cell survival, barrier function, and protective responses. Some of these beneficial effects result to be determined by secreted probiotic-derived factors that recently have been identified as "postbiotic" mediators. They have been reported for several probiotic strains but most available literature concerns Lactobacilli. In this review, we focus on the reported actions of several secretory products of different Lactobacillus species highlighting the available mechanistic data. The identification of soluble factors mediating the beneficial effects of probiotics may present an opportunity not only to understand their fine mechanisms of action, but also to develop effective pharmacological strategies that could integrate the action of treatments with live bacteria. PMID- 25291119 TI - 7th Probiotics Prebiotics & New Foods. Foreword. PMID- 25291120 TI - Peroxisome proliferator-activated receptor gamma in the colon: inflammation and innate antimicrobial immunity. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor, originally described in adipose tissue, which controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. Well known by endocrinologists, thiazolidinedionesare classical PPARgamma synthetic agonists, which were currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. Although the clinical benefits of thiazolidinediones in treating metabolic disorders have been clearly demonstrated, studies performed in animal models of colitis and in patients with ulcerative colitis have also revealed the key roles of PPARgamma activation in the regulation of inflammation and immune response, notably in the colon through epithelial cells. PMID- 25291121 TI - Gut microbiota, host gene expression, and aging. AB - Novel concepts of disease susceptibility and development suggest an important role of gastrointestinal microbiota and microbial pathogens. They can contribute to physiological systems and disease processes, even outside of the gastrointestinal tract. There is increasing evidence that genetics of the host influence and interact with gut microbiota. Moreover, aging-associated oxidative stress may cause morphologic alterations of bacterial cells, thus influencing the aggressive potential and virulence markers of an anaerobic bacterium and finally the type of interaction with the host. At the same time, microbiota may influence host gene expression and it is becoming apparent that it may occur through the regulation of microRNAs. They are short single-stranded noncoding RNAs that regulate posttranscriptional gene expression by affecting mRNA stability and/or translational repression of their target mRNAs. The introduction of -omics approaches (such as metagenomics, metaproteomics, and metatranscriptomics) in microbiota research will certainly advance our knowledge of this area. This will lead to greatly deepen our understanding of the molecular targets in the homeostatic interaction between the gut microbiota and the host and, thereby, promises to reveal new ways to treat diseases and maintain health. PMID- 25291122 TI - From basic to applied research: lessons from the human microbiome projects. AB - Two large-scale initiatives of major funding agencies aimed at deciphering the structure and function of the human gut microbiota, namely the NIH's Human Microbiome project and the European MetaHIT project, finalized their research program in 2012. PMID- 25291123 TI - Acute gastroenteritis. The COMMENT working group on acute diarrhea: Where are we now and where are we going? AB - Recently, the Consensus Group on Outcome Measures Made in Paediatric Enteral Nutrition Clinical Trials (COMMENT) was established. COMMENT agreed that consensus is needed on a core set of outcomes with agreed-upon definitions on what should be measured and reported in nutritional trials. To achieve this goal, 6 working groups were set up, including the working group on Acute Diarrhea. The following 4 steps are needed to complete the work: (1) to identify how outcomes related to acute diarrhea are reported; (2) to decide on the methodology for determining which outcomes to measure in clinical trials; (3) to develop a core outcome set for clinical trials performed in subjects with acute diarrhea; and (4) to determine how to measure the outcomes in the core set. The aim of this paper is to summarize what has been achieved and implemented so far, what is currently being done, and what we aim to achieve in the not so distant future. PMID- 25291124 TI - Preliminary results on clinical effects of probiotic Lactobacillus salivarius LS01 in children affected by atopic dermatitis. AB - GOALS: The goal of this study was to evaluate the clinical efficacy of an intake of Lactobacillus salivarius LS01 (DSM 22775) for the treatment of atopic dermatitis (AD) in children. BACKGROUND: AD is an inflammatory and pruritic chronic relapsing skin disorder with multifactorial etiopathology. Some evidence suggests that probiotics may improve AD by modulating the immune system and the composition of intestinal microbiota. STUDY: A total of 43 patients aged from 0 to 11 years were enrolled in the study (M/F ratio=1:1) and treated with the probiotic strain L. salivarius LS01. Clinical efficacy of probiotic treatment was assessed from baseline by changes in itch index and in the objective SCORAD/SCORAD index. RESULTS: Patients being given probiotic treatment showed a significant improvement in clinical parameters (SCORAD and itch values) from baseline. The reduction in SCORAD and itch index observed after 4 weeks of treatment also persisted after the cessation of probiotic supplementation. CONCLUSIONS: L. salivarius LS01 seems to be able to improve the quality of life of children affected by AD and, as a consequence, it may have promising clinical and research implications. PMID- 25291125 TI - Capability of the two microorganisms Bifidobacterium breve B632 and Bifidobacterium breve BR03 to colonize the intestinal microbiota of children. AB - BACKGROUND: The total number of bacteria present in the gut microbiota of a newborn is consistently lower than the average found in adults, with the extent of this difference being directly related to body weight and age. It could be assumed that a lower number of viable probiotic cells is necessary to achieve significant gut colonization in infants and children. This study assessed the capability of Bifidobacterium breve B632 (DSM 24706) and Bifidobacterium breve BR03 (DSM 16604), 2 strains able to significantly inhibit some gram-negative bacteria in vitro, to integrate into the intestinal microbiota of children. MATERIALS AND METHODS: Ten healthy children aged an average of 5.7+/-2.6 were given an oily suspension containing B. breve B632 and B. breve BR03 for 21 consecutive days. The daily dose was 100 million live cells of each strain. Fecal specimens were collected and analyzed at the beginning (d0) and at the end of the study (d21). Total fecal bifidobacteria and coliforms have been quantified by microbiological plate counts. RESULTS: A significant increase in total fecal bifidobacteria (from 8.99 to 9.47 log10 CFU/g, P=0.042) and a parallel decrease in total coliforms (from 8.60 to 7.93 log10 CFU/g, P=0.048) was recorded after 21 days of supplementation. CONCLUSIONS: An oily suspension has proved an effective way of providing probiotics to children. A lower viable cells concentration was sufficient to mediate this effect in the light of the fact that the intestinal microbiota of children harbors a considerably smaller amount of total bacteria compared with adults. In addition to gut colonization in healthy children, B. breve B632 and B. breve BR03 were able to decrease total fecal coliforms, therefore supporting their potential specific use in colicky infants. PMID- 25291126 TI - Correlation between chronic treatment with proton pump inhibitors and bacterial overgrowth in the stomach: any possible beneficial role for selected lactobacilli? AB - BACKGROUND: The inhibition of physiological gastric acid secretion induced by proton pump inhibitors (PPIs), the most widely used drugs in the world, may cause a significant bacterial overgrowth in the gastrointestinal tract as a side effect. This study was undertaken firstly to correlate PPI intake with concentration of specific bacterial groups in the stomach as well as possible Helicobacter pylori infection, and secondly to assess the efficacy of the 4 lactobacilli L. rhamnosus LR06 (DSM 21981), L. pentosus LPS01 (DSM 21980), L. plantarum LP01 (LMG P-21021), and L. delbrueckii subsp. delbrueckii LDD01 (DSM 22106) in the restoration of a physiological gastric barrier. METHODS: Total bacteria, sulphite-reducing bacteria (SRB), total coliforms, and total lactobacilli were quantified in samples of gastric juice from 29 subjects taking PPIs for at least 3 months compared with 36 control subjects. The presence of H. pylori was also assessed.The subjects treated with PPIs with a concentration of total bacteria in the gastric juice higher than 10(5) cells/mL were selected for an intervention study with the 4 lactobacilli L. rhamnosus LR06, L. pentosus LPS01, L. plantarum LP01, and L. delbrueckii subsp. delbrueckii LDD01. After 15 days of supplementation, the same bacterial groups were quantified to compare these values with the baseline. RESULTS: No significant correlation was found between the presence of H. pylori and PPI intake. The baseline quantification of bacterial groups (log10 CFU/mL of gastric juice, PPI group vs. control) showed: total bacteria 8.35 versus 3.95 (P<0.001); total coliforms 4.98 versus 2.35 (P<0.001); SRB 5.71 versus 2.28 (P=0.065); and total lactobacilli 3.85 versus 2.20 (P=0.005). After 15 days of treatment with the 4 lactobacilli, the quantification of bacterial groups gave the following results: total bacteria 7.91 versus 8.35 at time zero (P=0.002); total coliforms 4.21 versus 4.98 at time zero (P<0.001); SRB 4.94 versus 5.71 at baseline (P=0.060); and total lactobacilli 7.20 versus 3.85 at baseline (P=0.040). CONCLUSIONS: A significant impairment of intragastric acidity is sufficient to induce a relevant bacterial overgrowth, with particular reference to SRB and total coliforms. This fact can contribute to an increase in the risk of infections and intestinal diseases. It could be crucial to restore the physiological "gastric barrier." The 2-week supplementation with the 4 lactobacilli tested proved to be effective in significantly reducing total bacteria and coliforms in the gastric milieu in subjects chronically treated with PPIs. It is therefore possible to hopothesise a beneficial role for such lactobacilli in clinical practice. PMID- 25291127 TI - Treatment of atopic dermatitis eczema with a high concentration of Lactobacillus salivarius LS01 associated with an innovative gelling complex: a pilot study on adults. AB - GOALS: To evaluate the efficacy of a highly concentrated Lactobacillus salivarius preparation containing a gelling complex formed by Streptococcus thermophilus ST10 and tara gum in the treatment of atopic dermatitis (AD). BACKGROUND: Previous studies have demonstrated an improvement in AD symptoms after administration of the probiotic strain L. salivarius LS01. S. thermophilus ST10 and tara gum create a gelling complex that adheres to intestinal mucus and improves barrier function. STUDY: A prospective, controlled pilot trial was carried out to evaluate how the association of S. thermophilus ST10 and tara gum could improve the activity of L. salivarius LS01 administered at high doses to adults with AD. Twenty-five patients were included into the study: 13 were treated for 1 month with the active formulation, whereas 12 represented the placebo group. Scoring Atopic Dermatitis index was determined before and at the end of probiotic administration. Fecal samples were also collected to evaluate changes in bacterial counts of Staphylococcus aureus and clostridia. RESULTS: A significant improvement in SCORAD index was observed in the probiotic group after 1 month of treatment, whereas no significant changes occurred in placebo patients. A slight decrease in fecal S. aureus count was observed in probiotic treated patients. CONCLUSIONS: Data obtained in this study suggest a potential role for L. salivarius LS01 in the treatment of AD. The addition of tara gum and S. thermophilus ST10 seems to improve the overall efficacy of the probiotic strain, in particular shortening the time required for the onset of the positive effects. Further studies to investigate the activity of this preparation are advisable. PMID- 25291128 TI - Application of NMR-based metabolomics to the study of gut microbiota in obesity. AB - Lifestyle habits, host gene repertoire, and alterations in the intestinal microbiota concur to the development of obesity. A great deal of research has recently been focused on investigating the role gut microbiota plays in the pathogenesis of metabolic dysfunctions and increased adiposity. Altered microbiota can affect host physiology through several pathways, including enhanced energy harvest, and perturbations in immunity, metabolic signaling, and inflammatory pathways. A broad range of "omics" technologies is now available to help decipher the interactions between the host and the gut microbiota at detailed genetic and functional levels. In particular, metabolomics--the comprehensive analysis of metabolite composition of biological fluids and tissues -could provide breakthrough insights into the links among the gut microbiota, host genetic repertoire, and diet during the development and progression of obesity. Here, we briefly review the most insightful findings on the involvement of gut microbiota in the pathogenesis of obesity. We also discuss how metabolomic approaches based on nuclear magnetic resonance spectroscopy could help understand the activity of gut microbiota in relation to obesity, and assess the effects of gut microbiota modulation in the treatment of this condition. PMID- 25291129 TI - Small intestinal bacterial overgrowth in patients with chronic pancreatitis. AB - GOALS: To assess the prevalence of small intestinal bacterial overgrowth (SIBO) in chronic pancreatitis (CP), and analyze factors related with SIBO in CP. BACKGROUND: SIBO is to be considered a factor that worsens symptoms and nutritional status in patients with CP. However, the few studies evaluating the rate of SIBO in CP patients used nonuniform and nonstandardized procedures, and reported a wide range of positivity (0% to 92%). Those studies often investigated CP patients with previous resection surgery (cause of SIBO per se). STUDY: CP patients and controls evaluated for SIBO by the H2 glucose breath test with a standard protocol. For CP patients, the relationship between test results, abdominal symptoms, and clinical and biochemical variables was analyzed. RESULTS: A total of 43 CP patients and 43 controls were enrolled. Of the CP patients, 8 had advanced disease (defined by M-ANNHEIM index) and none had undergone previous surgery. The glucose breath test positivity rate was higher in the CP patients than in the controls (21% vs. 14%), albeit without a significant difference (P=0.57). Mean fasting H2 excretion and mean H2 excretion at 120 minutes also had a trend toward higher levels in CP patients. There were no clinical differences between CP patients with or without SIBO, but there were nutritional differences for lower levels of vitamin D and higher levels of folate in these patients with SIBO. CONCLUSIONS: Our findings suggest that SIBO is not uncommon in uncomplicated CP patients. The lack of a significant difference compared with controls might be due to the study being underpowered. SIBO in CP patients does not seem to be related to peculiar clinical features, but it might affect nutritional status. PMID- 25291130 TI - Assessment of the capability of a gelling complex made of tara gum and the exopolysaccharides produced by the microorganism Streptococcus thermophilus ST10 to prospectively restore the gut physiological barrier: a pilot study. AB - BACKGROUND: Leaky gut, or intestinal permeability, is the phenomenon of the gut wall exhibiting increased absorbency. It is pretty well recognised that an altered or damaged bowel lining or gut wall may result from unbalanced diet, parasites, infection, or medications and that this allows substances such as toxins, microbes, undigested food, or waste to leak through. As a natural consequence, this prompts the body to initiate an immune reaction leading to potentially severe health conditions. Different strategies may be used to improve, at least temporarily, the physiological intestinal barrier. The use of specific beneficial microorganisms, such as lactobacilli and bifidobacteria, has been suggested as an innovative tool to counteract an improper level of intestinal permeability. The association of bacteria with specific gelling agents, such as gums, may represent an improvement since these molecules are able to form hydrophilic gels that distribute uniformly over the inner intestinal surface. This pilot study was undertaken to evaluate intestinal permeability in subjects treated with a gelling complex, an association of tara gum and the microorganism Streptococcus thermophilus ST10 (DSM 25246), which has a well demonstrated in vitro ability to synthesise and secrete exopolysaccharides (EPSs). METHODS: Twenty-five healthy subjects were enrolled in this human intervention, double-blind, placebo-controlled, pilot trial (age between 21 and 57 y, mean 37.7+/-11.2). Subjects were then randomised into 2 groups: group A (13 subjects) was given an active formulation containing 250 mg of tara gum and 1 billion viable cells of S. thermophilus ST10, whereas group B (12 subjects) was given a placebo formulation. All the subjects participating in the study were directed to take 1 dose per day for 30 consecutive days. The presence and concentration of exopolysaccharides (EPSs) in the faeces was determined at time 0 (d0), after 30 days of treatment (d30), and at the end of the 2-week follow-up period (d45). The monosaccharide composition of EPSs was used to quantify the possible contribution of tara gum to the amount of polysaccharides detected in the faecal material. Intestinal permeability was evaluated at the same time by means of the lactitol/mannitol ratio (small intestine permeability) and sucralose concentration (colonic permeability) in urine specimens sampled after specified times. A statistical comparison was made between the concentration of EPSs, the lactulose/mannitol ratio, and the amount of excreted sucralose in the 2 groups at d0, d30, and d45. RESULTS: In the active group, supplementation with S. thermophilus ST10 and tara gum was able to significantly increase the faecal EPSs concentration compared with placebo (from 0.169 mg/g to 0.633 mg/g after 30 d, P<0.001). An interesting decrease in intestinal permeability, both of the small bowel and in the colon, was also recorded. The L/M ratio diminished from 0.021 in the active group to 0.014 and 0.015 after 30 and 45 days, respectively (P=0.045 and P=0.033 compared with placebo). The sucralose concentration decreased from 35.8 mg to 27.9 mg and 29.1 mg (P=0.038 and P=0.026 compared with placebo) at the end of the supplementation period and after the follow-up, respectively. No significant differences were recorded in the placebo after 30 days or at the end of the follow-up. CONCLUSIONS: The association of the EPSs produced by S. thermophilus ST10 and tara gum seems capable of significantly improving the intestinal functional barrier in healthy subjects. A wider study in subjects presenting impaired gut permeability would be useful in the future to confirm the positive results from this pilot trial. In any case, our findings are consistent with the parallel increase in exopolysaccharide concentration in the faecal material, thus suggesting the effective ability of the strain used to secrete EPSs in the gut lumen. An innovative approach of this type may be useful in helping to restore the physiological barrier by means of a merely natural and mechanical action. PMID- 25291132 TI - Diet, microbiota, and colorectal cancer. AB - Colorectal cancer (CRC) is the third most common cancer in the world causing nearly 500,000 deaths every year. In addition to genetic background, environmental factors including diet and lifestyle are accepted as major contributors to adenoma and CRC development. Lifestyle factors include high BMI, obesity, and reduced physical activity. Growing interest and accumulating data on human microbiota implicate that host-microbe interplay has an important role in the development of metabolic, neoplastic, and inflammatory diseases. Findings from recent studies suggest that colon cancer risk is determined by the interaction between diet and gut microbiota. Dietary changes affect gut microbiota and conversely microbiota mediates the generation of dietary factors triggering colon cancer. Identification of the microbial communities associated with carcinogenesis is of crucial importance. Nowadays, with the evolvement of culture-independent molecular techniques, it has become possible to identify main bacterial species in healthy individuals, inflammatory conditions, and CRC. Some recent studies have shown the differences in intestinal microbiota between colon cancer patients and healthy individuals. Animal studies have provided a better understanding of interaction between pathobionts and symbionts in the development of colon cancer. There is no single causative organism identified in CRC; however, there is strong evidence that reduction of protective bacteria, increase in some bacteria (ie, fusobacterium members; Bacteroides/Prevotella), and age related changes in microbiota have an impact on adenoma or cancer development. Future studies will enable us to understand procarcinogenic and anticarcinogenic mechanisms and give insights to rational manipulation of the microbiota with prebiotics, probiotics, or dietary modifications. PMID- 25291131 TI - Leaky gut, microbiota, and cancer: an incoming hypothesis. AB - Multigenic disease development is dependent on both missing and overactivated pathways, just as the homeostasis of our body systems is the product of many complex, redundant mechanisms. The goal of finding a common factor in the disease pathogenesis is difficult, as genetic and pathophysiological data are still incomplete, and the individual variability is enormous. Nevertheless, the examination of the role of human microbiota in illnesses using animal models of human diseases reared in defined (gnotobiotic) conditions could allow insight into the unusual complexity of the mechanisms involved in the initiation and maintenance of chronic diseases, including cancer. Although the most important findings in this fascinating field are still to come, a hypothesis, which is more than speculative, can be made, as it is clear that our bacterial companions affect our fates more than previously assumed. PMID- 25291133 TI - Can whole grain help in weight management? AB - BACKGROUND: Evidence from epidemiological studies suggests that higher whole grain intake is associated with improvements in body weight measures. Evidence from randomized controlled intervention studies is controversial. OBJECTIVE: To assess the scientific evidence, using a descriptive systematic approach, related to the relationship/effects of whole grain on weight management. METHODS: Medicine Medical Subject Headings (MeSH) were used to search in Medline and Scopus, dating from 1980 to July 2013. Subsequently, 2 researchers assessed independently the resulting abstracts, using hierarchically targeted selection criteria. RESULTS: A moderate body of evidence from epidemiological studies consistently demonstrates that a higher intake of whole grains is associated with lower body weight, BMI, waist circumference, abdominal adiposity, and weight gain. The evidence from intervention studies is, in comparison, limited and less consistent. Current evidence fails to clearly demonstrate that whole grain intake can contribute to weight loss independent of hypocaloric diets. The lack of consistency in intervention studies may partly be explained by heterogeneity in study duration, types and amounts of whole grain foods included, population, and sample sizes. CONCLUSIONS: Future epidemiological and intervention studies are needed to address the limitations observed in the current body of evidence, importantly using a consistent definition of whole grain foods, and the amount of whole grains consumed. Furthermore, studies need to be conducted on diets that potentially include single grains. PMID- 25291134 TI - Effect of excess body weight on the genetic susceptibility to cancer. AB - Excess body weight and genetics play important roles in cancer susceptibility. Although several studies have reported on obesity and genetic variants as separate risk factors for cancer, very few studies have investigated the interaction between excess body weight and genetic variants in cancer susceptibility. In this review, we focus on the interplay between these 2 risk factors, which are a major determinant of the individual risk of cancer onset. PMID- 25291135 TI - Intestinal colonization and programming of the intestinal immune response. AB - Initial bacterial colonization of the gut is a vital component of the development of the gastrointestinal tract, particularly mucosal immune protection, during the neonatal period. Newborn infants in their protected intrauterine environment are suddenly thrust into a highly contaminated extrauterine state. Although mucosal host defenses have developed in utero during fetal maturation because of the stimulation of ingested trophic factors in amniotic fluid, actual active protection only occurs when colonizing bacteria stimulate the gut mucosal barrier. Colonization evolves over a period of about 1 year and is dependent on the mode of delivery, use of perinatal antibiotics, age at birth, and infant feeding. A fully colonized gut consists of 10(14) bacteria, establishes a symbiotic relationship with the host and insures normal development and immune homeostasis. Colonizing bacteria can also affect the epithelial mucosal barrier and the innate and adaptive immune systems. Disruption of normal colonization, dysbiosis, is associated with increased expression of disease. Evidence exists that the use of probiotics with dysbiosis may prevent disease expression. PMID- 25291136 TI - Fecal microbiota transplantation: a new old kid on the block for the management of gut microbiota-related disease. AB - Gut microbiota is deeply involved in the regulation of both health and disease within our body. The restoration of a healthy gut microbiota is, therefore, a main clinical target in the management of diseases associated with its disruption. Fecal microbiota transplantation (FMT) is an old therapy that has recently been rediscovered, having proved a clear efficacy against recurrent Clostridium difficile infection. By restoring the altered gut microbiota in a substantial and durable manner, FMT is considered a cutting-edge promising option for the treatment of disease that recognize the alteration of the gut microbiota as having a pathogenic role. FMT has shown interesting (even if uncertain) results in diseases such as metabolic syndrome and inflammatory bowel diseases. Moreover, the definition of a standard procedural protocol for each specific disease, as well as exhaustive studies about the relationship between donor's microbiota composition and clinical results, will certainly improve the therapeutic potential of FMT. Both the application of cutting-edge technologies for the assessment of gut microbiota composition (such as metagenomics) and the development of well-designed, large randomized trials are needed to put such perspectives into practice. PMID- 25291137 TI - Skin microbiome and skin disease: the example of rosacea. AB - The imbalance and/or the perturbation of the microbial populations that colonize the skin and that contribute to its defense may represent one of the causes of the development of noninfectious skin diseases. Atopic dermatitis, psoriasis, acne, and rosacea can be listed among these kinds of pathologies. In particular, considering that microbes have been long addressed as having a role in rosacea, this common dermatosis can be an interesting model to evaluate the correlation between microbiome alterations and the occurrence of clinical manifestations. Different microorganisms have been suggested to have a role in rosacea, but no direct correlation with the incidence of the pathology has been clearly defined. Skin microbiome composition is crucial for the correct skin immune functions and recent findings indicate an abnormal activation of innate immune system associated with the rosacea. The enhanced expression of toll-like receptor 2 in the epidermis of rosacea patients can represent a possible explanation for the amplified inflammatory response to external stimuli observed during the disease. In addition, significantly higher small intestinal bacterial overgrowth prevalence in rosacea subjects has been found and its eradication has been associated with a regression of the skin lesions. In conclusion, both skin and gut microbiome seem to have a role, even if synergistic with other factors, in the pathogenesis of rosacea. A deeper knowledge of human microbiome composition and microbe-host interactions will contribute to clarify the mechanism of development of rosacea and possibly will provide innovative therapeutic approaches. PMID- 25291138 TI - Coffee and liver health. AB - Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for health. Several epidemiological studies associate coffee consumption with a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma. The mechanisms of action through which it exerts its beneficial effects are not fully understood. Experimental studies show that coffee consumption reduces fat accumulation and collagen deposition in the liver and promotes antioxidant capacity through an increase in glutathione as well as modulation of the gene and protein expression of several inflammatory mediators. Animal and in vitro studies indicate that cafestol and kahweol, 2 diterpens, can operate by modulating multiple enzymes involved in the detoxification process of carcinogens causing hepatocellular carcinoma. It is unclear whether the benefits are significant enough to "treat" patients with chronic liver disease. While we await clarification, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients. PMID- 25291139 TI - Screening of different probiotic strains for their in vitro ability to metabolise oxalates: any prospective use in humans? AB - BACKGROUND: Oxalate is the salt-forming ion of oxalic acid and can generate oxalate salts combining with various cations, such as sodium, potassium, magnesium, and calcium. Approximately 75% of all kidney stones are composed primarily of calcium oxalate (CaOx) and hyperoxaluria, a condition involving high urinary oxalate concentration, is considered a primary risk factor for kidney stone formation, known as nephrolithiasis. Current therapeutic strategies often fail in their compliance or effectiveness, and CaOx stone recurrence is still common. After an initial stone, there is a 50% chance of forming a second stone within 7 years if the condition is left untreated. The potential therapeutic application of some probiotics, mainly lactobacilli and bifidobacteria, in reducing hyperoxaluria in vivo through intestinal oxalate degrading activity is compelling and initial reports are promising. This study was undertaken to screen different Lactobacillus and Bifidobacterium strains for their capacity to degrade oxalate in vitro using reverse-phase high-performance liquid chromatography (HPLC). METHODS: The oxalate-degrading activity of 13 lactobacilli and 5 bifidobacteria was tested using a novel HPLC method after growth in a broth culture added with 10 mM ammonium oxalate. Experiments were repeated 3 times. Oxalobacter formigenes (DSM 4420) was used as positive reference to validate HPLC oxalate-degrading capability assays. RESULTS: Lactobacillus strains were more efficient than bifidobacteria in degrading oxalates. L. paracasei LPC09 (DSM 24243) gave the best result, as 68.5% of ammonium oxalate was converted at the end of incubation, whereas the following best converters belong to the L. gasseri and L. acidophilus species. The relatively low conversion rate observed for most bifidobacteria can probably be attributed to intrinsic oxalate toxicity toward this genus. CONCLUSIONS: Humans lack the enzymes needed to directly metabolise oxalate, and this potentially toxic compound is, therefore, managed using alternative pathways. As oxalate-degrading bacteria are present in the endogenous microbiota of the human intestine, although with significant individual differences, it is possible to hypothesise that the administration of selected oxalate-degrading probiotics could be an alternative and innovative approach to reducing the intestinal absorption of oxalate and the resulting urinary excretion. PMID- 25291140 TI - Effectiveness of an association of a cranberry dry extract, D-mannose, and the two microorganisms Lactobacillus plantarum LP01 and Lactobacillus paracasei LPC09 in women affected by cystitis: a pilot study. AB - BACKGROUND: Urinary tract infections (UTIs) are the most common bacterial infection in women. Most UTIs are acute uncomplicated cystitis caused by Escherichia coli (86%). This study was undertaken to assess the effectiveness of an association of a cranberry dry extract, D-mannose, a gelling complex composed of the exopolysaccharides produced by Streptococcus thermophilus ST10 (DSM 25246) and tara gum, as well as the 2 microorganisms Lactobacillus plantarum LP01 (LMG P 21021) and Lactobacillus paracasei LPC09 (DSM 24243) in women affected by acute uncomplicated cystitis. MATERIALS AND METHODS: Thirty-three premenopausal, nonpregnant women diagnosed with acute uncomplicated cystitis were enrolled in a pilot prospective study and completed the treatment protocol. Subjects were instructed to take 2 doses per day during the first month, and then to continue with 1 sachet per day until the sixtieth day. Nitrites and leukocyte esterase on urine dipstick testing were used as indicators of cystitis, with analysis performed at enrollment, after 30 and 60 days, and after 1 month of follow-up. Typical UTI symptoms, namely dysuria, frequent voiding of small volumes, urinary urgency, suprapubic pain, and gross hematuria were scored 0 to 3 and evaluated at each visit. RESULTS: Positive results for the presence of nitrites and leukocyte esterase were found in 14 and 20 subjects after 30 days and in 9 and 14 women after 60 days, respectively (P<0.001). At the end of the follow-up period, positive results for nitrites and leukocyte esterase were recorded in only 4 and 3 of 24 and 19 subjects (16.7%, P=0.103; 15.8%, P=0.325, respectively), with negative results after 60 days. Typical symptoms of cystitis, specifically dysuria, frequent voiding, urgency, and suprapubic pain were significantly improved as well. No significant differences were recorded in the incidence and severity of hematuria at any visit. CONCLUSION: The long-term ability of an association of cranberry, D-mannose, an innovative gelling complex, and the 2 microorganisms tested to significantly improve the uncomfortable symptoms reported by women with acute cystitis has been suggested. PMID- 25291141 TI - From Protein Synthesis to Molecular Biology: The Appealing Tale of eIF-5A. PMID- 25291142 TI - Clonal Dominance With Retroviral Vector Insertions Near the ANGPT1 and ANGPT2 Genes in a Human Xenotransplant Mouse Model. AB - Insertional leukemogenesis represents the major risk factor of hematopoietic stem cell (HSC) based gene therapy utilizing integrating viral vectors. To develop a pre-clinical model for the evaluation of vector-related genotoxicity directly in the relevant human target cells, cord blood CD34(+) HSCs were transplanted into immunodeficient NOD.SCID.IL2rg(-/-) (NSG) mice after transduction with an LTR driven gammaretroviral vector (GV). Furthermore, we specifically investigated the effect of prolonged in vitro culture in the presence of cytokines recently described to promote HSC expansion or maintenance. Clonality of human hematopoiesis in NSG mice was assessed by high throughput insertion site analyses and validated by insertion site-specific PCR depicting a GV typical integration profile with insertion sites resembling to 25% those of clinical studies. No overrepresentation of integrations in the vicinity of cancer-related genes was observed, however, several dominant clones were identified including two clones harboring integrations in the ANGPT1 and near the ANGPT2 genes associated with deregulated ANGPT1- and ANGPT2-mRNA levels. While these data underscore the potential value of the NSG model, our studies also identified short-comings such as overall low numbers of engrafted HSCs, limited in vivo observation time, and the challenges of in-depth insertion site analyses by low contribution of gene modified hematopoiesis. PMID- 25291144 TI - The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice. AB - BACKGROUND: It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1 receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance. METHODS: Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests. RESULTS: Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice. CONCLUSION: Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction. PMID- 25291143 TI - Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents. AB - Limited chemical diversity of nucleic acid libraries has long been suspected to be a major constraining factor in the overall success of SELEX (Systematic Evolution of Ligands by EXponential enrichment). Despite this constraint, SELEX has enjoyed considerable success over the past quarter of a century as a result of the enormous size of starting libraries and conformational richness of nucleic acids. With judicious introduction of functional groups absent in natural nucleic acids, the "diversity gap" between nucleic acid-based ligands and protein-based ligands can be substantially bridged, to generate a new class of ligands that represent the best of both worlds. We have explored the effect of various functional groups at the 5-position of uracil and found that hydrophobic aromatic side chains have the most profound influence on the success rate of SELEX and allow the identification of ligands with very low dissociation rate constants (named Slow Off-rate Modified Aptamers or SOMAmers). Such modified nucleotides create unique intramolecular motifs and make direct contacts with proteins. Importantly, SOMAmers engage their protein targets with surfaces that have significantly more hydrophobic character compared with conventional aptamers, thereby increasing the range of epitopes that are available for binding. These improvements have enabled us to build a collection of SOMAmers to over 3,000 human proteins encompassing major families such as growth factors, cytokines, enzymes, hormones, and receptors, with additional SOMAmers aimed at pathogen and rodent proteins. Such a large and growing collection of exquisite affinity reagents expands the scope of possible applications in diagnostics and therapeutics. PMID- 25291146 TI - Qualitative analysis of aphid and primary parasitoid trophic relations of genus Alloxysta (Hymenoptera: Cynipoidea: Figitidae: Charipinae). AB - Charipinae hyperparasitoids affect effectiveness of the primary parasitoids of aphids by decreasing their abundance and modifying their behavior. As a result, increase of aphid populations can cause severe yield losses in some crops. Therefore, ecological studies on the subfamily Charipinae have a great economical and biological importance. Host specificity of these hyperparasitoids is still under debate and for many Charipinae species very little is known about their trophic relations. Here, we give a comprehensive overview of the trophic relationships between the Charipinae species of the genus Alloxysta Forster and their aphid and primary parasitoids hosts, worldwide. Within this subfamily, Alloxysta arcuata (Kieffer), Alloxysta brevis (Thomson), Alloxysta fuscicornis (Hartig), and Alloxysta victrix (Westwood) are the most generalist species sharing many aphid hosts, while for primary parasitoid hosts these are A. arcuata, A. brevis, Alloxysta pleuralis (Cameron), and A. victrix. Alloxysta citripes (Thomson), Alloxysta halterata (Thomson), Alloxysta leunisii (Hartig), and Alloxysta ramulifera (Thomson) appear, up to now, as the most specialized in relation to the primary parasitoid hosts. Primary parasitoids of the genera Aphidius Nees, Lysiphlebus Forster, Praon Haliday, and Trioxys Haliday are the most common hosts for Alloxysta species, and the common host aphid species belong to the genera Aphis L., Uroleucon Mordvilko, Myzus Passerini, and Sitobion Mordvilko. Host range is analyzed for each Alloxysta species, as well as the extent of overlap between them. We used Jaccard's distance and a hierarchical cluster analysis to determine the host range dissimilarity. A permutation test has been applied to analyze if the host range dissimilarity is significantly different from what is expected by chance. We have calculated additional qualitative measures that complement well the Alloxysta niche overlap analysis and evaluated their host specificity using different indices and bipartite networks. PMID- 25291145 TI - Effects of cyclooxygenase inhibition on insulin release and pancreatic islet blood flow in rats. AB - OBJECTIVES: To examine the effects of inhibition of cyclooxygenase (COX) on islet hormone secretion in vitro and on pancreatic islet blood flow in vivo. METHODS: Insulin release was measured in a static incubation system of islets isolated from Wistar-F rats after inhibition of COX-1 and COX-2 with SC 560 (COX-1), FR 122047 (COX-1), rofecoxib (COX-2), or indomethacin (both COX-1 and COX-2). In other rats organ blood flow values were measured with a microsphere technique during both normo- and hyperglycemia after administration of these enzyme inhibitors. RESULTS: Serum insulin values were lower after pretreatment with a COX-1 inhibitor or a non-selective COX inhibitor in both control and glucose injected rats in vivo, whereas COX-2 inhibition had no such effects. However, inhibition of COX had only minor effects on insulin release in vitro. Inhibition of COX affected neither total pancreatic nor islet blood flow in normoglycemic rats. Hyperglycemia caused an increase in both these flow values and in the duodenum. The increase in total pancreatic and duodenal blood flow was prevented by inhibition of COX-2 or non-selective COX inhibition. However, no effects on islet blood flow were seen after COX inhibition. CONCLUSION: Inhibition of COX affects insulin release and blood glucose concentrations in vivo. However, COX inhibition has only minor effects on pancreatic islet blood flow, but prevents the glucose-induced increase in total pancreatic blood flow. PMID- 25291148 TI - Denoising of 3D magnetic resonance images by using higher-order singular value decomposition. AB - The denoising of magnetic resonance (MR) images is important to improve the inspection quality and reliability of quantitative image analysis. Nonlocal filters by exploiting similarity and/or sparseness among patches or cubes achieve excellent performance in denoising MR images. Recently, higher-order singular value decomposition (HOSVD) has been demonstrated to be a simple and effective method for exploiting redundancy in the 3D stack of similar patches during denoising 2D natural image. This work aims to investigate the application and improvement of HOSVD to denoising MR volume data. The wiener-augmented HOSVD method achieves comparable performance to that of BM4D. For further improvement, we propose to augment the standard HOSVD stage by a second recursive stage, which is a repeated HOSVD filtering of the weighted summation of the residual and denoised image in the first stage. The appropriate weights have been investigated by experiments with different image types and noise levels. Experimental results over synthetic and real 3D MR data demonstrate that the proposed method outperforms current state-of-the-art denoising methods. PMID- 25291149 TI - Visualization of monoamine oxidases in living cells using "Turn-ON" fluorescence resonance energy transfer probes. AB - Novel FRET-based small molecule probes targeting monoamine oxidases (MAOs) were designed and synthesized. These "Turn-ON" fluorescent probes were proved to be capable of directly reporting MAO activities in live mammalian cells. PMID- 25291147 TI - Eocene diversification of crown group rails (Aves: Gruiformes: Rallidae). AB - Central to our understanding of the timing of bird evolution is debate about an apparent conflict between fossil and molecular data. A deep age for higher level taxa within Neoaves is evident from molecular analyses but much remains to be learned about the age of diversification in modern bird families and their evolutionary ecology. In order to better understand the timing and pattern of diversification within the family Rallidae we used a relaxed molecular clock, fossil calibrations, and complete mitochondrial genomes from a range of rallid species analysed in a Bayesian framework. The estimated time of origin of Rallidae is Eocene, about 40.5 Mya, with evidence of intrafamiliar diversification from the Late Eocene to the Miocene. This timing is older than previously suggested for crown group Rallidae, but fossil calibrations, extent of taxon sampling and substantial sequence data give it credence. We note that fossils of Eocene age tentatively assigned to Rallidae are consistent with our findings. Compared to available studies of other bird lineages, the rail clade is old and supports an inference of deep ancestry of ground-dwelling habits among Neoaves. PMID- 25291150 TI - Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. AB - Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID- 25291153 TI - Surgical outcome of graded Y split in patients with Duane's retraction syndrome. PMID- 25291154 TI - The essentials of informed consent. PMID- 25291152 TI - Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients. AB - AIM: To investigate the influence of gestational diabetes mellitus (GDM) on the kinetic disposition and transplacental and amniotic fluid distribution of metoprolol and its metabolites O-desmethylmetoproloic acid and alpha hydroxymetoprolol stereoisomers in hypertensive parturients receiving a single dose of the racemic drug. METHODS: The study was conducted on hypertensive parturients with well-controlled GDM (n = 11) and non-diabetic hypertensive parturients (n = 24), all receiving a single 100 mg oral dose of racemic metoprolol tartrate before delivery. Serial maternal blood samples (0-24 h) and umbilical blood and amniotic fluid samples were collected for the quantitation of metoprolol and its metabolite stereoisomers using LC-MS/MS or fluorescence detection. RESULTS: The kinetic disposition of metoprolol and its metabolites was stereoselective in the diabetic and control groups. Well-controlled GDM prolonged tmax for both enantiomers of metoprolol (1.5 vs. 2.5 h R-(+)-MET; 1.5 vs. 2.75 h S-(-)-MET) and O-desmethylmetoproloic acid (2.0 vs. 3.5 h R-(+)-AOMD; 2.0 vs. 3.0 h S-(-)-OAMD), and for the four stereoisomers of alpha-hydroxymetoprolol (2.0 vs. 3.0 h for 1'S,2R-, 1'R,2R- and 1'R,2S-OHM; 2.0 vs. 3.5 h for 1'S,2S-OHM) and reduced the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM by approximately 20%. CONCLUSIONS: The kinetic disposition of metoprolol was enantioselective, with plasma accumulation of the S-(-)-MET eutomer. Well controlled GDM prolonged the tmax of metoprolol and O-desmethylmetoproloic acid enantiomers and the alpha-hydroxymetoprolol stereoisomers and reduced by about 20% the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM. Thus, well-controlled GDM did not change the activity of CYP2D6 and CYP3A involved in metoprolol metabolism. PMID- 25291155 TI - Concern for "crazy pupils" began in infancy. PMID- 25291156 TI - Seeing beyond the double helix. PMID- 25291157 TI - Children's experience in outpatient pediatric ophthalmology clinics. PMID- 25291158 TI - Spectral-domain optical coherence tomography appearance of a posterior pole retinoma. PMID- 25291159 TI - Pulmonary segmentectomy with tunneling stapler technique. AB - Pulmonary segmentectomy necessitates dissection of the lung parenchyma. Stapling is one method of dissecting the lung parenchyma. However, simple stapling of the segmental plane might result in restriction of residual lung inflation and a short margin from the lesion. Therefore, a technique of segmental plane dissection via staple incisions radially spreading out from the segmental bronchus stump has been developed, which is made possible by creating a tunnel passageway to maneuver the stapler's anvil. This procedure can reduce restriction of lung inflation and secure surgical margins from the lesion. PMID- 25291160 TI - Impact of hepatic cirrhosis on outcome in adult cardiac surgery. AB - Increasing prevalence of hepatic disease is likely to translate in a growing number of patients with significant hepatic disease requiring cardiac surgery. Available cardiac risk stratification models do not address the risk associated with hepatic disease. However, weighted mean mortality rates based on previous studies of cardiac surgery in patients with hepatic disease demonstrate operative mortality rates that range from 9.88% (standard deviation [SD] 9.69) for patients in Child-Turcotte-Pugh (CTP) class A cirrhosis to 69.23% (SD 28.55) for patients with CTP class C cirrhosis. This review comprehensively appraises the pathophysiology of hepatic disease, reported clinical outcomes and considerations for risk stratification. PMID- 25291161 TI - The lymphocyte membrane. PMID- 25291162 TI - William Henry hildemann (1927-1983). PMID- 25291163 TI - Mechanisms in chronic inflammation. AB - A meeting was held recently to bring together ideas from workers in several different fields relating to chronic inflammation in rheumatology. The protagonists were asked to explore four major themes: the acute-phase response; the control of lymphocyte function; the nature of the connective tissue matrix; and the role of iron in inflammation. PMID- 25291164 TI - This letter was shown to Dr Elson who replies as follows:. PMID- 25291166 TI - Residual heterozygosity in inbred mouse strains. PMID- 25291165 TI - Is IgA production T-cell dependent? PMID- 25291167 TI - The mechanism of immune precipitation. AB - Numerous analytical methods are based on immune precipitation because the proper use of antibodies ensures a high degree of sensitivity and a remarkable specificity. In addition most methods based on immune precipitation have a fairy simple protocol. Immune precipitation has been known now for more than 85 years(1) and has been used in countless studies, yet its molecular mechanism is still incompletely understood. Here, fens Steensgaard describes a two-stage model of the process, in which the second step is not immune-specific. This has implications for attempts to reproduce conventional antisera with cocktails of monoclonal reagents. PMID- 25291168 TI - T-cell antigen receptor function: the concept of autoaggression. AB - That T lymphocytes must recognize major histocompatibility complex (MHC)-encoded self antigen together with foreign antigen for effective interaction with antigen bearing cells has been known for a decade, yet the exact function of the MHC in regulating the action of T lymphocytes is still a matter of dispute. Theories advanced to explain T-cell function assign merely an accessory role to the MHC, namely to 'restrict' the ability of T cells to respond to foreign antigen. Here Michael Hoffmann discusses the possibility that, instead of restricting T-cell activity, recognition of MHC-encoded self-antigen by the T-cell receptor is actually the consequential event in T-cell ffector function and that foreign antigen plays an accessory role. PMID- 25291170 TI - Inhibitory T cells in haemopoietic failure. PMID- 25291169 TI - Anti-Ia antibodies: a revolutionary therapy for immune-mediated diseases? PMID- 25291171 TI - Cell-cycle control in lymphocyte stimulation. AB - Discussion of lymphocyte mitogenesis often gives the impression that the process, once started, continues inexorably. It does not. Here Gerry Klaus and Catherine Hawrylowicz discuss the arrest points now known to occur in the division cycle of T and B lymphocytes and the signals required for progression through the cycle. PMID- 25291172 TI - Antigenic modulation - a major mechanism of antibody action. AB - It is a prudent rule in science that any new indisputable observation is worthy of interest and further investigation, even when it seems a priori anecdotal or outside the scope of current studies. This was the case, in the early 1960s, with antigenic modulation, which was initially considered as an interesting serological curiosity and is now established as a major mechanism of antibody action. In this article Lucienne Chatenoud and Jean-Francois Bach discuss new roles for antigenic modulation in viral and autoimmune disease pathogenesis and in the escape from tumors and the therapeutic action of monoclonal antibodies. PMID- 25291178 TI - Autonomous stimulation of cancer cell plasticity by the human NKG2D lymphocyte receptor coexpressed with its ligands on cancer cells. AB - The stimulatory NKG2D receptor on lymphocytes promotes tumor immune surveillance by targeting ligands selectively induced on cancer cells. Progressing tumors counteract by employing tactics to disable lymphocyte NKG2D. This negative dynamic is escalated as some human cancer cells co-opt expression of NKG2D, thereby complementing the presence of its ligands for autonomous stimulation of oncogenic signaling. Clinical association data imply relationships between cancer cell NKG2D and metastatic disease. Here we show that NKG2D promotes cancer cell plasticity by induction of phenotypic, molecular, and functional signatures diagnostic of the epithelial-mesenchymal transition, and of stem-like traits via induction of Sox9, a key transcriptional regulator of breast stem cell maintenance. These findings obtained with model breast tumor lines and xenotransplants were recapitulated by ex vivo cancer cells from primary invasive breast carcinomas. Thus, NKG2D may have the capacity to drive high malignancy traits underlying metastatic disease. PMID- 25291179 TI - The impact of prior tonsillitis and treatment modality on the recurrence of peritonsillar abscess: a nationwide cohort study. AB - BACKGROUND: Studies suggest an increased risk of peritonsillar abscess (PTA) recurrence in patients with prior tonsillitis. However, this association is inconsistent and could be confounded by different treatment modalities. This study aimed to assess the risk of recurrence among PTA patients with different degrees of prior tonsillitis and treatment modalities, and the role of tonsillectomy in current practice. METHODS: All in-patients with peritonsillar abscess between January 2001 and December 2009 were identified in a nationwide, retrospective cohort study. Recurrence was defined as the first occurrence of PTA ?30 days from the initial PTA. Factors independently associated with recurrence were analyzed using Cox proportional hazard model after adjusting for demographic and clinical data. RESULTS: There were 28,837 patients, with a 5.15% recurrence rate and 4.74 years of follow-up. The recurrence rates were significantly higher among subjects with more than five prior tonsillitis or 1-4 prior tonsillitis compared to those without prior tonsillitis (adjusted hazard ratio, 2.82 [95% confidence interval, 2.39-3.33] and 1.59 [95% CI: 1.38-1.82]). The adjusted HR in patients treated with needle aspiration was 1.08 compared to those treated with incision & drainage (95% CI: 0.85-1.38). After age stratification, the adjusted HRs of more than five prior tonsillitis increased to 2.92 and 3.50 in patients aged ?18 and 19-29 years respectively. The adjusted HR of needle aspiration only increased in patients ?18 years old (aHR: 1.98 [95% CI: 0.99-3.97]). The overall tonsillectomy rate was 1.48% during our study period. CONCLUSIONS: The risk of PTA recurrence increases with higher degrees of prior tonsillitis in all age groups and management by needle aspiration only in the pediatric population. Patients younger than 30 years old with PTA and more than five prior tonsillitis have the greatest risk of recurrence. PMID- 25291181 TI - High altitude pulmonary edema in mountain climbers. AB - Every year thousands of ski, trekking or climbing fans travel to the mountains where they stay at the altitude of more than 2500-3000m above sea level or climb mountain peaks, often exceeding 7000-8000m. High mountain climbers are at a serious risk from the effects of adverse environmental conditions prevailing at higher elevations. They may experience health problems resulting from hypotension, hypoxia or exposure to low temperatures; the severity of those conditions is largely dependent on elevation, time of exposure as well as the rate of ascent and descent. A disease which poses a direct threat to the lives of mountain climbers is high altitude pulmonary edema (HAPE). It is a non cardiogenic pulmonary edema which typically occurs in rapidly climbing unacclimatized lowlanders usually within 2-4 days of ascent above 2500-3000m. It is the most common cause of death resulting from the exposure to high altitude. The risk of HAPE rises with increased altitude and faster ascent. HAPE incidence ranges from an estimated 0.01% to 15.5%. Climbers with a previous history of HAPE, who ascent rapidly above 4500m have a 60% chance of illness recurrence. The aim of this article was to present the relevant details concerning epidemiology, pathophysiology, clinical symptoms, prevention, and treatment of high altitude pulmonary edema among climbers in the mountain environment. PMID- 25291180 TI - Down-regulation of desmosomes in cultured cells: the roles of PKC, microtubules and lysosomal/proteasomal degradation. AB - Desmosomes are intercellular adhesive junctions of major importance for tissue integrity. To allow cell motility and migration they are down-regulated in epidermal wound healing. Electron microscopy indicates that whole desmosomes are internalised by cells in tissues, but the mechanism of down-regulation is unclear. In this paper we provide an overview of the internalisation of half desmosomes by cultured cells induced by calcium chelation. Our results show that: (i) half desmosome internalisation is dependent on conventional PKC isoforms; (ii) microtubules transport internalised half desmosomes to the region of the centrosome by a kinesin-dependent mechanism; (iii) desmosomal proteins remain colocalised after internalisation and are not recycled to the cell surface; (iv) internalised desmosomes are degraded by the combined action of lysosomes and proteasomes. We also confirm that half desmosome internalisation is dependent upon the actin cytoskeleton. These results suggest that half desmosomes are not disassembled and recycled during or after internalisation but instead are transported to the centrosomal region where they are degraded. These findings may have significance for the down-regulation of desmosomes in wounds. PMID- 25291182 TI - New insights into how increases in fertility improve the growth of rice at the seedling stage in red soil regions of subtropical China. AB - The differences in rhizosphere nitrification activities between high- and low- fertility soils appear to be related to differences in dissolved oxygen concentrations in the soil, implying a relationship to differences in the radial oxygen loss (ROL) of rice roots in these soils. A miniaturised Clark-type oxygen microelectrode system was used to determine rice root ROL and the rhizosphere oxygen profile, and rhizosphere nitrification activity was studied using a short term nitrification activity assay. Rice planting significantly altered the oxygen cycling in the water-soil system due to rice root ROL. Although the oxygen content in control high-fertility soil (without rice plants) was lower than that in control low-fertility soil, high rice root ROL significantly improved the rhizosphere oxygen concentration in the high-fertility soil. High soil fertility improved the rice root growth and root porosity as well as rice root ROL, resulting in enhanced rhizosphere nitrification. High fertility also increased the content of nitrification-induced nitrate in the rhizosphere, resulting in enhanced ammonium uptake and assimilation in the rice. Although high ammonium pools in the high-fertility soil increased rhizosphere nitrification, rice root ROL might also contribute to rhizosphere nitrification improvement. This study provides new insights into the reasons that an increase in soil fertility may enhance the growth of rice. Our results suggest that an amendment of the fertiliser used in nutrient- and nitrification-poor paddy soils in the red soil regions of China may significantly promote rice growth and rice N nutrition. PMID- 25291183 TI - Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet. AB - This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 ug/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles). Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy), cell adaptations (hypertrophy and hyperplasia), and cell survival (proliferation/regeneration) accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease. PMID- 25291185 TI - [Is ursodeoxycholic acid effective in primary biliary cirrhosis?]. AB - Ursodeoxycholic acid is considered as first line treatment in patients with primary biliary cirrhosis. Its mechanism of action in this disease is unknown and there is controversy about its clinical impact. Searching in Epistemonikos database, which is maintained by screening 19 databases, we identified four systematic reviews including 16 studies. We combined the evidence using tables with summary of findings following the GRADE approach and concluded ursodeoxycholic acid may not have any effect on pruritus, and there is uncertainty about its effect on mortality, need for liver transplantation or on any other important outcome for the patient. PMID- 25291184 TI - Mammary fat of breast cancer: gene expression profiling and functional characterization. AB - Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies. PMID- 25291186 TI - Does fire influence the landscape-scale distribution of an invasive mesopredator? AB - Predation and fire shape the structure and function of ecosystems globally. However, studies exploring interactions between these two processes are rare, especially at large spatial scales. This knowledge gap is significant not only for ecological theory, but also in an applied context, because it limits the ability of landscape managers to predict the outcomes of manipulating fire and predators. We examined the influence of fire on the occurrence of an introduced and widespread mesopredator, the red fox (Vulpes vulpes), in semi-arid Australia. We used two extensive and complimentary datasets collected at two spatial scales. At the landscape-scale, we surveyed red foxes using sand-plots within 28 study landscapes - which incorporated variation in the diversity and proportional extent of fire-age classes - located across a 104 000 km2 study area. At the site scale, we surveyed red foxes using camera traps at 108 sites stratified along a century-long post-fire chronosequence (0-105 years) within a 6630 km2 study area. Red foxes were widespread both at the landscape and site-scale. Fire did not influence fox distribution at either spatial scale, nor did other environmental variables that we measured. Our results show that red foxes exploit a broad range of environmental conditions within semi-arid Australia. The presence of red foxes throughout much of the landscape is likely to have significant implications for native fauna, particularly in recently burnt habitats where reduced cover may increase prey species' predation risk. PMID- 25291187 TI - Effects of warming and clipping on ecosystem carbon fluxes across two hydrologically contrasting years in an alpine meadow of the Qinghai-Tibet Plateau. AB - Responses of ecosystem carbon (C) fluxes to human disturbance and climatic warming will affect terrestrial ecosystem C storage and feedback to climate change. We conducted a manipulative experiment to investigate the effects of warming and clipping on soil respiration (Rs), ecosystem respiration (ER), net ecosystem exchange (NEE) and gross ecosystem production (GEP) in an alpine meadow in a permafrost region during two hydrologically contrasting years (2012, with 29.9% higher precipitation than the long-term mean, and 2013, with 18.9% lower precipitation than the long-tem mean). Our results showed that GEP was higher than ER, leading to a net C sink (measured by NEE) over the two growing seasons. Warming significantly stimulated ecosystem C fluxes in 2012 but did not significantly affect these fluxes in 2013. On average, the warming-induced increase in GEP (1.49 u mol m(-2) s(-1)) was higher than in ER (0.80 u mol m(-2) s(-1)), resulting in an increase in NEE (0.70 u mol m(-2) s(-1)). Clipping and its interaction with warming had no significant effects on C fluxes, whereas clipping significantly reduced aboveground biomass (AGB) by 51.5 g m(-2) in 2013. These results suggest the response of C fluxes to warming and clipping depends on hydrological variations. In the wet year, the warming treatment caused a reduction in water, but increases in soil temperature and AGB contributed to the positive response of ecosystem C fluxes to warming. In the dry year, the reduction in soil moisture, caused by warming, and the reduction in AGB, caused by clipping, were compensated by higher soil temperatures in warmed plots. Our findings highlight the importance of changes in soil moisture in mediating the responses of ecosystem C fluxes to climate warming in an alpine meadow ecosystem. PMID- 25291188 TI - Rapid Assessment Medical Support (RAMS) for active shooter incidents. AB - This country has witnessed a steady increase in the number of active shooter incidents in recent years. The traditional emergency medical services (EMS) response to such incidents has been to stage at a safe distance until the scene has been secured by law enforcement. Such an approach may lead to unnecessary delays in medical care and potentially needless loss of life. To address this issue locally, the Philadelphia Fire Department (PFD) and the Philadelphia Police Department (PPD) collaborated to develop the Rapid Assessment Medical Support (RAMS) program. All PFD paramedics have been equipped and trained to move with PPD officers into a scene that has been cleared by police but not yet secured in order to initiate emergency care, with an emphasis on hemorrhage control. Patients are then extracted to awaiting EMS resources in the cold zone. The history behind the program and the challenges and obstacles that had to be addressed in its development are described. These included initial and ongoing training and funding sources; buy-in from risk management, labor, and the individual providers; whether only paramedics should be included in the RAMS program or if the PFD's firefighter-EMTs should be included as well; the potential for mission creep as police recognized the value of this asset and its potential application to other scenarios; and how to involve the many nonmunicipal ambulance services that are not involved in the routine operation of Philadelphia's 9-1-1 system. To date, RAMS teams have been activated on multiple occasions, but fortunately the incidents were resolved without injury or loss of life. However, the program provides another valuable tool with which the City of Philadelphia can respond should another active shooter incident occur. PMID- 25291191 TI - Obituary. PMID- 25291189 TI - Short communication: high cellular iron levels are associated with increased HIV infection and replication. AB - HIV is a pandemic disease, and many cellular and systemic factors are known to alter its infectivity and replication. Earlier studies had suggested that anemia is common in HIV-infected patients; however, higher iron was also observed in AIDS patients prior to the introduction of antiretroviral therapy (ART). Therefore, the relationship between iron and viral infection is not well delineated. To address this issue, we altered the levels of cellular iron in primary CD4(+) T cells and showed that higher iron is associated with increased HIV infection and replication. In addition, HIV infection alone leads to increased cellular iron, and several ART drugs increase cellular iron independent of HIV infection. Finally, HIV infection is associated with increased serum iron in HIV-positive patients regardless of treatment with ART. These results establish a relationship between iron and HIV infection and suggest that iron homeostasis may be a viable therapeutic target for HIV. PMID- 25291192 TI - Fauci appointed MAID director. PMID- 25291193 TI - Useful guide to negotiating research agreements. PMID- 25291190 TI - The KRUPPEL-like transcription factor DATILOGRAFO is required in specific cholinergic neurons for sexual receptivity in Drosophila females. AB - Courtship is a widespread behavior in which one gender conveys to the other a series of cues about their species identity, gender, and suitability as mates. In many species, females decode these male displays and either accept or reject them. Despite the fact that courtship has been investigated for a long time, the genes and circuits that allow females to generate these mutually exclusive responses remain largely unknown. Here, we provide evidence that the Kruppel-like transcription factor datilografo (dati) is required for proper locomotion and courtship acceptance in adult Drosophila females. dati mutant females are completely unable to decode male courtship and almost invariably reject males. Molecular analyses reveal that dati is broadly expressed in the brain and its specific removal in excitatory cholinergic neurons recapitulates the female courtship behavioral phenotype but not the locomotor deficits, indicating that these are two separable functions. Clonal analyses in female brains identified three discrete foci where dati is required to generate acceptance. These include neurons around the antennal lobe, the lateral horn, and the posterior superior lateral protocerebrum. Together, these results show that dati is required to organize and maintain a relatively simple excitatory circuit in the brain that allows females to either accept or reject courting males. PMID- 25291194 TI - WHO committee report on rabies. PMID- 25291195 TI - Human IL-2 reference reagent available. PMID- 25291196 TI - Latin American association of immunology. PMID- 25291197 TI - A cell-mediated cause of chronic inflammation. PMID- 25291198 TI - The physiological interferon response. AB - Some years ago Velio Bocci proposed, 1,2 against then current thinking, 3-6 that interferon (IFN) was produced continuously in health, in low 'physiological' amounts which increased occasionally when a viral disease induced an acute response. Since then, he argues here, data have accumulated which indicate that this 'physiological' IFN response may indeed be a reality. PMID- 25291199 TI - Anti-idiotypic antibodies: what do they recognize? AB - On the basis of our present comprehension of the structure of ligand-binding proteins, B. F. Erlanger here discusses how anti-idiotypic antibodies react with their target epitopes, in particular, when anti-idiotypic antibodies cross-react with receptors or act as internal images of ligands. PMID- 25291200 TI - Genetically engineered antibodies. PMID- 25291201 TI - Cross-reacting idiotypes in human sera. PMID- 25291202 TI - The biosynthesis of secretory component and its role in the transepithelial transport of IgA dimer. AB - How animals protect their mucosal surfaces from environmental pathogens has been of much recent interest. Elucidation of the defence mechanisms involved led to the concept of a common mucosal immune system, characterized by an intimate relationship between mucosal epithelia and migrating populations of IgA-producing B cells(1). However, in order to protect mucosal surfaces fom environmental antigens the dimeric IgA antibodies must somehow be transported across the mucous or exocrine gland epithelia and released into the external secretions. In this article R. Solari and J.-P. Kraehenbuhl show how the secretory component may facilitate this movement and also discuss its possible biosynthesis and processing. PMID- 25291203 TI - The molecular mechanism of lymphocyte-mediated tumor cell lysis. AB - Lymphocyte-mediated cytolysis is an important mechanism of immune defense and possibly also of immune surveillance against cancer. Recent major advances in the understanding of its molecular mechanism came from the discovery that lysis was associated with the formation of membrane lesions on target cells caused by cytoplasmic granules from cytolytic lymphocytes. In this review Eckhard Podack summarizes our current knowledge of the molecular events resulting in target cell destruction by cytolytic T-lymphocytes (CTL) and natural killer (NK) cells. PMID- 25291204 TI - Antigenic variation in malaria parasites. AB - Antigenic variation and sequestration in organ capillary systems are two of the ways by which malaria parasites escape immune effector mechanisms. Here Marcel Hommel discusses the presence of variant antigens and endothelial-binding molecules on the surface of infected erythrocytes in the context of malaria immunity. PMID- 25291206 TI - Direct drug cocktail analyses using microscale vortex-assisted electroporation. AB - Combination therapy has become one of the leading approaches for treating complex diseases because it coadministers clinically proven drugs to concurrently target multiple signaling pathways of diseased cells. Identification of synergic drug combinations at their respective effective doses without unwanted accumulative side effects is the key to success for such therapy. In this work, we demonstrate the feasibility of the vortex-assisted microfluidic electroporation system for direct drug cocktail analyses where drug substances were individually delivered into cytosols in a sequential and dosage-controlled manner. Through quantitative analyses, the synergic combinational dosage ratios of the chemotherapeutic drug and the anticancer flavonoid were identified. When integrated with high throughput label-free rare cell purification techniques, the presented system has the potential for development of personalized medicines as the system would be capable of comprehensively assessing drug combinations directly on patients' cellular samples. PMID- 25291207 TI - Primum non nocere. PMID- 25291208 TI - Cellular level nanomanipulation using atomic force microscope aided with superresolution imaging. AB - Atomic force microscopes (AFM) provide topographical and mechanical information of the sample with very good axial resolution, but are limited in terms of chemical specificity and operation time-scale. An optical microscope coupled to an AFM can recognize and target an area of interest using specific identification markers like fluorescence tags. A high resolution fluorescence microscope can visualize fluorescence structures or molecules below the classical optical diffraction limit and reach nanometer scale resolution. A stimulated emission depletion (STED) microscopy superresolution (SR) microscope coupled to an AFM is an example in which the AFM tip gains nanoscale manipulation capabilities. The SR targeting and visualization ability help in fast and specific identification of subdiffraction-sized cellular structures and manoeuvring the AFM tip onto the target. We demonstrate how to build a STED AFM and use it for biological nanomanipulation aided with fast visualization. The STED AFM based bionanomanipulation is presented for the first time in this article. This study points to future nanosurgeries performable at single-cell level and a physical targeted manipulation of cellular features as it is currently used in research domains like nanomedicine and nanorobotics. PMID- 25291209 TI - Compact light-emitting diode lighting ring for video-assisted thoracic surgery. AB - In this work, a foldable ring-shaped light-emitting diode (LED) lighting assembly, designed to attach to a rubber wound retractor, is realized and tested through porcine animal experiments. Enabled by the small size and the high efficiency of LED chips, the lighting assembly is compact, flexible, and disposable while providing direct and high brightness lighting for more uniform background illumination in video-assisted thoracic surgery (VATS). When compared with a conventional fiber bundle coupled light source that is usually used in laparoscopy and endoscopy, the much broader solid angle of illumination enabled by the LED assembly allows greatly improved background lighting and imaging quality in VATS. PMID- 25291210 TI - Inexpensive diffuse reflectance spectroscopy system for measuring changes in tissue optical properties. AB - The measurement of changes in blood volume in tissue is important for monitoring the effects of a wide range of therapeutic interventions, from radiation therapy to skin-flap transplants. Many systems available for purchase are either expensive or difficult to use, limiting their utility in the clinical setting. A low-cost system, capable of measuring changes in tissue blood volume via diffuse reflectance spectroscopy is presented. The system consists of an integrating sphere coupled via optical fibers to a broadband light source and a spectrometer. Validation data are presented to illustrate the accuracy and reproducibility of the system. The validity and utility of this in vivo system were demonstrated in a skin blanching/reddening experiment using epinephrine and lidocaine, and in a study measuring the severity of radiation-induced erythema during radiation therapy. PMID- 25291211 TI - MicroRNA profile analysis of Epithelioma papulosum cyprini cell line before and after SVCV infection. AB - MicroRNAs (miRNAs) play significant roles in regulating almost all of the biological processes in eukaryotes. An accumulating body of evidence shows that miRNAs are associated with cellular changes following viral infection. Spring viremia of carp virus (SVCV) is the pathogen of Spring viremia of carp (SVC), which results in heavy losses in the cultured common carp (Cyprinus carpio) industry in many countries. To study the involvement of miRNAs during SVCV infection, we adopted the Solexa sequencing technology to sequence small RNA libraries from the Epithelioma papulosum cyprini (EPC) cell line before and after infection with SVCV. In this study, a total of 161 conserved and 26 novel miRNAs were identified. Subsequently, the expression patterns of these miRNAs were compared between the uninfected (control library, M) and SVCV-infected (infection library, E) libraries. In addition, to verify the Solexa sequencing results, the expression patterns of 14 randomly selected miRNAs were validated by qRT-PCR. The targets of the significantly differentially expressed miRNAs were then predicted, and the miRNAs that could directly target the SVCV genome were also predicted. No miRNA encoded by SVCV itself was detected. To the best of our knowledge, this study presents the first miRNA profiling assessment in association with fish rhabdovirus infection, and the data presented lay a foundation for further investigations to determine the roles of miRNAs in regulating the molecular mechanism during SVCV infection. PMID- 25291212 TI - First use of a computer-assisted operator-controlled flexible endoscope for transoral surgery. AB - Transoral robotic surgery (TORS) has become an accepted treatment option for head and neck cancer. However, anatomical limitations and a relevant financial burden require alternative developments in this field. To this end, a patient presenting with a T2 squamous cell carcinoma of the lower lateral oropharyngeal wall was effectively treated with a new Conformite Europeene-certified, computer-assisted, operator-controlled flexible endoscope (Flex). Intraoperative visualization and tissue handling were acceptable and safe. Transoral surgery with the flexible endoscope was safely conducted in a clinical setting. The introduction of alternative TORS systems will increase competition, drive scientific improvement, and reduce financial expenses. PMID- 25291213 TI - Examining the Traits-Desires-Intentions-Behavior (TDIB) model for fertility planning in women living with HIV in Ontario, Canada. AB - The objective of this study was to determine the predictors of fertility behavior (i.e., trying to become pregnant) in a large representative sample of women living with HIV of reproductive age in Ontario, Canada. The Traits-Desires Intentions-Behavior model was used to examine the key predictors of reproductive decision making and behavior. A total of 320 women living with HIV were included in the current analysis. The women living with HIV were between the ages of 18 and 52 (mean=37.23, SD=7.53), 56.4% had at least one child living in the home, over 40% identified as being of African ethnicity, and the average time since HIV diagnosis was 10.49 years (SD=5.71). In hierarchical multilevel analysis, perceived family support for trying to become pregnant, living in a large metropolitan city (i.e., Toronto), women's fertility desires, and fertility intentions were associated with fertility behavior (chi(2)9=59.97, p<0.001). As only 10.6% of participants reported engaging in fertility-related behavior, while 57.5% intended a pregnancy in the future, identifying barriers to fertility and discrepancies between intentions and behaviors can support policy programs and assist health care providers to better facilitate the fertility goals of women living with HIV. PMID- 25291215 TI - Immunogenetics of endocrine disorders. AB - There is much evidence that type I diabetes (also termed insulin-dependent diabetes mellitus) of man, the Biobreeding (BB) rat and the Non-Obese Diabetic (NOD) mouse results from autoimmune pancreatic beta cell destruction and that the most common forms of thyroid dysfunction (hypothyroidism associated with several different forms of 'thyroiditis' and the hyperthyroidism of Graves' disease) result from the interaction of autoantibodies or autoreactive T lymphocytes with thyroid follicular cells. The contribution of genes in the major histocompatibility complex (MHC) to the development of autoimmune beta cell destruction and thyroid autoimmunity was the focus of a recent meeting. PMID- 25291214 TI - A systematic review and meta-analysis of the efficacy of furosemide for exercise induced pulmonary haemorrhage in Thoroughbred and Standardbred racehorses. AB - REASONS FOR PERFORMING STUDY: Furosemide is the most commonly used medication for exercise-induced pulmonary haemorrhage (EIPH); however, critical evaluation of the strength of evidence for efficacy of furosemide is lacking and is warranted so that evidence-based treatment decisions can be made. OBJECTIVES: To evaluate the efficacy of furosemide to reduce the severity or frequency of detection of EIPH in Thoroughbred and Standardbred racehorses. STUDY DESIGN: Systematic review with meta-analyses. METHODS: Primary studies were identified via searches of electronic databases, relevant texts and reference lists of published articles. Studies were not restricted by date or publication status. Only studies published in English were eligible for inclusion. Searches were performed using a predetermined search string. Randomised controlled trials, nonrandomised trials and observational studies were included. Three authors independently assessed each study using the Cochrane collaboration guidelines and Grading of Recommendations Assessment, Development and Evaluation recommendations for rating quality of evidence. Meta-analysis of studies was performed with pooled data to determine whether furosemide reduced the frequency of detection of EIPH (yes or no) as evaluated by tracheobronchoscopy or bronchoalveolar lavage fluid red blood cell number, or if furosemide reduced the severity of EIPH by at least one tracheobronchoscopic grade. RESULTS: Seventeen studies fulfilled the inclusion criteria. The relative risk of detecting any EIPH by tracheobronchoscopy after administration of furosemide was 0.88 (pooled data from 11 studies, n = 5780; 95% confidence interval 0.79-0.97, P = 0.01). When data from only high-quality randomised controlled trials (2 studies, n = 405) were used, the relative risk of detecting endoscopically evident EIPH was 0.68 (95% confidence interval 0.58 0.79, P<0.001). The proportion of horses previously diagnosed with EIPH having a reduction of at least one EIPH grade after furosemide was 68% (2 studies, n = 405; 95% confidence interval 61-78%). CONCLUSIONS: There is high-quality evidence, albeit limited, that administration of furosemide reduces the incidence and severity of EIPH in Thoroughbred or Standardbred racehorses. PMID- 25291216 TI - Monoclonal antibodies against mycobacterial antigens. AB - The World Health Organization (WHO) scientific working groups on the Immunology of Leprosy (IMMLEP) and Tuberculosis (IMMTUB) recently organized two international workshops designed to characterize the specificity and reaction patterns of approximately 55 murine monoclonal antibodies (mAbs) which had been raised against Mycobacterium leprae or Mycobacterium tuberculosis and submitted to the IMMLEP and IMMTUB monoclonal antibody banks. PMID- 25291217 TI - Ontogeny of pre-B cells in the hatched chicken. PMID- 25291218 TI - Ontogeny of pre-B cells in the hatched chicken. PMID- 25291219 TI - Ontogeny of pre-B cells in the hatched chicken. PMID- 25291220 TI - H-Y antigen and sex determination. PMID- 25291221 TI - H-Y antigen and sex determination. PMID- 25291222 TI - The introversion of the immune response: a hypothesis for T-B interaction. AB - B cells present specific antigen efficiently(1-3) and, like macrophages, internalize antigen before apparently presenting it in association with class II MHC molecules. The association seems to occur when antigen bound to surface immunoglobulin (sIg) is internalized in a vesicle containing class IIMHC molecules(4). sIg is partly degraded in the vesicle and not re-expressed in native form' but class II molecules are re-expressed(6). Class II molecules have little or no polymorphism. How can they associate with all antigens in such a way that T helper cells can recognize the complex? Here Lee Leserman offers a solution to this problem based on the suggestion that T cells recognize the Ig in a complex of associated Ig and class II molecules, rather than the antigen in an antigen-class II complex. The system is antigen-dependent, not because the antigen has to associate with class II molecules, but because antigen is necessary for the internalization of sIg which is required for sIg association with class II. PMID- 25291223 TI - Natural antibodies and autoimmunity. PMID- 25291224 TI - A PERT solution for an old problem. PMID- 25291225 TI - Spontaneous autoimmune thyroiditis - a bird's eye view. AB - Lymphomatous goiter (struma lymphomatosa) first described by Hashimoto in 1912(1), was shown to be an autoimmune disorder 30years ago(2). In the sameyear an autoimmune thryoiditis was first induced experimentally by immunization with autologous thyroid extract and complete Freund's adjuvant(3). Among the many insights gainedfrom the study of such experimentally induced thyroiditis(3-5) is the notion that susceptibility to it is under a genetic control which influences both the reactivity of the immune systems and the properties of the thyroid gland(7). This is supported by the appearance of autoimmune thyroiditis in genetically restricted animal populations. Here Georg Wick and his colleagues review recent studies of the Obese strain (OS) of chickens and compare the pathogenesis of theirspontaneous autoimmune thyroiditis with that of Hashimoto's disease. PMID- 25291226 TI - Antigen-antibody interactions at the molecular level: adventures in peptide synthesis. AB - Following a binding interaction between a foreign molecule (antigen) and a receptor molecule on one or more vertebrate cell types, antibodies (immunoglobulins) are the major soluble effector molecules produced. Ideally, these bind only to the inducing antigen. Clearly, the specific and avid interaction of antigen with antibody, initially at the membrane of B lymphocytes and subsequently in circulation, is central to an effective defensive role for the antibody response. In order to provide for sufficient diversity to respond to many different foreign molecules, a number of sophisticated genetic mechanisms have evolved to maximize the pool of immunoglobulin receptors(1). Development of a procedure for the synthesis and testing of large numbers of peptides on solid supports(2) has provided new insights into the molecular basis for antibody specificity and the energetics of antigen-antibody interaction. In this article Mario Geysen summarizes observations made from the results obtained from the testing of a very large (>40 000) number of chemically synthesized peptides with a variety of monoclonal and poyclonal sera raised to diverse antigens (>10(6) individual assay values). PMID- 25291233 TI - Cost/benefit and predictive value of radioimmunoassay. PMID- 25291227 TI - 'Supernatural' killer cells. AB - The observation that lymphocytes from healthy individuals, without any known sensitization, could spontaneously lyse tumour target cells in vitro(1,2) was first thought to be an in-vitro artefact. Now the effector cells, known as natural killer (NK) cells, are accepted as a clearly distinct albeit heterogeneous subpopulation of lymphocytes. Yet their lineage remains controversial and despite much interest in the role of NK cells in protection against infection and cancer, their biological significance is far fiom clear(3 5). In this article Gordon Burns and his colleagues discuss recent research on NK cells which has illuminated the diverse effects of lymphokines, expanded knowledge on the mechanisms of cell recognition and killing by cytotoxic effector cells, and illustrated how a variety of leukocytes mediate more than one function - results of general interest to cell biologists. PMID- 25291236 TI - How a romantic relationship can protect same-sex attracted youth and young adults from the impact of expected rejection. AB - Same-sex attracted youth's well-being is jeopardized by components of minority stress, but this stress can be buffered by social support. What is unknown is whether a romantic relationship can also serve as a buffer. With an online survey we examined the link between components of minority stress, psychological well being, and its moderated relation by romantic relationship status among 309 Dutch same-sex attracted youth (16-24 years old, 52.9% female). The results showed that minority stress components (internalized homophobia, expected rejection, and meta stereotyping) were negatively related to psychological well-being. Moderation analyses revealed that only the impact of "expected rejection" on psychological well-being was buffered for those involved in a romantic relationship. This shows the particular functional link of romantic support in rejection contexts. PMID- 25291237 TI - Prenatal sodium arsenite affects early development of serotonergic neurons in the fetal rat brain. AB - Prenatal arsenite exposure has been associated with developmental disorders in children, including reduced IQ and language abnormalities. Animal experiments have also shown that exposure to arsenite during development induced developmental neurotoxicity after birth. However, the evidence is not enough, and the mechanism is poorly understood, especially on the exposure during early brain development. This study assessed effects of sodium (meta) arsenite shortly after exposure on early developing fetal rat brains. Pregnant rats were administered 50 mg/L arsenite in their drinking water or 20 mg/kg arsenite orally using a gastric tube, on gestational days (GD) 9-15. Fetal brains were examined on GD16. Pregnant rats administered 20 mg/kg arsenite showed reductions in maternal body weight gain and food consumption during treatment, but not with 50 mg/L arsenite. Arsenite did not affect fetal development, as determined by body weight, mortality and brain size. Arsenite also did not induce excessive cell death or affect neural cell division in any region of the fetal neuroepithelium. Thyrosine hydroxylase immunohistochemistry revealed no difference in the distribution of catecholaminergic neurons between fetuses of arsenite treated and control rats. However, reductions in the number of serotonin positive cells in the fetal median and dorsal raphe nuclei were observed following maternal treatment with 20mg/kg arsenite. Image analysis showed that the serotonin positive areas decreased in all fetal mid- and hind-brain areas without altering distribution patterns. Maternal stress induced by arsenite toxicity did not alter fetal development. These results suggest that arsenite-induced neurodevelopmental toxicity involves defects in the early development of the serotonin nervous system. PMID- 25291238 TI - Identifying functionally important cis-peptide containing segments in proteins and their utility in molecular function annotation. AB - Cis-peptide embedded segments are rare in proteins but often highlight their important role in molecular function when they do occur. The high evolutionary conservation of these segments illustrates this observation almost universally, although no attempt has been made to systematically use this information for the purpose of function annotation. In the present study, we demonstrate how geometric clustering and level-specific Gene Ontology molecular-function terms (also known as annotations) can be used in a statistically significant manner to identify cis-embedded segments in a protein linked to its molecular function. The present study identifies novel cis-peptide fragments, which are subsequently used for fragment-based function annotation. Annotation recall benchmarks interpreted using the receiver-operator characteristic plot returned an area-under-curve > 0.9, corroborating the utility of the annotation method. In addition, we identified cis-peptide fragments occurring in conjunction with functionally important trans-peptide fragments, providing additional insights into molecular function. We further illustrate the applicability of our method in function annotation where homology-based annotation transfer is not possible. The findings of the present study add to the repertoire of function annotation approaches and also facilitate engineering, design and allied studies around the cis-peptide neighborhood of proteins. PMID- 25291240 TI - Dissecting reactions of nonlinear precursor peptide processing of the class III lanthipeptide curvopeptin. AB - Lanthipeptides are ribosomally synthesized peptides which undergo extensive post translational modifications. In addition to novel structural features and bioactivities, the in vitro study on the biosynthesis of the class III lanthipeptide labyrinthopeptin revealed a unique C- to N-terminal directionality of biosynthetic processing. The recently described class III lanthipeptide curvopeptin allowed investigating the directionality aspect in much greater detail: Structural characterization of nine curvopeptin biosynthesis intermediates by high-resolution mass spectrometry combined with a deuterium labeling approach enabled for the first time building a comprehensive biosynthesis model featuring all three post-translational modification reactions: phosphorylation, elimination, and cyclization. These results point to a nonlinear processing scheme with a predominant C -> N-terminal directionality. Our data give important mechanistic insights into the concerted processing and directionality of the multifunctional class III modifying enzymes. The data are of significance in the light of obtaining a mechanistic understanding of the post translational biosynthesis machinery of the growing variety of ribosomally synthesized and post-translationally modified peptides. PMID- 25291241 TI - Calculations of pKa's and redox potentials of nucleobases with explicit waters and polarizable continuum solvation. AB - The SMD implicit solvation model augmented with one and four explicit water molecules was used to calculate pKa's and redox potentials of N-methyl substituted nucleic acid bases guanine, adenine, cytosine, thymine, and uracil. Calculations were carried out with the B3LYP/6-31+G(d,p) level of theory. The same numbers of water molecules were hydrogen bonded to the neutral, protonated, and deprotonated nucleobases in their unoxidized and oxidized forms. The improvement in pKa1 involving neutrals and cations was modest. By contrast, the improvement in pKa2 involving neutrals and anions was quite significant, reducing the mean absolute error from 4.6 pKa units with no waters, to 2.6 with one water and 1.7 with four waters. For the oxidation of nucleobases, adding explicit waters did little to improve E(X(*),H(+)/XH), possibly because both species in the redox couple are neutral molecules at pH 7. PMID- 25291239 TI - Association between breastfeeding and body mass index at age 6-7 years in an international survey. AB - BACKGROUND: Breastfeeding is believed to reduce children's risk for obesity but data are conflicting. It is also uncertain if breastfeeding has different effects on obesity in high- and low-income countries. OBJECTIVES: This study aimed to investigate the association between having been breastfed and body mass index (BMI) in 6- to 7-year-old children in a large international survey. METHODS: Parents/guardians reported whether their child had been breastfed and their current height and weight. Some centres measured height and weight directly. Analyses adjusted for whether height and weight were reported or measured, child's age, sex, country gross national income and centre. RESULTS: Data were available for 76,635 participants from 31 centres in 18 countries. Reported breastfeeding rates varied from 27 to 98%. After adjusting for potential confounders, the estimated BMI difference was 0.04 kg m(-2) lower among those who had been breastfed (P = 0.07). The risk for being overweight or obese was slightly lower among breastfed children (odds ratio = 0.95, P = 0.012). There was no evidence that the association between breastfeeding and BMI was different in lower income countries compared with higher income countries. CONCLUSIONS: The findings suggest that breastfeeding has little impact on children's BMI. Increasing breastfeeding is unlikely to reduce the global epidemic of childhood obesity. PMID- 25291242 TI - Vitamin D status in rheumatoid arthritis patients: relation to clinical manifestations, disease activity, quality of life and fibromyalgia syndrome. AB - AIM: To assess vitamin D levels in rheumatoid arthritis (RA) patients and to find their relation to clinical parameters, fibromyalgia syndrome (FMS), quality of life (QoL) and disease activity. METHODS: The study included 63 RA patients and 62 controls. Clinical examination and laboratory investigations were performed. For patients, the Disease Activity Score (DAS-28), QoL index, Health Assessment Questionnaire II (HAQ II) and Modified Larsen score were calculated. 25-OH vitamin D was measured in patients and controls. RESULTS: The patients' mean age was 41.59 +/- 9.69 years and disease duration 5.89 +/- 3.67 years. The level of vitamin D in RA patients was significantly lower (23.11 +/- 12.71 ng/mL) than that in the controls (32.59 +/- 13.06 ng/mL) (P = 0.005) being deficient in 50.8%, insufficient in 23.8% and normal in 25.4%. The RA patients with FMS (n = 33) had significantly lower levels of vitamin D (19.08 +/- 10.59 ng/mL) than those without (27.55 +/- 13.51 ng/mL) (P = 0.008). The difference was significant on comparing those receiving hydroxychloroquine (17.39 +/- 7.84 ng/mL) to those not (31.85 +/- 13.85 ng/mL) (P < 0.001). Vitamin D significantly correlated with QoL index (r = 0.58, P < 0.001) and negatively with HAQ II (r = -0.36, P = 0.004) and BMI (r = -0.39, P = 0.001). CONCLUSION: Special attention is required regarding vitamin D levels in RA patients with FMS and decreased QoL. Vitamin D should be corrected and supplementation considered among the RA management armamentarium. PMID- 25291243 TI - Vaccines and infectious disease. PMID- 25291244 TI - Heterogeneity under scrutiny. PMID- 25291245 TI - Paradigms regained. PMID- 25291246 TI - The first real human type-C retrovirus. PMID- 25291247 TI - The relationship between pre-B cells and primary B cells. PMID- 25291248 TI - Trophoblast and MHC antigens. PMID- 25291249 TI - The cell surface of mouse lymphoid dendritic cells. AB - Dendritic cells are irregularly shaped lymphoid cells that adhere to glass or plastic. They stimulate allogeneic and syngeneic mixed leucocyte reactions and serve as accessory cells in immune responses in vitro. This review summarises the surface properties useful in distinguishing and separating dendritic cells from other lymphoid types and in understanding their lineage and function. Monoclonal antibodies have recently identified the first dendritic-cell-specific surface marker. PMID- 25291250 TI - Genes coding for T-lymphocyte receptors. AB - An understanding of how T lymphocytes recognize antigen will require detailed knowledge of the assembly and expression of genes that encode T-cell receptors. In this article Alan Williamson discusses the properties required of these genes and the progress that has been made towards their identification. PMID- 25291251 TI - Regulation of immune responses to streptococcal protein antigens involved in dental caries. AB - Dental caries is probably man's most common disease and Streptococcus mutans is the organism most responsible for it. In this article Thomas Lehner discusses the part that helper T cells may play in protection against dental caries, and the prospects for immunizing against the disease. PMID- 25291252 TI - "AWAREness during CPR: be careful with what you say!". PMID- 25291253 TI - The next generation. PMID- 25291254 TI - Cognitive impairments after cardiac arrest: implications for clinical daily practice. PMID- 25291255 TI - Utility of magnetic resonance imaging for suspected appendicitis in pregnant women. AB - OBJECTIVE: The purpose of this study was to estimate the rate and risk of appendix nonvisualization and alternative diagnoses made with magnetic resonance imaging (MRI) for suspected appendicitis in pregnant women. STUDY DESIGN: We performed a retrospective cohort study of consecutive pregnant women who underwent MRI for suspected appendicitis at a single center from 2007-2012. Data on clinical presentation, imaging, and surgical pathologic evidence were extracted from electronic medical records. Odds ratios estimated risk factors for nondiagnosis. Radiologic diagnoses were identified, and rates of diagnoses were calculated. Subgroup analysis was performed among women who underwent initial imaging with ultrasound scanning. RESULTS: Over the 5-year period, 171 pregnant women underwent MRI for suspected appendicitis. The rate of nonvisualization was 30.9% (n = 53). Of the remaining 118 women with a visualized appendix, 18 women had imaging findings that were consistent with appendicitis and underwent appendectomy. Twelve cases of appendicitis were confirmed on pathologic evaluation (66.7%). Women with nonvisualization of the appendix on MRI were more likely to be beyond the first trimester (odds ratio, 2.1; 95% confidence interval, 1.0-4.5). Seventy-four women had disease diagnosed on MRI (43.3%). In the group of 43 women who had a nondiagnostic ultrasound scanning before the MRI, the rate of subsequent diagnostic MRI was 65% (n = 28). CONCLUSION: MRI yields a high diagnostic rate and accuracy in pregnant women with suspected appendicitis and provides alternative diagnoses to guide further management. Given the high rate of appendix nonvisualization on ultrasound scanning that has been reported in the literature, we recommend MRI as the imaging modality of choice for this population in settings in which MRI is readily available. PMID- 25291257 TI - Looking out for future scientists. AB - Proposals to reduce the number of students who do PhDs are misguided, writes Eve Marder, because they would exclude young scientists with qualities that do not show up in exam results and interviews. PMID- 25291256 TI - Neonatal morbidity associated with shoulder dystocia maneuvers. AB - OBJECTIVE: We sought to examine neonatal morbidity associated with different maneuvers used among term patients who experience a shoulder dystocia. STUDY DESIGN: We conducted a retrospective cohort study of all women who experienced a clinically diagnosed shoulder dystocia at term requiring obstetric maneuvers at a single tertiary care hospital from 2005 through 2008. We excluded women with major fetal anomaly, intrauterine death, multiple gestation, and preterm. Women exposed to Rubin maneuver, Wood's screw maneuver, or delivery of the posterior arm were compared to women delivered by McRoberts/suprapubic pressure only, which served as the reference group. The primary outcome was a composite morbidity of neonatal injury (defined as clavicular or humeral fracture or brachial plexus injury) and neonatal depression (defined as Apgar <7 at 5 minutes, arterial cord pH <7.1, continuous positive airway pressure use, intubation, or respiratory distress). Logistic regression was used to adjust for nulliparity and duration of shoulder dystocia, defined as time from delivery of fetal head to delivery of shoulders. RESULTS: Among the 231 women who met inclusion criteria, 135 were delivered by McRoberts/suprapubic pressure alone (57.9%), 83 women were exposed to Rubin maneuver, 53 women were exposed to Wood's screw, and 36 women were exposed to delivery of posterior arm. Individual maneuvers were not associated with composite morbidity, neonatal injury, or neonatal depression after adjusting for nulliparity and duration of shoulder dystocia. CONCLUSION: We found no association between shoulder dystocia maneuvers and neonatal morbidity after adjusting for duration, a surrogate for severity. Our results demonstrate that clinicians should utilize the maneuver most likely to result in successful delivery. PMID- 25291259 TI - Interactions between a series of pyrene end-labeled poly(ethylene oxide)s and sodium dodecyl sulfate in aqueous solution probed by fluorescence. AB - The interactions between a series of poly(ethylene oxide)s covalently labeled at both ends with pyrene pendants (PEO(X)-Py2, where X represents the number-average molecular weight of the PEO chains and equals 2K, 5K, 10K, and 16.5K) and an ionic surfactant, namely, sodium dodecyl sulfate (SDS), in water were investigated at a fixed pyrene concentration of 2.5 MUM corresponding to polymer concentrations smaller than 21 mg/L and with an SDS concentration range between 5 * 10(-6) and 0.02 M, thus encompassing the 8 mM critical micelle concentration (CMC) of SDS in water. The steady-state fluorescence spectra showed that the I1/I3 ratio decreased from 1.73 +/- 0.06 for SDS concentration smaller than 2 mM where pyrene was exposed to water to 1.43 +/- 0.03 for SDS concentration greater than 6 mM where pyrene was incorporated inside SDS micelles. The ratio of excimer to-monomer emission intensities (the IE/IM ratio) of all PEO(X)-Py2 samples remained constant at low SDS concentrations, then increased, passed through a maximum at the same SDS concentration of 4 mM before decreasing to a plateau value that is close to zero for PEO(10K)-Py2 and PEO(16.5K)-Py2 but nonzero for PEO(2K)-Py2 and PEO(5K)-Py2. The pyrene end groups of these two latter samples could not bridge two different micelles due to the short PEO chain, and excimer was formed by intramolecular diffusion inside the same SDS micelle. Time-resolved fluorescence decays of the pyrene monomer and excimer of the PEO(X)-Py2 samples were acquired at various SDS concentrations and globally fitted according to the "Model Free" analysis over the entire range of SDS concentration. The molar fractions of various excited pyrene species and the rate constant of pyrene excimer formation retrieved from the analysis of fluorescence decays were obtained as a function of SDS concentration. Interactions between SDS and PEO could not be detected by isothermal titration calorimetry, potentiometry with a surfactant selective electrode, and conductance measurements. PMID- 25291258 TI - Social and cognitive factors associated with children's secret-keeping for a parent. AB - This study examined children's secret-keeping for a parent and its relation to trust, theory of mind, secrecy endorsement, and executive functioning (EF). Children (N = 107) between 4 and 12 years of age participated in a procedure wherein parents broke a toy and asked children to promise secrecy. Responses to open-ended and direct questions were examined. Overall, secret-keeping increased with age and promising to keep the secret was related to fewer disclosures in open-ended questioning. Children who kept the secret in direct questioning exhibited greater trust and better parental ratings of EF than children who disclosed the secret. Findings highlight the importance of both social and cognitive factors in secret-keeping development. PMID- 25291260 TI - Endothelial lipase-384A/C polymorphism is associated with acute coronary syndrome and lipid status in elderly Uygur patients in Xinjiang. AB - OBJECTIVE: To explore the relationship between the endothelial lipase (EL) gene promoter -384A/C polymorphism and acute coronary syndrome (ACS) and lipid status in elderly Uygur patients in Xinjiang. METHODS: The polymerase chain reaction restriction fragment length polymorphism method was used to detect the EL gene promoter -384A/C genotype in 341 cases of elderly patients with ACS and 380 healthy subjects. RESULTS: In an elderly Chinese Han population, the EL-384A/C genotype and allele frequency distribution were significantly different between the ACS group and the control group (p<0.05); the frequency of the CC genotype in the ACS group was significantly higher than that in the control group (p<0.05). After adjusting for gender, age, diabetes, hypertension, smoking, hyperlipidemia, and other cardiovascular risk factors, the difference remains statistically significant (p<0.05). In the ACS group, C allele carriers had significantly higher serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol concentrations compared to AA genotypes (all p<0.05). CONCLUSION: EL 384A/C polymorphism was significantly associated with the ACS and lipids profile in an elderly Uygur population in Xinjiang. PMID- 25291261 TI - Perceptions of interprofessional education and practice within a complementary and alternative medicine institution. AB - A survey of the constituents of a complementary and alternative medicine (CAM) institution was conducted to identify perceptions of interprofessional education (IPE) and practice (IPP). A 22 question survey was developed and administered to: chiropractic students, acupuncture and oriental medicine students, faculty and alumni of both professions, staff and administrators. The majority of the 321 respondents demonstrated positive perceptions of IPE and IPP, however many reported a lack of understanding of the distinct roles of select healthcare professions. The study also suggested that the campus community is not homogenous in its understanding of CAM or allopathic professions, or is it homogenous in its understanding of IPE and IPP. While the overall positive attitudes toward IPE and IPP imply a willingness to improve collaboration between these groups, the lack of understanding of profession-specific roles must be addressed to support effective implementation of IPE. PMID- 25291262 TI - Interprofessional mental health training in rural primary care: findings from a mixed methods study. AB - The benefits of interprofessional care in providing mental health services have been widely recognized, particularly in rural communities where access to health services is limited. There continues to be a need for more continuing interprofessional education in mental health intervention in rural areas. There have been few reports of rural programs in which mental health content has been combined with training in collaborative practice. The current study used a sequential mixed-method and quasi-experimental design to evaluate the impact of an interprofessional, intersectoral education program designed to enhance collaborative mental health capacity in six rural sites. Quantitative results reveal a significant increase in positive attitudes toward interprofessional mental health care teams and self-reported increases in knowledge and understanding about collaborative mental health care delivery. The analysis of qualitative data collected following completion of the program, reinforced the value of teaching mental health content within the context of collaborative practice and revealed practice changes, including more interprofessional and intersectoral collaboration. This study suggests that imbedding explicit training in collaborative care in content focused continuing professional education for more complex and chronic health issues may increase the likelihood that professionals will work together to effectively meet client needs. PMID- 25291265 TI - A new editor for immunology today. PMID- 25291263 TI - A conference report of the interprofessional satellite symposium in Uonuma, Japan: an international exchange on the future of community care. PMID- 25291266 TI - Transient, local immunosuppression in recurrent vaginitis. PMID- 25291267 TI - The 65kDa antigen of mycobacteria. PMID- 25291268 TI - Immunologic privilege in the eye and the fetus. AB - Some regions of the body are notably tolerant to transplants of foreign tissues. This 'immunologic privilege' has previously been assigned to the isolation of these sites from the lymphatic system, thus preventing interaction with cells of the immune system. But recent work has largely overturned this theory; antigens can not only reach lymphatic and blood vasculature tissues but can also generate immune responses. Concentrating on the anterior chamber of the eye and the pregnant uterus, Wayne Streilein and Thomas Wegmann suggest that immunologic privilege arises instead from the specific active suppression of a rejection response. PMID- 25291269 TI - Altered expression of lymphocyte functional antigen in Down syndrome. AB - A chronic inability to resist infection is a major cause of death in patients suffering from Down syndrome. However, how this impairment in immune function is related to the diagnostic characteristic of the syndrome - possession of three copies of chromosome 21 - is currently far from clear. In this article, Malcolm Taylor argues that the presence of the gene encoding the beta subunit of the lymphocyte functional antigen on this chromosome suggests that immunodeficiency may be linked to the aberrant expression of this antigen on lymphocytes. PMID- 25291271 TI - Interferons and rheumatoid arthritis: insight into interferon biology? PMID- 25291270 TI - How do human immunodeficiency viruses enter cells? PMID- 25291272 TI - The genetic origin of autoantibodies. AB - Autoimmune disease appears to be a consequence of the generation of self-reactive antibodies. The relationship between these autoantibodies and antibodies directed against exogenous antigens has fostered much recent work, especially on the murine models of systemic lupus erythematosus and rheumatoid arthritis, as Reinhard Kofler and his colleagues review here. While the complexities surrounding the origin of self-specific antibodies are still to be completely unravelled, it appears that lupus autoantibody expression may not result from defects in lg germline genes nor in mechanisms generating antibody repertoires (variable region gene selection, rearrangement, somatic mutation) but follows the same general principles governing responses to foreign antigens. PMID- 25291273 TI - The regulation of human eosinophil function by cytokines. AB - The factors responsible for eosinophil regulation fall broadly into three categories - endogenous chemotactic molecules, factors derived from invading organisms and the cytokines. As David Silberstein and John David reveal, cytokines appear to prime eosinophils for a cytotoxic response to invading organisms. While it seems unlikely that there is a common mechanism for this enhancement of cytotoxicity (and the concomitant inflammation at the site of challenge), much effort is being expanded in order to determine the relationships between the less well characterized eosinophil-stimulating activities and their modes of action. PMID- 25291274 TI - Clonal analysis of the cytolytic T-cell response to human tumors. AB - A variety of cloning techniques are being applied to the analysis of phenotype, specificity and mechanism of action of cytolytic T cells on autologous tumor cells. Technical factors are influencing the results and interpretation of these studies but, as Andrea Anichini and colleagues show here, this analysis has revealed that the cytotoxic response can be multiclonal, mediated by multiple mechanisms and directed to different groups of determinants expressed on the same tumor cells. PMID- 25291275 TI - Remodelling the H-2 map. AB - Dabbling in the field of cell-mediated immune responses involves a considerable risk of stumbling over the major histocompatibility complex (MHC) if only because T cells have dual specificity for antigen and self-MHC molecules and because MHC molecules regulate T-cell responses. The amazing progress made by molecular biologists in examining the mouse MHC has led to the startling conclusion that more H-2 class-I genes have now been discovered by DNA technology than can be accounted for by immunologists, although admittedly some of these genes may behave as pseudogenes whose products are not expressed. The latest insights into the H-2 map were discussed at a recent meeting. PMID- 25291276 TI - Immortality by transfection. PMID- 25291277 TI - Monoclonal antibodies and human leucocyte antigens. PMID- 25291278 TI - Conditioning immune responses. PMID- 25291279 TI - [Not Available]. PMID- 25291280 TI - DNA strand breaks and differentiation. PMID- 25291281 TI - The role of purine metabolic enzymes and terminal deoxynucleotidyl transferase in intrathymic T-cell differentiation. AB - Most cortical thymocytes die within the thymus. It is proposed here that lethally high intracellular levels of deoxynucleosides are the cause of death. Developing thymocytes appropriately equipped for self-recognition are protected because contact with stromal cells prevents the lethal accumulation of deoxynucleosides. PMID- 25291282 TI - Monoclonal lupus autoantibodies. PMID- 25291283 TI - A cold-blooded look at T-cell education. PMID- 25291284 TI - The production of monoclonal antibodies from human lymphocytes. AB - Two conceptually unique approaches are currently available for the production of human monoclonal antibodies - the 'hybridoma' technique, based on the fusion of antibody-producing B lymphocytes with plasmacytoma cells or lymphoblastoid cell lines; and the use of Epstein-Barr virus (EBV) to 'immortalize' antigen-specific, human B lymphocytes. Here Danuta Kozbor and, John Roder discuss the contribution each technique is making, alone or in combination, towards the desired aim of producing human monoclonal antibodies with a defined specificity. PMID- 25291285 TI - DNA damage and repair in immunologically active cells. AB - Eukaryotic DNA can be altered by exogenous agents and through spontaneous intracellular processes. Proficiency in the repair of DNA is required for the maintenance of normal health and there is evidence that defective repair is associated with immunodeficiency states and perhaps with ageing changes in the immune system. In this, the first part of a two-part article, Gilmour Harris discusses different types of DNA damage and their repair. PMID- 25291286 TI - T-cell function and specificity in athymic mice. AB - It has recently become possible to study functional T cells of both cytotozic and helper cell lineages derived from athymic (nude) mice. In this review Thomas Hunig discusses how the new information obtained may contribute to our understanding of T-cell ontogeny and the generation of T-cell diversity. PMID- 25291287 TI - Structural and genetic similarities between immunoglobulins and class-1 histocompatibility antigens. AB - There are many similarities between the phenotype and genotype of immunoglobulins and class-1-major-histocompatibility antigens. These are summarised by W. Cushley and M. J. Owen who also consider their possible implications in the control of expression and function. PMID- 25291290 TI - A novel sulfur mustard (HD) vapor inhalation exposure system for accurate inhaled dose delivery. AB - INTRODUCTION: A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube. METHODS: Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by an in-line pneumotach, pressure transducer, and Buxco pulmonary analysis computer/software. For each exposure, the challenge atmosphere was allowed to stabilize at the desired concentration while the anesthetized animal was provided humidity controlled clean air. Once the target concentration was achieved and stable, a portion of the challenge atmosphere was drawn past the endotracheal tube, where the animal inhaled the exposure ad libitum. During the exposure, HD vapor concentration and animal weight were used to calculate the needed inhaled volume to achieve the target inhaled dose (MUg/kg). The exposures were halted when the inhaled volume was achieved. RESULTS: The exposure system successfully controlled HD concentrations from 22.2 to 278mg/m(3) and accurately delivered inhaled doses between 49.3 and 1120MUg/kg with actual administered doses being within 4% of the target level. DISCUSSION: This exposure system administers specific HD inhaled doses to evaluate physiological effects and for evaluation of potential medical countermeasure treatments. PMID- 25291292 TI - Leukaemia: fine-tuning metabolism. PMID- 25291293 TI - Angiogenesis: pushing through, branching out. PMID- 25291291 TI - Cancer cachexia: understanding the molecular basis. AB - Cancer cachexia is a devastating, multifactorial and often irreversible syndrome that affects around 50-80% of cancer patients, depending on the tumour type, and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. Since cachexia may account for up to 20% of cancer deaths, understanding the underlying molecular mechanisms is essential. The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria. Interestingly, crosstalk between different cell types ultimately seems to result in muscle wasting. Some of the recent progress in understanding the molecular mechanisms of cachexia may lead to new therapeutic approaches. PMID- 25291294 TI - Metabolism: reprogramming metabolic flux in glioma. PMID- 25291295 TI - A new acanthocephalan species (Archiacanthocephala: Oligacanthorhynchidae) from the crab-eating fox (Cerdocyon thous ) in the Brazilian pantanal wetlands. AB - A new species of Oligacanthorhynchidae (Acanthocephala) Prosthenorchis cerdocyonis n. sp. is described from 17 specimens collected from the small intestine of the crab-eating fox Cerdocyon thous Linnaeus, 1766 (Canidae: Carnivora) found in the Brazilian Pantanal wetlands. Specimens were studied using light and scanning electron microscopy. Characteristic features distinguishing the new species from others already described are presented, such as size of the body, the position of lemnisci, size of the eggs, host, and geographical distribution. Details of the body surface obtained by scanning electron microscopy, such as the presence of 2 lateral papillae in the proximal region of the proboscis, the presence of barbs in hooks, and a robust and festooned collar, helped to identify the species. Until now, specimens belonging to Prosthenorchis reported from Cerdocyon thous were not identified to species. Furthermore, the new species is the first to be recorded in C. thous found in the Pantanal wetlands. PMID- 25291296 TI - Large scale in vivo recordings to study neuronal biophysics. AB - Over the last several years, technological advances have enabled researchers to more readily observe single-cell membrane biophysics in awake, behaving animals. Studies utilizing these technologies have provided important insights into the mechanisms generating functional neural codes in both sensory and non-sensory cortical circuits. Crucial for a deeper understanding of how membrane biophysics control circuit dynamics however, is a continued effort to move toward large scale studies of membrane biophysics, in terms of the numbers of neurons and ion channels examined. Future work faces a number of theoretical and technical challenges on this front but recent technological developments hold great promise for a larger scale understanding of how membrane biophysics contribute to circuit coding and computation. PMID- 25291297 TI - Vestibular and balance issues following sport-related concussion. AB - PRIMARY OBJECTIVE: To review relevant literature regarding the effect of concussion on vestibular function, impairments, assessments and management strategies. REASONING: Dizziness and balance impairments are common following sport-related concussion. Recommendations regarding the management of sport related concussion suggest including tests of balance within the multifactorial assessment paradigm for concussive injuries. ANALYSIS: The literature was searched for guidelines and original studies related to vestibular impairments following concussion, oculomotor and balance assessments and treatment or rehabilitation of vestibular impairments. The databases searched included Medline, CINAHL, Sport Discus and the Cochrane Database of Systematic Reviews through October 2013. MAIN OUTCOMES AND RESULTS: Dizziness following concussion occurs in ~67-77% of cases and has been implicated as a risk factor for a prolonged recovery. Balance impairments also occur after concussion and last 3-10 days post-injury. Assessments of balance can be done using both clinical and instrumented measures with success. Vestibular rehabilitation has been shown to improve outcomes in patients with vestibular impairments, with one study demonstrating success in decreasing symptoms and increasing function following concussion. CONCLUSIONS: Best practices suggest that the assessment of vestibular function through cranial nerve, oculomotor and balance assessments are an important aspect of concussion management. Future studies should evaluate the effectiveness of vestibular rehabilitation for improving patient outcomes. PMID- 25291304 TI - Recommendations on vaccination for Asian small animal practitioners: a report of the WSAVA Vaccination Guidelines Group. AB - In 2012 and 2013, the World Small Animal Veterinary Association (WSAVA) Vaccination Guidelines Group (VGG) undertook fact-finding visits to several Asian countries, with a view to developing advice for small companion animal practitioners in Asia related to the administration of vaccines to dogs and cats. The VGG met with numerous first opinion practitioners, small animal association leaders, academic veterinarians, government regulators and industry representatives and gathered further information from a survey of almost 700 veterinarians in India, China, Japan and Thailand. Although there were substantial differences in the nature and magnitude of the challenges faced by veterinarians in each country, and also differences in the resources available to meet those challenges, overall, the VGG identified insufficient undergraduate and postgraduate training in small companion animal microbiology, immunology and vaccinology. In most of the countries, there has been little academic research into small animal infectious diseases. This, coupled with insufficient laboratory diagnostic support, has limited the growth of knowledge concerning the prevalence and circulating strains of key infectious agents in most of the countries visited. Asian practitioners continue to recognise clinical infections that are now considered uncommon or rare in western countries. In particular, canine rabies virus infection poses a continuing threat to animal and human health in this region. Both nationally manufactured and international dog and cat vaccines are variably available in the Asian countries, but the product ranges are small and dominated by multi-component vaccines with a licensed duration of immunity (DOI) of only 1 year, or no description of DOI. Asian practitioners are largely unaware of current global trends in small animal vaccinology or of the WSAVA vaccination guidelines. Consequently, most practitioners continue to deliver annual revaccination with both core and non-core vaccines to adult animals, with little understanding that "herd immunity" is more important than frequent revaccination of individual animals within the population. In this paper, the VGG presents the findings of this project and makes key recommendations for the Asian countries. The VGG recommends that (1) Asian veterinary schools review and increase as needed the amount of instruction in small animal vaccinology within their undergraduate curriculum and increase the availability of pertinent postgraduate education for practitioners; (2) national small animal veterinary associations, industry veterinarians and academic experts work together to improve the scientific evidence base concerning small animal infectious diseases and vaccination in their countries; (3) national small animal veterinary associations take leadership in providing advice to practitioners based on improved local knowledge and global vaccination guidelines; (4) licensing authorities use this enhanced evidence base to inform and support the registration of improved vaccine product ranges for use in their countries, ideally with DOI for core vaccines similar or equal to those of equivalent products available in western countries (i.e. 3 or 4 years). The VGG also endorses the efforts made by Asian governments, non-governmental organisations and veterinary practitioners in working towards the goal of global elimination of canine rabies virus infection. In this paper, the VGG offers both a current pragmatic and future aspirational approach to small animal vaccination in Asia. As part of this project, the VGG delivered continuing education to over 800 Asian practitioners at seven events in four countries. Accompanying this document is a list of 80 frequently asked questions (with answers) that arose during these discussions. The VGG believes that this information will be of particular value to Asian veterinarians as they move towards implementing global trends in small companion animal vaccinology. PMID- 25291305 TI - Nanosecond spin lifetimes in single- and few-layer graphene-hBN heterostructures at room temperature. AB - We present a new fabrication method of graphene spin-valve devices that yields enhanced spin and charge transport properties by improving both the electrode-to graphene and graphene-to-substrate interface. First, we prepare Co/MgO spin injection electrodes onto Si(++)/SiO2. Thereafter, we mechanically transfer a graphene-hBN heterostructure onto the prepatterned electrodes. We show that room temperature spin transport in single-, bi-, and trilayer graphene devices exhibit nanosecond spin lifetimes with spin diffusion lengths reaching 10 MUm combined with carrier mobilities exceeding 20,000 cm(2)/(V s). PMID- 25291306 TI - A cheat sheet to navigate the complex maze of exclusivities in the United States. PMID- 25291307 TI - The wake of FTC v. Actavis: practical implications on the pharmaceutical industry. PMID- 25291308 TI - Amendment to UK Patent Act provides further exception to patent infringement. PMID- 25291309 TI - First-to-invent versus first-to-file: impact of the AIA. AB - On March 16, 2013, the USPTO switched from a 'first-to-invent' to a 'first-to file' patent system. Under the 2011 America Invents Act, patents will be awarded to the first inventor to file a patent application as opposed to the date of invention. Now, over a year since the main provisions of the America Invents Act (AIA) came into effect, Pharmaceutical Patent Analyst has invited a selection of IP specialists and researchers from the US to discuss the implications of this new law and how it will affect future pharmaceutical and medical R&D. Interview conducted by Alexandra Sklan, Commissioning Editor. PMID- 25291312 TI - Recent advances in irreversible kinase inhibitors. AB - Despite concerns of off-target selectivity and cytotoxicity, there has been a resurgence in interest in irreversible kinase inhibitors resulting in more than 60 disclosed patent and patent applications over the past 4 years. Many of these inhibitors possess several key advantages over their reversible counterparts. The patent literature from 2010 to 2013 has been reviewed and novel irreversible kinase inhibitors for Bruton's tyrosine kinase, epidermal growth factor receptor, Janus kinase 3, phosphoinsitide 3 and other kinases are disclosed and discussed. These inhibitors offer novel treatments for mantle cell lymphoma, non-small-cell lung cancer, autoimmune disorders and severe metastatic cancers. A future perspective is presented on the likelihood of clinical success of these agents as well as the potential for new uses of irreversible kinase inhibitors in the future. PMID- 25291313 TI - Advances and strategies in NADPH oxidase inhibitors and activators patents. AB - The NADPH oxidase (NOX) enzymes were identified as a family of seven isoforms contributing to the production of reactive oxygen species. During the past 15 years, this class of enzymes has increasingly gained interest from the academic and pharmaceutical laboratories. Extensive research efforts focused on the decryption of their mechanism of action has shown that Nox enzymes are the most important source of reactive oxygen species and key contributors in the pathogenesis of several diseases. Recent publications and patents suggest that NOX modulators may provide major opportunities in many diseases as novel therapeutics. This review covers application patents and current state-of-the-art on Nox modulators from 2005 to December 2013 and examines the different approaches patented to modulate the activity of Nox enzymes. PMID- 25291314 TI - Novel anti-Helicobacter pylori therapies. AB - Helicobacter pylori is a ubiquitous gastropathogen infecting more than half of the world population. It is associated with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. Current recommended therapy does not eradicate infection in all treated cases and at least 20% post-treatment patients continue to suffer. Salvage therapy helps some of these nonresponders, but resistance to available antibiotics is mounting. Hence, its treatment still remains a daunting task for the practicing physician. Novel medications with improved efficacy and tolerability and with less chances of resistance are required. The present review attempts to discuss the newer patents in this field, which demonstrate a promising future role in the management of H. pylori infection and its consequent problems. PMID- 25291316 TI - Toward selective TYK2 inhibitors as therapeutic agents for the treatment of inflammatory diseases. AB - The family of JAK comprises four members and has received significant attention in recent years from the pharmaceutical industry as a therapeutic target. The role of JAK is central to cytokine signaling pathways. It is believed that selective modulation of one specific JAK can lead to the inhibition of a restricted set of cytokines, which should avoid undesired side effects and get closer to the profile of biologic therapies. Consequently, selective JAK inhibition has become a major focus area of drug discovery research. A review of the TYK2 patents indicates that industry attention has recently turned toward the development of specific inhibitors. Importantly, despite the increasing number of published patents, none of these drugs have yet made it to the clinical trials. PMID- 25291317 TI - Treatment relapse and behavioral momentum theory. AB - The relapse of problem behavior after apparently successful treatment is an enduring problem for the field of applied behavior analysis. Several theoretical accounts of treatment relapse have emerged over the years. However, one account that has received considerable recent attention is based on behavioral momentum theory (BMT). BMT has shown that behavior is more persistent in contexts that are correlated with higher rates of reinforcers after disruption of the response reinforcer relation. Accordingly, relapse after successful treatment can be viewed as the persistence of behavior when treatment is compromised in some manner. We review basic BMT research, alternative accounts of treatment relapse, and translational research studies derived from BMT research. The implications for applied behavior analysis in practice are discussed along with potential solutions to the problem of treatment relapse. PMID- 25291315 TI - Advances in recent patent and clinical trial drug development for Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease, involving a large number of genes, proteins and their complex interactions. Currently, no effective therapeutic agents are available to either stop or reverse the progression of this disease, likely due to its polygenic nature. The complicated pathophysiology of AD remains unresolved. Although it has been hypothesized that the amyloid beta cascade and the hyper-phosphorylated tau protein may be primarily involved, other mechanisms, such as oxidative stress, deficiency of central cholinergic neurotransmitter, mitochondrial dysfunction and inflammation have also been implicated. The main focus of this review is to document current therapeutic agents in clinical trials and patented candidate compounds under development based on their main mechanisms of action. It also discusses the relationship between the recent understanding of key targets and the development of potential therapeutic agents for the treatment of AD. PMID- 25291319 TI - Stimulate the phagocytes. AB - Investigators from Canada, several European countries, Israel, the Republic of South Africa and the United States of America met earlier this year* to discuss whether or not George Bernard Shaw's exhortation to stimulate the phagocytes' pertains equally to host defense against neoplastic cells and microorganisms. The focus was on macrophage activation for killing these diverse targets, and in particular on four questions. What are the characteristics of the macrophages involved in host defense against tumor cells and microorganisms? How are these cells stimulated? How do they mediate their cytotoxic effects? And do they have therapeutic potential? PMID- 25291318 TI - Blood glucose self-monitoring patterns in Mexican Americans: further lessons from the Starr County Border Health Initiative. AB - BACKGROUND: The purpose was to describe patterns of home self-monitoring of blood glucose (SMBG) in Mexican Americans with type 2 diabetes mellitus enrolled in a diabetes self-management education protocol. Research questions were as follows: (1) What were the patterns and rates of home glucose self-monitoring over the 6 month course of the study? (2) What were the differences in monitoring rates between experimental and control groups? (3) What were the relationships between rates of monitoring and glycosylated hemoglobin (A1C), gender, and years with diabetes? SUBJECTS AND METHODS: We used a randomized (by group) repeated-measures pretest/posttest control group design. Glucometer data from an experimental group (diabetes self-management education plus nurse case management) and a comparison group (diabetes self-management education only) were analyzed. Data were collected at baseline and at 3 and 6 months. RESULTS: Overall average SMBG rates were low. Experimental and control group monitoring levels were not significantly different. More females than males never monitored glucose values, but more females than males checked at least one time per week. Those participants who checked their glucose levels more than once per week had diabetes for a longer period of time. Rates of monitoring were not strongly associated with A1C levels at 3 and 6 months, but at 6 months A1C levels were statistically significantly different based on whether or not individuals monitored their glucose levels (P=0.03, n=71). CONCLUSIONS: SMBG rates were low in this study despite SMBG education and access to free glucometers and test strips. The lower rates of SMBG may reflect the effects of unexpected environmental challenges, but exact causes remain unclear. Reasons for low rates of SMBG need to be explored further, especially in underserved communities. PMID- 25291320 TI - Hybridomas from unimmunized individuals. AB - The products of hybridomas are widely used to define and characterize markers for diagnostic or therapeutic purposes. Little attention has been paid to the value of hybridoma products originating from the immunocytes of animals on people who have not been artificially immunized. At a recent French-Israeli meeting on this theme*, discussion focused on the analysis of natural autoantibodies and their role in autoimmunity, natural anti-tumor antibodies, and hybrids formed between somatic host cells and tumor cells. PMID- 25291321 TI - The control of blood cell production. AB - It is now more than twenty years since the discovery of the clonal growth of blood cells in vitro, but the last two years have seen remarkable developments which allow scientists to return to the study of the physiology of blood cell production. The concentrated blend of cell biology, protein chemistry, genetic engineering and animal studies presented at a recent meeting* highlighted the complexity of the control signals for blood cell production. Nevertheless, the animal studies indicated an immediate and powerful role for the blood cell growth factors during chemotherapy and infection control. PMID- 25291322 TI - A ternary cellular complex between B and T lymphocytes and antigen-presenting cells? PMID- 25291323 TI - Multispecific monoclonal antibodies. PMID- 25291324 TI - [Not Available]. PMID- 25291326 TI - [Not Available]. PMID- 25291325 TI - Immunosuppression by seminal plasma in vitro-an artefact? PMID- 25291327 TI - [Not Available]. PMID- 25291328 TI - [Not Available]. PMID- 25291329 TI - Interactions between epidermal cells and lymphocytes in psoriasis. PMID- 25291330 TI - Immune-mediated injury of virus-infected oligodendrocytes A model of multiple sclerosis. AB - The causes of primary demyelination in diseases such as multiple sclerosis are still unknown, but it is possible that immune attack triggered by virus infection may be responsible. Theiler's murine encephalitis is a popular animal model of demyelinating diseases, and in this article Moses Rodriguez and his colleagues describe a hypothetical scheme to explain differential susceptibility of inbred strains to infection. They propose a mechanism by which specific demyelination is produced when immune cells interact with viral antigen and major histocompatibility complex (MHC) antigens. PMID- 25291331 TI - Natural autoantibodies might prevent autoimmune disease. AB - Autoantibodies are common in healthy individuals and appear not to be harmful. It is not clear how they arise nor what their function is. Here Irun Cohen and Anne Cooke propose that these natural autoantibodies bind to self or self-mimicking epitopes and so prevent the initiation of a damaging auto immune response. PMID- 25291332 TI - Suppressor T-cell factors that bind immunoglobulin. PMID- 25291333 TI - The immune response against therapeutic monoclonal antibodies. PMID- 25291334 TI - Current status of antifertility vaccines using gonadotropin immunogens. AB - Immunological methods of birth control are being pursued by several routes. Leading this field are vaccines which may inhibit the function of the hormone human chorionic gonadotropin (hCG). Vaccines using at least three different immunogens and a variety of formulations have been in clinical trials during 1986. In this article Vernon Stevens describes the background of the research in this field, outlines the clinical trials planned or underway to test early hCG vaccine formulations, and gives a personal view of the research still needed to achieve a safe and effective vaccine. PMID- 25291335 TI - Thymic nurse cells: possible sites of T-cell selection. AB - The precise role of the thymic microenvironment in induction and selection of the T-cell repertoire, a matter of considerable interest to immunologists, has been difficult to define. Direct cell-cell interactions between thymocytes and distinct stromal cells are an important component of this thymic microenvironment. Thymic epithelial cells, in particular, have been suspected to select immature T cells for self MHC-specificity via direct cell-cell contact. Here, Bruno Kyewski discusses the type of epithelial cells known as thymic nurse cells and their remarkable association with the thymocytes which are completely enclosed within them. PMID- 25291336 TI - The production of more useful monoclonal antibodies 2. The use of somatic-cell genetic and recombinant-DNA technology to tailor-make monoclonal antibodies. AB - In last month's issue(1) Matthew Scharff and his colleagues discussed recent improvements in the technique of making monoclonal antibodies by cell fusion. However, not all the monoclonal antibodies generated by hybridoma technology have all of the properties required for a particular task. This second part of a two part review deals with ways in which these first-generation reagents can be improved by identifying somatic-cell mutants with the desired properties or by engineering new and even novel molecules using recombinant DNA technology. PMID- 25291338 TI - Editorial comment. PMID- 25291339 TI - Communicating and advocating for science and medicine: beyond the basics. AB - I have discussed several advocacy strategies to improve effective communications for those motivated to do the necessary work to make a difference in policy decisions involving science and health care. I encourage you to get involved personally with members of Congress, their key "staffers," and to contribute financially to their election efforts. Other suggestions are self-evident, for example, think strategically, only advocate for important policies and do not "over promise" or "under deliver." If you "get to yes," stop negotiating and leave gratefully. Remember, you are operating in a high stakes arena and while you understand the intended consequences, you may misjudge unintended consequences that could diminish success. But if you want to make a difference, you must become a "player in the policy and political game." And if you "get in the game," you should play to win! PMID- 25291340 TI - A non-galilean view of the immune network. PMID- 25291341 TI - Resistance to murine cytomegalovirus infection: H-2-linked genetic regulation of an immunopathological condition? PMID- 25291342 TI - Exploiting mouse train susceptibility differences in immunoparasitology. PMID- 25291343 TI - Evolution of the lymphocyte. AB - Invertebrates probably lack the cellular and molecular apparatus that characterizes vertebrate immunity but do have their own distinctive defense mechanisms (perhaps best termed 'quasi-immunity') worth investigation in their own right. Investigations of lymphocytes-like cells and immunity in animals near the transition point betweem invertebrates and vertebrates (e.g. the protochordates) may yet yield information on the early development of true vertebrate immunity. In this article Gregoru Warr discusses what light phylogenetic studies throw on the development of immunologically competent cells. PMID- 25291344 TI - The characterization and function of human immunoregulatory T lymphocyte subsets. AB - Functional T lymphocyte subpopulations can be identified in humans by antibodies which detect stable glycoprotein antigens on their surface. Thus, inducer T lymphocytes bear an antigen termed T4 while suppressor T lymphocytes bear an antigen termed T5. Immune homeostasis results from a delicate balance between inducer and suppressor subsets within the T-cell circuit and perturbation in subset dynamics may initiate a wide variety of immunopathological disorders. Here Ellis Reinherz and Stuart Schlossman discuss the present understanding of this circuit, its role in the pathogenesis of a number of diseases and how the human immune response can be manipulated in an orderly way through modulation of selected T-cell subsets. PMID- 25291345 TI - Immunological studies of hormone receptors: a two-way approach. AB - Recent progress in hormone receptor studies has resulted from a multidisciplinary approach involving pharmacologists, endocrinologists and biochemists. Immunology provides both tools and a source of concepts for these studies. Endocrine and immune networks share important features which become recognized both by the analysis of autoimmune diseases and of conventionally induced immune responses. The latest discoveries are discussed here. PMID- 25291346 TI - Physiological and morphological adaptations of herbaceous perennial legumes allow differential access to sources of varyingly soluble phosphate. AB - The aim of this study was to investigate the capacity of three perennial legume species to access sources of varyingly soluble phosphorus (P) and their associated morphological and physiological adaptations. Two Australian native legumes with pasture potential (Cullen australasicum and Kennedia prostrata) and Medicago sativa cv. SARDI 10 were grown in sand under two P levels (6 and 40 ug P g(-1) ) supplied as Ca(H2 PO4 )2 .H2 O (Ca-P, highly soluble, used in many fertilizers) or as one of three sparingly soluble forms: Ca10 (OH)2 (PO4 )6 (apatite-P, found in relatively young soils; major constituent of rock phosphate), C6 H6 O24 P6 Na12 (inositol-P, the most common form of organic P in soil) and FePO4 (Fe-P, a poorly-available inorganic source of P). All species grew well with soluble P. When 6 ug P g(-1) was supplied as sparingly soluble P, plant dry weight (DW) and P uptake were very low for C. australasicum and M. sativa (0.1-0.4 g DW) with the exception of M. sativa supplied with apatite-P (1.5 g). In contrast, K. prostrata grew well with inositol-P (1.0 g) and Fe-P (0.7 g), and even better with apatite-P (1.7 g), similar to that with Ca-P (1.9 g). Phosphorus uptake at 6 ug P g(-1) was highly correlated with total root length, total rhizosphere carboxylate content and total rhizosphere acid phosphatase (EC 3.1.3.2) activity. These findings provide strong indications that there are opportunities to utilize local Australian legumes in low P pasture systems to access sparingly soluble soil P and increase perennial legume productivity, diversity and sustainability. PMID- 25291347 TI - Increased Prevalence of Subcutaneous Lipomas in Patients With Wilson Disease. AB - GOALS: To determine the prevalence and characteristics of lipomas in patients with Wilson disease. BACKGROUND: Wilson disease is an autosomal recessive disorder resulting in copper accumulation in the liver and the central nervous tissue. Subcutaneous lipomas were often noted by the authors during clinical examinations of patients with Wilson disease. This is the first study to analyze the prevalence and progression of lipoma development in patients with Wilson disease. STUDY: Eighty consecutive patients attending a tertiary care center were examined for the presence of subcutaneous lipomas. RESULTS: Subcutaneous lipomas could be detected during the examination of 21 (26%) of the 80 patients with Wilson disease. Multiple subcutaneous lipomas were present in 16 (76%) of the 21 affected patients. Lipomas were mainly found on the extremities and the trunk. Neither initial presentation nor decoppering treatment influenced the presence or course of lipomas in these patients. CONCLUSIONS: Subcutaneous lipoma formation is more common in patients with Wilson disease than in the general population. We suggest that the presence of lipomas contributes to the differential diagnosis of Wilson disease. PMID- 25291348 TI - The Epidemiology of Cirrhosis in the United States: A Population-based Study. AB - BACKGROUND AND AIMS: Liver cirrhosis is an important public health concern in the United States and a significant source of morbidity and mortality. However, the epidemiology of cirrhosis is incompletely understood. The aims of this study were to estimate the prevalence of cirrhosis in the general US population, determine characteristics of affected Americans with a focus on health disparities, and calculate excess mortality attributable to cirrhosis. METHODS: National Health And Nutrition Examination Survey data conducted between 1999 and 2010 were used to estimate cirrhosis prevalence and factors associated with cirrhosis. The National Center for Health Statistics-linked death certificate data from the National Death Index were linked to the National Health And Nutrition Examination Survey database for the years 1999 to 2004, and attributable mortality was calculated using propensity score adjustment. Cirrhosis was ascertained by aspartate aminotransferase-to-platelet ratio of >2 and abnormal liver function tests. RESULTS: The prevalence of cirrhosis in the United States was approximately 0.27%, corresponding to 633,323 adults. Sixty-nine percent reported that they were unaware of having liver disease. The prevalence was higher in non Hispanic blacks and Mexican Americans, those living below the poverty level, and those with less than a 12th grade education. Diabetes, alcohol abuse, hepatitis C and B, male sex, and older age were all independently associated with cirrhosis, with a population attributable fraction of 53.5% from viral hepatitis (mostly hepatitis C), diabetes, and alcohol abuse. Mortality was 26.4% per 2-year interval in cirrhosis compared with 8.4% in propensity-matched controls. CONCLUSIONS: The prevalence of cirrhosis is higher than previously estimated. Many cases may be undiagnosed, and more than half are potentially preventable by controlling diabetes, alcohol abuse, and viral hepatitis. Public health efforts are needed to reduce this disease burden, particularly among racial/ethnic minorities and individuals at lower socioeconomic status. PMID- 25291350 TI - MRI Meets MPI: a bimodal MPI-MRI tomograph. AB - While magnetic particle imaging (MPI) constitutes a novel biomedical imaging technique for tracking superparamagnetic nanoparticles in vivo, unlike magnetic resonance imaging (MRI), it cannot provide anatomical background information. Until now these two modalities have been performed in separate scanners and image co-registration has been hampered by the need to reposition the sample in both systems as similarly as possible. This paper presents a bimodal MPI-MRI-tomograph that combines both modalities in a single system.MPI and MRI images can thus be acquired without moving the sample or replacing any parts in the setup. The images acquired with the presented setup show excellent agreement between the localization of the nanoparticles in MPI and the MRI background data. A combination of two highly complementary imaging modalities has been achieved. PMID- 25291349 TI - Protective effect of ethyl pyruvate on ischemia-reperfusion injury in rat ovary: biochemical and histopathological evaluation. AB - BACKGROUND: To investigate the protective effect of ethyl pyruvate (EP), an anti oxidant agent, against ischemia-reperfusion injury in a rat model of ovarian torsion, considering biochemical and histopathological aspects. METHODS: Forty Wistar Albino rats were divided into five groups: Group I, sham operation; Group II, ischemia alone, Group III, ischemia-reperfusion; Group IV, ischemia reperfusion+50 mg/kg EP; and Group V, ischemia-reperfusion+100 mg/kg EP. Through laparotomy, 360 degrees torsion was performed and maintained for 3 h, and detorsion was maintained for a further 3 h. Intraperitoneal EP was given 30 min before the surgical procedure. Ovarian tissues and blood samples were obtained after surgery. Malondialdehyde (MDA) and asymmetric dimethyl arginine (ADMA) levels were measured in both plasma and tissue samples. Tissue sections were evaluated histopatologically. Analysis of variance was used for statistical analyses. RESULTS: In both serum and tissue samples, ADMA and MDA levels were found to be significantly lower in the EP groups compared with the ischemia alone and ischemia-reperfusion groups (p=0.0001). However, no significant difference was found between groups treated with 50 mg/kg or 100 mg/kg EP. On histopathological evaluation, the total tissue injury score was found to be lower in rats treated with EP. No significant difference was detected between groups treated with 50 mg/kg or 100 mg/kg EP. CONCLUSION: Ethyl pyruvate may exert positive effects in ischemia-reperfusion injury in cases of ovarian torsion. However, no difference was detected between 50 mg/kg and 100 mg/kg EP. PMID- 25291351 TI - Alternating direction method of multiplier for tomography with nonlocal regularizers. AB - The ordered subset expectation maximization (OSEM) algorithm approximates the gradient of a likelihood function using a subset of projections instead of using all projections so that fast image reconstruction is possible for emission and transmission tomography such as SPECT, PET, and CT. However, OSEM does not significantly accelerate reconstruction with computationally expensive regularizers such as patch-based nonlocal (NL) regularizers, because the regularizer gradient is evaluated for every subset. We propose to use variable splitting to separate the likelihood term and the regularizer term for penalized emission tomographic image reconstruction problem and to optimize it using the alternating direction method of multiplier (ADMM). We also propose a fast algorithm to optimize the ADMM parameter based on convergence rate analysis. This new scheme enables more sub-iterations related to the likelihood term. We evaluated our ADMM for 3-D SPECT image reconstruction with a patch-based NL regularizer that uses the Fair potential function. Our proposed ADMM improved the speed of convergence substantially compared to other existing methods such as gradient descent, EM, and OSEM using De Pierro's approach, and the limited-memory Broyden-Fletcher-Goldfarb-Shanno algorithm. PMID- 25291352 TI - An exact arithmetic toolbox for a consistent and reproducible structural analysis of metabolic network models. AB - Constraint-based models are currently the only methodology that allows the study of metabolism at the whole-genome scale. Flux balance analysis is commonly used to analyse constraint-based models. Curiously, the results of this analysis vary with the software being run, a situation that we show can be remedied by using exact rather than floating-point arithmetic. Here we introduce MONGOOSE, a toolbox for analysing the structure of constraint-based metabolic models in exact arithmetic. We apply MONGOOSE to the analysis of 98 existing metabolic network models and find that the biomass reaction is surprisingly blocked (unable to sustain non-zero flux) in nearly half of them. We propose a principled approach for unblocking these reactions and extend it to the problems of identifying essential and synthetic lethal reactions and minimal media. Our structural insights enable a systematic study of constraint-based metabolic models, yielding a deeper understanding of their possibilities and limitations. PMID- 25291353 TI - Decoration of proteins with sugar chains: recent advances in glycoprotein synthesis. AB - Chemical or chemoenzymatic synthesis is an emerging approach to produce homogeneous glycoproteins, which are hard to obtain by conventional biotechnology methods. Recent advances in the synthetic methodologies for the decoration of protein molecules with oligosaccharides provide several remarkable syntheses of homogeneous glycoproteins. This short review highlights several of the latest syntheses of glycoproteins including therapeutically important glycoproteins, a highly glycosylated protein, and unnatural glycoproteins in order to illustrate the power of the modern glycoprotein synthesis. Structurally defined glycoproteins are a novel material for understanding the molecular basis of glycoprotein functions and for the development of the next generation of biopharmaceuticals. PMID- 25291355 TI - Healthcare experiences of lesbian and bisexual women in Cape Town, South Africa. AB - Understanding the health needs and experiences of South African lesbian and bisexual women is imperative for implementing effective and inclusive public health strategies. Such understanding, however, is limited due to the exclusion of these women from most existing research on healthcare access in the region. This paper bridges that gap by investigating the healthcare experiences of lesbian and bisexual women in Cape Town. Data were gathered from 22 interviews with self-identified lesbian and bisexual community members and university students in the Cape Town area. Interviews explored obstacles women face in accessing affirming services, different experiences with public and private healthcare, fear of stigma/discrimination, availability of relevant sexual health information and suggestions to improve existing programmes. Findings suggest that South African lesbians and bisexual women may have a range of both positive and negative experiences in public and private health services, that they use protective strategies when 'coming out' and that they find that sexual health information pertinent to them is largely unavailable. These discussions contribute to a more inclusive understanding of the experiences of lesbian and bisexual women accessing healthcare and other services and help to inform providers, thereby enabling them to deliver more meaningful care to lesbian, gay, bisexual and transgender persons in South Africa. PMID- 25291354 TI - Predictive Models Based on Support Vector Machines: Whole-Brain versus Regional Analysis of Structural MRI in the Alzheimer's Disease. AB - Decision-making systems trained on structural magnetic resonance imaging data of subjects affected by the Alzheimer's disease (AD) and healthy controls (CTRL) are becoming widespread prognostic tools for subjects with mild cognitive impairment (MCI). This study compares the performances of three classification methods based on support vector machines (SVMs), using as initial sets of brain voxels (ie, features): (1) the segmented grey matter (GM); (2) regions of interest (ROIs) by voxel-wise t-test filtering; (3) parceled ROIs, according to prior knowledge. The recursive feature elimination (RFE) is applied in all cases to investigate whether feature reduction improves the classification accuracy. We analyzed more than 600 AD Neuroimaging Initiative (ADNI) subjects, training the SVMs on the AD/CTRL dataset, and evaluating them on a trial MCI dataset. The classification performance, evaluated as the area under the receiver operating characteristic curve (AUC), reaches AUC = (88.9 +/- .5)% in 20-fold cross-validation on the AD/CTRL dataset, when the GM is classified as a whole. The highest discrimination accuracy between MCI converters and nonconverters is achieved when the SVM-RFE is applied to the whole GM: with AUC reaching (70.7 +/- .9)%, it outperforms both ROI-based approaches in predicting the AD conversion. PMID- 25291357 TI - Role of programmed necrosis and cell death in intestinal inflammation. AB - PURPOSE OF REVIEW: To critically review recent advances on the role of programmed necrosis and other cell death modalities in intestinal health and inflammatory bowel disease. RECENT FINDINGS: Tight regulation of intestinal epithelial cell proliferation and cell death is required for intestinal physiology, and to maintain an integral barrier that restricts microbiota translocation and ensures immune tolerance. Apoptosis has long been considered as a normal part of intestinal epithelial cell turnover. However, recent studies have demonstrated that excessive cell death leads to deleterious intestinal inflammation, as is observed in inflammatory bowel disease. Additionally, a novel form of cell death dubbed programmed necrosis, or necroptosis, has been recently shown to be pathological in the gut. SUMMARY: The role of cell death in the intestine is complex and its potential implication in intestinal diseases, and inflammatory bowel disease in particular, needs to be reevaluated. PMID- 25291356 TI - Autophagy, viruses, and intestinal immunity. AB - PURPOSE OF REVIEW: To highlight recent findings that identify an essential role for the cellular degradative pathway of autophagy in governing a balanced response to intestinal pathogens and commensals. RECENT FINDINGS: Following the genetic association of autophagy with inflammatory bowel disease susceptibility, increasing evidence indicates that this pathway functions in various epithelial lineages to support the intestinal barrier. New studies are also revealing that autophagy proteins dictate the quality and magnitude of immune responses. Mouse models, in particular, suggest that autophagy and inflammatory bowel disease susceptibility genes regulate inflammatory responses to viruses, a finding that coincides with an increasing appreciation that viruses have intricate interactions with the host and the microbiota beyond the obvious host-pathogen relationship. SUMMARY: Autophagy and other immunological or stress response pathways intersect in mucosal immunity to dictate the response to pathogenic and commensal agents. The development of novel treatment strategies, as well as prognostic and diagnostic tools for gastrointestinal disorders, will be greatly facilitated by a deeper understanding of these interactions at the cell type and microbe-specific manner, which includes less appreciated components of the microbiota, such as eukaryotic and prokaryotic viruses. PMID- 25291359 TI - Mesenchymal Stem Cells Overexpressing Angiotensin-Converting Enzyme 2 Rescue Lipopolysaccharide-Induced Lung Injury. AB - Bone marrow-derived mesenchymal stem cells (MSCs), which have beneficial effects in acute lung injury (ALI), can serve as a vehicle for gene therapy. Angiotensin converting enzyme 2 (ACE2), a counterregulatory enzyme of ACE that degrades angiotensin (Ang) II into Ang 1-7, has a protective role against ALI. Because ACE2 expression is severely reduced in the injured lung, a therapy targeted to improve ACE2 expression in lung might attenuate ALI. We hypothesized that MSCs overexpressing ACE2 would have further benefits in lipopolysaccharide (LPS) induced ALI mice, when compared with MSCs alone. MSCs were transduced with ACE2 gene (MSC-ACE2) by a lentiviral vector and then infused into wild-type (WT) and ACE2 knockout (ACE2(-/y)) mice following an LPS-induced intratracheal lung injury. The results demonstrated that the lung injury of ALI mice was alleviated at 24 and 72 h after MSC-ACE2 transplantation. MSC-ACE2 improved the lung histopathology and had additional anti-inflammatory effects when compared with MSCs alone in both WT and ACE2(-/y) ALI mice. MSC-ACE2 administration also reduced pulmonary vascular permeability, improved endothelial barrier integrity, and normalized lung eNOS expression relative to the MSC group. The beneficial effects of MSC-ACE2 could be attributed to its recruitment into the injured lung and enhanced local expression of ACE2 protein without changing the serum ACE2 levels after MSC-ACE2 transplantation. The biological activity of the increased ACE2 protein decreased the Ang II amount and increased the Ang 1-7 level in the lung when compared with the ALI and MSC-only groups, thereby inhibiting the detrimental effects of accumulating Ang II. Therefore, compared to MSCs alone, the administration of MSCs overexpressing ACE2 resulted in a further improvement in the inflammatory response and pulmonary endothelial function of LPS-induced ALI mice. These additional benefits could be due to the degradation of Ang II that accompanies the targeted overexpression of ACE2 in the lung. PMID- 25291358 TI - Lactation studies of anticonvulsants: a quality review. AB - AIM: The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. METHODS: We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). RESULTS: Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. CONCLUSION: The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed. PMID- 25291360 TI - Indications and contraindications: interspinous process decompression devices in lumbar spine surgery. AB - BACKGROUND: Interspinous process decompression devices (IPD) allow a minimally invasive treatment of lumbar spinal stenosis (LSS), but their use is discussed highly controversial. Several level I studies suggest that IPD implantation is a viable alternative for both conservative treatment and decompression, but clear indications and contraindications are still missing. This study was designed to explore the perspectives and limitations of IPDs and to evaluate the role of these devices in general. MATERIAL AND METHODS: The study is based on a questionnaire sent to all hospitals registered in the German Hospital Address Register 2010 with an orthopedic, neurosurgerical, or spine surgery department (n = 1,321). The questionnaire was reviewed by experienced spine surgeons and statisticians, and included both single-response, close-ended, and multiple response open-ended questions. RESULTS: We received 329 (24.9%) entirely analyzable questionnaires. A total of 164 respondents (49.8%) stated that IPDs are a treatment option for LSS, and 135 of the 164 respondents (82.3%) use them. Poor clinical experience (60%) and lack of evidence (53.9%) are the main reasons cited for not using IPDs. We detected a high negative correlation between the size of the hospital, the number of outpatients and inpatients treated for LSS and other spine pathologies, and the use of IPDs (p = 0.001). Most respondents prefer the combination of open decompression and IPD (64.4%; n = 87). A total of 9.6% (n = 13) of the users favor IPD implantation as a stand-alone procedure. Overall, 25.9% n = 35 use both options. Most surgeons aim to relieve the facet joints (87.7%) and to stabilize a preexisting instability (75.4%). They recommend IPDs in the segments L2-L3 (77%), L3-L4 (98.5%), and L4-l5 (99.3%) and consider that IPD implanation also could be done at the L5-S1 segment (40.1%). Overall, 64.4% (n = 87) of the users recommend limiting IPD implantation to two segments. Infection (96.3%), fracture (94.8%), isthmic spondylolisthesis (77%), degenerative spondylolisthesis (higher than Meyerding I [57%]), lumbar spine scoliosis (48.1%), and osteoporosis (50.4%) are seen as contraindications for IPD. CONCLUSION: No clear consensus exists among spine surgeons concerning the use of IPD for LSS treatment. The study showed that hospital-related parameters also influence decision making for or against the use of IPDs. However, despite the lack of evidence, the indications and contraindications which had been identified in the present study might contribute to improved outcomes after IPD implantation or at least prevent harm to patients. PMID- 25291361 TI - Subtle alterations in brain anatomy may change an individual's personality in chronic pain. AB - It is well established that gross prefrontal cortex damage can affect an individual's personality. It is also possible that subtle prefrontal cortex changes associated with conditions such as chronic pain, and not detectable until recent advances in human brain imaging, may also result in subtle changes in an individual's personality. In an animal model of chronic neuropathic pain, subtle prefrontal cortex changes including altered basal dendritic length, resulted in altered decision making ability. Using multiple magnetic resonance imaging techniques, we found in humans, although gray matter volume and on-going activity were unaltered, chronic neuropathic pain was associated with reduced free and bound proton movement, indicators of subtle anatomical changes, in the medial prefrontal cortex, anterior cingulate cortex and mediodorsal thalamus. Furthermore, proton spectroscopy revealed an increase in neural integrity in the medial prefrontal cortex in neuropathic pain patients, the degree of which was significantly correlated to the personality temperament of novelty seeking. These data reveal that even subtle changes in prefrontal cortex anatomy may result in a significant change in an individual's personality. PMID- 25291364 TI - Monoclonal antibodies to HLA-DR antigens. AB - Monoclonal antibodies (Mabs) have been invaluable in the study of human MHC class 11 (or la-like) antigens. For this to continue some pooling of resources was needed and in 1982 the British Medical Research Council's Clinical and Population Cytogenetics Unit in Edinburgh initiated an information exchange scheme on anti class-11 Mabs in an attempt to classify and group at least some of these reagents. Over 100 Mabs from 25 laboratories were screened by several centres in various serological, biochemical and functional assays and the data were discussed in Edinburgh on 2-6 September 1983. PMID- 25291363 TI - Polyomavirus-associated Trichodysplasia spinulosa involves hyperproliferation, pRB phosphorylation and upregulation of p16 and p21. AB - Trichodysplasia spinulosa (TS) is a proliferative skin disease observed in severely immunocompromized patients. It is characterized by papule and trichohyalin-rich spicule formation, epidermal acanthosis and distention of dysmorphic hair follicles overpopulated by inner root sheath cells (IRS). TS probably results from active infection with the TS-associated polyomavirus (TSPyV), as indicated by high viral-load, virus protein expression and particle formation. The underlying pathogenic mechanism imposed by TSPyV infection has not been solved yet. By analogy with other polyomaviruses, such as the Merkel cell polyomavirus associated with Merkel cell carcinoma, we hypothesized that TSPyV T antigen promotes proliferation of infected IRS cells. Therefore, we analyzed TS biopsy sections for markers of cell proliferation (Ki-67) and cell cycle regulation (p16ink4a, p21waf, pRB, phosphorylated pRB), and the putatively transforming TSPyV early large tumor (LT) antigen. Intense Ki-67 staining was detected especially in the margins of TS hair follicles, which colocalized with TSPyV LT-antigen detection. In this area, staining was also noted for pRB and particularly phosphorylated pRB, as well as p16ink4a and p21waf. Healthy control hair follicles did not or hardly stained for these markers. Trichohyalin was particularly detected in the center of TS follicles that stained negative for Ki 67 and TSPyV LT-antigen. In summary, we provide evidence for clustering of TSPyV LT-antigen-expressing and proliferating cells in the follicle margins that overproduce negative cell cycle regulatory proteins. These data are compatible with a scenario of TSPyV T-antigen-mediated cell cycle progression, potentially creating a pool of proliferating cells that enable viral DNA replication and drive papule and spicule formation. PMID- 25291365 TI - How parasites evade the immune response. AB - Infections caused by parasitic protozoa and worms are characteristically longlasting, 40-60 years in some forms of malaria and Chagas' disease for example. For years many parasitologists believed that there was no effective immunity against most parasites, but the prevalence of exacerbated or disseminated infections in immunosuppressed patients altered this viewpoint. It is now widely accepted that acquired immunity is the rule but that the parasites escape its consequences by actively evading the immune response. This evasion has important consequences because on one hand it is the cause of the immunopathology that does the real damage in most infections and on the other it places a major constraint on the development of vaccines. It was against this background that a recent symposium considered the immunological basis of the evasion of the immune response(*). PMID- 25291366 TI - Reassurance on immune effects of vasectomy. PMID- 25291362 TI - Mutation analysis of inhibitory guanine nucleotide binding protein alpha (GNAI) loci in young and familial pituitary adenomas. AB - Pituitary adenomas are neoplasms of the anterior pituitary lobe and account for 15-20% of all intracranial tumors. Although most pituitary tumors are benign they can cause severe symptoms related to tumor size as well as hypopituitarism and/or hypersecretion of one or more pituitary hormones. Most pituitary adenomas are sporadic, but it has been estimated that 5% of patients have a familial background. Germline mutations of the tumor suppressor gene aryl hydrocarbon receptor-interacting protein (AIP) predispose to hereditary pituitary neoplasia. Recently, it has been demonstrated that AIP mutations predispose to pituitary tumorigenesis through defective inhibitory GTP binding protein (Galphai) signaling. This finding prompted us to examine whether germline loss-of-function mutations in inhibitory guanine nucleotide (GTP) binding protein alpha (GNAI) loci are involved in genetic predisposition of pituitary tumors. To our knowledge, this is the first time GNAI genes are sequenced in order to examine the occurrence of inactivating germline mutations. Thus far, only somatic gain-of function hot-spot mutations have been studied in these loci. Here, we have analyzed the coding regions of GNAI1, GNAI2, and GNAI3 in a set of young sporadic somatotropinoma patients (n = 32; mean age of diagnosis 32 years) and familial index cases (n = 14), thus in patients with a disease phenotype similar to that observed in AIP mutation carriers. In addition, expression of Galphai proteins was studied in human growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH)-secreting and non-functional pituitary tumors. No pathogenic germline mutations affecting the Galphai proteins were detected. The result suggests that loss-of-function mutations of GNAI loci are rare or nonexistent in familial pituitary adenomas. PMID- 25291367 TI - Polymorphism and monomorphism in class-1 MHC antigens. PMID- 25291368 TI - [Not Available]. PMID- 25291369 TI - The interaction between macrophages and suppressor cells in immunological maturation in mice. AB - The immunological immaturity at birth characteristic of species such as the mouse has no certain explanation. Here Bertie Argyris suggests that in mice it is a consequence of high suppressor-cell activity and an absence of macrophage activity. Gradual alterations in the balance of these activities account for the gradual emergence of immunocompetence. PMID- 25291370 TI - Rearranging pre-B-cell genes. PMID- 25291371 TI - The importance of being nearest. PMID- 25291373 TI - Antigenic variation in African trypanosomes: DNA rearrangements program immune evasion. AB - Individual B cells express only one of the many variable-region genes of the VH gene repertoire. Likewise, individual African trypanosomes express only one surface-antigen gene of the large surface-antigen gene repertoire. In both kinds of cells, expression is controlled at the level of transcriptional activation and has been shown to involve rearrangement of genomic DNA. Here, Nina Agabian and her colleagues review recent studies on the molecular mechanisms controlling trypanosome surface-antigen gene expression. PMID- 25291372 TI - The avidin-biotin complex in immunology. AB - The tenacious interaction between the vitamin biotin and theglycoprotein avidin has been applied in many immunological systems for the isolation, localization and visualization of various antigens as well as drug delivery, lymphocyte stimulation and immunoassays. These are discussed hereby Meir Wilchek and Edward Bayer, who emphasize that with the increased refinement of affinity systems, the avidin-biotin complex will undoubtedly enable improved detectability and determination of minute amounts of antigens. PMID- 25291374 TI - MHC-restricted recognition by antigen-specific B cells: fact or artefact? AB - Over the past several years it has become generally accepted that T cells and B cells, the two classes of antigen-specific lymphoid cells, differ fundamentally in their modes of antigen-specific recognition. Thus, it has been widely accepted that most T cells do not recognise conventional (nominal) antigens alone, but rather recognise these antigens in association with cell-surface products encoded within the major histocompatibility complex (MHC. In contrast, it has generally been concluded that B cells do not exhibit similar requirements for recognition of self-MHC products, and do recognise antigen alone. Here Richard Hodes and Alfred Singer discuss a formulation, consistent with these notions, which attributes to T cells and B cells two distinct and potentially complementary functions in the defense of the host organism. PMID- 25291377 TI - Assessment of predictive markers for placental inflammatory response in preterm births. AB - Placental inflammatory response (PIR) is associated with adverse neonatal outcomes such as sepsis, cerebral palsy, low birth weight, preterm birth, and neonatal mortality. However, there is an urgent need for noninvasive and sensitive biomarkers for prediction of PIR. In this study, we evaluated the clinical usefulness of maternal serum inflammatory markers for prediction of PIR in women with impending preterm birth. We conducted a retrospective cohort study of 483 patients who delivered preterm neonates. Serum levels of leukocyte differential counts, C-reactive protein (CRP), and neutrophil to lymphocyte ratio (NLR) were compared between women with no placental inflammation and women with PIR. The mean neutrophil counts, CRP levels, and NLR in both the patients with histologic chorioamnionitis (HCA) alone and those with HCA with funisitis were significantly higher than those in women with no placental inflammation. Compared to leukocyte subset or CRP, NLR in women with funisitis was significantly higher than in women with HCA alone and showed higher predictive accuracy, along with 71.4% sensitivity, 77.9% specificity, 80.7% positive predictive value, and 67.8% negative predictive value for prediction of PIR. On Kaplan-Meier survival analysis, women with both an elevated level of CRP and a high NLR had a shorter admission-to-delivery interval compared to women with either an elevated level of CRP or a high NLR alone. NLR may be a predictive marker of PIR and could be used as a cost-effective parameter for identifying women at risk of PIR. PMID- 25291379 TI - Interleukin-26 in antibacterial host defense of human lungs. Effects on neutrophil mobilization. AB - RATIONALE: The role of the presumed Th17 cytokine IL-26 in antibacterial host defense of the lungs is not known. OBJECTIVES: To characterize the role of IL-26 in antibacterial host defense of human lungs. METHODS: Intrabronchial exposure of healthy volunteers to endotoxin and vehicle was performed during bronchoscopy and bronchoalveolar lavage (BAL) samples were harvested. Intracellular IL-26 was detected using immunocytochemistry and immunocytofluorescence. This IL-26 was also detected using flow cytometry, as was its receptor complex. Cytokines and phosphorylated signal transducer and activator of transcription (STAT) 1 plus STAT3 were quantified using ELISA. Gene expression was analyzed by real-time polymerase chain reaction and neutrophil migration was assessed in vitro. MEASUREMENTS AND MAIN RESULTS: Extracellular IL-26 was detected in BAL samples without prior exposure in vivo and was markedly increased after endotoxin exposure. Alveolar macrophages displayed gene expression for, contained, and released IL-26. Th and cytotoxic T cells also contained IL-26. In the BAL samples, IL-26 concentrations and innate effector cells displayed a correlation. Recombinant IL-26 potentiated neutrophil chemotaxis induced by IL-8 and fMLP but decreased chemokinesis for neutrophils. Myeloperoxidase in conditioned media from neutrophils was decreased. The IL-26 receptor complex was detected in neutrophils and IL-26 decreased phosphorylated STAT3 in these cells. In BAL and bronchial epithelial cells, IL-26 increased gene expression of the IL-26 receptor complex and STAT1 plus STAT3. Finally, IL-26 increased the release of neutrophil mobilizing cytokines in BAL but not in epithelial cells. CONCLUSIONS: This study implies that alveolar macrophages produce IL-26, which stimulates receptors on neutrophils and focuses their mobilization toward bacteria and accumulated immune cells in human lungs. PMID- 25291378 TI - Description of 3,180 courses of chelation with dimercaptosuccinic acid in children <= 5 y with severe lead poisoning in Zamfara, Northern Nigeria: a retrospective analysis of programme data. AB - BACKGROUND: In 2010, Medecins Sans Frontieres (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children <= 5 y of age with severe paediatric lead intoxication reported to date to our knowledge. METHODS AND FINDINGS: In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children <= 5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL >= 45 ug/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL >= 80 ug/dl and >= 120 ug/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%-79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%-57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged <= 5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in <2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for. CONCLUSIONS: Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and non-adherence may have influenced the impact of outpatient treatment. Please see later in the article for the Editors' Summary. PMID- 25291381 TI - Preliminary report of a mathematical model of ventilation and intrathoracic pressure applied to prehospital patients with severe traumatic brain injury. AB - BACKGROUND: Inadvertent hyperventilation is associated with poor outcomes from traumatic brain injury (TBI). Hypocapnic cerebral vasoconstriction is well described and causes an immediate and profound decrease in cerebral perfusion. The hemodynamic effects of positive-pressure ventilation (PPV) remain incompletely understood but may be equally important, particularly in the hypovolemic patient with TBI. OBJECTIVE: Preliminary report on the application of a previously described mathematical model of perfusion and ventilation to prehospital data to predict intrathoracic pressure. METHODS: Ventilation data from 108 TBI patients (76 ground transported, 32 helicopter transported) were used for this analysis. Ventilation rate (VR) and end-tidal carbon dioxide (PetCO2) values were used to estimate tidal volume (VT). The values for VR and estimated VT were then applied to a previously described mathematical model of perfusion and ventilation. This model allows input of various lung parameters to define a pressure-volume relationship, then derives mean intrathoracic pressure (MITP) for various VT and VR values. For this analysis, normal lung parameters were utilized. Separate analyses were performed assuming either fixed or variable PaCO2-PetCO2 differences. Ground and air medical patients were compared with regard to VR, PetCO2, estimated VT, and predicted MITP. RESULTS: A total of 10,647 measurements were included from the 108 TBI patients, representing about 13 minutes of ventilation per patient. Mean VR values were higher for ground patients versus air patients (21.6 vs. 19.7 breaths/min; p < 0.01). Estimated VT values were similar for ground and air patients (399 mL vs. 392 mL; p = NS) in the fixed model but not the variable (636 vs. 688 mL, respectively; p < 0.01). Mean PetCO2 values were lower for ground versus air patients (30.6 vs. 33.8 mmHg; p < 0.01). Predicted MITP values were higher for ground versus air patients, assuming either fixed (9.0 vs. 8.1 mmHg; p < 0.01) or variable (10.9 vs. 9.7 mmHg; p < 0.01) PaCO2-PetCO2 differences. CONCLUSIONS: Predicted MITP values increased with ventilation rates. Future studies to externally validate this model are warranted. PMID- 25291380 TI - Structural heterogeneity modulates effective refractory period: a mechanism of focal arrhythmia initiation. AB - Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and effective refractory periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium (72.6 vs 220.4 MUA/cm2), with faster maximum AP upstroke velocities (257.3 vs 147.3 mV/ms), although noticeably very similar APDs (167.7 vs 168.4 ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to 40 ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most effective induction sites were within channels of low ERPs between large vessels and epicardium. Significant differences in ERP driven by reductions in electrotonic loading due to fine-scale physiological structural heterogeneity provides an important mechanism of capture of focal activity and reentry induction. Application to pathological ventricles, particularly myocardial infarction, will have important implications in anti-arrhythmia therapy. PMID- 25291385 TI - The complete nucleotide sequence of the multi-drug resistance-encoding IncL/M plasmid pACM1. AB - The 89,977 bp nucleotide sequence of pACM1, isolated from a 1993 outbreak strain of cephalosporin-resistant Klebsiella oxytoca, has been completed and assigned GenBank accession number KJ541681. The plasmid has a single 31,842 bp mosaic multi-drug resistance-encoding (MDR) region comprising the mer resistance module of Tn1696, two integrons with a total of seven cassettes, one complete copy each of IS1R and IS26, and the bla(SHV-5)-carrying Tn2003 (with defective IS26 termini), all within a Tn1721-like element inserted into the mucB gene of the IncL/M plasmid backbone. The Tn1721-Tn1696 combination resembles sequence found in the chromosomal MDR islands of some Acinetobacter baumannii isolates. Among the completely sequenced IncL/M resistance plasmids, the Tn1721-based MDR region is unique, but data from older studies suggest that this type of plasmid was widespread in the 1990s. Since resistance gene dosage is affected by plasmid copy number (PCN), we used a relatively simple new "efficiency-corrected" qPCR assay to measure the PCN of pACM1. There are approximately three copies per chromosome in an Escherichia coli DH5alpha host, and two in the original Klebsiella oxytoca isolate. We could not find similar PCN data for other medically important plasmids for comparison. The study of this plasmid property and its effect on resistance levels should be facilitated in the future by the availability of qPCR instruments and complete genome sequences. PMID- 25291386 TI - Chemical-proteomic strategies to investigate cysteine posttranslational modifications. AB - The unique combination of nucleophilicity and redox-sensitivity that is characteristic of cysteine residues results in a variety of posttranslational modifications (PTMs), including oxidation, nitrosation, glutathionylation, prenylation, palmitoylation and Michael adducts with lipid-derived electrophiles (LDEs). These PTMs regulate the activity of diverse protein families by modulating the reactivity of cysteine nucleophiles within active sites of enzymes, and governing protein localization between soluble and membrane-bound forms. Many of these modifications are highly labile, sensitive to small changes in the environment, and dynamic, rendering it difficult to detect these modified species within a complex proteome. Several chemical-proteomic platforms have evolved to study these modifications and enable a better understanding of the diversity of proteins that are regulated by cysteine PTMs. These platforms include: (1) chemical probes to selectively tag PTM-modified cysteines; (2) differential labeling platforms that selectively reveal and tag PTM-modified cysteines; (3) lipid, isoprene and LDE derivatives containing bioorthogonal handles; and (4) cysteine-reactivity profiling to identify PTM-induced decreases in cysteine nucleophilicity. Here, we will provide an overview of these existing chemical-proteomic strategies and their effectiveness at identifying PTM-modified cysteine residues within native biological systems. PMID- 25291387 TI - Mechanisms of genetically determined immune dysfunction. AB - Spontaneous autoimmunity in New Zealand mice and the absence of a thymus in the hairless mutant nude mice were the first examples of genetically determined immunologic dysfunction to be discovered in mice. Now several others are known, involving different mutations such as beige (bg), X-linked immunodeficiency (xid), lymphoproliferativn (lpr), generalized lymphoproliferative disease (gld), lipopolysaccharide responsiveness(Lps), severe combined immunodeficiency (scid), motheaten (me), and the Y-linked autoimmune accelerator gene (Yaa) of BXSB mice. These have enhanced our understanding of immune deficiency autoimmunity, and the relationship between the two, as well as (in some instances) the development of lymphoma. PMID- 25291388 TI - Molecular cloning lends credence to lymphokine research. AB - There is no longer any doubt that lymphokines are real. At a recent meeting some major advances in lymphokine research were clear - most notably, the application of molecular cloning techniques which have given credence to lymphokines and provided the necessary homogeneous materials for in-vivo and in-vitro studies. Clarification of the structure and function of some lymphokines has diminished the use of assay-related acronyms to describe ill-defined activities and evidence is accumulating for cascades of lymphokines and synergy between molecules. The emerging picture is exciting but complicated. PMID- 25291389 TI - Veto in vivo? PMID- 25291390 TI - Antigen specific suppression of T-cell responses - the veto concept. PMID- 25291391 TI - IgA dysfunction in rheumatoid arthritis. PMID- 25291392 TI - Internalization of lymphocyte membrane components. AB - The functions of lymphocytes, in particular their participation in immune responses, depends on the expression and properties of several molecules that are present on their membranes at different steps in their development and activation. One way to probe this complex and various set of events is to follow the movement of the membrane molecules in different lymphocytes and in different functional conditions and, more specifically, to study their internalization and subsequent fate. In this article, Benvenuto Pernis summarizes the main facts concerning internalization of lymphocyte membrane components, either spontaneous or induced by cross-linking agents, and discusses what they tell us about the physiology of lymphocytes. PMID- 25291393 TI - Leukocytes in the intestinal epithelium: an unusual immunological compartment. AB - Antigens which penetrate the mucosal epithelium of the intestine stimulate B lymphocytes to produce local IgA that minimizes antigen uptake across the epithelium(1). Yet in the intestinal epithelium there are as many lymphocyte-like cells as in the spleen. Some are lymphocytes(2) but because the cells are heterogeneous a more precise term for them would be intraepithelial leukocytes (IEL). They are directly in line with macromolecules in transit across the epithelium(2,3) and increase in number in many enteric inflammatory processes(3,4). Here Peter Ernst and his colleagues review the diverse properties of IEL that have been uncovered by isolation procedures which separate IEL from lamina proprial cells, their potential role as effectors of cell-mediated immunity and their contribution to the prevention and pathogenesis of enteric disease. PMID- 25291394 TI - T-cell subsets in tumour rejection responses. AB - The roles and relative importance of the various T-cell subsets in the rejection of tumours have long been the subject of controversy. In view of the fine specificity of in-vivo rejection responses with, for example, chemically induced tumours, a highly specific means of target cell killing suggests itself. These rejection responses appear to be T-cell mediated, with little evidence for the participation of antibody dependent mechanisms, so the obvious candidate for the role of tumour cell destroyer would be the cytotoxic T cell (CTL). However, with the advent of monoclonal antibodies which were thought to separate T cells alongfunctional lines into helper and suppressor/cytotoxic subsets, amore direct evaluation of the role of CTL in tumour rejection becamefeasible. In this article R. A. Robins and R. W. Baldwin discuss T-cell subsets in tumour rejection responses. PMID- 25291395 TI - Tolerance in T-cell clones. AB - The interaction of antigen with immunologically competent cells may lead either to the induction of an immune response or to a state of antigen specific unresponsiveness complete orpartial, which is often called immunological 'tolerance'. This is believed to be a major mechanism of discrimination between self and non-self(1-3). In this review Marc Feldmann and his colleagues discuss new insights into T-cell tolerance in vivo and in vitro, and discuss their significance for our understanding of mechanisms of immune activation and regulation. PMID- 25291402 TI - Microwave-assisted one-pot synthesis of 1,6-anhydrosugars and orthogonally protected thioglycosides. AB - Living organisms employ glycans as recognition elements because of their large structural information density. Well-defined sugar structures are needed to fully understand and take advantage of glycan functions, but sufficient quantities of these compounds cannot be readily obtained from natural sources and have to be synthesized. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. Herein, we describe routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-O-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio)silane and ZnI2, respectively, under microwave irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages. PMID- 25291403 TI - Unilateral isometric muscle fatigue decreases force production and activation of contralateral knee extensors but not elbow flexors. AB - Nonlocal muscle fatigue occurs when fatiguing 1 muscle alters performance of another rested muscle. The purpose of the study was to investigate if fatiguing 2 separate muscles would affect the same rested muscle, and if fatiguing the same muscle would affect 2 separate muscles. Twenty-one trained males participated in 2 studies (n = 11; n = 10). Subjects performed 2 pre-test maximum voluntary contractions (MVCs) with the nondominant knee extensors. Thereafter they performed two 100-s MVCs with their dominant knee extensors, elbow flexors, or rested. Between and after the sets, a single MVC with the nondominant rested knee extensors was performed. Subsequently, 12 nondominant knee extensors repeated MVCs were completed. Force, quadriceps voluntary activation (VA), and electromyography (EMG) were measured. The same protocol was employed in study 2 except the nondominant elbow-flexors were tested. Study 1: Compared with control conditions, a significant decrease in nondominant knee extensors force, EMG, and VA was found under both fatiguing conditions (P <= 0.05; effect size (ES) = 0.91 1.15; 2%-8%). Additionally, decrements in all variables were found from the first post-intervention MVC to the last (P <= 0.05; ES = 0.82-2.40; 9%-20%). Study 2: No differences were found between conditions for all variables (P >= 0.33; ES <= 0.2; <=3.0%). However, all variables decreased from the first post-intervention MVC to the last (P <= 0.05; ES = 0.4-3.0; 7.2%-19.7%). Whereas the rested knee extensors demonstrated nonlocal effects regardless of the muscle being fatigued, the elbow-flexors remained unaffected. This suggests that nonlocal effects are muscle specific, which may hold functional implications for training and performance. PMID- 25291404 TI - Extracellular signal-regulated kinase pathway play distinct role in acetochlor mediated toxicity and intrinsic apoptosis in A549 cells. AB - Acetochlor (ACETO), a member of the chloroacetanilide family of herbicides, is widely used globally and is very frequently detected in watersheds of agricultural lands and fresh water streams. The human health consequences of environmental exposure to ACETO are unknown. This study was designed to elucidate the effect and molecular mechanisms of ACETO on human alveolar A549 cells. Established assays of cell viability and cytotoxicity were performed to detect the potential effects of ACETO on A549 cells. ACETO generated reactive oxygen species, which may have been crucial to apoptosis-mediated cytotoxicity. ACETO treatment showed a concentration dependent up-regulation of pro-apoptotic proteins including Bax, Bak, BID and Bad, but a differential level of expression of anti-apoptotic proteins were observed, leading to the release of cytochrome c from mitochondria to the cytoplasm as well as activation of caspase-3, and cleavage of caspase-9 and PARP. ACETO also induced activation of extracellular signal-regulated kinase (ERK). Inhibition of the expression of ERK by PD98059 partially reversed ACETO-induced cytotoxicity, apoptosis and the expression of caspase-3, -9 and PARP in A549 cells. Comparative evaluation of the results indicates that the principal mechanism underlying ACETO-mediated cytotoxicity is likely to be through ERK-mediated intrinsic pathway of apoptosis. PMID- 25291405 TI - The role of the medial temporal limbic system in processing emotions in voice and music. AB - Subcortical brain structures of the limbic system, such as the amygdala, are thought to decode the emotional value of sensory information. Recent neuroimaging studies, as well as lesion studies in patients, have shown that the amygdala is sensitive to emotions in voice and music. Similarly, the hippocampus, another part of the temporal limbic system (TLS), is responsive to vocal and musical emotions, but its specific roles in emotional processing from music and especially from voices have been largely neglected. Here we review recent research on vocal and musical emotions, and outline commonalities and differences in the neural processing of emotions in the TLS in terms of emotional valence, emotional intensity and arousal, as well as in terms of acoustic and structural features of voices and music. We summarize the findings in a neural framework including several subcortical and cortical functional pathways between the auditory system and the TLS. This framework proposes that some vocal expressions might already receive a fast emotional evaluation via a subcortical pathway to the amygdala, whereas cortical pathways to the TLS are thought to be equally used for vocal and musical emotions. While the amygdala might be specifically involved in a coarse decoding of the emotional value of voices and music, the hippocampus might process more complex vocal and musical emotions, and might have an important role especially for the decoding of musical emotions by providing memory-based and contextual associations. PMID- 25291406 TI - Nanotechnologies for the study of the central nervous system. AB - The impact of central nervous system (CNS) disorders on the human population is significant, contributing almost ?800 billion in annual European healthcare costs. These disorders not only have a disabling social impact but also a crippling economic drain on resources. Developing novel therapeutic strategies for these disorders requires a better understanding of events that underlie mechanisms of neural circuit physiology. Studying the relationship between genetic expression, synapse development and circuit physiology in CNS function is a challenging task, involving simultaneous analysis of multiple parameters and the convergence of several disciplines and technological approaches. However, current gold-standard techniques used to study the CNS have limitations that pose unique challenges to furthering our understanding of functional CNS development. The recent advancement in nanotechnologies for biomedical applications has seen the emergence of nanoscience as a key enabling technology for delivering a translational bridge between basic and clinical research. In particular, the development of neuroimaging and electrophysiology tools to identify the aetiology and progression of CNS disorders have led to new insights in our understanding of CNS physiology and the development of novel diagnostic modalities for therapeutic intervention. This review focuses on the latest applications of these nanotechnologies for investigating CNS function and the improved diagnosis of CNS disorders. PMID- 25291407 TI - Three new carbazole alkaloids and biological activities of Murraya koenigii. AB - Three new carbazole alkaloids, mukoenigatin (1), bikoeniquinonine (2) and murrayadinal (3), were isolated from the aerial parts of Murraya koenigii, along with mukeonine-B (4). Their molecular structures were determined on the basis of spectral analysis including UV, IR, MS, and 2D NMR spectroscopy. The antimicrobial activity of different fractions of plant extract was also determined. PMID- 25291408 TI - Recurrent varicose veins: causes and neovascularisation. A 17-year experience. AB - AIM: The aim of the paper was to determine the causes of varicose vein recurrence and, when neovascularisation is suspected, to confirm or exclude its presence and to establish its contribution to the recurrence of varicose veins. METHODS: A retrospective analysis of a set of 217 legs reoperated in our department over a period of 17 years with a two-year prospective histological and histochemical (nestin) analysis of resected veins. RESULTS: Reflux as a cause of varicose vein recurrence was identified in 93% of the limbs. It was most commonly found in the area of the saphenofemoral junction, followed by the area of the saphenopopliteal junction. Reflux in the perforating veins was almost invariably linked to that in the saphenofemoral junction or saphenopopliteal junction; an isolated damage to the perforating veins was only present in three limbs. Histological and histochemical analysis was performed for the samples of eleven veins in which neovascularisation was suspected based on preoperative duplex ultrasonography evaluation. Neovascularisation was confirmed in none of these veins and none of them was the cause of recurrence. CONCLUSION: The major cause of varicose vein recurrence is a reflux left unresolved during the primary surgery, particularly in the area of the saphenofemoral junction. A less common cause is progression of the disease and the occurrence of a new reflux. Neovascularisation is of no importance for the recurrence of varicose veins. PMID- 25291410 TI - Immune regulation. PMID- 25291409 TI - Effects of oral prednisolone on recovery after tonsillectomy. AB - OBJECTIVES/HYPOTHESIS: To evaluate the effect of oral prednisolone on recovery from tonsillectomy. STUDY DESIGN: Prospective, randomized, controlled trial of 198 consecutive patients, aged 4 years and older, with no previous or known contraindications to steroid therapy. METHODS: All 198 patients scheduled for elective tonsillectomy with or without adenoidectomy from April 2013 to April 2014 were included. The participants were then randomly assigned to receive a postoperative course of prednisolone 0.25 mg/kg/d or no prednisolone over 7 days. During the first postoperative day, pain, type of diet (none, fluid, soft, normal), type of activity (none, bed rest, quiet, restricted, normal), presence of nausea and vomiting, postoperative bleeding rate, and sleep disturbance were assessed using questionnaires. All patients were followed up on days 7 and 14 by endoscopic photographic examination of both tonsillar fossa and by completion of questionnaires. RESULTS: No statistically significant differences in pain, diet, activity, rate of minor bleeding, nausea/vomiting, fever, or sleep disturbance were observed between the groups on day 1. On day 7, however, in pediatric patients, differences in pain (P = .001), diet (P = .001), activity (P = .004), mean area of re-epithelialization (P = .000), fever (P = .04), and sleep disturbance (P = .04) were observed. On day 14, differences in the mean area of re-epithelialization (P = .000, .001) remained in both pediatric and adult patients. CONCLUSIONS: Oral prednisolone may be beneficial during recovery from tonsillectomy without causing any serious complications. PMID- 25291411 TI - Clinical immunology in Australia. PMID- 25291412 TI - Epithelial MHC class II sub-region expression in autoimmunity. PMID- 25291414 TI - Maternal antibody (a legacy). PMID- 25291413 TI - Immunology of reproduction in Israel. PMID- 25291415 TI - beta2-microglobulin and MHC antigen expression. PMID- 25291417 TI - NK cell lineage and target specificity: a unifying concept. AB - Natural killer (NK) cells play a part in tumor resistance, host immunity to viral and other microbial infections, and the regulation of lymphoid and other haemopoietic cell populations(1). Yet the lineage to which NK cells belong, and the nature of their target cell specificity remain uncertain. The phenotypic heterogeneity of cells with spontaneous cytotoxicity has led to the suggestion that NK activity is not restricted to a single cell type but is a property of cells of several different lineages at particular stages of maturation or activation. Do NK cells, like T and B lymphocytes, recognize their targets via clonally distributed receptors for distinct cell-surface antigens, or do they, like macrophages, bind to target cells via non-specific structures such as Fc receptors, complement receptors, or lectin-like receptors for ubiquitous cell surface carbohydrates? Joseph Kaplan has previously proposed(2) that both the nature and specificity of NK cells can be accounted for in terms of a single unifying concept - that NK cells are pre-thymic T cells which, as originally proposed by Jerne(3), express germ line V gene-encoded receptors for either self or non-self histocompatibility antigens. Here he discusses how this hypothesis fits with current evidence concerning NK cell lineage and target specificity. PMID- 25291416 TI - Lymphotoxin production in AIDS. AB - The etiological agent of the acquired immunodeficiency syndrome (AIDS), lymphadenopathy-associated virus/human T-lymphotropic virus III (LAV/HTLV-III), infects the OKT4(+) subset of T cells and causes their death. In this article Nancy Ruddle proposes that the trans acting protein of LAV/HTLV-III kills cells by inducing them to make a cellular cytotoxic protein, lymphotoxin, which in abnormally high quantities results in the cells' self-destruction. Lymphotoxin may even become serum detectable. It may induce immunosuppression and susceptibility to opportunistic infections by organisms such as Pneumocystis carinii. Defects in tumor immunity may result from depletion of OKT4(+) cells. PMID- 25291418 TI - Chronic, symptomatic Epstein-Barr virus infections. PMID- 25291419 TI - From parasites to allergy: a second receptor for IgE. AB - Human allergic responses are triggered when mast cells bind IgE antibodies. IgE production is also a regular feature of helminth infection and parasites can be killed by inflammatory cells such as macrophages, eosinophils and platelets sensitized by reaginic antibody. The IgE receptor they use has been identified only recently. Here Andre Capron and his colleagues discuss how it differs from the IgE receptor present on mast cells. PMID- 25291420 TI - The class I MHC gene family in mice. AB - Molecular genetic analysis of the murine MHC reveals that the class I gene family is far larger than expected from immunogenetic analysis of class I polypeptides. Of approximately 30 class I genes present in mouse DNA most are located telomeric to the H-2 regions in the adjacent Qa and Tla regions. Although it is not yet known how many class I genes from the Qa and Tla regions are expressed to produce class I polypeptides, evidence is accumulating that at least some of these genes encode polypeptides whose structure, and presumably function, is very different from the H-2K, D and L class I polypeptides. Here, Andrew Mellor reviews the structural data which reveals the unexpeted complexity of the class I gene family, particularly in the Qa and Tla regions. He discusses how molecular cloning and analysis of these genes are providing evidence that class I genes in these regions encode polypeptides which are highly homologous to the classical H 2 antigens but which are structurally and functionally quite distinct from them. PMID- 25291423 TI - Automated slice-specific simultaneous z-shim method for reducing B1 inhomogeneity and susceptibility-induced signal loss with parallel transmission at 3T. AB - PURPOSE: Through-plane susceptibility-induced signal loss in gradient recalled echo (GRE)-based sequences can considerably impair both the clinical diagnosis and functional analysis of certain brain areas. In this work, a fully automated simultaneous z-shim approach is proposed on the basis of parallel transmit (pTX) to reduce those signal dropouts at 3T. THEORY AND METHODS: The approach uses coil specific time-delayed excitations to impose a z-shim phase. It was extended toward B1 inhomogeneity mitigation and adequate slice-specific signal-dephasing cancellation on the basis of the prevailing B0 and B1 spatial information. Local signal recovery level and image quality preservation were analyzed using multi slice FLASH experiments in humans and compared to the standard excitation. Spatial blood-oxygen-level-dependent (BOLD) activation coverage was further compared in breath-hold functional MRI. RESULTS: The pTX z-shim approach recovered approximately 47% of brain areas affected by signal loss in standard excitation images across all subjects. At the same time, B1 shading effects could be substantially reduced. In these areas, BOLD activation coverage could be also increased by approximately 57%. CONCLUSION: The proposed fully automated pTX z shim method enables time-efficient and robust signal recovery in GRE-based sequences on a clinical scanner using two standard whole-body transmit coils. PMID- 25291424 TI - Disturbed excitation energy transfer in Arabidopsis thaliana mutants lacking minor antenna complexes of photosystem II. AB - Minor light-harvesting complexes (Lhcs) CP24, CP26 and CP29 occupy a position in photosystem II (PSII c' plants between the major light-harvesting complexes LHCII and the PSII core subunits. Lack of minor Lhcs in vivo causes impairment of PSII organization, and negatively affects electron transport rates anc photoprotection capacity. Here we used picosecond-fluorescence spectroscopy to study excitation energy transfer (EET) in thylakoid membranes isolated from Arabidopsis thaliana wild-type plants and knockout lines depleted of either two (koCP26/24 and koCP29/24) or all minor Lhcs (NoM). In the absence of all minor Lhcs. the functional connection ofLHCII to the PSII cores appears to be seriously impaired whereas the "disconnected" LHCII is substantially quenched. For both double knock out mutants, excitation trapping in PSII is faster than in NoM thylakoids but slower than in WT thylakoids. In NoM thylakoids, the loss of all minor Lhcs is accompanied by an over-accumulation ofLHCII, suggesting a compensating response to the reduced trapping efficiency in limiting light, which leads to a photosynthetic phenotype resembling that of low-light-acclimated plants. Finally. fluorescence kinetics and biochemical results show that the missing minor complexes are not replaced by other Lhcs, implying that they are unique among the antenna subunits and crucial for the functioning and macroorganization of PSII. PMID- 25291429 TI - The past 10 years of gastroenterology and hepatology-reflections and predictions. AB - In November 2004, the very first issue of this journal featured articles on the pathogenesis of ulcerative colitis, mechanisms leading to chronic pancreatitis, and treatment of recurrent Clostridium-difficile-associated diarrhoea. Although those topics might seem familiar, much has changed in the intervening years in our understanding, diagnosis and treatment of many different diseases across the field of gastroenterology and hepatology. Nonetheless, many challenges remain. Here, we have asked five of our Advisory Board members-international experts across different subspecialties in gastroenterology and hepatology-to reflect on the progress and frustrations of the past 10 years. They also comment on where effort and money should be invested now, as well as their predictions for progress in the next 10 years. PMID- 25291430 TI - Resolving fine structures of the electric double layer of electrochemical interfaces in ionic liquids with an AFM tip modification strategy. AB - We report enhanced force detection selectivity based on Coulombic interactions through AFM tip modification for probing fine structures of the electric double layer (EDL) in ionic liquids. When AFM tips anchored with alkylthiol molecular layers having end groups with different charge states (e.g., -CH3, -COO(-), and NH3(+)) are employed, Coulombic interactions between the tip and a specified layering structure are intensified or diminished depending on the polarities of the tip and the layering species. Systematic potential-dependent measurements of force curves with careful inspection of layered features and thickness analysis allows the fine structure of the EDL at the Au(111)-OMIPF6 interface to be resolved at the subionic level. The enhanced force detection selectivity provides a basis for thoroughly understanding the EDL in ionic liquids. PMID- 25291431 TI - Fetal DNA in maternal plasma in preeclamptic pregnancies. AB - Cell-free fetal DNA present in maternal circulation has revolutionized non invasive prenatal diagnosis of genetic diseases. In preeclampsia, the quantity of fetal DNA in maternal plasma has been studied and found to be higher in comparison to healthy pregnant women. Whether the quantity of fetal DNA can be used as a reliable predictive biomarker of preeclampsia is currently uncertain. This is a systematic review on studies quantifying fetal DNA in preeclamptic pregnancies. Using a PubMed search 22 studies were identified. In all of them, elevated levels of fetal DNA in maternal plasma in preeclampsia were found. In some of the studies, the higher concentration of fetal DNA was observed before the onset of clinical symptoms. This shows that fetal DNA levels might have a potential informative value as an early diagnostic biomarker of preeclampsia. However, in most of the studies important data are missing and there is an enormous variability in the reported results between the studies. From the available data it is currently not possible to perform a meta-analysis due to the variation between studies. If once fetal DNA should be used as a marker for determining preeclampsia at early stage, it is necessary to reduce these variations via standardized protocols for the quantification of cell-free fetal DNA as well as its reporting in the publications. PMID- 25291432 TI - Regulatory effect of interleukin-4 in the innate inflammatory response to Rhodococcus aurantiacus infection in mice. AB - Interleukin (IL)-4 promotes the regression of granulomas during the late phase of Rhodococcus aurantiacus infection. In this study, the contribution of IL-4 to the initial response against this bacterium was investigated using IL-4-deficient mice. Compared with wild-type (WT) mice, IL-4-deficient mice displayed remarkably lower tumor necrosis factor (TNF)-alpha and IL-6 secretion in the liver, spleen, and blood at the initial phase of infection, along with improved survival. IL-4 deficient mice also showed diminished IL-10 secretion in the spleen and blood; however, hepatic IL-10 levels were similar to those observed in WT animals, and were concomitant with augmented interferon (IFN)-gamma production and decreased bacterial burden in the liver at the early infection phase. Histological examination revealed reduced hepatic granuloma formation in infected IL-4 deficient mice. On challenge with heat-killed R. aurantiacus, IL-4-deficient mouse macrophages showed reduced expression of TNF-alpha, IL-6, and IL-10 at both the gene and protein levels compared with WT mouse cells. These findings indicate that during the initiation of R. aurantiacus-induced inflammation, IL-4 deficiency attenuates cytokine responses in macrophages, which contributes to amelioration in mouse survival and reduction of granulomatous inflammation, and augments a hepatic IFN-gamma response which transiently accelerates bacterial elimination. PMID- 25291433 TI - Error accumulations in adhesive energies of dihydrogen molecular chains: performances of the XYG3 type of doubly hybrid density functionals. AB - We have systematically analyzed the error accumulations in the adhesive energies for a series of hydrogen molecular chains calculated by various kinds of density functional theory (DFT) methods. In particular, we have focused on some representative doubly hybrid (DH) functionals of either the B2PLYP type (B2PLYP, B2PLYP-D, and B2GP-PLYP) or the XYG3 type (XYG3, XYGJ-OS, and xDH-PBE0). The hydrogen molecular chain models have recently been proposed by Zheng et al. (J. Chem. Phys. 2012, 137, 214106) to identify the delocalization errors (DEs) in thermodynamic properties. From the perspective of DEs, it is shown here that the XYG3 type of DH functionals yield good performance on the calculated adhesive energies due to the minimizing effects of DEs, highlighting the underlying physics for the successes or failures of the approximate functionals. Examination was also extended to HF-DFT, where DFT energies are evaluated with the Hartree Fock (HF) densities. PMID- 25291434 TI - Investigation on the effects of epsilon-poly-L-lysine on a producing strain Streptomyces ahygroscopicus GIM8, for better understanding its biosynthesis. AB - epsilon-Poly-L-lysine (epsilon-PL) is an L-lysine homopolymer with strong antimicrobial activity, which is generally produced by Streptomyces strains. epsilon-PL is only produced under acidic conditions in liquid culture, and to improve the current understanding of epsilon-PL biosynthesis, the present study was undertaken to investigate the effects of epsilon-PL on its producer Streptomyces ahygroscopicus GIM8, under acidic and neutral conditions. The results indicated that a neutral pH favored epsilon-PL adsorption onto the cells, whereas minimal adsorption occurred at pH 4.0, the maximum pH for epsilon-PL production. At pH 7.0, small amounts of epsilon-PL caused considerable ATP leakage from the cells, which showed increased membrane permeability. Conversely, ATP leakage was inhibited by epsilon-PL at pH 4.0. Transmission electron microscopy investigation indicated that the cytoplasmic membrane was the primary site of epsilon-PL activity at pH 7.0, and that cell shape was maintained. Metabolic activity profiles revealed that epsilon-PL decreased cellular metabolic activity at a relatively low rate at pH 7.0. However, the toxic effect was significantly enhanced at pH 4.0. Based on these data, a mechanism for the effect of epsilon-PL on epsilon-PL-producing cells under neutral and acidic conditions is proposed. Additionally, acidic conditions may potentially be required for epsilon-PL biosynthesis in liquid culture because low pH can increase membrane permeability and prevent binding of epsilon-PL onto cells, both of which favor the secretion of the epsilon-PL produced by the cells into the broth. This research contributes to the current understanding of epsilon-PL biosynthesis. PMID- 25291435 TI - Method for perfusion decellularization of porcine whole liver and kidney for use as a scaffold for clinical-scale bioengineering engrafts. AB - BACKGROUND: Whole-organ engineering provides a new alternative source of donor organs for xenotransplantation. Utilization of decellularized whole-organ scaffolds, which can be created by detergent perfusion, is a strategy for tissue engineering. In this article, our aim is to scale up the decellularization process to human-sized liver and kidney to generate a decellularized matrix with optimal and stable characteristics on a clinically relevant scale. METHODS: Whole porcine liver and kidney were decellularized by perfusion using different detergents (1% SDS, 1% Triton X-100, 1% peracetic acid (PAA), and 1% NaDOC) via the portal vein and renal artery of the liver and kidney, respectively. After rinsing with PBS to remove the detergents, the obtained liver and kidney extracellular matrix (ECM) were processed for histology, residual cellular content analysis, and ECM components evaluation to investigate decellularization efficiency, xenoantigens removal, and ECM preservation. RESULTS: The resulting liver and kidney scaffolds in the SDS-treated group showed the most efficient clearance of cellular components and xenoantigens, including DNA and protein, and preservation of the extracellular matrix composition. In comparison, cell debris was observed in the other decellularized groups that were generated using Triton X-100, PAA, and NaDOC. Special staining and immunochemistry of the porcine liver and kidney ECMs further confirmed the disrupted three-dimension ultrastructure of the ECM in the Triton X-100 and NaDOC groups. Additionally, Triton X-100 effectively eliminated the residual SDS in the SDS-treated group, which ensured the scaffolds were not cytotoxic to cells. Thus, we have developed an optimal method that can be scaled up for use with other solid whole organs. CONCLUSIONS: Our SDS-perfusion protocol can be used for porcine liver and kidney decellularization to obtain organ scaffolds cleared of cellular material, xenoimmunogens, and preserved vital ECM components. PMID- 25291436 TI - False-belief understanding and social preference over the first 2 years of school: a longitudinal study. AB - The role of false belief in establishing children's social relationships during the transition to school was examined and compared to other social cognitive constructs. One hundred and fourteen 5-year-olds were recruited during their 1st year of school (Time 1); 106 children were retained 1 year later. False belief, emotion expression recognition, empathy, verbal ability, and peer-rated social preference were measured at both times. False belief at Time 1 had a direct influence on concurrent social preference, over and above the influence of emotion expression recognition and empathy. False belief made no independent contribution to later social preference accounting for stability in social preference. The role of social cognitive development is discussed with respect to how children establish and maintain their position in a peer group. PMID- 25291437 TI - Anterior segment developmental anomalies in a 33-week-old fetus with MIDAS syndrome. AB - We report anterior segment abnormalities in both eyes of a 33-week-old fetus endorsing the diagnosis of MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome. After abortion, the fetus was examined by a standard pediatric autopsy that included macroscopic and microscopic examination of both eyes. Postmortem findings included craniofacial stigmata (such as hypertelorism, a flat nose and low-set ears) and an agenesis of the corpus callosum. Array comparative genomic hybridization revealed a deletion of the short arm of the X chromosome (region Xp22.2 to p22.32). Ophthalmopathologic examination of the eyes revealed microphthalmia with anterior segment developmental anomalies, in particular sclerocornea and Peters' anomaly, respectively. General pathology findings plus the ocular findings allowed the diagnosis of MIDAS syndrome. A discussion of differential diagnoses is provided. This case report indicates that ophthalmopathologic investigation of fetal eyes can be of great value for the further classification of syndromes. PMID- 25291442 TI - How we did the Question Time Forum (QTF). AB - BACKGROUND: We piloted a new method of feedback to supplement online surveys and student representation. METHODS: The face-to-face feedback session enabled all Year 5 students to ask questions directly to a faculty panel, regarding their curriculum. Questions were gathered in advance so the panel could review and prepare appropriate responses. "Ask the audience" questions were also included. EVALUATION: The panel and a convenience sample of 25 students (attenders and non attenders) were interviewed. All interviews were recorded, transcribed and themed using long table technique. QTF was also evaluated on-the-day by using "Ask the Audience" questions. RESULTS: Sixty-three Year 5 students attended (from a cohort of 337), of whom 96% felt it was a useful addition to current methods of feedback and 93% would attend again. Students felt QTF was "brilliant" and a "triumph in transparency" while the faculty hailed the "novel" event and "honest discussion". CONCLUSION: QTF was well-received by students and faculty. Both encouraged repetition of the event, thought to enhance the transparency of decisions about the running of the course and promote more in-depth dialogue between staff and students. PMID- 25291441 TI - DNA Y structure: a versatile, multidimensional single molecule assay. AB - Optical trapping is a powerful single molecule technique used to study dynamic biomolecular events, especially those involving DNA and DNA-binding proteins. Current implementations usually involve only one of stretching, unzipping, or twisting DNA along one dimension. To expand the capabilities of optical trapping for more complex measurements would require a multidimensional technique that combines all of these manipulations in a single experiment. Here, we report the development and utilization of such a novel optical trapping assay based on a three-branch DNA construct, termed a "Y structure". This multidimensional assay allows precise, real-time tracking of multiple configurational changes. When the Y structure template is unzipped under both force and torque, the force and extension of all three branches can be determined simultaneously. Moreover, the assay is readily compatible with fluorescence, as demonstrated by unzipping through a fluorescently labeled, paused transcription complex. This novel assay thus allows for the visualization and precision mapping of complex interactions of biomechanical events. PMID- 25291443 TI - Adsorption of proteins at the solution/air interface influenced by added nonionic surfactants at very low concentrations for both components. 2. Effect of different surfactants and theoretical model. AB - The influence of the addition of the nonionic surfactants dodecyl dimethyl phosphine oxide (C12DMPO), tetradecyl dimethyl phosphine oxide (C14DMPO), decyl alcohol (C10OH), and C10EO5 at concentrations between 10(-5) and 10(-1) mmol/L to solutions of beta-casein (BCS) and beta-lactoglobulin (BLG) at a fixed concentration of 10(-5) mmol/L on the surface tension is studied. It is shown that a significant decrease of the water/air surface tension occurs for all the surfactants studied at very low concentrations (10(-5)-10(-3) mmol/L). All measurements were performed with the buoyant bubble profile method. The dynamics of the surface tension was simulated using the Fick and Ward-Tordai equations. The calculation results agree well with the experimental data, indicating that the equilibration times in the system studied do not exceed 30 000 s, while the time required to attain the equilibrium on a plane surface is by one order of magnitude higher. To achieve agreement between theory and experiment for the mixtures, a supposition was made about the influence of the concentration of nonionic surfactant on the adsorption activity of the protein. The adsorption isotherm equation of the protein was modified accordingly, and this corrected model agrees well with all experimental data. PMID- 25291445 TI - Naming lymphocytespecific growth and differentiation factors. PMID- 25291446 TI - Conference in Turkey Societies asked to withdraw support. PMID- 25291444 TI - Computed tomographic findings in 44 dogs and 10 cats with grass seed foreign bodies. AB - OBJECTIVE: To supplement recent reports of computed tomographic (CT) findings in dogs and cats with grass seed foreign bodies. METHODS: Retrospective review of cases that had CT scan and subsequent retrieval of a grass seed during the same period of hospitalisation from a site included in the scan. RESULTS: Records of 44 dogs and 10 cats were reviewed. Most were presented in the months July to December. Median duration of clinical signs was 4 weeks (range 2 days to 2 years). The most frequent clinical signs were soft tissue swelling (30% cases), coughing (28%), sneezing (28%) and discharge (26%). Grass seeds were retrieved from the thorax (35% cases), nasal cavity (31%), ear (7%), other sites in the head and neck (22%), sublumbar muscles (2%) and pelvic limb (2%). The grass seed was visible in CT images in 10 (19%) cases. Secondary lesions were visible in CT images of 52 (96%) cases, including collection of exudate (37%), abscess (24%), enlarged lymph nodes (22%) and pulmonary consolidation (20%). CT images appeared normal in 4% animals. CLINICAL SIGNIFICANCE: Grass seeds within the respiratory tract are frequently visible in CT images, but in general CT appears to be more useful for localisation of secondary lesions than as a method of definite diagnosis. PMID- 25291447 TI - Through a glass, darkly .... PMID- 25291448 TI - Information overload of one type .... PMID- 25291449 TI - ... but not another. PMID- 25291450 TI - Some thoughts on idiotypic networks and immunoregulation. AB - The first of two articles in which J. Urbain and C. Wuilmart discuss the manipulation of idiotype-anti-idiotype interactions in immune responses. PMID- 25291451 TI - B-cell specific immunoregulatory lymphokines. PMID- 25291452 TI - Immortalizing human T-cell function. PMID- 25291453 TI - Acquisition of diverse T-cell isotypes. PMID- 25291454 TI - The role of H-Y as a minor transplantation antigen. AB - H-Y antigen is expressed in mammals only by males, so that grafts of male tissue are rejected by females within certain highly inbred strains. H-Y antigen appears to be a simple, non-polymorphic antigen and the genetic control of anti-H-Y responses has been extensively studied. In this article Elizabeth Simpson discusses the many insights obtained. PMID- 25291455 TI - Generation of immunoglobulin variable gene diversity. AB - Recent protein and gene sequences show that diversity in immunoglobulin variable genes is generated by multiple germline genes which then undergo somatic rearrangement and hypermutation. PMID- 25291456 TI - Interleukin 1 is more than an interleukin. AB - Gery and co-workers(1) first described lymphocyte activating factor (LAF) in 1972, as an activity produced by cultured human peripheral blood adherent leukocytes which was directly mitogenic for murine thymocytes but not for immunocompetent peripheral lymphocytes. Human LAF also synergistically augmented the mitogenic effects of the lectins ConA and PHA on murine thymocytes and splenic T lymphocytes(1). Since then LAF has been shown to promote lymphocyte differentiation and functions and even to affect a variety of nonlymphocytic larget cells. In view of the many biological activities attributed to this macrophage-derived factor, LAF was renamed 'interleukin 1' (IL 1) at the Second International Lymphokine Workshop at Ermatingen, Switzerland, in 1979(2). Partly as a consequence of the resultant controversy, this term has become widely known and will be used in this review, even though, as J. J. Oppenheim and Igal Gery show, IL 1 is more than a signal between leukocytes. PMID- 25291457 TI - Micro-RNA expression in hypoplastic left heart syndrome. AB - OBJECTIVE: Micro-RNAs (miRNAs) are important regulators of gene expression through interaction with the 3'UTR of target messenger RNAs (mRNAs). The role of miRNAs has been extensively studied in adult human and nonhuman animal models of heart disease. Hypoplastic left heart syndrome (HLHS) is the most common form of severe congenital heart disease and is an important cause of morbidity and mortality in infants and children. The objective of this work was to analyze the miRNA profile in HLHS patients. METHODS AND RESULTS: miRNA profile was determined in the right ventricle with the use of miRNA array, and expression was validated with the use of reverse-transcription polymerase chain reaction (RT-PCR). Based on bioinformatics analysis, targets were selected and their expression analyzed with the use of RT-PCR.We found that the miRNA profile of HLHS is novel, with few similarities between pediatric and adult idiopathic dilated cardiomyopathy. Moreover, our analysis identified putative targets for these miRNAs that are known to be important for cardiac development and disease, and that miRNAs and their putative targets are antithetically regulated. We also found that miRNA expression changes with stage of surgery, suggesting that volume unloading of the ventricle has important consequences for gene expression. CONCLUSIONS: Our data suggest a unique miRNA profile for HLHS that may be associated with defects in cardiac development and disease. PMID- 25291458 TI - Arterial spin labeling may contribute to the prediction of cognitive deterioration in healthy elderly individuals. AB - PURPOSE: To explore whether arterial spin labeling (ASL) imaging in cognitively intact elderly individuals may be used to predict subsequent early neuropsychological decline. MATERIALS AND METHODS: The local ethics committee approved this prospective study, and written informed consent was obtained from all participants. A total of 148 consecutive control subjects were included, 75 of whom had stable cognitive function (sCON) (mean age, 75.9 years +/- 3.4 [standard deviation]; 43 female) and 73 of whom had deteriorated cognitive function (dCON) at 18-month clinical follow-up (mean age, 76.8 years +/- 4.1; 44 female). An additional 65 patients with mild cognitive impairment (MCI) (mean age, 76.2 years +/- 6.1; 25 female) were also included. Two-dimensional pulsed ASL was performed at the baseline visit. Statistical analysis included whole brain voxelwise analysis of the ASL relative cerebral blood flow (CBF) data, receiver operating characteristic (ROC) curve analysis of the posterior cingulate cortex (PCC), and voxel-based morphometry analysis of gray matter. RESULTS: The voxelwise comparison of ASL revealed decreased relative CBF in the dCON group compared with that in the sCON group and slightly more pronounced relative CBF in the MCI group compared with that in the sCON group, most notably in the PCC (P < .05 corrected). Comparison of the dCON group with the MCI group revealed no significant differences. ROC analysis of relative CBF in the PCC enabled discrimination of dCON (P < .001; area under the ROC curve, 0.66). There was no confounding focal gray matter atrophy. CONCLUSION: Reduced ASL in the PCC at baseline is associated with the development of subsequent subtle neuropsychological deficits in healthy elderly control subjects. At a group level, ASL patterns in subjects with dCON are similar to those in patients with MCI at baseline, indicating that these subjects may initially maintain their cognitive status via mobilization of their neurocognitive reserve at baseline; however, they are likely to develop subsequent subtle cognitive deficits. PMID- 25291459 TI - Neuropsychological and psychological rehabilitation interventions in refractory sport-related post-concussive syndrome. AB - BACKGROUND: The neuropsychological, physical, vestibular and oculomotor sequelae of sports-related concussion are extremely well documented. However, there is a paucity of interventions for these symptoms in refractory sports-related concussions. AIM: The intent of this article is to review the known and emerging neuropsychological and psychological rehabilitation interventions for reducing morbidity in refractory sports-related concussions (SRCs). METHODS: The authors openly acknowledge the limited amount of empirical data available for review, as did the Zurich consensus papers, but posit a mindful and ethical approach towards rehabilitation interventions in the absence of evidence-based guidelines. Further, rehabilitation interventions proven useful with similar injuries or illnesses, particularly non-sports-related mild TBI, will be reviewed for applicability. Such interventions include Cognitive-Behavioural psychotherapy, biofeedback, cranial electrical stimulation, neurofeedback and cognitive rehabilitation. RESULTS AND CONCLUSIONS: Modified approaches for rehabilitation with young children within family and school systems are provided. Recommendations for further research are offered. PMID- 25291460 TI - Variability in Obstacle Clearance May (Not) Indicate Cognitive Disorders in Alzheimer Disease. AB - The aim of this study was to investigate obstacle clearance and its variability in individuals with Alzheimer dementia (AD) as well as healthy elderly individuals while they approached and crossed an obstacle in their path. Fifteen people with AD and 15 age-matched/sex-matched healthy individuals (control group) participated in this study. Clinical assessment of both groups was performed by a neuropsychiatrist. Spatial-temporal parameters of 5 trials of unobstructed walking and 5 trials of obstacle crossing during walking (approach and crossing phases) were measured using a 3-dimensional optoelectronic system. The results indicated that individuals with AD showed higher variability in the approach phase for stride length and the horizontal distance from their trailing limb foot to the obstacle. However, their gait variability in the crossing phase was similar to the control group. In addition, the individuals with AD were found to walk slowly and with a short stride length in both conditions. In conclusion, individuals with AD had increased gait variability while approaching an obstacle during walking, indicating a deficit in planning to avoid obstacles that could be related to cognitive disorders. However, gait variability during the crossing phase may not be indicative of cognitive disorders in AD. PMID- 25291462 TI - Where do mucosal mast cells acquire IgE? PMID- 25291463 TI - Lymphocyte migration and tissue specificity. PMID- 25291461 TI - Semantic Corticobasal Dementia: Challenging Nosology in Frontotemporal Lobe Degeneration. PMID- 25291464 TI - The effects of cyclosporin A on the immune system. AB - The use of cyclosporin A as an immunosuppressant in clinical transplantation is growing. At the same time more is becoming known about its influence on subpopulations of lymphoid cells. PMID- 25291465 TI - Current trends in multiple sclerosis research. AB - Byron Waksman discusses existing evidence which suggests that MS occurs in genetically predisposed individuals manifesting defects in immune regulation. It appears to be triggered by viral infection and to be virus or autoimmune in nature. Abnormalities in circulating immunoregulatory cells are very well correlated with disease activity. Animal models closely resembling MS also involve chronic virus or autoimmune disease in animals with a genetically determined abnormality of immune regulation. PMID- 25291466 TI - The measurement of immune complexes Is it clinically useful? AB - The discoveries made by academic immunologists must be examined for their possible clinical value, and every few years an in-vitro test applicable to patients is seized upon with particular enthusiasm. Some become laboratory investigations routinely ordered by clinicians, while others fall by the wayside. In the last decade many ways of measuring soluble immune complexes in biological fluids have been worked out (Table I) and applied in health and disease. At first the reports were greeted with enormous enthusiasm but lately there has been growing disillusion about their real importance in many disease processes. Has the pendulum swung too far? PMID- 25291468 TI - Killing often spoken of as natural Naming in clonal terms.... PMID- 25291469 TI - Killing often spoken of as natural hellip; the cryptic orphan killer cells. PMID- 25291467 TI - Investigating the role of GXXXG motifs in helical folding and self-association of plasticins, Gly/Leu-rich antimicrobial peptides. AB - Plasticins (PTC) are dermaseptin-related antimicrobial peptides characterized by a large number of leucine and glycine residues arranged in GXXXG motifs that are often described to promote helix association within biological membranes. We report the structure and interaction properties of two plasticins, PTC-B1 from Phyllomedusa bicolor and a cationic analog of PTC-DA1 from Pachymedusa dacnicolor, which exhibit membrane-lytic activities on a broad range of microorganisms. Despite a high number of glycine, CD and NMR spectroscopy show that the two plasticins adopt mainly alpha-helical conformations in a wide variety of environments such as trifluoroethanol, detergent micelles and lipid vesicles. In DPC and SDS, plasticins adopt well-defined helices that lie parallel to the micelle surface, all glycine residues being located on the solvent-exposed face. Spectroscopic data and cross-linking experiments indicate that the GXXXG repeats in these amphipathic helices do not provide a strong oligomerization interface, suggesting a different role from GXXXG motifs found in transmembrane helices. PMID- 25291470 TI - Advantages of rat monoclonal antibodies. PMID- 25291471 TI - Another look at chronic lymphocytic leukaemia in the context of B-cell differentiation. PMID- 25291472 TI - This letter was sent to Dr Johnstone. PMID- 25291473 TI - Phase variations in the modulation of the immune response. PMID- 25291474 TI - Mutant monoclonal antibodies. PMID- 25291476 TI - DNA damage and repair in immunologically active cells. PMID- 25291475 TI - Virus-infected cells, IgG, and the alternative complement pathway. PMID- 25291477 TI - Allotype suppression and epitope-specific regulation. AB - In neonatal (A x B) F1 mice, injections of maternal (A strain) antibody to-the Ig allotype of the paternal (B) strain chronically suppress theproduction of antibodies with the B-strain allotype. Here Leonore Herzenberg describes how, in such animals, this form of suppression influences the control of antibody responses to a thymus-dependent antigen that is subsequently encountered. PMID- 25291478 TI - Human neoplastic B cells: monoclonal models of B-cell differentiation. AB - Clones of normal antigen-specific B cells are not yet available but tumors derived from B cells are models of such clones and can be analysed biochemically and functionally. Here Tadamitsu Kishimoto discusses the value of these tumors in the study of B-cell activation. PMID- 25291481 TI - Contact sensitization to modern dressings: a multicentre study on 354 patients with chronic leg ulcers. AB - BACKGROUND: Modern dressings (MDs) may have a low sensitization rate, but there is a lack of prospective studies in patients with chronic leg ulcers (CLUs) to evaluate this. OBJECTIVES: To determine the rate of sensitization (contact allergy) to MDs and substances present in dressings. PATIENTS AND METHODS: A prospective multicentre study was carried out in patients with CLUs at five French dermatology departments; patch tests were performed with the European baseline series and with an additional 27 individual allergens and 10 MDs. RESULTS: Among 354 patients (226 women and 128 men) with CLUs, 59.6% had at least one positive patch test reaction to an MD and 19% had at least one sensitization to an MD. The number of positive test reactions per patient was correlated with the duration of ulcerative disease, but not with ulcer duration, the cause of the ulcer, or the presence of surrounding eczematous lesions. For 11 of 45 patients sensitized to Ialuset cream(r), more detailed information could be obtained with sensitization to sodium dehydroacetate (5 cases) or Lanette SX(r) (3 cases). CONCLUSIONS: Sensitization to MDs is not rare. It is absolutely necessary to label all components of MDs on their packaging and to avoid some sensitizing molecules, such as colophonium derivatives or any strong sensitizers. PMID- 25291482 TI - A near-infrared dithieno[2,3-a:3',2'-c]phenazine-based organic co-sensitizer for highly efficient and stable quasi-solid-state dye-sensitized solar cells. AB - A novel near-infrared (NIR) organic sensitizer FNE53 with a strong electron withdrawing unit, dithieno[2,3-a:3',2'-c]phenazine, has been designed and synthesized for quasi-solid-state dye-sensitized solar cells (DSSCs). By simply fusing the two thiophene rings on quinoxaline unit in sensitizer FNE48, the intramolecular charge transfer (ICT) band bathochromically shifts from 542 nm for FNE48 to 629 nm for FNE53 in toluene solution. The absorption spectrum of sensitizer FNE53 covers the whole visible region and extends to the NIR region, which exhibits complementary absorption profile to another organic dye FNE46 based on quinoxaline. When FNE46 and FNE53 are used as cosensitizers for metal free cocktail-type quasi-solid-state DSSCs, sensitizer FNE53 not only extends the photoresponse range but also suppresses the intermolecular interactions among the dye molecules. Therefore, the cocktail-type quasi-solid-state DSSC displays much higher IPCE value compared with that for the DSSC sensitizer based on FNE53 and a broader IPCE response in comparison to that for the DSSC sensitizers based on FNE46, respectively. After the molar ratio between the two cocktail dyes is optimized, the highest energy conversion efficiency of 8.04% is achieved in a metal-free quasi-solid-state DSSC cosensitized with FNE46 and FNE53, which exhibits good long-term stability after continuous light soaking for 1000 h. PMID- 25291483 TI - Characterization of human leukocyte differentiation antigens. AB - What would impel 190 different laboratories to work together in the performance of more than 150 000 assays to characterize about 800 antibodies? Participants in the 3rd International Workshop on Human Leukocyte Differentiation Antigens generally shared the conviction that such cooperative effort has the potential to bring order out of the chaos of molecules described on the surface of human leukocytes. PMID- 25291485 TI - Notes. PMID- 25291484 TI - Histocompatibility antigens and chemical reactivity in autoimmunity. AB - Much of current research in autoimmunity focuses on the role of major histocompatibility (MHC) antigens in the disease process and the relevance of chemicals as etiological agents. A recent workshop dealt with both topics. PMID- 25291486 TI - Fibroblast proliferation in vitro and fibrosis. PMID- 25291487 TI - HIV is an inappropriate name for the AIDS virus. PMID- 25291488 TI - On the interaction between antigen and MHC molecules. PMID- 25291489 TI - Lentiviruses and mycobacterial diseases. PMID- 25291490 TI - The two-chain structure of high-affinity IL-2 receptors. AB - Binding studies with radiolabeled interleukin 2 (IL-2) have suggested that T cells possess two classes of IL-2 binding site with different affinities but a shared epitope named Tac. The gene for a 55kDa Tac-positive protein has been cloned but on transfection induced only the expression of low-affinity IL-2 binding sites. The structure of the receptor has therefore been perplexing. Here Kendall Smith discusses recent studies which disclose the existence of a new Tac negative 75kDa IL-2 binding protein and he suggests that a high affinity IL-2 receptor consists of an alpha(p75) chain non-covalently linked to a beta(p55) chain. PMID- 25291491 TI - Suppression of IgE responses following inhalation of antigen A natural homeostatic mechanism which limits sensitization to aeroallergens. AB - Contract between immune cells and airborne antigens is limited in the upper respiratory tract (URT) by physical barriers such as mucous. But some antigen does penetrate the URT epithelium. In this article, Patrick Holt and Jon Sedgwick postulate the existence of back-up immune mechanisms which prevent sensitization to antigens which cross epithelial barriers. PMID- 25291492 TI - Control of messenger RNA stability. PMID- 25291493 TI - The immunology of new generation vaccines. AB - In the next decade immunoprophylaxis through vaccination will undergo new developments and further implementation. There is growing interest in new physical forms of immunogens for use in vaccines: the effectiveness of these immunogens will depend upon the optimization of their immunogenic properties. In this article, Maurizio Zanetti and his colleagues discuss some of the guiding principles of 'vaccinology', and the use of new technology in vaccine production, in relation to the immunological requirements for effective vaccines. PMID- 25291494 TI - Protein antigenicity: a static surface property. AB - Much recent progress has been made in understanding the nature of antigenicity in the generation of antibodies. In this article Jiri Novotny and his colleagues discuss properties such as accessibility, flexibility and shape which determine the antigenicity of sites on proteins and consider the influence of these properties on the formation of immune complexes and the composition of the idiotype network. PMID- 25291495 TI - Association of common polymorphisms in beta1-adrenergic receptor with antihypertensive response to carvedilol. AB - OBJECTIVES: Marked interpatient variability exists in the blood pressure response to carvedilol, a nonselective beta-blocker. Here we evaluated the influence of 4 common polymorphisms in genes of the beta-adrenergic receptor on the antihypertensive efficacy of carvedilol in patients in a double-blinded monotherapy study. METHODS: Eighty-seven subjects with uncomplicated essential hypertensive (49% men; age = 52.2 +/- 11.1 years) from Jilin province of China were enrolled in the study, and 5 of them discontinued the treatment due to adverse effects. Both systolic and diastolic blood pressures (DBPs) were measured before and after 7 days of treatment with carvedilol (10 mg/d). Genotypes of the beta1-adrenergic receptor (ADRB1 Ser49Gly and Arg389Gly) and beta2-adrenergic receptor (ADRB2 Gly16Arg and Glu27Gln) were determined by polymerase chain reaction with restriction fragment length polymorphism. RESULTS: Patients homozygous for ADRB1 Arg389 had an approximately 4-fold greater reduction in DBPs than those homozygous for ADRB1 Gly389 (10.61 vs. 2.62 mm Hg, P = 0.013). The ADRB1 haplotype was also a significant predictor of response, as patients with the Gly49Arg389/Ser49Arg389 haplotype pair had a 5.7-fold greater reduction in DBPs than those homozygous for the Ser49Gly389 haplotype (16.11 vs. 2.83 mm Hg, P = 0.0055). An association was not found between ADRB2 polymorphism and carvedilol responsiveness in antihypertensive therapy. CONCLUSIONS: This study provides the first evidence to support that ADRB1 polymorphisms play an important role in the DBPs response to carvedilol treatment in patients with essential hypertension. PMID- 25291497 TI - Effects of the number of subjects on the dark/light preference of Zebrafish (Danio rerio). AB - This research aims to describe the effects of a variable number of Danio rerio fish subjects, ranging from one to eight, in the light/dark box preference test. Four hundred eighty adult male short-finned phenotype zebrafish were tested in the light/dark box. There were four groups in this experiment and a different number of subjects was used in each group: the control group had only one subject, whereas the experimental groups had either two, four, or eight subjects simultaneously inside the apparatus in every session. The average occurrence (AO) of subjects in the white side of the aquarium and the first choice average (FC) were recorded. The AO revealed no difference between the control group and test groups with two and four subjects. The results for the test group with eight subjects showed significant difference when compared to the control group and from the test group with two subjects. The FC also showed no difference between the control group and test groups with two and four subjects. There was significant variation between the control and the test group with eight subjects. The results reflect a conflict between the animal's preference for dark places and the innate drive to explore new environments. Zebrafish are highly social animals, exhibiting preference for swimming in groups and other patterns of social cohesion. The reduced white avoidance behavior in the test group of eight subjects may possibly reflect the role of shoaling, which is a defensive behavior, in reducing anxiety and stress. On the other hand, the absence of difference between the control group and test groups with two and four subjects suggest that it is feasible to run the light/dark test with up to four subjects, becoming an alternative to streamline and simplify data collection and test analysis. PMID- 25291498 TI - Responding to climate change with a carbon tax. PMID- 25291496 TI - Zinc and the prooxidant heart failure phenotype. AB - Neurohormonal activation with attendant aldosteronism contributes to the clinical appearance of congestive heart failure (CHF). Aldosteronism is intrinsically coupled to Zn and Ca dyshomeostasis, in which consequent hypozincemia compromises Zn homeostasis and Zn-based antioxidant defenses that contribute to the CHF prooxidant phenotype. Ionized hypocalcemia leads to secondary hyperparathyroidism with parathyroid hormone-mediated Ca overloading of diverse cells, including cardiomyocytes. When mitochondrial Ca overload exceeds a threshold, myocyte necrosis follows. The reciprocal regulation involving cytosolic free [Zn]i as antioxidant and [Ca]i as prooxidant can be uncoupled in favor of Zn-based antioxidant defenses. Increased [Zn]i acts as a multifaceted antioxidant by: (1) inhibiting Ca entry through L-type channels and hence cardioprotectant from the Ca-driven mitochondriocentric signal-transducer effector pathway to nonischemic necrosis, (2) serving as catalytic regulator of Cu/Zn-superoxide dismutase, and (3) activating its cytosolic sensor, metal-responsive transcription factor that regulates the expression of relevant antioxidant defense genes. Albeit present in subnanomolar range, increased cytosolic free [Zn]i enhances antioxidant capacity that confers cardioprotection. It can be achieved exogenously by ZnSO4 supplementation or endogenously using a beta3-receptor agonist (eg, nebivolol) that enhances NO generation to release inactive cytosolic Zn bound to metallothionein. By recognizing the pathophysiologic relevance of Zn dyshomeostasis in the prooxidant CHF phenotype and by exploiting the pharmacophysiologic potential of [Zn]i as antioxidant, vulnerable cardiomyocytes under assault from neurohormonal activation can be protected and the myocardium spared from adverse structural remodeling. PMID- 25291499 TI - Short-term pretreatment with a dual 5alpha-reductase inhibitor before bipolar transurethral resection of the prostate (B-TURP): evaluation of prostate vascularity and decreased surgical blood loss in large prostates. AB - OBJECTIVE: To investigate if short-term treatment with dutasteride (8 weeks) before bipolar transurethral resection of the prostate (B-TURP) can reduce intraoperative bleeding, as dutasteride a dual 5alpha-reductase inhibitor (5-ARI) blocks the conversion of testosterone into its active form dihydrotestosterone (DHT), and reduces prostate volume and prostate-specific antigen (PSA) levels, while increasing urinary flow rate. PATIENTS AND METHODS: In all, 259 patients were enrolled and randomised to two groups: Group A, receiving placebo and Group B, receiving dutasteride (0.5 mg daily for 8 weeks). Blood samples were taken before and after B-TURP for serum chemistry evaluation. In particular we evaluated blood parameters associated with blood loss [haemoglobin (Hb) and haematocrit (Ht)] and prostate vascularity [vascular endothelial growth factor (VEGF) immunoreactivity and microvessel density (MVD) using cluster of differentiation 34 (CD34) immunoreactivity]. RESULTS: Total testosterone, DHT, PSA level and prostate volume were evaluated and with the exception of DHT and PSA level there was no statistically significant differences between the groups. When comparing changes in Hb and Ht between Group A and Group B before and after B-TURP, there was a statistically significant difference only in patients with large prostates of >=50 mL (DeltaHb 3.86 vs 2.05 g/dL and DeltaHt 4.98 vs 2.64%, in Groups A and B, respectively). There was no significant difference in MVD and VEGF index in prostates of <50 mL, conversely in large prostates the difference become statistically significant. CONCLUSIONS: Dutasteride was able to reduce operative and perioperative bleeding only in patients with large prostates (>=50 mL) that underwent B-TURP. Our findings are confirmed by Hb and Ht values reported before and after the B-TURP and reductions in the molecular markers for VEGF and CD34 in the dutasteride-treated specimens. PMID- 25291500 TI - Effect of temperature on the intrinsic flexibility of DNA and its interaction with architectural proteins. AB - The helical structure of double-stranded DNA is destabilized by increasing temperature. Above a critical temperature (the melting temperature), the two strands in duplex DNA become fully separated. Below this temperature, the structural effects are localized. Using tethered particle motion in a temperature controlled sample chamber, we systematically investigated the effect of increasing temperature on DNA structure and the interplay between this effect and protein binding. Our measurements revealed that (1) increasing temperature enhances DNA flexibility, effectively leading to more compact folding of the double-stranded DNA chain, and (2) temperature differentially affects different types of DNA-bending chromatin proteins from mesophilic and thermophilic organisms. Thus, our findings aid in understanding genome organization in organisms thriving at moderate as well as extreme temperatures. Moreover, our results underscore the importance of carefully controlling and measuring temperature in single-molecule DNA (micromanipulation) experiments. PMID- 25291501 TI - The pharmacokinetics of metformin and concentrations of haemoglobin A1C and lactate in Indigenous and non-Indigenous Australians with type 2 diabetes mellitus. AB - AIMS: To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients. METHODS: An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B12 concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters. RESULTS: The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6-14 years, P < 0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8-2.2%, P < 0.001). Indigenous patients had a higher creatinine clearance (4.3 l h(-1) ) than the non-Indigenous patients (4.0 l h(-1) ), with a median difference of 0.3 l h( 1) (0.07-1.17 l h(-1) ; P < 0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2-15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9-14.9). Median lactate concentrations were also similar [1.55 (1.20 1.88) vs. 1.60 (1.35-2.10) mmol l(-1) ] for Indigenous and non-Indigenous patients, respectively. The median vitamin B12 was 306 pmol l(-1) (range 105-920 pmol l(-1) ) for the Indigenous patients. CONCLUSIONS: There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance <30 ml min(-1) . PMID- 25291502 TI - A new diketopyrrolopyrrole-based probe for sensitive and selective detection of sulfite in aqueous solution. AB - A new probe was synthesized by incorporating an alpha,beta-unsaturated ketone to a diketopyrrolopyrrole fluorophore. The probe had exhibited a selective and sensitive response to the sulfite against other thirteen anions and biothiols (Cys, Hcy and GSH), through the nucleophilic addition of sulfite to the alkene of probe with the detection limit of 0.1 MUM in HEPES (10 mM, pH 7.4) THF/H2O (1:1, v/v). Meanwhile, it could be easily observed that the probe for sulfite changed from pink to colorless by the naked eye, and from pink to blue under UV lamp after the sulfite was added for 20 min. The NMR and Mass spectral analysis demonstrated the expected addition of sulfite to the C=C bonds. PMID- 25291503 TI - Effect of toxicity of Ag nanoparticles on SERS spectral variance of bacteria. AB - Ag nanoparticles (NPs) have been extensively utilized in surface-enhanced Raman scattering (SERS) spectroscopy for bacterial identification. However, Ag NPs are toxic to bacteria. Whether such toxicity can affect SERS features of bacteria and interfere with bacterial identification is still unknown and needed to explore. Here, by carrying out a comparative study on non-toxic Au NPs with that on toxic Ag NPs, we investigated the influence of nanoparticle concentration and incubation time on bacterial SERS spectral variance, both of which were demonstrated to be closely related to the toxicity of Ag NPs. Sensitive spectral alterations were observed on Ag NPs with increase of NPs concentration or incubation time, accompanied with an obvious decrease in number of viable bacteria. In contrast, SERS spectra and viable bacterial number on Au NPs were rather constant under the same conditions. A further analysis on spectral changes demonstrated that it was cell response (i.e. metabolic activity or death) to the toxicity of Ag NPs causing spectral variance. However, biochemical responses to the toxicity of Ag were very different in different bacteria, indicating the complex toxic mechanism of Ag NPs. Ag NPs are toxic to a great variety of organisms, including bacteria, fungi, algae, protozoa etc., therefore, this work will be helpful in guiding the future application of SERS technique in various complex biological systems. PMID- 25291506 TI - Changes underway in Italy. PMID- 25291504 TI - A novel series of thiosemicarbazone drugs: from synthesis to structure. AB - A new series of thiosemicarbazones (TSCs) and their 1,3,4-thiadiazolines (TDZs) containing acetamide group have been synthesized from thiosemicarbazide compounds by the reaction of TSCs with cyclic ketones as well as aromatic aldehydes. The structures of newly synthesized 1,3,4-thiadiazole derivatives obtained by heterocyclization of the TSCs with acetic anhydride were experimentally characterized by spectral methods using IR, (1)H NMR, (13)C NMR and mass spectroscopic methods. Furthermore, the structural, thermodynamic, and electronic properties of the studied compounds were also studied theoretically by performing Density Functional Theory (DFT) to access reliable results to the experimental values. The molecular geometry, the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO) and Mulliken atomic charges of the studied compounds have been calculated at the B3LYP method and standard 6 31+G(d,p) basis set starting from optimized geometry. The theoretical (13)C chemical shift results were also calculated using the gauge independent atomic orbital (GIAO) approach and their respective linear correlations were obtained. PMID- 25291505 TI - Serial MR Imaging in Suprasellar Xanthogranuloma: Growth Pattern and New Lesions. AB - Xanthogranuloma is a rare lesion of the sellar-suprasellar region. We describe a case of suprasellar xanthogranuloma in whom serial MRI revealed features that have not been previously described--development of dural tail, vascular encasement and intra-axial lesions in posterior fossa. PMID- 25291507 TI - Sponsorship of scientific work. PMID- 25291509 TI - Guides to company form and future fitness. AB - Look for the reference library of immunotechnology in dense volumes devoted to the commercial and academic aspects of biotechnology in general. These are just some sources of information about named companies and opinions of the state of biotechnology in general. PMID- 25291508 TI - A jungle full of pitfalls. PMID- 25291510 TI - Where the jobs have been (II). PMID- 25291511 TI - Chronic lymphocytic leukaemia and normal B lymphopoiesis. PMID- 25291512 TI - Do suppressor T cells become helper T cells? PMID- 25291513 TI - Priority of the anti-idiotypic response after antigen administration: artefact or intriguing network mechanism? AB - Immunization triggers at least two speck responses measurable at cellular and humoral levels: the antigen-driven proliferation of idiotype-bearing (idt+) cells; and an autochthonous anti-idt response'. As the expansion of the idt* clone(s) is presumed to provide the activating stimulus for the complementary response, one expects the proliferation of anti-idt clones to follow the idt response at an interval equivalent to the time required for ~pmphocyte activation. However, there have been several reports of an autochthonous anti-idt response preceding the expansion of antigen-driven idt' clone(s). In this brief commentary, we examine these reports and offer some suggestions that may resolve this apparent paradox. PMID- 25291514 TI - The basis of autoimmunity in MRL-lpr/lpr mice: a role for self Ia-reactive T cells. AB - Murine models of systemic lupus eRythematosus (SLE) have significantly contributed to our understanding of human autoimmunity. One such strain, the MRL lpr/lpr, spontaneously develops an autoimmune disease manifested clinically by arthritis, vasculitis, immune-complex glomerulonephritis and autoantibody production(1-3). In this article Yvonne Rosenberg and her colleagues suggest a theoretical basis for the development of autoimmunity in MRL-lpr/lpr mice. PMID- 25291515 TI - Helper T lymphocytes and isotype expression. PMID- 25291516 TI - All self antigens are not created (tolerated) equally. PMID- 25291517 TI - Lipids and lymphocyte function. AB - Lipids have a variety of important biological functions, serving as storage and transport forms of metabolic fuel, as structural membrane components, and as cell surface components conferring, for example, tissue and species specificity. Not surprisingly, because the immune system functions through a complex series of stimulatory and regulatory interactions, there has been speculation about the role of lipids as lymphocyte membrane components. Here Kay Traill and George Wick discuss recent research on the possible influence of lipids on receptor binding, signal transmission and the stimulation of lymphocytes to effector function. PMID- 25291518 TI - Hemopoietic colony-stimulating factors. AB - Hemopoietic colony-stimulatingfactors (CSFs) are glycoproteingrowth factors produced by many tissues in the body; they are essential for the survival, growth and differentiation of hemopoietic progenitor cells in vitro. In this article Nicos Nicola and Mathew TTadas discuss the classes of CSF that have now been purified (M-CSF, GM-CSF, G-CSF and Multi-CSF). Each is active in vitro at picomolar concentrations, but each can be distinguished from the others by its unique molecular properties and unique spectrum of biological activity. In addition to their proliferative effects, these regulators also appear able to stimulate functional activities in mature hemopoietic cells. PMID- 25291521 TI - Europe needs a central, transparent, and evidence-based approval process for behavioural prevention interventions. AB - Fabrizio Faggiano and colleagues discuss how a central, transparent, and evidence based approval process is needed for behavioral prevention interventions in Europe and propose a way forward. Please see later in the article for the Editors' Summary. PMID- 25291522 TI - Parenteral midazolam is superior to diazepam for treatment of prehospital seizures. AB - INTRODUCTION: Diazepam and midazolam are commonly used by paramedics to treat seizures. A period of drug scarcity was used as an opportunity to compare their effectiveness in treating prehospital seizures. METHODS: A retrospective chart review of a single, large, commercial agency during a 29-month period was performed. The period included alternating shortages of both medications. Ambulances were stocked with either diazepam or midazolam based on availability of the drugs. Adult patients who received at least 1 parenteral dose of diazepam or midazolam for treatment of seizures were included. The regional prehospital protocol recommended 5 mg intravenous (IV) diazepam, 5 mg intramuscular (IM) diazepam, 5 mg IM midazolam, or 2.5 mg IV midazolam. Medication effectiveness was compared with respect to the primary end point: cessation of seizure without repeat seizure during the prehospital encounter. RESULTS: A total of 440 study subjects received 577 administrations of diazepam or midazolam and met the study criteria. The subjects were 52% male, with a mean age of 48 (range 18-94) years. A total of 237 subjects received 329 doses of diazepam, 64 (27%) were treated with first-dose IM. A total of 203 subjects received 248 doses of midazolam; 71 (35%) were treated with first-dose IM. Seizure stopped and did not recur in 49% of subjects after parenteral diazepam and 65% of subjects after parenteral midazolam (p = 0.002). Diazepam and midazolam exhibited similar first dose success for IV administration (58 vs. 62%; p = 0.294). Age, gender, seizure history, hypoglycemia, the presence of trauma, time to first administration, prehospital contact time, and frequency of IM administration were similar between groups. CONCLUSION: For parenteral administration, midazolam demonstrated superior first-dose seizure suppression. This study demonstrates how periods of drug scarcity can be utilized to study prehospital medication effectiveness. PMID- 25291523 TI - Ex Vivo Propagation of Human Corneal Stromal "Activated Keratocytes" for Tissue Engineering. AB - Keratoconus is a corneal disorder characterized by a thinning of stromal tissue, and the affected patients have induced astigmatism and visual impairment. It is associated with a loss of corneal stromal keratocytes (CSKs). Hence, reconstructing stromal tissue with autologous CSK replacement can be a viable alternative to corneal transplantation, which is restricted by the global donor material shortage and graft rejection. Human CSKs are normally quiescent and express unique markers, like aldehyde dehydrogenases and keratocan. In serum culture, they proliferate, but lose their characteristic phenotype and become stromal fibroblasts. Here we report a novel culture cocktail to ex vivo propagate and maintain CSKs. Primary human CSKs were obtained from adult donors and cultured with soluble human amnion stromal extract (ASE), rho-associated coiled coil-forming protein serine/threonine kinase inhibitor Y-27632, and insulin-like growth factor-1 (collectively named as ERI). Protein profiling using mass spectrometry followed by MetaCoreTM pathway analysis predicted that ASE proteins might participate in transforming growth factor-beta (TGF-beta) signaling and fibroblast development, cell adhesion, extracellular matrix remodeling, and immune response. In culture with 0.5% fetal bovine serum and ERI, the population of "activated keratocytes" was expanded. They had much lowered expression of both keratocyte and fibroblast markers, suppressed TGF-beta-mediated Smad2/3 activation, and lacked fibroblast-mediated collagen contractibility. These "activated keratoctyes" could be propagated for six to eight passages ex vivo, and they regained CSK-specific dendritic morphology and gene marker expression, including aldehyde dehydrogenases, lumican, and keratocan biosynthesis, expression, and secretion when returned to serum-depleted ERI condition. This novel cocktail maintained human CSKs in both adherent and suspension cultures with proper keratocyte features and without the transformation to stromal fibroblasts. Thus, human CSKs can be ex vivo propagated as transient "activated keratocytes." This could provide sufficient number of genuine CSKs for corneal tissue engineering. PMID- 25291524 TI - New methods for investigation of neuronal migration in embryonic brain explants. AB - BACKGROUND: Proper migration of neurons is essential for the formation and normal functioning of the nervous system. Defects in neuronal migration underlie a number of neurologic diseases in humans. Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration remain to be elucidated fully. Newborn neurons from the embryonic medial ganglionic eminence (MGE) migrate a long distance dorsally in the developing brain, giving rise to several types of interneurons in the neocortex. NEW METHOD: In this study, we developed an immunocytochemistry (ICC) protocol to stain neurons migrating out of the MGE explant embedded in Matrigel. We also established a protocol to efficiently transfect cells in MGE explants, achieving a transduction efficiency of more than 30%. COMPARISON WITH EXISTING METHOD: In addition, we developed microfluidic chambers for explants that allow visualization of the vectorial migration of individual neurons from mouse embryonic MGE explants. Our microfluidic system allows monitoring of the distribution of cellular organelles (e.g. Golgi) within migrating neurons which have been stained with commercial molecular dyes or transfected with adeno-associated virus (AAV) expressing reporter proteins. CONCLUSION: These methods provide new paradigms to study neuronal migration in real-time. PMID- 25291525 TI - Quantifying the time for accurate EEG decoding of single value-based decisions. AB - BACKGROUND: Recent neuroimaging studies suggest that value-based decision-making may rely on mechanisms of evidence accumulation. However no studies have explicitly investigated the time when single decisions are taken based on such an accumulation process. NEW METHOD: Here, we outline a novel electroencephalography (EEG) decoding technique which is based on accumulating the probability of appearance of prototypical voltage topographies and can be used for predicting subjects' decisions. We use this approach for studying the time-course of single decisions, during a task where subjects were asked to compare reward vs. loss points for accepting or rejecting offers. RESULTS: We show that based on this new method, we can accurately decode decisions for the majority of the subjects. The typical time-period for accurate decoding was modulated by task difficulty on a trial-by-trial basis. Typical latencies of when decisions are made were detected at ~500 ms for 'easy' vs. ~700 ms for 'hard' decisions, well before subjects' response (~340 ms). Importantly, this decision time correlated with the drift rates of a diffusion model, evaluated independently at the behavioral level. COMPARISON WITH EXISTING METHOD(S): We compare the performance of our algorithm with logistic regression and support vector machine and show that we obtain significant results for a higher number of subjects than with these two approaches. We also carry out analyses at the average event-related potential level, for comparison with previous studies on decision-making. CONCLUSIONS: We present a novel approach for studying the timing of value-based decision-making, by accumulating patterns of topographic EEG activity at single-trial level. PMID- 25291526 TI - Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study. AB - OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether the following risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET, and other cancers, and personal history of diabetes as potential risk factors. METHODS: Patients with PNETs seen at Mayo Clinic Rochester between 2000 and 2011 were compared with controls seen for a general medical evaluation. Patients and controls completed the same questionnaires. After excluding insulinoma and high-grade PNETs, 355 cases were evaluated, and 309 were matched to 602 controls (2:1) on age, sex, and region of residence. RESULTS: Personal smoking history was not associated with PNETs. Alcohol use was less common among cases (54% vs 67%, P < 0.001). Cases were more likely to report a family member with sarcoma (P = 0.02), PNET (P = 0.02), gallbladder cancer (P = 0.02), ovarian cancer (P = 0.04), and gastric cancer (P = 0.01). There was no association with other cancers in family members. Diabetes was more commonly reported by cases than controls (19% vs 11%, P < 0.001). CONCLUSIONS: With the exception of diabetes, risk factors that are associated with pancreatic adenocarcinoma are not risk factors for PNETs. PMID- 25291528 TI - Intestinal immunity and inflammation. PMID- 25291529 TI - Molecules at work on the T-cell surface. AB - Over the past two years a series of molecules on the T-cell surface have been defined using monoclonal antibodies. These have been grouped according to an agreed nomenclature (Table 1) and at a recent meeting(*) there was conspicuous interest in the functional significance of some of these molecules. There was much new information on the T-cell antigen receptor which has been reviewed elsewhere(1). PMID- 25291527 TI - Use of lidocaine in endotracheal intubation. Blood and urine concentrations in patients and deceased after unsuccessful resuscitation. AB - In toxicological analysis of postmortem samples the local anesthetic lidocaine is often identified. In most cases, lidocaine levels result from its use as aid in endotracheal intubation. The range of the drug's concentration in blood and urine was studied under controlled conditions from a cohort of cardiac surgery patients (n=35). Plasma concentrations 1 h after exposure to lidocaine in the range of the recommended 81 mg coating the endotracheal tube were less than 0.2 mg/l, its metabolite monoethylglycinxylidide (MEGX) less than 0.05 mg/l (median ratio 0.18, range 0.03-1.23). Also the concentrations of lidocaine and MEGX in urine samples were low (less than 1.2 and 0.1 mg/l, respectively) with MEGX/lidocaine ratios of 0.11 (median, range up to 1.2). These data were compared with results obtained by analyzing postmortem blood and urine samples of 18 deceased with a documented cardiopulmonary resuscitation attempt prior to death. Blood concentrations were in the same range (lidocaine median 0.07, range 0.02-1.07 mg/l; MEGX median 0.01, range <0.001-0.044 mg/l); besides low lidocaine concentrations in urine. MEGX was detected only in 2 out of 9 urine samples. The results of the present study confirm that lidocaine is absorbed in the trachea from the endotracheal tube coated with lidocaine containing gel. Postmortem quantitative results can be explained on the basis of the data obtained in the controlled study. PMID- 25291530 TI - B cells in the pathogenesis of AIDS. PMID- 25291531 TI - Autoimmunity and epithelial cells bearing class II MHC antigen. PMID- 25291532 TI - Does T-cell restriction to Ia limit the need for self-tolerance? AB - Why did two classes ofMHC molecule evolve as restricting elements in T-cell function? Here Carol Cowing discusses the hypothesis that incomplete self tolerance may explain the necessity for class II MHC restriction. PMID- 25291533 TI - A molecular basis for thymic selection: regulation of T11 induced thymocyte expansion by the T3-Ti antigen/MHC receptor pathway. AB - T-cell activation is mediated through either the T3-Ti molecular complex or the TII sheep erythrocyte bindingglycoprotein. The former represents the nominal antigen/MHC receptor whereas the latter is a surface component of an alternative pathway which appears much earlier in intrathymic differentiation. Recent studies indicate that the T3-Ti complex regulates the TII activation pathway. Here, taking account of the ontogeny and physiology of this pathway, Ellis Reinherz offers a simple model to account for the selection in thymus against T cells with high-affinity, potentially autoreactive antigen receptors. PMID- 25291534 TI - A place for soluble immune complexes in clinical immunology. PMID- 25291535 TI - Abortive infection of human mononuclear cells with cytomegalovirus induces functional immunosuppression in vitro. PMID- 25291536 TI - Human retrovirus in adult T-cell leukemia/lymphoma. AB - In this review Kazuo Sugamura and Yorio Hinuma summarize developments in studies on the human retrovirus associated with a unique human T-cell malignancy, adult T cell leukemia; they also discuss the possible mechanisms of retrovirus-induced leukemogenesis. PMID- 25291537 TI - The HLA class II genes and products: the HLA-D region. AB - In the late 1960s it became clear that certain anomalous proliferative responses in mixed leukocyte cultures (MLC) (1,2) involving cells identical for the HLA A, B and C antigens were a result of disparity for what is now referred to as the HLAD-region(3-5). Later came thefirst evidence that products of the HLA-D region could be defined serologically(6) and a distinction emerged between epitopes recognized on D region products by antibodies (Ia) and those recognized by T lymphocytes (LD). HLA-A, Band C antigens are now known as class I MHC products and D antigens as class II products. Today our understanding of the D region is based not only on serological and T-lymphocyte responses to class II products but also on protein and DNA studies. Here Fritz Bach summarizes this understanding, with emphasis on the T-lymphocyte defined LD system. PMID- 25291538 TI - The molecular evolution of the immune response. AB - In recentyears the molecular basis of immunoglobulin diversity has been uncovered. Little is known, however, about its significance and the mechanisms that generate it in the whole organism. In this article Tim Manser and his colleagues discuss ways in which this diversity is used in the establishment of immunity, and seek to explain how genetically identical individuals generate widely diverse immune responses to the same antigen and some antigens reproducibly elicit similar immune responses (recurrent idiotypes) in all individuals. PMID- 25291539 TI - Antigen processing and presentation to T cells. AB - In this article Howard Grey and Robert Chesnut describe recent insights into the mechanism of antigen presentation and discuss the needfor antigen processing in the stimulation of T cells. PMID- 25291540 TI - Growth factors and oncogenes. AB - The regulation of the production of normal cells of the skin, blood and intestine has attracted considerable interest since the very earliest days of tissue culture(1,2). The proliferation of normal cells has long been known to depend on specific proteins called growth factors. However, the experimental systems were so complex and poorly understood, that only the persistence of a few biochemists kept the rather complex field of growth factor chemistry moving forward(3). Now, after the discovery of the retroviral oncogenes(4) and their cellular equivalents, it is our knowledge of growth factors(6-12) their receptors(9) and their mode of action (11,12), which is paving the way for understanding the functional nature of the molecular lesions which give rise to cancer cells(13 16). Each cellular system has its unique features but here Tony Burgess discusses some of the similarities in the molecular regulation of proliferation and differentiation in both normal and transformed cells from several different tissues. PMID- 25291542 TI - Prenatal diagnosis of androgen insensitivity syndrome using cell-free fetal DNA testing. PMID- 25291543 TI - Inhibition of PPARalpha attenuates vimentin phosphorylation on Ser-83 and collapse of vimentin filaments during exposure of rat Sertoli cells in vitro to DBP. AB - Dibutyl phthalate (DBP) is a peroxisome proliferator which can lead to germ cell loss from Sertoli cells. Collapse of vimentin filaments occurs in Sertoli cells after DBP exposure. Peroxisome proliferator activated receptor alpha (PPARalpha) is a key receptor which could be activated by DBP. The role of PPARalpha in this process was investigated. Results showed that, PPARalpha was activated in DBP exposed Sertoli cells, GW6471 inhibited the activity of PPARalpha, phosphorylation level of vimentin and concentration of soluble vimentin was higher in DBP-treated Sertoli cells than GW6471+DBP-treated cells. These results suggest that PPARalpha directly or indirectly mediated phosphorylation of vimentin on Ser 83, and PPARalpha may play an important role in regulating the reorganization of vimentin filaments during exposure of Sertoli cells to DBP. PMID- 25291545 TI - Complement research: the impact of molecular genetics. AB - The structure and function of the complement system, its genetics, its role in the physiological or pathological immune response and in host defence are now being analysed with the powerful techniques of molecular biology. New developments in complement research were discussed at a recent workshop representing the major scientific meeting in this area of immunology. PMID- 25291546 TI - Immunoregulation by iron-binding proteins. AB - Until recently there was little evidence to suggest that iron-binding proteins played any role in immunity beyond that of impeding microbial growth. Now it seems that iron, and its transport and storage proteins transferrin, lactoferrin and ferritin are associated with the major sets of cells of the immune system, and may be able to modulate a variety of immunological functions. Some effects may be linked to cells' requirement for iron for their metabolic activity, while others may be related to the still poorly-understood regulatory effects of metals on immune cells, which may include toxicity. In some instances iron-binding appears to be merely a coincidental property of a protein found to have an immunoregulatory function. It has been suggested, however, that iron-binding could be one important form of immune surveillance. A recent workshop attempted to define more closely our current state of knowledge in this developing area. PMID- 25291544 TI - Amplifying the red-emission of upconverting nanoparticles for biocompatible clinically used prodrug-induced photodynamic therapy. AB - A class of biocompatible upconverting nanoparticles (UCNPs) with largely amplified red-emissions was developed. The optimal UCNP shows a high absolute upconversion quantum yield of 3.2% in red-emission, which is 15-fold stronger than the known optimal beta-phase core/shell UCNPs. When conjugated to aminolevulinic acid, a clinically used photodynamic therapy (PDT) prodrug, significant PDT effect in tumor was demonstrated in a deep-tissue (>1.2 cm) setting in vivo at a biocompatible laser power density. Furthermore, we show that our UCNP-PDT system with NIR irradiation outperforms clinically used red light irradiation in a deep tumor setting in vivo. This study marks a major step forward in photodynamic therapy utilizing UCNPs to effectively access deep-set tumors. It also provides an opportunity for the wide application of upconverting red radiation in photonics and biophotonics. PMID- 25291547 TI - The faithlessness of the immunoglobulin molecule: can monoclonal antibodies ever be monospecific? PMID- 25291548 TI - AIDS as a consequence of la antigen recognition: a closer look. PMID- 25291549 TI - Are anti-arsonate antibody N-segments selected at both the protein and the DNA level? AB - The V-D junctional residue at position 99 of AIJ anti-arsonate antibodies with a major cross-reactive idiotype is invariably a serine. This serine is not encoded in the germline of either the VH or DH gene segments nor can it be generated by intracodonic recombination between VH and DH. It must, therefore, be generated somatically (N segment addition) and selected by antigen. Sequence data indicate that the serine is frequently encoded by the uncommon TCG triplet. Here J. D. Capra and his colleagues discuss several explanations for the repeated appearance of this unusual codon at this position. They conclude that whatever the mechanism, N segment additions are selected at both protein and DNA levels. PMID- 25291550 TI - Monoclonal antibodies to the T cell antigen receptor. PMID- 25291551 TI - The evolution of class I MHC genes. PMID- 25291552 TI - There is more than one interleukin 1. AB - In 1972, Gery and co-workers(1) detected a factor that promotes murine thymocyte proliferation in culture supernatants of human peripheral blood adherent leukocytes. This factor is active across species lines, does not support the growth of interleukin 2 (IL-2)-dependent lymphocyte lines, is produced by monocytic rather than lymphocytic leukocytes, and has subsequently been termed interleukin 1 (IL- 1)(2). More recently, it has become evident that IL-1 activities can be produced by virtually every nucleated cell type and, in addition, IL-1 has been reported to have stimulatory effects on the growth and differentiation of numerous cell types. In this review, Joost Oppenheim and his colleagues discuss the biochemical characteristics, gene cloning, cell sources, biological properties and actions of IL-1, and give reasons why this pleitotropic, nonspecific hormone-like cytokine is of considerable concern to immunologists. PMID- 25291553 TI - Cytomegalovirus - its cellular immunology and biology. AB - The biology of persistent virus infections presents many intriguing questions, which extend well beyond classical virology into molecular and cell biology and immunology. Here, Patrick Sissons and his colleagues review the current state of knowledge of the biology and immunology of one particular medically important persistent human virus - human cytomegalovirus (HCMV) and they discuss insights into the normal and pathological virus-host relationship provided by recent work both on HCMV itself, and on its murine counterpart mouse cytomegalovirus (MCMV). PMID- 25291556 TI - Potential of microneedles in enhancing delivery of photosensitising agents for photodynamic therapy. AB - Photodynamic therapy can be used in the treatment of pre-malignant and malignant diseases. It offers advantages over other therapies currently used in the treatment of skin lesions including avoidance of damage to surrounding tissue and minimal or no scarring. Unfortunately, systemic delivery of photosensitising agents can result in adverse effects, such as prolonged cutaneous photosensitivity; while topical administration lacks efficacy in the clearance of deeper skin lesions and those with a thick overlying keratotic layer. Therefore, enhancement of conventional photosensitiser delivery is desired. However, the physicochemical properties of photosensitising agents, such as extreme hydrophilicity or lipophilicity and large molecular weights make this challenging. This paper reviews the potential of microneedles as a viable method to overcome these delivery-limiting physicochemical characteristics and discusses the current benefits and limitations of solid, dissolving and hydrogel-forming microneedles. Clinical studies in which microneedles have successfully improved photodynamic therapy are also discussed, along with benefits which microneedles offer, such as precise photosensitiser localisation, painless application and reduction in waiting times between photosensitiser administration and irradiation highlighted. PMID- 25291557 TI - Oppositionality and sympathetic skin response in adolescents: specific associations with the headstrong/hurtful dimension. AB - Oppositionality encompasses distinct dimensions, and few studies have investigated the validity of such distinctions from a pathophysiological perspective. Our aim was to investigate the association between sympathetic skin responses (SSR) and distinct oppositional dimensions in a community sample of adolescents. Forty adolescents aged 13.84+/-1.46 years participated in this study. Oppositionality was measured by externalizing behavior and bullying scores (dependent variables), while SSR was recorded by electrical changes at the skin level (independent variables). Results showed that increased SSRs were associated with oppositionality; however, these associations were specific to the headstrong/hurtful dimension. Further exploratory analyses demonstrated that increased SSRs were associated with several types of headstrong/hurtful behaviors and underscore the importance of the first aversive stimuli to differentiate groups with low and high headstrong/hurtful behaviors. There were no differences between groups regarding time until habituation. This study provides insights about how dysfunctions in autonomic balance may contribute to the emergence of oppositional behavior among adolescents. PMID- 25291558 TI - The "Wagshurst study": p.Val40Ile transthyretin gene variant causes late-onset cardiomyopathy. AB - BACKGROUND: Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant. METHODS AND RESULTS: This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and (99m)Tc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by (99m)Tc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade (n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0-108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%. CONCLUSIONS: This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long term survival rates. PMID- 25291559 TI - Analysis of the difference in the course of the lingual arteries caused by tongue position change. AB - OBJECTIVES/HYPOTHESIS: To explore the difference in the course of the lingual arteries between the tongue in the fully extended position and in the resting position in obstructive sleep apnea hypopnea syndrome (OSAHS) patients. STUDY DESIGN: Prospective nonrandomized study. METHODS: Seventeen patients with OSAHS were included in the study. Each patient received two lingual artery computed tomography angiography (CTA) examinations. For the first CTA examination, each subject was requested to keep the mouth closed with the tongue in a resting position. For the second CTA examination, each subject was asked to keep the mouth open with the tongue in a fully extended position. The difference in the distances between the bilateral lingual arteries and the depths of the lingual artery beneath the lingual surface, based on three reference marks, was analyzed with the tongue in a resting and extended position using the CTA images. RESULTS: Both the depths of the lingual artery beneath the lingual surface and the distances between the bilateral lingual arteries based on three reference marks in the fully extended position were all significantly smaller than those in the resting position (P < .01 or .05). CONCLUSION: Performing lingual artery CTA on OSAHS patients with the tongue in the fully extended position preoperatively has higher sensitivity and specificity in predicting the course of the lingual artery during surgery because the mouth is open and the tongue is fully extended forward during midline glossectomy. PMID- 25291562 TI - Journey in Thick Wood: Childhood: Henry Norman Bethune. PMID- 25291563 TI - Efforts mount to curb carbapenem-resistant infections. PMID- 25291571 TI - Reconsidering isolation precautions for endemic methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. PMID- 25291572 TI - Sepsis mandates: improving inpatient care while advancing quality improvement. PMID- 25291573 TI - A piece of my mind. Healthy but harmed. PMID- 25291574 TI - Expanding the options for confronting pandemic influenza. PMID- 25291575 TI - Gastrointestinal endoscopes: a need to shift from disinfection to sterilization? PMID- 25291576 TI - Contemporary challenges to human health: infectious disease theme issue. PMID- 25291578 TI - Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial. AB - IMPORTANCE: The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine. OBJECTIVES: To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui). DESIGN, SETTING, AND PARTICIPANTS: Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 1 year previously with the Vietnam vaccine and 565 vaccine-naive adults. INTERVENTIONS: Participants who were previously vaccinated with 90 ug of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 ug of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 ug [n = 55 with MF59 and n = 59 without], 7.5 ug [n = 51 with MF59 and n = 57 without], 15 ug [n = 48 with MF59 and n = 44 without], 45 ug [n = 47 with MF59 and n = 47 without], or 90 ug [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28. MAIN OUTCOMES AND MEASURES: The primary immunogenicity outcome was hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events. RESULTS: Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine ("boosting"); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 ug of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95% CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 ug (GMT, 28.5; 95% CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 ug plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 ug of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups. CONCLUSIONS AND RELEVANCE: Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00680069. PMID- 25291577 TI - Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of use with MF59 adjuvant: a randomized clinical trial. AB - IMPORTANCE: Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China. OBJECTIVE: To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014. INTERVENTIONS: The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 ug of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700). MAIN OUTCOMES AND MEASURES: Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer >=40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7. RESULTS: Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 ug plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 ug of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 ug doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant. CONCLUSIONS AND RELEVANCE: Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01938742. PMID- 25291579 TI - Prevalence of antimicrobial use in US acute care hospitals, May-September 2011. AB - IMPORTANCE: Inappropriate antimicrobial drug use is associated with adverse events in hospitalized patients and contributes to the emergence and spread of resistant pathogens. Targeting effective interventions to improve antimicrobial use in the acute care setting requires understanding hospital prescribing practices. OBJECTIVE: To determine the prevalence of and describe the rationale for antimicrobial use in participating hospitals. DESIGN, SETTING, AND PARTICIPANTS: One-day prevalence surveys were conducted in acute care hospitals in 10 states between May and September 2011. Patients were randomly selected from each hospital's morning census on the survey date. Data collectors reviewed medical records retrospectively to gather data on antimicrobial drugs administered to patients on the survey date and the day prior to the survey date, including reasons for administration, infection sites treated, and whether treated infections began in community or health care settings. MAIN OUTCOMES AND MEASURES: Antimicrobial use prevalence, defined as the number of patients receiving antimicrobial drugs at the time of the survey divided by the total number of surveyed patients. RESULTS: Of 11,282 patients in 183 hospitals, 5635 (49.9%; 95% CI, 49.0%-50.9%) were administered at least 1 antimicrobial drug; 77.5% (95% CI, 76.6%-78.3%) of antimicrobial drugs were used to treat infections, most commonly involving the lower respiratory tract, urinary tract, or skin and soft tissues, whereas 12.2% (95% CI, 11.5%-12.8%) were given for surgical and 5.9% (95% CI, 5.5%-6.4%) for medical prophylaxis. Of 7641 drugs to treat infections, the most common were parenteral vancomycin (1103, 14.4%; 95% CI, 13.7%-15.2%), ceftriaxone (825, 10.8%; 95% CI, 10.1%-11.5%), piperacillin tazobactam (788, 10.3%; 95% CI, 9.6%-11.0%), and levofloxacin (694, 9.1%; 95% CI, 8.5%-9.7%). Most drugs administered to treat infections were given for community onset infections (69.0%; 95% CI, 68.0%-70.1%) and to patients outside critical care units (81.6%; 95% CI, 80.4%-82.7%). The 4 most common treatment antimicrobial drugs overall were also the most common drugs used for both community-onset and health care facility-onset infections and for infections in patients in critical care and noncritical care locations. CONCLUSIONS AND RELEVANCE: In this cross-sectional evaluation of antimicrobial use in US hospitals, use of broad-spectrum antimicrobial drugs such as piperacillin tazobactam and drugs such as vancomycin for resistant pathogens was common, including for treatment of community-onset infections and among patients outside critical care units. Further work is needed to understand the settings and indications for which reducing antimicrobial use can be most effectively and safely accomplished. PMID- 25291581 TI - Fever in critical neurologic illness. PMID- 25291580 TI - New Delhi metallo-beta-lactamase-producing carbapenem-resistant Escherichia coli associated with exposure to duodenoscopes. AB - IMPORTANCE: Carbapenem-resistant Enterobacteriaceae (CRE) producing the New Delhi metallo-beta-lactamase (NDM) are rare in the United States, but have the potential to add to the increasing CRE burden. Previous NDM-producing CRE clusters have been attributed to person-to-person transmission in health care facilities. OBJECTIVE: To identify a source for, and interrupt transmission of, NDM-producing CRE in a northeastern Illinois hospital. DESIGN, SETTING, AND PARTICIPANTS: Outbreak investigation among 39 case patients at a tertiary care hospital in northeastern Illinois, including a case-control study, infection control assessment, and collection of environmental and device cultures; patient and environmental isolate relatedness was evaluated with pulsed-field gel electrophoresis (PFGE). Following identification of a likely source, targeted patient notification and CRE screening cultures were performed. MAIN OUTCOMES AND MEASURES: Association between exposure and acquisition of NDM-producing CRE; results of environmental cultures and organism typing. RESULTS: In total, 39 case patients were identified from January 2013 through December 2013, 35 with duodenoscope exposure in 1 hospital. No lapses in duodenoscope reprocessing were identified; however, NDM-producing Escherichia coli was recovered from a reprocessed duodenoscope and shared more than 92% similarity to all case patient isolates by PFGE. Based on the case-control study, case patients had significantly higher odds of being exposed to a duodenoscope (odds ratio [OR], 78 [95% CI, 6.0-1008], P < .001). After the hospital changed its reprocessing procedure from automated high-level disinfection with ortho-phthalaldehyde to gas sterilization with ethylene oxide, no additional case patients were identified. CONCLUSIONS AND RELEVANCE: In this investigation, exposure to duodenoscopes with bacterial contamination was associated with apparent transmission of NDM producing E coli among patients at 1 hospital. Bacterial contamination of duodenoscopes appeared to persist despite the absence of recognized reprocessing lapses. Facilities should be aware of the potential for transmission of bacteria including antimicrobial-resistant organisms via this route and should conduct regular reviews of their duodenoscope reprocessing procedures to ensure optimal manual cleaning and disinfection. PMID- 25291582 TI - Intensely pruritic eruption in a college student. PMID- 25291583 TI - Interferon-gamma release assays for the evaluation of tuberculosis infection. PMID- 25291584 TI - Tobacco use and oral HPV-16 infection. PMID- 25291585 TI - Antipsychotic medications for schizophrenia. PMID- 25291586 TI - Antipsychotic medications for schizophrenia. PMID- 25291587 TI - Use of hemodynamic algorithm after gastrointestinal surgery. PMID- 25291588 TI - Antipsychotic medications for schizophrenia--reply. PMID- 25291589 TI - Use of hemodynamic algorithm after gastrointestinal surgery. PMID- 25291590 TI - Primary care physician-led health reform. PMID- 25291591 TI - Use of hemodynamic algorithm after gastrointestinal surgery--reply. PMID- 25291592 TI - Primary care physician-led health reform--reply. PMID- 25291597 TI - Antibiotic-resistant micrococcic infections. PMID- 25291598 TI - JAMA patient page. Influenza vaccine. PMID- 25291599 TI - Crystal structure of the vitamin B3 transporter PnuC, a full-length SWEET homolog. AB - PnuC transporters catalyze cellular uptake of the NAD+ precursor nicotinamide riboside (NR) and belong to a large superfamily that includes the SWEET sugar transporters. We present a crystal structure of Neisseria mucosa PnuC, which adopts a highly symmetrical fold with 3+1+3 membrane topology not previously observed in any protein. The high symmetry of PnuC with a single NR bound in the center suggests a simple alternating-access translocation mechanism. PMID- 25291600 TI - Effect of the bread-making process on zearalenone levels. AB - The effects of the bread-making process including fermentation with Saccharomyces cerevisiae and lactic acid bacteria (Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus acidophilus and Lactobacillus fermentum) and baking at 200 degrees C on zearalenone (ZEA) levels were investigated. Standard solutions of ZEA were added to flour and then loaves of bread were prepared. Sourdough and three types of yeast including active dry yeast, instant dry yeast and compressed yeast were used for the fermentation of dough. ZEA levels in flour, dough and bread were determined by HPLC with fluorescence detection after extraction and clean-up on an immunoaffinity column. The highest reduction in levels of ZEA was found in the first fermentation (first proof), while the lowest reduction was observed in the baking stage. In addition, the results showed that compressed yeast had the maximum reduction potential on ZEA levels even at the baking stage. PMID- 25291601 TI - Synthesis, physicochemical characterization and membrane interactions of a homologous series of N-acylserotonins: Bioactive, endogenous conjugates of serotonin with fatty acids. AB - N-Acylserotonins (NASTs), present in the mammalian gastro-intestinal tract and central nervous tissues, exhibit significant biological and pharmacological activities. In the present study, a homologous series of NASTs have been synthesized and characterized. Differential scanning calorimetric studies show that in the dry and hydrated states the transition temperatures, enthalpies, and entropies of NASTs exhibit odd-even alternation. Both odd and even chain length NASTs independently display linear dependence of the transition enthalpies and entropies on the chain length under dry as well as hydrated conditions, suggesting that the molecular packing and intermolecular interactions in each series (odd or even) are likely to be similar for NASTs with different acyl chain lengths in the dry state as well as in the hydrated state. Powder X-ray diffraction studies indicated that the incremental increase in the d-spacing per CH2group is 1.023 A, suggesting that the lipid acyl chains are most likely packed in an interdigitated fashion. Results of computational studies are consistent with this and suggest that the acyl chains of the NASTs are tilted with respect to the bilayer normal. Incorporation of N-myristoylserotonin (NMST) into dimyristoylphosphatidylcholine (DMPC) membranes did not significantly affect the phase transition properties at low mole fractions (1-5 mol%), although distinct decrease in the chain-melting transition temperature and increase in the pretransition temperature were observed at higher contents (7.5-30 mol%), suggesting that NMST increases the stability of the tilted gel phase (L(beta)') but destabilizes the ripple phase (P(beta)'). These observations provide a thermodynamic basis for understanding the functional role of NASTs in their parent tissues. PMID- 25291603 TI - Antimicrobial resistance: we need better stewardship in all sectors. PMID- 25291602 TI - Membrane translocation assay based on proteolytic cleavage: application to diphtheria toxin T domain. AB - The function of diphtheria toxin translocation (T) domain is to transfer the catalytic domain across the endosomal membrane upon acidification. The goal of this study was to develop and apply an in vitro functional assay for T domain activity, suitable for investigation of structure-function relationships of translocation across lipid bilayers of various compositions. Traditionally, T domain activity in vitro is estimated by measuring either conductance in planar lipid bilayers or the release of fluorescent markers from lipid vesicles. While an in vivo cell death assay is the most relevant to physiological function, it cannot be applied to studying the effects of pH or membrane lipid composition on translocation. Here we suggest an assay based on cleavage of the N-terminal part of T domain upon translocation into protease-loaded vesicles. A series of control experiment was used to confirm that cleavage occurs inside the vesicle and not as the result of vesicle disruption. Translocation of the N-terminus of the T domain is shown to require the presence of a critical fraction of anionic lipids, which is consistent with our previous biophysical measurements of insertion. Application of the proposed assay to a series of T domain mutants correlated well with the results of cytotoxicity assay. PMID- 25291604 TI - Rural health care: problems and solutions. PMID- 25291606 TI - Negotiating the radiologically isolated syndrome. AB - Multiple sclerosis, always challenging, hands down a particular gauntlet with the concept of the radiologically isolated syndrome. This article discusses what it is, recent developments in the field and how these patients should be managed. PMID- 25291607 TI - Is 'sinus' pain really sinusitis? AB - So-called 'sinus pain' is a common complaint in GP and ear, nose and throat clinics, and patients often receive treatment with antibiotics and decongestants. Recent evidence suggests that facial pain may not be related to the sinuses at all and that doctors may have to rethink their prescribing strategy. PMID- 25291608 TI - Persistent (unexplained) physical symptoms: evidence-based highlights. AB - Medically unexplained symptoms account for up to 50% of specialist referrals in the NHS, but because they tend to be seen in specialist clinics, health-care staff may not be aware of the variety of presentations and commonalties between different medically unexplained symptoms. This article gives an overview of this field. PMID- 25291609 TI - Abnormal antibodies: what do you do? AB - Systemic autoimmune rheumatic diseases encompass a vast array of autoantibodies which are very useful to confirm a suspected diagnosis. This article gives an overview of the most common autoantibodies, how they are tested and the significance of a positive test in a clinical context. PMID- 25291610 TI - Awareness under general anaesthesia. AB - Awareness under anaesthesia is a rare but important phenomenon which has become a source of fear - and of fascination - to the public and anaesthetists alike. This article discusses the incidence, aetiology, sequelae and prevention of awareness. PMID- 25291611 TI - Management of abdominal aortic aneurysms in the UK. AB - Outcomes of abdominal aortic aneurysm repair are improving in the UK, at least in part as a result of vascular specialization, the reconfiguration of services to dedicated vascular centres and the advent of the national screening programme. PMID- 25291612 TI - Why do medical trainees take time out of their specialty training programmes? AB - Postgraduate medical trainees may take time out of programme for personal or professional reasons which can delay completion of training. This survey of out of programme trainees in England explores a phenomenon that impacts significantly upon medical careers and workforce planning. PMID- 25291613 TI - Traveller's molluscum. PMID- 25291614 TI - A white man with a very African form of hereditary amyloid cardiomyopathy. PMID- 25291615 TI - Emergency bedside ultrasound in a case of chest pain and collapse. PMID- 25291616 TI - Nicorandil-associated skin necrosis around a stoma site. PMID- 25291618 TI - Harvey Cushing: father of modern neurosurgery. PMID- 25291619 TI - Is central venous pressure a reliable indicator of fluid responsiveness in the critically ill? PMID- 25291620 TI - Transcriptional adaptation of Shigella flexneri during adherence to epithelial cells. AB - Shigella adhesion to host cells is a transitional stage from an extracellular to an intracellular environment. However, the dynamic adaptations of Shigella during adhesion are poorly understood. To address this, we performed the first transcriptome analysis of Shigella flexneri 2457T during adhesion. A total of 1,757 genes were differentially regulated (>twofold). The majority of plasmid borne ipa-mxi-spa locus genes were downregulated, indicating these virulence genes were strictly regulated after successful adhesion. Altered expression of genes involved in stress response indicates that adherent S. flexneri encountered envelope stress and oxidative stress. Shigella flexneri also experienced reduced energy production during adherence. Transcript profiling and cell culture assays using glpD and glpK mutants showed that enhancement of glycerol catabolism were related with adhesion ability of S. flexneri. In addition, regulation of expression of some ionic transport system may be required for S. flexneri adhesion. Expression levels of 26 genes were further examined using qRT-PCR, which were congruent with transcriptome data. A comparison with expression profile during intracellular growth revealed major differences in genes involved in translation, surface modification, and utilization of carbon and iron. These results contribute to the knowledge of the adaptation mechanisms of S. flexneri during adhesion. PMID- 25291622 TI - Physical map of the human HLA region. PMID- 25291621 TI - Evaluation of commercial ELISA and RIA for measuring porcine C-peptide: implications for research. AB - BACKGROUND: Pre-clinical demonstration of porcine islet graft function is necessary to support the clinical transplantation of pig islets. C-peptide concentration is an especially useful marker of insulin secretion, because its measurement is not confounded by the presence of exogenous insulin. To measure porcine C-peptide (PCP), researchers in the field exclusively used the Millipore (previously Linco Research) radioimmunoassay (RIA) until 2011, when Mercodia released an alternative enzyme-linked immunosorbent assay (ELISA). (At the end of 2013, the Millipore RIA was withdrawn from the market for commercial reasons.) In our current study, to directly compare these two assays, we performed validation studies on each. We also performed interlaboratory comparisons. Then, to determine the level of agreement between the assays, we analyzed the porcine serum C-peptide concentration measurement results obtained from each assay. METHODS: Using pre-established method validation acceptance criteria, we determined and evaluated the detection limit, sensitivity, precision, linearity, and recovery of the two commercially available PCP assays described above (ELISA and RIA). After validation requirements were met, we performed a method comparison by determining C-peptide concentration in 60 serum samples collected from 31 normal, healthy adult Landrace pigs in the fasting state; a subset underwent an intravenous glucose challenge test, to stimulate the typical physiologic range of C-peptide. All analyses were performed according to manufacturer instructions. To compare the assays, we used Deming regression analysis. RESULTS: Both assays met acceptance criteria. The RIA had a sensitivity of 0.1 ng/ml; it was linear to 2.9 ng/ml. The ELISA had a detection limit of 0.03 ng/ml; it was linear to 1.2 ng/ml. Recovery ranged from 89 to 113% with both assays. The coefficient of variability was 8% in interlaboratory comparisons. Deming regression analysis directly comparing both assays revealed significant correlation between them (before log-transformation: R2=0.9803, P<0.0001; after log-transformation: R2=0.9727, P<0.0001). Measured C-peptide concentration was lower with the ELISA than with the RIA; individual measurements plotted against the averages of the pair demonstrated that the variability from the mean strongly depended on increasing concentration. To transform ELISA data, we used the standard regression equation y=2.191x+0.1119 and the log-transformed regression equation y=0.8101x+0.7502. Both the transformed and the log-transformed (exponential) values approximated the measured RIA levels with a high degree of accuracy in the concentration range of 0 to 1.0 ng/ml. CONCLUSIONS: Porcine C peptide concentration can be reliably measured in porcine serum samples with either assay (ELISA or RIA). However, the C-peptide results generated by these two assays are not equivalent. Therefore, assay bias must be considered before directly comparing pre-clinical studies that used either of these assays. We determined that harmonization between the assays is appropriate in a specific concentration range. Outside of that range, we do not know whether a linear correction function can be more broadly applied. The variation between the two assays may be related to calibration or reagent factors. To determine which assay is truly more accurate and to effectively compare interlaboratory results, we will need a traceable reference standard. PMID- 25291623 TI - Erratum: Mapping the autoimmunizing epitopes of acetylcholine receptors. PMID- 25291624 TI - Strategies for codon usage in human VH families. PMID- 25291625 TI - The immunobiology ofvitamin D William F.C. Rigby. AB - Vitamin D compounds are important components of the endocrine system - being largely responsible for calcium metabolism. But the most active member of the group (calcitriol)] also interacts extensively with the immune system, as William Rigby reviews, here. While an immunological role has not yet been definitively identified, calcitriol appears to act at sites of iflammation to limit T-cell activation and activate macrophage cytotoxicity. PMID- 25291627 TI - Amphipathic lignin derivatives to accelerate simultaneous saccharification and fermentation of unbleached softwood pulp for bioethanol production. AB - Amphipathic lignin derivatives (A-LDs) were already demonstrated to improve enzymatic saccharification of lignocellulose. Based on this knowledge, two kinds of A-LDs prepared from black liquor of soda pulping of Japanese cedar were applied to a fed-batch simultaneous saccharification and fermentation (SSF) process for unbleached soda pulp of Japanese cedar to produce bioethanol. Both lignin derivatives slightly accelerated yeast fermentation of glucose but not inhibited it. In addition, ethanol yields based on the theoretical maximum ethanol production in the fed-batch SSF process was increased from 49% without A LDs to 64% in the presence of A-LDs. PMID- 25291628 TI - Annealed Au-assisted epitaxial growth of si nanowires: control of alignment and density. AB - The epitaxial growth of 1D nanostructures is of particular interest for future nanoelectronic devices such as vertical field-effect transistors because it directly influences transistor densities and 3D logic or memory architectures. Silicon nanowires (SiNWs) are a particularly important 1D nanomaterial because they possess excellent electronic and optical properties. What is more, the scalable fabrication of vertically aligned SiNW arrays presents an opportunity for improved device applications if suitable properties can be achieved through controlling the alignment and density of SiNWs, yet this is something that has not been reported in the case of SiNWs synthesized from Au films. This work therefore explores the controllable synthesis of vertically aligned SiNWs through the introduction of an annealing process prior to growth via a Au-catalyzed vapor liquid-solid mechanism. The epitaxial growth of SiNWs was demonstrated to be achievable using SiCl4 as the Si precursor in chemical vapor deposition, whereas the alignment and density of the SiNWs could be controlled by manipulating the annealing time during the formation of Au nanoparticles (AuNPs) from Au films. During the annealing process, gold silicide was observed to form on the interface of the liquid-phase AuNPs, depending on the size of the AuNPs and the annealing time. This work therefore makes a valuable contribution to improving nanowire based engineering by controlling its alignment and density as well as providing greater insight into the epitaxial growth of 1D nanostructures. PMID- 25291629 TI - Nanoimprint lithography of Al nanovoids for deep-UV SERS. AB - Deep-ultraviolet surface-enhanced Raman scattering (UV-SERS) is a promising technique for bioimaging and detection because many biological molecules possess UV absorption lines leading to strongly resonant Raman scattering. Here, Al nanovoid substrates are developed by combining nanoimprint lithography of etched polymer/silica opal films with electron beam evaporation, to give a high performance sensing platform for UV-SERS. Enhancement by more than 3 orders of magnitude in the UV-SERS performance was obtained from the DNA base adenine, matching well the UV plasmonic optical signatures and simulations, demonstrating its suitability for biodetection. PMID- 25291630 TI - Overnight improvements in two REM sleep-sensitive tasks are associated with both REM and NREM sleep changes, sleep spindle features, and awakenings for dream recall. AB - Memory consolidation is associated with sleep physiology but the contribution of specific sleep stages remains controversial. To clarify the contribution of REM sleep, participants were administered two REM sleep-sensitive tasks to determine if associated changes occurred only in REM sleep. Twenty-two participants (7 men) were administered the Corsi Block Tapping and Tower of Hanoi tasks prior to and again after a night of sleep. Task improvers and non-improvers were compared for sleep structure, sleep spindles, and dream recall. Control participants (N = 15) completed the tasks twice during the day without intervening sleep. Overnight Corsi Block improvement was associated with more REM sleep whereas Tower of Hanoi improvement was associated with more N2 sleep. Corsi Block improvement correlated positively with %REM sleep and Tower of Hanoi improvement with %N2 sleep. Post hoc analyses suggest Tower of Hanoi effects-but not Corsi Block effects-are due to trait differences. Sleep spindle density was associated with Tower of Hanoi improvement whereas spindle amplitude correlated with Corsi Block improvement. Number of REM awakenings for dream reporting (but not dream recall per se) was associated with Corsi Block, but not Tower of Hanoi, improvement but was confounded with REM sleep time. This non-replication of one of 2 REM-sensitive task effects challenges both 'dual-process' and 'sequential' or 'sleep organization' models of sleep-dependent learning and points rather to capacity limitations on REM sleep. Experimental awakenings for sampling dream mentation may not perturb sleep-dependent learning effects; they may even enhance them. PMID- 25291632 TI - Fish cognition. PMID- 25291631 TI - Neocentromeres. PMID- 25291633 TI - Lithocytes are transported along the ciliary surface to build the statolith of ctenophores. PMID- 25291634 TI - Motor, not visual, encoding of potential reach targets. PMID- 25291635 TI - Speciation: the strength of natural selection driving reinforcement. AB - Our understanding of how natural selection drives the speciation process remains a mystery. A recent study shows how selection for flower color differences causes the evolution of reproductive isolation between two plant species of the genus Phlox. PMID- 25291636 TI - Neural coding: sparse but on time. AB - To code information efficiently, sensory systems use sparse representations. In a sparse code, a specific stimulus activates only few spikes in a small number of neurons. A new study shows that the temporal pattern across sparsely activated neurons encodes information, suggesting that the sparse code extends into the time domain. PMID- 25291637 TI - Natural selection: it's a many-small world after all. AB - Understanding adaptive phenotypic change and its genetic underpinnings is a major challenge in biology. Threespine stickleback fish, experimentally exposed to divergent semi-natural environments, reveal that adaptive diversification can happen readily, affects many traits and involves numerous genetic loci across the genome. PMID- 25291638 TI - Pericentrin: critical for spindle orientation. AB - Mutations in the pericentrin (PCNT) gene cause Majewski osteodysplastic primordial dwarfism type II (MOPDII). Recent work reveals that a discrete set of centrosome proteins require PCNT for their robust localization to mitotic spindle poles. Critically, this complex is crucial for mitotic spindle orientation and involved in the pathogenesis of MOPDII. PMID- 25291639 TI - Neurodevelopment: a novel role for activity in shaping retinal circuits. AB - The number of synaptic inputs onto retinal bipolar cells is influenced by transmitter release from neighboring bipolar cells, implicating a new form of population-based retrograde plasticity in the development of these neural circuits. PMID- 25291640 TI - Genetic conflicts: stronger centromeres win tug-of-war in female meiosis. AB - Female meiosis presents unique opportunities for competition between chromosomes for evolutionary dominance. A new study reveals that centromere strength dictates meiotic success, driving karyotype evolution and reproductive isolation in mice. PMID- 25291641 TI - Mitotic kinesins: a reason to delve into kinesin-12. AB - The failure of kinesin-targeting cancer drugs is thought to result from functional redundancy of mitotic kinesins. A new study provides mechanistic insights into kinesin-12 that help to explain its targeting to kinetochore fibers and its ability to compensate for inhibition of kinesin-5. PMID- 25291642 TI - Developmental neuroscience: how twitches make sense. AB - Animals refine the mechanics of their own bodies through sensorimotor feedback produced by physical interactions with the environment. A new study sheds light on how developing mammals may use sensations produced by spontaneous movements made during sleep to construct their sensorimotor maps. PMID- 25291644 TI - Therapeutic promise maintained. AB - Cyclosporin A (CS-A) is a fungal metabolite, one of many cyclosporins with a narrow spectrum of antibiotic activity, but one with profound immunosuppressive effects on cell-mediated cytolysis in vitro, graft v. host reactions and delayed type hypersensitivity. An international symposium on CS-A was held in Cambridge on 16-18th September 1981. PMID- 25291645 TI - Allo-I- J antigens in suppression of DTH to H-2 subregion antigens. PMID- 25291646 TI - This letter was sent to Dr Liew, who replied as follows. PMID- 25291647 TI - Some thoughts on idiotypic networks and immunoregulation. PMID- 25291643 TI - Multiciliated cells. AB - Cilia are microtubule-based projections that serve a wide variety of essential functions in animal cells. Defects in cilia structure or function have recently been found to underlie diverse human diseases. While many eukaryotic cells possess only one or two cilia, some cells, including those of many unicellular organisms, exhibit many cilia. In vertebrates, multiciliated cells are a specialized population of post-mitotic cells decorated with dozens of motile cilia that beat in a polarized and synchronized fashion to drive directed fluid flow across an epithelium. Dysfunction of human multiciliated cells is associated with diseases of the brain, airway and reproductive tracts. Despite their importance, multiciliated cells are relatively poorly studied and we are only beginning to understand the mechanisms underlying their development and function. Here, we review the general phylogeny and physiology of multiciliation and detail our current understanding of the developmental and cellular events underlying the specification, differentiation and function of multiciliated cells in vertebrates. PMID- 25291648 TI - EBV and rheumatoid arthritis. PMID- 25291649 TI - HLA-and Gm-linked genes and antigen non-specific immunoregulation. PMID- 25291650 TI - Challenges to Nature's transplant. PMID- 25291651 TI - Dextran hypersensitivity. AB - Dextran, a common plasma substitute, sometimes induces life-threatening hypersensitivity reactions. In this article Wolfgang Richter and Harriet Hedin discuss recent evidence that these Type III anaphylactic reactions, caused by natural antibodies, can be abolished by pretreatment o f patients with monovalent hapten dextran. PMID- 25291652 TI - T-cell membrane antigens associated with cytotoxic function. AB - In the past few years the first steps have been taken towards an understanding of the molecular basis of T-cell-mediated cytotoxicity. Particular attention has been paid to the part played in cytoxicity by idiotype-bearing antigen-receptors and other molecules on the T-cell surface. This article reviews these studies and focuses on the information obtained from studies on the inhibition of cytotoxic T cells with antisera or monoclonal antibodies directed against molecules on their surface. PMID- 25291653 TI - Regulation of human B-lymphocyte function in secondary humoral immune responses. AB - Here Ronald Stevens discusses recent work in which immunization of humans with tetanus toxoid in vivo has been combined with analyses of specific antibody production in vitro to study the dynamics of B-lymphocyte function in secondary humoral immune responses. These studies have shown that multiple B-cell subsets are generated following immunization, some of which can be rendered hyporesponsive in vivo by repetitive immunizations or in vitro by treatment with antigen. PMID- 25291655 TI - Glycosyltransferases and T-cell recognition. AB - Recent studies suggest that the AIIIC locus controls families of carbohydrate, as well as protein, histocompatibility antigens. In this article Christopher Parish and his colleagues discuss the molecular and genetic implications of these findings and present the hypothesis that the glycosyltransferase enzymes which construct the carbohydrate histocompatibility antigens may be involved in T-cell recognition. PMID- 25291656 TI - Immunodeficiency in the clinic and laboratory. PMID- 25291657 TI - The problem of self tolerance in F1 animals. PMID- 25291658 TI - B-cell differentiation in vivo. PMID- 25291659 TI - The enigma of oligoclonal immunoglobulin G in cerebrospinal fluid from multiple sclerosis patients. AB - The cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) contains immunoglobulin G (IgG) of restricted heterogeneity (oligoclonal IgG). Philip Paterson and Caroline Whitacre here review the core evidence that IgG in MS patients and normal subjects is synthezised intracerebrally and that most of it does- not have demonstrable antigenic specificity. They advance the view that the enigmatic oligoclonal IgG may be a product of B cells which are non-specifically activated by mitogenic stimuli originating within injured CNS tissue as a consequence of the MS process. PMID- 25291661 TI - Sporozoite antigen's novel structure. PMID- 25291660 TI - Inter-relationships between proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III and plasma apolipoprotein B-48 transport in obese subjects: a stable isotope study in the postprandial state. AB - Postprandial lipaemia, due to elevated plasma apolipoprotein (apo) B-48 concentrations, contributes to increased cardiovascular (CV) risk in obesity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apoC-III may play a role in regulating triacylglycerol-rich lipoprotein (TRL)-apoB-48 metabolism. We investigated the associations between plasma PCSK9 and apoC-III concentrations and the kinetics of apoB-48 in obese subjects. Seventeen obese subjects were given an oral fat load. ApoB-48 tracer/tracee ratios were measured after an intravenous 2H3-leucine administration using GC-MS. Kinetic parameters, including secretion and fractional catabolic rates (FCRs), were derived using a multi compartmental model. Plasma PCSK9 and apoC-III concentrations were significantly and positively (P<0.05 in all) associated with the total area-under-curve (AUC) and incremental AUC for apoB-48 and inversely with TRL-apoB-48 FCR. Plasma PCSK9 and apoC-III concentrations were not correlated (P>0.05 in all) with basal secretion or the number of TRL-apoB-48 secreted over the postprandial period. In the stepwise regression analysis, plasma PCSK9 was the best predictor of the total and incremental AUCs for plasma apoB-48 and the FCR of TRL-apoB-48. The association between plasma PCSK9 and apoC-III and TRL-apoB-48 FCR remained significant (P<0.05 in all) after adjusting for age, homoeostasis model assessment (HOMA) score, hepatic lipase or lipoprotein lipase (LPL). In a multiple regression model, 31% of variance in TRL-apoB-48 FCR was accounted for by plasma PCSK9 and apoC-III concentrations (adjusted R2=0.306, P<0.05). However, their associations with TRL-apoB-48 FCR were not independent of each other. Our results suggest that the catabolism of TRL-apoB-48 in the postprandial state may be co-ordinated by PCSK9 and apoC-III in obese individuals. PMID- 25291662 TI - Immunotechnology and industry. AB - In 1980, the year Immunology Today began, around 80 advertisements in Science offered jobs to postdoctoral scientists with experience of different aspects of immunology. 80 % of them were in academic institutions - universities, medical schools, research units and the like - while the remaining 20% were in industry. In 1982 the corresponding number of job offers was around 120 and industry supplied fully half of them - an indication of a three-fold increase in total recruitment. PMID- 25291663 TI - Inevitable and desirable. PMID- 25291664 TI - Too little ... and too late? PMID- 25291665 TI - Commercial vision needed in the kab and dogged finance outside it. PMID- 25291666 TI - Responding to climatic change. PMID- 25291667 TI - Whatever happed to the industry I was told to distrust? PMID- 25291668 TI - Academia to industry: business as usual. PMID- 25291669 TI - The challenge of being useful. PMID- 25291671 TI - Where the jobs have been. PMID- 25291670 TI - Generosity needed in spirit and purse. PMID- 25291673 TI - New forms of antibody probe for the TSH receptor. PMID- 25291672 TI - T-cell antigen receptors: fact and artefact. AB - Much has been written to support the view that T-cell antigen-recognition molecules share idiotypes with immunoglobulin and are encoded in the same VH genes. Here Jacques Miller and his colleagues disbute this view and argue instead, from recent evidence, that the genes for T-cell receptors are entirely different from Ig genes. PMID- 25291674 TI - Dual immunofluorescence - new frontiers in cell analysis and sorting. AB - Investigations of the nature and functions of the immune system and its cell populations have been revolutionized by the techniques of fluorescence-activated cell sorting (FA CS) and flow cytometry. Over the last few years, however, it has become increasingly clear that making only a single immunofluorescence measurement on each cell is not adequate for many investigations of lymphoid cell subpopulations. In this review the authors discuss why adequate resolution of functional subsets will increasingly require multiparameter definition including measurements on two or more fluorescent labels. PMID- 25291675 TI - The complement genes. AB - The structure, organization and control of the expression of complement genes is now being studied at the RNA and DNA levels. This work was prompted by recognized genetic polymorphisms and complement deficiencies in humans and animals. Here Harvey Colten discusses progress towards an understanding of the molecular basis of these variants and abnormalities. PMID- 25291678 TI - Methodological issues in behavioural immunology. AB - Sunrise over the Rincon Mountains revealed a procession of fifty horses groaning under their burden of psychologists and immunologists as a recent desert workshop got under way. The participants later sat, some rather gingerly, around a table to discuss methodological questions central to the new and sometimes embattled field variously called behavioural immunology, psychoneuroimmunology, and neuroimmunomodulation. PMID- 25291677 TI - Comparison of a novel polytitanium chloride coagulant with polyaluminium chloride: coagulation performance and floc characteristics. AB - Polymerized inorganic coagulants are increasingly being used in the water supply and wastewater treatment process, yet there is limited research on the development of polytitanium coagulants. The aim of this study is to synthesize polytitanium chloride (PTC) coagulants and investigate their coagulation behavior and floc characteristics for humic acid removal in comparison to polyaluminum chloride (PAC). The PTC samples with different B (molar ratios of OH/Ti) values were prepared using an instantaneous base-feeding method, employing sodium carbonate as the basification agent. The coagulation efficiency was significantly influenced by different B values. The results suggest that the humic acid removal increased with the increasing B value for PAC, while the inverse trend was observed for PTC. The optimum B value was chosen at 1.0 and 2.0 for PTC and PAC, respectively. Under the optimum coagulant dose and initial solution pH conditions, the PTC coagulant performed better than the PAC coagulant and the floc properties were significantly improved in terms of floc growth rate and floc size. However, the PAC coagulants produced flocs with better floc recoverability than the PTC coagulants. PMID- 25291679 TI - Still more genes in the MHC. AB - The major histocompatibility complex (MHC) encodes three major classes of molecules. Two of these, class I and class II molecules, act as templates to 'present' antigens. Class I molecules, expressed on most cells, are implicated particularly in presentation of antigens to cytotoxic T cells - by cells infected with virus, for example. Class II molecules, encoded by the so-called 'immune response' genes (HLA-D region in man, la in the mouse) are constitutively expressed on certain immunocompetent cells, such as B cells or macrophages, and can be induced on many others with gamma-interferon. Class II molecules generally present antigens to helper T cells and can, therefore, influence subsequent production of specific antibodies. The other major class of molecules in the MHC, class III, includes the complement components C2, C4 and factor B(1). The MHC has intrigued a generation of immunologists and geneticists because of its inordinate polymorphism, but in the past four or five years the field has been plundered by molecular biologists armed with recombinant DNA technology. Just how far this line of investigation has got in understanding the MHC was assessed at a recent conference. PMID- 25291680 TI - CD5-positive B cells in rheumatoid arthritis and chronic lymphocytic leukemia. PMID- 25291681 TI - I-E expression and susceptibility to parasite infection. AB - In most inbred strains of mice, antigen-presenting cells express I-A and I-E antigens (class II major histocompatibility complex antigens), and these antigens are involved in antigen-recognition by T cells. In some strains I-E products are not expressed or aberrantly expressed, yet these mice seem to be immunologically normal. In this article, Don Wassom and his colleagues discuss reports that antigen presented in the context of I-E produces a response which suppresses I-A restricted T-cell proliferation, in relation to their own findings that mice which do express I-E molecules are more susceptible to certain nematode infections than mice which do not express I-E. PMID- 25291682 TI - The antibody combining site: retrospect and prospect. PMID- 25291683 TI - The interleukin-1 receptor. AB - One of the pivotal events in the initiation of inflammatory responses is activation of both resident tissue macrophages at the site of damage and circulating monocytes infiltrating the area. The activated macrophages release a group of factors which influence inflammation and tissue regulation. In this review, Steven Dower and David Urdal centre attention on part of this group of factors; the interleukin-1 system, and in particular the interleukin-1 receptor on target cells. PMID- 25291684 TI - Synthetic peptides: a next generation of vaccines? AB - Of the strategies being considered in the search for new kinds of vaccine, one of the most powerful is the use of synthetic peptides. Here, Michael Steward and Colin Howard discuss recent insights into the nature of antigenicity which influence the use of such peptides, and review the value of peptide immunogens in a variety of diseases. PMID- 25291685 TI - Changes in the immune system during metamorphosis of Xenopus. AB - Profound immunological changes occur as tadpoles metamorphose into adult amphibians. These include the expression of a different antibody repertoire, a lessening of skin graft tolerance, the appearance on leukocytes of class I MHC antigens. Here Martin Flajnik and his colleagues review what is known of these changes in Xenopus and speculate on how they may occur. PMID- 25291692 TI - Characterization and anti-settlement aspects of surface micro-structures from Cancer pagurus. AB - Tuning surface and material properties to inhibit or prevent settlement and attachment of microorganisms is of interest for applications such as antifouling technologies. Here, optimization of nano- and microscale structures on immersed surfaces can be utilized to improve cell removal while reducing adhesion strength and the likelihood of initial cellular attachment. Engineered surfaces capable of controlling cellular behaviour under natural conditions are challenging to design due to the diversity of attaching cell types in environments such as marine waters, where many variations in cell shape, size and adhesion strategy exist. Nevertheless, understanding interactions between a cell and a potential substrate for adhesion, including topographically driven settlement cues, offers a route to designing surfaces capable of controlling cell settlement. Biomimetic design of artificial surfaces, based upon microscale features from natural surfaces, can be utilized as model surfaces to understand cell-surface interactions. The microscale surface features of the carapace from the crustacean Cancer pagurus has been previously found to influence the rate of attachment of particular organisms when compared to smooth controls. However, the nature of microscale topographic features from C. pagurus have not been examined in sufficient detail to allow design of biomimetic surfaces. In this work, the spatial distribution, chemical composition, size and shape descriptors of microscale surface features from C. pagurus are characterized in detail for the first time. Additionally, the influence of topography from C. pagurus on the settlement of marine diatoms is examined under field conditions. PMID- 25291693 TI - Inside the thymus. AB - The thymus has fascinated immunologists since the discovery that it influenced the maturation of T lymphocytes. However, only within the past five years have investigations of the thymus progressed beyond descriptive histology or functional studies performed at the population level. Our closeness to an understanding of the raison d'etre of the thymus was discussed at a recent meeting. PMID- 25291694 TI - A new classification of mouse VH sequences. AB - Renate Dildrop has compared heavy chain variable-region sequences of mouse immunoglobulins at the amino acid level and determined the homology within the coding region of the entire VHgene segment. The resulting homology plot defines seven separate groups of VHgene sequences which differ from the five groups of variable-region sequences in the previous classification of Kabat et al.' and accordfully with the recently identified chromosomal clusters of VHgenes. PMID- 25291695 TI - Primordial MHC function may be best served by monomorphism. PMID- 25291696 TI - Implications for a 'lymphoid adrenal axis'. PMID- 25291697 TI - Physiological role of autoantibodies. PMID- 25291698 TI - A repulsive view of MHC-restriction. AB - Recognition of foreign antigens by T lymphocytes is restricted by molecules of the major histocompatibility complex (MHC). This fact is now a corner-stone of immunology, but little is known about the molecular interactions involved in T cell recognition. Current models attribute MHC molecules with unusual properties, yet biochemically they seem conventional enough proteins. Here Peter Parham offers a reconciliation between the immunological and biochemical findings. PMID- 25291699 TI - Possible mechanism for down-regulation of autoantibody production by auto-anti idiotype. AB - Once it is recognized that antigen and anti-idiotype antibody can both react with idiotype-bearing cells, it becomes apparent that there are certain similarities and differences in the consequences of these interactions. It is therfoore interesting to consider why anti-idiotype antibody might differ from antigen in its effect on cells. Here the authors suggest a possible mechanism for down regulation of auto-antibody production by auto-anti-idiotype. PMID- 25291700 TI - The I-J dilemma: new developments. PMID- 25291701 TI - Immunosuppression as a physiological homeostatic mechanism. PMID- 25291702 TI - Selective delivery of antibodies to tumours. PMID- 25291703 TI - Quantitative variation in la antigen expression plays a central role in immune regulation. AB - The analysis of la antigen function has focused primarily on allelic variants of Ia molecules. In this review Charles Janeway and his colleagues discuss evidence that quantitative rather than qualitative variation in Ia antigen expression had a major role in immunoregulation and immunologically mediated disease. PMID- 25291704 TI - Cellular receptors for fragments of the third component of complement. AB - Many of the biological effects of the complement system are mediated by cellular receptors which can bind the fragments of C3 that are covalently attached to activators of complement. These receptors, which are termed CR1, CR2 and CR3, reside on lymphocytes, myelomonocytic cells, erythrocytes and renal podocytes. Progress in understanding their roles in im munological reactions has recently accelerated, as summarized in this review by Douglas Fearon, because of the molecular identification of these membrane proteins. PMID- 25291705 TI - Immunoregulation of host-versus-graft responses in the uterus. AB - The mammalian fetoplacental unit bears a variety of embryonal and paternally derived histocompatibiliy antigens against which the immune system of the mother can and does react(1-3). Nevertheless, there has been little evidence to suggest that these pregnancy-induced immune responses actually harm the fetus, and some investigators have suggested that immunization against paternal antigens may actually be helpful in ensuringfetal survival(2-4). In this review David Clark and his colleagues briefly outline data indicating that the so-called fetal allograft' is not always as successful as we have thought, and argue that a unique type of suppressor cell which accumulates at the implantation site in the decidua early in pregnancy may play an important role in preventing maternal refection of the embryo. They also summarize current information on the role of suppressor T cells and of fetal trophoblast cells in protection of the conceptus. PMID- 25291706 TI - Mucosal mast cells in vivo and in vitro. AB - There has recently been a flurry on the mast cell front caused, not least, by the publication of articles about the IL3-induced growth of mast cells in vitro from haemopoietic tissue. This has left bystanders, and one suspects not a few participants, confused about some of the issues involved. The reason for the confusion lies in the participation of disparate specialities - such as experimental haematology and immunoparasitology - among which communication has not been traditional: however, the revelations raise specific questions which demand an interdisciplinary approach. Thus the evidence is strong that the mast cells derived from cultured haemopoietic tissues are of a special type hitherto called atypical, intestinal or mucosal mast cells (MMC) which are known to occur in profusion in mucous membranes of helminth-infected animals. In this article Ellen Jarrett and David Haig link information about these cells obtained from both in-vivo and in-vitro experiments. PMID- 25291708 TI - Anomalous Origin of Left Vertebral Artery from Carotid Bulb Seen as "Trifurcation" of Left Common Carotid Artery with Acute Infarct in Ipsilateral Thalamus: A Case Report. AB - Anomalous origin of vertebral arteries is not common and usually seen as an incidental finding on imaging. We report a case of anomalous origin of left vertebral artery from left carotid bulb ("trifurcation" of left common carotid artery) on magnetic resonance angiography in a 64-year old male who also had ipsilateral thalamic acute infarct. PMID- 25291709 TI - The elegance of localization microscopy and the promise it holds. PMID- 25291710 TI - Cell-Based Therapies in Lower Urinary Tract Disorders. AB - Cell-based therapy for the bladder has its beginnings in the 1990s with the successful isolation and culture of bladder smooth muscle cells. Since then, several attempts have been made to artificially implant native cell types and stem cell-derived cells into damaged bladders in the form of single-cell injectables or as grafts seeded onto artificial extracellular matrix. We critically examined in the literature the types of cells and their probable role as an alternative to non-drug-based, non-bowel-based graft replacement therapy in disorders of the urinary bladder. The limitations and plausible improvements to these novel therapies have also been discussed, keeping in mind an ideal therapy that could suit most bladder abnormalities arising out of varied number of disorders. In conclusion, muscle-derived cell types have consistently proven to be a promising therapy to emerge in the coming decade. However, tissue-engineered constructs have yet to prove their success in preclinical and long-term clinical setting. PMID- 25291711 TI - Anodic and cathodic microbial communities in single chamber microbial fuel cells. AB - Microbial fuel cells (MFCs) are a rapidly growing technology for energy production from wastewater and biomasses. In a MFC, a microbial biofilm oxidizes organic matter and transfers electrons from reduced compounds to an anode as the electron acceptor by extracellular electron transfer (EET). The aim of this work was to characterize the microbial communities operating in a Single Chamber Microbial Fuel Cell (SCMFC) fed with acetate and inoculated with a biogas digestate in order to gain more insight into anodic and cathodic EET. Taxonomic characterization of the communities was carried out by Illumina sequencing of a fragment of the 16S rRNA gene. Microorganisms belonging to Geovibrio genus and purple non-sulfur (PNS) bacteria were found to be dominant in the anodic biofilm. The alkaliphilic genus Nitrincola and anaerobic microorganisms belonging to Porphyromonadaceae family were the most abundant bacteria in the cathodic biofilm. PMID- 25291713 TI - Immune complexes in humoral immune responses: suppressive and enhancing effects. PMID- 25291712 TI - Mini review on blood-brain barrier penetration of pyridinium aldoximes. AB - This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are highly charged hydrophilic compounds used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase reactivators. Pyridinium aldoximes have antidotal effects against poisoning with cholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This poses a severe challenge to all innocent and peace-loving people worldwide. This review gives a brief summary of BBB transporters and description of the current in vitro and in vivo methods for the characterization of BBB penetration of established and novel pyridinium aldoximes. The authors provide a putative mechanism of penetration, outline some future ways of formulation and discuss the possible advantages and disadvantages of increasing BBB penetration. PMID- 25291714 TI - Subpopulations of human T lymphocytes. PMID- 25291715 TI - Vasectomy, antibodies to sperm, and atherosclerosis. PMID- 25291716 TI - The case history of Mr T.I. Terminal patient or still curable? AB - Today we have a somewhat unusual Grand Rounds, because our case presentation, Mr T. I., has a non-identical twin, who also went through a period of ill-health in childhood, but now seems to be pretty fit, and we shall spend some time comparing the two brothers. Mr T. I. is about 25 years old, and at present appears to be in rather a serious state. The chief symptoms are fatigue and confusion, which have followed a period of unusually intense activity. The detailed history reveals that T.I. has never really been free of symptoms, and though his rate of growth was very rapid, especially during his teens, there have been periods of euphoria alternating with depression, and close observers have noted a certain malaise throughout. The laboratory tests have not contributed to the diagnosis, as some appear to suggest robust good health whereas others hint at a terminal state. Mr. T.I., whose full name is Tumor Immunology, is thus a diagnostic and prognostic puzzle. Perhaps a look at the case history of his non-identical twin brother will help us. Curiously, his initials are also T.I., the full name being Transplantation Immunology. This twin also experienced a very sick childhood, especially up to the age of 10, but since then has made steady progress and is now in fair health and holding down a useful job. While his problems were much easier to diagnose, treatment was not straightforward and management options continue to require detailed assessment. PMID- 25291717 TI - The organization and expression of immunoglobulin genes. PMID- 25291718 TI - Idiotypic network interactions. PMID- 25291719 TI - Monoclonal antibodies by cell fusion. AB - Monoclonal antibodies produced by hybrid myelomas ('hybridomas') have become an important tool in those areas of research that use immunological techniques. In this article, David Secher describes some examples of monoclonal antibodies to illustrate some of the principles, problems and applications of the method. PMID- 25291720 TI - A simple running model with rolling contact and its role as a template for dynamic locomotion on a hexapod robot. AB - We report on the development of a robot's dynamic locomotion based on a template which fits the robot's natural dynamics. The developed template is a low degree of-freedom planar model for running with rolling contact, which we call rolling spring loaded inverted pendulum (R-SLIP). Originating from a reduced-order model of the RHex-style robot with compliant circular legs, the R-SLIP model also acts as the template for general dynamic running. The model has a torsional spring and a large circular arc as the distributed foot, so during locomotion it rolls on the ground with varied equivalent linear stiffness. This differs from the well known spring loaded inverted pendulum (SLIP) model with fixed stiffness and ground contact points. Through dimensionless steps-to-fall and return map analysis, within a wide range of parameter spaces, the R-SLIP model is revealed to have self-stable gaits and a larger stability region than that of the SLIP model. The R-SLIP model is then embedded as the reduced-order 'template' in a more complex 'anchor', the RHex-style robot, via various mapping definitions between the template and the anchor. Experimental validation confirms that by merely deploying the stable running gaits of the R-SLIP model on the empirical robot with simple open-loop control strategy, the robot can easily initiate its dynamic running behaviors with a flight phase and can move with similar body state profiles to those of the model, in all five testing speeds. The robot, embedded with the SLIP model but performing walking locomotion, further confirms the importance of finding an adequate template of the robot for dynamic locomotion. PMID- 25291721 TI - Simulation in psychiatric nursing education. PMID- 25291722 TI - NAPHS survey indicates need for psychiatric services in inpatient hospitals. PMID- 25291724 TI - FDA-approved drugs to treat sleep disorders. PMID- 25291725 TI - Suvorexant: a novel therapy for the treatment of insomnia. AB - Suvorexant is a pharmacologically novel dual antagonist of orexin receptors OX1R and OX2R, which has an effect that promotes sleep by reducing arousal and wakefulness. Its approval for the treatment of insomnia was based on three clinical trials that found it to be efficacious and relatively well tolerated. Somnolence, headache, and dry mouth are the most common side effects. Because suvorexant has unique effects on arousal systems and rapid eye movement (REM) sleep, it is contraindicated in patients with narcolepsy, and its use should be avoided or closely monitored in patients at risk for REM sleep behavior disorder, depression, or delirium. PMID- 25291726 TI - Sleep problems in children: an overlooked factor in evaluating behavior. AB - Sleep disturbance is a problem for many children; however, it remains an underevaluated factor when assessing behavior. The purpose of the current article is to explore sleep problems in children, as well as the effects that disrupted sleep patterns have on child behavior. The authors recommend strategies to guide the assessment of sleep and improve children's sleep quality. PMID- 25291728 TI - Hearing distressing voices clinical simulation: "life changing" experiences of psychiatric-mental health nursing students. AB - The purpose of the current qualitative study was to investigate the experience of baccalaureate nursing (BSN) students with the clinical simulation of hearing distressing voices and derive themes from the written reflective data of students' evaluative statements. A purposive convenience sample of BSN students (N = 74) was recruited from two nursing cohorts at a private, religiously affiliated university BSN program in the northeastern United States. Student reflections on three evaluation questions of the simulation experience were analyzed using constant comparison as per naturalistic inquiry methodology. Themes emerged from each of the three questions related to students' experiences of hearing the simulated voices. Findings support the value of this simulation as a means to promote both active and affective learning in BSN students as they enter psychiatric-mental health clinical rotations. PMID- 25291730 TI - A new learning algorithm for a fully connected neuro-fuzzy inference system. AB - A traditional neuro-fuzzy system is transformed into an equivalent fully connected three layer neural network (NN), namely, the fully connected neuro fuzzy inference systems (F-CONFIS). The F-CONFIS differs from traditional NNs by its dependent and repeated weights between input and hidden layers and can be considered as the variation of a kind of multilayer NN. Therefore, an efficient learning algorithm for the F-CONFIS to cope these repeated weights is derived. Furthermore, a dynamic learning rate is proposed for neuro-fuzzy systems via F CONFIS where both premise (hidden) and consequent portions are considered. Several simulation results indicate that the proposed approach achieves much better accuracy and fast convergence. PMID- 25291731 TI - Synchronization of stochastic dynamical networks under impulsive control with time delays. AB - In this paper, the stochastic synchronization problem is studied for a class of delayed dynamical networks under delayed impulsive control. Different from the existing results on the synchronization of dynamical networks under impulsive control, impulsive input delays are considered in our model. By assuming that the impulsive intervals belong to a certain interval and using the mathematical induction method, several conditions are derived to guarantee that complex networks are exponentially synchronized in mean square. The derived conditions reveal that the frequency of impulsive occurrence, impulsive input delays, and stochastic perturbations can heavily affect the synchronization performance. A control algorithm is then presented for synchronizing stochastic dynamical networks with delayed synchronizing impulses. Finally, two examples are given to demonstrate the effectiveness of the proposed approach. PMID- 25291732 TI - Stochastic learning via optimizing the variational inequalities. AB - A wide variety of learning problems can be posed in the framework of convex optimization. Many efficient algorithms have been developed based on solving the induced optimization problems. However, there exists a gap between the theoretically unbeatable convergence rate and the practically efficient learning speed. In this paper, we use the variational inequality (VI) convergence to describe the learning speed. To this end, we avoid the hard concept of regret in online learning and directly discuss the stochastic learning algorithms. We first cast the regularized learning problem as a VI. Then, we present a stochastic version of alternating direction method of multipliers (ADMMs) to solve the induced VI. We define a new VI-criterion to measure the convergence of stochastic algorithms. While the rate of convergence for any iterative algorithms to solve nonsmooth convex optimization problems cannot be better than O(1/?t), the proposed stochastic ADMM (SADMM) is proved to have an O(1/t) VI-convergence rate for the l1-regularized hinge loss problems without strong convexity and smoothness. The derived VI-convergence results also support the viewpoint that the standard online analysis is too loose to analyze the stochastic setting properly. The experiments demonstrate that SADMM has almost the same performance as the state-of-the-art stochastic learning algorithms but its O(1/t) VI convergence rate is capable of tightly characterizing the real learning speed. PMID- 25291733 TI - Sparse alignment for robust tensor learning. AB - Multilinear/tensor extensions of manifold learning based algorithms have been widely used in computer vision and pattern recognition. This paper first provides a systematic analysis of the multilinear extensions for the most popular methods by using alignment techniques, thereby obtaining a general tensor alignment framework. From this framework, it is easy to show that the manifold learning based tensor learning methods are intrinsically different from the alignment techniques. Based on the alignment framework, a robust tensor learning method called sparse tensor alignment (STA) is then proposed for unsupervised tensor feature extraction. Different from the existing tensor learning methods, L1- and L2-norms are introduced to enhance the robustness in the alignment step of the STA. The advantage of the proposed technique is that the difficulty in selecting the size of the local neighborhood can be avoided in the manifold learning based tensor feature extraction algorithms. Although STA is an unsupervised learning method, the sparsity encodes the discriminative information in the alignment step and provides the robustness of STA. Extensive experiments on the well-known image databases as well as action and hand gesture databases by encoding object images as tensors demonstrate that the proposed STA algorithm gives the most competitive performance when compared with the tensor-based unsupervised learning methods. PMID- 25291734 TI - Pinning distributed synchronization of stochastic dynamical networks: a mixed optimization approach. AB - This paper is concerned with the problem of pinning synchronization of nonlinear dynamical networks with multiple stochastic disturbances. Two kinds of pinning schemes are considered: 1) pinned nodes are fixed along the time evolution and 2) pinned nodes are switched from time to time according to a set of Bernoulli stochastic variables. Using Lyapunov function methods and stochastic analysis techniques, several easily verifiable criteria are derived for the problem of pinning distributed synchronization. For the case of fixed pinned nodes, a novel mixed optimization method is developed to select the pinned nodes and find feasible solutions, which is composed of a traditional convex optimization method and a constraint optimization evolutionary algorithm. For the case of switching pinning scheme, upper bounds of the convergence rate and the mean control gain are obtained theoretically. Simulation examples are provided to show the advantages of our proposed optimization method over previous ones and verify the effectiveness of the obtained results. PMID- 25291735 TI - Deep networks are effective encoders of periodicity. AB - We present a comparative theoretical analysis of representation in artificial neural networks with two extreme architectures, a shallow wide network and a deep narrow network, devised to maximally decouple their representative power due to layer width and network depth. We show that, given a specific activation function, models with comparable VC-dimension are required to guarantee zero error modeling of real functions over a binary input. However, functions that exhibit repeating patterns can be encoded much more efficiently in the deep representation, resulting in significant reduction in complexity. This paper provides some initial theoretical evidence of when and how depth can be extremely effective. PMID- 25291736 TI - Parsimonious extreme learning machine using recursive orthogonal least squares. AB - Novel constructive and destructive parsimonious extreme learning machines (CP- and DP-ELM) are proposed in this paper. By virtue of the proposed ELMs, parsimonious structure and excellent generalization of multiinput-multioutput single hidden-layer feedforward networks (SLFNs) are obtained. The proposed ELMs are developed by innovative decomposition of the recursive orthogonal least squares procedure into sequential partial orthogonalization (SPO). The salient features of the proposed approaches are as follows: 1) Initial hidden nodes are randomly generated by the ELM methodology and recursively orthogonalized into an upper triangular matrix with dramatic reduction in matrix size; 2) the constructive SPO in the CP-ELM focuses on the partial matrix with the subcolumn of the selected regressor including nonzeros as the first column while the destructive SPO in the DP-ELM operates on the partial matrix including elements determined by the removed regressor; 3) termination criteria for CP- and DP-ELM are simplified by the additional residual error reduction method; and 4) the output weights of the SLFN need not be solved in the model selection procedure and is derived from the final upper triangular equation by backward substitution. Both single- and multi-output real-world regression data sets are used to verify the effectiveness and superiority of the CP- and DP-ELM in terms of parsimonious architecture and generalization accuracy. Innovative applications to nonlinear time-series modeling demonstrate superior identification results. PMID- 25291737 TI - LI-MLC: a label inference methodology for addressing high dimensionality in the label space for multilabel classification. AB - Multilabel classification (MLC) has generated considerable research interest in recent years, as a technique that can be applied to many real-world scenarios. To process them with binary or multiclass classifiers, methods for transforming multilabel data sets (MLDs) have been proposed, as well as adapted algorithms able to work with this type of data sets. However, until now, few studies have addressed the problem of how to deal with MLDs having a large number of labels. This characteristic can be defined as high dimensionality in the label space (output attributes), in contrast to the traditional high dimensionality problem, which is usually focused on the feature space (by means of feature selection) or sample space (by means of instance selection). The purpose of this paper is to analyze dimensionality in the label space in MLDs, and to present a transformation methodology based on the use of association rules to discover label dependencies. These dependencies are used to reduce the label space, to ease the work of any MLC algorithm, and to infer the deleted labels in a final postprocessing stage. The proposed process is validated in an extensive experimentation with several MLDs and classification algorithms, resulting in a statistically significant improvement of performance in some cases, as will be shown. PMID- 25291738 TI - A fast algorithm for nonnegative matrix factorization and its convergence. AB - Nonnegative matrix factorization (NMF) has recently become a very popular unsupervised learning method because of its representational properties of factors and simple multiplicative update algorithms for solving the NMF. However, for the common NMF approach of minimizing the Euclidean distance between approximate and true values, the convergence of multiplicative update algorithms has not been well resolved. This paper first discusses the convergence of existing multiplicative update algorithms. We then propose a new multiplicative update algorithm for minimizing the Euclidean distance between approximate and true values. Based on the optimization principle and the auxiliary function method, we prove that our new algorithm not only converges to a stationary point, but also does faster than existing ones. To verify our theoretical results, the experiments on three data sets have been conducted by comparing our proposed algorithm with other existing methods. PMID- 25291739 TI - Memristor crossbar-based neuromorphic computing system: a case study. AB - By mimicking the highly parallel biological systems, neuromorphic hardware provides the capability of information processing within a compact and energy efficient platform. However, traditional Von Neumann architecture and the limited signal connections have severely constrained the scalability and performance of such hardware implementations. Recently, many research efforts have been investigated in utilizing the latest discovered memristors in neuromorphic systems due to the similarity of memristors to biological synapses. In this paper, we explore the potential of a memristor crossbar array that functions as an autoassociative memory and apply it to brain-state-in-a-box (BSB) neural networks. Especially, the recall and training functions of a multianswer character recognition process based on the BSB model are studied. The robustness of the BSB circuit is analyzed and evaluated based on extensive Monte Carlo simulations, considering input defects, process variations, and electrical fluctuations. The results show that the hardware-based training scheme proposed in the paper can alleviate and even cancel out the majority of the noise issue. PMID- 25291740 TI - Multiobjective optimization for model selection in kernel methods in regression. AB - Regression plays a major role in many scientific and engineering problems. The goal of regression is to learn the unknown underlying function from a set of sample vectors with known outcomes. In recent years, kernel methods in regression have facilitated the estimation of nonlinear functions. However, two major (interconnected) problems remain open. The first problem is given by the bias versus-variance tradeoff. If the model used to estimate the underlying function is too flexible (i.e., high model complexity), the variance will be very large. If the model is fixed (i.e., low complexity), the bias will be large. The second problem is to define an approach for selecting the appropriate parameters of the kernel function. To address these two problems, this paper derives a new smoothing kernel criterion, which measures the roughness of the estimated function as a measure of model complexity. Then, we use multiobjective optimization to derive a criterion for selecting the parameters of that kernel. The goal of this criterion is to find a tradeoff between the bias and the variance of the learned function. That is, the goal is to increase the model fit while keeping the model complexity in check. We provide extensive experimental evaluations using a variety of problems in machine learning, pattern recognition, and computer vision. The results demonstrate that the proposed approach yields smaller estimation errors as compared with methods in the state of the art. PMID- 25291741 TI - Separation of synchronous sources through phase locked matrix factorization. AB - In this paper, we study the separation of synchronous sources (SSS) problem, which deals with the separation of sources whose phases are synchronous. This problem cannot be addressed through independent component analysis methods because synchronous sources are statistically dependent. We present a two-step algorithm, called phase locked matrix factorization (PLMF), to perform SSS. We also show that SSS is identifiable under some assumptions and that any global minimum of PLMFs cost function is a desirable solution for SSS. We extensively study the algorithm on simulated data and conclude that it can perform SSS with various numbers of sources and sensors and with various phase lags between the sources, both in the ideal (i.e., perfectly synchronous and nonnoisy) case, and with various levels of additive noise in the observed signals and of phase jitter in the sources. PMID- 25291742 TI - Clipping in neurocontrol by adaptive dynamic programming. AB - In adaptive dynamic programming, neurocontrol, and reinforcement learning, the objective is for an agent to learn to choose actions so as to minimize a total cost function. In this paper, we show that when discretized time is used to model the motion of the agent, it can be very important to do clipping on the motion of the agent in the final time step of the trajectory. By clipping, we mean that the final time step of the trajectory is to be truncated such that the agent stops exactly at the first terminal state reached, and no distance further. We demonstrate that when clipping is omitted, learning performance can fail to reach the optimum, and when clipping is done properly, learning performance can improve significantly. The clipping problem we describe affects algorithms that use explicit derivatives of the model functions of the environment to calculate a learning gradient. These include backpropagation through time for control and methods based on dual heuristic programming. However, the clipping problem does not significantly affect methods based on heuristic dynamic programming, temporal differences learning, or policy-gradient learning algorithms. PMID- 25291743 TI - Consensus acceleration in a class of predictive networks. AB - A fastest consensus problem of topology fixed networks has been formulated as an optimal linear iteration problem and efficiently solved in the literature. Considering a kind of predictive mechanism, we show that the consensus evolution can be further accelerated while physically maintaining the network topology. The underlying mechanism is that an effective prediction is able to induce a network with a virtually denser topology. With this topology, an even faster consensus is expected to occur. The result is motivated by the predictive mechanism widely existing in natural systems. PMID- 25291744 TI - Hinfinity output tracking control of discrete-time nonlinear systems via standard neural network models. AB - This brief proposes an output tracking control for a class of discrete-time nonlinear systems with disturbances. A standard neural network model is used to represent discrete-time nonlinear systems whose nonlinearity satisfies the sector conditions. Hinfinity control performance for the closed-loop system including the standard neural network model, the reference model, and state feedback controller is analyzed using Lyapunov-Krasovskii stability theorem and linear matrix inequality (LMI) approach. The Hinfinity controller, of which the parameters are obtained by solving LMIs, guarantees that the output of the closed loop system closely tracks the output of a given reference model well, and reduces the influence of disturbances on the tracking error. Three numerical examples are provided to show the effectiveness of the proposed Hinfinity output tracking design approach. PMID- 25291745 TI - Extended dissipative analysis for neural networks with time-varying delays. AB - In this brief, an extended dissipativity analysis was conducted for a neural network with time-varying delays. The concept of the extended dissipativity can be used to solve for the Hinfinity, L2-Linfinity, passive, and dissipative performance by adjusting the weighting matrices in a new performance index. In addition, the activation function dividing method is modified by introducing a tuning parameter. Examples are provided to show the effectiveness and less conservatism of the proposed method. PMID- 25291746 TI - Multilinear sparse principal component analysis. AB - In this brief, multilinear sparse principal component analysis (MSPCA) is proposed for feature extraction from the tensor data. MSPCA can be viewed as a further extension of the classical principal component analysis (PCA), sparse PCA (SPCA) and the recently proposed multilinear PCA (MPCA). The key operation of MSPCA is to rewrite the MPCA into multilinear regression forms and relax it for sparse regression. Differing from the recently proposed MPCA, MSPCA inherits the sparsity from the SPCA and iteratively learns a series of sparse projections that capture most of the variation of the tensor data. Each nonzero element in the sparse projections is selected from the most important variables/factors using the elastic net. Extensive experiments on Yale, Face Recognition Technology face databases, and COIL-20 object database encoded the object images as second-order tensors, and Weizmann action database as third-order tensors demonstrate that the proposed MSPCA algorithm has the potential to outperform the existing PCA-based subspace learning algorithms. PMID- 25291747 TI - JRS standard for reporting astigmatism outcomes of refractive surgery. PMID- 25291748 TI - Comparison of the mechanical properties of the anterior lens capsule following manual capsulorhexis and femtosecond laser capsulotomy. AB - PURPOSE: To evaluate and compare the mechanical properties of anterior capsule openings performed with the continuous curvilinear capsulorhexis (CCC) technique and femtosecond laser capsulotomy (FLC) in ex vivo porcine lens capsule specimens. METHODS: Fresh porcine eyes were included in the study (CCC group, n = 50; FLC group, n = 30). The capsule openings were stretched with universal testing equipment until they ruptured. The rupture force and circumference stretching ratio were evaluated. The morphologic profile of the cut capsule edges was evaluated using scanning electron microscopy (SEM). RESULTS: The average rupture force was higher in the CCC group (median: 155 mN; interquartile range [IQR]: 129 to 201 mN; range: 71 to 294 mN) than in the FLC group (median: 119 mN; IQR: 108 to 128 mN; range: 91 to 142 mN) (P < .01, Mann-Whitney U test). The average circumference stretching ratio in the CCC group was greater (median: 150%; IQR: 146% to 156%; range: 136% to 161%) than in the FLC group (median: 148%; IQR: 145% to 150%; range: 141% to 154%) (P = .0468, Mann-Whitney U test). When less than 71 mN, no capsular tear occurred in either group. When less than 91 mN, no capsular tear occurred in the FLC group, whereas at 91 mN, the probability of capsular tears was 9% for the CCC group. SEM examination found that the CCC group had smooth edges, whereas those of the FLC group were gently serrated. CONCLUSIONS: According to the current results in a porcine eye model, FLC had less average resistance to capsule tear than CCC, but the weakest openings were seen in the CCC group. PMID- 25291749 TI - Comparative analysis of the visual performance after cataract surgery with implantation of a bifocal or trifocal diffractive IOL. AB - PURPOSE: To evaluate and compare the visual, refractive, contrast sensitivity, and aberrometric outcomes with a diffractive bifocal and trifocal intraocular lens (IOL) of the same material and haptic design. METHODS: Sixty eyes of 30 patients undergoing bilateral cataract surgery were enrolled and randomly assigned to one of two groups: the bifocal group, including 30 eyes implanted with the bifocal diffractive IOL AT LISA 801 (Carl Zeiss Meditec, Jena, Germany), and the trifocal group, including eyes implanted with the trifocal diffractive IOL AT LISA tri 839 MP (Carl Zeiss Meditec). Analysis of visual and refractive outcomes, contrast sensitivity, ocular aberrations (OPD-Scan III; Nidek, Inc., Gagamori, Japan), and defocus curve were performed during a 3-month follow-up period. RESULTS: No statistically significant differences between groups were found in 3-month postoperative uncorrected and corrected distance visual acuity (P >= .21). However, uncorrected, corrected, and distance-corrected near and intermediate visual acuities were significantly better in the trifocal group (P < .01). No significant differences between groups were found in postoperative spherical equivalent (P = .22). In the binocular defocus curve, the visual acuity was significantly better for defocus of -0.50 to -1.50 diopters in the trifocal group (P <= .04) and -3.50 to -4.00 diopters in the bifocal group (P <= .03). No statistically significant differences were found between groups in most of the postoperative corneal, internal, and ocular aberrations (P <= .31), and in contrast sensitivity for most frequencies analyzed (P <= .15). CONCLUSIONS: Trifocal diffractive IOLs provide significantly better intermediate vision over bifocal IOLs, with equivalent postoperative levels of visual and ocular optical quality. PMID- 25291750 TI - Impact of personality characteristics on patient satisfaction after multifocal intraocular lens implantation: results from the "happy patient study". AB - PURPOSE: This prospective multicenter study assessed personality characteristics that may influence patient satisfaction after implantation of multifocal intraocular lenses (MIOLs). METHODS: One hundred eighty-three patients who underwent bilateral implantation of different MIOLs were enrolled. Uncorrected and corrected distance visual acuity for distance and near (ie, UDVA, UNVA, CDVA, and CNVA) were assessed preoperatively and 3 and 6 months after implantation. Before surgery, personality characteristics were evaluated using a questionnaire based on the NEO Personality Inventory Test and the Compulsiveness Inventory Test. At the 3- and 6-month postoperative visits, patients answered a questionnaire concerning overall satisfaction, need for spectacles at different distances, visual function at different distances and lighting conditions, photic phenomena, and ease of performing daily activities. RESULTS: Three months after surgery (n = 163), mean CDVA was 0.03 +/- 0.09 logMAR, UDVA was 0.05 +/- 0.09 logMAR, and UNVA was 0.04 +/- 0.11 logMAR. At the 6-month visit (n = 131), mean CDVA was 0.02 +/- 0.07 logMAR, UDVA was 0.06 +/- 0.09 logMAR, and UNVA was 0.05 +/- 0.01 logMAR. Most patients (82.2%) would opt for an MIOL again, 3.7% would not, and 14.1% were uncertain. Overall satisfaction with the procedure was correlated to low astigmatism, good visual function, low spectacle dependence, and less halos or glare. The personality characteristics of compulsive checking, orderliness, competence, and dutifulness were statistically significantly correlated to subjective disturbance by glare and halos. CONCLUSIONS: Postoperative patient satisfaction after MIOL implantation is correlated to visual performance, spectacle independence, and less photic phenomena. Personality characteristics have an impact on subjective disturbance by photic phenomena and thus are important for patient satisfaction. PMID- 25291751 TI - Topographic analysis of the centration of the treatment zone after SMILE for myopia and comparison to FS-LASIK: subjective versus objective alignment. AB - PURPOSE: To evaluate the centration of the treatment zone after small incision lenticule extraction (SMILE) and compare it to femtosecond laser-assisted LASIK (FS-LASIK). METHODS: Sixty-nine myopic eyes of 36 patients who underwent SMILE were compared to 69 myopic eyes of 36 patients treated with FS-LASIK. All procedures were performed by a single surgeon using the VisuMax platform (Carl Zeiss Meditec, Jena, Germany). The Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany) was used for preoperative and postoperative topography and pachymetry. The centration of the treatment zone was estimated pachymetrically by the distance of the thickest point on the corneal thickness differential map from the topographical center of the entrance pupil and the coaxial corneal light reflex. RESULTS: In SMILE cases, the mean decentration of the lenticule from the center of the entrance pupil was 0.326 +/- 0.196 mm (range: 0.014 to 1.062 mm), whereas the distribution of the lenticule centers demonstrated a nasalization pattern. In FS-LASIK cases, this value was 0.452 +/- 0.224 mm (range: 0.02 to 1.040 mm), whereas the ablation centers were distributed randomly. In relation to the coaxial corneal light reflex, the decentration in SMILE was 0.315 +/- 0.211 mm (range: 0.0 to 1.131 mm), whereas FS-LASIK eyes demonstrated a mean decentration of 0.516 +/- 0.254 mm (range: 0.103 to 1.265 mm). The decentration from the reference point of its technique (coaxial corneal light reflex in SMILE, the entrance pupil center in FS-LASIK) was significantly more extended in the FS LASIK group (P < .001). CONCLUSIONS: The centration of the treatment zone as measured by the Pentacam was better for patient-controlled fixation during SMILE than active eye tracker-assisted FS-LASIK. PMID- 25291752 TI - Non-topography-guided PRK combined with CXL for the correction of refractive errors in patients with early stage keratoconus. AB - PURPOSE: To evaluate the safety and clinical outcome of combined non-topography guided photorefractive keratectomy (PRK) and corneal collagen cross-linking (CXL) for the treatment of mild refractive errors in patients with early stage keratoconus. METHODS: A retrospective, nonrandomized study of patients with early stage keratoconus (stage 1 or 2) who underwent simultaneous non-topography-guided PRK and CXL. All patients had at least 2 years of follow-up. Data were collected preoperatively and postoperatively at the 6-month, 1-year, and 2-year follow-up visit after combined non-topography-guided PRK and CXL. RESULTS: Seventy-nine patients (140 eyes) were included in the study. Combined non-topography-guided PRK and CXL induced a significant improvement in both visual acuity and refraction. Uncorrected distance visual acuity significantly improved from 0.39 +/- 0.22 logMAR before combined non-topography-guided PRK and CXL to 0.12 +/- 0.14 logMAR at the last follow-up visit (P <.001) and corrected distance visual acuity remained stable (0.035 +/- 0.062 logMAR preoperatively vs 0.036 +/- 0.058 logMAR postoperatively, P =.79). The mean spherical equivalent decreased from 1.78 +/- 1.43 to -0.42 +/- 0.60 diopters (D) (P <.001), and the mean cylinder decreased from 1.47 +/- 1.10 to 0.83 +/- 0.55 D (P <.001). At the last follow-up visit mean keratometry flat was 43.30 +/- 1.75 vs 45.62 +/- 1.72 D preoperatively (P = .03) and mean keratometry steep was 44.39 +/- 3.14 vs 46.53 +/- 2.13 D preoperatively (P = .02). Mean central corneal thickness decreased from 501.74 +/ 13.11 to 475.93 +/- 12.25 um following combined non-topography-guided PRK and CXL (P < .001). No intraoperative complications occurred. Four eyes developed mild haze that responded well to a short course of topical steroids. No eye developed infectious keratitis. CONCLUSIONS: Combined non-topography-guided PRK and CXL is an effective and safe option for correcting mild refractive error and improving visual acuity in patients with early stable keratoconus. PMID- 25291753 TI - Measurement of pupil center shift in refractive surgery candidates with caucasian eyes using infrared pupillometry. AB - PURPOSE: To evaluate the effectiveness of the pupil center shift with changes in the state of pupil size and with other ocular variables. METHODS: Dynamic pupillometry with the Topolyzer Vario (Alcon Laboratories, Inc., Fort Worth, TX) was performed in 248 eyes of 124 patients scheduled for corneal laser refractive surgery. High-resolution images were obtained using the infrared-sensitive camera (incorporated in the videokeratoscope) under mesopic and photopic conditions. Measurements of pupil diameters, distance between the pupil center and keratoscopic axis, and spatial shift of the pupil center were obtained after analysis. RESULTS: The mean distance between the pupil center and the corneal vertex in mesopic and photopic conditions of illumination in myopic eyes was 0.27 +/- 0.14 (range: 0.02 to 0.70 mm) and 0.24 +/- 0.12 mm (range: 0.06 to 0.65 mm), respectively, whereas it was 0.36 +/- 0.15 (range: 0.03 to 0.70 mm) and 0.31 +/- 0.16 mm (range: 0.03 to 0.77 mm) in hyperopic eyes, respectively. The mean spatial pupil center shift was significant: 0.11 +/- 0.07 mm (range: 0.02 to 0.57 mm) in myopic eyes and 0.12 +/- 0.09 mm (range: 0.02 to 0.47 mm) in hyperopic eyes. The pupil center shifted consistently temporally as the pupil dilated. The pupil center shift was not significantly related to sex, age, eye (right or left), or refractive error. CONCLUSIONS: The mean distance between the pupil center and the corneal vertex is greater in hyperopic eyes than in myopic eyes, whereas the spatial shift of this pupil center has a temporal direction as the pupil dilates and is constantly small in all groups. However, pupil center shift can be important in a few patients. PMID- 25291755 TI - Effect of anterior corneal surface asphericity modification on fourth-order zernike spherical aberrations. AB - PURPOSE: To evaluate the theoretical influence of the change in corneal asphericity (DeltaQ) on the change in fourth-order Zernike spherical aberration coefficient (DeltaC(4)0) with customized aspheric refractive correction of myopia and hyperopia. METHODS: The initial anterior corneal surface profile was modeled as a conic section of apical radius of curvature R0 and asphericity Q0. The postoperative corneal profile was modeled as a conic section of apical curvature R1 and asphericity Q1, where R1 was computed from defocus D, and Q1 selected for controlling the postoperative asphericity. The corresponding change in fourth order spherical aberration (DeltaC(0)4) was computed within a 6-mm optical zone using inner products applied to the incurred optical path changes. These calculations were repeated for different values of D, R0, Q0, and various intended DeltaC(4)0 values. RESULTS: Increasing negative spherical aberration (DeltaC(4)(0) < 0) requires a change toward more negative values of asphericity (increased prolateness; DeltaQ < 0) for hyperopic and low myopic corrections, but more positive values (DeltaQ < 0) for high myopic correction. The larger the intended change in corneal spherical aberration (DeltaC(4)(0)), the more myopic the threshold value for which the required change in asphericity, DeltaQ, becomes positive. The influence of the magnitude of paraxial defocus correction is less pronounced when larger changes in C(4)(0) are intended. CONCLUSIONS: These results provide a basis for controlling the direction (sign) and the magnitude of spherical aberration changes when using customized aspheric profiles of ablation. PMID- 25291754 TI - Differences in the corneal biomechanical changes after SMILE and LASIK. AB - PURPOSE: To compare the corneal biomechanical properties before and after small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK in different levels of myopia with the Ocular Response Analyzer (Reichert Ophthalmic Instruments, Depew, NY). METHODS: A total of 187 and 79 eyes that received SMILE or LASIK, respectively, between January and June 2013 at Zhongshan Ophthalmic Center were enrolled in this study. Patients were grouped according to surgery type (SMILE or LASIK) and -6.00 diopters (D) or less (> -6.00 D) or myopia greater than -6.00 D (>-6.00 D). Corneal hysteresis, corneal resistance factor, and 37 waveform parameters were recorded and compared preoperatively and at 1 week and 1 and 3 months postoperatively. RESULTS: There was a significant decrease of corneal hysteresis, corneal resistance factor, p1area, and p2area, and an increase of path1 and path2 in both SMILE and LASIK. In myopia -6.00 D or less, the differences between SMILE and LASIK were not significant (P > .05), but in myopia greater than -6.00 D, the corneal hysteresis, corneal resistance factor, p1area, and p2area decreased significantly more in LASIK than in SMILE (P < .05). CONCLUSIONS: When comparing SMILE with LASIK, myopia was greater than 6.00 D, and the corneal hysteresis, corneal resistance factor, p1area, and p2area decrease was less after SMILE. PMID- 25291756 TI - Additive effect of repeated corneal collagen cross-linking in keratoconus. AB - PURPOSE: To report the long-term clinical outcome in a patient diagnosed as having bilateral progressive keratoconus who received a single corneal collagen cross-linking (CXL) treatment in the right eye and repeated CXL in the left eye. METHODS: Observational case report. Topographical changes were assessed by high resolution Scheimpflug imaging. The right eye underwent a standard epithelium-off CXL procedure in February 2008, followed by the left eye 4 weeks later. In 2012, the left eye was treated with CXL for a second time. Irradiation was performed in all cases at a fluence of 5.4 J/cm2. Energy settings were 30 minutes @ 3 mW/cm2 for the CXL procedures performed in 2008, and 10 minutes @ 9 mW/cm2 for the second CXL procedure of the left eye that was performed in 2012. RESULTS: The right eye that underwent a single CXL procedure showed a flattening of keratometry values between 2008 and 2012, followed by stabilization. The left eye showed a similar flattening effect between 2008 and 2012, followed by another flattening effect after the second CXL procedure and accompanied by a distinct increase in corrected distance visual acuity. CONCLUSIONS: Following repeated CXL, the corneal stroma and endothelium remained inconspicuous, and postoperative haze and visibility of the stromal demarcation line was similar to what is usually observed after a single CXL procedure. Whether the additive flattening effect of the anterior surface observed in this single case goes along with an additive increase in biomechanical stiffness remains to be seen. PMID- 25291757 TI - Assessment of ocular biomechanics using dynamic ultra high-speed Scheimpflug imaging in keratoconic and normal eyes. AB - PURPOSE: To introduce several new ocular biomechanical parameters for comparison between keratoconic and normal eyes using an analysis method based on corneal dynamic deformation video recorded by corneal visualization Scheimpflug technology (Corvis ST; Oculus Optikgerate GmbH, Wetzlar, Germany). METHODS: This comparative study comprised 52 keratoconic eyes of 43 patients with keratoconus and 52 normal eyes of 52 controls. An analysis method (PolyU [Labview 2009; National Instrument, Austin, TX]) was developed to introduce several new ocular biomechanical parameters and to compare the difference between keratoconic and normal eyes. The repeatability of the new parameters measurement was evaluated and compared with the Corvis ST measurement. Receiver operating characteristic curves were used to establish a cutoff value for the new biomechanical parameters. RESULTS: Intraclass correlation coefficients of the deformation amplitude, peak distance, corneal concave radius of curvature, maximum deformation area, maximum corneal inward velocity and outward velocity (Vin, max and Vout, max) were high in both the keratoconic and normal eyes (all intraclass correlation coefficients > 0.75). The measurement agreement of the PolyU analysis method and Corvis ST was good. Most of the biomechanical parameters of patients with keratoconus were significantly different from those of the controls. In the receiver operating characteristic analysis, the Vin, max was the best predictive parameter with an area under the curve of 0.79. CONCLUSIONS: The corneal deformation video recorded by the Corvis ST provides useful information for the study of ocular biomechanics. Most of the new ocular biomechanical parameters were significantly different between keratoconic and normal eyes. Further research is needed to develop more comprehensive clinical applications with these new ocular biomechanical parameters. PMID- 25291758 TI - Complete Genome Sequence of a Field Strain of Peste des Petits Ruminants Virus Isolated during 2010-2014 Epidemics in Senegal. AB - Peste des petits ruminants virus (PPRV) infection is expanding and results in regular epizootic activities in Africa, the Middle East, and Asia. Here, we report the complete genome sequence of a field strain of PPRV isolated in Senegal (SnDk11I13) in 2013. PMID- 25291759 TI - Genome sequence of two novel species of torque teno minivirus from the human oral cavity. AB - Anelloviridae is a family of circular, single-stranded DNA viruses highly prevalent among humans. We report the genome sequence of two torque teno miniviruses found in human oral mucosa samples. Genome organization, phylogenetic analysis, and pairwise comparisons reveal that they belong to novel species within the Betatorquevirus genus. PMID- 25291760 TI - Draft Genome Sequence of the Yeast Pseudozyma antarctica Type Strain JCM10317, a Producer of the Glycolipid Biosurfactants, Mannosylerythritol Lipids. AB - The basidiomycetous yeast Pseudozyma antarctica is known as a producer of industrial enzymes and the extracellular glycolipids, mannosylerythritol lipids. Here, we report the draft genome sequence of the type strain JCM10317. The draft genome assembly has a size of 18.1 Mb and a G+C content of 60.9%, and it consists of 197 scaffolds. PMID- 25291761 TI - Complete Genome Sequence of Klebsiella pneumoniae Strain ATCC 43816 KPPR1, a Rifampin-Resistant Mutant Commonly Used in Animal, Genetic, and Molecular Biology Studies. AB - Klebsiella pneumoniae is an urgent public health threat due to the spread of carbapenem-resistant strains causing serious, and frequently fatal, infections. To facilitate genetic, molecular, and immunological studies of this pathogen, we report the complete chromosomal sequence of a genetically tractable, prototypical strain used in animal models. PMID- 25291762 TI - Complete Genome Sequence of a Novel Reassortant Avian Influenza H9N9 Virus Isolated from Chicken in Eastern China. AB - The genome sequence of the strain A/chicken/Changzhou/C08/2013 (H9N9) shows that the hemagglutinin (HA) genes of this strain are closely related to those of the strain A/chicken/Shanghai/1107/2013 (H9N2) and share 99.2% nucleotide homology, while the other seven genes had the greatest sequence identities with the novel H7N9 virus. We speculate that this strain may be a novel natural reassortant avian influenza virus (AIV). PMID- 25291763 TI - Draft Genome Assembly of Klebsiella pneumoniae Type Strain ATCC 13883. AB - Klebsiella pneumoniae is a common cause of antibiotic-resistant bacterial infections in immunocompromised individuals. Here, we present the 5.54-Mb scaffolded assembly of the type strain K. pneumoniae type strain ATCC 13883, as deposited in GenBank under accession no. JOOW00000000. PMID- 25291764 TI - Whole-genome sequences of nine francisella isolates. AB - Primarily a zoonotic disease, Francisella tularensis is a fastidious intracellular pathogen and is listed as a CDC category A pathogen with notably high pathogenicity. Here we present the scaffolded genome assemblies of nine Francisella strains: eight F. tularensis and one F. philomiragia. PMID- 25291765 TI - Two Subgroups of Porcine Circovirus 2 Appearing among Pigs in Southern China. AB - We report here two complete genome sequences of porcine circovirus 2. The complete genomes of BH5 and BH6 were amplified and analyzed. Sequence analysis demonstrated that strains BH5 and BH6 belonged to PCV2d and PCV2b, respectively. Knowledge regarding the complete genome sequences of strains BH5 and BH6 will be useful for epidemiological surveillance. PMID- 25291766 TI - Draft Genome Sequence of "Candidatus Phytoplasma asteris" Strain OY-V, an Unculturable Plant-Pathogenic Bacterium. AB - Phytoplasmas are unculturable plant-pathogenic bacteria causing devastating damage to agricultural production worldwide. Here, we report the draft genome sequence of "Candidatus Phytoplasma asteris" strain OY-V. Most of the known virulence factors and host-interacting proteins were conserved in OY-V. This genome furthers our understanding of genetic diversity and pathogenicity of phytoplasmas. PMID- 25291767 TI - Genome Sequences of Two Nondomesticated Bacillus subtilis Strains Able To Form Thick Biofilms on Submerged Surfaces. AB - Genomes of two nondomesticated strains of Bacillus subtilis subspecies subtilis, NDmed and NDfood, have been sequenced. Both strains form very thick and spatially complex biofilms on submerged surfaces. Moreover, biofilms of the NDmed isolate were shown to be highly resistant to antimicrobials action. PMID- 25291768 TI - Genome Sequence of Porphyromonas gingivalis Strain HG66 (DSM 28984). AB - Porphyromonas gingivalis is considered a major etiologic agent in adult periodontitis. Gingipains are among its most important virulence factors, but their release is unique in strain HG66. We present the genome sequence of HG66 with a single contig of 2,441,680 bp and a G+C content of 48.1%. PMID- 25291769 TI - Genome Sequence and Annotation of Acremonium chrysogenum, Producer of the beta Lactam Antibiotic Cephalosporin C. AB - The filamentous fungus Acremonium chrysogenum is the industrial producer of the beta-lactam antibiotic cephalosporin C. Here, we present the genome sequence of strain ATCC 11550, which contains genes for 8,901 proteins, 127 tRNAs, and 22 rRNAs. Genome annotation led to the prediction of 42 gene clusters for secondary metabolites. PMID- 25291770 TI - Draft Genome Assembly of Neisseria lactamica Type Strain A7515. AB - We present the scaffolded genome assembly of Neisseria lactamica type strain A7515 (ATCC 23970) as submitted to NCBI under accession no. JOVI00000000. This type strain of the lactose-fermenting Neisseria species is often used in quality control testing and intra-genus phylogenetic analyses. The assembly includes four contigs placed into a single scaffold. PMID- 25291771 TI - Draft Genome Sequences of Three Escherichia coli Strains Investigated for the Effects of Lysogeny on Niche Diversification. AB - During the course of investigating the effects of lysogeny on niche diversification of Escherichia coli, we used the temperate phages induced from one E. coli strain to infect another and created an isogenic lysogen of the latter. The draft genome sequences of the three E. coli strains are reported herein. PMID- 25291772 TI - Complete Genome Assembly of Reference Strain Ochrobactrum anthropi ATCC 49687. AB - Ochrobactrum anthropi is an occasional cause of nosocomial infections; however, interest in the organism lies in its phylogenetic proximity to the genus Brucella. Here, we present the 4.9-Mb finished genome of Ochrobactrum anthropi ATCC 49687, most commonly used as an exclusionary reference organism. PMID- 25291773 TI - Draft Genome Sequence of the Flagellated Xanthomonas fuscans subsp. fuscans Strain CFBP 4884. AB - We report the draft genome sequence of the flagellated strain CFBP 4884 of Xanthomonas fuscans subsp. fuscans, which was isolated in an outbreak of common bacterial blight of beans along with non-flagellated strains. Comparative genomics will allow one to decipher the genomic diversity of strains cohabiting in epidemics. PMID- 25291774 TI - Genome Assembly of Serratia marcescens Type Strain ATCC 13880. AB - Serratia marcescens ATCC 13880 is the type strain of the species and a commonly used quality control strain. Here, we present the annotated genome assembly of 5.13 Mbp (59.8% G+C content) as submitted to NCBI under accession no. JOVM00000000. PMID- 25291775 TI - Complete Genome Assembly of Enterococcus faecalis 29212, a Laboratory Reference Strain. AB - Enterococcus faecalis is a nonmotile Gram-positive coccus, found both as a commensal organism in healthy humans and animals and as a causative agent of multiple diseases, in particular endocarditis. We sequenced the genome of E. faecalis ATCC 29212, a commonly used reference strain in laboratory studies, to complete "finished" annotated assembly (3 Mb). PMID- 25291776 TI - Complete Genome Assembly of Escherichia coli ATCC 25922, a Serotype O6 Reference Strain. AB - We present the complete genome assembly of Escherichia coli ATCC 25922 as submitted to NCBI under accession no. CP009072. This strain was originally isolated from a clinical sample in Seattle, Washington (1946), and is often used in quality control testing. The assembled genome is 5.20 Mb (50.4% G+C content) and includes two plasmids. PMID- 25291777 TI - Complete Genome Sequence of Chryseobacterium sp. Strain StRB126, an N Acylhomoserine Lactone-Degrading Bacterium Isolated from Potato Root. AB - Chryseobacterium sp. strain StRB126 was isolated from a potato root and showed N acylhomoserine lactone-degrading activity. Here, we present the complete 5,503,743-bp genome sequence of StRB126, which has a G+C content of 35.6% and carries 4,828 protein-coding genes, six rRNA operons, and 80 tRNA genes. PMID- 25291778 TI - Keratitis after corneal projection of biological fluids: a possible occupational prejudice? AB - This article describes a case of Pseudomonas aeruginosa keratitis resulting from projection of biological fluids (bronchial secretions) on the face, mainly in the right eye. The employee presented with keratitis complicated by a corneal abscess. Consequently, the employee had a chronic and severe ocular surface and stoma destruction, possibly due to microbial proliferation into the surface tissues exacerbated by contact lenses. The infection was determined to be work related by experts. [Workplace Health Saf 2014;62(10):400-402.]. PMID- 25291780 TI - Reinventing oneself--sustaining employability. AB - Acquiring additional education and certifications can transform occupational health nurses into leaders who can enhance the workplace. PMID- 25291781 TI - OCT angiography: the next era of OCT technology emerges. AB - This editorial outlines the development of optical coherence tomography (OCT) technology and discusses the emergence of OCT angiography as a true extension of capabilities from spectral-domain OCT. PMID- 25291782 TI - Ultra-widefield retinal imaging in the management of diabetic eye diseases. PMID- 25291783 TI - Swept-source OCT angiography of macular telangiectasia type 2. AB - BACKGROUND AND OBJECTIVE: To evaluate the central macular microvascular network in patients with macular telangiectasia type 2 (MacTel2) using optical coherence tomography (OCT)-based microangiography (OMAG). PATIENTS AND METHODS: Prospective, observational study of patients with MacTel2 evaluated using a swept source OCT (SS-OCT) prototype. OMAG was performed using a 3 mm * 3 mm central foveal raster scan. The algorithm segmented the retina into three layers. Microvascular distribution was depicted as en face images, and qualitative information was compared to fluorescein angiography (FA) images. RESULTS: OMAG detected abnormal microvasculature in all MacTel2 eyes, predominantly in the middle retinal layers with neovascularization in the outer retina. These vessels correlated well with the FA alterations. The abnormal temporal, juxtafoveal microvasculature in MacTel2 became apparent as the disease progressed and in later stages tended to extend circumferentially, with anastomotic vessels temporally. CONCLUSION: OMAG provided detailed, depth- resolved information about the perifoveal macular microvasculature in MacTel2. In most cases, images were better using OMAG than FA. The OMAG images demonstrated that most of the leakage seen on FA appeared to arise from the abnormal perifoveal microvasculature in the middle retinal layer. PMID- 25291784 TI - Pneumatic retinopexy for retinal detachment occurring after prior scleral buckle or pars plana vitrectomy. AB - BACKGROUND AND OBJECTIVE: To report outcomes of pneumatic retinopexy (PR) for retinal detachment (RD) occurring after prior scleral buckling surgery (SB) or pars plana vitrectomy (PPV). PATIENTS AND METHODS: Single-center study evaluating all patients treated between January 2000 and March 2013. RESULTS: Ten eyes underwent PR after prior SB. Nine of these 10 eyes had persistent subretinal fluid posterior to the buckle in the setting of an open break on the scleral buckle. The mean time to PR in these cases was 8.5 days after SB. PR achieved anatomic reattachment in eight of 10 eyes, but two of 10 eyes required additional PPV to achieve retinal reattachment. Seven eyes underwent PR after prior PPV. The average time to RD after PPV was 67 days (range: 15-232 days). The location of the break was superior in four eyes, horizontal in two, and inferior in one. Anatomic reattachment with PR alone occurred in four of seven eyes (57%). CONCLUSION: In the setting of recurrent RD after initial SB, pneumatic retinopexy was usually successful in the early postoperative course. In the setting of a new onset RD after PPV, pneumatic retinopexy was a useful option, but recurrent RD was more common. PMID- 25291785 TI - 8 questions with Dr. Puliafito. PMID- 25291787 TI - Cardiac fiber unfolding by semidefinite programming. AB - Diffusion-tensor imaging allows noninvasive assessment of the myocardial fiber architecture, which is fundamental in understanding the mechanics of the heart. In this context, tractography techniques are often used for representing and visualizing cardiac fibers, but their output is only qualitative. We introduce here a new framework toward a more quantitative description of the cardiac fiber architecture from tractography results. The proposed approach consists in taking three-dimensional (3-D) fiber tracts as inputs, and then unfolding these fibers in the Euclidean plane under local isometry constraints using semidefinite programming. The solution of the unfolding problem takes the form of a Gram matrix which defines the two-dimensional (2-D) embedding of the fibers and whose spectrum provides quantitative information on their organization. Experiments on synthetic and real data show that unfolding makes it easier to observe and to study the cardiac fiber architecture. Our conclusion is that 2-D embedding of cardiac fibers is a promising approach to supplement 3-D rendering for understanding the functioning of the heart. PMID- 25291789 TI - Optimal frequency-based weighting for spectral x-ray projection imaging. AB - The purpose of this work is to derive a weighting scheme that maximizes the frequency-dependent ideal observer signal-difference-to-noise ratio, commonly referred to as detectability index or Hotelling-SDNR, for spectral X-ray projection imaging. Starting from basic statistical decision theory, optimal frequency-dependent weights are derived for a multiple-bin system and the Hotelling-SDNR calculated. A 28% increase in detectability index is found for high frequency objects when applying optimal frequency-dependent weights instead of pixel-based weights to a simplified model of a silicon detector, decreasing towards 0% for low frequency objects. Simulation results indicate a potentially large increase in detectability for high-frequency object imaging using silicon detectors, thus meriting further evaluations on a real system. PMID- 25291788 TI - Ultrasound shear wave elasticity imaging quantifies coronary perfusion pressure effect on cardiac compliance. AB - Diastolic heart failure (DHF) is a major source of cardiac related morbidity and mortality in the world today. A major contributor to, or indicator of DHF is a change in cardiac compliance. Currently, there is no accepted clinical method to evaluate the compliance of cardiac tissue in diastolic dysfunction. Shear wave elasticity imaging (SWEI) is a novel ultrasound-based elastography technique that provides a measure of tissue stiffness. Coronary perfusion pressure affects cardiac stiffness during diastole; we sought to characterize the relationship between these two parameters using the SWEI technique. In this work, we demonstrate how changes in coronary perfusion pressure are reflected in a local SWEI measurement of stiffness during diastole. Eight Langendorff perfused isolated rabbit hearts were used in this study. Coronary perfusion pressure was changed in a randomized order (0-90 mmHg range) and SWEI measurements were recorded during diastole with each change. Coronary perfusion pressure and the SWEI measurement of stiffness had a positive linear correlation with the 95% confidence interval (CI) for the slope of 0.009-0.011 m/s/mmHg ( R(2) = 0.88 ). Furthermore, shear modulus was linearly correlated to the coronary perfusion pressure with the 95% CI of this slope of 0.035-0.042 kPa/mmHg ( R(2) = 0.83). In conclusion, diastolic SWEI measurements of stiffness can be used to characterize factors affecting cardiac compliance specifically the mechanical interaction (cross-talk) between perfusion pressure in the coronary vasculature and cardiac muscle. This relationship was found to be linear over the range of pressures tested. PMID- 25291790 TI - Fast catheter segmentation from echocardiographic sequences based on segmentation from corresponding X-ray fluoroscopy for cardiac catheterization interventions. AB - Echocardiography is a potential alternative to X-ray fluoroscopy in cardiac catheterization given its richness in soft tissue information and its lack of ionizing radiation. However, its small field of view and acoustic artifacts make direct automatic segmentation of the catheters very challenging. In this study, a fast catheter segmentation framework for echocardiographic imaging guided by the segmentation of corresponding X-ray fluoroscopic imaging is proposed. The complete framework consists of: 1) catheter initialization in the first X-ray frame; 2) catheter tracking in the rest of the X-ray sequence; 3) fast registration of corresponding X-ray and ultrasound frames; and 4) catheter segmentation in ultrasound images guided by the results of both X-ray tracking and fast registration. The main contributions include: 1) a Kalman filter-based growing strategy with more clinical data evalution; 2) a SURF detector applied in a constrained search space for catheter segmentation in ultrasound images; 3) a two layer hierarchical graph model to integrate and smooth catheter fragments into a complete catheter; and 4) the integration of these components into a system for clinical applications. This framework is evaluated on five sequences of porcine data and four sequences of patient data comprising more than 3000 X ray frames and more than 1000 ultrasound frames. The results show that our algorithm is able to track the catheter in ultrasound images at 1.3 s per frame, with an error of less than 2 mm. However, although this may satisfy the accuracy for visualization purposes and is also fast, the algorithm still needs to be further accelerated for real-time clinical applications. PMID- 25291791 TI - The evaluation of data completeness and image quality in multiplexing multi pinhole SPECT. AB - Multi-pinhole collimators are often used in pre-clinical SPECT systems because they have a better resolution-sensitivity tradeoff than parallel hole collimators when imaging small objects. Most multi-pinhole collimators are designed to allow no or only a limited amount of overlap between the different pinhole projections because the ambiguity introduced by multiplexing pinholes can result in artifacts. The origin of these artifacts is still not fully understood, but previous research has already shown that data incompleteness could be part of the explanation. Therefore, we developed a method to investigate data completeness in multiplexing multi-pinhole systems and showed that a certain activity distribution can be successfully reconstructed when the nonmultiplexed data is complete or when the overlap can be sufficiently de-multiplexed. We validated this method using computer simulated phantom data of different multiplexing systems. We also studied contrast-to-noise and nonprewhitening matched filter signal-to-noise ratio (NPW-SNR) to compare the image quality in a single pinhole system with multiplexing systems. We found that our method can indeed be used to evaluate data completeness in multiplexing systems and found no artifacts in the systems that had complete data. Sensitivity increased significantly with multiplexing but we found only small, nonsignificant differences in contrast-to noise ratio. However, the NPW-SNR did slightly improve in the multiplexing setups. We conclude that more multiplexing does not necessarily result in more artifacts and that even a high amount of multiplexing can still result in artifact-free images if the nonmultiplexed data is complete or when the overlap can be sufficiently de-multiplexed. PMID- 25291792 TI - A multisize superpixel approach for salient object detection based on multivariate normal distribution estimation. AB - This paper presents a new method for salient object detection based on a sophisticated appearance comparison of multisize superpixels. Those superpixels are modeled by multivariate normal distributions in CIE-Lab color space, which are estimated from the pixels they comprise. This fitting facilitates an efficient application of the Wasserstein distance on the Euclidean norm ( [Formula: see text]) to measure perceptual similarity between elements. Saliency is computed in two ways. On the one hand, we compute global saliency by probabilistically grouping visually similar superpixels into clusters and rate their compactness. On the other hand, we use the same distance measure to determine local center-surround contrasts between superpixels. Then, an innovative locally constrained random walk technique that considers local similarity between elements balances the saliency ratings inside probable objects and background. The results of our experiments show the robustness and efficiency of our approach against 11 recently published state-of-the-art saliency detection methods on five widely used benchmark data sets. PMID- 25291793 TI - High-quality depth map upsampling and completion for RGB-D cameras. AB - This paper describes an application framework to perform high-quality upsampling and completion on noisy depth maps. Our framework targets a complementary system setup, which consists of a depth camera coupled with an RGB camera. Inspired by a recent work that uses a nonlocal structure regularization, we regularize depth maps in order to maintain fine details and structures. We extend this regularization by combining the additional high-resolution RGB input when upsampling a low-resolution depth map together with a weighting scheme that favors structure details. Our technique is also able to repair large holes in a depth map with consideration of structures and discontinuities utilizing edge information from the RGB input. Quantitative and qualitative results show that our method outperforms existing approaches for depth map upsampling and completion. We describe the complete process for this system, including device calibration, scene warping for input alignment, and even how our framework can be extended for video depth-map completion with the consideration of temporal coherence. PMID- 25291794 TI - Multifeature-based surround inhibition improves contour detection in natural images. AB - To effectively perform visual tasks like detecting contours, the visual system normally needs to integrate multiple visual features. Sufficient physiological studies have revealed that for a large number of neurons in the primary visual cortex (V1) of monkeys and cats, neuronal responses elicited by the stimuli placed within the classical receptive field (CRF) are substantially modulated, normally inhibited, when difference exists between the CRF and its surround, namely, non-CRF, for various local features. The exquisite sensitivity of V1 neurons to the center-surround stimulus configuration is thought to serve important perceptual functions, including contour detection. In this paper, we propose a biologically motivated model to improve the performance of perceptually salient contour detection. The main contribution is the multifeature-based center surround framework, in which the surround inhibition weights of individual features, including orientation, luminance, and luminance contrast, are combined according to a scale-guided strategy, and the combined weights are then used to modulate the final surround inhibition of the neurons. The performance was compared with that of single-cue-based models and other existing methods (especially other biologically motivated ones). The results show that combining multiple cues can substantially improve the performance of contour detection compared with the models using single cue. In general, luminance and luminance contrast contribute much more than orientation to the specific task of contour extraction, at least in gray-scale natural images. PMID- 25291795 TI - Illusory sense of human touch from a warm and soft artificial hand. AB - To touch and be touched are vital to human development, well-being, and relationships. However, to those who have lost their arms and hands due to accident or war, touching becomes a serious concern that often leads to psychosocial issues and social stigma. In this paper, we demonstrate that the touch from a warm and soft rubber hand can be perceived by another person as if the touch were coming from a human hand. We describe a three-step process toward this goal. First, we made participants select artificial skin samples according to their preferred warmth and softness characteristics. At room temperature, the preferred warmth was found to be 28.4 degrees C at the skin surface of a soft silicone rubber material that has a Shore durometer value of 30 at the OO scale. Second, we developed a process to create a rubber hand replica of a human hand. To compare the skin softness of a human hand and artificial hands, a robotic indenter was employed to produce a softness map by recording the displacement data when constant indentation force of 1 N was applied to 780 data points on the palmar side of the hand. Results showed that an artificial hand with skeletal structure is as soft as a human hand. Lastly, the participants' arms were touched with human and artificial hands, but they were prevented from seeing the hand that touched them. Receiver operating characteristic curve analysis suggests that a warm and soft artificial hand can create an illusion that the touch is from a human hand. These findings open the possibilities for prosthetic and robotic hands that are life-like and are more socially acceptable. PMID- 25291796 TI - Synthesis of ZnO nanosphere for picomolar level detection of bovine serum albumin. AB - In this paper, we demonstrate an electrical detection technique based on solution processed zinc oxide nanosphere for ultra-low level detection of bovine serum albumin (BSA). Our sensor device works on the basis of the variation of conductance of the ZnO nanosphere with different concentration of BSA. The morphological and structural characterizations of ZnO nanosphere were carried out by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Circular dichroism (CD) spectroscopy was performed to investigate the chemical interaction between the BSA and zinc oxide nanosphere. Optical detection was performed using absorbance and Fourier transform infrared spectroscopy (FTIR) studies. Our device exhibits sensitivity 0.126 nA/pM, lower limit of detection (LOD) 10 pM and the fast response time around 5 s, confirming the highest sensitivity for BSA detection achieved so far. Sensing mechanism is governed on the basis of the charge transfer phenomenon between BSA and ZnO. All measurements were carried out at 1 V bias for low power operation. PMID- 25291797 TI - Development of a Guaranteed Stable Network of Telerobots with Kinesthetic Consensus. AB - We present the research advances on the development of 50-200 mJ energy range diode-pumped Yb:CaF2- based multipass amplifiers operating at relatively high repetition rates. These laser amplifiers are based on diverse innovative geometries. All these innovations aim to design compact, stable and reliable amplifiers adapted to our application that consists in pumping ultrashort-pulse OPCPA (optical parametric chirped pulse amplifier) systems in the frame of the Apollon 10 PW laser project. The targeted repetition rate is in the range of 20 100 Hz with energies of few tens of mJ for the first stages up to 1 J for the final stage. An analysis of the specificities of Yb:CaF2 is done to explain the different options we chose to fulfil these specifications. The critical points and limitations of the multipass Yb:CaF2-based amplifiers are subsequently discussed. To overcome the encountered problems, different issues are investigated such as crystal optimisation, laser head geometry, thermo-optical dynamics or coherent combining techniques. Experimental results for different multipass configurations are demonstrated and discussed. PMID- 25291798 TI - Opportunistic Behavior in Motivated Learning Agents. AB - This paper focuses on the novel motivated learning (ML) scheme and opportunistic behavior of an intelligent agent. It extends previously developed ML to opportunistic behavior in a multitask situation. Our paper describes the virtual world implementation of autonomous opportunistic agents learning in a dynamically changing environment, creating abstract goals, and taking advantage of arising opportunities to improve their performance. An opportunistic agent achieves better results than an agent based on ML only. It does so by minimizing the average value of all need signals rather than a dominating need. This paper applies to the design of autonomous embodied systems (robots) learning in real time how to operate in a complex environment. PMID- 25291799 TI - Adaptive Batch Mode Active Learning. AB - Active learning techniques have gained popularity to reduce human effort in labeling data instances for inducing a classifier. When faced with large amounts of unlabeled data, such algorithms automatically identify the exemplar and representative instances to be selected for manual annotation. More recently, there have been attempts toward a batch mode form of active learning, where a batch of data points is simultaneously selected from an unlabeled set. Real-world applications require adaptive approaches for batch selection in active learning, depending on the complexity of the data stream in question. However, the existing work in this field has primarily focused on static or heuristic batch size selection. In this paper, we propose two novel optimization-based frameworks for adaptive batch mode active learning (BMAL), where the batch size as well as the selection criteria are combined in a single formulation. We exploit gradient descent-based optimization strategies as well as properties of submodular functions to derive the adaptive BMAL algorithms. The solution procedures have the same computational complexity as existing state-of-the-art static BMAL techniques. Our empirical results on the widely used VidTIMIT and the mobile biometric (MOBIO) data sets portray the efficacy of the proposed frameworks and also certify the potential of these approaches in being used for real-world biometric recognition applications. PMID- 25291800 TI - Progressive Learning Machine: A New Approach for General Hybrid System Approximation. AB - As the most important property of neural networks (NNs), the universal approximation capability of NNs is widely used in many applications. However, this property is generally proven for continuous systems. Most industrial systems are hybrid systems (e.g., piecewise continuous), which is a significant limitation for real applications. Recently, many identification methods have been proposed for hybrid system approximation; however, these methods only operate in linear hybrid systems. In this paper, the progressive learning machine-a new learning algorithm based on multi-NNs-is proposed for general hybrid nonlinear/linear system approximation. This algorithm classifies hybrid systems into several continuous systems and can approximate any hybrid system with zero output error. The performance of the proposed learning method is demonstrated via numerical examples and with experimental data from real applications. PMID- 25291801 TI - A multistaged automatic restoration of noisy microscopy cell images. AB - Automated cell segmentation for microscopy cell images has recently become an initial step for further image analysis in cell biology. However, microscopy cell images are easily degraded by noise during the readout procedure via optical electronic imaging systems. Such noise degradations result in low signal-to-noise ratio (SNR) and poor image quality for cell identification. In order to improve SNR for subsequent segmentation and image-based quantitative analysis, the commonly used state-of-art restoration techniques are applied but few of them are suitable for corrupted microscopy cell images. In this paper, we propose a multistaged method based on a novel integration of trend surface analysis, quantile-quantile plot, bootstrapping, and the Gaussian spatial kernel for the restoration of noisy microscopy cell images. We show this multistaged approach achieves higher performance compared with other state-of-art restoration techniques in terms of peak signal-to-noise ratio and structure similarity in synthetic noise experiments. This paper also reports an experiment on real noisy microscopy data which demonstrated the advantages of the proposed restoration method for improving segmentation performance. PMID- 25291802 TI - Complexity index from a personalized wearable monitoring system for assessing remission in mental health. AB - This study discusses a personalized wearable monitoring system, which provides information and communication technologies to patients with mental disorders and physicians managing such diseases. The system, hereinafter called the PSYCHE system, is mainly comprised of a comfortable t-shirt with embedded sensors, such as textile electrodes, to monitor electrocardiogram-heart rate variability (HRV) series, piezoresistive sensors for respiration activity, and triaxial accelerometers for activity recognition. Moreover, on the patient-side, the PSYCHE system uses a smartphone-based interactive platform for electronic mood agenda and clinical scale administration, whereas on the physician-side provides data visualization and support to clinical decision. The smartphone collects the physiological and behavioral data and sends the information out to a centralized server for further processing. In this study, we present experimental results gathered from ten bipolar patients, wearing the PSYCHE system, with severe symptoms who exhibited mood states among depression (DP), hypomania(HM), mixed state (MX), and euthymia (EU), i.e., the good affective balance. In analyzing more than 400 h of cardiovascular dynamics, we found that patients experiencing mood transitions from a pathological mood state (HM, DP, or MX-where depressive and hypomanic symptoms are simultaneously present) to EU can be characterized through a commonly used measure of entropy. In particular, the SampEn estimated on long-term HRV series increases according to the patients' clinical improvement. These results are in agreement with the current literature reporting on the complexity dynamics of physiological systems and provides a promising and viable support to clinical decision in order to improve the diagnosis and management of psychiatric disorders. PMID- 25291804 TI - A consistency-specificity trade-off to select source behavior in information fusion. AB - Combining pieces of information provided by several sources without or with little prior knowledge about the behavior of the sources is an old yet still important and rather open problem in the belief function theory. In this paper, we propose an approach to select the behavior of sources based on a very general and expressive fusion scheme, that has the important advantage of making clear the assumptions made about the sources. The selection process itself relies on two cornerstones that are the notions of specificity and consistency of a knowledge representation, and that we adapt to the considered fusion scheme. We illustrate our proposal on different examples and show that the proposed approach actually encompasses some important existing fusion strategies. PMID- 25291803 TI - Embedded DSP-based telehealth radar system for remote in-door fall detection. AB - Telehealth systems and applications are extensively investigated nowadays to enhance the quality-of-care and, in particular, to detect emergency situations and to monitor the well-being of elderly people, allowing them to stay at home independently as long as possible. In this paper, an embedded telehealth system for continuous, automatic, and remote monitoring of real-time fall emergencies is presented and discussed. The system, consisting of a radar sensor and base station, represents a cost-effective and efficient healthcare solution. The implementation of the fall detection data processing technique, based on the least-square support vector machines, through a digital signal processor and the management of the communication between radar sensor and base station are detailed. Experimental tests, for a total of 65 mimicked fall incidents, recorded with 16 human subjects (14 men and two women) that have been monitored for 320 min, have been used to validate the proposed system under real circumstances. The subjects' weight is between 55 and 90 kg with heights between 1.65 and 1.82 m, while their age is between 25 and 39 years. The experimental results have shown a sensitivity to detect the fall events in real time of 100% without reporting false positives. The tests have been performed in an area where the radar's operation was not limited by practical situations, namely, signal power, coverage of the antennas, and presence of obstacles between the subject and the antennas. PMID- 25291805 TI - Hierarchical Bayesian inverse reinforcement learning. AB - Inverse reinforcement learning (IRL) is the problem of inferring the underlying reward function from the expert's behavior data. The difficulty in IRL mainly arises in choosing the best reward function since there are typically an infinite number of reward functions that yield the given behavior data as optimal. Another difficulty comes from the noisy behavior data due to sub-optimal experts. We propose a hierarchical Bayesian framework, which subsumes most of the previous IRL algorithms as well as models the sub-optimality of the expert's behavior. Using a number of experiments on a synthetic problem, we demonstrate the effectiveness of our approach including the robustness of our hierarchical Bayesian framework to the sub-optimal expert behavior data. Using a real dataset from taxi GPS traces, we additionally show that our approach predicts the driving behavior with a high accuracy. PMID- 25291806 TI - Segment Based Decision Tree Induction With Continuous Valued Attributes. AB - A key issue in decision tree (DT) induction with continuous valued attributes is to design an effective strategy for splitting nodes. The traditional approach to solving this problem is adopting the candidate cut point (CCP) with the highest discriminative ability, which is evaluated by some frequency based heuristic measures. However, such methods ignore the class permutation of examples in the node, and they cannot distinguish the CCPs with the same or similar frequency information, thus may fail to induce a better and smaller tree. In this paper, a new concept, i.e., segment of examples, is proposed to differentiate the CCPs with same frequency information. Then, a new hybrid scheme that combines the two heuristic measures, i.e., frequency and segment, is developed for splitting DT nodes. The relationship between frequency and the expected number of segments, which is regarded as a random variable, is also given. Experimental comparisons demonstrate that the proposed scheme is not only effective to improve the generalization capability, but also valid to reduce the size of the tree. PMID- 25291807 TI - LDA-Based Unified Topic Modeling for Similar TV User Grouping and TV Program Recommendation. AB - Social TV is a social media service via TV and social networks through which TV users exchange their experiences about TV programs that they are viewing. For social TV service, two technical aspects are envisioned: grouping of similar TV users to create social TV communities and recommending TV programs based on group and personal interests for personalizing TV. In this paper, we propose a unified topic model based on grouping of similar TV users and recommending TV programs as a social TV service. The proposed unified topic model employs two latent Dirichlet allocation (LDA) models. One is a topic model of TV users, and the other is a topic model of the description words for viewed TV programs. The two LDA models are then integrated via a topic proportion parameter for TV programs, which enforces the grouping of similar TV users and associated description words for watched TV programs at the same time in a unified topic modeling framework. The unified model identifies the semantic relation between TV user groups and TV program description word groups so that more meaningful TV program recommendations can be made. The unified topic model also overcomes an item ramp up problem such that new TV programs can be reliably recommended to TV users. Furthermore, from the topic model of TV users, TV users with similar tastes can be grouped as topics, which can then be recommended as social TV communities. To verify our proposed method of unified topic-modeling-based TV user grouping and TV program recommendation for social TV services, in our experiments, we used real TV viewing history data and electronic program guide data from a seven-month period collected by a TV poll agency. The experimental results show that the proposed unified topic model yields an average 81.4% precision for 50 topics in TV program recommendation and its performance is an average of 6.5% higher than that of the topic model of TV users only. For TV user prediction with new TV programs, the average prediction precision was 79.6%. Also, we showed the superiority of our proposed model in terms of both topic modeling performance and recommendation performance compared to two related topic models such as polylingual topic model and bilingual topic model. PMID- 25291808 TI - Learning Multiscale Active Facial Patches for Expression Analysis. AB - In this paper, we present a new idea to analyze facial expression by exploring some common and specific information among different expressions. Inspired by the observation that only a few facial parts are active in expression disclosure (e.g., around mouth, eye), we try to discover the common and specific patches which are important to discriminate all the expressions and only a particular expression, respectively. A two-stage multitask sparse learning (MTSL) framework is proposed to efficiently locate those discriminative patches. In the first stage MTSL, expression recognition tasks are combined to located common patches. Each of the tasks aims to find dominant patches for each expression. Secondly, two related tasks, facial expression recognition and face verification tasks, are coupled to learn specific facial patches for individual expression. The two-stage patch learning is performed on patches sampled by multiscale strategy. Extensive experiments validate the existence and significance of common and specific patches. Utilizing these learned patches, we achieve superior performances on expression recognition compared to the state-of-the-arts. PMID- 25291809 TI - Visual-Patch-Attention-Aware Saliency Detection. AB - The human visual system (HVS) can reliably perceive salient objects in an image, but, it remains a challenge to computationally model the process of detecting salient objects without prior knowledge of the image contents. This paper proposes a visual-attention-aware model to mimic the HVS for salient-object detection. The informative and directional patches can be seen as visual stimuli, and used as neuronal cues for humans to interpret and detect salient objects. In order to simulate this process, two typical patches are extracted individually and in parallel from the intensity channel and the discriminant color channel, respectively, as the primitives. In our algorithm, an improved wavelet-based salient-patch detector is used to extract the visually informative patches. In addition, as humans are sensitive to orientation features, and as directional patches are reliable cues, we also propose a method for extracting directional patches. These two different types of patches are then combined to form the most important patches, which are called preferential patches and are considered as the visual stimuli applied to the HVS for salient-object detection. Compared with the state-of-the-art methods for salient-object detection, experimental results using publicly available datasets show that our produced algorithm is reliable and effective. PMID- 25291810 TI - Irregular Cellular Learning Automata. AB - Cellular learning automaton (CLA) is a recently introduced model that combines cellular automaton (CA) and learning automaton (LA). The basic idea of CLA is to use LA to adjust the state transition probability of stochastic CA. This model has been used to solve problems in areas such as channel assignment in cellular networks, call admission control, image processing, and very large scale integration placement. In this paper, an extension of CLA called irregular CLA (ICLA) is introduced. This extension is obtained by removing the structure regularity assumption in CLA. Irregularity in the structure of ICLA is needed in some applications, such as computer networks, web mining, and grid computing. The concept of expediency has been introduced for ICLA and then, conditions under which an ICLA becomes expedient are analytically found. PMID- 25291811 TI - How Much Control is Enough for Network Connectivity Preservation and Collision Avoidance? AB - For a multiagent system in free space, the agents are required to generate sufficiently large cohesive force for network connectivity preservation and sufficiently large repulsive force for collision avoidance. This paper gives an energy function based approach for estimating the control force in a general setting. In particular, the force estimated for network connectivity preservation and collision avoidance is separated from the force for other collective behavior of the agents. Moreover, the estimation approach is applied in three typical collective control scenarios including swarming, flocking, and flocking without velocity measurement. PMID- 25291812 TI - Manifold Adaptive Label Propagation for Face Clustering. AB - In this paper, a novel label propagation (LP) method is presented, called the manifold adaptive label propagation (MALP) method, which is to extend original LP by integrating sparse representation constraint into regularization framework of LP method. Similar to most LP, first of all, MALP also finds graph edges from given data and gives weights to the graph edges. Our goal is to find graph weights matrix adaptively. The key advantage of our approach is that MALP simultaneously finds graph weights matrix and predicts the label of unlabeled data. This paper also derives efficient algorithm to solve the proposed problem. Extensions of our MALP in kernel space and robust version are presented. The proposed method has been applied to the problem of semi-supervised face clustering using the well-known ORL, Yale, extended YaleB, and PIE datasets. Our experimental evaluations show the effectiveness of our method. PMID- 25291814 TI - People with drug dependence need better access to health care. PMID- 25291813 TI - UN strengthens regulations on melamine, seafood, melons, dried figs and labelling. PMID- 25291815 TI - Ask the doctor. After several episodes where my heart suddenly started racing, I was diagnosed with supraventricular tachycardia. My doctor said I could try gagging or coughing to help slow down my heart when these episodes occur. Why would these things help? PMID- 25291816 TI - Vena cava filters: tiny cages that trap blood clots. These special filters protect against pulmonary embolism but also carry risks. PMID- 25291817 TI - Digoxin: old friend or old foe? The controversial heart failure drug has a new role in limiting hospital stays. PMID- 25291818 TI - Should an abnormal electrocardiogram be a cause for worry? Here's the truth about left and right bundle branch blocks that show up on some ECG readings. PMID- 25291819 TI - Blood transfusions for heart surgery: less necessary than in the past. Cardiac surgeons can take steps to avoid the need for a transfusion. PMID- 25291820 TI - Can calming your mind help your heart? Meditation offers promising benefits for the cardiovascular system. PMID- 25291821 TI - From hot dogs to heart failure. PMID- 25291822 TI - Long-term exposure to traffic fumes may damage blood vessels. PMID- 25291823 TI - Cardiac rehab after a heart attack. PMID- 25291824 TI - These are the "hard core spectators" or "spectator only" type. PMID- 25291825 TI - Crime and punishment. PMID- 25291826 TI - The dilemma of effectively communicating with members. PMID- 25291827 TI - The future of our profession. PMID- 25291828 TI - Oral pathology quiz #84. Case number 1. Pleomorphic adenoma. PMID- 25291829 TI - Oral pathology quiz #84. Case number 2. Lichenoid mucositis. PMID- 25291830 TI - Oral pathology quiz #84. Case number 3. Benign hyperkeratosis. PMID- 25291831 TI - Oral pathology quiz #84. Case number 4. Rarefying osteomyelitis. PMID- 25291832 TI - Blood clots. Good when you're bleeding; bad when you're not bleeding hypercoagulability and thrombophilia--overview and case report. AB - A critical and recurrent situation faced by the dental clinician (DC) is that of providing care to patients who may be at risk for excessive bleeding during care or post-operatively. Bleeding disorders may be due to congenital and/or acquired conditions affecting platelets and/or the coagulation process. Less often, the DC may be providing care to a patient who has an excessive clotting disorder. This paper will provide a brief overview the pathophysiology of these disorders and treatment considerations for these patients. The focus is to provide some background information for the DC so as to be better informed if a patient does present with a particular thrombotic problem. Specific details of each disorder can vessel be assessed on an individual basis pending the diagnostic category and the patient's therapy. A clinical case report will be presented. PMID- 25291833 TI - Clinical remount and occlusal equilibration. PMID- 25291834 TI - Sex and the dentist. PMID- 25291835 TI - Public health experts urge U.S. hospitals to be prepared as Ebola outbreak accelerates. AB - With the outbreak of Ebola virus disease (EBD) accelerating in West Africa, public health authorities are urging frontline providers in the United States to be vigilant in questioning patients who present with a suspected infectious disease, and in adhering to infection control practices. Recent travel to West Africa and contact with others who may have been exposed to EVD are key points that need to be covered at triage, say experts. The World Health Organization (WHO) indicates that mortality from the latest outbreak is 55%, although it is as high as 75% in Guinea. Health care workers are particularly vulnerable to EVD, with WHO noting that more than 250 workers in West Africa have contracted EVD and at least 120 have died from the disease. Experts say that one of the greatest times of risk for health care workers is while a patient is at triage because he or she has not yet been placed in isolation precautions. The CDC is recommending that hospitals rigorously apply standard infection control policies at a minimum, and that extra protective equipment may be required when there are body fluids in the patient environment. Hospitals in 27 states have reported dozens of suspected cases of EVD to the CDC, but at press time, none had yet tested positive. PMID- 25291836 TI - Improved awareness, better screening needed to identify delirium patients who present to the ED. AB - While many older patients experience symptoms of delirium while in the emergency setting, the condition often is not recognized by emergency providers. Further, a missed diagnosis can lead to enhanced caregiver stress as well as a higher risk of institutionalization, readmission, and death. Experts suggest that providers need to be better educated on the subtle clues that a patient may be delirious so that steps can be taken to find and address the inciting cause. Research shows that delirium is present in 7% to 10% of older patients who present to the ED, but it is unrecognized about 75% of the time. Most cases of delirium involve what is called the hypoactive subtype in which patients appear to be sedate or depressed, and they have difficulty paying attention. Many patients with hypoactive delirium are mistaken as being depressed, and as a result, this is a subtype that is frequently missed by clinicians. While no screening tool is 100% effective, researchers have had the best success with a two-step process that involves use of a rapid Delirium Triage Screen (DTS) to rule out delirium. Patients who are not ruled out by the DTS then undergo a more formal Brief Confusion Assessment Method or B-CAM, a tool that is a modified form of the CAM ICU. PMID- 25291837 TI - Unique program aims to connect frequent ED utilizers with medical homes, resources to meet complex needs. AB - Sinai Hospital of Baltimore in Baltimore, MD, is partnering with HealthCare Access Maryland, a non-profit organization in the state, to link patients who frequent the ED for care with medical homes and other resources that can better meet their medical and social needs. Under the Access Health Program, ED-based care coordinators intervene with patients who meet program criteria, linking them with medical homes and other resources that address their complex needs. The hospital has devised a flag to notify the ED when a frequent-utilizing patient presents in the department for care. Care coordinators then meet with these patients and get their consent to participate in the program. Within a week of the ED visit, care coordinators schedule a home visit with the patient to establish a care plan containing specific goals and a time frame to carry out these goals. Patients remain in the program for 90 days as care coordinators work to hand them off to longer-term resources. Many of the patients enrolled in the program have substance abuse and mental health problems. Patients are also often uninsured and/or homeless. Within two months of launching the program, care coordinators enrolled 74 patients, with the goal of eventually bringing that number to 200. PMID- 25291838 TI - [Ebola is not a danger for Europe]. PMID- 25291839 TI - [The breath of the newborn infant - therapeutic music for premature infants]. PMID- 25291840 TI - [Compatibility of family and career]. PMID- 25291841 TI - [Documentation and liability in pediatric home care nursing - a narrow level of responsibility. 1]. PMID- 25291842 TI - [What must be considered in hygienic preparation of milk?]. PMID- 25291843 TI - [Housekeeping help should supplement pediatric nursing care]. PMID- 25291845 TI - [U1, U2, U3... - the importance of routine]. PMID- 25291846 TI - [Fundraising for anxiety- and stress-free medicine]. PMID- 25291847 TI - [Do breast fed infants need a certain number of meals or feed "ad libitum"?]. PMID- 25291849 TI - More than one-fifth of docs avoiding MU program. PMID- 25291848 TI - Message to Congress: strengthen access to data. PMID- 25291850 TI - An all-star cast. HDM honors individuals and organizations that are leading the way with analytics. PMID- 25291851 TI - Sticking to the plan. New mobile hardware and apps are being used to tackle medication non-adherence, an enormous clinical and financial problem. PMID- 25291852 TI - Breaking down silos. Enterprise content management is liberating unstructured data for some providers. PMID- 25291853 TI - Analytics roundtable: disrupting the status quo. HIT leaders discuss the perplexities of the current health system and how analytics can help make sense of it all. PMID- 25291854 TI - Change through exchange. PMID- 25291855 TI - Histometry of high-grade cervical intraepithelial neoplasia and LEEP excision margin in HIV-infected and uninfected women. AB - OBJECTIVE: To investigate whether the size of the lesion correlates with the completeness of excision, and whether human immunodeficiency virus (HIV) infection was a risk factor for incompleteness of excision. We investigated the size of high-grade cervical intraepithelial lesions of loop electrosurgical excision procedure (LEEP) specimens to assess its effect on the status of the excision margins. Because of the possible negative effect of HIV infection on the completeness of excision, we compared HIV-positive with HIV-negative cases. STUDY DESIGN: Cross-sectional study of 226 consecutive LEEP specimens with cervical intraepithelial neoplasia (CIN). There were 126 CINs > or = 2; 59 (46.8%) were HIV positive. We measured the linear surface, the number of involved crypts, and the number of step sections involved by CIN > or = 2. RESULTS: The excision margins were involved in 65.1%. The measurable linear extent and the average number of involved crypts and sections were significantly higher with incomplete excision (p < 0.0001, p = 0.001, and p = 0.02, respectively). The endocervical excision margin was involved in 52.4% of incomplete excisions. The excision was incomplete in 43.9% of HIV-infected and 56.1% of HIV-uninfected cases (chi2 = 0.03, p = 0.88). CONCLUSION: It appears that instead of the linear surface involvement, it is rather the location in the endocervix and the extension inside the crypts that affects the excision margin status. HIV infection did not affect the completeness of excision. PMID- 25291856 TI - Classification of endometrial lesions by nuclear morphometry features extracted from liquid-based cytology samples: a system based on logistic regression model. AB - OBJECTIVE: To investigate the potential of a computerized system for the discrimination of benign from malignant endometrial nuclei and lesions. STUDY DESIGN: A total of 228 histologically confirmed liquid-based cytological smears were collected: 117 within normal limits cases, 66 malignant cases, 37 hyperplasias without atypia, and 8 cases of hyperplasia with atypia. From each case we extracted nuclear morphometric features from about 100 nuclei using a custom image analysis system. Initially we performed feature selection, and subsequently we applied a logistic regression model that classified each nucleus as benign or malignant. Based on the results of the nucleus classification process, we constructed an algorithm to discriminate endometrium cases as benign or malignant. RESULTS: The proposed system had an overall accuracy for the classification of endometrial nuclei equal to 83.02%, specificity of 85.09%, and sensitivity of 77.01%. For the case classification the overall accuracy was 92.98%, specificity was 92.86%, and sensitivity was 93.24%. CONCLUSION: The proposed computerized system can be applied for the classification of endometrial nuclei and lesions as it outperformed the standard cytological diagnosis. This study highlights interesting diagnostic features of endometrial nuclear morphology, and the proposed method can be a useful tool in the everyday practice of the cytological laboratory. PMID- 25291857 TI - Morphology and tissue distribution of four kinds of endocrine cells in the digestive tract of the Chinese yellow quail (Coturnix japonica). AB - OBJECTIVE: To describe the tissue distribution, density, and the morphological characteristics of 4 kinds of endocrine cells in the digestive tract of the Chinese yellow quail (Coturnix japonica). STUDY DESIGN: The streptavidin-biotin peroxidase complex immunohistochemical method was used to identify the distribution of somatostatin (SS), serotonin (5-HT), gastrin and neuropeptide Y (NPY) in digestive tracts including proventriculus, duodenum, jejunum, ileum, and rectum. SPSS 19.0 software was used to perform biological statistical analysis. RESULTS: The results showed that the SS and 5-HT secreting cells were mainly distributed in the proventriculus (19.2 +/- 6.9 and 16.1 +/- 3.4 cfu/mm2) and duodenum (2.9 +/- 2.0 and 1.9 +/- 0.6 cfu/mm2). Gastrin and NPY were not detected in each section of the digestive tract. Moreover, there was no significant difference in the quantitative distribution and morphological characteristics of SS and 5-HT secreting cells in the digestive tract between male and female quails. CONCLUSION: The distribution and morphological characteristics of endocrine cells were closely related to the physiological functions of different parts in the digestive tract. The preferential location of endocrine cells provides additional information for future studies on the physiological roles of gastrointestinal peptides in the gastrointestinal tract of the Chinese yellow quail. PMID- 25291858 TI - Cytological analysis of bronchoalveolar lavage in patients with interstitial lung diseases and the relation of cytological analysis to fibrosis in high-resolution computed tomography. AB - OBJECTIVE: To evaluate the value of differential cytology of bronchoalveolar lavage (BAL) in common interstitial lung diseases (ILDs) and its relation with high-resolution computed tomography (HRCT) fibrosis. STUDY DESIGN: A retrospective analysis of BAL from 91 patients. The total and percentage of cells were collected and analyzed according to published guidelines. RESULTS: The main diagnoses were connective tissue diseases (n = 24), hypersensitivity pneumonitis (HP) (n = 15), sarcoidosis (n = 12), idiopathic pulmonary fibrosis (IPF) (n = 14), smoking-related interstitial lung diseases (sr-ILDs) (n = 8), aspiration (n = 8), and others (n = 10). The lymphocyte percentages differed among diagnoses (F = 2.85, p = 0.008). A greater number of lymphocytes were found in sarcoidosis (Md = 20%, IQR = 12-45%), HP (Md = 29%, IQR = 13-55%), and organizing pneumonia (Md = 28, IQR = 9-50%). No patient with IPF presented with > 25% lymphocytes in BAL. In 6/15 (40%) of the HP cases, the percentage of lymphocytes was < 25%. A total of 56 participants (62%) displayed HRCT findings that were indicative of fibrosis. In those cases the percentage of lymphocytes was 10.1 (IQR = 6.1-18.0) as compared with 20.2% (IQR = 9.7-37.5) of those 35 cases without fibrosis (p = 0.007). In patients with fibrosis in HRCT, the percentage of neutrophils was 11.3 (IQR = 4.1-21.4) as compared with 3.8 (IQR = 1.4-3.8) in those without fibrosis (p = 0.009). CONCLUSION: Several patterns in differential cytology are observed in common ILDs. The presence of fibrosis has an impact on these findings. PMID- 25291859 TI - Effect of erythropoietin on acoustically traumatized rat cochlea: an immunohistochemical study. AB - OBJECTIVE: To investigate the audiological and histopathological effects of erythropoietin on acoustic overstimulation in rats. STUDY DESIGN: Twenty-two male Wistar albino rats were divided into 3 groups: sham group (n = 7), erythropoietin injection group (n = 8), and saline injection group (n = 7). Both erythropoietin and saline injection groups were exposed to white noise (100 decibel [dB] sound pressure level [SPL]) for 3 hours. Auditory brainstem responses were measured before, immediately after, and on the 7th day of noise exposure. All animals were sacrificed on the 7th day and temporal bones were collected. The serial sections of the cochleae were stained by caspase-3 and caspase-9 immunostaining and by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method in order to detect apoptotic cells. RESULTS: In the saline group statistically significant differences were detected between the baseline and immediate postacoustic overstimulation thresholds of click and 6 kHz stimuli. However, when the baseline and immediate postacoustic overstimulation thresholds of click and 6 kHz stimuli were compared in the erythropoietin injection group, no statistically significant difference was determined. Histopathologic evaluations demonstrated that erythropoietin decreased the amount of apoptotic cells in the cochlea. CONCLUSION: Erythropoietin is likely to prevent the acute threshold changes and decrease the amount of apoptosis in cochlea after acoustic overstimulation in rats. PMID- 25291860 TI - Role of mast cells in skin tag development: an immunohistochemical study. AB - OBJECTIVE: To detect mast cell density by toluidine blue and immunohistochemical staining for mast cell tryptase in skin tags as compared to normal skin to determine whether they have a role in skin tag development. STUDY DESIGN: This study was carried out on 30 patients with skin tags and 10 age- and sex-matched healthy controls without skin tags. RESULTS: There was a significant difference between skin tag and control groups regarding mast cell density evaluated by toluidine blue staining (p = 0.003) and mast cell tryptase expression (p = 0.001), where the density was higher in skin tags as compared to normal skin. Mast cells were higher in number using toluidine blue staining in lesions arising in sites other than the head and neck (p = 0.028). High expression of mast cell tryptase was significantly associated with marked collagenosis (p = 0.02) and presence of eosinophils (p = 0.04). CONCLUSION: The present study demonstrates the possible role of mast cells in promoting fibrosis and facilitating the development of skin tags. Mast cells may attract eosinophils to cooperate in inducing more fibrosis in skin tag development. PMID- 25291861 TI - Fine needle aspiration biopsy of complex renal cystic tumors in the era of modern imaging modalities: where shall we go? AB - OBJECTIVE: To report on a series of fine needle aspiration (FNA) biopsies for preoperative diagnosis of complex cystic renal mass. STUDY DESIGN: From August 2002 to February 2009, 32 patients with a complex cystic renal mass were studied. Tumor size ranged from 1.5-7.7 cm, with a median of 3.0 cm. Bosniak classification was 15 IIF, 12 III, and 5 IV. FNA biopsy was performed under CT guidance to obtain the fluid. Malignant and suspect cytological reports were considered as a positive diagnosis, and absence of epithelial cells as a negative diagnosis. RESULTS: Sufficient fluid was obtained in all cases. A positive preoperative diagnosis was found in 11 patients, and 21 cysts presented as absence of epithelial cells. Of the 26 patients who underwent surgery, pathology proved that there were 21 malignant and 5 benign cysts. Among the operated patients with a malignant cystic tumor, 11/21 (52.3%) presented a negative preoperative diagnosis. One preoperative positive diagnosis was proved to be a benign cyst. The accuracy of preoperative positive cytology was 10/11 (90.9%). CONCLUSION: No difficulty was noticed in obtaining the fluid by FNA of a cystic small renal mass. A false negative diagnosis was due mainly to the absence of malignant cells in the fluid of cysts. Biomarkers in fluid shall be studied to solve the diagnostic problem. PMID- 25291862 TI - Composite chromophobe renal cell carcinoma with sarcomatoid differentiation containing osteosarcoma, chondrosarcoma, squamous metaplasia and associated collecting duct carcinoma: a case report. AB - BACKGROUND: Chromophobe renal cell carcinoma (ChRCC) is a morphologically distinct renal cell carcinoma type which may rarely show composite morphology. CASE: A 61-year-old man presented with a composite ChRCC with sarcomatoid transformation containing osteosarcomatous, chondrosarcomatous and squamous metaplastic differentiation and associated with a high-grade collecting duct carcinoma (CDC). The patient presented with a metastatic disease in the regional lymph nodes, comprised only of CDC, and died after 21 months. CONCLUSION: Although ChRCC associated with sarcomatoid change has been well documented, the presence of osteosarcoma has been previously reported in only 5 ChRCCs, 2 of which also contained chondrosarcoma. Squamous differentiation has been previously found in only 2 ChRCCs with sarcomatoid change, and ChRCC associated with CDC has been previously reported in only 3 cases, but none with heterologous elements. To our knowledge this represents a previously unreported composite type of RCC, with an aggressive clinical behavior. PMID- 25291863 TI - Amyloid goiter: cytomorphological features and differential diagnosis on fine needle aspiration cytology: a case report. AB - BACKGROUND: Amyloid goiter is a rare cause of thyroid enlargement which can be confused clinically as well as cytologically with both colloid goiter and neoplastic process of thyroid. CASE: A 30-year-old man, diagnosed with chronic kidney disease 5 months previously and currently on dialysis and awaiting renal transplant, was referred by clinicians for fine needle aspiration cytology (FNAC) for thyroid swelling. FNAC showed dense amorphous clumps of extracellular material which appeared magenta colored on Giemsa and eosinophilic on Papanicolaou stain. Congo red staining and polarization showed characteristic apple green birefringence, thus confirming the material as amyloid, and the diagnosis of amyloid goiter was made. CONCLUSION: Amyloid on FNAC smears can be easily mistaken for colloid, and correct interpretation can avoid a false diagnosis of colloid goiter. A search should be made to look for any features suggestive of medullary carcinoma of the thyroid as amyloid is more often associated with it. PMID- 25291864 TI - Lipomatous myofibroblastoma of the breast: case report with diagnostic and histogenetic considerations. AB - We report rare case of myofibroblastoma (MFB) of the breast comprised predominantly of a mature fatty component, representing approximately 70% of the entire tumour area. This tumour, designated "lipomatous MFB", should be interpreted as the morphological result of an unbalanced bidirectional differentiation of the precursor mammary stromal cell, with the adipocytic component overwhelming the fibroblastic/myofibroblastic one. Lipomatous MFB is a rare variant of mammary MFB, which can mimic malignancy because of the close juxtaposition of fibroblasts/myofibroblasts with mature adipocytes, resulting in a finger-like infiltrative growth pattern of the former towards the latter. Histogenetic considerations and differential diagnostic problems with other bland looking spindle cell tumours containing infiltrating fat are provided. PMID- 25291865 TI - Cytological features of nipple adenoma in scraping smears. AB - INTRODUCTION: Nipple adenoma (NA) is a benign epithelial lesion of the breast that can clinically simulate Paget's disease or invasive ductal carcinoma. Therefore, correct pre-operative diagnosis is important for appropriate management. METHODS: Cytological samples may be obtained by different methods such as fine needle aspiration, nipple discharge or nipple scraping. Herein, the cytological features of three cases of NA are described in which samples were derived from nipple scraping. RESULTS: In all three cases, patients were adult females presenting with a sub-areolar nodule, showing skin ulceration in 2 of 3 cases. The nipple scraping cytological smears were characterised by a bloody background with epithelial cells arranged in clusters or singularly, showing an irregular nuclei profile. These features could simulate a malignant process. However, at higher magnification, fine nuclear chromatin with inconspicuous nucleoli and presence of myoepithelial cells were helpful to exclude malignancy. DISCUSSION: NA may present "worrisome" cytological features on smears derived from nipple scraping. Therefore, knowledge of the cytological spectrum of this lesion is important to avoid misdiagnosis. PMID- 25291866 TI - Cytologic features of solid pseudopapillary neoplasms of the pancreas: a single institutional experience based on evaluation of diagnostic utility of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). AB - BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an important modality for diagnosing solid and cystic pancreatic lesions. The objectives of this retrospective study are to review the cytologic criteria used to diagnose pancreatic solid pseudopapillary neoplasms (SPNs) and to evaluate the utility of EUS-FNA by correlating cytologic and histologic samples. CASE REVIEWS: Of the 924 pancreatic FNAs performed at our institution from January 2002 through February 2013, four histologically confirmed cases of SPN were identified; three had an initial cytologic diagnosis of SPN. All four cases lacked on-site evaluation. Cytologic smears were assessed by two reviewers for the presence of a cellular aspirate, fibrovascular stalks lined by neoplastic cells with pale to finely granular cytoplasm, and monotonous, oval nuclei containing delicate chromatin, inconspicuous nucleoli, and grooves and inclusions. Three cases were diagnosed as SPN on cytologic examination and confirmed histologically. The remaining case was deemed a pancreatic endocrine neoplasm on cytology, but SPN on final histology. The most consistent cytologic feature we encountered was the presence of a cellular aspirate containing fibrovascular stalks lined by monotonous neoplastic cells with oval nuclei and nuclear grooves. CONCLUSION: We conclude that EUS-FNA is an effective diagnostic tool in the diagnosis of pancreatic SPNs. PMID- 25291867 TI - Neuroendocrine tumours of the pancreas: a clinicopathological study of nine cases including six insulinomas. AB - BACKGROUND: Pancreatic neuroendocrine tumours (pNET) are relatively uncommon, accounting for 1-2% of all pancreatic neoplasms. They are characterised by varying clinical presentation, tumour biology and prognosis. AIM: To provide an updated overview on clinicopathological features, treatment and outcome of pNET. PATIENTS AND METHODS: In our retrospective study, we reviewed 9 cases of pNET that were diagnosed at the Pathology Department of Mongi Slim Hospital over an 11 year period (2003- 2013). Relevant clinical information and microscopic slides were available in all cases and were retrospectively reviewed. The latest WHO classification (2010) was adopted. RESULTS: Our study group included 3 men and 6 women (M/F ratio 0.5) with an age between 20 and 75 years (mean = 52 years). Pancreatic neuroendocrine tumours ranged in size from 0.5 to 10 cm (mean 4 cm). The sites of pNET were the head of the pancreas (n = 4), the body of the pancreas (n = 3) and the tail of the pancreas (n = 2). Enucleation of the tumour was performed in five cases, Three patients underwent distal pancreatectomy and splenectomy, whereas only one patient had central pancreatectomy. Histopathological examination of the surgical specimen coupled with immunohistochemical study established a diagnosis of pNET grade 1 (G1) in seven cases and grade 2 (G2) in two cases. CONCLUSION: Pancreatic neuroendocrine tumours are a heterogeneous group of neoplasms with distinct tumour genetics, biology and clinicopathological features. Accurate clinical and pathologic diagnosis is an important first step in developing an appropriate management plan. PMID- 25291868 TI - Pre-miR146a expression in follicular carcinomas of the thyroid. AB - INTRODUCTION: Micro-RNA, a new class of small, non-coding RNAs, have been shown to be deregulated in several human carcinomas. In particular, SNP rs2910164 in pre-miR146a appears to be correlated with papillary thyroid carcinoma and may be involved in its genetic predisposition. Since data on follicular thyroid carcinomas (FTC) are lacking, we evaluated the involvement of SNP rs2910164 in FTC. METHODS: Thirty-nine cases of FTC and 20 follicular adenomas, defined according to WHO criteria, were selected. DNA and RNA were extracted from formalin-fixed paraffin-embedded blocks of both neoplastic and non-neoplastic areas. The DNA region of pre-miR146a, containing SNP rs2910164, was sequenced. Total RNA including miRNAs was used for stem-loop RT reactions, and applying a standard TaqMan PCR kit protocol for real-time PCR. Wilcoxon signed-rank test and Friedman test were used for statistical analyses. RESULTS: In 31% of FTC, the G allele was observed in neoplastic tissues, compared with the non-neoplastic areas (p < 0.05), whereas the CC phenotype was completely absent in tumours. Moreover, the expression of pre-miR146a was found to be significantly down-regulated in neoplastic tissues from FTC cases (p = 0.043), although no significant differences were seen in follicular thyroid adenomas. DISCUSSION: The expression profile of pre-miR146a can be correlated with FTC tumourigenesis. The G allele in SNP rs2910164 appears to be correlated with the transition from normal to neoplastic tissue. The GG and GC alleles appear to be associated with an increased risk for FTC, while the CC allele seems to play a protective role. PMID- 25291869 TI - Olfactory neuroblastoma with focal ganglioneuroblastic differentiation: a case report with literature review. AB - Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumour, with clearly defined histologic and immunohistochemical features, that typically arises in the superior nasal cavity. Although the classical clinicopathological features leave little room for misinterpretation, the wide variability in this tumour, including occasional divergent differentiation, may cause diagnostic difficulty. Herein, an unusual case of ONB with focal ganglioneuroblastic differentiation in an 81-year-old woman arising from the anterior ethmoid, filling the upper portion of the left nasal cavity and sparing the sinus cavities, is described. Histologically, the tumour was composed of atypical monotonous round cells that were positive for NSE, CD56, chromogranin, synaptophysin, neurofilament and calretinin and exhibited an irregular lobulated and nested growth pattern and sparse mitotic figures (3 to 4 mitoses per 10 HPF). Focally, the histology changed to ganglioneuroblastic differentiation consisting of large ganglion and spindle cells, positively staining for S-100, GFAP, CD99, neurofilament, calretinin, chromogranin and synaptophysin. Neuroblastomas, occurring in the nasal cavity, in analogy to other sites, tend to have an aggressive biologic behaviour and can histologically mimic other undifferentiated malignant neoplasms of the sinonasal tract. Differential diagnostic problems are discussed; a comprehensive review of the literature has also been performed with a focus on survival. PMID- 25291870 TI - Papillary haemangioma: a case report of multiple facial location. AB - Papillary haemangiomas were recently defined as morphologically distinct and benign cutaneous haemangiomas showing a predominantly intravascular capillary proliferation within dilated thin-walled dermal blood vessels. We describe the case of a 45-year-old woman who presented with multiple eruptive red-bluish raised papules and nodules distributed over the skin of the chin that were related to a papillary haemangioma. PMID- 25291871 TI - Juvenile hyaline fibromatosis: a case report. AB - Juvenile hyaline fibromatosis is a rare, hereditary disease with distinct clinical and histopathological features. Clinically, it presents with gingival hypertrophy, pappulonodular skin lesions and joint contractures. Bone involvement is usually an uncommon finding. We report a case of a 2-year-old patient, daughter of consanguineous parents, who presented since the age of 2 months with impairment of mental development, multiple joint contractures, motion limitation and nodules on the scalp. The calvarian lesions were surgically removed, and histopathological examination concluded to juvenile hyaline fibromatosis. PMID- 25291872 TI - Uterine tumour resembling ovarian sex cord tumours presenting as multiple endometrial and cervical uterine polyps: a case report. AB - BACKGROUND: Uterine tumours resembling ovarian sex-cord tumours (UTROSCT) are very rare, benign uterine tumours, composed solely of sex cord elements. These tumours have a polyphenotypic immunophentype that favours a derivation from uterine mesenchymal stem cells. CASE REPORT: A 43-year-old female presented with recurrent vaginal bleeding. On hysteroscopy, she had multiple endometrial and cervical polyps that were removed endoscopically. Histologically, the specimen contained epithelioid cells arranged in tubules, trabeculae and anastomosing cords, without significant cellular atypia or mitotic activity. Immunohistochemical studies were performed. The tumour was found to be diffusely positive for vimentin, calretinin and desmin, focally positive for cytokeratin, CD99 and inhibin and negative for chromogranin and CD10. A subsequent total hysterectomy was performed and revealed neoplastic infiltration of the myometrium. CONCLUSION: A polyphenotypic immunophenotype is a characteristic feature of UTROSCT, and may be helpful in diagnosis and in exclusion of other lesions. Familiarity with this tumour by gynaecologists and pathologists is essential to avoid misdiagnosis:correct diagnosis of this neoplasm is important in patient management. PMID- 25291873 TI - Giant pedunculated polypoid submucosal lipoma of the splenic flexure of colon: case report and review of the literature. AB - Lipomas of the colon are rare but clinically important conditions that require suitable evaluation for guiding appropriate therapy. The majority of lipomas arise from the submucosal layer in the ascending colon, especially near the ileocecal valve, which causes difficulties in diagnosis. Giant lipomas may be misinterpreted as a premalignant adenomatous polyp, particularly when arising in the left colon. A 38-year-old man presented with manifestations including hypogastric pain, constipation, loss of appetite and weight, accompanied by anaemia, nausea, vomiting and haematochezia. Colonoscopy revealed a large submucosal polyp about 5 x 4 cm, which was located at the splenic flexure of colonic. Surgery detected an oval polypoid tumour measuring 70 x 50 x 45 mm in size, having a pedunculated appearance and a stalk diameter of 20 mm. Histopathologic examination of the biopsy from the lesion confirmed diagnosis of a giant submucosal lipoma. In our experience, most giant colonic lipomas are found to be sessile and occur in the ascending colon in older patients. Herein, we report a pedunculated tumour in a 38-year-old male located in the splenic flexure of colon. PMID- 25291875 TI - [Development of a nutritional policy designed to meet public health challenges]. PMID- 25291874 TI - "Pure" primary large cell neuroendocrine carcinoma of the urinary bladder: case report, literature review and diagnostic criteria. AB - INTRODUCTION: Large cell neuroendocrine carcinoma (LCNC) is defined in the urinary bladder, as in other sites, as a high-grade neoplasm exhibiting neuroendocrine features at the H&E level, high mitotic activity and evidence of neuroendocrine differentiation by immunohistochemistry. We report a case of pure bladder LCNC with review of the literature. METHODS: A 68-year-old male presented with gross haematuria of two weeks' duration in October 2011. Transurethral resection and subsequently radical cystoprostatectomy (CP) with bilateral lymphadenectomy (L) were performed in December 2012. RESULTS: Urinary cytology identified malignant cells. Histologically, the tumour showed organoid nesting, trabecular growth, rosettes and perilobular palisading patterns, suggesting neuroendocrine differentiation. Immunohistochemical staining showed intense positivity for CD56. DISCUSSION: We examined all published pure bladder LCNC (12 cases) excluding mixed neoplasms. Small cell carcinoma of the urinary bladder pure LCNC of the bladder is a very aggressive malignancy, unresponsive to therapy, presents in an advanced stage and has a propensity for early metastasis. Prior to the advent of immunohistochemistry, such cases would most likely have been categorised as poorly differentiated, high-grade urothelial carcinomas. PMID- 25291876 TI - [Paediatric specificities of the concept of therapeutic patient education: review of the literature from 1998 to 2012]. AB - BACKGROUND: The general concept of therapeutic patient education (TPE), defined by the European Office of the World Health Organization (WHO) in 1998, could be questionable when applied to children due to the many specificities of this population in the field of health and education. AIM: To identify the specificities of therapeutic patient education applied to the paediatric population. METHODS: Concept analysis is based on Rodgers' 5-activities method: 1) Identifying the concept 2) selecting the appropriate realm of literature 3) collecting data from selected publications 4) analysing the results to determine the characteristics of the concept studied 5) discussion of the implications and prospects for development of the concept. RESULTS: Thirty-five publications were included in this concept clarification. Five attributes emerged: relational triad, collaborative partnership, adaptation of learning, gradual and progressive acquisition of skills, and creativity. DISCUSSION: The results of this first concept analysis shed light on the process of knowledge transfer over time. The five characteristics, consistent with the field of health promotion, could be strengthened by a grounded theory. PMID- 25291877 TI - [The synergy between quality approach and health promotion: synergy between quality approach and health promotion: example of the Ile-de-France/Outre-Mer Legal Protection of Youth]. AB - AIM: Legal Protection of Youth is responsible for the education of juvenile offenders, and for the inspection and assessment of the bodies that supervise them. The objective of this project is to promote and strengthen the synergy between the quality approach and health promotion in the missions of the Ile-de France/ Outre-Mer Inter-regional Directorate of Legal Protection of Youth. METHODS: A participatory and cross-sectional methodology was used to study two strategies designed to integrate existing prevention and health promotion actions into a quality approach and to include prevention and health promotion in the existing quality approach. RESULTS: Three reference frameworks were constructed: a guide for the analysis of prevention and health promotion actions implemented by associations financed by the Ile-de-France Regional Health Agency; a guide for internal evaluation for health promotion in educational bodies; a technical data sheet proposing audit references for health promotion. CONCLUSIONS: The results of the project contributed to achieving the initial objective. The frameworks and tools should now be compared with prevention and health promotion actions, and activities and services provided by educational bodies, in order to measure their usefulness to improve quality. PMID- 25291878 TI - [Mapping of the key oncology indicators available in France]. AB - BACKGROUND: Available data in the field of oncology in France are scattered due to the large number of available indicators and their sources. In order to facilitate identification and analysis of these indicators, the French National Cancer Institute (INCa) has mapped the main indicators available in oncology. METHODS: Mapping was based on the needs of various categories of potential users. Standardized interviews were conducted face-to-face or by email among representatives to determine their needs and expectations. The underlying data sources were also identified: databases, national surveys, websites. A first selection of indicators was proposed in the report entitled "La situation du cancer en France en 2009" ("The state of cancer in France in 2009") and was expanded. Data collection concerning indicators was performed among INCa correspondents for each theme. RESULTS: Several themes were defined: epidemiology, prevention and risk factors, screening, medical demography, health care offer, living conditions, costs and expenses, research. Data were classified according to: geographical coverage, age, gender, type of cancer, occupational categories. This information was collected for each indicator selected and was made available via the cancer data website (http://lesdonnees.e-cancer.fr). CONCLUSIONS: The available oncology indicators are numerous and scattered. Mapping can be a useful tool to facilitate access to these indicators. It should be regularly updated to reflect the most recent data. PMID- 25291879 TI - [Accompaniment to improve public health professional practice]. AB - Accompaniment (professional support) is increasingly used to support improvement of public health practices. In the field of education, the term accompaniment is at the heart of a structured teaching approach. In public health, the term is commonly used, but has not been clearly defined, which means that proposals are often not sufficient to support real changes in practice. The present article proposes a reflection on accompaniment in the field of public health inspired by progress in the education sector. The actions of managing, guiding and supporting are derived from the action of accompaniment and are illustrated by the example of the Health Promotion Laboratory of the Montreal Public Health Department. Accompaniment requires knowledge that is acquired with practice, hence the importance of strategically targeting a project which could benefit from such an approach and supporting the development of professional skills. The improvement of public health professional practices and public health management, necessary for adaptation of the health system, is dependent on development of an expertise in accompaniment of the processes of change. PMID- 25291880 TI - [How do general practitioners limit their prescriptions? A qualitative study based on a focus group]. AB - AIM: There is no consensus on prescription of medicines in many situations in general medicine. The aim of this study was to identify the strategies used by general practitioners to limit prescriptions in order to make their prescriptions more effective. METHODS: A mixed sample of general practitioners in terms of age and types of practice were interviewed using the focus group method until a sufficient number of data were obtained. RESULTS: Fourteen women and ten men aged between 32 and 64 years were interviewed by means of three group interviews. Various strategies were identified: the practitioner's attitude (rapid identification of the patient's needs, listening and evaluation of symptoms, support by physical examination) and the use of resources (reference tools and news) during the consultation; the importance of the conclusion of the consultation (written advice or visit report, review of the previous prescription) and explanation (reasons for limitation, reassurance, arguments, proposal of a follow-up visit). Limitation of prescriptions also depends on the practitioner's own reasons (initial and continued training, motivation and personal objectives, part of a peer group) but equally on the health care system (institutional, specialist support). CONCLUSION: The study highlights numerous approach to facilitate limitation of prescriptions: training and informing practitioners and patients, consultation management, promote communication at the heart of the health care system and policy-makers. Training organizations and health authorities could facilitate these strategies for the benefit of patients. PMID- 25291881 TI - [Relevance of prison placements based on the perception of primary care medicine interns]. AB - INTRODUCTION: The growing need for new placement opportunities for primary care interns has opened the way to placements in prison health centres. No study has previously assessed the educational value of this type of placement and its relevance to primary care for the general population. METHODS: A qualitative pilot study was conducted in the Languedoc-Roussillon region of France by means of semistructured interviews and phenomenological and practical analysis based on all primary care interns completing a prison health centre placement in the region. ANALYSIS AND RESULTS: The key dimensions emerging from the analysis are: exposure to a range of situations that are very similar to primary care in a public health context; learning how to manage complex situations; stronger orientation towards ethical health care; firmer belief in multidisciplinary teams; and enhanced awareness of the social role of primary care physicians. DISCUSSION: All interns considered this type of placement (towards the end of their training) to be a good preparation for their future primary care role, especially in the context of multidisciplinary practices. PMID- 25291882 TI - [Psychometric properties of the Consumer Satisfaction Questionnaire (CSQ-8) and the Helping Alliance Questionnaire (HAQ)]. AB - BACKGROUND: This study was based on data from a quality of care assessment survey conducted in 2011 in outpatient polyclinics of the Vaud Canton in Switzerland, comprising questionnaires completed by 568 children over the age often and 672 parents of children of all ages. The objective of this study was to evaluate the psychometric qualities of the eight-item French versions for children of the Helping Alliance Questionnaire (HAQ) and the Consumer Satisfaction Questionnaire (CSQ-8) to allow formal validation and clinical application of these tools in the context of French-speaking child psychiatry. METHODOLOGY: Responses from children over the age often to the HAQ and CSQ-8 questionnaires were submitted to confirmatory factorial analysis (CFA) for ordinal data to verify their good fit with the original long versions. Construct validity (correspondence between scores on the scales and other external criteria considered to evaluate similar concepts) of the child questionnaires was tested by Spearman's correlation with the parents' responses and their feeling of being reassured or in agreement with respect to the first visit, and with the perception of the help provided by individual and family interviews. RESULTS: CFA showed an acceptable fit with the one-dimensional model of the original scales, both for the HAQ and the CSQ-8. Significant positive correlations of the scales with the parents' responses and with other convergent external criteria confirmed the good construct validity. CONCLUSIONS: These psychometric analyses provide a basis for the validation and clinical application of the abridged French versions of the HAQ and CSQ-8 in quality of care assessment in child psychiatry. PMID- 25291883 TI - [Measuring patient safety awareness among physicians in a Tunisian hospital]. AB - AIMS: The objective of this study was to measure the level of awareness of patient safety among physicians at Farhat Hached hospital in Sousse (Tunisia). METHODS: A cross-sectional descriptive study was conducted in 2012 using a validated survey based on pervious studies. This self-administered questionnaire was distributed to 116 physicians working in 16 different departments of Farhat Hached university hospital. This survey explores 10 dimensions of patient safety and each of these dimensions is composed of several items. The percentage of positive (positive attitudes) and negative responses for each item was calculated and a score was calculated for each dimension, corresponding to the mean percentages of positive answers to the respective items of the dimension. RESULTS: The response rate was 74.1%. The overall positive response rate of patient safety awareness ranged from 13.9% to 84%. The dimensions with the lowest positive response rates were "Hospital management support for patient safety" (13.9%) and "Teamwork within units" (45.4%). The highest percentage of positive responses was observed for "Supervisor expectations and safety-promoting actions" (82.3%) and "Frequency of event reporting" (84%). CONCLUSION: This study measured the level of awareness of patient safety among physicians at Farhat Hached university hospital. The results obtained will be used to guide safety-promoting actions. PMID- 25291884 TI - [Feasibility and practical value of statistical matching of a general practice database and a health insurance database applied to diabetes and hypertension]. AB - OBJECTIVES: Public Health actors in France are striving to improve the use of national databases for public health and research. The main objective of this project was to develop a research tool in ambulatory care by matching medical data and reimbursement data. METHODS: Data sources were the health insurance database (SNIIRAM) and the General Practice Observatory (OMG) database. The SNIIRAM is a national medical and administrative database comprising data used in healthcare reimbursement. The OMG is a medical database on ambulatory care recording presenting complaints called "Results of Consultation" (RC). Based on data for patients who consulted one of the 30 general practitioners selected in 2008, we performed a probabilistic matching of the two databases. RESULTS: The linkage procedure allowed matching of 89,211 consultations or doctor visits and 29,088 patients. Comparison of long-term diseases (ALD) and RC showed that 94% of patients with diabetes as ALD had at least one RC coded as diabetes during the year, but only 65% of patients with one RC coded as diabetes were reported as ALD for this disease. Matching of the databases identified 12% of diabetic patients without antidiabetic treatment and without ALD for this affection; these patients were therefore not identifiable in the SNIIRAM database. CONCLUSION: This study describes an innovative database matching methodology. It also illustrates the contribution of this model of matched data in terms of targeting populations at risk. Other approaches to analysis of comorbidities, medical practices and care pathways could be proposed. PMID- 25291885 TI - [Exploratory analysis of work engagement: use of the Utrecht scale in Benin]. AB - INTRODUCTION: Work engagement, an emerging concept in the field of positive psychology in the workplace is not well known in developing countries. Defined as a positive and and fulfilling mindset related to work, it recalls a positive attitude incentive of performance and need to be investigated. In the context of the socioeconomic crisis of health workers, and with the chronic issue of poor quality of data, this study was designed to identify the factors associated with work engagement among health workers. in charge of data collection in the Benin Routine Health Information System. METHODS: This study was a cross-sectional and analytical study targeting health workers in charge of data collection in public and private health centres. The dependent variable was work engagement and independent variables were sociodemographic and professional features, personal and professional resources and perception of technical factors. Logistic regression was used. The adequacy of the model was tested with the Hosmer Lemeshow goodness of fit test. RESULTS: The results indicate that the level of work engagement is similar with that observed in previous studies. Predictors identified in logistic regression are perception of technical factors, location of the job, and personal resources, such as level of effort and overcommitment. DISCUSSION: This study identified factors associated with work engagement in a developing country, and adds to the knowledge concerning this new concept in Benin. The findings can contribute to research for improvement of human resources management in the health sector to achieve real performance and development. PMID- 25291886 TI - [HIV/AIDS stigma in Africa: analysis of its forms and manifestations in Burkina Faso]. AB - INTRODUCTION: Negative impact of stigma on HIV care and prevention is documented. Qualitative approaches were used to describe its importance in Burkina Faso (1% of HIV prevalence) and need to be completed by quantitative estimations of the main manifestations and categories of stigma. METHODOLOGY: During the MATCH study (Multi-country African Study on Testing and Counselling for HIV) conducted in 2007-2008, 219 people tested HIV positive (PLWHA) were interviewed by means of a quantitative questionnaire. One of the topics concerned their experience of the consequences of HIV positive results using 20 items on stigma manifestations, classified into 3 categories: stigma in health care services (7 items), interpersonal stigma (10 items) and internal stigma (3 items). RESULTS: Internal stigma is the major category experienced by PLWHA in Burkina Faso (46%) compared to 40% for interpersonal stigma and 11% for stigma in health care facilities). PLWHA who disclosed their HIV result, widows or separated persons, those with a lower level of education, PLWHA who joined community-based organizations are more likely to experience interpersonal stigma. Stigma in health care facilities is more frequently reported by PLWHA who joined community-based organizations. Internal stigma affects all PLWHA, with no significant differences in terms of age categories or gender. CONCLUSION: Antiretroviral scaling-up programmes must integrate more adapted psychology support aspects. Psychosocial activities, targeting persons and not groups, must be part of PLWHA care in Burkina Faso, especially in community-based organizations. PMID- 25291887 TI - [Mental health professionals' representations of their practices in Rabat, Morocco]. AB - INTRODUCTION: The main challenges faced by the mental health system in Morocco are insufficient quality of care and limited human resources. Training of mental health providers therefore constitutes a way of improving quality of care. METHODS: We conducted 22 semi-structured interviews with mental health practitioners, mental health senior managers and psychiatry teachers in order to identify training needs. RESULTS: The main findings were the lack of communication, collaboration and updated knowledge especially concerning diagnosis, psychotropic drug prescriptions and addiction medicine. We also identified specific training needs for mental health specialists, such as geriatric psychiatry and paediatric psychiatry. DISCUSSION: Consequently, better training in these areas would contribute to the success of managed care strategies in primary healthcare facilities. PMID- 25291888 TI - [Incidence of rubella in 2010-2012 in Kinshasa, Democratic Republic of Congo: data from the measles case-based surveillance system]. AB - INTRODUCTION: No surveillance system or survey data on the congenital rubella syndrome are available in the Democratic Republic of Congo. This article describes the incidence of primary rubella infection between 2010 and 2012 based on the measles case-based surveillance system in Kinshasa. METHODS: Suspected cases of measles notified in Kinshasa between 2010 and 2012 were retrospectively analyzed. RESULTS: From January 2010 to December 2012, 1,892 suspected cases of measles were reported, and 1013 serum samples were collected according to the surveillance standard and analyzed in the laboratory. There were more cases of confirmed rubella than measles among the investigated cases. The proportion of confirmed cases of rubella has increased significantly over the last 3 years. The proportion of affected individuals of childbearing age was 15.4%, with a female predominance in this age-group. CONCLUSION: The Democratic Republic of Congo should consider revising the definition of cases used in the measles surveillance system in order to take into account the incidence of measle, establish sentinel sites for surveillance of CRS and use measles eradication activities and other mass activities to introduce rubella vaccination. PMID- 25291889 TI - Equity of care: eliminating disparities to ensure quality care for all. PMID- 25291890 TI - Baylor Health Care System's journey to provide equitable care. AB - Baylor Health Care System* has a long history of addressing health disparities at its hospitals and clinics and in the communities it serves. The organization's definition of health equity has evolved from simply providing care that looks the same for all patients to providing care that is tailored to and effective at producing equitable outcomes for the highly diverse populations of North Texas. Baylor's overarching framework for achieving health equity requires work in three dimensions: improving access to care, improving care delivery, and ultimately producing equitable outcomes for patients. The strategies and tactics used by Baylor have also evolved over time and range from initiatives supporting volunteerism and community service to the operation of a network of clinics tailored to meet the needs of uninsured and underinsured patients. The factors contributing to disparities among different populations include a broad range of health system, medical, and societal issues, many of which are outside the direct scope of influence of hospitals and other healthcare organizations. We share how Baylor has proactively addressed disparities within the organization and its community in the hope of encouraging other hospitals and providers to engage in similar efforts to improve care for all patients. PMID- 25291891 TI - In pursuit of high-value healthcare: the case for improving quality and achieving equity in a time of healthcare transformation. AB - The passage of the Patient Protection and Affordable Care Act and current efforts in payment reform signal the beginning of a significant transformation for the US healthcare system. As we embark on this transformation, disparities have emerged as the hallmark of low-value healthcare--care that does not meet quality standards, is inefficient, and is usually of high cost. A new set of structures is being developed to facilitate increased access to care that is cost-effective and high in quality--otherwise known as high-value healthcare. Addressing disparities and achieving equity are the perfect target areas for recouping value, and doing so will pave the way for high-value healthcare. As healthcare leaders make difficult choices, they should consider the realities of healthcare equity. First, racial and ethnic disparities in healthcare persist and are a clear sign of poor-quality, low-value healthcare. Second, the root causes of these disparities are complex, but a well-developed set of evidence-based approaches is available to help leaders address healthcare inequity. Third, evidence suggests that being inattentive to the root causes of disparities adversely affects efficiency and an organization's bottom line. Finally, if healthcare organizations are progressive, thoughtful, and prepared for success in such an environment, a new healthcare system that offers accessible, high-value, equitable, culturally competent, and high-quality care to all is well within reach. PMID- 25291892 TI - Ending healthcare disparities: an urgent priority and a growing possibility. PMID- 25291893 TI - Expanding the evidence base for health equity. PMID- 25291894 TI - A historical perspective on disparities as context for our work ahead. PMID- 25291895 TI - Nurses leading the way. PMID- 25291896 TI - Children's health and the environment. PMID- 25291897 TI - Senator Mike Folmer: medical cannabis a positive option. PMID- 25291898 TI - Improving the process of medication administration. PMID- 25291899 TI - A nurse called to Haiti. PMID- 25291900 TI - Baldrige: a powerful tool. PMID- 25291901 TI - Optimizing value(s) in health IT. PMID- 25291902 TI - Going beyond data capture: new ways to improve care and efficiency. PMID- 25291904 TI - Being a catalyst, architect and coach. PMID- 25291903 TI - Partners for success: the value of ACHE's chapters. PMID- 25291905 TI - Leading a career of significance. Getting to--and expressing--the heart of the business. PMID- 25291906 TI - Patient engagement and PHI. Organizations should make patient access to their personal health information a customer service priority. PMID- 25291907 TI - Using social media to engage communities. It's the new coffee shop for hospitals and health systems. PMID- 25291908 TI - The elections: health policy and politics. The next two years are prime for compromise. PMID- 25291909 TI - The rise of interim leadership. Trend offers new opportunities to veteran healthcare executives. PMID- 25291910 TI - Philanthropy and strategic direction. Executives, trustees and physicians should be the leading advocates of philanthropy. PMID- 25291911 TI - Enhancing prehospital emergency care. Doing so can influence hospital results. PMID- 25291912 TI - Physicians in management vs. leadership positions. Understanding the difference between the two is critical to success. PMID- 25291913 TI - 2014 hospital CEO survey on financial challenges: cost reduction and organizational strategies. PMID- 25291914 TI - Close-to-home education. ACHE chapters provide members with unique and plentiful learning opportunities. PMID- 25291920 TI - The transformation of nursing education through innovation. PMID- 25291921 TI - Effectiveness of strategies addressing the nurse faculty shortage. PMID- 25291922 TI - An evaluation of state-based support-for-service programs targeting nurse faculty. AB - AIM: The aim of the study was to assess how state-based support-for-service (SFS) programs are used by deans and directors of nursing programs and to evaluate their perceived impact. BACKGROUND: Given projected nurse faculty shortages, stakeholders are looking for ways to address the maldistribution and shortage of nurse faculty. One state-level strategy is the implementation of loan repayment and scholarship programs, which incentivize individuals with, or currently pursuing, graduate degrees to become or remain nurse faculty. METHOD: This study used a mixed-method and multilevel approach to assess the impact of SFS programs in seven states. RESULTS: Programs are perceived to affect both recruitment and retention of faculty and play a role in increasing the educational qualifications of current nurse faculty. CONCLUSION: Nurse educators need to be aware of SFS programs and how best to use them to support nurse faculty. PMID- 25291923 TI - Building the evidence for dedicated education unit sustainability and partnership success. AB - AIM: To evaluate the sustainability of dedicated education units (DEUs) within an academic-service partnership. BACKGROUND: A two-year, multisite, mixed-methods study with a randomized control trial was designed to isolate the effects of the DEU innovation on clinical education quality, teaching capacity, work life, and productivity. METHOD: Interview data from 34 participants were analyzed for interactions and behaviors that indicated sustainability. RESULTS: Seven themes portrayed successful participant interactions, revealing shifting roles based on mutual respect and collaboration among engaged partners working within complex adaptive systems. Relationship building and partnership achievements were confirmed as key components in DEU sustainability. CONCLUSION: Sustainable, mature clinical education partnerships depend on implementing routinizing, reinforcing, recognizing, and rewarding activities. Unit level success relies on foundational structures that support the ongoing development of DEU clinical instructors. DEU sustainability will depend on the continual creation of new meaning for participants and the generation of new resources and results. PMID- 25291924 TI - Dedicated education unit: nurse perspectives on their clinical teaching role. AB - AIM: The study compared the perceptions of nurses who participated in the clinical education of students using traditional and dedicated education unit (DEU) models. BACKGROUND: In the traditional model, faculty are the primary clinical instructors for students. In a DEU, nurses provide clinical instruction with faculty support. METHOD: This mixed-methods study used surveys and interviews. RESULTS: Compared to nurses on traditional units, DEU nurses were more likely to agree that their unit welcomed students, had a strong commitment to teaching, and received professional development from clinical faculty. The nurses rated the learning gains of students as greater on DEUs than traditional units and viewed the leadership of the nurse manager and the quality of patient care as similar. CONCLUSION: The study provides evidence that, from the nurses' perspective, the DEU faculty-nurse partnership provides students with superior clinical education experiences and may improve nurse work satisfaction. PMID- 25291925 TI - Dedicated education unit: student perspectives. AB - AIM: The study compared students' perceptions of their clinical learning experiences in a dedicated education unit (DEU) with their experiences in traditional clinical education. BACKGROUND: Unlike traditional academic instructor models, expert nurses in the DEU provide clinical education to students with faculty support. METHOD: This repeated measures design used student surveys, supplemented by focus group data. RESULTS: Students were more likely to agree that their clinical learning experience was high quality and they had a consistent mentoring relationship during DEU rotations. Students also reported the quality of the unit's learning environment, the leadership style of the nurse manager, and the nursing care on the unit was more favorable in DEUs than traditional units. Consistent with their changed role in DEUs, faculty members were less active in helping students integrate theory and practice. CONCLUSION: These findings provide additional evidence of the value that the DEU model contributes to high-quality clinical education. PMID- 25291926 TI - Increasing faculty capacity: findings from an evaluation of simulation clinical teaching. AB - AIM: To compare how the use of different "doses" of simulation in undergraduate clinical teaching affect faculty capacity. BACKGROUND: Since 2008, the NYU College of Nursing has used a "high dose" of simulation to substitute for 50 percent of the clinical hours in core medical-surgical courses to address a shortage of faculty and clinical sites. Johns Hopkins University School of Nursing has used limited, "low-dose" simulation hours to supplement clinical hours. METHOD: The evaluation included program data and surveys and qualitative interviews with faculty and students in each program. RESULTS: Implementing "high dose" clinical simulation resulted in a nearly 50 percent increase in faculty capacity at NYU, expanding undergraduate enrollment from 613 students in 2007 to 900 in 2012, with no negative impacts on faculty work life or student outcomes. CONCLUSION: Substituting simulation for traditional clinical hours can be a sustainable and educationally sound option to increase faculty capacity. PMID- 25291928 TI - An online approach to orienting clinical nursing faculty in baccalaureate nursing education. PMID- 25291927 TI - A statewide consortium's adoption of a unified nursing curriculum: evaluation of the first two years. AB - AIM: This article provides an evaluation of the first two years of implementation of a statewide nursing consortium (SNC) curriculum on nursing faculty work life, teaching productivity, and quality of education. BACKGROUND: In response to the call for nursing education reform, the SNC incorporated new approaches to competency-based, student-centered learning and clinical education. METHOD: Faculty and two cohorts of students were measured at three points over the first two years of the curriculum implementation. RESULTS: The expected positive impact of the SNC was documented at the start of the first year, but not sustained. Students reported having more confidence in their clinical skills at the start of the first year, yet demonstrated significantly less confidence in their ability after two years. CONCLUSION: Faculty indicated that the SNC allowed greater opportunity for collaboration, but that the experience did not alter their classroom performance or satisfaction beyond the first year. PMID- 25291929 TI - Novice nurse faculty: in search of a mentor. PMID- 25291930 TI - Nurse educators' perceptions about structured debriefing in clinical simulation. PMID- 25291931 TI - Comparison of select outcomes between traditional and accelerated BSN programs: a pilot study. PMID- 25291932 TI - Student characteristics and perceptions of learning and confidence acquisition associated with simulation. PMID- 25291933 TI - Using a telephone call to increase social presence in online classes. PMID- 25291934 TI - NLN's simulation leaders give SIRC bibliography site a makeover. PMID- 25291935 TI - Sharing classroom research and the scholarship of teaching: student resistance to active learning may not be as pervasive as is commonly believed. PMID- 25291936 TI - NLN scholars in residence conduct research on virtual simulation and the clinical faculty role. PMID- 25291937 TI - Cross reactivity of Neisseria meningitidis crgA diagnostic PCR primers with nontypeable haemophilus influenzae. AB - BACKGROUND: CrgA based PCR are usually used for diagnosis of Neisseria meningitidis while the crgA gene was observed in the genomes of Haemophilus influenzae. In this study, we aimed to evaluate whether the crgA primers routinely used in the diagnosis of N. meningitidis could cross react with H. influenzae isolates. METHODS: A diagnostic test study analysis of sixty-two H. influenzae isolates from oropharyngeal swabs of healthy individuals aged 9 to 11 years between 2011 and 2012, using commonly used crgA primers for diagnostic analysis of N. meningitidis. RESULTS: It revealed that 19.3% nontypable H. influenzae isolates were positive for the crgA gene. All the biotype IV H. influenzae isolates were crgA PCR positive. CONCLUSIONS: Our study has shown a significant finding of crgA gene especially in bitotype IV nontypable H. influenzae by N. meningitidis crgA diagnostic PCR primers. It is necessary to further evaluate the prevalence of the crgA gene in more non-typable H. influenzae strains, particularly invasive strains. PMID- 25291938 TI - Is there a relationship between small, dense LDL and lipoprotein--associated phospholipase A2 mass in dialysis patients? AB - BACKGROUND: We aimed to measure small, dense LDL (sdLDL) and lipoprotein associated phospholipase A2 (Lp-PLA2) concentrations and to evaluate their relationship with other risk factors of atherosclerotic heart disease in dialysis patients. METHODS: Study group consisted of 30 peritoneal dialysis and 20 hemodialysis patients with 20 healthy control subjects. sdLDL was measured by homogeneous LDL assay after precipitation of Apo B containing lipoproteins with heparin-magnesium. Lp-PLA2 mass was measured by immunoturbidimetric assay. RESULTS: sdLDL concentrations in the samples collected before hemodialysis and peritoneal dialysis treatment were significantly higher than the control group (p < 0.05). Lp-PLA2 concentrations of both pre-hemodialysis and peritoneal dialysis groups were higher than control group (p < 0.05). There was not a significant correlation between sdLDL and Lp-PLA2. sdLDL concentrations are significantly decreased after a hemodialysis session. CONCLUSIONS: sdLDL and Lp-PLA2 concentrations are increased independently in the end stage renal failure patients who are receiving dialysis treatment. PMID- 25291939 TI - Correlation between efficacy of the EGFR tyrosine kinase inhibitor and serum tumor markers in lung adenocarcinoma patients. AB - BACKGROUND: The mutation at epidermal growth factor receptor (EGFR) is a clinical predictor of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC). The serum carcinoembryonic antigen (CEA) level was regarded as a predictive factor for the EGFR-TKI efficacy. Are there any other serum markers? This study analysed the correlation between the EGFR-TKI treatment effect and multiple serum tumor markers only in lung adenocarcinoma to find serum predictive markers for the EGFR-TKI efficacy. METHODS: Clinical features, survival time, and serum tumor marker levels before EGFR-TKI treatment were analysed, retrospectively, in 48 advanced lung adenocarcinoma patients treated with EGFR-TKI. RESULTS: With EGFR-TKI treatment, the response rate was 58.3% and disease control rate was 65.6% in lung adenocarcinoma; median survival time was 13.2 months. The efficiency of EGFR-TKI significantly correlated with smoking history and the serum level of CEA and CA199 (p < 0.05). Patients with a higher level of serum CEA and CA199 had a higher disease control rate and longer survival time (p < 0.05). CONCLUSIONS: Serum CA199 and CEA levels can predict the response of EGFR-TKI in lung adenocarcinoma patients. PMID- 25291940 TI - Evaluation of resistance to anti-platelet therapy in patients with coronary heart disease in a developing country. AB - BACKGROUND: Resistance to anti-platelet therapy whether defined by the laboratory detection of platelet function or the recurrence of cardiovascular events, has received extensive coverage in the literature coming predominantly from developed countries and very scanty information comes from developing countries. We aim to document the prevalence of aspirin and clopidogrel resistance in Saudi patients with coronary heart disease (CHD) and to probe the possible responsible mechanism[s]. METHODS: 238 patients with CHD were enrolled from the outpatient clinic and wards of King Khalid University Hospital, Riyadh. Platelet function testing was undertaken using both optical aggregometry in platelet rich plasma as well as the Platelet Function Analyzer [PFA100] which uses whole blood. RESULTS: Agonist-induced platelet aggregation in response to arachidonic acid-induction: The prevalence of residual activity was detected in 12.6% patients. Resistance to clopidogrel as reflected by the residual aggregation responses to ADP was detected in 25.7%. PFA100 closure time: Closure times for collagen and epinephrine cartridges that are shorter than the maximum for local reference of 84 - 198 seconds were detected in around 30% of patients on therapy. There was no significant relationship between diabetes mellitus, smoking, dyslipidemia, or consumption of non-steroidal anti-inflammatory drugs and the resistance to anti platelet therapy. CONCLUSIONS: Resistance to anti-platelet therapy is quite prevalent among patients with CHD in Saudi Arabia and compares favorably with reports in the literature. However, the lack of a significant relationship between resistance to antiplatelet therapy and the above-mentioned conditions could be due to small numbers. PMID- 25291941 TI - The effectiveness of the serum surfactant protein D (Sp-D) level to indicate lung injury in pulmonary embolism. AB - BACKGROUND: Surfactant protein D (SP-D) is a biomarker specific to the lungs. Our aim was to investigate the relationship between clinical probability scores and the serum levels of SP-D to indicate the severity of lung injury that develops secondary to hypoxia in pulmonary embolism (PE). METHODS: We included three groups in the study: non-massive PE (n = 20), sub-massive PE (n = 20), and the control group (n = 20), which consisted of healthy volunteers. The modified Geneva and Wells clinical probability scoring systems were performed for PE, and the patients were classified as low risk, moderate risk, and high risk. SP-D levels were determined by the enzyme-linked immunosorbent assay. RESULTS: For risk factors, the most significant were deep vein thrombosis (DVT) and immobilization. There was no significant difference in SP-D levels between the patients identified with risk factors and those without risk factors in either the Geneva or Wells scores. Atelectasis was the most common radiographic finding, while tricuspid valve regurgitation was predominant in echocardiography. There was no significant difference between the non-massive PE group and the control group, while SP-D levels of the sub-massive group were significantly higher than the control group. CONCLUSIONS: In our study, SP-D levels were significantly higher in the sub-massive PE group overall. However, further prospective studies are required with a larger number of cases, including patients with massive PE, in order to clarify the findings. PMID- 25291942 TI - Abnormal methylation of the sex-determining region Y-box 17 (SOX17) promoter predicts poor prognosis in myelodysplastic syndrome. AB - BACKGROUND: The sex-determining region Y-box 17 (SOX17) is a member of the high mobility group (HMG) transcription factor family, which plays critical roles in the regulation of development and stem/precursor cell function. Recent evidence demonstrated that SOX17 acts as a tumor-suppressor gene, at least partly though repression of Wnt pathway activity. METHODS: Here we report that SOX17 methylation was detected in THP-1 and SKM-I cell lines and SOX17 mRNA levels was up-regulated by 5-aza-dC. To clarify the role of SOXI7 in MDS, methylation specific PCR (MSP) was employed to examine the methylation status of SOX17 in 164 adult de novo MDS patients and 6 normal samples. RESULTS: We found that SOX17 methylation was presented in 58.5% (n = 96) of these patients and none of the normal samples. Methylation was correlated significantly with World Health Organization (WHO) subtypes and international prognostic scoring system (IPSS) risk group. Patients with advanced stages of WHO subtypes (69.6% vs. 44.4%, p = 0.001) and higher risk IPSS subgroups (69.8% vs. 48.8%, p = 0.010) exhibited a significantly higher frequency of SOX17 methylation. Though multivariate analysis indicated that SOX17 methylation status was not the independent factor that impacted overall survival (OS) (HR = 0.097), there were significant differences in marrow blast levels and the IPSS risk subgroups between patients with and without SOX17 methylation. CONCLUSIONS: These findings suggest that the hypermethylation of SOX17 promoter may be one of the early events in the development of MDS and predicts poor prognosis. PMID- 25291943 TI - Detection of clopidogrel resistance using ADP induced aggregometry with specific inhibitor PGE1. AB - BACKROUND: Antiaggregation therapy is still the most frequently used approach to prevent thrombotic events in cardiovascular diseases. It has a good clinical effect but increasing evidence shows high residual platelet aggregation activity in a number of patients. Laboratory methods only allow us to detect clopidogrel "non-responders" or "low responders". Recent methods are based on monitoring residual platelet aggregation activity (aggregation methods) or detecting the number of free epitopes for binding a specific monoclonal antibody such as vasodilator-stimulated phosphoprotein phosphorylation (VASP). METHODS: The aims of our study were comparison light transmission aggregometry (LTA) and multiple electrode platelet aggregometry (MEA) with induction by ADP in concentrations of 20 micromol/L with or without prostaglandin E1 (PGE1) for monitoring clopidogrel resistance. RESULTS: In the group of 84 patients with cardiovascular disease (CAD) studied, an impaired individual response to clopidogrel therapy was found 11.9% and 10.7% of the patients using MEA and LTA, respectively, induced by ADP with PGE1. The LTA and MEA methods with induction by ADP with PGE1 and without PGE1 were statistically compared using Spearman's nonparametric correlation analysis. Both methods with using PGE, showed a positive significant correlation (p = 0.003) in contrast with the results without PGE1 with a no significant correlation (p = 0.732). CONCLUSIONS: The sensitivity for detecting clopidogrel resistance correlates well with other data in the literature suggesting that there are 5%-30% clopidogrel low-responders depending on the type of platelet function assay used and the criteria for defining a low-responder [16-18]. These results favor implementation of the ADP test with PGE1 by MEA specifically for identification of low-responders to clopidogrel. PMID- 25291944 TI - Proinflammatory cytokines in monitoring the course of disease and effectiveness of treatment with etanercept (ETN) of children with oligo- and polyarticular juvenile idiopathic arthritis (JIA). AB - BACKGROUND: The demonstration of the quantitative prevalence of specific cytokines in JIA formed the basis for the introduction of biological anticytokine drugs to treatment. Routine assessment of the concentration of these cytokines in blood serum may enable earlier decision making on the legitimacy of biological treatment (anti-TNF). The aim of the study was to assess the diagnostic value of TNFalpha, IL-6, and IL-1beta in monitoring the course of the disease and effectiveness of treatment with etanercept of children with oligo- and polyarticular JIA. METHODS: In a 1-year prospective study, cytokine levels were measured using ELISA in serum samples for 19 JIA patients in whom no clinical improvement was noted in spite of treatment with disease modifying antirheumatic drugs (DMARDs) and glucocorticosteroids (GCS). All the patients started treatment with ETN. The control group included healthy children (n = 18). RESULTS: Concentrations of TNF-a and IL-6 in blood serum at time 0 were significantly higher than in the control group. IL-6 concentration decreased during treatment with ETN in children in the inactive phase of the disease. Mean concentrations of TNF-a in serum increased several dozen times irrespective of clinical improvement. TNFalpha concentrations were statistically significantly higher in patients in the inactive phase of the disease in comparison with those in the active phase and correlated with the dose of ETN. Only the concentration of IL-6 correlated with the JADAS-27 value at all time points. CONCLUSIONS: We conclude that IL-6 may serve as a biomarker of activity of the disease in children with JIA treated with ETN. PMID- 25291945 TI - Analytical performance and diagnostic potential of immunoassays determining intact immunoglobulin kappa/lambda ratios in monoclonal gammopathies. AB - BACKGROUND: Hevylite chain (HLC) assays with specificity for epitopes at the junction between heavy and light chains of intact immunoglobulins (Ig) allow quantification of Ig kappa/lambda ratios of the three major Ig classes. Calculated Ig kappa/lambda ratios outside the reference range indicate a monoclonal background. The primary aim of the present study was to analytically validate HLC assays and to investigate their diagnostic potential in relation to immunofixation electrophoresis (IFE) as the standard method for identification of monoclonal proteins (MPs). A second aim was to investigate the diagnostic potential of HLC assays in disease monitoring. METHODS: Precision, linearity, accuracy, sensitivity, and specificity of HLC assays for Ig classes A, G, and M were determined as parameters of analytical performance. The diagnostic performance of HLC assays in the detection of MPs was investigated in patient sera revealing monoclonal bands in IFE (n = 156). The utility of the assays in disease monitoring was investigated in a proof of principal approach by quantification of HLC ratios in subsequent sera from stem cell transplanted (ScTx) myeloma patients (n = 4). RESULTS: All six HLC assays revealed analytical performances suitable for application in routine diagnostics. With regard to diagnostic performance, all samples with IgA MPs in IFE (n = 54) could be identified in the HLC IgA assay. Of sera showing IgG MP in IFE (n = 69), 57 could be identified in the HLC IgG assay, whereas 12 had normal IgG kappa/lambda ratios. Of sera showing IgM MP in IFE (n = 26), 25 could be identified in the HLC IgM assay, 1 serum revealed a normal IgM kappa/lambda ratio. ScTx patients achieving IFE-negative remission had normal HLC ratios. Those who failed to achieve IFE-negative remission showed normalization of conventional monitoring parameters but revealed HLC ratios never reaching reference range. CONCLUSIONS: HLC assays exhibit analytical performances suitable for clinical routine application. Our preliminary data from ScTx patients suggest a diagnostic potential especially of HLC IgA assay in disease monitoring. Other than that, combined application of HLC assays does not represent an alternative to IFE in first line diagnostics, in particular due to the limited diagnostic performance of the HLC IgG assay. PMID- 25291946 TI - Quantification of Atopobium vaginae loads may be a new method for the diagnosis of bacterial vaginosis. AB - BACKGROUND: Traditional methods for the diagnosis of BV is either with poor sensitivity or poor specificity. Thus, establishing a new method based on the vaginal flora is vital for the diagnosis of BV. METHODS: This article is a retrospective research. Based on the Amsel criteria and Nugent score, 230 BV positive patients and 360 healthy women were enrolled, specific PCR and quantitative PCR were applied to quantify 5 BV-associated bacteria, including Gardnerella vaginalis, Atopobium vaginae, Leptotrichia/Sneathia species, Megasphaera species and Mobiluncus mulieris. ROC curve was facilitated to screen a bacterial panel with optimal sensitivity and specificity. RESULTS: Specific PCR showed that the area under ROC curve of A.vag, G.vag + A.vag, G.vag + A.vag + Lepto, G.vag + A.vag + Mega and G.vag + A.vag + M.mul were 0.845, 0.862, 0.865, 0.869 and 0.867, the sensitivity and specificity were higher than 80%, which were practicable methods for the diagnosis of BV. Quantitative PCR showed the area under ROC curve of Gardnerella vaginalis, Atopobium vaginae, Leptotrichia/Sneathia species, Megasphaera species and Mobiluncus mulieris were 0.959, 0.996, 0.933, 0.748 and 0.639, when the cutoff value of Atopobium vaginae loads was 247,800 copies/mL, the optimal sensitivity and specificity were 0.979 and 0.952, which was distinctly better than specific PCR. CONCLUSIONS: Quantification ofAtopobium vaginae loads may be a new method of excellent sensitivity and specificity for the diagnosis of BV. PMID- 25291947 TI - Measurement procedure for glucose in serum using liquid chromatography isotope dilution--tandem mass spectrometry (LC-ID-MS/MS). AB - BACKGROUND: We developed and validated a measurement procedure for glucose using liquid chromatography-isotope dilution tandem mass spectrometry. The proposed method is intended to be used for setting target values in EQAS samples and for certification of glucose reference materials, including those in biological matrices. METHODS: Serum samples were spiked with internal standard 13C6 D glucose. Protein precipitation was performed with ethanol. The samples were vortexed and centrifuged. An aliquot of the supernatant was evaporated to dryness, the residue dissolved in elution buffer and injected into the LC-MS/MS system. Measurements were performed in the positive ion mode monitoring the Cs+ adducts for glucose at m/z 313 --> 132.9 and m/z 319 --> 132.9 for the internal standard. RESULTS: The coefficient of variation (CV) of the measurement procedure for lyophilized, liquid, and fresh serum samples was between 0.27 and 1.77%. The bias from certified target values for NIST reference materials was < or = 0.62%. A Deming regression comparison demonstrated a good correlation of results obtained with the proposed LC-ID-MS/MS method and target values obtained in the internationally accepted IFCC-RELA ring trial using JCTLM-recognized reference measurement procedures. CONCLUSIONS: The proposed LC-ID-MS/MS measurement procedure with traceability to SI units shows excellent accuracy and precision and is suitable for use as reference measurement procedure for certification of target values in lyophilized and fresh serum samples. PMID- 25291948 TI - Non-invasive detection of EGFR deletion at exon 19 in non-small cell lung cancer by real time diagnostic. AB - BACKGROUND: The non-invasive identification of epidermal growth factor receptor (EGFR) mutations is important for the institution of individualized therapy of non-small cell lung cancer (NSCLC). In this study, the feasibility of screening for EGFR exon 19 E746_A750del mutations in circulating DNA from plasma was assessed. METHODS: Mutant-specific primers with a Taqman probe (MST-PCR) were designed. The ability of this method to accurately detect decreasing concentrations of E746_A750del mutant within a wild type DNA background that mimics the situation of a plasma sample from patients with acquired mutations is verified. To verify the clinical applicability of this method, 55 plasma samples from NSCLC patients were tested, and the sensitivity of MST-PCR was compared to that of direct sequencing. RESULTS: The results showed that MST-PCR could detect 10 to 50 copies/microL of E746_A750del, representing 0.1% of the wild type EGFR allelic population. Among the 55 cases of NSCLC, 10 cases of E746_A750del were detected by MST-PCR, while only 1 case was revealed by direct sequencing. CONCLUSIONS: These findings demonstrate that MST-PCR provides superior sensitivity for the detection of the E746_A750del mutation, suggesting its potential application in the noninvasive detection of E746_A750del mutations in plasma samples from NSCLC patients. PMID- 25291949 TI - Serum functional dickkopf-1 levels are inversely correlated with radiographic severity of ankylosing spondylitis. AB - BACKGROUND: Dickkopf-1 (DKK-1) has been proved dysfunctional in ankylosing spondylitis (AS), and decreased serum functional DKK-1 levels have been identified to be decreased in AS patients. This study aims to examine the relation of binding (functional) DKK-1 levels in serum with the radiographic severity of AS. METHODS: Total Dkk1 levels were assessed by commercial sandwich enzyme-linked immunosorbent assay and functional DKK-1 levels of serum were measured using functional enzyme-linked immunosorbent assay method in 84 patients with AS and 79 healthy controls. The radiographic progression of AS was classified according to the radiographic events of modified New York Criteria for sacroiliac joints evaluation and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system for spine assessment. RESULTS: No significant difference was seen between AS patients and healthy controls for total Dkk1 levels (p = 0.273). Decreased levels of functional DKK-1 in serum were found in AS patients compared with healthy controls 17.24 (1.24-11.15) vs. 9.15 (5.33-13.35) pg/mL, p < 0.001]. Functional DKK-1 levels in serum of AS patients were significantly associated with the disease radiographic severity evaluated by modified New York grading criteria (r = -0.236, p = 0.04) and mSASSS system (r = -0.389, p = 0.025). CONCLUSIONS: Serum functional DKK-1 levels showed an independent and negative correlation with radiographic severity of the disease in patients with AS. Functional DKK-1 in serum might serve as a potential biomarker for reflecting the progression of ankylosing spondylitis. PMID- 25291950 TI - Aggregometric assessment of clonidine's impact on the efficacy of dual platelet inhibition. AB - BACKGROUND: Clonidine is commonly used as a calmative and antihypertensive agent in perioperative care. Due to the drug's alpha-2-agonistic effects, it has recently been hypothesised that clonidine may affect platelet aggregability. The present investigation aimed to study the potential impact of clonidine on the efficacy of dual antiplatelet therapy. METHODS: In this prospective, observational, single-centre study, patients treated with dual antiplatelet therapy were screened for eligibility. The patients were enrolled in the study if ex vivo thrombin-induced (TRAPtest), arachidonic acid-induced (ASPItest) and adenosine diphosphate-induced (ADPtest) platelet aggregation, as measured using multiple electrode aggregometry (MEA; Multiplate, Roche AG, Grenzach, Germany), confirmed efficient dual platelet inhibition. Ex vivo induced platelet aggregation was assessed before (baseline) and 3 minutes after (T1) spiking blood samples with either 1 ng/mL clonidine or sodium chloride 0.9% (control group). RESULTS: In total, 34 patients were finally enrolled in the study. Compared with baseline, platelet aggregation in the ASPItest and ADPtest was significantly increased at T1 in both groups. Platelet aggregation in the TRAPtest remained unchanged between baseline and T1 in both groups. Comparing platelet aggregation at T1, we detected no differences between blood samples that were spiked with clonidine and blood samples that were spiked with sodium chloride 0.9% in the TRAPtest, the ASPItest, or the ADPtest. CONCLUSIONS: The results of this study indicate that clonidine does not affect platelet aggregability in patients treated with dual antiplatelet therapy. The findings of the study also indicate that ex vivo induced platelet aggregation in the ASPItest and ADPtest increases with the duration between blood drawing and MEA analyses. PMID- 25291951 TI - 25-hydroxy-Vitamin D status: limitations in comparison and clinical interpretation of serum-levels across different assay methods. AB - Background: Over the last decade, clinical interest to evaluate human 25-hydroxy vitamin D (25[OH]D) serum levels has increased exponentially. In the present study, four chemiluminescence immunoassays (CLIA), one radioimmunoassy (RIA), and one high performance liquid chromatography (HPLC) method were compared and also with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in view of 25(OH)D serum level determination. Methods: For the method comparison, blood samples from 133 consecutive patients were prospectively collected. All participants gave written informed consent for their blood samples to be used in this study. They came to the Department of Nuclear Medicine of the Central Hospital Steyr (Austria) for osteodensidometric measurement as part of their preventive medical check-up. Pearson's correlation coefficients, Bland-Altman plots, and paired t-tests were calculated. Assay-specific reference ranges were considered using blood samples from persons with normal parathormone, calcium, and total-protein values (n = 97). Results: The highest correlation was between the HPLC and the LC-MS/MS method (r = 0.96). The lowest correlation was between the cobas Vitamin D3 assay (Roche) and any of the evaluated assays (r = 0.46 - 0.63). Bland-Altman plots revealed a big negative mean bias in three assays (cobas Vitamin D3 assay [Roche]: -22.8; DiaSorin LIAISON [25[OH]D total CLIA [Diasorin]: -18.4; Diasorin 25[OH]D125 I RIA [Diasorin]: -23.8 [nmol/L]) and a much smaller positive mean bias in the other assays (ClinRep complete 25[OH]D2/D3 HPLC kit [Recipe]: 2.7; ADVIA Centaur Vitamin D total assay [Siemens]: 8.2; IDS total vitamin D assay [Immunodiagnostic Systems]: 12.1 [nmol/L]) compared to the LC-MS/MS method. Meanwhile, the manufacturer has withdrawn the cobas Vitamin D3 assay from the market. Conclusions: Poor antibody specificity with cross reactivity to other vitamin D metabolites, incomplete extraction of the 25(OH)D analyte from the vitamin D-binding protein (DBP), and confounding matrix substances such as lipids could be potential reasons for the unacceptable performance of the cobas Vitamin D3 assay (Roche) and also the significant differences in the 25(OH)D determination between various assays. Standardization and harmonization of 25(OH)D measurements are therefore urgently needed. The widespread introduction of well standardized assays in clinical laboratories is the challenge in the next years. (Clin. Lab. 2014;60:1541-1550. DOI: 10.7754/Clin.Lab.2014.131114) PMID- 25291953 TI - Omalizumab (anti-IgE) therapy increases blood glucose levels in severe persistent allergic asthma patients with diabetes mellitus: 18 month follow-up. AB - BACKGROUND: Therapeutic anti-IgE antibodies (Xolair, omalizumab) able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross linking IgE and triggering degranulation of IgE-sensitised cells have been developed. METHODS: We had two male patients of severe persistent allergic asthma with type-2 diabetes mellitus at the ages of 57 and 52 and who had suffered a side-effect of increased blood glucose level that caused a need for an extra insulin injection to control the hyperglycemia. Their asthma was not under control, frequent emergency department admissions lead us to use omalizumab treatment. Assessment of clinical changes and adverse effects were evaluated at each bimonthly patient visit including vital signs, full physical examination, details of any allergy incidents, total and specific IgE levels, serum ECP (eosinophilic cationic peptid) levels, pulmonary function test, exhaled nitric oxide concentrations, and asthma control test. RESULTS: Both patients were on week 42 - 45 of omalizumab treatment with a the dosage of 375 and 300 mg when they had the adverse reaction we reported here; they also had no other complaints. Blood levels of ECP and high sensitive CRP (hs-CRP) were decreased after starting the treatment of anti-IgE. CONCLUSIONS: To our knowledge, this is the first time an association between omalizumab use and hyperglycemia has been documented. Every vial of Xolair (150 mg) contains 145.5 mg sucrose and it might increase the blood levels of glucose in diabetics. As a conclusion the prescribing information might have been revised based on post marketing surveillance data and reported such cases indicating that different side effects may occur beyond 2 hours of the injection. PMID- 25291952 TI - Thyroid analytes TSH, FT3 and FT4 in serum of healthy elderly subjects as measured by the Roche modular system: do we need age and gender dependent reference levels? AB - BACKGROUND: Age and gender may be involved in the regulation of TSH and thyroid hormones. Reliable investigations concerned with the matter of whether or not these factors are of importance for diagnostic evaluation of the thyroid function are scarce. We used serum values of the CARLA study to calculate reference intervals for TSH, FT3, and FT4 and examine these parameters for their association with age or gender. METHODS: The CARLA study included 967 men and 812 women aged 45 to 83 years. We defined a reference group of 1002 subjects that were free of thyroid disease for data analysis by laboratory analysis and questionnaire, calculated age-dependent moving percentiles (2.5th/97.5th) for TSH, FT4, and FT3 and tested this data set for the confounding factors age and gender. Thereafter, the results were compared to data from the Leipzig Blood Donor study established in 2005. RESULTS: TSH (significant in trend (p = 0.064)) and FT3 (p = 0.001) were inversely associated with age. The correlation of FT3 with age was furthermore influenced by gender (p < 0.001). Neither gender nor age influenced values of FT4. CONCLUSIONS: The decreased TSH and FT3 levels with increasing age suggest a diagnostically relevant modification in the feed back regulation of thyroid function of the elderly. FT3 data should thus be interpreted gender-dependent and even age-dependent for males. These findings should be considered for the diagnostic examination of older patients with suspected disorders of thyroid function. PMID- 25291954 TI - Osteomyelitis caused by Burkholderia pseudomallei: relapse six years after pulmonary infection. AB - BACKGROUND: Burkholderia pseudomallei is highly endemic in Southeast Asia, whereas in Europe usually only few imported cases of melioidosis occur. CASE REPORT: In 2006, a 52-year-old male patient had been admitted to hospital with pneumonia after returning from a trip to Thailand. A blood culture isolate had been identified as Pseudomonas fluorescens and the patient had been treated with Piperacillin according to the antibiogram. Six years later the patient developed osteomyelitis of the leg and Burkholderia pseudomallei was identified as the causative agent. CONCLUSIONS: Misidentification of the cultural isolate in 2006 had led to inadequate therapy and to an unusually late relapse of melioidosis six years later. PMID- 25291955 TI - Cutaneous Alternaria infectoria infection diagnosed by molecular techniques in a renal transplant patient. AB - Organ transplant recipients under immunosuppressive therapy have a highly increased risk of opportunistic fungal infections. Cutaneous infection caused by Alternaria species are relatively rare in humans and most cases reported in the literature are in immunocompromised individuals. We report here on a 33-year old male renal transplant patient with diabetes mellitus who presented with cutaneous alternariosis caused by Alternaria infectoria, two years after the transplant. The diagnosis was performed by real-time polymerase chain reaction assay and histopathologic examination. The extension of the lesion under itraconazole treatment required treatment consisting of a combination of surgical excision and liposomal amphotericin B. PMID- 25291956 TI - VEGF levels in diagnosis of vasculitic neuropathy. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is secreted from endothelial cells and pericytes in response to hypoxia. It induces angiogenesis and microvascular hyperpermeability. We observe serum VEGF concentrations in some patients with vasculitic neuropathy. METHODS: Plasma VEGF was measured using GenWay's human VEGF ELISA Kit, which is based on standard sandwich enzyme-linked immune-sorbent assay technology. Human VEGF specific-specific monoclonal antibodies are precoated onto 96-well plates. The human specific detection polyclonal antibodies are biotinylated. The test samples and biotinylated detection antibodies were added to the wells subsequently and then followed by washing with PBS or TBS buffer. Avidin-Biotin-Peroxidase Complex was added and unbound conjugates were washed away with PBS or TBS buffer. HRP substrate TMB was used to visualize HRP enzymatic reaction. The VEGF levels were measured in 5 patients with vasculitic neuropathy and 8 healthy controls. RESULTS: Plasma VEGF was higher in subjects with vasculitic neuropathy as compared to controls. In the control group, we obtained VEGF levels from 9.8 pg/mL up to 15 pg/mL with an average of 11.6 pg/mL for males and 8.9 pg/mL up to 14.5 pg/mL with average of 11.2 pg/mL for females. In female patients with vasculitic neuropathy the plasma VEGF levels were between 79.9 pg/mL and 111.2 pg/mL, with an average of 92.375 pg/mL. We had one case with vasculitic neuropathy in men, in which the plasma VEGF level was 102.9 pg/mL. CONCLUSIONS: The results from our study indicate that plasma VEGF levels are significantly associated with vasculitic neuropathy and may be used to predict this disease. PMID- 25291957 TI - Differential behavior of serum and red blood cell folate during a treatment with levofolinic acid. Gender differences. AB - BACKGROUND: Folates are essential nutrients that maintain nucleotide synthesis and methylation reactions. Folate levels depend essentially on the diet. In the present work, the changes in the folate-homocysteine (Hcy) metabolic axis were studied in response to treatment with levofolinic acid. METHODS: 49 college students (23 men and 26 women) underwent a treatment voluntarily with 5 mg/day levofolinic acid for one month. Serum and red blood cell folate, vitamin B12, and Hcy levels were determined on days 2, 5, 10, and 30 during treatment and 30 days after completion of treatment. RESULTS: Serum folate and Hcy levels showed a plateau beginning on day 10, while red blood cell folate increased towards treatment completion. Gender differences were found in basal levels of Hcy, these differences remaining until the 10th day of treatment and reappearing 30 days after the treatment was finished. Between gender differences in treatment evolution were found only in percentage changes in red blood cell folate in women and men at day 30 of treatment. CONCLUSIONS: There is a compartmentalization of folates in the body that presents a plateau in serum and an erythrocyte reservoir. Folate metabolism presents differential features between genders. The greater physiological need for folate in women of childbearing age could be the determining factor in this difference. PMID- 25291958 TI - Alpha-1-fetoprotein (AFP) measurements and the high-dose hook effect. PMID- 25291959 TI - Comparison of radiation dose and image quality from single-energy and dual-energy CT examinations in the same patients screened for hepatocellular carcinoma. AB - AIM: To compare radiation dose surrogates [volume CT dose index (CTDIvol), dose length product (DLP), size-specific dose estimate (SSDE), and effective dose] and image noise in a cohort of patients undergoing hepatocellular carcinoma screening who underwent both single-energy CT (SECT) and dual-energy CT (DECT). MATERIALS AND METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, 74 adults (mean age 59.5 years) underwent 64 section SECT (120 kVp and weight-based reference mAs) and 128 section dual-source DECT (100/Sn 140 kVp and CTDIvol, adjusted to match the CDTIvol of the SECT protocol) on different occasions. Noise levels were measured in the liver, inferior vena cava (IVC), retroperitoneal (RP) fat, and aorta. Generalized linear models were constructed to compare dose and noise, adjusting for effective diameter. RESULTS: The total DLP (1371.11 mGy-cm, SD = 527.91) and effective dose (20.57 mSv, SD = 7.92) with SECT were significantly higher than the DLP (864.84 mGy-cm, SD = 322.10) and effective dose (12.97 mSv, SD = 4.83) with DECT (p < 0.001). The differences between SECT and DECT increased as the patient's effective diameter increased (p < 0.001). Noise levels in the liver (22.4 versus 21.9 HU), IVC (22.3 versus 23.4 HU), and RP fat (23.5 versus 23 HU) were similar for DECT and SECT (p > 0.05) but were significantly lower in the aorta for DECT (25.3 versus 26.4 HU; p = 0.006). CONCLUSION: DECT imaging of the abdomen can achieve noise levels comparable to those seen with SECT imaging without a dose penalty to patients. PMID- 25291960 TI - The effectiveness of sit-stand workstations for changing office workers' sitting time: results from the Stand@Work randomized controlled trial pilot. AB - BACKGROUND: Prolonged sitting time is detrimental for health. Individuals with desk-based occupations tend to sit a great deal and sit-stand workstations have been identified as a potential strategy to reduce sitting time. Hence, the objective of the current study was to examine the effects of using sit-stand workstations on office workers' sitting time at work and over the whole day. METHODS: We conducted a randomized controlled trial pilot with crossover design and waiting list control in Sydney, Australia from September 2011 to July 2012 (n = 42; 86% female; mean age 38 +/- 11 years). Participants used a sit-stand workstation for four weeks in the intervention condition. In the time-matched control condition, participants received nothing and crossed over to the intervention condition after four weeks. The primary outcomes, sitting, standing and walking time at work, were assessed before and after using the workstations with ActivPALs and self-report questionnaires. Secondary outcomes, domain specific sitting over the whole day, were assessed by self-report. Linear mixed models estimated changes in outcomes adjusting for measurement time, study grouping and covariates. RESULTS: Intervention participants significantly reduced objectively assessed time spent sitting at work by 73 min/workday (95% CI: -106, 39) and increased standing time at work by 65 min/workday (95% CI: 47, 83); these changes were significant relative to controls (p = 0.004 and p < 0.001, respectively). Total sitting time significantly declined in intervention participants (-80 min/workday; 95% CI: -155, -4). CONCLUSIONS: This study shows that introducing sit-stand workstations in the office can reduce desk-based workers' sitting time at work in the short term. Larger scale studies on more representative samples are needed to determine the public health impact of sit stand workstations. TRIAL REGISTRATION: ACTRN12612000072819. PMID- 25291961 TI - Aspartate aminotransferase-to-platelet ratio index is associated with liver cirrhosis in patients undergoing surgery for hepatocellular carcinoma. AB - BACKGROUND: Among various preoperative evaluations of liver function, accurate assessment of liver cirrhosis (LC) is especially important in patients undergoing surgery for hepatocellular carcinoma (HCC). OBJECTIVE: To explore the most significant laboratory parameter associated with LC in patients undergoing surgery for HCC. METHODS: From among 588 HCC patients in our collected database who underwent liver surgery, 371 for whom sufficient laboratory data were evaluable, including direct serum fibrosis markers such as hyaluronic acid and type 3 procollagen peptide (P-3-P), were enrolled. Receiver operating characteristic (ROC) curve analysis was used to define the ideal cutoff values of laboratory parameters, and the area under the ROC curve for LC was measured. Univariate and multivariate analyses were performed to clarify the laboratory parameter most significantly associated with LC. RESULTS: Multivariate analysis of 13 laboratory parameters that had been selected by univariate analysis showed that the aspartate aminotransferase-to-platelet ratio index (APRI) (<= 0.8/>0.8) (odds ratio, 2.687; 95% confidence interval 1.215-5.940; P = 0.015) was associated with LC, along with the aspartate aminotransferase to alanine aminotransferase ratio, the indocyanine green retention ratio at 15 min (ICG R15), and the level of hyaluronic acid. Among these four parameters associated with LC, ROC curve analysis revealed that APRI (0.757) had the largest area under the ROC (aspartate aminotransferase to alanine aminotransferase 0.505, ICG R15 0.714, and hyaluronic acid 0.743). CONCLUSIONS: APRI is closely associated with LC in patients undergoing surgery for HCC. PMID- 25291962 TI - Betulinic acid negates oxidative lung injury in surgical sepsis model. AB - BACKGROUND: Sepsis commonly progresses to acute lung injury and is associated with high morbidity and mortality. Septic acute lung injury is characterized by severe oxidative stress response, remained refractory to present therapies, and new therapies need to be developed to improve further clinical outcomes. We determined the effect of betulinic acid (BA) on oxidative lung injury in mice using cecal ligation and puncture (CLP) model. MATERIALS AND METHODS: Five groups of mice (six in each group) received three pretreatments at 24-h interval before surgery. Surgery was done 1 h after last dosing. Sham and CLP control group mice received vehicle. BA was administered to other three groups of mice at 3, 10, and 30 mg/kg dose. Lung and plasma samples were collected for analysis by sacrificing the mice at 18 h of surgery. RESULTS: Compared with sham, CLP significantly increased total protein, nitrite, malondialdehyde, isoprostane, superoxide, protein carbonyl, oxidative stress index, inducible nitric oxide synthase protein, and histopathologic changes and reduced the superoxide dismutase, catalase activity, and total thiol levels in lungs and plasma, which were restored by BA pretreatment. CONCLUSIONS: BA pretreatment decreased the levels of oxidants, increased the levels of antioxidants in lungs and plasma thereby reducing the oxidative lung injury in CLP mice. Additionally, BA was found to scavenge the superoxide and nitric oxide radical in vitro. Thus, BA is suggested to be effective in treatment of oxidative lung injury in sepsis. PMID- 25291963 TI - The effects of tetracycline-loaded silk fibroin membrane on proliferation and osteogenic potential of mesenchymal stem cells. AB - BACKGROUND: The main objective of this study was to investigate the effect of tetracycline-loaded silk fibroin membranes (TC-SFMs) on the proliferation and the osteogenic differentiation of human mesenchymal stem cells. MATERIALS AND METHODS: Four groups (0, 1, 5, and 10% concentration) of TC-SFMs were prepared for the experiments. We investigated cumulative tetracycline (TC) release profile for 7 d. Human gingiva-derived mesenchymal stem cells (GMSCs) were isolated from our previous study and seeded to the TC-SFMs. WST-8 assay (Cell Counting Kit-8; SigmaeAldrich Co, St. Louis, MO), staining of Phalloidin-FITC, and scanning electron microscope analyzed the cellular attachment and viability. Staining of Alizarin Red S (Sigma-Aldrich Co.) and osteogenic marker (osteocalcin) analyzed osteogenic differentiation. Additionally, quantitative polymerase chain reaction measured the expression of osteogenic lineage genes, including bone gamma carboxyglutamic acid protein, bone sialoprotein, runt-related transcription factor 2, and collagen type I alpha1 according to TC concentration (0.05, 0.1, 0.25, and 0.5 mg/mL). RESULTS: The release of TC from TC-SFMs plateaued and neared completion in 24 h. Significantly higher viability was noted achieved in 1% and 5% TC-SFMs. The morphology of GMSCs on TC-SFMs at 0% and 1% concentration showed spindle shapes, but cells in 10% TC-SFMs appeared spheroid. During Alizarin Red S staining at 21 d of osteogenic differentiation, calcium and osteocalcin formation were significantly lower in the 10% TC-SFM group than in the 0, 1, and 5 groups. Compared with the control group, bone gamma carboxyglutamic acid protein showed significantly low expression rate at TC concentration >=0.05 mg/mL. Bone sialoprotein was low at TC concentration >=0.1 mg/mL. Likewise, runt-related transcription factor 2 and collagen type I alpha1 were low at TC concentration of 0.5 mg/mL. CONCLUSIONS: Within the limits of this study, 1% and 5% TC-SFMs showed higher proliferation and osteogenic potential of GMSCs than 10% TC-SFM. Therefore, the use of 1% to 5% range of TC may be more suitable to silk fibroin membrane for stem cell tissue engineering. PMID- 25291964 TI - Cardiac fibroblasts: contributory role in septic cardiac dysfunction. AB - BACKGROUND: Cardiac dysfunction is a frequent and severe complication of septic shock and contributes to the high mortality of sepsis. Although several mechanisms have been suspected to be responsible for sepsis-associated cardiac dysfunction, the precise cause(s) remains unclear to date. MATERIALS AND METHODS: We tested the hypothesis that cardiac fibroblasts may play a critical role as a disease modifier involved in sepsis-associated cardiac dysfunction. Human cardiac fibroblasts (HCFs) cultured in vitro were exposed to lipopolysaccharide (LPS). Changes in cardiac morphology and function were assessed in mice with cecal ligation and puncture-induced sepsis. RESULTS: In LPS-stimulated HCFs, messenger RNA and protein levels of proinflammatory molecules, including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and monocyte chemoattractant protein-1, were strikingly upregulated. LPS also increased expression and activity of matrix metalloproteinase (MMP)-9, but not MMP-2. LPS-induced expression of alpha-smooth muscle actin, a classical marker for myoblast differentiation, which was abrogated when MMP-9 small interfering RNA was transfected into HCFs. High gene expression levels of proinflammatory cytokines and MMP-9 were observed in the heart tissues of cecal ligation and puncture induced septic mice. Histology sections of the hearts from septic mice showed perivascular and interstitial cardiac fibrosis, and echocardiography demonstrated that septic mice had profound cardiac dysfunction. The broad-spectrum MMP inhibitor ONO-4817 significantly alleviated these histologic and functional changes during the acute phase. CONCLUSIONS: We suggest that cardiac fibroblasts are of pathogenetic importance in inflammation and fibrosis in the heart during sepsis, leading to cardiac dysfunction that would affect the outcome of sepsis syndrome. PMID- 25291965 TI - Pro-inflammatory IL-1beta and/or TNF-alpha up-regulate matrix metalloproteases-1 and -3 mRNA in chondrocyte subpopulations potentially pathogenic in osteoarthritis: in situ hybridization studies on a single cell level. AB - AIM: In osteoarthritis chondrocytes, matrix metalloproteases (MMPs) and their inhibitors are induced by interleukin (IL)-1beta or tumor necrosis factor (TNF) alpha and balanced by inhibitors, but their messenger RNA (mRNA) expression has not been studied in individual cells. METHODS: Normal articular chondrocytes (10 donors; age 50 +/- 6 years, mean +/- SEM) were stimulated in a monolayer for 24 h with IL-1beta, TNF-alpha, or transforming growth factor (TGF)-beta1 (10 ng/mL each), alone or in combination. mRNA expression for MMP-1, MMP-3 and tissue inhibitor of metalloproteinase (TIMP)-1 was studied by in situ hybridization ((35) S-cRNA) and quantitative reverse transcription polymerase chain reaction (RT-PCR) (n >= 3 each). RESULTS: Whereas < 5% chondrocytes constitutively expressed MMP-1, a higher percentage expressed MMP-3 and TIMP-1 (31.1 +/- 1.8%; 36.7 +/- 2.8%, respectively). Upon stimulation with IL-1beta, TNF-alpha or IL 1beta/TNF-alpha, the percentage of cells positive for MMP-1, MMP-3 and TIMP-1 rose significantly (IL-1beta: 31.5%, 54.5% and 60.2%, respectively; TNF-alpha: 35.4%, 56.6%, 50.9%; IL-1beta/TNF-alpha: 38.8%, 45.2%, 52.1%). In bulk population (RT-PCR), mRNA for MMP-1 and MMP-3 was also induced by IL-1beta (11.9-fold, 1.2 fold, respectively), TNF-alpha (4.8-fold, 1.0-fold) or IL-1beta/TNF-alpha (14.7 fold, 1.4-fold), an effect attenuated by TGF-beta1. TIMP-1 mRNA, in contrast, was down-regulated by IL-1beta, TNF-alpha or IL-1beta/TNF-alpha, an effect again partially reverted by TGF-beta1. Finally, collagen type II mRNA was down regulated by IL-1beta, TNF-alpha or IL-1beta/TNF-alpha (by 90%, 50% and 98%, respectively) and that of collagen type I was up-regulated (5.7-fold, 3.0-fold, 3.7-fold). CONCLUSIONS: Up-regulation of MMP-1/MMP-3 by IL-1beta and/or TNF-alpha in a fraction of chondrocytes in vitro suggests that a subpopulation of catabolic cells may also exist in osteoarthritis. These cells may undergo considerable dedifferentiation, as indicated by a decreased collagen-II/collagen-I ratio. PMID- 25291966 TI - A theoretical physicist's journey into biology: from quarks and strings to cells and whales. AB - Biology will almost certainly be the predominant science of the twenty-first century but, for it to become successfully so, it will need to embrace some of the quantitative, analytic, predictive culture that has made physics so successful. This includes the search for underlying principles, systemic thinking at all scales, the development of coarse-grained models, and closer ongoing collaboration between theorists and experimentalists. This article presents a personal, slightly provocative, perspective of a theoretical physicist working in close collaboration with biologists at the interface between the physical and biological sciences. PMID- 25291967 TI - Characterization of rheotaxis of bull sperm using microfluidics. AB - We study rheotaxis of bull sperm inside microchannels to characterize the effects of flow and wall shape on sperm swimming behavior. We found that a large percentage of sperm cells, 80 to 84%, exhibited positive rheotaxis (sperm cells swimming against the flow) within flow velocities of 33 to 134 MUm s(-1). Sperm cells were also found to reverse their swimming direction when the liquid flow direction was reversed. Time taken by sperm cells to reverse their swimming direction was inversely proportional to the flow velocity. Sperm behavior was significantly affected by the sperm position with respect to the channel wall. Sperm cells close to the channel wall moved upstream faster than sperm cells moving along the channel centerline. Shear stress, which is an indicator of velocity distribution, was found to play an important role in regulating rheotactic behavior of sperm cells. Side pockets were added to some microchannels to mimic storage sites in mucosal folds and pockets in the fallopian tube of the female reproductive system and sperm interaction with these pockets was monitored. We found that sperm cells tend to follow channel walls and enter these pockets without any chemical binding, which further confirms the wall tracking behavior of mammalian sperm cells. Our results confirm that sperm rheotaxis is a strong mechanism for guiding sperm cells towards the oocyte along the female genital tract. PMID- 25291968 TI - Optical coherence tomography imaging of the patent ductus arteriosus: first known uses in congenital heart disease. AB - BACKGROUND: Angiography is used to assess ductal morphology and caliber during interventional closure of the ductus arteriosus. We are evaluating the use of optical coherence tomography (OCT) to evaluate ductal anatomy given the potential benefit of superior resolution and lower radiation. METHODS: Standard angiograms were performed on two patients with patent ductus arteriosus prior to device occlusion. OCT was then used to obtain high-resolution three-dimensional vessel reconstructions. Devices were chosen based on angiographic measurements. RESULTS: OCT resulted in excellent three-dimensional anatomic definition, with elliptical narrowest lumenal measurements of 2.2 * 3.1 mm and 1.6 * 2.3 mm, respectively, compared with angiographic measurements of 2.6 and 1.4 mm. CONCLUSIONS: To our knowledge, this is the first reported use of OCT use in pediatric patients outside the coronaries, and in patients with congenital heart disease. We found OCT imaging of the PDA to be feasible, and only used a small amount of additional radiation and contrast. The three-dimensional OCT reconstructions provided additional anatomic information that could potentially improve device selection, and in both cases may have led to choosing larger devices than what was chosen based on angiography. In addition, once the technique is perfected, little or no angiography or fluoroscopy will be required to perform imaging runs, and only a small injection of contrast appears to be sufficient for vessel imaging. However, there are certain limitations to OCT imaging that are unlikely to make it the method of choice specifically for imaging the patent ductus arteriosus, but we have shown its ability to provide high resolution imaging in a relatively simple fashion which may prove useful for other purposes. (c) 2014 Wiley Periodicals, Inc. PMID- 25291969 TI - Increased serum C-reactive protein level in Japanese patients of psoriasis with cardio- and cerebrovascular disease. AB - Psoriasis is a chronic inflammatory skin disease, which may be associated with metabolic syndrome accompanied by cardio- and cerebrovascular diseases. We investigated the relation between serum C-reactive protein (CRP) and cardio- and cerebrovascular diseases in Japanese psoriasis vulgaris patients. Ninety-seven psoriasis vulgaris patients and 79 healthy controls were assessed for serum CRP levels by immunoturbidimetry. The data were analyzed in terms of Psoriasis Area and Severity Index (PASI) scores, and comorbidity of cardio- and cerebrovascular disease and metabolic syndrome. Serum CRP levels in psoriasis vulgaris patients were significantly higher than those of healthy controls. There was no significant difference between male and female CRP levels in either psoriasis or healthy controls. No correlation was detected between PASI scores and serum CRP levels, either. Psoriasis with cardio- and cerebrovascular disease showed significantly higher CRP levels compared with those without the diseases. Furthermore, psoriasis with metabolic syndrome showed significantly higher serum CRP levels than those without the metabolic syndrome. In conclusion, serum CRP level is increased in psoriasis, and may be a useful marker for the prediction of the future risk of cardio- and cerebrovascular disease. PMID- 25291970 TI - Source of nitrogen associated with recovery of relative growth rate in Arabidopsis thaliana acclimated to sustained cold treatment. AB - To determine (1) whether acclimation of carbon metabolism to low temperatures results in recovery of the relative growth rate (RGR) of plants in the cold and (2) the source of N underpinning cold acclimation in Arabidopsis thaliana, we supplied plants with a nutrient solution labelled with (15) N and subjected them to a temperature shift (from 23 to 5 degrees C). Whole-plant RGR of cold-treated plants was initially less than 30% of that of warm-maintained control plants. After 14 d, new leaves with a cold-acclimated phenotype emerged, with the RGR of cold-treated plants increasing by 50%; there was an associated recovery of root RGR and doubling of the net assimilation rate (NAR). The development of new tissues in the cold was supported initially by re-allocation of internal sources of N. In the longer term, the majority (80%) of N in the new leaves was derived from the external solution. Hence, both the nutrient status of the plant and the current availability of N from external sources are important in determining recovery of growth at low temperature. Collectively, our results reveal that both increased N use efficiency and increases in nitrogen content per se play a role in the recovery of carbon metabolism in the cold. PMID- 25291971 TI - Perspectives on working at the physics-biology interface. PMID- 25291973 TI - MIL-101-SO3H: a highly efficient Bronsted acid catalyst for heterogeneous alcoholysis of epoxides under ambient conditions. AB - For the first time, a ~100% sulfonic acid functionalized metal-organic framework (MOF), MIL-101-SO3H, with giant pores has been prepared by a hydrothermal process followed by a facile postsynthetic HCl treatment strategy. The replete readily accessible Lewis acidic and especially Bronsted acidic sites distributed throughout the framework as well as high stability endow the resultant MOF exceptionally high efficiency and recyclability, which surpass all other MOF based catalysts, for the ring opening of epoxides with alcohols (especially, methanol) as nucleophiles under ambient conditions. PMID- 25291974 TI - Pharmacokinetics of sifuvirtide in treatment-naive and treatment-experienced HIV infected patients. AB - The pharmacokinetics assessment in two clinical studies of sifuvirtide (a novel HIV fusion inhibitor) was first reported in Chinese HIV patients. Nineteen treatment-naive HIV patients were treated with s.c.(subcutaneous injection) sifuvirtide [10 or 20 mg q.d.(quaque die)] for 28 days in study 1, and eight treatment-experienced HIV patients were treated with s.c. sifuvirtide (20 mg q.d.) in combination with HAART drugs (lamivudine, didanosine, and Kaletra) for 168 days in study 2. In study 1, T1/2 was 17.8 +/- 3.7 h for 10 mg group and 39.0 +/- 3.5 h for 20 mg group; the mean Cmax of last dose was 498 +/- 54 ng/mL for 10 mg group and 897 +/- 136 ng/mL for 20 mg group. In study 2, T1/2 was 6.71 +/- 2.17 h in treatment-experienced patients. Cmax was 765 +/- 288 ng/mL after last 168th dosage. Sifuvirtide showed improved clinical pharmacokinetics characteristics compared with Enfuvirtide, and showed very different pharmacokinetic characteristics between treatment-naive and treatment-experienced patients. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4038-4047, 2014. PMID- 25291975 TI - Sublaminar bands: are they safe? AB - BACKGROUND: Sublaminar bands (SB) are frequently used as implants in spine deviation correction. PURPOSE: Our purpose is to demonstrate their safety on a large series of patients. STUDY DESIGN: This is a retrospective study. METHODS: Our department treated 378 spine deviations on children and adolescents via a hybrid posterior technique (lumbar screws, hook and thoracic SB). Each surgery was undertaken using anesthesiologic and a neurophysiologic monitoring using somatosensory evoked potentials (SSEP) and neurogenic mixed evoked potentials (NMEP). An alert was described as an amplitude decrease of 50 % and/or a latency increase of 10 %. Data were analyzed using Student or Wilcoxon tests. RESULTS: We used 2,223 SB in 378 operative procedures. We described ten neurophysiologic alerts during the passage of the band under the lamina. There were no significative differences between the two groups concerning the age and the severity of the deformation (p > 0.05). These neurophysiologic alerts were associated with a dysautonomic trouble (hypertension and bradycardia). The lesional level was determined using a spinal electrode. In six cases, the responsible SB was removed. Three patients had post-operative neurologic deficiency (0.8 %) without complete recovery for one of them (localized incomplete sensitive deficiency). Within the group of 378 patients, 21 alerts were reported due to a screw or a hook, or during the correction manoeuver, without dysautonomic trouble. CONCLUSION: SB neurologic complications rate is as high as other implants' complication rate. Simultaneous hemodynamic and neurophysiologic change is an argument for vegetative response due to SB passage. Their optimal use requires a strict learning of their insertion under the lamina to be as less traumatic as possible. SB are as safe as any other spine implants. PMID- 25291976 TI - Patients' expectations of lumbar spine surgery. AB - PURPOSE: Patients undergoing lumbar spine surgery are a heterogeneous population and their expectations of surgery are likely to vary depending on individual and group characteristics. Our goal was to assess associations between expectations and demographic, psychological, and clinical characteristics in patients undergoing lumbar spine surgery. METHODS: Shortly before surgery (mean 7 +/- 3 days) 420 patients completed the valid and reliable Hospital for Special Surgery, Lumbar Spine Surgery Expectations Survey, which encompasses physical and psychological expectations; scores range from 0 to 100, higher scores reflect greater expectations. Patients completed additional surveys addressing multiple variables, including disability due to pain with a modified version of the Oswestry Disability Index (ODI). RESULTS: The mean age was 55 +/- 15 years, 57 % were men, and most surgery was for painful conditions. The mean Expectations Survey score was 72 +/- 20 (range 2.5-100). In multivariate analysis, patients had higher scores (i.e., greater expectations) if they were younger (OR 1.02, CI 1.01, 1.04; p = .002), were not widowed (OR 4.9; CI 1.5, 15.5; p = .007), had prior chiropractic care (OR 1.8; CI 1.1, 2.8; p = .02), had worse ODI scores (OR 2.3; CI 1.5, 3.5; p = .0001), and had worse mental health scores (OR 1.8; CI 1.2, 2.8; p = .006). In additional multivariate analyses, worse ODI score was the clinical variable most closely associated with expecting more Expectations Survey items and expecting more improvement per item. CONCLUSIONS: There were wide variations in expectations among patients. Multiple demographic, psychological, and clinical characteristics were associated with expectations, with disability due to pain being the most consistently associated variable. PMID- 25291972 TI - Models of vertical cytomegalovirus (CMV) transmission and pathogenesis. AB - Despite the considerable clinical impact of congenital human cytomegalovirus (HCMV) infection, the mechanisms of maternal-fetal transmission and the resultant placental and fetal damage are largely unknown. Here, we discuss animal models for the evaluation of CMV vaccines and virus-induced pathology and particularly explore surrogate human models for HCMV transmission and pathogenesis in the maternal-fetal interface. Studies in floating and anchoring placental villi and more recently, ex vivo modeling of HCMV infection in integral human decidual tissues, provide unique insights into patterns of viral tropism, spread, and injury, defining the outcome of congenital infection, and the effect of potential antiviral interventions. PMID- 25291978 TI - NMR study of non-structural proteins--part II: (1)H, (13)C, (15)N backbone and side-chain resonance assignment of macro domain from Venezuelan equine encephalitis virus (VEEV). AB - Macro domains consist of 130-190 amino acid residues and appear to be highly conserved in all kingdoms of life. Intense research on this field has shown that macro domains bind ADP-ribose and other similar molecules, but their exact function still remains intangible. Macro domains are highly conserved in the Alphavirus genus and the Venezuelan equine encephalitis virus (VEEV) is a member of this genus that causes fatal encephalitis to equines and humans. In this study we report the high yield recombinant expression and preliminary solution NMR study of the macro domain of VEEV. An almost complete sequence-specific assignment of its (1)H, (15)N and (13)C resonances was obtained and its secondary structure predicted by TALOS+. The protein shows a unique mixed alpha/beta-fold. PMID- 25291979 TI - Backbone (1)H, (13)C, and (15)N resonance assignments of the Fc fragment of human immunoglobulin G glycoprotein. AB - The Fc portion of immunoglobulin G (IgG) recruits complements and its cognate receptors, thereby promoting defensive mechanisms in the humoral immune system. These effector functions critically depend on N-glycosylation at the Fc region, which is therefore regarded as a crucial factor in the design and production of therapeutic antibodies. NMR spectroscopy plays a unique role in the characterization of conformational dynamics and intermolecular interactions of IgG-Fc in solutions. Here, we report NMR assignments of the glycosylated Fc fragment (Mr 53 kDa), cleaved from a chimeric antibody with human IgG1 constant regions, which was produced in Chinese hamster ovary cells with uniform (13)C- and (15)N-labeling. PMID- 25291977 TI - Cost-effectiveness of rapid hepatitis C virus (HCV) testing and simultaneous rapid HCV and HIV testing in substance abuse treatment programs. AB - AIMS: To evaluate the cost-effectiveness of rapid hepatitis C virus (HCV) and simultaneous HCV/HIV antibody testing in substance abuse treatment programs. DESIGN: We used a decision analytic model to compare the cost-effectiveness of no HCV testing referral or offer, off-site HCV testing referral, on-site rapid HCV testing offer and on-site rapid HCV and HIV testing offer. Base case inputs included 11% undetected chronic HCV, 0.4% undetected HIV, 35% HCV co-infection among HIV-infected, 53% linked to HCV care after testing antibody-positive and 67% linked to HIV care. Disease outcomes were estimated from established computer simulation models of HCV [Hepatitis C Cost-Effectiveness (HEP-CE)] and HIV [Cost Effectiveness of Preventing AIDS Complications (CEPAC)]. SETTING AND PARTICIPANTS: Data on test acceptance and costs were from a national randomized trial of HIV testing strategies conducted at 12 substance abuse treatment programs in the United States. MEASUREMENTS: Lifetime costs (2011 US$) and quality-adjusted life years (QALYs) discounted at 3% annually; incremental cost effectiveness ratios (ICERs). FINDINGS: On-site rapid HCV testing had an ICER of $18,300/QALY compared with no testing, and was more efficient than (dominated) off-site HCV testing referral. On-site rapid HCV and HIV testing had an ICER of $64,500/QALY compared with on-site rapid HCV testing alone. In one- and two-way sensitivity analyses, the ICER of on-site rapid HCV and HIV testing remained <$100,000/QALY, except when undetected HIV prevalence was <0.1% or when we assumed frequent HIV testing elsewhere. The ICER remained <$100,000/QALY in 91% of probabilistic sensitivity analyses. CONCLUSIONS: On-site rapid hepatitis C virus and HIV testing in substance abuse treatment programs is cost-effective at a <$100,000/quality-adjusted life year threshold. PMID- 25291980 TI - Sudden cardiac death in the young (5-39 years) in the canton of Vaud, Switzerland. AB - BACKGROUND: Sudden cardiac death (SCD) among the young is a rare and devastating event, but its exact incidence in many countries remains unknown. An autopsy is recommended in every case because some of the cardiac pathologies may have a genetic origin, which can have an impact on the living family members. The aims of this retrospective study completed in the canton of Vaud, Switzerland were to determine both the incidence of SCD and the autopsy rate for individuals from 5 to 39 years of age. METHODS: The study was conducted from 2000 to 2007 on the basis of official statistics and analysis of the International Classification of Diseases codes for potential SCDs and other deaths that might have been due to cardiac disease. RESULTS: During the 8 year study period there was an average of 292'546 persons aged 5-39 and there were a total of 1122 deaths, certified as potential SCDs in 3.6% of cases. The calculated incidence is 1.71/100'000 person years (2.73 for men and 0.69 for women). If all possible cases of SCD (unexplained deaths, drowning, traffic accidents, etc.) are included, the incidence increases to 13.67/100'000 person-years. However, the quality of the officially available data was insufficient to provide an accurate incidence of SCD as well as autopsy rates. The presumed autopsy rate of sudden deaths classified as diseases of the circulatory system is 47.5%. For deaths of unknown cause (11.1% of the deaths), the autopsy was conducted in 13.7% of the cases according to codified data. CONCLUSIONS: The incidence of presumed SCD in the canton of Vaud, Switzerland, is comparable to the data published in the literature for other geographic regions but may be underestimated as it does not take into account other potential SCDs, as unexplained deaths. Increasing the autopsy rate of SCD in the young, better management of information obtained from autopsies as well developing of structured registry could improve the reliability of the statistical data, optimize the diagnostic procedures, and the preventive measures for the family members. PMID- 25291981 TI - Sjogren's syndrome and neuromyelitis optica spectrum disorders (NMOSD)--a case report and review of literature. AB - BACKGROUND: Neuromyelitis optica (NMO) is a rare relapsing auto-immune disease of the central nervous system which is sometimes found in association with other autoimmune disorders including Sjogren's syndrome. We present the case of a middle aged female with Sjogren's syndrome (SS) and Neuromyelitis optica spectrum disorders (NMOSD) who had a rapidly declining neurological illness that responded to immunosuppressive therapy. CASE PRESENTATION: A 51-year-old female with Sjogren's syndrome and recent history of varicella zoster infection presented with right upper and lower extremity weakness of one week duration. She was noted to have contrast enhancement at C2-C4 cord levels on cervico-thoracic MRI. Comprehensive work up was negative except for presence of a mild lymphocytic pleocytosis and oligoclonal bands in the CSF. She was diagnosed with transverse myelitis secondary to varicella zoster infection and was treated with high dose steroids in addition to acyclovir with improvement in her symptoms. Two months later she developed left upper and lower extremity weakness, bilateral dysesthesias and urinary incontinence. Repeat MRI of the cervico-thoracic spine revealed worsening enhancement at lower cervical cord levels (C5-7) with extension to T1. CSF analysis was unchanged; however immunological work up was abnormal for elevated NMO-IgG/AQP4 antibody. She was diagnosed with NMOSD and was treated with immunosuppressive therapy. Initially with IV methylprednisone and Cyclophosphamide therapy followed by Mycophenolate mofetil (MMF) maintenance therapy with good response. Repeat MRI 6 months later showed near complete resolution of previous abnormal cord signal changes. CONCLUSION: One needs to recognize the relationship between autoimmune diseases especially SS and NMOSD. The presence of NMO antibody has been associated with a relapsing disease course and a careful follow-up, besides use of remission maintenance agents such as MMF and Azathioprine are important to consider. PMID- 25291982 TI - The evidence based dilemma of intraperitoneal drainage for pancreatic resection - a systematic review and meta-analysis. AB - BACKGROUND: Routine placement of intraperitoneal drains has been shown to be ineffective or potentially harmful in various abdominal surgical procedures. Studies assessing risks and benefits of abdominal drains for pancreatic resections have demonstrated inconsistent results. We thus performed a systematic review of the literature and meta-analyzed outcomes of pancreatic resections with and without intraoperative placement of drains. METHODS: A database search according to the PRISMA guidelines was performed for studies on pancreatic resection with and without intraperitoneal drainage. The subgroup 'pancreaticoduodenectomy' was analyzed separately. The quality of studies was assessed using the MINORS and STROBE criteria. Pooled estimates of morbidity, mortality and length of hospital stay were calculated using random effects models. RESULTS: Only two randomized trials were identified. Their results were contradictory. We thus included six further, retrospective studies in the meta analysis. However, with I2 = 68% for any kind of complication, the estimate of inter-study heterogeneity was high. While overall morbidity after any kind of pancreatic resection was lower without drains (p = 0.04), there was no significant difference in mortality rates. In contrast, pooled estimates of outcomes after pancreaticoduodenectomy demonstrated no differences in morbidity (p = 0.40) but increased rates of intraabdominal abscesses (p = 0.04) and mortality (p = 0.04) without intraperitoneal drainage. CONCLUSION: Although drains are associated with slightly increased morbidity for pancreatic resections, routine omission of drains cannot be advocated, especially after pancreaticoduodenectomy. While selective drainage seems reasonable, further efforts to generate more reliable data are questionable because of the current studies and the presumed small differences in outcomes. TRIAL REGISTRATION: Systematic review registration number CRD42014007497. PMID- 25291983 TI - The influence of demographics and working conditions on self-reported injuries among Latino day laborers. AB - BACKGROUND: The majority of day laborers in the USA are Latinos. They are engaged in high-risk occupations and suffer high occupational injury rates. OBJECTIVES: To describe on-the-job injuries reported by Latino day laborers, explore the extent that demographic and occupational factors predict injuries, and whether summative measures for total job types, job conditions, and personal protective equipment (PPE) predict injuries. METHODS: A community survey was conducted with 327 participants at 15 corners in Houston, Texas. Hierarchical and multiple logistic regressions explored predictors of occupational injury odds in the last year. RESULTS: Thirty-four percent of respondents reported an occupational injury in the previous year. Education, exposure to loud noises, cold temperatures, vibrating machinery, use of hard hats, total number of job conditions, and total PPE significantly predicted injury odds. CONCLUSION: Risk for injury among day laborers is not only the product of a specific hazard, but also the result of their exposure to multiple occupational hazards. PMID- 25291984 TI - Exposure to polycyclic aromatic hydrocarbons (PAHs) and bladder cancer: evaluation from a gene-environment perspective in a hospital-based case-control study in the Canary Islands (Spain). AB - BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been linked to bladder cancer. OBJECTIVE: To evaluate the role of PAHs in bladder cancer, PAHs serum levels were measured in patients and controls from a case-control study. METHODS: A total of 140 bladder cancer patients and 206 healthy controls were included in the study. Sixteen PAHs were analyzed from the serum of subjects by gas chromatography-mass spectrometry. RESULTS: Serum PAHs did not appear to be related to bladder cancer risk, although the profile of contamination by PAHs was different between patients and controls: pyrene (Pyr) was solely detected in controls and chrysene (Chry) was exclusively detected in the cases. Phenanthrene (Phe) serum levels were inversely associated with bladder cancer (OR = 0.79, 95%CI = 0.64-0.99, P = 0.030), although this effect disappeared when the allelic distribution of glutathione-S-transferase polymorphisms of the population was introduced into the model (multinomial logistic regression test, P = 0.933). Smoking (OR = 3.62, 95%CI = 1.93-6.79, P<0.0001) and coffee consumption (OR = 1.73, 95%CI = 1.04-2.86, P = 0.033) were relevant risk factors for bladder cancer. CONCLUSIONS: Specific PAH mixtures may play a relevant role in bladder cancer, although such effect seems to be highly modulated by polymorphisms in genes encoding xenobiotic-metabolizing enzymes. PMID- 25291986 TI - A century of research on the larval distributions of the Atlantic eels: a re examination of the data. AB - The spawning areas of the Atlantic freshwater eels were discovered about a century ago by the Danish scientist Johannes Schmidt who after years of searching found newly hatched larvae of the European eel, Anguilla anguilla, and the American eel, Anguilla rostrata, in the southern Sargasso Sea. The discovery showed that anguillid eels migrate thousands of kilometers to offshore spawning areas for reproduction, and that their larvae, called leptocephali, are transported equally long distances by ocean currents to their continental recruitment areas. The spawning sites were found to be related to oceanographic conditions several decades later by German and American surveys from 1979 to 1989 and by a Danish survey in 2007 and a German survey in 2011. All these later surveys showed that spawning occurred within a restricted latitudinal range, between temperature fronts within the Subtropical Convergence Zone of the Sargasso Sea. New data and re-examinations of Schmidt's data confirmed his original conclusions about the two species having some overlap in spawning areas. Although there have been additional collections of leptocephali in various parts of the North Atlantic, and both otolith research and transport modelling studies have subsequently been carried out, there is still a range of unresolved questions about the routes of larval transport and durations of migration. This paper reviews the history and basic findings of surveys for anguillid leptocephali in the North Atlantic and analyses a new comprehensive database that includes 22612 A. anguilla and 9634 A. rostrata leptocephali, which provides a detailed view of the spatial and temporal distributions and size of the larvae across the Atlantic basin and in the Mediterranean Sea. The differences in distributions, maximum sizes, and growth rates of the two species of larvae are likely linked to the contrasting migration distances to their recruitment areas on each side of the basin. Anguilla rostrata leptocephali originate from a more western spawning area, grow faster, and metamorphose at smaller sizes of <70 mm than the larvae of A. anguilla, which mostly are spawned further east and can reach sizes of almost 90 mm. The larvae of A. rostrata spread west and northwest from the spawning area as they grow larger, with some being present in the western Caribbean and eastern Gulf of Mexico. Larvae of A. anguilla appear to be able to reach Europe by entering the Gulf Stream system or by being entrained into frontal countercurrents that transport them directly northeastward. The larval duration of A. anguilla is suggested to be quite variable, but gaps in sampling effort prevent firm conclusions. Although knowledge about larval behaviour is lacking, some influences of directional swimming are implicated by the temporal distributions of the largest larvae. Ocean-atmosphere changes have been hypothesized to affect the survival of the larvae and cause reduced recruitment, so even after about a century following the discovery of their spawning areas, mysteries still remain about the marine life histories of the Atlantic eels. PMID- 25291985 TI - Maturation of mast cell progenitors to mucosal mast cells during allergic pulmonary inflammation in mice. AB - In contrast to resident constitutive mast cells (CMCs), mucosal MCs (MMCs) appear in the lung and trachea of sensitized mice only following inhalation challenge. We monitored the influx and maturation of MCs by their expression of Kit, FcERI, beta7-integrin and side scatter (SSC) by flow cytometry. Influx of MC progenitors (MCps) (FcERI(lo), Kit(int), beta7(hi), and SSC(lo)) peaks 1 day after challenges and subsides to baseline by day 7 after challenge. The mature MMCs appear as a distinct population on day 7 and peak at day 14 with higher SSC and FcERI expression, but lower beta7 and Kit expression. A distinct transitional population is present between 1 and 7 days after challenge. Maturation occurs more rapidly in the trachea. The resident tracheal CMCs had higher SSC, FcERI, and Kit and lower beta7-integrin expression than the MMCs. By histology, the MMCs follow similar kinetics to the flow cytometry-identified mature MMCs and are notably persistent for >42 days. Steroid treatment reduced inflammation and MCp influx but had no effect on established MMCs. Thus, changes in SSC, FcERI, and Kit together with the expression of alphaE/alpha4:beta7-integrins characterizes the development of induced MMCs from MCps and distinguishes them from resident CMCs in the trachea and large airways. PMID- 25291987 TI - Jejunal overexpression of peptide YY in celiac disease complicated with pneumatosis cystoides intestinalis. AB - A 61-year old man with coeliac disease and chronic lack of appetite, malabsorption and weight loss, despite the gluten-free diet, was operated because of a sub-diaphragmatic free air due to a small-bowel pneumatosis cystoides intestinalis (PCI). The jejunum showed granulomatous lesions with a honeycombed appearance of air cysts in the submucosa/subserosa. We found overexpression of peptide YY (PYY) into only the jejunum with PCI, while the expression was very weak or absent in the tissue without cysts. One year after surgery, he had no abdominal pain or PCI recurrence. The above chronic symptoms were plausibly attributable to the PYY. PMID- 25291988 TI - The importance of lizards and small mammals as reservoirs for Borrelia lusitaniae in Portugal. AB - Borrelia lusitaniae is a pathogen frequent in the Mediterranean area. Apart from lizards, evidence for birds and small mammals as competent reservoirs for this genospecies has been occasional. We collected questing ticks, skin biopsies and Ixodes sp. ticks feeding on lizards, birds and small mammals in a B. burgdorferi s.l. (sensu lato) enzootic area to assess their importance in the maintenance of B. lusitaniae. Borrelia lusitaniae was the most prevalent genospecies in questing ticks and was commonly found in larvae feeding on Psammodromus algirus. One biopsy infected with B. lusitaniae was collected from the tail of one Podarcis hispanica, which suggests systemic infection. Ixodes ricinus larvae feeding on Apodemus sylvaticus were infected with B. lusitaniae but with a lower prevalence. Our results reinforce the importance of lizards as reservoirs for B. lusitaniae, suggesting that P. algirus, in particular, acts as main reservoir for B. lusitaniae in Portugal. PMID- 25291989 TI - Anti-Mullerian hormone concentration and antral ovarian follicle population in Murrah heifers compared to Holstein and Gyr kept under the same management. AB - This study was performed to evaluate plasma concentrations of anti-Mullerian hormone (AMH) and the ovarian antral follicle population (AFP) in different genetic groups. Cyclic heifers (13 Bubalus bubalis [Murrah]; 15 Bos taurus [Holstein] and 10 Bos indicus [Gyr]) were maintained under the same management and were synchronized with two doses of 150 MUg IM d-cloprostenol administered 14 days apart. After the second d-cloprostenol treatment, heifers had their ovaries scanned daily by ultrasound to define the day of ovulation. On the same day, the AFP was determined and a plasma sample was collected to measure AMH. Murrah heifers had less AFP (25.6 +/- 2.1 follicles; p = 0.01) and plasma AMH concentration (0.18 +/- 0.03 ng/ml; p < 0.001) than Gyr (60.0 +/- 12.2 follicles and 0.60 +/- 0.12 ng/ml of AMH); however, data were similar when compared to Holstein (35.9 +/- 6.8 follicles and 0.24 +/- 0.06 ng/ml of AMH) heifers. Regardless of genetic background, there was a positive relationship between the AFP and plasmatic AMH concentration (Murrah [r = 0.62; p < 0.01], Holstein [r = 0.66; p < 0.001] and Gyr [r = 0.88; p < 0.001]). Also, when heifers were classified according to high- or low-AMH concentration based on the average within each genetic group, high-AMH heifers had greater (p < 0.0001) AFP than low AMH heifers. In conclusion, both Murrah and Holstein heifers presented lower plasma AMH concentration and AFP when compared to Gyr. PMID- 25291990 TI - New microsatellite loci for the green sea urchin Strongylocentrotus droebachiensis using universal M13 labelled markers. AB - BACKGROUND: The green sea urchin Strongylocentrotus droebachiensis has a wide circumpolar distribution and plays a key role in coastal ecosystems worldwide by destructively grazing macroalgae beds and turn them into marine deserts, so called barren grounds. In the past decades, large established kelp forests have been overgrazed and transformed to such barren grounds on the Norwegian coast. This has important repercussions for the coastal diversity and production, including reproduction of several fish species relying on the kelp forests as nurseries. Genetic diversity is an important parameter for the study and further anticipation of this large scale phenomenon. FINDINGS: Microsatellites were developed using a Norwegian S. droebachiensis individual primarily for the study of Northeast Atlantic populations. The 10 new microsatellite loci were amplified using M13 forward tails, enabling the use of M13 fluorescent tagged primers for multiplex reading. Among these loci, 2 acted polysomic and should therefore not be considered useful for population genetic analysis. We screened 96 individuals sampled from 4 different sites along the Norwegian coast which have shown unexpected diversity. CONCLUSIONS: The new microsatellite loci should be a useful resource for further research into connectivity among S. droebachiensis populations, and assessing the risks for spreading and new overgrazing events. PMID- 25291991 TI - Statins, mood, sleep, and physical function: a systematic review. AB - PURPOSE: We aimed to evaluate the effects of statins on mood, sleep, and physical function. METHODS: We performed a systematic computer-aided search of MEDLINE/PubMed, EMBASE, and the Cochrane Central Register and augmented this search by scrutinizing reference lists and making inquiries among colleagues and experts in the field. All patient populations and study types were considered. We selected studies of statin therapy compared with no statin or placebo. Outcome measures included mood, sleep, and physical function. RESULTS: Thirty-four studies were included in qualitative synthesis. Seven of eight (88 %) observational studies, 4/6 (66 %) randomized trials with mood as a primary endpoint (487 total participants; exposure 4 weeks to 1 year), and 3/3 (100 %) randomized trials with mood as a secondary endpoint (2,851 total participants; exposure 1-4 years) were not compatible with a negative mood effect of statins. Comparatively, fewer studies examined statin effects on sleep and physical function. Studies reporting negative effects contained potential sources of bias, including multiple testing or lack of adjustment for confounders in observational studies, and failure to prespecify outcomes or report blinding in trials. CONCLUSIONS: A limited body of available evidence is most compatible with no adverse effect of statins on quality of life measures, namely, mood, sleep, and physical function. Studies suggesting such effects suffer from an increased risk of bias. High-quality, prospective, and adequately powered studies are needed, especially in the domains of sleep and physical function, with careful attention to patients who may be most vulnerable to adverse effects. PMID- 25291994 TI - [Which patients with (pre) malignant changes in the esophagus can we treat with endoscopic therapy?]. PMID- 25291993 TI - Discovery of selective small-molecule activators of a bacterial glycoside hydrolase. AB - Fragment-based approaches are used routinely to discover enzyme inhibitors as cellular tools and potential therapeutic agents. There have been few reports, however, of the discovery of small-molecule enzyme activators. Herein, we describe the discovery and characterization of small-molecule activators of a glycoside hydrolase (a bacterial O-GlcNAc hydrolase). A ligand-observed NMR screen of a library of commercially available fragments identified an enzyme activator which yielded an approximate 90 % increase in kcat /KM values (kcat =catalytic rate constant; KM =Michaelis constant). This compound binds to the enzyme in close proximity to the catalytic center. Evolution of the initial hits led to improved compounds that behave as nonessential activators effecting both KM and Vmax values (Vmax =maximum rate of reaction). The compounds appear to stabilize an active "closed" form of the enzyme. Such activators could offer an orthogonal alternative to enzyme inhibitors for perturbation of enzyme activity in vivo, and could also be used for glycoside hydrolase activation in many industrial processes. PMID- 25291992 TI - Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients. AB - PURPOSE: Alterations in one-carbon metabolism (OCM) have been repeatedly reported in schizophrenia. However, there is a scarcity of studies addressing the effects of antipsychotics on selected OCM markers in schizophrenia and provided results are inconsistent. METHODS: We recruited 39 first-episode schizophrenia (FES) patients and determined serum profile of total homocysteine (tHcy), folate, vitamin B12, lipoproteins and glucose at baseline and after 12 weeks of treatment with second-generation antipsychotics (SGA) including olanzapine and risperidone in monotherapy. RESULTS: After 12 weeks of treatment, all patients had significantly higher body mass index (BMI), serum levels of total cholesterol (TC), low-density lipoproteins (LDL), triglycerides (TG) and tHcy together with significantly lower levels of folate and vitamin B12. The analysis of differences between SGA revealed the same biochemical alterations in patients treated with olanzapine as in the whole group, while those receiving risperidone had no statistically significant changes in serum folate, vitamin B12 and TG. There was a significantly higher increase in BMI and TC in patients treated with olanzapine in comparison with those treated with risperidone. Patients receiving olanzapine had a higher decrease in vitamin B12 than those assigned to the treatment with risperidone. Changes in folate, vitamin B12, tHcy and TC levels were significant only in males, even after Bonferroni correction. Multiple regression analysis revealed that changes in tHcy levels are associated with gender and baseline metabolic parameters (BMI, glucose, TC, LDL and HDL) but not with selected SGA. CONCLUSIONS: These results indicate that SGA may influence OCM, especially in first-episode schizophrenia (FES) males. PMID- 25291995 TI - [Is patients' information seeking an opportunity or a problem?]. PMID- 25291996 TI - [Non-invasive ventilation in pneumonia: effective ventilation support or delaying treatment]. PMID- 25291997 TI - [Aclidinium bromide improves the lung function and reduces dyspnoea in patients with COPD]. AB - Long-acting bronchodilators are central for treatment of COPD. This short review provides an overview of studies evaluating the efficacy of aclidinium bromide, a long-acting anticholinergic bronchodilator, for the treatment of COPD. Twice daily dosing of aclidinium leads to clinically important improvements in forced expiratory volume in 1 second, health status, use of rescue medication, day-time dyspnoea and exercise tolerance. The available studies also suggest an effect on night-time dyspnoea and exacerbation rate in patients with COPD. Aclidinium seems to have potential for a significant role in the future management of COPD. PMID- 25291998 TI - [The initial treatment of multitrauma patients]. AB - Multitrauma is usually defined as injury to several organ systems. The more severe the injury, the higher is the mortality. It is essential that a trauma team assess and treat these patients using a rapid, structured approach in order to increase the survival. Damage control surgery and resuscitation should be applied in the very unstable patients. Following the initial treatment, an early activation and coordination of all involved specialties are very important. PMID- 25291999 TI - [Canine cancer patients are included in translational research]. AB - Cancer bearing dogs represent a unique clinical cancer model with a direct potential for accelerating translation into human patients. A research collaboration between the veterinary and human medical facilities at Copenhagen University and Rigshospitalet has taken offset in this. Canine cancer patients are implemented for development of new strategies in molecular imaging and radiotherapy. The obtained results will be used to guide human clinical trials. PMID- 25292000 TI - [ADHD in children and adults]. AB - ADHD, affecting 2-3% of children, is characterised by problems with attention, hyperactivity and impulsivity. Co-morbid psychiatric problems are very frequent. Causal factors are primarily genetics but environmental influences such as smoking during pregnancy or preterm birth are contributing factors. For children and adults psychoeducation is essential, for younger children training of the parents are recommended. The most efficient psychopharmacological treatment is with central stimulants or atomoxetine. PMID- 25292001 TI - [Severe sepsis and septic shock]. AB - Sepsis, severe sepsis and septic shock are syndromes. The incidence of sepsis is as high as 35% and with mortality rates in the intensive care unit from 27% to 54% in sepsis and septic shock, respectively. Many new treatments have been tested but only few have been implemented in clinical practise. The treatment of severe sepsis and septic shock is based on the Surviving Sepsis Campaign guidelines developed by an international expert panel. Early diagnosis, optimization of haemodynamics, rapid identification of focus and adequate antibiotic treatment are the most important strategies. PMID- 25292002 TI - [Anisometropia can only be detected by a monocular vision examination]. AB - In recent years the Eye Department at Aalborg University Hospital has had many referrals of older children with severe amblyopia due to anisometropia. Anisometropia is not visible, thus a monocular vision examination is needed in order to detect it. Early detection increases the possibilities for a better post treatment visual acuity. Recent studies indicate positive treatment response also in older children, and some older individuals respond dramatically. Currently it is not possible to predict who will respond, and therefore treatment should be offered despite the age of the child if the child and parents are motivated for it. PMID- 25292003 TI - [Acute liver failure following heat stroke after participating in a running event]. AB - We describe two cases of acute liver failure following heat stroke after participation in a running event. At admission both patients had a severely affected circulation, altered consciousness and hyperthermia, with a core temperature of > 40 degrees Celsius. Within the first 24 hours both patients suffered from acute liver failure, kidney failure and coagulopathy. No other causes but dehydration and hyperthermia could explain the liver failure. The treatment of heat stroke is symptomatic, but liver transplantation may be an option in case of fulminant liver failure. PMID- 25292004 TI - [Phyto-photo dermatitis]. PMID- 25292005 TI - [Rare, severe hypersensitivity reaction to potassium iodide]. AB - The literature reports a large variety of adverse reactions to potassium iodide. A severe hypersensitivity reaction to potassium iodide in a 51-year-old woman with Graves' thyrotoxicosis is described. Following administration the patient developed sialadenitis, conjunctivitis, stomatitis and acneiform iododerma that responded dramatically to withdrawal of the potassium iodide and administration with corticosteroids. Awareness of these adverse reactions may prevent prolonged hospitalization and unnecessary tests and treatments. PMID- 25292007 TI - [Tension haemothorax after removal of pleural pigtail catheter]. AB - Today, standard treatment of pleural effusion is ultrasound guided insertion of a pleural pigtail catheter. This procedure is known to have a low complication rate, but complications as pneumothorax, haemorrhage and infection are occurring. The most frequent complications are seen at the time of insertion. We present a case of a 68-year-old woman in the intensive care unit with normal coagulation status who after an uneventful removal of a pleural pigtail catheter developed a tension haemothorax requiring acute evacuation. PMID- 25292006 TI - [Methods for detection of myocardial viability in patients with heart failure]. AB - Myocardial ischaemia may lead to impaired function of the myocardium. Chronic severe myocardial ischaemia may lead to hibernation, a vegetative state with long lasting dysfunction of the heart. Hibernation is a potentially reversible condition, which may respond to successful revascularization. If myocardial viability is proven, revascularization of the myocardial territory in question might translate into improved subject prognosis. We present an overview of the existing literature on methods for detection of myocardial viability, and the clinical effects of revascularization. PMID- 25292008 TI - [Mondor's disease in the chest wall six months after excision of malignant melanoma]. AB - This case report presents a 39-year-old woman with Mondor's disease in the left chest wall six months after excision of a malignant melanoma in the left lumbar region, with sentinel lymph node-biopsy from the left axilla. Mondor's disease is a rare, benign and self-limiting superficial thrombophlebitis, which can appear after surgery on the breast or thorax. Aetiology, pathophysiology, clinical presentation and disease course are reviewed. PMID- 25292009 TI - [Mediterranean diet and cardiovascular disease]. AB - Epidemiological studies have suggested a lower risk of morbidity and mortality from cardiovascular disease associated with a Mediterranean dietary pattern. There is limited evidence from interventional studies, but a large recent study supports a beneficial effect. It is most likely that the beneficial effect is attributable to several components in this dietary pattern rather than a single component. In conclusion, it seems reasonable to recommend a Mediterranean diet to persons with known or high risk of cardiovascular disease. PMID- 25292010 TI - [Endovacular treatment of mycotic iliac aneurysm]. AB - No gold standard exists in the treatment of mycotic aorto-iliac aneurysms. Surgical debridement and revascularization with bypass remain as the most definitive surgical solution, but also carry a relatively high risk of perioperative morbidity as compared to an endovascular approach. We present a case story with a mycotic a. iliac aneurysm treated successfully with an endoluminal covered stent graft. The patient had severe co-morbidity that ruled out open surgery. PMID- 25292011 TI - Thrombotic Primary Antiphospholipid Syndrome: the profile of antibody positivity in patients from North India. AB - AIM: We evaluated the frequency of antiphospholipid antibody syndrome (APS) in patients presenting with thrombosis of various vascular beds from North India and report the antibody profiles encountered. PATIENTS AND METHODS: A retrospective analysis was performed on the laboratory results of aCL (anticardiolipin), abeta2 Gp1 (anti-betaeta-2 glycoprotein 1) antibody and LAC (lupus anticoagulant) of 1222 consecutive patients referred to the coagulation laboratory work-up for a hypercoagulable/thrombophilic state over a period of 4 years between 2009 and 2013. LAC was screened with dRVVT (diluted Russel Viper Venom Test) and KCT (Kaolin clotting time), and aCL and abeta2 Gp1 antibodies with commercial enzyme linked immunosorbent assy kits. RESULTS: The current APS criteria was satisfied in 3.85% of all patients and 4.2% of pediatric patients with thrombosis. The venous circulation was more frequently affected (59.6%). Cerebral arterial and intra-abdominal vein involvement was common. Transient antibody positivity was seen in 44 (3.6%) cases. abeta2 Gp1, aCL and LAC were positive in 95%, 54.5% and 23% of patients with APS, respectively, during the initial visit and 93.6%, 23% and 17%, respectively, during the follow-up visit. Persistent triple positivity was seen in only three cases. At initial testing, positivity for both aCL and abeta2 Gp1 was the most frequent pattern (38% of cases). CONCLUSIONS: abeta2 Gp1 antibody was the commonest antibody that was persistently positive in patients with thrombosis. Triple positivity for all antibodies had the highest specificity and positive predictive value to diagnose APS in the first visit, whereas abeta2 Gp1 antibody had the highest sensitivity and negative predictive value. PMID- 25292012 TI - Iatrogenic synostosis of the toes and phalanges. PMID- 25292013 TI - Glucotoxic and diabetic conditions induce caspase 6-mediated degradation of nuclear lamin A in human islets, rodent islets and INS-1 832/13 cells. AB - Nuclear lamins form the lamina on the interior surface of the nuclear envelope, and regulate nuclear metabolic events, including DNA replication and organization of chromatin. The current study is aimed at understanding the role of executioner caspase 6 on lamin A integrity in islet beta-cells under duress of glucotoxic (20 mM glucose; 24 h) and diabetic conditions. Under glucotoxic conditions, glucose stimulated insulin secretion and metabolic cell viability were significantly attenuated in INS-1 832/13 cells. Further, exposure of normal human islets, rat islets and INS-1 832/13 cells to glucotoxic conditions leads to caspase 6 activation and lamin A degradation, which is also observed in islets from the Zucker diabetic fatty rat, a model for type 2 diabetes (T2D), and in islets from a human donor with T2D. Z-Val-Glu-Ile-Asp-fluoromethylketone, a specific inhibitor of caspase 6, markedly attenuated high glucose-induced caspase 6 activation and lamin A degradation, confirming that caspase 6 mediates lamin A degradation under high glucose exposure conditions. Moreover, Z-Asp-Glu-Val-Asp fluoromethylketone, a known caspase 3 inhibitor, significantly inhibited high glucose-induced caspase 6 activation and lamin A degradation, suggesting that activation of caspase 3 might be upstream to caspase 6 activation in the islet beta-cell under glucotoxic conditions. Lastly, we report expression of ZMPSTE24, a zinc metallopeptidase involved in the processing of prelamin A to mature lamin A, in INS-1 832/13 cells and human islets; was unaffected by high glucose. We conclude that caspases 3 and 6 could contribute to alterations in the integrity of nuclear lamins leading to metabolic dysregulation and failure of the islet beta-cell. PMID- 25292015 TI - Erratum to: Juvenile osteochondritis of femoral condyles: treatment with transchondral drilling. Analysis of 40 cases. PMID- 25292014 TI - Chromatin status of apoptosis genes correlates with sensitivity to chemo-, immune and radiation therapy in colorectal cancer cell lines. AB - The apoptosis pathway of programmed cell death is frequently deregulated in cancer. An intact apoptosis pathway is required for proper response to anti cancer treatment. We investigated the chromatin status of key apoptosis genes in the apoptosis pathway in colorectal cancer cell lines in relation to apoptosis induced by chemo-, immune- or radiation therapy. Using chromatin immunoprecipitation (ChIP), we measured the presence of transcription-activating histone modifications H3Ac and H3K4me3 and silencing modifications H3K9me3 and H3K27me3 at the gene promoter regions of key apoptosis genes Bax, Bcl2, Caspase 9, Fas (CD95) and p53. Cell lines DLD1, SW620, Colo320, Caco2, Lovo and HT29 were treated with cisplatin, anti-Fas or radiation. The apoptotic response was measured by flow cytometry using propidium iodide and annexin V-FITC. The chromatin status of the apoptosis genes reflected the activation status of the intrinsic (Bax, Bcl2, Caspase-9 and p53) and extrinsic (Fas) pathways. An active intrinsic apoptotic pathway corresponded to sensitivity to cisplatin and radiation treatment of cell lines DLD1, SW620 and Colo320. An active Fas promoter corresponded to an active extrinsic apoptotic pathway in cell line DLD1. mRNA expression data correlated with the chromatin status of the apoptosis genes as measured by ChIP. In conclusion, the results presented in this study indicate that the balance between activating and silencing histone modifications, reflecting the chromatin status of apoptosis genes, can be used to predict the response of tumor cells to different anti-cancer therapies and could provide a novel target to sensitize tumors to obtain adequate treatment responses. PMID- 25292016 TI - Use of health care services by patients with psoriasis: a population-based study. AB - BACKGROUND: Although psoriasis is seldom life threatening, very few studies have compared differences in health care service use between patients with and without psoriasis. OBJECTIVES: To investigate differences in health care service use between patients with and without psoriasis. METHODS: Patient details and data on their use of health services were retrieved from the Taiwan Longitudinal Health Insurance Database 2000. We included 3649 patients with psoriasis and 3649 without it. Each patient was followed for a 1-year period to estimate their utilization of health care resources. Student t-tests were used to compare differences in health care services use between patients with and without psoriasis. RESULTS: For dermatology services, patients with psoriasis had significantly more outpatient visits (3.5 vs. 0.9), and higher outpatient and total costs (US$148.00 vs. US$12.20 and US$581.60 vs. US$347.20, respectively) than those without psoriasis. For nondermatology services, patients with psoriasis had more outpatient visits (21.3 vs. 17.6), and higher outpatient and total costs (US$904.60 vs. US$663.50 and US$1335.50 vs. US$998.30, respectively) than those without psoriasis. For overall health care service use, patients with psoriasis had significantly more outpatient visits (24.8 vs. 18.5; P < 0.01) and greater total costs (US$1917.10 vs. US$1345.60; P < 0.01) than those without psoriasis. This indicates that the total cost was about 1.4-fold greater for patients with psoriasis than those without it. CONCLUSIONS: Patients with psoriasis used health care services significantly more often than those without psoriasis. PMID- 25292018 TI - MicroRNAs: biogenesis, roles for carcinogenesis and as potential biomarkers for cancer diagnosis and prognosis. AB - MicroRNAs (miRNAs) are short non-coding RNAs of 20-24 nucleotides that play important roles in carcinogenesis. Accordingly, miRNAs control numerous cancer relevant biological events such as cell proliferation, cell cycle control, metabolism and apoptosis. In this review, we summarize the current knowledge and concepts concerning the biogenesis of miRNAs, miRNA roles in cancer and their potential as biomarkers for cancer diagnosis and prognosis including the regulation of key cancer-related pathways, such as cell cycle control and miRNA dysregulation. Moreover, microRNA molecules are already receiving the attention of world researchers as therapeutic targets and agents. Therefore, in-depth knowledge of microRNAs has the potential not only to identify their roles in cancer, but also to exploit them as potential biomarkers for cancer diagnosis and identify therapeutic targets for new drug discovery. PMID- 25292019 TI - Health and economic costs of physical inactivity. AB - Physical inactivity has reached epidemic levels in developed countries and is being recognized as a serious public health problem. Recent evidence shows a high percentages of individuals worldwide who are physically inactive, i.e. do not achieve the WHO's present recommendation of 150 minutes of moderate to vigorous intensity per week in addition to usual activities. Living in sedentary lifestyle is one of the leading causes of deaths and a high risk factor for several chronic diseases, like cancer, cardiovascular disease, diabetes type 2, and osteoporosis. This article summarizes evidence for relative risk of the civilization diseases attributable to physical inactivity and the most important conclusions available from the recent investigations computing the economic costs specific to physical inactivity. The findings provide health and economic arguments needed for people to understand the meaning of a sedentary lifestyle. This may be also useful for public health policy in the creation of programmes for prevention of physical inactivity. PMID- 25292017 TI - Is nicotine replacement therapy overvalued in smoking cessation? Analysis of smokers' and quitters' communication in social media. AB - BACKGROUND: Internet discussion forums provide new, albeit less used data sources for exploring personal experiences of illness and treatment strategies. OBJECTIVE: To gain an understanding of how discussion forum participants value nicotine replacement therapy (NRT) in smoking cessation (SC). SETTING: Finnish national Internet-based discussion forum, STUMPPI, supporting SC and consisting of ten free discussion areas, each with a different focus. The analysis was based on STUMPPI forum participants' postings (n = 24 481) in five discussion areas during January 2007-January 2012. DESIGN: Inductive content analysis of the postings concerning NRT use or comparing NRT to other SC methods. RESULTS: Three major themes related to NRT in SC emerged from the discussions. These were as follows: (I) distrust and negative attitude towards NRT; (II) neutral acceptance of NRT as a useful SC method; and (III) trust on the crucial role of NRT and other SC medicines. The negative attitude was related to following perceptions: NRT use maintains tobacco dependence, fear of NRT dependence or experience of not gaining help from NRT use. NRT was perceived to be useful particularly in the initiation of SC attempts and in dealing with physiological dependence. The most highlighted factors of successful quitting were quitters' own psychological empowerment and peer support from the discussion community. CONCLUSIONS: The majority of STUMPPI forum participants had low or balanced expectations towards the role of NRT in SC. More research from the smokers' and quitters' perspective is needed to assess the real value of NRT compared to other methods in SC. PMID- 25292020 TI - Multiple effects of bracken fern under in vivo and in vitro conditions. AB - Several toxic substances have been detected in plants which are responsible for animal and human diseases. Bracken fern (Pteridium aquilinum) is one example, widely distributed in many parts of the world. It is known to cause cancer in humans and other animals. In fact, man can be directly or indirectly exposed to the danger by consuming fern, contaminated water, milk, meat, and spore inhalation. Experimental studies have shown an association between bracken exposure and gastric cancer, and research has shown genotoxic and cytotoxic effects in vitro. This paper describes and reviews toxic, carcinogenic, genotoxic/cytotoxic, and immunomodulatory effects of bracken and included possible toxic agents. The chemistry of Ptaquiloside (PT) reactions is emphasized, along with bracken problems in livestock, possible pathways of exposure in man, and control for human health. PMID- 25292021 TI - Adiponectin receptor 1 (ADIPOR1) rs1342387 polymorphism and risk of cancer: a meta-analysis. AB - Many studies have indicated possible associations between a polymorphism of adiponectin receptor 1 (ADIPOR1) rs1342387 and risk of cancer, but contradictory results have been reported. The main aim of this study was to draw a reliable conclusion about the relationship between the rs1342387 polymorphism and cancer incidence, by conducting a literature search of Pubmed, Embase, Wanfang and Cochrane libraries. Eleven studies including 3, 738 cases and 4, 748 controls were identified in this meta-analysis. The ADIPOR1 rs1342387 polymorphism was associated with risk of colorectal cancer for all genetic comparison models (GG vs AA, OR: 1.44, 95%CI: 1.21 -1.70; G carriers vs A carriers, OR: 1.23, 95%CI: 1.11 -1.36; dominant model, OR: 1.28, 95%CI: 1.10 -1.49 and recessive model, OR: 1.31, 95%CI: 1.12 -1.55). Stratified by ethnicity, the rs1342387 polymorphism was significantly associated with risk of colorectal cancer in Asian ancestry for all genetic comparison models (GG vs AA, OR: 1.56, 95%CI: 1.26-1.92; G carriers vs. A carriers OR: 1.30, 95%CI: 1.18 -1.43; dominant model OR: 1.31, 95%CI: 1.08 -1.60 and recessive model OR: 1.44, 95%CI: 1.26 -1.64), but not in Caucasian or mixed (Caucasian mainly) groups. In summary, the ADIPOR1 rs1342387 polymorphism is significantly associated with risk of colorectal cancer among individuals of Asian ancestry. PMID- 25292022 TI - Amentoflavone acts as a radioprotector for irradiated v79 cells by regulating reactive oxygen species (ROS), cell cycle and mitochondrial mass. AB - Radioprotective effects of amentoflavone were investigated by examining cell viability, apoptosis, cell cycling concentrations of intracellular ROS (reactive oxygen species), and relative mitochondrial mass by flow cytometry after 60Co irradiation. Pretreatment with amentoflavone 24 hours prior to 8 Gy 60Co gamma ray irradiation significantly inhibited apoptosis, promoted the G2 phase, decreased the concentration of ROS and mitochondrial mass. These results collectively indicate that amentoflavone is an effective radioprotective agent. PMID- 25292023 TI - Anticancer potential of an ethanol extract of Saussurea involucrata against hepatic cancer cells in vitro. AB - Saussurea involucrata is a Mongolian medicinal plant well known for its effects in promoting blood circulation, and anti-inflammation and analgesic functions. Earlier studies reported that Saussurea involucrata has anti- cancer activity. The purpose of this study was to confirm the anticancer activity of an ethanol extract of Saussurea involucrata against hepatic cancer and elucidate its mechanisms of action. Hepatocellular carcinoma cells were tested in vitro for cytotoxicity, AO/EB staining for apoptotic cells, apoptotic DNA fragmentation and cell cycle distribution in response to Saussurea involucrata extract (SIE). The mRNA expression of caspase-3,-9 and Cdk2 and protein expression of caspase-3,-9, PARP, XIAP, Cdk2 and p21 were analyzed through real time PCR and Western blotting. Treatment with SIE inhibited HepG2 cell proliferation dose- and time dependently, but SIE only exerted a modest cytotoxic effect on a viability of Chang human liver cells. Cells exposed to SIE showed typical hallmarks of apoptotic cell death. Cell cycle analysis revealed that SIE caused G1-phase arrest in HepG2 cells. In conclusion, Saussurea involucrata ethanol extract has potential cytotoxic and apoptotic effects on human hepatocellular carcinoma cells. Its mechanism of action might be associated with the inhibition of DNA synthesis, cell cycle (G1) arrest and apoptosis induction through up-regulation of the protein expressions of caspase-3,-9 and p21, degradation of PARP and down regulation of the protein expression of Cdk2 and XIAP. PMID- 25292024 TI - Breast cancer in Bedouin-Arab patients in southern Israel: epidemiologic and biologic features in comparison with Jewish patients. AB - BACKGROUND: Breast cancer (BC) is the most frequent cancer type, and the leading cause of death from cancer among women in Israel. The Bedouin-Arab (BA) population in southern Israel is characterized by a high rate of consanguinity, common hereditary disorders, and transition from a semi-nomadic, traditional society to a more sedentary and urbanized society. In this hospital-based study, the demographic and the clinicopathological characteristics of BC in BA were compared with Jewish patients. MATERIALS AND METHODS: 85 BA patients treated at the Soroka Medical Center, Beer Sheba, during the years 2004-2012, were studied and compared with 180 consecutive Jewish patients treated during the year 2007. Clinicopathological features compared included age, menopausal state, number of births, a history of BC in first-degree relatives, tumor size (T), extent of lymph- node involvement (N), distant metastases (M), stage, grade, estrogen and progesterone receptor (ER/PR), and Her2 status. Types of treatment, relapse rate and site, as well as outcome were also studied. Cox's regression models were applied for studying disease-free, and overall survival. RESULTS: Compared with Jewish patients, BA patients were younger (average age 49+/-12 yrs vs 59+/-13, p<0.001), had a lower rate of BC in first-degree relatives (p<0.001), and a larger number of births (6+/-4.2 vs 2.5+/-1.9, p<0.001). BA patients had larger tumors (p=0.02), more extensive lymph-node involvement (p=0.002), and more advanced stage (p=0.003). Grade, ER, PR, and Her2 status were similar in the two ethnic groups. Relapse type was most commonly systemic in BA patients (p=0.05), and loco-regional in Jewish patients (p=0.02). Median survival was 63, and 35 months for Jewish and BA patients, respectively (log-rank test, p=0.02). In Cox multivariate analysis, stage and PR status (HR-0.14, p<0.0001; HR-3.11, p=0.046), but not ethnicity, influenced overall survival. CONCLUSIONS: BC presents a decade earlier, and with more advanced disease in BA compared with Jewish patients. Biologic parameters including grade, ER, PR, and Her2 status were similar in both groups. Although prognosis was worse in BA than in Jewish patients, it was affected only by stage and PR status, but not by ethnicity. PMID- 25292025 TI - Exercise barriers in Korean colorectal cancer patients. AB - BACKGROUND: To identify barriers to exercise in Korean colorectal cancer patients and survivors, and to analyze differences in exercise barriers by age, gender, treatment status, and physical activity level. MATERIALS AND METHODS: A total of 427 colorectal cancer patients and survivors from different stages and medical status completed a self-administered questionnaire that surveyed their barriers to exercise and exercise participation. RESULTS: The greatest perceived exercise barriers for the sampled population as a whole were fatigue, low level of physical fitness, and poor health. Those under 60-years old reported lack of time (p=0.008), whereas those over 60 reported low level of physical fitness (p=0.014) as greater exercise barriers than their counterparts. Women reported fatigue as a greater barrier than men (p<0.001). Those who were receiving treatment rated poor health (p=0.0005) and cancer-related factors as greater exercise barriers compared to those who were not receiving treatment. A multivariate model found that other demographic and medical status were not potential factors that may affect exercise participation. Further, for those who were not participating in physical activity, tendency to be physically inactive (p<0.001) and lack of exercise skill (p<0.001) were highly significant barriers, compared to those who were participating in physical activity. Also, for those who were not meeting ACSM guidelines, cancer-related exercise barriers were additionally reported (p<0.001), compared to those who were. CONCLUSIONS: Our study suggests that fatigue, low level of physical fitness, and poor health are most reported exercise barriers for Korean colorectal cancer survivors and there are differences in exercise barriers by age, sex, treatment status, and physical activity level. Therefore, support for cancer patients should be provided considering these variables to increase exercise participation. PMID- 25292026 TI - Evolution of the mir-155 family and possible targets in cancers and the immune system. AB - The mir-155 family is not only involved in a diversity of cancers, but also as a regulator of the immune system. However, the evolutionary history of this family is still unclear. The present study indicates that mir-155 evolved independently with lineage-specific gain of miRNAs. In addition, arm switching has occurred in the mir-155 family, and alternative splicing could produce two different lengths of ancestral sequences, implying the alternative splicing can also drive evolution for intragenic miRNAs. Here we screened validated target genes and immunity- related proteins, followed by analyzation of the mir-155 family function by high-throughput methods like the gene ontology (GO) and Kyoto Eneyclopedin of Genes and Genemes (KEGG) pathway enrichment analysis. The high throughput analysis showed that the CCND1 and EGFR genes were outstanding in being significantly enriched, and the target genes cebpb and VCAM1 and the protein SMAD2 were also vital in mir-155-related immune reponse activities. Therefore, we conclude that the mir-155 family is highly conserved in evolution, and CCND1 and EGFR genes might be potential targets of mir-155 with regard to progress of cancers, while the cebpb and VCAM1 genes and the protein SMAD2 might be key factors in the mir-155 regulated immune activities. PMID- 25292027 TI - Overexpression of hiwi promotes growth of human breast cancer cells. AB - The Piwi subfamily comprises two argonaute (Ago) family proteins, which are defined by the presence of PAZ and Piwi domains, with well known roles in RNA silencing. Hiwi, a human Piwi subfamily member, has been shown to play essential roles in stem cell self-renewal and gametogenesis. Recently, accumulating reports have indicated that abnormal hiwi expression is associated with poorer prognosis of multiple types of human cancers, including examples in the breast. However, little is known about details of the oncogenic role of hiwi in breast cancers. In present study, we confirmed overexpression of hiwi in breast cancer specimens and breast cancer cell lines at both mRNA and protein levels. Thus both RT-qPCR and Western blot data revealed significantly higher hiwi in intratumor than peritumor specimens, overexpression being associated with tumor size, lymph node metastasis and histological grade. Hiwi overexpression was also identified in breast cancer cell lines, MDA- MB-231 and MCF-7, and gain-of-function and loss-of-function strategies were adopted to identify the role of hiwi in the MCF-7 cell growth. Results demonstrated that hiwi expression in MCF-7 cells was significantly up- or down- regulated by the two strategies. We next evaluated the influence of hiwi overexpression or knockdown on the growth of breast cancer cells. Both cell count and colony formation assays confirmed promoting roles of hiwi in MCF-7 cells, which could be inhibited by hiwi specific blockage by siRNAs. In summary, the present study confirmed overexpression of hiwi in breast cancer specimens and breast cancer cell lines, and provided evidence of promotion by hiwi of cell growth. The results imply an oncogenic role of hiwi in breast cancers. PMID- 25292028 TI - Number of mediastinal lymph nodes as a prognostic factor in PN2 non small cell lung cancer: a single centre experience and review of the literature. AB - Currently the most important prognostic factor in lung cancer is the stage. In the current lung TNM classification system, N category is defined exclusively by anatomic nodal location though, in other type of tumours, number of lymph nodes is confirmed to be a fundamental prognostic factor. Therefore we evaluated the number of mediastinal lymph nodes as a prognostic factor in locally advanced NSCLC after multimodality treatment, observing a significant effect of the number of lymph nodes in terms of OS (p<0.01) and DFS (p<0.001): patients with a low number of positive mediastinal nodes have a better prognosis. PMID- 25292029 TI - Comparison of viral hepatitis-associated hepatocellular carcinoma due to HBV and HCV - cohort from liver clinics in Pakistan. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the first cause of death in cirrhotic patients, mostly due to viral hepatitis with HCV or HBV infection. This study was performed to estimate the true prevalence of viral hepatitis-related HCC and the demographic and clinical-pathological associations with the two virus types. MATERIALS AND METHODS: This cross sectional observational study enrolled clinical data base of 188 HCC patients and variables included from baseline were age, sex, area of residence, clinical-pathological features such as underlying co morbidity, presence or absence of liver cirrhosis, macrovascular involvement, tumor extension and metastasis, liver lobes involved, serum alpha-fetoprotein level, and hepatitis serologies. RESULTS: Overall prevalence of HCV- and HBV related HCC was 66.0% and 34.0%, respectively. Patients with HCV were more likely to develop HCC at advanced age (52.4+/-11.9 vs. 40.7+/-12.09 years), with highly raised serum AFP levels (>=400ng/ml) 78.2% (HBV 67.1%), large tumor size (HCV-66% >5 cm, HBV-59.3%), and presence of portal vein thrombosis (8.06%, HBV 1.56%). A binominal multivariate analysis showed that HCV-HCC group were more likely to be cirrhotic (OR=0.245, 95%CI: 0.117, 0.516) and had more than two times higher rate of solitary macrovascular involvement (OR=2.533, 95%CI: 1.162, 5.521) as compared with HBV associated HCC. CONCLUSIONS: Statistically significant variations were observed from baseline to clinical-pathological characteristics in HCV vs HBV associated HCC. Our study suggests prompt and early screening for high risk patients so that the rate of progression of these chronic viral diseases to cirrhosis and cancer can be decreased. PMID- 25292030 TI - Female breast cancer mortality rates in Turkey. AB - The main objective of this study was to analyze the mortality trends of female breast cancer in Turkey between the years 1987-2008. The rates per 100,000 age standardized to the European standard population were assessed and time trends presented using joinpoint regression analysis. Average annual percent change (AAPC), anual percent change (APC) and 95% confidence interval (CI) was calculated. Nearly 23,000 breast cancer deaths occurred in Turkey during the period 1987-2008, with the average annual age-standardized mortality rate (ASR) being 11.9 per 100,000 women. In the last five years, significant increases were observed in all age groups, but there was no significant change over the age of 65. In this period, the biggest significant increase was in the 45-54 age group (AAPC=4.3, 95%CI=2.6 to 6.0). PMID- 25292031 TI - Five miRNAs as novel diagnostic biomarker candidates for primary nasopharyngeal carcinoma. AB - MicroRNAs (miRNAs) play an essential role in the development and progression of nasopharyngeal carcinomas (NPC). Despite advances in the field of cancer molecular biology and biomarker discovery, the development of clinically validated biomarkers for primary NPC has remained elusive. In this study, we investigated the expression and clinical significance of miRNAs as novel primary NPC diagnostic biomarkers. We used an array containing 2, 500 miRNAs to identify 22 significant miRNAs, and these candidate miRNAs were validated using 67 fresh NPC and 25 normal control tissues via quantitative real-time PCR (qRT-PCR). Expression and correlation analyses were performed with various statistical approaches, in addition to logistic regression and receiver operating characteristic curve analyses to evaluate diagnostic efficacy. qRT-PCR revealed five differentially expressed miRNAs (miR-93-5p, miR-135b-5p, miR-205-5p and miR 183-5p) in NPC tissue samples relative to control samples (p<0.05), with miR-135b 5p and miR-205-5p being of significant diagnostic value (p<0.01). Moreover, comparison of NPC patient clinicopathologic data revealed a negative correlation between miR-93-5p and miR- 183-5p expression levels and lymph node status (p<0.05). These findings display an altered expression of many miRNAs in NPC tissues, thus providing information pertinent to pathophysiological and diagnostic research. Ultimately, miR-135b-5p and miR-205-5p may be implicated as novel NPC candidate biomarkers, while miR- 93-5p, miR-650 and miR-183-5p may find application as relevant clinical pathology and diagnostic candidate biomarkers. PMID- 25292032 TI - Detection of microRNA-21 expression as a potential screening biomarker for colorectal cancer: a meta-analysis. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer-related death and cancer-related incidence worldwide. The potential of microRNA-21 (miR-21) as a biomarker for CRC detection has been studied in several studies. However, the results were inconsistent. Therefore, we conducted the present meta-analysis to systematically assess the diagnostic value of miR-21 for CRC. MATERIALS AND METHODS: Using a random-effect model, the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated to evaluate the diagnostic performance of miR-21 for CRC. A summary receiver operating characteristic (SROC) curve and an area under the curve (AUC) were also generated to assess the diagnosis accuracy of miR-21 for CRC. Q test and I2 statistics were used to assess between- study heterogeneity. Publication bias was evaluated by the Deeks' funnel plot asymmetry test. RESULTS: A total of 986 CRC patients and 702 matched healthy controls from 8 studies were involved in the meta-analysis. The pooled results for SEN, SPE, PLR, NLR, DOR, and AUC were 57% (95%CI: 39%-74%), 87% (95%CI: 78%- 93%), 4.4 (95%CI: 2.4-8.0), 0.49 (95%CI: 0.32-0.74), 9 (95%CI: 4 22), and 0.83 (95%CI: 0.79-0.86), respectively. Subgroup analyses further suggested that blood-based studies showed a better diagnostic accuracy compared with feces-based studies, indicating that blood may be a better matrix for miR-21 assay and CRC detection. CONCLUSIONS: Our findings suggest that miR-21 has a potential diagnostic value for CRC with a moderate level of overall diagnostic accuracy. Hence, it could be used as auxiliary means for the initial screening of CRC and avoid unnecessary colonoscopy, which is an invasive and expensive procedure. PMID- 25292033 TI - Germline variations of apurinic/apyrimidinic endonuclease 1 (APEX1) detected in female breast cancer patients. AB - Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein which plays a central role in the BER pathway. APEX1 gene being highly polymorphic in cancer patients and has been indicated to have a contributive role in Apurinic/apyrimidinic (AP) site accumulation in DNA and consequently an increased risk of cancer development. In this case-control study, all exons of the APEX1 gene and its exon/intron boundaries were amplified in 530 breast cancer patients and 395 matched healthy controls and then analyzed by single-stranded conformational polymorphism followed by sequencing. Sequence analysis revealed fourteen heterozygous mutations, seven 5'UTR, one 3 'UTR, two intronic and four missense. Among identified mutations one 5'UTR (rs41561214), one 3'UTR (rs17112002) and one missense mutation (Ser129Arg, Mahjabeen et al., 2013) had already been reported while the remaining eleven mutations. Six novel mutations (g.20923366T>G, g.20923435G>A, g.20923462G>A, g.20923516G>A, 20923539G>A, g.20923529C>T) were observed in 5'UTR region, two (g.20923585T>G, g.20923589T>G) in intron1 and three missense (Glu101Lys, Ala121Pro, Ser123Trp) in exon 4. Frequencues of 5'UTR mutations; g.20923366T>G, g.20923435G>A and 3'UTR (rs17112002) werecalculated as 0.13, 0.1 and 0.1 respectively. Whereas, the frequency of missense mutations Glu101Lys, Ser123Trp and Ser129Arg was calculated as 0.05. A significant association was observed between APEX1 mutations and increased breast cancer by ~9 fold (OR=8.68, 95%CI=2.64 to 28.5) with g.20923435G>A (5'UTR) , ~13 fold (OR= 12.6, 95%CI=3.01 to 53.0) with g.20923539G>A (5'UTR) and~5 fold increase with three missense mutations [Glu101Lys (OR=4.82, 95%CI=1.97 to 11.80), Ser123Trp (OR=4.62, 95%CI=1.7 to 12.19), Ser129Arg (OR=4.86, 95%CI=1.43 to 16.53)]. The incidence of observed mutations was found higher in patients with family history and with early menopause. In conclusion, our study demonstrates a significant association between germ line APEX1 mutations and breast cancer patients in the Pakistani population. PMID- 25292034 TI - Evaluation of HER-2/neu overexpression in gastric carcinoma using a tissue microarray. AB - BACKGROUND: Amplification and overexpression of human epidermal growth factor receptor 2 (HER2 / neu) oncogene has considerable prognostic value in breast and gastric cancers. This study aimed to evaluate the frequency, overexpression pattern, clinical significance, and concordance between the results for protein expression and gene amplification of HER-2/neu in gastric and gastro-esophageal junction carcinomas. MATERIALS AND METHODS: In this study, 101 gastric tissue samples which were included in tissue microarray were immunohistochemically examined for overexpression of HER2/neu. Chromogenic in situ hybridization (CISH) was used for HER-2/neu amplification. The correlation of HER2/neu amplification with clinicopathological parameters was also assessed. In addition, concordance between CISH and IHC was detected. RESULTS: This study demonstrated a significant difference in the overexpression of HER2/neu in gastric tumors. The overexpression of HER2/neu was significantly higher in intestinal type, poorly differentiated grade, large size (5 cm<=) and positive nodal involvement tumors (p-value=0.041, 0.015, 0.038 and 0.071, respectively). Also, amplification of HER2/neu according to CISH test, had a significant positive correlation with tumor size and tumor type (p-value=0.018 and 0.058, respectively).Concordance between CISH and IHC was 76.9% in 101 evaluable samples. CONCLUSIONS: IHC/CISH differences were attributed to basolateral membranous immunoreactivity of glandular cells resulting in incomplete membranous reactivity and/or a higher rate of tumor heterogeneity in gastric cancers compared to breast cancers. Therefore, this can be a potential marker for targeted therapy of malignant gastric tumors. PMID- 25292035 TI - Prognostic significance of altered blood and tissue glutathione levels in head and neck squamous cell carcinoma cases. AB - Glutathione is a thiol compound that plays an important role in the antioxidant defense system of the cell and its deficiency leads to an increased susceptibility to oxidative stress and, thus, progression of many disease states including head and neck cancer. In the present study, alterations of glutathione levels were investigated in study cohort of 500 samples (cohort 1 containing 200 head and neck cancer blood samples along with 200 healthy controls and cohort II with 50 head and neck squamous cell carcinoma tissue samples along with 50 control tissues) by high performance liquid chromatography. The results indicated that mean blood glutathione levels were significantly reduced in head and neck cancer patients (p<0.001) compared to respective controls. In contrast, the levels of glutathione total (p<0.05) and glutathione reduced (p<0.05) were significantly elevated in head and neck squamous cell carcinoma tissues compared to the adjacent cancer-free control tissues. In addition to this, pearson correlation performed to correlate different tissue glutathione levels (GSH) with clinical/ pathological parameters demonstrated a significant negative correlation between pT-stage and GSH level (r=- 0.263**; p<0.01), C-stage and GSH level (r= 0.335**; p<0.01), grade and GSH (r=-0.329**; p<0.01) and grade versus redox index (r=-0.213**; p<0.01) in HNSCC tissues. Our study suggests that dysregulation of glutathione levels in head and neck cancer has the potential to predict metastasis, and may serve as a prognostic marker. PMID- 25292036 TI - Preparation of 5-fluorouracil-loaded nanoparticles and study of interaction with gastric cancer cells. AB - AIMS: To prepare 5-fluorouracil (5-Fu) nanoparticles with higher encapsulation efficiency and drug loading, and then investigate interaction with the SGC-7901 gastric cancer cell line. MATERIALS AND METHODS: Prescription was optimized by orthogonal experiments, the encapsulation efficiency and loading capacity were tested by high- performance liquid chromatography, and inhibition of proliferation by 5-Fu nanoparticles and 5-Fu given to cells for 24, 48 and 72 hours was investigated by methyl thiazolyl tetrazolium assay (MTT). In addition, 5-Fu nanoparticles were labeled by fluorescein isothiocyanate (FITC), and absorption into cells was tested by flow cytometry. RESULTS: The optimal conditions for preparation were concentrations of 5-Fu of 5mg/ml, of CaCl2 of 60 mg/ml and of chitosan of 2 mg/ml. With a stirring speed of 1200rpm, encapsulation efficiency of 5-Fu nanoparticles was 55.4+/-1.10% and loading capacity was 4.22+/ 0.14%; gastric cancer cells were significantly inhibited by 5-Fu nanoparticles in a time and concentration dependent manner, and compared to 5-Fu with slower drug release, in a certain concentration range, inhibition with 5-Fu nanoparticles was stronger. 5-Fu nanoparticles were absorbed by the cells in line with the concentration. CONCLUSIONS: 5-Fu nanoparticles can inhibit growth of gastric cancer cells in vitro to a greater extent than with 5-Fu with good adsorption characteristics, supporting feasibility as a carrier. PMID- 25292037 TI - Mechanism of fatty acid synthase in drug tolerance related to epithelial mesenchymal transition of breast cancer. AB - OBJECTIVE: The mechanism of action of fatty acid synthase (FASN) in drug tolerance of breast cancer cells with epithelial-mesenchymal transition (EMT) features was investigated. METHODS: The breast cancer cell line MCF-7-MEK5 with stably occurring EMT and tumour necrosis factor-alpha (TNF-alpha) tolerance was used as the experimental model, whereas MCF-7 acted as the control. Tumour cells were implanted into nude mice for in vivo analysis, and cerulenin was used as a FASN inhibitor. RT-PCR, real-time quantitative PCR and Western blot were employed to detect the expression of FASN, TNFR-1, TNFR-2, Wnt-1, beta-catenin and cytC at the RNA and protein levels. RESULTS: Compared with MCF-7, TNFR-1 expression in MCF-7-MEK5 was slightly changed, TNFR-2 was decreased, and FASN, Wnt-1, beta catenin and cytC were increased. The expression of Wnt-1 and beta-catenin in MCF 7-MEK5 decreased after cerulenin treatment, whereas cytC expression increased. CONCLUSIONS: The important function of FASN in the drug tolerance of breast cancer may be due to the following mechanisms: FASN downregulated TNFR-2 expression through lipid rafts to make the cells less sensitive to TNF-alpha, and simultaneously activated the Wnt-1/beta-catenin signalling pathway. Thus, cytC expression increased, which provided cells with anti-apoptotic capacity and induced drug tolerance. PMID- 25292038 TI - A bibliometric analysis of diets and breast cancer research. AB - Breast cancer is the most common cancer among women worldwide. The primary aim of this work was to provide an in-depth evaluation of research publications in the field of diets and breast cancer. The impact of economic outcome on national academic productivity was also investigated. Data were retrieved using Pubmed for English-language publications. The search included all research for which articles included words relating to "diets and breast cancer". Population and national income data were obtained from publicly available databases. Impact factors for journals were obtained from Journal Citation Reports(r) (Thomson Scientific). There were 2,396 publications from 60 countries in 384 journals with an impact factor. Among them, 1,652 (68.94%) publications were Original articles. The United States had the highest quantity (51% of total) and highest of mean impact factor (8.852) for publication. Sweden had the highest productivity of publication when adjusted for number of population (6 publications per million population). Publications from the Asian nation increased from 5.3% in 2006 to 14.6% in 2012. The Original article type was also associated with geography (p<0.001; OR=2.183; 95%CI=1.526-3.123), Asian countries produced more proportion of Original articles (82%) than those of rest of the world (67.6%). Diets and breast cancer-associated research output continues to increase annually worldwide including publications from Asian countries. Although the United States produced the most publications, European nations per capita were higher in publication output. PMID- 25292039 TI - Psychological problems and psychosocial predictors of cigarette smoking behavior among undergraduate students in Malaysia. AB - BACKGROUND: Cigarette smokers have their own motivation and justification to smoke. For example, smoking reduces their stress or enhances their pleasure. This study aimed to identify the (a) prevalence of cigarette smokers among undergraduates in Malaysia, (b) gender differences in nicotine dependence among current smokers, (c) differences in psychological problems (depression, anxiety and stress) based on the status of smoking cigarettes (current, former and non smokers) and (d) extent to which precipitating factors (tension reduction, addiction, automatism, handling, social interaction, pleasure, and stimulation) predict the smoking behavior among current smokers. MATERIALS AND METHODS: In this study 780 undergraduate students participated from a private university in Kuala Lumpur and Selangor state in Malaysia. The Depression, Stress and Anxiety Scale, Modified Reason for Smoking Scale and Fagerstrom Nicotine Dependence Test were used to measure psychological problems, predictors of smoking behavior and nicotine dependency among current smokers. RESULTS: The results showed that 14.7%(n=106) of the students were smokers. Current smokers exhibited more psychological problems (depression, anxiety and stress) compared to former and non-smokers. Addiction, tension reduction, pleasure and automatism were predictors of smoking behavior among the current smoking students. Step wise regression analysis showed that smoking behavior was highly predicted by nicotine dependency or addiction. Smoking students were motivated to smoke cigarettes as they believed that it reduced their tension and enhance pleasure. CONCLUSIONS: Hence, there is a need for health promotion and anti-tobacco prevention as cigarette smokers experience more psychological problems. Nicotine dependency or addition was one of the major causes for smoking behavior among the student population in Malaysia. PMID- 25292040 TI - Screening of precancerous gastric lesions by serum pepsinogen, gastrin-17, anti helicobacter pylori and anti- CagA antibodies in dyspeptic patients over 50 years old in Guilan Province, north of Iran. AB - BACKGROUND: The aim of this study was to investigate the value of serum gastric markers to differentiate between patients with precancerous lesions and nonatrophic chronic gastritis. MATERIALS AND METHODS: Serum samples of 128 patients with dyspepsia who were candidates for endoscopic examination were tested for pepsinogen (PG I and PG II), PG I/II ratio, gastrin 17(G-17), anti Helicobacter pylori (anti-H pylori ) and anti- CagA antibodies. Two sample t tests, chi-square tests and Pearson's correlation analyses were used for analysis using SPSS (version 20). RESULTS: PGI, PG I/II ratio values were decreased significantly in the precancerous lesion group (0.05, 0.001 respectively). The frequency of H pylori infection was significantly (p=0.03) different between the two groups ofthe study. CONCLUSIONS: We suggest PGI and the PG I/II ratio as valuable markers for screening of premalignant gastric lesions. PMID- 25292041 TI - Associations of ERCC4 rs1800067 polymorphism with cancer risk: an updated meta analysis. AB - BACKGROUND: RESULTS from previous studies concerning the association of ERCC4 rs1800067 polymorphism with risk of cancer were inconsistent. To explore the exact relation with susceptibility, we conducted the present meta-analysis. MATERIALS AND METHODS: Literature of electronic databases including PubMed, Web of Science, EMBASE, Wanfang and Chinese National Knowledge Infrastructure (CNKI) were systematically searched. ORs and their 95%CIs were used to assess the strength of associations between ERCC4 polymorphism and cancer risk. RESULTS: There was no significant association between ERCC4 rs1800067 AA or AG genotypes and overall risk of cancer (AA vs. GG: OR=0.998, 95%CI=0.670-1.486, P=0.992; AG vs. GG: OR=0.970, 95%CI=0.888- 1.061, P=0.508). A dominant genetic model also did not demonstrate significant association of (AA+AG) genotype carriers with altered risk of overall cancer (OR=0.985, 95%CI=0.909-1.068, P=0.719). In addition, no significant association was observed between A allele of ERCC4 rs1800067 A/G polymorphism and altered cancer risk compared with G allele (OR=0.952, 95%CI=0.851-1.063, P=0.381). Subgroup analysis suggested that AA genotype carriers were significantly associated with decreased risk of glioma compared with wild-type GG genotype individuals (OR=0.523, 95%CI=0.275-0.993, P=0.048). For subgroup of lung cancer, A allele of ERCC4 rs1800067 A/G polymorphism was significantly associated with decreased risk of lung cancer compared with G allele (OR=0.806, 95%CI=0.697-0.931, P=0.003). CONCLUSIONS: This meta-analysis indicated that ERCC4 rs1800067 A/G polymorphism might not be associated with risk of overall cancer. However, individuals with the AA genotype were associated with significantly reduced risk of glioma compared with wild-type GG genotype; The A allele was associated with significantly reduced risk of lung cancer compared with G allele. Future large- scale studies performed in multiple populations are warranted to confirm our results. PMID- 25292042 TI - Regulatory network analysis of microRNAs and genes in neuroblastoma. AB - Neuroblastoma (NB), the most common extracranial solid tumor, accounts for 10% of childhood cancer. To date, scientists have gained quite a lot of knowledge about microRNAs (miRNAs) and their genes in NB. Discovering inner regulation networks, however, still presents problems. Our study was focused on determining differentially-expressed miRNAs, their target genes and transcription factors (TFs) which exert profound influence on the pathogenesis of NB. Here we constructed three regulatory networks: differentially-expressed, related and global. We compared and analyzed the differences between the three networks to distinguish key pathways and significant nodes. Certain pathways demonstrated specific features. The differentially-expressed network consists of already identified differentially-expressed genes, miRNAs and their host genes. With this network, we can clearly see how pathways of differentially expressed genes, differentially expressed miRNAs and TFs affect on the progression of NB. MYCN, for example, which is a mutated gene of NB, is targeted by hsa-miR-29a and hsa miR-34a, and regulates another eight differentially-expressed miRNAs that target genes VEGFA, BCL2, REL2 and so on. Further related genes and miRNAs were obtained to construct the related network and it was observed that a miRNA and its target gene exhibit special features. Hsa-miR-34a, for example, targets gene MYC, which regulates hsa-miR-34a in turn. This forms a self-adaption association. TFs like MYC and PTEN having six types of adjacent nodes and other classes of TFs investigated really can help to demonstrate that TFs affect pathways through expressions of significant miRNAs involved in the pathogenesis of NB. The present study providing comprehensive data partially reveals the mechanism of NB and should facilitate future studies to gain more significant and related data results for NB. PMID- 25292043 TI - Quality of life and psychological well-being of colorectal cancer survivors in Jordan. AB - BACKGROUND: Colorectal ranked first among cancers reported in males and ranked second amongst females in Jordan, accounting for 12.7% and 10.5% of cancers in males and females, respectively. Colorectal cancer patients can suffer several consequences after treatment that include pain and fatigue, constipation, stoma complications, sexual problems, appearance and body-image concerns as well as psychological dysfunction. There is no published quantitative data on the health related quality of life and psychological wellbeing of Jordanian colorectal cancer survivors. METHOD: This project was a cross-sectional study of colorectal cancer survivors diagnosed in 2009 and 2010. Assessment was performed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the colorectal cancer specific module (EORTC QLQ CR 29) and the Hospital Anxiety and Depression Scale (HADS). Data on potential predictors of scores were also collected. RESULTS: A total of 241 subjects completed the study with mean age of 56.7+/-13.6. Males represented 52.3% of study participants. A majority of participants reported good to high overall health; the mean Global health score was 79.74+/- 23.31 with only 6.64% of study participants scoring less than 33.3%. The striking result in this study was that none of the study participants participated in a psychosocial support group; only 4 of them (1.7%) were even offered such support. The mean scores for HADS, depression score, and anxiety score were 8.25+/-9, 4.35+/-4.9 and 3.9+/-4.6, respectively. However, 77.1% of study participants were within the normal category for the depression score and 81.7% were within this category for anxiety score; 5.4% of participants had severe anxiety and 5.4% of them had severe depression. DISCUSSION: Patients with colorectal cancer in Jordan have a good quality of life and psychological wellbeing scores when compared with patients from western countries. None of the colorectal cancer patients managed at the Ministry of Health received any formal counselling, or participated in psychological or social support programmes. This highlights the urgent need for a psychosocial support programme, psychological screening and consultations for patients diagnosed with colorectal cancer at the Ministry of Health Hospitals. PMID- 25292044 TI - Body mass index effects on risk of ovarian cancer: a meta- analysis. AB - OBJECTIVES: The association between body mass index (BMI) and ovarian cancer risk is unclear and requires further investigation. The present meta-analysis was conducted to assess the effect of overweight and obesity on ovarian cancer risk in the premenopausal and postmenopausal periods. DATA SOURCES: Major electronic databases were searched until February 2014 including Medline and Scopus. Reference lists and relevant conference databases were searched and the authors were contacted for additional unpublished references. REVIEW METHODS: All cohort and case-control studies addressing the effect of BMI on ovarian cancer were included, irrespective of publication date and language. The effect measure of choice was risk ratio (RR) for cohort studies and odds ratio (OR) for case control studies. The results were reported using a random effects model with 95% confidence intervals (CIs). RESULTS: Of 3,776 retrieved studies, 19 were ultimately analyzed including 10 cohort studies involving 29,237,219 person-years and 9 case-control studies involving 96,965 people. The results of both cohort and case-control studies showed being overweight and obesity increased the risk of ovarian cancer compared to women with normal weight during both premenopausal and postmenopausal periods: RR=1.08 (95%CI: 0.97, 1.19) and OR=1.26 (95%CI: 0.97, 1.63) for overweight and RR=1.27 (95%CI: 1.16, 1.38) and OR=1.26 (95%CI: 1.06, 1.50) for obesity. CONCLUSIONS: There is sufficient evidence that an increase in BMI can increase the risk of ovarian cancer regardless of the menopausal status, mimicking a dose-response relationship although the association is not very strong. PMID- 25292045 TI - Histopathological profile of benign colorectal diseases in Al- Madinah region of Saudi Arabia. AB - BACKGROUND: Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Colon cancer risk in IBD increases with longer duration and greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. This study aimed to characterize the histopathological pattern of benign colorectal diseases among Saudi patients and to highlight age and gender variations of lesions as base line data for future studies to investigate the link between benign / IBD and colorectal cancers in the local population. MATERIALS AND METHODS: The materials consisted of 684 biopsies, reported as benign (excluding malignancies and polyps) at the Department of Pathology, King Fahad Hospital, Madinah, Saudi Arabia from January 2006 to December 2013. Data collected and entered in MS-Excel and were analyzed using SPSS-20. RESULTS: Of 684 colorectal tissues reviewed, 408 specimens (59.6%) were from male patients and 276 specimens (40.4%) were from females giving a male: female ratio of 1.5:1. Age of the patients ranged from 4 to 75 years with a mean of 39.6 years. The most frequent histologic diagnosis was a chronic non specific proctocolitis followed by ulcerative colitis, accounting respectively for 52.6% and 31.7% of all cases. These were followed by Crohn's disease 22 (3.2%), ischemic bowel disease 20 (2.9%), diverticular disease 14 (2%), eosinophilic colitis 12 (1.7%) and solitary rectal ulcer 12 (1.7%). A minority of 21 patients (3.1%) were cases of acute nonspecific proctocolitis, schistosomiasis, tuberculosis, volvulus and pseudomembranous colitis. CONCLUSIONS: These data show that although chronic non specific proctocolitis and ulcerative colitis were the dominant diagnoses, Crohn's disease, ischemic bowel disease and diverticular disease also existed to a lesser extent and should be considered in the differential diagnosis of benign colorectal diseases. This study provides a base line data for future studies which would be taken up to investigate the link between benign / IBD and colorectal cancers in the local population. PMID- 25292046 TI - Hong Kong Chinese women's lay beliefs about cervical cancer causation and prevention. AB - BACKGROUND: This study aimed to seek insights into Chinese women's lay beliefs about cervical cancer causal attributions and prevention. MATERIALS AND METHODS: Twenty-three new immigrant adult women from Mainland China and thirty-five Hong Kong adult women underwent semi-structured in-depth interviews. Interviews were audio taped, transcribed and analyzed using a Grounded Theory approach. RESULTS: This study generated three foci: causal beliefs about cervical cancer, perceived risk of cervical cancer, and beliefs about cervical cancer prevention. Personal risky practices, contaminated food and environment pollution were perceived as the primary causes of cervical cancer. New immigrant women more likely attributed cervical cancer to external factors. Most participants perceived cervical cancer as an important common fatal female cancer with increased risk/prevalence. Many participants, particularly new immigrant women participants, expressed helplessness about cervical cancer prevention due to lack of knowledge of prevention, it being perceived as beyond individual control. Many new immigrant participants had never undergone regular cervical screening while almost all Hong Kong participants had done so. CONCLUSIONS: Some Chinese women hold pessimistic beliefs about cervical cancer prevention with inadequate knowledge about risk factors. Future cervical cancer prevention programs should provide more information and include capacity building to increase Chinese women's knowledge and self-efficacy towards cervical cancer prevention. PMID- 25292047 TI - A novel all-trans retinoid acid derivative N-(3-trifluoromethyl- phenyl)- retinamide inhibits lung adenocarcinoma A549 cell migration through down regulating expression of myosin light chain kinase. AB - AIM: To observe the effects of a novel all-trans retinoid acid (ATRA) derivative, N-(3-trifluoromethyl-phenyl)- retinamide (ATPR), on lung adenocarcinoma A549 cells and to explore the potential mechanism of ATPR inhibiting of A549 cell migration. MATERIALS AND METHODS: The cytotoxicity of ATRA and ATPR on A549 cells was assessed using MTT assay. Wound healing assays were used to analyze the influences of ATRA, ATPR, ML-7 (a highly selective inhibitor of myosin light chain kinase (MLCK)), PMA (an activator of MAPKs) and PD98059 (a selective inhibitor of ERK1/2) on the migration of A549 cells. Expression of MLCK and phosphorylation of myosin light chain (MLC) were assessed by Western blotting. RESULTS: ATRA and ATPR inhibited the proliferation of A549 cells in a dose- and time-dependent manner, and the effect of ATPR was much more remarkable compared with ATRA. Relative migration rate and migration distance of A549 cells both decreased significantly after treatment with ATPR or ML-7. The effect on cell migration of PD98059 combining ATPR treatment was more notable than that of ATPR alone. Moreover, compared with control groups, the expression levels of MLCK and phosphorylated MLC in A549 cells were both clearly reduced in ATRA and ATPR groups. CONCLUSIONS: ATPR could suppress the migration and invasion of A549 cells, and the mechanism might be concerned with down- regulating the expression of MLCK in the ERK-MAPK signaling pathway, pointing to therapeutic prospects in lung cancer. PMID- 25292048 TI - Knowledge, attitudes, practices and barriers towards HPV vaccination among nurses in Turkey: a longitudinal study. AB - BACKGROUND: Human papilloma virus (HPV) occurs in women of all age groups, and causes cervical, anal, vaginal, vulvar, penile and oropharyngeal cancers. The aim of the study was to discover what nurses know about HPV infection, testing and vaccination and to determine vaccine practice of their daughters and perceived barriers. MATERIALS AND METHODS: This cross-sectional and prospective study was carried out nurses who have worked in a hospital between January and June 2014. Pre-test and post-test were used to evaluate the nurses' knowledge about HPV infection, testing and vaccination. This study was performed with nurses who had girls between 9 and 26 years of age for evaluating the behavior of vaccination after three months of education. RESULTS: The mean of pre-test and post-test scores about HPV infection, which included 22 items, were 8.2+/-5.6 and 19.2+/ 1.5, respectively. Before education the HPV testing knowledge score was remarkably poor (1.9+/-1.7 over 5), after education it increased to 4.8+/-0.5. The mean HPV vaccine knowledge score were 3.7+/-2.7 (pre-test) 7.3+/-0.8 (post test) on a 0-8 scale. The difference between mean total pre-test (13.9+/-9.1) and post-test (31.3+/-1.9) scores was statistically significant (p<0.001). After three months of education, only two of the nurses' daughters were vaccinated. The main reason was noted by nurses were not willing to be vaccinated was cost, doubts about safety and efficacy related to the vaccine. About one-third of nurses declared that they would receive the vaccine for their daughter later. CONCLUSIONS: Nurses have a crucial role in the prevention, treatment, increasing public awareness and care for population. The education of the nurses about HPV infection, test and vaccination will play an important part decreasing cancer mortality and morbidity. PMID- 25292049 TI - Are so-called cancer-testis genes expressed only in testis? AB - Cancer-testis (CT) antigens are a group of tumor-associated antigens with restricted expression in normal tissues except for testis and expression in a wide variety of tumor tissues. This pattern of expression makes them suitable targets for immunotherapy as well as potential biomarkers for early detection of cancer. However, some genes attributed to this family are now known to be expressed in other normal tissues which put their potential applications in immunotherapy and cancer detection under question. Here we analyzed expression of two previously known CT antigens, RHOXF2 and PIWIL2, in AML patients versus normal donors and found no significant difference in the expression of these genes between the two groups. As these two genes showed expression in normal leukocytes, their expression pattern seems to be wider than to be attributed to the CT gene family. Future research should focus on the expression profiles of so called CT antigens to find those with more testis specific expression. PMID- 25292050 TI - Impact of poster presentations on academic knowledge transfer from the oncologist perspective in Turkey. AB - BACKGROUND: Currently poster presentations offer a common visual medium for knowledge transfer by a wide range of health professionals. Our study aimed to determine the scientific importance of poster presentations for Medical and Radiation Oncologists. METHODS: A survey form including 40 questions was distributed to a total of 131 oncologists experienced in poster presentations. One hundred completed survey forms were included in the study. Descriptive statistics and modified thematic analyses were performed on the responses. RESULTS: Overall 64% of the participants agreed that posters were a good medium for knowledge transfer. Some 88% agreed that concise and clear styled presentations would increase appealing interests for poster contents. Visual appearance was cited more influential than content of the subject; 70% of participants agreed that appearances of posters could help to draw more viewer attention. Of respondents, 63% believed that posters accompanied by their author were more attractive for congress attendees, and 33% of them declared that the halo effect of the poster presenter was also important. CONCLUSION: The present study indicated that intelligibility, appearance and visuality of posters are most important factors from the aspect of oncologist participants. Presenters must take into account these important points when preparing their academic posters. PMID- 25292051 TI - Impact of caspase-8 (CASP8) -652 6N del and D302H polymorphisms on prostate cancer in different ethnic groups. AB - BACKGROUND: Despite evidence suggesting roles for caspase-8 (CASP8) -652 6N del and D302H polymorphisms in prostate cancer (PCa), the association of these polymorphisms with PCa risk remains inconclusive. Therefore, a meta-analysis was performed to more precisely estimate the association of CASP8 -652 6N del and D302H polymorphisms with PCa susceptibility. MATERIALS AND METHODS: A comprehensive literature search was conducted to identify all case-control studies of CASP8 D302H and -652 6N del polymorphisms and PCa risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association and the precision of the estimate, respectively. RESULTS: Nine -625 6N del studies and 4 D302H studies were included. CASP8 -652 6N del and D302H polymorphisms were not significantly associated with PCa risk in the overall analyses. However, in the subgroup analysis stratified by ethnicity, -625 6N del was significantly associated with PCa risk in the East Asian and Indian populations under the recessive model. Furthermore, the subgroup analysis strongly suggested that D302H was associated with lower PCa risk in the Non Indian population under the dominant model. CONCLUSIONS: In our meta-analysis, ethnic-specific differences were evident in the association of CASP8 -625 6N del and D302H polymorphisms with PCa risk. PMID- 25292052 TI - Combination of FDG PET/CT and contrast-enhanced MSCT in detecting lymph node metastasis of esophageal cancer. AB - BACKGROUND: Lymph node metastasis is believed to be a dependent negative prognostic factor of esophageal cancer. To explore detection methods with high sensitivity and accuracy for metastases to regional and distant lymph nodes in the clinic is of great significance. This study focused on clinical application of FDG PET/CT and contrast-enhanced multiple-slice helical computed tomography (MSCT) in lymph node staging of esophageal cancer. MATERIALS AND METHODS: One hundred and fifteen cases were examined with enhanced 64-slice-MSCT scan, and FDG PET/CT imaging was conducted for neck, chest and upper abdomen within one week. The primary lesion, location and numbers of metastatic lymph nodes were observed. Surgery was performed within one week after FDG PET/CT detection. All resected lesions were confirmed histopathologically as the gold standard. Comparative analysis of the sensitivity, specificity, and accuracy based on FDG PET/CT and MSCT was conducted. RESULTS: There were 946 lymph node groups resected during surgery from 115 patients, and 221 were confirmed to have metastasis pathologically. The sensitivity, specificity, accuracy of FDG PET/CT in detecting lymph node metastasis were 74.7%, 97.2% and 92.0%, while with MSCT they were 64.7%, 96.4%, and 89.0%, respectively. A significance difference was observed in sensitivity (p=0.030), but not the others (p>0.05). The accuracy of FDG PET/CT in detecting regional lymph node with or without metastasis were 91.9%, as compared to 89.4% for MSCT, while FDG PET/CT and MSCT values for detecting distant lymph node with or without metastasis were 94.4% and 94.7%. No significant difference was observed for either regional or distant lymph node metastasis. Additionally, for detecting para-esophageal lymph nodes metastasis, the sensitivity of FDG PET/CT was 72%, compared with 54.7% for MSCT (p=0.029). CONCLUSIONS: FDG PET/CT is more sensitive than MSCT in detecting lymph node metastasis, especially for para-esophageal lymph nodes in esophageal cancer cases, although no significant difference was observed between FDG PET/CT and MSCT in detecting both regional and distant lymph node metastasis. However, enhanced MSCT was found to be of great value in distinguishing false negative metastatic lymph nodes from FDG PET/CT. The combination of FDG PET/CT with MSCT should improve the accuracy in lymph node metastasis staging of esophageal cancer. PMID- 25292053 TI - Hepatitis C virus prevalence and genotyping among hepatocellular carcinoma patients in Baghdad. AB - Hepatocellular carcinoma (HCC) is the third most common cause for cancer death in the world, now being especially linked to chronic hepatitis C virus (HCV) infection. This case-control study consisting of 65 HCC patients and 82 patients with other malignant tumours as controls was conducted to determine the association of HCV markers with HCC. Serum of each participant was obtained for detection of HCV Ab and RNA by DNA enzyme immunoassay (DEIA). Twenty six per cent (26.0%) of HCC patients had positive anti-HCV which was significantly greater than the control group (p=0.001). HCC patients significantly have a risk of exposure to HCV infection almost 3 times than the control group (OR=2.87, 95% C.I=1.1-7). Anti-HCV seropositive rate was significantly (p=0.03) higher among old age HCC patients and increases with age. Males with HCC significantly showed to have more than 9 times risk of exposure to HCV infection (OR=9.375, 95 % CI=1.299-67.647) than females. HCV-RNA seropositive rate was (70.8%) significantly higher among HCC patients compared to (22.2%) the control group (p=0.019). The most prevalent genotype (as a single or mixed pattern of infection) was HCV- 1b. This study detected a significantly higher HCV seropositive rate of antibodies and RNA in HCC patients. PMID- 25292054 TI - Methylenetetrahydrofolate reductase gene germ-line C677T and A1298C SNPs are associated with colorectal cancer risk in the Turkish population. AB - Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and the incidence is also increasing in Turkey. Our present aim was to investigate any association between germ-line methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey. A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study. Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reverse- hybridization principle and real-time PCR methods. Results were compared in Pearson Chi-square and multiple logistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allele frequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC (homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group. The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>C genotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a larger sample size. PMID- 25292055 TI - The neutrophil to lymphocyte ratio has a high negative predictive value for pathologic complete response in locally advanced breast cancer patients receiving neoadjuvant chemotherapy. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a strong predictor of mortality in patients with pancreatic, colorectal, lung, gastric cancer and renal cell carcinoma. The aim of this study was to determine the relationship between pathological complete response (pCR) and pretreatment NLR values in locally advanced breast cancer (BC) patients receiving neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: Datawere collected retrospectively from the Akdeniz University School of Medicine Database for locally advanced BC patients treated with NACT between January 2000- December 2013. RESULTS: A total of 78 patients were analyzed. Sixteen (20%) patients achieved pCR. Estrogen receptor (ER) positivity was lower in pCR+ than pCR- cases (p=0.011). The median NLR values were similar in both arms. The optimum NLR cut-off point for BC patients with PCR+ was 2.33 (AUC:0.544, 95%CI [0.401- 0.688], p=0.586) with sensitivity, specificity, positive predictive value and negative predictive value (NPV) of 50%, 51,6%, 21,1%, and 80%, respectively. CONCLUSIONS: This study showed no relationship between the pCR and pretreatment NLR values. Because of a considerable high NPV, in the patients with higher NLR who had luminal type BC in which pCR is lower after NACT, such treatment may not be recommended. PMID- 25292056 TI - GSTM1 polymorphisms and lung cancer risk in the Chinese population: a meta analysis based on 47 studies. AB - Although a number of studies have been conducted on the association between GSTM1 polymorphisms and lung cancer in China, this association remains elusive and controversial. To clarify the effects of GSTM1 polymorphisms on the risk of lung cancer, a meta-analysis was performed in the Chinese population. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) up to 5th April 2014. A total of 45 articles (47 studies) including 6,623 cases and 7,865 controls were involved in this meta-analysis. Overall, a significant association (OR = 1.45, 95%CI: 1.32-1.60) was found between the null GSTM1 and lung cancer risk when all studies in Chinese population pooled into the meta-analysis. In subgroup analyses stratified by quality score, geographic area and source of controls, the same results were observed under all the models. This meta-analysis showed that the null GSTM1 may be a potential biomarker for lung cancer risk in Chinese, but further studies with gene-gene and gene-environment interactions are required for definite conclusions. PMID- 25292057 TI - Synergistic anti-tumor effect of KLF4 and curcumin in human gastric carcinoma cell line. AB - Kruppel-like factor 4 is a transcription factor which plays an important role in development and progression of various carcinomas. Curcumin characterized by excellent anti-cancer properties is regarded as a serviceable natural compound used in carcinoma therapy. This study aimed at exploring the impact of KLF4 overexpression in cooperation with curcumin on the proliferation, apoptosis and invasion of human gastric carcinoma BGC- 823 cells. Flow cytometry analysis, CCK 8 assays, transwell assays and Western blot results showed that KLF4 overexpression combined with curcumin had significant anti-proliferation, pro apoptosis and anti-invasion effects on BGC-823 cells. We also found that KLF4 had synergistic effects with curcumin, better promoting apoptosis and inhibiting proliferation and invasion of gastric carcinona cells. These results indicate that KLF4 could be used as a potential therapeutic target; curcumin could act as an auxiliary and provide a promising therapeutic strategy in stomach cancer. PMID- 25292058 TI - Trends in incidence of head and neck cancer in the northern territory, Australia, between 2007 and 2010. AB - Incidence trends of head and neck cancer (HNC) have implications for screening strategies, disease management, guiding health policy making, and are needed to further oral cancer research. This paper aims to describe trends in age-adjusted HNC incidence rates focusing on changes across calendar period between 2007 and 2010 in Australian Northern Territory. Age-adjusted incidence rates of HNC were calculated for 2007- 2010 using Northern Territory population based data assembled by Department of Health, Northern Territory Government of Australia. Changes in the HNC rate ratio (RR) and Estimated Annual Percentage Change (EAPC) between 2007-2008, 2008-2009 and 2009-2010 were calculated. A total of 171 HNC patients were recorded by the Northern Territory Department of Health during the time period between 2007 and 2010, out of which, 135 were males (78.9% of male HNC patients) and 36 were females (21.1% of female HNC patients). In conclusion, HNC incidence rate has decreased in the Northern Territory Australian males but remains unchanged in Australian females. High incidences of HNC may be associated with the high smoking rate and high alcohol consumption in the Northern Territory. Continued monitoring of trends in HNC incidence rates is crucial to inform Northern Territory based cancer prevention strategies. PMID- 25292059 TI - Long term outcomes of laser conization for high grade cervical intraepithelial neoplasia in Thai women. AB - AIM: To report long term outcomes of laser conization for high grade cervical intraepithelial neoplasia (CIN) in Thai women. MATERIALS AND METHODS: A retrospective cohort study was conducted in patients undergoing laser conization due to abnormal cervical cytology suggesting neoplasia during 1989 to 1994 and having follow-up data until December 2010. Conization was performed under colposcopy using a 0.5-mm CO2 laser beam with power density of 18,000-20,000 watts/cm2, and the surgical base was vaporized using a low power defocused beam. The follow-up protocol included cervical cytology and colposcopy. Long term outcome measures were failure rate (persistence and recurrence), post-conization status of transformation zone, and obstetric outcomes. RESULTS: Of 104 patients undergoing conization, 71 had therapeutic conization for high grade CIN and were followed up for a median time of 115 (range 12-260) months. There was one case of persistent and one of recurrent disease comprising a failure rate of 2.8%. The post treatment transformation zone was well visualized in 68.3% of 63 patients with an intact uterus. Sixteen patients achieved 25 pregnancies; none had second trimester miscarriage. The obstetric outcomes were unremarkable. CONCLUSIONS: Laser conization under colposcopic visualization for the treatment of high grade CIN in Thai women has a low failure rate of 2.8%. The post-conization transformation zone could not be evaluated completely in approximately 30% of cases; therefore the follow-up protocol should include both cytology and colposcopy. Obstetric outcomes are not adversely affected by this therapeutic procedure. PMID- 25292060 TI - Association of cytokine gene polymorphisms with gastritis in a Kazakh population. AB - BACKGROUND: Gastritis and gastric cancer are the most common diseases in the Kazakh population. Polymorphisms in genes coding of cytokines have been played important role with gastric disease risk. The risk alleles of cytokines in patients with gastritis can predict the risk of developing gastric cancer. The aim of this study was to investigate cytokine gene polymorphisms as risk factors for the development of gastritis in a case-control study with gastritis patients and healthy individuals from the Kazakh ethnic group, living in North Kazakhstan. MATERIALS AND METHODS: The polymerase chain reaction followed by direct sequencing were used for detection of two functional polymorphisms in the IL1 gene family, and TaqMan SNP Genotyping Assay Sets were applied for three potentially functional polymorphisms in the IL10 gene, and one in the TNFA promoter. RESULTS: Association analysis of studied allelic variants and the development of gastritis in H. pylori- positive patients showed that IL1B -31C/C, IL1B -511T/T and IL1RN -2/2 allelic variants were associated with development of gastritis (OR=1.8 (1.07-3.16), p=0.025; OR=1.7 (1.04-2.99), p=0.035, and OR=4.92 (2.45-9.85), p<0.001) respectively. Haplotype C-T that combines both homozygous allelic variants of IL1B gene also had a statistically significant association with slightly higher OR (OR: 1.43, 95% CI: 1.08-1.88). CONCLUSIONS: The data from the current study showed that the genotype IL-1B -511T/-31C-IL1-RN-2 and H. pylori infection increase risk of gastritis in the Kazakh population. That genotype combination might be a factor increasing the risk of developing gastric cancer. PMID- 25292061 TI - AIDS-related non-Hodgkin lymphoma: imaging feature analysis of 27 cases and correlation with pathologic findings. AB - BACKGROUND: Some tumor types are related to HIV, including non-Hodgkin lymphoma (NHL). The morbidity and mortality of NHL has remained high, even after highly active antiretroviral therapy (HAART) was introduced. We collected cases of AIDS with NHL, and evaluated the imaging features and strategies for diagnosis. MATERIALS AND METHODS: There were 27 patients with AIDS and tumors confirmed by pathology. There were 9 patients with Burkitt lymphoma, 16 with diffuse large B cell lymphomas (DLBCLs), and 2 with primary central nervous system (PCNS) lymphomas. All of the patients underwent a series of imaging studies. Three radiologists analyzed the images, and any disagreement was discussed until consensus was reached. RESULTS: The radiologic manifestations of AIDS with NHL were mainly masses and lymphadenopathy, 3 patients having one mass and 12 two or more masses. 7 patients had lymphadenopathy in one site and 3patients had lymphadenopathy in two or more sites. Coarse mucosal folds, thickening of the gastrointestinal wall, and lumen narrowing were typical manifestations of NHL within the gastrointestinal tract. There were 4 patients with masses and 5 with lymphadenopathy inthe 9 with Burkitt lymphoma, and 11 patients with masses 5 with lymphadenopathy in the 16 with DLBCLs. CONCLUSION: NHL is a malignancy that usually occurs in patients with AIDS. Imaging is an important method by which to evaluate lesions, masses, and lymphadenopathy. Fine needle aspiration biopsy and stereotaxis biopsy are useful methods by which to diagnose NHL. PMID- 25292062 TI - Cancer prediction based on radical basis function neural network with particle swarm optimization. AB - This paper addresses cancer prediction based on radial basis function neural network optimized by particle swarm optimization. Today, cancer hazard to people is increasing, and it is often difficult to cure cancer. The occurrence of cancer can be predicted by the method of the computer so that people can take timely and effective measures to prevent the occurrence of cancer. In this paper, the occurrence of cancer is predicted by the means of Radial Basis Function Neural Network Optimized by Particle Swarm Optimization. The neural network parameters to be optimized include the weight vector between network hidden layer and output layer, and the threshold of output layer neurons. The experimental data were obtained from the Wisconsin breast cancer database. A total of 12 experiments were done by setting 12 different sets of experimental result reliability. The findings show that the method can improve the accuracy, reliability and stability of cancer prediction greatly and effectively. PMID- 25292063 TI - Red cell distribution width as a predictor of prostate cancer progression. AB - BACKGROUND: The aims of this study were to investigate the utility of red blood cell distribution width (RDW) as a simple and readily available marker in prostate cancer, as well as to evaluate RDW as a predictor of progression in prostate cancer patients. MATERIALS AND METHODS: We evaluated 62 newly diagnosed prostate cancer patients who underwent transrectal ultrasound (TRUS)-guided biopsy and 62 healthy controls of mean age 64 (range, 45-75) years at the Urology Clinic of Bozok University Hospital. Data collection was performed using our laboratory information system database to retrieve findings regarding RDW, hemoglobin, prostate- specific antigen (PSA), and age. The RDW values were compared between the healthy control group and prostate cancer patients. A high risk of progression as defined as a Gleason score (GS) >6, total number of cores positive for cancer >33%, each core containing >50% cancer cells, and a prostate specific antigen (PSA) level >10 ng/ mL. Patients were classified according to risk of progression, as well as divided into subgroups according to the RDW quartile. RESULTS: The mean RDW value of prostate cancer patients was 14.6, compared with 13.7 in the healthy control group (p=0.001). A higher RDW was associated with an increased risk of progression, whereas a lower RDW value was correlated with a low risk of progression. CONCLUSIONS: RDW is an easily derived measure that might, in combination with other markers, help predict prostate cancer risk and progression. We suggest that RDW may be used in combination with other parameters in the assessment of prostate cancer. PMID- 25292064 TI - Biological screening of novel derivatives of valproic acid for anticancer and antiangiogenic properties. AB - BACKGROUND: Valproic acid (VPA) is a potent anticancer and antiangiogenic agent. However, design and synthesis of chemical derivatives with improved antiangiogenic and anticancer activities are still necessary. In this study a library of novel derivatives of VPA was synthesized and tested. METHODS: A human liver cancer cell line (HepG2) and a human normal embryonic kidney cell line (HEK 293) were exposed to various concentrations of VPA derivatives for 24 hours and cell viability was checked by MTT colorimetric assay. Anti-angiogenic properties were evaluated in transgenic zebrafish embryos. RESULTS: N-valproylglycine derivatives suppressed survival almost 70% (p value 0.001) in HepG2 cells but only 10-12% in HEK 293 cells (p value 0.133). They also suppressed angiogenic blood vessel formation by 80% when used between 2-20 MUM in zebrafish embryos. Valproic acid hydrazides showed moderate level of anticancer activity by affecting 30-50% (p value 0.001) of cell viability in HepG2 cells and 8-10% in HEK293 cells (p value 0.034). CONCLUSION: The majority of compounds in this study showed potent and stronger antiangiogenic and anticancer activity than VPA. They proved selectively toxic to cancer cells and safer for normal cells. Moreover, these compounds inhibited developmental angiogenesis in zebrafish embryos. Based on the fact that liver is a highly vascularized organ, in case of liver carcinoma these compounds have the potential to target the pathological angiogenesis and could be an effective strategy to treat hepatocellular carcinoma. PMID- 25292065 TI - Role of a risk of malignancy index in clinical approaches to adnexal masses. AB - OBJECTIVE: The aim of this study was to evaluate predictive role of risk of malignancy index in discriminating between benign and malignant adnexal masses preoperatively. METHODS: This retrospective study was conducted with a total of 569 patients with adnexal masses/ovarian cysts managed surgically at our clinic between January 2006 and January 2012. Obtained data from patient files were age, gravidity, parity, menopause status, ultrasound findings and CA125 levels. For all patients ultrasound scans were performed. For the assessment of risk of malignancy index (RMI) Jacobs' model was used. Histopathologic results of all patients were recorded postoperatively. Malignancy status of the surgically removed adnexal mass was the gold standard. RESULTS: Of the total masses, 245 (43.1%) were malignant, 316 (55.5%) were benign and 8 (1.4%) were borderline. The mean age of benign cases was lower than malign cases (35.2+/-10.9 versus 50.8+/ 13.4, p<0.001). Four hundred and five of them (71.2%) were in premenopausal period. Malignant tumors were more frequent in postmenopausal women (81% versus 29%, p<0.001). All ultrasound parameters of RMI were statistically significantly favorable for malignant masses. In our study ROC curve analysis for RMI provided maximum Youden index at level of 163.85. When we based on cutoff level for RMI as 163.85 sensitivity, specificity , PPV, NPV was calculated 74.7%, 96.2%, 94% and 82.6%, respectively. CONCLUSIONS: RMI was found to be a significant marker in preoperative evaluation and management of patients with an adnexal mass, and was useful for referring patients to tertiary care centers. Although utilization of RMI provides increased diagnostic accuracy in preoperative evaluation of patient with an adnexal mass, new diagnostic tools with higher sensitivity and specificity are needed to discriminate ovarian cancer from benign masses. PMID- 25292066 TI - Loss of imprinting of insulin-like growth factor 2 is associated with increased risk of primary lung cancer in the central China region. AB - BACKGROUND: To determine the imprinting status of the IGF2 in Chinese patients with primary lung cancer and to analyze the clinical significance of the loss of imprinting (LOI) of IGF2. MATERIALS AND METHODS: PCR- RFLP and RT-PCR-RFLP were carried out to select heterozygous cases for the ApaI polymorphism within exon 9 of the IGF2 gene and further analyze IGF2 LOI in 64 lung cancer patients, respectively. RESULTS: Of 64 lung cancer patients, 31 were heterozygous for IGF2. The positive rates of IGF2 LOI of lung cancer foci, matched paracancer tissues, and normal lung tissues were 77.4% (24/31), 61.3% (19/31), and 29.0% (9/31), respectively. The LOI differences for IGF2 among the three groups were statistically significant (chi2=15.267, p=0.000), and the LOI frequency of IGF2 in normal lung tissue was significantly lower than that in lung cancer foci and paracancer tissues (chi2=14.577, p=0.000; chi2=6.513, p=0.011). No statistical difference was observed between the lung tumor group and the matched paracancer group (chi2=1.897, p=0.168). The prevalence of advanced clinical stages (chi2=2.379; p=0.017) and lymph node metastasis (chi2=5.552; p=0.018) was significantly higher for LOI- positive paracancer tissues than for LOI-negative paracancer tissues. CONCLUSIONS: IGF2 LOI is highly frequent in Chinese primary lung cancer patients, especially those with increased risk of lymph node metastasis and advanced clinical stages. IGF2 LOI may be an early epigenetic event in human lung carcinogenesis. PMID- 25292067 TI - Clinical efficacy and prognostic factors of chemoreduction combined with topical treatment for advanced intraocular retinoblastoma. AB - OBJECTIVE: To explore the clinical efficacy and prognostic factors of chemoreduction combined with topical treatment of advanced intraocular retinoblastoma (RB). MATERIALS AND METHODS: A total of 22 eyes from 17 children with RB were selected for the study and treated with chemoreduction combined with topical cryotherapy, transpupillary thermotherapy (TTT) or episcleral plaque brachytherapy. Clinical and follow-up data were retrospectively analyzed. RESULTS: All children received 2~6 courses of chemoreduction treatment, (4.5+/ 0.8 courses on average); 17 eyes from 13 children were treated by chemoreduction combined with cryotherapy or TTT and 5 eyes from 4 children with chemoreduction combined with 125I episcleral plaque brachytherapy. The eye retention rate was 81.8% (18/22), among which 38.9% (7/18) featured restored or maintained good vision. Postoperative follow-up period was 7 to 34 months, (18.6 +/- 5.2 months on average). The recurrence rate was 41.2% (7/17), among which 57.1% (4/7) were controlled by supplementing or appending cryotherapy or TTT treatment during the follow-up period. The tumor basal diameter and thickness were significantly reduced (P<0.05 or P<0.01) after treatment. All children demonstrated different degrees of hair loss, 70.6% (12/17) with different degrees of gastrointestinal reactions, 5.88% (1/17) with neutropenia and 11.8% (2/17) being seriously infected during the chemotherapeutic treatment. Univariate and logistic regression analysis showed that tumor basal diameter before treatment had a significant effect on the prognosis (P<0.01). CONCLUSIONS: Chemoreduction combined with topical therapy can effectively control RB in the short term, and tumor basal diameter before treatment is an independent risk factor for prognosis. PMID- 25292068 TI - Comparison of linear accelerator and helical tomotherapy plans for glioblastoma multiforme patients. AB - BACKGROUND: Despite advances in radiotherapy, overall survival of glioblastoma multiforme (GBM) patients is still poor. Moreover dosimetrical analyses with these newer treatment methods are insufficient. The current study is aimed to compare intensity modulated radiation therapy (IMRT) linear accelerator (linac) and helical tomotherapy (HT) treatment plans for patients with prognostic aggressive brain tumors. MATERIAL AND METHODS: A total of 20 GBM patient plans were prospectively evaluated in both linac and HT planning systems. Plans are compared with respect to homogenity index, conformity index and organs at risk (OAR) sparing effects of the treatments. RESULTS: Both treatment plans provided good results that can be applied to GBM patients but it was concluded that if the critical organs with relatively lower dose constraints are closer to the target region, HT for radiotherapeutical application could be preferred. CONCLUSION: Tomotherapy plans were superior to linear accelerator plans from the aspect of OAR sparing with slightly broader low dose ranges over the healthy tissues. In case a clinic has both of these IMRT systems, employment of HT is recommended based on the observed results and future re-irradiation strategies must be considered. PMID- 25292069 TI - Overview of childhood cancers at a regional cancer centre in North-East India. AB - Childhood cancers are relatively uncommon in comparison to adult cancers. There is no literature available to shed light on clinic-pathological types and patterns of care for childhood cancers in our population in North-East India. In this analysis we therefore tried to determine the common childhood cancers diagnosed in our institute, clinical profile of the patients, types of treatment and compliance, and median survival estimates. Leukemia was most common, followed by retinoblastoma, central nervous system tumours and lymphomas. Ascertaining the clinic-pathological profile of childhood cancers in our population is essential for allocation and management of resources for this small but important group of patients. PMID- 25292070 TI - Standardized uptake values highly correlate with tumor size and Fuhrman grade in patients with clear cell renal cell carcinoma. AB - BACKGROUND: We investigated the correlation between standardized uptake value (SUVmax), tumor size and Fuhrman grade in patients with renal cell carcinoma (RC). MATERIALS AND METHODS: We retrospectively analyzed the data of 54 patients with clear cell renal cell carcinoma histopathologically diagnosed who underwent fluorine-18 fluoro-2 deoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) between January 2005 and March 2014. RESULTS: Avarage tumor sizes were 5.64+/-1.85, 6.85+/-2.24 and 7.98+/-2.45 in low, medium and high SUVmax groups, respectively. The Spearman's correlation coefficient between the tumor size and SUVmax was 0.385 (p=0.004) and between the Fuhrman grade and SUVmax was 0.578 (p<0.001). CONCLUSIONS: SUVmax appears highly correlated with tumor size and Fuhrman grade in patients with histopathologically confirmed clear cell RC. Multicenter studies are needed to provide larger series for more accurate results. PMID- 25292071 TI - Experimental study on inhibition effects of the XAF1 gene against lung cancer cell proliferation. AB - OBJECTIVE: To investigate the effect of high expression of XAF1 in vivo or in vitro on lung cancer cell growth and apoptosis. METHODS: 1. The A549 human lung cancer cell line was transfected with Ad5/F35 - XAF1, or Ad5/ F35 - Null at the same multiplicity of infection (MOI); (hereinafter referred to as transient transfected cell strain); XAF1 gene mRNA and protein expression was detected by reverse transcription polymerase chain reaction (RT- PCR) and Western blotting respectively. 2. Methyl thiazolyl tetrazolium (MTT) and annexin V-FITC/PI double staining were used to detect cell proliferation and apoptosis before and after infection of Ad5/F35 - XAF1 with Western blotting for apoptosis related proteins, caspase 3, caspase - 8 and PARP. 3. After the XAF1 gene was transfected into lung cancer A549 cells by lentiviral vectors, and selected by screening with Blasticidin, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were applied to detect mRNA and protein expression, to establish a line with a stable high expression of XAF1 (hereinafter referred to as stable expression cell strain). Twenty nude mice were randomly divided into groups A and B, 10 in each group: A549/ XAF1 stable expression cell strain was subcutaneously injected in group A, and A549/Ctrl stable cell line stable expression cell strain in group B (control group), to observe transplanted tumor growth in nude mice. RESULTS: The mRNA and protein expression of XAF1 in A549 cells transfected by Ad5/F35 - XAF1 was significantly higher than in the control group. XAF1 mediated by adenovirus vector demonstrated a dose dependent inhibition of lung cancer cell proliferation and induction of apoptosis. This was accompanied by cleavage of caspase -3, -8, -9 and PARP, suggesting activation of intrinsic or extrinsic apoptotic pathways. A cell strain of lung cancer highly expressing XAF1 was established, and this demonstrated delayed tumor growth after transplantation in vivo. CONCLUSION: Adenovirus mediated XAF1 gene expression could inhibit proliferation and induce apoptosis in lung cancer cells in vitro; highly stable expression of XAF1 could also significantly inhibit the growth of transplanted tumors in nude mouse, with no obvious adverse reactions observed. Therefore, the XAF1 gene could become a new target for lung cancer treatment. PMID- 25292072 TI - Influence of autologous and homologous blood transfusion on interleukins and tumor necrosis factor-alpha in peri-operative patients with esophageal cancer. AB - OBJECTIVE: To explore the influence of different ways of blood transfusion on the expression levels of interleukins (IL) and tumor necrosis factor-alpha (TNF alpha) inperi-operative patients with esophageal cancer. MATERIALS AND METHODS: A total of 80 patients with esophageal cancer who underwent radical operations were selected as study patients and randomly divided into an observation group (treated with autologous blood transfusion) and control group (with homologous blood transfusion). Changes of intra-operative indexes and peri-operative blood indexes, from hemoglobin (Hb) and hematocrit value (Hct), to levels of inflammatory factors like interleukins-6 (IL-6), IL-8, IL-10 and tumor necrosis factor-alpha (TNF-alpha) were compared. RESULTS: Operations for patients in both groups were successfully conducted, and no significant differences in mean surgical duration and intra-operative hemorrhage volume, fluid infusion volume and blood transfusion volume were detected (p>0.05). Compared with values before surgery, Hb and Hct levels decreased significantly while white blood cell count (WBC) increased 1, 5 and 7 d after operation (p<0.05, p<0.01). In addition, WBC was apparently higher in observation group than in control group 5 and 7 d after operation (p<0.01). Compared with before surgery, in the observation group, levels of IL-6, IL-8 and IL-10 had no significant differences after operation (P>0.05), but TNF-alpha level increased y (p<0.01), whereas in control group, IL 6 level had no significant difference (p>0.05), IL-8 level decreased obviously (p<0.05), IL-10 level increased markedly first and then decreased gradually as time passed but its level remained elevated (p<0.01), and TNF-alpha level increased first and then decreased, and there was no significant difference 7 d after operation (p>0.05). CONCLUSIONS: Decreased IL-8 and increased IL-10 levels are two important reasons forimmunosuppression after homologous blood transfusion, whereas autologous blood transfusion can alleviate this while increasing the TNF-alpha level, which also has potential to improve anti-tumor immunity in the human body. PMID- 25292073 TI - Neuroendocrine tumors in the Iran Cancer Institute: predictive factors of patient survival. AB - BACKGROUND: Neuroendocrine tumors have widespread and different clinical presentations and prognoses. This study was conducted to assess their survival time and prognostic factors in Iran. MATERIALS AND METHODS: In a retrospective cohort study, 189 patients diagnosed of having neuroendocrine carcinoma were chosen. The tumor and clinical characteristics of the patients were modeled with a Cox proportional hazard approach. Survival was assessed using Kaplan-Meyer curves. RESULTS: Crude median survival time was 30 months. Women survived longer than men (the median survival time for women was 40 and for men was 24 months). Age (<60 vs >60 years old with hazard ratio (HR) of 2.43, 95% CI 1.3-4.5), primary pathology report (carcinoid vs. others with HR 5.85 cm, 95% CI 2.4-14.3), tumor size (for 5-10, HR of 3.1, 95% CI 1.6 and for >10 HR of 8.2, 95% with 95% CI 3.1-21.9), and chemotherapy with single drug (taking vs. not taking with a HR 2.2, 95% CI 1.1-4.8) had significant effects on overall survival of patients. CONCLUSIONS: Survival time in patients with neuroendocrine carcinomas is related to demographics, clinical characteristics, tumor histology, and subtype specific treatment. PMID- 25292074 TI - Clinico-morphological profile and receptor status in breast cancer patients in a South Indian institution. AB - BACKGROUND: Breast cancer is the most common malignancy in women worldwide and the second most common cancer in females in India. Receptor status may be important for survival. OBJECTIVE: To analyse and correlate the clinical and morphological parameters with receptor status in breast carcinoma patients in a tertiary care institution in Southern India. MATERIALS AND METHODS: This retrospective study involved 320 patients of breast cancer diagnosed in an oncology hospital over a period of 31/2 years. Data was analysed using SPSS Version 21. RESULTS: Some 60.6% patients with breast carcinomas belonged to the age group of 40 to 60 years. The most common histological type was infiltrating ductal carcinoma, not otherwise specified, accounting for 84.4% of patients. On immunohistochemistry, estrogen receptor (ER) and progesterone receptor (PR) were expressed in 56.3% and 53.1% of cases, respectively. CONCLUSIONS: Breast cancers in India, a developing country, occur in younger women and tend to be more aggressive with lower rates of ER and PR expression and higher histological tumor grades. Both ER and PR status of the tumors had significant associations with the patient age, pathological TNM stage and histological tumor grade. PMID- 25292075 TI - Distinct postsurgical management in young and elderly breast cancer patients results in equal survival rates. AB - BACKGROUND: Although breast cancer (BC) is one of the most common malignant diseases in women, the majority of the studies describing the characteristics of BC in elderly patients have been limited to survival assessments or tumor features, without using younger BC patients as a reference group. The aim of our study was to describe and compare tumor characteristics and management patterns in elderly versus younger breast cancer patients in Turkey. MATERIALS AND METHODS: We retrospectively analyzed 152 patients with invasive breast cancer who underwent surgery in our institution between 2002 and 2012. Patients were divided into 2 groups according to age at the time of diagnosis. RESULTS: There were 62 patients in the elderly group (>=65 years) and 90 patients in the younger group (<65 years). Compared to the younger group, tumors in the elderly group were more likely to be larger (p=0.018), of lower grade (p=0.005), and hormone receptor positive (p>0.001). There were no significant differences regarding histology, localization, lymph node involvement, or types of surgical procedures between the 2 groups. Comorbidities were more common in elderly patients (p<0.001). In addition, elderly patients were more likely to receive hormonal therapy (p<0.001) and less likely to receive radiotherapy (p=0.08) and chemotherapy (p=0.003). There was no difference in survival and locoregional recurrence rates between the groups. CONCLUSIONS: The results of this study demonstrate that breast cancer in elderly patients has more favorable tumor features, warranting less aggressive treatment regimens after surgery. PMID- 25292076 TI - Effect of trichostatin A on anti HepG2 liver carcinoma cells: inhibition of HDAC activity and activation of Wnt/beta-Catenin signaling. AB - PURPOSE: To investigate the effect of deacetylase inhibitory trichostatin A (TSA) on anti HepG2 liver carcinoma cells and explore the underlying mechanisms. MATERIALS AND METHODS: HepG2 cells exposed to different concentrations of TSA for 24, 48, or 72h were examined for cell growth inhibition using CCK8, changes in cell cycle distribution with flow cytometry, cell apoptosis with annexin V FTIC/PI double staining, and cell morphology changes under an inverted microscope. Expression of beta-catenin, HDAC1, HDAC3, H3K9, CyclinD1 and Bax proteins was tested by Western blotting. Gene expression for beta-catenin, HDAC1and HDAC3 was tested by q-PCR. beta-Catenin and H3K9 proteins were also tested by immunofluorescence. Activity of Renilla luciferase (pTCF/LEF-luc) was assessed using the Luciferase Reporter Assay system reagent. The activity of total HDACs was detected with a HDACs colorimetric kit. RESULTS: Exposure to TSA caused significant dose-and time-dependent inhibition of HepG2 cell proliferation (p<0.05) and resulted in increased cell percentages in G0/ G1 and G2/M phases and decrease in the S phase. The apoptotic index in the control group was 6.22+/ 0.25%, which increased to 7.17+/-0.20% and 18.1+/-0.42% in the treatment group. Exposure to 250 and 500nmol/L TSA also caused cell morphology changes with numerous floating cells. Expression of beta-catenin, H3K9and Bax proteins was significantly increased, expression levels of CyclinD1, HDAC1, HDAC3 were decreased. Expression of beta-catenin at the genetic level was significantly increased, with no significant difference in HDAC1and HDAC3 genes. In the cytoplasm, expression of beta-catenin fluorescence protein was not obvious changed and in the nucleus, small amounts of green fluorescence were observed. H3K9 fluorescence protein were increased. Expression levels of the transcription factor TCF werealso increased in HepG2 cells following induction by TSA, whikle the activity of total HDACs was decreased. CONCLUSIONS: TSA inhibits HDAC activity, promotes histone acetylation, and activates Wnt/beta-catenin signaling to inhibit proliferation of HepG2 cell, arrest cell cycling and induce apoptosis. PMID- 25292077 TI - Interleukin-18 synergism with interleukin-2 in cytotoxicity and NKG2D expression of human natural killer cells. AB - Natural killer (NK) cells play an important role in anti-tumor immunity. Interleukin (IL)-18 is an immunoregulatory cytokine that induces potent NK cell dependent anti-tumor responses when administrated with other cytokines. In this study, we explored the effects of combining IL-18 and IL-2 on NK cytotoxicity as well as expression levels of the NK cell receptor NKG2D in vitro. Freshly isolated PBMCs were incubated for 48 h with IL-18 and IL-2, then CD107a expression on CD3-CD56+ NK cells was determined by three-colour flow cytometry to evaluate the cytotoxicity of NK cells against human erythroleukemia K562 cells and human colon carcinoma HT29 cells. Flow cytometric analysis was also employed to determine NKG2D expression on NK cells. The combined use of IL-18 and IL-2 significantly increased CD107a expression on NK cells compared with using IL-18 or IL-2 alone, suggesting that the combination of these two cytokines exerted synergistic enhancement of NK cytotoxicity. IL-18 also enhanced NKG2D expression on NK cells when administered with IL-2. In addition, blockade of NKG2D signaling with NKG2D-blocking antibody attenuated the up-regulatory effect of combining IL 18 and IL-2 on NK cytolysis. Our data revealed that IL-18 synergized with IL-2 to dramatically enhance the cytolytic activity of human NK cells in a NKG2D dependent manner. The results appear encouraging for the use of combined IL-18 and IL-2 in tumor immunotherapy. PMID- 25292078 TI - Presentation of retinoblastoma patients in Malaysia. AB - BACKGROUND: Retinoblastoma is a rare type of cancer that usually develops in early childhood. If left untreated it can cause blindness and even death. The aim of this study is to determine sociodemographic and clinical features of retinoblastoma patients and also to determine the treatment pattern and outcome in Malaysia. MATERIALS AND METHODS: Data for this study were retrieved from the Retinoblastoma Registry of the National Eye Database (NED) in Malaysia. Hospital Kuala Lumpur, Hospital Umum Kuching, Sarawak and Hospital Queen Elizabeth, Kota Kinabalu were the major source data providers for this study. Data collected in the registry cover demography, clinical presentation, modes of treatment, outcomes and complications. RESULTS: The study group consisted of 119 patients (162 eyes) diagnosed with retinoblastoma between 2004 and 2012. There were 68 male (57.1%) and 51 (42.9%) female. The median age at presentation was 22 months. A majority of patients were Malays (54.6%), followed by Chinese (18, 5%), Indians (8.4%), and indigenous races (15.9%). Seventy six (63.8%) patients had unilateral involvement whereas 43 patients had bilateral disease (36.1%). It was found that most children presented with leukocoria (110 patients), followed by strabismus (19), and protopsis (12). Among the 76 with unilateral involvement (76 eyes), enucleation was performed for a majority (79%). More than half of these patients had extraocular extension. Of the 40 who received chemotherapy, 95% were given drugs systemically. Furthermore, in 43 patients with bilateral involvement (86 eyes), 35 (41%) eyes were enucleated and 17 (49%) showed extraocular extension. Seventy-two percent of these patients received systemic chemotherapy. The patients were followed up 1 year after diagnosis, whereby 66 were found to be alive and 4 dead. Sixteen patients defaulted treatment and were lost to follow up, whereas follow-up data were not available in 33 patients. CONCLUSIONS: Patients with retinoblastoma in this middle-income Asian setting are presenting at late stages. As a result, a high proportion of patients warrant aggressive management such as enucleation. We also showed that a high number of patients default follow-up. Therefore, reduction in refusal or delay to initial treatment, and follow-up should be emphasized in order to improve the survival rates of retinoblastoma in this part of the world. PMID- 25292079 TI - Interleukin-12 and interleukin-6 gene polymorphisms and risk of bladder cancer in the Iranian population. AB - Interleukin-12 (IL-12) as an antitumor and interleukin-6 (IL-6) as an inflammatory cytokine, are immunomodulatory products that play important roles in responses in cancers and inflammation. We tested the association between two polymorphisms of IL-12(1188A>C; rs3212227) and IL-6 (-174 C>G) and the risk of bladder cancer in 261 patients and 251 healthy individuals. We also investigated the possible association of these SNPs in patients with high-risk jobs and smoking habits with the incidence of bladder cancer. The genotype distributions of IL-6 (-174 C/G) genotype were similar between the cases and the control groups; however, among patients with smoking habits, the association between IL-6 gene polymorphism and incidence of bladder cancer was significant. After a control adjustment for age and sex, the following results were recorded: CC genotype (OR= 2.11, 95%CI=1.56-2.87, p=0.007), GC genotype (OR=2.18, 95%CI=1.16 4.12, p=0.014) and GC+ CC (OR=2.6, 95%CI=1.43-4.47, p=0.011). A significant risk of bladder cancer was observed for the heterozygous genotype (AC) of IL-12 (OR=1.47, 95%CI=1.01-2.14, p=0.045) in all cases, and among smokers (AC) (OR=3.13, 95%CI=1.82-5.37, p=0.00014), combined AC+CC (OR=3.05, 95%CI=1.8-5.18, p=0.000015). Moreover among high risk job patients, there was more than a 3-fold increased risk of cancer in the carriers of IL-12 beta heterozygous (OR=3.7, 95%CI=2.04-6.57, p=0.000056) and combined AC+CC(OR=3.29, 95%CI=1.58-5.86, p=0.00002) genotypes as compared with the AA genotype with low-risk jobs. As a conclusion, this study suggests that IL-12(3'UTR A>C) and IL-6 (-174 C>G) genotypes are significantly associated with an increased risk of bladder cancer in the Iranian population with smoking habits and/or performing high-risk jobs. PMID- 25292080 TI - Awareness of breast cancer risk among female university students from 24 low, middle income and emerging economy countries. AB - BACKGROUND: The aim of this study was to investigate the awareness of breast cancer risk factors among female university students in 24 low, middle income and emerging economy countries. A cross-sectional survey was conducted with 10,242 undergraduate university students (mean age 20.7, SD=2.9) from 25 universities in 24 countries across Asia, Africa and the Americas. Using anonymous questionnaires the awareness of links between breast cancer and heredity, diet, overweight, exercise, alcohol use, smoking and stress was assessed. Results indicated that 35.4% of the women were not aware that any of these risk factors could influence breast cancer, 43.8% were aware of a genetic link, and only 12.5%, 10.9% and 10.6% correctly identified alcohol use, overweight and physical inactivity, respectively, as factors causing breast cancer. Moreover, 13.3% rated dietary fat and 11.5% fibre as influencing breast cancer; both low-fat and high-fibre diets may be weakly protective against breast cancer, and smoking (19.4%) and stress (13.5%), the most commonly chosen breast cancer lifestyle risk factors, have less clear impact on breast cancer. There were marked country differences, e.g., in regards of being aware of genetic causes of breast cancer risk in female students from Ivory Coast, India, Madagascar, Nigeria and Laos below 30% and female students from Pakistan, Singapore, Turkey, Grenada and Philippines 60 or more percent. This study provides insight in the breast cancer risk perception of young women, which can be utilized in breast cancer awareness and prevention programmes. PMID- 25292081 TI - Intake of freshwater fish and associated fatty acids and risk of breast cancer. AB - To investigate the association between intake of freshwater fish and their fatty acids and the risk of breast cancer in Chinese women, we conducted a case-control study with 669 cases and 682 population-based controls in Jiangsu Province of China. A structured questionnaire was used to elicit detailed information. Unconditional logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Total freshwater fish intake was linked to decrease in the adjusted OR for breast cancer, but without dose-dependence. Analyses by freshwater fish species showed that consumption of black carp and silver carp was inversely related to breast cancer risk, with adjusted-ORs for the highest intake category of black carp (>=500g/month) of 0.54 (95%CI=0.33 0.92; P trend<0.002) and for silver carp (>=1000g/month) of 0.19 (95%CI=0.11 0.33; P trend<0.001). In contrast, consumption of crucian carp was positively related to breast cancer risk, with an adjusted OR for the highest intake category (>=1000g/month) of 6.09 (95%CI=3.04-12.2; P trend<0.001). Moderate intakes of SFA, PUFA, n3-PUFA and n6-PUFA from freshwater fish may decrease the risk of breast cancer among premenopausal women. The findings of this study suggest that intake of freshwater fish and their fatty acids may modify risk of breast cancer, and that different species of freshwater fish could have a different actions on breast cancer risk. Future epidemiologic studies are needed to know the effects of freshwater fish intake on breast cancer risk and the cause of these effects. PMID- 25292082 TI - High feasibility of liquid-based cytological samples for detection of EGFR mutations in Chinese patients with NSCLC. AB - BACKGROUND: Activating mutations of epidermal growth factor receptor (EGFR) could predict response to tyrosine kinase inhibitor (TKI) treatment in patients with non-small cell lung cancer (NSCLC). However, the detection of EGFR mutation is frequently challenging in clinical practice for the lack of tumor tissue. The aim of this study was to investigate the feasibility of performing EGFR mutation testing on various types of liquid-based cytology (LBC) samples. MATERIALS AND METHODS: A total of 434 liquid-based cytology samples were collected from March 2010 and November 2013. Among them, 101 with diagnosis of lung adenocarcinoma had paired surgically resected specimens. The ADx Amplification Refractory Mutation System (ADx-ARMS) was used to determine EGFR mutation status both in LBC and resected samples. RESULTS: All liquid-based cytology samples were adequate for EGFR mutation analysis. The mutation rate was 50.5% in the 434 NSCLC patients with LBC samples and the incidence rates of EGFR mutation were consistent among different specimens. We also detected EGFR positives in 52.5% (53/101) patients with paired histologic specimens. The concordance rate of EGFR mutation between LBC samples and paired histologic specimens was 92.1%. CONCLUSIONS: Our results suggest that liquid-based cytology samples are highly reliable for EGFR mutation testing in patients with NSCLC. PMID- 25292083 TI - Evaluation of the knowledge and perceptions with regards to pictorial health warnings on tobacco products among tobacco users diagnosed with head and neck carcinoma: a study from the Kumaon Hills of India. AB - BACKGROUND: Tobacco products continue to be used in large quantities in India despite the mandatory inclusion of pictorial health warnings (PHWs) on all tobacco packaging. The circumstances as to how people could continue the use of tobacco to the point of developing head and neck cancer despite enhanced awareness about the ill effects of tobacco is the main focus of this study. MATERIALS AND METHODS: This study concerned patients with least 5-years history of tobacco use, having been diagnosed with histopathologically proven malignancies of the hypopharynx, larynx, oropharynx and oral cavity presenting at the Government Medical College-Haldwani, Nainital, India. A total of 183 patients were eligible for inclusion during July 1 2013- June 30 2014. Of these, 59 patients used smoked tobacco exclusively, 22 patients used smokeless tobacco exclusively, and 102 patients used both forms of tobacco. Among users of smoked forms, 75.2% (n=121) were beedi users, and 24.8% (n=40) were cigarette users. Patients were asked direct questions as to whether they had noticed the presence of PHWs upon tobacco products. The reasons as to why PHWs were not effective in stopping the patients from tobacco use were investigated. RESULTS: Of the 183 patients, 146 reported being aware about the presence of PHWs, and when they were asked reasons as to why they continued tobacco despite being aware of ill effects, the commonest reason chosen (by 53.4%) was that patients had not regarded themselves as using tobacco heavy enough to cause cancer. Among the 36 patients who reported as being oblivious to the presence of PHWs on tobacco products, 63.9% reported that the products they used never displayed any PHWs, and 36.1% reported never having paid attention to the packaging. The awareness about PHWs was higher among cigarette smokers in comparison to beedi smokers (100% vs 76.1%, p=0.0002). CONCLUSIONS: Locally produced and marketed tobacco products such as beedis and oral tobacco often fail to display PHWs. The presence of PHWs without doubt enhances awareness about the carcinogenic risks of tobacco. However, enhanced awareness alone may not be enough, and as elucidated by this study, some persons continue to use tobacco to the point of developing malignancies. The need of the hour is the implementation of legal and economic sanctions discouraging the use of tobacco products. PMID- 25292084 TI - Profile of non-communicable disease risk factors among employees at a Saudi university. AB - BACKGROUND: There is paucity of studies defining the prevalence of non communicable disease (NCD) risk factors in Saudi Arabia despite the surging epidemic of obesity, change in dietary habits and sedentary lifestyle. OBJECTIVES: This cross-sectional study aimed to assess the prevalence of NCDs risk factors among employees at King Faisal University in Al Hassa, Saudi Arabia and to determine the possible correlates for clustering of NCDs risk factors among them. MATERIALS AND METHODS: All employees were invited to participate; the World Health Organization STEPwise approach was used for data collection which consisted of a personal interview to collect socio-demographic characteristics, NCD history, tobacco use, vegetables and fruit consumption, and physical activity (PA), followed by anthropometric measurements namely weight, height and waist circumference and blood pressure measurements, subjects were finally subjected to biochemical tests with determination of fasting plasma glucose, serum triglycerides, cholesterol and high density lipoproteins. RESULTS: Of the surveyed employees (n=691), daily current smokers accounted for 22.7%. 94.9%, 95.1% and 86% consumed < 5 servings per day of vegetables, fruits and both fruits and vegetables respectively, 73% were physically inactive, 64% were overweight or obese, 22.1% had hypertension, and 21.5% were diabetics. Elevated cholesterol levels were found in 36.6%, low high density lipoproteins in 36.8%, and elevated triglycerides in 36.1%. Only 3% had no NCD risk factors, and 57.6% had >=3 factors. Multivariate logistic regression showed that gender (being male, adjusted odds ratio 'aOR'=1.51), aged >= 50 years (aOR=3.06), < college education (aOR=1.75), current smokers (aOR=2.37), being obese (aOR=6.96) and having a low PA level (aOR=4.59) were the significant positive predictors for clustering of NCD risk factors. CONCLUSIONS: Over fifty percent of the studied university's employees had multiple (>=3) NCD risk factors. Screening and health promotion initiatives should be launched at least targeting the modifiable factors to avert the excessive risk for cardiovascular disease, diabetes mellitus and several types of cancers. PMID- 25292085 TI - Prognostic value of preoperative inflammation-based prognostic scores on hospital mortality after gastric cancer surgery. AB - Gastric cancer is the fourth most common malignancy worldwide. Poor prognosis in gastric cancer is linked with hypoalbuminemia. Previous studies demonstrated relationships between gastric cancer and chronic inflammation. The aim of this study was to assess the prognostic value of preoperative inflammation-based prognostic scores regarding hospital mortality after gastrectomy. Unlike other recent articles on the same topic; we could only verify prognostic value of prognostic nutritional index for in hospital mortality after surgery. PMID- 25292086 TI - Over-expression of Beclin-1 facilitates acquired resistance to histone deacetylase inhibitor-induced apoptosis. AB - Apoptotic cell death plays a predominant role in histone deacetylase (HDAC) inhibitor-induced cytotoxicity. Nuclear morphological changes and activation of apoptotic executors are involved in CTS203-induced cell death. However, emerging issues of HDAC inhibitor-resistance have been observed in patients. Herein, MCF-7 cells were continuously exposed to CTS203 until the derived cells could proliferate normally in its presence. The newly obtained CTS203-resistant cells were nominated as MCF-7/203R. Compared to MCF-7 original cells, the MCF-7/203R cells were less sensitive to CTS203-induced apoptosis, with a minimal 6-fold higher IC50 value. In contrast, the expression of Beclin-1 was dramatically up regulated, positively correlated to the acquisition of CTS203-resistance. Our results revealed the participation of autophagy in acquired HDAC inhibitor resistance and further identified Beclin-1 as a promising target for anti-drug resistance. PMID- 25292087 TI - 20(S)-Protopanaxadiol induces human breast cancer MCF-7 apoptosis through a caspase-mediated pathway. AB - 20(S)-Protopanaxadiol (PPD), a ginsenoside isolated from Pananx quinquefolium L., has been shown to inhibit growth and proliferation in several cancer cell lines. The aim of this study was to evaluate its anticancer activity in human breast cancer cells. MCF-7 cells were incubated with different concentrations of 20(S) PPD and cytotoxicity was evaluated by MTT assay. Occurrence of apoptosis was detected by DAPI and Annexin V-FITC/PI double staining. Mitochondrial membrane potential was measured with Rhodamine 123. The Bcl-2 and Bax expression were determined by Western blot analysis. Caspase activity was measured by colorimetric assay. 20(S)-PPD dose-dependently inhibited cell proliferation in MCF-7 cells, with an IC50 value of 33.3 MUM at 24h. MCF-7 cells treated with 20(S)-PPD presented typical apoptosis, as observed by morphological analysis in cell stained with DAPI. The percentages of annexin V-FITC positive cells were 8.92%, 17.8%, 24.5% and 30.5% in MCF-7 cells treated with 0, 15, 30 and 60MUM of 20(S)-PPD, respectively. Moreover, 20(S)-PPD could induce mitochondrial membrane potential loss, up-regulate Bax expression and down-regulate Bcl-2 expression. These events paralleled activation of caspase-9, -3 and PARP cleavage. Apoptosis induced by 20(S)-PPD was blocked by z-VAD-fmk, a pan-caspase inhibitor, suggesting induction of caspase-mediated apoptotic cell death. In conclusion, the 20(S)-PPD investigated is able to inhibit cell proliferation and to induce cancer cell death by a caspase-mediated apoptosis pathway. PMID- 25292088 TI - Metabolic syndrome prevalence in renal cell cancer patients. AB - PURPOSE: Renal cell carcinoma (RCC) is increasingly being recognized as a metabolic disease in recent studies. The aim of the present study was to identify the prevalence of metabolic syndrome (MetS) and its association with RCC among urologic patients. MATERIALS AND METHODS: The study included a total of 355 participants (117 adult RCC patients and 238 age matched controls) divided into groups, with and without MetS diagnosed using the criteria of the American Heart Association/The National Heart Lung and Blood Institute. Groups were compared statistically and logistic regression analysis was performed to investigate the impact of MetS criteria on RCC risk. RESULTS: Of the 117 RCC patients, 52 (44.4%) and of the 238 controls, 37 (15.5%) had MetS. A significant association (p<0.001) was found between the presence of MetS and RCC (OR: 4.35; 95% CI=2.62- 7.21). As the number of MetS components accumulated from 3 to 5, RCC risk increased likewise from 4 to 6 times. CONCLUSIONS: MetS is more prevalent in RCC patients in Turkey compared to controls. Risk increases with the number of coexisting MetS components. PMID- 25292089 TI - Proportion of ovarian cancers in overall ovarian masses in Thailand. AB - BACKGROUND: The primary objective of this study was to assess the proportion of malignancies in ovarian masses during 1st January 2002, to 31st December 2011 at the Department of Obstetrics and Gynecology, King Chulalongkorn Memorial Hospital. A secondary objective was to evaluate associations with patients' clinical characteristics and ovarian malignancy proportion and subtypes. MATERIALS AND METHODS: Retrospective descriptive study analyzed data of ovarian masses larger than 3 centimeters in maximal diameter, from the division of Gynecologic Cyto-Pathology at KCMH. SPSS software version 17 (SPSS, Inc, Chicago, IL, USA) was used. RESULTS: A total number of 6,115 patients were included. Among the total ovarian masses studied, 13.7% were malignant. After the age of sixty, the proportion reached almost 40%. It was also above 20% in women younger than 20 years old. During premenarche period, proportion of ovarian malignancies was 50%. Only 1% of ovarian masses were found to be malignant during the pregnancy and post-partum periods. Parity decreasedthe probability of ovarian malignancy during postmenopausal years. Period of menopause did not have any impact on this probability. During the first two decades of life, germ cell malignancy dominated. As the age increased, the percentage of surface epithelial-stromal malignancy increased with a peak at the fifth decade. In contrast, malignant sex cord-stromal cell tumors occurred at a constant rate in each age group after the thirties. CONCLUSIONS: Proportion of ovarian cancers in each age group, menstrual and pregnancy status are similar. However there are differences in the distribution of ovarian subtypes especially for the surface epithelial- stromal category. PMID- 25292090 TI - Turkish social attitudes towards to cancer prevention: a health belief model study. AB - This research was planned to reveal society's attitude towards cancer and early diagnosis using the health belief model. This study was planned as descriptive research in Isparta. A random sample of n=256 individuals of both genders was recruited at the largest shopping center. As a means of collection tool, a survey consisted of two forms, the first designed for sociodemographic information and the second covering 29 questions suitable for the content of Health Belief Model. Of the participants, 66.8% were female and 33.2% were male, and the average age was 33.3+/-11.0 years. Some 46.1% partly thought that they may develop cancer, and 49.6% were afraid of this possibility. As many as 50% indicated that cancer is an issue that comes from Allah. A significant difference was found between not going for control unless feeling bad, and blood analysis for cancer screening (chi2=3.780 p= 0.03). It was seen that in an area with a high rate of cancer, people's awareness of cancer prevention and early diagnosis and attitudes towards these are insufficient. PMID- 25292091 TI - Lack of association between the COMT rs4680 polymorphism and ovarian cancer risk: evidence from a meta-analysis of 3,940 individuals. AB - Catechol-O-methyltransferase (COMT) is involved in estrogen metabolism and is vital to estrogen-induced carcinogenesis, including that of ovarian cancer. Although many recent epidemiologic studies have investigated associations between the COMT rs4680 polymorphism and ovarian cancer risk, the results remain inconclusive. We therefore performed a meta-analysis to derive a more precise estimate of associations. Systematic searches of the PubMed, Embase, Web of Science, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and Chinese Biomedicine databases were undertaken to retrieve eligible studies. Odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were pooled to assess the strength of the association. In total, 8 case-control studies involving 1,293 cases and 2,647 controls were included in the meta-analysis. Overall, the results showed no evidence of significant association between the COMT rs4680 polymorphism and ovarian cancer risk in any of the assessed genetic models. Subgroup analyses by ethnicity also did not reveal any significant association in any genetic model (p>0.05). In conclusion, our findings suggest that the COMT rs4680 polymorphism may not contribute to the risk of ovarian cancer. PMID- 25292092 TI - Dietary factors and risk of pancreatic cancer: a multi-centre case-control study in China. AB - BACKGROUND: Pancreatic cancer is the sixth leading cause of cancer death with an increasing trend in China. Dietary intake is believed to play an important role in pancreatic cancer carcinogenesis. The aim of this paper was to evaluate associations between some dietary factors and risk of pancreatic cancer in a multi-centre case-control study conducted in China. MATERIALS AND METHODS: Cases (n=323) were ascertained from four provincial cancer hospitals. Controls (n=323) were randomly selected from the family members of patients without pancreatic cancer in the same hospitals, 1:1 matched to cases by gender, age and study center. Data were collected with a questionnaire by personal interview. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression. RESULTS: Tea intake (OR =0.49; 95%CI: 0.30-0.80) was associated with a half reduction in risk of pancreatic cancer. Reduced vegetable consumption (P trend: 0.04) was significant related to pancreatic cancer. Although no significant association was found for meat and fruit, ORs were all above or below the reference group. A protective effect was found for fruit (OR=1.73 for consumption of 1-2 times/week vs more than 3 times/week; 95%CI: 1.05 2.86). A high intake of meat was associated to a higher risk of pancreatic cancer (OR=0.59 for consumption of 1-2 times /week vs. more than 3 times /week; 95%CI: 0.35-0.97). CONCLUSIONS: The present study supports fruit consumption to reduce pancreatic cancer risk and indicates that high consumption of meat is related to an elevated risk. Direct inverse relations with tea and vegetable intake were also confirmed. PMID- 25292093 TI - Cervical pathology in cytology-negative/HPV-positive women: results from Lampang Cancer Hospital, Thailand. AB - BACKGROUND: To evaluate the cervical pathology of cytology-negative/high-risk human papillomavirus (HR-HPV) positive-women. MATERIALS AND METHODS: This study recruited 4,583 women aged 30-70 years who had undergone cervical screening by liquid-based cytology and HR-HPV test (14 HR-HPV types) at Lampang Cancer Hospital during October 2012 to July 2013. Colposcopy was carried out in all women. RESULTS: One hundred and ninety-two (4.19%) women were found to be cytology-negative/HR-HPV-positive. However, 23 cases were excluded because of incomplete information, leaving 169 women for further analyses. Of these 169, 45 (26.6%) were infected with HPV 16/18 and 49 (29.0%) with multiple genotypes of HR HPV. Nineteen of 169 (11.24%) women were found to have CIN 2-3. No women in the present study had AIS or invasive cervical lesions. Prevalence of CIN 2-3 among women infected with HPV 16/18 was 15.6% which was higher than the 9.68% in those with non-HPV 16/18 oncogenic types. CONCLUSIONS: Overall, 11% of cytology negative/HR-HPV-positive women had significant cervical lesions. Risk of harboring such lesions was substantially increased among those who were HPV 16/18 positive. PMID- 25292094 TI - Association of rs1219648 in FGFR2 and rs1042522 in TP53 with premenopausal breast cancer in an Iranian Azeri population. AB - Breast cancer is the most common cancer among women in the world. In Iran, the incidence of breast cancer is on the increase. We here studied the association of rs1219648 in FGFR2 and rs1042522 in TP53 and their interaction in development of early onset sporadic breast cancer in Iranian Azeri population to evaluate epistatic effects on the risk of mammary neoplasia. We genotyped the two polymorphisms in 100 women with early onset breast cancer and 100 healthy women by PCR-RFLP. Allele frequency differences were tested using chi2-test with 95% confident intervals. Our results indicated a statistically significant association (p<0.05) between rs1219648, but not rs1042522, and risk of breast cancer. We also found that the combination of FGFR2 major genotype and TP53 hetero genotype had protective effects against breast cancer , while the hetero allele of FGFR2 in combination with the minor genotype of TP53 was associated with a high risk. This study revealed an important crosstalk between two polymorphisms in FGFR2 and TP53 in development of breast cancer. These candidates risk variants should be further evaluated in studies with a larger sample size. PMID- 25292095 TI - Do clinical features and survival of single hormone receptor positive breast cancers differ from double hormone receptor positive breast cancers? AB - The significance of the single hormone receptor positive phenotype of breast cancer is still poorly understood. The use of hormone therapy has been found to be less effective for this type, which has a survival outcome midway between double positive and double negative phenotypes. The aim of this study was to investigate differences in patient and tumor characteristics and survival between double-receptor positive (ER+PR+), double receptor negative (ER-PR-) and single receptor positive (ER+PR- and ER-PR+) breast cancer in an Asian setting. A total of 1,992 patients with newly diagnosed stage I to IV breast cancer between 2003 and 2008, and where information on ER and PR were available, were included in this study. The majority of patients had ER+PR+ tumors (n=903: 45.3%), followed by 741 (37.2%) ER-PR-, 247 (12.4%) ER+PR-, and 101 (5.1%) ER-PR+ tumors. Using multivariate analysis, ER+PR- tumors were 2.4 times more likely to be grade 3 compared to ER+PR+ tumors. ER+PR- and ER-PR+ tumors were 82% and 86% respectively less likely to be grade 3 compared with ER-PR- tumors. ER-PR+ tumours were associated with younger age. There were no survival differences between patients with ER+PR+ and ER-PR+ tumors. However, ER+PR- tumors have poorer survival compared with ER+PR+ tumours. ER-PR- tumours had the worst survival. Adjuvant hormonal therapy with tamoxifen was found to have identical survival advantage in patients with ER+PR+ and ER-PR+ tumors whereas impact was slightly lower in patients with ER+PR- tumors. In conclusion, we found ER+PR- tumors to be more aggressive and have poorer survival when compared to ER+PR+ tumors, while patients with ER-PR+ tumours were younger, but had a similar survival to their counterparts with ER+PR+ tumours. PMID- 25292096 TI - Impact of IL-2 and IL-2R SNPs on proliferation and tumor- killing activity of lymphokine-activated killer cells from healthy chinese blood donors. AB - One of the goals of tumor immunotherapy is to generate immune cells with potent anti-tumor activity through in vitro techniques using peripheral blood collected from patients. However, cancer patients generally have poor immunological function. Thus using patient T cells, which have reduced in vitro proliferative capabilities and less tumor cell killing activity to generate lymphokine activated killer (LAK) cells, fails to achieve optimal clinical efficacy. Interleukin-2 (IL-2) is a potent activating cytokine for both T cells and natural killer cells. Thus, this study aimed to identify optimal donors for allogeneic LAK cell immunotherapy based on single nucleotide polymorphisms (SNP) in the IL-2 and IL-2R genes. IL-2 and IL-2R SNPs were analyzed using HRM- PCR. LAK cells were derived from peripheral blood mononuclear cells by culturing with IL-2. The frequency and tumor-killing activity of LAK cells in each group were analyzed by flow cytometry and tumor cell killing assays, respectively. Regarding polymorphisms at IL-2-330 (rs2069762) T/G, LAK cells from GG donors had significantly greater proliferation, tumor-killing activity, and IFN-gamma production than LAK cells from TT donors (P<0.05). Regarding polymorphisms at IL 2R rs2104286 A/G, LAK cell proliferation and tumor cell killing were significantly greater in LAK cells from AA donors than GG donors (P<0.05). These data suggest that either IL- 2-330(rs2069762)T/G GG donors or IL-2R rs2104286 A/G AA donors are excellent candidates for allogeneic LAK cell immunotherapy. PMID- 25292097 TI - CCNA1 promoter methylation: a potential marker for grading Papanicolaou smear cervical squamous intraepithelial lesions. AB - BACKGROUND: From our previous study, we established that cyclin A1 (CCNA1) promoter methylation is strongly correlated with multistep progression of HPV associated cervical cancer, suggesting potential use as a diagnostic maker of disease. OBJECTIVES: The purpose of the present study was to assess the prevalence of CCNA1 promoter methylation in residual cervical cells isolated from liquid-based cytology that underwent hrHPV DNA screening for cervical cancer, and then to evaluate this marker for diagnostic accuracy using parameters like sensitivity, specificity, predictive values and likelihood ratio. METHODS: In this retrospective study, histopathology was used as the gold standard method with specimens separated into the following groups: negative (n=31), low- grade squamous intraepithelial lesions (LSIL, n=34) and high-grade squamous intraepithelial lesions or worse (HSIL+, n=32). The hrHPV was detected by Hybrid Capture 2 (HC2) and CCNA1 promoter methylation was examined by CCNA1 duplex methylation specific PCR. RESULTS: The results showed the frequencies of CCNA1 promoter methylation were 0%, 5.88% and 83.33%, while the percentages of hrHPV were 66.67%, 82.35% and 100% in the negative, LSIL and HSIL+ groups, respectively. Although hrHPV infection showed high frequency in all three groups, it could not differentiate between the different groups and grades of precancerous lesions. In contrast, CCNA1 promoter methylation clearly distinguished between negative/LSIL and HSIL+, with high levels of all statistic parameters. CONCLUSION: CCNA1 promoter methylation is a potential marker for distinguishing between histologic negative/LSIL and HSIL+using cervical cytology samples. PMID- 25292098 TI - Cervical pathology in high-risk human papillomavirus- positive, cytologically normal women. AB - This study was undertaken to evaluate the prevalence of significant cervical pathology among women who are high-risk human papillomavirus (HR-HPV) positive/cytology negative, the most common combination of positive co-tests. The records of 244 women HR-HPV-positive/cytology-negative who had undergone colposcopy at Srinagarind Hospital, Khon Kaen University during January 2010 and April 2014 were reviewed. Mean age was 46.4 years. Of these 224 women, 75 were positive for HPV types 16/18 (33.5%) and 123 were positive for non-16/18 types (54.9%). HR-HPV was not genotyped in the remaining 26 women (11.6%). Prevalence of significant lesions for the entire cohort was 2.4%, and 2.6% and 3.3%, respectively, for those with HPV 16/18 and other oncogenic HPV types. One woman with HPV 16/18 (1.3%) had invasive cervical cancer. Multiparous women were more likely to be infected with HPV 16/18 compared to nulliparous women (36.3% versus 17.6%, respectively). In conclusion, the prevalence of significant cervical lesion among our study population was 2.4%. Multiparous women were more likely to be infected with HPV 16/18 compared to nulliparous women. PMID- 25292099 TI - Accuracy of self-checked fecal occult blood testing for colorectal cancer in Thai patients. AB - PURPOSE: Colorectal cancer (CRC) screening with fecal occult blood testing (FOBT) has been associated with a reduction in CRC incidence and CRC-related mortality. However, a conventional FOBT requires stool collection and handling, which may be inconvenient for participants. The EZ-DetectTM (Siam Pharmaceutical Thailand) is a FDA-approved chromogen-substrate based FOBT which is basically a self-checked FOBT (no stool handling required). This study aimed to evaluate the accuracy of EZ-Detect for CRC detection. METHODS: This prospective study was conducted in the Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand between November 2013 and May 2014. Some 96 patients with histologically-proven CRC and 101 patients with normal colonoscopic findings were invited to perform self-checked FOBT according to the manufacturer's instructions. RESULTS were compared with endoscopic and pathologic findings. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for CRC detection were calculated. RESULTS: The present study revealed the sensitivity, specificity, PPV and NPV of this self-checked FOBT for CRC detection to be 41% (95% CI: 31-51), 97% (95% CI: 92-99), 93% (95% CI: 81-98) and 63% (95% CI: 55-70), respectively. The overall accuracy of the self-checked FOBT for identifying CRC was 70%. The sensitivity for CRC detection based on 7th AJCC staging was 29% for stage I, 32% for stage II and 50% for stage III/IV (P=0.19). The sensitivity was 33% for proximal colon and 42% for distal colon and rectal cancer (P=0.76). Notably, none of nine infiltrative lesions gave a positive FOBT. CONCLUSIONS: The self-checked FOBT had an acceptable accuracy of CRC detection except for infiltrative tumors. This home-administrated or 'DIY' do-it-yourself FOBT could be considered as one non-invasive and convenient tool for CRC screening. PMID- 25292100 TI - Data quality of childhood cancer in Khon Kaen, Thailand, 1990-2007. AB - INTRODUCTION: Khon Kaen Cancer Registry (KKCR) was established in 1984. KKCR aims to collect all cancer cases in Khon Kaen Province. The poorly qualified data may lead to distort the cancer burden and misinterpretation of policy maker. OBJECTIVE: To assess data quality in childhood cancer between 1990 and 2007 in Khon Kaen Province, Thailand. MATERIALS AND METHODS: Data of childhood cancer cases aged less than 20 years diagnosed during 1990-2007 were retrieved from the population-based data set of KKCR. All childhood cancer data were verified before data entry. Internal consistency, percentage of morphological verification (MV%) and cancer cased of the basis of diagnosis by death certificate only (DCO%) were evaluated. The age-adjusted rate (ASR) was calculated by standard method. RESULTS: The data of childhood cancer from KKCR is acceptably qualified which reflects the quality of the whole registration. PMID- 25292101 TI - Childhood cancer incidence and survival 1985-2009, Khon Kaen, Thailand. AB - BACKGROUND: The Khon Kaen Cancer Registry (KKCR) was established in 1984. Previous population-based incidences and survivals of childhood cancer in Thailand were determined using a short cancer registration period. MATERIALS AND METHODS: Data were retrieved of all children residing in Khon Kaen, between 0-15 years, diagnosed as having cancer and registered in the KKCR (1985-2009). The follow-up censored date was December 31, 2012. The childhood cancers were classified into 12 diagnostic groups, according to the International Classification of Childhood Cancer. The incidence was calculated by the standard method. Survival of childhood cancer was investigated using the KKCR population based registration data and overall survival calculated using the Kaplan Meier method. RESULTS: In the study period, 912 newly diagnosed cases of childhood cancer were registered. The respective mean and median age was 6.4 (SD=4.6) and 6 (0-14) years. The age-peak for incidence was 0-4 years. The age-standardized rate (ASR) was 83 per million. Leukemia was the most common cancer (N=360, ASR 33.8) followed by neoplasms of the central nervous system (CNS, N=150, ASR 12.8) and lymphoma (N=79, ASR 7.0). The follow-up duration totaled 101,250 months. The death rate was 1.11 per 100 person-months (95%CI: 1.02 -1.20). The 5-year overall survival was 52% (95%CI: 53-56.9) for all cancers. The respective 5-year overall survival for (1) acute lymphoblastic leukemia (ALL), (2) acute non-lymphoblastic leukemia (ANLL), (3) lymphoma, (4) germ cell tumors, (5) renal tumors, (6) retinoblastoma, (7) soft tissue tumors, (8) CNS tumors, (9) bone tumors, (10) liver tumors, and (11) neuroblastoma was (1) 51%, (2) 37%, (3) 63%, (4) 74%, (5) 67%, (6) 55%, (7) 46%, (8) 44%, (9) 36%, (10) 34%, and (11) 25%. CONCLUSIONS: The incidence of childhood cancer is lower than those of western countries. Respective overall survival for ALL, lymphoma, renal tumors, liver tumors, retinoblastoma, soft tissue tumors is lower than that reported in developed countries while survival for CNS tumors, neuroblastoma and germ cell tumors is comparable. PMID- 25292102 TI - Induction of indoleamine 2,3-dioxygenase (IDO) enzymatic activity contributes to interferon-gamma induced apoptosis and death receptor 5 expression in human non small cell lung cancer cells. AB - Interferon-gamma (IFN-gamma) has been used to treat various malignant tumors. However, the molecular mechanisms underlying the direct anti-proliferative activity of IFN-gamma are poorly understood. In the present study, we examined the in vitro antitumor activity of IFN-gamma on two human non-small-cell lung carcinoma (NSCLC) cell lines, H322M and H226. Our findings indicated that IFN gamma treatment caused a time-dependent reduction in cell viability and induced apoptosis through a FADD-mediated caspase-8/tBid/mitochondria-dependent pathway in both cell lines. Notably, we also postulated that IFN-gamma increased indoleamine 2,3-dioxygenase (IDO) expression and enzymatic activity in H322M and H226 cells. In addition, inhibition of IDO activity by the IDO inhibitor 1-MT or tryptophan significantly reduced IFN-gamma-induced apoptosis and death receptor 5 (DR5) expression, which suggests that IDO enzymatic activity plays an important role in the anti-NSCLC cancer effect of IFN-gamma. These results provide new mechanistic insights into interferon-gamma antitumor activity and further support IFN-gamma as a potential therapeutic adjuvant for the treatment of NCSLC. PMID- 25292103 TI - Is MPV a real prognostic indicator for non-small cell lung cancer? PMID- 25292104 TI - Is waterpipe smoking becoming increasingly widespread among the youth? PMID- 25292105 TI - Morphometric analysis of the peroneal tubercle using a three-dimensional computed tomography model. AB - BACKGROUND: The peroneal tubercle is a small bony ridge located on the lateral wall on the calcaneus immediately inferior to the lateral malleolus and separates the peroneus brevis and peroneus longus tendons. The size and configuration of the peroneal tubercle has been implicated in the pathogenesis of peroneal tendon tears and tenosynovitis and is the increasing object of clinical interest. However, the morphology of the tubercle is difficult to assess with precision. METHODS: We utilized a new method to evaluate the three-dimensional (3D) geometry of 46 calcanei from 34 consecutive patients; average patient age was 48.0 years who underwent lower extremity computed tomography (CT) for clinical treatment of non-peroneal tubercle-related conditions. The 3D geometries of calcanei were reconstructed by using the computer software to calculate the surface 3D models. To measure the size of the peroneal tubercle, we virtually excised it from the 3D calcaneus model and made a precise measurement of the height. RESULTS: Peroneal tubercles with measured heights of 1mm or more were detected in 65% of the feet, with an average tubercle height of 2.59mm. Peroneal tubercles were larger and more frequent in middle-aged or older than younger patients. PMID- 25292106 TI - Visible-light-responsive multielectron redox catalysis of lacunary polyoxometalates induced by substrate coordination to their lacuna. AB - We describe herein the efficient visible-light-responsive polyoxometalate-based multielectron photoredox catalysis induced by in situ coordination of alcohols to the lacuna of TBA4 H4 [gamma-SiW10 O36 ] (I, TBA=tetra-n-butylammonium). The coordination of alcohols to the lacuna of I generated a new highest occupied molecular orbital as the electron donor level and enabled the visible-light responsive multielectron transfer from alcohols to I, which could be utilized for aerobic alcohol oxidation and one-pot synthesis of N-arylimines starting from nitroarenes and primary alcohols. PMID- 25292107 TI - Concurrent Bartonella henselae infection in a dog with panniculitis and owner with ulcerated nodular skin lesions. AB - BACKGROUND: Bartonella henselae, a Gram-negative, zoonotic Alphaproteobacteria that infects erythrocytes, endothelial cells and dendritic cells, has previously been implicated as a cause of panniculitis in dogs and a human. ANIMAL AND OWNER: An 8-year-old, spayed female Labrador retriever and its 78-year-old male owner living in the same household. METHODS AND RESULTS: When preliminary and advanced testing failed to identify the cause of near-simultaneous-onset dermatological lesions, Bartonella serology, Bartonella Alphaproteobacteria growth medium (BAPGM) enrichment blood culture/PCR and immunohistochemistry were used to test specimens from the dog and owner. Bartonella henselae, genotype San Antonio 2 DNA was amplified and sequenced from the man's BAPGM enrichment blood culture and the dog's panniculitis lesion. The bacterium was visualized by immunohistochemistry in the dog's panniculitis lesion; however, neither the dog nor the owner was B. henselae seroreactive. Antibiotic therapy elicited dermatological improvement in both dog and owner. CONCLUSIONS AND CLINICAL IMPORTANCE: Bartonella henselae is an emerging zoonotic pathogen that induces granulomatous inflammatory lesions in various tissues of animals, including humans. We conclude that this bacterium had a contributory or causative role in the development of the dermatological lesions in the dog and owner. PMID- 25292109 TI - Changes in pig production in China and their effects on nitrogen and phosphorus use and losses. AB - China's pig production has increased manifold in the past 50 years, and this has greatly affected the nitrogen and phosphorus use and losses in the pig production sector. However, the magnitude of these changes are not well-known. Here, we provide an in-depth account of the changes in pig production--N and P use and total N and P losses in the whole pig production chain during the period 1960 2010--through simulation modeling and using data from national statistics and farm surveys. For the period of 2010-2030, we explored possible effects of technological and managerial measures aimed at improving the performances of pig production via scenario analysis. We used and further developed the NUtrient flows in Food chains, Environment and Resources use (NUFER) model to calculate the feed requirement and consumption, and N and P losses in different pig production systems for all the years. Between 1960 and 2010, pig production has largely shifted from the so-called backyard system to landless systems. The N use efficiencies at fattener level increased from 18 to 28%, due to the increased animal productivity. However, the N use efficiencies at the whole-system level decreased from 46 to 11% during this period, mainly due to the increase of landless pig farms, which rely on imported feed and have no land-base for manure disposal. The total N and P losses were 5289 and 829 Gg in 2010, which is 30 and 95 times higher than in 1960. In the business as usual scenario, the total N and P losses were projected to increase by 25 and 55% between 2010 and 2030, respectively. Analyses of other scenarios indicate that packages of technological and managerial measures can decrease total N and P losses by 64 and 95%, respectively. Such improvements require major transition in the pig production sector, notably, in manure management, herd management, and feeding practices. PMID- 25292110 TI - Screening for anthrax occurrence in soil of flooded rural areas in Poland after rainfalls in spring 2010. AB - INTRODUCTION AND OBJECTIVE: Anthrax spores remain viable and infectious in soil for decades. Flood water can percolate towards the surface the spores buried in soil. Moreover, the flood water might transport spores to areas previously unaffected. After the water recedes the spores located on the surface of the ground can be consumed by grazing animals and cause outbreaks of anthrax. MATERIALS AND METHOD: Soil samples were collected in areas of Poland most affected by floods in 2010 (Lubelskie, Swietokrzyskie, Podkarpackie and Mazowieckie provinces). After heating with the aim to kill vegetative forms of bacteria, the samples were cultured on PLET agar and the resulted colonies were investigated in terms of motility and presence of anthrax specific chromosomal (SG-749, plcR) and plasmid markers (capB, pagA). RESULTS: In total, 424 spore forming, aerobically growing isolates were collected from the tested soil samples. Eighty-nine of them were non-motile. All the isolates were negative in PCR for anthrax specific chromosomal and plasmid markers. CONCLUSIONS: Spores of B. anthracis that could be related to risk of anthrax outbreaks were not detected in soil samples tested in this study. The negative results presented may not be proof that Poland is country free of anthrax. The results, however, may suggest a relatively low risk of anthrax outbreaks being triggered in the sampled areas. PMID- 25292111 TI - Airborne virus sampling: Efficiencies of samplers and their detection limits for infectious bursal disease virus (IBDV). AB - INTRODUCTION: The airborne transmission of infectious diseases in livestock production is increasingly receiving research attention. Reliable techniques of air sampling are crucial to underpin the findings of such studies. This study evaluated the physical and biological efficiencies and detection limits of four samplers (Andersen 6-stage impactor, all-glass impinger "AGI-30", OMNI-3000 and MD8 with gelatin filter) for collecting aerosols of infectious bursal disease virus (IBDV). MATERIALS AND METHOD: IBDV aerosols mixed with a physical tracer (uranine) were generated in an isolator, and then collected by the bioaerosol samplers. Samplers' physical and biological efficiencies were derived based on the tracer concentration and the virus/tracer ratio, respectively. Detection limits for the samplers were estimated with the obtained efficiency data. RESULTS: Physical efficiencies of the AGI-30 (96%) and the MD8 (100%) were significantly higher than that of the OMNI-3000 (60%). Biological efficiency of the OMNI-3000 (23%) was significantly lower than 100% (P < 0.01), indicating inactivation of airborne virus during sampling. The AGI-30, the Andersen impactor and the MD8 did not significantly inactivate virus during sampling. The 2-min detection limits of the samplers on airborne IBDV were 4.1 log10 50% egg infective dose (EID50) m (-3) for the Andersen impactor, 3.3 log10 EID50 m (-3) for the AGI-30, 2.5 log10 EID50 m (-3) for the OMNI-3000, and 2.9 log10 EID50 m ( 3) for the MD8. The mean half-life of IBDV aerosolized at 20 degrees C and 70% was 11.9 min. CONCLUSION: Efficiencies of different samplers vary. Despite its relatively low sampling efficiency, the OMNI-3000 is suitable for use in environments with low viral concentrations because its high flow rate gives a low detection limit. With the 4 samplers investigated, negative air samples cannot guarantee virus-free aerial environments, which means that transmission of infectious agents between farms may still occur even when no virus has been detected. PMID- 25292112 TI - Exposure levels of farmers and veterinarians to particulate matter and gases during operational tasks in pig-fattening houses. AB - The main objective of the study was to assess particulate matter (PM) exposure levels for both the farmer and the veterinarian during different operational tasks in pig-fattening houses, and to estimate their exposure levels on a daily working basis (time-weighted average (TWA)). The measured PM fractions were: inhalable and respirable PM, PM10, PM2.5 and PM1. The effects of pig age, pen floor type (conventional or low emission surface) and cleaning of the pens on the personal PM exposure were also investigated. Indoor concentrations of NH3, CH4, and CO2 were additionally measured during some operational tasks. The results showed that personal exposure levels can become extremely high during some operational tasks performed by the farmer or veterinarian. The highest concentration levels were observed during feed shovelling and blood sampling, the lowest during the weighing of the pigs. For the farmer, the estimated TWA exposure levels of inhalable and respirable PM were 6.0 and 0.29 mg m(-3), respectively. These exposure levels for the veterinarian were, respectively, 10.6 and 0.74 mg m(-3). The PM concentration levels were mainly determined by the performed operational tasks. There was no significant effect of pig age, pen floor type, nor cleaning of the pens on the personal exposure levels. PMID- 25292113 TI - Short term exposure to low amounts of airway irritants in a swine confinement building and inflammatory markers in blood and exhaled air. AB - INTRODUCTION AND OBJECTIVE: Swine confinement buildings are known to contain large concentrations of airway irritants, and a number of studies have shown acute inflammatory effects in previously unexposed subjects when introduced to the environment in such buildings. However, studies comparing different methods of assessing such reactions are lacking, and it is not known if a measurable response could be found at lower exposure rates. The purpose of this study was to investigate exposure levels in a Norwegian swine confinement building, the airway response to such exposure, and to compare invasive and non-invasive methods of response measurement. MATERIALS AND METHOD: Twelve medical students who were previously unexposed to swine dust stayed in a swine confinement building in Norway for 4 hours, and underwent measurements before and after the start of exposure. The same measurements were also performed beforehand, on the same weekday without exposure, in such a manner that the subjects were their own controls. RESULTS: The exposure assessment showed considerably lower concentrations of organic dust and endotoxin than earlier studies. However, small, but significant increases in markers of airway inflammation, were found. CONCLUSIONS: Airway response can be measured after lower exposure to airborne irritants in swine confinement buildings than previously known. Further research is needed to assess whether this finding can be utilized for preventive purposes. PMID- 25292114 TI - Viability of Clostridium sporogenes spores after CaO hygienization of meat waste. AB - The occurrence of the pathogenic species C. perfringens and C. botulinum spores in animal by-products poses a potential epidemiological hazard. Strong entero- and neurotoxins produced by these bacteria adversely affect human health. To inactivate pathogens present in animal by-products, waste must be subjected to various methods of sanitization. The aim of the presented study was to estimate the effect of different doses of CaO on the viability of spores Clostridium sporogenes in meat wastes category 3. During the research, two doses of burnt lime were added to the poultry mince meat and meat mixed with swine blood contaminated with Clostridium sporogenes spore suspension. Half of the samples collected for microbiological analyses were buffered to achieve the pH level ~7, the other were examined without pH neutralization. To estimate the spore number, 10-fold dilution series in peptone water was prepared and heat-treated at 80 degrees C for 10 min. After cooling-down, one milliliter of each dilution was pour-plated onto DRCM medium solidified with agar. Statistical analysis were performed using the Statistica software. Application of 70% CaO caused complete inactivation of Clostridium spores in meat wastes after 48 hours. The highest temperature achieved during the experiment was 67 degrees C. Rapid alkalization of the biomass resulted in increasing pH to values exceeding 12. The effect of liming was not dependent on the meat wastes composition nor CaO dose. The experiment proved the efficiency of liming as a method of animal by-products sanitization. Application of the obtained results may help reduce the epidemiological risk and ensure safety to people handling meat wastes at each stage of their processing and utilization. PMID- 25292108 TI - The impact of triathlon training and racing on athletes' general health. AB - Although the sport of triathlon provides an opportunity to research the effect of multi-disciplinary exercise on health across the lifespan, much remains to be done. The literature has failed to consistently or adequately report subject age group, sex, ability level, and/or event-distance specialization. The demands of training and racing are relatively unquantified. Multiple definitions and reporting methods for injury and illness have been implemented. In general, risk factors for maladaptation have not been well-described. The data thus far collected indicate that the sport of triathlon is relatively safe for the well prepared, well-supplied athlete. Most injuries 'causing cessation or reduction of training or seeking of medical aid' are not serious. However, as the extent to which they recur may be high and is undocumented, injury outcome is unclear. The sudden death rate for competition is 1.5 (0.9-2.5) [mostly swim-related] occurrences for every 100,000 participations. The sudden death rate is unknown for training, although stroke risk may be increased, in the long-term, in genetically susceptible athletes. During heavy training and up to 5 days post competition, host protection against pathogens may also be compromised. The incidence of illness seems low, but its outcome is unclear. More prospective investigation of the immunological, oxidative stress-related and cardiovascular effects of triathlon training and competition is warranted. Training diaries may prove to be a promising method of monitoring negative adaptation and its potential risk factors. More longitudinal, medical-tent-based studies of the aetiology and treatment demands of race-related injury and illness are needed. PMID- 25292115 TI - Legionella spp., amoebae and not-fermenting Gram negative bacteria in an Italian university hospital water system. AB - INTRODUCTION: In hospital and other health care facilities, contamination of water systems by potentially infectious microorganisms, such as bacteria, viruses and protozoa, is a source of nosocomial infections, which may originate fromcolonization of water pipes, cooling towers, spa pools, taps, showers and water supplies. Objective. The study focuses on the occurrence of Legionella spp., free-living amoebae and non-fermenting Gram-negative microorganisms in a University hospital water system located in the town of Messina (Sicily, Italy), which had never been examined previously. MATERIALS AND METHODS: From January 2008 - March 2009, hot tap water samples were collected from 10 wards. Legionella spp. recovered on selective culture medium were identified by microagglutination latex test; free-living amoebae were cultured using Escherichia coli as a food source. Non-fermenting Gram negative microorganisms were identified by API 20 NE strips. RESULTS: Legionella spp. were found in 33.33% of the samples. L. pneumophila serogroup 1 was recovered from the Laboratory Diagnostic and Anaesthesia-Neurology Wards, with a peak of 3.5 * 10(4) cfu/L in May 2008. L. pneumophila serogroups 2-14 were found in the Othorhinolaryngology, Pathologic Anatomy, Paediatrics and Surgery Wards, and peaked (4 * 10(4) cfu/L) in April 2008. Pseudomonadaceae and Hyphomycetes were also detected. Legionella spp. were recovered from samples positive for non-pathogenic amoebae Hartmannella spp. CONCLUSION: This first study of a Messina hospital water system suggested potential health risks related to the detection of Hartmannella spp., as reservoirs for Legionella spp., and Pseudomonas aeruginosa, a Gram negative non fermenting bacterium frequently causing nosocomial pneumonia. The urgent need for monitoring programmes and prevention measures to ensure hospital water safety is stressed. PMID- 25292116 TI - Effects of disinfectant fogging procedure on dust, ammonia concentration, aerobic bacteria and fungal spores in a farrowing-weaning room. AB - INTRODUCTION AND OBJECTIVE: In the last decades, large-scale swine production has led to intensive rearing systems in which air quality can be easily degraded by aerial contaminants that can pose a health risk to the pigs and farm workers. This study evaluated the effects of fogging disinfectant procedure on productive performance, ammonia and dust concentration, aerobic bacteria and fungal spores spreading in the farrowing-weaning room. MATERIALS AND METHOD: This trial was conducted in 2 identical farrowing-weaning rooms of a piggery. In both rooms, 30 pregnant sows were lodged in individual cages. At 75 days of age, the piglets were moved to the fattening room. In the treated room, with the birth of the first suckling-pig, the fogging disinfection with diluted Virkon S was applied once a day in the experimental room per 15 minutes at 11:00. The fogging disinfectant treatment was switched between rooms at the end of the first trial period. Temperature, relative humidity, dust (TSP-RF fractions and number of particles), ammonia concentration and aerial contaminants (enterococci, Micrococcaeae and fungal spores) were monitored in both rooms. RESULTS: Ammonia concentration reduction induced by fogging disinfection was estimated 18%, total suspended particles and the respirable fraction were significantly lower in the experimental room. Fungal spores resulted in a significant reduction by the fogging procedure, together with dust respirable fraction and fine particulate matter abatement. CONCLUSIONS: The fogging disinfection procedure improved air quality in the piggery, thereby enhancing workers and animals health. PMID- 25292117 TI - The first evidence for vertical transmission of Babesia canis in a litter of Central Asian Shepherd dogs. AB - INTRODUCTION AND OBJECTIVE: Tick-borne infections constitute an increasing health problem in dogs and may lead to death, especially in young or elderly individuals. Canine babesiosis constitutes a serious health problem in dogs worldwide. The aim of the study was to verify the probability of vertical transmission of Babesia canis between the bitch and the pups. MATERIALS AND METHODS: In Autumn 2011, cases of babesiosis were diagnosed in a litter of 6-week old puppies of a Central Asian Shepherd dog. Immediately following the first case of infection, blood samples were collected from all the pups in the litter (n=10) and from the female. Detection of Babesia infection was performed by molecular and microscopical techniques. RESULTS: The presence of B. canis DNA was detected using PCR in three pups, presenting at the time or 24-48 hours later with babesiosis symptoms, and in their asymptomatic mother. The isolates derived from the pups and the female - 520 bp 18S rRNA gene fragment - were compared and analyzed. All isolates from the pups and their mother were identical and showed 100% homology with B. canis group B (EU622793), supporting the same source of infection. Additionally, the USG of the peritoneal cavity was performed in the female, presenting evidence for splenomegaly. CONCLUSIONS: On the basis of (1) the same timing of three pup cases; (2) the identical B. canis sequences derived from all positive dogs; (3) evident splenomegaly in the asymptomatic female, this provides the first evidence of the vertical transmission of this piroplasm in dogs. PMID- 25292118 TI - Contamination of wheat grain with microscopic fungi and their metabolites in Poland in 2006-2009. AB - Microscopic fungi are microorganisms commonly found in cereal products. Pathogens of cereals colonising kernels are responsible, among other things, for deterioration of the technological value of grain. However, the greatest threat is posed by mycotoxins produced by toxin-forming strains of these microorganisms. The aim of the present study was to determine the level of contamination with microscopic fungi and mycotoxins from the group of trichothecenes in wheat grain from Poland in a 4-year cycle. In the period 2006-2009, studies were conducted on the content of fungal metabolites (ergosterol [ERG] and type A and B trichothecenes) and the content of microscopic fungi expressed in colony-forming units (CFU) in wheat grain. A total of 129 grain samples were examined. Analysed wheat samples had similar contents of both the investigated fungal metabolites and levels of microscopic fungi. Contents of microscopic fungi were low. Concentration of ERG, on average, was 2.64 mg/kg, while in colony forming units this value ranged from 10(1) CFU/g to over 10(3) CFU/g. The total concentration of type A and B trichothecenes was also low and within the 4 years of the investigation did not exceed 0.062 mg/kg. Concentration of DON did not exceed 1,250 ug/kg, established as safe in grain for human consumption, in any of the tested samples. For the results collected in the years 2006-2009 and presented in this paper, correlations were calculated between the amount of mycoflora and analysed metabolites in 3 possible combinations: 0.7096 for ERG/total toxin concentration, 0.6086 for ERG/log CFU/g, and 0.4016 for the concentration of total toxins/log CFU/g. Highly significant correlations between the content of trichothecenes and the concentration of ERG indicate that the level of this metabolite is closely related to the content of mycotoxins in grain. PMID- 25292119 TI - Analysis of a child infected with Hymenolepis diminuta in Poland. AB - Hymenolepis diminuta is a cosmopolitan parasite of rats and mice which is very rare in humans. This study presents the case of a 3-year-old boy infected with Hymenolepis diminuta in Poland. The diagnosis was based on eggs found and their morphology in the patient's stool. PMID- 25292120 TI - Exposure to ticks and seroprevalence of Borrelia burgdorferi among a healthy young population living in the area of southern Podlasie, Poland. AB - OBJECTIVES: The objective of the study was assessment of risk of infection with Borrelia burgdorferi in the area of southern Podlasie in Poland, near the border with Belarus, by analysis of post-exposure procedure, and evaluation of asymptomatic infection in adolescents bitten by a tick, confirmed by serologic tests. MATERIAL AND METHODS: The study was conducted among 128 healthy individuals aged 16-20 who declared being bitten by a tick. The level of IgM and IgG class antibodies was determined using the immunoenzymatic test (Borrelia 14 kD + OspC IgM ELISA and Borrelia IgG + VlsE ELISA, DRG Diagnostics). Positive and doubtful results were confirmed using the Western blot method (EUROLINE-WB, EUROIMMUN). RESULTS: In the study group, the largest number of respondents (59.4%) declared tick bite in the region of the lower extremities, most often in the knee pit. Among the methods for removing the tick the largest number of respondents indicated removing it with the use of tweezers, with a simple, swift steady movement (29.7%), and pulling it out with the fingers (22.7%). In the ELISA test, a positive or doubtful result in at least one class was observed in 25.0% of respondents (n=32/128): in IgM class - 23.4% (n=30/128), and in IgG class - 4.7% (n=6/128). After verification with the Western blot test, infection was confirmed in 5.5% of respondents (n=7/128): in IgM class - 1.6% (n=2/128), in IgG class - 3.9% (n=5/128). In IgM class antibodies, the Western blot test confirmed positive or doubtful results of the ELISA test in 6.7%, while in IgG class antibodies in 83.3%. CONCLUSION: Evaluation of the actual infection with Borrelia spp. using serologic tests is difficult due to a certain non-specificity of the ELISA test, especially in IgM class antibodies, and difficulties with performance of a wide scope of specific Western blot tests. The variety of methods of tick removal declared by adolescents suggests that a wider education of society concerning appropriate methods of removing the tick should become an especially important element of prophylactic actions in the area of borreliosis. PMID- 25292121 TI - Influence of dioxin intoxication on the human system and possibilities of limiting its negative effects on the environment and living organisms. AB - INTRODUCTION AND OBJECTIVE: Despite the restrictive legal regulations related to the reduction of dioxins emission, their concentration in the environment is still too high. Mainly, this is related to the illegal utilisation of electronic equipment and combustion of wastes, and also to intensified activity and maintenance of ships, especially in developing countries. The most important remaining source in Europe is the metal industry. Studies on the mechanism of impact of dioxins are still being carried out. This review points at new possibilities for limiting the molecular mechanisms of dioxins activity, inter alia, through the application of high doses of tocopherol and acetylsalicylic acid while treating dioxins intoxication. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Apart from the knowledge of dioxins affinity to the aryl hydrocarbon receptor (AhR), the multi-stage radical-form actions and the pro-inflammatory mechanism associated with cyclooxygenase-II enzyme (COX-2) are under intense investigation at the moment. Due to the high affinity of dioxins to animals adipose tissue and their ability to accumulate in it, they can enter the food chain. Furthermore, high dioxin doses can cause poisoning manifested as advanced clinical symptoms, whereas in smaller doses, when cumulated, can cause metabolic changes which are often difficult to associate with their presence. Recently, some serious food contaminations by dioxins have been demonstrated. Sea fish and products from contaminated aqueducts still constitute potential sources of dioxins pollution. CONCLUSION: According to recent studies, dioxins are present in different concentrations in the environment and cause specific and long-time effects. These effects could be limited by the use of tocopherol and acetylsalicylic acid. PMID- 25292122 TI - Quantification of C. globosum spores in house dust samples. AB - Chaetomium globosum is one of the most common fungi that grows in damp buildings and occurs in agricultural and forestry workplaces. Using sera from atopic patients, we characterized and purified an extracellular chitosanase (Chg47) from C. globosum that is antigenic to humans. The study reports the production of monoclonal antibodies to the protein. Three capture ELISAs were developed for Chg47 for detection of spores and spore and mycelial fragments in dust samples using different mono- and polyclonal antibody combinations. One method is based on an enhanced biotinylated polyclonal antibody as the secondary antibody and coating anti-IgM to capture one of two clones of IgM monoclonal antibodies as the capture antibody. The other method makes use of an enhanced rabbit polyclonal antibody as both the primary and capture antibody. The detection limit of the double PAb method for the Chg47 antigen was 7.6 pg/ml. When the anti-IgM+10B3 clone was used, the detection limit was 61 pg/ml and for anti-IgM+5F12, 122 pg/ml. The detection limit of double PAb method is comparable to methods for the allergen and spores of Aspergillus versicolor in house dust and is more sensitive than other immunoassays for allergens in house including for Stachybotrys chartarum, Aspergillus fumigatus and Alternaria alternata. All three methods had limited cross-reactivity to fungi common in house dust representing a diverse array of taxa. PMID- 25292123 TI - Air-borne dermatitis from Chrysanthemum--case report with a discussion of diagnostic procedures and therapy. AB - Airborne dermatitis belongs to a heterogeneous group of dermatoses of various etiopathology and clinical characteristics. This disease is characterized by acute or chronic inflammation of the uncovered skin exposed to irritants or allergens. Initially skin lesions are transient. The paper presents a description of chrysanthemum growers diagnosed with air-borne dermatitis from chrysanthemum. Etiology, pathomechanism, clinical course, diagnostics and therapeutical methods are described. PMID- 25292124 TI - Change in airway inflammatory markers in Danish energy plant workers during a working week. AB - INTRODUCTION: It is well known that exposure to organic dust can cause adverse respiratory effect. The pathogen-associated molecular patterns (PAMPS) in the organic dust, such as endotoxin from Gram-negative bacteria cell wall and fungal components, can trigger the release of cytokine (e.g. Interleukin 1beta (IL 1beta)) and chemokine (e.g. Interleukin 8 (IL-8)) from the immune cells in the airways. OBJECTIVE: To evaluate the potential inflammatory effects of organic dust exposure in energy plants in Denmark. MATERIALS AND METHODS: Nasal lavage (NAL) and exhaled breath condensate (EBC) were sampled at Monday morning (referred to as before work) and again at Thursday afternoon (referred to as after work). NAL IL-8, EBC pH, IL-1beta concentration were measured. Personal exposure to endotoxin and dust was calculated from time spent on different tasks and measured average work area exposures. RESULTS: Before work, workers from biofuel plants had a higher IL-1beta and IL-8 concentration compared to conventional fuel plants (control group). Specifically, the IL-1beta level of moderately and most exposed group, and IL-8 level of the least exposed group were higher compared to the control group. The changes of IL-1beta, pH and IL-8 during a work week were not significant. Workers with rhinitis had a lower percentage change of IL-8 compared to healthy workers. CONCLUSIONS: An increased level of EBC IL-1beta in biofuel energy plant workers before work indicated a chronic or sub-chronic inflammation. The percentage change of IL-8 was lower in workers with rhinitis compared to healthy workers. PMID- 25292125 TI - The airborne pollen calendar for Lublin, central-eastern Poland. AB - An aerobiological study was conducted to investigate the quantity and quality of pollen in the atmosphere of Lublin in central-eastern Poland. Pollen monitoring was carried out in the period 2001-2012 using a Hirst-type volumetric spore trap. The atmospheric pollen season in Lublin lasted, on average, from the end of January to the beginning of October. The mean air temperature during the study period was found to be higher by 1.1 degrees C than the mean temperature in the period 1951-2000. 56 types of pollen of plants belonging to 41 families were identified. 28 types represented woody plants and 28 represented herbaceous plants. The study distinguished 5 plant taxa the pollen of which was present most abundantly in the air of Lublin, which altogether accounted for 73.4%: Betula, Urtica, Pinus, Poaceae, and Alnus. The mean annual pollen index was 68 706; the largest amount of pollen was recorded in April and accounted for 33.3% of the annual pollen index. The pollen calendar included 28 allergenic plant taxa. The pollen of woody plants had the highest percentage in the pollen spectrum, on average 58.4%. The parameters of the pollen calendar for Lublin were compared with the calendar for central-eastern Europe with regard to the start of the pollen season of particular taxa. The pollen calendar for Lublin was demonstrated to show greater similarity to the calendar for Munster (Germany) than to the calendar for Bratislava (Slovakia). PMID- 25292126 TI - Matrix metalloproteinase 3 polymorphisms as a potential marker of enhanced susceptibility to lung cancer in chronic obstructive pulmonary disease subjects. AB - INTRODUCTION AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is often accompanied by lung cancer. Among the genes that may play a role in the occurrence of COPD and lung cancer are those encoding the proteolytic enzymes, such as matrix metalloproteinases (MMPs) and their tissue inhibitors. The objective of this study was to find MMPs-associated markers useful in the identification of COPD subjects with increased susceptibility to developing lung cancer. MATERIALS AND METHODS: We compared the frequency of single nucleotide polymorphisms in genes coding for matrix proteinases (MMP1, MMP2, MMP3, MMP9, MMP12) as well as tissue inhibitor of metalloproteinases (TIMP1) in two groups of subjects: COPD patients (54 subjects) and COPD patients diagnosed for lung cancer occurrence (53 subjects).The levels of the respective proteins in blood serum were also analyzed. RESULTS: The frequencies of 2 genotypes, MMP3 rs3025058 and MMP3 rs678815, were significantly different between the studied groups. In both cases, more heterozygotes and less homozygotes (both types) were observed in the COPD group than in the COPD + cancer group. A significantly higher TIMP1 level in blood serum was observed in the COPD + cancer group than in the COPD group. There were no statistically significant differences in MMPs blood levels between the studied groups. In addition, no genotype-associated differences in TIMP1 or MMPs blood levels were observed. CONCLUSIONS: Homozygocity for MMP3 rs3025058 and rs678815 polymorphisms is a potential marker of enhanced susceptibility to lung cancer development among COPD subjects. PMID- 25292127 TI - Alcohol consumption in Polish middle and high school pupils--has this rapidly increased during 2009-11? AB - INTRODUCTION: The dynamic rise of alcohol consumption in adolescents is a matter of serious concern, requiring frequently updated monitoring. By such means, it is possible to optimise preventative measures for dealing with this problem. OBJECTIVE: To estimate the magnitude/amount and frequency of alcohol consumed by middle and high school pupils in Poland, including the circumstances when alcohol was first drunk. MATERIALS AND METHODS: A randomised survey was performed throughout Poland on middle school (junior high school) pupils, (n=9360) in 2009, followed by both middle and high school pupils in 2011 (n=7971). The questionnaire was devised by the Polish Chief Sanitary Inspectorate (GIS). RESULTS: A strikingly sharp increase in alcohol consumption (29%) was observed in subjects between 2009 - 2011. In the latter year, 1 month prior to survey, respectively, 50% and 71% of middle school and high school pupils drank alcohol, and correspondingly, 36% and 63% of these pupils ever became intoxicated/drunk. CONCLUSIONS: 1) Adolescent alcohol consumption increases with age and is highest in girls. Monitoring as well as in-depth analysis thus becomes necessary. 2) Systematic monitoring and analysis of changing healthy lifestyle behaviour should be used for taking the necessary corrective action. This should happen concurrently and consist of planned health education programmes, including health promotion. PMID- 25292128 TI - Thirty years of evolution of oral health behaviours and dental caries in urban and rural areas in Poland. AB - INTRODUCTION AND OBJECTIVE: 34 years ago, children living in rural areas had almost 2 more teeth affected by decay than those living in cities. Environmental differences are being reduced along with Poland's civilization development. The aim of the study is to assess the extent to which the differences in the intensity of caries and oral health behaviours between the urban rural environment have been reduced have been reduced in the past 3 decades. MATERIALS AND METHODS: The data from 9 national surveys of 14,338 children aged 12 years and 5,425 adults aged 35-44 who lived in the city and in the countryside were analysed. Mean number of decayed (D), missing (M) and filled (F) teeth (DMFT) was determined during the examination, as well as oral health behaviours. RESULTS: During the past 3 decades, in the statistical 12-year-old Polish child, tooth decay has been reduced from 7.3 to 3.6 teeth, and the environmental difference between the town and village children is now almost 5 times smaller. A similar trend is observed in children's dental behaviours. Improving the oral health status and levelling of the environmental differences in the population aged 35 44 is much slower than in children. CONCLUSIONS: In the last three decades, the level of tooth decay has been reduced by half, but it is still 3 times higher than in other European countries. Environmental differences have been reduced particularly in children. Both the oral health status and urban/rural environment differences in the intensity of tooth decay may be regarded as one of the many measures of Poland's social and civilization development. However, the analysed process is not monotonic; instead, it has some turning points. PMID- 25292129 TI - Plasma and erythrocyte relationship of catecholamines in hemodialysis patients. AB - The function of the autonomic nervous system is based on reciprocal interaction between the sympathetic and parasympathetic parts, most frequently in the form of antagonistic action on target organs. The main mediators of the sympathetic nervous system in the effectors part are catecholamines (CA), which are involved in various physiological processes. Moreover, CA also has a profound effect on the kidneys, being factors that impact on renal haemodynamics, and have been reported to be altered in pathological disorders, e.g. extracellular volume expression, hypertension and cardiovascular complications. The increased sympathetic nerve activity, at least in part, can explain the raised in plasma CA observed in chronic kidney diseases. Furthermore, plasma CA levels in ureamic patients cannot be considered a reliable index of sympathetic activity, due to existence of many factors which may affect their values. In addition, CA released into the circulation, as one of many substances, may penetrate across the cellular membranes of erytrocytes (RBC). Taking these observations together, the aim of the presented study was to investigate for the first time the plasma and erythrocyte relationship of catecholamines in haemodialysis. The studies were performed among 37 haemodialysed patients who were inhabitants of the Lublin commune. Plasma and intracellular concentration of CA were measured prior to and following haemodialysis by high performance liquid chromatography with electrochemical detection. The results suggest that RBC are able to accumulate CA at the stage of terminal renal failure; in addition, the levels of adrenaline and dopamine in RBC depend on the accumulation of urea in plasma. It was also found that the dynamic changes in concentration of RBC adrenaline are an independent predictor of mortality in haemodialysis patients. PMID- 25292130 TI - Impact of copper (Cu) at the dose of 50 mg on haematological and biochemical blood parameters in turkeys, and level of Cu accumulation in the selected tissues as a source of information on product safety for consumers. AB - INTRODUCTION: The current state-of the art points to a positive impact of copper (Cu) supplements on the general health status in poultry. Copper induces beneficial changes in the haematological and biochemical blood parameters. It also displays immunostimulating properties and helps maintain a proper microbiological balance in the digestive tract. OBJECTIVE: The objective of this study was to investigate the impact of Cu at the dose of 50 mg/kg BW, administered in organic and inorganic form, on the haematological and biochemical blood parameters and level of Cu bioaccumulation in the liver and pectoral muscle. MATERIALS AND METHOD: The study was carried out on 45 BUT-9 turkeys which had been were reared for 16 weeks. They were divided into 3 experimental groups: I - the control group; II - fed with CuSO4 at the dose of 50 mg Cu*dm (-3) H2O; III - received a Cu chelate with lysine at the same dose. RESULTS: The administration of Cu at the dose exceeding the nutritional recommendations did not induce beneficial changes in the examined birds. This indicates that it is not necessary to administer Cu doses higher than the recommended levels. The extent of Cu accumulation in the pectoral muscle increased by 40% compared to the control group, whereas in the liver it was higher by 30-35% than in the birds without Cu administration. The level of Cu in tissues does not pose a risk to consumers. CONCLUSIONS: The supplementation of Cu at the dose of 50 mg has a negative impact on the level of the analyzed parameters. The results of the presented study indicate that the administered Cu dose exceeds birds' demand for this element. PMID- 25292132 TI - Life style and risk of development of dental caries in a population of adolescents. AB - INTRODUCTION: Oxygen is an essential element for sustaining the life of aerobes; however, in certain conditions it may be toxic for these organisms. This is due to so-called reactive oxygen species - ROS. Factors which cause the production of free radicals include ionizing radiation, UV radiation, high temperature, and hazardous substances, such as phenols, carbon monoxide, e.g. in smokers, also air pollution and drugs. OBJECTIVE: The objective of the study was analysis of the total antioxidant status (TAS) in stimulated and unstimulated saliva, according to the number of active carious lesions in generally healthy non-smokers aged 15 17. MATERIALS AND METHOD: The study covered 113 adolescents aged 15-17 in whom the state of dentition was evaluated using the DMFT (Decayed-Missing-Filled) index, and oral hygiene assessed based on the OHI-S (Oral Hygiene Index Simplified) index. TAS in saliva was determined by means of a Randox Labolatories Ltd. test kit, by the spectrophotometric method. RESULTS: Based on the results of the study, it was found that in the population examined an increase in the number of carious lesions was accompanied by a significant decrease in the TAS, both in stimulated and unstimulated saliva. CONCLUSIONS. A health-promoting life style, maintenance of basic principles of oral hygiene and care of general health through the elimination of harmful habits decrease the risk of dental caries. PMID- 25292131 TI - The interaction between menstrual cycle, Tumour Necrosis Factor alpha receptors and sex hormones in healthy non-obese women--results from an observational study. AB - There is growing evidence that TNF-alpha and its two receptors play an important role in hormonal regulation, metabolism, inflammation and cancer. The biological effects of TNF-alpha are mediated by two receptors, p55 and p75. The aim of this study was to analyze serum concentrations of p55 and p75 and hormonal status in healthy women during the normal menstrual cycle. Eight women aged 20-22 with regular menstrual cycles were scheduled for examination on 3(rd) , 8(th) , 14(th) and 25(th) day of their menstrual cycle. We only observed a positive correlation of p75 subunit with prolactin level (correlation coefficient 0.417; p=0.0116) and negative correlation with insulin level (correlation coefficient -0.35; p=0.032) and HOMAIR insulin resistance index correlation coefficient 0.39; p=0.0185). Furthermore, a negative correlation of p55/p75 ratio with prolactin (correlation coefficient -0.42; p=0.0101) and a positive correlations of p55/p75 ratio with insulin level (correlation coefficient 0.43; p=0.008) and HOMAIR insulin resistance factor correlation coefficient 0.45; p=0.0065) were found. PMID- 25292133 TI - Effect of a plant preparation Citrosept on selected immunity indices in blood of slaughter turkey hens. AB - INTRODUCTION AND OBJECTIVE: The objective of this study was to determine the effect of per os administration of 3 various dosages of a Citrosept preparation (a grapefruit extract)to growing turkey hens on changes in their selected haematological and immunological blood indices. An attempt was also undertaken to select the most efficient dose of the preparation with respect to the mentioned indices in turkey hens. MATERIALS AND METHODS: The experiment was conducted on 180 turkey hens allocated at random to 4 groups, 45 birds in each group. Samples of their full blood were analyzed for haematological indices, such as red blood cell count (RBS), haemoglobin content (Hb), haematocrit value (Ht), and white blood cell count (WBC). Samples of blood plasma were assayed to determine the activity of lysozyme (chamber-diffusive method) and heterophils capability to reduce nitro blue tetrazolium (stimulated and spontaneous NBT test). Phagocytic activity of leucocytes against Staphylococcus aureus 209P strain was assessed and expressed as the percentage of phagocytic cells (% PC) and phagocytic index (PI). RESULTS: The administration of the grapefruit extract to turkey hens with drinking water caused a significant increase in haemoglobin content in blood, as well as an increase in non-specific humoral immunity marker (activity of lysozyme) and non-specific cellular immunity marker (percentage of phagocytic cells; P <= 0.05). CONCLUSIONS: The results obtained enabled the positive evaluation of the advisability of applying the Citrosept preparation in the feeding of turkey hens at the age of 6-9 weeks. Among the doses examined, the most efficient with respect to the stimulation of the non-specific humoral and cellular immunity was the dose of 0.021 ml/kg of body weight. PMID- 25292134 TI - The influence of 9-day trekking in the Alps on the level of oxidative stress parameters and blood parameters in native lowlanders. AB - BACKGROUND: The stimuli acting on a person in a high mountain environment (such as hypobaric hypoxia with subsequent reoxygenation, physical exercise) can significantly increase oxidative stress, stimulate erythropoiesis, lead to changes in the blood count and participate in the development of altitude sickness. OBJECTIVE: The aim was to investigate changes in haematological parameters, indicators of oxidative stress (malondialdehyde - MDA) and antioxidant defences: catalase (CAT), superoxide dismutase (SOD), and total antioxidant status (TAS) in the plasma of young, healthy people after a 9-day expedition in the Alps. MATERIALS AND METHOD: A total of 5 patients (4 men and 1 woman), members of the Wroclaw Mountaineering Club, aged 24-26 years. Collection of blood samples was carried out immediately before departure and 3 days after the end of exposure to high-altitude conditions. During the expedition, the subjects were exposed to heights: 2,050-4,165 m.a.s.l., and exercise associated with climbing. RESULTS: Trekking in the Alps neither caused significant changes in the parameters of red blood cells nor increased the level of oxidative stress parameters in plasma. CAT activity increased, the ratio of SOD / CAT decreased. There was also a decrease in the total number of leukocytes, mainly monocytes and basophils. CONCLUSIONS: 9-day exposure to high-altitude conditions is not a substantial burden for the organism of young, physically active people. The increase in antioxidant capacity is sufficient to stop oxidative processes, which are severe in these conditions, and to prevent the occurrence of significant oxidative stress. Discontinuation of exposure to allergens and dust pollution clears the airways, which is indicated by the reduction in the number of monocytes and basophils. PMID- 25292135 TI - Obesity and poverty paradox in developed countries. AB - Obesity is a civilization disease and the proportion of people suffering from it continues to grow, especially in the developed countries. Number of obese people in Europe has increased threefold over the last 20 years. The paradox of obesity and poverty relationship is observed especially in the developed and developing countries. In developing countries, along with economic development and income growth, the number of people with overweight and obesity is increasing. This paradox has a relationship with both the easy availability and low cost of highly processed foods containing 'empty calories' and no nutritional value. To date, this paradox has been described in the United States and the United Kingdom, although many European countries are also experiencing high percentages of obese people. Among the reasons for the growing obesity in the population of poor people are: higher unemployment, lower education level, and irregular meals. Another cause of obesity is low physical activity, which among the poor is associated with a lack of money for sports equipment. Due to the large rate of deaths caused by diseases directly linked to obesity, the governments of many countries implement prevention programmes of overweight and obesity. These programmes are based primarily on educating the public about a healthy lifestyle based on healthy eating, daily physical activity and avoiding alcohol and cigarettes. PMID- 25292136 TI - The influence of Citrosept addition to drinking water and Scutellaria baicalensis root extract on the content of selected mineral elements in the blood plasma of turkey hens. AB - The aim of this research work was to indicate the influence of Citrosept preparation and Scutellaria baicalensis root extract, administered per os to growing turkey hens in 3 different dosages, on the content of selected mineral elements in blood plasma of slaughter turkey hens. An attempt was also made to specify the most effective dosage of the applied preparations with the highest efficiency as regards increased levels of examined macro- and microelements in the birds' blood. The research experiment was conducted on 315 turkey hens randomly divided into seven groups, each consisting of 45 turkey hens. Group K constituted the control group without experimental additions of the above mentioned preparations. When it comes to turkey hens which belonged to groups II IV, Citrosept preparation was instilled to water in the following dosages: Group II - 0.011 ml/kg of bm; Group III - 0.021 ml/kg of bm; Group IV - 0.042 ml/kg bm. For birds which belonged to groups V-VII preparation, which was Scutellaria baicalensis root extract, was instilled to water in the following dosages: Group V - 0.009 ml/kg of bm; Group VI - 0.018 ml/kg of bm, Group VII - 0.036 ml/kg bm. In the examined plant extracts and blood plasma of the birds the levels of Na, K, Ca, Mg, Cu, Zn, and Fe were identified. The use of examined extracts influenced the changes in the levels of all tested elements in slaughter turkey hens' blood plasma. An upward tendency was recorded which regarded the level of calcium and magnesium, and a downward tendency of sodium, potassium, copper, zinc, and iron in relation to the results achieved in the control group. PMID- 25292137 TI - Can deep vein thrombosis be predicted after varicose vein operation in women in rural areas? AB - INTRODUCTION: Chronic venous disease is a group of symptoms caused by functional and structural defects of the venous vessels. One of the most common aspects of this disease is the occurrence of varicose veins. There are many ways of prevention and treatment of varicose veins, but in Poland the leading one is still surgery. As in every medical procedure there is the possibility of some complications. One of them is deep vein thrombosis (DVT). The diagnosis of DVT can be difficult, especially when access to a specialist is limited, such as in case of rural patients. The aim of the study. The aim of the study was estimation of the influence of LMWH primary prophylaxis on the formation of postoperative DVT, as well as sensitivity and specificity of clinical examination and D-dimer value in diagnosis of postoperative DVT in women. MATERIALS AND METHODS: The study was conducted in a group of 93 women operated on in the Department of General, Vascular Surgery and Angiology at the Karol Marcinkowski University of Medical Sciences in Poznan, Poland. The patients had undergone a varicose vein operation and were randomly divided into two groups: A - 48 women receiving LMWH during two days of the perioperative period, B - 45 women receiving LMWH during seven days of the perioperative period. RESULTS: There was no significant difference in the postoperative DVT complications in both groups. The value of D dimer > 0.987 mcg/ml and swelling > 1.5 cm of shin (in comparison to the preoperative period) plays a significant role in diagnosis of DVT. CONCLUSIONS: The extended primary prophylaxis with LMWH does not affect the amount or quality of thrombotic complications after varicose vein operation. If the DVT occurs, the evaluation of the D - dimer and careful clinical examination can be a useful method for its diagnosis. PMID- 25292138 TI - Assessing physical activity and sedentary lifestyle behaviours for children and adolescents living in a district of Poland. What are the key determinants for improving health? AB - INTRODUCTION: Adequate levels of physical activity throughout an individual's life ensure an optimal state of health. Only 30% of adolescents and 10% of adults perform sufficient physical activity to facilitate proper physical, psychological/mental and emotional development. OBJECTIVE: Determining physical activity behaviour in children and adolescents through surveying the opinions of school pupils and parents, in order to lend support for optimised educational programmes designed to promote healthy lifestyle behaviour, as well as establishing consistent answers. MATERIALS AND METHODS: A randomised survey was conducted on two groups of n=1100 pupil subjects, each attending elementary or secondary school, with the former in Classes 5 and 6, whereas the latter were aged between 16-19 years old; in both instances parents were also included in the survey. All subjects came from the Kalisz District in western-central Poland, and were divided into those living in the city of Kalisz and those in the surrounding rural areas. RESULTS: It was found that 87%, 96% and 89% of elementary, middle and secondary school pupils, respectively, participated in Physical Education (PE) lessons. The numbers of pupils who daily, or almost daily, spent time on a computer, were 52%, 60% and 70%, respectively, for elementary, middle and secondary schools, and likewise 70%, 62% and 48% for watching TV. CONCLUSIONS: It is vital that education programmes with a focus on a healthy lifestyle are introduced and targeted at teenagers in order to promote physical activity during the crucial time of the body's development. The period of maturing into adulthood is particularly crucial for acquiring the right knowledge, convictions, skills and attitudes that help shape a pro-healthy lifestyle in later years. PMID- 25292139 TI - Factors determining physical activity of Ukrainian students. AB - OBJECTIVE: Scientific reports provide information concerning an insufficient level of physical activity of societies. The objective of the study is recognition of the level of physical activity among Ukrainian students, and factors which condition this activity: gender, place of residence, self-reported physical fitness, and the BMI. METHODS: The study was conducted in 2013 among 2,125 Ukrainian students using a long version of the International Physical Activity Questionnaire (IPAQ), supplemented with data concerning the respondents' physical development. RESULTS: The results of the study showed that the mean total physical activity of students was 3.560 MET, and its highest percentage pertained to the area of activity in sports - 1.124 MET. Significantly higher statistically physical activity was observed among males than females. In males, the highest activity was related to participation in sports classes, while in females - engagement in household chores. It was found that males, compared to females, were significantly more physically active in such areas as occupational activity (education) and sports activity, whereas females showed higher activity performing household chores. According to the place of residence, inhabitants of medium-size towns and rural areas obtained the most favourable results in activity, while the inhabitants of large cities the poorest. Self-reported physical fitness was significantly correlated with the results in physical activity obtained by the students. No relationship was found between the BMI and the level of student's physical activity. CONCLUSION: Considering the very large population of respondents, the results obtained may be considered as an up-to date pattern of physical activity among Ukrainian students. PMID- 25292140 TI - Health-Related Physical Fitness, BMI, physical activity and time spent at a computer screen in 6 and 7-year-old children from rural areas in Poland. AB - The objective of the study was determination of the effect of various forms of physical activity, BMI, and time devoted to computer games on the level of Health Related Physical Fitness (H-RF) in 6-7-year-old children from Polish rural areas. The study covered 25,816 children aged 6-7: 12,693 girls and 13,123 boys. The evaluations included body height and weight, and 4 H-RF fitness components (trunk strength, explosive leg power, arm strength and flexibility). The BMI was calculated for each child. The Questionnaire directed to parents was designed to collect information concerning the time devoted by children to computer games, spontaneous and additional physical activity. The strength of the relationships between dependent and independent variables was determined using the Spearman's rank correlation (RSp), and the relationship by using the regression analysis. The BMI negatively affected the level of all the H-RF components analysed (p=0.000). The negative effect of computer games revealed itself only with respect to flexibility (p=0.000), explosive leg power (p=0.000) and trunk muscle strength (p=0.000). A positive effect of spontaneous activity was observed for flexibility (p=0.047), explosive leg power (p=0.000), and arm strength (p=0.000). Additional activity showed a positive relationship with trunk muscles strength (p=0.000), and explosive leg power (p=0.000). The results of studies suggest that it is necessary to pay attention to the prevention of diseases related with the risk of obesity and overweight among Polish rural children as early as at pre school age. There is also a need during education for shaping in these children the awareness of concern about own body, and the need for active participation in various forms of physical activity. PMID- 25292141 TI - Leisure time physical activity of young women from the Carpathian Euroregion in relation to the Body Mass Index. AB - Carpathian Euroregion gathers the population of 5 countries, including Poland, Slovakia, Hungary and Romania- the European Union members, as well as Ukraine. Young women are statistically less involved in high-intensity physical activity than young men. The objective of this work was to assess the relation between physical activity of young women aged 18-21 years old and BMI and conditioning factors. The study was conducted between 2010 and 2011 among 2339 women. The Minnesota Leisure Time Physical Activity Questionnarie (MLTPAQ) was applied. It results from the study that 74,2% of young women is considered to have the proper BMI rate (18,5-24,9). As many as 16,2% is considered underweight and almost 10% have higher BMI rate and are overweight. More than one third of respondents did not gain the level of physical activity of 1000 kcal/week, and that is the minimum recommended amount of leisure physical activity time per week. In case of women with low level of physical activity (<1000 kcal), as many as 52% of week activity considered low-intensity activity EEPAlight. The character of changes of the BMI index with reference to the level of physical activity is very similar in the women from towns/cities and the women from villages. An increase of BMI along with the total physical activity was related among all to the increase of free fat mass FFM despite of the level of physical. PMID- 25292142 TI - Emotions experienced in association with agricultural work performed in childhood -in opinions of adults. AB - INTRODUCTION: Performance of work is related with experiencing various emotions, from positive - indicating full satisfaction with work, to negative - describing failures, and even harm caused by work. Such emotions are also experienced by children engaged in work on family farms. OBJECTIVE: The objective of the study is the determination of emotions experienced in association with performing agricultural work in childhood, and indication of the factors conditioning the occurrence of positive and negative emotions. MATERIALS AND METHOD: The study was conducted by the method of a diagnostic survey using a questionnaire technique, and covered a group of 482 adults from agricultural families. RESULTS: In childhood, positive emotions related with the performance of work are more often experienced than negative emotions. The occurrence of positive emotions is positively related with willingness to perform work activities, working time, respondent's age, age at which a child started to perform work, and age at which a child discontinued helping on a farm. The occurrence of negative emotions is positively related with unwillingness to perform work, performing work activities beyond the physical capabilities of a child, neglecting school duties, missing classes at school due to work, and with working time. CONCLUSION: With work performed in childhood are associated positive and negative emotions experienced in childhood and adulthood. The performance of work in childhood shapes emotions experienced by an adult which may affect his/her quality of life and functioning in adulthood. PMID- 25292143 TI - Ten-year secular trend of overweight and obesity in school children in south eastern Poland. AB - OBJECTIVE: To examine the trend in prevalence of overweight and obesity in schoolchildren from south-eastern Poland over a 10-year period. MATERIALS AND METHOD: A cross-sectional study was conducted in randomly selected primary schools. In total, 4,248 children (2,182 boys and 2,066 girls), mean age 10.5+/ 2.4 years, were examined in 1998, and 2,412 children (1,184 boys and 1,228 girls), mean age 10.5+/-2.3 years in 2008. In each school the entire population was studied. RESULTS: In 2008, the prevalence of overweight in girls was 13.3% and obesity 7.7%, compared to 12.0% and 10.1% in 1998. The decrease in obesity prevalence was statistically significant. In boys, the prevalence of overweight in 2008 was 14.2% and obesity 6.4%, compared to 10.5% and 6.8% in 1998. The increase in overweight prevalence among boys was statistically significant. CONCLUSIONS: A trend toward stabilization of the prevalence of overweight and obesity was noted in school children from south-eastern Poland between 1998-2008. The declining prevalence of obesity in girls and increased prevalence of overweight in boys demonstrates that in this age group of children the secular trend is gender dependent. PMID- 25292144 TI - Study on the concentration of airbone respirable asbestos fibres in rural areas of the Lublin region in south-east Poland. AB - OBJECTIVE: The objective of the study was measurement of the concentrations of airborne asbestos fibres in the rural environment of the Lublin Region in south east Poland. METHODS: Measurements of concentrations of respirable asbestos fibres were carried out in the rural areas of the Lublin Region (Lublin and Wlodawa counties) for a period of 24 months. The studies were conducted on 3 farms with various technical conditions of asbestos-containing materials: Farm A good technical condition of asbestos products, Farm B - poor technical condition, and Farm C - with no asbestos containing products and no such products in its direct vicinity (up to 500 m). On the selected farms, 3 samples on each were simultaneously collected at 3 measuring sites. During the period 2009-2011, a total number of 216 samples were collected on all farms. Sampling was performed using JSH 16,000 stationary aspirators, with air flow velocity of 16 l/min. and sampling time 60-80 minutes. The number of fibres on filters was determined using an optical phase contrast microscope. RESULTS: The study showed that the mean concentration of respirable asbestos fibres on the farms examined was 296 fibres*m (-3). The highest concentrations were noted on Farm B was 529 fibres*m ( 3), on average; on farm A the mean concentration of respirable fibres was 328 fibres*m (-3), whereas the lowest mean concentration of airborne respirable asbestos fibres was noted on farm C, where there were no asbestos products (30 fibres*m(-3)). PMID- 25292145 TI - Characteristics of back pain in Polish youth depending on place of residence. AB - INTRODUCTION AND OBJECTIVE: Spinal pain (SP) has become a very common problem in contemporary societies and occurs in adults, youths, and even children. The aim of the study was to determine whether the prevalence and characteristics of SP, as well as the determinants leading to SP in Polish youths, vary depending on the place of residence. The determinants considered were out-of-school physical activity (PA) and physical work (PW), time spent at a computer and TV, and the level of psychosocial development expressed as the level of anxiety-trait. The restricting effect of the experienced SP on everyday functioning of youths was also analysed. MATERIALS AND METHOD: A cross-sectional, population-based study comprising 502 village residents (VR) and 1,593 city residents (CR) aged 13-19, residing in 3 random Polish provinces. The tools used were a custom-designed survey and the State-Trait Anxiety Inventory (STAI) filled by students during classes. RESULTS: The frequency and localisation of SP, the time and circumstances in which SP episodes occur, as well as the influence of the pain on everyday functioning, are the same in youths living in villages and youths living in cities. Slight differences in the correlation between the prevalence of SP and determinants of SP development related to lifestyle depending on the place of residence were observed. However, in both VR and CR the occurrence of SP is significantly correlated negatively with the level of psychosocial development. CONCLUSIONS: At present, the conditions of living in a rural and in an urban environment in Poland pose no specific threat determining the occurrence of SP in youths, and increasing the negative effect of the pain on the functioning of youths. PMID- 25292146 TI - An evaluation of antisocial behaviour in children after traumatic brain injury: the prospect of improving the quality of life in rehabilitation. AB - INTRODUCTION AND OBJECTIVE: The aim of the article is to present the consequences of traumatic brain injury in children, associated with general cognition and behavioural disorders, mainly of the antisocial type. MATERIAL AND METHODS: A total of 20 school-age children took part in the study, including six girls and 14 boys. The average age of the children was 13.35 years (standard deviation SD = 1.95). The research instruments included an analysis of documentation, a structured clinical interview, MMSE and Frontal Behavioral Inventory (FBInv) with additional set of five supplementary questions directed for detection of antisocial behavior. The research was conducted from the beginning of January 2009 until the end of May 2009. RESULTS: As hypothesized, the functioning of the children with traumatic brain injury is severely disrupted, because of the presence of cognitive impairment, however, dementia is not manifested. In a significant number of the children with traumatic brain injury we found not only the frontal syndrome, but also the occurrence of antisocial behaviour. The most commonly reported behavioural problems were: disorganization commonly referred to as laziness, hypersensitivity, and anxiety. The most common types of anti-social behaviour were: impulsivity, physical and verbal aggression, and also an outburst of anger. CONCLUSIONS: The children with traumatic brain injury suffer from a cognitive disorders and behavioural problems, especially impulsivity, physical and verbal aggression, increased anxiety, and disorganization. The occurrence of frontal syndrome is related to the development of antisocial behaviour. PMID- 25292147 TI - The social origin of the illness experience--an outline of problems. AB - INTRODUCTION AND OBJECTIVE: The main research objective is a study of social influences on the processes of experiencing illness in the sociological meaning of the term 'illness experience' focusing attention on the subjective activity inspired by being ill, taking into account interpretive (meaning-making) activity. The goal of the analysis is to specify 'social actors' jointly creating the phenomena of 'illness' and 'being ill', taking into consideration the evolution of the position of medical sociology on this issue. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: The ways of experiencing illness in contemporary society, including processes of creating the meanings of the phenomena of 'illness' and 'being ill', are the outcome of not only the application of biomedical knowledge, but are also parallelly a sociocultural 'construct' in the sense that they are under the impact of social and cultural influences. In the sociology of illness experience it is pointed out that illness experience develops in connection with experiencing somatic discomfort, this process occurring in the context of influences of culture, society and socially accepted norms and values. These relationships are interpreted by the sociological, interactionist model which presents illness as a 'social construct'. CONCLUSIONS: Sociological studies on the social construction of 'illness' and 'being ill' construct a model of these phenomena, complementary to the biomedical model, conducive to the validation of the patient's perspective in the processes of medical treatment, and to the humanization of the naturalistically oriented, biomedical approach to illness, i.e. to adjust it more accurately to typically human needs manifesting themselves in the situation of being ill. PMID- 25292148 TI - Emotional changes occurring in women in pregnancy, parturition and lying-in period according to factors exerting an effect on a woman during the peripartum period. AB - INTRODUCTION: Pregnancy, parturition and childcare, which are important moments in a woman's life, are connected with many emotional states of a future mother, a pregnant woman and a lying-in woman. The perinatal period is the time when the risk of psychological disorders in a pregnant woman may increase by even several times. Objective. The objective of the study was recognition of the main emotional and psychological changes in pregnant women, those in labour and lying in, according to the factors occurring during the peripartum period. MATERIAL AND METHOD: The study was conducted in the form of a survey and covered a group of 108 mothers who were hospitalized in gynaecological-obstetric and obstetric wards in the Karol Marcinkowski Gynaecological-Obstetric University Hospital in Poznan. RESULTS: There are a number of factors which may exert a negative effect on the emotions of women in pregnancy, parturition, and during lying-in. The study showed that there is a close relationship between the occurrence of these factors and emotional states of the mothers after giving birth. CONCLUSION: Special attention should be given to women in whom already during pregnancy factors arise which may have a negative impact on their mental state. Emotions during pregnancy, parturition and lying-in are often quite extreme, and achieve a high intensity, as well being very variable within a short period of time. PMID- 25292149 TI - Perception and degree of acceptance of menopause-related changes in various spheres of life by postmenopausal women. AB - OBJECTIVE: The objective of the study was retrospective analysis of self-reported perception and acceptance of changes related to menopause among women 1-10 years after the occurrence of their last menstrual period. The selected aspects covered social contacts with the family level (social wellbeing), perception of own physicality and inner feelings concerning sex life (psychological wellbeing). MATERIALS AND METHODS: The study covered 204 postmenopausal women 1-10 years after the last menstrual period. Analysis was performed based on a self-designed questionnaire and the data obtained were subjected to statistical analysis. Relationships were detected using the chi (2) test. The p values p<0.05 were considered statistically significant (5% level of error probability). RESULTS: Women who coped with the menopausal transition easier more rarely perceived unfavourable changes in their family life. In the group of women with a high or very high level of difficulties in adaptation to menopause, the women twice less frequently declared positive sexual sensations or lack of changes. No significant differences were observed in the perception of own physicality and degree of experiencing the transition through menopause. CONCLUSIONS: The perimenopausal period exerts a great effect on the psychological and social wellbeing of women. The degree of difficulties in experiencing the menopausal transition is important. Women who adapt to changes associated with menopause with more ease have fewer difficulties in their family life, and statistically less frequently report negative experiences in sexual contacts. PMID- 25292150 TI - Factors that Influence Trajectories of Delinquency Throughout Adolescence. AB - Given that one of the most powerful predictors of adult crime is the presence of behavior problems in childhood and adolescence, there is a need to further understand factors that determine behavior patterns during this developmental stage. This study focuses on stressful life experiences such as exposure to delinquent peers, racial discrimination, as well as family characteristics such as parenting style and family transitions. Data come from four waves of the Family and Community Health Survey, an African-American sample. The present study investigates 354 males from this dataset. We utilize a group-based trajectory model to estimate the number and type of trajectories of delinquency. We then estimate multinomial regression models to predict trajectory group membership. The results indicated that there were four distinct groups of offenders (negligible delinquents; early starter/declining; late starter; and early starter/chronic offenders). We predicted group membership using both early predictors and measures of change in these predictors across the study period. The results indicated that individuals who experience greater racial discrimination (both early in childhood and throughout adolescence) are more likely to be in trajectory groups that begin offending early and persist through adolescence. Additionally, those respondents who reported having friends with greater delinquent behavior were more likely to be in groups that began their offending early in life and persisted when compared to groups who started later or desisted as they entered adulthood. The results contribute to developmental research and provide information that may be helpful in preventing adolescents from persisting in antisocial behavior as they enter adulthood. PMID- 25292151 TI - Inhibitory and stimulating effect of single and multi-metal ions on hexavalent chromium reduction by Acinetobacter sp. Cr-B2. AB - Potential application of chromium reducing bacteria for industrial scale wastewater treatment demands that effect of presence of other metal ions on rate of Cr(VI) reduction be investigated, as industrial wastewaters contain many toxic metal ions. In the current study, the effect of different heavy metal ions (nickel, zinc, cadmium, copper, lead, iron) on chromium reduction by a novel strain of Acinetobacter sp. Cr-B2 that shows high tolerance up to 1,100 mg/L and high Cr(VI) reducing capacity was investigated. The alteration in Cr(VI) reduction capacity of Cr-B2 was studied both in presence of individual metal ions and in the presence of multi-metal ions at different concentrations. The study showed that the Cr(VI) reduction rates decreased in presence of Ni(2+), Zn(2+) and Cd(2+) when present individually. Pb(2+) at lower concentration did not show significant effect while Cu(2+) and Fe(3+) stimulated the rate of Cr(VI) reduction. In the studies on multi-metal ions, it was observed that in presence of Cu(2+) and Fe(3+), the inhibiting effect of Ni(2+), Zn(2+), Cd(2+) and Pb(2+) on Cr(VI) reduction was reduced. Each of these metals affect the overall rate of Cr(VI) reduction by Cr-B2. This work highlights the need to consider the presence of other heavy metal ions in wastewater when assessing the bioreduction of Cr(VI) and while designing the bioreactors for the purpose, as rate of reduction is altered by their presence. PMID- 25292152 TI - Effects of fungal species, cultivation time, growth substrate, and air exposure velocity on the fluorescence properties of airborne fungal spores. AB - Real-time bioaerosol monitoring is possible with fluorescence based instruments. This study provides information on major factors that can affect the fluorescence properties of airborne fungal spores. Two fluorescence-based bioaerosol detectors, BioScout, and ultraviolet aerodynamic particle sizer (UVAPS), were used to study fluorescent particle fractions (FPFs) of released spores of three fungal species (Aspergillus versicolor, Cladosporium cladosporioides, and Penicillium brevicompactum). Two culture media (agar and gypsum board), three ages of the culture (one week, one month, and four months), and three aerosolization air velocities (5, 15, and 27 m/s) were tested. The results showed that the FPF values for spores released from gypsum were typically lower than for those released from agar indicating that poor nutrient substrate produces spores with lower amounts of fluorescent compounds. The results also showed higher FPF values with lower air velocities in aerosolization. This indicates that easily released fully developed spores have more fluorescent compounds compared to forcibly extracted non-matured spores. The FPFs typically were lower with older samples. The FPF results between the two instruments were similar, except with four-month-old samples. The results can be utilized in field measurements of fungal spores to estimate actual concentrations and compare different instruments with fluorescence-based devices as well as in instrument calibration and testing in laboratory conditions. PRACTICAL IMPLICATIONS: Fluorescence-based instruments are the only choice for real-time detection of fungal spores at the moment. In general, all fluorescence-based bioaerosol instruments are tested against known bacterial and fungal spores in laboratory conditions. This study showed that fungal species, growth substrate, age of culture, and air current exposure rate have an effect on detection efficiency of fungal spores in the fluorescence-based instruments. Therefore, these factors should be considered in the instrument calibration process. The results are also important when interpreting results of fluorescence-based field measurements of fungal spores. PMID- 25292153 TI - Human immunodeficiency virus and liver transplantation: Hepatitis C is the last hurdle. PMID- 25292154 TI - Inflammation markers and incident venous thromboembolism: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. AB - BACKGROUND: Inflammation biomarkers are associated with the venous thromboembolism (VTE) risk factors obesity and age; however, the relationships of inflammation with VTE risk remain controversial. OBJECTIVES: To examine associations of four inflammation biomarkers, i.e. C-reactive protein (CRP), serum albumin, white blood cell (WBC) count, and platelet count (PLTC), with incident VTE, and to determine whether they mediate the association of age or obesity with VTE. PATIENTS/METHODS: Hazards models adjusted for VTE risk factors were used to calculate the prospective association of each biomarker with incident VTE in 30,239 participants of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Mediation of the associations of obesity and age with VTE were examined by bootstrapping. Over a period of 4.6 years, there were 268 incident VTE events. After adjustment for VTE risk factors, the hazard ratios (HRs) were 1.25 (95% confidence interval [CI] 1.09-1.43) per standard deviation (SD) higher log-CRP and 1.25 (95% CI 1.06-1.48) per SD lower albumin; there were no associations for WBC count or PLTC. The association of body mass index (BMI), but not age, with VTE was partially mediated by CRP and albumin. In risk factor-adjusted models, the percentage attenuations of the BMI HR for VTE after introduction of CRP or albumin into the models were 15.4% (95% CI 7.7-33.3%) and 41.0% (95% CI 12.8-79.5%), respectively. CONCLUSION: Higher CRP levels and lower serum albumin levels were associated with increased VTE risk, and statistically mediated part of the association of BMI with VTE. These data suggest that inflammation may be a potential mechanism underlying the relationship between obesity and VTE risk. PMID- 25292156 TI - The associations between parenting styles and proactive and reactive aggression in Hong Kong children and adolescents. AB - Previous research suggests that reactive and proactive aggression may be differentially related to family contextual (e.g. parenting practices) factors. However, the existing research has focused largely on children and adolescents from Western countries, and no study has examined the parenting-aggression association using a parenting style measure sensitive to Asian culture. In this study parenting styles (i.e. warmth, control and guan/training) and proactive and reactive aggression were assessed in a large sample of school children in Hong Kong, China (N = 4,175, mean age = 11.75). We found that: (a) both low warmth (in boys only) and guan (i.e. high expectation and close supervision, in both boys and girls) were associated with elevated parent-reported proactive aggression, (b) high restrictive control (i.e. dominating and rejecting) was associated with high reactive aggression (in both boys and girls) based on parent- or child report data, and with high proactive aggression (in boys only) based on parent report data, and (c) guan was also positively associated with parent-reported reactive aggression. Findings provide more information about the Parenting Inventory using a large Asian sample, and extend existing research on familial correlates of different types of aggression. PMID- 25292157 TI - Prostaglandin dependent control of an endogenous estrogen receptor agonist by osteoblasts. AB - Estrogen receptor (ER) activation has complex effects on bone cells, and loss of circulating estradiol adversely affects skeletal status in women. Hormone replacement therapy effectively circumvents bone loss after menopause, but enhances disease risk in other tissues. Here we show that prostaglandin E2 (PGE2) augments the activity of an osteoblast-derived selective ER modulator, ObSERM. The stimulatory effect of PGE2 is replicated in part by either the PG receptor EP3 agonist 17-phenyl trinor PGE2 or by the PG receptor FP agonist PGF2alpha? Whereas activation of the various PG receptors induces multiple downstream signals, the response to PGE2 was mimicked by activators of protein kinase C, and suppressed by inhibition of protein kinase C but not by inhibition of protein kinase A. Moreover, inhibition of nitric oxide synthesis and activation of the PTH and Wnt pathways increases ObSERM activity. Our studies therefore reveal that ObSERM activity is controlled in distinct ways and revise our understanding of ER activation within bone by agents or events associated with PG expression. They also predict ways to sustain or improve bone formation, fracture repair, and surgical healing without adding the risk of disease in other tissues where ER activation also has important biological functions. PMID- 25292155 TI - Reduced uterine receptivity for mouse embryos developed from in-vitro matured oocytes. AB - PURPOSE: The outcomes of in-vitro maturation (IVM) are inferior compared to those of IVF. The purpose of the study was to compare the implantation rates of IVM- and in-vivo maturation (IVO)- derived embryos, and to evaluate their effects on uterine receptivity. METHODS: The IVM- and IVO- oocytes were obtained from female mice, fertilized and transferred to separate oviducts of the same pseudo-pregnant mice. After 5 days, the implanted blastocysts were dissected out of the uterine horns, and the uterine horns were analyzed for the expression of mRNAs encoding leukemia inhibitory factor, heparin-binding epidermal growth factor, insulin-like growth factor binding protein-4, progesterone receptor, and Hoxa-10. RESULTS: The maturation rate of the IVM- oocytes was 81.2%. The fertilization rate of the IVM oocytes was lower than that of the IVO oocytes (50.5% vs. 78.0%, p = 0.038), as was their implantation rate (14.5% vs. 74.7%, p < 0.001). All 5 mRNAs examined were expressed at significantly lower levels in the uterine horns that received the IVM-derived embryos than in those that received the IVO-derived embryos. CONCLUSIONS: The IVM-derived embryos are less competent in inducing expression of implantation-related mRNAs in the uterine horn. PMID- 25292158 TI - Sustainability of a community-based anti-retroviral care delivery model - a qualitative research study in Tete, Mozambique. AB - INTRODUCTION: To overcome patients' reported barriers to accessing anti retroviral therapy (ART), a community-based delivery model was piloted in Tete, Mozambique. Community ART Groups (CAGs) of maximum six patients stable on ART offered cost- and time-saving benefits and mutual psychosocial support, which resulted in better adherence and retention outcomes. To date, Medecins Sans Frontieres has coordinated and supported these community-driven activities. METHODS: To better understand the sustainability of the CAG model, we developed a conceptual framework on sustainability of community-based programmes. This was used to explore the data retrieved from 16 focus group discussions and 24 in depth interviews with different stakeholder groups involved in the CAG model and to identify factors influencing the sustainability of the CAG model. RESULTS: We report the findings according to the framework's five components. (1) The CAG model was designed to overcome patients' barriers to ART and was built on a concept of self-management and patient empowerment to reach effective results. (2) Despite the progressive Ministry of Health (MoH) involvement, the daily management of the model is still strongly dependent on external resources, especially the need for a regulatory cadre to form and monitor the groups. These additional resources are in contrast to the limited MoH resources available. (3) The model is strongly embedded in the community, with patients taking a more active role in their own healthcare and that of their peers. They are considered as partners in healthcare, which implies a new healthcare approach. (4) There is a growing enabling environment with political will and general acceptance to support the CAG model. (5) However, contextual factors, such as poverty, illiteracy and the weak health system, influence the community-based model and need to be addressed. CONCLUSIONS: The community embeddedness of the model, together with patient empowerment, high acceptability and progressive MoH involvement strongly favour the future sustainability of the CAG model. The high dependency on external resources for the model's daily management, however, can potentially jeopardize its sustainability. Further reflections are required on possible solutions to solve these challenges, especially in terms of human resources. PMID- 25292159 TI - Effects of dietary water-soaked barley on amino acid digestibility, growth performance, pork quality and Longissimus dorsi muscle fatty acid profiles in pigs. AB - Two experiments were conducted to assess the feeding value of water-soaked barley (WB) as a replacement for dehulled barley (DB) in pigs. In experiment (Exp.) 1, eight barrows (body weight = 30.56 +/- 0.78 kg) were fitted with a T-cannula and allotted to a duplicated 4 * 4 Latin square design: WB10, 100g/kg WB; WB20, 200 g/kg WB; DB10, 100 g/kg DB; and DB20, 200 g/kg DB. In Exp. 2, 80 barrows (body weight = 70.56 +/- 1.29 kg) were used in a 56-day experiment: (i) WB15, 150 g/kg WB; (ii) WBD10, 100 g/kg WB and 50 g/kg DB; (iii) WBD5, 50 g/kg WB and 100 g/kg DB; and (iv) DB15, 150 g/kg DB. In Exp. 1, the apparent ileal digestibilities of total essential amino acids were higher (P < 0.05) in WB10 treatment than DB20. For Exp.2, the WB15 and WBD10 had higher pH and lower cooking loss (P < 0.05) than other two treatments. The WB15 treatment decreased (P < 0.05) the contents of palmitic acid (C16:0) in Longissimus dorsi muscle than WBD5 and DB15 treatments. In conclusion, it is suggested that water-soaked barley improved some amino acid digestibility and the cooking loss and moderate fatty acid profiles in Longissimus dorsi muscle. PMID- 25292161 TI - Panchromatic symmetrical squaraines: a step forward in the molecular engineering of low cost blue-greenish sensitizers for dye-sensitized solar cells. AB - Two novel symmetrical blue squaraine sensitizers were synthesized, which exhibit panchromatic light harvesting and a record efficiency over 6% with Jsc exceeding 14 mA cm(-2), and Voc over 620 mV under 1 sun. Their color, low cost, easiness of synthesis, and relatively high photo- and thermal stability open up the way for commercial applications. PMID- 25292160 TI - Accuracy of residential geocoding in the Agricultural Health Study. AB - BACKGROUND: Environmental exposure assessments often require a study participant's residential location, but the positional accuracy of geocoding varies by method and the rural status of an address. We evaluated geocoding error in the Agricultural Health Study (AHS), a cohort of pesticide applicators and their spouses in Iowa and North Carolina, U.S.A. METHODS: For 5,064 AHS addresses in Iowa, we compared rooftop coordinates as a gold standard to two alternate locations: 1) E911 locations (intersection of the private and public road), and 2) geocodes generated by matching addresses to a commercial street database (NAVTEQ) or placed manually. Positional error (distance in meters (m) from the rooftop) was assessed overall and separately for addresses inside (non-rural) or outside town boundaries (rural). We estimated the sensitivity and specificity of proximity-based exposures (crops, animal feeding operations (AFOs)) and the attenuation in odds ratios (ORs) for a hypothetical nested case-control study. We also evaluated geocoding errors within two AHS subcohorts in Iowa and North Carolina by comparing them to GPS points taken at residences. RESULTS: Nearly two thirds of the addresses represented rural locations. Compared to the rooftop gold standard, E911 locations were more accurate overall than address-matched geocodes (median error 39 and 90 m, respectively). Rural addresses generally had greater error than non-rural addresses, although errors were smaller for E911 locations. For highly prevalent crops within 500 m (>97% of homes), sensitivity was >95% using both data sources; however, lower specificities with address-matched geocodes (more common for rural addresses) led to substantial attenuation of ORs (e.g., corn <500 m ORobs = 1.47 vs. ORtrue = 2.0). Error in the address-matched geocodes resulted in even greater ORobs attenuation for AFO exposures. Errors for North Carolina addresses were generally smaller than those in Iowa. CONCLUSIONS: Geocoding error can be minimized when known coordinates are available to test alternative data and methods. Our assessment suggests that where E911 locations are available, they offer an improvement upon address-matched geocodes for rural addresses. Exposure misclassification resulting from positional error is dependent on the geographic database, geocoding method, and the prevalence of exposure. PMID- 25292162 TI - [Prediction in cerebrovascular diseases]. AB - Prediction of the outcome of cerebrovascular diseases or of the effects and complications of various forms of treatment are essential components of all stroke treatment regimens. This review focuses on the prediction of the stroke risk in primary prevention, the prediction of the risk of secondary stroke following a transient ischemic attack (TIA), the estimation of the outcome following manifest stroke and the treatment effects, the prediction of secondary cerebrovascular events and the prediction of vascular cognitive impairment following stroke. All predictive activities in cerebrovascular disease are hindered by the translation of predictive results from studies and patient populations to the individual patient. Future efforts in genetic analyses may be able to overcome this barrier and to enable individual prediction in the area of so-called personalized medicine. In all the various fields of prediction in cerebrovascular diseases, three major variables are always important: age of the patient, severity and subtype of the stroke. Increasing age, more severe stroke symptoms and the cardioembolic stroke subtype predict a poor outcome regarding both survival and permanent disability. This finding is somewhat banal and will therefore never replace the well experienced clinician judging the chances of a patient and taking into account the personal situation of this patient, e.g. for initiation of a rehabilitation program. Besides the individualized prediction, in times of restricted economic resources and increasing tendency to clarify questions of medical treatment in court, it seems unavoidable to use prediction in economic and medicolegal interaction with clinical medicine. This tendency will be accompanied by difficult ethical problems which neurologists must be aware of. Improved prediction should not be used to allocate or restrict resources or to restrict medically indicated treatment. PMID- 25292164 TI - The clinical utility of anti-ribosomal P autoantibodies in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that can affect multiple organs and thus has a large spectrum of clinical presentations. Assessment of the autoantibody profile is fundamental for the clinical management of SLE patients, providing important data for diagnosis, clinical characterization and disease activity evaluation. Anti-ribosomal P protein (anti Rib-P, anti-P) antibody, described in the 1980s, is a serological marker for SLE that is present in 13-20% of cases. This reactivity was initially thought to be associated with neuropsychiatric involvement in SLE, with certain conflicting results. Subsequently, associations of anti-Rib-P with liver and renal involvement in lupus were reported. Recently, anti-Rib-P was detected in autoimmune hepatitis patients. Anti-Rib-P reactivity to Trypanosoma cruzi ribosomal target antigens in patients with Chagas heart disease has also been described. This review focuses on the usefulness of the determination of anti-Rib P in SLE and in other autoimmune and non-autoimmune disorders in clinical practice. PMID- 25292166 TI - Laser-induced retinal damage threshold for repetitive-pulse exposure to 100-MUs pulses. AB - The laser-induced retinal injury thresholds for repetitive-pulse exposures to 100 MUs-duration pulses at a wavelength of 532 nm have been determined for exposures of up to 1000 pulses in an in vivo model. The ED50 was measured for pulse repetition frequencies of 50 and 1000 Hz. Exposures to collimated beams producing a minimal retinal beam spot and to divergent beams producing a 100-MUm-diameter retinal beam spot were considered. The ED50 for a 100-MUs exposure was measured to be 12.8 MUJ total intraocular energy for a minimal retinal beam spot exposure and 18.1 MUJ total intraocular energy for a 100-MUm-diameter retinal beam spot. The threshold for exposures to N > 1 pulse was found to be the same for both pulse repetition frequencies. The variation of the ED50 with the number of pulses is described well by the probability summation model, in which each pulse is considered an independent event. This is consistent with a threshold-level damage mechanism of microcavitation for single-pulse 100-MUs-duration exposures. The data support the maximum permissible exposure levels for repetitive-pulse exposure promulgated in the most recent laser safety guidelines. PMID- 25292163 TI - [HIV 1-associated neurocognitive disorder: current epidemiology, pathogenesis, diagnosis and management]. AB - By restoring the immunological function the modern antiretroviral treatment of human immunodeficiency virus (HIV-1) infection has considerably lowered the incidence of opportunistic infections. As opposed to the classical manifestations of HIV-induced immunosuppression the incidence and prevalence of HIV-associated neurocognitive disorders (HAND) has not noticeably decreased and HAND continues to be relevant in daily clinical practice. At present, HAND occurs in earlier stages of HIV infection, and the clinical course differs from that before the introduction of combination antiretroviral treatment (cART). The predominant clinical manifestation is a subcortical dementia with deficits in the domains attention, concentration and memory. Signs of central motor pathway lesions have become less frequent and less prominent. Prior to the advent of cART the cerebral dysfunction could at least partially be explained by the viral load and by virus associated histopathological findings. In patients with at least partially successfully treated infections, this relationship no longer exists, but a plethora of poorly understood immunological and probably toxic phenomena are under discussion.This consensus paper summarizes the progress made in the last 12 years in the field of HAND and provides suggestions for the diagnostic and therapeutic management. PMID- 25292165 TI - 980-nm infrared laser modulation of sodium channel kinetics in a neuron cell linearly mediated by photothermal effect. AB - Photothermal effect (PE) plays a major role in the near-infrared laser interaction with biological tissue. But, quite few interactions can be quantitatively depicted. Here, a two-step model is proposed to describe a 980-nm infrared laser interaction with neuron cell in vitro. First, the laser-induced temperature rises in the cell surrounding area were measured by using an open pipette method and also calculated by solving the heat conduction equation. Second, we recorded the modifications on sodium (Na) channel current in neuron cells directly by using a patch clamp to synchronize the 980-nm laser irradiation and obtained how the electrophysiological function of neuron cells respond to the temperature rise. Then, the activation time constants, tau(m), were extracted by fitting the sodium currents with the Hodgkin-Huxley model. The infrared laser modulation effect on sodium currents kinetics was examined by taking a ratio between the time constants with and without the laser irradiations. The analysis revealed that the averaged ratio at a specific laser exposure could be well related to the temperature properties of the Na channel protein. These results proved that the modulation of sodium current kinetics of a neuron cell in vitro by 980-nm laser with different-irradiation levels was linearly mediated corresponding to the laser-induced PE. PMID- 25292167 TI - Transcranial low-level laser therapy enhances learning, memory, and neuroprogenitor cells after traumatic brain injury in mice. AB - The use of transcranial low-level laser (light) therapy (tLLLT) to treat stroke and traumatic brain injury (TBI) is attracting increasing attention. We previously showed that LLLT using an 810-nm laser 4 h after controlled cortical impact (CCI)-TBI in mice could significantly improve the neurological severity score, decrease lesion volume, and reduce Fluoro-Jade staining for degenerating neurons. We obtained some evidence for neurogenesis in the region of the lesion. We now tested the hypothesis that tLLLT can improve performance on the Morris water maze (MWM, learning, and memory) and increase neurogenesis in the hippocampus and subventricular zone (SVZ) after CCI-TBI in mice. One and (to a greater extent) three daily laser treatments commencing 4-h post-TBI improved neurological performance as measured by wire grip and motion test especially at 3 and 4 weeks post-TBI. Improvements in visible and hidden platform latency and probe tests in MWM were seen at 4 weeks. Caspase-3 expression was lower in the lesion region at 4 days post-TBI. Double-stained BrdU-NeuN (neuroprogenitor cells) was increased in the dentate gyrus and SVZ. Increases in double-cortin (DCX) and TUJ-1 were also seen. Our study results suggest that tLLLT may improve TBI both by reducing cell death in the lesion and by stimulating neurogenesis. PMID- 25292168 TI - Treatment of a large cystlike inflammatory periapical lesion associated with mature necrotic teeth using regenerative endodontic therapy. AB - INTRODUCTION: Regenerative endodontic therapy is currently used to treat immature permanent teeth with necrotic pulp and/or apical periodontitis. However, mature teeth with necrotic pulp and apical periodontitis have also been treated using regenerative endodontic therapy. The treatment resulted in resolution of apical periodontitis, regression of clinical signs and symptoms but no apparent thickening of the canal walls, and/or continued root development. A recent study in an animal model showed that the tissues formed in the canals of mature teeth with apical periodontitis after regenerative endodontic therapy were cementumlike, bonelike, and periodontal ligament-like tissue with numerous blood vessels. These tissues are similar to the tissues observed in immature permanent teeth with apical periodontitis after regenerative endodontic therapy. METHODS: A 23-year-old woman had a history of traumatic injury to her upper anterior teeth when she was 8 years old. Subsequently, #8 developed pulp necrosis and an acute apical abscess and #7 symptomatic apical periodontitis. The apex of #8 was slightly open, and the apex of #7 was completely formed. Instead of nonsurgical root canal therapy, regenerative endodontic therapy was attempted, including complete chemomechanical debridement on #8 and #7. This was based on the premise that filling of disinfected root canals with the host's biological vital tissue might be better than filling with foreign materials. RESULTS: After regenerative endodontic therapy of #8 and #7, there was radiographic evidence of periapical osseous healing and regression of clinical signs and symptoms. The pulp cavity of #8 decreased in size, and the apex closed. The pulp cavity of #7 appeared to be obliterated by mineralized tissue. These indicated ingrowth of new vital tissue into the chemomechanically debrided canals. CONCLUSIONS: Regenerative endodontic therapy of mature teeth with apical periodontitis and apical abscess can result in the regression of clinical signs and/or symptoms and healing of apical periodontitis but no apparent thickening of the canal walls or continued root development. Filling of the disinfected canals with the host's vital tissue may be better than with foreign materials because vital tissue has innate and adaptive immune defense mechanisms. PMID- 25292169 TI - Provider and interpreter preferences among Somali women in a primary care setting. AB - OBJECTIVES: Somali people are among the largest refugee populations to resettle in North America and Europe over the past 2 decades, and health disparities are well documented, including barriers to effective navigation of primary health care systems. Patient-provider gender discordance has been described as a barrier to health-seeking behaviors and effective communication by Somali women in past qualitative work. The objective of this study was to elucidate provider and interpreter preferences during clinical encounters according to gender and race among Somali women in the United States. METHODS: Fifty Somali women empanelled to a large primary care practice completed pictorial surveys to elucidate preferences of Somali women for providers of different genders and race for different components of the clinical examination using a Likert-type scale. RESULTS: We found that Somali women generally preferred a female provider for conducting the physical examination, particularly for the pelvic, breast, and abdominal examinations. Likewise, Somali women strongly preferred female interpreters to be present during the physical examination. There was no stated preference for patient-provider racial concordance. CONCLUSIONS: These findings have implications for structural health care changes aimed at delivering culturally sensitive and effective primary care to Somali patients. PMID- 25292170 TI - Temporally isolated lineages of pink salmon reveal unique signatures of selection on distinct pools of standing genetic variation. AB - A species' genetic diversity bears the marks of evolutionary processes that have occurred throughout its history. However, robust detection of selection in wild populations is difficult and often impeded by lack of replicate tests. Here, we investigate selection in pink salmon (Oncorhynchus gorbuscha) using genome scans coupled with inference from a haploid-assisted linkage map. Pink salmon have a strict 2-year semelparous life history which has resulted in temporally isolated (allochronic) lineages that remain sympatric through sharing of spawning habitats in alternate years. The lineages differ in a range of adaptive traits, suggesting different genetic backgrounds. We used genotyping by sequencing of haploids to generate a high-density linkage map with 7035 loci and screened an existing panel of 8036 loci for signatures of selection. The linkage map enabled identification of novel genomic regions displaying signatures of parallel selection shared between lineages. Furthermore, 24 loci demonstrated divergent selection and differences in genetic diversity between lineages, suggesting that adaptation in the 2 lineages has arisen from different pools of standing genetic variation. Findings have implications for understanding asynchronous population abundances as well as predicting future ecosystem impacts from lineage-specific responses to climate change. PMID- 25292171 TI - Obama calls on other nations to step up their efforts to end Ebola outbreak. PMID- 25292172 TI - Correlation between the histological features of corneal surface pannus following ocular surface burns and the final outcome of cultivated limbal epithelial transplantation. AB - BACKGROUND/AIMS: To report the influence of histological features of corneal surface pannus following ocular surface burn on the outcome of cultivated limbal epithelial transplantation (CLET). METHODS: On retrospectively reviewing the medical records of the patients who underwent autologous CLET from April 2002 to June 2012 at L V Prasad Eye Institute, Hyderabad, India, we could trace the histological reports in only 90 records. These 90 records, besides clinical parameters, were reviewed for the influence of various histological features on the final outcome of CLET. RESULTS: The histological features include epithelial hyperplasia (21.1%), surface ulceration (2.2%), goblet cells (62.2%), squamous metaplasia (11.1%), active fibrosis (31.1%), severe inflammation (8.9%), multinucleated giant cells (3.3%), stromal calcification (8.9%) and active proliferating vessels (5.6%). Among these histological features, patients with either hyperplasia or calcification in their excised corneal pannus show an unfavourable outcome compared with patients without hyperplasia (p=0.003) or calcification (p=0.018). A similar unfavourable outcome was not seen with other histological features and various clinical parameters. CONCLUSIONS: Presence of either calcific deposits or hyperplasia in the excised corneal pannus provides poor prognostication; hence, a proper counselling of such patients is mandatory along with a close follow-up. PMID- 25292175 TI - The emergence of a new kind of biology. AB - 'It is happily no longer axiomatic that a biophysicist is a physiologist who can fix his own amplifier. Fortunately, physicists are still drifting into biology and bringing new ideas. Please dear colleagues, do take the time to learn biochemistry.' Harold Morowitz provides a personal perspective on working at the interface between the physical and biological sciences. PMID- 25292173 TI - Propofol exerts anti-hepatocellular carcinoma by microvesicle-mediated transfer of miR-142-3p from macrophage to cancer cells. AB - OBJECTIVE: We previously confirmed that propofol directly inhibited the viability, proliferation, and invasiveness of hepatocellular carcinoma cells in vitro. In this study, we investigated the mechanism underlying the anti-HCC effects of propofol. METHODS: In vivo antitumor activity was investigated in tumor-bearing mice following an intraperitoneal injection of propofol, with or without clodrolip. The co-culture system was used to verify that miR-142-3p was transported from macrophages to HCC cells. A miR-142-3p inhibitor was used to down-regulate the expression of miR-142-3p. RESULTS: Propofol drastically inhibited tumor growth in tomor-bearing mice through macrophage activation, and stimulated tumor-associated macrophages (TAMs) to secrete microvesicles (MVs), which delivered miR-142-3p to HCC cells, resulting in the inhibition of HCC cell invasion. In addition, MVs collected from the plasma of the tumor-bearing mice injected with propofol suppressed tumor growth. More importantly, down-regulation of the expression miR-142-3p reversed the effect of propofol on HCC cell migration. CONCLUSIONS: This study reveals a novel role for propofol in the inhibition of HCC through MV-mediated transfer of miR-142-3p from macrophages to cancer cells in vivo. PMID- 25292174 TI - Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression. AB - OBJECTIVES: To evaluate whether reduced activity of the anti-inflammatory HSP70 pathway correlates with nonalcoholic fatty liver disease (NAFLD) progression and with markers of oxidative stress because obesity activates inflammatory JNKs, whereas HSP70 exerts the opposite effect. METHODS: Adult obese patients (N = 95) undergoing bariatric surgery were divided into steatosis (ST), steatohepatitis (SH), and fibrosis (SH+F) groups. The levels of HSP70, its major transcription factor, HSF1, and JNKs were assessed by immunoblotting hepatic and visceral adipose tissue; data were confirmed by immunohistochemistry. Plasma biochemistry (lipids, HbA1c , HOMA, hepatic enzymes, and redox markers) was also evaluated. RESULTS: In both liver and adipose tissue, decreased HSP70 levels, paralleled by similar reductions in HSF1 and reduced plasma antioxidant enzyme activities, correlated with insulin resistance and with NAFLD progression (expression levels were as follows: ST > SH > SH + F). The immunohistochemistry results suggested Kupffer cells as a site of HSP70 inhibition. Conversely, JNK1 content and phosphorylation increased. CONCLUSIONS: Decreased HSF1 levels in the liver and fat of obese patients correlated with impairment of HSP70 in an NAFLD stage dependent manner. This impairment may affect HSP70-dependent anti-inflammation, with consequent oxidative stress and insulin resistance in advanced stages of NAFLD. Possible causal effects of fat cell senescence are discussed. PMID- 25292176 TI - Understanding immunology: fun at an intersection of the physical, life, and clinical sciences. AB - Understanding how the immune system works is a grand challenge in science with myriad direct implications for improving human health. The immune system protects us from infectious pathogens and cancer, and maintains a harmonious steady state with essential microbiota in our gut. Vaccination, the medical procedure that has saved more lives than any other, involves manipulating the immune system. Unfortunately, the immune system can also go awry to cause autoimmune diseases. Immune responses are the product of stochastic collective dynamic processes involving many interacting components. These processes span multiple scales of length and time. Thus, statistical mechanics has much to contribute to immunology, and the oeuvre of biological physics will be further enriched if the number of physical scientists interested in immunology continues to increase. I describe how I got interested in immunology and provide a glimpse of my experiences working on immunology using approaches from statistical mechanics and collaborating closely with immunologists. PMID- 25292177 TI - Speckle tracking echocardiography in the diagnosis of early left ventricular systolic dysfunction in type II diabetic mice. AB - BACKGROUND: The leptin receptor-deficient db/db mouse is a well-established type II diabetes animal model used to investigate diabetic cardiomyopathy. Previous reports have documented diabetic cardiomyopathy is accompanied by cardiac structural and functional abnormalities. To better elucidate early or subtle changes in cardiac performance in db/db mice, we used speckle tracking echocardiography to assess systolic myocardial strain in vivo with diabetic db/db mice in order to study early changes of left ventricle contractile function in type II diabetes model. METHODS: Male diabetic db/db mice and age-matched control mice from C57BL/6J strain at 8,12 and 16 weeks of age were subjected to echocardiography. At the midpapillary level in the parasternal left ventricular short-axis view, end diastolic and systolic left ventricular diameter, interventricular septal thickness and posterior wall thicknesses, ejection fraction, fractional shortening were determined by M-mode echocardiography. Using speckle-tracking based strain analysis of two-dimensional echocardiographic images acquired from the parasternal short-axis views at the mid-papillary level, systolic global radial and circumferential strain values were analyzed. RESULTS: There was no significant difference in interventricular septal thickness, posterior wall thicknesses, end diastolic and systolic left ventricular diameter, ejection fraction and fractional shortening between db/db and age-matched control mice at 8,12 or 16 weeks of age (P > 0.05). At 8 and 12 weeks of age, there was no significant difference in left ventricular radial strain and circumferential strain between db/db mice and age-matched controls (P > 0.05). But at 16 weeks of age, the left ventricular radial strain and circumferential strain in db/db mice were lower than in control mice (P < 0.01). CONCLUSION: The present study shows that speckle tracking echocardiography can be used to evaluate cardiac functional alterations in mouse models of cardiovascular disease. Radial and circumferential strain are more sensitive and can be used for detection of early left ventricular contractile dysfunction in db/db type II diabetic mice. PMID- 25292178 TI - Enhanced non-homologous end joining contributes toward synthetic lethality of pathological RAD51C mutants with poly (ADP-ribose) polymerase. AB - Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are actively under clinical trials for the treatment of breast and ovarian cancers that arise due to mutations in BRCA1 and BRCA2. The RAD51 paralog RAD51C has been identified as a breast and ovarian cancer susceptibility gene. The pathological RAD51C mutants that were identified in cancer patients are hypomorphic with partial repair function. However, targeting cancer cells that express hypomorphic mutants of RAD51C is highly challenging. Here, we report that RAD51C-deficient cells can be targeted by a 'synthetic lethal' approach using PARP inhibitor and this sensitivity was attributed to accumulation of cells in the G2/M and chromosomal aberrations. In addition, spontaneous hyperactivation of PARP1 was evident in RAD51C-deficient cells. Interestingly, RAD51C-negative cells exhibited enhanced recruitment of non-homologous end joining (NHEJ) proteins onto chromatin and this accumulation correlated with increased activity of error-prone NHEJ as well as genome instability leading to cell death. Notably, inhibition of DNA-PKcs or depletion of KU70 or Ligase IV rescued this phenotype. Strikingly, stimulation of NHEJ by low dose of ionizing radiation (IR) in the PARP inhibitor-treated RAD51C deficient cells and cells expressing pathological RAD51C mutants induced enhanced toxicity 'synergistically'. These results demonstrate that cancer cells arising due to hypomorphic mutations in RAD51C can be specifically targeted by a 'synergistic approach' and imply that this strategy can be potentially applied to cancers with hypomorphic mutations in other homologous recombination pathway genes. PMID- 25292182 TI - Lemierre's syndrome - an unusual complication of otitis externa in a young, healthy female. AB - BACKGROUND: Lemierre's syndrome, which affects previously healthy, young adults, is a rare complication secondary to infections in the head and neck that result in septic thrombophlebitis of the internal jugular vein. METHOD: This paper reports a case of a young, healthy female with malignant otitis externa, which resulted in the development of Lemierre's syndrome. A review of the relevant literature was also carried out. This involved a search of the Medline database using multiple search terms including 'Lemierre', 'septic thrombophlebitis', 'otitis externa', 'internal jugular vein thrombosis' and 'management'. RESULTS: The patient presented with fever, left-sided otalgia, otorrhoea, neck swelling and pain. She was subsequently diagnosed with Lemierre's syndrome and managed accordingly. CONCLUSION: Lemierre's syndrome is a potentially fatal complication associated with significant morbidity. A high index of suspicion is required for prompt recognition and the early institution of treatment. PMID- 25292181 TI - Atomoxetine prevents dexamethasone-induced skeletal muscle atrophy in mice. AB - Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. beta2-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha) isoforms, ATP synthase beta, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naive mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1alpha-4-IGF1-Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1alpha expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy. PMID- 25292180 TI - Interleukin-driven insulin-like growth factor promotes prostatic inflammatory hyperplasia. AB - Prostatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1-driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation. PMID- 25292183 TI - Platelet aggregation and clot formation in comatose survivors of cardiac arrest treated with induced hypothermia and dual platelet inhibition with aspirin and ticagrelor; a prospective observational study. AB - INTRODUCTION: We conducted a prospective observational study in cardiac arrest survivors treated with mild induced hypothermia, evaluating different platelet function tests at hypo- and normothermia. We also investigated the relation between gastric emptying and vasodilator stimulated phosphoprotein (VASP). METHODS: Comatose survivors of out of hospital cardiac arrest were included and divided into two groups, depending on whether dual platelet inhibition with peroral ticagrelor and aspirin was given or not. The first blood samples (T1) were collected 12-24 hours after reaching target temperature (33 degrees C) and were compared to blood samples collected 12-28 hours after reaching normothermia (37 degrees C) (T2) within each group. All samples were analysed by Sonoclot viscoelasticity, flow cytometry based VASP and with multiple electrode aggregometry, Multiplate(r); adenosine diphosphate (ADP), collagen (COL), thrombin receptor agonist peptide (TRAP) and arachidonic acid (ASPI). Sonoclot and Multiplate(r) instruments were set on in vivo temperatures. Gastric secretion from the nasogastric tube was measured to assess absorption of per orally administered antiplatelet drugs. Differences between T1 and T2 within each group were calculated using Wilcoxon matched pairs signed test. Significance levels were set at P <0.01. RESULTS: In total, 23 patients were included. In patients with dual platelet inhibition (n =14) Multiplate(r)-analyses showed no changes in ADP stimulated platelets. COL, TRAP and ASPI aggregations were higher at T2 compared to T1. Sonoclot-analyses showed that activated clotting time (ACT) was unchanged but both clot rate (CR) and platelet function (PF) were higher at T2 compared to T1. VASP decreased from 53 +/- 28(T1) to 24 +/- 22(T2), (P <0.001). The average volume of gastric secretion aspirated before T1 correlated well with VASP (T1), r =0.81 (P <0.001). In patients with no platelet inhibition, (n =9) similar changes between T1 and T2 were seen as in patients with dual platelet inhibition while VASP was unchanged. CONCLUSIONS: We have demonstrated increased platelet aggregation and strengthened clot formation over time in out of hospital cardiac arrest patients treated with hypothermia. In patients on oral dual platelet inhibition, the effect of ticagrelor was delayed, probably due to slow gastric emptying. PMID- 25292184 TI - A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria. AB - BACKGROUND: Familial Hyperparathyroidism (HPT) and Familial benign Hypocalciuric Hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. FHH has been demonstrated to be caused by inactivating mutations of calcium-sensing receptor (CaSR) gene, involved in PTH regulation as well as in renal calcium excretion. CASE PRESENTATION: In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene. The hypercalcemia was present only in father, which, by contrast to the classic form of FHH showed hypercalciuria (from 300 to 600 mg/24 h in different evaluations) and a Calcium/Creatinine ratio of 0.031, instead of low or normal calciuria (<0.01 typical finding in FHH). His son showed the same mutation in CaSR gene, but no clinical signs or hypercalcemia although serum ionized calcium levels were close to the upper limit of normal values (1.30 mmol/L: normal range: 1.12-1.31 mmol/L). Sequence analysis revealed a point mutation at codon 972 of CaSR gene (chromosome 3q), located within cytoplasmic domain of the CaSR, that changes Threonine with Methionine. The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl. CONCLUSION: This is a case of a novel inactivating point mutation of CaSR gene that determines an atypical clinical presentation of FHH, characterized by hypercalcemia, hypercalciuria and inadequate normal PTH levels. Functional assay demonstrated that the 972 M variant influenced the maturation of the protein, in terms of the post-translational glycosylation. The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney. PMID- 25292185 TI - Blood lipids and the incidence of atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis and the Framingham Heart Study. AB - BACKGROUND: Dyslipidemia is a major contributor to the development of atherosclerosis and coronary disease. Its role in the etiology of atrial fibrillation (AF) is uncertain. METHODS AND RESULTS: We studied 7142 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study who did not have prevalent AF at baseline and were not on lipid lowering medications. Total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were measured using standard procedures. Incident AF during follow-up was identified from hospital discharge codes; review of medical charts; study electrocardiograms; and, in MESA only, Medicare claims. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of AF by clinical categories of blood lipids in each cohort. Study-specific results were meta-analyzed using inverse of variance weighting. During 9.6 years of mean follow-up, 480 AF cases were identified. In a combined analysis of multivariable-adjusted results from both cohorts, high levels of high-density lipoprotein cholesterol were associated with lower AF risk (hazard ratio 0.64, 95% CI 0.48 to 0.87 in those with levels >=60 mg/dL versus <40 mg/dL), whereas high triglycerides were associated with higher risk of AF (hazard ratio 1.60, 95% CI 1.25 to 2.05 in those with levels >=200 mg/dL versus <150 mg/dL). Total cholesterol and low-density lipoprotein cholesterol were not associated with the risk of AF. CONCLUSION: In these 2 community-based cohorts, high-density lipoprotein cholesterol and triglycerides but not low-density lipoprotein cholesterol or total cholesterol were associated with the risk of AF, accounting for other cardiometabolic risk factors. PMID- 25292186 TI - Prolonged PR interval predicts clinical recurrence of atrial fibrillation after catheter ablation. AB - BACKGROUND: A prolonged PR interval is known to be a poor prognostic factor in cardiovascular disease. The aim of this study was to investigate the association between PR interval and clinical outcome in patients undergoing radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). METHODS AND RESULTS: We prospectively included 576 patients with AF (75.5% male, 57.8+/-11.6 years old, 68.8% paroxysmal AF) who underwent RFCA. We analyzed preprocedural sinus rhythm ECGs obtained in the absence of antiarrhythmic drug, and all enrolled patients were categorized into 4 groups based on the quartile values of the PR interval (166, 182, and 202 ms), and were analyzed according to the left atrium (LA) volume (CT; Computed tomography), LA voltage (NavX), and clinical outcome of AF ablation. Based on quartile value of PR interval, the highest quartile of PR interval (Q4; PR >=202 ms) was oldest (P<0.001), and most likely to have persistent AF (P<0.001) and hypertension (P=0.013) compared with the other groups. However, there was no significant difference in LA conduction velocity and atrial effective refractory period. Q4 had the greatest LA dimension (P<0.001) and volume index (P<0.001), and lowest LA appendage-emptying velocity (P<0.032) and LA voltage (P<0.001) compared with the others. For 13.1+/-7.5 months, the classification based on the PR interval was a significant predictor of AF recurrence after RFCA of AF (HR=1.969, 95% CI 1.343 to 2.886, P=0.001). CONCLUSIONS: The PR interval was closely associated with advanced LA remodeling due to AF, and had a noninvasive significant predictive value of clinical recurrence of AF after RFCA. PMID- 25292187 TI - Node retraction during patterning of the urinary collecting duct system. AB - This report presents a novel mechanism for remodelling a branched epithelial tree. The mouse renal collecting duct develops by growth and repeated branching of an initially unbranched ureteric bud: this mechanism initially produces an almost fractal form with young branches connected to the centre of the kidney via a sequence of nodes (branch points) distributed widely throughout the developing organ. The collecting ducts of a mature kidney have a different form: from the nephrons in the renal cortex, long, straight lengths of collecting duct run almost parallel to one another through the renal medulla, and open together to the renal pelvis. Here we present time-lapse studies of E11.5 kidneys growing in culture: after about 5 days, the collecting duct trees show evidence of 'node retraction', in which the node of a 'Y'-shaped branch moves downwards, shortening the stalk of the 'Y', lengthening its arms and narrowing their divergence angle so that the 'Y' becomes a 'V'. Computer simulation suggests that node retraction can transform a spread tree, like that of an early kidney, into one with long, almost-parallel medullary rays similar to those seen in a mature real kidney. PMID- 25292188 TI - Exchange transfusion can be life-saving in severe propanil poisoning: a case report. AB - BACKGROUND: Propanil is an important cause of herbicide poisoning in Sri Lanka, accounting for about 2% of all cases of self-poisoning. The outcome is extremely poor when the poisoning is severe and current medical care is of limited efficacy. Death usually occurs due to the severe and prolonged methaemoglobinaemia. We describe a case of severe Propanil poisoning, successfully treated by exchange transfusion at a tertiary care hospital in Sri Lanka. CASE PRESENTATION: A 17-year old Sri Lankan male (body weight--42 kg), presented to a local hospital 1 hour after self-ingestion of nearly 500 ml (4.3 g/kg) of liquid Propanil (concentration--360 g/l). On admission he had dizziness and peripheral cyanosis. He was given intravenous methylene blue (1 mg/kg) within one hour of admission, which was repeated subsequently due to minimal response. The next day morning, (18 hours after poisoning) the patient was transferred to the National Hospital of Sri Lanka (NHSL) for further management. On admission to NHSL, he was drowsy and confused, had a shallow respiratory effort and marked central and peripheral cyanosis. Respiratory rate was 20/min, with a pulse oximetry of 77% on room air. The arterial blood gas analysis was as follows; pH- 7.24, HCO3(-)--12 mmol/l, pCO2--28 mmHg, pO2--239 mmHg and O2 saturation--100%. Exchange transfusion was commenced within two hours of admission to NHSL. A dramatic improvement in oxygen saturation was observed immediately afterwards, with the saturation in pulse-oximetry rising to >95%. The level of consciousness and respiratory effort also improved. He was discharged subsequently 8 days after the initial poisoning. CONCLUSION: Propanil has potential to produce severe life threatening clinical manifestations, despite categorization as a herbicide with low toxicity. In cases of severe poisoning, exchange transfusion may be life saving. Since methylene blue, intensive care and exchange transfusion facilities are also not readily available in local hospitals, which frequently encounter cases of severe Propanil poisoning, early transfer of patients to tertiary care hospitals should be considered. Exchange transfusion may be helpful even in late stages in patients with severe poisoning. PMID- 25292189 TI - First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. AB - Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 * 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity. PMID- 25292190 TI - miR-382 inhibits osteosarcoma metastasis and relapse by targeting Y box-binding protein 1. AB - Lung metastasis and relapse in osteosarcoma (OS) patients indicate poor prognosis. Here, we identified significantly decreased expression of miR-382 in highly metastatic OS cell lines and relapsed OS samples compared to their parental cell lines and primary OS samples, respectively. In addition, our clinical data showed that the miR-382 expression level was inversely associated with relapse and positively associated with metastasis-free survival in OS patients. The overexpression of miR-382 suppressed epithelial-mesenchymal transition (EMT) and metastasis. This overexpression also decreased the cancer stem cell (CSC) population and function in OS cells. In contrast, inhibition of miR-382 stimulated EMT and metastasis and increased CSC population in OS cells. In addition, our in vivo experiments showed that the overexpression of miR-382 inhibited CSC-induced tumor formation, and the combination of miR-382 with doxorubicin prevented disease relapse in OS patients. Furthermore, we demonstrated that miR-382 exerted its tumor-suppressing potential by directly targeting Y box-binding protein 1 (YB-1) in OS. Taken together, our findings suggest that miR-382 functions as a tumor suppressor function and that the overexpression of miR-382 is a novel strategy to inhibit tumor metastasis and prevent CSC-induced relapse in OS. PMID- 25292192 TI - Isolation of Aureimonas altamirensis, a Brucella canis-like bacterium, from an edematous canine testicle. AB - Microbiological and histological analysis of a sample from a swollen testicle of a 2-year-old Border Collie dog revealed a mixed infection of the fungus Blastomyces dermatitidis and the Gram-negative bacterium Aureimonas altamirensis. When subjected to an automated microbial identification system, the latter isolate was provisionally identified as Psychrobacter phenylpyruvicus, but the organism shared several biochemical features with Brucella canis and exhibited agglutination, albeit weakly, with anti-B. canis antiserum. Unequivocal identification of the organism was only achieved by 16S ribosomal RNA gene sequencing, ultimately establishing the identity as A. altamirensis. Since its first description in 2006, this organism has been isolated infrequently from human clinical samples, but, to the authors' knowledge, has not been reported from a veterinary clinical sample. While of unknown clinical significance with respect to the pathology observed for the polymicrobial infection described herein, it highlights the critical importance to unambiguously identify the microbe for diagnostic, epidemiological, infection control, and public health purposes. PMID- 25292193 TI - Abortion in cattle due to infection with Staphylococcus lugdunensis. AB - An aborted fetus of 7 months gestation, the associated placenta, and a single blood sample from the dam were submitted for diagnostic investigation to the diagnostic laboratory of the Lombardy and Emilia-Romagna Experimental Zooprophylactic Institute in Parma, Italy. The serum was negative for Neospora caninum, Coxiella burnetii, Chlamydophila abortus, Bovine herpesvirus 1 (BHV-1), Bovine viral diarrhea virus (BVDV), Brucella abortus, and Brucella melitensis. Fetal tissues and placental cotyledons were pooled and tested by polymerase chain reaction (PCR) for the presence of BHV-1, Bovine herpesvirus 4, BVDV, N. caninum, C. burnetii, Chlamydophila spp., Schmallemberg virus, and Leptospira interrogans. All PCR assays were negative. Bacteriological examinations performed on the fetal organs revealed a pure growth of Staphylococcus lugdunensis in all organs cultured. In human beings, S. lugdunensis is responsible for community-acquired and nosocomial infections, in both immunocompetent and immunocompromised patients. In veterinary medicine, the pathogenic potential of S. lugdunensis has not been fully investigated. The incidence of S. lugdunensis is regarded as being underreported because it could be easily misidentified as Staphylococcus aureus. The current report documents the ability of S. lugdunensis to cause abortion in cattle, indicating the need for accurate diagnostic procedures to identify this emerging and zoonotic pathogen whose incidence is likely underestimated in both human and veterinary medicine. PMID- 25292191 TI - SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that stem cell leukemia (SCL) overexpression accelerates the emergence of hemato endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryopoiesis from hESCs. We show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes (MKs), and platelets in vitro. SCL-overexpressing MKs and platelets respond to different activating stimuli similar to their control counterparts. Gene expression profiling of megakaryocytic precursors shows that SCL overexpression renders a megakaryopoietic molecular signature. Connectivity Map analysis reveals that trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), both histone deacetylase (HDAC) inhibitors, functionally mimic SCL-induced effects. Finally, we confirm that both TSA and SAHA treatment promote the emergence of CD34(+) progenitors, whereas valproic acid, another HDAC inhibitor, potentiates MK and platelet production. We demonstrate that SCL and HDAC inhibitors are megakaryopoiesis regulators in hESCs. PMID- 25292194 TI - Interlaboratory and between-specimen comparisons of diagnostic tests for leptospirosis in sheep and cattle. AB - A study was performed to investigate interlaboratory test agreement between a research and a commercial veterinary diagnostic laboratory on blood and urine samples, and to investigate test agreement between blood, urine, and kidney samples (research laboratory) for leptospirosis diagnosis. Samples were sourced from 399 sheep and 146 beef cattle from a local abattoir. Interlaboratory agreement for real-time quantitative polymerase chain reaction (qPCR) results on urine samples was almost perfect (kappa = 0.90), despite the use of different amplification targets (DNA gyrase subunit B gene vs. 16s ribosomal RNA gene), chemistries (SYTO9 vs. TaqMan probe), and pre-PCR processing. Interlaboratory agreement for microscopic agglutination test (MAT) positivity was almost perfect (kappa = 0.93) for Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis (Hardjobovis) but moderate (kappa = 0.53) for Leptospira interrogans serovar Pomona (Pomona). Among animals that had different titers recorded, higher Hardjobovis and lower Pomona titers were reported by the commercial laboratory than by the research laboratory (P < 0.005). These interlaboratory comparisons can assist researchers and diagnosticians in interpreting the sometimes discrepant test results. Within the research laboratory, the comparison of qPCR results on urine and kidney showed almost perfect agreement (kappa = 0.84), suggesting that the qPCR on these 2 specimens can be used interchangeably. The agreement between MAT positivity and urine and kidney qPCR results was fair (kappa = 0.32 and kappa = 0.33, respectively). However, the prevalence ratio of urine and kidney qPCR positivity in Hardjobovis-seropositive versus Hardjobovis seronegative sheep indicated that Hardjobovis seropositivity found in sheep may be able to predict shedding or renal carriage. PMID- 25292195 TI - Hyperplastic goiter in two adult dairy cows. AB - Iodine excess and resultant hyperplastic goiter are well documented in neonatal ruminants, but little is reported on iodine excess in adult ruminants and associated histological changes of the thyroid gland. Two adult Holstein cows from a Michigan dairy herd that had lost several other animals had nonspecific clinical signs of illness and were submitted for necropsy. Thyroid glands of one of these 2 animals were grossly and markedly enlarged, and histologically, thyroid glands from both animals had regions of cystic nodular hyperplasia and follicular atrophy. Thyroid glands from both animals had markedly elevated iodine concentrations. Investigation into the potential source of excessive iodine on the farm revealed multiple sources of supplemental dietary iodine and probable uneven feed and mineral mixing. Based on the findings of this investigation, adult cattle could be susceptible to excessive doses of iodine. Possibility of previous iodine deficiency before supplementation period, with subsequent development and persistence of thyroid hyperplasia and cystic change, cannot be completely excluded. Current findings suggested that iodine excess in adult cattle can result in nodular hyperplastic goiter. Use of iodized salt in mineral supplements in adult dairy herds is common practice, and accidental excessive iodine supplement may be more common than reported. Recognizing gross and histological thyroid gland changes, consisting of concurrent cystic follicular hyperplasia, atrophy, and fibrosis should raise suspicion of iodine excess and/or prior deficiency in a cattle herd, and ancillary tests such as serum iodine measurements should be part of the diagnostic workup in suspected cases. PMID- 25292196 TI - Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations. AB - Lymphatic malformations (LMs) are developmental anomalies of the lymphatic system associated with the dysmorphogenesis of vascular channels lined by lymphatic endothelial cells (LECs). Seeking to identify intrinsic defects in affected LECs, cells were isolated from malformation tissue or fluid on the basis of CD31 and podoplanin (PDPN) expression. LECs from five unrelated LM lesions were characterized, including cells derived from one patient previously diagnosed with CLOVES. CLOVES-related LECs carried a known, activating mutation in PIK3CA (p.H1047L), confirmed by direct sequencing. Activating PIK3CA mutations (p.E542K and p.E545A) were identified in lesion-derived cells from the other four patients, also by direct sequencing. The five LM-LEC cultures shared a lymphangiogenic phenotype distinguished by PI3K/AKT activation, enhanced sprouting efficiency, elevated VEGF-C expression and COX2 expression, shorter doubling times and reduced expression of angiopoietin 2 and CXCR4. Nine additional LM-LEC populations and 12 of 15 archived LM tissue samples were shown to bear common PIK3CA variants by allele-specific PCR. The activation of a central growth/survival pathway (PI3K/AKT) represents a feasible target for the non-invasive treatment of LMs bearing in mind that background genetics may individualize lesions and influence treatments. PMID- 25292198 TI - LncRNA-HOST2 regulates cell biological behaviors in epithelial ovarian cancer through a mechanism involving microRNA let-7b. AB - Recently, a large number of long non-coding RNAs (lncRNAs) have been reported in mammalian genomes and are evolutionarily conserved and presumably function in many biological events, especially in the pathogenesis of diverse human cancers. A lncRNA, named HOST2 (human ovarian cancer-specific transcript 2), was once reported to specifically be expressed at high level in human ovarian cancer. However, how HOST2 acts to regulate gene functions in ovarian carcinogenesis has remained enigmatic. Here we report, for the first time, that HOST2 promotes tumor cell migration, invasion and proliferation in epithelial ovarian cancer by working in key aspects of biological behaviors. In the present study, bioinformatics analysis indicated that HOST2 binds with microRNA let-7b, a potent tumor suppressor, which was then verified to target HOST2. Our results showed that HOST2 harbors a let-7b binding site and modulates let-7b availability by acting as a molecular sponge. HOST2 inhibits let-7b functions, which post transcriptionally suppress the expression of targets, including some oncogenes that regulate cell growth and motility. Additionally, understanding HOST2/let-7b dependent regulation may lead to alternative approaches for the diagnosis and cure of this deadly disease. PMID- 25292200 TI - [Bronchoscopic lung volume reduction is a treatment offered to patients with severe heterogenous emphysema]. AB - Introduction of bronchoscopic lung volume reduction as a treatment for severe emphysema has been defined as an area of development by The Danish Health and Medicines Authority. We here present the rationale for treatment, in- and exclusion criteria, and ultimately the organization for assessment, treatment and follow-up in Denmark. The treatment aim is to lower dyspnoea. There is a national protocol for patient selection according to in- and exclusion criteria. Different commercial devices are available, but endobronchial valves have been the devices mostly applied. A national database has been established to evaluate cost effectiveness. PMID- 25292201 TI - [Pregnancy complications in a patient with systemic lupus erythematosus and lupus nephritis]. AB - A woman with systemic lupus erythematosus (SLE) and lupus nephritis had two pregnancies which both resulted in complications known to be associated with SLE, i.e. late abortion, preterm delivery and pre-eclampsia. We conclude that disease quiescence is important for a successful outcome and that pregnant women with SLE should be followed in a multidisciplinary setting. PMID- 25292197 TI - Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. AB - Mutations in the RP2 gene lead to a severe form of X-linked retinitis pigmentosa. RP2 patients frequently present with nonsense mutations and no treatments are currently available to restore RP2 function. In this study, we reprogrammed fibroblasts from an RP2 patient carrying the nonsense mutation c.519C>T (p.R120X) into induced pluripotent stem cells (iPSC), and differentiated these cells into retinal pigment epithelial cells (RPE) to study the mechanisms of disease and test potential therapies. RP2 protein was undetectable in the RP2 R120X patient cells, suggesting a disease mechanism caused by complete lack of RP2 protein. The RP2 patient fibroblasts and iPSC-derived RPE cells showed phenotypic defects in IFT20 localization, Golgi cohesion and Gbeta1 trafficking. These phenotypes were corrected by over-expressing GFP-tagged RP2. Using the translational read-through inducing drugs (TRIDs) G418 and PTC124 (Ataluren), we were able to restore up to 20% of endogenous, full-length RP2 protein in R120X cells. This level of restored RP2 was sufficient to reverse the cellular phenotypic defects observed in both the R120X patient fibroblasts and iPSC-RPE cells. This is the first proof-of concept study to demonstrate successful read-through and restoration of RP2 function for the R120X nonsense mutation. The ability of the restored RP2 protein level to reverse the observed cellular phenotypes in cells lacking RP2 indicates that translational read-through could be clinically beneficial for patients. PMID- 25292202 TI - [Severe osteoporosis in a patient with polycythaemia vera]. AB - This case report is about severe osteoporosis in a woman known with polycythaemia vera (PV). A 51-year-old woman with hereditary predisposition to osteoporosis had a dual X-ray absorptiometry scan without osteoporosis. Only one year later she was diagnosed with PV. Re-scan eight years later showed progression to severe osteoporosis. Whether this is secondary osteoporosis, initiated or accelerated by the presence of PV is not known. A recent Danish registry study has shown that PV patients have an increased incidence of fractures compared with the general population. PMID- 25292199 TI - Co-ordinated brain and craniofacial development depend upon Patched1/XIAP regulation of cell survival. AB - Congenital brain and craniofacial defects often occur together as a consequence of their developmental dependency on common progenitor tissue interactions and signaling pathways during embryogenesis. A classic example of this is perturbation of midline embryo development, and disruption of Hedgehog (Hh) signaling in the pathogenesis of holoprosencephaly. However, our understanding of how Hh signaling governs cell and tissue survival remains incomplete. Patched1 (Ptch1) is a well-known receptor for Hh ligands and Ptch1 overexpression is associated with cell and tissue-specific apoptosis. Here, we demonstrate that the X-linked inhibitory apoptosis protein (XIAP) associates with the C terminus of Ptch1 (Ptch1-C) in primary cilia to inhibit Ptch1-mediated cell death. Consistent with this observation, inhibition of XIAP suppresses cell proliferation, resulting in cell death and pathogenesis of an Hh loss-of-function phenotype. Thus, co-ordinated development of the brain and face is dependent in part upon XIAP mediation of Hh/Ptch1-regulated cell survival and apoptosis during embryogenesis. PMID- 25292203 TI - [Ramadan, fasting and pregnancy]. AB - In Islam, the month of Ramadan is a period of fasting lasting 29 or 30 days. Epidemiological studies among Muslims in Denmark have not been conducted, but studies show, that fasting among pregnant Muslim women is common. Fasting does not increase the risk of growth restriction or preterm delivery, but there are reports of decreased foetal movements. Furthermore, the fasting may have long term health consequences for the offspring, especially when they reach their middle age. According to Islam and the interpretation, pregnant and breast feeding women are allowed to postpone the fasting of the month of Ramadan to a later period. PMID- 25292204 TI - [Post-partum transient osteoporosis of the hip causing pain]. AB - Transient osteoporosis of the hip (TOH) affects pregnant women in the third trimester of pregnancy. Magnetic resonance imaging plays an important role in the diagnosis and shows a pattern of bone marrow oedema. We report a case of TOH post partum with involvement of both hips in a 34-year-old woman. She was known with undifferentiated spondyloartritis since 2004, which posed a diagnostic challenge. The reported patient was treated conservatively avoiding lactation, weight bearing activities, increased intake of calcium and vitamin D and recovered without further medical treatment. PMID- 25292205 TI - [New classification and genetic background of inherited ichthyoses]. AB - A new classification of inherited ichthyoses is presented based on clinical features, genetic background and pathophysiology. Ichthyoses are disorders of cornification and may be part of syndromes. Ichthyosis vulgaris, X-linked ichthyosis, autosomal recessive congenital ichthyosis and syndrome-related variants are described. Severe forms can be potentially life-threatening. Dry scaly skin can be disabling and time-consuming, as the patient needs topical therapy and sometimes also systemic retinoids. Treatment today is symptomatic, but hopefully new knowledge will lead to targeted therapies. PMID- 25292206 TI - Cerebral pathology post heart transplantation. AB - Cerebral pathology is frequently encountered post heart transplantation with a cumulative incidence of about 80% after 15 years. A broad spectrum of disease entities is reported, from minor abnormalities to life-threatening diseases. Although cerebral infections and malignancies are rare in this patient population, they have a high mortality rate. Since 1991, 171 orthotopic heart transplantations were performed at the Ghent University Hospital with a 10-year survival rate of 75%. Severe cerebral complications occurred in 10 patients, with epilepsy in 2 patients, cerebrovascular accidents in 4 patients, cerebral infections in 3 patients and a cerebral malignancy in 1 patient, resulting in a fatal outcome in 7 patients. We present four of these cases. PMID- 25292207 TI - Role of a remote leucine residue in the catalytic function of polyol dehydrogenase. AB - Studies on the protein-metal binding sites have mainly focused on the residues immediately surrounding the reacting substrate, cofactors, and metal ions. The contribution of residues in remote layers to the highly optimized microenvironments of catalytic active sites is not well understood. To improve our understanding, the present study examined the role of remote residues on the structure and function of zinc-dependent polyol dehydrogenases. We used an integrated computational and biochemical approach to determine the role of L136 in the third shell of the l-arabinitol 4-dehydrogenase (LAD) from Neurospora crassa. Substitution of L136 with charged (Asp, Lys, or His) and bulky (Trp) side chain amino acids abolished enzyme activity. Whereas the L136A mutant exhibited a 95% decrease in catalytic efficiency (kcat/Km), the L136C mutant exhibited a 39% decrease in kcat/Km. Additionally, molecular docking and dynamic simulations on the mutant (L136A, L136C, L136H, and L136P) complexes showed the loss of crucial H-bonds between G77 and the corresponding mutated residue. It is evident from theoretical and biochemical studies that the L136 is part of the extensive hydrogen bonding network coupled to the reaction catalyzed at the active site. We propose that L136, critically positioned behind the active site residues H78 and E79 in the third shell of LAD, plays a crucial role in modulating catalysis or substrate binding by stabilizing the GHE motif in the LAD active site. PMID- 25292208 TI - Two-dimensional inverse opal hydrogel for pH sensing. AB - A novel hydrogel film with a highly ordered macropore monolayer on its surface was prepared by templated photo-polymerization of hydrogel monomers on a two dimensional (2D) polystyrene colloidal array. The 2D inverse opal hydrogel has prominent advantages over traditional three-dimensional (3D) inverse opal hydrogels. First, the formation of the 2D array template through a self-assembly method is considerably faster and simpler. Second, the stable ordering structure of the 2D array template makes it easier to introduce the polymerization solution into the template. Third, a simple measurement, a Debye diffraction ring, is utilized to characterize the neighboring pore spacing of the 2D inverse opal hydrogel. Acrylic acid was copolymerized into the hydrogel; thus, the hydrogel responded to pH through volume change, which resulted from the formation of the Donnan potential. The 2D inverse opal hydrogel showed that the neighboring pore spacing increased by about 150 nm and diffracted color red-shifted from blue to red as the pH increased from pH 2 to 7. In addition, the pH response kinetics and ionic strength effect of this 2D mesoporous polymer film were also investigated. PMID- 25292209 TI - Two-dimensional transition metal dichalcogenide nanosheet-based composites. AB - Ultrathin two-dimensional (2D) nanosheets of layered transition metal dichalcogenides (TMDs), such as MoS2, TiS2, TaS2, WS2, MoSe2, WSe2, etc., are emerging as a class of key materials in chemistry and electronics due to their intriguing chemical and electronic properties. The ability to prepare these TMD nanosheets in high yield and large scale via various methods has led to increasing studies on their hybridization with other materials to create novel functional composites, aiming to engineer their chemical, physical and electronic properties and thus achieve good performance for some specific applications. In this critical review, we will introduce the recent progress in hybrid nanoarchitectures based on 2D TMD nanosheets. Their synthetic strategies, properties and applications are systematically summarized and discussed, with emphasis on those new appealing structures, properties and functions. In addition, we will also give some perspectives on the challenges and opportunities in this promising research area. PMID- 25292210 TI - A brief report on Primary Care Service Area catchment geographies in New South Wales Australia. AB - BACKGROUND: To develop a method to use survey data to establish catchment areas of primary care or Primary Care Service Areas. Primary Care Service Areas are small areas, the majority of patients resident in which obtain their primary care services from within the geography. METHODS: The data are from a large health survey (n =267,153, year 2006-2009) linked to General Practitioner service use data (year 2002-2010) from New South Wales, Australia. Our methods broadly follow those used previously by researchers in the United States of America and Switzerland, with significant modifications to improve robustness. This algorithm allocates post code areas to Primary Care Service Areas that receive the plurality of patient visits from the post code area. RESULTS: Consistent with international findings the median Localization Index or the median percentage of patients that obtain their primary care from within a Primary Care Service Area is 55% with localization increasing with rurality. CONCLUSIONS: With the additional methodological refinements in this study, Australian Primary Care Service Areas have great potential to be of value to policymakers and researchers. PMID- 25292211 TI - The tao of IGF-1: insulin-like growth factor receptor activation increases pain by enhancing T-type calcium channel activity. AB - T-type calcium channels are important players in the transmission of pain signals in the primary afferent pathway. Indeed, inhibiting or depleting T-type calcium channels in dorsal root ganglion (DRG) neurons mediates analgesia. Conversely, nerve injury or peripheral inflammation have been shown to induce T-type calcium channel activity in DRG neurons, and this in turn has been linked to the development of chronic pain states. The mechanisms that underlie this enhancement of T-type channels remain incompletely understood and may include changes in channel stability in the plasma membrane or alterations in channel function. In this issue of Science Signaling, Zhang and colleagues identify a cell signaling pathway that potently regulates T-type calcium channel activity in afferent neurons and link this process to pain hypersensitivity. Specifically, they show that insulin-like growth factor-1 receptors in DRG neurons mediate a protein kinase C alpha (PKCalpha)-dependent enhancement of T-type calcium currents and that interfering with this pathway reduces both mechanical and thermal pain hypersensitivity in rodents. Targeting this process offers a new avenue for developing pain therapeutics. PMID- 25292212 TI - Distinct integrin-dependent signals define requirements for lytic granule convergence and polarization in natural killer cells. AB - Lytic granules in natural killer (NK) cells represent a dangerous cargo that is targeted for secretion to destroy diseased cells. The appropriate management of these organelles enables the mounting of a precise and valuable host defense. The process of NK cell adhesion to a target cell through engagement of the integrin LFA-1 (lymphocyte function-associated antigen 1) promotes lytic granule organization through complex cellular mechanics and a signaling pathway characterized by Zhang et al. in this issue of Science Signaling. A set of signaling molecules was defined for their ability to promote the polarization of NK cell lytic granules and the microtubule organizing center (MTOC) toward the interface with a target cell. A subset of these signaling molecules was also required for the convergence of lytic granules on the MTOC. PMID- 25292213 TI - Peripheral pain is enhanced by insulin-like growth factor 1 through a G protein mediated stimulation of T-type calcium channels. AB - Insulin-like growth factor 1 (IGF-1) is implicated in the nociceptive (pain) sensitivity of primary afferent neurons. We found that the IGF-1 receptor (IGF 1R) functionally stimulated voltage-gated T-type Ca(2+) (CaV3) channels in mouse dorsal root ganglia (DRG) neurons through a mechanism dependent on heterotrimeric G protein (heterotrimeric guanine nucleotide-binding protein) signaling. IGF-1 increased T-type channel currents in small-diameter DRG neurons in a manner dependent on IGF-1 concentration and IGF-1R but independent of phosphatidylinositol 3-kinase (PI3K). The intracellular subunit of IGF-1R coimmunoprecipitated with Galphao. Blocking G protein signaling by the intracellular application of guanosine diphosphate (GDP)-beta-S or with pertussis toxin abolished the stimulatory effects of IGF-1. Antagonists of protein kinase Calpha (PKCalpha), but not of PKCbeta, abolished the IGF-1-induced T-type channel current increase. Application of IGF-1 increased membrane abundance of PKCalpha, and PKCalpha inhibition (either pharmacologically or genetically) abolished the increase in T-type channel currents stimulated by IGF-1. IGF-1 increased action potential firing in DRG neurons and increased the sensitivity of mice to both thermal and mechanical stimuli applied to the hindpaw, both of which were attenuated by intraplantar injection of a T-type channel inhibitor. Furthermore, inhibiting IGF-1R signaling or knocking down CaV3.2 or PKCalpha in DRG neurons abolished the increased mechanical and thermal sensitivity that mice exhibited under conditions modeling chronic hindpaw inflammation. Together, our results showed that IGF-1 enhances T-type channel currents through the activation of IGF 1R that is coupled to a G protein-dependent PKCalpha pathway, thereby increasing the excitability of DRG neurons and the sensitivity to pain. PMID- 25292216 TI - Two cultures? Experiences at the physics-biology interface. AB - 'I didn't really think of this as moving into biology, but rather as exploring another venue in which to do physics.' John Hopfield provides a personal perspective on working on the border between physical and biological sciences. PMID- 25292214 TI - Tyrosine phosphorylation of NEDD4 activates its ubiquitin ligase activity. AB - Ligand binding to the receptor tyrosine kinase fibroblast growth factor (FGF) receptor 1 (FGFR1) causes dimerization and activation by transphosphorylation of tyrosine residues in the kinase domain. FGFR1 is ubiquitylated by the E3 ligase NEDD4 (also known as NEDD4-1), which promotes FGFR1 internalization and degradation. Although phosphorylation of FGFR1 is required for NEDD4-dependent endocytosis, NEDD4 directly binds to a nonphosphorylated region of FGFR1. We found that activation of FGFR1 led to activation of c-Src kinase-dependent tyrosine phosphorylation of NEDD4, enhancing the ubiquitin ligase activity of NEDD4. Using mass spectrometry, we identified several FGF-dependent phosphorylated tyrosines in NEDD4, including Tyr(43) in the C2 domain and Tyr(585) in the HECT domain. Mutating these tyrosines to phenylalanine to prevent phosphorylation inhibited FGF-dependent NEDD4 activity and FGFR1 endocytosis and enhanced cell proliferation. Mutating the tyrosines to glutamic acid to mimic phosphorylation enhanced NEDD4 activity. Moreover, the NEDD4 C2 domain bound the HECT domain, and the presence of phosphomimetic mutations inhibited this interaction, suggesting that phosphorylation of NEDD4 relieves an inhibitory intra- or intermolecular interaction. Accordingly, activation of FGFR1 was not required for activation of NEDD4 that lacked its C2 domain. Activation of c-Src by epidermal growth factor (EGF) also promoted tyrosine phosphorylation and enhanced the activity of NEDD4. Thus, we identified a feedback mechanism by which receptor tyrosine kinases promote catalytic activation of NEDD4 and that may represent a mechanism of receptor crosstalk. PMID- 25292215 TI - A signaling network stimulated by beta2 integrin promotes the polarization of lytic granules in cytotoxic cells. AB - Cytotoxic lymphocytes kill target cells through the polarized release of the contents of intracellular perforin-containing granules. In natural killer (NK) cells, the binding of beta2 integrin to members of the intercellular adhesion molecule family is sufficient to promote not only the adhesion of NK cells to target cells but also the polarization of intracellular lytic granules toward the target. We used NK cells in an experimental system designed to enable us to study the polarization of lytic granules in the absence of their release through degranulation, as well as beta2 integrin signaling independently of inside-out signals from other receptors. Through a proteomics approach, we identified a signaling network centered on an integrin-linked kinase (ILK)-Pyk2-paxillin core that was required for granule and microtubule-organizing center (MTOC) polarization. The conserved Cdc42-Par6 signaling pathway, which controls cell polarity, was also activated by ILK and was required for granule polarization toward the target cell. A subset of the signaling components required for polarization contributed also to the convergence of granules on the MTOC. These results delineate two connected signaling networks that are stimulated upon beta2 integrin engagement and control the polarization of the MTOC and associated lytic granules toward the site of contact with target cells to mediate cellular cytotoxicity. PMID- 25292217 TI - Prevalence of antibacterial resistant bacterial contaminants from mobile phones of hospital inpatients. AB - Mobile phones contaminated with bacteria may act as fomites. Antibiotic resistant bacterial contamination of mobile phones of inpatients was studied. One hundred and six samples were collected from mobile phones of patients admitted in various hospitals in Jazan province of Saudi Arabia. Eighty-nine (83.9%) out of 106 mobile phones were found to be contaminated with bacteria. Fifty-two (49.0%) coagulase-negative Staphylococcus, 12 (11.3%) Staphylococcus aureus, 7 (6.6%) Enterobacter cloacae, 3 (2.83%) Pseudomonas stutzeri, 3 (2.83%) Sphingomonas paucimobilis, 2 (1.8%) Enterococcus faecalis and 10 (9.4%) aerobic spore bearers were isolated. All the isolated bacteria were found to be resistant to various antibiotics. Hence, regular disinfection of mobile phones of hospital inpatients is advised. PMID- 25292218 TI - An evaluative study of the benefits of participating in intergenerational playgroups in aged care for older people. AB - BACKGROUND: Intergenerational playgroups in aged care are limited and little is known about the perceptions of individuals who have participated in such programs. Most research is focused on intergenerational programs that involved two generations of people--young people and older people or young people and people with dementia reported the significant outcomes for each group of participants. In this study a number of generations participated in the intergenerational playgroup intervention that included older people, child carers who were parents, grandparents or nannies and children aged 0-4 years old. The objective of this study was to explore the benefits of participating in an intergenerational playgroup program IPP in an aged care facility. METHODS: This mixed methods quantitative and qualitative design explored the benefits of participating in an intergenerational playgroup program IPP in aged care settings. The intervention is an intergenerational playgroup program (IPP) offered in the aged care facility where intergenerational socialisation and interaction occurred between different generations. The SF36 and Geriatric Depression Scale (GDS) were used to collect pre-test post test data. The qualitative interpretive research approach used semi-structured interviews to develop the descriptive interpretation of the intergenerational playgroup experience. Interviews were conducted with aged care residents and child carers. RESULTS: The pre-test post-test results for the SF36 revealed a declining trend in one scale only energy/fatigue and no significant differences on the Geriatric Depression Scale GDS. The interview analyses revealed the following themes (1) intergenerational experiences, (2) two-way contributions, (3) friendships work, (4) personal growth, and (5) environmental considerations and nineteen subthemes were extracted to provide meanings. CONCLUSIONS: The IPP provided a successful innovative intergenerational program intervention where older people and people with dementia interacted and connected with a number of people from different generations. The IPP provided meaningful engagement for all participants considered important for self-esteem and the ability to participate fully in society. This allowed people to develop a sense of connectedness and friendships in a safe and secure environment. This increased the dignity of older people and people with dementia within the community and increased public awareness about the existing care and support services available to them. PMID- 25292219 TI - Rejoice in the hubris: useful things biologists could do for physicists. AB - Political correctness urges us to state how wonderful it is to work with biologists and how, just as the lion will someday lie down with the lamb, so will interdisciplinary work, where biologists and physicists are mixed together in light, airy buildings designed to force socialization, give rise to wonderful new science. But it has been said that the only drive in human nature stronger than the sex drive is the drive to censor and suppress, and so I claim that it is OK for physicists and biologists to maintain a wary distance from each other, so that neither one censors or suppresses the wild ideas of the other. PMID- 25292220 TI - Severe rickets in a young girl caused by celiac disease: the tragedy of delayed diagnosis: a case report. AB - BACKGROUND: Celiac disease is a systemic immune mediated disease which usually presents with gastrointestinal symptoms, but it may present with extra gastrointestinal manifestations such as metabolic bone disease and failure to thrive. This may lead to a delay in the diagnosis. CASE PRESENTATION: We present a 13 year old female from the middle east with an 8 year history of severe rickets causing multiple bone deformities leaving the child crippled with bowing of both of her arms and legs. The patient was also found to have growth failure, anemia and on further workup she was found to have celiac disease. CONCLUSION: We are presenting this case because it shows a severe case of rickets after malabsorption for many years. Celiac disease should be kept in mind as a cause of rickets in patients not responding to usual forms of treatment or when associated with other manifestations of malabsorption. PMID- 25292221 TI - Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery. AB - INTRODUCTION: Thromboembolic complications contribute substantially to perioperative morbidity and mortality. Routine laboratory tests do not detect patients with acquired or congenital hypercoagulability who may be at increased risk of perioperative thromboembolism. Rotational thromboelastometry (ROTEM) is a digitized modification of conventional thromboelastography that is stable and technically easy to use. We designed a prospective observational study to evaluate whether preoperative ROTEM can identify patients at increased risk for postoperative thromboembolic complications after major non-cardiac surgery. METHODS: Preoperative ROTEM analysis using extrinsic rotational thromboelastometry (EXTEM), intrinsic rotational thromboelastometry (INTEM), and fibrinogen rotational thromboelastometry (FIBTEM) activators was performed on 313 patients undergoing major non-cardiac surgery. Patients' medical records were reviewed after discharge for results of standard coagulation studies - partial thromboplastin time (PTT), international normalized ratio (INR), platelet count - and evidence of thromboembolic complications during their hospital stay. A thromboembolic complication was defined as a new arterial or deep venous thrombosis, catheter thrombosis, or pulmonary embolism diagnosed by ultrasound or spiral chest computed tomography. RESULTS: Ten patients developed postoperative thromboembolic complications, of whom 9 had received standard prophylaxis with subcutaneous enoxaparin or heparin. There was no indication of by PTT, INR, or platelet count. Preoperative EXTEM and INTEM activators that assess fibrin clot formation and platelet interaction indicated that these patients had significantly lower clot formation time (CFT) and significantly higher alpha angle (alpha) and maximum clot firmness (MCF), compared to patients without thromboembolic complications. There was no significant difference for any parameter using FIBTEM activator, which excludes platelet interaction. Receiver operating characteristic (ROC) curves were constructed for these variables. INTEM clot firmness at 10 min (A10) was the best predictor of thromboembolic complications, with an ROC area under the curve of 0.751. CONCLUSIONS: Our results indicate that preoperative ROTEM assays that include fibrin clot and platelet interaction may detect patients at increased risk for postoperative thromboembolic complications after major non-cardiac surgery. Future studies need to evaluate the clinical utility and cost effectiveness of preoperative ROTEM and better define the association between ROTEM values and specific hypercoagulable conditions. PMID- 25292222 TI - GluN2B protein deficits in the left, but not the right, hippocampus in schizophrenia. AB - BACKGROUND: Increasing evidence indicates that alterations to the function and subunit composition of the glutamatergic NMDA receptor are associated with the pathophysiology of schizophrenia. The GluN2B protein is a structural and functional subunit of the NMDA receptor, with a growing body of evidence indicating it plays a critical role in cognitive functions mediated by the NMDA receptor. The hippocampus plays a key role in cognitive function, with studies suggesting lateralised glutamatergic dysfunction in this region may contribute to the cognitive deficits observed in schizophrenia patients. The present study, for the first time, investigated GluN2B protein and binding density in the left and right hippocampus of 20 schizophrenia subjects compared to 20 matched controls. METHODS: The dentate gyrus of 20 schizophrenia and 20 control subjects, matched for age, post-mortem interval, and pH, was obtained from the NSW Tissue Resource Centre, Australia. Each group consisted of dentate gyrus from the left hemisphere (n = 10) and right hemisphere (n = 10). GluN2B protein density was measured via immunoblotting. GluN2B binding density was measured using the GluN2B antagonist, [3H] Ifenprodil. Analyses of covariance, covarying for demographic variables that influenced the data, were used to test for statistical significance between schizophrenia and control groups. Pearson's correlations were used to determine the association of GluN2B protein and binding density with demographic and clinical variables, including lifetime antipsychotic drug exposure. RESULTS: GluN2B protein levels were decreased by 43% in the left hemisphere of schizophrenia subjects compared to controls (p = 0.012). There was no difference in GluN2B protein levels in the right hemisphere of schizophrenia subjects compared to controls. There were no differences in [(3)H] Ifenprodil binding according to diagnosis or hemisphere. There were no associations between GluN2B measures and lifetime antipsychotic drug exposure. CONCLUSIONS: Our findings provide the first evidence of GluN2 protein abnormalities in the hippocampus in schizophrenia, highlighting the hippocampal lateralisation in this disorder. We suggest this deficit could contribute to the cognitive dysfunctions that arise in patients. These findings provide preliminary support for the development of therapeutics that target the GluN2B subunit, as a novel therapy for schizophrenia, especially the cognitive dysfunctions. PMID- 25292223 TI - Optimal intervention time of vagal stimulation attenuating myocardial ischemia/reperfusion injury in rats. AB - OBJECTIVE: To determine the optimal intervention time of the vagal stimulation (VS) attenuating myocardial ischemia/reperfusion injury (IRI). METHODS: One hundred and twenty male SD rats were randomly allocated into six groups: sham group, IRI group, the VS performed at 15 min of ischemia (VSI15) group, the VS performed immediately before reperfusion (VSR0) group, the VS performed at 30 min of reperfusion (VSR30) group, and the VS performed at 60 min of reperfusion (VSR60) group. Rats in each group were further allocated into subgroups A and B. In each group, the hemodynamics and ventricular arrhythmias were continuously observed. In the subgroup A, serum inflammatory cytokine levels were tested, and infarct size was assessed. In the subgroup B, myocardial inflammatory cytokine levels in both ischemic and non-ischemic regions were assayed. RESULTS: As compared to the IRI, VSR0, VSR30 and VSR60 groups, infarct size, serum HMGB-1 and ICAM-1 levels at 120 min of reperfusion, myocardial HMGB-1, IL-1 and IL-6 levels in non-ischemic region, myocardial ICAM-1 level in ischemic region were all significantly decreased in the VSI15 group. Compared with the IRI group, myocardial IL-10 levels in both ischemic and non-ischemic regions were significantly increased in the VSI15 group. Compared to the IRI, VSR0, VSR30 and VSR60 groups, incidence and score of ventricular arrhythmia during initial reperfusion were significantly decreased in the VSI15 group. CONCLUSIONS: The VS performed at 15 min of ischemia provides the best protection against myocardial IRI. Also, early modulation on inflammatory responses caused by myocardial IRI may contribute to this best cardioprotection. PMID- 25292224 TI - ["Disappeared intrauterine devices" should be sought for]. PMID- 25292225 TI - [Optimal treatment of pneumothorax]. PMID- 25292226 TI - [Array-comparative genomic hybridization is a new and promising method for prenatal chromosomal diagnosis]. AB - Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying chromosomal imbalances and is now used on a clinical basis for prenatal diagnosis. This article reviews the advantages and disadvantages of the method, the ethical considerations and the current recommendations for prenatal use in Denmark according to a new national guideline from The Danish Society of Foetal Medicine and the Danish Society of Medical Genetics. PMID- 25292227 TI - [Hip dysplasia]. AB - Hip dysplasia and femoroacetabular impingement are frequent causes of hip pain and can often be treated with joint preserving surgery to prevent secondary osteoarthritis (OA). Patient education, progressive resistance training and weight loss at a BMI > 27 kg/m(2) has documented effect on pain and function in primary hip OA. If wound infection occurs after total hip arthroplasty the patient should not be treated with peroral antibiotics but instead be referred to an orthopaedic surgeon. There is no documentation that post-operative movement restrictions prevent dislocation of hip after total hip arthroplasty. PMID- 25292228 TI - [Segmental reversal of the small bowel as treatment of short bowel syndrome in adults]. AB - Short bowel syndrome is the result of extensive surgical resection, inherited defects or loss of functional absorbing intestine. Parenteral nutrition is associated with high economical expenses, increased morbidity and decreased quality of life. Intestinal transplantation is associated with high morbidity and mortality rates. Segmental reversal of the small bowel can prolong the transit time in the small bowel and in many cases permanently end parenteral nutrition dependency. Segmental reversal of the small bowel should be integrated in the surgical treatment of adults with short bowel syndrome. PMID- 25292229 TI - [Implementation of the shared medication record is difficult]. AB - The aim of the study was to examine the implementation of the shared medication record (SMR) and the barriers to lack of implementation. The research was done in three hospitals in Denmark. Data showed that SMR was not used systematically in the period 5-19 March 2012 at a hospital in the Capital Region of Denmark. We found that motivation, technical problems, time, and competencies were barriers to using SMR. Although all the doctors liked the idea of SMR, they did not find the present version of SMR to be fully developed for use in practice. PMID- 25292230 TI - [Hyperbaric oxygen treatment of poisoning]. AB - Experiments have suggested reduction of neurological sequelae from carbon monoxide (CO) poisoning by treatment with hyper-baric oxygen (HBO). Randomised clinical trials have, however, been ambiguous. The discrepancy may be explained by timing of HBO relative to exposure. For other asphyxiants data are too sparse for a qualified judgement. Until more evidence is available, we suggest that HBO is used exclusively for moderate and severe CO poisoning within a time window of 12 hours. PMID- 25292231 TI - [Danish studies of acute treatment after initiation of emergency departments]. AB - In Denmark, hospitals in these years reorganize the overall acute treatment of patients with the aim of providing better quality of treatment during several common interventions. This paper presents a status of the limited number of Danish studies, which have examined the acute care and knowledge about the planned interventions in the emergency departments. The new concept for the reception and treatment of emergency patients opens up new areas of research in a Danish context. The number of preliminary published results that have been presented by Danish acute conferences testify this. PMID- 25292232 TI - [Radium-223 treatment of bone metastases from castration-resistant prostate cancer]. AB - The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I III tests showing significant reduction in alkaline phosphatase- and PSA level and prolonged survival. Adverse events are usually mild to moderate and comprise gastrointestinal and myelotoxic symptoms. Intravenously administered (22)3Ra-Cl2 (half-life 11.4 days) will likely be given every four weeks for six treatments to out-patients. PMID- 25292233 TI - [Individualized treatment of osteoarticular infections in children may shorten the treatment course]. AB - Older studies have suggested that antibiotic treatment for less than 21 days in children with osteoarticular infections is associated with relapse, and therefore traditionally these infections have been treated for six weeks with an intravenous phase of one week. However, four new prospective studies suggest that if the duration of treatment is individualized and made dependent on the clinical response and the C-reactive protein level, the treatment course may be shortened substantially without increasing the risk of relapse or sequelae. This article reviews older and newer literature on this subject. PMID- 25292234 TI - [After weight loss a child fits a smaller blood pressure cuff but gets elevated blood pressure]. AB - A ten-year-old boy referred to childhood obesity treatment lost weight after one year of lifestyle intervention to a degree where he was no longer obese. Contrary to anticipated beyond the effect of a normal growth, his clinical blood pressure (BP) was higher after weight loss. This observation was caused by the use of a smaller BP cuff compared to a larger cuff at baseline. In general, weight loss in obese children during growth and development pose a challenge in regard to which BP cuff size should be used and in regard to interpretive challenges of the BP. PMID- 25292235 TI - [Severe fractures while driving a Segway personal transporter]. AB - We present two cases of patients who sustained severe fractures while driving a Segway in an amusement park. The first, a 59-year-old man, had a displaced femoral neck fracture operated with three screws. After two and a half months he had a total hip replacement. After three weeks he had another re-placement due to infection. The second, a 26-year-old male, had a displaced femoral neck fracture operated with three screws. The fracture healed uneventfully. The Segway's legal position, in Denmark, is like bicycles. For statistics, we have specific codes for trauma with a Segway. PMID- 25292236 TI - [Serious complications to a weight loss programme with HCG]. AB - A 28-year-old woman presented with abdominal pain. Prior to admission she had injected human chorionic gonadotropin (hCG) intramuscularly as part of a weight loss programme. A computed tomography detected a thrombosis of the superior mesenteric vein and with a gynaecologic scan she was found to be six weeks pregnant despite using oral contraception. Treatment with anticoagulant therapy was started, and a surgical abortion was performed. hCG bought illegal is used as a part of a weight loss program. Whether HCG injected in small amounts is a risk factor of venous thrombosis and whether it is able to reduce the effect of oral contraception is unknown. PMID- 25292237 TI - [Heterotopic ossification in the brain can occur without preceding trauma]. AB - Heterotopic ossification (HO) is a relatively common complication to e.g. hip arthroplasty. This case report is the first description of a patient, who developed intracranial HO without previous trauma or other provoking events including hereditary disease. PMID- 25292238 TI - [Forced treatment of a periappendicular abscess in a paranoid schizophrenic]. AB - A paranoid schizophrenic 34-year-old man presented with acute lower right abdominal pain. A periappendicular abscess was discovered and the septic patient was offered drainage - which he refused. He was found to be psychotic with auditory hallucinations and a lack of insight into the severity of his condition. In respect of the patient's wishes, conservative treatment was chosen. The patient's condition worsened and the abscess was then drained against his will in accordance with the Danish mental health law. After the drainage, he had a cardiac arrest, presumably from hypoxia following aspiration. PMID- 25292239 TI - [Optimized assessment of intestinal perfusion may reduce the risk of anastomotic leakage in the gastrointestinal tract]. AB - The risk of anastomotic leakage is still high. Evaluation of blood perfusion intraoperatively may give the surgeon the possibility of changing strategy during the operation when needed. A review of the literature shows three different methods, none of which have been implemented in the surgical everyday. There is a need for more research in this field before any of the methods are ready to be used in the surgical standard procedure. PMID- 25292240 TI - [Scintigraphy showing bladder in the scrotum by coincidence]. AB - Inguinoscrotal bladder herniation (ISBH) is rare and often asymptomatic, but complications such as renal failure can occur. We present a case of a 70-year-old man with hydrocele. A bone scan showed tracer accumulation in the left scrotum, and a SPECT/CT while urinating revealed that most of the bladder was in the scrotum. Renal function was normal and a cystoscopy was done. The patient did not want surgery. Hydrocele has not been described as the primary cause of referral in patients with ISBH. It is important to diagnose ISBH because of the risk of complications and risk of underlying malignancy. PMID- 25292241 TI - [On the brink of a new era in the treatment of chronic hepatitis C virus infection in Denmark]. AB - Treatment of chronic hepatitis C virus (HCV) has for more than a decade been based upon use of pegylated interferon in combination with ribavirin. Sustained virologic response rates are in general at a moderate level and severe adverse effects are frequent. With the introduction of direct acting antivirals (DAA) we now face the possibility of interferon-free treatment with higher response rates and less severe adverse effects. However, the costs of the DAAs are high presenting an additional economical burden to the health sector calling for necessary priorities to be taken. PMID- 25292242 TI - [Denosumab normalized plasma calcium concentration in malignancy-associated hypercalcaemia]. AB - This case report shows how denosumab apparently treated bisphosphonate-refractory hypercalcaemia caused by a neuroendocrine tumour of the pancreas in a 48-year-old woman. We cannot eliminate the possibility that the patient's DOTATOC-treatment contributed to the decline in plasma calcium concentration. Preliminary results from a recent large, clinical trial, suggest that denosumab is a more potent treatment of malignancy-associated hypercalcaemia than bisphosphonates. PMID- 25292243 TI - [Propofol-induced trismus, causing an unanticipated difficult intubation due to masseter spasm]. AB - We report a case of a 54-year-old male who within a month had two events of bilateral masseter spasm (BMS) at induction of anaesthesia. The first time BMS caused unanticipated difficult intubation after infusion of remifentanil and propofol, and conseqeuently the general anaesthesia was terminated. The second time an awake fiberoptic intubation was planned followed by infusion of propofol, and once again there was a BMS breakout. This side effect of propofol has been reported to the Danish Health and Medicines Authority. PMID- 25292244 TI - [Digoxin intoxication in an infant because of confusion of bottles of magistral preparations of medicine]. AB - We hereby describe a case report of a 9-month-old girl, who was accidentally intoxicated with digoxin since her parents by mistake gave her digoxin instead of propranolol. At admission sinusbradycardia and a first-degree atrioventricular block was found and she was treated with antidigitalis Fab-fragment and atropine. After three days of hospitalization she was discharged well-being. We suspect that the explanation for this intoxication is due to confusion of bottles of magistral preparations of medicine, as they were very identical. Therefore we call for increased attention in children receiving this type of medicine. PMID- 25292245 TI - [Pulmonary tuberculosis]. PMID- 25292246 TI - [Reducing postpolypectomy bleeding in colon and rectum]. AB - Postpolypectomy bleeding is the most common complication of colonoscopic polypectomy. When the Danish colorectal cancer screening programme is fully implemented it will generate approximately 40,000 colonoscopies and thousands of polypectomies, all with a bleeding risk. In that context we find it important to give evidence-based recommendations regarding techniques used to prevent postpolypectomy bleeding. A literature search was conducted for studies that investigate the various techniques used and recommendations are given. PMID- 25292247 TI - Retraction: Methanol-induced conformation transition of gland fibroin monitored by FTIR spectroscopy and terahertz spectroscopy. AB - Retraction of 'Methanol-induced conformation transition of gland fibroin monitored by FTIR spectroscopy and terahertz spectroscopy' by Chao Yan et al., Analyst, 2014, 139, 1967-1972. PMID- 25292248 TI - Arsenic-containing hydrocarbons are toxic in the in vivo model Drosophila melanogaster. AB - Arsenic-containing hydrocarbons (AsHC) constitute one group of arsenolipids that have been identified in seafood. In this first in vivo toxicity study for AsHCs, we show that AsHCs exert toxic effects in Drosophila melanogaster in a concentration range similar to that of arsenite. In contrast to arsenite, however, AsHCs cause developmental toxicity in the late developmental stages of Drosophila melanogaster. This work illustrates the need for a full characterisation of the toxicity of AsHCs in experimental animals to finally assess the risk to human health related to the presence of arsenolipids in seafood. PMID- 25292249 TI - Potential mode of protection of silkworm pupae from environmental stress by harboring the bacterial biofilm on the surfaces of silk cocoons. AB - The silkworm forms cocoon to protect its pupa that survives for months inside the cocoon without being affected by various environmental stresses. To understand the possible mode of pupal survival within the cocoon encasement, we investigate the cause that protects the cocoon. During the end of the spinning process, we have isolated different bacterial species from the cocoon surface. These are identified using molecular techniques and checked for their abilities to form biofilm in vitro. The bacteria are able to form biofilm either individually or in consortia. Of which, Bacillus and Erwinia species are prominent biofilm formers. Interestingly, these bacteria have the ability to form biofilm on the cocoon mimetic surface of the silk protein Sericin Hope that contains only sericin. The origin and the behavior of the bacteria lead us to hypothesize the possible role of biofilm layer on the cocoon surface, which provides protection from adverse environmental conditions. PMID- 25292250 TI - Bacillus vanillea sp. nov., Isolated from the Cured Vanilla Bean. AB - A Gram-positive bacterium, designated strain XY18(T), was isolated from a cured vanilla bean in Hainan province, China. Cells were rod-shaped, endospore producing, and peritrichous flagella. Strain XY18(T) grew at salinities of 0-8 % (w/v) NaCl (optimally 1-4 %), pH 4.0-8.0 (optimally 5.0-7.0 %) and temperature range 20-45 degrees C (optimally 28-35 degrees C). The predominant menaquinone was MK-7. The major cellular fatty acids were anteiso-C15:0, iso-C15:0, anteiso C17:0, and iso-C17:0. Phylogenetic analysis based on 16S rRNA gene sequence indicated that strain XY18(T) was a member of the genus Bacillus, and closely related to B. amyloliquefaciens NBRC 15535(T) and B. siamensis PD-A10(T), with 99.1 and 99.2 % sequence similarity, respectively. However, the DNA-DNA hybridization value between strain XY18(T) and B. amyloliquefaciens NBRC 15535(T) was 35.7 %. The genomic DNA G+C content of strain XY18(T) was 46.4 mol%, significantly differed from B. siamensis PD-A10(T) (41.4 %), which was higher than the range of 4 % indicative of species. On the basis of polyphasic taxonomic study, including phenotypic features, chemotaxonomy, and phylogenetic analyses, strain XY18(T) represents a novel species within the genus Bacillus, for which the name Bacillus vanillea sp. nov. is proposed. The type strain is XY18(T) (=CGMCC 8629 = NCCB 100507). PMID- 25292255 TI - Peripheral immature B cells: modulators of autoimmunity. AB - B cells play an essential role in humoral immunity by producing antigen-specific antibodies. However, B cells also participate in cellular immune responses by presenting antigens, providing costimulation, and producing cytokines to activate and expand effectors and memory T cell populations. Recent identification of antibody-independent functions of B cells has reawakened interest in the many roles of B cells in normal immune responses as well as in autoimmune diseases. B cells interact with other immunocompetent cells during a tightly regulated immune activation process, acting as both effector and regulator. If this balance between effector and regulatory B cell functions is disrupted, harmful effects of immune activation such as autoimmunity can occur. In this review, we will discuss the role of human peripheral immature B cells in normal immune responses as a modulator of autoimmunity. We will also discuss abnormalities of these cells in pathogenesis of systemic autoimmunity with particular focus on systemic lupus erythematosus pathogenesis. PMID- 25292256 TI - Calcium carbonate crystal growth beneath Langmuir monolayers of acidic beta hairpin peptides. AB - Four amphiphilic peptides with designed hairpin structure were synthesized and their monolayers were employed as model systems to study biologically inspired calcium carbonate crystallization. Langmuir monolayers of hairpin peptides were investigated by surface pressure area isotherms, surface potential isotherms, Brewster angle microscopy (BAM), atomic force microscopy (AFM) and Fourier transform infrared (FTIR) spectroscopy. A beta-hairpin conformation was found for all peptides at the air-water interface although their packing arrangements seem to be different. Crystallization of calcium carbonate under these peptide monolayers was investigated at different surface pressures and growth times both by in situ optical microscopy, BAM and ex situ investigations such as scanning electron microscopy (SEM) and transmission electron microscopy (TEM). An amorphous calcium carbonate precursor was found at the initial crystallization stage. The crystallization process occurred in three stages. It starts from the nucleation of amorphous particles being a kinetically controlled process. Crystal nuclei subsequently aggregate to large particles and vaterite crystals start to form inside the amorphous layer, with the monolayer fluidity exerting an important role. The third process includes the re-crystallization of vaterite to calcite, which is thermodynamically controlled by monolayer structural factors including the monolayer flexibility and packing arrangement of the polar headgroups. Thus, the kinetic factors, monolayer fluidity and flexibility as well as structure factors govern the crystal morphology and polymorph distribution simultaneously and synergistically. PMID- 25292257 TI - Excising stem samples underwater at native tension does not induce xylem cavitation. AB - Xylem resistance to water stress-induced cavitation is an important trait that is associated with drought tolerance of plants. The level of xylem cavitation experienced by a plant is often assessed as the percentage loss in conductivity (PLC) at different water potentials. Such measurements are constructed with samples that are excised underwater at native tensions. However, a recent study concluded that cutting conduits under significant tension induced cavitation, even when samples were held underwater during cutting. This resulted in artificially increased PLC because of what we have termed a 'tension-cutting artefact'. We tested the hypothesized tension-cutting artefact on five species by measuring PLC at native tension compared with after xylem tensions had been relaxed. Our results did not support the tension-cutting artefact hypothesis, as no differences were observed between native and relaxed samples in four of five species. In a fifth species (Laurus nobilis), differences between native and relaxed samples appear to be due to vessel refilling rather than a tension cutting effect. We avoided the tension-cutting artefact by cutting samples to slightly longer than their measurement length and subsequent trimming of at least 0.5 cm of sample ends prior to measurement. PMID- 25292259 TI - Blepharochalasis showing prominent infiltration of neutrophils in dermal vessels. PMID- 25292258 TI - The involvement of high mobility group 1 cytokine and phospholipases A2 in diabetic retinopathy. AB - BACKGROUND: Diabetic retinopathy, the main microvascular complications of diabetes and one of the leading causes of blindness worldwide. Interesting reports on the role of inflammatory/proangiogenic high mobility group 1 (HMGB-1) cytokine and phospholipases A2 (PLA2) in neovascularization have diverted our concentration to reveal whether HMGB-1 and PLA2 plays role in diabetic retinopathy. METHODS: We performed our study in streptozotocin (STZ)-induced diabetic rat model. The expression levels of the cytokines, chemokines, and cell adhesion molecules in retinal tissues were evaluated by quantitative RT-PCR. HMGB 1 and PLA2 protein levels along with VEGF, TNF-alpha, IL-1beta and ICAM-1 levels were also measured. RESULTS: We observed the retinal pericytes, endothelial injury/death and breakdown of blood-retinal barrier (BRB). The protein expression of HMGB-1, PLA2 and IL-1beta were significantly increased in micro vessels from retina of diabetic rats. Diabetic rats had also high retinal levels of VEGF, ICAM 1 and TNF-alpha. Further investigation revealed that pericyte death is mediated by HMGB-1-induced cytotoxic activity of glial cells, while HMGB-1 can directly mediate endothelial cell death. Similarly, increased expression of PLA2 represents the diabetic mediated alteration of BRB, perhaps up regulating the VEGF. CONCLUSIONS: Our data suggest that HMGB-1 and PLA2 involved in retinal pericyte and endothelial injury and cell death in diabetic retinopathy. From this study, we suggest that HMGB-1 and PLA2 may be interesting targets in managing diabetic retinopathy. PMID- 25292260 TI - Primary mucosal melanoma of the sinonasal tract: a clinicopathologic and immunohistochemical study of thirty-two cases. AB - Sinonasal mucosal melanoma is a rare disease with poor survival. These tumors may have associated intraepithelial melanocytic proliferations, which are not extensively characterized. This retrospective analysis of 32 patients with sinonasal mucosal melanoma examined associated intraepithelial melanocytic proliferations in the context of diagnostic and prognostic features. Patient age ranged from 30 to 90 years (median 71) with a male to female ratio of approximately 3:2. Follow up for 31 patients ranged from 5 to 211 months (mean 42 months). Most patients died from melanoma-associated causes (18/31, 58 %), six (19 %) died from unknown causes, two (6 %) were alive with metastatic disease, and only five patients (16 %) remained alive without melanoma. The tumors were histopathologically heterogeneous, displaying epithelioid, spindled, and small cell cytomorphology. The presence of >2 mitoses/mm(2) and necrosis correlated with tumor progression and overall survival, respectively (p = 0.04 for both). Melanoma in situ, defined as a confluent intraepithelial proliferation of cytologically atypical melanocytes, was identified in 20 of 30 evaluable cases (67 %) and confirmed with immunohistochemical staining for microphthalmia associated transcription factor. Melanocytic hyperplasia, defined as intraepithelial melanocytic proliferation without confluent growth or marked atypia, was seen in five cases (16 %). This incidence of associated intraepithelial melanocytic proliferations (83 %) is higher than previously reported. Because of the locally aggressive nature of these tumors, an awareness of the high rate of associated intraepithelial melanocytic proliferations may inform future studies of therapeutic options. PMID- 25292262 TI - Generics in chronic myeloid leukemia: current arguments for and against and the established evidence. AB - Tyrosine kinase inhibitors became the mainstay of management in patients with chronic myeloid leukemia. The substantially high treatment cost has unfortunately been a major issue. Recent market entry of the imatinib generics are expected to lower the price and increase the availability of the drug worldwide. However, concerns about their efficacy and safety seem to slacken the approval of the generics in many countries. In this editorial, we discuss the current evidence on imatinib generics based mainly on Turkish experience and other limited data available. PMID- 25292261 TI - Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression. AB - Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation. PMID- 25292263 TI - Sharing the Knowledge: Sharing Aggregate Genomic Findings with Research Participants in Developing Countries. AB - Returning research results to participants is recognised as an obligation that researchers should always try to fulfil. But can we ascribe the same obligation to researchers who conduct genomics research producing only aggregated findings? And what about genomics research conducted in developing countries? This paper considers Beskow's et al. argument that aggregated findings should also be returned to research participants. This recommendation is examined in the context of genomics research conducted in developing countries. The risks and benefits of attempting such an exercise are identified, and suggestions on ways to avoid some of the challenges are proposed. I argue that disseminating the findings of genomic research to participating communities should be seen as sharing knowledge rather than returning results. Calling the dissemination of aggregate, population level information returning results can be confusing and misleading as participants might expect to receive individual level information. Talking about sharing knowledge is a more appropriate way of expressing and communicating the outcome of population genomic research. Considering the knowledge produced by genomics research a worthwhile output that should be shared with the participants and approaching the exercise as a 'sharing of knowledge', could help mitigate the risks of unrealistic expectations and misunderstanding of findings, whilst promoting trusting and long lasting relationships with the participating communities. PMID- 25292265 TI - A perspective: Robert B Laughlin. AB - Despite their cultural differences, physics and biology are destined to interact with each other more in the future. The reason is that modern physics is fundamentally about codification of emergent law, and life is the greatest of all emergent phenomena. PMID- 25292266 TI - Medical education, cost and policy: what are the drivers for change? Commentary. AB - Medical education is expensive. Its expense has led many stakeholders to speculate on how costs could be reduced. In an ideal world such decisions would be made on sound evidence; however this is impossible in the absence of evidence. Sometimes practice will be informed by policy, but policy will not always be evidence based. So how is policy in the field of cost and value in medical education actually developed? The foremost influence on policy in cost and value should be evidence-based knowledge. Unfortunately policy is sometimes influenced by what might at best be termed tradition and at worst inertia. Another influence on policy will be people--but some individuals may have more influence than others. A further influence on policy in this field is events, and mainly events that have gone wrong. One final influence on emerging policy in medical education cost analysis is that of the media. PMID- 25292264 TI - The Curvature Induction of Surface-Bound Antimicrobial Peptides Piscidin 1 and Piscidin 3 Varies with Lipid Chain Length. AB - The initial steps of membrane disruption by antimicrobial peptides (AMPs) involve binding to bacterial membranes in a surface-bound (S) orientation. To evaluate the effects of lipid composition on the S state, molecular dynamics simulations of the AMPs piscidin 1 (p1) and piscidin 3 (p3) were carried out in four different bilayers: 3:1 DMPC/DMPG, 3:1 POPC/POPG, 1:1 POPE/POPG, and 4:1 POPC/cholesterol. In all cases, the addition of 1:40 piscidin caused thinning of the bilayer, though thinning was least for DMPC/DMPG. The peptides also insert most deeply into DMPC/DMPG, spanning the region from the bilayer midplane to the headgroups, and thereby only mildly disrupting the acyl chains. In contrast, the peptides insert less deeply in the palmitoyl-oleoyl containing membranes, do not reach the midplane, and substantially disrupt the chains, i.e., the neighboring acyl chains bend under the peptide, forming a basket-like conformation. Curvature free energy derivatives calculated from the simulation pressure profiles reveal that the peptides generate positive curvature in membranes with palmitoyl and oleoyl chains but negative curvature in those with myristoyl chains. Curvature inductions predicted with a continuum elastic model follow the same trends, though the effect is weaker, and a small negative curvature induction is obtained in POPC/POPG. These results do not directly speak to the relative stability of the inserted (I) states or ease of pore formation, which requires the free energy pathway between the S and I states. Nevertheless, they do highlight the importance of lipid composition and acyl chain packing. PMID- 25292267 TI - Monographic section: clinical, bioethical and experimental considerations behind the study of coma patients. Preface. PMID- 25292268 TI - Technology-based assessment in patients with disorders of consciousness. AB - INTRODUCTION: A number of studies highlight the difficulty in forming a diagnosis for patients with disorders of consciousness when this is established merely on behavioral assessments. BACKGROUND: Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and electroencephalography combined with transcranial magnetic stimulation (TMS-EEG) techniques are promoting the clinical characterization of this challenging population. With such technology-based "objective" tools, patients are also differentially able to follow simple commands and in some cases even communicate through modified brain activity. Consequently, the vegetative state and minimally conscious state have been revised and new nosologies have been proposed, namely the unresponsive wakefulness syndrome, the minimally conscious state plus and minus, and the functional locked-in syndrome. AIM: To our mind, an integration of different technical modalities is important to gain a holistic vision of the underlying pathophysiology of disorders of consciousness in general and to promote single-patient medical management in particular. PMID- 25292269 TI - Biomedical research involving patients with disorders of consciousness: ethical and legal dimensions. AB - THE DIRECTIVE 2001/20/UE AND THE RESEARCH INVOLVING PATIENTS WITH DOCS: Research involving patients with disorders of consciousness (DOCs) deserves special ethical and legal attention because of its Janus-faced nature. On the one hand, it raises concerns about the risk to expose the involved subjects to disproportionate risks not respecting their individual dignity, particularly their right to be cared for; on the other hand, research is an essential tool in order to improve the clinical condition of patients with DOCs. The present paper concerns the ethical and legal dimensions of biomedical research involving patients with disorders of consciousness. In particular, it focuses on informed consent to experimental treatments, which is a challenging issue both from an ethical and legal point of view. The first part reads the Directive 2001/20/EU in the light of the experimentation of patients with DOCs, and suggests a revision in order to better assess the issue of informed consent. THE PARTICULAR CASE OF INFORMED CONSENT FOR OBSERVATIONAL STUDIES OF NON-COMMUNICATIVE PATIENTS: The second part presents an informed consent form for studies through video-recording of patients unable to communicate their own consent. This form has been elaborated by the bioethics unit of the project "Review of the nosography of vegetative states: application of methods of behavioral analysis to individuals in coma or vegetative state" developed at the Italian National Institute of Health. RELEVANCE OF THE SUGGESTED FORM: The paper describes the conceptual framework of the form for informed consent to studies through video-recoding, which is a relevant example of what issues should be included in an informed consent for any type of studies through video-recording of patients unable to express their own consent. The article has been sent on November the 7th 2013, before the adoption of the Regulation (EU) no. 536/2014 (and consequent abrogation of the Directive 2001/20/EU) and the release of the new edition of the Italian Code of Medical Ethics. PMID- 25292270 TI - Misdiagnosis as an ethical and scientific challenge. AB - DIFFICULTIES OF BEHAVIORAL ASSESSMENT OF CONSCIOUSNESS: An astonishingly high rate of misdiagnosis between vegetative state/unresponsive wakefulness syndrome and minimally conscious state has been detected. This raises the issue of the adequacy of the consciousness' assessment in patients with disorders of consciousness. The behavioral assessment of consciousness could be not able to detect covert awareness, which is increasingly identified by the instrumental assessment. ANCILLARY METHODS: Neurotechnology, particularly neuroimaging, provides relevant data concerning the neurological underlying condition of patients with DOCs, but the instrumental approach has still to assess some technical issues. ETHICAL CONSIDERATIONS: A correct diagnosis of a DOC is not only an instrumental issue, but also an ethically relevant demand to the scientific community. Finally, an integration between behavioral and instrumental assessments seems to be the most adequate strategy in order to decrease the rate of misdiagnosis. PMID- 25292271 TI - Advances in the neurorehabilitation of severe disorder of consciousness. AB - INTRODUCTION: The paper describes the evolution of knowledge concerning severe brain injury which determines the Vegetative State/Unresponsive Wakefulness Syndrome. BACKGROUND: The term Vegetative State was proposed by Jennet and Plum in 1972. Later on, the Intensive Care Units progresses increased the survival of these patients and, contemporary, decreased their characteristic conditions of cachexia and severe dystonia. In 1994, the disease was conceived as a disconnection syndrome of the hemispheres from the brainstem, mainly due to a temporary or permanent deficit of the functions of the white matter. From 2005 on, the psychophysiological parameters relative to an emotional consciousness, albeit submerged, were described. Since then, it has been recognized that the brain of these patients was not only to be considered living but also working. CONCLUSION: The latest studies that have greatly improved the knowledge of the physiopathology of this particular state of consciousness. These new insights have led to the formation of a European Union Task Force, which has proposed in 2009 to change the name from a Vegetative State to Unresponsive Wakefulness Syndrome, outlining the character of syndrome and not that of state, as forms of even late recovery in consciousness levels have been observed and described. PMID- 25292272 TI - Coma and vegetative states: state of the art and proposal of a novel approach combining existing coma scales. AB - Brain damage of various aetiologies can lead to different disorders of consciousness (DOC), varying from coma to vegetative, to minimally conscious states. Each state is characterised by a different degree of wakefulness, awareness, pain sensitivity and is differentially handled with respect to treatment, ethical considerations and end-oflife decisions. Thus, its correct identification is crucial while devising or modulating appropriate treatment strategies. Actually, the main coma scales cannot always accurately determine the state of consciousness of an individual, while other tools (e.g. imaging techniques) present a certain degree of uncertainty. A complementary approach may be constituted by a 24-hour observation of patients, for a sufficient period of days, using an ad hoc behavioural scale, further correlated with physiological and pharmacological parameters measured on patients. The method herein described might help recognising the presence of consciousness of the different DOC patients, and thus discerning a vegetative from a minimally conscious state. PMID- 25292273 TI - What death is. A literary approach between fears and hope. PMID- 25292274 TI - New epistemological foundations for cultural psychology: from an atomistic to a self-organizing view of living systems. AB - An epistemological foundation for cultural psychology is essential to neuro- and behavioural sciences for the challenge psychological sciences must currently face: searching for an explanation of how a brain can become a mind and how individuals assign a sense to the world and their life. Biological systems are very likely determined by physical and chemical laws of spontaneous self organization and endogenous constraints but, even if the major result of the Darwinian revolution is "the discovery that living species are their story", the modern synthesis of the evolution theory adopted only continuist and gradualist hypotheses. This nourished the analogy between the theory of natural selection and the theory of operant conditioning, thereby supporting empiricist associationism and the methodological positivism of behavioural and "classical" cognitive psychologists. Current scientific contributions provide evidence to the need for psychotherapy and psychopathology of a new epistemological approach in order to connect research stemming from animal models, up to the most abstract levels of personal meaning. The complex system oriented approach, here described, called "post-rationalism", shaped by a change initiated by evolutionary epistemology. The regulation of emotions initially develops within interpersonal relationships and evolves during both phylogeny and ontogeny, according to complex self-organization processes, leading to the acquisition of Self organizing abilities and the construction of personal meaning. Endorsing the epistemological similarities of neo-Darwinism and behaviourism, and differentiating from this, the above mentioned approach, emphasises the fact that clinical and psycho-therapeutical practice must be founded on the laws of biological organisation: the ongoing activity of neurobiological systems, including the more abstract domains of thought and language. PMID- 25292275 TI - A meta-analysis of mortality data in Italian contaminated sites with industrial waste landfills or illegal dumps. AB - OBJECTIVES: Adverse effects of waste management represent a public health issue. Mortality meta-analysis in Italian National Priority Contaminated Sites (NPCSs) with industrial waste landfills or illegal dumps is presented. METHODS: 24 NPCSs include industrial waste landfills or illegal dumps. Class 1 (10 NPCSs with industrial waste landfills) and Class 2 (14 NPCSs with illegal dumps) were categorized. Random-effects model meta-analyses of Standardized Mortality Ratios non-adjusted (SMRs) and adjusted for Deprivation (DI-SMRs) computed for each CS (1995-2002) were performed for overall 24 NPCSs and the two classes. The North- Southern gradient was considered. RESULTS: 24 CSs pooled-SMRs are significantly increased in both genders for cancer of liver (men: SMR=1.13; women: SMR=1.18), bladder (men: SMR=1.06; women: SMR=1.11), and for cirrhosis (men: SMR=1.09; women: SMR=1.13). In Class 2 the increase is confirmed in both genders for liver and bladder cancers and for cirrhosis and in men only for lung cancer. Congenital anomalies and adverse perinatal conditions are not increased. CONCLUSION: The results are consistent with the hypothesis of adverse health effects of non adequately managed hazardous waste. Causal interpretation is not allowed, but the meta-analytic approach provides more confidence in the findings. PMID- 25292276 TI - Brain tumor stem cell dancing. AB - BACKGROUND: Issues regarding cancer stem cell (CSC) movement are important in neurosphere biology as cell-cell or cell-environment interactions may have significant impacts on CSC differentiation and contribute to the heterogeneity of the neurosphere. AIMS: Despite the growing body of literature data on the biology of brain tumor stem cells, floating CSC-derived neurospheres have been scarcely characterized from a morphological and ultrastructural point of view. RESULTS: Here we report a morphological and ultrastructural characterization performed by live imaging and scanning electron microscopy. Glioblastoma multiforme (GBM) CSC derived neurospheres are heterogeneous and are constituted by cells, morphologically different, capable of forming highly dynamic structures. These dynamic structures are regulated by not serendipitous cell-cell interactions, and they synchronously pulsate following a cyclic course made of "fast" and "slow" alternate phases. Autocrine/paracrine non canonical Wnt signalling appears to be correlated with the association status of neurospheres. CONCLUSIONS: The results obtained suggest that GBM CSCs can behave both as independents cells and as "social" cells, highly interactive with other members of its species, giving rise to a sort of "multicellular organism". PMID- 25292277 TI - The continued ageing of people with AIDS in Italy: recent trend from the national AIDS Registry. AB - Introduction. In industrialized countries, the availability of highly active antiretroviral therapy (HAART) caused a slow but substantial ageing of the AIDS epidemic mainly due to the longer survival of persons with HIV/AIDS which has turned HIV into a manageable, chronic disease. The number of older people with AIDS is growing in many European countries. We described the impact of AIDS among persons aged 50 years or more in Italy and compared the characteristics of these cases with those of persons diagnosed with AIDS at an age younger than 50. Methods. The source of data was the Italian AIDS Registry, from 1982 to 2011. We defined "older" persons those aged 50 years or more, and younger individuals those aged less than 50 years. We built two multivariate logistic regression models: the first one to identify factors associated with being older, and the second one to identify AIDS-defining diseases correlated with being older. Variables with a P value of <0.05 were entered in the model. Results. Of the total AIDS cases, 10.5% were among persons older than 49 years. This proportion progressively increased from 0.0% in 1983 to 26.4% in 2011. Among older cases, the incidence of AIDS was 2.0 per 100 000 residents in 1996, then decreased to 1.4 per 100 000 in 2000 and levelled off around 1 per 100 000 residents until 2011. Compared to younger cases, older cases were more frequently males, Italians, diagnosed with AIDS in recent years, residing in Northern or Central Italy, non-injecting drug users, and late testers. Discussion. These findings stress the need for physicians to consider carefully the possibility of HIV infection among older individuals not to miss the opportunity to deliver prevention messages, offer HIV testing, and make an early diagnosis. PMID- 25292278 TI - Combined HLA matched limbal stem cells allograft with amniotic membrane transplantation as a prophylactic surgical procedure to prevent corneal graft rejection after penetrating keratoplasty: case report. AB - PURPOSE: To determine if the use of combined HLA matched limbal stem cells allograft with amniotic membrane transplantation (AMT) is a safe and effective prophylactic surgical procedure to prevent corneal graft after penetrating keratoplasty (PK). METHODS: We report the case of a 17 years old patient with a history of congenital glaucoma, trabeculectomy and multiple corneal graft rejections, presenting total limbal cell deficiency. To reduce the possibility of graft rejection in the left eye after a new PK, a two step procedure was performed. At first the patient underwent a combined HLA matched limbal stem cells allograft (LAT) and AMT and then, 10 months later, a new PK. RESULTS: During 12 months of follow-up, the corneal graft remained stable and smooth, with no sign of graft rejection. CONCLUSIONS: In our patient, the prophylactic use of LAT from HLA-matched donors and AMT before PK, may result in a better prognosis of corneal graft survival. PMID- 25292279 TI - Anti-angiogenic therapy versus dose-dense paclitaxel therapy for frontline treatment of epithelial ovarian cancer: review of phase III randomized clinical trials. AB - The investigation of anti-angiogenic agents and dose-dense paclitaxel therapy in epithelial ovarian cancer is an active area of research. To date several phase III trials have shown both approaches to be effective strategies for the frontline treatment of ovarian cancer over standard every 21 day chemotherapy alone. However, most of the improvement is seen only in progression-free survival, with added toxicity (e.g., hypertension, diarrhea, sensory neuropathy, fatigue). Subset analyses based on clinical predictors (e.g., residual disease) have been able to identify patients more likely to benefit from anti-angiogenic agents. And more recently, molecular profiling of tumor genetics has shown similar promising results. Ongoing research will help enhance our ability to match patients to therapeutic strategies most likely to optimize outcomes and minimize risk. PMID- 25292280 TI - Plain cigarette packs do not exert Pavlovian to instrumental transfer of control over tobacco-seeking. AB - AIMS: To gain insight into the potential impact of plain tobacco packaging policy, two experiments were undertaken to test whether 'prototype' plain compared with branded UK cigarette pack stimuli would differentially elicit instrumental tobacco-seeking in a nominal Pavlovian to instrumental transfer (PIT) procedure. DESIGN, SETTING AND PARTICIPANTS: Two experiments were undertaken at the University of Bristol UK, with a convenience sample of adult smokers (experiment 1, n = 23, experiment 2, n = 121). MEASUREMENT: In both experiments, smokers were trained on a concurrent choice procedure in which two responses earned points for cigarettes and chocolate, respectively, before images of branded and plain packs were tested for capacity to elicit the tobacco-seeking response in extinction. The primary outcome was percentage choice of the tobacco- over the chocolate-seeking response in plain pack, branded pack and no-stimulus conditions. FINDINGS: Both experiments found that branded packs primed a greater percentage of tobacco-seeking (overall mean = 62%) than plain packs (overall mean = 53%) and the no-stimulus condition (overall mean = 52%; Ps <= 0.01, np (2) s >= 0.16), and that there was no difference in percentage tobacco-seeking between plain packs and the no-stimulus condition (Ps >= 0.17, np (2) s <= 0.04). Plain tobacco packs showed an overall 9% reduction in the priming of a tobacco choice response compared to branded tobacco packs. CONCLUSIONS: Plain packaging may reduce smoking in current smokers by degrading cue-elicited tobacco-seeking. PMID- 25292281 TI - The cooperative function of arginine residues in the Prototype Foamy Virus Gag C terminus mediates viral and cellular RNA encapsidation. AB - BACKGROUND: One unique feature of the foamy virus (FV) capsid protein Gag is the absence of Cys-His motifs, which in orthoretroviruses are irreplaceable for multitude functions including viral RNA genome recognition and packaging. Instead, FV Gag contains glycine-arginine-rich (GR) sequences at its C-terminus. In case of prototype FV (PFV) these are historically grouped in three boxes, which have been shown to play essential functions in genome reverse transcription, virion infectivity and particle morphogenesis. Additional functions for RNA packaging and Pol encapsidation were suggested, but have not been conclusively addressed. RESULTS: Here we show that released wild type PFV particles, like orthoretroviruses, contain various cellular RNAs in addition to viral genome. Unlike orthoretroviruses, the content of selected cellular RNAs in capsids of PFV vector particles was not altered by viral genome encapsidation. Deletion of individual GR boxes had only minor negative effects (2 to 4-fold) on viral and cellular RNA encapsidation over a wide range of cellular Gag to viral genome ratios examined. Only the concurrent deletion of all three PFV Gag GR boxes, or the substitution of multiple arginine residues residing in the C terminal GR box region by alanine, abolished both viral and cellular RNA encapsidation (>50 to >3,000-fold reduced), independent of the viral production system used. Consequently, those mutants also lacked detectable amounts of encapsidated Pol and were non-infectious. In contrast, particle release was reduced to a much lower extent (3 to 20-fold). CONCLUSIONS: Taken together, our data provides the first identification of a full-length PFV Gag mutant devoid in genome packaging and the first report of cellular RNA encapsidation into PFV particles. Our results suggest that the cooperative action of C-terminal clustered positively charged residues, present in all FV Gag proteins, is the main viral protein determinant for viral and cellular RNA encapsidation. The viral genome independent efficiency of cellular RNA encapsidation suggests differential packaging mechanisms for both types of RNAs. Finally, this study indicates that analogous to orthoretroviruses, Gag - nucleic acid interactions are required for FV capsid assembly and efficient particle release. PMID- 25292282 TI - Progressive migration and anagenesis in Drimys confertifolia of the Juan Fernandez Archipelago, Chile. AB - A common mode of speciation in oceanic islands is by anagenesis, wherein an immigrant arrives and through time transforms by mutation, recombination, and drift into a morphologically and genetically distinct species, with the new species accumulating a high level of genetic diversity. We investigate speciation in Drimys confertifolia, endemic to the two major islands of the Juan Fernandez Archipelago, Chile, to determine genetic consequences of anagenesis, to examine relationships among populations of D. confertifolia and the continental species D. winteri and D. andina, and to test probable migration routes between the major islands. Population genetic analyses were conducted using AFLPs and nuclear microsatellites of 421 individuals from 42 populations from the Juan Fernandez islands and the continent. Drimys confertifolia shows a wide genetic variation within populations on both islands, and values of genetic diversity within populations are similar to those found within populations of the continental progenitor. The genetic results are compatible with the hypothesis of high levels of genetic variation accumulating within anagenetically derived species in oceanic islands, and with the concept of little or no geographical partitioning of this variation over the landscape. Analysis of the probability of migration within the archipelago confirms colonization from the older island, Robinson Crusoe, to the younger island Alejandro Selkirk. PMID- 25292285 TI - A rare cause of spiculated breast mass mimicking carcinoma: silicone granuloma following breast implant removal. PMID- 25292284 TI - Characterisation of rebound depolarisation in mice deep dorsal horn neurons in vitro. AB - Spinal dorsal horn neurons constitute the first relay for pain processing and participate in the processing of other sensory, motor and autonomic information. At the cellular level, intrinsic excitability is a factor contributing to network function. In turn, excitability is set by the array of ionic conductance expressed by neurons. Here, we set out to characterise rebound depolarisation following hyperpolarisation, a feature frequently described in dorsal horn neurons but never addressed in depth. To this end, an in vitro preparation of the spinal cord from mice pups was used combined with whole-cell recordings in current and voltage clamp modes. Results show the expression of H- and/or T-type currents in a significant proportion of dorsal horn neurons. The expression of these currents determines the presence of rebound behaviour at the end of hyperpolarising pulses. T-type calcium currents were associated to high-amplitude rebounds usually involving high-frequency action potential firing. H-currents were associated to low-amplitude rebounds less prone to elicit firing or firing at lower frequencies. For a large proportion of neurons expressing both currents, the H-current constitutes a mechanism to ensure a faster response after hyperpolarisations, adjusting the latency of the rebound firing. We conclude that rebound depolarisation and firing are intrinsic factors to many dorsal horn neurons that may constitute a mechanism to integrate somatosensory information in the spinal cord, allowing for a rapid switch from inhibited-to-excited states. PMID- 25292283 TI - The angiotensin-(1-7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice. AB - Angiotensin-(1-7) [Ang (1-7)] is a peptide belonging to the non-classical renin angiotensin system (RAS). Ang (1-7), through its receptor Mas, has an opposite action to angiotensin II (Ang II), the typical peptide of the classical RAS axis. Ang II produces skeletal muscle atrophy, a pathological condition characterised by the loss of strength and muscle mass. A feature of muscle atrophy is the decrease of the myofibrillar proteins produced by the activation of the ubiquitin proteasome pathway (UPP), evidenced by the increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. In addition, it has been described that Ang II also induces myonuclear apoptosis during muscle atrophy. We assessed the effects of Ang (1-7) and Mas participation on myonuclear apoptosis during skeletal muscle atrophy induced by Ang II. Our results show that Ang (1 7), through Mas, prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm (increased apoptotic nuclei, increased expression of caspase-8 and caspase-9, increased caspase-3 activity and increased Bax/Bcl-2 ratio). Concomitantly, Ang (1-7) also attenuates the decrease in fibre diameter and muscle strength, and prevents the increase in atrogin-1 and MuRF-1 during the muscle wasting induced by Ang II. Interestingly, these effects of Ang (1-7) are dependent on the Mas receptor. Thus, we demonstrated for the first time that Ang (1-7) prevents myonuclear apoptosis during the recovery of skeletal muscle atrophy induced by Ang II. PMID- 25292286 TI - Detection of Mediterranean fever gene mutations in Egyptian children with inflammatory bowel disease. AB - AIM: The aim of the current study is to investigate the prevalence of familial Mediterranean fever gene (MEFV) mutations in a cohort of Egyptian children with inflammatory bowel disease (IBD), and to characterize familial Mediterranean fever (FMF)-IBD patients, helping better understanding of IBD pathogenesis. METHODS: The study enrolled 17 patients with ulcerative colitis (UC), 15 with Crohn's disease(CD), 10 with indeterminate colitis (IC) and 33 healthy children as controls. All cases and controls were tested for 12 FMF gene mutations by reverse hybridization after multiplex polymerase chain reaction amplification and DNA sampling. RESULTS: Eighty-eight percent of the IBD patients carried the mutations, with Sequence variant V627A being the commonest versus 42.4% of controls. No associations were found between MEFV gene mutations, and phenotypic characteristics of IBD patients. CONCLUSION: IBD patients, in populations with a high background carrier rate of MEFV variants, should be screened for MEFV gene mutations, especially those diagnosed as indeterminate colitis. Testing larger numbers of healthy Egyptian children for MEFV gene mutation is important to further determine the allele frequency in Egypt. PMID- 25292287 TI - Seeking informal and formal help for mental health problems in the community: a secondary analysis from a psychiatric morbidity survey in South London. AB - BackgroundOnly 30-35% of people with mental health problems seek help from professionals. Informal help, usually from friends, family and religious leaders, is often sought but is under-researched. This study aimed to contrast patterns of informal and formal help-seeking using data from a community psychiatric morbidity survey (n=1692) (South East London Community Health (SELCOH) Study).MethodsPatterns of help-seeking were analysed by clinical, sociodemographic and socioeconomic indicators. Factors associated with informal and formal help-seeking were investigated using logistic regression. Cross tabulations examined informal help-seeking patterns from different sources.Results'Cases? (n = 386) were participants who had scores of ? 12 on the Revised Clinical Interview Schedule (CIS-R), indicating a common mental disorder. Of these, 40.1% had sought formal help, (of whom three-quarters (29%) had also sought informal help), 33.6% had sought informal help only and only 26.3% had sought no help. When controlling for non-clinical variables, severity, depression, suicidal ideas, functioning and longstanding illnesses were associated with formal rather than informal help-seeking. Age and ethnic group influenced sources of informal help used. Younger people most frequently sought informal help only whereas older people tended to seek help from their family. There were ethnic group differences in whether help was sought from friends, family or religious leaders.ConclusionsThis study has shown how frequently informal help is used, whether in conjunction with formal help or not. Among the 'cases?, over 60% had sought informal help, whether on its own or together with formal help. Severity was associated with formal help-seeking. Patterns of informal help use have been found. The use and effectiveness of informal help merit urgent research. PMID- 25292289 TI - Cutaneous gamma-delta T-cell lymphoma with central nervous system involvement: report of a rarity with review of literature. AB - Primary cutaneous gamma-delta (gammadelta) T-cell lymphoma is an extremely rare and aggressive variant of cutaneous lymphoma. Central nervous system (CNS) involvement, a rare finding, and hemophagocytic syndrome are two complications that are commonly fatal. We describe a 58-year-old patient presenting with skin plaque who subsequently developed subcutaneous nodules diagnosed as cutaneous T cell lymphoma (CTCL), clinically resembling 'mycosis fungoides'. The patient was treated with repeat topical radiation therapies but had frequent relapsed disease. Approximately 4.5 years after, the patient presented with third and sixth cranial nerve palsies and was found to have CNS involvement by lymphoma per positron emission tomography-computed tomography (PET/CT) and a biopsy of foramen magnum. Phenotypically, the tumor cells were CD3(+)/CD4(-)/CD8(-)/CD7(+)/CD5( )/CD30(-)/TCRalphabeta(-)/TCRgammadelta(+). Despite aggressive strategies taken, the patient expired 3 months after the diagnosis of the CNS lesion. A retrospective investigation proved the original CTCL to be gammadelta T-cell in origin, confirming an indolent cutaneous gammadelta T-cell lymphoma with eventual CNS manifestation. We present this case to draw attention to the entity, which can occasionally present with misleading histopathologic and clinical features. In addition, we provide a review of the literature to summarize clinical and pathologic features of the reported similar cases. PMID- 25292290 TI - Analysis of the factors creating consumer attributes of roasted beef steaks. AB - The aim of the study was to analyze the factors creating consumer attributes of roasted beef steaks of various animals. Eight cuts from 30 carcasses (characterized by various types of animal, conformation and fat class, rib fat thickness, ossification score) were selected. Samples were prepared using the roasting method and consumers rated the tenderness, juiciness, flavor, overall acceptability (rated in a 100-point scale), and satisfaction (rated from 2 to 5) for analyzed samples. No influence of type of animal, fat class, conformation class or ossification score on the results of consumer analysis was observed. For all analyzed factors, the influence of cut on consumer analysis was observed (the highest values of all consumer attributes were observed for tenderloin - for juiciness significantly higher than for other cuts, for tenderness, flavor and MQ4 comparable only with rump (RMP231), while for overall acceptability and satisfaction - with both rump cuts). For rib fat thickness consumer attributes of roasted beef meat were not linear, but the influence was observed - the highest values of consumer attributes were observed for 13 mm rib fat thickness. PMID- 25292288 TI - Characterization of beta2-microglobulin expression in different types of breast cancer. AB - BACKGROUND: Betaeta-2-microglobulin (beta2-M) has been demonstrated as a growth factor and signaling molecule in breast cancer and leukemia. The purpose of the study is to characterize beta2-M expression in molecular subtypes of breast cancer, thereby investigating the mechanism of beta2-M action in breast cancer. METHODS: beta2-M and B-Cell Lymphoma/Leukemia 2 (Bcl-2) transcript expression levels in breast cancer tissue and the corresponding normal tissue were quantified using real-time PCR. The protein expression levels of beta2-M, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), tumor protein 53 (p53) and Ki67 were determined by immunohistochemical (IHC) staining. Following silencing of the beta2-M by siRNA, the levels of Bcl-2, ER, PR and HER-2 transcripts and the protein expression levels in human breast cancer cells were measured by real-time PCR and western blotting, respectively. RESULTS: The expression of beta2-M transcripts demonstrated no significant differences between the four breast cancer molecular subtypes and no significant correlations with age, clinical stage or lymph node metastasis. beta2-M transcript expression demonstrated a positive correlation when compared to Bcl-2 transcript expression (P<0.05). The beta2-M protein expression was significantly higher in breast cancer when compared with benign breast tumors (P<0.01), and have no significant correlation with age, clinical stage or lymph node metastasis. There was a significant difference demonstrated in beta2-M protein expression in the four breast cancer molecular subtypes (P<0.05), and between the ER+ and ER- groups (P<0.01); however, no significant difference was demonstrated between the HER-2+ and HER-2- groups. beta2-M protein expression had a negative correlation with ER protein expression (P<0.01), a positive correlation with p53 protein expression (P<0.01), and no correlation with Ki67 protein expression. beta2-M silencing significantly inhibited Bcl-2 mRNA expression, but did not inhibit ER, PR and HER-2 mRNA expression in MCF-7 cells (ER+, PR+ and HER-2-). In addition, Bcl-2 and HER-2 mRNA expression were significantly up-regulated in MDA-MB-231 cells (ER-, PR- and HER-2-), which is consistent with the silencing effect seen at the protein level. CONCLUSIONS: beta2-M expression demonstrated a significant difference in the four breast cancer molecular subtypes, and may be related to apoptosis regulation in breast cancer. PMID- 25292291 TI - Harmful misuse of white vinegar in a wrong combination. PMID- 25292292 TI - Epidemiological description of cystic ovarian disease in argentine dairy herds: risk factors and effects on the reproductive performance of lactating cows. AB - To describe the epidemiology of cystic ovarian disease (COD), to find possible risk factors associated with the incidence of cysts and to analyse the impact of COD on the reproductive performance of dairy cows, databases from 22 dairy herds from the main dairy region in Argentina were retrospectively evaluated throughout a 3-year period (2009-2011). A total of 248 COD cases over 9156 parturitions were recorded, resulting in a cumulative incidence rate of 2.7%. Cystic ovarian disease incidence density was lower during the first 100 days post-partum (DPP) than during later stages of lactation. Seasonality had a significant influence on the disease presentation with higher incidence rates during winter and spring. Cows with a previous diagnosis of clinical mastitis showed 2.72 times more chances of developing ovarian cysts. Cystic cows had longer calving to first service and calving to conception intervals and lower conception rate than controls. PMID- 25292293 TI - Socio-economic profile of patients with community-acquired skin and soft tissue infections in Delhi. AB - AIM: To study the socio-demographic and clinical profile of patients with community-acquired skin and soft tissue infections (CA-SSTIs). METHODS: This study was a cross sectional, observational study. Patients with CA-SSTIs (ICD-10 L00-L08) were enrolled from February to August 2013. Clinical and microbiological data of all patients were recorded. Socioeconomic status (SES) of each patient was calculated using the Modified Kuppuswamy Scale. RESULTS: Seventy-three patients were studied, of whom 45 had SSTIs caused by Staphylococcus aureus. Of the 45, 11 (24%) were methicillin-resistant S. aureus (MRSA) and 34 (76%) were methicillin-sensitive S. aureus (MSSA). Patients with MRSA infections had significantly lower monthly income and lower educational status than those with MSSA infections. However, SES was not significantly different in the two groups. CONCLUSION: S. aureus was the most common cause of CA-SSTIs, of which, MRSA was isolated in 24% of the cases. Patients with MRSA SSTIs had significantly lesser family income and lower education levels compared to patients with MSSA SSTIs. PMID- 25292295 TI - Diurnal and seasonal variation of mixing ratio and delta13C of air CO2 observed at an urban station Bangalore, India. AB - We present here observations on diurnal and seasonal variation of mixing ratio and delta(13)C of air CO2, from an urban station-Bangalore (BLR), India, monitored between October 2008 and December 2011. On a diurnal scale, higher mixing ratio with depleted delta(13)C of air CO2 was found for the samples collected during early morning compared to the samples collected during late afternoon. On a seasonal scale, mixing ratio was found to be higher for dry summer months (April-May) and lower for southwest monsoon months (June-July). The maximum enrichment in delta(13)C of air CO2 (-8.04 +/- 0.020/00) was seen in October, then delta(13)C started depleting and maximum depletion (-9.31 +/- 0.070/00) was observed during dry summer months. Immediately after that an increasing trend in delta(13)C was monitored coincidental with the advancement of southwest monsoon months and maximum enrichment was seen again in October. Although a similar pattern in seasonal variation was observed for the three consecutive years, the dry summer months of 2011 captured distinctly lower amplitude in both the mixing ratio and delta(13)C of air CO2 compared to the dry summer months of 2009 and 2010. This was explained with reduced biomass burning and increased productivity associated with prominent La Nina condition. While compared with the observations from the nearest coastal and open ocean stations Cabo de Rama (CRI) and Seychelles (SEY), BLR being located within an urban region captured higher amplitude of seasonal variation. The average delta(13)C value of the end member source CO2 was identified based on both diurnal and seasonal scale variation. The delta(13)C value of source CO2 (-24.9 +/- 30/00) determined based on diurnal variation was found to differ drastically from the source value (-14.6 +/- 0.70/00) identified based on seasonal scale variation. The source CO2 identified based on diurnal variation incorporated both early morning and late afternoon sample; whereas, the source CO2 identified based on seasonal variation included only afternoon samples. Thus, it is evident from the study that sampling timing is one of the important factors while characterizing the composition of end member source CO2 for a particular station. The difference in delta(13)C value of source CO2 obtained based on both diurnal and seasonal variation might be due to possible contribution from cement industry along with fossil fuel / biomass burning as predominant sources for the station along with differential meteorological conditions prevailed. PMID- 25292294 TI - Mammographic breast density refines Tyrer-Cuzick estimates of breast cancer risk in high-risk women: findings from the placebo arm of the International Breast Cancer Intervention Study I. AB - INTRODUCTION: Mammographic density is well-established as a risk factor for breast cancer, however, adjustment for age and body mass index (BMI) is vital to its clinical interpretation when assessing individual risk. In this paper we develop a model to adjust mammographic density for age and BMI and show how this adjusted mammographic density measure might be used with existing risk prediction models to identify high-risk women more precisely. METHODS: We explored the association between age, BMI, visually assessed percent dense area and breast cancer risk in a nested case-control study of women from the placebo arm of the International Breast Cancer Intervention Study I (72 cases, 486 controls). Linear regression was used to adjust mammographic density for age and BMI. This adjusted measure was evaluated in a multivariable logistic regression model that included the Tyrer-Cuzick (TC) risk score, which is based on classical breast cancer risk factors. RESULTS: Percent dense area adjusted for age and BMI (the density residual) was a stronger measure of breast cancer risk than unadjusted percent dense area (odds ratio per standard deviation 1.55 versus 1.38; area under the curve (AUC) 0.62 versus 0.59). Furthermore, in this population at increased risk of breast cancer, the density residual added information beyond that obtained from the TC model alone, with the AUC for the model containing both TC risk and density residual being 0.62 compared to 0.51 for the model containing TC risk alone (P =0.002). CONCLUSIONS: In women at high risk of breast cancer, adjusting percent mammographic density for age and BMI provides additional predictive information to the TC risk score, which already incorporates BMI, age, family history and other classic breast cancer risk factors. Furthermore, simple selection criteria can be developed using mammographic density, age and BMI to identify women at increased risk in a clinical setting. CLINICAL TRIAL REGISTRATION NUMBER: http://www.controlled-trials.com/ISRCTN91879928 (Registered: 1 June 2006). PMID- 25292296 TI - Particulate matter mass and chemical component concentrations over four Chinese cities along the western Pacific coast. AB - China has witnessed rapid economic growth in the past three decades, especially in coastal areas. Particulate matter (PM) pollution is becoming increasingly serious in China's cities along the western Pacific coast with the rapid development of China's society and economy. This study analyzed PM (PM10 and PM2.5) in terms of their mass and chemical composition in four coastal Chinese cities. The goal was to study the spatial variation and characteristics of PM pollution in sites under different levels of economic development and in diverse natural environments. A distinct trend for concentrations of PM and related chemical species was observed and increased from south to north in Haikou, Ningbo, Qingdao, and Tianjin. Secondary inorganic aerosols, crustal materials, and organic matter dominated the composition of both PM10 and PM2.5. Crustal materials were the most abundant species in the northern coastal areas because these areas have less vegetation cover and lower humidity than southern coastal areas. The presence of high SO4 (2-)/nitrate (NO3 (-)) concentrations indicated that the burning of coals gives significant contributions to PM10 and PM2.5. The differences observed in the characteristics of PM pollution in these coastal cities are probably caused by different levels of industrial and urban development. PMID- 25292297 TI - Content of lead and cadmium in aboveground plant organs of grasses growing on the areas adjacent to a route of big traffic. AB - The effect of traffic on the content of lead and cadmium in grass morphological parts-leaves, shoots, and inflorescences-was studied. The samples were taken on a part of the European route E30 (Siedlce by road). The following plants were tested: Dactylis glomerata, Arrhenatherum elatius, and Alopecurus pratensis. During the flowering of grasses, the plant material was collected at distances of 1, 5, 10, and 15 m from the edge of the road, on the strip of road with a length of 9 km. In the collected plant parts, the content of lead and cadmium using the atomic absorption spectroscopy (AAS) method was determined. The effect of distance from the road on the content of lead and cadmium was evaluated using regression equations. Average lead content in the above parts of tested grass species was 3.56, while cadmium 0.307 mg kg(-1) dry matter (DM). Lead content in plants of Alopecurus pratensis (average 4.11 mg kg(-1) DM) was significantly higher than in other grasses. The lowest cadmium content, significantly different from the other species, was found in plants of Arrhenatherum elatius (0.251 mg kg(-1) DM). Distance of sampling sites from the roadway significantly affects the differences in the content of cadmium and lead in plants. Analyzed aboveground plant organs of studied grasses were significantly different in contents of lead and cadmium. There were species differences in the proportions of cadmium concentration in various organs of plants. The obtained results indicate the possibility of species composition selection of grassland sward in areas with a higher risk of heavy metals associated with dust sedimentation. PMID- 25292298 TI - Relationship between haze and acute cardiovascular, cerebrovascular, and respiratory diseases in Beijing. AB - Haze is an atmospheric phenomenon in which dry particulate pollutants obscure the sky. Haze has been associated with chronic diseases, but its relationship with acute diseases is less clear. We aimed to determine the association between haze and acute cardiovascular, cerebrovascular, and respiratory diseases, in order to determine the influence of haze on human health. We compared the number of cases of acute cardiovascular, cerebrovascular, and respiratory diseases in Beijing Emergency Center between 2006 and 2013, with haze data from Beijing Observatory. The relationship between the number of hazy days and the number of cases of the above types of diseases was analyzed using univariate analyses. Both the number of cases and the number of hazy days showed a rising trend. The average number of cases per day for all three diseases was higher on hazy days than on non-hazy days. There was a positive correlation between the number of hazy days and the number of cases, and this correlation showed a hysteretic quality. Haze has an influence on acute cardiovascular (CVDs), cerebrovascular (CBDs), and respiratory system (RSDs) diseases. Haze seems to have an additive effect, since the associations between haze and number of cases were stronger in the following month than in the preceding month. The increasing trend in the number of hazy days might worsen the problem of haze-related diseases. PMID- 25292299 TI - Characterization and estimation of human airway deposition of size-resolved particulate-bound trace elements during a recent haze episode in Southeast Asia. AB - Toxic elements present in airborne particulate matter (PM) are associated with human health effects; however, their toxic characteristics depend on the source of their origins and their concentrations in ambient air. Twenty four elements (Al, B, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ga, K, Li, Mg, Mn, Na, Ni, Pb, Se, Sr, Te, Tl, and Zn) in 12 different size fractions of PM ranging from 10 nm to 10 MUm were characterized in Singapore during two different atmospheric conditions (smoke haze and non-haze periods) in 2012 for the first time. In addition, their possible sources were identified based on backward air trajectory analysis and principal component analysis (PCA). The health implications of inhalable particles were assessed using a human airway deposition model, the Multiple-Path Particle Dosimetry model (MPPD). The results concerning particle-bound trace elements are interpreted in terms of coarse (PM2.5-10), fine (PM2.5), ultrafine (PM0.01-0.1, 0.01 MUm < Dp < 0.10 MUm), and nano (PM0.01-0.056, 0.01 MUm < Dp < 0.056 MUm) particles. The ratios of elemental concentrations measured between the smoke haze episode and the non-haze period in coarse, fine, ultrafine, and nano particles varied from 1.2 (Bi) to 6.6 (Co). Both the PCA and backward trajectory analysis revealed that trans-boundary biomass-burning emissions from Indonesia were primarily responsible for enhanced concentrations of particulate-bound elements during the smoke haze episode. The particle depositions in the respiratory system were higher during the smoke haze episode compared to the non haze period. The study finds that ultrafine and nano particles present in the atmosphere have higher tendencies to be deposited into the deeper parts of the respiratory system, compared to coarse and fine particles. PMID- 25292300 TI - Derivation of marine water quality criteria for metals based on a novel QICAR-SSD model. AB - Establishment of water quality criteria (WQC) is one procedure for protection of marine organisms and their ecosystems. This study, which integrated two separate approaches, quantitative ion character-activity relationships (QICARs) and species sensitivity distributions (SSDs), developed a novel QICAR-SSD model. The QICARs predict relative potencies of individual elements while SSDs integrate relative sensitivities among organisms. The QICAR-SSD approach was applied to derive saltwater WQC for 34 metals or metalloids. Relationships between physicochemical properties of metal ions and their corresponding potencies for acute toxicity to eight selected marine species were determined. The softness index (sigmap) exhibited the strongest correlation with the acute toxicity of metals (r (2) > 0.66, F > 5.88, P < 0.94 * 10(-2)). Predictive criteria maximum concentrations for the eight metals, derived by applying the SSD approach to values predicted by use of QICARs, were within the same order of magnitude as values recommended by the US EPA (2009). In general, the results support that the QICAR-SSD approach is a rapid method to estimate WQC for metals for which little or no information is available for marine organisms. PMID- 25292301 TI - Dissipation of phenanthrene and pyrene at the aerobic-anaerobic soil interface: differentiation induced by the rhizosphere of PAH-tolerant and PAH-sensitive rice (Oryza sativa L.) cultivars. AB - A pot experiment was conducted to reveal the removal of two polycyclic aromatic hydrocarbons (PAHs) (phenanthrene, PHE, and pyrene, PYR) during rice cultivation in a paddy field. The rhizosphere effect on facilitating dissipation of PAHs varied simultaneously as a function of soil properties, PAH types, cultivation time, and genotypes within rice cultivars, with differences performed for PYR but not PHE. Changes in soil PLFA profiles evidenced that the growth of rice roots modified the dominant species within rhizosphere microbial communities and induced a selective enrichment of Gram-negative aerobic bacteria capable of degrading, thereby resulting in the differentiated dissipation of PYR. While the insignificant differences in PHE dissipation might be attributed to its higher solubility and availability under flooded condition that concealed the differences in improvement of bioavailability for microorganisms between rhizosphere and non-rhizosphere, and between both soils and both rice cultivars. Our findings illustrate that the removal of PAHs in paddy soils was more complex relative to those in dryland soils. This was possibly due to the specialty of rice roots for oxygen secretion that provides development of redox heterogeneous microbial habitats at root-soil interface under flooded condition. PMID- 25292302 TI - An integrated GIS-based interval-probabilistic programming model for land-use planning management under uncertainty--a case study at Suzhou, China. AB - A large number of mathematical models have been developed for supporting optimization of land-use allocation; however, few of them simultaneously consider land suitability (e.g., physical features and spatial information) and various uncertainties existing in many factors (e.g., land availabilities, land demands, land-use patterns, and ecological requirements). This paper incorporates geographic information system (GIS) technology into interval-probabilistic programming (IPP) for land-use planning management (IPP-LUPM). GIS is utilized to assemble data for the aggregated land-use alternatives, and IPP is developed for tackling uncertainties presented as discrete intervals and probability distribution. Based on GIS, the suitability maps of different land users are provided by the outcomes of land suitability assessment and spatial analysis. The maximum area of every type of land use obtained from the suitability maps, as well as various objectives/constraints (i.e., land supply, land demand of socioeconomic development, future development strategies, and environmental capacity), is used as input data for the optimization of land-use areas with IPP LUPM model. The proposed model not only considers the outcomes of land suitability evaluation (i.e., topography, ground conditions, hydrology, and spatial location) but also involves economic factors, food security, and eco environmental constraints, which can effectively reflect various interrelations among different aspects in a land-use planning management system. The case study results at Suzhou, China, demonstrate that the model can help to examine the reliability of satisfying (or risk of violating) system constraints under uncertainty. Moreover, it may identify the quantitative relationship between land suitability and system benefits. Willingness to arrange the land areas based on the condition of highly suitable land will not only reduce the potential conflicts on the environmental system but also lead to a lower economic benefit. However, a strong desire to develop lower suitable land areas will bring not only a higher economic benefit but also higher risks of violating environmental and ecological constraints. The land manager should make decisions through trade-offs between economic objectives and environmental/ecological objectives. PMID- 25292303 TI - Toxicities of 48 pharmaceuticals and their freshwater and marine environmental assessment in northwestern France. AB - A risk assessment for freshwater and marine ecosystems is presented for 48 pharmaceutical compounds, belonging to 16 therapeutic classes, and prescribed in northwestern France. Ecotoxicity data were obtained on two freshwater organisms, i.e., crustacean Daphnia magna and the green algae Pseudokirchneriella subcapitata, and on two marine organisms, i.e., the crustacean Artemia salina and the diatom Skeletonema marinoi. Measured environmental concentrations (MEC), in the Orne River and sea off Merville-Franceville in the Basse-Normandie region, were compared to the predicted environmental concentrations (PEC). Predicted no effect concentrations (PNEC) were derived from acute data for each compound. Then, a risk assessment for each compound and the mixture was performed by calculating risk quotients (RQ as PEC or MEC/PNEC ratio). Results showed that no immediate acute toxicities were expected even if some compounds displayed strong toxicities at very low concentrations. Antibiotics, antidepressants, and antifungals would deserve attention because of their high or median ecological risk suspected on marine and freshwater ecosystems. Marine ecosystems would be more sensitive to pharmaceutical residues. PMID- 25292304 TI - Distribution, mobility, and pollution assessment of Cd, Cu, Ni, Pb, Zn, and Fe in intertidal surface sediments of Sg. Puloh mangrove estuary, Malaysia. AB - Sungai Puloh mangrove estuary supports a large diversity of macrobenthic organisms and provides social benefits to the local community. Recently, it became a major recipient of heavy metals originating from industries in the hinterland as a result of industrialization and urbanization. This study was conducted to evaluate mobility and pollution status of heavy metals (Cd, Cu, Ni, Pb, Zn, and Fe) in intertidal surface sediments of this area. Surface sediment samples were collected based on four different anthropogenic sources. Metals concentrations were analyzed using an atomic absorption spectrophotometer (AAS). Results revealed that the mean concentrations were Zn (1023.68 +/- 762.93 MUg/g), Pb (78.8 +/- 49.61 MUg/g), Cu (46.89 +/- 43.79 MUg/g), Ni (35.54 +/- 10.75 MUg/g), Cd (0.94 +/- 0.29 MUg/g), and Fe (7.14 +/- 0.94%). Most of the mean values of analyzed metals were below both the interim sediment quality guidelines (ISQG-low and ISQG-high), except for Pb concentration (above ISQG-low) and Zn concentration (above ISQG-high), thus suggesting that Pb and Zn may pose some environmental concern. Cadmium, Pb, and Zn concentrations were above the threshold effect level (TEL), indicating seldom adverse effect of these metals on macrobenthic organisms. Pollution load index (PLI) indicated deterioration and other indices revealed the intertidal surface sediment is moderately polluted with Cd, Pb, and Zn. Therefore, this mangrove area requires urgent attention to mitigate further contamination. Finally, this study will contribute to data sources for Malaysia in establishing her own ISQG since it is a baseline study with detailed contamination assessment indices for surface sediment of intertidal mangrove area. PMID- 25292305 TI - Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in sediments of Liaohe River: levels, spatial and temporal distribution, possible sources, and inventory. AB - Spatial and seasonal variations of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in the sediment of Liaohe River were investigated in this study. A total of 29 surface sediment samples were collected in May and September in 2013. Results showed that levels of the two classes of compounds were higher in September than in May. The total concentration of PBDEs (?8PBDEs) ranged from 0.30 to 5.09 ng g(-1) in May and from 0.17 to 13.73 ng g( 1) in September, respectively, and BDE 209 was the dominant compound. The total concentration of PCBs (?33PCBs) was in the range of 4.92-76.86 and 11.69-179.61 ng g(-1) in May and September, respectively, with tri- and tetra-CBs dominated in the total PCBs in the sediments. According to the congener profiles and the principal component analysis, the major sources of PCBs and PBDEs in sediments of Liaohe River were from the usage of commercial products and industrial activities, and the degradation of high brominated BDEs also contributed to the current PBDEs in the sediments. The mass inventories of PBDEs and PCBs in the sediments of Liaohe River were 1.74 and 21.96 t, respectively, indicating that Liaohe River sediments may act as the potential sources of PBDEs and PCBs to the downstream coastal areas. PMID- 25292306 TI - Bacterial properties changing under Triton X-100 presence in the diesel oil biodegradation systems: from surface and cellular changes to mono- and dioxygenases activities. AB - Triton X-100, as one of the most popular surfactants used in bioremediation techniques, has been reported as an effective agent enhancing the biodegradation of hydrocarbons. However efficient, the surfactant's role in different processes that together enable the satisfying biodegradation should be thoroughly analysed and verified. In this research, we present the interactions of Triton X-100 with the bacterial surfaces (hydrophobicity and zeta potential), its influence on the enzymatic properties (considering mono- and dioxygenases) and profiles of fatty acids, which then all together were compared with the biodegradation rates. The addition of various concentrations of Triton X-100 to diesel oil system revealed different cell surface hydrophobicity (CSH) of the tested strains. The results demonstrated that for Pseudomonas stutzeri strain 9, higher diesel oil biodegradation was correlated with hydrophilic properties of the tested strain and lower Triton X-100 biodegradation. Furthermore, an increase of the branched fatty acids was observed for this strain. PMID- 25292308 TI - [Nosocomial infections in urology]. AB - Nosocomial infections (NI) may be a serious and mostly avoidable consequence of medical procedures and often cause a significant aggravation of the patients underlying disease. Following surgical site infections, urinary tract infections (UTI) represent the second most common fraction of NIs (22.4%) in Germany and contribute to approximately 155,000 nosocomial UTIs (nUTI) every year.Prevention of NI is of utmost individual as well as socioeconomic importance especially regarding the continuing worldwide increase in antibiotic resistance. National legislature has responded to this challenge by amending the German Law on the Prevention and Control of Infectious Diseases (IfSG) and other measures. Their practical importance for various clinical settings in urology is outlined in this overview.The correct use of urinary catheters has the greatest impact for prevention and control as nUTIs are associated with urinary catheters in most of the cases (80%). The recently updated guidelines of the Commission for Hospital Hygiene and Infection Prevention of the Robert Koch Institute (KRINKO) and the Association of the Scientific Medical Societies in Germany (AWMF) provide detailed recommendations in an evidence-based and practice-oriented manner as summarized in this article. PMID- 25292307 TI - Recurrence of differentiated thyroid carcinoma during full TSH suppression: is the tumor now thyroid hormone dependent? AB - Well-standardized primary treatment and long-term management of differentiated thyroid carcinoma (DTC) include lowering or suppression of host thyrotropin (TSH) with exogenous L-thyroxine (T4). This treatment recognizes the trophic action of TSH on DTC cells. Suppression of endogenous TSH with T4 is continued in recurrent disease. However, T4 can induce proliferation of follicular and papillary thyroid carcinoma cell lines and of other human carcinoma cells. The proliferative mechanism is initiated at a cell surface receptor for T4 on integrin alphavbeta3, a receptor by which the hormone also inhibits p53-dependent apoptosis in tumor cells. In recurrent DTC with satisfactory suppression of endogenous TSH, we discuss here the possibility that the tumor is no longer TSH dependent and that T4 has become a critical growth factor for the cancer. PMID- 25292309 TI - [Prophylaxis of recurrent urinary tract infections]. AB - BACKGROUND: Recurrent urinary tract infections (rUTI), defined as >= 3 UTIs per year, mostly affect young and postmenopausal women. Treatable predisposing factors are rare. METHODS: General recommendations to reduce rUTIs lower the recurrence rate by up to approximately two thirds. Continuous long-term prophylaxis (LP) with low dose antibiotics or single postcoital doses can reduce the recurrence rate of rUTIs to as low as 5%. According to the European Association of Urology guidelines nitrofurantoin, trimethoprim and co-trimoxazole are the first-line drugs and cephalosporins or fluoroquinolones should be restricted to specific indications. Oral and parenteral immunotherapy were found to be effective in several controlled studies for prevention of rUTIs and can be combined with acute antibiotic therapy. CONCLUSIONS: Vaginal prophylaxis with estriol has proven its positive effect without serious gynecological side effects and there is also increasing evidence that cranberries prevent rUTIs but the exact mode of this therapy remains to be defined. There are also other promising modalities, such as phytotherapeutics, mannose, urine acidification, influencing bacterial intestinal and vaginal flora and the general immune response by e.g. acupuncture and inpatient rehabilitation, the therapeutic value of which still has to be proven. PMID- 25292311 TI - [History in the public communication of specialist scientific societies: history marketing]. AB - History is nowadays used as an economic factor. The past is therefore specifically targeted and cultivated, which for specialist scientific associations and societies often fullfils totally different functions in comparison to the open market, although the techniques and requirements are similar. Within medical specialties these facts are often still unknown. Museums and archives as well as the historians and curators working in them are very familiar with the special cultures of communication within these scientific communities and they play a major role in the establishment and development of history as a modern part of public relations and public identity. PMID- 25292312 TI - Efficient apoptosis and necrosis induction by proteasome inhibitor: bortezomib in the DLD-1 human colon cancer cell line. AB - The inhibition of the 26S proteasome evokes endoplasmic reticulum stress, which has been shown to be implicated in the antitumoral effects of proteasome inhibitors. The cellular and molecular effects of the proteasome inhibitor bortezomib-on human colon cancer cells are as yet poorly characterized. Bortezomib selectively induces apoptosis in some cancer cells. However, the nature of its selectivity remains unknown. Previously, we demonstrated that, in contrast to normal fibroblasts, bortezomib treatment evoked strong effect on apoptosis of breast cancer cells incubated in hypoxic and normoxic conditions. The study presented here provides novel information on the cellular effects of bortezomib in DLD-1 colon cancer cells line. We observe twofold higher percentage of apoptotic cells incubated for 48 h with 25 and 50 nmol/l of bortezomib in hypoxic conditions and four-, fivefold increase in normoxic conditions in comparison to control cells, incubated without bortezomib. It is of interest that bortezomib evokes strong effect on necrosis of DLD-1 colon cancer cell line. We observe the sixfold increase in necrosis of DLD-1 cells incubated with 25 or 50 nmol/l of bortezomib for 48 h in hypoxia and fourfold increase in normoxic conditions in comparison to adequate controls. We suggest that bortezomib may be candidates for further evaluation as chemotherapeutic agents for human colon cancer. PMID- 25292313 TI - The effects of galectin-1 on the gene expression of the transcription factors TBX21, GATA-3, FOXP3 and RORC. AB - CD4(+) T cells orchestrate the immune response by differentiating into T helper (Th) or regulatory (Treg) cell subsets that secrete distinct sets of cytokines. They also play a critical role in the pathogenesis of autoimmunity, asthma, allergy and, likely, cancer. The mechanisms involved in the regulation of CD4(+) T cell homeostasis by galectin-1 remain poorly characterized. To investigate whether galectin-1 modulates the differentiation of CD4(+) T cells, the effects of galectin-1 on the mRNA expression levels of TBX21, GATA-3, FOXP3 and RORC in activated peripheral blood mononuclear cells were examined. The expression levels of GATA-3 and FOXP3 mRNA were up-regulated after treatment with 1.0 MUg/ml galectin-1 and were unchanged (for GATA-3) or slightly elevated (for FOXP3) compared with untreated cells when 2.0 MUg/ml galectin-1 was added. At the same time, at both concentrations of galectin-1, we observed reduced TBX21 and RORC mRNA expression levels. These findings support the concept that galectin-1 skews the differentiation of CD4(+) T cells towards Th2 and Treg cells. PMID- 25292314 TI - Type-2 cannabinoid receptor regulates proliferation, apoptosis, differentiation, and OPG/RANKL ratio of MC3T3-E1 cells exposed to Titanium particles. AB - The type-2 cannabinoid receptor (CB2) is expressed in osteoblasts and plays a role in bone metabolism through regulation on bone mass and bone turnover, but the functional importance of CB2 in osteoblasts under Titanium (Ti) stimulation is incompletely understood. This study aimed to investigate the CB2 expression in osteoblasts under Ti stimulation and the effects of CB2 activation on proliferation, apoptosis, differentiation, mineralization, OPG, and RANKL expression of MC3T3-E1 cells exposed to Ti particles. MC3T3-E1 cells were incubated in the presence of Ti particles with or without CB2-specific agonist HU 308 and antagonist SR144528. Ti particles treatment obviously induced the CB2 expression in MC3T3-E1 cells, and reduced the cell survival in a dose- and time dependent manner (p < 0.05). Addition of HU-308 could dose-dependently alleviate the Ti-induced decrease of cell survival (p < 0.05). The flow cytometry assay showed that comparing with the control group, the apoptosis rate and caspase-3 activity in the Ti group were significantly elevated (p < 0.05), which could be alleviated by HU-308. Moreover, HU-308 effectively attenuated the decrease of cell mineralization capability, alkaline phosphates (ALP) and osteocalcin activity, and increase of OPG/RANKL ratio induced by Ti particles treatment (p < 0.05). These effects were partially counteracted by combined treatment of CB2 antagonist SR144528 (p < 0.05). In conclusion, CB2 activation has a favorable inhibitory effect on Ti-induced reactions in MC3T3-E1 cell through modulating proliferation, apoptosis, differentiation, and RANKL expression. These findings suggest that activation of CB2 might be an effective therapeutic strategy to promote bone formation and reduce bone dissolution. PMID- 25292315 TI - The novel role of TRPC6 in vitamin D ameliorating podocyte injury in STZ-induced diabetic rats. AB - Podocyte injury plays a critical role in the development and progression of diabetic nephropathy (DN). Over expression of TRPC6 on the podocytes has been revealed to cause podocyte injury in non-diabetic states. Besides, the emerging evidence from clinic revealed that vitamin D could reduce albuminuria and improve renal function, which was associated with podocyte protection. Our study aimed to investigate whether calcitriol ameliorating podocyte impairment is associated with regulation of the expression of TRPC6 in STZ-induced rats. Sprague-Dawley rats were randomly divided into three groups: normal control, DN, and DN treated with calcitriol (DN + VD); VD rats were treated with 0.1 MUg/kg/d calcitriol by gavage. DN model rats were established by intraperitoneal injections of streptozocin. The rats were sacrificed after 18 weeks treatment. DN rats exhibited increased proteinuria accompanied by elevated TRPC6 expression. Treatment with calcitriol not only reduced proteinuria, but also normalized TRPC6 expression. Meanwhile, in DN rats, the expression of podocyte specific markers including nephrin and podocin was significantly decreased, accompanied by increased desmin, a marker of podocyte injury. Treatment with calcitriol reversed above changes. In addition, vitamin D receptor (VDR) was significantly decreased, whereas this reduction was attenuated by the calcitriol treatment. Moreover, TRPC6 was positively correlated with both 24 h urinary protein and desmin. In contrast, TRPC6 was negatively correlated with both VDR and nephrin expression in podocytes. Calcitriol can ameliorate podocyte injury, which is contributed by the inhibition of enhanced TRPC6 expression in the early stages of DN rats. PMID- 25292316 TI - A computational model of urinary bladder smooth muscle syncytium : validation and investigation of electrical properties. AB - Certain smooth muscles, such as the detrusor of the urinary bladder, exhibit a variety of spikes that differ markedly in their amplitudes and time courses. The origin of this diversity is poorly understood but is often attributed to the syncytial nature of smooth muscle and its distributed innervation. In order to help clarify such issues, we present here a three-dimensional electrical model of syncytial smooth muscle developed using the compartmental modeling technique, with special reference to the bladder detrusor. Values of model parameters were sourced or derived from experimental data. The model was validated against various modes of stimulation employed experimentally and the results were found to accord with both theoretical predictions and experimental observations. Model outputs also satisfied criteria characteristic of electrical syncytia such as correlation between the spatial spread and temporal decay of electrotonic potentials as well as positively skewed amplitude frequency histogram for sub threshold potentials, and lead to interesting conclusions. Based on analysis of syncytia of different sizes, it was found that a size of 21-cube may be considered the critical minimum size for an electrically infinite syncytium. Set against experimental results, we conjecture the existence of electrically sub infinite bundles in the detrusor. Moreover, the absence of coincident activity between closely spaced cells potentially implies, counterintuitively, highly efficient electrical coupling between such cells. The model thus provides a heuristic platform for the interpretation of electrical activity in syncytial tissues. PMID- 25292317 TI - Relevance of depression for anticoagulation management in a routine medical care setting: results from the ThrombEVAL study program. AB - BACKGROUND: Depressive symptoms have detrimental effects on quality of life and mortality. Poor adherence to a treatment regimen is a potential mechanism for the increased risk of adverse medical events associated with depression. Regarding oral anticoagulation with vitamin K antagonists, adherence is crucial for the outcome. Little is known about the clinical relevance of current depressiveness for anticoagulation treatment. OBJECTIVES: To examine the impact of current depressiveness on anticoagulation treatment in regular medical care. PATIENTS/METHODS: We examined the association between clinically significant depressiveness as assessed by the Patient Health Questionnaire-2 >= 2 (PHQ-2 >= 2) with the percentage of time in the therapeutic range (TTR), self-rated compliance, several aspects of health literacy, anticoagulation side-effects and treatment satisfaction in a cross-sectional study of 1790 oral anticoagulation outpatients. RESULTS: Seven hundred and sixteen participants (40.0%) had clinically significant depressive symptoms. Depressed persons reported lower compliance with intake of prescribed medication and regular visits for control of anticoagulation, more unspecific side-effects (e.g. pruritus) and lower satisfaction with the anticoagulation treatment and their doctors' expertise and empathy. Depressed as compared with non-depressed individuals had a lower TTR ( 4.67; 95% CI, -8.39 to -0.95). Increasing severity of depressiveness was related with decreasing TTR. However, depressiveness lost its significant impact on TTR after multivariable adjustment (-3.11; 95% CI, -6.88 to 0.66). CONCLUSIONS: Clinically significant depressiveness was highly prevalent and impaired several aspects of anticoagulation treatment. Depressiveness should be regarded as a clinically significant condition that needs to be addressed in the management of anticoagulation patients. PMID- 25292319 TI - Interventions aimed at reducing obesity in early childhood: a meta-analysis of programs that involve parents. AB - BACKGROUND: Obesity is a growing problem even in very young childhood, resulting in high costs for individuals and society. As a response, numerous obesity prevention and intervention programs have been developed. Previous research has shown that early intervention programs are more effective when parents are involved, but the effectiveness of specific aspects of programs with parental involvement has not been investigated. This meta-analysis aims to investigate the features related to the effectiveness of different types of obesity intervention programs involving parents and targeting young children (0-6-year-olds). METHODS: The Web of Science, PubMed, PsycInfo, CINAHL, and ERIC databases were searched for childhood obesity prevention and intervention programs involving parents. Data were analyzed using the Comprehensive Meta-analysis (CMA) software. RESULTS: Fifty studies with effect sizes measured at short-term follow-up (within 3 months from the end of the intervention) and 26 studies with effect sizes measured at long-term follow-up (all reported in a total of 49 publications) were identified. The combined effect size of interventions was small but significant at short-term follow-up (d = .08, p < .01). The results suggested the presence of a potential publication bias in studies providing results at long-term follow-up, with a nonsignificant adjusted effect size (d = .02), which indicated that obesity interventions were not effective at long-term follow-up. Multivariate meta regression analyses showed that interventions were more effective when including either interactive sessions or educational materials as opposed to those including both interactive sessions and noninteractive educational materials. No other moderators regarding sample characteristics, study design, or methodological quality were significant. CONCLUSION: Interventions targeting young children that require parental involvement are effective at short-term follow-up, specifically when interventions include one mode of intervention rather than two. However, results were not retained in the long run. PMID- 25292321 TI - [Diagnostics on noise-induced hearing loss]. AB - Occupational noise-induced hearing loss (NIHL) may qualify to compensation and must be distinguished from the ski slope hearing loss (SKI) which is a hereditary type of hearing loss. By combining the NIHL and presbyacusis tables of ISO 1999 it was concluded that in a hearing loss caused solely by noise and ageing the median threshold at 2 kHz is never poorer than 35 dB, and that the ratio between the actual 3 kHz threshold and the average 2-4 kHz threshold does not exceed 1.3. Thus, the audiometric characteristics of the 2-3 kHz segment can distinguish between NIHL and SKI. PMID- 25292320 TI - Molecular insights into the anti-cancer properties of traditional Tibetan medicine Yukyung Karne. AB - BACKGROUND: Yukyung karne (YK) is a traditional Tibetan formulation used for many centuries for the treatment of ovarian cancer. However, the pharmacological basis of its anticancer property is not well understood. In the present study, the anticancer property of YK was investigated in cell culture. METHODS: The growth inhibitory property of YK was evaluated in SKOV6, IHH, HepG2 and HEK293 cell lines using MTT assay. The pro-apoptotic activity of drug was analyzed by terminal deoxynuleotidyl transferase dUTP nick end labeling (TUNEL) and DNA fragmentation assays. Confocal microscopy was used to show the release of cytochrome c and its co-localization with mitochondria with the help of dsRed mitotracker in SKOV6 cells. The inhibition in cell proliferation was also visualized by confocal microscopy after BrDU incorporation. The activation of tumor suppressor p53 was evaluated by Western blotting while VEGF levels in culture supernatant were measured by a colorimetric method. RESULTS: YK specifically and efficiently induced apoptotic killing of the human ovarian cancer SKOV6 cells as indicated by increased DNA fragmentation and nick end DNA labeling. Confocal microscopy suggested inhibition of cell proliferation and increase in cytochrome c release via perturbation in mitochondrial membrane potential (Deltapsim). Further, YK up-regulated the expression of tumor suppressor p53 and key cyclin-dependent kinase inhibitor p21, and inhibited VEGF secretion by cells. Interestingly, YK also exhibited a synergy with paclitaxel which is a well-known anti-cancer therapeutic drug. CONCLUSIONS: The pharmacological properties of YK to impose growth arrest and trigger pro apoptotic death in cells amply justify its usage in primary as well as adjunct therapy for ovarian cancer. PMID- 25292318 TI - Mutations in the voltage-gated sodium channel gene of anophelines and their association with resistance to pyrethroids - a review. AB - Constant and extensive use of chemical insecticides has created a selection pressure and favored resistance development in many insect species worldwide. One of the most important pyrethroid resistance mechanisms is classified as target site insensitivity, due to conformational changes in the target site that impair a proper binding of the insecticide molecule. The voltage-gated sodium channel (NaV) is the target of pyrethroids and DDT insecticides, used to control insects of medical, agricultural and veterinary importance, such as anophelines. It has been reported that the presence of a few non-silent point mutations in the NaV gene are associated with pyrethroid resistance, termed as 'kdr' (knockdown resistance) for preventing the knockdown effect of these insecticides. The presence of these mutations, as well as their effects, has been thoroughly studied in Anopheles mosquitoes. So far, kdr mutations have already been detected in at least 13 species (Anopheles gambiae, Anopheles arabiensis, Anopheles sinensis, Anopheles stephensi, Anopheles subpictus, Anopheles sacharovi, Anopheles culicifacies, Anopheles sundaicus, Anopheles aconitus, Anopheles vagus, Anopheles paraliae, Anopheles peditaeniatus and Anopheles albimanus) from populations of African, Asian and, more recently, American continents. Seven mutational variants (L1014F, L1014S, L1014C, L1014W, N1013S, N1575Y and V1010L) were described, with the highest prevalence of L1014F, which occurs at the 1014 site in NaV IIS6 domain. The increase of frequency and distribution of kdr mutations clearly shows the importance of this mechanism in the process of pyrethroid resistance. In this sense, several species-specific and highly sensitive methods have been designed in order to genotype individual mosquitoes for kdr in large scale, which may serve as important tolls for monitoring the dynamics of pyrethroid resistance in natural populations. We also briefly discuss investigations concerning the course of Plasmodium infection in kdr individuals. Considering the limitation of insecticides available for employment in public health campaigns and the absence of a vaccine able to brake the life cycle of the malaria parasites, the use of pyrethroids is likely to remain as the main strategy against mosquitoes by either indoor residual spraying (IR) and insecticide treated nets (ITN). Therefore, monitoring insecticide resistance programs is a crucial need in malaria endemic countries. PMID- 25292322 TI - [Lower benefit and higher total costs because of unrestricted use of endovascular repair procedures for treatment of abdominal aortic aneurysms]. AB - A rapid increase in endovascular aortic repair (EVAR) procedures for treatment of asymptomatic abdominal aortic aneurysms has occurred in Denmark. However, the newest level 1A evidence suggests that unrestricted use of EVAR in patients suitable for open repair lead to lower benefit and higher total costs as compared with open surgery. Amongst cases with relative and absolute contraindications for open surgery, use of EVAR is likely to lead to more benefit, however at a relatively high cost per quality-adjusted life year (QALY). This calls for a more restrictive use. PMID- 25292324 TI - [Patient empowerment]. AB - It is the explicit, political ambition of the Region of the capital in Denmark to apply the principle of patient empowerment on all levels of the health-care system. However, precise operationalized criteria for the application of patient empowerment are still not well-defined. In this article the premises of such an application is analysed and it is shown what kind of evidence should be required as criteria for interventions by the health-care system. A differentiation between two forms of interventions is made: one supporting patients who already control most of their own health care, an other increasing patients' responsibilities. PMID- 25292323 TI - [Pancreatic tumour in a child]. AB - Abdominal pain is a common symptom in children and recurrent abdominal pain (RAP) has a prevalence of 8.4% in childhood. In 90-95% of RAPs no organic disease is identified. Thus, it is important that the few of somatic origin are diagnosed. We describe a case concerning a 12-year-old girl, diagnosed with a solid pseudopapillary tumour of the pancreas. The symptoms were RAP and postprandial vomiting. The purpose of this article is to increase the knowledge of "alarm findings" indicating an organic disease in children with RAP. PMID- 25292325 TI - [Withdrawal versus continuation of antipsychotic drugs in people with dementia]. AB - Antipsychotics are often prescribed for treatment of psychiatric symptoms. The efficacy is very limited and must be weighed against the risk of adverse effects. A Cochrane review included randomized, placebo-controlled trials comparing an antipsychotic withdrawal with continuing treatment. Nine studies (606 patients) were included. Only in two studies with patients who had responded to antipsychotic treatment, withdrawal resulted in an increased risk of relapse. Withdrawal of antipsychotics should be incorporated in daily practice in primary care. PMID- 25292326 TI - [Myopathy causing acute tetraparesis in the intensive care unit]. AB - This is a case report of a 52-year-old woman with acute respiratory distress who shortly after admission to the intensive care unit developed flaccid tetraparesis with areflexia and elevated serum creatine kinase concentration. Typical clinical presentation, clinical neurophysiological examination and histology confirmed the presence of a necrotizing severe myopathy known as "myopathy with thick fibre loss", a serious but also most often spontaneously reversible condition. PMID- 25292327 TI - [Gynaecological cancer patients' view on follow-up programmes differ from health professionals']. AB - Evidence shows that survival after low-stage gynaecological cancer is not improved by follow-up programmes. Using a qualitative approach this study explores reassurance in follow-up after cancer from both patients' and health professionals' viewpoints. Patients associated the purpose of follow-up with a guarantee of no recurrence of cancer. Paradoxically, the health professionals were aware that this is not evident. However, patients were not informed about this. This may generate false reassurance and poor utilization of resources. PMID- 25292328 TI - [Autoinflammatory bone disorders in childhood]. AB - Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disease with unpredictable, painful courses of osteolytic lesions in the bones. CNO is frequently associated with psoriasis and inflammatory bowel disease. In cases with multifocal lesions the term chronic recurrent multifocal osteomyelitis (CRMO) is preferably used. SAPHO (synovitis, acne, pustulosis palmoplantaris, hyperostosis and osteitis) syndrome is regarded as CRMO in adults. New knowledge of the hereditary forms like Majeed syndrome, deficiency of IL-1-receptor antagonist and cherubism is described. PMID- 25292330 TI - Carbon-centered radicals add reversibly to histidine--implications. AB - Carbon-centered radicals of alcohols commonly used as hydroxyl radical scavengers (MeOH, EtOH, i-PrOH and t-BuOH) add reversibly to histidine with equilibrium constants up to 3 * 10(3) M(-1) and rate constants on the order of 10(9) M(-1) s( 1). Similar equilibria may compromise determinations of one-electron (radical) electrode potentials. PMID- 25292329 TI - To pay or not to pay? A multicountry study on informal payments for health-care services and consumers' perceptions. AB - BACKGROUND: Although the literature offers various theoretical explanations for the existence of informal patient payments, empirical research has mostly focused on socio-demographic features as determinants of these payments. The role of health-care users' perceptions on informal payments are rarely taken into account especially in multicountry surveys. OBJECTIVE: Our aim is to examine the association between informal payments for health-care services and perceptions of health-care consumers about paying informally as well as socio-demographic characteristics. DESIGN: We use data from a multicountry quantitative empirical research conducted in 2010. SETTING AND PARTICIPANTS: A national representative sample is drawn in six Central and Eastern European countries - Bulgaria, Hungary, Lithuania, Poland, Romania and Ukraine. In each country, about 1000 respondents are interviewed. MAIN VARIABLES STUDIED: Data related to informal payments for health-care services consumed during the preceding 12 months are analysed in addition to data on respondents' perceptions about paying informally and socio-demographic data. RESULTS: Health-care users in Bulgaria and Poland are less inclined to make informal payments, while health-care users in Romania and Ukraine most often report such payments. The informal payment rates for Hungary and Lithuania fall between these two groups. In all six countries, individuals who feel uncomfortable when leaving the physician's office without a gratuity and who feel unable to refuse the request of medical staff to pay informally, more often make informal payments. CONCLUSIONS: Such consumers' perceptions can undermine policy efforts to eradicate these payments; therefore, health policy measures should reinforce social resistance to informal payments. PMID- 25292331 TI - Effects of trophic similarity on community composition. AB - Understanding how ecological processes determine patterns among species coexisting within ecosystems is central to ecology. Here, we explore relationships between species' local coexistence and their trophic niches in terms of their feeding relationships both as consumers and as resources. We build on recent concepts and methods from community phylogenetics to develop a framework for analysing mechanisms responsible for community composition using trophic similarity among species and null models of community assembly. We apply this framework to 50 food webs found in 50 Adirondack lakes and find that species composition in these communities appears to be driven by both bottom-up effects by which the presence of prey species selects for predators of those prey, and top-down effects by which prey more tolerant of predation out-compete less tolerant prey of the same predators. This approach to community food webs is broadly applicable and shows how species interaction networks can inform an increasingly large array of theory central to community ecology. PMID- 25292332 TI - Relevance of congenital melanocytic naevi in vitiligo. AB - BACKGROUND: Some case reports concerning the concomitant presence of congenital melanocytic naevi (CMN), halo naevi and vitiligo have been published. However, their possible link has never been investigated in a large patient population. OBJECTIVES: To evaluate the relevance of CMN in patients with vitiligo with respect to the presence of halo naevi and some general clinical variables such as age of onset, Koebner phenomenon and body surface area (BSA) involvement. METHODS: In total, 1004 patients with vitiligo (nonsegmental) and 291 control patients were included in this observational study. CMN were scored in size, location and halo formation, and classified into clinical convincing or possible lesions. RESULTS: Convincing CMN were present in 3.3% of the patient population and in 1.0% of the control population. The presence of halo naevi was significantly higher (P = 0.01) and age of onset of vitiligo was significantly lower (P < 0.01) in the presence of CMN. Halo formation around the CMN, as observed in 30.3% of cases, was associated with a higher diameter of the CMN. Patients with congenital naevi had a particular predisposition to having lesions on joints/acral areas and reported more often signs of Koebner phenomenon (P = 0.01). No clear difference in disease activity, BSA involvement, associated autoimmune diseases or treatment response was observed in patients with vitiligo with or without congenital naevi. CONCLUSIONS: This study provides clinical evidence that CMN may influence the age of onset of vitiligo and trigger the development of halo naevi in patients with vitiligo. PMID- 25292333 TI - Immunohistochemical evidence of leptin and its receptor in the carpal glands of domestic pigs and wild boar. AB - BACKGROUND: In recent years, the protein hormone leptin has been the subject of numerous studies designed to clarify and interpret its functional significance; it has been speculated that this goes well beyond the control of appetite and energy metabolism. In particular, the presence of leptin and its receptor has been observed in various glands anatomically and functionally related to the reproductive apparatus. This has led to the hypothesis that leptin may act directly in the functional control of these glands and, in general, the control of reproductive function. HYPOTHESIS/OBJECTIVES: The presence and distribution of leptin and its receptor in the carpal glands of domestic pigs and wild boar are examined, using immunohistochemical techniques. ANIMALS: Tissue samples were collected from five domestic pigs and five wild boar, following slaughter. RESULTS: The presence of leptin and its receptor was demonstrated in the glands, localized in the dark cells of the glandular secretory epithelium. In addition, no difference was observed between wild boar and domestic pigs. CONCLUSIONS AND CLINICAL IMPORTANCE: We hypothesize that leptin may be produced by the carpal gland and may act on the gland's secretory epithelial cells with an autocrine/paracrine mechanism, thus affecting the secretory activity of the gland itself. PMID- 25292334 TI - Discovery of a silicon-based ferrimagnetic wheel structure in V(x)Si(12)(-) (x = 1-3) clusters: photoelectron spectroscopy and density functional theory investigation. AB - Our studies show that VSi(12)(-) adopts a V-centered hexagonal prism with a singlet spin state. The addition of the second V atom leads to a capped hexagonal antiprism for V(2)Si(12)(-) in a doublet spin state. Most interestingly, V(3)Si(12)(-) exhibits a ferrimagnetic, bicapped hexagonal antiprism wheel-like structure with a total spin of 4 MU(B). PMID- 25292335 TI - Impact of dental treatment under general anesthesia on the oral health-related quality of life of adolescents and adults with special needs. AB - This study aimed to assess the perception of the family's primary caregiver on the oral health-related quality of life (OHRQoL), and the impact on family dynamics, of dental treatment under general anesthesia (GA) in adolescent and adult patients with intellectual and developmental disabilities (IDD) and neurocognitive disorders. Self-administered questionnaires were completed, before dental treatment, by 116 primary family caregivers of patients who received dental treatment under GA, and 102 (88%) of these caregivers completed the same questionnaires within 4 wk after treatment. The Child Oral Health Impact Profile (COHIP) and the Family Impact Scale (FIS) were shortened to a 14-item COHIP (COHIP-14) and a 12-item FIS (FIS-12) based on the limitations of patients' communication. The COHIP-14 and FIS-12 scores and each subscale improved after treatment. The baseline scores varied based on certain characteristics of the patients, such as age, disabilities, medications, caregivers, meal types, cooperation levels, and treatment needs. The postoperative improvement in OHRQoL was significant in the patients who were older than 30 yr of age, originally eating soft meals, displaying no or very low levels of cooperation, or receiving endodontic treatment. Based on the primary caregiver perceptions, the OHRQoL of adolescents and adults with IDD and neurocognitive disorders was improved by dental treatment under GA. PMID- 25292336 TI - CaV1.2 and CaV1.3 channel hyperactivation in mouse islet beta cells exposed to type 1 diabetic serum. AB - The voltage-gated Ca(2+) (CaV) channel acts as a key player in beta cell physiology and pathophysiology. beta cell CaV channels undergo hyperactivation subsequent to exposure to type 1 diabetic (T1D) serum resulting in increased cytosolic free Ca(2+) concentration and thereby Ca(2+)-triggered beta cell apoptosis. The present study was aimed at revealing the subtypes of CaV1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of beta cell CaV1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic beta cells from CaV1 channel knockout and corresponding control mice. We now show that functional CaV1.3 channels are expressed in a subgroup of islet beta cells from CaV1.2 knockout mice (CaV1.2(-/-)). T1D serum enhanced whole-cell CaV currents in islet beta cells from CaV1.3 knockout mice (CaV1.3(-/-)). T1D serum increased the open probability and number of functional unitary CaV1 channels in CaV1.2(-/-) and CaV1.3(-/-) beta cells. These data demonstrate that T1D serum hyperactivates both CaV1.2 and CaV1.3 channels by increasing their conductivity and number. These findings suggest CaV1.2 and CaV1.3 channels as potential targets for anti diabetes therapy. PMID- 25292337 TI - ARTC1-mediated ADP-ribosylation of GRP78/BiP: a new player in endoplasmic reticulum stress responses. AB - Protein mono-ADP-ribosylation is a reversible post-translational modification of cellular proteins. This scheme of amino-acid modification is used not only by bacterial toxins to attack host cells, but also by endogenous ADP ribosyltransferases (ARTs) in mammalian cells. These latter ARTs include members of three different families of proteins: the well characterised arginine-specific ecto-enzymes (ARTCs), two sirtuins, and some members of the poly(ADP-ribose) polymerase (PARP/ARTD) family. In the present study, we demonstrate that human ARTC1 is localised to the endoplasmic reticulum (ER), in contrast to the previously characterised ARTC proteins, which are typical GPI-anchored ecto enzymes. Moreover, using the "macro domain" cognitive binding module to identify ADP-ribosylated proteins, we show here that the ER luminal chaperone GRP78/BiP (glucose-regulated protein of 78 kDa/immunoglobulin heavy-chain-binding protein) is a cellular target of human ARTC1 and hamster ARTC2. We further developed a procedure to visualise ADP-ribosylated proteins using immunofluorescence. With this approach, in cells overexpressing ARTC1, we detected staining of the ER that co-localises with GRP78/BiP, thus confirming that this modification occurs in living cells. In line with the key role of GRP78/BiP in the ER stress response system, we provide evidence here that ARTC1 is activated during the ER stress response, which results in acute ADP-ribosylation of GRP78/BiP paralleling translational inhibition. Thus, this identification of ARTC1 as a regulator of GRP78/BiP defines a novel, previously unsuspected, player in GRP78-mediated ER stress responses. PMID- 25292339 TI - Traditional Chinese medicine for treatment of liver diseases: progress, challenges and opportunities. AB - Traditional Chinese medicine (TCM) is commonly used in treating liver diseases worldwide, especially in China. The advantages of using TCM for treatment of liver diseases include: protecting hepatocytes, inhibiting hepatic inflammation and antifibrosis in the liver. In this article, we introduce TCM herbal preparations from the Chinese materia medica (such as Fuzheng Huayu) that are typically used for the treatment of liver diseases. Literature surrounding the mechanisms of TCM therapy for treatment of liver diseases is presented and discussed. We propose that side effects of herbal compounds are often under appreciated, and that more care should be taken in the prescription of potentially hepatotoxic medicines. Further, to deepen the understanding of TCM mechanisms, new techniques and methodologies must be developed. Future studies will lead to the enhancement of clinical outcomes of TCM. As complementary and alternative therapies, TCMs will play an expanding role in the future of liver disease treatment. PMID- 25292340 TI - Interpretation of illness in patients with chronic diseases from Shanghai and their associations with life satisfaction, escape from illness, and ability to reflect the implications of illness. AB - OBJECTIVE: The aim of this study is to analyze how patients with chronic diseases from Shanghai interpret their disease, and how these interpretations influence patients' life satisfaction, intention to escape from their illness and their ability to reflect on the implications of their illness. METHODS: A cross sectional study enrolling 142 patients (mean age (50 +/- 16) years; 63% men, 37% women) with chronic diseases (60% cancer) was recruited in the Changhai Hospital of Traditional Chinese Medicine, Shanghai, China and surveyed using standardized questionnaires. RESULTS: Patients with chronic diseases from Shanghai interpreted their illness mostly as an Adverse Interruption of Life (55%), as a Threat/Enemy (50%), but also as a Challenge (49%), and only rarely as a Call for Help (18%) or as a Punishment (13%). Particularly fatalistic negative (i.e., Threat/Enemy, Adverse Interruption of Life) and strategy-associated disease interpretations (i.e., Relieving Break, Call for Help) were moderately associated with patients' intention to escape from illness. In contrast, positive interpretations (i.e., something of Value, Challenge) and also the guilt-associated negative interpretation Failure were moderately related with patients' ability to reflect on their illness. However, life satisfaction was weakly associated only with the view that illness might be a Challenge. Interestingly, 58% of those who would see their illness as an Adverse Interruption (AI+) could see it also as a Challenge (Ch+). Detailed analyses showed that AI+Ch+ patients differ from their AI+Ch- counterparts significantly with respect to their ability to reflect life and implications of illness (F=9.1; P=0.004). CONCLUSION: The observed interpretations of illness, particularly the negative perceptions, could be used as indicators that patients require further psychological assistance to cope with their burden. Helping AI+ patients see their illness also as a Challenge, and thus develop a higher Reflection on Life Concerns, would be greatly beneficial, and encourages further research. PMID- 25292341 TI - Electroacupuncture at Feishu (BL13) and Zusanli (ST36) down-regulates the expression of orexins and their receptors in rats with chronic obstructive pulmonary disease. AB - OBJECTIVE: Inflammation and lung function decline are the main pathophysiological features of chronic obstructive pulmonary disease (COPD). Acupuncture can improve lung function in patients with COPD, but the underlying mechanisms are not well understood. Orexins (OXs), which are found in peripheral plasma, are neuropeptides that regulate respiration and their levels are related to COPD. Therefore, we hypothesized that acupuncture might alter OXs, reduce lung inflammation and improve lung function in COPD. METHODS: COPD was induced in rats by exposure to cigarette smoke for 8 weeks and injecting with lipopolysaccharide twice. Electroacupuncture (EA) was performed at Feishu (BL13) and Zusanli (ST36) for 30 min/d for 2 weeks. Rat lung function and morphology were assessed after EA. The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in bronchoalveolar lavage fluid (BALF) and orexin A and B levels in the lung tissue were detected by enzyme-linked immunosorbent assay. OX receptor mRNA levels and immunopositive cells were assessed with real-time polymerase chain reaction and immunohistochemical methods, respectively. The relationships among lung function, cell factors, and OX levels were analyzed by Pearson correlation analyses. RESULTS: Compared with the control group, lung function was significantly decreased in the rats with COPD (P<0.05). There were increases in TNF-alpha and IL-1beta levels in BALF (P<0.05 and P<0.01, respectively), orexin A level in lung tissue (P<0.01; but not orexin B) and mRNA expressions of OX (OXR1) and OX 2 (OXR2) in lung tissue (P<0.05 and P<0.01, respectively); the integrative optical densities (IODs) of both receptors were greater in the COPD group (P<0.05). For rats with COPD subjected to EA, lung function was improved (P<0.05). There were notable decreases in TNF-alpha and IL-1beta levels (P<0.05 and <0.01, respectively) in BALF. Orexin A, but not orexinB, levels in lung tissue also decreased (P<0.01), as did mRNA expression of OX1R and OX2R in lung tissue (P<0.05 and P<0.01, respectively). Receptor IODs were also reduced after EA treatment (P<0.05). Furthermore, orexin A levels and ratio of forced expiratory volume in 0.3 s to forced vital capacity were strongly negatively correlated (P<0.01), and orexin A was positively correlated with TNF-alpha and IL 1beta (P<0.001 and P<0.05, respectively). CONCLUSION: EA at Zusanli and Feishu improved lung function of rats with COPD and had an anti-inflammatory effect, which may be related to down-regulation of OXA and its receptors. PMID- 25292338 TI - Histone chaperone CAF-1: essential roles in multi-cellular organism development. AB - More and more studies have shown chromatin remodelers and histone modifiers play essential roles in regulating developmental patterns by organizing specific chromosomal architecture to establish programmed transcriptional profiles, with implications that histone chaperones execute a coordinating role in these processes. Chromatin assembly factor-1 (CAF-1), an evolutionarily conserved three subunit protein complex, was identified as a histone chaperone coupled with DNA replication and repair in cultured mammalian cells and yeasts. Interestingly, recent findings indicate CAF-1 may have important regulatory roles during development by interacting with specific transcription factors and epigenetic regulators. In this review, we focus on the essential roles of CAF-1 in regulating heterochromatin organization, asymmetric cell division, and specific signal transduction through epigenetic modulations of the chromatin. In the end, we aim at providing a current image of facets of CAF-1 as a histone chaperone to orchestrate cell proliferation and differentiation during multi-cellular organism development. PMID- 25292342 TI - Low doses of ethanolic extract of Boldo (Peumus boldus) can ameliorate toxicity generated by cisplatin in normal liver cells of mice in vivo and in WRL-68 cells in vitro, but not in cancer cells in vivo or in vitro. AB - OBJECTIVE: Use of cisplatin, a conventional anticancer drug, is restricted because it generates strong hepatotoxicity by accumulating in liver. Therefore its anticancer potential can only be fully exploited if its own toxicity is considerably reduced. Towards this goal, ethanolic extract of the plant, Boldo (Peumus boldus), known for its antihepatotoxic effects, was used simultaneously with cisplatin, to test its ability to reduce cisplatin's cytotoxicity without affecting its anticancer potential. METHODS: The cytotoxicity of Boldo extract (BE) and cisplatin, administered alone and in combination, was determined in three cancer cell lines (A549, HeLa, and HepG2) and in normal liver cells (WRL 68). Drug-DNA interaction, DNA damage, cell cycle, apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP, DeltaPsi) were also studied. Hepatotoxicity and antioxidant activity levels were determined by alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and glutathione assays in mice. The cytotoxicity of related proteins was tested by Western blotting. RESULTS: Co-administration of BE and cisplatin increased viability of normal cells, but had no effect on the viability of cancer cells. Boldo protected liver from damage and normalized different antioxidant enzyme levels in vivo and also reduced ROS and re-polarized MMP in vitro. Bax and cytochrome c translocation was reduced with caspase 3 down-regulation. Further, a drug-DNA interaction study revealed that BE reduced cisplatin's DNA-binding capacity, resulting in a reduction in DNA damage. CONCLUSION: Results indicated that a low dose of BE could be used beneficially in combination with cisplatin to reduce its toxicity without hampering cisplatin's anticancer effect. These findings signify a potential future use of BE in cancer therapy. PMID- 25292343 TI - Effect of aqueous extract of Solanum xanthocarpum Schrad. & Wendl. on postmenopausal syndrome in ovariectomized rats. AB - OBJECTIVE: Solanum xanthocarpum Schrad. & Wendl. (Solanaceae) is present in many Ayurveda compound formulations including Chavanaprasha and Dasamoolarishta. The whole plant is used in conditions such as inflammation, constipation and promoting conception in females. In the present study, we carried out different tests to evaluate the effect of aqueous extract of Solanum xanthocarpum (SXE) in postmenopausal syndrome. METHODS: The study was carried out in bilaterally ovariectomized one-month-old Wistar rats (40-50 g). Bilaterally ovariectomized (OVX) Wistar rats were divided into four groups (n=6) receiving different treatments, consisting of a vehicle (distilled water), aqueous extract of Solanum xanthocarpum at two different doses (200 and 400 mg/kg) administered orally daily for 90 d and standard drug beta estradiol at a dose of 1 mg/kg administered subcutaneously biweekly for 90 d. Estrogenic activity was assessed by vaginal cornification, sexual behavior, serum estradiol and uterine weight to body weight ratio. Antiosteoporotic activity was assessed on the basis of biomechanical and biochemical parameters followed by histopathological studies, and antidepressant activity was assessed by forced swim test. RESULTS: SXE showed presence of steroids. At the dose of 200 mg/kg, it significantly improved all the parameters of sexual behavior (P<0.01), caused vaginal cornification, and increased serum estradiol and uterine weight (P<0.01). It also significantly improved all the parameters of bone strength as well as depression (P<0.01). Histopathology of bones confirmed the above findings. CONCLUSION: The study indicated that SXE may provide an effective treatment in the prevention of postmenopausal symptoms. PMID- 25292344 TI - Liuwei Dihuang, a traditional Chinese herbal formula, suppresses chronic inflammation and oxidative stress in obese rats. AB - OBJECTIVE: To investigate the anti-inflammatory, anti-oxidative stress, and adipokine-ameliorating effects of Liuwei Dihuang (LWDH), a traditional Chinese herbal formula, in obese rats. METHODS: After 2 weeks of acclimation with free access to regular rodent chow and water, obese-prone-caesarean-derived (OP-CD) rats were fed a modified AIN-93G diet containing 60% energy from fat. Treatment was performed twice daily by gavage feeding with 500, 1 500, or 3 500 mg/kg body weight LWDH suspended in water (n=12 rats per group). Twelve obese-resistant-CD (OR-CD) rats were fed the atherogenic diet and gavaged with water, and served as the normal control. Blood biomarkers of inflammation, oxidative stress and adiponectin were measured post-sacrifice and used to determine the treatment effect of LWDH and assess the suitability of OR/OP-CD rats for studying these parameters. RESULTS: After 9 weeks of treatment, LWDH lowered serum C-reactive protein (CRP) and tumour necrosis factor-alpha (TNF-alpha) levels. Serum interleukin-6 (IL-6) levels showed a tendency towards reduction, but were not significantly different from the OP-CD control. Liver superoxide dismutase (SOD) activity was increased in response to all three doses of LWDH, while the levels of reduced (GSH) and oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS) were unchanged. Serum adiponectin levels were increased in response to oral administration of LWDH at the dose of either 500 or 1 500 mg/kg body weight. In addition, comparisons between OR-CD and OP-CD rats revealed differential, and for some biomarkers, conflicting characteristics of high-fat diet-fed OP-CD rats in reference to obese human subjects in terms of inflammatory and oxidative stress biomarkers and circulating adiponectin levels. CONCLUSION: The results show, for the first time, the anti-inflammatory, anti-oxidative stress and adiponectin-ameliorating effects of LWDH in obese rats. The suitability of the OR/OP-CD rat model as a research tool to study inflammation, oxidative stress, and adipokine production requires further investigation. PMID- 25292345 TI - Simultaneous determination of five anthraquinones in a Chinese traditional preparation by RP-HPLC using an improved extraction procedure. AB - OBJECTIVE: The stable quality of Chinese herbal medicines is a critical factor for their reliable clinical efficiency. An improved liquid-liquid extraction procedure and a liquid chromatographic method were developed to simultaneously analyze five anthraquinones (aloe-emodin, rhein, emodin, chrysophanol and physcion) in a Chinese traditional hospital preparation, Fuyankang mixture, in order to quantitatively control its quality in a more effective way. METHODS: A more economical and repeatable extraction procedure based on conventional liquid liquid extraction technique was developed and used to extract five marker components in Fuyankang mixture. These anthraquinones were separated in less than 20 min on a C18 column with methanol and 0.1% phosphoric acid (88:12, v/v) as mobile phase. The method was validated for specificity, precision, spiked recovery and stability. RESULTS: Compared to conventional liquid-liquid extraction, the improved liquid-liquid extraction was found to be more effective for simultaneous extraction of anthraquinones from an aqueous Chinese herbal preparation, especially for hydrophobic compounds. The improved extraction method was successfully applied to determine the content of five marker components in Fuyankang mixture by the means of reverse phase high-performance liquid chromatography. CONCLUSION: The improved extraction procedure may be suitable for routine quality control of Fuyankang mixture and other traditional preparations at city-level hospitals in China. PMID- 25292346 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: diseases of Gynecology and Obstetrics (Part 3). PMID- 25292348 TI - Erratum to: Biotransformation of 1,3-propanediol cyclic sulfate and its derivatives to diols by Rhodococcus sp. PMID- 25292347 TI - Effect of anti-tumor necrosis factor alpha treatment of rheumatoid arthritis and chronic kidney disease. AB - Although chronic kidney disease (CKD) may constitute a chronic inflammatory state indicated by elevated inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), the impact of anti-TNF-alpha therapy on progression of CKD in patients with rheumatoid arthritis (RA) is unclear. Seventy patients with RA and CKD were retrospectively analyzed. Outcomes were evaluated using the difference in the annual change of estimated glomerular filtration rate (eGFR) between patients treated with anti-TNF-alpha or without. Anti-TNF-alpha therapy significantly decreased disease activity score (DAS) 28 from 5.32 +/- 0.78 to 3.59 +/- 0.85 (p < 0.001). There was a tendency toward stabilization of eGFR after a mean of 2.9 +/- 1.1 years from 50.3 +/- 8.4 ml/min/1.73 m(2) to 54.5 +/- 16.0 ml/min/1.73 m(2) in patients received anti-TNF-alpha therapy along with decreased DAS28 (p = 0.084). Conversely, eGFR decreased significantly in patients not receiving anti-TNF-alpha therapy after a mean of 2.8 +/- 1.7 years from 52.6 +/- 7.5 ml/min/1.73 m(2) to 46.5 +/- 11.5 ml/min/1.73 m(2) (p = 0.041) without significant DAS28 change (p = 0.078). The annual change of eGFR was significantly different between patients treated with anti-TNF-alpha drugs and without (2.0 +/- 7.0 ml/min/1.73 m(2)/year vs. -1.9 +/- 4.0 ml/min/1.73 m(2)/year; difference in mean vs. -3.9 +/- 7.3 ml/min/1.73 m(2)/year; p = 0.006). Use of anti-TNF-alpha drugs was significantly associated with positive annual change of eGFR in multivariate logistic regression analysis (p = 0.019). Among patients with RA and CKD, treatment with anti-TNF-alpha drugs was associated with less renal function decline. Anti-TNF-alpha drugs may be beneficial for managing RA combined with CKD. PMID- 25292349 TI - Baseline serum level of matrix metalloproteinase-3 as a biomarker of progressive joint damage in rheumatoid arthritis patients. AB - AIM: Matrix metalloproteinase-3 (MMP-3) plays a pivotal role in the destruction of bone and degradation of cartilage components in rheumatoid arthritis (RA). We aimed in this study to analyze the relation between baseline levels of MMP-3 and the progression of joint damage in RA. METHODS: Eighty-one untreated RA patients with joint symptoms for <1 year were evaluated at baseline and after 12 months as regards erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and plain X ray of both hands and wrists. Baseline levels of MMP-3 were measured by enzyme linked immunosorbent assay and magnetic resonance imaging (MRI) of hands/wrists was performed. Disease Activity Score (DAS28) and Health Assessment Questionnaire (HAQ) were performed at baseline evaluation and after 12 months. RESULTS: The baseline MMP-3 levels were significantly higher in the high-progression group compared with the low-progression one (95.75 +/- 42.84 vs. 50.45 +/- 12.83, P < 0.001). There was a positive correlation between baseline levels of MMP-3 and MRI erosion score and other baseline clinical parameters, except for HAQ and the van der Heijde modification of the Sharp scoring system (SvdH) scores, while after 12 months, there were high positive correlations between MMP-3 and SvdH score, as well as all parameters except for ESR. CONCLUSION: Serum baseline levels of MMP-3 are strong prognostic markers of disease activity, and act well as an early predictor of progressive joint damage in recent-onset RA disease. PMID- 25292350 TI - Detailed clinicopathological characterization of progressive alopecia areata patients treated with i.v. corticosteroid pulse therapy toward optimization of inclusion criteria. AB - The management of progressive alopecia areata (AA) is often challenging. Recently, i.v. corticosteroid pulse therapy has been reported to be effective for acute and severe AA, however, inclusion criteria have not been sufficiently precise, leaving a chance that its efficacy could be further improved by optimizing therapeutic indications. In our attempts to delineate the factors that correlate with favorable outcomes, we minutely evaluated the clinicopathological findings and the prognoses of single-round steroid pulse-treated progressive AA cases with full sets of image and pathology records during the course. Almost complete hair regrowth has been achieved and maintained up to 2 years in five out of seven AA patients with varying degrees of clinical severity. Interestingly, the worst clinical presentation observed during the course correlated with the size of the area where hairs with dystrophic roots were pulled rather than the extent of visible hair loss on the first visit. Dermoscopy detected disease spread but contributed little in assessing prognoses. Dense perifollicular cell infiltration was detected in all cases treated within 4 weeks of onset and those treated later but with excellent response. Importantly, the cases with poor or incomplete hair regrowth were treated 6-8 weeks of onset and showed moderate inflammatory change with high telogen conversion rate. These findings mandate global dermoscopy and hair pull test for judging the treatment indication and suggest that early administration of high-dose corticosteroid, ideally within 4 weeks of onset, enable efficient suppression of active inflammation and maximize the effectiveness of the remedy. PMID- 25292351 TI - Disorder-dissociated effects of fluoxetine on brain function of working memory in attention deficit hyperactivity disorder and autism spectrum disorder. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are often co-morbid and share performance and brain dysfunctions during working memory (WM). Serotonin agonists modulate WM and there is evidence of positive behavioural effects in both disorders. We therefore used functional magnetic resonance imaging (fMRI) to investigate shared and disorder-specific brain dysfunctions of WM in these disorders, and the effects of a single dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. METHOD: Age-matched boys with ADHD (n = 17), ASD (n = 17) and controls (n = 22) were compared using fMRI during an N-back WM task. Patients were scanned twice, under either an acute dose of fluoxetine or placebo in a double-blind, placebo-controlled randomized design. Repeated-measures analyses within patients assessed drug effects on performance and brain function. To test for normalization effects of brain dysfunctions, patients under each drug condition were compared to controls. RESULTS: Under placebo, relative to controls, both ADHD and ASD boys shared underactivation in the right dorsolateral prefrontal cortex (DLPFC). Fluoxetine significantly normalized the DLPFC underactivation in ASD relative to controls whereas it increased posterior cingulate cortex (PCC) deactivation in ADHD relative to control boys. Within-patient analyses showed inverse effects of fluoxetine on PCC deactivation, which it enhanced in ADHD and decreased in ASD. CONCLUSIONS: The findings show that fluoxetine modulates brain activation during WM in a disorder-specific manner by normalizing task-positive DLPFC dysfunction in ASD boys and enhancing task-negative default mode network (DMN) deactivation in ADHD. PMID- 25292352 TI - Genetic association of APOB polymorphisms with variation in serum lipid profile among the Kuwait population. AB - BACKGROUND: Several studies have identified APOB as a candidate gene predisposing individuals to dyslipidemia. Polymorphisms including the signal peptide (rs11279109), codon 2488 XbaI (rs1042031), codon 3611 MspI (rs693), codon 4154 EcoRI (rs1801701) and the 3' variable number of tandem repeats have been reported to be associated with dyslipidemia in several populations. With limited studies on Arabs, this study aimed to investigate the genetic association of APOB polymorphisms and assess the potential influence of minor and rare alleles on serum lipid levels in the Kuwaiti population. METHODS: A total of 795 Kuwaiti subjects, documented with phenotypic data and fasting serum lipid levels, were genotyped for the five polymorphisms using PCR, PCR-RFLP and gene fragment analysis. Genotype and allele association with variation in serum lipid levels as well as haplotypes were analyzed using chi-square test, univariate and logistic regression analysis. RESULTS: Analysis of the genotype and allele frequencies distribution revealed a significant positive association between the APOB signal peptide and 3611 MspI polymorphisms with increased levels of triglycerides (statistical power of 80%). Haplotype analysis further supported the findings by showing that carriers of haplotypes (IX-M-E+M) had significantly lower mean (SD) TG levels (0.86 +/- 0.07) as compared to non-carriers (1.01 +/- 0.02). Significance was also observed with regards to positive family history of hypercholesterolemia. CONCLUSION: The results imply a "protective role" for two alleles (rs11279109 and rs1801701) in which logistic regression analysis showed a significant half-fold decrease in the risk for heterozygotes of rs11279109 and an 8.8 fold decrease in the risk for homozygous M-M- of rs1801701 of having lower TG levels (<1.70 mmol/L) in individuals. This suggests that genetic interaction between various polymorphisms at different gene loci act in linkage disequilibrium to affect serum TG levels. Apo B genotyping may be a useful adjunct for the identification of individuals at risk of developing dyslipidemia in order to provide them with lifestyle modifications and/or pharmacological intervention to mitigate the effects of gene interaction and environmental influence. PMID- 25292354 TI - Ask not what physics can do for biology--ask what biology can do for physics. AB - Stan Ulam, the famous mathematician, said once to Hans Frauenfelder: 'Ask not what Physics can do for biology, ask what biology can do for physics'. The interaction between biologists and physicists is a two-way street. Biology reveals the secrets of complex systems, physics provides the physical tools and the theoretical concepts to understand the complexity. The perspective gives a personal view of the path to some of the physical concepts that are relevant for biology and physics (Frauenfelder et al 1999 Rev. Mod. Phys. 71 S419-S442). Schrodinger's book (Schrodinger 1944 What is Life? (Cambridge: Cambridge University Press)), loved by physicists and hated by eminent biologists (Dronamraju 1999 Genetics 153 1071-6), still shows how a great physicist looked at biology well before the first protein structure was known. PMID- 25292353 TI - Childhood encephalitis: relationship between diffusion abnormalities and clinical outcome. AB - INTRODUCTION: The impact of restricted diffusion on clinical outcome has not been well studied in childhood encephalitis. We hypothesized that the patients with lesions with restricted diffusion (LRD) would have worse clinical outcome. METHODS: We reviewed the MR studies of 83 children with encephalitis for LRD. An MRI scoring system (0-12) based on fluid-attenuated inversion recovery (FLAIR) imaging was created to evaluate the extent of imaging abnormality. Clinical outcome was graded by using Glasgow outcome scale (GOS) (1-5) in 1st and 12th month: 1 for death and five for full recovery. With respect to diffusion, the correlation between imaging score and GOS was assessed. Logistic regression analysis was used to explore the impact of diffusion and imaging score on clinical outcome. The patients were divided into three subgroups regarding imaging score: I, 0-4; II, 5-8; and III, 9-12. RESULTS: LRD was found in 28 patients. Negative significant correlation was found between imaging score and GOS in the group with LRD in both 1st month (R = -0.67, P < 0.001) and 12th month (R = -0.56, P = 0.001). Multivariate logistic regression showed that LRD (P < 0.001) and age (P = 0.026) were significant independent risk factors for unfavorable outcome in 1st month, and both LRD (P = 0.001) and imaging score (P = 0.043) were significant risk factors for unfavorable outcome in 12th month. CONCLUSIONS: Patients with LRD have a worse clinical outcome than those without LRD. In patients with LRD, those with a greater extent of abnormality have a poorer outcome. PMID- 25292355 TI - Alterity and the transformation of social representations: a sociocultural account. AB - This article uses sociocultural theories of self-reflection to theorize how social representations are transformed. While there are several ways in which social representations change, we focus on one way that entails interactions with alterity, that is, other people, groups and representations. We use sociocultural psychology to explore how social representations can shift from being the medium of thought and action to becoming the object of thought and action. This process, we argue, entails alternative representations becoming the new medium of thought and action. Although this account relies upon the psychological process of self reflection, it avoids psychological reductionism, because the psychological process is based on social and sociological processes. Self-reflection, however, is more of an exception than a rule, and the ways in which self-reflection is blocked are also examined. Future research, it is argued, should examine the ways in which self-reflection arises through the interaction of representations within situated contexts, thus forging a third way between psychological and sociological reductionism. PMID- 25292358 TI - Population genomics of transposable elements in Drosophila. AB - Studies of the population dynamics of transposable elements (TEs) in Drosophila melanogaster indicate that consistent forces are affecting TEs independently of their modes of transposition and regulation. New sequencing technologies enable biologists to sample genomes at an unprecedented scale in order to quantify genome-wide polymorphism for annotated and novel TE insertions. In this review, we first present new insights gleaned from high-throughput data for population genomics studies of D. melanogaster. We then consider the latest population genomics models for TE evolution and present examples of functional evidence revealed by genome-wide studies of TE population dynamics in D. melanogaster. Although most of the TE insertions are deleterious or neutral, some TE insertions increase the fitness of the individual that carries them and play a role in genome adaptation. PMID- 25292359 TI - Cancer: evolution within a lifetime. AB - Subclonal cancer populations change spatially and temporally during the disease course. Studies are revealing branched evolutionary cancer growth with low frequency driver events present in subpopulations of cells, providing escape mechanisms for targeted therapeutic approaches. Despite such complexity, evidence is emerging for parallel evolution of subclones, mediated through distinct somatic events converging on the same gene, signal transduction pathway, or protein complex in different subclones within the same tumor. Tumors may follow gradualist paths (microevolution) as well as major shifts in evolutionary trajectories (macroevolution). Although macroevolution has been subject to considerable controversy in post-Darwinian evolutionary theory, we review evidence that such nongradual, saltatory leaps, driven through chromosomal rearrangements or genome doubling, may be particularly relevant to tumor evolution. Adapting cancer care to the challenges imposed by tumor micro- and macroevolution and developing deeper insight into parallel evolutionary events may prove central to improving outcome and reducing drug development costs. PMID- 25292360 TI - Site specific spin dynamics in BaFe2As2: tuning the ground state by orbital differentiation. AB - The role of orbital differentiation on the emergence of superconductivity in the Fe-based superconductors remains an open question to the scientific community. In this investigation, we employ a suitable microscopic spin probe technique, namely Electron Spin Resonance (ESR), to investigate this issue on selected chemically substituted BaFe2As2 single crystals. As the spin-density wave (SDW) phase is suppressed, we observe a clear increase of the Fe 3d bands anisotropy along with their localization at the FeAs plane. Such an increase of the planar orbital content is interestingly independent of the chemical substitution responsible for suppressing the SDW phase. As a consequence, the magnetic fluctuations in combination with this particular symmetry of the Fe 3d bands are propitious ingredients for the emergence of superconductivity in this class of materials. PMID- 25292357 TI - Messenger RNA degradation in bacterial cells. AB - mRNA degradation is an important mechanism for controlling gene expression in bacterial cells. This process involves the orderly action of a battery of cellular endonucleases and exonucleases, some universal and others present only in certain species. These ribonucleases function with the assistance of ancillary enzymes that covalently modify the 5' or 3' end of RNA or unwind base-paired regions. Triggered by initiating events at either the 5' terminus or an internal site, mRNA decay occurs at diverse rates that are transcript specific and governed by RNA sequence and structure, translating ribosomes, and bound sRNAs or proteins. In response to environmental cues, bacteria are able to orchestrate widespread changes in mRNA lifetimes by modulating the concentration or specific activity of cellular ribonucleases or by unmasking the mRNA-degrading activity of cellular toxins. PMID- 25292361 TI - Blocking the QB-binding site of photosystem II by tenuazonic acid, a non-host specific toxin of Alternaria alternata, activates singlet oxygen-mediated and EXECUTER-dependent signalling in Arabidopsis. AB - Necrotrophic fungal pathogens produce toxic compounds that induce cell death in infected plants. Often, the primary targets of these toxins and the way a plant responds to them are not known. In the present work, the effect of tenuazonic acid (TeA), a non-host-specific toxin of Alternaria alternata, on Arabidopsis thaliana has been analysed. TeA blocks the QB -binding site at the acceptor side of photosystem II (PSII). As a result, charge recombination at the reaction centre (RC) of PSII is expected to enhance the formation of the excited triplet state of the RC chlorophyll that promotes generation of singlet oxygen ((1)O2). (1)O2 activates a signalling pathway that depends on the two EXECUTER (EX) proteins EX1 and EX2 and triggers a programmed cell death response. In seedlings treated with TeA at half-inhibition concentration (1)O2-mediated and EX-dependent signalling is activated as indicated by the rapid and transient up-regulation of (1)O2-responsive genes in wild type, and its suppression in ex1/ex2 mutants. Lesion formation occurs when seedlings are exposed to higher concentrations of TeA for a longer period of time. Under these conditions, the programmed cell death response triggered by (1)O2-mediated and EX-dependent signalling is superimposed by other events that also contribute to lesion formation. PMID- 25292356 TI - Genetic, epigenetic, and environmental contributions to neural tube closure. AB - The formation of the embryonic brain and spinal cord begins as the neural plate bends to form the neural folds, which meet and adhere to close the neural tube. The neural ectoderm and surrounding tissues also coordinate proliferation, differentiation, and patterning. This highly orchestrated process is susceptible to disruption, leading to neural tube defects (NTDs), a common birth defect. Here, we highlight genetic and epigenetic contributions to neural tube closure. We describe an online database we created as a resource for researchers, geneticists, and clinicians. Neural tube closure is sensitive to environmental influences, and we discuss disruptive causes, preventative measures, and possible mechanisms. New technologies will move beyond candidate genes in small cohort studies toward unbiased discoveries in sporadic NTD cases. This will uncover the genetic complexity of NTDs and critical gene-gene interactions. Animal models can reveal the causative nature of genetic variants, the genetic interrelationships, and the mechanisms underlying environmental influences. PMID- 25292363 TI - Special issue on anthocyanins. PMID- 25292364 TI - Learning curve of laparoscopic low anterior resection in terms of local recurrence. AB - BACKGROUND: Experience in terms of surgical case numbers required to develop proficiency for oncologic adequacy after sphincter-saving laparoscopic rectal cancer surgery has not been established. METHOD: Three hundred seventeen consecutive patients underwent sphincter-saving laparoscopic rectal cancer surgery with curative intent performed by single surgeon. The learning curve was estimated using risk-adjusted cumulative sum (RA-CUSUM) and the graph of 195 consecutive patients who were treated by another surgeon was used to evaluate inter-surgeon variability in the learning curve. RESULTS: Overall, the 3-year local recurrence rate was 7.7% (95% confidence interval [CI], 6.4%-9.0%). The RA CUSUM analysis demonstrated a learning curve of 110 cases for local recurrence for both of surgeons and 50-70 cases for CRM involvement. The 3-year local recurrence-free rate was better during the experienced period than during the learning period (95.1% [95% CI, 91.6%-97.1%] vs. 89.5% [95% CI, 84.4%-93.0%]; P = 0.029). These differences were obvious in subgroup analysis of stage III tumors (93.4% [95% CI, 86.6%-96.8%] vs. 78.6% [95% CI, 68.5%-85.3%]; P = 0.013). CONCLUSIONS: Local recurrence rates decreased with increasing surgeon experience, as did other short-term outcomes, especially in advanced disease cases. PMID- 25292362 TI - Fatty acids rehabilitated long-term neurodegenerative: like symptoms in olfactory bulbectomized rats. AB - Our previous study demonstrated that an olfactory bulbectomy in rats induced short-term, multifaceted, devastating Alzheimer's-like effects, which included cognitive impairment, hyperactivity, hyperthermia, and increased levels of homocysteine and pro-inflammatory cytokines, including IL-17A. In addition, the rats exhibited an increase in the hyperphosphorylation of brain Tau proteins and in the number of neurofibrillary tangles. Here, we examined the long-term effects of the surgery and found that olfactory bulbectomy also rendered the rats to become anemic with brain iron overload. Additionally, a significant reduction in the membrane fluidity index in frontal cortex synaptosomes was found. Treatment with a mixture of n - 3/n - 6 of fatty acids restored the unwanted effect. The beneficial effects of fatty acids are mediated via the effects of fatty acids on the neuronal membrane structure and fluidity. These findings are similar to Alzheimer's symptoms, which suggest this model can be used as an animal model for Alzheimer's disease. We recommend using this model to scan potential new anti Alzheimer's drugs. PMID- 25292365 TI - Sexual selection on female ornaments in the sex-role-reversed Gulf pipefish (Syngnathus scovelli). AB - Understanding how selection acts on traits individually and in combination is an important step in deciphering the mechanisms driving evolutionary change, but for most species, and especially those in which sexual selection acts more strongly on females than on males, we have no estimates of selection coefficients pertaining to the multivariate sexually selected phenotype. Here, we use a laboratory-based mesocosm experiment to quantify pre- and post-mating selection on female secondary sexual traits in the Gulf pipefish (Syngnathus scovelli), a sexually dimorphic, sex-role-reversed species in which ornamented females compete for access to choosy males. We calculate selection differentials and gradients on female traits, including ornament area, ornament number and body size for three episodes of selection related to female reproductive success (number of mates, number of eggs transferred and number of surviving embryos). Selection is strong on both ornament area and ornament size, and the majority of selection occurs during the premating episode of selection. Interestingly, selection on female body size, which has been detected in previous studies of Gulf pipefish, appears to be indirect, as evidenced by a multivariate analysis of selection gradients. Our results show that sexual selection favours either many bands or larger bands in female Gulf pipefish. PMID- 25292368 TI - Development of a halide-free aluminium-based catalyst for the synthesis of cyclic carbonates from epoxides and carbon dioxide. AB - Kinetic studies of the synthesis of glycerol carbonate from glycidol and carbon dioxide have been carried out. These showed that under suitable reaction conditions, bimetallic aluminium(salen) complex 4 is able to catalyse the conversion of epoxides into the corresponding cyclic carbonates without the need for a co-catalyst. PMID- 25292366 TI - Micro- and nano-CT for the study of bone ultrastructure. AB - Micro-computed tomography (micro-CT)-a version of X-ray CT operating at high spatial resolution-has had a considerable success for the investigation of trabecular bone micro-architecture. Currently, there is a lot of interest in exploiting CT techniques at even higher spatial resolutions to assess bone tissue at the cellular scale. After recalling the basic principles of micro-CT, we review the different existing system, based on either standard X-ray tubes or synchrotron sources. Then, we present recent applications of micro- and nano-CT for the analysis of osteocyte lacunae and the lacunar-canalicular network. We also address the question of the quantification of bone ultrastructure to go beyond the sole visualization. PMID- 25292369 TI - [Clinical analysis of delayed hemothorax due to diaphragmatic injury treated by emergent video-assisted thoracic surgery]. AB - We encountered 5 cases of delayed massive hemothorax due to diaphragmatic injury. Delayed hemothorax presented 2~11 days after injury, with lower rib fractures seen all cases. We performed emergent video-assisted thoracic surgery with mini thoracotomy for all patients. Lacerations could be clearly visualized in the diaphragm after evacuation of blood clots, which were then sutured. In four cases, the sharp edges of the broken ribs were thought to have caused the diaphragmatic lacerations. The mean blood loss volume was 2,905 ml, and all patients required blood transfusions. However, homeostasis was achieved after surgery, and all patients had an uneventful postoperative course. Although, delayed hemothorax is relatively uncommon, it needs to be considered a lethal condition. PMID- 25292367 TI - Short versus long silver nanowires: a comparison of in vivo pulmonary effects post instillation. AB - BACKGROUND: Silver nanowires (Ag NWs) are increasingly being used to produce touchscreens for smart phones and computers. When applied in a thin film over a plastic substrate, Ag NWs create a transparent, highly-conductive network of fibers enabling the touch interface between consumers and their electronics. Large-scale application methods utilize techniques whereby Ag NW suspensions are deposited onto substrates via droplets. Aerosolized droplets increase risk of occupational Ag NW exposure. Currently, there are few published studies on Ag NW exposure-related health effects. Concerns have risen about the potential for greater toxicity from exposure to high-aspect ratio nanomaterials compared to their non-fibrous counterparts. This study examines whether Ag NWs of varying lengths affect biological responses and silver distribution within the lungs at different time-points. METHODS: Two different sizes of Ag NWs (2 MUm [S-Ag NWs] and 20 MUm [L-Ag NWs]) were tested. Male, Sprague-Dawley rats were intratracheally instilled with Ag NWs (0, 0.1, 0.5, or 1.0 mg/kg). Broncho alveolar lavage fluid (BALF) and lung tissues were obtained at 1, 7, and 21 days post exposure for analysis of BAL total cells, cell differentials, and total protein as well as tissue pathology and silver distribution. RESULTS AND CONCLUSIONS: The two highest doses produced significant increases in BAL endpoints. At Day 1, Ag NWs increased total cells, inflammatory polymorphonuclear cells (PMNs), and total protein. PMNs persisted for both Ag NW types at Day 7, though not significantly so, and by Day 21, PMNs appeared in line with sham control values. Striking histopathological features associated with Ag NWs included 1) a strong influx of eosinophils at Days 1 and 7; and 2) formation of Langhans and foreign body giant cells at Days 7 and 21. Epithelial sloughing in the terminal bronchioles (TB) and cellular exudate in alveolar regions were also common. By Day 21, Ag NWs were primarily enclosed in granulomas or surrounded by numerous macrophages in the TB-alveolar duct junction. These findings suggest short and long Ag NWs produce pulmonary toxicity; thus, further research into exposure-related health effects and possible exposure scenarios are necessary to ensure human safety as Ag NW demand increases. PMID- 25292370 TI - [Diaphragmatic hernia complicated with diaphragmatic resection by automatic stapling device]. AB - Nowadays, a diaphragmatic lesion is sometimes resected with use of an automatic stapling device, especially through video-assisted thoracoscopic procedure. We herein report 2 patients with a diaphragmatic hernia after diaphragmatic resection by automatic stapling devices. Etiology and cause of postoperative diaphragmatic hernia are discussed. Diaphragmatic resection by mechanical stapler was performed for thymic epithelial tumor recurring at the diaphragmatic pleura in both patients: 48-year-old man and 72-year-old woman. The former patient underwent a right diaphragmatic resection (3*4 cm in size) with a cartridge of mechanical stapler. Computed tomography (CT) and magnetic resonance imaging showed asymptomatic right diaphragmatic hernia 2 months after surgery. No symptom and progression occurred 8 years later. The latter patient underwent a right diaphragmatic resection (6*7 cm in size) with 2 cartridges of mechanical stapler. Diaphragmatic hernia advanced 7 months after surgery and required surgical intervention. Diaphragmatic repair was successful with the use of 8*6 cm expanded polytetrafluoroethylene patch. Surgical stump after diaphragmatic resection with automatic stapling device is easy to rupture during diaphragmatic movement synchronized with respiratory movement. Diaphragmatic resection with use of stapling device, which is a simple procedure, should be contraindicated. PMID- 25292371 TI - [Video-assisted thoracoscopic surgery for pleuroperitoneal communications as a complication of continuous ambulatory peritoneal dialysis( CAPD)]. AB - A 54-year-old female who was started on continuous ambulatory peritoneal dialysis( CAPD) for endstage renal disease secondary to focal developed 2 pleuroperitoneal communications. At first, she developed chest pain and cough on the day following introduction. A 99m-technetium-macroaggregated albumin (99mTc MAA) radionuclide scan showed a communication between the abdomen and the right pleural cavity. We diagnosed a right pleuroperitoneal communication. Four months later, she developed similar symptoms and was diagnosed with a left pleuroperitoneal communication. Video-assisted thoracoscopic surgery was performed for each lesion. However, the communications were detected using different methods. During the 1st surgery, the communication was detected using peritoneal dialysis fluid containing indigocarmine introduced through a CAPD catheter. During the 2nd surgery, the communication was detected by pneumoperitoneum. With regards to diaphragmatic pressure regulation, pneumoperitoneum was more rapid and convenient, so pneumoperitoneum was considered more effective for the identification and treatment of pleuroperitoneal communications. Diaphragmatic plication and pleurodesis with polyglycolic acid felt and fibrin glue on both sides were performed. No recurrence of hydrothorax was detected after treatment. PMID- 25292372 TI - [Detection of the communication site by dye injection method at the surgery for pleuroperitoneal communication]. AB - A 65-year-old male with end stage renal failure due to IgA nephritis commenced continuous ambulatory peritoneal dialysis (CAPD). Three weeks after initiation of CAPD, right hydrothorax developed. Then, we strongly assumed pleuroperitoneal communication( PPC) although the pleural effusion did not show high concentration of glucose. He underwent thoracoscopic surgery for PPC. On the inner, central tendons part of the diaphragm, there were a few blebs. One hour after 3 l of peritoneal dialysis solution containing 15 ml indigocarmine was instilled into the abdomen through a CAPD catheter, the blebs were tense and colored blue by the dye solution. The blebs were directly sutured and diaphragm was covered by polyglycolic acid sheet and fibrin glue all over. Since then, he resumed CAPD, without recurrence of hydrothorax. Then we investigated the treatment outcome of video-assisted thoracic surgery (VATS) for PPC in Japan. The outcome was poorer in cases in which communication was not detected intraoperatively. These patients should be given sufficient consideration for surgical procedure. PMID- 25292373 TI - [Two types of diaphragmatic plication; therapeutic plication and prophylactic plication]. AB - Plication of the hemidiaphragm is effective to relieve respiratory symptoms such as exertional dyspnea and orthopnea of the patients with unilateral diaphragmatic paralysis. We have experiences of 2 types of diaphragmatic plication;one for the symptomatic patients with unilateral diaphragmatic paralysis, and the other for the patients who underwent phrenicotomy during extended surgery for a recurrent thymoma. The former plication was performed for a therapeutic purpose to alleviate the patient's symptoms. The latter was performed for a prophylactic purpose to keep the patient free from possible symptoms or postoperative morbidity after phrenicotomy. Case 1:A 65-year-old female with an eventration of the right diaphragm underwent a sternal resection and reconstruction for a large desmoid tumor. After continuous mechanical ventilation for 3 months, she was still under noninvasive positive pressure ventilation( NPPV) for 24 hours a day. Plication of the right hemidiaphragm was performed and the patient was successfully weaned from NPPV. Case 2:A 41-year-old female with myasthenia gravis underwent a surgery for a recurrent thymoma. Left phrenicotomy was necessary to achieve a complete resection of the tumor. Plication of the left diaphragm was performed during the tumor resection to prevent possible respiratory complications. Postoperative course was uneventful, and her vital capacity was well maintained. PMID- 25292374 TI - [Thoracoscopic diaphragmatic plication for eventration of diaphragm in children using no-knife automatic suturing device]. AB - Diaphragm eventration could inhibit the lung development due to compression. Thus diaphragm plication is required for the diaphragm eventration to prevent lung compression causing lung immaturity. However, we sometimes encounter the difficulty in endoscopic plication for fragile diaphragm without damaging it in narrow thoracic space in children. We demonstrate the plication using no-knife automatic suturing device. METHOD: Two linear ridges are made using stapler on the flaccid diaphragm without cutting the tissue. Then the created 2 ridges are sutured so that the diaphragm is plicated. BENEFITS: Once the stapler was applied to make 2 linear ridges, we easily sutured and gathered them without checking the damage of the intra-abdominal organs. Furthermore, reinforced ridges could be plicated without damaging the fragile diaphragm. We conclude that above described method is preferable for the diaphragm eventration in pediatric patients with fragile diaphragm and limited thoracic space. PMID- 25292375 TI - [Tumors of the diaphragm, diagnosis and surgical treatment]. AB - Primary tumors of the diaphragm are very rare, and we often have difficulties in preoperative diagnosis and accurate evaluation of invasion. We experienced 3 surgical cases of tumor of diaphragm:primary mucinous adenocarcinoma, metastatic gastrointestinal stromal tumor, and mesothelioma. Besides computed tomography (CT) and conventional magnetic resonance imaging(MRI), respiratory dynamic cine magnetic resonance imaging (cine MRI) was performed. Cine MRI was acquired using steady state free precession (SSFP) sequence, and about 80 consecutive images of the same slice were taken while a patient breathed deeply. In all cases, cine MRI showed lack of tumor movement along the diaphragm during respiration. During surgery, we found that tumor was originated from diaphragm and there was no adhesion to other organs. Securing a sufficient margin, we resected tumor including the diaphragm. Since the defect of diaphragm was from 4 to 5cm in short diameter, we could close the diaphragm by direct suture. Cine MRI could provide useful information concerning discrimination between diaphragmatic and para diaphragmatic tumor. PMID- 25292376 TI - [Epithelioid cell granuloma of the liver mimicking a primary phrenic tumor]. AB - We here report an epithelioid cell granuloma of the liver, imaging of which mimicked a phrenic tumor. A 75-year-old woman was admitted to the hospital for evaluation of an abnormal shadow in the left lower lung field on a chest X-ray. Surgery was performed for a suspected schwannoma arising from the phrenic nerve or a primary diaphragmatic tumor based on chest computed tomography(CT) and magnetic resonance imaging (MRI). The intra-operative findings showed that the tumor did not originate from the diaphragm but from the left lobe of the liver with feeding vessels from the liver. Securing a sufficient margin, the tumor was surgically resected as a primary liver tumor. Histologically, the tumor was diagnosed as an epithelioid cell granuloma of the liver. It is sometimes difficult to discriminate organs from which tumors developing around the diaphragm because of the difficulty to perform biopsy or the presence of many candidate organs neighboring the diaphragm. PMID- 25292377 TI - [Reconstructive method after resection of chest wall, diaphragm and pericardium, mainly using Composix-mesh]. AB - This study examined utility and question about the reconstructive prostheses in 11 cases which were resected chest wall and/or diaphragm and/or pericardium. One of 3 patients, who were used metal plates after chest wall resection, was prevented from post-operative irradiation therapy by limitation and diffuse reflection of beam by the metal plates. Gore-Tex( ePTFE) sheets, which were used for coverage of diaphragm defect and pericardium defect, occurred no problems. Composix-meshes (Composix-Kugel, Hernia-patch) were used for 7 cases which had large defects due to resection of chest wall and diaphragm. These kinds of meshes (or patches) consist of double layer mesh and memory recoil ring and then have airtightness and rigidity. After reconstruction of chest wall and diaphragm there were no problems without any flail chest. PMID- 25292378 TI - [Pleuro-peritoneal shunt in a patient with intractable pleural effusion after cardiac surgery]. AB - A 45-year-old man experienced dyspnea on effort and was hospitalized due to severe mitral valve regurgitation and atrial fibrillation. He also had alcoholic cirrhosis. After he was stabilized, mitral valve plasty and Maze procedure were performed. The postoperative clinical course was satisfactory. During the follow up period, he began to suffer from persistent left pleural effusion, which amounted to about 2,500 to 3,000 ml, and required intercostal tube drainage weekly. Therefore a pleuro-peritoneal shunt was implanted. The pleural effusion decreased, and he obtained significant relief from dyspnea. After one year, we confirmed that pleural effusion had not reoccurred, and removed the pleuro peritoneal shunt. PMID- 25292379 TI - [Successful treatment of Candida albicans mediastinitis after open-heart surgery using vacuum-assisted closure device]. AB - An 82-year-old man suffered from Candida albicans mediastinitis following emergency aortic valve replacement. After repeated debridement of the anterior portion of the mediastinum, we applied a vacuum assisted closure device with UrgoTul Absorb placed on the right ventricle. Despite relatively short-term application of this device, mediastinitis was cured in combination with transposition of the great omentum. PMID- 25292380 TI - [Redo double valve replacement in a patient with bioprosthetic valve malfunction by pannus formation; report of a case]. AB - A 76-year-old female, who had received Carpentier-Edwards perimount (CEP) pericardial bioprostheses for aortic and mitral valves 6 years before, was diagnosed with reduced mobility of the valvular cusps by echocardiogram 2 years after the surgery. The symptoms of heart failure gradually aggravated. Significant stenosis and regurgitation were observed of the prosthetic valves, and a second surgery was performed. Calcification and severe pannnus formation were observed of both CEP valves that were excised. PMID- 25292381 TI - [Papillary fibroelastoma derived from the left ventricular wall just under the mitral leaflet; report of a case]. AB - A 74-year-old male was referred to our department due to a mobile solid mass of 10 mm in diameter on the left ventricular interior wall just below the posterior leaflet of the mitral valve. Mild mitral regurgitation and moderate tricuspid regurgitation were also detected. A high serum level of IL-6 was detected(33.0 pg/ml), and myxoma was suspected. The tumor, which was bright yellowish brown with a partly jelly-like surface, was successfully removed surgically through the mitral valve under cardiopulmonary bypass. Pathological findings of the mass was papillary fibroelastoma. Papillary fibroelastoma derived from the left ventricular wall is very rare. PMID- 25292382 TI - [Usefulness of echocardiography for detecting prosthetic valve dysfunction; report of a case]. AB - A 78-year-old woman with a history of mitral valve stenosis underwent open mitral commissurotomy in 1976. In 1990, she underwent mitral valve replacement (Medtronic-Hall 29 mm), tricuspid annuloplasty(DeVega method), and pacemaker implantation for bradycardiac atrial fibrillation. However, in June 2012, she developed anemia of unknown cause. Prosthetic valve dysfunction was suspected, because intermittent changes in the left ventricular inflow was detected by echocardiography. Fluoroscopy actually confirmed the presence of prosthetic valve dysfunction. Therefore mitral valve re-replacement(ATS Medical, Inc. 29 mm) and tricuspid annuloplasty (Cosgrove ring 30 mm) were performed. Monitoring the changes in the left ventricular inflow is recommended when prosthetic valve dysfunction in a single leaflet is suspected. PMID- 25292383 TI - [Emergency coronary artery bypass grafting for acute myocardial infarction presenting as cardio-pulmonary arrest during a marathon race; report of a case]. AB - We report a case of coronary artery bypass grafting for acute myocardial infarction which presented as cardio-pulmonary arrest during a marathon race. A 57-year-old man collapsed at the 18-km point in the Toyohashi half marathon. He was treated with an automated electrical defibrillator( AED) for ventricular fibrillation in an ambulance. Immediately after arriving at our emergency department, he was diagnosed with acute myocardial infarction by electrocardiography. Emergency coronary angiography revealed severe stenosis of the left anterior descending artery. Percutaneous coronary intervention was tried, but it was given up because calcification of the stenotic lesion was severe. He was then referred to our department for emergency coronary artery bypass grafting. Complete re-vascularization was accomplished and the patient has been doing well with no signs of angina. PMID- 25292384 TI - [Surgical treatment of unroofed coronary sinus coexisting with paroxysmal atrial fibrillation; diagnosis by multidetector computed tomography; report of a case]. AB - We experienced a rare case of an unroofed coronary sinus without a persistent left superior vena cava. A 55-year-old man, who was diagnosed with cerebral infarction, presented with suspected atrial septal defect (ASD) coexisting with paroxysmal atrial fibrillation. Before the operation, we diagnosed this case as coronary sinus ASD by contrast-enhanced coronary computed tomography (CT). There was a 20 mm segment of abnormal communication between the base of the left atrium and the roof of the coronary sinus. We repaired the defect by simple direct closure from the left atrium side, so that the coronary veins drained into the right atrium. The postoperative course was uneventful. Imaging played a crucial role in the diagnosis. Coronary CT angiography is well suited to help identify asymptomatic congenital heart disease. PMID- 25292386 TI - The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen: a cross-sectional comparison of established screening tools in a German-Swiss population. AB - The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) has recently been developed as a fast and easy cognitive screening tool specifically designed for patients with motor impairments in routine clinical use. The German/Swiss-German version of the ECAS was validated in a German-Swiss consortium. One hundred and thirty-six non-demented ALS patients and 160 healthy controls were included in the study. In addition, the Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MoCA) and Consortium to Establish a Registry for Alzheimer's Disease plus Scale (CERAD plus) were administered to subgroups of patients. Results showed that administration of ECAS was fast (mean 24 min). Similar to the population in the UK version, ALS patients performed significantly worse in the ALS-specific functions (p < 0.001), specifically in the domain of language (p < 0.001), verbal fluency (p = 0.005) and executive functions (p = 0.02), but not for the non-ALS-specific functions. Carers reported behavioural abnormalities in about 30% and psychotic symptoms in 6% of the patients. Compared to ECAS, FAB, MoCA and CERAD were more generic and performance was not adjusted to motor speed. We conclude that the German/Swiss-German version of the ECAS is a fast and easy to administer cognitive screening instrument sensitive for ALS-specific dysfunctions and behaviour change. PMID- 25292387 TI - Assessing assay agreement estimation for multiple left-censored data: a multiple imputation approach. AB - Agreement between two assays is usually based on the concordance correlation coefficient (CCC), estimated from the means, standard deviations, and correlation coefficient of these assays. However, such data will often suffer from left censoring because of lower limits of detection of these assays. To handle such data, we propose to extend a multiple imputation approach by chained equations (MICE) developed in a close setting of one left-censored assay. The performance of this two-step approach is compared with that of a previously published maximum likelihood estimation through a simulation study. Results show close estimates of the CCC by both methods, although the coverage is improved by our MICE proposal. An application to cytomegalovirus quantification data is provided. PMID- 25292385 TI - Transferring biomarker into molecular probe: melanin nanoparticle as a naturally active platform for multimodality imaging. AB - Developing multifunctional and easily prepared nanoplatforms with integrated different modalities is highly challenging for molecular imaging. Here, we report the successful transfer of an important molecular target, melanin, into a novel multimodality imaging nanoplatform. Melanin is abundantly expressed in melanotic melanomas and thus has been actively studied as a target for melanoma imaging. In our work, the multifunctional biopolymer nanoplatform based on ultrasmall (<10 nm) water-soluble melanin nanoparticle (MNP) was developed and showed unique photoacoustic property and natural binding ability with metal ions (for example, (64)Cu(2+), Fe(3+)). Therefore, MNP can serve not only as a photoacoustic contrast agent, but also as a nanoplatform for positron emission tomography (PET) and magnetic resonance imaging (MRI). Traditional passive nanoplatforms require complicated and time-consuming processes for prebuilding reporting moieties or chemical modifications using active groups to integrate different contrast properties into one entity. In comparison, utilizing functional biomarker melanin can greatly simplify the building process. We further conjugated alphavbeta3 integrins, cyclic c(RGDfC) peptide, to MNPs to allow for U87MG tumor accumulation due to its targeting property combined with the enhanced permeability and retention (EPR) effect. The multimodal properties of MNPs demonstrate the high potential of endogenous materials with multifunctions as nanoplatforms for molecular theranostics and clinical translation. PMID- 25292388 TI - Blood transfusion is associated with impaired outcome after transcatheter aortic valve implantation. AB - OBJECTIVES: We sought to evaluate the relationship of blood transfusion after transcatheter aortic valve implantation (TAVI) and mid-term outcome to improve patient selection and periprocedural treatment. BACKGROUND: Increasing evidence suggests a negative influence of blood transfusion on outcomes of patients with cardiovascular diseases. While the adverse impact of bleeding events on survival has been documented after TAVI, data on the impact of postoperative blood transfusions are scarce. METHODS: TAVI was performed in 700 consecutive patients; 14.7% of TAVI patients suffered from bleeding or access site complications and were excluded from analysis to minimize confounding. Outcomes were analyzed with emphasis on blood transfusions and according to the Valve Academic Research Consortium definitions. Median follow-up duration was 364 days. Multivariable analyses were performed to identify predictors for transfusion and 1-year mortality. RESULTS: 33.0% of patients received blood transfusions after TAVI, irrespective of access choice. Blood transfusions were associated with a higher baseline risk profile (median logistic EuroSCORE 21.0 vs. 17.0%), increased rates of postoperative complications and impaired survival (21.2 vs. 36.1% all-cause 1 year mortality). Transfusion was an independent predictor of mortality at 1 year (OR 2.78 [CI 1.59-4.86]). Low body mass index (OR 0.94 [0.89-1.0]), low baseline hemoglobin (OR 0.39 [0.33-0.47]) and combined anticoagulation/antiplatelet therapy were identified as independent predictors of blood transfusion after TAVI. CONCLUSIONS: Blood transfusions were frequently required after TAVI even in the absence of overt bleeding or access site complications and were identified as an independent predictor of impaired mid-term outcome. Optimization of baseline factors, strict blood conservation strategies, and individualized antiplatelet or anticoagulant regimens may improve outcome after TAVI. PMID- 25292389 TI - Erratum to: DRR and portal image registration for automatic patient positioning in radiotherapy treatment. PMID- 25292398 TI - Thyroid axis function after in-patient treatment of acute psychosis with antipsychotics: a naturalistic study. AB - BACKGROUND: Endocrine function in psychiatric patients may be affected by mental disorder itself as well as by antipsychotic medications.The aim of this naturalistic observational study was to determine if treatment of acute psychotic episode with antipsychotic medication affects thyroid axis hormone concentrations and if such changes are associated with symptomatic improvement. METHODS: Eighty six adult acute psychotic patients, consecutively admitted to a mental hospital, were recruited for the study. All patients were physically healthy and without thyroid disease. During the hospitalization period all study patients received treatment with antipsychotic medication according to clinical need. Severity of the psychotic episode was evaluated using the Brief Psychiatric Rating Scale (BPRS) and venous blood samples were drawn for analysis of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) concentrations on the day of admission and on the day of discharge from the hospital. RESULTS: Antipsychotic drug treatment was associated with decrease of mean FT3 (p < 0.001) and FT4 (p = 0.002) concentrations; and with increase of mean TSH (p = 0.016) concentrations. Changes in thyroid hormone concentrations were mostly predicted by baseline hormone concentrations. Individual changes were not limited to decrease in high hormone concentrations; in patients who had low FT3 or FT4 concentrations, treatment resulted in increase in concentrations. Such an increase was established in one-quarter of patients for FT3 concentrations and in one-third of patients for FT4 concentrations. Fall in FT4 concentrations negatively correlated with the improvement in the BPRS score (r = -0.235, p = 0.023). CONCLUSIONS: The study indicates that antipsychotic treatment resulted in a decrease in mean FT3 concentrations and in an increase in mean TSH concentrations after recovery from acute psychosis. Symptomatic improvement was less evident in patients who experienced a decrease in FT4 concentrations. TRIAL REGISTRATION: EudraCT No.2007-001541-18. PMID- 25292399 TI - Employment-based abstinence reinforcement promotes opiate and cocaine abstinence in out-of-treatment injection drug users. AB - We examined the use of employment-based abstinence reinforcement in out-of treatment injection drug users, in this secondary analysis of a previously reported trial. Participants (N = 33) could work in the therapeutic workplace, a model employment-based program for drug addiction, for 30 weeks and could earn approximately $10 per hr. During a 4-week induction, participants only had to work to earn pay. After induction, access to the workplace was contingent on enrollment in methadone treatment. After participants met the methadone contingency for 3 weeks, they had to provide opiate-negative urine samples to maintain maximum pay. After participants met those contingencies for 3 weeks, they had to provide opiate- and cocaine-negative urine samples to maintain maximum pay. The percentage of drug-negative urine samples remained stable until the abstinence reinforcement contingency for each drug was applied. The percentage of opiate- and cocaine-negative urine samples increased abruptly and significantly after the opiate- and cocaine-abstinence contingencies, respectively, were applied. These results demonstrate that the sequential administration of employment-based abstinence reinforcement can increase opiate and cocaine abstinence among out-of-treatment injection drug users. PMID- 25292400 TI - Increased frequency of class I and II anti-human leukocyte antigen antibodies in systemic lupus erythematosus and scleroderma and associated factors: a comparative study. AB - AIM: There is significant autoantibody production in systemic lupus erythematosus (SLE) and scleroderma (SSc); microchimerism is also thought to play a role in pathogenesis. We determined the frequency of anti-HLA antibodies in SLE and SSc patients and evaluated associated clinical factors. METHODS: We included 77 SLE patients, 46 SSc patients and 53 healthy controls into the study. Clinical data about the patients were obtained from hospital records. Anti-human leukocyte (anti-HLA) antigen antibody analysis of sera was performed by applying Lifecodes anti-HLA Class I and Class II Screening kits based on xMAP technology. RESULTS: The frequencies of class I and II anti-HLA antibodies were significantly higher in SLE (27.3% and 41.6%) and SSc (26.1% and 41.3%) groups than in healthy controls (1.9% and 5.7%) (all P < 0.001). Frequencies of thrombocytopenia (P = 0.021), anti-ribonucleoprotein (P = 0.037) and anti-Ro (P = 0.027) were significantly higher in the class I antibody-positive SLE group; however, pericarditis was less frequent (P = 0.05). On the other hand, the class II antibody-positive SLE group had more frequent anti-ribosomal P antibody (P = 0.038), but less frequent active disease (P = 0.038). In the SSc group, class I antibody-positive patients had more frequent digital ulcers (P = 0.048) and anti centromere antibodies (P = 0.01). There was no association of anti-HLA antibodies with pulmonary hypertension and interstitial fibrosis in SSc patients. CONCLUSIONS: Both class I and class II antibodies were found to be significantly increased in SLE and SSc. Rather than major organ involvement, anti-HLA antibodies were associated with the presence of other antibodies in both diseases. PMID- 25292401 TI - Peritoneal resting with heparinized lavage reverses peritoneal type I membrane failure. A comparative study of the resting effects on normal membranes. AB - BACKGROUND: Ultrafiltration failure (UFF) is a serious complication of long-term peritoneal dialysis (PD). Peritoneal rest (PR) has been demonstrated as a valid treatment to reverse the functional changes that occur in UFF. The effects of PR on a normally functioning human peritoneum are unknown but are expected to be neutral. Our hypothesis was that PR positively modifies peritoneal function in patients with UFF, in contrast to the absence of effects when PR is applied under normal conditions. PATIENTS AND METHODS: We studied 84 PR periods, comparing 35 patients with UFF and 49 controls (resting for abdominal surgery with temporary discontinuation of PD). We analyzed peritoneal transport pre-PR and post-PR by calculating the mass transfer coefficients of creatinine (Cr-MTAC), the dialysate/plasma creatinine ratio (D/P Cr) and the ultrafiltration (UF). RESULTS: Baseline data was similar for the 2 groups, although the UFF group had a longer median time in PD (39 [18 - 60] vs 10 [5 - 23] months; p = 0.00001). Peritoneal rest induced a decrease in D/P Cr, Cr-MTAC and an increase in UF capacity in the UFF group (p = 0.0001, p = 0.004 and p = 0.001, respectively), without causing changes in the control group. Peritoneal rest in patients with more than 6 months of UFF was not able to reduce peritoneal solute transport or improve UF capacity. Response to PR did not differ among UFF patients with or without a previous history of peritonitis. Peritoneal rest enabled patients with UFF to continue on PD for a median time of 23 months (range, 13 - 46 months). CONCLUSIONS: Peritoneal rest induces functional changes in patients with UFF but not in those with no functional abnormalities. This demonstrates that PR works only when abnormal but reversible functional conditions are present. However, the effect is highly dependent on how early PR is applied. PMID- 25292402 TI - Financial implications to Medicare from changing the dialysis modality mix under the bundled prospective payment system. AB - BACKGROUND: The economic burden of treating end-stage renal disease (ESRD) continues to grow. As one response, effective January 1, 2011, Medicare implemented a bundled prospective payment system (PPS, including injectable drugs) for dialysis patients. This study investigated the 5-year budget impact on Medicare under the new PPS of changes in the distribution of patients undergoing peritoneal dialysis (PD), in-center hemodialysis (ICHD), and home hemodialysis (HHD). METHODS: An Excel-based budget impact model was created to assess dialysis associated Medicare costs. The model accounted for dialysis access establishment, the current monthly capitation physician payment for ESRD, Medicare dialysis payments (including start-up costs), training, oral drug costs, and the costs and probabilities of adverse events including access failure, hospitalization for access infection, pneumonia, septicemia, and cardiovascular events. United States Renal Data System (USRDS) data were used to project the US Medicare dialysis patient population across time. The baseline scenario assumed a stable distribution of PD (7.7%), HHD (1.3%) and ICHD (91.0%) over 5 years. Three comparison scenarios raised the proportions of PD and HHD by (1) 1% and 0.5%, (2) 2% and 0.75%, and (3) 3% and 1% each year; a fourth scenario held HHD constant and lowered PD by 1% per year. RESULTS: Under the bundled PPS, scenarios that increased PD and HHD from 7.7% and 1.3% over 5 years resulted in cumulative savings to Medicare of $114.8M (Scenario 1, 11.7% PD and 3.3% HHD at year 5), $232.9M (Scenario 2, 15.7% PD and 4.3% HHD at year 5), and $350.9M (Scenario 3, 19.7% PD and 5.3% HHD at year 5). When the PD population was decreased from 7.7% in 2013 to 3.7% by 2017 with a constant HHD population, the total Medicare payment for dialysis patients increased by over $121.2M. CONCLUSIONS: Under Medicare bundled PPS, increasing the proportion of patients on PD and HHD vs ICHD could generate substantial savings in dialysis-associated costs to Medicare. PMID- 25292403 TI - Embedded Catheters: Minimizing Excessive Embedment Time and Futile Placement while Maintaining Procedure Benefits. AB - BACKGROUND: Embedding peritoneal catheters far in advance of anticipated need may successfully commit patients to their modality choice and reduce central venous catheter use but can be complicated by excessive embedment periods and futile catheter placement. OBJECTIVE: Embedded catheter outcomes were studied to identify factors that minimize inordinate embedment time and futile placement while maintaining procedure benefits. METHODS: Clinical and laboratory data were examined in 107 patients with embedded catheters that were either externalized, remained embedded, or were futilely placed. RESULTS: Externalization of 84 catheters was performed after a median embedment period of 9.4 months. Flow dysfunction occurred in 14.3% of externalized catheters. Overall function rate was 98.8% after laparoscopic revision. One patient changed their mind about modality choice. Except for 1 patient hospitalized acutely in a facility unfamiliar with embedded catheters, none remaining on a peritoneal dialysis pathway initiated dialysis with a central venous catheter. Including catheters with extremely long embedment periods, the incidence of futile placement was 13.1%. Multiple regression analysis identified estimated glomerular filtration rate (eGFR) and serum albumin as the 2 variables best associated with catheter embedment duration (r(2) = 0.44, p < 0.0001). Diabetic nephropathy was statistically more likely to be associated with lower serum albumin values (p < 0.0001); however, no association was noted between diabetic status and embedment duration (p = 0.62). CONCLUSIONS: Timing of the embedment procedure should include appraisal of both eGFR and serum albumin. Appropriate consideration of these values together may help minimize excessive embedment periods and decrease futile placements while preserving procedure benefits. PMID- 25292404 TI - Effects of Fructo-Oligosaccharide Supplementation on Constipation in Elderly Continuous Ambulatory Peritoneal Dialysis Patients. AB - ? BACKGROUND: Fructo-oligosaccharides (FOS) exhibit soluble-fiber properties that beneficially affect bowel function and relieve constipation. The effects of FOS supplementation on constipation and biochemical parameters were examined in elderly continuous ambulatory peritoneal dialysis (CAPD) patients. ? METHODS: This randomized, double-blind, placebo-controlled, cross-over study was performed in elderly CAPD patients (5 males and 4 females) with chronic constipation. All subjects were randomly assigned to receive either 20 g FOS or placebo daily for 30 days. After a 14-day washout period, the patients were switched to the other substance for 1 more month. Before and after each treatment period, frequency of defecation, characteristics of feces, and colonic transit were evaluated. Biochemical parameters were also assessed. ? RESULTS: Fructo-oligosaccharides significantly increased the frequency of defecation (10.5 +/- 2.0 vs 6.2 +/- 1.4 times per week, p < 0.005) and changed the feces' appearance from type 1 (nut like) to type 4 (sausage-like). The colonic transit determined by geometric center (GC) was augmented after FOS supplementation (3.9 +/- 0.3 vs 3.2 +/- 0.4, p < 0.05). Fructo-oligosaccharides had no effects on biochemical parameters. Fructo-oligosaccharides caused mild discomforts which were well tolerated after dose adjustment. ? CONCLUSIONS: Fructo-oligosaccharide supplementation is effective, well tolerated, and can be an alternative to other laxatives in CAPD patients with constipation. Further studies are needed to better assess the biochemical effects of FOS in the chronic kidney disease population. PMID- 25292405 TI - The Impact of Timing of Dialysis Initiation on Mortality in Patients with Peritoneal Dialysis. AB - ? BACKGROUND: The impact of timing of dialysis initiation on mortality is controversial in patients with peritoneal dialysis (PD). In this study, we analyzed the impact of timing of dialysis initiation on mortality in the incident PD population. ? METHODS: Incident patients with PD were selected from the Clinical Research Center (CRC) registry for end-stage renal disease (ESRD), a prospective cohort study on dialysis in Korea. Patients were categorized into 3 groups according to the estimated glomerular filtration rate (eGFR) at the initiation of PD using the Modification of Diet in Renal Disease (MDRD) equation. Group A was defined as eGFR < 5 mL/min/1.73m(2), group B as eGFR 5 - 10 mL/min/1.73m(2), and group C as eGFR > 10 mL/min/1.73m(2). Cox regression analysis was used to calculate the adjusted hazard ratio (HR) of mortality with group B as the reference. The primary outcome was all-cause mortality. ? RESULTS: A total of 495 incident PD patients were included. The number of patients in group A was 109, group B was 279, and group C was 107. The median follow-up period was 23 months. Multivariate Cox regression analysis showed that group A had a significantly higher risk of all-cause mortality compared with group B (HR 4.13, 95% confidence interval [CI], 1.55 - 11.03, p = 0.005) after adjustment for age, gender, cause of ESRD, serum albumin level, diabetes mellitus, and cardiovascular disease. There was no significant difference in mortality between group C and group B (HR 1.50, 95% CI, 0.59 - 3.80, p = 0.398) after adjustment for clinical variables. ? CONCLUSION: An eGFR < 5 mL/min/1.73m(2) at the initiation of PD was a significant risk factor for death, while an eGFR >10 mL/min/1.73m(2) at the initiation of PD was not associated with improved survival compared with an eGFR of 5 - 10 mL/min/1.73m(2) at the initiation of PD. PMID- 25292406 TI - Identification of Targets for Prevention of Peritoneal Catheter Tunnel and Exit Site Infections in Low Incidence Settings. AB - ? BACKGROUND: Peritoneal catheter tunnel and exit-site infection (TESI) complicates the clinical course of peritoneal dialysis (PD) patients. Adherence to recommendations for catheter insertion, exit-site care, and management of Staphylococcus aureus (SAu) carriage reduces, but does not abrogate the risk of these infections. ? OBJECTIVE: To reappraise the risk profile for TESI in an experienced center with a long-term focus on management of SAu carriage and a low incidence of these infections. ? METHOD: Following a retrospective, observational design, we investigated 665 patients incident on PD. The main study variable was survival to the first episode of TESI. We considered selected demographic, clinical, and technical variables, applying multivariate strategies of analysis. ? MAIN RESULTS: The overall incidence of TESI was 1 episode/68.5 patient-months. Staphylococcus aureus carriage disclosed at inception of PD (but not if observed sporadically during follow-up) (hazard ratio [HR] 1.53, p = 0.009), PD started shortly after catheter insertion (HR 0.98 per day, p = 0.011), PD after kidney transplant failure (HR 2.18, p = 0.017), lower hemoglobin levels (HR 0.88 per g/dL, p = 0.013) and fast peritoneal transport rates (HR 2.92, p = 0.03) portended an increased risk of TESI. Delaying PD >= 30 days after catheter insertion markedly improved the probability of TESI. Carriage of methicillin resistant SAu since the start of PD was associated with a high incidence of TESI by these bacteria. On the contrary, resistance to mupirocin did not predict such a risk, probably due to the use of an alternative regime in affected patients. ? CONCLUSIONS: Adherence to current recommendations results in a low incidence of TESI in PD patients. Interventions on specific risk subsets have a potential to bring incidence close to negligible levels. Despite systematic screening and management, SAu carriage is still a predictor of TESI. Antibiotic susceptibility patterns may help to refine stratification of the risk of TESI by these bacteria. Early insertion of the peritoneal catheter should be considered whenever possible, to reduce the risk of later TESI. PMID- 25292407 TI - Higher Dialysate Matrix Metalloproteinase-2 Levels Are Associated with Peritoneal Membrane Dysfunction. AB - ? BACKGROUND: Peritoneal dialysis (PD) patients develop progressive and cumulative peritoneal injury with longer time spent on PD. The present study aimed to a) describe the trend of peritoneal injury biomarkers, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), in incident PD patients, b) to explore the capacity of dialysate MMP-2 to predict peritoneal solute transport rate (PSTR) and peritonitis, and c) to evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solution on these outcomes. ? METHODS: The study included 178 participants from the balANZ trial who had at least 1 stored dialysate sample. Changes in PSTR and peritonitis were primary outcome measures, and the utility of MMP-2 in predicting these outcomes was analyzed using multilevel linear regression and multilevel Poisson regression, respectively. ? RESULTS: Significant linear increases in dialysate MMP-2 and TIMP-1 concentrations were observed (p < 0.001), but neither was affected by the type of PD solutions received (MMP-2: p = 0.07; TIMP-1: p = 0.63). An increase in PSTR from baseline was associated with higher levels of MMP 2 (p = 0.02), and the use of standard solutions over longer PD duration (p = 0.001). The risk of peritonitis was independently predicted by higher dialysate MMP-2 levels (incidence rate ratio [IRR] per ng/mL 1.01, 95% confidence interval [CI] 1.005 - 1.02, p = 0.002) and use of standard solutions (Biocompatible solution: IRR 0.45, 95% CI 0.24 - 0.85, p = 0.01). ? CONCLUSION: Dialysate MMP-2 and TIMP-1 concentrations increased with longer PD duration. Higher MMP-2 levels were associated with faster PSTR and future peritonitis risk. Administration of biocompatible solutions exerted no significant effect on dialysate levels of MMP 2 or TIMP-1, but did counteract the increase in PSTR and the risk of peritonitis associated with the use of standard PD solutions. This is the first longitudinal study to examine the clinical utility of MMP-2 as a predictor of patient-level outcomes. PMID- 25292408 TI - Peritoneal Dialysis Can Be an Option for Dominant Polycystic Kidney Disease: an Observational Study. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) has been considered a relative contraindication for peritoneal dialysis (PD), although there are few specific studies available. METHODS: A multicenter historical prospective matched-cohort study was conducted to describe the outcome of ADPKD patients who have chosen PD. All ADPKD patients starting PD (n = 106) between January 2003 and December 2010 and a control group (2 consecutive patients without ADPKD) were studied. Mortality, PD-technique failure, peritonitis, abdominal wall leaks and cyst infections were compared. RESULTS: Patients with ADPKD had similar age but less comorbidity at PD inclusion: Charlson comorbidity index (CCI) 4.3 (standard deviation [SD] 1.6) vs 5.3 (SD 2.5) p < 0.001, diabetes mellitus 5.7% vs 29.2%, p < 0.001 and previous cardiovascular events 10.4% vs 27.8%, p < 0.001. No differences were observed in clinical events that required transient transfer to hemodialysis, nor in peritoneal leakage episodes or delivered dialysis dose. The cyst infection rate was low (0.09 episodes per patient-year) and cyst infections were not associated to peritonitis episodes. Overall technique survival was similar in both groups. Permanent transfer to hemodialysis because of surgery or peritoneal leakage was more frequent in ADPKD. More ADPKD patients were included in the transplant waiting list (69.8 vs 58%, p = 0.04) but mean time to transplantation was similar (2.08 [1.69 - 2.47] years). The mortality rate was lower (2.5 vs 7.6 deaths/100 patient-year, p = 0.02) and the median patient survival was longer in ADPKD patients (6.04 [5.39 - 6.69] vs 5.57 [4.95 - 6.18] years, p = 0.024). CONCLUSION: Peritoneal dialysis is a suitable renal replacement therapy option for ADPKD patients. PMID- 25292410 TI - Exogenous H2 S enhances mice gastric smooth muscle tension through S sulfhydration of KV 4.3, mediating the inhibition of the voltage-dependent potassium current. AB - BACKGROUND: Hydrogen sulfide (H2 S) has been shown to have an excitatory effect on gastric motility, but the underlying molecular mechanism is unclear. In this study, we aimed to investigate the possible targets of H2 S and determine how H2 S affects its target proteins during H2 S-induced contraction. METHODS: Patch clamp and potentiometric fluorescence dye were utilized to measure the electrophysiological changes. The Biotin-switch assay was utilized to detect the protein S-sulfhydration. The isometric tension measurement was conducted too. KEY RESULTS: Exogenous H2 S enhanced the tonic contraction of gastric antral smooth muscle, and voltage-dependent potassium channel (KV ) blocker and Dithiothreitol (DTT, a reducing agent) abolished the excitatory effect of NaHS. Exogenous H2 S inhibited the fast inactivation component of the voltage-dependent potassium channel current (IKVfast ) in isolated gastric antral smooth muscle cells. H2 S inhibited the KV 4.3 current in H293 cells with heterologous expression of KV 4.3, but did not inhibit the KV 4.1 and KV 4.2 currents, which together contribute greatly to IKVfast . NaHS significantly decreased the membrane potential in cultured gastric smooth muscle cells, but the NaHS-induced depolarization was suppressed by knockdown of KV 4.3 and N-ethylamaleimide (NEM), a free thiol group blocker. In addition, NaHS sulfhydrated KV 4.3 in H293 cells and in gastric smooth muscle tissue. However, this S-sulfhydration was inhibited by NEM and DTT. Meanwhile the NaHS-induced inhibition of IKVfast and KV 4.3 was also blocked by NEM and DTT. CONCLUSIONS & INFERENCES: These results suggest that exogenous H2 S sulfhydrates KV 4.3 to decrease the membrane potential, thereby enhancing the basal tension of gastric antral smooth muscle. PMID- 25292411 TI - Probing planar defects in nanoparticle superlattices by 3D small-angle electron diffraction tomography and real space imaging. AB - We demonstrate how the acquisition and processing of 3D electron diffraction data can be extended to characterize structural features on the mesoscale, and show how lattice distortions in superlattices of self-assembled spherical Pd nanoparticles can be quantified by three-dimensional small-angle electron diffraction tomography (3D SA-EDT). Transmission electron microscopy real space imaging and 3D SA-EDT reveal a high density of stacking faults that was related to a competition between fcc and hcp arrangements during assembly. Information on the orientation of the stacking faults was used to make analogies between planar defects in the superlattices and Shockley partial dislocations in metallic systems. PMID- 25292409 TI - Oral Astaxanthin Supplementation Prevents Peritoneal Fibrosis in Rats. AB - BACKGROUND: Preventing peritoneal damage during peritoneal dialysis is critical. Reactive oxygen species (ROS) have an important role in peritoneal damage; however, few studies have investigated this. We aimed to determine the effects of oral astaxanthin (AST) supplementation in a peritoneal fibrosis (PF) rat model. METHODS: Thirty-seven Sprague-Dawley rats were divided into 5 groups: Control 1 (fed a normal diet without stimulation), Control 2 (fed an AST-supplemented diet without stimulation), Group 1 (fed a normal diet with 8% chlorhexidine gluconate [CG] stimulation for 3 weeks), Group 2 (fed a 0.06% AST-supplemented diet with CG stimulation), and Group 3 (fed a 0.06% AST-supplemented diet that was initiated 4 weeks before CG stimulation). Peritoneal fibrosis, vascular proliferation, and fibrosis-related factor expression were examined. RESULTS: Peritoneal thickness was significantly suppressed by AST supplementation. Astaxanthin diminished the number of CD68-, 8-hydroxy-2'-deoxyguanosine (8-OHdG)-, and monocyte chemoattractant protein-1 (MCP-1)-positive cells. Type 3 collagen, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and MCP-1 mRNA expression was significantly lower in Group 3 than in Group 1. Increased transforming growth factor-beta (TGF-beta) and Snail mRNA expression, vascular density, and the number of alpha-smooth muscle actin (alpha-SMA)-positive cells were also decreased in Group 3. CONCLUSION: Astaxanthin suppressed PF development through the inhibition of inflammation and oxidation in PF rats. It appears that the anti oxidative agent AST may be useful for the prevention of peritoneal damage. PMID- 25292412 TI - Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling. AB - Platelet-derived growth factors (PDGF) bind to two related receptor tyrosine kinases, which are encoded by the PDGFRA and PDGFRB genes. Recently, heterozygous PDGFRB mutations have been described in patients diagnosed with idiopathic basal ganglia calcification (IBGC or Fahr disease), a rare inherited neurological disorder. The goal of the present study was to determine whether these mutations had a positive or negative impact on the PDGFRB activity. We first showed that the E1071V mutant behaved like wild-type PDGFRB and may represent a polymorphism unrelated to IBGC. In contrast, the L658P mutant had no kinase activity and failed to activate any of the pathways normally stimulated by PDGF. The R987W mutant activated Akt and MAP kinases but did not induce the phosphorylation of signal transducer and activator of transcription 3 (STAT3) after PDGF stimulation. Phosphorylation of phospholipase Cgamma was also decreased. Finally, we showed that the R987W mutant was more rapidly degraded upon PDGF binding compared to wild-type PDGFRB. In conclusion, PDGFRB mutations associated with IBGC impair the receptor signalling. PDGFRB loss of function in IBGC is consistent with recently described inactivating mutations in the PDGF-B ligand. These results raise concerns about the long-term safety of PDGF receptor inhibition by drugs such as imatinib. PMID- 25292413 TI - Effects of tissue plasminogen activator timing on blood-brain barrier permeability and hemorrhagic transformation in rats with transient ischemic stroke. AB - The goal of our study was to determine if the timing of the tissue plasminogen activator (tPA) administration influenced its effect on blood-brain barrier (BBB) permeability and the subsequent risk of hemorrhagic transformation. Thirty spontaneously hypertensive male rats were subjected to a 90-minute unilateral middle cerebral artery occlusion. Six rats did not receive tPA treatment (vehicle control: Group 0), intravenous tPA was administered immediately after reperfusion (Group 1) or 4h after reperfusion (Group 2). Dynamic contrast enhancement (DCE) and gradient-echo (GRE) MR sequences were used to assess the dynamic evolution of BBB permeability and hemorrhagic transformation changes at the following time points: during occlusion, and 3h, 6h, and 24h post reperfusion. In all groups, BBB permeability values in the ischemic tissue were low during occlusion. In Group 0, BBB permeability values increased at 3h after reperfusion (p=0.007, compared with the values during occlusion), and further at 6h after reperfusion (p=0.004, compared with those at 3h post reperfusion). At 24h post reperfusion, the values decreased to a level relative to but still higher than those during occlusion (p=0.025, compared with the values during occlusion). At 3h after reperfusion, BBB permeability values in the ischemic tissue increased, but to a greater extent in Group 1 than in Group 0 (p=0.034) and Group 2 (p=0.010). At 6h after reperfusion, BBB permeability values in the ischemic tissue increased further in Group 2 than in Group 0 (p=0.006) and Group 1 (p=0.001), while Group 1 exhibited BBB permeability that were still abnormal but less than those observed at 3h (p=0.001). Group 2 tended to have a higher hemorrhage incidence (36.4%, 4/11) than Group 1 (10.0%, 1/10, p=0.311) and Group 0 (0%), and hemorrhages occurred around 6h after reperfusion when BBB permeability values were the highest. Mortality was higher in Group 2 (63.6%, 7/11) than in Group 0 (0%) and Group 1 (10.0%, 1/10, p=0.024). The findings suggest that the timing of tPA administration is of importance for its impact on BBB permeability and subsequent risk of hemorrhagic transformation. PMID- 25292415 TI - Training of cardiologists in China: catching up with the rest of the world. PMID- 25292414 TI - Under-reporting of Parkinson's disease on death certificates: a population-based study (NEDICES). AB - BACKGROUND: Parkinson's disease is frequently omitted as a cause of death from death certificates. A limitation of previous studies that attempted to assess the validity of death certificates is that population-dwelling cases, with milder, undiagnosed Parkinson's disease were likely excluded. As a result, those studies likely overestimated the validity of death certificates because they did not include these milder cases. We assessed the validity of death certificates in a prospective population-based study (NEDICES), which includes previously undiagnosed Parkinson's disease cases detected during the assessment. METHODS: 3926 community-dwelling elderly subjects with and without Parkinson's disease were followed during a median of 12.6 years, after which the death certificates of those who died were examined. We calculated the proportion of cases of clinically diagnosed Parkinson's disease for whom a diagnosis of Parkinson's disease was certified as the basic cause of death on death certificates. RESULTS: 1791 (45.6%) of the 3926 participants died over a median follow-up of 7.1 years, including 82 (73.9%) deaths among 111 participants with Parkinson's disease. Parkinson's disease was rarely certified as the basic cause of death (14.6%). Gender, disease stage and the period during which the study was conducted (i.e., 1994 to 2007) did not influence the likelihood that Parkinson's disease would be reported. CONCLUSIONS: Our findings reinforce the notion that the reporting of Parkinson's disease on death certificates remains poor. This suggests a lack of awareness of the importance of Parkinson's disease as a cause of death. PMID- 25292416 TI - Review article: Maxillofacial emergencies: Maxillofacial trauma. AB - Fractures of the facial skeleton are a common reason for patients to present to EDs and general medical practice in Australia. Trauma to the maxillofacial region can lead to airway obstruction, intracranial injuries, loss of vision or long term cosmetic and functional deficits. This article focuses on the emergency assessment, triage and non-specialist management of traumatic injuries of the orbit and facial skeleton. PMID- 25292417 TI - Salinity tolerance in soybean is modulated by natural variation in GmSALT3. AB - The identification of genes that improve the salt tolerance of crops is essential for the effective utilization of saline soils for agriculture. Here, we use fine mapping in a soybean (Glycine max (L.) Merr.) population derived from the commercial cultivars Tiefeng 8 and 85-140 to identify GmSALT3 (salt tolerance associated gene on chromosome 3), a dominant gene associated with limiting the accumulation of sodium ions (Na+) in shoots and a substantial enhancement in salt tolerance in soybean. GmSALT3 encodes a protein from the cation/H+ exchanger family that we localized to the endoplasmic reticulum and which is preferentially expressed in the salt-tolerant parent Tiefeng 8 within root cells associated with phloem and xylem. We identified in the salt-sensitive parent, 85-140, a 3.78-kb copia retrotransposon insertion in exon 3 of Gmsalt3 that truncates the transcript. By sequencing 31 soybean landraces and 22 wild soybean (Glycine soja) a total of nine haplotypes including two salt-tolerant haplotypes and seven salt sensitive haplotypes were identified. By analysing the distribution of haplotypes among 172 Chinese soybean landraces and 57 wild soybean we found that haplotype 1 (H1, found in Tiefeng 8) was strongly associated with salt tolerance and is likely to be the ancestral allele. Alleles H2-H6, H8 and H9, which do not confer salinity tolerance, were acquired more recently. H1, unlike other alleles, has a wide geographical range including saline areas, which indicates it is maintained when required but its potent stress tolerance can be lost during natural selection and domestication. GmSALT3 is a gene associated with salt tolerance with great potential for soybean improvement. PMID- 25292418 TI - Contemporary outcomes with percutaneous vascular interventions for peripheral critical limb ischemia in those with and without poly-vascular disease. AB - Given the very ill nature of patients with critical limb ischemia (CLI), the use of percutaneous vascular interventions (PVIs) for limb salvage may or may not be efficacious; in particular, for those with polyvascular arterial disease. Herein, we reviewed large, multi-institutional outcomes of PVI in polyvascular and peripheral arterial disease (PAD) patients with CLI. An 18-hospital consortium collected prospective data on patients undergoing endovascular interventions for PAD with 6-month follow-up from January 2008 to December 2011. The patient cohort included 4459 patients with CLI; of those, 3141 patients had polyvascular (coronary artery disease, cerebrovascular disease and PAD) disease, whereas 1318 patients suffered from only PAD. All patients were elderly and with significant comorbidities. The mean ankle-brachial index (ABI) was 0.44 and was not different between those with and without polyvascular disease. Polyvascular patients had more femoropopliteal and infra-inguinal interventions and less aortoiliac interventions than PAD patients. Pre- and post-procedural cardioprotective medication use was less in the PAD patients as compared with polyvascular patients. Vascular complications requiring surgery were higher in PAD patients whereas other access complications were similar between groups. At 6-month follow up, death was more common in the polyvascular group (6.7% vs 4.1%, p<0.001) as was repeat PVI, but no difference was found in the amputation rate. Considering the group as a whole at the 6-month follow-up, predictors of amputation/death included age (HR=1.01; 95% CI=1.002-1.02), anemia (HR=2.6; 95% CI=2.1-3.2), diabetes mellitus (HR=1.6; 95% CI=1.3-1.9), congestive heart failure (HR=1.6; 95% CI=1.4-1.9), and end-stage renal failure (HR=1.9; 95% CI=1.5-2.3), while female sex was protective (HR=0.7; 95% CI=0.6-0.8). In conclusion, from examination of this large, multicenter, multi-specialist practice registry, patients with polyvascular disease had higher 6-month mortality than PAD patients, but this was not a factor in 6-month limb amputation outcomes. This study also underscores that PAD patients still lag in cardioprotective medication use as compared with polyvascular patients. PMID- 25292419 TI - Tamoxifen-associated skin reactions in breast cancer patients: from case report to literature review. AB - The purpose of this study was to firstly present the maiden case of tamoxifen induced acute cutaneous lupus erythematosus (ACLE), and secondly, to broaden the discussion into a systematic review of the various tamoxifen-related skin changes documented in patients with breast cancer. We searched PubMed, Cochrane, Embase, CancerLit, Scopus, Web of Science, and Google Scholar databases using keywords to identify reported cases of tamoxifen-related cutaneous adverse events. Outcomes captured included type of cutaneous reaction, time to adverse event, pathologic mechanism, and possible treatment. From 17 clinical studies identified, over ten distinct types of adverse reactions of the skin were itemized. The character of these cutaneous events ranged from the relatively common hot flashes to the rare, but potentially life-threatening, Steven Johnson syndrome. Overall, tamoxifen is generally a well-tolerated hormone therapy with decades of supporting safety data. Based on current medical literature, we present the first case of tamoxifen induced ACLE. Our clinical experience of managing this case revealed that despite its broad use and the frequency of associated skin reactions, there is a lack of concise information detailing the cutaneous adverse events associated with tamoxifen. The absence of summarized information concerning tamoxifen-related skin changes prompted us to perform a review herein. PMID- 25292420 TI - Polyamines metabolism and breast cancer: state of the art and perspectives. AB - Breast cancer (BC) is a common disease that generally occurs in women over the age of 50, and the risk is especially high for women over 60 years of age. One of the major BC therapeutic problems is that tumors initially responsive to chemotherapeutic approaches can progress to more aggressive forms poorly responsive to therapies. Polyamines (PAs) are small polycationic alkylamines, naturally occurring and essential for normal cell growth and development in eukaryotes. The intracellular concentration of PA is maintained within strongly controlled contents, while a dysregulation occurs in BC cells. Polyamines facilitate the interactions of transcription factors, such as estrogen receptors with their specific response element, and are involved in the proliferation of ER negative and highly invasive BC tumor cells. Since PA metabolism has a critical role in cell death and proliferation, it represents a potential target for intervention in BC. The goal of this study was to perform a literature search reviewing the association between PA metabolism and BC, and the current evidence supporting the BC treatment targeting PA metabolism. We here describe in vitro and in vivo models, as well as the clinical trials that have been utilized to unveil the relationship between PA metabolism and BC. Polyamine pathway is still an important target for the development of BC chemotherapy via enzyme inhibitors. Furthermore, a recent promising strategy in breast anticancer therapy is to exploit the self-regulatory nature of PA metabolism using PA analogs to affect PA homeostasis. Nowadays, antineoplastic compounds targeting the PA pathway with novel mechanisms are of great interest and high social impact for BC chemotherapy. PMID- 25292421 TI - Generation of MCF-7 cells with aggressive metastatic potential in vitro and in vivo. AB - Epithelial-mesenchymal transition (EMT) is a cellular development program characterized by loss of cell adhesion and increased cell mobility. It is essential for numerous processes including metastasis. In this study we have generated "aggressive" MCF-7 breast cancer cells (MCF-7-EMT), which show significantly increased invasion in contrast to wild type MCF-7 (MCF-7 WT) cells. In addition, we have analyzed, whether these cell lines differ in their metastatic behavior in vivo and in expression of invasion and/or EMT-relevant genes. Invasive behavior of different human breast cancer cell lines was tested. "Aggressive" MCF-7 cells (MCF-7-EMT) were generated using coculture and mammosphere culture techniques. To analyze whether or not MCF-7-EMT cells in contrast to MCF-7 WT cells form metastases in vivo, we assessed metastases in a nude mouse model. mRNA expression profiles of MCF-7 WT cells and MCF-7-EMT cells were compared using the Affymetrix micro array technique. Expression of selected genes was validated using real-time PCR. In addition, protein expression of epithelial marker E-cadherin (CDH1) and mesenchymal markers N-cadherin (CDH2), Vimentin (VIM), and TWIST was compared. The breast cancer cell lines showed different invasive behavior from hardly any invasion to a stronger cell movement. Coculture with osteoblast-like MG63 cells led to significantly increased cell invasion rates. The highest increase was shown using MCF-7 WT cells. Generated MCF-7-EMT cells showed significantly increased invasion as compared to MCF-7 WT cells. In 8 of 10 mice bearing orthotopically growing MCF-7-EMT tumors, we could detect metastases in liver and lung. In mice bearing MCF-7 WT tumors (n = 10), no metastases were found. MCF-7 WT cells and MCF-7-EMT cells were different in expression of 325 genes. Forty-four of the most regulated 50 invasion and/or EMT related genes were upregulated and 6 genes were downregulated in MCF-7-EMT cells. Protein expression of mesenchymal markers CDH2, VIM, and TWIST was clearly increased in MCF-7-EMT cells. Protein expression of epithelial marker CDH1 was clearly decreased. With the breast cancer cell lines, MCF-7-EMT and MCF-7 WT cells, we have an excellent model of cells for further studies of EMT and invasion in vitro and in vivo. PMID- 25292422 TI - Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma. AB - Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-gamma, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard. PMID- 25292423 TI - Alleviation of glutamate mediated neuronal insult by piroxicam in rodent model of focal cerebral ischemia: a possible mechanism of GABA agonism. AB - Neurotransmitter imbalance is an inevitable outcome in cerebral ischemia that leads to neuronal death. In the present study, we evaluated the effects of piroxicam, a nonsteroidal anti-inflammatory drug (NSAID), on extracellular brain glutamate and gamma-aminobutyric acid (GABA) release, survival time, and neuronal cell death. Transient focal cerebral ischemia in male Charles Foster rat led to neuronal infarction and compromised intrinsic antioxidant status. Thirty-minute preadministration of piroxicam (10 mg/kg b.w.) showed a significant (P < 0.01) reduction in cerebral infarct volume and potentiation of the intrinsic antioxidant status. High-performance liquid chromatography of brain cortex and striatum revealed changes in extracellular concentrations of neurotransmitters which were found to be 0.519 +/- 0.44 pmole/mg (GABA); 1.18 +/- 0.28 pmole/mg (glutamate), and 0.63 +/- 0.21 pmole/mg (serotonin), respectively. Hydroxyl radical (.OH) adduct of salicylate in the frontal cortex and striatum in control, untreated, and treated groups was found to be 0.261 +/- 0.06, 0.68 +/- 0.52, and 0.401 +/- 0.68 pmole/mg, respectively. After stroke, the extracellular level of glutamate in rat brain increases continuously as compared to that of control group. However, piroxicam administration in stroke rat significantly reduced (P < 0.05) elevated extracellular cerebral glutamate. This indicates that piroxicam attenuates extracellular glutamate release and also reduces neuronal cell death due to reduction in oxidative stress in cerebral ischemia. Our results also indicate a consequent increase of extracellular GABA in brain regions administered with piroxicam, which hints that piroxicam alleviates glutamate excitotoxicity possibly by GABA agonism. PMID- 25292425 TI - The use of biomarkers in human pharmacology (Phase I) studies. AB - The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development. PMID- 25292424 TI - Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal. AB - This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and beta cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6 bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and beta cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent. PMID- 25292426 TI - Predicting toxicities of reactive metabolite-positive drug candidates. AB - Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed. PMID- 25292430 TI - Learning by failing: ideas and concepts to tackle gamma-secretases in Alzheimer's disease and beyond. AB - gamma-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum gamma-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all gamma-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of gamma-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious gamma-secretase inhibition in various disorders. PMID- 25292427 TI - Eph receptors and ephrins: therapeutic opportunities. AB - The erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis, and various diseases. Interaction with Eph receptor-interacting protein (ephrin) ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets, and various strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offer opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules. PMID- 25292429 TI - Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. AB - Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support. PMID- 25292431 TI - Pharmacogenomics in asthma therapy: where are we and where do we go? AB - The response to drug treatment in asthma is a complex trait and is markedly variable even in patients with apparently similar clinical features. Pharmaco genomics, which is the study of variations of human genome characteristics as related to drug response, can play a role in asthma therapy. Both a traditional candidate-gene approach to conducting genetic association studies and genome-wide association studies have provided an increasing list of genes and variants associated with the three major classes of asthma medications: beta2-agonists, inhaled corticosteroids, and leukotriene modifiers. Moreover, a recent integrative, systems-level approach has offered a promising opportunity to identify important pharmacogenomics loci in asthma treatment. However, we are still a long way away from making this discipline directly relevant to patients. The combination of network modeling, functional validation, and integrative omics technologies will likely be needed to move asthma pharmacogenomics closer to clinical relevance. PMID- 25292428 TI - Therapeutic applications of extracellular vesicles: clinical promise and open questions. AB - This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury. PMID- 25292433 TI - DREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. AB - In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics. PMID- 25292432 TI - A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant. AB - Asian Americans are one of the fastest-growing populations in the United States. A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2. Found in approximately 560 million people of East Asian descent, ALDH2*2 reduces enzymatic activity by approximately 60% to 80% in heterozygotes. Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis. In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant. We also discuss future clinical and translational perspectives regarding ALDH2*2 research. PMID- 25292435 TI - Improving postapproval drug safety surveillance: getting better information sooner. AB - Adverse drug events (ADEs) are an important public health concern, accounting for 5% of all hospital admissions and two-thirds of all complications occurring shortly after hospital discharge. There are often long delays between when a drug is approved and when serious ADEs are identified. Recent and ongoing advances in drug safety surveillance include the establishment of government-sponsored networks of population databases, the use of data mining approaches, and the formal integration of diverse sources of drug safety information. These advances promise to reduce delays in identifying drug-related risks and in providing reassurance about the absence of such risks. PMID- 25292436 TI - MUSIC: identification of enriched regions in ChIP-Seq experiments using a mappability-corrected multiscale signal processing framework. AB - We present MUSIC, a signal processing approach for identification of enriched regions in ChIP-Seq data, available atmusic.gersteinlab.org. MUSIC first filters the ChIP-Seq read-depth signal for systematic noise from non-uniformmappability, which fragments enriched regions. Then it performs a multiscale decomposition, using median filtering, identifying enriched regions at multiple length scales. This is useful given the wide range of scales probed in ChIP-Seq assays. MUSIC performs favorably in terms of accuracy and reproducibility compared with other methods.In particular, analysis of RNA polymerase II data reveals a clear distinction between the stalled and elongating forms of the polymerase. PMID- 25292434 TI - Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. AB - Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief but do not modify disease progression. Here we explore a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polyglutamine androgen receptor in spinal and bulbar muscular atrophy, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and tau in Alzheimer's disease, are client proteins of heat shock protein 90 (Hsp90), and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. Hsp90 and Hsp70 have opposing effects on client protein stability in protein quality control; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes ubiquitination dependent on CHIP (C terminus of Hsc70-interacting protein) and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models. PMID- 25292437 TI - Spatial and temporal localization of homogalacturonans in Hyacinthus orientalis L. ovule cells before and after fertilization. AB - KEY MESSAGE: The composition of homogalacturonans (HGs) in the ovule and the female gametophyte cell walls was shown to be rearranged dynamically during sexual reproduction of H. orientalis. In angiosperms, homogalacturonans (HGs) play an important role in the interaction between the male gametophyte and the pistil transmitting tract, but little is known about the participation of these molecules at the final stage of the progamic phase and fertilization. The aim of our study was to perform immunocytochemical localization of highly (JIM7 MAb) and weakly (JIM5 MAb) methyl esterified and Ca(2+)-associated HG (2F4 MAb) in the ovule and female gametophyte cells of Hyacinthus orientalis before and after fertilization. It was found that pollination induced the rearrangement of HG in (1) the micropylar canal of the ovule, (2) the filiform apparatus of the synergids, and (3) the region of fusion between sperm cells and their target cells. Fertilization led to further changes in pectin composition of these three regions of the ovule. A new cell wall was synthesized around the zygote with a characteristic pattern of localization of all examined HG fractions, which we called "sporoderm-like". The developing endosperm prepared for cellularization by synthesizing highly methyl-esterified HG, which was stored in the cytoplasm. Pollination- and fertilization-induced changes in the composition of the HG in the micropyle of the ovule and the apoplast of female gametophyte cells are discussed in the context of: (1) micropylar pollen tube guidance, (2) preparation of the egg cell and the central cells for fusion with sperm cells, and (3) the polyspermy block. PMID- 25292438 TI - The intron and 5' distal region of the soybean Gmubi promoter contribute to very high levels of gene expression in transiently and stably transformed tissues. AB - KEY MESSAGE: An extended version of an intron-containing soybean polyubiquitin promoter gave very high levels of gene expression using three different validation tools. The intron-containing Glycine max polyubiquitin promoter (Gmubi) is able to regulate expression levels five times higher than the widely used CaMV35S promoter. In this study, eleven Gmubi derivatives were designed and evaluated to determine which regions contributed to the high levels of gene expression, observed with this promoter. Derivative constructs regulating GFP were evaluated using transient expression in lima bean cotyledons and stable expression in soybean hairy roots. With both expression systems, removal of the intron in the 5'UTR led to reduced levels of gene expression suggesting a role of the intron in promoter activity. Promoter constructs containing an internal intron duplication and upstream translocations of the intron resulted in higher and similar expression levels to Gmubi, respectively, indicating the presence of enhancers within the intron. Evaluation of 5' distal extensions of the Gmubi promoter resulted in significantly higher levels of GFP expression, suggesting the presence of upstream regulatory elements. A twofold increase in promoter strength was obtained when Gmubi was extended 1.5 kb upstream to generate GmubiXL (2.4 kb total length). In stably transformed soybean plants containing GFP regulated by CaMV35S, Gmubi and GmubiXL, the GmubiXL promoter clearly produced the highest levels of gene expression, with especially high GFP fluorescence in the vascular tissue and root tips. Use of GmubiXL leads to very high levels of gene expression in soybean and represents a native soybean promoter, which may be useful for regulating transgene expression for both basic and applied research. PMID- 25292441 TI - Pilot and Revision of a Basal-Bolus Dosing Guideline for the Management of Hyperglycemia in Noncritically Ill Adult Patients. AB - The use of basal-bolus insulin (BBI) regimens for the treatment of inpatient hyperglycemia has become standard of care. The purpose of this study was to develop and evaluate a newly piloted dosing guideline and utilize the results to adjust it prior to its implementation hospital-wide. This was an institutional review board approved, prospective, and multiphase study. An interdisciplinary team was developed and created a dosing guideline, which was followed by a 3 month, single-unit pilot of the guideline in noncritically ill adult patients. The resulting data were used to revise the guideline. Forty-three patients were included. There was a significant decrease in median blood glucose (BG) with use of the guideline (219 mg/dL [162-281] vs 190 mg/dL [136-246], P < .05) in patients not utilizing it. There was also a significant increase in the number of values within the target range of 70 to 180 mg/dL (30.2% vs 41.4%, P < .05). Moreover, there was comparable hypoglycemia before and after the intervention (1.6% vs 2.4%, P = .51). Based on these results, the dosing factor used for the total daily dose of insulin was increased in certain populations. Use of a BBI dosing guideline is safe and effective in decreasing BG values in noncritically ill patients at our institution. PMID- 25292440 TI - Modelling of OGTT curve identifies 1 h plasma glucose level as a strong predictor of incident type 2 diabetes: results from two prospective cohorts. AB - AIMS/HYPOTHESIS: The relevance of the OGTT in predicting type 2 diabetes is unclear. We assessed the performance of 14 OGTT glucose traits in type 2 diabetes prediction. METHODS: We studied 2,603 and 2,386 Europeans from the Botnia study and Malmo Prevention Project (MPP) cohorts with baseline OGTT data. Over a follow up period of 4.94 years and 23.5 years, 155 (5.95%) and 467 (19.57%) participants, respectively, developed type 2 diabetes. The main outcome was incident type 2 diabetes. RESULTS: One-hour plasma glucose (1h-PG) was a fair/good predictor of incident type 2 diabetes in the Botnia study and MPP (AUC for receiver operating characteristic [AUCROC] 0.80 [0.77, 0.84] and 0.70 [0.68, 0.73]). 1h-PG alone outperformed the prediction model of multiple clinical risk factors (age, sex, BMI, family history of type 2 diabetes) in the Botnia study and MPP (AUCROC 0.75 [0.72, 0.79] and 0.67 [0.64, 0.70]). The same clinical risk factors added to 1h-PG modestly increased prediction for incident type 2 diabetes (Botnia, AUCROC 0.83 [0.80, 0.86]; MPP, AUCROC 0.74 [0.72, 0.77]). 1h-PG also outperformed HbA1c in predicting type 2 diabetes in the Botnia cohort. A 1h-PG value of 8.9 mmol/l and 8.4 mmol/l was the optimal cut-point for initial screening and selection of high-risk individuals in the Botnia study and MPP, respectively, and represented 30% and 37% of all participants in these cohorts. High-risk individuals had a substantially increased risk of incident type 2 diabetes (OR 8.0 [5.5, 11.6] and 3.8 [3.1, 4.7]) and captured 75% and 62% of all incident type 2 diabetes in the Botnia study and MPP. CONCLUSIONS/INTERPRETATION: 1h-PG is a valuable prediction tool for identifying adults at risk for future type 2 diabetes. PMID- 25292439 TI - Phenolic composition, antioxidant, anti-wrinkles and tyrosinase inhibitory activities of cocoa pod extract. AB - BACKGROUND: Cocoa pod is an outer part of cocoa fruits being discarded during cocoa bean processing. Authors found out that data on its usage in literature as cosmetic materials was not recorded in vast. In this study, cocoa pod extract was investigated for its potential as a cosmetic ingredient. METHODS: Cocoa pod extract (CPE) composition was accomplished using UHPLC. The antioxidant capacity were measured using scavenging assay of 1,2-diphenyl-2-picrylhydrazyl (DPPH), beta-carotene bleaching assay (BCB) and ferric reducing antioxidant power (FRAP). Inhibiting effect on skin degradation enzymes was carried out using elastase and collagenase assays. The skin whitening effect of CPE was determined based on mushroom tyrosinase assay and sun screening effect (UV-absorbance at 200-400 nm wavelength). RESULTS: LC-MS/MS data showed the presence of carboxylic acid, phenolic acid, fatty acid, flavonoids (flavonol and flavones), stilbenoids and terpenoids in CPE. Results for antioxidant activity exhibited that CPE possessed good antioxidant activity, based on the mechanism of the assays compared with ascorbic acid (AA) and standardized pine bark extract (PBE); DPPH: AA > CPE > PBE; FRAP: PBE > CPE > AA; and BCB: BHT > CPE > PBE. Cocoa pod extract showed better action against elastase and collagenase enzymes in comparison with PBE and AA. Higher inhibition towards tyrosinase enzyme was exhibited by CPE than kojic acid and AA, although lower than PBE. CPE induced proliferation when tested on human fibroblast cell at low concentration. CPE also exhibited a potential as UVB sunscreen despite its low performance as a UVA sunscreen agent. CONCLUSIONS: Therefore, the CPE has high potential as a cosmetic ingredient due to its anti wrinkle, skin whitening, and sunscreen effects. PMID- 25292442 TI - Adherence With Therapeutic Regimens: Behavioral and Pharmacoeconomic Perspectives. AB - There is an extensive literature regarding nonadherence with both therapeutic regimens and medication. This literature includes reviews of empirical research regarding the factors associated with nonadherence. Health care system, provider, and patient factors as well as the nature of the illness and therapeutic regimen all effect adherence rates. Different behavioral models for adherence counseling such as the Health Belief Model, the Theory of Reasoned Action, the Medication Interest Model, and Motivational Interviewing have also been reported in the research literature. This article will discuss the development of a brief model for patient counseling with specific techniques illustrated for pharmacists based on empirical findings that have demonstrated effectiveness in the adherence research literature. In addition, the article will address the measurement of the economic impact of medication nonadherence and propose a framework for assessing the cost-effectiveness of pharmacist counseling to increase adherence. The problem of nonadherence has significant effects upon health care expenditures through increase in physician's visits, emergency department incidents, rehospitalizations, and nursing home readmissions. Thus, the overall goal is to assist the pharmacist in developing a brief adherence counseling program in community pharmacy and evaluating the economic feasibility of the intervention demonstrating the value-added proposition of pharmacist intervention. PMID- 25292443 TI - Assessment of knowledge on sexually transmitted infections and sexual risk behaviour in two rural districts of Bhutan. AB - BACKGROUND: The incidence of STI is high and increasing in Bhutan. Poor understanding of risky sexual behavior could be a cause. Comprehensive community surveys have not been previously done. This study was conducted to assess local knowledge on STIs and sexual risk behaviour in two rural districts of Bhutan: Gasa and Zhemgang. METHODS: The study population included residents aged 15-49 years in the two districts. Health Assistants (HAs) visited all households to distribute questionnaires assessing understanding of knowledge on STIs and risk behaviour. Questionnaires were scored and analyzed. RESULTS: The average score was 61.6%. Respondents had highest knowledge about prevention and lowest about disease and complications. There was a positive correlation between level of education and knowledge on STI (P < 0.05). Almost 37% of students scored low. Nearly one-third of the study population was practicing risky sexual behavior with 31.2% having sexual relationships with non-regular partners and 10.9% had extramarital sexual contacts. Regular use of condoms with non-regular partners was 49.1%. The most common reason for not using condom was unavailability during the sexual encounter. The study showed that despite increasing knowledge there was no reduction in risky sexual behaviour (p > 0.05). CONCLUSIONS: The study population had variable understanding of STIs and their complications. One in three persons practiced risky sexual behaviour, higher in men. Condom use was low. There was no reduction of risky sexual behaviour with increasing level of knowledge indicating that increasing level of knowledge does not necessarily reduce risky sexual behaviour. PMID- 25292444 TI - Associations of working models of the self and other with Cloninger's personality dimensions. AB - The present study examined the associations of working models of the self and other, one of the key concepts of Bowlby's attachment theory, with the seven dimensions of Cloninger's personality model. The subjects were 542 healthy Japanese volunteers. Working models of the self and other were assessed by the Relationship Scales Questionnaire, and the seven dimensions of personality were evaluated by the Temperament and Character Inventory. In the correlation analysis, the self-model was correlated most strongly with self-directedness (SD) (r=0.50, P<0.001) and second strongly with harm avoidance (HA) (r=-0.43, P<0.001), while the other-model was correlated most strongly with cooperativeness (C) (r=0.43, P<0.001) and second strongly with reward dependence (RD) (r=0.41, P<0.001). In the principal component analysis, the self-model formed a group with SD and HA, while the other-model formed a group with C and RD. The present study suggests that the self-model is reflected in SD and HA, while the other-model is reflected in C and RD. PMID- 25292445 TI - Effect of oestrus synchronization with PGF2alpha/eCG/hCG on luteal P4 synthesis in early pregnant gilts. AB - Administration of hormones to synchronize oestrus is a useful tool in animal breeding. However, exogenous ovarian stimulation may be detrimental to reproductive function. This study was aimed to examine whether an oestrus synchronization with PGF2alpha/eCG/hCG could affect luteal P4 synthesis in early pregnant gilts. Corpora lutea (CLs) were collected on days 9, 12 and 16 of pregnancy from gilts with natural (n = 16) and synchronized (n = 18) oestrus and analysed for (i) the expre-ssion of steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A polypeptide (CYP11A1), and 3beta hydroxysteroid dehydrogenase (3betaHSD); (ii) the concentration of P4 in the luteal tissue and blood; and (iii) the expression of luteinizing hormone receptors (LHR) and oestrogen receptors (ERalpha and ERbeta). Additionally, the effect of LH on P4 secretion from CL slices collected from synchronized and naturally ovulated animals has been studied in vitro. PGF2alpha /eCG/hCG administration increased mRNA expression of StAR, CYP11A1, 3betaHSD, and LHR on day 9 and CYP11A1 and LHR on day 12 of pregnancy compared with the control group (p < 0.05). CYP11A1, 3betaHSD, LHR, ERalpha and ERbeta proteins were not affected by synchronization; only StAR protein increased in hormonally treated animals (p = 0.017). The concentration of P4 in luteal tissue was greater on day 9 (p < 0.01), but lower on day 16 (p < 0.05) in gilts with hormonally induced oestrus compared with control animals. Blood serum levels of P4 were lower in synchronized than control gilts (p < 0.001). Synchronization did not affect LH stimulated P4 secretion from luteal slices; however, greater basal concentration of P4 in incubation medium was detected for CLs collected from synchronized than control gilts (p < 0.05). In conclusion, synchronization of oestrus with PGF2alpha/eCG/hCG protocol in gilts did not impair the expression of luteal P4 synthesis system, although decreased P4 concentration in the blood. PMID- 25292446 TI - Fumarate hydratase immunohistochemical staining may help to identify patients with multiple cutaneous and uterine leiomyomatosis (MCUL) and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. AB - AIMS: Multiple cutaneous and uterine leiomyomatosis (MCUL) also named as hereditary leiomyomatosis and renal cancer syndrome (HLRCC) is an autosomal dominant disorder caused by heterozygotic germline mutations in fumarate hydratase (FH) with incomplete penetrance and clinically challenging to diagnose. To test immunohistochemistry for FH as a potential marker for the detection of FH deficiency. METHODS AND RESULTS: We have tested 42 smooth muscle neoplasms, 13 lesions of patients with suspicious or confirmed HLRCC, 20 sporadic piloleiomyomas, two angioleiomyomas and 7 leiomyosarcomas. FH staining grades from 1 to 3. Ten of the 13 lesions from the patients with HLRCC syndrome showed negative FH staining. Most sporadic piloleiomyomas presented grade 3 FH staining although five cases presented grade 1 FH staining. Sensitivity of FH staining in our series is 83.3% but specificity is 75%. CONCLUSIONS: This staining could indicate a high risk of HLRCC in most of the confirmed cases but it could also suggest the presence of a syndrome in up to 25% of sporadic cases. HLRCC syndrome should be rule out in FH negative piloleiomyomas after complete anamnesis if multiple lesions or positive familiar history is found. PMID- 25292447 TI - In situ atom scale visualization of domain wall dynamics in VO2 insulator-metal phase transition. AB - A domain wall, as a device, can bring about a revolution in developing manipulation of semiconductor heterostructures devices at the atom scale. However, it is a challenge for these new devices to control domain wall motion through insulator-metal transition of correlated-electron materials. To fully understand and harness this motion, it requires visualization of domain wall dynamics in real space. Here, domain wall dynamics in VO2 insulator-metal phase transition was observed directly by in situ TEM at atom scale. Experimental results depict atom scale evolution of domain morphologies and domain wall exact positions in (202) and (040) planes referring to rutile structure at 50 degrees C. In addition, microscopic mechanism of domain wall dynamics and accurate lattice basis vector relationship of two domains were investigated with the assistance of X-ray diffraction, ab initio calculations and image simulations. This work offers a route to atom scale tunable heterostructure device application. PMID- 25292448 TI - A model for translating ethnography and theory into culturally constructed clinical practices. AB - This article describes the development of a dynamic culturally constructed clinical practice model for HIV/STI prevention, the Narrative Intervention Model (NIM), and illustrates its application in practice, within the context of a 6 year transdisciplinary research program in Mumbai, India. Theory and research from anthropology, psychology, and public health, and mixed-method ethnographic research with practitioners, patients, and community members, contributed to the articulation of the NIM for HIV/STI risk reduction and prevention among married men living in low-income communities. The NIM involves a process of negotiation of patient narratives regarding their sexual health problems and related risk factors to facilitate risk reduction. The goal of the NIM is to facilitate cognitive-behavioral change through a three-stage process of co-construction (eliciting patient narrative), deconstruction (articulating discrepancies between current and desired narrative), and reconstruction (proposing alternative narratives that facilitate risk reduction). The NIM process extends the traditional clinical approach through the integration of biological, psychological, interpersonal, and cultural factors as depicted in the patient narrative. Our work demonstrates the use of a recursive integration of research and practice to address limitations of current evidence-based intervention approaches that fail to address the diversity of cultural constructions across populations and contexts. PMID- 25292449 TI - Trauma, workfare and the social contingency of precarity and its sufferings: the story of Marius, a street-youth. AB - Based on ethnographic fieldwork in London, Ontario, Canada, with homeless and street-involved youth in a youth drop-in shelter that I call "At Home", this paper is an ethnographically grounded narrative analysis of interview content and participant observation with a centre focus on my key informant, a youth from Eastern Europe whom I call "Marius". Like many other street youth, Marius lives a life marked by precarity. His daily life is marked by traumatic memories of abandonment and abuse, which has lead to an inability to work; and structural violence facilitated by Ontario's workfare program called Ontario Works, especially its mandate that all "participants" (i.e. those in receipt of social assistance, such as Marius) seek employment or face termination of their social assistance check. For Marius, the recounting of traumatic memories at At Home opened up a shared rhetorical space from which he could narratively align himself vis-a-vis other street youth as a victim of precarity and trauma and therefore absolve himself of the onus to find employment. Regardless of his narrative positioning, he is constantly terminated from Ontario Works for not submitting proof of citizenship and proof of job-seeking activities. In conclusion, the only way for Marius to find any form of solace from his past and the constraints of OW is through isolation: a cultural stance that serves as a coping mechanism, and allows Marius to muddle through each day, all the while holding precarity and its pursuant anxiety and depression at bay. PMID- 25292450 TI - Numerical analysis and experimental observation of guidewire motion in a blood vessel model. AB - We have developed a computer-based system to simulate a guidewire in blood vessels for surgical planning, intra-operative assistance, and to facilitate the design of new guidewires. In this study, we compared simulation results with experimental results for validation of the simulation system. First, we inserted a commercial guidewire into a poly (vinyl alcohol) hydrogel blood vessel model using a two-axis automatic stage and measured the position of the guidewire tip and the contact force between the guidewire and the vessel. The experimental apparatus can be used not only for the validation of numerical analyses, but also as a simulation system. Second, similarly to the experiment, the motion of the guidewire in the blood vessel model was calculated when the proximal part of the guidewire model was pushed and twisted. The model of the guidewire is constructed with viscoelastic springs and segments, and the proximal part of the guidewire model is constrained by the fixed catheter model. Collisions between the guidewire and the vessel are calculated, and the contact forces are determined according to the stiffness of the vessel wall. The same tendency was seen in the trajectories and the contact force of both the experimental and simulated guidewire tips. PMID- 25292451 TI - Feature dimensionality reduction for myoelectric pattern recognition: a comparison study of feature selection and feature projection methods. AB - This study investigates the effect of the feature dimensionality reduction strategies on the classification of surface electromyography (EMG) signals toward developing a practical myoelectric control system. Two dimensionality reduction strategies, feature selection and feature projection, were tested on both EMG feature sets, respectively. A feature selection based myoelectric pattern recognition system was introduced to select the features by eliminating the redundant features of EMG recordings instead of directly choosing a subset of EMG channels. The Markov random field (MRF) method and a forward orthogonal search algorithm were employed to evaluate the contribution of each individual feature to the classification, respectively. Our results from 15 healthy subjects indicate that, with a feature selection analysis, independent of the type of feature set, across all subjects high overall accuracies can be achieved in classification of seven different forearm motions with a small number of top ranked original EMG features obtained from the forearm muscles (average overall classification accuracy >95% with 12 selected EMG features). Compared to various feature dimensionality reduction techniques in myoelectric pattern recognition, the proposed filter-based feature selection approach is independent of the type of classification algorithms and features, which can effectively reduce the redundant information not only across different channels, but also cross different features in the same channel. This may enable robust EMG feature dimensionality reduction without needing to change ongoing, practical use of classification algorithms, an important step toward clinical utility. PMID- 25292452 TI - Submucosal invasive carcinoma arising from a sessile serrated adenoma/polyp, 20 mm in diameter, with lymph node metastasis. PMID- 25292453 TI - A case of anaplastic large cell lymphoma of skeletal muscle. AB - Anaplastic large cell lymphoma (ALCL) is a high grade non-Hodgkin lymphoma (NHL) that is comprised of the malignant proliferation of large lymphoid cells, which express CD30. Primary ALCL of the skeletal muscle is extremely uncommon. A 51 year-old Japanese female presented at our hospital with a 2-month history of severe pain and swelling of the right leg. A gallium-67 SPECT/CT scan showed a large mass involving the skeletal muscles from the gluteus to femoris. A biopsy of the mass demonstrated diffuse infiltration of medium and large neoplastic cells with round or lobulated hyperchromatic pleomorphic nuclei. A subset of Reed Sternberg-like cells was also identified. Immunohistochemically, the neoplastic cells were strongly positive for CD4 and CD30, but negative for CD3, CD8, anaplastic lymphoma kinase (ALK), CD20, CD79alpha, CD21 and CD23. Based on the histological examination, this patient was diagnosed to have ALK-negative ALCL of the skeletal muscle. Further studies are needed to clarify the biological behavior of primary skeletal muscle ALCL. PMID- 25292455 TI - Stem CO2 efflux in six co-occurring tree species: underlying factors and ecological implications. AB - Stem respiration plays a role in species coexistence and forest dynamics. Here we examined the intra- and inter-specific variability of stem CO2 efflux (E) in dominant and suppressed trees of six deciduous species in a mixed forest stand: Fagus sylvatica L., Quercus petraea [Matt.] Liebl, Quercus pyrenaica Willd., Prunus avium L., Sorbus aucuparia L. and Crataegus monogyna Jacq. We conducted measurements in late autumn. Within species, dominants had higher E per unit stem surface area (Es ) mainly because sapwood depth was higher than in suppressed trees. Across species, however, differences in Es corresponded with differences in the proportion of living parenchyma in sapwood and concentration of non structural carbohydrates (NSC). Across species, Es was strongly and NSC marginally positively related with an index of drought tolerance, suggesting that slow growth of drought-tolerant trees is related to higher NSC concentration and Es . We conclude that, during the leafless period, E is indicative of maintenance respiration and is related with some ecological characteristics of the species, such as drought resistance; that sapwood depth is the main factor explaining variability in Es within species; and that the proportion of NSC in the sapwood is the main factor behind variability in Es among species. PMID- 25292454 TI - Neural reward and punishment sensitivity in cigarette smokers. AB - BACKGROUND: Nicotine addiction remains a major public health problem but the neural substrates of addictive behavior remain unknown. One characteristic of smoking behavior is impulsive choice, selecting the immediate reward of smoking despite the potential long-term negative consequences. This suggests that drug users, including cigarette smokers, may be more sensitive to rewards and less sensitive to punishment. METHODS: We used event-related potentials (ERPs) to test the hypothesis that smokers are more responsive to reward signals and less responsive to punishment, potentially predisposing them to risky behavior. We conducted two experiments, one using a reward prediction design to elicit a Medial Frontal Negativity (MFN) and one using a reward- and punishment-motivated flanker task to elicit an Error Related Negativity (ERN), ERP components thought to index activity in the cortical projection of the dopaminergic reward system. RESULTS AND CONCLUSIONS: The smokers had a greater MFN response to unpredicted rewards, and non-smokers, but not smokers, had a larger ERN on punishment motivated trials indicating that smokers are more reward sensitive and less punishment sensitive than nonsmokers, overestimating the appetitive value and underestimating aversive outcomes of stimuli and actions. PMID- 25292456 TI - Why some children with externalising problems develop internalising symptoms: testing two pathways in a genetically sensitive cohort study. AB - BACKGROUND: Children with externalising problems are at risk of developing internalising problems as they grow older. The pathways underlying this developmental association remain to be elucidated. We tested two processes that could explain why some children with externalising problems develop internalising symptoms in preadolescence: a mediation model whereby the association between early externalising and later new internalising symptoms is explained by negative experiences; and a genetic model, whereby genes influence both problems. METHODS: We used data from the Environmental Risk (E-Risk) Study, a 1994-1995 birth cohort of 2,232 twins born in England and Wales. We assessed externalising and internalising problems using combined mothers' and teachers' ratings at age 5 and 12. We measured bullying victimisation, maternal dissatisfaction and academic difficulties between age 7 and 10 and used linear regression analyses to test the effects of these negative experiences on the association between early externalising and later internalising problems. We employed a Cholesky decomposition to examine the genetic influences on the association. RESULTS: Children with externalising problems at age 5 showed increased rates of new internalising problems at age 12 (r = .24, p < .001). Negative experiences accounted for some of the association between early externalising and later internalising problems. Behavioural-genetic analyses indicated that genes influencing early externalising problems also affected later internalising problems. CONCLUSIONS: Our findings highlight the role of genetic influences in explaining why some children with externalising problems develop internalising symptoms in preadolescence. Negative experiences also contribute to the association, possibly through gene-environment interplay. Mental health professionals should monitor the development of internalising symptoms in young children with externalising problems. PMID- 25292457 TI - Status of the diabetes epidemic in the Kingdom of Saudi Arabia, 2013. AB - OBJECTIVES: In the Kingdom of Saudi Arabia (KSA), current data on diabetes are lacking, and a rise of the epidemic is feared, given the epidemiologic transition in the country. To inform public health authorities on the current status of the diabetes epidemic, we analyzed data from the Saudi Health Interview Survey (SHIS). METHODS: Saudi Health Interview Survey is a cross-sectional national multistage survey of individuals aged 15 years or older. A total of 10,735 participants completed a health questionnaire and were invited to the local health clinics for biomedical exams. RESULTS: 1,745,532 (13.4 %) Saudis aged 15 years or older have diabetes. Among those, 57.8, 20.2, 16.6, and 5.4 % are undiagnosed, treated uncontrolled, treated controlled, and untreated, respectively. Males, older individuals, and those who were previously diagnosed with hypertension or hypercholesterolemia were more likely to be diabetic. CONCLUSIONS: Our findings call for increased awareness of pre-diabetes, diabetes, and undiagnosed diabetes in KSA. Combatting diabetes and other non-communicable diseases should be the task of the Ministry of Health and other ministries as well, to offer a comprehensive socio-cultural approach to fighting this epidemic. PMID- 25292458 TI - How strict should specimen acceptance or rejection criteria be for diagnostic semen analysis? An opinion. AB - Medical laboratory accreditation (previously by Clinical Pathology Accreditation UK Ltd and now by the United Kingdom Accreditation Service) has been integral to improving standards and service quality in the UK. With the recent introduction of the ISO15189 standard, all laboratories offering a clinical diagnostic service are required to demonstrate further improvement, with more emphasis on validation and assessment of the uncertainty levels associated with testing. This applies not only to 'bench testing', but also to the evidence-base for all pre-analytical and post-analytical procedures. To reduce the risk of external influences on andrology test results, semen sample rejection criteria were developed, including confirmation of patient identity, a strict time limit from sample production to testing, the use of toxicity-tested containers, a prescribed sexual abstinence and a need for complete sample collection. However, such criteria were originally developed by the World Health Organization in order to standardise analysis rather than reject testing outright, and should therefore be implemented with caution. Rejecting samples with normal semen parameters because they fail to meet some of the criteria as outlined above would be a waste of resources and adversely affect user (the person who requested or provided the sample) satisfaction. This document evaluates the evidence base underlying commonly used criteria for specimen rejection and suggests how they may be applied more pragmatically in order to improve efficiency and reduce the waste of resources. PMID- 25292459 TI - Associations between N-terminal procollagen type III, fibrosis and echocardiographic indices in dogs that died due to myxomatous mitral valve disease. AB - OBJECTIVES: To evaluate associations between N-terminal procollagen type III (PIIINP), a serum biomarker of collagen biosynthesis, and myocardial fibrosis in dogs with naturally-occurring myxomatous mitral valve disease (MMVD). ANIMALS: Twenty-two dogs with echocardiographically-confirmed MMVD were prospectively recruited from a hospital population. All died as a result of MMVD and their hearts were available for post mortem examination. METHODS: Echocardiographic measurements and serum PIIINP concentrations were obtained from all dogs prior to death or euthanasia. Serum PIIINP concentrations (MUg/mL) were measured using a validated commercially available radioimmunoassay. Myocardial tissue samples were collected post mortem and myocardial fibrosis was scored. The average fibrosis score for all cardiac sites in the heart was designated the global fibrosis score (GFS). The average fibrosis score for all papillary muscle sites was designated the papillary fibrosis score (PFS). Univariate and multivariate linear regression analyses were used separately to evaluate associations between GFS and PFS, respectively, and PIIINP and echocardiographic variables. RESULTS: Left ventricular end-diastolic diameter normalized for body weight (LVEDDN) and PIIINP were weakly independently positively associated with both GFS and PFS. LVEDDN and PIIINP were weakly negatively correlated. CONCLUSIONS: Both LVEDDN and serum PIIINP increase with increasing fibrosis score, although these relationships were not strong enough to be clinically useful. Although LVEDDN and PIIINP were positively correlated with fibrosis, PIIINP decreased with increasing LVEDDN, suggesting a complex interplay between fibrosis and remodeling in MMVD. PMID- 25292460 TI - Occurrence, sources, and potential toxicity of polycyclic aromatic hydrocarbons in surface soils from the Yellow River Delta Natural Reserve, China. AB - A total of 46 surface soil samples collected from the experimental area, buffer area, and core area of the Yellow River Delta Natural Reserve (YRDNR), China, and an adjacent area outside the reserve were analyzed for 23 PAHs including highly carcinogenic dibenzopyrene isomers. The total concentrations ranged from 87.2 to 319 ng/g for ?23PAHs and 79.2 to 311 ng/g for ?16PAHs with average concentrations of 133 and 119 ng/g, respectively. Pearson correlation analysis implied that the total polycyclic aromatic compound (PAH) concentrations had a significant positive correlation with the total organic carbon content on the condition that four sites with abnormal values were removed. Low molecular-weight 2- to 3-ring PAHs predominated in the present study. Source diagnostics based on PAHs isomer ratios, principal component analysis, and multiple linear regression suggested that petroleum contributed most to the PAH contamination in the YRDNR, whereas a potential toxicity assessment using BaPeq indicated that the four dibenzopyrenes were the major carcinogenic PAH contributors in the area under investigation, although their concentrations only represented a small proportion of the total PAH concentrations. PMID- 25292461 TI - Two-layer contractive encodings for learning stable nonlinear features. AB - Unsupervised learning of feature hierarchies is often a good strategy to initialize deep architectures for supervised learning. Most existing deep learning methods build these feature hierarchies layer by layer in a greedy fashion using either auto-encoders or restricted Boltzmann machines. Both yield encoders which compute linear projections of input followed by a smooth thresholding function. In this work, we demonstrate that these encoders fail to find stable features when the required computation is in the exclusive-or class. To overcome this limitation, we propose a two-layer encoder which is less restricted in the type of features it can learn. The proposed encoder is regularized by an extension of previous work on contractive regularization. This proposed two-layer contractive encoder potentially poses a more difficult optimization problem, and we further propose to linearly transform hidden neurons of the encoder to make learning easier. We demonstrate the advantages of the two layer encoders qualitatively on artificially constructed datasets as well as commonly used benchmark datasets. We also conduct experiments on a semi supervised learning task and show the benefits of the proposed two-layer encoders trained with the linear transformation of perceptrons. PMID- 25292463 TI - Erratum to: Reducing Recidivism and Symptoms in Emerging Adults with Serious Mental Health Conditions and Justice System Involvement. PMID- 25292462 TI - Transitioning Youth into Adult Mental Health and Addiction Services: An Outcomes Evaluation of the Youth Transition Project. AB - The Youth Transition Project was designed to provide youth with mental health and addiction issues with individualized transitional care plans as they transition from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS). Over an 18-month period, a total of 127 (59.1%) youth were transitioned and seen by an AMHS provider, 41 (19.1%) remained on a waitlist for services and 47 (21.8%) canceled services. The average time to transition was 110 days (SD = 100). Youth exhibited a wide range of diagnoses; 100% of the population was identified as having serious psychiatric problems. Findings demonstrate that the Youth Transition Project has been successful in promoting continuity of care by transitioning youth seamlessly from youth to adult services. Inconsistencies in wait times and service delivery suggest that further model development is needed to enhance the long-term sustainability of the Youth Transition Project. PMID- 25292464 TI - Editorial overview--New frontiers of biophysical methods: tools for structural biology and beyond. PMID- 25292465 TI - [Medical complications associated with bariatric surgery]. PMID- 25292466 TI - [Iron deficiency and pregnancy after gastric bypass surgery]. AB - In Denmark, the number of women in reproductive age having Roux-en-Y gastric bypass surgery increased in the period 2007-2010. The malabsorption related to the operation implies a predisposition to macro- and micronutrient deficiencies, which in pregnancy may influence the development of the foetus. The article concerns the need for managing the malabsorption syndrome, iron deficiency in particular, both in antenatal care, during pregnancy, delivery and in the lactation period. We suggest frequent follow-up in these patients and intravenous iron therapy, when oral iron treatment is inadequate. PMID- 25292467 TI - [Depression]. AB - The prevalence of depression is not clearly established, but estimated to 3-4% in a Danish questionnaire study. Lifetime's prevalences of 12-17% are reported in other community samples. In the current diagnostic system depression is defined categorically and operationally. It has been argued, that these diagnostic criteria represent an oversimplification, which has blurred the concept of depression. We suggest a greater emphasis on the depressed mood as the core symptom of depression, which may increase the specificity of the diagnosis. Furthermore, basic principles for the treatment of depression are presented. PMID- 25292468 TI - [Use of elastic compression stockings]. AB - Post-thrombotic syndrome (PTS) is caused by venous insufficiency and is a frequent complication of deep venous thrombosis. Patients with PTS have reduced quality of life and an increased risk of recurrent deep venous thrombosis. Importantly, the risk of PTS is halved by the use of elastic compression stockings. This review outlines important practical aspects related to correct clinical use of these stockings. PMID- 25292470 TI - [Quantitative cellular metabolism can be estimated by hyperpolarized magnetic resonance]. AB - A new MR methodology, hyperpolarized MR spectroscopy (MRS), enhances the MRS signals by more than a factor 10,000, enabling fast and unique insight into in situ metabolic processes. So far the method has provided new and exciting metabolic details in prostate, heart, brain, kidney and liver examinations. In diseases characterized by abnormal metabolic profiles, such as in diabetes and tumour tissue, hyperpolarized MRS provides highly detailed spatial information as well as quantitative estimates of individual steps in glycolysis and real-time amino acid metabolism. PMID- 25292469 TI - [Patient safety culture can be a driver for high clinical quality]. AB - More and more health care organisations strive for a cost-effective, safe quality of care. Some studies have found simultaneous improved safety culture and reduction of patient harm following improvement activities like patient safety walk around, team training or multifaceted intervention programmes. There is a lack of evidence concerning the relationship between improved patient safety culture and reduction of patient harm in a Danish health-care setting. Currently a Danish validation of the Safety Attitude Questionnaire and an intervention study to improve patient safety culture is ongoing. PMID- 25292471 TI - [Circulating tumour cells is a promising prognostic and predictive marker of gastric cancer]. AB - Despite chemotherapy and intended curative surgery, approximately 50% of patients with gastric cancer develop recurrence and eventually die of metastatic disease. The detection of circulating tumour cells (CTC) in peripheral blood is a promising prognostic and predictive marker. The most typically applied approaches to the detection of CTC are RT-PCR and immunological assays. Measurement of CTC in gastric cancer seems useful for predicting prognosis and monitoring response of chemotherapy. There is still no gold standard for CTC-detection in gastric cancer patients and larger studies are needed. PMID- 25292472 TI - [High complication rate after surgical treatment of ankle fractures]. AB - The purpose of this study was to determine the quality and re-operation rate of the surgical treatment of ankle fractures at a large university hospital. X-rays and patient records of 137 patients surgically treated for ankle fractures were analyzed for: 1) correct classification according to Lauge-Hansen, 2) if congruity of the ankle joint was achieved, 3) selection and placement of the hardware, and 4) the surgeon's level of education. Totally 32 of 137 did not receive an optimal treatment, 11 were re-operated. There was no clear correlation between incorrect operation and the surgeon's level of education. PMID- 25292473 TI - [Pseudoangiomatosis]. PMID- 25292474 TI - [Transmission and modulation of itch]. AB - Chronic itch is an annoying and disabling symptom that severely affects patients' quality of life in several dermatological as well as non-dermatological disorders. Chronic itch may be maintained and even aggravated by sensitization of peripheral and central neuronal structures. The possibilities to effectively relieve chronic itch are often limited and the need of more specific, effective and quick-acting treatment options is huge. This review summarizes the fundamental aspects of itch, the neuronal transmission and modulation of itch, and discusses new treatment opportunities. PMID- 25292475 TI - [Atraumatic pneumorrhachis in a young man with chest pain]. AB - A 22-year-old man experienced sudden chest pains after riding a mountain bike. The clinical examination showed subcutaneous emphysema on collum and a CAT-scan showed intraspinal air known as pneumorrhachis (PR). The treatment had to be based on the individual findings depending on the cause of PR and often needed a multidisciplinary effort. In this case the patient's condition improved and he was discharged after three days of observation without further treatment. PMID- 25292476 TI - [Stress fractures of the distal fibula in an osteoporotic woman]. AB - We report a case of an 81-year-old osteoporotic woman, who suffered stress fractures of the distal fibula on both sides within a two-year period. The risk factors for stress fractures are reviewed and the importance of a high index of suspicion for stress fractures is emphasized. When a stress fracture is suspected it should lead to plain radiography and treatment with protected weight-bearing with crutches or a brace. PMID- 25292477 TI - [Sumatriptan plus naproxen for acute migraine attacks in adults]. AB - It is of great importance to improve acute treatment of migraine attacks. Non steroidal anti-inflammatory drugs (NSAID) and triptans have different anti nociceptive effects, so a combination of these could theoretically lead to more effective acute migraine treatment. A recent meta-analysis investigated the combined effect of sumatriptan and naproxen and found it to be more effective than sumatriptan alone. However, the number needed to treat was high. Combined sumatriptan/naproxen should be reserved to those without efficient response to triptans. PMID- 25292478 TI - [Subglottic haemangioma]. AB - Subglottic haemangioma (SGH) is the rare condition of an infantile haemangioma in the subglottic space. The diagnostics is complicated due to the clinical symptoms mimicking pseudocroup, and difficulties in visualization of the subglottic space. A two-month-old girl with a cycle of repeated hospitalizations due to recurrent and progressive croupal cough and stridor was diagnosed with SGH by laryngoscopy and initiated propranolol treatment with effect after 48 hours. SGH is rare but should be kept in mind in infants with recurrent croupal cough and stridor. PMID- 25292479 TI - [Acute lower abdominal pain caused by adnexal torsion in a ten-year-old girl]. AB - A ten-year-old girl presented with four days of lower abdominal pain. A diagnostic laparoscopy on the suspicion of acute appendicitis revealed left-sided adnexal torsion. The cyanotic ovary was detorsed and recovered. At three-month follow-up there were no clinical or ultrasonic signs of pathology. The clinical presentation of adnexal torsion is unspecific and mimics several differential diagnosis. Adnexal torsion is a rare condition, especially in pre-pubertal girls. However, it must still be kept in mind when evaluating girls regardless of age with lower abdominal pain. PMID- 25292480 TI - [Dream Team--a pre-graduate surgical talent development project]. AB - In 2009 surgeons from Aarhus University Hospital founded an extracurricular talent development project based on a skill-acquisition training programme for medical students at Aarhus University. The training program, named Dream Team, provides medical students with the opportunity to pursue a career in surgery. This paper presents and discusses the organizational and pedagogical framework of the concept Dream Team, as well as the results from two inquiries: a survey and an exploratory observational study. The inquiries were conducted in summer 2013. PMID- 25292482 TI - IgA rheumatoid factor as a serological predictor of poor response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis. AB - AIM: The main objective of this study is to elucidate the role of immunoglobulin A (IgA) rheumatoid factor (RF) in predicting the clinical response to tumour necrosis factor alpha inhibitors (TNFi) among patients with rheumatoid arthritis (RA). METHOD: We recruited all patients with RA who were ever on TNFi for a minimum duration of 3 months at our centre. Based on the European League Against Rheumatism response criteria, subjects were further divided into responders and non-responders. Age-matched RA patients who were on conventional disease modifying anti-rheumatic drugs and in remission were enrolled as controls. Subjects were tested for quantitative values of IgA, IgM, IgG RF and anti citrulinated cyclic peptides (CCP). Further, all subjects were assessed for the disease activity score that includes 28 joints (DAS28) and Stanford Health Assessment Questionnaire (HAQ) 8-item Disability Index (HAQ-DI). RESULTS: A total of 31 subjects with RA who had received TNFi and 15 controls were enrolled in this study. There was a trend for the non-responders (n = 10) to have higher levels of all isotypes of RF and anti-CCP. However, only the IgA RF and anti-CCP levels were significantly higher in the non-responder group compared to the responders and controls (P = 0.001, P = 0.034, respectively). On multivariate analysis, only the IgA RF remained significant (OR 0.989; 95% CI 0.980-0.999; P = 0.026). CONCLUSION: IgA RF is potentially a novel predictor of response to TNFi in RA patients. Testing for pretreatment IgA RF levels could be a reasonable consideration before commencement of TNFi. PMID- 25292483 TI - Universal relations in the self-assembly of proteins and RNA. AB - Concepts rooted in physics are becoming increasingly important in biology as we transition to an era in which quantitative descriptions of all processes from molecular to cellular level are needed. In this perspective I discuss two unexpected findings of universal behavior, uncommon in biology, in the self assembly of proteins and RNA. These findings, which are surprising, reveal that physics ideas applied to biological problems, ranging from folding to gene expression to cellular movement and communication between cells, might lead to discovery of universal principles operating in adoptable living systems. PMID- 25292484 TI - Assessing margin expansions of internal target volumes in 3D and 4D PET: a phantom study. AB - BACKGROUND AND PURPOSE: To quantify tumor volume coverage and excess normal tissue coverage using margin expansions of mobile target internal target volumes (ITVs) in the lung. MATERIALS AND METHODS: FDG-PET list-mode data were acquired for four spheres ranging from 1 to 4 cm as they underwent 1D motion based on four patient breathing trajectories. Both ungated PET images and PET maximum intensity projections (PET-MIPs) were examined. Amplitude-based gating was performed on sequential list-mode files of varying signal-to-background ratios to generate PET MIPs. ITVs were first post-processed using either a Gaussian filter or a custom two-step module, and then segmented by applying a gradient-based watershed algorithm. Uniform and non-uniform 1 mm margins were added to segmented ITVs until complete target coverage was achieved. RESULTS: PET-MIPs required smaller uniform margins (4.7 vs. 11.3 mm) than ungated PET, with correspondingly smaller over-coverage volumes (OCVs). Non-uniform margins consistently resulted in smaller OCVs when compared to uniform margins. PET-MIPs and ungated PET had comparable OCVs with non-uniform margins, but PET-MIPs required smaller longitudinal margins (4.7 vs. 8.5 mm). Non-uniform margins were independent of sphere size. CONCLUSIONS: Gated PET-MIP images and non-uniform margins result in more accurate ITV delineation while reducing normal tissue coverage. PMID- 25293311 TI - Coordination frameworks assembled from Cu(II) ions and H2-1,3-bdpb ligands: X-ray and magneto structural investigations, and catalytic activity in the aerobic oxidation of tetralin. AB - The syntheses and crystal structures of H2-1,3-bdpb.MeOH, [Cu(II)2(1,3 bdpb)(OCH3)2] (CFA-5) and [Cu(I)Cl(H2-1,3-bdpb)] (H2-1,3-bdpb = 1,3-bis(3,5 dimethyl-1H-pyrazol-4-yl)benzene) are described. The copper(II) containing metal organic framework (termed Coordination Framework Augsburg University-5, CFA-5) crystallizes in the trigonal crystal system, within the space group R3 (no. 148) and the unit cell parameters are as follows: a = 26.839(3), c = 15.8317(16) A, V = 9876.2(19) A(3). CFA-5 features a two-fold interpenetrated 3-D microporous framework structure of cross-linked wheel-shaped {Cu(II)(pz)(OMe)}12 fundamental building units, each containing twelve copper(II) ions, MU2-bridging MeO(-) groups and pyrazolate (pz(-)) ligands. Replacing copper(II) acetate by copper(II) chloride in the synthesis leads to compound [Cu(I)Cl(H2-1,3-bdpb)], which crystallizes in the orthorhombic crystal system, within the space group Pnma (no. 62) and the unit cell parameters are as follows: a = 6.1784(8), b = 6.1784(8), c = 6.1784(8) A, V = 1583.8(4) A(3). In contrast to the former compound, CuCl(H2 1,3-bdpb) is a non-porous compound consisting of Cu(I)-Cl zigzag chains expanding in the direction [100] and H2-1,3-bdpb ligands. CFA-5 is characterized by elemental and thermogravimetric analyses, variable temperature powder X-ray diffraction and IR-spectroscopy; and its porosity and magnetic properties are described in detail. CFA-5 shows a promising catalytic activity in the heterogeneously catalyzed aerobic oxidation of tetralin, which is compared with other catalytically active metal-organic frameworks. PMID- 25292485 TI - Differential regulation patterns of the anti-CD20 antibodies obinutuzumab and rituximab in mantle cell lymphoma. PMID- 25292481 TI - Immune modulation by helminth parasites of ruminants: implications for vaccine development and host immune competence. AB - Parasitic helminths reside in immunologically-exposed extracellular locations within their hosts, yet they are capable of surviving for extended periods. To enable this survival, these parasites have developed complex and multifaceted mechanisms to subvert or suppress host immunity. This review summarises current knowledge of immune modulation by helminth parasites of ruminants and the parasite-derived molecules involved in driving this modulation. Such immunomodulatory molecules have considerable promise as vaccine targets, as neutralisation of their function is predicted to enhance anti-parasite immunity and, as such, current knowledge in this area is presented herein. Furthermore, we summarise current evidence that, as well as affecting parasite-specific immunity, immune modulation by these parasites may also affect the ability of ruminant hosts to control concurrent diseases or mount effective responses to vaccination. PMID- 25293312 TI - Overview of genetic analysis of human opioid receptors. AB - The human MU-opioid receptor gene (OPRM1), due to its genetic and structural variation, has been a target of interest in several pharmacogenetic studies. The MU-opioid receptor (MOR), encoded by OPRM1, contributes to regulate the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Genetic polymorphisms of opioid receptors are candidates for the variability of clinical opioid effects. The non synonymous polymorphism A118G of the OPRM1 has been repeatedly associated with the efficacy of opioid treatments for pain and various types of dependence. Genetic analysis of human opioid receptors has evidenced the presence of numerous polymorphisms either in exonic or in intronic sequences as well as the presence of synonymous coding variants that may have important effects on transcription, mRNA stability, and splicing, thus affecting gene function despite not directly disrupting any specific residue. Genotyping of opioid receptors is still in its infancy and a relevant progress in this field can be achieved by using advanced gene sequencing techniques described in this review that allow the researchers to obtain vast quantities of data on human genomes and transcriptomes in a brief period of time and with affordable costs. PMID- 25293313 TI - Computational structural biology of opioid receptors. AB - The publication of high-resolution structures for all of the opioid receptor subfamilies has unveiled exciting opportunities for mechanistic insight into the molecular mechanisms underlying the biology of nociception, reward, and higher cognitive functions, as well as promises for progress in several clinical areas such as pain management, physiological dependence, addiction, and mood disorders. To turn this promise into novel and improved therapeutic entities, however, this information needs to be supplemented with research strategies that explore the dynamic behavior of the proteins and their interactions with other receptors and ligands in their physiological environment.Here we describe state-of-the-art molecular dynamics computational protocols, based on all-atom and coarse-grained modeling techniques, designed to estimate crucial thermodynamic and kinetic parameters describing the binding of small-molecule ligands and the formation of supramolecular complexes. PMID- 25293314 TI - Analysis of epigenetic mechanisms regulating opioid receptor gene transcription. AB - Opioid drugs are generally used for moderate and severe pain reductions which act through opioid receptors. Studies on transcriptional regulation of opioid receptors are still invaluable because not only transcription is the first step to produce protein products in cells, but the receptor transcription levels also affect the pain reduction by opioids, as observed in studies of heterozygous opioid receptor knockout mice.There are growing evidences that epigenetic regulation has played significant roles in transcriptional regulation of genes, including opioid receptors. In general, epigenetic mechanisms include three main regulatory factors: DNA methylation, chromatin modification, and noncoding RNAs (such as microRNA). From previous studies of ours and others on opioid receptors, those epigenetic factors were clearly involved in regulating opioid receptor expression in vivo and in vitro. In this chapter, among those three techniques we describe more details of DNA methylation methods because of emerging concepts of DNA methylation with the recent discovery of 5-hydroxymethylcytosine converting enzyme, TET1. Another analytical method of the epigenetic factors, chromatin modification, will be described briefly and information of analyzing noncoding RNAs is briefly mentioned in Subheading 1. PMID- 25293315 TI - Renilla luciferase reporter assay to study 3'UTR-driven posttranscriptional regulations of OPRM1. AB - The regulation of MOR expression at the level of mRNA is relevant for its role in pain transmission and in other functions involving opioid receptors. Recently, the role of the 3'UTR in the posttranscriptional regulation of MOR expression has been highlighted. Here we describe a Renilla luciferase reporter assay for the study of the effect of any selective treatment on the 3'UTR-dependent regulation of OPRM1 in a model of glial cells. PMID- 25293316 TI - High-throughput gene expression profiling of opioid-induced alterations in discrete brain areas. AB - Whole-genome screening methods are unique approach to search for novel genes and molecular pathways involved in drug action. High-throughput profiling allows the gene expression levels of tens of thousands of transcripts to be measured simultaneously. Here, we describe transcriptional profiling in a specific area of the brain using DNA microarrays and next-generation sequencing. PMID- 25293317 TI - Real-time imaging of mu opioid receptors by total internal reflection fluorescence microscopy. AB - Receptor trafficking and signaling are intimately linked, especially in the Mu opioid receptor (MOR) where ligand-dependent endocytosis and recycling have been associated with opioid tolerance and dependence. Ligands of MOR can induce receptor endocytosis and recycling within minutes of exposure in heterologous systems and cultured neurons. Endocytosis removes desensitized receptors after their activation from the plasma membrane, while recycling promotes resensitization by delivering functional receptors to the cell surface. These rapid mechanisms can escape traditional analytical methods where only snapshots are obtained from highly dynamic events.Total internal reflection fluorescence (TIRF) microscopy is a powerful tool that can be used to investigate, in real time, surface trafficking events at the single molecule level. The restricted excitation of fluorophores located at or near the plasma membrane in combination with high sensitivity quantitative cameras makes it possible to record and analyze individual endocytic and recycling event in real time. In this chapter, we describe a TIRF microscopy protocol to investigate in real time, the ligand dependent MOR trafficking in Human Embryonic Kidney 293 cells and dissociated striatal neuronal cultures. This approach can provide unique spatio-temporal resolution to understand the fundamental events controlling MOR trafficking at the plasma membrane. PMID- 25293319 TI - Monitoring opioid receptor dimerization in living cells by bioluminescence resonance energy transfer (BRET). AB - Bioluminescence resonance energy transfer (BRET) is a natural phenomenon that has been successfully applied for the study of protein-protein interactions, including opioid receptor oligomers. The discovery of opioid receptor homomers and heteromers has brought to the finding of new functions and new way of signaling and trafficking; therefore, opioid receptor oligomers may be considered as novel drug targets. Fusing receptors of interest with Renilla luciferase and with a fluorescent protein (such as EYFP), it is possible to study opioid receptor dimerization using BRET. PMID- 25293320 TI - Bioluminescence resonance energy transfer (BRET) to detect the interactions between kappa opioid receptor and non visual arrestins. AB - Bioluminescence resonance energy transfer (BRET) is a very sensitive technique employed to study protein-protein interactions, including G-protein-coupled receptors (GPCRs) hetero- and homo-dimerization. Recently, BRET has also been used to investigate the interaction between GPCRs (e.g., beta2 adrenergic receptor, muscarinic M2 receptor, dopaminergic D2 receptor) and non-visual arrestins. Here a BRET protocol is described to investigate interactions between the kappa opioid receptor (KOR) and non visual arrestins (arrestin-2 and arrestin 3) in HEK-293 cells, both under basal conditions and after exposure to KOR ligands. PMID- 25293318 TI - In vivo techniques to investigate the internalization profile of opioid receptors. AB - G-protein-coupled receptors (GPCRs) regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Receptor internalization is commonly observed following agonist binding and activation. Receptor trafficking events have been well characterized in cell systems, but the in vivo significance of GPCR internalization is still poorly understood. To address this issue, we have developed an innovative knock-in mouse model, where an opioid receptor is directly visible in vivo. These knockin mice express functional fluorescent delta opioid receptors (DOR-eGFP) in place of the endogenous receptor, and these receptors are expressed at physiological levels within their native environment. DOR-eGFP mice have proven to be an extraordinary tool in studying receptor neuroanatomy, real-time receptor trafficking in live neurons, and in vivo receptor internalization. We have used this animal model to determine the relationship between receptor trafficking in neurons and receptor function at a behavioral level. Here, we describe in detail the construction and characterization of this knockin mouse. We also outline how to use these mice to examine the behavioral consequences of agonist-specific trafficking at the delta opioid receptor. These techniques are potentially applicable to any GPCR, and highlight the powerful nature of this imaging tool. PMID- 25293321 TI - Identification and verification of proteins interacting with the kappa opioid receptor (KOPR). AB - Proteins that interact with the human kappa opioid receptor (hKOPR) may contribute to regulation and signaling of the receptor. In this paper, we focus on the protein 14-3-3zeta that regulates anterograde transport of the hKOPR from the endoplasmic reticulum (ER) to the Golgi apparatus. 14-3-3zeta interacts with the C-terminal domain of the receptor and promotes cell surface expression of the hKOPR by inhibiting coatomer protein I (COPI) and RVR motif-mediated ER retension of the hKOPR. Here we describe three experimental procedures we used to evaluate the interaction between hKOPR and 14-3-3zeta: co-immunoprecipitation, pull-down assay and immunofluorescence microscopy. PMID- 25293322 TI - Detection of mu opioid receptor (MOPR) and its glycosylation in rat and mouse brains by western blot with anti-MUC, an affinity-purified polyclonal anti-MOPR antibody. AB - Our experience demonstrates that it is difficult to identify MOPR in rat and mouse brains by western blot, in part due to low abundance of the receptor and a wide relative molecular mass (Mr) range of the receptor associated with its heterogeneous glycosylation states. Here, we describe generation and purification of anti-MUC (a rabbit polyclonal anti-MOPR antibody), characterization of its specificity in immunoblotting of HA-tagged MOPR expressed in a cell line, and ultimately, unequivocal detection of the MOPR in brain tissues by western blot with multiple rigorous controls. In particular, using brain tissues from MOPR knockout (K/O) mice as the negative controls allowed unambiguous identification of the MOPR band, since the anti-MOPR antibody, even after affinity purification, recognizes nonspecific protein bands. The MOPR was resolved as a faint, broad, and diffuse band with a wide Mr range of 58-84 kDa depending on brain regions and species. Upon deglycosylation to remove N-linked glycans by PNGase F (but not Endo H), the MOPR became a dense and sharp band with Mr of ~43 kDa, close to the theoretical Mr of its deduced amino acid sequences. Thus, MOPRs in rodent brains are differentially glycosylated by complex type of N-linked glycans in brain region- and species-specific manners. Furthermore, we characterized the MOPR in an A112G/N38D-MOPR knockin mouse model that possesses the equivalent substitution of the A118G/N40D SNP in the human MOPR gene. The substitution removes one of the four and five N-linked consensus glycosylation sites of the mouse and human MOPR, respectively. We demonstrated that the Mr of the MOPR in A112G mouse brains was lower than that in wild-type mouse brains, and that the difference was due to lower degrees of N-linked glycosylation. PMID- 25293323 TI - Immunohistochemical analysis of opioid receptors in peripheral tissues. AB - Immunohistochemical staining is widely used to identify opioid receptors in specific cell types or anatomical structures throughout the nervous system. Opioid receptors are not restricted to the central nervous system, but are also present in peripheral sensory neurons, where their activation exerts analgesic effects without inducing centrally mediated side effects. Here, we describe immunohistochemical analysis of opioid receptors in the peripheral sensory neuron cell bodies, along the axons and their peripheral endings in the hind paw skin, as well as in the spinal cord, under naive and sciatic nerve damage conditions in mice. Moreover, we consider the current debate on the specificity of antibodies. PMID- 25293324 TI - [(35)S]GTPgammaS autoradiography for studies of opioid receptor functionality. AB - The opioid receptors have been an interesting target for the drug industry for decades. These receptors were pharmacologically characterized in the 1970s and several drugs and peptides have emerged over the years. In 2012, the crystal structures were also demonstrated, with new data on the receptor sites, and thus new possibilities will appear. The role of opioids in the brain has attracted considerable interest in several diseases, especially pain and drug dependence. The opioid receptors are G-protein-coupled receptors (GPCR) that are Gi-coupled which make them suitable for studying the receptor functionality. The [(35)S]GTPgammaS autoradiography assay is a good option that has the benefit of generating both anatomical and functional data in the area of interest. It is based on the first step of the signaling mechanism of GPCRs. When a ligand binds to the receptor GTP will replace GDP on the alpha-subunit of the G protein, leading to a dissociation of the betagamma-subunit. These subunits will start a cascade of second messengers and subsequently a physiological response. PMID- 25293325 TI - Fluorescence-based, high-throughput assays for MU-opioid receptor activation using a membrane potential-sensitive dye. AB - The development of new and improved opioid analgesics requires high-throughput screening (HTS) methods to identify potential therapeutics from large libraries of lead compounds. Here we describe two simple, real-time fluorescence-based assays of MU-opioid receptor activation that may be scaled up for HTS. In AtT-20 cells expressing the MU-opioid receptor (MOPr), opioids activate endogenous G protein gated inwardly rectifying K channels (GIRK channels), leading to membrane hyperpolarization. In Chinese hamster ovary cells expressing MOPr, adenylyl cyclase activation via forskolin results in membrane hyperpolarization, which is inhibited by opioids. Changes in membrane potential can be measured using a proprietary membrane potential-sensitive dye. In contrast to many HTS methods currently available, these assays reflect naturalistic coupling of the receptor to effector molecules. PMID- 25293326 TI - Analysis of potassium and calcium imaging to assay the function of opioid receptors. AB - As the activation of opioid receptors leads to the modulation of potassium and calcium channels, the ion imaging represents an attractive method to analyze the function of the receptors. Here, we describe the imaging of potassium using the FluxORTM potassium ion channel assay, and of calcium using Fura-2 acetoxymethyl ester. Specifically, we (1) characterize the activation of the G-protein-coupled inwardly rectifying potassium 2 channel by agonists of MU- and delta-opioid receptors with the aid of the FluxORTM assay in cultured mouse dorsal root ganglion neurons, and (2) describe calcium imaging protocols to measure capsaicin induced transient receptor potential vanilloid 1 channel activity during opioid withdrawal in transfected human embryonic kidney 293 cells. PMID- 25293327 TI - Electrophysiological patch clamp assay to monitor the action of opioid receptors. AB - The patch clamp is a valuable electrophysiological technique, which allows the study of single or multiple ion channels in cells, and it is particularly useful in testing the excitable cells such as neurons. Activation of neuronal opioid receptors results in the modulation of various ion channels, which enables to examine the receptors' action with the patch clamp. In this chapter, we analyze the activation of the G-protein-coupled inwardly rectifying potassium channel 2 by opioids, and the capsaicin-induced transient receptor potential vanilloid 1 channel currents during opioid withdrawal, using the whole cell patch clamp in transfected human embryonic kidney 293 cells as well as in mouse and rat primary dorsal root ganglion neurons. PMID- 25293328 TI - Skin-nerve preparation to assay the function of opioid receptors in peripheral endings of sensory neurons. AB - This chapter describes the methodology of the in vitro skin-saphenous nerve preparation and its application to test for the modulatory effects of opioids on the function of cutaneous sensory neurons in experimental models of pain. We detail the skin-nerve setup requirements and the technique to record action potentials from single sensory fibers. We address how to test for inhibitory effects of opioid receptor activation on mechanical and thermal sensitivity of nociceptors and mechanoreceptors in the complete Freund's adjuvant-induced inflammation and the chronic constriction injury model of neuropathic pain. PMID- 25293329 TI - Mechanical nociception measurement in mice and rats with automated Von Frey equipment. AB - Von Frey hairs are important tools for the study of mechanisms of cutaneous stimulation-induced sensory input. Mechanical force is exerted via application of a particular hair to the cutaneous receptive field until buckling of the hair occurs. The most commonly used Von Frey filaments are productive in evaluating behavioral responses of neuropathic pain in preclinical and clinical research. To reduce the potential experimenter bias, automated instruments are being developed for behavioral assessment. PMID- 25293330 TI - Detecting zinc release induced by mu-opioid receptor agonists in brain slices. AB - After iron, zinc is the second most abundant transition metal in living organisms and it is known to be a contributory factor in a series of neurological disorders. In biological systems zinc exists as either bound Zn(2+), representing the majority of the total zinc in tissues, or free (chelatable) Zn(2+). Several fluorescents dyes have been developed to detect free zinc when it is released from zinc-binding proteins, which occurs via redox mechanisms in response to the stimulation of a number of neurotransmitter receptors, including the MU opioid receptor. Here we describe a detailed protocol to detect drug stimulated intracellular zinc release in rodent brain slices using time-lapse microscopy and fluorescence imaging. PMID- 25293331 TI - Opioid receptors: methods for detection and their modes of actions in the eye. AB - This study provides evidence for the presence of opioid-receptors in the retina, optic nerve, and optic nerve head astrocytes. These receptors were measured by more than one technique including Western blotting, immunohistochemistry, and functional assays such as scotopic electroretinogram (ERG) and Pattern ERG. I also have provided evidence in recently published work from my laboratory that opioid receptors, more specifically delta-opioid receptors, play crucial roles in retina neuroprotection against ischemic and glaucomatous injuries. This chapter provides detailed procedures to measure opioid receptor activation and their roles in retina neuroprotection using functional assays such as scotopic ERG and pattern ERG. PMID- 25293332 TI - Evaluation of murine macrophage cytokine production after in vivo morphine treatment. AB - The discovery of opioid receptors expression on immune cells has originated a large research activity on the possible modulation by opioid drugs of immune system responses. In the present chapter we describe an easy methodology useful to obtain information about the potential immunomodulatory activity of opioid drugs. An in vivo treatment schedule is used, and macrophages are studied for their ability to release different cytokines. PMID- 25293333 TI - Measurement of macrophage toll-like receptor 4 expression after morphine treatment. AB - The immune system is a complex and finely orchestrated system, and many soluble molecules and receptors contribute to its regulation.Recent studies have suggested that many of the modulatory effects induced by morphine on innate immunity, and in particular the effects on macrophage activation and function, can be due to the modulation of an important macrophage surface receptor, the toll-like receptor (TLR), that is primarily involved in early regulatory steps. In the present chapter we describe a Reverse transcription (RT)-real time PCR method for assessing TLR expression in macrophage after in vivo morphine treatment. PMID- 25293334 TI - The role of opioid receptors in migration and wound recovery in vitro in cultured human keratinocytes and fibroblasts. AB - We have previously described significant changes in skin differentiation and the delay in wound healing from delta-opioid receptor knockout mice. In addition, we have shown that opioid receptor ligands and their receptor systems affect wound healing in vitro and the migration pattern of human skin cells, such as keratinocytes and fibroblasts (Bigliardi-Qi et al., Differentiation 74:174-185, 2006; Bigliardi et al., Exp Dermatol 18:424-430, 2009; Bigliardi et al., J Recept Signal Transduct Res 22:191-199, 2002). This observation is true for both primary keratinocytes and fibroblasts derived from foreskin or normal human skin as well as for immortalized cell lines such as HaCaT cells. PMID- 25293335 TI - Role of opioid receptors in the reinstatement of opioid-seeking behavior: an overview. AB - Opioid abuse in humans is characterized by discontinuous periods of drug use and abstinence. With time, the probability of falling into renewed drug consumption becomes particularly high and constitutes a considerable problem in the management of heroin addicts. The major problem in the treatment of opioid dependence still remains the occurrence of relapse, to which stressful life events, renewed use of heroin, and exposure to drug-associated environmental cues are all positively correlated. To study the neurobiology of relapse, many research groups currently use the reinstatement animal model, which greatly contributed to disentangle the mechanisms underlying relapse to drug-seeking in laboratory animals. The use of this model is becoming increasingly popular worldwide, and new versions have been recently developed to better appreciate the differential contribution of each opioid receptor subtype to the relapse phenomenon. In this chapter we review the state of the art of our knowledge on the specific role of the opioid receptors as unrevealed by the reinstatement animal model of opioid-seeking behavior. PMID- 25293336 TI - Analysis of opioid-seeking reinstatement in the rat. AB - The inability to maintain drug abstinence is often referred to as relapse and consists of a process by which an abstaining individual slips back into old behavioral patterns and substance use. Animal models of relapse have been developed and validated over the last decades, and significantly contributed to shed light on the neurobiological mechanisms underlying vulnerability to relapse. The most common procedure to study drug-seeking and relapse-like behavior in animals is the "reinstatement model." Originally elaborated by Pavlov and Skinner, the concepts of reinforced operant responding and conditioned behavior were applied to addiction research not before 1971 (Stretch et al., Can J Physiol Pharmacol 49:581-589, 1971), and the first report of a reinstatement animal model as it is now used worldwide was published only 10 years later (De Wit and Stewart, Psychopharmacology 75:134-143, 1981). According to the proposed model, opioids are typically self-administered intravenously, as humans do, and although rodents are most often employed in these studies, this model has been used with a variety of species including nonhuman primates, dogs, cats, and pigeons. A variety of operant responses are available, depending on the species studied. For example, a lever press or a nose poke response typically is used for rodents, whereas a panel press response typically is used for nonhuman primates. Here, we describe a simple and easily reproducible protocol of heroin-seeking reinstatement in rats, which proved useful to study the neurobiological mechanisms underlying relapse to heroin and vulnerability factors enhancing the resumption of heroin-seeking behavior. PMID- 25293337 TI - Induction of a high alcohol consumption in rats and mice: role of opioid receptors. AB - Alcohol dependence continues to be an important health concern and animal models are critical to furthering our understanding of this complex disease. A hallmark feature of alcoholism is a significant increase in alcohol drinking over time. While several different animal models of excessive alcohol (ethanol) drinking exist for mice and rats, a growing number of laboratories are using a model that combines chronic ethanol exposure procedures with voluntary ethanol drinking with mice as experimental subjects. In the last years several experimental evidences have shown an involvement of opioid system in alcoholism. PMID- 25293338 TI - Evaluation of social and nonsocial behaviors mediated by opioids in mouse pups. AB - The experimental approach to carry out a behavioral study involving opioids in mouse pups needs equipments and procedures different from those used for adult animals. Pups are immature at birth and only slowly acquire all the potentialities that characterize adult con-specifics. The standard and abnormal development of behavioral systems and their neural correlates can be followed during the first postnatal weeks, using appropriate methodologies that exploit characteristic pups' capabilities. Behavioral tests designed for pups to evaluate the activity and involvement of the opioid system, according to the well-known role of the system in adult animals, are described in this chapter. PMID- 25293339 TI - The cellular homeostasis of the gut: what the Drosophila model points out. AB - The digestive tract is subjected to many aggressions throughout animal life. Since disruptions of gut physiology impact on animal fitness and survival, maintenance of gut integrity and functionality is essential for the individual. Over the last 40 years, research on rodents has aimed at understanding how cellular homeostasis of the digestive tract is maintained when challenged with disruptions. Following the discovery of stem cells in the digestive tract of Drosophila, a flurry of studies made an important contribution to our understanding of how the proliferation and the differentiation of these cells are controlled and participate in the renewal of the digestive tract. Insights into these mechanisms in Drosophila have revealed many similarities with mammalian intestinal stem cells. For instance, the highly conserved EGFR, JAK/STAT, Wingless/Wnt, Hedgehog, Integrins, BMP/TGFbeta, Hippo and Insulin pathways all participate in adult intestinal cellular homeostasis. Here, we provide a literature review of recent advances in the field highlighting the adult Drosophila midgut as a convenient model for dissecting mechanisms involved in the maintenance of the cellular homeostasis of the digestive tract in conventionally reared conditions. In addition, we shed light on recently published data putting Drosophila forward as a genetic tool to decipher the mechanisms underlying intestinal diseases and intestinal tumour progression. PMID- 25293340 TI - Childhood obesity and insulin resistance: how should it be managed? AB - OPINION STATEMENT: Concomitant with the rise in global pediatric obesity in the past decades, there has been a significant increase in the number of children and adolescents with clinical signs of insulin resistance. Given insulin resistance is the important link between obesity and the associated metabolic abnormalities and cardiovascular risk, clinicians should be aware of high risk groups and treatment options. As there is no universally accepted biochemical definition of insulin resistance in children and adolescents, identification and diagnosis of insulin resistance usually relies on clinical features such as acanthosis nigricans, polycystic ovary syndrome, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. Treatment for reducing insulin resistance and other obesity-associated comorbidities should focus on changes in health behaviors to achieve effective weight management. Lifestyle interventions incorporating dietary change, increased physical activity, and decreased sedentary behaviors, with the involvement of family and adoption of a developmentally appropriate approach, should be used as the first line treatment. Current evidence suggests that the primary objective of dietary interventions should be to reduce total energy intake and a combination of aerobic and resistance training should be encouraged. Metformin can be used in conjunction with a lifestyle intervention program in obese adolescents with clinical insulin resistance to achieve weight loss and to improve insulin sensitivity. Ongoing evaluation and research are required to explore optimal protocol and long-term effectiveness of lifestyle interventions, as well as to determine whether the improvements in insulin sensitivity induced by lifestyle interventions and weight loss will lead to a clinical benefit including reduced cardiovascular morbidity and mortality. PMID- 25293341 TI - Injuries in men's international ice hockey: a 7-year study of the International Ice Hockey Federation Adult World Championship Tournaments and Olympic Winter Games. AB - BACKGROUND: Information on ice hockey injuries at the international level is very limited. The aim of the study was to analyse the incidence, type, mechanism and severity of ice hockey injuries in men's international ice hockey tournaments. METHODS: All the injuries in men's International Ice Hockey Federation World Championship tournaments over a 7-year period were analysed using a strict definition of injury, standardised reporting strategies and an injury diagnosis made by a team physician. RESULTS: 528 injuries were recorded in games resulting in an injury rate of 14.2 per 1000 player-games (52.1/1000 player-game hours). Additionally, 27 injuries occurred during practice. For WC A-pool Tournaments and Olympic Winter Games (OWG) the injury rate was 16.3/1000 player-games (59.6/1000 player-game hours). Body checking, and stick and puck contact caused 60.7% of the injuries. The most common types of injuries were lacerations, sprains, contusions and fractures. A laceration was the most common facial injury and was typically caused by a stick. The knee was the most frequently injured part of the lower body and the shoulder was the most common site of an upper body injury. Arenas with flexible boards and glass reduced the risk of injury by 29% (IRR 0.71, (95% CI 0.56 to 0.91)). CONCLUSIONS: The incidence of injury during international ice hockey competition is relatively high. Arena characteristics, such as flexible boards and glass, appeared to reduce the risk of injury. PMID- 25293342 TI - The impact of psychological readiness to return to sport and recreational activities after anterior cruciate ligament reconstruction. AB - BACKGROUND: This cross-sectional study aimed to examine whether appraisal of knee function, psychological and demographic factors were related to returning to the preinjury sport and recreational activity following anterior cruciate ligament (ACL) reconstruction. METHOD: 164 participants completed a questionnaire battery at 1-7 years after primary ACL reconstruction. The battery included questionnaires evaluating knee self-efficacy, health locus of control, psychological readiness to return to sport and recreational activity, and fear of reinjury; and self-reported knee function in sport-specific tasks, knee-related quality of life and satisfaction with knee function. The primary outcome was returning to the preinjury sport or recreational activity. RESULTS: At follow-up, 40% (66/164) had returned to their preinjury activity. Those who returned had more positive psychological responses, reported better knee function in sport and recreational activities, perceived a higher knee-related quality of life and were more satisfied with their current knee function. The main reasons for not returning were not trusting the knee (28%), fear of a new injury (24%) and poor knee function (22%). Psychological readiness to return to sport and recreational activity, measured with the ACL-Return to Sport after Injury scale (was most strongly associated with returning to the preinjury activity). Age, sex and preinjury activity level were not related. CONCLUSIONS: Less than 50% returned to their preinjury sport or recreational activity after ACL reconstruction. Psychological readiness to return to sport and recreation was the factor most strongly associated with returning to the preinjury activity. Including interventions aimed at improving this in postoperative rehabilitation programmes could be warranted to improve the rate of return to sport and recreational activities. PMID- 25293343 TI - Primary tumor size predicts pathologic findings in the retroperitoneal lymph nodes in patients with paratesticular rhabdomyosarcoma. AB - To determine patient and tumor characteristics that could predict pathologic findings after retroperitoneal lymph node dissection (RPLND) in paratesticular rhabdomyosarcoma (PTRMS), a total of 266 cases of PTRMS diagnosed between 1973 and 2010 were identified from a national database. RPLND dissection was performed in 67 patients, with a mean age of 14.9 years and median survival of 80 months. PTRMS occurred more often on the right side, had embryonal histology, and had an average size of 6.7 cm. Retroperitoneal lymph node (RPLN) metastasis occurred in 40 % (n = 27) of patients. Tumor size and age were strong predictors of finding rhabdomyosarcoma in the retroperitoneal lymph nodes when examined by pathologists. Primary tumors larger than 7 cm in size developing in males 12 years or older had four times more odds of being associated with positive findings on pathologic examinations of the retroperitoneal lymph nodes. Patient race, histology, and tumor laterality were not significant predictors of PTRMS metastasis to the RPLN basin. Patients 12 years or older with PTRMS larger than 7 cm have a significant risk of retroperitoneal lymph nodes involvement with PTRMS. Detailed pathologic examination of the lymph nodes in these patients is recommended. PMID- 25293344 TI - Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus. AB - Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture. PMID- 25293345 TI - Systematic review on clinical outcomes following selection of human preimplantation embryos with time-lapse monitoring. PMID- 25293346 TI - Reply: Clinical outcomes following selection of human preimplantation embryos with time-lapse monitoring: a systematic review. PMID- 25293347 TI - Pathophysiology of the pancreas after oral infection of genetically diverse mice with coxsackievirus B4-E2. AB - Coxsackievirus B4 strain E2 (CVB4-E2) and its association with type 1 diabetes (T1D) have been studied in experimental in vitro and in vivo murine models. CVB4 E2, known to be pancreotropic and diabetogenic in nature, is associated with acute pancreatitis in mice but shows differences in the induction of glycemia after intraperitoneal (i.p.) infection. Therefore, the aim of this work was to study the outcome of oral infection with CVB4-E2 in five mouse strains with different genetic backgrounds: two outbred (Swiss albino, CD1), two inbred (SJL, NOD) and one transgenic (NOD.SCID). Survival rates, fasting blood glucose, histopathology, viral titres and persistence were studied in selected organs and stool samples. Viral protein (VP1), proinflammatory cytokines, and interferon alpha (IFN-alpha) were analyzed by immunohistochemistry. We observed mortality only in infected NOD and NOD.SCID mice, with differing survival rates implying initial innate protection in the NOD.SCID mice and low virus clearance with replicating virus titres in the studied organs and stool up to day 40 post infection (p.i.). Independent of the mouse strain hyperglycemia, proinflammatory cytokines and histopathological changes were absent in the endocrine pancreas of infected mice. Only the pancreata of the dead NOD.SCID mice showed inflammation even in presence of IFN-alpha. Host-dependent viral RNA persistence was observed in all outbred mice. In conclusion, oral infection with CVB4-E2, despite the known affinity of this strain towards the pancreatic tissue and the presence of replicating virus, conferred total protection to the endocrine pancreas in all mice and failed to induce the proinflammatory cytokines studied by us. PMID- 25293348 TI - Reporter mice express green fluorescent protein at initiation of meiosis in spermatocytes. AB - Transgenic mice were generated using a heat shock protein 2 (Hspa2) gene promoter to express green fluorescent protein (GFP) at the beginning of meiotic prophase I in spermatocytes. Expression was confirmed in four lines by in situ fluorescence, immunohistochemistry, western blotting, and PCR assays. The expression and distribution of the GFP and HSPA2 proteins co-localized in spermatocytes and spermatids in three lines, but GFP expression was variegated in one line (F46), being present in some clones of meiotic and post-meiotic germ cells and not in others. Fluorescence activated cell sorting (FACS) was used to isolate purified populations of spermatocytes and spermatids. Although bisulfite sequencing revealed differences in the DNA methylation patterns in the promoter regions of the transgene of the variegated expressing GFP line, a uniformly expressing GFP reporter line, and the Hspa2 gene, these differences did not correlate with variegated expression. The Hspa2-GFP reporter mice provide a novel tool for studies of meiosis by allowing detection of GFP in situ and in isolated spermatogenic cells. They will allow sorting of meiotic and post-meiotic germ cells for characterization of molecular features and correlation of expression of GFP with stage-specific spermatogenic cell proteins and developmental events. PMID- 25293349 TI - Association between the 8-item Morisky medication adherence scale (MMAS-8) score and glycaemic control among Chinese diabetes patients. AB - Adherence with oral hypoglycaemic agent is crucial to achieve optimal glycaemic control. The 8-item Morisky Medication Adherence Scale (MMAS-8) has been frequently used, yet the association between MMAS-8 score and glycaemic control among Chinese diabetes patients is largely unknown. Two general out-patient clinics were randomly selected in a district with socio-demographic characteristics representative of the entire Hong Kong population. A consecutive sample of adult type-2 diabetes patients currently taking oral hypoglycaemic agents was included. The glycaemic control was reflected by the level of hemoglobin A1c (HbA1c) taken within the previous 6 months. Factors associated with poor glycaemic control (HbA1c >= 7.0%) were evaluated by linear regression analysis. From 565 eligible Chinese patients with an average age of 63.2 years (SD 9.7) and male proportion of 46.5%, the average HbA1c was 7.1% (SD 1.1%), and 52.0% had poor glycaemic control. The proportion of poor medication adherence (MMAS-8 <= 6) was 32.2%. After controlling for socio-demographics, lifestyle, medication use, and health characteristics, the MMAS-8 score was correlated with better glycaemic control (beta -0.095; 95%CI -0.164 to -0.026, P = .007). The MMAS-8 score had a weak and negative correlation with HbA1c level. The instrument should be applied with caution when predicting glycaemic control in clinical practice. PMID- 25293350 TI - Pine (Pinus morrisonicola Hayata) needle extracts sensitize GBM8901 human glioblastoma cells to temozolomide by downregulating autophagy and O(6) methylguanine-DNA methyltransferase expression. AB - Pine needle extracts of Pinus morrisonicola (Hayata) are commonly used as a functional health beverage. However, it remains unclear what the mechanism is underlying the antitumor activity of pine needle extract. The aims of present study were to investigate the anti-glioblastoma effects of pine needle extracts as well as its bioactive compounds. From three different solvent extracts of pine needles, the water extract displayed the strongest cytotoxicity effects on GBM8901 glioblastoma cells. The isolated compounds were identified as pinocembrin, chrysin, and tiliroside. Chrysin was the most active ingredient of pine needle extract for the induction of apoptosis and suppression of migration and invasion. It also markedly inhibited temozolomide (TMZ)-induced autophagy and O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Because both autophagy and MGMT overexpression have been implicated to TMZ-induced drug resistance in glioblastoma, our results showed that pine needle extract and chrysin may serve as a potential anticancer agent against glioblastoma, especially with regard to sensitizing glioblastoma cells resistant to TMZ. PMID- 25293352 TI - Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms. AB - Our objective was to examine whether functional polymorphisms in hemochromatosis (HFE; H63D and C282Y), transferrin (TfC2), and glutathione-s-transferase Pi1 (GSTP1; Ile105Val) genes modify any lead-ALS association. We measured blood lead using atomic absorption spectroscopy and bone lead - a biomarker of cumulative lead exposure - using K-shell-X-ray fluorescence in 100 neurologist-confirmed ALS cases and 194 controls, the latter recruited as part of two separate studies; all subjects lived in New England. Participants were considered variant carriers or wild-type for each polymorphism. To assess effect modification, we included cross product terms between lead biomarkers and each polymorphism in separate adjusted polytomous logistic regression models. Compared with wild-type, the odds ratio (OR) per 15.6 MUg/g patella lead (interquartile range; IQR) was 8.24 (95% CI 0.94 72.19) times greater among C282Y variant carriers, and 0.34 (95% CI 0.15-0.78) times smaller among H63D variant carriers. Results were weaker for tibia lead. Compared with wild-type the OR per 2 MUg/dl blood lead (IQR) was 0.36 (95% CI 0.19-0.68) times smaller among H63D variant carriers, and 1.96 (95% CI 0.98-3.92) times greater among GSTP1 variant carriers. In conclusion, we found that HFE and GSTP1 genotypes modified the association between lead biomarkers and ALS. Contrasting modification by the HFE polymorphisms H63D and C282Y may suggest that the modification is not simply the result of increased iron. PMID- 25293351 TI - Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants. AB - Epigenetic regulation of imprinted genes is regarded as a highly plausible explanation for linking dietary exposures in early life with the onset of diseases during childhood and adulthood. We sought to test whether prenatal dietary supplementation with docosahexaenoic acid (DHA) during pregnancy may modulate epigenetic states at birth. This study was based on a randomized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg of DHA or a placebo from gestation week 18-22 to parturition. We applied quantitative profiling of DNA methylation states at IGF2 promoter 3 (IGF2 P3), IGF2 differentially methylated region (DMR), and H19 DMR in cord blood mononuclear cells of the DHA-supplemented group (n = 131) and the control group (n = 130). In stratified analyses, DNA methylation levels in IGF2 P3 were significantly higher in the DHA group than the control group in preterm infants (P = 0.04). We also observed a positive association between DNA methylation levels and maternal body mass index; IGF2 DMR methylation was higher in the DHA group than the control group in infants of overweight mothers (P = 0.03). In addition, at H19 DMR, methylation levels were significantly lower in the DHA group than the control group in infants of normal weight mothers (P = 0.01). Finally, methylation levels at IGF2/H19 imprinted regions were associated with maternal BMI. These findings suggest that epigenetic mechanisms may be modulated by DHA, with potential impacts on child growth and development. PMID- 25293353 TI - A tight-binding study of single-atom transistors. AB - A detailed theoretical study of the electronic and transport properties of a single atom transistor, where a single phosphorus atom is embedded within a single crystal transistor architecture, is presented. Using a recently reported deterministic single-atom transistor as a reference, the electronic structure of the device is represented atomistically with a tight-binding model, and the channel modulation is simulated self-consistently with a Thomas-Fermi method. The multi-scale modeling approach used allows confirmation of the charging energy of the one-electron donor charge state and explains how the electrostatic environments of the device electrodes affects the donor confinement potential and hence extent in gate voltage of the two-electron charge state. Importantly, whilst devices are relatively insensitive to dopant ordering in the highly doped leads, a ~1% variation of the charging energy is observed when a dopant is moved just one lattice spacing within the device. The multi-scale modeling method presented here lays a strong foundation for the understanding of single-atom device structures: essential for both classical and quantum information processing. PMID- 25293355 TI - Preoperative computed tomography-guided microcoil localization of small peripheral pulmonary nodules: a prospective randomized controlled trial. AB - OBJECTIVES: Growing, small, peripheral, pulmonary nodules in patients at high risk for lung cancer lead to requests for video-assisted thoracoscopic (VATS) resection for pathologic diagnosis. The purpose of this randomized controlled trial was to determine if preoperative localization using percutaneously placed computed tomography (CT)-guided platinum microcoils decreases the need for thoracotomy or VATS anatomic resection (segmentectomy/lobectomy) for diagnosis. METHODS: Patients with undiagnosed nodules of 15 mm or less were randomized to either no localization or preoperative microcoil localization. Coils were placed with the distal end deep to the nodule and the superficial end coiled on the visceral pleural surface with subsequent visualization by intraoperative fluoroscopy and VATS. Nodules were removed by VATS wedge excision using endostaplers. The primary outcome was a VATS wedge excision for pathologic diagnosis of the nodule without the need for either thoracotomy or VATS anatomic resection. RESULTS: Sixty patients were randomized and 56 underwent surgery between March 2010 and June 2012. Twenty-nine underwent microcoil localization and 27 did not. The baseline characteristics (age, sex, forced expiratory volume in the first second of expiration, nodule size/depth) were similar. The coil group had a higher rate of successful diagnosis with VATS wedge resection alone (27/29 vs 13/27; P < .001), decreased operative time to nodule excision (37 +/- 39 vs 100 +/- 67 minutes; P < .001), and reduced stapler firings (3.7 +/- 2.0 vs 5.9 +/- 31; P = .003) with no difference in total costs. Pathologic diagnoses included 14 benign nodules, 32 primary lung malignancies, and 10 metastases. There were no clinically significant complications related to the coil placement or wedge resection. CONCLUSIONS: Preoperative CT-guided microcoil localization decreases the need for thoracotomy or VATS anatomic resection for the diagnosis of small peripheral pulmonary nodules. PMID- 25293358 TI - Discussion. PMID- 25293357 TI - Uniform standards do not apply to readmission following coronary artery bypass surgery: a multi-institutional study. AB - OBJECTIVES: Reducing hospital readmissions is a national priority, with coronary artery bypass graft (CABG) surgery slated for upcoming reimbursement decisions. Clear understanding of the elements associated with readmissions is essential for developing a coherent prevention strategy. Patterns of readmission vary considerably based on diagnosis. We therefore sought to clarify the factors most clearly associated with 30-day readmission following CABG surgery in an academically affiliated community hospital network. METHODS: All patients undergoing isolated CABG in an 11-hospital network from 2007 to 2011 were entered into a Society of Thoracic Surgeons (STS) compliant registry that tracks hospital readmission within 30 days of surgery. Data were split at random into training and validation groups that were used to create and validate a logistic regression model of pre-, intra-, and postoperative factors associated with readmission. Subanalyses included development of logistic models predicting readmission for the 2 largest institutions individually, and relatedness of readmission to CABG procedure. RESULTS: The readmission rate for the entire 4861 patient group was 9.2% and varied between hospitals from 6.1% to 18.0%. Factors associated with readmission were moderate chronic obstructed pulmonary disease (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.04-3.14; P = .036), cerebrovascular disease (OR, 1.56; 95% CI, 1.09-2.24; P = .016), diabetes (OR, 1.44; 95% CI, 1.08-1.93; P = .014), congestive heart failure (OR, 2.12; 95% CI, 1.23-3.66; P = .007), intra aortic balloon pump (OR, 0.40; 95% CI, 0.19-0.83; P = .015), and use of blood products (OR, 1.76; 95% CI, 1.31-2.37; P = .0002). Although the c statistic for the training model (n = 2341) was 0.643, when applied to the validation dataset (n = 2520) the area under the receiver operating curve was reduced to 0.57. Separate analyses of factors for the 2 largest hospitals revealed marked differences, with only body mass index (OR, 1.08; 95% CI, 1.04-1.12; P = .0001) significantly associated with readmission at 1 hospital, and discharge to extended care (OR, 2.11; 95% CI, 1.02-4.33; P = .043) and renal failure (OR, 2.64; 95% CI, 1.21-5.76; P = .0149) significant at the other hospital. Most readmissions (60.8%) occurred within 10 days of discharge. Nearly one-third (31.3%) were categorized as unlikely to be CABG-related. The mean number of days from surgery to readmission was less for readmissions clearly related to CABG (15.5 +/- 6.4 days), compared with those unlikely to be CABG-related (17.4 +/- 7.0 days) (P = .05). CONCLUSIONS: Analysis of CABG readmission data from a network of community hospitals that vary in size and patient demographic characteristics suggests that there are many nonclinical factors influencing readmission; readmission rates and associated risk factors may vary considerably between centers; earlier readmissions are more likely to be procedure-related than patient-related; and therefore, considerable caution should be exercised in attempting to apply uniform standards or strategies to address post-CABG readmission. PMID- 25293359 TI - Humanitarian congenital heart surgery: template for success. PMID- 25293356 TI - Avoiding aortic clamping during coronary artery bypass grafting reduces postoperative stroke. AB - OBJECTIVE: The purpose of this study was to determine whether the incidence of postoperative stroke could be reduced by eliminating aortic clamping during coronary artery bypass grafting. METHODS: From 2002 to 2013, 12,079 patients underwent primary, isolated coronary artery bypass grafting at a single US academic institution. Aortic manipulation was completely avoided by using in situ internal thoracic arteries for inflow in 1552 patients (12.9%) (no-touch), a clampless facilitating device for proximal anastomoses in 1548 patients (12.8%), and aortic clamping in 8979 patients (74.3%). These strategies were assessed in a logistic regression model controlling for relevant variables. RESULTS: The overall incidence of postoperative stroke was 1.4% (n = 165), with an unadjusted incidence of 0.6% (n = 10) in the no-touch group, 1.2% (n = 18) in the clampless facilitating device group, and 1.5% (n = 137) in the clamp group (P < .01 for no touch vs clamp). The ratio of observed to expected stroke rate increased as the degree of aortic manipulation increased, from 0.48 in the no-touch group, to 0.61 in the clampless facilitating device group, and to 0.95 in the clamp group. Aortic clamping was independently associated with an increase in postoperative stroke compared with a no-touch technique (adjusted odds ratio, 2.50; P < .01). When separated by cardiopulmonary bypass use, both the off-pump partial clamp and the on-pump crossclamp techniques increased the risk of postoperative stroke compared with no-touch (adjusted odds ratio, 2.52, P < .01; and adjusted odds ratio, 4.25, P < .001, respectively). CONCLUSIONS: A no-aortic touch technique has the lowest risk for postoperative stroke for patients undergoing coronary artery bypass grafting. Clamping the aorta during coronary artery bypass grafting increases the risk of postoperative stroke, regardless of the severity of aortic disease. PMID- 25293360 TI - Process versus outcome: The sugar window. PMID- 25293361 TI - Selecting a separable parametric spatiotemporal covariance structure for longitudinal imaging data. AB - Longitudinal imaging studies allow great insight into how the structure and function of a subject's internal anatomy changes over time. Unfortunately, the analysis of longitudinal imaging data is complicated by inherent spatial and temporal correlation: the temporal from the repeated measures and the spatial from the outcomes of interest being observed at multiple points in a patient's body. We propose the use of a linear model with a separable parametric spatiotemporal error structure for the analysis of repeated imaging data. The model makes use of spatial (exponential, spherical, and Matern) and temporal (compound symmetric, autoregressive-1, Toeplitz, and unstructured) parametric correlation functions. A simulation study, inspired by a longitudinal cardiac imaging study on mitral regurgitation patients, compared different information criteria for selecting a particular separable parametric spatiotemporal correlation structure as well as the effects on types I and II error rates for inference on fixed effects when the specified model is incorrect. Information criteria were found to be highly accurate at choosing between separable parametric spatiotemporal correlation structures. Misspecification of the covariance structure was found to have the ability to inflate the type I error or have an overly conservative test size, which corresponded to decreased power. An example with clinical data is given illustrating how the covariance structure procedure can be performed in practice, as well as how covariance structure choice can change inferences about fixed effects. PMID- 25293362 TI - Clinical differences between Thai systemic sclerosis patients with positive versus negative anti-topoisomerase I. AB - BACKGROUND: Anti-topoisomerase I antibody (ATA) carries an increased risk of systemic sclerosis (SSc) internal organ involvement. There have been no published comparisons of the clinical characteristics of patients positive and negative for ATA in Thailand, where the positive rate for ATA is higher than among Caucasians. OBJECTIVE: To define the clinical differences between SSc, positive versus negative, for ATA. METHODS: A retrospective cohort study was performed among SSc patients over 18 at Srinagarind Hospital, Khon Kaen University, Thailand, during January 2006-December 2013. SSc-overlap syndrome was excluded. RESULTS: Two hundred and ninety-four SSc patients were included (female : male 2.5 : 1). The majority (68.6%) were the diffuse cutaneous SSc subset (dcSSc). ATA was positive in 252 patients (85.7%), among whom 71.7% had dcSSc and 28.2% limited cutaneous SSc (lcSSc). Using a multivariate analysis, hand deformity had a significantly positive association with ATA (odds ratio [OR] 7.01; 95% CI 1.02-48.69), whereas being anti-centromere (ACA) positive had a negative association (OR 0.17; 95% CI 0.03-0.92). After doing a subgroup analysis of the SSc subset, the median duration of disease at time of pulmonary fibrosis detection among ATA positive dcSSc was significantly shorter than the ATA negative group (1.05 vs. 6.77 years, P = 0.01). Raynaud's phenomenon (RP) at onset was significantly more frequent in lcSSc sufferers who were ATA negative than those who were ATA positive (90.5% vs. 56.9%, P = 0.005). CONCLUSIONS: A high prevalence of ATA positivity was found among Thai SSc patients and this was associated with a high frequency of hand deformity, ACA negativity, a short duration of pulmonary fibrosis in dcSSc and a lower frequency of RP in lcSSc. PMID- 25293364 TI - Differential lateralization of hippocampal connectivity reflects features of recent context and ongoing demands: an examination of immediate post-task activity. AB - Neuroimaging studies have shown that task demands affect connectivity patterns in the human brain not only during task performance but also during subsequent rest periods. Our goal was to determine whether ongoing connectivity patterns during rest contain information about both the current rest state, as well as the recently terminated task. Our experimental design consisted of two types of active tasks that were followed by two types of low-demand rest states. Using this design, we examined whether hippocampal functional connectivity during wakeful rest reflects both features of a recently terminated task and those of the current resting-state condition. We identified four types of networks: (i) one whose connectivity with the hippocampus was determined only by features of a recently terminated task, (ii) one whose connectivity was determined only by features of the current resting-state, (iii) one whose connectivity reflected aspects of both the recently terminated task and ongoing resting-state features, and (iv) one whose connectivity with the hippocampus was strong, but not affected by any external factor. The left and right hippocampi played distinct roles in these networks. These findings suggest that ongoing hippocampal connectivity networks mediate information integration across multiple temporal scales, with hippocampal laterality moderating these connectivity patterns. PMID- 25293363 TI - Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma. AB - High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 * 10(6) CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively. PMID- 25293365 TI - A zinc phthalocyanine based periodic mesoporous organosilica exhibiting charge transfer to fullerenes. AB - Periodic mesoporous organosilica (PMO) materials offer a strategy to position molecular semiconductors within a highly defined, porous network. We developed thin films of a new semiconducting zinc phthalocyanine-bridged PMO exhibiting a face-centered orthorhombic pore structure with an average pore diameter of 11 nm. The exceptional degree of order achieved with this PMO enabled us to create thin films consisting of a single porous domain throughout their entire thickness, thus providing maximal accessibility for subsequent incorporation of a complementary phase. The phthalocyanine building blocks inside the pore walls were found to be well-aggregated, enabling electronic conductivity and extending the light-harvesting capabilities to the near IR region. Ordered 3D heterojunctions capable of promoting photo-induced charge transfer were constructed by impregnation of the PMO with a fullerene derivative. When integrated into a photovoltaic device, the infiltrated PMO is capable of producing a high open-circuit voltage and a considerable photocurrent, which represents a significant step towards potential applications of PMOs in optoelectronics. PMID- 25293366 TI - Evidence for clonal expansion after antibiotic selection pressure: pneumococcal multilocus sequence types before and after mass azithromycin treatments. AB - BACKGROUND: A clinical trial of mass azithromycin distributions for trachoma created a convenient experiment to test the hypothesis that antibiotic use selects for clonal expansion of preexisting resistant bacterial strains. METHODS: Twelve communities in Ethiopia received mass azithromycin distributions every 3 months for 1 year. A random sample of 10 children aged 0-9 years from each community was monitored by means of nasopharyngeal swab sampling before mass azithromycin distribution and after 4 mass treatments. Swab specimens were tested for Streptococcus pneumoniae, and isolates underwent multilocus sequence typing. RESULTS: Of 82 pneumococcal isolates identified before treatment, 4 (5%) exhibited azithromycin resistance, representing 3 different sequence types (STs): 177, 6449, and 6494. The proportion of isolates that were classified as one of these 3 STs and were resistant to azithromycin increased after 4 mass azithromycin treatments (14 of 96 isolates [15%]; P = .04). Using a classification index, we found evidence for a relationship between ST and macrolide resistance after mass treatments (P < .0001). The diversity of STs-as calculated by the unbiased Simpson index-decreased significantly after mass azithromycin treatment (P = .045). CONCLUSIONS: Resistant clones present before mass azithromycin treatments increased in frequency after treatment, consistent with the theory that antibiotic selection pressure results in clonal expansion of existing resistant strains. PMID- 25293367 TI - Polymorphisms in HLA-DPB1 are associated with differences in rubella virus specific humoral immunity after vaccination. AB - Vaccination with live attenuated rubella virus induces a strong immune response in most individuals. However, small numbers of subjects never reach or maintain protective antibody levels, and there is a high degree of variability in immune response. We have previously described genetic polymorphisms in HLA and other candidate genes that are associated with interindividual differences in humoral immunity to rubella virus. To expand our previous work, we performed a genome wide association study (GWAS) to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus-specific neutralizing antibodies. We identified rs2064479 in the HLA-DPB1 genetic region as being significantly associated with humoral immune response variations after rubella vaccination (P = 8.62 * 10(-8)). All other significant SNPs in this GWAS were located near the HLA-DPB1 gene (P <= 1 * 10(-7)). These findings demonstrate that polymorphisms in HLA-DPB1 are strongly associated with interindividual differences in neutralizing antibody levels to rubella vaccination and represent a validation of our previous HLA work. PMID- 25293368 TI - AS03B-adjuvanted H5N1 influenza vaccine in children 6 months through 17 years of age: a phase 2/3 randomized, placebo-controlled, observer-blinded trial. AB - BACKGROUND: This phase 2/3, randomized, placebo-controlled, observer-blinded study assessed the immunogenicity, reactogenicity, and safety of an inactivated, split-virion H5N1 influenza vaccine (A/Indonesia/5/2005) in children aged 6 months through 17 years. METHODS: Children received 2 influenza vaccine doses 21 days apart, each containing 1.9 ug of hemagglutinin and AS03B adjuvant (5.93 mg of alpha-tocopherol). The randomization ratio was 8:3 for vaccine to placebo, with equal allocation between 3 age strata (6-35 months, 3-8 years, and 9-17 years). Immunogenicity against the vaccine strain was assessed 21 days after the first and second vaccine doses for all vaccinees, at day 182 for half, and at day 385 for the remaining half. Reactogenicity after each dose and safety up to 1 year after vaccination were evaluated. RESULTS: Within each age stratum, the lower limit of the 98.3% confidence interval for the day 42 seroprotection rate was >=70%, thus fulfilling the US and European licensure criteria. The immune responses elicited by vaccine persisted well above baseline levels for 1 year. The vaccine was more reactogenic than placebo, but no major safety concerns were identified. CONCLUSIONS: AS03B-adjuvanted H5N1 influenza vaccine was immunogenic and showed an acceptable safety profile in all age groups studied. Clinical Trials Registration: NCT01310413. PMID- 25293370 TI - Cube-like alpha-Fe2O3 supported on ordered multimodal porous carbon as high performance electrode material for supercapacitors. AB - Well-dispersed cube-like iron oxide (alpha-Fe2O3) nanoparticles (NPs) supported on ordered multimodal porous carbon (OMPC) are synthesized for the first time by a facile and efficient glycine-assisted hydrothermal route. The effect of OPMC support on growth and formation mechanism of the Fe2O3 NPs is discussed. OMPC as a supporting material plays a pivotal role of controlling the shape, size, and dispersion of the Fe2O3 NPs. As-synthesized alpha-Fe2O3/OMPC composites reveal significant improvement in the performance as electrode material for supercapacitors. Compared to the bare Fe2O3 and OMPC, the composite exhibits excellent cycling stability, rate capability, and enhanced specific capacitances of 294 F g(-1) at 1.5 A g(-1), which is twice that of OMPC (145 F g(-1)) and about four times higher than that of bare Fe2O3 (85 F g(-1)). The improved electrochemical performance of the composite can be attributed to the well defined structure, high conductivity, and hierarchical porosity of OMPC as well as the unique alpha-Fe2O3 NPs with cube-like morphology well-anchored on the OMPC support, which makes the composite a promising candidate for supercapacitors. PMID- 25293369 TI - A comparison of seminal hepatitis C virus (HCV) RNA levels during recent and chronic HCV infection in HIV-infected and HIV-uninfected individuals. AB - BACKGROUND: We aimed to characterize seminal hepatitis C virus (HCV) RNA dynamics in human immunodeficiency virus (HIV)-positive men with acute HCV infection given its potential role in sexual transmission of HCV. METHODS: Men with acute HCV infection (duration, <=12 months) or chronic HCV infection (duration, >12 months) were prospectively recruited. Paired semen and blood samples were assayed for HCV RNA levels. Results were analyzed using chi(2), Fisher exact, Mann-Whitney U, and Kruskal-Wallis tests. RESULTS: Eighteen men (27.3%) had acute HCV and HIV coinfection, 22 (33.3%) had chronic HCV infection and HIV coinfection, and 26 (39.4%) had chronic HCV monoinfection. HCV RNA was detected in semen specimens from 29 of 66 men (43.9%). The median HCV RNA level in blood was 4.0 log IU/mL higher than that in semen. HCV RNA levels were correlated in semen and blood (r(2) = 0.142). Neither HIV positivity nor acute HCV infection was associated with an increased frequency of seminal HCV RNA detection. Among men with acute HCV and HIV coinfection, the median HCV RNA level in blood specimens from those with seminal HCV RNA was higher than that in blood specimens from those without seminal HCV RNA (P = .001). Seminal HCV RNA was detected in >=1 sample for 26 of 35 men (74.3%) attending follow up. CONCLUSIONS: HCV RNA was detected in semen during both acute and chronic HCV infection. This was unaffected by HIV positivity or the phase of HCV infection. Elevated seminal HCV RNA levels could contribute to sexual transmission of HCV, but other factors, including high-risk behaviors, may be the main drivers for HCV transmission in HIV-infected individuals. PMID- 25293371 TI - Comparison of morphologic findings obtained by optical coherence tomography in acute coronary syndrome caused by vasospasm and chronic stable variant angina. AB - This study used optical coherence tomography (OCT) to evaluate morphologic changes in vasospastic lesions, which can cause acute coronary syndrome (ACS) or chronic stable VA. Thirty-nine patients (52.4 +/- 9.0 years, 33 males) with vasospasm-induced ACS who presented with chest pain and displayed transient ST segment elevation on electrocardiography were included in the ACS group. Forty one patients (49.3 +/- 7.7 years, 33 males) who presented with chronic stable variant angina were included in the VA group. The clinical characteristics and morphologic OCT results of the two groups were compared. There were no differences in baseline characteristics, including the proportions of hypertension, diabetes mellitus, and smoking, between the two groups. Intimal tear, erosion, and intra-luminal thrombi were more frequent in the ACS group than the VA group (P < 0.001, P < 0.001, and P = 0.006, respectively). High sensitivity C-reactive protein level was higher in the ACS group than the VA group (1.33 +/- 1.93 vs 0.48 +/- 0.50 mg/l, P = 0.011). Maximal intima thickness of spastic segment (0.38 +/- 0.06 vs 0.31 +/- 0.05 mm, P < 0.001) was significantly greater in the ACS group than in the VA group. In patients with vasospasm-induced ACS, intimal tear, intimal erosion, and microthrombi are major abnormal morphologic findings of OCT compared with patients with chronic stable VA. PMID- 25293372 TI - Coexistence of 3d-ferromagnetism and superconductivity in [(Li1-x Fex )OH](Fe1-y Liy )Se. AB - Superconducting [(Li1-x Fex )OH](Fe1-y Liy )Se (x~0.2, y~0.08) was synthesized by hydrothermal methods and characterized by single-crystal and powder X-ray diffraction. The structure contains alternating layers of anti-PbO type (Fe1-y Liy )Se and (Li1-x Fex )OH. Electrical resistivity and magnetic susceptibility measurements reveal superconductivity at 43 K. An anomaly in the diamagnetic shielding indicates ferromagnetic ordering near 10 K while superconductivity is retained. The ferromagnetism is from the iron atoms in the (Li1-x Fex )OH layer. Isothermal magnetization measurements confirm the superposition of ferromagnetic and superconducting hysteresis. The internal ferromagnetic field is larger than the lower, but smaller than the upper critical field of the superconductor. The formation of a spontaneous vortex phase where both orders coexist is supported by (57) Fe-Mossbauer spectra, (7) Li-NMR spectra, and MUSR experiments. PMID- 25293373 TI - Controlled synthesis, asymmetrical transport behavior and luminescence properties of lanthanide doped ZnO mushroom-like 3D hierarchical structures. AB - Lanthanide doped ZnO mushroom-like 3D hierarchical structures have been fabricated by polyol-mediated method and characterized by various microstructural and optical techniques. The results indicate that the as-prepared ZnO:Ln(3+) (Ln = Tb, Eu) samples have a hexagonal phase structure and possess a mushroom-like 3D hierarchical morphology. The length of the whole mushroom from stipe bottom to pileus top is about 1.0 MUm, and the diameters of pileus and stipe are about 0.8 MUm and 0.4 MUm, respectively. It is found that the flow of N2 is the key parameter for the formation of the novel ZnO structure and the addition of (NH4)2HPO4 has a prominent effect on the phase structure and the growth of mushroom-like morphology. The potential mechanism of forming this morphology is proposed. The pileus of the formed mushroom is assembled by several radial ZnO:Ln(3+) nanorods, whereas the stipe is composed of over layered ZnO:Ln(3+) nanosheets. Moreover, asymmetrical I-V characteristic curves of ZnO:Ln(3+) mushrooms indicate that the texture composition of the 3D hierarchical morphology might lead to the asymmetrical transport behavior of electrical conductivity. Lanthanide doped ZnO samples can exhibit red or green emission under the excitation of UV light. PMID- 25293374 TI - Emotional well-being of living kidney donors: findings from the RELIVE Study. AB - Following kidney donation, short-term quality of life outcomes compare favorably to US normative data but long-term effects on mood are not known. In the Renal and Lung Living Donors Evaluation Study (RELIVE), records from donations performed 1963-2005 were reviewed for depression and antidepressant use predonation. Postdonation, in a cross-sectional cohort design 2010-2012, donors completed the Patient Health Questionnaire (PHQ-9) depression screening instrument, the Life Orientation Test-Revised, 36-Item Short Form Health Survey and donation experience questions. Of 6909 eligible donors, 3470 were contacted and 2455 participated (71%). The percent with depressive symptoms (8%; PHQ-9>10) was similar to National Health and Nutrition Examination Survey participants (7%, p=0.30). Predonation psychiatric disorders were more common in unrelated than related donors (p=0.05). Postdonation predictors of depressive symptoms included nonwhite race OR=2.00, p=0.020), younger age at donation (OR=1.33 per 10 years, p=0.002), longer recovery time from donation (OR=1.74, p=0.0009), greater financial burden (OR=1.32, p=0.013) and feeling morally obligated to donate (OR=1.23, p=0.003). While cross-sectional prevalence of depression is comparable to population normative data, some factors identifiable around time of donation, including longer recovery, financial stressors, younger age and moral obligation to donate may identify donors more likely to develop future depression, providing an opportunity for intervention. PMID- 25293375 TI - Validation of the Edinburgh Postnatal Depression Scale (EPDS) for screening of major depressive episode among adults from the general population. AB - BACKGROUND: Standardized questionnaires designed for the identification of depression are useful for monitoring individual as well as population mental health. The Edinburgh Postnatal Depression Scale (EPDS) has originally been developed to assist primary care health professionals to detect postnatal depression, but several authors recommend its use outside of the postpartum period. In Brazil, the use of the EPDS for screening depression outside the postpartum period and among non-selected populations has not been validated. The present study aimed to assess the validity of the EPDS as a screening instrument for major depressive episode (MDE) among adults from the general population. METHODS: This is a validation study that used a population-based sampling technique to select the participants. The study was conducted in the city of Pelotas, Brazil. Households were randomly selected by two stage conglomerates with probability proportional to size. EPDS was administered to 447 adults (>=20 years). Approximately 17 days later, participants were reinterviewed by psychiatrics and psychologists using a structured diagnostic interview (Mini International Neuropsychiatric Interview, MINI). We calculated the sensitivity and specificity of each cutoff point of EPDS, and values were plotted as a receiver operator characteristic curve. RESULTS: The best cutoff point for screening depression was >=8, with 80.0% (64.4 - 90.9%) sensitivity and 87.0% (83.3 - 90.1%) specificity. Among women the best cutoff point was >=8 too with values of sensitivity and specificity of 84.4% (67.2 - 94.7%) and 81.3% (75.5 - 86.1%), respectively. Among men, the best cutoff point was >=7 (75% sensitivity and 89% specificity). CONCLUSIONS: The EPDS was shown to be suitable for screening MDE among adults in the community. PMID- 25293376 TI - Oxygen regulates human cytotrophoblast migration by controlling chemokine and receptor expression. AB - INTRODUCTION: Placental development involves the variation of oxygen supply due to vascular changes and cytotrophoblast invasion. Chemokines and their receptors play an important role during placental formation. Herein, the analysis of the chemokine/receptor pair CXCL12/CXCR4 and further chemokine receptors, such as CCR1, CCR7 and CXCR6 expression in human cytotrophoblasts was conducted. METHODS: Human cytotrophoblasts were examined directly after isolation or after incubation with different oxygen tensions and a chemical HIF-stimulator for 12 h with realtime PCR, immunoblot, immunohistochemistry. Conditioned media of placental villi, decidua, and endothelial cells was used for ELISA analysis of CXL12. Cytotrophoblast migration assays were conducted applying conditioned media of endothelial cells, a CXCL12 gradient, and different oxygen level. Endometrial and decidual tissue was stained for CXCL12 expression. RESULTS: An upregulation of CXCL12, CXCR4, CCR1, CCR7 and CXCR6 was observed after cytotrophoblast differentiation. Low oxygen supply upregulated CXCR4, CCR7 and CXCR6, but downregulated CXCL12 and CCR1. In contrast to the HIF associated upregulation of the aforementioned proteins, downregulation of CXCL12 and CCR1 seemed to be HIF independent. Cytotrophoblast migration was stimulated by low oxygen, the application of a CXCL12 gradient and endothelial cell conditioned media. CXCL12 was detected in endometrial vessels, glands and conditioned media of placental and decidual tissue, but not decidual vessels. DISCUSSION/CONCLUSION: Taken together, oxygen supply and cytotrophoblast differentiation seem to be regulators of chemokine and receptor expression and function in human cytotrophoblasts. Therefore, this system seems to be involved in placental development, directed cytotrophoblast migration in the decidual compartment and a subsequent sufficient supply of the growing fetus. PMID- 25293377 TI - N-linked glycosylation of AtVSR1 is important for vacuolar protein sorting in Arabidopsis. AB - Vacuolar sorting receptors (VSRs) in Arabidopsis mediate the sorting of soluble proteins to vacuoles in the secretory pathway. The VSRs are post-translationally modified by the attachment of N-glycans, but the functional significance of such a modification remains unknown. Here we have studied the role(s) of glycosylation in the stability, trafficking and vacuolar protein transport of AtVSR1 in Arabidopsis protoplasts. AtVSR1 harbors three complex-type N-glycans, which are located in the N-terminal 'PA domain', the central region and the C-terminal epidermal growth factor repeat domain, respectively. We have demonstrated that: (i) the N-glycans do not affect the targeting of AtVSR1 to pre-vacuolar compartments (PVCs) and its vacuolar degradation; and (ii) N-glycosylation alters the binding affinity of AtVSR1 to cargo proteins and affects the transport of cargo into the vacuole. Hence, N-glycosylation of AtVSR1 plays a critical role in its function as a VSR in plants. PMID- 25293378 TI - Human enteric neurons: morphological, electrophysiological, and neurochemical identification. AB - BACKGROUND: Access to tissue, difficulties with dissection, and poor visibility of enteric ganglia have hampered electrophysiological recordings of human enteric neurons. Here, we report a method to combine intracellular recording with simultaneous morphological identification of neurons in the intact myenteric plexus of human colon ex vivo. METHODS: Specimens of human colon were dissected into flat-sheet preparations with the myenteric plexus exposed. Myenteric neurons were impaled with conventional microelectrodes containing 5% 5,6 carboxyfluorescein in 20 mM Tris buffer and 1 M KCl. KEY RESULTS: Electrophysiological recordings identified myenteric neurons with S and AH type properties (n = 13, N = 7) which were dye filled and classified during the recording as Dogiel type I (n = 10), Dogiel type II (n = 2), or filamentous (n = 1) cells. This classification was confirmed after fixation, in combination with immunohistochemical characterization. CONCLUSIONS & INFERENCES: This method allows electrophysiological characterization with simultaneous identification of morphology. It can be used to identify recorded cells immediately after impalement and greatly facilitates recordings of human myenteric neurons in freshly dissected specimens of tissue. It can also be combined with immunohistochemical labeling of recorded cells. PMID- 25293380 TI - The nearest relative and s 3 of the Mental Health Act 1983 again. AB - The nearest relatives of mental patients play an important role. They refer them informally or formally (by making an application for their admission) to hospital; they are consulted about applications for admission for treatment under s 3 of the Mental Health Act (made by Approved Mental Health Professionals); they can order, subject to a medical veto, the discharge of some compulsorily detained patients; they make applications to the Mental Health Review Tribunal, etc. However, choosing which is the nearest relative for this purpose is not open to even a competent mental patient but has to be selected from a prescribed list under s 26 of the Mental Health Act 1983 though a patient can initiate proceedings to displace their statutory "nearest relative". This has resulted in court cases, most recently JT v United Kingdom [2000] 1 FLR 909. Further, when an application for treatment under s 3 of the Mental Health Act 1983 is made by an Approved Mental Health Professional, s 11(4) of the Act requires that applicant, first, to consult with the patient's nearest relative. This issue arose in TW v Enfield LBC [2014] EWCA Civ. 362. This paper considers and comments on these and other issues and identifies two unsatisfactory features of the law and makes recommendations for reform. PMID- 25293379 TI - Functional phylogenomics analysis of bacteria and archaea using consistent genome annotation with UniFam. AB - BACKGROUND: Phylogenetic studies have provided detailed knowledge on the evolutionary mechanisms of genes and species in Bacteria and Archaea. However, the evolution of cellular functions, represented by metabolic pathways and biological processes, has not been systematically characterized. Many clades in the prokaryotic tree of life have now been covered by sequenced genomes in GenBank. This enables a large-scale functional phylogenomics study of many computationally inferred cellular functions across all sequenced prokaryotes. RESULTS: A total of 14,727 GenBank prokaryotic genomes were re-annotated using a new protein family database, UniFam, to obtain consistent functional annotations for accurate comparison. The functional profile of a genome was represented by the biological process Gene Ontology (GO) terms in its annotation. The GO term enrichment analysis differentiated the functional profiles between selected archaeal taxa. 706 prokaryotic metabolic pathways were inferred from these genomes using Pathway Tools and MetaCyc. The consistency between the distribution of metabolic pathways in the genomes and the phylogenetic tree of the genomes was measured using parsimony scores and retention indices. The ancestral functional profiles at the internal nodes of the phylogenetic tree were reconstructed to track the gains and losses of metabolic pathways in evolutionary history. CONCLUSIONS: Our functional phylogenomics analysis shows divergent functional profiles of taxa and clades. Such function-phylogeny correlation stems from a set of clade-specific cellular functions with low parsimony scores. On the other hand, many cellular functions are sparsely dispersed across many clades with high parsimony scores. These different types of cellular functions have distinct evolutionary patterns reconstructed from the prokaryotic tree. PMID- 25293381 TI - Optimising treatment distance and treatment area for HDR surface mould brachytherapy. AB - The purpose of this study was to quantify the effect of treatment area and treatment distance on dose distributions for geometrically optimised surface mould plans in order to provide guidance in choosing treatment parameters and constructing moulds for individual patients. Geometrically optimised plans were generated with a typical brachytherapy planning system and measurements were taken with radiochromic film over depths of 5-32 mm with an (192)Ir high dose rate source. Films were calibrated with a cylindrical geometry technique utilising the (192)Ir source and readout was performed with a flatbed scanner. The rate of dose fall-off about the prescription plane, as well as the magnitude and extent of local dose maxima superficial to the prescription plane, increased with decreasing treatment areas when inter-catheter spacing and treatment distance were kept constant. The dose fall-off was highly dependent on treatment distance, with a 16 % reduction in dose 4 mm superficial to the treatment depth occurring when the distance was increased from 10 to 20 mm while maintaining a 10 mm inter-catheter spacing. The table generated using the measured planar geometry data, can be used as an initial guide for mould construction and planning. The properties of high dose regions near to the catheter plane are highly dependent on the treatment area, which must be considered when normal tissue dose tolerances are a concern. Treatment distance is a key variable influencing the overall dose distribution and should be adjusted as a function of the desired tumour to skin dose ratio, controlled by mould thickness. PMID- 25293383 TI - Examination of the relation between an assessment of skills and performance on auditory-visual conditional discriminations for children with autism spectrum disorder. AB - The current investigation evaluated repertoires that may be related to performance on auditory-to-visual conditional discrimination training with 9 students who had been diagnosed with autism spectrum disorder. The skills included in the assessment were matching, imitation, scanning, an auditory discrimination, and a visual discrimination. The results of the skills assessment showed that 4 participants failed to demonstrate mastery of at least 1 of the skills. We compared the outcomes of the assessment to the results of auditory visual conditional discrimination training and found that training outcomes were related to the assessment outcomes for 7 of the 9 participants. One participant who did not demonstrate mastery of all assessment skills subsequently learned several conditional discriminations when blocked training trials were conducted. Another participant who did not demonstrate mastery of the auditory discrimination skill subsequently acquired conditional discriminations in 1 of the training conditions. We discuss the implications of the assessment for practice and suggest additional areas of research on this topic. PMID- 25293382 TI - The mediation of social influences on smoking cessation and awareness of the early signs of lung cancer. AB - BACKGROUND: Whilst there has been no clear consensus on the potential for earlier diagnosis of lung cancer, recent research has suggested that the time between symptom onset and consultation can be long enough to plausibly affect prognosis. In this article, we present findings from a qualitative study involving in-depth interviews with patients who had been diagnosed with lung cancer (n = 11), and people who were at heightened risk of developing the disease (n = 14). METHODS: A grounded theory methodology was drawn upon to conduct thematic and narrative based approaches to analysis. RESULTS: The paper focuses on three main themes which emerged from the study: i) fatalism and resignation in pathways to help seeking and the process of diagnosis; ii) Awareness of smoking risk and response to cessation information and advice. iii) The role of social and other networks on help-seeking. Key findings included: poor awareness among participants of the symptoms of lung cancer; ambivalence about the dangers of smoking; the perception of lung cancer as part of a homogenisation of multiple illnesses; close social networks as a key trigger in help-seeking. CONCLUSIONS: We suggest that future smoking cessation and lung cancer awareness campaigns could usefully capitalise on the influence of close social networks, and would benefit from taking a 'softer' approach. PMID- 25293384 TI - A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record. AB - OBJECTIVE: Recently, the European Medicines Agency reported that strontium ranelate increases myocardial infarction risk in postmenopausal women, 8.5 years after it was registered for use in osteoporosis. Unreported serious adverse events in clinical trials for other pharmaceuticals have been described in recent years. We assessed reporting of adverse events and fracture efficacy of strontium. METHODS: We compared data on adverse effects (myocardial infarction, venous thromboembolism and pulmonary embolism) and fracture efficacy of strontium in publicly available regulatory documents with data in publications retrieved from searching PubMed. RESULTS: We identified 5 regulatory documents and 9 primary publications of 7 randomised, placebo-controlled trials of strontium that reported relevant data. We identified several areas of concern in these reports: the increased risk of myocardial infarction with strontium was not identified in a pivotal phase 3 clinical trial despite specific regulatory review of cardiovascular events; data on myocardial infarction were not included in any primary publication; increased risks of venous thromboembolism and pulmonary embolism with strontium were not reported in either of the phase 3 clinical trials; data on venous thromboembolism were reported in only 5 of 9 primary publications, data on pulmonary embolism in only 2 of 9 primary publications, and either was discussed in <50% of subsequent review articles. There were differences in participant numbers, fracture cases and venous thromboembolism cases between regulatory documents and primary publications. Based on all available data from primary publications and regulatory documents, the number of fractures prevented by strontium use is similar to the number of extra cases of venous thromboembolism, pulmonary embolism and myocardial infarction caused by strontium use. CONCLUSIONS: The risks of strontium use are similar to the benefits. Full disclosure of the clinical trial data and regulatory documents would allow clinicians and their patients to decide whether use of the drug is worthwhile. PMID- 25293385 TI - An investigation into the role of alcohol in self-harm in rural Sri Lanka: a protocol for a multimethod, qualitative study. AB - INTRODUCTION: Sri Lanka has one of the highest suicide and self-harm rates in the world and although alcohol has been found to be a risk factor for self-harm in Sri Lanka, we know little about the connection between the two. This paper comprises a protocol for a qualitative study investigating alcohol's role in self harm in rural Sri Lanka at three levels: the individual, community and policy level. The analysis will bring new understanding of the link between alcohol and self-harm in Sri Lanka, drawing on structural, cultural and social concepts. It will equip researchers, health systems and policy makers with vital information for developing strategies to address alcohol-related problems as they relate to self-harm. METHODS AND ANALYSIS: To capture the complexity of the link between alcohol and self-harm in the Anuradhapura district in the North Central Province in Sri Lanka, qualitative methods will be utilised. Specifically, the data will consist of serial narrative life-story interviews with up to 20 individuals who have non-fatally self-harmed and where alcohol directly or indirectly was involved in the incidence as well as with their significant others; observations in communities and families; six focus group discussions with community members; and key-informant interviews with 15-25 stakeholders who have a stake in alcohol distribution, marketing, policies, prevention and treatment as they relate to self-harm. ETHICS AND DISSEMINATION: The study has received ethical approval from the Ethical Review Committee of the Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka. A sensitive data collection technique will be used and ethical issues will be considered throughout the study. RESULTS: The results will be disseminated in scientific peer-reviewed articles in collaboration with Sri Lankan and other international research partners. PMID- 25293387 TI - Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping of blood pressure during night time: protocol for a randomised, placebo-controlled, double-blind, two-way crossover study. AB - INTRODUCTION: Cardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes. MATERIALS AND METHODS: In a randomised, double blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass. ETHICS AND DISSEMINATION: The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT (2012- 002136-90). PMID- 25293389 TI - Correlation between the levels of non-specific physical symptoms and pressure pain thresholds measured by algometry in patients with temporomandibular disorders. AB - Recent studies showed that patients with chronic TMD pain also feature increased sensitivity in other craniofacial regions, and even in remote peripheral areas, suggesting that nociceptive processing is centrally facilitated in this patient population. The aim of this study was to investigate the existence of a negative correlation between the levels of non-specific physical symptoms and pressure pain thresholds measured by algometry at sites distant from the chief complaint of oro-facial pain in patients with TMD. A total of 20 female patients were evaluated comprising 11 patients diagnosed with myofascial pain (Group I of RDC/TMD) and 9 patients with arthralgia (Group III of RDC/TMD), with both reporting chronic TMD pain for at least 3 months. Patients were tested by the pressure algometry technique, and, in the same visit, clinical diagnosis and levels of non-specific physical symptoms, including pain-related issues or not, were obtained. The raw scores were then standardised into a T-score. The possible correlation between the dependent variable levels of non-specific physical symptoms and pressure pain thresholds measured by algometry at sites distant from the chief complaint of oro-facial pain was assessed with Spearman's correlation coefficient. Results were considered statistically significant, which stood a lower than 5% probability of occurring by chance (P < 0.05). A statistically significant (P = 0.02) negative correlation (-0.51) was found to exist between the levels of non-specific physical symptoms, only if including issues involving pain-related symptoms, and experimental pressure pain thresholds in patients with painful TMD. PMID- 25293388 TI - Echium oil is not protective against weight loss in head and neck cancer patients undergoing curative radio(chemo)therapy: a randomised-controlled trial. AB - BACKGROUND: Therapy-induced mucositis and dysphagia puts head and neck (H&N) cancer patients at increased risk for developing cachexia. Omega-3 fatty acids (n 3 FA) have been suggested to protect against cachexia. We aimed to examine if echium oil, a plant source of n-3 FA, could reduce weight loss in H&N cancer patients undergoing radio(chemo)therapy with curative intent. METHODS: In a double-blind trial, patients were randomly assigned to echium oil (intervention (I) group; 7.5 ml bis in die (b.i.d.), 235 mg/ml alpha-linolenic acid (ALA) + 95 mg/ml stearidonic acid (SDA) + 79 mg/ml gamma-linolenic acid (GLA)) or n-3 FA deficient sunflower oil high oleic (control (C) group; 7.5 ml b.i.d.) additional to standard nutritional support during treatment. Differences in percentage weight loss between both groups were analysed according to the intention-to-treat principle. Erythrocyte FA profile, body composition, nutritional status and quality of life were collected. RESULTS: Ninety-one eligible patients were randomised, of whom 83 were evaluable. Dietary supplement adherence was comparable in both groups (median, I: 87%, C: 81%). At week 4, the I group showed significantly increased values of erythrocyte n-3 eicosapentanoic acid (EPA, 14% vs -5%) and n-6 GLA (42% vs -20%) compared to the C group, without a significant change in n-6 arachidonic acid (AA, 2% vs -1%). Intention-to-treat analysis could not reveal a significant reduction in weight loss related to echium oil consumption (median weight loss, I: 8.9%, C: 7.6%). Also, no significant improvement was observed in the other evaluated anthropometric parameters. CONCLUSIONS: Echium oil effectively increased erythrocyte EPA and GLA FAs in H&N cancer patients. It failed however to protect against weight loss, or improve nutritional parameters. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01596933. PMID- 25293390 TI - Efficient generation of knock-in transgenic zebrafish carrying reporter/driver genes by CRISPR/Cas9-mediated genome engineering. AB - The type II bacterial CRISPR/Cas9 system is rapidly becoming popular for genome engineering due to its simplicity, flexibility, and high efficiency. Recently, targeted knock-in of a long DNA fragment via homology-independent DNA repair has been achieved in zebrafish using CRISPR/Cas9 system. This raised the possibility that knock-in transgenic zebrafish could be efficiently generated using CRISPR/Cas9. However, how widely this method can be applied for the targeting integration of foreign genes into endogenous genomic loci is unclear. Here, we report efficient generation of knock-in transgenic zebrafish that have cell-type specific Gal4 or reporter gene expression. A donor plasmid containing a heat shock promoter was co-injected with a short guide RNA (sgRNA) targeted for genome digestion, a sgRNA targeted for donor plasmid digestion, and Cas9 mRNA. We have succeeded in establishing stable knock-in transgenic fish with several different constructs for 4 genetic loci at a frequency being exceeding 25%. Due to its simplicity, design flexibility, and high efficiency, we propose that CRISPR/Cas9 mediated knock-in will become a standard method for the generation transgenic zebrafish. PMID- 25293391 TI - Molecules in motion: chemical reaction and allied dynamics in solution and elsewhere. AB - After my acceptance of the kind invitation from Todd Martinez and Mark Johnson, Co-Editors of this journal, to write this article, I had to decide just how to actually do this, given the existence of a fairly personal and extended autobiographical account of recent vintage detailing my youth, education, and assorted experiences and activities at the University of Colorado, Boulder, and later also at Ecole Normale Superieure in Paris ( 1 ). In the end, I settled on a differently styled recounting of the adventures with my students, postdocs, collaborators, and colleagues in trying to unravel, comprehend, describe, and occasionally even predict the manifestations and consequences of the myriad assortment of molecular dances that contribute to and govern the rates and mechanisms of chemical reactions in solution (and elsewhere). The result follows. PMID- 25293386 TI - Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium. AB - OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged >=16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety. PMID- 25293392 TI - Assessment of fluoride intake through food chain and mapping of endemic areas of Gaya district, Bihar, India. AB - Accumulation of Fluoride (F) was found in the soil and vegetation of the F endemic villages of Gaya district, Bihar, India. The mean F level in the groundwater of F non-endemic (control) area was 0.59 +/- 0.03 (n = 11), while that of F-endemic area was 2.36 +/- 0.23 (n = 27). Water soluble F (WSF) and total F (TF) in the soil of F-endemic villages were significantly higher as compared to the F non-endemic area. Similarly, WSF and TF in the vegetables and the grain crops (cereals, legumes and oilseeds) of the F-endemic area were significantly higher as compared that of the control area. Leafy vegetables showed higher accumulation of F with WSF and TF in spinach ranging from 3.62 to 4.82 and 9.88-12.88 mg/kg respectively. The WSF and TF in coriander ranged from 9.66 to 10.88 and 23.11-25.73 mg/kg respectively. PMID- 25293393 TI - Effect of heavy metals on soil enzyme activity at different field conditions in Middle Spis mining area (Slovakia). AB - Heavy metals concentrations were measured in the former mining area located in Hornad river valley (Slovakia). Soil samples were taken in 2012 from 20 sites at two field types (grasslands, heaps of waste material) and two different areas. Total content of heavy metals (Cu, Pb, Zn, Hg), urease (URE), acid phosphatase (ACP), alkaline phosphatase (ALP), soil reaction (pH) were changing depending on the field/area type. The tailing pond and processing plants have been found as the biggest sources of pollution. URE, ACP and ALP activities significantly decreased while the heavy metal contents increased. Significant differences were found among area types in the heavy metal contents and activity of URE. No statistical differences in the content of heavy metals but significant statistical differences for soil pH were found for field types (grassland and heaps). Significant negative correlation was found for URE-Pb, URE-Zn and also between soil reaction and ACP and ALP. PMID- 25293394 TI - Super-infection with Staphylococcus aureus inhibits influenza virus-induced type I IFN signalling through impaired STAT1-STAT2 dimerization. AB - Bacterial super-infections are a major complication in influenza virus-infected patients. In response to infection with influenza viruses and bacteria, a complex interplay of cellular signalling mechanisms is initiated, regulating the anti pathogen response but also pathogen-supportive functions. Here, we show that influenza viruses replicate to a higher efficiency in cells co-infected with Staphylococcus aureus (S. aureus). While cells initially respond with increased induction of interferon beta upon super-infection, subsequent interferon signalling and interferon-stimulated gene expression are rather impaired due to a block of STAT1-STAT2 dimerization. Thus, S. aureus interrupts the first line of defence against influenza viruses, resulting in a boost of viral replication, which may lead to enhanced viral pathogenicity. PMID- 25293395 TI - Risk of Parkinson's disease following severe constipation: a nationwide population-based cohort study. AB - INTRODUCTION: Constipation is a non-motor symptom of Parkinson's disease (PD). We investigated the association between the severity of constipation and subsequent risk of PD in a population-based sample. METHODS: 551,324 participants free of PD, dementia, and stroke were retrospectively ascertained between January 1, 2005 and December 31, 2005 using the Taiwan National Health Insurance Research Database. The association between constipation at the beginning of the study and the incidence of PD was examined using a Cox regression model. Information regarding comorbidities and concomitant medications use was adjusted in the proportional hazards models. RESULTS: After an average follow-up of 5.5 years, 2336 incident PD cases were diagnosed. The crude incidence rate of PD per 1,000,000 person-days was 1.57 for subjects without constipation and 4.04, 5.28, and 12.67 for mild, moderate, and severe constipation, respectively. After adjusting for age, sex, comorbidities, and concomitant medication use, patients with constipation were more likely to develop PD than subjects without constipation; the adjusted hazard ratio (aHR) was 3.28 (95% CI: 2.14-5.03), 3.83 (2.51-5.84), and 4.22 (2.95-6.05) for individual constipation severity categories. Constipation severity was also associated with an increased likelihood of PD in the time-varying analysis; the aHR was 2.84 (2.43-3.33), 5.22 (4.61-5.92), and 10.47 (9.46-11.58) for mild, moderate, and severe constipation, respectively (P < 0.0001). After excluding PD patients diagnosed within 3 years of constipation, the association remained significant. CONCLUSIONS: Our study suggests that the severity of constipation is associated with a future diagnosis of PD in a dose-dependent manner. PMID- 25293396 TI - [Scheimpflug procedure]. PMID- 25293397 TI - Vaccination with recombinant 4 * M2e.HSP70c fusion protein as a universal vaccine candidate enhances both humoral and cell-mediated immune responses and decreases viral shedding against experimental challenge of H9N2 influenza in chickens. AB - As cellular immunity is essential for virus clearance, it is commonly accepted that no adequate cellular immunity is achieved by all available inactivated HA based influenza vaccines. Thus, an improved influenza vaccine to induce both humoral and cell-mediated immune responses is urgently required to control LPAI H9N2 outbreaks in poultry farms. M2e-based vaccines have been suggested and developed as a new generation of universal vaccine candidate against influenza A infection. Our previous study have shown that a prime-boost administration of recombinant 4*M2e.HSP70c (r4M2e/H70c) fusion protein compared to conventional HA based influenza vaccines provided full protection against lethal dose of influenza A viruses in mice. In the present study, the immunogenicity and protective efficacy of (r4M2e/H70c) was examined in chickens. The data reported herein show that protection against H9N2 viral challenge was significantly increased in chickens by injection of r4M2e/H70c compared with injection of conventional HA-based influenza vaccine adjuvanted with MF59 or recombinant 4*M2e (r4M2e) without HSP70c. Oropharyngeal and cloacal shedding of the virus was detected in all of the r4M2e/H70c vaccinated birds at 2 days after challenge, but the titer was low and decreased rapidly to reach undetectable levels at 7 days after challenge. Moreover, comparison of protective efficacy against LPAI H9N2 in birds intramuscularly immunized with r4M2e/H70c likely represented the ability of the M2e-based vaccine in providing cross-protection against heterosubtypic H9N2 challenge and also allowed the host immune system to induce HA-homosubtype neutralizing antibody against H9N2 challenge. This protective immunity might be attributed to enhanced cell-mediated immunity, which is interpreted as increased lymphocytes proliferation, increased levels of Th1-type (IFN-gamma) and Th2-type (IL-4) cytokines production and increased CD4(+) to CD8(+) ratios, resulting from the injection of four tandem repeats of the ectodomain of the conserved influenza matrix protein M2 (4*M2e) genetically fused to C-terminus of Mycobacterium tuberculosis HSP70 (mHSP70c). PMID- 25293398 TI - Pathogenicity and genomic characterization of a pseudorabies virus variant isolated from Bartha-K61-vaccinated swine population in China. AB - Pseudorabies (PR) or Aujeszky's disease (AD), caused by pseudorabies virus (PRV), is an economically important viral disease worldwide. Recently, PR outbreaks occurred in a large number of Bartha-K61-vaccinated swine herds in many regions of China. Here, we isolated a PRV variant, named TJ strain, from a Bartha-K61 vaccinated pig farm in China, evaluated the pathogenicity of the TJ strain in susceptible animals and analyzed its complete genomic sequence obtained by 454 pyrosequencing. Vaccination-challenge experiment in sheep showed that the classical Bartha-K61 vaccine could not provide complete protection against the challenge with the PRV TJ strain. In mice, the 50% lethal dose (LD50) of the TJ strain (10(2.3) TCID50) was lower than that of the classical PRV SC strain (10(3.0) TCID50). Furthermore, the TJ strain displayed higher mortality for pigs, as compared with the SC strain. The PRV TJ strain genome was determined to be 143,642 bp in length, encoding 67 open reading frames. The TJ strain was clustered to an independent branch together with some recent PRV isolates in China in the phylogenetic tree, which was relatively distant from previous PRV isolates. The TJ strain showed unique variations in the viral proteins that play key roles in the viral replication cycle. Taken together, the TJ strain is a highly pathogenic PRV variant with unique molecular signatures. Further studies are needed to explore the relevance of the sequence differences to the virulence alteration of the PRV variant. PMID- 25293399 TI - Pathogenesis in lambs and sequence analysis of putative virulence genes of Brazilian orf virus isolates. AB - The parapoxvirus orf virus (ORFV) is the agent of contagious ecthyma, an ubiquitous mucocutaneous disease of sheep and goats that may present variable clinical presentations. We herein studied the pathogenesis of ORFV infection in lambs and analyzed three putative virulence genes of four Brazilian ORFV isolates. Lambs inoculated in the labial commissures with each ORFV isolate (n=4, viral titer 10(5.6) TCID50/ml) developed classical orf lesions, characterized by a progressive course of erythema/macules, vesicles, pustules and proliferative scabs. Lesions lasted an average of 22.9 days (18-26) and virus shedding was detected for approximately 24.6 days (18-30). Two isolates (SV269/11 and SV820/10) produced more severe, long-lasting lesions resulting in highest clinical scores. Lambs inoculated with isolate SV581/11 developed lesions markedly milder (lower clinical scores [p<0.05]) and more limited than the other groups. Virus shedding by SV581/11 group, however, lasted similarly or even longer than the other groups. Sequence analysis of three virulence genes (VEGF, VIR and IL-10v) revealed amino acid deletions and mutations in VEGF and IL-10v genes of SV581/11 and SV252/11, the isolate(s) producing milder lesions. Additionally, the VEGF gene of isolate SV581/11 presented the lowest amino acid identity with the other isolates and with ORFV standard strain OV-IA82. Thus, these results demonstrate that ORFV isolates may display differential virulence in lambs and these differences might be associated with genetic changes in putative virulence genes. PMID- 25293401 TI - Effects of riparian canopy cover on salmonid diet and prey selectivity in low nutrient streams. AB - This study focuses on stream sections within a relatively low nutrient catchment in south-east Ireland in an attempt to characterize the probable effects of riparian canopy on salmonid diet and prey selectivity within two size classes of nursery stream. Sampling found that brown trout Salmo trutta diet changed significantly in response to riparian canopy regardless of stream size. The observation that S. trutta within unshaded stream sites did not feed on drifting terrestrial prey items to the same extent as those within shaded streams was not due to a lack of availability of this food source. There was no evidence to suggest that S. trutta selectively choose particular prey items. PMID- 25293400 TI - Within-plant distribution of 1,4-benzoxazin-3-ones contributes to herbivore niche differentiation in maize. AB - Plant defences vary in space and time, which may translate into specific herbivore-foraging patterns and feeding niche differentiation. To date, little is known about the effect of secondary metabolite patterning on within-plant herbivore foraging. We investigated how variation in the major maize secondary metabolites, 1,4-benzoxazin-3-one derivatives (BXDs), affects the foraging behaviour of two leaf-chewing herbivores. BXD levels varied substantially within plants. Older leaves had higher levels of constitutive BXDs while younger leaves were consistently more inducible. These differences were observed independently of plant age, even though the concentrations of most BXDs declined markedly in older plants. Larvae of the well-adapted maize pest Spodoptera frugiperda preferred and grew better on young inducible leaves irrespective of plant age, while larvae of the generalist Spodoptera littoralis preferred and tended to grow better on old leaves. In BXD-free mutants, the differences in herbivore weight gain between old and young leaves were absent for both species, and leaf preferences of S. frugiperda were attenuated. In contrast, S. littoralis foraging patterns were not affected. In summary, our study shows that plant secondary metabolites differentially affect performance and foraging of adapted and non adapted herbivores and thereby likely contribute to feeding niche differentiation. PMID- 25293402 TI - Alternative approach for right ventricular failure after left ventricular assist device placement in animal model. AB - OBJECTIVES: Right ventricular failure after left ventricular assist device (LVAD) implantation is associated with high mortality. This study was designed to evaluate the effectiveness of an atrial septostomy with a membrane oxygenator incorporated in an LVAD as a novel approach for right ventricular failure after LVAD implantation. METHODS: The outflow and inflow cannulae were placed in the carotid artery and left ventricular apex, respectively. A centrifugal pump and an oxygenator were sequentially placed between the inflow and outflow cannulae in seven anesthetized goats. While right ventricular failure was induced by pulmonary artery banding, a balloon atrial septostomy was performed using a 19-mm balloon catheter under echocardiographic guidance. We investigated the effects of the interatrial shunt on LVAD flow and haemodynamics. RESULTS: Development of right ventricular failure decreased LVAD flow (2.7 +/- 0.6-0.9 +/- 0.6 l/min), causing a state of shock [mean arterial pressure (MAP) of 41 +/- 12 mmHg]. Following a balloon atrial septostomy, LVAD flow and MAP were significantly improved to 2.7 +/- 0.4 l/min (P < 0.001) and 53 +/- 18 mmHg (P = 0.006), respectively, while right atrial pressure decreased from 18 +/- 5 to 15 +/- 5 mmHg (P = 0.001). Furthermore, arterial blood oxygenation was maintained by the membrane oxygenator incorporated in the LVAD. CONCLUSIONS: In the present model of right ventricular failure after LVAD implantation, LVAD flow was significantly increased and haemodynamics improved without compromising systemic oxygenation by the use of an interatrial shunt and a membrane oxygenator incorporated in the LVAD. Our results indicate that this novel approach may be less invasive for a right ventricular failure after LVAD implantation. PMID- 25293403 TI - Prediction of lymph node status in clinical stage IA squamous cell carcinoma of the lung. AB - OBJECTIVE: This multicentre study aimed to investigate the predictors of pathological lymph node status in patients with clinical stage IA squamous cell carcinoma of the lung, to select candidates for sublobar resection. METHODS: In total, we analysed 100 patients with clinical stage IA squamous cell carcinoma of the lung who underwent lobectomy or segmentectomy with systematic lymph node dissection. The relationship between lymph node status and tumour size on computed tomography, maximum standardized uptake value (SUV) on [18F]-fluoro-2 deoxy-d-glucose positron emission tomography (FDG-PET) and serum tumour markers were examined. RESULTS: Lymph node metastases were present in 12% of the study subjects, and 54% had evidence of pathological tumour invasiveness such as lymph node metastasis and/or lymphatic, vascular or pleural invasion. The areas under the receiver operating characteristic (ROC) curves for tumour size, maximum SUV, serum carcinoembryonic antigen and serum cytokeratin-19 fragments used to predict lymph node metastasis were 0.54 (P = 0.69), 0.46 (P = 0.67), 0.47 (P = 0.74) and 0.42 (P = 0.37), respectively. After multivariate analysis, no independent predictive factors for lymph node metastasis remained among those preoperative parameters. Likewise, we could find no preoperative predictors from either the ROC curves or multivariate analysis for pathological tumour invasiveness. CONCLUSIONS: All examined factors in this dataset were not predictive for lymph node metastasis or pathological invasiveness in patients with clinical stage IA squamous cell carcinoma of the lung. Systematic lymphadenectomy is advisable for this type of tumour. PMID- 25293404 TI - Successful resection of thymoma directly invading the right atrium under cardiopulmonary bypass. AB - We present the case of an invasive thymoma with severe compression of the right atrium, and infiltration of the atrial wall, causing a superior vena cava (SVC) syndrome. The tumour was resected under cardiopulmonary bypass en bloc with the atrial wall. A bovine pericardial patch was used for atrial reconstruction. We obtained a complete resection of the tumour and regression of symptoms, and, after 1 year of the follow-up, no signs of recurrence are evident. To our knowledge, this is the first case of thymoma directly invading the right atrium, without involvement of the SVC. In this setting, the aggressive surgical approach led to an immediate resolution of the symptoms and contributed to prolonged long term survival. PMID- 25293405 TI - Psychological distress, emotional stability, and emotion regulation moderate dynamics of herpes simplex virus type 2 recurrence. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) genital lesion recurrence is modulated by psychological factors, but no such link with viral shedding (and thus asymptomatic transmission) has been observed in humans. PURPOSE: The moderating effects of average psychological distress, emotional stability, and emotion regulation on HSV-2 recurrence were tested. METHODS: Nineteen HSV-2 seropositive women were followed over 22 weeks. Daily measures of HSV-2 recurrence and psychological distress were collected. HSV-2 lesions and viral shedding were modeled as linear oscillator systems, with psychological distress moderating the periodicity of each process. RESULTS: High levels of distress, more labile moods, and less ability to regulate emotional states were associated with fewer days elapsed between the onset of lesion episodes. Viral shedding showed the same pattern. CONCLUSIONS: Results are consistent with research indicating that psychological distress suppresses immune system functioning, and provide new evidence that genital HSV-2 viral shedding is related to, and regulated by, psychological distress. PMID- 25293406 TI - Calm temperament improves reproductive performance of beef cows. AB - Profitability of a beef operation is determined by the proportion of cows attaining pregnancy early in the breeding season and those that are pregnant at the end of breeding season. Many factors, including temperament, contribute to those reproductive parameters. The objective of this study was to evaluate effects of temperament on reproductive performance of beef cows. In Experiment 1, Angus and Angus-cross beef cows (n = 1546) from eight locations were assigned a body condition score (BCS; 1 = emaciated; 9 = obese) and chute exit and gait score (1 = slow exit, walk; calm temperament; 2 = jump, trot or run; excitable temperament). Cows were grouped with bulls (1 : 25 to 1 : 30; with satisfactory breeding potential and free of venereal disease) for an 85-day breeding season. Pregnancy status and stage of gestation were determined (transrectal palpation) 35 days after the end of the breeding season. Controlling for BCS (p < 0.01) and handling facility (p < 0.0001) and handling facility by temperament score interaction (p < 0.001), breeding season pregnancy rate was lower in excited versus calm cows [88.6% (798/901) vs 94.1% (607/645); p < 0.001]. Cows with an excitable temperament took 24 more days to become pregnant compared to calm cows (median days to pregnancy, 35 vs 59 days; p < 0.0001). In Experiment 2, Angus and Angus-cross beef cows (n = 1407) from 8 locations were assigned scores for body condition and chute exit and gait (as described in Experiment 1) and assigned to bulls (breeding sound and free of venereal disease; 1 : 25 to 1 : 30) for 85 days. Pregnancy status was determined by transrectal palpation at 2 and 6 months after the onset of the breeding season. Controlling for BCS (p < 0.05), pregnancy loss was higher in excited versus calm cows [5.5% (36/651) vs 3.2% (20/623), p < 0.0001]. In conclusion, beef cows with an excitable temperament had significantly lower reproductive performance than calmer cows. The modified two-point chute exit-gait scoring method was repeatable and identified cattle with an excitable temperament. PMID- 25293407 TI - [A three-day course can increase knowledge and interest in disaster medicine for medical students]. AB - The incidence of disasters increases and the need for physicians with an interest in disaster medicine is essential. As an early introduction of disaster medicine, medical students from Denmark, members of the Students' Society for Anesthesiology and Traumatology, participated on a three-day course, Trauma Days 2013, with full-scale simulations. The students underwent debriefings and questionnaires were handed out. 94% of the students increased their interest in disaster medicine. PMID- 25293408 TI - [Diagnosis and treatment of cerebral venous sinus thrombosis]. AB - Thrombosis of the cerebral sinuses most often affects younger adults. Headache is a common complaint and can be accompanied by vomiting and papilloedema. The diagnosis rests on magnetic resonance imaging and the treatment consists of heparin or low-molecular weight heparin followed by vitamin K antagonists for three months or more. In fulminant cases local thrombolysis is administered, while symptomatic treatment for increased intracranial pressure is given. In retrospective analyses this approach has been associated with a good outcome - even in cases treated by decompressive craniectomy. PMID- 25293409 TI - [Cat Scratch Disease as a differential diagnosis in a patient with swelling in the groin]. AB - at Scratch Disease is caused by the bacteria Bartonella henselae and presents in patients exposed to a scratch/bite from cats. We present a case with a 12-year old boy with an enlarged inguinal lymph node, initially suspected to be a femoral hernia by ultrasonography. Histologic examination of an inguinal lymph node showed necrosis and B. henselae infection. It is important with a thorough anamnesis including any history of animal bites/scratch and it should be kept in mind as a differential diagnosis in patients with swelling in the groin, despite the rare diagnosis of this disease. PMID- 25293410 TI - [Chronic hepatitis C presenting with a diagnosis of hepatocellular carcinoma]. AB - Chronic hepatitis C (CHC) affects around 16,000 individuals in Denmark of whom about 50% are diagnosed. In the presence of CHC and cirrhosis the annual risk of hepatocellular carcinoma (HCC) is 1-5%. We report on two patients who presented with disseminated HCC at the time of CHC diagnosis. At the time of diagnosis only non-curative treatment was available. An earlier diagnosis of CHC could potentially have led to a cure and prevention of HCC. PMID- 25293411 TI - [The bone-anchored hearing aid]. AB - The bone-anchored hearing aid (Baha) was introduced in 1977 by Tjellstrom and colleagues and has now been used clinically for over 30 years. Generally, the outcomes are good, and several studies have shown improved audiological- and quality of life outcomes. The principle of the Baha is, that sound vibrations are led directly to the inner ear via the mastoid bone, bypassing the middle ear. This is achieved via an osseointegrated implant and a skin-penetrating abutment. Studies report high success rates and a majority of complications as typically minor in nature. PMID- 25293412 TI - [Congenital aplasia of cruciate ligaments causing knee osteoarthritis]. AB - We report a case of a 56-year-old women with severe unilateral osteoarthritis and translation due to congenital aplasia of both cruciate ligaments, which was found during knee arthroplasty surgery. Cruciate ligament insufficiency is a known risk factor in osteoarthritis but is very rarely caused by congenital aplasia and is most often due to trauma. While the patient had several common risk factors for the development of osteoarthritis the congenital aplasia may have contributed significantly in this case of osteoarthritis. PMID- 25293414 TI - Quality of life improves after minimally invasive repair of pectus excavatum. AB - BACKGROUND: Pectus excavatum is the most common chest wall deformity. This deformity may cause physical limitations and psychosocial problems. In this study, we aimed to investigate the effect of minimally invasive repair of pectus excavatum on the quality of life. METHODS: This study included 88 patients, aged 18.44 +/- 3.93 years (85.2% male), who underwent minimally invasive repair of pectus excavatum; 40.9% had an associated anomaly or disease, and 17.0% had scoliosis. The patients and their parents completed the patient and parent forms of the Nuss questionnaire modified for adults preoperatively and 6 months after the operation. RESULTS: The patients' median Nuss score increased from 31 (interquartile range 31-35) preoperatively to 43 (interquartile range 43-46) at 6 months after the operation (p = 0.000). The parents' preoperative score of 33 (interquartile range 29-36) increased to 38 (interquartile range 34-41; p = 0.000). Improvements in the physical and psychosocial component scores of the Nuss questionnaire were also significant in the patient (p = 0.000, p = 0.000, respectively) and parent forms (p = 0.005, p = 0.000, respectively). CONCLUSIONS: Minimally invasive repair of pectus excavatum significantly improved the physical and psychosocial wellbeing of patients. Longitudinal studies are needed to determine the long-term changes related to quality of life. PMID- 25293413 TI - Regulation of the alternative pathway of complement modulates injury and immunity in a chronic model of dextran sulphate sodium-induced colitis. AB - The role of complement in inflammatory bowel disease (IBD) has been studied primarily using acute models, and it is unclear how complement affects processes in more relevant chronic models of IBD in which modulation of adaptive immunity and development of fibrosis have pathogenic roles. Using mice deficient in C1q/mannose-binding lectin (MBL) or C3, we demonstrated an important role for these opsonins and/or the classical pathway C3 convertase in providing protection against mucosal injury and infection in a model of chronic dextran sulphate sodium (DSS)-induced colitis. In contrast, deficiency of the alternative pathway (fB(-/-) mice) had significantly less impact on injury profiles. Consequently, the effect of a targeted inhibitor of the alternative pathway was investigated in a therapeutic protocol. Following the establishment of colitis, mice were treated with CR2-fH during subsequent periods of DSS treatment and acute injury (modelling relapse). CR2-fH significantly reduced complement activation, inflammation and injury in the colon, and additionally reduced fibrosis. Alternative pathway inhibition also altered the immune response in the chronic state in terms of reducing numbers of B cells, macrophages and mature dendritic cells in the lamina propria. This study indicates an important role for the alternative pathway of complement in the pathogenesis and the shaping of an immune response in chronic DSS-induced colitis, and supports further investigation into the use of targeted alternative pathway inhibition for the treatment of IBD. PMID- 25293415 TI - Subclavian artery aneurysm in a patient with vascular Ehlers-Danlos syndrome. AB - We describe our experience of surgical treatment in a 28-year-old woman with vascular Ehlers-Danlos syndrome. A right subclavian artery aneurysm was detected. The right vertebral artery arose from the aneurysm. Digital subtraction angiography showed interruption of the left vertebral artery. The aneurysm was excised and the right vertebral artery was anastomosed end-to-side to the right common carotid artery under deep hypothermia and circulatory arrest. The patient remained very well 4 years after surgery, with no late vascular complication. PMID- 25293416 TI - Mediastinal neurothekeoma: a rare tumor. AB - Neurothekeoma, also known as nerve sheath myxoma, is a benign nerve sheath tumor that usually arises in the cutaneous nerves of the head, neck, or upper extremities. Extracutaneous placement is very rare. Mediastinal neurothekeoma has not previously been reported in the English literature. A 30-year-old woman was admitted to our clinic with back pain. A smooth-edged mass found in her paravertebral region, and a neurogenic tumor was suspected. The tumor was completely excised. Final pathology revealed it to be a mediastinal neurothekeoma. PMID- 25293417 TI - Unusual complication of permanent pacemaker lead: Intraabdominal migration. PMID- 25293418 TI - Pulmonary valvuloplasty for pulmonary atresia-restrictive ventricular septal defect. AB - Pulmonary atresia with restrictive ventricular septal defect is a rare congenital cardiac anomaly. A Blalock-Taussig shunt and surgical perforation of the atretic pulmonary valve is often performed as the initial palliation. We present our experience of utilizing both transesophageal and epicardial echocardiography during surgical pulmonary valvuloplasty in a 22-day-old neonate with pulmonary atresia with restrictive ventricular septal defect. The atretic pulmonary valve was perforated using a sheath introduced through the pulmonary artery. PMID- 25293419 TI - Seamless adaptive servo-ventilation therapy after triple-valve surgery. AB - A 70-year-old man with severe multivalvular disease, atrial fibrillation, and kyphoscoliosis, had Cheyne-Stokes respiration with central sleep apnea. After triple-valve surgery with the maze procedure, adjunctive adaptive servo ventilation therapy was initiated on the first postoperative day and continued seamlessly in the postoperative period. Seamless adaptive servo-ventilation therapy as an adjunct to triple-valve surgery is more likely to prevent heart failure remodeling without worsening of pulmonary hypertension and recurrence of atrial fibrillation. PMID- 25293420 TI - Dysregulation of calcium homeostasis in muscular dystrophies. AB - Muscular dystrophies are a group of diseases characterised by the primary wasting of skeletal muscle, which compromises patient mobility and in the most severe cases originate a complete paralysis and premature death. Existing evidence implicates calcium dysregulation as an underlying crucial event in the pathophysiology of several muscular dystrophies, such as dystrophinopathies, calpainopathies or myotonic dystrophy among others. Duchenne muscular dystrophy is the most frequent myopathy in childhood, and calpainopathy or LGMD2A is the most common form of limb-girdle muscular dystrophy, whereas myotonic dystrophy is the most frequent inherited muscle disease worldwide. In this review, we summarise recent advances in our understanding of calcium ion cycling through the sarcolemma, the sarcoplasmic reticulum and mitochondria, and its involvement in the pathogenesis of these dystrophies. We also discuss some of the clinical implications of recent findings regarding Ca2+ handling as well as novel approaches to treat muscular dystrophies targeting Ca2+ regulatory proteins. PMID- 25293422 TI - Predicting 3D pose in partially overlapped X-ray images of knee prostheses using model-based Roentgen stereophotogrammetric analysis (RSA). AB - After total knee replacement, the model-based Roentgen stereophotogrammetric analysis (RSA) technique has been used to monitor the status of prosthetic wear, misalignment, and even failure. However, the overlap of the prosthetic outlines inevitably increases errors in the estimation of prosthetic poses due to the limited amount of available outlines. In the literature, quite a few studies have investigated the problems induced by the overlapped outlines, and manual adjustment is still the mainstream. This study proposes two methods to automate the image processing of overlapped outlines prior to the pose registration of prosthetic models. The outline-separated method defines the intersected points and segments the overlapped outlines. The feature-recognized method uses the point and line features of the remaining outlines to initiate registration. Overlap percentage is defined as the ratio of overlapped to non-overlapped outlines. The simulated images with five overlapping percentages are used to evaluate the robustness and accuracy of the proposed methods. Compared with non overlapped images, overlapped images reduce the number of outlines available for model-based RSA calculation. The maximum and root mean square errors for a prosthetic outline are 0.35 and 0.04 mm, respectively. The mean translation and rotation errors are 0.11 mm and 0.18 degrees , respectively. The errors of the model-based RSA results are increased when the overlap percentage is beyond about 9%. In conclusion, both outline-separated and feature-recognized methods can be seamlessly integrated to automate the calculation of rough registration. This can significantly increase the clinical practicability of the model-based RSA technique. PMID- 25293423 TI - Publishing journal's prestige does not influence critical appraisal. PMID- 25293421 TI - Oleuropein aglycone protects against pyroglutamylated-3 amyloid-beta toxicity: biochemical, epigenetic and functional correlates. AB - Amyloid-beta (Abeta) fragments, oligomeric Abeta aggregates, and pyroglutamylated Abeta peptides, as well as epigenetic mechanisms and autophagy dysfunction all appear to contribute in various ways to Alzheimer's disease progression. We previously showed that dietary supplementation of oleuropein aglycone, a natural phenol abundant in the extra virgin olive oil, can be protective by reducing Abeta42 deposits in the brain of young and middle-aged TgCRND8 mice. Here, we extended our study to aged TgCRND8 mice showing increased pE3-Abeta in the brain deposits. We report that oleuropein aglycone is active against glutaminylcyclase catalyzed pE3-Abeta generation reducing enzyme expression and interferes both with Abeta42 and pE3-Abeta aggregation. Moreover, the phenol astonishingly activates neuronal autophagy even in mice at advanced stage of pathology, where it increases histone 3 and 4 acetylation, which matches both a decrease of histone deacetylase 2 expression and a significant improvement of synaptic function. The occurrence of these functional, epigenetic, and histopathologic beneficial effects even at a late stage of the pathology suggests that the phenol could be beneficial at the therapeutic, in addition to the prevention, level. PMID- 25293424 TI - Five-year follow-up study of the association between periodontal disease and myocardial infarction among Japanese male workers: MY Health Up Study. AB - BACKGROUND: An association between chronic oral infections and coronary heart disease has been suggested. METHODS: The study participants were male employees aged 36-59 years. Data were extracted from the MY Health Up Study, comprising a baseline questionnaire survey and succeeding annual health examinations for financial firm workers in Japan. Using a self-administered questionnaire at baseline, participants' oral status was classified into three types of periodontal indicators: (i) periodontal score, (ii) periodontitis and (iii) tooth loss (<5 and >=5 teeth). An incidence of myocardial infarction (MI) was determined by annual health examination records. RESULTS: Of the 4037 candidates for follow-up in the baseline year of 2004, 3081 males were eligible for the analysis, 17 of whom experienced MI in the subsequent 5 years. The periodontal score model was associated with an increase in developing MI [odds ratio (OR) = 2.11, 95% confidence interval (CI) = 1.29-3.44], after adjusting for other confounding variables. The periodontitis (OR = 2.26, 95% CI = 0.84-6.02) and tooth loss (OR = 1.97, 95% CI = 0.71-5.45) models showed similar trends, although the difference was not significant. CONCLUSIONS: Periodontal disease may be a mild but independent risk factor for MI among Japanese male workers. PMID- 25293425 TI - Association of blood products administration during cardiopulmonary bypass and excessive post-operative bleeding in pediatric cardiac surgery. AB - Our objectives were to study risk factors and post-operative outcomes associated with excessive post-operative bleeding in pediatric cardiac surgeries performed using cardiopulmonary bypass (CPB) support. A retrospective observational study was undertaken, and all consecutive pediatric heart surgeries over 1 year period were studied. Excessive post-operative bleeding was defined as 10 ml/kg/h of chest tube output for 1 h or 5 ml/kg/h for three consecutive hours in the first 12 h of pediatric cardiac intensive care unit (PCICU) stay. Risk factors including demographics, complexity of cardiac defect, CPB parameters, hematological studies, and post-operative morbidity and mortality were evaluated for excessive bleeding. 253 patients were studied, and 107 (42 %) met the criteria for excessive bleeding. Bayesian model averaging revealed that greater volume of blood products transfusion during CPB was significantly associated with excessive bleeding. Multiple logistic regression analysis of blood products transfusion revealed that increased volume of packed red blood cells (PRBCs) administration for CPB prime and during CPB was significantly associated with excessive bleeding (p = 0.028 and p = 0.0012, respectively). Proportional odds logistic regression revealed that excessive bleeding was associated with greater time to achieve negative fluid balance, prolonged mechanical ventilation, and duration of PCICU stay (p < 0.001) after adjusting for multiple parameters. A greater volume of blood products administration, especially PRBCs transfusion for CPB prime, and during the CPB period is associated with excessive post-operative bleeding. Excessive bleeding is associated with worse post-operative outcomes. PMID- 25293426 TI - Early detection of right ventricular diastolic dysfunction by pulsed tissue Doppler echocardiography in iron loaded beta thalassemia patients. AB - Early heart iron overload in beta thalassemia major patients can be quantified through T2* cardiovascular magnetic resonance (CMR). To clarify the value of tissue Doppler imaging (TDI) in early detection of myocardial dysfunction in iron loaded thalassemia patients diagnosed by CMR. Two groups were included in the study; Group I: 69 asymptomatic thalassemia patients (28 females, 41 males), mean age 18.1 +/- 7.03 years (range 6-39 years); Group II (n = 41) healthy normal controls matched for age and sex. Serum ferritin and CMR were performed to assess the cardiac siderosis (T2* < 20 ms). Group I was subdivided into two subgroups; Group Ia (n = 26) T2* < 20 ms and Group Ib (n = 43) T2* > 20 ms. Conventional and Doppler echocardiography of LV, RV dimensions and functions and pulmonary artery pressure were evaluated. Right ventricular diastolic function assessed by tricuspid annular E'/A' was positively correlated with T2* value; lower tricuspid E'/A' ratios were correlated with lower T2* values (r = 0.366, P = 0.002). Tricuspid annular A' was significantly higher in group Ia compared to group Ib (16.7 +/- 5.2 vs 12.1 +/- 4.0 cm/s, P < 0.001). Tricuspid E'/A' < 1 was common in group Ia compared to group Ib (19/26 (73.0) vs 3/43 (6.97%), P < 0.001). By multivariate analysis, right ventricular diastolic dysfunction (tricuspid E'/A' < 1) was associated with serum ferritin and T2* level of the thalassemia patients. TDI is a promising tool for quantitative assessment of myocardial function and early detection of right ventricular diastolic dysfunction in iron loaded beta thalassemia major patients. PMID- 25293427 TI - Does surgically induced right bundle branch block really effect ventricular function in children after ventricular septal defect closure? AB - In this prospective study, we aimed to assess left and right ventricular function in terms of the presence of right bundle branch block (RBBB) in the cases with repaired ventricular septal defect (VSD). Fifty-three patients who had VSD surgery at least 1-year preceding admission and 52 healthy controls were enrolled into the study. All the participants underwent electrocardiographic and echocardiographic examination. The cases with RBBB were determined. The conventional and tissue Doppler echocardiographic measurements of the patients with and without RBBB were compared with each other and healthy controls. Twenty eight of VSD repair groups were male and 25 were female. Control group consisted of 30 males and 22 females. The mean age of the study and control groups was 7.5 +/- 5.0 and 6.9 +/- 4.3 years, respectively. RBBB was detected in 20 of 53 (37.7 %) operated patients. The only significant difference between the cases with and without RBBB was decreased right ventricular fractional area change (%) in the former group (33 +/- 7 vs. 39 +/- 5 p < 0.05). When compared to controls, operated group had statistically lower [corrected] tricuspid annular plane systolic excursion (p < 0.05), lower systolic, early diastolic, and late diastolic myocardial velocities, higher left and right ventricular myocardial performance indices, irrespective of the presence of RBBB. The ratios of mitral or tricuspid inflow to left or right ventricular myocardial in early diastolic velocities measured from lateral annular levels were increased in operated group (all p values <0.05). In conclusion, RBBB in the cases with surgical VSD repair might be associated with right ventricular dysfunction. Biventricular systolic and diastolic dysfunction may develop following VSD repair irrespective of the presence of RBBB. Tissue Doppler-derived myocardial performance indices are useful in detection of those subclinical dysfunctions. PMID- 25293428 TI - Post-pericardiotomy syndrome in pediatric patients following surgical closure of secundum atrial septal defects: incidence and risk factors. AB - Surgical repair for atrial septal defects (ASD) generally occurs during childhood. Post-pericardiotomy syndrome (PPS) after cardiac surgery has a reported incidence of 1-40 %. We focused exclusively on secundum ASD repair to evaluate the incidence of PPS. The purpose of this study is to determine the incidence of PPS after surgical repair of secundum ASD and investigate what risk factors may be predictive of its development. A retrospective study was performed, and 97 patients who underwent surgical closure of a secundum ASD were identified. 27 (28 %) were diagnosed with PPS within the first postoperative year. Diagnosis was made if they had evidence of new or worsening pericardial effusion and the presence of >=2 of the following criteria: fever >72 h postoperatively, irritability, pleuritic chest pain, or pericardial friction rub. Closure of secundum ASDs was performed at a median age of 3.8 years (Interquartile Range (IQR): 2.2-6.0 years) and a median weight of 14.3 kilograms (IQR: 10.9-19.3 kilograms). The median time for development of PPS was 8 days post-op (IQR: 5-14). Significantly, 19 (27 %) of 70 patients in the non-PPS group had a small pericardial effusion on their discharge echocardiogram, while of the 27 patients who developed PPS, 17 (63 %) had a small pericardial effusion on their discharge echocardiogram (p = 0.001). PPS is relatively common following surgical closure of secundum ASDs. A small pericardial effusion on discharge echocardiogram is predictive of development of PPS postoperatively. In patients who develop PPS, there is a good response to therapy with a benign course. PMID- 25293429 TI - Stenotrophomonas maltophilia infection among young children in a cardiac intensive care unit: a single institution experience. AB - Stenotrophomonas maltophilia can present as bacteremia, respiratory tract infection, urinary tract infection, soft tissue and wound infections, bone and joint infections, meningitis, and endocarditis especially in immunosuppressed patients and those with underlying medical conditions. The incidence and impact of S. maltophilia in young children with heart disease are poorly defined. A single center retrospective observational study was conducted in infants <180 days of age with positive S. maltophilia cultures over a period of 5 years. The overall incidence for S. maltophilia infection was 0.8 % (n = 32/3656). Among 32 identified infants, there were 47 episodes of S. maltophilia infection 66 % of infants had prior exposure to broad spectrum antibiotics. 97 % of positive isolates were susceptible to trimethoprim/sulfamethoxazole and 91 % to levofloxacin as well as ticarcillin/clavulanate. Ventilator-free days and absolute lymphocyte count prior to acquiring infection were significantly lower in non-survivors than in survivors. 100 % of survivors had clearance of positive cultures compared to 50 % in non-survivors (p < 0.05). The crude all-cause mortality rate was 37.5 %. All non-survivors had increased length of ICU stay and duration of mechanical ventilation and had delayed clearance of infection and required longer duration of treatment. PMID- 25293430 TI - 25-hydroxyvitamin D, APOE E4 genotype and cognitive function: findings from the 1958 British birth cohort. AB - Both high and low vitamin D statuses have been associated with lower memory function. Apolipoprotein E (APOE) E4 alleles have been associated with reduced memory function, and separately with higher vitamin D concentrations. This report aims to examine if the presence of APOE E4 alleles contributes to the relationship between vitamin D and memory function. A total of 4848 (46% female) participants from the 1958 British birth cohort had information on APOE genotypes and completed memory tests at 50 years, where 4644 also had 25-hydroxyvitamin D (25(OH)D) concentrations measured at 45 years. Both low and high 25(OH)D concentrations were associated with lower memory function after adjustment for number of APOE E4 alleles (P curvature=0.02). There was evidence of interaction between APOE E4 and 25(OH)D, suggesting the association between 25(OH)D concentrations and memory function is different for those with two APOE E4 alleles compared with those with zero or one APOE E4 alleles (recessive model P interaction=0.01). Among participants with two APOE E4 alleles, higher 25(OH)D concentrations were associated with higher memory function, whereas in others, memory scores were slightly lower for individuals with higher versus lower concentrations. Further studies are required to replicate these findings. PMID- 25293431 TI - Effect of resistance training on resting metabolic rate and its estimation by a dual-energy X-ray absorptiometry metabolic map. AB - BACKGROUND/OBJECTIVES: Fat-free mass (FFM) is the major predictor of resting metabolic rate (RMR). As protein supplementation during resistance training may augment gains in FFM, we investigated the effects of resistance training combined with protein supplementation on RMR and whether RMR responses could be estimated by a dual-energy X-ray absorptiometry (DXA) metabolic map. SUBJECTS/METHODS: Healthy adults completed a whole-body periodized resistance training program consisting of 96 workouts (~9 months). Participants were randomly assigned to supplement with whey protein (whey; n=18), soy protein (soy; n=21) or carbohydrate (carb; n=22). RMR was measured using indirect calorimetry (RMR(IC)) and estimated by DXA metabolic mapping (RMR(MM)) pretraining and posttraining. RESULTS: RMR(IC) increased from pretraining to posttraining in the whole cohort (1653+/-302 to 1726+/-291 kcal/day, P=0.001) without differences between the groups. Delta RMR(IC) and RMR(MM) (73+/-158 vs 52+/-41 kcal/day were not significantly different by t-test (P=0.303), although they were not significantly correlated (r=0.081; P=0.535). Stepwise regression identified 43% of the shared variance in delta RMR(IC) using total serum thyroxine, RMR(IC) and FFM at baseline (P=0.009). CONCLUSIONS: These results indicate that 9 months of resistance training significantly increased RMR ~5% on average, but there was wide variability between individuals, which can be partially accounted for by changes in FFM and thyroid hormones. PMID- 25293432 TI - Dietary strategies for adult type 1 diabetes in light of outcome evidence. AB - Individuals who have type 1 diabetes need individualised medical nutrition therapies whose goals are to improve overall health and metabolic outcomes. However, interventions in the field of nutrition are challenging, as diet-related correlations with disease remain difficult to detect and the certainty of outcome in this area is elusive. Currently, patients are not meeting recommended dietary guidelines. Several alternative approaches for teaching meal planning to people with diabetes have been proposed: basic nutrition guidelines, basic diabetes guidelines, menu approaches to meal planning, exchange lists for meal planning and carbohydrate counting. The review provides an overview of suggested strategies for achieving the proposed goals and summarises evidence of outcomes. PMID- 25293433 TI - High sodium intake is associated with important risk factors in a large cohort of chronic kidney disease patients. AB - BACKGROUND/OBJECTIVES: An increased risk of mortality and cardiovascular disease (CVD) is observed in people with chronic kidney disease (CKD) even in early stages. Dietary sodium intake has been associated with important CVD and CKD progression risk factors such as hypertension and proteinuria in this population. We aimed to investigate the relationship between sodium intake and CVD or CKD progression risk factors in a large cohort of patients with CKD stage 3 recruited from primary care. SUBJECTS/METHODS: A total of 1733 patients with previous estimated glomerular filtration rate (eGFR) of 30-59 ml/min/1.73m(2), with a mean age 72.9+/-9.0 years, were recruited from 32 general practices in primary care in England. Medical history was obtained and participants underwent clinical assessment, urine and serum biochemistry testing. Sodium intake was estimated from three early-morning urine specimens using an equation validated for this study population. RESULTS: Sixty percent of participants who had estimated sodium intake above recommendation (>100 mmol/day or 6 g salt/day) also had higher diastolic blood pressure, mean arterial pressure (MAP), urinary albumin-to creatinine ratio, high-sensitive C-reactive protein and uric acid and used a greater number of anti-hypertensive drugs. In multivariable regression analysis, excessive sodium intake was an independent predictor of MAP (B=1.57, 95% confidence interval (CI) 0.41-2.72; P=0.008) and albuminuria (B=1.35, 95% CI 1.02 1.79; P=0.03). CONCLUSIONS: High sodium intake was associated with CVD and CKD progression risk factors in patients with predominantly early stages of CKD followed up in primary care. This suggests that dietary sodium intake could afffect CVD risk even in early or mild CKD. Intervention studies are warranted to investigate the potential benefit of dietary advice to reduce sodium intake in this population. PMID- 25293434 TI - Daily iodine intake and the impact of salt reduction on iodine prophylaxis in the Italian population. AB - BACKGROUND/OBJECTIVES: Salt iodization is one of the preferred strategies to eradicate iodine-deficiency disorders worldwide. The aim of this study was (i) to estimate the daily iodine intake in the Italian population, (ii) to verify whether the recently recommended salt intake of 5 g/day in adults and less in children may be sufficient to achieve the adequate daily iodine intake, (iii) to estimate the contribution of iodine-enriched vegetables to the total daily iodine intake. SUBJECTS/METHODS: The content of iodine has been evaluated in 288 food samples highly representative of Italian eating habits. The contribution of foods and iodized salt to the total daily iodine intake was estimated in adults, adolescents, and children on the basis of available nationwide data of food consumption. RESULTS: The total daily iodine intake owing to food and uniodized salt consumption resulted lower than the daily requirement in all age groups. With a daily consumption of 5 g of salt iodized at 30 mg/kg, the estimated daily iodine intake resulted within the range of optimal iodine intake in all age groups. In children the recommended iodine intake is achieved with a daily consumption of 3 g of iodized salt. Moreover, the daily iodine intake significantly increased in all age groups if the consumption of iodine-enriched vegetables was considered in substitution of non iodine-enriched ones. CONCLUSIONS: Our study suggests that the recommended quantities of salt, if iodized at 30 mg/kg, are sufficient to achieve the adequate daily iodine intake both in adults and children. PMID- 25293435 TI - The association between nut consumption and the risk of total and ischemic stroke in a German cohort study. AB - BACKGROUND/OBJECTIVES: Nuts have beneficial effects on coronary heart disease and many cardiovascular risk factors. However, their effect on stroke is less established, and no studies on the topic are available in Northern and Central European populations. Therefore, we aimed at investigating the association between nut consumption and the risk of stroke in a German population. SUBJECTS/METHODS: We used data from a prospective cohort of 26,285 participants of the European Prospective Investigation into the Cancer and Nutrition Potsdam Study. During a median follow-up time of 8.3 years (interquartile range: 7.5 9.2), 288 incident cases of stroke occurred. Nut consumption (standard portion size of 50 g) was assessed at baseline with a semiquantitative food-frequency questionnaire. RESULTS: The median nut intake was 0.82 g per day, interquartile range: 0.41-4.11. In the multivariable model, an increased risk of stroke was observed among participants who never consumed nuts (hazard ratio (HR): 1.56, 95% confidence interval: 1.17-2.08), compared with those consuming <1/2 portion/week. However, there was no evidence of a dose-response relationship between nut consumption and stroke. Compared with those who consumed <1/2 portion/week, the multivariable HR for total stroke was 1.06 (0.75-1.52) among those who consumed 1/2 to 1 portion/week and 1.37 (0.92-2.05) for those who consumed >1 portion/week. Similar nonsignificant associations were observed in stratified analysis for gender, or for fatal and nonfatal stroke. CONCLUSIONS: We could not observe an association between nut consumption and the risk of developing stroke (fatal/nonfatal) in a population with low habitual nut consumption. PMID- 25293436 TI - Nuclear Factor I-C acts as a regulator of hepatocyte proliferation at the onset of liver regeneration. AB - BACKGROUND & AIMS: Knockout studies of the murine Nuclear Factor I-C (NFI-C) transcription factor revealed abnormal skin wound healing and growth of its appendages, suggesting a role in controlling cell proliferation in adult regenerative processes. Liver regeneration following partial hepatectomy (PH) is a well-established regenerative model whereby changes elicited in hepatocytes lead to their rapid and phased proliferation. Although NFI-C is highly expressed in the liver, no hepatic function was yet established for this transcription factor. This study aimed to determine whether NFI-C may play a role in hepatocyte proliferation and liver regeneration. METHODS: Liver regeneration and cell proliferation pathways following two-thirds PH were investigated in NFI-C knockout (ko) and wild-type (wt) mice. RESULTS: We show that the absence of NFI-C impaired hepatocyte proliferation because of plasminogen activator I (PAI-1) overexpression and the subsequent suppression of urokinase plasminogen activator (uPA) activity and hepatocyte growth factor (HGF) signalling, a potent hepatocyte mitogen. This indicated that NFI-C first acts to promote hepatocyte proliferation at the onset of liver regeneration in wt mice. The subsequent transient down regulation of NFI-C, as can be explained by a self-regulatory feedback loop with transforming growth factor beta 1 (TGF-beta1), may limit the number of hepatocytes entering the first wave of cell division and/or prevent late initiations of mitosis. CONCLUSION: NFI-C acts as a regulator of the phased hepatocyte proliferation during liver regeneration. PMID- 25293437 TI - Quantitative analysis of tumor volume reduction after three-dimensional conformal radiation therapy for intracranial meningiomas. AB - To provide radiobiological information on the inherent response of intracranial meningiomas after three-dimensional conformal radiation therapy. Quantitative tumor volume measurements were generated from 120 magnetic resonance images of a total of 24 patients. Gross tumor volumes were delineated on a series of contrast enhanced T1-weighted magnetic resonance images by using commercial software. The percentage of tumor volume reduction at each follow-up was determined and compared to the baseline tumor volume. The median follow-up time was 103.5 months (range 30-137 months). The mean pre-radiation therapy tumor volume was 30.0 cm(3) (range 1.3-167.4 cm(3)). Tumor volume reduction was observed in 96 % of the study population. The mean absolute and relative tumor volume reduction were 14.0 cm(3) (range -0.6-84.5 cm(3)) and 40.8 % (range -6.8-82.9 %), respectively. The mean relative tumor volume reduction was 15.9, 28.9, 40.5, 50.3, and 52.6 % at 2, 4, 6, 8, and 10 years after irradiation. The quantitative volumetric analysis of the pattern of tumor volume reduction in response to irradiation gives an insight into the radiobiological nature of intracranial meningiomas after conventionally fractionated radiation therapy. PMID- 25293439 TI - Characterization of spinal findings in children and adults with neurofibromatosis type 1 enrolled in a natural history study using magnetic resonance imaging. AB - To characterize spinal abnormalities in patients with neurofibromatosis type 1 (NF1) using magnetic resonance imaging (MRI). NF1 patients with at least one spine MRI were selected from participants prospectively enrolled in the National Cancer Institute NF1 Natural History Study. Data were analyzed retrospectively. Ninety-seven patients (38 females, median age 14.2 years, standard deviation [SD] 7.6) had baseline imaging of the spine, and 26 patients (27 %) had one follow-up spine MRI (follow up time 2.5 years, SD 1.1, range 0.7-4.7). Seventy-eight patients (80 %) had spinal neurofibromas, with rising frequency from 70 % in patients younger than 10 years to 80 % in patients aged 10-18 years to 89 % in individuals older than 18 years of age. At baseline, 33/97 patients (34 %) had MRI changes consistent with spinal cord compression that was most prevalent at the cervical (43 %) and lumbar spine region (40 %). Seven of nine patients with progression of their spinal neurofibromas developed cord compression. Paraspinal plexiform neurofibromas (PNs) were present in 77/97 patients (79 %), of which 68 patients (88 %) had concomitant spinal neurofibromas. Spinal curvature abnormality was present in 50/97 patients (51 %, 20 females, median age 14.6 years, SD 7.6). Patients with paraspinal PNs had six-fold higher odds of developing spinal curvature abnormalities compared to patients without PN (OR = 5.9, 95 % CI 1.81 to 19.44, p = 0.0033). A total of 58/97 patients (60 %, median age 16.1 years, SD 7.8, range 4.8-48.2 years) presented with neurologic abnormalities that progressed in 12/26 patients (46 %). Substantial spinal neurofibroma and paraspinal PN burden was observed in our study population, which represents a selective group of patients with specifically more severe tumor involvement than the general NF1 population. Occurrence and progression of spinal neurofibromas on repeat evaluations highlight the need for longitudinal clinical monitoring in patients with known spinal disease. PMID- 25293441 TI - Endoscopic transpapillary sampling methods for bile duct cancer: may intraductal aspiration improve diagnosis? PMID- 25293440 TI - Strong therapeutic potential of gamma-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells. AB - The Notch signal regulates both cell viability and apoptosis, and maintains stemness of various cancers including glioblastoma (GBM). Although Notch signal inhibition may be an effective strategy in treating GBM initiating cells (GICs), its applicability to the different subtypes of GBM remains unclear. Here, we analyzed the effectiveness of MRK003, a preclinical gamma-secretase inhibitor, on GICs. Nine patient-derived GICs were treated by MRK003, and its efficacy on cell viability, apoptosis, sphere forming ability and Akt expression level which might be related to Notch downstream and be greatly important signals in GBM was evaluated. MRK003 suppressed viability and sphere-formation ability, and induced apoptosis in all GICs in varying doses of MRK003. Based on their sensitivities to MRK003, the nine GICs were divided into "relatively sensitive" and "relatively resistant" GICs. Sensitivity to MRK003 was associated with its inhibitory effect on Akt pathway. Transgenic expression of the myristoylated Akt vector in relatively sensitive GICs partially rescued the effect of MRK003, suggesting that the effect of MRK003 was, at least in part, mediated through inhibition of the Akt pathway. These GICs were differentiated by the expression of CD44 and CD133 with flow cytometric analysis. The relatively sensitive GICs are CD44-high and CD133-low. The IC50 of MRK003 in a set of GICs exhibited a negative correlation with CD44 and positive correlation with CD133. Collectively, MRK003 is partially mediated by the Akt pathway and has strong therapeutic potential for CD44-high and CD133-low GICs. PMID- 25293443 TI - Neuroinflammation in Parkinson's disease animal models: a cell stress response or a step in neurodegeneration? AB - The motor symptoms of Parkinson's disease are due to the progressive degeneration of dopaminergic neurons in the substantia nigra. Multiple neuroinflammatory processes are exacerbated in Parkinson's disease, including glial-mediated reactions, increased expression of proinflammatory substances, and lymphocytic infiltration, particularly in the substantia nigra. Neuroinflammation is also implicated in the neurodegeneration and consequent behavioral symptoms of many Parkinson's disease animal models, although it is not clear whether these features emulate pathogenic steps in the genuine disorder or if some inflammatory features provide protective stress responses. Here, we compare and summarize findings on neuroinflammatory responses and effects on behavior in a wide range of toxin-based, inflammatory and genetic Parkinson's disease animal models. PMID- 25293444 TI - Meningococcal septic arthritis: an unexpected cause with public health implications. PMID- 25293442 TI - Effects of a community-based weight loss intervention on adipose tissue circulating factors. AB - AIMS: Obesity is associated with metabolic dysfunctions, which may be mediated by changes in adipose tissue signaling factors. These molecules are denoted as Adipose Tissue Generated Mediators of CardioVascular Risk (ATGMCVR) here, and include leptin, adiponectin, C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and plasminogen activator inhibitor 1 (PAI-1). This study examined the effect of a weight loss program on ATGMCVR in obese adults with prediabetes. MATERIALS AND METHODS: Subjects were randomized to usual care (UC; n=15) or lifestyle weight loss groups (LWL; n=15). LWL was a community-based weight loss intervention to promote physical activity and healthy eating. ATGMCVR at 1-year were compared between groups by analysis of covariance; baseline value of the mediator was the covariate. Baseline means for ATGMCVR were compared between those with (n=21) and without (n=9) metabolic syndrome (MetS). RESULTS: At baseline, subjects were 58+/-9 (SD) years, 70% female, with a BMI of 34+/-4kg/m(2). One-year weight loss (%) was 7.8+/-6.0% for LWL and 1.7+/-4.5% for UC. Group differences at 1-year were noted (adjusted means [95%CI] for UC and LWL, respectively) for adiponectin (8526.3 [7397.7, 9827]; 10,870.9 [9432.0, 12,529.3]ng/ml; p=0.02), leptin (30.4 [26.1, 35.4]; 23.7 [20.3, 27.5]ng/ml; p=0.02), IL-6 (0.4 [0.3, 0.5]; 0.2 [0.1, 0.2] pg/ml; p=0.001), and PAI-1 (50 [42.7, 58.7]; 36.2 [30.8, 42.4]pg/ml; p=0.01). No differences in baseline ATGMCVR were seen between subjects with and without MetS. CONCLUSION: These findings suggest ATGMCVR can be improved with weight loss; larger studies are needed to determine if improvements in metabolic dysfunction are related to changes in ATGMCVR. PMID- 25293445 TI - Elevated plasma homocysteine level is possibly associated with skin sclerosis in a series of Japanese patients with systemic sclerosis. AB - Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease (PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon (RP), digital ulcers (DU) in systemic sclerosis (SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti topoisomerase I antibody positivity, complications of DU, acro-osteolysis (AO) and interstitial lung disease (ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness (IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO. PMID- 25293446 TI - Formaldehyde chemistry in cometary ices: the case of HOCH2OH formation. AB - Laboratory experiments devoted to simulate the chemistry occurring in interstellar and cometary ice analogues are of paramount importance to understand the formation of complex organic molecules that are detected throughout the universe. These laboratory simulations provide relevant hints on the fundamental physical and chemical steps associated with the increase of the molecular complexity in space and, moreover, give benchmark results for dedicated space missions. In the present work, we study the thermally promoted reactivity of H2O dominated and D2O-dominated cometary ice analogues that contain various amounts of H2CO and NH3 by means of Fourier-transform infrared spectroscopy (FTIR), mass spectrometry and DFT calculations. Experimental measurements show that methyleneglycol (HOCH2OH) and D2-methyleneglycol (DOCH2OD, the corresponding isotopologue) are formed from the H2O- and D2O-dominated ices, respectively, only if ammonia is present. We also reported for the first time the mass spectrum of methyleneglycol and D2-methyleneglycol. B3LYP calculations have also been used to characterize the potential energy surface of the mechanistic steps associated with the formation of HOCH2OH as well as to simulate the IR spectrum of this compound. The fruitful interplay between theory and experiment has allowed us to elucidate the exact role of ammonia during the warming, which essentially stands for the formation and stabilization of the NH4(+)/OH(-) ion pair, thus enabling the OH(-) species to react with formaldehyde. The present results reproduce the heating of circumstellar ices in star formation regions and can be applied to the late thermal evolution of comets. In addition, the mass spectrum of methyleneglycol represents a benchmark for the analysis of the data coming from the ROSINA on-board instrument of the Rosetta mission. PMID- 25293447 TI - Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases. AB - We identified and characterized beta-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. beta-Aminoketones with certain structural features form alpha,beta-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP. PMID- 25293448 TI - MRI Findings in Childhood PRES: What is Different than the Adults? AB - PURPOSE: Posterior reversible encephalopathy syndrome (PRES) is a clinical scenario with convulsion, vision abnormalities, altered mental status, and headaches in the presence of an underlying etiology, and the diagnosis can be made by support of radiological studies. In this study, we evaluated the magnetic resonance imaging (MRI) findings of PRES in children and compared our findings with that of the known features in adults, and reviewed the possible pathophysiological reasons that may cause the difference. MATERIALS AND METHODS: A total of 29 children (13 male, 16 female, aged 1-17 years, mean age: 10 years) diagnosed as having PRES were retrospectively reviewed. Clinical records were analyzed for the clinical symptoms and the underlying etiology. MR images were evaluated for the distribution of lesions, contrast enhancement, diffusion restriction, and hemorrhage. RESULTS: Presenting symptoms and underlying etiologies were variable. Frontal lobe (66 %) edema was almost as common as parietal and occipital involvement. Cerebellar involvement was present in almost half of the patients (48 %), which was more frequent than in the adult patients. Contrast enhancement is another finding that was found to be more common in children than in the adults (39 %). Four patients had diffusion restriction (15 %) and four patients had hemorrhage (%15), which are almost the same frequency as in the adults. CONCLUSION: The increased incidence of cerebellar involvement may show that the posterior circulation in children is more vulnerable than the adults. The contrast enhancement in children, which is seen more commonly than in the adults, may show that the pathophysiology in children may be more commonly related to blood-brain barrier breakdown, which can support the theory of the toxic endothelial injury. PMID- 25293449 TI - ELN 2013 response status criteria: relevance for de novo imatinib chronic phase chronic myeloid leukemia patients? AB - The response definitions proposed by the European Leukemia Net (ELN) have been recently modified. We evaluated the new criteria for de novo imatinib (400 mg/d) chronic phase chronic myeloid leukemia (CP-CML) patients. Response status according to the 2009 and 2013 criteria were determined in 180 unselected patients. Outcome of the subgroups of patients were then compared. The 180 patients were classified as optimal responders (OR2009; n = 113, 62.7%), suboptimal responders (SOR2009; n = 47, 26.1%) and failures (FAIL2009; n = 20, 11.1%) according to the 2009 ELN criteria and optimal responders (OR2013; n = 77, 42.7%), warnings (WAR2013; n = 59, 32.7%), and failures (FAIL2013; n = 44, 24.4%) according to the 2013 ELN criteria. No difference in terms of outcome was observed between OR2009 patients who became WAR2013 when compared with OR2013 patients. When compared with FAIL2009 patients, SOR2009 patients who became WAR2013 had better EFS, FFS, PFS, and OS. No difference was observed in PFS or OS in SOR2009 patients who became FAIL2013. The 2013 ELN response status criteria have improved patients classification in terms of response status. However, in our patient population this improvement is related to a better definition of failure rather than that of optimal response for CP-CML patients treated with IM frontline therapy. PMID- 25293472 TI - Physics transforming the life sciences. AB - Biological physics is clearly becoming one of the leading sciences of the 21st century. This field involves the cross-fertilization of ideas and methods from biology and biochemistry on the one hand and the physics of complex and far from equilibrium systems on the other. Here I want to discuss how biological physics is a new area of physics and not simply applications of known physics to biological problems. I will focus in particular on the new advances in theoretical physics that are already flourishing today. They will become central pieces in the creation of this new frontier of science. PMID- 25293471 TI - A meta-analysis comparing the efficacy of entecavir and tenofovir for the treatment of chronic hepatitis B infection. AB - The efficacy of entecavir and tenofovir in patients with chronic hepatitis B virus (HBV) is inconsistent. To address this issue, we conducted a meta-analysis based on a current review of the literature addressing the efficacy and safety of entecavir and tenofovir. Electronic databases were searched through June 2014 for relevant clinical trials. We included 2 randomized controlled trials, 2 prospective cohort studies, and 7 case-control studies that included 1,656 patients. In the entecavir group, 842 of 992 were nucleos(t)ide-naive chronic HBV patients, and in the tenofovir group 481 of 664 were nucleos(t)ide-naive. The virological response to tenofovir was superior to entecavir (RR: 0.82; 95%CI: 0.72-0.93), especially in nucleos(t)ide-naive chronic HBV patients at 48 weeks (RR: 0.78; 95%CI: 0.65-0.92). Additionally, there was no difference between entecavir and tenofovir for virological response at 24 weeks (RR: 0.87, 95%CI: 0.71-1.05). The alanine aminotransferase normalization rate, serological response, and adverse event rate were also not significantly different between entecavir and tenofovir at 24 or 48 weeks after treatment. These results suggest that tenofovir is a better choice to treat chronic HBV patients than entecavir as it is better able to suppress HBV viral load and has a similar safety profile. PMID- 25293473 TI - Guidelines regarding the ineffective maintenance of organ functions (futile therapy) in ICU patients incapable of giving informed statements of will. PMID- 25293474 TI - The 2014 guidelines for post-operative pain management. PMID- 25293475 TI - Validation of a novel method for measuring intra-abdominal pressure and gastric residual volume in critically ill patients. AB - BACKGROUND: Gastric residual volume (GRV) can be measured in a variety of ways in critically ill patients, most often, the nasogastric tube is disconnected and the GRV is aspirated via a 60 mL syringe. Bladder pressure (IBP) measurement is the gold standard for intra-abdominal pressure (IAP) estimation. This study will look at the validation of a novel method combining measurement of GRV and estimation of IAP via intra-gastric pressure (IGP). METHODS: In total 135 paired IAP and 146 paired GRV measurements were performed in 37 mechanically ventilated ICU patients. The IAP was estimated via the bladder (i.e. IBP) using the FoleyManometer and via the stomach (i.e. IGP) with the new device. The GRV was measured with the new device (GRVprototype) and via the classic method (GRVclassic). The devices were provided by Holtech Medical (Charlottenlund, Denmark) and data were retrospectively analysed. RESULTS: The number of paired measurements in each patient was 4 +/- 1. The mean IBP was 10.7 +/- 4.1 and mean IGP was 11.6 +/- 4.1 mm Hg. Correlation between the IBP and IGP was significant, however moderate (R2 = 0.51). Analysis according to Bland and Altman showed a bias and precision of 0.8 and 2.7 mm Hg respectively, however the limits of agreement (LA) were large and ranged from -4.5 to 6.1 mm Hg. Changes in IGP correlated well with changes in IBP. The median GRVprototype was 80 mL (0-1050) and equal to the median GRVclassic of 80 mL (0-1250). Correlation between the 2 methods was excellent (R2 = 0.89). Analysis according to Bland and Altman showed a bias and precision of -0.8 and 52.3 mL respectively and the LA ranged from -103 to 102 mL. Changes in GRVclassic correlated well with changes in GRVprototype. CONCLUSIONS: The results of this multicentre pilot study show that GRV can be measured with the new device. Furthermore this allows simultaneous screening for intra-abdominal hypertension with IAP estimation via IGP. PMID- 25293476 TI - Sympathetic nerve blocks for the management of postherpetic neuralgia - 19 years of pain clinic experience. AB - BACKGROUND: Sympathetic system involvement in postherpetic neuralgia (PHN) has been targeted using peripheral sympathetic nerve blocks for a number of years with variable efficacy. The aim of this report is to present the outcomes of PHN management with concomitant use of pharmacological treatment and sympathetic nerve blocks. METHODS: We retrospectively evaluated clinical data on 563 patients with PHN symptoms treated in the pain clinic and identified cases in which sympathetic nerve blocks were implemented in the years 1992-2010. A Numeric Rating Scale was used as a pain severity assessment, with a reduction to values under 3 considered a positive therapy result. Three time intervals were considered: years 1992-1997 (I), 1998-2002 (II) and 2003-2010 (III). RESULTS: In group I, 27% of patients had poor treatment results, while in group II, the failure rate dropped to 18%. The same 18% failure rate was observed in group III as well. Treatment introduced early yielded the best results, but there was no difference among groups with a similar duration from herpes zoster onset to treatment commencement in the time periods assessed; however, from 1998 onward, the same rate of poor outcomes was also noted in the groups who started the sympathetic blockade, which aided pain clinic treatment up to 3 months and between 3 and 6 months from the onset of herpes zoster. CONCLUSION: Major progress in the pharmacological treatment of PHN appears to be an obvious factor contributing to the overall improvement in PHN management (introduction of gabapentin). Nevertheless, safely administered regional anaesthesia techniques, although performed in a very similar manner for many years, appear to provide some support as part of a multimodal approach to PHN management. PMID- 25293477 TI - Serum procalcitonin is a sensitive marker for septic shock and mortality in secondary peritonitis. AB - BACKGROUND: Serum procalcitonin (PCT) is considered to be a sensitive marker for the early recognition of severe infection. The aim of this study was to review the diagnostic accuracy of serum procalcitonin levels to predict the risk of septic shock and mortality in patients with secondary peritonitis. METHODS: We carried out a retrospective review of patients (November 2010 to November 2012) admitted to the surgical intensive care unit (ICU) with secondary peritonitis classified into localised peritonitis (LP) or diffuse peritonitis (DP) groups. Organ dysfunction was assessed with the SOFA score. Demographic data was collected as well as results for neutrophil count, C- reactive protein, blood lactate, and PCT levels. The primary end-point was ICU mortality. RESULTS: From a total of 222 patients, 123 were allocated to the LP group and 99 to the DP group. Severe sepsis was observed in 41.9% of all patients in the DP group. The PCT levels increased significantly in the DP group, with the development of septic shock in 29 patients. Higher PCT levels were associated with an increased risk for septic shock with a cut-off value of 15.3 ng mL-1 and an increased risk for mortality with a cut-off value 19.6 ng mL-1. A total of 59.1% of those who developed septic shock died. CONCLUSION: An increase in PCT levels is an indirect sign of diffuse secondary peritonitis and this is associated with an increased risk of septic shock. Increased PCT level on admission is associated with an increased risk of mortality in this category of patients. PMID- 25293478 TI - Assessment of the depth of anaesthesia during inhalational and intravenous induction of general anaesthesia. AB - BACKGROUND: Tracheal intubation is one of the strongest stimuli during general anaesthesia and may result in an insufficient depth of anaesthesia. The aim of the study was to compare the clinical evaluation of the depth of anaesthesia with an evaluation using entropy during inhalational and intravenous induction of general anaesthesia. METHODS: This study involved 60 patients undergoing elective surgery under general anaesthesia. Patients were divided into two groups, group E (etomidate induction) and group S (sevoflurane induction). The systolic arterial pressure (SAP), heart rate (HR), response entropy (RE), and state entropy (SE) were determined at the following seven measurement points: before anaesthesia induction, at the loss of consciousness (LOC) point, before tracheal intubation, immediately after intubation, and 2 min., 4 min. and 6 min. after tracheal intubation. An increase in HR and/or SAP of more than 20% and/or the occurrence of lacrimation and/or perspiration in response to tracheal intubation was considered a marker of inadequate anaesthesia in the clinical evaluation. The depth of anaesthesia was considered insufficient according to entropy monitoring if the RE and SE were above 60. RESULTS: In clinical evaluation, insufficient anaesthesia in response to tracheal intubation was observed in all the patients in group E and in more than half of the patients in group S. At the same time, the majority of patients in both groups had entropy values that did not exceed the recommended value as an appropriate level of anaesthesia. CONCLUSIONS: We found a discrepancy in the evaluation of the depth of anaesthesia based on clinical criteria compared with evaluations based on entropy values during both intravenous and inhalational induction of general anaesthesia. PMID- 25293479 TI - The prevalence of infections and colonisation with Klebsiella pneumoniae strains isolated in ICU patients. AB - BACKGROUND: Klebsiella spp. are among the bacteria most commonly isolated from patients with infections in ICUs. The source of these infections may be the microflora of the patient or the hospital environment. Increasingly, Klebsiella strains are also being isolated from epidemic outbreaks. This situation is largely the result of widespread, irrational antibiotic use, the virulence of the bacterial strains and their ability to survive in the hospital environment. The purpose of this dissertation was to estimate the prevalence of Klebsiella pneumoniae strains isolated from patients hospitalised in a single ICU. METHODS: Seventy-eight isolates of K. pneumoniae were studied. The identification and the susceptibility to selected antibiotics were tested by an automated system, VITEK2 Compact. For the analysed strains, the production of different beta-lactamases was noted. RESULTS: Production of ESBL was detected in 64.1% of the K. pneumoniae strains isolated from infections and 74.4% from rectal swabs. Most of the strains were susceptible to imipenem (97.7%) and meropenem (96.1%). Sixty-nine (57.0%) of the analysed strains were identified as multidrug resistant. CONCLUSION: Most of the analysed Klebsiella pneumoniae strains produced ESBL-beta-lactamases. The frequency of colonisation and infection with multidrug resistant strains of K. pneumoniae in patients hospitalised in the ICU is very high. PMID- 25293480 TI - The effect of bispectral index monitoring on anaesthetic requirements in target controlled infusion for lumbar microdiscectomy. AB - BACKGROUND: Target-controlled infusion (TCI) is used to maintain the desired concentration of a hypnotic drug in the plasma and brain. However, pharmacodynamic variability can cause problems with maintaining the adequate level of anaesthesia. The bispectral index (BIS) is one of only a few parameters that allow an assessment of the depth of anaesthesia. In the present study, we attempted to determine the optimal dosages of drugs used for total intravenous anaesthesia with TCI based on BIS-guided monitoring of depth of anaesthesia. METHODS: The study was conducted in 60 ASA I patients undergoing elective surgery due to lumbar discopathy. The participants were divided into two groups of 30 individuals. The patients were premedicated with 15 mg oral midazolam. Group I was the control group; group II received BIS monitoring. Anaesthesia was induced with TCI propofol (4 mg mL-1), fentanyl (2 mg kg-1) and vecuronium (0.12 mg kg-1) and maintained with TCI propofol, continuous infusion of vecuronium (0.03 mg kg-1 h-1) and fractionated doses of fentanyl. ECG, HR, MAP, SaO2, ETCO2, and the degree of neuromuscular blockade were monitored, specifically at the following time points: T1 - before induction, T2 - after induction, T3 - after intubation, T4 - after positioning of the patient, T5-T13 - every 5 min during surgery, T14 - on completion of surgery, T15 - before extubation, T16 - after extubation. RESULTS: The study groups were comparable in terms of age, body weight, duration of anaesthesia and recovery time. The haemodynamic parameters, such as HR and MAP, did not differ significantly between the groups. In both groups, changes in the mean MAP values were observed between T1 and T2, T2 and T3, T3 and T4 as well as T14and T15. The total dose of fentanyl and the doses of propofol were lower in the group that received BIS monitoring. CONCLUSION: BIS monitoring reduces the doses of opioids and hypnotics used during total intravenous anaesthesia by TCI. PMID- 25293481 TI - Subarachnoid haemorrhage imitating acute coronary syndrome as a cause of out-of hospital cardiac arrest - case report. AB - BACKGROUND: Severe subarachnoid haemorrhage (SAH) is a common cause of cardiac arrest. The survival of patients with out-of-hospital cardiac arrest (OHCA) due to SAH is extremely poor. Electrocardiographic and echocardiographic changes associated with SAH may mimic changes caused by acute coronary syndromes (ACS) and thus lead to delayed treatment of the primary disease. Misdiagnosed SAH due to ACS mask can have an influence on patient outcomes. CASE REPORT: A 47-year-old man presented with a history of out-of-hospital cardiac arrest due to asystole. He had a medical history of hypertension, smoking, and a diffuse, severe headache for one week. The ECG showed atrial fibrillation, 0,2 mV ST-segment elevation in leads aVR and V1-V3 and 0.2 mV ST-segment depression in leads I, II, aVL and V4 V6. Echocardiography revealed left ventricular function impairment (ejection fraction < 20%). The CK-MB activity was 98 U L-1 and the troponin I concentration was 0.59 MUg L-1. ACS was suspected. Coronarography did not reveal any changes in the coronary arteries. An urgent CT of the head was arranged and showed an extensive SAH. CONCLUSIONS: It appears that an urgent CT of the head is the most effective method for the early identification of SAH-induced OHCA, especially in patients with prodromal headache, no history of the symptoms of ACS and CA due to asystole/pulseless electrical activity (PEA). Out-of-hospital cardiac arrest (OHCA) predominantly develops due to acute coronary syndrome (ACS). Extra-cardiac causes, e.g., subarachnoid haemorrhage (SAH), are less common. The purpose of the present case report was to describe a patient with OHCA due to subarachnoid haemorrhage imitating acute coronary syndrome. PMID- 25293482 TI - Current treatment of convulsive status epilepticus - a therapeutic protocol and review. AB - The management of status epilepticus (SE) has changed in recent years. Substantial differences exist regarding the definition and time frame of a seizure, which has been operationally defined as lasting for 5 min. Not only have many new intravenous drugs, such as levetiracetam and lacosamide been introduced but other routes of administration, such as intranasal or buccal administration for midazolam, are also being developed. Optimal and successful therapy initiated at the appropriate moment, adequately tailored to the clinical state of the patient, determines the first step in the normalisation of vital functions and leads to the restoration of the physiological homeostatic mechanisms of the organism. The aim of this review is to present the current treatment options for the management of convulsive status epilepticus (CSE) that have been widely confirmed as the most effective in clinical trials and approved by the international neurology authorities as the actual therapeutic standards. We also intend to indicate distinct and unequivocal differentiation and therapeutic indications for each phase of CSE, including the precise doses of the related medications, to present practical guidelines for clinicians. The treatment of patients with CSE requires emergency physicians, neurologists and specialists in intensive care to work together to provide optimal care that should be initiated as soon as possible and conducted as a unified procedure to improve neurocritical care in patients who are transferred from the ambulance service, through the emergency department and finally to the neurology department or ICU. Appropriate treatment also involves avoiding mistakes associated with inadequate doses of medications, overdosing a patient or choosing an inappropriate medication. PMID- 25293483 TI - Cardiogenic shock - diagnostic and therapeutic options in the light of new scientific data. AB - Shock is a manifestation of circulatory failure related to an inadequate supply of oxygenated blood to the tissues. One type of shock is cardiogenic shock resulting from abnormalities of myocardial structure and function, impairment of mechanical function of the heart, or arrhythmia. Most commonly, cardiogenic shock is due to an acute myocardial infarction, particularly involving the anterior wall. However, establishing the diagnosis of cardiogenic shock and determining its aetiology is not always easy. Techniques of invasive haemodynamic monitoring, measurements of specific biomarkers, and noninvasive bedside echocardiography may be helpful. The effectiveness of shock management depends on the ability to institute appropriate therapy rapidly and to remove the underlying aetiologic factor(s). We present a state-of-the-art review of basic approaches used for the diagnosis and management of cardiogenic shock. PMID- 25293484 TI - Drug administration via enteral feeding tubes in intensive therapy - terra incognita? AB - The use of enteral feeding tubes has become more frequent, both in hospital settings and in home care. The feeding tubes serve not only to deliver nutrients, but also as a route for medication provision. Nonetheless, the pharmaceutical, legal and technical implications of medication delivery via enteral feeding tubes are not widely understood by doctors and nurses. Not only is the type of medication relevant, but also the type of feeding tube. Crushing tablets may have detrimental effects for a patient and a staff member too. Administering a drug via enteral feeding tubes usually falls outside the terms of the licence (off label), so burdening medical staff with the entire responsibility for potential adverse reactions. PMID- 25293485 TI - 2-(1-Aryliminoethyl)-9-arylimino-5,6,7,8-tetrahydrocycloheptapyridyl iron(II) dichloride: synthesis, characterization, and the highly active and tunable active species in ethylene polymerization. AB - A series of 2-(1-arylimino)ethyl-9-arylimino-5,6,7,8-tetrahydrocycloheptapyridine derivatives was synthesized and fully characterized, and thereafter reacted with iron dichloride to form their corresponding iron(II) complexes. The single crystals of representative organic and iron complex compounds were obtained and analyzed by the X-ray diffraction analysis, indicating the distorted bipyramidal geometry around the iron core. Moreover, DFT calculations were performed on selected species to determine their structural features. On treatment with either MAO or MMAO, all iron complex pre-catalysts showed high activities (up to 1.56 * 10(7) gPE mol(-1)(Fe) h(-1)) toward ethylene polymerization. Regarding the nature of the ligands and reaction parameters, their catalytic activities and the characters of the obtained polyethylenes have been carefully investigated. The ring strain of the fused-cycloheptane of the ligands within iron complexes was considered to affect their catalytic performance in ethylene polymerization. The active species were activated and controlled by using a co-catalyst of MMAO preferred over MAO, and the obtained polyethylenes with MMAO showed narrower molecular polydispersity than the corresponding polyethylenes with MAO. PMID- 25293486 TI - [Dysthyroidism with anti-VEGF treatment, a class effect? about one case report]. AB - Tyrosine-kinase inhibitors are recent therapy used in different neoplastic diseases. Dysthyroidism seems to be a class effect of these drugs with a potentially cross cumulative effect. We describe here the case of a man who first developed dysthyroidism with sunitinib, then a deep and permanent hypothyroidism when axitinib was introduced. PMID- 25293487 TI - [Hypersexuality associated with aripiprazole: a new case and review of the literature]. AB - We report the case of a patient with hypersexuality while he was treated with aripiprazole since 6 months. Clinical manifestations were an increased libido, unusual frequent masturbation and sexual instincts. All have resolved upon discontinuation of aripiprazole, and recurred after it was restarted. The partial dopaminergic agonist effect of aripiprazole could probably explain the occurrence of this compulsive behaviour. PMID- 25293489 TI - Association of the time that elapsed from last vaccination with protective effectiveness against foot-and-mouth disease in small ruminants. AB - Routine and emergency vaccination of small ruminants against foot-and-mouth disease (FMD) is mandatory in many endemic countries, yet data on the field effectiveness of the vaccines used is scarce. We conducted an investigation of a serotype O FMD outbreak that took place in a sheep and goat pen, and estimated the effectiveness of various routine vaccination statuses. We also evaluated the protection provided by colostrum administration and emergency vaccination. Animals which were routinely vaccinated twice were not clinically affected while disease incidence was observed among animals routinely vaccinated only once (p = 0.004 according to a two-sided Fisher's exact test). In groups vaccinated only once, there was a significant association between the average time that elapsed since last vaccination and the disease incidence (n = 5; Spearman correlation coefficient: rs = 1.0, p < 0.01). In addition, non-vaccinated lambs fed colostrum from dams vaccinated more than 2 months before parturition had a mortality rate of 33%. Administration of emergency vaccination 2 days after the occurrence of the index case was the probable reason for the rapid blocking of the FMD spread within 6 days from its onset in the pen. PMID- 25293490 TI - Factors affecting the success of resynchronization protocols with or without progesterone supplementation in dairy cows. AB - The objective of this study was to investigate factors that influence the success of resynchronization protocols for bovines with and without progesterone supplementation. Cow synchronized and not found pregnant were randomly assigned to two resynchronization protocols: ovsynch without progesterone (P4) supplementation (n = 66) or with exogenous P4 administered from Days 0 to 7 (n = 67). Progesterone levels were measured on Days 0 and 7 of these protocols as well as 4 and 5 days post-insemination. Progesterone supplementation raised the P4 levels on Day 7 (p < 0.05), but had no overall effect on resynchronization rates (RRs) or pregnancy per artificial insemination (P/AI). However, cows with Body Condition Score (BCS) > 3.5 had increased P/AI values while cows with BCS < 2.75 had decreased P/AI rates after P4 supplementation. Primiparous cows had higher P4 values on Day 7 than pluriparous animals (p = 0.04) and tended to have higher RRs (p = 0.06). Results of this study indicate that progesterone supplementation in resynchronization protocols has minimal effects on outcomes. Parity had an effect on the levels of circulating progesterone at initiation of the protocol, which in turn influenced the RR. PMID- 25293488 TI - Treadmill exercise prevents diabetes-induced increases in lipid peroxidation and decreases in Cu,Zn-superoxide dismutase levels in the hippocampus of Zucker diabetic fatty rats. AB - In the present study, we investigated the effects of treadmill exercise on lipid peroxidation and Cu,Zn-superoxide dismutase (SOD1) levels in the hippocampus of Zucker diabetic fatty (ZDF) rats and lean control rats (ZLC) during the onset of diabetes. At 7 weeks of age, ZLC and ZDF rats were either placed on a stationary treadmill or made to run for 1 h/day for 5 consecutive days at 16~22 m/min for 5 weeks. At 12 weeks of age, the ZDF rats had significantly higher blood glucose levels and body weight than the ZLC rats. In addition, malondialdehyde (MDA) levels in the hippocampus of the ZDF rats were significantly higher than those of the ZLC rats whereas SOD1 levels in the hippocampus of the ZDF rats were moderately decreased. Notably, treadmill exercise prevented the increase of blood glucose levels in ZDF rats. In addition, treadmill exercise significantly ameliorated changes in MDA and SOD1 levels in the hippocampus although SOD activity was not altered. These findings suggest that diabetes increases lipid peroxidation and decreases SOD1 levels, and treadmill exercise can mitigate diabetes-induced oxidative damage in the hippocampus. PMID- 25293492 TI - It is time to revisit current dietary recommendations for saturated fat. AB - The extent to which a high intake of saturated fat (SFA) increases the risk of cardiovascular disease (CVD) has become a highly controversial topic. Dietary SFA primarily raises low-density lipoprotein cholesterol, while having a relatively neutral impact on other key CVD risk factors. Recent epidemiological data also challenge the concept that SFA increases the risk of CVD. This short review provides arguments for the urgency to re-assess the association between dietary SFA and CVD risk in light of recent data on the subject. PMID- 25293494 TI - Nonfluorescent chlorophyll catabolites in loquat fruits (Eriobotrya japonica Lindl.). AB - Nonfluorescent chlorophyll catabolites (NCCs) and nonfluorescent dioxobilane chlorophyll catabolites (NDCCs) are the terminal compounds of the chlorophyll degradation pathway that may display beneficial properties to human health related to their antioxidant properties, which were recently shown. A profile of NCCs/NDCC of the loquat fruit Eriobotrya japonica Lindl. is described. From the 13 known different NCC structures described to date, three have been identified in loquats. Two new structures not defined so far were characterized in loquat fruits: Ej-NCC2, which corresponds to the methyl ester at C13(2) of Bn-NCC1 and in very low amount Ej-NDCC1, the only NDCC found in loquats. Keto-enol tautomerism at the C13(1) position in NCCs is described for the first time as a regular process in chlorophyll catabolism, probably through a nonspecific mechanism since almost all the chlorophyll catabolites structures detected in fruits of loquat present keto and enol tautomers. The results obtained have been possible through a high-performance liquid chromatography coupled with electrospray ionization ion trap and quadropole time-of-flight mass spectrometry fitted with a powerful postprocessing software. PMID- 25293495 TI - Selection on female behaviour fluctuates with offspring environment. AB - Temporal variation in selection has long been proposed as a mechanism by which genetic variation could be maintained despite short-term strong directional selection and has been invoked to explain the maintenance of consistent individual differences in behaviour. We tested the hypothesis that ecological changes through time lead to fluctuating selection, which could promote the maintenance of variation in female behavioural traits in a wild population of North American red squirrels. As predicted, linear selection gradients on female aggression and activity significantly fluctuated across years depending on the level of competition among juveniles for vacant territories. This selection acted primarily through juvenile overwinter survival rather than maternal fecundity. Incorporating uncertainty in individual measures of behaviour reduced the magnitude of annual selection gradients and increased uncertainty in these estimates, but did not affect the overall pattern of temporal fluctuations in natural selection that coincided with the intensity of competition for vacant territories. These temporal fluctuations in selection might, therefore, promote the maintenance of heritable individual differences in behaviour in this wild red squirrel population. PMID- 25293496 TI - CORR Insights: Subject-specific patterns of femur-labrum contact are complex and vary in asymptomatic hips and hips with femoroacetabular impingement. PMID- 25293493 TI - Sex differences in mitochondrial (dys)function: Implications for neuroprotection. AB - Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development. PMID- 25293497 TI - Abnormal quantitative sensory testing is associated with persistent pain one year after TKA. AB - BACKGROUND: Up to 15% of patients report at least moderate persistent pain after TKA. Such pain may be associated with the presence of widespread hyperalgesia and neuropathic-type pain. QUESTIONS/PURPOSES: We asked if there was a difference among patients who report moderate to severe pain or no pain at least 12 months after TKA regarding (1) pressure pain threshold, (2) thermal (cold/heat) pain and detection thresholds, and (3) self-reported neuropathic pain. PATIENTS AND METHOD: Fifty-three volunteers were recruited from patients reporting no pain or moderate to severe pain, according to the Knee Society Score(c). Differences between the moderate-to-severe and no-pain groups regarding pressure pain, heat and cold thresholds, and self-reported neuropathic-type pain were analyzed using independent t-tests. RESULTS: Patients in the moderate-to-severe pain group exhibited reduced pressure pain threshold in the knee with the TKA (p=0.025) and at the elbow (p=0.002). This group also showed greater pain sensitivity to cold at the knee (p=0.008) and elbow (p=0.010), and increased heat pain sensitivity at the elbow (p=0.032). Cold and heat detection thresholds were impaired in this group at the elbow (cold, p=0.034; heat, p=0.010), although only heat detection was impaired at the knee (p=0.009). The moderate-to-severe pain group also reported more neuropathic-type pain (p=0.001). CONCLUSION: Persistent pain after TKA was associated with widespread pressure, cold hyperalgesia, and greater neuropathic-type pain. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25293499 TI - Chassis organism from Corynebacterium glutamicum: the way towards biotechnological domestication of Corynebacteria. PMID- 25293498 TI - Long-term periodontal tissue outcome in regenerated infrabony and furcation defects: a systematic review. AB - OBJECTIVES: This study aimed to systematically evaluate the long-term results of periodontal tissues in regenerated infrabony and furcation defects. MATERIAL AND METHODS: A search of the Medline database was performed (1960 to 2012), complimented by an additional hand search. For inclusion in the review, clinical trials had to include the long-term evaluation of infrabony and furcation defects submitted to periodontal regeneration for up to 3 years of follow-up. Changes in clinical attachment level (CAL) from pre-surgery, at the first post-surgical, and final evaluations were used to analyze the effects of regenerative treatments over time. RESULTS: A total of 866 articles were found using the descriptors employed. Of these, 216 papers were selected for abstract reading by two evaluators. One hundred and eighty-nine were excluded for not fulfilling the eligibility criteria. Twenty-seven papers were selected for the analysis of the full texts, and 13 were excluded. Two studies were included after a manual search. Finally, 16 papers were selected for the present review. CONCLUSIONS: Regenerative techniques for the treatment of infrabony and furcation defects resulted in improved CAL during long-term follow-up periods, even when attachment losses occurred during this period. This improvement should be carefully evaluated with regard to its clinical relevance for dental longevity. CLINICAL RELEVANCE: The improvement in clinical attachment level achieved by regenerative techniques with biomaterials demonstrated satisfactory results over the long term. However, regenerative techniques still present different success rates with regard to gain in clinical attachment level. PMID- 25293500 TI - Correlation of structural abnormalities of the wrist and metacarpophalangeal joints evaluated by high-resolution peripheral quantitative computed tomography, 3 Tesla magnetic resonance imaging and conventional radiographs in rheumatoid arthritis. AB - AIM: In rheumatoid arthritis (RA) hands, we applied high-resolution peripheral quantitative computed tomography (HR-pQCT) and 3 Tesla (3 T) magnetic resonance imaging (MRI), which are new methods for erosion detection and bone marrow edema (BME) quantification. We compared the erosion measurements between these techniques with conventional radiographs (CR) in order to examine their significance for evaluating structural abnormalities. METHODS: In 16 RA patients, HR-pQCT of metacarpophalangeal and wrist joints, 3 T MRI of wrist joints, as well as CR in both hands and feet were performed. Ten patients had 1-year follow-up CR. CRs were graded according to the modified Sharp score (MSS). Bone erosions were evaluated in HR-pQCT and MRI. BME pattern was quantified from MRI for volume, signal change and total burden. RESULTS: The erosion detection sensitivity of MRI was 85.7% and CR was 60.9% when HR-pQCT was considered as a reference method. The smallest dimensions of erosion detected by HR-pQCT, MRI and CR were 0.09, 0.14 and 0.66 cm, respectively. Baseline total MSS was correlated with HR-pQCT erosion measures, MRI erosion measures and MRI BME volume (P < 0.05). The mean difference between baseline and 1-year follow-up MSS (delta MSS) was 1.2. A trend was observed toward a correlation between delta MSS and MRI BME volume and burden. CONCLUSION: This study demonstrates that HR-pQCT detects more and smaller bone erosions compared to MRI and CR. In addition, 3 T MRI can provide quantitative measurement of BME. Combination of HR-pQCT and MRI modalities may provide powerful tools to evaluate joint inflammation and bone damage in RA. PMID- 25293501 TI - Sunlight-driven hydrogen peroxide production from water and molecular oxygen by metal-free photocatalysts. AB - Design of green, safe, and sustainable process for the synthesis of hydrogen peroxide (H2 O2 ) is a very important subject. Early reported processes, however, require hydrogen (H2 ) and palladium-based catalysts. Herein we propose a photocatalytic process for H2 O2 synthesis driven by metal-free catalysts with earth-abundant water and molecular oxygen (O2 ) as resources under sunlight irradiation (lambda>400 nm). We use graphitic carbon nitride (g-C3 N4 ) containing electron-deficient aromatic diimide units as catalysts. Incorporating the diimide units positively shifts the valence-band potential of the catalysts, while maintaining sufficient conduction-band potential for O2 reduction. Visible light irradiation of the catalysts in pure water with O2 successfully produces H2 O2 by oxidation of water by the photoformed valence-band holes and selective two electron reduction of O2 by the conduction band electrons. PMID- 25293502 TI - Factors that contribute to underrecognition of delirium by registered nurses in acute care settings: a scoping review of the literature to explain this phenomenon. AB - AIMS AND OBJECTIVES: In order to obtain more information regarding this phenomenon, a scoping review of the literature was undertaken to analyse current research on the recognition of delirium by registered nurses in acute care settings. BACKGROUND: Delirium is often manifested as a sign of an underlying undiagnosed condition that requires immediate intervention and is frequently manifested in acute care settings. Unfortunately, registered nurses often do not recognise delirium and its occurrence goes under-reported. DESIGN/METHODS: Based on six inclusion criteria, a search in numerous databases using terms such as delirium detection, recognition and diagnosis by registered nurses was undertaken. Eight quantitative studies were deemed relevant and analysed for this scoping review. RESULTS: Seven major categories emerged: the fluctuating nature of delirium, the impact of delirium education on its recognition, communication barriers, inadequate use of delirium assessment tools, lack of conceptual understanding of delirium, delirium as a burden and the likeness of delirium and dementia. A brief summary of the findings in each category is reported here. CONCLUSIONS: The scoping review revealed that delirium remains underrecognised by registered nurses, which potentially contributes to reduced quality of nursing care for clients experiencing this condition. Further research on delirium and the processes that registered nurses use to recognise it is timely and will facilitate the development of evidence-based interventions to manage it. RELEVANCE TO CLINICAL PRACTICE: While acute care registered nurses have historically reported dramatic changes in cognitive and neuro-biological functions in ill older adults, the literature highlighted in this scoping review revealed the following: (1) the need for further research to validate delirium assessment tools and, (2) the need for education and training for registered nurses on the use of these assessment tools to promote early recognition and thereby decrease the incidence of delirium in older adults. PMID- 25293503 TI - Thyroid-like follicular carcinoma of the kidney: a case report and review of the literature. AB - Thyroid-like follicular carcinoma of the kidney is an extremely rare histological variant of renal cell carcinoma. It was described only recently and is not included in the World Health Organization classification of renal tumors. This tumor characteristically shows similar histology to thyroid follicular carcinoma but lacks typical thyroid markers. Herein, we report a new case of thyroid-like follicular carcinoma of the kidney diagnosed in a partial nephrectomy specimen in a 68-year-old-woman. We present typical histological and immunohistochemical findings, discuss differential diagnosis and provide a review of the literature.Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_186. PMID- 25293504 TI - A full compositional range for a (Ga1-x Zn x )(N1-x O x ) nanostructure: high efficiency for overall water splitting and optical properties. AB - Bulk (Ga1-x Zn x )(N1-x O x ) as a photocatalyst has received increasing attention as a potential solution for the energy shortage challenge; however, its catalytic performance is highly limited by its bulk form. To improve the photochemical potential, the nanoscale form of this multiple-metal oxynitrides is desirable. In this work, a new type of (Ga1-x Zn x )(N1-x O x ) nanostructure is obtained. Its composition can tuned to the full range (0.18 < x < 0.95). The (Ga1 x Zn x )(N1-x O x ) nanostructure exhibits excellent photocatalytic activity for overall water splitting, and the highest quantum efficiency of (Ga1-x Zn x )(N1-x O x ) is as high as 17.3% under visible light irradiation. Using this new type of (Ga1-x Zn x )(N1-x O x ) nanostructure, the narrowing of the bandgap for (Ga1-x Zn x )(N1-x O x ) is not only due to an increase in the valence band maximum, but it is also related to a decrease in the conduction band minimum. PMID- 25293505 TI - Functional brain networks: linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study. AB - Thalamic atrophy is known to be one of the most important predictors for clinical dysfunction in multiple sclerosis (MS). As the thalamus is highly connected to many cortical areas, this suggests that thalamic atrophy is associated with disruption of cortical functional networks. We investigated this thalamo-cortical system to explain the presence of physical and cognitive problems in MS. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were performed in 86 MS patients and 21 healthy subjects. We computed cortical functional networks for fMRI and MEG by respectively the Pearson's correlation coefficient and the phase lag index using the same automated anatomical labeling atlas for both modalities. Thalamo-cortical functional connectivity was only estimated using fMRI. We computed conventional network metrics such as clustering coefficient and path length and analyzed the minimum spanning tree (MST), a subnetwork and backbone of the original network. MS patients showed reduced thalamic volumes and increased thalamo-cortical connectivity. MEG cortical functional networks showed a lower level of integration in MS in terms of the MST, whereas fMRI cortical networks did not differ between groups. Lower integration of MEG cortical functional networks was both related to thalamic atrophy as well as to increased thalamo-cortical functional connectivity in fMRI and to worse cognitive and clinical status. This study demonstrated for the first time that thalamic atrophy is associated with global disruption of cortical functional networks in MS and this global disruption of network activity was related to worse cognitive and clinical function in MS. Hum Brain Mapp 36:603 618, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25293507 TI - Electrical conduction of nanoparticle monolayer for accurate tracking of mechanical stimulus in finger touch sensing. AB - A flexible strain gauge is an essential component in advanced human-machine interfacing, especially when it comes to many important mobile and biomedical appliances that require the detection of finger touches. In this paper, we report one such strain gauge made from a strip of nanoparticle monolayer onto a flexible substrate. This proposed gauge operates on the observation that there is a linear relationship between electrical conduction and mechanical displacement in a compressive state. Due to its prompt temporal response, the gauge can accurately track various mechanical stimuli running at the frequencies of interest. Experiments have confirmed that the proposed strain gauge has a strain detection limit as low as 9.4 * 10(-5), and its gauge factor can be as large as 70, making this device particularly suitable for sensitive finger touch sensing. Furthermore, negligible degradation in the gauge's output electrical signal is observed even after 9000 loading/unloading cycles. PMID- 25293506 TI - Hydrogen sulfide-induced processing of the amyloid precursor protein in SH-SY5Y human neuroblastoma cells involves the PI3-K/Akt signaling pathway. AB - Hydrogen sulfide (H2S) has been recently categorized as a gasotransmitter, and it may be involved in the pathology of Alzheimer's disease. However, whether H2S induces amyloid precursor protein (APP) processing remains unknown. In the present study, we tested the ability of H2S to mediate APP processing in SH-SY5Y human neuroblastoma cells. We treated SH-SY5Y human neuroblastoma cells with a range of sodium hydrosulfide (H2S donor) concentrations. Western blot analysis showed that H2S increased the generation of C83 and decreased the production of C99. Meanwhile, H2S increased the levels of a disintegrin and metalloprotease 10 (ADAM10) mRNA and protein, but had no effect on TNF-alpha-converting enzyme (TACE, also known as ADAM17) mRNA and protein levels. H2S also induced a significant decrease of extracellular amyloid-beta42 (Abeta42). Furthermore, SH SY5Y human neuroblastoma cells were assayed for activation of the phosphoinositide 3-kinase (PI3-K) pathway. H2S activated the PI3-K pathway. Using specific inhibitor of PI3-K, we determined that the effects of H2S on APP processing and Abeta42 were blocked by LY 294002 (PI3-K inhibitor). These data indicate that H2S can induce APP processing, and this effect is dependent on activation of the PI3-K signaling pathway. PMID- 25293508 TI - Ordered hierarchically porous carbon codoped with iron and nitrogen as electrocatalyst for the oxygen reduction reaction. AB - N-doped carbon catalysts have attracted great attention as potential alternatives to expensive Pt-based catalysts used in fuel cells. Herein, an ordered hierarchically porous carbon codoped with N and Fe (Fe-NOHPC) is prepared by an evaporation-induced self-assembly process followed by carbonization under ammonia. The soft template and Fe species promote the formation of the porous structure and facilitate the oxygen reduction reaction (ORR).The catalyst possesses an ordered hierarchically porous structure with a large surface area (1172.5 m(2) g(-1) ) and pore volume of 1.03 cm(3) g(-1) . Compared to commercial 20% Pt/C, it exhibits better ORR catalytic activity and higher stability as well as higher methanol tolerance in an alkaline electrolyte, which demonstrates its potential use in fuel cells as a nonprecious cathode catalyst. The N configuration, Fe species, and pore structure of the catalysts are believed to correlate with its high catalytic activity. PMID- 25293509 TI - A synthetic stimulant never tested in humans, 1,3-dimethylbutylamine (DMBA), is identified in multiple dietary supplements. AB - A synthetic stimulant never before studied in humans, 1,3-dimethylbutylamine (DMBA), was suspected of being present in dietary supplements. DMBA is an analogue of the pharmaceutical stimulant, 1,3-dimethylamylamine (DMAA), which was recently banned by the US Food and Drug Administration. We obtained all dietary supplements sold by US distributors that listed an ingredient on the label, such as AMP Citrate, that might be a marketing name for DMBA. Supplements were analyzed for the presence and quantity of DMBA. Fourteen supplements met our inclusion criteria and were analyzed by two separate laboratories using ultra high performance liquid chromatography (UHPLC) - mass spectrometry and a reference standard. The identity of DMBA was confirmed in 12 supplements in the range of 13 to 120 mg DMBA per serving. Following recommendations on the supplement label for maximum daily intake, customers would consume from 26 to 320 mg of DMBA per day. Supplements containing DMBA were marketed to improve athletic performance, increase weight loss and enhance brain function. DMBA has never before been detected in supplements. The stimulant has never been studied in humans; its efficacy and safety are entirely unknown. Regulatory agencies should act expeditiously to warn consumers and remove DMBA from all dietary supplements. PMID- 25293510 TI - Comprehensive bio-imaging using myocardial perfusion reserve index during cardiac magnetic resonance imaging and high-sensitive troponin T for the prediction of outcomes in heart transplant recipients. AB - We sought to determine the ability of quantitative myocardial perfusion reserve index (MPRI) by cardiac magnetic resonance (CMR) and high-sensitive troponin T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant (HT) recipients. In 108 consecutive HT recipients (organ age 4.1+/-4.7 years, 25 [23%] with diabetes mellitus) who underwent cardiac catheterization, CAV grade by International Society for Heart & Lung Transplantation (ISHLT) criteria, MPRI, late gadolinium enhancement (LGE) and hsTnT values were obtained. Outcome data including cardiac death and urgent revascularization ("hard cardiac events") and revascularization procedures were prospectively collected. During a follow-up duration of 4.2+/-1.4 years, seven patients experienced hard cardiac events and 11 patients underwent elective revascularization procedures. By multivariable analysis, hsTnT and MPRI both independently predicted cardiac events, surpassing the value of LGE and CAV by ISHLT criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and low MPRI showed the highest rates of cardiac events (annual event rate=14.5%), while those with low hsTnT and high MPRI exhibited excellent outcomes (annual event rate=0%). In conclusion, comprehensive "bio imaging" using hsTnT, as a marker of myocardial microinjury, and CMR, as a marker of microvascular integrity and myocardial damage by LGE, may aid personalized risk-stratification in HT recipients. PMID- 25293511 TI - Iridium-catalyst-based autonomous bubble-propelled graphene micromotors with ultralow catalyst loading. AB - A novel concept of an iridium-based bubble-propelled Janus-particle-type graphene micromotor with very high surface area and with very low catalyst loading is described. The low loading of Ir catalyst (0.54 at %) allows for fast motion of graphene microparticles with high surface area of 316.2 m(2) g(-1). The micromotor was prepared with a simple and scalable method by thermal exfoliation of iridium-doped graphite oxide precursor composite in hydrogen atmosphere. Oxygen bubbles generated from the decomposition of hydrogen peroxide at the iridium catalytic sites provide robust propulsion thrust for the graphene micromotor. The high surface area and low iridium catalyst loading of the bubble propelled graphene motors offer great possibilities for dramatically enhanced cargo delivery. PMID- 25293513 TI - Getting rid of the unwanted: highlights of developments and challenges of biobeneficiation of iron ore minerals-a review. AB - The quest for quality mineral resources has led to the development of many technologies that can be used to refine minerals. Biohydrometallurgy is becoming an increasingly acceptable technology worldwide because it is cheap and environmentally friendly. This technology has been successfully developed for some sulphidic minerals such as gold and copper. In spite of wide acceptability of this technology, there are limitations to its applications especially in the treatment of non-sulphidic minerals such as iron ore minerals. High levels of elements such as potassium (K) and phosphorus (P) in iron ore minerals are known to reduce the quality and price of these minerals. Hydrometallurgical methods that are non-biological involving the use of chemicals are usually used to deal with this problem. However, recent advances in mining technologies favour green technologies, known as biohydrometallurgy, with minimal impact on the environment. This technology can be divided into two, namely bioleaching and biobeneficiation. This review focuses on Biobeneficiation of iron ore minerals. Biobeneficiation of iron ore is very challenging due to the low price and chemical constitution of the ore. There are substantial interests in the exploration of this technology for improving the quality of iron ore minerals. In this review, current developments in the biobeneficiation of iron ore minerals are considered, and potential solutions to challenges faced in the wider adoption of this technology are proposed. PMID- 25293512 TI - Assessment of immune cells and function of the residual spleen after subtotal splenectomy due to splenomegaly in cirrhotic patients. AB - BACKGROUND: The spleen is thought to be central in regulating the immune system, a metabolic asset involved in endocrine function. Overwhelming postsplenectomy infection leads to a mortality rate of up to 50%. However, there is still controversy on performing subtotal splenectomy as treatment of splenomegaly due to portal hypertension in cirrhotic patients. In the present study, immunocytes and the indexes of splenic size, hemodynamics, hematology and immunology in the residual spleen were analyzed to support subtotal splenectomy due to splenomegaly. RESULTS: In residual spleen, T lymphocytes mainly were focal aggregation in the periarterial lymphatic sheath. While B lymphocytes densely distributed in splenic corpuscle. In red pulp, macrophages were equally distributed in the xsplenic cord and adhered to the wall of splenic sinus with high density. The number of unit area T and B lymphocytes of splenic corpuscle and marginal zone as well as macrophages of red pulp were obviously increased in the residual spleen, while the number of macrophages didn't be changed among the three groups in white pulp. While there were some beneficial changes (i.e., Counts of platelet and leucocyte as well as serum proportion of CD3+ T cells, CD4+ T cells, CD8+ T cells were increased markedly; serum levels of M-CSF and GM CSF were decreased significantly; The proportion of granulocyte, erythrocyte, megakaryocyte in bone marrow were changed obviously; But serum IgA, IgM, IgG, Tuftsin level, there was no significant difference; splenic artery flow volume, portal venous diameter and portal venous flow volume, a significant difference was observed in residual spleen) in the clinical indices. CONCLUSION: After subtotal splenectomy with splenomegaly due to portal hypertension in cirrhotic patients, the number of unit area T and B lymphocytes, and MO in red pulp of residual spleen increased significantly. However, whether increase of T, B lymphocytes and MOs in residual splenic tissue can enhance the immune function of the spleen, still need further research to confirm. PMID- 25293514 TI - Prevalence and factors determining psychoactive substance (PAS) use among Hawassa University (HU) undergraduate students, Hawassa Ethiopia. AB - BACKGROUND: Use of psychoactive substances (PAS) early in school age implies drug dependence in later life. Although no studies have been conducted on undergraduate students of Hawassa University, a few studies in Ethiopia have reported that alcohol, khat, and cigarette are the commonly abused PASs among young high school/undergraduate university students. Therefore, this study was designed to establish the prevalence of and predictors for PAS use among undergraduate HU Students. METHODS: An institution-based quantitative cross sectional study using the self-administered WHO Model Core Questionnaire to collect information on use of various Psychoactive Substances (PASs) was conducted from June to July 2011. A multistage stratified sampling method was employed to select a total of 586 undergraduate HU students as study participants. Bivariate and multivariate logistic regression analysis were done to determine factors affecting PAS use. RESULTS: Lifetime, past 12 months, and current prevalence rate for overall PAS were 53.6%, 45.7%, and 35.5% respectively. The study depicted that in the past 12 months of the study period 40.8% used alcohol, 20.3% chewed khat, 11.9% smoked cigarettes, and 0.9% used marijuana. The prevalence of other illicit PASs such as Ecstasy, lysergic diethylamide (LSD), cocaine, crack, heroin, solvents or inhalants and un prescribed psycho active medications was found zero percent (0%). Having family members who used PAS, peer influence, being male, and living alone during school age were found to be positively associated with overall PAS use in the past 12 months. CONCLUSION: The prevalence of PAS use among undergraduate HU students is high. Designing effective strategies to reduce PAS use should be everyone's priority. PMID- 25293515 TI - Microvascular density, CD68 and tryptase expression in human diffuse large B-cell lymphoma. AB - Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin lymphoma characterized by clinical and biological heterogeneity attributable both to the tumor cells and the complex tumor-microenvironment surrounding them. Tumor associated macrophages (TAMs) and mast cells are two major components of the tumor inflammatory infiltrate with a definite role in enhancing tumor angiogenesis. In this study, we have investigated CD68 and tryptase expression and their relationship with microvascular density (MVD) in chemo-resistant and chemosensitive patients affected by DLBCL. CD68 and tryptase expression as well as MVD were increased in chemo-resistant patients when compared with chemosensitive patients. Tryptase expression showed a positive correlation with MVD, supporting a role for mast cell in DLBCL tumor angiogenesis, while CD68 correlation with MVD was not significant, indicating a different role for TAMs than angiogenesis in DLBCL. PMID- 25293516 TI - Polypharmacy in AML: the tip of the iceberg. PMID- 25293517 TI - Invasive fungal infection in patients receiving chemotherapy for hematological malignancy: a multicenter, prospective, observational study in China. AB - This stud y examined the epidemiology, risk factors, management, and outcome of invasive fungal infection (IFI) in patients receiving chemotherapy for hematological malignancy in China. IFI risk factors were analyzed using univariate analysis and multivariate logistic regression. In total, 4,192 patients receiving 4,889 chemotherapy courses were enrolled [mean age 40.7 years, 58.4% male, 16.9% children (<18 years)]. The most common hematological diseases were acute myeloid leukemia (AML, 28.5%), non-Hodgkin lymphoma (NHL, 26.3%), and acute lymphoblastic leukemia (ALL, 20.2%). Severe neutropenia (absolute neutrophil count [ANC] <500/mm(3)) occurred after one third (1,633/4,889, 33.4%) of chemotherapy courses. Incidence of proven/probable IFI was 2.1% per chemotherapy course and higher in patients with myelodysplastic syndrome (MDS, 4.94%), acute hyperleukocytic leukemia (AHL, 4.76%), AML (3.83%), or induction chemotherapy. Risk factors included ANC <500/mm(3) [odds ratio (OR) 3.60], AML or MDS (OR 1.97), induction chemotherapy (OR 2.58), previous IFI (OR 3.08), and being male (OR 1.74). Antifungal agents, prescribed in one quarter (1,211/4,889, 24.8%) of chemotherapy courses, included primary/secondary prophylaxis (n = 827, 16.9%) and/or treatment (n = 655, 13.4%; 86.9 % triazoles), which was empirical (84.3%), pre-emptive (8.6%), or targeted (7.1%). Overall mortality following each chemotherapy course (1.5%) increased in proven/probable (11.7%) and possible IFI (8.2%). In summary, IFI was more common in MDS, AHL, AML, or induction chemotherapy, and substantially increased mortality. Neutropenic patients receiving induction chemotherapy for AML or MDS and those with previous IFI were at particular risk. Antifungal prophylaxis showed an independent protective effect but was not commonly used, even in high-risk patients. By contrast, empiric antifungals were widely used. PMID- 25293518 TI - EGFR inhibitors and autophagy in cancer treatment. AB - Epidermal growth factor receptor (EGFR) inhibitor treatment is a strategy for cancer therapy. However, innate and acquired resistance is a major obstacle of the efficacy. Autophagy is a self-digesting process in cells, which is considered to be associated with anti-cancer drug resistance. The activation of EGFR can regulate autophagy through multiple signal pathways. EGFR inhibitors can induce autophagy, but the specific function of the induction of autophagy by EGFR inhibitors remains biphasic. On the one hand, autophagy induced by EGFR inhibitors acts as a cytoprotective response in cancer cells, and autophagy inhibitors can enhance the cytotoxic effects of EGFR inhibitors. On the other hand, a high level of autophagy after treatment of EGFR inhibitors can also result in autophagic cell death lacking features of apoptosis, and the combination of EGFR inhibitors with an autophagy inducer might be beneficial. Thus, autophagy regulation represents a promising approach for improving the efficacy of EGFR inhibitors in the treatment of cancer patients. PMID- 25293519 TI - Zoledronic acid increases cytotoxicity by inducing apoptosis in hormone and docetaxel-resistant prostate cancer cell lines. AB - Our aim was to investigate the possible synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and zoledronic acid (ZA), in PC-3 hormone-refractory prostate cancer cells (HRPC), as well as their docetaxel resistant sublines. We established a docetaxel-resistant cell line (PC-3R) from PC-3 prostate cancer cells, by intermittent exposure to increasing concentrations of docetaxel in vitro. We then examined the effect of ZA and docetaxel on cell proliferation in both PC-3 and PC-3R prostate cancer cells. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 enzyme activity were measured to verify apoptosis. According to our results, docetaxel and ZA were found to be synergistically cytotoxic and apoptotic in both PC-3 and docetaxel-resistant PC-3R cells, in a dose- and time dependent manner. Combined treatment with docetaxel and ZA synergistically inhibited PC-3 cell growth in vitro through an enhanced induction of cell death, compared with either agent alone; this result was also evident on PC-3R cells. Moreover, we have also demonstrated that apoptosis was induced in prostate cancer cells exposed to these drugs by a concentration-dependent increase in DNA fragmentation and caspase 3/7 enzyme activity. We concluded that ZA, either with docetaxel or not, might still exert some cytotoxicity even in docetaxel-resistant cells. From the clinical perspective, when the clinician decided to change the treatment in the post-docetaxel setting, continuing or combination with ZA may be an effective therapeutic approach for the treatment of HRPC patients. PMID- 25293520 TI - WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma. AB - Whelming evidence has demonstrated that WW domain containing E3 ubiquitin protein ligase 1 (WWP1) participates in a wide variety of biological processes and is tightly related to the initiation and progression of many tumors. Currently, although mounting evidence supports a role of WWP1 in tumor promotion and tumorigenesis, the potential roles of WWP1 and its biological functions in gastric carcinoma are not fully understood. Here, we found that WWP1 messenger RNA (mRNA) and protein were highly expressed in gastric carcinoma tissues and cells. High WWP1 mRNA and protein levels were tightly related to differentiation status, TNM stage, invasive depth, lymph node metastasis, and poor prognosis in gastric carcinoma. Furthermore, WWP1 siRNA significantly decreased WWP1 protein level in MKN-45 and AGS cells; meanwhile, WWP1 depletion markedly inhibited tumor proliferation in vitro and in vivo, arrested cell cycle at G0/G1 phase, and induced cell apoptosis in MKN-45 and AGS cells. Most notably, WWP1 downregulation both inactivated PTEN-Akt signaling pathway in MKN-45 and AGS cells. Taken altogether, our findings suggest that WWP1 acts as an oncogenic factor and should be considered as a novel interfering molecular target for gastric carcinoma. PMID- 25293521 TI - The XIAP inhibitor Embelin enhances TRAIL-induced apoptosis in human leukemia cells by DR4 and DR5 upregulation. AB - The present study was designed to explore the effects of low-toxicity Embelin on TRAIL-induced apoptosis and its possible mechanism in human leukemia cells. Our study showed that low-toxicity Embelin enhanced TRAIL-induced apoptosis through DR4 and DR5 upregulation and caspase activation in HL-60 cells. Pan-caspase inhibitor Z-VAD-FMK inhibited cell apoptosis induced by TRAIL alone or combined with low-toxicity Embelin, which indicated the cytotoxic effect is mediated by caspase-dependent apoptosis. Although Embelin is an X chromosome-linked inhibitor of-apoptosis protein (XIAP) inhibitor, an XIAP independent effect on cell death was detected in HL-60 cells exposed to low-toxicity Embelin and TRAIL. Low toxicity Embelin upregulated DR4 and DR5 expression to enhance TRAIL-induced apoptosis. The sensitizing effects of Embelin on TRAIL-induced apoptosis were markedly attenuated when DR4/DR5 was knocked down. These data suggested that low toxicity Embelin enhanced TRAIL-induced cell apoptosis through DR4 and DR5 upregulation, indicating that combination of low-toxicity Embelin and TRAIL may become as a potential antileukemia strategy. PMID- 25293522 TI - Syringe fading as treatment for feeding refusal. AB - The efficacy of nonremoval of the cup or spoon as treatment for feeding refusal is dependent on prevention of escape from presentations. In the current investigation, 1 child with feeding refusal escaped presentations during nonremoval of the cup and spoon by clenching his teeth. Therefore, we used a syringe to deposit liquids and solids, increased the volume of liquids and solids in the syringe, and conducted syringe-to-cup and syringe-to-spoon fading. PMID- 25293523 TI - Antimicrobial activity, toxicity and selectivity index of two biflavonoids and a flavone isolated from Podocarpus henkelii (Podocarpaceae) leaves. AB - BACKGROUND: Different parts of Podocarpus henkelii have been used in many cultures around the world to treat ailments such as cholera, stomach diseases, rheumatism, cancer, canine distemper in dogs and gall sickness in cattle. The aim of this study was to evaluate the biological activity and toxicity of isolated compounds from Podocarpus henkelii after an earlier study indicated a promising activity in crude extracts against viral pathogens of veterinary importance. METHODS: The antibacterial and antifungal activity of two biflavonoids 7, 4', 7", 4"'-tetramethoxy amentoflavone (TMA), isoginkgetin (IGG) and podocarpus flavone-A (PFA) isolated from the leaves of Podocarpus henkelii were determined using a serial microplate dilution method with tetrazolium violet as growth indicator. The cytotoxicity of compounds TMA and IGG were determined on different cell types using a tetrazolium-based colorimetric cellular assay (MTT). The Ames test was used to determine their mutagenic activities. RESULTS: TMA had reasonable antifungal activity against Aspergillus fumigatus (MIC = 30 MUg/ml). IGG had a wide spectrum of activity against four bacterial and two fungal pathogens with much higher selectivity index values obtained for A. fumigatus and Cryptococcus neoformans (SI > 30). PFA had a broad spectrum of activity against Enterococcus faecalis and Pseudomonas aeruginosa (SI > 15) and less activity against the two fungal pathogens. In both the cytotoxicity assays and Ames mutagenicity test using Salmonella typhimurium strains TA98 and TA100, TMA and IGG had no deleterious effect on the different cell types and did not induce mutations in the Ames test. CONCLUSION: Although the antimicrobial activities of the isolated compounds were not that exciting, the compounds had no cytotoxic activity at the highest concentration (1000 MUg/ml) tested against all three cell lines. IGG was the most active against E. coli, S. aureus, A. fumigatus and C. neoformans, exhibiting both antibacterial and antifungal activity with good selectivity index values. PFA had a broad spectrum of activity against E. faecalis and P. aeruginosa. The two compounds isolated had low toxicity and no genotoxic activity in the Ames test. PMID- 25293524 TI - Small doses of droperidol do not present relevant torsadogenic actions: a double blind, ondansetron-controlled study. AB - AIM: Drugs used for postoperative nausea and vomiting prophylaxis are believed to provoke torsadogenic changes in cardiac repolarization. The aim of this study was to assess the effect of small doses of droperidol on the parameters of cardiac repolarization, including the QTc interval and transmural dispersion of repolarization. METHODS: A total of 75 patients were randomly allocated to receive 0.625 or 1.25 mg droperidol or 8 mg ondansetron. The QTc interval was calculated using Bazett's formula and the Framingham correction. The transmural dispersion of repolarization was determined as Tpeak -Tend time. RESULTS: Transient QT prolongation, corrected with both formulae, followed 1.25 mg of droperidol 10 min after administration. No change in the QTc value was observed in the other groups. When corrected with Bazett's formula, QTc was prolonged above 480 ms in two patients receiving 1.25 mg droperidol (at the 10(th) and 20(th) minute of the study) and in one receiving ondansetron. No patients developed a QTc B prolongation over 500 ms. No increase above 480 ms was observed relative to the Framingham correction method. There were no significant differences in the Tpeak -Tend time either between or within the groups. CONCLUSION: In men without cardiovascular disorders small doses (1.25 mg) of droperidol prophylaxis induced transient QTc prolongation without changes in transmural dispersion of repolarization. The apparently low risk of the drug applies only in low risk male patients with a low pro-QTc score. PMID- 25293525 TI - Time-dependent gas-liquid interaction in molecular-sized nanopores. AB - Different from a bulk phase, a gas nanophase can have a significant effect on liquid motion. Herein we report a series of experimental results on molecular behaviors of water in a zeolite beta of molecular-sized nanopores. If sufficient time is provided, the confined water molecules can be "locked" inside a nanopore; otherwise, gas nanophase provides a driving force for water "outflow". This is due to the difficult molecular site exchanges and the relatively slow gas-liquid diffusion in the nanoenvironment. Depending on the loading rate, the zeolite beta/water system may exhibit either liquid-spring or energy-absorber characteristics. PMID- 25293527 TI - Hippo pathway regulation of gastrointestinal tissues. AB - The Hippo pathway plays a crucial role in regulating tissue homeostasis and organ size, and its deregulation is frequently observed in human cancer. Yap is the major effector of and is inhibited by the Hippo pathway. In mouse model studies, inducible Yap expression in multiple tissues results in organ overgrowth. In the liver, knockout of upstream Hippo pathway components or transgenic expression of Yap leads to liver enlargement and hepatocellular carcinoma. In the small intestine or colon, deletion of upstream Hippo pathway components also results in expansion of intestinal progenitor cells and eventual development of adenomas. Genetic deletion of Yap in the intestine does not change the intestinal structure, but Yap is essential for intestinal repair upon certain types of tissue injury. The function of the Hippo pathway has also been studied in other gastrointestinal tissues, including the pancreas and stomach. Here we provide a brief overview of the Hippo pathway and discuss the physiological and pathological functions of this tumor suppressor pathway in gastrointestinal tissues. PMID- 25293528 TI - Alternative paradigms for ion channelopathies: disorders of ion channel membrane trafficking and posttranslational modification. AB - Channelopathies are a diverse set of disorders associated with defects in ion channel (and transporter) function. Although the vast majority of channelopathies are linked with inherited mutations that alter ion channel biophysical properties, another group of similar disorders has emerged that alter ion channel synthesis, membrane trafficking, and/or posttranslational modifications. In fact, some electrical and episodic disorders have now been identified that are not defects in the ion channel but instead reflect dysfunction in an ion channel (or transporter) regulatory protein. This review focuses on alternative paradigms for physiological disorders associated with protein biosynthesis, folding, trafficking, and membrane retention. Furthermore, the review highlights the role of aberrant posttranslational modifications in acquired channelopathies. PMID- 25293529 TI - Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. AB - Mesenchymal stem cells (MSCs), whose mechanism of action is predominantly paracrine, are being widely tested for the treatment of a variety of human diseases. No one factor has been proven sufficient to mediate the therapeutic effects of MSCs. However, exosomes--membrane vesicles secreted by many cells, including MSCs--are appealing candidates as vectors of their efficacy. Exosomes can transport and deliver a large cargo of proteins, lipids, and nucleic acids and can modify cell and organ function. In addition to their key role as vehicles of intercellular communication, exosomes are increasingly recognized as biomarkers and prognosticators of disease. Moreover, they have the potential to be used as vehicles of gene and drug delivery for clinical application. This article reviews the biogenesis of exosomes, their molecular composition, and their role as messengers of intercellular communication, focusing on their potential as therapeutic vectors for stem cell therapy. PMID- 25293530 TI - Acute asymmetrical spinal infarct secondary to fibrocartilaginous embolism. AB - INTRODUCTION: Spinal cord infarction is extremely rare in childhood and can result from a wide range of causes. Fibrocartilaginous embolism can give rise to spinal stroke and mimic non-vascular disease such as acute transverse myelitis. CASE: We report two children who suffered an asymmetrical spinal cord infarction due to fibrocartilaginous embolism. The clinical presentation, radiological findings, and pathophysiology of fibrocartilaginous embolism are described. Each patient demonstrated marked clinical improvement after receiving extensive physical therapy and rehabilitation. One child demonstrated complete clinical recovery. The other had persistent asymmetrical foot weakness and distal sensory deficits. CONCLUSION: We outline the key clinical and radiographic features that enable spinal cord infarction to be differentiated from transverse myelitis. Prognosis depends on many factors such as extent and type of injury, level of the cord affected, and age at the time of spinal cord infarction. PMID- 25293526 TI - Phosphoinositide control of membrane protein function: a frontier led by studies on ion channels. AB - Anionic phospholipids are critical constituents of the inner leaflet of the plasma membrane, ensuring appropriate membrane topology of transmembrane proteins. Additionally, in eukaryotes, the negatively charged phosphoinositides serve as key signals not only through their hydrolysis products but also through direct control of transmembrane protein function. Direct phosphoinositide control of the activity of ion channels and transporters has been the most convincing case of the critical importance of phospholipid-protein interactions in the functional control of membrane proteins. Furthermore, second messengers, such as [Ca(2+)]i, or posttranslational modifications, such as phosphorylation, can directly or allosterically fine-tune phospholipid-protein interactions and modulate activity. Recent advances in structure determination of membrane proteins have allowed investigators to obtain complexes of ion channels with phosphoinositides and to use computational and experimental approaches to probe the dynamic mechanisms by which lipid-protein interactions control active and inactive protein states. PMID- 25293531 TI - Langer-Giedion syndrome associated with congenital dural arterio-venous fistula. AB - Langer-Giedion syndrome (LGS) is a rare disease caused by deletion of chromosome 8q23.3-q24.11. Clinical manifestations include among others multiple exostoses, short stature, intellectual disability, and typical facial dysmorphism. Dural arterio-venous shunts (DAVS) in the pediatric age are rare lesions, which have been classified into three types: dural sinus malformations (DSM), infantile type DAVS (IDAVS), and adult type DAVS (ADAVS). We report a case of a patient with a known LGS who was diagnosed with complex intracranial dural AV fistula at the age of 20. An association between LGS and intracranial dural AV fistulas has to our knowledge never been reported before. PMID- 25293532 TI - ICT and the future of health care: aspects of health promotion. AB - PURPOSE: Increasingly, Information and Communication Technology (ICT) applications enter the daily lives of consumers. Availability of various multimedia interfaces offers the opportunity to develop and adjust ICT solutions to all aspects of society including health care. To address the challenges of the ongoing adaptive progress of ICT, decision makers profit from estimates of expectable merits and risks of future technological developments. The aim of the present study was to assess the prevailing opinions and expectations among Austrian stakeholders regarding ICT-assisted health promotion. METHODS: In total, 73 experts (74% males) engaged in the Austrian health care sector participated in a biphasic online Delphi survey. Panellists were assigned to three groups representing medical professionals, patient advocates, and administrative personnel. In a scenario-based questionnaire, experts evaluated potential advantages and barriers as well as degree of innovation, desirability, and estimated date of implementation of six future ICT scenarios. Scenario-specific and consolidated overall opinions were ranked. Inter-group differences were assessed using ANOVA. RESULTS: Panellists expected the future ICT-supported health promotion strategies to especially improve the factors living standard (56%), quality of health care (53%), and patient's knowledge (44%). Nevertheless, monetary aspects (57%), acceptance by patient advocates (45%), and data security and privacy (27%) were considered as the three most substantial hampering factors for ICT applications. Although overall mean desirability of the scenarios was quite high (80%) amongst panellists, it was considerably lower in medical professionals compared to patient advocates and administrative personnel (p=0.006). This observation suggests a more precautious attitude of this specific interest group regarding technological innovations. CONCLUSIONS: The present Delphi survey identified issues relevant for successful implementation of ICT based health care solutions, providing a compilation of several areas that might require further research. In the light of ageing societies facing the perceived threat of permanent online surveillance, different requirements and expectations of end users should be accounted for by various stakeholders. Thus, close collaboration could facilitate the harmonization process on hot health topics among interest groups. PMID- 25293533 TI - Design of telehealth trials--introducing adaptive approaches. AB - BACKGROUND: The field of telehealth and telemedicine is expanding as the need to improve efficiency of health care becomes more pressing. The decision to implement a telehealth system is generally an expensive undertaking that impacts a large number of patients and other stakeholders. It is therefore extremely important that the decision is fully supported by accurate evaluation of telehealth interventions. OBJECTIVE: Numerous reviews of telehealth have described the evidence base as inconsistent. In response they call for larger, more rigorously controlled trials, and trials which go beyond evaluation of clinical effectiveness alone. The aim of this paper is to discuss various ways in which evaluation of telehealth could be improved by the use of adaptive trial designs. RESULTS: We discuss various adaptive design options, such as sample size reviews and changing the study hypothesis to address uncertain parameters, group sequential trials and multi-arm multi-stage trials to improve efficiency, and enrichment designs to maximise the chances of obtaining clear evidence about the telehealth intervention. CONCLUSION: There is potential to address the flaws discussed in the telehealth literature through the adoption of adaptive approaches to trial design. Such designs could lead to improvements in efficiency, allow the evaluation of multiple telehealth interventions in a cost effective way, or accurately assess a range of endpoints that are important in the overall success of a telehealth programme. PMID- 25293534 TI - A polar-localized iron-binding protein determines the polar targeting of Burkholderia BimA autotransporter and actin tail formation. AB - Intracellular bacterial pathogens including Shigella, Listeria, Mycobacteria, Rickettsia and Burkholderia spp. deploy a specialized surface protein onto one pole of the bacteria to induce filamentous actin tail formation for directional movement within host cytosol. The mechanism underlying polar targeting of the actin tail proteins is unknown. Here we perform a transposon screen in Burkholderia thailandensis and identify a conserved bimC that is required for actin tail formation mediated by BimA from B. thailandensis and its closely related pathogenic species B. pseudomallei and B. mallei. bimC is located upstream of bimA in the same operon. Loss of bimC results in even distribution of BimA on the outer membrane surface, where actin polymerization still occurs. BimC is targeted to the same bacterial pole independently of BimA. BimC confers polar targeting of BimA prior to BimA translocation across bacterial inner membrane. BimC is an iron-binding protein, requiring a four-cysteine cluster at the carboxyl terminus. Mutation of the cysteine cluster disrupts BimC polar localization. Truncation analyses identify the transmembrane domain in BimA being responsible for its polar targeting. Consistently, BimC can interact with BimA transmembrane domain in an iron binding-dependent manner. Our study uncovers a new mechanism that determines the polar distribution of bacteria-induced actin tail in infected host cells. PMID- 25293535 TI - Association between intravenous chloride load during resuscitation and in hospital mortality among patients with SIRS. AB - PURPOSE: Recent data suggest that both elevated serum chloride levels and volume overload may be harmful during fluid resuscitation. The purpose of this study was to examine the relationship between the intravenous chloride load and in-hospital mortality among patients with systemic inflammatory response syndrome (SIRS), with and without adjustment for the crystalloid volume administered. METHODS: We conducted a retrospective analysis of 109,836 patients >= 18 years old that met criteria for SIRS and received fluid resuscitation with crystalloids. We examined the association between changes in serum chloride concentration, the administered chloride load and fluid volume, and the 'volume-adjusted chloride load' and in hospital mortality. RESULTS: In general, increases in the serum chloride concentration were associated with increased mortality. Mortality was lowest (3.7%) among patients with minimal increases in serum chloride concentration (0 10 mmol/L) and when the total administered chloride load was low (3.5% among patients receiving 100-200 mmol; P < 0.05 versus patients receiving >= 500 mmol). After controlling for crystalloid fluid volume, mortality was lowest (2.6%) when the volume-adjusted chloride load was 105-115 mmol/L. With adjustment for severity of illness, the odds of mortality increased (1.094, 95% CI 1.062, 1.127) with increasing volume-adjusted chloride load (>= 105 mmol/L). CONCLUSIONS: Among patients with SIRS, a fluid resuscitation strategy employing lower chloride loads was associated with lower in-hospital mortality. This association was independent of the total fluid volume administered and remained significant after adjustment for severity of illness, supporting the hypothesis that crystalloids with lower chloride content may be preferable for managing patients with SIRS. PMID- 25293536 TI - Induction of ovulation with buserelin in jennies: in search of the minimum effective dose. AB - The aim of this study was to evaluate the minimum dose of buserelin acetate (buserelin) able to induce ovulation between 24 and 48 h from treatment (positive response) in estrous jennies. Jennies were studied during a total of 172 estrous cycles: ovarian activity was routinely monitored by ultrasound; when the dominant follicle reached a diameter of 33 +/- 1 mm, estrous jennies were treated by subcutaneous administration of different doses of buserelin, 3.3mg (N = 11), 1.5mg (N = 21), 0.8 mg (N = 12), 0.4 mg (N = 16), 0.2mg (N = 13), 0.1mg (N = 16), 0.04 mg (N = 14), 0.02 mg (N = 16), or employed as controls (N = 53). Single jennies (P = 0.0001) and GnRH dose (P = 0.003) significantly affected ovulation rates. Ovulation rates between 24 and 48 h of each treated group, except for the 0.02 mg group, was higher than in the control group (P < 0.05). The minimum dose of buserelin effective to induce ovulation in estrous jennies was 0.04 mg. PMID- 25293537 TI - Sugar demand of ripening grape berries leads to recycling of surplus phloem water via the xylem. AB - We tested the common assumption that fleshy fruits become dependent on phloem water supply because xylem inflow declines at the onset of ripening. Using two distinct grape genotypes exposed to drought stress, we found that a sink-driven rise in phloem inflow at the beginning of ripening was sufficient to reverse drought-induced berry shrinkage. Rewatering accelerated berry growth and sugar accumulation concurrently with leaf photosynthetic recovery. Interrupting phloem flow through the peduncle prevented the increase in berry growth after rewatering, but interrupting xylem flow did not. Nevertheless, xylem flow in ripening berries, but not berry size, remained responsive to root or shoot pressurization. A mass balance analysis on ripening berries sampled in the field suggested that phloem water inflow may exceed growth and transpiration water demands. Collecting apoplastic sap from ripening berries showed that osmotic pressure increased at distinct rates in berry vacuoles and apoplast. Our results indicate that the decrease in xylem inflow at the onset of ripening may be a consequence of the sink-driven increase in phloem inflow. We propose a conceptual model in which surplus phloem water bypasses the fruit cells and partly evaporates from the berry surface and partly moves apoplastically to the xylem for outflow. PMID- 25293538 TI - Executive summary of NIH workshop on the Use and Biology of Energy Drinks: Current Knowledge and Critical Gaps. AB - Sales of energy drinks in the United States reached $12.5 billion in 2012. Emergency department visits related to consumption of these products have increased sharply, and while these numbers remain small relative to product sales, they raise important questions regarding biological and behavioral effects. Although some common ingredients of energy drinks have been extensively studied (e.g., caffeine, B vitamins, sugars, inositol), data on other ingredients (e.g., taurine) are limited. Summarized here are data presented elsewhere in this issue on the prevalence and patterns of caffeine-containing energy drink use, the effects of these products on alertness, fatigue, cognitive functions, sleep, mood, homeostasis, as well as on exercise physiology and metabolism, and the biological mechanisms mediating the observed effects. There are substantial data on the effects of some energy drink ingredients, such as caffeine and sugars, on many of these outcomes; however, even for these ingredients many controversies and gaps remain, and data on other ingredients in caffeine-containing energy drinks, and on ingredient interactions, are sparse. This summary concludes with a discussion of critical gaps in the data and potential next steps. PMID- 25293539 TI - Estimating caffeine intake from energy drinks and dietary supplements in the United States. AB - No consistent definition exists for energy products in the United States. These products have been marketed and sold as beverages (conventional foods), energy shots (dietary supplements), and in pill or tablet form. Recently, the number of available products has surged, and formulations have changed to include caffeine. To help characterize the use of caffeine-containing energy products in the United States, three sources of data were analyzed: sales data, data from federal sources, and reports from the Drug Abuse Warning Network. These data indicate that sales of caffeine-containing energy products and emergency room visits involving their consumption appear to be increasing over time. Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 indicate that 2.7% [standard error (SE) 0.2%] of the US population >=1 year of age used a caffeine-containing energy product, providing approximately 150-200 mg/day of caffeine per day in addition to caffeine from traditional sources like coffee, tea, and colas. The highest usage of these products was among males between the ages of 19 and 30 years (7.6%, SE 1.0). Although the prevalence of caffeine containing energy product use remains low overall in the US population, certain subgroups appear to be using these products in larger amounts. Several challenges remain in determining the level of caffeine exposure from and accurate usage patterns of caffeine-containing energy products. PMID- 25293541 TI - Regulatory status of caffeine in the United States. AB - This article summarizes the history of the regulation of caffeine, a key component of caffeine-containing energy drinks and other caffeine-containing energy products, in the United States. Caffeine as an ingredient in food has been regulated by the US Food and Drug Administration (FDA) since 1958, when the Food Additives Amendment to the Federal Food, Drug and Cosmetic Act was enacted. It is listed as a substance that is generally recognized as safe by experts for its intended use in cola-type beverages at levels not to exceed 200 parts per million. Here, the history of FDA evaluations of the safe use of, as well as consumer exposure to, caffeine in food in the United States is outlined. Finally, the FDA's current concerns about caffeine and caffeine-containing energy products are reported, along with the current activities to address those concerns. PMID- 25293540 TI - Implications of sleep and energy drink use for health disparities. AB - The popularity of energy drinks has increased rapidly in the past decade. One of the main reasons people use energy drinks is to counteract effects of insufficient sleep or sleepiness. Risks associated with energy drink use, including those related to sleep loss, may be disproportionately borne by racial minorities and those of lower socioeconomic status. In this review, a brief introduction to the issue of health disparities is provided, population-level disparities and inequalities in sleep are described, and the social-ecological model of sleep and health is presented. Social and demographic patterns of energy drink use are then presented, followed by discussion of the potential ways in which energy drink use may contribute to health disparities, including the following: 1) effects of excessive caffeine in energy drinks, 2) effects of energy drinks as sugar-sweetened beverages, 3) association between energy drinks and risk-taking behaviors when mixed with alcohol, 4) association between energy drink use and short sleep duration, and 5) role of energy drinks in cardiometabolic disease. The review concludes with a research agenda of critical unanswered questions. PMID- 25293543 TI - Influence of energy drink ingredients on mood and cognitive performance. AB - Sales of energy products have grown enormously in recent years. Manufacturers claim that the products, in the form of drinks, shots, supplements, and gels, enhance physical and cognitive performance, while users believe the products promote concentration, alertness, and fun. Most of these products contain caffeine, a mild psychostimulant, as their foremost active ingredient. However, they also contain additional ingredients, e.g., carbohydrates, amino acids, herbal extracts, vitamins, and minerals, often in unspecified amounts and labeled as an "energy blend." It is not clear whether these additional ingredients provide any physical or cognitive enhancement beyond that provided by caffeine alone. This article reviews the available empirical data on the interactive effects of these ingredients and caffeine on sleep and cognitive performance and suggests objectives for future study. PMID- 25293544 TI - Developmental changes in sleep biology and potential effects on adolescent behavior and caffeine use. AB - Adolescent development includes changes in the biological regulatory processes for the timing of sleep. Circadian rhythm changes and changes to the sleep pressure system (sleep homeostasis) during adolescence both favor later timing of sleep. These changes, combined with prevailing social pressures, are responsible for most teens sleeping too late and too little; those who sleep least report consuming more caffeine. Although direct research findings are scarce, the likelihood of use and abuse of caffeine-laden products grows across the adolescent years due, in part, to excessive sleepiness. PMID- 25293546 TI - Energy drink and energy shot use in the military. AB - Use of energy drinks and energy shots among military personnel is controversial. High amounts of caffeine (the primary active ingredient in these products) may impact performance of military duties. The impact of caffeine overconsumption and potential subsequent side effects that might be experienced by service members with unique roles and responsibilities is a concern. Reported here are the prevalence of use, reasons for use, and side effects associated with consumption of energy drinks and energy shots among several populations of active duty personnel in the US military. A snowball survey was sent to over 10,000 active duty personnel. A total of 586 (~6% response rate) individuals completed a 30 item electronic survey. Over half of respondents (53%) reported consuming an energy drink at least once in the past 30 days. One in five (19%) reported energy shot consumption in the prior 30 days. One in five (19%) also reported consuming an energy drink in combination with an alcoholic beverage. Age and gender were significantly associated with energy drink consumption. Young male respondents (18-29 years) reported the highest use of both energy drinks and energy shots. Among those reporting energy drink and energy shot use, the most common reasons for consumption were to improve mental alertness (61%) and to improve mental (29%) and physical (20%) endurance. Nearly two-thirds (65%) of users self reported at least one side effect. The most commonly reported side effects included increased pulse rate/palpitations, restlessness, and difficulty sleeping. Use of energy products among military personnel is common and has the potential to impact warrior health and military readiness. PMID- 25293545 TI - Effect of energy drink and caffeinated beverage consumption on sleep, mood, and performance in children and adolescents. AB - The increasing availability of highly caffeinated beverages, including energy drinks, in the United States has resulted in a rise in consumption by children and adolescents. In addition, there is mounting evidence that these products are often consumed by youth for their perceived fatigue-mitigating and mood- or performance-enhancing effects. Although such perceptions by children and adolescents about the potential consequences of caffeine consumption are highly likely to influence decision making regarding the use of such products, there is still a relative paucity of studies that focus on the effect of caffeinated beverages on sleep, mood, and performance in the pediatric population. This review summarizes the following aspects of this topic, as derived from the information currently available: 1) the perception, among youth, of caffeine's risks and benefits and the sources of information about caffeine, particularly with regard to sleep, mood, and performance; 2) the bidirectional effect of caffeine on sleep in children and adolescents and the association of caffeine with other sleep-related practices, and 3) the evidence that supports caffeine as a performance and mood enhancer as well as a countermeasure to sleepiness in the pediatric population. Finally, gaps in knowledge are identified, and a direction for future research is outlined. PMID- 25293547 TI - Legitimacy of concerns about caffeine and energy drink consumption. AB - Whether caffeine and energy drink consumption presents a critical emerging health problem is not currently known. Available evidence suggests that energy drink consumption represents a change in the ways in which individuals in the United States consume caffeine but that the amount of caffeine consumed daily has not appreciably increased. In the present review, the question of whether Americans are sleep deprived (a potential reason for using caffeine) is briefly explored. Reported rates of daily caffeine consumption (based on beverage formulation) and data obtained from both civilian and military populations in the United States are examined, the efficacy of ingredients other than caffeine in energy drinks is discussed, and the safety and side effects of caffeine are addressed, including whether evidence supports the contention that excessive caffeine/energy drink consumption induces risky behavior. The available evidence suggests that the main legitimate concern regarding caffeine and energy drink use is the potential negative impact on sleep but that, otherwise, there is no cause for concern regarding caffeine use in the general population. PMID- 25293542 TI - Cumulative neurobehavioral and physiological effects of chronic caffeine intake: individual differences and implications for the use of caffeinated energy products. AB - The use of caffeine-containing energy products has increased worldwide in recent years. All of the top-selling energy drinks contain caffeine, which is likely to be the primary psychoactive ingredient in these products. Research shows that caffeine-containing energy products can improve cognitive and physical performance. Presumably, individuals consume caffeine-containing energy products to counteract feelings of low energy in situations causing tiredness, fatigue, and/or reduced alertness. This review discusses the scientific evidence for sleep loss, circadian phase, sleep inertia, and the time-on-task effect as causes of low energy and summarizes research assessing the efficacy of caffeine to counteract decreased alertness and increased fatigue in such situations. The results of a placebo-controlled experiment in healthy adults who had 3 nights of total sleep deprivation (with or without 2-hour naps every 12 hours) are presented to illustrate the physiological and neurobehavioral effects of sustained low-dose caffeine. Individual differences, including genetic factors, in the response to caffeine and to sleep loss are discussed. The review concludes with future directions for research on this important and evolving topic. PMID- 25293548 TI - Evidence and knowledge gaps for the association between energy drink use and high risk behaviors among adolescents and young adults. AB - Sales of energy drinks have increased rapidly since their introduction to the marketplace in the 1990s. Despite the health concerns raised about these beverages, which are often highly caffeinated, surprisingly little data are available to estimate the prevalence of their use. This review presents the results of secondary data analyses of a nationally representative data set of schoolchildren in the United States and reviews the available research on the association between energy drink use and risk-taking behaviors. Approximately one third of the students surveyed were recent users of energy drinks, with substantial variation by age, sex, and race/ethnicity. Among the health and safety concerns related to energy drinks and their consumption is the possible potentiation of risk-taking behaviors. The review of available research reveals that, although there does appear to be a strong and consistent positive association between the use of energy drinks and risk-taking behavior, all but one of the available studies used cross-sectional designs, thereby limiting the ability to make inferences about the temporal nature of the association. Thus, more research is needed to understand the nature of this association and how energy drinks, particularly those containing caffeine, might impact adolescent health and safety, especially given the high prevalence of their use among youth. PMID- 25293550 TI - Performance outcomes and unwanted side effects associated with energy drinks. AB - Energy drinks are increasingly popular among athletes and others. Advertising for these products typically features images conjuring great muscle power and endurance; however, the scientific literature provides sparse evidence for an ergogenic role of energy drinks. Although the composition of energy drinks varies, most contain caffeine; carbohydrates, amino acids, herbs, and vitamins are other typical ingredients. This report analyzes the effects of energy drink ingredients on prolonged submaximal (endurance) exercise as well as on short-term strength and power (neuromuscular performance). It also analyzes the effects of energy drink ingredients on the fluid and electrolyte deficit during prolonged exercise. In several studies, energy drinks have been found to improve endurance performance, although the effects could be attributable to the caffeine and/or carbohydrate content. In contrast, fewer studies find an ergogenic effect of energy drinks on muscle strength and power. The existing data suggest that the caffeine dose given in studies of energy drinks is insufficient to enhance neuromuscular performance. Finally, it is unclear if energy drinks are the optimal vehicle to deliver caffeine when high doses are needed to improve neuromuscular performance. PMID- 25293549 TI - Energy drinks mixed with alcohol: what are the risks? AB - Energy drinks are popular beverages that typically include high levels of caffeine and other ingredients such as taurine, or caffeine-containing herbs, such as guarana. While energy drinks are often consumed alone, they are also frequently used as mixers for alcoholic beverages. This review summarizes what is known about the scope of use of alcohol mixed with energy drinks, the risks associated with such mixtures, and the objective laboratory data examining how the effects of their consumption differ from consuming alcohol alone. The weight of the evidence reveals that consuming alcohol mixed with energy drinks is riskier than consuming alcohol alone and constitutes a public health concern. Consumption of these mixed beverages is frequent, especially in young and underage drinkers, and compared with alcohol alone, their use is associated with elevated rates of binge drinking, impaired driving, risky sexual behavior, and risk of alcohol dependence. Laboratory research (human and animal) has demonstrated that consuming alcohol mixed with energy drinks leads to altered subjective states including decreased perceived intoxication, enhanced stimulation, and increased desire to drink/increased drinking compared to consuming alcohol alone. Possible underlying mechanisms explaining these observations are highlighted in this review. PMID- 25293551 TI - Performance effects and metabolic consequences of caffeine and caffeinated energy drink consumption on glucose disposal. AB - This review documents two opposing effects of caffeine and caffeine-containing energy drinks, i.e., their positive effects on athletic performance and their negative impacts on glucose tolerance in the sedentary state. Analysis of studies examining caffeine administration prior to performance-based exercise showed caffeine improved completion time by 3.6%. Similar analyses following consumption of caffeine-containing energy drinks yielded positive, but more varied, benefits, which were likely due to the diverse nature of the studies performed, the highly variable composition of the beverages consumed, and the range of caffeine doses administered. Conversely, analyses of studies administering caffeine prior to either an oral glucose tolerance test or insulin clamp showed a decline in whole body glucose disposal of ~30%. The consequences of this resistance are unknown, but there may be implications for the development of a number of chronic diseases. Both caffeine-induced performance enhancement and insulin resistance converge with the primary actions of caffeine on skeletal muscle. PMID- 25293552 TI - Methodological and metabolic considerations in the study of caffeine-containing energy drinks. AB - Caffeine-containing energy drinks are popular and widely available beverages. Despite large increases in consumption, studies documenting the nutritional, metabolic, and health implications of these beverages are limited. This review provides some important methodological considerations in the examination of these drinks and highlights their potential impact on the gastrointestinal system, liver, and metabolic health. The gastrointestinal system is important as it comes into contact with the highest concentration of energy drink ingredients and initiates a chain of events to communicate with peripheral tissues. Although energy drinks have diverse compositions, including taurine, ginseng, and carnitine, the most metabolically deleterious ingredients appear to be simple sugars (such as glucose and fructose) and caffeine. In combination, these last two ingredients have the greatest metabolic impact and potential influence on overall health. PMID- 25293553 TI - Serum copper is a simple but valuable prognostic marker in B-cell chronic lymphocytic leukemia. AB - We investigated the relationship between serum copper and various prognostic factors, time to start treatment, and treatment response in patients with B-cell chronic lymphocytic leukemia (B-CLL) and related disorders. Fifty newly diagnosed CLL patients aged 36-70 years were included. Patients were studied for serum lactate dehydrogenase (LDH), serum copper, direct Coombs' test, serum beta(2) microglobulin (beta(2)M), immunophenotyping for diagnosis of B-CLL, evaluation of CD38 and zeta-associated protein (ZAP-70) expression, and fluorescence in situ hybridization technique for cytogenetic analysis. Fourteen of 50 patients had high serum copper level; they had a significant increase in LDH, serum beta(2)M, incidence of positive Coombs' test, CD38 and ZAP-70, incidence of 17p del, and a decrease in hemoglobin concentration, lymphocyte doubling time and time to start treatment with a lower treatment response rate. No significant difference was found with regard to Rai staging for CLL. These results indicate that serum copper level, a cheap and simple laboratory test, is of great value in CLL patients as it showed a significant association with some important adverse prognostic markers such as increased expression of ZAP-70 and CD38, shorter time to start treatment and poor response to treatment. PMID- 25293554 TI - Azurophilic granular and rod-like inclusion bodies in mature B-cell neoplasm. PMID- 25293555 TI - Thrombocytopenia in pregnancy: do the time of diagnosis and delivery route affect pregnancy outcome in parturients with idiopathic thrombocytopenic purpura? AB - The objective of this study was to investigate the determining effects of diagnosis time on pregnancy outcomes in a population of pregnant women with idiopathic thrombocytopenic purpura (ITP). Records of all the pregnant women with thrombocytopenia were evaluated. Those with a confirmed diagnosis of ITP were included in the study. Main outcome measures were antenatal thrombocyte count, postpartum haemorrhage rate, and route of delivery. Foetal outcomes such as foetal thrombocyte count, haemorrhage, and birth weight were also reported as secondary outcome measures. Time of diagnosis either antenatal or preconception did not significantly alter the investigated parameters. Delivery route had no impact on complication rates. Time of diagnosis also did not affect treatment modality. ITP is rare disorder accounting for less than 5 % of all pregnant thrombocytopenias. Time of diagnosis does not affect maternal-foetal outcomes or treatment modality unless diagnosis is made during labour. Compared to gestational thrombocytopenia, treatment rates may differ but treatment modalities remain the same and the effort put into making the differential should be weighed against maternal stress factors for lengthy laboratory evaluation as long as the thrombocytopenia is of pure nature without any systemic involvement. PMID- 25293556 TI - Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. AB - The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy. SIGNIFICANCE: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted. PMID- 25293557 TI - Germline TP53 mutations is common in patients with two early-onset primary malignancies. PMID- 25293558 TI - [Intensive smoking cessation as secondary prevention in many diseases is evidence based and calls for action]. PMID- 25293559 TI - [Should all elderly patients have a CT of the cervical spine after fall injuries?]. PMID- 25293560 TI - [The significance of testicular microlithiasis]. AB - Testicular microlithiasis (TM) has been reported in up to 46% of men with testicular cancer. This has given rise to the suspicion that TM is a premalignant condition. In studies of healthy men there is, however, no association between TM and development of cancer. Nonetheless, patients with TM and contralateral testicular cancer, testicular atrophy, inhomogeneous parenchyma, infertility or a history of maldescensus are at increased risk of having carcinoma in situ (CIS) and cancer development. Men with TM and one or more of the above mentioned risk factors should be offered a testicular biopsy to rule out CIS. PMID- 25293561 TI - [Potential neurotoxicity of general anaesthetics to the developing brain]. AB - Animal studies (including non-human primates) have shown that most general anaesthetics cause enhanced neuroapoptosis with subsequent long-term neurocognitive deficits later in life. Some human cohort studies have indicated an association between anaesthesia/surgery and adverse neurocognitive outcome whereas other studies have not. Overall, the data do not justify any change in paediatric anaesthetic clinical practice. Naturally, the risks and benefits of a procedure should always be carefully considered before exposing a child to general anaesthesia. PMID- 25293562 TI - [Treatment of cardiac arrest in potential organ donors creates ethical conflicts]. AB - This article describes the results of an interview study on the ethical issues related to treating cardiac arrest in potential organ donors in Denmark. The medical background and the Danish guidelines relevant to the issue are described. The results from the interview study are then summarized and analyzed from an ethical perspective in order to clarify the ethical issues and value conflicts experienced by health personnel in this situation. It is recommended that the ethical components in the decision-making process and the dilemmatic nature of the situation are made transparent. PMID- 25293563 TI - [Evidence for emergency treatment of chemical eye burns]. AB - The purpose of this article was to review the existing evidence on emergency treatment of chemical eye burns. Clinical studies show that patients receiving prompt eye irrigation after chemical burns had a significantly better clinical outcome. This is further collaborated in animal studies where prompt irrigation with diphoterine or borate buffer significantly lowered pH in the eye after alkali burns. Two of three studies showed that tap water significantly lowered pH as well, but only if it was administered within 60 seconds after exposure. Saline, however, did not cause any significant decrease in pH at all. PMID- 25293564 TI - [Diffuse lung disease in children]. AB - Diffuse lung disease in children represents a heterogeneous group of respiratory disorders with high morbidity and mortality. Typical features include tachypnoea, failure to thrive, diffuse radiological and histopathological abnormalities. Advances in genetics and pathophysiology, combined with a recent paediatric classification have improved our understanding of these disorders. The workup, diagnosis and management of these rare paediatric pulmonary diseases are difficult and require centralised, interdisciplinary team approach in experienced paediatric pulmonary centres. PMID- 25293565 TI - [Metal-on-metal hip arthroplasty]. AB - In Denmark 4,456 metal-on-metal (MoM) hip prostheses have been implanted. Evidence demonstrates that some patients develope adverse biological reactions causing failures of MoM hip arthroplasty. Some reactions might be systemic. Failure rates are associated with the type and the design of the MoM hip implant. A Danish surveillance programme has been initiated addressing these problems. PMID- 25293566 TI - [Smartphone apps as a new psychiatric treatment]. AB - The number of smartphone apps for people with mental health issues is undergoing a dramatical growth in these years. We review the available literature on the topic, discuss opportunities and theoretical considerations using smartphone apps in psychiatric treatment and provide an overview of approaches that are currently in progress in this field in Denmark. In a systematic literature search we found four small clinical trials with positive results. However, none of the studies were randomised controlled trials, and the results have to be interpreted with caution. PMID- 25293567 TI - [Every sixth patient in amiodarone treatment develops thyrotoxicosis or hypothyreosis]. AB - Amiodarone is associated with multiple side effects among which a substantial number of patients are suffering from amiodarone-induced thyroid disease. In this review we present difficulties in diagnosing, sub typing and treating amiodarone induced thyroid disease and give views on the future of this drug and one of the alternatives, dronedarone. Amiodarone holds a place in modern medicine due to its unique antiarrhythmic effects and associated thyroid diseases requires collaboration between cardiologists and endocrinologists due to the complexity hereof. PMID- 25293568 TI - [The smartphone in anesthesia]. PMID- 25293569 TI - [Clinical communication skills training is an educational challenge]. AB - This qualitative study presents results from a development project of clinical communication skills training for physicians in a paediatric ward. Overall, the doctors express that the training positively supports their clinical work and that it provides a model for discussing communication challenges with colleagues. Challenges, however, are time constraints and overcoming conventional hierarchical structures. Prerequisites for ward-based communication training thus are: a suitable timeframe, use of a structured feedback model, managerial backup, and support from external expertise. PMID- 25293570 TI - [Imaging of hepatic angiosarcoma]. AB - Primary hepatic angiosarcoma (PHA) is a very rare malignant tumour with imaging characteristics that can mimic atypical haemangioma (HA). This is a case report of a 47-year-old male with PHA. Contrast-enhanced ultrasound (CEUS) has shown to be effective in differentiating PHA from HA, CT has more variable findings, in MRI PHA can mimic HA, arteriovenous malformations and cystic metastases, and PET/CT can be used to verify the diagnosis. In this case CEUS was supplied with a contrast CT, MRI and PET/CT. An elevated fluorodeoxyglucose uptake within the left liver lobe was shown on PET/CT. PMID- 25293571 TI - [Life-threatening bleeding during dabigatran treatment because of acute renal failure]. AB - We report a case where a 64-year-old woman treated with dabigatran developed life threatening bleeding due to lack of dose adjustment following identification of acute renal failure. Many commonly used drugs, e.g. new oral anticoagulants, digoxin, ACE-inhibitors, antibiotics, are eliminated by the kidneys. The case illustrates that lack of medication reconciliation can lead to serious adverse events in case of deteriorating organ function. The use of medication reconciliation should be performed on a daily basis and special attention should be exercised in case of reduced kidney function. PMID- 25293572 TI - [Gut microbiota may influence childhood and adolescent onset obesity]. AB - Childhood and adolescent onset obesity has reached epidemical proportions worldwide. Recent evidence suggests that obesity is associated with phylogenetic changes in the gut microbiota, which could potentially reveal new avenues for obesity prevention and treatment. A vast number of variables are influencing the gut microbial ecology and though many are proposed, the exact physiological processes behind the relationship are yet to be revealed. This review is focusing on recent advances addressing the potential role of the human gut microbiota in childhood and adolescent onset obesity. PMID- 25293573 TI - [Thrombotic thrombocytopenic purpura in a child with low ADAMTS13 enzyme level]. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare condition, but important to consider in case of thrombocytopenia and haemolysis. It is imperative to proceed with the correct treatment, in order to ensure a satisfactory outcome. TTP is either acquired or idiopathic. This case report shows that a 14-year-old boy has acquired TTP due to an infection with Campylobacter jejuni and Samonella szentes. Plasma exchange plays an essential role in the treatment of TTP. PMID- 25293574 TI - Nanoscale segregation of actin nucleation and elongation factors determines dendritic spine protrusion. AB - Actin dynamics drive morphological remodeling of neuronal dendritic spines and changes in synaptic transmission. Yet, the spatiotemporal coordination of actin regulators in spines is unknown. Using single protein tracking and super resolution imaging, we revealed the nanoscale organization and dynamics of branched F-actin regulators in spines. Branched F-actin nucleation occurs at the PSD vicinity, while elongation occurs at the tip of finger-like protrusions. This spatial segregation differs from lamellipodia where both branched F-actin nucleation and elongation occur at protrusion tips. The PSD is a persistent confinement zone for IRSp53 and the WAVE complex, an activator of the Arp2/3 complex. In contrast, filament elongators like VASP and formin-like protein-2 move outwards from the PSD with protrusion tips. Accordingly, Arp2/3 complexes associated with F-actin are immobile and surround the PSD. Arp2/3 and Rac1 GTPase converge to the PSD, respectively, by cytosolic and free-diffusion on the membrane. Enhanced Rac1 activation and Shank3 over-expression, both associated with spine enlargement, induce delocalization of the WAVE complex from the PSD. Thus, the specific localization of branched F-actin regulators in spines might be reorganized during spine morphological remodeling often associated with synaptic plasticity. PMID- 25293575 TI - Combination of individualized local control and target-specific agent to improve unresectable liver cancer managements: a matched case-control study. AB - Management of late-stage hepatocellular carcinoma is difficult. A direct comparison of clinical data is needed in order to demonstrate the survival benefits of different therapies. We directly compared various therapies in a retrospective matched case-control study. A total of 79 patients with unresectable tumors greater than 10 cm in size were included in the study between 2008 and 2012. Thirty-five patients were treated with transarterial chemoembolization for local control, 20 were treated with sorafenib systemic chemotherapy, and 24 received combination treatment. The total follow-up time after initial therapy was 4.5 years. Survival time after treatment was significantly longer in the combination therapy group (P < 0.0001). The median survival times for combination, local control, and systemic chemotherapy were 15 (12-21), 10 (9-13), and 3.5 (2.5-9.0) months (95 % confidence interval), respectively. The hazard ratios for local control and systemic chemotherapy were 1.985 and 5.102, respectively, with combination treatment as the reference. There was no observed difference in combination therapy from the side effects of the individual therapies. In conclusion, the limited availability of therapeutic options for late-stage liver cancer necessitates reliance on multidisciplinary personalized medicine approaches with target-specific medications to increase survival time. Combining individualized local control therapy and drugs that target specific disease markers provides more benefits to patients. PMID- 25293576 TI - Receptors for luteinizing hormone-releasing hormone (GnRH) as therapeutic targets in triple negative breast cancers (TNBC). AB - Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50% of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 +/- 0.21 and 58.50 +/- 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated. PMID- 25293578 TI - Microbiological interaction studies between ceftazidime-avibactam and pulmonary surfactant and between ceftazidime-avibactam and antibacterial agents of other classes. AB - For an antibacterial agent to be considered for clinical studies in nosocomial pneumonia (NP), it should be active in the presence of pulmonary surfactant. Furthermore, owing to the common practice of treating such infections with more than one antibacterial agent, it should be free of antagonistic interactions with agents of other classes. The aim of this study was to demonstrate the effect of pulmonary surfactant on the activity of ceftazidime and ceftazidime-avibactam and to determine the interaction (if any) of ceftazidime-avibactam and six antimicrobial agents common in the treatment of NP. Minimum inhibitory concentration (MIC) determination for ceftazidime and ceftazidime-avibactam was performed with and without the presence of four concentrations of bovine pulmonary surfactant, and a chequerboard assay was used to determine any interaction between ceftazidime and ceftazidime-avibactam with tobramycin, levofloxacin, linezolid, vancomycin, tigecycline and colistin. Here we report that the in vitro antimicrobial activity of ceftazidime-avibactam against beta lactamase-producing Gram-negative bacteria remained unaltered in the presence of pulmonary surfactant at concentrations that antagonised the antimicrobial activity of daptomycin. Furthermore, in chequerboard interaction studies, an absence of antagonism was demonstrated between ceftazidime-avibactam and six antimicrobial agents of different classes when tested against aerobic species frequently isolated from NP. The results support the further investigation of ceftazidime-avibactam as a potential treatment for NP caused by susceptible bacteria. PMID- 25293577 TI - Comparison of tyrosine kinase receptors HER2, EGFR, and VEGFR expression in micropapillary urothelial carcinoma with invasive urothelial carcinoma. AB - Invasive micropapillary urothelial carcinomas (MPUC) emerge at higher stages and follow a more aggressive course than conventional invasive urothelial carcinomas (UC). Little is known about the target therapies using tyrosine kinase inhibitors in MPUC. This study is to investigate potential effectiveness of tyrosine kinase receptor inhibitors by determining expression of epidermal growth factor receptor (EGFR), human epidermal receptor 2 (HER2), and vascular endothelial growth factor receptor 2 (VEGFR) proteins in MPUC and UC. 16 cases of MPUC and 16 stage-matched UC were identified. Immunohistochemistry for EGFR, HER2, and VEGFR2 and HER2 gene amplification by fluorescence in situ hybridization (FISH) were performed. HER2 and EGFR proteins were expressed in MPUC and UC, with significantly higher HER2 expression in MPUC (ratio 1.82, p < 0.01). HER2 gene amplification was identified in 4 of 16 MPUC (25 %). Amplification was limited to cases with 3+ HER2 expression (100% concordance). EGFR expression in MPUC was slightly higher than UC but not statistically significant (ratio 1.57, p = 0.19). EGFR and HER2 coexpression was noted in 75% of MPUC and 37.5% of UC. No VEGFR expression was identified in the urothelium. Strong VEGFR expression was noted in stromal vessels in both MPUC and UC. In conclusion, EGFR and HER2 are potential targets for neoadjuvant chemotherapy in MPUC and UC. There is no direct anti-tumor effect expected for VEGFR inhibitors. PMID- 25293579 TI - A case of chromoblastomycosis caused by Fonsecaea pedrosoi in a patient with rheumatoid arthritis. PMID- 25293580 TI - Benzotriazole: An overview on its versatile biological behavior. AB - Discovered in late 1960, azoles are heterocyclic compounds class which constitute the largest group of available antifungal drugs. Particularly, the imidazole ring is the chemical component that confers activity to azoles. Triazoles are obtained by a slight modification of this ring and similar or improved activities as well as less adverse effects are reported for triazole derivatives. Consequently, it is not surprising that benzimidazole/benzotriazole derivatives have been found to be biologically active. Since benzimidazole has been widely investigated, this review is focused on defining the place of benzotriazole derivatives in biomedical research, highlighting their versatile biological properties, the mode of action and Structure Activity Relationship (SAR) studies for a variety of antimicrobial, antiparasitic, and even antitumor, choleretic, cholesterol lowering agents. PMID- 25293582 TI - Efficiency of different strategies for gene silencing in Botrytis cinerea. AB - The generation of knock-out mutants in fungal pathogens by gene replacement and insertional mutagenesis is the classical method to validate virulence factors. An alternative strategy consists of silencing the candidate virulence gene by making use of the phenomenon of RNA interference (RNAi), adding features such as the possibility of generating knock-down mutants with variable expression levels of the target gene or the ability to simultaneously target multiple genes. Two different approaches have been assayed to generate knock-down mutants by RNAi in the phytopathogenic fungus Botrytis cinerea. In the first one, the single nitrate reductase gene in the B. cinerea genome, niaD, was silenced by transformation with a construct containing a 400-bp niaD fragment between two opposing promoters, so that a dsRNA fragment was generated. As an alternative approach, the mgfp4 gene coding for the green fluorescent protein (GFP) was silenced by transforming two different GFP-expressing strains of B. cinerea with a hairpin RNA (hpRNA)-expressing vector, containing two inverted copies of a 300-bp mgfp4 fragment separated by a spacer DNA. While the opposing dual-promoter strategy produced gene silencing in about half of the transformants assayed, the efficiency of the hpRNA-expressing vector was higher, inducing a decrease in GFP levels in more than 90 % of transformants. The degree of silencing achieved was high with both methods, but the hpRNA strategy resulted in a higher proportion of strongly silenced transformants. PMID- 25293581 TI - HCMV induces dysregulation of glutamate uptake and transporter expression in human fetal astrocytes. AB - Human cytomegalovirus (HCMV) infections are the leading cause of viral induced birth defects, affecting the central nervous system (CNS) primarily. Fetal CNS is especially vulnerable to CMV induced injury. As HCMV permissive cells, astrocytes are responsible for major glutamate transport and regulate extracellular levels of glutamate avoiding its accumulation which is implicated in neurodegenerative disorders. In this study, highly purified astrocytes isolated from human first trimester aborted fetal brain were infected with HCMV AD169, glutamate uptake function was detected by (3)H labeling technic, and the expression level alterations of glutamate transporters (GLAST, GLT-1), glutamine synthetase (GS) and its activity were also investigated. Protein kinases C (PKC) inhibitor treatment was to identify whether PKC signalling involved in regulating glutamate uptake, protein expression of GLAST, GLT-1, GS and GS activity. Results indicated HCMV AD169 infection could modulate glutamate uptake, expression levels of GLAST, GLT-1, GS and it activity through PKC signalling, suggesting a great susceptibility of human fetal astrocytes to HCMV infection, which significantly alters the uptake and metabolism of an important excitatory amino acid, glutamate, may be a potential mechanism for HCMV associated neurological disease, and an effective therapeutic target in neural diseases. PMID- 25293583 TI - Acute renal failure in a patient with mantle cell lymphoma. AB - Mantle cell lymphoma is a rare form of B-cell lymphoma. We present a 54-year-old gentleman with mantle cell lymphoma. It was diagnosed based on the demonstration of B-cell antigens CD20 and CD5. It was further confirmed by demonstration of overexpression of cyclin D1 on these atypical lymphocytes in the immunohistochemical staining. He also had acute renal failure and proteinuria. Renal biopsy revealed crescents and lymphomatous infiltration of tubulointerstitium. The presence of infiltrating cells with similar markers in both the lymph node and the kidney confirmed the infiltration of kidney with lymphomatous cells. Our present patient, after a thorough literature search, is found to be the second one with a glomerular lesion and tubulointerstitial infiltration by malignant lymphoma cells. PMID- 25293584 TI - Formation, isomerization, and dissociation of epsilon- and alpha-carbon-centered tyrosylglycylglycine radical cations. AB - The fragmentation products of the epsilon-carbon-centered radical cations [Y(epsilon)LG](+) and [Y(epsilon)GL](+), made by 266 nm laser photolysis of protonated 3-iodotyrosine-containing peptides, are substantially different from those of their pi-centered isomers [Y(pi)LG](+) and [Y(pi)GL](+), made by dissociative electron transfer from ternary metal-ligand-peptide complexes. For leucine-containing peptides the major pathway for the epsilon-carbon-centered radical cations is loss of the side chain of the leucine residue forming [YG(alpha)G](+) and [YGG(alpha)](+), whereas for the pi-radicals it is the side chain of the tyrosine residue that is lost, giving [G(alpha)LG](+) and [G(alpha)GL](+). The fragmentations of the product ions [YG(alpha)G](+) and [YGG(alpha)](+) are compared with those of the isomeric [Y(epsilon)GG](+) and [Y(pi)GG](+) ions. The collision-induced spectra of ions [Y(epsilon)GG](+) and [YGG(alpha)](+) are identical, showing that interconversion occurs prior to dissociation. For ions [Y(epsilon)GG](+), [Y(pi)GG](+) and [YG(alpha)G](+) the dissociation products are all distinctly different, indicating that dissociation occurs more readily than isomerization. Density functional theory calculations at B3LYP/6-31++G(d,p) gave the relative enthalpies (in kcal mol(-1) at 0 K) of the five isomers to be [Y(epsilon)GG](+) 0, [Y(pi)GG](+) -23.7, [YGG(alpha)](+) 28.7, [YG(alpha)G](+) -31.0 and [Y(alpha)GG](+) -38.5. Migration of an alpha-C-H atom from the terminal glycine residue to the epsilon-carbon-centered radical in the tyrosine residue, a 1-11 hydrogen atom shift, has a low barrier, 15.5 kcal mol(-1) above [Y(epsilon)GG](+). By comparison, isomerization of [Y(epsilon)GG](+) to [YG(alpha)G](+) by a 1-8 hydrogen atom migration from the alpha-C-H atom of the central glycine residue has a much higher barrier (50.6 kcal mol(-1)); similarly conversion of [Y(epsilon)GG](+) into [Y(pi)GG](+) has a higher energy (24.4 kcal mol(-1)). PMID- 25293585 TI - Measuring and reporting attrition from obesity treatment programs: A call to action! AB - The high attrition rates in obesity interventions are associated with poorer weight loss and maintenance for the individual and poorer overall treatment effectiveness and cost-effectiveness for the treatment provider. Increased knowledge about factors associated with attrition can facilitate the identification of individuals at risk of drop-out and inform treatment program improvements with the aim of maximising treatment retention. To date, a relatively small body of literature has explored attrition from weight-loss interventions using two methods of attrition assessment: identification of pre treatment predictors of attrition and eliciting post-treatment reasons for attrition. A range of attrition rates have been reported and no reliable or consistent predictors of attrition have been found. It is unknown whether the lack of consistent findings reflects population or treatment differences, or if the discrepant findings simply reflect differences in definition and measurement of attrition. Further research is required to address these limitations. There is a need for a recognised definition of obesity treatment attrition, the consideration of predictors that are theoretically and empirically associated with attrition, the development of a well-validated and standardised measure of barriers to attendance, and assessment of both treatment completers and drop outs. Understanding the factors that influence attrition can be used to inform the modification of treatment programs and to target those most at risk of drop out so as to maximise the success of obesity interventions. PMID- 25293587 TI - Preoperative biliary drainage. AB - The role of preoperative biliary drainage (PBD) in patients with distal or proximal biliary obstruction secondary to resectable tumors has been a matter for debate. A review of the literature using Medline, Embase and Cochrane databases was undertaken for studies evaluating routes of drainage (endoscopic or percutaneous) and stent types (plastic or metal) in patients with resectable disease. Preoperative biliary drainage is indicated for relief of symptomatic jaundice, cholangitis, patients undergoing neoadjuvant therapy or those patients where surgery may be delayed. Endoscopic methods are preferred over percutaneous methods because of lower complication rates. In patients with proximal biliary obstruction, PBD should be guided by imaging studies to aid in selective biliary cannulation for unilateral drainage in order to reduce the risk of cholangitis in undrained liver segments. PMID- 25293586 TI - Effects of weight regain following intentional weight loss on glucoregulatory function in overweight and obese adults with pre-diabetes. AB - OBJECTIVE: To assess the extent to which initial, intentional weight loss associated improvements in glucose tolerance and insulin action are diminished with weight regain. METHODS: 138 overweight and obese (BMI: 32.4+/-3.9kg/m(2)), adults (59.0+/-9.7 years), with pre-diabetes were followed through a 6-month weight loss intervention and subsequent 18-month weight maintenance period, or usual care control condition. Longitudinal change in weight (baseline, 6, 24 months) was used to classify individuals into weight pattern categories (Loser/Maintainer (LM), n= 50; Loser/Regainer (LR), n=51; and Weight Stable (WS), n=37). Fasting plasma glucose (FPG), insulin, and insulin resistance (HOMA-IR) were measured at baseline, 6, 12, 18 and 24 months and model adjusted changes, by weight pattern category, were assessed. RESULTS: LMs and LRs lost 8.3+/-4.7kg (8.7+/-4.5%) and 9.6+/-4.7kg (10.2+/-4.7%) during the first 6 months, respectively. LM continued to lose 1.1+/-3.4kg over the next 18 months (9.9+/ 6.5% reduction from baseline; p<0.05), while LRs regained 6.5+/-3.7kg (3.3+/-5.3% reduction from baseline; p<0.05). Weight change was directly associated with change in all DM risk factors (all p<0.01). Notably, despite an absolute reduction in body weight (from baseline to 24 months) achieved in the LR group, 24-month changes in FPG, insulin, and HOMA-IR did not differ between WS and LR groups. Conversely, LM saw sustained improvements in all measured DM risk factors. CONCLUSIONS: Significant weight loss followed by weight loss maintenance is associated with sustained improvements in FPG, insulin, and HOMA-IR; conversely, even partial weight regain is associated with regression of initial improvements in these risk factors towards baseline values. PMID- 25293588 TI - Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy endoperoxides: a potential P450 and lipoxygenase interaction. AB - Herein, we characterize a generally applicable transformation of fatty acid epoxides by lipoxygenase (LOX) enzymes that results in the formation of a five membered endoperoxide ring in the end product. We demonstrated this transformation using soybean LOX-1 in the metabolism of 15,16-epoxy-alpha linolenic acid, and murine platelet-type 12-LOX and human 15-LOX-1 in the metabolism of 14,15-epoxyeicosatrienoic acid (14,15-EET). A detailed examination of the transformation of the two enantiomers of 15,16-epoxy-alpha-linolenic acid by soybean LOX-1 revealed that the expected primary product, a 13S-hydroperoxy 15,16-epoxide, underwent a nonenzymatic transformation in buffer into a new derivative that was purified by HPLC and identified by UV, LC-MS, and 1H-NMR as a 13,15-endoperoxy-16-hydroxy-octadeca-9,11-dienoic acid. The configuration of the endoperoxide (cis or trans side chains) depended on the steric relationship of the new hydroperoxy moiety to the enantiomeric configuration of the fatty acid epoxide. The reaction mechanism involves intramolecular nucleophilic substitution (SNi) between the hydroperoxy (nucleophile) and epoxy group (electrophile). Equivalent transformations were documented in metabolism of the enantiomers of 14,15-EET by the two mammalian LOX enzymes, 15-LOX-1 and platelet-type 12-LOX. We conclude that this type of transformation could occur naturally with the co occurrence of LOX and cytochrome P450 or peroxygenase enzymes, and it could also contribute to the complexity of products formed in the autoxidation reactions of polyunsaturated fatty acids. PMID- 25293589 TI - Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions. AB - Sphingosine 1-phosphate receptor 1 (S1P1), an abundantly-expressed G protein coupled receptor which regulates key vascular and immune responses, is a therapeutic target in autoimmune diseases. Fingolimod/Gilenya (FTY720), an oral medication for relapsing-remitting multiple sclerosis, targets S1P1 receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P1 receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P1 coding region from exon sequencing of >12,000 individuals and their functional consequences. We conducted functional analyses of 14 nonsynonymous single nucleotide polymorphisms (SNPs) of the S1PR1 gene. One SNP mutant (Arg120 to Pro) failed to transmit sphingosine 1-phosphate (S1P)-induced intracellular signals such as calcium increase and activation of p44/42 MAPK and Akt. Two other mutants (Ile45 to Thr and Gly305 to Cys) showed normal intracellular signals but impaired S1P-induced endocytosis, which made the receptor resistant to FTY720-induced degradation. Another SNP mutant (Arg13 to Gly) demonstrated protection from coronary artery disease in a high cardiovascular risk population. Individuals with this mutation showed a significantly lower percentage of multi-vessel coronary obstruction in a risk factor-matched case-control study. This study suggests that individual genetic variations of S1P1 can influence receptor function and, therefore, infer differential disease risks and interaction with S1P1-targeted therapeutics. PMID- 25293591 TI - Pathophysiology of ischaemic acute kidney injury. AB - Acute kidney injury is common, dangerous and costly, affecting around one in five patients emergency admissions to hospital. Although survival decreases as disease worsens, it is now apparent that even modest degrees of dysfunction are not only associated with higher mortality but are an independent risk factor for death. This review focuses on the pathophysiology of acute kidney injury secondary to ischaemia - its commonest aetiology. The haemodynamic disturbances, endothelial injury, epithelial cell injury and immunological mechanisms underpinning its initiation and extension will be discussed along with the considerable and complex interplay between these factors that lead to an intense, pro-inflammatory state. Mechanisms of tubular recovery will be discussed but also the pathophysiology of abnormal repair with its direct consequences for long-term renal function. Finally, the concept of 'organ cross-talk' will be introduced as a potential explanation for the higher mortality observed with acute kidney injury that might be deemed modest in conventional biochemical terms. PMID- 25293592 TI - Occurrence of soluble supra-molecular FN-fibrin complexes in the plasma of children with recurrent respiratory infection. AB - OBJECTIVES: Fibronectin (FN) is able to bind fibrin and FN-fibrin complexes and is found in the plasma of some patients suffering from inflammatory disease. The present study was undertaken to determine whether soluble supra-molecular FN fibrin complexes were present in the plasma of children with recurrent respiratory infections (RRI). DESIGN AND METHODS: The frequency of occurrence and relative amounts of the supra-molecular FN-fibrin forms, concentrations of immunoglobulins and numbers of natural killer cells (NK) were determined in the plasma of children with recurrent respiratory infections. The frequencies of these parameters were compared with their frequencies in the plasma of children with acute respiratory infections and plasma from healthy children. RESULTS: SDS agarose immunoblotting of patients' plasma revealed the presence of several additional FN-fibrin bands, with decreasing electrophoretic mobilities and increasing molecular masses of 750 kDa, 1000 kDa, 1300 kDa, 1600 kDa and 1900 kDa. Such FN-fibrin complexes occurred with higher frequency and in larger amounts in the plasma of children with RRI and acute infection than they did in plasma from normal children. Moreover, bands above 1000 kDa were absent in most young healthy individuals. The occurrence of FN-fibrin complexes did not correlate with either immunoglobulin concentrations, or with the number of NK cells. CONCLUSIONS: The occurrence of plasma supra-molecular FN-fibrin complexes is associated with acute and recurrent respiratory infections of children. PMID- 25293590 TI - Pathways of cholesterol homeostasis in mouse retina responsive to dietary and pharmacologic treatments. AB - Effects of serum cholesterol on cholesterol content in the retina are currently unknown. It is also unclear how cholesterol levels are controlled in the retina. High-cholesterol diet and oral administrations of simvastatin were used to modulate serum cholesterol in mice. These treatments only modestly affected cholesterol content in the retina and had no significant effect on retinal expression of the major cholesterol- and vision-related genes; the sterol regulatory element binding protein pathway of transcriptional regulation does not seem to be operative in the retina under the experimental conditions used. Evidence is obtained that posttranslational mechanisms play a role in the control of retinal cholesterol. Retinal genes were only upregulated by oral administrations of TO901317 activating liver X receptors. Three of the upregulated genes could be of particular importance (apoD, Idol, and Rpe65) and have not yet been considered in the context of cholesterol homeostasis in the retina. Collectively, the data obtained identify specific features of retinal cholesterol maintenance and suggest additional therapies for age-related macular degeneration, a blinding disease characterized by cholesterol and lipid accumulations in chorioretinal tissues. PMID- 25293593 TI - Adult weight loss diets: metabolic effects and outcomes. AB - The global prevalence of overweight and obesity as a public health concern is well established and reflects the overall lack of success in our ability to achieve and maintain a healthy body weight. Being overweight and obese is associated with numerous comorbidities and is a risk factor for several of the leading causes of death, including cardiovascular disease, diabetes mellitus, and many types of cancer. The foundation of treatment has been diet and exercise. There are >1,000 published weight loss diets, with more appearing in the lay literature and the media on a regular basis. The sheer number of existing diet regimens would suggest that no one diet has been universally successful at inducing and maintaining weight loss. Many of these dietary programs are based on sound scientific evidence and follow contemporary principles of weight loss. Others simply eliminate 1 or more of the essential food groups or recommend consumption of 1 type of food at the expense of other foods with little to no supporting evidence. The focus of this review is on weight loss diets, specifically those with the most supporting scientific evidence and those that are most likely to succeed in achievement and maintenance of desirable body weight. The effects of weight loss diets on energy expenditure, body weight, body composition, and metabolic parameters will be evaluated. Ultimately, the best diet is the one the patient will follow and incorporate into his or her daily life for lifelong maintenance of a healthy body weight. PMID- 25293594 TI - Supplements for weight loss: hype or help for obesity? PMID- 25293595 TI - Gastrostomy tube placement in patients with advanced dementia or near end of life. AB - Based on current scientific literature, gastrostomy tube (G-tube) placement or other long-term enteral access devices should be withheld in patients with advanced dementia or other near end-of-life conditions. In many instances healthcare providers are not optimally equipped to implement this recommendation at the bedside. Autonomy of the patient or surrogate decision maker should be respected, as should the patient's cultural, religious, social, and emotional value system. Clinical practice needs to address risks, burdens, benefits, and expected short-term and long-term outcomes in order to clarify practice changes. This paper recommends a change in clinical practice and care strategy based on the results of a thorough literature review and provides tools for healthcare clinicians, particularly in the hospital setting, including an algorithm for decision making and a checklist to use prior to the placement of G-tubes or other long-term enteral access devices. Integrating concepts of patient-centered care, shared decision making, health literacy, and the teach-back method of education enhances the desired outcome of ethical dilemma prevention. The goal is advance care planning and a timely consensus among health team members, family members, and significant others regarding end-of-life care for patients who do not have an advance directive and lack the capacity to advocate for themselves. Achieving this goal requires interdisciplinary collaboration and proactive planning within a supportive healthcare institution environment. PMID- 25293596 TI - [Organizational models of inpatient emergency and acute care]. PMID- 25293597 TI - [Albumin in severe sepsis or septic shock: should it be administered?]. PMID- 25293598 TI - Effects of vitamin C and E supplementation on endogenous antioxidant systems and heat shock proteins in response to endurance training. AB - Reactive oxygen and nitrogen species are important signal molecules for adaptations to training. Due to the antioxidant properties of vitamin C and E, supplementation has been shown to blunt adaptations to endurance training. In this study, we investigated the effects of vitamin C and E supplementation and endurance training on adaptations in endogenous antioxidants and heat shock proteins (HSP). Thirty seven males and females were randomly assigned to receive Vitamin C and E (C + E; C: 1000 mg, E: 235 mg daily) or placebo (PLA), and underwent endurance training for 11 weeks. After 5 weeks, a subgroup conducted a high intensity interval session to investigate acute stress responses. Muscle and blood samples were obtained to investigate changes in proteins and mRNA related to the antioxidant and HSP system. The acute response to the interval session revealed no effects of C + E supplementation on NFkappaB activation. However, higher stress responses to exercise in C + E group was indicated by larger translocation of HSPs and a more pronounced gene expression compared to PLA. Eleven weeks of endurance training decreased muscle GPx1, HSP27 and alphaB crystallin, while mnSOD, HSP70 and GSH remained unchanged, with no influence of supplementation. Plasma GSH increased in both groups, while uric acid decreased in the C + E group only. Our results showed that C + E did not affect long-term training adaptations in the antioxidant- and HSP systems. However, the greater stress responses to exercise in the C + E group might indicate that long-term adaptations occurs through different mechanisms in the two groups. PMID- 25293599 TI - Mechanisms underlying the postexercise baroreceptor-mediated suppression of heat loss. AB - Reports indicate that postexercise heat loss is modulated by baroreceptor input; however, the mechanisms remain unknown. We examined the time-dependent involvement of adenosine receptors, noradrenergic transmitters, and nitric oxide (NO) in modulating baroreceptor-mediated changes in postexercise heat loss. Eight males performed two 15-min cycling bouts (85% VO2max) each followed by a 45-min recovery in the heat (35 degrees C). Lower body positive (LBPP), negative (LBNP), or no (Control) pressure were applied in three separate sessions during the final 30-min of each recovery. Four microdialysis fibres in the forearm skin were perfused with: (1) lactated Ringer's (Ringer's); (2) 4 mmol.L(-1) Theophylline (inhibits adenosine receptors); (3) 10 mmol.L(-1) Bretylium (inhibits noradrenergic transmitter release); or (4) 10 mmol.L(-1) l-NAME (inhibits NO synthase). We measured cutaneous vascular conductance (CVC; percentage of maximum) calculated as perfusion units divided by mean arterial pressure, and local sweat rate. Compared to Control, LBPP did not influence CVC at l-NAME, Theophylline or Bretylium during either recovery (P > 0.07); however, CVC at Ringer's was increased by ~5-8% throughout 30 min of LBPP during Recovery 1 (all P < 0.02). In fact, CVC at Ringer's was similar to Theophylline and Bretylium during LBPP. Conversely, LBNP reduced CVC at all microdialysis sites by ~7-10% in the last 15 min of Recovery 2 (all P < 0.05). Local sweat rate was similar at all treatment sites as a function of pressure condition (P > 0.10). We show that baroreceptor input modulates postexercise CVC to some extent via adenosine receptors, noradrenergic vasoconstriction, and NO whereas no influence was observed for postexercise sweating. PMID- 25293600 TI - Different modulation of short- and long-latency interhemispheric inhibition from active to resting primary motor cortex during a fine-motor manipulation task. AB - Performing a complex unimanual motor task markedly increases activation not only in the hemisphere contralateral to the task-performing hand but also in the ipsilateral hemisphere. Transcranial magnetic stimulation studies showed increased motor evoked potential amplitude recorded in resting hand muscles contralateral to the task-performing hand during a unimanual motor task, and transcallosal inputs from the active hemisphere have been suggested to have responsibilities for this phenomenon. In the present study, we used a well established double-pulse transcranial magnetic stimulation paradigm to measure two phases of interhemispheric inhibition from the active to the resting primary motor cortex during the performance of a complex unimanual motor task. Two different unimanual motor tasks were carried out: a fine-motor manipulation task (using chopsticks to pick up, transport, and release glass balls) as a complex task and a pseudo fine-motor manipulation task as a control task (mimicking the fine-motor manipulation task without using chopsticks and picking glass balls). We found increased short-latency interhemispheric inhibition and decreased long latency interhemispheric inhibition from the active to the resting primary motor cortex during the fine-motor manipulation task. To the best of our knowledge, the present study is the first to demonstrate different modulation of two phases of interhemispheric inhibition from the active to the resting primary motor cortex during the performance of a complex unimanual motor task. The different modulation of short- and long-latency interhemispheric inhibition may suggest that two phases of interhemispheric inhibition are implemented in distinct circuits with different functional meaning. PMID- 25293601 TI - A high ratio of G1 to G0 phase cells and an accumulation of G1 phase cells before S phase progression after injurious stimuli in the proximal tubule. AB - Proximal tubule (PT) cells can proliferate explosively after injurious stimuli. To investigate this proliferative capacity, we examined cell cycle status and the expression of cyclin-dependent kinase inhibitor p27, a G1 phase mediator, in PT cells after a proliferative or injurious stimulus. Rats were treated with lead acetate (proliferative stimulus) or uranyl acetate (UA; injurious stimulus). Isolated tubular cells were separated into PT and distal tubule (DT) cells by density-gradient centrifugation. Cell cycle status was analyzed with flow cytometry by using the Hoechst 33342/pyronin Y method. Most PT and DT cells from control rats were in G0/G1 phase, with a higher percentage of PT cells than DT cells in G1 phase. Lead acetate and UA administration promoted the G0-G1 transition and the accumulation of G1 phase cells before S phase progression. In PT cells from rats treated with lead acetate or a subnephrotoxic dose of UA, p27 levels increased or did not change, possibly reflecting G1 arrest. In contrast, p27 became undetectable before the appearance of apoptotic cells in rats treated with a nephrotoxic dose of UA. The decrease in p27 might facilitate rapid cell cycling. The decreased number of p27-positive cells was associated with PT cell proliferation in renal tissues after a proliferative or injurious stimulus. The findings suggest that a high ratio of G1 to G0 phase cells and a rapid accumulation of G1 phase cells before S phase progression in the PT is a biological strategy for safe, timely, and explosive cell proliferation in response to injurious stimuli. PMID- 25293603 TI - Inguinal hernia: follow or repair? AB - Observation is an acceptable management strategy for asymptomatic and minimally symptomatic inguinal hernias because it is safe. The rate of hernia accident is very low and is not an indication for surgery. However, patients who present to their physician with a hernia will almost certainly undergo a hernia repair if they live long enough. PMID- 25293602 TI - Frequency dependence of power and its implications for contractile function of muscle fibers from the digital flexors of horses. AB - The digital flexors of horses must produce high force to support the body weight during running, and a need for these muscles to generate power is likely limited during locomotion over level ground. Measurements of power output from horse muscle fibers close to physiological temperatures, and when cyclic strain is imposed, will help to better understand the in vivo performance of the muscles as power absorbers and generators. Skinned fibers from the deep (DDF) and superficial (SDF) digital flexors, and the soleus (SOL) underwent sinusoidal oscillations in length over a range of frequencies (0.5-16 Hz) and strain amplitudes (0.01-0.06) under maximum activation (pCa 5) at 30 degrees C. Results were analyzed using both workloop and Nyquist plot analyses to determine the ability of the fibers to absorb or generate power and the frequency dependence of those abilities. Power absorption was dominant at most cycling frequencies and strain amplitudes in fibers from all three muscles. However, small amounts of power were generated (0.002-0.05 Wkg(-1)) at 0.01 strain by all three muscles at relatively slow cycling frequencies: DDF (4-7 Hz), SDF (4-5 Hz) and SOL (0.5-1 Hz). Nyquist analysis, reflecting the influence of cross-bridge kinetics on power generation, corroborated these results. The similar capacity for power generation by DDF and SDF versus lower for SOL, and the faster frequency at which this power was realized in DDF and SDF fibers, are largely explained by the fast myosin heavy chain isoform content in each muscle. Contractile function of DDF and SDF as power absorbers and generators, respectively, during locomotion may therefore be more dependent on their fiber architectural arrangement than on the physiological properties of their muscle fibers. PMID- 25293605 TI - Endoscopic myotomy for achalasia. AB - POEM is an effective treatment of functional manometric esophageal outflow obstructive disorders with excellent relief of dysphagia. Reflux rates seem to be similar to that seen with traditional Heller myotomy with fundoplication. The POEM technique provides a true surgical esophageal myotomy without incisional pain. As such, POEM represents the first truly practical application of natural orifice surgery. PMID- 25293604 TI - Is it safe to follow side branch IPMNs? AB - Management of Bd-IPMN remains challenging. Critical appraisal of the published literature reveals that the actual treatment of what is presumed to be Bd-IPMN remains unsatisfactory, with a high rate of surgically overtreated patients. Until we accrue more precise knowledge of the natural history of Bd-IPMN, management of patients with this presumed diagnosis should be individually tailored and preferably carried out in centers with a high expertise. For now, the authors strongly think that the old guidelines should be followed in most patients because these have proven to correctly identify lesions that can be safely followed. Although the new guidelines allow for follow-up of lesions greater than 3 cm, and for the most part this is safe, they should be used cautiously in younger patients because very close surveillance would be required for their long remaining lifespan. PMID- 25293606 TI - Can interventionalists do endovascular aortic aneurysm repair as well as vascular surgeons? PMID- 25293607 TI - Does walking speed predict postoperative morbidity? PMID- 25293608 TI - Does close temperature regulation affect surgical site infection rates? AB - The argument for close temperature control, to which regulatory bodies have held health systems in an effort to reduce the burden of hospital-acquired infections, is not fully supported by current evidence. The literature is complex on the topic, and overinterpretation of historical data supporting close temperature regulation does not preclude an important recognition of these early works' contribution to high-quality surgical care. Avoidance of hypothermia through the regular use of active rewarming should be a routine part of safe surgical care. The biochemical basis of emphasizing temperature regulation is sound, and ample evidence shows the frank physiologic derangements seen when biological processes occur at suboptimal temperature. It is also recognized that patients tend to do better when warmed during the perioperative period, suggesting that warming devices are an important and essential adjunct to good perioperative care. Clinicians, researchers, and policymakers must be careful in how they apply these well-supported findings to process metrics in an era of limited resources with increasingly stringent quality guidelines and outcomes measures. Discrete temperature targets in current measures are not supported by the existing literature. Not only do these targets artificially anchor clinicians to temperature values with an inadequate scientific basis but they demand intensive resources from health institutions that could potentially be better used on quality requirements with stronger evidence of their ultimate effect on patient care. PMID- 25293609 TI - The utility of the robot in pancreatic resections. AB - Robotic pancreatic resections have been established as safe alternatives to the open and laparoscopic approaches. The platform has proven to be versatile, and discriminable, allowing an increasing number of surgeons to perform complex pancreatic resections in minimally invasive fashion. To date, the realized advantages of the robotic technique are decreased blood loss, and fewer conversions to laparotomy. Although these are 2 very important metrics, larger experiences comparing robotics to open and/or laparoscopic surgery are ultimately needed if the true potential of robotic pancreatic resections are to be realized. PMID- 25293610 TI - Current treatment for small (< 5 cm) hepatocellular carcinoma: evolving roles for ablation and resection. PMID- 25293611 TI - Screening for pancreatic cancer. AB - Even with improved cancer care generally, the incidence and death rate is increasing for pancreatic cancer. Concern exists that a further increase in deaths caused by pancreatic cancer will be seen as other causes of death, such as heart disease and other cancers, decline. Critical exploration of screening high risk patients as a tool to reduce deaths from pancreatic cancer should be considered. Technological advances and improved understanding of pancreatic cancer biology provides an opportunity to identify and test a panel of early detection biomarkers easily, accurately, and inexpensively measured in blood, urine, stool, or saliva samples. These biomarkers may have additional usefulness in staging, stratification for treatment, establishing prognosis, and assessing response to therapy in this disease. Screening may prove to be one of several strategies to improve outcomes in a disease that has otherwise been difficult to defeat. PMID- 25293612 TI - Tissue engineering. AB - Ultimately much work remains to be done in the companion fields of biomaterials and stem cells. Nonetheless, the monumental progress in TE that has been reported in the studies summarized here demonstrates that regenerative approaches to problems in general surgery need to be explored in more depth. Furthermore, the surgical disciplines of reconstruction and transplantation need to recognize their research counterparts in TE, given its potential to actualize freedom from immunosuppression, one of the most elusive goals in modern surgery. The engineering and proliferation of autologous cells, tissues, and organs ex vivo before surgical operation can significantly reduce the obstacles current practitioners are intimately familiar with: donor site morbidity and immunologic rejection. Therefore, in addition to the truly exciting research and development prospects and implications for the commercial sector, patients with end-stage diseases and debilitating injury stand to gain the most from clinically adapted TE therapies. PMID- 25293613 TI - Acute cholecystitis: early versus delayed surgery. AB - Laparoscopic cholecystectomy is widely established as the standard operation in acute cholecystectomy. Valid data from several prospective studies, including a recent large randomized multicenter trial, are available, demonstrating that early cholecystectomy is associated with less morbidity, a shorter length of hospital stay, and lower total hospital costs compared with delayed cholecystectomy after a conservative treatment period with antibiotics. Early cholecystectomy within 24 hours of hospital admission is the therapy of choice in patients fit for surgery and should be implemented as the standard treatment algorithm for this condition. PMID- 25293615 TI - Readmission after surgery. AB - Readmission is a large problem after both medical and surgical admissions. Recent policy changes that include substantial financial penalties have made readmission an important, if not the most important, pay-for-performance program for health care in the United States. The CMS Hospital Readmissions Reduction Program currently applies only to patients with certain medical diagnoses, but it is expanding into orthopedic surgery in 2014, and will likely involve more surgical procedures in the future. Accordingly, hospitals and researchers will increasingly be focused on understanding and preventing readmission. Definitions of readmission must be standardized between organizations to allow for comparison. The accepted definition for any organization tracking rehospitalization should be 30-day all-cause readmission. In addition, any hospital profiling applications or studies comparing readmission rates between hospitals should use hierarchical rather than standard logistic regression modeling. Rather than relying on findings from medical patients, further studies on the specific causes of readmission after surgery should be conducted. Predictive modeling has some utility in focusing readmission prevention efforts on high-risk patients, but understanding the underlying causes of readmission is key to designing effective prevention interventions. Current evidence suggests that postoperative complications play a key role in surgical readmission, but efforts on improving discharge planning and coordination of care developed in medical patients will also be critical in decreasing unnecessary readmissions in the future. PMID- 25293614 TI - Gastrointestinal stromal tumors: who should get imatinib and for how long? AB - The application of imatinib for the treatment of GIST remains a remarkable illustration of the ability and promise of targeted molecular therapy. It is gradually becoming evident that the benefit of imatinib depends on the complex interplay between mutational variations that govern tumor sensitivity to the drug, and biological variables that drive clinical outcome. Evidence is mounting that only a select fraction of patients in the adjuvant setting may benefit from imatinib. Unfortunately, most patients with metastatic disease develop resistance to imatinib, as occurs in other diseases treated with kinase inhibitors. Thus, although imatinib has demonstrated that kinase inhibitor therapy is an integral component of cancer care, it has also revealed the challenges in treating a dynamic cancer with a static monotherapy. As greater insight is gained into when imatinib does not help, it will uncover the obvious next pathway in cancer treatment, namely individualized, genotype-directed therapy that is modulated according to the genetic and immunologic landscape of the tumor. PMID- 25293616 TI - What is wrong with the training of general surgery? AB - The practice of surgery has undergone tumultuous changes over the last 30 years. Disease management, trauma volume, operative techniques, supervision requirements, and allocation of work hours have all changed, resulting in a substantial impact on general surgical training. Changes need to occur in the structure, assessment, and mentorship of future residents to prepare them to enter the marketplace and practice safe medicine with confidence and authority. PMID- 25293617 TI - Aspirin, clopidogrel, and the surgeon. AB - The rising use of antiplatelet therapy for primary prevention and secondary prevention of cardiovascular and cerebrovascular events poses a dilemma for physicians in the perioperative period. The proven benefits of aspirin in preventing further thrombotic events in patients with prior ACS or stroke make it difficult to withdraw this therapy. The risk of hypercoagulability associated with surgery is also independent of antiplatelet withdrawal, but adds to the rebound effect of platelet responsiveness. Therefore, aspirin should be continued whenever feasible. Similarly, the use of thienopyridines such as clopidogrel, especially for the prevention of stent thrombosis, should be maintained for at least the recommended time frame, if not longer. It is recognized that maintaining antiplatelet therapy is also not without risk, as bleeding complications have been well documented. Unfortunately, current perioperative guidelines do not often provide a simple solution for management. Therefore, the risk of bleeding has to be weighed against the risk of thrombosis, and decisions should be made with all providers caring for the patient on an individual basis. PMID- 25293619 TI - Liver transplantation for metastatic neuroendocrine tumors. AB - The ideal management of NET must be addressed on a case-by-case basis, with consideration given to patient factors, disease burden, and clinical tumor activity. Outcome improvement for LT in the setting of metastatic disease requires better characterization of the biological behavior of NETs and further identification of factors to be included in the selection criteria. Box 3 summarizes the many areas that have been, and are currently, undergoing investigation. LT as an attempt for cure rather than palliation is a justified treatment option for well-selected patients with metastatic neuroendocrine tumors of the pancreas and GI system. Optimization of pretransplantation staging and patient management algorithms, patient selection, and posttransplant management options are areas that need to be better defined. Further investigations for defining reproducible prognostic factors, consistent histopathologic evaluation, and uniform preoperative staging and site-specific data are needed. With the advancement of newer treatment modalities, it is necessary to define the role of LT along with the optimal perioperative management of existing and recurrent disease. PMID- 25293618 TI - Islet autotransplantation and total pancreatectomy. AB - The goal of IAT is the preservation of beta-cell mass at the time of pancreatectomy. The majority of recipients have significant endogenous beta-cell function with positive blood C-peptide after surgery, even if only approximately one third achieve insulin independence. In appropriately selected patients, total pancreatectomy combined with IAT achieves relief of pain and improves quality of life with relatively easier-to-manage glycemic control and avoidance of hyper- and hypoglycemic episodes. Current research is focused on improving techniques of islet isolation and engraftment as well as long-term survival of autografted islets. PMID- 25293620 TI - Irreversible electroporation: a novel therapy for stage III pancreatic cancer. PMID- 25293625 TI - Research at the interface of physics and biology: bridging the two fields. AB - I firmly believe that interaction between physics and biology is not only natural, but inevitable. Kamal Shukla provides a personal perspective on working at the interface between the physical and biological sciences. PMID- 25293626 TI - Role of permissive hypotension, hypertonic resuscitation and the global increased permeability syndrome in patients with severe hemorrhage: adjuncts to damage control resuscitation to prevent intra-abdominal hypertension. AB - Secondary intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are closely related to fluid resuscitation. IAH causes major deterioration of the cardiac function by affecting preload, contractility and afterload. The aim of this review is to discuss the different interactions between IAH, ACS and resuscitation, and to explore a new hypothesis with regard to damage control resuscitation, permissive hypotension and global increased permeability syndrome. Review of the relevant literature via PubMed search. The recognition of the association between the development of ACS and resuscitation urged the need for new approach in traumatic shock management. Over a decade after wide spread application of damage control surgery damage control resuscitation was developed. DCR differs from previous resuscitation approaches by attempting an earlier and more aggressive correction of coagulopathy, as well as metabolic derangements like acidosis and hypothermia, often referred to as the 'deadly triad' or the 'bloody vicious cycle'. Permissive hypotension involves keeping the blood pressure low enough to avoid exacerbating uncontrolled haemorrhage while maintaining perfusion to vital end organs. The potential detrimental mechanisms of early, aggressive crystalloid resuscitation have been described. Limitation of fluid intake by using colloids, hypertonic saline (HTS) or hyperoncotic albumin solutions have been associated with favourable effects. HTS allows not only for rapid restoration of circulating intravascular volume with less administered fluid, but also attenuates post-injury oedema at the microcirculatory level and may improve microvascular perfusion. Capillary leak represents the maladaptive, often excessive, and undesirable loss of fluid and electrolytes with or without protein into the interstitium that generates oedema. The global increased permeability syndrome (GIPS) has been articulated in patients with persistent systemic inflammation failing to curtail transcapillary albumin leakage and resulting in increasingly positive net fluid balances. GIPS may represent a third hit after the initial insult and the ischaemia reperfusion injury. Novel markers like the capillary leak index, extravascular lung water and pulmonary permeability index may help the clinician in guiding appropriate fluid management. Capillary leak is an inflammatory condition with diverse triggers that results from a common pathway that includes ischaemia-reperfusion, toxic oxygen metabolite generation, cell wall and enzyme injury leading to a loss of capillary endothelial barrier function. Fluid overload should be avoided in this setting. PMID- 25293624 TI - Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation. AB - HbA1c is commonly used to monitor glycemic control. However, there is growing evidence that the relationship between HbA1c and mean blood glucose (MBG) is influenced by variation in red blood cell (RBC) lifespan in hematologically normal individuals. Correction of HbA1c for mean RBC age (MRBC ) requires a noninvasive, accurate, and affordable method to measure RBC survival. In this study, we evaluated whether a stable isotope approach would satisfy these requirements. RBC lifespan and MRBC were determined in a group of nine hematologically normal diabetic and nondiabetic subjects using oral (15) N glycine to label heme in an age cohort of RBC. The MRBC was 58.7 +/- 9.1 (2SD) days and RBC lifespan was 106 +/- 21 (2SD) days. This degree of variation (+/-15 20%) is consistent with previous studies using other techniques. In a subset of seven subjects, MRBC determined with the biotin label technique were available from approximately five years prior, and strongly correlated with the stable isotope values (R(2) = 0.79). This study suggests that the MRBC is stable over time but varies substantially among individuals, and supports the importance of its variation in HbA1c interpretation. The characteristics of the stable isotope method support its suitability for studies to directly evaluate the impact of variation in MRBC on the interpretation of HbA1c. PMID- 25293628 TI - Transformation of a layered perovskite to a defect perovskite via cooperative Li insertion and O/N substitution. AB - Defect perovskite oxynitrides containing lithium on the octahedral sites, i.e., Sr(1-x)(Li(x)Ta(1-x))(O(3.5-3x-3y)N(2y)), were produced by the ammonolytic heating of a layered perovskite, Sr2Ta2O7, with Li2CO3. The above phase evolution involved the thermal diffusion of Li(+) into the Sr2Ta2O7 lattice and concurrent 3O(2-) -> 2N(3-) substitution. The concentrations of Li, N, and anion vacancies in the product oxynitride could be controlled by adjusting the Li2CO3 to Sr2Ta2O7 ratio in the reactant mixture. This study identified three different compositions, Sr(0.92)Li(0.08)Ta(0.92)O(1.91)N(0.89), Sr(0.83)Li(0.17)Ta(0.83)O(1.88)N(0.74) and Sr(0.73)Li(0.27)Ta(0.73)O(1.82)N(0.58), where an increase in the Li composition accompanied decreases in the a- and c-parameters of the tetragonal cell, along with an increase in the band gap. Neutron diffraction and solid state (7)Li nuclear magnetic resonance spectroscopy of Sr(1-x)(Li(x)Ta(1-x))(O(3.5-3x 3y)N(2y)) showed that Li occupied the octahedral site, and these oxynitrides exhibited enhanced bond covalency compared to similar oxides. PMID- 25293627 TI - Metabolomic profiling of human serum in lung cancer patients using liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry and gas chromatography/mass spectrometry. AB - PURPOSE: Lung cancer is one of the most common causes of death from cancer. Serum markers that enable diagnosis of the disease in the early stage have not been found. METHODS: Serum samples were collected from 30 healthy volunteers and from 30 lung cancer patients preoperatively and postoperatively. Samples were subjected to metabolomic analysis using liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry and gas chromatography/mass spectrometry. Differences in metabolomic profiles among the three groups were characterized by multivariate statistical techniques such as principal components analysis and partial least squares discriminant analysis (PLS-DA). An independent t test was used to determine whether levels of biomarker candidates identified using PLS-DA modeling were significantly different among groups at the univariate analysis level (p < 0.05). RESULTS: Based on pattern recognition results and univariate analysis, we showed that levels of ten potential biomarkers in serum were significantly different in the preoperative lung cancer patients compared with healthy volunteers and/or the postoperative lung cancer patients. The levels of sphingosine, phosphorylcholine, glycerophospho-N-arachidonoyl ethanolamine, gamma linolenic acid, 9,12-octadecadienoic acid, oleic acid, and serine were significantly different in preoperative lung cancer patients compared to healthy volunteers and to postoperative lung cancer patients. For prasterone sulfate, alpha-hydroxyisobutyric acid, 2,3,4-trihydroxybutyric acid, the levels were statistically different in preoperative and postoperative lung cancer patients compared with the healthy volunteers. CONCLUSIONS: Our study identified potential metabolic biomarkers for diagnosis of lung cancer. PMID- 25293629 TI - Improvement of a Sulfolobus-E. coli shuttle vector for heterologous gene expression in Sulfolobus acidocaldarius. AB - A Sulfolobus-E. coli shuttle vector for an efficient expression of the target gene in S. acidocaldarius strain was constructed. The plasmid-based vector pSM21 and its derivative pSM21N were generated based on the pUC18 and Sulfolobus cryptic plasmid pRN1. They carried the S. solfataricus P2 pyrEF gene for the selection marker, a multiple cloning site (MCS) with C-terminal histidine tag, and a constitutive promoter of the S. acidocaldarius gdhA gene for strong expression of the target gene, as well as the pBR322 origin and ampicillin resistant gene for E. coli propagation. The advantage of pSM21 over other Sulfolobus shuttle vectors is that it contains a MCS and a histidine tag for the simple and easy cloning of a target gene as well as one-step purification by histidine affinity chromatography. For successful expression of the foreign genes, two genes from archaeal origins (PH0193 and Ta0298) were cloned into pSM21N and the functional expression was examined by enzyme activity assay. The recombinant PH0193 was successfully expressed under the control of the gdhA promoter and purified from the cultures by His-tag affinity chromatography. The yield was approximately 1 mg of protein per liter of cultures. The enzyme activity measurements of PH0913 and Ta0298 revealed that both proteins were expressed as an active form in S. acidocaldarius. These results indicate that the pSM21N shuttle vector can be used for the functional expression of foreign archaeal genes that form insoluble aggregates in the E. coli system. PMID- 25293630 TI - Comparison of traditional and commercial vinegars based on metabolite profiling and antioxidant activity. AB - Metabolite profiles of seven commercial vinegars and two traditional vinegars were performed by gas chromatography time-of-flight mass spectrometry with multivariate statistical analysis. During alcohol fermentation, yeast, nuruk, and koji were used as sugars for nutrients and as fermentation substrates. Commercial and traditional vinegars were significantly separated in the principal component analysis and orthogonal partial least square discriminant analysis. Six sugars and sugar alcohols, three organic acids, and two other components were selected as different metabolites. Target analysis by ultra-performance liquid chromatography quadruple-time-of-flight mass spectrometry and liquid chromatographyion trap-mass spectrometry/mass spectrometry were used to detect several metabolites having antioxidant activity, such as cyanidin-3 xylosylrutinoside, cyanidin-3-rutinoside, and quercetin, which were mainly detected in Rural Korean Black raspberry vinegar (RKB). These metabolites contributed to the highest antioxidant activity measured in RKB among the nine vinegars. This study revealed that MS-based metabolite profiling was useful in helping to understand the metabolite differences between commercial and traditional vinegars and to evaluate the association between active compounds of vinegar and antioxidant activity. PMID- 25293631 TI - Retraction: Relation between HPV genotypes and BRCA mutation in familial breast cancer. PMID- 25293632 TI - Changes in erectile dysfunction over time in relation to Framingham cardiovascular risk in the Boston Area Community Health (BACH) Survey. AB - INTRODUCTION: Erectile dysfunction (ED) is associated with cardiovascular disease (CVD); however, the association between change in ED status over time and future underlying CVD risk is unclear. AIM: The aim of this study was to investigate the association between change in ED status and Framingham CVD risk, as well change in Framingham risk. METHODS: We studied 965 men free of CVD in the Boston Area Community Health (BACH) Survey, a longitudinal cohort study with three assessments. ED was assessed with the five-item International Index of Erectile Function at BACH I (2002-2005) and BACH II (2007-2010) and classified as no ED/transient ED/persistent ED. CVD risk was assessed with 10-year Framingham CVD risk algorithm at BACH I and BACH III (2010-2012). Linear regression models controlled for baseline age, socio-demographic and lifestyle factors, as well as baseline Framingham risk. Models were also stratified by age (>=/< 50 years). MAIN OUTCOME MEASURES: Framingham CVD risk and change in Framingham CVD risk were the main outcome measures. RESULTS: Transient and persistent ED was significantly associated with increased Framingham risk and change in risk over time in univariate and age-adjusted models. In younger men, persistent ED was associated with a Framingham risk that was 1.58 percentage points higher (95% confidence interval [CI]: 0.11, 3.06) and in older men, a Framingham risk that was 2.54 percentage points higher (95% CI: -1.5, 6.59), compared with those without ED. Change in Framingham risk over time was also associated with transient and persistent ED in men <50 years, but not in older men. CONCLUSIONS: Data suggest that even after taking into account other CVD risk factors, transient and persistent ED is associated with Framingham CVD risk and a greater increase in Framingham risk over time, particularly in younger men. Findings further support clinical assessment of CVD risk in men presenting with ED, especially those under 50 years. PMID- 25293633 TI - Anti-inflammatory activity of grains of paradise (Aframomum melegueta Schum) extract. AB - The ethanolic extract of grains of paradise (Aframomum melegueta Schum, Zingiberaceae) has been evaluated for inhibitory activity on cyclooxygenase-2 (COX-2) enzyme, in vivo for the anti-inflammatory activity and expression of several pro-inflammatory genes. Bioactivity-guided fractionation showed that the most active COX-2 inhibitory compound in the extract was [6]-paradol. [6] Shogaol, another compound from the extract, was the most active inhibitory compound in pro-inflammatory gene expression assays. In a rat paw edema model, the whole extract reduced inflammation by 49% at 1000 mg/kg. Major gingerols from the extract [6]-paradol, [6]-gingerol, and [6]-shogaol reduced inflammation by 20, 25 and 38%. respectively when administered individually at a dose of 150 mg/kg. [6]-Shogaol efficacy was at the level of aspirin, used as a positive control. Grains of paradise extract has demonstrated an anti-inflammatory activity, which is in part due to the inhibition of COX-2 enzyme activity and expression of pro-inflammatory genes. PMID- 25293635 TI - Retraction Note to: Preference for immediate reinforcement over delayed reinforcement: relation between delay discounting and health behavior. PMID- 25293634 TI - Volitional processes and daily smoking: examining inter- and intraindividual associations around a quit attempt. AB - The Health Action Process Approach (HAPA) assumes that volitional processes are important for effective behavioral change. However, intraindividual associations have not yet been tested in the context of smoking cessation. This study examined the inter- and intraindividual associations between volitional HAPA variables and daily smoking before and after a quit attempt. Overall, 100 smokers completed daily surveys on mobile phones from 10 days before until 21 days after a self-set quit date, including self-efficacy, action planning, action control, and numbers of cigarettes smoked. Negative associations between volitional variables and daily numbers of cigarettes smoked emerged at the inter- and intraindividual level. Except for interindividual action planning, associations were stronger after the quit date than before the quit date. Self-efficacy, planning and action control were identified as critical inter- and intraindividual processes in smoking cessation, particularly after a self-set quit attempt when actual behavior change is performed. PMID- 25293636 TI - Introduction. PMID- 25293637 TI - Sleeping like a baby? Infant sleep: impact on caregivers and current controversies. AB - This annotation discusses definitions of 'sleep problems', the impacts of infant sleep on maternal and paternal well-being, and the evidence behind two areas of current controversy - the role of attachment versus behaviourally based parenting in infant sleep and management strategies for sleep problems in infants aged less than 6 months. PMID- 25293638 TI - Nutrient removal using algal-bacterial mixed culture. AB - Simultaneous nitrate (N), phosphate (P), and COD removal was investigated in photobioreactors containing both algae and bacteria. The reactors were operated in the semi-batch mode with a hydraulic retention time of 2 days. Reactors were operated in two phases, (1) with 33 % biomass recycle and (2) with no biomass recycle. In both phases, more than 90 % of N and P and 80 % of COD present in synthetic wastewaters with initial N and P concentrations of up to 110 and 25 mg/L, respectively, and initial COD of 45 mg/L could be removed. Biomass growth in reactors did not increase with the increase in initial N and P concentration in either phase. However, biomass growth was slightly more in reactors operated with no biomass recycle. In both phases, N and P uptake was greater in reactors with greater initial N and P concentrations. Also in all cases, N and P uptake in the reactors was far in excess of the stoichiometric requirements for the observed biomass growth. This "luxury uptake" of nitrogen and phosphorus by biomass was responsible for excellent nitrogen and phosphorus removal as observed. However, based on the results of this study, no advantage of biomass recycling could be demonstrated. PMID- 25293639 TI - Effect of metal ions and redox mediators on decolorization of synthetic dyes by crude laccase from a novel white rot fungus Peniophora sp. (NFCCI-2131). AB - The effect of different metal ions and two redox mediators on laccase activity and laccase-catalyzed decolorization of five synthetic dyes was investigated in vitro using crude laccase from a novel white rot fungus Peniophora sp. (NFCCI 2131). The fungus effectively decolorized crystal violet and brilliant green on malt extract agar medium. Laccase activity was enhanced by metal ions such as Cd(2+), Mn(2+), Ni(2+), Co(2+), Na(+) Ca(2+), and Cu(2+). Among the different dyes tested, highest decolorization of crystal violet (96.30 %) was obtained in the presence of 1 mM ABTS followed by 86.01 % by HBT. The results conspicuously indicated that laccase from Peniophora sp. has the potential for color removal from textile dye effluent even in the presence of toxic metal ions. PMID- 25293640 TI - Bis(nitroamino-1,2,4-triazolates): N-bridging strategy toward insensitive energetic materials. AB - Modern energetic motifs for military and civilian applications are most often evaluated using various criteria, for example, energetic properties, production costs, and safety issues. Given this background, the design of energetic materials requires a deep understanding of both detonation performance and molecular stability. Here a new family of energetic bis(nitroamino-1,2,4 triazolates), which exhibit good thermal stabilities, excellent detonation properties, and low sensitivities, has been designed. Furthermore, two hydroxylammonium bis(azolates) with pyrazole and tetrazole backbones were synthesized, and they exhibit energetic properties analogous to the triazoles. This work highlights the application potential of N-bridged bis(azolates) as promising energetic materials. PMID- 25293641 TI - Adenosine reagent-free detection by co-immobilization of adenosine deaminase and phenol red on an optical biostrip. AB - Adenosine detection in human serum is important because this ribonucleoside has established clinical applications, modulating many physiological processes. Furthermore, a simple and cheap detection method is useful in adenosine production processes. Adenosine can be determined enzymatically using either S adenosyl-homocysteine hydrolase and (3) [H]-adenosine, or adenosine kinase combined with GTP and luciferase, or an amperometric biosensor carrying adenosine deaminase (ADA), purine nucleoside phosphorylase, and xanthine oxidase. We developed a simple and cheap method relying on a transparent biostrip bearing ADA and the indicator phenol red (PR), co-immobilized to polyacrylamide, itself chemically adhered to a derivatized glass strip. The ADA-catalyzed conversion of adenosine to inosine and ammonia leads to a local pH alteration, changing the absorbance maximum of PR (from 425 to 567 nm), which is measured optically. The biostrip shows an analytical range 0.05-1.5 mM adenosine and is reusable when stored at 4 degrees C. When the biostrip was tested with serum, spiked with adenosine (70 and 100 MUM), and filtered for protein and adenosine phosphates depletion, it showed good adenosine recovery. In summary, we show the proof-of concept that adenosine can be determined reagent-free, at moderate sensitivity on an easy to construct, cheap, and reusable biostrip, based on commercially available molecular entities. PMID- 25293642 TI - Histopathological environment besides the focus score in Sjogren's syndrome. AB - AIM: To compare the prevalence of diverse histopathologic features among patients with Sjogren's syndrome (SS) and controls, and to evaluate their relationship with age, a focus score (FS) >= 1 and some clinical and serological SS features. METHODS: A blinded pathologist examined 63 SS and 11 control minor salivary gland biopsies. Focal lymphocytic sialadenitis (FLS) was defined as a focus score (FS) >= 1. We also evaluated lymphoepithelial lesions, germinal centers (GCs), epithelial metaplasia, dilatation and hyperplasia in the main secretory duct, perivascular cell infiltrate, adipose infiltration, acinar atrophy, interstitial fibrosis and lymphocytes/plasma cells remote from the FLS. We registered demographics, anti-Ro/La status and clinical features. We used Kendall's tau coefficients and logistic regression analysis. RESULTS: Sjogren's syndrome patients had a higher frequency of FS >= 1 (92% vs. 27%), acinar atrophy (78% vs. 18%), lymphocytes and plasma cells external to the FSL (92% vs. 64%) and stromal fibrosis (68% vs. 36%). A FS >= 1 correlated with the presence of GCs and acinar atrophy; whereas age correlated with duct dilation, duct epithelial hyperplasia, adipose infiltration and fibrosis. SS patients with hepatic involvement exhibited more frequent duct dilatation. After adjusting by age, anti-Ro/SSA (odds ratio [OR] 30.8, 95% CI 2.2-423.5, P = 0.01), a FS >= 1 (OR 54.3, 95% CI 4.8-612, P = 0.001) and fibrosis (OR 15.2, 95% CI 1.2-186.2, P = 0.03) were associated with SS. CONCLUSION: Other histologic findings coexist with FLS, but only GC formation and acinar atrophy correlated with a FS >= 1. Age is mostly correlated with the remaining histological features. However, the clinical relevance of these findings is unknown. PMID- 25293644 TI - Effects of a continuum of care intervention on frail older persons' life satisfaction: a randomized controlled study. AB - AIMS AND OBJECTIVES: The aim of this study was to analyse effects of a comprehensive continuum of care (intervention group) on frail older persons' life satisfaction, as compared to those receiving usual care (control group). The intervention included geriatric assessment, case management, interprofessional collaboration, support for relatives and organising of care-planning meetings in older persons' own homes. BACKGROUND: Improvements in older persons' subjective well-being have been shown in studies including care planning and coordination by a case manager. However, effects of more complex continuum of care interventions on frail older persons' life satisfaction are not well explored. DESIGN: Randomised controlled study. METHODS: The validated LiSat-11 scale was used in face-to-face interviews to assess older persons' life satisfaction at baseline and at three, six and 12 months after the baseline. The odds ratio for improving or maintaining satisfaction was compared for intervention and control groups from baseline to three-month, three- to six-month as well as six- to 12-month follow ups. RESULTS: Older persons who received the intervention were more likely to improve or maintain satisfaction than those who received usual care, between 6 and 12 month follow-ups, for satisfaction regarding functional capacity, psychological health and financial situation. CONCLUSIONS: A comprehensive continuum of care intervention comprising several components had a positive effect on frail older persons' satisfaction with functional capacity, psychological health and financial situation. RELEVANCE TO CLINICAL PRACTICE: Frail older persons represent a great proportion of the persons in need of support from the health care system. Health care professionals need to consider continuum of care interventions' impact on life satisfaction. As life satisfaction is an essential part of older persons' well-being, we propose that policy makers and managers promote comprehensive continuum of care solutions. PMID- 25293643 TI - Behavioural and emotional problems in moderately preterm children with low socioeconomic status: a population-based study. AB - Moderately preterm (MP) birth is associated with higher rates of behavioural and emotional problems. To determine the extent to which low socioeconomic status (SES) contributes to these higher rates, we assessed independent and joint effects of MP birth and low SES, overall and by gender. Dutch preventive child health care centres provided a population-based sample of 915 MP children (32-36 weeks gestation) and 543 term-born children, born in 2002/2003. In multivariable logistic regression analyses, we determined the risk of behavioural and emotional problems per standard deviation (SD) decrease in gestational age and SES, using standardized measures for both. We also assessed three SES categories, being low (1SD or more below mean of standardized SES), intermediate (mean +/- 1SD), and high (greater than mean + 1SD). The Child Behavior Checklist for 1.5-5 years was used to assess behavioural (externalizing), emotional (internalizing), and total problems at age 4 years. MP children with low SES had significantly higher total problem scores than those with high SES (11.3 vs. 5.1%, respectively). Each SD decrease in SES was associated with a 42% higher odds of elevated total problem scores (OR 1.42, 95% CI 1.14-1.77). No joint effects were found, meaning that lower gestational age independently added to the risk of behaviour problems (OR 1.24, 95% CI 1.00-1.56). Effects of MP birth and low SES were more pronounced in girls. In conclusion, MP birth and low SES multiply the risk of behavioural and emotional problems. The combination of risk factors identifies children who could benefit greatly from early intervention. PMID- 25293645 TI - Marine pollution effects on the southern surf crab Ovalipes trimaculatus (Crustacea: Brachyura: Polybiidae) in Patagonia Argentina. AB - We compared the carapace shape and thickness as well as the energy density of Ovalipes trimaculatus inhabiting areas comprising a gradient of marine pollution: high, moderate and undetected, in the Nuevo gulf (Patagonia Argentina). The carapace shape was evaluated by means of individual asymmetry scores (=fluctuating asymmetry) whereas the carapace thickness was assessed by measuring the carapace dry weight. The energy density was analyzed through its negative relationship with water content in muscle tissue. The individual asymmetry scores as well as the percentage of water content in muscle tissue were proportional to the marine pollution gradient, whereas the carapaces thickness did not differ among sampling sites. Our results are consistent with previous findings and demonstrate the direct effect of marine pollution on other taxa different from gastropods, cephalopods and polyplacophora and add to long-standing concerns about detrimental effects caused by marine pollution on the benthic community of the Nuevo gulf. PMID- 25293646 TI - Limitations of percutaneous osteotomy for malunited tongue-type calcaneal fractures. PMID- 25293647 TI - Response to Li et al, "Limitations of percutaneous osteotomy for malunited tongue type calcaneal fractures". PMID- 25293649 TI - Transparent and flexible cellulose nanocrystal/reduced graphene oxide film for proximity sensing. AB - The rapid development of touch screens as well as photoelectric sensors has stimulated the fabrication of reliable, convenient, and human-friendly devices. Other than sensors that detect physical touch or are based on pressure sensing, proximity sensors offer controlled sensibility without physical contact. In this work we present a transparent and eco-friendly sensor made through layer-by-layer spraying of modified graphene oxide filled cellulose nanocrystals on lithographic patterns of interdigitated electrodes on polymer substrates, which help to realize the precise location of approaching objects. Stable and reproducible signals generated by keeping the finger in close proximity to the sensor can be controlled by humidity, temperature, and the distance and number of sprayed layers. The chemical modification and reduction of the graphene oxide/cellulose crystal composite and its excellent nanostructure enable the development of proximity sensors with faster response and higher sensitivity, the integration of which resolves nearly all of the technological issues imposed on optoelectronic sensing devices. PMID- 25293650 TI - Anxiety Disorders in Caucasian and African American Children: A Comparison of Clinical Characteristics, Treatment Process Variables, and Treatment Outcomes. AB - This study examined racial differences in anxious youth using data from the Child/Adolescent Anxiety Multimodal Study (CAMS) [1]. Specifically, the study aims addressed whether African American (n = 44) versus Caucasian (n = 359) children varied on (1) baseline clinical characteristics, (2) treatment process variables, and (3) treatment outcomes. Participants were ages 7-17 and met DSM-IV TR criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder. Baseline data, as well as outcome data at 12 and 24 weeks, were obtained by independent evaluators. Weekly treatment process variables were collected by therapists. Results indicated no racial differences on baseline clinical characteristics. However, African American participants attended fewer psychotherapy and pharmacotherapy sessions, and were rated by therapists as less involved and compliant, in addition to showing lower mastery of CBT. Once these and other demographic factors were accounted for, race was not a significant predictor of response, remission, or relapse. Implications of these findings suggest African American and Caucasian youth are more similar than different with respect to the manifestations of anxiety and differences in outcomes are likely due to treatment barriers to session attendance and therapist engagement. PMID- 25293651 TI - Drivers of telemedicine use: comparative evidence from samples of Spanish, Colombian and Bolivian physicians. AB - BACKGROUND: The aim of the study presented in this article is to analyse the determinants of telemedicine use. To that end, the study makes two basic contributions. First, it considers six working hypotheses in the context of technology acceptance models (TAMs). Second, it uses data obtained for three samples of physicians from three different countries (Spain, Colombia and Bolivia). Obtaining and comparing evidence on an international scale allows determinants of telemedicine use to be evaluated across different contexts. METHODS: In Bolivia, the survey was conducted in hospitals and health care centres of the urban and rural districts of the municipality of Sucre, in a population comprising a total of 350 physicians. In Spain, the survey population consisted of medical professionals of all profiles affiliated with health care within the Canary Islands Health Service, comprising a total of 356 physicians. Finally, in Colombia, it was conducted in the Society of Surgery Service at San Jose Hospital of Bogota, in a population comprising a total of 184 physicians. Using an extended TAM and survey data from 510 physicians (113 in Spain, 118 in Colombia and 279 in Bolivia), binary logistic regression analysis was performed. RESULTS: In the three samples, it was found that the physician's level of information and communication technology (ICT) use in his/her personal life was the variable that had the highest explanatory power regarding telemedicine use. In the Spanish sample, the physicians' perceived ease-of-use of ICTs in clinical practice and propensity to innovate were the two other variables that determined telemedicine use, whereas in the Colombian and Bolivian samples, it was the level of optimism about ICTs. CONCLUSION: The results facilitated a more complete model that includes personal, usability, and innovatory aspects in the explanation of Telemedicine use in Spain, whereas the results for the Latin American samples indicated a more primary model in the explanation of Telemedicine use, which was completed by an optimism factor that did not emerge in the Spanish sample. PMID- 25293652 TI - The inclusion of students with dyslexia in higher education: a systematic review using narrative synthesis. AB - This article reports on a study focusing on the inclusion of students with dyslexia in higher education (HE). A systematic review was carried out to retrieve, critically appraise and synthesize the available evidence on how the inclusion of students with dyslexia can be fostered in HE. The 15 studies included in the final synthesis employed descriptive designs and overwhelmingly used qualitative methods to explore dyslexic students' perceptions on the impact of teaching, support and accommodation in their own learning experience. A critical appraisal of these studies revealed a landscape of significant gaps in the available stock of evidence on the inclusion of students with dyslexia in HE. The synthesis of the available evidence is presented in a narrative of five cross study thematic areas: student coping strategies, being identified as dyslexic, interaction with academic staff, accessibility and accommodations, and using assistive technologies and information and communication technologies. Implications for practice and future research are discussed. PMID- 25293653 TI - Enhanced visible-light photocatalytic H2 production by Znx Cd1-x S modified with earth-abundant nickel-based cocatalysts. AB - The application of various earth-abundant Ni species, such as NiS, Ni, Ni(OH)2 , and NiO, as a co-catalyst in a Znx Cd1-x S system for visible-light photocatalytic H2 production was investigated for the first time. The loading of Ni or NiS enhanced the photocatalytic activity of Znx Cd1-x S because they could promote the electron transfer at the interface with Znx Cd1-x S and catalyze the H2 evolution. Surprisingly, Ni(OH)2 -loaded Znx Cd1-x S exhibits a very high photocatalytic H2 -production rate of 7160 MUmol h(-1) g(-1) with a quantum efficiency of 29.5 % at 420 nm, which represents one of the most efficient metal sulfide photocatalysts without a Pt co-catalyst to date. This outstanding activity arises from the pronounced synergetic effect between Ni(OH)2 and metallic Ni formed in situ during the photocatalytic reaction. However, the loading of NiO deactivated the activity of Znx Cd1-x S because of their unmatched conduction band positions. This paper reports the optimization of the Znx Cd1-x S system by selecting an appropriate Ni-based co-catalyst, Ni(OH)2 , from a series of Ni species to achieve the highest photocatalytic H2 -production activity for the first time and also reveals the roles of these Ni species in the photocatalytic activity. PMID- 25293655 TI - Proceedings of the 8th congress of the European academy of andrology, 15 - 17 october 2014, barcelona, Spain. PMID- 25293654 TI - NiP2 nanosheet arrays supported on carbon cloth: an efficient 3D hydrogen evolution cathode in both acidic and alkaline solutions. AB - Designing efficient and stable hydrogen evolution catalysts made from earth abundant elements is essential to the development of solar-driven water-splitting devices. In this communication, we develop a two-step strategy for constructing NiP2 nanosheet arrays on carbon cloth (NiP2 NS/CC). As a novel 3D hydrogen evolution cathode, the NiP2 NS/CC electrode is highly active in acidic solutions and needs an overpotential of 75 and 204 mV to achieve current densities of 10 and 100 mA cm(-2), respectively, and it preserves its catalytic activity for at least 57 h. Moreover, it also operates efficiently under alkaline conditions. PMID- 25293656 TI - Properties of cellular and serum forms of thymidine kinase 1 (TK1) in dogs with acute lymphocytic leukemia (ALL) and canine mammary tumors (CMTs): implications for TK1 as a proliferation biomarker. AB - BACKGROUND: Thymidine kinase 1 (TK1) is a deoxyribonucleic acid (DNA) precursor enzyme and a proliferation biomarker used for prognosis and treatment monitoring of breast cancer in humans. The aim was to determine if serum thymidine kinase 1 (sTK1) activity and sTK1 protein levels in dogs with mammary tumors could be useful in veterinary medicine. RESULTS: Serum samples from 20 healthy dogs and 27 dogs with mammary tumors were analyzed for sTK1 activity, using an [(3)H] deoxythymidine (dThd) phosphorylation assay, and for sTK1 protein levels by immune affinity/Western blot assay. The molecular forms of sTK1 in acute lymphocytic leukemia (ALL), canine mammary tumor (CMT), and healthy sera were determined by size exclusion chromatography. Mean sTK1 activities in CMT were 1.0 +/- 0.36 pmol/min/mL, differing significantly from healthy dogs (mean +/- SD = 0.73 +/- 0.26 pmol/min/mL). Serum TK1 protein (26 kDa polypeptide) levels were also significantly higher in CMTs compared to healthy dogs (mean +/- SD = 28.5 +/ 11.4, and 8.5 +/- 4 ng/mL, respectively). Cellular TK1 isolated from ALL tumor cells was predominantly a dimer, while the serum TK1 activity eluted as a high molecular weight (MW) oligomer. In analyses of CMT tissue extracts, TK1 activity eluted in two peaks, a minor peak with a high MW oligomer and a major tetramer peak. Western blot analysis of chromatographic fractions showed that cellular TK1 protein in both ALL and CMT dogs, and to some extent serum TK1 from ALL dogs, correlated with activity profiles, but a large fraction of inactive TK1 protein was detected in CMT. CONCLUSIONS: Serum TK1 protein and activity levels were significantly higher in CMT than in healthy dogs. Size exclusion chromatography demonstrated major differences in the molecular forms of sTK1 in ALL, healthy, and CMT dogs, with a large fraction of inactive TK1 protein in CMT. Our results showed that the sTK1 protein assay can differentiate benign tumors (early stage tumors) from healthy more efficiently than sTK1 activity assay. This preliminary data supports that sTK1 protein assay is clinically useful. Further studies are needed to evaluate the diagnostic or prognostic role of serum TK1 protein in CMTs. PMID- 25293657 TI - Multimodal 3 Tesla MRI confirms intact arterial wall in acute stroke patients after stent-retriever thrombectomy. AB - BACKGROUND AND PURPOSE: The aim of this prospective study was to assess vascular integrity after stent-retriever thrombectomy. METHODS: Dissection, contrast medium extravasation, and vasospasm were evaluated in 23 patients after thrombectomy with biplane or 3D-digital subtraction angiography and 3-Tesla vessel wall MRI. RESULTS: Vasospasm was detected angiographically in 10 patients, necessitating intra-arterial nimodipine in 2 of them. Contrast extravasation, intramural hemorrhage, or iatrogenic dissection were not detected on multimodal MRI in any patient even after Y-double stent-retriever technique. CONCLUSIONS: Our findings suggest that clinically relevant vessel wall injuries occur rarely after stent-retriever thrombectomy. PMID- 25293658 TI - Early onset seizures in stroke. PMID- 25293659 TI - Socioeconomic position and survival after stroke in Denmark 2003 to 2012: nationwide hospital-based study. AB - BACKGROUND AND PURPOSE: The risk for stroke is higher in low-income groups. It is not clear whether these groups also have a higher risk for death after a stroke. METHODS: We studied survival in relation to income and level of education in all patients aged >40 years admitted to hospital for stroke in Denmark in 2003 to 2012. All Danish hospitals report data to the Danish Stroke Register for all patients admitted for acute stroke, including age, sex, stroke severity, subtype, and a cardiovascular risk profile. Information on income and education was obtained from Statistics Denmark; deaths from all causes from the Civil Registration Registry. RESULTS: Information on education and disposable income was available for 56 581 Danes hospitalized for stroke during the 9.5-year study period. Median length of follow-up was 3.1 years. For the entire follow-up period, there was a significant, stepwise, independent relation between income and risk for death after stroke, which was 30% higher for the lowest than for the highest quintile income group (relative risk, 0.70, 95% confidence interval, 0.65 0.74). People aged <65 years with basic education had a slightly higher risk for death than those with the longest (relative risk, 1.15; 95% confidence interval, 1.02-1.30). Death within 1 month was not associated with income or education. CONCLUSIONS: The survival of patients with low income was reduced by 30% as compared with those with high income. Education had only a modest effect and only in patients aged <65 years. The impact of socioeconomic position was on late but not on early poststroke death. PMID- 25293661 TI - NeuroThera Effectiveness and Safety Trial 3: how do we align corporate and scientific integrity to complete and report pharma-sponsored trials properly? PMID- 25293662 TI - Application of single-stage stereotactic radiosurgery for cerebral arteriovenous malformations >10 cm3. AB - BACKGROUND AND PURPOSE: Stereotactic radiosurgery (SRS) is a safe and effective treatment for small arteriovenous malformations (AVMs), the use of this modality for the treatment of large AVMs is still controversial, although it has been used in difficult cases. The aim of this study was to evaluate the treatment outcomes of patients who underwent single-stage SRS for large AVMs and to discuss the role of SRS in the treatment of these challenging lesions. METHODS: Between 1998 and 2010, 65 patients with AVMs >10 cm(3) underwent single-stage SRS using the Leksell Gamma Knife. Patients who had prospective volume-staged SRS were excluded from this series. Outcomes including the rates of obliteration, hemorrhage after treatment, and adverse events were retrospectively evaluated. RESULTS: The mean nidus volume was 14.9 cm(3) (+/-3.8 cm(3)), and a mean margin dose of 20 Gy (+/ 1.5 Gy) was applied. The mean observation period was 60 months (range, 7-178 months). The nidus obliteration rates after SRS were 44%, 76%, and 81% at 3, 5, and 6 years, respectively. The annual hemorrhage rate after SRS was 1.94% and permanent adverse events were observed in 2 patients (3%). CONCLUSIONS: For large AVMs <20 cm(3), single-stage radiosurgery by applying >16 Gy marginal dose presented favorable obliteration rates with relatively low rate of morbidity. Further accumulation of cases is awaited to fully evaluate the results of single stage radiosurgery for large AVMs. PMID- 25293663 TI - Emerging spectra of silent brain infarction. PMID- 25293664 TI - Recurrent stroke and patent foramen ovale: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Recurrent cerebrovascular events are frequent in medically treated patients with patent foramen ovale (PFO), but it still remains unclear whether PFO is a causal or an incidental finding. Further uncertainty exists on whether the size of functional shunting could represent a potential risk factor. The aim of the present study was to evaluate if the presence of PFO is associated with an increased risk of recurrent stroke or transient ischemic attack and to investigate further if this relationship is related to the shunt size. METHODS: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of all available prospective studies reporting recurrent cerebrovascular events defined as cryptogenic stroke and transient ischemic attacks in medically treated patients with PFO diagnosed by echocardiography or transcranial sonography. RESULTS: We identified 14 eligible studies including a total of 4251 patients. Patients with stroke with PFO did not have a higher risk of the combined outcome of recurrent stroke/transient ischemic attack (risk ratio=1.18; 95% confidence interval=0.78-1.79; P=0.43) or in the incidence of recurrent strokes (risk ratio =0.85; 95% confidence interval=0.59-1.22; P=0.37) in comparison with stroke patients without PFO. In addition, PFO size was not associated with the risk of recurrent stroke or transient ischemic attack. We also documented no evidence of heterogeneity across the included studies. CONCLUSIONS: Our findings indicate that medically treated patients with PFO do not have a higher risk for recurrent cryptogenic cerebrovascular events, compared with those without PFO. No relation between the degree of PFO and the risk of future cerebrovascular events was identified. PMID- 25293666 TI - Letter by Liao et al regarding article, "socioeconomic status inconsistency and risk of stroke among Japanese middle-aged women". PMID- 25293667 TI - Derivation and external validation of a case mix model for the standardized reporting of 30-day stroke mortality rates. AB - BACKGROUND AND PURPOSE: Case mix adjustment is required to allow valid comparison of outcomes across care providers. However, there is a lack of externally validated models suitable for use in unselected stroke admissions. We therefore aimed to develop and externally validate prediction models to enable comparison of 30-day post-stroke mortality outcomes using routine clinical data. METHODS: Models were derived (n=9000 patients) and internally validated (n=18 169 patients) using data from the Sentinel Stroke National Audit Program, the national register of acute stroke in England and Wales. External validation (n=1470 patients) was performed in the South London Stroke Register, a population based longitudinal study. Models were fitted using general estimating equations. Discrimination and calibration were assessed using receiver operating characteristic curve analysis and correlation plots. RESULTS: Two final models were derived. Model A included age (<60, 60-69, 70-79, 80-89, and >=90 years), National Institutes of Health Stroke Severity Score (NIHSS) on admission, presence of atrial fibrillation on admission, and stroke type (ischemic versus primary intracerebral hemorrhage). Model B was similar but included only the consciousness component of the NIHSS in place of the full NIHSS. Both models showed excellent discrimination and calibration in internal and external validation. The c-statistics in external validation were 0.87 (95% confidence interval, 0.84-0.89) and 0.86 (95% confidence interval, 0.83-0.89) for models A and B, respectively. CONCLUSIONS: We have derived and externally validated 2 models to predict mortality in unselected patients with acute stroke using commonly collected clinical variables. In settings where the ability to record the full NIHSS on admission is limited, the level of consciousness component of the NIHSS provides a good approximation of the full NIHSS for mortality prediction. PMID- 25293665 TI - Transcranial laser therapy in acute stroke treatment: results of neurothera effectiveness and safety trial 3, a phase III clinical end point device trial. AB - BACKGROUND AND PURPOSE: On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. METHODS: We studied transcranial laser therapy in a double blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated <=24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. RESULTS: The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0-2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705-1.488). CONCLUSIONS: Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01120301. PMID- 25293668 TI - Helminths and helminthoses in Central Europe: general overview and diseases caused by trematodes (flukes). AB - Parasitic helminths and helminthoses do not only occur in the tropics and subtropics but are also prevalent in Austria and other Central European countries. Their prevalence is, however, more or less rather low. In total, we know more than 20 helminth species, which are diagnosed regularly in Austria; some of them occur in Austria autochthonously, some others are acquired abroad and are transferred as souvenirs to Central Europe. The spectrum of helminths described in this overview comprises species of the trematodes (flukes), cestodes (tapeworms), and nematodes (roundworms).The topic "Helminths and helminthoses in Central Europe" is divided into three parts: The first part comprises a short introduction into the field of medical helminthology and is primarily dedicated to the description of trematodes and trematode-caused diseases. PMID- 25293670 TI - Revised role of selectfluor in homogeneous Au-catalyzed oxidative C-O bond formations. AB - The pairing of transition metal catalysis with the reagent Selectfluor (F-TEDA BF4) has attracted considerable attention due to its utility in myriad C-C and C heteroatom bond-forming reactions. However, little mechanistic information is available for Selectfluor-mediated transition metal-catalyzed reactions and controversy surrounds the precise role of Selectfluor in these processes. We present herein a systematic investigation of homogeneous Au-catalyzed oxidative C O bond-forming reactions using density functional theory calculations. Currently, Selectfluor is thought to serve as an external oxidant in Au(I)/Au(III) catalysis. However, our investigations suggest that these reactions follow a newly proposed mechanism in which Selectfluor functions as an electrophilic fluorinating reagent involved in a fluorination/defluorination cycle. We have also explored Selectfluor-mediated gold-catalyzed homocoupling reactions, which, when cyclopropyl propargylbenzoate is used as a substrate, lead to an unexpected byproduct. PMID- 25293669 TI - Insecticide resistance and role in malaria transmission of Anopheles funestus populations from Zambia and Zimbabwe. AB - BACKGROUND: Two mitochondrial DNA clades have been described in Anopheles funestus populations from southern Africa. Clade I is common across the continent while clade II is known only from Mozambique and Madagascar. The specific biological status of these clades is at present unknown. We investigated the possible role that each clade might play in the transmission of Plasmodium falciparum and the insecticide resistance status of An. funestus from Zimbabwe and Zambia. METHODS: Mosquitoes were collected inside houses from Nchelenge District, Zambia and Honde Valley, Zimbabwe in 2013 and 2014. WHO susceptibility tests, synergist assays and resistance intensity tests were conducted on wild females and progeny of wild females. ELISA was used to detect Plasmodium falciparum circumsporozoite protein. Specimens were identified to species and mtDNA clades using standard molecular methods. RESULTS: The Zimbabwean samples were all clade I while the Zambian population comprised 80% clade I and 20% clade II in both years of collection. ELISA tests gave an overall infection rate of 2.3% and 2.1% in 2013, and 3.5% and 9.2% in 2014 for Zimbabwe and Zambia respectively. No significant difference was observed between the clades. All populations were resistant to pyrethroids and carbamates but susceptible to organochlorines and organophosphates. Synergist assays indicated that pyrethroid resistance is mediated by cytochrome P450 mono-oxygenases. Resistance intensity tests showed high survival rates after 8-hrs continuous exposure to pyrethroids but exposure to bendiocarb gave the same results as the susceptible control. CONCLUSIONS: This is the first record of An. funestus mtDNA clade II occurring in Zambia. No evidence was found to suggest that the clades are markers of biologically separate populations. The ability of An. funestus to withstand prolonged exposure to pyrethroids has serious implications for the use of these insecticides, either through LLINs or IRS, in southern Africa in general and resistance management strategies should be urgently implemented. PMID- 25293671 TI - Building new hearts: a review of trends in cardiac tissue engineering. AB - Cardiovascular disease (CVD) is the number one cause of death in the United States. However, few treatments for CVD provide a means to regain full cardiac function with no long-term side effects. Novel tissue-engineered products may provide a way to overcome the limitations of current CVD therapies by replacing injured myocardium with functioning tissue or by inducing more constructive forms of endogenous repair. In this review, we discuss some of the factors that should be considered in the development of tissue-engineered products, and we review the methods currently being investigated to generate more effective heart valves, cardiac patches and whole hearts. PMID- 25293672 TI - Transitions in the Swedish school system and the impact on student's positive self-reported-health. AB - BACKGROUND: To explore three school based transitions and their impact on positive self-reported-health (SRH), pre-school to elementary school (6-10 y), elementary school to junior high school (10-13 y), and junior high school to upper secondary school/high school (13-16 y), in a long-term longitudinal population based study. METHODS: The study followed three cohorts through one school transition each. A longitudinal study with data from 6693 Health Dialogue questionnaires were used. Data were collected in the middle of Sweden during 2007 2012 with school children age 6-16 years old. RESULTS: Several significant factors were identified with an impact for a positive self-reported-health among children age 6-16 y; not feeling sad or depressed, afraid or worried, positive school environment (schoolyard and restrooms), not bullied, good sleep, daily physical activity and ability to concentrate. There was no single factor identified, the factors differed according to gender and age. CONCLUSION: The study have identified several gender and age specific factors for successful school transitions relevant for a positive SRH. This is valuable information for school staff, parents and school children and provides a possibility to provide support and assistance when needed. PMID- 25293673 TI - A novel Bacillus pumilus-related strain from tropical landfarm soil is capable of rapid dibenzothiophene degradation and biodesulfurization. AB - BACKGROUND: The presence of organic sulfur-containing compounds in the environment is harmful to animals and human health. The combustion of these compounds in fossil fuels tends to release sulfur dioxide in the atmosphere, which leads to acid rain, corrosion, damage to crops, and an array of other problems. The process of biodesulfurization rationally exploits the ability of certain microorganisms in the removal of sulfur prior to fuel burning, without loss of calorific value. In this sense, we hypothesized that bacterial isolates from tropical landfarm soils can demonstrate the ability to degrade dibenzothiophene (DBT), the major sulfur-containing compound present in fuels. RESULTS: Nine bacterial isolates previously obtained from a tropical landfarm soil were tested for their ability to degrade dibenzothiophene (DBT). An isolate labeled as RR-3 has shown the best performance and was further characterized in the present study. Based on physiological aspects and 16 s rDNA sequencing, this isolate was found to be very closely related to the Bacillus pumillus species. During its growth, high levels of DBT were removed in the first 24 hours, and a rapid DBT degradation within the first hour of incubation was observed when resting cells were used. Detection of 2-hydroxybiphenyl (HBP), a marker for the 4S pathway, suggests this strain has metabolical capability for DBT desulfurization. The presence of MgSO4 in growth medium as an additional sulfur source has interfered with DBT degradation. CONCLUSIONS: To our knowledge, this is the first study showing that a Bacillus strain can metabolize DBT via the 4S pathway. However, further evidences suggest RR-3 can also use DBT (and/or its derivative metabolites) as carbon/sulfur source through another type of metabolism. Compared to other reported DBT-degrading strains, the RR-3 isolate showed the highest capacity for DBT degradation ever described in quantitative terms. The potential application of this isolate for the biodesulfurization of this sulfur-containing compound in fuels prior to combustion was discussed. PMID- 25293674 TI - Organic silicon protects human neuroblastoma SH-SY5Y cells against hydrogen peroxide effects. AB - BACKGROUND: Hydrogen peroxide (H2O2) is a toxic agent that induces oxidative stress and cell death. Silicon (Si) is a biological element involved in limiting aluminium (Al) absorption with possible preventive effects in Alzheimer's disease. However, Si has not yet been associated with other neuroprotective mechanisms. METHODS: The present experiments evaluated in the SH-SY5Y human neuroblastoma cell line the possible role of different Si G5 (50-1000 ng/mL) concentrations in preventing cellular death induced by H2O2 (400 MUM, 24 hours). RESULTS: Our findings showed that H2O2 promoted cell death in the human SH-SY5Y cell cultures and this could be prevented by Si treatment. The loss in cell viability mediated by H2O2 was due to an apoptotic and necrotic process. Apoptotic death was incurred by regulating caspase-8 activity in the extrinsic pathway. The apoptotic and necrotic cell death induced by H2O2 was almost totally reversed by Si (50-500 ng/mL), indicating that it down-regulates both processes in H2O2 treated cells. CONCLUSIONS: According to our data, Si is able to increase SH-SY5Y cell survival throughout partially blocking cellular damage related to oxidative stress through a mechanism that would affect H2O2/ROS elimination. PMID- 25293675 TI - Large-scale experience with an anchorless vascular closure device in a real-life clinical setting. AB - AIMS: This study was designed to evaluate safety and effectiveness of the vascular closure device Exoseal (Cordis) for hemostatic control following cardiac catheterization in a real-life clinical setting. METHODS AND RESULTS: This prospective, single-center study enrolled n = 2,031 consecutive patients who underwent coronary angiography via the femoral artery +/- PCI (n = 801). Patients were excluded if they had radial access, percutaneous repair of structural heart disease, or if they had severe peripheral artery disease. If clinical abnormalities were discovered at the access site, color Doppler ultrasound was performed. The composite primary endpoint was defined as bleeding/vascular complications and device failure, and it was experienced by 5.4 % (n = 110) of patients. The most frequent complications were pseudoaneurysm (2.9 %, n = 58) and access-site hematoma >6 cm (1.8 %, n = 37). The overall device failure rate was 0.7 % (n = 14). Multiple logistic regression analysis demonstrated that the strongest independent predictors of bleeding/vascular complications and/or device failure were procedure duration (OR 2.1, CI 1.4-3.2), PCI (OR 2.7, CI 1.7-4.2), GP IIb/IIIa inhibitors (OR 2.9, CI 1.5-5.7), and age (OR 2.2, CI 1.4-3.5). CONCLUSIONS: These results indicate that Exoseal was safe in a broad collective of patients. However, lengthy procedures, PCIs, the use of GP IIb/IIIa inhibitors, and elderly patients require special attention. PMID- 25293676 TI - Increase in ACL and PCL injuries after implementation of a new professional football league. AB - PURPOSE: In the season 2008-2009, a third professional football league was established in Germany. This study analysed the influence of increased training and playing intensity on severe knee injuries in football players. METHODS: In a prospective controlled one-season trial, injury incidence and injury patterns of players of the newly established professional football league were analysed, particularly with regard to ruptures of the anterior (ACL) and posterior (PCL) cruciate ligaments. Players of the highest amateur level served as a control group. RESULTS: Four hundred and eight players of 24 teams were allocated to two groups. The overall training exposure was significantly (p < 0.001) higher in the new professional league (335.3 h per player) than at the amateur level (286.6 h per player). Players at both levels showed similar overall injury rates and injury patterns. However, players in the professional league had a significantly higher (p = 0.04) incidence of ACL and PCL injuries, than players at the amateur level. More than 90 % of all ACL and PCL ruptures in both groups were sustained by players, who had played at least one level lower in the previous season. In addition, injuries of players who had sustained repeat injuries over the season were more severe. CONCLUSION: The introduction of a new professional football league increased the training and playing intensity of players as well as the number of ACL and PCL ruptures. A specific injury prevention concept, particularly for players facing rapidly increasing training and playing intensity, seems to be mandatory. LEVEL OF EVIDENCE: Prospective controlled cohort study, Level II. PMID- 25293678 TI - Behavioral variability and autism spectrum disorder. AB - Restricted and repetitive behavior is a diagnostic characteristic of autism spectrum disorder (ASD). To the extent that the behavior of individuals with ASD can be conceptualized as problems of invariance, our understanding of environmental variables that influence restricted and repetitive behavior may be informed by the basic and applied literature on response variability. The purposes of this paper are (a) to describe how restricted and repetitive behavior can be conceptualized as problems of invariance, (b) to consider the implications of a lack of varied responding for individuals with ASD, (c) to review relevant basic and applied research on response variability, (d) to present methods to address invariant responding for individuals with ASD, and (e) to suggest areas for future research. PMID- 25293677 TI - The biomechanical performance of a new forked knotless biceps tenodesis compared to a knotless and suture anchor tenodesis. AB - PURPOSE: Biomechanical comparison of three different fixation techniques for a proximal biceps tenodesis. METHODS: Eighteen human cadaver specimens were used for the testing. A tenodesis of the proximal biceps tendon was performed using a double-loaded suture anchor (5.5-mm Corkscrew, Arthrex), a knotless anchor (5.5 mm SwiveLock, Arthrex) or a forked knotless anchor (8-mm SwiveLock, Arthrex). Reconstructions were cyclically loaded for 50 cycles from 10-60 to 10-100 N. Cyclic displacement and ultimate failure loads were determined, and mode of failure was evaluated. RESULTS: Cyclic displacement at 60 N revealed a mean of 3.3 +/- 1.1 mm for the Corkscrew, 5.4 +/- 1.4 mm for the 5.5-mm SwiveLock and 2.9 +/- 1.6 mm for the 8-mm forked SwiveLock. At 100 N, 5.1 +/- 2.2 mm were seen for the Corkscrew anchor, 8.7 +/- 2.5 mm for the 5.5-mm SwiveLock and 4.8 +/- 3.3 mm for the 8-mm forked SwiveLock anchor. Significant lower cyclic displacement was seen for the Corkscrew anchor (p < 0.020) as well as the 8-mm SwiveLock anchor (p < 0.023) compared to the 5.5-mm SwiveLock anchor at 60 N. An ultimate load to failure of 109 +/- 27 N was found for the Corkscrew anchor, 125 +/- 25 N were measured for the 5.5-mm SwiveLock anchor, and 175 +/- 42 N were found for the 8 mm forked SwiveLock anchor. Significant differences were seen between the 8-mm SwiveLock compared to the 5.5-mm SwiveLock (p < 0.044) as well as the Corkscrew anchor (p < 0.009). No significant differences were seen between the Corkscrew and the 5.5-mm SwiveLock anchor. CONCLUSIONS: The new 8-mm forked SwiveLock anchor significantly enhances construct stability compared to a 5.5-mm double loaded Corkscrew anchor as well as the 5.5-mm SwiveLock suture anchor. However, a restrictive postoperative rehabilitation seems to be important in all tested reconstructions in order to avoid early failure of the construct. PMID- 25293679 TI - A case of cochlear implantation in a patient with Epstein syndrome. AB - Epstein syndrome is a rare autosomal dominant platelet disorder characterized by thrombocytopenia, giant platelets, and sensorineural hearing loss. It is included among four overlapping syndromes, the others being May-Hegglin anomaly, Fechtner syndrome, and Sebastian syndrome. It is now established that all four disorders are caused by mutations in the MYH9 gene. We report the case of a patient with Epstein syndrome in whom bilateral profound hearing impairment developed and cochlear implantation was carried out. A cochlear implant was successfully used with a speech discrimination score of 100% on a Japanese sentence recognition test. This report offers the second description of the performance of a cochlear implant in a patient with Epstein syndrome. This case study may offer hope for patients and their family members with this kind of mutation. PMID- 25293680 TI - Emotionally-intense situations can result in rhabdomyolysis in McArdle disease. AB - Despite the majority of patients with McArdle disease reporting symptoms including fatigue, cramps and episodes of myoglobinuria from early childhood, diagnosis is often delayed by several decades. Additionally, many individuals with rhabdomyolysis remain undiagnosed. The occurrence of symptoms during exercise, particularly isometric muscle contraction such as heavy lifting, is well known in McArdle disease. However, isometric muscle contraction that occurs with emotion is not recognised as exercise and may be missed as a trigger for rhabdomyolysis, potentially leading to a delay in diagnosis. Three patients are presented here, all with symptoms from childhood including episodes of rhabdomyolysis induced by tense emotional situations without physical exertion; two patients reported recurrent episodes while watching rather than playing football. The remaining patient developed rhabdomyolysis during a heated argument. These patients' histories emphasise the risk from sustained isometric muscle contraction that occurs in emotive situations for patients with McArdle disease. PMID- 25293681 TI - Percutaneous retrieval of an intrathecal foreign body: technical note. AB - A 58-year-old man had an intrathecal baclofen pump implanted. A guidewire used during removal of a previously placed lumbar drain catheter fractured, and a fragment was left within the thecal sac. Using fluoroscopic guidance, a loop snare device was used to retrieve the intrathecal foreign body successfully and without complication. The pump was placed without any difficulty, and the patient's hospital course was uneventful. PMID- 25293682 TI - Inflammatory myopathy and interstitial lung disease in antisynthetase syndrome with PL-7 antibody. AB - We report a case of a 72-year-old Caucasian woman with PL-7 positive antisynthetase syndrome. Clinical presentation included interstitial lung disease, myositis, 'mechanic's hands' and dysphagia. As lung injury was the main concern, treatment consisted of prednisolone and cyclophosphamide. Complete remission with reversal of pulmonary damage was achieved, as reported by CT scan, pulmonary function tests and functional status. PMID- 25293683 TI - An unusual diagnosis of splenic rupture. AB - A 22-year-old woman presented with a 3-day history of worsening epigastric pain, non-productive cough and vomiting. On examination she was pale and had abdominal tenderness predominant in the right upper quadrant. Abdominal ultrasound excluded the presence of gall stones, but was unable to rule out free fluid in the abdomen. CT demonstrated extensive high-density ascites; however, no source of bleeding could be demonstrated. Clinically the patient's condition deteriorated, and an exploratory laparotomy was performed. In theatre the splenic capsule was found to have detached from the splenic body and emergency splenectomy was performed. Virology serology later demonstrated acute cytomegalovirus (CMV) infection, although tissue microscopy and CMV staining were negative. No other cause of rupture was found. The interesting aspects of this case include the poor correlation between initial presenting symptoms and subsequent diagnosis, the difficulty encountered in making a firm diagnosis and the atypical cause of rupture. PMID- 25293684 TI - Acute pancreatitis: pancreas divisum with ventral duct intraductal papillary mucinous neoplasms. AB - Acute recurrent pancreatitis occurs rarely in individuals with pancreas divisum. A 39-year-old woman with no significant history presented with pancreatitis. CT scan and MRI suggested acute on chronic pancreatitis with calcifications and pancreatic divisum. An endoscopic ultrasound demonstrated complete pancreas divisum. A large calcification measuring 12 mm * 6 mm was seen in the head of the pancreas with associated dilation of the ventral pancreatic duct. Fine-needle aspiration of the dilated ventral pancreatic duct showed an amylase level of 36,923 U/L and a carcinoembryonic antigen of 194. A ventral duct intraductal papillary mucinous neoplasm was suspected and a pancreaticoduodenectomy procedure was recommended. After the procedure, pathology demonstrated an intraductal papillary lesion in the main duct with moderate dysplasia. A pancreatic intraepithelial neoplasia, grade 2 was also present. Margins of resection were clear. This case represents the importance of assessing for secondary causes of pancreatitis in pancreas divisum. PMID- 25293685 TI - Spontaneous acalculous gallbladder perforation. AB - An 86-year-old woman, 4 days post-operative following a right-sided Austin-Moore arthroplasty, reported abdominal pain around a known umbilical hernia and became increasingly confused. A diagnosis of incarcerated umbilical hernia was made. At surgery, on entering the peritoneal cavity, bile was immediately noted. The operation was converted to a laparotomy and a perforation was noted in the gallbladder. An open cholecystectomy was performed. Macroscopically the gallbladder was perforated in multiple places, was thin walled and did not contain gallstones. This case demonstrates the difficulty in diagnosing an apparently spontaneous gallbladder perforation in a cognitively frail patient. PMID- 25293686 TI - Massive surgical emphysema after perineal proctosigmoidectomy. AB - An 83-year-old woman underwent an elective perineal proctosigmoidectomy (Altemeier procedure) for a rectal prolapse. On postoperative day 1, the patient presented with impressive subcutaneous emphysema involving the chest, neck and face without any other symptoms. A CT scan showed free air in the retroperitoneum, the intraperitoneal cavity, the mediastinum and a subcutaneous emphysema of the neck and the face. Air was also found around the coloanal anastomosis and an anastomotic leak was proven by rectal contrast agent. In this situation, a rectoscopy followed by a laparoscopy were immediately performed. The leak could not be visualised. Peritoneal lavage and drainage, followed by protective sigmoidostomy were carried out. After surgery, the follow-up was uneventful except a persistent but asymptomatic leak with a presacral cavity. The coloanal dehiscence was later proven in rectoscopy. Although sutured, it is still present and colostomy closure will eventually be possible in a few months. PMID- 25293687 TI - Large vegetation in a 60-year-old man with Enterococcus faecalis cardiac implantable electronic device infection. PMID- 25293688 TI - Klippel-Trenaunay syndrome and cavernous malformations. PMID- 25293689 TI - The science of mind wandering: empirically navigating the stream of consciousness. AB - Conscious experience is fluid; it rarely remains on one topic for an extended period without deviation. Its dynamic nature is illustrated by the experience of mind wandering, in which attention switches from a current task to unrelated thoughts and feelings. Studies exploring the phenomenology of mind wandering highlight the importance of its content and relation to meta-cognition in determining its functional outcomes. Examination of the information-processing demands of the mind-wandering state suggests that it involves perceptual decoupling to escape the constraints of the moment, its content arises from episodic and affective processes, and its regulation relies on executive control. Mind wandering also involves a complex balance of costs and benefits: Its association with various kinds of error underlines its cost, whereas its relationship to creativity and future planning suggest its potential value. Although essential to the stream of consciousness, various strategies may minimize the downsides of mind wandering while maintaining its productive aspects. PMID- 25293690 TI - Feature binding and the processing of global-local shapes in bilingual and monolingual children. AB - In the present study, we examined the effects of bilingualism and age on a color shape binding task (assessing visual working memory) and a global-local task (assessing inhibitory processes) in a sample of 55 bilingual and 49 monolingual children 8 and 10 years old. In the color-shape binding task, corrected recognition scores increased in older children; bilingual children performed better than monolinguals in the shape-only condition, but the two groups were equally accurate in the color-only and combination conditions. In the global local task, accuracy was higher in bilingual than in monolingual children, particularly on incongruent trials; monolingual children showed a strong global precedence effect (higher accuracy in the global than in the local conditions and greater global-to-local interference), whereas bilingual children exhibited a small, but significant, local precedence effect (higher accuracy in the local than in the global conditions and greater local-to-global interference). These findings confirm and extend previous evidence indicating that the bilingualism advantage is more pronounced in working memory tasks involving inhibitory processes. PMID- 25293691 TI - Proteolytic processing of the cilium adhesin MHJ_0194 (P123J ) in Mycoplasma hyopneumoniae generates a functionally diverse array of cleavage fragments that bind multiple host molecules. AB - Mycoplasma hyopneumoniae, the aetiological agent of porcine enzootic pneumonia, regulates the presentation of proteins on its cell surface via endoproteolysis, including those of the cilial adhesin P123 (MHJ_0194). These proteolytic cleavage events create functional adhesins that bind to proteoglycans and glycoproteins on the surface of ciliated and non-ciliated epithelial cells and to the circulatory host molecule plasminogen. Two dominant cleavage events of the P123 preprotein have been previously characterized; however, immunoblotting studies suggest that more complex processing events occur. These extensive processing events are characterized here. The functional significance of the P97 cleavage fragments is also poorly understood. Affinity chromatography using heparin, fibronectin and plasminogen as bait and peptide arrays were used to expand our knowledge of the adhesive capabilities of P123 cleavage fragments and characterize a novel binding motif in the C-terminus of P123. Further, we use immunohistochemistry to examine in vivo, the biological significance of interactions between M. hyopneumoniae and fibronectin and show that M. hyopneumoniae induces fibronectin deposition at the site of infection on the ciliated epithelium. Our data supports the hypothesis that M. hyopneumoniae possesses the molecular machinery to influence key molecular communication pathways in host cells. PMID- 25293692 TI - Reorganization of the bacterial and archaeal populations associated with organic loading conditions in a thermophilic anaerobic digester. AB - Organic loading conditions are an important factor influencing reactor performances in methanogenic bioreactors. Yet the underlying microbiological basis of the process stability, deterioration, and recovery remains to be understood. Here, structural responses of the bacterial and archaeal populations to the change of organic loading conditions in a thermophilic anaerobic digester were investigated by process analyses and 16S rRNA gene-based molecular approaches. The biogas was produced stably without the accumulation of volatile fatty acids (VFAs) at low organic loading rates (OLRs) in the beginning of reactor operation. Increasing OLR in stages disrupted the stable reactor performance, and high OLR conditions continued the deteriorated performance with slight biogas production and high accumulation of VFAs. Thereafter, the gradual decrease of OLR resulted in the recovery from the deterioration, giving rise to the stable performance again. The stable performances before and after the high OLR conditions conducted were associated with compositionally similar but not identical methanogenic consortia. The bacterial and archaeal populations were synchronously changed at both the transient phases toward the deteriorated performance and in recovery process, during which the dynamic shift of aceticlastic and hydrogenotrophic methanogens including the recently identified Methanomassiliicoccus might contribute to the maintenance of the methanogenic activity. The distinctive bacterial population with a high predominance of Methanobacterium formicicum as archaeal member was found for the deteriorated performance. The results in this study indicate the coordinated reorganization of the bacterial and archaeal populations in response to functional states induced by the change of organic loading conditions in the anaerobic digester. PMID- 25293693 TI - Spin-orbit torque in a bulk perpendicular magnetic anisotropy Pd/FePd/MgO system. AB - Spin-orbit torques, including the Rashba and spin Hall effects, have been widely observed and investigated in various systems. Since interesting spin-orbit torque (SOT) arises at the interface between heavy nonmagnetic metals and ferromagnetic metals, most studies have focused on the ultra-thin ferromagnetic layer with interface perpendicular magnetic anisotropy. Here, we measured the effective longitudinal and transverse fields of bulk perpendicular magnetic anisotropy Pd/FePd (1.54 to 2.43 nm)/MgO systems using harmonic methods with careful correction procedures. We found that in our range of thicknesses, the effective longitudinal and transverse fields are five to ten times larger than those reported in interface perpendicular magnetic anisotropy systems. The observed magnitude and thickness dependence of the effective fields suggest that the SOT do not have a purely interfacial origin in our samples. PMID- 25293694 TI - Distinct palisade tissue development processes promoted by leaf autonomous signalling and long-distance signalling in Arabidopsis thaliana. AB - Plants develop palisade tissue consisting of cylindrical mesophyll cells located at the adaxial side of leaves in response to high light. To understand high light signalling in palisade tissue development, we investigated leaf autonomous and long-distance signal responses of palisade tissue development using Arabidopsis thaliana. Illumination of a developing leaf with high light induced cell height elongation, whereas illumination of mature leaves with high light increased cell density and suppressed cell width expansion in palisade tissue of new leaves. Examination using phototropin1 phototropin2 showed that blue light signalling mediated by phototropins was involved in cell height elongation of the leaf autonomous response rather than the cell density increase induced by long distance signalling. Hydrogen peroxide treatment induced cylindrical palisade tissue cell formation in both a leaf autonomous and long-distance manner, suggesting involvement of oxidative signals. Although constitutive expression of transcription factors involved in systemic-acquired acclimation to excess light, ZAT10 and ZAT12, induced cylindrical palisade tissue cell formation, knockout of these genes did not affect cylindrical palisade tissue cell formation. We conclude that two distinct signalling pathways - leaf autonomous signalling mostly dependent on blue light signalling and long-distance signalling from mature leaves that sense high light and oxidative stress - control palisade tissue development in A. thaliana. PMID- 25293695 TI - A simple set for intrauterine fetal blood transfusion constructed by readily available materials in every clinic. AB - Intrauterine fetal transfusion needs extensive experience and requires excellent eye-hand coordination, good equipment and experienced team workers to achieve success. While the needle is in the umbilical vein, an assistant withdraws and/or transfuses blood. The needle point should be kept still to prevent lacerations and dislodging. We propose a simple set for Intrauterine Fetal blood transfusion is constructed by readily available materials in every clinic to minimize needle tip movement and movements during syringe attachments and withdrawals during the intrauterine fetal transfusion. This makes possible to withdraw fetal blood sample, and to transfuse blood with minimal intervention. PMID- 25293696 TI - Design and testing of a low impedance transceiver circuit for nitrogen-14 nuclear quadrupole resonance. AB - A low impedance transceiver circuit consisting of a transmit-receive switch circuit, a class-D amplifier and a transimpedance amplifier (TIA) was newly designed and tested for a nitrogen-14 NQR. An NQR signal at 1.37MHz from imidazole was successfully observed with the dead time of ~85us under the high Q transmission (Q~120) and reception (Q~140). The noise performance of the low impedance TIA with an NQR probe was comparable with a commercial low noise 50Omega amplifier (voltage input noise: 0.25 nV/Hz) which was also connected to the probe. The protection voltage for the pre-amplifier using the low impedance transceiver was ~10 times smaller than that for the pre-amplifier using a 50Omega conventional transceiver, which is suitable for NQR remote sensing applications. PMID- 25293697 TI - A revised method for determination of dialkylphosphate levels in human urine by solid-phase extraction and liquid chromatography with tandem mass spectrometry: application to human urine samples from Japanese children. AB - OBJECTIVES: Biological monitoring of organophosphorus insecticide (OP) metabolites, specifically dialkylphosphates (DAP) in urine, plays a key role in low-level exposure assessment of OP in individuals. The aims of this study are to develop a simple and sensitive method for determining four urinary DAPs using high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS), and to assess the concentration range of urinary DAP in Japanese children. METHODS: Deuterium-labeled DAPs were used as internal standards. Urinary dimethylphosphate (DMP) and diethylphosphate (DEP), which passed through the solid-phase extraction (SPE) column, and dimethylthiophosphate (DMTP) and diethylthiophosphate (DETP), which were extracted from a SPE column using 2.5 % NH3 water including 50 % acetonitrile, were prepared for separation analysis. The samples were then injected into LC-MS/MS. The optimized method was applied to spot urine samples from 3-year-old children (109 males and 116 females) living in Aichi Prefecture in Japan. RESULTS: Results from the validation study demonstrated good within- and between-run precisions (<10.7 %) with low detection limits (0.4 for DMP and DMTP, 0.2 for DEP and 0.1 MUg/L for DETP). The geometric mean values and detection rates of the urinary DAPs in Japanese children were 14.4 MUg/L and 100 % for DMP, 5.3 MUg/L and 98 % for DMTP, 5.5 MUg/L and 99 % for DEP, and 0.6 MUg/L and 80 % for DETP, respectively. CONCLUSIONS: The present high throughput method is simple and reliable, and can thereby further contribute to development of an exposure assessment of OP. The present study is the first to reveal the DAP concentrations in young Japanese children. PMID- 25293699 TI - The application of Kinesio Taping in children with cerebral palsy. PMID- 25293698 TI - Biomonitoring of mercury, cadmium, and lead exposure in Japanese children: a cross-sectional study. AB - OBJECTIVES: To measure current Hg, Cd, and Pb exposure in Japanese children, and to estimate dietary intakes of foods responsible for high body burden. METHODS: Blood, hair, and urine samples were collected from 9 to 10-year-old 229 children in Asahikawa and measured for Hg, Cd, and Pb in these matrices. Diet history questionnaire was used to estimate intake of marine foods and other food items. Hg level was measured by cold vapor atomic absorption spectrometry. Cd and Pb levels were determined with inductively coupled plasma mass spectrometry. RESULTS: Geometric mean (GM) of blood Hg, Cd, and Pb was 4.55 MUg/L, 0.34 MUg/L, and 0.96 MUg/dL, respectively. Urinary Cd level was 0.34 MUg/g creatinine (GM) and hair Hg was 1.31 MUg/g (GM). Approximately one-third (35%) of blood samples had Hg level above the U.S. EPA reference dose (RfD; 5.8 MUg/L). Hair Hg level exceeded U.S. EPA RfD (1.2 MUg/g) in 59 % samples. Children in the upper quartile of blood Hg level had significantly higher intake of large predatory fish species compared to those in the lower quartile of blood Hg. CONCLUSIONS: Those with high blood Hg level may be explained by more frequent intake of big predatory fish. Cd and Pb exposure is generally low among Japanese children. As no safety margin exists for Pb exposure and high exposure to MeHg is noted in Japanese population; periodic biomonitoring and potential health risk assessment should continue in high-risk populations, notably among children. PMID- 25293700 TI - MRI appearances of the anterior fibulocalcaneus muscle: a rare anterior compartment muscle. AB - MRI of a 62-year-old female presenting with ankle pain demonstrated an accessory muscle within the anterior compartment of the lower leg. The muscle originated from the fibula and anterior crural septum. The tendon passed anterior to the lateral malleolus and inserted at the critical angle of Gissane on the calcaneus. This muscle was initially described in the anatomic literature by Lambert and Atsas in 2010. To our knowledge, this is the first time the MRI appearances of this muscle has been described in the radiological literature. Awareness of the fibulocalcaneal muscle is important as it may represent a cause of ankle pain. In addition, the tendon could potentially be harvested for use in reconstructive procedures. PMID- 25293701 TI - [Shared decision making in psychiatry]. AB - In the paradigm of recovery-oriented care in mental health the central decision model is shared decision making (SDM). In the article we describe the model of SDM and the reason why it has been identified as important in mental health care. We also review the central literature of SDM in mental health and some of the decision aids just beginning to be developed to enhance SDM, thereby pointing to the need of documenting the effect of using decision aids and to further research on the effect of SDM on the recovery process of people in mental health care. PMID- 25293702 TI - [Differential diagnostic considerations about a tumour on the tongue of a 43-year old man]. AB - Schwannomas are benign tumours originating from the Schwann cells that ensheath peripheral nerves. 25-40% of schwannomas are located in the head and neck area, only 1% of these are found in the oral cavity. Schwannomas are slow-growing benign tumours with little or no occurrence of malignant transformation. A case report of a 43-year-old man presenting with a 2 ' 1.5 cm protruding tumour on the anterior part of the tongue is reported. The patient complained of difficulty eating and a tendency to bite on the tumour. Biopsy showed a benign schwannoma. Total excision in local anaesthesia was performed. PMID- 25293703 TI - [Steroid treatment and risk of glaucoma]. AB - The risk of steroid-induced elevation of intraocular pressure and glaucoma is clinical relevant and require monitoring of patients at risk. The risk depends on route of administration, potency and individual risk factors such as primary open glaucoma (POAG), first-degree relative with POAG, age (children) and myopia. Steroid-induced elevation of intraocular pressure is most commonly associated with ocular application and systemic administration but may occur after periocular cutaneous application and nasal and inhalation therapy in patients with individual risk factors. PMID- 25293704 TI - [Life-threatening malnutrition after a laparoscopic gastric bypass operation reverting the gastrointestinal tract into normal anatomy]. AB - We present a case report of a woman who had repeating episodes of severe life threatening malnutrition four years after a laparoscopic gastric bypass operation for severe overweight. Despite several normal examinations her condition remained unstable. She was offered a laparoscopic operation reverting the stomach and small intestine into normal anatomy and it was performed without complications so the condition resolved. The malnutrition was probably caused by a mixture of an eating disorder and the effects of the operation influencing gut hormones. It is important to handle this category of patients in a competent multidisciplinary team. PMID- 25293705 TI - [Patient with intractable delirium successfully treated with electroconvulsive therapy]. AB - Delirium is a frequent and serious condition often seen in hospitalized patients, especially the elderly. Treatment of the somatic illness causing the delirium, and antipsychotic medication will usually resolve the condition. Sometimes, however, the condition is refractory towards medical treatment and in this situation electroconvulsive therapy (ECT) can be a quick and efficient treatment. In this case report of a 26-year-old man a post-operative intractable delirium persisting for three weeks was efficiently and swiftly relieved by three consecutive ECTs. The patient was discharged without need for further treatment. PMID- 25293707 TI - [Cardiac arrest due to torsades de pointes ventricular tachycardia in a patient with Lyme carditis]. AB - A 45-year-old female presented with third degree atrioventricular block and was diagnosed with Lyme carditis. Despite appropriate antibiotic treatment and continuous ventricular pacing, she suffered sudden cardiac arrest due to torsades de pointes ventricular tachycardia. Although rare, severe and potentially fatal ventricular tachyarrhythmias can occur in patients with Lyme borreliosis. PMID- 25293706 TI - [Natalizumab can induce progressive multifocal leucoencephalopathy]. AB - A 41-year-old woman with relapsing-remitting multiple sclerosis came to the outpatient-clinic, prior to a scheduled infusion with natalizumab. She had been treated with natalizumab for four years. Prior to treatment she did not wish to have her John Cunningham virus status tested. At the consultation she appeared disoriented and answered questions inadequately. An MRI was consistent with progressive multifocal leucoencephalopathy, and treatment with plasmapheresis was startet immediatly. The patient deceased four months later. PMID- 25293708 TI - [The value of ultrasound in the follow-up of thyroid cancer]. AB - The commonly used tumour-node-metastasis (TNM) staging system is designed to predict death and not recurrence. Based on this, patients with thyroid cancer are grouped into risk categories at the time of initial treatment. However, recent guidelines proposed a novel staging system focusing on microscopic invasion into the perithyroidal tissues, neck lymph node involvement and 131I uptake outside the thyroid bed following treatment. This risk re-assessment improves the prediction of recurrent/persistent disease. The cornerstone in the follow-up is measurement of plasma-thyroglobulin concentration and ultrasound of the neck focusing on the thyroid bed and classification of lymph nodes according to their location and high risk signs. PMID- 25293709 TI - [IgE-induced anaphylactic reaction after eating lamb meat]. AB - This article presents the case of a 54-year-old male, who was admitted to hospital after suffering a severe anaphylactic reaction after tasting a spoonful of chili con carne and four months later after eating lamb meat. Galactose-alpha 1,3-galactose allergy was suspected and the subsequent blood test showed highly elevated specific IgE levels. Delayed allergy to meat is a relatively new type of allergy and the delayed onset of allergic symptoms poses a diagnostic challenge to the physician. This type of allergy should be considered when there has been no obvious allergen exposition prior to the allergic reaction. PMID- 25293710 TI - [Prolonged penile strangulation can cause serious problems]. AB - A 45-year-old male fell asleep with a plastic ring around both scrotum and penis after intake of 100 mg of Viagra. He woke up several hours later with pain and oedema of the external genitalia. He was able to cut off the ring, but a concentrically wound around the base of scrotum had already been formed. He went to see a doctor ten days later and was referred to an urological department. The wound was purified and sutured in general anaesthesia, because the cremaster muscle was exposed. The patient was discharged the next day. PMID- 25293711 TI - Medication use review in Qatar: are community pharmacists prepared for the extended professional role? AB - BACKGROUND: The incidence of chronic illnesses is increasing globally. Non adherence to medications and other medication-related problems are common among patients receiving long-term medications. Medication use review (MUR) is a service provision with an accredited pharmacist undertaking structured, adherence centered reviews with patients receiving multiple medications. MUR services are not yet available in community pharmacies in Qatar. OBJECTIVE: The current study aims to evaluate community pharmacists' knowledge, attitudes, and perception towards establishing MUR as an extended role in patient care. SETTING: Private community pharmacies in Qatar including chains and independent pharmacies. Methodology A cross-sectional survey using a self-administered questionnaire was conducted among licensed community pharmacists from December 2012 to January 2013. Data analysis was conducted using descriptive and inferential statistics. MAIN OUTCOME MEASURES: Knowledge, attitudes, and practices related to MUR concept and services. RESULTS: A total of 123 participants responded to the survey (response rate 56%). The mean total knowledge score was 71.4 +/- 14.7%. An overwhelming proportion of the participants (97%) were able to identify the scope of MUR in relation to chronic illnesses and at enhancing the quality of pharmaceutical care. Furthermore, 80% of the respondents were able to identify patients of priority for inclusion in an MUR program. However, only 43% of the participants knew that acute medical conditions were not the principal focus of an MUR service, while at least 97% acknowledged that the provision of MUR services is a great opportunity for an extended role of community pharmacists and that MUR makes excellent use of the pharmacist's professional skills in the community. The participants generally reported concerns about time, dedicated consultation area, and support staff as significant barriers towards MUR implementation. CONCLUSION: This study suggests that community pharmacists in Qatar had sufficient knowledge about the concept of MUR and its scope, but there were still important deficiencies that warrant further education. The findings have important implications on policy and practice pertaining to the implementation of MUR as an extended role of pharmacists and as part of Qatar's National Health Strategy to move primary health care forward. PMID- 25293712 TI - Being baby friendly: evidence-based breastfeeding support. AB - Breast feeding improves important outcomes for mothers and infants. In the UK, breastfeeding rates have historically been low, particularly among socially disadvantaged young women. Although there have been gradual increases in breastfeeding initiation rates since 2000, rates of exclusive breast feeding and continuation until 6 months remain lower than those in similar countries. This review summarises the evidence for effective and cost-effective strategies to help women, particularly those in low income groups, make informed choices, overcome barriers and establish and maintain breast feeding. We describe the development and impact of the Unicef Baby Friendly Initiative, and the roles and responsibilities, and challenges and opportunities that clinicians have in promoting breast feeding and maintaining a baby-friendly culture and environment. PMID- 25293714 TI - Towards a quantitative science of sustainability. PMID- 25293713 TI - Aberrant GITR expression on different T cell subsets and the regulation by glucocorticoid in systemic lupus erythematosus. AB - AIM: The dysfunction of T regulatory cells is important for the pathogenesis of systemic lupus erythematosus (SLE). Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is expressed at low levels on resting responder T lymphocytes (Tresps) and is up-regulated on T regulatory cells (Tregs) and activated T cells, diminishing suppressive activity of Tregs and/or leading to resistance to suppression of Tregs by activated effector T cells. We aimed to explore whether SLE patients had an aberrant expression of GITR on Tregs and responder T cells (Tresps) and the regulation by glucocorticoids. METHODS: The surface GITR expression on Tregs and Tresps cells were analyzed by flow cytometry in 32 patients and 15 normal controls. Purified Tregs or Tresps were cultured with glucocorticoid. Apoptosis of the cells were determined by the staining of Annexin V. RESULTS: Systemic lupus erythematosus patients had higher levels of GITR expressed on CD4(+) CD25(+) , CD4(+) CD25(high) and CD4(+) CD25(+) CD127(low/-) Tregs as well as on CD4(+) CD25(-) Tresps compared to healthy controls. The expression of GITR on Tregs and Tresps were positively correlated with score of SLE disease activity index (SLEDAI). In vitro glucocorticoid induced GITR expression on purified Tresp cells, but not on Tregs, and almost all of the GITR positive cells induced by glucocorticoid encountered apoptosis. CONCLUSION: Aberrant expression of GITR may contribute to SLE pathogenesis. Glucocorticoid may achieve its therapeutic effect partly by inducing GITR expression on Tresps rather than Tregs, which initiates the apoptosis of Tresp cells in SLE patients. PMID- 25293715 TI - Do early paternal exposures to lifestyle factors such as smoking increase the risk of chronic diseases in the offspring? PMID- 25293716 TI - Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients. AB - Immunoglobulin A nephropathy (IgAN) is a complex multifactorial disease characterized by genetic factors that influence the pathogenesis of the disease. In this context, an intriguing role could be ascribed to copy number variants (CNVs). We performed the whole-genome screening of CNVs in familial IgAN patients, their healthy relatives and healthy subjects (HSs). In the initial screening, we included 217 individuals consisting of 51 biopsy-proven familial IgAN cases and 166 healthy relatives. We identified 148 IgAN-specific aberrations, specifically 105 loss and 43 gain, using a new statistical approach that allowed us to identify aberrations that were concordant across multiple samples. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. We focused our attention on a CNV located in chromosome 3, which contains the TLR9 gene and found that IgAN patients characterized by deteriorated renal function carried low copy number of this CNV. Moreover, the TLR9 gene expression was low and significantly correlated with the loss aberration. Conversely, IgAN patients with normal renal function had no aberration and the TLR9 mRNA was expressed at the same level as in HSs. We confirmed our data in another cohort of Greek subjects. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying structural variants that could help the genetic dissection of this complex disease, and pointed out a loss aberration in the chromosome 3, which is responsible for the downregulation of TLR9 expression that, in turn, could contribute to the deterioration of the renal function in IgAN patients. PMID- 25293717 TI - Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient. AB - Neurofibromatosis type 1 (NF1) (MIM#162200) is a relatively frequent genetic condition that predisposes to tumor formation. The main types of tumors occurring in NF1 patients are cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors. To search for somatic mutations in cutaneous (dermal) neurofibromas, whole-exome sequencing (WES) was performed on seven spatially separated tumors and two reference tissues (blood and unaffected skin) from a single NF1 patient. Validation of WES findings was done using routine Sanger sequencing or Sequenom IPlex SNP genotyping. Exome sequencing confirmed the existence of a known familial splice-site mutation NM_000267.3:c.3113+1G>A in exon 23 of NF1 gene (HGMD ID CS951480) in blood, unaffected skin, and all tumor samples. In five out of seven analyzed tumors, we additionally detected second-hit mutations in the NF1 gene. Four of them were novel and one was previously observed. Each mutation was distinct, demonstrating the independent origin of each tumor. Only in two of seven tumors we detected an additional somatic mutation that was not associated with NF1. Our study demonstrated that somatic mutations of NF1 are likely the main drivers of cutaneous tumor formation. The study provides evidence for the rareness of single base pair level alterations in the exomes of benign NF1 cutaneous tumors. PMID- 25293718 TI - The correlation between ancestry and color in two cities of Northeast Brazil with contrasting ethnic compositions. AB - The degree of admixture in Brazil between historically isolated populations is complex and geographically variable. Studies differ as to what the genetic and phenotypic consequences of this mixing have been. In Northeastern Brazil, we enrolled 522 residents of Salvador and 620 of Fortaleza whose distributions of self-declared color were comparable to those in the national census. Using the program Structure and principal components analysis there was a clear correlation between biogeographic ancestry and categories of skin color. This correlation with African ancestry was stronger in Salvador (r=0.585; P<0.001) than in Fortaleza (r=0.236; P<0.001). In Fortaleza, although self-declared blacks had a greater proportion of European ancestry, they had more African ancestry than the other categories. When the populations were analyzed without pseudoancestors, as in some studies, the relationship of 'race' to genetic ancestry tended to diffuse or disappear. The inclusion of different African populations also influenced ancestry estimates. The percentage of unlinked ancestry informative markers in linkage disequilibrium, a measure of population structure, was 3-5 times higher in both Brazilian populations than expected by chance. We propose that certain methods, ascertainment bias and population history of the specific populations surveyed can result in failure to demonstrate a correlation between skin color and genetic ancestry. Population structure in Brazil has important implications for genetic studies, but genetic ancestry is irrelevant for how individuals are treated in society, their health, their income or their inclusion. These track more closely with perceived skin color than genetic ancestry. PMID- 25293719 TI - A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency. AB - Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene. PMID- 25293721 TI - A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study. AB - Genetic risk scores (GRS), summing up the total effect of several single nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmo Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P=0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P=0.25), MDC (1.168 (1.060-1.288); P=0.002) and SAHLSIS (1.124 (0.997-1.267); P=0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension. PMID- 25293722 TI - Detection and measurement of surface contamination by multiple antineoplastic drugs using multiplex bead assay. AB - OBJECTIVES: Contamination of workplace surfaces by antineoplastic drugs presents an exposure risk for healthcare workers. Traditional instrumental methods to detect contamination such as liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) are sensitive and accurate but expensive. Since immunochemical methods may be cheaper and faster than instrumental methods, we wanted to explore their use for routine drug residue detection for preventing worker exposure. METHODS: In this study we examined the feasibility of using fluorescence covalent microbead immunosorbent assay (FCMIA) for simultaneous detection and semi-quantitative measurement of three antineoplastic drugs (5 fluorouracil, paclitaxel, and doxorubicin). The concentration ranges for the assay were 0-1000 ng/ml for 5-fluorouracil, 0-100 ng/ml for paclitaxel, and 0-2 ng/ml for doxorubicin. The surface sampling technique involved wiping a loaded surface with a swab wetted with wash buffer, extracting the swab in storage/blocking buffer, and measuring drugs in the extract using FCMIA. RESULTS: There was no significant cross-reactivity between these drugs at the ranges studied indicated by a lack of response in the assay to cross analytes. The limit of detection (LOD) for 5-fluorouracil on the surface studied was 0.93 ng/cm(2) with a limit of quantitation (LOQ) of 2.8 ng/cm(2), the LOD for paclitaxel was 0.57 ng/cm(2) with an LOQ of 2.06 ng/cm(2), and the LOD for doxorubicin was 0.0036 ng/cm(2) with an LOQ of 0.013 ng/cm(2). CONCLUSION: The use of FCMIA with a simple sampling technique has potential for low cost simultaneous detection and semi-quantitative measurement of surface contamination from multiple antineoplastic drugs. PMID- 25293723 TI - Pathogenicity and tissue distribution of grass carp reovirus after intraperitoneal administration. AB - Grass carp reovirus (GCRV) is the causative agent of grass carp hemorrhage and causes significant loss of fingerlings. However, little is known about how the virus is distributed in organs and tissues. The aim of the present study was to investigate the distribution of different GCRV stains in tissues and organs of grass carp. The pathogenicity and tissue distribution of GCRV were monitored after intraperitoneal administration. The study showed a distribution of GCRV in different tissues and organs, particularly in the liver, spleen, kidney, intestine, and muscle, which had a higher number of viral RNA copies during the sixth to ninth days. The kidney had the highest numbers of viral RNA copies, as high as 24000 copies. Until the fourteenth day, nearly no viral RNA copies could be detected. This study defined the virus distribution in different tissues of grass carp inoculated by i.p. and supplied clues for the pathogenesis of GCRV. PMID- 25293724 TI - Eutectic melting of LiBH4-KBH4. AB - Eutectic melting in mixtures of alkali and alkali earth metal borohydrides can pave the way for new applications as fast ionic conductors, and facilitate hydrogen release by low temperature chemical reactions and convenient nanoconfinement. Here, we determine the eutectic composition for the lithium potassium borohydride system, 0.725LiBH4-0.275KBH4, with the lowest melting point, Tmelt ~105 degrees C, of all known alkali and alkali earth metal borohydride mixtures. Mechanochemistry and manual mixing of LiBH4-KBH4 mixtures facilitate the formation of LiK(BH4)2. However, the melting or heat treatments used in this work do not produce LiK(BH4)2. The bimetallic borohydride dissociates into the monometallic borohydrides at ~95 degrees C and partial melting occurs at ~105 degrees C. Analysis of the unit cell volumes of LiBH4, KBH4 and LiK(BH4)2 in the temperature range 25 to 90 degrees C indicates that the formation of the bimetallic borohydride is facilitated by a more dense packing as compared to the reactants. Thus, LiK(BH4)2 is considered metastable and the formation is pressure induced. A phase diagram for the LiBH4-KBH4 system is established, which illustrates the low eutectic melting point and the stability range for the bimetallic borohydride, LiK(BH4)2. PMID- 25293720 TI - Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs. AB - The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating ~200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and IMPUTE-INFO metrics should be used to efficiently filter badly imputed rare variants. This study thus provides general guidelines for researchers planning large-scale genetic studies. PMID- 25293725 TI - Prognosis following acute coronary syndromes according to prior coronary artery bypass grafting: Meta-analysis. AB - PURPOSE: Conduct a meta-analysis to study the prognostic influence of a previous coronary artery bypass grafting (CABG) in patients admitted for an acute coronary syndrome (ACS). METHODS: A systematic review of the literature was performed using electronic reference databases through January 2013 (MEDLINE, Cochrane Library, Web of Knowledge, Google Scholar and references cited in other studies). Studies in which ACS outcomes with a previous history of CABG were compared with ACS outcomes with no history of previous CABG were considered for inclusion. The main endpoints of interest were mortality and non-fatal acute myocardial infarction. Data was aggregated at three follow-up times using random-effects meta-analysis models. RESULTS: Twenty-four studies were included which provided 387,181 patients for analysis. Previous CABG ACS patients were older, more diabetic and had a more frequent history of a previous myocardial infarction. Pooled in-hospital mortality was higher for the previous CABG ACS patients (OR 1.22 [1.04-1.44], p<0.01, I(2) 88%). The pooled adjusted OR showed no significant differences for the two groups (adjusted OR 1.13 [0.93-1.37], p=0.22, I(2) 92%). Previous CABG ACS patient had a higher pooled 30-day mortality (OR 1.28 [1.05 1.55], p=0.02, I(2) 74%); a higher non-adjusted (OR 1.61 [1.38-1.88], p<0.01, I(2) 70%) and adjusted (adjusted OR 1.37 [1.15-1.65], p<0.01, I(2) 0%) long-term mortality. Both the in-hospital and the long-term re-infarction rates were higher for the previous CABG ACS patients. CONCLUSIONS: According to our data, ACS patients with previous CABG history had a higher risk for short- and long-term adverse events. PMID- 25293726 TI - Regional nodal relapse in surgically staged Merkel cell carcinoma. AB - PURPOSE: The nodal relapse pattern of surgically staged Merkel cell carcinoma (MCC) with/without elective nodal radiotherapy (RT) was studied in a single institution. METHOD: A total of 51 patients with MCC, 33% UICC stage I, 14% II, 53% III (4 lymph node metastases of unknown primary) were eligible. All patients had surgical staging: 23 patients sentinel node biopsy (SNB), 22 patients SNB followed by lymphadenectomy (LAD) and 6 patients LAD. In all, 94% of the primary tumors (PT) were completely resected; 57% of patients received RT, 51% of known PT sites, 33% (8/24 patients) regional RT to snN0 nodes and 68% (17/27 patients) to pN+ nodes, mean reference dose 51.5 and 50 Gy, respectively. Mean follow-up was 6 years (range 2-14 years). RESULTS: A total of 22% (11/51) patients developed regional relapses (RR); the 5-year RR rate was 27%. In snN0 sites (stage I/II), relapse occurred in 5 of 14 nonirradiated vs. none of 8 irradiated sites (p = 0.054), resulting in a 5-year RR rate of 33% versus 0% (p = 0.16). The crude RR rate was lower in stage I (12%, 2/17 patients) than for stage II (43%, 3/7 patients). In stage III (pN+), RR appeared to be less frequent in irradiated sites (18%, 3/14 patients) compared with nonirradiated sites (33%, 3/10 patients, p = 0.45) with 5-year RR rates of 23% vs. 34%, respectively. DISCUSSION: Our data suggest that adjuvant nodal RT plays a major role even if the sentinel nodes were negative. CONCLUSION: Adjuvant RT of the lymph nodes in patients with stage IIa tumors and RT after LAD in stage III tumors is proposed and should be evaluated prospectively. PMID- 25293727 TI - Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients with resected pancreatic adenocarcinoma. AB - BACKGROUND: To analyze prognostic factors associated with long-term outcomes in patients with resected pancreatic cancer treated with chemotherapy (CT) and surgery with or without external beam radiotherapy (EBRT). PATIENTS AND METHODS: From January 1995 to December 2012, 95 patients with adenocarcinoma of the pancreas and locoregional disease [clinical stage IB-IIA (n = 45; 47%), IIB-IIIC (n = 50; 53%)] were treated with curative resection [R0 (n = 52; 55%), R1 (n = 43, 45%)] and CT with (n = 60; 63%) or without (n = 35; 37%) EBRT (45-50.4 Gy). Additionally, 29 patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7-10 cm; dose, 10-15 Gy; beam energy, 9-18 MeV). RESULTS: With a median follow-up of 17.2 months (range, 1-182), 2-year overall survival (OS), disease-free survival (DFS), and locoregional control were 28, 20, and 53%, respectively. Univariate analyses showed that IIB-IIIC stage (HR, 2.23; p = 0.04), R1 margin resection status (HR, 2.09; p = 0.04), no vascular resection (HR, 0.42; p = 0.02), and not receiving external beam radiotherapy (HR, 2.70; p = 0.004) were associated with locoregional recurrence. In the multivariate analysis, only R1 margin resection status (HR, 2.63; p = 0.009) and not receiving EBRT (HR, 2.91; p = 0.002) retained significance with regard to locoregional recurrence. We observed no difference in toxicity between patients treated with or without EBRT (p = 0.44). Overall treatment mortality was 3%. No long-term treatment-related death occurred. CONCLUSIONS: Although adjuvant CT is still the standard of care for resected pancreatic tumors, OS remains modest owing to the high risk of distant metastases. Locoregional treatment needs to be tested in the context of more efficient systemic therapy. PMID- 25293728 TI - Coplanar VMAT vs. noncoplanar VMAT in the treatment of sinonasal cancer. AB - BACKGROUND: Previous studies showed that noncoplanar intensity-modulated radiotherapy (NC-IMRT) for sinonasal cancer is superior to coplanar intensity modulated radiotherapy (IMRT). Volumetric-modulated arc therapy (VMAT) is a newly introduced treatment modality, and the performance of noncoplanar VMAT for sinonasal cancer has not been well described to date. PURPOSE: To compare the dosimetry difference of noncoplanar VMAT (NC-VMAT), coplanar VMAT (co-VMAT), and NC-IMRT for sinonasal cancer. PATIENTS AND METHODS: Ten postoperative patients with sinonasal cancer were randomly selected for planning with NC-VMAT, co-VMAT, and NC-IMRT. Two planning target volumes (PTVs) were contoured representing high risk and low-risk regions set to receive a median absorbed dose (D50%) of 68 Gy and 59 Gy, respectively. The homogeneity index (HI), conformity index (CI), dose volume histograms (DVHs), and delivery efficiency were all evaluated. RESULTS: Both NC-VMAT and co-VMAT showed superior dose homogeneity and conformity in PTVs compared with NC-IMRT. There was no significant difference between NC-VMAT and co VMAT in PTV coverage. Both VMAT plans provided a better protection for organs at risk (OARs) than NC-IMRT plans, and NC-VMAT showed a small improvement over co VMAT in sparing of OARs. For peripheral doses, the doses to breast, thyroid, and larynx in the NC-IMRT plans were significantly higher than those in both VMAT plans. Compared to NC-VMAT, co-VMAT significantly reduced peripheral doses. NC VMAT and co-VMAT reduced the average delivery time by 63.2 and 64.2%, respectively, in comparison with NC-IMRT. No differences in delivery efficiency were observed between the two VMAT plans. CONCLUSION: Compared to NC-VMAT, co VMAT showed similar PTV coverage and comparable OAR sparing but significantly reduced peripheral doses and positioning uncertainty. We propose to give priority to coplanar VMAT in the treatment of sinonasal cancer. PMID- 25293729 TI - Let's not forget plants. AB - 'Many physicists see the interface with biology as an exciting place to be'. Athene Donald provides a personal perspective on working at the interface between the physical and biological sciences. PMID- 25293755 TI - Arabidopsis lipins, PDAT1 acyltransferase, and SDP1 triacylglycerol lipase synergistically direct fatty acids toward beta-oxidation, thereby maintaining membrane lipid homeostasis. AB - Triacylglycerol (TAG) metabolism is a key aspect of intracellular lipid homeostasis in yeast and mammals, but its role in vegetative tissues of plants remains poorly defined. We previously reported that PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1 (PDAT1) is crucial for diverting fatty acids (FAs) from membrane lipid synthesis to TAG and thereby protecting against FA-induced cell death in leaves. Here, we show that overexpression of PDAT1 enhances the turnover of FAs in leaf lipids. Using the trigalactosyldiacylglycerol1-1 (tgd1-1) mutant, which displays substantially enhanced PDAT1-mediated TAG synthesis, we demonstrate that disruption of SUGAR-DEPENDENT1 (SDP1) TAG lipase or PEROXISOMAL TRANSPORTER1 (PXA1) severely decreases FA turnover, leading to increases in leaf TAG accumulation, to 9% of dry weight, and in total leaf lipid, by 3-fold. The membrane lipid composition of tgd1-1 sdp1-4 and tgd1-1 pxa1-2 double mutants is altered, and their growth and development are compromised. We also show that two Arabidopsis thaliana lipin homologs provide most of the diacylglycerol for TAG synthesis and that loss of their functions markedly reduces TAG content, but with only minor impact on eukaryotic galactolipid synthesis. Collectively, these results show that Arabidopsis lipins, along with PDAT1 and SDP1, function synergistically in directing FAs toward peroxisomal beta-oxidation via TAG intermediates, thereby maintaining membrane lipid homeostasis in leaves. PMID- 25293756 TI - A proteomic strategy for global analysis of plant protein complexes. AB - Global analyses of protein complex assembly, composition, and location are needed to fully understand how cells coordinate diverse metabolic, mechanical, and developmental activities. The most common methods for proteome-wide analysis of protein complexes rely on affinity purification-mass spectrometry or yeast two hybrid approaches. These methods are time consuming and are not suitable for many plant species that are refractory to transformation or genome-wide cloning of open reading frames. Here, we describe the proof of concept for a method allowing simultaneous global analysis of endogenous protein complexes that begins with intact leaves and combines chromatographic separation of extracts from subcellular fractions with quantitative label-free protein abundance profiling by liquid chromatography-coupled mass spectrometry. Applying this approach to the crude cytosolic fraction of Arabidopsis thaliana leaves using size exclusion chromatography, we identified hundreds of cytosolic proteins that appeared to exist as components of stable protein complexes. The reliability of the method was validated by protein immunoblot analysis and comparisons with published size exclusion chromatography data and the masses of known complexes. The method can be implemented with appropriate instrumentation, is applicable to any biological system, and has the potential to be further developed to characterize the composition of protein complexes and measure the dynamics of protein complex localization and assembly under different conditions. PMID- 25293757 TI - Absence of patient-to-patient intrahospital transmission of Staphylococcus aureus as determined by whole-genome sequencing. AB - Nosocomial transmission of pathogens is a major health care challenge. The increasing spread of antibiotic-resistant strains represents an ongoing threat to public health. Previous Staphylococcus aureus transmission studies have focused on transmission of S. aureus between asymptomatic carriers or used low-resolution typing methods such as multilocus sequence typing (MLST) or spa typing. To identify patient-to-patient intrahospital transmission using high-resolution genetic analysis, we sequenced the genomes of a consecutive set of 398 S. aureus isolates from sterile-site infections. The S. aureus strains were collected from four hospitals in the Houston Methodist Hospital System over a 6-month period. Importantly, we discovered no evidence of transmission of S. aureus between patients with sterile-site infections. The lack of intrahospital transmission may reflect a fundamental difference between day-to-day transmission events in the hospital setting and the more frequently studied outbreak scenarios. Importance: Previous studies have suggested that nosocomial transmission of S. aureus is common. Our data revealed an unexpected lack of evidence for intrahospital transmission of S. aureus between patients with invasive infections. This finding has important implications for hospital infection control and public health efforts. In addition, our data demonstrate that highly related pools of S. aureus strains exist in the community which may complicate outbreak investigations. PMID- 25293759 TI - Movement of IS26-associated antibiotic resistance genes occurs via a translocatable unit that includes a single IS26 and preferentially inserts adjacent to another IS26. AB - The insertion sequence IS26 plays a key role in disseminating antibiotic resistance genes in Gram-negative bacteria, forming regions containing more than one antibiotic resistance gene that are flanked by and interspersed with copies of IS26. A model presented for a second mode of IS26 movement that explains the structure of these regions involves a translocatable unit consisting of a unique DNA segment carrying an antibiotic resistance (or other) gene and a single IS copy. Structures resembling class I transposons are generated via RecA independent incorporation of a translocatable unit next to a second IS26 such that the ISs are in direct orientation. Repeating this process would lead to arrays of resistance genes with directly oriented copies of IS26 at each end and between each unique segment. This model requires that IS26 recognizes another IS26 as a target, and in transposition experiments, the frequency of cointegrate formation was 60-fold higher when the target plasmid contained IS26. This reaction was conservative, with no additional IS26 or target site duplication generated, and orientation specific as the IS26s in the cointegrates were always in the same orientation. Consequently, the cointegrates were identical to those formed via the known mode of IS26 movement when a target IS26 was not present. Intact transposase genes in both IS26s were required for high-frequency cointegrate formation as inactivation of either one reduced the frequency 30 fold. However, the IS26 target specificity was retained. Conversion of each residue in the DDE motif of the Tnp26 transposase also reduced the cointegration frequency. Importance: Resistance to antibiotics belonging to several of the different classes used to treat infections is a critical problem. Multiply antibiotic-resistant bacteria usually carry large regions containing several antibiotic resistance genes, and in Gram-negative bacteria, IS26 is often seen in these clusters. A model to explain the unusual structure of regions containing multiple IS26 copies, each associated with a resistance gene, was not available, and the mechanism of their formation was unexplored. IS26-flanked structures deceptively resemble class I transposons, but this work reveals that the features of IS26 movement do not resemble those of the IS and class I transposons studied to date. IS26 uses a novel movement mechanism that defines a new family of mobile genetic elements that we have called "translocatable units." The IS26 mechanism also explains the properties of IS257 (IS431) and IS1216, which belong to the same IS family and mobilize resistance genes in Gram-positive staphylococci and enterococci. PMID- 25293758 TI - Pneumolysin activates macrophage lysosomal membrane permeabilization and executes apoptosis by distinct mechanisms without membrane pore formation. AB - Intracellular killing of Streptococcus pneumoniae is complemented by induction of macrophage apoptosis. Here, we show that the toxin pneumolysin (PLY) contributes both to lysosomal/phagolysosomal membrane permeabilization (LMP), an upstream event programing susceptibility to apoptosis, and to apoptosis execution via a mitochondrial pathway, through distinct mechanisms. PLY is necessary but not sufficient for the maximal induction of LMP and apoptosis. PLY's ability to induce both LMP and apoptosis is independent of its ability to form cytolytic pores and requires only the first three domains of PLY. LMP involves TLR (Toll like receptor) but not NLRP3/ASC (nucleotide-binding oligomerization domain [Nod] like receptor family, pyrin domain-containing protein 3/apoptosis-associated speck-like protein containing a caspase recruitment domain) signaling and is part of a PLY-dependent but phagocytosis-independent host response that includes the production of cytokines, including interleukin-1 beta (IL-1beta). LMP involves progressive and selective permeability to 40-kDa but not to 250-kDa fluorescein isothiocyanate (FITC)-labeled dextran, as PLY accumulates in the cytoplasm. In contrast, the PLY-dependent execution of apoptosis requires phagocytosis and is part of a host response to intracellular bacteria that also includes NO generation. In cells challenged with PLY-deficient bacteria, reconstitution of LMP using the lysomotrophic detergent LeuLeuOMe favored cell necrosis whereas PLY reconstituted apoptosis. The results suggest that PLY contributes to macrophage activation and cytokine production but also engages LMP. Following bacterial phagocytosis, PLY triggers apoptosis and prevents macrophage necrosis as a component of a broad-based antimicrobial strategy. This illustrates how a key virulence factor can become the focus of a multilayered and coordinated innate response by macrophages, optimizing pathogen clearance and limiting inflammation. Importance: Streptococcus pneumoniae, the commonest cause of bacterial pneumonia, expresses the toxin pneumolysin, which can make holes in cell surfaces, causing tissue damage. Macrophages, resident immune cells essential for responses to bacteria in tissues, activate a program of cell suicide called apoptosis, maximizing bacterial clearance and limiting harmful inflammation. We examined pneumolysin's role in activating this response. We demonstrate that pneumolysin did not directly form holes in cells to trigger apoptosis and show that pneumolysin has two distinct roles which require only part of the molecule. Pneumolysin and other bacterial factors released by bacteria that have not been eaten by macrophages activate macrophages to release inflammatory factors but also make the cell compartment containing ingested bacteria leaky. Once inside the cell, pneumolysin ensures that the bacteria activate macrophage apoptosis, rather than necrosis, enhancing bacterial killing and limiting inflammation. This dual response to pneumolysin is critical for an effective immune response to S. pneumoniae. PMID- 25293760 TI - Septins arrange F-actin-containing fibers on the Chlamydia trachomatis inclusion and are required for normal release of the inclusion by extrusion. AB - Chlamydia trachomatis is an obligate intracellular human pathogen that grows inside a membranous, cytosolic vacuole termed an inclusion. Septins are a group of 13 GTP-binding proteins that assemble into oligomeric complexes and that can form higher-order filaments. We report here that the septins SEPT2, -9, -11, and probably -7 form fibrillar structures around the chlamydial inclusion. Colocalization studies suggest that these septins combine with F actin into fibers that encase the inclusion. Targeting the expression of individual septins by RNA interference (RNAi) prevented the formation of septin fibers as well as the recruitment of actin to the inclusion. At the end of the developmental cycle of C. trachomatis, newly formed, infectious elementary bodies are released, and this release occurs at least in part through the organized extrusion of intact inclusions. RNAi against SEPT9 or against the combination of SEPT2/7/9 substantially reduced the number of extrusions from a culture of infected HeLa cells. The data suggest that a higher-order structure of four septins is involved in the recruitment or stabilization of the actin coat around the chlamydial inclusion and that this actin recruitment by septins is instrumental for the coordinated egress of C. trachomatis from human cells. The organization of F actin around parasite-containing vacuoles may be a broader response mechanism of mammalian cells to the infection by intracellular, vacuole-dwelling pathogens. Importance: Chlamydia trachomatis is a frequent bacterial pathogen throughout the world, causing mostly eye and genital infections. C. trachomatis can develop only inside host cells; it multiplies inside a membranous vacuole in the cytosol, termed an inclusion. The inclusion is covered by cytoskeletal "coats" or "cages," whose organization and function are poorly understood. We here report that a relatively little-characterized group of proteins, septins, is required to organize actin fibers on the inclusion and probably through actin the release of the inclusion. Septins are a group of GTP-binding proteins that can organize into heteromeric complexes and then into large filaments. Septins have previously been found to be involved in the interaction of the cell with bacteria in the cytosol. Our observation that they also organize a reaction to bacteria living in vacuoles suggests that they have a function in the recognition of foreign compartments by a parasitized human cell. PMID- 25293761 TI - Nuclear herpesvirus capsid motility is not dependent on F-actin. AB - A considerable part of the herpesvirus life cycle takes place in the host nucleus. While much progress has been made to understand the molecular processes required for virus replication in the nucleus, much less is known about the temporal and spatial dynamics of these events. Previous studies have suggested that nuclear capsid motility is directed and dependent on actin filaments (F actin), possibly using a myosin-based, ATP-dependent mechanism. However, the conclusions from these studies were indirect. They either relied on the effects of F-actin depolymerizing drugs to deduce an F-actin dependency or they visualized nuclear F-actin but failed to show a direct link to capsid motility. Moreover, no direct link between nuclear capsid motility and a molecular motor has been established. In this report, we reinvestigate the involvement of F-actin in nuclear herpesvirus capsid transport. We show for representative members of all three herpesvirus subfamilies that nuclear capsid motility is not dependent on nuclear F-actin and that herpesvirus infection does not induce nuclear F-actin in primary fibroblasts. Moreover, in these cells, three F-actin-inhibiting drugs failed to effect capsid motility. Only latrunculin A treatment stalled nuclear capsids but did so by an unexpected effect: the drug induced actin rods in the nucleus. Immobile capsids accumulated around actin rods, and immunoprecipitation experiments suggested that capsid motility stopped because latrunculin-induced actin rods nonspecifically bind nuclear capsids. Interestingly, capsid motility was unaffected in cells that do not induce actin rods. Based on these data, we conclude that herpesvirus nuclear capsid motility is not dependent on F-actin. Importance: Herpesviruses are large DNA viruses whose replication is dependent on the host nucleus. However, we do not understand how key nuclear processes, including capsid assembly, genome replication, capsid packaging, and nuclear egress, are dynamically connected in space and time. Fluorescence live-cell microscopy revealed that nuclear capsids are highly mobile early in infection. Two studies suggested that this motility might be due to active myosin-based transport of capsids on nuclear F-actin. However, direct evidence for such motor based transport is lacking. We revisited this phenomenon and found no evidence that nuclear capsid motility depended on F-actin. Our results reopen the question of how nuclear herpesvirus capsids move in the host nucleus. PMID- 25293762 TI - Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals. AB - How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum beta-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. Importance: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to biocides and heavy metals. In this report, we show that very low concentrations of single antibiotics and heavy metals or combinations of compounds can select for a large plasmid that carries resistance to aminoglycosides, beta-lactams, tetracycline, macrolides, trimethoprim, sulfonamide, silver, copper, and arsenic. Our findings suggest that the low levels of antibiotics and heavy metals present in polluted external environments and in treated animals and humans could allow for selection and enrichment of bacteria with multiresistance plasmids and thereby contribute to the emergence, maintenance, and transmission of antibiotic-resistant disease causing bacteria. PMID- 25293764 TI - Randomized open-label pilot study of the influence of probiotics and the gut microbiome on toxic metal levels in Tanzanian pregnant women and school children. AB - Exposure to environmental toxins is a 21st century global health problem that is often the result of dietary intake. Although efforts are made to reduce dietary toxin levels, they are often unsuccessful, warranting research into novel methods to reduce host exposure. Food-grade microbes that can be delivered to the gastrointestinal tract and that are capable of sequestering toxins present a safe and cost-effective intervention. We sought to investigate the potential for probiotic-supplemented yogurt to lower heavy metal levels in at-risk populations of pregnant women and in children in Mwanza, Tanzania, and to examine the microbiome in relation to toxin levels. Two populations suspected to have high toxic metal exposures were studied. A group of 44 school-aged children was followed over 25 days, and 60 pregnant women were followed over their last two trimesters until birth. A yogurt containing 10(10) CFU Lactobacillus rhamnosus GR 1 per 250 g was administered, while control groups received either whole milk or no intervention. Changes in blood metal levels were assessed, and the gut microbiomes of the children were profiled by analyzing 16S rRNA sequencing via the Ion Torrent platform. The children and pregnant women in the study were found to have elevated blood levels of lead and mercury compared to age- and sex matched Canadians. Consumption of probiotic yogurt had a protective effect against further increases in mercury (3.2 nmol/liter; P = 0.035) and arsenic (2.3 nmol/liter; P = 0.011) blood levels in the pregnant women, but this trend was not statistically significant in the children. Elevated blood lead was associated with increases in Succinivibrionaceae and Gammaproteobacteria relative abundance levels in stool. Importance: Probiotic food produced locally represents a nutritious and affordable means for people in some developing countries to counter exposures to toxic metals. Further research and field trials are warranted to explore this approach in countries where communities are located near mining sites and agricultural areas, two types of areas where toxins are likely to be elevated. PMID- 25293763 TI - Bacterial nucleoid-associated protein uncouples transcription levels from transcription timing. AB - The histone-like nucleoid-structuring (H-NS) protein binds to horizontally acquired genes in the bacterium Salmonella enterica serovar Typhimurium, silencing their expression. We now report that overcoming the silencing effects of H-NS imposes a delay in the expression of genes activated by the transcriptional regulator PhoP. We determine that PhoP-activated genes ancestral to Salmonella are expressed before those acquired horizontally. This expression timing reflects the in vivo occupancy of the corresponding promoters by the PhoP protein. These results are surprising because some of these horizontally acquired genes reached higher mRNA levels than ancestral genes expressed earlier and were transcribed from promoters harboring PhoP-binding sites with higher in vitro affinity for the PhoP protein. Our findings challenge the often-made assumption that for genes coregulated by a given transcription factor, early genes are transcribed to higher mRNA levels than those transcribed at later times. Moreover, they provide a singular example of how gene ancestry can impact expression timing. Importance: We report that gene ancestry dictates the expression behavior of genes under the direct control of the Salmonella transcriptional regulator PhoP. That is, ancestral genes are transcribed before horizontally acquired genes. This reflects both the need to overcome silencing by the H-NS protein of the latter genes and the architecture of the corresponding promoters. Unexpectedly, transcription levels do not reflect transcription timing. Our results illustrate how a bacterium can exhibit an elaborate temporal expression behavior among genes coregulated by a transcription factor even though the products encoded by the target genes do not participate in a morphological or developmental pathway. PMID- 25293766 TI - Controllable synthesis of Ni/SiO2 hollow spheres and their excellent catalytic performance in 4-nitrophenol reduction. AB - The high cost of noble metal nanoparticles used for catalytic reduction of 4 nitrophenol (4-NP) leads to an extensive study of Ni nanoparticles (NPs) for their low cost and magnetic properties. However, the conventional routes for preparing the ferromagnetic Ni NPs usually lead to large particle size and aggregation. In this study, we propose a simple two-step method for the synthesis of hierarchical Ni NP supported silica magnetic hollow microspheres (Ni/SiO2 MHMs). Tiny Ni NPs are well dispersed on the supports with high loading amounts (15 wt%). The size of Ni NPs can be tuned from 10 nm to 21 nm with the size of Ni/SiO2 MHMs increasing from 230 nm to 800 nm. The as-prepared samples exhibit excellent catalytic activity in the reduction of 4-NP. Furthermore, the experimental results prove that the size of Ni NPs plays an important role in the catalytic activity. The catalytic activity of small sized Ni NPs is higher than that of large sized and many other supported Ni NP catalysts as reported. In particular, the magnetic properties of Ni/SiO2 MHMs make them easy to recycle for reuse. PMID- 25293765 TI - The crowding effect in Ancylostoma ceylanicum: density-dependent effects on an experimental model of infection. AB - This study compared the course of Ancylostoma ceylanicum infection in hamsters infected with different inocula and the consequences for the host and helminth populations. The average of adult worms recovered, according to the number of third stage larva used, were 28.0, 24.8, 24.6, and 24.8% to inocula size of 25 L3, 75 L3, 125 L3, and 250 L3, respectively. The size of the inoculum did not affect the establishment, survival, or fecundity of adult helminths. Reductions in the red blood cell and hemoglobin levels in the infected group were inversely proportional to the number of white blood cells. Moreover, differential cell counting revealed a positive correlation between the worm load and leucocyte numbers. The humoral response against excretion-secretion antigens was more robust and sensitive compared with the response against crude extract, with no direct linear correlation with the number of worms. The effect of the population density was more evident in females. PMID- 25293767 TI - Assessment of tolerance induction by Origanum vulgare L. essential oil or carvacrol in Pseudomonas aeruginosa cultivated in a meat-based broth and in a meat model. AB - This study assessed the efficacy of Origanum vulgare L. essential oil (OVEO) and carvacrol in inhibiting the growth of Pseudomonas aeruginosa ATCC 9027, as well as the development of direct tolerance and cross-tolerance when this bacterium was challenged with sublethal amounts of these substances in a meat-based broth and in a meat model. OVEO and carvacrol at their minimum inhibitory concentrations (MICs), 1/2 MIC and 1/4 MIC decreased the viable cell counts of P. aeruginosa in meat-based broth. Direct tolerance or cross-tolerance was not induced after exposure of the assayed bacterial strain to sublethal amounts of OVEO or carvacrol in meat-based broth and in an artificially contaminated ground beef. Bacterial cells progressively subcultured in meat-based broth with increasing amounts of the tested substances survived up to the MIC of OVEO and to 1/2 MIC of carvacrol. The results reveal a lack of induction of tolerance in P. aeruginosa by exposure to OVEO or carvacrol in meat-based broth and in a meat model. PMID- 25293768 TI - Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. AB - We conducted a prospective multicenter registry of 248 adult patients with immune thrombocytopenia (ITP) treated with rituximab to assess safety. We also assessed response and predictive factors of sustained response. In total, 173 patients received 4 infusions of 375 mg/m(2) and 72 received 2 fixed 1-g infusions 2 weeks apart. The choice of the rituximab regimen was based on the physician's preference and not patient characteristics. Overall, 38 patients showed minor intolerance to rituximab infusions; infusions had to be stopped for only 3 patients. Seven showed infection (n = 11 cases), with an incidence of 2.3 infections/100 patient-years. Three patients died of infection 12 to 14 months after rituximab infusions, but the role of rituximab was questionable. In total, 152 patients (61%) showed an overall initial response (platelet count >=30 * 10(9)/L and >=2 baseline value). At a median follow-up of 24 months, 96 patients (39%) showed a lasting response. On multivariate analysis, the probability of sustained response at 1 year was significantly associated with ITP duration <1 year (P = .02) and previous transient complete response to corticosteroids (P = .05). The pattern of response was similar with the 2 rituximab regimens. With its benefit/risk ratio, rituximab used off-label may remain a valid option for treating persistent or chronic ITP in adults. This trial was registered at www.clinicaltrials.gov as #NC1101295. PMID- 25293769 TI - PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression. AB - Tissue factor (TF) (CD142) is a 47 kDa transmembrane cell surface glycoprotein that triggers the extrinsic coagulation cascade and links thrombosis with inflammation. Although macrophage TF expression is known to be regulated at the RNA level, very little is known about the mechanisms involved. Poly(adenosine 5' diphosphate [ADP]-ribose)-polymerase (PARP)-14 belongs to a family of intracellular proteins that generate ADP-ribose posttranslational adducts. Functional screening of PARP-14-deficient macrophages mice revealed that PARP-14 deficiency leads to increased TF expression and functional activity in macrophages after challenge with bacterial lipopolysaccharide. This was related to an increase in TF messenger RNA (mRNA) stability. Ribonucleoprotein complex immunoprecipitation and biotinylated RNA pull-down assays demonstrated that PARP 14 forms a complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved adenylate-uridylate-rich element in the TF mRNA 3' untranslated region. TF mRNA regulation by PARP-14 was selective, as tumor necrosis factor (TNF)alpha mRNA, which is also regulated by TTP, was not altered in PARP-14 deficient macrophages. Consistent with the in vitro data, TF expression and TF activity, but not TNFalpha expression, were increased in Parp14(-/-) mice in vivo. Our study provides a novel mechanism for the posttranscriptional regulation of TF expression, indicating that this is selectively regulated by PARP-14. PMID- 25293771 TI - How I treat patients with massive hemorrhage. AB - Massive hemorrhage is associated with coagulopathy and high mortality. The transfusion guidelines up to 2006 recommended that resuscitation of massive hemorrhage should occur in successive steps using crystalloids, colloids, and red blood cells (RBCs) in the early phase and plasma and platelets in the late phase. With the introduction of the cell-based model of hemostasis in the mid-1990s, our understanding of the hemostatic process and of coagulopathy has improved. This has contributed to a change in resuscitation strategy and transfusion therapy of massive hemorrhage along with an acceptance of the adequacy of whole blood hemostatic tests to monitor these patients. Thus, in 2005, a strategy aiming at avoiding coagulopathy by proactive resuscitation with blood products in a balanced ratio of RBC:plasma:platelets was introduced, and this has been reported to be associated with reduced mortality in observational studies. Concurrently, whole blood viscoelastic hemostatic assays have gained acceptance by allowing a rapid and timely identification of coagulopathy along with enabling an individualized, goal-directed transfusion therapy. These strategies joined together seem beneficial for patient outcome, although final evidence on outcome from randomized controlled trials are lacking. We present how we in Copenhagen and Houston, today, manage patients with massive hemorrhage. PMID- 25293772 TI - Brentuximab vedotin. AB - Brentuximab vedotin is an anti-CD30 antibody-drug conjugate with proven efficacy in patients with CD30(+) malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma. Promising activity has also been seen in other lymphomas that express CD30. Because of its acceptable toxicity profile and significant clinical efficacy, single-agent brentuximab vedotin is an approved treatment for relapsed patients with these diseases. Brentuximab vedotin has safely been combined with chemotherapy and is now being compared with standard treatments in randomized trials. PMID- 25293770 TI - OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells. AB - Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9 mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL. PMID- 25293773 TI - Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma. AB - Advanced stage follicular lymphoma (FL) is incurable by conventional therapies. In the present pilot clinical trial, we explored the efficacy and immunogenicity of a novel in situ immunotherapeutic strategy. Fourteen patients with untreated or relapsed stage III/IV FL were included and received local radiotherapy to solitary lymphoma nodes and intranodal injections of low-dose rituximab (5 mg), immature autologous dendritic cells, and granulocyte-macrophage colony stimulating factor at the same site. The treatment was repeated 3 times targeting different lymphoma nodes. Primary end points were clinical responses and induction of systemic immunity. Five out of 14 patients (36%) displayed objective clinical responses, including 1 patient with cutaneous FL who showed regression of skin lesions. Two of the patients had durable complete remissions. Notably, the magnitude of vaccination-induced systemic CD8 T-cell-mediated responses correlated closely with reduction in total tumor area (r = 0.71, P = .006), and immune responders showed prolonged time to next treatment. Clinical responders did not have a lower tumor burden than nonresponders pretreatment, suggesting that the T cells could eliminate large tumor masses once immune responses were induced. In conclusion, the combined use of 3 treatment modalities, and in situ administration in single lymphoma nodes, mediated systemic T-cell immunity accompanied by regression of disseminated FL. The trial was registered at www.clinicaltrials.gov as #NCT01926639. PMID- 25293774 TI - CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells. AB - Dysregulated donor T cells lead to destruction of host tissues resulting in graft versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We investigated the impact of highly purified (>95%) donor CD4(+) invariant natural killer T (iNKT) cells on GVHD in a murine model of allogeneic HCT. We found that low doses of adoptively transferred donor CD4(+) iNKT cells protect from GVHD morbidity and mortality through an expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). These Tregs express high levels of the Ikaros transcription factor Helios and expand from the Treg pool of the donor graft. Furthermore, CD4(+) iNKT cells preserve T-cell-mediated graft-versus tumor effects. Our studies reveal new aspects of the cellular interplay between iNKT cells and Tregs in the context of tolerance induction after allogeneic HCT and set the stage for clinical translation. PMID- 25293775 TI - Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency. AB - A rare point mutation in the core promoter -270GC-rich box of PIGM, a housekeeping gene, disrupts binding of the generic transcription factor (TF) Sp1 and causes inherited glycosylphosphatidylinositol (GPI) deficiency (IGD). We show that whereas PIGM messenger RNA levels and surface GPI expression in IGD B cells are low, GPI expression is near normal in IGD erythroid cells. This divergent phenotype results from differential promoter chromatin accessibility and binding of Sp1. Specifically, whereas PIGM transcription in B cells is dependent on Sp1 binding to the -270GC-rich box and is associated with lower promoter accessibility, in erythroid cells, Sp1 activates PIGM transcription by binding upstream of (but not to) the -270GC-rich box. These findings explain intact PIGM transcription in IGD erythroid cells and the lack of clinically significant intravascular hemolysis in patients with IGD. Furthermore, they provide novel insights into tissue-specific transcriptional control of a housekeeping gene by a generic TF. PMID- 25293776 TI - Curing myeloma at last: defining criteria and providing the evidence. AB - Does the dogma that multiple myeloma is incurable still hold?. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of Total Therapy (TT) program. The TT approach uses all myeloma-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. Long-term follow-up of 1202 patients (TT1: n = 231, median follow-up: 21 years; TT2: 668, median follow-up: 12 years; TT3a: n = 303, median follow-up: 9 years) permitted investigation of whether progression free survival (PFS) and complete response (CR) duration were consistent with curability, ie observation of plateaus in Kaplan-Meier plots for PFS and CR duration. In the subset of 627 patients with plasma cell gene expression profiling data, cure plateaus were apparent at 5 years in the 14% with high-risk myeloma compared with 10 years in the remainder with low-risk disease. A parametric model based on PFS and CR duration supported an increase in curability: 10-year PFS and CR estimates increased from 8.8%/17.9% in TT1 to 15.5%/28.2% in TT2's control arm to 25.1%/35.6% in TT2's thalidomide arm and to 32.9%/48.8% in TT3a. Toward developing novel therapies, we recommend a concerted focus on patients with high-risk myeloma whose outcome has not been advanced. PMID- 25293777 TI - GPR84 sustains aberrant beta-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. AB - beta-catenin is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Targeted inhibition of beta-catenin signaling has been hampered by the lack of pathway components amenable to pharmacologic manipulation. Here we identified a novel beta-catenin regulator, GPR84, a member of the G protein-coupled receptor family that represents a highly tractable class of drug targets. High GPR84 expression levels were confirmed in human and mouse AML LSCs compared with hematopoietic stem cells (HSCs). Suppression of GPR84 significantly inhibited cell growth by inducing G1-phase cell-cycle arrest in pre LSCs, reduced LSC frequency, and impaired reconstitution of stem cell-derived mixed-lineage leukemia (MLL) AML, which represents an aggressive and drug resistant subtype of AML. The GPR84-deficient phenotype in established AML could be rescued by expression of constitutively active beta-catenin. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a-transduced stem cells. Microarray analysis demonstrated that GPR84 significantly upregulated a small set of MLL-fusion targets and beta-catenin coeffectors, and downregulated a hematopoietic cell-cycle inhibitor. Altogether, our data reveal a previously unrecognized role of GPR84 in maintaining fully developed AML by sustaining aberrant beta-catenin signaling in LSCs, and suggest that targeting the oncogenic GPR84/beta-catenin signaling axis may represent a novel therapeutic strategy for AML. PMID- 25293778 TI - BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. AB - Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(CK-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27(T187A)) or nuclear retention (p27(S10A)) attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization. PMID- 25293779 TI - Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. AB - Human platelets express 2 thrombin receptors: protease-activated receptor (PAR)-1 and PAR4. Recently, we reported 3.7-fold increased PAR4-mediated aggregation kinetics in platelets from black subjects compared with white subjects. We now show that platelets from blacks (n = 70) express 14% more PAR4 protein than those from whites (n = 84), but this difference is not associated with platelet PAR4 function. Quantitative trait locus analysis identified 3 common single nucleotide polymorphisms in the PAR4 gene (F2RL3) associated with PAR4-induced platelet aggregation. Among these single nucleotide polymorphisms, rs773902 determines whether residue 120 in transmembrane domain 2 is an alanine (Ala) or threonine (Thr). Compared with the Ala120 variant, Thr120 was more common in black subjects than in white subjects (63% vs 19%), was associated with higher PAR4-induced human platelet aggregation and Ca2+ flux, and generated greater inositol 1,4,5 triphosphate in transfected cells. A second, less frequent F2RL3 variant, Phe296Val, was only observed in blacks and abolished the enhanced PAR4-induced platelet aggregation and 1,4,5-triphosphate generation associated with PAR4 Thr120. PAR4 genotype did not affect vorapaxar inhibition of platelet PAR1 function, but a strong pharmacogenetic effect was observed with the PAR4-specific antagonist YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole]. These findings may have an important pharmacogenetic effect on the development of new PAR antagonists. PMID- 25293781 TI - Sexual activity and vaginal topography in women with symptomatic pelvic floor disorders. AB - INTRODUCTION: Pelvic floor disorders affect vaginal anatomy and may affect sexual function. AIMS: The aims of this study were to explore the relationship between vaginal anatomy and sexual activity in women with symptomatic pelvic floor disorders and to assess whether vaginal measurements (topography) correlate with sexual function. METHODS: This is a retrospective cohort study comparing sexually active and nonsexually active women planning urogynecologic surgery. Our primary outcome was the difference in vaginal topography based on Pelvic Organ Prolapse Quantification (POP-Q) exam between cohorts. Correlations between POP-Q measurements and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short form (PISQ-12) scores were assessed in sexually active women. MAIN OUTCOME MEASURE: The POP-Q is a quantitative and standardized examination for prolapse. The PISQ-12 is a condition-specific sexual function questionnaire validated in sexually active women with pelvic floor disorders. RESULTS: Of 535 women, 208 (39%) were sexually active and 327 (61%) were not. Median genital hiatus (GH) and perineal body (PB) measurements and a PB:GH ratio were not significantly different between the two cohorts. Total vaginal length (TVL) was longer in sexually active women (median 9 vs. 8 cm, P<0.001). In a linear regression analysis controlling for potential confounders, sexually active women still had a longer TVL by 0.4 cm (95% confidence interval 0.07, 0.6 cm) compared with those who were not sexually active. Of the 327 nonsexually active women, 28% indicated they avoided sexual activity because of pelvic floor symptoms. There was poor correlation between TVL, GH, PB, and PB : GH ratio with PISQ-12 scores (r=0.10, 0.05, -0.09, -0.03, respectively). CONCLUSIONS: In women with pelvic floor disorders, sexual activity is associated with a longer vaginal length. One quarter of women indicated they avoided sexual activity because of pelvic floor symptoms. Vaginal topography does not correlate with sexual function based on PISQ-12 scores. PMID- 25293782 TI - Spectrally matched duplexed nucleic acid bioassay using two-colors from a single form of upconversion nanoparticle. AB - Optical sensing can provide opportunity for simultaneous determination of multiple targets as well as for implementation of ratiometric methods that can improve accuracy and precision. Herein we report a paper-based two-color oligonucleotide detection assay with tunable sensitivity that is based on use of a single type of upconversion nanoparticle (UCNP). Water-soluble UCNPs were designed to concurrently offer green and red emission. These avidin functionalized UCNPs were adsorbed onto a cellulose support, and Cy3 was used as a green channel acceptor for Survival Motor Neuron (SMN1) target, and Cy5.5 was the red channel acceptor for the glucuronidase gene (uidA) target. Selective DNA hybridization of the labeled targets with the corresponding probe provided emission from dyes, which was the basis for concurrent quantification of both targets. The limit of detection (LOD) could be tuned by changing the relative ratio of the SMN1 and uidA probes. A higher proportion of a probe provided for a lower LOD. When the SMN1/uidA probe ratio was 1:4, the LOD for SMN1 and uidA target were 54.3 and 30.5 fmol, and when the probe ratio was 4:1, the LOD for the above targets were 22.1 and 1260 fmol, respectively. Selectivity evaluation showed that one base pair mismatched DNA for SMN1 and uidA could be discriminated in most cases. The assay showed resistance to nonspecific adsorption of interfering DNA and protein and was even functional for targets in undiluted serum. This work represents a significant step in the development of paper-based multiplexed UCNP luminescence assays. PMID- 25293780 TI - Exploiting the kinetic interplay between GPIbalpha-VWF binding interfaces to regulate hemostasis and thrombosis. AB - Platelet-von Willebrand factor (VWF) interactions must be tightly regulated in order to promote effective hemostasis and prevent occlusive thrombus formation. However, it is unclear what role the inherent properties of the bond formed between the platelet receptor glycoprotein Ibalpha and the A1 domain of VWF play in these processes. Using VWF-A1 knock-in mice with mutations that enhance (I1309V) or disrupt (R1326H) platelet receptor glycoprotein Ibalpha binding, we now demonstrate that the kinetic interplay between two distinct contact surfaces influences the site and extent to which platelets bind VWF. Incorporation of R1326H mutation into the major site shortened bond lifetime, yielding defects in hemostasis and thrombosis comparable to VWF-deficient animals. Similarly, disrupting this region of contact with an allosteric inhibitor impaired human platelet accrual in damaged arterioles. In contrast, the I1309V mutation near the minor site prolonged bond lifetime, which was essential for the development of a type 2B-like VWD phenotype. However, combining the R1326H and I1309V mutations normalized both bond kinetics and the hemostatic and thrombotic properties of VWF. These findings broaden our understanding of mechanisms governing platelet VWF interactions in health and disease, and underscore the importance of combined biophysical and genetic approaches in identifying potential therapeutic avenues for treating bleeding and thrombotic disorders. PMID- 25293783 TI - Mechanism of mast cell adhesion to human tenocytes in vitro. AB - Mast cells and fibroblasts are two key players involved in many fibrotic and degenerative disorders. In the present study we examined the nature of binding interactions between human mast cells and tendon fibroblasts (tenocytes). In the mast cell-fibroblast co-culture model, mast cells were shown to spontaneously bind to tenocytes, in a process that was partially mediated by alpha5beta1 integrin receptors. The same receptors on mast cells significantly mediated binding of these cells to tissue culture plates in the presence of tenocyte conditioned media; the tenocyte-derived fibronectin in the media was shown to also play a major role in these binding activities. Upon binding to tenocytes or tissue culture plates, mast cells acquired an elongated phenotype, which was dependent on alpha5beta1 integrin and tenocyte fibronectin. Additionally, tenocyte-derived fibronectin significantly enhanced mRNA expression of the adhesion molecule, THY1, by mast cells. Our data suggests that alpha5beta1 integrin mediates binding of mast cells to human tenocyte and to tenocyte-derived ECM proteins, in particular fibronectin. PMID- 25293785 TI - Implementing and evaluating a program to facilitate chronic disease prevention and screening in primary care: a mixed methods program evaluation. AB - BACKGROUND: The objectives of this paper are to describe the planned implementation and evaluation of the Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Primary Care (BETTER 2) program which originated from the BETTER trial. The pragmatic trial, informed by the Chronic Care Model, demonstrated the effectiveness of an approach to Chronic Disease Prevention and Screening (CDPS) involving the use of a new role, the prevention practitioner. The desired goals of the program are improved clinical outcomes, reduction in the burden of chronic disease, and improved sustainability of the health-care system through improved CDPS in primary care. METHODS/DESIGN: The BETTER 2 program aims to expand the implementation of the intervention used in the original BETTER trial into communities across Canada (Alberta, Ontario, Newfoundland and Labrador, the Northwest Territories and Nova Scotia). This proactive approach provides at-risk patients with an intervention from the prevention practitioner, a health-care professional. Using the BETTER toolkit, the prevention practitioner determines which CDPS actions the patient is eligible to receive, and through shared decision-making and motivational interviewing, develops a unique and individualized 'prevention prescription' with the patient. This intervention is 1) personalized; 2) addressing multiple conditions; 3) integrated through linkages to local, regional, or national resources; and 4) longitudinal by assessing patients over time. The BETTER 2 program brings together primary care providers, policy/decision makers and researchers to work towards improving CDPS in primary care. The target patient population is adults aged 40-65. The reach, effectiveness, adoption, implementation, maintain (RE-AIM) framework will inform the evaluation of the program through qualitative and quantitative methods. A composite index will be used to quantitatively assess the effectiveness of the prevention practitioner intervention. The CDPS actions comprising the composite index include the following: process measures, referral/treatment measures, and target/change outcome measures related to cardiovascular disease, diabetes, cancer and associated lifestyle factors. DISCUSSION: The BETTER 2 program is a collaborative approach grounded in practice and built from existing work (i.e., integration not creation). The program evaluation is designed to provide an understanding of issues impacting the implementation of an effective approach for CDPS within primary care that may be adapted to become sustainable in the non-research setting. PMID- 25293786 TI - Cooking increases net energy gain from a lipid-rich food. AB - Starch, protein, and lipid are three major sources of calories in the human diet. The unique and universal human practice of cooking has been demonstrated to increase the energy gained from foods rich in starch or protein. Yet no studies have tested whether cooking has equivalent effects on the energy gained from lipid-rich foods. Using mice as a model, we addressed this question by examining the impact of cooking on the energy gained from peanuts, a lipid-rich oilseed, and compared this impact against that of nonthermal processing (blending). We found that cooking consistently increased the energy gained per calorie, whereas blending had no detectable energetic benefits. Assessment of fecal fat excretion showed increases in lipid digestibility when peanuts were cooked, and examination of diet microstructure revealed concomitant alterations to the integrity of cell walls and the oleosin layer of proteins that otherwise shield lipids from digestive lipases. Both effects were consistent with the greater energy gain observed with cooking. Our findings highlight the importance of cooking in increasing dietary energy returns for humans, both past and present. PMID- 25293787 TI - Implantable hearing devices: the Ototronix MAXUM system. AB - For many hearing-impaired individuals, the benefits of conventional amplification may be limited by acoustic feedback, occlusion effect, and/or ear discomfort. The MAXUM system and other implantable hearing devices have been developed as an option for patients who derive inadequate assistance from traditional HAs, but who are not yet candidates for cochlear implants. The MAXUM system is based on the SOUNDTEC Direct System technology, which has been shown to provide improved functional gain as well as reduced feedback and occlusion effect compared to hearing aids. This and other implantable hearing devices may have increasing importance as future aural rehabilitation options. PMID- 25293788 TI - Effectiveness of combined (131)I-chTNT and radiofrequency ablation therapy in treating advanced hepatocellular carcinoma. AB - To investigate the effectiveness of monoclonal antibody ((131)I-chTNT) and radiofrequency ablation (RFA) combination therapy in treating middle-advanced stage hepatocellular carcinoma (HCC). Thirty-four patients diagnosed with HCC patients, divided into two groups comprised of 22 and 12 cases were included in this retrospective study. The two groups received RFA with or without ((131)I chTNT) therapy, respectively. The patients in these groups were followed up for a median of 31 and 35 months, respectively. Patient survival was evaluated using Kaplan-Meier method and safety profiles were determined by analyzing liver, thyroid, and bone marrow toxicities. This retrospective study showed that survival time of the patients who received combination therapy was significantly longer than that of the RFA group (P = 0.052). The median progress-free survival of patients in the two groups was 23 and 7 months, respectively, and the difference was significant (P = 0.04). Tumor recurred in 3.5-8.7 months in four of the combination group patients, among which three had newly developed lesions. The red blood cells and platelets counts were not altered on day 7 and 1 month of the treatment, however, number of white blood cells was significantly increased on day 7 which was reversed back to the normal range in 2 weeks. The ALT and AST were also not significantly altered on day 7 and 1 month of therapy. In middle advanced stage HCC patients, the combination of (131)I-chTNT and RFA therapy was found to be significantly more effective than the RFA treatment alone as assessed in short-term follow-up. However, the dose we used was insufficient to completely block the local recurrence of the lesions with a diameter of 5 cm or larger. PMID- 25293789 TI - Activated protein C resistance testing for factor V Leiden. AB - Activated protein C resistance assays can detect factor V Leiden with high accuracy, depending on the method used. Factor Xa inhibitors such as rivaroxaban and direct thrombin inhibitors including dabigatran, argatroban, and bivalirudin can cause falsely normal results. Lupus anticoagulants can cause incorrect results in most current assays. Assays that include dilution into factor V deficient plasma are needed to avoid interference from factor deficiencies or elevations, which can arise from a wide variety of conditions such as warfarin, liver dysfunction, or pregnancy. The pros and cons of the currently available assays are discussed. PMID- 25293790 TI - Long-term risks of kidney donation: age known. PMID- 25293791 TI - Regioselective C-F bond activation of hexafluoropropylene on palladium(0): formation of a cationic eta(2) -perfluoroallylpalladium complex. AB - A chemoselective C(sp(2) )?F or C(sp(3) )?F bond activation of hexafluoropropylene (HFP) was achieved by adopting the proper combination of a Lewis acid co-additive with a ligand which coordinates Pd(0) . The treatment of [(eta(2) -HFP)Pd(PCy3 )2 ] with B(C6 F5 )3 allowed a chemoselective C(sp(3) )?F bond cleavage of HFP to give a unique cationic perfluoroallypalladium complex. In this complex, the coordination mode of the perfluoroallyl ligand was considered to be of the unique eta(2) -fashion. PMID- 25293793 TI - [Clinical study on patients with renal-cell carcinoma accompanied with Von Hippel Lindau disease treated with radiofrequency ablation]. AB - We report 12 renal cell carcinomas in 6 patients with Von Hippel-Lindau (VHL) disease treated with radiofrequency ablation (RFA). The mean age of the patients was 46 (range 38-53) years (male : 4, female : 2). Computed tomography (CT) guided transcutaneous RFA was performed under conscious sedation with local anesthetics. The mean size of the tumors was 2.4 (range 0.7-8.1) cm. Nine of the 12 tumors (75%) were locally well controlled. However, 3 tumors in 2 patients developed visceral metastases after RFA. While minimal flank pain, nausea, perinephritic hematoma and lumbago were observed, there was no major complication during or after the procedure. The therapy with CT-guided transcutaneous RFA is efficient and minimal invasive for renal cell carcinoma in patients with VHL, leading to preservation of renal function. PMID- 25293794 TI - [Sharing information of urological cancer patient in terminal stage using Cybozulive(r) for home medical care]. AB - It is very important to share patient information because home patient care involves several different specialties of care. We introduced Cybozulive (r) , a cloud-based free groupware, for 14 terminal-stage patients with urological cancer to share information among doctors and co-medical staff. This system enables access to patient information regardless of time and place. Of the 14 patients (mean age 74.4 years), 11 died of cancer. The average period in which Cybozulive(r) was used for the patients was 210 days. The average number of entries to the electronic bulletin board in this period was 88.4. We were able to obtain more information about the patients from the website. There was no difference in the average number of times that the patient consulted the out patient clinic before and after the introduction of Cybozulive(r) (before 7.0 ; after 6.3). After introduction of this system, eleven patients were hospitalized in our department 21 times. Eighteen of these 21 times, since we had acquired patient information from the website beforehand, there was a quick response for management of the emergency admission. This system could be used to construct a network for home care and may be helpful for sharing patient information in homecare. PMID- 25293792 TI - Biofilms constructed for the removal of hydrocarbon pollutants from hypersaline liquids. AB - Hydrocarbonoclastic biofilms were established on sterile glass plates vertically submerged for 1 month in a hypersaline soil/water suspension containing 0.3% crude oil. The culture-dependent analysis of the microbial community in those biofilms revealed hydrocarbonoclastic species in the magnitude of 10(3) cells cm( 2). Those species belonged to the halophilic bacterial genera Marinobacter, Halomonas, Dietzia, Bacillus, Arhodomonas, Aeromonas and Kocuria as well as to the haloarchaeal genera Haloferax and Halobacterium. Those organisms were not evenly distributed over the biofilm surface area. The culture-independent analysis revealed a different community composition, which was based on four uncultured and four cultured taxa. Depending on the culture conditions and the sort of chemical amendments, the biofilms succeeded in removing in 2 weeks up to about 60-70% of crude oil, pure n-hexadecane and pure phenanthrene in hypersaline pond water samples. The amendment with KCl, MgSO4 and a vitamin mixture composed of thiamin, pyridoxine, vitamin B12, biotin, riboflavin and folic acid was most effective. PMID- 25293795 TI - [Six cases of renal collecting duct carcinoma]. AB - We treated 6 patients with renal collecting duct carcinoma (CDC) in our hospital from December 2004 to December 2011. We compared clinico-pathological findings among all patients. The median age was 58 years (range, 37-77 years). Hematuria, back pain, and fatigue were observed in 5 patients with CDC. Five patients were pathologically diagnosed by radical nephrectomy while a patient was diagnosed by percutaneous renal biopsy without radical nephrectomy. Lymph node metastasis and distant metastasis were observed at diagnosis in 3 and 2 patients, respectively. Five of the 6 patients received systemic therapy after surgery, cytokine therapy in 2 patients, systemic chemotherapy in a patient, and molecular-targeting therapy in 2 patients, respectively. The median overall survival was 15 months (range, 1-44 months). Overall, the 1- and 3-year survival rates were 67 and 33%, respectively. Most of the patients had symptomatic advanced disease at diagnosis. Even though nephrectomy was performed, systemic treatment was not effective in such patients. PMID- 25293796 TI - [Renal arteriovenous fistula (AVF) following nephrectomy : a case of arterial embolization treatment]. AB - The patient was a 78-year-old female. At the age of 76, the patient had undergone computed tomographic scanning for left lower abdominal pain. A retroperitoneal mass was detected on the right side of the abdomen. The patient had been subject to right nephrectomy due to renal calculus at the age of 33. With Doppler echocardiography and magnetic resonance imaging (MRI), based on the nephrectomy the patient was diagnosed with a renal arteriovenous fistula developed in the right renal bed. Following the wishes of the patient a follow-up examination was conducted. Because of poor heart condition and renal dysfunction, percutaneous arterial embolization was performed. After the embolization, the heart condition and renal dysfunction indicators improved and the blood flow in the arteriovenous fistula disappeared. Cases of renal arteriovenous fistulae after nephrectomy are rare, with only 90 reported worldwide, and percutaneous arterial embolization has been used as the first choice of treatment in recent years. PMID- 25293797 TI - [Long survival in a patient with advanced ureteral carcinoma treated with TIN regimen (paclitaxel, ifosfamide, nedaplatin) and radiotherapy : a case report]. AB - A 69-year-old man diagnosed with right ureteral carcinoma pT3N0M1 (PUL) underwent nephroureterectomy. He was treated with MVAC chemotherapy (methotrexate, vinblastin, adriamycin, cisplatin), but local recurrence and right pelvic lymph node metastasis occurred. Radiotherapy to both metastatic lesions was well tolerated, but the pulmonary metastases increased. After treatment with TIN chemotherapy (paclitaxel, ifosfamide and nedaplatin), pulmonary metastases almost disappeared. He was treated with radiotherapy to remaining pulmonary metastasis. Now 7 years after operation, pulmonary metastasis appears to have diminished. PMID- 25293798 TI - [A case of neuroendocrine carcinoma in a diverticulum of the bladder]. AB - We report a case of neuroendocrine carcinoma in a diverticulum of the bladder. A 65-year-old Japanese woman visited our hospital with the chief complaint of gross hematuria. Cystoscopy revealed a non-papillary broad-based tumor in a diverticulum of the posterior wall. She underwent transurethral resection of bladder tumor (TURBT) and subsequently total cystectomy with ileal conduit on the diagnosis of an invasive urothelial carcinoma. There was no residual tumor in the surgical specimen. Immunohistochemistry of TUR specimens showed positive synaptophysin, chromogranin A, CD56 and high ratio of positive Ki-67. Finally, it was diagnosed as a neuroendocrine carcinoma of the bladder. To our knowledge, this is the second case report of the neuroendocrine tumor or small cell carcinoma in a diverticulum of the urinary bladder in the Japanese literature. PMID- 25293799 TI - [A case of percutaneous BCG perfusion therapy for CIS of upper urinary tract CIS after radical cystectomy with ileal neobladder]. AB - We report a case of percutaneous bacillus Calmette-Guerin (BCG) perfusion therapy for carcinoma in situ (CIS) of upper urinary tract after radical cystectomy with ileal neobladder. A 42-year-old man underwent radical cystectomy and ileal neobladder diversion due to the recurrence of CIS in prostatic urethra after transurethral resection of bladder tumor 3 times and 2 courses of intravesical BCG therapy. Final pathological findings showed the presence of CIS in the right distal ureteral margin. After the radical cystectomy, our diagnosis was CIS in the right residual ureter, because of positive urine cytology and negative radiographic findings in the upper urinary tract. We performed the percutaneous BCG perfusion therapy for CIS of the right upper urinary tract after the construction of the percutaneous nephrostomy by intentionally inducing hydronephrosis. No recurrence was found after 3 years of BCG perfusion therapy. PMID- 25293800 TI - [A case report of eosinophilic cystitis treated with oral suplatast tosilate]. AB - A 61-year-old female was referred to our hospital presenting with micturition pain and urinary frequency, which was not relieved by antibiotics. A cystoscopic examination revealed an erosion, reddening and edematous lesion in the left bladder wall. Pathological examination of transurethral biopsy showed erosion and cystitis. After biopsy, micturition pain and urinary frequency became worse. The pathological examination was reviewed, and the diagnosis of eosinophilic cystitis was made. Administration of a corticosteroid had provided a short duration of relief, but her symptoms recurred within the five weeks of treatment. Therefore, she was treated with a combination of corticosteroid and suplatast tolilate, followed by monotherapy with suplatast tolilate. The relief of the symptoms by suplatast to lilate therapy continued for five months. However, the symptoms relapsed. Re-administration of steroidal agents was considered, but the patient suffered from uncontrolled diabetes. Therefore, she was treated with a combination of suplatast tosilate, anti-allergic drugs and mirabegron. Fourteen months after treatment with suplatast tosilate, no disease progression was noted. PMID- 25293801 TI - [A case of advanced prostate fibrosarcoma that reacted well to chemotherapy]. AB - Prostate fibrosarcoma is an extremely rare tumor for which complete excision has been the mainstay of treatment. Although chemotherapy has been attempted in cases with positive surgical margins and/or advanced stage disease, the effectiveness of this therapy has not been established. Herein, we report a case of advanced prostate fibrosarcoma that reacted well to chemotherapy. A 40-year-old man was referred for treatment of a large prostatic tumor with multiple lung, liver, and bone metastases. Needle biopsy of the prostate revealed that the tumor was a high grade undifferentiated sarcoma. Chemotherapy with doxorubicin and ifosfamide was administered. After five courses of chemotherapy, the primary prostate tumor decreased markedly, and the lung and liver metastases almost disappeared. Radical cystoprostatectomy and ileal conduit formation were performed. Pathological diagnosis was fibrosarcoma. Another three courses of doxorubicin and ifosfamide therapy were performed, and doxorubicin was replaced by etoposide because the maximum dose of doxorubicin was reached. However, the effectiveness of the second line therapy was poor, and the tumor progressed again. The patient died of lung metastasis 15 months later. PMID- 25293802 TI - [Giant subcutaneous hematoma with hemorrhagic shock induced by goserelin acetate injection for prostate cancer : report of a case]. AB - A 87-year-old man was diagnosed with prostate cancer (cT2aN0M0 Gleason score 4+4 with initial prostate specific antigen of 23.4 ng/ml). Prostate cancer was treated with combined androgen blockade (goserelin acetate plus flutamide). He was administered goserelin acetate depot injection without any complications as an outpatient. However, 5 hours after he left the hospital, he came back to the hospital, complaining of lower abdominal pain. Abdominal computed tomography revealed a giant subcutaneous hematoma in the lower abdomen. Hemoglobin was 6.9 g/dl and blood pressure was lower than 80 mmHg. He was admitted and given a blood transfusion. Because of pre-disseminated intravascular coagulation score 6, it was hard to antagonize warfarin by Vitamin K (he had taken warfarin because of atrial fibrillation). Arteriography was performed and injury to a branch of the lower epigastric artery was found. Transcatheter arterial embolization was performed at the same time. Injecting goserelin acetate may cause severe arterial injury. PMID- 25293803 TI - Prescribing practices of primary-care veterinary practitioners in dogs diagnosed with bacterial pyoderma. AB - BACKGROUND: Concern has been raised regarding the potential contributions of veterinary antimicrobial use to increasing levels of resistance in bacteria critically important to human health. Canine pyoderma is a frequent, often recurrent diagnosis in pet dogs, usually attributable to secondary bacterial infection of the skin. Lesions can range in severity based on the location, total area and depth of tissue affected and antimicrobial therapy is recommended for resolution. This study aimed to describe patient signalment, disease characteristics and treatment prescribed in a large number of UK, primary-care canine pyoderma cases and to estimate pyoderma prevalence in the UK vet-visiting canine population. RESULTS: Of 54,600 dogs presented to 73 participating practices in 2010, 683 (1.3%) had a pyoderma diagnosis recorded in available electronic patient record (EPR) data. Antimicrobials were dispensed in 97% of cases and most dogs were prescribed systemic therapy (92%). Agents most frequently prescribed were amoxicillin-clavulanate, cefalexin, clindamycin and cefovecin. Systemic antimicrobials were prescribed for fewer than 14 days in around 40% of study cases reviewed in detail. Prescribed daily doses were below minimum recommended daily dose (MRDD) in 26% of 43 dogs with sufficient information for calculation of minimum dose. CONCLUSIONS: Antimicrobial prescribing behaviour for treatment of canine pyoderma was variable but frequently appeared inconsistent with current recommendations. Use of clinical data from primary practice EPRs can provide valuable insight into common clinical conditions and associated prescribing. PMID- 25293806 TI - Gene expression analysis of histamine receptors in peripheral blood mononuclear cells from individuals with clinically-isolated syndrome and different stages of multiple sclerosis. AB - Along with their established role in allergic reactions, histamine and its receptors have been implicated in the pathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis. In this study we analyzed the gene expression of histamine receptor 1 (HRH1), HRH2 and HRH4 in peripheral blood mononuclear cells derived from patients with clinically isolated syndrome (CIS), relapsing-remitting (RR) MS, secondary-progressive (SP) MS, primary-progressive (PP) MS, and healthy controls (HC). We found that HRH1 transcript was significantly down-modulated in SP-MS compared with HC, and HRH4 was increased in this group compared to HC, CIS and RR-MS. No other differences in the expression of histamine receptors were observed between HC, CIS and other clinical forms of definite MS. PMID- 25293805 TI - Inducing RNA interference in the arbovirus vector, Culicoides sonorensis. AB - Biting midges in the genus Culicoides are important vectors of arboviral diseases, including epizootic haemorrhagic disease, bluetongue and most likely Schmallenberg, which cause significant economic burdens worldwide. Research on these vectors has been hindered by the lack of a sequenced genome, the difficulty of consistent culturing of certain species and the absence of molecular techniques such as RNA interference (RNAi). Here, we report the establishment of RNAi as a research tool for the adult midge, Culicoides sonorensis. Based on previous research and transcriptome analysis, which revealed putative small interfering RNA pathway member orthologues, we hypothesized that adult C. sonorensis midges have the molecular machinery needed to perform RNA silencing. Injection of control double-stranded RNA targeting green fluorescent protein (dsGFP), into the haemocoel of 2-3-day-old adult female midges resulted in survival curves that support virus transmission. dsRNA injection targeting the newly identified C. sonorensis inhibitor of apoptosis protein 1 (CsIAP1) orthologue resulted in a 40% decrease of transcript levels and 73% shorter median survivals as compared with dsGFP-injected controls. These results reveal the conserved function of IAP1. Importantly, they also demonstrate the feasibility of RNAi by dsRNA injection in adult midges, which will greatly facilitate studies of the underlying mechanisms of vector competence in C. sonorensis. PMID- 25293807 TI - CD19 mRNA quantification improves rituximab treatment-to-target approach: a proof of concept study. AB - We compared pre-amplification (PA) RT-PCR blood CD19 mRNA quantification with flow cytometry (FC), to personalize rituximab re-treatment in neuromyelitis optica spectrum disorders (NMOSDs) patients. 47 blood samples from 3 NMOSDs patients were studied. PA-RT-PCR quantified CD19 in all samples, and a positivity threshold was defined, whereas CD19+ B cells were under threshold in 31/47 samples by FC. In all samples where CD19+ B cells were above FC threshold, they resulted above the PA-RT-PCR threshold. CD19 mRNA was above threshold in 8 other samples, resulted negative by FC, and preceded the FC positivity in 7/8 samples by 1-3 months, showing major sensitivity. PMID- 25293808 TI - Nanostructured organosilicon luminophores and their application in highly efficient plastic scintillators. AB - Organic luminophores are widely used in various optoelectronic devices, which serve for photonics, nuclear and particle physics, quantum electronics, medical diagnostics and many other fields of science and technology. Improving their spectral-luminescent characteristics for particular technical requirements of the devices is a challenging task. Here we show a new concept to universal solution of this problem by creation of nanostructured organosilicon luminophores (NOLs), which are a particular type of dendritic molecular antennas. They combine the best properties of organic luminophores and inorganic quantum dots: high absorption cross-section, excellent photoluminescence quantum yield, fast luminescence decay time and good processability. A NOL consists of two types of covalently bonded via silicon atoms organic luminophores with efficient Forster energy transfer between them. Using NOLs in plastic scintillators, widely utilized for radiation detection and in elementary particles discoveries, led to a breakthrough in their efficiency, which combines both high light output and fast decay time. Moreover, for the first time plastic scintillators, which emit light in the desired wavelength region ranging from 370 to 700 nm, have been created. We anticipate further applications of NOLs as working elements of pulsed dye lasers in photonics, optoelectronics and as fluorescent labels in biology and medical diagnostics. PMID- 25293809 TI - Dithienopyrrole as a rigid alternative to the bithiophene pi relay in chromophores with second-order nonlinear optical properties. AB - 4H-Pyranylidene-containing push-pull chromophores built around a bithiophene (BT) pi relay or a rigidified thiophene-based unit, namely cyclopenta[1,2-b:3,4 b']dithiophene (CPDT) or dithieno[3,2-b:2',3'-d]pyrrole (DTP), have been synthesized and characterized. The effect of these different relays on the polarization and the second-order nonlinear optical (NLO) properties has been studied. For the sake of comparison, the corresponding reported dithieno[3,2 b:2',3'-d]thiophene (DTT) derivatives have also been included in the discussion. Replacement of the BT core by a rigidified unit (CPDT, DTP) leads to more polarized systems. Calculated NBO charges and electrochemical measurements show that dithienopyrrole has a remarkable donor character that allows an important charge transfer between the donor and the acceptor. The influence of the rigidification of the BT relay on the NLO responses depends on the acceptor strength. For the weakest acceptor used (thiobarbituric acid), passing from the BT relay to the rigidified units always involves an increase in the MUbeta0 figure of merit. Nevertheless, for the strongest acceptor (2-dicyanomethylene-3 cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF)), a slight increase in MUbeta0 with respect to the BT chromophore is only observed for the DTP derivative. Thus, rigidification of the BT core is not enough to improve the second-order nonlinearity and the incorporation of a DTP moiety has proven to be the most efficient approach for this purpose. PMID- 25293804 TI - Cancer evolution: mathematical models and computational inference. AB - Cancer is a somatic evolutionary process characterized by the accumulation of mutations, which contribute to tumor growth, clinical progression, immune escape, and drug resistance development. Evolutionary theory can be used to analyze the dynamics of tumor cell populations and to make inference about the evolutionary history of a tumor from molecular data. We review recent approaches to modeling the evolution of cancer, including population dynamics models of tumor initiation and progression, phylogenetic methods to model the evolutionary relationship between tumor subclones, and probabilistic graphical models to describe dependencies among mutations. Evolutionary modeling helps to understand how tumors arise and will also play an increasingly important prognostic role in predicting disease progression and the outcome of medical interventions, such as targeted therapy. PMID- 25293810 TI - Combined impact of high body mass index and in vitro fertilization on preeclampsia risk: a hospital-based cohort study. AB - OBJECTIVES: Overweight and obese women may be heavy users of in vitro fertilization (IVF) owing to obesity-related oligo-anovulation. The higher doses of gonadotropins required to achieve pregnancy in obese women may contribute to impaired placentation and the development of preeclampsia. This study was designed to assess the combined effect of high maternal body mass index (BMI) and IVF on risk of preeclampsia and to evaluate for an interaction between the two factors. METHODS: This is a hospital-based cohort study of 10,013 singleton pregnancies that delivered from 2001 to 2008 at a tertiary hospital in Montreal, Canada. The combined effect of high BMI and IVF on preeclampsia versus no risk factors was estimated in multivariate logistic regression models fitted with an interaction term between high BMI (> 25 or > 30 kg/m(2) ) and IVF. RESULTS: IVF pregnancies in obese women had a considerably higher risk of preeclampsia than spontaneous nonobese pregnancies (OR 6.7, 95% CI 3.3-13.8; p interaction 0.03). IVF was not independently associated with preeclampsia (OR 0.6, 95% CI 0.3-1.4). Analyses were similar in subgroup analyses and in analyses correcting for bias. CONCLUSIONS: High BMI is strongly associated with preeclampsia, and this risk is compounded in IVF pregnancies. PMID- 25293811 TI - Can currently available advanced combustion biomass cook-stoves provide health relevant exposure reductions? Results from initial assessment of select commercial models in India. AB - Household air pollution from use of solid fuels is a major contributor to the national burden of disease in India. Currently available models of advanced combustion biomass cook-stoves (ACS) report significantly higher efficiencies and lower emissions in the laboratory when compared to traditional cook-stoves, but relatively little is known about household level exposure reductions, achieved under routine conditions of use. We report results from initial field assessments of six commercial ACS models from the states of Tamil Nadu and Uttar Pradesh in India. We monitored 72 households (divided into six arms to each receive an ACS model) for 24-h kitchen area concentrations of PM2.5 and CO before and (1-6 months) after installation of the new stove together with detailed information on fixed and time-varying household characteristics. Detailed surveys collected information on user perceptions regarding acceptability for routine use. While the median percent reductions in 24-h PM2.5 and CO concentrations ranged from 2 to 71% and 10-66%, respectively, concentrations consistently exceeded WHO air quality guideline values across all models raising questions regarding the health relevance of such reductions. Most models were perceived to be sub-optimally designed for routine use often resulting in inappropriate and inadequate levels of use. Household concentration reductions also run the risk of being compromised by high ambient backgrounds from community level solid-fuel use and contributions from surrounding fossil fuel sources. Results indicate that achieving health relevant exposure reductions in solid-fuel using households will require integration of emissions reductions with ease of use and adoption at community scale, in cook-stove technologies. Imminent efforts are also needed to accelerate the progress towards cleaner fuels. PMID- 25293813 TI - Proteomic pattern changes associated with obesity-induced asthenozoospermia. AB - Obesity, an increasingly frequent societal disease can also be accompanied by declines in spermatozoa quality and male subfecundity. To determine if there are obesity-associated proteomic changes potentially affecting sperm quality and motility, differential proteomic analysis was performed on spermatozoa from both obesity-associated asthenozoospermia and clinically healthy individuals, using a label-free quantitative LC-MS/MS approach. We resolved 1975 proteins in the human sperm proteome, amongst which, 105 proteins were less abundant, whereas 22 other proteins increased in obesity-associated asthenozoospermia. Functional category analyses indicated that the differentially expressed proteins are mainly related to cytoskeletal regulation, vesicle biogenesis, metabolism, and protein degradation involved in spermiogenesis and sperm motility. Furthermore, declines in endoplasmic reticulum protein 57 (ERp57) and actin-binding-related protein T2 (ACTRT2) expression were verified by immunofluorescence, Western blot, and flow cytometry analyses. It is evident that ERp57 is localized in the acrosome region, neck and principal piece of human spermatozoa, whereas ACTRT2 is localized in the post-acrosomal region and middle piece. Thus, these differences in protein expression in asthenozoospermia may contribute to the underlying sperm quality defects afflicting these individuals. Notably, declines in ERp57 and ACTRT2 expression in obesity-associated asthenozoospermia may play critical roles in reducing sperm motility. PMID- 25293812 TI - Vaginal hysterectomy for uterovaginal prolapse: what is the incidence of concurrent gynecological malignancy? AB - INTRODUCTION AND HYPOTHESIS: Vaginal hysterectomy (VH) is a commonly performed procedure for the operative treatment of uterovaginal prolapse (UVP). The reported incidence of unexpected gynecological cancer in cases of VH for UVP ranges between 0.3 and 0.8 %. Aim of the study is to assess the incidence of malignant and premalignant gynecological histopathological findings among women who underwent a VH for UVP and had a normal preoperative workup. METHODS: The histopathology reports of women who underwent VH for the treatment of UVP were retrospectively assessed. All women had a history of normal cervical smear tests and a normal preoperative transvaginal scan. Patients with a history of a premalignant or malignant gynecological pathological condition and women with abnormal uterine bleeding were excluded. RESULTS: Overall, 14 out of 333 women who underwent VH (4.2 %) were found to have abnormal histopathological findings of the uterus. Among them, there were 9 cases of endometrial hyperplasia of any type (2.7 %), 1 case of cervical cancer (0.3 %), 1 case of cervical intraepithelial neoplasia (CIN) III (0.3 %), and 3 cases of CINI (0.9 %). No cases of endometrial cancer were detected. Among women who underwent salpingo oophorectomy (n = 86) three simple serous cysts (3.5 %) were found, with no cases of ovarian cancer. CONCLUSIONS: The incidence of unexpected premalignant or malignant gynecological pathological conditions among asymptomatic women who underwent VH, with a history of normal cervical smear tests and normal preoperative TVS, was low but not negligible. This information should be included in the preoperative counseling of women planning to undergo surgery for UVP. PMID- 25293814 TI - X-ray and ultraviolet C irradiation-induced gamma-H2AX and p53 formation in normal human periosteal cells in vitro: markers for quality control in cell therapy. AB - BACKGROUND AIMS: For successful cell transplantation therapy, the quality of cells must be strictly controlled. Unfortunately, to exclude inappropriate cells that possess structurally abnormal chromosomes, currently only karyotyping functions as an assessment. Unfortunately, this methodology is time-consuming and only effective for metaphasic cells. To develop a more efficient, inclusive and sensitive methodology, we examined the phosphorylation of histone H2AX and the p53 levels in normal human periosteal cells exposed to x-rays or other oxidative stressors. METHODS: Periosteal cells were obtained from human alveolar bone before being exposed to x-rays, ultraviolet C or hydrogen peroxide. The cell cycle, electric nuclear volume and CD44 expression were evaluated using flow cytometry, and the phosphorylated H2AX (gamma-H2AX), p53, p21 and proliferating cell nuclear antigen (PCNA) levels were evaluated by Western blot analyses. RESULTS: Each oxidative stress dose-dependently arrested cell growth and partially induced premature cellular senescence. In parallel, each oxidative stress rapidly phosphorylated H2AX and stabilized p53, and intense stress sustained these high levels for at least 8 days. CONCLUSIONS: Intensive oxidative stress induces sustained high levels of gamma-H2AX and p53, which force cells toward senescence or non-apoptotic cell death. Lower doses of oxidative stress induced more modest and transient increases in gamma-H2AX and p53, and these cells eventually survive. However, because DNA is repaired without a template in the majority of these cells, G1 mutations accumulate. Therefore, we recommend that any cell population expressing elevated gamma-H2AX and p53 levels be excluded from cell transplantation therapy. PMID- 25293815 TI - The effect of isolation and culture methods on epithelial stem cell populations and their progeny-toward an improved cell expansion protocol for clinical application. AB - BACKGROUND AIMS: The use of cultured epithelial keratinocytes in the treatment of burns and skin graft donor sites is well established in clinical practice. The most widely used culture method for clinical use was originally developed by Rheinwald and Green 40 years ago. This system uses irradiated mouse dermal fibroblasts as a feeder cell layer to promote keratinocyte growth, a process that is costly and labor-intensive for health care providers. The medium formulation contains several components of animal origin, which pose further safety risks for patients. Improvements and simplification in the culturing process would lead to clear advantages: improved safety through reduction of xenobiotic components and reduction in cost for health care providers by dispensing with feeder cells. METHODS: We compared the Rheinwald and Green method to culture in three commercially available, feeder-free media systems with defined/absent components of animal origin. RESULTS: During the isolation process, short incubation times in high-strength trypsin resulted in increased numbers of liberated keratinocyte stem cells compared with longer incubation times. All three commercially available media tested in this study could support the expansion of keratinocytes, with phenotypes comparable to cells expanded using the established Rheinwald and Green method. Growth rates varied, with two of the media displaying comparable growth rates, whereas the third was significantly slower. DISCUSSION: Our study demonstrates the suitability of such feeder-free media systems in clinical use. It further outlines a range of techniques to evaluate keratinocyte phenotype when assessing the suitability of cells for clinical application. PMID- 25293816 TI - The puzzling situation of hospital exemption for advanced therapy medicinal products in Europe and stakeholders' concerns. PMID- 25293817 TI - Frustrated Lewis pair catalyzed hydrosilylation and hydrosilane mediated hydrogenation of fulvenes. AB - The frustrated Lewis pair (FLP) mediated hydrosilylation of pentafulvenes is described yielding allyl silanes with high regioselectivity in excellent yields. While phenyl substituted allyl silanes undergo B(C6F5)3-mediated rearrangement to vinyl silanes, dimethyl derivatives experience FLP-catalyzed hydrogenation followed by an unprecedented protodesilylation. This observation allowed the metal-free hydrogenation of 6,6-dimethylfulvene to iso-propyl cyclopentene according to a FLP-catalyzed triple domino reaction consisting of hydrosilylation, hydrogenation and protodesilylation. The mechanisms were investigated by deuteration experiments. PMID- 25293818 TI - Ultra low-dose of gadobenate dimeglumine for late gadolinium enhancement (LGE) imaging in acute myocardial infarction: a feasibility study. AB - PURPOSE: To assess the feasibility of using an ultra-low dose (0.05 mmol/kg of body weight [BW]) of high relaxivity contrast agent for late gadolinium enhancement (LGE) imaging in patients with acute myocardial infarction (AMI). MATERIALS AND METHODS: 17 consecutive patients (mean age, 60.1 +/- 10.3 years) with ST-segment elevation AMI underwent two randomized cardiac magnetic resonance studies (exam intervals between 24 and 48h) on a 1.5T unit during the first week after the event using gadobenate dimeglumine (Gd-BOPTA) at the dose of 0.1 mmol/kg BW (standard dose or SD group) and 0.05 mmol/kg BW (half dose or HD group). Image quality was qualitatively assessed. Quantitative analysis of LGE were performed by measuring signal intensity (SI), signal-to-noise ratio (SNR) in the infarcted myocardium (IM), non-infarcted myocardium (N-IM) and left ventricular cavity (LVC) in images acquired at 1, 3, 5, 10, 15 and 20 min after administration of Gd-BOPTA using both contrast media protocol. Contrast-to-noise ratio (CNR) between IM and N-IM (CNR IM/N-IM) and between IM and LVC (CNR IM/LVC) were also quantified for each time point. Moreover the extent of infarcted myocardium was measured. RESULTS: 102 LGE images were evaluated for each dose group. Quality score was significantly higher for SD at 1, 15 and 20 min (0.002=200 ERCPs/year) and 7 low-volume endoscopists (LVEs). Radiation exposure for each ERCP was adjusted against a validated procedure complexity scale and the Stanford Fluoroscopy Complexity Score, which was created based on the numbers of interventions that would mandate additional radiation exposure. RESULTS: ERCPs performed by LVEs were associated with a significantly higher median total radiation dose (98.30 mGy vs 74.13 mGy), dose area product (13.98 Gy-cm(2) vs 8.8 Gy-cm(2)), and effective dose (3.63 mSv vs 2.28 mSv), despite lower median Stanford Fluoroscopy Complexity Scores (3.0 vs 6.0) compared with HVEs. No significant difference was noted in median fluoroscopy time (4.0 minutes vs 3.30 minutes) between LVEs and HVEs. LIMITATIONS: Retrospective, single-center study at a tertiary referral center. CONCLUSION: ERCPs performed by LVEs are associated with significantly higher radiation exposure to patients compared with those performed by HVEs despite the fact that procedures performed by HVEs are of greater complexity. PMID- 25293826 TI - Endoscopic optical coherence tomography as a tool to evaluate successful myotomy after a peroral endoscopic myotomy. PMID- 25293827 TI - Factors associated with false-positive and false-negative fecal immunochemical test results for colorectal cancer screening. AB - BACKGROUND: Certain subgroups have higher rates of false fecal immunochemical test (FIT) results, yet few studies have addressed this topic. OBJECTIVE: To identify demographic factors associated with false-positive and false-negative FIT results in colorectal cancer screening. DESIGN: Retrospective database review of prospectively collected data. SETTING: A bowel cancer screening center in Hong Kong invited participants for colorectal cancer screening (2008-2012). PATIENTS: Study participants who underwent both FIT and colonoscopy in the first year (n = 4482) and underwent colonoscopy after negative FIT results for 3 consecutive years (n = 857). MAIN OUTCOME MEASUREMENTS: The diagnostic accuracy and predictive values of FIT according to participant characteristics. RESULTS: The sensitivity, specificity, positive predictive values, and negative predictive values for advanced neoplasia were 33.1%, 91.9%, 19.0%, and 96.0%, respectively. Participants 66 to 70 years of age had higher sensitivity, whereas older age, smoking, and use of aspirin/nonsteroidal anti-inflammatory drugs were associated with lower specificity. The rates of false-positive and false-negative results were 8.1% and 66.9%, respectively. Older age (66-70 years; adjusted odds ratio [AOR] 1.95; 95% confidence interval [CI], 1.35-2.81; P < .001), smoking (AOR 1.68; 95% CI, 1.08-2.61; P = .020), and the presence of polypoid adenoma (AOR 1.71; 95% CI, 1.14-2.57; P = .009) were associated with false-positive results. Younger participants (AOR for elderly participants 0.31) and the use of aspirin/nonsteroidal anti-inflammatory drugs (AOR 4.44) in participants with 1 FIT with negative results and the absence of high-grade dysplasia (AOR for presence 0.41) were associated with false-negative results. LIMITATIONS: Self referred participants who received one type of qualitative FIT. CONCLUSION: These findings could be used to target screening more toward those with a higher risk of false-negative results and those with a lower risk of false-positive results for earlier colonoscopy. PMID- 25293828 TI - Duodenal perforation secondary to migrated biliary stent in a liver transplant patient: successful endoscopic closure with an over-the-scope clip. PMID- 25293830 TI - Health behaviour interventions should not neglect people with serious mental health problems. PMID- 25293833 TI - Ordered mesoporous ZSM-5 employing an imidazolium-based ionic liquid. AB - Hierarchically porous ZSM-5 was achieved by using a simple bottom-up strategy combining zeolite seeds with imidazolium-based ionic liquids. The bimodal ZSM-5 with hexagonal arranged mesopores (3 nm) shows important activity in the acid catalysis of bulky compounds relative to conventional ZSM-5. PMID- 25293829 TI - Development and validation of the PROcedural Sedation Assessment Survey (PROSAS) for assessment of procedural sedation quality. AB - BACKGROUND: More than 20 million invasive procedures are performed annually in the United States. The vast majority are performed with moderate sedation or deep sedation, yet there is limited understanding of the drivers of sedation quality and patient satisfaction. Currently, the major gap in quality assurance for invasive procedures is the lack of procedural sedation quality measures. OBJECTIVE: To develop and validate a robust, patient-centered measure of procedural sedation quality, the PROcedural Sedation Assessment Survey (PROSAS). DESIGN: Through a series of interviews with patients, proceduralists, nurses, anesthesiologists, and an interactive patient focus group, major domains influencing procedural sedation quality were used to create a multipart survey. The pilot survey was administered and revised in sequential cohorts of adults receiving moderate sedation for GI endoscopy. After revision, the PROSAS was administered to a validation cohort. SETTING: GI endoscopy unit. PATIENTS: A expert panel of proceduralists, nurses, and anesthesiologists, an initial survey development cohort of 40 patients, and a validation cohort of 858 patients undergoing sedation for outpatient GI endoscopy with additional surveys completed by the gastroenterologist, procedure nurse, and recovery nurse. MAIN OUTCOMES AND MEASUREMENTS: Survey characteristics of the PROSAS. RESULTS: Patients were able to independently complete the PROSAS after procedural sedation before discharge. Of the patients, 91.6% reported minimal discomfort; however, 8.4% of patients reported significant discomfort and 2.4% of patients experienced hemodynamic and/or respiratory instability. There was a high correlation between patient reported intraprocedure discomfort and both clinician assessments of procedural discomfort and patient recall of procedural pain 24 to 48 hours post procedure (P < .001 for all), suggesting high external validity. LIMITATIONS: Single-center study, variability of sedation technique between providers, inclusion of patients with chronic pain taking analgesics. CONCLUSIONS: The PROSAS is a clinically relevant, patient-centered, easily administered instrument that allows for standardized evaluation of procedural sedation quality. The PROSAS may be useful in both research and clinical settings. PMID- 25293834 TI - Treatment of severe fear of childbirth with haptotherapy: design of a multicenter randomized controlled trial. AB - BACKGROUND: About six percent of pregnant women suffer from severe fear of childbirth. These women are at increased risk of obstetric labour and delivery interventions and pre- and postpartum complications, e.g., preterm delivery, emergency caesarean section, caesarean section at maternal request, severe postpartum fear of childbirth and trauma anxiety. During the last decade, there is increasing clinical evidence suggesting that haptotherapy might be an effective intervention to reduce fear of childbirth in pregnant women. The present study has been designed to evaluate the effects of such intervention. METHODS/DESIGN: Included are singleton pregnant women with severe fear of childbirth, age >= 18 year, randomised into three arms: (1) treatment with haptotherapy, (2) internet psycho-education or (3) care as usual. The main study outcome is fear of childbirth. Measurements are taken at baseline in gestation week 20-24, directly after the intervention is completed in gestation week 36, six weeks postpartum and six months postpartum. Secondary study outcomes are distress, general anxiety, depression, somatization, social support, mother-child bonding, pregnancy and delivery complications, traumatic anxiety symptoms, duration of delivery, birth weight, and care satisfaction. DISCUSSION: The treatment, a standard haptotherapeutical treatment for pregnant women with severe fear of childbirth, implies teaching a combination of skills in eight one hour sessions. The internet group follows an eight-week internet course containing information about pregnancy and childbirth comparable to childbirth classes. The control group has care as usual according to the standards of the Royal Dutch Organisation of Midwives and the Dutch Organization of Obstetrics and Gynaecology. TRIAL REGISTRATION: This trial was entered in the Dutch Trial Register and registered under number NTR3339 on March 4th, 2012. PMID- 25293835 TI - The safety of functional analyses of self-injurious behavior. AB - Functional analysis is the most precise method of identifying variables that maintain self-injurious behavior (SIB), and its use may lead to more effective treatment. One criticism and potential limitation of a functional analysis is that it may unnecessarily expose individuals to a higher risk of injury (Betz & Fisher, 2011). The purpose of this study was to determine if there were higher levels and severity of injury during the functional analysis than outside the functional analysis. We conducted a retrospective records review of 99 participants admitted to an inpatient unit for the treatment of SIB. The results showed that injury rates were relatively low across all situations and that when injuries occurred, they were usually not severe. These findings suggest that the functional analysis of SIB is relatively safe when appropriate precautions are taken. PMID- 25293836 TI - An update on overweight and obesity in rural Northeast China: from lifestyle risk factors to cardiometabolic comorbidities. AB - BACKGROUND: Not enough is known about the prevalence of overweight and obesity in rural China in the current decade. We aim to update our knowledge of the prevalence of obesity and its associated risk factors and comorbidities in a large population sample in rural Northeast China. METHODS: A population-based survey of 11,579 participants aged 35 years and older was conducted in rural areas of Liaoning Province during 2012-2013. Anthropometric measurements, information on health-related variables and blood biochemical indexes were collected by well-trained personnel. RESULTS: The prevalence of general obesity and overweight was found to be 7.8% and 37.2%, respectively. The overall prevalence of abdominal obesity was 15.1%. Female gender, ethnic minority, middle school education and a family income of 5,000-20,000 CNY per year were found to be risk factors for general obesity, while older age, female gender, ethnic minority and longer sleep duration (>8 h/d) increased the risk of abdominal obesity, after adjusting for confounders. Overweight and obese participants had significantly higher risks to develop prehypertension, hypertension, high LDL-C and low HDL-C compared with normal weight participants, while abdominal obesity was associated with increased risks of diabetes and high TG after adjusted for multiple factors. Compared with participants with a normal BMI and no abdominal obesity, the participants classified as abdominally obese and normal BMI; as abdominally obese and overweight; and abdominally obese and generally obese each had a progressive increase in the odds of hypertension (OR: 1.961, 95% CI: 1.154 to 3.331, OR: 2.744, 95% CI: 2.126 to 3.541, and OR: 8.990, 95% CI: 5.858 to 13.795, respectively) and high TG (OR: 3.165, 95% CI: 2.183 to 4.588, OR: 3.980, 95% CI: 3.332 to 4.755, and OR: 4.340, 95% CI: 3.574 to 5.271, respectively). CONCLUSIONS: The prevalence of obesity in rural Northeast China exhibited a remarkably increasing upwards trend. General and abdominal obesity were associated with different subtypes of cardiometabolic comorbidities, the combined effects of which on the comorbidities dramatically increased. PMID- 25293838 TI - Do not count too slowly: evidence for a temporal limitation in short-term memory. AB - Some data in the time perception literature have indicated that Weber's law for time does not hold: The Weber fraction gets higher with longer intervals. It is posited that this increase may reflect a fundamental information-processing limitation. If that is true, counting at a pace at which the intervals between counts remain within this capacity limitation should be more accurate than counting with intervals exceeding this capacity. In a task in which participants had to count up to a target number for a series of trials, the variability of the durations covered for reaching the target was higher when the intercount interval lasted 1,600 ms than when it lasted 800 ms. This finding provides evidence pointing toward the existence of a fundamental temporal limitation for processing information efficiently. PMID- 25293837 TI - Chronic intermittent ethanol exposure and withdrawal alters (3alpha,5alpha)-3 hydroxy-pregnan-20-one immunostaining in cortical and limbic brain regions of C57BL/6J mice. AB - BACKGROUND: The GABAergic neuroactive steroid (3alpha,5alpha)-3-hydroxy-pregnan 20-one (3alpha,5alpha-THP; allopregnanolone) has been studied during withdrawal from ethanol (EtOH) in humans, rats, and mice. Serum 3alpha,5alpha-THP levels decreased, and brain levels were not altered following acute EtOH administration (2 g/kg) in male C57BL/6J mice; however, the effects of chronic intermittent ethanol (CIE) exposure on 3alpha,5alpha-THP levels have not been examined. Given that CIE exposure changes subsequent voluntary EtOH drinking in a time-dependent fashion following repeated cycles of EtOH exposure, we conducted a time-course analysis of CIE effects on 3alpha,5alpha-THP levels in specific brain regions known to influence drinking behavior. METHODS: Adult male C57BL/6J mice were exposed to 4 cycles of CIE to induce EtOH dependence. All mice were sacrificed and perfused at 1 of 2 time points, 8 or 72 hours following the final exposure cycle. Free-floating brain sections (40 MUm; 3 to 5 sections/region/animal) were immunostained and analyzed to determine relative levels of cellular 3alpha,5alpha THP. RESULTS: Withdrawal from CIE exposure produced time-dependent and region specific effects on immunohistochemical detection of 3alpha,5alpha-THP levels across cortical and limbic brain regions. A transient reduction in 3alpha,5alpha THP immunoreactivity was observed in the central nucleus of the amygdala 8 hours after withdrawal from CIE (-31.4 +/- 9.3%). Decreases in 3alpha,5alpha-THP immunoreactivity were observed 72 hours following withdrawal in the medial prefrontal cortex (-25.0 +/- 9.3%), nucleus accumbens core (-29.9 +/- 6.6%), and dorsolateral striatum (-18.5 +/- 6.0%), while an increase was observed in the CA3 pyramidal cell layer of the hippocampus (+42.8 +/- 19.5%). Sustained reductions in 3alpha,5alpha-THP immunoreactivity were observed at both time points in the lateral amygdala (8 hours -28.3 +/- 12.8%; 72 hours -27.5 +/- 12.4%) and in the ventral tegmental area (8 hours -26.5 +/- 9.9%; 72 hours -31.6 +/- 13.8%). CONCLUSIONS: These data suggest that specific neuroadaptations in 3alpha,5alpha THP levels may be present in regions of brain that mediate anxiety, stress, and reinforcement relevant to EtOH dependence. The changes that occur at different time points likely modulate neurocircuitry involved in EtOH withdrawal as well as the elevated drinking observed after CIE exposure. PMID- 25293839 TI - Prevalence of Salmonella spp. and Yersinia enterocolitica in/on tonsils and mandibular lymph nodes of slaughtered pigs. AB - A total of 156 tonsils and 156 mandibular lymph nodes from fattening pigs originating from 13 farms were sampled in Croatian slaughterhouses and examined for Salmonella spp. (n=78 per organ) and Yersinia enterocolitica (n=78 per organ) by cultural methods. Salmonella was isolated from two tonsils only, both originated from animals from the same farm (5.12%), while Y. enterocolitica were recovered from 26 tonsils (33.33%) which could be traced back to 10 farms. Salmonella was absent in mandibular lymph nodes, and Y. enterocolitica was isolated from eight lymph nodes (10.25%) which originated from six farms. Y. enterocolitica was present inside the lymph nodes of two pigs. The high prevalence of Y. enterocolitica in/on pig tonsils could be the result of cross contamination during splitting the carcasses with head. This procedure may result in higher prevalence of Y. enterocolitica on surface of mandibular lymph nodes than in their depth. Traditional veterinary postmortem examination of pig halves will not necessarily contribute to cross-contamination with Salmonella or Yersinia under conditions of present slaughter practice. PMID- 25293840 TI - Cervical dilatation thresholds for initiation of group B streptococcus antibiotic prophylaxis for women with spontaneous preterm labor. AB - OBJECTIVE: To determine the optimal time for initiating group B streptococcus (GBS) antibiotic prophylaxis for women in spontaneous preterm labor. METHODS: In total, 227 women delivering singleton infants after presenting with spontaneous preterm labor and intact membranes at 24 0/7-36 6/7 weeks were evaluated, as well as 150 undelivered women with threatened preterm labor during the same time period. The date and time of each cervical examination throughout labor were recorded. We calculated the percentages who would have correctly received at least 4 h of GBS prophylaxis if antibiotics were routinely initiated for various cervical dilatation thresholds during labor, as well as the percentage of undelivered women who would have received unnecessary antibiotic exposure at each cervical dilatation cutoff. RESULTS: Delaying antibiotics until cervical dilatation reached 2 cm or greater would have resulted in 62.1% receiving four or more hours of antibiotics, compared to 66.5% if antibiotics were started on all women at admission (p = 0.33), while significantly reducing unnecessary antibiotic exposure in undelivered women from 100% to 62.0% (p < 0.001). The 2-cm threshold was applicable regardless of gestational age period or prior vaginal delivery >= 20 weeks. CONCLUSIONS: GBS antibiotic prophylaxis may reasonably be withheld for women with suspected preterm labor until the cervix reaches 2 cm or greater at any time during labor. PMID- 25293841 TI - [In Process Citation]. PMID- 25293842 TI - [In Process Citation]. PMID- 25293843 TI - [E-cigarettes also contain detrimental chemicals]. AB - This article reviews studies dealing with the content of electronic (e-) cigarettes. Based on measurements of the e-juice, the inhaled and the exhaled vapour, it is sound to assume that smoking e-cigarettes might have much less detrimental health effects than smoking conventional cigarettes. However, propylene glycol and glycerine are abundant in e-cigarettes and although they are generally perceived as relatively harmless, the long-term effects of heavy exposure to these substances are unknown. PMID- 25293844 TI - [Health consequences of smoking electronic cigarettes are poorly described]. AB - Despite increasing popularity, health consequences of vaping (smoking electronic cigarettes, e-cigarettes) are poorly described. Few studies suggest that vaping has less deleterious effects on lung function than smoking conventional cigarettes. One large study found that e-cigarettes were as efficient as nicotine patches in smoking cessation. The long-term consequences of vaping are however unknown and while some experts are open towards e-cigarettes as a safer way of satisfying nicotine addiction, others worry that vaping in addition to presenting a health hazard may lead to an increased number of smokers of conventional cigarettes. PMID- 25293845 TI - [Data from automated external defibrillators provide important information on the quality of in-hospital resuscitation]. AB - International guidelines recommend monitoring the outcome following in-hospital cardiac arrest. Using data from automatic external defibrillators (AED) prospectively collected during a three-year period in a regional hospital, we evaluated the treatment quality of resuscitation. Time to defibrillation was acceptable, but quality of chest compressions did not comply with current international recommendations. AED use led to a high fraction of time with no chest compressions. Survival to discharge was 11%. Consequently, training in basic and advanced life support of hospital staff has been modified. PMID- 25293846 TI - [Estimation of burn injuries]. AB - Estimation of acute burn injuries is known to be difficult, but a thorough and precise evaluation is essential in order to initiate relevant treatment. The initial estimation relates to the size, depth and localisation of the injury as well as a number of concomitant factors. This article reviews the literature concerning the initial evaluation of burns and highlights the areas, which most often cause difficulties. The initial treatment and the types of burn injuries needing referral to specialist care are summarized. PMID- 25293847 TI - [Pharmacotherapy effectiveness for some symptoms of borderline personality disorder]. AB - A high percentage of patients with borderline personality disorder (BPD) are prescribed psychotropic medications. Recent meta-analyses of randomized controlled trials suggested evidence of effects of antiepileptics on impulsivity and anger and of atypical antipsychotics on cognitive-perceptual symptoms and anger. Antidepressants had no or negligible effect. Total BPD severity was not significantly reduced by pharmacotherapy. Longitudinal studies suggest that BPD tends to improve, but it is not clarified whether long-term pharmacotherapy make the naturalistic recovery occur more rapidly. PMID- 25293848 TI - [Endovascular treatment of ruptured abdominal aortic aneurysm]. AB - Endovascular treatment of ruptured abdominal aortic aneurysms (REVAR) is increasingly used. Retrospective pooled data indicate that REVAR is associated with decreased morbidity and mortality, but in two small randomized clinical trials this has not been evidenced. However, REVAR seems associated with lower total costs and better long-term survival rates than open surgical repair. Consequently, REVAR could be at least as good a treatment as open surgery in suitable patients, when local facilities and expertise exist. PMID- 25293849 TI - [Endovascular repair of a ruptured abdominal aortic aneurysm]. AB - Endovascular repair of ruptured aortic aneurysm (REVAR) has been used worldwide in high volume centres since 1994. Observational studies indicate that this treatment modality is equally as good as or maybe even better than open surgery. Until recently, open surgery was the only treatment option in Denmark, but since 2012 REVAR has been introduced at Odense University Hospital and is now performed around the clock in eligible patients. We present a case report of the first patient in Denmark treated with REVAR and briefly discuss complications, prognosis and cost-effectiveness. PMID- 25293850 TI - [Rape of men happens too]. AB - The Department of Forensic Medicine, Copenhagen, perform clinical forensic examinations of sexually assaulted victims at the request of the police. Three cases with male victims are presented and the forensic focus in these cases is discussed. It is important to report lesions and to secure saliva and semen for DNA analysis correctly to form an important part of the subsequent police investigation and ultimately the legal proceeding. We believe that rape of men is underreported, and that more information can help men initially with reporting to the police and help focusing on the right prophylaxis for this group. PMID- 25293851 TI - [Cowper's syringocele as cause of low urinary tract symptoms in a young man]. AB - Cowper's syringocele (CS) is a very rare deformity of male urethra causing obstructive voiding symptoms. This case presents a 39-year-old man suffering from classical low urinary tract symptoms for five years, though without nocturia. The work-up showed normal prostate-specific antigen level, benign conditions by digital rectal examination, and normal-sized prostate on ultrasound. An urodynamic study showed outlet resistance and a supplementary ultrasound of prostate indicated a cyst structure around it. The magnetic resonance imaging confirmed a CS. Marsupialisation is the treatment of choice and was implemented. PMID- 25293852 TI - [Dislocation of the ankle without simoustaneously fracture of the bones]. AB - The ankle is a unique modified saddle joint that, together with the subtalar joint, provides range of motion in several physical planes while maintaining stability. The ankle complex functions as a pivoting structure positioned to bear the entire weight of the body which leaves it vulnerable to injuries. Pure dislocation without associated fracture is rare; however, cases of isolated ankle dislocation without fracture have been reported. We report a case of a closed ankle dislocation without an associated fracture in a 17-year-old boy. PMID- 25293853 TI - [Exercise can be an addiction]. AB - Exercise is normally a healthy activity, which leads to enjoyment and wellness. But some people appear to become addicted and continue to exercise even to the detriment of their social lives and health. The symptoms are e.g. increasing exercise amounts, withdrawal symptoms, euphoria and relapse. The Exercise Addiction Inventory is a screening tool validated in Danish, which identifies 3 10% of the exercisers at risk of addiction. Exercise addiction can be a symptom of an eating disorder, but it seems to exist independently though it is not recognized as a diagnosis. PMID- 25293854 TI - [Manedens billede]. PMID- 25293855 TI - [Simultaneous bilateral peripheral facial paralysis is a rare variant of Guillain Barre syndrome]. AB - This case report describes a 63-year-old male presenting with five days progressing bilateral peripheral facial paralysis and mild sensory symptoms. Cerebrospinal fluid showed albumin-cytological dissociation. Nerve conduction studies showed slightly reduced conduction velocity, slightly prolonged F-wave latency and temporal dispersion. Following treatment with IV immunoglobulin (0.4 g/kg/day for five consecutive days) recovery was prominent, though incomplete. This is believed to be the first described case in Denmark of the very rare variant of Guillain-Barre syndrome termed "facial diplegia and paraesthesias". PMID- 25293856 TI - [The use of pre-hospital tourniquets in life-threatening in extremity traumas]. AB - Tourniquets have been used for centuries. They have been called lifesavers and "an invention of the evil one". 90.9% of deaths on the battlefields result from haemorrhage. Lessons learned du-ring the wars in Iraq and Afghanistan have developed the treat-ment given to hypovolaemic patients on the battlefield. Treating bleeding and hypovolaemia is now considered as the primary intervention. The tourniquet has proven to be an indis-pensable tool treating wounded soldiers, with little risk of complications. The tourniquet might also show to be a valuable asset in a pre-hospital urban setting. PMID- 25293857 TI - [Inhaled corticosteroid treatment increases the risk of pneumonia in patients with CPOD]. AB - Clinical studies have suggested that inhaled corticosteroid (ICS) increases the frequency of pneumonia in patients with chronic obstructive pulmonary disease (COPD). This article summarizes the risk of pneumonia by reviewing the largest clinical studies addressing pneumonia as an adverse effect of ICS treatment. The collected data show that treatment of COPD patients with ICS increases the rate of pneumonia compared with b2-agonists or placebo. Physicians are recommended to follow guidelines and solely treat COPD patients with ICS if the patients are at high risk of exacerbations. PMID- 25293858 TI - [Osteoporosis often occurs in Parkinson's disease patients]. AB - The risk of developing osteoporosis, as well as Parkinson's disease (PD) is increased with increasing age, resulting in increased risk of fracture, particularly hip fractures. Each one of these two conditions can be debilitating and affect the individual patient's quality of life negatively. PD patients have higher risk of developing osteoporosis and hip fracture compared to those without PD because of lower bone mineral density (BMD) and lack of vitamin D. Prevention of fracture in PD patients should include fall-risk screening, BMD measurements by DXA scan and screening for risk factors for osteoporosis. PMID- 25293859 TI - [Screening mammography may be a rapid and effective investigation of mamma cancer in asymptomatic women]. AB - The purpose of this article was to describe the incidence of mamma cancer and ductal carcinoma in situ (DCIS) two years after a screening mammography in women offered a screening mammography instead of a clinical mammography. The mammography was abnormal for 6.3% of the women, 0.1% had DCIS and 1.0% was diagnosed with mamma cancer. 1.0% of women with a normal mammography were diagnosed with cancer within two years of the mammography. More widespread use of screening mammography may contribute to a rapid and effective investigation of mamma cancer in asymptomatic women. PMID- 25293860 TI - [Paediatric palliative care in Denmark should be strengthened]. AB - Paediatric palliative care is the total care for the child's body, mind and spirit, and involves support to the family. It begins when a life-threatening disease is diagnosed and depends on an interdisciplinary team approach. In 2013, 295 children under the age of 16 years died in Denmark. Of these, 195 were less than one year old. Most children and their families may prefer death at home if possible. Early planning allows for better integration of home-care services and ensures that death occurs at the place that is best for the child and family. PMID- 25293861 TI - [Prevention of hospital-acquired hyponatremia]. AB - The hospitalized patient is at risk of hyponatraemia caused by reduced electrolyte free water clearance and prescription of hypotonic fluids. Hospital acquired hyponatraemia is common and associated with increased mortality/morbidity. Hyponatraemia in itself can cause severe cerebral symptoms. Small decreases in P-[Na+] in patients with reduced intracranial compliance (e.g. meningitis) can be dangerous. To reduce iatrogenic hyponatraemia the understanding of P-[Na+] is fundamental. Next, meticulously prescription of fluid amount/quality and reevaluation as with any other drug is of paramount importance. PMID- 25293862 TI - [Virus infections are important in acute asthma exacerbations]. AB - Upper respiratory tract infections with common virusses is the most frequent cause of asthma exacerbations. Numerous defects in both epithelial function, pathogen recognition and innate immune signalling has been demonstrated in patients with asthma. The subject of this review is these recent findings and the potential therapeutic targets that are being identified. PMID- 25293863 TI - [Clear cell adenocarcinoma of the uterine cervix in a 17-year-old girl]. AB - Clear cell adenocarcinoma of the uterine cervix (CCEA) is a rare disease, accounting for only 1% of all cervical cancers. The disease in young women is linked to diethylstilbestrol (DES) exposure in utero. Following the ban of DES in 1979, CCEA rarely occurs in young women, but still remains a challenge in diagnosis and fertility preservation. We report on a 17-year-old girl, unexposed to DES, diagnosed with clear cell adenocarcinoma in a cervical polyp. PMID- 25293864 TI - [Preoperative assessment and optimization]. AB - Identification of patients with high risk for post-operative complications is instrumental in all surgical specialities. Proper identification can in some cases lead to preoperative or intraoperative optimization resulting in reduced morbidity and morbidity. Several scoring systems exist for assessing overall mortality risk. Preoperative functional tests and biochemical risk markers have shown to be effective in predicting post-operative medical complications and mortality. Optimization can be done by medical interventions, improved anaesthesiological care and optimization directed towards improved communication in the surgical team. PMID- 25293865 TI - In vivo visualization of prostate-specific membrane antigen in glioblastoma. PMID- 25293866 TI - (68)Ga-PSMA ligand PET versus (18)F-NaF PET: evaluation of response to (223)Ra therapy in a prostate cancer patient. PMID- 25293867 TI - Nonalcoholic fatty liver disease vs. obesity on the risk of erosive oesophagitis. AB - BACKGROUND: Erosive oesophagitis (EE) may be complicated by oesophageal ulcers, peptic stricture, Barrett's oesophagus and oesophageal adenocarcinoma. There have been few studies examining the influence of nonalcoholic fatty liver disease (NAFLD) on EE, and even fewer exploring the simultaneous effects of NAFLD, general and central obesity on EE. We thus aim to clarify the relationship between NAFLD and EE when general and/or central obesity are considered simultaneously. MATERIALS AND METHODS: In this cross-sectional study, we enrolled 12 090 subjects who underwent a health check-up at the Health Examination Center of a university hospital between January 2000 and August 2009 for analysis. NAFLD was diagnosed using liver ultrasound and EE was defined according to the Los Angeles classification by oesophagogastroduodenoscopy. RESULTS: Subjects with EE (1922; 15.9%) had a higher proportion of NAFLD, general and central obesity. With adjustment for age, gender, hypertension, diabetes mellitus, hiatal hernia, hypertriglyceridemia, high-density lipoprotein cholesterol, alcohol consumption, tea drinking, smoking and habitual exercise, the results of the multivariate analyses showed that general obesity, central obesity and NAFLD were all significantly associated with EE in their separate models. When considering general obesity, central obesity and NAFLD simultaneously, NAFLD, but neither general nor central obesity, remained positively correlated to EE. In addition, male gender, hiatal hernia and hypertriglyceridemia were all significantly associated with EE. CONCLUSION: In addition to general and central obesity, NAFLD is independently associated with increased risk of EE, and the detrimental effect of NAFLD on EE might be greater than those of general and central obesity. PMID- 25293868 TI - Elevated plasma pigment epithelium-derived factor in children with type 2 diabetes mellitus is attributable to obesity. AB - BACKGROUND: Pigment epithelium-derived factor (PEDF) is a member of the serpin family secreted by adipocytes. Plasma PEDF is increased in obese children and adults. Adults with type 2 diabetes mellitus (T2DM) have higher circulating PEDF but there are no reports in children with T2DM. OBJECTIVE: To compare PEDF concentration in children with T2DM to normal weight and obese children without T2DM and determine associations with anthropometric or serum factors. METHODS: Participants were 34 obese children with T2DM diagnosed by American Diabetes Association (ADA) criteria, 61 normal weight [body mass index (BMI) 25-75 percentile] and 63 obese (BMI >= 95 percentile) children of age 8-18 yr. Plasma PEDF was measured in fasting plasma samples. Anthropometric, serum, and body composition (dual-energy x-ray absorptiometry, DXA) data were obtained for each subject to identify potential predictor variables. RESULTS: PEDF was 55% higher (p = 0.001) in the T2DM group compared with normal weight children, but did not differ from obese children. In the T2DM group, fat mass and lean mass both individually predicted PEDF (r2 = 0.22 and 0.17, p = 0.02 and p < 0.01, respectively). PEDF was positively correlated with homeostatic model assessment - insulin resistance (HOMA-IR) when all groups were combined (r2 = 0.15, p<0.001). CONCLUSIONS: Plasma PEDF was similar in the T2DM and obese groups, therefore, obesity, rather than diabetes, may account for the higher PEDF in children with T2DM compared with normal weight children. PEDF was positively associated with both lean mass and fat mass both of which may contribute to the circulating level of the protein, and potentially to PEDF's association with insulin resistance in obese children with and without diabetes. PMID- 25293869 TI - High-risk behaviors among adult men and women in Botswana: implications for HIV/AIDS prevention efforts. AB - The government of Botswana has been spending a lot of money in the prevention, treatment, care and support for HIV/AIDS patient for decades. This paper uses data from the third Botswana AIDS Impact Survey (BAIS III) to explore high-risk behaviors of adults and how they affect government efforts to stop the spread of HIV/AIDS. The objective of this paper is to fill in the gap on the assessment of high-risk behaviors associated with HIV/AIDS and their implications on HIV/AIDS prevention efforts. A nationally representative sample of 10,159 men and women aged 20-64 years who had successfully completed the BAIS III individual questionnaire were used in the study. Both descriptive and binary logistic regression analyses were used for analysis. Crude odds ratios were obtained from gross effects model while adjusted odds ratios (AOR) were obtained from the net effects model. Statistically significant association was observed between multiple current partners and alcohol consumption (AOR = 1.5), drug abuse (AOR = 1.7), transactional sex (AOR = 2.6) and intergenerational sex (AOR = 1.07). Furthermore, statistically significant association was seen for inconsistent condom use and having tested for HIV (AOR = 1.5). These results show a worrying tendency that despite government's efforts to stop the spread of HIV/AIDS, adults in Botswana continue to indulge in high-risk behaviors. Therefore, any programs and policies on HIV/AIDS should first target these high-risk behaviors. PMID- 25293870 TI - Amorphous calcium phosphate nanospheres/polylactide composite coated tantalum scaffold: facile preparation, fast biomineralization and subchondral bone defect repair application. AB - Calcium phosphate (CaP) materials are widely used in various biomedical areas such as drug/gene delivery and bone repair/tissue engineering. In this study, amorphous CaP nanospheres synthesized by a simple co-precipitation method are used to prepare the CaP-polylactide (CaP-PLA) composite. Then, the as-prepared CaP-PLA composite is used to coat tantalum (Ta) plates and porous scaffolds. Compared with bare Ta plate, CaP-PLA coated Ta plates show a high performance of surface biomineralization in simulated body fluid (SBF). In addition, the hydrophilicity of the CaP-PLA coated Ta plates is significantly improved. CaP-PLA coated Ta plates with bovine serum albumin (BSA) are prepared and used for the investigation of BSA release in vitro. The experimental results indicate a sustained BSA release property and simultaneous biomineralization of the as prepared BSA-containing CaP-PLA coated Ta plates. Furthermore, CaP-PLA coated Ta scaffolds are favorable for the human osteoblast-like MG63 cells adhesion and spreading. The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-containing CaP-PLA coated porous Ta scaffolds are used for the study of rabbit subchondral bone defect repair, covering with autogeneic periosteums. The as-prepared CaP-PLA composite coated Ta scaffolds are useful to guide the bone regeneration in vivo. PMID- 25293872 TI - Prevalence of depressive and anxiety disorders and validation of the Hospital Anxiety and Depression Scale as a screening tool in axial spondyloarthritis patients. AB - OBJECTIVE: To determine the prevalence of anxiety and depression in axial spondyloarthritis (SpA) patients by a psychiatrist using the Chinese-bilingual Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition patient research version (CB-SCID-I/P), and to examine the effectiveness of the Hospital Anxiety and Depression Scale (HADS) as a screening tool. METHODS: We recruited 160 Chinese axial-SpA patients to determine the prevalence of anxiety and depression using the CB-SCID-I/P. Recruited subjects were asked to complete the HADS. HADS, HADS-depression (HADS-D) subscale and HADS-anxiety (HADS-A) subscale were analyzed to determine their effectiveness in screening for depressive and anxiety disorders. RESULTS: The prevalence of current major depressive disorder (MDD) and anxiety disorder were 10.6% and 15.6%, respectively. The full-scale HADS outperformed the HADS-D subscale in screening for current MDD (area under the curve [AUC] 0.889; 0.844) and all depressive disorders (AUC 0.885; 0.862) while the HADS-A subscale outperformed the full scale HADS in screening for anxiety disorders (AUC 0.894; 0.846). The optimal cut-off point of the full scale HADS for screening current MDD and all depressive disorders were 7/8 and 6/7, yielding a sensitivity of 82.4% and 83.9%, specificity of 78.7% and 74.8%, respectively. The optimal cut-off point of HADS-A subscale for screening anxiety disorders was 6/7, yielding a sensitivity of 88.0% and specificity of 74.4%. CONCLUSION: The prevalence of MDD and anxiety disorder in SpA patients were 10.6% and 15.6%, respectively. We recommend using the full scale HADS in screening for depressive disorders and HADS-A subscale for anxiety disorders. PMID- 25293871 TI - Activation tagging of ATHB13 in Arabidopsis thaliana confers broad-spectrum disease resistance. AB - Powdery mildew species Oidium neolycopersici (On) can cause serious yield losses in tomato production worldwide. Besides on tomato, On is able to grow and reproduce on Arabidopsis. In this study we screened a collection of activation tagged Arabidopsis mutants and identified one mutant, 3221, which displayed resistance to On, and in addition showed a reduced stature and serrated leaves. Additional disease tests demonstrated that the 3221 mutant exhibited resistance to downy mildew (Hyaloperonospora arabidopsidis) and green peach aphid (Myzus persicae), but retained susceptibility to bacterial pathogen Pseudomonas syringae pv tomato DC3000. The resistance trait and morphological alteration were mutually linked in 3221. Identification of the activation tag insertion site and microarray analysis revealed that ATHB13, a homeodomain-leucine zipper (HD-Zip) transcription factor, was constitutively overexpressed in 3221. Silencing of ATHB13 in 3221 resulted in the loss of both the morphological alteration and resistance, whereas overexpression of the cloned ATHB13 in Col-0 and Col-eds1-2 backgrounds resulted in morphological alteration and resistance. Microarray analysis further revealed that overexpression of ATHB13 influenced the expression of a large number of genes. Previously, it was reported that ATHB13 overexpressing lines conferred tolerance to abiotic stress. Together with our results, it appears that ATHB13 is involved in the crosstalk between abiotic and biotic stress resistance pathways. PMID- 25293873 TI - Rethinking phenotypic plasticity and its consequences for individuals, populations and species. AB - Much research has been devoted to identify the conditions under which selection favours flexible individuals or genotypes that are able to modify their growth, development and behaviour in response to environmental cues, to unravel the mechanisms of plasticity and to explore its influence on patterns of diversity among individuals, populations and species. The consequences of developmental plasticity and phenotypic flexibility for the performance and ecological success of populations and species have attracted a comparatively limited but currently growing interest. Here, I re-emphasize that an increased understanding of the roles of plasticity in these contexts requires a 'whole organism' (rather than 'single trait') approach, taking into consideration that organisms are integrated complex phenotypes. I further argue that plasticity and genetic polymorphism should be analysed and discussed within a common framework. I summarize predictions from theory on how phenotypic variation stemming from developmental plasticity and phenotypic flexibility may affect different aspects of population level performance. I argue that it is important to distinguish between effects associated with greater interindividual phenotypic variation resulting from plasticity, and effects mediated by variation among individuals in the capacity to express plasticity and flexibility as such. Finally, I claim that rigorous testing of predictions requires methods that allow for quantifying and comparing whole organism plasticity, as well as the ability to experimentally manipulate the level of and capacity for developmental plasticity and phenotypic flexibility independent of genetic variation. PMID- 25293874 TI - The roles of genetic drift and natural selection in quantitative trait divergence along an altitudinal gradient in Arabidopsis thaliana. AB - Understanding how natural selection and genetic drift shape biological variation is a central topic in biology, yet our understanding of the agents of natural selection and their target traits is limited. We investigated to what extent selection along an altitudinal gradient or genetic drift contributed to variation in ecologically relevant traits in Arabidopsis thaliana. We collected seeds from 8 to 14 individuals from each of 14 A. thaliana populations originating from sites between 800 and 2700 m above sea level in the Swiss Alps. Seed families were grown with and without vernalization, corresponding to winter-annual and summer-annual life histories, respectively. We analyzed putatively neutral genetic divergence between these populations using 24 simple sequence repeat markers. We measured seven traits related to growth, phenology and leaf morphology that are rarely reported in A. thaliana and performed analyses of altitudinal clines, as well as overall QST-FST comparisons and correlation analyses among pair-wise QST, FST and altitude of origin differences. Multivariate analyses suggested adaptive differentiation along altitude in the entire suite of traits, particularly when expressed in the summer-annual life history. Of the individual traits, a decrease in rosette leaf number in the vegetative state and an increase in leaf succulence with increasing altitude could be attributed to adaptive divergence. Interestingly, these patterns relate well to common within- and between-species trends of smaller plant size and thicker leaves at high altitude. Our results thus offer exciting possibilities to unravel the underlying mechanisms for these conspicuous trends using the model species A. thaliana. PMID- 25293875 TI - Improving soil bacterial taxa-area relationships assessment using DNA meta barcoding. AB - The evaluation of the taxa-area relationship (TAR) with molecular fingerprinting data demonstrated the spatial structuration of soil microorganisms and provided insights into the processes shaping their diversity. The increasing use of massive sequencing technologies in biodiversity investigations has now raised the question of the advantages of such technologies over the fingerprinting approach for elucidation of the determinism of soil microbial community assembly in broad scale biogeographic studies. Our objectives in this study were to compare DNA fingerprinting and meta-barcoding approaches for evaluating soil bacterial TAR and the determinism of soil bacterial community assembly on a broad scale. This comparison was performed on 392 soil samples from four French geographic regions with different levels of environmental heterogeneity. Both molecular approaches demonstrated a TAR with a significant slope but, because of its more sensitive description of soil bacterial community richness, meta-barcoding provided significantly higher and more accurate estimates of turnover rates. Both approaches were useful in evidencing the processes shaping bacterial diversity variations on a broad scale. When different taxonomic resolutions were considered for meta-barcoding data, they significantly influenced the estimation of turnover rates but not the relative importance of each component process. Altogether, DNA meta-barcoding provides a more accurate evaluation of the TAR and may lead to re examination of the processes shaping soil bacterial community assembly. This should provide new insights into soil microbial ecology in the context of sustainable use of soil resources. PMID- 25293876 TI - Multitarget effects of quercetin in leukemia. AB - This study proposes to investigate quercetin antitumor efficacy in vitro and in vivo, using the P39 cell line as a model. The experimental design comprised leukemic cells or xenografts of P39 cells, treated in vitro or in vivo, respectively, with quercetin; apoptosis, cell-cycle and autophagy activation were then evaluated. Quercetin caused pronounced apoptosis in P39 leukemia cells, followed by Bcl-2, Bcl-xL, Mcl-1 downregulation, Bax upregulation, and mitochondrial translocation, triggering cytochrome c release and caspases activation. Quercetin also induced the expression of FasL protein. Furthermore, our results demonstrated an antioxidant activity of quercetin. Quercetin treatment resulted in an increased cell arrest in G1 phase of the cell cycle, with pronounced decrease in CDK2, CDK6, cyclin D, cyclin E, and cyclin A proteins, decreased Rb phosphorylation and increased p21 and p27 expression. Quercetin induced autophagosome formation in the P39 cell line. Autophagy inhibition induced by quercetin with chloroquine triggered apoptosis but did not alter quercetin modulation in the G1 phase. P39 cell treatment with a combination of quercetin and selective inhibitors of ERK1/2 and/or JNK (PD184352 or SP600125, respectively), significantly decreased cells in G1 phase, this treatment, however, did not change the apoptotic cell number. Furthermore, in vivo administration of quercetin significantly reduced tumor volume in P39 xenografts and confirmed in vitro results regarding apoptosis, autophagy, and cell-cycle arrest. The antitumor activity of quercetin both in vitro and in vivo revealed in this study, point to quercetin as an attractive antitumor agent for hematologic malignancies. PMID- 25293878 TI - Renal sympathetic denervation in patients with hypertension and chronic kidney disease: does improvement in renal function follow blood pressure control? AB - Twenty-seven patients with resistant hypertension and chronic kidney disease were treated by renal sympathetic denervation (RSD) and followed for 12 months. Patients were retrospectively divided into controlled and uncontrolled blood pressure (BP) groups. Increases in mean estimated glomerular filtration rate (eGFR) were found at months 1, 3, 6, and 12 in the controlled group (P < .0001, for every time point). The mean change in eGFR after 12 months was 18.54 +/- 8.15 mL/min/1.73 m(2) higher in the controlled group (P=.0318). In patients in the controlled group with baseline eGFR < 45 mL/min/1.73 m(2), responders (with an increase in eGFR > 6.2%) corresponded to 50% at 6 months and 83% at 12 months. In the patients with baseline eGFR >= 45 mL/min/1.73 m(2), all patients were labeled as responders at months 6 and 12. Median albumin:creatinine ratio after 12 months was lower than baseline only in the controlled group (P = .0003). Our results suggest that patients with this profile who reached BP control by RSD also experienced a significant improvement in renal function. PMID- 25293877 TI - Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice. AB - Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-kappaB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2alpha activation, and inositol requiring 1alpha-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, beta-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. PMID- 25293879 TI - Pooled analysis of mitochondrial DNA copy number and lung cancer risk in three prospective studies. AB - BACKGROUND: We previously reported that higher levels of mitochondrial DNA copy number (mtDNA CN) were associated with lung cancer risk among male heavy smokers (i.e., >=20 cigarettes per day) in the Alpha-Tocopherol Beta-Carotene (ATBC) study. Here, we present two additional prospective investigations nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and the Shanghai Women's Health Study (SWHS), and pooled with previously published data from ATBC. MATERIALS: All DNA were extracted from peripheral whole blood samples using the phenol-chloroform method, and mtDNA CN was assayed by fluorescence based qPCR. Multivariate unconditional logistic regression models were used to estimate ORs and 95% confidence intervals for the association of mtDNA CN and lung cancer risk. RESULTS: Overall, mtDNA CN was not associated with lung cancer risk in the PLCO, SWHS, or pooled populations (all P trends > 0.42, P heterogeneity = 0.0001), and mtDNA CN was inversely associated with lung cancer risk among male smokers in PLCO, the opposite direction observed in ATBC. In addition, the mtDNA CN association observed among male heavy smokers in ATBC was the opposite direction in PLCO. CONCLUSIONS: mtDNA CN was not consistently associated with lung cancer risk across three prospective study populations from Europe, Asia, and the United States. IMPACT: This pooled study suggests no consistent association between prediagnostic mtDNA CN levels and lung cancer risk across several populations. Cancer Epidemiol Biomarkers Prev; 23(12); 2977-80. (c)2014 AACR. PMID- 25293880 TI - Mitochondrial DNA copy number and chronic lymphocytic leukemia/small lymphocytic lymphoma risk in two prospective studies. AB - BACKGROUND: Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data. METHODS: In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from prediagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR, 2.21; 95% CI, 1.03-4.72; Ptrend: 0.049) and pooled (T3 vs. T1: OR, 3.12; 95% CI, 1.72-5.68; Ptrend: 0.0002). Association was stronger among male smokers (Ptrend: <0.0001) and essentially identical for cases diagnosed <6, >6-8, and >8 years from blood draw (pooled: Pinteraction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association. CONCLUSIONS AND IMPACT: Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as 8 years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development. PMID- 25293883 TI - DFT computations support the sigma-complex assisted metathesis (sigma-CAM) mechanism for the 1,4-Rh shift of Cp*Rh(III)-(eta(1)-beta-styryl) complexes. AB - DFT calculations support the sigma-complex assisted metathesis (sigma-CAM) mechanism recently proposed for the first 1,4-Rh shift of a Rh(III) complex rather than the oxidative addition/reductive elimination pathway characteristic of Rh(i). A single, concerted TS (DeltaG(?) = 27-34 kcal mol(-1)) was found and its electronic structure characterized by Bader's AIM analysis. The 4-centered TS is characterized by a enhanced charge separation (Rh and H atoms - positive, both C atoms - negative) relative to the sigma-vinyl Rh starting material and the sigma-aryl-Rh product. The AIM topological analysis of the electron density reveals a network of interactions: Rh with H as well as both Rh and H with both C(vinyl) and C(aryl) in the TS and confirms the C(vinyl)-Rh agnostic interaction observed experimentally in the sigma-aryl-Rh product. PMID- 25293882 TI - The role of extended-release niacin on immune activation and neurocognition in HIV-infected patients treated with antiretroviral therapy - CTN PT006: study protocol for a randomized controlled trial. AB - BACKGROUND: Approximately 30% of HIV-1-infected patients receiving antiretroviral therapy who achieve virologic control have unsatisfactory immune reconstitution, with CD4+ T-cell counts persistently below 350 cells/MUL. These patients are at elevated risk for clinical progression to AIDS and non-AIDS events. CD4+ T-cell depletion following infection and persistent immune activation can partially explain this low CD4+ T-cell recovery. Recent data suggest a link between the tryptophan oxidation pathway, immune activation and HIV disease progression based on overstimulation of the tryptophan oxidation pathway by HIV antigens and by interferon-gamma. This overstimulation reduces levels of circulating tryptophan, resulting in inflammation which has been implicated in the development of neurocognitive dysfunction. Niacin (vitamin B3) is able to control the excess tryptophan oxidation, correcting tryptophan depletion, and therefore represents an interesting strategy to improve CD4 recovery.We aim to design a crossover proof-of-concept study to assess supplementation with an extended-release form of niacin (Niaspan FCTTM) in combination with antiretroviral therapy, compared to antiretroviral therapy alone, on T-cell immune activation as defined by changes in the percentage of CD8+ CD38+ HLA-DR+ T-cells. METHODS/DESIGN: This randomized, open-label, interventional crossover study with an immediate versus deferred use of Niaspan FCT for 24 weeks will assess its ability to reduce immune activation and thus increase CD4 recovery in 20 HIV-infected individuals with suboptimal immune responses despite sustained virologic suppression. A substudy evaluating neurocognitive function will also be conducted. DISCUSSION: This randomized trial will provide an opportunity to evaluate the potential benefit of oral extended release niacin, a drug that can indirectly increase tryptophan, to reduce immune activation and in turn increase CD4+ T-cell recovery. The study will also allow for the evaluation of the impact of Niaspan FCT on neurocognitive function in HIV infected individuals with suboptimal immune responses despite sustained virologic suppression. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov on 17 December 2013 (registration number: NCT02018965). PMID- 25293884 TI - [The design of a nationwide cohort study in Germany : the pretest studies of the German National Cohort (GNC)]. AB - The German National Cohort (GNC) is the largest population-based cohort study in Germany. Beginning in 2014, a total of 200,000 women and men aged 20-69 years will be examined in 18 study centers. The aim of the study is to investigate the etiology of chronic diseases in relation to lifestyle, genetic, socioeconomic, and environmental factors and to develop appropriate methods for early diagnosis and prevention of diseases such as cardiovascular and respiratory diseases, cancer, diabetes, neurodegenerative/psychiatric diseases, as well as musculoskeletal and infectious diseases. Pretest studies (phase 1 and 2) were conducted to select methods, instruments, and procedures for the main study, to develop standard operating procedures, and to design and test the examination program according to acceptance, expected duration, and feasibility. The pretest studies included testing of interviews, questionnaires, anthropometric measurements, several medical examinations, and the collection of biosamples. In addition, the logistic, technical, and personnel infrastructure for the main study could be established including the study centers, the central infrastructure for data management, processes to coordinate the study, and data protection and quality management concepts. The examination program for the main phase of the GNC was designed and optimized based on the results of the pretest studies. The GNC is a population-based, highly standardized and excellently phenotyped cohort that will be the basis for new strategies for risk assessment and identification, early diagnosis, and prevention of multifactorial diseases. PMID- 25293881 TI - The contribution of common genetic variation to nicotine and cotinine glucuronidation in multiple ethnic/racial populations. AB - BACKGROUND: The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism. METHODS: We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined. RESULTS: Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5*10(-8)). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 * 10(-155)). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 * 10( 43)) was in high LD (r(2) = 0.99) with rs115765562. CONCLUSIONS: Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose. IMPACT: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk. PMID- 25293885 TI - Test-retest reliability of an infectious disease questionnaire and evaluation of self-assessed vulnerability to infections : findings of Pretest 2 of the German National Cohort. AB - INTRODUCTION/OBJECTIVES: Large scale population-based studies focusing on infectious diseases are scarce. This may be explained by methodological obstacles concerning ascertainment of data on infectious diseases requiring, e.g. collection of data on relatively short-termed symptoms and/or collection of biosamples for pathogen identification during a narrow time window. In the German National Cohort (GNC), a novel self-administered questionnaire will be used in addition to biosampling to collect data on selected infectious diseases and symptoms. The aim of this study was to evaluate in Pretest 2 of the GNC newly added items on self-assessed vulnerability to several infectious diseases and to assess test-retest reliability of the questionnaire. METHODS: The study was conducted in two study centres (Hamburg and Hanover) during Pretest 2 of the GNC. A self-administered paper questionnaire was applied. In Hamburg, participants were asked to fill in the questionnaire during their regular visit at the study centre. For test-retest reliability, participants in Hanover filled in the same questionnaire at home twice. To evaluate agreement, item-related percentage agreement and kappa (kappa) were calculated. In addition, we computed Bennet's S and Krippendorf's alpha (alpha). Items on self-assessed vulnerability to infections were evaluated by comparing them with the corresponding self-reported frequency of infections. An explanatory factor analysis was applied to construct the scores of self-reported infection frequency and self-assessed vulnerability to infections. RESULTS: The evaluation of the internal consistency of the five item instrument of self-assessed vulnerability to infections resulted in a Cronbach's alpha of 0.78. The factor analysis yielded evidence of one factor. The factor was divided into three groups (lowest quintile classified as "less prone to infections" compared to peers; second, middle and fourth quintiles classified as "similarly prone to infections" and highest quintile classified as "more prone to infections"). Participants classified as "less prone to infections" reported fewer infections than participants classified as "more prone to infections". Spearman's correlation of the two scores (self-reported infection frequency and self-assessed vulnerability to infection) was 0.50 (p < 0.0001). For quantifying reliability, 88 participants with a median time of 8 days between filling in both questionnaires could be included in the analysis; for items sensitive to disease occurrence between both questionnaires only participants with no relevant disease in this time interval were included (n = 75). The weighted kappa ranged between 0.65 and 0.87 for the items on infectious disease frequency in the last 12 months, for items on symptom frequency in the past 12 months between 0.77 and 0.90, and for items on vulnerability compared to peers between 0.68 and 0.76. CONCLUSION: A five-item instrument on self-assessed vulnerability to infections seems to be promising, but requires further evaluation. Overall, the questionnaire on self-reported infectious diseases used in Pretest 2 of the GNC is a moderately reliable instrument and, thus, can be applied in future studies on infectious diseases. PMID- 25293886 TI - Feasibility and quality development of biomaterials in the pretest studies of the German National Cohort. AB - BACKGROUND: The German National Cohort (GNC) is designed to address research questions concerning a wide range of possible causes of major chronic diseases (e.g. cancer, diabetes, infectious, allergic, neurologic and cardiovascular diseases) as well as to identify risk factors and prognostic biomarkers for early diagnosis and prevention of these diseases. The collection of biomaterials in combination with extensive information from questionnaires and medical examinations represents one of the central study components. OBJECTIVES: In two pretest studies of the German National Cohort conducted between 2011 and 2013, a range of biomaterials from a defined number of participants was collected. Ten study centres were involved in pretest 1 and 18 study centres were involved in pretest 2. Standard operation procedures (SOP) were developed and evaluated to minimize pre-analytical artefacts during biosample collection. Within the pretest studies different aspects concerning feasibility of sample collection/preparation [pretest 1 (a)] and quality control of biomarkers and proteome analyses were investigated [pretest 1 (b), (c)]. Additionally, recruitment of study participants for specific projects and examination procedures of all study centres in a defined time period according to common standards as well as transportation and decentralized storage of biological samples were tested (pretest 2). These analyses will serve as the basis for the biomaterial collection in the main study of the GNC starting in 2014. MATERIALS AND METHODS: Participants, randomly chosen from the population (n = 1000 subjects recruited at ten study sites in pretest 1) were asked to donate blood, urine, saliva and stool samples. Additionally, nasal and oropharyngeal swabs were collected at the study sites and nasal swabs were collected by the participants at home. SOPs for sample collection, preparation, storage and transportation were developed and adopted for pretest 2. In pretest 2, 18 study sites (n = 599 subjects) collected biomaterials mostly identical to pretest 1. Biomarker analyses to test the quality of the biomaterials were performed. RESULTS: In pretest 1 and 2, it was feasible to collect all biomaterials from nearly all invited participants without major problems. The mean response rate of the subjects was 95 %. As one important result we found for example that after blood draw the cellular fraction should be separated from the plasma and serum fractions during the first hour with no significant variation for up to 6 h at 4 C for all analysed biomarkers. Moreover, quality control of samples using a proteomics approach showed no significant clustering of proteins according to different storage conditions. All developed SOPs were validated for use in the main study after some adaptation and modification. Additionally, electronic and paper documentation sheets were developed and tested to record time stamps, volumes, freezing times, and aliquot numbers of the collected biomaterials. DISCUSSION: The collection of the biomaterials was feasible without major problems at all participating study sites. However, the processing times were in some cases too long. To avoid pre analytical artefacts in sample collection, appropriate standardisation among the study sites is necessary. To achieve this, blood and urine collection will have to be adapted to specific conditions of usage of liquid handling robots, which will be available at all participating study centres in the main study of the GNC. Strict compliance with the SOPs, thorough training of the staff and accurate documentation are mandatory to obtain high sample quality for later analyses. The so obtained biomaterials represent a valuable resource for research on infectious and other common complex diseases in the GNC. PMID- 25293887 TI - Web-based questionnaires to capture acute infections in long-term cohorts : findings of a feasibility study. AB - BACKGROUND: Incidence of acute respiratory infections (ARI) and gastrointestinal infections (GII) are difficult to assess due to high frequency episodes, limited severity and short duration. Retrospective assessments therefore are particularly prone to recall bias, while prospective assessment with conventional questionnaires requires high discipline from participants which is difficult to maintain over longer time periods. Web-based questionnaires (WQ) allow integration of a recall system and thus carry the potential to prospectively capture acute infections. We investigated the feasibility of a weekly WQ assessing symptoms of ARI and GII among participants of the German National Cohort (GNC). MATERIAL AND METHODS: In the study centres Hamburg and Bremen of the GNC participants of the Pretest 1 phase (September to November 2011) were invited to additionally take part in this feasibility study testing the WQ. Every Monday participants received an e-mail, containing a link to the WQ, asking for occurrence of ARI or GII symptoms during the past 7 days. The study took place from the beginning of February until mid-July 2012. We calculated the overall proportion of participation, weekly participation and the number of weekly reports per participant and we estimated incidences of ARI, ILI and GII. RESULTS: Of 200 Pretest 1 participants 171 (86 %) reported having an email address and thus were eligible for the web-based study. A total of 167 (98 %) agreed to participate. Participants of the web-based study were younger and better educated than non-participants. Access to Internet decreased with increasing age. Of the 167 participants in the feasibility study, 144 (86 %) responded at least once during the study period of 23 weeks, 5 persons (3 %) had non-functioning email addresses and 18 (11 %) did not respond at all. The weekly response varied between 62 % and 81 %, the median was 74 % (IQR: 71-77 %). Weekly median reports per person were 20 (IQR: 14-22; range 1-23). More than 90 % of participants responded during the first 3 days. The following mean incidence rates were found: ARI, 12 %; ILI, 0.49 %; and GII, 3 %. CONCLUSION: Use of WQ in prospective studies seems well possible, as Internet access is frequent among study participants and major technical problems did not occur. We observed high participation during the study period of 6 months and low drop out numbers. Participants of the web-based study were slightly younger and better educated than non-participants, so selection bias is possible and must be kept in mind when discussing generalizability of the results. PMID- 25293888 TI - Collection of vaccination data in the German National Cohort : Findings of a feasibility study in three study centers. AB - BACKGROUND: Data about the vaccination status of participants are required in epidemiological cohort studies whenever infection or immunity is considered as potential exposure or outcome. Within Pretest 2 of the German National Cohort (GNC) we therefore investigated the acceptance and feasibility of extracting vaccination status from vaccination certificates provided by the participants of the study. METHODS: This study was conducted in three study centers (Bremen, n = 73; Hamburg, n = 200; Hannover, n = 193). In order to test if an additional reminder would prevent participants from forgetting their vaccination certificates at home persons willing to participate in Pretest 2 were randomly assigned to one of three invitation groups (IG). About one third of the participants received either no further reminder (IG1), a reminder card together with the appointment letter (IG2) or a separate reminder card 4 days before the appointment (IG3). At the study center, vaccination data were scanned or copied and entered into a database using a unique identification number. Participants were also asked to fill in a short questionnaire to assess the completeness of the provided vaccination data. Additionally, in one of the three participating study centers, general practitioners (GP) were asked to provide vaccination data from their records following respective participants' consent. Finally, we compared the influenza data from the vaccination certificates with the influenza data obtained from participants in Pretest 2 by use of a self-administered questionnaire (ID-Screen). RESULTS: Due to different starting dates of the study the intended reminder procedure was implemented only in Hamburg and Hannover. In Hamburg, significantly more vaccination certificates were submitted by the group which received the reminder card separately 4 days before the examination (IG3) compared to IG1 and IG2 (p = 0.04). In Hannover, in contrast, most vaccination certificates were brought by those who received the reminder card together with the appointment letter. Overall, the use of a reminder card had a positive but not significant effect as 89 % (185/209) of participants who received the reminder card submitted vaccination data versus 81 % (84/104) of participants who did not receive any reminder card (p = 0.06). Of all Pretest 2 participants in Hannover, 62 % (120/193) gave written consent for data collection by the GPs. In total, 114 practices were contacted of which 49 (43 %) sent vaccination data. All in all, 360 vaccination certificates with 5065 documented vaccinations were entered into a database, of which 4830 (95 %) were valid for analysis covering a period from 1946 to 2012. The comparison of influenza vaccination data from vaccination certificates to the remembered data from a self-completed questionnaire showed an agreement of data in 46 % (84/184) of cases (Kappa = 0.48). Influenza vaccinations were underreported in 4 % (7/170) of self-completed questionnaires. CONCLUSION: The reliable documentation of vaccinations within the context of the GNC proved to be feasible and thus recommendable at a large scale within the GNC as participants showed high willingness and compliance in providing available vaccination documents. An additional validation by means of documents provided by physicians seems to be possible for more than a quarter of participants. In order to maximize the likelyhood of participants' of bringing their vaccination certificates it would be sufficient to send a reminder card together with the appointment letter. PMID- 25293889 TI - Comparison of stool collection on site versus at home in a population-based study : feasibility and participants' preference in Pretest 2 of the German National Cohort. AB - BACKGROUND: For certain laboratory investigations it is necessary to obtain native stool samples and process them within a narrow time window at the point of contact or a nearby laboratory. However, it is not known whether it is feasible to obtain stool samples from asymptomatic individuals during an appointment in a study center (SC). We therefore compared participants' preference, feasibility and acceptance of stool sample collection during the appointment at the study center (on-site sampling) to collection at home after the appointment. METHODS: The study was conducted at two sites in Northern Germany (Bremen, n = 156; Hannover, n = 147) during the Pretest 2 phase of the German National Cohort (GNC), drawing upon a randomly selected population supplemented by a small convenience sample. In the study center, the participants were given the choice to provide a stool sample during the appointment or to collect a sample later at home and return it by mail. RESULTS: In all, 303 of the 351 participants (86 %) of Pretest 2 at these sites participated in this feasibility study. Only 7.9 % (24/303) of the participants chose on-site collection, whereas 92 % (279/303) chose at-home collection. There were significant differences between the two study sites in that 14 % (21/147) of participants in Hannover and 2 % (3/156) of participants in Bremen chose on-site collection. Compliance was high in both groups, as 100 % (24/24) and 98 % (272/279) of participants in the on-site and at home groups, respectively, provided complete samples. Both methods were highly accepted, as 92 % of the participants in each group (22/24 and 227/248) stated that stool collection at the respective site was acceptable. CONCLUSION: When given a choice, most participants in this population-based study preferred home collection of stool samples to collection in the study center. Thus, native stool samples for immediate processing in the study center may potentially be obtained only from a subpopulation of participants, which may lead to selection bias. Home collection, on the other hand, proved to be a highly feasible method for studies that do not require freshly collected native stool. PMID- 25293891 TI - The effect of total hip and hip resurfacing arthroplasty on vertical ground reaction force and impulse symmetry during a sit-to-stand task. AB - BACKGROUND: The aim of this study was to determine the influence of total hip arthroplasty and hip resurfacing arthroplasty on limb loading symmetry before, and after, hip reconstruction surgery during a sit-to-stand task. METHODS: Fourteen patients were recruited that were about to receive either a total hip prosthesis (n=7) or a hip resurfacing prosthesis (n=7), as well as matched controls. Patients performed a sit-to-stand movement before, 3 months after, and 12 months after surgery. Peak vertical ground reaction force and impulse were measured for each leg, from which ground reaction force and impulse symmetry ratios were calculated. FINDINGS: Before surgery, hip resurfacing patients showed a small asymmetry which was not different to normal for ground reaction force (0.88(0.28) vs. 1.00(0.11); p=0.311) or impulse (0.87(0.29) vs. 0.99(0.09); p=0.324) symmetry ratios. Total hip patients offloaded their affected hip by 30% in terms of impulse symmetry ratio (0.71(0.36) vs. 0.99(0.23); p=0.018). At 3 months following surgery asymmetries were seen that were different to normal in both hip resurfacing patients for ground reaction force (0.77(0.16); p=0.007), and total hip patients for ground reaction force (0.70(0.15); p=0.018) and impulse (0.72(0.16); p=0.011) symmetry ratios. By 12 months after surgery total hip patients regained a symmetrical loading pattern for both ground reaction force (0.95(0.06); p=0.676) and impulse (1.00(0.06); p=0.702) symmetry ratios. Hip resurfacing patients, however, performed the task by overloading their operated hip, with impulse symmetry ratio being larger than normal (1.16(0.16); p=0.035). INTERPRETATION: Physiotherapists should appreciate the need for early recovery of limb loading symmetry as well as subsequent differences in the responses observed with different prostheses. PMID- 25293892 TI - My encounters with bacteria--learning about communication, cooperation and choice. AB - My journey into the physics of living systems began with the most fundamental organisms on Earth, bacteria, that three decades ago were perceived as solitary, primitive creatures of limited capabilities. A decade later this notion had faded away and bacteria came to be recognized as the smart beasts they are, engaging in intricate social life through a sophisticated chemical language. Acting jointly, these tiny organisms can sense the environment, process information, solve problems and make decisions so as to thrive in harsh environments. The bacterial power of cooperation manifests in their ability to develop large colonies of astonishing complexity. The number of bacteria in a colony can amount to many billions, yet they exchange 'chemical tweets' that reach each and every one of them so they all know what they're all doing, each cell being both actor and spectator in the bacterial Game of Life. I share my encounters with bacteria, what I learned about the secrets of their social life and wisdom of the crowd, and why and how, starting as a theoretical physicist, I found myself studying social intelligence of bacteria. The story ends with a bacteria guide to cyber war on cancer. PMID- 25293893 TI - Minimally invasive percutaneous compression plating versus dynamic hip screw for intertrochanteric fractures: a randomized control trial. AB - OBJECTIVE: Intertrochanteric femur fracture is a common injury in elderly patients. The dynamic hip screw (DHS) has served as the standard choice for fixation; however it has several drawbacks. Studies of the percutaneous compression plate (PCCP) are still inconclusive in regards to its efficacy and safety. By comparing the two methods, we assessed their clinical therapeutic outcome. METHODS: A total of 121 elderly patients with intertrochanteric femur fractures (type AO/OTA 31.A1-A2, Evans type 1) were divided randomly into two groups undergoing either a minimally invasive PCCP procedure or a conventional DHS fixation. RESULTS: The mean operation duration was significantly shorter in the PCCP group (55.2 min versus 88.5 min, P<0.01). The blood loss was 156.5 ml+/ 18.3 ml in the PCCP group and 513.2 ml+/-66.2 ml in the DHS group (P<0.01). Among the patients treated with PCCP, 3.1% needed blood transfusions, compared with 44.6% of those that had DHS surgery (P<0.01). The PCCP group displayed less postoperative complications (P<0.05). The mean American Society of Anesthesiologists score and Harris hip score in the PCCP group were better than those in the DHS group. There were no significant differences in the mean hospital stay, mortality rates, or fracture healing. CONCLUSION: Due to several advantages, PCCP has the potential to become the ideal choice for treating intertrochanteric fractures (type AO/OTA 31.A1-A2, Evans type 1), particularly in the elderly. PMID- 25293894 TI - Consecutive flap transfer for repairing massive soft tissue defects in the opisthenar with improved donor site closure. AB - OBJECTIVE: To explore a surgical model of utilizing consecutive free scapular flap and adjacent pedicled flap transfer for repairing massive soft tissue defects on the dorsum of the hand while minimizing the donor site morbidity. METHODS: Six patients with massive soft tissue injuries on the opisthenar and forearm were treated with free scapular flaps. Afterwards, a pedicled flap adjacent to the donor site was transferred to cover the donor site defect by direct closure. RESULTS: All six free scapular flaps survived without signs of infection. Three adjacent pedicled flaps presented minor signs of insufficient blood flow on the distal apex, which resolved after six weeks with only conservative therapy. All the incisions healed without other complications. At six-month follow-up, the patients regained full shoulder function. CONCLUSION: With the assistance of an adjacent pedicled flap, the scapular flap is a highly applicable approach in repairing massive soft tissue defects in the opisthenar. It can achieve positive outcomes in both reconstructive and aesthetic aspects. PMID- 25293895 TI - Error rate of multi-level rapid prototyping trajectories for pedicle screw placement in lumbar and sacral spine. AB - OBJECTIVE: Free-hand pedicle screw placement has a high incidence of pedicle perforation which can be reduced with fluoroscopy, navigation or an alternative rapid prototyping drill guide template. In our study the error rate of multi level templates for pedicle screw placement in lumbar and sacral regions was evaluated. METHODS: A case series study was performed on 11 patients. Seventy-two screws were implanted using multi-level drill guide templates manufactured with selective laser sintering. According to the optimal screw direction preoperatively defined, an analysis of screw misplacement was performed. Displacement, deviation and screw length difference were measured. The learning curve was also estimated. RESULTS: Twelve screws (17%) were placed more than 3.125 mm out of its optimal position in the centre of pedicle. The tip of the 16 screws (22%) was misplaced more than 6.25 mm out of the predicted optimal position. According to our predefined goal, 19 screws (26%) were implanted inaccurately. In 10 cases the screw length was selected incorrectly: 1 (1%) screw was too long and 9 (13%) were too short. No clinical signs of neurovascular lesion were observed. Learning curve was insignificantly noticeable (P=0.129). CONCLUSION: In our study, the procedure of manufacturing and applying multi-level drill guide templates has a 26% chance of screw misplacement. However, that rate does not coincide with pedicle perforation incidence and neurovascular injury. These facts along with a comparison to compatible studies make it possible to summarize that multi-level templates are satisfactorily accurate and allow precise screw placement with a clinically irrelevant mistake factor. Therefore templates could potentially represent a useful tool for routine pedicle screw placement. PMID- 25293896 TI - Influence of S3 electrical stimulation on gastrointestinal dysfunction after spinal cord injury in rabbits. AB - OBJECTIVE: To investigate the effect of electrical stimulation to sacral spinal nerve 3 (S3 stimulation) on gastrointestinal dysfunction after spinal cord injury (SCI). METHODS: Six rabbits were taken as normal controls to record their gastrointestinal multipoint biological discharge, colon pressure and rectoanal inhibitory reflex. Electrodes were implanted into S3 in another 18 rabbits. Then the model of SCI was conducted following Fehling's method: the rabbit S3 was clamped to induce transverse injury, which was claimed by both somatosensory evoked potential and motion evoked potential. Two hours after SCI, S3 stimulation was conducted. The 18 rabbits were subdivided into 3 groups to respectively record their gastrointestinal electric activities (n=6), colon pressure (n=6), and rectum pressure (n=6). Firstly the wave frequency was fixed at 15 Hz and pulse width at 400 MUs and three stimulus intensities (6 V, 8 V, 10 V) were tested. Then the voltage was fixed at 6 V and the pulse width changed from 200 MUs, 400 MUs to 600 MUs. The response was recorded and analyzed. The condition of defecation was also investigated. RESULTS: After SCI, the mainly demonstrated change was dyskinesia of the single haustrum and distal colon. The rectoanal inhibitory reflex almost disappeared. S3 stimulation partly recovered the intestinal movement after denervation, promoting defecation. The proper stimulus parameters were 15 Hz, 400 MUs, 6 V, 10 s with 20 s intervals and 10 min with 10 min intervals, total 2 h. CONCLUSION: S3 stimulation is able to restore the intestinal movement after denervation (especially single haustrum and distal colon), which promotes defecation. PMID- 25293897 TI - Effect of dynamic hip system blade on the treatment of femoral neck fractures in elderly patients with osteoporosis. AB - OBJECTIVE: To discuss the curative effect of the dynamic hip system blade (DHS blade) on the treatment of femoral neck fractures in elderly patients with osteoporosis. METHODS: A retrospective study was conducted to analyse the clinical data of 60 elderly patients with osteoporosis who had been treated for femoral neck fractures with DHS-blade in our department between September 2012 and February 2014. There were 22 males and 38 females with a mean age of (66.8+/ 3.2) years. According to the Singh Index Classification, all the patients'Singh index was below level 3. The Harris criterion and function recovery after operation were analysed. RESULTS: All patients were followed up for 12-17 months (mean 14 months). No femoral head necrosis, femoral neck shortening, internal fixation loosening or backing out of the nails occurred. Bone nonunion was found in one case and he had a good recovery after total hip arthroplasty. The time for fracture healing ranged from 3-6 months (average 3.5 months). According to Harris criterion, 35 cases were rated as excellent, 22 good, 2 fair and 1 poor. The Harris scale was significantly improved from 28.46+/-2.35 preoperatively to 91.98+/-3.26 at 6 months postoperatively (P<0.05). CONCLUSION: DHS-blade, being minimally invasive, allowing earlier postoperative exercise and avoiding the complications elicited by traditional internal fixation, is advisable for treatment of femoral neck fractured patients with osteoporosis. PMID- 25293898 TI - Surgical treatment of proximal humerus fractures using PHILOS plate. AB - OBJECTIVE: To evaluate functional outcome and complications of open reduction and internal fixation with proximal humeral internal locking system (PHILOS) plate for proximal humerus fractures. METHODS: We reviewed 51 patients who underwent open reduction and internal fixation with PHILOS plate between the years 2007 to 2012. There were 35 men and 16 women with a mean age of 38 years (range 24-68). There were 41 patients in the age group of <60 years and 10 patients in the age group of >60 years. According to Neer classification system, 8, 15 and 23 patients had 2-part, 3-part, and 4-part fractures, respectively and 5 patients had 4-part fracture dislocation. All surgeries were carried out at our tertiary care trauma centre. Functional evaluation of the shoulder at final follow-up was done using Constant-Murley score. RESULTS: The mean follow-up period was 30 months (range 12-44 months). Two patients were lost to follow-up. Of the remaining 49 patients, all fractures were united clinically and radiologically. The mean time for radiological union was 12 weeks (range 8-20 weeks). At the final follow-up the mean Constant-Murley score was 79 (range 50-100). The results were excellent in 25 patients, good in 13 patients, fair in 6 patients and poor in 5 patients. During the follow-up, four cases of varus malunion, one case of subacromial impingement, one case of deep infection, one case of intraarticular screw penetration and one case of failure of fixation were noted. No cases of avascular necrosis, hardware failure, locking screw loosening or nonunion were noted. CONCLUSION: PHILOS provides stable fixation in proximal humerus fractures. To prevent potential complications like avascular necrosis, meticulous surgical dissection to preserve vascularity of humeral head is necessary. PMID- 25293899 TI - Surgical treatment of traumatic lower limb pseudoaneurysm. AB - OBJECTIVE: To summarize our experience in surgical treatment of traumatic lower limb pseudoaneurysm. METHODS: Twenty patients with traumatic lower limb pseudoaneurysm were surgically treated in our department from January 2007 to January 2012. The treatment protocols included interventional covered-stent placement (10 cases), spring coil embolization (2 cases), and surgical operation (8 cases). Surgical operations included pseudoaneurysm repair (2 cases), autologous-vein transplantation (1 case), and artificial-vessel bypass graft (5 cases). RESULTS: All the patients were successfully treated without aggravating lower limb ischemia. Pseudoaneurysm disappeared after treatment. A surgical operation is suitable to most pseudoaneurysms, but its damage is relatively obvious and usually leads to more bleeding. It also requires a longer operating time. Compared to a surgical operation, interventional therapy is less traumatic and patients usually have a quicker recovery (P<0.05). All patients were followed up once per month for 12-36 months by color Doppler ultrasound examination. There were no cases of pseudoaneurysm recurrence. CONCLUSION: Both surgical operation and interventional therapy are safe and effective in the treatment of pseudoaneurysm. PMID- 25293900 TI - The efficacy of a first aid training course for drivers: an experience from northern Iran. AB - OBJECTIVE: To evaluate the efficacy of a first aid training course for a group of drivers. METHODS: This study comprised 500 drivers, randomly selected from the road transport companies. They underwent a course of first aid training and the results were evaluated at 0-3 and 4-6 months after training. RESULTS: Both quantitative and qualitative improvements were observed in the drivers'efficacy in giving first aid. Also the rate of correct interventions was higher at 4-6 months than at 0-3 months. The exception was airway management which was not favorably improved after training. CONCLUSION: The first aid training course for drivers is beneficial and helpful for prehospital care system in road traffic accidents. PMID- 25293901 TI - Local infiltration analgesia following total hip replacement: a review of current literature. AB - Controlling postoperative pain after total hip replacement is important and controversy remains regarding different regimens. By reviewing 18 studies, we attempt to find whether local infiltration analgesia after total hip replacement has any effect on postoperative pain, length of hospital stay and opioid consumption. We conclude that local infiltration analgesia is an effective method for decreasing postoperative pain. PMID- 25293902 TI - Multiple bilateral lower limb fractures in a 2-year-old child: previously unreported injury with a unique mechanism. AB - Fall from height is a common cause of unintentional injuries in children and accounts for 6% of all trauma-related childhood deaths, usually from head injury. We report a case of a 2-year-old child with multiple fractures of the bilateral lower limbs due to this reason. A child fell from a height of around 15 feet after toppling from a balcony. He developed multiple fractures involving the right femoral shaft, right distal femoral epiphysis (Salter Harris type 2), right distal metaphysis of the tibia and fibula, and undisplaced Salter Harris type 2 epiphyseal injury of the left distal tibia. There were no head, abdominal or spinal injuries. The patient was taken into emergency operation theatre after initial management which consisted of intravenous fluids, blood transfusion, and splintage of both lower limbs. Fracture of the femoral shaft was treated by closed reduction and fixation using two titanium elastic nails. Distal femoral physeal injury required open reduction and fixation with K wires. Distal tibia fractures were closely reduced and managed nonoperatively in both the lower limbs. All the fractures united in four weeks. At the last follow-up, the child had no disability and was able to perform daily activities comfortably. We also proposed the unique mechanism of injury in this report. PMID- 25293903 TI - Nonoperatively treated infraglenoid tubercle avulsion. AB - Infraglenoid tubercle avulsion fractures are extremely rare injuries. We report a 38-year-old male with glenoid cavity fracture and infraglenoid tubercle avulsion of the left shoulder following a fall from bike. He refused surgery and was treated nonoperatively. Follow-up radiography and CT at 18 months revealed a malunited infraglenoid tubercle with signs of early glenohumeral osteoarthritis. He did not have shoulder instability or pain and had a fair-good functional outcome. There are no previously published data on the anatomic outcome of nonoperatively treated displaced infraglenoid tubercle avulsion fractures based on CT. PMID- 25293904 TI - Winging of scapula due to serratus anterior tear. AB - Winging of scapula occurs most commonly due to injury to long thoracic nerve supplying serratus anterior muscle. Traumatic injury to serratus anterior muscle itself is very rare. We reported a case of traumatic winging of scapula due to tear of serratus anterior muscle in a 19-year-old male. Winging was present in neutral position and in extension of right shoulder joint but not on "push on wall" test. Patient was managed conservatively and achieved satisfactory result. PMID- 25293905 TI - Complete L5 burst fracture treated by 270-degree decompression and reconstruction using titanium mesh cage via a single posterior vertebrectomy. AB - Complete burst fractures of the L5 is relatively uncommon. How to accomplish a rigid internal fixation as well as preserve motor function is an enormous challenge. We report such a case treated via a single posterior vertebrectomy with 270-degree decompression and reconstruction using titanium mesh cage. The disc between L5/S1 was preserved by placing the titanium mesh cage on the inferior endplate of the L5. We hope this method can offer a possible solution for other surgeons when they meet a similar fracture pattern. PMID- 25293934 TI - Quantitative assessment of the influence of common variation rs16892766 at 8q23.3 with colorectal adenoma and cancer susceptibility. AB - Epidemiological studies indicate a genetic contribution to colorectal cancer (CRC) and colorectal adenoma (CRA) risk, but specific genetic variants remain unknown. Recently, genome-wide association studies have identified 8q23.3 rs16892766 as a new CRC susceptibility locus in populations of European descent. Since then, the relationship between 8q23.3-rs16892766 and CRC/CRA has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency and derive a more precise estimation of the relationship, we conducted a meta-analysis of 13 studies, including 41,728 patients and 44,393 controls for CRC, and 3,767 patients and 11,607 controls for CRA. An overall random-effects per-allele odds ratio of 1.19 (95 % CI: 1.13-1.25, P < 10(-5)) was found for the rs16892766 polymorphism and CRC/CRA risk. When stratified by outcome, the rs16892766 polymorphism was significantly associated with increased CRC risk with per-allele OR of 1.22 (95 % CI: 1.18-1.27, P < 10(-5)), while no associations were found for CRA (OR = 1.05, 95 % CI: 0.91-1.25, P = 0.49). In the subgroup analysis by ethnicity, significantly increased CRC risks were found among Caucasians (OR = 1.23, 95 % CI: 1.17-1.29, P < 10(-5)) and African American (OR = 1.18, 95 % CI: 1.07-1.29, P = 0.001); while no significant associations were found among other ethnic populations. Similar results were also observed under dominant and recessive genetic models. Ethnicity was identified as a potential source of between-study heterogeneity for rs16892766. When stratified by sample size and study design, significantly increased CRC risks were found for the polymorphism in all genetic models. Our findings demonstrated that rs16892766-C allele might be risk conferring factors for the development of CRC, but not for CRA. PMID- 25293936 TI - pH-induced Dy4 and Dy10 cluster-based 1D chains with different magnetic relaxation features. AB - Two novel tetra- and deca-nuclear dysprosium compounds, namely, [Dy4(MU3 OH)2(L)10(bipy)2(H2O)2]n (1) and {[Dy10(MU3-OH)8(L)22(bipy)2(H2O)2].5H2O}n (2) (L = 3-fluoro-4-(trifluoromethyl)benzoic acid; bipy = 2,2'-bipyridine), have been successfully obtained by hydrothermal reaction at different pH values. The solid state structures of 1 and 2 were established by the single crystal X-ray diffraction technique, and both of them exhibit complicated 1D chains with [Dy4] (1) and [Dy10] (2) cluster units, respectively. Adjacent [Dy4] in 1 and [Dy10] in 2 are connected by two bridging carboxylate groups in the eta(1):eta(1):MU2 mode. Magnetic studies reveal that they exhibit different magnetic relaxation behaviors with the energy barrier of 23.6 K for 1 and 3.2 K for 2. Interestingly, the large divergence in both the structures and magnetic properties for 1 and 2 only originated from the different pH values in preparing them. PMID- 25293935 TI - Ectopic expression of miR156 represses nodulation and causes morphological and developmental changes in Lotus japonicus. AB - The effects of microRNA156 overexpression on general plant architecture, branching, flowering time and nodulation were investigated in the model legume, Lotus japonicus. We cloned an miR156 homolog, LjmiR156a, from L. japonicus, and investigated its SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) genes and its biological function at enhancing vegetative biomass yield, extending flowering time, and its impact on nodulation. Thirteen potential targets for LjmiR156 were identified in vitro and their expression profiles were determined in aerial and underground parts of mature plants, including genes coding for eight SPLs, one WD 40, one RNA-directed DNA polymerase, two transport proteins, and one histidine phosphotransfer protein. Two SPL and one WD-40 cleavage targets for LjmiR156 TC70253, AU089191, and TC57859-were identified. Transgenic plants with ectopic expression of LjmiR156a showed enhanced branching, dramatically delayed flowering, underdeveloped roots, and reduced nodulation. We also examined the transcript levels of key genes involved in nodule organogenesis and infection thread formation to determine the role of miR156 in regulating symbiosis. Overexpression of LjmiR156a led to repression of several nodulation genes during the early stages of root development such as three ENOD genes, SymPK, POLLUX, CYCLOPS, Cerberus, and Nsp1, and the stimulation of NFR1. Our results show that miR156 regulates vegetative biomass yield, flowering time and nodulation by silencing downstream target SPLs and other genes, suggesting that the miR156 regulatory network could be modified in forage legumes (such as alfalfa and trefoils) and in leafy vegetables (like lettuce and spinach) to positively impact economically valuable crop species. PMID- 25293937 TI - Hypertension control prevalence estimates should account for age. PMID- 25293938 TI - Response to "hypertension control prevalence estimates should account for age". PMID- 25293943 TI - Emerging Piglet Models of Neonatal Short Bowel Syndrome. AB - Short bowel syndrome (SBS) is a growing problem in the human neonatal population. In infants, SBS is the leading cause of intestinal failure, the state of being unable to absorb sufficient nutrients for growth and development. Neonates with SBS are dependent on long-term parenteral nutrition therapy, but many succumb to the complications of sepsis and liver disease. Research in neonatal SBS is challenged by the ethical limits of studying sick human neonates and the heterogeneous nature of the disease process. Outcomes in SBS vary depending on residual intestinal anatomy, intestinal length, patient age, and exposure to nutrition therapies. The neonatal piglet serves as an appropriate translational model of the human neonate because of similarities in gastrointestinal ontogeny, physiological maturity, and adaptive processes. Re-creating the disease process in a piglet model presents a unique opportunity for researchers to discover novel insights and therapies in SBS. Emerging piglet models of neonatal SBS now represent the entire spectrum of disease seen in human infants. This review aims to contextualize these emerging piglet models within the context of SBS as a heterogeneous disease. We first explore the factors that account for SBS heterogeneity and then explore the suitability of the neonatal piglet as an appropriate translational animal model. We then examine differences between the emerging piglet models of neonatal SBS and how these differences affect their translational potential to human neonates with SBS. PMID- 25293944 TI - Preliminary findings of long-term neurodevelopmental outcomes of infants treated with intravenous fat emulsion reduction for the management of parenteral nutrition-associated cholestasis. AB - INTRODUCTION: Parenteral nutrition-associated cholestasis (PNAC) is linked with the administration of soybean-based intravenous fat emulsion (IVFE). IVFE reduction (IFER) may be an effective management strategy for PNAC; however, long term associated neurodevelopmental outcomes (NDOs) for infants undergoing IFER have not been measured previously. This single-institution, prospective study examined the risk for negative NDOs and key predictors of NDOs associated with IFER. METHODS: Patients (2-5 years) treated with soybean-based IFER as neonates underwent NDO measurements, including Ages and Stages Questionnaires-3 (ASQ-3), Parents' Evaluations of Developmental Status (PEDS), and Behavior Assessment System for Children, Second Edition Preschool, Parent (BASC-2 PRS-P). The relationship between NDOs and predictive variables was evaluated. RESULTS: A total of 25 children had a complete PEDS survey, and 17 were found to be "not at risk." The BASC-2 PRS-P evaluation (n = 18 patients) showed that all 4 composite domains fell within the normative developmental range, and 67%-89% of patients were observed to be "typically developing." For the primary outcome measure, ASQ 3, 82.4%-94.4% of patients were "not at risk." Logistical regression analyses were performed to examine risk factors contributing to negative NDOs. Of children completing all NDO studies, IFER-related variables (eg, development of essential fatty acid deficiency, duration of IFER, and mean IVFE dose) were not found to be predictors of adverse NDOs. CONCLUSIONS: This study represents the first report of NDOs in pediatric patients treated with IFER. IFER-treated patients score within the normative range most of the time. IFER-related variables were not found to be associated with negative NDOs. The results set the stage for a larger, multicenter, prospective study. PMID- 25293945 TI - Diastolic dysfunction in chronic hypoxia: IL-18 provides the elusive link. PMID- 25293946 TI - Understanding confidence intervals. PMID- 25293947 TI - Proteogenomics of Gammarus fossarum to document the reproductive system of amphipods. AB - Because of their ecological importance, amphipod crustacea are employed worldwide as test species in environmental risk assessment. Although proteomics allows new insights into the molecular mechanisms related to the stress response, such investigations are rare for these organisms because of the lack of comprehensive protein sequence databases. Here, we propose a proteogenomic approach for identifying specific proteins of the freshwater amphipod Gammarus fossarum, a keystone species in European freshwater ecosystems. After deep RNA sequencing, we created a comprehensive ORF database. We identified and annotated the most relevant proteins detected through a shotgun tandem mass spectrometry analysis carried out on the proteomes from three major tissues involved in the organism's reproductive function: the male and female reproductive systems, and the cephalon, where different neuroendocrine glands are present. The 1,873 mass spectrometry-certified proteins represent the largest crustacean proteomic resource to date, with 218 proteins being lineage specific. Comparative proteomics between the male and female reproductive systems indicated key proteins with strong sexual dimorphism. Protein expression profiles during spermatogenesis at seven different stages highlighted the major gammarid proteins involved in the different facets of reproduction. PMID- 25293949 TI - Computed tomography features of benign and malignant solid thyroid nodules. AB - BACKGROUND: No previous study has investigated computed tomography (CT) features of benign and malignant solid thyroid nodules using detailed CT features and histopathological results. PURPOSE: To assess CT features of benign and malignant solid thyroid nodules in patients who underwent thyroid surgery. MATERIAL AND METHODS: From January to April 2014, 151 consecutive patients underwent neck CT before thyroid surgery. In each case, neck CT was retrospectively examined by a single radiologist. We evaluated the diagnostic accuracy of specific CT features for differentiating malignant from benign thyroid nodules using histopathological results as a reference standard. RESULTS: Of 173 thyroid nodules in 142 patients, 162 (mean diameter, 12.8 +/- 10.3 mm; range, 5.0-93.7 mm) were visualized on neck CT. Of 162 nodules in 133 patients, 116 were malignant and 46 were benign as confirmed by histopathology. A multivariate logistic regression analysis showed a significant difference between malignant and benign thyroid nodules in the degree and pattern of nodular enhancement, but there were no significant differences in other CT features. In particular, thyroid nodules with exophytic configuration, irregular margin, taller-than-wide shape, punctate calcifications, or homogeneously decreased enhancement showed a high malignancy rate. CONCLUSION: The study demonstrated that the degree and pattern of nodular enhancement are helpful CT features for differentiating malignant from benign solid thyroid nodules. PMID- 25293950 TI - CT angiography in non-traumatic subarachnoid hemorrhage: the importance of arterial attenuation for the detection of intracranial aneurysms. AB - BACKGROUND: Computed tomography angiography (CTA) is today the primary method for the detection of intracranial aneurysms. The technique has evolved considerably during the last decade, and it is important to establish criteria for high image quality, especially with regard to improving the diagnosis of small aneurysms. PURPOSE: To evaluate diagnostic accuracy and image quality by arterial attenuation of CTA in patients with non-traumatic subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: Between 2005 and 2011, CTA and digital subtraction angiography (DSA) were performed in 326 patients with non-traumatic SAH. Sensitivity and specificity for aneurysm detection were evaluated per patient, per aneurysm, and per ruptured aneurysm. The image quality of CTA was evaluated by arterial attenuation measurements (mean Hounsfield units [HU]) in the internal carotid artery (ICA). RESULTS: In all, 285 aneurysms in 235 patients were detected by DSA, 19 aneurysms were missed on CTA, and 223 aneurysms were classified as ruptured. In 91 patients, no aneurysm was found. Correct diagnosis with CTA was made in 28 patients with perimesencephalic hemorrhage. Sensitivity and specificity (95% confidence interval) calculated per patient were 91.6% (87.3 94.9) and 87.9% (79.8-93.6), respectively, per aneurysm 93.3% (89.7-95.9) and 88% (79.9-93.6), and per ruptured aneurysm 94.9% (91.3-97.3) and 96.7% (90.7-99.3). Arterial attenuation (in HU) in CTA revealing true positive ruptured aneurysms and true negative aneurysms (mean 535 +/- 110 HU) differed significantly (P = 0.02) from false negative ruptured aneurysms (mean 424 +/- 30 HU). CONCLUSION: CTA has high sensitivity and specificity for the detection of ruptured aneurysms. The sensitivity is related to arterial attenuation in the ICA. PMID- 25293948 TI - Systematic analysis of the phosphoproteome and kinase-substrate networks in the mouse testis. AB - Spermatogenesis is a complex process closely associated with the phosphorylation orchestrated cell cycle. Elucidating the phosphorylation-based regulations should advance our understanding of the underlying molecular mechanisms. Here we present an integrative study of phosphorylation events in the testis. Large-scale phosphoproteome profiling in the adult mouse testis identified 17,829 phosphorylation sites in 3955 phosphoproteins. Although only approximately half of the phosphorylation sites enriched by IMAC were also captured by TiO2, both the phosphoprotein data sets identified by the two methods significantly enriched the functional annotation of spermatogenesis. Thus, the phosphoproteome profiled in this study is a highly useful snapshot of the phosphorylation events in spermatogenesis. To further understand phosphoregulation in the testis, the site specific kinase-substrate relations were computationally predicted for reconstructing kinase-substrate phosphorylation networks. A core sub-kinase substrate phosphorylation networks among the spermatogenesis-related proteins was retrieved and analyzed to explore the phosphoregulation during spermatogenesis. Moreover, network-based analyses demonstrated that a number of protein kinases such as MAPKs, CDK2, and CDC2 with statistically more site-specific kinase substrate relations might have significantly higher activities and play an essential role in spermatogenesis, and the predictions were consistent with previous studies on the regulatory roles of these kinases. In particular, the analyses proposed that the activities of POLO-like kinases (PLKs) might be dramatically higher, while the prediction was experimentally validated by detecting and comparing the phosphorylation levels of pT210, an indicator of PLK1 activation, in testis and other tissues. Further experiments showed that the inhibition of POLO-like kinases decreases cell proliferation by inducing G2/M cell cycle arrest. Taken together, this systematic study provides a global landscape of phosphoregulation in the testis, and should prove to be of value in future studies of spermatogenesis. PMID- 25293951 TI - Inter-reader variability when applying the 2013 Fleischner guidelines for potential solitary subsolid lung nodules. AB - BACKGROUND: In 2013, the Fleischner Society published recommendations for managing subsolid pulmonary nodules. Inter-reader variability has not yet been defined and has potential implications for the ease and reproducibility of applying the guidelines to clinical practice. PURPOSE: To evaluate inter-reader variability when applying the 2013 Fleischner guidelines for potential solitary subsolid lung nodules. MATERIAL AND METHODS: Potential nodules were identified through a systematic retrospective review of CT studies that reported a ground glass lesion. Three radiologists decided whether these lesions fit criteria of a subsolid nodule and thus merit application of the Fleischner Society guidelines, determined if a solid component was present, and measured each component in two dimensions. Final management recommendations were based on these intermediate decisions. Inter-reader variability for management was calculated and Fleiss' kappa was used to determine significance. Logistic regression and Fisher's exact test determined whether management was contingent on each intermediate decision. RESULTS: Forty-four nodules with mean diameter of 9.4 mm were evaluated by three radiologists. Final management recommendations were in agreement for 93 out of 132 cases (70.4%, kappa = 0.56). Inter-reader variability in management recommendation was contingent on disagreement over whether a pulmonary lesion fit criteria of a subsolid nodule for 24 cases (P < 0.01), whether there was a solid component for 10 cases (P = 0.01), and whether the measurement met the threshold of 5 mm for five cases (P = 0.12). CONCLUSION: There is moderate inter-reader variability when applying the 2013 Fleischner Society management recommendations. Significant contributors of variability include whether the potential lesions fit subsolid nodule criteria and whether a solid component is present. Measurement variability does not significantly affect the final management decisions. PMID- 25293952 TI - On the RF heating of coronary stents at 7.0 Tesla MRI. AB - PURPOSE: Examine radiofrequency (RF) induced heating of coronary stents at 7.0 Tesla (T) to derive an analytical approach which supports RF heating assessment of arbitrary stent geometries and RF coils. METHODS: Simulations are performed to detail electromagnetic fields (EMF), local specific absorption rates (SAR) and temperature changes. For validation E-field measurements and RF heating experiments are conducted. To progress to clinical setups RF coils tailored for cardiac MRI at 7.0T and coronary stents are incorporated into EMF simulations using a human voxel model. RESULTS: Our simulations of coronary stents at 297 MHz were confirmed by E-field and temperature measurements. An analytical solution which describes SAR(1g tissue voxel) induced by an arbitrary coronary stent interfering with E-fields generated by an arbitrary RF coil was derived. The analytical approach yielded a conservative estimation of induced SAR(1g tissue voxel) maxima without the need for integrating the stent into EMF simulations of the human voxel model. CONCLUSION: The proposed analytical approach can be applied for any patient, coronary stent type, RF coil configuration and RF transmission regime. The generalized approach is of value for RF heating assessment of other passive electrically conductive implants and provides a novel design criterion for RF coils. PMID- 25293954 TI - ABO-compatible retransplantation after ABO-incompatible infant heart transplantation: absence of donor specific isohemagglutinins. AB - Implementation of ABO-incompatible (ABOi) pediatric heart transplantation has contributed to significant reduction in the mortality of infants on the waiting list, without increasing the risk of rejection. This has been attributed to the immature and therefore not fully competent immune system in this population group, which results in lower production of isohemagglutinins compared to older children and adults. Serial evaluations of isohemagglutinin titers in infants revealed cases with absence of donor specific anti-blood group antibodies. However, it is currently unknown whether continuous exposure to donor antigens is necessary to prevent formation of donor specific isohemagglutinins (DSI) in recipients. We are reporting a case of an infant who underwent ABOi heart transplantation, with no evidence of DSI even 4 years after ABO-compatible retransplantation. Hence, temporary exposure to donor antigens in infants may contribute to permanent absence of donor specific anti-blood group antibodies, suggesting the possibility of induced permanent B cell tolerance. PMID- 25293953 TI - OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium. AB - PURPOSE: To identify the genetic cause of autosomal-dominant pattern dystrophy (PD) of the retinal pigment epithelium (RPE) in two families. METHODS AND RESULTS: Two families with autosomal-dominant PD were identified. Eight members of family 1 (five affected) were subjected to whole-genome SNP genotyping; multipoint genome-wide linkage analysis identified 7 regions of potential linkage, and genotyping four additional individuals from family 1 resulted in a maximum logarithm of odds score of 2.09 observed across four chromosomal regions. Exome sequencing of two affected family 1 members identified 15 shared non synonymous rare coding sequence variants within the linked regions; candidate genes were prioritised and further analysed. Sanger sequencing confirmed a novel heterozygous missense variant (E79K) in orthodenticle homeobox 2 (OTX2) that segregated with the disease phenotype. Family 2 with PD (two affected) harboured the same missense variant in OTX2. A shared haplotype of 19.68 cM encompassing OTX2 was identified between affected individuals in the two families. Within the two families, all except one affected demonstrated distinct 'patterns' at the macula. In vivo structural retinal imaging showed discrete areas of RPE photoreceptor separation at the macula in all cases. Electroretinogram testing showed generalised photoreceptor degeneration in three cases. Mild developmental anomalies were observed, including optic nerve head dysplasia (four cases), microcornea (one case) and Rathke's cleft cyst (one case); pituitary hormone levels were normal. CONCLUSIONS: This is the first report implicating OTX2 to underlie PD. The retinal disease resembles conditional mice models that show slow photoreceptor degeneration secondary to loss of Otx2 function in the adult RPE. PMID- 25293955 TI - The effect of smoke-free policies on hospitality industry revenues in Cyprus: an econometric approach. AB - OBJECTIVE: Smoke-free policies aiming to improve quality of indoor air and significantly reduce exposure to secondhand smoke in the hospitality industry are faced with strong opposition from the tobacco industry and hospitality venue owners claiming that they lead to reductions of revenues. The objective of our study was to examine the impact of a recently introduced smoke-free legislation on the revenues of the hospitality industry in Cyprus. METHODS: Anonymous information on revenues was obtained from the Cyprus government value added tax office for the entire hospitality industry in Cyprus including hotels, bars, restaurants and cafeterias between 2005 and 2011. Panel data methodology was used to examine the effect of a smoke-free legislation, on tourism, businesses' revenues adjusting for gross domestic product, inflation, unemployment rate, tourists' arrivals, seasonal variation and the economic crisis. RESULTS: Our study showed that the implementation of the smoke-free policy did not have negative effects on the hospitality industry profitability. CONCLUSIONS: We conclude that even in regions with relatively high smoking rates, pro-smoking societal attitudes and weak social norms against tobacco control, and even during periods of economic crisis, smoke-free legislation does not impact negatively on hospitality industry revenues and if anything may lead to a small positive increase. PMID- 25293957 TI - Ratiometric two-photon fluorescent probe for quantitative detection of beta galactosidase activity in senescent cells. AB - We reported a ratiometric two-photon fluorescent probe (SG1) for beta galactosidase (beta-gal) and its application to quantitative detection of beta gal activity during cellular senescence in live cells and in aged tissues. This probe is characterized by a significant two-photon excited fluorescence, a marked blue-to-yellow emission color change in response to beta-gal, easy loading, insensitivity to pH and reactive oxygen species (ROS), high photostability, and low cytotoxicity. In addition, we show that SG1 labeling is an effective tool for quantitative detection of senescence-associated beta-gal activity at the subcellular level in situ. This finding demonstrates that SG1 will find useful applications in biomedical research, including studies of cell aging. PMID- 25293956 TI - Predicting geriatric falls following an episode of emergency department care: a systematic review. AB - BACKGROUND: Falls are the leading cause of traumatic mortality in geriatric adults. Despite recent multispecialty guideline recommendations that advocate for proactive fall prevention protocols in the emergency department (ED), the ability of risk factors or risk stratification instruments to identify subsets of geriatric patients at increased risk for short-term falls is largely unexplored. OBJECTIVES: This was a systematic review and meta-analysis of ED-based history, physical examination, and fall risk stratification instruments with the primary objective of providing a quantitative estimate for each risk factor's accuracy to predict future falls. A secondary objective was to quantify ED fall risk assessment test and treatment thresholds using derived estimates of sensitivity and specificity. METHODS: A medical librarian and two emergency physicians (EPs) conducted a medical literature search of PUBMED, EMBASE, CINAHL, CENTRAL, DARE, the Cochrane Registry, and Clinical Trials. Unpublished research was located by a hand search of emergency medicine (EM) research abstracts from national meetings. Inclusion criteria for original studies included ED-based assessment of pre-ED or post-ED fall risk in patients 65 years and older with sufficient detail to reproduce contingency tables for meta-analysis. Original study authors were contacted for additional details when necessary. The Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) was used to assess individual study quality for those studies that met inclusion criteria. When more than one qualitatively similar study assessed the same risk factor for falls at the same interval following an ED evaluation, then meta-analysis was performed using Meta DiSc software. The primary outcomes were sensitivity, specificity, and likelihood ratios for fall risk factors or risk stratification instruments. Secondary outcomes included estimates of test and treatment thresholds using the Pauker method based on accuracy, screening risk, and the projected benefits or harms of fall prevention interventions in the ED. RESULTS: A total of 608 unique and potentially relevant studies were identified, but only three met our inclusion criteria. Two studies that included 660 patients assessed 29 risk factors and two risk stratification instruments for falls in geriatric patients in the 6 months following an ED evaluation, while one study of 107 patients assessed the risk of falls in the preceding 12 months. A self-report of depression was associated with the highest positive likelihood ratio (LR) of 6.55 (95% confidence interval [CI] = 1.41 to 30.48). Six fall predictors were identified in more than one study (past falls, living alone, use of walking aid, depression, cognitive deficit, and more than six medications) and meta-analysis was performed for these risk factors. One screening instrument was sufficiently accurate to identify a subset of geriatric ED patients at low risk for falls with a negative LR of 0.11 (95% CI = 0.06 to 0.20). The test threshold was 6.6% and the treatment threshold was 27.5%. CONCLUSIONS: This study demonstrates the paucity of evidence in the literature regarding ED-based screening for risk of future falls among older adults. The screening tools and individual characteristics identified in this study provide an evidentiary basis on which to develop screening protocols for geriatrics adults in the ED to reduce fall risk. PMID- 25293958 TI - Multiple paramagnetic effects through a tagged reporter protein. AB - Paramagnetic effects provide unique information about the structure and dynamics of biomolecules. We developed a method in which the lanthanoid tag is not directly attached to the protein of interest, but instead to a "reporter" protein, which binds and then transmits paramagnetic information to the target. The designed method allows access to a large number of paramagnetic restraints and residual dipolar couplings produced from independent molecular alignments in high-molecular-weight proteins with unknown 3D structure. PMID- 25293960 TI - Large root cortical cell size improves drought tolerance in maize. AB - The objective of this study was to test the hypothesis that large cortical cell size (CCS) would improve drought tolerance by reducing root metabolic costs. Maize (Zea mays) lines contrasting in root CCS measured as cross-sectional area were grown under well-watered and water-stressed conditions in greenhouse mesocosms and in the field in the United States and Malawi. CCS varied among genotypes, ranging from 101 to 533 um(2). In mesocosms, large CCS reduced respiration per unit of root length by 59%. Under water stress in mesocosms, lines with large CCS had between 21% and 27% deeper rooting (depth above which 95% of total root length is located in the soil profile), 50% greater stomatal conductance, 59% greater leaf CO2 assimilation, and between 34% and 44% greater shoot biomass than lines with small CCS. Under water stress in the field, lines with large CCS had between 32% and 41% deeper rooting (depth above which 95% of total root length is located in the soil profile), 32% lighter stem water isotopic ratio of (18)O to (16)O signature, signifying deeper water capture, between 22% and 30% greater leaf relative water content, between 51% and 100% greater shoot biomass at flowering, and between 99% and 145% greater yield than lines with small cells. Our results are consistent with the hypothesis that large CCS improves drought tolerance by reducing the metabolic cost of soil exploration, enabling deeper soil exploration, greater water acquisition, and improved growth and yield under water stress. These results, coupled with the substantial genetic variation for CCS in diverse maize germplasm, suggest that CCS merits attention as a potential breeding target to improve the drought tolerance of maize and possibly other cereal crops. PMID- 25293959 TI - Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects. AB - BACKGROUND: Neural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population. METHODS: Replication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS. RESULTS: Of the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans. CONCLUSIONS: We report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis. PMID- 25293962 TI - beta-Amylase1 and beta-amylase3 are plastidic starch hydrolases in Arabidopsis That Seem to Be Adapted for Different Thermal, pH, and stress conditions. AB - Starch degradation in chloroplasts requires beta-amylase (BAM) activity, which is encoded by a multigene family. Of nine Arabidopsis (Arabidopsis thaliana) BAM genes, six encode plastidic enzymes, but only four of these are catalytically active. In vegetative plants, BAM1 acts during the day in guard cells, whereas BAM3 is the dominant activity in mesophyll cells at night. Plastidic BAMs have been difficult to assay in leaf extracts, in part because of a cytosolic activity encoded by BAM5. We generated a series of double mutants lacking BAM5 and each of the active plastidic enzymes (BAM1, BAM2, BAM3, and BAM6) and found that most of the plastidic activity in 5-week-old plants was encoded by BAM1 and BAM3. Both of these activities were relatively constant during the day and the night. Analysis of leaf extracts from double mutants and purified BAM1 and BAM3 proteins revealed that these proteins have distinct properties. Using soluble starch as the substrate, BAM1 and BAM3 had optimum activity at pH 6.0 to 6.5, but at high pH, BAM1 was more active than BAM3, consistent with its known daytime role in the guard cell stroma. The optimum temperature for BAM1, which is transcriptionally induced by heat stress, was about 10 degrees C higher than that of BAM3, which is transcriptionally induced by cold stress. The amino acid composition of BAM1 and BAM3 orthologs reflected differences that are consistent with known adaptations of proteins from heat- and cold-adapted organisms, suggesting that these day- and night-active enzymes have undergone thermal adaptation. PMID- 25293961 TI - Regulatory properties of ADP glucose pyrophosphorylase are required for adjustment of leaf starch synthesis in different photoperiods. AB - Arabidopsis (Arabidopsis thaliana) leaves synthesize starch faster in short days than in long days, but the mechanism that adjusts the rate of starch synthesis to daylength is unknown. To understand this mechanism, we first investigated whether adjustment occurs in mutants lacking components of the circadian clock or clock output pathways. Most mutants adjusted starch synthesis to daylength, but adjustment was compromised in plants lacking the GIGANTEA or FLAVIN-BINDING, KELCH REPEAT, F BOX1 components of the photoperiod-signaling pathway involved in flowering. We then examined whether the properties of the starch synthesis enzyme adenosine 5'-diphosphate-glucose pyrophosphorylase (AGPase) are important for adjustment of starch synthesis to daylength. Modulation of AGPase activity is known to bring about short-term adjustments of photosynthate partitioning between starch and sucrose (Suc) synthesis. We found that adjustment of starch synthesis to daylength was compromised in plants expressing a deregulated bacterial AGPase in place of the endogenous AGPase and in plants containing mutant forms of the endogenous AGPase with altered allosteric regulatory properties. We suggest that the rate of starch synthesis is in part determined by growth rate at the end of the preceding night. If growth at night is low, as in short days, there is a delay before growth recovers during the next day, leading to accumulation of Suc and stimulation of starch synthesis via activation of AGPase. If growth at night is fast, photosynthate is used for growth at the start of the day, Suc does not accumulate, and starch synthesis is not up-regulated. PMID- 25293964 TI - The timing of spheno-occipital fusion in hominoids. AB - The degree of spheno-occipital fusion has been used to assign a relative age to dentally mature hominoid cranial specimens. However, a recent study of captive individuals (Poe: Am J Phys Anthropol 144 (2011) 162-165) concluded that fusion of the spheno-occipital suture in great ape taxa is of little utility for aging dentally mature individuals. In this contribution, I use dentally mature samples of extant hominoid taxa (Homo sapiens, Pan troglodytes schweinfurthii, Gorilla gorilla gorilla, Pongo pygmaeus pygmaeus and Hylobates lar) to investigate a) the temporal relationship between spheno-occipital fusion and dental maturity, b) whether there is an association between the degree of spheno-occipital fusion and relative age, c) whether there are differences in relative timing of spheno occipital fusion between taxa, and d) whether there are sex differences in the relative timing of spheno-occipital fusion. Results suggest that a) a substantial proportion of dentally mature wild-shot chimpanzee, gorilla and orang-utans have unfused or partially fused spheno-occipital synchondoses, b) there is an association between the degree of spheno-occipital fusion and age, c) there are interspecific differences in the timing of spheno-occipital fusion, and d) there are significant sex differences in spheno-occipital fusion in chimpanzees, orang utans and gibbons. Thus, contrary to previous work, degree of spheno-occipital fusion is a potentially useful indicator of relative maturity, especially in great ape taxa. PMID- 25293965 TI - Exploring the psychological impact of Mayer-Rokitansky-Kuster-Hauser syndrome on young women: An interpretative phenomenological analysis. AB - This study explored five young women's experiences of living with Mayer Rokitansky-Kuster-Hauser to offer a unique insight into the social challenges of Mayer-Rokitansky-Kuster-Hauser in the transition to adulthood. Non-directive semi structured interviews took place within the National Health Service settings, and transcripts were analysed using interpretative phenomenological analysis. Four inter-related themes were identified: hindering independence, a sensitivity to difference, managing intimacy and managing threat to identity. The women managed their presentation to others in order to minimise the impact of their diagnosis. Recommendations for further research and implications for services are noted. PMID- 25293963 TI - Abscisic acid promotion of arbuscular mycorrhizal colonization requires a component of the PROTEIN PHOSPHATASE 2A complex. AB - Legumes can establish intracellular interactions with symbiotic microbes to enhance their fitness, including the interaction with arbuscular mycorrhizal (AM) fungi. AM fungi colonize root epidermal cells to gain access to the root cortex, and this requires the recognition by the host plant of fungus-made mycorrhizal factors. Genetic dissection has revealed the symbiosis signaling pathway that allows the recognition of AM fungi, but the downstream processes that are required to promote fungal infection are poorly understood. Abscisic acid (ABA) has been shown to promote arbuscule formation in tomato (Solanum lycopersicum). Here, we show that ABA modulates the establishment of the AM symbiosis in Medicago truncatula by promoting fungal colonization at low concentrations and impairing it at high concentrations. We show that the positive regulation of AM colonization via ABA requires a PROTEIN PHOSPHATASE 2A (PP2A) holoenzyme subunit, PP2AB'1. Mutations in PP2AB'1 cause reduced levels of AM colonization that cannot be rescued with permissive ABA application. The action of PP2AB'1 in response to ABA is unlinked to the generation of calcium oscillations, as the pp2aB'1 mutant displays a normal calcium response. This contrasts with the application of high concentrations of ABA that impairs mycorrhizal factor-induced calcium oscillations, suggesting different modes of action of ABA on the AM symbiosis. Our work reveals that ABA functions at multiple levels to regulate the AM symbiosis and that a PP2A phosphatase is required for the ABA promotion of AM colonization. PMID- 25293967 TI - Masculinity impediments: Internalized masculinity contributes to healthcare avoidance in men and women. AB - Gender beliefs contribute to men's healthcare avoidance, but little research examines these outcomes in women. This article models healthcare avoidance related to masculine contingencies of self-worth in men and women. Nested path modelling tested relationships between social role beliefs, masculine contingencies of self-worth, barriers to help seeking and avoidance of health care in university and non-university-student adult samples. Results indicated social role beliefs predicted masculine contingencies of self-worth in men but not in women. Regardless of gender, masculine contingencies of self-worth predicted barriers to help seeking, which predicted healthcare avoidance in both men and women. Thus, masculine contingencies of self-worth have downstream consequences for men and women through barriers to help seeking. PMID- 25293966 TI - Effects of psychotherapy in combination with pharmacotherapy, when compared to pharmacotherapy only on blood pressure, depression, and anxiety in female patients with hypertension. AB - We investigated effects of metacognitive detached mindfulness therapy and stress management training on hypertension and symptoms of depression and anxiety, as compared to a control condition. A total of 45 female patients (mean age: M = 36.49 years) were randomly assigned to one of three conditions: metacognitive detached mindfulness therapy, stress management training, and the control condition. Blood pressure and symptoms of depression and anxiety decreased from baseline to post-test, to follow-up. Group comparisons showed that blood pressure and symptoms of depression and anxiety decreased more in psychotherapeutic groups than in the control group. Psychotherapeutic treatment of hypertension reduced blood pressure and symptoms of depression and anxiety. Positive effects were observable at follow-up 8 weeks later. PMID- 25293968 TI - Exploring the role of ethnicity on perceptions of cancer and physical health recovery during the first year of survivorship. AB - This study examined the role of ethnicity (Black vs White) in the extent to which patients' appraisal of the impact of cancer on themselves and their family members relates to their physical health. Colorectal cancer patients provided self-reports for study variables at 2 and 12 months post-diagnosis (N = 60). Hierarchical regression analysis revealed that African American patients' perception of the cancer as disruptive to their family, but not to themselves, related to poorer health recovery, which association was absent among Whites (p < .02). Findings suggest that cancer-related family stress plays a different role between two ethnic groups in elucidating their health recovery during the early survivorship. PMID- 25293969 TI - Psychometric properties of a MOVE!23 subscale: Perceived Contributors to Weight Change in a national sample of veterans. AB - The MOVE!23, a questionnaire to assess weight-related domains in veterans, was examined. Factor analysis of Perceived Contributors to Weight Change revealed three factors (psychosocial, eating behavior, and medical) that were positively correlated with body mass index, and psychiatric and medical comorbidity (p's < 0.001). Multivariable cumulative logit models modeling the factor scores indicated that women were more likely than men to endorse psychosocial (odds ratio = 2.15, confidence interval = 2.04-2.27) and medical (odds ratio = 1.69, confidence interval = 1.59-1.79) items. The MOVE!23 Perceived Contributors to Weight Change subscale is a reliable and valid measure that is associated with body mass index and may assist in tailoring treatments according to gender and comorbidity. PMID- 25293970 TI - Medical mistrust is related to lower longitudinal medication adherence among African-American males with HIV. AB - African-Americans living with HIV show worse health behaviors (e.g. medication adherence) and outcomes (e.g. viral suppression) than do their White counterparts. In a 6-month longitudinal study, we investigated whether medical mistrust among African-American males with HIV (214 enrolled, 140 with longitudinal data) predicted lower electronically monitored antiretroviral medication adherence. General medical mistrust (e.g. suspicion toward providers), but not racism-related mistrust (e.g. belief that providers treat African Americans poorly due to race), predicted lower continuous medication adherence over time (b = -.08, standard error = .04, p = .03). Medical mistrust may contribute to poor health outcomes. Intervention efforts that address mistrust may improve adherence among African-Americans with HIV. PMID- 25293971 TI - Variations in coping stages for individuals with chronic kidney disease: Results from an exploratory study with patient navigators. AB - Using a cross-sectional design, we examined coping stages (Kubler-Ross) among patients with end-stage renal disease at nephrology practices incorporating professional social workers as patient navigators, providing person-centered education and support (N = 420). We evaluated associations with behavioral counseling constructs (assess-advise-agree-assist-arrange). Coping stages comprised denial = 35.24 percent, acceptance = 24.05 percent, depression = 21.43 percent, bargaining = 12.86 percent, and anger = 6.43 percent. Compared to denial, other coping stages showed increased odds ratios for transplant referral agreement, transplant referral evaluations, understanding treatments, understanding donation procedures, plans to recruit donors, active donor recruitment, and potential living donor(s). Assessment of coping stages, and strategies to influence these, may be key factors in guiding patients to living donor kidney transplantation. PMID- 25293973 TI - Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas. AB - The potent anti-proliferative and pro-apoptotic actions of tocotrienols (T3) against cancer, but not normal tissues, have been hampered by their limited systemic bioavailabilty. Recent expansive development of diverse nanoemulsion (NE) vehicles emphasized their vast potential to improve the effective dosing of different clinical and experimental drugs of lipophilic nature, such as T3. The emphasis of the present work is to develop a pharmaceutically scalable, low energy nano-emulsification approach for optimized incorporation of T3-rich palm oil (Tocomin(r)), possessing anticancer activity as a potential cutaneous delivery platform for adjunctive therapy of skin carcinomas, either alone or in combination with other chemotherapeutic agents. Different Tocomin(r)-NEs, obtained with different homogenization strategies, were screened based on physicochemical uniformity (droplet size, charge and polydispersity) and subjected to stress physical stability testing, along with chemical content analysis (>=90% Tocomin(r) - incorporation efficiency). Adopted hybrid nano emulsification of Tocomin(r), correlated with highest preservation of DPPH radical scavenging capacity of active T3 in prototype formulation, Tocomin(r)-NE, which effectively permeated diffusion cell membranes 4-folds higher than propyleneglycol (PG)-admixed Tocomin(r) control. Against two different cell models of human cutaneous carcinoma, Tocomin(r)-hybrid NE demonstrated significantly stronger cytotoxic profiles (p <= 0.01), visible in both concentration- and time- dependent manners, with at least 5-folds lower IC50 values, compared to those estimated for the closest Tocomin(r)-control. The proposed hybrid nano-emulsified formulation of Tocomin(r) provides simple and stable delivery platform, for effective topical application against keratinocyte tumors. PMID- 25293974 TI - SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling. AB - The tumor-suppressor protein promyelocytic leukemia (PML) is aberrantly degraded in multiple types of human cancers through mechanisms that are incompletely understood. Here, we show that the phosphatase SCP1 and its isoforms SCP2/3 dephosphorylate PML at S518, thereby blocking PML ubiquitination and degradation mediated by the prolyl isomerase Pin1 and the ubiquitin ligase KLHL20. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these events correlated with PMLS518 phosphorylation, PML turnover, and high-grade tumors. Restoring SCP1-mediated PML stabilization not only inhibited malignant features of ccRCC, including proliferation, migration, invasion, tumor growth, and tumor angiogenesis, but also suppressed the mTOR-HIF pathway. Furthermore, blocking PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhanced the tumor-suppressive effects of the mTOR inhibitor temsirolimus. Taken together, our results define a novel pathway of PML degradation in ccRCC that involves SCP downregulation, revealing contributions of this pathway to ccRCC progression and offering a mechanistic rationale for combination therapies that jointly target PML degradation and mTOR inhibition for ccRCC treatment. PMID- 25293972 TI - Increased meiotic crossovers and reduced genome stability in absence of Schizosaccharomyces pombe Rad16 (XPF). AB - Schizosaccharomyces pombe Rad16 is the ortholog of the XPF structure-specific endonuclease, which is required for nucleotide excision repair and implicated in the single strand annealing mechanism of recombination. We show that Rad16 is important for proper completion of meiosis. In its absence, cells suffer reduced spore viability and abnormal chromosome segregation with evidence for fragmentation. Recombination between homologous chromosomes is increased, while recombination within sister chromatids is reduced, suggesting that Rad16 is not required for typical homolog crossovers but influences the balance of recombination between the homolog and the sister. In vegetative cells, rad16 mutants show evidence for genome instability. Similar phenotypes are associated with mutants affecting Rhp14(XPA) but are independent of other nucleotide excision repair proteins such as Rad13(XPG). Thus, the XPF/XPA module of the nucleotide excision repair pathway is incorporated into multiple aspects of genome maintenance even in the absence of external DNA damage. PMID- 25293975 TI - Study protocol of an economic evaluation of an extended implementation strategy for the treatment of low back pain in general practice: a cluster randomised controlled trial. AB - BACKGROUND: In Denmark, guidelines on low back pain management are currently being implemented; in association with this, a clinical trial is conducted. A health economic evaluation is carried out alongside the clinical trial to assess the cost-effectiveness of an extended implementation strategy to increase the general practitioners' adherence to the guidelines. In addition to usual dissemination, the extended implementation strategy is composed of visits from a guideline facilitator, stratification tools, and feedback on guideline adherence. The aim of this paper is to provide the considerations on the design of the health economic evaluation. METHODS/DESIGN: The economic evaluation is carried out alongside a cluster randomised controlled trial consisting of 60 general practices in the North Denmark Region. An expected 1,200 patients between the age of 18 and 65 years with a low back pain diagnosis will be enrolled. The economic evaluation comprises both a cost-effectiveness analyses and a cost-utility analysis. Effectiveness measures include referral to secondary care, health related quality of life measured by EQ-5D-5L, and disability measured by the Roland Morris disability questionnaire. Cost measures include all relevant additional costs of the extended implementation strategy compared to usual implementation. The economic evaluation will be performed from both a societal perspective and a health sector perspective with a 12-month time horizon. DISCUSSION: It is expected that the extended implementation strategy will reduce the number of patients referred to secondary care. It is hypothesised that the additional upfront cost of extended implementation will be counterbalanced by improvements in clinical practice and patient-related outcomes, thereby rendering the extended implementation strategy cost-effective. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01699256. PMID- 25293976 TI - Effect of citric acid crosslinking cellulose-based hydrogels on osteogenic differentiation. AB - Understanding the relationships between material surface properties and cellular responses is essential to designing optimal material surfaces for implantation and tissue engineering. In this study, cellulose hydrogels were crosslinked using a non-toxic and natural component namely citric acid. The chemical treatment induces ?COOH functional groups that improve the hydrophilicity, roughness, and materials rheological properties. The physiochemical, morphological, and mechanical analyses were performed to analyze the material surface before and after crosslinking. This approach would help determine if the effect of chemical treatment on cellulose hydrogel improves the hydrophilicity, roughness, and rheological properties of the scaffold. In this study, it was demonstrated that the biological responses of human mesenchymal stem cell with regard to cell adhesion, proliferation, and differentiation were influenced in vitro by changing the surface chemistry and roughness. PMID- 25293977 TI - Antimicrobial activity of a quinuclidine-based FtsZ inhibitor and its synergistic potential with beta-lactam antibiotics. AB - Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein that cooperates in the formation of the cytokinetic Z-ring in most bacteria and has thus been recognized as a promising antimicrobial drug target. We have recently used a structure-based virtual screening approach to identify pyrimidine-linked quinuclidines as a novel class of FtsZ inhibitors. In this study, we further investigated the antibacterial properties of one of the most potent compounds (quinuclidine 1) and its synergistic activity with beta-lactam antibiotics. Susceptibility results showed that quinuclidine 1 was active against multiple antibiotic-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium with minimal inhibitory concentrations of 24 MUg ml(-1). When quinuclidine 1 was combined with beta-lactam antibiotics, synergistic antimicrobial activities against antibiotic resistant strains of S. aureus were found. Further in vitro studies suggest that prevention of FtsZ protofilament formation by quinuclidine 1 impairs the formation of Z-ring, and thus inhibits bacterial division. These findings open a new approach for development of quinuclidine-based FtsZ inhibitors into potent antimicrobial agents. PMID- 25293978 TI - Characterization of four new antifungal yanuthones from Aspergillus niger. AB - Four new yanuthone analogs (1-4) were isolated from the filamentous fungus Aspergillus niger. The structures of the new compounds were elucidated on the basis of UHPLC-DAD-HRMS data and one-dimensional and two-dimensional NMR spectroscopy. Labeling studies with (13)C8-6-methylsalicylic acid identified three class I yanuthones originating from the polyketide 6-methylsalicylic acid (yanuthone K, L and M (1-3)) and a class II yanuthone, which was named yanuthone X2 (4). The four new compounds were tested toward the pathogenic yeast Candida albicans and all displayed antifungal activity. Yanuthone X2 represents the first example of a bioactive class II yanuthone, demonstrating the pharmaceutical potential of this class. PMID- 25293979 TI - A wolf in sheep's clothing: how Monitor is using licensing powers to reduce hospital and community services in England under the guise of continuity. PMID- 25293980 TI - Adult-onset inflammatory myofibroblastic tumour of the stomach with a TFG-ROS1 fusion. PMID- 25293981 TI - On the importance of thermal effects and crystalline disorder in the magnetism of benzotriazinyl-derived organic radicals. AB - Recent experiments suggest that benzotriazinyl-derived radicals are promising building blocks for the design of new functional materials. Herein, a detailed computational study of the main structural and magnetic features of two prototypes of this family of radicals is presented. By means of several computational techniques within the DFT framework, this work unveils the key importance of the thermal contraction of the crystal to quantitatively predict the magnetism of the studied compounds. In this sense, for the first time in the context of molecular magnetism, we propose to use variable-cell geometry optimizations as an efficient alternative to obtain an estimation of low temperature crystal structures. The crucial role of crystalline disorder in defining the structure present at low temperature, and thus, the magnetic response, is revealed. Altogether, these are important elements for the rational design of future materials of this family of compounds. PMID- 25293982 TI - An investigation of the relationship between ethnicity and success in a BSc (Hons) Physiotherapy degree programme in the UK. AB - OBJECTIVES: To explore the potential relationship between ethnicity and achievement within undergraduate physiotherapy education. DESIGN: A retrospective analysis of assessment marks awarded for academic and clinical modules. SETTING: A London University offering undergraduate physiotherapy education. PARTICIPANTS: Four hundred forty-eight undergraduate students enrolled onto the Physiotherapy honours degree programme between 2005 and 2009. MAIN OUTCOME MEASURES: Marks awarded following academic or clinical assessment. These were modelled through multivariable regression analysis to evaluate the relationship between marks awarded and ethnicity. RESULTS: Differences were noted between ethnic categories in final programme success and across academic and clinical modules. Our multivariable analysis demonstrated students from Asian backgrounds had decreased odds of succeeding compared with white British students (adjusted OR 0.43 95%CI 0.24, 0.79 P=0.006), as had Black students (adjusted OR 0.42 95%CI 0.19, 0.95 P=0.036) and students from Other ethnic backgrounds (adjusted OR 0.41 95%CI 0.20, 0.87 P=0.020). CONCLUSIONS: This analysis of undergraduate physiotherapy students illustrated a persistent difference in attainment between students from white British and those from BME backgrounds. Heterogeneity in academic outcomes both within and between minority ethnic groups was illustrated. This study not only reinforces the need to consider ethnicity within physiotherapy education but also raises further questions about why physiotherapy students from BME groups perform less well than their white British peers. PMID- 25293983 TI - Comparison of static postural stability in exercising and non-exercising women during the perinatal period. AB - BACKGROUND: The purpose of the study was to determine whether women who exercised during and after pregnancy had better static postural stability compared to those who did not exercise. MATERIAL AND METHODS: Posturographic tests were performed in 31 women at 34-39 weeks gestation, and again at 6-10 weeks postpartum. The center of pressure mean velocity (with directional subcomponents) and sway area were computed from 30-s quiet standing trials on a stationary force plate with eyes open or closed. The women were surveyed about their lifestyle and physical activity in the perinatal period. Based on the survey, 12 of the women were assigned as regular exercisers and 19 as non-exercisers. A Mann-Whitney U test was used to compare data of the exercisers and the non-exercisers in their advanced pregnancy and again at 2 months postpartum. RESULTS: Postural sway measures were not significantly different between the exercisers and the non exercisers in advanced pregnancy and at 2 months postpartum (p>0.05). CONCLUSIONS: Individually performed physical activity during the perinatal period did not affect pregnant/postpartum women's postural stability characteristics of quiet standing. PMID- 25293985 TI - [Hepatitis C: pending challenges]. PMID- 25293986 TI - [Antitransglutaminase antibody positivity in adults histologically compatible with celiac disease]. AB - OBJECTIVE: To determine the frequency of positive results for antitransglutaminase antibody in adult patients histologically compatible with celiac disease. MATERIAL AND METHODS: Cross sectional, descriptive study with research-oriented regime, which included medical records of Gastroenterology Service of San Pablo Clinic, Lima, Peru from 1994 to 2011 with biopsies histologically compatible with CD and antitransglutaminase antibodies to find the frequency of positive serology. RESULTS: According to criteria established by the present study, we worked on a total of 44 medical records which included 18 (40.9%) men and 26 (59.1%) women, mean age at diagnosis of 51 +/- 16.23 years at the total. From all, 12 (27.27%) were positive for AATG, 2 (4.54%) values were indeterminate and 30 (68.18%) were negative with histological findings compatible with CD. CONCLUSION: It is not frequent positive results for antitransglutaminase antibody in adult patients histologically compatible with celiac disease. PMID- 25293984 TI - Words matter: distinguishing "personalized medicine" and "biologically personalized therapeutics". AB - "Personalized medicine" has become a generic term referring to techniques that evaluate either the host or the disease to enhance the likelihood of beneficial patient outcomes from treatment interventions. There is, however, much more to personalization of care than just identifying the biotherapeutic strategy with the highest likelihood of benefit. In its new meaning, "personalized medicine" could overshadow the individually tailored, whole-person care that is at the bedrock of what people need and want when they are ill. Since names and definitional terms set the scope of the discourse, they have the power to define what personalized medicine includes or does not include, thus influencing the scope of the professional purview regarding the delivery of personalized care. Taxonomic accuracy is important in understanding the differences between therapeutic interventions that are distinguishable in their aims, indications, scope, benefits, and risks. In order to restore the due emphasis to the patient and his or her needs, we assert that it is necessary, albeit belated, to deconflate the contemporary term "personalized medicine" by taxonomizing this therapeutic strategy more accurately as "biologically personalized therapeutics" (BPT). The scope of truly personalized medicine and its relationship to biologically personalized therapeutics is described, emphasizing that the best of care must give due recognition and emphasis to both BPT and truly personalized medicine. PMID- 25293987 TI - [Intraductal papillary mucinous neoplasms of the pancreas in Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru]. AB - OBJECTIVE: To analyze retrospectively the clinical, radiologic and pathologic features as well as the surgical results of the patients with diagnosis of intraductal papillary mucinous neoplasms of the pancreas (IPMN). MATERIALS AND METHODS: Patients with diagnosis of IPMN who underwent pancreatectomy were identified from January 2006 to September 2013, using the prospective data base of the Pancreas, Spleen and retroperitoneum HNGAI service. RESULTS: A total of 11 patients were found (9 females and 2 males). The mean age was 67.36 years. 2 were main duct type IPMN, 3 branch type and 6 mixed type. All patients had symptoms. The pain was the most frequent symptom, 27% had pancreatitis. For the diagnosis 100% had CT scan, 90% MRI. 10 patients underwent pancreaticoduodenectomy and 1 distal pancreatectomy. 2 patients had type C pancreatic fistula. 2 patients underwent reoperation and 1 died. 5 patients had low grade dysplasia, 2 moderate dysplasia, 1 high grade dysplasia and 3 invasive carcinoma. CONCLUSIONS: This entity is present in our country being more common in women. The mixed type IPMN is the most frequent type. Complication with the highest incidence is the pancreatic fistula and the mortality rate is low. The IPMN's malignancy potential founded was high. PMID- 25293988 TI - [Clinical, radiological and laboratory features of liver hydatidosis of patients from a hospital of national reference, Lima 1997-2010]. AB - OBJECTIVE: To describe the clinical, laboratory and radiological features of patients with hepatic hydatid cyst treated at the department of general surgery of a national referral hospital in Lima (Peru). MATERIALS AND METHODS: A cross sectional study was performed, all patients diagnosed with hepatic hydatid cyst hospitalized between 1997 and 2010 were included. Sociodemographic data (age, sex, origin and usual activity), clinical, laboratory, radiographic and data referrals to treatment were collected. RESULTS: The most common symptom was abdominal pain (93.9%), while the most frequent sign was the increase in liver span (68.7%). 86.4% of patients had a leukocyte formulated within normal ranges, eosinophilia was only present in 25.9% of cases. The right hepatic lobe was the most affected (80%) and in 40.8% of patient's condition one segment was found. In 75.4% of patients the cysts were unique. The most frequent complications were: communication to the bile duct (48.9%), hydatid abscesses (32.6%), cholangitis (4%), hydatid cyst and broken more peritonitis (4%). CONCLUSION: The population more affected was young adults aged 30 to 39 years. The population studied lives mostly in the department of Lima, but come from departments where hepatic hydatid disease has been described as endemic. Although this population is mostly urban, epidemiological characteristics do not vary in relation to that described in previous research. PMID- 25293989 TI - [Systemic inflammatory response syndrome as prognostic indicator in hospitalized cirrhotic patients]. AB - OBJECTIVE: The systemic inflammation worsens circulatory disorders in cirrhotic patients and recently the systemic inflammatory response syndrome (SIRS) may be a prognostic indicator therein. The aim of the study was to determine whether the presence of SIRS at admission in hospitalized cirrhotic patients is associated with complications or mortality. MATERIALS AND METHODS: A retrospective cohorts study was conducted at the Daniel Alcides Carrion National Hospital.Hospitalized cirrhotic patients admitted from July 2008 to December 2010 without significant comorbidities, malignancy,HIV infection, or stay less than 72 hours were included. Presence of SIRS at admission and the occurrence of complications or death after 72 hours of admission were evaluated. RESULTS: 150 cirrhotic patients were admitted, six were excluded;three for lower survival at 72 hours, one for neoplasia, one for severe heart failure and two for chronic renal failure. One hundred forty four patients were included, 95 (66%) patients had SIRS at admission. There was no significant difference in age, sex, etiology, in both groups. SIRS was associated with higher scores of MELD and Child-Turcotte Pugh. Of the group of patients with SIRS, 41 (43%) had complications and 16 (16.8%) died, while the group without SIRS 5 (10.2%) had complications and two (4%) died p < 0.0001 and p=0.028 respectively. The most common complications were infections and hepatic encephalopathy. In multivariate analysis SIRS was associated with complications (p < 0.006) but not with mortality(p < 0.276). CONCLUSIONS: SIRS is common in hospitalized cirrhotic patients and is associated with in-hospital complications. PMID- 25293990 TI - Systematic review and meta-analysis of endoscopic ablative treatment of Barrett's esophagus. AB - BACKGROUND: Barrett's esophagus (BE) is the main risk factor for esophageal adenocarcinoma. Its therapeutic approach is controversial and surgical treatment in the presence of high-grade intraepithelial neoplasia may be indicated. Endoscopic approach is an alternative with lower mortality and morbidity rates and favorable results. OBJECTIVE: To define the best option, according to literature, to treat Barrett's Esophagus. MATERIALS AND METHODS: DESIGN: Systematic review of PUBMED, EMBASE, LILACS, and Cochrane Library databases was conducted and articles of randomized, controlled studies on BE endoscopic ablative treatment were selected. The systematic review through PUBMED retrieved results with higher evidence level and available recommendation grade regarding BE ablative therapy. Nine articles on randomized, controlled studies classified as A or B according to the Oxford table were selected. Cryotherapy, laser, photodynamic therapy (PDT), multipolar electrocoagulation (MPEC), and ablation through argon plasma coagulation (APC) and radiofrequency were considered ablation therapies. PATIENTS: 649 patients from 10 different studies were analysed. RESULTS: PDT was found to present an increase in treatment failure compared with APC, NNH = -7. BE ablation through MPEC or APC was found to have similar risk for treatment failure in meta-analysis. PDT associated with proton pump inhibitor (PPI) is beneficial for BE ablation regarding PPI use alone, NNT = 2.Radiofrequency with PPI is an efficient method to reduce risk of treatment failure, NNT = 1. CONCLUSIONS: There are no studies demonstrating the benefit of indicating cryotherapy or laser therapy for BE endoscopic approach. APC ablation was found to have superior efficacy compared with PDT and ablation through APC and MPEC was found to present effective, similar results. Radiofrequency is the most recent approach requiring comparative studies for indication. PMID- 25293991 TI - A review on endoscopic palliation of obstructive jaundice before surgery. AB - Since its development, endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a simple diagnostic technique to an important therapeutic procedure. Obstructive jaundice is often the first and most common complication in patients with malignant disease of the extrahepatic biliary tract. Although preoperative biliary drainage (PBD) may be instituted in many centers, different studies have reported divergent results regarding its benefits in reducing the complications of hepatopancreatobiliary surgery, especially with regard to pancreatoduodenectomy for pancreatic cancer. In this review, we will summarize the current literature of PBD and describe its indications, possible benefits, and, when indicated, the appropriate interval before surgery. PMID- 25293992 TI - Metagenomic analysis of the gastric microbiota cultivable from a patient with gastritis concomitant with Barrett's esophagus. AB - Barrett's esophagus is a distal metaplasia characterized by the transformation of squamous mucosa into columnar mucosa. This esophageal phenotype is a product not only of the chronic reflux of gastric acids, but also by microorganisms that colonize the oral cavity and stomach. Two classes of microbiota can be identified in Barrett's esophagus; microbiota type I is associated with the normal esophagus and type II with an inflamed esophagus. The present study describes the gastric microbiota of a patient with antral gastritis concomitant with Barrett's esophagus absent infection with Helicobacter pylori. Gastric biopsies were obtained following the protocol of Sydney and following ethical practices. The isolates were cultivated under microaerophilic conditions on Columbia Agar supplemented with IsoVitaleXTM and 7% sterile blood. Extracted DNA was sequenced using 454-GS and the results analyzed on the MG-RAST server. Gram negative isolates were found and bacteria resistant to levofloxacin, amoxicillin, tetracycline, erythromycin, and clarithromycin. The phyla Bacteroidetes, Firmicutes, Fusobacteria and Proteobacteria, the genus Bacteroides and the species group Bacteroides fragilis were most abundant. Functionally, the metabolism of carbohydrates, amino acids, and to a lesser extent, the metabolism of cofactors and vitamins were most dominant, and of which the enzymes beta glucosidase (EC 3.2.1.21), beta-galactosidase (EC 3.2.1.23) and beta-N acetylhexosaminidase (EC 3.2.1.52) were most dominant. The findings of this study, because they are of only one case may probably suggest a possible pathogenic role, previously undescribed for Bacteroides fragilis, associated with human gastritis when concomitant esophageal pathology exists. PMID- 25293993 TI - [Gastrointestinal stroma tumor]. AB - Gastrointestinal stromal tumor (GIST) represents less than 3% of gastrointestinal malignancies. However, it is the most common mesenchymal tumor of the digestive tract. GIST is characterized by the expression tyrosine kinase CD117, which differentiates it from other mesenchymal tumors such as leiomyomas, leio miosarcomas, leiomyoblastoma and neurogenic tumors that do not express this protein. 70-80% of the GIST are benign and located mostly in the stomach and small intestine (> 90%).They can also arise from any portion of the digestive tract, mesentery, omentum and retroperitoneum. Malignant GISTs are usually large (> 5 cm), with a high mitotic index, and it can metastasize to the liver and peritoneum. The treatment is surgical resection.Good results have been reported with tyrosine kinase inhibitor STI571. The treatment is the surgical resection; in cases of surgical resection tumors cannot do it, radiotherapy and chemotherapy is carried out. A 43 year-old patient is presented, admitted to present pain in the epigastrium, melena in an occasion. The ecography, CT scan, and laparoscopic view, showed a tumor in the second portion of the duodenum, approximately 10 cm size. Whipple's operation was carried out (cephalic pancreatoduodenectomy) with conservation of the pylorus (Traverso-Longmire), resecting the entirely tumor. Final results of pathological anatomy informed: fusocelular tumor of the gastrointestinal estroma (GIST of duodenal wall), with high potential of malignancy. Size of the tumor 9,5 cm, mitotic index of 9 for 50 HPF with high positive for CD117, CD34. Two years later of the intervention he presents a good evolution. PMID- 25293994 TI - [Colorectal cancer in children: report of three cases]. AB - Colorectal cancer (CRC) is extremely infrequent in children and adolescents. There is little information about this entity, mainly case reports and review articles. We describe three cases of children with poor-differentiated colorectal carcinoma and advanced disease at onset. The presenting symptoms were abdominal pain and constipation, with a median of latency of symptoms of 4-48 months. None of these patients had operable disease at onset; having a disease progression despite therapy in two cases. This study reaffirms poor prognosis of pediatric CRC, probably due to an aggressive tumoral biology and advanced stage at diagnosis. Therapeutic guidelines are based in adult treatment; therefore, efforts should be made to improve tools in early diagnosis and future therapies for a better survival in childhood. PMID- 25293995 TI - [Pancreatoduodenectomy for ampullary adenocarcinoma and and re-intervention for ganglinonar recurrency]. AB - A 30 years old woman in the 13 week of her second pregnancy who had severe anemia, upper gastrointestinal bleeding and weight loss. She was given the endoscopic diagnosis of a well differentiated ampullary adenocarcinoma. She underwent a pancreato duodenectomy during the 16 week of pregnancy without complications. After 4 months of follow up we identified a ganglionar local recurrence so that's why she underwent a cesarean in the 34 week of pregnancy. The product was a healthy 2500 gr. newborn. We decided a reoperation for the resection of the recurrence and it was carried out successfully. Currently the patient has 36 months of follow up without evidence of recurrence and her baby has a normal grow up. PMID- 25293996 TI - [Profile of bacterial drug resistance in spontaneous bacterial peritonitis, a current alert status]. PMID- 25293997 TI - [Efects of Probiotics in decreasing the adverse effects of the eradication treatment for Helicobacter Pylori]. PMID- 25293998 TI - Thioridazine for treatment of tuberculosis: promises and pitfalls. AB - The articles by De Knegt et al. and Singh et al. in a recent issue of this Journal address one of the current debates regarding the potential role of thioridazine in the treatment of tuberculosis. This commentary presents a summary of the available evidence, and, emphasizing the need for further research, asks the question: "How far can we go in repurposing thioridazine?" PMID- 25293999 TI - Letter to the editor. PMID- 25294001 TI - A risk-based approach to management of leachables utilizing statistical analysis of extractables. AB - To incorporate quality by design concepts into the management of leachables, an emphasis is often put on understanding the extractable profile for the materials of construction for manufacturing disposables, container-closure, or delivery systems. Component manufacturing processes may also impact the extractable profile. An approach was developed to (1) identify critical components that may be sources of leachables, (2) enable an understanding of manufacturing process factors that affect extractable profiles, (3) determine if quantitative models can be developed that predict the effect of those key factors, and (4) evaluate the practical impact of the key factors on the product. A risk evaluation for an inhalation product identified injection molding as a key process. Designed experiments were performed to evaluate the impact of molding process parameters on the extractable profile from an ABS inhaler component. Statistical analysis of the resulting GC chromatographic profiles identified processing factors that were correlated with peak levels in the extractable profiles. The combination of statistically significant molding process parameters was different for different types of extractable compounds. ANOVA models were used to obtain optimal process settings and predict extractable levels for a selected number of compounds. The proposed paradigm may be applied to evaluate the impact of material composition and processing parameters on extractable profiles and utilized to manage product leachables early in the development process and throughout the product lifecycle. PMID- 25294000 TI - AGXT2: a promiscuous aminotransferase. AB - Alanine-glyoxylate aminotransferase 2 (AGXT2) is a multifunctional mitochondrial aminotransferase that was first identified in 1978. The physiological importance of AGXT2 was largely overlooked for three decades because AGXT2 is less active in glyoxylate metabolism than AGXT1, the enzyme that is deficient in primary hyperoxaluria type I. Recently, several novel functions of AGXT2 have been 'rediscovered' in the setting of modern genomic and metabolomic studies. It is now apparent that AGXT2 has multiple substrates and products and that altered AGXT2 activity may contribute to the pathogenesis of cardiovascular, renal, neurological, and hematological diseases. This article reviews the biochemical properties and physiological functions of AGXT2, its unique role at the intersection of key mitochondrial pathways, and its potential as a drug target. PMID- 25294003 TI - Chimeric DNA Vaccines: An Effective Way to Overcome Immune Tolerance. AB - The fact that cancer immunotherapy is considered to be a safe and successful weapon for use in combination with surgery, radiation, and chemotherapy treatments means that it has recently been chosen as Breakthrough of the Year 2013 by Science editors. Anticancer vaccines have been extensively tested, in this field, both in preclinical cancer models and in the clinic. However, tumor associated antigens (TAAs) are often self-tolerated molecules and cancer patients suffer from strong immunosuppressive effects, meaning that the triggering of an effective anti-tumor immune response is difficult. One possible means to overcome immunological tolerance to self-TAAs is of course the use of vaccines that code for xenogeneic proteins. However, a low-affinity antibody response against the self-homologous protein expressed by cancer cells is generally induced by xenovaccination. This issue becomes extremely limiting when working with tumors in which the contribution of the humoral rather than the cellular immune response is required if tumor growth is to be hampered. A possible way to avoid this problem is to use hybrid vaccines which code for chimeric proteins that include both homologous and xenogeneic moieties. In fact, a superior protective anti tumor immune response against ErbB2+ transplantable and autochthonous mammary tumors was observed over plasmids that coded for the fully rat or fully human proteins when hybrid plasmids that coded for chimeric rat/human ErbB2 protein were tested in ErbB2 transgenic mice. In principle, these findings may become the basis for a new rational means of designing effective vaccines against TAAs. PMID- 25294002 TI - Study on salvianolic acid B in the reduction of epidural fibrosis in laminectomy rats. AB - BACKGROUND: Epidural fibrosis (EF) is a common complication after laminectomy. Salvianolic acid B (Sal B) is a major bioactive component of a traditional Chinese medical agent, Salvia miltiorrhiza, which has shown anti-inflammatory, anti-fibrotic and anti-proliferative properties. The object of this study was to investigate the effect of Sal B on the prevention of epidural fibrosis in laminectomy rats. METHODS: A controlled double-blinded study was conducted in sixty healthy adult Wistar rats that underwent laminectomy at the L1-L2 levels. The rats were randomly divided into 3 groups of 20: (1) Sal B treatment group; (2) Vehicle group; (3) Sham group (laminectomy without treatment). All rats were sacrificed 4 weeks post-operatively. The extent of epidural fibrosis, fibroblast proliferation and the expression of vascular endothelial growth factor (VEGF) and inflammatory factors were analyzed. RESULTS: The recovery of all rats was uneventful. In the laminectomy sites treated with Sal B, the dura mater showed no adhesion. Collagen deposition was significantly lower in the Sal B group than the other two groups. In addition, both fibroblast and inflammatory cell counting in the laminectomy sites treated with Sal B showed better grades than the other two groups. The expression of VEGF and inflammatory factors in operative sites also suggested better results in the Sal B group than the other two groups. CONCLUSIONS: Sal B inhibits fibroblast proliferation, blood vessel regeneration, and inflammatory factor expression. Thus, Sal B is able to prevent epidural scar adhesion in post-laminectomy rats. PMID- 25294004 TI - Improved delay-range-dependent robust stability for uncertain systems with interval time-varying delay. AB - This paper is concerned with the improved delay-range-dependent stability and robust stability criteria for linear systems with time-varying delay and norm bounded uncertainties. In order to obtain much less conservative criteria, a Lyapunov-Krasovskii functional (LKF), which makes use of the information of both the lower and upper bounds of the interval time-varying delay, is proposed to derive new stability criteria. By using delayed decomposition approach (DDA), a tighter upper bound of the derivative of Lyapunov functional can be obtained, and thus the proposed criteria give results with less conservatism compared with some previous ones. The resulting criteria have advantages over some previous ones in that it involves fewer matrix variables but has less conservatism, which are established theoretically. We show, by four well known examples, that our result overcomes the previous allowable maximum admissible upper bound (MAUB) of the time-delay and it is less conservative than the previous results having a relatively small upper bound in the derivative of time delay. PMID- 25294005 TI - A metal-organic framework containing unusual eight-connected Zr-oxo secondary building units and orthogonal carboxylic acids for ultra-sensitive metal detection. AB - Two metal-organic frameworks (MOFs) with Zr-oxo secondary building units (SBUs) were prepared by using p,p'-terphenyldicarboxylate (TPDC) bridging ligands pre functionalized with orthogonal succinic acid (MOF-1) and maleic acid groups (MOF 2). Single-crystal X-ray structure analysis of MOF-1 provides the first direct evidence for eight-connected SBUs in UiO-type MOFs. In contrast, MOF-2 contains twelve-connected SBUs as seen in the traditional UiO MOF topology. These structural assignments were confirmed by extended X-ray absorption fine structure (EXAFS) analysis. The highly porous MOF-1 is an excellent fluorescence sensor for metal ions with the detection limit of <0.5 ppb for Mn(2+) and three to four orders of magnitude greater sensitivity for metal ions than previously reported luminescent MOFs. PMID- 25294007 TI - Image-guided percutaneous drainage vs. surgical repair of gastrointestinal anastomotic leaks: is there a difference in hospital course or hospitalization cost? AB - PURPOSE: To identify differences in hospital course and hospitalization cost when comparing image-guided percutaneous drainage with surgical repair for gastrointestinal anastomotic leaks. MATERIALS AND METHODS: A retrospective IRB approved search using key words "leak" and/or "anastomotic" was performed on all adult CT reports from 2002 to 2011. CT examinations were reviewed for evidence of a postoperative gastrointestinal leak and assigned a confidence score of 1-5 (1 = no leak, 5 = definite leak). Patients with an average confidence score <4 were excluded. Type of surgery, patient data, method of leak management, number of hospital admissions, length of hospital stay, discharge disposition, number of CT examinations, number of drains, and hospitalization costs were collected. RESULTS: One hundred thirty-nine patients had radiographic evidence of a gastrointestinal anastomotic leak (esophageal, gastric, small bowel or colonic). Nine patients were excluded due to low confidence scores. Twenty-seven patients underwent surgical repair (Group A) and 103 were managed entirely with percutaneous image-guided drainage (Group B). There was no significant difference in patient demographics or number of hospital admissions. Patients in Group A had longer median hospital stays compared to Group B (48 vs. 32 days, p = 0.007). The median total hospitalization cost for Group A was more than twice that for Group B ($99,995 vs. $47,838, p = 0.001). Differences in hospital disposition, number of CT examinations, number of drains, and time between original surgery and first CT examination were statistically significant. CONCLUSION: Gastrointestinal anastomotic leaks managed by percutaneous drainage are associated with lower hospital cost and shorter hospital stays compared with surgical management. PMID- 25294006 TI - Simultaneous measurement of hepatic and splenic stiffness using MR elastography: preliminary experience. AB - PURPOSE: To compare MR elastography (MRE) using a single and a dual driver excitation for the quantification of hepatic and splenic stiffness (HS and SS), and to investigate the performance of HS and SS measured with single or dual driver excitation for the detection of liver cirrhosis in subjects with liver disease. PATIENTS AND METHODS: This prospective HIPAA compliant and IRB approved study involved 49 subjects who underwent MRE at 3.0T, comparing three different acquisition methods (single driver on the liver, single driver on the spleen and dual driver acoustic excitation). A Mann-Whitney test was used to assess changes in stiffness values. Bland-Altman analysis was used to compare single and dual driver configurations for each organ. Performance for detection of liver cirrhosis was assessed using ROC analysis. Pearson correlation was used to estimate the dependence of HS and SS on spleen size. RESULTS: There were 40 noncirrhotic and 9 cirrhotic patients. There was good agreement between stiffness values measured with a single or a dual driver (Bland-Altman limits of agreement 14.3 % to 18.9 % and -18.1 % to 29.7 %, CV 6.4 % and 9.4 %, for HS and SS. respectively). HS and SS were higher in subjects with liver cirrhosis (p < 0.001), with excellent detection performance (AUROC range 0.87-0.93). SS correlated strongly with spleen size (r = 0.69, p < 0.001), while HS showed weak correlation (r = 0.38, p = 0.006). CONCLUSION: Using a dual acoustic driver configuration, hepatic and splenic stiffness can be simultaneously estimated with good concordance with single driver measurement. PMID- 25294008 TI - FGF23 is associated with disease severity and prognosis in chronic heart failure. AB - BACKGROUND: Elevated levels of fibroblast growth factor 23 (FGF23) are associated with incident heart failure in individuals with or without chronic kidney disease. We aimed to investigate the association between serum FGF23 concentrations and disease severity and long-term outcome in patients with stable heart failure. MATERIALS AND METHODS: Serum levels of C-term FGF23 (Ct-FGF23) concentrations, inorganic phosphate (Pi ), parathormone (PTH) and 25 hydroxyvitamin D (25(OH)D) were measured in 208 patients with nonischaemic heart failure (age 48 +/- 15 years; 70% male; NYHA Class I 27.8%, NYHA Class II 43.4%, NYHA Class III/IV 28.8%; LV-EF 34 +/- 15%; eGFR >=60 mL/min/1.73 m(2) in 86%). RESULTS: Median Ct-FGF23 levels were 18.2 RU/mL (7.5-40.8RU/mL). A dose-response relationship was found between median Ct-FGF23 levels and increasing NYHA class (I: 11.9 RU/mL, II: 15.8 RU/mL, III/IV: 38.8 RU/mL; P < 0.001). Ct-FGF23 correlated with NTproBNP (r = 0.307, P < 0.001), central venous pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure and inversely correlated with cardiac output after adjustment for renal function (eGFR) and Pi . LnCt-FGF23 was related with the combined endpoint of death or heart transplantation (hazard ratio 1.452 [1.029-2.048]; P = 0.034) independent of Pi , PTH, 25(OH)D, age and sex. CONCLUSION: The phosphatonin FGF23 is strongly associated with disease severity and long-term outcome in patients with nonischaemic heart failure and preserved renal function. Further studies are needed to evaluate the pathophysiologic role of FGF23 and its potential as a biomarker in heart failure. PMID- 25294009 TI - Discovery and characterization of a novel extremely acidic bacterial N-glycanase with combined advantages of PNGase F and A. AB - Peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine amidases [PNGases (peptide N glycosidases), N-glycanases, EC 3.5.1.52] are essential tools in the release of N glycans from glycoproteins. We hereby report the discovery and characterization of a novel bacterial N-glycanase from Terriglobus roseus with an extremely low pH optimum of 2.6, and annotated it therefore as PNGase H+. The gene of PNGase H+ was cloned and the recombinant protein was successfully expressed in Escherichia coli. The recombinant PNGase H+ could liberate high mannose-, hybrid- and complex type N-glycans including core alpha1,3-fucosylated oligosaccharides from both glycoproteins and glycopeptides. In addition, PNGase H+ exhibited better release efficiency over N-glycans without core alpha1,3-fucose compared with PNGase A. The facile expression, non-glycosylated nature, unusual pH optimum and broad substrate specificity of this novel type of N-glycanase makes recombinant PNGase H+ a versatile tool in N-glycan analysis. PMID- 25294010 TI - Microsymbionts of Phaseolus vulgaris in acid and alkaline soils of Mexico. AB - In order to investigate bean-nodulating rhizobia in different types of soil, 41 nodule isolates from acid and alkaline soils in Mexico were characterized. Based upon the phylogenetic studies of 16S rRNA, atpD, glnII, recA, rpoB, gyrB, nifH and nodC genes, the isolates originating from acid soils were identified as the phaseoli symbiovar of the Rhizobium leguminosarum-like group and Rhizobium grahamii, whereas the isolates from alkaline soils were defined as Ensifer americanum sv. mediterranense and Rhizobium radiobacter. The isolates of "R. leguminosarum" and E. americanum harbored nodC and nifH genes, but the symbiotic genes were not detected in the four isolates of the other two species. It was the first time that "R. leguminosarum" and E. americanum have been reported as bean nodulating bacteria in Mexico. The high similarity of symbiotic genes in the Rhizobium and Ensifer populations showed that these genes had the same origin and have diversified recently in different rhizobial species. Phenotypic characterization revealed that the "R. leguminosarum" population was more adapted to the acid and low salinity conditions, while the E. americanum population preferred alkaline conditions. The findings of this study have improved the knowledge of the diversity, geographic distribution and evolution of bean nodulating rhizobia in Mexico. PMID- 25294011 TI - Effect of orlistat on weight loss, hormonal and metabolic profiles in women with polycystic ovarian syndrome: a randomized double-blind placebo-controlled trial. PMID- 25294014 TI - The relationship between circulating TRAIL and endothelial dysfunction in subclinical hypothyroidism. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is associated with atherosclerosis. Subclinical hypothyroidism (sHT) is associated with the increased prevalence of atherosclerotic lesions and cardiovascular events. Therefore, we hypothesized that circulating TRAIL levels are associated with endothelial dysfunction in sHT patients. Two hundred and four patients with newly diagnosed sHT and 52 healthy subjects were recruited. Circulating TRAIL concentration was measured by an ELISA, and flow-mediated dilation (FMD) of brachial artery was measured using high-resolution ultrasound. The mean value of circulating TRAIL in newly diagnosed sHT patients was 67.2 pg/ml, which was lower than that in controls (78.5 pg/ml, p < 0.001). By dividing the distribution of FMD levels into quartiles, TRAIL levels were increased gradually with the increase of FMD levels (p < 0.001). Multivariate regression analysis demonstrated that serum TRAIL levels were independently associated with FMD (p = 0.007). By logistic regression analysis, the odds ratio for lower FMD levels was reduced by 12.1 % per 1 pg/ml increase in serum TRAIL concentration after adjustment for multivariate metabolic factors [OR (95 % CI); 0.879 (0.721-0.973)]. Circulating TRAIL level decreased in newly diagnosed sHT patients and is positively associated with endothelial function, suggesting that circulating TRAIL level may be a protective marker of endothelial function in sHT patients. PMID- 25294013 TI - Chemical contamination and the thyroid. AB - Industrial chemical contaminants have a variable impact on the hypothalamic pituitary-thyroid axis, this depending both on their class and on confounding factors. Today, mounting evidence is pointing to the role of environmental factors, and specifically EDCs, in the current distressing upsurge in the incidence of thyroid disease. The unease is warranted. These substances, which are nowadays rife in our environments (including in foodstuffs), have been shown to interfere with thyroid hormone action, biosynthesis, and metabolism, resulting in disruption of tissue homeostasis and/or thyroid function. Importantly, based on the concept of the "nonmonotonic dose-response curve", the relationship between dose and effect has often been found to be nonlinear. Thus, small doses can induce unpredictable, adverse effects, one case being polychlorinated biphenyls (PCBs), of which congener(s) may centrally inhibit the hypothalamic pituitary-thyroid axis, or dissociate thyroid receptor and selectively affect thyroid hormone signaling and action. This means that PCBs can act as agonists or antagonists at the receptor level, underlining the complexity of the interaction. This review highlights the multifold activity of chemicals demonstrated to cause thyroid disruption. It also represents a call to action among clinicians to undertake systematic monitoring of thyroid function and registering of the classes of EDs and additionally urges broader scientific collaborations to clarify these chemicals' molecular mechanisms of action, substances whose prevalence in our environments is disrupting not only the thyroid but all life on earth. PMID- 25294015 TI - Structural Validity of the WISC-IV for Students With ADHD. AB - OBJECTIVE: To evaluate the structural validity of the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). METHOD: Confirmatory factor analyses were applied to a sample of 233 students diagnosed with ADHD by school multidisciplinary evaluation teams to evaluate the relative fit of the following competing models: (a) one factor, (b) two oblique verbal and nonverbal factors, (c) three oblique verbal, perceptual, and combined working memory/processing speed factors, (d) four oblique verbal, perceptual, working memory, and processing speed factors, (e) a higher-order model with four first-order factors, and (f) a bifactor model with four domain-specific factors. RESULTS: A higher order four-factor model fit the data best, which was composed of a general intelligence factor and four domain-specific factors that matched the four factors specified in the WISC-IV technical and interpretive manual. Moreover, the general intelligence factor explained more than two times the total variance contributed by all four domain-specific factors combined. CONCLUSIONS: Results substantiate previous research on the WISC-IV, indicating that the general intelligence factor contributes the most reliable information. Consequently, it is recommended that interpretation of the WISC-IV remain at the Full-Scale IQ score level. PMID- 25294017 TI - Three genes encoding citrate synthases in Saccharopolyspora erythraea are regulated by the global nutrient-sensing regulators GlnR, DasR, and CRP. AB - Saccharopolyspora erythraea has three citrate synthases encoded by gltA-2, citA, and citA4. Here, we characterized and identified the expression and regulatory properties of these synthases. Three pleiotropic global regulatory proteins of S. erythraea - CRP, GlnR, and DasR - are involved in carbon metabolism, nitrogen metabolism, and amino-sugar (chitin and GlcNAc) metabolism. Using electrophoretic mobility shift assays (EMSAs), we identified these regulators as proteins that bind directly to the promoter regions of all citrate synthase genes (gltA-2, citA, and citA4). Footprinting assays indicated the exact protect sequences of CRP, GlnR, and DasR on the promoter region of gltA-2, revealing binding competition between GlnR and DasR. Moreover, by comparing the transcription levels of citrate synthase genes between parental and glnR mutant or dasR mutant strains, or by comparing the transcription response of citrate synthases under various nutrient conditions, we found that GlnR and DasR negatively regulated citA and citA4 transcription but had no regulatory effects on the gltA-2 gene. Although no CRP mutant was available, the results indicated that CRP was a cAMP binding receptor affecting gltA-2 transcription when the intracellular cAMP concentration increased. Thus, an overall model of CS regulation by C and/or N metabolism regulators and cAMP receptor protein was proposed. PMID- 25294012 TI - Prediabetes and associated disorders. AB - Prediabetes represents an elevation of plasma glucose above the normal range but below that of clinical diabetes. Prediabetes includes individuals with IFG, IGT, IFG with IGT and elevated HbA1c levels. Insulin resistance and beta-cell dysfunction are characteristic of this disorder. The diagnosis of prediabetesis is vital as both IFG and IGT are indeed well-known risk factors for type 2 diabetes with a greater risk in the presence of combined IFG and IGT. Furthermore, as will be illustrated in this review, prediabetes is associated with associated disorders typically only considered in with established diabetes. These include cardiovascular disease, periodontal disease, cognitive dysfunction, microvascular disease, blood pressure abnormalities, obstructive sleep apnea, low testosterone, metabolic syndrome, various biomarkers, fatty liver disease, and cancer. As the vast majority of individuals with prediabetes are unaware of their diagnosis, it is therefore vital that the associated conditions are identified, particularly in the presence of mild hyperglycemia, so they may benefit from early intervention. PMID- 25294016 TI - A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. AB - We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade >=3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma. PMID- 25294019 TI - Yes, breast surgeons may provide breast cancer genetic assessment and testing. PMID- 25294018 TI - Using Dynamic 99mT c-GSA SPECT/CT fusion images for hepatectomy planning and postoperative liver failure prediction. AB - BACKGROUND: Available tools in liver surgery planning rely on the future remnant liver (FRL) volume. Inappropriate decision might be made since the same FRL volume might represent different liver functions depending on the severity of underlying liver damage. This study developed an alternative system to estimate FRL function and to predict the risk of postoperative liver failure. METHODS: Current study recruited 71 prehepatectomy patients and 71 healthy volunteers. A technetium-99-labelled asialoglycoproteins was given to participants and SPECT was used to capture the intensity of the signal, represented by uptake index (UI). The agreement between preoperative UI values, liver function tests, and Child scores were evaluated. Linear regression was used to evaluate the agreement between predicted UI for FRL and postoperative UI values. Area under the receiver operating characteristic (AUC) curve was used to evaluate the discriminative performance of UI in differentiating patient with high risk of liver failure. RESULTS: Preoperative UIs are highly correlated with Child score (P < 0.0001), especially to identify patients with ascites and elevated bilirubin. The predicted UIs were in close agreement with the actual postoperative UI values (r = 0.95 P < 0.001). The AUC analysis indicated that UI values had a high accuracy in predicting the risk of liver failure (AUC = 0.95, P < 0.0001). The best cut off point was 0.9 and the corresponding sensitivity was 100 % and specificity was 92 %. CONCLUSIONS: The new methodology reliably estimates FRL function and predicts the risk of liver failure. It provides a visual aid for liver surgeon in surgery planning and risk assessment. PMID- 25294022 TI - Laparoscopic modified Sugarbaker technique for the repair of an urostomal hernia a video vignette. PMID- 25294021 TI - Nonocclusive mesenteric ischaemia: think about it. AB - Nonocclusive mesenteric ischaemia (NOMI) is an acute mesenteric circulatory disorder that is not caused by an organic occlusion of blood vessels. It could involve all the abdominal parenchymas and viscera and the whole gastrointestinal tract (from the oesophagus to the rectum), insomuch that the involvement of the entire colon should be considered a distinctive tract in diagnosing this condition in respect of the occlusive forms of ischaemia. The aim of this article is to review the role of imaging in the diagnosis of NOMI and in particular its CT appearances. Recognition of the characteristic CT appearances and the variations associated with a reperfusion event may help in the accurate interpretation of CT in the diagnosis and management of NOMI. PMID- 25294023 TI - Detection of parametric changes in the Peyrard-Bishop- Dauxois model of DNA using nonlinear Kalman filtering. AB - The derivative-free nonlinear Kalman filter is proposed for state estimation and fault diagnosis in distributed parameter systems of the wave-type and particularly in the Peyrard-Bishop-Dauxois model of DNA dynamics. At a first stage, a nonlinear filtering approach is introduced for estimating the dynamics of the Peyrard-Bishop-Dauxois 1D nonlinear wave equation, through the processing of a small number of measurements. It is shown that the numerical solution of the associated partial differential equation results in a set of nonlinear ordinary differential equations. With the application of a diffeomorphism that is based on differential flatness theory it is shown that an equivalent description of the system is obtained in the linear canonical (Brunovsky) form. This transformation enables to obtain local estimates about the state vector of the DNA model through the application us of the standard Kalman filter recursion. At a second stage, the local statistical approach to fault diagnosis is used to perform fault diagnosis for this distributed parameter system by processing with statistical tools the differences (residuals) between the output of the Kalman filter and the measurements obtained from the distributed parameter system. Optimal selection of the fault threshold is succeeded by using the local statistical approach to fault diagnosis. The efficiency of the proposed filtering approach in the problem of fault diagnosis for parametric change detection, in nonlinear wave-type models of DNA dynamics, is confirmed through simulation experiments. PMID- 25294024 TI - Short-term effects of vision trainer rehabilitation in patients affected by anisometropic amblyopia: electrofunctional evaluation. AB - PURPOSE: The aim of the present study was to evaluate the short-term effects of the vision trainer rehabilitation technique on retinal and post-retinal function in young amblyopic patients outside the critical visual developmental period. METHODS: Twenty-one patients (mean age 12.2 +/- 2.7 years, ranging from 9.1 to 18 years) affected by unilateral anisometropic amblyopia were studied, providing 21 amblyopic eyes (AE) and 21 sound eyes (SE). Thirty eyes from 15 age-similar normal subjects served as controls. All subjects underwent extensive ophthalmologic characterization to exclude any disease not related to amblyopia. All AE were subjected to rehabilitation sessions performed by the Retimax vision trainer (VT) program. The protocol consisted of 2 sessions per week, each lasting 10 min, for 10 consecutive weeks. Before and after the rehabilitation, electrophysiological [pattern electroretinogram (PERG) and visual evoked potential (VEP)] and psychophysical [best corrected visual acuity (BCVA) and microperimetry] data were collected from AE and SE. RESULTS: When comparing baseline data with those collected at the end of the study, PERG P50-N95 amplitude and BCVA values from AE had improved significantly by the end of the study (p < 0.05). Our electrophysiological findings also showed some abnormalities in SE when the data were compared to control eyes. We found a significant correlation (p < 0.05) between PERG amplitude and VEP implicit time in SE after visual rehabilitation. CONCLUSIONS: Short-term visual rehabilitation performed by the VT program ameliorated the electrofunctional and psychophysical parameters of vision in children outside the critical developmental period, thus indicating that VT might be a potential adjuvant therapy of traditional patching treatment. PMID- 25294026 TI - Ten-year incidences of self-reported non-vertebral fractures in Japanese patients with rheumatoid arthritis: discrepancy between disease activity control and the incidence of non-vertebral fracture. AB - Despite improvements in rheumatoid arthritis disease activity of in the past 10 years, the incidence of self-reported non-vertebral fractures did not decrease in our cohort of 9,987 patients. This study may indicate that osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the rheumatoid arthritis disease activity. INTRODUCTION: Although rheumatoid arthritis (RA) is a risk factor for osteoporosis and fractures, few studies have described the association between disease activity and the fracture incidence in patients with RA. This study aimed to investigate changes in the non-vertebral fracture incidence between 2001 and 2010 in our Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort. METHODS: The IORRA is a prospective observational cohort study of Japanese RA patients. A total of 9,987 patients with RA were enrolled in this cohort from 2000 to 2010. The clinical parameter and non-vertebral fracture occurrence data were collected biannually through self reported questionnaires. Incidences of self-reported non-vertebral fractures were also analyzed via standardization according to gender, age, and disease activity during each 2-year period. RESULTS: From 2001 to 2010, the percentage of patients with 28-joint disease activity score remission increased from 7.8 to 39.7%, prednisolone intake decreased from 51.4 to 41.3%, and bisphosphonate intake increased from 5.0 to 23.4%. The non-vertebral fracture incidence rates were 24.6/1,000 person-years in 2001 and 35.5/1,000 person-years in 2010, with no apparent change even after standardization. The overall non-vertebral fracture incidence was significantly higher in the autumn/winter than in the spring/summer (p = 0.02). CONCLUSION: Despite improvements in disease activity and functional disability, the non-vertebral fracture incidence exhibited no apparent change between 2001 and 2010 in our patients with RA. Osteoporosis treatment and non vertebral fracture prevention remain important regardless of the disease control in patients with RA. PMID- 25294027 TI - Relationship between fetuin-A levels and bone mineral density: response to Agilli et al. PMID- 25294025 TI - Whole-genome expression profile in zebrafish embryos after chronic exposure to morphine: identification of new genes associated with neuronal function and mu opioid receptor expression. AB - BACKGROUND: A great number of studies have investigated changes induced by morphine exposure in gene expression using several experimental models. In this study, we examined gene expression changes during chronic exposure to morphine during maturation and differentiation of zebrafish CNS. RESULTS: Microarray analysis showed 254 genes whose expression was identified as different by at least 1.3 fold change following chronic morphine exposure as compared to controls. Of these, several novel genes (grb2, copb2, otpb, magi1b, grik-l, bnip4 and sox19b) have been detected for the first time in an experimental animal model treated with morphine. We have also identified a subset of genes (dao.1, wls, bnip4 and camk1gammab) differentially expressed by chronic morphine exposure whose expression is related to mu opioid receptor gene expression. Altered expression of copb2, bnip4, sox19b, otpb, dao.1, grik-l and wls is indicative of modified neuronal development, CNS patterning processes, differentiation and dopaminergic neurotransmission, serotonergic signaling pathway, and glutamatergic neurotransmission. The deregulation of camk1gammab signaling genes suggests an activation of axonogenesis and dendritogenesis. CONCLUSIONS: Our study identified different functional classes of genes and individual candidates involved in the mechanisms underlying susceptibility to morphine actions related to CNS development. These results open new lines to study the treatment of pain and the molecular mechanisms involved in addiction. We also found a set of zebrafish specific morphine-induced genes, which may be putative targets in human models for addiction and pain processes. PMID- 25294028 TI - Relationship between fetuin-A levels and bone mineral density. PMID- 25294029 TI - Contemporary population structure and post-glacial genetic demography in a migratory marine species, the blacknose shark, Carcharhinus acronotus. AB - Patterns of population structure and historical genetic demography of blacknose sharks in the western North Atlantic Ocean were assessed using variation in nuclear-encoded microsatellites and sequences of mitochondrial (mt)DNA. Significant heterogeneity and/or inferred barriers to gene flow, based on microsatellites and/or mtDNA, revealed the occurrence of five genetic populations localized to five geographic regions: the southeastern U.S Atlantic coast, the eastern Gulf of Mexico, the western Gulf of Mexico, Bay of Campeche in the southern Gulf of Mexico and the Bahamas. Pairwise estimates of genetic divergence between sharks in the Bahamas and those in all other localities were more than an order of magnitude higher than between pairwise comparisons involving the other localities. Demographic modelling indicated that sharks in all five regions diverged after the last glacial maximum and, except for the Bahamas, experienced post-glacial, population expansion. The patterns of genetic variation also suggest that the southern Gulf of Mexico may have served as a glacial refuge and source for the expansion. Results of the study demonstrate that barriers to gene flow and historical genetic demography contributed to contemporary patterns of population structure in a coastal migratory species living in an otherwise continuous marine habitat. The results also indicate that for many marine species, failure to properly characterize barriers in terms of levels of contemporary gene flow could in part be due to inferences based solely on equilibrium assumptions. This could lead to erroneous conclusions regarding levels of connectivity in species of conservation concern. PMID- 25294030 TI - [Physical activity benefits patients with age-related macular degeneration]. AB - We have reviewed studies investigating the effect of physical activity on prevention of early age-related macular degeneration (AMD), progression to late AMD, and risk modulation of morbidity and mortality in patients with AMD. Regular physical activity may lower risk of developing early AMD and progression of early AMD to late AMD at a level comparable with smoking cessation or dietary supplements. Studies suggest that AMD itself is associated with physical inactivity which can result in higher morbidity levels. Patients with AMD may benefit from physical activity counselling at all stages of the disease. PMID- 25294031 TI - [Alcohol use disorders in elderly people calls for treatment]. AB - The complications related to use of alcohol occur at lower levels of alcohol use in the elderly. Alcohol use disorders (AUD) in the elderly are underestimated and often incorrectly diagnosed. However, evidence indicates that elderly are as likely to benefit from treatment as younger. Screening using Alcohol Use Disorders Identification Test seems to be accurate in identifying AUD among elderly, if the cut-off point is tailored for this age group. The recommended treatment strategy is naltrexone and brief approaches such as motivational interview and supportive consultation in general practice. PMID- 25294032 TI - [Trigeminal neuralgia treatment may have masked an undiagnosed bipolar disorder]. AB - Antiepileptical drugs (AD) are not only being used in the treatment of seizures and neuralgias but are also used for psychiatric disorders due to their mood stabilizing effect. This case report presents a 59-year-old woman with trigeminal neuralgia who was treated with AD for 25 years. After successful surgery AD were withdrawn and subsequently she developed symptoms according to bipolar disorder. We suggest that an undiagnosed bipolar disorder for years had been masked by the AD and we encourage to pay attention to the mood stabilizing effects of AD - even when used for other purposes. PMID- 25294033 TI - [Attacks of abdominal pain can be abdominal migraine]. AB - A lot of patients suffer from abdominal pain, nausea and vomiting. They are often seen in many departments and specialities. A few of these may suffer from abdominal migraine and can be treated well with antimigraine medication. This is a case report of a 25-year-old woman predisposed to migraine and with migraine headache who suffered from attacks of abdominal pain, anorexia, nausea and vomiting. She was thoroughly examined without any signs of abdominal pathology and was then referred to a neurological specialist who successfully treated her with propranolol. PMID- 25294034 TI - [Migrating foreign body from hypopharynx]. AB - In this case report we present a 20-month-old girl with a migrating foreign body, a "smiley" sticker, that migrated from hypopharynx to surrounding tissue and created an abscess with a fistula, one year after ingestion. The foreign body was removed without difficulty under general anaesthesia, and the patient was discharged after few days with peroral antibiotics. PMID- 25294035 TI - [Faecal calprotectin is a useful biomarker for intestinal inflammation]. AB - Faecal calprotectin is a biomarker for inflammation in the intestinal mucosa. Faecal calprotectin has the ability to detect inflammatory causes of gastrointestinal symptoms and to distinguish these from irritable bowel syndrome. The test is very sensitive but not specific to any particular gastrointestinal disease. In inflammatory bowel disease, faecal calprotectin correlates with symptoms, biochemical markers and the endoscopic findings. It can be used to monitor disease activity, treatment response and mucosal healing as well as predict relapse. We propose an algorithm for the use of faecal calprotectin in patients with unspecific abdominal complaints. PMID- 25294036 TI - [Insufficient evidence on the effectiveness of brief alcohol interventions in health care]. AB - Very brief alcohol interventions (approx. 5 min.) are recommended for implementation in Danish municipalities by the The Danish Health and Medicines Authority. We have investigated the evidence supporting this recommendation. A lack of clarity remains about the active components in brief interventions and the extent to which the existing evidence base can be interpreted as efficacy or effectiveness studies. This has important implications for the generalizability of the trials. There is insufficient evidence on the effectiveness of very brief alcohol interventions and implementation is premature. PMID- 25294037 TI - [The age at first intercourse has been stable since the 1960s, and early coital debut is linked to sexual risk situations]. AB - This article reviews the 17 most robust Danish studies performed 1944-2006, in which coital debut was included as a specific variable. Women and men born before 1920 had their first sexual intercourse at the mean age of 21 and 20 years, respectively. Today, however, the median age of debut for both sexes is 16 years. The decrease in coital debut age culminated in the late 1960s, and no major changes have since occurred. Early debut is linked to sexual risk-taking and sexually transmitted infections. One fourth of current Danish adolescents do not use any protection at their sexual debut, and strengthened preventive measures are still needed. PMID- 25294038 TI - [Duodenal-jejunal bypass sleeve - a potential alternative to bariatric surgery?]. AB - Overweight and obesity are risk factors for several co-morbidities reducing life expectancy. Conservative treatment of obesity is generally ineffective in the long-term. Bariatric surgery has proven effective, but is associated with potential complications. Duodenal-jejunal bypass sleeve is a novel minimal invasive and fully reversible endoscopic treatment modality approved for treatment of obesity with or without concomitant type 2 diabetes. Here we review present data for the efficacy and safety of this treatment modality. PMID- 25294039 TI - [Occupational asthma caused by maleic anhydride]. AB - Organic acid anhydrides (OAA) are widely used in the chemical industry. They are irritants and can cause sensitization and asthma. We describe the first documented case of occupational asthma caused by the OAA maleic anhydride (MA) in the production of insecticides. A 60-year-old man developed work-related respiratory symptoms after eight years of intermittent exposure to MA. Peak expiratory flow measurements showed greater variance on work days than on days off. Both a basophilic activation test and determination of the MA-specific IgE level in serum showed sensitization to MA. PMID- 25294040 TI - Contribution of trehalose biosynthetic pathway to drought stress tolerance of Capparis ovata Desf. AB - Trehalose and the trehalose biosynthetic pathway are important contributors and regulators of stress responses in plants. Among recent findings for trehalose and its metabolism, the role of signalling in the regulation of growth and development and its potential for use as a storage energy source can be listed. The xerophytic plant Capparis ovata (caper) is well adapted to drought and high temperature stress in arid and semi-arid regions of the Mediterranean. The contribution of trehalose and the trehalose biosynthetic pathway to drought stress responses and tolerance in C. ovata are not known. We investigated the effects of PEG-mediated drought stress in caper plants and analysed physiological parameters and trehalose biosynthetic pathway components, trehalose-6-phosphate synthase (TPS), trehalose-6-phosphate phosphatase (TPP), trehalase activity, trehalose and proline content in drought stress-treated and untreated plants. Our results indicated that trehalose and the trehalose biosynthetic pathway contributed to drought stress tolerance of C. ovata. Overall growth and leaf water status were not dramatically affected by drought, as both high relative growth rate and relative water content were recorded even after 14 days of drought stress. Trehalose accumulation increased in parallel to induced TPS and TPP activities and decreased trehalase activity in caper plants on day 14. Constitutive trehalose levels were 28.75 to 74.75 MUg.g.FW(-1) , and drought stress significantly induced trehalose accumulation (385.25 MUg.g.FW(-1) on day 14) in leaves of caper. On day 14 of drought, proline levels were lower than on day 7. Under drought stress the discrepancy between trehalose and proline accumulation trends might result from the mode of action of these osmoprotectant molecules in C. ovata. PMID- 25294041 TI - Affective norms for 1,586 Polish words (ANPW): Duality-of-mind approach. AB - This article presents valence/pleasantness, activity/arousal, power/dominance, origin, subjective significance, and source-of-experience norms for 1,586 Polish words (primarily nouns), adapted from the Affective Norms for English Words list (1,040 words) and from my own previous research (546 words), regarding the duality-of-mind approach for emotion formation. This is a first attempt at creating affective norms for Polish words. The norms are based on ratings by a total of 1,670 college students (852 females and 818 males) from different Warsaw universities and academies, studying various disciplines in equal proportions (humanities, engineering, and social and natural sciences) using a 9-point Likert Self-Assessment Manikin scale. Each participant assessed 240 words on six different scales (40 words per scale) using a paper-and-pencil group survey procedure. These affective norms for Polish words are a valid and useful tool that will allow researchers to use standard, well-known verbal materials comparable to the materials used in other languages (English, German, Portuguese, Spanish, French, Dutch, etc.). The normative values of the Polish adaptation of affective norms are included in the online supplemental materials for this article. PMID- 25294042 TI - Classification of collective behavior: a comparison of tracking and machine learning methods to study the effect of ambient light on fish shoaling. AB - Traditional approaches for the analysis of collective behavior entail digitizing the position of each individual, followed by evaluation of pertinent group observables, such as cohesion and polarization. Machine learning may enable considerable advancements in this area by affording the classification of these observables directly from images. While such methods have been successfully implemented in the classification of individual behavior, their potential in the study collective behavior is largely untested. In this paper, we compare three methods for the analysis of collective behavior: simple tracking (ST) without resolving occlusions, machine learning with real data (MLR), and machine learning with synthetic data (MLS). These methods are evaluated on videos recorded from an experiment studying the effect of ambient light on the shoaling tendency of Giant danios. In particular, we compute average nearest-neighbor distance (ANND) and polarization using the three methods and compare the values with manually verified ground-truth data. To further assess possible dependence on sampling rate for computing ANND, the comparison is also performed at a low frame rate. Results show that while ST is the most accurate at higher frame rate for both ANND and polarization, at low frame rate for ANND there is no significant difference in accuracy between the three methods. In terms of computational speed, MLR and MLS take significantly less time to process an image, with MLS better addressing constraints related to generation of training data. Finally, all methods are able to successfully detect a significant difference in ANND as the ambient light intensity is varied irrespective of the direction of intensity change. PMID- 25294043 TI - A method for resolving occlusions when multitracking individuals in a shoal. AB - Studying the collective behavior of fishes often requires tracking a great number of individuals. When many fishes move together, it is common for individuals to move so close to each other that some fishes superimpose themselves on others during one or several units of time, which impacts on tracking accuracy (i.e., loss of fish trajectories, interchange of fish identities). Type 1 occlusions arise when two fishes swim so near each other that they look like one long fish, whereas type 2 occlusions occur when the fishes' trajectories cross to create a T or X-shaped individual. We propose an image processing method for resolving these types of occlusions when multitracking shoals in two dimensions. We assessed processing effectiveness after videorecording shoals of 20 and 40 individuals of two species that exhibit different shoal styles: zebrafish (Danio rerio) and black neon tetras (Hyphessobrycon herbertaxelrodi). Results show that, although the number of occlusions depended on both the number of individuals and the species, the method is able to effectively resolve a great deal of occlusions, irrespective of the species and the number of individuals. It also produces images that can be used in a multitracking system to detect individual fish trajectories. Compared to other methods, our approach makes it possible to study shoals with water depths similar to those seen in the natural conditions of the two species studied. PMID- 25294044 TI - Testing evolutionary models of senescence: traditional approaches and future directions. AB - From an evolutionary perspective, the existence of senescence is a paradox. Why has senescence not been more effectively selected against given its associated decreases in Darwinian fitness? Why does senescence exist and how has it evolved? Three major theories offer explanations: (1) the theory of mutation accumulation suggested by PB Medawar; (2) the theory of antagonistic pleiotropy suggested by GC Williams; and (3) the disposable soma theory suggested by TBL Kirkwood. These three theories differ in the underlying causes of aging that they propose but are not mutually exclusive. This paper compares the specific biological predictions of each theory and discusses the methods and results of previous empirical tests. Lifespan is found to be the most frequently used estimate of senescence in evolutionary investigations. This measurement acts as a proxy for an individual's rate of senescence, but provides no information on an individual's senescent state or "biological age" throughout life. In the future, use of alternative longitudinal measures of senescence may facilitate investigation of previously neglected aspects of evolutionary models, such as intra- and inter-individual heterogeneity in the process of aging. DNA methylation data are newly proposed to measure biological aging and are suggested to be particularly useful for such investigations. PMID- 25294046 TI - Survey of findings in patients having persistent heartburn on proton pump inhibitor therapy. AB - In patients with refractory heartburn while on proton pump inhibitor (PPI) therapy, changing drugs or increasing treatment to a twice a day (b.i.d.) dose has become a common practice. This study aims to study patients with persistent heartburn while on PPI therapy and to determine if persistent symptom indicates the need for more aggressive or different therapy. A retrospective review of impedance-pH tracings on PPI therapy (q.d. or b.i.d.) for patients with persistent heartburn was performed. DeMeester score, impedance, and symptom sensitive index (SSI) were used as indices. Statistical analyses were performed using chi-squared test with Yates correction and paired t-test. One hundred consecutive patients, (female 50%, male 50%, mean age 54 [range 16-83] years) were studied on q.d. (n = 45) or b.i.d. PPI (n = 55). Only 20% of the patients had abnormal DeMeester score; 41% had an abnormal impedance score and 56% had abnormal SSI; 29% had all indices normal. There was no difference between patients taking q.d. versus b.i.d. PPI for abnormal DeMeester score (22 vs. 18%), impedance (38 vs. 44%) and SSI (53 vs. 58%); P = 0.80, 0.69, and 0.77, respectively. In 56 patients with positive SSI, symptoms were due to acid reflux in 8 (14%) patients, nonacid reflux in 31 (55%) patients, and combined acid and nonacid reflux in 17 (30%) patients. Patients with persistent heartburn on PPI therapy show a variety of disorders: (i) acid reflux (20%); (ii) nonacid reflux (26%); (iii) positive SSI (56%); (iv) all normal indices (29%). These studies indicate that persistent heartburn on PPI therapy is a complex problem that may not respond to simply increasing acid inhibition. PMID- 25294045 TI - Gene-expression profiling of calves 6 and 9 months after inoculation with Mycobacterium avium subspecies paratuberculosis. AB - Early detection of Johne's disease (JD) caused by Mycobacterium avium subspecies paratuberculosis (MAP) is essential to reduce transmission; consequently, new diagnostic techniques and approaches to detect MAP or markers of early MAP infection are being explored. The objective was to identify biomarkers associated with MAP infection at 6 and 9 months after oral inoculation. Therefore, gene expression analysis was done using whole blood cells obtained from MAP-infected calves. All MAP-inoculated calves had a cell-mediated immune response (IFN-gamma) to Johnin PPD specific antigens, and 60% had an antibody response to MAP antigens. Gene expression analysis at 6 months after inoculation revealed downregulation of chemoattractants, namely neutrophil beta-defensin-9 like peptide (BNBD9-Like), S100 calcium binding protein A9 (s100A9) and G protein coupled receptor 77 (GPR77) or C5a anaphylatoxin chemotactic receptor (C5a2). Furthermore, BOLA/MHC-1 intracellular antigen presentation gene was downregulated 9 months after inoculation. In parallel, qPCR experiments to evaluate the robustness of some differentially expressed genes revealed consistent downregulation of BOLA/MHC-I, BNBD9-Like and upregulation of CD46 at 3, 6, 9, 12, and 15 months after inoculation. In conclusion, measuring the expression of these genes has potential for implementation in a diagnostic tool for the early detection of MAP infection. PMID- 25294047 TI - Imidazolium salts as antifungal agents: strong antibiofilm activity against multidrug-resistant Candida tropicalis isolates. AB - The in vitro activity of the imidazolium salt C16 MImCl against planktonic and biofilm cells of multidrug-resistant isolates of Candida tropicalis was evaluated, both in solution and applied on a commercial catheter surface. This was determined by inhibition and susceptibility assays of biofilm and planktonic cells. In both cases, C16 MImCl prevented in vitro biofilm formation of C. tropicalis strains, including multidrug-resistant ones. Outstanding performances were observed, even at extremely low concentrations. Furthermore, this is the first report of the antifungal lock property of C16 MImCl, using a tracheal catheter as the test specimen to mimic a clinical in vivo condition. As such, C16 MImCl has been identified as a promising antimicotic pharmaceutical candidate for the treatment of candidiasis infections. SIGNIFICANCE AND IMPACT OF THE STUDY: The imidazolium salt 1-n-hexadecyl-3-methylimidazolium chloride (C16 MImCl) strongly prevents, in concentrations as low as 0.028 MUg ml(-1) , the biofilm formation of multidrug-resistant Candida tropicalis isolates, either in solution or applied on the surface of commercial catheters. This presents an effective antimicotic candidate and alternative for invasive clinical procedure toolset asepsis. PMID- 25294048 TI - Attitudes among the general Austrian population towards neonatal euthanasia: a survey. AB - BACKGROUND: The Groningen Protocol aims at providing guidance in end-of-life decision-making for severely impaired newborns. Since its publication in 2005 many bioethicists and health care professionals have written articles in response. However, only very little is known about the opinion among the general population on this subject. The aim of this study was to present the general attitude towards neonatal euthanasia (NE) among the Austrian population and the factors associated with the respondents' opinion. METHODS: A cross-sectional study was conducted among the general Austrian population. Computer-assisted telephone interviews were performed with 1,000 interviewees aged 16 years and older. Binary logistic regression was performed in order to determine factors that are independently associated with the respondents' opinion about neonatal euthanasia. RESULTS: While 63.6% of the participants rejected the idea of neonatal euthanasia for severely impaired newborns, 36.4% opted either in favor or were undecided. Regression analysis has shown the respondents' educational level (p = 0.005) and experience in the care of terminally ill persons (p = 0.001) to be factors that are positively associated with the rejection of neonatal euthanasia, whereas a higher age was associated with a lower degree of rejection (p = 0.021). CONCLUSIONS: We found that the majority of the Austrian population rejects the idea of neonatal euthanasia for severely impaired newborns. However, given the increasing levels of rejection of NE among the younger generations and among people with a higher educational level, it cannot be precluded that the rejection rate might in future increase even further, rather than decrease. PMID- 25294049 TI - [Total thyroidectomy with lymph node dissection of the central compartment for node-positive, capsular invasive papillary thyroid cancer: video contribution]. AB - The aim of radical oncological surgery for nodal metastasized papillary thyroid cancer is, as for other oncological interventions in visceral surgery, the anatomy-related implementation of the concept of en bloc (no touch) resection of the organ bearing the primary tumor together with the first lymph node station, while the structures of the aerodigestive tract, the recurrent laryngeal nerves and parathyroid glands are preserved. The surgical technique is demonstrated in detail with the help of a video of the operation and which is available on-line, the advantages and disadvantages of the technique are discussed. PMID- 25294050 TI - Endoscopic skull base training using 3D printed models with pre-existing pathology. AB - Endoscopic base of skull surgery has been growing in acceptance in the recent past due to improvements in visualisation and micro instrumentation as well as the surgical maturing of early endoscopic skull base practitioners. Unfortunately, these demanding procedures have a steep learning curve. A physical simulation that is able to reproduce the complex anatomy of the anterior skull base provides very useful means of learning the necessary skills in a safe and effective environment. This paper aims to assess the ease of learning endoscopic skull base exposure and drilling techniques using an anatomically accurate physical model with a pre-existing pathology (i.e., basilar invagination) created from actual patient data. Five models of a patient with platy-basia and basilar invagination were created from the original MRI and CT imaging data of a patient. The models were used as part of a training workshop for ENT surgeons with varying degrees of experience in endoscopic base of skull surgery, from trainees to experienced consultants. The surgeons were given a list of key steps to achieve in exposing and drilling the skull base using the simulation model. They were then asked to list the level of difficulty of learning these steps using the model. The participants found the models suitable for learning registration, navigation and skull base drilling techniques. All participants also found the deep structures to be accurately represented spatially as confirmed by the navigation system. These models allow structured simulation to be conducted in a workshop environment where surgeons and trainees can practice to perform complex procedures in a controlled fashion under the supervision of experts. PMID- 25294051 TI - Cervical lymphadenopathy: study of 251 patients. AB - Correct diagnosis of cervical lymphadenopathy is often a great challenge. The objective of this case study is to describe the distribution of the most common causes of unclear neck swellings presented in an ENT-Department and to evaluate the clinical history, examination and laboratory findings. In a retrospective study at the Department of Otorhinolaryngology, University Medical Center Homburg/Saar, 251 patients were enrolled with clinical and ultrasound signs of cervical lymphadenopathy as well as lymph node extirpation for histopathological evaluation. 127 patients (50.6 %) had a histological malignant finding. The distribution of the most common pathological conditions was as follows: Non specific reactive hyperplasia n = 89 (35.5 %), metastases n = 86 (34.3 %), lymphoma n = 41 (16.3 %), granulomatous lesions n = 15 (6 %), abscess formations n = 5 (2 %), necrotic lymphadenitis and Castleman's disease one case of each, lymph node with normal architecture n = 7 (2.8 %), and neck masses mimicking lymphadenopathy n = 6 cases (2.4 %). The following factors identified by multivariate logistic regression were significantly associated to malignant lymphadenopathy: increasing age, generalized lymphadenopathy and history of malignant disorder, fixed neck masses and increasing diameter in ENT examination, bulky lesion, absence of hilus, blurred outer contour, protective role of the long form and decreasing Solbiati-index values by ultrasound B-Mode gray scale examination. Level II contained more benign lymphatic lesions, while the malignancy rate in level IV and V was enhanced. Laboratory parameters significantly associated to malignancies were CRP, LDH and thrombocytopenia. Patients with persisting cervical lymphadenopathy and over 3 weeks of antibiotic treatment should be considered for early biopsy, especially if some of the risk factors, pointed out in this study, are present. PMID- 25294052 TI - Endonasal modification of the frontal sinus drainage type IIb according to Draf. AB - The description of different endonasal drainage options (type I, II and III according to Draf) and their successful use in numerous patients has reached a milestone in frontal sinus surgery. We herein describe a modification of an endonasal frontal sinus drainage type IIb with the additional removal of the lower part of the frontal sinus septum without opening the frontal recess of the other side and without resection of the nasal septum. The modified endonasal endoscopic frontal sinus drainage type IIb was performed on 9 patients at the Department of Otorhinolaryngology, University Medical Center, Homburg/Saar between 02/2011 and 6/2013 after having gained patients' consent. Follow-ups with endoscopic examination were performed after 6, 12 and 24 months (median follow up: 14 months). Endonasal endoscopic opening of the frontal sinus was achieved in all patients. Endoscopic examination 6, 12 and 24 months after surgery revealed patent frontal sinus drainage in 8 patients. The frontal sinus drainage could not be visualized endoscopically in one patient who was free of symptoms for 24 months and where a ventilated frontal sinus was proven radiologically by computed tomography. The study demonstrates the option to additionally remove the lower part of the inter-frontal septum with a frontal sinus drainage type IIb. As the number of patients treated by this modified frontal sinus type IIb drainage is limited, further investigations are needed to define the value of a modified frontal sinus drainage type IIb. PMID- 25294053 TI - Progress of hearing loss in neurofibromatosis type 2: implications for future management. AB - The objective of this study was to describe changes in hearing over time in patients with neurofibromatosis type 2 (NF2) treated conservatively. A retrospective case review was conducted in a tertiary referral centre. Pure tone audiometry, speech discrimination scores, serviceable hearing (American Academy of Otolaryngology class A or B) and measurement of vestibular schwannoma (VS) size on magnetic resonance imaging were evaluated in 56 patients (89 ears) with NF2 with at least one conservatively managed VS. Over a mean follow-up period of 7 years (range 0.8-21 years) pure tone average thresholds increased gradually with a mean annual rate of 1.3 dB for the right ear (p = 0.0003) and 2 dB for the left ear (p = 0.0009). Speech discrimination scores dropped with an average annual rate of 1.3 and 0.34% in the right and left ear, respectively. Patients maintained serviceable hearing for an average of 7.6 years (range 2.7-19.3 years). The average annual VS growth was 0.4 mm without any correlation with hearing loss. There was a correlation between patients' age and pure tone threshold increase (p < 0.05 for both ears). In this selected population of patients with NF2, hearing threshold increases were very slow. In NF2 patients with indolently behaving tumours, serviceable hearing can be maintained for a significant length of time, making conservative management an attractive option. PMID- 25294054 TI - Epidermal growth factor receptor (EGFR) expression in patients with laryngeal squamous cell carcinoma. AB - To assess the epidermal growth factor receptor (EGFR) correlation with histopathologic and clinical characteristics of laryngeal squamous cell carcinoma (SCC) and the impact of EGFR overexpression on patient survival. This retrospective study included 185 SCC patients treated at Clinical Department of ENT, Head and Neck Surgery, Split University Hospital Center between January 1, 2000 and December 31, 2009. A statistically significant correlation (p < 0.001) was recorded between the level of EGFR expression and SCC histopathologic grade, stage, metastasizing potential, relapsing potential, and patient survival. Kaplan Meier survival curve yielded a statistically significant difference (chi(2) = 75.05; p < 0.001) among the four patient groups with different levels of EGFR expression. The higher the level of EGFR expression, the poorer is the patient prognosis and survival. In our study, expression of EGFR as a biomarker showed a potential predictive value in laryngeal SCC. PMID- 25294055 TI - Rationale and design of a multicenter, phase 2 clinical trial to investigate the efficacy of traditional Chinese medicine SaiLuoTong in vascular dementia. AB - BACKGROUND: Vascular dementia (VaD) is the second most prevalent type of dementia among the aged, for whom limited pharmacologic options are available so far. SaiLuoTong capsule is a modern traditional Chinese medicine formula, which has been demonstrated to improve cognition of VaD by the reports of animal experiments and preliminary clinical trial. However, evaluation of this therapy in randomized multicenter trials is needed. In this article, we present the rationale and design of the SaiLuoTong in Vascular Dementia Study. METHODS: This phase 2 clinical trial of SaiLuoTong among patients with mild-to-moderate VaD is a 26-week, multicenter, randomized, double-blind, placebo-controlled study with a subsequent 26-week, open-label extension. After a 4-week placebo run-in period, participants are centrally randomized (1:1:1) to 3 groups: group A receives SaiLuoTong 360 mg per day for 52 weeks; group B receives SaiLuoTong 240 mg per day for 52 weeks; group C (the control group) are further randomly assigned to 2 groups in a 1:1 ratio and receives placebo during the double-blind phase, then SaiLuoTong 360 mg per day or SaiLuoTong 240 mg per day during the extension phase. The primary outcome measures include the VaD assessment scale cognitive subscale and the Alzheimer Disease Cooperative Study-clinical global impression of change. Safety measures include body weight, vital signs, electrocardiography, laboratory tests, and records of adverse events. Assuming an attrition rate of 20%, at least 372 patients are required to obtain a statistical power of 80%. RESULTS: The first patient was enrolled into the study in April 2012 and the completion of the study is expected in September 2014. CONCLUSIONS: The rigorous methodology of the study will hopefully move forward the scientific evaluation of traditional Chinese medicine in treatment of VaD. The results of the present study will provide high-quality evidence on the effect of SaiLuoTong in patients with VaD and has the potential to establish a novel therapeutic approach for this disorder. PMID- 25294056 TI - Clinical outcomes of persistent and paroxysmal atrial fibrillation in patients with stroke. AB - BACKGROUND: We compared the clinical outcomes of persistent atrial fibrillation (PeAF) and paroxysmal atrial fibrillation (PAF) in patients with cardioembolic stroke caused by nonvalvular atrial fibrillation (NVAF) because the nature of the fibrillation can cause persistent cerebral infarction. METHODS: We classified 619 of 964 patients hospitalized with cardioembolic stroke between April 2007 and December 2013 within 24 hours of onset as having PeAF (n = 447) and PAF (n = 172) according to a retrospective analysis of their clinical records, including National Institutes of Health Stroke Scale (NIHSS) scores on admission, clinical outcomes (modified Rankin Scale [mRS] scores) at 90 days after admission, and major cerebral artery occlusion. RESULTS: The PeAF group was significantly older (P < .001) and had a higher prevalence of hypertension (P = .007), diabetes (P = .039), heart failure (P = .004), previous coronary artery disease (P = .002) and cerebral infarction (P < .001), medication with anticoagulants (P < .001), and elevated blood glucose on admission (P = .002). Neurologic severity assessed by NIHSS scores on admission was significantly worse in the PeAF than in the PAF group (P < .001). Significantly more patients in the PAF group had favorable outcomes (mRS, 0-2) after 90 days (P < .001). The incidence of major cerebral artery occlusion was significantly higher in the PeAF group (P < .001). CONCLUSIONS: Patients with PeAF and cardioembolic stroke due to NVAF had more severe neurologic deficits on admission, more frequent major arterial occlusion, and poorer outcomes than those with PAF. PMID- 25294057 TI - A geographic information system analysis of the impact of a statewide acute stroke emergency medical services routing protocol on community hospital bypass. AB - BACKGROUND: Our goal was to determine if a statewide Emergency Medical Services (EMSs) Stroke Triage and Destination Plan (STDP), specifying bypass of hospitals unable to routinely treat stroke patients with thrombolytics (community hospitals), changed bypass frequency of those hospitals. METHODS: Using a statewide EMS database, we identified stroke patients eligible for community hospital bypass and compared bypass frequency 1-year before and after STDP implementation. RESULTS: Symptom onset time was missing for 48% of pre-STDP (n = 2385) and 29% of post-STDP (n = 1612) cases. Of the remaining cases with geocodable scene addresses, 58% (1301) in the pre-STDP group and 61% (2,078) in the post-STDP group were ineligible for bypass, because a community hospital was not the closest hospital to the stroke event location. Because of missing data records for some EMS agencies in 1 or both study periods, we included EMS agencies from only 49 of 100 North Carolina counties in our analysis. Additionally, we found conflicting hospital classifications by different EMS agencies for 35% of all hospitals (n = 38 of 108). Given these limitations, we found similar community hospital bypass rates before and after STDP implementation (64%, n = 332 of 520 vs. 63%, n = 345 of 552; P = .65). CONCLUSIONS: Missing symptom duration time and data records in our state's EMS data system, along with conflicting hospital classifications between EMS agencies limit the ability to study statewide stroke routing protocols. Bypass policies may apply to a minority of patients because a community hospital is not the closest hospital to most stroke events. Given these limitations, we found no difference in community hospital bypass rates after implementation of the STDP. PMID- 25294058 TI - Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia. AB - BACKGROUND: This study was performed to determine whether there is an association between microregional O2 balance and neuronal survival in cerebral ischemia reperfusion using dexmedetomidine, an alpha2-adrenoreceptor agonist and a sedative. METHODS: Rats were subjected to 1 hour middle cerebral artery occlusion and a 2-hour reperfusion. During reperfusion, normal saline (n = 14) or dexmedetomidine 1 MUg/kg/minute (n = 14) was infused intravenously. At 2 hours of reperfusion, regional cerebral blood flow using (14)C-iodoantipyrine autoradiography, microregional arterial and venous (20-60 MUm in diameter) O2 saturation (SvO2) using cryomicrospectrophotometry, and the size of cortical infarction were determined. RESULTS: Ischemia-reperfusion decreased microregional SvO2 (52.9 +/- 3.7% vs. 61.1 +/- .6%, P < .005) with increased variation or heterogeneity (P < .0001) with similar regional cerebral blood flow and O2 consumption. Dexmedetomidine during reperfusion decreased the heterogeneity of SvO2 that was analyzed with an analysis of variance (P < .01) and reported as coefficient of variation (100 * standard deviation/Mean) (11.8 vs. 16.4). The number of veins with O2 saturation less than 50% decreased with dexmedetomidine (13/80 vs. 27/81, P < .01). The percentage of cortical infarct in total cortex was smaller with dexmedetomidine (8.3 +/- 2.2% vs. 12.6 +/- 1.5%, P < .005). CONCLUSIONS: In the cerebral ischemic reperfused cortex, dexmedetomidine decreased the heterogeneity of SvO2 and the number of small veins with low O2 saturation suggesting improved microregional O2 supply/consumption balance. The improvement was accompanied by the reduced size of cortical infarction. PMID- 25294059 TI - Clinical associations of cerebral microbleeds on magnetic resonance neuroimaging. AB - Susceptibility-weighted and gradient-recalled echo T2* magnetic resonance imaging have enabled the detection of very small foci of blood within the brain, which have been termed "cerebral microbleeds." These petechial intraparenchymal hemorrhages have begun to emerge as diagnostically and prognostically useful markers in a variety of disease states. Severe hypertension and cerebral amyloid angiopathy are perhaps the best established microhemorrhagic conditions from neuroimaging literature; however, many others are also recognized including cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL), moyamoya disease, fat embolism, cerebral malaria, and infective endocarditis. Microbleeds are also a common finding in the setting of trauma and stroke. The purpose of this review is to broadly describe the neuroimaging of cerebral microbleeds in a wide variety of conditions, including the differences in their appearance and distribution in different disease states. In a few situations, the presence of microbleeds may influence clinical management, and we discuss these situations in detail. The major importance of this emerging field in neuroimaging is the potential to identify microvascular pathology at an asymptomatic or minimally symptomatic stage and create a window of therapeutic opportunity. PMID- 25294060 TI - Obstetrician who blamed delay in a Caesarean section on a "stupid midwife" is struck off. PMID- 25294061 TI - Hospital care and early breastfeeding outcomes among late preterm, early-term, and term infants. AB - BACKGROUND: Compared with term infants (39-41 weeks), early-term (37-38 weeks) and late preterm (34-36 weeks) infants have increased breastfeeding difficulties. We evaluated how hospital practices affect breastfeeding by gestational age. METHODS: This Listening to Mothers III survey cohort included 1,860 mothers who delivered a 34-41-week singleton from July 2011 to June 2012. High hospital support was defined as at least seven practices consistent with the Baby-Friendly Hospital Initiative's Ten Steps for United States hospitals. Logistic regression tested mediating effects of hospital support on the relationship between gestational age and breastfeeding at 1 week postpartum. RESULTS: High hospital support was associated with increased exclusive breastfeeding (AOR 2.21 [95% CI 1.58-3.09]). Just 16.4 percent of late preterm infants experienced such support, compared with early-term (37.9%) and term (30.7%) infants (p = 0.004). Although overall breastfeeding rates among late preterm, early-term, and term infants were 87, 88, and 92 percent, respectively, (p = 0.21), late preterm versus term infants were less likely to exclusively breastfeed (39.8 vs. 62.3%, p = 0.002). Inclusion of hospital support in multivariable modeling did not attenuate the effect of late preterm gestation. DISCUSSION: Differences in practices do not account for decreased exclusive breastfeeding among late preterm infants. Hospital supportive practices increase the likelihood of any breastfeeding. PMID- 25294062 TI - [Study on the relationship between level of glucose metabolism and risk of cancer incidents]. AB - OBJECTIVE: To explore the relationship between level of glucose metabolism and risk of cancer incidents. METHODS: 10 079 aged >= 40, local residents in Jiashan were enrolled by stratified cluster sampling method in 2011. All the subjects accepted retrospective investigation on incidents of diabetes mellitus and cancers plus blood testing for level of glucose metabolism. Differences between glucose metabolism level and cancer incidence were analyzed by trend Chi-square test. RESULTS: The prevalence of cancers in female diabetes mellitus patients was 268.79 per 100 000, higher than in males-124.31 per 100 000 (chi2 = 4.012 2, P < 0.05). The incidence rates of cancers in groups of normal glucose regulation (NGR), impaired glucose regulation (IGR), and diabetes mellitus (DM) patients were 77.32 per 100 000, 115.40 per 100 000 and 204.08 per 100 000, respectively. The incidence of cancers in local residents who were older than 40 years had increased with the decrease of glucose regulation ability. The subjects were divided into three groups by FPG, 2h-PG and HbA1c levels respectively and the incident risks on cancers under each index increased 30.0%, 39.0% and 62.4%, respectively. Compared to the general population, the cancer incidence in DM group increased 1.67 times and 2.62 times increase in women but did not show significant difference in men (chi2 = 0.524 0, P > 0.05). Breast and colorectal cancers were the most common tumors that accompanied with DM, and their incidence increased along with the decrease of glucose regulation ability. The incidence rates of breast and colorectal cancer in T2DM were 2.36 and 1.87 times more than in general population, and the incidence rates of female patients had an increase of 2.53 and 6.74 times, respectively. CONCLUSION: The cancer incidence was higher in DM group than in the non-DM group while the incidence rates of both breast and colorectal cancer were relevant to the levels of glucose metabolism. PMID- 25294063 TI - [Weight change in association with the incidence of type 2 diabetes in adults from Qingdao, China]. AB - OBJECTIVE: Since the incidence rates and risk factor for type 2 diabetes in Chinese populations had not been well known, the aim of this study was to evaluate the impact of weight change and other risk factors on incident type 2 diabetes in Qingdao, China. METHODS: A prospective population-based cohort study was carried out, based on subjects aged 35-74 years who participated in the 'Qingdao Diabetes Survey' in 2006. Subjects were free of diabetes at baseline. A total of 1 294 subjects attended the follow up survey between 2009 and 2011. The diagnostic criteria for Diabetes was classified according to both the World Health Organization and the International Diabetes Federation 2006. A logistic regression was built using the backward stepwise selection to assess the effects of risk factors on the incident type 2 diabetes. RESULTS: During a 4-year follow up period, 120 cases with incident type 2 diabetes were identified, with cumulative incidence of diabetes as 11.8% . Participants who developed type 2 diabetes were significantly older, having significantly higher age-adjusted BMI/waist circumference/systolic blood pressure and total cholesterol, than those subjects who remained non-diabetic both in urban and rural areas. Among individuals with no diabetes at the baseline, factors as age, living in the rural areas, baseline BMI and weight change had all independently contributed to the development of diabetes. The multivariate adjusted relative risks (95%CIs) related to the incidence of diabetes were 1.45 (1.13-1.87), 1.93 (1.12-3.34), 1.46 (1.05-2.03) and 1.49 (1.18-1.88), respectively, for a one standard deviation increase in continuous variables. Compared with the reference group of non-obese and with stable weight, factor as weight loss >5% and BMI <28 kg/m2 were independently associated with a 67% (RR = 0.33, 95% CI: 0.11-0.97)reduction in the risk of type 2 diabetes, while BMI >28 kg/m2 could increase the risk across the levels of weight change. Similar trends were observed in higher waist and weight gain at baseline. CONCLUSION: This study confirmed the critical importance of obesity in the development of type 2 diabetes. Baseline BMI and weight gain appeared independent predictors on type 2 diabetes. PMID- 25294064 TI - [Evaluation on the effectiveness of intervention comprehensive program on child obesity, using Generalized Estimating Equation]. AB - OBJECTIVE: To evaluate the effect of child obesity intervention comprehensive program on the improvement of overweight, obese control and knowledge-attitude practice. METHODS: The study design was under cluster-randomized controlled trial, with 965 children in the intervention and 895 children in the control groups. Repeated measurement data on child obesity was analyzed through Generalized Estimating Equation models. RESULTS: The risk of becoming overweight or obesity in the intervention group was 0.824 times more than children in the control group, showing a reduction of 17.6% the risk of being overweight or obese (P = 0.031). In addition, the possibility of increasing one unit of correct rate on obesity related knowledge, children in the intervention group children was 1.044 times (P = 0.001)than in the control group. On the mean obesity related correct attitude rate, it was 1.023 times (P = 0.001) in the intervention group of the control group. Regarding the possibility of increasing one unit om the mean obesity related behavior score, children in the intervention group was 1.522 times (P = 0.001)than those in the control group (P = 0.046). CONCLUSION: The comprehensive child obesity intervention program could effectively reduce the risk of developing overweight or obesity and improving the obesity related knowledge, attitude and behavior in children. PMID- 25294065 TI - [Influence of low birth weight on the increased risk of post-partum hypertension]. AB - OBJECTIVE: To compare the prevalence of hypertension between low birth weight infant (LBWI) women and non-LBWI women. METHODS: A retrospective cohort study was applied and 3 172 pregnant women giving births during October 1976 to December 2008 in our hospital and underwent physical check-up between 2010 and 2011 at the Kailuan medical group were included and divided into LBWI group and non-LBWI group by the history of LBWI. Prevalence of hypertension was obtained during the follow-up program. Multiple logistic regression analysis was used to assess the relative risk of hypertension. RESULTS: A total number of 3 172 women, with an average age of 42.3 years old were divided into LBWI group (n = 147) and non-LBWI group (n = 3 025), with the average birth weights of their infants were 2.31 kg and 3.39 kg, respectively. The prevalence of hypertension from the follow-up program was significantly higher in LBWI group than that in the non-LBWI group (23.8% vs. 16.9%, P < 0.05). After adjustment for other traditional risk factors, the risk of hypertension in LBWI group was 1.60 (95%CI:1.02-2.53) folds higher than that in the non-LBWI group. CONCLUSION: Prevalence of hypertension in women with LBWI was higher than that in those women without LBWI. History of LBWI seemed to have had an increased risk to develop hypertension. PMID- 25294066 TI - [Effect of type 2 diabetes with hypertension on cognitive function-a study on elderly living in the communities of Beijing]. AB - OBJECTIVE: To study the effects of type 2 diabetes (T2DM) with hypertension on cognitive function in those community-based elderly who were aged 60 and over, in Beijing. METHODS: 82 patients with T2DM, 142 patients with both T2DM and hypertension and 277 normal controls were investigated in this study. Both methods as: the Montreal Cognitive Assessment (MoCA) and Mini-Mental Status Examination (MMSE)were used to determine cognitive change. RESULTS: The total MMSE scores showed significant decrease between T2DM with hypertension and controls [(28.42 +/- 1.52) vs. (28.88 +/- 1.47), P < 0.05]. The MoCA score of the total scores [(25.20 +/- 3.91) vs. (26.50 +/- 3.29), P < 0.05], sub-scores of visuospatial, executive [(3.60 +/- 1.56) vs. (3.96 +/- 1.18), P < 0.05] and language [(2.10 +/- 0.80) vs. (2.37 +/- 0.80), P < 0.05] significantly decreased in T2DM patients with hypertension and in the normal controls. Data from the Multiple logistic regression analysis showed that older age and less education were risk factors for cognitive impairment. CONCLUSION: T2DM and hypertension damaged the cognitive function of patients. PMID- 25294067 TI - [Association between polymorphisms, haplotypes of peroxisome proliferators activated receptor a gene and the level of lipoprotein (a)]. AB - OBJECTIVE: The aim of this study was to investigate the association between three single-nucleotide polymorphisms (SNP) of in the peroxisome proliferator-activated receptor (PPAR) alpha gene and the level of lipoprotein (a) [Lp(a)]. METHODS: Participants were recruited under the framework of a cohort populations survey from the PMMJS (Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province) which was conducted in the urban community of Jiangsu province from 1999 to 2007. 644 subjects (234 males, 410 females) were randomly selected and genotyped for three polymorphisms which were used as genetic marker for PPARalpha gene (rs1800206, rs4253778 and rs135539). Data related to individual polymorphism and haplotype were available for analysis. chi2 test was used to determine if the whole population was in Hardy-Weinberg genetic equilibrium. Linear regression models were used to analyze the association between SNPs in PPARalpha gene and the level of Lp(a). Associations between PPARalpha haplotypes and serum Lp(a) levels were analyzed by the SNPstats software. RESULTS: In the dominant model, after factors as sex, age, smoking, alcohol and BMI were adjusted, the presence of the V162 allele of L162V appeared associated with a high level of Lp(a) (mean difference was 57.70 mg/L (95% CI: 32.03-83.37 mg/L), P < 0.001. Data from the haplotype analysis revealed that A-G-V and C-G-V haplotype (established by 1A > C, 7G > C L162V) were significantly associated with a higher level of Lp(a) (P = 0.012 0 and 0.009 7). CONCLUSION: Results from our study might help to clarify the role of PPARalpha gene in regulation of Lp(a) and the evaluation of its polymorphisms and haplotypes which were characterized as genetic factors for Lp(a). PMID- 25294068 TI - [Predictors for 'successful quitting smoking' among males carried out in a smoking cessation clinic]. AB - OBJECTIVE: To investigate the predictors for 'quitting' among male smokers in a smoking cessation clinic. METHODS: The target population consisted of smokers who volunteered to seek treatment for cessation at our clinic in Beijing. Smokers received face-to-face counseling and psychological intervention at the first visit by trained physicians and standardized telephone discussion, was carried out with counselors at 1 week, 1/3/6 months a follow-up study. The main outcomes would involve 'successful quitting' at the 7-day point, continuous quit rates at 3 and 6 months as well as the predictors of 'quitting'. RESULTS: From October 2008 to December 2012, we collected 355 eligible male smokers among whom 255 had completed the 6-month follow-up program. Results from the analysis (n = 255) showed that the quitting rates at the 7-day point and 3 months were 34.9% and 25.5%, while the rates were 25.1% and 18.3% among the 355 smokers who had the intention for treatment. Data from the stepwise logistic regression model analysis showed that lower exhaled CO level at the first visit, higher perceived confidence in quitting, lower expenditure on cigarettes and had diagnosed tobacco related chronic diseases by physicians, were important predictors for quitting smoking. The main reasons of failure to quit were addiction of tobacco cigarette, craving for cigarettes to relieve pressure from work, peer influence from other smokers, lack of mental preparation and perseverance to quit, etc. CONCLUSION: Smokers who smoked less cigarettes, had higher perceived confidence in quitting and had physician-diagnosed tobacco-related chronic diseases seemed easier to quit. Regular follow-up intervention services for smokers should be established to enhance the motivation for quitting so as to create a favorable environment for the smokers. PMID- 25294069 TI - [Current status of smoking and passive smoking among aged 45 to 65 years old females in five cities of China]. AB - OBJECTIVE: To investigate the current status of smoking and passive smoking among Chinese females to provide evidence for related strategy development. METHODS: Data from 32 720 women aged 45-65 years old who participated in the 2008 to 2010 Chinese Multi-center Women Breast Cancer Screening Project, were used to analyze the prevalence rates of smoking/heavy smoking, daily smoking, smoking cessation, successful smoking cessation, passive smoking, etc. RESULTS: A total of 913 females, accounted for 2.8% of all the women in the study, had reported the history of smoking. There were significant differences seen regarding the prevalence rates of smoking in different regions (Beijing, 2.8%; Tianjin, 5.9%; Nanchang, 1.7%; Feicheng, 0.9%; Shenyang, 1.8%). The prevalence rates of current smoking, daily smoking, and heavy smoking were 1.8%, 1.0% and 0.2%, respectively. The prevalence rates of smoking and current smoking increased with age but not the prevalence rates of daily smoking and heavy smoking. Among the smokers, the median initiation age of smoking, the median daily cigarette per day, and median year of smoking were 30 years old, 10 cigarette, and 16 years, respectively. And the prevalence rates of smoking cessation and successful smoking cessation were 19.1% and 8.2%. The prevalence rate of passive smoking was 45.7% (12 730/27 874). After combing the number of smokers and the number of passive smokers, the total exposure rate to tobacco was 41.8% (13 670/32 720). CONCLUSION: There was a relatively low level of smoking among Chinese females, so as the rate of smoking cessation. However, passive smoking presented a relatively high level among Chinese females. PMID- 25294070 TI - [Association between dyslipidemia and 8-OHdG/Cr among a population exposed to chronic arsenic]. AB - OBJECTIVE: To explore the association between dyslipidemia and the level of 8 OHdG/Cr in urine among a population exposed to chronic arsenic. METHODS: Four hundred and seven subjects were randomly selected in an arsenic-affected area in Inner Mongolia. After blood biochemical examination, all the subjects were divided into 4 groups based on the results of total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C)and low density lipoprotein cholesterol (LDL-C). The groups consisted of hypercholesterolemia, HDL-C ratio anomaly, combined hypercholesterolemia and HDL-C ratio anomaly, as well as a normal lipid group. Urine samples were collected and 8-OHdG/Cr was measured using the ELISA method. A generalized linear mixed model was used to analyze the association between dyslipidemia and 8-OHdG/Cr. RESULTS: The levels of 8-OHdG/Cr as 55.73 (39.90-79.94) ng/mg, 58.08 (44.94-69.91)ng/mg, 65.28 (49.29 92.95) ng/mg and 51.43 (36.86-68.57) ng/mgin the HDL-C ratio anomaly, hypercholesterolemia, combined hypercholesterolemia and HDL-C ratio anomaly groups and the control group, respectively, which showed significant differences on the levels of 8-OHdG/Cr in the four groups(P = 0.006). From the linear regression analysis results showed that the 8-OHdG/Cr level in combined hypercholesterolemia and HDL-C ratio anomaly group was higher (4.25 +/- 0.55 ng/mg) than in the control group (3.96 +/- 0.55 ng/mg) (P = 0.018). After adjusting for important covariates, there was a linear trend between the levels of 8-OHdG/Cr and dyslipidemia (P = 0.016). CONCLUSION: Data from our study showed a linear relation between hypercholesterolemia, HDL-C ratio anomaly and the 8 OHdG/Cr level, suggesting that dyslipidemia was associated with oxidative DNA damage among those . PMID- 25294071 TI - [A cross-sectional study on physically violent behavior among youth males in Chengdu, Sichuan province]. AB - OBJECTIVE: To investigate the prevalence of physically violent behavior among 18 34 years old males in Chengdu. METHODS: 2 151 males aged 18-34 years was recruited in Chengdu, using a multistage stratified random sampling method. "Men's health and modern lifestyles survey questionnaire" was adopted to collect information on demography, physical violent behavior, attitude and reactions to violence. RESULTS: Self-reported prevalence of physical violent behavior since 15 years of age among those 18-34 year-old males was 51.8%. 17.8% of the young males reported having violent behavior in the past 5 years, but the prevalence declined progressively with age (P < 0.01). People who were religious or remained single had higher prevalence rates than those non-religious, married or having regular sex partners (P < 0.01). Prevalence seemed relatively high in students or workers at service/commercial fields, with rates as 24.5% and 20.3%. CONCLUSION: Data from our study suggested that physical violence was an important problem among young males in Chengdu. Factors as being young, single, divorced or widowed were associated with self-reported violent behavior. People who were religious, being students or working at the service/commercial fields seemed to be under high risk of carrying physical violence. PMID- 25294072 TI - [Situation and correlated behavior of HIV infection among currently married MSM in Gansu province]. AB - OBJECTIVE: To explore the situation of HIV infection among currently married MSM and the features of related sexual behavior on both males and females in Gansu province. METHODS: By "Place the recruitment" methodology, 297 currently married MSM were recruited in Lanzhou and Tianshui cities of Gansu province. Participants filled in a questionnaire and underwent HIV antibody testing. SPSS 17.0 software was used to analyze the result and differences between positive HIV MSM and negative HIV MSM. Possible factors that influencing the HIV infection among currently married MSM were analyzed. RESULTS: Among those currently married MSM, the HIV positive rate was 4.7%. 94.6% participants admitted having had anal sex with male partners in the past 6 months while 30.9% participants had more than 2 male sex partners in the past week, with the rate of condoms use as 45.9%. 69.0% of the participants had sex with females in the past 6 months, with the rate of condoms use as 24.9%. 59.0% of the participants did not use condoms when having sexual relations with partners. Among HIV positive married MSM, the rate of AIDS awareness was 64.3% and 7.1% of them ever having had HIV testing last year and 92.9% of them had anal sex with males. In the recent 6 months, 14.3% had ever used condom each time when having anal sex with males. 35.7% of the cases ever having had sex with females, with the rate of condom use as 60.0%. CONCLUSION: HIV prevalence, low AIDS awareness, low HIV rate of testing and high rate of unprotected sex behavior with either sex partners were found among currently married MSM in Gansu province. RESULTS: of this study called for behavioral intervention and HIV testing measures should be taken immediately. PMID- 25294073 TI - [Survival rate and risk factors of mortality among first-ever stroke patients]. AB - OBJECTIVE: To describe the survival status and to analyze the factors associated with mortality on first-ever stroke patients. METHODS: The first-ever stroke patients registered in 2009 were collected from "Zhejiang provincial information system for NCDs' surveillance and management". Survival status and the cause of death through active and passive follow-up programs, were collected. Kaplan-Meier methods were used for survival description. Monovariant and multivariant Cox's proportional hazard regression models were used to analyze risk factors on mortality. RESULTS: A total of 78 189 patients, who suffered from cerebral infarctions (ICD-10:I63), intracerebral haemorrhages(I61), subarachnoid haemorrhages (I60) and unspecified strokes (I64), accounted for 61.65%, 30.42%, 2.32% and 5.62%, were recruited. 33 265 cases died during the period of this study. 27 147 cases were stroke related, accounted for 81.61%. 6 122 cases died on the same day, with one-day case fatality as 7.83% and the overall 28-day case fatality as 21.01%. The survival rates from one-year to four-year were 72.04% , 68.92%, 66.27% and 64.29%, respectively. The four-year survival rates of I63, I61, I60 and I64 were 80.06%, 50.15%, 71.80% and 21.41%, respectively. Effect of the model showed that the risk factors associated with mortality were age, gender, educational level, the diagnosis and quality of the hospitals on treatment, hypertension and the types of stroke incidences. Age had interacted with gender (P < 0.001). Results from the 'single effect' showed that males had higher risk than females in those younger than 75 years old, but vice versa in those older than 75 of age. CONCLUSION: Patients appeared very high risk of death in both acute and sub-acute phases. Factors including age, gender, educational level, both quality on diagnosis and treatment of the hospitals, clinical types of hypertension and stroke etc. were at risk, associated with prognosis of the disease. PMID- 25294074 TI - [Epidemiological analysis on malaria prevalence in Shanghai from 2003 to 2012]. AB - OBJECTIVE: To understand the epidemiological characteristics of malaria in Shanghai. METHODS: Data related to malaria cases during 2003 to 2012 year in Shanghai was collected and analyzed according to the 3 stages as malaria pre elimination (2003-2008), pilot malaria elimination (2009-2010) and malaria elimination (2011-2012), respectively. RESULTS: A total number of 936 malaria cases were collected, including 616 cases of Plasmodium (P.) vivax, 110 cases of P. falciparum and 210 cases of unidentified plasmodium. The overall annual incidence rate of malaria was lower than 1 per one hundred thousand and showing a gradual downward trend after 2008. P. vivax was mostly seen during 2003-2008 while the proportion of P. falciparum increased gradually during 2009-2010 and the case of P. falciparum occupied the most during 2011-2012. During 2003-2008, most malaria cases were infected in other provinces but diagnosed in Shanghai. However, between 2008 and 2012, malaria cases were mainly imported from overseas which accounted for 82.80% of the total identified cases, particularly in 2012 that all the malaria cases were imported from Africa and South-East Asia. No indigenous malaria case had been identified since 2009. CONCLUSION: The annual incidence rate of malaria in Shanghai showed a gradual downward trend. Not a single indigenous malaria case had been found for the last 4 years. However, the fact that the situation of importation called for special attention. PMID- 25294075 TI - [Using Breteau Index to analyze the nature of sporadic and outbreak cases of Dengue fever]. AB - OBJECTIVE: To understand the threshold of Breteau Index (BI) on Dengue fever outbreak in Guangzhou. METHODS: Dengue cases from Guangzhou during 2006 to 2012 in the National Infectious Disease Report and Management System were collected and described. Receiver-operating characteristic (ROC) curve was used to judge the threshold of BI on the outbreaks of Dengue fever. RESULTS: A total of 1 038 local cases were reported from 2006 to 2012 in Guangzhou city, with a total of 71 outbreaks and 259 sporadic episodes. Data from the ROC curve analysis showed that the highest Youden index that BI predicting Dengue fever outbreaks or sporadic were 6.4 and 9.5, respectively. When using BI = 6.4 in predicting the sporadic case of Dengue, sensitivity and specificity were 67.8% , 79.1% , respectively. When using BI = 9.5 in predicting the outbreaks of Dengue, sensitivity and specificity were 81.7%, 90.9%, respectively. CONCLUSION: Both BI = 5.0 and BI = 9.5 showed effects on predicting the nature of sporadic or outbreak on Dengue, suggesting that the threshold need to be monitored, according to the purpose of control and availability of manpower, in order to get better sensitivity and specificity. PMID- 25294076 TI - [Etiologic characteristics of Vibrio cholerae in Guangdong province in 2009 2013]. AB - OBJECTIVE: To analyze the etiologic characteristics of O1/O139 Vibrio cholerae in Guangdong province in 2009-2013. METHODS: Isolates from cholera cases and from the environment surveillance points were investigated by serological typing, antibiotic susceptibility testings, toxic genes detection and molecular typing to analyze the similarities and differences of the identified species. RESULTS: Totally, 190 isolations of O1/O139 V. cholerae were obtained from cholera cases (16 strains) and environmental samples (174 strains) in Guangdong province in 2009-2013. The sero-types would include Inaba (3 isolates), Ogawa (7 isolates) and O139 (6 isolates) in all the isolates from the cholera cases. Ten strains from the ctxA positive cases were detected by PCR. Two Ogawa strains carried incomplete CTXPhi phage. Results from the antibiotic susceptibility test indicated that 5 strains were absolutely sensitive to 11 antibiotic discs in vitro, while another 3 strains were simultaneously resistant to 4 antibiotic discs. Except for 2 stains, all the O139 strains from the environment were ctxA negative, detected by PCR. Incomplete CTXPhi phage was found in the Inaba (53 isolates), Ogawa (22 isolates) and O139 (2 isolates), respectively. Results from the antibiotic susceptibility test exhibited that 25 strains were resistant simultaneously to 4 and/or more antibiotic discs, especially the Inaba strains from the seafoods(13 isolates). 2 Inaba strains from seafood were simultaneously resistant to 7 antibiotic discs. Results from PFGE molecular typing indicated that the PFGE types digested by Not I expressed significant diversity. Inaba and O139 strains from cases were gathered in the same clusters, while the Ogawa strains from cases scattered in different clusters but no significant correlation among these strains were found. Our results suggested that a distant genetic relationship might exist between these two different sources strains. CONCLUSION: Complex and diverse as the virulence genes and genetic characteristics and with the grim situation of multi-drug resistant strains, all seemed important to strengthen the surveillance programs on the variation of strain types and antibiotics resistance of O1/O139 V. cholerae in Guangdong province. PMID- 25294077 TI - [Effects of resting days on live poultry markets in controlling the avian influenza pollution]. AB - OBJECTIVE: To analyze the results of nine-round environmental specimen surveillance programs in five live poultry markets pre-, during and post the 'closing days' and to evaluate the effects of 'closing days' on live poultry markets regarding the control against avian influenza pollution. METHODS: In January 2014, control measures including culling poultry, completely cleaning and disinfecting and a 'three-day-closing' measure were conducted in five live poultry markets which were found positive for H7N9 nucleic acid in the 1(st) round environmental specimen surveillance program. Second surveillance program was conducted after a thorough disinfection campaign was launched. Several times surveillance were conducted in one week, after the markets were reopened. RT-PCR was used to test the nucleic acid of HA, H5, H7 and H9 viruses. RESULTS: 654 specimens from the environment were collected and tested. During the first round surveillance program, positive rates for influenza A and H5/H7/H9 nucleic acid of poultry stalls appeared to be 94.44% and 61.11% respectively. The positive rates of poultry stalls reduced to 0 after the disinfection campaign but increased again after the markets reopened. The positive rate for influenza A of poultry stalls slightly increased from 50.00% in the third surveillance to 72.22% in the ninth surveillance (P > 0.05). The positive rate for H5/H7/H9 of poultry stalls showed a significantly increasing trend, from 0 in the third surveillance to 44.44% in the ninth surveillance (P < 0.01). The positive rates for influenza A and H5/H7/H9 nucleic acid of specimens were 28.89% and 17.78% respectively. The positive rate of specimens reduced to 0 after disinfection while increased again after reopening of the markets. The positive rate for influenza A of specimens slightly increased from 19.67% in the third surveillance to 27.54% in the ninth surveillance programs (P > 0.05). The positive rate for H5/H7/H9 of specimen showed a significant increasing trend, from 0 in the third surveillance to 8.70% in the ninth-round surveillance programs (P < 0.01). The positive rate for influenza A was the highest for slaughter- related specimens of 22.4% (35/156). The positive rates for influenza A from sewage and drinking water being collected on the later stage after the markets reopened (25.9%, 12.4%)were higher than those on the early stage (8.3%, 8.6%) (P > 0.05). The positive rate for influenza A of poultry stalls with overnight poultry storage (91.7%) was significant higher than that of poultry stalls without the overnight storage (33.3%). The positive rate for influenza A of poultry stalls in which simultaneously selling different kinds of poultry (85.7%) was significant higher than that of poultry stalls in which selling only one kind of poultry at one time (25.0%) (P < 0.05). CONCLUSION: Slaughter in live poultry markets posed a large risk of pollution diffusion. Sewage and drinking water showed an accumulation effect for avian influenza virus. Overnight poultry storage and selling different kinds of poultry at one time at the poultry stalls seemed the risk factors for avian influenza virus transmission. Complete cleaning, disinfecting and several 'closing days' for live poultry markets seemed effective in eliminating avian influenza virus. Once the markets were reopened, they seemed to be soon polluted again. PMID- 25294078 TI - [Sequencing and analysis of N gene of street rabies virus isolated from different hosts in Zhejiang province]. AB - OBJECTIVE: To elucidate the characteristics of genetic variability and its relationship with prevalence, through sequencing and analysis of N gene among street rabies virus isolated from different hosts (homo sapiens, ferret badger, dog) in Zhejiang province. METHODS: Samples were screened and confirmed by direct fluorescence assay and reverse transcript PCR. Sequences were analyzed using bio information software. RESULTS: Eighteen street rabies virus strains were identified, including 2 from homo sapiens, 5 from ferret badger, and 11 from dog. Similarities of N gene and N protein were calculated to be 89.7%-100.0% and 98.4% 100.0% respectively. Mutations occurred in N gene were almost non-sense mutations. In addition,Data from phylogenetic analysis showed that all these strains could be classified into traditional genotype 1. CONCLUSION: The prevalence of rabies viruses among different hosts in Zhejiang province had certain regional properties. Rabies viruses isolated from the same kind of host or from the same/adjacent county/counties had the closest relationship. However, the characteristics of rabies virus prevalent in homo sapiens were somewhat complicated. In summary, the transmission of street rabies virus in Zhejiang province was from dogs to ferret badgers and homo sapiens, and the virus could circulate and cross-regional transmit among dogs and ferret badgers. PMID- 25294079 TI - [Study on the molecular epidemiology and antibiotic resistance of Salmonella enterica serovar Pomona]. AB - OBJECTIVE: To study the epidemiological characteristics and antibiotic resistance of Salmonella enterica serovar Pomona (S. Pomona). METHODS: Antimicrobial susceptible testing (AST) and pulsed field gel electrophoresis (PFGE) methods were used to analyze on S. Pomona strains that were isolated from diarrhea cases through the diarrhea network monitoring program, environment and food samples in Shanghai as well as from reptiles in Guangxi Zhuang Autonomous Region. RESULTS: 4 553 clinic Salmonella (S.) strains were isolated from the Shanghai network laboratories from 2005 to 2012. The top 10 serotypes would include 20 serotypes all belonged to A-F groups, while S. Pomona was next to S. Wandsworth, according to the non- A-F groups. Young children seemed to be susceptible to S. Pomona, and might cause bloody stools and super-infection. The top 10 serotypes from 1 805 foodborne Salmonella strains were significantly more extensive than those from the human S. Pomona strains, followed by those rare serotypes which were mostly isolated from turtle, sea-shellfish and reptiles. Antibiotic resistance of S. Pomona strains from other sources were significantly more severe than those from human samples, and belonged to A and B clones by means of PFGE. Clone A strains were non-epidemic strains which showed multi-drug resistance (MDR) to antimicrobials. Clone B was the main epidemic-causing strain that not resistant to drugs, which consisting B- I from young-age-groups and B-II were from the seniors. B-I strains were homologous to those from shellfish, tortoises and lizards, while B-II strains only showing homology to those from shellfish. One S. Pomona strain-MDR, isolated from human was homologous to 8 antimicrobials. CONCLUSION: S. Pomona was a quite common serotype among those rare serotypes, which showed higher pathogenicity to infants while genetic evolution might take place when comparing them with the strains isolated from the clinics in 2005. Surveillance programs should be intensified along with the early warnings systems on infections which were from seafood and reptiles. PMID- 25294080 TI - [Association between early life exposure to famine and damaging the liver and kidney function]. AB - OBJECTIVE: To examine how early life exposure to famine would impact on liver and kidney functions and related chronic metabolic diseases during adulthood. METHODS: A random cluster sampling method was adopted in Anhui province, 2011 from a physical examination center, in a first-class hospital. 4 252 study subjects were born between 1957 and 1963. According to the time of birth:the study subjects were divided into three groups, respectively: 1957-1958 (983 persons as pre-famine), 1959-1961 (1 247 persons as exposed to famine) or 1962 1963(2 022 persons as controls, also the post-famine). Variances between groups AST, ALT, r-GGT, differences in the levels of SCr, UA, UREA and the change trend were compared. RESULTS: ALT,IBIL, TBIL, SCr, UREA were statistically different (P < 0.05) among subjects born in the different years. r-GGT, ALT, AST, ALB, SCr were statistically different (P < 0.05) among males born in different years so as the r-GGT, AST, ALB, GLB, TP, SCr, UA, UREA in females (P < 0.05). r-GGT, ALT, ALB, SCr differences statistically significant (P < 0.05) and r-GGT, AST, ALB, GLB, TP, SCr, UA, UREA in females were statistically significantly different (P < 0.05). CONCLUSION: Early life poor nutrition could lead to developmental disorders, organ function damage in liver and kidney function during adulthood. Women appeared to have balanced diet nutrition during pregnancy which was far important in the prevention on adulthood chronic metabolic diseases. PMID- 25294081 TI - [Effects related to experiences of famine during early life on diabetes mellitus and impaired fasting glucose during adulthood]. AB - OBJECTIVE: To investigate the effects of famine-experience during early life on diabetes mellitus and impaired fasting glucose in the adulthood. METHODS: In a total of 101 510 employees who took part in the health examination at the Kailuan Group between 2006 to 2007 were recruited. All the study subjects were born in Hebei province between 1956-10-01 and 1964-09-30 but those who had incomplete data were excluded. 19 347 subjects were finally included for analysis. Members from the famine-exposed group were born between Oct. 1, 1959 and Sep. 30, 1961. There was a semi-exposed group with members born between Oct. 1, 1958 and Sept. 30, 1959 and from Oct. 1, 1961 to Sept. 30, 1962 but members from the control group were born from Oct. 1, 1956 to Sept. 30, 1958 and from Oct. 1, 1962 to Sept. 30, 1964. Prevalence rates on diabetes mellitus and the detection rate of impaired fasting glucose among the three groups were compared. Logistic regression model was used to analyze the effects of famine-experience during early life with the prevalence of diabetes mellitus and the detection rate of impaired fasting glucose during adulthood. RESULTS: Prevalence of diabetes mellitus and the detection rate of impaired fasting glucose in the famine-exposed adult-cohort groups were 8.99%, 8.96% while 8.05% and 9.35% in the semi-exposure groups, 7.71% and 8.20% in the control group. Results from the multivariate logistic regression analysis showed that experiences of famine during early life increased the risk of diabetes mellitus and impaired fasting glucose in adulthood with the odds ratios as 1.218 (95% CI: 1.056-1.404, P = 0.007) and 1.142 (95% CI: 0.994-1.312, P = 0.061). After stratification by sex, odds ratios in males were 1.163 (95% CI: 1.001-1.350, P = 0.048)and 1.213(95% CI:1.039-1.417, P = 0.015). The odds ratios in females were 1.319 (95% CI: 0.920-1.891, P = 0.132) and 0.990 (95% CI: 0.679-1.444, P = 0.959). CONCLUSION: Experiences of famine during early life increased the risk of diabetes mellitus and impaired fasting glucose in the adulthood. However, this negative effect existed mainly in the males, according to the results from our study. PMID- 25294082 TI - [Relation of admission neutrophil/lymphocyte ratio to angiographic no-reflow phenomenon in patients with ST-elevated myocardial infarction undergoing primary coronary intervention]. AB - OBJECTIVE: To investigate the relationship of the neutrophil/lymphocyte ratio (NLR) on admission and angiographic no-reflow phenomenon in patients with ST segment elevation myocardial infarction (STEMI) who had undergone primary percutaneous coronary intervention (PCI). METHODS: 232 patients who had undergone PCI between 2010 and 2013, were included and divided into two groups based upon the thrombolysis in myocardial infarction (TIMI) flow gradings. No-reflow was defined as post-PCI TIMI Grade 0, 1 and 2 flows (group I). Normal-flow was defined as TIMI 3 flow (group II). Receiver operating characteristic curve (ROC) analysis was used to identify the predictive effect of NLR on no-reflow phenomenon. Relationship of NLR and no-reflow was assessed by multivariate logistic regression. All statistical calculations and analyses were performed using SPSS 11.0. RESULTS: NLR was significantly higher in group I (n = 45) compared with group II (n = 187) [4.1(2.4-6.5) vs. 2.4 (1.7-3.8), P = 0.001]. In ROC analysis, NLR>3.2 predicted no reflow with 80% sensitivity and 73% specificity. Patients with elevated NLR had a higher incidence of no-reflow phenomenon than those with non-elevated NLR (34.8% vs. 9.3%, P < 0.001). Also, NLR (>3.2) was an independent predictor of no-reflow development [odds ratio 3.70, 95% confidence interval(1.39-9.80), P = 0.009]. CONCLUSION: NLR was an independent predicator for no-reflow development in STEMI patients who had undergone PCI. This simple and low-cost parameter could provide useful information for the early risk evaluation on these patients. PMID- 25294083 TI - [Neutrophil ratio/blood glucose and poor short outcome among patients with acute ischemic stroke]. AB - OBJECTIVE: To investigate the relationship between neutrophil ratio/blood glucose and short outcome among patients with acute ischemic stroke admitted to hospitals. METHODS: A total of 2 265 acute ischemic stroke patients in four hospitals in Shandong province were included in this study. Through access to patients' files, data on demographic, lifestyle, medical history, family history and laboratory findings were collected from all participants at admission. Endpoint of the study was defined as poor short-term prognosis of acute cerebral infarction (NIHSS >= 5) at discharge or death during hospitalization. Subjects of this study were divided into four groups: normal neutrophil ratio with normal blood glucose (NN/NG); normal neutrophil ratio with high blood glucose (NN/IG); high neutrophil ratio with normal blood glucose (IN/NG) and high neutrophil ratio with high blood glucose (IN/IG). Non-conditional logistic regression analysis was used to evaluate the association between blood glucose/neutrophil ratio and the short outcome of acute ischemic stroke. RESULTS: Neutrophil ratio and the level of blood glucose in patients with study endpoints were both higher than those without the study endpoints, and the difference was statistically significant (all P < 0.05). After multivariate adjustment, when compared to NN/NG group, the ORs (95% CI) of NN/IG, IN/NG and IN/IG group were 1.356 (0.942-1.953), 1.879 (1.113-3.171) and 2.210 (1.477-3.307), respectively. CONCLUSION: Neutrophil ratio at admission was an independent risk factor of poor short outcome in patients with acute ischemic stroke. IN/IG group was considered at a highest risk in general population. Neutrophil ratio/glucose was valuable in predicting the incidence of poor short outcome in acute ischemic stroke patients. PMID- 25294084 TI - [The application of trajectory model in epidemiological research]. AB - This article introduced the application of trajectory model in epidemiological study on fat development in sixty teenagers. Results showed that fat developing trend on three trajectories-normal fat group, high fat group and very high fat group, with independently different developing trend. Trajectory model seemed a suitable model for fitting the longitudinal data with heterogeneity. PMID- 25294085 TI - [Progress on the studies of association between hormone and suicidal behavior]. PMID- 25294086 TI - Assessing the impact of HAART on the incidence of defining and non-defining AIDS cancers among patients with HIV/AIDS: a systematic review. AB - After highly active antiretroviral therapy (HAART) became widespread, several studies demonstrated changes in the incidence of defining and non-defining AIDS cancers among HIV/AIDS patients. We conducted a systematic review of observational studies evaluating the incidence of malignancies before and after the introduction of HAART in people with HIV/AIDS. Eligible studies were searched up to December 2012 in the following databases: Pubmed, Embase, Scielo, Cancerlit and Google Scholar. In this study, we determined the cancer risk ratio by comparing the pre- and post-HAART eras. Twenty-one relevant articles were found, involving more than 600,000 people with HIV/AIDS and 10,891 new cases of cancers. The risk for the development of an AIDS-defining cancer decreased after the introduction of HAART: Kaposi's sarcoma (RR=0.30, 95% CI: 0.28-0.33) and non Hodgkin's lymphoma (RR=0.52, 95% CI: 0.48-0.56), in contrast to invasive cervical cancer (RR=1.46, 95% CI: 1.09-1.94). Among the non-AIDS-defining cancers, the overall risk increased after the introduction of HAART (RR=2.00, 95% CI: 1.79 2.23). The incidence of AIDS-defining cancers decreased and the incidence of non AIDS-defining cancers increased after the early use of HAART, probably due to better control of viral replication, increased immunity and increased survival provided by new drugs. PMID- 25294087 TI - Uncertainties in predicting rice yield by current crop models under a wide range of climatic conditions. AB - Predicting rice (Oryza sativa) productivity under future climates is important for global food security. Ecophysiological crop models in combination with climate model outputs are commonly used in yield prediction, but uncertainties associated with crop models remain largely unquantified. We evaluated 13 rice models against multi-year experimental yield data at four sites with diverse climatic conditions in Asia and examined whether different modeling approaches on major physiological processes attribute to the uncertainties of prediction to field measured yields and to the uncertainties of sensitivity to changes in temperature and CO2 concentration [CO2 ]. We also examined whether a use of an ensemble of crop models can reduce the uncertainties. Individual models did not consistently reproduce both experimental and regional yields well, and uncertainty was larger at the warmest and coolest sites. The variation in yield projections was larger among crop models than variation resulting from 16 global climate model-based scenarios. However, the mean of predictions of all crop models reproduced experimental data, with an uncertainty of less than 10% of measured yields. Using an ensemble of eight models calibrated only for phenology or five models calibrated in detail resulted in the uncertainty equivalent to that of the measured yield in well-controlled agronomic field experiments. Sensitivity analysis indicates the necessity to improve the accuracy in predicting both biomass and harvest index in response to increasing [CO2 ] and temperature. PMID- 25294088 TI - Chemical and biological evaluation of unusual sugars, alpha-aculosides, as novel Michael acceptors. AB - The unusual sugars, alpha-aculosides, which appear in certain antibiotics and have an alpha,beta-unsaturated ketone structure, were found to be novel and selective Michael acceptors for the thiol function of cysteine residues. A coumarin derivative possessing alpha-aculoside as a Michael acceptor effectively and irreversibly operated as a fluorescent probe in cells. Furthermore, alpha aculosides exhibited cytotoxic activity against several cancer cell lines. PMID- 25294090 TI - The thermic effect of sugar-free Red Bull: do the non-caffeine bioactive ingredients in energy drinks play a role? AB - OBJECTIVE: Consumption of energy drinks is increasing amongst athletes and the general public. By virtue of their bioactive ingredients (including caffeine, taurine, glucuronolactone, and B-group vitamins) and paucity of calories, sugar free "diet" versions of these drinks could be a useful aid for weight maintenance. Yet little is known about the acute influence of these drinks, and specifically the role of the cocktail of non-caffeine ingredients, on resting energy expenditure (REE) and substrate oxidation. Therefore, the metabolic impact of sugar-free Red Bull (sfRB) to a comparable amount of caffeine was compared. METHODS: REE and respiratory quotient (RQ) were measured in eight healthy young men by ventilated-hood indirect calorimetry for 30 min baseline and 2 h following ingestion of 355 ml of either: sfRB + placebo, water + 120 mg caffeine, or water + placebo, according to a randomized cross-over design. RESULTS: sfRB and water + caffeine both increased REE to the same degree (+4%). Additionally, sfRB briefly increased RQ. Water + caffeine had no effect on RQ relative to water + placebo. CONCLUSIONS: sfRB enhanced thermogenesis and marginally shifted RQ to favor carbohydrate oxidation. The stimulatory effects of sfRB on REE are mimicked by water + caffeine, indicating that the auxiliary ingredients do not influence this thermic effect. The metabolic effects of sfRB are primarily due to caffeine alone. PMID- 25294092 TI - Working together at the interface of physics and biology. AB - Good communication, whether it is between quorum-sensing bacteria or the different scientists studying those critters, is the key to a successful interdisciplinary collaboration, Bonnie Bassler and Ned Wingreen provide a personal perspective on working at the interface between the physical and biological sciences. PMID- 25294089 TI - Amine-functionalized polypyrrole: Inherently cell adhesive conducting polymer. AB - Electrically conducting polymers (CPs) have been recognized as novel biomaterials that can electrically communicate with biological systems. For their tissue engineering applications, CPs have been modified to promote cell adhesion for improved interactions between biomaterials and cells/tissues. Conventional approaches to improve cell adhesion involve the surface modification of CPs with biomolecules, such as physical adsorption of cell adhesive proteins and polycationic polymers, or their chemical immobilization; however, these approaches require additional multiple modification steps with expensive biomolecules. In this study, as a simple and effective alternative to such additional biomolecule treatment, we synthesized amine-functionalized polypyrrole (APPy) that inherently presents cell adhesion-supporting positive charges under physiological conditions. The synthesized APPy provides electrical activity in a moderate range and a hydrophilic surface compared to regular polypyrrole (PPy) homopolymers. Under both serum and serum-free conditions, APPy exhibited superior attachment of human dermal fibroblasts and Schwann cells compared to PPy homopolymer controls. Moreover, Schwann cell adhesion onto the APPy copolymer was at least similar to that on poly-l-lysine treated PPy controls. Our results indicate that amine-functionalized CP substrates will be useful to achieve good cell adhesion and potentially electrically stimulate various cells. In addition, amine functionality present on CPs can further serve as a novel and flexible platform to chemically tether various bioactive molecules, such as growth factors, antibodies, and chemical drugs. PMID- 25294091 TI - Subclinical inflammation with tocilizumab treatment of rheumatoid arthritis: MRI evaluation for 2 years. PMID- 25294093 TI - Cryotolerance of stallion spermatozoa is related to ROS production and mitochondrial membrane potential rather than to the integrity of sperm nucleus. AB - Although cryopreservation of stallion spermatozoa allows long-term preservation of spermatozoa from particular stallions and facilitates international trade, it is understood to inflict damages on sperm cells that may finally reduce their fertilizing ability. In addition, individual differences are known to exist in the sperm ability to withstand freeze-thawing protocols. To date, these differences have mainly been reported on the basis of sperm motility and membrane integrity. For this reason, the present work sought to determine differences between good (good freezability ejaculates: GFE) and poor (poor freezability ejaculates: PFE) freezability stallion ejaculates in other sperm parameters, including peroxide and superoxide levels, potential of mitochondrial membrane and nuclear integrity. With this purpose, a total of 24 stallion ejaculates were cryopreserved and classified into two groups (GFE vs. PFE), depending on their sperm membrane integrity and motility after freeze-thawing. From the total of 24 ejaculates, 13 were classified as GFE and the other 11 were classified as PFE. Apart from differences in sperm membrane permeability and lipid disorder after freeze-thawing, GFE presented significantly (p < 0.05) higher percentages of viable spermatozoa with high content of peroxides and of superoxides than PFE. In contrast, and despite cryopreservation of stallion spermatozoa increasing DNA fragmentation and disrupting disulphide bonds in sperm head proteins, no significant differences between GFE and PFE were seen. We can thus conclude that good and poor freezability stallion ejaculates differ in their reactive oxygen species levels after cryopreservation, but not in the damage extent on sperm nucleus. PMID- 25294095 TI - An M12(L(1))12(L(2))12 cantellated tetrahedron: a case study on mixed-ligand self assembly. AB - In the self-assembly of Pd(II) ions and two different, but similarly shaped, ligands (1 and 2), neither random mixing nor self-sorting of the two ligands into two unmixed structures was observed. Instead a mixed, yet sorted, Pd12 (1)12 (2)12 cantellated tetrahedron (and its pseudoisomer) was selectively formed, thus revealing a fine example of intramolecular self-sorting. A case study showed that a homothetic ratio of >2 is necessary to observe cantellated tetrahedra. PMID- 25294094 TI - Natural daucane esters induces apoptosis in leukaemic cells through ROS production. AB - Continuing our research on antiproliferative agents from plants, we extended our interest on further compounds isolated from Ferula communis and Ferulago campestris. One new daucane (DE-20) and one new phenol derivative (PH-3) were isolated and characterized in addition to six daucane, three coumarins and four simple phenolics. The cytotoxic activity was evaluated against a panel of six human tumor cell lines. The derivative DE-17 that resulted moderately active on all the studied cell lines was studied to evaluate its possible mechanism of action. DE-17 was able to induce apoptosis in a time and concentration-dependent manner in SEM and Jurkat cell lines. We observed that DE-17 just after 1h of treatment increased the reactive oxygen species (ROS) production and that the co incubation of DE-17 with ROS scavengers significantly increased cell viability suggesting that ROS-mediated downstream signaling is essential for the antiproliferative effects of DE-17. At later times of incubation DE-17 induced mitochondrial depolarization, as well as caspase-3 and -9 activation suggesting that apoptosis follow the mitochondrial pathway. Concomitantly to ROS induction, a remarkable decrease of mRNA expression of several antioxidant enzymes and intracellular GSH content was detected in treated cells compared to controls further indicative of oxidative stress. Taken together our results showed for the first time that daucane esters induces apoptotic cell death through a ROS mediated mechanism in human leukemia cells. PMID- 25294096 TI - Transnational Disorders: Returned Migrants at Oaxaca's Psychiatric Hospital. AB - This article examines experiences of returned migrants seeking mental health care at the public psychiatric hospital in Oaxaca, Mexico. Approximately one-third of the hospital's patients have migration experience, and many return to Oaxaca due to mental health crises precipitated by conditions of structural vulnerability and "illegality" in the United States. Once home, migrants, their families, and their doctors struggle to interpret and allay these "transnational disorders" disorders structurally produced and personally experienced within the borders of more than one country. Considering how space and time shape illness and treatment among transnational migrants, I contend that a critical phenomenology of illegality must incorporate migrant experience and political economy on both sides of the border before, during, and after migration. PMID- 25294097 TI - The activity of satellite cells and myonuclei following 8 weeks of strength training in young men with suppressed testosterone levels. AB - AIM: To investigate how suppression of endogenous testosterone during an 8-week strength training period influences the activity of satellite cells and myonuclei. METHODS: Twenty-two moderately trained young men participated in this randomized, placebo-controlled, and double-blinded intervention study. The participants were randomized to treatment with a GnRH analogue, goserelin (n = 12), which suppresses testosterone or placebo (n = 10) for 12 weeks. The strength training period of 8 weeks started after 4 weeks of treatment and included exercises for all major muscles. Biopsies were obtained from the mid-portion of the vastus lateralis muscle. RESULTS: Testosterone resting level in goserelin was 10-20 times lower compared with placebo, and the training-induced increase in the level of testosterone was abolished in goserelin. Training increased satellite cells number in type II fibres by 20% in placebo and by 52% in goserelin (P < 0.01), whereas the myonuclear number significantly increased by 12% in type II fibres in placebo and remained unchanged in goserelin (P < 0.05). No changes in satellite cells and myonuclei were seen in type I fibres in either group. Data from the microarray analysis indicated that low testosterone affects the bone morphogenetic proteins signalling, which might regulate proliferation vs. differentiation of satellite cells. CONCLUSION: Eight weeks of strength training enhances the myonuclear number in type II fibres, and this is largely blocked by the suppression of testosterone. The data indicate that low testosterone levels could reduce the differentiation of satellite cells to myonuclei via the bone morphogenetic proteins signalling pathway, resulting in reduced increases in lean leg mass. PMID- 25294099 TI - Live birth after single embryo transfer of autologous cryopreserved oocytes from a patient with myelodysplastic syndrome who underwent allogenic peripheral blood stem cell transplantation. AB - We report a live birth after single embryo transfer derived from autologous cryopreserved oocytes of a patient with myelodysplastic syndrome who had undergone allogenic peripheral blood stem cell transplantation (PBSCT). In 2006, a 24-year-old female diagnosed with myelodysplastic syndrome was referred for fertility preservation before she underwent PBSCT. After controlled ovarian stimulation, 38 oocytes were retrieved for cryopreservation using a slow-freezing protocol. She was cured by PBSCT and entered menopause. After seven years, she requested thawing of the oocytes. She was prepared for a thawing cycle using hormone replacement therapy. Twenty-two cryopreserved oocytes were thawed, and 20 (91%) oocytes survived. Thirteen mature oocytes were inseminated by intracytoplasmic sperm injection. Ten (77%) oocytes were normally fertilized and 6 (60%) oocytes developed into blastocysts. Embryo transfer to her own uterus with one blastocyst was performed. Five blastocysts were vitrified. A sonographic exam at 7 weeks of gestation revealed one gestational sac with positive cardiac motion. A normal female baby weighing 2704 g was delivered at 40 weeks of gestation. A successful pregnancy from autologous cryopreserved oocytes is encouraging for cancer patients undergoing fertility preservation. For infertile cancer patients after PBSCT, we suggest the transfer of one embryo to reduce the risk of multiple pregnancies. PMID- 25294098 TI - Emerging drugs and vaccines for candidemia. AB - Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords 'Candida' or 'Candidemia' or 'Candidiasis' and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarised. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161 and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still, there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life threatening mycoses. PMID- 25294100 TI - Validity and reliability of the Functioning Disability Evaluation Scale-Adult Version based on the WHODAS 2.0--36 items. AB - BACKGROUND/PURPOSE: The disability eligibility determination system is based on the International Classification of Functioning, Disability and Health (ICF) framework in Taiwan. The Functioning Disability Evaluation Scale (FUNDES) has been developed since 2007 for assessing the status of an individual's activities and participation in the disability eligibility system. The purpose of this study was to examine the reliability and validity of the FUNDES-Adult Version (FUNDES Adult). METHODS: During 2011-2012, a total of 5736 adults with disabilities (aged 58.4 +/- 18.2 years) were randomly recruited for a national population-based study. These adults were assessed in person by certified professionals in the authorized hospitals. Domains 1-6 of the FUNDES-Adult addressing the performance and capability dimensions are modified from the World Health Organization Disability Assessment Schedule 2.0-36-item version, and Domain 7 (Environmental attribute) and capability and capacity dimensions of Domain 8 (Motor action) are designed based on the ICF coding system. RESULTS: The internal consistency was excellent (Cronbach's alpha >= 0.9). An exploratory factor analysis yielded a five-factor FUNDES structure with a variance of 76.1% and 76.9% and factor loadings of 0.56-0.94 and 0.55-0.94 for the performance and capability dimensions, respectively. The factor loadings for the second-order confirmatory factor analysis for the performance and capability dimensions were from 0.81 to 0.89. In Domains 1-6 and 8, the ceiling effects were from 9% to 36%, and the floor effects were from 5% to 45%. CONCLUSION: FUNDES-Adult has acceptable reliability and validity and can be used to measure activities and participation for people with disabilities. PMID- 25294101 TI - Protein-silver nanoparticle interactions to colloidal stability in acidic environments. AB - We report a kinetic study of Ag nanoparticles (AgNPs) under acidic environments (i.e., pH 2.3 to pH ~7) and systematically investigate the impact of protein interactions [i.e., bovine serum albumin (BSA) as representative] to the colloidal stability of AgNPs. Electrospray-differential mobility analysis (ES DMA) was used to characterize the particle size distributions and the number concentrations of AgNPs. Transmission electron microscopy was employed orthogonally to provide visualization of AgNPs. For unconjugated AgNPs, the extent of aggregation, or the average particle size, was shown to be increased significantly with an increase of acidity, where a partial coalescence was found between the primary particles of unconjugated AgNP clusters. Aggregation rate constant, kD, was also shown to be proportional to acidity, following a correlation of log(kD) = -1.627(pH)-9.3715. Using ES-DMA, we observe BSA had a strong binding affinity (equilibrium binding constant, ~ 1.1 * 10(6) L/mol) to the surface of AgNPs, with an estimated maximum molecular surface density of ~0.012 nm(-2). BSA-functionalized AgNPs exhibited highly-improved colloidal stability compared to the unconjugated AgNPs under acidic environments, where both the acid-induced interfacial dissolution and the particle aggregation became negligible. Results confirm a complex mechanism of colloidal stability of AgNPs: the aggregation process was shown to be dominant, and the formation of BSA corona on AgNPs suppressed both particle aggregation and interfacial dissolution of AgNP samples under acidic environments. PMID- 25294102 TI - Enhanced photoelectrochemical strategy for ultrasensitive DNA detection based on two different sizes of CdTe quantum dots cosensitized TiO2/CdS:Mn hybrid structure. AB - A TiO2/CdS:Mn hybrid structure cosensitized with two different sizes of CdTe quantum dots (QDs) was designed to develop a novel and ultrasensitive photoelectrochemical DNA assay. In this protocol, TiO2/CdS:Mn hybrid structure was prepared by successive adsorption and reaction of Cd(2+)/Mn(2+) and S(2-) ions on the surface of TiO2 film and then was employed as matrix for immobilization of hairpin DNA probe, whereas large-sized CdTe-COOH QDs and small sized CdTe-NH2 QDs as signal amplification elements were successively labeled on the terminal of hairpin DNA probe. The target DNA detection was based upon the photocurrent change originated from conformation change of the hairpin DNA probe after hybridization with target DNA. In the absence of target DNA, the immobilized DNA probe was in the hairpin form and the anchored different sizes of CdTe-COOH and CdTe-NH2 QDs were close to the TiO2/CdS:Mn electrode surface, which led to a very strong photocurrent intensity because of the formation of the cosensitized structure. However, in the presence of target DNA, the hairpin DNA probe hybridized with target DNA and changed into a more rigid, rodlike double helix, which forced the multianchored CdTe QDs away from the TiO2/CdS:Mn electrode surface, resulting in significantly decreased photocurrent intensity because of the vanished cosensitization effect. By using this cosensitization signal amplification strategy, the proposed DNA assay could offer an ultrasensitive and specific detection of DNA down to 27 aM, and it opened up a new promising platform to detect various DNA targets at ultralow levels for early diagnoses of different diseases. PMID- 25294103 TI - Behavioral interventions to improve hypertension control in the Veterans Affairs healthcare system. AB - Hypertension is a common and costly disease among US veterans. The Veterans Affairs (VA) healthcare system is the largest integrated healthcare provider in the United States and reviewing hypertension interventions developed in the VA may inform interventions delivered in other integrated healthcare systems. This review describes behavioral interventions to improve hypertension control that have been conducted in the VA since 1970. The authors identified 27 articles representing 15 behavioral interventional trials. Studies were heterogeneous across patients, providers, interventionist, and intervention components. The VA bridges services related to diagnosis, treatment, medication management, and behavioral counseling in a unified approach that supports collaboration and provides infrastructure for hypertension management. PMID- 25294104 TI - Effects of varenicline and cognitive bias modification on neural response to smoking-related cues: study protocol for a randomized controlled study. AB - BACKGROUND: Smoking-related cues can trigger drug-seeking behaviors, and computer based interventions that reduce cognitive biases towards such cues may be efficacious and cost-effective cessation aids. In order to optimize such interventions, there needs to be better understanding of the mechanisms underlying the effects of cognitive bias modification (CBM). Here we present a protocol for an investigation of the neural effects of CBM and varenicline in non quitting daily smokers. METHODS/DESIGN: We will recruit 72 daily smokers who report smoking at least 10 manufactured cigarettes or 15 roll-ups per day and who smoke within one hour of waking. Participants will attend two sessions approximately one week apart. At the first session participants will be screened for eligibility and randomized to receive either varenicline or a placebo over a seven-day period. On the final drug-taking day (day seven) participants will attend a second session and be further randomized to one of three CBM conditions (training towards smoking cues, training away from smoking cues, or control training). Participants will then undergo a functional magnetic resonance imaging scan during which they will view smoking-related pictorial cues. Primary outcome measures are changes in cognitive bias as measured by the visual dot-probe task, and neural responses to smoking-related cues. Secondary outcome measures will be cognitive bias as measured by a transfer task (modified Stroop test of smoking related cognitive bias) and subjective mood and cigarette craving. DISCUSSION: This study will add to the relatively small literature examining the effects of CBM in addictions. It will address novel questions regarding the neural effects of CBM. It will also investigate whether varenicline treatment alters neural response to smoking-related cues. These findings will inform future research that can develop behavioral treatments that target relapse prevention. TRIAL REGISTRATION: Registered with Current Controlled Trials: ISRCTN65690030. Registered on 30 January 2014. PMID- 25294105 TI - Metabolic regulation of phytoplasma malic enzyme and phosphotransacetylase supports the use of malate as an energy source in these plant pathogens. AB - Phytoplasmas ('Candidatus Phytoplasma') are insect-vectored plant pathogens. The genomes of these bacteria are small with limited metabolic capacities making them dependent on their plant and insect hosts for survival. In contrast to mycoplasmas and other relatives in the class Mollicutes, phytoplasmas encode genes for malate transporters and malic enzyme (ME) for conversion of malate into pyruvate. It was hypothesized that malate is probably a major energy source for phytoplasmas as these bacteria are limited in the uptake and processing of carbohydrates. In this study, we investigated the metabolic capabilities of 'Candidatus (Ca.) phytoplasma' aster yellows witches'-broom (AYWB) malic enzyme (ME). We found that AYWB-ME has malate oxidative decarboxylation activity, being able to convert malate to pyruvate and CO2 with the reduction of either NAD or NADP, and displays distinctive kinetic mechanisms depending on the relative concentration of the substrates. AYWB-ME activity was strictly modulated by the ATP/ADP ratio, a feature which has not been found in other ME isoforms characterized to date. In addition, we found that the 'Ca. Phytoplasma' AYWB PduL like enzyme (AYWB-PduL) harbours phosphotransacetylase activity, being able to convert acetyl-CoA to acetyl phosphate downstream of pyruvate. ATP also inhibited AYWB-PduL activity, as with AYWB-ME, and the product of the reaction catalysed by AYWB-PduL, acetyl phosphate, stimulated AYWB-ME activity. Overall, our data indicate that AYWB-ME and AYWB-PduL activities are finely coordinated by common metabolic signals, like ATP/ADP ratios and acetyl phosphate, which support their participation in energy (ATP) and reducing power [NAD(P)H] generation from malate in phytoplasmas. PMID- 25294106 TI - LdrP, a cAMP receptor protein/FNR family transcriptional regulator, serves as a positive regulator for the light-inducible gene cluster in the megaplasmid of Thermus thermophilus. AB - LdrP (TT_P0055) (LitR-dependent regulatory protein) is one of the four cAMP receptor protein (CRP)/FNR family transcriptional regulators retained by the extremely thermophilic bacterium Thermus thermophilus. Previously, we reported that LdrP served as a positive regulator for the light-induced transcription of crtB, a carotenoid biosynthesis gene encoded on the megaplasmid of this organism. Here, we showed that LdrP also functions as an activator of the expression of genes clustered around the crtB gene under the control of LitR, an adenosyl B12 bound light-sensitive regulator. Transcriptome analysis revealed the existence of 19 LitR-dependent genes on the megaplasmid. S1 nuclease protection assay confirmed that the promoters preceding TT_P0044 (P44), TT_P0049 (P49) and TT_P0070 (P70) were activated upon illumination in the WT strain. An ldrP mutant lost the ability to activate P44, P49 and P70, whilst disruption of litR resulted in constitutive transcription from these promoters irrespective of illumination, indicating that these genes were photo-dependently regulated by LdrP and LitR. An in vitro transcription experiment demonstrated that LdrP directly activated mRNA synthesis from P44 and P70 by the Thermus RNA polymerase holocomplex. The present evidence indicated that LdrP was the positive regulator essential for the transcription of the T. thermophilus light-inducible cluster encoded on the megaplasmid. PMID- 25294108 TI - trans/cis-Isomerization of fluorene-bridged azo chromophore with significant two photon absorbability at near-infrared wavelength. AB - Azo-containing materials have been proven to possess second-order nonlinear optical (NLO) properties, but their third-order NLO properties, which involves two-photon absorption (2PA), has rarely been reported. In this study, we demonstrate a significant 2PA behavior of the novel azo chromophore incorporated with bilateral diphenylaminofluorenes (DPAFs) as a pi framework. The electron donating DPAF moieties cause a redshifted pi-pi* absorption band centered at 470 nm, thus allowing efficient blue-light-induced trans-to-cis photoisomerization with a rate constant of 2.04 * 10(-1) min(-1) at the photostationary state (PSS). The open-aperture Z-scan technique that adopted a femtosecond (fs) pulse laser as excitation source shows an appreciably higher 2PA cross-section for the fluorene derived azo chromophore than that for common azobenzene dyes at near-infrared wavelength (lambdaex =800 nm). Furthermore, the fs 2PA response is quite uniform regardless of the molecular geometry. On the basis of the computational modeling, the intramolecular charge-transfer (ICT) process from peripheral diphenylamines to the central azo group through a fluorene pi bridge is crucial to this remarkable 2PA behavior. PMID- 25294107 TI - Cytosine chemoreceptor McpC in Pseudomonas putida F1 also detects nicotinic acid. AB - Soil bacteria are generally capable of growth on a wide range of organic chemicals, and pseudomonads are particularly adept at utilizing aromatic compounds. Pseudomonads are motile bacteria that are capable of sensing a wide range of chemicals, using both energy taxis and chemotaxis. Whilst the identification of specific chemicals detected by the >=26 chemoreceptors encoded in Pseudomonas genomes is ongoing, the functions of only a limited number of Pseudomonas chemoreceptors have been revealed to date. We report here that McpC, a methyl-accepting chemotaxis protein in Pseudomonas putida F1 that was previously shown to function as a receptor for cytosine, was also responsible for the chemotactic response to the carboxylated pyridine nicotinic acid. PMID- 25294109 TI - A cross-sectional survey of supports for evidence-informed decision-making in healthcare organisations: a research protocol. AB - BACKGROUND: This protocol builds on the development of a) a framework that identified the various supports (i.e. positions, activities, interventions) that a healthcare organisation or health system can implement for evidence-informed decision-making (EIDM) and b) a qualitative study that showed the current mix of supports that some Canadian healthcare organisations have in place and the ones that are perceived to facilitate the use of research evidence in decision-making. Based on these findings, we developed a web survey to collect cross-sectional data about the specific supports that regional health authorities and hospitals in two Canadian provinces (Ontario and Quebec) have in place to facilitate EIDM. METHODS/DESIGN: This paper describes the methods for a cross-sectional web survey among 32 regional health authorities and 253 hospitals in the provinces of Quebec and Ontario (Canada) to collect data on the current mix of organisational supports that these organisations have in place to facilitate evidence-informed decision-making. The data will be obtained through a two-step survey design: a 10 min survey among CEOs to identify key units and individuals in regard to our objectives (step 1) and a 20-min survey among managers of the key units identified in step 1 to collect information about the activities performed by their unit regarding the acquisition, assessment, adaptation and/or dissemination of research evidence in decision-making (step 2). The study will target three types of informants: CEOs, library/documentation centre managers and all other key managers whose unit is involved in the acquisition, assessment, adaptation/packaging and/or dissemination of research evidence in decision making. We developed an innovative data collection system to increase the likelihood that only the best-informed respondent available answers each survey question. The reporting of the results will be done using descriptive statistics of supports by organisation type and by province. DISCUSSION: This study will be the first to collect and report large-scale cross-sectional data on the current mix of supports health system organisations in the two most populous Canadian provinces have in place for evidence-informed decision-making. The study will also provide useful information to researchers on how to collect organisation level data with reduced risk of self-reporting bias. PMID- 25294110 TI - Effectiveness of brief school-based interventions for adolescents: a meta analysis of alcohol use prevention programs. AB - To conduct a meta-analysis summarizing the effectiveness of school-based brief alcohol interventions (BAIs) among adolescents and to examine possible iatrogenic effects due to deviancy training in group-delivered interventions, a systematic search for eligible studies was undertaken, current through December 31, 2012. Studies were eligible for inclusion if they used an experimental/quasi experimental design; focused on school-based BAIs; enrolled adolescent participants; and reported an alcohol-related outcome measure. Studies were coded for key variables, and outcome effect sizes were analyzed as standardized mean differences adjusted for small samples (Hedges' g). Analyses were conducted using inverse-variance weighted mixed-effects meta-regression models. Sensitivity analyses were also conducted. Across all 17 studies eligible for inclusion, school-based BAIs were associated with significant improvements among adolescents, whereby adolescents in the BAI groups reduced their alcohol consumption relative to the control groups (= 0.34, 95 % CI [0.11, 0.56]). Subgroup analyses indicated that whereas individually-delivered BAIs were effective (= 0.58, 95 % CI [0.23, 0.92]), there was no evidence that group delivered BAIs were associated with reductions in alcohol use (= -0.02, 95 % CI [ 0.17, 0.14]). Delivery format was confounded with program modality, however, such that motivational enhancement therapy was the most effective modality, but was rarely implemented in group-delivered interventions. Some school-based BAIs are effective in reducing adolescent alcohol consumption, but may be ineffective if delivered in group settings. Future research should explore whether group delivered BAIs that use motivational enhancement therapy components may yield beneficial outcomes like those observed in individually-delivered programs. PMID- 25294111 TI - Computed Tomography and Magnetic Resonance Anatomy of the Normal Orbit and Eye of the Horse. AB - Traumatic and infectious diseases of the eye and orbit can occur in horses. For diagnosis and monitoring of such diseases, medical imaging is useful including computed tomography (CT) and magnetic resonance imaging (MRI). The aim of the current study was to describe CT and MRI anatomy of the equine orbit and ocular globe. The heads from four adult horses were scanned with a 6-slice Emotion 6 CT (Siemens, Erlangen), and a 3.0 Tesla Siemens Verio 6 MRI using T1 and T2-weighted sequences. To validate CT and MR reference images, these were compared with anatomical models and gross anatomical sections. The bony limits of the orbital cavity, the relationship of the orbit with sinuses and foramina of the skull were well identified by CT. MRI was useful to observe soft tissues and was able to identify adnexae of the ocular globe (eyelids, periorbital fat, extraocular muscles, lacrymal and tarsal glands). Although MRI was able to identify all components of the eye (including the posterior chamber), it could not differentiate sclera from choroid and retina. The only nerve identified was the optic nerve. Vessels were not seen in this series of cadaver heads. This study showed that CT and MRI are useful techniques to image the equine orbit and eye that can have clinical applications. PMID- 25294112 TI - Systematic review of molecular mechanism of action of negative-pressure wound therapy. AB - BACKGROUND: Negative-pressure wound therapy (NPWT) promotes angiogenesis and granulation, in part by strain-induced production of growth factors and cytokines. As their expression profiles are being unravelled, it is pertinent to consider the mode of action of NPWT at the molecular level. METHODS: MEDLINE (January 1997 to present), Embase (January 1997 to present), PubMed (no time limit), the Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials Register were searched for articles that evaluated the influence of NPWT on growth factor expression quantitatively. RESULTS: Sixteen studies met the inclusion criteria. Tumour necrosis factor expression was reduced in acute and chronic wounds, whereas expression of interleukin (IL) 1beta was reduced in acute wounds only. Systemic IL-10 and local IL-8 expression were increased by NPWT. Expression of vascular endothelial growth factor, fibroblast growth factor 2, transforming growth factor beta and platelet-derived growth factor was increased, consistent with mechanoreceptor and chemoreceptor transduction in response to stress and hypoxia. Matrix metalloproteinase-1, -2, -9 and -13 expression was reduced but there was no effect on their enzymatic inhibitor, tissue inhibitor of metalloproteinase 1. CONCLUSION: Cytokine and growth factor expression profiles under NPWT suggest that promotion of wound healing occurs by modulation of cytokines to an anti-inflammatory profile, and mechanoreceptor and chemoreceptor mediated cell signalling, culminating in angiogenesis, extracellular matrix remodelling and deposition of granulation tissue. This provides a molecular basis for understanding NPWT. PMID- 25294113 TI - Innovative therapeutic approach: sequential treatment with plasma exchange and eculizumab in a pregnant woman affected by atypical hemolytic-uremic syndrome. AB - The atypical HUS (aHUS) is a rare genetic disease, with poor prognosis, characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. This syndrome is often related to mutations in the genes encoding complement regulatory proteins. A 26-year-old woman with homozygous mutation in complement factor H (CFH) developed a relapse of aHUS at 17th week of pregnancy. Despite treatment with plasma exchange (PEX), at the 26th week of gestation eculizumab was started. The sequential treatment with eculizumab after PEX was well tolerated and it has led to clinical remission. PMID- 25294114 TI - Antibody screening in multitransfused patients: a prerequisite before each transfusion. AB - Life-long red blood cell (RBC) transfusions remain the main treatment for severe thalassemia. We hereby report a case of anti S and anti Lu(a) in a beta thalassemia major patient detected incidentally on antibody screening. The patient was a known case of beta-thalassemia major and was on regular blood transfusion every 3 weeks from the institute from the age of 6 months. Subsequently, on one occasion, patient's crossmatch was compatible despite positive antibody screen using microcolumn gel technique. Autocontrol and direct antiglobulin test were negative on microcolumn gel. Anti S and anti Lu(a) antibodies were identified. Blood unit found compatible was negative for S and Lu(a) antigens. Antibody titers were 1:1 for both anti S and anti Lu(a) in AHG phase using tube technique and antibodies were of IgG type. Blood unit was transfused uneventfully to the patient. Donors were traced back (last three donations) and called for repeat blood sample testing for S and Lu(a) antigen. Two out of three donors were found to be S antigen positive and one out of these two was Lu(a) antigen positive. Anti S and anti Lu(a) antibodies were again identified on patient's subsequent visit for transfusion. The present case re emphasize the importance of antibody screening at each visit in earlier detection of antibodies in multi transfused patients. Encouraging patients to receive transfusion from one center and dedicating donors could reduce alloimmunization rate but larger studies are required. PMID- 25294115 TI - Relationship of clinical and microbiological variables in patients with type 1 diabetes mellitus and periodontitis. AB - BACKGROUND: The aim of the study was to analyze how metabolic control of type 1 diabetes is related to clinical and microbiological periodontal parameters. MATERIAL AND METHODS: The study involved 56 subjects aged from 19 to 50 years divided into 2 groups: healthy subjects (the H group), and diabetic (type 1 diabetes) patients with chronic untreated generalized periodontitis (the DM group). The glycosylated hemoglobin value (HbA1c) was determined using the UniCel DxC 800 SYNCHRON System (Beckman Coulter, USA), and the concentration in blood was measured by the turbidimetric immunoinhibition method. A molecular genetic assay (Micro-IDent plus, Germany) was used to detect periodontopathogenic bacteria in plaque samples. Periodontitis was confirmed by clinical and radiological examination. RESULTS: Fusobacterium nucleatum, Capnocytophaga species, and Eikenella corrodens were the most frequently found bacteria in dental plaque samples (77.8%, 66.7%, and 33.4%, respectively), whereas Aggregatibacter actinomycetemcomitans was identified 40.7% less frequently in the DM group than in the H group. The strongest relationship was observed between the presence of 2 periodontal pathogens - F. nucleatum and Capnocytophaga spp. - and poorer metabolic control in type 1 diabetes patients (HbA1c) and all clinical parameters of periodontal pathology. CONCLUSIONS: Periodontal disease was more evident in type 1 diabetic patients, and the prevalence of periodontitis was greatly increased in subjects with poorer metabolic control. PMID- 25294116 TI - Quantitative analysis of the reversibility of knee flexion contractures with time: an experimental study using the rat model. AB - BACKGROUND: Knee flexion contractures prevent the full extension of the knee joint and cause disability. The etiology is not well defined. Extended periods of immobilization of joints lead to contractures difficult to completely reverse by rehabilitation treatments. Recovery of the complete range of motion without intervention has not been studied but is of importance to optimize clinical management. This study was designed to quantify the spontaneous reversibility of knee flexion contractures over time. METHODS: Knee flexion contractures of increasing severities were induced by internally fixing one knee of 250 adult male rats for 6 increasing durations. The contractures were followed for four different durations of spontaneous recovery up to 48 weeks (24 groups, target n=10 per group). The angle of knee of extension at a standardized torque was measured. Contralateral knees constituted controls. RESULTS: Full reversibility characterized by knee extension similar to controls was only measured in the lowest severity group where 4 weeks of spontaneous recovery reversed early-onset contractures. Spontaneous recovery of 2, 4 and 8 weeks caused partial gain of knee extension in longer-lasting contractures (P <= 0.05; all 4 comparisons). Extending the durations of spontaneous recovery failed to further improve knee extension (P>0.05, all 12 comparisons). No reversal occurred in the highest severity group (32 week; P>0.05). CONCLUSIONS: Reversibility of knee flexion contractures was dependent on their severity. Full spontaneous recovery was limited to the least severe contractures. While contractures initially improved, a plateau was reached beyond which additional durations of spontaneous recovery led to no additional gain of knee extension. These results support our view that without treatment, permanent losses in knee mobility must be anticipated in immobility-induced contractures. PMID- 25294117 TI - Improvements in hip fracture incidence counterbalanced by the rise of other fracture types: data from Spain 2000-2010. AB - BACKGROUND: In recent years, the incidence of injury in older people has increased. The aim of this study is to address the hypothesis that this increase is due to an increase in the incidence of some injuries that, while less common than hip fractures, are sufficient jointly to counteract the decrease or stabilisation in hip fracture rates observed in most countries. METHODS: We performed a descriptive study of trends using data from the National Hospital Discharge Register. We included individuals 65 years and older who were discharged from a Spanish hospital during the period 2000-2010 with at least one injury diagnosis in the primary diagnosis field on the discharge form. The dependent variables were the following injury groups, classified using the Barell Matrix: hip fracture, shoulder and upper arm fractures, forearm and elbow fractures, thoracic fractures, lower leg and ankle fractures, and TBI type 1 internal injury. Incidence rates were calculated per 100,000 inhabitants (data from National Statistics Institute) and stratified by sex and age group. Trends, in terms of Annual Percent Change (APC), were assessed using Poisson Regression with discharge year as the independent variable. RESULTS: Hip fracture continues to be the most important injury type in older people. Thoracic fractures and TBI internal injuries are more common in men, while fractures in the upper extremities are more common in women. All injuries increased in frequency with age, except lower leg and ankle fractures, which decreased. While a secular decreasing trend in hip fracture was noted, the incidences of fractures of the shoulder and upper arm, forearm and elbow, and lower leg and ankle, as well as of TBI type 1 internal injuries have increased steadily. CONCLUSIONS: Although hip fracture continue to be the most common type of injury in older people, this study has allowed identifying other types of injury that are becoming increasingly common. These trends are driving paradigm changes in the burden of injuries requiring treatment within the hospital system, and must be taken into account in the design of preventative programs and actions. PMID- 25294118 TI - The medial arm pedicled perforator flap: application of phenomenon of one perforator perfusing multiple perforator angiosomes. AB - BACKGROUND: The medial arm is an optimal potential donor site for treating skin defects around the elbow. However, whether a reliable pedicled perforator flap could be harvested from the medial arm remains unanswered. The purpose of this study was to report the technique and our results using the medial arm pedicled perforator flaps. METHODS: A total of eight flaps in seven patients underwent the medial arm pedicled perforator flaps to treat skin defects around the elbow. The flap was pedicled on one perforator 1.3+/-0.3mm in diameter within 3cm above the medial epicondyle. The flap size varied between 10 and 20cm in length and between 6 and 10cm in width. RESULTS: Of the eight flaps in seven patients, seven flaps survived uneventfully except that one suffered venous insufficiency. Six patients were followed up for 1 month to 2 years. One patient was lost to follow-up after 7 days. The wounds in all patients healed satisfactorily. No deep wound infection and wound dehiscence developed. No revision surgery was performed in the survived flaps. CONCLUSIONS: The survival of the medial arm pedicled perforator flap confirms the phenomenon of one perforator perfusing multiple perforator angiosomes in the medial arm, although this study has the retrospective clinical nature and limited number of the patients. The medial arm pedicled perforator flap is a useful tool to treat skin defects around the elbow. PMID- 25294119 TI - Anxiety and depression following traumatic limb amputation: a systematic review. AB - BACKGROUND: Traumatic amputation can result in multiple physical, psychological and socio-economic sequalae. While there has been a significant increase in investment and public profile of the rehabilitation of patients who have experienced traumatic limb amputation, little is known about the prevalence of anxiety and depression, especially in the long term. OBJECTIVE: To determine the association between traumatic limb amputation and anxiety and depression. DATA SOURCES: A literature search of available databases including Cochrane, Medline, Embase, and PsycINFO was performed for relevant studies since 2002. Secondary outcomes included the effect on employment, substance misuse, relationships and quality of life. SELECTION CRITERIA: Randomised control trials, observational studies or reviews which met the inclusion, exclusion and quality criteria. RESULTS: Levels of anxiety and depression are significantly higher than in the general population. Significant heterogeneity exists between studies making meta analyses inappropriate. Improved rehabilitation is having a positive effect on employment rates. There appears to be no significant effect on substance abuse and relationships. CONCLUSIONS: All studies demonstrated high prevalence of anxiety and depression in post-traumatic amputees. No good prospective data exists for levels of anxiety and depression beyond two years of follow up and this should be an area of future study. PMID- 25294120 TI - Controlled growth and gas sorption properties of IRMOF-3 nano/microcrystals. AB - IRMOF-3 nano/microcrystals with controllable morphologies and sizes were successfully obtained by a simple solvothermal method. The shape evolution of IRMOF-3 crystals from cube to truncated cube, cuboctahedron, truncated octahedron and finally to octahedron was achieved by adjusting the amount of surfactant. The surfaces of the IRMOF-3 nano/microstructures are affected by the reaction temperature, and the nano/microparticles show shape-dependent sorption properties. PMID- 25294121 TI - The structures and thermodynamic stability of copper(II) chloride surfaces. AB - Using density functional theory calculations of periodic slabs, within the generalised gradient approximation, this study provides optimised structures for all plausible terminations of copper(II) chloride surfaces along the three low index orientations. The ab initio atomistic thermodynamic approach serves to construct a thermodynamic stability diagram for CuCl2 configurations as a function of the chemical potential of chlorine (DeltaMUCl(T,P)). We observe a shift in thermodynamic stability ordering at around DeltaMUCl(T,P) = -1.0 eV between a copper-chlorine terminated (001) surface (i.e., (001)CuCl) and a (001) chlorine-covered surface (i.e., (001)Cl). This conclusion accords with experimental observations that report CuCl-bulk like structures, acting as a prerequisite for the formation of CuCl2-bulk like arrangements in the course of copper chlorination. Profound stabilities and optimised structures of (001)CuCl and (001)Cl configurations are discussed within the context of the functionality of CuCl2 as the chief chlorination and condensation catalyst of aromatic pollutants under conditions relevant to their formation in thermal systems, i.e. 400-1000 K, a total operating pressure of 1.0 atm and PCl2 = 10(-6)-10(-4) atm (1.0-100.0 ppm). PMID- 25294125 TI - Shaped by asymmetrical interdependence: a qualitative case study of the external influences on international non-governmental organizations' implementation of equity principles in HIV/AIDS work. AB - INTRODUCTION: Addressing inequities is a key role for international non governmental organizations (INGOs) working in health and development. Yet, putting equity principles into practice can prove challenging. In-depth empirical research examining what influences INGOs' implementation of equity principles is limited. This study examined the influences on one INGO's implementation of equity principles in its HIV/AIDS programs. METHODS: This research employed a case study with nested components (an INGO operating in Kenya, with offices in North America). We used multiple data collection methods, including document reviews, interviews (with staff, partners and clients of the INGO in Kenya), and participant observation (with Kenyan INGO staff). Participant observation was conducted with 10 people over three months. Forty-one interviews were completed, and 127 documents analyzed. Data analysis followed Auerbach and Silverstein's analytic process (2003), with qualitative coding conducted in multiple stages, using descriptive matrices, visual displays and networks (Miles and Huberman, 1994). RESULTS: There was a gap between the INGO's intent to implement equity principles and actual practice due to multiple influences from various players, including donors and country governments. The INGO was reliant on donor funding and needed permission from the Kenyan government to work in-country. Major influences included donor agendas and funding, donor country policies, and Southern country government priorities and legislation. The INGO privileged particular vulnerable populations (based on its reputation, its history, and the priorities of the Kenyan government and the donors). To balance its equity commitment with the influences from other players, the INGO aligned with the system as well as pushed back incrementally on the donors and the Kenyan government to influence these organizations' equity agendas. By moving its equity agenda forward incrementally and using its reputational advantage, the INGO avoided potential negative repercussions that might result from pushing too fast or working outside the system. CONCLUSIONS: The INGO aligned the implementation of equity principles in its HIV/AIDS initiatives by working within a system characterized by asymmetrical interdependence. Influences from the donors and Kenyan government contributed to an implementation gap between what the INGO intended to accomplish in implementing equity principles in HIV/AIDS work and actual practice. PMID- 25294122 TI - Fibrinolysis and the control of blood coagulation. AB - Fibrin plays an essential role in hemostasis as both the primary product of the coagulation cascade and the ultimate substrate for fibrinolysis. Fibrinolysis efficiency is greatly influenced by clot structure, fibrinogen isoforms and polymorphisms, the rate of thrombin generation, the reactivity of thrombus associated cells such as platelets, and the overall biochemical environment. Regulation of the fibrinolytic system, like that of the coagulation cascade, is accomplished by a wide array of cofactors, receptors, and inhibitors. Fibrinolytic activity can be generated either on the surface of a fibrin containing thrombus, or on cells that express profibrinolytic receptors. In a widening spectrum of clinical disorders, acquired and congenital defects in fibrinolysis contribute to disease morbidity, and new assays of global fibrinolysis now have potential predictive value in multiple clinical settings. Here, we summarize the basic elements of the fibrinolytic system, points of interaction with the coagulation pathway, and some recent clinical advances. PMID- 25294126 TI - GLUT2-mediated glucose uptake and availability are required for embryonic brain development in zebrafish. AB - Glucose transporter 2 (GLUT2; gene name SLC2A2) has a key role in the regulation of glucose dynamics in organs central to metabolism. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, its role in the brain is not well understood. To decipher the role of GLUT2 in brain development, we knocked down slc2a2 (glut2), the functional ortholog of human GLUT2, in zebrafish. Abrogation of glut2 led to defective brain organogenesis, reduced glucose uptake and increased programmed cell death in the brain. Coinciding with the observed localization of glut2 expression in the zebrafish hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a but not those expressing neurod. Specificity of the morphant phenotype was demonstrated by the restoration of brain organogenesis, whole-embryo glucose uptake, brain apoptosis, and expression of proneural markers in rescue experiments. These results indicate that glut2 has an essential role during brain development by facilitating the uptake and availability of glucose and support the involvement of glut2 in brain glucose sensing. PMID- 25294124 TI - An exome study of Parkinson's disease in Sardinia, a Mediterranean genetic isolate. AB - Parkinson's disease (PD) is a common neurodegenerative disorder of complex aetiology. Rare, highly penetrant PD-causing mutations and common risk factors of small effect size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs absent from dbSNP129 and 1000 Genomes, shared by at least five patients, and of functional effects were genotyped in an independent Sardinian case-control sample (n = 500). Variants associated with PD with nominal p value <0.05 and those with odds ratio (OR) >=3 were validated by Sanger sequencing and typed in a replication sample of 2965 patients and 2678 controls from Italy, Spain, and Portugal. We identified novel moderately rare variants in several genes, including SCAPER, HYDIN, UBE2H, EZR, MMRN2 and OGFOD1 that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD, although no variants achieved genome-wide significance after Bonferroni correction. Our results suggest that the genetic bases of PD are highly heterogeneous, with implications for the design of future large-scale exome or whole-genome analyses of this disease. PMID- 25294123 TI - The development of potential antibody-based therapies for myeloma. AB - With optimal target antigen selection antibody-based therapeutics can be very effective agents for hematologic malignancies, but none have yet been approved for myeloma. Rituximab and brentuximab vedotin are examples of success for the naked antibody and antibody-drug conjugate classes, respectively. Plasma cell myeloma is an attractive disease for antibody-based targeting due to target cell accessibility and the complementary mechanism of action with approved therapies. Initial antibodies tested in myeloma were disappointing. However, recent results from targeting well-characterized antigens have been more encouraging. In particular, the CD38 and CD138 targeted therapies are showing single-agent activity in early phase clinical trials. Here we will review the development pipeline for naked antibodies and antibody-drug conjugates for myeloma. There is clear clinical need for new treatments, as myeloma inevitably becomes refractory to standard agents. The full impact is yet to be established, but we are optimistic that the first FDA-approved antibody therapeutic(s) for this disease will emerge in the near future. PMID- 25294127 TI - Cellular origin and regulation of D- and L-serine in in vitro and in vivo models of cerebral ischemia. AB - D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-serine from L-serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-serine remain elusive. The D-/L-serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-serine is derived from neurons, while L-serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3 PGDH), which synthesizes L-serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH. PMID- 25294130 TI - Interaction of Aquifer and River-Canal Network near Well Field. AB - The article presents semi-analytical mathematical models to asses (1) enhancements of seepage from a canal and (2) induced flow from a partially penetrating river in an unconfined aquifer consequent to groundwater withdrawal in a well field in the vicinity of the river and canal. The nonlinear exponential relation between seepage from a canal reach and hydraulic head in the aquifer beneath the canal reach is used for quantifying seepage from the canal reach. Hantush's (1967) basic solution for water table rise due to recharge from a rectangular spreading basin in absence of pumping well is used for generating unit pulse response function coefficients for water table rise in the aquifer. Duhamel's convolution theory and method of superposition are applied to obtain water table position due to pumping and recharge from different canal reaches. Hunt's (1999) basic solution for river depletion due to constant pumping from a well in the vicinity of a partially penetrating river is used to generate unit pulse response function coefficients. Applying convolution technique and superposition, treating the recharge from canal reaches as recharge through conceptual injection wells, river depletion consequent to variable pumping and recharge is quantified. The integrated model is applied to a case study in Haridwar (India). The well field consists of 22 pumping wells located in the vicinity of a perennial river and a canal network. The river bank filtrate portion consequent to pumping is quantified. PMID- 25294129 TI - Hierarchical multivariate covariance analysis of metabolic connectivity. AB - Conventional brain connectivity analysis is typically based on the assessment of interregional correlations. Given that correlation coefficients are derived from both covariance and variance, group differences in covariance may be obscured by differences in the variance terms. To facilitate a comprehensive assessment of connectivity, we propose a unified statistical framework that interrogates the individual terms of the correlation coefficient. We have evaluated the utility of this method for metabolic connectivity analysis using [18F]2-fluoro-2 deoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. As an illustrative example of the utility of this approach, we examined metabolic connectivity in angular gyrus and precuneus seed regions of mild cognitive impairment (MCI) subjects with low and high beta-amyloid burdens. This new multivariate method allowed us to identify alterations in the metabolic connectome, which would not have been detected using classic seed-based correlation analysis. Ultimately, this novel approach should be extensible to brain network analysis and broadly applicable to other imaging modalities, such as functional magnetic resonance imaging (MRI). PMID- 25294128 TI - Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients. AB - The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients. PMID- 25294156 TI - Criminal careers in self-reports compared with official records. PMID- 25294157 TI - Understanding the relationship between self-reported offending and official criminal charges across early adulthood. AB - BACKGROUND: There has been very little research examining criminal careers in adulthood using both self-report data and official records. AIMS: The aims of this paper are to use self-reports and official criminal records to explore (1) the prevalences and frequencies of offending behaviour in adulthood; (2) continuity in offending behaviour across the life course; and (3) predictors of official court charges in adulthood. METHOD: Data are drawn from the Seattle Social Development Project, a longitudinal study of 808 participants followed from childhood into early adulthood. Data from ages 21 through 33 are used to examine criminal careers. RESULTS: Prevalences of offending behaviour decreased with age, whilst frequency amongst offenders remained stable or increased. There was significant continuity in offending from adolescence to adulthood in both self-reports and official records, especially for violence. Violent offences were most likely to result in a court charge. Even after controlling for self-reported frequency of offending, demographic variables (gender, ethnicity, and poverty) were significantly related to a court charge. CONCLUSIONS: Self-report and official records, both separately and together, provide valuable information for understanding criminal careers in adulthood, especially with regard to offending continuity across the life course and predicting the likelihood of a court charge. PMID- 25294155 TI - A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival. AB - BACKGROUND: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. METHODS: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. RESULTS: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 *10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09 4.79, prandom = 5.24 *10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival. CONCLUSIONS: The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS. PMID- 25294158 TI - Prevalence, frequency, onset, desistance and criminal career duration in self reports compared with official records. AB - AIM: The main aim of this article is to compare prevalence and frequency, ages of onset and desistance, and criminal career duration, according to self-reports and convictions. METHOD: In the Cambridge Study in Delinquent Development, 411 London males have been followed up from age 8 to age 48, in interviews and criminal records. RESULTS: Virtually all males admitted at least one of eight offences, compared with about one third who were convicted. In self-reports, the number of offences was over 30 times greater, the age of onset was earlier and the career duration was longer, compared with convictions. However, the age of desistance was generally later according to convictions. CONCLUSIONS: Self-reported ages of desistance may be affected by increasing concealment with age. The gap between the first self-reported offence and the first conviction provides an opportunity for early intervention. PMID- 25294159 TI - Assessing the nature and mix of offences among serious adolescent offenders. AB - BACKGROUND: Much of the research on specialisation in offending tends to show that offending careers are marked by more versatile than specific criminal activity. One key limitation of this research has been that very few studies have used both official records and self-reports to study the longitudinal mix of offences. AIMS: This study uses longitudinal data to examine the mixture of offences during mid-adolescence and into early adulthood, a key transitionary period of the life course, using both self-reports and official records. METHOD: Data from 1354 serious adolescent offenders are used to study the mixture of offences over a 7-year period. RESULTS: The results point strongly to the conclusion that generality is typical and specialisation is exceptional. PMID- 25294160 TI - Scaling up from convictions to self-reported offending. AB - AIM: The main aims of this article are to estimate the number of offences that are committed for every one that leads to conviction, and to estimate the probability of an offender being convicted. METHOD: In the Pittsburgh Youth Study, 506 boys were followed up from age 13 to age 24 years, in interviews and criminal records. Self-reports and convictions for serious theft, moderate theft, serious violence and moderate violence were compared. RESULTS: On average, 22 offences were self-reported for every conviction. This scaling-up factor increased with age and was the highest for moderate theft and the lowest for serious theft. The probability of a self-reported offender being convicted was 54%. This percentage increased with the frequency and seriousness of offending and was always higher for African American boys than for Caucasian boys. These race differences probably reflected differences in exposure to risk factors. CONCLUSIONS: More research is needed on scaling-up factors, on frequent and serious offenders who are not convicted, on self-reported non-offenders who are convicted and on why African American boys are more likely than Caucasian boys to be convicted. PMID- 25294161 TI - Links between trajectories of self-reported violent and nonviolent offending and official offending during adolescence and adulthood. AB - BACKGROUND: Little is known about the associations between self-reported offending and official offending whilst considering different types of offences. AIMS: The aims of the present study are to identify developmental trajectories of self-reported violent and nonviolent offending (SRVO; SRNVO) and to examine their associations with official violent and nonviolent offences (as juveniles and adults). METHODS: Developmental trajectories of SRVO and SRNVO from 11 to 17 years of age were estimated with data from the Montreal Longitudinal and Experimental Study, a prospective longitudinal study of 1037 boys from disadvantaged neighbourhoods. RESULTS: Five trajectories of SRVO (i.e. Chronic, Desisting, Delayed, Moderate and Low) and three trajectories of SRNVO (Chronic, Moderate and Low) were identified. Chronic, Desisting and Delayed trajectories of SRVO were associated with violent and nonviolent official offending in adolescence and early adulthood, over and above the trajectories of SRNVO. In comparison, trajectories of SRNVO were weakly and inconsistently associated with official offending, once controlling for their overlap with trajectories of SRVO. CONCLUSIONS: Individuals on high trajectories of violent offending during adolescence are most at risk for being exposed to the justice system both concurrently and longitudinally. Differentiating violent and nonviolent offending can help resolve part of the discordance between self-reported and official offending. PMID- 25294162 TI - Childhood predictors and age 48 outcomes of self-reports and official records of offending. AB - BACKGROUND: The key question is: are self-reports and official records equally valid indicators of criminal offending? AIMS: We examine the correspondence between self-reports and official records of offending, the similarity of childhood and adolescent individual and contextual predictors of both measures of offending, and the similarity of age 48 correlates of both measures of offending. METHODS: Men (N=436) from the Columbia County Longitudinal Study, a sample of all 3rd graders in Columbia County, New York, in 1959-60, participated. The youth, their peers and their parents were interviewed when the youth were age 8; the youth were later interviewed at ages 19, 30 and 48. RESULTS: We found moderate to high correspondence between self-reports of having been in trouble with the law and official arrest records. Lifetime self-reports and official records of offending were generally predicted by the same childhood and adolescent variables, and were correlated with many of the same adult outcome measures. By age 48, life-course non-offenders defined by either self-reports or official records had better outcomes than offenders. CONCLUSIONS: The results validate the use of adolescent and adult self-reports of offending, and the early identification of individuals at risk for adult criminal behaviour through childhood parent and peer reports and adolescent self and peer reports. PMID- 25294163 TI - Individual differences in the concordance of self-reports and official records. AB - BACKGROUND: Although self-reported and official measures of criminal behaviour are highly correlated, the concordance between self-reports and official records appears to vary across the population. Few studies, however, have considered the range of individual traits and characteristics that might influence the relative accuracy of self-reports and official records. METHOD: Using data collected from the Australian Temperament Project, we investigated the concordance between official records and self-reports together with some of the factors that might influence it. RESULTS: Those with criminal records were 3.5 times more likely to report police contact than those with no criminal record. However, there were significant sources of individual-level variation in their convergence, and notably honest respondents were less likely to report an interaction with police. Those at risk of crime and delinquency were less likely to consent to official records searches. CONCLUSIONS: Many individual characteristics that predisposed individuals towards a criminal career also affected their willingness to consent to official records searches and the concordance between criminal records and self-reports. PMID- 25294164 TI - Role of microRNAs in cancers of the female reproductive tract: insights from recent clinical and experimental discovery studies. AB - microRNAs (miRNAs) are small RNA molecules that represent the top of the pyramid of many tumorigenesis cascade pathways as they have the ability to affect multiple, intricate, and still undiscovered downstream targets. Understanding how miRNA molecules serve as master regulators in these important networks involved in cancer initiation and progression open up significant innovative areas for therapy and diagnosis that have been sadly lacking for deadly female reproductive tract cancers. This review will highlight the recent advances in the field of miRNAs in epithelial ovarian cancer, endometrioid endometrial cancer and squamous cell cervical carcinoma focusing on studies associated with actual clinical information in humans. Importantly, recent miRNA profiling studies have included well-characterized clinical specimens of female reproductive tract cancers, allowing for studies correlating miRNA expression with clinical outcomes. This review will summarize the current thoughts on the role of miRNA processing in unique miRNA species present in these cancers. In addition, this review will focus on current data regarding miRNA molecules as unique biomarkers associated with clinically significant outcomes such as overall survival and chemotherapy resistance. We will also discuss why specific miRNA molecules are not recapitulated across multiple studies of the same cancer type. Although the mechanistic contributions of miRNA molecules to these clinical phenomena have been confirmed using in vitro and pre-clinical mouse model systems, these studies are truly only the beginning of our understanding of the roles miRNAs play in cancers of the female reproductive tract. This review will also highlight useful areas for future research regarding miRNAs as therapeutic targets in cancers of the female reproductive tract. PMID- 25294165 TI - Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions. AB - CCN family protein 2 (CCN2), also widely known as connective tissue growth factor (CTGF), is one of the founding members of the CCN family of matricellular proteins. Extensive investigation on CCN2 over decades has revealed the novel molecular action and functional properties of this unique signalling modulator. By its interaction with multiple molecular counterparts, CCN2 yields highly diverse and context-dependent biological outcomes in a variety of microenvironments. Nowadays, CCN2 is recognized to conduct the harmonized development of relevant tissues, such as cartilage and bone, in the skeletal system, by manipulating extracellular signalling molecules involved therein by acting as a hub through a web. However, on the other hand, CCN2 occasionally plays profound roles in major human biological disorders, including fibrosis and malignancies in major organs and tissues, by modulating the actions of key molecules involved in these clinical entities. In this review, the physiological and pathological roles of this unique protein are comprehensively summarized from a molecular network-based viewpoint of CCN2 functionalities. PMID- 25294166 TI - All systems red. PMID- 25294167 TI - Insight into normal thymic activity by assessment of peripheral blood samples. AB - The thymus is a highly specialized organ for T cell receptor (TCR) rearrangement and selection mechanisms that ensure the formation of functional and self tolerant cells. Little is known about how peripheral blood assessment of thymic function reflects thymus activity during infancy. We compared thymic function related markers in the thymus with those in peripheral blood in order to check their correlations. We concomitantly blood samples from immunocompetent infants who underwent cardiac surgery that involved thymectomy. The studied thymic markers included TCR excision circles (TRECs), four different TCRD (TCR delta chain) gene rearrangements, the TCR repertoire, regulatory T cells (Tregs, defined as the CD4+CD25+FOXP3+ cell population) and real-time quantitative polymerase chain reaction (RQ-PCR) mRNA expression of forkhead box P3 (FOXP3). Twenty patients were enrolled in this study. Their mean age at the time of the surgery was 3 months/5 days +/- 3 months/18 days. There was a significant correlation between thymic and peripheral blood levels of TREC, all four TCRD gene rearrangements and the amount of Tregs. The levels of these parameters were significantly higher in the thymus than those detected in the peripheral blood. The TCR repertoire distribution in both samples was similar. FOXP3 mRNA levels in the thymus and peripheral blood correlated well. Our findings demonstrated a strong and significant correlation between peripheral blood and intra-thymic activity parameters during infancy. Assessment of these parameters in peripheral blood can be used to accurately estimate different intra-thymic capacities for assessing T cell function in health and disease. PMID- 25294169 TI - Altered expression of an RBP-associated arginine methyltransferase 7 in Leishmania major affects parasite infection. AB - Protein arginine methylation is a widely conserved post-translational modification performed by arginine methyltransferases (PRMTs). However, its functional role in parasitic protozoa is still under-explored. The Leishmania major genome encodes five PRMT homologs, including PRMT7. Here we show that LmjPRMT7 expression and arginine monomethylation are tightly regulated in a lifecycle stage-dependent manner. LmjPRMT7 levels are higher during the early promastigote logarithmic phase, negligible at stationary and late-stationary phases and rise once more post-differentiation to intracellular amastigotes. Immunofluorescence and co-immunoprecipitation studies demonstrate that LmjPRMT7 is a cytosolic protein associated with several RNA-binding proteins (RBPs) from which Alba20 is monomethylated only in LmjPRMT7-expressing promastigote stages. In addition, Alba20 protein levels are significantly altered in stationary promastigotes of the LmjPRMT7 knockout mutant. Considering RBPs are well-known mammalian PRMT substrates, our data suggest that arginine methylation via LmjPRMT7 may modulate RBP function during Leishmania spp. lifecycle progression. Importantly, genomic deletion of the LmjPRMT7 gene leads to an increase in parasite infectivity both in vitro and in vivo, while lesion progression is significantly reduced in LmjPRMT7-overexpressing parasites. This study is the first to describe a role of Leishmania protein arginine methylation in host parasite interactions. PMID- 25294168 TI - Medical devices and diagnostics for cardiovascular diseases in low-resource settings. AB - Noncommunicable diseases (NCDs), including cardiovascular diseases and diabetes, have emerged as an underappreciated health threat with enormous economic and public health implications for populations in low-resource settings. In order to address these diseases, devices that are to be used in low-resource settings have to conform to requirements that are generally more challenging than those developed for traditional markets. Characteristics and issues that must be considered when working in low- and middle-income countries (LMICs) include challenging environmental conditions, a complex supply chain, sometimes inadequate operator training, and cost. Somewhat counterintuitively, devices for low-resource setting (LRS) markets need to be of at least as high quality and reliability as those for developed countries to be setting-appropriate and achieve impact. Finally, the devices need to be designed and tested for the populations in which they are to be used in order to achieve the performance that is needed. In this review, we focus on technologies for primary and secondary health-care settings and group them according to the continuum of care from prevention to treatment. PMID- 25294170 TI - Automated auditory brainstem response in preterm newborns with histological chorioamnionitis. AB - OBJECTIVE: We investigated whether histological chorioamnionitis is associated with an adverse neonatal hearing outcome. METHODS: Two cohorts of very preterm newborns (n = 548, gestational age <= 32.0 weeks) were linked to placental histology and automated auditory brainstem response (AABR) outcome. RESULTS: In multivariable analyses, an abnormal AABR was not predicted by the presence of histological chorioamnionitis, either with or without fetal involvement (OR 1.4, 95% CI 0.5 - 3.8, p = 0.54 and OR 1.1, 95% CI 0.4-3.0, p = 0.79, respectively). Significant predictors of abnormal AABR included, e.g. birth weight (per kg increase: OR 0.2, 95% CI 0.0-0.6, p = 0.006), umbilical cord artery pH (per 0.1 increase: OR 0.7, 95% CI 0.5-0.9, p = 0.005) and mechanical ventilation (OR 3.7, 95% CI 1.2-11.6, p = 0.03). CONCLUSIONS: Histological chorioamnionitis was not associated with an adverse neonatal hearing outcome in two cohorts of very preterm newborns. Indicators of a complicated neonatal clinical course were the most important predictors of an abnormal hearing screening. PMID- 25294171 TI - Successful repair despite late diagnosis of traumatic pericardial rupture with cardiac herniation. PMID- 25294172 TI - Aortic coral reef as an unusual possible cause of heart failure. PMID- 25294173 TI - Athlete's syndrome X. PMID- 25294174 TI - The third ventricle--a case of a giant post infarct pseudoaneurysm. PMID- 25294175 TI - Brugada phenocopy in acute pulmonary embolism. PMID- 25294176 TI - Myocarditis in association with giardia intestinalis infection. PMID- 25294177 TI - Neointimal thickening resulting in artery stenosis following renal sympathetic denervation. PMID- 25294178 TI - A novel cardiovascular presentation of Alport Syndrome: spontaneous coronary artery dissection. PMID- 25294179 TI - Takotsubo cardiomyopathy induced by epileptic seizure. PMID- 25294180 TI - Random blood glucose may be used to assess long-term glycaemic control among patients with type 2 diabetes mellitus in a rural African clinical setting. AB - OBJECTIVES: To investigate the diagnostic accuracy of random blood glucose (RBG) on good glycaemic control among patients with diabetes mellitus (DM) in a rural African setting. METHODS: Cross-sectional study at St. Francis' Hospital in eastern Zambia. RBG and HbA1c were measured during one clinical review only. Other information obtained was age, sex, body mass index, waist circumference, blood pressure, urine albumin-creatinine ratio, duration since diagnosis and medication. RESULTS: One hundred and one patients with DM (type 1 DM = 23, type 2 DM = 78) were included. Spearman's rank correlation coefficient revealed a significant correlation between RBG and HbA1c among the patients with type 2 DM (r = 0.73, P < 0.001) but not patients with type 1 DM (r = 0.17, P = 0.44). Furthermore, in a multivariate linear regression model (R(2) = 0.71) RBG (per mmol/l increment) (B = 0.28, 95% CI:0.24-0.32, P < 0.001) was significantly associated with HbA1c among the patients with type 2 DM. Based on ROC analysis (AUC = 0.80, SE = 0.05), RBG <=7.5 mmol/l was determined as the optimal cut-off value for good glycaemic control (HbA1c <7.0% [53 mmol/mol]) among patients with type 2 DM (sensitivity = 76.7%; specificity = 70.8%; positive predictive value = 62.2%; negative predictive value = 82.9%). CONCLUSIONS: Random blood glucose could possibly be used to assess glycaemic control among patients with type 2 DM in rural settings of sub-Saharan Africa. PMID- 25294181 TI - A highly selective and turn-on fluorescence sensor for detection of cyanide. AB - 2-Hydroxy-1-naphthaldehyde (receptor 1) serves as a selective chemosensor for cyanide anion (CN(-)). In the presence of CN(-), an enhanced fluorescent intensity and red shift were observed. The observed complexation between receptor 1 and CN(-) may cause from a formation of phenoxide anion by nucleophilic addition of the CN(-) to carbonyl group. PMID- 25294182 TI - A highly sensitive solid substrate room temperature phosphorimetry for carbaryl detection based on its activating effect on NaIO4 oxidizing fluorescein. AB - Fluorescein (HFin) could emit strong and stable room temperature phosphorescence (RTP) signal on polyamide membrane (PAM) using Pb(2+) as the ion perturber. Carbaryl could activate effect on NaIO4 oxidating HFin, which caused the RTP signal of the system to quench sharply. The phosphorescence intensity (DeltaI p) of activating system higher 3.3 times (119.4/36.0) than that of non-activating system, and is directly proportional to the content of carbaryl. Thus, an activating solid substrate room temperature phosphorimetry (SSRTP) for carbaryl detection has been established. This sensitive (the limit of quantification (LOQ) was 2.0 * 10(-13) g mL(-1)), selective, simple and rapid method has been applied to determine trace carbaryl in water samples with the results consisting with those obtained by fluorimetry, showing its high accuracy. The apparent activation energy (E) and rate constant (k) of this activating reaction were 20.77 kJ mol( 1) and 1.85 * 10(-4) s(-1), respectively. Meanwhile, the mechanism of activating SSRTP for carbaryl detection was also discussed using infrared spectra (IR). PMID- 25294183 TI - Preparation, characterization and solid-state emission of metal complex-cloisite nanohybrids (MC-C, M = Ru (II) and Cu (II)). AB - The presence of Na(+) in the Cloisite Na(+) mineral allows modification of its interlayer space to achieve a better compatibility with the host matrix and ion exchange with a cationic metal complex. The aim of this research is to prepare two new metal complex-Cloisite (MC-C) nanohybrids using reaction of Cloisite Na(+) with the cationic Ru (II) and Cu (II) complexes, [Ru (tpy) 2] (2+) and [Cu (Pir) (phen) (H2O) 2](+), in an aqueous solution for the first time. The X-ray diffraction (XRD) analysis of the modified clays has shown an increase in its interlayer distance as compared to the unmodified Cloisite Na(+). The positions of the basal reflections in the XRD patterns of the modified clays were shifted to a higher d value indicating the expansion in their interlayer distances. The field-emission scanning electron microscopy has shown a homogeneous morphology for the modified clays. The thermal behavior of these novel hybrid materials was also investigated by thermogravimetric analysis. The solid state fluorescence spectra of the modified clays have shown that both cationic complexes exhibit a significant fluorescence emission at room temperature when intercalated into Cloisite. PMID- 25294184 TI - Changing trends in the causes and management of male urethral stricture disease in China: an observational descriptive study from 13 centres. AB - OBJECTIVE: To determine whether there have been any changes in the causes and management of urethral strictures in China. PATIENTS AND METHODS: The data from 4,764 men with urethral stricture disease who underwent treatment at 13 medical centres in China between 2005 and 2010 were retrospectively collected. The databases were analysed for the possible causes, site and treatment techniques for the urethral stricture, as well as for changes in the causes and management of urethral strictures. RESULTS: The most common cause of urethral strictures was trauma, which occurred in 2,466 patients (51.76%). The second most common cause was iatrogenic injures, which occurred in 1,643 patients (34.49%). The most common techniques to treat urethral strictures were endourological surgery (1,740, 36.52%), anastomotic urethroplasty (1,498, 31.44%) and substitution urethroplasty (1,039, 21.81%). A comparison between the first 3 years and the last 3 years showed that the constituent ratio of endourological surgery decreased from 54% to 32.75%, whereas the constituent ratios of anastomotic urethroplasty and substitution urethroplasty increased from 26.73% and 19.18% to 39.93% and 27.32%, respectively (P < 0.05). CONCLUSIONS: During recent years, there has been an increase in the incidence of urethral strictures caused by trauma and iatrogenic injury. Endourological urethral surgery rates decreased significantly, and open urethroplasty rates increased significantly during the last 3 years. PMID- 25294185 TI - Gastrocolic fistula: a rare sequela of colonic adenocarcinoma. PMID- 25294186 TI - Cohen's h for detection of disease association with rare genetic variants. AB - BACKGROUND: The power of the genome wide association studies starts to go down when the minor allele frequency (MAF) is below 0.05. Here, we proposed the use of Cohen's h in detecting disease associated rare variants. The variance stabilizing effect based on the arcsine square root transformation of MAFs to generate Cohen's h contributed to the statistical power for rare variants analysis. We re analyzed published datasets, one microarray and one sequencing based, and used simulation to compare the performance of Cohen's h with the risk difference (RD) and odds ratio (OR). RESULTS: The analysis showed that the type 1 error rate of Cohen's h was as expected and Cohen's h and RD were both less biased and had higher power than OR. The advantage of Cohen's h was more obvious when MAF was less than 0.01. CONCLUSIONS: Cohen's h can increase the power to find genetic association of rare variants and diseases, especially when MAF is less than 0.01. PMID- 25294187 TI - Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. AB - PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD >=8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors. PMID- 25294188 TI - Characterization of 'Candidatus Syngnamydia salmonis' (Chlamydiales, Simkaniaceae), a bacterium associated with epitheliocystis in Atlantic salmon (Salmo salar L.). AB - Two Chlamydiales have previously been found to infect Atlantic salmon (Salmo salar L.), Candidatus Piscichlamydia salmonis and Candidatus Clavichlamydia salmonicola. Both develop intracellularly in cyst-like inclusions in gill cells, generally referred to as epitheliocysts. Here, we present evidence for the association of a novel species of Chlamydiales with epitheliocystis in Atlantic salmon. Based on its partial 16S rRNA gene sequence, it is a new member of the family Simkaniaceae, and a 95.7 % identity to the type species Candidatus Syngnamydia venezia suggests inclusion in the candidate genus Syngnamydia. The presence of the bacterium in epitheliocysts in gills of Atlantic salmon was demonstrated by RNA-RNA hybridization. Ultrastructurally, the novel bacterium produces pleomorphic reticulate bodies and elementary bodies (EBs) with a characteristic morphology. The EBs are short rods with a terminal disc-like cap area, a sub-apical spherical vacuole-like electron-lucent structure and a post equatorial nucleoid. We propose the name Candidatus Syngnamydia salmonis for this new agent from epitheliocysts in seawater-reared salmon . PMID- 25294189 TI - Bacillus lonarensis sp. nov., an alkalitolerant bacterium isolated from a soda lake. AB - A novel Gram-stain-positive, rod-shaped, motile and endospore-forming novel bacterial strain 25nlg(T) was isolated from Lonar soda lake, in India. Based on the 16S rRNA gene sequence analysis, it was identified as a member of Firmicutes, being most closely related to Bacillus patagoniensis PAT 05(T) (96.6 %) and other members in the genus Bacillus (<96.0 %). Strain 25nlg(T) was catalase and oxidase positive. The strain grows optimally at a pH of 9.5 with 4-6 % (w/v) NaCl and temperature of 35-37 degrees C. The cell wall of the strain 25nlg(T) contains meso-diaminopimelic acid as the diagnostic amino acid. Polar lipids include diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unknown phospholipid (PL2), an aminophospholipid (APL2) and three unknown lipids (L2-4). The predominant isoprenoid quinone was MK-7. iso-C15:0 (41.7 %) was the predominant fatty acid, and significant proportions of anteiso-C15:0 (20.8 %), C12:0 (5.5 %), anteiso-C17:0 (4.9 %), iso-C17:0 (4.5 %) were also detected in the strain 25nlg(T). The DNA G+C content of the strain 25nlg(T) was 40.5 mol%. The results of molecular, physiological and biochemical tests allowed a clear phenotypic differentiation of strain 25nlg(T) from all other members of the genus Bacillus. Strain 25nlg(T) represents a novel member of the genus Bacillus, for which the name Bacillus lonarensis sp. nov. is proposed. The type strain is 25nlg(T) (=KCTC 33413(T) = LMG 27974(T) = CGMCC = 1.12817(T)). PMID- 25294190 TI - Roles of bacterial membrane vesicles. AB - Outer membrane vesicles (OMVs) are released from the outer membrane of Gram negative bacteria. Moreover, Gram-positive bacteria also produce membrane-derived vesicles. As OMVs transport several bacterial components, especially from the cell envelope, their interaction with the host cell, with other bacteria or as immunogens, have been studied intensely. Several functions have been ascribed to OMVs, especially those related to the transport of virulence factors, antigenic protein composition, and development as acellular vaccines. In this work, we review some of the recent findings about OMVs produced by specific pathogenic bacterial species. PMID- 25294191 TI - Bioactive organic-inorganic poly(CLMA-co-HEA)/silica nanocomposites. AB - A series of novel poly(CLMA-co-HEA)/silica nanocomposites is synthesized from caprolactone 2-(methacryloyloxy)ethyl ester (CLMA) and 2-hydroxyethyl acrylate (HEA) as organic comonomers and the simultaneous sol-gel polymerization of tetraethyloxysilane (TEOS) as silica precursor, in different mass ratios up to a 30 wt% of silica. The nanocomposites are characterized as to their mechanical and thermal properties, water sorption, bioactivity and biocompatibility, reflecting the effect on the organic matrix provided by the silica network formation. The nanocomposites nucleate the growth of hydroxyapatite (HAp) on their surfaces when immersed in the simulated body fluid of the composition used in this work. Proliferation of the MC3T3 osteoblast-like cells on the materials was assessed with the MTS assay showing their biocompatibility. Immunocytochemistry reveals osteocalcin and type I collagen production, indicating that osteoblast differentiation was promoted by the materials, and calcium deposition was confirmed by von Kossa staining. The results indicate that these poly(CLMA-co HEA)/silica nanocomposites could be a promising biomaterial for bone tissue engineering. PMID- 25294192 TI - Mitochondrial genomes of domestic animals need scrutiny. AB - More than 1000 complete or near-complete mitochondrial DNA (mtDNA) sequences have been deposited in GenBank for eight common domestic animals (cattle, dog, goat, horse, pig, sheep, yak and chicken) and their close wild ancestors or relatives, as well. Nevertheless, few efforts have been performed to evaluate the sequence data quality. Herein, we conducted a phylogenetic survey of these complete or near-complete mtDNA sequences based on mtDNA haplogroup trees for the eight animals. We show that errors due to artificial recombination, surplus of mutations and phantom mutations do exist in 14.5% (194/1342) of mtDNA sequences and all of them should be treated with wide caution. We propose some caveats for future mtDNA studies of domestic animals. PMID- 25294193 TI - [In Process Citation]. PMID- 25294194 TI - [In Process Citation]. PMID- 25294195 TI - [In Process Citation]. PMID- 25294196 TI - [Percutaneous closure of the left atrial appendage for stroke prevention]. AB - In patients with atrial fibrillation (AF) and increased risk of stroke, oral anticoagulation (OAC) is the standard treatment for stroke prevention - however, this therapy also carries a high risk of bleeding. Percutaneous closure of the left atrial appendage (LAA) has been suggested to be an alternative option for stroke prevention in AF patients with contraindication(s) for OAC treatment. In this paper, we discuss the rationale for LAA closure, the importance of a proper patient selection, as well as some pre- and post-procedural issues. PMID- 25294197 TI - [Stimulation of labour with oxytocin and ventouse deliveries are inadequately documented]. AB - A retrospective sample of 180 records from four regional hospitals and five university hospitals in Denmark was collected and the documentation for use of oxytocin in augmentation of labour and ventouse deliveries according to the national guidelines was registered. Only approximately half of the elements in the national guidelines were documented. This shows that there is a potential for improvement in the ongoing Danish national quality improvement project Safe Deliveries (Sikre Fodsler). PMID- 25294198 TI - [Hormone replacement therapy after salpingo-oophorectomy in BRCA 1/2 mutation carriers does not increase the risk of breast cancer]. AB - Prophylactic bilateral salpingo-oophorectomy (PBSO) reduces the risk of breast- and ovarian cancer in breast cancer gene (BRCA)1/2 mutation carriers. Women choose hormone replacement therapy (HT) to alleviate climacteric symptoms. Studies have shown a higher risk of breast cancer in healthy post-menopausal women getting HT. Further research among women with BRCA1/2 mutations is essential. No studies showed significantly that short-term use of HT alters the reduction in breast cancer risk associated with PBSO. Neither was there found any significant difference in type of HT chosen. PMID- 25294199 TI - [The complex clinical presentation of hereditary mitochondrial diseases]. AB - Mitochondria produce cellular energy, which is of vital importance for cellular metabolism. The organelles contain their own genetic material (i.e. mitochondrial DNA (mtDNA)) with a matrilineal inheritance. Mutations in the mtDNA may cause mitochondrial disease affecting multiple organs leading to diabetes, hearing impairment, muscle fatigue, ptosis and stroke-like episodes in varying combinations and severity. The variable phenotypic presentations make it a challenge to recognize mitochondrial diseases and, consequently, the correct diagnosis is often delayed. PMID- 25294200 TI - [Diabetes and hearing impairment due to mitochondrial mutation]. AB - Mutations in the mitochondrial genome can cause mitochondrial diabetes. We present two cases in which the same mutation, mtDNA3243A>G, caused two different phenotypes: maternally inherited diabetes and deafness and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Mitochondrial disease can imitate a variety of common con-ditions and should be considered in the case of multisystem disease, complex neurological symptoms or neurological symptoms combined with symptoms of other organ systems. PMID- 25294201 TI - [Liposarcoma in the lung misinterpreted as an infection of Echinococcus multicularis]. AB - Primary liposarcoma of the lung is an extremely rare disease. Only 14 cases have been reported in the literature in English. Liposarcoma is not sensitive to chemotherapy or radiotherapy. Surgical resection is considered the only therapeutic option. We present a case of a giant liposarcoma occupying two thirds of the right thoracic cavity. PMID- 25294202 TI - [Manedens billede]. PMID- 25294203 TI - [Anaesthetics and porphyria]. AB - Patients with acute porphyria are at risk of life-threatening attacks when exposed to stress, fast, infection, alcohol and especially some drugs, including older anaesthetics. Acute porphyrias are rare inherited diseases caused by inefficient enzymatic activity within the haem synthesis. During attacks the patient suffers from severe abdominal pain, cardiovascular instability, neurological symptoms etc. Preventive measures and treatment should be known to anaesthesiologists and surgeons in particular and known to other clinicians in general. In order to assist the clinicians, drug databases are available online. PMID- 25294204 TI - [Management of patients with liver traumas]. AB - Development of a hepatic pseudoaneurysm (HPA) is a well-known, yet rare complication after liver trauma. We found 135 cases reported in the literature since 1965. Ruptured HPAs may have severe consequences with sudden massive haemorrhage and death. A clear strategy towards diagnosis and management of HPA post liver trauma is needed and outlined in this paper. We recommend early detection and definitive treatment before enlargement and rupture. PMID- 25294205 TI - [Entrapped nerve causing severe post-operative pain from scar tissue]. AB - Entrapment of a cutaneous nerve in a surgical scar may cause chronic post operative pain. The condition presents with similar symptoms as a traumatic neuroma or as an anterior cutaneous nerve entrapment syndrome, which, however, is often idiopathic. We present a case, where entrapment of a cutaneous nerve in a laparotomy scar caused chronic pain. The symptoms were immediately relieved after selective neurectomy. PMID- 25294206 TI - [Gelatinous transformation of the bone marrow caused by excessive physical activity and insufficient calorie intake]. AB - Gelatinous transformation (GT) of the bone marrow is rare and associated with a variety of clinical diseases from malignancy to chronic infection in combination with malnutrition or wasting. A new clinical picture of GT has emerged with excessive physical activity in combination with a voluntary insufficient calorie intake in the young adult male. Overtraining syndrome and systemic inflammation may play a role in the pathogenesis of GT in these patients, but further studies on GT and the effect of training and overtraining on the bone marrow are needed. PMID- 25294207 TI - [SMS reminders can reduce non-attendance at consultations]. AB - Each year, thousands of patients fail to attend their consulta-tions. In January 2014, 89/955 (9.3%) planned consultations were misheld at the Dermatology Department of Bispebjerg Hospital, Denmark. A total of 209 patients were interviewed about SMS (short message service) reminders. 82% of re-spondents had a positive opinion of SMS reminders, however, reminders were only enrolled in 17.7% and awareness unknown in 33%. Reminders guaranteed attendance in 6.2%, otherwise forgotten, but the system has a significant untapped potential. It can be improved through automatic enrolment already when referring the patient. PMID- 25294208 TI - [Wilson disease often debuts with psychiatric symptoms]. AB - We present a case of a 17-year-old girl initially suspected of having a psychiatric disease within the affective spectrum. However, thorough evaluation of the overall symptomatology, and a combination of repeated physical examinations and paraclinical testing led to the diagnosis of Wilson disease. This case emphasizes the importance of a broad diagnostic approach to psychiatric patients. PMID- 25294209 TI - [The assessment of clinical skills is imperative in postgraduate specialty training]. AB - According to the Danish Ministry of Health recommendations, workplace-based assessment (WPBA) should be a central component in postgraduate specialty training. In this review the potential impact of WPBA with regard to patient safety, medical licensing and effects on doctors' learning is explored. The utility of WPBA instruments is reviewed with respect to their reliability, validity, cost, acceptability, and educational impact. Finally, the concept of Entrusted Professional Activities is discussed in view of the utility framework, and recommendations for future practice are provided. PMID- 25294210 TI - [Accidential consumption of wart remover]. AB - Not seldom do people buy medicine abroad while on business or holiday, where international labelling is less than optimal. Once home, the medication is often kept alongside every-day products, sometimes resulting in home accidents due to a confusion of products. In this case a six-month-old girl was administered five drops of monochloroacetic acid orally as a result of mistaking a bottle of D vitamin with a bottle of acid for the removal of warts. She suffered a mild poisoning, chemical burns and required intubation due to oedema of the upper airways, but no long-term effects. PMID- 25294211 TI - [The combination of indacaterol and glycopyrronium has effects on symptoms, lung function, and rate of exacerbations in COPD patients]. AB - Long-acting bronchodilators are the mainstay of pharmacological therapy for chronic obstructive pulmonary disease (COPD). This paper reviews the efficacy of the once-daily fixed-dose dual bronchodilator combination of indacaterol and glycopyrronium in COPD patients. Compared with single therapy with indacaterol, glycopyrronium and tiotropium and fixed combination salmeterol/fluticasone, fixed dose indacaterol/glycopyrronium has clinically relevant effects on symptoms, health status, lung function, and rate of exacerbations and by that suggests a potential for dual bronchodilation as an important maintenance therapeutic option for some patients with COPD. PMID- 25294212 TI - [Rhabdomyolysis caused by thiazid-induced hypokalaemia]. AB - This case report presents a 38-year-old woman who developed rhabdomyolysis following severe hypokalaemia due to a thiazid diuretic. Rhabdomyolysis is a severe condition with an incidence of 28% in hypokalaemic patients. It should be considered to measure concentrations of S-myoglobin and S-creatine kinase in severe cases of hypokalaemia. Thiazid diuretics can cause severe hypokalaemia with life-threatening complications and monitoring of S-potassium is advised during therapy. PMID- 25294213 TI - Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups. AB - Early deficiency of the methyl donors folate and vitamin B12 produces hyperhomocysteinemia and cognitive and motor disorders in 21-day-old rat pups from dams fed a diet deficient in methyl donors during gestation and lactation. These disorders are associated with impaired neurogenesis and altered synaptic plasticity in cerebellum. We aimed to investigate whether these disorders could be related to impaired expression of neurosteroidogenesis-associated proteins, key regulator receptors, and some steroid content in the cerebellum. The methyl donor deficiency produced a decreased concentration of folate and vitamin B12, along with accumulation of homocysteine in Purkinje cells in both sexes, whereas the S-adenosylmethionine/S-adenosylhomocysteine ratio was reduced only in females. The transcription level and protein expression of StAR, aromatase, ERalpha, ERbeta, and LH receptors were decreased only in females, with a marked effect in Purkinje cells, as shown by immunohistochemistry. Consistently, reduced levels of estradiol and pregnenolone were measured in cerebellar extracts of females only. The decreased expression levels of the transcriptional factors CREB, phospho-CREB, and SF-1, the lesser increase of cAMP concentration, and the lower level of phospho-PKC in the cerebellum of deficient females suggest that the activation of neurosteroidogenesis via cAMP-mediated signaling pathways associated with LHR activation would be altered. In conclusion, a gestational methyl donor deficiency impairs neurosteroidogenesis in cerebellum in a sex dependent manner. PMID- 25294214 TI - Effects of weight gain induced by controlled overfeeding on physical activity. AB - It is unclear whether physical activity changes following long-term overfeeding and in response to different dietary protein intakes. Twenty-five (16 males, 9 females) healthy adults (18-35 yr) with BMI ranging from 19 to 30 kg/m(2) enrolled in this inpatient study. In a parallel group design, participants were fed 140% of energy needs, with 5, 15, or 25% of energy from protein, for 56 days. Participants wore an RT3 accelerometer for at least 59 days throughout baseline and during overfeeding and completed 24-h whole room metabolic chamber assessments at baseline and on days 1, 14, and 56 of overfeeding and on day 57, when the baseline energy intake was consumed, to measure percent of time active and spontaneous physical activity (SPA; kcal/day). Changes in activity were also assessed by doubly labeled water (DLW). From accelerometry, vector magnitude (VM), a weight-independent measure of activity, and activity energy expenditure (AEE) increased with weight gain during overfeeding. AEE remained increased after adjusting for changes in body composition. Activity-related energy expenditure (AREE) from DLW and percent activity and SPA in the metabolic chamber increased with overfeeding, but SPA was no longer significant after adjusting for change in body composition. Change in VM and AEE were positively correlated with weight gain; however, change in activity was not affected by protein intake. Overfeeding produces an increase in physical activity and in energy expended in physical activity after adjusting for changes in body composition, suggesting that increased activity in response to weight gain might be one mechanism to support adaptive thermogenesis. PMID- 25294216 TI - Type 2 iodothyronine deiodinase is upregulated in rat slow- and fast-twitch skeletal muscle during cold exposure. AB - During cold acclimation, shivering is progressively replaced by nonshivering thermogenesis. Brown adipose tissue (BAT) and skeletal muscle are relevant for nonshivering thermogenesis, which depends largely on thyroid hormone. Since the skeletal muscle fibers progressively adapt to cold exposure through poorly defined mechanisms, our intent was to determine whether skeletal muscle type 2 deiodinase (D2) induction could be implicated in the long-term skeletal muscle cold acclimation. We demonstrate that in the red oxidative soleus muscle, D2 activity increased 2.3-fold after 3 days at 4 degrees C together with the brown adipose tissue D2 activity, which increased 10-fold. Soleus muscle and BAT D2 activities returned to the control levels after 10 days of cold exposure, when an increase of 2.8-fold in D2 activity was detected in white glycolytic gastrocnemius but not in red oxidative gastrocnemius fibers. Propranolol did not prevent muscle D2 induction, but it impaired the decrease of D2 in BAT and soleus after 10 days at 4 degrees C. Cold exposure is accompanied by increased oxygen consumption, UCP3, and PGC-1alpha genes expression in skeletal muscles, which were partialy prevented by propranolol in soleus and gastrocnemius. Serum total and free T3 is increased during cold exposure in rats, even after 10 days, when BAT D2 is already normalized, suggesting that skeletal muscle D2 activity contributes significantly to circulating T3 under this adaptive condition. In conclusion, cold exposure is accompanied by concerted changes in the metabolism of BAT and oxidative and glycolytic skeletal muscles that are paralleled by type 2 deiodinase activation. PMID- 25294217 TI - Reproducing under a warming climate: long winter flowering and extended flower longevity in the only Mediterranean and maritime Primula. AB - Under the pressure of global warming, general expectations of species migration and evolution of adaptive traits should always be confirmed with species-specific studies. Within this framework, some species can be used as study systems to predict possible consequences of global warming also on other relatives. Unlike its mountain congeneric, Primula palinuri Petagn. has endured all the climatic fluctuations since the Pleistocene, while surviving on Mediterranean coastal cliffs. The aim of this work was to investigate the possible evolution of reproductive biological and ecological traits in P. palinuri adaptation to a warmer environment. Data showed that flowering starts in mid-winter; single flowers remain open for over a month, changing from pendulous to erect. The number of insects visiting flowers of P. palinuri increases during the flowering season, and pollination reduces flower longevity. Overall, the best pollen performances, in terms of viability and germinability, occur at winter temperatures, while pollinator activity prolongs flowering until spring. Moreover, extended longevity of single flowers optimises reproductive success. Both phenotypic plasticity and selective processes might have occurred in P. palinuri. However, we found that reproductive traits of the only Mediterranean Primula remain more associated with cold mountain habitats than warm coastal cliffs. Given the rapid trend of climate warming, migration and new adaptive processes in P. palinuri are unlikely. Response to past climate warming of P. palinuri provides useful indications for future scenarios in other Primula species. PMID- 25294215 TI - Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia. AB - The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies. PMID- 25294219 TI - Activation of the Nrf2-ARE pathway in hepatocytes protects against steatosis in nutritionally induced non-alcoholic steatohepatitis in mice. AB - Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2- animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and beta-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2- and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model. PMID- 25294220 TI - Personality affects the foraging response of a mammalian herbivore to the dual costs of food and fear. AB - Predators attack and plants defend, so herbivores face the dilemma of how to eat enough without being eaten. But do differences in the personality of herbivores affect the foraging choices of individuals? We explored the ecological impact of personality in a generalist herbivore, the brushtail possum (Trichosurus vulpecula). After quantifying personality traits in wild individuals brought temporarily into captivity, we tested how these traits altered foraging by individuals when free-ranging in their natural habitat. To measure their responses to the dual costs of predation risk and plant toxin, we varied the toxin concentration of food in safe foraging patches against paired, non-toxic risky patches, and used a novel synthesis of a manipulative Giving-Up-Density (GUD) experiment and video behavioural analysis. At the population level, the cost of safe patches pivoted around that of risky patches depending on food toxin concentration. At the individual level, boldness affected foraging at risky high quality food patches (as behavioural differences between bold and shy), and at safe patches only when food toxin concentration was low (as differences in foraging outcome). Our results ecologically validate the personality trait of boldness, in brushtail possums. They also reveal, for the first time, a nuanced link between personality and the way in which individuals balance the costs of food and fear. Importantly, they suggest that high plant defence effectively attenuates differences in foraging behaviour arising from variation in personality, but poorly defended plants in safe areas should be differentially subject to herbivory depending on the personality of the herbivore. PMID- 25294218 TI - Comparing gene expression during cadmium uptake and distribution: untreated versus oral Cd-treated wild-type and ZIP14 knockout mice. AB - The nonessential metal cadmium (Cd) is toxic only after entering the cell. Proteins possibly relevant to intracellular Cd accumulation include the divalent metal transporter-1 (DMT1) and all 14 zinc-like iron-like protein (ZIP) importers, 10 zinc transporter (ZnT) exporters, and metallothionein chaperones MT1 and MT2. Comparing oral Cd-treated ZIP14 knockout (KO) with wild-type (WT) mice, we predicted Cd uptake and distribution would be diminished in the KO because ZIP14 is very highly expressed in GI tract and liver; this was indeed observed for Cd content in liver. However, the reverse was found in kidney and lung from 6 or 12 h through 10 days of Cd exposure; at these times, Cd accumulation was unexpectedly greater in KO than WT mice; mRNA levels of the 27 above-mentioned genes were thus examined in proximal small intestine (PSI) versus kidney to see if these paradoxical effects could be explained by substantial alterations in any of the other 26 genes. PSI genes highly expressed in untreated WT animals included seven ZIP and five ZnT transporters, DMT1, MT1, and MT2; kidney genes included 11 ZIP and 7 ZnT transporters, DMT1, MT1, and MT2. Over 10 days of oral Cd, a bimodal response was seen for Cd content in PSI and for various mRNAs; initially, acute effects caused by the toxic metal; subsequently, the up- or down-regulation of important genes presumably to combat the sustained adversity. These data underscore the complex interplay between the gastrointestinal tract and renal proteins that might be relevant to Cd uptake and distribution in animals exposed to oral Cd. PMID- 25294221 TI - A Novel Insulinotropic Peptide from the Skin Secretions of Amolops loloensis Frog. AB - Various kinds of biologically active peptides have previously been isolated from the skin secretions of Amolops loloensis frog, such as antimicrobial peptides, bradykinin-like peptides and algesic peptides. A novel insulinotropic peptide named amolopin was identified in A. loloensis frog's skin secretion. Its primary structure sequence was determined by Edman degradation as: FLPIVGKSLSGLSGKL-NH2. BLAST search indicates that the amino acid sequence of amolopin is quite different from other known insulin secretagogues, including mastoparan, exendins and alpha-latrotoxin, nor does it like incretins (e.g. glucagons like peptide-1 and glucose-dependent insulinotropic ploypeptide) either. However, amolopin shows certain structural similarity with amphibian antimicrobial temporins and vespid chemotactic peptides isolated from Vespa magnifica. Amolopin can stimulate insulin release in INS-1 cells in a dose-dependent manner. Primary investigation on its action mechanisms reveals that amolopin does not increase the influx of Ca(2+). In conclusion, a novel 16-amino acid peptide with insulin-releasing activity is initially discovered from the skin secretion of A. loloensis frog. Further work is necessary to evaluate its potential as novel anti-diabetic candidate. PMID- 25294222 TI - Comparative histopathological and immunological study of two field strains of chicken anemia virus. AB - Infection of poultry with chicken anemia virus (CAV) is implicated in several field problems in broiler flocks due to the immunosuppression generated and, consequently, the increased susceptibility to secondary infections. Recently, we have reported an increased occurrence of clinical cases caused by CAV strains distantly related to those commonly used for vaccination. In order to understand the behavior of two Argentinean CAV strains (CAV-10 and CAV-18) in two-week-old chickens, an immune and histopathological study was performed. Neither mortality nor clinical signs were observed in the infected or control groups. Thymus lobes from chickens infected with both CAV viruses were smaller compared to the negative control group. At 14 days post-infection (dpi), only chickens inoculated with CAV-10 show a severe depletion of lymphocytes in the thymus cortex and in follicles from the bursa of Fabricius. Also thymopoiesis disorders, such as reduction in the percentage of total DP (CD4 + CD8alpha+) thymocytes and alteration in the percentages of DP subpopulations, were more important in animals inoculated with the CAV-10 than the CAV-18 strain. In addition, only animals infected with CAV-10 show a decrease in CD8alphabeta splenocytes. Altogether our results show that, although both Argentinean CAV strains produce subclinical infections in chickens causing immunosuppression at 14 dpi, they might differ in their in vivo pathogenicity. PMID- 25294223 TI - Effects of probiotic Lactobacillus brevis KB290 on incidence of influenza infection among schoolchildren: an open-label pilot study. AB - We investigated the efficacy of dietary consumption of Lactobacillus brevis KB290 (KB290) against influenza in humans by a preliminary intervention study on elementary schoolchildren, using a commercially available probiotic drink. Subjects were divided into Groups A and B, and an open-label, parallel-group trial was conducted in two 8-week periods at a 1-month interval in winter 2013/2014. Group A was provided with a bottle of the test drink containing KB290 (about 6 billion colony-forming units) every school day in the first period and had no treatment in the second period, and vice versa for Group B. Epidemic influenza was not observed during the first period and only two of 1783 subjects were diagnosed. In the second period, the incidence of influenza in Groups A (no treatment) and B (provided the test drink) was 23.9 and 15.7%, respectively, and the difference was statistically significant (P < 0.001). The reduction in the incidence of influenza by KB290 consumption was especially remarkable in unvaccinated individuals. This is believed to be the first study to show a probiotic food reducing the incidence of influenza in schoolchildren, although further studies are needed to confirm the effectiveness of the probiotic strain KB290. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrated a reduction in the incidence of influenza in 1089 schoolchildren by continual intake of a probiotic drink containing Lactobacillus brevis KB290 (KB290), isolated from a traditional Japanese pickle 'Suguki'. The effect was especially evident in subjects not inoculated with influenza vaccine. This is believed to be the first report to show reduced incidence of influenza in schoolchildren taking a probiotic food. Further studies are needed to confirm the effectiveness of the probiotic strain KB290, which may be useful in the development of potential anti-influenza agents derived from common foods. PMID- 25294224 TI - A Review of the Construct of Demoralization: History, Definitions, and Future Directions for Palliative Care. AB - Demoralization has been the subject of discussion in relation to end-of-life care. It is characterized by hopelessness and helplessness due to a loss of purpose and meaning. The purpose of this review was to consolidate the conceptual understanding of demoralization and argue for its existence as a psychiatric syndrome. The history of the construct is explored, including the nature of existential distress and related psychological conditions that precipitate demoralization. Recent definitions of demoralization are described and differentiated from similar constructs. Future directions are highlighted, specifically in relation to the assessment, diagnosis, and treatment of demoralization in palliative care. Overall, demoralization is a clinically useful construct for those facing existential threat, guiding the clinician toward efforts to restore morale, meaning, and purpose. PMID- 25294225 TI - Opioids, Exertion, and Dyspnea: A Review of the Evidence. AB - The aim of this paper is to review the evidence for a role for opioids as an intervention for exertion induced breathlessness with regard to exercise tolerance and breathlessness intensity. Current knowledge about exogenous opioids in exertion-induced breathlessness due to disease comes from a variety of phase 2 feasibility or pilot designs with differing duration, doses, drugs, exercise regimes, underlying aetiologies, and outcome measures. They provide interesting data but firm conclusions for either breathlessness severity or exercise endurance cannot be drawn. There are no adequately powered phase 3 trials of opioids which show improved exercise tolerance and/or exertion induced breathlessness. Low dose oral morphine seems well tolerated by most, and is beneficial for breathlessness intensity. Current work to investigate the effect on exercise tolerance is ongoing. PMID- 25294226 TI - Evaluation of Hospital-Based Palliative Care Programs. AB - This study evaluated current hospital-based palliative care programs using recommendations from the Center to Advance Palliative Care (CAPC) as a framework. Seven hospitals located in Buffalo, New York were included based on the existence of a hospital-based palliative care program. Data was collected from August through October of 2013 by means of key informant interviews with nine staff members from these hospitals using a guide comprised of questions based on CAPC's recommendations. A gap analysis was conducted to analyze the current state of each hospital's program based upon CAPC's definition of a quality palliative care program. The findings identify challenges facing both existing/evolving palliative care programs, and establish a foundation for strategies to attain best practices not yet implemented. This study affirms the growing availability of palliative care services among these selected hospitals along with opportunities to improve the scope of services in line with national recommendations. PMID- 25294227 TI - Symptom Prevalence, Symptom Severity, and Health-Related Quality of Life Among Young, Middle, and Older Adults With Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic, life threatening illness that affects primarily women. The purpose of this study was to describe the prevalence of PAH symptoms and to determine whether there are differences in symptom severity and HRQOL in PAH symptoms among young, middle, and older adults with PAH. A cross sectional design was utilized. For all the age groups, shortness of breath (SOB) on exertion and fatigue were the two most prevalent symptoms. SOB on exertion had the highest symptom severity scores followed by fatigue for all groups. Symptom severity was significantly different among the groups for palpitations, abdominal swelling and nausea. For components of HRQOL, physical functioning worsened with age. All groups had diminished general health, role physical and vitality levels. There are some differences in symptom prevalence, symptom severity and HRQOL among young, middle and older adults. Awareness of these differences is important for healthcare providers to know and assess overtime. Palliative care should be an integral part of caring for patients with PAH. PMID- 25294228 TI - Retraction: Physiological basis and image processing in functional magnetic resonance imaging: neuronal and motor activity in brain. AB - This article has been retracted by the publisher because of significant overlap with figures from previously published work without appropriate attribution or permissions. We were unable to contact the authors of the article, despite our best efforts. We apologise to all affected parties for the inconvenience caused. PMID- 25294229 TI - [Surgical therapy of lung metastases from head and neck cancer]. AB - Pulmonary metastasectomy is an established procedure in oncological therapeutic concepts. A systematic literature search and an analysis of all studies published since 01.01.2000 should evaluate the advantage of pulmonary metastasectomy for patients with primary head and neck cancer. Lung metastases develop in 1.9-13% of head and neck cancer patients. Following metastasectomy, patients reach a median survival of 9.5-78 months and 5-year survival rates of up to 58% are achieved. Intrathoracic recurrence occurs in 18.4-81.8% of patients, selected instances of which can be successfully treated by remetastasectomy. Patients with squamous cell carcinoma have the worst prognosis, but could also become long-term survivors (>= 60 months). Pulmonary metastasectomy is frequently the only potentially curative therapeutic approach and offers a better long-term survival than nonsurgical therapies. Lung metastasectomy is thus the treatment of choice in selected patients with pulmonary metastases from primary head and neck cancer. PMID- 25294230 TI - Mental health disorders in young urban sexual minority men. AB - PURPOSE: Very few studies have examined mental disorders among male sexual minority youth. We describe demographic correlates, comorbidity, and history of mental disorders and suicidality in a large sample of male sexual minority youth. METHODS: Structured diagnostic interviews were conducted with 449 racially diverse urban sexual minority males, aged 16-20 years, who were recruited using a social network-driven sampling methodology. RESULTS: Lifetime major depressive episode (MDE) affected 33.2% of the youth. Lifetime conduct disorder (23.6%), alcohol abuse/dependence (19.6%), posttraumatic stress disorder (PTSD; 16.0%), and nicotine dependence (10.7%) were also common. Black participants were less likely than white participants to be diagnosed with lifetime MDE, alcohol abuse/dependence, nicotine dependence, suicidal ideation, and anorexia, as well as past 12-month alcohol abuse/dependence (odds ratios [ORs] range from .08 to .46). Relative to participants identifying as gay, bisexual identified youth were at higher risk for lifetime PTSD (OR = 2.04), and participants who did not identify as gay or bisexual were at higher risk for both lifetime and past 12 month nicotine dependence (OR = 4.36 and 3.46, respectively). Most participants with mental disorders never received treatment, and comorbidity was common. CONCLUSIONS: MDE, conduct disorder, alcohol abuse/dependence, PTSD, and nicotine dependence are common and infrequently treated in young sexual minority men. Some within-group disparities emerged, suggesting that factors related to racial background and self-identification may help to understand resilience to the unique stressors experienced by these young men. PMID- 25294231 TI - Mediation analysis of aortic stiffness and renal microvascular function. AB - Aortic stiffening, assessed by carotid-femoral pulse wave velocity, is associated with CKD. Transmission of excessive flow pulsatility into the low-impedance renal microvasculature may mediate this association. However, direct analyses of macrovascular-microvascular relations in the kidney are limited. Using arterial tonometry, iohexol clearance, and magnetic resonance imaging, we related arterial stiffness, GFR, urinary albumin excretion, and potential mediators, including renal artery pulsatility index, renal vascular resistance, and arterial volume in the cortex, in 367 older adults (ages 72-92 years) participating in the Age, Gene/Environment Susceptibility-Reykjavik Study. In a model adjusted for age, sex, heart rate, and body size, aortic stiffness was related to GFR (Slope of regression B=-2.28+/-0.85 ml/min per SD, P=0.008) but not urine albumin (P=0.09). After accounting for pulsatility index, the relation between aortic stiffness and GFR was no longer significant (P=0.10). Mediation analysis showed that 34% of the relation between aortic stiffness and GFR was mediated by pulsatility index (95% confidence interval of indirect effect, -1.35 to -0.29). An additional 20% or 36% of the relation was mediated by lower arterial volume in the cortex or higher renal vascular resistance, respectively, when offered as mediators downstream from higher pulsatility index (95% confidence interval of indirect effect including arterial volume in the cortex, -2.22 to -0.40; 95% confidence interval of indirect effect including renal vascular resistance, -2.51 to -0.76). These analyses provide the first evidence that aortic stiffness may contribute to lower GFR by transferring excessive flow pulsatility into the susceptible renal microvasculature, leading to dynamic constriction or vessel loss. PMID- 25294232 TI - Role of the vascular wall in sodium homeostasis and salt sensitivity. AB - Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume. PMID- 25294234 TI - Cystatin C-based estimated glomerular filtration rate and periodontitis. AB - BACKGROUND AND OBJECTIVE: Accumulating evidence suggests that decreased kidney function characterised by low estimated glomerular filtration rate (eGFR) may be associated with periodontitis. Recent studies have suggested that the use of cystatin C strengthens the association between the eGFR and the risks of adverse outcomes in decreased kidney function. The aim of this cross-sectional study was to investigate the association of cystatin C-based eGFR (eGFRcys) and creatinine based eGFR (eGFRcreat), the commonly used method to assess kidney function, with periodontitis in 502 Japanese women (average age, 68.6 years). MATERIALS AND METHODS: GFR was estimated from serum cystatin C and serum creatinine, respectively, using the Japanese equation for GFR. Participants were classified into five groups according to their eGFRcys and eGFRcreat values. Poisson regression models with robust error variance assessed the associations of eGFRcys and eGFRcreat with periodontitis. Tests for trends were performed by fitting the five-category eGFR variables in their continuous form to the regression models. RESULTS: Participants with eGFRcys < 50 ml/min/1.73 m(2) were at significantly higher risk of periodontitis compared with the reference group (>=90 ml/min/1.73 m(2) ) (adjusted relative risk = 2.12, 95% confidence interval = 1.12 to 4.02). Additionally, there was a trend towards a higher risk of periodontitis among participants with lower eGFRcys values (p for trend in the multivariable model = 0.008). In contrast, eGFRcreat did not show a significant association with periodontitis. CONCLUSION: The findings of this study of Japanese older women showed that eGFRcys had a stronger and more linear association with periodontitis than eGFRcreat. PMID- 25294233 TI - Reduction in maternal circulating ouabain impairs offspring growth and kidney development. AB - Ouabain, a steroid present in the circulation and in various tissues, was shown to affect the growth and viability of various cells in culture. To test for the possible influence of this steroid on growth and viability in vivo, we investigated the involvement of maternal circulating ouabain in the regulation of fetal growth and organ development. We show that intraperitoneal administration of anti-ouabain antibodies to pregnant mice resulted in a >80% decline in the circulating ouabain level. This reduction caused a significant decrease in offspring body weight, accompanied by enlargement of the offspring heart and inhibition of kidney and liver growth. Kidney growth inhibition was manifested by a decrease in the size and number of nephrons. After the reduction in maternal circulating ouabain, kidney expression of cyclin D1 was reduced and the expression of the alpha1 isoform of the Na(+), K(+)-ATPase was increased. In addition, the elevation of proliferation signals including ERK1/2, p-90RSK, Akt, PCNA, and Ki-67, and a reduction in apoptotic factors such as Bax, caspase-3, and TUNEL were detected. During human pregnancy, the circulating maternal ouabain level increased and the highest concentration of the steroid was found in the placenta. Furthermore, circulating ouabain levels in women with small-for gestational age neonates were significantly lower than the levels in women with normal-for-gestational age newborns. These results support the notion that ouabain is a growth factor and suggest that a reduction in the concentration of this hormone during pregnancy may increase the risk of impaired growth and kidney development. PMID- 25294235 TI - Impact of intraoperatively salvaged and washed blood on stimulated cytokine release in vitro. AB - BACKGROUND: Intraoperative blood salvage and processing it with commercially available devices is a widespread standard procedure to reduce allogeneic blood transfusion in patients undergoing major orthopedic surgery. The aim of this study was to investigate the impact of such processed blood on the immune system by measuring pro- and anti-inflammatory cytokines. STUDY DESIGN AND METHODS: Salvaged blood from 20 patients undergoing hip arthroplasty was processed with a continuous autotransfusion system. One part of the processed blood was left without further treatment, one part was additionally leukoreduced, one part was irradiated, and one part was separated into its cellular and soluble fraction by centrifugation. Specimens from each part were mixed in vitro with venous blood from the patient in ratios of 3:1, 1:1, and 1:3 and incubated with endotoxin for 24 hours. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were measured in cell culture supernatants by enzyme-linked immunosorbent assay. RESULTS: All parts of the salvaged blood were without a significant influence on TNF-alpha release. In contrast, IL-10 was significantly increased, independently of the admixtured salvaged blood being plain, additionally irradiated, or additionally leukoreduced. This IL-10 increase was also found with the cellular fraction of the plain salvaged blood, whereas the soluble fraction had no influence on IL-10 release. CONCLUSION: Intraoperative salvaged blood is not immunologically inert. We observed a significant increase in the anti-inflammatory IL-10 response without affecting the proinflammatory TNF-alpha release. Neither leukofiltration nor gamma irradiation eliminated this effect that was limited only to the cellular fraction of the salvaged blood, suggesting red blood cells to be responsible for the observed immunomodulation. PMID- 25294238 TI - Pronounced chemical response of Subarctic lakes to climate-driven losses in surface area. AB - Losses in lake area have been observed for several Arctic and Subarctic regions in recent decades, with unknown consequences for lake ecosystems. These reductions are primarily attributed to two climate-sensitive mechanisms, both of which may also cause changes in water chemistry: (i) increased imbalance of evaporation relative to inflow, whereby increased evaporation and decreased inflow act to concentrate solutes into smaller volumes; and (ii) accelerated permafrost degradation, which enhances sublacustrine drainage while simultaneously leaching previously frozen solutes into lakes. We documented changes in nutrients [total nitrogen (TN), total phosphorus (TP)] and ions (calcium, chloride, magnesium, sodium) over a 25 year interval in shrinking, stable, and expanding Subarctic lakes of the Yukon Flats, Alaska. Concentrations of all six solutes increased in shrinking lakes from 1985-1989 to 2010-2012, while simultaneously undergoing little change in stable or expanding lakes. This created a present-day pattern, much weaker or absent in the 1980s, in which shrinking lakes had higher solute concentrations than their stable or expanding counterparts. An imbalanced evaporation-to-inflow ratio (E/I) was the most likely mechanism behind such changes; all four ions, which behave semiconservatively and are prone to evapoconcentration, increased in shrinking lakes and, along with TN and TP, were positively related to isotopically derived E/I estimates. Moreover, the most conservative ion, chloride, increased >500% in shrinking lakes. Conversely, only TP concentration was related to probability of permafrost presence, being highest at intermediate probabilities. Overall, the substantial increases of nutrients (TN >200%, TP >100%) and ions (>100%) may shift shrinking lakes towards overly eutrophic or saline states, with potentially severe consequences for ecosystems of northern lakes. PMID- 25294240 TI - Pathological consequences of systemic measles virus infection. AB - The identification of poliovirus receptor-like 4 (PVRL4) as the second natural receptor for measles virus (MV) has closed a major gap in our understanding of measles pathogenesis, and explains how this predominantly lymphotropic virus breaks through epithelial barriers to transmit to a susceptible host. Advances in the development of wild-type, recombinant MVs which express fluorescent proteins making infected cells readily detectable in living tissues and animals, has also increased our understanding of this important and highly transmissible human disease. Thus, it is timely to review how these advances have provided new insights into MV infection of immune, epithelial and neural cells. This demands access to primate samples that help us understand the early and acute stages of the disease, which are challenging to dissect due to the mild/self-limiting nature of the infection. It also requires well-characterized and rather rare human tissue samples from patients who succumb to neurological sequelae to help study the consequences of the long-term persistence of this RNA virus in vivo. Collectively, these studies have provided unique insights into how the use of two cellular receptors, CD150 and PVRL4, governs the in vivo tissue-specific temporal patterns of virus spread and resulting pathological lesions. Analysis of tissue samples has also demonstrated the importance of differing mechanisms of virus cell-to-cell spread within lymphoid, epithelial and neural tissues in the dissemination of MV during acute and long-term persistent infections. Given the incentive to eradicate MV globally, and the inevitable question as to whether or not vaccination should cease in light of the existence of closely related morbilliviruses, a thorough understanding of measles pathological lesions is essential. PMID- 25294241 TI - NHS is close to "buckling," doctors' leaders warn politicians. PMID- 25294242 TI - A heparin-mimicking reverse thermal gel for controlled delivery of positively charged proteins. AB - Positively charged therapeutic proteins have been used extensively for biomedical applications. However, the safety and efficacy of proteins are mostly limited by their physical and chemical instability and short half-lives in physiological conditions. To this end, we created a heparin-mimicking sulfonated reverse thermal gel as a novel protein delivery system by sulfonation of a graft copolymer, poly(serinol hexamethylene urea)-co-poly(N-isopropylacylamide), or PSHU-NIPAAm. The net charge of the sulfonated PSHU-NIPAAm was negative due to the presence of sulfonate groups. The sulfonated PSHU-NIPAAm showed a typical temperature-dependent sol-gel phase transition, where polymer solutions turned to a physical gel at around 32 degrees C and maintained gel status at body temperature. Both in vitro cytotoxicity tests using C2C12 myoblast cells and in vivo cytotoxicity tests by subcutaneous injections demonstrated excellent biocompatibility. In vitro release tests using bovine serum albumin revealed that the release from the sulfonated PSHU-NIPAAm was more sustained than that from the plain PSHU-NIPAAm. Furthermore, this sulfonated PSHU-NIPAAm system did not affect protein structure after 70-day observation periods. PMID- 25294243 TI - Cyclooxygenase-2 regulates NLRP3 inflammasome-derived IL-1beta production. AB - The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a reactive oxygen species-sensitive multiprotein complex that regulates IL-1beta maturation via caspase-1. It also plays an important role in the pathogenesis of inflammation-related disease. Cyclooxygenase-2 (COX-2) is induced by inflammatory stimuli and contributes to the pathogenesis of inflammation-related diseases. However, there is currently little known about the relationship between COX-2 and the NLRP3 inflammasome. Here, we describe a novel role for COX-2 in regulating the activation of the NLRP3 inflammasome. NLRP3 inflammasome-derived IL-1beta secretion and pyroptosis in macrophages were reduced by pharmaceutical inhibition or genetic knockdown of COX-2. COX-2 catalyzes the synthesis of prostaglandin E2 and increases IL-1beta secretion. Conversely, pharmaceutical inhibition or genetic knockdown of prostaglandin E2 receptor 3 reduced IL-1beta secretion. The underlying mechanisms for the COX-2-mediated increase in NLRP3 inflammasome activation were determined to be the following: (1) enhancement of lipopolysaccharide-induced proIL-1beta and NLRP3 expression by increasing NF kappaB activation and (2) enhancement of the caspase-1 activation by increasing damaged mitochondria, mitochondrial reactive oxygen species production and release of mitochondrial DNA into cytosol. Furthermore, inhibition of COX-2 in mice in vivo with celecoxib reduced serum levels of IL-1beta and caspase-1 activity in the spleen and liver in response to lipopolysaccharide (LPS) challenge. These findings provide new insights into how COX-2 regulates the activation of the NLRP3 inflammasome and suggest that it may be a new potential therapeutic target in NLRP3 inflammasome-related diseases. PMID- 25294245 TI - Molecular dissection of the genetic mechanisms that underlie expression conservation in orthologous yeast ribosomal promoters. AB - Recent studies have shown a surprising phenomenon, whereby orthologous regulatory regions from different species drive similar expression levels despite being highly diverged in sequence. Here, we investigated this phenomenon by genomically integrating hundreds of ribosomal protein (RP) promoters from nine different yeast species into S. cerevisiae and accurately measuring their activity. We found that orthologous RP promoters have extreme expression conservation even across evolutionarily distinct yeast species. Notably, our measurements reveal two distinct mechanisms that underlie this conservation and which act in different regions of the promoter. In the core promoter region, we found compensatory changes, whereby effects of sequence variations in one part of the core promoter were reversed by variations in another part. In contrast, we observed robustness in Rap1 transcription factor binding sites, whereby significant sequence variations had little effect on promoter activity. Finally, cases in which orthologous promoter activities were not conserved could largely be explained by the sequence variation within the core promoter. Together, our results provide novel insights into the mechanisms by which expression is conserved throughout evolution across diverged promoter sequences. PMID- 25294244 TI - Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal. AB - The gene regulatory network (GRN) that supports neural stem cell (NS cell) self renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence. PMID- 25294247 TI - Weight bias in 2001 versus 2013: contradictory attitudes among obesity researchers and health professionals. AB - OBJECTIVES: To assess levels of two types of anti-fat bias in obesity specialists, explicit bias, or consciously accessible anti-fat attitudes, and implicit bias, or attitudes that are activated outside of conscious awareness, were examined. This study also assessed changes over time by comparing levels of bias in 2013 to published data from 2001. METHODS: In 232 attendees at the ObesityWeek 2013 conference, we measured explicit anti-fat bias and conducted the Implicit Association Test. These data were compared to those from a study conducted at the 2001 meeting of this group. RESULTS: Participants exhibited significant implicit and explicit anti-fat/pro-thin bias. Positivity of professional experience with obesity, but not type of professional experience, was correlated with lower explicit anti-fat bias. Compared to 2001, the 2013 sample had lower levels of implicit bias and higher levels of explicit bias. CONCLUSIONS: Although implicit anti-fat attitudes appeared to decrease from 2001 to 2013, explicit anti-fat attitudes increased. Future research should examine whether increasing positive experiences with obese patients reduces anti-fat bias among health professionals. Together, these results suggest that despite the current climate of widespread anti-fat bias, there are pathways toward understanding and ameliorating this bias. PMID- 25294246 TI - Accounting for biases in riboprofiling data indicates a major role for proline in stalling translation. AB - The recent advent of ribosome profiling-sequencing of short ribosome-bound fragments of mRNA-has offered an unprecedented opportunity to interrogate the sequence features responsible for modulating translational rates. Nevertheless, numerous analyses of the first riboprofiling data set have produced equivocal and often incompatible results. Here we analyze three independent yeast riboprofiling data sets, including two with much higher coverage than previously available, and find that all three show substantial technical sequence biases that confound interpretations of ribosomal occupancy. After accounting for these biases, we find no effect of previously implicated factors on ribosomal pausing. Rather, we find that incorporation of proline, whose unique side-chain stalls peptide synthesis in vitro, also slows the ribosome in vivo. We also reanalyze a method that implicated positively charged amino acids as the major determinant of ribosomal stalling and demonstrate that it produces false signals of stalling in low-coverage data. Our results suggest that any analysis of riboprofiling data should account for sequencing biases and sparse coverage. To this end, we establish a robust methodology that enables analysis of ribosome profiling data without prior assumptions regarding which positions spanned by the ribosome cause stalling. PMID- 25294248 TI - Learning physics of living systems from Dictyostelium. AB - Unlike a new generation of scientists that are being trained directly to work on the physics of living systems, most of us more senior members of the community had to find our way from other research areas. We all have our own stories as to how we made this transition. Here, I describe how a chance encounter with the eukaryotic microorganism Dictyostelium discoideum led to a decades-long research project and taught me valuable lessons about how physics and biology can be mutually supportive disciplines. PMID- 25294249 TI - Isotretinoin-induced arthritis mimicking both rheumatoid arthritis and axial spondyloarthritis. AB - Isotretinoin is used for the treatment of various acne lesions that are resistant to other treatments. The most frequent rheumatologic side effect of isotretinoin is transient muscle and/or joint pains. Here, we report a case with bilateral wrist and metacarpophalangeal joint arthritis and unilateral sacroiliitis associated with isotretinoin usage to attract attention, particularly from physiatrists, rheumatologists and dermatologists, to this rare adverse effect of isotretinoin. PMID- 25294250 TI - Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study. AB - BACKGROUND: Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment. METHODS: In a randomized, double blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7 10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48-72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7-14 days after end of treatment; and (3) >=20% reduction in lesion area at 48-72 hours. RESULTS: A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], -7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, -2.6 to 7.0), and proportion of patients attaining >=20% reduction in lesion area (85.9% vs 85.3%; 95% CI, -3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups. CONCLUSIONS: A single 1200-mg dose of oritavancin was noninferior to 7-10 days of vancomycin in treating ABSSSIs caused by gram positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs. Clinical Trials Registration. NCT01252732. PMID- 25294251 TI - Comparison of cross sectional area and fat infiltration of the epaxial muscles in dogs with and without spinal cord compression. AB - This study investigated the cross sectional area (CSA) and fat infiltration of the epaxial muscles in Dachshunds with compressive spinal cord lesions due to intervertebral disc herniation (IVDH) and in dogs with non-compressive spinal cord lesions with fibrocartilaginous embolism (FCE). The CSA and fat infiltration of the multifidi and longissimus dorsi muscles were determined from T1 weighted magnetic resonance images. Difference in CSA and fat infiltration between the lesion- and non-lesion side in the Dachshunds was assessed using mixed model analysis. Difference in CSA and fat infiltration between Dachshunds and FCE dogs was analysed with independent sample t-tests. There was no difference in CSA or fat infiltration between sides in the Dachshunds. FCE dogs had greater CSA (multifidus P = 0.036, longissimus P < 0.001) and less fat infiltration compared to Dachshunds (longissimus P = 0.017). Duration of neurological deficits, age, body size and conformation are likely to have influenced the difference between the groups. PMID- 25294252 TI - CD44 deficiency leads to decreased proinflammatory cytokine production in lung induced by PCV2 in mice. AB - Porcine circovirus type 2 (PCV2) is the primary etiological agent of postweaning multisystemic wasting syndrome (PMWS). CD44 is a widely expressed class I transmembrane glycoprotein implicated in immunological and inflammatory responses. In previous studies, the role of CD44 in host defense against microorganism infection remains controversial. The role of CD44 in host defense against PCV2 infection has never been studied before. In this study, we investigated the role of CD44 in the development of pneumonia induced by PCV2 in mice model. Upon infection, CD44 mRNA level in lung tissue was upregulated, and we confirmed a detrimental role of CD44 in host defense against PCV2 infection. The results demonstrated that CD44 deficiency could result in decreased proinflammatory cytokine production in lung induced by PCV2 in mice, suggesting a previously unrecognized role for CD44 in the development of pneumonia response to PCV2 infection. PMID- 25294255 TI - Self-assembly behavior of hairy colloidal particles with different architectures: mixed versus janus. AB - In this paper, we investigated the aggregation and assembly behavior of hairy core-shell particles with different architectures consisting of a hard silica core and soft polymer brush shells. We varied the nature of the polymers which form the shell: we used different hydrophilic positively (poly(2 (dimethylamino)ethyl methacrylate), PDMAEMA) and negatively (poly(acrylic acid), PAA) charged polymers, uncharged hydrophilic (polyethylene glycol, PEG) polymers, and hydrophobic (poly(lauryl methacrylate), PLMA; polystyrene, PS) polymers. We synthesized particles covered by polymer of one sort (homogeneously coated particles) as well as Janus particles (two polymers are grafted to the opposite sides of the core) and investigated/compared the aggregation behavior of different fully covered particles, their mixtures, and Janus particles. PMID- 25294253 TI - Non-natural olefin cyclopropanation catalyzed by diverse cytochrome P450s and other hemoproteins. AB - Recent work has shown that engineered variants of cytochrome P450BM3 (CYP102A1) efficiently catalyze non-natural reactions, including carbene and nitrene transfer reactions. Given the broad substrate range of natural P450 enzymes, we set out to explore if this diversity could be leveraged to generate a broad panel of new catalysts for olefin cyclopropanation (i.e., carbene transfer). Here, we took a step towards this goal by characterizing the carbene transfer activities of four new wild-type P450s that have different native substrates. All four were active and exhibited a range of product selectivities in the model reaction: cyclopropanation of styrene by using ethyl diazoacetate (EDA). Previous work on P450BM3 demonstrated that mutation of the axial coordinating cysteine, universally conserved among P450 enzymes, to a serine residue, increased activity for this non-natural reaction. The equivalent mutation in the selected P450s was found to activate carbene transfer chemistry both in vitro and in vivo. Furthermore, serum albumins complexed with hemin were also found to be efficient in vitro cyclopropanation catalysts. PMID- 25294254 TI - Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice. AB - There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2-32,400 ng/mL in plasma, 16.2 6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4-6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from -8.50 to 13.92%. The relative recoveries were 85.6-113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141. PMID- 25294256 TI - Salutogenic Education? Movement and Whole Child Health in a Waldorf (Steiner) School. AB - Waldorf education, an independent alternative to public schooling, aims to produce holistically healthy graduates in a formulation that rejects the conventional distinction between education and health. Also striving to bridge that divide, this article characterizes the pedagogically salutogenic techniques Waldorf teachers use in pre-kindergarten (pre-K) and lower grade classes and explicates the ethnomedical understandings underlying them. Waldorf teachers position children as budding participants in a unified field of spiritual and other forces, prioritizing whole-child activities that keep these forces healthfully motile. Their work entails a critique not only of mainstream public schooling's ostensibly pathogenic "head-to-head" focus, but also of the biomedical approach to pediatric health. My analysis of this conjoined critique takes into account the cultural, structural, and existential realities within which Waldorf education's salutary pedagogy is daily framed and fabricated. Further, it explores the implications for anthropology of attending to movement as a key feature of healthful human experience. PMID- 25294257 TI - Diverse strategies conferring extreme cadmium (Cd) tolerance in the dark septate endophyte (DSE), Exophiala pisciphila: evidence from RNA-seq data. AB - Dark septate endophytes (DSE) ubiquitously colonize the roots of plants growing in extreme heavy metals (HMs)-contaminated soils. Little is known about the overall molecular response of DSE to excessive HMs. Therefore, RNA-seq was performed through Illumina Hiseq 2000 sequencing based on two cDNA libraries of the DSE strain Exophiala pisciphila, cultured under cadmium (Cd)-free and Cd stressed conditions, and 21,376 unigenes were generated. In total, 575 differentially expressed genes (DEGs) were obtained. Approximately 40% of the DEGs (228 unigenes) were involved in 10 well-known HMs-tolerant pathways, conferring the extreme cadmium (Cd) tolerance of E. pisciphila, including metal ion binding and transportation, organic acid metabolism and transportation, reactive oxygen species (ROS) scavenging, redox homeostasis, transcription factors production, sulfate assimilation, DNA repair and cell wall integrity maintenance, etc. Our results indicate that integral tactics associated with the collaboration of extracellular and intracellular mechanisms contribute to the enhanced HMs tolerance of this fungus. This study represents the first investigation of the transcriptome of DSE under Cd stress, and our results provide valuable information for future molecular studies of HMs tolerance in fungi. PMID- 25294258 TI - Pudendal nerve block for vaginal birth. AB - Pudendal nerve block is a safe and effective pain relief method for vaginal birth. Providing analgesia to the vulva and anus, it is used for operative vaginal birth and subsequent repair, late second stage pain relief with spontaneous vaginal birth, repair of complex lacerations, or repair of lacerations in women who are unable to achieve adequate or satisfactory pain relief during perineal repair with local anesthesia. Key to its efficacy is the knowledge of pudendal nerve anatomy, the optimal point of infiltration of local anesthetic, and an understanding of the amount of time necessary to effect adequate analgesia. PMID- 25294260 TI - [In Process Citation]. PMID- 25294259 TI - Antimicrobial peptide CRAMP (16-33) stalls bacterial cytokinesis by inhibiting FtsZ assembly. AB - A cathelin-related antimicrobial peptide (CRAMP) of 37 amino acid residues is thought to regulate innate immunity and provide a host defense mechanism in mammals. Here, a part of the CRAMP peptide, CRAMP (16-33) (GEKLKKIGQKIKNFFQKL), was found to bind to FtsZ and to inhibit the assembly and GTPase activity of FtsZ in vitro. A computational analysis indicated that CRAMP (16-33) binds in the cavity of the T7 loop of FtsZ. Both hydrophobic and ionic interactions were involved in the binding interactions. Further, CRAMP (16-33) inhibited the formation of the FtsZ ring in bacteria, indicating that it inhibited bacterial cell division by inhibiting FtsZ assembly. PMID- 25294261 TI - [Motility and functional gastrointestinal disorders]. AB - This article discusses the studies on functional and motor gastrointestinal disorders presented at the 2014 Digestive Diseases Week conference that are of greatest interest to us. New data have been provided on the clinical importance of functional gastrointestinal disorders, with recent prevalence data for irritable bowel syndrome and fecal incontinence. We know more about the pathophysiological mechanisms of the various functional disorders, especially irritable bowel syndrome, which has had the largest number of studies. Thus, we have gained new data on microinflammation, genetics, microbiota, psychological aspects, etc. Symptoms such as abdominal distension have gained interest in the scientific community, both in terms of patients with irritable bowel syndrome and those with constipation. From the diagnostic point of view, the search continues for a biomarker for functional gastrointestinal disorders, especially for irritable bowel syndrome. In the therapeutic area, the importance of diet for these patients (FODMAP, fructans, etc.) is once again confirmed, and data is provided that backs the efficacy of already marketed drugs such as linaclotide, which rule out the use of other drugs such as mesalazine for patients with irritable bowel syndrome. This year, new forms of drug administration have been presented, including metoclopramide nasal sprays and granisetron transdermal patches for patients with gastroparesis. Lastly, a curiosity that caught our attention was the use of a vibrating capsule to stimulate gastrointestinal transit in patients with constipation. PMID- 25294262 TI - [Developments in the treatment of inflammatory bowel disease: 2014 overview]. AB - The way we treat inflammatory bowel disease is rapidly changing. Biologics have accounted for the biggest change in recent years, and they are being used on a more regular basis, on more indications and at earlier stages. However, primary response failure and, above all, secondary response failure and cost represent serious limitations for their use. Combination immunosuppressant therapy, individualization depending on levels and response, increasing compliance and a more suitable choice of cases can all enhance effectiveness. However in many cases, new alternatives will be necessary. Recently, 2 new antibodies have been approved: golimumab is a new option for ulcerative colitis and with another more selective mechanism of action; vedolizumab could be useful for ulcerative colitis as well as Crohn's disease. Ustekinumab is an alternative treatment option for refractory Crohn's disease. In addition to biologics, autologous bone marrow transplants and, anecdotally, the use of immunoglobulins have been suggested as alternatives in some carefully selected cases. Although effective for Clostridium difficile infection, the potential role of fecal transplants in inflammatory bowel disease is still to be determined, without initially observing very promising results. The use of probiotics has not produced significant positive results. PMID- 25294263 TI - [What useful developments for my inflammatory bowel disease practice have come from Digestive Disease Week 2014?]. AB - The objective of this article is to summarize reports presented at Digestive Disease Week 2014 that relate to fertility and pregnancy, inflammatory bowel disease in elderly patients, the risk of cancer and its relationship to treatment and finally, developments regarding psychological aspects that may affect patients with inflammatory bowel disease. Studies were selected at the discretion of the author, mainly considering those with conclusions that can be applied immediately to clinical practice. Using anti-TNF drugs during pregnancy is safe in the short term. This currently seems to be true for the medium and the long term. To limit fetal exposure, the mother can safely stop taking the anti-TNF drugs in the second trimester of the pregnancy if she is in remission. Elderly patients with inflammatory bowel disease require stricter monitoring than younger patients due to the risk of complications, especially infections associated with the disease and treatments. The effect of inflammatory bowel disease and the drugs for its treatment on the risk of development is still not well established, but the magnitude of the effect seems possibly lower than previously described. The causal link between psychological factors and the occurrence of IBD relapse is by no means established. PMID- 25294264 TI - [Follow-up of patients with inflammatory bowel disease: developments presented at Digestive Disease Week 2014]. AB - A lot of data were reported about monitoring patients with inflammatory bowel disease, with varying degrees of practical applicability. Concerning the evaluation of disease activity, it was established that objective assessments are needed. Among the techniques that we use, although endoscopy is undoubtedly the reference standard, a lot of data were presented regarding less invasive techniques. The importance of MRIs, CTs and ultrasounds (with some variations) was thus reiterated. The importance of fecal calprotectin is also reiterated, not only for colon disease, but probably small intestine disease as well. Regarding treatment monitoring, a great deal was reported about anti-TNF therapy, demonstrating again its potential role when properly used. In addition to results with infliximab, results with adalimumab were reported as very consistent. For colon cancer prevention, it seems that the clinical guidelines are achieving their objective. It also seems clear that we must improve conventional endoscopic techniques. Finally, there are other aspects that need to be considered when monitoring our patients, such as adequate sleeping patterns, anxiety or depression. PMID- 25294265 TI - [Diseases linked to Helicobacter pylori infection]. AB - Below is a summary of the main conclusions that came from reports presented at this year's Digestive Disease Week (2014) relating to Helicobacter pylori infection. Despite the undeniable decline of the infection's frequency, in the near future, developed countries--or at least some sub-populations--will continue to have a significant prevalence of the infection. Clarithromycin, metronidazole and quinolone resistance rates are considerably high in most countries and these rates are on the rise. The eradication of H. pylori improves symptoms of functional dyspepsia, although only in a minority of patients; adding antidepressants to eradication therapy could improve long-term response. In patients who were admitted with gastrointestinal bleeding from peptic ulcers, it is necessary to thoroughly study the presence of H. pylori infection and administer eradication therapy as early as possible. Eradication of H. pylori in patients undergoing endoscopic resection of early-stage gastric cancer reduces incidence of metachronous tumors. We have some diagnostic innovations, such as carrying out various techniques--a rapid urease test, culture or PCR--based on gastric samples obtained by scraping the mucosa. The effectiveness of conventional triple therapy is clearly insufficient and continues to decline. The superiority of sequential therapy over conventional triple therapies has not been definitively established. Concomitant therapy is simpler and more effective than sequential therapy. Optimized concomitant therapy (with high doses of proton-pump inhibitors [PPI] and over 14 days) is highly effective, more so than standard concomitant therapy. For patients who are allergic to penicillin, 2 treatment options were essentially described: PPI-clarithromycin-metronidazole (clarithromycin-sensitive strains) and quadruple therapy with bismuth (when the bacterial sensitivity is unknown). If conventional triple therapy fails, second line therapy with levofloxacin is effective and is also easier and better tolerated than quadruple therapy with bismuth. Triple therapy with levofloxacin is also a promising alternative if sequential or concomitant therapy fails. New generation quinolones, such as moxifloxacin, could be useful as part of rescue eradication therapy. Even after 3 eradication therapies have failed, a fourth empirical rescue therapy (with rifabutin) could be effective. The eradication of H. pylori can finally be obtained in the vast majority of patients by using a rescue strategy of up to 4 consecutive empirical therapies, without conducting bacterial cultures. PMID- 25294266 TI - [Esophageal diseases: GERD, Barrett, achalasia and eosinophilic esophagitis]. AB - At Digestive Disease Week (DDW) 2014, developments in esophageal disease were presented. Highlights include: the usefulness of impedancemetry to diagnose reflux disease, or the effectiveness of PPIs for treating non-cardiac chest pain. Concerning Barrett's esophagus, its prevalence is identical in patients with and without reflux symptoms, Barrett segments less than 1cm probably do not require follow-up, and in older patients with long-segment Barrett, initial endoscopies overlooked up to 2% of significant lesions. Regarding achalasia, surgical myotomy is no more effective than endoscopic dilation and may even be less effective than peroral endoscopic myotomy (POEM). In terms of eosinophilic esophagitis, it is important to systematically take biopsies in patients with dysphagia so that cases of eosinophilic esophagitis are not overlooked. In addition, for this condition, routine endoscopic dilations not only do not seem useful in improving the course of the disease, but could also worsen the response to medical treatment. PMID- 25294267 TI - [Gastrointestinal bleeding, NSAIDs, aspirin and anticoagulants]. AB - The studies presented at the recent American Congress of Gastroenterology in the field of non-variceal upper gastrointestinal bleeding (associated or not to NSAIDs or ASA use) have not been numerous but interesting. The key findings are: a) rabeprazole, the only PPI that had few studies in this field, is effective in the prevention of gastric ulcers; b) famotidine could also be effective in the prevention of complications by AAS; c) the new competitive inhibitors of the acid potassium pump are effective (as much as PPIs) on the recurrence of peptic ulcers by ASA; d) early endoscop (<8 h) in non-variceal upper gastrointestinal bleeding seems to offer no better results than those made in the first 24 h; e) endoscopic therapy in Forrest 1a ulcers does not obliterate the bleeding artery in 30% of cases and is the cause of bleeding recurrence; f) alternative therapies with glue or clotting products are being increasingly used in endoscopic therapy of gastrointestinal bleeding; g) liberal administration of blood in the GI bleeding is associated with poor prognosis; h) lesions of the small intestine are frequent cause of gastrointestinal bleeding when upper endoscopy shows no positive stigmata; and i) capsule endoscopy studies have high performance in gastrointestinal bleeding of obscure origin, if performed early in the first two days after the beginning of the bleeding episode. PMID- 25294268 TI - [The usefulness of fecal tests in colorectal cancer screening]. AB - Colorectal cancer is a paradigm of neoplasms that are amenable to preventative measures, especially screening. Currently, to carry this out, there are various strategies that have proven effective and efficient. In countries that have organized population-level screening programs, the most common strategy is fecal occult blood testing. In recent years, new methods have appeared that could constitute viable alternatives in the near future, among which the detection of changes in fecal DNA is emphasized. In this article, we review the most relevant papers on colorectal cancer screening presented at the annual meeting of the American Gastroenterological Association held in Chicago in May 2014, with special emphasis on the medium and long-term performance of strategies to detect occult blood in feces and the first results obtained with fecal DNA testing. PMID- 25294269 TI - [Hereditary and familial colorectal cancer]. AB - Up to 5% of all colorectal cancer cases are caused by a known hereditary syndrome. These hereditary types often need a higher degree of clinical suspicion to be diagnosed and require specific and specialized management. In addition, diagnosing hereditary colorectal cancer has significant consequences not only for the patient, for whom there are effective preventative measures, but also for their families, who could be carriers of the condition. The most significant advances in the field of colorectal cancer have come from the diagnosis and characterization of these syndromes. PMID- 25294270 TI - [Colonoscopies for colorectal cancer screening]. AB - Colonoscopies play a vital role in population screening programs, either for initial examinations or as a test carried out after a positive result from a fecal occult blood test or sigmoidoscopy. Colonoscopies, and ancillary techniques such as polipectomies, must comply with basic quality criteria that must be reflected in the quality standards of screening programs. A quality colonoscopy is absolutely vital to avoid the occurrence of interval cancers. It is extremely important to detect any proximal lesions during a colonoscopy, especially those which are serrated, because they are difficult to identify and due to the increased risk of colorectal cancer. Regarding follow-up programs for resected colorectal polyps, current evidence of the relationship between the risk of neoplasia and certain variables (age, sex, smoker, BMI, diabetes, etc.) must allow for individualized risk and algorithms for screening and follow-up frequency to be developed for these patients. However, initial endoscopic exploration in a screening colonoscopy is essential to establishing the optimum interval and ensuring follow-up. Despite poor adherence to follow-up programs, mostly due to their overuse, follow-up colonoscopies 3 years after resection of all polypoid lesions detect clinically significant lesions as effectively as colonoscopies at one year. PMID- 25294271 TI - [Latest advances in chronic pancreatitis]. AB - This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the prediction of the fibrosis degree of the gland, the evaluation of patients with asymptomatic hyperenzimemia, the medical and surgical treatment of abdominal pain and the knowledge of the natural history of the autoimmune pancreatitis. In patients with indetermined EUS findings of chronic pancreatitis, a new endoscopic ultrasound examination in the follow-up is of help to confirm or to exclude the disease. Smoking, number of relapses, results of pancreatic function tests and EUS findings allow predicting the degree of pancreatic fibrosis in patients with chronic pancreatitis. Antioxidant therapy has shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Development of intestinal bacterial overgrowth is frequent in patients with chronic pancreatitis, but its impact on symptoms is unknown and deserves further investigations. Finally, autoimmune pancreatitis relapses in about half of the patients with either type 1 or type 2 disease; relapses frequently occur within the first two years of follow-up. PMID- 25294272 TI - [Pancreatic tumors: recent developments]. AB - Pancreatic cancer (PC) still typically has a poor prognosis. In addition to smoking, obesity and new-onset diabetes mellitus are considered to be significant risk factors. An endoscopic ultrasound (EUS) remains the mainstay for diagnosis and on which the majority of advances are based. In this sense, needle-based confocal laser endomicroscopy (nCLE) is gaining importance in the differential diagnosis of solid pancreatic lesions and studies comparing different needle types (cytology vs. histology) for EUS-guided puncture. Intravenous contrast (IC EUS) and elastography are additional tools associated with EUS that can assist in diagnosing PC. Regarding prognostic factors, the importance of the role of mesenteric-portal vein resection was emphasized, given the limited advances in treatment, as in previous years. Regarding cystic tumors, work focuses on validating the new international guidelines from Fukuoka 2012 (revised Sendai criteria) and on determining predictors of cystic lesion malignancy, mainly of intraductal papillary mucinous neoplasm (IPMN). From a therapeutic point of view, there are theories regarding the usefulness of alcohol and the gemcitabine paclitaxel combination in the ablation of small mucinous cystic lesions through EUS-injection. PMID- 25294273 TI - [Pancreas and biliary tract: recent developments]. AB - Acute pancreatitis (AP) is a common disease that is associated with significant morbidity and considerable mortality. In this article, developments relating to this disease that were presented in DDW 2014 are reviewed. Pancreatic steatosis could be a cause of recurrent AP. Patients with DM have an increased incidence of AP and pancreatic cancer. The use of anti-TNF drugs in inflammatory bowel disease may protect against the occurrence of AP. The presence of pancreas divisum protects against acute biliary pancreatitis. The PANCODE system for describing local complications of AP has good interobserver agreement, when the new definitions of the revised Atlanta classification are applied. The use of prophylactic antibiotics in early-stage AP predisposes the development of intra abdominal fungal infections. Fluid sequestration in AP is linked with young age, alcoholism and indicators of systemic inflammatory response syndrome. The most common cause of mortality in AP is early onset of multiple organ failure, not pancreatic necrosis infection. Patients with AP and vitamin D deficiency could benefit from taking vitamin D supplements. Moderate fluid administration in emergencies (500-1000 mL) could be associated with better AP development. PMID- 25294274 TI - Extraction of incarcerated medial epicondyle from the elbow joint using conventional nerve stimulator: a case report. AB - INTRODUCTION: Incarceration of the medial epicondyle is a well-recognised sequelae following closed reduction of the elbow. Manipulation for extraction is not usually successful and hence an incarcerated medial epicondyle is usually an indication for open reduction and fixation. CASE PRESENTATION: We describe a simple technique of closed reduction using a conventional nerve stimulator to extract an incarcerated medial epicondyle in a 13-year-old Caucasian boy. This technique uses contraction of the attached common flexor muscles to indirectly extract the trapped medial epicondyle. CONCLUSIONS: This is a simple technique using a commonly available nerve stimulator and may obviate the need for extensile open reduction for extraction of the incarcerated medial epicondyle. We would recommend this technique where closed reduction methods have failed. PMID- 25294275 TI - Logic gate system with three outputs and three inputs based on switchable electrocatalysis of glucose by glucose oxidase entrapped in chitosan films. AB - A logic-gate system with three outputs and three inputs was developed based on the bioelectrocatalysis of glucose by glucose oxidase (GOx) entrapped in chitosan films on the electrode surface by means of ferrocenedicarboxylic acid (Fc(COOH)2 ). Cyclic voltammetric (CV) signals of Fc(COOH)2 exhibited pH-triggered on/off behavior owing to electrostatic interactions between the film and the probe at different pH levels. The addition of glucose greatly increased the oxidation peak current (Ipa ) through the electrocatalytic reaction. pH and glucose were selected as two inputs. As a reversible inhibitor of GOx, Cu(2+) was chosen as the third input. The combination of three inputs led to Ipa with different values according to different mechanisms, which were defined as three outputs with two thresholds. The logic gate with three outputs by using one type of enzyme provided a novel model to build logic circuits based on biomacromolecules, which might be applied to the intelligent medical diagnostics as smart biosensors in the future. PMID- 25294276 TI - Rates and correlations of change in three dimensions of recovery within a recovery model oriented therapeutic community. AB - This is a 10 year longitudinal study of recovery progress within a residential program based upon therapeutic community principles and a Seven Domains Enhanced Recovery Model (Young and Ensing, 1999). A broad suite of measures associated with one of three definitions of recovery (symptom, function, and personal focused recovery) were administered along three longitudinal courses. Normalized mean rates of change and mean shared variances for these scales were examined for three subgroups based on length of stay. Measures associated with the same definition of recovery correlated moderately to strongly but measures did not correlate between facets, suggesting relative independence between definition facets. The results of this analysis suggest the existence of qualitatively distinct subgroups with different change dynamics. The aggregate means of these facets showed correlated change, while individual recovery pathways did not, suggesting significant heterogeneity in individual pathways of recovery. These findings support the conceptualization of recovery as a complex, heterogeneous and multi-faceted process. Practically, these findings emphasize the need for holistic, flexible and individualized recovery supports and that research into these constructs should include at least these facets over a longitudinal time frame. PMID- 25294277 TI - Comparing antipsychotic treatments for schizophrenia: a health state approach. AB - The overall impact of first and second generation antipsychotics on quality of life and symptoms of people with schizophrenia remains controversial. We applied health state modeling to data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia study, a randomized trial of antipsychotic medications, and evaluated the likelihood of patients moving to more favorable health states over time. We applied K-means clustering to the data to create discrete groupings of patients with symptom and side effect characteristics that were then validated using quality of life measures. We compared cluster distributions across medications at baseline and 6 months after randomization. 1,049 patients were included in the initial cluster analysis. Five health states were identified: (1) low symptoms and low side effects (LS + LSE) (2) low symptoms and obesity (LS + Ob) (3) high symptoms and low side effects (HS + LSE) (4) high symptoms with depression and akathisia (HS + Dp + Ak) and (5) moderate symptoms and high side effects (MS + HSE). Six-month outcomes among patients randomly assigned to perphenazine, olanzapine, risperidone and quetiapine were compared. At baseline, almost 20% of patients were in the worst health state (HS + Dp + Ak), with greater decreases at 6 months in this health state for perphenazine (9.2% decrease) and olanzapine (11.1%) groups compared to risperidone (4.7%) and quetiapine (6.7%). This study demonstrated that health state analysis can provide insight into the overall clinical state of patients beyond the mere comparison of average scores and largely confirmed original CATIE findings. PMID- 25294278 TI - Plant villins: versatile actin regulatory proteins. AB - Regulation of actin dynamics is a central theme in cell biology that is important for different aspects of cell physiology. Villin, a member of the villin/gelsolin/fragmin superfamily of proteins, is an important regulator of actin. Villins contain six gelsolin homology domains (G1-G6) and an extra headpiece domain. In contrast to their mammalian counterparts, plant villins are expressed widely, implying that plant villins play a more general role in regulating actin dynamics. Some plant villins have a defined role in modifying actin dynamics in the pollen tube; most of their in vivo activities remain to be ascertained. Recently, our understanding of the functions and mechanisms of action for plant villins has progressed rapidly, primarily due to the advent of Arabidopsis thaliana genetic approaches and imaging capabilities that can visualize actin dynamics at the single filament level in vitro and in living plant cells. In this review, we focus on discussing the biochemical activities and modes of regulation of plant villins. Here, we present current understanding of the functions of plant villins. Finally, we highlight some of the key unanswered questions regarding the functions and regulation of plant villins for future research. PMID- 25294279 TI - The roles and influence of actors in the uptake of evidence: the case of malaria treatment policy change in Uganda. AB - BACKGROUND: Uganda changed its malaria treatment policy in response to evidence of resistance to commonly used antimalarials. The use of evidence in policy development--also referred to as knowledge translation (KT)--is crucial, especially in resource-limited settings. However, KT processes occur amidst a complex web of stakeholder interactions. Stakeholder involvement in evidence generation and in KT activities is essential. In the present study, we explored how stakeholders impacted the uptake of evidence in the malaria treatment policy change in Uganda. METHODS: We employed a qualitative case study methodology involving interviews with key informants and review of documents. A timeline of events was developed, which guided the purposive sampling of respondents and identification of relevant documents. Data were analysed using inductive content analysis techniques. RESULTS: Stakeholders played multiple roles in evidence uptake in the malaria treatment policy change. Donors, the Ministry of Health (MoH), service providers, and researchers engaged in the role of evidence generation. The MoH, parliamentarians, and opinion leaders at the national and local levels engaged in dissemination of evidence. The donors, MoH, researchers, and service providers engaged in the uptake of evidence in policy development and implementation. Stakeholders exerted varying levels of support and influence for different reasons. It is noteworthy that all of the influential stakeholders were divided regarding the best antimalarial alternative to adopt. CONCLUSION: Our results showed a diverse group of stakeholders who played multiple roles, with varying levels of support and influence on the uptake of evidence in the malaria treatment policy change. For a given KT processes, mapping the relevant stakeholders and devising mechanism for their engagement and for how to resolve conflicts of interest and disagreements a priori will enhance uptake of evidence in policy development. PMID- 25294280 TI - Case of anti-laminin gamma-1 pemphigoid with antibody against C-terminal domain of BP180 in a patient with psoriasis vulgaris. PMID- 25294281 TI - Outcomes of a minimally invasive surgical approach to manage persistent high grade vesicoureteric reflux post successful augmentation cystoplasty of patients with non-compliant bladder. AB - INTRODUCTION: Secondary vesicoureteric reflux (VUR) is a common problem associated with non-compliant bladders. Management of this disorder is debatable in literature. Many authors reported high resolution rate of VUR with augmentation cystoplasty (ACP) alone. Others showed significant residual VUR after ACP and recommend ureteric re-implantation (UR) at time of augmentation. OBJECTIVE: Studying efficacy of endoscopic correction of persistent high-grade VUR (ECVUR) post successful ACP. DESIGN: Patients with non-compliant bladders and high-grade VUR are enrolled in the program of our institute, where they are initially managed conservatively. Those not responding are managed endoscopically using intravesical botulinum toxin A and ECVUR. Patients who are not candidates or failed this approach undergo ACP without UR. A total of 82 patients with non compliant bladder underwent ACP between 2001 and 2011. Of those, 24 patients had high-grade VUR with 44 refluxing units (RU), 20 bilateral and 4 unilateral. The mean age at intervention was 7.62 years with a mean follow-up of 5.6 years. Patients with persistent high-grade VUR and recurrent breakthrough febrile UTI despite antibiotic prophylaxis following ACP were identified and enrolled in our prospective trial of interval ECVUR. Statistical analyses was performed to identify predictors of high-grade VUR resolution after ACP and ECVUR. A p value <0.05 was considered statistically significant (Table 1). RESULTS: Of the 24 patients, 17 underwent ileocystoplasty and 7 underwent ureterocystoplasty. One of the patients that underwent ileocystoplasty found to have a blind ending RU that was excised. Of the 36 remaining RU, 21/36 (58.3%) showed complete resolution in the first follow-up cystogram, and 1 showed complete resolution after 1 year. Two patients, each with single RU, received repeat ACP because of poor compliance and/or inadequate bladder capacity post ureterocystoplasty and showed complete resolution of reflux post-operatively, which increased the resolution rate post ACP to 66.6% (24/36) (Table 2). Of the remaining 12 RU in 7 patients, 10 underwent trial of ECVUR. VUR resolved in 8 RU after the first trial and in another 2 after the second trial (Table 3). Parents of 1 patient with the remaining 2 RU preferred to continue with conservative management (Table 2). DISCUSSION: VUR in patients with non-compliant bladder is usually secondary to high detrusor pressure, low compliance and small capacity. Whereas some investigators showed high resolution rate of VUR post augmentation without UR, claiming that by successfully augmenting the bladder, compliance will increase, detrusor pressure will decrease, and as a result, VUR will spontaneously resolve. Others showed high incidence of persistent VUR (47-57%) and recommend UR at time of ACP. In our study, the incidence of spontaneous resolution was 66.6% (24/36). In cases where VUR persists, ECVUR was performed. With this approach, VUR resolution increased to 94% (34/36). This study is limited by the small number of patients, lack of randomization and lack of comparison group in which patients undergo ACP with UR. CONCLUSION: ACP without UR with interval endoscopic management seems to be an effective and adequate treatment for high pressure, non compliant bladder as well as high-grade VUR when conservative management fails. PMID- 25294282 TI - Prognosis of arterial aneurysm after surgery in patients with Behcet's disease. AB - AIM: Despite improvements in therapeutic modalities, the treatment of arterial aneurysms complicating Behcet's disease (BD) is still challenging. This study examined the long-term prognosis after surgery for arterial aneurysms in BD. METHODS: This study included 9 patients with BD (8 men and 1 woman) who underwent surgery for arterial aneurysms between 1989 and 2008. The outcomes after the surgical intervention were assessed, including procedure-related complications and survival. RESULTS: The initial surgical procedures were performed for aortic or iliac aneurysms in 5 patients and for lower-extremity aneurysms in 4 patients. There was no operative mortality. The mean follow-up period was 135+/-69 months, ranging from 53 to 259 months. Patients with aortic or iliac aneurysms underwent graft interposition with Dacron prostheses. Their postoperative courses were uneventful, and all patients were alive during the follow-up with no procedure related complications. Those treated for lower-extremity aneurysms tended to show perioperative and postoperative complications, including aneurysmal degeneration of the autogenous vein graft in 2 patients. One patient who initially underwent surgery for a popliteal artery aneurysm died due to the rupture of a dissecting aortic aneurysm after serial surgical interventions for multiple aneurysms. Concomitant aortic or iliac aneurysms in 2 patients were followed up without any change in size under medical treatment using colchicine and corticosteroids. CONCLUSION: Although we cannot draw a firm conclusion because of the small number of cases in the present series, graft interposition can lead to a favorable prognosis in BD patients with aortic or iliac aneurysms, whereas surgical treatment of BD-related lower-extremity aneurysms is frequently associated with short- and long-term postoperative complications. Immunosuppressive therapy might possibly improve treatment outcomes. PMID- 25294283 TI - Usefulness of the Bollinger scoring method in evaluating peripheral artery angiography with 64-low computed tomography in patients with peripheral arterial disease. AB - AIM: There are various angiographic and runoff scoring systems for evaluating stenosis and arterial occlusion in patients with peripheral artery disease (PAD). The report from the BASIL trial revealed that the Bollinger scoring system, originally designed to classify intra-arterial digital subtraction angiography (IADSA), was sensitive to differences in PAD. The purpose of the present study was to evaluate the application of the Bollinger scoring system to a 64-low multidetector computed tomography (MDCT) in PAD patients. METHODS: Patients with PAD who underwent both a 64-MDCT and DSA within a 4-year period were enrolled in the study. Two observers analyzed the MDCT and DSA images for each patient. We divided the arterial tree from the common iliac artery to the plantar arch into 16 segments and scored 0-15 points for each segment as reported by Bollinger, according to the severity and extent of disease. We analyzed the reliability of differences in scores between the DSA and MDCT by the intraclass correlation coefficients (ICCs). RESULTS: We reviewed 100 consecutive patients (127 limbs) and assessed a total of 1929 segments. The Bollinger score of the 2 tests were same in 39.6% of all segments. The difference between the 2 tests were within 2 points in 77.3% of the above-knee segments (70.1-91.6% in each segments), 58.8% of the below-knee segments with the exception of plantar arch (42-74%). The ICC values showed relatively good reliability, but in the CFA the ICC values showed poor reliability. CONCLUSION: The Bollinger scoring method is a useful tool to evaluate peripheral artery angiography with 64-low CT in patients with PAD. PMID- 25294284 TI - Polymorphisms +45T>G and +276G>T of the adiponectin gene does not affect plasma adiponectin level and carotid intima-media thickness in patients with diabetes mellitus type 2. AB - AIM: Despite increasing evidence of adiponectin's anti-inflammatory and antiatherogenic effects, its role in atherogenesis remains uncertain. The aim of the present study is to investigate the association between +45T>G and +276G>T polymorphisms of the adiponectin gene and both plasma adiponectin levels and carotid intima-media thickness in patients with diabetes mellitus type 2. METHODS: 301 diabetic patients, divided into three categories on the basis on BMI were enrolled in the study. Carotid intima-media thickness (CIMT) was assessed ultrasonographically. Plasma adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Genotypes were determined by real-time PCR. RESULTS: Adiponectin level and prevalence of the G allele of 45T>G polymorphism decreased significantly with increasing BMI category. G allele of +45T>G polymorphism was associated with higher plasma adiponectin level only after adjustment for age, sex and BMI. No statistically significant difference in CIMT and +276T>G genotypes distribution was observed between BMI categories. None of the polymorphisms as well as plasma adiponectin level was associated with CIMT after adjustment for covariates. CONCLUSION: The G allele of the +45T>G polymorphism is not independently associated with plasma adiponectin level and is not associated with CIMT. +276G>T polymorphism is not associated with plasma adiponectin levels and CIMT in diabetic patients. PMID- 25294285 TI - CUSUM analysis of brachial artery access for peripheral endovascular interventions. AB - AIM: Evaluate efficacy and safety of diagnostic and therapeutic endovascular interventions performed through transbrachial approach. Transbrachial artery catheterization has long been considered a secondary access site due to its related complication rate (7-11%). Low-profile and long-delivery endovascular systems, however, are reviving the interest in this approach. METHODS: We retrospectively analysed all endovascular interventions attempted through a brachial artery access from 2003 to 2010. Two hundredth thirty seven consecutive patients (mean age 68.5 years, 89.5% male) underwent 168 transbrachial diagnostic (70.9%) and 69 therapeutic procedures (29.1%), characterised by micropuncture access (100%), 4-to-7 Fr sheath delivery systems and final digital compression (100%). CUSUM curves were created to evaluate learning effects and quality of care. RESULTS: All but one procedure were completed according to their scheduled intention. The overall complication rate was 5.5% (5 pseudoaneurysms (2.1%), 4 transient ischemic attack (1.7%), 3 brachial artery thromboses (1.3%) and 1 cardiac tamponade (0.4%). Surgical intervention was required in four of these patients (30.8%). No significant differences were observed according to age or sex. CUSUM curves created at a 2% theoretical risk showed two statistically significant upward inflections: one early in the series associated with diagnostic procedures (P=0.043) and another at the end of the study related to therapeutic interventions (P=0.018). CONCLUSION: Transbrachial catheterization is an effective and relatively safe access site for endovascular procedures. Its complication rate, although lower than before, still deserve it as a secondary access site. CUSUM curves let identify learning effects in diagnostic and interventional procedures. PMID- 25294286 TI - Regional intensity of neurosurgical care and integration of aneurysm coiling in the United States. AB - AIM: There is wide regional variability in the volume of procedures performed for similar surgical patients throughout the United States. We investigated the association of the intensity of neurosurgical care with the diffusion of the novel technology of cerebral aneurysm coiling. METHODS: We performed a retrospective cohort study involving patients who underwent any neurosurgical procedure from 2005-2010 and were registered in the National Inpatient Sample (NIS) database. A sub-cohort of patients undergoing aneurysm clipping or coiling was also created. Regression techniques were used to investigate the association of the average risk-adjusted intensity of neurosurgical care with the average rate of coiling. RESULTS: There were significant disparities in the rate of coiling among several states (ANOVA, P<0.0001). It ranged from 0.24 in Maryland, where clipping was very predominant, to 0.82 in Minnesota, where coiling was the main treatment modality used. In multivariate analysis, higher coiling rate was associated with increased age, higher income, rural hospital location, and small institution size. The Midwest was association with higher rate in comparison to the Northeast, whereas the West and the South had even lower rates. Increasing rate of coiling was associated with increasing intensity of neurosurgical care. There was a positive correlation of the average risk-adjusted intensity of neurosurgical care with the average rate of coiling per state (Pearson's rho=0.43, P<0.001). CONCLUSION: We observed significant disparities in the rate of coiling in the United States. Increased intensity of neurosurgical care was positively associated with the integration of coiling in treatment of cerebral aneurysms. PMID- 25294287 TI - A decreased serum omentin-1 level may be an independent risk factor for peripheral arterial disease. AB - AIM: Recent evidence suggests that omentin-1, a visceral adipose-derived cytokine, may play a role in atherosclerosis The aim of this study was to evaluate whether serum omentin-1 levels are associated with peripheral artery disease (PAD) and its severity. METHODS: The present study was cross-sectional and observational. We enrolled 123 patients with PAD and 50 age-matched subjects without PAD. The cardiovascular risk factors, ankle-brachial index (ABI), and serum omentin-1 levels were assessed in all participants RESULTS: Patients with PAD had significantly lower omentin-1 levels than those without PAD (206. +/-48.4 vs. 345. +/-80 ng/mL, respectively; 0.001). A correlation analysis revealed positive correlations between the omentin-1 level and the ABI ( 0.52, P=0.008). After adjusting for cardiovascular risk factors, a decreased omentin-1 level was found to be an independent predictor of both PAD and its severity as measured by ABI in multivariate logistic regression analysis. CONCLUSION: The current study suggests a strong association between decreased serum omentin-1 levels and PAD and its severity. Thus, omentin-1 may be a novel biomarker for PAD. PMID- 25294288 TI - Coexistence of low ankle-brachial index and intra-cranial atherosclerosis? AB - AIM: Low ankle-brachial index (ABI<0.9) is considered a risk factor for stroke. However, there are disputes regarding the relationship between low ABI and intra cranial atherosclerosis. The relationship between low ABI and intra/extracranial atherosclerosis was analyzed in the present study. METHODS: Patients with large artery atherosclerosis (LAA) and small artery disease (SAD) were enrolled in this study according to the classic Trial of ORG 10172 in Acute Stroke Treatment (TOAST) subtypes. Subjects were divided into three groups: intracranial atherosclerosis (IAS), extracranial atherosclerosis (EAS) and the small artery disease group. All of the enrolled patients underwent ABI measurement and were assessed for risk factors. The association between low ABI (<0.9) and extra/intra cranial atherosclerosis were examined using logistic regression. RESULTS: Altogether, 31.51% of LAA patients were diagnosed with peripheral artery disease, which was much higher than that of the SAD patients (19.75%, P=0.045). There was a remarkable difference in the prevalence of abnormal ABI in the EAS stenosis and IAS stenosis patients (47.17% vs. 22.31%, P=0.001). Multivariable logistic regression identified peripheral artery disease (OR=2.759, 95% CI: 1.485-5.124) and smoking (OR=2.032, 95%CI:1.093-3.779) as independent risk factors for EAS stenosis. However hypertension (OR=1.957, 95%CI: 1.119-3.421) as well as male sex (OR=2.024, 95%CI: 1.251-3.274) were found to be independent risk factors for IAS stenosis. Peripheral artery disease was not associated with IAS stenosis (OR=1.075, 95%CI: 0.516-2.238). CONCLUSION: Intracranial atherosclerosis was not associated with a low ABI (<0.9) in the stroke patients. Low ABI is significantly associated with age (>65 years), extra-cranial atherosclerotic and diabetes mellitus. Among ischemic stroke patients, a low ABI can be useful in predicting EAS. PMID- 25294289 TI - Juxtarenal aortic aneurysm with hostile neck anatomy: midterm results of minilaparotomy versus f-EVAR. AB - AIM: The aim of this study was to compare the results of complex aneurysm (hostile neck anatomies) repair in high-risk patients with two minimally invasive techniques, fenestrated endografting (f-EVAR where EVAR stands for endovascular aneurysm repair) and minilaparotomy. METHODS: All high-risk patients (N.=50, group 1) with hostile neck abdominal aortic aneurysms (AAAs) operated in the vascular surgery department of the "Policlinico Universitario G. Martino" of Messina (Italy) during a 5-year period (January 2006-December 2010) were cross matched with 50 similar patients (group 2) treated in the Vascular Surgery Department of the "Hopital Cardiologique" University of Lille (France) with similar anatomies, comorbidities and risk factors. The patients in group 1 underwent open minilaparotomy surgery, and the patients in group 2 were treated with f-EVAR. The aim of our study was to compare perioperative complications, survival and reintervention rates. RESULTS: Perioperative cardiac complications occurred in 5 patients (10%) in group 1, and 1 patient (2%) in group 2 (P<0.092). Renal impairment not requiring permanent hemodialysis was significantly higher in group 1 (14% vs. 2% P<0.027), as well as respiratory complications (32% vs. 2% P<0.0001). Five patients (10%) in group 1 underwent reintervention vs. 4 patients in group 2 (P<0.7268). There was no statistically significant difference for survival rates at 30 days (92% in group 1 and 96% in group 2; P=0.399); at six months (90% vs. 96%; P=0.239); at one year (90% vs. 96%; P=0.239); and at two years (84% vs. 94%; P=0.110). However, we observed statistically significant differences in survival rates at three years (74% vs. 94%; P<0.006); at four years (70% vs. 86%; P<0.005); and at five years (65% vs. 68%; P<0.003). CONCLUSION: Our results showed that both techniques are effective in the treatment of AAA with hostile neck in high-risk patients. Although operative mortality rate was not statistically different, f-EVAR showed better results in terms of early complications and late survival. PMID- 25294290 TI - No benefit of screening for abdominal aortic aneurysm among 70- instead of 65 year-old men. AB - AIM: Screening 65-year-old men for abdominal aortic aneurysm (AAA) reduces mortality from ruptured AAA (rAAA). Lower than expected prevalence of AAA is now found, why screening at a higher age and rescreening has been discussed. Our aim was to determine if screening at 70 years of age, instead of 65, increases clinical effectiveness. METHODS: Seven thousand nine hundred fifty-one and 5623 previously un-screened 65- and 70-year old men were invited to ultrasound screening. RESULTS: The attendance rate was 85.7% and 84.0%, P<0.01, for the 65- and 70-year old men respectively. The screening-detected prevalence did not differ, being 1.9% and 2.3%, P=0.15, respectively, probably due to the fact that 23.5% and 37.4% of all known AAA among 65- and 70-year-old men, were detected by other means prior to screening, P<0.01. However, the total known prevalence differed between the age-groups, being at least 2.1% and 3.0% respectively, P<0.001. CONCLUSION: The screening-detected AAA-prevalence did not differ between 65- and 70-year-old men, due to the greater number of AAA known prior to screening among 70- compared to 65-year-old men. Screening men at 70 instead of 65 years of age would not result in detection of substantially more previously unknown AAA, thus not preventing rAAA and consequently not more saved life-years. Further, data also indicates that it is questionable if re-screening the 65-year old male population after five years would generate any important clinical effect. PMID- 25294291 TI - Multidisciplinary care as a holistic approach to the management of vascular disease. PMID- 25294292 TI - Asterios Katsamouris. Professor of vascular surgery "Aristotle" University of Thessaloniki, Greece, 1947-2014. PMID- 25294294 TI - A novel mixed phospholipid functionalized monolithic column for early screening of drug induced phospholipidosis risk. AB - Drug-induced phospholipidosis (PLD) is characterized by the excessive accumulation of phospholipids, resulting in multilamellar vesicle structure within lysosomes. In the present study, a novel mixed phospholipid functionalized monolithic column was developed for the first time through a facile one-step co polymerization approach. The phospholipid composition of the monolith can be adjusted quantitatively and accurately to mimic the mixed phospholipid environment of different biomembranes on a solid matrix. The mixed phospholipid functionalized monolith as a promising immobilized artificial membrane technique was used to study drug-phospholipid interaction. Scanning electron microscopy, elemental analysis, FT-IR spectra, zeta-potential analysis and micro-HPLC were carried out to characterize the physicochemical properties and separation performance of the monolith. Mechanism studies revealed that both hydrophobic and electrostatic interactions play an important role in the retention of analytes. The ratio of their contributions to retention can be easily manipulated by adjusting the composition of the mixed phospholipids, in order to better mimic the interaction between drugs and cell membrane. The obtained mixed phospholipid functionalized monolithic columns were applied to the screening of drug-induced PLD potency. Data from 79 drugs on the market demonstrated that the chromatographic hydrophobicity index referring to the mixed phospholipid functionalized monolith at pH 7.4 (CHI IAM7.4) for the selected drugs were highly correlated with the drug-induced PLD potency data obtained from other in vivo or in vitro assays. Moreover, the effect of the acidic phospholipid phosphatidylserine proportion on prediction accuracy was also investigated. The monolith containing 20% phosphatidylserine and 80% phosphatidylcholine exhibited the best prediction ability for the drug-induced PLD potency of the tested compounds. This research has led to the successful development of a novel and facile approach to prepare a mixed phospholipids functionalized monolith, which offers a reliable, cost-effective and high-throughput screening tool for early prediction of the PLD potency of drug candidates. PMID- 25294295 TI - Evaluation of non-covalent interactions between serum albumin and green tea catechins by affinity capillary electrophoresis. AB - The natural antioxidant-associated biological responses appear contradictory since biologically active dosages registered in vitro experiments are considerably higher if compared to concentrations found in vivo. The recent research indicates that natural antioxidants, including the major catechins of green tea epicatechin (EC), epigallocatechin (EGC), epicatechingallate (ECG) and epigallocatechingallate (EGCG) form non-covalent complexes with albumin, a crucial aspect that may modulate their plasma concentration, tissue delivery and biological activity. Affinity capillary electrophoresis (ACE) was used to characterize the binding of the four catechins to human serum albumin (HSA) and bovine serum albumin (BSA) at near-physiological conditions: 10 mmol/L phosphate buffer, HEPES 50 mmol/L (pH 7.5), temperature 37 degrees C. The studied flavonoids displayed affinities toward the albumin with binding constants in the range 10(3)-10(5)M(-1), with a greater affinity of catechins toward HSA than BSA (between 3 and 3.5 fold higher). We also confirmed that catechins having a galloyl moiety (ECG and EGCG) have a higher binding affinity toward albumin than the catechins lacking the galloyl moiety (EC and EGC), and that for both albumins the order of affinity is EC= 256 MUg/mL, 1-4 MUg/mL, and 8-16 MUg/mL, respectively. The 3 S. hominis presented MIC values 32 to >256 MUg/mL, 2-4 MUg/mL, and 12-24 MUg/mL, and all carried the nontypeable SCCmec (ccr1 + mecA class) and belonged to 2 different genotypes. The cfr gene was not found, but the mutation G2603T was detected in S. haemolyticus and C2190T and G2603T in Staphylococcus hominis in 23S rRNA. This study demonstrates the spread of a linezolid-resistant S. haemolyticus genotype and, for the first time, describes the mutation C2190T among S. hominis isolates with a double mutation in Brazil. PMID- 25294303 TI - In vitro activity of oritavancin against Gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2013. AB - Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus (n=1460; oritavancin MIC90, 0.06 MUg/mL; 99.7% oritavancin-susceptible), methicillin resistant S. aureus (n=427; oritavancin MIC90, 0.06 MUg/mL; 99.5% oritavancin susceptible), Streptococcus pyogenes (n=132; oritavancin MIC90, 0.25 MUg/mL; 99.2% oritavancin-susceptible), Streptococcus agalactiae (n=156; oritavancin MIC90, 0.12 MUg/mL; 100% oritavancin-susceptible), and Enterococcus faecalis (n=304; oritavancin MIC90, 0.06 MUg/mL; 98.7% oritavancin-susceptible) tested. PMID- 25294304 TI - Social determinants of health in India: progress and inequities across states. AB - INTRODUCTION: Despite the recognized importance of social determinants of health (SDH) in India, no compilation of the status of and inequities in SDH across India has been published. To address this gap, we assessed the levels and trends in major SDH in India from 1990 onwards and explored inequities by state, gender, caste, and urbanicity. METHODS: Household- and individual-level SDH indicators were extracted from national household surveys conducted between 1990 and 2011 and means were computed across population subgroups and over time. The multidimensional poverty index (MPI), a composite measure of health, education, and standard of living, was calculated for all three rounds of the National Family Health Survey, adjusting the methodology to generate comparable findings from the three datasets. Data from government agencies were analyzed to assess voting patterns, political participation, and air and water pollution. RESULTS: Changes in the MPI demonstrate progress in each domain over time, but high rates persist in important areas: the majority of households in India use indoor biomass fuel and have unimproved sanitation, and over one-third of households with a child under the age of 3 years have undernourished children. There are large, but narrowing, gender gaps in education indicators, but no measurable change in women's participation in governance or the labor force. Less than 25% of workers have job security and fewer than 15% have any social security benefit. Alarming rates of air pollution are observed, with particulate matter concentrations persistently above the critical level at over 50% of monitoring stations. CONCLUSIONS: This assessment indicates that air pollution (indoor and outdoor), child undernutrition, unimproved sanitation, employment conditions, and gender inequality are priority areas for public policy related to SDH in India. PMID- 25294306 TI - The opportunity costs of informal elder-care in the United States: new estimates from the American Time Use Survey. AB - OBJECTIVES: To provide nationally representative estimates of the opportunity costs of informal elder-care in the United States. DATA SOURCES: Data from the 2011 and 2012 American Time Use Survey. STUDY DESIGN: Wage is used as the measure of an individual's value of time (opportunity cost), with wages being imputed for nonworking individuals using a selection-corrected regression methodology. PRINCIPAL FINDINGS: The total opportunity costs of informal elder-care amount to $522 billion annually, while the costs of replacing this care by unskilled and skilled paid care are $221 billion and $642 billion, respectively. CONCLUSIONS: Informal caregiving remains a significant phenomenon in the United States with a high opportunity cost, although it remains more economical (in the aggregate) than skilled paid care. PMID- 25294305 TI - Evaluation of a spatially resolved forest fire smoke model for population-based epidemiologic exposure assessment. AB - Exposure to forest fire smoke (FFS) is associated with multiple adverse health effects, mostly respiratory. Findings for cardiovascular effects have been inconsistent, possibly related to the limitations of conventional methods to assess FFS exposure. In previous work, we developed an empirical model to estimate smoke-related fine particulate matter (PM2.5) for all populated areas in British Columbia (BC), Canada. Here, we evaluate the utility of our model by comparing epidemiologic associations between modeled and measured PM2.5. For each local health area (LHA), we used Poisson regression to estimate the effects of PM2.5 estimates and measurements on counts of medication dispensations and outpatient physician visits. We then used meta-regression to estimate the overall effects. A 10 MUg/m(3) increase in modeled PM2.5 was associated with increased sabutamol dispensations (RR=1.04, 95% CI 1.03-1.06), and physician visits for asthma (1.06, 1.04-1.08), COPD (1.02, 1.00-1.03), lower respiratory infections (1.03, 1.00-1.05), and otitis media (1.05, 1.03-1.07), all comparable to measured PM2.5. Effects on cardiovascular outcomes were only significant using model estimates in all LHAs during extreme fire days. This suggests that the exposure model is a promising tool for increasing the power of epidemiologic studies to detect the health effects of FFS via improved spatial coverage and resolution. PMID- 25294307 TI - Dynamic quantification of tibio-femoral rotation in postero-lateral bundle insufficiency of the anterior cruciate ligament: a cadaver study. AB - PURPOSE: Anterior cruciate ligament (ACL) injury represents one of the most common diagnoses in orthopaedic sports medicine. In the past, anatomic knowledge about the different bundles within the cruciate ligaments triggered new treatment concepts, such as double-bundle ACL reconstruction. Recently, besides complete tearing, partial ACL ruptures and bundle augmentation became a focus. However, only little is known regarding rotational stability of the knee with an isolated torn postero-lateral (PL) bundle. Therefore, the aim of the present study was the torsiometric analysis of tibio-femoral restraint patterns of the PL-insufficient knee joint. METHODS: Fresh human whole body cadavers were enrolled. After diagnostic arthroscopy to ensure the structural integrity of the cruciate ligaments, knee joints underwent torsiometry at 0 degrees , 30 degrees , and 90 degrees degree flexion. Then stepwise the PL bundle and the anteromedial (AM) bundle were arthroscopically resected, while torsiometry of the PL- as well as of the ACL-deficient knee joints was repeated. An area under the curve (AUC) was calculated. All statistical analyses were conducted using a p-value of 0.05 as level of significance. RESULTS: The comparison of charged and equilibrated curves during internal rotation revealed significant results at low flexion (30 degrees flexion) angles between the ACL intact versus PL absent conditions (p = 0.04). In addition, charged and equilibrated curves during external rotation at 90 degrees flexion, thus high angles, resulted in a significant difference when comparing the ACL-intact with the PL-deficient condition (p = 0.01). CONCLUSIONS: In the present cadaver study using the Torsiometer tool we found a distinct destabilization of the rotational restraints in full knee extension only after total ACL resection. In contrast, no significant findings resulted after an isolated dissection of the PL bundle during internal deflection. Nevertheless, a significant loss of stability was found during unstressed external deflection after isolated PL bundle dissection. Therefore patients, undergoing PL augmentation might benefit regarding rotational instability patterns. PMID- 25294308 TI - Extrapontine myelinolysis associated with pituitrin: case report and literature review. AB - BACKGROUND: Hyponatremia is the most common electrolyte abnormality encountered in hospitalized patients, resulting from a varied spectrum of conditions. Both the primary disturbance and its correction can result in life-threatening neurological consequences. Extrapontine myelinolysis is one such complication that is associated with the rapid correction of hyponatremia. Here we describe a patient who developed extrapontine myelinolysis unexpectedly after the correction of hyponatremia, which involved the drug pituitrin. CASE PRESENTATION: A 24-year old Chinese woman was transferred to our neurology department with the symptoms of dysarthria and quadriparesis developing one day after the correction of hyponatremia (from 118 mmol/L to 140 mmol/L), which followed with a continuous intravenous drip of pituitrin used to control hemoptysis in the emergency room. During the course, she developed involuntary movement. Magnetic resonance imaging changes were consistent with extrapontine myelinolysis. CONCLUSION: This present case describes the mechanism of profound hyponatremia involving pituitrin, and the subsequent development of extrapontine myelinolysis. Physicians may approach effective clinical management of patients through awareness of the adverse effect of pituitrin on serum sodium levels, and avoid rapid correction of hyponatremia in clinical practice. PMID- 25294310 TI - Are there any lessons to be learnt from psychiatric epidemiology? PMID- 25294309 TI - Activity-regulated gene expression in immature neurons in the dentate gyrus following re-exposure to a cocaine-paired environment. AB - Intense craving for drug and relapse are observed in addicts who are exposed to environmental stimuli associated with drug-taking behavior even after long periods of abstinence. The hippocampus is a brain region known to be involved in contextual processing, taking place predominantly in the septal hippocampus, and emotional processing, taking place predominantly in the temporal hippocampus. Conditioned place preference is an animal model of context-conditioned reward. The dentate gyrus is a hippocampal sub-region particularly important for the acquisition of cocaine-induced place preference and is a site of continuous neurogenesis, which has been implicated in the vulnerability to drug-taking behavior. Therefore, these experiments explored the role of newly generated neurons in drug reward-context association by examining the activation, as determined by expression of the immediate early gene cfos, of young and mature granule cells in the septal and temporal dentate gyrus of adult rats that were re exposed to a drug-paired environment following the development of cocaine place preference. The overall level of cfos expression was increased in both the septal and temporal dentate gyrus of animals that developed place preference and were re exposed to the drug paired environment compared with re-exposure to a neutral environment. Overall level of neurogenesis, as detected by the S-phase marker 5' bromo-2'-deoxyuridine (BrdU) and the immature neuron marker doublecortin (DCX), was unaltered by cocaine conditioning. However, the number of activated new neurons (DCX + cfos) was greater in the temporal dentate gyrus of cocaine conditioned rats re-exposed to the drug-paired environment as compared to those re-exposed to a neutral environment. Further understanding of the role of dentate gyrus neurogenesis on the conditioned effects of drugs of abuse may provide new insights into the role of this process in the expression of addictive behaviors. PMID- 25294311 TI - (18) F labeled RGD-A7R peptide for dual integrin and VEGF-targeted tumor imaging in mice bearing U87MG tumors. AB - The aim of this study is to develop a novel Arg-Gly-Asp acid (RGD) and Ala-Thr Trp-Leu-Pro-Pro-Arg (ATWLPPR A7R) peptide-containing ligand for (18) F labeling as alphavbeta3 and vascular endothelial growth factor receptor-targeted imaging agent. (18) F-RGD-A7R was prepared by conjugation with (18) F-SFB. The final product was purified by high-performance liquid chromatography and tested in vitro and in vivo. Cell-binding assays of RGD-A7R, RGD and RGD-A7R, A7R were tested in U87MG cells ((125) I-RGDyK and (125) I-A7RY as radioligand, respectively). Preliminary biodistribution of the (18) F-RGD-A7R was also evaluated. The RGD-A7R had good integrin binding affinity (50% inhibitory concentration (IC50 ) = 21.67 and 23.68 nM, slightly lower than unmodified RGD (40.02 nM) and A7R (50.18 nM)). The radiotracer had receptor-mediated activity accumulation in U87MG tumor (1.90 +/- 0.34 percentage of injected dose per gram (%ID/g) at 0.5 h postinjection), which is known to be integrin positive. After blocking with RGD-A7R, the tumor uptake was reduced to 0.47 +/- 0.06 %ID/g at 0.5 h postinjection. (18) F-RGD-A7R exhibited dual receptor targeting properties both in vitro and in vivo. The favorable characterizations of (18) F-RGD-A7RY, such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging. PMID- 25294312 TI - Muscarinic M1 receptors regulate propofol modulation of GABAergic transmission in rat ventrolateral preoptic neurons. AB - GABAergic neurons within the ventrolateral preoptic area (VLPO) play an important role in sleep-wakefulness regulation. Propofol, a widely used systemic anesthetic, has lately been reported to excite noradrenaline (NA)-inhibited type of VLPO neurons. Present study tested if acetylcholine system takes part in the propofol modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat VLPO neurons using a conventional whole-cell patch clamp technique. Propofol reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that propofol acts presynaptically to decrease the probability of spontaneous GABA release. The propofol action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective muscarinic acetylcholine (mACh) receptor antagonist, and pirenzepine, a selective M1 receptor antagonist. These results suggest that propofol acts on M1 receptors on GABAergic nerve terminals projecting to VLPO neurons to inhibit spontaneous GABA release. The M1 receptor-mediated modulation of GABAergic transmission onto VLPO neurons may contribute to the regulation of loss of consciousness induced by propofol. PMID- 25294314 TI - The Aspergillus nidulans signalling mucin MsbA regulates starvation responses, adhesion and affects cellulase secretion in response to environmental cues. AB - In the heterogeneous semi-solid environment naturally occupied by lignocellulolytic fungi the majority of nutrients are locked away as insoluble plant biomass. Hence, lignocellulolytic fungi must actively search for, and attach to, a desirable source of nutrients. During growth on lignocellulose a period of carbon deprivation provokes carbon catabolite derepression and scavenging hydrolase secretion. Subsequently, starvation and/or contact sensing was hypothesized to play a role in lignocellulose attachment and degradation. In Aspergillus nidulans the extracellular signalling mucin, MsbA, influences growth under nutrient-poor conditions including lignocellulose. Cellulase secretion and activity was affected by MsbA via a mechanism that was independent of cellulase transcription. MsbA modulated both the cell wall integrity and filamentous growth MAPK pathways influencing adhesion, biofilm formation and secretion. The constitutive activation of MsbA subsequently enhanced cellulase activity by increasing the secretion of the cellobiohydrolase, CbhA, while improved substrate attachment and may contribute to an enhanced starvation response. Starvation and/or contact sensing therefore represents a new dimension to the already multifaceted regulation of cellulase activity. PMID- 25294313 TI - Optimal surveillance for postoperative metastasis in breast cancer patients. AB - PURPOSE: To establish an optimal surveillance schedule after surgery for breast cancer, patients included in an institutional database were retrospectively investigated with respect to the first metastatic site and timing of recurrence. PATIENTS AND METHODS: We investigated 11,676 pT1-4pN0-2M0 breast cancer patients treated from 1985 to 2009 and followed up until June 2014. Our surveillance protocol included physician visits and examinations with bone scans, liver echography, chest roentgenography and laboratory tests. We evaluated the liver, bones, lungs and pleura as surveillance covering sites (SCS) in addition to parameters such as time points exceeding 80 % with respect to the accumulated percentage of patients of recurrence and the number of surveillance per one recurrence (NSR), calculated by dividing the number of patients at risk of recurrence at the start of a particular time frame by the number of patients of recurrence at SCS within that period. RESULTS: There were a total of 1,962 recurrent patients, including 601 patients with locoregional recurrence, nine patients with recurrence in the opposite breast, 1,349 patients with recurrence at distant sites and three unknown patients. The number of patients with the bones, lungs, liver and pleura as the first site of recurrence was 447, 324, 144 and 69, respectively, and 72.9 % of the distant metastatic lesions belonged to SCS. The five-year overall survival rate after recurrence among the patients with single recurrent site was longer than that observed among the patients with multiple sites of recurrence (43.3 vs 25.3 %; p < 0.0001). In addition, more than 80 % of the patients of liver metastasis were detected within 5 years after surgery, while 80 % of the patients of pleura metastasis were detected within 10 years. The NSR was below 200 for the 10-year period, as was the NSR of the patients with lymph node metastasis and a positive hormone receptor status. In contrast, the NSR of the patients with a negative hormone receptor status was above 200 after 5 years. CONCLUSIONS: In this study, the prognosis of the patients with a single site of recurrence was superior to that of the patients with multiple sites. Curable patients with distant metastases included those with single metastatic sites. The optimal surveillance schedule should be established taking into consideration that the incidence of metastasis differs among metastatic sites during follow-up. PMID- 25294315 TI - An analytical approach to corneal mechanics for determining practical, clinically meaningful patient-specific tissue mechanical properties in the rehabilitation of vision. AB - Patient-specific biomechanical properties of the human cornea are rarely used with finite elements analysis. In order for that to be possible, a proper formulation for biomechanical properties that is based on patient-specific measurable values must be used. In this study, we propose a formula that simulates hyperelastic stress-strain curves based on non-invasive clinical measurements that can be acquired in vivo. These consist of, but are not limited to, center corneal thickness and center corneal curvature as well as corneal resistance factor and applanation diameter that are measured during non-contact tonometry. The presented formulation was demonstrated and validated through several computer simulations. First, mean values that were reported in literature were inputted into the formula to simulate a curve that represents a healthy case. This case was compared to two independent in vitro studies. Then, a sensitivity analysis was carried to identify inputs that have the most dominant effect. Finally, a finite element analysis simulating elevations in intraocular pressure was conducted; the corneal model comprised of patient-specific corneal geometry that was measured in vivo in our clinic as well as the current formulation for patient-specific corneal biomechanics. "Strong" and "weak" corneal tissue cases were simulated and deformations as well as instantaneous curvature optical maps were derived. Results for the simulated healthy curve showed good agreement with the in vitro studies. The sensitivity analysis found the corneal resistance factor and applanation diameter to have the most dominant influence. The finite element analysis of strong and weak biomechanical properties resulted in corneal deformations and instantaneous curvature optical maps that are common for healthy and pathological conditions respectively. In conclusion, the presented modeling technique can be used to assess corneal biomechanics in vivo and therefor may enhance follow-up on the effectiveness of clinical treatments, rehabilitation of vision and perhaps improve the diagnosis of pathologies that are related to corneal biomechanics. PMID- 25294316 TI - Never ending stories: visual diarizing to recreate autobiographical memory of intensive care unit survivors. AB - AIM: The aim of this study was to explore the potential use of visual diarizing to enable intensive care unit (ICU) survivors to create their story of recovery. BACKGROUND: An ICU experience can have deleterious psychological and physical effects on survivors leading to reductions in quality of life which for some may be of significant duration. Although there has been exploration of many interventions to support recovery in this group, service provision for survivors remains inconsistent and inadequate. DESIGN AND PARTICIPANTS: A qualitative interpretive biographical exploration of the ICU experience and recovery phase of ICU survivors using visual diarizing as method. This paper is a component of a larger study and presents an analyses of one participant's visual diary in detail. METHODS: Data collection was twofold. The participant was supplied with visual diary materials at 2 months post-hospital discharge and depicted his story in words and pictures for a 3-month period, after which he was interviewed. The interview enabled the participant and researcher to interpret the visual diary and create a biographical account of his ICU stay and recovery journey. FINDINGS: The analysis of one participant's visual diary yielded a wealth of information about his recovery trajectory articulated through the images he chose to symbolize his story. The participant confirmed feelings of persecution whilst in ICU and was unprepared for the physical and psychological disability which ensued following his discharge from hospital. However, his story was one of hope for the future and a determination that good would come out of his experience. He considered using the visual diary enhanced his recovery. CONCLUSIONS: The participant perceived that visual diarizing enhanced his recovery trajectory by enabling him to recreate his story using visual imagery in a prospective diary. RELEVANCE TO CLINICAL PRACTICE: Prospective visual diarizing with ICU survivors may have potential as an aid to recovery. PMID- 25294317 TI - Prevalence of antimicrobial resistance in enteric Escherichia coli from domestic pets and assessment of associated risk markers using a generalized linear mixed model. AB - Antimicrobial resistance (AMR) is a growing global public health problem, which is caused by the use of antimicrobials in both human and animal medical practice. The objectives of the present cross-sectional study were as follows: (1) to determine the prevalence of resistance in Escherichia coli isolated from the feces of pets from the Porto region of Portugal against 19 antimicrobial agents and (2) to assess the individual, clinical and environmental characteristics associated with each pet as risk markers for the AMR of the E. coli isolates. From September 2009 to May 2012, rectal swabs were collected from pets selected using a systematic random procedure from the ordinary population of animals attending the Veterinary Hospital of Porto University. A total of 78 dogs and 22 cats were sampled with the objective of isolating E. coli. The animals' owners, who allowed the collection of fecal samples from their pets, answered a questionnaire to collect information about the markers that could influence the AMR of the enteric E. coli. Chromocult tryptone bile X-glucuronide agar was used for E. coli isolation, and the disk diffusion method was used to determine the antimicrobial susceptibility. The data were analyzed using a multilevel, univariable and multivariable generalized linear mixed model (GLMM). Several (49.7%) of the 396 isolates obtained in this study were multidrug-resistant. The E. coli isolates exhibited resistance to the antimicrobial agent's ampicillin (51.3%), cephalothin (46.7%), tetracycline (45.2%) and streptomycin (43.4%). Previous quinolone treatment was the main risk marker for the presence of AMR for 12 (ampicillin, cephalothin, ceftazidime, cefotaxime, nalidixic acid, ciprofloxacin, gentamicin, tetracycline, streptomycin, chloramphenicol, trimethoprim-sulfamethoxazole and aztreonam) of the 15 antimicrobials assessed. Coprophagic habits were also positively associated with an increased risk of AMR for six drugs, ampicillin, amoxicillin-clavulanic acid, cephamycin, ciprofloxacin, streptomycin, and trimethoprim-sulfamethoxazole. In summary, pets with a record of one or more previous quinolone treatments and exhibiting coprophagic habits were at an increased risk of harboring multidrug-resistant E. coli strains in their feces compared to pets without these characteristics. AMR is a serious global problem, and assessing the risk markers for the presence of drug-resistant bacteria in pets, a very close source of resistance determinants to humans, is essential for the implementation of safe handling procedures for companion animals and for the prudent selection of antimicrobial compounds in veterinary practice. PMID- 25294318 TI - Perceptions and Attitudes About Genetic Counseling Among Residents of a Midwestern Rural Area. AB - Relatively few investigations of the public's perceptions and attitudes about genetic counseling exist, and most are limited to individuals at-risk for a specific disease. In this study 203 individuals from a Midwest rural area completed an anonymous survey assessing their familiarity with genetic counseling; perceptions of genetic counseling purpose, scope, and practice; attitudes toward genetic counseling/counselors; and willingness to use genetic counseling services. Although very few respondents were familiar with genetic counseling, most reported accurate perceptions and positive attitudes; mean ratings, however, showed less endorsement of trust in information provided by genetic counselors and less agreement that genetic counseling aligns with their values. Logistic regression indicated reported willingness to use genetic counseling services increased if respondents: had completed some college; rated their familiarity with genetic counseling as high; agreed with the statements: genetic counseling may be useful to someone with cancer in their family, genetic counseling is in line with my values, and genetic counselors advise women to get abortions when there is a problem; and disagreed with the statements: genetic counseling is only useful to a small group of people with rare diseases, and genetic counselors must receive a lot of special training. Additional findings, practice implications, and research recommendations are presented. PMID- 25294319 TI - Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy. AB - OBJECTIVE: To describe both clinical and pathological response rates, survival, and predictors of survival when using contemporary perioperative chemotherapy and surgical resection for patients with regionally advanced squamous cell carcinoma (SCC) of the penis. PATIENTS AND METHODS: Retrospective review of all patients diagnosed with SCC of the penis and regional lymph node metastases that were treated with chemotherapy with the intent to undergo lymphadenectomy. Clinical and pathological responses were reported. Recurrence-free and overall survival was estimated using Kaplan-Meier analysis. Cox proportional hazards regression was used to assess factors for survival. RESULTS: In all, 61 patients were identified, of which 54 (90%) received chemotherapy with paclitaxel/ifosfamide/cisplatin. In all, 39 patients (65%) had either a partial (PR) or complete response (CR) to chemotherapy. The 5-year survival varied significantly (P = 0.045-0.001) among patients achieving a CR/PR (50%), stable disease (25%), and progression (7.7%). In all, 10 patients (16.4%) were rendered pN0 with combined therapy and 20 patients (33%) were alive and disease free at a median follow-up of 67 months, while 32 (52%) died from disease. Long-term survival was associated with response to chemotherapy and favourable pathological findings after resection. CONCLUSION: Contemporary chemotherapy resulted in clinically significant responses among patients with regionally advanced penile cancer. About 50% of such patients with an objective response to chemotherapy who undergo consolidative lymphadenectomy will remain alive at 5 years. PMID- 25294320 TI - Residents' final transition: the graduation clinic hand-off. PMID- 25294321 TI - Statistical measures of transcriptional diversity capture genomic heterogeneity of cancer. AB - BACKGROUND: Molecular heterogeneity of tumors suggests the presence of multiple different subclones that may limit response to targeted therapies and contribute to acquisition of drug resistance, but its quantification has remained challenging. RESULTS: We performed simulations to evaluate statistical measures that best capture the molecular diversity within a group of tumors for either continuous (gene expression) or discrete (mutations, copy number alterations) molecular data. Dispersion based metrics in the principal component space best captured the underlying heterogeneity. To demonstrate utility of these measures, we characterized the diversity in transcriptional and genomic profiles of different breast tumor subtypes, and showed that basal-like or triple-negative breast cancers (TNBC) are significantly more heterogeneous molecularly than other subtypes. Our analysis also suggests that transcriptional diversity is a global characteristic of the tumors observed across the majority of molecular pathways. Among basal-like tumors, those that were resistant to multi-agent chemotherapy showed greater transcriptional diversity compared to chemotherapy-sensitive tumors, suggesting that potentially multiple mechanisms may be contributing to chemotherapy resistance. CONCLUSIONS: We proposed and validated measures of transcriptional and genomic diversity that can quantify the molecular diversity of tumors. We applied the new measures to genomic data from breast tumors and demonstrated that basal-like breast cancers are significantly more diverse than other breast cancers. The observation that chemo-resistant tumors are significantly more diverse molecularly than chemosensitive tumors implies that multiple resistance mechanisms may be active, thus limiting the sensitivity and accuracy of predictive markers of chemotherapy response. PMID- 25294322 TI - Statistical strategies for averaging EC50 from multiple dose-response experiments. AB - In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments. PMID- 25294323 TI - Sterigmatocystin induces G1 arrest in primary human esophageal epithelial cells but induces G2 arrest in immortalized cells: key mechanistic differences in these two models. AB - Sterigmatocystin (ST), a mycotoxin commonly found in food and feed commodities, has been classified as a "possible human carcinogen." Our previous studies suggested that ST exposure might be a risk factor for esophageal cancer and that ST may induce DNA damage and G2 phase arrest in immortalized human esophageal epithelial cells (Het-1A). To further confirm and explore the cellular responses of ST in human esophageal epithelia, we comparatively evaluated DNA damage, cell cycle distribution and the relative mechanisms in primary cultured human esophageal epithelial cells (EPC), which represent a more representative model of the in vivo state, and Het-1A cells. In this study, we found that ST could induce DNA damage in both EPC and Het-1A cells but led to G1 phase arrest in EPC cells and G2 phase arrest in Het-1A cells. Furthermore, our results indicated that the activation of the ATM-Chk2 pathway was involved in ST-induced G1 phase arrest in EPC cells, whereas the p53-p21 pathway activation in ST-induced G2 phase arrest in Het-1A cells. Studies have demonstrated that SV40 large T-antigen (SV40LT) may disturb cell cycle progression by inactivating some of the proteins involved in the G1/S checkpoint. Het-1A is a non-cancerous epithelial cell line immortalized by SV40LT. To evaluate the possible perturbation effect of SV40LT on ST-induced cell cycle disturbance in Het-1A cells, we knocked down SV40LT of Het-1A cells with siRNA and found that under this condition, ST-induced G2 arrest was significantly attenuated, whereas the proportion of cells in the G1 phase was significantly increased. Furthermore, SV40LT-siRNA also inhibited the activation of the p53-p21 signaling pathway induced by ST. In conclusion, our data indicated that ST could induce DNA damage in both primary cultured and immortalized esophageal epithelial cells. In primary human esophageal epithelial cells, ST induced DNA damage and then triggered the ATM-Chk2 pathway, resulting in G1 phase arrest, whereas in SV40LT-immortalized human esophageal epithelial cells, SV40LT mediated G1 checkpoint inactivation occurred, and ST-DNA damage activated p53-p21 signaling pathway, up-regulating G2/M phase regulatory proteins and finally leading to a G2 phase arrest. Thus, the SV40LT-mediated G1 checkpoint inactivation is responsible for the difference in the cell cycle arrest by ST between immortalized and primary cultured human esophageal epithelial cells. PMID- 25294324 TI - Matching oceanography and genetics at the basin scale. Seascape connectivity of the Mediterranean shore crab in the Adriatic Sea. AB - Investigating the interactions between the physical environment and early life history is crucial to understand the mechanisms that shape the genetic structure of marine populations. Here, we assessed the genetic differentiation in a species with larval dispersal, the Mediterranean shore crab (Carcinus aestuarii) in the Adriatic Sea (central Mediterranean), and we investigated the role of oceanic circulation in shaping population structure. To this end, we screened 11 polymorphic microsatellite loci from 431 individuals collected at eight different sites. We found a weak, yet significant, genetic structure into three major clusters: a northern Adriatic group, a central Adriatic group and one group including samples from southern Adriatic and Ionian seas. Genetic analyses were compared, under a seascape genetics approach, with estimates of potential larval connectivity obtained with a coupled physical-biological model that integrates a water circulation model and a description of biological traits affecting dispersal. The cross-validation of the results of the two approaches supported the view that genetic differentiation reflects an oceanographic subdivision of the Adriatic Sea into three subbasins, with circulation patterns allowing the exchange of larvae through permanent connections linking north Adriatic sites and ephemeral connections like those linking the central Adriatic with northern and southern locations. PMID- 25294325 TI - [Laparoscopy can be used to diagnose peritoneal tuberculosis]. AB - A 17-year-old man with weight loss, abdominal pain and fever for three months was admitted to the Digestive Disease Centre. Laboratory tests revealed leucocytosis and a low haemoglobin level, and a CT-scan of the abdomen indicated non-specific abscess cavities. Diagnostic laparoscopy was conducted and widespread pale nodules were found throughout the peritoneum. Consequently, the patient was diagnosed with peritoneal tuberculosis. This case demonstrates that atypical manifestations of tuberculosis exist in Denmark and that laparoscopy with biopsy can be performed to obtain the diagnosis when suspecting peritoneal tuberculosis. PMID- 25294326 TI - [Treatment of traumatic facial injuries]. AB - Correct treatment of traumatic facial lacerations is essential to achieve the best cosmetic and functional outcome. This article discusses wound management, anatomy and techniques to repair lacerations of scalp, eyelid, nose, lip and ear. Scalp lacerations should be sutured in layers. Injury to the eyelid mandates a careful examination of the eye. Accurate adaptation of the lid margin is required. Nasal septum haematoma must be drained and the nares and alar margins aligned. The key to proper repair of lip laceration is alignment of the vermillion border. Injury to the ear can often be closed in one layer. PMID- 25294327 TI - [The use of antithyroid drugs should be reduced as much as possible in the first trimester]. AB - The treatment of choice for hyperthyroidism in pregnancy is antithyroid drugs, but the potential risk of birth defects is of major concern. For the use of thiamazole and carbimazole, there is consistent evidence of an increased risk of birth defects, which are often severe. For the use of propylthiouracil, the evidence is less clear. These birth defects may be less severe, and a Danish study which included all birth defects diagnosed before the age of two years showed an increased risk of birth defects in the face and neck region and in the urinary system after the use of propylthouracil. PMID- 25294328 TI - [Quick simultaneous analyses are important when MERS-coronavirus infection is suspected]. AB - In September 2012 a novel coronavirus (CoV) caused severe respiratory tract infections in patients from The Arabian Peninsula. It was named Middle East respiratory syndrome (MERS)-CoV. Here, a small series of case stories illustrates how simultaneous analyses for MERS-CoV and other agents of infections at the loca l laboratory resulted in rapid rejection of suspicion of MERS and establishment of the true cause of disease. Relevant treatment was initiated and the patients were discharged from hospital. PMID- 25294329 TI - [The Danish National Quality Project about heart failure indicates lack of reporting and treatment of the elderly]. AB - The Danish National Quality Project about heart failure has improved care for the patients considerably by insisting on evidence-based treatment in hospitals and heart failure clinics. Regrettably, according to data there is marked underrepresentation of patients 75-year-old and older, and especially a lack of women in this age group in the project. This discrimination towards the elderly and especially towards elderly women could possibly be solved by out-of-hospital screening for heart failure among these patients. PMID- 25294330 TI - [Mechanical circulatory support by means of a subclavian pump in a patient suffering acute heart failure]. AB - A 65-year-old female patient suffered biventricular failure due to severe lymphoid myocarditis. Mechanical circulatory support was established with peripheral arterial-venous extracorporeal membrane oxygenation (AV-ECMO). The left ventricle was relieved by subclavian Impella 5.0. AV-ECMO was weaned with the use of only Impella 5.0 until the 17th day of use, whereupon Impella was phased out. This case report illustrates the use-fulness of combined peripheral VA-ECMO with subclavian Impella 5.0 with the prospect of single use of the subclavian Impella 5.0 until cardiac recovery thereby avoiding central cannulation. PMID- 25294331 TI - [Idiopathic pulmonary haemosiderosis in a one-year-old girl with Down syndrome]. AB - Idiopathic pulmonary haemosiderosis (IPH) is a rare disease. We describe a girl with Down syndrome who had no major respiratory symptoms until one year of age, where recurrent airway infections and chronic anaemia of unknown aetiology developed. At 20 months of age she had intermittent haemo-ptysis, was investigated with computed tomography and broncho-alveolar lavage and was diagnosed with IPH. After treatment, respiratory symptoms and anaemia resolved and a positive impact on previously impaired growth and psychomotor development was seen. Paediatricians should consider IPH in children with recurrent respiratory symptoms and anaemia. PMID- 25294332 TI - [Pompe disease is a differential diagnosis in case of reduced physical capacity and abnormal muscular fatigue]. AB - Late-onset Pompe disease is an inherited metabolic myopathy with low activity of alpha glucosidase and variable clinical symptoms. In this case report we describe a woman with long standing muscular fatigue and malaise with the diagnosis initially established by pathologic findings in the muscle biopsy. Enzyme replacement therapy is now a treatment option, and a prompt diagnosis is therefore relevant. This disease should be considered in patients with unexplained fatigue and reduced physical capacity, especially in case of concurrent elevated levels of creatine kinase and liver enzymes. PMID- 25294333 TI - [Acute haemorrhagic oedema of infancy]. AB - This is a case report of acute haemorrhagic oedema of infancy. An 11-month-old boy with a prolonged relapsing course within three weeks with fever and an increase in CRP necessitating antibiotic treatment. This disease is a leukocytoclastic vasculitis sharing features with Schonlein-Henoch purpura, but with a more benign self-limiting course with minimal risk of organ involvement. The characteristic distribution and appearance of the cutaneous symptoms often allows a clinical diagnosis of the condition. PMID- 25294334 TI - [Two cases of severe variceal haemorrhage from an ileal conduit]. AB - Variceal haemorrhage from an ileal conduit is a rare but well-known complication to portal hypertension. Many treatments are described and a transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice if possible, because this addresses the underlying portal hypertension. We report two cases of haemorrhage from an ileal conduit, which illustrates that treatment must be individualized with attention to life expectancy, co-morbidities and degree of the portosystemic pressure gradient, but TIPS treatment has to be considered even if there is no history of liver disease. PMID- 25294335 TI - Mathematical model of adherent Vero cell growth and poliovirus production in animal component free medium. AB - Sabin-IPV (or sIPV, inactivated polio vaccine based on attenuated Sabin strains) is anticipated to replace the oral polio vaccine for the endgame in polio eradication. Optimization of sIPV production will lead to a better economically feasible vaccine. To assist process optimization, we studied Sabin type 1 poliovirus (PV) infection kinetics on Vero cells in controlled bioreactor vessels. The aim of our study was to develop a descriptive mathematical model able to capture the dynamics of adherent Vero cell growth and PV infection kinetics in animal component free medium. The model predicts the cell density, metabolites profiles, and viral yields in time. We found that the multiplicity of infection (MOI) and the time of infection (TOI) within the investigated range did not affect maximal PV yields, but they did affect the process time. The latter may be reduced by selecting a low TOI and a high MOI. Additionally, we present a correlation between viral titers and D-antigen, a measure for immunogenicity, of Sabin type 1 PV. The developed model is adequate for further studies of the cell metabolism and infection kinetics and may be used to identify control strategies to increase viral productivity. Increased viral yields reduce costs of polio vaccines with large implications on public health. PMID- 25294336 TI - Proteomic analysis of residual proteins in blades and petioles of fallen leaves of Brassica napus. AB - Brassica napus L. is an important crop plant, characterised by high nitrogen (N) levels in fallen leaves, leading to a significant restitution of this element to the soil, with important consequences at the economic and environmental levels. It is now well established that the N in fallen leaves is due to weak N remobilisation that is especially related to incomplete degradation of foliar proteins during leaf senescence. Identification of residual proteins in a fallen leaf (i.e. incompletely degraded in the last step of the N remobilisation process) constitutes important information for improving nutrient use efficiency. Proteome analysis of the vascular system (petioles) and blades from fallen leaves of Brassica napus was performed, and the 30 most abundant residual proteins in each tissue were identified. Among them, several proteins involved in N recycling remain in the leaf after abscission. Moreover, this study reveals that some residual proteins are associated with energy metabolism, protection against oxidative stress, and more surprisingly, photosynthesis. Finally, comparison of blade and petiole proteomes show that, despite their different physiological roles in the non-senescing leaf, both organs redirect their metabolism in order to ensure catabolic reactions. Taken together, the results suggest that a better degradation of these leaf proteins during the senescence process could enable improvements in the N use efficiency of Brassica napus. PMID- 25294337 TI - Combining Peyton's four-step approach and Gagne's instructional model in teaching slit-lamp examination. AB - Developing skills in performing basic slit-lamp biomicroscopy is an important element of the ophthalmology undergraduate curriculum. As a doctor working in an ophthalmology department, I often provide slit-lamp teaching for medical students. This paper describes a lesson plan for this technique using Gagne's nine events of instruction. The presented lesson plan is a combination of Gagne's nine events of instruction and Peyton's four-step approach. Gagne's nine events of instruction correlate with and address the mental conditions of learning when adult learners are presented with various stimuli. Peyton's four-step approach is a model for teaching practical skills that consists of demonstration, deconstruction, explanation, and performance. This article describes a slit-lamp biomicroscopy teaching session using Gagne's nine events of instruction. Each step is carefully elaborated with relevant activities to suit learners with various learning styles. Peyton's approach is used to teach the actual skill. This lesson plan is particularly relevant for tutors designing slit-lamp biomicroscopy teaching for undergraduate students, foundation doctors, general practitioners and emergency department staff. Ultimately, this lesson plan also serves as a model that is applicable for acquiring many other practical skills. The flexible adoption of Gagne's nine events of instruction in combination with other teaching models helps in the planning of effective teaching sessions. PMID- 25294339 TI - A low-cost mesocosm for the study of behaviour and reproductive potential in Afrotropical mosquito (Diptera: Culicidae) vectors of malaria. AB - A large-scale mesocosm was constructed and tested for its effectiveness for use in experiments on behaviour, reproduction and adult survivorship in the Afrotropical malaria vector Anopheles gambiae s.s. Giles (Diptera: Culicidae) in temperate climates. The large space (82.69 m(3) ) allowed for semi-natural experiments that increased demand on a mosquito's energetic reserves in an environment of widely distributed resources. A one-piece prefabricated enclosure, made with white netting and vinyl, prevented the ingress of predators and the egress of mosquitoes. Daylight and white materials prompted the mosquitoes to seclude themselves in restricted daytime resting sites and allowed the easy collection of dead bodies so that daily mortality could be assessed accurately using a method that accounts for the loss of a proportion of bodies. Here, daily, age-dependent mortality rates of males and females were estimated using Bayesian Markov chain Monte Carlo simulation. In overnight experiments, mosquitoes successfully located plants and took sugar meals. A 3-week survival trial with a single cohort demonstrated successful mating, blood feeding, oviposition and long life. The relatively low cost of the mesocosm and the performance of the mosquitoes in it make it a viable option for any behavioural or ecological study of tropical mosquitoes in which space and seasonal cold are constraining factors. PMID- 25294338 TI - Ostreid herpesvirus type 1 replication and host response in adult Pacific oysters, Crassostrea gigas. AB - Since 2008, massive mortality outbreaks associated with OsHV-1 detection have been reported in Crassostrea gigas spat and juveniles in several countries. Nevertheless, adult oysters do not demonstrate mortality in the field related to OsHV-1 detection and were thus assumed to be more resistant to viral infection. Determining how virus and adult oyster interact is a major goal in understanding why mortality events are not reported among adult Pacific oysters. Dual transcriptomics of virus-host interactions were explored by real-time PCR in adult oysters after a virus injection. Thirty-nine viral genes and five host genes including MyD88, IFI44, IkB2, IAP and Gly were measured at 0.5, 10, 26, 72 and 144 hours post infection (hpi). No viral RNA among the 39 genes was detected at 144 hpi suggesting the adult oysters are able to inhibit viral replication. Moreover, the IAP gene (oyster gene) shows significant up-regulation in infected adults compared to control adults. This result suggests that over-expression of IAP could be a reaction to OsHV-1 infection, which may induce the apoptotic process. Apoptosis could be a main mechanism involved in disease resistance in adults. Antiviral activity of haemolymph against herpes simplex virus (HSV-1) was not significantly different between infected adults versus control. PMID- 25294340 TI - Success stories of implementation of antimicrobial stewardship: a narrative review. AB - It has been increasingly recognized that antimicrobial stewardship (AMS) has to be a key component of any efforts that aim to mitigate the current global antimicrobial resistance (AMR) crisis. It has also become evident that AMR is a problem that cannot be tackled by single institutions or physicians, but needs concerted actions at regional, national and supra-national levels. However, it is easy to become discouraged, given the problems that are often encountered when implementing AMS. The aim of this review is to highlight some of the success stories of AMS strategies, and to describe the actions that have been taken, the outcomes that have been obtained, and the obstacles that have been met. Although the best approach to effective AMS remains elusive and may vary significantly among settings, these diverse examples from a range of healthcare contexts demonstrate that effective AMS is possible. Such examples will inform others and encourage them to formally evaluate and share their results with the global stewardship community. PMID- 25294341 TI - Opportunities and challenges of nanotechnology in the green economy. AB - In a world of finite resources and ecosystem capacity, the prevailing model of economic growth, founded on ever-increasing consumption of resources and emission pollutants, cannot be sustained any longer. In this context, the "green economy" concept has offered the opportunity to change the way that society manages the interaction of the environmental and economic domains. To enable society to build and sustain a green economy, the associated concept of "green nanotechnology" aims to exploit nano-innovations in materials science and engineering to generate products and processes that are energy efficient as well as economically and environmentally sustainable. These applications are expected to impact a large range of economic sectors, such as energy production and storage, clean up technologies, as well as construction and related infrastructure industries. These solutions may offer the opportunities to reduce pressure on raw materials trading on renewable energy, to improve power delivery systems to be more reliable, efficient and safe as well as to use unconventional water sources or nano-enabled construction products therefore providing better ecosystem and livelihood conditions.However, the benefits of incorporating nanomaterials in green products and processes may bring challenges with them for environmental, health and safety risks, ethical and social issues, as well as uncertainty concerning market and consumer acceptance. Therefore, our aim is to examine the relationships among guiding principles for a green economy and opportunities for introducing nano-applications in this field as well as to critically analyze their practical challenges, especially related to the impact that they may have on the health and safety of workers involved in this innovative sector. These are principally due to the not fully known nanomaterial hazardous properties, as well as to the difficulties in characterizing exposure and defining emerging risks for the workforce. Interestingly, this review proposes action strategies for the assessment, management and communication of risks aimed to precautionary adopt preventive measures including formation and training of employees, collective and personal protective equipment, health surveillance programs to protect the health and safety of nano-workers. It finally underlines the importance that occupational health considerations will have on achieving an effectively sustainable development of nanotechnology. PMID- 25294342 TI - Involvement of inducible nitric oxide synthase and dimethyl arginine dimethylaminohydrolase in Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. AB - Chronic administration of Nomega-nitro-L-arginine methyl ester (L-NAME) in rats is a chemical method to study the induction and progression of nitric oxide (NO) deficiency-induced endothelial dysfunction. Male Wistar rats received L-NAME (50 mg/kg/day in drinking water) or no drug for 6 weeks. Mean arterial pressure (MAP) was measured on Day 43 by carotid artery cannulation. Plasma interleukin 1beta (IL-1beta) level was measured by enzyme-linked immunosorbent assay. Aorta and carotid artery were isolated for determination of basal nitrite, cGMP production, soluble guanylylcyclase (sGC) activity, phosphodiesterase-5 (PDE5) activity, and dimethylarginine dimethylaminohydrolase (DDAH) activity. mRNA expression studies were done by real time-polymerase chain reaction. L-NAME induced an increase in MAP and plasma IL-1beta. The treatment had varied effect on endothelial nitric oxide synthase (eNOS), sGC, and PDE5 but showed an increase in inducible NOS (iNOS) mRNA expression and plasma asymmetric dimethyl arginine levels. Basal nitrite, cGMP levels, sGC activity, and DDAH activity were significantly decreased in the tissues. Brief incubation of tissues in vitro with 1400 W, a specific iNOS blocker, partially reversed sGC activity, and cGMP levels. The results of this study showed that L-NAME-mediated inhibition of eNOS is only partially responsible for the vascular pathology observed in this model. Secondary effects that include an increase in iNOS and a decrease in DDAH activity are likely to be the causative factors for the progression of vascular dysfunction. PMID- 25294343 TI - The healing journey: help seeking for self-injury among a community population. AB - Help seeking is known to be a complex and difficult journey for people who self injure. In this article, we explore the process of help seeking from the perspective of a group of people living in Northern Ireland with a history of self-injury. We conducted 10 semistructured interviews and employed a grounded theory approach to data analysis. We created two major categories from the interview transcript data: (a) "involution of feeling," which depicts participants' perspectives on barriers to help seeking; and (b) "to be treated like a person," in which participants communicate their experiences of help seeking. The findings pose important implications for policy, practice, theory, and future research, including the need to increase the uptake of follow-up care among people who arrive at hospitals as a result of self-injury, self-harm, or suicidal behaviors. PMID- 25294344 TI - Same agency, different teams: perspectives from home and inpatient hospice care. AB - Tremendous growth in hospice over the past 30 years in the United States has increased the number of terminally ill patients dying at home. Recently, however, more hospice patients are dying at inpatient facilities. To understand the varying perceptions about care in the home and inpatient hospice, we conducted semistructured interviews with 24 interdisciplinary team (IDT) members and analyzed the data using the constant comparative method. Core interdisciplinary tasks, including identifying the focus of energy, tailoring family caregiver involvement, acknowledging who is in charge, and knowing both sides differed in the home and inpatient settings. Despite the overarching umbrella of hospice care, home and inpatient hospice settings create different foci for IDT members, burdens and privileges for family caregivers, and control of the care plan. Key differences between home and inpatient hospice processes of care highlight the complexity of patient-centered end-of-life care in the United States. PMID- 25294345 TI - Preparing Heart and Mind for Becoming a Parent Following a Diagnosis of Fetal Anomaly. AB - Using a cross-sectional, grounded dimensional analysis study design, we collected demographic and health information and conducted telephone interviews with 37 expectant parents of 26 fetuses within 25 families. We describe a theoretical model with a core process of preparing heart and mind for becoming a parent following a diagnosis of fetal anomaly. The process of preparing was influenced by fetal and future child health, experiences of previous loss, and social interactions within both new and familiar settings. Expectant parents reported varying turning points and strategies associated with three distinct trajectories of relating to the fetus or "baby" yet to be born. These relational trajectories include claiming the child as one's own, delaying the connection to the fetus, and doing the routine of pregnancy. With the findings presented in this article, we extend the understanding of how parenting develops during pregnancy in the context of a fetal anomaly. PMID- 25294346 TI - Accounting for psychotropic medication changes in prisons: patient and doctor perspectives. AB - Psychotropic medicines are widely used to treat mental illness; however, people entering prison commonly report that prescribed psychotropic medicines are changed or withdrawn, adding to their distress in difficult times. Drawing on three extracts from a larger qualitative dataset in which patients and doctors were interviewed about psychotropic medication use in English prisons, we combined discursive psychological and Foucauldian discourse analysis techniques to examine how individuals accounted for medication changes. Patients used four discursive strategies to organize descriptions of medication changes: they established entitlement to psychotropic medication, questioned the clinical judgment of prison doctors; highlighted communication problems; and attributed negative health outcomes to medication regime changes. In contrast, we examined an effective defense by a general practitioner, which showed how clinical needs were prioritized over previously held prescriptions when making prescribing decisions. Wider implications for continuity and equivalence of care between prisons and the wider community are discussed. PMID- 25294347 TI - Characteristics of lifelong physically active older adults. AB - Most adults in developed countries fail to accrue enough regular physical activity to prevent or decrease the impact of chronic diseases associated with aging. I conducted semistructured interviews with 16 purposely selected older adults ranging in age from 53 to 70 years to explore the practices of successful lifelong adherents to physical activity. I used an interpretive descriptive approach to data analysis. My findings suggest that both social and competitive motivations were important during early adulthood, although for many participants the latter were more likely to endure over time. Based on these findings, I recommend that programmers be aware of the potential for older participants to be less fulfilled by social motivations as they become more experienced exercisers. PMID- 25294348 TI - Foucault, surveillance, and carbon monoxide testing within stop-smoking services. AB - Health professionals have adopted proactive testing for early evidence of disease. Researchers have identified that this leads to enumerated understandings and shapes behavior in productive ways. Smoking-cessation advisors regularly test clients for carbon monoxide (CO), but client views of this had not previously been explored. We interviewed 23 clients of a United Kingdom-based stop-smoking service regarding their experiences of CO testing. The majority of participants were successful quitters. We used ATLAS.ti 7 as a data-management tool during structured qualitative analysis. Our findings reveal that clients believed the results of their CO tests. Many became enumerated in their understanding, and thus placed themselves in a hierarchy with other members of their group. Almost all clients found that knowing their CO test score was motivating. We conclude that additional research is needed to understand the experiences of CO testing among clients who do not quit. PMID- 25294349 TI - Exploring the experiences of people with hypo- and hyperthyroidism. AB - Thyroid diseases evoke a complex range of psychological and physical symptoms. The psychosocial aspects of living with diseases causing hypo- or hyperthyroidism are poorly understood. In this article, we report the findings of a qualitative interview study in which we explored the lived experiences of 16 people with hypo or hyperthyroidism. We purposefully selected participants from Danish outpatient clinics according to their diagnosis (Hashimoto's thyroiditis or Graves' disease with or without orbitopathy), age (18 to 65 years), and duration of treatment (more than 6 months). We used interpretative phenomenological analysis (IPA) as a theoretical frame and analytical approach and identified three superordinate themes: losing control over mental and physical states, ambiguous signs of disease, and negotiating sickness. We discuss the findings in the context of the recent literature on chronic illness and argue that these themes play an important role in the conceptualization and management of thyroid diseases. PMID- 25294350 TI - Emerging practice concerning vitamin D in primary care. AB - The establishment of practice patterns concerning the diagnosis and management of hypovitaminosis D seems to be heterogeneous among primary care physicians. We conducted a qualitative study to explore the emerging practices among primary care providers regarding screening and treatment for hypovitaminosis D, as well as factors that influence practice patterns. Trained researchers facilitated focus groups among primary care providers. We followed a grounded theory approach to transcript coding and analysis using ATLAS.ti analysis software. Testing or screening for hypovitaminosis D and subsequent replacement or supplementation practices varied among participants. Emerging practice concerning vitamin D appears to be constructed and reinforced by patient demand; incidental reading; brief, purposeful research; conversations with colleagues; results of consultations by specialists; and more patient demand. A multifaceted approach to promoting guideline adherence will be required to influence this practice. PMID- 25294351 TI - Families, markets, and medicalization: the role of paid support for childbirth and breastfeeding. AB - Much attention has been given to the commercialization of care and its relationship to the outsourcing of family life, as well as larger social and cultural processes that can change the nature of caring. I engage with this question of why certain aspects of care are provided by the market, using 72 interviews with lactation consultants, doulas, clients, and clinicians, as well as 150 hours of ethnographic observation in the USA. Examining how participants understood the role of these services in the maternity care system and the reasons why clients turned to these services, I found that, in several ways, these forms of care work reflected outsourcing trends. However, lactation consultants and doulas were also acting as advocates and guides, helping their clients navigate the complex medical maternity system. This reflects a fundamental transformation in the nature of maternity support, attributed to the impact of medicalization, both historically and currently. PMID- 25294352 TI - Do Drug-Dependent Patients Attending Alcoholics Anonymous Rather than Narcotics Anonymous Do As Well? A Prospective, Lagged, Matching Analysis. AB - AIMS: Alcoholics Anonymous (AA) is the most prevalent 12-step mutual-help organization (MHO), yet debate has persisted clinically regarding whether patients whose primary substance is not alcohol should be referred to AA. Narcotics Anonymous (NA) was created as a more specific fit to enhance recovery from drug addiction; however, compared with AA, NA meetings are not as ubiquitous. Little is known about the effects of a mismatch between individuals' primary substance and MHOs, and whether any incongruence might result in a lower likelihood of continuation and benefit. More research would inform clinical recommendations. METHOD: Young adults (N = 279, M age 20.4, SD 1.6, 27% female; 95% White) in a treatment effectiveness study completed assessments at intake, and 3, 6, and 12 months post-treatment. A matching variable was created for 'primary drug' patients (i.e. those reporting cannabis, opiates or stimulants as primary substance; n = 198/279), reflecting the proportion of total 12-step meetings attended that were AA. Hierarchical linear models (HLMs) tested this variable's effects on future 12-step participation and percent days abstinent (PDA). RESULTS: The majority of meetings attended by both alcohol and drug patients was AA. Drug patients attending proportionately more AA than NA meetings (i.e. mismatched) were no different than those who were better matched to NA with respect to future 12-step participation or PDA. CONCLUSION: Drug patients may be at no greater risk of discontinuation or diminished recovery benefit from participation in AA relative to NA. Findings may boost clinical confidence in making AA referrals for drug patients when NA is less available. PMID- 25294354 TI - Participation: are we there yet... PMID- 25294353 TI - Evaluation of proliferating cell abundance and phenotypes in proliferative diabetic retinopathy. AB - BACKGROUND: The aim of this work is to evaluate the abundance, origins, and phenotypes of actively proliferating cells in proliferative diabetic retinopathy (PDR). METHODS: Eleven epiretinal membranes from patients undergoing surgery for PDR were evaluated by indirect immunofluorescence for evidence of cell proliferation using the nuclear cell proliferation marker Ki67 and for cell identities using glial fibrillary acidic protein (GFAP), glutamine synthetase, and alpha-smooth muscle actin (alphaSMA). RESULTS: Ki67 positivity was consistently rare in PDR epiretinal membranes at 3.02 +/- 1.42 % of the total cell population. The majority of the Ki67-positive cells were also positive for GFAP (74.0 %) with lower proportions positive for alphaSMA (30.7 %) and glutamine synthetase (1.5 %). Co-localization studies using glial and myoid markers revealed that virtually all (92 %) of the alphaSMA-positive cells are also GFAP positive and thus derive from glia. CONCLUSIONS: Entry into cell cycle and thus cell proliferation appears to be a rare phenomenon in PDR involving only a small percentage of the total cell population. Glia and/or glial-derived myofibroblasts appear to be the predominate cell types in epiretinal scar tissues and also account for the majority of the actively proliferating cells. PMID- 25294355 TI - A peer-mediated school intervention significantly improved the social skills and playground interactions of children with autism spectrum disorder. PMID- 25294356 TI - An online psycho-educational intervention for parents did not impact parent or child post-traumatic stress symptoms more than usual care for children following injury. PMID- 25294358 TI - Kikuchi-Fujimoto disease: report of 4 cases and review of the literature. AB - INTRODUCTION: Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a benign disease of unknown origin predominantly affecting young women and presenting in the form of cervical lymphadenopathy and/or prolonged fever. MATERIAL AND METHODS: The authors report 4 cases of Kikuchi-Fujimoto disease diagnosed in the Internal Medicine Department of Ibn Sina university hospital in Rabat between 2009 and 2010. RESULTS: These 4 women with a mean age of 27+/ 8.6years [16-37] were admitted with febrile syndrome and cervical lymphadenopathy. The diagnosis was based on histological examination of a lymph node biopsy. The disease was associated with systemic lupus erythematosus in one case and actinomycosis in another case. A favourable course was observed in response to corticosteroid therapy in two patients, antibiotic therapy in one patient and antipyretic treatment alone in the fourth patient. CONCLUSION: In the light of these four cases, the authors discuss the diagnostic difficulties, the modalities of treatment of Kikuchi-Fujimoto disease and its clinical course. PMID- 25294359 TI - Greater shrub dominance alters breeding habitat and food resources for migratory songbirds in Alaskan arctic tundra. AB - Climate warming is affecting the Arctic in multiple ways, including via increased dominance of deciduous shrubs. Although many studies have focused on how this vegetation shift is altering nutrient cycling and energy balance, few have explicitly considered effects on tundra fauna, such as the millions of migratory songbirds that breed in northern regions every year. To understand how increasing deciduous shrub dominance may alter breeding songbird habitat, we quantified vegetation and arthropod community characteristics in both graminoid and shrub dominated tundra. We combined measurements of preferred nest site characteristics for Lapland longspurs (Calcarius lapponicus) and Gambel's White-crowned sparrows (Zonotrichia leucophrys gambelii) with modeled predictions for the distribution of plant community types in the Alaskan arctic foothills region for the year 2050. Lapland longspur nests were found in sedge-dominated tussock tundra where shrub height does not exceed 20 cm, whereas White-crowned sparrows nested only under shrubs between 20 cm and 1 m in height, with no preference for shrub species. Shrub canopies had higher canopy-dwelling arthropod availability (i.e. small flies and spiders) but lower ground-dwelling arthropod availability (i.e. large spiders and beetles). Since flies are the birds' preferred prey, increasing shrubs may result in a net enhancement in preferred prey availability. Acknowledging the coarse resolution of existing tundra vegetation models, we predict that by 2050 there will be a northward shift in current White-crowned sparrow habitat range and a 20-60% increase in their preferred habitat extent, while Lapland longspur habitat extent will be equivalently reduced. Our findings can be used to make first approximations of future habitat change for species with similar nesting requirements. However, we contend that as exemplified by this study's findings, existing tundra modeling tools cannot yet simulate the fine-scale habitat characteristics that are critical to accurately predicting future habitat extent for many wildlife species. PMID- 25294360 TI - Y chromosome in Turner syndrome: detection of hidden mosaicism and the report of a rare X;Y translocation case. AB - Turner syndrome (TS) is a common genetic disorder in females associated with the absence of complete or parts of a second sex chromosome. In 5-12% of patients, mosaicism for a cell line with a normal or structurally abnormal Y chromosome is identified. The presence of Y-chromosome material is of medical importance because it results in an increased risk of developing gonadal tumours and virilisation. Molecular study and fluorescence in situ hybridisation approaches were used to study 74 Brazilian TS patients in order to determine the frequency of hidden Y-chromosome mosaicism, and to infer the potential risk of developing malignancies. Additionally, we describe one TS girl with a very uncommon karyotype 46,X,der(X)t(X;Y)(p22.3?2;q11.23) comprising a partial monosomy of Xp22.3?2 together with a partial monosomy of Yq11.23. The presence of cryptic Y chromosome-specific sequences was detected in 2.7% of the cases. All patients with Y-chromosome-positive sequences showed normal female genitalia with no signs of virilisation. Indeed, the clinical data from Y-chromosome-positive patients was very similar to those with Y-negative results. Therefore, we recommend that the search for hidden Y-chromosome mosaicism should be carried out in all TS cases and not be limited to virilised patients or carriers of a specific karyotype. PMID- 25294361 TI - Structure, histochemistry, ultrastructure and seasonal variations of the male prostatic complex in the black Myotis bat, Myotis nigricans (Chiroptera: Vespertilionidae). AB - Chiroptera are one of the most diverse orders of mammals and a unique group within Mammalia that posses a wide geographic distribution and considerable variability in reproductive strategies. The aims of the present study were to characterise the male prostatic complex of the bat Myotis nigricans (Vespertilionidae) and evaluate seasonal variations in the prostatic complex of M. nigricans specifically. Twenty-three sexually mature specimens (four sample groups: winter, spring, summer and autumn) were subjected to macroscopic, microscopic, morphometric and ultrastructural analyses. The reproductive accessory glands of M. nigricans were found to be composed of a multilobed complex associated with the urethra and a pair of inguinal bulbourethral glands. The complex was composed of three bilobed prostatic regions (ventral, dorsolateral and dorsal) with no ampullary gland and seminal vesicles. This pattern of lobulation is very similar to that described for the prostate of rodents; however, it differs from that of other mammals and even other families of bats (e.g. Phyllostomidae and Molossidae). Each prostatic region in M. nigricans has unique and distinctive characteristics, which synchronise to establish the main reproductive peak of the species in summer. The data also indicated an asynchrony in the activity of primary and secondary reproductive organs in the annual reproductive cycle of M. nigricans in Sao Paulo State, Brazil. PMID- 25294363 TI - How polymers lose memory with age. AB - Uniquely in the world of materials, polymers deformed at high temperature and subsequently quenched at low temperature, memorize the temperature at which they have been processed. Polymers can even memorize multiple temperatures. This temperature memory is reflected by a maximum of residual stress restored at the temperature of initial processing. It has been speculated that this capability could arise from the presence of dynamical heterogeneities in glassy domains of polymers. Processing the material at a given temperature would result in the selection of certain heterogeneities that participate in the storage of mechanical stress. Because dynamical heterogeneities are associated with particular relaxation times, the temperature memory of polymers should depend on the time, for example, the glass transition temperature depends on the frequency. The first experimental study of temporal effects on the temperature memory of polymers is presently reported. It is found that aging at high temperature shifts the maximum of residual stress towards greater temperatures. The corresponding loss of memory is explained by the relaxation of dynamical heterogeneities with short characteristic times. The present results clarify the origin of the temperature memory and provide insights into their efficient exploitation in applications. PMID- 25294362 TI - Determinants of Quality of Life in Stroke Survivors After 6 Months, from a Comprehensive Stroke Unit: A Longitudinal Study. AB - BACKGROUND: In the social model of stroke, health-related quality of life (HRQoL) is the result of interplay among stroke severity, social support, and health promoting behaviors. Our objective was to identify determinants of HRQoL in stroke survivors. METHODS: Ischemic stroke patients were evaluated at 6 months with the Short Form 12 Health Survey, including physical component survey (PCS) and mental health component survey (MCS) summary scores. Multivariate stepwise regression analyses determined independent predictors of scores. Models included age, gender, socioeconomic class, education, residential environment, social support, previous comorbidity (Charlson Index), previous stroke, side of stroke, National Institutes of Health Stroke Scale (NIHSS) score at admission, Barthel Index (BI) and modified Rankin Scale (mRS) scores at discharge, and length of stay. RESULTS: A total of 131 patients participated (mean age 70.1, SD = 12.5; 62.6% males). In all, 33.6% had a BI score <90 and an mRS score >2 (poor outcome). The mean (SD) PCS score was 39.46 (9.3) and mean (SD) MCS score was 34.86 (10.1). Lower PCS score was associated with female sex (beta = 0.204, p = .009), poor social support (beta = -0.225, p = .003), and poor Charlson Index (beta = -0.162, p = .032) and BI scores (beta = 0.384, p < .0001). Lower MCS score was associated with female sex (beta = 0.162, p = .062) and poor NIHSS (beta = -0.265, p = .019) and BI scores (beta = 0.203, p < .071). CONCLUSION: Stroke severity, disability, gender, social support, and previous stroke have significant impacts on the physical and mental domains of generic HRQoL. PMID- 25294365 TI - Oral hygiene reduces the mortality from aspiration pneumonia in frail elders. PMID- 25294364 TI - Denture wearing during sleep doubles the risk of pneumonia in the very elderly. AB - Poor oral health and hygiene are increasingly recognized as major risk factors for pneumonia among the elderly. To identify modifiable oral health-related risk factors, we prospectively investigated associations between a constellation of oral health behaviors and incident pneumonia in the community-living very elderly (i.e., 85 years of age or older). At baseline, 524 randomly selected seniors (228 men and 296 women; mean age, 87.8 years) were examined for oral health status and oral hygiene behaviors as well as medical assessment, including blood chemistry analysis, and followed up annually until first hospitalization for or death from pneumonia. During a 3-year follow-up period, 48 events associated with pneumonia (20 deaths and 28 acute hospitalizations) were identified. Among 453 denture wearers, 186 (40.8%) who wore their dentures during sleep were at higher risk for pneumonia than those who removed their dentures at night (log rank P = 0.021). In a multivariate Cox model, both perceived swallowing difficulties and overnight denture wearing were independently associated with an approximately 2.3-fold higher risk of the incidence of pneumonia (for perceived swallowing difficulties, hazard ratio [HR], 2.31; and 95% confidence interval [CI], 1.11-4.82; and for denture wearing during sleep, HR, 2.38; and 95% CI, 1.25-4.56), which was comparable with the HR attributable to cognitive impairment (HR, 2.15; 95% CI, 1.06-4.34), history of stroke (HR, 2.46; 95% CI, 1.13-5.35), and respiratory disease (HR, 2.25; 95% CI, 1.20-4.23). In addition, those who wore dentures during sleep were more likely to have tongue and denture plaque, gum inflammation, positive culture for Candida albicans, and higher levels of circulating interleukin-6 as compared with their counterparts. This study provided empirical evidence that denture wearing during sleep is associated not only with oral inflammatory and microbial burden but also with incident pneumonia, suggesting potential implications of oral hygiene programs for pneumonia prevention in the community. PMID- 25294367 TI - Methods and procedures in adipose stem cells: state of the art and perspective for translation medicine. AB - Stem cells have potential in the retrieval and repair of injured tissue and renovation of organ function. To date, several studies have been carried out to elucidate how differentiation of stem cells can be used in regenerative medicine applications. Adipose tissue is an abundant and accessible source of stem cell, useful for regenerative therapeutic use. Adipose stem cells (ASCs) are favorable for future translational research and can be applied in many clinical settings. Adipose tissue repair has been recently adopted in clinical trials to prove that ASCs can be successfully used in patients. Variability in cell culture procedures (isolation, characterization, and differentiation) may have an influence on the experimental outcome. In this report, we consider the selection mechanisms of ASCs using flow cytometry, cell culture, freezing/thawing, cell cycle evaluation, histochemistry/immunofluorescence, and differentiation of ASCs. Both researchers and regulatory institutions should consider a new policy for GMP procedures and protocols, paying special attention to stem cell bio-physiology, to facilitate more clinically oriented studies. ASCs show angiogenic properties, with prospects of repairing tissue damaged by radiotherapy, as well as possessing the ability to heal chronic wounds. They can also be useful in surgical practice. We focus on the potential clinical application of ASCs that are currently available regarding translational medicine and the methods and procedures for their isolation, differentiation, and characterization. PMID- 25294366 TI - Pathogenesis of Middle East respiratory syndrome coronavirus. AB - Human coronaviruses (CoVs) mostly cause a common cold that is mild and self limiting. Zoonotic transmission of CoVs such as the recently identified Middle East respiratory syndrome (MERS)-CoV and severe acute respiratory syndrome (SARS) CoV, on the other hand, may be associated with severe lower respiratory tract infection. This article reviews the clinical and pathological data available on MERS and compares it to SARS. Most importantly, chest radiographs and imaging results of patients with MERS show features that resemble the findings of organizing pneumonia, different from the lesions in SARS patients, which show fibrocellular intra-alveolar organization with a bronchiolitis obliterans organizing pneumonia-like pattern. These findings are in line with differences in the induction of cytopathological changes, induction of host gene responses and sensitivity to the antiviral effect of interferons in vitro when comparing both MERS-CoV and SARS-CoV. The challenge will be to translate these findings into an integrated picture of MERS pathogenesis in humans and to develop intervention strategies that will eventually allow the effective control of this newly emerging infectious disease. PMID- 25294368 TI - VA-086 methacrylate gelatine photopolymerizable hydrogels: A parametric study for highly biocompatible 3D cell embedding. AB - The ability to replicate in vitro the native extracellular matrix (ECM) features and to control the three-dimensional (3D) cell organization plays a fundamental role in obtaining functional engineered bioconstructs. In tissue engineering (TE) applications, hydrogels have been successfully implied as biomatrices for 3D cell embedding, exhibiting high similarities to the natural ECM and holding easily tunable mechanical properties. In the present study, we characterized a promising photocrosslinking process to generate cell-laden methacrylate gelatin (GelMA) hydrogels in the presence of VA-086 photoinitiator using a ultraviolet LED source. We investigated the influence of prepolymer concentration and light irradiance on mechanical and biomimetic properties of resulting hydrogels. In details, the increasing of gelatin concentration resulted in enhanced rheological properties and shorter polymerization time. We then defined and validated a reliable photopolymerization protocol for cell embedding (1.5% VA-086, LED 2 mW/cm2) within GelMA hydrogels, which demonstrated to support bone marrow stromal cells viability when cultured up to 7 days. Moreover, we showed how different mechanical properties, derived from different crosslinking parameters, strongly influence cell behavior. In conclusion, this protocol can be considered a versatile tool to obtain biocompatible cell-laden hydrogels with properties easily adaptable for different TE applications. PMID- 25294369 TI - Independent associations of sodium intake with measures of body size and predictive body fatness. AB - OBJECTIVE: Observational studies highlight a possible relationship between sodium intake and obesity. This investigation explores the cross-sectional relationships between sodium intake and measures of body size and fatness (body mass index [BMI], weight, waist circumference, predictive body fatness). METHODS: Analyses were performed using data from participants in the National Health and Nutrition Examination Survey (NHANES) 2009-10 with two 24-h dietary recalls and measures of body size and fatness (n = 4,613). Regression analyses assessed the relationships of sodium (1,000 mg/day) with outcomes, adjusting for caloric intake. Analyses are presented overall and by sex; data were weighted to be representative of the non-institutionalized US adult population. RESULTS: Positive associations between sodium intake and measures of body size and predictive body fatness were observed, and the magnitude of association was larger in women than in men. For each 1,000 mg/day higher sodium intake, BMI was 1.03 kg/m(2) higher; weight was 2.75 kg higher; waist circumference was 2.15 cm higher; and predictive body fatness was 1.18% higher after adjustment for energy intake. CONCLUSIONS: Longitudinal analyses examining associations between sodium intake and measures of body size and body fatness are needed. PMID- 25294370 TI - Letting the cat out of the bag: a personal journey in Biophysics. AB - When the author arrived in Berkeley, in the mid 1970s, to study Biophysics he soon felt as if he was engaging himself in a somewhat marginal activity. Biology was then entering another of its cyclical periods of annotation that was to culminate with the human genome project. Two decades later, however, at the end of this process, it had become clear that two main tasks were acquiring a central importance in biological research: a renewed push for a quantitative, precise description of biological systems at the molecular level, and efforts towards an integrated understanding of the operation, control, and coordination of cellular processes. Today, these have become two of the most fertile research areas in Biophysics. PMID- 25294371 TI - Hand function in rheumatic diseases: patient and physician evaluations. AB - AIM: Rheumatic diseases have repercussions in hand function. The m-SACRAH (modified Score for the Assessment and quantification of Chronic Rheumatoid Affections of the Hands) questionnaire evaluates hand function according to the patient's opinion. Our aim was to look for the clinical and para-clinical variables that correlate with m-SACRAH in rheumatic diseases. METHODS: Consecutive patients with diagnoses of rheumatoid arthritis (RA), osteoarthritis (OA), gout, and systemic sclerosis (SS) with hand involvement and who agreed to participate, answered the m-SACRAH and Health Assessment Questionnaire Disability Index (HAQ-DI) and underwent blinded and independent rheumatologist and physiatrist evaluations. Nerve conduction studies (NCS) and hand ultrasonography (USG) were performed. STATISTICAL ANALYSIS: Spearman's correlation and the Mann Whitney U-test. RESULTS: Forty patients were included. There were 72% women and mean age of 49.25 +/- 14.2 years. According to m-SACRAH patients were dived into two groups (mild vs. moderate-severe), only the number limited to motion joints were different among them (median 2 vs. 8 P = 0.036). Patients' perspective variables had a good correlation (HAQ-DI/mSACRAH: r = 0.43, P < 0.05), but only correlated with limited motion joints (r = 0.41, P < 0.05 for m-SACRAH and r = 0.31, P < 0.05 for HAQ-DI). Physician's evaluations had a good correlation. Visual analog scale of hand function with physiatrist evaluations: passive range of motion (r = -0.49, P = 0.001), sum of affected pinches (r = 0.66, P = 0.001), limited to motion joints (r = 0.34, P < 0.05) and palm-finger distance (r = 0.50, P = 0.05). Regarding para-clinical evaluations, only tenosynovitis by ultrasonography correlated with HAQ-Di (r = 0.357, P < 0.05). CONCLUSIONS: Patients' perspectives correlated with the number of limited motion joints but with none of the other physicians' and para-clinical evaluations. The patients' opinion about their function should play a major role in their management. PMID- 25294372 TI - Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative immunohistochemical study of 46 cases. AB - Twenty-two paragangliomas from different anatomical sites and 24 thymic neuroendocrine carcinomas (carcinoid tumors) were analyzed for traditional and novel immunohistochemical markers. In the paraganglioma group, there were 8 men and 14 women between the ages of 23 and 79 years (mean, 46 years). Their symptoms depended on the location of the tumor and included neck swelling and Horner syndrome for neck tumors, whereas abdominal and chest pain was present in tumors of the abdomen and mediastinum, respectively. One patient had Carney triad. In the carcinoid group, the patients were 20 men and 4 women between the ages of 25 and 78 years (mean, 48 years). These patients were symptomatic with chest pain, shortness of breath, and dyspnea. One patient presented with multiple endocrine neoplasia syndrome. Complete surgical resection was accomplished in all patients. The 46 neuroendocrine tumors were evaluated for GATA-3, pancytokeratin, thryoid transcription factor 1 (TTF-1), napsin A, chromogranin A, and synaptophysin. All paragangliomas were universally positive for chromogranin A and synaptophysin, but negative for pancytokeratin, TTF-1, and napsin A. GATA-3 was expressed in 12 (55%) of 22 tumors. The thymic neuroendocrine carcinomas (carcinoid tumors) were universally positive for pancytokeratin, but negative for GATA-3 and napsin A. Chromogranin A and synaptophysin were expressed in 92% and 88% of cases, respectively, and TTF-1 in 4 (17%) of 24 cases. Based on these results, we recommend that the workup of neuroendocrine tumors should include not only the conventional neuroendocrine markers and pancytokeratin but also other markers such as GATA-3 and TTF-1 in order to arrive at a better interpretation. PMID- 25294373 TI - Clinical and pathologic analysis of extramedullary tumors after hematopoietic stem cell transplantation. AB - Clinical and pathologic analyses of 41 extramedullary biopsy/resection specimens of extramedullary tumors (EMTs) after hematopoietic stem cell transplantation (HSCT) were performed. The 41 EMT specimens were from 28 patients, with 11 having more than 1 consecutive EMT in different anatomic locations at different times post-HSCT. The median age at EMT diagnosis was 45 years (range, 17-73 years), and the male/female ratio was 17:11. The most common initial diagnosis was acute myeloid leukemia (21), followed by chronic myeloid leukemia with myeloid blast phase (2), primary myelofibrosis with acute leukemic transformation (1), acute lymphoblastic leukemia (2), mixed lineage T/myeloid leukemia (1), and plasma cell myeloma (1). All initial presentations were limited to bone marrow-only disease. Twenty patients had abnormal chromosomal karyotypes, whereas 6 had normal cytogenetics with their original disease. All patients received standard chemotherapy followed by allogeneic (27) or autologous (1) HSCT. The EMTs occurred 2 to 177 months (median, 16.5 months) after HSCT and were diagnosed as solid mass lesions as follows: skin and soft tissue (10), central nervous system and paraspinal tissue (9), breast (7), gastrointestinal tract (4), lymph node (4), genitourinary system (4), and mediastinum (3). Interestingly, all but 3 patients had negative bone marrows at the time their EMT was diagnosed, indicating that most EMTs presented as sole lesion of relapsed disease. The overall outcome was dismal for patients with EMT, with 20 (71%) of 28 patients deceased at 1 to 26 months after EMT diagnosis, with a median overall survival of only 6.5 months. PMID- 25294375 TI - Assessment of internal mammary artery injury after blunt chest trauma: a literature review. AB - The occurrence, bleeding, and treatment of internal mammary artery (IMA) injury after blunt chest trauma have not been well described in the literature. We reviewed articles published from July 1977 to February 2014 describing IMA injury after blunt chest trauma in 49 patients. There was a predominant incidence in males and on the left side. Blunt trauma to the IMA can cause anterior mediastinal hematoma, hemothorax, pseudoaneurysm, arteriovenous fistula, and extra-pleural hematoma. Of the 49 patients studied, 20 underwent embolization, 22 underwent surgical operation, 4 were managed by clinical observation, and 3 had undescribed treatment. Different parts and extents of IMA injury, adjacent vein injury, as well as the integrity of the pleura determined differences in bleeding modality. Prompt diagnosis, complete hemostasis, aggressive resuscitation, and multidisciplinary teams are recommended for patients with IMA injury. PMID- 25294374 TI - Therapeutic radionuclides in nuclear medicine: current and future prospects. AB - The potential use of radionuclides in therapy has been recognized for many decades. A number of radionuclides, such as iodine-131 ((131)I), phosphorous-32 ((32)P), strontium-90 ((90)Sr), and yttrium-90 ((90)Y), have been used successfully for the treatment of many benign and malignant disorders. Recently, the rapid growth of this branch of nuclear medicine has been stimulated by the introduction of a number of new radionuclides and radiopharmaceuticals for the treatment of metastatic bone pain and neuroendocrine and other malignant or non malignant tumours. Today, the field of radionuclide therapy is enjoying an exciting phase and is poised for greater growth and development in the coming years. For example, in Asia, the high prevalence of thyroid and liver diseases has prompted many novel developments and clinical trials using targeted radionuclide therapy. This paper reviews the characteristics and clinical applications of the commonly available therapeutic radionuclides, as well as the problems and issues involved in translating novel radionuclides into clinical therapies. PMID- 25294376 TI - Relationship between post-operative cognitive dysfunction and regional cerebral oxygen saturation and beta-amyloid protein. AB - OBJECTIVE: To investigate the relationship between post-operative cognitive dysfunction (POCD) and regional cerebral oxygen saturation (rSO2) and beta amyloid protein (Abeta) in patients undergoing laparoscopic pancreaticoduodenectomy. METHODS: Fifty patients undergoing elective laparoscopic pancreaticoduodenectomy received five groups of neuropsychological tests 1 d pre operatively and 7 d post-operatively, with continuous monitoring of rSO2 intra operatively. Before anesthesia induction (t0), at the beginning of laparoscopy (t1), and at the time of pneumoperitoneum 120 min (t2), pneumoperitoneum 240 min (t3), pneumoperitoneum 480 min (t4), the end of pneumoperitoneum (t5), and 24 h after surgery, jugular venous blood was drawn respectively for the measurement of Abeta by enzyme-linked immunosorbent assay (ELISA). RESULTS: Twenty-one cases of the fifty patients suffered from POCD after operation. We found that the maximum percentage drop in rSO2 (rSO(2, %max)) was significantly higher in the POCD group than in the non-POCD group. The rSO(2, %max) value of over 10.2% might be a potential predictor of neurocognitive injury for those patients. In the POCD group, the plasma Abeta levels after 24 h were significantly higher than those of pre-operative values (P<0.01). After 24 h, levels of plasma Abeta in the POCD group were significantly higher than those in the non-POCD group (P<0.01). CONCLUSIONS: The development of POCD in patients undergoing laparoscopic pancreaticoduodenectomy is associated with alterations of rSO2 and Abeta. Monitoring of rSO2 might be useful in the prediction of POCD, and Abeta might be used as a sensitive biochemical marker to predict the occurrence of POCD. PMID- 25294377 TI - Association between non-alcoholic fatty liver disease and arterial stiffness in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population. AB - BACKGROUND AND OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is associated with arterial stiffness in the general population. Age, obesity, hypertension, and diabetics are risk factors for arterial stiffness. In this study, we aimed to investigate the association between NAFLD and arterial stiffness as measured by brachial-ankle pulse wave velocity (baPWV) in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population. METHODS: A cross sectional study with 1296 non-obese, non-hypertensive, and non-diabetic young and middle-aged (20-65 years) subjects undergoing routine medical check-ups in the International Health Care Center of the Second Affiliated Hospital of School of Medicine of Zhejiang University was carried out. Fatty liver was diagnosed by ultrasonography, and baPWV was measured using an automatic waveform analyzer. The subjects were classified into two groups according to the presence of NAFLD, and divided into a further two groups according to their baPWV. RESULTS: The overall incidence of NAFLD was 19.0%, and NAFLD patients had a significantly higher level of baPWV than the controls ((1321+/-158) cm/s vs. (1244+/-154) cm/s; P<0.001). The incidence of NAFLD was clearly higher in the increased baPWV group than in the normal baPWV group (29.3% vs. 16.9%; P<0.001), and the incidence increased in line with the increase of baPWV quartiles in the normal range as well as with the severity of arterial stiffness (both P for trend <0.001). Multiple linear logistic regression analysis showed that the presence of NAFLD was positively and independently associated with baPWV. CONCLUSIONS: Our results suggest that the presence of NAFLD is associated with arterial stiffness as measured by baPWV in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population. PMID- 25294378 TI - Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment. AB - Insulin is widely used in treating diabetes, but still needs to be administered by needle injection. This study investigated a new needle-free approach for insulin delivery. A portable powder needleless injection (PNI) device with an automatic mechanical unit was designed. Its efficiency in delivering insulin was evaluated in alloxan-induced diabetic rabbits. The skin irritation caused by the device was investigated and the results were analyzed in relation to aerodynamic parameters. Inorganic salt-carried insulin powders had hypoglycemic effects, while raw insulin powders were not effective when delivered by PNI, indicating that salt carriers play an important role in the delivery of insulin via PNI. The relative delivery efficiency of phosphate-carried insulin powder using the PNI device was 72.25%. A safety assessment test showed that three key factors (gas pressure, cylinder volume, and nozzle distance) were related to the amount of skin irritation caused by the PNI device. Optimized injection conditions caused minimal skin lesions and are safe to use in practice. The results suggest that PNI has promising prospects as a novel technology for delivering insulin and other biological drugs. PMID- 25294379 TI - Association between serum vitamin D and severity of liver fibrosis in chronic hepatitis C patients: a systematic meta-analysis. AB - To conduct a systematic review of group studies assessing the association of serum vitamin D status with the severity of liver fibrosis in chronic hepatitis C patients using meta-analysis. The relevant research literatures were identified by searching PubMed and EMBASE databases prior to October 2013 with no restrictions. We included group studies that reported odds ratio (OR) estimates with 95% confidence intervals (CIs) or a mean with standard deviation (SD) for the association between serum vitamin D status and the severity of liver fibrosis in chronic hepatitis C patients. Approximately 8321 participants from several countries were included in this analysis. Six studies on serum vitamin D status and the severity of liver fibrosis were included in this meta-analysis. ORs with 95% CIs were extracted from four studies and the pooled ORs were 0.866 (95% CI, 0.649 to 1.157). The means with SDs were extracted from three studies and the pooled means were -0.487 (95% CI, -0.659 to -0.315). There was statistically significant heterogeneity among the mean data extracted studies (P=0.029; I(2)=71.8%) but not among the OR data extracted studies (P=0.061; I(2)=55.6%). Finally, results from the mean data extracted studies suggest that lower serum vitamin D is a risk factor for the severity of liver fibrosis in chronic hepatitis C patients. However, there is no conclusive evidence on this association because of inconsistencies between the OR data extracted studies and the mean data extracted studies. PMID- 25294380 TI - Visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction and low-grade inflammation in a subset of irritable bowel syndrome patients. AB - The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS (D IBS). Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits (AML) protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls (P<0.001). Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin (P<0.001). We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS. PMID- 25294381 TI - Non-pulmonary vein foci induced before and after pulmonary vein isolation in patients undergoing ablation therapy for paroxysmal atrial fibrillation: incidence and clinical outcome. AB - OBJECTIVE: To evaluate the incidence and clinical outcome of adenosine triphosphate (ATP) plus isoproterenol (ISP)-induced non-pulmonary vein (PV) foci before and after circumferential PV isolation (CPVI) during index ablation in patients with paroxysmal atrial fibrillation (PAF). METHODS: In 80 consecutive patients undergoing catheter ablation for drug-refractory, symptomatic PAF at our hospital from April 2010 to January 2011, atrial fibrillation (AF) was provoked with ATP (20 mg) and ISP (20 ug/min) administration before and after CPVI. The spontaneous initiation of AF was mapped and recorded. RESULTS: Before ablation, AF mostly originating from PVs (PV vs. non-PV, 36/70 vs. 3/70; P<0.01) was induced in 39 patients with sinus rhythm. CPVI significantly suppressed AF inducibility; however, more non-PV foci were provoked (post-CPVI vs. pre-CPVI, 13/76 vs. 3/70; P=0.016). Patients with pre- and post-CPVI induced AF (n=49) were divided according to non-PV foci being induced (group N, n=17) or not (group P, n=32). After mean (19.2+/-8.2) months follow-up, 88.2% (15/17) and 65.6% (21/32) of patients in groups N and P, respectively, were free from AF recurrence (P=0.088). CONCLUSIONS: ATP+ISP administration effectively provokes non-PV foci, especially after CPVI in PAF patients. Although in this study difference did not achieve statistical significance, supplementary ablation targeting non-PV foci might benefit clinical outcome. PMID- 25294382 TI - Inverse associations of outdoor activity and vitamin D intake with the risk of Parkinson's disease. AB - Early studies had suggested that vitamin D intake was inversely associated with neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. However, the associations of vitamin D intake and outdoor activities with Parkinson's disease (PD) are still unclear, so this study is to evaluate these relationships from a case-control study in elderly Chinese. The study population involved 209 cases with new onsets of PD and 210 controls without neurodegenerative diseases. The data on dietary vitamin D and outdoor activities were collected using a food-frequency questionnaire and self-report questionnaire. Multivariable logistic regressions were used to examine the associations between dietary outdoor activities, vitamin D intake and PD. Adjustment was made for sex, age, smoking, alcohol use, education, and body mass index (BMI). Adjusted odds ratios (ORs) for PD in quartiles for outdoor physical activity were 1 (reference), 0.739 (0.413, 1.321), 0.501 (0.282, 0.891), and 0.437 (0.241, 0.795), respectively (P=0.002 for trend). Adjusted ORs for PD in quartiles for total vitamin D intake were 1 (reference), 0.647 (0.357, 1.170), 0.571 (0.318, 1.022), and 0.538 (0.301, 0.960), respectively (P=0.011 for trend). Our study suggested that outdoor activity and total vitamin D intake were inversely associated with PD, and outdoor activity seems to be more significantly associated with decreased risk for PD. PMID- 25294385 TI - Recent bioanalytical methods for quantification of third-generation cephalosporins using HPLC and LC-MS(/MS) and their applications in pharmacokinetic studies. AB - Third-generation cephalosporins are semi-synthetic antibiotics with enhanced activity against Gram-negative organisms. The cephalosporins in biological samples are mostly determined using high-performance liquid chromatography (HPLC) and HPLC-mass spectrometry (LC-MS) or tandem mass spectrometry (LC-MS/MS). In recent years, numerous bioanalytical methods have been developed to improve the sensitivity and specificity of cephalosporin quantification using the powerful LC MS/MS systems that are common in research laboratories. This review article presents recently developed bioanalytical methods by HPLC or LC-MS(/MS) for 12 third-generation cephalosporins, including five oral third-generation cephalosporins, and further discusses their application in pharmacokinetic studies of animals and humans. PMID- 25294384 TI - Single-molecule imaging reveals that small amyloid-beta1-42 oligomers interact with the cellular prion protein (PrP(C)). AB - Oligomers of the amyloid-beta peptide (Abeta) play a central role in the pathogenesis of Alzheimer's disease and have been suggested to induce neurotoxicity by binding to a plethora of cell-surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Abeta42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single-molecule imaging to characterize Abeta42 oligomers (oAbeta42) and to confirm the controversial interaction of oAbeta42 with the cellular prion protein (PrP(C)) on live neuronal cells. Our results show that, at nanomolar concentrations, oAbeta42 interacts with PrP(C) and that the species bound to PrP(C) are predominantly small oligomers (dimers and trimers). Single-molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor-mediated oAbeta-induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways. PMID- 25294386 TI - UK based neuroscientist wins Nobel Prize for work on the brain's "inner GPS". PMID- 25294387 TI - The development and characterization of a 57K single nucleotide polymorphism array for rainbow trout. AB - In this study, we describe the development and characterization of the first high density single nucleotide polymorphism (SNP) genotyping array for rainbow trout. The SNP array is publically available from a commercial vendor (Affymetrix). The SNP genotyping quality was high, and validation rate was close to 90%. This is comparable to other farm animals and is much higher than previous smaller scale SNP validation studies in rainbow trout. High quality and integrity of the genotypes are evident from sample reproducibility and from nearly 100% agreement in genotyping results from other methods. The array is very useful for rainbow trout aquaculture populations with more than 40 900 polymorphic markers per population. For wild populations that were confounded by a smaller sample size, the number of polymorphic markers was between 10 577 and 24 330. Comparison between genotypes from individual populations suggests good potential for identifying candidate markers for populations' traceability. Linkage analysis and mapping of the SNPs to the reference genome assembly provide strong evidence for a wide distribution throughout the genome with good representation in all 29 chromosomes. A total of 68% of the genome scaffolds and contigs were anchored through linkage analysis using the SNP array genotypes, including ~20% of the genome assembly that has not been previously anchored to chromosomes. PMID- 25294388 TI - Mapping substrate interactions of the human membrane-associated neuraminidase, NEU3, using STD NMR. AB - Saturation transfer difference (STD) nuclear magnetic resonance (NMR) is a powerful technique which can be used to investigate interactions between proteins and their substrates. The method identifies specific sites of interaction found on a small molecule ligand when in complex with a protein. The ability of STD NMR to provide specific insight into binding interactions in the absence of other structural data is an attractive feature for its use with membrane proteins. We chose to employ STD NMR in our ongoing investigations of the human membrane associated neuraminidase NEU3 and its interaction with glycolipid substrates (e.g., GM3). In order to identify critical substrate-enzyme interactions, we performed STD NMR with a catalytically inactive form of the enzyme, NEU3(Y370F), containing an N-terminal maltose-binding protein (MBP)-affinity tag. In the absence of crystallographic data on the enzyme, these data represent a critical experimental test of proposed homology models, as well as valuable new structural data. To aid interpretation of the STD NMR data, we compared the results with molecular dynamics (MD) simulations of the enzyme-substrate complexes. We find that the homology model is able to predict essential features of the experimental data, including close contact of the hydrophobic aglycone and the Neu5Ac residue with the enzyme. Additionally, the model and STD NMR data agree on the facial recognition of the galactose and glucose residues of the GM3-analog studied. We conclude that the homology model of NEU3 can be used to predict substrate recognition, but our data indicate that unstructured portions of the NEU3 model may require further refinement. PMID- 25294389 TI - Cetuximab reduces the accumulation of radiolabeled bevacizumab in cancer xenografts without decreasing VEGF expression. AB - Bevacizumab and cetuximab are approved for the treatment of cancer. However, in advanced colorectal cancer, addition of cetuximab to chemotherapy with bevacizumab did not improve survival. The reason for the lack of activity remains unclear. The aim of this study was to determine the effect of cetuximab on VEGF expression and targeting of bevacizumab to the tumor. Mice with subcutaneous SUM149 or WiDr xenografts were treated with cetuximab, bevacizumab, or a combination of the two. Before the start of cetuximab treatment and after 7 and 21 days of treatment, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Tumor growth of SUM149 xenografts was significantly inhibited by cetuximab, bevacizumab, or their combination, whereas growth of WiDr xenografts was not affected. Cetuximab caused a significant reduction of bevacizumab uptake in SUM149 xenografts, whereas tumor-to-blood ratios in mice with WiDr xenografts did not change. Biodistribution studies with an irrelevant antibody in the SUM149 model also showed significantly reduced tumor-to-blood ratios. Cetuximab treatment did not decrease VEGF expression. Without decreasing VEGF levels, cetuximab reduces tumor targeting of bevacizumab. This could, at least partly, explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy. PMID- 25294390 TI - Fossil wood from the Miocene and Oligocene epoch: chemistry and morphology. AB - Fossil wood is the naturally preserved remain of the secondary xylem of plants that lived before the Holocene epoch. Typically, fossil wood is preserved as coalified or petrified and rarely as mummified tissue. The process of fossilization is very complex and it is still unknown why in the same fossil record, wood can be found in different fossilisation forms. In 2007, a fossil forest was found in the Bukkabrany open-pit coal mine in Hungary. The non petrified forest is estimated to be 7 million years old (Miocene epoch) and its trees were found standing in an upright position. This fossil assemblage is exceptionally rare because wood has been preserved as soft waterlogged tissue. This study aimed to investigate this remarkable way of fossil wood preservation, by examining its chemistry with (13)C CPMAS NMR and its morphology with light and electron microscopy. For comparison reasons, a petrified wood trunk from the Oligocene epoch (30 Myr) found in 2001 at Porrentruy region in Switzerland and two fresh wood samples of the modern equivalents of the Miocene sample were also examined. The results obtained showed that the outstanding preservation state of the Miocene fossil is not owed to petrification or coalification. Mummification is a potential mechanism that could explain Bukkabrany trunks' condition, however this fossilisation process is not well studied and therefore this hypothesis needs to be further investigated. PMID- 25294391 TI - The future of the clinical nurse specialist role in Finland. AB - PURPOSE: To identify and examine the expert panelists' visions on the future implementation of the clinical nurse specialist (CNS) role in Finland. DESIGN AND METHODS: A policy Delphi design was conducted in 2013. A purposive sampling method was used to recognize expert panelists in the areas of advanced practice nursing (APN), healthcare management, and advanced practice nurse education. Three iterative Web-based survey rounds were conducted (n = 25, n = 22, n = 19). Both qualitative and quantitative methods were used to analyze the data. FINDINGS: The expert panelists envisioned the future of the CNS role in Finland. This study portrayed the CNS role in Finland as generally consistent with the international role. CNS have comprehensive skills and knowledge that they use to guide and develop nursing practice; however, several threats may affect their role achievement. The existing national consensus, contradiction, and ambivalence related to CNS roles were revealed through the examination of the results, thus pointing out the areas for consideration when further developing these roles and role policies. CONCLUSIONS: This is the first national study to examine the implementation of the CNS role in Finland. Expert panelists' views regarding the CNS role will be valuable in the forthcoming national policy formulation process. Although the policy Delphi design is not often utilized, this study reveals that it is very well suited to guide and inform national and international APN policy development. CLINICAL RELEVANCE: This study contributes to CNS role development and describes the methods facilitating the essential policy formulation process. PMID- 25294392 TI - Improving the quality of care for patients diagnosed with glioma during the perioperative period. AB - PURPOSE: Although there is agreement on the oncologic management of patients with glioma, few guidelines exist to standardize other aspects of care, including supportive care. METHODS: A quality improvement (QI) project was chartered to improve the care provided to patients with glioma. A multidisciplinary team was convened and identified 10 best-practice measures. Using a plan-do-study-act framework, the team brainstormed and implemented various improvement interventions between June 2011 and October 2012. Statistical process control charts were used to evaluate progress. A dashboard of quality measures was generated to allow for ongoing measurement and reporting. RESULTS: The retrospective assessment phase consisted of 43 patients with diagnosis of glioma. A manual medical record review for these patients showed that compliance with 10 best-practice measures ranged from 23% to 100%. Several factors contributed to less-than-ideal process performance, including poor communication among disciplines and lack of familiarity with the larger system of care. After implementing improvement interventions, performance was measured in 96 consecutive patients with glioma. The proportion of patients who met criteria for 10 practice measures significantly improved (pre-QI work, 63%; post-QI work, 85%; P = .003). The largest improvement was observed in the measure assessing for preoperative notification of the neuro-oncology program (pre-QI work, 39%; post QI work, 97%; P < .001). CONCLUSION: QI principles were used by a multidisciplinary team to improve the quality of care for patients with glioma during the perioperative period. Leadership involvement, ongoing dialogue across departments, and reporting of system performance were important for sustaining process improvements. PMID- 25294394 TI - Introduction: titanium dioxide (TiO2) nanomaterials. PMID- 25294395 TI - TiO2 nanoparticles as functional building blocks. PMID- 25294393 TI - End-of-life care for blood cancers: a series of focus groups with hematologic oncologists. AB - PURPOSE: Hematologic cancers are associated with aggressive cancer-directed care near death and underuse of hospice and palliative care services. We sought to explore hematologic oncologists' perspectives and decision-making processes regarding end-of-life (EOL) care. METHODS: Between September 2013 and January 2014, 20 hematologic oncologists from the Dana-Farber/Harvard Cancer Center participated in four focus groups regarding EOL care for leukemia, lymphoma, multiple myeloma, and hematopoietic stem-cell transplantation. Focus groups employed a semistructured format with case vignettes and open-ended questions and were followed by thematic analysis. RESULTS: Many participants felt that identifying the EOL phase for patients with hematologic cancers was challenging as a result of the continuing potential for cure with advanced disease and the often rapid pace of decline near death. This difficulty was reported to result in later initiation of EOL care. Barriers to high-quality EOL care were also reported to be multifactorial, including unrealistic expectations from both physicians and patients, long-term patient-physician relationships resulting in difficulty conducting EOL discussions, and inadequacy of existing home-based EOL services. Participants also expressed concern that some EOL quality measures developed for solid tumors may be unacceptable for patients with blood cancers given their unique needs at the EOL (eg, palliative transfusions). CONCLUSION: Our analysis suggests that hematologic oncologists need better clinical markers for when to initiate EOL care. In addition, current quality measures may be inappropriate for identifying overly aggressive care for patients with blood cancers. Further research is needed to develop effective interventions to improve EOL care for this patient population. PMID- 25294396 TI - Selenium deficiency in children and adolescents nourished by parenteral nutrition and/or selenium-deficient enteral formula. AB - The authors analyzed serum selenium levels of 95 children and adolescents with intestinal dysfunction and/or neurological disabilities [age range: 7 months-20 years; mean+/-standard deviation (SD): 8.0+/-5.3 years] who received parenteral nutrition (PN) and/or enteral nutrition (EN) with either reduced or no selenium doses for more than 3 months. Twenty-eight patients (29%) showed serum selenium levels below 4.0MUg/dL. Five patients whose serum selenium levels were below 2MUg/dL presented various clinical manifestations, including hair browning (n=5), macrocythemia (n=4), nail whitening (n=3) and cardiac dysfunction (n=1). None of these 5 patients were nourished through ordinary diets. Three of these patients were nourished through selenium-free enteral nutritional products, 1 through selenium-deficient PN and 1 through PN and a formula with reduced selenium. After selenium supplement therapy for 1 year, all 5 patients exhibited improvement in their serum selenium levels and clinical features of selenium deficiency. It is important to be cautious about secondary selenium deficiency in children and adolescents nourished only through EN/PN without an adequate dose of selenium. PMID- 25294397 TI - Influence of different prosthodontic rehabilitation options on oral health related quality of life, orofacial esthetics and chewing function based on patient-reported outcomes. AB - PURPOSE: The aim was to assess influence of different prosthodontic rehabilitation options on improvement of orofacial esthetics, chewing function (CF) and oral health-related quality of life. METHODS: Patients treated with 70 conventional complete dentures (CDs), 38 implant-supported mandibular complete dentures opposed to maxillary CDs, 56 conventional removable partial dentures, 15 implant-supported removable partial dentures, 25 conventional fixed partial dentures (FPDs) and 59 implant-supported fixed partial dentures (IFPDs) were included. The survey was conducted using the three questionnaires: the OHIP CRO14, the Orofacial Esthetic Scale (OES-CRO) and the Chewing Function Questionnaire (CFQ), and administrated twice: at the baseline prior the therapy and 3 months after prosthodontic rehabilitation had been finished. RESULTS: The after-treatment scores were significantly better than the baseline scores (p < 0.001) for the OES, OHIP14 and CF questionnaires in all types of treatments. The two-factor ANOVA showed no significant difference for the OES after-treatment scores between different rehabilitation options and implant presence, but the OHIP14 and CFQ after-treatment scores were significantly better in FPD and IFPDs than in removable implant and conventional denture wearers. The score change was significantly higher in all implant removable denture patients for the OES, OHIP and CFQ. The lowest score change was registered in the FPD wearers. (p < 0.01). CONCLUSIONS: Removable denture implant patients most benefited from implant support, but IFPD and FPD had the best after-treatment scores. The assessed clinical parameters may help dentists in choice of the best rehabilitation option with the highest treatment effect. PMID- 25294398 TI - A naphthalimide-based fluorescence "turn-on" probe for the detection of Pb(2+) in aqueous solution and living cells. AB - An easily available naphthalimide-based fluorescent probe NPA for Pb(2+) detection was successfully developed. NPA exhibited an obvious fluorescence turn on response toward Pb(2+) in aqueous solution and in living cells. Moreover, a series of model compounds were rationally designed and synthesized in order to explore the sensing mechanism and binding mode of NPA with Pb(2+) . PMID- 25294399 TI - Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes. AB - BACKGROUND: Nonatherosclerotic spontaneous coronary artery dissection (NA-SCAD) is underdiagnosed and an important cause of myocardial infarction in young women. The frequency of predisposing and precipitating conditions and cardiovascular outcomes remains poorly described. METHODS AND RESULTS: Patients with NA-SCAD prospectively evaluated (retrospectively or prospectively identified) at Vancouver General Hospital were included. Angiographic SCAD diagnosis was confirmed by 2 experienced interventional cardiologists and categorized as type 1 (multiple lumen), 2 (diffuse stenosis), or 3 (mimic atherosclerosis). Fibromuscular dysplasia screening of renal, iliac, and cerebrovascular arteries were performed with angiography or computed tomographic angiography/MR angiography. Baseline, predisposing and precipitating conditions, angiographic, revascularization, in-hospital, and long-term events were recorded. We prospectively evaluated 168 patients with NA-SCAD. Average age was 52.1+/-9.2 years, 92.3% were women (62.3% postmenopausal). All presented with myocardial infarction. ECG showed ST-segment elevation in 26.1%, and 3.6% had ventricular tachycardia/ventricular fibrillation arrest. Fibromuscular dysplasia was diagnosed in 72.0%. Precipitating emotional or physical stress was reported in 56.5%. Majority had type 2 angiographic SCAD (67.0%), only 29.1% had type 1, and 3.9% had type 3. The majority (134/168) were initially treated conservatively. Overall, 6 of 168 patients had coronary artery bypass surgery and 33 of 168 had percutaneous coronary intervention in-hospital. Of those treated conservatively (n=134), 3 required revascularization for SCAD extension, and all 79 who had repeat angiogram >=26 days later had spontaneous healing. Two-year major adverse cardiac events were 16.9% (retrospectively identified group) and 10.4% (prospectively identified group). Recurrent SCAD occurred in 13.1%. CONCLUSIONS: Majority of patients with NA-SCAD had fibromuscular dysplasia and type 2 angiographic SCAD. Conservative therapy was associated with spontaneous healing. NA-SCAD survivors are at risk for recurrent cardiovascular events, including recurrent SCAD. PMID- 25294400 TI - Intracoronary infusion of encapsulated glucagon-like peptide-1-eluting mesenchymal stem cells preserves left ventricular function in a porcine model of acute myocardial infarction. AB - BACKGROUND: Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI). METHODS AND RESULTS: One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive either intracoronary infusion of 3 incremental doses of eMSC or Ringers' lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (P=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4+/-0.9/mm(2) in controls versus 22.2+/ 2.6/mm(2) in eMSC group; P<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1+/-99.7/mm(2) in control versus 1209.0+/-64.6/mm(2) in eMSC group; P=ns). CONCLUSIONS: eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angiogenesis and preserving contractile function in an animal AMI model. PMID- 25294401 TI - Gastrointestinal parasites in an isolated Norwegian population of wild red deer (Cervus elaphus). AB - BACKGROUND: Thirteen red deer (Cervus elaphus), culled from the isolated population at the Mongstad Oil Refinery, Norway, were investigated for gastrointestinal helminths. These animals, enclosed by the refinery fence, do not have contact with other ruminants and have a high population density considering the available browsing area (1 km(2)) within the refinery site (3 km(2)). The population was estimated to be 110-130 at the time of culling. RESULTS: The helminth fauna among these sampled red deer was enumerated and species were identified based on morphology. Ostertagia leptospicularis/O. kolchida was detected in 83% [CI 55 - 95%], Spiculopteragia spiculoptera/S. mathevossiani in 92% [CI 65 - 99%] and Trichostrongylus axei in 42%, [CI 19 - 68%] of the abomasa examined. Characterisation of the intestinal parasite fauna revealed Capillaria bovis, Cooperia oncophora, Oesophagostomum venulosum, Trichuris globulosa and tapeworm fragments (presumed anoplocephalids) in seven individuals. Only one calf had an infection with more than one intestinal helminth (tapeworm fragment and Trichuris globulosa). The remaining six deer had single species intestinal infections. No significant age related trends were seen, with the exception of higher intensity of infection of T. axei in yearlings relative to other age classes. Assessment of abomasal parasite burden and body condition revealed no significant trends. In calves, statistically non-significant correlation was seen between increased parasite burden and decreased slaughter weight, whilst the opposite was seen in adults with the heaviest adults exhibiting the higher burdens. Given the small sample size the trends that were seen need further investigation. The parasite burden was aggregated with three adult red deer harbouring 75% of the total abomasal parasite count. CONCLUSION: This isolated population was parasitised by a reduced subset of gastrointestinal nematodes typical of this cervid across an extensive geographic range in Eurasia. The intensity and abundance of abomasal nematodes was higher in this isolated population than reported in similar studies of red deer populations across Europe. PMID- 25294402 TI - Increased expression of the retinoic acid-metabolizing enzyme CYP26A1 during the progression of cervical squamous neoplasia and head and neck cancer. AB - BACKGROUND: Retinoic acid (RA) is a critical regulator of cell differentiation, proliferation, and apoptosis in various cell types. Recently, the RA-metabolizing enzyme CYP26A1 (cytochrome P450, family 26, subfamily A, polypeptide 1) has been shown to have an oncogenic function in breast carcinogenesis. However, the relevance of elevated CYP26A1 expression in human cancers remains to be clarified. METHODS: We immunohistochemically examined the expression of CYP26A1 in cervical squamous cell carcinoma (SCC) and its precursors, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as head and neck cancer (HNC). The association between CYP26A1 expression and a number of clinicopathological parameters was also evaluated. RESULTS: CYP26A1 was not expressed in normal cervical epithelium. CYP26A1 expression was present in LSIL but limited to basal and parabasal cells. HSIL cases exhibited strong nuclear expression of CYP26A1 and mixed cytoplasmic expression patterns with widely distributed expression toward the epithelial surface. Importantly, strong cytoplasmic staining of CYP26A1 was observed in 19 of 50 (38%) patients with cervical SCC. Elevated expression of CYP26A1 was significantly associated with younger age (<50 years) and lymph node involvement (pN). Similarly, CYP26A1 was not expressed in non-neoplastic tissues of the head and neck, but strong cytoplasmic staining of CYP26A1 was observed in 52 of 128 (41%) HNC cases. Such strong CYP26A1 expression was significantly associated with the primary tumor stage of carcinomas (pT) and the pathological tumor-node-metastasis (pTNM) stage in HNC. CONCLUSION: Our results indicated an elevated CYP26A1 expression in malignant and precancerous dysplastic lesions of the human cervix, which also increased with the progression of cervical squamous neoplasia. In addition, this report is the first to demonstrate the increased expression of CYP26A1 in HNC and its significant correlation with primary tumor growth. These data suggested that CYP26A1 overexpression might contribute to the development and progression of cervical malignancies and squamous neoplasia of the head and neck. PMID- 25294403 TI - Antitumor necrosis factor alpha inhibitor-induced dermatomyositis and interstitial lung disease with anti-PL12 autoantibody: signs of antisynthetase syndrome. PMID- 25294404 TI - Diffuse large B-cell lymphoma of the colon with synchronous liver metastasis: a rare case report mimicking metastatic colorectal adenocarcinoma. AB - BACKGROUND: Primary colorectal lymphoma represents a rare minority among the colonic neoplasms. Early diagnosis is often difficult because of unspecific symptoms, with subsequent delays in diagnosis and management. We describe a rare case of colonic lymphoma presenting with synchronous liver metastasis. CASE PRESENTATION: A 70-year-old male with a 6-mo history of vague abdominal pain, constipation and melena was referred to our hospital. Computed tomography scan of abdomen revealed the presence of a mass along the proximal ascending colon. Colonoscopy biopsy showed external compression of the cecum with two ulcerations of mucosa, but it was not consistent for a definitive diagnosis. Because the difficulties in the preoperative pathological diagnosis, the high risk of bowel obstruction and the correlated hemorrhagic risk, the patient underwent a right hemicolectomy associated with locoregional lymphadenectomy and liver resection.The surgically resected right colon and liver tumors were all immunohistochemically diagnosed as diffuse large B-cell lymphomas (DLBCL). The patient refused any other antineoplastic treatment; he is alive and free of disease at 3 years after initial diagnosis. CONCLUSIONS: Primary colonic lymphomas represent a rare minority among the colonic neoplasms. Their correct pre-operative identification is crucial for the design of treatment. This case highlights the difficulty in diagnosing of primary colonic lymphoma. To our knowledge, this is the first report of a colonic lymphoma presenting with a colonic mass and a synchronous liver metastasis. PMID- 25294406 TI - Maternal diet during early childhood, but not pregnancy, predicts diet quality and fruit and vegetable acceptance in offspring. AB - Studies have identified prenatal flavour exposure as a determinant of taste preferences in infants; however, these studies have focused on relatively small samples and limited flavours. As many parents struggle with getting children to accept a variety of nutritious foods, a study of the factors influencing food acceptance is warranted. The objective of this study was to determine whether exposure to a wider variety of fruit and vegetables and overall higher diet quality in utero results in acceptance of a greater variety of these foods and better diet quality for offspring during childhood. This study is a secondary data analysis of pregnant women (n = 52) and their resulting offspring recruited for the Women and Their Children's Health study in NSW, Australia. Dietary intake of mothers and children was measured using food frequency questionnaires. Diet quality and vegetable and fruit variety were calculated using the Australian Recommended Food Score and the Australian Child and Adolescent Recommended Food Score. Associations between maternal and child diet quality and variety were assessed using Pearson's correlations and the total effect of in utero maternal pregnancy diet on childhood diet was decomposed into direct and indirect effect using mediation analysis. Maternal pregnancy and post-natal diet were both correlated with child diet for overall diet quality and fruit and vegetable variety (P < 0.001). Mediation analyses showed that the indirect effect of maternal pregnancy diet on child diet was mediated through maternal post-natal diet, particularly for fruit (P = 0.045) and vegetables (P = 0.055). Nutrition intervention should therefore be aimed at improving diet quality and variety in mothers with young children, in order to subsequently improve eating habits of offspring. PMID- 25294405 TI - Mediastinal sarcoidosis mimicking lymph malignancy recurrence after anti neoplastic therapy. AB - The aim of our work is to promote the awareness about the development of sarcoidosis after antineoplastic therapy in order to avoid diagnostic errors with FDG-PET/CT findings. We report the observation of three women with breast, cervix and stomach treated cancers who developed a sarcoidosis after the end of anti neoplastic therapy. The utility of FDG-PET/CT is in pinpointing the organs candidates for diagnostic biopsy and not distinguishing between the malignancy and granulomatous or inflammatory diseases. PMID- 25294407 TI - Comprehensive longitudinal health care in the home for high-cost beneficiaries: a critical strategy for population health management. PMID- 25294408 TI - Systems biology defines the biological significance of redox-active proteins during cellulose degradation in an aerobic bacterium. AB - Microbial depolymerization of plant cell walls contributes to global carbon balance and is a critical component of renewable energy. The genomes of lignocellulose degrading microorganisms encode diverse classes of carbohydrate modifying enzymes, although currently there is a paucity of knowledge on the role of these proteins in vivo. We report the comprehensive analysis of the cellulose degradation system in the saprophytic bacterium Cellvibrio japonicus. Gene expression profiling of C. japonicus demonstrated that three of the 12 predicted beta-1,4 endoglucanases (cel5A, cel5B, and cel45A) and the sole predicted cellobiohydrolase (cel6A) showed elevated expression during growth on cellulose. Targeted gene disruptions of all 13 predicted cellulase genes showed that only cel5B and cel6A were required for optimal growth on cellulose. Our analysis also identified three additional genes required for cellulose degradation: lpmo10B encodes a lytic polysaccharide monooxygenase (LPMO), while cbp2D and cbp2E encode proteins containing carbohydrate binding modules and predicted cytochrome domains for electron transfer. CjLPMO10B oxidized cellulose and Cbp2D demonstrated spectral properties consistent with redox function. Collectively, this report provides insight into the biological role of LPMOs and redox proteins in cellulose utilization and suggests that C. japonicus utilizes a combination of hydrolytic and oxidative cleavage mechanisms to degrade cellulose. PMID- 25294409 TI - Throw rug-related injuries treated in US EDs: are children the same as adults? AB - BACKGROUND: Various characteristics of floors and floor coverings are well established as injury hazards. Loose carpeting, such as rugs, is often cited as a hazard leading to injury. PURPOSE: To describe the epidemiology and patterns of rug, mat, and runner-related injuries in patients seeking emergency treatment. METHODS: Data from the National Electronic Injury Surveillance System from 1990 through 2009 were investigated. Sample weights were used to calculate national estimates. US Census Bureau data were used to calculate injury rates per 100 000 individuals. Linear regression and computation of relative risks (RRs) with 95% confidence intervals (CIs) were performed. RESULTS: An estimated 245 605 patients were treated in US emergency departments for rug-related injuries during the study period, with an average of 12 280 cases per year. Females (72.3%) and individuals older than 64 years (47.1%) sustained the largest number of injuries. Patients younger than 6 years were more likely to injure the head or neck region (RR, 3.52 [95% CI, 3.26-3.81]) compared with all other groups. Patients older than 18 years were more likely to experience a fracture or dislocation (RR, 2.52 [95% CI, 2.13-2.88]) and sustain an injury as a result of tripping or slipping on a rug (RR, 1.36 [95% CI, 1.26-1.41] compared with other age groups. Increasing age was associated with increased risk of hospitalization in this study. Patients who sustained an injury from a rubber or plastic mat/rug were significantly less likely to be admitted (RR, 0.67 [95% CI, 0.55-0.83]). Injuries occurring in kitchens or bathrooms resulted in significantly higher admission rates (RR, 1.45 [95% CI, 1.34-1.54]). CONCLUSIONS: Rug-related injuries are an important source of injury for individuals of all ages. PMID- 25294410 TI - The author response--end-tidal CO2 prediction of Chronic Obstructive Pulmonary Disease exacerbations. PMID- 25294411 TI - The use of transcallosal-interforniceal approach for microsurgical removal of the third ventricle tumors. AB - AIM: The third ventricle is located deep in the brain and is adjacent to important neurovascular structures. This makes tumor resection in this region difficult and causes more postoperative complications than surgeries in other regions of the brain. The objective of this study was to investigate the feasibility and clinical effects of transcallosal-interforniceal approach for microsurgical removal of the third ventricle tumors. METHODS: After preoperative evaluation, 23 patients with the third ventricle tumors were microsurgically operated using the transcallosal-interforniceal approach. RESULTS: Of these 23 patients, 12 (52.2%) underwent total excision, 9 (39.1%) had subtotal resection, and the remaining 2 (8.7%) underwent partial excision. After surgery, the following complications were observed: diabetes insipidus (11 patients), hemorrhages of the upper digestive tract (2 patients), central fever (1 patient), and memory impairment (1 patient). No mortality in the perioperative period was reported. CONCLUSION: The surgical procedure using the transcallosal interforniceal approach is direct and provides good surgical field exposure and fewer post operational compilations. This approach should be considered as the method of choice for surgical removal of the third ventricle tumors. PMID- 25294413 TI - Individual Income, Area Deprivation, and Health: Do Income-Related Health Inequalities Vary by Small Area Deprivation? AB - This paper aims to explore potential associations between health inequalities related to socioeconomic deprivation at the individual and the small area level. We use German cross-sectional survey data for the years 2002 and 2006, and measure small area deprivation via the German Index of Multiple Deprivation. We test the differences between concentration indices of income-related and small area deprivation related inequalities in obesity, hypertension, and diabetes. Our results suggest that small area deprivation and individual income both yield inequalities in health favoring the better-off, where individual income-related inequalities are significantly more pronounced than those related to small area deprivation. We then apply a semiparametric extension of Wagstaff's corrected concentration index to explore how individual-level health inequalities vary with the degree of regional deprivation. We find that the concentration of obesity, hypertension, and diabetes among lower income groups also exists at the small area level. The degree of deprivation-specific income-related inequalities in the three health outcomes exhibits only little variations across different levels of multiple deprivation for both sexes. PMID- 25294412 TI - Adaptation to environmental factors shapes the organization of regulatory regions in microbial communities. AB - BACKGROUND: It has been shown in a number of metagenomic studies that the addition and removal of specific genes have allowed microbiomes to adapt to specific environmental conditions by losing and gaining specific functions. But it is not known whether and how the regulation of gene expression also contributes to adaptation. RESULTS: We have here characterized and analyzed the metaregulome of three different environments, as well as their impact in the adaptation to particular variable physico-chemical conditions. For this, we have developed a computational protocol to extract regulatory regions and their corresponding transcription factors binding sites directly from metagenomic reads and applied it to three well known environments: Acid Mine, Whale Fall, and Waseca Farm. Taking the density of regulatory sites in promoters as a measure of the potential and complexity of gene regulation, we found it to be quantitatively the same in all three environments, despite their different physico-chemical conditions and species composition. However, we found that each environment distributes their regulatory potential differently across their functional space. Among the functions with highest regulatory potential in each niche, we found significant enrichment of processes related to sensing and buffering external variable factors specific to each environment, like for example, the availability of co-factors in deep sea, of oligosaccharides in soil and the regulation of pH in the acid mine. CONCLUSIONS: These results highlight the potential impact of gene regulation in the adaptation of bacteria to the different habitats through the distribution of their regulatory potential among specific functions, and point to critical environmental factors that challenge the growth of any microbial community. PMID- 25294414 TI - Assessing the impact of anion-pi effects on phenylalanine ion structures using IRMPD spectroscopy. AB - The gas-phase structures of two halide-bound phenylalanine anions (PheX(-), X = Cl(-) or Br(-)) and five fluorinated derivatives have been identified using infrared multiple photon dissociation (IRMPD) spectroscopy. The addition of electron-withdrawing groups to the aromatic ring creates a pi-acidic system that additionally stabilizes the halide above the ring face. Detailed ion structures were determined by comparing the IRMPD spectra with harmonic and anharmonic infrared spectra computed using B3LYP/6-311++G(d,p) as well as with 298 K enthalpies and Gibbs energies determined by the MP2(full)/6 311++G(2d,2p)//B3LYP/6-311++G(d,p) and MP2(full)/aug-cc-pVTZ//B3LYP/6-311++G(d,p) methods. PheX(-) structures were found to be dependent on both the nature of the anion and the extent of ring fluorination. Canonical isomers were established to be the dominant structures in every case, but halide addition significantly narrowed the energy gap with zwitterionic potential energy surfaces. This enabled zwitterions to appear as minor contributors to the gas-phase populations of Phe35F2Cl(-) and PheF5Br(-). PMID- 25294416 TI - Falling Through the Cracks: Lack of Health Insurance Among Elderly Foreign- and Native-Born Blacks. AB - Little research examines lack of health insurance among elderly Black immigrants in the US. We use data from the 2008 American Community Survey to describe variation in insurance coverage and conduct multivariate logistic regression analyses of uninsurance. Among elderly Blacks, 1.7% of the US-born were uninsured, compared to 8.4% of the Latin American and Caribbean-born, 23.2% of the African-born, and 9.3% of those born in other regions. In multivariate models, relative to the US-born, the odds of being uninsured were significantly higher among each immigrant group. Among immigrants, the odds of being uninsured were 3.80 times higher among African-born than Latin American and Caribbean-born immigrants net of demographic and socioeconomic controls. This difference was explained by the inclusion of either year of immigration or length of residence. Relative to Latin America and Caribbean-born immigrants, the odds of being uninsured were significantly higher among immigrants from "other" regions only in the model that included the immigration-related variables. This suppression effect was evident when either length of residence or citizenship was controlled. Recently-arrived, elderly Black immigrants fall through the cracks of insurance coverage. Results are discussed in relation to public and private safety net options. PMID- 25294417 TI - Can the tools of activity theory help us in advancing understanding and organisational change in undergraduate medical education? AB - Continued changes to healthcare delivery in the UK, and an increasing focus on patient safety and quality improvement, require a radical rethink on how we enable graduates to begin work in challenging, complex environments. Professional regulatory bodies now require undergraduate medical schools to implement an 'assistantship' period in the final year of study, where senior medical students 'shadow' the work of junior doctors, with an expectation that they will be better 'prepared' for work. However, there is little guidance about what an 'assistantship' entails and the current emphasis on preparedness of students arguably underplays the importance of contextualised learning within the workplace environment. This paper will describe a modified Development Work Research (DWR) (Engestrom in Developmental work research: activity theory in practice. Lehmanns Media, Berlin, 2005) approach to organisational change, enabling academic, clinical and administrative partners to develop assistantship placements in different hospitals. Our findings indicate that a modified DWR approach can reveal factors indicating organisational readiness to support change within a locally contextualised framework. The process has significant practical applications across a range of healthcare disciplines, as all professions seek to engage with the challenge of enabling successful transitions of graduates to the workplace. PMID- 25294418 TI - Proceedings of the 9th European Mucosal Immunology Group Meeting, Bute Hall, University Of Glasgow, Scotland, October 2014. Guest Editor: Allan Mowat and Simon Milling. PMID- 25294415 TI - Health Care Experiences and Perceived Barriers to Health Care Access: A Qualitative Study Among African Migrants in Guangzhou, Guangdong Province, China. AB - Guangzhou, one of China's largest cities and a main trading port in South China, has attracted many African businessmen and traders migrating to the city for financial gains. Previous research has explored the cultural and economic roles of this newly emerging population; however, little is known about their health care experiences while in China. Semi-structured interviews and focus groups were used to assess health care experiences and perceived barriers to health care access among African migrants in Guangzhou, China. Overall, African migrants experienced various barriers to accessing health care and were dissatisfied with local health services. The principal barriers to care reported included affordability, legal issues, language barriers, and cultural differences. Facing multiple barriers, African migrants have limited access to care in Guangzhou. Local health settings are not accustomed to the African migrant population, suggesting that providing linguistically and culturally appropriate services may improve access to care for the migrants. PMID- 25294419 TI - Biomass of speckled alder on an air-polluted mountain site and its response to fertilization. AB - The article summarizes outcomes of a biomass study conducted in a young speckled alder plantation on a cold mountain site. At this location, the previously existing old forest was clear felled because of damage from air pollution, and present-day surface humus is in need of restoration. The intention of this study was to quantify the biomass and nutrients accumulated by alders and their components and assess whether the initial fertilization resulted in increased biomass production and nutrient accumulation in the biomass. Besides the control, two fertilized treatments were installed. In the surface treatment (SUT), the amendment was applied as a base dressing in small circles around trees. In the planting-hole treatment (PHT), the amendment was incorporated into soil inside the planting holes. Five growth seasons after planting and fertilization, six alders from each treatment were harvested including roots. Their biomass was quantified and analyzed for macroelements. The greatest pool of dry mass (DM) was branches in the control and stem wood in the fertilized treatments. The greatest pools of macroelements were leaves and branches. The most pronounced effects of fertilization were recorded in the DM and consequently in the absolute quantities of nutrients. The DM of an average tree in the control, SUT, and PHT was 85, 226, and 231 g, respectively. The absolute contents of nutrients per tree in the fertilized treatments showed the following increases, as compared with the control: (N) 2.5-2.6 times; (P) 1.6-2.4 times; (K) 1.8-2.1 times; and (Mg) 1.8 2.0 times, respectively. Speckled alder responded positively to fertilization. PMID- 25294420 TI - Water monitoring: automated and real time identification and classification of algae using digital microscopy. AB - Microalgae are unicellular photoautotrophs that grow in any habitat from fresh and saline water bodies, to hot springs and ice. Microalgae can be used as indicators to monitor water ecosystem conditions. These organisms react quickly and predictably to a broad range of environmental stressors, thus providing early signals of a changing environment. When grown extensively, microalgae may produce harmful effects on marine or freshwater ecology and fishery resources. Rapid and accurate recognition and classification of microalgae is one of the most important issues in water resource management. In this paper, a methodology for automatic and real time identification and enumeration of microalgae by means of image analysis is presented. The methodology is based on segmentation, shape feature extraction, pigment signature determination and neural network grouping; it attained 98.6% accuracy from a set of 53,869 images of 23 different microalgae representing the major algal phyla. In our opinion this methodology partly overcomes the lack of automated identification systems and is on the forefront of developing a computer-based image processing technique to automatically detect, recognize, identify and enumerate microalgae genera and species from all the divisions. This methodology could be useful for an appropriate and effective water resource management. PMID- 25294421 TI - Long-term analysis of oncological outcomes after laparoscopic radical cystectomy in Europe: results from a multicentre study by the European Association of Urology (EAU) section of Uro-technology. AB - OBJECTIVE: To report long-term outcomes of laparoscopic radical cystectomy (LRC) in a multicentre European cohort, and explore feasibility and safety of LRC. PATIENTS AND METHODS: This study was coordinated by European Association of Urology (EAU)-section of Uro-technology (ESUT) with nine centres enrolling 503 patients undergoing LRC for bladder cancer prospectively between 2000 and 2013. Data were retrospectively analysed. Descriptive statistics were used to explore peri- and postoperative characteristics of th ecohort. Kaplan-Meier curves were constructed to evaluate recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Outcomes were also stratified according to tumour stage, lymph node (LN) involvement and surgical margin status. RESULTS: Minor complications (Clavien I-II) occurred in 39% and major (IIIa-IVb) in 17%. In all, 10 (2%) postoperative deaths were recorded. The median (interquartile, IQR) LN retrieval was 14 (9-17) and positive surgical margins were detected in 29 (5.8%) patients. The median (mean, IQR) follow-up was 50 (60, 19-90), during which 134 (27%) recurrences were detected. Actuarial RFS, CSS and OS rates were 66%, 75% and 62% at 5 years and 62%, 55%, 38% at 10 years. Significant differences in RFS, CSS and OS were found according to tumour stage, LN involvement and margin status (log-rank P < 0.001). On multivariate Cox analysis, T stage and LN involvement (both P < 0.001) were significant predictors of RFS, CSS and OS. Positive margins were significant predictors of RFS (P = 0.016) and CSS (P = 0.043). CONCLUSIONS: In this European LRC multicentre study, the largest to date, long-term RFS, CSS and OS rates after LRC appear comparable to those reported in current open RC series. Further randomised controlled trials are necessary to assess the global impact of LRC. PMID- 25294422 TI - Development of a resonant-type microwave reactor and its application to the synthesis of positron emission tomography radiopharmaceuticals. AB - Microwave technology has been successfully applied to enhance the effectiveness of radiolabeling reactions. The use of a microwave as a source of heat energy can allow chemical reactions to proceed over much shorter reaction times and in higher yields than they would do under conventional thermal conditions. A microwave reactor developed by Resonance Instrument Inc. (Model 520/521) and CEM (PETWave) has been used exclusively for the synthesis of radiolabeled agents for positron emission tomography by numerous groups throughout the world. In this study, we have developed a novel resonant-type microwave reactor powered by a solid-state device and confirmed that this system can focus microwave power on a small amount of reaction solution. Furthermore, we have demonstrated the rapid and facile radiosynthesis of 16alpha-[(18)F]fluoroestradiol, 4-[(18)F]fluoro-N-[2 (1-methoxyphenyl)-1-piperazinyl]ethyl-N-2-pyridinylbenzamide, and N-succinimidyl 4-[(18)F]fluorobenzoate using our newly developed microwave reactor. PMID- 25294423 TI - Survivin as prognostic and predictive factor in patients treated with gemcitabine, dexamethasone, and cisplatin for relapsed or refractory aggressive NHL. AB - The prognosis of relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) after front-line therapy remains poor. The development of more effective and less toxic salvage regimens remains a major challenge. Survivin is a member of the family of inhibitors of apoptosis, and survivin was associated with short survival and bad prognosis. This study was to evaluate the efficacy of GDP regimen (gemcitabine, dexamethasone and cisplatin) on relapsed or refractory aggressive NHL and various prognostic factors with special emphasis on survivin and observe the . Forty-six patients with relapsed and refractory NHL, intermediate or high-grade NHL (Revised European American Lymphoma Classification), who at least one regimen were enrolled into this study, which was carried out at Department, , Tanta University from July 2012 to July 2014. The patients were treated with GDP regimen (gemcitabine 1,000 mg/m(2) on days one and eight, dexamethasone 40 mg on days 1-3, and cisplatin 25 mg/m(2) on days 1-3) every 3 weeks. The efficacy and adverse events were evaluated according to the WHO criteria. All patients were assessed for efficacy and toxicity. The overall response rate was 58.7 %. Fourteen patients showed a complete response, thirteen partial responses, twelve stable diseases, and seven progressive disease. The 24 month overall survival was 50.8 %. Survivin is associated with low overall response and shorter overall survival. Grade 3 anemia was observed in four patients, grade 3 leucopenia in six patients, grade 3 neutropenia in six patients, and grade 3 thrombocytopenia in four patients. Non-hematologic toxicity included grade 3 infection in four patients. The present schedule of GDP showed modest efficacy and mild toxicity in patients with relapsed or refractory aggressive NHL. PMID- 25294424 TI - Overexpression of enhancer of zeste human homolog 2 (EZH2) gene in human cytomegalovirus positive glioblastoma multiforme tissues. AB - Glioblastoma multiforme (GBM) is considered to be one of the most invasive human cancers, characterized by a high mortality rate and an average survival is <1 year. These tumors are highly aggressive and insensitive to conventional radio and chemotherapy. An interesting aspect of glioblastoma is the association of active human cytomegalovirus (HCMV) infection, which is evident by the presence of viral DNA, mRNA and protein level in most glioblastoma tissues. Although the presence of the HCMV infection in glioblastoma is well established, but the oncomodulatory role of HCMV is not defined yet. Enhancer of zeste human homolog 2 (EZH2) is a key protein of the polycomb repressive complex 2, epigenetic gene silencers. There have been several reports that EZH2 activity is essential in GBM pathogenesis. In our previous research, we have found a high rate of HCMV infection in a cohort of Iranian glioblastoma patients. In this study, we investigated the expression of EZH2 in HCMV-negative versus HCMV-positive GBM tissues in comparison to non-tumor tissues. The level of expression was determined by real time PCR and the differences were calculated using the Livac or 2(-DeltaDeltaCt) and analysis of variance (ANOVA). Relative expression of EZH2 in HCMV-negative glioblastoma tissues were increased 6.053-fold compared to non neoplastic brain tissues, while EZH2 gene expression was increased 41.098-fold in HCMV-positive glioblastoma tissues. ANOVA test showed that there is a significant difference in EZH2 expression between normal brain tissue, HCMV-negative and HCMV positive glioblastoma tumors (p value = 0.0001). Our data indicate that EZH2 expression can be considered a risk factor in glioblastoma and EZH2 inhibitors may serve as potential new treatment in glioblastoma. This would be an interesting new field to investigate in more detail. PMID- 25294425 TI - High ATF5 expression is a favorable prognostic indicator in patients with hepatocellular carcinoma after hepatectomy. AB - Activating transcription factor 5 (ATF5) is a member of the ATF/CREB family involved in diverse physiological functions, ranging from metabolite homeostasis to cellular differentiations and regulation of the cell cycle. However, the clinical significance of ATF5 expression in patients with hepatocellular carcinoma (HCC) is unknown. We investigated ATF5 mRNA expression in tumors and adjacent non-tumor hepatic tissues from 119 HCC patients using quantitative real time PCR. Association between the ATF5 mRNA expression level and clinical and pathological parameters, including recurrence-free survival (RFS) and overall survival, were also evaluated using appropriate statistical methods. ATF5 was downregulated significantly (P < 0.001) in the tumor versus matched HCC non-tumor hepatic tissue, with average mRNA expression levels of 0.25 +/- 0.92 and 0.41 +/- 1.19, respectively. Low ATF5 expression was correlated significantly with liver cirrhosis, intrahepatic metastasis, and TNM stage (P < 0.05). Additionally, both Kaplan-Meier survival curve and multivariate analyses showed a relationship between ATF5 and RFS. In conclusion, a low expression level of ATF5 in HCC indicated aggressive tumor behavior and predicted a worse clinical outcome. ATF5 may be useful as a novel prognostic indicator in hepatocellular carcinoma. PMID- 25294426 TI - Thirty-minutes infusion rate is safe enough for bevacizumab; no need for initial prolong infusion. AB - Bevacizumab (Bev) is a vascular endothelial growth factor-A monoclonal antibody that targets tumor angiogenesis. The transfusion rate of Bev is 90 min in the first dose, 60 min in the second and than from the third dose it is 30 min if no hypersensitivity reaction occurs in the first two doses. The purpose of this study determines whether these initial prolonged infusions are really necessary or not. Between 2007 and 2009, we were using the standard schedule for Bev infusions. In July 2009, we reviewed our medical reports, nursing orders and adverse drug reaction forms to identify the Bev used patients and possible hypersensitivity reactions (HSRs). Depending on that information between August 2009 and July 2014, we started to make Bev infusions in 30 min from the first dose of the therapy. In this study, we documented the findings of these 30-min infusion used patients. From August 2009 to July 2014, we treated 145 patients with 1,145 Bev infusions each one in 30 min. Out of 145 patients, 12 of them received only single dosage of Bev infusion treatment. Bev doses were 5 mg/kg for 87 patients, 7.5 mg/kg for 64 patients, 10 mg/kg for four patients and 15 mg/kg for only one patient. No HSRs were reported during these transfusions. Initial prolonged infusion times are unnecessary for Bev. Thirty-minute infusion rates can be used safely for all courses. PMID- 25294427 TI - Umeclidinium for treating COPD: an evaluation of pharmacologic properties, safety and clinical use. AB - INTRODUCTION: Umeclidinium (UMEC) is a long-acting inhaled antagonist of muscarinic cholinergic receptors. The FDA approved UMEC for maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 and it became available for commercial use as a single agent in 2014. After tiotropium, this is the only other once daily LAMA available for COPD patients. AREAS COVERED: In this article, we have comprehensively reviewed the pharmacokinetic properties and analyzed the currently available randomized controlled trials on the efficacy and safety profile of UMEC. We have discussed the current clinical application of UMEC and its future implication. EXPERT OPINION: UMEC is the newer long-acting antimuscarinic agent (LAMA) that has demonstrated significant improvement in lung function and improved the quality of life in moderate-to-severe COPD patients. It is suitable for once daily dosing, has low anticholinergic side effects and is well tolerated. Overall, it is a safe, effective and convenient LAMA for maintenance therapy in COPD patients. PMID- 25294428 TI - Selection and characterization of llama single domain antibodies against N terminal huntingtin. AB - Huntington disease is caused by expansion of a CAG repeat in the huntingtin gene that is translated into an elongated polyglutamine stretch within the N-terminal domain of the huntingtin protein. The mutation is thought to introduce a gain-of toxic function in the mutant huntingtin protein, and blocking this toxicity by antibody binding could alleviate Huntington disease pathology. Llama single domain antibodies (VHH) directed against mutant huntingtin are interesting candidates as therapeutic agents or research tools in Huntington disease because of their small size, high thermostability, low cost of production, possibility of intracellular expression, and potency of blood-brain barrier passage. We have selected VHH from llama phage display libraries that specifically target the N terminal domain of the huntingtin protein. Our VHH are capable of binding wild type and mutant human huntingtin under native and denatured conditions and can be used in Huntington disease studies as a novel antibody that is easy to produce and manipulate. PMID- 25294429 TI - Sleep continuity scale in Alzheimer's disease (SCADS): application in daily clinical practice in an Italian center for dementia. AB - Sleep disorders can occur in many neurodegenerative disorders; in a previous paper we constructed a scale investigating sleep discontinuity/fragmentation with the aim to obtain a rapidly and easily administered tool suitable for early identification and longitudinal monitoring of sleep disturbances in Alzheimer's disease (AD). We introduced this instrument in the daily clinical practice in a center for dementia; here we present the results of our experience. Two hundred and sixteen AD outpatients referred to the Alzheimer's Disease Assessment Unit at the IRCCS C. Mondino National Neurological Institute, Pavia, Italy, in the period October 2012 to March 2014 were administered the scale. The questionnaire global score was correlated with measures of cognitive, functional and behavioral impairment; a significant association was found with Mini-Mental State (p = 0.005), Activities of Daily Living (p = 0.01), Neuropsychiatric Inventory (p = 0.01) and Clinical Dementia Rating (p = 0.0005). The present data indicate that the previously validated questionnaire proves to be a suitable, rapid and easy to use tool in investigating sleep quality in AD in daily clinical practice. An early identification and longitudinal monitoring of sleep disturbances in AD may improve pharmacological and non-pharmacological interventions. PMID- 25294431 TI - Call me Alix, not Elix: vowels are more important than consonants in own-name recognition at 5 months. AB - Consonants and vowels differ acoustically and articulatorily, but also functionally: Consonants are more relevant for lexical processing, and vowels for prosodic/syntactic processing. These functional biases could be powerful bootstrapping mechanisms for learning language, but their developmental origin remains unclear. The relative importance of consonants and vowels at the onset of lexical acquisition was assessed in French-learning 5-month-olds by testing sensitivity to minimal phonetic changes in their own name. Infants' reactions to mispronunciations revealed sensitivity to vowel but not consonant changes. Vowels were also more salient (on duration and intensity) but less distinct (on spectrally based measures) than consonants. Lastly, vowel (but not consonant) mispronunciation detection was modulated by acoustic factors, in particular spectrally based distance. These results establish that consonant changes do not affect lexical recognition at 5 months, while vowel changes do; the consonant bias observed later in development does not emerge until after 5 months through additional language exposure. PMID- 25294430 TI - Management of oral anticoagulation after cardioembolic stroke and stroke survival data from a population based stroke registry (LuSSt). AB - BACKGROUND: Cardioembolic stroke (CES) due to atrial fibrillation (AF) is associated with high stroke mortality. Oral anticoagulation (OAC) reduces stroke mortality, however, the impact of OAC-administration during hospital stay post ischemic stroke on mortality is unclear. We determined whether the timing of OAC initiation among other prognostic factors influenced mortality after CES. METHODS: Within the Ludwigshafen Stroke Study (LuSSt), a prospective population based stroke register, we analysed all patients with a first ever ischemic stroke or TIA due to AF from 2006 until 2010. We analysed whether treatment or non treatment with OAC and initiation of OAC-therapy during and after hospitalization influenced stroke mortality within 500 days after stroke/TIA due to AF. RESULTS: In total 479 patients had a first-ever ischemic stroke (n = 394) or TIA (n = 85) due to AF. One-year mortality rate was 28.4%. Overall, 252 patients (52.6%) received OAC. In 181 patients (37.8%), OAC treatment was started in hospital and continued thereafter. Recommendation to start OAC post discharge was given in 110 patients (23.0%) of whom 71 patients received OAC with VKA (14.8%). No OAC recommendation was given in 158 patients (33.0%). In multivariate Cox regression analysis, higher age (HR 1.04; 95% CI 1.02-1.07), coronary artery disease (HR: 1.6; 95% CI 1.1-2.3), higher mRS-score at discharge (HR 1.24; 95% CI 1.09-1.4), and OAC treatment ((no OAC vs started in hospital (HR: 5.4; 95% CI 2.8-10.5), were independently associated with stroke mortality. OAC-timing did not significantly influence stroke mortality (started post discharge vs. started in hospital (HR 0.3; 95% CI 0.07-1.4)). CONCLUSIONS: OAC non-treatment is the main predictor for stroke mortality. Although OAC initiation during hospital stay showed a trend towards higher mortality, early initiation in selected patients is an option as recommendation to start OAC post hospital was implemented in only 64.5%. This rate might be elevated by implementation of special intervention programs. PMID- 25294432 TI - Direct myocardial ischemia imaging with exercise 18FDG. PMID- 25294433 TI - Absolute myocardial blood flow quantification with SPECT/CT: is it possible? PMID- 25294434 TI - Can advances in nuclear cardiology hardware overcome the challenges of imaging obese patients? PMID- 25294435 TI - Screening for coronary artery disease in kidney transplant candidates. PMID- 25294436 TI - Dependency of cardiac rubidium-82 imaging quantitative measures on age, gender, vascular territory, and software in a cardiovascular normal population. AB - OBJECTIVES: Recent technological improvements to PET imaging equipment combined with the availability of software optimized to calculate regional myocardial blood flow (MBF) and myocardial flow reserve (MFR) create a paradigm shifting opportunity to provide new clinically relevant quantitative information to cardiologists. However, clinical interpretation of the MBF and MFR is entirely dependent upon knowledge of MBF and MFR values in normal populations and subpopulations. This work reports Rb-82-based MBF and MFR measurements for a series of 49 verified cardiovascularly normal subjects as a preliminary baseline for future clinical studies. METHODS: Forty-nine subjects (24F/25M, ages 41-69) with low probability for coronary artery disease and with normal exercise stress test were included. These subjects underwent rest/dipyridamole stress Rb-82 myocardial perfusion imaging using standard clinical techniques (40 mCi injection, 6-minute acquisition) using a Siemens Biograph 40 PET/CT scanner with high count rate detector option. List mode data was rehistogrammed into 26 dynamic frames (12 * 5 seconds, 6 * 10 seconds, 4 * 20 seconds, 4 * 40 seconds). Cardiac images were processed, and MBF and MFR calculated using Siemens syngo MBF, PMOD, and FlowQuant software using a single compartment Rb-82 model. RESULTS: Global myocardial blood flow under pharmacological stress for the 24 females as measured by PMOD, syngo MBF, and FlowQuant were 3.10 +/- 0.72, 2.80 +/ 0.66, and 2.60 +/- 0.63 mL.minute(-1).g(-1), and for the 25 males was 2.60 +/- 0.84, 2.33 +/- 0.75, 2.15 +/- 0.62 mL.minute(-1).g(-1), respectively. Rest flows for PMOD, syngo MBF, and FlowQuant averaged 1.32 +/- 0.42, 1.20 +/- 0.33, and 1.06 +/- 0.38 mL.minute(-1).g(-1) for the female subjects, and 1.12 +/- 0.29, 0.90 +/- 0.26, and 0.85 +/- 0.24 mL.minute(-1).g(-1) for the males. Myocardial flow reserves for PMOD, syngo MBF, and FlowQuant for the female normals were calculated to be 2.50 +/- 0.80, 2.53 +/- 0.67, 2.71 +/- 0.90, and 2.50 +/- 1.19, 2.85 +/- 1.19, 2.94 +/- 1.31 mL.minute(-1).g(-1) for males. CONCLUSION: Quantitative normal MBF and MFR values averaged for age and sex have been compiled for three commercial pharmacokinetic software packages. The current collection of data consisting of 49 subjects resulted in several statistically significant conclusions that support the need for a software specific, age, and sex-matched database to aid in interpretation of quantitative clinical myocardial perfusion studies. PMID- 25294438 TI - Listen to the evidence on safe staffing levels. PMID- 25294439 TI - Older nurses threatening to leave as NMC approves hike in fees. PMID- 25294437 TI - Cardiac imaging for the assessment of patients being evaluated for kidney or liver transplantation. AB - Cardiac risk assessment prior to kidney and liver transplantation is controversial. Given the paucity of available organs, selecting appropriate recipients with favorable short- and long-term cardiovascular risk profile is crucial. Using noninvasive cardiac imaging tools to guide cardiovascular risk assessment and management can also be challenging and controversial. In this article, we address the burden of coronary artery disease among kidney and liver transplant candidates and review the literature pertaining to the diagnostic accuracy and the prognostic value of noninvasive cardiac imaging techniques in this population. PMID- 25294440 TI - Regulator could end up footing the majority of bill for PSA. PMID- 25294441 TI - BBC rapped over Nightingale portrayal. PMID- 25294442 TI - 'Don't blame nurses for poor patient satisfaction, blame staff shortages'. PMID- 25294443 TI - Lib Dems shore up support for safe staffing levels. PMID- 25294444 TI - The RCN will hold all parties to their conference pledges, says Peter Carter. PMID- 25294445 TI - More practice nurses needed to stem GP crisis. PMID- 25294446 TI - Better long-term workforce planning urgently needed, says health leader. PMID- 25294447 TI - Ebola nurse calls on world to help. PMID- 25294448 TI - Nursing care toolkit helps ensure safety in numbers. PMID- 25294450 TI - RCN CAMHS expert advises ministers. PMID- 25294451 TI - Our strategy is to make MPs think about nurses' vote, says Peter Carter. PMID- 25294454 TI - Nurse awarded MBE tells others to 'aim high'. PMID- 25294455 TI - Staff face fight to keep weekend pay if 24/7 services are introduced. PMID- 25294456 TI - To the rescue--the NHS rests its hopes on former registrants returning. PMID- 25294462 TI - Postnatal care planning. PMID- 25294463 TI - Action stations against the 'silent epidemic'. PMID- 25294464 TI - Counting the hours to stay on the register. PMID- 25294473 TI - Crohn's and Colitis UK. PMID- 25294475 TI - WhatsMyM3 app. PMID- 25294477 TI - Over-reliance on technology may be at the expense of care. PMID- 25294478 TI - The latest registration fee rise is a kick in the teeth for nurses. PMID- 25294479 TI - Lessons from the military in working together for the benefit of patients. PMID- 25294482 TI - If Ebola were to become airborne, it would be a global catastrophe. PMID- 25294483 TI - Nurses are in the forefront of Ebola virus disease outbreak. PMID- 25294484 TI - A global community for safe, healthy and nourished eaters. PMID- 25294485 TI - Healthcare-associated infections: the value of patient isolation. AB - This article focuses on information about reducing or preventing the transmission of infection from patients with known, suspected or high risk of developing a multidrug-resistant organism infection such as meticillin-resistant Staphylococcus aureus. Since the literature addresses infection prevention and control measures in relation to isolation practices, the literature is evaluated for its effectiveness in supporting patient safety and informing practice that enhances the quality of inpatient care. A review of articles retrieved from several databases is conducted to identify research findings regarding some of the evidence for the effectiveness of isolation in reducing the risk of healthcare-associated infections. The cost, advantages and disadvantages of isolation practices and cohort nursing are also explored, with emphasis on patient wellbeing and safety. PMID- 25294486 TI - Improving access to health care for homeless people. AB - Homeless people have the poorest health outcomes in our society and the number of people who are homeless is increasing. This article explores the effect that homelessness has on health, provides details of organisations that offer services to the homeless population of London, and highlights the role of nurses in advocating for improved services for homeless patients. The need to understand and address inequalities in access to health care is also discussed. An example of the authors' practice is provided in the form of a case study. PMID- 25294487 TI - Clinical commissioning: the nurse's role. AB - The move to place clinicians at the centre of healthcare commissioning has been an integral aspect of reforms to health and social care in England. This article outlines the background to clinical commissioning and considers the roles and responsibilities of clinical commissioning groups (CCGs) and the nurses working in them. One CCG is used as an example to illustrate how policy has been put into practice. PMID- 25294488 TI - Oral cancer. PMID- 25294489 TI - Aspiring to the UK way. PMID- 25294490 TI - Principled and calm in a crisis. PMID- 25294493 TI - Here they come, ready or not. PMID- 25294495 TI - Nanofibrous hydrogel composites as mechanically robust tissue engineering scaffolds. AB - Hydrogels closely resemble the extracellular matrix (ECM) and can support cell proliferation while new tissue is formed, making them materials of choice as tissue engineering scaffolds. However, their sometimes-poor mechanical properties can hinder their application. The addition of meshes of nanofibers embedded in their matrix forms a composite that draws from the advantages of both components. Given that these materials are still in the early stages of development, there is a lack of uniformity across methods for characterizing their mechanical properties. Here, we propose a simple metric to enable comparisons between materials. The fibrous constituent improves the mechanical properties of the hydrogel, while the biocompatibility and functionality of the gels are maintained or even improved. PMID- 25294494 TI - In vitro neural differentiation of CD34 (+) stem cell populations in hair follicles by three different neural induction protocols. AB - Differentiation of hair follicle stem cells (HFSCs) into neurons and glial cells represents a promising cell-based therapy for neurodegenerative diseases. The hair follicle bulge area is reported as a putative source of new stem cell population for many years. In vitro studies have implicated neural differentiation of HFSCs. Here, we report the identification and purification of CD34 (+) cells from hair follicle by magnetic activated cell sorting (MACS). We next determined the cytotoxic effects of all-trans retinoic acid (RA) by using cell viability assays. Moreover, the neural differentiation potential of CD34 (+) cells was evaluated in the presence of RA, serum-free condition, and neural differentiation medium (NDM) treatments by using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). Our results showed that the isolated CD34 (+) stem cells were 12% of the total cells in the bulge area, and the neural cells derived from the stem cells expressed nestin, microtubule associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP). Interestingly, all the neural induction media supported neuronal differentiation most effectively, but treatment with serum-free medium significantly increased the number of GFAP-positive glial cells. Moreover, increasing RA concentration (>=10 MUM) leads to increased cell death in the cells, but a lower concentration of RA (1 MUM) treatment results in a decrease in CD34-expressing stem cells. These findings show an instructive neuronal effect of three neural induction media in HFSCs, indicating the important role of this induction media in the specification of the stem cells toward a neural phenotype. PMID- 25294496 TI - Roles of galactose 3'-O- sulfation in signaling. AB - Galactose-3'-O- sulfation is specific and exists in many important molecules from various human tissues, and the sulfation modification results in alteration of host molecule recognition and interaction with partner molecules which lead to signaling. The modification is thus associated with the regulation of cellular adhesion and interaction, and involved in cell recognition and even in tumor metastasis process since the binding affinity to their extracellular ligands has changed. Sulfated glycoproteins or glycolipids may also trigger signaling in the cells, which is important in regulating cell-cell and cell-extracellular matrix interaction, and in adhesion molecule transcription activation. PMID- 25294497 TI - Glycosyltransferases, glycosylation and atherosclerosis. AB - Cardiovascular diseases arising from atherosclerosis are currently the leading cause of mortality worldwide. Leukocyte recruitment is a key step for the successful initiation of atherosclerosis and occurs predominantly in the inflamed endothelium. Leukocyte recruitment is mediated by a group of adhesive molecules and chemokine receptors, which are often glycosylated protein. Recent studies demonstrated that post-translational glycosylation by glycosyltransferases is necessary for adhesive molecules and chemokine receptors activities. Several glycosyltransferases, such as alpha2,3-sialyltransferases IV, alpha1,3 fucosyltransferases IV and VII, core 2 beta1,6-N-acetylglucosaminyltransferase-I, are considered to participate in the synthesis of glycosylation for adhesive molecules and chemokine receptors, and the initiation of atherosclerotic lesions. In this review, we will discuss new data concerning the roles of different glycosyltransferases in atherogenesis. The knowledge of glycosyltransferases in atherogenesis offers the opportunity to develop novel therapeutic strategies. PMID- 25294498 TI - Postural adjustments to support surface perturbations during reaching depend upon body-target reference frame. AB - We investigated whether target position relative to the body modifies the postural adjustments produced when reaching movements are perturbed by unexpected displacements of the support surface. Eleven healthy participants reached to a target located at their midline, acromion height and at 130% their outstretched arm length. They stood on two force plates mounted on a moveable platform, capable of delivering horizontal forward ramp-and-hold perturbations. Three types of trial were given: reach only (R), perturbations only (P) and reaching movements during which a perturbation was given at a random delay after reach onset (RP). The target could be mounted either on a frame suspended from the ceiling such that it remained world-fixed (exocentric target, RP/X) or at an equivalent position on the moving platform so that it moved with the body (egocentric target, RP/E). Arm and body 3D kinematics and muscle activity from the right tibialis anterior (rTA) and soleus (rSOL) muscles were recorded. Normalised rTA activity was significantly lower in RP than in P trials. Furthermore, long-latency rTA muscle activity was lower in RP/E than in RP/X conditions when perturbations were given during either the arm deceleration phase of reaching. The rSOL muscle activity was lowest for the RP/E (arm deceleration) condition. When balance is perturbed during reaching, the manner in which the target moves relative to the body determines the muscle activity produced in the lower-limb muscles. Furthermore, a target that moves with the body requires a different regulation of muscle activity compared with one that moves independently of the body. PMID- 25294499 TI - Illusory movements induced by tendon vibration in right- and left-handed people. AB - Frequency-specific vibratory stimulation of peripheral tendons induces an illusion of limb movement that may be useful for restoring proprioceptive information in people with sensorimotor disability. This potential application may be limited by inter- and intra-subject variability in the susceptibility to such an illusion, which may depend on a variety of factors. To explore the influence of stimulation parameters and participants' handedness on the movement illusion, we vibrated the right and left tendon of the biceps brachii in a group of right- and left-handed people with five stimulation frequencies (from 40 to 120 Hz in step of 20 Hz). We found that all participants reported the expected illusion of elbow extension, especially after 40 and 60 Hz. Left-handers exhibited less variability in reporting the illusion compared to right-handers across the different stimulation frequencies. Moreover, the stimulation of the non-dominant arm elicited a more vivid illusion with faster onset relative to the stimulation of the dominant arm, an effect that was independent from participants' handedness. Overall, our data show that stimulation frequency, handedness and arm dominance influence the tendon vibration movement illusion. The results are discussed in reference to their relevance in linking motor awareness, improving current devices for motor ability recovery after brain or spinal damage and developing prosthetics and virtual embodiment systems. PMID- 25294500 TI - Intended rather than actual movement velocity determines the latency of anticipatory postural adjustments. AB - The literature reports that anticipatory postural adjustments (APAs) are programmed according to movement velocity. However, the linkage between APAs and velocity has been highlighted within single subjects who were asked to voluntarily change movement velocity; therefore, till now, it has been impossible to discern whether the key factor determining APA latency was the intended movement velocity or the actual one. Aim of this study was to distinguish between these two factors. We analyzed the APA chain that stabilizes the arm during a brisk index finger flexion in two groups of subjects: (1) 29 who composed our database from previous experiments and were asked to "go-as-fast-as-possible" (go fast), but actually performed the movement with different speeds (238-1, 180 degrees /s), and (2) ten new subjects who performed the go-fast movement at more than 500 degrees /s and were then asked to go-slow at about 50% of their initial velocity, thus moving at 300-800 degrees /s. No correlation between APA latency and actual movement speed was observed when all subjects had to go-fast (p > 0.50), while delayed APAs were found in the ten new subjects when they had to go slow (p < 0.001). Moreover, in the speed range between 300 and 800 degrees /s, the APA latency depended only on movement instruction: subjects going fast showed earlier APAs than those going slow (p < 0.001). These data suggest a stronger role of the intended movement velocity versus the actual one in modifying the timing of postural muscles recruitment with respect to the prime mover. These results also strengthen the idea of a shared postural and voluntary command within the same motor act. PMID- 25294502 TI - [In Process Citation]. PMID- 25294503 TI - [In Process Citation]. PMID- 25294501 TI - Natural selection in a postglacial range expansion: the case of the colour cline in the European barn owl. AB - Gradients of variation--or clines--have always intrigued biologists. Classically, they have been interpreted as the outcomes of antagonistic interactions between selection and gene flow. Alternatively, clines may also establish neutrally with isolation by distance (IBD) or secondary contact between previously isolated populations. The relative importance of natural selection and these two neutral processes in the establishment of clinal variation can be tested by comparing genetic differentiation at neutral genetic markers and at the studied trait. A third neutral process, surfing of a newly arisen mutation during the colonization of a new habitat, is more difficult to test. Here, we designed a spatially explicit approximate Bayesian computation (ABC) simulation framework to evaluate whether the strong cline in the genetically based reddish coloration observed in the European barn owl (Tyto alba) arose as a by-product of a range expansion or whether selection has to be invoked to explain this colour cline, for which we have previously ruled out the actions of IBD or secondary contact. Using ABC simulations and genetic data on 390 individuals from 20 locations genotyped at 22 microsatellites loci, we first determined how barn owls colonized Europe after the last glaciation. Using these results in new simulations on the evolution of the colour phenotype, and assuming various genetic architectures for the colour trait, we demonstrate that the observed colour cline cannot be due to the surfing of a neutral mutation. Taking advantage of spatially explicit ABC, which proved to be a powerful method to disentangle the respective roles of selection and drift in range expansions, we conclude that the formation of the colour cline observed in the barn owl must be due to natural selection. PMID- 25294504 TI - [In Process Citation]. PMID- 25294505 TI - [Sparse evidence of antipsychotic drugs for the treatment of delirium]. AB - Traditionally, haloperidol has been the recommended antipsychotic drug for pharmacological treatment of delirium, which is a frequent complication in the critical care setting. Due to a less frequent occurrence of extrapyramidal adverse effects, second-generation antipsychotic drugs have been evaluated. In the present paper we review the current randomized prospective studies of second generation antipsychotics as treatment for delirium in hospitalized patients and conclude that so far the evidence in favour of these drugs compared with haloperidol is still sparse. PMID- 25294506 TI - [Residents' laparoscopic skills are improved by simulation training]. AB - Many laparoscopic simulation techniques exist. In Denmark, laparoscopic simulation models, such as virtual reality trainers and video box trainers are poorly implemented at surgical departments in spite of convincing evidence of their effect. Implementation is most likely limited by the considerable costs of certain commercial models. However, recent studies have shown that low-cost models in fact may have better effect than the more costly ones. Focus should therefore be channelled towards implementation of low-cost simulation training at all surgical departments throughout the country. PMID- 25294507 TI - [Confocal laser endomicroscopy is a new endoscopic technique for diagnosing colorectal neoplasia and inflammatory bowel disease]. AB - Confocal laser endomicroscopy (CLE) is a new endoscopic technique that allows in vivo real time histopathology. The method provides "optical" biopsies, giving the endoscopist the possibility of immediate interpretation and intervention. In colorectal cancer CLE has been used to distinguish neoplastic from non-neoplastic lesions. Lately, CLE has been used to monitor anti-angiogenic therapy by fluorescence labelled antibodies targeted against endothelial markers. The review describes CLE and the potential of the method in relation to colorectal polyps, cancer and inflammatory bowel disease. PMID- 25294508 TI - [Obstetric dermatoses]. AB - The specific dermatoses of pregnancy are rare and consist of pemphigoid gestationis (PG), intrahepatic cholestasis of pregnancy (ICP), polymorphic eruption of pregnancy and atopic eruption of pregnancy. The dermatoses are characterized by pruritus, and they are important to recognize since PG and ICP increase the risk of prematurity, fetal distress and stillbirth. Diagnosis is based on medical history, morphology, blood sample and biopsy. The dermatoses are treated with respectively ursodeoxycholic acid (in case of ICP) and steroids. Breast-feeding is recommended and induction of labour is not normally indicated. PMID- 25294509 TI - [Bilateral elastofibroma dorsi]. AB - Elastofibroma dorsi (ED) is a benign, slow-growing soft tissue pseudo-tumor and is regarded as rare. The aetiology is unclear and ED is often associated with only distinct symptoms. This case report describes a 55-year-old woman with bilateral ED, who underwent surgical treatment with great result. Some prevalence studies suggest that ED is more common than previously assumed, and on suspicion of a low diagnostic rate the importance of sufficient primary examination is therefore emphasized, especially since surgical treatment of symptomatic ED is associated with fine results in case of symptoms, and low complication rate. PMID- 25294510 TI - [Liver lesion in a cardiac arrest patient treated with therapeutic hypothermia]. AB - Cardiac arrest patients receive cardiopulmonary resuscitation. If resuscitated therapeutic hypothermia (TH) improves outcome. The following coagulopathy caused by TH, antithrombotic drugs and acidosis can induce severe haemorrhage from non acknowledged organ lesions. This story illustrates a liver lesion caused by cardiac compressions. By coincidence the lesion was found on a computed tomography scan. The patient remained circulatory stabil during TH and was discharged in good cerebral state. However, should these patients rutinely be scanned? PMID- 25294511 TI - [Manedens billede]. PMID- 25294512 TI - [CDKN2A-mutation in a family with hereditary malignant melanoma]. AB - Malignant melanoma (MM) is a frequent form of cancer with increasing incidence. 6 10% of patients with MM report a family history of MM, and in most populations 2% of unselected cases of MM carry a CDKN2A mutation. tvWe present a family with 24 cases of MM in nine persons from several generations, caused by a previously undescribed germ-line intronic mutation in CDKN2A. Through genetic counselling and genetic testing high-risk persons in the family are located and offered regular screening for MM. PMID- 25294513 TI - [Diabetes in Greenland - from Alfred Bertelsen to molecular diagnostics]. AB - Health changes in Greenland have evolved in association with rapid social changes, ageing of the population, urbanisation, changes in diet and physical activity. Two population-based studies found a notably high prevalence of diabetes (9%) and pre-diabetes (19%) among Greenland Inuit. Contrary to most other studies, the highest prevalence of diabetes and pre-diabetes was observed in the least urbanised areas, and the traditional Inuit diet was associated with a higher risk of glucose intolerance. A recent study identified a strong association of a common TBC1D4 nonsense variant with diabetes. PMID- 25294514 TI - [Compartment syndrome can also be seen in the forearm]. AB - Chronic compartment syndrome is a challenge for the clinician and symptomatic similar to neuropathies, tenosynovitis, stress fractures and referred pain from lumbar cervicalis. Thus, chronic compartment syndrome of the upper extremities is probably an underdiagnosed condition. In patients with stress-induced pain in the upper limbs, chronic compartment syndrome should be considered - particularly in young patients with high physical activity. Despite limited literature, the effect of surgical treatment is promising. PMID- 25294515 TI - [Chronic obstructive lung disease management programmes do not benefit the coordination of care pathways]. AB - Chronic obstructive lung disease (COLD) is a challenging condition for both primary and secondary health-care providers. Disease management programmes (DMP's) have been expected to lead to evident improvements in the continuum of care for COLD. The utility of a COLD management programme was evaluated in a study based on interviews among general practitioners and COLD specialists. Clinicians preferred short practical guidelines to the DMP. The DMP was found useless as a tool to improve the coordination of care pathways. Complimentary interventions to improve clinical cooperation across sectors are recommended. PMID- 25294516 TI - [A unique author ID is a possible solution to the name ambiguity problem]. AB - When more than one person have the same name, names cannot be used to identify authors, which makes it difficult to connect authors with their scholarly work. Open Researcher and Contributor ID (ORCID) is a non-profit organization that aims to solve the name ambiguity problem by providing a personalized 16-digit ID to use as author identification for scholars. The main objective for ORCID is to become the focal point for the validation of scientific work. The outcome of the implementation of ORCID will provide a litmus test for the spread of this new initiative in the scientific communities. PMID- 25294517 TI - [Successful patient-activated help call for a doctor during in-hospital stay]. AB - Department of Medicine, Randers Regional Hospital, conducted a study of patient activated help call, involving 1,050 patients with nearly 3,700 days in-hospital stay. Patients were encou-raged to bypass traditional clinical hierarchy of communication when they felt, that their concern was not met by the staff. Three help calls were related to the management of pain. In two cases it resulted in a surgical procedure. A survey including 104 patients revealed that one third reported that patient safety was improved by the initiative and nearly three quarters re-ported that they would be willing to activate the call. PMID- 25294518 TI - [Asthma among mink workers]. AB - We report two cases of asthma among mink workers. The first case is about a mink farmer who had asthma that was difficult to treat. In the medical history there was no clear relation to work, and no conclusive work relation with peak flow monitoring. He had a positive histamine release test to mink urine. The second case is about a mink farm worker, who had an asthma attack when handling mink furs. Peak flow monitoring showed a clear relation to this work, but there were no signs of allergy. We conclude that these two cases suggest an increased risk of asthma among mink workers. PMID- 25294519 TI - [A gastropleural fistula can be treated thoracoscopically]. AB - Gastropleural fistula (GPF) is although uncommon a severe and sometimes fatal complication after prior thoracic surgery, trauma or malignancy. Standard therapy has often included major surgery such as laparotomia with gastrectomi. In this case report we present a patient with GPF who underwent thoracoscopia for closure of the fistula. To our knowledge this is the first report of its kind in the Danish and English literature. Thoracoscopic treatment of GPF may be associated with less morbidity and mortality, and should be considered as the initial procedure of choice. PMID- 25294520 TI - [Lung cavities caused by Nocardia cyriacigeorgica in an immunosuppressed boy]. AB - The identification of nodules and/or cavitations in the chest X-ray of a chronically or acute ill patient will rise the suspicion of tuberculosis. However, it is important to be aware of pulmonary nocardiosis as a rare but important differential diagnosis, especially in case of no hilar adenitis. In this case report, we describe a six-year-old boy receiving prednisolone due to nephrotic syndrome, who developed pneumothorax because of pulmonal nocardiosis. The prognosis is good in case of early diagnosis and antibiotic treatment. PMID- 25294521 TI - Cotton LIM domain-containing protein GhPLIM1 is specifically expressed in anthers and participates in modulating F-actin. AB - As one form of actin binding protein (ABP), LIM domain protein can trigger the formation of actin bundles during plant growth and development. In this study, a cDNA (designated GhPLIM1) encoding a LIM domain protein with 216 amino acid residues was identified from a cotton flower cDNA library. Quantitative RT-PCR indicated that GhPLIM1 is specifically expressed in cotton anthers, and its expression levels are regulated during anther development of cotton. GhPLIM1:eGFP transformed cotton cells display a distributed network of eGFP fluorescence, suggesting that GhPLIM1 protein is mainly localised to the cell cytoskeleton. In vitro high-speed co-sedimentation and low co-sedimentation assays indicate that GhPLIM1 protein not only directly binds actin filaments but also bundles F-actin. Further biochemical experiments verified that GhPLIM1 protein can protect F-actin against depolymerisation by Lat B. Thus, our data demonstrate that GhPLIM1 functions as an actin binding protein (ABP) in modulating actin filaments in vitro, suggesting that GhPLIM1 may be involved in regulating the actin cytoskeleton required for pollen development in cotton. PMID- 25294522 TI - Laparoscopic redo paraesophageal hernia repair with collis gastroplasty for shortened esophagus. AB - Esophageal shortening can be seen in patients with chronic inflammation associated with gastroesophageal reflux disease and paraesophageal hernias. During surgical treatment of these conditions, it is important to address the esophageal shortening during the operation for optimal outcomes. Ideally, 2.5-3 cm of tension-free intraabdominal esophagus is recommended. During this video, we show a redo paraesophageal hernia repair in which we were unable to achieve adequate esophageal lengthening despite extensive mediastinal dissection. We therefore proceeded with Collis gastroplasty with Toupet fundoplication. PMID- 25294523 TI - Hospital admissions greater than 30 days following bariatric surgery: patient and procedure matter. AB - INTRODUCTION: Assessment of hospital admission in the 30-day period following bariatric surgery likely underestimates true hospital utilization. The purpose of this study is to assess hospital admissions for 2 years following bariatric surgery to identify potential differences by patient and procedure. METHODS: New York State Planning and Research Cooperative System (SPARCS) longitudinal administrative data were used to identify 22,139 adult patients who underwent a primary bariatric surgery from 2006 to 2008. Bariatric operations included laparoscopic gastric banding (LGB), laparoscopic Roux-en-y gastric bypass (RYGB), and laparoscopic sleeve gastrectomy (LSG). Patients were followed for 2 years after surgery to identify all-cause hospital admissions. Statistical correlation between postoperative hospital admission and patient demographics, comorbid conditions, and bariatric procedure was performed. RESULTS: Of the 22,139 patients, 5,718 (26 %) patients were admitted within 2 years of surgery for a total of 9,502 admissions. Thirty-day admission rate was 5 %. The number of admissions per patient ranged from 1 to 22. Assessing the number of admissions per patient demonstrated that 3,741 (17 %) patients had one, 1,575 (7 %) had 2-3, and 402 (2 %) patients had greater than 4 admissions. LSG had both the highest admission rate and percentage of patients with >4 admissions, followed by RYGB and then LGB (p < 0.001). Risk factors for admission included black race, female gender, age > 50, Medicaid/Medicare as payer, congestive heart failure, pulmonary disease, diabetes, rheumatoid arthritis, history of substance abuse, and psychoses/depression. CONCLUSION: One out of four bariatric patients will be admitted to the hospital within 2 years of surgery. While most patients are admitted only once, a subset of patients requiring numerous hospital admissions was identified. LSG is associated with both the highest rate as well as highest frequency of hospital admissions. Several patient factors were also identified that significantly increased admission risk. Consideration and attention to these factors are necessary for operative planning, preoperative patient education, and postoperative monitoring. PMID- 25294524 TI - Safety and feasibility during the initial learning process of intracorporeal Billroth I (delta-shaped) anastomosis for laparoscopic distal gastrectomy. AB - BACKGROUND: Intracorporeal Billroth I (ICBI) (delta-shaped) anastomosis is being increasingly used for laparoscopic distal gastrectomy. However, few studies have focused on the safety and feasibility of adopting this new technique. The present study aimed to review the surgical outcomes after the initial experience of performing ICBI anastomosis and to evaluate whether this technique can be safely adopted without increasing operative risk during the early learning process. METHODS: Forty-two consecutive patients who underwent ICBI anastomosis with laparoscopic distal gastrectomy by a single surgeon were enrolled, and their operative outcomes and hospital course were compared with those of 179 patients who underwent conventional extracorporeal Billroth I (ECBI) anastomosis by the same operator. The learning curve was assessed by evaluating the moving average of anastomosis time. RESULTS: The operating time in the ICBI group was significantly longer than that in the ECBI group (142 vs. 116 min, p < 0.001). However, there were no significant differences in the postoperative hospital course such as gas passage, diet initiation, postoperative fever, and hospital stay between the two groups. Postoperative morbidity did not significantly differ between the ICBI and ECBI groups (7.1 vs. 12.3 %, p = 0.428). No anastomosis related complications occurred in the ICBI group. The mean anastomosis time for ICBI anastomosis was 24 +/- 5 min, and the anastomosis average time curve showed that it reached a plateau approximately after the 14th case. CONCLUSIONS: ICBI anastomosis has a steep learning curve without increasing operative risk in the early learning process, when performed by experienced laparoscopic surgeons. The technical feasibility and clinical advantages of intracorporeal anastomosis need to be proven in future clinical trials. PMID- 25294525 TI - Single-incision versus multiport laparoscopic appendectomy: a case-matched comparative analysis. AB - BACKGROUND: The multiport technique is the gold standard for laparoscopic appendectomy, but the use of single-incision laparoscopy is on the increase. The aim of the present study was to compare case-matched cohorts of patients who had undergone single-incision laparoscopic appendectomy (SILA) with those who had undergone conventional multiport laparoscopic appendectomy (MLA). METHODS: In a case-matched analysis, all single-incision laparoscopic appendectomies performed between July 2009 and December 2013 at one institution were reviewed and compared to multiport laparoscopic appendectomies performed during the same period. Patients who had undergone SILA were matched in terms of age, gender, body mass index (BMI), and American Society of Anesthesiologists (ASA) scores with the same number of patients who had undergone MLA. Statistical evaluation included the description and comparison of demographic factors, details of surgery, and histological data. A univariate analysis was performed to assess potential risk factors for morbidity after SILA. RESULTS: One hundred and fifty-six patients who had undergone SILA were reviewed, matched, and compared to the same number of patients who had undergone MLA. No significant difference was noted in mean operating times (50.83 vs. 50.61 min for SILA and MLA, respectively; p = 0.924) and the length of hospital stay (3.60 vs. 3.66 days; p = 0.704). No patient in either group required conversion to the open procedure while 6 (3.8 %) SILA patients were converted to multiport laparoscopy. SILA was not associated with significantly higher postoperative morbidity compared to MLA (9.6 % vs. 5.8 %; p = 0.288). Postoperative wound infection rates were higher after SILA (3.2 % vs. 0.6 %), but did not achieve statistical significance (p = 0.214). Statistical analysis revealed no risk factors for developing postoperative complications after the single-incision procedure. CONCLUSION: SILA is a technically feasible and safe alternative to conventional MLA. The two procedures did not differ in terms of operating times, length of hospital stay, and postoperative outcomes. PMID- 25294526 TI - Quality of D2 lymphadenectomy for advanced gastric cancer: is laparoscopic assisted distal gastrectomy as effective as open distal gastrectomy? AB - OBJECTIVE: To determine by meta-analysis, whether D2 lymphadenectomy at laparoscopic-assisted distal gastrectomy (LADG) is as effective as that during open distal gastrectomy (ODG) for patients with advanced gastric cancer (AGC). DATA SOURCES AND REVIEW METHODS: All clinical trials that compared laparoscopic with open D2 lymphadenectomy for AGC published in English from January 1995 to June 2013 were identified in PubMed, Embase, Web of Science, and Cochrane library searches. A modified scale was used to assess the quality of the literature. We analyzed the number of harvested lymph nodes (HLNs), body mass index (BMI), tumor size, serosa invasion status, and positive lymph node rate. Meta-analyses were performed using weighted mean differences (WMD) for continuous variables, and risk differences (RD) or odds ratios (OR) for dichotomous variables. RESULTS: No eligible randomized trials were identified, but eight non-randomized trials were analyzed. In the pooled data of 677 patients who underwent LADG and 687 ODG, there were no significant differences the number of HLN (WMD: -0.98, 95 % confidence interval, CI -3.21 to 1.26), BMI (WMD: -1.20, 95 % CI -2.64 to 0.24), tumor size (WMD: -0.30, 95 % CI -0.65 to 0.05), serosa invasion status (RD: 0.04, 95 % CI -0.03 to 0.11), and positive lymph node rate (OR: 0.66, 95 % CI -0.44 to 1.01) between the groups. CONCLUSION: Our findings suggest that for patients with comparable BMI and tumor status, surgical technique did not significantly influence the number of HLNs, suggesting that D2 lymphadenectomy performed laparoscopically is as effective as an open procedure in AGC. PMID- 25294527 TI - Efficacy and adverse events of laparoscopic gastrostomy placement in children: results of a large cohort study. AB - INTRODUCTION: A gastrostomy placement is frequently performed in pediatric patients who require long-term enteral tube feeding. However, data on efficacy, perioperative complications and postoperative gastroesophageal reflux (GER) after laparoscopic gastrostomy (LAG) placement is limited. The aim of this study is to evaluate long-term efficacy and adverse events after LAG in a large cohort and determine whether routine preoperative 24-h pH monitoring should be used to predict postoperative GER. METHOD: A retrospective observational cohort study was performed including 300 patients (75 % neurologically impaired) that underwent LAG. RESULTS: After a median follow-up of 2.63 years, feeding was successful in 95.9 % of patients. Weight-for-length z-scores significantly increased (p < 0.0005). Major complications were seen in only 6 patients (2.0 %), but minor complications occurred frequently (73.6 %). Overall incidence of GER remained unchanged after LAG. Sensitivity and specificity of preoperative pH monitoring were 17.5 and 76.9 %, respectively. CONCLUSION: LAG placement in pediatric patients leads to successful feeding in 96 % of patients and serious adverse events are rare. However, the minor complication rate is high. Overall incidence of GER does not increase after LAG. Preoperative 24-h pH monitoring is not a reliable tool to predict postoperative GER. This invasive investigation technique should therefore not be routinely performed. PMID- 25294528 TI - Outcomes of ESD for patients with early gastric cancer and comorbid liver cirrhosis: a propensity score analysis. AB - BACKGROUND: Gastric cancer and liver cirrhosis (LC) are often comorbid. However, little is known about the clinical outcomes of gastric endoscopic submucosal dissection (ESD) in patients with comorbid LC. METHODS: This case-control study used a multicentre retrospective cohort. We identified 69 LC patients from the cohort of patients with early gastric cancer, who underwent gastric ESD at 12 hospitals from March 2003 to November 2010. Using the propensity score matching method, 69 patients without LC were used to compare the short- and long-term outcomes of ESD. RESULTS: Among the 69 LC patients, 53 (77 %) were Child-Pugh grade A (CP-A) and 16 (28 %) had past or present histories of hepatocellular carcinoma (HCC). Short-term outcomes did not differ between the LC patients and controls or between the CP-A and CP-B/C patients. Although the LC patients had significantly worse long-term outcomes than the controls (the 5-year overall survival rates were 60 vs. 91 %, respectively), patients with CP-A liver function without HCC histories had an overall survival almost equivalent to that of patients without LC (controls). CONCLUSIONS: LC patients appear to be good candidates for ESD if they have CP-A liver function and no history of HCC. Although their short-term outcomes were not inferior, the patients with Child Pugh grades B/C or with histories of HCC benefited less from ESD. PMID- 25294529 TI - Obesity does not affect the outcome of laparoscopic antireflux surgery. AB - BACKGROUND: Obesity has been reported to adversely affect the outcome of laparoscopic antireflux surgery (LARS). This study examined pre- and postoperative clinical and objective outcomes and quality of life in obese and normal-weight patients following LARS at a specialized centre. METHODS: Prospective data from patients subjected to LARS (Nissen or Toupet fundoplication) for symptomatic gastroesophageal reflux disease in the General Public Hospital of Zell am See were analyzed. Patients were divided in two groups: normal weight [body mass index (BMI) 20-25 kg/m(2)] and obese (BMI >= 30 kg/m(2)). Gastrointestinal quality of life index (GIQLI), symptom grading, esophageal manometry and multichannel intraluminal impedance monitoring data were documented and compared preoperatively and at 1 year postoperatively. RESULT: The study cohort included forty normal-weight and forty obese patients. Mean follow up was 14.7 +/- 2.4 months. The mean GIQLI improved significantly after surgery in both groups (p < 0.001, for both). Clinical outcomes improved following surgery regardless of BMI. There were significant improvements of typical and atypical reflux symptoms in normal weight and obese (p = 0.007; p = 0.006, respectively), but no difference in gas bloat and bowel dysfunction symptoms could be found. No intra- or perioperative complications occurred. A total of six patients had to be reoperated (7.5 %), two (5 %) in the obese group and four (10 %) in the normal-weight group, because of recurrent hiatal hernia and slipping of the wrap or persistent dysphagia due to closure of the wrap. CONCLUSION: Obesity is not associated with a poorer clinical and objective outcome after LARS. Increased BMI seems not to be a risk factor for recurrent symptomatology and reoperation. PMID- 25294530 TI - Imaging visceral adhesion to polymeric mesh using pneumoperitoneal-MRI in an experimental rat model. AB - BACKGROUND: Intraperitoneal mesh implantation is often associated with formation of adhesion to the mesh. This experimental study examines the potential of minimally invasive pneumoperitoneal-MRI to assess these adhesions in a preclinical context. METHODS: Uncoated polyethylene terephthalate meshes were placed intraperitoneally in rats, in regard to the caecum previously scraped to promote petechial bleeding and subsequent adhesions. Examinations were performed 2-weeks post mesh implantation using a rodent dedicated high field MRI. Respiratory-triggered T2-weighted images were acquired prior to and after intraperitoneal injection of ~8-10 mL gas to induce a mechanical stress on the abdominal wall. RESULTS: Adhesions are occasionally seen in sham-operated rats as opposed to rats receiving polyethylene terephthalate meshes. On high-resolution images, meshes can be detected due to their characteristic net shape. However, evidence of adherence is only found if intraperitoneal gas injection is performed, when a ~1-cm elevation of the abdominal wall is observed. When adherence occurs between the mesh and the caecum, the latter remains in contact with the wall. Looser adherences between visceral tissue and meshes are also observed. CONCLUSIONS: T2-weighted pneumoperitoneal-MRI is a powerful tool for assessing adherence after intraperitoneal mesh implantation. According to the mini-invasive procedure adopted here, this approach may allow a temporal follow up of adherence fate. PMID- 25294531 TI - Should prophylactic cholecystectomy be performed in patients with concomitant gallstones after endoscopic sphincterotomy for bile duct stones? AB - BACKGROUND: Endoscopic sphincterotomy (EST) is the standard treatment for biliary duct stones. However, performing additional cholecystectomy after EST is controversial. In this study, we aimed to evaluate the effects of cholecystectomy after EST. METHODS: Between December 2008 and July 2011, we performed a prospective, randomized, single-center trial in 90 patients with proven gallstones who underwent EST and stone extraction. After the procedure, patients were randomly allocated to undergo cholecystectomy (n = 45) or to the group of GB left in situ (n = 45). The primary outcome was biliary complications at follow up. RESULTS: Cholecystectomy was performed in 26 patients (60.5 %) in cholecystectomy group and in 13 patients (28.9 %) in intended conservative group. The median follow-up was 41 months. An intention-to-treat analysis showed that 8 patients (18.6 %) in the cholecystectomy group and 9 (20.0 %) in those who had their GB left in situ had recurrent biliary events (Kaplan-Meier curve, Breslow test, p = 0.555). In an as-treated analysis, 4 patients (10.3 %) who underwent cholecystectomy and 13 patients (26.5 %) who did not undergo cholecystectomy had additional biliary events during the follow-up period (Log-rank, p = 0.037). However, additional biliary events of cholangitis were similar in the two groups, except for a case of cholecystitis (Log-rank, p = 0.998). CONCLUSIONS: Cholecystectomy after EST for biliary duct stones fails to reduce additional recurrent cholangitis but reduces additional cholecystitis. PMID- 25294532 TI - Long-term results of palliative stent placement for acute malignant colonic obstruction. AB - BACKGROUND: Endoscopic placement of self-expanding-metal-stents (SEMS) is widely performed as palliative treatment for acute malignant colonic obstruction. There is ongoing debate regarding risks and benefits associated with SEMS placement. This study aimed to evaluate long-term outcomes of palliative SEMS placement in patients presenting with acute malignant colonic obstruction. METHODS: A prospectively collected patient cohort (2005-2013) from a general teaching hospital was used. In this hospital, all consecutive patients presenting with acute malignant large bowel obstruction are treated with endoscopic SEMS placement. Only colon cancer patients who underwent palliative SEMS placement were selected. RESULTS: In total, 48 patients were included. The technical and short-term clinical success rates were 91 % (44/48) and 85 % (36/48), respectively. SEMS-related mortality occurred in 6/48 patients (13 %) (early n = 4, late n = 2) and was caused by SEMS-related perforation in all cases. The SEMS related morbidity rate was 38 % (18/48) (early n = 7, late n = 11). Endoscopic re intervention was performed 14 times and 13 patients eventually underwent surgical treatment during follow-up. The stoma-formation rate was 15 % (7/48). Long-term clinical success was 48 % (23/48). The estimated stent patency rate (95 % confidence interval) was 69 % (52-79) at 1 month, 54 % (37-66) at 6 months and 50 % (33-62) at 12 months. CONCLUSION: Palliative SEMS placement provides rapid relief of obstruction and avoids a stoma in most patients with acute colonic obstruction caused by incurable or inoperable colon cancer. However, these benefits should be weighed against mortality and morbidity related to SEMS placement. PMID- 25294533 TI - Single center experience of endoscopic submucosal dissection (ESD) in early Barrett's adenocarcinoma. AB - BACKGROUND: Endoscopic mucosal resection (EMR) or radical surgical resection are the standard treatment options for patients with early Barrett's adenocarcinoma (EBAC). Endoscopic submucosal dissection (ESD) is a new endoscopic technique, which allows--in contrast to EMR--endoscopic en-bloc resection of neoplastic lesions greater than 2 cm with complete histological evaluation of the resected specimen. In contrast to Western countries, Barrett's esophagus is less common in Asia indicating the low volume of published data of ESD in EBAC in Japanese series. Therefore, the aim of the present study is to describe the results of ESD in patients with EBAC performed in a German tertiary referral center. METHODS: Between November 2009 and April 2014 ESDs were performed in 22 patients with histologically proven EBAC. Data were given for the en-bloc, the R0, the R0 en bloc, and the curative resection rate as well as for the complication and the local recurrence rate. RESULTS: ESD was technically possible in all of the 22 patients. 20 of the resected EBAC were mucosal carcinomas, whereas in two patients the tumor showed submucosal invasion. The en-bloc, R0, R0 en-bloc, and curative resection rates were 95.5, 81.8, 81.8 %, and 77.3 %, resp. Complication rate was 27.3 % (perforation n = 1, bleeding n = 2, stenosis n = 3). In case of curative tumor resection, only one local tumor recurrence (5.9 %) occurred after a medium follow-up of 1.6 years. CONCLUSIONS: Despite the small number of patients and a relatively short follow-up, the present data underline the value of ESD, especially in case of curative resections in the definite and less invasive therapy of EBAC. Attention should be drawn toward subsquamous extension of EBAC requiring a sufficient safety margin as an obligate condition for curative R0 resections. Due to the required learning curve and the management of potential complications, ESD should be restricted to greater endoscopic centers. PMID- 25294534 TI - Perioperative risk and complications of revisional bariatric surgery compared to primary Roux-en-Y gastric bypass. AB - INTRODUCTION: Growing number of patients requires revisional bariatric surgery. This study compares perioperative course and outcomes of revisional versus primary bariatric surgery. METHODS: Patients who underwent revisional bariatric surgery from Jan 1997 to Sept 2012 were reviewed retrospectively. Every revisional patient with BMI >35 and age <70 was matched with a primary Roux-en-Y gastric bypass control patient based on preoperative BMI, age, sex, and year of surgery. Patients' preoperative indications, intraoperative/postoperative course, and complications were analyzed. RESULTS: Two hundred and fifty five patients underwent revisional bariatric surgery with resulting Roux-en-Y gastric bypass anatomy while 1,674 patients underwent primary gastric bypass in the same time interval. Of 255 patients, 172 patients were paired with 172 primary gastric bypass patients. Revisional bariatric group had preoperative BMI 48 +/- 9, age 52 +/- 9 years, 93 % female, 44 % laparoscopic, 30 % diabetic, 60 % hypertensive. Primary bypass patients had preoperative BMI 49 +/- 8, age 52 +/- 9 years, 93 % female, 97 % laparoscopic, 49 % diabetic, 67 % hypertensive. Compared to primary bypass patients, revisional patients had significantly higher estimated blood loss (463.7 vs. 113.3 mL), longer operative time (272.5 vs. 175.5 min), greater risk for ICU stay (N = 24, 14 % vs. N = 2, 1 %), and longer hospital stay (5.6 vs. 2.5 days). There were significantly more intraoperative liver (N = 13, 8 % vs. N = 1, 1 %) and spleen (N = 18, 10 % vs. N = 0) injuries, and more enterotomies (N = 9, 5 % vs. N = 0) in the revisional group. There were also significantly more postoperative complications (N = 94, 55 % vs. N = 48, 28 %), readmissions (N = 27, 16 % vs. N = 12, 7 %), and reoperations (N = 16, 9 % vs. N = 3, 2 %) within 30 days of surgery. Mean percentage weight loss at 1 year was significantly less for revisional patients (27 vs. 37 %). There was no significant difference in 30 day mortality between the two groups (N = 6 vs. 0). CONCLUSION: Even in experienced hands, complex revisional bariatric surgery should be approached with significant caution, especially given that weight loss is less substantial. PMID- 25294535 TI - Laparoscopic versus open Ladd's procedure for intestinal malrotation in adults. AB - BACKGROUND: Intestinal malrotation results from errors in fetal intestinal rotation and fixation. While most patients are diagnosed in childhood, some present as adults. Laparoscopic Ladd's procedure is an accepted alternative to laparotomy in children but has not been well-studied in adults. This study was designed to investigate outcomes for adults undergoing laparoscopic Ladd's repair for malrotation. METHODS: We performed a single-institution retrospective chart review over 11 years. Data collected included patient age, details of pre operative work-up and diagnosis, surgical management, complications, rates of re operation, and symptom resolution. Patients were evaluated on an intent-to-treat basis based on their planned operative approach. Categorical data were analyzed using Fisher's exact test. Continuous data were analyzed using Student's t test. RESULTS: Twenty-two patients were identified (age range 18-63). Fifteen were diagnosed pre-operatively; of the remaining seven patients, four received an intra-operative malrotation diagnosis during elective surgery for another problem. Most had some type of pre-operative imaging, with computed tomography being the most common (77.3 %). Comparing patients on an intent-to-treat basis, the two groups were similar with respect to age, operative time, and estimated blood loss. Six patients underwent successful laparoscopic repair; three began laparoscopically but were converted to laparotomy. There was a statistically significant difference in hospital length of stay (LOS) (5.0 +/- 2.5 days vs 11.6 +/- 8.1 days, p = 0.0148) favoring the laparoscopic approach. Three patients required re-operation: two underwent side-to-side duodeno-duodenostomy and one underwent a re-do Ladd's procedure. Ultimately, three (two laparoscopic, one open) had persistent symptoms of bloating (n = 2), constipation (n = 2), and/or pain (n = 1). CONCLUSION: Laparoscopic repair appears to be safe and effective in adults. While a small sample size limits the power of this study, we found a statistically significant decrease in LOS and a trend toward decreased postoperative nasogastric decompression. There were no significant differences in complication rates, re-operation, or persistence of symptoms between groups. PMID- 25294536 TI - Evaluation of absorbable mesh fixation devices at various deployment angles. AB - BACKGROUND: Hernia repair failure may occur due to suboptimal mesh fixation by mechanical constructs before mesh integration. Construct design and acute penetration angle may alter mesh-tissue fixation strength. We compared acute fixation strengths of absorbable fixation devices at various deployment angles, directions of loading, and construct orientations. METHODS: Porcine abdominal walls were sectioned. Constructs were deployed at 30 degrees , 45 degrees , 60 degrees , and 90 degrees angles to fix mesh to the tissue specimens. Lap-shear testing was performed in upward, downward, and lateral directions in relation to the abdominal wall cranial-caudal axis to evaluate fixation. AbsorbatackTM (AT), SorbaFixTM (SF), and SecureStrapTM in vertical (SSV) and horizontal (SSH) orientations in relation to the abdominal wall cranial-caudal axis were tested. Ten tests were performed for each combination of device, angle, and loading direction. Failure types and strength data were recorded. ANOVA with Tukey-Kramer adjustments for multiple comparisons and chi (2) tests were performed as appropriate (p < 0.05 considered significant). RESULTS: At 30 degrees , SSH and SSV had greater fixation strengths (12.95, 12.98 N, respectively) than SF (5.70 N; p = 0.0057, p = 0.0053, respectively). At 45 degrees , mean fixation strength of SSH was significantly greater than SF (18.14, 11.40 N; p = 0.0002). No differences in strength were identified at 60 degrees or 90 degrees . No differences in strength were noted between SSV and SSH with different directions of loading. No differences were noted between SS and AT at any angle. Immediate failure was associated with SF (p < 0.0001) and the 30 degrees tacking angle (p < 0.01). CONCLUSIONS: Mesh-tissue fixation was stronger at acute deployment angles with SS compared to SF constructs. The 30 degrees angle and the SF device were associated with increased immediate failures. Varying construct and loading direction did not generate statistically significant differences in the fixation strength of absorbable fixation devices in this study. PMID- 25294538 TI - Is endoscopic resection an alternative to surgery for early low-risk submucosal gastric cancers: analysis of a large surgical database. AB - BACKGROUND: Although endoscopic resection (ER) for early gastric cancers (EGCs) has become popular with the development of endoscopic instruments and skillful endoscopists, the risk of lymph node metastasis (LNM) is still an obstacle in performing ER. In this study, we aimed to identify the risk factors of LNM and validated the expanded criteria, with the goal of suggesting modified criteria for ER in submucosal EGCs. METHODS: Of patients who underwent gastrectomy with LN dissection and were diagnosed as EGCs with depth of invasion such as sm1, sm2 or <= 500 MUm from 1999 to 2008, 318 EGCs with submucosal invasion <= 500 MUm were enrolled through pathologic evaluations. To identify the risk factors of LNM, a multivariate analysis of clinicopathologic factors was performed. By combining the independent risk factors of LNM, the risk of LNM was analyzed. RESULT: LNM were detected in 35 cases (11.0 %). Tumors >30 mm in size and with lymphatic invasion were identified as an independent risk factor for LNM in EGCs with depth of invasion <= 500 MUm. Among 94 cases meeting the expanded criteria, two cases (2.1 %) were found to have LNM. Based on the submucosal invasion <300 MUm, there was no LNM in EGCs with a size <= 30 mm and no lymphovascular invasion, regardless of differentiation grade. CONCLUSION: To exclude the possibility of LNM, applying the modified criteria based on the submucosal invasion <300 MUm in performing ER might be worthwhile. PMID- 25294539 TI - A novel semi-automatic snake robot for natural orifice transluminal endoscopic surgery: preclinical tests in animal and human cadaver models (with video). AB - BACKGROUND AND STUDY AIMS: Natural orifice transluminal endoscopic surgery (NOTES) is an emerging surgical technique. We aimed to design, create, and evaluate a new semi-automatic snake robot for NOTES. MATERIALS AND METHODS: The snake robot employs the characteristics of both a manual endoscope and a multi segment snake robot. This robot is inserted and retracted manually, like a classical endoscope, while its shape is controlled using embedded robot technology. The feasibility of a prototype robot for NOTES was evaluated in animals and human cadavers. RESULTS: The transverse stiffness and maneuverability of the snake robot appeared satisfactory. It could be advanced through the anus as far as the peritoneal cavity without any injury to adjacent organs. Preclinical tests showed that the device could navigate the peritoneal cavity. CONCLUSIONS: The snake robot has advantages of high transverse force and intuitive control. This new robot may be clinically superior to conventional tools for transanal NOTES. PMID- 25294540 TI - Tacks, staples, or suture: method of peritoneal closure in laparoscopic transabdominal preperitoneal inguinal hernia repair effects early quality of life. AB - INTRODUCTION: TAPP inguinal hernia repair (IHR) entails the development of a peritoneal flap (PF) in order to reduce the hernia sac and create a preperitoneal space in which to place mesh. Many methods for closure of the PF exist including sutures, tacks, and staples. We hypothesized that patients who had PF closure with suture would have better short-term QOL outcomes. METHODS AND PROCEDURES: A prospective institutional hernia-specific database was queried for all adult, TAPP IHRs from July 2012 to August 2013. Unilateral and bilateral patients were included and each hernia was analyzed separately. The main outcome of interest was quality of life (QOL) at two- and four-week follow-up, as measured by the Carolinas Comfort Scale. RESULTS: There were 227 patients who underwent TAPP, with 99 bilateral and 128 unilateral IHR, for a total of 326 IHR. PF closure was performed using tacks in 45.1%, suture in 19.0%, and staples in 35.9%. Patient characteristics were statistically similar between the tack, suture, and staple group. There were 32.9% direct, 46.5% indirect, and 20.6% pantaloon hernias, which were not significantly different when compared by PF closure method. Post operative complications and length of stay were same for the three groups. There were no hernia recurrences. Post-operative activity limitation at two weeks was significantly better in the suture group when compared to the stapled group (p = 0.005). Additionally, sutured PF closure had less early post-operative pain when compared to the tack group (p = 0.038). CONCLUSIONS: Following TAPP IHR, suture closure of the PF significantly improves 2-week post-operative movement limitation compared to stapled and tacked PF closure. Continued randomized studies are needed to determine the best surgical hernia repair methods for ideal post-op QOL. PMID- 25294537 TI - Guidelines for laparoscopic peritoneal dialysis access surgery. PMID- 25294541 TI - Laparoscopic repair reduces incidence of surgical site infections for all ventral hernias. AB - BACKGROUND: The role of laparoscopic repair of ventral hernias remains incompletely defined. We hypothesize that laparoscopy, compared to open repair with mesh, decreases surgical site infection (SSI) for all ventral hernia types. METHODS: MEDLINE, EMBASE, and Cochrane databases were reviewed to identify studies evaluating outcomes of laparoscopic versus open repair with mesh of ventral hernias and divided into groups (primary or incisional). Studies with high risk of bias were excluded. Primary outcomes of interest were recurrence and SSI. Fixed effects model was used unless significant heterogeneity, assessed with the Higgins I square (I(2)), was encountered. RESULTS: There were 5 and 15 studies for primary and incisional cohorts. No difference was seen in recurrence between laparoscopic and open repair in the two hernia groups. SSI was more common with open repair in both hernia groups: primary (OR 4.17, 95%CI [2.03 8.55]) and incisional (OR 5.16, 95%CI [2.79-9.57]). CONCLUSIONS: Laparoscopic repair, compared to open repair with mesh, decreases rates of SSI in all types of ventral hernias with no difference in recurrence. These data suggest that laparoscopic approach may be the treatment of choice for all types of ventral hernias. PMID- 25294542 TI - Relaparoscopy for management of postoperative complications following colorectal surgery: ten years experience in a single center. AB - BACKGROUND: Laparoscopy has increasingly become the standard of care for patients who undergo colorectal surgery for both benign and malignant disease. On the basis of this growing experience, there is now an expanded role for laparoscopic approach to postoperative complications after primary colorectal resection. However, there is little literature specific to this topic. We report a ten-year experience with laparoscopic treatment of early complications following laparoscopic colorectal surgery. METHODS: From January 2003 to December 2012, a total of 1,292 patients underwent elective laparoscopic colorectal surgery in our department. One hundred and two (7.9%) patients required reoperation for a postoperative complication. Laparoscopy has been also adopted as the preferred procedure for management of postoperative complications. A retrospective review of 84 patients who had relaparoscopy (RL) for postoperative complications, including peritonitis, ureteral injury, bowel obstruction, and bleeding, was performed. RESULTS: Reoperation was carried out laparoscopically in 79 (94.0%) patients. Five (6.0%) conversions were necessary because of massive colonic ischemia, generalized fecal peritonitis, and lack of working space. The most common finding at RL was anastomotic leakage (57.1%) that was managed by peritoneal lavage and ileostomy in 91.7% of cases. Six percent of patients had negative RL. Overall morbidity rate was 25.0%. Five patients required additional surgery: four (5.1%) after RL and one after a converted procedure. There were five (6.0%) deaths from septic shock, myocardial infarction, and pulmonary embolism. CONCLUSIONS: Laparoscopy is a safe and effective tool for management of complications following laparoscopic colorectal surgery. In this setting, RL represents the first step of re-exploration and treatment, with no delay to conversion to open procedure even in skilled laparoscopic hands. PMID- 25294543 TI - An evaluation of the endoscopic surgical skills assessment using a video analysis software program. AB - BACKGROUNDS: Recently, the endoscopic surgical skills of surgeons have become a focus of many investigators and society as a whole. Hence, the importance of the training and education programs used to ensure safer endoscopic surgery has been gradually increasing. We developed our own motion analysis system called the HUESAD, and already demonstrated its construct validity. In this study, we verified that another motion analysis system (which uses the Dartfish Software program) could assess surgeons' endoscopic surgical skills. METHODS: Experts (who had performed more than 100 laparoscopic surgeries) and novices (who had no experience performing laparoscopic surgery) were recruited for this study. The task was suturing in a dry box trainer. The time and the locus tracing of both sides' needle holders were analyzed using the new video analysis system (Dartfish Software). RESULTS: There were statistically significant differences between the experts and novices in all three variables assessed (task time: p = 0.0011, the locus tracing of the left sides' needle holders: p = 0.0011, the locus tracing of the right sides' needle holders: p = 0.0011). CONCLUSIONS: The results of this study demonstrated that the results of the motion analysis by the Dartfish Software were well correlated with the surgeon's skill level. PMID- 25294544 TI - Flexible videoscope for thoracoscopic lobectomy: evolution of uniportal technique. AB - BACKGROUND: Over the years reducing the number of ports during Video-assisted thoracic surgery (VATS) has allowed to accomplish pulmonary lobectomy with a single incision. Endoscopic view and instruments maneuvers issues could be improved by using flexible endoscope. We report our experience of fifteen uniportal VATS (UVATS) using a flexible thoracoscope. METHODS: A single incision of about 4-5 cm long was performed at the 5th intercostal space along the anterior axillary line. No additional skin incisions were made. A flexible videoscope and multiple VATS instruments were simultaneously inserted into the uniport. Pulmonary lobectomy with systematic mediastinal lymph node dissection was performed. Verbal pain scores were registered using the visual analog scale from 0 to 10 at the first post-operative day. RESULTS: No post-operative complications or hospital mortality were recorded. Mean operative time was 112.6 min (range 70-200) and mean postoperative hospital stay 3.2 days (range 2-6). Mean pain score was 0.5 (range 0-2). CONCLUSIONS: Single-incision VATS lobectomy using a flexible thoracoscope is a feasible and safe approach. PMID- 25294545 TI - Groin defects seen at extra-peritoneal laparoscopic dissection during surgical treatment of athletic pubalgia. AB - BACKGROUND: Recently new disease process, often referred to as athletic pubalgia (AP), has been acknowledged by the medical community. The patients suffering from this ailment present with unilateral or bilateral chronic groin pain associated with physical activity without a clear diagnosis of a groin hernia. Though physical therapy and medical treatments are considered first line remedies, some believe that surgical treatment may have better, quicker, and more durable outcomes and procedures aimed at groin reinforcement seem to relieve most of symptoms in the majority of the patients. Despite many surgeons consistently noting rectus insertion or adductor thinning, multiple hernia defects are often seen during dissections and the clinical significance of these findings is still not known. MATERIALS AND METHODS: Between 2007 and 2011, 40 patients underwent an extra-peritoneal laparoscopic reinforcement of rectus abdominals and insertion of adductor muscles for AP. All patients underwent wide and bilateral groin dissection and the findings were cataloged. RESULTS: All of the patients presented with groin defects upon wide dissection. Thirty-four patients (85%) presented with small bilateral indirect inguinal defects and 28 (70%) of these patients did not have any additional defects. Five patients (12.5%) were found to have only unilateral inguinal hernia defects. One patient presented with a small direct defect. In addition to these defects, five patients (12.5%) had additional unilateral femoral hernias, whereas no patient had solitary femoral hernia defects. CONCLUSION: AP is a new diagnostic entity with poorly understood etiology. It mostly affects young active adults, often involved in competitive sports and surgical methods may be most effective at achieving the cure. In our experience all of the patients presented with groin defects, though not all were the same. It is our belief that these defects, although likely not the only component, play a significant role in the pathophysiology of AP. PMID- 25294546 TI - Intraoperative use of fluorescent imaging with indocyanine green changes management of abdominal wall flaps during open ventral hernia repair. AB - BACKGROUND: Wound complications including infection and necrosis remain common during complex open ventral hernia repair. Advancements or enhancements in imaging technology may abate some of these issues but requires more investigation. Laser-assisted fluorescent imaging with indocyanine green (Spy Elite, LifeCell Corporation, Branchburg, NJ) allows visualization and quantification of perfusion, facilitating management of poorly perfused tissue. METHODS: Ten patients, who underwent large or massive ventral or incisional hernia repair with biologic graft reinforcement and either perforator-sparing components separation or primary open repair, underwent intraoperative laser assisted fluorescent imaging with indocyanine green from August 2012 to August 2013. The cases were reviewed by an independent data collector with primary outcomes of postoperative skin infection and/or abdominal wall necrosis. RESULTS: Three (30%) patients had adequate perfusion, while seven (70%) patients had inadequate skin perfusion and necessitated excision of additional tissue. Of the patients whose ischemic tissue was removed, four (57%) patients had an infection and no patients developed necrosis postoperatively. Of the patients who had no removal of additional skin, one (33%) patient developed an infection and one (33%) patients developed skin necrosis. CONCLUSION: The intraoperative use of laser-assisted fluorescent imaging with indocyanine green may change management of abdominal wall flaps, even in perforator-sparing operations. Our study series is small and cannot suggest statistical significance in the potential benefit of intraoperative imaging, but shows that up to 70% of patients may require change in management due to poorly perfused tissue flaps. PMID- 25294547 TI - Bariatric postoperative fistula: a life-saving endoscopic procedure. AB - BACKGROUND: Gastric fistula after bariatric surgery has high morbi-mortality, and treatment is a challenge due to persistent abscess and/or distal stenosis. The present study evaluated the efficacy and safety of stricturotomy/internal drainage, a novel endoscopic procedure that can avoid re-operation and allow early oral feeding. METHODS: This prospective, non-randomized study, with no control or sham group, included 27 patients (74.07% were female), approved by the local IRB, who underwent the following bariatric surgeries: Roux-en-Y gastric bypass (RYGB; n = 14, 51.85%), laparoscopic sleeve gastrectomy (LSG; n = 9, 33.33%) and duodenal switch (DS; n = 4, 14.81%). The patients presented with gastric fistulas which were treated by internal drainage/stricturotomy. The mean patient age was 42.67 years, and the mean pre-operative BMI was 40.69 kg/m(2). Balloon dilation was performed if distal stenosis and/or axis deviation was present. The first endoscopic procedure was applied on the 15th day after RYGB and the 30th day after LSG and DS. RESULTS: All patients presented with His angle fistula. Eight patients (57.1%) had stenosis of the anastomosis after RYGB and were treated with balloon dilatation (20 mm). The patients submitted to LSG and DS had stenosis at the angularis incisure and were treated with achalasia balloon dilation (30 mm). The number of endoscopic sessions for stricturotomy ranged from 1 to 6. Two patients experienced bleeding after dilation, and one had perforation. The mean time to achieve fistula closure was 18.11 days (range, 1-72 days) without mortality. All the fistulas closed. CONCLUSIONS: This novel endoscopic procedure is safe, feasible, and effective, avoiding re-operation, allowing early oral feeding and discharge. PMID- 25294548 TI - Transvaginal cholecystectomy learning curve. AB - BACKGROUND: There are few surgeons in the United States, within private practice and academic centers, currently performing transvaginal cholecystectomies (TVC). The lack of exposure to TVC during residency or fellowship training, coupled with a poorly defined learning curve, further limits interested surgeons who want to apply this technique to their practice. This study describes the learning curve encountered during the introduction of TVC to our academic facility. METHODS: This study is an analysis of consecutive TVCs performed between August 14, 2009 and August 3, 2012 at an academic center. The TVC patients were divided into sequential quartiles (n = 15/16). The learning curve outcome was measured as the operative time of TVC patients and compared to the operative time of female laparoscopic cholecystectomy (LC) patients performed during the same time period. RESULTS: Sixty-one patients underwent a TVC with a mean age of 38 +/- 12 years and mean BMI was 29 +/- 6 kg/m(2). Sixty-seven female patients who underwent a LC with average age 41 +/- 15 years and average BMI 33 +/- 12 kg/m(2). The average operative time of LC patients and TVC patients was 48 +/- 20 and 60 +/- 17 min, respectively. Significant improvement in TVC operative times was seen between the first (n = 15 TVCs) and second quartiles (p = 0.04) and stayed relatively constant for third quartile, during which there was no statistically significant difference between the mean LC operative time for the second and third TVC quartiles CONCLUSIONS: The learning curve of a fellowship-trained surgeon introducing TVC to their surgical repertoire, as measured by improved operative times, can be achieved with approximately 15 cases. PMID- 25294549 TI - Non-curative endoscopic resection does not always lead to grave outcomes in submucosal invasive early gastric cancer. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has been widely performed for the treatment of early gastric cancer (EGC). The aim of this study is to examine the effectiveness of ESD in submucosal invasive gastric cancers (SM-GC), with a special focus on patients who underwent non-curative resection. METHODS: Data for 1,246 patients who underwent ESD for treatment of EGC at six medical centers in Daegu-Gyeongbuk, Korea, between February 2003 and May 2010 were collected. After retrospective analysis of ESD databases, 118 patients were enrolled and classified into three groups: (1) EGC with submucosal invasion less than 500 MUm (SM1-GC) that met the expanded criteria (EC) (SM1 EC, n = 42); (2) SM1-GC that did not meet the EC (SM1 non-EC, n = 38); and (3) EGC with submucosal invasion greater than 500 MUm (SM2-GC, n = 38). RESULTS: The en bloc and complete resection rates did not differ significantly among the three groups. However, the curative resection rate was significantly better in the SM1 EC group (69.0%) compared to that in SM1 non-EC and SM2-GC groups (0% in both cases). Out of a total of 118 patients, 89 (75.4%) underwent non-curative resection, and cancer recurrence was observed in 9 (9/89, 10.1%). We analyzed the survival rate in these non-curative patients and the overall survival and disease-free survival did not differ significantly between patients that were treated with additional surgical resection and those that were simply followed up after ESD. CONCLUSIONS: Non-curative resection in SM-GC does not always lead to cancer recurrence. Thus, if additional surgery cannot be performed because of the patient's unsuitable condition or refusal, a close follow-up with endoscopy can be considered as an alternative for carefully selected patients. Moreover, as the ESD technology continues to evolve, it might be possible to expand the criteria for curative ESD in patients with SM-GC. PMID- 25294550 TI - Laparoscopic repair of paraesophageal hernia with anterior gastropexy: a multicenter study. AB - BACKGROUND: The approach to repair of paraesophageal hernias (PEHs) is controversial. Recent data suggest that mesh repair leads to recurrence rates similar to non-mesh approaches, while subjecting patients to mesh-associated complications. Routine fundoplication during PEH repair has been favored despite significant dysphagia rates. We present our multicenter prospective data on laparoscopic PEH repairs using a modified Boerema anterior gastropexy without fundoplication. METHODS: We prospectively followed patients after modified Boerema PEH repair at three institutions. Patient demographics, perioperative data, and postoperative outcomes were evaluated. Subjective and objective outcomes were assessed via clinical assessment, follow-up questioning, endoscopy, and radiographic swallow studies. RESULTS: A total of 101 patients were followed a mean of 10.8 (median, 12) months. We encountered 9 (8.9%) intraoperative complications and 13 (12.9%) postoperative complications. There was no mortality. Reflux symptoms were absent in 71 patients (70.3%) postoperatively. Of the remaining subjects, 8 (7.9%) had mild intermittent reflux without the need for proton pump inhibitors (PPI), 12 (11.9%) had moderate reflux necessitating PPI as needed, and 10 (9.9%) had reflux requiring daily PPI. Our recurrence rate, assessed at postoperative endoscopy/barium swallow, was 16.8%. Of these, 10 (9.9%) were small segmental recurrences and 7 (6.9%) were large recurrences. CONCLUSION: Herein, we demonstrate a favorable recurrence rate while avoiding the potential major complications associated with mesh hiatoplasty. Our data tend to support a tailored approach to incorporation of fundoplication during PEH repair. Postoperative acid reflux was absent in most of our patients, and pharmacotherapy alone was sufficient for those experiencing reflux symptoms. PMID- 25294551 TI - Results of 100 consecutive laparoscopic distal pancreatectomies: postoperative outcome, cost-benefit analysis, and quality of life assessment. AB - BACKGROUND: Laparoscopic distal pancreatectomy (LDP) has been recently proposed as the procedure of choice for lesions of the pancreatic body and tail in experienced centres. The purpose of this study is to assess the potential advantages of LDP in a consecutive series of 100 patients. METHODS: Propensity score matching was used to identify patients for comparison between LDP and control open group. Match criteria were: age, gender, ASA score, BMI, lesion site and size, and malignancy. All patients were treated according to an early feeding recovery policy. Primary endpoint was postoperative morbidity rate. Secondary endpoints were operative time, blood transfusion, length of hospital stay (LOS), hospital costs, and quality of life. RESULTS: Thirty patients of the LDP group had pancreatic adenocarcinoma. Conversion to open surgery was necessary in 23 patients. Mean operative time was 29 min shorter in the open group (p = 0.002). No significant difference between groups was found in blood transfusion rate and postoperative morbidity rate. LDP was associated with an early postoperative rehabilitation and a shorter LOS in uneventful patients. Economic analysis showed 775 extra cost per patient of the LDP group. General health perception and vitality were better in the LDP group one month after surgery. CONCLUSION: Laparoscopic distal pancreatectomy improved short-term postoperative recovery and quality of life in a consecutive series of both cancer and non-cancer patients. Despite the extra cost, the laparoscopic approach should be considered the first option in patients undergoing distal pancreatectomy. PMID- 25294552 TI - Long-term symptoms, quality of life, and fertility after colorectal resection for endometriosis: extended analysis of a randomized controlled trial comparing laparoscopically assisted to open surgery. AB - BACKGROUND: To evaluate the long-term symptoms, quality of life (QOL), and fertility after colorectal resection for endometriosis. METHODS: Extended analysis of a randomized controlled trial including 52 patients with colorectal endometriosis, comparing laparoscopically assisted to open colorectal resection. All included patients were invited to complete questionnaires evaluating the presence and intensity of symptoms and QOL using the SF-36 and fertility at a mean (SD) follow-up of 50.7 (13.8) months. We compared symptoms intensity and QOL before and after surgery at short- (mean follow-up of 19 months) and long-term (mean follow-up of 51 months). RESULTS: Persistent improvement in QOL was noted after surgery without differences between short and long term. Self catheterization >6 months was the sole factor decreasing the long-term QOL (P = 0.02). No difference in symptoms and QOL was noted according to the route. Among the 28 patients (53.8%) wishing to conceive, 12 (42.9%) conceived within a mean (SD) time of 17 (13) months. No difference in fertility including pregnancy after IVF was noted between the routes, but spontaneous pregnancy occurred only after laparoscopy (P = 0.016). CONCLUSIONS: Symptoms and QOL improvements after colorectal resection last for over 4 years without difference between the routes. Thank to a lower intra- and postoperative complications and higher spontaneous pregnancy rate, laparoscopic colorectal resection should be the first surgical approach. PMID- 25294553 TI - The frequency of lymph node metastasis in early-stage adenocarcinoma of the esophagus with incipient submucosal invasion (pT1b sm1) depending on histological risk patterns. AB - BACKGROUND: A prerequisite for endoscopic treatment (ET) of not only mucosal, but also submucosal early adenocarcinoma of the esophagus (EAC) would be a rate of lymph node (LN) metastasis below the mortality rate of esophagectomy (2-5%). The aim of the present study was to evaluate the rate of LN metastasis in patients with pT1b sm1 EAC. METHODS: 1996-2010, 1,718 patients with suspicion of EAC were referred to the Department of Internal Medicine II at HSK Wiesbaden. In 123/1718 patients, the suspicion (endoscopic ultrasound, EUS) or definitive diagnosis of sm1 EAC (ER/surgery) was made. Rate of LN metastasis was analyzed separately for low-risk (LR; G1-2, L0, V0) and high-risk lesions (HR; G3, L1, V1; >= 1 risk factor). LN metastasis was only evaluated in patients who had a proven maximum invasion depth of sm1 (ER and/or surgery), and who in case of ET had a follow-up (FU) by EUS of at least 24 months. RESULTS: Of the 72/123 patients included into the study, 49 patients had LR (68%) and 23 HR lesions (32%). In endoscopically treated LR patients (37/49), mean EUS-FU was 60 +/- 30 mo (range 25-146); in HR patients undergoing ET (6/23), it was 63 +/- 17 mo (46-86; p = 0.4). Mean number of resected LN was 27 +/- 16 (12-62) in operated LR patients and 27 +/- 10 (12 47) in HR-patients. The rate of LN metastasis was 2% in the LR (1 patient) and 9% in the HR group (2 patients; p = 0.24). Mortality of esophagectomy was 3%. CONCLUSIONS: The rate of LN metastasis in pT1b sm1 early adenocarcinoma with histological LR pattern was lower than the mortality rate of esophagectomy. ER may therefore be used alternatively to surgery in this group of patients. PMID- 25294554 TI - Appendicitis in the modern era: universal problem and variable treatment. AB - BACKGROUND: Acute appendicitis is the second most common gastrointestinal diagnosis mandating urgent operation in the U.S. The current state of adult appendectomy, including patient and hospital characteristics, complications, and predictors for complications, are unknown. METHODS: Retrospective review of U.S. Nationwide Inpatient Sample 2003-2011 for appendectomy in >=18-year-olds was performed. Primary outcomes measures included postoperative complications, length of stay, and patient mortality. Categorical variables were analyzed by chi2, trend analyses by Cochran-Armitage. Multivariable logistic regression was performed to adjust for predictors of developing complications. RESULTS: 1,663,238 weighted appendectomy discharges occurred. Over the study period, complications increased from 3.2 to 3.8% (p < 0.0001), but the overall mortality decreased from 0.14 to 0.09% (p < 0.0001) and mean LOS decreased from 3.1 to 2.6 days (p < 0.0001). The proportion of laparoscopic appendectomy increased over time, 41.7-80.1% (p < 0.0001). Patients were increasingly older (>=65 years: 9.4 11.6%, p < 0.0001), more obese (3.8-8.9%, p < 0.0001), and with more comorbidities (Elixhauser score >=3: 4.7-9.8%, p < 0.0001). After adjustment, independent predictors for postoperative complications included: open surgery (OR 1.5, 95% C.I. 1.4-1.5), male sex (OR 1.6, 95% CI 1.5-1.6), black race (vs. white: OR 1.5, 95% CI 1.4-1.6), perforated appendix (OR 2.8, 95% CI 2.7-3.0), greater comorbidity (Elixhauser >=3 vs. 0, OR 11.3, 95% CI 10.5-12.1), non-private insurance status (vs. private: Medicaid OR 1.3, 95% CI 1.2-1.4; Medicare OR 1.7, 95% CI 1.6-1.8), increasing age (>52 years vs. <=27: OR 1.3; 95% CI 1.2-1.4), and hospital volume (vs. high: low OR 1.2; 95% CI 1.1-1.3). Predictors of laparoscopic appendectomy were age, ethnicity, insurance status, comorbidities, and hospital location. CONCLUSIONS: Laparoscopic appendectomy is increasing but is unevenly deployed across patient groups. Appendectomy patients were increasingly older, with more comorbidities and with increasing rates of obesity. Black patients and patients with public insurance had less utilization of laparoscopy and inferior outcomes. PMID- 25294556 TI - Eyelid and brow asymmetry in patients evaluated for upper lid blepharoplasty. AB - INTRODUCTION: In evaluation for blepharoplasty, patients often desire improved cosmesis and/or correction of visual field deficits. However, patients are usually unaware of eyelid or brow asymmetry. Furthermore, the prevalence of eyelid and brow asymmetry is infrequently reported in the medical literature. PURPOSE: To determine the prevalence of brow and eyelid asymmetry in patients evaluated for upper lid blepharoplasty. METHODS: One hundred consecutive patients evaluated for upper lid blepharoplasty were included in the study. Standard pre operative photographs were taken of all patients using consistent background and photographic equipment. Two of the authors (KM & AM) independently recorded the margin pupil (MPD), central eyebrow (CED), nasal eyebrow (NED) and temporal eyebrow (TED) distances. To test the inter-observer reliability, the senior author (SMT) recorded the same measurements for 10% of randomly selected patients. We calculated 95% confidence intervals to compare symmetry between the right and left sides. RESULTS: One hundred patients (94 female, mean age 57.7) were included in the study. The average MPD, CED, NED and TED distances were 0.55 mm (95% CI 0.45-0.65), 1.77 mm (95% CI 1.47-2.07), 1.34 mm (95% CI 1.14-1.54), and 1.78 mm (95% CI 1.50-2.06), respectively. Ninety-three percent of patients had at least one asymmetric measurement of greater than 1 mm. Seventy-five percent of patients studied had at least one measurement greater than 2 mm while 37 percent had at least one greater than 3 mm. CONCLUSION: Brow and eyelid asymmetry is common in patients being evaluated for upper lid blepharoplasty. The facial plastic surgeon should identify and document facial asymmetry pre operatively, and discuss it with prospective blepharoplasty patients. This will improve informed consent and patient expectations. PMID- 25294557 TI - Use of computed tomography as a non-invasive method for diagnosing cephenemyiosis in roe deer (Capreolus capreolus). AB - This study was conducted to assess the reliability of computed tomography (CT) for diagnosing bot fly infestations by Cephenemyia stimulator (Clark) (Diptera: Oestridae) in roe deer (Capreolus capreolus L.) (Artiodactyla: Cervidae). For this purpose, the heads of 30 animals were analysed, firstly by CT and then by necropsy, which was used as the reference standard method. The prevalence values obtained by both methods were identical; the prevalence of infestation was 40.0% overall, and was higher in males (45.5%) than in females (25.0%). These results highlight the usefulness of CT as an alternative or non-invasive method for diagnosing cephenemyiosis in live-captured roe deer and in hunting trophies or museum collections that cannot be destroyed or damaged. PMID- 25294555 TI - Migraine-related healthcare resource use and costs for subjects prescribed fixed dose combination sumatriptan/naproxen sodium vs. single-entity oral triptans in a managed care population in the USA. AB - BACKGROUND: Randomized clinical trials have demonstrated that the efficacy of a fixed-dose single-tablet combination containing sumatriptan and naproxen sodium (S/NS) was greater than either of its individual components. Simplifying drug regimens (e.g., via a fixed-dose combination) has been shown to improve "real world" outcomes by reducing pill burden and treatment regimen complexity, improving adherence, and reducing healthcare resource use and associated costs; however, no studies assessing such outcomes have been conducted to date for the acute treatment of migraine. OBJECTIVE: To assess migraine-related healthcare resource use and associated costs for subjects prescribed S/NS vs. subjects prescribed single-entity oral triptans (SOTs) within a managed care population in the USA. METHODS: In this retrospective analysis of administrative claims data from July 1, 2008 to December 31, 2009 (IMS LifeLink), subjects meeting the following criteria were selected: one or more pharmacy claim(s) for either S/NS or SOT (index date), aged 18-64 years; at least one migraine diagnosis, and continuous enrollment in the 6 months prior to and post the index date. The study population was subsequently stratified for two analyses: triptan-naive (triptan naive in the 6-month period prior to the index date) and triptan-switch (triptan user in the 6-month period prior to the index date and switching to another triptan). Subjects prescribed S/NS were propensity-score matched with subjects prescribed SOT (triptan-naive analysis: 1:3; triptan-switch analysis: 1:1) to assess differences in healthcare resource use and associated costs (2009 US$) between the S/NS and SOT groups. RESULTS: Results from the triptan-naive and triptan-switch analyses suggest that subjects prescribed S/NS are likely to have similar healthcare resource use patterns as those either newly initiated on an SOT or switching SOTs, as measured by migraine medication use, migraine-related healthcare resource use, and all-cause healthcare resource use. One exception was the observed increased use of opioids in the SOT group compared with the S/NS group (change in mean number of tablets pre-index vs. post-index, S/NS vs. SOT; triptan-naive analysis: 8.6 vs.18.3, p = 0.045; triptan-switch analysis: -8.2 vs. 17.7; p = 0.120). Total costs from the triptan-naive analysis indicated that the S/NS group had lower migraine-related (US$744 vs. US$820; p = 0.067) and all cause healthcare costs (US$4,391 vs. US$4,870; p = 0.040) when compared with the SOT group, driven by savings in medical costs (migraine-related: US$252 vs. US$380; p = 0.001; all-cause: US$3,023 vs. US$3,599; p = 0.014). However, no significant differences were observed for total costs from the triptan-switch analysis (migraine-related healthcare costs, S/NS vs. SOT: US$1,159 vs. US$1,117; p = 0.929; all-cause healthcare costs: US$5,128 vs. US$4,788; p = 0.381). CONCLUSION: Study results suggest similar healthcare resource use patterns and associated costs when comparing S/NS and SOT across a triptan-naive and triptan experienced population. While the current study focuses on direct medical costs, future studies should extend beyond such a perspective to explore functional status, productivity, and health-related quality of life and satisfaction, attributes not captured in administrative claims data, but nonetheless important treatment goals. PMID- 25294558 TI - Cytochrome P450 oxidoreductase deficiency: rare congenital disorder leading to skeletal malformations and steroidogenic defects. AB - Cytochrome P450 oxidoreductase (POR) deficiency (PORD) is a newly characterized disorder. PORD is caused by homozygous or compound heterozygous mutations in POR encoding an electron donor for several microsomal enzymes such as CYP21A2, CYP17A1, CYP19A1, CYP51A1, and CYP26A1-C1. Molecular defects of PORD include a Japanese founder mutation p.R457H, as well as various missense, nonsense, frameshift, and splice-site mutations and exonic deletions. PORD leads to unique skeletal malformations referred to as Antley-Bixler syndrome, in addition to 46,XX and 46,XY disorders of sex development, pubertal failure, adrenal dysfunction, and maternal virilization during pregnancy. Such clinical features are ascribable to impaired activities of the POR-dependent microsomal enzymes. PORD represents one form of congenital adrenal hyperplasia, although it can occur as a congenital malformation syndrome and a disorder of sex development. Phenotypic severity of PORD is highly variable and only partly depends on the residual activity of the mutant proteins. It is possible that PORD remains undiagnosed in several patients. Detailed hormonal assessment and molecular analysis are useful for diagnosis of PORD. PMID- 25294559 TI - Particulate matter and risk of Parkinson disease in a large prospective study of women. AB - BACKGROUND: Exposure to air pollution has been implicated in a number of adverse health outcomes and the effect of particulate matter (PM) on the brain is beginning to be recognized. Yet, no prospective study has examined the association between PM and risk of Parkinson Disease. Thus, our goal was assess if exposure to particulate matter air pollution is related to risk of Parkinson's disease (PD) in the Nurses' Health Study (NHS), a large prospective cohort of women. METHODS: Cumulative average exposure to different size fractions of PM up to 2 years before the onset of PD, was estimated using a spatio-temporal model by linking each individual's places of residence throughout the study with location specific air pollution levels. We prospectively followed 115,767 women in the NHS, identified 508 incident PD cases and used multivariable Cox proportional hazards models to estimate the risk of PD associated with each size fraction of PM independently. RESULTS: In models adjusted for age in months, smoking, region, population density, caffeine and ibuprofen intake, we observed no statistically significant associations between exposure to air pollution and PD risk. The relative risk (RR) comparing the top quartile to the bottom quartile of PM exposure was 0.99 (95% Confidence Intervals (CI): 0.84,1.16) for PM10 (<=10 microns in diameter), 1.08 (95% CI: 0.81, 1.45) for PM2.5 (<=2.5 microns in diameter), and 0.92 (95% CI: 0.71, 1.19) for PM(10-2.5) (2.5 to 10 microns in diameter). CONCLUSIONS: In this study, we found no evidence that exposure to air pollution is a risk factor for PD. PMID- 25294560 TI - [Detection of intrinsic ligament and TFCC lesions of the wrist. Direct versus indirect MRI arthrography]. AB - BACKGROUND: The purpose of this study was to validate the diagnostic value of direct magnetic resonance imaging (dMRI) arthrography and indirect MRI (iMRI) arthrography concerning intrinsic ligament injuries and tears of the triangular fibrocartilage complex (TFCC). PATIENTS AND METHODS: A randomized prospective trial was conducted with patients who presented with wrist pain potentially due to carpal lesions and 10 patients aged 19-60 years (3 female and 7 male) were included. Between the clinical examination and the diagnostic and therapeutic arthroscopy, dMRI and iMRI arthrography were performed for the diagnostics of injuries of the intrinsic ligaments or the TFCC. The results of dMRI and iMRI arthrography were evaluated by two radiologists blinded to the injuries of the patients and a consensus was reached. The results were compared with the findings obtained by arthroscopy. RESULTS: In the arthroscopy five lesions of the scapholunate ligament (SL), one of the lunotriquetral ligament (LT) and seven of the TFCC were identified. The sensitivity of iMRI and dMRI for carpal ligament lesions (SL and LT) was low (50 %) whereas the specificity was high (93 %). For injuries of the TFCC the sensitivity (up to 100 %) and the specificity (100 %) were both excellent. The area under the curve (AUC) in the receiver operating characteristics (ROC) analysis was high for TFCC lesions in both dMRI and iMRI arthrography. CONCLUSION: Indirect MRI arthrography is a suitable method for detection of injuries of the TFCC and intrinsic ligaments of the wrist with good sensitivity and specificity. Despite the low number of patients the results of this study showed that there were no essential differences between dMRI and iMRI arthrography with respect to the diagnostic value for carpal injuries of the wrist. PMID- 25294561 TI - Cerebral vasculopathy in children with sickle cell anemia. AB - Sickle cell anemia (SCA)-associated cerebral vasculopathy and moyamoya is a unique entity reflecting the abnormal interactions between sickled red blood cells (RBCs) and the cerebral arterial endothelium. Endothelial injury, coagulation activation, and the inflammatory response generated by sickled RBCs are implicated in the development of cerebral vasculopathy, but the pathophysiology remains incompletely understood. SCA-specific screening and treatment guidelines have successfully reduced the incidence of overt strokes in this high-risk population. However, despite aggressive hematological management, many children with cerebral vasculopathy due to SCA have progressive vasculopathy and recurrent strokes; therefore, more effective therapies, such as revascularization surgery and curative hematopoietic stem cell transplant, are urgently needed. PMID- 25294562 TI - Coordinated expression of H3K9 histone methyltransferases during tooth development in mice. AB - Tissue-specific gene expression is subjected to epigenetic and genetic regulation. Posttranslational modifications of histone tails alter the accessibility of nuclear proteins to DNA, thus affecting the activity of the regulatory complex of nuclear proteins. Methylation at histone 3 lysine 9 (H3K9) is a crucial modification that affects gene expression and cell differentiation. H3K9 is known to have 0-3 methylation states, and these four methylated states are determined by the expression of sets of histone methyltransferases. During development, teeth are formed through mutual interactions between the mesenchyme and epithelium via a process that is subjected to the epigenetic regulation. In this study, we examined the expression of all H3K9 methyltransferases (H3K9MTases) during mouse tooth development. We found that four H3K9MTases-G9a, Glp, Prdm2, and Suv39h1-were highly expressed in the tooth germ, with expression peaks at around embryonic days 16.5 and 17.5 in mice. Immunohistochemical and in situ hybridization analyses revealed that all four H3K9MTases were enriched in the mesenchyme more than in the epithelium. Substrates of H3K9MTases, H3K9me1, H3K9me2, and H3K9me3 were also enriched in the mesenchyme. Taken together, these data suggested that coordinated expression of four H3K9MTases in the dental mesenchyme might play important roles in tooth development. PMID- 25294563 TI - Convergent innovation for affordable nutrition, health, and health care: the global pulse roadmap. AB - The paper outlines how the principles of convergent innovation (CI) can be applied to bring about a transformation in the pulse value chain. The paper presents three pioneering CI initiatives--two in conception and one in operation- by various actors in the pulse ecosystem, which are delivering economic and human development impact in particular segments of the pulse value chain. It goes on to propose the way forward to scale up these efforts and connect them into a roadmap so as to achieve transformation throughout society, calling into action a number of actors in the ecosystem. PMID- 25294564 TI - Subgroup differences in having a usual source of health care among working-age adults with and without disabilities. AB - BACKGROUND: Having a usual source of health care is positively associated with regular health maintenance visits and receipt of preventive services. People with disabilities are, overall, more likely than those without disabilities to have a usual source of care (USC). However, the population of people with disabilities is quite heterogenous, and some segments of the population may have less access to a USC than others. OBJECTIVE: To determine whether there are significant subgroup differences in having a USC within the U.S. population of working-age adults with disabilities, and to compare adults with and without disabilities while controlling for other subgroup differences. METHODS: We analyzed Medical Expenditure Panel Survey annual data files from 2002 to 2008. We performed both bivariate and multivariate logistic regression analyses to examine the relationship of sociodemographic and disability subgroup variables with having a USC. RESULTS: Within the disability population, individuals who were younger; male; Black, Hispanic, or other (non-White) race; less educated; of lower income; or uninsured for part or all of the year were significantly less likely to have a USC. These differences mirrored those among adults without disabilities. When controlling for these differences, people with physical, hearing, or multiple disabilities had greater odds of having a USC than people without disabilities, but those with vision or cognitive limitations did not differ significantly from the non-disabled referent group. CONCLUSIONS: Disparities among people with and without disabilities are similar, underscoring the need for attention to disparities within the disability population. PMID- 25294565 TI - Engineered nanoparticles for drug delivery in cancer therapy. AB - In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications. PMID- 25294566 TI - Detailed simulation of the role of functionalized polymer chains on the structural, dynamic and mechanical properties of polymer nanocomposites. AB - To systematically study the effect of functionalized chain groups on polymer nanocomposites, we perform our simulation work in the following two ways. In the case of dilute loading of nanoparticles (NPs) with different geometries (spherical, sheet-like, rod-like NPs), we adopt coarse-grained molecular dynamics simulation to study the structural, dynamic and mechanical properties of polymer nanocomposites influenced by the terminal groups of linear polymer chains. We observe that the terminal groups have more probability to be adsorbed onto the surface of NPs with decreasing temperature, chain molecular weight and increasing chain stiffness. For all NPs with different geometries, more terminal groups segregate into the surface of NPs with increase in the interaction energy epsilonf-n between the terminal groups and the NPs. We also notice that the attractive interaction between the terminal groups and the sheet-like NPs induces the appearance of a gradient of translational dynamics of polymer chains, and the relaxation at the chain length scale is evidently different for various adsorbed layers, whereas the segmental relaxation only becomes slightly slower nearby the sheet-like NPs. For both pure and filled systems with spherical NPs, it is found that the stress-strain curves and bond orientations are significantly enhanced with increase in the interaction strength between the terminal groups as well as terminal groups and NPs. In the case of concentrated loading of NPs, we construct the atomistic models of C60, CNT and graphene to accurately account for the "many body effect." We explore the influence of the functionalization position along the chain backbone on the dispersion kinetics, realizing that the end functionalization is more effective. The end-groups effect on the chain configuration, chain packing and graphene equilibrium dispersibility is examined. The translational and rotational (segmental and terminal relaxation) dynamics influenced by the interactions between the end groups and graphene are probed by tuning epsilonf-n and the volume fraction of graphene phi. Moreover, the shift in the glass transition temperature influenced by epsilonf-n and phi is quantitatively estimated by fitting the temperature dependence of the relaxation time using the Vogel-Fulcher-Tammann (VFT) equation. This work is hoped to provide a deep understanding of the polymer nanocomposites with functionalized polymer chains. PMID- 25294568 TI - [Intestinal cancer screening in Denmark. Evidence and feasibility]. PMID- 25294567 TI - The Epstein-Barr virus and the pathogenesis of lymphoma. AB - Since the discovery in 1964 of the Epstein-Barr virus (EBV) in African Burkitt lymphoma, this virus has been associated with a remarkably diverse range of cancer types. Because EBV persists in the B cells of the asymptomatic host, it can easily be envisaged how it contributes to the development of B-cell lymphomas. However, EBV is also found in other cancers, including T-cell/natural killer cell lymphomas and several epithelial malignancies. Explaining the aetiological role of EBV is challenging, partly because the virus probably contributes differently to each tumour and partly because the available disease models cannot adequately recapitulate the subtle variations in the virus-host balance that exist between the different EBV-associated cancers. A further challenge is to identify the co-factors involved; because most persistently infected individuals will never develop an EBV-associated cancer, the virus cannot be working alone. This article will review what is known about the contribution of EBV to lymphoma development. PMID- 25294569 TI - [Kidney transplantation is cheaper for society than dialysis]. PMID- 25294570 TI - [Diagnosis and treatment of neuromyelitis optica]. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease characterized by antibodies against aquaporin-4 in up to 80% of the cases and even less in the NMO spectrum disorders, which may be difficult to distinguish from early multiple sclerosis. While immunosuppressive therapy should be introduced in definite NMO, treatment strategies of NMO spectrum disorders are less clearly defined. Here, we review the current guidelines for treatment of NMO and NMO spectrum disorders in the light of two cases, and suggest a practical approach to the management of these disorders. PMID- 25294571 TI - [Scintigraphy of the heart using noradrenaline has a prognostic value when visualising heart failure]. AB - A number of cardiac diseases are associated with dysfunction of the autonomic nervous system, which causes an increased risk of heart failure progression. Visualisation of the heart's sympathetic nervous system, using dedicated radiolabelled tracers (which is so far mostly done with iod-123 metaiodobenzylguanidine), is a strong diagnostic tool to visualise the molecular mechanisms of heart failure and it has a different potential than more traditional image modalities. PMID- 25294572 TI - [Dementia in people with Down syndrome]. AB - In developed countries the population of elderly people with Down syndrome expands resulting in an increasing incidence of age-related diseases, including dementia. The assessment of dementia in individuals with intellectual disability is often complicated due to large intra-individual variability in cognitive functioning prior to dementia and to lack of standardised measures to detect dementia. Structured observations of symptoms of dementia and assessment techniques tailored for people with intellectual disability are increasingly needed. PMID- 25294573 TI - [Epilepsy]. AB - Epilepsy affects around 33,000 people in Denmark. The classification of the epilepsies is currently under revision and the clinical course of the disease depends on the underlying aetiology. Diagnostic evaluation includes EEG and often long-term video-EEG monitoring to ensure the diagnosis and clas-sification. More than two thirds of patients with epilepsy can obtain complete seizure control. The remainders, counting around 12.000 patients in Denmark, having medical refractory epilepsy should be considered for other treatment options; epilepsy surgery or other non-pharmacological treatment. PMID- 25294574 TI - [Anus neoplasms]. PMID- 25294575 TI - [Carriers of fragile X syndrome can present with a broad spectrum of clinical disorders]. AB - Fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are three clinically distinct disorders caused by expansions of a CGG repeat sequence in the non coding part of the FMR1. FXTAS and FXPOI are seen in carriers of smaller repeat expansions (55-200). Carriers were for many years thought to be clinically unaffected, but along with the discovery of FXPOI and FXTAS a growing number of additional clinical manifestations have been identified. We wish to make Danish physicians more aware of these conditions which we review in this paper. PMID- 25294576 TI - [Serious adverse effect of combined oral contraceptive pills among teenagers]. AB - PubMed-search found studies investigating adverse effects of combined oral contraceptive pills (COC) among teenagers. Four studies found a small negative impact of COC on acquisition of bone mineral density. COC is associated with elevated risk of venous thrombotic events (VTE), especially during the first year of usage. VTE risk increases with EE dose and progestin of 3rd and 4th generation. There are several difficulties in studying COC use in teenagers: high dropout rates, ethical considerations and many different COC formulas. PMID- 25294577 TI - [Case study shows that the case manager function for cancer patients is used unevenly across the different cancer forms]. AB - This case study of the obligatory case manager function for cancer patients explores by whom and for what the function is used. It draws on quantitative data from a database, focus group interviews with case managers at Rigshospitalet and telephone interviews with patients and relatives. The conclusion is that across the different cancer forms patients are using the function unevenly. This can probably be explained by the varying organizational set-ups for patient trajectories across departments. The individual patients and relatives express satisfaction with the information and assistance received from the case managers. PMID- 25294578 TI - [Weight loss guidance for patients with heart failure is complex]. AB - Observation studies have shown that overweight in patients with congestive heart failure is associated with lower risk of all-cause mortality and cardiovascular mortality. This is called the paradox of obesity. Other studies do not support this correla-tion. In conclusion, a stable body weight is recommended for patients with a BMI of 25-29.9 kg/m2. If BMI >= 40 kg/m2, weight loss is recommended. There is no consensus for weight reduction if BMI is 30-40 kg/m2. PMID- 25294579 TI - [Colectomy in a patient with pneumatosis coli]. AB - Pneumatosis coli (PC) is a rare condition which may be difficult to diagnose. We report a case of PC in a 46-year-old woman, where colonoscopy and biopsies showed signs of widespread polyposis. She had a prophylactic colectomy. Pathologic examination of the specimen showed multiple air-filled cysts in the colonic wall. By analysis of a preoperative abdominal computed tomography with lung window the cysts could be visualised. This procedure could be a valuable diagnostic tool for excluding PC in patients suspected for polyposis, but with a negative family history of familial adenomatous polyposis. PMID- 25294580 TI - Pregnane X receptor as the "sensor and effector" in regulating epigenome. AB - The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor which plays an essential role in organism's metabolic detoxification system by sensing the presence of xenobiotics and triggering detoxification responses. In addition to its role in xenobiotic metabolism, PXR has pleiotropic functions in regulating immune/inflammatory responses, cell proliferation, bile acid/cholesterol metabolism, glucose and lipid metabolism, steroid/endocrine homeostasis, and bone metabolism. Recent research suggests that the PXR is required for maintaining healthy commensalism between microbiota and gut. Interestingly, the metabolites such as indole derivatives from commensal microbes serve as the ligands for the PXR in intestinal epithelium forming an intricate mutualistic interaction between host and microbiota. PXR-regulated gene responses are controlled at epigenetic level by chromatin modifications, DNA methylation and noncoding RNA. Developmental alterations of the epigenome by exposure to the xenobiotics or diseases may produce persistent changes in PXR-regulated physiological responses. These new areas of research promise to vastly increase our understanding of PXR regulated responses. In this review we highlight recent results on the epigenetic mechanisms for the PXR-regulated gene expression and discuss the physiological significance of these findings. PMID- 25294581 TI - Three-layered scaffolds for artificial esophagus using poly(E-caprolactone) nanofibers and silk fibroin: An experimental study in a rat model. AB - The purpose of this study was to determine the feasibility of an artificial esophagus using a three-layered poly(epsilon-caprolactone) (PCL)-silk fibroin (SF) scaffold in a rat model. The artificial esophagus was a three-layered, hybrid-type prosthesis composed of an outer and inner layer of PCL with a middle layer of SF. After depositing the inner layer of the PCL scaffold by electrospinning, the lyophilized middle SF layer was created. The outer layer of PCL was produced following the same procedure used to make the inner PCL layer. Eleven rats were anesthetized using inhaled anesthesia. Circumferential defects of the cervical esophagus (n=11) were created and reconstructed. Groups of rats were sacrificed after the 1st and 2nd weeks. Three rats died of an esophageal fistula and wound infection. No gross evidence of a fistula, perforation, abscess formation, seroma accumulation, or surrounding soft-tissue necrosis was observed in the other rats sacrificed after the 1st and 2nd weeks. The artificial esophagus constructs produced complete healing of the circumferential defects by the 2nd week. The composition of the three-layered artificial esophagus was confirmed histologically to have an outer and inner layer of PCL and a middle layer of SF. The fusion of the PCL-SF scaffold and the regenerative tissue remained intact. Our study proposes a more practical experimental model for studying a three-layered PCL-SF scaffold in the esophagus. However, further studies on circumferential defect reconstruction in a rat model are still required. PMID- 25294582 TI - Coming unmoored: disproportionate increases in obesity prevalence among young, disadvantaged white women. AB - OBJECTIVES: Since the 1980s, older, low-educated White women experienced an unprecedented decrease in life expectancy. We investigated whether a similar phenomenon was evident among younger women for obesity. METHODS: Using the National Health and Nutrition Examination Survey, age-adjusted changes were estimated in the prevalence of overall and abdominal obesity (BMI >= 30 kg/m(2) , waist circumference > 88 cm) between 1988-1994 and 2003-2010 among non-Hispanic White women aged 25-44 years, stratified by educational attainment (= 1 mg/kg/day were the important associated factors of SDM (P <= 0.05). Meanwhile, hydroxychloroquine (HCQ) use was associated with reduced SDM prevalence (P < 0.05). CONCLUSION: The prevalence of SDM among SLE patients was 13% and Indians were more prone to develop SDM compared to other races. Higher numbers of system involvement, abdominal obesity, hypertriglyceridemia and the use of oral prednisolone of >= 1 mg/kg/day were associated with SDM, while HCQ use potentially protects against SDM. PMID- 25294585 TI - Schistosomes versus platelets. AB - Schistosomes are parasitic platyhelminths that currently infect >200million people and cause the chronic debilitating disease schistosomiasis. While these large intravascular parasites can disturb blood flow, they do not appear to activate platelets and provoke thrombus formation. Host-interactive tegumental molecules have been proposed to be important in this regard. For example, tegumental apyrase, SmATPDase1 can degrade the platelet-activating molecule ADP in the extracellular environment. The parasites themselves can produce prostaglandins (or may induce prostaglandin production by host cells) which could inhibit platelet aggregation. Additional tegumental proteins have been proposed to impede the coagulation cascade and to promote fibrinolysis. Platelets have been shown to be directly toxic to schistosomes. Platelets recovered from infected rats are able to kill larval parasites in culture and platelets obtained at later times post-infection are generally better at killing. Even platelets from uninfected rats can rapidly kill larval schistosomes if first exposed to a variety of activators (such as: serum from infected rats, the IgE fraction of that serum, C-reactive protein, cytokines (TNFalpha or TNFbeta)). Passive transfer of stimulated platelets can protect rats against a challenge schistosome infection. Cytokines (TNFalpha, TNFbeta, IFNgamma or IL-6) have been shown to similarly promote normal human platelet killing of schistosomes in vitro. Platelet antimicrobial effector molecules (e.g. platelet microbicidal proteins) may mediate such killing. While platelets can be protective against schistosomes following infection of humans and mice, platelet numbers decline (but not so in the non-permissive rat host) and coagulopathy becomes more apparent as schistosome-induced pathology increases. PMID- 25294586 TI - Apixaban exerts anti-inflammatory effects in mesangial cells by blocking thrombin/protease-activated receptor-1 system. PMID- 25294583 TI - Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions. AB - The rotation of the earth and associated alternating cycles of light and dark- the basis of our circadian rhythms--are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the past few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly affect patient outcomes. Intriguingly, sedatives, anesthetics, and the intensive care unit environment have all been shown to disrupt the circadian system in patients. In the current review, we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts. PMID- 25294587 TI - Risk-assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease. AB - INTRODUCTION: There is a lack of evidence regarding the need for thromboprophylaxis in hospitalized patients with liver disease. The purpose of this study was to evaluate the Padua Predictor Score (PPS) as a risk stratification tool for the development of venous thromboembolism (VTE) in patients with chronic liver disease. METHODS: This was a retrospective cohort study conducted in an academic medical center in the United States. Consecutive adult patients admitted with chronic liver disease were included. Patients were categorized into two groups based on whether they developed a VTE or not. The risk for VTE in each patient was evaluated using the Padua Predictor Score (PPS). Patients were risk stratified using the PPS score as high-risk (score >=4) and low-risk (score <4). The risk of VTE based on PPS categorization was evaluated using logistic regression. RESULTS: A total of 163 patients with liver disease were included in the study cohort. Of these, 18 (11%) developed VTE. Mean PPS was significantly greater in the VTE group than the non-VTE group (5.8 +/- 2.0 versus 3.0 +/- 2.1, respectively; p<0.001). In high-risk patients 22% (n=16/72) developed VTE and in low-risk patients 2% (2/91) developed VTE (p<0.001). High risk patients were more likely to have VTE (OR 12.7, 95% CI 2.8 to 57.4, p=0.001). CONCLUSION: The PPS is an effective risk assessment tool for VTE in patients hospitalized with chronic liver disease. PMID- 25294588 TI - Ex vivo and in vivo studies of CME-1, a novel polysaccharide purified from the mycelia of Cordyceps sinensis that inhibits human platelet activation by activating adenylate cyclase/cyclic AMP. AB - INTRODUCTION: CME-1, a novel water-soluble polysaccharide, was purified from the mycelia of Cordyceps sinensis, and its chemical structure was characterized to contain mannose and galactose in a ratio of 4:6 (27.6 kDa). CME-1 was originally observed to exert a potent inhibitory effect on tumor migration and a cytoprotective effect against oxidative stress. Activation of platelets caused by arterial thrombosis is relevant to various cardiovascular diseases (CVDs). However, no data are available concerning the effects of CME-1 on platelet activation. Hence, the purpose of this study was to examine the ex vivo and in vivo antithrombotic effects of CME-1 and its possible mechanisms in platelet activation. METHODS: The aggregometry, immunoblotting, flow cytometric analysis and platelet functional analysis were used in this study. RESULTS: CME-1 (2.3-7.6 MUM) exhibited highly potent activity in inhibiting human platelet aggregation when stimulated by collagen, thrombin, and arachidonic acid but not by U46619. CME-1 inhibited platelet activation accompanied by inhibiting Akt, mitogen activated protein kinases (MAPKs), thromboxane B2 (TxB2) and hydroxyl radical (OH(?)) formation. However, CME-1 interrupted neither FITC-triflavin nor FITC collagen binding to platelets. CME-1 markedly increased cyclic AMP levels, but not cyclic GMP levels, and stimulated vasodilator-stimulated phosphoprotein (VASP) phosphorylation. SQ22536, an inhibitor of adenylate cyclase, but not ODQ, an inhibitor of guanylate cyclase, obviously reversed the CME-1-mediated effects on platelet aggregation and vasodilator-stimulated phosphoprotein (VASP), Akt, p38 MAPK phosphorylation, and TxB2 formation. CME-1 substantially prolonged the closure time of whole blood and the occlusion time of platelet plug formation. CONCLUSION: This study demonstrates for the first time that CME-1 exhibits highly potent antiplatelet activity that may initially activate adenylate cyclase/cyclic AMP and, subsequently, inhibit intracellular signals (such as Akt and MAPKs), ultimately inhibiting platelet activation. This novel role of CME-1 indicates that CME-1 exhibits high potential for application in treating and preventing CVDs. PMID- 25294590 TI - A modified prothrombin time to measure the anticoagulant activity of dabigatran. PMID- 25294591 TI - Light-induced self-assembly and decay of J aggregates of thiamonomethinecyanine dyes. AB - Formation of J aggregates, that is, one-dimensional supramolecular self organizations in which the transition moments of individual molecules are aligned parallel to the line joining their centers through a "head-to-tail" arrangement, normally proceed via electrostatic interactions between oppositely charged molecular groups; this is facilitated by an electrolyte medium. Here, we show that J aggregates of thiamonomethinecyanine dyes in a solution can be assembled from dye dimers by illuminating the solution with light of the appropriate wavelength to induce excitation of the dye dimers. The reverse process is also demonstrated by application of light of the correct wavelength to induce excitation of the J aggregates. Our results indicate that spontaneous J aggregation in the dark and formation of J aggregates through illumination proceed through different mechanisms; the former resulting in an increase in the number of the aggregates and the latter in an increase in the size of the aggregates. PMID- 25294589 TI - Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. AB - INTRODUCTION: This phase 3 trial compared the safety and efficacy of edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy study, patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU (equivalent to 20 mg) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions. RESULTS: Of 716 patients enrolled, 360 and 356 were randomized to receive edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the edoxaban and enoxaparin groups, respectively (relative risk reduction=46.8%), indicating non inferiority (P <0.001) and superiority (P=0.010) of edoxaban versus enoxaparin. In the edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients (P=0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients (P=0.129), respectively. CONCLUSIONS: Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events. PMID- 25294592 TI - Determination of sunitinib and its active metabolite, N-desethyl sunitinib in mouse plasma and tissues by UPLC-MS/MS: assay development and application to pharmacokinetic and tissue distribution studies. AB - A simple, sensitive and specific method using ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was developed to determine sunitinib and N-desethyl sunitinib in mouse plasma and tissues. The analytes were separated by an isocratic mobile phase consisting of acetonitrile and buffer solution (water with 0.1% formic acid and 5 m m ammonium acetate; 40: 60, v/v) running at a flow rate of 0.35 mL/min for 2 min. Quantification was performed using a mass spectrometer by multiple reaction monitoring in positive electrospray ionization mode. The transition was monitored at m/z 399 -> 283, m/z 371 -> 283 and m/z 327 -> 270 for sunitinib, N-desethyl sunitinib and internal standard, respectively. Calibration curves were linear over concentration ranges of 2-500, 0.5-50 and 1-250 ng/mL for plasma, heart and other biosamples. The method was successfully applied to animal experiments. The pharmacokinetic study indicated that sunitinib was eliminated quickly in mice with a half-life of 1.2 h; tissue distribution data showed more sunitinib and its metabolite in liver, spleen and lung, which provided reference for further study. PMID- 25294593 TI - A hermeneutic phenomenological understanding of men's healing from childhood maltreatment. AB - PURPOSE: To describe and interpret men's experience of healing from childhood maltreatment. DESIGN: Hermeneutic phenomenological. METHOD: In-depth interviews. Community-based purposive, maximum variation sampling approach. Recruitment occurred through posting flyers and advertisements. Verbatim data were analyzed and themes of the meaning of healing were identified. FINDINGS: The meaning of healing was interpreted as "moving beyond suffering." Five themes were identified to capture the multidimensional nature of the phenomenon: (a) breaking through the masculine veneer, (b) finding meaning, (c) choosing to live well, (d) caring for the self using holistic healing methods, and (e) engaging in humanizing relationships. CONCLUSIONS: Men who survived childhood maltreatment have needs to heal holistically mind, body, and spirit. Meeting their needs requires the provision of highly compassionate humanistic healing environments and healing promotive nursing care. PMID- 25294594 TI - Health empowerment among immigrant women in transnational marriages in Taiwan. AB - PURPOSE: The aim of this study was to develop, implement, and evaluate a theory based intervention designed to promote increased health empowerment for marriage migrant women in Taiwan. The rapid increase of international marriage immigration through matchmaking agencies has received great attention recently because of its impact on social and public health issues in the receiving countries. DESIGN AND METHODS: A participatory action research (PAR) and in-depth interviews were adopted. Sixty-eight women participated in this study. Eight workshops of the health empowerment project were completed. FINDINGS: Through a PAR-based project, participants received positive outcomes. Four outcome themes were identified: (a) increasing health literacy, (b) facilitating capacity to build social networks, (c) enhancing sense of self-worth, and (d) building psychological resilience. CONCLUSIONS: PAR was a helpful strategy that enabled disadvantaged migrant women to increase their health literacy, psychological and social health, and well being. CLINICAL RELEVANCE: The findings can be referenced by the government in making health-promoting policies for Southeast Asian immigrant women to increase their well-being. Community health nurses can apply PAR strategies to plan and design health promotion intervention for disadvantaged migrant women. PMID- 25294595 TI - Hyponatremia and Fractures: Findings From the MrOS Study. AB - Hyponatremia may be a risk factor for fracture. To determine the relationship between hyponatremia and fracture we conducted cross-sectional and longitudinal analyses using data from the Osteoporotic Fractures in Men (MrOS) study. The MrOS study enrolled 5122 community dwelling men aged >=65 years from six centers across the United States. We excluded men taking bisphosphonates, those with unknown medication history, those without serum sodium measures, or those with out of range assays for serum sodium. Serum sodium was measured at study entry. Subjects were followed for fractures (nonspine [including hip], hip, incident morphometric, and prevalent morphometric) for up to 9 years. We used Cox proportional hazards models to analyze the association between serum sodium levels (<135 mmol/L versus >=135 mmol/L) and risk of nonspine and hip fractures, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). We examined the association between morphometric vertebral fractures and serum sodium using logistic regression models, presented as odds ratios (ORs) and 95% CI. Hyponatremia was observed in 64 men (1.2% of the cohort). After adjusting for age, BMI, study center, and other covariates, we found that, compared to men with serum sodium >=135 mmol/L, those with serum sodium <135 mmol/L, had an increased risk of hip fracture (HR = 3.04; 95% CI, 1.37 to 6.75), prevalent morphometric spine fracture (OR = 2.46; 95% CI, 1.22 to 4.95), and incident morphometric spine fracture (OR = 3.53; 95% CI, 1.35 to 9.19), but not nonspine fracture (OR = 1.44; 95% CI, 0.85 to 2.44). Adjusting for bone mineral density (BMD) did not change our findings. Our data show that hyponatremia is associated with up to a doubling in the risk of hip and morphometric spine fractures, independent of BMD. Further studies, to determine how hyponatremia causes fractures and if correction of hyponatremia decreases fractures, are needed. PMID- 25294596 TI - End stage renal disease risk and neighbourhood deprivation: a nationwide cohort study in Sweden. AB - BACKGROUND: Chronic kidney disease has been associated with socioeconomic disparities and neighbourhood deprivation. We aimed to determine whether there is an association between neighbourhood deprivation and end stage renal disease (ESRD), and whether this association is independent of individual-level sociodemographic factors and comorbidities. METHODS: National Swedish data registers were used. The entire Swedish population aged 20-69 years was followed from January 1, 2001 until December 31, 2010. Data were analysed by multilevel logistic regression, with individual-level sociodemographic factors (age, marital status, family income, education level, country of birth, urban/rural status, and mobility) and comorbidities at the first level and neighbourhood deprivation at the second level. RESULTS: Neighbourhood deprivation was significantly associated with ESRD (age-adjusted odds ratio [OR] 1.45, 95% confidence interval [CI] 1.34 1.56 in men and OR 1.59, 95% CI 1.44-1.75 in women). The ORs for ESRD in men and women living in the most deprived neighbourhoods remained significantly increased when adjusted for age and individual-level sociodemographic factors (OR 1.25, 95% CI 1.15-1.35 in men and OR 1.30, 95% CI 1.17-1.44 in women). In the full model, which took account of sociodemographic factors and comorbidities, the ORs for ESRD remained significantly increased (OR 1.17, 95% CI 1.07-1.27 in men and OR 1.18, 95% CI 1.06-1.31 in women). CONCLUSION: Neighbourhood deprivation is independently associated with ESRD in both men and women irrespective of individual-level sociodemographic factors and comorbidities. PMID- 25294597 TI - The prevalence of heifer mastitis and its associated risk factors in Huanggang, Central China. AB - The purposes of this study were to determine the prevalence of heifer clinical mastitis (HCM) and heifer subclinical mastitis (HSCM), isolate HCM-causing bacteria, and assess the association of some risk factors in Huanggang, Central China. A total of 1,374 lactating heifers from three dairy farms were examined in the present study; 22.64% of heifers were positive for mastitis, out of which, 3.86 and 18.78% were with HCM and HSCM, respectively. Of the 67 HCM samples, 91.05% were single growth, 7.46% mixed growth, and 1.49% no bacterial growth. Coagulase-negative staphylococci (CNS) accounted for 30.98% of the isolates followed by Escherichia coli (29.58%), Staphylococcus aureus (16.9%), and Streptococcus uberis (11.27%). Logistic regression analyses showed that heifer milk yield lower than 3 L had the highest prevalence of HCM compared to heifer milk yield of more than 3 L (P < 0.01), and prevalence of HCM was significantly high in heifers with the presence of teat lesions (P < 0.01). Moreover, the heifer milk yield lower than 3 L had the highest prevalence of HSCM compared to heifer milk yield of more than 3 L (P < 0.01). These two factors were significantly associated with the occurrence of heifer mastitis, which needs to be considered in the prevention and control strategies of the disease. PMID- 25294598 TI - Phototandem catalysis: efficient synthesis of 3-ester-3-hydroxy-2-oxindoles by a visible light-induced cyclization of diazoamides through an aerobic oxidation sequence. AB - An unprecedented phototandem catalysis based on a single iridium photocatalyst has been successfully developed. This powerful strategy consists of two mechanistically distinct catalytic cycles, namely, photocatalytic energy transfer (ET) and single electron transfer (SET). The novel protocol allows a rapid and efficient construction of biologically and synthetically important 3-ester-3 hydroxy-2-oxindole derivatives from readily available diazoamides through a cyclization/aerobic oxidation sequence under very mild conditions. PMID- 25294599 TI - Conflicts of interest may affect conclusions of systematic reviews of flu drugs, study indicates. PMID- 25294600 TI - Re: "Exposure to maternal smoking during pregnancy as a risk factor for tobacco use in adult offspring". PMID- 25294601 TI - Serial intervals of respiratory infectious diseases: a systematic review and analysis. AB - The serial interval of an infectious disease represents the duration between symptom onset of a primary case and symptom onset of its secondary cases. A good evidence base for such values is essential, because they allow investigators to identify epidemiologic links between cases and serve as an important parameter in epidemic transmission models used to design infection control strategies. We reviewed the literature for available data sets containing serial intervals and for reported values of serial intervals. We were able to collect data on outbreaks within households, which we reanalyzed to infer a mean serial interval using a common statistical method. We estimated the mean serial intervals for influenza A(H3N2) (2.2 days), pandemic influenza A(H1N1)pdm09 (2.8 days), respiratory syncytial virus (7.5 days), measles (11.7 days), varicella (14.0 days), smallpox (17.7 days), mumps (18.0 days), rubella (18.3 days), and pertussis (22.8 days). For varicella, we found an evidence-based value that deviates substantially from the 21 days commonly used in transmission models. This value of the serial interval for pertussis is, to the best of our knowledge, the first that is based on observations. Our review reveals that, for most infectious diseases, there is very limited evidence to support the serial intervals that are often cited. PMID- 25294602 TI - Airway metabolic anomalies in adolescents with bronchopulmonary dysplasia: new insights from the metabolomic approach. AB - OBJECTIVES: To assess a group of adolescents with bronchopulmonary dysplasia (BPD) from a biochemical-metabolic standpoint, applying the metabolomic approach to studying their exhaled breath condensate (EBC). STUDY DESIGN: Twenty adolescents with BPD (mean age 14.8 years) and 15 healthy controls (mean age 15.2 years) were recruited for EBC collection, exhaled nitric oxide measurement, and spirometry. The EBC samples were analyzed using a metabolomic approach based on mass spectrometry. The obtained spectra were analyzed using multivariate statistical analysis tools. RESULTS: A reliable Orthogonal Projections to Latent Structures-Discriminant Analysis model showed a clear discrimination between cases of BPD and healthy controls (R(2) = 0.95 and Q(2) = 0.92). The search for putative biomarkers identified an altered complex lipid profile in the adolescents with BPD. CONCLUSIONS: The metabolomic analysis of EBC distinguishes cases of BPD from healthy individuals, suggesting that the lung of survivors of BPD is characterized by long-term metabolic abnormalities. The search for putative biomarkers indicated a possible role of an altered surfactant composition, which may persist far beyond infancy. PMID- 25294603 TI - Energy drink consumption and the risk of alcohol use disorder among a national sample of adolescents and young adults. AB - OBJECTIVE: To assess the association between energy drink use and hazardous alcohol use among a national sample of adolescents and young adults. STUDY DESIGN: Cross-sectional analysis of 3342 youth aged 15-23 years recruited for a national survey about media and alcohol use. Energy drink use was defined as recent use or ever mixed-use with alcohol. Outcomes were ever alcohol use and 3 hazardous alcohol use outcomes measured with the Alcohol Use Disorders Identification Test (AUDIT): ever consuming 6 or more drinks at once (6+ binge drinking) and clinical criteria for hazardous alcohol use as defined for adults (8+AUDIT) and for adolescents (4+AUDIT). RESULTS: Among 15-17 year olds (n = 1508), 13.3% recently consumed an energy drink, 9.7% ever consumed an energy drink mixed with alcohol, and 47.1% ever drank alcohol. Recent energy drink use predicted ever alcohol use among 15-17-year-olds only (OR 2.58; 95% CI 1.77 3.77). Of these 15-17-year-olds, 17% met the 6+ binge drinking criteria, 7.2% met the 8+AUDIT criteria, and 16.0% met the 4+AUDIT criteria. Rates of energy drink use and all alcohol use outcomes increased with age. Ever mixed-use with alcohol predicted 6+ binge drinking (OR 4.69; 95% CI 3.70-5.94), 8+AUDIT (OR 3.25; 95% CI 2.51-4.21), and 4+AUDIT (OR 4.15; 95% CI 3.27-5.25) criteria in adjusted models among all participants, with no evidence of modification by age. CONCLUSIONS: Positive associations between energy drink use and hazardous alcohol use behaviors are not limited to youth in college settings. PMID- 25294606 TI - Novel frame-shift mutation of ATP2A2 gene in one sporadic patient with Darier's disease. PMID- 25294605 TI - SNPest: a probabilistic graphical model for estimating genotypes. AB - BACKGROUND: As the use of next-generation sequencing technologies is becoming more widespread, the need for robust software to help with the analysis is growing as well. A key challenge when analyzing sequencing data is the prediction of genotypes from the reads, i.e. correct inference of the underlying DNA sequences that gave rise to the sequenced fragments. For diploid organisms, the genotyper should be able to predict both alleles in the individual. Variations between the individual and the population can then be analyzed by looking for SNPs (single nucleotide polymorphisms) in order to investigate diseases or phenotypic features. To perform robust and high confidence genotyping and SNP calling, methods are needed that take the technology specific limitations into account and can model different sources of error. As an example, ancient DNA poses special challenges as the data is often shallow and subject to errors induced by post mortem damage. FINDINGS: We present a novel approach to the genotyping problem where a probabilistic framework describing the process from sampling to sequencing is implemented as a graphical model. This makes it possible to model technology specific errors and other sources of variation that can affect the result. The inferred genotype is given a posterior probability to signify the confidence in the result. SNPest has already been used to genotype large scale projects such as the first ancient human genome published in 2010. CONCLUSIONS: We compare the performance of SNPest to a number of other widely used genotypers on both real and simulated data, covering both haploid and diploid genomes. We investigate the effects of read depth, of removing adapters before mapping and genotyping, of using different mapping tools, and of using the correct model in the genotyping process. We show that the performance of SNPest is comparable to existing methods, and we also illustrate cases where SNPest has an advantage over other methods, e.g. when dealing with simulated ancient DNA. PMID- 25294607 TI - Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID). AB - Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America. PMID- 25294604 TI - Emergency department practice variation in computed tomography use for children with minor blunt head trauma. AB - OBJECTIVE: To describe factors associated with computed tomography (CT) use for children with minor blunt head trauma that are evaluated in emergency departments. STUDY DESIGN: Planned secondary analysis of a prospective observational study of children <18 years with minor blunt head trauma between 2004 and 2006 at 25 emergency departments. CT scans were obtained at the discretion of treating clinicians. We risk-adjusted patients for clinically important traumatic brain injuries and performed multivariable regression analyses. Outcome measures were rates of CT use by hospital and by clinician training type. RESULTS: CT rates varied between 19.2% and 69.2% across hospitals. Risk adjustment had little effect on the differential rate of CT use. In low- and middle-risk patients, clinicians obtained CTs more frequently at suburban and nonfreestanding children's hospitals. Physicians with emergency medicine (EM) residency training obtained CTs at greater rates than physicians with pediatric residency or pediatric EM training. In multivariable analyses, compared with pediatric EM-trained physicians, the OR for CT use among EM-trained physicians in children <2 years was 1.24 (95% CI 1.04-1.46), and for children >2 years was 1.68 (95% CI 1.50-1.89). Physicians of all training backgrounds, however, overused CT scans in low-risk children. CONCLUSIONS: Substantial variation exists in the use of CT for children with minor blunt head trauma not explained by patient severity or rates of positive CT scans or clinically important traumatic brain injuries. PMID- 25294608 TI - Crystal structures and kinetics of Type III 3-phosphoglycerate dehydrogenase reveal catalysis by lysine. AB - D-Phosphoglycerate dehydrogenase (PGDH) catalyzes the first committed step of the phosphorylated serine biosynthesis pathway. Here, we report for the first time, the crystal structures of Type IIIK PGDH from Entamoeba histolytica in the apo form, as well as in complexes with substrate (3-phosphoglyceric acid) and cofactor (NAD(+) ) to 2.45, 1.8 and 2.2 A resolution, respectively. Comparison of the apo structure with the substrate-bound structure shows that the substrate binding domain is rotated by ~ 20 degrees to close the active-site cleft. The cofactor-bound structure also shows a closed-cleft conformation, in which NAD(+) is bound to the nucleotide-binding domain and a formate ion occupies the substrate-binding site. Superposition of the substrate- and cofactor-bound structures represents a snapshot of the enzyme in the active form, where C2 of the substrate and C4N of the cofactor are 2.2 A apart, and the amino group of Lys263 is close enough to the substrate to remove the proton from the hydroxyl group of PGA, indicating the role of Lys in the catalysis. Mutation of Lys263 to Ala yields just 0.8% of the specific activity of the wild-type enzyme, revealing that Lys263 indeed plays an integral role in the catalytic activity. The detectable activity of the mutant, however, indicates that after 20 degrees rotation of the substrate-binding domain, the resulting positions of the substrate and cofactor are sufficiently close to make a productive reaction. PMID- 25294609 TI - Comparison of the measurement of heart rate in adult free-range chickens (Gallus domesticus) by auscultation and electrocardiography. AB - OBJECTIVE: To compare the heart rates of adult free-range chickens (Gallus domesticus) measured by auscultation with a stethoscope with those measured simultaneously using electrocardiography (ECG). METHODS: With each bird in a standing position, estimation of the heart rate was performed by placing a mark on paper for every 4 beats for roosters and 8 beats for hens as detected by auscultation over 30 s, while simultaneous ECG was performed. RESULTS: Heart rates measured by auscultation showed a high correlation (r = 0.97) with those measured by ECG. CONCLUSION: There was a high correlation between the heart rates of adult free-range chickens measured by auscultation with a stethoscope and those measured simultaneously using ECG. PMID- 25294610 TI - Semi-quantitative HPV viral load in patients with ASC-US cytology: viral load correlates strongly with the presence of CIN, but only weakly with its severity: letter to the editor. PMID- 25294611 TI - Inhaled budesonide prevents acute mountain sickness in young Chinese men. AB - BACKGROUND: Oral glucocorticoids can prevent acute mountain sickness (AMS). Whether inhaled budesonide (BUD) can prevent AMS remains unknown. OBJECTIVE: Our aim was to investigate the effectiveness of BUD in AMS prevention. METHODS: Eighty subjects were randomly assigned to receive budesonide (BUD, inhaled), procaterol tablet (PT), budesonide/formoterol (BUD/FM, inhaled), or placebo tablet (n = 20 in each group). Subjects were treated for 3 days before ascending from 500 m to 3700 m within 2.5 h by air. Lake Louis AMS questionnaire, blood pressure, heart rate, and oxygen saturation (SpO2) were examined at 20, 72, and 120 h after high-altitude exposure. Pulmonary function was measured at 20 h after exposure. RESULTS: Compared with placebo, BUD significantly reduced the incidence of AMS (70% vs. 25% at 20 h, p < 0.05; both 10% vs. 5% at 72 and 120 h, both p > 0.05) without side effects. The relative risk was 0.357, and the risk difference was 0.45. Mean SpO2 was higher in BUD, BUD/FM, and PT groups than in the placebo group at 20 h (p < 0.05). SpO2 in all 80 subjects dropped after ascent (98.1% to 88.12%, p < 0.01) and increased gradually, but it was still lower at 120 h than at baseline (92.04% vs. 98.1%, p < 0.01). Pulmonary function did not differ among the four groups at 20 h. CONCLUSION: BUD can prevent AMS without side effects. The alleviation of AMS may be related to increased blood oxygen levels rather than pulmonary function. PMID- 25294612 TI - Seroreactivity to a large panel of field-derived Plasmodium falciparum apical membrane antigen 1 and merozoite surface protein 1 variants reflects seasonal and lifetime acquired responses to malaria. AB - Parasite antigen diversity poses an obstacle to developing an effective malaria vaccine. A protein microarray containing Plasmodium falciparum apical membrane antigen 1 (AMA1, n = 57) and merozoite surface protein 1 19-kD (MSP119, n = 10) variants prevalent at a malaria vaccine testing site in Bandiagara, Mali, was used to assess changes in seroreactivity caused by seasonal and lifetime exposure to malaria. Malian adults had significantly higher magnitude and breadth of seroreactivity to variants of both antigens than did Malian children. Seroreactivity increased over the course of the malaria season in children and adults, but the difference was more dramatic in children. These results help to validate diversity-covering protein microarrays as a promising tool for measuring the breadth of antibody responses to highly variant proteins, and demonstrate the potential of this new tool to help guide the development of malaria vaccines with strain-transcending efficacy. PMID- 25294613 TI - Seroprevalence of neutralizing antibodies against dengue virus in two localities in the state of Morelos, Mexico. AB - Humoral immune response against dengue virus (DENV) is an important component in dengue-endemic transmission. We conducted a cross-sectional nested cohort study to determine the seroprevalence and frequency of neutralizing antibodies against DENV serotypes in two endemic localities in the state of Morelos, Mexico. The cohort participants (N = 1,196) were screened to determine previous exposure to DENV. Overall seroprevalence was 76.6% (95% confidence interval [95% CI] = 73.6 79.2), and prevalence of neutralizing antibodies in the 5- to 9-year-old group was 82.5% (95% CI = 67.2-92.7), 45% (95% CI = 29.3-61.5), and 65% (95% CI = 48.3 79.4) for DENV-1, DENV-2, and DENV-3, respectively. For participants older than 10 years, the observed seroprevalence was above 60% for each serotype, except DENV-4 in the 10- to 25-year-old group (42.9%); 81% of humoral responses were multitypic. The outcomes of our study contribute to understanding the immune component of dengue transmission and provide focal information for the evaluation of vaccine candidates under development. PMID- 25294614 TI - Evaluation of targeted mass cholera vaccination strategies in Bangladesh: a demonstration of a new cost-effectiveness calculator. AB - Growing interest in mass vaccination with oral cholera vaccine in endemic and epidemic settings will require policymakers to evaluate how to allocate these vaccines in the most efficient manner. Because cholera, when treated properly, has a low case fatality rate, it may not be economically feasible to vaccinate an entire population. Using a new publicly available calculator for estimating the cost-effectiveness of mass vaccination, we show how targeting high-risk subpopulations for vaccination could be cost-effective in Bangladesh. The approach described here is general enough to adapt to different settings or to other vaccine-preventable diseases. PMID- 25294615 TI - Malaria-induced splenic infarction. AB - Splenic infarction is a rare complication of malaria. We report two recent cases of splenic infarction after Plasmodium vivax infection. No systematic review of malaria-induced splenic infarction was available, therefore we conducted a systematic review of the English, French, and Spanish literature in PubMed and KoreaMed for reports of malaria-associated splenic infarction from 1960 to 2012. Of the 40 cases collected on splenic infarction by Plasmodium species, 23 involved P. vivax, 11 Plasmodium falciparum, one Plasmodium ovale, and five a mixed infection of P. vivax and P. falciparum. Of the 40 cases, 2 (5.0%) involved splenectomy and 5 (12.5%) were accompanied by splenic rupture. The median time from symptom onset to diagnosis was 8.5 days (range, 3-90 days). Improved findings after treatment were observed in 8 (88.9%) of 9 patients with splenic infarction on follow-up by computed tomography or ultrasonography. All patients survived after treatment with the exception of one patient with cerebral malaria. Clinicians should consider the possibility of splenic infarction when malaria infected patients have left upper quadrant pain. PMID- 25294616 TI - Economic and disease burden of dengue illness in India. AB - Between 2006 and 2012 India reported an annual average of 20,474 dengue cases. Although dengue has been notifiable since 1996, regional comparisons suggest that reported numbers substantially underrepresent the full impact of the disease. Adjustment for underreporting from a case study in Madurai district and an expert Delphi panel yielded an annual average of 5,778,406 clinically diagnosed dengue cases between 2006 and 2012, or 282 times the reported number per year. The total direct annual medical cost was US$548 million. Ambulatory settings treated 67% of cases representing 18% of costs, whereas 33% of cases were hospitalized, comprising 82% of costs. Eighty percent of expenditures went to private facilities. Including non-medical and indirect costs based on other dengue endemic countries raises the economic cost to $1.11 billion, or $0.88 per capita. The economic and disease burden of dengue in India is substantially more than captured by officially reported cases, and increased control measures merit serious consideration. PMID- 25294617 TI - Respiratory syncytial virus-associated hospitalizations in pre-mature infants in Lima, Peru. AB - We conducted a prospective cohort study in four hospitals in Lima, Peru in infants with a birth weight <= 1,500 g followed from birth hospital discharge up to 1 year of age to determine the incidence of respiratory syncytial virus (RSV) hospitalizations. We enrolled 222 infants from March of 2009 to March of 2010: 48 infants with a birth weight < 1,000 g and 174 infants with a birth weight of 1,000-1,500 g (birth weight = 1,197 +/- 224 g; gestational age = 30.1 +/- 2.6 weeks). There were 936 episodes of respiratory infections; the incidence of respiratory infections during the first 1 year of life was 5.7 episodes/child years. The incidence of RSV respiratory infections that required emergency room management was 103.9 per 1,000 child-years, and the incidence of RSV hospitalizations was 116.2 per 1,000 child-years (244.9 in infants with a birth weight < 1,000 g and 88.9 in infants 1,000-1,500 g; P < 0.05). The incidence of RSV respiratory infections that required emergency management or hospitalization is high among pre-mature infants in Lima. PMID- 25294618 TI - Pediatric cutaneous leishmaniasis in an endemic region in India. AB - Cutaneous leishmaniasis (CL) is endemic in the Bikaner region situated in the Thar Desert of Rajasthan, India. This study describes clinicoepidemiological data of pediatric CL in pre-school children (0-5 years of age) from this region during 2001-2012. In total, 151 patients with 217 lesions were reported during the study period. The mean age of the study group was 3.29 +/- 1.43 years (0.25-5 years), with many (41.7%) cases being in the age group of 2-4 years. Face was the most common site involved, and morphologically, the lesions were either plaque type or papulonodular. Smear for parasitologic examination was positive in 84 (70%) of 120 cases, and histopathologic examination confirmed CL in 10 (55.55%) of 18 cases. Parasite species identification conducted for 13 randomly selected patients by polymerase chain reaction identified Leishmania tropica as the causative species. Intralesional sodium stibogluconate was the most commonly used treatment and found to be well-tolerated. Other therapies that were effective included oral rifampicin, oral dapsone, radiofrequency heat therapy (RFHT), and combinations of the three therapies. PMID- 25294619 TI - First case of Zika virus infection in a returning Canadian traveler. AB - A woman who recently traveled to Thailand came to a local emergency department with a fever and papular rash. She was tested for measles, malaria, and dengue. Positive finding for IgM antibody against dengue and a failure to seroconvert for IgG against dengue for multiple blood samples suggested an alternate flavivirus etiology. Amplification of a conserved region of the non-structural protein 5 gene of the genus Flavivirus yielded a polymerase chain reaction product with a matching sequence of 99% identity with Zika virus. A urine sample and a nasopharygeal swab specimen obtained for the measles investigation were also positive for this virus by reverse transcription polymerase chain reaction. Subsequently, the urine sample yielded a Zika virus isolate in cell culture. This case report describes a number of novel clinical and laboratory findings, the first documentation of this virus in Canada, and the second documentation from this region in Thailand. PMID- 25294620 TI - Atrial fibrillation is associated with impaired mobility in community-dwelling older adults. AB - OBJECTIVES: To examine the independent associations between atrial fibrillation (AF) and objectively measured mobility in a nationally representative cohort. DESIGN: Wave 1 of The Irish Longitudinal Study on Ageing (TILDA), a population based study assessing health, economic, and social aspects of ageing. SETTING: Community-dwelling adults completed a home-based interview and a center-based health assessment. PARTICIPANTS: Participants aged 50 years or older, with Mini Mental State Examination score of 24 or higher, and who completed at least 1 mobility test (n = 4525). MEASUREMENTS: Mobility was assessed with the Timed Up and-Go (TUG) test and usual and dual task gait speed obtained using a 4.88-m GAITRite(r) mat. AF was diagnosed using a 10-minute surface electrocardiogram recording. Linear regression analyses were performed to compare mobility in participants with and without AF, adjusting for confounders. RESULTS: In this sample (mean age 62.3 years; range 51-89), overall prevalence of AF was 3.1%, increasing to 6.7% in the over 70s (11.8% men; 2.8% women). In multivariate analysis, AF was independently associated with slower TUG (beta 0.37; 95% confidence interval [CI] 0.07-0.71; P = .043) and slower usual gait speed (beta 3.59; 95% CI -7.05 to -0.12; P = .030). There was a significant age*AF interaction effect for usual gait speed (beta -0.480, 95% CI -0.907 to -0.053, P = .028). Adults with AF walked 3.77 cm/s more slowly than adults without AF at age 70, declining by 4.8 cm/s for each additional decade. CONCLUSION: AF is independently associated with lower usual gait speed in community-dwelling adults and this effect is magnified in those aged 70 and older. This may place them at increased risk of falls, hospitalization, cognitive decline, and mortality, as well as stroke and heart failure. Early recognition and treatment of AF is vital to improve physical function and reduce this risk. PMID- 25294622 TI - Distance to Cannabis Shops and Age of Onset of Cannabis Use. AB - In the Netherlands, cannabis use is quasi-legalized. Small quantities of cannabis can be bought in cannabis shops. We investigate how the distance to the nearest cannabis shop affects the age of onset of cannabis use. We use a mixed proportional hazard rate framework to take account of observable as well as unobservable characteristics that influence the uptake of cannabis. We find that distance matters. Individuals who grow up within 20 km of a cannabis shop have a lower age of onset. PMID- 25294621 TI - Strength training and light physical activity reduces the apnea-hypopnea index in institutionalized older adults. AB - OBJECTIVES: To determine the effect of 7 weeks of resistance training and walking on the apnea-hypopnea index (AHI) in institutionalized older adults compared with a usual care control group. DESIGN: Secondary analysis of data from a randomized controlled trial. SETTING: Ten nursing and 3 assisted living facilities in Arkansas. PARTICIPANTS: Institutionalized older adults. INTERVENTIONS: Exercise group (EG) performed supervised resistance training to arm and hip extensors on 3 days a week with additional 2 days a week of light walking. Usual care group (UC) participated in the usual activities provided within their living facility. MEASUREMENTS: Two nights of polysomnography before and following 7-week intervention. RESULTS: Adjusted means in the EG group showed a decrease in AHI from 20.2 (SD +/-1.3) at baseline to 16.7 (SD +/-0.9) at 7 weeks. Absolute strength gains were not associated with improved AHI. CONCLUSION: Supervised resistance training and light walking reduced the severity of obstructive sleep apnea in institutionalized older adults. PMID- 25294624 TI - Response to Lilienfield. AB - The article by Lillienfeld in this issue comprises a thoughtful critique of the Research Domain Criteria (RDoC) project initiated by the National Institute of Mental Health, and includes four specific theoretical and methodological challenges along with recommendations to address each one. In this commentary, I briefly consider each of the four challenges in turn, noting points of agreement and also clarifying selected points from the NIMH RDoC perspective. Overall, Lillienfeld's paper represents a valuable contribution to the RDoC literature as research conducted with the new framework continues to accelerate. PMID- 25294623 TI - Establishment of a quantitative PCR system for discriminating chitinase-like proteins: catalytically inactive breast regression protein-39 and Ym1 are constitutive genes in mouse lung. AB - BACKGROUND: Mice and humans produce chitinase-like proteins (CLPs), which are highly homologous to chitinases but lack chitinolytic activity. Mice express primarily three CLPs, including breast regression protein-39 (BRP-39) [chitinase 3-like-1 (Chi3l1) or 38-kDa glycoprotein (gp38k)], Ym1 (Chi3l3) and Ym2 (Chi3l4). Recently, CLPs have attracted considerable attention due to their increased expression in a number of pathological conditions, including asthma, allergies, rheumatoid arthritis and malignant tumors. Although the exact functions of CLPs are largely unknown, the significance of their increased expression levels during pathophysiological states needs to be determined. The quantification of BRP-39, Ym1 and Ym2 is an important step in gaining insight into the in vivo regulation of the CLPs. METHODS: We constructed a standard DNA for quantitative real-time PCR (qPCR) by containing three CLPs target fragments and five reference genes cDNA in a one-to-one ratio. We evaluated this system by analyzing the eight target cDNA sequences. Tissue cDNAs obtained by reverse transcription from total RNA from four embryonic stages and eight adult tissues were analyzed using the qPCR system with the standard DNA. RESULTS: We established a qPCR system detecting CLPs and comparing their expression levels with those of five reference genes using the same scale in mouse tissues. We found that BRP-39 and Ym1 were abundant in the mouse lung, whereas Ym2 mRNA was abundant in the stomach, followed by lung. The expression levels of BRP-39 and Ym1 in the mouse lung were higher than those of two active chitinases and were comparable to glyceraldehyde 3-phosphate dehydrogenase, a housekeeping gene which is constitutively expressed in all tissues. CONCLUSION: Our results indicate that catalytically inactive BRP 39 and Ym1 are constitutive genes in normal mouse lung. PMID- 25294626 TI - Theoretical analysis of the intermolecular interactions in naphthalene diimide and pyrene complexes. AB - Supramolecular assembly of donor-acceptor complexes as the key component in organic functional nanomaterials is a promising approach for future electronic devices. One representative example of the donor-acceptor complexes is the naphthalene diimide-pyrene (NDI-Py) system, which shows fascinating photoelectric properties. Herein, the analysis of the pi-pi interactions between NDI and Py has been investigated using the DFT/M06-2X and reduced density gradient methods. According to the calculations, the attractive forces for the stabilization of the NDI-Py dimer are dependent on the rotation angles, which provide physical insight into the experimental data reported by Wilson and co-workers (Langmuir, 2011, 27, 6554). Our results not only provide computational evidence for the origin of the rotation in the crystal structure of the NDI-Py but also address the role of the charge-transfer attractions in the complexes. PMID- 25294625 TI - Clinical outcomes after continuous-flow left ventricular assist device: a systematic review. AB - BACKGROUND: Conveying the complex trade-offs of continuous-flow left ventricular assist devices is challenging and made more difficult by absence of an evidence summary for the full range of possible outcomes. We aimed to summarize the current evidence on outcomes of continuous-flow left ventricular assist devices. METHODS AND RESULTS: PubMed and Cochrane Library were searched from January 2007 to December 2013, supplemented with manual review. Three reviewers independently assessed each study for saliency on patient-centered outcomes. Data were summarized in tabular form. Overall study characteristics encouraged inclusion of all indications (destination therapy and bridge to transplant) and prevented meta analysis. The electronic search identified 465 abstracts, of which 50 met inclusion criteria; manual review added 2 articles in press. The articles included 10 industry-funded trials and registries, 10 multicenter reports, and the remainder single-center observational experiences. Estimated actuarial survival after continuous-flow left ventricular assist devices ranged from 56% to 87% at 1 year, 43% to 84% at 2 years, and 47% at 4 years. Improvements in functional class and quality of life were reported, but missing data complicated interpretation. Adverse events were experienced by the majority of patients, but estimates for bleeding, stroke, infection, right heart failure, arrhythmias, and rehospitalizations varied greatly. CONCLUSIONS: The totality of data for continuous-flow left ventricular assist devices show consistent improvements in survival and quality of life counterbalanced by a range of common complications. Although this summary should provide a practical resource for healthcare provider led discussions with patients, it highlights the critical need for high-quality patient-centered data collected with standard definitions. PMID- 25294627 TI - Re-visioning medicine. AB - Studies suggest that medical students and physicians have higher rates of anxiety, depression, and suicidal ideation than their peers in the general population. Some authors have suggested that medical culture perpetuates these problems by erecting "barriers to treatment," preventing students and physicians from getting the help they need. Here, the author begins a broader examination of the potential role of culture by examining the myths and symbols that form the basis for medical culture and the medical self-image. The author argues that a medical self-image based on a de-contextualized medical mythology, the Asclepius myth, results in a sense of professional identity that is unbalanced, dehumanized, and characterized by unattainable expectations. The outward expression of this medical self-image, the medical culture, is often a relational, unhealthy, stressed, or even toxic. The author suggests some ways of re-modeling medical culture, including its rituals and symbols, and medical education in ways that incorporate what is currently kept in its shadow. PMID- 25294628 TI - Medical thrillers: doctored fiction for future doctors? AB - Medical thrillers have been a mainstay of popular fiction since the late 1970s and still attract a wide readership today. This article examines this specialized genre and its core conventions within the context of professionally-based fiction, i.e. the class of thrillers written by professionals or former professionals. The author maps this largely unchartered territory and analyzes the fictional representations of doctors and medicine provided in such novels. He argues that medical thrillers, which are not originally aimed at specialized readers and sometimes project a flawed image of medicine, may be used as a pedagogical tool with non-native learners of medical English. PMID- 25294629 TI - Migrant Workers in Kazakhstan: Gender Differences in HIV Knowledge and Sexual Risk Behaviors. AB - This study compares sexual risk behaviors among male and female migrant market vendors in Almaty, Kazakhstan. From the Barakholka Market, 209 male and 213 female market vendors were randomly recruited. Self-reported data were collected through standardized face-to-face interviews. Dry blood spot was used as specimen for syphilis testing. Propensity score stratification was used to estimate adjusted prevalence or rate ratios by gender. Compared to male migrant workers, females had lower HIV knowledge and were less likely to have multiple sexual partners. There was no evidence of a gender difference for prevalence of syphilis, condom use with unsteady partners, and safe sex communication between couples. Associations between mobility patterns and engagement in multiple sexual partnerships were stronger among women than men. Efforts should be made to mitigate the gender differential in HIV knowledge among migrants, especially women. Such efforts need to be implemented in both home and host countries. PMID- 25294630 TI - The level of elements and antioxidant activity of commercial dietary supplement formulations based on edible mushrooms. AB - Commercial preparations of Cordyceps sinensis, Ganoderma lucidum and Coprinus comatus mushroom marketed as healthy food supplements in Serbia were analyzed by atomic absorption spectrometry with a graphite furnace (GFAAS) for their element content. Antioxidant activity potential and total phenolics of the same mushrooms were determined. The element content of mushroom samples was in the range of 0.130-0.360 mg kg(-1) for lead (Pb), <0.03-0.46 mg kg(-1) for arsenic (As), 0.09 0.39 mg kg(-1) for cadmium (Cd), 98.14-989.18 mg kg(-1) for iron (Fe), 0.10 101.32 mg kg(-1) for nickel (Ni), 5.06-26.50 mg kg(-1) for copper (Cu), 0.20-0.70 mg kg(-1) for cobalt (Co), 1.74-136.33 mg kg(-1) for chromium (Cr) and 2.19-21.54 mg kg(-1) for manganese (Mn). In the tests for measuring the antioxidant activity, the methanolic extract of C. sinensis showed the best properties. The same was seen for the analysis of selected phenolic compounds; C. sinensis was found to have the highest content. Commercial preparations of C. sinensis and C. comatus can be considered to be safe and suitable food supplements included in well-balanced diets. PMID- 25294631 TI - Contacting a 19 month-old mute autistic girl: a clinical narrative. AB - Conveying that psychoanalysis offers rich opportunities for the very early treatment of autistic spectrum disorders, this clinical communication unfolds the clinical process of a 19-month-old 'shell-type' encapsulated mute autistic girl. It details how, in a four-weekly-sessions schedule, infant Lila evolved within two years from being emotionally out-of-contact to the affective aliveness of oedipal involvement. Following Frances Tustin's emphasis on the analyst's 'quality of attention' and Justin Call's advice that in baby-mother interaction the infant is the initiator and the mother is the follower, it is described how the analyst must, amid excruciating non-response, even-mindedly sustain her attention in order to meet the child half-way at those infrequent points where flickers of initiative on her side are adumbrated. This helps attain evanescent 'moments of contact' which coalesce later into 'moments of sharing', eventually leading to acknowledgment of the analyst's humanness and a receptiveness for to and-fro communication. Thus the 'primal dialogue' (Spitz) is reawakened and, by experiencing herself in the mirror of the analyst, the child's sense of I-ness is reinstated. As evinced by the literature, the mainstream stance rests on systematic early interpretation of the transference, which has in our view strongly deterred progress in the psychoanalytic treatment of autistic spectrum disorders. PMID- 25294632 TI - Phase II trial of carboplatin and pemetrexed as first-line chemotherapy for non squamous non-small cell lung cancer, and correlation between the efficacy/toxicity and genetic polymorphisms associated with pemetrexed metabolism: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0902. AB - PURPOSE: This phase II study evaluated the response rate (RR) and safety of combination therapy with carboplatin (CBDCA) and pemetrexed (PEM) in Japanese patients with non-squamous non-small cell lung cancer (non-sq NSCLC). Further, the relationship between therapy efficacy/toxicity and genetic polymorphisms associated with PEM metabolism was analyzed. METHODS: Forty-one patients received CBDCA at a dose targeting an area under the concentration-time curve of 5 mg/mL * min and PEM of 500 mg/m(2) on day 1 every 3 weeks. Single-nucleotide polymorphisms of the thymidylate synthase (TYMS) coding gene, the variable number of tandem repeat (VNTR) in the TYMS, and the methylenetetrahydrofolate reductase (MTHFR) coding gene were analyzed. RESULTS: The overall RR was 36.6 %. Median progression-free survival and median survival time were 4.7 months [95 % confidence interval (CI) 3.9-5.6 months] and 16.2 months (95 % CI 6.1-26.2 months), respectively. Epidermal growth factor receptor gene mutations were detected in 6 patients (14.6 %). The VNTR in the TYMS significantly correlated with anemia (p = 0.047) and thrombocytopenia (p = 0.038). CONCLUSIONS: This combination therapy was effective and tolerable in patients with advanced non-sq NSCLC. The VNTR in the TYMS appears to be a predictive factor for anemia and thrombocytopenia in patients treated with this regimen. PMID- 25294633 TI - Three-dimensional navigation system integrating position-tracking technology with a movable tablet display for percutaneous targeting. AB - OBJECTIVES: To assess the feasibility of a novel percutaneous navigation system (Translucent Medical, Inc., Santa Cruz, CA, USA) that integrates position tracking technology with a movable tablet display. MATERIALS AND METHODS: A total of 18 fiducial markers, which served as the target centres for the virtual tumours (target fiducials), were implanted in the prostate and kidney of a fresh cadaver, and preoperative computed tomography (CT) was performed to allow three dimensional model reconstruction of the surgical regions, which were registered on the body intra-operatively. The position of the movable tablet's display could be selected to obtain the best recognition of the interior anatomy. The system was used to navigate the puncture needle (with position-tracking sensor attached) using a colour-coded, predictive puncture-line. When the operator punctured the target fiducial, another fiducial, serving as the centre of the ablative treatment (treatment fiducial), was placed. Postoperative CT was performed to assess the digitized distance (representing the real distance) between the target and treatment fiducials to evaluate the accuracy of the procedure. RESULTS: The movable tablet display, with position-tracking sensor attached, enabled the surgeon to visualize the three-dimensional anatomy of the internal organs with the help of an overlaid puncture line for the puncture needle, which also had a position-tracking sensor attached. The mean (virtual) distance from the needle tip to the target (calculated using the computer workstation), was 2.5 mm. In an analysis of each digitalized axial component, the errors were significantly greater along the z-axis (P < 0.01), suggesting that the errors were caused by organ shift or deformation. CONCLUSION: This virtual navigation system, integrating a position-tracking sensor with a movable tablet display, is a promising advancement for facilitating percutaneous interventions. The movable display over the patient shows a preoperative three-dimensional image that is aligned to the patient. Moving the display moves the image, creating the feeling of looking through a window into the patient, resulting in instant perception and a direct, intuitive connection between the physician and the anatomy. PMID- 25294634 TI - Restoration of Normal Prothrombin Time/International Normalized Ratio With Fresh Frozen Plasma in Hypocoagulable Patients. AB - Fresh frozen plasma (FFP) is an effective reversal agent for hypocoagulable patients. Its proven efficacy continues to prompt its usage as both a prophylactic and a therapeutic therapy. Although published guidelines encouraging the appropriate administration of FFP exist, overutilization continues. The purpose of these ex vivo studies was to determine the effects of succeeding volumes of FFP supplementation on hypocoagulable plasma prothrombin time/international normalized ratio (PT/INR). By analyzing the decline in PT/INR with varying volumes of FFP, a minimal required volume of FFP could be identified representing the optimal volume to administer while still providing therapeutic effect. A total of 497 plasma samples were screened for elevated PT/INR values and 50 samples were selected for inclusion in this experiment. The initial PTs/INRs ranged from 12.5 to 43.4 seconds/1.42 to 4.91. Subsequent declines in PT/INR values were analyzed following addition of 50, 100, and 150 uL of FFP to a fixed volume of 250 uL of plasma (26.4 +/- 5.318 seconds/2.99 +/- 0.603, 13.3 +/- 1.077 seconds/1.51 +/- 0.122, 11.2 +/- 0.712 seconds/1.27 +/- 0.081, and 10.3 +/- 0.533 seconds/1.16 +/- 0.06, respectively). A nonlinear relationship between decline in INR values and percentage of FFP supplementation was demonstrated. The greatest effect on INR was obtained after supplementation with 50 uL (49%). Doubling and tripling the volume of FFP lead to significantly lower declines in INR (16% and 8%, respectively). Analysis of variance indicated a statistical significance with subsequent volume supplementation of FFP, but marginal clinical benefits exist between the PTs/INRs obtainable with increased FFP volume administration. PMID- 25294636 TI - Evaluation of Risk Factors for Rectus Sheath Hematoma. AB - Rectus sheath hematoma (RSH) develops due to rupture of epigastric arteries or the rectus muscle. Although RSH incidence rate is low, it poses a significant diagnostic dilemma. We evaluated the risk factors for RSH, its presentation, management, and outcomes for 115 patients hospitalized with confirmed RSH by computed tomography scan between January 2005 and June 2009. More than three fourth (77.4%) of the patients were on anticoagulation therapy, 58.3% patients had chronic kidney disease (CKD) stage >=3, 51.3% had abdominal injections, 41.7% were on steroids/immunosuppressant therapy, 37.4% had abdominal surgery/trauma, 33.9% had cough, femoral puncture was performed in 31.3% of patients, and 29.5% were on antiplatelet therapy. Rectus sheath hematoma was not an attributable cause in any of the 17 deaths. Mortality was significantly higher in patients with CKD stage >=3 (P = .03) or who required transfusion (P = .007). Better understanding of RSH risk factors will facilitate early diagnoses and improve management. PMID- 25294635 TI - Risk of Venous Thromboembolic Events in Pregnant Patients With Autoimmune Diseases: A Population-Based Study. AB - OBJECTIVE: The objective of this study is to evaluate the effect of autoimmune disease on the risk of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) in pregnant women. METHODS: Using the Health Care Cost and Utilization Project, Nationwide Inpatient Sample database from 2003 to 2011, the risk of developing DVT, PE, and VTE among pregnant patients with selected autoimmune diseases was estimated using unconditional logistic regression analysis. RESULTS: Our study cohort consisted of 7 917 453 women of which 43 523 had underlying autoimmune diseases. Risk of VTE was high in pregnant women with systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, type 1 diabetes mellitus, ulcerative colitis, and Crohn's disease. CONCLUSION: Most autoimmune diseases considerably increase the risk of VTE. Thromboprophylaxis may be considered in pregnancies with autoimmune disease, particularly those with systemic lupus erythematosus and dermatomyositis. PMID- 25294637 TI - Genetics and celiac disease: the importance of screening. AB - The prevalence of celiac disease (CD) is increasing. Despite an increased awareness and an improvement in diagnostic testing, the majority of individuals with CD remain undiagnosed. Currently, genetic testing in screening for CD is used only to exclude a diagnosis or reinforce a strong clinical suspicion. In this paper, we review the most current literature regarding genetic testing in CD. In response to important data revealing that an individual's HLA haplotype is one of the strongest known predictors of CD, we propose genetic screening for at risk infants to stratify individuals based on genetic risk to ultimately create genetic specific screening algorithms. PMID- 25294639 TI - Erratum to: Impact of the expression of thymidylate synthase and dihydropyrimidine dehydrogenase genes on survival in stage II/III gastric cancer. PMID- 25294640 TI - Changing viewer perspectives reveals constraints to implicit visual statistical learning. AB - Statistical learning-learning environmental regularities to guide behavior-likely plays an important role in natural human behavior. One potential use is in search for valuable items. Because visual statistical learning can be acquired quickly and without intention or awareness, it could optimize search and thereby conserve energy. For this to be true, however, visual statistical learning needs to be viewpoint invariant, facilitating search even when people walk around. To test whether implicit visual statistical learning of spatial information is viewpoint independent, we asked participants to perform a visual search task from variable locations around a monitor placed flat on a stand. Unbeknownst to participants, the target was more often in some locations than others. In contrast to previous research on stationary observers, visual statistical learning failed to produce a search advantage for targets in high-probable regions that were stable within the environment but variable relative to the viewer. This failure was observed even when conditions for spatial updating were optimized. However, learning was successful when the rich locations were referenced relative to the viewer. We conclude that changing viewer perspective disrupts implicit learning of the target's location probability. This form of learning shows limited integration with spatial updating or spatiotopic representations. PMID- 25294641 TI - Emotional content of an image attracts attention more than visually salient features in various signal-to-noise ratio conditions. AB - Emotional images are processed in a prioritized manner, attracting attention almost immediately. In the present study we used eye tracking to reveal what type of features within neutral, positive, and negative images attract early visual attention: semantics, visual saliency, or their interaction. Semantic regions of interest were selected by observers, while visual saliency was determined using the Graph-Based Visual Saliency model. Images were transformed by adding pink noise in several proportions to be presented in a sequence of increasing and decreasing clarity. Locations of the first two fixations were analyzed. The results showed dominance of semantic features over visual saliency in attracting attention. This dominance was linearly related to the signal-to-noise ratio. Semantic regions were fixated more often in emotional images than in neutral ones, if signal-to-noise ratio was high enough to allow participants to comprehend the gist of a scene. Visual saliency on its own did not attract attention above chance, even in the case of pure noise images. Regions both visually salient and semantically relevant attracted a similar amount of fixation compared to semantic regions alone, or even more in the case of neutral pictures. Results provide evidence for fast and robust detection of semantically relevant features. PMID- 25294642 TI - Addition of heart score to high-sensitivity troponin T versus conventional troponin T in risk stratification of patients with chest pain at the coronary emergency rooms. AB - Patients with chest pain have a large impact on available resources in coronary emergency rooms (CER). Clinical judgement, ECG, risk scores and biomarkers guide in risk stratification. We investigated if high-sensitivity troponin T (HsT) and the HEART Score could contribute to risk stratification at the CER. All patients with chest pain, without elevated conventional troponin levels at presentation, were included. HsT levels were determined at admission (T1), at 4-6 h (T2) and 8 10 h after symptom onset (T3). The HEART Score was calculated as risk score for the occurrence of a major adverse cardiac event (MACE). Thirty days after discharge, occurrence of MACE was registered. Eighty-nine patients were included (overall mean age 61 years (range 20-90)). At presentation, 68 patients (76 %) had a HsT below cut-off value of 14 ng/l (mean HEART Score 3.7, range 1-9). Thirty-one of these 68 patients had a HEART Score between 1-3, no MACE occurred in this group. For 3 patients (4 %) HsT levels increased above 14 ng/l. These 3 patients had a HEART Score between 4-6. The majority of patients with chest pain can be safely discharged within 4-6 h after onset of symptoms using HsT and the HEART Score. In contrast, patients with initially normal HsT but a high HEART Score need longer follow-up and repeat HsT determination. PMID- 25294638 TI - Withania somnifera Improves Ischemic Stroke Outcomes by Attenuating PARP1-AIF Mediated Caspase-Independent Apoptosis. AB - Withania somnifera (WS), popularly known as "Ashwagandha" has been used for centuries as a nerve tonic. Its protective effect has been elucidated in many neurodegenerative pathologies, although there is a paucity of data regarding its effects in ischemic stroke. We examined the neuroprotective properties of an aqueous extract of WS in both pre- and poststroke treatment regimens in a mouse model of permanent distal middle cerebral artery occlusion (pMCAO). WS (200 mg/kg) improved functional recovery and significantly reduced the infarct volume in mice, when compared to those treated with vehicle, in both paradigms. We investigated the protective mechanism/s induced by WS using brain cortices by testing its ability to modulate the expression of key proteins in the ischemic apoptotic cascade. The Western blots and immunofluorescence analyses of mice cortices revealed that WS upregulated the expression of hemeoxygenase 1 (HO1) and attenuated the expression of the proapoptotic protein poly (ADP-ribose) polymerase-1 (PARP1) via the PARP1-AIF pathway, thus preventing the nuclear translocation of apoptosis-inducing factor (AIF), and subsequent apoptosis. Semaphorin-3A (Sema3A) expression was reduced in WS-treated group, whereas Wnt, pGSK3beta, and pCRMP2 expression levels were virtually unaltered. These results indicate the interplay of antioxidant-antiapoptic pathways and the possible involvement of angiogenesis in the protective mechanism of WS while emphasizing the noninvolvement of one of the prime pathways of neurogenesis. Our results suggest that WS could be a potential prophylactic as well as a therapeutic agent aiding stroke repair, and that part of its mechanism could be attributed to its antiapoptotic and antioxidant properties. PMID- 25294643 TI - CMR-derived TAPSE measurement: a semi-quantitative method of right ventricular function assessment in patients with hypertrophic cardiomyopathy. AB - AIM: To compare cardiovascular magnetic resonance (CMR)-derived right ventricular fractional shortening (RVFS), tricuspid annular plane systolic excursion with a reference point within the right ventricular apex (TAPSEin) and with one outside the ventricle (TAPSEout) with the standard volumetric approach in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: 105 patients with HCM and 20 healthy subjects underwent CMR. In patients with HCM, TAPSEin (r = 0.31, p = 0.001) and RVFS (r = 0.35, p = 0.0002) revealed a significant but weak correlation with right ventricular ejection fraction (RVEF), whereas TAPSEout (r = 0.57, p < 0.0001) showed a moderate correlation with RVEF. The ability to predict RVEF < 45 % in HCM patients was best for TAPSEout. In patients with hypertrophic obstructive cardiomyopathy (HOCM), RVEF showed a significant but weak correlation with TAPSEout (r = 0.36, p = 0.02) and no correlation with TAPSEin (r = 0.05, p = 0.07) and RVFS (r = 0.02, p = 0.2). In patients with hypertrophic non-obstructive cardiomyopathy (HNCM), there was a moderate correlation between RVEF and TAPSEout (r = 0.57, p < 0.0001) and a weak correlation with TAPSEin (r = 0.39, p = 0.001) and RVFS (r = 0.38, p = 0.002). In the 20 healthy controls, there was a strong correlation between RVEF and all semi quantitative measurements. CONCLUSION: CMR-derived TAPSEin is not suitable to determine right ventricular function in HCM patients. TAPSEout showed a good correlation with RVEF in HNCM patients but only a weak correlation in HOCM patients. TAPSEout might be used for screening but the detection of subtle changes in RV function requires the 3D volumetric approach. PMID- 25294644 TI - Skeletal muscle: a brief review of structure and function. AB - Skeletal muscle is one of the most dynamic and plastic tissues of the human body. In humans, skeletal muscle comprises approximately 40% of total body weight and contains 50-75% of all body proteins. In general, muscle mass depends on the balance between protein synthesis and degradation and both processes are sensitive to factors such as nutritional status, hormonal balance, physical activity/exercise, and injury or disease, among others. In this review, we discuss the various domains of muscle structure and function including its cytoskeletal architecture, excitation-contraction coupling, energy metabolism, and force and power generation. We will limit the discussion to human skeletal muscle and emphasize recent scientific literature on single muscle fibers. PMID- 25294645 TI - Testing models of speciation from genome sequences: divergence and asymmetric admixture in Island South-East Asian Sus species during the Plio-Pleistocene climatic fluctuations. AB - In many temperate regions, ice ages promoted range contractions into refugia resulting in divergence (and potentially speciation), while warmer periods led to range expansions and hybridization. However, the impact these climatic oscillations had in many parts of the tropics remains elusive. Here, we investigate this issue using genome sequences of three pig (Sus) species, two of which are found on islands of the Sunda-shelf shallow seas in Island South-East Asia (ISEA). A previous study revealed signatures of interspecific admixture between these Sus species (Genome biology, 14, 2013, R107). However, the timing, directionality and extent of this admixture remain unknown. Here, we use a likelihood-based model comparison to more finely resolve this admixture history and test whether it was mediated by humans or occurred naturally. Our analyses suggest that interspecific admixture between Sunda-shelf species was most likely asymmetric and occurred long before the arrival of humans in the region. More precisely, we show that these species diverged during the late Pliocene but around 23% of their genomes have been affected by admixture during the later Pleistocene climatic transition. In addition, we show that our method provides a significant improvement over D-statistics which are uninformative about the direction of admixture. PMID- 25294647 TI - Long term outcome after mononuclear bone marrow or peripheral blood cells infusion after myocardial infarction. AB - OBJECTIVES: This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65). METHODS: In addition to 3-5 days, and 4 months after AMI, all patients underwent cardiac MRI after 2 years. A follow-up for 5 years after AMI was performed to assess clinical adverse events, including death, myocardial reinfarction and hospitalisation for heart failure. RESULTS: Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5 years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5+/-16.9 mL/m(2)) compared with (11.2+/-19.8 mL/m(2), p=0.03) in the control group, with no difference between the PBMC group (9.2+/-20.9 mL/m(2)) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (-1.8+/-15.0 mL/m(2)) as compared with controls (3.0+/-16.3 mL/m(2), p=0.07), with again no difference between PBMC (3.3+/-18.8 mL/m(2)) and controls (p=0.66). The combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67). CONCLUSIONS: Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse events were significantly more frequent in the PBMC group. TRIAL REGISTRATION NUMBER: The Netherlands Trial Register #NTR166 (http://www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org). PMID- 25294646 TI - CYP105-diverse structures, functions and roles in an intriguing family of enzymes in Streptomyces. AB - The cytochromes P450 (CYP or P450) are a large superfamily of haem-containing enzymes found in all domains of life. They catalyse a variety of complex reactions, predominantly mixed-function oxidations, often displaying highly regio and/or stereospecific chemistry. In streptomycetes, they are predominantly associated with secondary metabolite biosynthetic pathways or with xenobiotic catabolism. Homologues of one family, CYP105, have been found in all Streptomyces species thus far sequenced. This review looks at the diverse biological functions of CYP105s and the biosynthetic/catabolic pathways they are associated with. Examples are presented showing a range of biotransformative abilities and different contexts. As biocatalysts capable of some remarkable chemistry, CYP105s have great biotechnological potential and merit detailed study. Recent developments in biotechnological applications which utilize CYP105s are described, alongside a brief overview of the benefits and drawbacks of using P450s in commercial applications. The role of CYP105s in vivo is in many cases undefined and provides a rich source for further investigation into the functions these enzymes fulfil and the metabolic pathways they participate in, in the natural environment. PMID- 25294648 TI - Using iPads to Teach Communication Skills of Students with Autism. AB - The purpose of this study was to examine the effects of using an iPad to assist students with autism in learning communication skills. Three, 10 years old learners diagnosed with autism who present little or no functional speech, participated in the study. A multiple baseline design with AB phases across academic and social settings was used. During the baseline, students were given access to an iPad with the SonoFlex speech-generating device application, while no communicative attempts were observed. During the intervention, the students were taught to use the iPad to communicate with their teacher and peers for 6 weeks. With a least-to-most prompting hierarchy, all students increased initiating requests, responding to questions and making social comments in both class and recess settings. PMID- 25294649 TI - Applying machine learning to facilitate autism diagnostics: pitfalls and promises. AB - Machine learning has immense potential to enhance diagnostic and intervention research in the behavioral sciences, and may be especially useful in investigations involving the highly prevalent and heterogeneous syndrome of autism spectrum disorder. However, use of machine learning in the absence of clinical domain expertise can be tenuous and lead to misinformed conclusions. To illustrate this concern, the current paper critically evaluates and attempts to reproduce results from two studies (Wall et al. in Transl Psychiatry 2(4):e100, 2012a; PloS One 7(8), 2012b) that claim to drastically reduce time to diagnose autism using machine learning. Our failure to generate comparable findings to those reported by Wall and colleagues using larger and more balanced data underscores several conceptual and methodological problems associated with these studies. We conclude with proposed best-practices when using machine learning in autism research, and highlight some especially promising areas for collaborative work at the intersection of computational and behavioral science. PMID- 25294650 TI - Disease, risk, and contagion: French colonial and postcolonial constructions of "African" bodies. AB - In this article, we explore how sub-Saharan African immigrant populations in France have been constructed as risk groups by media sources, in political rhetoric, and among medical professionals, drawing on constructs dating to the colonial period. We also examine how political and economic issues have been mirrored and advanced in media visibility and ask why particular populations and the diseases associated with them in the popular imagination have received more attention at certain historical moments. In the contemporary period we analyze how the bodies of West African women and men have become powerful metaphors in the politics of discrimination prevalent in France, in spite of Republican precepts that theoretically disavow cultural and social difference. PMID- 25294651 TI - Ebola virus in West Africa: waiting for the owl of Minerva. AB - The evolving Ebola epidemic in West Africa is unprecedented in its size and scope, requiring the rapid mobilization of resources. It is too early to determine all of the ethical challenges associated with the outbreak, but these should be monitored closely. Two issues that can be discussed are (1) the decision to implement and evaluate unregistered agents to determine therapeutic or prophylactic safety and efficacy and (2) the justification behind this decision. In this paper, I argue that it is not compassionate use that justifies this decision and suggest three lines of reasoning to support the decision. PMID- 25294653 TI - Benefits and risks of using smart pumps to reduce medication error rates: a systematic review. AB - BACKGROUND: Smart infusion pumps have been introduced to prevent medication errors and have been widely adopted nationally in the USA, though they are not always used in Europe or other regions. Despite widespread usage of smart pumps, intravenous medication errors have not been fully eliminated. OBJECTIVE: Through a systematic review of recent studies and reports regarding smart pump implementation and use, we aimed to identify the impact of smart pumps on error reduction and on the complex process of medication administration, and strategies to maximize the benefits of smart pumps. METHODS: The medical literature related to the effects of smart pumps for improving patient safety was searched in PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) (2000-2014) and relevant papers were selected by two researchers. RESULTS: After the literature search, 231 papers were identified and the full texts of 138 articles were assessed for eligibility. Of these, 22 were included after removal of papers that did not meet the inclusion criteria. We assessed both the benefits and negative effects of smart pumps from these studies. One of the benefits of using smart pumps was intercepting errors such as the wrong rate, wrong dose, and pump setting errors. Other benefits include reduction of adverse drug event rates, practice improvements, and cost effectiveness. Meanwhile, the current issues or negative effects related to using smart pumps were lower compliance rates of using smart pumps, the overriding of soft alerts, non-intercepted errors, or the possibility of using the wrong drug library. CONCLUSION: The literature suggests that smart pumps reduce but do not eliminate programming errors. Although the hard limits of a drug library play a main role in intercepting medication errors, soft limits were still not as effective as hard limits because of high override rates. Compliance in using smart pumps is key towards effectively preventing errors. Opportunities for improvement include upgrading drug libraries, developing standardized drug libraries, decreasing the number of unnecessary warnings, and developing stronger approaches to minimize workarounds. Also, as with other clinical information systems, smart pumps should be implemented with the idea of using continuous quality improvement processes to iteratively improve their use. PMID- 25294654 TI - Laser suture stretch: report of a new technique to aid intraocular pressure control following filtering surgery. PMID- 25294655 TI - A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia. AB - WHAT IS KNOWN AND OBJECTIVE: Fibromyalgia is a painful disease affecting 1-2% of the United States population. Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and milnacipran, are well studied and frequently used for treating this disorder. However, efficacy data are limited for the SNRI venlafaxine despite its use in nearly a quarter of patients with fibromyalgia. Accordingly, we systematically reviewed the efficacy of venlafaxine for treatment of fibromyalgia. METHODS: PubMed, Web of Science and the Cochrane Database were searched using the terms 'venlafaxine' and 'fibromyalgia'. Results were classified as primary studies or review articles based on abstract review. References of review articles were evaluated to ensure no primary studies evaluating venlafaxine were overlooked. All clinical studies that investigated venlafaxine for the treatment of fibromyalgia were included and graded on strength of evidence. RESULTS AND DISCUSSION: Five studies met the inclusion criteria, including 4 open-label cohort studies and 1 randomized, controlled trial. Study durations ranged from 6 weeks to 6 months, and study sizes ranged from 11 to 102 participants. Four of the five published studies reported improvement in at least one outcome. Generally consistent improvements were observed in pain-related outcome measures, including the Fibromyalgia Impact Questionnaire (range, 26-29% reduction; n = 2 studies), Visual Analog Scale (range, 36-45% reduction; n = 2 studies), McGill Pain Questionnaire (48% reduction; n = 1 study) and Clinical Global Impression scale (51% had significant score change; n = 1 study). However, the few studies identified were limited by small sample size, inconsistent use of outcomes and methodological concerns. WHAT IS NEW AND CONCLUSION: Studies assessing the efficacy of venlafaxine in the treatment of fibromyalgia to date have been limited by small sample size, inconsistent venlafaxine dosing, lack of placebo control and lack of blinding. In the context of these limitations, venlafaxine appears to be at least modestly effective in treating fibromyalgia. Larger randomized controlled trials are needed to further elucidate the full benefit of venlafaxine. PMID- 25294656 TI - Role of stereotactic body radiotherapy for symptom control in head and neck cancer patients. AB - PURPOSE: Our aim was to determine the efficacy and quality of life outcomes of head and neck (HN) stereotactic body radiotherapy (SBRT) in a palliative population with significant proportions of de novo HN tumors not amenable to surgery or protracted course of curative radiotherapy (RT). METHODS: A retrospective review of a prospective database identified 21 patients with 24 sites that were treated. Patients were treated with intensity modulated RT (IMRT), usually 7-9 static fields with a 2-3-mm margin from gross tumor volume to planning target volume only with no microscopic margin added. Electronic patient records and treatment plans were reviewed. Basic demographic information was collected. The EORTC QLQ-H&N35 questionnaire was the tool used to collect QOL data both pre- and on-treatment fraction 5. Univariate analysis was performed for predictors of local control (LC) and prognostic factors for overall survival (OS). RESULTS: A total of 21 patients had 24 sites that were treated. The median age was 87 (range 25-103) and median KPS was 70. The most common histology was squamous cell carcinoma (SCC) 19/24 (79 %), basal cell carcinoma (BCC) 3/24 (16 %), and melanoma (4 %). The median maximal diameter was 3.7 cm (range 1-10 cm). The most commonly treated site was lymph nodes in the neck 13/24 (54 %), skin 8/24 (33 %), 4/24 (16 %) other HN mucosal primary sites. Of the 24 lesions, 17 (71 %) were de novo, without prior treatment and 7/24 (29 %) were recurrent. The most commonly used dose/fraction (fx) was 40 Gy/5 (fx) (range 35/5fx-48/6fx). Of the 24 lesions, 6 (25 %) had complete response, 16/24 (67 %) had partial response, and 2/24 (8 %) had no response. Control was defined as no further progression after treatment. For the entire cohort, LC at 3, 6, and 9 months were 66, 50, and 33 %, respectively. In the de novo group, 2/16 (12.5 %) had local failures with the LC rate of 94, 94, and 87 % at 3 months, 6 months, and 1 year, respectively. In the recurrent group, 4/8 (50 %) had failure with LC rates of 87. 5, 62.5, and 50 % at 3 months, 6 months, and 1 year, respectively. Of the 21 patients, 10 died during follow up, with the OS rate at 3 months, 6 months, and 1 year of 90, 70, and 60 %, respectively. Being defined "de novo" showed a trend toward statistical significance p = 0.046 for local failure. Overall survival did not show significant difference between de novo and recurrent with a p value of 0.267. No significant prognostic variables for OS were found. Pre-treatment QOL scores for the entire cohort were 53/130 versus 38/130 (lower scores indicating better QOL) scores with a trend toward statistical significance p = 0.05. CONCLUSIONS: SBRT is efficacious with improved quality of life within this elderly frail population in the treatment of de novo and recurrent tumors of the head and neck with promising quality of life scores. PMID- 25294657 TI - Effect of endurance for adverse drug reactions on the preference for aggressive treatments in cancer patients. AB - PURPOSE: Cancer patients receiving chemotherapy will sometimes conceal their discomfort, but an excessive endurance for adverse drug reactions (ADRs) can lead to a poorer prognosis. The aim of this study was to clarify the association between ADR endurance and a preference of cancer patients for aggressive treatments. METHODS: A cross-sectional study was undertaken of inpatients under 75 years of age receiving injectable systemic chemotherapy or oral chronic medications at hospitals in Japan. Subjects were asked to respond to a validated questionnaire to assess the extent of their ADR endurance and whether they would choose a novel, more aggressive therapy if their life expectancy was estimated at 2 years. RESULTS: Study participants were separated into the chemotherapy group (n = 36) and the non-chemotherapy group (n = 78). In the chemotherapy group, patients who had moderate ADR endurance scores were more likely to choose the new therapy (0-33, 34-67, and 68-100 points: 0.0, 54.5, and 27.3 %; chi (2) test, p = 0.15). Additionally, every patient on long-term chemotherapy (>=3 years) had high ADR endurance scores but did not choose the new, riskier treatment. In the non chemotherapy group, the proportion of those choosing the new therapy was linearly associated with higher ADR endurance scores (25.9, 38.2, and 64.7 %; p = 0.04). CONCLUSION: Cancer patients may prefer aggressive therapies, even when self estimations of ADR endurance are not very high, especially if they have been receiving chemotherapy for a short period of time. These patients should be observed with great caution. PMID- 25294659 TI - Reply to "the pain, the oncologist". PMID- 25294658 TI - Adolescents and young adult cancer survivors: exercise habits, quality of life and physical activity preferences. AB - INTRODUCTION: Given the decades of survivorship for adolescent and young adult (AYA) cancer survivors, it is important to promote behaviours that enhance physical and mental well-being and quality of life (QoL). The purpose of this study was to explore the exercise programming preferences and information needs of AYA survivors and to examine the impact of a cancer diagnosis on physical activity behavior and QoL. METHODS: Participants aged 15-25 years at time of diagnosis and referred to a specialist AYA cancer service between January 2008 and February 2012 were recruited. Eligible participants were mailed a self administered questionnaire assessing demographic and disease-related information, physical activity levels over time and exercise information preferences. QoL was measured using the Assessment of Quality of Life-6D (AQoL-6D). RESULTS: Seventy four (response rate 52 %) participants completed the questionnaire. The mean age was 23 years with 54 % female, with prevalent diagnoses included hematological malignancy (45 %) and sarcoma (24 %). Results indicated a significant reduction in the average minutes of physical activity post diagnosis (p =< 0.001) and during treatment (p = < 0.001). AYA who met public health physical activity guidelines (n = 36) at questionnaire completion had significantly higher QoL than those not meeting the guidelines (n = 38) (median (Mdn) = 0.87, interquartile range (IQR) = 0.73 to 0.98 and Mdn = 0.81, IQR = 0.57 to 0.93, respectively; p = 0.034). Most participants wanted exercise information at some point after diagnosis (85 %) but many did not receive any information (45 %). CONCLUSIONS: Findings suggest that AYA with cancer experience a significant impact on physical activity levels and QoL. Moreover, survivors experience considerable difficulty returning to premorbid levels of activity. Our study suggests that interventions promoting physical activity and healthy lifestyle behaviours would be well accepted within this population and may be essential to improve their long-term health and QoL during survivorship. PMID- 25294660 TI - Altered endothelial nitric oxide synthesis in preterm and small for gestational age infants. AB - BACKGROUND: Preterm infants are often exposed to neuronal and endothelial damage. The aim of the present study was to investigate the correlation between endothelial dysfunction and neuronal injury in preterm infants. METHODS: We compared serum nitric oxide (NO), endothelial nitric oxide synthase (eNOS) and neuron-specific enolase (NSE) concentrations in 33 moderate preterm (MP) and 47 late preterm (LP) infants using standard ELISA. Each group was classified as appropriate for gestational age (AGA) or small for gestational age (SGA). RESULTS: Compared to the AGA infants, the SGA infants had higher NO on day 1 (MP: mean, 72.3 ng/mL, range, 50.9-99.5 ng/mL vs 52.2 ng/mL, range, 28.1-68.2 ng/mL, P < 0.05; LP: mean, 58.4 ng/mL, range, 25.7-66.4 ng/mL vs 43.7 ng/mL, range, 21.2 60.6 ng/mL, P < 0.05), lower eNOS concentration on day 3 in the MP group (mean, 5.8 IU/mL, range, 1.2-7.9 IU/mL vs 8.9 IU/mL, range, 4.2-14.6 IU/mL, P < 0.05), and on day 1 in the LP group (mean, 5.5 IU/mL, range, 1.5-8.1 IU/mL vs 7.7 IU/mL, range, 4.4-13.8 IU/mL, P < 0.05). The NO/eNOS ratio was higher in SGA infants compared with the AGA subgroups (MP: mean, 13.8, range, 9.9-20.2 vs mean, 9.9, range, 4.7-13.1, P < 0.05; LP: mean, 12.2, range, 9.2-19.9 vs mean, 9.9, range, 5.4-14.4, P < 0.05). AGA infants had lower NSE concentration compared with the SGA infants on day 1 in the LP group (mean, 27.4 ng/mL, range, 20-43 ng/mL vs mean, 40.89 ng/mL, range, 34-51 ng/mL, P < 0.05). A positive correlation was found between NO/eNOS ratio and NSE concentration (r = 0.75, P < 0.05 and r = 0.64, P < 0.05 on days 1 and 3, respectively). CONCLUSION: High NO concentration in the context of low eNOS activity suggests a possible role of NO in the development of neuronal injury in SGA infants. PMID- 25294661 TI - Characterization of pantropic canine coronavirus from Brazil. AB - Characterization of canine coronavirus (CCoV) strains currently in circulation is essential for understanding viral evolution. The aim of this study was to determine the presence of pantropic CCoV type IIa in tissue samples from five puppies that died in Southern Brazil as a result of severe gastroenteritis. Reverse-transcriptase PCR was used to generate amplicons for sequence analysis. Phylogenetic analysis of the CCoV-IIa strains indicated that they were similar to those found in other countries, suggesting a common ancestor of these Brazilian isolates. This is the first report of pantropic CCoV-II in puppies from Latin America and our findings highlight that CCoV should be included as a differential diagnosis when dogs present with clinical signs and lesions typically seen with canine parvovirus infection. PMID- 25294662 TI - Influence of racing on the serum concentrations of acute-phase proteins and bone metabolism biomarkers in racing greyhounds. AB - This study was designed to evaluate the influence of racing on the serum concentrations of the acute-phase proteins (APPs) C-reactive protein (CRP), haptoglobin (Hp) and serum amyloid A (SAA) in 32 endurance-racing greyhounds. The study also aimed to investigate the effect of a 7 km race on the bone biomarkers osteocalcin (OC), bone-specific alkaline phosphatase (b-ALP) and pyridinoline cross-links (PYD). Total white blood cell (WBC) count, and the serum concentrations of cortisol, tumour necrosis factor-alpha (TNF-alpha), vitamin D and testosterone were also determined. Blood samples were collected 24 h prior to (T0) and within 2 h of completion of the race (T1). Compared to baseline values, WBC count did not change significantly (P = 0.2300), serum cortisol, Hp and SAA increased, while TNF-alpha and CRP decreased (P <0.0001 for each). There were no significant differences between the pre- and post-race serum concentrations of OC and PYD (P = 0.9500 and P = 0.2600, respectively), but serum b-ALP increased significantly (P = 0.0004). Serum concentrations of vitamin D and testosterone increased after racing (P = 0.0100 and P <0.0001, respectively). In this study, a 7 km race stimulated an acute-phase response, demonstrated by significant increases in the serum concentrations Hp and SAA in racing greyhounds. Increased serum b-ALP post-race probably indicates a change in bone metabolism and deserves further study. PMID- 25294663 TI - The application of maximal heart rate predictive equations in hypoxic conditions. AB - PURPOSE: Peak heart rate (HRpeak) is a common tool used in exercise prescription for groups in which maximal exercise intensity is contraindicated; however, the application of this method in normobaric hypoxia is unknown. Therefore, this study investigated the response of HRpeak and the application of predictive HRpeak equations to prescribe exercise intensity in acute normobaric hypoxia. Results were used to examine whether age-derived HRpeak predictive equations are valid in hypoxic conditions. METHODS: Fifteen untrained (eight men) volunteers (age 22 +/- 2 years; peak rate of oxygen consumption 46.3 +/- 7.0 ml kg(-1) min( 1)) completed incremental cycle ergometer tests (randomised order) to measure HRpeak at sea-level (SL (ambient inspiratory oxygen fraction (FIO2) 0.209)) and four normobaric hypoxic conditions FIO2: 0.185, 0.165, 0.142, 0.125 (~1,000-4,000 m). RESULTS: HRpeak was similar across all conditions (SL, 182 +/- 13; 0.185, 178 +/- 11; 0.165, 177 +/- 9; 0.142, 178 +/- 9; 0.125, 175 +/- 10 b min(-1)) despite a reduction in oxygen saturation with increasing hypoxia (SL, 95 +/- 5; 0.185, 95 +/- 2; 0.165, 92 +/- 2; 0.142, 88 +/- 3; 0.125, 82 +/- 4 %; P <= 0.05). The HRpeak was overestimated by all equations compared to the measured value (P < 0.05). Four equations overestimated HRpeak in all conditions (P < 0.01); two in four conditions (0.185, 0.165, 0.142, 0.125; P < 0.01); and two in three conditions (0.165, 0.142, 0.125; P < 0.01). CONCLUSION: The overestimation of HRpeak by commonly used age-derived predictive equations in normobaric hypoxic conditions suggests that despite possible contraindications researchers should directly measure HRpeak whenever possible if it is to be used to prescribe exercise intensities. PMID- 25294664 TI - Trunk extensor fatigue decreases jump height similarly under stable and unstable conditions with experienced jumpers. AB - PURPOSE: The purpose of this study was to investigate the effects of back extensor fatigue on performance measures and electromyographic (EMG) activity of leg and trunk muscles during jumping on stable and unstable surfaces. METHODS: Before and after a modified Biering-Sorensen fatigue protocol for the back extensors, countermovement (CMJ) and lateral jumps (LJ) were performed on a force plate under stable and unstable (balance pad on the force plate) conditions. Performance measures for LJ (contact time) and CMJ height and leg and trunk muscles EMG activity were tested in 14 male experienced jumpers during 2 time intervals for CMJ (braking phase, push-off phase) and 5 intervals for LJ (-30 to 0, 0-30, 30-60, 60-90, and 90-120 ms) in non-fatigued and fatigued conditions. RESULTS: A significant main effect of test (fatigue) (p = 0.007, f = 0.57) was observed for CMJ height. EMG analysis showed a significant fatigue-induced decrease in biceps femoris and gastrocnemius activity with CMJ (p = 0.008, f = 0.58 andp = 0.04, f = 0.422, respectively). LJ contact time was not affected by fatigue or surface interaction. EMG activity was significantly lower in the tibialis anterior with LJ following fatigue (p = 0.05, f = 0.405). A test x surface (p = 0.04, f = 0.438) interaction revealed that the non-fatigued unstable CMJ gastrocnemius EMG activity was lower than the non-fatigued stable condition during the onset-of-force phase. CONCLUSION: The findings revealed that fatiguing the trunk negatively impacts CMJ height and muscle activity during the performance of CMJs. However, skilled jumpers are not additionally affected by a moderately unstable surface as compared to a stable surface. PMID- 25294665 TI - Increase in vastus lateralis aponeurosis width induced by resistance training: implications for a hypertrophic model of pennate muscle. AB - PURPOSE: This study aimed to ascertain whether training-induced muscle hypertrophy is accompanied by an increase in the aponeurosis width, and to infer its impact on the training-induced increase in the pennation angle. METHODS: Eleven young men completed a resistance training program of unilateral knee extensions for 12 weeks. Before and after training, anatomical cross-sectional area (ACSA) of the vastus lateralis and its distal aponeurosis width in the transverse plane were measured with magnetic resonance imaging. The pennation angle and fascicle length were also determined with ultrasonography at the midbelly of the muscle. The effect of change in aponeurosis width on the magnitude of training-induced increase in pennation angle was estimated by using a parallelepipedon model. RESULTS: After the training, there were significant increases in ACSA (10.7 +/- 7.6 %), pennation angle (10.8 +/- 7.3 %) and aponeurosis width (1.9 +/- 3.1 %), whereas no significant change was found in the fascicle length. The model simulation shows that the increase in aponeurosis width by 1.9 % reduces the magnitude of increase in pennation angle by only 0.4 degrees . CONCLUSIONS: These results indicate that (1) the aponeurosis width of the vastus lateralis increases after 12 weeks of resistance training and (2) the increase in the aponeurosis width accompanying muscle hypertrophy by the amount of ~10 % does not substantially affect the increase in pennation angle. PMID- 25294666 TI - Short rest interval lengths between sets optimally enhance body composition and performance with 8 weeks of strength resistance training in older men. AB - PURPOSE: To determine if 8 weeks of periodized strength resistance training (RT) utilizing relatively short rest interval lengths (RI) in between sets (SS) would induce greater improvements in body composition and muscular performance, compared to the same RT program utilizing extended RI (SL). METHODS: 22 male volunteers (SS: n = 11, 65.6 +/- 3.4 years; SL: n = 11, 70.3 +/- 4.9 years) were assigned to one of two strength RT groups, following 4 weeks of periodized hypertrophic RT (PHRT): strength RT with 60-s RI (SS) or strength RT with 4-min RI (SL). Prior to randomization, all 22 study participants trained 3 days/week, for 4 weeks, targeting hypertrophy; from week 4 to week 12, SS and SL followed the same periodized strength RT program for 8 weeks, with RI the only difference in their RT prescription. RESULTS: Following PHRT, all study participants experienced increases in lean body mass (LBM) (p < 0.01), upper and lower body strength (p < 0.001), and dynamic power (p < 0.001), as well as decreases in percentage body fat (p < 0.05). Across the 8-week strength RT phase, SS experienced significantly greater increases in LBM (p = 0.001), flat machine bench press 1-RM (p < 0.001), bilateral leg press 1-RM (p < 0.001), narrow/neutral grip lat pulldown (p < 0.01), and Margaria stair-climbing power (p < 0.001), compared to SL. CONCLUSIONS: This study suggests 8 weeks of periodized high-intensity strength RT with shortened RI induces significantly greater enhancements in body composition, muscular performance, and functional performance, compared to the same RT prescription with extended RI, in older men. Applied professionals may optimize certain RT-induced adaptations, by incorporating shortened RI. PMID- 25294667 TI - [Drug safety: challenge in an aging society]. AB - BACKGROUND: Within the context of the demographic change the proportion of the elderly in the overall population is steadily increasing. At the same time elderly patients are prescribed a disproportionately high number of medicines in comparison to younger patients. In the light of multimorbidity and polypharmacy which affect a relevant portion of the older population, drug safety is of particular importance. RESULTS AND DISCUSSION: In recent years, the prescription of psychiatric drugs to elderly patients was repeatedly subjected to regulatory assessment and recommendations, for example the safety of antipsychotics in patients with dementia. As only limited information is often available with respect to the risks of medicines in the elderly population, additional efforts are necessary for improvement of the database. In this context, the system of spontaneous reporting, e.g. the reporting of cases of suspected adverse drug reactions to the responsible authorities, plays an important role with respect to the additional knowledge to be gathered. By reporting observed adverse drug reactions as well as by the quality of the reported information, physicians are able to significantly influence the effectiveness of this system in a positive way. OUTLOOK: As medical care for the majority of the elderly population is provided by general practitioners, adequate longitudinal studies are of special interest for investigating drug safety in the elderly. This aim is being pursued by the AgeCoDe study (German study on aging, cognition and dementia in primary care patients), a prospective, multicentre observational study, which is being carried out within the German competence network of degenerative dementia (Kompetenznetz Degenerative Demenzen). PMID- 25294668 TI - Convergent innovation for sustainable economic growth and affordable universal health care: innovating the way we innovate. AB - This paper introduces convergent innovation (CI) as a form of meta-innovation-an innovation in the way we innovate. CI integrates human and economic development outcomes, through behavioral and ecosystem transformation at scale, for sustainable prosperity and affordable universal health care within a whole-of society paradigm. To this end, CI combines technological and social innovation (including organizational, social process, financial, and institutional), with a special focus on the most underserved populations. CI takes a modular approach that convenes around roadmaps for real world change-a portfolio of loosely coupled complementary partners from the business community, civil society, and the public sector. Roadmaps serve as collaborative platforms for focused, achievable, and time-bound projects to provide scalable, sustainable, and resilient solutions to complex challenges, with benefits both to participating partners and to society. In this paper, we first briefly review the literature on technological innovation that sets the foundations of CI and motivates its feasibility. We then describe CI, its building blocks, and enabling conditions for deployment and scaling up, illustrating its operational forms through examples of existing CI-sensitive innovation. PMID- 25294671 TI - [Fulminant pneumococcal septicaemia in a patient with systemic lupus erythematosus and functional asplenia]. AB - Autosplenectomy is a rare phenomenon in patients with systemic lupus erythematosus (SLE). We present a case of pneumococcal septicaemia in an SLE patient. A CT-scan of the abdomen showed complete autosplenectomy, but a CT scan from years prior showed a normal size spleen. SLE patients have an increased risk of invasive pneumococcal disease and asplenia increases this risk. In Denmark there are no guidelines for vaccination of SLE patients. On the basis of this case report and the guidelines from European League Against Rheumatism we propose that the 23-polyvalent pneumococcal vaccine should be part of the standard regime in the management of SLE. PMID- 25294670 TI - Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV associated nasopharyngeal carcinoma. AB - Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease. PMID- 25294672 TI - [Late mesh migration into the colon after laparoscopic herniotomy]. AB - Long-term complications after laparoscopic ventral hernia repair with mesh reinforcement are not well documented in the literature. We describe a case of a 63-year-old woman with repeated hernia operations due to a ventral hernia, which ultimately was complicated with mesh migration into the transverse colon. PMID- 25294673 TI - [Intrapulmonary schwannoma presenting as a primary lung cancer]. AB - A 61-year-old woman was referred to the hospital by her general practitioner due to non-response to antibiotic treatment. By chest X-ray and subsequently CT scan a 9 cm tumour was detected in the right upper lobe. In addition, severe destruction of the corpus of Th2, Th3 and Th4 was found. A biopsy revealed a schwannoma. Surgery with curative intent was subsequently made, and a 10 * 10 cm big process was removed. The patient had an uneventfull recovery. PMID- 25294674 TI - [Assessment of the prognosis in patients who remain comatose after resuscitation from cardiac arrest]. AB - In Denmark there are around 3,500 unexpected cardiac arrests (CA) out of hospital each year. There is an unknown number of CA in hospitals. The survival rate after CA outside a hospital in Denmark is 10% after 30 days. There are varying data for the neurological outcome in this group of patients. The purpose of this work is to disseminate new knowledge and to help standardizing the treatment in the group of patients who remain comatose after being resuscitated from CA. Assessment of the prognosis for a patient in this group can be made after 72 hours and a multi modal approach to the patient is required. PMID- 25294675 TI - [Dubious effect of surgical masks during surgery]. AB - This article clarifies the use of surgical masks during surgery and the evidence for this. A search performed in PubMed found four studies based on 6.006 patients. The studies described the use of surgical masks in surgery with post operative infections as endpoint, and the studies had to include a control group. None of the four studies found a difference in the number of post-operative infections whether you used a surgical mask or not. However, the limited numbers of studies make it unsafe to conclude whether or not surgical face masks reduce post-operative infections. PMID- 25294676 TI - [A practical guide for writing an original scientific article]. AB - Writing scientific articles is an integrated part of being a medical doctor at academic institutions, and the demand for publishing scientific work has increased during recent years. The discipline of writing scientific articles can be troublesome and complicated, especially for young inexperienced researchers. This article is a guide to structuring and writing an original scientific article. PMID- 25294677 TI - An in vitro model for preclinical testing of thrombogenicity of resorbable metallic stents. AB - Vascular stents that can biodegrade and disappear in time have been reported as a promising solution to the problems of late-stent thrombosis and in-stent restenosis. Iron alloys in particular have many advantages in terms of cytocompatibility and mechanical properties. Despite mechanical behavior and biocompatibility studies, little attention has been given to the thrombogenic potential of these stents. This article presents the first study that aims to close this gap by addressing the hemocompatibility of resorbable iron-based alloys and composites in an in vitro porcine blood model. The investigated braided biodegradable stents included 99.95% pure Fe (50% cold worked), Fe35Mn alloy, Fe35Mn-25% ZM21 (ZM21 is 2% Zn, 0.5% Mn, balance Mg), Fe-25% Mg, and Fe 57% Mg. All stents were formed by braiding 127 um diameter wires into stents with an outer diameter of 6.35 mm. Inflammatory reaction and thrombocyte activation were examined by assessment of beta-thromboglobulin, thrombin-antithrombin complex, and polymorphonuclear elastase levels. The potential of Fe35Mn for use in vascular stenting is demonstrated by its exhibition of the least thrombogenic potential among tested materials. All bioresorbable Fe-Mn alloy compositions showed a reduced propensity towards platelet adhesion compared to 316L stainless steel, further indicating a general positive shift towards reduced thrombogenicity compared to traditional stents. PMID- 25294678 TI - MicroRNA and cancer--a brief overview. AB - MicroRNAs (miRNAs) are short non-coding RNAs with a length of ~22 nucleotides, involved in posttranscriptional regulation of gene expression. Until now, over 2588 miRNAs have been identified in humans and the list is growing. MicroRNAs have an important role in all biological processes and aberrant miRNA expression is associated with many diseases including cancer. In the year 2002 the first connection between cancer and miRNA deregulation was discovered. Since then, a lot of information about the key role which miRNAs play in cancer development and drug resistance has been gained. However, there is still a long way to go to fully understand the miRNA world. In this review, we briefly describe miRNA biogenesis and discuss the role of miRNAs in cancer development and drug resistance. Finally we explain how miRNAs can be used as biomarkers and as a novel therapeutic approach in cancer. PMID- 25294679 TI - The Ras/Rap GTPase activating protein RASA3: from gene structure to in vivo functions. AB - RASA3 (or GTPase Activating Protein III, R-Ras GTPase-activating protein, GAP1(IP4BP)) is a GTPase activating protein of the GAP1 subfamily which targets Ras and Rap1. RASA3 was originally purified from pig platelet membranes through its intrinsic ability to bind inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with high affinity, hence its first name GAP1(IP4BP) (for GAP1 subfamily member which binds I(1,3,4,5)P4). RASA3 was thus the first I(1,3,4,5)P4 receptor identified and cloned. The in vitro and in vivo functions of RASA3 remained somewhat elusive for a long time. However, recently, using genetically-modified mice and cells derived from these mice, the function of RASA3 during megakaryopoiesis, megakaryocyte adhesion and migration as well as integrin signaling has been reported. The goal of this review is thus to summarize and comment recent and less recent data in the literature on RASA3, in particular on the in vivo function of this specific GAP1 subfamily member. PMID- 25294680 TI - Membrane-spanning DNA nanopores with cytotoxic effect. AB - DNA-based cytotoxic agents: Nanopores composed of folded DNA featuring a hydrophobic belt of ethyl phosphorothioate groups insert into bilayer membranes and kill cancer cells. The mode by which the pores achieve cell killing is elucidated with confocal microscopy. PMID- 25294681 TI - Counterintuitive relationship between visceral fat and all-cause mortality in an elderly Asian population. AB - OBJECTIVE: Abdominal obesity is considered to be a risk factor for mortality. However, recent studies indicate that overweight may be negatively associated with mortality ("obesity paradox"). The relationships between mortality and various obesity markers in an elderly Asian cohort were evaluated. METHODS: Subjects of the Korean Longitudinal Study on Health and Aging (KLoSHA) (n = 1000, age >=65 years) were included. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured using computed tomography. RESULTS: A total of 222 deaths occurred during the 6-year follow-up (median = 5.2 [range 0.1-6.3] years). Body mass index (BMI), VFA, SFA, and total fat mass were negatively associated with all-cause mortality in the univariable analyses (hazard ratio [HR] 0.67 per 1 SD [95% CI 0.57-0.77], 0.66 [0.55-0.79], 0.73 [0.61-0.86], and 0.74 [0.63 0.87], respectively). BMI and VFA were significantly associated with all-cause mortality in the multivariable analyses (HR 0.85 per 1 SD [95% CI 0.73-0.99] and 0.64 [0.47-0.87], respectively). When stratified by quartiles, the HR associated with VFA was the lowest in the third quartile. CONCLUSIONS: In this observational study with a short follow-up of elderly Asian people, higher amounts of visceral fat, a marker for central obesity, were associated with decreased all-cause mortality. PMID- 25294682 TI - Prevalence of abnormalities on shoulder MRI in symptomatic and asymptomatic older adults. AB - AIM: The aim of this study was to determine the prevalence of structural shoulder pathology using magnetic resonance imaging (MRI) in three groups of older people: those with current shoulder pain, those with a previous history of shoulder pain and those with no history of shoulder pain, within a community-based sample. METHODS: Thirty subjects (10 within each of the three groups) participated in the study. Subjects were recruited by telephone and underwent a clinical examination of shoulder and neck range of movement (to ensure pain was not referred from the neck). Subjects completed the Shoulder Pain and Disability Index (SPADI) and underwent MRI and X-ray of the relevant shoulder. The X-rays and MRI were read independently by two experienced musculoskeletal radiologists blinded to each participant's symptoms. The MRIs were read using a structured reporting system. RESULTS: The mean range of shoulder movement on both the right and left sides was lower for the current pain group compared to both the no and previous pain groups. On X-ray, there was no significant difference between groups in terms of glenohumeral and/or acromioclavicular degenerative changes. Tendinosis and tears of the rotator cuff were present in the majority of participants in each group. Labral abnormalities were rare among all groups. CONCLUSION: Shoulder pathology is apparent in both symptomatic and asymptomatic shoulders and clinical symptoms may not match radiological findings. The cost burden of ordering MRI scans is significant and the relevance of the findings are questionable when investigating shoulder pain. PMID- 25294683 TI - Role of methionine adenosyltransferase alpha2 and beta phosphorylation and stabilization in human hepatic stellate cell trans-differentiation. AB - Myofibroblastic trans-differentiation of hepatic stellate cells (HSCs) is an essential event in the development of liver fibrogenesis. These changes involve modulation of key regulators of the genome and the proteome. Methionine adenosyltransferases (MAT) catalyze the biosynthesis of the methyl donor, S adenosylmethionine (SAMe) from methionine. We have previously shown that two MAT genes, MAT2A and MAT2B (encoding MATalpha2 and MATbeta proteins respectively), are required for HSC activation and loss of MAT2A transcriptional control favors its up-regulation during trans-differentiation. Hence MAT genes are intrinsically linked to the HSC machinery during activation. In the current study, we have identified for the first time, post-translational modifications in the MATalpha2 and MATbeta proteins that stabilize them and favor human HSC trans differentiation. Culture-activation of human HSCs induced the MATalpha2 and MATbeta proteins. Using mass spectrometry, we identified phosphorylation sites in MATalpha2 and MATbeta predicted to be phosphorylated by mitogen-activated protein kinase (MAPK) family members (ERK1/2, V-Raf Murine Sarcoma Viral Oncogene Homolog B1 [B-Raf], MEK). Phosphorylation of both proteins was enhanced during HSC activation. Blocking MEK activation lowered the phosphorylation and stability of MAT proteins without influencing their mRNA levels. Silencing ERK1/2 or B-Raf lowered the phosphorylation and stability of MATbeta but not MATalpha2. Reversal of the activated human HSC cell line, LX2 to quiescence lowered phosphorylation and destabilized MAT proteins. Mutagenesis of MATalpha2 and MATbeta phospho-sites destabilized them and prevented HSC trans-differentiation. The data reveal that phosphorylation of MAT proteins during HSC activation stabilizes them thereby positively regulating trans-differentiation. PMID- 25294684 TI - Interleukin-1beta/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)-1beta was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL 1beta/interleukin-1 receptor-associated kinase 1 (IRAK-1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK 1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time polymerase chain reaction, or immunoblotting further confirmed the up-regulation of Gankyrin by IL-1beta/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein p300 (p300) or CREB-binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1beta stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1beta/IRAK-1 signaling-mediated up-regulation of Gankyrin. CONCLUSION: The finding of IL-1beta/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis. PMID- 25294686 TI - Amelioration of oxidative stress in the joint tissue may be the basis for the antiarthritic activity of Terminalia arjuna bark extract. AB - AIM: In this study we have evaluated the antioxidant and antiarthritic activity of Terminalia arjuna bark extract (TABE) in collagen-induced arthritis (CIA) in rats. METHODS: Arthritis was induced in rats by intradermal injection of the collagen-complete Freund's adjuvant emulsion. Right hind paw thickness was measured as a primary marker for severity of arthritis. Biochemical parameters such as tissue levels of superoxide dismutase (SOD), catalase, reduced glutathione (GSH), nitrites and thiobarbituric acid reactive substances (TBARS) were measured to determine the effect of treatment on antioxidant defenses. Articular elastase (ELA) level in the arthritic tissue was measured as a marker for neutrophil infiltration. RESULT: Terminalia arjuna bark extract administration significantly inhibited the increase in paw thickness induced by immunization with collagen as compared to CIA-control animals. Further, it attenuated the fall in tissue SOD and GSH levels and mitigated the increase in tissue nitrites and TBARS levels as compared to CIA-control animals. Tissue ELA levels, which were significantly increased in the CIA-control animals as compared to normal animals were also significantly reduced by TABE administration. CONCLUSION: Results of our study demonstrate the antioxidant and antiarthritic activity of TABE in CIA in rats. We believe that TABE could find clinical application in the management of rheumatoid arthritis and associated disorders. PMID- 25294685 TI - Improving the field-effect performance of Bi2S3 single nanowires by an asymmetric device fabrication. AB - High-quality Bi2 S3 nanowires are synthesized by chemical vapor deposition and their intrinsic photoresponsive and field-effect characteristics are explored in detail. Among the studied Au-Au, Ag-Ag, and Au-Ag electrode pairs, the device with stepwise band alignment of asymmetric Au-Ag electrodes has the highest mobility. Furthermore, it is shown that light can cause a sevenfold decrease of the on/off ratio. This can be explained by the photoexcited charge carriers that are more beneficial to the increase of Ioff than Ion . The photoresponsive properties of the asymmetric Au-Ag electrode devices were also explored, and the results show a photoconductive gain of seven with a rise time of 2.9 s and a decay time of 1.6 s. PMID- 25294687 TI - Fruit and vegetable intake and risk of hip fracture: a cohort study of Swedish men and women. AB - Dietary guidelines recommend a daily intake of 5 servings of fruits and vegetables. Whether such intakes are associated with a lower risk of hip fracture is at present unclear. The aim of the present study was to investigate the dose response association between habitual fruit and vegetable intake and hip fracture in a cohort study based on 40,644 men from the Cohort of Swedish Men (COSM) and 34,947 women from the Swedish Mammography Cohort (SMC) (total n = 75,591), free from cardiovascular disease and cancer, who answered lifestyle questionnaires in 1997 (age 45 to 83 years). Intake of fruits and vegetables (servings/day) was assessed by food frequency questionnaire and incident hip fractures were retrieved from the Swedish Patient Register (1998 to 2010). The mean follow-up time was 14.2 years. One-third of the participants reported an intake of fruits and vegetables of >5 servings/day, one-third reported >3 to <=5 servings/day, 28% reported >1 to <=3 servings/day, and 6% reported <=1 serving/day. During 1,037,645 person-years we observed 3644 hip fractures (2266 or 62% in women). The dose-response association was found to be strongly nonlinear (p < 0.001). Men and women with zero consumption had 88% higher rate of hip fracture compared with those consuming 5 servings/day; adjusted hazard ratio (HR) was 1.88 (95% CI, 1.53 to 2.32). The rate was gradually lower with higher intakes; adjusted HR for 1 versus 5 servings/day was 1.35 (95% CI, 1.21 to 1.58). However, more than 5 servings/day did not confer additionally lower HRs (adjusted HR for 8 versus 5 servings/day was 0.96; 95% CI, 0.90 to 1.03). Similar results were observed when men and women were analyzed separately. We conclude that there is a dose-response association between fruit and vegetable intake and hip fracture such that an intake below the recommended five servings/day confers higher rates of hip fracture. Intakes above this recommendation do not seem to further lower the risk. PMID- 25294689 TI - Age-related differences in recommended anthropometric cut-off point validity to identify cardiovascular risk factors in ostensibly healthy women. AB - AIM: To investigate validity of widely recommended anthropometric and total fat percentage cut-off points in screening for cardiovascular risk factors in women of different ages. METHODS: A population-based sample of 1002 Swedish women aged 38, 50, 75 (younger, middle-aged and elderly, respectively) underwent anthropometry, health examinations and blood tests. Total fat was estimated (bioimpedance) in 670 women. Sensitivity, specificity of body mass index (BMI; >=25 and >=30), waist circumference (WC; >=80 cm and >=88 cm) and total fat percentage (TF; >=35%) cut-off points for cardiovascular risk factors (dyslipidaemias, hypertension and hyperglycaemia) were calculated for each age. Cut-off points yielding high sensitivity together with modest specificity were considered valid. Women reporting hospital admission for cardiovascular disease were excluded. RESULTS: The sensitivity of WC >=80 cm for one or more risk factors was ~60% in younger and middle-aged women, and 80% in elderly women. The specificity of WC >=80 cm for one or more risk factors was 69%, 57% and 40% at the three ages (p < .05 for age trends). WC >=80 cm yielded ~80% sensitivity for two or more risk factors across all ages. However, specificity decreased with increasing age (p < .0001), being 33% in elderly. WC >=88 cm provided better specificity in elderly women. BMI and TF % cut-off points were not better than WC. CONCLUSIONS: Validity of recommended anthropometric cut-off points in screening asymptomatic women varies with age. In younger and middle-age, WC >=80 cm yielded high sensitivity and modest specificity for two or more risk factors, however, sensitivity for one or more risk factor was less than optimal. WC >=88 cm showed better validity than WC >=80 cm in elderly. Our results support age specific screening cut-off points for women. PMID- 25294690 TI - Effect of lead pollution control on environmental and childhood blood lead level in Nantong, China: an interventional study. AB - Children's blood lead levels and prevalence of lead poisoning in China are significantly higher than in developed countries, though a substantial decrease has been observed. Since 2011, strict lead control policies in lead-related industries have been implemented in China, but the success of these policies is unknown. In this study, we collected environmental samples, questionnaire data, and blood samples from 106 children from 1 to 14 years old, before and after implementation of lead-usage control policy in wire rope factories by local government in Zhuhang, Nantong in 2012. Results showed that, one year after the lead control, lead concentrations sharply decreased in both environmental and biological samples with a decrease of 0.43 MUg/m3 (-84.3%) in ambient air samples, 0.22 mg/kg (-36.1%) in vegetable samples, 441.1 mg/kg (-43.7%) in dust samples, and 6.24 MUg/dL (-51.5%) in childhood blood lead levels (BLL). This study demonstrates the success of lead control policies in promoting the prevention and control of childhood lead poisoning in Nantong, China. PMID- 25294691 TI - Impact of an integrated disease management program in reducing exacerbations in patients with severe asthma and COPD. AB - BACKGROUND: Conflicting data exists on the effectiveness of integrated programs in reducing recurrent exacerbations and hospitalizations in patients with Asthma and chronic obstructive lung disease (COPD). We developed a Pulmonologist-led Chronic Lung Disease Program (CLDP) for patients with severe asthma and COPD and analyzed its impact on healthcare utilization and predictors of its effectiveness. METHODS: CLDP elements included clinical evaluation, onsite pulmonary function testing, health education, and self-management action plan along with close scheduled and on-demand follow-up. Patients with >=2 asthma or COPD exacerbations requiring emergency room visit or hospitalization within the prior year were enrolled, and followed for respiratory related ER visits (RER) and hospitalizations (RHA) over the year (357 +/- 43 days) after CLDP interventions. RESULTS: A total of 106 patients were enrolled, and 104 patients were subject to analyses. During the year of follow-up after CLDP enrollment, there was a significant decrease in mean RER (0.56 +/- 1.48 versus 2.62 +/- 2.81, p < 0.0001), mean RHA (0.39 +/- 0.08 versus 1.1 +/- 1.62, p < 0.0001), and 30 day rehospitalizations (0.05 +/- 0.02 versus 0.28 +/- 0.07, p < 0.0001). Reduction of healthcare utilization was strongly associated with GERD and sinusitis therapy, and was independent of pulmonary rehabilitation. Direct variable cost analyses estimated annual savings at $1.17 million. Multivariate logistic regression analysis revealed lack of spirometry utilization as an independent risk factor for severe exacerbations. CONCLUSIONS: A Pulmonologist-led disease management program integrating key elements of care is cost effective and significantly decreases severe exacerbations. Integrated programs should be encouraged for care of frequent exacerbators of asthma and COPD. PMID- 25294692 TI - Validation of the Asthma Control Test in pregnant asthmatic women. AB - OBJECTIVE: To determine the validity of the Asthma Control Test (ACT) questionnaire for assessing pregnant asthmatic women. METHODS: The study involved 40 pregnant asthmatic women over a total of 113 medical visits. On each occasion the participants had a pulmonary function test and a clinical evaluation to assess the level of asthma control. In addition, the ACT was carried out with the obstetrician being blinded to its results. RESULTS: The most accurate cut-off point was 16, with a sensitivity of 95.4%, specificity of 68.8%, a negative predictive value of 91.7% and a positive predictive value of 80.5%. The positive and negative likelihood ratios were 3.052 and 0.067 respectively. The questionnaire was found to be highly effective for discriminating between controlled and uncontrolled asthma, with an area under the receiver operating characteristic (ROC) curve of 0.846 (95%CI: 0.748-0.92). Reliability assessed in patients with the same clinical classification resulted in an intra-class correlation coefficient of 0.86 (95%CI: 0.75-0.93). Improved clinical conditions corresponded to a significant increase in the ACT score (p < 0.005), indicating good responsiveness to changes in clinical status. CONCLUSIONS: The ACT proved to be reliable and could discriminate between levels of asthma control in pregnant women confirming its value as a useful tool for the management of asthma during pregnancy. PMID- 25294694 TI - Layer-by-layer-based silica encapsulation of individual yeast with thickness control. AB - In the area of cell-surface engineering with nanomaterials, the metabolic and functional activities of the encapsulated cells are manipulated and controlled by various parameters of the artificial shells that encase the cells, such as stiffness and elasticity, thickness, and porosity. The mechanical durability and physicochemical stability of inorganic shells prove superior to layer-by-layer based organic shells with regard to cytoprotection, but it has been difficult to vary the parameters of inorganic shells including their thickness. In this work, we combine the layer-by-layer technique with a process of bioinspired silicification to control the thickness of the silica shells that encapsulate yeast Saccharomyces cerevisiae cells individually, and investigate the thickness dependent microbial growth. PMID- 25294695 TI - Microcellular open porous monoliths for cell growth by thiol-ene polymerization of low-toxicity monomers in high internal phase emulsions. AB - Open porous microcellular polymers with high degrees of porosity are prepared from divinyl adipate and pentaerythritol tetrakis(3-mercaptopropionate) by thiol ene polymerization within high internal phase emulsions. The influence of monomer ratio, droplet phase volume, and emulsion stirring rate on the morphology and mechanical properties of the products is studied. The newly produced material is successfully applied as a scaffold for osteoblastic MC3T3-E1 cells in vitro, showing increased rates of cell growth compared to material prepared by standard methods. PMID- 25294697 TI - Successful treatment of refractory pyoderma gangrenosum with ustekinumab only after excision of renal cell carcinoma. PMID- 25294696 TI - Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy? Analysis of prostate cancer-specific mortality by nomogram predicted risks of biochemical recurrence. AB - BACKGROUND: Due to the protracted natural history of the clinical progression of prostate cancer, biochemical recurrence (BCR) is often used to compare treatment modalities. However, BCR definitions and posttreatment prostate-specific antigen kinetics vary considerably among treatments, calling into the question the validity of such comparisons. OBJECTIVE: To analyze prostate cancer-specific mortality (PCSM) according to treatment-specific nomogram-predicted risk of BCR for men treated by radical prostatectomy (RP), external-beam radiation therapy (EBRT), and brachytherapy. DESIGN, SETTING, AND PARTICIPANTS: A total of 13 803 men who underwent RP, EBRT, or brachytherapy at two US high-volume hospitals between 1995 and 2008. INTERVENTION: RP, EBRT, and brachytherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The 5-yr progression-free probability (5Y PFP) was calculated for each patient based on the treatment received using a validated treatment-specific nomogram. Fine and Gray competing risk analysis was then used to estimate PCSM by a patient's predicted 5Y-PFP. Multivariable competing risk regression analysis was used to determine the association of treatment with PCSM after adjusting for nomogram-predicted 5Y-PFP. RESULTS AND LIMITATIONS: Men receiving EBRT had higher 10-yr PCSM compared with those treated by RP across the range of nomogram-predicted risks of BCR: 5Y-PFP >75%, 3% versus 0.9%; 5Y-PFP 51-75%, 6.8% versus 5.9%; 5Y-PFP 26-50%, 12.2% versus 10.6%; and 5Y PFP <=25%, 26.6% versus 21.2%. After adjusting for nomogram-predicted 5Y-PFP, EBRT was associated with a significantly increased PCSM risk compared with RP (hazard ratio: 1.5; 95% confidence interval, 1.1-2.0; p=0.006). No statistically significant difference in PCSM was observed between patients treated by brachytherapy and RP, although patient selection factors and lack of statistical power limited this analysis. CONCLUSIONS: EBRT patients with similar nomogram predicted 5Y-PFP appear to have a significantly increased risk of PCSM compared with those treated by RP. Comparison of treatments using nomogram-predicted BCR end points may not be valid. PATIENT SUMMARY: Biochemical recurrence (BCR) outcomes after external-beam radiation therapy and radical prostatectomy are associated with different risks of subsequent prostate cancer-specific mortality. Physicians and patients should cautiously interpret BCR end points when comparing treatments to make treatment decisions. PMID- 25294698 TI - Modulating speed-accuracy strategies in major depression. AB - BACKGROUND: Depression is associated with deficits in cognitive flexibility. The role of general slowing in modulating more specific cognitive deficits is however unclear. AIM: We assessed how depression affects the capacity to strategically adapt behavior between harsh and prudent response modalities and how general and specific processes may contribute to performance deficits. METHODS: Patients suffering from major depression and age- and education-matched healthy controls were asked to randomly stress either speed or accuracy during perceptual decision making. RESULTS: Diffusion models showed that patients with depression kept using a less conservative strategy after a trial with speed vs. accuracy instructions. Additionally, the depression group showed a slower rate of evidence accumulation as indicated by a generally lower drift rate. CONCLUSIONS: These data demonstrate that less efficient strategic regulation of behavior in depression is due not only to general slowing, but also to more specific deficits, such as a rigid dependence on past contextual instructions. Future studies should investigate the neuro-anatomical basis of this deficit. PMID- 25294699 TI - European Medicines Agency pledges to publish clinical reports. PMID- 25294700 TI - Evidence-based topical treatments for tinea cruris and tinea corporis: a summary of a Cochrane systematic review. AB - Tinea cruris and tinea corporis are common fungal infections. Most can be treated with a variety of topical antifungals. This review aimed to assess the evidence for the effectiveness and safety of topical treatments for tinea cruris and tinea corporis. Searches included the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, Medline, Embase, LILACS and ongoing trials registries (August 2013). One hundred and twenty-nine randomized controlled trials (RCTs) with 18 086 participants evaluated a range of interventions - mostly azoles. Pooling of data for several outcomes was only possible for two individual treatments. In five studies, terbinafine showed a statistically significant higher clinical cure rate compared with placebo [risk ratio (RR) 4.51, 95% confidence interval (CI) 3.10-6.56]. Data for mycological cure could not be pooled owing to substantial heterogeneity. Across three studies, mycological cure rates favoured naftifine (1%) compared with placebo (RR 2.38, 95% CI 1.80-3.14) but the quality of the evidence was low. Combinations of azoles with corticosteroids were slightly more effective than azoles for clinical cure, but there was no statistically significant difference with regard to mycological cure. Sixty-five studies were assessed as 'unclear' and 64 as being at 'high risk' of bias; many were over 20 years old, and most were poorly designed and inadequately reported. Although most active interventions showed sufficient therapeutic effect, this review highlights the need for further, high-quality, adequately powered RCTs to evaluate the effects of these interventions, which can ultimately provide reliable evidence to inform clinical decision making. PMID- 25294701 TI - Semi-quantitative HPV viral load in patients with ASC-US cytology: viral load correlates strongly with the presence of CIN, but only weakly with its severity: Response. PMID- 25294702 TI - Expression of GBGT1 is epigenetically regulated by DNA methylation in ovarian cancer cells. AB - BACKGROUND: The GBGT1 gene encodes the globoside alpha-1,3-N acetylgalactosaminyltransferase 1. This enzyme catalyzes the last step in the multi-step biosynthesis of the Forssman (Fs) antigen, a pentaglycosyl ceramide of the globo series glycosphingolipids. While differential GBGT1 mRNA expression has been observed in a variety of human tissues being highest in placenta and ovary, the expression of GBGT1 and the genes encoding the glycosyltransferases and glycosidases involved in the biosynthesis of Fs as well as the possible involvement of DNA methylation in transcriptional regulation of GBGT1 expression have not yet been investigated. RESULTS: RT-qPCR profiling showed high GBGT1 expression in normal ovary surface epithelial (HOSE) cell lines and low GBGT1 expression in all (e.g. A2780, SKOV3) except one (OVCAR3) investigated ovarian cancer cell lines, a finding that was confirmed by Western blot analysis. Hierarchical cluster analysis showed that GBGT1 was even the most variably expressed gene of Fs biosynthesis-relevant glycogenes and among the investigated cell lines, whereas NAGA which encodes the alpha-N-acetylgalactosaminidase hydrolyzing Fs was not differentially expressed. Bisulfite- and COBRA-analysis of the CpG island methylation status in the GBGT1 promoter region demonstrated high or intermediate levels of GBGT1 DNA methylation in all ovarian cancer cell lines (except for OVCAR3) but marginal levels of DNA methylation in the two HOSE cell lines. The extent of DNA methylation inversely correlated with GBGT1 mRNA and protein expression. Bioinformatic analysis of GBGT1 in The Cancer Genome Atlas ovarian cancer dataset demonstrated that this inverse correlation was also found in primary ovarian cancer tissue samples confirming our cell line-based findings. Restoration of GBGT1 mRNA and protein expression in low GBGT1-expressing A2780 cells was achieved by 5-aza-2'-deoxycytidine treatment and these treated cells exhibited increased helix pomatia agglutinin-staining, reflecting the elevated presence of Fs disaccharide on these cells. CONCLUSIONS: GBGT1 expression is epigenetically silenced through promoter hypermethylation in ovarian cancer. Our findings not only suggest an involvement of DNA methylation in the synthesis of Fs antigen but may also explain earlier studies showing differential GBGT1 expression in various human tissue samples and disease stages. PMID- 25294703 TI - Laparoscopic treatment of abdominal hernia - 5 years of experience. AB - Laparoscopic surgery has become a well approved method of abdominal hernias treatment in recent years. Due to the advancement of laparoscopy and the use of improved synthetic materials laparoscopic surgery is characterized not only by low complication but also by a short period of recovery after surgery. The aim of the study was a retrospective analysis of the results of laparoscopic abdominal hernia surgeries (IPOM). MATERIAL AND METHODS: Between year 2007 and 2012, 65 patients aged between 29 to 76 underwent laproscopic abdominal hernia surgeries due to either primary or postoperative abdominal hernias. All patients were examined in perioperative period, after 12 and 24 months after surgery in search of complications, pain and reccurence. Recovery period was also estimated. RESULTS: In most cases postoperative pain was estimated from 1 to 4 on VAS scale. The most frequent complications were seromas that occured in 3 patients. The other complications were pneumothorax, wound hematoma and wound infection that occured once each. One patient required reoperation due to wound hematoma. Chronic postoperative pain was diagnosed in 3 patients and 4 recurrences were stated. CONCLUSIONS: Laparoscopic therapy of abdominal hernias is a safe operative method characterized by low recurrence and complication rates as well as short hospital stay and quick recovery. This technique is restricted by high material costs and the lack of full refund for the procedure. PMID- 25294704 TI - Efficacy evaluation of bio trombina (r) 400 in mini mall y invasive treatment of complications (pseudoaneurysms), after venipuncture for diagnostic purposes. Authors' own experience - case study of 38 patients. AB - Common use of venipuncture on upper and lower limbs for diagnostic purposes (such as coronarography or arteriography), and also during the course of treatment (angioplasty), very often bares a complication in the form of pseudoaneurysms. According to various reports, the incidence of pseudoaneurysms ranges from 0.005% to 0.5% of all vascular procedures requiring arterial cannulation (Common Femoral Artery, Brachial Artery, Radial Artery). The use of Bio Trombina(r) 400 in the embolization of pseudoaneurysms allows minimally invasive and effective treatment. The aim of the study was to evaluate the efficacy of pseudoaneurysm embolization with the use of Trombina 400, authors' own experience. MATERIAL AND METHODS: In the years 2011 - 2013, the authors of this study performed 38 vascular interventional procedures involving pseudoaneurysms as complications of venipuncture in upper and lower limbs for diagnostic and treatment purposes. All procedures involved the direct injection of thrombin into the chamber of the pseudoaneurysm under the guidance of USG Doppler (6.2 MHz linear head). 34 cases presented single chamber pseudoaneurysms while 4 cases involved multi- chamber pseudoaneurysms, which required several thrombin reinjections (Bio Trombina(r) 400) into each of the chambers. Pseudoaneurysm maximum size of 4 cm was set as an inclusion criterion for the embolization procedure. Furthermore, all pseudoaneurysms with a significantly wide tract in transverse dimensions were treated as an exclusion criterion because of high risk of the peripheral arteries embolization. RESULTS: Initial success was observed in 36 patients (94.73%) in the first day after the procedure, 1 patient (2.63%) underwent thrombin reinjection procedure in the second day after the first embolization. Another patient (2.63%) underwent an open procedure in which the Common Femoral Artery was accessed, the clot evacuated, and CFA was sutured with continuous suture Prolene 6-0. CONCLUSIONS: 1. Embolization of pseudoaneurysms with USG Doppler guided thrombin injection is an effective course of treatment for complications of cannulation. 2. The safety of pseudoaneurysm embolization depends on a surgeon's experience. It is also crucial to keep in mind the inclusion and exclusion criteria for this type of procedure (the size of a pseudoaneurysm, the width of its base). 3. Furthermore, its cost effectiveness and short hospitalization period make pseudoaneurysm embolization an effective and valuable alternative to the classic approach. PMID- 25294705 TI - Damage of facial soft tissues as a result of being bitten by a dog. AB - Being bitten by a dog can have serious health effects. That is why, never underestimate even the smallest soft tissue injuries inflicted by aggressive animals. This incident may have an impact on the further condition of a patient. From our first aid will also depend the aesthetic and functional effect of the scar on the face. We should pay attention to the use of antibiotic prophylaxis. The aim of the study was to perform the analysis of the soft tissue bitten injuries made by dogs in patients treated in the years 2004-2009 in the Clinic of Cranio-Maxillo-Facial and Oncological Surgery in Lodz. The most frequent attacked areas were analyzed in the cases of single and multiple face wounds. The dependence of the dog attacks and the alcohol consumption by the victims. The use of an early antibiotic prophylaxis and the number of the infectious complications. MATERIAL AND METHODS: The material studied is a group of 26 patients, including 17 women and 9 men. In the majority patients were older than 20 years old. RESULTS: The analysis of our data shows that most of the victims were aged 19-30 and 51-60 years. 14 patients have been mutilated on one area of the face, the remaining patients at least two areas. Most injuries underwent upper or lower lip. In all cases, the initial supply has been applied to the wounds. Antibiotic prophylaxis was used in 23 patients. In one of the other three cases, patient who have not been applied to the prevention of complications in the form of phlegmon face. Half of the attack dogs have been known to the victims. All patients had implemented prevention of tetanus, or held-to-date vaccinations. In eight cases, patients reported that at the time of the event they were under the influence of alcohol. CONCLUSIONS: Primary supply of bitten wounds of face at the moment seems to be the standard. In our study, in cases where patients has been treated with an antibiotic, there was no case of infection in the wound. Late complication in the form of phlegmon occurred in one patient who had not used prophylaxis. As the most of the authors note lower lip is the most vulnerable for the bite in the case of adult people. Analysis of our data is consistent with these reports. It has also been found that people under the influence of alcohol are often attacked by unknown dogs. PMID- 25294706 TI - Association of polymorphism of Lys589Glu Exo1 gene with the risk of colorectal cancer in the Polish population. AB - The incidence of colorectal cancer (CRC) is increasing from year to year. Despite intensive research CRC etiology remains unknown. Studies suggest that at the basis of the process of carcinogenesis can lie reduced efficiency of DNA repair mechanisms, often caused by polymorphisms in DNA repair genes. The aim of the study was to determine the relationship between gene polymorphism Lys589Glu of EXO1 gene and modulation of the risk of colorectal cancer in the Polish population. Determination of the molecular basis of carcinogenesis process and predicting increased risk will allow qualifying patients to increased risk group and including them in preventive program. MATERIAL AND METHODS: The material used in study was blood collected from 130 patients diagnosed with colorectal cancer. The control group consisted of 135 healthy people. Genotyping was performed by TaqMan method. RESULTS: The results obtained indicate that the genotype Lys/Glu is associated with an increased risk of colorectal cancer (OR 1.811, 95% Cl 1.031 3.181, p = 0.038). CONCLUSION: On the basis of these results, we conclude that Exo1 gene polymorphism Lys589Glu may be associated with an increased risk of colorectal cancer. PMID- 25294707 TI - Acute ischemia of the lower extremity during renal transplantation - case report. AB - Acute ischemia of the lower extremity during renal transplantation is a rare complication of such procedure, but if it occurs, requires immediate vascular repair. This paper present one case of such complication that occurred during many years of renal transplantation at the Department of General and Transplantation Surgery, Public Hospital No. 4 in Lublin. Furthermore, a method to solve this problem is presented. PMID- 25294708 TI - Laparoscopically treated small bowel obstruction due to internal herniation through the broad ligament. AB - The authors reported a case of small bowel obstruction secondary to internal herniation through a defect of the broad ligament. This is a rare cause of small bowel obstruction. A 42 year-old woman without previous abdominal surgery presented with episodes of abdominal pain, nausea and vomiting. Due to rather unspecific and changing symptoms and the fact that objective findings were normal the patient was discharged and admitted a couple of times before a computed tomography-scan showed small bowel obstruction. Acute diagnostic laparoscopy showed internal herniation of a loop of small bowel trapped in a 2 cm defect in the right side of the broad ligament. The defect was gently expanded bluntly and it was then possible to retract the strangulated part of the small bowel which afterwards was vital. The defect was sutured laparoscopically. The postoperative recovery was uneventful. This case demonstrates that a preoperative diagnosis is difficult and a high index of suspicion is necessary to prevent diagnostic delay. Internal herniation through a defect in the broad ligament should be considered as a differential diagnosis in female patients presenting with symptoms of small bowel obstruction without a history of prior abdominal surgery, especially in parous women. PMID- 25294709 TI - Giant splenic hematoma can be a hidden condition. AB - An otherwise healthy 28-year old male presented to his general practitioner with dyspnoea in the morning and abdominal discomfort through months. Four months earlier, he had experienced a blunt trauma to the left side of his abdomen. Abdominal ultrasonography revealed a splenic hematoma and the patient was admitted to hospital. Vital signs were normal, and blood samples revealed a marginal anaemia and elevated C-reactive protein, but were otherwise normal. Computed tomography showed an 18 centimetre wide splenic hematoma. The patient was referred to another hospital for conservative treatment in the outpatient clinic. PMID- 25294710 TI - Usefulness of magnetic resonance imaging in diagnosis and monitoring of treatment of perianal fistulas. PMID- 25294711 TI - Polish consensus statement on the protective stoma. PMID- 25294712 TI - Non-immune hydrops fetalis as a diagnostic and survival problems: what do we tell the parents? AB - OBJECTIVE: Nonimmune hydrops fetalis (NIHF) is one of the most difficult problems related to pregnancy. The aim of this study was to evaluate the etiological analysis as well as the fetal and neonatal outcomes of NIHF. METHODS: We reviewed the prenatal sonographic data and postnatal medical records of pregnant women diagnosed as NIHF in our hospital between January 2001 and May 2013. All cases were categorized using 12 etiological classification groups. Demographic data, diagnostic laboratory parameters, karyotyping results, sonographic and autopsy findings, postnatal final diagnoses, and perinatal mortality rates were also recorded. RESULTS: This study included 147 cases. The mean gestational age at the time of the initial diagnosis was 23.84+/-6.30 weeks. Cardiovascular causes were the most common (21.7%), followed by structural abnormalities (17.0%), chromosomal abnormalities (6.8%), and skeletal dysplasias (5.4%). Chromosomal abnormalities were detected in 12.8% of these cases. The most common karyotype abnormality was monosomy X. Postmortem autopsy was performed in 50 (34%) cases, and at least one finding was detected in 40 (80%) of these cases. The overall mortality rate was 78.2%. The gestational week at delivery, birth weight, and Apgar score (1st and 5th min) showed a statistically significant difference between exitus and surviving fetuses (P<0.05). CONCLUSION: NIHF can lead to high perinatal morbidity and mortality, yet its etiopathology remains poorly understood. Early diagnosis of NIHF gives parents an opportunity to make an informed choice about the possible complications of a pregnancy. PMID- 25294713 TI - Differential utilization of expanded genetic screening tests in patients of reproductive ages from private and academic practices. AB - OBJECTIVE: We sought to evaluate the types of genetic screening tests that are performed in women of childbearing ages in New Jersey. METHOD: Data from patients who had a reproductive genetics consultation between January 1, 2012, and July 31, 2012, were stratified according to the referring providers, i.e., those from academic or private practices, and descriptive analyses performed. Unconventional genetic screening was defined as any test ordered by the referring health care provider outside the recommendations from the American Congress of Obstetricians and Gynecologists or the American College of Medical Genetics and Genomics. RESULTS: Overall, 30% of 371 patients referred for a genetic consultation underwent unconventional screening. As compared to patients from academic practices, the relative rate of unconventional screening was 10-fold higher among patients from private practices, resulting in a relative 34-fold increase in the estimated cost in genetic screening (P<0.01). CONCLUSION: This set of preliminary observations highlight the need for further state, nationwide, and international studies to understand the financial, personal, and societal impact that this discrepancy health care system in the use of genetic carrier screening portends. PMID- 25294714 TI - Can routine laboratory parameters predict adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy? AB - AIM: Our aim was to investigate whether any hematological changes readily detectable by simple complete blood count (CBC), as well as fasting and postprandial total serum bile acid (SBA) levels, have diagnostic values for the prediction of adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy (ICP). METHODS: A prospective, case control study was carried out including 217 pregnant women (117 women with ICP and 100 healthy controls). The main outcome measures investigated were preterm delivery, APGAR scores, and neonatal unit admission. A multivariate logistic regression model was used to identify the independent risk factors of adverse pregnancy outcomes. RESULTS: Compared with controls, women with ICP had significantly higher mean platelet volume (MPV) (mean 10.2+/-1.0 vs. 11.0+/-1.3; P<0.001) and platelet distribution width (PDW) (mean 13.1+/-2.3 vs. 14.7+/-2.8; P<0.001) values. Analysis with logistic regression revealed that the probability of preterm delivery did not increase until MPV levels exceeded 11.2 fL [odds ratio (OR)=2.68, 95% confidence interval (CI)=1.13-6.32, P=0.025], and total bilirubin levels exceeded 0.6 mg/dL (OR=3.13, 95% CI=1.21-8.09, P=0.019). Considering the low APGAR scores, only increased postprandial total SBA levels of >=51 MUmol/L were found to be predictive significantly (OR=3.02, 95% CI=1.07-8.53, P=0.037). CONCLUSIONS: Our study suggests that increased MPV and total bilirubin levels are associated with preterm delivery, and increased postprandial total SBA levels are predictive for low APGAR in ICP patients. PMID- 25294715 TI - Glucose measurements and gold standards. PMID- 25294716 TI - Large sample bounds on the survivor average causal effect in the presence of a binary covariate with conditionally ignorable treatment assignment. AB - A common problem when conducting an experiment or observational study for the purpose of causal inference is "censoring by death," in which an event occurring during the experiment causes the desired outcome value - such as quality of life (QOL) - not to be defined for some subjects. One approach to this is to estimate the Survivor Average Causal Effect (SACE), which is the difference in the mean QOL between the treated and control arms, considering only those individuals who would have had well-defined QOL regardless of whether they received the treatment of interest, where the treatment is imposed by the researcher in an experiment or by the subject in the case of an observational study. Zhang and Rubin [5] (Estimation of causal effects via principal stratification when some outcomes are truncated by "death". J Educ Behav Stat 2003;28:353-68) have proposed a methodology to calculate large sample bounds - bounds on the SACE that assume that the exact QOL distribution for each arm is known or that the finite sample size can be ignored - in the case of a randomized experiment. We examine a modification of these bounds in the case where a binary covariate describing each of the subjects is available and assignment to the treatment or control group is ignorable conditional on the covariate. Using a dataset involving an employment training program, we find that the use of the covariate does not substantially change the bounds in this case, although it does weaken the assumptions about the sample and thus make the bounds more widely applicable. However, simulations show that the use of a binary covariate can in some cases dramatically narrow the bounds. Extensions and generalizations to more complicated variants of this situation are discussed, although the amount of computation increases very quickly as the number of covariates and the number of possible values of each covariate increase. PMID- 25294717 TI - Practices and attitudes toward complementary and alternative medicine in inflammatory bowel disease: a survey of gastroenterologists. AB - BACKGROUND: Use of complementary and alternative medicine (CAM) is increasingly prevalent among patients with inflammatory bowel disease (IBD). We sought to characterize the practices and attitudes of IBD physician providers toward CAM. METHODS: A web-based survey was sent to non-trainee physician members of the American Gastroenterological Association with an interest in IBD. The survey included multiple-choice and Likert scale questions which queried physician perceptions of CAM and their willingness to discuss CAM with patients. RESULTS: The vast majority of respondents (80%) considered themselves IBD subspecialists with 75% holding academic appointments. Nearly a third reported initiating conversations on CAM in the majority of their patient interactions, while 90% perceived that a majority of their patients were reluctant to bring up the topic of CAM. Nearly three quarters (72%) of respondents felt comfortable discussing CAM, while those that did not most frequently cited lack of knowledge as the reason. More than half (55%) stated they had no systematic approach to discussing CAM. Most gastroenterologists (65%) reported no formal training in CAM. Most gastroenterologists had recommended use of probiotics, and nearly half had recommended acupuncture. A vast majority believed that there was adjunctive role for CAM in treatment of IBD. CONCLUSIONS: Academic IBD specialists were receptive to the use of CAM, and most felt that it had a role in the treatment of IBD, without necessarily compromising conventional therapy. Formal educational initiatives and societal recommendations on the use of CAM may facilitate a more systematic approach to its use in daily practice. PMID- 25294718 TI - Hypolipidaemic and haematological evaluation of the hydromethanolic extract of Ficus glumosa stem bark in alloxan-induced diabetic rats. AB - BACKGROUND: Diabetes mellitus is associated with dyslipidaemia and haematological disorders which lead to cardiovascular complications and anaemia respectively. In this study, hydromethanolic extract of Ficus glumosa was evaluated for its hypolipidaemic and haematological effects in alloxan-induced diabetic rats. METHODS: Treatment was done orally using 62.5, 125 and 250 mg/kg of F. glumosa extract (FGE) with glibenclamide (2 mg/kg) as standard reference drug for 21 days. At the end of the treatment, blood collected through direct heart puncture was used for evaluation of serum lipid profile and determination of haematological parameters. Organosomatic index evaluation of the liver, spleen and kidney was also done using standard procedures. RESULTS: All doses of the extract and glibenclamide (2 mg/kg) caused dose-dependent and significant (p<0.05) reduction in serum levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) of the treated rats when compared with the control group. The extract and glibenclamide produced significant (p<0.05) increase in the serum levels of high-density lipoprotein cholesterol (HDL-C) in the treated rats. The extract (62.5 mg/kg) and glibenclamide (2 mg/kg) caused a significant (p<0.05) increase in red blood cell (RBC), haemoglobin (Hb), packed cell volume (PCV) and mean corpuscular haemoglobin concentration (MCHC) in the treated rats when compared to the negative control group. However, FGE (62.5 mg/kg) and glibenclamide (2 mg/kg) produced a significant (p<0.05) decrease in mean corpuscular volume (MCV) value of the treated rats. FGE (125 and 250 mg/kg) produced a significant (p<0.05) increase in the organosomatic index of kidney in treated rats. CONCLUSIONS: The results suggest that F. glumosa may be of help in diabetes-induced anaemia and dyslipidaemia associated with diabetes mellitus. PMID- 25294719 TI - Tai Chi and meditation-plus-exercise benefit neural substrates of executive function: a cross-sectional, controlled study. AB - BACKGROUND: We report the first controlled study of Tai Chi effects on the P300 event-related potential, a neuroelectric index of human executive function. Tai Chi is a form of exercise and moving meditation. Exercise and meditation have been associated with enhanced executive function. This cross-sectional, controlled study utilized the P300 event-related potential (ERP) to compare executive network neural function between self-selected long-term Tai Chi, meditation, aerobic fitness, and sedentary groups. We hypothesized that because Tai Chi requires moderate aerobic and mental exertion, this group would show similar or better executive neural function compared to meditation and aerobic exercise groups. We predicted all health training groups would outperform sedentary controls. METHODS: Fifty-four volunteers (Tai Chi, n=10; meditation, n=16; aerobic exercise, n=16; sedentary, n=12) were tested with the Rockport 1 mile walk (estimated VO2 Max), a well-validated measure of aerobic capacity, and an ecologically valid visuo-spatial, randomized, alternating runs Task Switch test during dense-array electroencephalographic (EEG) recording. RESULTS: Only Tai Chi and meditation plus exercise groups demonstrated larger P3b ERP switch trial amplitudes compared to sedentary controls. CONCLUSIONS: Our results suggest long-term Tai Chi practice, and meditation plus exercise may benefit the neural substrates of executive function. PMID- 25294720 TI - Pigmented epithelioid melanocytoma with lymph node metastasis in a patient with uncontrolled atopic dermatitis. PMID- 25294721 TI - Transthoracic echocardiography in the diagnosis of coronary fistula. PMID- 25294722 TI - The Meth Project and Teen Meth Use: New Estimates from the National and State Youth Risk Behavior Surveys. AB - In this note, we use data from the national and state Youth Risk Behavior Surveys for the period 1999 through 2011 to estimate the relationship between the Meth Project, an anti-methamphetamine advertising campaign, and meth use among high school students. During this period, a total of eight states adopted anti-meth advertising campaigns. After accounting for pre-existing downward trends in meth use, we find little evidence that the campaign curbed meth use in the full sample. We do find, however, some evidence that the Meth Project may have decreased meth use among White high school students. PMID- 25294723 TI - Identification and characterization of a type-2 diacylglycerol acyltransferase (DGAT2) from Rhodosporidium diobovatum. AB - Triacylglycerols (TAGs), synthesized in the microsomal membranes of eukaryotes, serve as a primary storage form of carbon and energy in microorganisms. For this reason, TAGs produced by organisms have great potential to become biofuels and facilitate researchers to look for alternative renewable sources of energy. The present study describes the identification and functional characterization of a type-2 diacylglycerol acyltransferase from Rhodosporidium diobovatum, designated as RdDGAT, which catalyzed the final step of TAG synthesis. A full-length cDNA clone for RdDGAT was obtained, and its biological activity was proven by being expressed in a Saccharomyces cerevisiae quadruple mutant that was defective in TAG synthesis. Enzymatic assays were performed and finally the existence of TAGs in the transformed Saccharomyces cerevisiae quadruple mutant was determined using the method of thin-layer chromatography. Substrate preference experiments revealed that RdDGAT preferred unsaturated fatty acids over saturated ones. Through further analysis, we assume that the evolution and expression characteristics of the RdDGAT gene perhaps is the result of adaption to its oligotrophic and cold living environment. PMID- 25294724 TI - Studies of plant colonisation by closely related Bacillus amyloliquefaciens biocontrol agents using strain specific quantitative PCR assays. AB - Certain strains of Bacillus amyloliquefaciens can colonize plants and improve growth and stress management. In order to study these effects, bacterial growth dynamics on plants and in the rhizosphere are of interest calling for specific analytical tools. For that purpose, quantitative real-time PCR (qPCR) assays were developed in order to differentiate among three closely related B. amyloliquefaciens subsp. plantarum strains (UCMB5033, UCMB5036, UCMB5113) and to determine their levels with high accuracy. Oligonucleotide primers were designed for strain unique gene sequences and used for SYBR green based qPCR analysis. Standard curves covered a wide linear range (10(6)) of DNA amounts with the lowest detection level at 50 fg. Post-reaction melting curve analysis showed only a single product. Accurate threshold cycles were obtained, even in the presence of high excess of related Bacillus strains and total bacterial DNA from soil. Analysis of Bacillus colonisation after seed treatment of two oilseed rape cultivars (Oase and Ritz) grown on agar support showed a time dependent effect but that the bacteria mostly were found on root tissues and little on green tissues. The colonisation on plants grown in soil varied among the Bacillus strains where Oase seemed to house more bacteria than Ritz. Applied as a mixture, all three Bacillus strains co-existed on the roots of plants grown in soil. The qPCR assay in combination with other techniques will be a powerful tool to study plant interactions of these B. amyloliquefaciens biocontrol agents to further understand the requirements for successful interactions and improvement of plant properties. PMID- 25294725 TI - Sphaerisporangium dianthi sp. nov., an endophytic actinomycete isolated from a root of Dianthus chinensis L. AB - A novel actinomycete, designated strain NEAU-CY18(T), was isolated from the root of a Chinese medicinal plant Dianthus chinensis L and subjected to a polyphasic taxonomic study. The novel strain was found to develop spherical sporangia with non-motile spores on aerial mycelium. The cell-wall peptidoglycan was found to contain meso-diaminopimelic acid. The whole-cell sugars were identified as madurose, mannose, ribose, galactose and glucose. The phospholipid profile was found to contain diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, hydroxy-phosphatidylmethylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides and an unidentified phospholipid. The predominant menaquinones were identified as MK 9(H4), MK-9(H2) and MK-9(H6). The major fatty acids were identified as C17:0 10 methyl, iso-C16:0 and C16:0. EzTaxon-e analysis of the 16S rRNA gene sequence indicated that the strain belongs to the genus Sphaerisporangium and was most closely related to Sphaerisporangium cinnabarinum JCM 3291(T) (98.9 %) and Sphaerisporangium melleum JCM 13064(T) (98.3 %). Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain NEAU-CY18(T) forms a monophyletic clade with S. cinnabarinum JCM 3291(T), an association that was supported by a bootstrap value of 97 % in the neighbour-joining tree and also recovered with the maximum-likelihood algorithm. Comparisons of some phenotypic properties and low DNA-DNA relatedness values enabled the strain to be differentiated from S. cinnabarinum JCM 3291(T) and S. melleum JCM 13064(T). Therefore, it is concluded that strain NEAU-CY18(T) represents a novel Sphaerisporangium species, for which the name Sphaerisporangium dianthi sp. nov. is proposed. The type strain is NEAU-CY18(T) ( = CGMCC 4.7132(T) = DSM 46736(T)). PMID- 25294726 TI - Streptomyces vulcanius sp. nov., a novel actinomycete isolated from volcanic sediment. AB - A novel actinomycete, designated strain NEAU-C3(T), was isolated from volcanic sediment collected from Longwan, Jilin province, north China and characterized using a polyphasic approach. The organism was found to have morphological and chemotaxonomic characteristics typical of the members of the genus Streptomyces. EzTaxon-e analysis of the 16S rRNA gene sequence indicated strain NEAU-C3(T) to be most closely related to Streptomyces hygroscopicus subsp. ossamyceticus JCM 4965(T) (97.7 % sequence similarity) and Streptomyces torulosus JCM 4872(T) (97.7 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NEAU-C3(T) belongs within the genus Streptomyces and forms a separate subclade, an association that was supported by a bootstrap value of 72 % in the neighbour joining tree and also recovered with the maximum-likelihood algorithm. The DNA DNA hybridization values between strain NEAU-C3(T) and the two most closely related type strains were low enough to justify the assignment of the strain to a novel species. On the basis of these phenotypic, phylogenetic and chemotaxonomic characteristics, it is concluded that strain NEAU-C3(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces vulcanius sp. nov. is proposed. The type strain is NEAU-C3(T) (=CGMCC 4.7177(T)=DSM 42139(T)). PMID- 25294727 TI - Does the economy affect functional restoration outcomes for patients with chronic disabling occupational musculoskeletal disorders? AB - PURPOSE: To determine how the economy affects psychosocial and socioeconomic treatment outcomes in a cohort of chronic disabling occupational musculoskeletal disorder (CDOMD) patients who completed a functional restoration program (FRP). METHODS: A cohort of 969 CDOMD patients with active workers' compensation claims completed an FRP (a medically-supervised, quantitatively-directed exercise progression program, with multi-modal disability management). A good economy (GE) group (n = 532) was released to work during a low unemployment period (2005 2007), and a poor economy (PE) group (n = 437) was released during a higher unemployment period (2008-2010). Patients were evaluated upon admission for demographic and psychosocial variables, and were reassessed at discharge. Socioeconomic outcomes, including work return and work retention 1 year post discharge, were collected. RESULTS: Some significant differences in psychosocial self-report data were found, but most of the effect sizes were small, so caution should be made when interpreting the data. Compared to the PE group, the GE group reported more depressive symptoms and disability at admission, but demonstrated a larger decrease in depressive symptoms and disability and increase in self reported quality of life at discharge. The PE group had lower rates of work return and retention 1-year after discharge, even after controlling for other factors such as length of disability and admission work status. CONCLUSIONS: CDOMD patients who completed an FRP in a PE year were less likely to return to, or retain, work 1-year after discharge, demonstrating that a PE can be an additional barrier to post-discharge work outcomes. A difference in State unemployment rates of <3% (7 vs. 5%) had a disproportionate effect on patients' failure to return to (19 vs. 6%) or retain (28 vs. 15%) work. PMID- 25294729 TI - Dreaming the other's past: why remembering may still be relevant to psychoanalytic therapy, at least in some traditions. AB - Against the background of a reconstruction of the reasons for the vanishing role of remembering in the history of psychoanalysis, Botella's (2014, Int J Psychoanal, 95) arguments regarding the therapeutic significance of reconstruction and remembering and of the therapist's role are discussed. The difference between intellectual reconstruction and actual emotional remembering are underlined, the term regredience is compared to competing concepts such as equally suspended attention, countertransference and reverie. It is argued that to conceptualize the use of countertransferential associations for reconstructing past traumatic events is difficult with a monadic conception of the unconscious and problematic both in terms of truth claims and in terms of achieving a shared creative atmosphere in which therapist and patient participate alike. It is concluded that historical truth may be important for traumatic experiences, and that biographical reconstruction and change in the subjective life story help to make sense of neurotic patterns and integrate diachronic identity. PMID- 25294730 TI - CDC Kerala 17: Early detection of developmental delay/disability among children below 3 y in Kerala--a cross sectional survey. AB - OBJECTIVE: To conduct a community survey to understand the prevalence and type of developmental delay/disability among a representative state wide community sample of children below 3 y. METHODS: A state wide community based cross sectional survey was done with the help of the Integrated Child Development Services (ICDS) network in Kerala after giving one day training program at Child Development Centre (CDC), for one randomly selected anganwadi worker in each of the panchayath/municipal ward, from all districts of Kerala, to equip them to screen all children below 3 y in their anganwadi areas, using simple community screening tools like Trivandrum Developmental Screening Chart (TDSC) 0-3 and Language Evaluation Scale Trivandrum (LEST) 0-3. Those children with one or more item delay in TDSC or LEST were called to the developmental evaluation camps held at ICDS block level and trained pediatrician/medical officer re-evaluated the children with developmental delay. RESULTS: A total of 32,664 children below 3 y were screened across the state and overall 2.5% prevalence of developmental delay was observed using TDSC and 2.8% using LEST 0-3 y and 3.4% using TDSC and/or LEST positive. Out of the total 1,110 children clinically evaluated by a trained pediatrician, 69.3% children had developmental delay, 14.3% speech delay, 5.7% global delay, 5.3% gross motor delay and 3.6% suspected of hearing impairment. CONCLUSIONS: The study results showing 3.4% prevalence of developmental delay using TDSC and/or LEST by trained anganwadi workers or ASHA workers could be replicated in other states in India, under Rashtria Bal Swasthya Kariyakram. PMID- 25294731 TI - Quality of patient information on the internet for the treatment of anal fistula and anal fissure. PMID- 25294732 TI - Depression, anxiety and disease-related distress in couples affected by advanced lung cancer. AB - OBJECTIVES: Lung cancer patients and their partners are prone to high levels of depression and anxiety or severe distress related to the poor prognosis of the illness. However, there remain doubts regarding the extent to which this distress exceeds levels in the general population. This study explored levels of depression and generalized anxiety for comparison with matched data of a representative sample from the general population. Additionally, covariance of distress between the two partners, together with disease-specific components and differences were investigated. MATERIALS AND METHODS: In a cross-sectional survey, 54 pairs of lung cancer patients and their partners (n=108) were assessed for depression and anxiety, cancer-related distress, unmet needs and disclosure in communication. Comparisons between distress levels of participating couples and matched community-comparisons (n=162) were conducted. Additionally, multilevel analysis for estimating intra-dyadic associations of anxiety and depression was computed. Components of distress, needs and aspects of communication were explored via item mean values. RESULTS: Lung cancer patients as well as their partners exhibited significantly higher levels of depression and anxiety when compared to community-based comparison subjects (patients: mean difference of 1.01 for depression with a relative risk (RR) of 4.5 and 0.84 for anxiety with RR=6.1; partners: 1.17 for depression with RR=4.6 and 1.59 for anxiety with RR=7.6). Partial intraclass correlations between patients and partners were weak (PIC=.29 for depression; PIC=.21 for anxiety). Fear of progression emerged as main component of distress for both patients and partners, although differing stressors were described. CONCLUSION: Lung cancer-affected couples exhibit levels of depression and anxiety far exceeding those of the general community. In clinical practice, patients and partners should be assessed separately for distress against the background of weak intra-dyadic associations. In cases of significant depression or anxiety, referral for psychosocial treatment is indicated and has been shown to improve quality of life. PMID- 25294733 TI - Interaction effects between the 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype and family conflict on adolescent alcohol use and misuse. AB - AIMS: To investigate whether the effects of family conflict on adolescent drinking differed as a function of 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype cross-sectionally and prospectively in two independent samples of adolescents. DESIGN: Path analysis and multi-group analysis of two prospective datasets were conducted. SETTINGS: United States and United Kingdom. PARTICIPANTS: Sample 1 was 175 adolescents in the United States (mean age = 15 at times 1 and 2 with a 6-month interval); Sample 2 was 4916 adolescents in the United Kingdon (mean age = 12 at time 1 and 15 at time 2). MEASUREMENTS: In both samples, demographics, tri-allelic 5-HTTLPR genotype and perceived family conflict were assessed at time 1. Alcohol use (frequency of drinking) and alcohol misuse (frequency of intoxication, frequency of drinking three or more drinks, maximum number of drinks) were assessed at times 1 and 2. FINDINGS: A significant gene-environment interaction on alcohol misuse at time 1 was found in both sample 1 (beta = 0.57, P = 0.001) and sample 2 (beta = 0.19, P = 0.01), indicating that the 5-HTTLPR low-activity allele carriers exposed to higher levels of family conflict were more likely to engage in alcohol misuse than non-carriers. A significant gene-environment interaction effect on change in alcohol misuse over time was found only in sample 1 (beta = 0.48, P = 0.04) but not in sample 2. CONCLUSIONS: Compared with non-carriers, adolescents carrying the 5-HTTLPR low-activity allele are more susceptible to the effects of family conflict on alcohol misuse. PMID- 25294734 TI - Comparative study on gastrointestinal microbiota of eight fish species with different feeding habits. AB - AIMS: To reveal the effects of fish genotype, feeding habits and serum physiological index on the composition of gastrointestinal microbiota, eight fish species with four different feeding habits were investigated. METHODS AND RESULTS: The V1 to V3 regions of 16S rRNA gene were analysed by high-throughput sequencing (454 platform) to compare the gut microbiota of different fish species. A total of 551 995 high-quality sequences with an average length of 463 bp were obtained from the 48 samples. No significant difference was observed among the detected sequences obtained from fishes with different feeding habits (One-way anova, F = 1.003, P = 0.400), but the number of OTUs among different feeding habits was significantly different (One-way anova, F = 7.564, P < 0.001). Additionally, significant correlations were detected between the fish genotype and microbial composition (partial Mantel test, all P values = 0.001) in the stomach, foregut and hindgut. Moreover, different core intestinal microbiota was also noticed in the eight fish species with different feeding habits. CONCLUSIONS: Feeding habits and genotype clearly affected the gastrointestinal microbiota of fish. Moreover, the evolutionary process shaped the serum physiological indexes of fish. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provided much important information for developing commercial fish feeds. PMID- 25294735 TI - Enhanced early sensory outcome after nerve repair as a result of immediate post operative re-learning: a randomized controlled trial. AB - We assessed the use of guided plasticity training to improve the outcome in the first 6 months after nerve repair. In a multicentre randomized controlled trial, 37 adults with median or ulnar nerve repair at the distal forearm were randomized to intervention, starting the first week after surgery with sensory and motor re learning using mirror visual feedback and observation of touch, or to a control group with re-learning starting when reinnervation could be detected. The primary outcome at 3 and 6 months post-operatively was discriminative touch (shape texture identification test, part of the Rosen score). At 6 months, discriminative touch was significantly better in the early intervention group. Improvement of discriminative touch between 3 and 6 months was also significantly greater in that group. There were no significant differences in motor function, pain or in the total score. We conclude that early re-learning using guided plasticity may have a potential to improve the outcomes after nerve repair. LEVEL OF EVIDENCE II. PMID- 25294736 TI - Clinical outcomes of proximal row carpectomy versus four-corner arthrodesis for post-traumatic wrist arthropathy: a systematic review. AB - We conducted a systematic review of studies reporting clinical outcomes after proximal row carpectomy or to four-corner arthrodesis for scaphoid non-union advanced collapse or scapholunate advanced collapse arthritis. Seven studies (Levels I-III; 240 patients, 242 wrists) were evaluated. Significantly different post-operative values were as follows for four-corner arthrodesis versus proximal row carpectomy groups: wrist extension, 39 (SD 11o) versus 43 (SD 11o); wrist flexion, 32 (SD 10o) versus 36 (SD 11o); flexion-extension arc, 62 (SD 14o) versus 75 (SD 10o); radial deviation, 14 (SD 5o) versus 10 (SD 5o); hand grip strength as a percentage of contralateral side, 74% (SD 13) versus 67% (SD 16); overall complication rate, 29% versus 14%. The most common post-operative complications were non-union (grouped incidence, 7%) after four-corner arthrodesis and synovitis and clinically significant oedema (3.1%) after proximal row carpectomy. Radial deviation and post-operative hand grip strength (as a percentage of the contralateral side) were significantly better after four-corner arthrodesis. Four-corner arthrodesis gave significantly greater post-operative radial deviation and grip strength as a percentage of the opposite side. Wrist flexion, extension, and the flexion-extension arc were better after proximal row carpectomy, which also had a lower overall complication rate. PMID- 25294737 TI - Management of infraclavicular (Chuang Level IV) brachial plexus injuries: A single surgeon experience with 75 cases. AB - Infraclavicular brachial plexus injuries (Level IV in Chuang's classification) have special characteristics, including high incidences of associated scapular fractures, glenohumeral dislocations, and vascular injuries. In addition, there are specific difficulties in surgical dissection and nerve repairs, especially if surgery is delayed (>3 months). A total of 153 patients with Level IV brachial plexus injuries underwent surgery between 1987 and 2008 with 75 patients (average age 29 years) available for a minimum of 4 years follow-up. Accompanying fractures/dislocations were suffered by 48 (64%) patients, and 17 (23%) had associated vascular injuries. The most common nerves to be injured were the axillary and musculocutaneous nerves. Nerve grafts to the axillary, musculocutaneous, and radial nerves achieved impressive results, but less reliable outcomes were achieved with the median and ulnar nerves. Decompression and/or external neurolysis were also beneficial for nerve recovery. Some surgical tips are presented, and the use of the C-loop vascularized ulnar nerve graft and functioning muscle transfers are discussed. LEVEL OF EVIDENCE: IV. PMID- 25294738 TI - Clinical evolution, management, and resolution of type II necrotizing fasciitis. PMID- 25294739 TI - Cataract and quality of life in patients with glaucoma. AB - BACKGROUND: To assess the impact of cataract on quality of life (QoL) for patients with glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Two hundred forty-two patients with mild (n = 67), moderate (n = 80) or severe (n = 45) glaucoma and 50 controls (glaucoma suspects). Patients with cataract of any severity were included. METHODS: The following data were collected: sociodemographic information, phakic/pseudophakic status, cataract grade according to the Lens Opacities Classification System (LOCS) III, visual acuity and visual field test parameters. Glaucoma severity was stratified according to binocular visual field loss. Visually significant cataract was defined as: LOCS III criteria nuclear cataract >=3/6.9, cortical cataract >=3/5.9 or posterior subcapsular cataract >=2/5.9. MAIN OUTCOME MEASURES: Patients' QoL was measured using Rasch-transformed scores from the Glaucoma Activity Limitation-9 (GAL-9) questionnaire. Multiple linear regression models were used to determine the association between cataract and GAL-9 (logit) score. RESULTS: Fifty-six (23.1%) patients had at least one visually significant cataract. At least one visually significant cataract (standardized coefficient [beta] 1.19, 95% confidence interval 1.04-1.34, P = 0.011) and poor visual field index (better eye) (beta 1.47, 95% confidence interval 1.36-1.88, P < 0.001) were independently associated with worse GAL-9 score. CONCLUSIONS: Cataract influences glaucoma-related QoL among glaucoma patients of all severity levels and is an important cause of potentially reversible visual impairment among glaucoma patients. The Rasch analysed GAL-9 questionnaire is a useful metric to quantify visual disability related to cataract in glaucoma patients. PMID- 25294740 TI - Mammography and osteoporosis screening--clinical risk factors and their association with digital X-ray radiogrammetry bone mineral density. AB - The aim of this study was to study the association between digital X-ray radiogrammetry (DXR) T-score and clinical risk factors for osteoporosis. Women were recruited 2 d per wk at a single mammography screening center between year 2010 and 2012. Included women answered a questionnaire about risk factors for osteoporosis, and a radiograph of the nondominant hand was obtained for DXR analysis. Univariate associations between DXR T-score and risk factors were examined. A generalized linear regression model was fitted to independent variables with univariate associations at p<0.05. The multivariable model was reduced through manual backward elimination, with p>0.1 as the exclusion criterion. Seventy-six percent of the women chose to participate in the study (n=8810). The difference in number of daily mammograms performed on study vs nonstudy days was not significant. All univariate associations between DXR T score and potential risk factors were highly significant. The multivariable model included height, weight, age, right-handedness, menopause before age 45, alcohol consumption, cortisone treatment, rheumatic disease, and age*smoking status. The coefficient of determination of the model was 0.37. The association between risk factors for osteoporosis and DXR T-score is similar to previously reported associations with dual-energy X-ray absorptiometry. PMID- 25294741 TI - Foveal target repetitions reduce crowding. AB - Crowding is the limitation of peripheral vision by clutter. Objects that are easily identified when presented in isolation are hard to identify when presented flanked by similar close-by objects. It is often assumed that the signal of a crowded target is irretrievably lost because it is combined with the signals of the flankers. Here, we asked whether a target signal can be enhanced (or retrieved) by items presented far outside the crowding region. We investigated whether remote items matching a peripheral, crowded target enhanced discrimination compared to remote items not matching the target. In Experiment 1, we presented the remote item at different locations in the visual field and found that, when presented in the fovea, a matching remote item improved target discrimination compared to a nonmatching remote item. In Experiment 2, we varied stimulus onset asynchronies between target and remote items and found a strong effect when the remote item was presented simultaneously with the target. The effect diminished (or was absent) with increasing temporal separation. In Experiment 3, we asked whether semantic knowledge of a target was sufficient to improve target discrimination and found that this was not the case. We conclude that crowded target signals are not irretrievably lost. Rather, their accurate recognition is facilitated in the presence of remote items that match the target. We suggest that long-range grouping mechanisms underlie this "uncrowding" effect. PMID- 25294743 TI - The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. AB - The olfactory nerve consists mainly of olfactory receptor neurons and directly connects the nasal cavity with the central nervous system (CNS). Each olfactory receptor neuron projects a dendrite into the nasal cavity on the apical side, and on the basal side extends its axon through the cribriform plate into the olfactory bulb of the brain. Viruses that can use the olfactory nerve as a shortcut into the CNS include influenza A virus, herpesviruses, poliovirus, paramyxoviruses, vesicular stomatitis virus, rabies virus, parainfluenza virus, adenoviruses, Japanese encephalitis virus, West Nile virus, chikungunya virus, La Crosse virus, mouse hepatitis virus, and bunyaviruses. However, mechanisms of transport via the olfactory nerve and subsequent spread through the CNS are poorly understood. Proposed mechanisms are either infection of olfactory receptor neurons themselves or diffusion through channels formed by olfactory ensheathing cells. Subsequent virus spread through the CNS could occur by multiple mechanisms, including trans-synaptic transport and microfusion. Viral infection of the CNS can lead to damage from infection of nerve cells per se, from the immune response, or from a combination of both. Clinical consequences range from nervous dysfunction in the absence of histopathological changes to severe meningoencephalitis and neurodegenerative disease. PMID- 25294742 TI - Questioning the association between bisphosphonates and atypical femoral fractures. AB - Bisphosphonates are the first-line treatment for osteoporosis. Structurally, they are stable analogues of pyrophosphate and therefore exhibit a high affinity for bone mineral. They reduce bone loss by attenuating the ability of the osteoclast to resorb bone, decreasing activation frequency, and the rate of remodeling. Large prospective randomized placebo-control trials provide unequivocal evidence for a reduction in the incidence of fractures. Impressively, 40 years since their first use in patients, the safety profile of bisphosphonates has been equally reassuring. Questions have arisen lately as to whether bisphosphonates could cause atypical fractures, a rare type of atraumatic or minimal trauma femur fracture occurring below the great trochanter. This question has prompted calls for a broader examination of the long-term effects of bisphosphonate use. An attempt by the Food and Drug Administration to garner consensus and provide definitive views was not successful. This has led to continued anxiety among treating physicians and patients alike, resulting in an overall reduction in prescriptions for bisphosphonates and for osteoporosis therapies in general. Here, we provide an overview of the current data on atypical fractures and bisphosphonate use. PMID- 25294744 TI - Surface chemistry gradients on silicone elastomers for high-throughput modulation of cell-adhesive interfaces. AB - Combinatorial and high-throughput approaches to screening cell responses to material properties accelerate the speed of discovery and facilitate the identification of cell instructive cues or trends that may be missed by discrete sampling. However, these technologies have not yet been widely applied to materials with tissue-like stiffness. The fabrication of monotonically varying surface chemistry gradients on polydimethylsiloxane, an elastic biomaterial, and the influence of these engineered surfaces on protein adsorption and adherent cell morphology were explored in this study. Crosslinked networks of polydimethylsiloxane were functionalized with a hydrophobic self-assembled monolayer and then modified by spatiotemporally regulated ultraviolet ozonolysis to obtain gradients of oxygenated species ranging from ~10 degrees to ~100 degrees in water contact angle. Automated microscopy and image analysis of fibroblast cell morphology revealed a strong correlation between cell spreading and hydrophobicity. However, structural and functional analysis of the fibronectin interface indicated a proportional increase in cell spreading with adsorption, but a biphasic relationship with fibronectin conformation, underscoring the complexity of the adhesive interface. This work demonstrates the development of an elastomer surface modification platform that can be extended to future combinatorial studies of biological responses to chemical and mechanical material properties. PMID- 25294745 TI - How absorbed hydrogen affects the catalytic activity of transition metals. AB - Heterogeneous catalysis is commonly governed by surface active sites. Yet, areas just below the surface can also influence catalytic activity, for instance, when fragmentation products of catalytic feeds penetrate into catalysts. In particular, H absorbed below the surface is required for certain hydrogenation reactions on metals. Herein, we show that a sufficient concentration of subsurface hydrogen, H(sub) , may either significantly increase or decrease the bond energy and the reactivity of the adsorbed hydrogen, H(ad) , depending on the metal. We predict a representative reaction, ethyl hydrogenation, to speed up on Pd and Pt, but to slow down on Ni and Rh in the presence of H(sub) , especially on metal nanoparticles. The identified effects of subsurface H on surface reactivity are indispensable for an atomistic understanding of hydrogenation processes on transition metals and interactions of hydrogen with metals in general. PMID- 25294747 TI - Effect of rMnSOD on survival signaling in pediatric high risk T-cell acute lymphoblastic leukaemia. AB - Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that defends against oxidative damage due to reactive oxygen species (ROS). A new isoform of MnSOD with cytotoxic activity was recently discovered in liposarcoma cells. Here, we tested the effectiveness of a recombinant form of this isoform (rMnSOD) on leukemic T cells, Jurkat cells, and lymphocytes. Our results confirm that leukemic T cells can internalize rMnSOD and that rMnSOD causes apoptosis of 99% of leukemic cells without showing toxic effects on healthy cells. Using light and electron microscopy, we determined that an rMnSOD concentration of 0.067 MUM most effective on apoptosis induction. Western blot analysis showed that treatment with 0.067 MUM rMnSOD resulted in high expression of the pro-apoptotic protein Bax and low expression of the anti-apoptotic protein Bcl-2 in leukemia cells. Concerning signal transduction pathway no influence was observed after treatment except for Jurkat cells showing a slightly decreased expression of ERK phosphorylation. These results suggest that rMnSOD may be an effective and non toxic treatment option for T-cell leukemia. PMID- 25294746 TI - Weight loss increases follicle stimulating hormone in overweight postmenopausal women [corrected]. AB - OBJECTIVES: To examine the impact of a weight loss intervention upon follicle stimulating hormone (FSH) levels in postmenopause. METHODS: Participants were postmenopausal, overweight, glucose-intolerant women not using exogenous estrogen (n = 382) in the Diabetes Prevention Program. Women were randomized to intensive lifestyle change (ILS) with the goals of weight reduction of at least 7% of initial weight and 150 min per week of moderate-intensity exercise, metformin 850 mg twice a day, or placebo administered twice a day. RESULTS: Randomization to ILS led to small increases in FSH between baseline and 1-year follow-up vs. placebo (2.3 IU/l vs. -0.81 IU/l, P < 0.01). Increases in FSH were correlated with decreases in weight (r = -0.165, P < 0.01) and estradiol (E2) (r = -0.464, P < 0.0001) after adjustment for age, race/ethnicity, and randomization arm. Changes in FSH were still significantly associated with changes in weight even after adjustment for E2 levels. Metformin users had reductions in weight but non significant changes in FSH and E2 levels vs. placebo. CONCLUSIONS: Weight loss leads to small increases in FSH among overweight, postmenopausal women, potentially through pathways mediated by endogenous estrogen as well as other pathways. PMID- 25294748 TI - Relationships between oxygen consumption rate, viability, and subsequent development of in vivo-derived porcine embryos. AB - Oxygen consumption rate of in vivo-derived porcine embryos was measured, and its value as an objective method for the assessment of embryo quality was evaluated. Embryos were surgically collected 5 or 6 days after artificial insemination (AI), and oxygen consumption rate of embryos was measured using an embryo respirometer. The average oxygen consumption rate (F * 10(14)/mol s(-1)) of the embryos that developed to the compacted morula stage on Day 5 (Day 0 = the day of artificial insemination) was 0.58 +/- 0.03 (mean +/- standard error of the mean). The Day-6 embryos had consumption rates of 0.56 +/- 0.13, 0.87 +/- 0.06, and 1.13 +/- 0.07 at the early blastocyst, blastocyst, and expanded blastocyst stages, respectively, showing a gradual increase as the embryos developed. Just after collection, the average oxygen consumption rates of embryos that hatched and of those that did not hatch after culture were 0.60 +/- 0.04 and 0.50 +/- 0.04 for Day 5 (P = 0.08) and 1.05 +/- 0.09 and 0.77 +/- 0.05 for Day 6 (P < 0.05), respectively. The value and probability of discrimination by measuring the oxygen consumption rates of embryos to predict their hatching ability after culture were 0.56 and 63.6% for Day-5 embryos and 0.91 and 68.4% for Day-6 blastocysts, respectively. When Day-5 embryos were classified based on the oxygen consumption rate and then transferred non-surgically to recipient sows, three of the seven sows, to which embryos having a high oxygen consumption rate (>= 0.59) were transferred, became pregnant and farrowed a total of 20 piglets. However, none of the four sows, to which embryos having low oxygen consumption rate (< 0.59) were transferred, became pregnant. These results suggest that the viability of in vivo derived porcine embryos and subsequent development can be estimated by measuring the oxygen consumption rate. PMID- 25294749 TI - Effects of gonadotropin on Fas and/or FasL expression and proliferation in rat ovary. AB - Although gonadotropin is a dominant hormone involved in promoting ovarian follicle development in females, the mechanism by which gonadotropin regulates follicular development is still unknown. To systematically evaluate the effectiveness of the gonadotropin on apoptosis and proliferation of ovarian cells in vivo, rats were injected subcutaneously with eCG and/or anti-eCG antiserum. Equine chorionic gonadotropin treatment increased ovarian cell proliferation and expression of FSH receptors (FSHR) as revealed by increased immunostaining of proliferating cell nuclear antigen and FSHR in rat ovary. These effects did not occur in a follicular stage-dependent manner. Moreover, these actions were abolished by anti-eCG antiserum. However, granulosa cells exhibited more intense Fas- and FasL-positive immunostaining during all follicular stages in the anti eCG antiserum group. We used Western blot analysis to confirm these results; Fas and FasL protein contents in rat ovaries were decreased by eCG. Meanwhile, proliferating cell nuclear antigen and FSHR expression were upregulated by eCG. However, all these eCG-induced regulations were reversed by anti-eCG antiserum treatment. Furthermore, there were no significant differences between the anti eCG antiserum and control groups. These results indicate that eCG promotes follicular development via downregulation of death-inducer Fas/FasL expression and promotion of ovarian cell proliferation, which is partially mediated by FSHR. PMID- 25294750 TI - Follicles, germinal centers, and immune mechanisms in primary biliary cirrhosis. PMID- 25294751 TI - Structural and magnetic properties of CoGe(n)- (n=2-11) clusters: photoelectron spectroscopy and density functional calculations. AB - A series of cobalt-doped germanium clusters, CoGe(n)(-/0) (n=2-11), are investigated by using anion photoelectron spectroscopy combined with density functional theory calculations. For both anionic and neutral CoGe(n) (n=2-11) clusters, the critical size of the transition from exo- to endohedral structures is n=9. Natural population analysis shows that there is electron transfer from the Ge(n) framework to the Co atom at n=7-11 for both anionic and neutral CoGe(n) clusters. The magnetic moments of the anionic and neutral CoGe(n) clusters decrease to the lowest values at n=10 and 11. The transfer of electrons from the Gen framework to the Co atom and the minimization of the magnetic moments are related to the evolution of CoGe(n) structures from exo- to endohedral. PMID- 25294752 TI - Towards multifunctional materials incorporating elastomers and reversible redox active fragments. AB - This paper presents a novel and unique feature of metallacarboranes, consisting of the linkage of this redox electro-active site to a stretchable polymer. This is based on polyTHF, a known and applied material. This hybrid material has the two ends functionalized: one with the aforementioned redox molecule and the other with a terminal OH group, both linked by a molecular spring. Moreover, the redox electro-active molecules can be synthesized with either cobalt (cobaltabisdicarbollide) or with iron (ferrabisdicarbollide), species whose respective E(1/2) value differs by almost 1 V. The polymerization mechanism, based on an intermediate molecular crystal structure, is explained through an unexpected cyclization process of the dioxanate derivative of the metallacarboranes with an additional THF molecule. This is achieved in the absence of any metal or external electrophile. Surface functionalization of a Pt electrode by the electropolymerization of pyrrole doped with the pristine metallacarboranes and with the polyTHF hybrid materials is reported in this paper. PMID- 25294753 TI - [Long-term acting insulin analogues and the risks of hypoglycemic incidence]. AB - As recommendation for treatment of type 2 diabetes mellitus, incorporating individualization of therapeutic targets for patients with co-morbidities, for whom hypoglycemia increases the risk of complications. The sufficient target value is 60 mmol/mol of HbA1c under the guidelines of Czech Diabetesl Society. Insulin therapy becomes essential for a whole line of patients, including those of advanced age, in relation to duration of diabetes and progression of the disease. The Diabetes and Aging Study observed patients of 60 years age with diabetes, in which hypoglycemia ranked among the most frequent side effects of therapy and where incidence increased with age. It is necessary to select simple insulin regimens which are in accordance with the associated diseases and the age of the person. A therapy of basal insulin analogues, linked to a low risk rate of hypoglycemic incidence, enables combination with oral antidiabetic drugs and GLP 1 receptor agonists.Key words: basal insulin analogues - hypoglycemia - type 2 diabetes mellitus. PMID- 25294754 TI - [Factors causing damage and destruction of beta-cells of the islets of Langerhans in the pancreas]. AB - Insulin secretion in patients with manifested diabetes mellitus tends to disappear months to decades after the diagnosis, which is a clear sign of a gradual loss of pancreatic islet beta-cells. In our sample of 30 type 2 diabetic patients, whose disease manifested between 30 and 45 years of age, about a half have retained or even increased insulin secretion 30 years later, while the other half exhibit a much diminished or lost insulin secretion. Factors that can damage or destroy beta-cells can be divided into the following groups: Metabolic factors: hyperglycemia and glucotoxicity, lipotoxicity, hypoxia, reactive oxygen species; Pharmacological factors: antimicrobial medication pentamidine, SSRI antidepressants; Factors related to impaired insulin secretion: MODY type diabetes; Environmental toxic factors: rat poison Vacor, streptozotocin, polychlorinated and polybrominated hydrocarbons; Disorders of the exocrine pancreas: tumor infiltration, fibrous infiltration, chronic pancreatitis, cystic fibrosis; Infections, inflammation, autoimmunity, viral factors: Coxsackie viruses, H1N1 influenza, enteroviruses. We are currently working on finding other factors leading to beta-cell damage, studying their effect on apoptosis and necrosis and looking for possible protective factors to prevent this damage. We our increasing knowledge about the mechanisms of beta-cell damage and destruction we come ever closer to suggest measures for their prevention. In this review we offer a brief and simplified summary of some of the findings related to this area.Key words: pancreatic islet beta-cells of Langerhans - factors damaging or destroying beta-cells - insulin secretion. PMID- 25294755 TI - [Calcium, vitamin D and health]. AB - The authors describe briefly recent views on physiological, pathological and practical aspects of calcium and vitamin D. The sources of calcium are the nutrients, mammal milk and milk products as well as pharmaceutical products. Their beneficial and potentially hazardous effects are discussed. The insufficiency of vitamin D [25(OH)D3] is a global health problem and the necessity of monitoring of this hepatic metabolite (as a marker) is emphasized due to its role in physio-logical and pathological processes.Key words: calcium - physiological and pathophysiological effects - vitamin D. PMID- 25294756 TI - [SOLOSTAR study demonstrated high levels of patient satisfaction with the use of the insulin pen SoloStar(r) in the Czech Republic]. AB - INTRODUCTION: The aim of the observational, prospective and non-interventional survey SOLOSTAR was to obtain, in a clinical practice setting in the Czech Republic, information about patient satisfaction with the use of the pre-filled insulin pen SoloStar. METHODOLOGY: 1 805 patients suffering from type 1 or 2 diabetes who began using the pen SoloStar were observed for 3 to 4 months. Satisfaction of patients with SoloStar and with its particular features was evaluated in the group of all patients and in subgroups defined by demographic parameters including the type of handicap. Patients also compared SoloStar with the pens used before the entry into the survey. RESULTS: 98.3 % of patients rated overall satisfaction with the pen SoloStar as "excellent" and "good" (the highest and second highest rating on a 5-point scale). Demographic criteria, including visual handicap and manual dexterity handicap, did not have any statistically significant effect on the rating of the overall satisfaction with SoloStar. Features of SoloStar were rated as "excellent" and "good" by more than 90% of patients. Higher rating of some of the features of Solo-Star was awarded mostly by patients without prior experience with insulin application. Patients who used other insulin applicators before entering into the survey were more satisfied with the pen SoloStar than with the previously used applicator and most of them rated the use of SoloStar (93.1 %) and insulin application with SoloStar (83.5 %) as "much easier" and "easier" (the highest and second highest rating on a 5-point scale) in comparison with the previously used pen. CONCLUSION: The use of the pen SoloStar in a clinical practice setting in the Czech Republic is associated with high levels of satisfaction of patients, including handicapped patients. In addition, patients preferred SoloStar over insulin pens used before the entry into the survey.Key words: diabetes mellitus - insulin pen - patient satisfaction. PMID- 25294757 TI - [News and perspectives in insulin treatment]. AB - Insulin therapy is a therapeutic cornerstone in patients with type 1 diabetes and also in numerous patients with type 2 diabetes especially with longer history of diabetes. The initiation of insulin therapy in type 2 diabetes patients is often delayed which is at least partially due to suboptimal pharmacokinetic characteristics of available insulins. The development of novel insulins with more favorable characteristics than those of current insulins is therefore still ongoing. The aim of this paper is to review current knowledge of novel insulins that have been recently introduced to the market or are getting close to routine clinical use. We will also focus on the perspectives of insulin therapy in the long-term run including the alternative routes of insulin administration beyond its classical subcutaneous injection treatment.Key words: alternative routes of insulin administration - diabetes mellitus - hypoglycemia - insulin - insulin analogues. PMID- 25294758 TI - [Basal insulin glargine using a basal-bolus regimen in a common clinical practice: observational, non-interventional, multicenter, national project LINDA (Lantus in daily practice - safety and efficacy in basal bolus regimen)]. AB - OBJECTIVE: To evaluate the safety and efficacy of basal insulin glargine using a basal-bolus regimen in a common clinical practice setting in the Czech Republic. PATIENTS AND METHODS: The LINDA project was a non-interventional, multicenter (n = 255), national, observational project. A total of 4,998 patients with Type 1 and 2 diabetes mellitus (T1DM, T2DM) with predominantly insulin therapy (99,7 %), after switch on insulin glargine at basal-bolus regimen, were enrolled in this project. The patients were followed up for 6 months after initiation of the therapy with insulin glargine. The primary objective of the project was to investigate the incidence of severe hypoglycemic episodes during the treatment with basal insulin analogue glargine (Lantus(r)) in a common clinical practice setting. The se-condary endpoints were changes in glycosylated hemoglobin (HbA1c) levels, fasting plasma glucose (FPG), body weight, insulin dose, change of number of hypoglycemic episodes in comparison the previous therapy and the frequency of adverse effects. RESULTS: Severe hypoglycaemia were observed during treatment with insulin glargine at 0.8 % patients. When comparing the incidence of hypoglycemia with the previous therapy, we demonstrated a clinically and statistically significant reduction in their frequencies. The percentage of patients with hypoglycemic episodes (17.6 %), severe hypoglycemia (0.8 %) and severe nocturnal hypoglycemia (0.3 %) over the last month of treatment with insulin glargine using the basal-bolus regimen was consistently lower compared to the last month of treatment before initiation of this therapy (42.5 %, 17.6 %, and 13.8 % of the patients, respectively). In patients with T1DM, the incidence of hypoglycemia decreased from 37.80 +/- 15.95 episodes/patient/year to 8.76 +/- 4.38 epi-sodes/patient/year (p < 0.001) for all hypoglycemic episodes; from 5.64 +/- 3.27 episodes/patient/year to 0.0396 +/- 0.012 episodes/patient/year (p < 0.001) for severe hypoglycemia; and from 3.84 +/- 2.04 episodes/patient/year to 0.0096 +/- 0.003 episodes/patient/year (p < 0.001) for severe nocturnal hypoglycemia. In patients with T2DM, the incidence of hypoglycemia decreased from 12.48 +/- 7.57 episodes/patient/year to 1.68 +/- 0.78 episodes/patient/year (p < 0.001) for all hypoglycemic episodes; from 2.04 +/- 0.94 episodes/patient/year to 0.0132 +/- 0.005 episodes/patient/year (p < 0.001) for severe hypoglycemia; and from 1.32 +/- 0.77 episodes/patient/year to 0.0048 +/- 0.0008 episodes/patient/year (p < 0.001) for severe nocturnal hypoglycemia. A statistically significant improvement in the metabolic control was demonstrated when using insulin glargine. The glycated hemoglobin (HbA1c) decreased from 7.74 +/- 1.71 % to 6.43 +/- 1.39 % ( -1.31 +/- 0.32 %, p < 0.001) in patients with T1DM, and from 8.13 +/- 1.56 % to 6.72 +/- 1.40 % ( -1.41 +/- 0.28 %, p < 0.001) in patients with T2DM. A statistically significant (p < 0.001) increase in the number of patients with HbA1c < 5.4 % was further demonstrated. The decrease in fasting blood glucose (FBG) and 6-point blood sugar profile was also statistically significant in both types of diabetes (p < 0.001). Changes in therapy and subsequent treatment with insulin glargine were perceived positively by both physicians and patients. CONCLUSION: In the common clinical practice setting, the initiation of treatment with insulin glargine using the basal-bolus regime in patients with previous insulin therapy resulted in a reduction in the incidence of hypoglycemic events, including severe hypoglycemia and severe nocturnal hypoglycemia, and improved metabolic control in patients with diabetes (reduced glycated hemoglobin, fasting glucose values and 6-point blood glucose profile). Greater satisfaction with the current treatment was reported by both patients and physicians.Key words: basal-bolus regimen - diabetes mellitus - insulin glargine - observational project. PMID- 25294759 TI - [AGEs and RAGE - advanced glycation end-products and their receptor in questions and answers]. AB - Advanced glycation end products (AGEs) play an important role in the pathogenesis of chronic diseases and their complications, especially diabetic complications, atherosclerosis, complications of chronic kidney diseases and neurodegenerative diseases. These substances are formed via non-enzymatic glycation and their formation is potentiated in case of carbonyl stress. AGEs are represented by a heterogeneous group of compounds, e.g. carboxymethyllysine, pentosine, methylglyoxallysin dimer, vesperlysine, imidazolones etc. AGEs can modify proteins and so change their physical and chemical properties and can act also via specific receptors, among them RAGE (receptor for advanced glycation end products) is the best known but not the unique one. RAGE is a multiligand receptor capable to bind also HMGB1 (high mobility group box protein 1), S100 proteins or amyloid fibrils. RAGE - ligand interactions results to activation of a variety of signaling pathways including oxidative stress and activation of nuclear factor kappaB and subsequent proinflammatory response depending on the cell type. AGEs and RAGE together with further mechanisms - hexosamine pathway, polyol pathway, lipid metabolism disorder, activation of proteinkinase C, oxidative stress and inflammatory reaction take part in the pathogenesis of diabetic complications. Terapeuticaly it is possible to decrease endogenous formation of AGEs, influence the AGEs intake to the organism and their absorption in the intestine or stimulate their degradation.Key words: AGEs - advanced glycation end-products - carbonyl stress - diabetes mellitus - inflammation - oxidative stress - RAGE - receptor for AGEs - sRAGE. PMID- 25294760 TI - [Liver, kidneys and diabetes: three faces of HNF1B gene deficit]. AB - The renal cysts and diabetes syndrome (RCAD), also known as HNF1B-MODYor MODY5, is caused by the deletion or point mutation of HNF1B gene which leads to the depletion of HNF1B transcription factor. The main clinical components of RCAD include cystic kidney disease or other developmental anomalies of the kidneys and diabetes mellitus which typically manifests in the second decade of life or later. Renal disorders may lead to the development of chronic renal insufficiency already in childhood or young adulthood. The other symptoms include hepatic impairment - cholestatic jaundice in middle-aged patients, sometimes even neonatal cholestasis, atrophy of the pancreas with the impairment of exocrine pancreatic secretion and some congenital anomalies of the genital tract. As opposed to the other forms of MODY diabetes, the family history may not be positive because most of the deviations of HNF1B appear de novo. We associate RCAD in particular with adults suffering from diabetes and cystic kidney disease and/or cholestatic jaundice and children with cystic kidney disease of unclear etiology, even without the presence of diabetes. A supportive finding may be hypomagnesemia which occurs in up to 70 % of patients diagnosed with HNF1B related disease and hyperuricemia.Key words: HNF1B - MODY - RCAD - diabetes mellitus - cholestatic jaundice. PMID- 25294761 TI - [Problems of differential diagnosis of paraneoplastic hypoglycaemia]. AB - Paraneoplastic hypoglycaemia is relatively rare. The most common cause is insulinoma, tumour from pancreatic beta cells with insulin production. Fasting glycaemia together with hyperinsulinaemia during 24 hours of fasting is characteristically present. Endoscopic ultrasonography is the most sensitive method for localization of insulinoma, scintigraphy with labelled GLP-1 analogs and modified positron emission tomography are new perspective methods. Non-beta cells tumours are mesenchymal or epithelial tumours with huge size, slow growth and increased production of insulin like growth factor IGF-2 (IGF-2oma). Fasting hypoglycaemia in this case is associated with increased levels of total and free IGF-2 as well as big IGF-2 form. Due to suppression effect there are decreased levels of insulin, growth hormone and IGF-1 and ratio IGF-2/IGF-1 is typically increased. In opposite to insulinoma diagnosis of non-beta-cells tumour mostly precedes the occurrence of hypoglycaemia.Key words: insulin like growth factor-2 (IGF-2) - insulinoma - non-beta-cells tumours - paraneoplastic hypoglycaemia insulin. PMID- 25294762 TI - [Hypoglycemia as a limitation to the treatment of diabetes mellitus]. AB - In his paper, the author deals with hypoglycemia-related problems as the most frequent complication of the therapy for diabetes mellitus (DM). He points to threats that patients with hypoglycemia are exposed to, but also gives attention to risk groups of patients with regard to hypoglycemia development as well as different levels of the risk related to different antidiabetics.Key words: antidiabetics - diabetes mellitus - hypoglycemia. PMID- 25294763 TI - [Changes of bone metabolism in diabetics]. AB - The effect of impaired regulation of the glucose metabolism on the bone tissue metabolism is many-sided and very complicated. In most cases we observe an increased risk of fracture in people with diabetes. The reasons causing this condition are varied. Its main cause in diabetic patients is typically not the decrease in bone mineral density, it is rather deterioration of bone tissue and its structure. An important role of insulin and insulin resistance is beyond dispute, with numerous other factors at work, such as increased glycation of proteins, including increased glycation of collagen in bones, change in sclerostin production and levels, intervention in the pluripotent stem cells differentiation and reversal of their differentiation toward adipocytes and many more. Some antidiabetics, mainly oral, may also significantly contribute to the increased risk of fracture. Given the increasing incidence of both diseases, diabetes and osteoporosis, it will be also necessary to examine in greater detail their mutual relations and effects.Key words: antidiabetics - bone metabolism - diabetes mellitus - insulin resistance - osteoporosis. PMID- 25294764 TI - [Insulin resistance - its causes and therapy possibilities]. AB - Insulin resistance (IR) is defined as a condition where normal plasma free insuconcentrations induce a reduced response of the body. In the narrower sense we understand IR as the impairment of insulin action in the target structure which may arise at any level of the insulin signalling cascade. In the clinical conditions we usually define it as the impairment of insulin action in glucose metabolism, although it is true that the impairment may concern different effects of insulin and different cell structures. The characteristic feature of IR linked to the metabolic syndrome or Type 2 diabetes is defective signalling which affects PI3-kinase branch of insulin signalling cascade. Other insulin actions depending on the signalling through the Ras complex and MAP-kinase, may not be affected. Due to compensatory hyperinsulinemia they may be even increased. The article summarizes some recent findings regarding the structure and regulation of insulin signalling cascade and analyses selected primary and secondary causes of IR which include genetic and epigenetic factors, the microRNA regulation role, metabolic, humoral and immunological factors. The detailed knowledge of the causes of IR opens possibilities of its rational treatment. This is currently based on the treatment of curable causes of IR, i.e. consistent compensation of diabetes, weight reduction, regimen arrangements (diet, physical activity), re assessment of the need to use corticosteroids in therapy, treatment of coexisting conditions and possibly administration of metformin or pioglitazone.Key words: cytokines - insulin resistance - insulin signalling cascade. PMID- 25294765 TI - [Glycemic variability and continuous monitoring of glycemia]. AB - Blood glucose levels are not constant in ther human body even in physiological status. It fluctuates depending on food intake, exercise, psychological and other factors. Normally it fluctuates between 3.9 to 7.5 mmol/l and in fasting in the standard conditions it does not exceed even more narrow range 3.9 to 5.5 mmol/l. Fluctuations are more pronounced in patient with diabetes. Hyperglycemia is a common and basic pathology in diabetes, however, antidiabetic drug often cause hypoglycemia, both increasing the range for glucose fluctuations. The level of glucose fluctuation is called glycemic variability (GV). Glycemic variability is now a favorite target of scientific research in dia-betology. Increased glycemic variability is associated with hypoglycemia, possibly may contribute to chronic dia-betes complications and negatively influences quality of life of diabetic patients. Last but not least, thanks to the new technology of continuous glucose monitoring, we can better describe and measure it. Finally, glycemic variability emerges as a potentially important therapeutical target.Key words: continuous glucose monitoring - glycemic variability - insulin pump - sensor augmented pump. PMID- 25294766 TI - [Life expectancy of people with type 1 diabetes in the past and today]. AB - The life expectancy of Type 1 diabetes mellitus (T1DM) dramatically improved after the discovery of insulin in 1922, but was still 25 years shorter than that of non-diabetic population. Some people with T1DM, however, lived to the same age as a non-diabetic population and had no late complications of diabetes. They began to be awarded medals in appreciation of their long life with diabetes. They also became the subject of a research examining why they lived so long and what was the difference between them and those patients with T1DM, whose lives were much shorter. The paper deals with the differences observed in the 'medallists' and discusses various hypotheses that might account for them. It seems that reliable control of diabetes within the first 20 years following the diagnosis is very important, in relation to the existence of "glycemic memory" which may significantly affect life expectancy in the following years. Human lifespan in general has been linearly extended since the early 19th century and the same holds for lifespans of people with T1DM. This is due to the higher quality control of glycemia on the one hand, and a better prevention and treatment of complications. It is observed that the incidence of terminal stages of diabetic nephropathy has been dropping, the primary as well as secondary prevention of cardiovascular complications, cardiological treatment and heart surgery have been improving. Manifest proteinuria, diabetic neuropathy and hypertension appear to be major prognostic factors of increased mortality. If these indicators are not present, the life expectancy of patients with T1DM does not significantly differ from that of the non-diabetic population.Key words: diabetic nephropathy - glycemia - glycemic memory - ICHS - late complications of diabetes - mortality - prognosis - type1 diabetes mellitus. PMID- 25294767 TI - [Gliptins: a safe and effective treatment of diabetes mellitus]. AB - Gliptins are well recognized substances modulating incretin system via inhibition of dipeptidylpeptidase IV. Their efficacy was demonstrated both in monotherapy and in combination with metformin, where they act synergistically. Hence, a better control of diabetes might be assumed. This short article aims to show current trends in their prescription in the Czech Republic.Key words: diabetes mellitus - dipeptidylpeptidase IV - gliptins - oral antidiabetics. PMID- 25294768 TI - [How we indicate oral antidiabetics today (from metformin to gliptins and gliflozins)]. AB - Today we treat Type 2 diabetes mellitus by gradually adding antidiabetics from monotherapy to double, triple and multi combinations of medicines. Metformin still remains the first-line medicine, if well tolerated and not contraindicated. In the next step, we have a wide choice of 5 groups of medicines at least. The new algorithms used in the U.S.A. introduce some degree of preference for the incretin therapy (gliptins and incretin analogues) and the new groups of gliflozins over the standard treatments. In the near future, the indication of antidiabetics is therefore about to undergo big changes or at least a discussion about the preferences of the individual groups of medicines including those new to diabetology.Key words: gliflozins - gliptins - incretin therapy - metformin - oral antidiabetics - type 2 diabetes mellitus. PMID- 25294769 TI - [Receptor pro konecne produkty pokrocile glykace (RAGE) - klicovy hrac diabeticke angiopatie?]. AB - Receptor for advanced glycation end-products plays a crucial role in chronic diabetes complications. It is supposed to be involved in the development of all kinds of diabetic angiopathy. Advanced glycation end-products (AGEs) excessively accumulated in diabetes belong to the most important ligands of RAGE, however there are more potent activators of this receptor - especially alarmins, often involved in inflammatory reactions. Activated RAGE triggers pathways leading to excessive accumulation of AGEs, reactive oxygen species and sustained inflammatory reactions via NF-kappaB. Central role of RAGE in the pathogenesis of vascular changes in diabetes represents suitable target for new therapeutic or preventive approach.Key words: advanced glycation end-products - diabetes mellitus - hyperglycaemia - macroangiopathy - methylglyoxal - microangiopathy - receptor for advanced glycation end-products. PMID- 25294770 TI - [Diabetes mellitus and pancreatic cancer - cause or result?]. AB - Pancreatic cancer is a malignancy with a poor prognosis. Its increased incidence was observed in diabetic patients in the past. However, there is no evidence, whether diabetes is a risk factor for neoplastic transformation, or if it arises secondarily as a result of the tumor. The key is an early detection of cancer to perform pancreatectomy - the only possible curative therapy yet. This requires early diagnostic markers.Key words: diabetes mellitus - pancreatectomy - pancreatic cancer. PMID- 25294771 TI - [Diabetes mellitus and pancreatic cancer - cause or result?]. AB - Incretin glucagon like peptid-1 receptor agonists are also known as incretin mimetics. These are the new drugs for the treatment of type 2 diabetes, which have a significant antihyperglycemic effect. For the individual treatment can be used short- acting and long-acting drugs. In addition to glucose effect there are influenced another factors, especially weight and hypertension. The patophysiological mechanism of their action, pharmacological and clinical differences and their use in clinical practice are described.Key words: glucagon like peptid 1 - glucagon-like peptid 1 agonists short-acting/long-acting - clinical effects. PMID- 25294772 TI - [Personalized therapy for diabetes in retrospect and prospect]. AB - In recent years, the term "personalized medicine" has been increasingly mentioned in relation to the endeavours to tailor the pharmaceutical as well as regimen therapy to the needs and requirements of individual patients. The personalization of antidiabetic treatment has undergone a dramatic advancement in relation to the expansion of knowledge about diabetes. From the empirical it moved forward to the phenotypic level which made it possible to differentiate between individual types of diabetes. The pathogenetic personalization which began to be used within Type 2 diabetes in the 1960s, was based on the assumption that while insulin resistance predominates in some patients, others are mainly affected by insulin secretion deficit. Biostatistics-personalized medicine (evidence based medicine) gathered evidence based on which metformin was included in recommendations on the therapy for Type 2 diabetes as a first-line drug. Although randomized studies during the first decade of the 21st century did not prove superiority of any other treatment modality as an adjunctive therapy used with metformin, they brought with them individualization of the goals of glycemic con-trol. At present, personalization is heading towards the pharmacogenetic level that will enable in the near future individualized therapy in terms of choice of first-, second- and third-line drugs depending on the panel of key gene polymorphisms which characterize sensitivity of an individual to specific antidiabetics. Finally, the "tailor-maded therapy" should be chosen based on a synthesis of pathogenetic, biostatistic and pharmacogenetic knowledge that will reflect the translation of results of the basic biomedical research into the clinical practice.Key words: evidence based medicine - pathogenesis - personalized therapy - pharmacogenetics - type 2 diabetes. PMID- 25294773 TI - [First fixed dose combination perindopril arginine-indapamide-amlodipine: new approach in combination therapy in hypertension]. AB - Use of fixed combination of antihypertensive drugs clearly improves compliance to the pharmacological therapy, control of hypertension and prognosis. Based on the current guidelines triple antihypertensive therapy with RAS-blocker, calcium channel blocker (CCB) and diuretic represents the standard and best option. The article introduces first and innovative fixed triple combination of perindopril arginine + indapamide + amlodipine (Triplixam(r)). This type of therapy is suitable for patients already treated with free combinations of three antihypertensive drugs or in those hypertensives with uncontrolled hypertension on two antihypertensive molecules (approx. 60% of all hypertensive population). Fixed combination of perindopril arginine + indapamid + amlodipin is indicated also in severe hypertension (approx. 30% of pts). Large clinical data from various morbidity-mortality studies related to each of these substances are discussed as well as basic pharmacological characteristics. Based on the results from ADVANCE-CCB study combination of perindopril arginine + indapamide + CCB decreases total mortality in hypertension by 28%. Another discussed study-PIANIST confirmed significant antihypertensive effect of Triplixam(r) on large sample of patients with various stages of hypertension. Triplixam(r) in addition to that has very good tolerance with low side effects profile, flexibility of the dosages and large body of evidence of positive impact on prognosis of hypertensive patients. Use of Triplixam(r) may improve control of hypertension in the Czech Republic.Key words: amlodipine - fixed combination - hypertension - indapamide - perindopril arginine - therapy. PMID- 25294774 TI - Left ventricular external buttress technique for repair of ventricular septal perforation?. AB - Because of the difficulty in placing a suture-supporting extension to a non infarcted area, ventricular septal perforation repair in the presence of large myocardial infarctions can give rise to life-threatening tears or ruptures of the left ventricular free wall. We report a case of successful reinforcement of an infarction area from outside of the left ventricle using a large, thick polytetrafluoroethylene felt patch. After surgery, the patient was weaned from cardiopulmonary bypass without difficulty. Postoperative echocardiography revealed no residual shunting and he was alive without complications 3 years after surgery. PMID- 25294775 TI - Molecular characterization of Chilli leaf curl viruses infecting new host plant Petunia hybrida in India. AB - Petunia hybrida is an important ornamental plant grown in many countries including India. It is a good model plant for the study of genetics and molecular biology. During a survey in 2013-2014, severe leaf curling was observed on most of the P. hybrida grown in the Sikar district, Rajasthan. The infected plants were analyzed for begomovirus infection by rolling circular amplification (RCA) and sequenced. Full length sequences confirmed the association of monopartite begomovirus with betasatellites. Phylogenetic analysis showed the highest percentage of identity with Chilli leaf curl virus (ChLCuV) and therefore considered to be an isolate of ChLCuV. Recombination analysis showed that ChLCuV has broadened its host range by recombination process. To the best our knowledge, this is the first report of natural occurrence of ChLCuV on P. hybrida in India. PMID- 25294777 TI - Synthesis of nucleobase-functionalized carbon nanotubes and their hybridization with single-stranded DNA. AB - For the first time ssDNA (25-aptamer of mixed dA, dT, dG, and dC) was wrapped around functionalized single-walled carbon nanotubes (SWCNTs), whose external surfaces were attached to multiple triazole-(ethylene glycol)-dA ligands. This method of hybridization involved the formation of hydrogen bonds between dT of ssDNA and dA of functionalized SWCNTs. It deviates from the reported pi-pi stacking between the nucleobases of DNA and the external sidewalls of nanotubes. The structural properties of the functionalized SWCNTs and its ssDNA complex were characterized by spectroscopic (including CD and Raman), thermogravimetric, and microscopic (TEM) methods. The results thus obtained establish a new platform of DNA delivery by use of nanotubes as a new vehicle with great potential in biomedical applications and drug development. PMID- 25294776 TI - Anti-inflammatory and joint protective effects of extra-virgin olive-oil polyphenol extract in experimental arthritis. AB - The consumption of extra virgin olive oil (EVOO) in Mediterranean countries has shown beneficial effects. A wide range of evidence indicates that phenolic compounds present in EVOO are endowed with anti-inflammatory properties. In this work, we evaluated the effects of EVOO-polyphenol extract (PE) in a model of rheumatoid arthritis, the collagen-induced arthritis model in mice. On day 0, DBA 1/J mice were immunized with bovine type II collagen. On day 21, mice received a booster injection. PE (100 and 200 mg/kg) was orally administered once a day from days 29 to 41 to arthritic mice. We have demonstrated that PE decreases joint edema, cell migration, cartilage degradation and bone erosion. PE significantly reduced the levels of proinflammatory cytokines and prostaglandin E2 in the joint as well as the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1. Our data indicate that PE inhibits c-Jun N-terminal kinase, p38 and signal transducer and activator of transcription-3. In addition, PE decreases nuclear factor kappaB translocation leading to the down-regulation of the arthritic process. These results support the interest of natural diet components in the development of therapeutic products for arthritic conditions. PMID- 25294778 TI - Developmental trends in eating self-regulation and dietary intake in adolescents. AB - BACKGROUND: Research suggests that while capacities for self-regulation gradually improve during adolescence, eating habits become unhealthier. This study investigated whether there are age-related patterns in using self-regulation strategies (SRS) as well as in the self-reported dietary intake of fruit, vegetables, and unhealthy snacks. Moreover, we tested the strength of the relationship between different SRS (aimed at goal versus aimed at temptations) and dietary intake across different ages in adolescents. METHODS: In total, 11,392 adolescents (49.5% boys, age range 10-17) from nine European countries took part at this study. Eating SRS, daily intake of fruit, vegetables, and unhealthy snacks were assessed. RESULTS: Older adolescents had lower scores on self-regulation measures compared to younger ones, as well as lower intakes of fruit and vegetables and higher intakes of unhealthy snacks. The strength of the associations between strategies aimed at goal and unhealthy dietary intake, as well as between strategies aimed at temptation and healthy dietary intake, were generally small and/or insignificant. There were small age differences in the direction and strength of these patterns. CONCLUSION: The trends in SRS and dietary intake of fruit, vegetables and unhealthy snacks suggest that middle (13 15-years-old) but also older adolescents might benefit greatly from interventions focused on boosting eating SRS. PMID- 25294780 TI - MMPI-2-RF characteristics of individuals with interstitial cystitis. AB - OBJECTIVES: This study aimed to describe the psychological functioning of interstitial cystitis/bladder pain syndrome patients utilizing MMPI-2-RF scoring. METHODS: The MMPI-2 was administered to 60 individuals who reported a diagnosis of IC. Responses were scored in the MMPI-2-RF format. Fifty-one protocols were deemed valid. RESULTS: Elevations were discovered on scales FBS-r (symptom validity), RC1 (somatic complaints), and MLS (malaise). Participants were split into two groups based on extreme elevations on RC1; the high RC1 group produced higher scores on 39 scales including clinically significant elevations on 17 scales. CONCLUSION: Over 25% of this sample had an emotional component to their physical concerns. This knowledge about the psychological characteristics of IC patients may have clinical utility for physicians and other treatment providers. The results argue strongly for psychological evaluation as a component of IC diagnosis and treatment. Those with significant emotional overlay to their somatic complaints may be best managed through psychological interventions and minimally invasive treatments. PMID- 25294779 TI - Epistemology of contaminants of emerging concern and literature meta-analysis. AB - A meta-analysis was conducted to inform the epistemology, or theory of knowledge, of contaminants of emerging concern (CECs). The CEC terminology acknowledges the existence of harmful environmental agents whose identities, occurrences, hazards, and effects are not sufficiently understood. Here, data on publishing activity were analyzed for 12 CECs, revealing a common pattern of emergence, suitable for identifying past years of peak concern and forecasting future ones: dichlorodiphenyltrichloroethane (DDT; 1972, 2008), trichloroacetic acid (TCAA; 1972, 2009), nitrosodimethylamine (1984), methyl tert-butyl ether (2001), trichloroethylene (2005), perchlorate (2006), 1,4-dioxane (2009), prions (2009), triclocarban (2010), triclosan (2012), nanomaterials (by 2016), and microplastics (2022 +/- 4). CECs were found to emerge from obscurity to the height of concern in 14.1 +/- 3.6 years, and subside to a new baseline level of concern in 14.5 +/- 4.5 years. CECs can emerge more than once (e.g., TCAA, DDT) and the multifactorial process of emergence may be driven by inception of novel scientific methods (e.g., ion chromatography, mass spectrometry and nanometrology), scientific paradigm shifts (discovery of infectious proteins), and the development, marketing and mass consumption of novel products (antimicrobial personal care products, microplastics and nanomaterials). Publishing activity and U.S. regulatory actions were correlated for several CECs investigated. PMID- 25294781 TI - Cognitive adaptation theory as a predictor of adjustment to emerging adulthood for youth with and without type 1 diabetes. AB - OBJECTIVE: The purpose of the study was to determine whether resilience, defined by cognitive adaptation theory, predicted emerging adulthood outcomes among youth with and without type 1 diabetes. METHODS: Youth with (n=118) and without type 1 diabetes (n=122), who were part of a previous longitudinal study during adolescence, completed on-line questionnaires during their senior year of high school and one and two years later. They were average age 18, 53% female, and 93% white. Questionnaires assessed cognitive adaptation theory (CAT) indicators (self esteem, mastery, optimism) and psychological, relationship, behavioral, vocational, and, for those with diabetes, diabetes outcomes. RESULTS: The CAT index at baseline predicted reduced psychological distress, enhanced psychological well-being, increased friend support, reduced friend conflict, the presence of romantic relationships, reduced likelihood of romantic breakups, higher GPA, higher work satisfaction, and lower work stress during the transition to emerging adulthood. Among those with diabetes, the CAT index predicted better self-care behavior and revealed a marginal relation to better glycemic control. Analyses controlled for baseline levels when appropriate. Findings were stronger one year than two years post high school graduation, and findings were stronger for those with than without diabetes. Youth with diabetes also scored lower on the CAT index than youth without diabetes. CONCLUSIONS: These findings suggest that the implications of CAT include not only psychological health but also relationship, vocational, and diabetes outcomes. Those who score lower on CAT indicators should be identified as children so that interventions designed to enhance resilience can be implemented. PMID- 25294782 TI - Brain responses to olfactory and trigeminal exposure in idiopathic environmental illness (IEI) attributed to smells -- an fMRI study. AB - OBJECTIVE: Idiopathic environmental intolerance (IEI) to smells is a prevalent medically unexplained illness. Sufferers attribute severe symptoms to low doses of non-toxic chemicals. Despite the label, IEI is not characterized by acute chemical senses. Theoretical models suggest that sensitized responses in the limbic system of the brain constitute an important mechanism behind the symptoms. The aim was to investigate whether and how brain reactions to low-levels of olfactory and trigeminal stimuli differ in individuals with and without IEI. METHODS: Brain responses to intranasally delivered isoamyl acetate and carbon dioxide were assessed in 25 women with IEI and 26 non-ill controls using functional magnetic resonance imaging. RESULTS: The IEI group had higher blood oxygenated-level-dependent (BOLD) signal than controls in the thalamus and a number of, mainly, parietal areas, and lower BOLD signal in the superior frontal gyrus. The IEI group did not rate the exposures as more intense than the control group did, and there were no BOLD signal differences between groups in the piriform cortex or olfactory regions of the orbitofrontal cortex. CONCLUSIONS: The IEI reactions were not characterized by hyper-responsiveness in sensory areas. The results can be interpreted as a limbic hyperreactivity and speculatively as an inability to inhibit salient external stimuli. PMID- 25294783 TI - Electrophysiologic substrate in congenital Long QT syndrome: noninvasive mapping with electrocardiographic imaging (ECGI). AB - BACKGROUND: Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. METHODS AND RESULTS: Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation-recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312+/-30 ms versus 235+/-21 ms in control). Activation-recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119+/-19 ms/cm versus 2.0+/ 2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130+/-27 ms/cm in 12 symptomatic patients versus 98+/-19 ms/cm in 13 asymptomatic patients; P<0.05). CONCLUSIONS: LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification. PMID- 25294784 TI - New insights into the arrhythmogenic substrate of the long QT syndrome. PMID- 25294785 TI - New biomarkers and risk stratification in atrial fibrillation: simplicity and practicality matter. PMID- 25294787 TI - mTORC2 takes the longevity stAGE. PMID- 25294786 TI - Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. AB - BACKGROUND: Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. METHODS AND RESULTS: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. CONCLUSIONS: GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high sensitivity troponin I. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. PMID- 25294788 TI - The incremental hospital cost and length-of-stay associated with treating adverse events among Medicare beneficiaries undergoing TKA. AB - This paper estimates the incremental hospital resource consumption associated with treating selected adverse events experienced by Medicare beneficiaries undergoing TKA. This retrospective study, using the Medicare Provider Analysis and Review file, identified 353,650 Medicare beneficiaries who underwent a primary TKA during 2011. Overall, 11.82% of Medicare beneficiaries (MBs) undergoing TKA experienced at least one of the study's adverse events. MBs experiencing any adverse event consumed significantly more unadjusted hospital resources ($3110 cost) and had longer stays (1.3 days). The risk-adjusting incremental cost of treating adverse events ranged between $30,902 (pneumonia) and $2167 (hemorrhage or post-operative shock requiring transfusion). Most major adverse events occur infrequently; however when an adverse event occurs following TKA, it adds substantially to hospital costs. PMID- 25294789 TI - carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) regulates Notch signaling and vascular development in zebrafish. AB - BACKGROUND: The interplay between Notch and Vegf signaling regulates angiogenesis in the embryo. Notch signaling limits the responsiveness of endothelial cells to Vegf to control sprouting. Despite the importance of this regulatory relationship, much remains to be understood about extrinsic factors that modulate the pathway. RESULTS: During a forward genetic screen for novel regulators of lymphangiogenesis, we isolated a mutant with reduced lymphatic vessel development. This mutant also exhibited hyperbranching arteries, reminiscent of Notch pathway mutants. Positional cloning identified a missense mutation in the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) gene. Cad is essential for UDP biosynthesis, which is necessary for protein glycosylation and de novo biosynthesis of pyrimidine-based nucleotides. Using a transgenic reporter of Notch activity, we demonstrate that Notch signaling is significantly reduced in cad(hu10125) mutants. In this context, genetic epistasis showed that increased endothelial cell responsiveness to Vegfc/Vegfr3 signaling drives excessive artery branching. CONCLUSIONS: These findings suggest important posttranslational modifications requiring Cad as an unappreciated mechanism that regulates Notch/Vegf signaling during angiogenesis. PMID- 25294790 TI - India sets targets to slash neonatal mortality, with known interventions that haven't spread enough. PMID- 25294791 TI - Transumbilical Thoracoscopy Versus Conventional Thoracoscopy for Lung Wedge Resection: Safety and Efficacy in a Live Canine Model. AB - PURPOSE: Transumbilical single-port surgery has been associated with less postoperative pain and offers better cosmetic outcomes than conventional 3-port laparoscopic surgery. This study compares the safety and efficacy of transumbilical thoracoscopy and conventional thoracoscopy for lung wedge resection. METHODS: The animals (n = 16) were randomly assigned to the transumbilical thoracoscopic approach group (n = 8) or conventional thoracoscopic approach group (n = 8). Transumbilical lung resection was performed via an umbilical incision and a diaphragmatic incision. In the conventional thoracoscopic group, lung resection was completed through a thoracic incision. For both procedures, we compared the surgical outcomes, for example, operating time and operative complications; physiologic parameters, for example, respiratory rate and body temperature; inflammatory parameters, for example, white blood cell count; and pulmonary parameters, for example, arterial blood gas levels. The animals were euthanized 2 weeks after the surgery for gross and histologic evaluations. RESULTS: The lung wedge resection was successfully performed in all animals. There was no significant difference in the mean operating times or complications between the transumbilical and the conventional thoracoscopic approach groups. With regard to the physiologic impact of the surgeries, the transumbilical approach was associated with significant elevations in body temperature on postoperative day 1, when compared with the standard thoracoscopic approach. CONCLUSIONS: This study suggests that both approaches for performing lung wedge resection were comparable in efficacy and postoperative complications. PMID- 25294792 TI - Gastric supply manipulation to modulate ghrelin production and enhance vascularization to the cardia: proof of the concept in a porcine model. AB - INTRODUCTION: Selective embolization of the left-gastric artery (LGA) reduces levels of ghrelin and achieves significant short-term weight loss. However, embolization of the LGA would prevent the performance of bariatric procedures because the high-risk leakage area (gastroesophageal junction [GEJ]) would be devascularized. AIM: To assess an alternative vascular approach to the modulation of ghrelin levels and generate a blood flow manipulation, consequently increasing the vascular supply to the GEJ. MATERIALS AND METHODS: A total of 6 pigs underwent a laparoscopic clipping of the left gastroepiploic artery. Preoperative and postoperative CT angiographies were performed. Ghrelin levels were assessed perioperatively and then once per week for 3 weeks. Reactive oxygen species (ROS; expressed as ROS/mg of dry weight [DW]), mitochondria respiratory rate, and capillary lactates were assessed before and 1 hour after clipping (T0 and T1) and after 3 weeks of survival (T2), on seromuscular biopsies. A celiac trunk angiography was performed at 3 weeks. RESULTS: Mean (+/-standard deviation) ghrelin levels were significantly reduced 1 hour after clipping (1902 +/- 307.8 pg/mL vs. 1084 +/- 680.0; P = .04) and at 3 weeks (954.5 +/- 473.2 pg/mL; P = .01). Mean ROS levels were statistically significantly decreased at the cardia at T2 when compared with T0 (0.018 +/- 0.006 mg/DW vs. 0.02957 +/- 0.0096 mg/DW; P = .01) and T1 (0.0376 +/- 0.008 mg/DW; P = .007). Capillary lactates were significantly decreased after 3 weeks, and the mitochondria respiratory rate remained constant over time at the cardia and pylorus, showing significant regional differences. CONCLUSIONS: Manipulation of the gastric flow targeting the gastroepiploic arcade induces ghrelin reduction. An endovascular approach is currently under evaluation. PMID- 25294793 TI - Occupational Therapy Students' Perceptions of Spirituality in Training. AB - Spirituality is recognized as an essential and integral component of a holistic approach in occupational therapy practice. However, little is known about occupational therapy students' perceptions regarding spirituality in learning context. This study used qualitative exploratory, descriptive design to explore the occupational therapy students' perceptions about spirituality in training. Using purposive sampling, four semi-structured interviews were conducted with two students, a lecturer and an occupational therapist. In addition, two focus groups were conducted with students in order to collect data. Data collected were audio taped; transcribed and thematic analysis was used to identify themes. The analysis resulted in emergence of four themes: "Unique to every individual," "Spirituality in occupational therapy," "To be or not to be taught," and "The Real world." Participants perceived spirituality as an individually experienced. The study contributes to the body of knowledge base of occupational therapy education regarding spirituality. However, there is a need for guidelines to integrate spirituality in occupational therapy training. PMID- 25294794 TI - Religious convictions in patients with epilepsy-associated affective disorders: a controlled study from a psychiatric acute department. AB - Patients with epilepsy often have different mood symptoms and behavioral trait characteristics compared to the non-epileptic population. In the present prospective study, we aimed to assess differences in behavioral trait characteristics between acutely admitted, psychiatric in-patients with epilepsy associated depressive symptoms and gender/age-matched patients with major depression. Patients with epilepsy-associated depression had significantly higher scores for "religious convictions," "philosophical and intellectual interests" and "sense of personal destiny." These behavioral trait characteristics at admission or in clinical history should alert the psychiatrist and lead to closer examination for a possible convulsive disorder. PMID- 25294795 TI - Prevalence and risk factors of Clostridium difficile infection in patients hospitalized for flare of inflammatory bowel disease: a retrospective assessment. AB - BACKGROUND: Recent studies have identified a high frequency of Clostridium difficile infections in patients with active inflammatory bowel disease. AIMS: To retrospectively assess the determinants and results of Clostridium difficile testing upon the admission of patients hospitalized with active inflammatory bowel disease in a tertiary care centre and to determine the predicting factors of Clostridium difficile infections. METHODS: We reviewed all admissions from January 2008 and December 2010 for inflammatory bowel disease flare-ups. A toxigenic culture and a stool cytotoxicity assay were performed for all patients tested for Clostridium difficile. RESULTS: Out of 813 consecutive stays, Clostridium difficile diagnostic assays have been performed in 59% of inpatients. The independent predictive factors for the testing were IBD (ulcerative colitis: OR 2.0, 95% CI 1.5-2.9; p<0.0001) and colonic involvement at admission (OR 2.2, 95% CI 1.5-3.1, p<0.0001). Clostridium difficile infection was present in 7.0% of the inpatients who underwent testing. In a multivariate analysis, the only independent predictor was the intake of nonsteroidal anti-inflammatory drugs within the two months before admission (OR 3.8, 95% CI 1.2-12.3; p=0.02). CONCLUSIONS: Clostridium difficile infection is frequently associated with active inflammatory bowel disease. Our study suggests that a recent intake of nonsteroidal anti-inflammatory drugs is a risk factor for inflammatory bowel disease -associated Clostridium difficile infection. PMID- 25294796 TI - Is there a 'suboptimal' woody species height? A response to Scheffer et al. PMID- 25294797 TI - All-oral combination of lapatinib and capecitabine in patients with brain metastases from HER2-positive breast cancer--a phase II study. AB - PURPOSE: Approximately one-third of patients with advanced, HER2+ve breast cancer (BC) develop brain metastases (BMs). The aim of this study is to investigate efficacy and tolerability of the combination of lapatinib and capecitabine (LC) in HER2+ve BC patients with brain metastases (BCBM). PATIENTS AND METHODS: Between January 2011 and January 2013, 21 patients with HER2+ve BCBM were included. Sixteen patients (76.19%) progressed after whole brain radiotherapy (WBRT) and 5 patients (23.81%) were treatment-naive for BM. Patients received lapatinib (1250 mg/day continuously) and capecitabine (2000 mg/m2 on days 1-14 of a 21-day cycle). All patients were treated with trastuzumab either in the adjuvant or metastatic setting. No patients had received prior lapatinib and/or capecitabine. End-points were response rate (RR), progression free survival (PFS), overall survival (OS) and toxicity. RESULTS: The overall response rate (ORR) was 33.3% (7/21) and all were partial response. For patients receiving prior WBRT and patients receiving LC as first line treatment for BCBM the ORR was 31.2% (5/16) and 40.0% (2/5) respectively. Median PFS was 5.5 months. Median OS was 11 months. Treatment-related adverse events were manageable. Grade 3-4 toxicities were hand-foot syndrome (14.3%), diarrhea (14.3%), nausea/vomiting (9.5%), mucositis (4.8%), and skin rash (4.8%). CONCLUSION: The combination of LC is active and well-tolerated treatment in patients with HER2+ve BCBM. PMID- 25294798 TI - Ocular delivery of flurbiprofen based on Eudragit((r)) E-flurbiprofen complex dispersed in aqueous solution: preparation, characterization, in vitro corneal penetration, and ocular irritation. AB - A novel ophthalmic formulation based on the ionic complexation between Eudragit E 100 (EU) and flurbiprofen (FB) is proposed. The selected complex composition, named EU-FBH50 Cl50 , had the basic groups of EU completely neutralized with equal molar amounts of FB and HCl. This complex, obtained in the solid state, exhibited a high aqueous compatibility producing a colloidal dispersion with a high positive electrokinetic potential, in which more than 99% of FB was ionically condensed with EU. In bicompartimental Franz cells, FB diffusion from the complex was very slow. However, dispersion in 0.9% NaCl increased the FB release through an ionic exchange, providing an optimal constant rate of delivery. Corneal FB permeation from 0.1% EU-FBH50 -Cl50 dispersed in 0.9% NaCl solution was substantially more effective compared with 0.1% FB solution, EU FBH50 -Cl50 (Dex), or Tolerane((r)) (a marketed formulation). This complex formulation was shown to be innocuous for rabbit ocular tissues because no irritant effects were evidenced. PMID- 25294799 TI - Disciformycins A and B: 12-membered macrolide glycoside antibiotics from the myxobacterium Pyxidicoccus fallax active against multiresistant staphylococci. AB - Two macrolide glycosides with a unique scaffold were isolated from cultures of the myxobacterium Pyxidicoccus fallax. Their structures, including absolute configurations, were elucidated by a combination of NMR, MS, degradation, and molecular modeling techniques. Analysis of the proposed biosynthetic gene cluster led to insights into the biosynthesis of the polyketide and confirmed the structure assignment. The more active compound, disciformycin B, potently inhibits methicillin- and vancomycin-resistant Staphylococcus aureus. PMID- 25294800 TI - Peripheral blood mononuclear cells as a potential source of biomarkers to test the efficacy of weight-loss strategies. AB - OBJECTIVES: Peripheral blood mononuclear cells (PBMC) constitute an easily obtainable blood cell fraction useful in nutrition and obesity studies. Our aim was to study the potential use of PBMC to reflect metabolic recovery associated with weight loss in rats. METHODS: By real-time PCR, the fasting response of key energy homeostatic genes in PBMC samples of control and cafeteria-obese rats and of rats fed a control diet after the intake of a cafeteria diet (post-cafeteria model) was analyzed. RESULTS: Fasting caused decreased mRNA expression of lipogenic (Fasn and Srebp1a) and adipogenic (Ppargamma) genes in PBMC, whereas it increased the expression of the key beta-oxidation gene Cpt1a and the orexigenic gene Npy. Fasting response of the genes studied was impaired in cafeteria-obese animals but was recovered in post-cafeteria rats, which showed a significant body weight decrease and normalization of adipose and metabolic parameters. Npy expression analyzed in PBMC has been revealed to be especially useful as a marker of fasting sensitivity, as its fasting response is not affected by the age of the animals and it is recovered even after shorter time of exposure to a balanced diet. CONCLUSIONS: PBMC reflect homeostatic balance recovery associated with weight loss in obese animals, when reverting from a hyperlipidic to a control balanced diet. PMID- 25294801 TI - DNA-PKcs deficiency inhibits glioblastoma cell-derived angiogenesis after ionizing radiation. AB - DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a critical role in non-homologous end-joining repair of DNA double-strand breaks (DSB) induced by ionizing radiation (IR). Little is known, however, regarding the relationship between DNA-PKcs and IR-induced angiogenesis; thus, in this study we aimed to further elucidate this relationship. Our findings revealed that lack of DNA-PKcs expression or activity sensitized glioma cells to radiation due to the defective DNA DSB repairs and inhibition of phosphorylated Akt(Ser473) . Moreover, DNA-PKcs deficiency apparently mitigated IR-induced migration, invasion and tube formation of human microvascular endothelial cell (HMEC-1) in conditioned media derived from irradiated DNA-PKcs mutant M059J glioma cells or M059K glioma cells that have inhibited DNA-PKcs kinase activity due to the specific inhibitor NU7026 or siRNA knockdown. Moreover, IR-elevated vascular endothelial growth factor (VEGF) secretion was abrogated by DNA-PKcs suppression. Supplemental VEGF antibody to irradiated-conditioned media was negated enhanced cell motility with a concomitant decrease in phosphorylation of the FAK(Try925) and Src(Try416) . Furthermore, DNA-PKcs suppression was markedly abrogated in IR-induced transcription factor hypoxia inducible factor-1alpha (HIF-1alpha) accumulation, which is related to activation of VEGF transcription. These findings, taken together, demonstrate that depletion of DNA-PKcs in glioblastoma cells at least partly suppressed IR-inflicted migration, invasion, and tube formation of HMEC-1 cells, which may be associated with the reduced HIF-1alpha level and VEGF secretion. Inhibition of DNA-PKcs may be a promising therapeutic approach to enhance radio-therapeutic efficacy for glioblastoma by hindering its angiogenesis. PMID- 25294802 TI - Detection of Bacillus anthracis spores by super-paramagnetic lateral-flow immunoassays based on "Road Closure". AB - Detection of Bacillus anthracis in the field, whether as a natural infection or as a biothreat remains challenging. Here we have developed a new lateral-flow immunochromatographic assay (LFIA) for B. anthracis spore detection based on the fact that conjugates of B. anthracis spores and super-paramagnetic particles labeled with antibodies will block the pores of chromatographic strips and form retention lines on the strips, instead of the conventionally reported test lines and control lines in classic LFIA. As a result, this new LFIA can simultaneously realize optical, magnetic and naked-eye detection by analyzing signals from the retention lines. As few as 500-700 pure B. anthracis spores can be recognized with CV values less than 8.31% within 5 min of chromatography and a total time of 20 min. For powdery sample tests, this LFIA can endure interference from 25% (w/v) milk, 10% (w/v) baking soda and 10% (w/v) starch without any sample pre treatment, and has a corresponding detection limit of 6*10(4) spores/g milk powder, 2*10(5) spores/g starch and 5*10(5) spores/g baking soda. Compared with existing methods, this new approach is very competitive in terms of sensitivity, specificity, cost and ease of operation. This proof-of-concept study can also be extended for detection of many other large-sized analytes. PMID- 25294803 TI - Single amino acid substitution in homogentisate 1,2-dioxygenase is responsible for pigmentation in a subset of Burkholderia cepacia complex isolates. AB - The Burkholderia cepacia complex (Bcc) is a group of Gram-negative bacilli that are ubiquitous in the environment and have emerged over the past 30 years as opportunistic pathogens in immunocompromised populations, specifically individuals with cystic fibrosis (CF) and chronic granulomatous disease. This complex of at least 18 distinct species is phenotypically and genetically diverse. One phenotype observed in a subset of Burkholderia cenocepacia (a prominent Bcc pathogen) isolates is the ability to produce a melanin-like pigment. Melanins have antioxidant properties and have been shown to act as virulence factors allowing pathogens to resist killing by the host immune system. The melanin-like pigment expressed by B. cenocepacia is produced through tyrosine catabolism, specifically through the autoxidation and polymerization of homogentisate. Burkholderia cenocepacia J2315 is a CF clinical isolate that displays a pigmented phenotype when grown under normal laboratory conditions. We examined the amino acid sequences of critical enzymes in the melanin synthesis pathway in pigmented and non-pigmented Bcc isolates, and found that an amino acid substitution of glycine for arginine at amino acid 378 in homogentisate 1,2 dioxygenase correlated with pigment production; we identify this as one mechanism for expression of pigment in Bcc isolates. PMID- 25294804 TI - Factors affecting the depth of burns occurring in medical institutions. AB - INTRODUCTION: Most cases of burns occurring in medical institutions are associated with activities involving heat. It is very difficult to detect these burns. To date, there are few reports on burns occurring in medical institutions. The purpose of this paper was to analyze the etiology of burns occurring in medical institutions and to elucidate the factors affecting burn depth. METHODS: We conducted a retrospective analysis of the medical records of patients who visited our center from April 2008 to February 2013. This study enrolled all patients with burns occurring in the medical institution during or related to treatment. We excluded burn patients whose burns were not related to treatment (for example, we excluded patients with scalding burns that occurred in the hospital cafeteria and pediatric patients with hot water burns from the water purifier). However, patients with burns that occurred in the recovery room after general anesthesia were included. RESULTS: A total of 115 patients were enrolled in this study. The average patient age was 41.5 years, with more women than men (M:F=31:84). There were 29 cases (25.3%) of superficial burns (first-degree and superficial second-degree) and 86 cases (74.7%) of deep burns (deep second-degree and third-degree). Hot packs were the most common cause of burns (27 cases, 23.5%), followed by laser therapy, heating pads, and grounding pads, accounting for 15 cases each. There were 89 cases (77.4%) of contact burns and 26 cases (22.6%) of non-contact burns. The most common site of burns was the lower extremities (41 cases, 35.7%). The burn site and contact burns were both factors affecting burn depth. The rate of deep burns was higher in patients with contact burns than in those with non-contact burns (odds ratio 4.26) and was associated with lower body burns (odds ratio 2.85). CONCLUSION: In burns occurring in medical institutions, there is a high probability of a deep burn if it is a contact burn or occurs in the lower body. Therefore, safety guidelines are needed for the use of hot packs, heating pads, and grounding pads to prevent such incidents. PMID- 25294805 TI - Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers. AB - Upregulated expression and activation of human telomerase reverse transcriptase (hTERT) is a hallmarker of lung tumorigenesis. However, the mechanism underlying the aberrant hTERT activity in lung cancer cells remains poorly understood. In this study, we found the transcriptional co-activator CBP as a new hTERT promoter binding protein that regulated hTERT expression and tumor growth in lung adenocarcinoma cells using a biotin-streptavidin-bead pulldown technique. Chromatin immunoprecipitation assay verified the immortalized cell and tumor cell specific binding of CBP on hTERT promoter. Overexpression of exogenous CBP upregulated the expression of the hTERT promoter-driven luciferase and endogenous hTERT protein in lung cancer cells. Conversely, inhibition of CBP by CBP-specific siRNA or its chemical inhibitor repressed the expression of hTERT promoter-driven luciferase and endogenous hTERT protein as well as telomerase activity. Moreover, inhibition of CBP expression or activity also significantly reduced the proliferation of lung cancer cells in vitro and tumor growth in an xenograft mouse model in vivo. Immunohistochemical analysis of tissue microarrays of lung cancers revealed a positive correlation between CBP and hTERT. Importantly, the patients with high CBP and hTERT expression had a significantly shorter overall survival. Furthermore, CBP was found to interact with and acetylate transactivator Sp1 in lung cancer cells. Inhibition of CBP by CBP-specific siRNA or its chemical inhibitor significantly inhibited Sp1 acetylation and its binding to the hTERT promoter. Collectively, our results indicate that CBP contributes to the upregulation of hTERT expression and tumor growth, and overexpression of CBP predicts poor prognosis in human lung cancers. PMID- 25294806 TI - GUCY2C lysosomotropic endocytosis delivers immunotoxin therapy to metastatic colorectal cancer. AB - The emergence of targeted cancer therapy has been limited by the paucity of determinants which are tumor-specific and generally associated with disease, and have cell dynamics which effectively deploy cytotoxic payloads. Guanylyl cyclase C (GUCY2C) may be ideal for targeting because it is normally expressed only in insulated barrier compartments, including intestine and brain, but over-expressed by systemic metastatic colorectal tumors. Here, we reveal that GUCY2C rapidly internalizes from the cell surface to lysosomes in intestinal and colorectal cancer cells. Endocytosis is independent of ligand binding and receptor activation, and is mediated by clathrin. This mechanism suggests a design for immunotoxins comprising a GUCY2C-directed monoclonal antibody conjugated through a reducible disulfide linkage to ricin A chain, which is activated to a potent cytotoxin in lysosomes. Indeed, this immunotoxin specifically killed GUCY2C expressing colorectal cancer cells in a lysosomal- and clathrin-dependent fashion. Moreover, this immunotoxin reduced pulmonary tumors>80% (p<0.001), and improved survival 25% (p<0.001), in mice with established colorectal cancer metastases. Further, therapeutic efficacy was achieved without histologic evidence of toxicity in normal tissues. These observations support GUCY2C targeted immunotoxins as novel therapeutics for metastatic tumors originating in the GI tract, including colorectum, stomach, esophagus, and pancreas. PMID- 25294808 TI - Epigenetic signatures of alcohol abuse and hepatitis infection during human hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Deregulated DNA methylation landscapes are ubiquitous in human cancers. Interpretation of epigenetic aberrations in HCC is confounded by multiple etiologic drivers and underlying cirrhosis. We globally profiled the DNA methylome of 34 normal and 122 liver disease tissues arising in settings of hepatitis B (HBV) or C (HCV) viral infection, alcoholism (EtOH), and other causes to examine how these environmental agents impact DNA methylation in a manner that contributes to liver disease. Our results demonstrate that each 'exposure' leaves unique and overlapping signatures on the methylome. CpGs aberrantly methylated in cirrhosis-HCV and conserved in HCC were enriched for cancer driver genes, suggesting a pathogenic role for HCV-induced methylation changes. Additionally, large genomic regions displaying stepwise hypermethylation or hypomethylation during disease progression were identified. HCC-HCV/EtOH methylomes overlap highly with cryptogenic HCC, suggesting shared epigenetically deregulated pathways for hepatocarcinogenesis. Finally, overlapping methylation abnormalities between primary and cultured tumors unveil conserved epigenetic signatures in HCC. Taken together, this study reveals profound epigenome deregulation in HCC beginning during cirrhosis and influenced by common environmental agents. These results lay the foundation for defining epigenetic drivers and clinically useful methylation markers for HCC. PMID- 25294809 TI - Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism. AB - NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure/function to the most common p53 missense mutant (p53-R175H). We investigated the mechanism by which ZMC1 reactivates p53-R175H and provide evidence that ZMC1: 1) restores WT structure by functioning as a zinc metallochaperone, providing an optimal concentration of zinc to facilitate proper folding; and 2) increases cellular reactive oxygen species that transactivate the newly conformed p53-R175H (via post-translational modifications), inducing an apoptotic program. We not only demonstrate that this zinc metallochaperone function is possessed by other zinc-binding small molecules, but that it can reactivate other p53 mutants with impaired zinc binding. This represents a novel mechanism for an anti-cancer drug and a new pathway to drug mutant p53. SIGNIFICANCE: We have elucidated a novel mechanism to restore wild-type structure/function to mutant p53 using small molecules functioning as zinc metallochaperones. The pharmacologic delivery of a metal ion to restore proper folding of a mutant protein is unique to medicinal chemistry and represents a new pathway to drug mutant p53. PMID- 25294810 TI - The nuclear import of ribosomal proteins is regulated by mTOR. AB - Mechanistic target of rapamycin (mTOR) is a central component of the essential signaling pathway that regulates cell growth and proliferation by controlling anabolic processes in cells. mTOR exists in two distinct mTOR complexes known as mTORC1 and mTORC2 that reside mostly in cytoplasm. In our study, the biochemical characterization of mTOR led to discovery of its novel localization on nuclear envelope where it associates with a critical regulator of nuclear import Ran Binding Protein 2 (RanBP2). We show that association of mTOR with RanBP2 is dependent on the mTOR kinase activity that regulates the nuclear import of ribosomal proteins. The mTOR kinase inhibitors within thirty minutes caused a substantial decrease of ribosomal proteins in the nuclear but not cytoplasmic fraction. Detection of a nuclear accumulation of the GFP-tagged ribosomal protein rpL7a also indicated its dependence on the mTOR kinase activity. The nuclear abundance of ribosomal proteins was not affected by inhibition of mTOR Complex 1 (mTORC1) by rapamycin or deficiency of mTORC2, suggesting a distinctive role of the nuclear envelope mTOR complex in the nuclear import. Thus, we identified that mTOR in association with RanBP2 mediates the active nuclear import of ribosomal proteins. PMID- 25294811 TI - Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer. AB - In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer. Using pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in CD11b+/Gr1(high/low) MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both cancer models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represents a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression. PMID- 25294812 TI - Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway. AB - Ciclopirox olamine (CPX), a fungicide, has been demonstrated as a potential anticancer agent. However, the underlying anticancer mechanism is not well understood. Here, we found that CPX induced autophagy in human rhabdomyosarcoma (Rh30 and RD) cells. It appeared that CPX-induced autophagy was attributed to induction of reactive oxygen species (ROS), as N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, prevented this process. Furthermore, we observed that CPX induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK, which was also blocked by NAC. However, only inhibition of JNK (with SP600125) or expression of dominant negative c-Jun partially prevented CPX induced autophagy, indicating that ROS-mediated activation of JNK signaling pathway contributed to CPX-induced autophagy. Of interest, inhibition of autophagy by chloroquine (CQ) enhanced CPX-induced cell death, indicating that CPX-induced autophagy plays a pro-survival role in human rhabdomyosarcoma cells. Our finding suggests that the combination with autophagy inhibitors may be a novel strategy in potentiating the anticancer activity of CPX for treatment of rhabdomyosarcoma. PMID- 25294813 TI - The Hippo transducer TAZ as a biomarker of pathological complete response in HER2 positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy. AB - Activation of the Hippo transducer TAZ is emerging as a novel oncogenic route in breast cancer and it has been associated with breast cancer stem cells. Additionally, TAZ expression has been linked with HER-2 positivity. We investigated the association between TAZ expression and pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy.TAZ was assessed in diagnostic core biopsies by immunohistochemistry. To categorize samples with low TAZ and samples with high TAZ we generated a score by combining staining intensity and cellular localization. The pathological complete response rate was 78.6% in patients with low TAZ tumors and 57.6% in patients with high TAZ tumors (p=0.082). In HER2 enriched tumors there was no significant association between TAZ and pathological complete response, whereas in the luminal B subtype the pathological complete response rate was 82.4% in tumors with low TAZ and 44.4% in tumors with high TAZ (p=0.035). This association remained statistically significant when restricting our analysis to triple-positive tumors with expression of both estrogen receptor and progesterone receptor >= 50% (p=0.035). Results from this exploratory study suggest that the TAZ score efficiently predicts pathological complete response in Luminal B, HER2-positive breast cancer patients who received neoadjuvant chemotherapy and trastuzumab. PMID- 25294814 TI - Functional modification of adipocytes by grape seed extract impairs their pro tumorigenic signaling on colon cancer stem cells and the daughter cancer cells. AB - With global rise in obesity, it is imperative that we identify obesity-driven factors that increase growth and progression of colorectal cancer (CRC), and also discover and develop agents with anti-CRC efficacy under obese conditions. Here in, we investigated grape seed extract (GSE), a well-defined agent with both preventive and anti-CRC efficacy, for its potential to impair pro-tumorigenic signaling of adipocytes on CRC/colon cancer stem cells (CSCs) and associated molecular mechanisms, to control CRC under obese conditions. GSE treatment significantly decreased the growth and invasion promoting effects of both mouse and human adipocytes on CRC cells. Moreover, GSE exerted a direct inhibitory effect, as well as it strongly reduced the growth promoting signals of adipocytes, on colon CSCs. These GSE effects were associated with a decrease in both mRNA and protein levels of various CSC-associated molecules. Notably, GSE effects on adipocytes were not due to changes in lipid content, but by inducing the 'browning' of adipocytes as evidenced by an increase in UCP-1 mRNA level and mitochondriogenesis. Together, these findings, for the first time, suggest the ability of GSE to induce 'brown remodeling' of white adipocytes, which causes functional modification of adipocytes thus impairing their pro-tumorigenic signals on colon CSCs/CRC cells. PMID- 25294815 TI - Melanoma-initiating cells exploit M2 macrophage TGFbeta and arginase pathway for survival and proliferation. AB - M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34- but not CD34+ tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34- TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34- TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-beta (TGFbeta) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth. PMID- 25294816 TI - Targeting L1 cell adhesion molecule expression using liposome-encapsulated siRNA suppresses prostate cancer bone metastasis and growth. AB - The L1 cell adhesion molecule (L1CAM) has been implicated in tumor progression of many types of cancers, but its role in prostate cancer and its application in targeted gene therapy have not been investigated. Herein, we demonstrated that the L1CAM was expressed in androgen-insensitive and highly metastatic human prostate cancer cell lines. The correlation between L1CAM expression and prostate cancer metastasis was also validated in serum samples of prostate cancer patients. Knockdown of L1CAM expression in prostate cancer cells by RNA interference significantly decreased their aggressive behaviors, including colony formation, migration and invasion in vitro, and tumor formation in a metastatic murine model. These anti-malignant phenotypes of L1CAM-knockdown cancer cells were accompanied by G0/G1 cell cycle arrest and suppression of matrix metalloproteinase (MMP)-2 and MMP-9 expression and nuclear factor NF-kappaB activation. In vivo targeting of L1CAM expression using liposome-encapsulated L1CAM siRNAs effectively inhibited prostate cancer growth in mouse bone, which was associated with decreased L1CAM expression and cell proliferation by tumor cells. These results provide the first evidence for L1CAM being a major contributor to prostate cancer metastasis and translational application of siRNA based L1CAM-targeted therapy. PMID- 25294817 TI - MYCN-targeting miRNAs are predominantly downregulated during MYCN-driven neuroblastoma tumor formation. AB - MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects regulated by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly controlled at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression. PMID- 25294818 TI - Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis. AB - Angiogenesis is involved in the development, progression and metastasis of various human cancers. Herein, we report the discovery of glipizide, a widely used drug for type 2 diabetes mellitus, as a promising anticancer agent through the inhibition of tumor angiogenesis. By high-throughput screening (HTS) of an FDA approved drug library utilizing our in vivo chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, glipizide has been identified to significantly inhibit blood vessel formation and development. Moreover, glipizide was found to suppress tumor angiogenesis, tumor growth and metastasis using xenograft tumor and MMTV-PyMT transgenic mouse models. We further revealed that the anticancer capability of glipizide is not attributed to its antiproliferative effects, which are not significant against various human cancer cell lines. To investigate whether its anticancer efficacy is associated with the glucose level alteration induced by glipizide application, glimepiride, another medium to long-acting sulfonylurea antidiabetic drug in the same class, was employed for the comparison studies in the same fashion. Interestingly, glimepiride has demonstrated no significant impact on the tumor growth and metastasis, indicating that the anticancer effects of glipizide is not ascribed to its antidiabetic properties. Furthermore, glipizide suppresses endothelial cell migration and the formation of tubular structures, thereby inhibiting angiogenesis by up-regulating the expression of natriuretic peptide receptor A. These findings uncover a novel mechanism of glipizide as a potential cancer therapy, and also for the first time, provide direct evidence to support that treatment with glipizide may reduce the cancer risk for diabetic patients. PMID- 25294819 TI - Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. AB - Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4 mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL. PMID- 25294821 TI - Fusibacter bizertensis sp. nov., isolated from a corroded kerosene storage tank. AB - Strain LTF Kr01(T), a novel mesophilic, anaerobic, halotolerant, rod-shaped bacterium, was isolated from a drain at the bottom of a corroded kerosene storage tank of the Societe Tunisienne des Industries de Raffinage (STIR), Bizerte, northern Tunisia. Cells were Gram-positive-staining rods, occurred singly or in pairs, and were motile by one lateral flagellum. Strain LTF Kr01(T) grew at temperatures between 15 and 40 degrees C (optimum 30 degrees C), between pH 5.5 and 8.2 (optimum pH 7.2) and at NaCl concentrations between 0 and 50 g l(-1) (optimum 5 g l(-1)). It reduced thiosulfate and elemental sulfur into sulfide, but did not reduce sulfate or sulfite. It utilized a wide range of carbohydrates (cellobiose, d-glucose, d-fructose, d-mannitol, d-ribose, sucrose, d-xylose, maltose, d-galactose, starch and trehalose) and produced acetate, CO2 and H2 as end products from glucose fermentation. The DNA G+C content was 37.4 mol%. The predominant cellular fatty acids were C14:0 and C16:0. Phylogenetic analysis of the 16S rRNA gene sequence suggested that Fusibacter tunisiensis was the closest relative of strain LTF Kr01(T) (gene sequence similarity of 94.6%). Based on phenotypic, phylogenetic and genotypic taxonomic characteristics, strain LTF Kr01(T) is proposed to represent a novel species of the genus Fusibacter, order Clostridiales, for which the name Fusibacter bizertensis sp. nov. is proposed. The type strain is LTF Kr01(T) ( = DSM 28034(T) = JCM 19376(T)). PMID- 25294820 TI - Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1. AB - Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis. PMID- 25294822 TI - svaseq: removing batch effects and other unwanted noise from sequencing data. AB - It is now known that unwanted noise and unmodeled artifacts such as batch effects can dramatically reduce the accuracy of statistical inference in genomic experiments. These sources of noise must be modeled and removed to accurately measure biological variability and to obtain correct statistical inference when performing high-throughput genomic analysis. We introduced surrogate variable analysis (sva) for estimating these artifacts by (i) identifying the part of the genomic data only affected by artifacts and (ii) estimating the artifacts with principal components or singular vectors of the subset of the data matrix. The resulting estimates of artifacts can be used in subsequent analyses as adjustment factors to correct analyses. Here I describe a version of the sva approach specifically created for count data or FPKMs from sequencing experiments based on appropriate data transformation. I also describe the addition of supervised sva (ssva) for using control probes to identify the part of the genomic data only affected by artifacts. I present a comparison between these versions of sva and other methods for batch effect estimation on simulated data, real count-based data and FPKM-based data. These updates are available through the sva Bioconductor package and I have made fully reproducible analysis using these methods available from: https://github.com/jtleek/svaseq. PMID- 25294823 TI - Removal of 8-oxo-GTP by MutT hydrolase is not a major contributor to transcriptional fidelity. AB - Living in an oxygen-rich environment is dangerous for a cell. Reactive oxygen species can damage DNA, RNA, protein and lipids. The MutT protein in Escherichia coli removes 8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) and 8-oxo-guanosine triphosphate (8-oxo-GTP) from the nucleotide pools precluding incorporation into DNA and RNA. While 8-oxo-dGTP incorporation into DNA is mutagenic, it is not clear if 8-oxo-GTP incorporation into RNA can have phenotypic consequences for the cell. We use a bistable epigenetic switch sensitive to transcription errors in the Escherichia coli lacI transcript to monitor transient RNA errors. We do not observe any increase in epigenetic switching in mutT cells. We revisit the original observation of partial phenotypic suppression of a lacZamber allele in a mutT background that was attributed to RNA errors. We find that Lac+ revertants can completely account for the increase in beta-galactosidase levels in mutT lacZamber cultures, without invoking participation of transient transcription errors. Moreover, we observe a fluctuation type of distribution of beta galactosidase appearance in a growing culture, consistent with Lac+ DNA revertant events. We conclude that the absence of MutT produces a DNA mutator but does not equally create an RNA mutator. PMID- 25294824 TI - A genome-wide function of THSC/TREX-2 at active genes prevents transcription replication collisions. AB - The THSC/TREX-2 complex of Saccharomyces cerevisiae mediates the anchoring of transcribed genes to the nuclear pore, linking transcription elongation with mRNA export and genome stability, as shown for specific reporters. However, it is still unknown whether the function of TREX-2 is global and the reason for its relevant role in genome integrity. Here, by studying two TREX-2 representative subunits, Thp1 and Sac3, we show that TREX-2 has a genome-wide role in gene expression. Both proteins show similar distributions along the genome, with a gradient disposition at active genes that increases towards the 3' end. Thp1 and Sac3 have a relevant impact on the expression of long, G+C-rich and highly transcribed genes. Interestingly, replication impairment detected by the genome wide accumulation of the replicative Rrm3 helicase is increased preferentially at highly expressed genes in the thp1Delta and sac3Delta mutants analyzed. Therefore, our work provides evidence of a function of TREX-2 at the genome-wide level and suggests a role for TREX-2 in preventing transcription-replication conflicts, as a source of genome instability derived from a defective messenger ribonucleoprotein particle (mRNP) biogenesis. PMID- 25294825 TI - ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. AB - The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells. In vivo screening of candidate ETS proteins revealed that ETS1 is specifically required for migration of RAS/ERK activated cells. Furthermore, both migration and transcriptional activation through ETS/AP-1 required ERK phosphorylation of ETS1. Genome-wide mapping of multiple ETS proteins demonstrated that ETS1 binds specifically to enhancer ETS/AP-1 sequences. ETS1 occupancy, and its role in cell migration, was conserved in epithelial cells derived from multiple tissues, consistent with a chromatin organization common to epithelial cell lines. Genome wide expression analysis showed that ETS1 was required for activation of RAS regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway. Consistently, ETS1 was required for robust RAS/ERK pathway activation. Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions. PMID- 25294826 TI - MethBank: a database integrating next-generation sequencing single-base resolution DNA methylation programming data. AB - DNA methylation plays crucial roles during embryonic development. Here we present MethBank (http://dnamethylome.org), a DNA methylome programming database that integrates the genome-wide single-base nucleotide methylomes of gametes and early embryos in different model organisms. Unlike extant relevant databases, MethBank incorporates the whole-genome single-base-resolution methylomes of gametes and early embryos at multiple different developmental stages in zebrafish and mouse. MethBank allows users to retrieve methylation levels, differentially methylated regions, CpG islands, gene expression profiles and genetic polymorphisms for a specific gene or genomic region. Moreover, it offers a methylome browser that is capable of visualizing high-resolution DNA methylation profiles as well as other related data in an interactive manner and thus is of great helpfulness for users to investigate methylation patterns and changes of gametes and early embryos at different developmental stages. Ongoing efforts are focused on incorporation of methylomes and related data from other organisms. Together, MethBank features integration and visualization of high-resolution DNA methylation data as well as other related data, enabling identification of potential DNA methylation signatures in different developmental stages and accordingly providing an important resource for the epigenetic and developmental studies. PMID- 25294827 TI - Efficient in silico exploration of RNA interhelical conformations using Euler angles and WExplore. AB - HIV-1 TAR RNA is a two-helix bulge motif that plays a critical role in HIV viral replication and is an important drug target. However, efforts at designing TAR inhibitors have been challenged by its high degree of structural flexibility, which includes slow large-amplitude reorientations of its helices with respect to one another. Here, we use the recently introduced algorithm WExplore in combination with Euler angles to achieve unprecedented sampling of the TAR conformational ensemble. Our ensemble achieves similar agreement with experimental NMR data when compared with previous TAR computational studies, and is generated at a fraction of the computational cost. It clearly emerges from configuration space network analysis that the intermittent formation of the A22 U40 base pair acts as a reversible switch that enables sampling of interhelical conformations that would otherwise be topologically disallowed. We find that most previously determined ligand-bound structures are found in similar location in the network, and we use a sample-and-select approach to guide the construction of a set of novel conformations which can serve as the basis for future drug development efforts. Collectively, our findings demonstrate the utility of WExplore in combination with suitable order parameters as a method for exploring RNA conformational space. PMID- 25294828 TI - Explicit DNase sequence bias modeling enables high-resolution transcription factor footprint detection. AB - DNaseI footprinting is an established assay for identifying transcription factor (TF)-DNA interactions with single base pair resolution. High-throughput DNase-seq assays have recently been used to detect in vivo DNase footprints across the genome. Multiple computational approaches have been developed to identify DNase seq footprints as predictors of TF binding. However, recent studies have pointed to a substantial cleavage bias of DNase and its negative impact on predictive performance of footprinting. To assess the potential for using DNase-seq to identify individual binding sites, we performed DNase-seq on deproteinized genomic DNA and determined sequence cleavage bias. This allowed us to build bias corrected and TF-specific footprint models. The predictive performance of these models demonstrated that predicted footprints corresponded to high-confidence TF DNA interactions. DNase-seq footprints were absent under a fraction of ChIP-seq peaks, which we show to be indicative of weaker binding, indirect TF-DNA interactions or possible ChIP artifacts. The modeling approach was also able to detect variation in the consensus motifs that TFs bind to. Finally, cell type specific footprints were detected within DNase hypersensitive sites that are present in multiple cell types, further supporting that footprints can identify changes in TF binding that are not detectable using other strategies. PMID- 25294829 TI - Quantitative effect of target translation on small RNA efficacy reveals a novel mode of interaction. AB - Small regulatory RNAs (sRNAs) in bacteria regulate many important cellular activities under normal conditions and in response to stress. Many sRNAs bind to the mRNA targets at or near the 5' untranslated region (UTR) resulting in translation inhibition and accelerated degradation. Often the sRNA-binding site is adjacent to or overlapping with the ribosomal binding site (RBS), suggesting a possible interplay between sRNA and ribosome binding. Here we combine quantitative experiments with mathematical modeling to reveal novel features of the interaction between small RNAs and the translation machinery at the 5'UTR of a target mRNA. By measuring the response of a library of reporter targets with varied RBSs, we find that increasing translation rate can lead to increased repression. Quantitative analysis of these data suggests a recruitment model, where bound ribosomes facilitate binding of the sRNA. We experimentally verified predictions of this model for the cell-to-cell variability of target expression. Our findings offer a framework for understanding sRNA silencing in the context of bacterial physiology. PMID- 25294830 TI - Structural requirement of Ntc77 for spliceosome activation and first catalytic step. AB - The Prp19-associated complex is required for spliceosome activation by stabilizing the binding of U5 and U6 on the spliceosome after the release of U4. The complex comprises at least eight proteins, among which Ntc90 and Ntc77 contain multiple tetratricopeptide repeat (TPR) elements. We have previously shown that Ntc90 is not involved in spliceosome activation, but is required for the recruitment of essential first-step factor Yju2 to the spliceosome. We demonstrate here that Ntc77 has dual functions in both spliceosome activation and the first catalytic step in recruiting Yju2. We have identified an amino-terminal region of Ntc77, which encompasses the N-terminal domain and the first three TPR motifs, dispensable for spliceosome activation but required for stable interaction of Yju2 with the spliceosome. Deletion of this region had no severe effect on the integrity of the NTC, binding of NTC to the spliceosome or spliceosome activation, but impaired splicing and exhibited a dominant-negative growth phenotype. Our data reveal functional roles of Ntc77 in both spliceosome activation and the first catalytic step, and distinct structural domains of Ntc77 required for these two steps. PMID- 25294831 TI - Homodimerization of HYL1 ensures the correct selection of cleavage sites in primary miRNA. AB - MicroRNA (miRNA) plays an important role in the control of gene expression. HYPONASTIC LEAVES1 (HYL1) is a double-stranded RNA-binding protein that forms a complex with DICER-LIKE1 (DCL1) and SERRATE (SE) to process primary miRNA (pri miRNA) into mature miRNA. Although HYL1 has been shown to partner with DCL1 to enhance miRNA accuracy, the mechanism by which HYL1 selects the DCL1-targeted cleavage sites in pri-miRNA has remained unknown. By mutagenesis of HYL1 and analysis of in vivo pri-miRNA processing, we investigated the role of HYL1 in pri miRNA cleavage. HYL1 forms homodimers in which the residues Gly147 and Leu165 in the dsRBD2 domain are shown to be critical. Disruption of HYL1 homodimerization causes incorrect cleavage at sites in pri-miRNA without interrupting the interaction of HYL1 with DCL1 and accumulation of pri-miRNAs in HYL1/pri-miRNA complexes, leading to a reduction in the efficiency and accuracy of miRNAs that results in strong mutant phenotypes of the plants. HYL1 homodimers may function as a molecular anchor for DCL1 to cleave at a distance from the ssRNA-dsRNA junction in pri-miRNA. These results suggest that HYL1 ensures the correct selection of pri-miRNA cleavage sites through homodimerization and thus contributes to gene silencing and plant development. PMID- 25294832 TI - Mechanical force antagonizes the inhibitory effects of RecX on RecA filament formation in Mycobacterium tuberculosis. AB - Efficient bacterial recombinational DNA repair involves rapid cycles of RecA filament assembly and disassembly. The RecX protein plays a crucial inhibitory role in RecA filament formation and stability. As the broken ends of DNA are tethered during homologous search, RecA filaments assembled at the ends are likely subject to force. In this work, we investigated the interplay between RecX and force on RecA filament formation and stability. Using magnetic tweezers, at single molecular level, we found that Mycobacterium tuberculosis (Mt) RecX could catalyze stepwise de-polymerization of preformed MtRecA filament in the presence of ATP hydrolysis at low forces (<7 pN). However, applying larger forces antagonized the inhibitory effects of MtRecX, and a partially de-polymerized MtRecA filament could re-polymerize in the presence of MtRecX, which cannot be explained by previous models. Theoretical analysis of force-dependent conformational free energies of naked ssDNA and RecA nucleoprotein filament suggests that mechanical force stabilizes RecA filament, which provides a possible mechanism for the observation. As the antagonizing effect of force on the inhibitory function of RecX takes place in a physiological range; these findings broadly suggest a potential mechanosensitive regulation during homologous recombination. PMID- 25294833 TI - CTCF induces histone variant incorporation, erases the H3K27me3 histone mark and opens chromatin. AB - Insulators functionally separate active chromatin domains from inactive ones. The insulator factor, CTCF, has been found to bind to boundaries and to mediate insulator function. CTCF binding sites are depleted for the histone modification H3K27me3 and are enriched for the histone variant H3.3. In order to determine whether demethylation of H3K27me3 and H3.3 incorporation are a requirement for CTCF binding at domain boundaries or whether CTCF causes these changes, we made use of the LacI DNA binding domain to control CTCF binding by the Lac inducer IPTG. Here we show that, in contrast to the related factor CTCFL, the N-terminus plus zinc finger domain of CTCF is sufficient to open compact chromatin rapidly. This is preceded by incorporation of the histone variant H3.3, which thereby removes the H3K27me3 mark. This demonstrates the causal role for CTCF in generating the chromatin features found at insulators. Thereby, spreading of a histone modification from one domain through the insulator into the neighbouring domain is inhibited. PMID- 25294834 TI - Large-scale modeling of condition-specific gene regulatory networks by information integration and inference. AB - Understanding how regulatory networks globally coordinate the response of a cell to changing conditions, such as perturbations by shifting environments, is an elementary challenge in systems biology which has yet to be met. Genome-wide gene expression measurements are high dimensional as these are reflecting the condition-specific interplay of thousands of cellular components. The integration of prior biological knowledge into the modeling process of systems-wide gene regulation enables the large-scale interpretation of gene expression signals in the context of known regulatory relations. We developed COGERE (http://mips.helmholtz-muenchen.de/cogere), a method for the inference of condition-specific gene regulatory networks in human and mouse. We integrated existing knowledge of regulatory interactions from multiple sources to a comprehensive model of prior information. COGERE infers condition-specific regulation by evaluating the mutual dependency between regulator (transcription factor or miRNA) and target gene expression using prior information. This dependency is scored by the non-parametric, nonlinear correlation coefficient eta(2) (eta squared) that is derived by a two-way analysis of variance. We show that COGERE significantly outperforms alternative methods in predicting condition specific gene regulatory networks on simulated data sets. Furthermore, by inferring the cancer-specific gene regulatory network from the NCI-60 expression study, we demonstrate the utility of COGERE to promote hypothesis-driven clinical research. PMID- 25294835 TI - The Werner syndrome protein limits the error-prone 8-oxo-dG lesion bypass activity of human DNA polymerase kappa. AB - Human DNA polymerase kappa (hpol kappa) is the only Y-family member to preferentially insert dAMP opposite 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo dG) during translesion DNA synthesis. We have studied the mechanism of action by which hpol kappa activity is modulated by the Werner syndrome protein (WRN), a RecQ helicase known to influence repair of 8-oxo-dG. Here we show that WRN stimulates the 8-oxo-dG bypass activity of hpol kappa in vitro by enhancing the correct base insertion opposite the lesion, as well as extension from dC:8-oxo-dG base pairs. Steady-state kinetic analysis reveals that WRN improves hpol kappa catalyzed dCMP insertion opposite 8-oxo-dG ~10-fold and extension from dC:8-oxo dG by 2.4-fold. Stimulation is primarily due to an increase in the rate constant for polymerization (kpol), as assessed by pre-steady-state kinetics, and it requires the RecQ C-terminal (RQC) domain. In support of the functional data, recombinant WRN and hpol kappa were found to physically interact through the exo and RQC domains of WRN, and co-localization of WRN and hpol kappa was observed in human cells treated with hydrogen peroxide. Thus, WRN limits the error-prone bypass of 8-oxo-dG by hpol kappa, which could influence the sensitivity to oxidative damage that has previously been observed for Werner's syndrome cells. PMID- 25294836 TI - Rio1 mediates ATP-dependent final maturation of 40S ribosomal subunits. AB - During the last step in 40S ribosome subunit biogenesis, the PIN-domain endonuclease Nob1 cleaves the 20S pre-rRNA at site D, to form the mature 18S rRNAs. Here we report that cleavage occurs in particles that have largely been stripped of previously characterized pre-40S components, but retain the endonuclease Nob1, its binding partner Pno1 (Dim2) and the atypical ATPase Rio1. Within the Rio1-associated pre-40S particles, in vitro pre-rRNA cleavage was strongly stimulated by ATP and required nucleotide binding by Rio1. In vivo binding sites for Rio1, Pno1 and Nob1 were mapped by UV cross-linking in actively growing cells. Nob1 and Pno1 bind overlapping regions within the internal transcribed spacer 1, and both bind directly over cleavage site D. Binding sites for Rio1 were within the core of the 18S rRNA, overlapping tRNA interaction sites and distinct from the related kinase Rio2. Site D cleavage occurs within pre-40S 60S complexes and Rio1-associated particles efficiently assemble into these complexes, whereas Pno1 appeared to be depleted relative to Nob1. We speculate that Rio1-mediated dissociation of Pno1 from cleavage site D is the trigger for final 18S rRNA maturation. PMID- 25294838 TI - Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5' splice site selection. AB - Alternative splicing (AS) modulates many physiological and pathological processes. For instance, AS of the BCL-X gene balances cell survival and apoptosis in development and cancer. Herein, we identified the polypyrimidine tract binding protein (PTBP1) as a direct regulator of BCL-X AS. Overexpression of PTBP1 promotes selection of the distal 5' splice site in BCL-X exon 2, generating the pro-apoptotic BCL-Xs splice variant. Conversely, depletion of PTBP1 enhanced splicing of the anti-apoptotic BCL-XL variant. In vivo cross linking experiments and site-directed mutagenesis restricted the PTBP1 binding site to a polypyrimidine tract located between the two alternative 5' splice sites. Binding of PTBP1 to this site was required for its effect on splicing. Notably, a similar function of PTBP1 in the selection of alternative 5' splice sites was confirmed using the USP5 gene as additional model. Mechanistically, PTBP1 displaces SRSF1 binding from the proximal 5' splice site, thus repressing its selection. Our study provides a novel mechanism of alternative 5' splice site selection by PTBP1 and indicates that the presence of a PTBP1 binding site between two alternative 5' splice sites promotes selection of the distal one, while repressing the proximal site by competing for binding of a positive regulator. PMID- 25294839 TI - Effects of vertical and side-alternating vibration training on fall risk factors and bone turnover in older people at risk of falls. AB - BACKGROUND: whole-body vibration training may improve neuromuscular function, falls risk and bone density, but previous studies have had conflicting findings. OBJECTIVE: this study aimed to evaluate the influence of vertical vibration (VV) and side-alternating vibration (SV) on musculoskeletal health in older people at risk of falls. DESIGN: single-blind, randomised, controlled trial comparing vibration training to sham vibration (Sham) in addition to usual care. PARTICIPANTS: participants were 61 older people (37 women and 24 men), aged 80.2 + 6.5 years, referred to an outpatient falls prevention service. METHODS: participants were randomly assigned to VV, SV or Sham in addition to the usual falls prevention programme. Participants were requested to attend three vibration sessions per week for 12 weeks, with sessions increasing to six, 1 min bouts of vibration. Falls risk factors and neuromuscular tests were assessed, and blood samples collected for determination of bone turnover, at baseline and following the intervention. RESULTS: chair stand time, timed-up-and-go time, fear of falling, NEADL index and postural sway with eyes open improved in the Sham group. There were significantly greater gains in leg power in the VV than in the Sham group and in bone formation in SV and VV compared with the Sham group. Conversely, body sway improved less in the VV than in the Sham group. Changes in falls risk factors did not differ between the groups. CONCLUSIONS: whole-body vibration increased leg power and bone formation, but it did not provide any additional benefits to balance or fall risk factors beyond a falls prevention programme in older people at risk of falls. PMID- 25294837 TI - Multiplex sequencing of pooled mitochondrial genomes-a crucial step toward biodiversity analysis using mito-metagenomics. AB - The advent in high-throughput-sequencing (HTS) technologies has revolutionized conventional biodiversity research by enabling parallel capture of DNA sequences possessing species-level diagnosis. However, polymerase chain reaction (PCR) based implementation is biased by the efficiency of primer binding across lineages of organisms. A PCR-free HTS approach will alleviate this artefact and significantly improve upon the multi-locus method utilizing full mitogenomes. Here we developed a novel multiplex sequencing and assembly pipeline allowing for simultaneous acquisition of full mitogenomes from pooled animals without DNA enrichment or amplification. By concatenating assemblies from three de novo assemblers, we obtained high-quality mitogenomes for all 49 pooled taxa, with 36 species >15 kb and the remaining >10 kb, including 20 complete mitogenomes and nearly all protein coding genes (99.6%). The assembly quality was carefully validated with Sanger sequences, reference genomes and conservativeness of protein coding genes across taxa. The new method was effective even for closely related taxa, e.g. three Drosophila spp., demonstrating its broad utility for biodiversity research and mito-phylogenomics. Finally, the in silico simulation showed that by recruiting multiple mito-loci, taxon detection was improved at a fixed sequencing depth. Combined, these results demonstrate the plausibility of a multi-locus mito-metagenomics approach as the next phase of the current single locus metabarcoding method. PMID- 25294842 TI - Campaigners warn that EU trade deal with US could threaten drug prices. PMID- 25294841 TI - Factors related to the psychosocial functioning of youth with neonatal brachial plexus injuries. AB - OBJECTIVE: Owing to the possible visible nature and functional impairments associated with neonatal brachial plexus injuries (NBPI), the current study investigated the relations of injury severity, social support, and coping strategies to social difficulties and self-concept in youth with NBPI. METHODS: 88 children (aged 10-17 years) with NBPI and their parent(s) were recruited from a national organization and two brachial plexus clinics. Participants completed a variety of questionnaires during their scheduled clinic visits. RESULTS: More social support from classmates was associated with better self-concept and fewer social difficulties. Less frequent use of negative coping strategies was associated with better self-concept and fewer social difficulties and was a significant moderator of the relation between injury severity and self-concept. CONCLUSIONS: Clinicians who work with children with NBPI should consider peer support and coping strategies when promoting the psychosocial functioning of these youth. PMID- 25294840 TI - Adolescent weight control: an intervention targeting parent communication and modeling compared with minimal parental involvement. AB - OBJECTIVE: Adolescent weight control interventions demonstrate variable findings, with inconsistent data regarding the appropriate role for parents. The current study examined the efficacy of a standard adolescent behavioral weight control (BWC) intervention that also targeted parent-adolescent communication and parental modeling of healthy behaviors (Standard Behavioral Treatment + Enhanced Parenting; SBT + EP) compared with a standard BWC intervention (SBT). METHODS: 49 obese adolescents (M age = 15.10; SD = 1.33; 76% female; 67.3% non-Hispanic White) and a caregiver were randomly assigned to SBT or SBT + EP. Adolescent and caregiver weight and height, parental modeling, and weight-related communication were obtained at baseline and end of the 16-week intervention. RESULTS: Significant decreases in adolescent weight and increases in parental self monitoring were observed across both conditions. Analyses of covariance revealed a trend for greater reduction in weight and negative maternal commentary among SBT condition participants. CONCLUSIONS: Contrary to hypotheses, targeting parent adolescent communication and parental modeling did not lead to better outcomes in adolescent weight control. PMID- 25294843 TI - The value of a multi-specialty service, including genitourinary medicine, dermatology and urology input, in the management of male genital dermatoses. AB - We undertook a retrospective case note review of our monthly multi-specialty penile dermatoses clinic (which includes clinicians from Genitourinary medicine, Dermatology and Urology), to examine conditions presenting to the service, and compare clinical management and outcomes with other similar services in the UK. Over the 3-year study period, 226 patients were reviewed over 240 individual episodes. Lichenoid conditions were the most common category of genital pathologies seen (n = 60, 24%), but non-specific balanitis was the most common individual diagnosis (n = 55, 22%). Other common conditions seen included eczema and psoriasis (n = 28, 11%), Zoon/plasma cell balanitis (n = 26, 10%), malignancy/pre-malignant change (n = 25, 10%) and infective conditions (n = 24, 9%). The clinic had a biopsy rate of 10%; the most common indication was for confirmation of a clinical suspicion of malignancy/pre-malignancy. There was a high clinical-to-histological correlation in the biopsies of 79%. The most common treatment prescribed was topical corticosteroids and the clinic had a high discharge rate of 93%, the majority of patients discharged back to General Practice. PMID- 25294844 TI - Sociocultural factors perpetuating the practices of early marriage and childbirth in Sylhet District, Bangladesh. AB - BACKGROUND: The practice of adolescent marriage continues in communities throughout Bangladesh, with adolescent childbearing a common result. This early childbearing is associated with increased medical risks for both mothers and their newborns. METHODS: Because of the need to understand the persistence of these behaviors in spite of the risks, various qualitative research methods were used to identify and better understand the various socio cultural factors perpetuating the practices of early marriage and childbirth. RESULTS: Delaying the first birth after marriage can cause rumors of infertility, bring shame on the family, and in some cases lead the husband's family to seek another wife for their son. In addition, social stigma for childless women, emigration of husbands, and the belief that using modern contraceptives prior to the birth of the first child results in infertility also inhibits couples from delaying their first pregnancy. DISCUSSION AND CONCLUSIONS: Future efforts to promote delay in marriage and subsequent early childbearing should focus on allaying the fears of infertility related to delay in childbearing or secondary to contraceptive use, both for newly married couples and household decision-makers such as mothers-in law. PMID- 25294845 TI - An update on the efficacy of oral corticosteroids in the treatment of wheezing episodes in preschool children. AB - Traditionally, oral corticosteroids (OCSs) have been the mainstay of treatment for acute wheezing episodes among preschool children with a history of recurrent wheezing. Although there is substantial evidence for the efficacy of OCSs as a treatment for asthma exacerbations in school-aged children and adolescents, recent clinical studies questioned the benefits of OCSs as a treatment for acute wheezing in preschool children. This review summarizes the current evidence on the efficacy of OCSs as a treatment for acute wheezing episodes among preschool age children with episodic wheezing, focusing on studies performed in three different settings: OCS treatment initiated by parents in the outpatient setting, OCS treatment initiated in the emergency department (ED), and OCS treatment among hospitalized preschool children. The results of most studies reviewed in this paper do not support the efficacy of OCS treatment among preschool children with recurrent wheezing. The heterogeneity of early childhood wheezing and asthma might be part of the explanation for lack of efficacy of this intervention noted in multiple studies. PMID- 25294846 TI - VEGFR2-Targeted Ultrasound Imaging Agent Enhances the Detection of Ovarian Tumors at Early Stage in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer. AB - Tumor-associated neoangiogenesis (TAN) is an early event in ovarian cancer (OVCA) development. Increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) by TAN vessels presents a potential target for early detection by ultrasound imaging. The goal of this study was to examine the suitability of VEGFR2-targeted ultrasound contrast agents in detecting spontaneous OVCA in laying hens. Effects of VEGFR2-targeted contrast agents in enhancing the intensity of ultrasound imaging from spontaneous ovarian tumors in hens were examined in a cross-sectional study. Enhancement in the intensity of ultrasound imaging was determined before and after injection of VEGFR2-targeted contrast agents. All ultrasound images were digitally stored and analyzed off-line. Following scanning, ovarian tissues were collected and processed for histology and detection of VEGFR2-expressing microvessels. Enhancement in visualization of ovarian morphology was detected by gray-scale imaging following injection of VEGFR2-targeted contrast agents. Compared with pre-contrast, contrast imaging enhanced the intensities of ultrasound imaging significantly (p < 0.0001) irrespective of the pathological status of ovaries. In contrast to normal hens, the intensity of ultrasound imaging was significantly (p < 0.0001) higher in hens with early stage OVCA and increased further in hens with late stage OVCA. Higher intensities of ultrasound imaging in hens with OVCA were positively correlated with increased (p < 0.0001) frequencies of VEGFR2-expressing microvessels. The results of this study suggest that VEGFR2-targeted contrast agents enhance the visualization of spontaneous ovarian tumors in hens at early and late stages of OVCA. The laying hen may be a suitable model to test new imaging agents and develop targeted therapeutics. PMID- 25294847 TI - Doppler assessment of renal hemodynamic alterations in homozygous sickle cell disease and sickle Beta-thalassemia. AB - We evaluated the renal vascular indices in children and adolescents with sickle cell disease (SCD) using Doppler ultrasonography. We also assessed the renal hemodynamics alterations in patients with homozygous SCD and sickle beta thalassemia (sickle beta-thalassemia). We studied 75 patients (age range = 3-20 years; M = 9.95 +/- 4.15) with SCD: 42 patients suffering from homozygous SCD and 33 patients diagnosed with sickle beta-thalassemia. Thirty, age- and sex-matched, normal subjects were also included as a control group. Both patients and control groups had Doppler assessment of pulsatility (PI) and resistivity (RI) indices of main renal, segmental, interlobar, and arcuate arteries. Both PIs and RIs were significantly higher in SCD patients, compared with the control group. Among patients, PIs and RIs in the main renal, segmental, interlobar, and arcuate arteries were significantly higher in patients with homozygous SCD as compared with those with sickle beta-thalassemia (p values <0.01, <0.001, <0.001, and <0.001 for PIs and <0.001, <0.001, <0.001, and <0.01 for RIs, respectively). We concluded that renal vascular resistance is raised in children and adolescents with SCD. This is more pronounced in patients with homozygous SCD as compared with those with sickle beta-thalassemia. PMID- 25294848 TI - Kidney paired donation: principles, protocols and programs. AB - Due to the ongoing shortage of deceased-donor organs, novel strategies to augment kidney transplantation rates through expanded living donation strategies have become essential. These include desensitization in antibody-incompatible transplants and kidney paired donation (KPD) programs. KPD enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible pairs in order to find potentially compatible transplant solutions. Given the significant immunologic barriers with fewer donor options, single-center or small KPD programs may be less successful in transplanting the more sensitized patients; the optimal solution for the difficult-to-match patient is access to more potential donors and large multicenter or national registries are essential. Multicenter KPD programs have become common in the last decade, and now represent one of the most promising opportunities to improve transplant rates. To maximize donor-recipient matching, and minimize immunologic risk, these multicenter KPD programs use sophisticated algorithms to identify optimal match potential, with simultaneous two-, three- or more complex multiway exchanges. The article focuses on the recent progresses in KPD and it also reviews some of the differences and commonalities across four different national KPD programs. PMID- 25294849 TI - Prevention of peritoneal dialysis-related infections. AB - The use of peritoneal dialysis (PD) varies widely from country to country, with the main limitation being infectious complications, particularly peritonitis, which leads to technique failure, hospitalization and increased mortality. A large number of prophylactic strategies have been employed to reduce the occurrence of peritonitis, including the use of oral, nasal and topical antibiotics, disinfection of the exit site, modification of the transfer set used in continuous ambulatory PD exchanges, changes to the design of the PD catheter implanted, the surgical method by which the PD catheter is inserted, the type and length of training given to patients, the occurrence of home visits by trained PD nurses, the use of antibiotic prophylaxis in patients undergoing certain invasive procedures and the administration of antifungal prophylaxis to PD patients whenever they are given an antibiotic treatment course. This review summarizes the existing evidence evaluating these interventions to prevent exit-site/tunnel infections and peritonitis. PMID- 25294850 TI - Increased plasma dipeptidyl peptidase 4 activities predict new-onset microalbuminuria in association with its proinflammatory effects in Chinese without diabetes: a four-year prospective study. AB - BACKGROUND: Recent evidence supports a protective role of dipeptidyl peptidase 4 (DPP4) inhibitors in lowering microalbuminuria (MAU) in diabetes but till now few studies have investigated the associations between DPP4 activity and MAU in nondiabetic Chinese individuals. This study tested whether DPP4 activity could predict new-onset MAU in Chinese without diabetes. METHODS: This was a 4-year prospective study conducted in Sichuan, China. A total of 664 Chinese women and men aged 18-70 years were studied. Circulating DPP4 activity, inflammatory markers and urinary albumin-to-creatinine ratio (ACR) were measured at baseline and 4 years later. RESULTS: The incidence of MAU during follow-up was 33.1 per 1000 patient-years. At baseline, individuals in the highest quartile of DPP4 activity had higher age, body mass index, waist/hip ratio, systolic blood pressure, diastolic blood pressure, fasting insulin, low-density lipoprotein cholesterol, interleukin-6, high-sensitivity C-reactive protein, urinary albumin to-creatinine ratio and lower high-density lipoprotein-cholesterol compared with individuals in the lowest quartile. After a 4-year follow-up, 88 individuals developed MAU. In multiple linear regression analysis, baseline DPP4 activity was an independent predictor of an increase in inflammatory markers and ACR over a 4 year period (all P < 0.05). In multivariable-adjusted models, the odds ratio for incident MAU comparing the highest with the lowest quartiles of DPP4 activity was 3.48 (95% CI: 1.50-8.09) after adjustment for confounding risk factors (P < 0.01). The incidence of MAU owing to DPP4 activity increased by 18.59%. CONCLUSION: DPP4 activity is an important predictor of the onset of inflammation and MAU in Chinese apparently without diabetes. This finding may have important implications for understanding the proinflammatory role of DPP-4 in the pathogenesis of MAU. TRIAL REGISTRATION NUMBER: #TR-CCH-Chi CTR-CCH-00000361. PMID- 25294852 TI - Gender Differences in Risk Factors for Delayed Diagnosis of HIV/AIDS in a Midsized City of Brazil. AB - Patients treated in the specialized service at a midsized city in Brazil participated in a cross-sectional study that aimed to identify the risk factors for delayed diagnosis of HIV/AIDS. Through interviews and review of medical records, information was collected on sociodemographic and clinical characteristics and diagnoses. The study included 403 patients, of whom 216 (53.6%) were male and 311 (77.1%) had <=8 years of education. According to the criteria adopted in this study, 162 (40.2%) of the participants had a late diagnosis of AIDS. Only 19 (4.7%) were diagnosed by routine examinations and 45 (11.2%) presented with AIDS-defining disease at the time of diagnosis. After adjustments, the results showed that having more education was protective against a late diagnosis for women. With the advance of the AIDS epidemic to small town and rural Brazil, vulnerable populations now include low-income and less educated women, most of whom have had monogamous relationships throughout their lives. PMID- 25294851 TI - The induction of C/EBPbeta contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease. AB - BACKGROUND: In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-alpha (TGFalpha) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFalpha, the most potent EGFR-activating ligand. METHODS: Computer analysis of the ADAM17 promoter identified TGFalpha and C/EBPbeta as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFalpha/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFalpha signals, active vitamin D to induce C/EBPbeta or the combination. RESULTS: While TGFalpha induced ADAM17-promoter activity by 2.2-fold exacerbating TGFalpha/EGFR driven growth, ectopic C/EBPbeta expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFalpha and inversely with C/EBPbeta. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFalpha/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPbeta to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPbeta to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%. CONCLUSION: In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPbeta to efficaciously attenuate the severe ADAM17/TGFalpha synergy, which drives PTG enlargement and high PTH. PMID- 25294853 TI - Validation of 2 Spanish-Language Scales to Assess HIV-Related Stigma in Communities. AB - We report the psychometric properties of 2 Spanish-language scales designed to measure (1) opinions about HIV in the community and particularly among health care workers and (2) observed acts of stigma toward people living with HIV/AIDS (PLWHA) by health care workers. The Opinions about HIV Scale included 3 components (policy, avoidance, and empathy) and 9 items, while an adapted version of the HIV/AIDS Stigma Instrument-Nurse, designed to capture acts of stigma, included 2 components (discrimination related to clinical care and refusal to share or exchange food/gifts). Scales demonstrated good reliability and construct validity. Relative to community health workers, treatment supporters were more likely to have stigmatizing opinions related to avoidance and empathy. We offer 2 Spanish-language scales that could be used to identify populations with high levels of stigmatizing opinions and behaviors toward PLWHA. Formal training of health care workers, especially treatment supporters, may raise awareness and reduce stigma toward HIV. PMID- 25294854 TI - Nonoccupational post-exposure prophylaxis for HIV in New York State Emergency Departments. AB - New York State (NYS) established guidelines for nonoccupational post-exposure prophylaxis (nPEP) to HIV in 1997. To assess current nPEP practices in NYS Emergency Departments (EDs), we electronically surveyed all ED directors in NYS, excluding Veterans' Affairs hospitals, about nPEP and linkage-to-care protocols in the EDs. Basic descriptive statistics were used for analysis. The response rate was 96% (184/191). Of respondents, 88% reported evaluating any patient with a possible nonoccupational exposure to HIV, in accordance with NYS guidelines. Of these, 83% provided the patient with a starter pack of medications, while 4% neither supplied nor prescribed antiretroviral drugs in the ED. Sexually transmitted infection screening, risk reduction counseling, and education about symptoms of acute HIV seroconversion were performed inconsistently, despite NYS guidelines recommendations. Only 22% of EDs confirmed whether linkage to follow up care was successful. Most NYS EDs prescribe nPEP to appropriate patients but full implementation of guidelines remains incomplete. PMID- 25294855 TI - Risk Factors for Early Mortality on Antiretroviral Treatment of Elderly People Infected with HIV in Burkina Faso. AB - BACKGROUND: Age is a key determinant of mortality due to diseases including HIV infection. METHODS: A retrospective and descriptive cohort study used a computerized database to compare HIV-infected patients diagnosed in late adulthood to a group of patients diagnosed before their 49 years of age, without matching the characteristics of HIV infection. The study included patients who visited the day hospital (outpatient clinic) of the Sanou Souro Teaching Hospital of Bobo-Dioulasso, in Burkina Faso, from January 2007 to December 2011. Older adults were defined as those aged 50 years and more. RESULTS: Participants in the study consisted of 2572 patients (265 older adults and 2307 young patients living with HIV. Based on Markov chain method, 32.1% of the older adults living with HIV were found to be seroconvert at 50 years or older. The median follow-up time on antiretroviral treatment (ART) was 32.7 months (range 0.03-65.4 months). Two hundred and ninety-five (11.5%) patients died, including 21.1% of older adults and 10.4% of young (P < .01). World Health Organization stage 3 or 4 and the lowest CD4 count reached <200 cells/mm(3) were the factors associated with early mortality of older adults on ART. CONCLUSION: Mortality rate of older adult patients living with HIV in Burkina Faso is high. Early diagnosis, early treatment, and primary prevention of HIV infection in the older adults are the main keys that could help reduce such mortality. PMID- 25294857 TI - Positive group psychotherapy modified for adults with intellectual disabilities. AB - Mental health disorders are considerably more prevalent among people with intellectual disabilities than in the general population, yet research on psychotherapy for people with dual diagnosis is scarce. However, there is mounting evidence to show that adults with a dual diagnosis can find help through group therapy and have more productive and meaningful lives with improved relationships. This article focuses on a review of evidence for interactive behavioral therapy, a widely used model of group psychotherapy for these conditions, and reviews the modifications drawn from the field of positive psychology and positive psychotherapy being incorporated into the model. A sample of a modified positive intervention, the virtual gratitude visit, is explained and suggestions for future research are given. PMID- 25294856 TI - Antiretroviral therapy in Zambia: do partners on ART enhance adherence? AB - BACKGROUND: Adherence to antiretroviral therapy (ART) is essential to optimize HIV treatment outcomes. Among individuals on ART, targeted peer support has been found to support adherence. This study of Zambian heterosexual couples living with HIV examined whether partners would exert a positive influence on each other's adherence, and compared adherence between couples in which either one or both members were on ART. METHODS: Couples (n = 446 participants), in which either or both member were on ART were assessed at baseline, 6 and 12 months. RESULTS: Most participants (64%, n = 263) were on ART; overall, uptake of ART increased to 74% at 12 months. At baseline, 76% reported near perfect adherence; at 6 and 12 months, 66% and 70% were adherent, respectively. A regression analysis indicated that the decline in adherence did not differ between those couples in which one or both partners were on ART [F (2, 624) = 0.37, p = .692]. Pairwise comparison indicated that adherence primarily decreased between baseline and 6 months (t = 2.72, p = .007), and was stable 6 to 12 months. CONCLUSIONS: This study of couples in Zambia found adherence was not enhanced by having a partner on ART, and that adherence declined over time. Partners on ART may not necessarily provide support for adherence to each other. Partners may represent an untapped resource for optimizing adherence; results highlight the need for provider guidance and structured adherence interventions targeting partner adherence support. PMID- 25294858 TI - Re: Occupation and thyroid cancer. PMID- 25294859 TI - Author response to "re: occupation and thyroid cancer.". PMID- 25294860 TI - Secondary cell walls: biosynthesis, patterned deposition and transcriptional regulation. AB - Secondary walls are mainly composed of cellulose, hemicelluloses (xylan and glucomannan) and lignin, and are deposited in some specialized cells, such as tracheary elements, fibers and other sclerenchymatous cells. Secondary walls provide strength to these cells, which lend mechanical support and protection to the plant body and, in the case of tracheary elements, enable them to function as conduits for transporting water. Formation of secondary walls is a complex process that requires the co-ordinated expression of secondary wall biosynthetic genes, biosynthesis and targeted secretion of secondary wall components, and patterned deposition and assembly of secondary walls. Here, we provide a comprehensive review of genes involved in secondary wall biosynthesis and deposition. Most of the genes involved in the biosynthesis of secondary wall components, including cellulose, xylan, glucomannan and lignin, have been identified and their co-ordinated activation has been shown to be mediated by a transcriptional network encompassing the secondary wall NAC and MYB master switches and their downstream transcription factors. It has been demonstrated that cortical microtubules and microtubule-associated proteins play important roles in the targeted secretion of cellulose synthase complexes, the oriented deposition of cellulose microfibrils and the patterned deposition of secondary walls. Further investigation of many secondary wall-associated genes with unknown functions will provide new insights into the mechanisms controlling the formation of secondary walls that constitute the bulk of plant biomass. PMID- 25294865 TI - Correlation Between Testosterone and PSA Kinetics in Metastatic Prostate Cancer Patients Treated With Diverse Chemical Castrations. AB - To assess total testosterone and prostatic-specific antigen (PSA) kinetics among diverse chemical castrations, advanced-stage prostate cancer patients were randomized into three groups of 20: Group 1, Leuprolide 3.75 mg; Group 2, Leuprolide 7.5 mg; and Group 3, Goserelin 3.6 mg. All groups were treated with monthly application of the respective drugs. The patients' levels of serum total testosterone and PSA were evaluated at two time periods: before the treatment and 3 months after the treatment. Spearman's rank correlation coefficient was utilized to verify the hypothesis of linear correlation between total testosterone and PSA levels. At the beginning the patients' age, stage, grade, PSA, and total testosterone were similar within the three groups, with median age 72, 70, and 70 years in Groups 1, 2, and 3, respectively. Three months after the treatment, patients who received Leuprolide 7.5 mg presented significantly lower median total testosterone levels compared with Goserelin 3.6 mg and Leuprolide 3.75 mg (9.5 ng/dL vs. 20.0 ng/dL vs. 30.0 ng/dL, respectively; p = .0072), while those who received Goserelin 3.6 mg presented significantly lower PSA levels compared with Leuprolide 7.5 mg and Leuprolide 3.75 mg (0.67 vs. 1.86 vs. 2.57, respectively; p = .0067). There was no linear correlation between total testosterone and PSA levels. Overall, regarding castration levels of total testosterone, 28.77% of patients did not obtain levels <=50 ng/dL and 47.80% did not obtain levels <=20 ng/dL. There was no correlation between total testosterone and PSA kinetics and no equivalence among different pharmacological castrations. PMID- 25294866 TI - Variability in Depressive Symptoms of Cognitive Deficit and Cognitive Bias During the First 2 Years After Diagnosis in Australian Men With Prostate Cancer. AB - The incidence and contribution to total depression of the depressive symptoms of cognitive deficit and cognitive bias in prostate cancer (PCa) patients were compared from cohorts sampled during the first 2 years after diagnosis. Survey data were collected from 394 patients with PCa, including background information, treatments, and disease status, plus total scores of depression and scores for subscales of the depressive symptoms of cognitive bias and cognitive deficit via the Zung Self-Rating Depression Scale. The sample was divided into eight 3 monthly time-since-diagnosis cohorts and according to depression severity. Mean scores for the depressive symptoms of cognitive deficit were significantly higher than those for cognitive bias for the whole sample, but the contribution of cognitive bias to total depression was stronger than that for cognitive deficit. When divided according to overall depression severity, patients with clinically significant depression showed reversed patterns of association between the two subsets of cognitive symptoms of depression and total depression compared with those patients who reported less severe depression. Differences in the incidence and contribution of these two different aspects of the cognitive symptoms of depression for patients with more severe depression argue for consideration of them when assessing and diagnosing depression in patients with PCa. Treatment requirements are also different between the two types of cognitive symptoms of depression, and several suggestions for matching treatment to illness via a personalized medicine approach are discussed. PMID- 25294867 TI - Men, Masculinities, and Murder-Suicide. AB - Murder-suicide (M-S) is a complex phenomenon that can involve a multifaceted set of interrelated biological and social factors. M-S is also sexed and gendered in that the perpetrators are most often male and their underpinning motives and actions link to masculinities in an array of diverse ways. With the overarching goal to describe connections between men, masculinities, and M-S, 296 newspaper articles describing 45 North American M-S cases were analyzed. The inductively derived findings revealed three themes: (a) domestic desperation, (b) workplace justice, and (c) school retaliation. Cases in the domestic desperation theme were characterized by the murder of a family member(s) and were often underpinned by men's self-perceptions of failing to provide economic security. Workplace justice cases emerged from men's grievances around paid-work, job insecurity, and perceptions of being bullied and/or marginalized by coworkers or supervisors. The school retaliation cases were strongly linked to "pay back" against individuals and/or society for the hardships endured by M-S perpetrators. Prevailing across the three themes was men's loss of control in their lives, hopelessness, and marginalized masculine identities. Also evident were men's alignments to hegemonic masculinities in reasserting one's masculine self by protesting the perceived marginalization invoked on them. Overall, the findings give pause to consider the need for men-centered M-S prevention strategies to quell the catastrophic impacts of this long-standing but understudied men's health issue. PMID- 25294868 TI - Perceptions of Men With Moderate to Severe Hemophilia Regarding the Management of Their Chronic Disorder and Utilization of Community-Based Support. AB - Hemophilia is a genetic bleeding disorder that almost exclusively affects men. There is a nationwide network of nonprofit organizations providing support to men with hemophilia, which are affiliated with localized agencies that serve affected individuals within specific regions of the country. This community-based study was implemented in response to a local Utah agency's concern that men with hemophilia may be disengaged from and underserved by their local support network. The goal of the study was to gain a better understanding of the (a) unique challenges, (b) adaptations, and (c) physical, financial, psychological, and social needs of adult men with moderate to severe hemophilia from the local community. Over a period of 9 months, verbal qualitative interviews were conducted with 10 affected individuals, and written interviews were obtained from 3 additional participants. Using a grounded-theory approach, six themes were identified, based on men's commentary from interviews, across a spectrum of physical, social, communal, personal, medical, and vocational dimensions. Resilience theory, which explores internal resources that assist in coping with adverse situations, was used as a framework for interpreting research results. Findings indicate that men value the array of educational, social, and medical services that are available to them but choose to manage their hemophilia independently from the community and access support according to their individual needs. Understanding this dynamic may be helpful in developing services that are more specifically tailored to the physical and psychosocial needs of adult men with hemophilia and, potentially, men with other chronic health disorders. PMID- 25294869 TI - Risk factors for short-term adverse events and readmission after arthroscopic meniscectomy: does age matter? AB - BACKGROUND: Recent studies have questioned the efficacy of meniscectomy in older patients with and without evidence of osteoarthritis; however, it continues to be frequently performed. There is limited information about age and other risk factors for adverse events and readmission after the procedure. This knowledge is vital to understand the true risk profile of this common surgery. PURPOSE: To investigate if age and medical comorbidities were risk factors for postoperative adverse events and readmission after meniscectomy. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Patients who underwent arthroscopic meniscectomy between 2005 and 2012 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Age>=65 years and medical comorbidities were evaluated as risk factors for any adverse event (AAE), severe adverse events (SAEs), and readmission after meniscectomy using univariate and multivariate analyses. RESULTS: A total of 17,774 patients who underwent meniscectomy were identified. The mean age was 53.0+/-13.6 years. A total of 3420 patients (19.2%) were >=65 years. Overall, 208 patients (1.17%) had AAE, 203 patients (1.14%) had an SAE, and 102 patients were readmitted (0.97%). Multivariate logistic regression analyses demonstrated no significant differences between age groups for the occurrence of AAE, SAEs, and readmission. Patients with American Society of Anesthesiologists classification>=3 had increased odds of AAE (odds ratio [OR], 1.58), SAEs (OR, 1.59), and readmission (OR, 1.99). Patients with diabetes had increased odds of AAE (OR, 1.57) and SAEs (OR, 1.51). Smokers had increased odds of readmission (OR, 1.67). Patients with pulmonary disease had increased odds of AAE (OR, 1.76) and SAEs (OR, 1.70). CONCLUSION: Meniscectomy is a safe procedure in older patients, as age over 65 years did not increase the odds of any of the adverse events studied. However, regardless of age, patients with an increased comorbidity burden and those with a history of smoking are at increased risk of adverse events and/or readmission after the procedure. CLINICAL RELEVANCE: Knowledge of these risk factors for adverse events and readmission provides essential information for patient selection and preoperative counseling. PMID- 25294870 TI - Association of ARRB1 polymorphisms with the risk of major depressive disorder and with treatment response to mirtazapine. AB - beta-Arrestin 1 is known to be involved in the pathophysiology of major depressive disorder (MDD) and in the underlying mechanism of action of antidepressant therapies. After we screened 39 ARRB1 polymorphisms, we investigated the associations of seven ARRB1 single-nucleotide polymorphisms (SNPs) with the risk of MDD in 270 patients with MDD and 204 normal subjects, and with mirtazapine treatment response in patients with MDD. The genotype distributions of -132C>T and IVS1+85T>C showed significant deviations from Hardy Weinberg equilibrium in patients with MDD but not in normal subjects. After four and 12 weeks of mirtazapine treatment, the proportion of haplotype 1 (ht1) carriers was significantly higher in remitters than in non-remitters after corrections for multiple comparisons (corrected p=0.006 and 0.014 at four and 12 weeks, respectively). After eight and 12 weeks of treatment, scores on the 21 item Hamilton Depression Rating Scale (HAMD21) were significantly lower in patients with MDD with ARRB1 ht1 than in those without ht1. Similarly, after 8 and 12 weeks of treatment, the percent reduction in HAMD21 scores was significantly higher in patients with MDD with ARRB1 ht1 than in those without ht1. The ARRB1 polymorphisms represent promising genetic markers for the prediction of treatment responses to mirtazapine. PMID- 25294871 TI - Molecular phylogeny and evolutionary history of the Eurasiatic orchid genus Himantoglossum s.l. (Orchidaceae). AB - BACKGROUND AND AIMS: Lizard orchids of the genus Himantoglossum include many of Eurasia's most spectacular orchids, producing substantial spikes of showy flowers. However, until recently the genus had received only limited, and entirely traditional, systematic study. The aim of the current work was to provide a more robust molecular phylogeny in order to better understand the evolutionary relationships among species of particular conservation concern. METHODS: All putative species of Himantoglossum s.l. were sampled across its geographical range. A large subsample of the 153 populations studied contributed to an initial survey of nuclear ribosomal internal transcribed spacer (nrITS) ribotypes. Smaller subsets were then sequenced for four plastid regions and the first intron of the low-copy-number nuclear gene LEAFY. Rooted using Steveniella as outgroup, phylogenetic trees were generated using parsimony and Bayesian methods from each of the three datasets, supplemented with a ribotype network. KEY RESULTS: The resulting trees collectively determined the order of branching of the early divergent taxa as Himantoglossum comperianum > H. robertianum group > H. formosum, events that also involved significant morphological divergence. Relaxed molecular clock dating suggested that these divergences preceded the Pleistocene glaciations (the origin of the H. robertianum group may have coincided with the Messinian salinity crisis) and occurred in Asia Minor and/or the Caucasus. Among more controversial taxa of the H. hircinum-jankae clade, which are only subtly morphologically divergent, topological resolution was poorer and topological incongruence between datasets was consequently greater. CONCLUSIONS: Plastid sequence divergence is broadly consistent with prior, morphologically circumscribed taxa and indicates a division between H. hircinum adriaticum to the west of the Carpathians and H. jankae-caprinum (plus local endemics) to the east, a distinction also suggested by nrITS ribotypes. LEAFY phylogenies are less congruent with prior taxonomic arrangements and include one likely example of paralogy. Himantoglossum metlesicsianum fully merits its IUCN Endangered status. Potentially significant genetic variation was detected within Steveniella satyrioides, H. robertianum and H. hircinum. However, confident circumscription of the more derived species of Himantoglossum s.s., including local endemics of hybrid origin, must await future morphometric and population genetic analyses. PMID- 25294872 TI - Promoter activation by CII, a potent transcriptional activator from bacteriophage 186. AB - The lysogeny promoting protein CII from bacteriophage 186 is a potent transcriptional activator, capable of mediating at least a 400-fold increase in transcription over basal activity. Despite being functionally similar to its counterpart in phage lambda, it shows no homology at the level of protein sequence and does not belong to any known family of transcriptional activators. It also has the unusual property of binding DNA half-sites that are separated by 20 base pairs, center to center. Here we investigate the structural and functional properties of CII using a combination of genetics, in vitro assays, and mutational analysis. We find that 186 CII possesses two functional domains, with an independent activation epitope in each. 186 CII owes its potent activity to activation mechanisms that are dependent on both the sigma(70) and alpha C terminal domain (alphaCTD) components of RNA polymerase, contacting different functional domains. We also present evidence that like lambda CII, 186 CII is proteolytically degraded in vivo, but unlike lambda CII, 186 CII proteolysis results in a specific, transcriptionally inactive, degradation product with altered self-association properties. PMID- 25294873 TI - Substrate specificity of human protein arginine methyltransferase 7 (PRMT7): the importance of acidic residues in the double E loop. AB - Protein arginine methyltransferase 7 (PRMT7) methylates arginine residues on various protein substrates and is involved in DNA transcription, RNA splicing, DNA repair, cell differentiation, and metastasis. The substrate sequences it recognizes in vivo and the enzymatic mechanism behind it, however, remain to be explored. Here we characterize methylation catalyzed by a bacterially expressed GST-tagged human PRMT7 fusion protein with a broad range of peptide and protein substrates. After confirming its type III activity generating only omega-N(G) monomethylarginine and its distinct substrate specificity for RXR motifs surrounded by basic residues, we performed site-directed mutagenesis studies on this enzyme, revealing that two acidic residues within the double E loop, Asp-147 and Glu-149, modulate the substrate preference. Furthermore, altering a single acidic residue, Glu-478, on the C-terminal domain to glutamine nearly abolished the activity of the enzyme. Additionally, we demonstrate that PRMT7 has unusual temperature dependence and salt tolerance. These results provide a biochemical foundation to understanding the broad biological functions of PRMT7 in health and disease. PMID- 25294874 TI - Toll-like receptors as a target of food-derived anti-inflammatory compounds. AB - Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for TLR-inhibiting activity in HEK293 cells co expressing TLR with the NF-kappaB reporter gene, we found cabbage and onion extracts to be the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin 4'-O-beta-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain insight into the inhibitory mechanism of TLR dimerization, we developed a novel probe combining an isothiocyanate-reactive group and an alkyne functionality for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds. PMID- 25294875 TI - Changes in transcription and metabolism during the early stage of replicative cellular senescence in budding yeast. AB - Age-related damage accumulates and a variety of biological activities and functions deteriorate in senescent cells. However, little is known about when cellular aging behaviors begin and what cellular aging processes change. Previous research demonstrated age-related mRNA changes in budding yeast by the 18th to 20th generation, which is the average replicative lifespan of yeast (i.e. about half of the population is dead by this time point). Here, we performed transcriptional and metabolic profiling for yeast at early stages of senescence (4th, 7th, and 11th generation), that is, for populations in which most cells are still alive. Transcriptional profiles showed up- and down-regulation for ~20% of the genes profiled after the first four generations, few further changes by the 7th generation, and an additional 12% of the genes were up- and down-regulated after 11 generations. Pathway analysis revealed that these 11th generation cells had accumulated transcripts coding for enzymes involved in sugar metabolism, the TCA cycle, and amino acid degradation and showed decreased levels of mRNAs coding for enzymes involved in amino acid biosynthetic pathways. These observations were consistent with the metabolomic profiles of aging cells: an accumulation of pyruvic acid and TCA cycle intermediates and depletion of most amino acids, especially branched-chain amino acids. Stationary phase-induced genes were highly expressed after 11 generations even though the growth medium contained adequate levels of nutrients, indicating deterioration of the nutrient sensing and/or signaling pathways by the 11th generation. These changes are presumably early indications of replicative senescence. PMID- 25294876 TI - Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) promotes non-homologous end joining and inhibits homologous recombination repair upon DNA damage. AB - Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) has been shown to be involved in gene silencing and DNA damage. However, the exact mechanisms of how SMCHD1 participates in DNA damage remains largely unknown. Here we present evidence that SMCHD1 recruitment to DNA damage foci is regulated by 53BP1. Knocking out SMCHD1 led to aberrant gammaH2AX foci accumulation and compromised cell survival upon DNA damage, demonstrating the critical role of SMCHD1 in DNA damage repair. Following DNA damage induction, SMCHD1 depletion resulted in reduced 53BP1 foci and increased BRCA1 foci, as well as less efficient non-homologous end joining (NHEJ) and elevated levels of homologous recombination (HR). Taken together, these results suggest an important function of SMCHD1 in promoting NHEJ and repressing HR repair in response to DNA damage. PMID- 25294877 TI - 67-kDa laminin receptor-dependent protein phosphatase 2A (PP2A) activation elicits melanoma-specific antitumor activity overcoming drug resistance. AB - The Ras/Raf/MEK/ERK pathway has been identified as a major, druggable regulator of melanoma. Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, resulting in constitutive melanoma hyperproliferation. A selective BRAF inhibitor showed remarkable clinical activity in patients with mutated BRAF. Unfortunately, most patients acquire resistance to the BRAF inhibitor, highlighting the urgent need for new melanoma treatment strategies. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) inhibits cell proliferation independently of BRAF inhibitor sensitivity, suggesting that increased understanding of the anti-melanoma activity of EGCG may provide a novel therapeutic target. Here, by performing functional genetic screening, we identified protein phosphatase 2A (PP2A) as a critical factor in the suppression of melanoma cell proliferation. We demonstrated that tumor overexpressed 67-kDa laminin receptor (67LR) activates PP2A through adenylate cyclase/cAMP pathway eliciting inhibitions of oncoproteins and activation of tumor suppressor Merlin. Activating 67LR/PP2A pathway leading to melanoma specific mTOR inhibition shows strong synergy with the BRAF inhibitor PLX4720 in the drug-resistant melanoma. Moreover, SET, a potent inhibitor of PP2A, is overexpressed on malignant melanoma. Silencing of SET enhances 67LR/PP2A signaling. Collectively, activation of 67LR/PP2A signaling may thus be a novel rational strategy for melanoma-specific treatment. PMID- 25294879 TI - Connexin 46 (cx46) gap junctions provide a pathway for the delivery of glutathione to the lens nucleus. AB - Maintenance of adequate levels of glutathione (GSH) in the lens nucleus is critical for protection of lens proteins from the effects of oxidative stress and for lens transparency. How GSH is transported to the nucleus is unknown. We show that GSH diffuses to the nucleus from the outer cortex, where a high concentration of the anti-oxidant is established by synthesis or uptake, via the network of gap junctions. Using electrophysiological measurements, we found that channels formed by Cx46 and Cx50, the two connexin isoforms expressed in the lens, were moderately cation-selective (P(Na)/P(Cl) ~5 for Cx46 and ~3 for Cx50). Single channel permeation of the larger GSH anion was low but detectable (P(Na)/P(GSH) ~12 for Cx46 and ~8 for Cx50), whereas permeation of divalent anion glutathione disulfide (GSSG) was undetectable. Measurement of GSH levels in the lenses from connexin knock-out (KO) mice indicated Cx46, and not Cx50, is necessary for transport of GSH to the core. Levels of GSH in the nucleus were markedly reduced in Cx46 KO, whereas they were unaffected by Cx50 KO. We also show that GSH delivery to the nucleus is not dependent on the lens microcirculation, which is believed to be responsible for extracellular transport of other nutrients to membrane transporters in the core. These results indicate that glutathione diffuses from cortical fiber cells to the nucleus via gap junction channels formed by Cx46. We present a model of GSH diffusion from outer cells to inner fiber cells through gap junctions. PMID- 25294880 TI - Biochemical and biophysical characterization of an unexpected bacteriolytic activity of VanX, a member of the vancomycin-resistance vanA gene cluster. AB - VanX is a d-alanyl-d-alanine (d-Ala-d-Ala) dipeptidase encoded in the vancomycin resistance vanA gene cluster. Here we report that strong bacteriolysis occurred when isolated VanX was expressed in Escherichia coli at temperatures lower than 30 degrees C, which was unexpected because the vanA operon confers vancomycin resistance by protecting the cell wall. Therefore, we monitored cell lysis by measuring sample turbidity with absorbance at 590 nm and VanX expression using SDS-PAGE. No cell lysis was observed when VanX was expressed, even in large quantities, in the cell inclusion bodies at 37 degrees C, suggesting that a natively folded VanX is required for lysis. In addition, VanX mutants with suppressed dipeptidase activity did not lyse E. coli cells, confirming that bacteriolysis originated from the dipeptidase activity of VanX. We also observed shape changes in E. coli cells undergoing VanX-mediated lysis with optical microscopy and classified these changes into three classes: bursting, deformation, and leaking fluid. Optical microscopic image analysis fully corroborated our interpretation of the turbidity changes in the samples. From a practical perspective, the finding that VanX expressed in isolation induces cell lysis suggests that inhibitors of VanA and VanH that act downstream from VanX could provide a new class of therapeutic chemicals against bacteria expressing the vancomycin-resistance gene cluster. PMID- 25294878 TI - Amyloid formation by human carboxypeptidase D transthyretin-like domain under physiological conditions. AB - Protein aggregation is linked to a growing list of diseases, but it is also an intrinsic property of polypeptides, because the formation of functional globular proteins comes at the expense of an inherent aggregation propensity. Certain proteins can access aggregation-prone states from native-like conformations without the need to cross the energy barrier for unfolding. This is the case of transthyretin (TTR), a homotetrameric protein whose dissociation into its monomers initiates the aggregation cascade. Domains with structural homology to TTR exist in a number of proteins, including the M14B subfamily carboxypeptidases. We show here that the monomeric transthyretin-like domain of human carboxypeptidase D aggregates under close to physiological conditions into amyloid structures, with the population of folded but aggregation-prone states being controlled by the conformational stability of the domain. We thus confirm that the TTR fold keeps a generic residual aggregation propensity upon folding, resulting from the presence of preformed amyloidogenic beta-strands in the native state. These structural elements should serve for functional/structural purposes, because they have not been purged out by evolution, but at the same time they put proteins like carboxypeptidase D at risk of aggregation in biological environments and thus can potentially lead to deposition diseases. PMID- 25294881 TI - The CpxR/CpxA two-component regulatory system up-regulates the multidrug resistance cascade to facilitate Escherichia coli resistance to a model antimicrobial peptide. AB - A genome-wide susceptibility assay was used to identify specific CpxR-dependent genes that facilitate Escherichia coli resistance to a model cationic antimicrobial peptide, protamine. A total of 115 strains from the Keio Collection, each of which contained a deletion at a demonstrated or predicted CpxR/CpxA-dependent locus, were tested for protamine susceptibility. One strain that exhibited high susceptibility carried a deletion of tolC, a gene that encodes the outer membrane component of multiple tripartite multidrug transporters. Concomitantly, two of these efflux systems, AcrAB/TolC and EmrAB/TolC, play major roles in protamine resistance. Activation of the CpxR/CpxA system stimulates mar transcription, suggesting a new regulatory circuit that enhances the multidrug resistance cascade. Tripartite multidrug efflux systems contribute to bacterial resistance to protamine differently from the Tat system. DNase I footprinting analysis demonstrated that the CpxR protein binds to a sequence located in the -35 and -10 regions of mar promoter. This sequence resembles the consensus CpxR binding site, however, on the opposite strand. aroK, a CpxR-dependent gene that encodes a shikimate kinase in the tryptophan biosynthesis pathway, was also found to facilitate protamine resistance. Specific aromatic metabolites from this pathway, such as indole, can stimulate expression of well studied CpxR-dependent genes degP and cpxP, which are not components of the tripartite multidrug transporters. Thus, we propose a novel mechanism for E. coli to modulate resistance to protamine and likely other cationic antimicrobial peptides in which the CpxR/CpxA system up-regulates mar transcription in response to specific aromatic metabolites, subsequently stimulating the multidrug resistance cascade. PMID- 25294882 TI - Therapeutic potential of induced neural stem cells for spinal cord injury. AB - The spinal cord does not spontaneously regenerate, and treatment that ensures functional recovery after spinal cord injury (SCI) is still not available. Recently, fibroblasts have been directly converted into induced neural stem cells (iNSCs) by the forced expression defined transcription factors. Although directly converted iNSCs have been considered to be a cell source for clinical applications, their therapeutic potential has not yet been investigated. Here we show that iNSCs directly converted from mouse fibroblasts enhance the functional recovery of SCI animals. Engrafted iNSCs could differentiate into all neuronal lineages, including different subtypes of mature neurons. Furthermore, iNSC derived neurons could form synapses with host neurons, thus enhancing the locomotor function recovery. A time course analysis of iNSC-treated SCI animals revealed that engrafted iNSCs effectively reduced the inflammatory response and apoptosis in the injured area. iNSC transplantation also promoted the active regeneration of the endogenous recipient environment in the absence of tumor formation. Therefore, our data suggest that directly converted iNSCs hold therapeutic potential for treatment of SCI and may thus represent a promising cell source for transplantation therapy in patients with SCI. PMID- 25294884 TI - The accuracy of C-reactive protein, procalcitonin, and s-TREM-1 in the prediction of serious bacterial infection in neonates. AB - In this prospective study, we examined the usefulness of C-reactive protein (CRP), soluble triggering receptor expressed on myeloid cells (s-TREM-1), and procalcitonin (PCT), in identifying serious bacterial infection (SBI) among neonates. Infants younger than 3 months with suspected SBI were included and serum concentrations of CRP, PCT, and s-TREM-1 were determined. RESULTS: A total of 112 patients (19 with SBI and 93 with negative cultures) were evaluated. There were no statistical differences between the 2 groups regarding age, presence of fever, and serum concentrations of the different biomarkers. Performance of the different biomarkers were as follows: The sensitivities were 45%, 55%, and 82% for CRP, PCT, and s-TREM-1, respectively, whereas the specificities we 82%, 75%, and 48% for CRP, PCT, and s-TREM-1, respectively. The areas under the receiver operating characteristic curve were 0.6, 0.63, and 0.61, for CRP, PCT, and s-TREM 1, respectively. CONCLUSIONS: In real-life pediatric practice, none of the tested biomarkers was sufficiently accurate to serve as a reliable indicator for the identification of SBI in neonates. PMID- 25294883 TI - Sumoylated human histone H4 prevents chromatin compaction by inhibiting long range internucleosomal interactions. AB - The structure of eukaryotic chromatin directly influences gene function, and is regulated by chemical modifications of the core histone proteins. Modification of the human histone H4 N-terminal tail region by the small ubiquitin-like modifier protein, SUMO-3, is associated with transcription repression. However, the direct effect of sumoylation on chromatin structure and function remains unknown. Therefore, we employed a disulfide-directed strategy to generate H4 homogenously and site-specifically sumoylated at Lys-12 (suH4ss). Chromatin compaction and oligomerization assays with nucleosomal arrays containing suH4ss established that SUMO-3 inhibits array folding and higher order oligomerization, which underlie chromatin fiber formation. Moreover, the effect of sumoylation differed from that of acetylation, and could be recapitulated with the structurally similar protein ubiquitin. Mechanistic studies at the level of single nucleosomes revealed that, unlike acetylation, the effect of SUMO-3 arises from the attenuation of long range internucleosomal interactions more than from the destabilization of a compacted dinucleosome state. Altogether, our results present the first insight on the direct structural effects of histone H4 sumoylation and reveal a novel mechanism by which SUMO-3 inhibits chromatin compaction. PMID- 25294885 TI - Goniothalamin enhances the ATPase activity of the molecular chaperone Hsp90 but inhibits its chaperone activity. AB - Hsp90 is an ATP-dependent molecular chaperone that is involved in important cellular pathways such as signal transduction pathways. It is a potential cancer drug target because it plays a critical role for stabilization and activation of oncoproteins. Thus, small molecule compounds that control the Hsp90 function are useful to elucidate potential lead compounds against cancer. We studied effect of a naturally occurring styryl-lactone goniothalamin on the activity of Hsp90. Although many drugs targeting Hsp90 inhibit the ATPase activity of Hsp90, goniothalamin enhanced rather than inhibited the ATPase activity of a cyanobacterial Hsp90 (HtpG) and a yeast Hsp90. It increased both K(m) and k(cat) of the Hsp90s. Domain competition assays and tryptophan fluorescence measurements with various truncated derivatives of HtpG indicated that goniothalamin binds to the N-terminal domain of HtpG. Goniothalamin did not influence on the interaction of HtpG with a non-native protein or the anti-aggregation activity of HtpG significantly. However, it inhibited the activity of HtpG that assists refolding of a non-native protein in cooperation with the Hsp70 chaperone system. This is the first report to show that a small molecule that binds to the N-terminal domain of Hsp90 activates its ATPase activity, while inhibiting the chaperone function of Hsp90. PMID- 25294887 TI - Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials. AB - BACKGROUND: The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT. PATIENTS AND METHODS: Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor. RESULTS: A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40 years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms. CONCLUSION: Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care. PMID- 25294888 TI - Comparison of salivary and serum glucose levels in diabetic patients. AB - Diabetes mellitus is a noncommunicable disease with a rising prevalence worldwide and in developing countries. The most commonly used diagnostic biofluid for detection of glucose levels is blood, but sample collection is an invasive and painful procedure. Thus, there arises a need for a noninvasive and painless technique to detect glucose levels. The objectives of the present study were to estimate the glucose levels of saliva, to assess if any significant correlation existed between the serum and salivary glucose levels, and to correlate salivary glucose levels with regard to duration of diabetes, age, and gender. In the present study, serum and salivary glucose levels of 200 subjects (100 diabetic subjects and 100 nondiabetic subjects) were estimated by glucose oxidase method. Glycosylated hemoglobin levels were also measured in randomly selected 40 diabetic subjects. The findings of present study revealed a significant correlation between salivary and serum glucose levels in both diabetic and nondiabetic subjects. No significant relationship was observed between salivary glucose levels and gender or age in both diabetics and nondiabetics and between salivary glucose levels and duration of diabetes in diabetics. On the basis of the findings, it was concluded that salivary glucose levels could serve as a potentially noninvasive adjunct to monitor glycemic control in diabetic patients. PMID- 25294889 TI - Is neuroendocrine differentiation useful to discriminate primary sinonasal intestinal-type adenocarcinomas from metastatic colorectal adenocarcinomas? AB - Primary sinonasal intestinal-type adenocarcinomas (ITAC) are defined on the basis of their morphological similarities to colorectal adenocarcinomas (CRA). Thus, differential diagnosis with sinonasal metastasis of CRA could be a real challenge. Neuroendocrine differentiation has been variably described in several types of adenocarcinomas and notably in ITACs and CRAs. In a series of 25 ITACs and 25 lymph node metastasis of CRAs (nmCRA), we analysed neuroendocrine differentiation by immunohistochemistry with anti-chromogranin A and synaptophysin antibodies. Neuroendocrine differentiation (chromogranin A and/or synaptophysin positivity) was significantly different (p=0.0002) in ITACs (72%) and in nmCRAs (20%). In conclusion, presence of neuroendocrine cells seems more in favour of a sinonasal intestinal-type adenocarcinoma, than metastatic CRA. This immunohistochemical study could be useful in difficult cases and should be an interesting complement in a clinical discussion. PMID- 25294890 TI - Question 1: Treatment of mild to moderate ketoacidosis in children and adolescents with subcutaneous insulin. PMID- 25294891 TI - Isolation and characterization of multipotent mesenchymal stem cells in nasal polyps. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells in adult tissues. This study aimed to investigate nasal polyp (NP) tissues as a potential new source of multipotent MSCs that maintain their stemness and differentiation potential following multiple rounds of passaging. NP tissues were obtained from 10 patients during endoscopic sinus surgery. After isolating and culturing NP derived MSCs (npMSCs), the expression levels of the surface markers CD34, CD44, CD45, CD73, CD90, CD105, CD106, CD146 and human leukocyte antigens-class II DR antigen (HLA-DR) were estimated by flow cytometry. NpMSCs were cultured in chondrogenic, osteogenic, adipogenic, or neurogenic differentiation medium. The differentiation potential of npMSCs was analyzed by Alcian blue, alizarin red S, oil red O, and immunocytochemical staining and reverse transcription-polymerase chain reaction. The clonogenic potential of npMSCs was measured using a colony forming unit assay. Cell proliferation of npMSCs was measured using the 3-(4,5 Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. Flow cytometry analysis revealed that npMSCs were negative for hematopoietic lineage markers (CD34, CD45, and HLA-DR) and positive for MSC markers (CD44, CD73, CD90, and CD105). The npMSCs differentiated into osteogenic, adipogenic, chondrogenic, and neurogenic lineages, respectively. Chondrogenically differentiated npMSCs were stained with Alcian blue, osteogenically differentiated npMSCs were stained with alizarin red S, and adipogenically differentiated npMSCs were stained with oil red O. Real-time polymerase chain reaction results showed that the differentiated npMSCs expressed the respective differentiation markers (Sox 9 and Col2A for chondrogenesis, Runx2 and osteocalcin for osteogenesis, fatty acid-binding protein 4 and peroxisome proliferator-activated receptor gamma for adipogenesis, TuJ1, neurofilament light chain, and neurofilament heavy chain for neurogenesis). There were no significant differences in the clonogenic potential and proliferation rate between early and late passage npMSCs. These results show that npMSCs possess the characteristics of MSCs in terms of morphology, multipotent differentiation capacity, cell surface marker expression, and clonogenicity. Thus, npMSCs may represent an alternative source of MSCs. PMID- 25294892 TI - The effect of deferoxamine on angiogenesis and bone repair in steroid-induced osteonecrosis of rabbit femoral heads. AB - In this study, we examined whether local deferoxamine (DFO) administration can promote angiogenesis and bone repair in steroid-induced osteonecrosis of the femoral head (ONFH). Steroid-induced ONFH was induced in 65 mature male New Zealand white rabbits by methylprednisolone in combination with lipopolysaccharide. Six weeks later, the rabbits received no treatment (model group, N = 15), bilateral core decompression (CD group, N = 20) or CD in combination with local DFO administration (DFO group, N = 20). Six weeks after the surgery, vascularization in the femoral head was evaluated by ink artery infusion angiography and immunohistochemical staining for von Willebrand Factor (vWF). Bone repair was assessed by histologic analysis and micro-computed tomography (micro-CT). Immunohistochemical staining was performed to analyze the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1alpha (HIF-1alpha), bone morphogenetic protein-2 (BMP-2), and osteocalcin (OCN). Ink artery infusion angiography and microvessel analysis by immuohistochemical staining for vWF showed more blood vessels in the DFO group than other groups. The expression of HIF-1alpha, VEGF, BMP-2, and OCN, indicated by immunohistochemical staining, was higher in the DFO group compared with other groups. Micro-CT scanning results indicated that the DFO group had larger volume of newly formed bone than the CD group. This work indicated that local DFO administration improved angiogenesis and bone repair of early stage ONFH in rabbit model, and it may offer an efficient, economic, and simple therapy for early stage ONFH. PMID- 25294893 TI - Identification of differentially expressed genes related to metabolic syndrome induced with high-fat diet in E3 rats. AB - Understanding the genes differentially expressing in aberrant organs of metabolic syndrome (MetS) facilitates the uncovering of molecular mechanisms and the identification of novel therapeutic targets for the disease. This study aimed to identify differentially expressed genes related to MetS in livers of E3 rats with high-fat-diet-induced metabolic syndrome (HFD-MetS). E3 rats were fed with high fat diet for 24 weeks to induce MetS. Then, suppression subtractive hybridization (SSH) technology was used to identify the genes differentially expressed between HFD-MetS and control E3 rat livers. Twenty positive recombinant clones were chosen randomly from forward subtractive library and sent to sequence. BLAST analysis in GenBank database was used to determine the property of each cDNA fragment. In total, 11 annotated genes, 3 ESTs, and 2 novel gene fragments were identified by SSH technology. The expression of four genes (Alb, Pip4k2a, Scd1, and Tf) known to be associated with MetS and other five genes (Eif1, Rnase4, Rps12, Rup2, and Tmsb4) unknown to be relevant to MetS was significantly up regulated in the livers of HFD-MetS E3 rats compared with control rats using real time quantitative PCR (RT-qPCR). By analyzing the correlations between the expression of these nine genes and serum concentrations of TG, Tch, HDL-C, and LDL-C, we found that there were significant positive correlations between TG and the expression of five genes (Alb, Eif1, Pip4k2a, Rps12, and Tmsb4x), Tch and three genes (Rnase4, Scd1, and Tmsb4x), and LDL-C and two genes (Rnase4 and Scd1), as well there were significant negative correlations between HDL-C and the expression of three genes (Rup2, Scd1, and Tf). This study provides important clues for unraveling the molecular mechanisms of MetS. PMID- 25294894 TI - A glossary of policy frameworks: the many forms of 'universalism' and policy 'targeting'. AB - The recognition that certain characteristics (such as poverty, disadvantage or membership of marginalised social or cultural groups) can make individuals more susceptible to illness has reignited interest in how to combine universal programmes and policies with ones targeted at specific groups. However, 'universalism' and 'targeting' are used in different ways for different purposes. In this glossary, we define different types and approaches to universalism and targeting. We anticipate that greater clarity in relation to what is meant by 'universalism' and 'targeting' will lead to a more nuanced debate and practice in this area. PMID- 25294895 TI - After the RCT: who comes to a family-based intervention for childhood overweight or obesity when it is implemented at scale in the community? AB - BACKGROUND: When implemented at scale, the impact on health and health inequalities of public health interventions depends on who receives them in addition to intervention effectiveness. METHODS: The MEND 7-13 (Mind, Exercise, Nutrition...Do it!) programme is a family-based weight management intervention for childhood overweight and obesity implemented at scale in the community. We compare the characteristics of children referred to the MEND programme (N=18 289 referred to 1940 programmes) with those of the population eligible for the intervention, and assess what predicts completion of the intervention. RESULTS: Compared to the MEND-eligible population, proportionally more children who started MEND were: obese rather than overweight excluding obese; girls; Asian; from families with a lone parent; living in less favourable socioeconomic circumstances; and living in urban rather than rural or suburban areas. Having started the programme, children were relatively less likely to complete it if they: reported 'abnormal' compared to 'normal' levels of psychological distress; were boys; were from lone parent families; lived in less favourable socioeconomic circumstances; and had participated in a relatively large MEND programme group; or where managers had run more programmes. CONCLUSIONS: The provision and/or uptake of MEND did not appear to compromise and, if anything, promoted participation of those from disadvantaged circumstances and ethnic minority groups. However, this tendency was diminished because programme completion was less likely for those living in less favourable socioeconomic circumstances. Further research should explore how completion rates of this intervention could be improved for particular groups. PMID- 25294886 TI - Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. AB - BACKGROUND: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. PATIENTS AND METHODS: We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX +/- cetuximab therapy included in the PETACC8 trial. Patients with BRAF mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model. RESULTS: KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051). CONCLUSION: KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors. CLINICAL TRIAL NUMBER: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23. PMID- 25294896 TI - Is changing status through housing tenure associated with changes in mental health? Results from the British Household Panel Survey. AB - BACKGROUND: Actual or perceived status, such as housing tenure, may impact on health through stress-inducing social comparisons. Studies of how status change impacts mental health change are rare but important because they are less prone to confounding. METHODS: We used data from the British Household Panel Survey to compare psychological distress in local authority renters who opted to buy their home under the UK's Right to Buy (RTB) policy versus those who continued to rent the same (social non-mover (SNM)) or a different (social mover (SM)) local authority property or who bought privately (owner mover (OM)). General Health Questionnaire (GHQ-12) scores before and after any change in tenure and/or address were compared across groups using a difference-in-difference approach. RESULTS: Individuals who moved house (bought or rented) were younger while those who bought (the same or different house) were better off, more likely to be employed, and had higher educational qualifications. Individuals who bought their home (under RTB or privately) had lower distress scores from the outset. Individuals who moved house (bought or rented) experienced a rise in distress prior to moving that was no longer evident 1 year after the move. There was no evidence that changing tenure reduced psychological distress comparing (difference (95% CI)) average GHQ score 2 years preaddress and 1 year postaddress/tenure change in RTB vs SNM, SM, OM: -0.08 (-0.68 to 0.51), 0.16 ( 0.70 to 1.01) and -0.17 (-1.28 to 0.94), respectively). CONCLUSIONS: Changing tenure under RTB did not, on average, impact psychological distress, suggesting that this status change did not change mental health. PMID- 25294897 TI - A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. AB - PURPOSE: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177). EXPERIMENTAL DESIGN: Eligible patients received twice daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade >= 2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability. RESULTS: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients. CONCLUSIONS: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. PMID- 25294899 TI - Whole-body low-dose computed tomography and advanced imaging techniques for multiple myeloma bone disease. AB - Detection of lytic bone lesions is crucial in the workup for multiple myeloma and very often dictates the decision to start treatment. Conventional radiography, despite decades of use, is often insufficient for detection of bone disease in multiple myeloma. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Novel whole-body low-dose computed tomography (WBLDCT) protocols allow for collection of superior image detail of the skeleton at doses of radiation similar to those used for conventional planar radiography. Several studies have shown that WBLDCT has a superior detection rate for lytic bone lesions compared with whole-body X-ray (WBXR), potentially leading to restaging and changes in therapy. MRI and PET provide imaging data important for assessing disease activity and prognostication. Because of several advantages over WBXR, WBLDCT is already the standard imaging technique for use in patients with multiple myeloma in many European institutions. However, the radiographic skeletal survey or WBXR is still the initial study of choice used to screen for myeloma bone disease in many institutions. In this review, we aim to explore the changing landscape of imaging for myeloma bone disease through use of modern imaging techniques. PMID- 25294898 TI - New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. AB - Over the past two decades, slow but deliberate progress has been made in understanding the genetics of chronic lymphocytic leukemia (CLL) and how the surrounding microenvironment influences leukemia cell survival. The complexity of CLL with respect to different chromosomal aberrations, lack of a common aberrant signaling pathway activation, and associated immune suppression of the disease has been seen a major stumbling block for developing a single targeted therapy similar to imatinib used in chronic myeloid leukemia. The upcoming therapeutic era we are entering with the B-cell receptor (BCR) tyrosine kinase inhibitors ibrutinib and idelalisib appears to be overcoming this obstacle. Indeed, for the large majority of patients, it appears that application of BCR kinase inhibitors can promote durable remissions without the need for chemotherapy. Where other very active targeted agents such as ABT-199, therapeutic antibodies, and chimeric antigen receptor-modified T-cells will be used in CLL also represents a major question that future clinical trials will answer. PMID- 25294900 TI - Team work matters: dual inhibition puts non-hodgkin lymphoma under siege. AB - Inhibitors of PI3K/mTOR and histone deacetylases (HDAC) are effective in non Hodgkin lymphoma (NHL). However, clinical resistance eventually ensues and combinatory therapies are sought to prevent it. Preclinical evaluation of dual PI3K/mTOR and HDAC inhibition is synergistic against NHL, paving the way for bench-to-bedside translation. PMID- 25294901 TI - miR-204-5p inhibits proliferation and invasion and enhances chemotherapeutic sensitivity of colorectal cancer cells by downregulating RAB22A. AB - PURPOSE: miR-204-5p was found to be downregulated in colorectal cancer tissues in our preliminary microarray analyses. However, the function of miR-204-5p in colorectal cancer remains unknown. We therefore investigated the role, mechanism, and clinical significance of miR-204-5p in colorectal cancer development and progression. EXPERIMENTAL DESIGN: We measured the expression of miR-204-5p and determined its correlation with patient prognoses. Ectopic expression in colorectal cancer cells, xenografts, and pulmonary metastasis models was used to evaluate the effects of miR-204-5p on proliferation, migration, and chemotherapy sensitivity. Luciferase assay and Western blotting were performed to validate the potential targets of miR-204-5p after the preliminary screening by a microarray analysis and computer-aided algorithms. RESULTS: miR-204-5p is frequently downregulated in colorectal cancer tissues, and survival analysis showed that the downregulation of miR-204-5p in colorectal cancer was associated with poor prognoses. Ectopic miR-204-5p expression repressed colorectal cancer cell growth both in vitro and in vivo. Moreover, restoring miR-204-5p expression inhibited colorectal cancer migration and invasion and promoted tumor sensitivity to chemotherapy. Mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in colorectal cancer. Furthermore, RAB22A protein levels in colorectal cancer tissues were frequently increased and negatively associated with miR-204-5p levels and survival time. CONCLUSIONS: Our results demonstrate for the first time that miR 204-5p acts as a tumor suppressor in colorectal cancer through inhibiting RAB22A and reveal RAB22A to be a new oncogene and prognostic factor for colorectal cancer. PMID- 25294902 TI - Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma. AB - PURPOSE: To better understand the complete genomic architecture of lung adenocarcinoma. EXPERIMENTAL DESIGN: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes. RESULTS: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma. CONCLUSIONS: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients. PMID- 25294903 TI - DNA methylation status of key cell-cycle regulators such as CDKNA2/p16 and CCNA1 correlates with treatment response to doxorubicin and 5-fluorouracil in locally advanced breast tumors. AB - PURPOSE: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5 fluorouracil and mitomycin C in human breast cancers. EXPERIMENTAL DESIGN: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis. RESULTS: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, galphai signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status. CONCLUSION: We identified and validated key cell cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity. PMID- 25294904 TI - Genetic evolution of T-cell resistance in the course of melanoma progression. AB - PURPOSE: CD8(+) T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells. EXPERIMENTAL DESIGN: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell-stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor-T-cell interaction. RESULTS: Metastases Ma-Mel-48a and Ma-Mel 48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I-negative due to an inactivating mutation in one allele of the beta-2 microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel 48b cells, pointing to an early acquired genetic event predisposing to development of beta2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second beta2m-deficient melanoma model. CONCLUSION: Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell-based immunotherapy. PMID- 25294905 TI - Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts. AB - PURPOSE: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts. EXPERIMENTAL DESIGN: Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. RESULTS: HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2 amplified models, and was associated with increased apoptosis and decreased proliferation. CONCLUSIONS: Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation. PMID- 25294907 TI - Efficacy of anti-RON antibody Zt/g4-drug maytansinoid conjugation (Anti-RON ADC) as a novel therapeutics for targeted colorectal cancer therapy. AB - PURPOSE: The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4-maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy. EXPERIMENTAL DESIGN: Zt/g4 (IgG1a/kappa) was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4-DM1-induced RON endocytosis, cell cycle arrest, and cytotoxicity. Efficacy of Zt/g4-DM1 in vivo was evaluated in mouse xenograft CRC tumor model. RESULTS: Zt/g4-DM1 rapidly induced RON endocytosis, arrested cell cycle at G2-M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4 DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4-DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4-DM1 is stable at 37 degrees C for up to 30 days. At 60 mg/kg, Zt/g4-DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight. CONCLUSION: Zt/g4-DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4 DM1 for RON-targeted CRC therapy in the future. PMID- 25294906 TI - MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro. AB - PURPOSE: To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines. EXPERIMENTAL DESIGN: MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNalpha or IFNgamma, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T cell activation and cytokine production. RESULTS: Both MHC class I and beta2 microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25(+) of CD3(+)) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment. CONCLUSIONS: MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC. PMID- 25294908 TI - Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma. AB - PURPOSE: Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC to define additional treatment options. EXPERIMENTAL DESIGN: We analyzed 576 lung adenocarcinomas from patients of Asian and Caucasian ethnicity. We identified a subset of cancers that did not harbor any known oncogenic alteration. We performed targeted next-generation sequencing (NGS) assay on 24 patients from this set with >75% tumor cell content. RESULTS: EGFR mutations were the most common oncogenic alteration from both Asian (53%) and Caucasian (41.6%) patients. No known oncogenic alterations were present in 25.7% of Asian and 31% of Caucasian tumor specimens. We identified a FGFR3-TACC3 fusion event in one of 24 patients from this subset using targeted NGS. Two additional patients harboring FGFR3-TACC3 were identified by screening our entire cohort (overall prevalence, 0.5%). Expression of FGFR3-TACC3 led to IL3 independent growth in Ba/F3 cells. These cells were sensitive to pan-fibroblast growth factor receptor (pan-FGFR) inhibitors but not the epidermal growth factor (EGFR) inhibitor gefitinib. CONCLUSIONS: FGFR3-TACC3 rearrangements occur in a subset of patients with lung adenocarcinoma. Such patients should be considered for clinical trials featuring FGFR inhibitors. PMID- 25294910 TI - Asparagine synthetase polymorphisms and toxicity and efficacy of asparaginases. AB - Asparaginases develop innovative "tumor starvation" conditions for all antileukemia treatments; however, administrations are limited by the toxicities of this drug. Patients exhibiting moderate toxicity have optimal treatment outcomes. Certain asparagine synthetase polymorphisms may contribute to severe host toxicities in divergent subsets of patients, whereas others do not. Clinical correlations should be evaluated. PMID- 25294909 TI - Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer. AB - PURPOSE: Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here, we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell-specific nestin promoter, and encoding for antiangiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer. EXPERIMENTAL DESIGN: Antitumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites-derived tumor cells, and primary patient ascites-derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a Transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou Talalay synergy analysis. Viral replication, herpes simplex virus receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer. RESULTS: Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites-derived and patient ascites derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. CONCLUSIONS: This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer. PMID- 25294911 TI - T-cell levels are prognostic in mantle cell lymphoma. AB - PURPOSE: The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL). EXPERIMENTAL DESIGN: Cell populations were investigated using flow cytometry in diagnostic MCL (n = 153) and reactive (n = 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters. RESULTS: MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4(+) T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P = 0.007; P = 0.003) and in the diffuse compared with the nodular subtype (P = 0.022; P = 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P = 0.003). Higher levels of CD3(+) and CD4(+) T cells and higher CD4:CD8 ratios were associated with indolent disease (P = 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P = 0.023). CONCLUSION: CD3(+), CD8(+), and particularly CD4(+) T cell levels are higher in indolent MCL and decrease with more aggressive histology as reflected by a diffuse growth pattern. High CD4:CD8 ratio correlated independently of other high-risk prognostic factors with longer OS, suggesting a prognostic role for T cells in MCL. PMID- 25294912 TI - Complement pathway is frequently altered in endometriosis and endometriosis associated ovarian cancer. AB - PURPOSE: Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). EXPERIMENTAL DESIGN: RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes. RESULTS: One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. CONCLUSIONS: These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC. PMID- 25294914 TI - Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a european multicenter analysis based on ConticaGIST. AB - PURPOSE: Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST. EXPERIMENTAL DESIGN: Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months. RESULTS: On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P = 0.037] and KIT exon 11 deletions involving codons 557 and/or 558 [KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P = 0.004]. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis [HR, 0.23; 95% CI, 0.1-0.6; P = 0.002]. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS. CONCLUSIONS: In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment. PMID- 25294913 TI - A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma. AB - PURPOSE: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies. EXPERIMENTAL DESIGN: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti reovirus antibody assay was performed weekly during cycle 1. RESULTS: There were no dose-limiting toxicities, patients reached the 3 * 10(10) TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months. CONCLUSIONS: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. PMID- 25294915 TI - Elevated serum angiopoietin-like protein 2 correlates with the metastatic properties of colorectal cancer: a serum biomarker for early diagnosis and recurrence. AB - PURPOSE: Angiopoietin-like protein 2 (ANGPTL2) is a mediator of chronic inflammation and inflammatory carcinogenesis. The biologic and clinical significance of ANGPTL2 remains unknown in human cancer. Therefore, we investigated the function of ANGPTL2 and evaluated its clinical significance in both primary tumors and matched sera in patients with colorectal cancer. EXPERIMENTAL DESIGN: A colorectal cancer cell line was transfected with siRNA against ANGPTL2 for the assessment of its function. We examined ANGPTL2 expression in colorectal cancer tissues (n = 195) by immunohistochemistry. Finally, we screened serum ANGPTL2 levels from 32 colorectal cancers and 23 normal controls (NC), and validated these results in serum samples obtained from 195 colorectal cancers and 45 NCs by ELISA. RESULTS: Knockdown of ANGPTL2 in vitro significantly inhibited cell proliferation, migration, and invasion, whereas it enhanced anoikis. ANGPTL2 was overexpressed in colorectal cancer tissues, and was significantly associated with advanced T stage, lymph node, and liver metastasis. Likewise, serum ANGPTL2 levels in colorectal cancers were significantly higher than NCs (P < 0.01), and allowed distinguishing of colorectal cancers from NCs with high accuracy (AUC = 0.837). The subsequent validation step confirmed that serum ANGPTL2 levels in colorectal cancers were significantly higher than in NCs (P < 0.0001), and had a high AUC value (0.885) for distinguishing colorectal cancers from NCs. High serum ANGPTL2 was significantly associated with advanced T stage, lymph node and liver metastasis, early relapse, and poor prognosis in colorectal cancers. CONCLUSION: Serum ANGPTL2 is a novel diagnostic and recurrence-predictive biomarker in patients with colorectal cancer. PMID- 25294916 TI - Predicting breast tumor response to neoadjuvant chemotherapy with diffuse optical spectroscopic tomography prior to treatment. AB - PURPOSE: To determine whether pretreatment biomarkers obtained from diffuse optical spectroscopic tomographic (DOST) imaging predicts breast tumor response to neoadjuvant chemotherapy (NAC), which would have value to potentially eliminate delays in prescribing definitive local regional therapy that may occur from a standard complete 6- to 8-month course of NAC. EXPERIMENTAL DESIGN: Nineteen patients undergoing NAC were imaged with DOST before, during, and after treatment. The DOST images of total hemoglobin concentration (HbT), tissue oxygen saturation (StO2), and water (H2O) fraction at different time points have been used for testing the abilities of differentiating patients having pathologic complete response (pCR) versus pathologic incomplete response (pIR). RESULTS: Significant differences (P < 0.001, AUC = 1.0) were found between pCR patients versus pIR in outcome, based on the percentage change in tumor HbT within the first cycle of treatment. In addition, pretreatment tumor HbT (pretreatment HbT) relative to the contralateral breast was statistically significant (P = 0.01, AUC = 0.92) in differentiating pCR from pIR. CONCLUSIONS: This is the first clinical evidence that DOST HbT may differentiate the two groups with predictive significance based on data acquired before NAC even begins. The study also demonstrates the potential of accelerating the validation of optimal NAC regimens through future randomized clinical trials by reducing the number of patients required and the length of time they need to be followed by using a validated imaging surrogate as an outcome measure. PMID- 25294918 TI - The hydroxyl radical in plants: from seed to seed. AB - The hydroxyl radical (OH(*)) is the most potent yet short-lived of the reactive oxygen species (ROS) radicals. Just as hydrogen peroxide was once considered to be simply a deleterious by-product of oxidative metabolism but is now acknowledged to have signalling roles in plant cells, so evidence is mounting for the hydroxyl radical as being more than merely an agent of destruction. Its oxidative power is harnessed to facilitate germination, growth, stomatal closure, reproduction, the immune response, and adaptation to stress. It features in plant cell death and is a key tool in microbial degradation of plant matter for recycling. Production of the hydroxyl radical in the wall, at the plasma membrane, and intracellularly is facilitated by a range of peroxidases, superoxide dismutases, NADPH oxidases, and transition metal catalysts. The spatio temporal activity of these must be tightly regulated to target substrates precisely to the site of radical production, both to prevent damage and to accommodate the short half life and diffusive capacity of the hydroxyl radical. Whilst research has focussed mainly on the hydroxyl radical's mode of action in wall loosening, studies now extend to elucidating which proteins are targets in signalling systems. Despite the difficulties in detecting and manipulating this ROS, there is sufficient evidence now to acknowledge the hydroxyl radical as a potent regulator in plant cell biology. PMID- 25294917 TI - A tissue biomarker-based model that identifies patients with a high risk of distant metastasis and differential survival by length of androgen deprivation therapy in RTOG protocol 92-02. AB - PURPOSE: To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox 2) and risk of distant metastasis. EXPERIMENTAL DESIGN: RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy + short-term androgen deprivation therapy (STADT) with EBRT + long-term ADT (LTADT). Immunohistochemical analysis was available for >=4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment. RESULTS: Modeling identified four biomarkers (Ki-67, MDM2, p16 and Cox-2) that were jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P < 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT + STADT and 31% with EBRT + LTADT; associated 10-year prostate cancer-specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT. CONCLUSION: Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT + STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup. PMID- 25294920 TI - DupliPHY-Web: a web server for DupliPHY and DupliPHY-ML. AB - SUMMARY: Gene duplication and loss are important processes in the evolution of gene families. Moreover, growth of families by duplication and retention is an important mechanism by which organisms gain new functions. Therefore the ability to infer the evolutionary histories of families is an important step in understanding the evolution of function. We have recently developed DupliPHY, a software tool to infer gene family histories using parsimony and maximum likelihood. Here, we present DupliPHY-Web a web server for DupliPHY that implements additional maximum likelihood functionality and provides users an intuitive interface to run DupliPHY. AVAILABILITY AND IMPLEMENTATION: DupliPHY Web is available at www.bioinf.manchester.ac.uk/dupliphy/ CONTACT: : ryan.ames@manchester.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25294919 TI - A crowd-sourcing approach for the construction of species-specific cell signaling networks. AB - MOTIVATION: Animal models are important tools in drug discovery and for understanding human biology in general. However, many drugs that initially show promising results in rodents fail in later stages of clinical trials. Understanding the commonalities and differences between human and rat cell signaling networks can lead to better experimental designs, improved allocation of resources and ultimately better drugs. RESULTS: The sbv IMPROVER Species Specific Network Inference challenge was designed to use the power of the crowds to build two species-specific cell signaling networks given phosphoproteomics, transcriptomics and cytokine data generated from NHBE and NRBE cells exposed to various stimuli. A common literature-inspired reference network with 220 nodes and 501 edges was also provided as prior knowledge from which challenge participants could add or remove edges but not nodes. Such a large network inference challenge not based on synthetic simulations but on real data presented unique difficulties in scoring and interpreting the results. Because any prior knowledge about the networks was already provided to the participants for reference, novel ways for scoring and aggregating the results were developed. Two human and rat consensus networks were obtained by combining all the inferred networks. Further analysis showed that major signaling pathways were conserved between the two species with only isolated components diverging, as in the case of ribosomal S6 kinase RPS6KA1. Overall, the consensus between inferred edges was relatively high with the exception of the downstream targets of transcription factors, which seemed more difficult to predict. CONTACT: ebilal@us.ibm.com or gustavo@us.ibm.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25294921 TI - FungiFun2: a comprehensive online resource for systematic analysis of gene lists from fungal species. AB - SUMMARY: Systematically extracting biological meaning from omics data is a major challenge in systems biology. Enrichment analysis is often used to identify characteristic patterns in candidate lists. FungiFun is a user-friendly Web tool for functional enrichment analysis of fungal genes and proteins. The novel tool FungiFun2 uses a completely revised data management system and thus allows enrichment analysis for 298 currently available fungal strains published in standard databases. FungiFun2 offers a modern Web interface and creates interactive tables, charts and figures, which users can directly manipulate to their needs. AVAILABILITY AND IMPLEMENTATION: FungiFun2, examples and tutorials are publicly available at https://elbe.hki-jena.de/fungifun/. CONTACT: steffen.priebe@hki-jena.de or joerg.linde@hki-jena.de. PMID- 25294923 TI - Glucose control in the intensive care unit by use of continuous glucose monitoring: what level of measurement error is acceptable? AB - BACKGROUND: Accuracy and frequency of glucose measurement is essential to achieve safe and efficacious glucose control in the intensive care unit. Emerging continuous glucose monitors provide frequent measurements, trending information, and alarms. The objective of this study was to establish the level of accuracy of continuous glucose monitoring (CGM) associated with safe and efficacious glucose control in the intensive care unit. METHODS: We evaluated 3 established glucose control protocols [Yale, University of Washington, and Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR)] by use of computer simulations. Insulin delivery was informed by intermittent blood glucose (BG) measurements or CGM levels with an increasing level of measurement error. Measures of glucose control included mean glucose, glucose variability, proportion of time glucose was in target range, and hypoglycemia episodes. RESULTS: Apart from the Washington protocol, CGM with mean absolute relative deviation (MARD) <= 15% resulted in similar mean glucose as with the use of intermittent BG measurements. Glucose variability was also similar between CGM and BG-informed protocols. Frequency and duration of hypoglycemia were not worse by use of CGM with MARD <= 10%. Measures of glucose control varied more between protocols than at different levels of the CGM error. CONCLUSIONS: The efficacy of CGM-informed and BG-informed commonly used glucose protocols is similar, but the risk of hypoglycemia may be reduced by use of CGM with MARD <= 10%. Protocol choice has greater influence on glucose control measures than the glucose measurement method. PMID- 25294922 TI - Log-odds sequence logos. AB - MOTIVATION: DNA and protein patterns are usefully represented by sequence logos. However, the methods for logo generation in common use lack a proper statistical basis, and are non-optimal for recognizing functionally relevant alignment columns. RESULTS: We redefine the information at a logo position as a per observation multiple alignment log-odds score. Such scores are positive or negative, depending on whether a column's observations are better explained as arising from relatedness or chance. Within this framework, we propose distinct normalized maximum likelihood and Bayesian measures of column information. We illustrate these measures on High Mobility Group B (HMGB) box proteins and a dataset of enzyme alignments. Particularly in the context of protein alignments, our measures improve the discrimination of biologically relevant positions. AVAILABILITY AND IMPLEMENTATION: Our new measures are implemented in an open source Web-based logo generation program, which is available at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/logoddslogo/index.html. A stand-alone version of the program is also available from this site. CONTACT: altschul@ncbi.nlm.nih.gov SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25294924 TI - Circulating long noncoding RNATapSaki is a predictor of mortality in critically ill patients with acute kidney injury. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating gene expression. Intriguingly, these RNA transcripts are detectable and stable in the blood of patients with cancer and cardiovascular disease. We tested whether circulating lncRNAs in plasma of critically ill patients with acute kidney injury (AKI) at inception of renal replacement therapy were deregulated and might predict survival. METHODS: We performed a global lncRNA expression analysis using RNA isolated from plasma of patients with AKI, healthy controls, and ischemic disease controls. This global screen revealed several deregulated lncRNAs in plasma samples of patients with AKI. lncRNA-array based alterations were confirmed in kidney biopsies of patients as well as in plasma of 109 patients with AKI, 30 age-matched healthy controls, and 30 disease controls by quantitative real-time PCR. RESULTS: Circulating concentrations of the novel intronic antisense lncRNA TrAnscript Predicting Survival in AKI (TapSAKI) (P < 0.0001) were detectable in kidney biopsies and upregulated in plasma of patients with AKI. Cox regression and Kaplan-Meier curve analysis revealed TapSAKI as an independent predictor of 28-day survival (P < 0.01). TapSAKI was enriched in tubular epithelial cells subjected to ATP depletion (P = 0.03). CONCLUSIONS: The alteration of circulating concentrations of lncRNAs in patients with AKI supports TapSAKI as a predictor of mortality in this patient cohort. PMID- 25294925 TI - Opinion: Conservation and stewardship of the human microbiome. PMID- 25294928 TI - Intrinsic conduction through topological surface states of insulating Bi2Te3 epitaxial thin films. AB - Topological insulators represent a novel state of matter with surface charge carriers having a massless Dirac dispersion and locked helical spin polarization. Many exciting experiments have been proposed by theory, yet their execution has been hampered by the extrinsic conductivity associated with the unavoidable presence of defects in Bi2Te3 and Bi2Se3 bulk single crystals, as well as impurities on their surfaces. Here we present the preparation of Bi2Te3 thin films that are insulating in the bulk and the four-point probe measurement of the conductivity of the Dirac states on surfaces that are intrinsically clean. The total amount of charge carriers in the experiment is of the order of 10(12) cm( 2) only, and mobilities up to 4,600 cm(2)/Vs have been observed. These values are achieved by carrying out the preparation, structural characterization, angle resolved and X-ray photoemission analysis, and temperature-dependent four-point probe conductivity measurement all in situ under ultra-high-vacuum conditions. This experimental approach opens the way to prepare devices that can exploit the intrinsic topological properties of the Dirac surface states. PMID- 25294927 TI - Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. AB - Mitophagy is a cellular quality control pathway in which the E3 ubiquitin ligase parkin targets damaged mitochondria for degradation by autophagosomes. We examined the role of optineurin in mitophagy, as mutations in optineurin are causative for amyotrophic lateral sclerosis (ALS) and glaucoma, diseases in which mitochondrial dysfunction has been implicated. Using live cell imaging, we demonstrate the parkin-dependent recruitment of optineurin to mitochondria damaged by depolarization or reactive oxygen species. Parkin's E3 ubiquitin ligase activity is required to ubiquitinate outer mitochondrial membrane proteins, allowing optineurin to stably associate with ubiquitinated mitochondria via its ubiquitin binding domain; in the absence of parkin, optineurin transiently localizes to damaged mitochondrial tips. Following optineurin recruitment, the omegasome protein double FYVE-containing protein 1 (DFCP1) transiently localizes to damaged mitochondria to initialize autophagosome formation and the recruitment of microtubule-associated protein light chain 3 (LC3). Optineurin then induces autophagosome formation around damaged mitochondria via its LC3 interaction region (LIR) domain. Depletion of endogenous optineurin inhibits LC3 recruitment to mitochondria and inhibits mitochondrial degradation. These defects are rescued by expression of siRNA-resistant wild-type optineurin, but not by an ALS-associated mutant in the ubiquitin binding domain (E478G), or by optineurin with a mutation in the LIR domain. Optineurin and p62/SQSTM1 are independently recruited to separate domains on damaged mitochondria, and p62 is not required for the recruitment of either optineurin or LC3 to damaged mitochondria. Thus, our study establishes an important role for optineurin as an autophagy receptor in parkin-mediated mitophagy and demonstrates that defects in a single pathway can lead to neurodegenerative diseases with distinct pathologies. PMID- 25294930 TI - Tracking sustainable development with a national barometer for South Africa using a downscaled "safe and just space" framework. AB - Nations in the 21st century face a complex mix of environmental and social challenges, as highlighted by the on-going Sustainable Development Goals process. The "planetary boundaries" concept [Rockstrom J, et al. (2009) Nature 461(7263):472-475], and its extension through the addition of social well-being indicators to create a framework for "safe and just" inclusive sustainable development [Raworth K (2012) Nature Climate Change 2(4):225-226], have received considerable attention in science and policy circles. As the chief aim of this framework is to influence public policy, and this happens largely at the national level, we assess whether it can be used at the national scale, using South Africa as a test case. We developed a decision-based methodology for downscaling the framework and created a national "barometer" for South Africa, combining 20 indicators and boundaries for environmental stress and social deprivation. We find that it is possible to maintain the original design and concept of the framework while making it meaningful in the national context, raising new questions and identifying priority areas for action. Our results show that South Africa has exceeded its environmental boundaries for biodiversity loss, marine harvesting, freshwater use, and climate change, and social deprivation is most severe in the areas of safety, income, and employment. Trends since 1994 show improvement in nearly all social indicators, but progression toward or over boundaries for most environmental indicators. The barometer shows that achieving inclusive sustainable development in South Africa requires national and global action on multiple fronts, and careful consideration of the interplay between different environmental domains and development strategies. PMID- 25294929 TI - Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells. AB - IL-1 family member IL-37 limits innate inflammation in models of colitis and LPS induced shock, but a role in adaptive immunity remains unknown. Here, we studied mice expressing human IL-37b isoform (IL-37tg) subjected to skin contact hypersensitivity (CHS) to dinitrofluorobenzene. CHS challenge to the hapten was significantly decreased in IL-37tg mice compared with wild-type (WT) mice (-61%; P < 0.001 at 48 h). Skin dendritic cells (DCs) were present and migrated to lymph nodes after antigen uptake in IL-37tg mice. When hapten-sensitized DCs were adoptively transferred to WT mice, antigen challenge was greatly impaired in mice receiving DCs from IL-37tg mice compared with those receiving DCs from WT mice ( 60%; P < 0.01 at 48 h). In DCs isolated from IL-37tg mice, LPS-induced increase of MHC II and costimulatory molecule CD40 was reduced by 51 and 31%, respectively. In these DCs, release of IL-1beta, IL-6, and IL-12 was reduced whereas IL-10 secretion increased (37%). Consistent with these findings, DCs from IL-37tg mice exhibited a lower ability to stimulate syngeneic and allogeneic naive T cells as well as antigen-specific T cells and displayed enhanced induction of T regulatory (Treg) cells (86%; P < 0.001) in vitro. Histological analysis of CHS skin in mice receiving hapten-sensitized DCs from IL-37tg mice revealed a marked reduction in CD8(+) T cells (-74%) but an increase in Treg cells (2.6-fold). Together, these findings reveal that DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells. IL-37 thus emerges as an inhibitor of adaptive immunity. PMID- 25294931 TI - Sexual selection on wing interference patterns in Drosophila melanogaster. AB - Animals with color vision use color information in intra- and interspecific communication, which in turn may drive the evolution of conspicuous colored body traits via natural and sexual selection. A recent study found that the transparent wings of small flies and wasps in lower-reflectance light environments display vivid and stable structural color patterns, called "wing interference patterns" (WIPs). Such WIPs were hypothesized to function in sexual selection among small insects with wing displays, but this has not been experimentally verified. Here, to our knowledge we present the first experimental evidence that WIPs in males of Drosophila melanogaster are targets of mate choice from females, and that two different color traits--saturation and hue--experience directional and stabilizing sexual selection, respectively. Using isogenic lines from the D. melanogaster Genetic Reference Panel, we compare attractiveness of different male WIPs against black and white visual backgrounds. We show that males with more vivid wings are more attractive to females than are males with dull wings. Wings with a large magenta area (i.e., intermediate trait values) were also preferred over those with a large blue or yellow area. These experimental results add a visual element to the Drosophila mating array, integrating sexual selection with elements of genetics and evo-devo, potentially applicable to a wide array of small insects with hyaline wings. Our results further underscore that the mode of sexual selection on such visual signals can differ profoundly between different color components, in this case hue and saturation. PMID- 25294933 TI - Electronic cigarettes: peering through the smokescreen. PMID- 25294934 TI - Delayed presentation of diaphragmatic rupture: an unusual case of dyspnea. PMID- 25294932 TI - CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. AB - Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis. PMID- 25294935 TI - Sequential application of oxygen therapy via high-flow nasal cannula and noninvasive ventilation in acute respiratory failure: an observational pilot study. AB - BACKGROUND: The aim of this study was to evaluate the clinical efficacy of humidified oxygen via high-flow nasal cannula (HFNC) alternating with noninvasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF). METHODS: We performed a prospective observational study in a 12-bed ICU of a university hospital. All subjects with a PaO2 /FIO2 of <=300 mm Hg with standard mask oxygen and a breathing frequency of > 30 breaths/min or signs of respiratory distress were included and treated with HFNC first and then NIV. Ventilatory parameters, blood gases, and tolerance were recorded during 2 consecutive sessions of NIV and HFNC. Outcome was assessed after continuation of this noninvasive strategy. RESULTS: Twenty-eight subjects with AHRF were studied, including 23 (82%) with ARDS. Compared with standard oxygen therapy, PaO2 significantly increased from 83 (68-97) mm Hg to 108 (83-140) mm Hg using HFNC and to 125 (97-200) mm Hg using NIV (P<.01), whereas breathing frequency significantly decreased. HFNC was significantly better tolerated than NIV, with a lower score on the visual analog scale. The non-intubated subjects received HFNC for 75 (27-127) h and NIV for 23 (8-31) h. Intubation was required in 10 of 28 subjects (36%), including 8 of 23 subjects with ARDS (35%). After HFNC initiation, a breathing frequency of >=30 breaths/min was an early factor associated with intubation. CONCLUSIONS: HFNC was better tolerated than NIV and allowed for significant improvement in oxygenation and tachypnea compared with standard oxygen therapy in subjects with AHRF, a large majority of whom had ARDS. Thus, HFNC may be used between NIV sessions to avoid marked impairment of oxygenation. PMID- 25294937 TI - New insights into the maternal to zygotic transition. AB - The initial phases of embryonic development occur in the absence of de novo transcription and are instead controlled by maternally inherited mRNAs and proteins. During this initial period, cell cycles are synchronous and lack gap phases. Following this period of transcriptional silence, zygotic transcription begins, the maternal influence on development starts to decrease, and dramatic changes to the cell cycle take place. Here, we discuss recent work that is shedding light on the maternal to zygotic transition and the interrelated but distinct mechanisms regulating the onset of zygotic transcription and changes to the cell cycle during early embryonic development. PMID- 25294938 TI - Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells. AB - Pluripotent embryonic stem cells (ESCs) generate rostral paraxial mesoderm-like progeny in 5-6 days of differentiation induced by Wnt3a and Noggin (Nog). We report that canonical Wnt signaling introduced either by forced expression of activated beta-catenin, or the small-molecule inhibitor of Gsk3, CHIR99021, satisfied the need for Wnt3a signaling, and that the small-molecule inhibitor of BMP type I receptors, LDN193189, was able to replace Nog. Mesodermal progeny generated using such small molecules were chondrogenic in vitro, and expressed trunk paraxial mesoderm markers such as Tcf15 and Meox1, and somite markers such as Uncx, but failed to express sclerotome markers such as Pax1. Induction of the osteochondrogenically committed sclerotome from somite requires sonic hedgehog and Nog. Consistently, Pax1 and Bapx1 expression was induced when the isolated paraxial mesodermal progeny were treated with SAG1 (a hedgehog receptor agonist) and LDN193189, then Sox9 expression was induced, leading to cartilaginous nodules and particles in the presence of BMP, indicative of chondrogenesis via sclerotome specification. By contrast, treatment with TGFbeta also supported chondrogenesis and stimulated Sox9 expression, but failed to induce the expression of Pax1 and Bapx1. On ectopic transplantation to immunocompromised mice, the cartilage particles developed under either condition became similarly mineralized and formed pieces of bone with marrow. Thus, the use of small molecules led to the effective generation from ESCs of paraxial mesodermal progeny, and to their further differentiation in vitro through sclerotome specification into growth plate-like chondrocytes, a mechanism resembling in vivo somitic chondrogenesis that is not recapitulated with TGFbeta. PMID- 25294936 TI - The T-box gene family: emerging roles in development, stem cells and cancer. AB - The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. T-box proteins are characterized by a DNA-binding motif known as the T-domain that binds DNA in a sequence-specific manner. In humans, mutations in many of the genes within the T-box family result in developmental syndromes, and there is increasing evidence to support a role for these factors in certain cancers. In addition, although early studies focused on the role of T-box factors in early embryogenesis, recent studies in mice have uncovered additional roles in unsuspected places, for example in adult stem cell populations. Here, I provide an overview of the key features of T-box transcription factors and highlight their roles and mechanisms of action during various stages of development and in stem/progenitor cell populations. PMID- 25294939 TI - A theoretical framework for the regulation of Shh morphogen-controlled gene expression. AB - How morphogen gradients govern the pattern of gene expression in developing tissues is not well understood. Here, we describe a statistical thermodynamic model of gene regulation that combines the activity of a morphogen with the transcriptional network it controls. Using Sonic hedgehog (Shh) patterning of the ventral neural tube as an example, we show that the framework can be used together with the principled parameter selection technique of approximate Bayesian computation to obtain a dynamical model that accurately predicts tissue patterning. The analysis indicates that, for each target gene regulated by Gli, which is the transcriptional effector of Shh signalling, there is a neutral point in the gradient, either side of which altering the Gli binding affinity has opposite effects on gene expression. This explains recent counterintuitive experimental observations. The approach is broadly applicable and provides a unifying framework to explain the temporospatial pattern of morphogen-regulated gene expression. PMID- 25294940 TI - Partial interchangeability of Fz3 and Fz6 in tissue polarity signaling for epithelial orientation and axon growth and guidance. AB - In mammals, a set of anatomically diverse polarity processes - including axon growth and guidance, hair follicle orientation, and stereociliary bundle orientation in inner ear sensory hair cells - appear to be mechanistically related, as judged by their dependence on vertebrate homologues of core tissue polarity/planar cell polarity (PCP) genes in Drosophila. To explore more deeply the mechanistic similarities between different polarity processes, we have determined the extent to which frizzled 3 (Fz3) can rescue the hair follicle and Merkel cell polarity defects in frizzled 6-null (Fz6(-/-)) mice, and, reciprocally, the extent to which Fz6 can rescue the axon growth and guidance defects in Fz3(-/-) mice. These experiments reveal full rescue of the Fz6(-/-) phenotype by Fz3 and partial rescue of the Fz3(-/-) phenotype by Fz6, implying that these two proteins are likely to act in a conserved manner in these two contexts. Stimulated by these observations, we searched for additional anatomical structures that exhibit macroscopic polarity and that might plausibly use Fz3 and/or Fz6 signaling. This search has revealed a hitherto unappreciated pattern of papillae on the dorsal surface of the tongue that depends, at least in part, on redundant signaling by Fz3 and Fz6. Taken together, these experiments provide compelling evidence for a close mechanistic relationship between multiple anatomically diverse polarity processes. PMID- 25294941 TI - ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis. AB - Initially identified in DNA damage repair, ATM-interactor (ATMIN) further functions as a transcriptional regulator of lung morphogenesis. Here we analyse three mouse mutants, Atmin(gpg6/gpg6), Atmin(H210Q/H210Q) and Dynll1(GT/GT), revealing how ATMIN and its transcriptional target dynein light chain LC8-type 1 (DYNLL1) are required for normal lung morphogenesis and ciliogenesis. Expression screening of ciliogenic genes confirmed Dynll1 to be controlled by ATMIN and further revealed moderately altered expression of known intraflagellar transport (IFT) protein-encoding loci in Atmin mutant embryos. Significantly, Dynll1(GT/GT) embryonic cilia exhibited shortening and bulging, highly similar to the characterised retrograde IFT phenotype of Dync2h1. Depletion of ATMIN or DYNLL1 in cultured cells recapitulated the in vivo ciliogenesis phenotypes and expression of DYNLL1 or the related DYNLL2 rescued the effects of loss of ATMIN, demonstrating that ATMIN primarily promotes ciliogenesis by regulating Dynll1 expression. Furthermore, DYNLL1 as well as DYNLL2 localised to cilia in puncta, consistent with IFT particles, and physically interacted with WDR34, a mammalian homologue of the Chlamydomonas cytoplasmic dynein 2 intermediate chain that also localised to the cilium. This study extends the established Atmin-Dynll1 relationship into a developmental and a ciliary context, uncovering a novel series of interactions between DYNLL1, WDR34 and ATMIN. This identifies potential novel components of cytoplasmic dynein 2 and furthermore provides fresh insights into the molecular pathogenesis of human skeletal ciliopathies. PMID- 25294942 TI - BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH. AB - The relative timing of SHH and BMP signals controls whether presomitic mesoderm (PSM) cells will adopt either a chondrogenic or lateral plate mesoderm fate. Here we document that SHH-mediated induction of Nkx3.2 maintains the competence of somitic cells to initiate chondrogenesis in response to subsequent BMP signals by repressing BMP-dependent induction of GATA genes. Conversely, administration of BMP signals to PSM or forced expression of GATA family members in chick PSM explants blocks induction of hedgehog-dependent gene expression. We demonstrate that GATA factors can interact with Gli factors and can recruit the transcriptional co-factor FOG1 (ZFPM1) to the regulatory region of the mouse Gli1 gene, repressing the induction of Gli1 by SHH by binding to both GATA and Gli binding sites. Knockdown of FOG1 reverses the ability of GATA factors to repress Gli1 expression. Our findings uncover a novel role for GATA transcription factors as repressors of hedgehog signaling, and document that NKX3.2 maintains the ability of sclerotomal cells to express SHH transcriptional targets in the presence of BMP signals by repressing the induction of Gata4/5/6. PMID- 25294946 TI - On the robustness of the adaptive lasso to model misspecification. AB - Penalization methods have been shown to yield both consistent variable selection and oracle parameter estimation under correct model specification. In this article, we study such methods under model misspecification, where the assumed form of the regression function is incorrect, including generalized linear models for uncensored outcomes and the proportional hazards model for censored responses. Estimation with the adaptive least absolute shrinkage and selection operator, lasso, penalty is proven to achieve sparse estimation of regression coefficients under misspecification. The resulting estimators are selection consistent, asymptotically normal and oracle, where the selection is based on the limiting values of the parameter estimators obtained using the misspecified model without penalization. We further derive conditions under which the penalized estimators from the misspecified model may yield selection consistency under the true model. The robustness is explored numerically via simulation and an application to the Wisconsin Epidemiological Study of Diabetic Retinopathy. PMID- 25294943 TI - Analysis of the expression patterns, subcellular localisations and interaction partners of Drosophila proteins using a pigP protein trap library. AB - Although we now have a wealth of information on the transcription patterns of all the genes in the Drosophila genome, much less is known about the properties of the encoded proteins. To provide information on the expression patterns and subcellular localisations of many proteins in parallel, we have performed a large scale protein trap screen using a hybrid piggyBac vector carrying an artificial exon encoding yellow fluorescent protein (YFP) and protein affinity tags. From screening 41 million embryos, we recovered 616 verified independent YFP-positive lines representing protein traps in 374 genes, two-thirds of which had not been tagged in previous P element protein trap screens. Over 20 different research groups then characterized the expression patterns of the tagged proteins in a variety of tissues and at several developmental stages. In parallel, we purified many of the tagged proteins from embryos using the affinity tags and identified co-purifying proteins by mass spectrometry. The fly stocks are publicly available through the Kyoto Drosophila Genetics Resource Center. All our data are available via an open access database (Flannotator), which provides comprehensive information on the expression patterns, subcellular localisations and in vivo interaction partners of the trapped proteins. Our resource substantially increases the number of available protein traps in Drosophila and identifies new markers for cellular organelles and structures. PMID- 25294945 TI - Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice. AB - Type 2 diabetes (T2D) is a metabolic disease affecting >370 million people worldwide. It is characterized by obesity-induced insulin resistance, and growing evidence has indicated that this causative link between obesity and insulin resistance is associated with visceral adipose tissue inflammation. However, using anti-inflammatory drugs to treat insulin resistance and T2D is not a common practice. We recently applied a bioinformatics methodology to open public data and found that CD44 plays a critical role in the development of adipose tissue inflammation and insulin resistance. In this report, we examined the role of CD44 in T2D by administering daily injections of anti-CD44 monoclonal antibody (mAb) in a high-fat-diet mouse model. Four weeks of therapy with CD44 mAb suppressed visceral adipose tissue inflammation compared with controls and reduced fasting blood glucose levels, weight gain, liver steatosis, and insulin resistance to levels comparable to or better than therapy with the drugs metformin and pioglitazone. These findings suggest that CD44 mAb may be useful as a prototype drug for therapy of T2D by breaking the links between obesity and insulin resistance. PMID- 25294944 TI - Subcellular localisations of the CPTI collection of YFP-tagged proteins in Drosophila embryos. AB - A key challenge in the post-genomic area is to identify the function of the genes discovered, with many still uncharacterised in all metazoans. A first step is transcription pattern characterisation, for which we now have near whole-genome coverage in Drosophila. However, we have much more limited information about the expression and subcellular localisation of the corresponding proteins. The Cambridge Protein Trap Consortium generated, via piggyBac transposition, over 600 novel YFP-trap proteins tagging just under 400 Drosophila loci. Here, we characterise the subcellular localisations and expression patterns of these insertions, called the CPTI lines, in Drosophila embryos. We have systematically analysed subcellular localisations at cellularisation (stage 5) and recorded expression patterns at stage 5, at mid-embryogenesis (stage 11) and at late embryogenesis (stages 15-17). At stage 5, 31% of the nuclear lines (41) and 26% of the cytoplasmic lines (67) show discrete localisations that provide clues on the function of the protein and markers for organelles or regions, including nucleoli, the nuclear envelope, nuclear speckles, centrosomes, mitochondria, the endoplasmic reticulum, Golgi, lysosomes and peroxisomes. We characterised the membranous/cortical lines (102) throughout stage 5 to 10 during epithelial morphogenesis, documenting their apico-basal position and identifying those secreted in the extracellular space. We identified the tricellular vertices as a specialized membrane domain marked by the integral membrane protein Sidekick. Finally, we categorised the localisation of the membranous/cortical proteins during cytokinesis. PMID- 25294947 TI - Detecting phylogenetic signal in mutualistic interaction networks using a Markov process model. AB - Ecological interaction networks, such as those describing the mutualistic interactions between plants and their pollinators or between plants and their frugivores, exhibit non-random structural properties that cannot be explained by simple models of network formation. One factor affecting the formation and eventual structure of such a network is its evolutionary history. We argue that this, in many cases, is closely linked to the evolutionary histories of the species involved in the interactions. Indeed, empirical studies of interaction networks along with the phylogenies of the interacting species have demonstrated significant associations between phylogeny and network structure. To date, however, no generative model explaining the way in which the evolution of individual species affects the evolution of interaction networks has been proposed. We present a model describing the evolution of pairwise interactions as a branching Markov process, drawing on phylogenetic models of molecular evolution. Using knowledge of the phylogenies of the interacting species, our model yielded a significantly better fit to 21% of a set of plant - pollinator and plant - frugivore mutualistic networks. This highlights the importance, in a substantial minority of cases, of inheritance of interaction patterns without excluding the potential role of ecological novelties in forming the current network architecture. We suggest that our model can be used as a null model for controlling evolutionary signals when evaluating the role of other factors in shaping the emergence of ecological networks. PMID- 25294948 TI - Copper-Catalyzed Decarboxylative Trifluoromethylation of Propargyl Bromodifluoroacetates. AB - The development of efficient methods for accessing fluorinated functional groups is desirable. Herein, we report a two-step method that utilizes catalytic Cu for the decarboxylative trifluoromethylation of propargyl bromodifluoroacetates. This protocol affords a mixture of propargyl trifluoromethanes and trifluoromethyl allenes. PMID- 25294949 TI - Cognitive Distortions and Suicide Attempts. AB - Although theorists have posited that suicidal individuals are more likely than non-suicidal individuals to experience cognitive distortions, little empirical work has examined whether those who recently attempted suicide are more likely to engage in cognitive distortions than those who have not recently attempted suicide. In the present study, 111 participants who attempted suicide in the 30 days prior to participation and 57 psychiatric control participants completed measures of cognitive distortions, depression, and hopelessness. Findings support the hypothesis that individuals who recently attempted suicide are more likely than psychiatric controls to experience cognitive distortions, even when controlling for depression and hopelessness. Fortune telling was the only cognitive distortion uniquely associated with suicide attempt status. However, fortune telling was no longer significantly associated with suicide attempt status when controlling for hopelessness. Findings underscore the importance of directly targeting cognitive distortions when treating individuals at risk for suicide. PMID- 25294950 TI - Skull developmental modularity: a view from a single bone - or two. AB - I review recent studies that connect development and evolution of skull bones in teleosts. Development uses genetic information to build a structured, modular phenotype, and since selection acts on the phenotype, developmental modularity may influence evolvability. Just how is a complex developing morphology spatially partitioned into modules? Here I briefly examine cellular, molecular genetic, and multivariate statistical approaches to the identification of developmental modules. Furthermore I review our evidence that developmental modularity provides evolutionarily labile regions within the skull and hence potentially biases evolutionary change in a positive manner. This view is rather different from early ones in the field of evolutionary developmental biology, in which developmental constraint due to patterns such as heterochronies were supposed to negatively impact evolution. PMID- 25294951 TI - Strategies for Managing Difficult Clinical Situations in Between Sessions. AB - Therapists often have to deal with situations that make them uneasy to leave their clients on their own. They can go home and wonder what their clients are doing, whether they are safe, have a place to stay, even whether or not they are fighting. These thoughts can be overwhelming for the therapist. They may think about their clients' safety, they may also be worried about their own professional way of dealing with these situations, and its implications for them as clinician. The aim of this paper is to assist therapists to manage their own anxiety and to help them help their clients in between sessions in difficult situations such as suicidality, child abuse and neglect, intimate partner violence, crisis and stress management. PMID- 25294952 TI - Ecotin-like ISP of L. major promastigotes fine-tunes macrophage phagocytosis by limiting the pericellular release of bradykinin from surface-bound kininogens: a survival strategy based on the silencing of proinflammatory G-protein coupled kinin B2 and B1 receptors. AB - Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and Deltaisp2/3 mutants) potently induced plasma leakage through the activation of bradykinin B2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Deltaisp2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of Deltaisp2/3 mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R. PMID- 25294953 TI - Resolution of sterile inflammation: role for vitamin C. AB - INTRODUCTION: Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited. METHODS: To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-gamma-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages. RESULTS: VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response to in vitro LPS stimulation. VitC sufficiency and in vivo VitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS induced proinflammatory responses. CONCLUSION: VitC sufficiency favorably modulates macrophage function. In vivo or in vitro VitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation. PMID- 25294954 TI - alphaMSH blunts endotoxin-induced MuRF1 and atrogin-1 upregulation in skeletal muscle by modulating NF-kappaB and Akt/FoxO1 pathway. AB - Alpha melanocyte stimulating hormone (alphaMSH) has been shown to have anti inflammatory and anticachectic actions. We hypothesized that alphaMSH administration could attenuate the effect of lipopolysaccharide (LPS) on the skeletal muscle through modifications in IGF-Akt-FoxO1 pathway, or/and in serum corticosterone. Adult male Wistar rats were injected with LPS and/or alphaMSH. alphaMSH administration reduced LPS-induced increase in liver TNFalpha and serum nitrites as well as NF-kappaB activation in skeletal muscle. In contrast, alphaMSH was not able to prevent the stimulatory effect of LPS on serum concentration of ACTH and corticosterone. LPS decreased serum levels of IGF-I and IGFBP3 and their expression in the liver (P < 0.01). However IGFBP3 expression in the gastrocnemius was increased by LPS. Treatment with alphaMSH prevented the effects of LPS on IGFBP3 but not on IGF-I. In the gastrocnemius alphaMSH blocked LPS-induced decrease in pAkt as well as the increase in pNF-kappaB(p65), FoxO1, atrogin-1, and MuRF1 levels. These results suggest that alphaMSH blunts skeletal muscle response to endotoxin by downregulating atrogenes and FoxO1 at least in part by controlling NF-kappaB activation and Akt signalling, but not through modifications in the secretion of corticosterone or IGF-I. PMID- 25294955 TI - The influence of autologous bone marrow stem cell transplantation on matrix metalloproteinases in patients treated for acute ST-elevation myocardial infarction. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9), regulated by tissue inhibitor of metalloproteinase-9 (TIMP-1) and the extracellular matrix metalloproteinase inducer (EMMPRIN), contributes to plaque instability. Autologous stem cells from bone marrow (mBMC) treatment are suggested to reduce myocardial damage; however, limited data exists on the influence of mBMC on MMPs. AIM: We investigated the influence of mBMC on circulating levels of MMP-9, TIMP-1, and EMMPRIN at different time points in patients included in the randomized Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial (n = 100). Gene expression analyses were additionally performed. RESULTS: After 2-3 weeks we observed a more pronounced increase in MMP-9 levels in the mBMC group, compared to controls (P = 0.030), whereas EMMPRIN levels were reduced from baseline to 2-3 weeks and 3 months in both groups (P < 0.0001). Gene expression of both MMP-9 and EMMPRIN was reduced from baseline to 3 months. MMP-9 and EMMPRIN were significantly correlated to myocardial injury (CK: P = 0.005 and P < 0.001, resp.) and infarct size (SPECT: P = 0.018 and P = 0.008, resp.). CONCLUSION: The results indicate that the regulation of metalloproteinases is important during AMI, however, limited influenced by mBMC. PMID- 25294956 TI - Insulin-like growth factor-I induces arginase activity in Leishmania amazonensis amastigote-infected macrophages through a cytokine-independent mechanism. AB - Leishmania (Leishmania) amazonensis exhibits peculiarities in its interactions with hosts. Because amastigotes are the primary form associated with the progression of infection, we studied the effect of insulin-like growth factor (IGF)-I on interactions between L. (L.) amazonensis amastigotes and macrophages. Upon stimulation of infected macrophages with IGF-I, we observed decreased nitric oxide production but increased arginase expression and activity, which lead to increased parasitism. However, stimulation of amastigote-infected macrophages with IGF-I did not result in altered cytokine levels compared to unstimulated controls. Because IGF-I is present in tissue fluids and also within macrophages, we examined the possible effect of this factor on phosphatidylserine (PS) exposure on amastigotes, seen previously in tissue-derived amastigotes leading to increased parasitism. Stimulation with IGF-I induced PS exposure on amastigotes but not on promastigotes. Using a PS-liposome instead of amastigotes, we observed that the PS-liposome but not the control phosphatidylcholine-liposome led to increased arginase activity in macrophages, and this process was not blocked by anti-TGF-beta antibodies. Our results suggest that in L. (L.) amazonensis amastigote-infected macrophages, IGF-I induces arginase activity directly in amastigotes and in macrophages through the induction of PS exposure on amastigotes in the latter, which could lead to the alternative activation of macrophages through cytokine-independent mechanisms. PMID- 25294957 TI - TLR4-mediated blunting of inflammatory responses to eccentric exercise in young women. AB - This study assessed the inflammatory response mediated by the toll-like receptor 4 (TLR4) signaling pathway after acute eccentric exercise before and after an eccentric training program in women. Twenty women performed two acute eccentric bouts using a squat machine over a ~9 week interval. The training group (TG) carried out an eccentric training program during 6 weeks, while the control group (CG) did not follow any training. Protein content of markers involved in the TLR4 mediated activation of several nuclear transcription factors, such as nuclear factor kappaB (NF-kappaB), and interferon regulatory transcription factor 3 (IRF3), was analyzed. The inflammatory response after the first acute bout was similar between TG and CG, showing an upregulation of all the markers analyzed, with the exception of IRF3. After the second bout, the upregulation of TLR4 signaling pathway was blunted in TG, but not in CG, through both the myeloid differentiation factor 88- and toll/interleukin-1 receptor domain containing adapter inducing interferon-beta-dependent pathways. These results highlight the role of the TLR4 in controlling the exercise-induced inflammatory response in young women. More importantly, these data suggest eccentric training may help to prevent TLR4 activation principally through NF-kappaB, and perhaps IRF3, downstream signaling in this population. PMID- 25294959 TI - Clinical Features and Outcomes Differ between Skeletal and Extraskeletal Osteosarcoma. AB - Background. Extraskeletal osteosarcoma (ESOS) is a rare subtype of osteosarcoma. We investigated patient characteristics, overall survival, and prognostic factors in ESOS. Methods. We identified cases of high-grade osteosarcoma with known tissue of origin in the Surveillance, Epidemiology, and End Results database from 1973 to 2009. Demographics were compared using univariate tests. Overall survival was compared with log-rank tests and multivariate analysis using Cox proportional hazards methods. Results. 256/4,173 (6%) patients with high-grade osteosarcoma had ESOS. Patients with ESOS were older, were more likely to have an axial tumor and regional lymph node involvement, and were female. Multivariate analysis showed ESOS to be favorable after controlling for stage, age, tumor site, gender, and year of diagnosis [hazard ratio 0.75 (95% CI 0.62 to 0.90); p = 0.002]. There was an interaction between age and tissue of origin such that older patients with ESOS had superior outcomes compared to older patients with skeletal osteosarcoma. Adverse prognostic factors in ESOS included metastatic disease, larger tumor size, older age, and axial tumor site. Conclusion. Patients with ESOS have distinct clinical features but similar prognostic factors compared to skeletal osteosarcoma. Older patients with ESOS have superior outcomes compared to older patients with skeletal osteosarcoma. PMID- 25294958 TI - Changes in cerebrospinal fluid biomarkers in human herpesvirus-6-associated acute encephalopathy/febrile seizures. AB - To determine the involvement of oxidative stress in the pathogenesis of acute encephalopathy associated with human herpesvirus-6 (HHV-6) infection, we measured the levels of oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL), tau protein, and cytokines in cerebrospinal fluid (CSF) obtained from patients with HHV-6-associated acute encephalopathy (HHV-6 encephalopathy) (n = 16) and complex febrile seizures associated with HHV-6 (HHV 6 complex FS) (n = 10). We also examined changes in CSF-8OHdG and CSF-HEL levels in patients with HHV-6 encephalopathy before and after treatment with edaravone, a free radical scavenger. CSF-8-OHdG levels in HHV-6 encephalopathy and HHV-6 complex FS were significantly higher than in control subjects. In contrast, CSF HEL levels showed no significant difference between groups. The levels of total tau protein in HHV-6 encephalopathy were significantly higher than in control subjects. In six patients with HHV-6 infection (5 encephalopathy and 1 febrile seizure), the CSF-8-OHdG levels of five patients decreased after edaravone treatment. Our results suggest that oxidative DNA damage is involved in acute encephalopathy associated with HHV-6 infection. PMID- 25294960 TI - Nonlinear bending models for beams and plates. AB - A new nonlinear model for large deflections of a beam is proposed. It comprises the Euler-Bernoulli boundary value problem for the deflection and a nonlinear integral condition. When bending does not alter the beam length, this condition guarantees that the deflected beam has the original length and fixes the horizontal displacement of the free end. The numerical results are in good agreement with the ones provided by the elastica model. Dynamic and two dimensional generalizations of this nonlinear one-dimensional static model are also discussed. The model problem for an inextensible rectangular Kirchhoff plate, when one side is clamped, the opposite one is subjected to a shear force, and the others are free of moments and forces, is reduced to a singular integral equation with two fixed singularities. The singularities of the unknown function are examined, and a series-form solution is derived by the collocation method in terms of the associated Jacobi polynomials. The procedure requires solving an infinite system of linear algebraic equations for the expansion coefficients subject to the inextensibility condition. PMID- 25294961 TI - Decay of (p,q)-Fourier coefficients. AB - We show that essentially the speed of decay of the Fourier sine coefficients of a function in a Lebesgue space is comparable to that of the corresponding coefficients with respect to the basis formed by the generalized sine functions sin p,q . PMID- 25294962 TI - How modular structure can simplify tasks on networks: parameterizing graph optimization by fast local community detection. AB - By considering the task of finding the shortest walk through a Network, we find an algorithm for which the run time is not as O(2 n ), with n being the number of nodes, but instead scales with the number of nodes in a coarsened network. This coarsened network has a number of nodes related to the number of dense regions in the original graph. Since we exploit a form of local community detection as a preprocessing, this work gives support to the project of developing heuristic algorithms for detecting dense regions in networks: preprocessing of this kind can accelerate optimization tasks on networks. Our work also suggests a class of empirical conjectures for how structural features of efficient networked systems might scale with system size. PMID- 25294963 TI - Adapting to a changing environment: non-obvious thresholds in multi-scale systems. AB - Many natural and technological systems fail to adapt to changing external conditions and move to a different state if the conditions vary too fast. Such 'non-adiabatic' processes are ubiquitous, but little understood. We identify these processes with a new nonlinear phenomenon-an intricate threshold where a forced system fails to adiabatically follow a changing stable state. In systems with multiple time scales, we derive existence conditions that show such thresholds to be generic, but non-obvious, meaning they cannot be captured by traditional stability theory. Rather, the phenomenon can be analysed using concepts from modern singular perturbation theory: folded singularities and canard trajectories, including composite canards. Thus, non-obvious thresholds should explain the failure to adapt to a changing environment in a wide range of multi-scale systems including: tipping points in the climate system, regime shifts in ecosystems, excitability in nerve cells, adaptation failure in regulatory genes and adiabatic switching in technology. PMID- 25294964 TI - Tsirelson's bound and supersymmetric entangled states. AB - A superqubit, belonging to a (2|1)-dimensional super-Hilbert space, constitutes the minimal supersymmetric extension of the conventional qubit. In order to see whether superqubits are more non-local than ordinary qubits, we construct a class of two-superqubit entangled states as a non-local resource in the CHSH game. Since super Hilbert space amplitudes are Grassmann numbers, the result depends on how we extract real probabilities and we examine three choices of map: (1) DeWitt (2) Trigonometric and (3) Modified Rogers. In cases (1) and (2), the winning probability reaches the Tsirelson bound [Formula: see text] of standard quantum mechanics. Case (3) crosses Tsirelson's bound with pwin?0.9265. Although all states used in the game involve probabilities lying between 0 and 1, case (3) permits other changes of basis inducing negative transition probabilities. PMID- 25294965 TI - Interaction of a screw dislocation with a nano-sized, arbitrarily shaped inhomogeneity with interface stresses under anti-plane deformations. AB - We propose an elegant and concise general method for the solution of a problem involving the interaction of a screw dislocation and a nano-sized, arbitrarily shaped, elastic inhomogeneity in which the contribution of interface/surface elasticity is incorporated using a version of the Gurtin-Murdoch model. The analytic function inside the arbitrarily shaped inhomogeneity is represented in the form of a Faber series. The real periodic function arising from the contribution of the surface mechanics is then expanded as a Fourier series. The resulting system of linear algebraic equations is solved through the use of simple matrix algebra. When the elastic inhomogeneity represents a hole, our solution method simplifies considerably. Furthermore, we undertake an analytical investigation of the challenging problem of a screw dislocation interacting with two closely spaced nano-sized holes of arbitrary shape in the presence of surface stresses. Our solutions quite clearly demonstrate that the induced elastic fields and image force acting on the dislocation are indeed size-dependent. PMID- 25294966 TI - Influence of turbulence on the wake of a marine current turbine simulator. AB - Marine current turbine commercial prototypes have now been deployed and arrays of multiple turbines under design. The tidal flows in which they operate are highly turbulent, but the characteristics of the inflow turbulence have not being considered in present design methods. This work considers the effects of inflow turbulence on the wake behind an actuator disc representation of a marine current turbine. Different turbulence intensities and integral length scales were generated in a large eddy simulation using a gridInlet, which produces turbulence from a grid pattern on the inlet boundary. The results highlight the significance of turbulence on the wake profile, with a different flow regime occurring for the zero turbulence case. Increasing the turbulence intensity reduced the velocity deficit and shifted the maximum deficit closer to the turbine. Increasing the integral length scale increased the velocity deficit close to the turbine due to an increased production of turbulent energy. However, the wake recovery was increased due to the higher rate of turbulent mixing causing the wake to expand. The implication of this work is that marine current turbine arrays could be further optimized, increasing the energy yield of the array when the site specific turbulence characteristics are considered. PMID- 25294967 TI - A remark on constrained von Karman theories. AB - We derive the Euler-Lagrange equation corresponding to 'non-Euclidean' convex constrained von Karman theories. PMID- 25294968 TI - Manipulating flow separation: sensitivity of stagnation points, separatrix angles and recirculation area to steady actuation. AB - A variational technique is used to derive analytical expressions for the sensitivity of several geometric indicators of flow separation to steady actuation. Considering the boundary layer flow above a wall-mounted bump, the six following representative quantities are considered: the locations of the separation point and reattachment point connected by the separatrix, the separation angles at these stagnation points, the backflow area and the recirculation area. For each geometric quantity, linear sensitivity analysis allows us to identify regions which are the most sensitive to volume forcing and wall blowing/suction. Validations against full nonlinear Navier-Stokes calculations show excellent agreement for small-amplitude control for all considered indicators. With very resemblant sensitivity maps, the reattachment point, the backflow and recirculation areas are seen to be easily manipulated. By contrast, the upstream separation point and the separatrix angles are seen to remain extremely robust with respect to external steady actuation. PMID- 25294969 TI - Multiple solutions and numerical analysis to the dynamic and stationary models coupling a delayed energy balance model involving latent heat and discontinuous albedo with a deep ocean. AB - We study a climatologically important interaction of two of the main components of the geophysical system by adding an energy balance model for the averaged atmospheric temperature as dynamic boundary condition to a diagnostic ocean model having an additional spatial dimension. In this work, we give deeper insight than previous papers in the literature, mainly with respect to the 1990 pioneering model by Watts and Morantine. We are taking into consideration the latent heat for the two phase ocean as well as a possible delayed term. Non-uniqueness for the initial boundary value problem, uniqueness under a non-degeneracy condition and the existence of multiple stationary solutions are proved here. These multiplicity results suggest that an S-shaped bifurcation diagram should be expected to occur in this class of models generalizing previous energy balance models. The numerical method applied to the model is based on a finite volume scheme with nonlinear weighted essentially non-oscillatory reconstruction and Runge-Kutta total variation diminishing for time integration. PMID- 25294970 TI - Trapped modes around freely floating bodies in a two-layer fluid channel. AB - Unlike the trapping of time-harmonic water waves by fixed obstacles, the oscillation of freely floating structures gives rise to a complex nonlinear spectral problem. Still, through a convenient elimination scheme the system simplifies to a linear spectral problem for a self-adjoint operator in a Hilbert space. Under symmetry assumptions on the geometry of the fluid domain, we present conditions guaranteeing the existence of trapped modes in a two-layer fluid channel. Numerous examples of floating bodies supporting trapped modes are given. PMID- 25294971 TI - Detecting the mass and position of an adsorbate on a drum resonator. AB - The resonant frequency shifts of a circular membrane caused by an adsorbate are the sensing mechanism for a drum resonator. The adsorbate mass and position are the two major (unknown) parameters determining the resonant frequency shifts. There are infinite combinations of mass and position which can cause the same shift of one resonant frequency. Finding the mass and position of an adsorbate from the experimentally measured resonant frequencies forms an inverse problem. This study presents a straightforward method to determine the adsorbate mass and position by using the changes of two resonant frequencies. Because detecting the position of an adsorbate can be extremely difficult, especially when the adsorbate is as small as an atom or a molecule, this new inverse problem-solving method should be of some help to the mass resonator sensor application of detecting a single adsorbate. How to apply this method to the case of multiple adsorbates is also discussed. PMID- 25294972 TI - Optimal fine-scale structures in compliance minimization for a uniaxial load. AB - We consider the optimization of the topology and geometry of an elastic structure [Formula: see text] subjected to a fixed boundary load, i.e. we aim to minimize a weighted sum of material volume [Formula: see text], structure perimeter [Formula: see text] and structure compliance [Formula: see text] (which is the work done by the load). As a first simple and instructive case, this paper treats the situation of an imposed uniform uniaxial tension load in two dimensions. If the weight epsilon of the perimeter is small, optimal geometries exhibit very fine-scale structure which cannot be resolved by numerical optimization. Instead, we prove how the minimum energy scales in epsilon, which involves the construction of a family of near-optimal geometries and thus provides qualitative insights. The construction is based on a classical branching procedure with some features unique to compliance minimization. The proof of the energy scaling also requires an ansatz-independent lower bound, which we derive once via a classical convex duality argument (which is restricted to two dimensions and the uniaxial load) and once via a Fourier-based refinement of the Hashin-Shtrikman bounds for the effective elastic moduli of composite materials. We also highlight the close relation to and the differences from shape optimization with a scalar PDE constraint and a link to the pattern formation observed in intermediate states of type-I superconductors. PMID- 25294973 TI - Hypotensive Resuscitation. AB - Hypotensive resuscitation is a component of damage control resuscitation, the evolving approach to resuscitation in severely injured trauma patients. Resuscitation strategies used in treating severely injured trauma patients have changed dramatically over the last 20 years. The purpose of this review is to examine the current literature pertaining to hypotensive resuscitation, explore its use in damage control resuscitation, and examine blood pressure management in the setting of severe trauma. PMID- 25294974 TI - Enabling large-scale next-generation sequence assembly with Blacklight. AB - A variety of extremely challenging biological sequence analyses were conducted on the XSEDE large shared memory resource Blacklight, using current bioinformatics tools and encompassing a wide range of scientific applications. These include genomic sequence assembly, very large metagenomic sequence assembly, transcriptome assembly, and sequencing error correction. The data sets used in these analyses included uncategorized fungal species, reference microbial data, very large soil and human gut microbiome sequence data, and primate transcriptomes, composed of both short-read and long-read sequence data. A new parallel command execution program was developed on the Blacklight resource to handle some of these analyses. These results, initially reported previously at XSEDE13 and expanded here, represent significant advances for their respective scientific communities. The breadth and depth of the results achieved demonstrate the ease of use, versatility, and unique capabilities of the Blacklight XSEDE resource for scientific analysis of genomic and transcriptomic sequence data, and the power of these resources, together with XSEDE support, in meeting the most challenging scientific problems. PMID- 25294975 TI - Ab initio design of nanostructures for solar energy conversion: a case study on silicon nitride nanowire. AB - Design of novel materials for efficient solar energy conversion is critical to the development of green energy technology. In this work, we present a first principles study on the design of nanostructures for solar energy harvesting on the basis of the density functional theory. We show that the indirect band structure of bulk silicon nitride is transferred to direct bandgap in nanowire. We find that intermediate bands can be created by doping, leading to enhancement of sunlight absorption. We further show that codoping not only reduces the bandgap and introduces intermediate bands but also enhances the solubility of dopants in silicon nitride nanowires due to reduced formation energy of substitution. Importantly, the codoped nanowire is ferromagnetic, leading to the improvement of carrier mobility. The silicon nitride nanowires with direct bandgap, intermediate bands, and ferromagnetism may be applicable to solar energy harvesting. PMID- 25294976 TI - The effects of surface spin on magnetic properties of weak magnetic ZnLa0.02Fe1.98O4 nanoparticles. AB - In order to prominently investigate the effects of the surface spin on the magnetic properties, the weak magnetic ZnLa0.02Fe1.98O4 nanoparticles were chosen as studying objects which benefit to reduce as possibly the effects of interparticle dipolar interaction and crystalline anisotropy energies. By annealing the undiluted and diluted ZnLa0.02Fe1.98O4 nanoparticles at different temperatures, we observed the rich variations of magnetic ordering states (superparamagnetism, weak ferromagnetism, and paramagnetism). The magnetic properties can be well understood by considering the effects of the surface spin of the magnetic nanoparticles. Our results indicate that in the nano-sized magnets with weak magnetism, the surface spin plays a crucial rule in the magnetic properties. PMID- 25294977 TI - Self-rectifying performance in the sandwiched structure of Ag/In-Ga-Zn-O/Pt bipolar resistive switching memory. AB - We reported that the resistive switching of Ag/In-Ga-Zn-O/Pt cells exhibited self rectifying performance at low-resistance state (LRS). The self-rectifying behavior with reliability was dynamic at elevated temperature from 303 to 393 K. The Schottky barrier originated from the interface between Ag electrode and In-Ga Zn-O films, identified by replacing Ag electrode with Cu and Ti metals. The reverse current at 1.2 V of LRS is strongly suppressed and more than three orders of magnitude lower than the forward current. The Schottky barrier height was calculated as approximately 0.32 eV, and the electron injection process and resistive switching mechanism were discussed. PMID- 25294978 TI - Synthesis of Imine-Naphthol Tripodal Ligand and Study of Its Coordination Behaviour towards Fe(III), Al(III), and Cr(III) Metal Ions. AB - A hexadentate Schiff base tripodal ligand is synthesized by the condensation of tris (2-aminoethyl) amine with 2-hydroxy-1-naphthaldehyde and characterized by various spectroscopic techniques like UV-VIS, IR, NMR, MASS, and elemental analysis. The solution studies by potentiometric and spectrophotometric methods are done at 25 +/- 1 degrees C, u = 0.1 M KCl, to calculate the protonation constants of the ligand and formation constants of metal complexes formed by the ligand with Fe(III), Al(III), and Cr(III) metal ions. The affinity of the ligand towards Fe(III) is compared with deferiprone (a drug applied for iron intoxication) and transferrin (the main Fe(III) binding protein in plasma). Structural analysis of the ligand and the metal complexes was done using semiempirical PM6 method. Electronic and IR spectra are calculated by semiempirical methods and compared with experimental one. PMID- 25294979 TI - Time-resolved coherent X-ray diffraction imaging of surface acoustic waves. AB - Time-resolved coherent X-ray diffraction experiments of standing surface acoustic waves, illuminated under grazing incidence by a nanofocused synchrotron beam, are reported. The data have been recorded in stroboscopic mode at controlled and varied phase between the acoustic frequency generator and the synchrotron bunch train. At each time delay (phase angle), the coherent far-field diffraction pattern in the small-angle regime is inverted by an iterative algorithm to yield the local instantaneous surface height profile along the optical axis. The results show that periodic nanoscale dynamics can be imaged at high temporal resolution in the range of 50 ps (pulse length). PMID- 25294980 TI - Mass-fractal growth in niobia/silsesquioxane mixtures: a small-angle X-ray scattering study. AB - The nucleation and growth of niobium pentaethoxide (NPE)-derived clusters in ethanol, through acid-catalyzed hydrolysis/condensation in the presence and absence of the silsesquioxane 1,2-bis(triethoxysilyl)ethane (BTESE), was monitored at 298-333 K by small-angle X-ray scattering. The data were analyzed with a newly derived model for polydisperse mass-fractal-like structures. At 298 313 K in the absence of BTESE the data indicated the development of relatively monodisperse NPE-derived structures with self-preserving polydispersity during growth. The growth exponent was consistent with irreversible diffusion-limited cluster agglomeration. At 333 K the growth exponent was characteristic for fast gelling reaction-limited cluster agglomeration. The reaction yielded substantially higher degrees of polydispersity. In the presence of BTESE the growth exponents were substantially smaller. The smaller growth exponent in this case is not consistent with irreversible Smoluchowski-type agglomeration. Instead, reversible Lifshitz-Slyozov-type agglomeration seems to be more consistent with the experimental data. PMID- 25294981 TI - SynchLink: an iOS app for ISPyB. AB - The macromolecular crystallography (MX) user experience at synchrotron radiation facilities continues to evolve, with the impact of developments in X-ray detectors, computer hardware and automation methods making it possible for complete data sets to be collected on timescales of tens of seconds. Data can be reduced in a couple of minutes and in favourable cases structures solved and refined shortly after. The information-rich database ISPyB, automatically populated by data acquisition software, data processing and structure solution pipelines at the Diamond Light Source beamlines, allows users to automatically track MX experiments in real time. In order to improve the synchrotron users' experience, efficient access to the data contained in ISPyB is now provided via an iOS 6.0+ app for iPhones and iPads. This provides users, both local and remote, with a succinct summary of data collection, visualization of diffraction images and crystals, and key metrics for data quality in real time. PMID- 25294982 TI - A customizable software for fast reduction and analysis of large X-ray scattering data sets: applications of the new DPDAK package to small-angle X-ray scattering and grazing-incidence small-angle X-ray scattering. AB - X-ray scattering experiments at synchrotron sources are characterized by large and constantly increasing amounts of data. The great number of files generated during a synchrotron experiment is often a limiting factor in the analysis of the data, since appropriate software is rarely available to perform fast and tailored data processing. Furthermore, it is often necessary to perform online data reduction and analysis during the experiment in order to interactively optimize experimental design. This article presents an open-source software package developed to process large amounts of data from synchrotron scattering experiments. These data reduction processes involve calibration and correction of raw data, one- or two-dimensional integration, as well as fitting and further analysis of the data, including the extraction of certain parameters. The software, DPDAK (directly programmable data analysis kit), is based on a plug-in structure and allows individual extension in accordance with the requirements of the user. The article demonstrates the use of DPDAK for on- and offline analysis of scanning small-angle X-ray scattering (SAXS) data on biological samples and microfluidic systems, as well as for a comprehensive analysis of grazing incidence SAXS data. In addition to a comparison with existing software packages, the structure of DPDAK and the possibilities and limitations are discussed. PMID- 25294983 TI - The lipid cubic phase or in meso method for crystallizing proteins. Bushings for better manual dispensing. AB - The lipid cubic phase or in meso method can be used to set up crystallization trials of soluble and membrane proteins. The cubic phase is noted for being a sticky and viscous mesophase. Dispensing the protein-laden mesophase by hand into wells on crystallization plates has been facilitated by the use of an inexpensive repeat dispenser. However, the assembled dispensing device is prone to damage. Specifically, the delicate plunger used to dispense the viscous mesophase by positive displacement can be bent and scarred when the locking nut that fixes the plunger to the ratchet-driven dispensing mechanism is inadvertently overtightened. A defective plunger can render the device useless as a dispensing tool. More importantly, it can lead to catastrophic loss of valuable protein and lipid due to leakage when the dispensing syringe is being recharged with fresh mesophase. This note describes two types of bushings designed to protect the plunger from mechanical damage, which provide facile and reliable dispenser performance. One is a split bushing in brass and is a highly durable solution. The other is a small sleeve made from readily available plastic tubing. While it lacks durability, the plastic sleeve is simple yet highly effective, and can be replaced as the need arises. PMID- 25294985 TI - The non-human primate striatum undergoes marked prolonged remodeling during postnatal development. AB - We examined the postnatal ontogeny of the striatum in rhesus monkeys (Macaca mulatta) to identify temporal and spatial patterns of histological and chemical maturation. Our goal was to determine whether this forebrain structure is developmentally static or dynamic in postnatal life. Brains from monkeys at 1 day, 1, 4, 6, 9, and 12 months of age (N = 12) and adult monkeys (N = 4) were analyzed. Nissl staining was used to assess striatal volume, cytoarchitecture, and apoptosis. Immunohistochemistry was used to localize and measure substance P (SP), leucine-enkephalin (LENK), tyrosine hydroxylase (TH), and calbindin D28 (CAL) immunoreactivities. Mature brain to body weight ratio was achieved at 4 months of age, and striatal volume increased from ~1.2 to ~1.4 cm(3) during the first postnatal year. Nissl staining identified, prominently in the caudate nucleus, developmentally persistent discrete cell islands with neuronal densities greater than the surrounding striatal parenchyma (matrix). Losses in neuronal density were observed in island and matrix regions during maturation, and differential developmental programmed cell death was observed in islands and matrix regions. Immunohistochemistry revealed striking changes occurring postnatally in striatal chemical neuroanatomy. At birth, the immature dopaminergic nigrostriatal innervation was characterized by islands enriched in TH-immunoreactive puncta (putative terminals) in the neuropil; TH-enriched islands aligned completely with areas enriched in SP immunoreactivity but low in LENK immunoreactivity. These areas enriched in SP immunoreactivity but low in LENK immunoreactivity were identified as striosome and matrix areas, respectively, because CAL immunoreactivity clearly delineated these territories. SP, LENK, and CAL immunoreactivities appeared as positive neuronal cell bodies, processes, and puncta. The matrix compartment at birth contained relatively low TH-immunoreactive processes and few SP-positive neurons but was densely populated with LENK-immunoreactive neurons. The nucleus accumbens part of the ventral striatum also showed prominent differences in SP, LENK, and CAL immunoreactivities in shell and core territories. During 12 months of postnatal maturation salient changes occurred in neurotransmitter marker localization: TH positive afferents densely innervated the matrix to exceed levels of immunoreactivity in the striosomes; SP immunoreactivity levels increased in the matrix; and LENK-immunoreactivity levels decreased in the matrix and increased in the striosomes. At 12 months of age, striatal chemoarchitecture was similar qualitatively to adult patterns, but quantitatively different in LENK and SP in caudate, putamen, and nucleus accumbens. This study shows for the first time that the rhesus monkey striatum requires more than 12 months after birth to develop an adult-like pattern of chemical neuroanatomy and that principal neurons within striosomes and matrix have different developmental programs for neuropeptide expression. We conclude that postnatal maturation of the striatal mosaic in primates is not static but, rather, is a protracted and dynamic process that requires many synchronous and compartment-selective changes in afferent innervation and in the expression of genes that regulate neuronal phenotypes. PMID- 25294986 TI - Molecular identity of axonal sodium channels in human cortical pyramidal cells. AB - Studies in rodents revealed that selective accumulation of Na(+) channel subtypes at the axon initial segment (AIS) determines action potential (AP) initiation and backpropagation in cortical pyramidal cells (PCs); however, in human cortex, the molecular identity of Na(+) channels distributed at PC axons, including the AIS and the nodes of Ranvier, remains unclear. We performed immunostaining experiments in human cortical tissues removed surgically to cure brain diseases. We found strong immunosignals of Na(+) channels and two channel subtypes, NaV1.2 and NaV1.6, at the AIS of human cortical PCs. Although both channel subtypes were expressed along the entire AIS, the peak immunosignals of NaV1.2 and NaV1.6 were found at proximal and distal AIS regions, respectively. Surprisingly, in addition to the presence of NaV1.6 at the nodes of Ranvier, NaV1.2 was also found in a subpopulation of nodes in the adult human cortex, different from the absence of NaV1.2 in myelinated axons in rodents. NaV1.1 immunosignals were not detected at either the AIS or the nodes of Ranvier of PCs; however, they were expressed at interneuron axons with different distribution patterns. Further experiments revealed that parvalbumin-positive GABAergic axon cartridges selectively innervated distal AIS regions with relatively high immunosignals of NaV1.6 but not the proximal NaV1.2-enriched compartments, suggesting an important role of axo-axonic cells in regulating AP initiation in human PCs. Together, our results show that both NaV1.2 and NaV1.6 (but not NaV1.1) channel subtypes are expressed at the AIS and the nodes of Ranvier in adult human cortical PCs, suggesting that these channel subtypes control neuronal excitability and signal conduction in PC axons. PMID- 25294988 TI - Closed-loop neuroscience and neuroengineering. PMID- 25294989 TI - Self-organized criticality as a fundamental property of neural systems. AB - The neural criticality hypothesis states that the brain may be poised in a critical state at a boundary between different types of dynamics. Theoretical and experimental studies show that critical systems often exhibit optimal computational properties, suggesting the possibility that criticality has been evolutionarily selected as a useful trait for our nervous system. Evidence for criticality has been found in cell cultures, brain slices, and anesthetized animals. Yet, inconsistent results were reported for recordings in awake animals and humans, and current results point to open questions about the exact nature and mechanism of criticality, as well as its functional role. Therefore, the criticality hypothesis has remained a controversial proposition. Here, we provide an account of the mathematical and physical foundations of criticality. In the light of this conceptual framework, we then review and discuss recent experimental studies with the aim of identifying important next steps to be taken and connections to other fields that should be explored. PMID- 25294987 TI - Diffusion dynamics of synaptic molecules during inhibitory postsynaptic plasticity. AB - The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. At postsynaptic level, the expression of inhibitory synaptic plasticity involves the rearrangement of the postsynaptic molecular components of the GABAergic synapse, including GABAA receptors, scaffold proteins and structural molecules. This implies a dynamic modulation of receptor intracellular trafficking and receptor surface lateral diffusion, along with regulation of the availability and distribution of scaffold proteins. This Review will focus on the mechanisms of the multifaceted molecular reorganization of the inhibitory synapse during postsynaptic plasticity, with special emphasis on the key role of protein dynamics to ensure prompt and reliable activity-dependent adjustments of synaptic strength. PMID- 25294990 TI - Mapping and morphometric analysis of synapses and spines on fusiform cells in the dorsal cochlear nucleus. AB - Fusiform cells are the main integrative units of the mammalian dorsal cochlear nucleus (DCN), collecting and processing inputs from auditory and other sources before transmitting information to higher levels of the auditory system. Despite much previous work describing these cells and the sources and pharmacological identity of their synaptic inputs, information on the three-dimensional organization and utltrastructure of synapses on these cells is currently very limited. This information is essential since an understanding of synaptic plasticity and remodeling and pathologies underlying disease states and hearing disorders must begin with knowledge of the normal characteristics of synapses on these cells, particularly those features that determine the strength of their influence on the various compartments of the cell. Here, we employed serial block face scanning electron microscopy (SBFSEM) followed by 3D reconstructions to map and quantitatively characterize synaptic features on DCN fusiform cells. Our results reveal a relative sparseness of synapses on the somata of fusiform cells but a dense distribution of synapses on apical and basal dendrites. Synapses on apical dendrites were smaller and more numerous than on basal dendrites. The vast majority of axosomatic terminals were found to be linked to other terminals connected by the same axon or different branches of the same axon, suggesting a high degree of divergent input to fusiform cells. The size of terminals was correlated with the number of mitochondria and with the number of active zones, which was highly correlated with the number of postsynaptic densities, suggesting that larger terminals exert more powerful influence on the cell than smaller terminals. These size differences suggest that the input to basal dendrites, most likely those from the auditory nerve, provide the most powerful sources of input to fusiform cells, while those to apical dendrites (e.g., parallel fiber) are weaker but more numerous. PMID- 25294991 TI - A model of hippocampal spiking responses to items during learning of a context dependent task. AB - Single unit recordings in the rat hippocampus have demonstrated shifts in the specificity of spiking activity during learning of a contextual item-reward association task. In this task, rats received reward for responding to different items dependent upon the context an item appeared in, but not dependent upon the location an item appears at. Initially, neurons in the rat hippocampus primarily show firing based on place, but as the rat learns the task this firing became more selective for items. We simulated this effect using a simple circuit model with discrete inputs driving spiking activity representing place and item followed sequentially by a discrete representation of the motor actions involving a response to an item (digging for food) or the movement to a different item (movement to a different pot for food). We implemented spiking replay in the network representing neural activity observed during sharp-wave ripple events, and modified synaptic connections based on a simple representation of spike timing dependent synaptic plasticity. This simple network was able to consistently learn the context-dependent responses, and transitioned from dominant coding of place to a gradual increase in specificity to items consistent with analysis of the experimental data. In addition, the model showed an increase in specificity toward context. The increase of selectivity in the model is accompanied by an increase in binariness of the synaptic weights for cells that are part of the functional network. PMID- 25294992 TI - Abnormal anxiety- and depression-like behaviors in mice lacking both central serotonergic neurons and pancreatic islet cells. AB - Dysfunction of central serotonin (5-HT) system has been proposed to be one of the underlying mechanisms for anxiety and depression, and the association of diabetes mellitus and psychiatric disorders has been noticed by the high prevalence of anxiety/depression in patients with diabetes mellitus. This promoted us to examine these behaviors in central 5-HT-deficient mice and those also suffering with diabetes mellitus. Mice lacking either 5-HT or central serotonergic neurons were generated by conditional deletion of Tph2 or Lmx1b respectively. Simultaneous depletion of both central serotonergic neurons and pancreatic islet cells was achieved by administration of diphtheria toxin (DT) in Pet1-Cre;Rosa26 DT receptor (DTR) mice. The central 5-HT-deficient mice showed reduced anxiety like behaviors as they spent more time in and entered more often into the light box in the light/dark box test compared with controls; similar results were observed in the elevated plus maze test. However, they displayed no differences in the immobility time of the forced swimming and tail suspension tests suggesting normal depression-like behaviors in central 5-HT-deficient mice. As expected, DT-treated Pet1-Cre;Rosa26-DTR mice lacking both central serotonergic neurons and pancreatic islet endocrine cells exhibited several classic diabetic symptoms. Interestingly, they displayed increased anxiety-like behaviors but reduced immobility time in the forced swimming and tail suspension tests. Furthermore, the hippocampal neurogenesis was dramatically enhanced in these mice. These results suggest that the deficiency of central 5-HT may not be sufficient to induce anxiety/depression-like behaviors in mice, and the enhanced hippocampal neurogenesis may contribute to the altered depression-like behaviors in the 5-HT-deficient mice with diabetes. Our current investigation provides understanding the relationship between diabetes mellitus and psychiatric disorders. PMID- 25294993 TI - The Body Action Coding System II: muscle activations during the perception and expression of emotion. AB - Research into the expression and perception of emotions has mostly focused on facial expressions. Recently, body postures have become increasingly important in research, but knowledge on muscle activity during the perception or expression of emotion is lacking. The current study continues the development of a Body Action Coding System (BACS), which was initiated in a previous study, and described the involvement of muscles in the neck, shoulders and arms during expression of fear and anger. The current study expands the BACS by assessing the activity patterns of three additional muscles. Surface electromyography of muscles in the neck (upper trapezius descendens), forearms (extensor carpi ulnaris), lower back (erector spinae longissimus) and calves (peroneus longus) were measured during active expression and passive viewing of fearful and angry body expressions. The muscles in the forearm were strongly active for anger expression and to a lesser extent for fear expression. In contrast, muscles in the calves were recruited slightly more for fearful expressions. It was also found that muscles automatically responded to the perception of emotion, without any overt movement. The observer's forearms responded to the perception of fear, while the muscles used for leaning backwards were activated when faced with an angry adversary. Lastly, the calf responded immediately when a fearful person was seen, but responded slower to anger. There is increasing interest in developing systems that are able to create or recognize emotional body language for the development of avatars, robots, and online environments. To that end, multiple coding systems have been developed that can either interpret or create bodily expressions based on static postures, motion capture data or videos. However, the BACS is the first coding system based on muscle activity. PMID- 25294994 TI - Varied behavioral responses induced by morphine in the tree shrew: a possible model for human opiate addiction. AB - Tree shrews represent a suitable animal model to study the pathogenesis of human diseases as they are phylogenetically close to primates and have a well-developed central nervous system that possesses many homologies with primates. Therefore, in our study, we investigated whether tree shrews can be used to explore the addictive behaviors induced by morphine. Firstly, to investigate the psychoactive effect of morphine on tree shrews' behavior, the number of jumping and shuttling, which represent the vertical and horizontal locomotor activity respectively, was examined following the injection of different dosage of morphine. Our results showed intramuscular (IM) injection of morphine (5 or 10 mg/kg) significantly increased the locomotor activity of tree shrews 30-60 min post-injection. Then, using the conditioned place preference/aversion (CPP/CPA) paradigm, we found morphine-conditioned tree shrews exhibited place preference in the morphine paired chamber on the test day. In addition, naloxone-precipitated withdrawal induced place aversion in the chronic morphine-dependent tree shrews. We evaluated the craving for morphine drinking by assessing the break point that reflects the maximum effort animals will expend to get the drug. Our data showed the break point was significantly increased when compared to the baseline on the 1st, 7th and 14th day after the abstinence. Moreover, in the intravenous morphine self-administration experiment, tree shrews conditioned with morphine responded on the active lever significantly more frequently than on the inactive lever after training. These results suggest that tree shrew may be a potential candidate for study the addictive behaviors and the underling neurological mechanisms. PMID- 25294996 TI - Order short-term memory is not impaired in dyslexia and does not affect orthographic learning. AB - This article reports two studies that investigate short-term memory (STM) deficits in dyslexic children and explores the relationship between STM and reading acquisition. In the first experiment, 36 dyslexic children and 61 control children performed an item STM task and a serial order STM task. The results of this experiment show that dyslexic children do not suffer from a specific serial order STM deficit. In addition, the results demonstrate that phonological processing skills are as closely related to both item STM and serial order STM. However, non-verbal intelligence was more strongly involved in serial order STM than in item STM. In the second experiment, the same two STM tasks were administered and reading acquisition was assessed by measuring orthographic learning in a group of 188 children. The results of this study show that orthographic learning is exclusively related to item STM and not to order STM. It is concluded that serial order STM is not the right place to look for a causal explanation of reading disability, nor for differences in word reading acquisition. PMID- 25294997 TI - Dissociable neural systems underwrite logical reasoning in the context of induced emotions with positive and negative valence. AB - How emotions influence syllogistic reasoning is not well understood. fMRI was employed to investigate the effects of induced positive or negative emotion on syllogistic reasoning. Specifically, on a trial-by-trial basis participants were exposed to a positive, negative, or neutral picture, immediately prior to engagement in a reasoning task. After viewing and rating the valence and intensity of each picture, participants indicated by keypress whether or not the conclusion of the syllogism followed logically from the premises. The content of all syllogisms was neutral, and the influence of belief-bias was controlled for in the study design. Emotion did not affect reasoning performance, although there was a trend in the expected direction based on accuracy rates for the positive (63%) and negative (64%) versus neutral (70%) condition. Nevertheless, exposure to positive and negative pictures led to dissociable patterns of neural activation during reasoning. Therefore, the neural basis of deductive reasoning differs as a function of the valence of the context. PMID- 25294998 TI - Cortex integrity relevance in muscle synergies in severe chronic stroke. AB - BACKGROUND: Recent experimental evidence has indicated that the motor system coordinates muscle activations through a linear combination of muscle synergies that are specified at the spinal or brainstem networks level. After stroke upper limb impairment is characterized by abnormal patterns of muscle activations or synergies. OBJECTIVE: This study aimed at characterizing the muscle synergies in severely affected chronic stroke patients. Furthermore, the influence of integrity of the sensorimotor cortex on synergy modularity and its relation with motor impairment was evaluated. METHODS: Surface electromyography from 33 severely impaired chronic stroke patients was recorded during 6 bilateral movements. Muscle synergies were extracted and synergy patterns were correlated with motor impairment scales. RESULTS: Muscle synergies extracted revealed different physiological patterns dependent on the preservation of the sensorimotor cortex. Patients without intact sensorimotor cortex showed a high preservation of muscle synergies. On the contrary, patients with intact sensorimotor cortex showed poorer muscle synergies preservation and an increase in new generated synergies. Furthermore, the preservation of muscle synergies correlated positively with hand functionality in patients with intact sensorimotor cortex and subcortical lesions only. CONCLUSION: Our results indicate that severely paralyzed chronic stroke patient with intact sensorimotor cortex might sculpt new synergy patterns as a response to maladaptive compensatory strategies. PMID- 25294995 TI - Motoneuron firing in amyotrophic lateral sclerosis (ALS). AB - Amyotrophic lateral sclerosis is an inexorably progressive neurodegenerative disorder involving the classical motor system and the frontal effector brain, causing muscular weakness and atrophy, with variable upper motor neuron signs and often an associated fronto-temporal dementia. The physiological disturbance consequent on the motor system degeneration is beginning to be well understood. In this review we describe aspects of the motor cortical, neuronal, and lower motor neuron dysfunction. We show how studies of the changes in the pattern of motor unit firing help delineate the underlying pathophysiological disturbance as the disease progresses. Such studies are beginning to illuminate the underlying disordered pathophysiological processes in the disease, and are important in designing new approaches to therapy and especially for clinical trials. PMID- 25294999 TI - Effects of aging and involuntary capture of attention on event-related potentials associated with the processing of and the response to a target stimulus. AB - The main aim of the present study was to assess whether aging modulates the effects of involuntary capture of attention by novel stimuli on performance, and on event-related potentials (ERPs) associated with target processing (N2b and P3b) and subsequent response processes (stimulus-locked Lateralized Readiness Potential -sLRP- and response-locked Lateralized Readiness Potential -rLRP-). An auditory-visual distraction-attention task was performed by 77 healthy participants, divided into three age groups (Young: 21-29, Middle-aged: 51-64, Old: 65-84 years old). Participants were asked to attend to visual stimuli and to ignore auditory stimuli. Aging was associated with slowed reaction times, target stimulus processing in working memory (WM, longer N2b and P3b latencies) and selection and preparation of the motor response (longer sLRP and earlier rLRP onset latencies). In the novel relative to the standard condition we observed, in the three age groups: (1) a distraction effect, reflected in a slowing of reaction times, of stimuli categorization in WM (longer P3b latency), and of motor response selection (longer sLRP onset latency); (2) a facilitation effect on response preparation (later rLRP onset latency), and (3) an increase in arousal (larger amplitudes of all ERPs evaluated, except for N2b amplitude in the Old group). A distraction effect on the stimulus evaluation processes (longer N2b latency) were also observed, but only in middle-aged and old participants, indicating that the attentional capture slows the stimulus evaluation in WM from early ages (from 50 years onwards, without differences between middle-age and older adults), but not in young adults. PMID- 25295001 TI - Investigating alterations of social interaction in psychiatric disorders with dual interactive eye tracking and virtual faces. PMID- 25295000 TI - Loss of agency in apraxia. AB - The feeling of acting voluntarily is a fundamental component of human behavior and social life and is usually accompanied by a sense of agency. However, this ability can be impaired in a number of diseases and disorders. An important example is apraxia, a disturbance traditionally defined as a disorder of voluntary skillful movements that often results from frontal-parietal brain damage. The first part of this article focuses on direct evidence of some core symptoms of apraxia, emphasizing those with connections to agency and free will. The loss of agency in apraxia is reflected in the monitoring of internally driven action, in the perception of specifically self-intended movements and in the neural intention to act. The second part presents an outline of the evidences supporting the functional and anatomical link between apraxia and agency. The available structural and functional results converge to reveal that the frontal parietal network contributes to the sense of agency and its impairment in disorders such as apraxia. The current knowledge on the generation of motor intentions and action monitoring could potentially be applied to develop therapeutic strategies for the clinical rehabilitation of voluntary action. PMID- 25295002 TI - SIMA: Python software for analysis of dynamic fluorescence imaging data. AB - Fluorescence imaging is a powerful method for monitoring dynamic signals in the nervous system. However, analysis of dynamic fluorescence imaging data remains burdensome, in part due to the shortage of available software tools. To address this need, we have developed SIMA, an open source Python package that facilitates common analysis tasks related to fluorescence imaging. Functionality of this package includes correction of motion artifacts occurring during in vivo imaging with laser-scanning microscopy, segmentation of imaged fields into regions of interest (ROIs), and extraction of signals from the segmented ROIs. We have also developed a graphical user interface (GUI) for manual editing of the automatically segmented ROIs and automated registration of ROIs across multiple imaging datasets. This software has been designed with flexibility in mind to allow for future extension with different analysis methods and potential integration with other packages. Software, documentation, and source code for the SIMA package and ROI Buddy GUI are freely available at http://www.losonczylab.org/sima/. PMID- 25295004 TI - Transcranial direct current stimulation of the primary motor cortex improves word retrieval in older adults. AB - Language facilitation by transcranial direct current stimulation (tDCS) in healthy individuals has generated hope that tDCS may also allow improving language impairment after stroke (aphasia). However, current stimulation protocols have yielded variable results and may require identification of residual language cortex using functional magnetic resonance imaging (fMRI), which complicates incorporation into clinical practice. Based on previous behavioral studies that demonstrated improved language processing by motor system pre-activation, the present study assessed whether tDCS administered to the primary motor cortex (M1) can enhance language functions. This proof-of-concept study employed a sham-tDCS controlled, cross-over, within-subject design and assessed the impact of unilateral excitatory (anodal) and bihemispheric (dual) tDCS in 18 healthy older adults during semantic word-retrieval and motor speech tasks. Simultaneous fMRI scrutinized the neural mechanisms underlying tDCS effects. Both active tDCS conditions significantly improved word-retrieval compared to sham-tDCS. The direct comparison of activity elicited by word retrieval vs. motor-speech trials revealed bilateral frontal activity increases during both anodal- and dual-tDCS compared to sham-tDCS. This effect was driven by more pronounced deactivation of frontal regions during the motor-speech task, while activity during word-retrieval trials was unaffected by the stimulation. No effects were found in M1 and secondary motor regions. Our results show that tDCS administered to M1 can improve word-retrieval in healthy individuals, thereby providing a rationale to explore whether M1-tDCS may offer a novel approach to improve language functions in aphasia. Functional magnetic resonance imaging revealed neural facilitation specifically during motor speech trials, which may have reduced switching costs between the overlapping neural systems for lexical retrieval and speech processing, thereby resulting in improved performance. PMID- 25295005 TI - Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals. AB - Current treatment options for patients with Alzheimer's disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (Abeta) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long term depression (LTD). These findings led to the development of potential anti amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of Abeta early in the cascade of amyloidogenic events, and by its gamma-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity. PMID- 25295006 TI - Epoxyeicosatrienoic acid analog attenuates angiotensin II hypertension and kidney injury. AB - Epoxyeicosatrienoic acids (EETs) contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end organ damage. In the present study, we investigated anti hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II)-induced hypertension. EET-B was administered in drinking water for 14 days (10 mg/kg/d) and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension. PMID- 25295003 TI - Regulation of satellite cell function in sarcopenia. AB - The mechanisms contributing to sarcopenia include reduced satellite cell (myogenic stem cell) function that is impacted by the environment (niche) of these cells. Satellite cell function is affected by oxidative stress, which is elevated in aged muscles, and this along with changes in largely unknown systemic factors, likely contribute to the manner in which satellite cells respond to stressors such as exercise, disuse, or rehabilitation in sarcopenic muscles. Nutritional intervention provides one therapeutic strategy to improve the satellite cell niche and systemic factors, with the goal of improving satellite cell function in aging muscles. Although many elderly persons consume various nutraceuticals with the hope of improving health, most of these compounds have not been thoroughly tested, and the impacts that they might have on sarcopenia and satellite cell function are not clear. This review discusses data pertaining to the satellite cell responses and function in aging skeletal muscle, and the impact that three compounds: resveratrol, green tea catechins, and beta-Hydroxy beta-methylbutyrate have on regulating satellite cell function and therefore contributing to reducing sarcopenia or improving muscle mass after disuse in aging. The data suggest that these nutraceutical compounds improve satellite cell function during rehabilitative loading in animal models of aging after disuse (i.e., muscle regeneration). While these compounds have not been rigorously tested in humans, the data from animal models of aging provide a strong basis for conducting additional focused work to determine if these or other nutraceuticals can offset the muscle losses, or improve regeneration in sarcopenic muscles of older humans via improving satellite cell function. PMID- 25295007 TI - Randomized controlled trials of iron chelators for the treatment of cardiac siderosis in thalassaemia major. AB - In conditions requiring repeated blood transfusion or where iron metabolism is abnormal, heart failure may result from accumulation of iron in the heart (cardiac siderosis). Death due to heart failure from cardiac iron overload has accounted for considerable early mortality in beta-thalassemia major. The ability to detect iron loading in the heart by cardiovascular magnetic resonance using T2* sequences has created an opportunity to intervene in the natural history of such conditions. However, effective and well tolerated therapy is required to remove iron from the heart. There are currently three approved commercially available iron chelators: deferoxamine, deferiprone and deferasirox. We review the high quality randomized controlled trials in this area for iron chelation therapy in the management of cardiac siderosis. PMID- 25295008 TI - Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations. AB - Cardiac hypertrophy represents one of the most important cardiovascular problems yet the mechanisms responsible for hypertrophic remodeling of the heart are poorly understood. In this report we aimed to explore the molecular pathways leading to two different phenotypes of cardiac hypertrophy in transgenic mice carrying mutations in the human ventricular myosin essential light chain (ELC). Mutation-induced alterations in the heart structure and function were studied in two transgenic (Tg) mouse models carrying the A57G (alanine to glycine) substitution or lacking the N-terminal 43 amino acid residues (Delta43) from the ELC sequence. The first model represents an HCM disease as the A57G mutation was shown to cause malignant HCM outcomes in humans. The second mouse model is lacking the region of the ELC that was shown to be important for a direct interaction between the ELC and actin during muscle contraction. Our earlier studies demonstrated that >7 month old Tg-Delta43 mice developed substantial cardiac hypertrophy with no signs of histopathology or fibrosis. Tg mice did not show abnormal cardiac function compared to Tg-WT expressing the full length human ventricular ELC. Previously reported pathological morphology in Tg-A57G mice included extensive disorganization of myocytes and interstitial fibrosis with no abnormal increase in heart mass observed in >6 month-old animals. In this report we show that strenuous exercise can trigger hypertrophy and pathologic cardiac remodeling in Tg-A57G mice as early as 3 months of age. In contrast, no exercise induced changes were noted for Tg-Delta43 hearts and the mice maintained a non pathological cardiac phenotype. Based on our results, we suggest that exercise elicited heart remodeling in Tg-A57G mice follows the pathological pathway leading to HCM, while it induces no abnormal response in Tg-Delta43 mice. PMID- 25295009 TI - Mechanistic target of rapamycin (mTOR): a point of convergence in the action of insulin/IGF-1 and G protein-coupled receptor agonists in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is one of the most lethal human diseases. PDAC is now the fourth leading cause of cancer mortality in both men and women and deaths due to PDAC are projected to increase dramatically. Novel targets and agents for chemoprevention are urgently needed and will most likely arise from a more detailed understanding of the signaling mechanisms that stimulate the promotion and progression of sub malignant cells into pancreatic cancer cells and from the identification of modifiable risk factors for PDAC. Many epidemiological studies have linked obesity and long-standing type 2 diabetes mellitus (T2DM) with increased risk and worse clinical outcomes for developing PDAC. These diet-related metabolic disorders are multifaceted but characterized by peripheral insulin resistance, compensatory overproduction of insulin and increased bioavailability of insulin like growth factor-1 (IGF-1). Mounting evidence indicates that the insulin/IGF-1 receptor system plays a critical role in PDAC development and multiple studies support the notion that crosstalk between the insulin receptor and heptahelical G protein-coupled receptor (GPCR) signaling systems is an important element in the biological responses elicited by these signaling systems, including cell proliferation. This article highlights the central role of the mechanistic target of rapamycin (mTOR) in mediating crosstalk between insulin/IGF-1 and GPCR signaling in pancreatic cancer cells and proposes strategies, including the use of metformin, to target this signaling system in PDAC cells. PMID- 25295012 TI - Cardiac tissue engineering: a reflection after a decade of hurry. PMID- 25295013 TI - Perceptual inequality between two neighboring time intervals defined by sound markers: correspondence between neurophysiological and psychological data. AB - Brain activity related to time estimation processes in humans was analyzed using a perceptual phenomenon called auditory temporal assimilation. In a typical stimulus condition, two neighboring time intervals (T1 and T2 in this order) are perceived as equal even when the physical lengths of these time intervals are considerably different. Our previous event-related potential (ERP) study demonstrated that a slow negative component (SNCt) appears in the right-frontal brain area (around the F8 electrode) after T2, which is associated with judgment of the equality/inequality of T1 and T2. In the present study, we conducted two ERP experiments to further confirm the robustness of the SNCt. The stimulus patterns consisted of two neighboring time intervals marked by three successive tone bursts. Thirteen participants only listened to the patterns in the first session, and judged the equality/inequality of T1 and T2 in the next session. Behavioral data showed typical temporal assimilation. The ERP data revealed that three components (N1; contingent negative variation, CNV; and SNCt) emerged related to the temporal judgment. The N1 appeared in the central area, and its peak latencies corresponded to the physical timing of each marker onset. The CNV component appeared in the frontal area during T2 presentation, and its amplitude increased as a function of T1. The SNCt appeared in the right-frontal area after the presentation of T1 and T2, and its magnitude was larger for the temporal patterns causing perceptual inequality. The SNCt was also correlated with the perceptual equality/inequality of the same stimulus pattern, and continued up to about 400 ms after the end of T2. These results suggest that the SNCt can be a signature of equality/inequality judgment, which derives from the comparison of the two neighboring time intervals. PMID- 25295014 TI - Sensory trick phenomenon improves motor control in pianists with dystonia: prognostic value of glove-effect. AB - Musician's dystonia (MD) is a task-specific movement disorder that causes loss of voluntary motor control while playing the instrument. A subgroup of patients displays the so-called sensory trick: alteration of somatosensory input, e.g., by wearing a latex glove, may result in short-term improvement of motor control. In this study, the glove-effect in pianists with MD was quantified and its potential association with MD-severity and outcome after treatment was investigated. Thirty affected pianists were included in the study. Music instrument digital interface based scale analysis was used for assessment of fine motor control. Therapeutic options included botulinum toxin, pedagogical retraining and anticholinergic medication (trihexyphenidyl). 19% of patients showed significant improvement of fine motor control through wearing a glove. After treatment, outcome was significantly better in patients with a significant pre-treatment sensory trick. We conclude that the sensory trick may have a prognostic value for the outcome after treatment in pianists with MD. PMID- 25295010 TI - The efficacy of antihypertensive drugs in chronic intermittent hypoxia conditions. AB - Sleep apnea/hypopnea disorders include centrally originated diseases and obstructive sleep apnea (OSA). This last condition is renowned as a frequent secondary cause of hypertension (HT). The mechanisms involved in the pathogenesis of HT can be summarized in relation to two main pathways: sympathetic nervous system stimulation mediated mainly by activation of carotid body (CB) chemoreflexes and/or asphyxia, and, by no means the least important, the systemic effects of chronic intermittent hypoxia (CIH). The use of animal models has revealed that CIH is the critical stimulus underlying sympathetic activity and hypertension, and that this effect requires the presence of functional arterial chemoreceptors, which are hyperactive in CIH. These models of CIH mimic the HT observed in humans and allow the study of CIH independently without the mechanical obstruction component. The effect of continuous positive airway pressure (CPAP), the gold standard treatment for OSA patients, to reduce blood pressure seems to be modest and concomitant antihypertensive therapy is still required. We focus this review on the efficacy of pharmacological interventions to revert HT associated with CIH conditions in both animal models and humans. First, we explore the experimental animal models, developed to mimic HT related to CIH, which have been used to investigate the effect of antihypertensive drugs (AHDs). Second, we review what is known about drug efficacy to reverse HT induced by CIH in animals. Moreover, findings in humans with OSA are cited to demonstrate the lack of strong evidence for the establishment of a first-line antihypertensive regimen for these patients. Indeed, specific therapeutic guidelines for the pharmacological treatment of HT in these patients are still lacking. Finally, we discuss the future perspectives concerning the non pharmacological and pharmacological management of this particular type of HT. PMID- 25295011 TI - Skeletal muscle tissue engineering: strategies for volumetric constructs. AB - Skeletal muscle tissue is characterized by high metabolic requirements, defined structure and high regenerative potential. As such, it constitutes an appealing platform for tissue engineering to address volumetric defects, as proven by recent works in this field. Several issues common to all engineered constructs constrain the variety of tissues that can be realized in vitro, principal among them the lack of a vascular system and the absence of reliable cell sources; as it is, the only successful tissue engineering constructs are not characterized by active function, present limited cellular survival at implantation and possess low metabolic requirements. Recently, functionally competent constructs have been engineered, with vascular structures supporting their metabolic requirements. In addition to the use of biochemical cues, physical means, mechanical stimulation and the application of electric tension have proven effective in stimulating the differentiation of cells and the maturation of the constructs; while the use of co-cultures provided fine control of cellular developments through paracrine activity. This review will provide a brief analysis of some of the most promising improvements in the field, with particular attention to the techniques that could prove easily transferable to other branches of tissue engineering. PMID- 25295016 TI - Measurement bias detection with Kronecker product restricted models for multivariate longitudinal data: an illustration with health-related quality of life data from thirteen measurement occasions. AB - HIGHLIGHTS: Application of Kronecker product to construct parsimonious structural equation models for multivariate longitudinal data.A method for the investigation of measurement bias with Kronecker product restricted models.Application of these methods to health-related quality of life data from bone metastasis patients, collected at 13 consecutive measurement occasions.The use of curves to facilitate substantive interpretation of apparent measurement bias.Assessment of change in common factor means, after accounting for apparent measurement bias.Longitudinal measurement invariance is usually investigated with a longitudinal factor model (LFM). However, with multiple measurement occasions, the number of parameters to be estimated increases with a multiple of the number of measurement occasions. To guard against too low ratios of numbers of subjects and numbers of parameters, we can use Kronecker product restrictions to model the multivariate longitudinal structure of the data. These restrictions can be imposed on all parameter matrices, including measurement invariance restrictions on factor loadings and intercepts. The resulting models are parsimonious and have attractive interpretation, but require different methods for the investigation of measurement bias. Specifically, additional parameter matrices are introduced to accommodate possible violations of measurement invariance. These additional matrices consist of measurement bias parameters that are either fixed at zero or free to be estimated. In cases of measurement bias, it is also possible to model the bias over time, e.g., with linear or non-linear curves. Measurement bias detection with Kronecker product restricted models will be illustrated with multivariate longitudinal data from 682 bone metastasis patients whose health related quality of life (HRQL) was measured at 13 consecutive weeks. PMID- 25295017 TI - Facing the music: three issues in current research on singing and aphasia. PMID- 25295015 TI - Using brain stimulation to disentangle neural correlates of conscious vision. AB - Research into the neural correlates of consciousness (NCCs) has blossomed, due to the advent of new and increasingly sophisticated brain research tools. Neuroimaging has uncovered a variety of brain processes that relate to conscious perception, obtained in a range of experimental paradigms. But methods such as functional magnetic resonance imaging or electroencephalography do not always afford inference on the functional role these brain processes play in conscious vision. Such empirical NCCs could reflect neural prerequisites, neural consequences, or neural substrates of a conscious experience. Here, we take a closer look at the use of non-invasive brain stimulation (NIBS) techniques in this context. We discuss and review how NIBS methodology can enlighten our understanding of brain mechanisms underlying conscious vision by disentangling the empirical NCCs. PMID- 25295019 TI - Emotionality differences between a native and foreign language: theoretical implications. PMID- 25295018 TI - Predictive uncertainty in auditory sequence processing. AB - Previous studies of auditory expectation have focused on the expectedness perceived by listeners retrospectively in response to events. In contrast, this research examines predictive uncertainty-a property of listeners' prospective state of expectation prior to the onset of an event. We examine the information theoretic concept of Shannon entropy as a model of predictive uncertainty in music cognition. This is motivated by the Statistical Learning Hypothesis, which proposes that schematic expectations reflect probabilistic relationships between sensory events learned implicitly through exposure. Using probability estimates from an unsupervised, variable-order Markov model, 12 melodic contexts high in entropy and 12 melodic contexts low in entropy were selected from two musical repertoires differing in structural complexity (simple and complex). Musicians and non-musicians listened to the stimuli and provided explicit judgments of perceived uncertainty (explicit uncertainty). We also examined an indirect measure of uncertainty computed as the entropy of expectedness distributions obtained using a classical probe-tone paradigm where listeners rated the perceived expectedness of the final note in a melodic sequence (inferred uncertainty). Finally, we simulate listeners' perception of expectedness and uncertainty using computational models of auditory expectation. A detailed model comparison indicates which model parameters maximize fit to the data and how they compare to existing models in the literature. The results show that listeners experience greater uncertainty in high-entropy musical contexts than low-entropy contexts. This effect is particularly apparent for inferred uncertainty and is stronger in musicians than non-musicians. Consistent with the Statistical Learning Hypothesis, the results suggest that increased domain-relevant training is associated with an increasingly accurate cognitive model of probabilistic structure in music. PMID- 25295020 TI - Instituting interaction: normative transformations in human communicative practices. AB - Recent experiments in semiotics and linguistics demonstrate that groups tend to converge on a common set of signs or terms in response to presented problems, experiments which potentially bear on the emergence and establishment of institutional interactions. Taken together, these studies indicate a spectrum, ranging from the spontaneous convergence of communicative practices to their eventual conventionalization, a process which might be described as an implicit institutionalization of those practices. However, the emergence of such convergence and conventionalization does not in itself constitute an institution, in the strict sense of a social organization partly created and governed by explicit rules. A further step toward institutions proper may occur when others are instructed about a task. That is, given task situations which select for successful practices, instructions about such situations make explicit what was tacit practice, instructions which can then be followed correctly or incorrectly. This transition gives rise to the normative distinction between conditions of success versus conditions of correctness, a distinction which will be explored and complicated in the course of this paper. Using these experiments as a basis, then, the emergence of institutions will be characterized in evolutionary and normative terms, beginning with our adaptive responses to the selective pressures of certain situational environments, and continuing with our capacity to then shape, constrain, and institute those environments to further refine and streamline our problem-solving activity. PMID- 25295021 TI - Scaffolded reaching experiences encourage grasping activity in infants at high risk for autism. AB - Recent findings suggest impaired motor skill development during infancy in children later diagnosed with autism spectrum disorders (ASD). However, it remains unclear whether infants at high familial risk for ASD would benefit from early interventions targeting the motor domain. The current study investigated this issue by providing 3-month-old infants at high familial risk for ASD with training experiences aimed at facilitating independent reaching. A group of 17 high-risk (HR) infants received 2 weeks of scaffolded reaching experiences using "sticky mittens," and was compared to 72 low-risk (LR) infants experiencing the same or alternative training procedures. Results indicate that HR infants - just like LR infants - show an increase in grasping activity following "sticky mittens" training. In contrast to LR infants, evidence that motor training encouraged a preference for faces in HR infants was inconclusive. PMID- 25295022 TI - The role of oxytocin and alexithymia in the therapeutic process. PMID- 25295024 TI - Evidence of weak conscious experiences in the exclusion task. AB - Exclusion tasks have been proposed as objective measures of unconscious perception as they do not depend upon subjective ratings. In exclusion tasks, participants have to complete a task without using a previously presented prime. Use of the prime is taken as evidence for unconscious processing in the absence of awareness, yet it may also simply indicate that participants have weak experiences but fail to realize that these affect the response or fail to counter the effect on the response. Here, we tested this claim by allowing participants to rate their experience of a masked prime on the perceptual awareness scale (PAS) after the exclusion task. Results showed that the prime was used almost as often when participants reported having seen a "weak glimpse" of the prime as when they claimed to have "no experience" of the prime, thus suggesting participants frequently have weak (possibly contentless) experiences of the stimulus when failing to exclude. This indicates that the criteria for report of awareness is lower (i.e., more liberal) than that for exclusion and that failure to exclude should not be taken as evidence of complete absence of awareness. PMID- 25295025 TI - Focused attention, open monitoring and loving kindness meditation: effects on attention, conflict monitoring, and creativity - A review. AB - Meditation is becoming increasingly popular as a topic for scientific research and theories on meditation are becoming ever more specific. We distinguish between what is called focused Attention meditation, open Monitoring meditation, and loving kindness (or compassion) meditation. Research suggests that these meditations have differential, dissociable effects on a wide range of cognitive (control) processes, such as attentional selection, conflict monitoring, divergent, and convergent thinking. Although research on exactly how the various meditations operate on these processes is still missing, different kinds of meditations are associated with different neural structures and different patterns of electroencephalographic activity. In this review we discuss recent findings on meditation and suggest how the different meditations may affect cognitive processes, and we give suggestions for directions of future research. PMID- 25295023 TI - Pickles and ice cream! Food cravings in pregnancy: hypotheses, preliminary evidence, and directions for future research. AB - Women in the United States experience an increase in food cravings at two specific times during their life, (1) perimenstrually and (2) prenatally. The prevalence of excess gestational weight gain (GWG) is a growing concern due to its association with adverse health outcomes in both mothers and children. To the extent that prenatal food cravings may be a determinant of energy intake in pregnancy, a better understanding of craving etiology could be crucial in addressing the issue of excessive GWG. This paper reviews the available literature to corroborate and/or dispute some of the most commonly accepted hypotheses regarding the causes of food cravings during pregnancy, including a role of (1) hormonal changes, (2) nutritional deficits, (3) pharmacologically active ingredients in the desired foods, and (4) cultural and psychosocial factors. An existing model of perimenstrual chocolate craving etiology serves to structure the discussion of these hypotheses. The main hypotheses discussed receive little support, with the notable exception of a postulated role of cultural and psychosocial factors. The presence of cravings during pregnancy is a common phenomenon across different cultures, but the types of foods desired and the adverse impact of cravings on health may be culture-specific. Various psychosocial factors appear to correlate with excess GWG, including the presence of restrained eating. Findings strongly suggest that more research be conducted in this area. We propose that future investigations fall into one of the four following categories: (1) validation of food craving and eating-related measures specifically in pregnant populations, (2) use of ecological momentary assessment to obtain real time data on cravings during pregnancy, (3) implementation of longitudinal studies to address causality between eating disorder symptoms, food cravings, and GWG, and (4) development of interventions to ensure proper prenatal nutrition and prevent excess GWG. PMID- 25295027 TI - To Tube or Not to Tube? The Role of Intubation during Stroke Thrombectomy. AB - In the 10 years since the FDA first cleared the use of endovascular devices for the treatment of acute stroke, definitive evidence that such therapy improves outcomes remains lacking. The decision to intubate patients undergoing stroke thrombectomy impacts multiple variables that may influence outcomes after stroke. Three main areas where intubation may deleteriously affect acute stroke management include the introduction of delays in revascularization, fluctuations in peri-procedural blood pressure, and hypocapnia, resulting in cerebral vasoconstriction. In this mini-review, we discuss the evidence supporting these limitations of intubation during stroke thrombectomy and encourage neurohospitalists, neurocritical care specialists, and neurointerventionalists to carefully consider the decision to intubate during thrombectomy and provide strategies to avoid potential complications associated with its use in acute stroke. PMID- 25295026 TI - Mitochondrial Gene Expression Profiles and Metabolic Pathways in the Amygdala Associated with Exaggerated Fear in an Animal Model of PTSD. AB - The metabolic mechanisms underlying the development of exaggerated fear in post traumatic stress disorder (PTSD) are not well defined. In the present study, alteration in the expression of genes associated with mitochondrial function in the amygdala of an animal model of PTSD was determined. Amygdala tissue samples were excised from 10 non-stressed control rats and 10 stressed rats, 14 days post stress treatment. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined using a cDNA microarray. During the development of the exaggerated fear associated with PTSD, 48 genes were found to be significantly upregulated and 37 were significantly downregulated in the amygdala complex based on stringent criteria (p < 0.01). Ingenuity pathway analysis revealed up- or downregulation in the amygdala complex of four signaling networks - one associated with inflammatory and apoptotic pathways, one with immune mediators and metabolism, one with transcriptional factors, and one with chromatin remodeling. Thus, informatics of a neuronal gene array allowed us to determine the expression profile of mitochondrial genes in the amygdala complex of an animal model of PTSD. The result is a further understanding of the metabolic and neuronal signaling mechanisms associated with delayed and exaggerated fear. PMID- 25295028 TI - SPECT in the Kleine-Levin Syndrome, a Possible Diagnostic and Prognostic Aid? AB - INTRODUCTION: Kleine-Levin syndrome (KLS) is a rare syndrome of periodic hypersomnia and behavioral and cognitive symptoms based on clinical criteria. In the setting of differential diagnosis of hypersomnia disorders, an objective diagnostic aid is desirable. A promising modality is single photon emission computed tomography (SPECT). As intraepisodal investigations are difficult to perform, an interepisodal investigation would be very helpful. Another aim of the study was to correlate SPECT findings to prognosis. METHODS AND MATERIALS: Twenty four KLS-patients were categorized as severe or non-severe based on clinical characteristics. The clinical characteristics were analyzed in relation to SPECT examinations performed between hypersomnia periods (interepisodal) or after remission, as a clinical routine investigation. RESULTS: Forty-eight percent of the KLS-patients have hypoperfusion in the temporal or fronto-temporal regions. In patients that have undergone remission, 56% show that pattern. There were no specific findings related to prognosis. DISCUSSION/CONCLUSION: SPECT might be a diagnostic aid, in a setting of hypersomnia experience. With a sensitivity of 48%, interepisodal SPECT alone cannot be used for diagnosing KLS. PMID- 25295029 TI - PET Neuroimaging: Insights on Dystonia and Tourette Syndrome and Potential Applications. AB - Primary dystonia (pD) is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric developmental disorder characterized by motor and phonic tics, which could progress to behavioral changes. GTS and obsessive-compulsive disorders are often seen in comorbidity, also suggesting that a possible overlap in the pathophysiological bases of these two conditions. PET techniques are of considerable value in detecting functional and molecular abnormalities in vivo, according to the adopted radioligands. For example, PET is the unique technique that allows in vivo investigation of neurotransmitter systems, providing evidence of changes in GTS or pD. For example, presynaptic and post-synaptic dopaminergic studies with PET have shown alterations compatible with dysfunction or loss of D2 receptors bearing neurons, increased synaptic dopamine levels, or both. Measures of cerebral glucose metabolism with (18)F-fluorodeoxyglucose PET ((18)F-FDG PET) are very sensitive in showing brain functional alterations as well. (18)F-FDG PET data have shown metabolic changes within the cortico-striato-pallido-thalamo cortical and cerebello-thalamo-cortical networks, revealing possible involvement of brain circuits not limited to basal ganglia in pD and GTS. The aim of this work is to overview PET consistent neuroimaging literature on pD and GTS that has provided functional and molecular knowledge of the underlying neural dysfunction. Furthermore, we suggest potential applications of these techniques in monitoring treatments. PMID- 25295030 TI - Gene polymorphisms in pattern recognition receptors and susceptibility to idiopathic recurrent vulvovaginal candidiasis. AB - OBJECTIVE: Approximately 5% of women suffer from recurrent vulvovaginal candidiasis (RVVC). It has been hypothesized that genetic factors play an important role in the susceptibility to RVVC. The aim of this study was to assess the effect of genetic variants of genes encoding for pattern recognition receptors (PRRs) on susceptibility to RVVC. STUDY DESIGN: For the study, 119 RVVC patients and 263 healthy controls were recruited. Prevalence of polymorphisms in five PRRs involved in recognition of Candida were investigated in patients and controls. In silico and functional studies were performed to assess their functional effects. RESULTS: Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to RVVC. In contrast, a non-synonymous polymorphism in TLR2 (rs5743704, Pro631His) increased the susceptibility to RVVC almost 3-fold. Furthermore, the TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNgamma upon stimulation of peripheral blood mononuclear cells with Candida albicans. No effects were observed on serum mannose-binding lectin concentrations. CONDENSATION: This study demonstrates the association of susceptibility to RVVC with genetic variation in TLR2, most likely caused by decreased induction of mucosal antifungal host defense. CONCLUSION: Genetic variation in TLR2 may significantly enhance susceptibility to RVVC by modulating host defense mechanisms against Candida. Additional studies are warranted to assess systematically the role of host genetic variation for susceptibility to RVVC. PMID- 25295031 TI - Aerobic methanotrophic communities at the Red Sea brine-seawater interface. AB - The central rift of the Red Sea contains 25 brine pools with different physicochemical conditions, dictating the diversity and abundance of the microbial community. Three of these pools, the Atlantis II, Kebrit and Discovery Deeps, are uniquely characterized by a high concentration of hydrocarbons. The brine-seawater interface, described as an anoxic-oxic (brine-seawater) boundary, is characterized by a high methane concentration, thus favoring aerobic methane oxidation. The current study analyzed the aerobic free-living methane-oxidizing bacterial communities that potentially contribute to methane oxidation at the brine-seawater interfaces of the three aforementioned brine pools, using metagenomic pyrosequencing, 16S rRNA pyrotags and pmoA library constructs. The sequencing of 16S rRNA pyrotags revealed that these interfaces are characterized by high microbial community diversity. Signatures of aerobic methane-oxidizing bacteria were detected in the Atlantis II Interface (ATII-I) and the Kebrit Deep Upper (KB-U) and Lower (KB-L) brine-seawater interfaces. Through phylogenetic analysis of pmoA, we further demonstrated that the ATII-I aerobic methanotroph community is highly diverse. We propose four ATII-I pmoA clusters. Most importantly, cluster 2 groups with marine methane seep methanotrophs, and cluster 4 represent a unique lineage of an uncultured bacterium with divergent alkane monooxygenases. Moreover, non-metric multidimensional scaling (NMDS) based on the ordination of putative enzymes involved in methane metabolism showed that the Kebrit interface layers were distinct from the ATII-I and DD-I brine-seawater interfaces. PMID- 25295032 TI - Unprecedented evidence for high viral abundance and lytic activity in coral reef waters of the South Pacific Ocean. AB - Despite nutrient-depleted conditions, coral reef waters harbor abundant and diverse microbes; as major agents of microbial mortality, viruses are likely to influence microbial processes in these ecosystems. However, little is known about marine viruses in these rapidly changing ecosystems. Here we examined spatial and short-term temporal variability in marine viral abundance (VA) and viral lytic activity across various reef habitats surrounding Moorea Island (French Polynesia) in the South Pacific. Water samples were collected along four regional cross-reef transects and during a time-series in Opunohu Bay. Results revealed high VA (range: 5.6 * 10(6)-3.6 * 10(7) viruses ml(-1)) and lytic viral production (range: 1.5 * 10(9)-9.2 * 10(10) viruses l(-1) d(-1)). Flow cytometry revealed that viral assemblages were composed of three subsets that each displayed distinct spatiotemporal relationships with nutrient concentrations and autotrophic and heterotrophic microbial abundances. The results highlight dynamic shifts in viral community structure and imply that each of these three subsets is ecologically important and likely to infect distinct microbial hosts in reef waters. Based on viral-reduction approach, we estimate that lytic viruses were responsible for the removal of ca. 24-367% of bacterial standing stock d(-1) and the release of ca. 1.0-62 MUg of organic carbon l(-1) d(-1) in reef waters. Overall, this work demonstrates the highly dynamic distribution of viruses and their critical roles in controlling microbial mortality and nutrient cycling in coral reef water ecosystems. PMID- 25295033 TI - Diet and the development of the human intestinal microbiome. AB - The important role of the gut microbiome in maintaining human health has necessitated a better understanding of the temporal dynamics of intestinal microbial communities as well as the host and environmental factors driving these dynamics. Genetics, mode of birth, infant feeding patterns, antibiotic usage, sanitary living conditions and long term dietary habits contribute to shaping the composition of the gut microbiome. This review focuses primarily on diet, as it is one of the most pivotal factors in the development of the human gut microbiome from infancy to the elderly. The infant gut microbiota is characterized by a high degree of instability, only reaching a state similar to that of adults by 2-3 years of age; consistent with the establishment of a varied solid food diet. The diet-related factors influencing the development of the infant gut microbiome include whether the child is breast or formula-fed as well as how and when solid foods are introduced. In contrast to the infant gut, the adult gut microbiome is resilient to large shifts in community structure. Several studies have shown that dietary changes induce transient fluctuations in the adult microbiome, sometimes in as little as 24 h; however, the microbial community rapidly returns to its stable state. Current knowledge of how long-term dietary habits shape the gut microbiome is limited by the lack of long-term feeding studies coupled with temporal gut microbiota characterization. However, long-term weight loss studies have been shown to alter the ratio of the Bacteroidetes and Firmicutes, the two major bacterial phyla residing in the human gastrointestinal tract. With aging, diet-related factors such as malnutrition are associated with microbiome shifts, although the cause and effect relationship between these factors has not been established. Increased pharmaceutical usage is also more prevalent in the elderly and can contribute to reduced gut microbiota stability and diversity. Foods containing prebiotic oligosaccharide components that nurture beneficial commensals in the gut community and probiotic supplements are being explored as interventions to manipulate the gut microbiome, potentially improving health status. PMID- 25295034 TI - The stability region of the Streptomyces lividans plasmid pIJ101 encodes a DNA binding protein recognizing a highly conserved short palindromic sequence motif. AB - Conjugation is a driving force in the evolution and shaping of bacterial genomes. In antibiotic producing streptomycetes even small plasmids replicating via the rolling-circle mechanism are conjugative. Although they encode only genes involved in replication and transfer, the molecular function of most plasmid encoded proteins is unknown. In this work we show that the conjugative plasmid pIJ101 encodes an overlooked protein, SpdA2. We show that SpdA2 is a DNA binding protein which specifically recognizes a palindromic DNA sequence (sps). sps is localized within the spdA2 coding region and highly conserved in many Streptomyces plasmids. Elimination of the palindrome or deletion of spdA2 in plasmid pIJ303 did not interfere with conjugative plasmid transfer or pock formation, but affected segregational stability. PMID- 25295035 TI - Histamine poisoning and control measures in fish and fishery products. AB - Histamine poisoning is one of the most common form of intoxication caused by the ingestion of fish and fishery products. Cooking, canning, or freezing cannot reduce the levels of histamine because this compound is heat stable. All humans are susceptible to histamine and its effects can be described as intolerance or intoxication depending on the severity of the symptoms. The amount of histamine in food, the individual sensitivity, and the detoxification activity in human organism represent the main factors affecting the toxicological response in consumers. Histamine is the only biogenic amine with regulatory limits set by European Legislation, up to a maximum of 200 mg/kg in fresh fish and 400 mg/kg in fishery products treated by enzyme maturation in brine. PMID- 25295036 TI - Age-Dependent Immune Events during HBV Infection from Birth to Adulthood: An Alternative Interpretation. AB - Immune responses change during the life of an individual. While this concept has been well accepted for adaptive immunity, only recently it is becoming clear that the innate immune responses also acquire distinct features in different phases of life. We believe that this concept can offer a different interpretation of the pathological manifestations that can be observed in HBV-infected subjects during the patient's life. Here, we will review the age-related immunopathological features of HBV infection and discuss how the different virological and clinical manifestations might be linked to the developmental pathway of the immune system from newborns to adults. We will discuss how the age of patients can affect the degree of inflammatory responses, but not the levels of antiviral specific immunity. We then propose that the different clinical manifestations occurring during the natural history of HBV infection are related to the host ability to trigger an inflammatory immune response. PMID- 25295039 TI - HIV-1 Intersection with CD4 T Cell Vesicle Exocytosis: Intercellular Communication Goes Viral. AB - In cells of the immune system, the secretion of extracellular vesicles is modulated through cellular activation. In particular, T cell activation is achieved through cell-cell contacts with antigen presenting cells and the consequent formation of a specialized signaling junction called the immunological synapse. Recent works on CD4 T cells have elucidated that cognate antigen recognition by the T cell receptor (TCR) engages two distinct exocytic events. The first involves the exocytic targeting of signaling molecules at the synaptic membrane and drives the functional architecture of the immunological synapse. The second enlists the extracellular secretion of the TCR itself, once the functional architecture of the immunological synapse is accomplished. HIV-1, a human lymphotropic virus, has evolved sophisticated mechanisms to co-opt CD4 T cell physiology. Notably, it has become apparent that HIV-1 intersects the regulated secretory system of CD4 T cells in order to bud from the plasma membrane of the infected cell and to promote bystander cell death. Here, I review the relevance of CD4 vesicle exocytosis to immune regulation and to HIV-1 pathogenesis and discuss their potential therapeutic applications. PMID- 25295037 TI - Elucidation of pathways driving asthma pathogenesis: development of a systems level analytic strategy. AB - Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene * environment interactions occurring over a period of years, but these interactions are very poorly understood (1-6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis. PMID- 25295040 TI - Revisiting the 1986 molecular cloning of interleukin 6. PMID- 25295038 TI - Vesicular trafficking and signaling for cytokine and chemokine secretion in mast cells. AB - Upon activation mast cells (MCs) secrete numerous inflammatory compounds stored in their cytoplasmic secretory granules by a process called anaphylactic degranulation, which is responsible for type I hypersensitivity responses. Prestored mediators include histamine and MC proteases but also some cytokines and growth factors making them available within minutes for a maximal biological effect. Degranulation is followed by the de novo synthesis of lipid mediators such as prostaglandins and leukotrienes as well as a vast array of cytokines, chemokines, and growth factors, which are responsible for late phase inflammatory responses. While lipid mediators diffuse freely out of the cell through lipid bilayers, both anaphylactic degranulation and secretion of cytokines, chemokines, and growth factors depends on highly regulated vesicular trafficking steps that occur along the secretory pathway starting with the translocation of proteins to the endoplasmic reticulum. Vesicular trafficking in MCs also intersects with endocytic routes, notably to form specialized cytoplasmic granules called secretory lysosomes. Some of the mediators like histamine reach granules via specific vesicular monoamine transporters directly from the cytoplasm. In this review, we try to summarize the available data on granule biogenesis and signaling events that coordinate the complex steps that lead to the release of the inflammatory mediators from the various vesicular carriers in MCs. PMID- 25295041 TI - Evolution of Innate Immunity: Clues from Invertebrates via Fish to Mammals. AB - Host responses against invading pathogens are basic physiological reactions of all living organisms. Since the appearance of the first eukaryotic cells, a series of defense mechanisms have evolved in order to secure cellular integrity, homeostasis, and survival of the host. Invertebrates, ranging from protozoans to metazoans, possess cellular receptors, which bind to foreign elements and differentiate self from non-self. This ability is in multicellular animals associated with presence of phagocytes, bearing different names (amebocytes, hemocytes, coelomocytes) in various groups including animal sponges, worms, cnidarians, mollusks, crustaceans, chelicerates, insects, and echinoderms (sea stars and urchins). Basically, these cells have a macrophage-like appearance and function and the repair and/or fight functions associated with these cells are prominent even at the earliest evolutionary stage. The cells possess pathogen recognition receptors recognizing pathogen-associated molecular patterns, which are well-conserved molecular structures expressed by various pathogens (virus, bacteria, fungi, protozoans, helminths). Scavenger receptors, Toll-like receptors, and Nod-like receptors (NLRs) are prominent representatives within this group of host receptors. Following receptor-ligand binding, signal transduction initiates a complex cascade of cellular reactions, which lead to production of one or more of a wide array of effector molecules. Cytokines take part in this orchestration of responses even in lower invertebrates, which eventually may result in elimination or inactivation of the intruder. Important innate effector molecules are oxygen and nitrogen species, antimicrobial peptides, lectins, fibrinogen-related peptides, leucine rich repeats (LRRs), pentraxins, and complement-related proteins. Echinoderms represent the most developed invertebrates and the bridge leading to the primitive chordates, cephalochordates, and urochordates, in which many autologous genes and functions from their ancestors can be found. They exhibit numerous variants of innate recognition and effector molecules, which allow fast and innate responses toward diverse pathogens despite lack of adaptive responses. The primitive vertebrates (agnathans also termed jawless fish) were the first to supplement innate responses with adaptive elements. Thus hagfish and lampreys use LRRs as variable lymphocyte receptors, whereas higher vertebrates [cartilaginous and bony fishes (jawed fish), amphibians, reptiles, birds, and mammals] developed the major histocompatibility complex, T-cell receptors, and B-cell receptors (immunoglobulins) as additional adaptive weaponry to assist innate responses. Extensive cytokine networks are recognized in fish, but related signal molecules can be traced among invertebrates. The high specificity, antibody maturation, immunological memory, and secondary responses of adaptive immunity were so successful that it allowed higher vertebrates to reduce the number of variants of the innate molecules originating from both invertebrates and lower vertebrates. Nonetheless, vertebrates combine the two arms in an intricate inter-dependent network. Organisms at all developmental stages have, in order to survive, applied available genes and functions of which some may have been lost or may have changed function through evolution. The molecular mechanisms involved in evolution of immune molecules, might apart from simple base substitutions be as diverse as gene duplication, deletions, alternative splicing, gene recombination, domain shuffling, retrotransposition, and gene conversion. Further, variable regulation of gene expression may have played a role. PMID- 25295042 TI - Extracellular signals and receptor-like kinases regulating ROP GTPases in plants. AB - Rho-like GTPase from plants (ROPs) function as signaling switches that control a wide variety of cellular functions and behaviors including cell morphogenesis, cell division and cell differentiation. The Arabidopsis thaliana genome encodes 11 ROPs that form a distinct single subfamily contrarily to animal or fungal counterparts where multiple subfamilies of Rho GTPases exist. Since Rho proteins bind to their downstream effector proteins only in their GTP-bound "active" state, the activation of ROPs by upstream factor(s) is a critical step in the regulation of ROP signaling. Therefore, it is critical to examine the input signals that lead to the activation of ROPs. Recent findings showed that the plant hormone auxin is an important signal for the activation of ROPs during pavement cell morphogenesis as well as for other developmental processes. In contrast to auxin, another plant hormone, abscisic acid, negatively regulates ROP signaling. Calcium is another emerging signal in the regulation of ROP signaling. Several lines of evidence indicate that plasma membrane localized-receptor like kinases play a critical role in the transmission of the extracellular signals to intracellular ROP signaling pathways. This review focuses on how these signals impinge upon various direct regulators of ROPs to modulate various plant processes. PMID- 25295044 TI - The radical induced cell death protein 1 (RCD1) supports transcriptional activation of genes for chloroplast antioxidant enzymes. AB - The rimb1 (redox imbalanced 1) mutation was mapped to the RCD1 locus (radical induced cell death 1; At1g32230) demonstrating that a major factor involved in redox-regulation genes for chloroplast antioxidant enzymes and protection against photooxidative stress, RIMB1, is identical to the regulator of disease response reactions and cell death, RCD1. Discovering this link let to our investigation of its regulatory mechanism. We show in yeast that RCD1 can physically interact with the transcription factor Rap2.4a which provides redox-sensitivity to nuclear expression of genes for chloroplast antioxidant enzymes. In the rimb1 (rcd1-6) mutant, a single nucleotide exchange results in a truncated RCD1 protein lacking the transcription factor binding site. Protein-protein interaction between full length RCD1 and Rap2.4a is supported by H2O2, but not sensitive to the antioxidants dithiotreitol and ascorbate. In combination with transcript abundance analysis in Arabidopsis, it is concluded that RCD1 stabilizes the Rap2.4-dependent redox-regulation of the genes encoding chloroplast antioxidant enzymes in a widely redox-independent manner. Over the years, rcd1-mutant alleles have been described to develop symptoms like chlorosis, lesions along the leaf rims and in the mesophyll and (secondary) induction of extra- and intra-plastidic antioxidant defense mechanisms. All these rcd1 mutant characteristics were observed in rcd1-6 to succeed low activation of the chloroplast antioxidant system and glutathione biosynthesis. We conclude that RCD1 protects plant cells from running into reactive oxygen species (ROS)-triggered programs, such as cell death and activation of pathogen-responsive genes (PR genes) and extra-plastidic antioxidant enzymes, by supporting the induction of the chloroplast antioxidant system. PMID- 25295043 TI - The puzzle of chloroplast vesicle transport - involvement of GTPases. AB - In the cytosol of plant cells vesicle transport occurs via secretory pathways among the endoplasmic reticulum network, Golgi bodies, secretory granules, endosome, and plasma membrane. Three systems transfer lipids, proteins and other important molecules through aqueous spaces to membrane-enclosed compartments, via vesicles that bud from donor membranes, being coated and uncoated before tethered and fused with acceptor membranes. In addition, molecular, biochemical and ultrastructural evidence indicates presence of a vesicle transport system in chloroplasts. Little is known about the protein components of this system. However, as chloroplasts harbor the photosynthetic apparatus that ultimately supports most organisms on the planet, close attention to their pathways is warranted. This may also reveal novel diversification and/or distinct solutions to the problems posed by the targeted intra-cellular trafficking of important molecules. To date two homologs to well-known yeast cytosolic vesicle transport proteins, CPSAR1 and CPRabA5e (CP, chloroplast localized), have been shown to have roles in chloroplast vesicle transport, both being GTPases. Bioinformatic data indicate that several homologs of cytosolic vesicle transport system components are putatively chloroplast-localized and in addition other proteins have been implicated to participate in chloroplast vesicle transport, including vesicle-inducing protein in plastids 1, thylakoid formation 1, snowy cotyledon 2/cotyledon chloroplast biogenesis factor, curvature thylakoid 1 proteins, and a dynamin like GTPase FZO-like protein. Several putative potential cargo proteins have also been identified, including building blocks of the photosynthetic apparatus. Here we discuss details of the largely unknown putative chloroplast vesicle transport system, focusing on GTPase-related components. PMID- 25295045 TI - Foliar treatments with Gaultheria procumbens essential oil induce defense responses and resistance against a fungal pathogen in Arabidopsis. AB - Essential oil from Gaultheria procumbens is mainly composed of methylsalicylate (MeSA) (>96%), a compound which can be metabolized in plant tissues to salicylic acid, a phytohormone inducing plant immunity against microbial pathogens. The potential use of G. procumbens essential oil as a biocontrol agent was evaluated on the model plant Arabidopsis thaliana. Expression of a selection of defense genes was detected 1, 6, and 24 h after essential oil treatment (0.1 ml/L) using a high-throughput qPCR-based microfluidic technology. Control treatments included methyl jasmonate and a commercialized salicylic acid (SA) analog, benzo(1,2,3) thiadiazole-7carbothiolic acid (BTH). Strong induction of defense markers known to be regulated by the SA pathway was observed after the treatment with G. procumbens essential oil. Treatment induced the accumulation of total SA in the wild-type Arabidopsis line Col-0 and analysis of the Arabidopsis line sid2, mutated in a SA biosynthetic gene, revealed that approximately 30% of MeSA sprayed on the leaves penetrated inside plant tissues and was demethylated by endogenous esterases. Induction of plant resistance by G. procumbens essential oil was tested following inoculation with a GFP-expressing strain of the Arabidopsis fungal pathogen Colletotrichum higginsianum. Fluorescence measurement of infected tissues revealed that treatments led to a strong reduction (60%) of pathogen development and that the efficacy of the G. procumbens essential oil was similar to the commercial product BION((r)). Together, these results show that the G. procubens essential oil is a natural source of MeSA which can be formulated to develop new biocontrol products. PMID- 25295046 TI - The type of ploidy of chrysanthemum is not black or white: a comparison of a molecular approach to published cytological methods. AB - Polyploidy is a widespread phenomenon among higher plants and a major factor shaping the structure and evolution of plant genomes. The important ornamental chrysanthemum (Chrysanthemum indicum hybrid) possesses a hexaploid genome with 54 chromosomes and was classified based on its evolutionary origin and cytological methods as an allopolyploid. However, it is questionable whether cytological methods are sufficient to determine the type of ploidy, and there are more informative methods available based on molecular marker analyses. Therefore, we collected segregation data for 406 dominant molecular marker alleles [327 amplified fragment length polymorphism (AFLPs), 65 single-strand conformation polymorphism (SSCPs) and 14 microsatellites (EST-SSRs)] in a biparental F1 population of 160 individuals. We analyzed these data for the characteristics that differ between allopolyploids and autopolyploids, including the segregation ratio of each marker, the ratio of single-dose (SD) to multi-dose (MD) markers, the ratio of SD markers in coupling to those in repulsion and the banding patterns of the SSRs. Whereas the analysis of the segregation ratio of each polymorphic marker indicated disomic (13 markers) as well as hexasomic (eight markers) inheritance, the ratio of SD markers in coupling to those in repulsion was 1:0, which is characteristic of autopolyploids. The observed ratio of SD to MD markers was 0.67:0.33 which is significantly different to the expected segregation for auto- and allohexaploids. Furthermore, the three EST-SSR alleles were inherited in all possible combinations and were not independent of each other, as expected for fixed heterozygosity in allopolyploids. Combining our results with published cytological data indicates that cultivated chrysanthemums should be classified as segmental allohexaploids. PMID- 25295047 TI - From dusk till dawn: the Arabidopsis thaliana sugar starving responsive network. AB - Plant growth and development are tightly controlled by photosynthetic carbon availability. The understanding of mechanisms governing carbon partitioning in plants will be a valuable tool in order to satisfy the rising global demand for food and biofuel. The goal of this study was to determine if sugar starvation responses were transcriptionally coordinated in Arabidopsis thaliana. A set of sugar-starvation responsive (SSR) genes was selected to perform a co-expression network analysis. Posteriorly, a guided-gene approach was used to identify the SSR-network from public data and to discover candidate regulators of this network. In order to validate the SSR network, a global transcriptome analysis was realized on three A. thaliana starch-deficient mutants. The starch-deficient phenotype in leaves induces sugar starvation syndrome at the end of the night due to the absence of photosynthesis. Promoter sequences of genes belonging to the SSR-network were analyzed in silico reveling over-represented motifs implicated in light, abscisic acid, and sugar responses. A small cluster of protein encoding genes belonging to different metabolic pathways, including three regulatory proteins, a protein kinase, a transcription factor, and a blue light receptor, were identified as the cornerstones of the SSR co-expression network. In summary, a large transcriptionally coordinated SSR network was identified and was validated with transcriptional data from three starch-deficient mutant lines. Candidate master regulators of this network were point out. PMID- 25295048 TI - Maintenance of genome stability in plants: repairing DNA double strand breaks and chromatin structure stability. AB - Plant cells are subject to high levels of DNA damage resulting from plant's obligatory dependence on sunlight and the associated exposure to environmental stresses like solar UV radiation, high soil salinity, drought, chilling injury, and other air and soil pollutants including heavy metals and metabolic by products from endogenous processes. The irreversible DNA damages, generated by the environmental and genotoxic stresses affect plant growth and development, reproduction, and crop productivity. Thus, for maintaining genome stability, plants have developed an extensive array of mechanisms for the detection and repair of DNA damages. This review will focus recent advances in our understanding of mechanisms regulating plant genome stability in the context of repairing of double stand breaks and chromatin structure maintenance. PMID- 25295049 TI - 1064 nm FT-Raman spectroscopy for investigations of plant cell walls and other biomass materials. AB - Raman spectroscopy with its various special techniques and methods has been applied to study plant biomass for about 30 years. Such investigations have been performed at both macro- and micro-levels. However, with the availability of the Near Infrared (NIR) (1064 nm) Fourier Transform (FT)-Raman instruments where, in most materials, successful fluorescence suppression can be achieved, the utility of the Raman investigations has increased significantly. Moreover, the development of several new capabilities such as estimation of cellulose crystallinity, ability to analyze changes in cellulose conformation at the local and molecular level, and examination of water-cellulose interactions have made this technique essential for research in the field of plant science. The FT-Raman method has also been applied to research studies in the arenas of biofuels and nanocelluloses. Moreover, the ability to investigate plant lignins has been further refined with the availability of near-IR Raman. In this paper, we present 1064-nm FT-Raman spectroscopy methodology to investigate various compositional and structural properties of plant material. It is hoped that the described studies will motivate the research community in the plant biomass field to adapt this technique to investigate their specific research needs. PMID- 25295051 TI - Recent advances in understanding of meiosis initiation and the apomictic pathway in plants. AB - Meiosis, a specialized cell division to produce haploid cells, marks the transition from a sporophytic to a gametophytic generation in the life cycle of plants. In angiosperms, meiosis takes place in sporogenous cells that develop de novo from somatic cells in anthers or ovules. A successful transition from the mitotic cycle to the meiotic program in sporogenous cells is crucial for sexual reproduction. By contrast, when meiosis is bypassed or a mitosis-like division occurs to produce unreduced cells, followed by the development of an embryo sac, clonal seeds can be produced by apomixis, an asexual reproduction pathway found in 400 species of flowering plants. An understanding of the regulation of entry into meiosis and molecular mechanisms of apomictic pathway will provide vital insight into reproduction for plant breeding. Recent findings suggest that AM1/SWI1 may be the key gene for entry into meiosis, and increasing evidence has shown that the apomictic pathway is epigenetically controlled. However, the mechanism for the initiation of meiosis during sexual reproduction or for its omission in the apomictic pathway still remains largely unknown. Here we review the current understanding of meiosis initiation and the apomictic pathway and raised several questions that are awaiting further investigation. PMID- 25295050 TI - Cell cycle control and seed development. AB - Seed development is a complex process that requires coordinated integration of many genetic, metabolic, and physiological pathways and environmental cues. Different cell cycle types, such as asymmetric cell division, acytokinetic mitosis, mitotic cell division, and endoreduplication, frequently occur in sequential yet overlapping manner during the development of the embryo and the endosperm, seed structures that are both products of double fertilization. Asymmetric cell divisions in the embryo generate polarized daughter cells with different cell fates. While nuclear and cell division cycles play a key role in determining final seed cell numbers, endoreduplication is often associated with processes such as cell enlargement and accumulation of storage metabolites that underlie cell differentiation and growth of the different seed compartments. This review focuses on recent advances in our understanding of different cell cycle mechanisms operating during seed development and their impact on the growth, development, and function of seed tissues. Particularly, the roles of core cell cycle regulators, such as cyclin-dependent-kinases and their inhibitors, the Retinoblastoma-Related/E2F pathway and the proteasome-ubiquitin system, are discussed in the contexts of different cell cycle types that characterize seed development. The contributions of nuclear and cellular proliferative cycles and endoreduplication to cereal endosperm development are also discussed. PMID- 25295052 TI - Toxicogenetics: in search of host susceptibility to environmental toxicants. AB - Heavy metals, various pesticide and herbicides are implicated as risk factors for human health. Paraquat, maneb, and rotenone, carbamate, and organophosphorous insecticides are examples of toxicants for which acute and chronic exposure are associated with multiple neurological disorders including Parkinson's disease. Nevertheless, the role of pesticide exposure in neurodegenerative diseases is not clear-cut, as there are inconsistencies in both the epidemiological and preclinical research. The aim of this short review is to show that at least, some of the inconsistencies are related to individual differences in susceptibility to the effects of neurotoxicants, individual differences that can be traced to the genetic constitution of the individuals and animals studies, i.e., host-based susceptibility. PMID- 25295053 TI - Genetic diversity and population structure among six cattle breeds in South Africa using a whole genome SNP panel. AB - Information about genetic diversity and population structure among cattle breeds is essential for genetic improvement, understanding of environmental adaptation as well as utilization and conservation of cattle breeds. This study investigated genetic diversity and the population structure among six cattle breeds in South African (SA) including Afrikaner (n = 44), Nguni (n = 54), Drakensberger (n = 47), Bonsmara (n = 44), Angus (n = 31), and Holstein (n = 29). Genetic diversity within cattle breeds was analyzed using three measures of genetic diversity namely allelic richness (AR), expected heterozygosity (He) and inbreeding coefficient (f). Genetic distances between breed pairs were evaluated using Nei's genetic distance. Population structure was assessed using model-based clustering (ADMIXTURE). Results of this study revealed that the allelic richness ranged from 1.88 (Afrikaner) to 1.73 (Nguni). Afrikaner cattle had the lowest level of genetic diversity (He = 0.24) and the Drakensberger cattle (He = 0.30) had the highest level of genetic variation among indigenous and locally-developed cattle breeds. The level of inbreeding was lower across the studied cattle breeds. As expected the average genetic distance was the greatest between indigenous cattle breeds and Bos taurus cattle breeds but the lowest among indigenous and locally developed breeds. Model-based clustering revealed some level of admixture among indigenous and locally-developed breeds and supported the clustering of the breeds according to their history of origin. The results of this study provided useful insight regarding genetic structure of SA cattle breeds. PMID- 25295054 TI - Computational and experimental methods to decipher the epigenetic code. AB - A multi-layered set of epigenetic marks, including post-translational modifications of histones and methylation of DNA, is finely tuned to define the epigenetic state of chromatin in any given cell type under specific conditions. Recently, the knowledge about the combinations of epigenetic marks occurring in the genome of different cell types under various conditions is rapidly increasing. Computational methods were developed for the identification of these states, unraveling the combinatorial nature of epigenetic marks and their association to genomic functional elements and transcriptional states. Nevertheless, the precise rules defining the interplay between all these marks remain poorly characterized. In this perspective we review the current state of this research field, illustrating the power and the limitations of current approaches. Finally, we sketch future avenues of research illustrating how the adoption of specific experimental designs coupled with available experimental approaches could be critical for a significant progress in this area. PMID- 25295055 TI - Welcome to the new tRNA world! PMID- 25295057 TI - Patch testing in suspected allergic contact dermatitis to cosmetics. AB - Background. Increasing use of cosmetics has contributed to a rise in the incidence of allergic contact dermatitis (ACD) to cosmetics. It is estimated that 1-5.4% of the population is sensitized to a cosmetic ingredient. Patch testing helps to confirm the presence of an allergy and to identify the actual allergens which are chemical mixtures of various ingredients. Objectives. The aims of this study are to perform patch testing in suspected ACD to cosmetics and to identify the most common allergen and cosmetic product causing dermatitis. Methods. Fifty patients with suspected ACD to cosmetics were patch-tested with 38 antigens of the Indian Cosmetic Series and 12 antigens of the Indian Standard Series. Results. The majority (58%) of patients belonged to the 21-40 years age group. The presence of ACD to cosmetics was confirmed in 38 (76%) patients. Face creams (20%), hair dyes (14%), and soaps (12%) were the most commonly implicated. The most common allergens identified were gallate mix (40%), cetrimide (28%), and thiomersal (20%). Out of a total of 2531 patches applied, positive reactions were obtained in 3.75%. Conclusion. Incidence of ACD to cosmetics was greater in females. Face creams and hair dyes were the most common cosmetic products implicated. The principal allergens were gallate mix, cetrimide, and thiomersal. PMID- 25295056 TI - A non-canonical landscape of the microRNA system. AB - Microribonucleic acids, best known as microRNAs or miRNAs, are small, non-coding RNAs with important regulatory roles in eukaryotic cells. Here, I present a broad review on highly relevant but generally non-depicted features of miRNAs, among which stand out the non-conventional miRNA seed sites, the unusual messenger RNA (mRNA) target regions, the non-canonical miRNA-guided mechanisms of gene expression regulation, and the recently identified new class of miRNA ligands. Furthermore, I address the miRNA uncommon genomic location, transcription, and subcellular localization. Altogether, these unusual features and roles place the miRNA system as a very diverse, complex, and intriguing biological mechanism. PMID- 25295058 TI - A novel dry model for practicable sphincterotomy and precut needle knife sphincterotomy. AB - Aim. We aimed to develop a simulation dry model for endoscopic sphincterotomy (ES) and needle knife precut sphincterotomy (NKP) and to evaluate its usefulness as a training simulator. Materials and Methods. An endoscopic retrograde cholangiopancreatography trainer was used as a duodenum, bile duct, and papilla simulator. A simulated papilla was created with a piece of rolled uncured ham, and ES and NKP were performed. Hands-on training was carried out using this model, and success and failure of the procedures were evaluated. A questionnaire survey was conducted among the participants to assess the performance and usefulness of the dry model for ES and NKP training. Results. Twenty-two endoscopists participated in the hands-on training using this dry model. ES was successful in 33 out of 34 attempts (97%) whereas NKP was successful in all 7 attempts (100%). Based on the results of the questionnaire survey, the median score for realism was 7 (range: 2-9) for ES and 8 for NKP on a scale of 1 to 10. Conclusions. The dry model using an uncured ham provides a condition closely similar to actual clinical practice and is useful as a training model for ES and NKP. PMID- 25295059 TI - The emerging role of telemedicine in managing glycemic control and psychobehavioral aspects of pregnancy complicated by diabetes. AB - There is a gradual decline in concern of specialists who follow up the care of pregnant women with diabetes. In addition, due to the dwindling economic resources allocated to health services, access to specialized healthcare facilities is becoming more difficult. Telemedicine, or medicine practiced at a distance, is inserted in this context with applications differing for type of interaction (real-time or deferred, i.e., videoconferencing versus store-and forward data transmission), type of monitoring (automatic versus requesting cooperation from the patient), and type of devices used (web connections and use of mobile phones or smartphones). Telemedicine can cope with the current lack of ability to ensure these patients frequent direct contact with their caregivers. This approach may have an impact not only on the classical maternal-fetal outcome, but also on some underestimated aspects of patients with diabetes in pregnancy, in this case their quality of life, the perception of "diabetes self efficacy," and the glycemic variability. In this paper, we will analyze the current evidence regarding the use of telemedicine in pregnancies complicated by diabetes, trying to highlight the main limitations of these studies and possible strategies to overcome them in order to improve the effectiveness of future clinical interventions with these medical applications. PMID- 25295060 TI - A Novel Rat Model of Orthodontic Tooth Movement Using Temporary Skeletal Anchorage Devices: 3D Finite Element Analysis and In Vivo Validation. AB - The aim of this animal study was to develop a model of orthodontic tooth movement using a microimplant as a TSAD in rodents. A finite element model of the TSAD in alveolar bone was built using MUCT images of rat maxilla to determine the von Mises stresses and displacement in the alveolar bone surrounding the TSAD. For in vivo validation of the FE model, Sprague-Dawley rats (n = 25) were used and a Stryker 1.2 * 3 mm microimplant was inserted in the right maxilla and used to protract the right first permanent molar using a NiTi closed coil spring. Tooth movement measurements were taken at baseline, 4 and 8 weeks. At 8 weeks, animals were euthanized and tissues were analyzed by histology and EPMA. FE modeling showed maximum von Mises stress of 45 Mpa near the apex of TSAD but the average von Mises stress was under 25 Mpa. Appreciable tooth movement of 0.62 +/- 0.04 mm at 4 weeks and 1.99 +/- 0.14 mm at 8 weeks was obtained. Histological and EPMA results demonstrated no active bone remodeling around the TSAD at 8 weeks depicting good secondary stability. This study provided evidence that protracted tooth movement is achieved in small animals using TSADs. PMID- 25295061 TI - Intracranial Meningioma Diagnosed during Pregnancy Caused Maternal Death. AB - Brain tumors are rarely diagnosed during pregnancy. Accelerated growth of intracranial meningiomas during pregnancy sometimes requires urgent surgical intervention. We describe a 41-year-old pregnant woman with severe neurological decompensation requiring immediate neurosurgery. Cesarean section resulted in maternal death. Meningioma diagnosed during a viable pregnancy should be managed according to the severity of maternal neurological symptoms and gestational age of pregnancy. Early intervention for intracranial tumors during pregnancy may save maternal and fetal lives. PMID- 25295062 TI - Breast cancer presenting as paraneoplastic erythroderma: an extremely rare case. AB - The skin may exhibit the first clinical evidence of a systemic disease and may provide the first clues to a diagnosis in malignancies. Erythroderma is defined as generalized redness and scaling and it is a clinical manifestation of a variety of underlying diseases including, rarely, solid tumors. Breast cancer is associated with a variety of skin paraneoplastic manifestations like acanthosis nigricans, erythromelalgia, thrombotic thrombocytopenic purpura, acrokeratosis paraneoplastica, dermatomyositis, systemic sclerosis, and scleroderma. However, in the literature, the correlation of erythroderma with breast cancer is quite infrequent. Here, we describe a case of a 76-year-old woman who presented with a paraneoplastic manifestation of erythroderma due to breast cancer. PMID- 25295063 TI - A Pancreatic Head Tumor Arising as a Duodenal GIST: A Case Report and Review of the Literature. AB - Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract that originate from the intestinal cells of Cajal (ICC) (Fletcher et al., 2002). Only a few cases have been described with extragastrointestinal stromal tumors (Kim et al., 2012; Soufi et al., 2013; Meng et al., 2011). They are often diagnosed as a pancreatic head tumor as they are very difficult to relate to the duodenum with CT, MRI, or ultrasound. We present a case of a sixty-four-year-old woman who presented with abdominal pain and cardialgia for a follow-up examination after breast cancer surgery. On laparotomy there was a 3 * 5 cm hypervascular mass arising from the pancreatic head with macroscopically no attachment to the duodenum. The patient underwent pancreatoduodenectomy (PD) modified after Traverso-Longmire, histopathology proved a duodenal GIST. This case proves that duodenal GISTs can grow invasively into the pancreas and appear as solid pancreas head tumor; therefore, these tumors should be included into differential diagnosis. PMID- 25295064 TI - Bone marrow-derived multipotent stromal cells attenuate inflammation in obliterative airway disease in mouse tracheal allografts. AB - Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response. PMID- 25295065 TI - Evidence for Transfer of Membranes from Mesenchymal Stem Cells to HL-1 Cardiac Cells. AB - This study examined the interaction of mouse bone marrow mesenchymal stem cells (MSC) with cardiac HL-1 cells during coculture by fluorescent dye labeling and then flow cytometry. MSC were layered onto confluent HL-1 cell cultures in a 1 : 4 ratio. MSC gained gap junction permeant calcein from HL-1 cells after 4 hours which was partially reduced by oleamide. After 20 hours, 99% MSC gained calcein, unaffected by oleamide. Double-labeling HL-1 cells with calcein and the membrane dye DiO resulted in transfer of both calcein and DiO to MSC. When HL-1 cells were labeled with calcein and MSC with DiO, MSC gained calcein while HL-1 cells gained DiO. Very little fusion was observed since more than 90% Sca-1 positive MSC gained DiO from HL-1 cells while less than 9% gained gap junction impermeant CMFDA after 20 hours with no Sca-1 transfer to HL-1 cells. Time dependent transfer of membrane DiD was observed from HL-1 cells to MSC (100%) and vice versa (50%) after 20 hours with more limited transfer of CMFDA. These results demonstrate that MSC and HL-1 cells exchange membrane components which may account for some of the beneficial effect of MSC in the heart after myocardial infarction. PMID- 25295066 TI - Mindfulness-based therapies in the treatment of functional gastrointestinal disorders: a meta-analysis. AB - Background. Functional gastrointestinal disorders are highly prevalent and standard treatments are often unsatisfactory. Mindfulness-based therapy has shown benefit in conditions including chronic pain, mood, and somatization disorders. Objectives. To assess the quality and effectiveness reported in existing literature, we conducted a meta-analysis of mindfulness-based therapy in functional gastrointestinal disorders. Methods. Pubmed, EBSCO, and Cochrane databases were searched from inception to May 2014. Study inclusion criteria included randomized, controlled studies of adults using mindfulness-based therapy in the treatment of functional gastrointestinal disorders. Study quality was evaluated using the Cochrane risk of bias. Effect sizes were calculated and pooled to achieve a summary effect for the intervention on symptom severity and quality of life. Results. Of 119 records, eight articles, describing seven studies, met inclusion criteria. In six studies, significant improvements were achieved or maintained at the end of intervention or follow-up time points. The studies had an unclear or high risk of bias. Pooled effects were statistically significant for IBS severity (0.59, 95% CI 0.33 to 0.86) and quality of life (0.56, 95% CI 0.47 to 0.79). Conclusion. Studies suggest that mindfulness based interventions may provide benefit in functional gastrointestinal disorders; however, substantial improvements in methodological quality and reporting are needed. PMID- 25295067 TI - Lipid Lowering Effect of Punica granatum L. Peel in High Lipid Diet Fed Male Rats. AB - Many herbal medicines have been recommended for the treatment of dyslipidemia. The antilipidemic effect of hydroethanolic extract of pomegranate peel (Punica granatum L.) was investigated in high lipid diet fed male rats. Intraperitoneally administration of pomegranate peel extract (50, 100, 200, and 300 mg/kg body weight) for 23 days on the levels of serum cholesterol, triglycerides, LDL, HDL, alkaline phosphatase (AP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in high lipid diet fed male rats was evaluated. Treatment of pomegranate extract decreased body weight in treated rats, significantly. Administration of the plant extract significantly decreased serum total cholesterol, triglycerides, LDL-C, alkaline phosphatise, AST, and ALT levels, whereas it increased serum HDL-C in high lipid diet fed rats in comparison to saline control group. Also, histopathological study showed that treatment of pomegranate peel extract attenuates liver damage in high lipid diet fed rats in comparison to saline group. It is concluded that the plant should be considered as an excellent candidate for future studies on dyslipidemia. PMID- 25295068 TI - Balance Performance in Irradiated Survivors of Nasopharyngeal Cancer with and without Tai Chi Qigong Training. AB - This cross-sectional exploratory study aimed to compare the one-leg-stance time and the six-minute walk distance among TC Qigong-trained NPC survivors, untrained NPC survivors, and healthy individuals. Twenty-five survivors of NPC with TC Qigong experience, 27 survivors of NPC without TC Qigong experience, and 68 healthy individuals formed the NPC-TC Qigong group, NPC-control group, and healthy-control group, respectively. The one-leg-stance (OLS) timed test was conducted to assess the single-leg standing balance performance of the participants in four conditions: (1) standing on a stable surface with eyes open, (2) standing on a compliant surface with eyes open, (3) standing on a stable surface with eyes closed, and (4) standing on a compliant surface with eyes closed. The six-minute walk test (6MWT) was used to determine the functional balance performance of the participants. Results showed that the NPC-control group had a shorter OLS time in all of the visual and supporting surface conditions than the healthy control group (P < 0.05). The OLS time of the TC Qigong-NPC group was comparable to that of the healthy control group in the somatosensory-challenging condition (condition 3) (P = 0.168) only. Additionally, there was no significant difference in the 6MWT distance among the three groups (P > 0.05). TC Qigong may be a rehabilitation exercise that improves somatosensory function and OLS balance performance among survivors of NPC. PMID- 25295069 TI - Inhibition of Adipogenesis by Oligonol through Akt-mTOR Inhibition in 3T3-L1 Adipocytes. AB - Polyphenols have recently become an important focus of study in obesity research. Oligonol is an oligomerized polyphenol, typically comprised of catechin-type polyphenols from a variety of fruits, which has been found to exhibit better bioavailability and bioreactivity than natural polyphenol compounds. Here, we demonstrated that Oligonol inhibits 3T3-L1 adipocyte differentiation by reducing adipogenic gene expression. During adipogenesis, Oligonol downregulated the mRNA levels of peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer binding proteins alpha (C/EBPalpha), and delta (C/EBPdelta) in a dose-dependent manner and the expression of genes involved in lipid biosynthesis. The antiadipogenic effect of Oligonol appears to originate from its ability to inhibit the Akt and mammalian target of rapamycin (mTOR) signaling pathway by diminishing the phosphorylation of ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR and forkhead box protein O1 (Foxo1). These results suggest that Oligonol may be a potent regulator of obesity by repressing major adipogenic genes through inhibition of the Akt signaling pathway, which induces the inhibition of lipid accumulation, ultimately inhibiting adipogenesis. PMID- 25295070 TI - Resistance training exercise program for intervention to enhance gait function in elderly chronically ill patients: multivariate multiscale entropy for center of pressure signal analysis. AB - Falls are unpredictable accidents, and the resulting injuries can be serious in the elderly, particularly those with chronic diseases. Regular exercise is recommended to prevent and treat hypertension and other chronic diseases by reducing clinical blood pressure. The "complexity index" (CI), based on multiscale entropy (MSE) algorithm, has been applied in recent studies to show a person's adaptability to intrinsic and external perturbations and widely used measure of postural sway or stability. The multivariate multiscale entropy (MMSE) was advanced algorithm used to calculate the complexity index (CI) values of the center of pressure (COP) data. In this study, we applied the MSE & MMSE to analyze gait function of 24 elderly, chronically ill patients (44% female; 56% male; mean age, 67.56 +/- 10.70 years) with either cardiovascular disease, diabetes mellitus, or osteoporosis. After a 12-week training program, postural stability measurements showed significant improvements. Our results showed beneficial effects of resistance training, which can be used to improve postural stability in the elderly and indicated that MMSE algorithms to calculate CI of the COP data were superior to the multiscale entropy (MSE) algorithm to identify the sense of balance in the elderly. PMID- 25295071 TI - Human resource management in post-conflict health systems: review of research and knowledge gaps. AB - In post-conflict settings, severe disruption to health systems invariably leaves populations at high risk of disease and in greater need of health provision than more stable resource-poor countries. The health workforce is often a direct victim of conflict. Effective human resource management (HRM) strategies and policies are critical to addressing the systemic effects of conflict on the health workforce such as flight of human capital, mismatches between skills and service needs, breakdown of pre-service training, and lack of human resource data. This paper reviews published literatures across three functional areas of HRM in post-conflict settings: workforce supply, workforce distribution, and workforce performance. We searched published literatures for articles published in English between 2003 and 2013. The search used context-specific keywords (e.g. post-conflict, reconstruction) in combination with topic-related keywords based on an analytical framework containing the three functional areas of HRM (supply, distribution, and performance) and several corresponding HRM topic areas under these. In addition, the framework includes a number of cross-cutting topics such as leadership and governance, finance, and gender. The literature is growing but still limited. Many publications have focused on health workforce supply issues, including pre-service education and training, pay, and recruitment. Less is known about workforce distribution, especially governance and administrative systems for deployment and incentive policies to redress geographical workforce imbalances. Apart from in-service training, workforce performance is particularly under-researched in the areas of performance-based incentives, management and supervision, work organisation and job design, and performance appraisal. Research is largely on HRM in the early post-conflict period and has relied on secondary data. More primary research is needed across the areas of workforce supply, workforce distribution, and workforce performance. However, this should apply a longer-term focus throughout the different post-conflict phases, while paying attention to key cross-cutting themes such as leadership and governance, gender equity, and task shifting. The research gaps identified should enable future studies to examine how HRM could be used to meet both short and long term objectives for rebuilding health workforces and thereby contribute to achieving more equitable and sustainable health systems outcomes after conflict. PMID- 25295072 TI - Interstitial microduplication at 2p11.2 in a patient with syndromic intellectual disability: 30-year follow-up. AB - BACKGROUND: Copy number variations at 2p11.2 have been rare and to our knowledge, no abnormal phenotype with an interstitial 2p11.2 duplication has yet been reported. Here we report the first case with syndromic intellectual disability associated with microduplication at 2p11.2. RESULTS: We revisited a white female subject with a chromosome translocation, t(8;10)(p23;q23)mat and a 10q telomeric deletion suspected by G-banding 30 years ago. This female with severe intellectual disability, no speech, facial dysmorphism, intractable epilepsy, recurrent infection, and skeletal abnormalities has been observed from the birth until her death. The karyotype analysis reconfirmed the previously reported chromosome translocation with a revision as 46,XX,t(8;10)(p23.3;q23.2)mat by adding more detail in chromosomal sub-bands. The array comparative genomic hybridization, however, did not detect the 10q terminal deletion originally reported, but instead, revealed a 390 kb duplication at 2p11.2; 46,XX,t(8;10)(p23.3;q23.2)mat.arr[hg 19] 2p11.2(85469151x2,85474356 85864257x3,85868355x2). This duplication region was confirmed by real-time quantitative PCR and real-time reverse transcriptase quantitative PCR. CONCLUSIONS: We suggest three positional candidate genes for intellectual disability and recurrent infection based upon gene function and data from real time reverse transcriptase quantitative PCR-VAMP8 and RNF181 for intellectual disability and CAPG for recurrent infection. PMID- 25295073 TI - Decitabine inhibits the cell growth of cholangiocarcinoma in cultured cell lines and mouse xenografts. AB - Decitabine (DAC), an inhibitor of DNA methyltransferase, demonstrates antitumor activities in various types of cancer. However, its therapeutic potential for cholangiocarcinoma (CCA), one of the most aggressive gastrointestinal malignancies, remains to be explored. The present study investigated the antiproliferative effects of DAC on CCA cells in vitro and in vivo. Human CCA cell lines, TFK-1 and QBC939, were used as models to investigate DAC on the cell growth and proliferation of CCA. Cell proliferation was evaluated by Cell Counting Kit-8 assay combined with clonogenic survival assay. Flow cytometry, Hoechst 33342/propidium iodide staining and green fluorescent protein-tagged MAP LC3 detection were applied to determine cell cycle progression, apoptosis and autophagy. Nude mice with TFK-1 xenografts were evaluated for tumor growth following DAC treatment. DAC was observed to significantly suppress the proliferation of cultured TFK-1 and QBC939 cells, accompanied with enhanced apoptosis, autophagy and cell cycle arrest at G2/M phase. In TFK-1 mouse xenografts, DAC retarded the tumor growth and increased the survival of CCA tumor bearing mice. PMID- 25295074 TI - Primary paraganglioma located between the thyroid gland and the left common carotid artery: A case report. AB - Head and neck paraganglioma is a rare and predominantly asymptomatic tumor. In the present study, an extremely rare case of asymptomatic paraganglioma located between the left common carotid artery and the left thyroid is described. The clinical presentation, cytomorphology and the immunohistochemical characteristics for the diagnosis of head and neck paraganglioma are described. To the best of our knowledge, only two cases of paraganglioma located between the left common carotid artery and the left thyroid have previously been reported. PMID- 25295075 TI - Suppressor of Zeste 12 homolog RNA interference inhibits retinoblastoma cell invasion. AB - Suppressor of Zeste 12 homolog (SUZ12) is known to regulate tumor phenotype through altering gene expression, with an important regulatory role in tumor genesis and development. SUZ12 has been widely investigated; however, no studies regarding the role of the SUZ12 gene in retinoblastoma (RB) have been conducted. In this study, SUZ12 small interfering (si)RNA was transfected into SO-RB50 human RB cells. The influence of SUZ siRNA on RB cell invasion was detected using a soft agar colony forming assay and a Transwell cabin model. The effect of the SUZ12 siRNA on the expression levels of the associated proteins, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9 and MMP-2, was detected by western blotting. The number of cell clones was found to be reduced by the siRNA in a dose-dependent manner, and the number of cells that had permeated through the filter membrane was reduced following transfection with the siRNA. SUZ12 inhibition resulted in a marked reduction in VEGF, MMP-2 and MMP-9 expression levels (0.26+/-0.04, 0.16+/-0.02 and 0.12+/-0.02, respectively) compared with the levels in the non-transfected group (0.80+/-0.10, 0.94+/-0.16 and 1.15+/-0.18, respectively) (P<0.01). In conclusion, SUZ12 siRNA inhibited cell invasion and the expression of VEGF, MMP-2 and MMP-9 in SO-RB50 retinoblastoma cells. PMID- 25295076 TI - Schwannoma with an uncommon anal location. AB - Schwannomas are slow-growing mesenchymal neoplasms that arise from Schwann cells with low malignant potential. These uncommon neoplasms are nerve sheath tumors that arise at almost any anatomical site. The majority of schwannomas are benign, and few are malignant. The current study presents the rare case of an anal schwannoma that was successfully treated by surgery; there are few such cases previously reported in the literature. The patient was admitted to hospital following the identification of a mass incidentally. The tumor was so large that it compressed the tissue around it, although no symptoms were caused. The pre operative clinical diagnosis was inconclusive in this case, and a final diagnosis was established based on radiographic and histopathological examination. The current study aimed to provide a possible differential diagnosis for such anally located masses. PMID- 25295077 TI - Overexpression of the Survivin gene in SGC7901 cell resistance to cisplatin. AB - The aim of the present study was to investigate the mechanism of SGC7901 cell resistance to cisplatin (CDDP). SGC7901/CDDP cells were established by the long term continuous exposure of SGC7901 cells to CDDP in stepwise concentration increments. The morphologies of the SGC7901/CDDP and SGC7901 cells were observed by microscopy. The expression levels of Survivin mRNA and protein in the SGC7901/CDDP and SGC7901 cells were examined by reverse transcription polymerase chain reaction and western blotting respectively. The results revealed morphological differences between the SGC7901 and SGC7901/CDDP cells. The expression levels of Survivin mRNA and protein were significantly higher in the SGC7901/CDDP cells than in the SGC7901 cells. Therefore, high expression levels of the Survivin gene may explain SGC7901 cell resistance to CDDP. PMID- 25295078 TI - Giant appendiceal neurofibroma in von Recklinghausen's disease: A case report and literature review. AB - A 62-year-old female with neurofibromatosis type 1 (NF1; also von Recklinghausen's disease) was diagnosed with a giant, thick-walled tubular mass, mainly located in the right abdominal area on computed tomography, following an examination for intermittent abdominal pain and increasing abdominal distension. According to the clinical manifestations and imaging features, the giant tubular mass was considered most likely to be a dilated fallopian tube associated with infection, while the possibility of obstructed bowel loops was excluded. However, the subsequent laparotomy revealed a giant appendix, caused by a large neurofibroma in the root region of the appendix, which occluded the lumen. Neurofibroma of the appendix is extremely rare, even in patients with NF1. To the best of our knowledge, only three such cases have previously been reported in the English literature to date. PMID- 25295079 TI - Antitumor activity of cobrotoxin in human lung adenocarcinoma A549 cells and following transplantation in nude mice. AB - The aim of the present study was to investigate cobra neurotoxin (cobrotoxin) activity in A549 cell lines transplanted into nude mice, and to explore its molecular mechanism. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the growth inhibition rate of cobrotoxin in human lung A549 adenocarcinoma cells and HFL1 lung fibroblasts. Cell colony formation assays were performed to determine the effect of cobrotoxin on A549 cell colony formation, and transmission electron microscopy was used to detect cobrotoxin autophagy. In addition, western blot analysis was performed to determine the effect of 3-methyl adenine (3-MA) activity on the inhibition of autophagy, SB203580 inhibition of the p38-mitogen-activated protein kinase (MAPK) pathway, and Beclin 1, LC3, p62, p38 and phosphorylated (p)-p38 protein expression. Nude mice were injected with human lung A549 cells, and intervention and control groups were compared with regard to tumor suppression. The MTT assay revealed that various concentrations of cobrotoxin inhibited growth of A549 cells, but not HFL1 cells. A549 cell colony formation decreased and autophagosome activity was significantly increased compared with the controls. Following 3-MA administration, SB203580 autophagosome activity decreased, and following cobrotoxin administration, Beclin 1, p-p38, and LC3-II protein expression significantly increased, whereas p62 expression significantly decreased. Following 3-MA inhibition of autophagy, Beclin 1, LC3-II and p62 expression increased. Furthermore, following SB203580 inhibition of the p38-MAPK pathway, Beclin 1, p-p38, LC3-II and p62 protein expression increased. Cobrotoxin exhibited inhibitory activity on the human lung cancer A549 cells transplanted into the nude mice, suppressing the tumor growth rate by 43.4% (cobrotoxin 40 MUg/kg group). However, following the addition of 3-MA (10 mmol/kg) and SB203580 (5 mg/kg), the suppression of the tumor growth rate decreased significantly. Cobrotoxin inhibits the growth of human lung cancer A549 cells in vitro and A549 cells transplanted into nude mice. Furthermore, the induction of autophagy may be associated with the activation of the p38-MAPK pathway. PMID- 25295080 TI - Limb salvage surgery following resection of a melanoma: Foot and ankle reconstruction using cutaneous flaps. AB - Melanomas affect the foot and ankle region and are associated with a poor prognosis. The aim of the current study was to evaluate the functional and oncological outcomes of salvage surgery using cutaneous flaps for soft tissue reconstruction of the foot and ankle following the extended resection of a melanoma. A retrospective review was conducted to evaluate patients who presented with foot melanoma and underwent salvage surgery and defect reconstruction using three types of cutaneous flap (group S) or amputation (group A) between January 1999 and December 2010 at the First Hospital of Jilin University (Changchun, China). The postoperative mortality, surgical complications, functional outcomes and oncological outcomes were evaluated. Of the 21 patients, 11 were enrolled into group S and 10 were enrolled into group A. The median follow-up time of the patients was 58 months (range, 6-92 months). In group S, a reverse sural neurocutaneous island flap was used in six patients to perform the foot reconstruction, medial plantar flaps were used in four patients and lateral malleolus flaps were used in one patient. All 11 cutaneous flaps survived and provided satisfactory coverage. Only one cutaneous flap showed partial necrosis and required treatment comprising of debridement and regular changes to the wound dressing. The overall survival rate of patients was 65.0% and patients in the two groups experienced similar oncological outcomes. Salvage surgery with cutaneous flap reconstruction was found to be a reliable option for patients presenting with malignant melanoma of the foot and ankle. PMID- 25295081 TI - Aggressive renal angiomyolipoma with vena cava extension: A case report and literature review. AB - Renal angiomyolipoma (AML) is the most common type of benign mesenchymal tumor of the kidney. AMLs typically present as benign lesions without local invasion. However, the tumor may exhibit aggressive behavior. Intravascular extension into the inferior vena cava (IVC) and hemorrhagic aneurysm formation associated with AML has rarely been reported in the past. In the current study, the novel case of a 77-year-old female is described who presented with a tumor thrombus extending to the IVC. The patient subsequently underwent a radical nephrectomy and an IVC tumor thrombectomy. In addition, the available literature regarding this unusual complication of a common renal neoplasm has been reviewed. It is essential for radiologists and clinicians to be aware that AMLs may exhibit these types of aggressive behaviors. PMID- 25295082 TI - Isolated oculomotor nerve palsy as a paraneoplastic manifestation of gastric diffuse large B-cell lymphoma: A case report. AB - Isolated oculomotor nerve palsy (ONP) is rare. The major causes are aneurysm of the posterior communicating artery, microvascular ischemia, neoplasm, inflammation and trauma. The present study reports the case of a 72-year-old female with left isolated pupil-sparing ONP and severe anemia as the initial manifestations of gastric diffuse large B-cell lymphoma (DLBCL). Systemic chemotherapy without any central nervous system (CNS)-directed treatment led to a complete resolution of the ONP, suggesting that it was most likely to be a paraneoplastic phenomenon. If CNS involvement cannot be demonstrated by brain magnetic resonance imaging and cerebrospinal fluid assessment, the present case suggests that it may be acceptable to omit CNS-directed therapy in such cases of ONP, since it may be paraneoplastic in nature and may resolve following successful treatment of the underlying malignancy. PMID- 25295083 TI - Congenital mesoblastic nephroma: Clinical analysis of eight cases and a review of the literature. AB - Congenital mesoblastic nephroma (CMN) is a mesenchymal renal tumor. The aim of the present study was to review the clinical characteristics and outcome of CMN in infants. A retrospective file review was conducted of eight cases of CMN treated at the Children's Hospital of Fudan University between 2004 and 2012. Ultrasound and computerized tomography scans had been performed on all eight patients. Two cases presented with a solid tumor and exhibited pathological features consistent with those of classic CMN, five cases exhibited cystic, hemorrhagic and necrotic characteristics, with calcification and pathology consistent with the cellular variant of CMN and one case presented with a solid tumor, which exhibited pathological features consistent with ceullular CMN. Histology confirmed classic CMN in two patients and cellular CMN in six patients. For surgical intervention, four cases had radical nephrectomy, one case had a half nephrectomy and three cases had tumor enucleation performed. Two cases had received pre-operative chemotherapy, but exhibited no response, and three cases received post-operative chemotherapy. Two patients were lost to follow-up, but the remaining six patients survived to the end of follow-up without further complications. The mean follow-up time was 24.6 months. In conclusion, the differential diagnosis between CMN and Wilms' tumor is critical. Imaging characteristics are partially correlated with pathological characteristics. Surgery is the main treatment for CMN, but pre-operative chemotherapy is not particularly effective. The efficacy of post-operative chemotherapy requires further investigation, but the prognosis is positive. PMID- 25295084 TI - Salvage therapy with mitoxantrone, etoposide, bleomycin and dexamethasone for refractory or relapsed aggressive non-Hodgkin's lymphoma patients with a poor performance status or comorbidity. AB - The treatment of refractory or relapsed aggressive non-Hodgkin's lymphoma (NHL) in patients in a state of poor health is difficult due to their ineligibility to receive intensive salvage chemotherapy. In the present study, 16 refractory or relapsed aggressive NHL patients with a poor performance status or comorbidities were treated with mitoxantrone, etoposide, bleomycin and dexamethasone (MEBD) therapy. The treatment consisted of 10 mg/m2 intravenous (IV) mitoxantrone on day 1, 75 mg/m2 IV etoposide on days 1-3, 20 mg IV dexamethasone on days 1-4 and 15 mg intramuscular bleomycin on days 1, 4, 8 and 12, every 21 days. The efficacy and toxicity of the regimen were evaluated. The overall response rate was 68.8%, with a complete response rate of 18.8% and a partial response rate of 50.0%. The efficacy of the treatment for B-cell lymphoma was greater than that for T-cell lymphoma. The median progression-free survival time for the patients was 16.7 months and the median overall survival time was 22.4 months. The one-year overall survival rate was 62.5% and the two-year overall survival rate was 43.8%. The most common toxicity symptom was myelosuppression. In conclusion, refractory or relapsed aggressive NHL patients with a poor performance status or comorbidity are eligible for chemotherapy. MEBD therapy is an effective and feasible salvage regimen for NHL patients in a state of poor health. PMID- 25295085 TI - Expression of insulin-like growth factor-II mRNA-binding protein-3 as a marker for predicting clinical outcome in patients with esophageal squamous cell carcinoma. AB - Insulin-like growth factor-II mRNA-binding protein-3 (IMP3) is an important factor in carcinogenesis, although its clinical significance in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study investigated the associations between IMP3 expression and the clinicopathological parameters. IMP3 expression was assessed in 191 resected ESCC specimens, and the associations between IMP3 expression in ESCC, the clinicopathological parameters and patient prognosis were examined. Using immunohistochemistry, 113 (59.2%) tumors were identified as IMP3-positive. IMP3 positivity correlated significantly with high pathological (p)Stage, pT stage and pN stage. The IMP3-positive patients exhibited a poorer prognosis compared with the IMP3-negative patients. In univariate analyses, histology [hazard ratio (HR), 1.94; 95% confidence interval (CI), 1.18-3.49; P=0.0082], pT (HR, 2.34; 95% CI, 1.55-3.62; P<0.0001), pN (HR, 2.85; 95% CI, 1.81-4.69; P<0.0001), lymphatic invasion (HR, 2.08; 95% CI, 1.26 3.70; P=0.0036), venous invasion (HR, 1.79; 95% CI, 1.21-2.64; P=0.0039), neoadjuvant chemotherapy (NAC) (HR, 2.01; 95% CI, 1.35-3.00; P=0.0005) and IMP3 expression (HR, 2.12; 95% CI, 1.40-3.29; P=0.0003) were significantly associated with overall survival. Using multivariate analyses, histology (HR, 1.87; 95% CI, 1.13-3.29; P=0.014), pN (HR, 2.19; 95% CI, 1.36-3.66; P=0.0010), NAC (HR, 1.88; 95% CI, 1.24-2.86; P=0.0028) and IMP3 expression (HR, 1.84; 95% CI, 1.18-2.93; P=0.0064) were significant prognostic factors. IMP3 may therefore be a prognostic factor for patients with ESCC who have undergone a curative resection. PMID- 25295086 TI - Erythropoietin production in renal cell carcinoma and renal cysts in autosomal dominant polycystic kidney disease in a chronic dialysis patient with polycythemia: A case report. AB - In patients undergoing chronic hemodialysis (HD), erythropoietin (EPO) production from the kidney generally decreases and renal anemia develops. Patients without anemia, but with high serum EPO (sEPO) levels are rare among HD patients. The current study presents the case of a 67-year-old female HD patient with autosomal dominant polycystic kidney disease (ADPKD) and renal cell carcinoma (RCC), manifesting polycythemia with elevated sEPO levels. A radical nephrectomy was performed, which diminished the polycythemia, but the sEPO levels remained high. To determine the origin of the EPO production, immunohistochemistry was performed to detect EPO in the RCC and the renal cysts of the surgically resected kidney. In addition, the sEPO and EPO levels in a renal cyst were determined by enzyme immunoassay. EPO expression was demonstrated in RCC and cyst epithelial cells using immunohistochemistry, revealing extremely high EPO levels in the cyst fluid. Due to the remission of polycythemia following the nephrectomy, EPO production from the resected kidney appeared to have been the cause of the polycythemia. Positive EPO staining of the renal cysts in the resected polycystic kidney and sustained sEPO elevation following nephrectomy led to the hypothesis of EPO production in the renal cysts of the contralateral polycystic kidney. Although the postoperative EPO level was higher than the normal range, the hematocrit (Hct) level gradually decreased and recombinant human EPO was required again three months following the nephrectomy. Eight months after the nephrectomy, the Hct level was 30.2% with the use of rHuEPO. In conclusion, EPO production from RCC and renal cysts in ADPKD appeared to cause polycythemia in the HD patient. PMID- 25295087 TI - Prostate cancer with cyst formation detected by whole body positron emission tomography/computed tomography: A case report. AB - The present study reports a case of prostate adenocarcinoma with cyst formation. A 72-year-old male diagnosed with multiple lung metastases at a local clinic was referred to Tokai University Hachioji Hospital (Tokyo, Japan) for detection of a primary lesion. Whole body positron emission tomography/computed tomography showed strong accumulation of [18F]-fluoro-deoxy-2-glucose (FDG) in the small pelvis, and pelvic magnetic resonance imaging revealed a 60*40-mm cystic lesion, with an irregular thickened wall, behind the prostate. The serum prostate specific antigen (PSA) level was elevated to 211.99 ng/ml, therefore, the patient underwent a transperineal prostate needle biopsy, and was diagnosed with prostate adenocarcinoma with cyst formation. Androgen deprivation therapy was administered for 8 months following the diagnosis of prostate cancer; consequently, the cyst reduced in size and the serum PSA level decreased to 0.14 ng/ml. To the best of our knowledge, this is the first report of a malignant prostatic cyst detected by FDG-positron emission tomography/computed tomography. PMID- 25295088 TI - Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma. AB - Endometrial carcinoma is the second most common gynecological malignancy of the female genital tract worldwide. Enhancer of zeste homolog 2 (EZH2), a critical component of the polycomb repressive complex 2, has been found to be involved in multiple biological processes and is overexpressed in several types of cancer. Previous studies have demonstrated that EZH2 is associated with endometrial carcinoma. The present study showed that EZH2 was overexpressed in complex hyperplasia, atypical hyperplasia and endometrial cancer, but not in simple hyperplasia and normal endometrium. Additionally, by analyzing the correlation between EZH2 expression and clinicopathological characteristics, the expression of EZH2 was found to be associated with myometrial invasion and lymph-vascular space invasion of endometrial cancer. Furthermore, small interfering RNA was utilized to investigate the role of EZH2 in endometrial carcinoma cell proliferation, and the results showed that EZH2 knockdown suppressed the proliferation of endometrial carcinoma cells in vitro. Therefore, these findings indicate that EZH2 expression may predict a more aggressive biological behavior in endometrial carcinoma and it may provide potential therapeutic targets for treatment of endometrial carcinoma. PMID- 25295089 TI - High temperature hyperthermia treatment for canines exhibiting superficial tumors: A report of three cases. AB - High temperature hyperthermia (HTH) treatment has previously been demonstrated to suppress tumor growth in a tumor-bearing rat model. In the present study, the effects of HTH therapy for the treatment of spontaneous tumors in canines was evaluated. In case 1, an 18-year-old female Papillon presented with a right forelimb rhabdomyosarcoma. Case 2 was a 13-year-old male English Cocker Spaniel with a right external auditory canal ceruminous adenocarcinoma and case 3 was a 14-year-old male Golden Retriever that exhibited a perianal gland adenocarcinoma, which surrounded the anus. HTH treatment was performed in all three cases for 10 min at 45-65 degrees C with or without the inhalation of isoflurane. In case 1, the tumor disappeared four weeks following HTH treatment. In case 2, the tumor volume had decreased by day 21, and in case 3, HTH was performed three times and the tumor disappeared following the third procedure. HTH is considered to be a simple procedure with no severe side effects. Consequently, this treatment modality is hypothesized to become a useful alternative therapy for superficial tumors in companion animals. PMID- 25295090 TI - Goiter and hearing impairment: A case of a male patient with Pendred syndrome. AB - Pendred syndrome is a rare genetic disease that causes a disturbance in thyroid hormone synthesis, which results in thyroid dysfunction and the development of goiter and sensorineural deafness. The present report describes the case of a young euthyroid male, who developed a large goiter and hearing impairment, despite no family history of these conditions. A left lobectomy and a subtotal right lobectomy were performed, and the patient was administered permanent hormone replacement therapy with thyroxine. Patients with Pendred syndrome exhibit distinct clinical features and the mechanisms associated with the molecular genetics of this disease have been clarified. Thus, gene detection is considered to be a reliable diagnostic method. Certain patients require surgical intervention in order to relieve the symptoms. Misdiagnosis can be significantly reduced by increasing the understanding of Pendred syndrome. PMID- 25295091 TI - RNA interference-mediated knockdown of Aurora-B alters the metastatic behavior of A549 cells via modulation of the phosphoinositide 3-kinase/Akt signaling pathway. AB - Accumulating evidence has revealed that an elevated expression level of Aurora-B is associated with metastasis in various types of malignant tumor. However, it is currently unclear whether this molecule is involved in non-small lung cancer (NSCLC) metastasis, and the molecular mechanisms associated with Aurora-B and metastasis remain unknown. In the present study, in order to investigate whether Aurora-B is involved in the development and metastasis of NSCLC, the Aurora-B protein expression in NSCLC tissues was detected by immunohistochemistry and its association with metastasis was analyzed. The results revealed that the expression levels of the Aurora-B protein in tissues obtained from NSCLC patients with lymph node metastasis were significantly higher than those without metastatic disease. Furthermore, the effect of Aurora-B inhibition on A549 cell migration and invasion, as well as the activity of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was evaluated. Aurora-B was inhibited in the A549 cells using short hairpin RNA, and the cell migration and invasion rates were investigated using wound healing and Transwell invasion assays. In addition, the expression of the main proteins in the PI3K/Akt/nuclear factor-kappaB (NF-kappaB) signaling pathway, and matrix metalloproteinase (MMP)-2 and -9 were measured by western blot analysis. The results demonstrated that cell migration and invasion were decreased as a result of silencing Aurora-B. Furthermore, the activity of the PI3K/Akt/NF-kappaB signaling pathway and the expression of MMP-2 and -9 protein were suppressed by silencing Aurora-B. The results of the present study indicate that the knockdown of Aurora-B suppresses A549 cell invasion and migration via the inhibition of the PI3K/Akt signaling pathway in vitro and thus, targeting Aurora-B may present a potential treatment strategy for NSCLC. PMID- 25295092 TI - Differential beta-catenin expression levels are associated with morphological features and prognosis of colorectal cancer. AB - beta-catenin, an epithelial-mesenchymal transition (EMT)-associated marker, is key in the progression of colorectal cancer (CRC). However, the prognostic significance of beta-catenin expression in patients with CRC remains controversial. In the present study, the expression of beta-catenin at the tumor invasive front and the tumor center was investigated, and the correlations amongst beta-catenin differential expression patterns and the clinicopathological characteristics and prognosis of CRC patients were determined. In total, 181 patients that were diagnosed with CRC (as determined by histopathological evaluation) and subjected to surgical resection at the First Hospital of China Medical University between 2000 and 2001 were examined, and CRC specimens were obtained. Immunohistochemical (IHC) staining of beta-catenin was performed for each specimen. The nuclear beta-catenin expression levels were identified to be significantly lower in the tumor center than at the tumor invasive front (immunoreactivity score, 0.05+/-0.303 versus 2.18+/-3.917; P<0.001). The presence of nuclear beta-catenin overexpression at the tumor invasive front was found to be correlated with the tumor, node, metastasis stage (P=0.020), lymph node metastasis (P=0.016) and histological differentiation (P=0.006). Survival analysis revealed that reduced membranous expression levels and increased nuclear expression levels of beta-catenin were statistically significantly associated with poor survival times. Furthermore, differential beta-catenin expression levels were associated with aggressive morphological features, EMT and a poor prognosis in CRC. Therefore, IHC analysis of beta-catenin is considered to be a useful marker to predict the prognosis in patients with CRC. PMID- 25295093 TI - Involvement of the Akt signaling pathway in ER-alpha36/GRP94-mediated signaling in gastric cancer. AB - Glucose-regulated protein 94 (GRP94) has been implicated in the promotion of tumor proliferation and metastasis. Previous studies have found that GRP94 is involved in the malignant growth of gastric carcinoma cells through estrogen receptor-alpha36 (ER-alpha36)-mediated estrogen signaling, but the underlying mechanism remains unclear. In the present study, we examined the expression levels of GRP94 and ER-alpha36 in tumor specimens from gastric cancer patients by immunohistochemistry, and found that both GRP94 and ER-alpha36 were highly expressed in the cytoplasms of gastric carcinoma cells. Furthermore, treatment with 17beta-estradiol at a concentration of 10-12 M for 24 h increased the expression levels of GRP94 and ER-alpha36, and the phosphorylation levels of Akt at the Ser473 site (Ser473-Akt). In established SGC7901 gastric cancer cells with knockdown of ER-alpha36 expression, the levels of GRP94 and Ser473-Akt expression were significantly reduced. Thus, the Akt signaling pathway is a potentially important signaling pathway in ER-alpha36-GRP94-mediated gastric carcinogenesis. PMID- 25295094 TI - Comparative gene expression profiling of normal and human colorectal adenomatous tissues. AB - Adenomatous colorectal polyps are the precursors of the majority of colorectal cancers. Investigation into the gene expression changes in the progression of colorectal adenoma may offer potential targets for the development of novel diagnostic strategies. Previous gene expression studies have generally been based on a limited number of cases or only focused on a single or a few genes. The present study aimed to identify molecular characteristics of colorectal adenoma through analysis of pathways and gene ontology. The study identified 808 upregulated and 857 downregulated genes. Among the 40 pathways enriched with differentially-expressed genes, the Staphylococcus aureus infection pathway and the intestinal immune network for immunoglobulin A production pathway were identified as the most statistically noteworthy pathways at the early stage for colorectal tumorigenesis (P<0.05). These results provide new understanding of colorectal adenoma pathogenesis, with the hope of offering theoretical support for future therapeutic studies. PMID- 25295095 TI - Liver kinase B1 enhances chemoresistance to gemcitabine in breast cancer MDA-MB 231 cells. AB - Liver kinase B1 (LKB1) is a well-known tumor suppressor gene in a variety of human cancers, including breast cancer. However, its role in gemcitabine resistance is unclear. Since gemcitabine in combination with other chemotherapeutic reagents is the first-line treatment in advanced breast cancer, the aim of the present study was to determine the effect of ectopic expression of LKB1 on chemosensitivity to gemcitabine in the breast cancer MDA-MB-231 cell line. Increasing the expression of LKB1 was found to directly correlate with gemcitabine chemoresistance. Although LKB1 suppressed the cell proliferation rate and clonogenicity in the absence of gemcitabine, it increased the median inhibitory concentration of gemcitabine and clonogenicity of cells in the presence of gemcitabine. Mechanistic analysis indicated that LKB1 was able to protect cells from DNA damage caused by gemcitabine. Furthermore, it was found that LKB1 induced a significant upregulation of cytidine deaminase expression, an important enzyme that accelerates gemcitabine catabolization. Overall, dual characteristics of LKB1 were identified: Suppressing cell growth in normal conditions and enhancing chemoresisitance to gemcitabine, possibly by accelerating degradation of gemcitabine, and protecting cells from DNA damage caused by gemcitabine. PMID- 25295096 TI - Heterogeneity of epidermal growth factor receptor mutations in lung adenocarcinoma harboring anaplastic lymphoma kinase rearrangements: A case report. AB - Lung cancer is a heterogeneous and complex disease that remains the leading cause of cancer-related mortality worldwide. The identification of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangements has changed the treatment of non-small cell lung cancer, creating a personalized treatment era that is based on the appropriate molecular selection of patients. In spite of the efficacy of tyrosine kinase inhibitors (TKIs), acquired resistance remains inevitable due to various mechanisms. The present study reports the case of a 30-year-old patient with stage IV lung adenocarcinoma initially harboring an EGFR mutation. However, following disease progression and a series of treatments, the wild-type EGFR gene was observed and the ALK rearrangements were revealed. Erlotinib administration resulted in a good response in the patient initially, but crizotinib did not. This indicated an association between the secondary mutations in kinases and the drug resistance to TKIs. This case should also highlight the clinical significance of repeat biopsies for the subsequent therapeutic choices at the onset of clinical progression. PMID- 25295097 TI - Combined detection of serum UL16-binding protein 2 and macrophage inhibitory cytokine-1 improves early diagnosis and prognostic prediction of pancreatic cancer. AB - Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality in the United States. There is no effective serum biomarker for the early diagnosis of PC at present. Although serum UL16-binding protein 2 (ULBP2) and macrophage inhibitory cytokine-1 (MIC-1) levels are reported to be elevated in PC patients, the diagnostic and prognostic value of ULBP2 and MIC-1 alone or in combination remains unknown. The aim of the present case-control study was to compare the diagnostic value of ULBP2, MIC-1 and carbohydrate antigen 19-9 (CA19-9) in 359 serum samples, consisting of 152 cases of PC, 20 cases of pre-pancreatic cancer, 91 cases of chronic pancreatitis (CP) and 96 normal controls (NC). All patients were followed up for a median of 2 years. It was found that the serum levels of ULBP2, MIC-1 and CA19-9 were significantly higher in the PC patients compared with those in the NC group. In distinguishing PC from the CP, the highest sensitivity and specificity were ULBP2 (0.878) and CA19-9 (0.816), respectively. The area under the receiver operating characteristic curve of ULBP2 was 0.923, which was the highest of the three biomarkers. MIC-1 was the optimal choice for the diagnosis of early-stage PC (area under the curve, 0.831). Overall, MIC-1 in combination with ULBP2 improved the diagnostic accuracy in differentiating PC from CP and NC. In addition, a higher level of MIC-1 was correlated with a poorer prognosis, as calculated by the Kaplan-Meier test (P=0.039). Patients with serum MIC-1 levels of >=1,932 ng/ml had a median survival time of 15.62+/-2.44 months (mean +/- standard deviation) vs. 18.66+/-2.43 months in patients with a lower level of MIC-1. Overall, combined detection of serum MIC-1 and ULBP2 improved the diagnostic accuracy in differentiating PC from CP and NC, and serum MIC-1 level alone was a predictor of survival in the patients with PC. PMID- 25295098 TI - Expression of multidrug resistance proteins in invasive ductal carcinoma of the breast. AB - Chemotherapy is commonly used for the treatment of breast cancer. However, the resistance to chemotherapeutic agents, often mediated by multidrug resistance (MDR) mechanisms, is a common occurrence. The present study examined the expression of several MDR-related proteins (MRPs) in invasive ductal carcinoma (IDC) of the breast, and assessed their association with clinicopathological variables and their prognostic significance. In addition, immunohistochemistry was used to measure the expression of MRP, p-glycoprotein (P-gp), topoisomerase 2alpha (Topo2alpha), thymidylate synthase (TS) and glutathione-S-transferase pi (GST-pi) in 156 resected IDCs of the breast. Pearson's chi2 test and Spearman's correlation coefficient were used to analyze the association between MDR protein expression and several clinicopathological variables. The association between each of the five MDR proteins was also examined. Furthermore, Kaplan-Meier analysis and Cox regression modeling were used to assess overall survival. The expression of MRP, P-gp, Topo2alpha, TS and GST-pi was detected in 20.5% (32/156), 25.0% (39/156), 84.0% (131/156), 41.7% (65/156) and 41.0% (64/156) of cases examined, respectively. No correlation was identified between MRP and Topo 2alpha and the clinicopathological variables examined. By contrast, P-gp (chi2=20.226; P<0.0001) and GST-pi (chi2=35.032; P<0.0001) were found to positively correlate with tumor grade. In addition, staining for TS was associated with axillary lymph node metastasis (chi2=42.281; P<0.0001). The expression levels of P-gp and GST-pi were found to be significantly correlated (r= 0.319; P<0.0001). Furthermore, GST-pi expression was elevated in estrogen receptor-negative breast cancer (chi2=17.407; P<0.0001). Tumor histological grade, in addition to TS and GST-pi expression, were significant predictors of a poor survival outcome. TS and GST-pi are consequently useful prognostic biomarkers in IDC, therefore, when establishing a personalized chemotherapeutic plan, the expression of MDR proteins must be considered. PMID- 25295099 TI - Primary neuroendocrine tumors of the thymus: Clinical review of 22 cases. AB - Primary neuroendocrine tumors of the thymus are rare mediastinum tumors, which present a distinct type of tumor, which exhibit morpholgical and biological neuroendorcine features including the production of numerous biogenic amines. The aim of the present study was to evaluate factors influencing long-term survival in patients with primary neuroendocrine tumors of the thymus. A total of 22 patients exhibiting primary thymic neuroendocrine tumors, who were treated at the Zhejiang Cancer Hospital (Hangzhou, China), between 1995 and 2012 were reviewed. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model was used for multivariate analysis. The overall five year survival rate was 45.5% and the median survival time was 59 months in all of the patients. Histological grade (P<0.001), Masaoka-Koga stage (P=0.003) and surgical resection status (P=0.004) were identified to be associated with patient survival time. Furthermore, multivariate analysis identified that the histological grade was an independent prognostic factor, which was applicable to all patients (P=0.009). Therefore, the histological grade and Masaoka-Koga stage, as well as surgical resection status present three prognostic factors in patients exhibiting primary thymic neuroendocrine tumors. PMID- 25295100 TI - Deficiency of MSH2 expression is associated with clear cell renal cell carcinoma. AB - DNA hypermethylation plays a major role in the regulation of gene expression in differentiation, development and diseases. The DNA mismatch repair system, which includes Mut-S-Homologon-2 (MSH2) protein, is essential to maintain the stability of the genome during repeated duplication. This study aimed to investigate tumoral MSH2 immunohistochemical expression in clear cell renal cell carcinoma (RCC), and the associations between tumoral MSH2 immunohistochemical expression and clinicopathological parameters. Previously, we reported a high-throughput method for analyzing the methylation status of 807 preselected genes; Illumina's GoldenGate Methylation Cancer Panel I microarray. The MSH2 gene was identified to be hypermethylated in cancer tissue compared with normal tissue. From January 2000 to December 2012, 129 clear cell RCC cases (median age, 61 years) were included in the immunohistochemical analysis of the present study. Patients were divided according to MSH2 expression status (MSH2-negative, n=53; MSH2-positive, n=76). T stage was significantly higher in the MSH2-negative group than in the MSH2 positive-group (P=0.021). There was no significant difference in terms of N stage, M stage and Fuhrman's nuclear grade between the MSH2-negative and MSH2 positive group (N stage, P=0.072; M stage, P=0.759; Fuhrman's nuclear grade, P=0118). The MSH2-negative group showed decreased rates of recurrence-free survival, progression-free survival and overall survival, without statistically significant results (P=0.232, P=0.268 and P=0.311, respectively). MSH2 protein expression may be a useful marker for predicting TNM stage and prognosis and, thus, MSH2 may be a prognostic factor in clear cell RCC. PMID- 25295101 TI - Expression of metastasis suppressor 1 in cervical carcinoma and the clinical significance. AB - This study aimed to investigate the expression of metastasis suppressor 1 (MTSS1) in cervical intraepithelial neoplasia (CIN) and malignant cervical tissues, and the role of MTSS1 in carcinogenesis. MTSS1 expression was detected by immunohistochemistry in 147 cervical tissue specimens collected from 30 healthy individuals, 30 patients with cervical CIN I, 30 patients with CIN II-III and 57 patients with cervical cancer. The association between MTSS1 expression and clinicopathological factors was also examined. MTSS1 was found to be positively expressed in 43.33% CIN I cervical tissues, 100% CIN II-III cervical tissues and 100% malignant cervical tissues, but was weakly or negatively expressed in benign cervical tissues. The positive expression rates of MTSS1 were significantly higher in CIN II-III and malignant cervical tissues than in CIN I or normal cervical tissues (P<0.05). When examining MTSS1 expression and clinicopathological factors, the strong positive MTSS1 expression rates in early stage versus middle- and advanced-stage cervical cancer tissues were 39.13% and 82.35%, respectively. Furthermore, the positive expression rates of MTSS1 were significantly higher in cervical tissues at an advanced clinical stage than those at an early clinical stage (P<0.05). The results suggest that the dysregulation of MTSS1 may be involved in cervical carcinogenesis, and thus MTSS1 may be a novel diagnostic biomarker or therapeutic target in cervical cancer patients. PMID- 25295102 TI - Primary hepatic malignant fibrous histiocytoma mimicking hepatocellular carcinoma: A report of two cases. AB - Malignant fibrous histiocytoma (MFH) is a tumor that occurs throughout the body as a relatively uncommon entity. The current study presents two cases of primary malignant fibrous histiocytoma of the liver. The first case was of a 67-year-old male who exhibited no symptoms or abnormal physical signs, and in whom the lesion was found by ultrasound examination during a routine physical examination. The second case was of a 35-year-old male who presented with persistent malaise, weight loss and intermittent right upper quadrant pain. The presence of liver cirrhosis due to hepatitis B virus, which was identified 10 years previously, and the clinical appearance caused MFH to appear as hepatocellular carcinoma at the time of the initial diagnosis. Abdominal magnetic resonance imaging scans were the main tools of diagnosis, but the MFH mimicked hepatocellular carcinoma due to the similar morphological characteristics, the rare occurrence of MFH and the underlying diseases of the liver. The first patient underwent a complete resection and recovered well, while the second patient underwent palliative treatment due to the large size of the tumor and the obstructive emboli in the portal vein. The diagnoses of the tumors were confirmed as MFH by histopathology and immunohistochemistry. PMID- 25295104 TI - Synovial sarcoma of the infratemporal fossa: A case report. AB - Synovial sarcomas (SS) are high-grade soft-tissue sarcomas, predominantly found in the deep soft tissues of the lower extremities, with only 3-5% occurring in the head and neck region. Primary SS of the infratemporal fossa (ITF) is exceptionally uncommon. The present study reports the case of a 23-year-old female with an SS arising in the ITF. To the best of our knowledge, this case is only the second patient with intracranial involvement recorded in the literature. The patient was treated primarily with surgery, followed by a total of 60 Gy adjuvant radiotherapy and chemotherapy, consisting of cisplatin (25 mg/m2 intravenously on days one to three), epirubicin (25 mg/m2 intravenously on days one and two) and ifosfamide (1.8 g/m2 intravenously on days one to five) for three cycles. At present, two years after this multimodal therapy, the patient exhibits no signs of loco-regional recurrence or distant metastases. This study highlights the importance of a multidisciplinary approach in the diagnosis and treatment of this extremely rare entity with intracranial extension. In addition, the study reviews the English literature with regard to SS of ITF and discusses the clinicopathological features, management and outcome. PMID- 25295103 TI - Evaluation of immunohistochemistry using two different antibodies and procedures for primary lung adenocarcinoma harboring anaplastic lymphoma kinase rearrangement. AB - Rearrangements of anaplastic lymphoma kinase (ALK) have been recently identified in non-small cell lung carcinomas. Previous studies have revealed characteristic features, including adenocarcinoma histology and mucin production, in ALK positive lung carcinoma. The present study evaluated immunohistochemistry (IHC) in ALK-positive lung carcinoma using two different antibodies, clone 5A4 and D5F3, and compared the results. On the basis of the aforementioned characteristic features, out of 359 primary lung carcinomas, the ALK status of 14 adenocarcinomas was screened using the intercalated antibody-enhanced polymer (iAEP) method with antibody 5A4, and this was compared with the ALK status obtained using rabbit monoclonal antibody D5F3 and fluorescence in situ hybridization for ALK. Eight cases were demonstrated to be ALK-positive by IHC. Seven cases exhibited ALK rearrangement, which was demonstrated by fluorescence in situ hybridization. The IHC for ALK obtained using D5F3 was comparable with that of the iAEP and exhibited low heterogeneity. This finding suggests that IHC for ALK could be useful in limited tissue samples, such as biopsy specimens or cytology, for the screening of ALK-positive lung carcinoma. In the present study, it was demonstrated that IHC with ALK monoclonal antibody D5F3 was useful for screening lung adenocarcinoma harboring ALK rearrangement. PMID- 25295105 TI - Expression and significance of transforming growth factor-beta1 in epithelial ovarian cancer and its extracellular matrix. AB - The aim of the present study was to investigate the expression and significance of transforming growth factor-beta1 (TGF-beta1) in the cytoplasm and extracellular matrix (ECM) of epithelial ovarian cancer cells. The expression of TGF-beta1 protein was detected in paraffin-embedded sections of 25 normal ovarian epithelial tissues, 10 benign epithelial cysts and 72 epithelial ovarian cancer specimens, using the Strept Avidin Biotin Peroxidase Complex immunohistochemistry method. In addition, the expression of TGF-beta1 mRNA in normal fibroblasts (NFs) and ovarian cancer-associated fibroblasts (CAFs) was assessed using semi quantitative polymerase chain reaction (PCR). TGF-beta1 protein was expressed in the cytoplasm and ECM, and no significant difference was identified between normal and benign ovarian tissues (P>0.05). However, the cytosolic expression of TGF-beta1 declined gradually between the benign ovarian tumor and epithelial ovarian cancer, while its expression in the ECM significantly increased (P<0.05). The expression of TGF-beta1 in the cytoplasm and ECM in epithelial ovarian cancer was found to negatively correlate with tumor differentiation, however, it was positively associated with the clinical stages. The positive rates of TGF-beta1 in the cytoplasm and ECM between ovarian cancers in clinical stages I-II and III IV were significantly different (P<0.05). Furthermore, the PCR data indicated that the relative expression of TGF-beta1 mRNA in ovarian CAFs (1.0270+/-0.0539) was significantly higher than that in NFs (0.7131+/-0.0186). Therefore, the expression of TGF-beta1 was identified to be associated with the development and progression of epithelial ovarian cancer, and the high expression of TGF-beta1 in the ECM may be associated with the invasion and metastasis of ovarian cancer. PMID- 25295106 TI - Clinical outcome of thymic lymphoepithelioma-like carcinoma: Case report of a 14 year-old male. AB - Thymic carcinoma is a rare type of cancer, which arises from the thymic epithelium and accounts for ~1-4% of anterior mediastinal tumors in the USA. It rarely occurs in children, and is rarer among adults. Thymic lymphoepithelioma like carcinoma (LELC) is an uncommon subtype of thymic carcinoma in children, however, it is one of the common histological subtypes of thymic carcinoma in adults. In the present study, a 14-year-old male patient presented to the Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital (Tokoyo, Japan) with chest pain due to a large anterior mediastinal mass. The patient was histologically diagnosed with thymic LELC via a needle biopsy specimen, which was obtained from the primary site and indicated the Epstein-Barr virus infection, whose markers are also associated with oncogenesis. Immunohistochemical analysis demonstrated positive staining for keratin (AE1/AE3), epithelial membrane antigen, and latent membrane protein-1 and negative staining for cluster of differentiation 5. Thus, the patient was diagnosed with metastatic thymic LELC. First-line chemotherapy comprising of a cisplatin- and adriamycin-based chemotherapy regimen achieved a partial response, however, the patient succumbed within 10 months of the initial diagnosis due to rapid disease progression and refractory to subsequent cycles of chemotherapy. Thus, the current study, as well as previously reported cases, demonstrates that pediatric patients with thymic LELC continue to have a poor prognosis. PMID- 25295107 TI - Effects of transforming growth factor-beta1 on the proliferation and invasion of the HTR-8/SVneo cell line. AB - Transforming growth factor-beta1 (TGF-beta1) is involved in the regulation of trophoblast cell proliferation and invasion. However, the mechanism underlying this process remains unknown, which is predominantly due to the difficulty in obtaining and maintaining primary trophoblast cells in culture over a long period of time. The HTR-8/SVneo cell line is an immortalized trophoblast cell line, which has been reported to exhibit a number of similar characteristics to those of parental trophoblast cells. Therefore, the cell line has been a useful tool for the investigation of placental function and tumor progression. In the present study, the HTR-8/SVneo cell line was used as a model to investigate the TGF beta1/SMAD signaling pathway in the proliferation and invasion of trophoblast cells. The proliferation and invasion ability of HTR-8/SVneo cells was determined using the MTT and Transwell assays, respectively. In addition, reverse transcription polymerase chain reactions were performed to detect the mRNA expression of a panel of known downstream mediators of TGF-beta1, including TGF beta receptor I (TbetaRI), SMAD4, SMAD3, SMAD7 and tissue inhibitor of metalloproteinases-1 (TIMP-1). The results indicated that TGF-beta1 promotes the proliferation and invasion of the HTR-8/SVneo cell line at passage 90. Furthermore, the expression of TbetaRI, SMAD3 and SMAD4 were reduced following treatment with TGF-beta1, while the expression of SMAD7 was increased and the expression of TIMP-1 remained unchanged following TGF-beta1 treatment. These observations indicated that the effects of TGF-beta1 on the proliferation and invasion of the HTR-8/SVneo cell line at passage 90 were different from those of parental trophoblasts, which is in contrast to the results of previous studies. It was concluded that the HTR-8/SVneo cell lines, which have been grown for over 90 passages, do not accurately represent parental trophoblast cells in studies of the TGF-beta/SMAD signaling pathway. PMID- 25295108 TI - Oncolytic adenovirus-expressed RNA interference of O6-methylguanine DNA methyltransferase activity may enhance the antitumor effects of temozolomide. AB - Temozolomide (TMZ) is an example of an alkylating agent, which are known to be effective anticancer drugs for the treatment of various solid tumors, including glioma and melanoma. TMZ acts predominantly through the mutagenic product O6 methylguanine, a cytotoxic DNA lesion. The DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), which functions in the resistance of cancers to TMZ, can repair this damage. RNA interference (RNAi) has been previously shown to be a potent tool for the knockdown of genes, and has potential for use in cancer treatment. Oncolytic adenoviruses not only have the ability to destroy cancer cells, but may also be possible vectors for the expression of therapeutic genes. We therefore hypothesized that the oncolytic virus-mediated RNAi of MGMT activity may enhance the antitumor effect of TMZ and provide a promising method for cancer therapy. PMID- 25295109 TI - Hedgehog-glioma-associated oncogene homolog-1 signaling in colon cancer cells and its role in the celecoxib-mediated anti-cancer effect. AB - Hedgehog (Hh) signaling is activated in numerous malignant tumors, but its role in human colorectal cancer remains uncertain. Celecoxib, a selective cyclooxygenase-2 inhibitor, has been shown to exhibit chemoprevention in colorectal cancer, however, the effects of celecoxib on Hh signaling remain unknown. The current study presents an evaluation of Hh signaling in colon cancer cell lines and the effects of celecoxib in vitro. Active Hh signaling was observed in LoVo and HT-29 cells, with particularly high levels in the LoVo cells. However, Hh signaling activity was absent in HCT-116 cells. Quantitative polymerase chain reaction indicated that the expression of Hh receptor patched homolog 1 (PTCH1) was absent in the LoVo cells, but that they exhibited high levels of glioma-associated oncogene homolog-1 (GLI1) expression, while high expression levels of PTCH1 and low expression levels of smoothened (SMO) and GLI1 were observed in the HCT-116 cells. The HCT-116 cells were extremely sensitive to celecoxib, whereas the LoVo cells were resistant to the anticancer effect of the drug. Celecoxib downregulated the expression of GLI1 in the HCT-116 and HT-29 cells, but did not change the expression of GLI1 in the LoVo cells. The results presented in this study indicated that the anticancer effect of celecoxib is selective in colon cancer cells; celecoxib may target cancer cells via the SMO independent modulation of GLI1 activity, and Hh signaling may be significant in maintaining the malignant state of LoVo cells. These findings may aid in improving our understanding of the carcinogenesis of colon cancer and the development of novel approaches for the targeted therapy of this disease. PMID- 25295111 TI - Genotyping the GALNT14 gene by joint analysis of two linked single nucleotide polymorphisms using liver tissues for clinical and geographical comparisons. AB - A GALNT14 single nucleotide polymorphism, rs9679162, has recently been found to be capable of predicting chemotherapy responses in patients with far-advanced hepatocellular carcinoma (HCC). In the present study, a novel assay was designed and genotyping was performed on 244 surgically removed liver tissues. This assay employed two polymerase chain reaction (PCR)-generated restriction enzyme sites to simultaneously determine the genotypes of two adjacent single nucleotide polymorphisms (SNPs), rs9679162 and rs6752303, on the GALNT14 gene. Genotypes determined by this assay reached 100% concordance with those detected by the direct sequencing method. Clinical analysis showed that the TT genotype of rs9679162 was lower in percentage among patients with virus-originated HCC compared with those with non-viral HCC (22.57 vs. 47.06%, respectively; P=0.023). The proportion of the TT genotype in the 244 HCC patients (24.18%) did not deviate significantly from those of two public-domain (HapMap) Chinese cohorts from Denver, Colorado, USA (28.44%) and Beijing, China (30.15%) (P>0.05). The proportion of the TT genotype was significantly higher in Japanese and African populations (42.11-54.55%; P<0.0001) but significantly lower in an Italian cohort (7.84%; P=0.0004). In conclusion, the novel PCR-generated double restriction enzyme sites method could correctly determine the genotypes of two target SNPs in GALNT14 in liver tissues. The TT genotype was associated with the non-viral etiology of HCC. A marked variation in ethnicity was found for the distribution of this genotype. PMID- 25295110 TI - Antitumor and antimetastasis effects of carboplatin liposomes with polyethylene glycol-2000 on SGC-7901 gastric cell-bearing nude mice. AB - The present study aimed to analyze the characteristics of polyethylene glycol (PEG)ylated carboplatin liposomes (PL-CBPs), including size, stability, their release, entrapping and loading efficiencies, and their antitumor and antimetastatic effects on the lymph nodes. The PL-CBPs were prepared using PEG 2000 with the thin film hydration method. The liposome size and release, entrapping and loading efficiencies were detected by ultra-violet/visible spectrophotometry. A nude mouse model was established with the SGC-7901 gastric cell line to evaluate the antitumor effect of the PL-CBP. After 7 days, the mice were randomly divided into three groups (the control, CBP, and PL-CBP groups). CBP and PL-CBP were administered at a dose of 10 mg/kg for two consecutive cycles of treatment, 5 days apart, to their respective groups. In each group, two doses of 5 mg/kg were administered every 48 h. The tumor weight and volume were detected, and the food intake and body weight were measured during the administration. Apoptosis in the tumor cells was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and platinum (Pt) accumulation was detected by atomic absorption spectroscopy. Lastly, lymph node metastasis was evaluated by hematoxylin and eosin staining. The PL-CBPs were more stable when comapred with CBP alone, and the drug release efficiency was 0.7, 22.5, 48.7 and 65.1% at 37 degrees C for 0, 12, 24 and 48 h. The results showed that the encapsulation efficiency was 85% and the loading efficiency was 0.15 mg/mg lipid. After 35 days, PL-CBP induced potent antitumor effects compared with the control and CBP groups (PL-CBP vs. control, P<0.01; PL-CBP vs. CBP, P<0.05). PL-CBP and CBP induced a lower and the lowest body weight and level of food intake, respectively, compared with the control group (CBP vs. control, P<0.05). The apoptosis rate and lymph node metastasis in the PL-CBP group was higher than that in the CBP and control groups (PL-CBP vs. control, P<0.01; PL-CBP vs. CBP, P<0.05). Pt accumulation in the tumors was higher in the PL-CBP group than in the CBP group (PL-CBP vs. CBP, P<0.05). The PL-CBPs were more stable in the circulation and could be released more slowly at the tumor site than compared with CBP injection. The PL-CBPs showed potent antitumor and antimetastatic effects on the lymph nodes. PMID- 25295112 TI - Positive resection margins may not reflect the true margin in patients undergoing radical prostatectomy. AB - The aim of the present study was to evaluate the hypothesis that a positive resection margin (RM1) of an excised specimen may not reflect the true margin in patients that have undergone radical prostatectomy (RP). Between September 2003 and March 2011, 370 Japanese patients underwent an antegrade RP at the National Kyushu Cancer Center (Fukuoka, Japan), however, 95 of these patients were excluded from the study due to a history of receiving hormonal therapy or insufficient preoperative clinical data. The incidence of biochemical failure (BCF) was evaluated using multivariate analysis, which revealed that the preoperative prostate-specific antigen (PSA) level, pathological tumor stage, RP Gleason score and a PSA nadir <0.008 ng/ml were significant predictors (P=0.0065, 0.0006, 0.0002 and <0.0001, respectively). By contrast, an RM1 was not found to be a significant predictor of BCF, while the parameter with the highest hazard ratio (HR) was a PSA nadir <0.008 ng/ml (HR, 10.055; 95% confidence interval, 5.005-20.200). From the 56 cases that were RM1, 41 cases (73.2%) exhibited a PSA nadir <0.008 ng/ml. There were 42 cases (75.0%) in which only one site was identified to be RM1; among these cases, no significant difference was observed between a PSA level <0.008 ng/ml and a PSA level >=0.008 ng/ml at the RM1 site (apex, P=0.1460; base, P=0.1384; anterior, P=0.3870; and posterolateral, P=0.5040). There were 14 cases (25.0%) in which multiple sites were RM1; these cases were classified by the number of sites that were RM1 (one vs. multiple) and no significant difference was observed between a PSA level <0.008 ng/ml and a PSA level >=0.008 ng/ml (P=0.6090). Based on these results, an RM1 of an excised specimen may not reflect the true margin in patients that are treated with RP, specifically in cases where the PSA level is identified to decrease to below the postoperative measurement threshold value (PSA nadir <0.008 ng/ml). PMID- 25295113 TI - Recurrent desmoid tumor of the mediastinum: A case report. AB - Desmoid tumors (DTs) are rare, benign soft-tissue tumors that have the potential for local invasion, but not for metastasis. The tumors are commonly characterized by a palpable mass, but present a variable and unpredictable clinical course. The current study presents the case of a giant mediastinal DT exhibiting lung involvement. A 50-year-old female was referred to the West China Hospital (Chengdu, Sichuan, China) due to a recurrent DT that was identified one year following radical surgery. The patient subsequently received radiation therapy. The DT arose from the mediastinum, unlike the usual presentation, and recurrence presented as extensive invasion into the lung tissue, almost being misdiagnosed as lung cancer with brain metastasis. Tumor recurrence was diagnosed through contrast-enhanced computed tomography and histological examination of the tumor. A routine follow-up revealed no further tumor progression at 9 months post admission. Taking into account the unpredictable treatment complications, recurrent DTs can be managed simply and efficiently. A 'wait-and-see' policy could be a viable therapeutic option for this disease. PMID- 25295114 TI - Investigating urachal carcinoma for more than 15 years. AB - Urachal carcinomas are rare bladder malignances, which usually present at an advanced stage with a high risk of distant metastases and a poor prognosis. To improve understanding of this uncommon carcinoma, a retrospective review was conducted for the cases observed at Peking University Shenzhen Hospital and Peking University First Hospital. The clinical outcomes were analyzed for 17 patients with a diagnosis of urachal cancer, who were admitted to Peking University Shenzhen Hospital (Shenzhen, China) and Peking University First Hospital (Beijing, China) between 1998 and 2013. The TNM staging system was used to predict outcomes. Among the 17 study patients, there were 10 males and seven females, with a median age at diagnosis of 50 years. A total of four (23%) patients presented with lymph node or distant metastasis. The median overall survival time for all stages was 57.6 months, with five patients (38.4%) alive for more than five years following treatment. The application of the TNM staging system demonstrated a median survival time of 6.2 years for stage I/II patients, compared with a median survival of 1.8 years (log-rank, P<0.001) for patients with advanced disease (stages III and IV). In addition, no significant correlation was observed between tumor size and age, and survival. In conclusion, urachal carcinomas are usually locally advanced at presentation. Surgical excision remains the predominant choice of treatment and lymph node dissection is not required unless lymph node involvement is confirmed by preoperative examination. The current results indicated that the most significant predictor of prognosis was the tumor grade. PMID- 25295115 TI - Alternating expression levels of WWOX tumor suppressor and cancer-related genes in patients with bladder cancer. AB - The aim of the present study was to determine the roles of the WWOX tumor suppressor and cancer-related genes in bladder tumor carcinogenesis. Reverse transcription-quantitative polymerase chain reaction was used to analyze the status of WWOX promoter methylation (using MethylScreenTM technology) and loss of heterozygosity (LOH) in papillary urothelial cancer tissues. The associations between the expression levels of the following tumorigenesis-related genes were also assessed: The WWOX tumor suppressor gene, the MKI67 proliferation gene, the BAX, BCL2 and BIRC5 apoptotic genes, the EGFR signal transduction gene, the VEGF vascular endothelial growth factor gene, and the CCND1 and CCNE1 cell cycle genes. The results reveal a high frequency of LOH in intron 1 in the WWOX gene, as well as an association between reduced WWOX expression levels and increased promoter methylation. In addition, the present study demonstrates that in bladder tumors, apoptosis is inhibited by increased expression levels of the BCL2 gene. A correlation between the proliferation indices of the MKI67 and the BIRC5 genes was also revealed. Furthermore, the expression levels of VEGF were identified to be positively associated with those of the EGFR gene. PMID- 25295116 TI - MACC1 expression levels as a novel prognostic marker for colorectal cancer. AB - Metastasis-associated in colon cancer-1 (MACC1) is key in promoting tumor proliferation and invasion, and is mediated by the hepatocyte growth factor (HGF) and mesenchymal-epithelial transition factor. Previous reports have revealed that MACC1 is a novel oncogene that is expressed in various types of gastrointestinal cancer. The present study comprised of 174 patients who underwent curative surgery for colorectal cancer (CRC). The correlation between gene expression and clinical parameters of the patients was assessed. It was identified that patients exhibiting high MACC1 expression levels were statistically more susceptible to distant metastases and a poor prognosis, and those exhibiting low MACC1 expression showed improved disease-free and overall survival than those with high expression. Therefore, the present data indicates that MACC1 expression levels may present as a prognostic factor in CRC patients. PMID- 25295117 TI - Oral anticancer agent medication adherence by outpatients. AB - In the present study, medication adherence and factors affecting adherence were examined in patients taking oral anticancer agents. In June 2013, 172 outpatients who had been prescribed oral anticancer agents by Ogaki Municipal Hospital (Ogaki, Gifu, Japan) completed a questionnaire survey, with answers rated on a five-point Likert scale. The factors that affect medication adherence were evaluated using a customer satisfaction (CS) analysis. For patients with good and insufficient adherence to medication, the median ages were 66 years (range, 21-85 years) and 73 years (range, 30-90 years), respectively (P=0.0004), while the median dosing time was 131 days (range, 3-3,585 days) and 219 days (24-3,465 days), respectively (P=0.0447). In 36.0% (62 out of 172) of the cases, there was insufficient medication adherence; 64.5% of those cases (40 out of 62) showed good medication compliance (4-5 point rating score). However, these patients did not fully understand the effects or side-effects of the drugs, giving a score of three points or less. The percentage of patients with good medication compliance was 87.2% (150 out of 172). Through the CS analysis, three items, the interest in the drug, the desire to consult about the drug and the condition of the patient, were extracted as items for improvement. Overall, the medication compliance of the patients taking the oral anticancer agents was good, but the medication adherence was insufficient. To improve medication adherence, a better understanding of the effectiveness and necessity of drugs and their side-effects is required. In addition, the interest of patients in their medication should be encouraged and intervention should be tailored to the condition of the patient. These steps should lead to improved medication adherence. PMID- 25295118 TI - Mixed adenocarcinoma, sarcomatoid carcinoma and adenosquamous carcinoma of the prostate: A case report. AB - Adenosquamous carcinoma (ASC) and sarcomatoid carcinoma (SC) of the prostate are rare, but highly aggressive tumors. The occurrence of mixed carcinomas in the prostate is even more rarely reported. The present study reports the case of a 62 year-old male who was diagnosed with prostatic adenocarcinoma accompanied by multiple bone metastases, as shown by a needle biopsy and skeletal computed tomography scan. The patient was treated with hormonal therapy, but thereafter, specimens from a transurethral resection of the prostate (TURP) were found to be composed of three histologically distinct elements: ASC, SC and adenocarcinoma. The level of p53 was evaluated by immunohistochemistry in detail, and it was found that this was significantly increased in the TURP samples compared with the needle biopsy samples. The abnormal level of p53 was likely associated with the prognosis of the patient; the patient succumbed to prostate carcinoma two months after the confirmation of the diagnosis. PMID- 25295119 TI - Pattern of malignant solid tumors and lymphomas in children in the east delta of Egypt: A five-year study. AB - Worldwide, the incidence and mortality rates of childhood cancers differ. The study of incidence patterns and survival rates in childhood malignancies is important in aiding in the planning of treatment centers and in obtaining further information with regard to the etiology. Few studies have investigated the survival in cases of childhood solid tumors in Egypt. The aim of the current study was to evaluate the patterns, frequency and outcome of solid tumors and lymphomas in children admitted to and followed up at the Pediatric Oncology Department of Zagazig University Hospital (Zagazig, Egypt) over a duration of 5 years (January 2004 to December 2008). A retrospective study was conducted, which included 155 children with solid tumors and lymphomas. The medical records were reviewed and the relevant data collected, in particular, those concerning demographic, clinical, histopathological, laboratory and imaging data as well as the treatment plans and outcomes. The mean age of patients was 5.6+/-3.04 years at diagnosis. The patients comprised 94 males and 61 females. Non-Hodgkin lymphoma (NHL) was the most common tumor type, followed by neuroblastoma (31.0 and 29.0%, respectively). When patients were stratified in terms of age (<5, >=5 but <10, and >=10 years), the <5-years-of-age group exhibited the greatest number of patients. Fever, pallor and pain were the most frequent initial clinical presentations among the patients and stage II was the most common stage (39.1%) followed by stage IV, III and I (35.0, 20.3 and 5.6% respectively). The overall 5 year survival rate in the study group was 66.7%. The survival rate was significantly higher in patients with Wilm's tumor and Hodgkin lymphoma, followed by NHL (92.0, 88.0 and 72.0%, respectively; P<0.001), while the mortality rate was significantly higher in patients with neuroblastoma (P<0.001). In conclusion, NHL and neuroblastoma were the most common tumors; the survival rates were higher in patients with Wilm's tumor and Hodgkin lymphoma and lower in patients with neuroblastoma. A larger multicenter study is required to further investigate the conclusions drawn from this study. PMID- 25295120 TI - Reversing multidrug resistance in hepatocellular carcinoma cells by inhibiting extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway activity. AB - The aim of the present study was to evaluate whether downregulation of extracellular signal-regulated kinase 1/2 (ERK1/2) is involved in conventional reversal methods and whether the inhibitors of the ERK signaling pathway reverse multidrug resistance (MDR) in hepatocellular carcinoma (HCC) cells. The sensitivities of SMMC7721 and BEL7402, and the MDR SMMC7721/Adriamycin (ADM) and BEL7402/ADM HCC cell lines to ADM were evaluated by CellTiter-Glo(r) luminescent cell viability assay through calculating the half maximal inhibitory concentration (IC50) of ADM. In addition, the expression levels of ERK1/2 and phosphorylated (p)ERK1/2 were determined by western blot analysis subsequent to treatment of the cells with PD98059, an MEK inhibitor, or sorafenib, a multikinase inhibitor. The results revealed that the ADM IC50 for the SMMC7721/ADM cells was 16.44 times higher than that of the SMMC7721 cells (P<0.05), and the ADM IC50 for the BEL7402/ADM cells was 20.34 times higher than that of the BEL7402 cells (P<0.05). Following treatment with PD98059 or sorafenib, the expression levels of pERK1/2 in the MDR cells decreased in a dose dependent manner. Subsequent to treatment with 5 MUM PD98059, the ADM IC50 values for the SMMC7721/ADM and BEL7402/ADM cells were reduced to 0.8+/-0.056 and 1.583+/-0.284 MUg/ml, respectively. Following treatment with 2.5 MUM sorafenib, the ADM IC50 values for the SMMC7721/ADM and BEL7402/ADM cells were reduced to 0.264+/-0.049 and 1.099+/-0.135 MUg/ml, respectively. Subsequent to incubation with 4 MUg/ml cyclosporine A (CsA), a classic MDR reversal agent, the ADM IC50 values in the SMMC7721/ADM and BEL7402/ADM cells were reduced to 0.349+/-0.023 and 0.427+/-0.039 MUg/ml, respectively. CsA treatment also increased the expression levels of pERK1/2 without affecting the total ERK1/2 levels. Therefore, the inhibition of ERK signaling pathway activity may be an important method to reverse the MDR of HCC cells, but is not unique. PMID- 25295121 TI - Occurrence of HHIP gene CpG island methylation in gastric cancer. AB - The present study aimed to observe the methylation status of the CpG islands at the human hedgehog interacting protein (HHIP) gene in gastric cancer tissues, peritumoral tissues and the AGS cell line, to analyze the association between the methylation status of the CpG islands and the tumorigenesis of gastric cancer. The HHIP mRNA expression in 60 human gastric carcinnoma tissues, peritumoral tissues and the gastric carcinoma AGS cell line were detected by reverse transcription polymerase chain reaction (RT-PCR). The HHIP methylation status of the promoter region in the gastric carcinnoma tissues and peritumoral tissues was detected by methylation-specific PCR (MSP). Prior to and following treatment with methyl transferase inhibitor 5-aza-2'-deoxycitydine (5-aza-dc), the HHIP mRNA expression level, the methylation status of the promoter region and the methylation site loci on the CpG islands in the AGS cells were detected by RT PCR, MSP and bisulfite sequencing PCR (BSP), respectively. The correlation between the methylation status of the CpG islands at the HHIP promoter region and the HHIP mRNA expression level were analyzed. It was found that the expression level of the HHIP mRNA in the gastric carcinoma tissues was significantly lower than that in the adjacent tissues (0.82+/-0.38 vs. 1.60+/-0.26, respectively; P<0.001). No significant correlations were observed between the expression of HHIP mRNA and age, gender, tumor-node-metastasis stage, differentiation degree and presence of lymph node metastasis (P>0.05). The degree of methylation of the HHIP gene promotor in the peritumoral tissues (17.7+/-3.59%) was significantly lower than that in the gastric cancer tissues (62.9+/-6.14%) and in the AGS cells (99.7+/-0.67%) (P<0.05). Compared with prior to 5-aza-dc intervention, the HHIP mRNA expression level in the AGS cells was significantly increased subsequent to intervention (0.21+/-0.12 vs. 4.68+/-0.22; P<0.01), while the degree of methylation in the AGS cells was significantly decreased (90.2+/-0.67 vs. 10.1+/ 0.21%; P<0.01), and the methylation sites in CpG islands were significantly reduced. The degree of HHIP methylation showed a negative correlation with the level of mRNA expression (r=-0.693; P<0.01). It can be hypothesized that a high degree of methylation of the HHIP gene promoter CpG islands in gastric cancer tissues and cells causes a decrease in HHIP mRNA expression, which may be involved in the carcinogenesis of gastric cancer. PMID- 25295122 TI - MicroRNA-183 inhibits gastric cancer proliferation and invasion via directly targeting Bmi-1. AB - The aberrant expression of microRNA-183 (miRNA/miR-183) has been found to be involved in numerous tumor types. However, the role of miR-183 in gastric cancer pathology is unclear and requires investigation. In the present study, the miR 183 expression levels of gastric cancer cell lines and tissues obtained from gastric cancer patients were measured by reverse transcription quantitative polymerase chain reaction analysis. The effect of miR-183 on gastric cancer cell proliferation and invasion was evaluated using MTT, colony formation and Transwell assays. The target of miR-183 was identified and confirmed using a luciferase activity assay. The results revealed that miR-183 was significantly downregulated in gastric cancer cells compared with GES-1 normal gastric epithelial cells. In addition, miR-183 was reduced in gastric cancer tissues compared with adjacent normal tissues. The ectopic expression of miR-183 significantly inhibited gastric cancer cell proliferation, colony formation and invasion. Bmi-1 was also confirmed as a downstream target of miR-183 in the gastric cancer cells by western blot analysis and luciferase activity assays. In conclusion, miR-183 is downregulated in gastric cancer cells and tissues, and inhibits gastric cancer cell proliferation and invasion by targeting Bmi-1. Therefore, targeting miR-183 may be a potential therapeutic strategy in gastric cancer patients. PMID- 25295123 TI - Effectiveness and efficacy of minimally invasive lung volume reduction surgery for emphysema. AB - Lung emphysema is a chronic, progressive and irreversible destruction of the lung tissue. Besides non-medical therapies and the well established medical treatment there are surgical and minimally invasive methods for lung volume reduction (LVR) to treat severe emphysema. This report deals with the effectiveness and cost effectiveness of minimally invasive methods compared to other treatments for LVR in patients with lung emphysema. Furthermore, legal and ethical aspects are discussed. No clear benefit of minimally invasive methods compared to surgical methods can be demonstrated based on the identified and included evidence. In order to assess the different methods for LVR regarding their relative effectiveness and safety in patients with lung emphysema direct comparative studies are necessary. PMID- 25295124 TI - Clinical effectiveness and cost-effectiveness of fissure sealants in children and adolescents with a high caries risk. AB - In Germany, the application of resin-based pits and fissures sealants on the occlusal surfaces of permanent molars is part of individual prophylaxis for children and adolescents between six and 18 years. The individual prophylaxis is covered by the Statutory Health Insurance since 1993. The report addresses questions on medical effectiveness, cost-effectiveness, as well as ethical, social, and legal implications of pit and fissure sealants in preventing dental caries for children and adolescents at high caries risk. The results of the studies indicate a protective effect of pit and fissure sealants, particularly for children and adolescents at high caries risk. Additionally, the economic evaluation suggests a tendency for cost savings in this group. Nevertheless, a general expansion of the intervention cannot be recommended. All studies show a risk of bias in favour of pit and fissure sealing and a limited transferability to the German health care system. Studies included in the economic evaluation revealed methodological flaws. Both the economic models and primary studies do not provide reliable results. PMID- 25295125 TI - Depolarization of Cellular Resting Membrane Potential Promotes Neonatal Cardiomyocyte Proliferation In Vitro. AB - Cardiomyocytes (CMs) undergo a rapid transition from hyperplastic to hypertrophic growth soon after birth, which is a major challenge to the development of engineered cardiac tissue for pediatric patients. Resting membrane potential (Vmem) has been shown to play an important role in cell differentiation and proliferation during development. We hypothesized that depolarization of neonatal CMs would stimulate or maintain CM proliferation in vitro. To test our hypothesis, we isolated postnatal day 3 neonatal rat CMs and subjected them to sustained depolarization via the addition of potassium gluconate or Ouabain to the culture medium. Cell density and CM percentage measurements demonstrated an increase in mitotic CMs along with a ~2 fold increase in CM numbers with depolarization. In addition, depolarization led to an increase in cells in G2 and S phase, indicating increased proliferation, as measured by flow cytometry. Surprisingly depolarization of Vmem with either treatment led to inhibition of proliferation in cardiac fibroblasts. This effect is abrogated when the study was carried out on postnatal day 7 neonatal CMs, which are less proliferative, indicating that the likely mechanism of depolarization is the maintenance of the proliferating CM population. In summary, our findings suggest that depolarization maintains postnatal CM proliferation and may be a novel approach to encourage growth of engineered tissue and cardiac regeneration in pediatric patients. PMID- 25295126 TI - A multicentre analysis of abiraterone acetate in Canadian patients with metastatic castration-resistant prostate cancer. AB - INTRODUCTON: The COU-AA-301 trial showed that abiraterone acetate (abiraterone), an oral cytochrome p450 CYP17 inhibitor, improved survival for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel. To better understand the non-clinical trial experience with abiraterone, we undertook a multicentre retrospective analysis of Canadian mCRPC patients treated with abiraterone. METHODS: Consecutive patients with mCRPC who received abiraterone post-docetaxel were identified using centralized pharmacy records. These patients came from 5 Canadian tertiary cancer centres. Patients who received abiraterone for approved indications were included. Demographics, prognostic factors, treatment outcomes and adverse events were abstracted. RESULTS: We included 187 patients who initiated abiraterone between January 2011 and June 2012. The median age at diagnosis and abiraterone start was 65 and 73 years, respectively. Seventy-three (39%) patients had metastatic disease at diagnosis. The Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 and 3 was noted in 17, 96, 39 and 8 patients, respectively. The median prostate-specific antigen (PSA) at abiraterone start was 132, with a median PSA doubling time of 2.8 months. The median follow-up of patients still on active follow-up was 13 months. The proportion of patients achieving a >=50% PSA reduction was 64/177 (36%). PSA progression-free survival was 3.5 months (95% confidence interval [CI], 3.0, 4.0). Median overall survival from start of abiraterone was 11 months (95% CI, 8.0, 13) and 38 months (95% CI, 31, 41) from date of mCRPC. Anemia and fatigue were the most commonly reported adverse events. CONCLUSIONS: This study carries the inherent limitations of a retrospective chart review. The outcomes in this series of men treated with abiraterone in a non trial setting were expected, considering previous clinical trials. Our results, therefore, support the generalizability of the COU-AA-301 study results. PMID- 25295127 TI - Flexible ureteroscopic renal stone extraction during laparoscopic ureterolithotomy in patients with large upper ureteral stone and small renal stones. AB - INTRODUCTION: We describe laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy. We describe its efficacy through a laparoscopic port and a ureterotomy site in patients with large upper ureteral stone and small renal stones. METHODS: Between January 2009 and February 2012, we performed laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy in 11 patients who had upper ureteral and renal stones. The retroperitoneal approaches were used in all patients using 3-4 trocars. RESULTS: All procedures were performed successfully without significant complications. Mean operative time was 78.5 minutes (range: 52-114 minutes). The mean size of ureteral stone was 19.91 mm (range: 15-25 mm). In addition, 25 renal stones (mean size 7.48 mm, range: 2-12 mm) were removed from 11 patients. The mean length of hospital stay was 3.5 days (range: 2-6 days). CONCLUSIONS: Laparoscopic ureterolithotomy with renal stone extraction using a stone basket under flexible ureteroscopy can be considered one of treatment modalities for patients with large upper ureteral stones accompanied by renal stones who are indicated in laparoscopic ureterolithotomy. PMID- 25295128 TI - Plasmakinetic vaporization versus plasmakinetic resection to treat benign prostatic hyperplasia: A prospective randomized trial with 1 year follow-up. AB - INTRODUCTION: We evaluate the efficacy and outcomes of plasma-kinetic vaporization (PKVP) and plasmakinetic resection (PKR) to treat benign prostatic hyperplasia (BPH). METHODS: A total of 183 patients with BPH underwent plasma kinetic prostatic surgery between 2008 and 2012 at Kars State Hospital and Kafkas University Faculty of Medicine, Turkey. After clinical and preoperative evaluation, the patients were randomized to PKRP or PKVP groups sequentially by using computer-generated numbers. Group 1 included 96 patients treated with PKR. Group 2 included 87 patients treated with PKVP. Patients in both groups were compared in terms of hemoglobin drop, operation time, catheter duration, reobstruction, incontinence and recatheterization. RESULTS: When we compared the maximum flow rates (Qmax values) at the 12th month, there was no statistical difference between 2 groups. Group 1 had a mean Qmax value of 17.92 +/- 3.819 and Group 2 had a 18.15 +/- 3.832 value (p > 0.05). There was a statistical difference between the groups in terms of hemoglobin drop, catheter duration and operation time. The mean catheter duration in Group 1 was 3.74 +/- 1.049 days, and in Group 2 it was 2.64 +/- 0.849 days (p < 0.05). Operation time was statistically longer in Group 2 (PKVP) and hemoglobin drop was statistically higher in Group 1 (PKR). CONCLUSION: PKVP for BPH is safe and effective. When compared with PKRP, it provides a significantly shorter catheter duration and less bleeding due to hemostasis control with similar IPSS and Qmax improvements after 1 year. PMID- 25295129 TI - Comorbidity and nutritional indices as predictors of morbidity after transurethral procedures: A prospective cohort study. AB - INTRODUCTION: Preoperative scores are widely used predictors of complications after major surgery. These scores, however, are not widely used in transurethral procedures. The aim of this study was to assess the value of the Charlson Comorbidity Index (CCI), the age-adjusted CCI, the American Society of Anesthesiologist score (ASA) and the Nutritional Risk Score (NRS) in predicting early morbidity after transurethral urological procedures. METHODS: Consecutive patients undergoing transurethral resection of the bladder or the prostate were prospectively enrolled. The scores were calculated preoperatively; 30-day complications were prospectively recorded according to the Dindo-Clavien classification. Univariate logistic regression was performed to investigate the value of each score and of other factors (i.e., age, sex, body mass index, anemia, smoking habit, type of operation and anaesthesia) as predictors of complications. A multivariate model was then calculated using these predictors. RESULTS: Overall, 197 patients were included. The mean age was 72 (standard deviation +/- 10). In total, 26.9% patients had at least 1 complication. Using univariate analysis, we found that each score significantly predicted complications. In multivariate analysis, only the ASA (odds ration [OR] 2.11; 95% confidence interval [CI] 1.01-4.43) and the NRS (OR 2.42; 95% CI 1.56-3.74) remained independent predictors. The best model incorporated ASA, NRS and gender, and predicted morbidity with an area under the curve of 76%. Our study's main limitations are population heterogeneity and limited sample size. CONCLUSION: The ASA and the NRS are important and independent determinants of early morbidity after transurethral procedures. The use of these indices may assist clinicians in the decision-making process to balance the possible benefits of transurethral procedures with the potential risks. PMID- 25295130 TI - Morbidity and functional mid-term outcomes using Prolift pelvic floor repair systems. AB - INTRODUCTION: We assess midterm morbidity and functional outcomes using the Prolift (Gynecare/Ethicon, Somerville, NJ) system and identify potential related risk factors. The Prolift mesh system to treat genital prolapse was introduced in 2005. It was withdrawn from the market in early 2013 after rising doubts about safety. METHODS: Over a 7-year period, we retrospectively analyzed a cohort of 112 consecutive patients who underwent the Prolift procedure since 2006. Intraoperative and postoperative complications, anatomical and functional outcomes were recorded. RESULTS: The median follow-up was 49.5 months (range: 16 85). The mean age was 64.7 +/- 10.9 years (range: 40-86). Of the 112 patients, 74 patients had stage 3 (66.1%) and 8 patients had stage 4 (7.14%) vaginal prolapse. Prolift surgery was performed for pro-lapse recurrence for 26 patients (23.2%). Total mesh was used in 32 patients (29%), an isolated anterior mesh in 57 patients (51%) and an isolated posterior mesh in 23 patients (21%). Concomitant surgical procedures were performed for 44 patients (39.3%). Overall, 72% (18/25) of the complications were managed medically. We reported a failure rate of 8% (n = 9) occurring after a median follow-up of 9.5 months (range: 1-45). Among the 64 patients who had preoperative sexual activity (57.1%), de novo dyspareunia occurred in 9 patients (16.07%). We extracted predictive factors concerning failure, complications and sexuality. CONCLUSION: Despite its market withdrawal, the Prolift system was associated with good midterm anatomic outcomes and few severe complications. Long-term follow-up data are still lacking, but surgeons and patients may be reassured. PMID- 25295131 TI - Clinical comparision of intravesical hyaluronic acid and hyaluronic acid chondroitin sulphate therapy for patients with bladder pain syndrome/interstitital cystitis. AB - INTRODUCTION: Patients with a history of bladder pain syndrome/interstitial cystitis (BPS/IC) and who responded poorly or unsatisfactorily with previous treatment were compared taking intravesical hyaluronic acid (HA) or hyaluronic acid-chondroitin sulphate (HA-CS). METHODS: Patients were treated with intravesical instillation with 50 mL sterile sodium hyalurinic acid (Hyacyst, Syner-Med, Surrey, UK) (n = 32) and sodium hyaluronate 1.6% sodium chondroitin sulphate 2% (Ialuril, Aspire Pharma, UK) (n = 33). Intravesical instillations were performed weekly in first month, every 15 days in the second month and monthly in third and fourth months, for a total of 8 doses. Patients were evaluated using a visual analog pain scale (VAS), interstitial cystitis symptom index (ICSI), interstitial cystitis problem index (ICPI), voiding diary for frequency/nocturia, cystometric bladder capacity and voided volume at the beginning and at 6 months. All patients had a potassium sensitivity test (PST) initially. Wilcoxon and Mann-Whitney U tests were used for statistical analysis. RESULTS: In total, 53 patients met the study criteria. There were 30 patients in the HA-CS group (mean age: 48.47) and 23 patients in the HA group (mean age: 49.61) (p > 0.05). The initial PST was positive in 71.7% patients (38/53) overall with no difference between groups (p > 0.05). Responses for VAS, ICCS, ICPS, 24 hour frequency/nocturia statistically improved in both groups at 6 months. There was no significant difference in symptomatic improvement (p > 0.05). Eight patients had mild adverse events. CONCLUSION: HA and HA/CS instillation can be effective in BPS/IC patients who do not respond to conservative treatment. An important limitation of our study is that the HA dosage of the 2 treatment arms were different. It would be more appropriate with same HA dosage in both groups; however, there was no commercially available glycosaminoglycan (GAG) substance with same HA dosage for single and combination therapy. Large, long-term randomized studies are required to determine if there is a difference between these treatments. PMID- 25295132 TI - Utility and cost-effectiveness of uroflowmetry in a busy pediatric urology practice. AB - INTRODUCTION: Uroflowmetry (UF) is frequently employed in daily pediatric urology practice for diagnostic and follow-up purposes. We assess the utility and cost effectiveness of UF in the management of patients seen at a tertiary care centre. METHODS: We retrospectively reviewed the charts of consecutive patients who had a UF between January 1, 2010 and March 31, 2010. We collected data on demographics, diagnosis, UF parameters and the impact of the UF on management. The impact on management was defined as indication for surgery, introduction of new medications and bladder retraining based on clinical and UF findings. RESULTS: In total, 524 patients were included in the study. In 63 (12%) patients, UF was performed as part of the evaluation at the first clinic appointment. The most common diagnoses were voiding dysfunction (VD) 41%, hypospadias 26%, vesicoureteric reflux (VUR) 16%, monosymptomatic nocturnal enuresis (NE) 8%, posterior urethral valves 5% and meatal stenosis (MS) 4%. In the VD group, UF contributed to a management decision in 25.2% of patients. In the MS group, surgical intervention was based on symptoms and supported by the UF in 41% of patients; in the PUV group, 50% of patients demonstrated high (>20 cc) post-void residual, which aided in management decisions. In contrast, there were virtually no changes in management supported by the UF in the NE, VUR and hypospadias groups. Overall, UF parameters had a direct influence in the management decisions in only 67 (12.8%) patients. Nonetheless, a repeat test was ordered for 44.5% of patients. CONCLUSIONS: In an era of financial restraints and in a busy tertiary pediatric urology practice, judicious use of UF for specific indications may translate into a more cost effective use of time and resources. As expected, patients with VD were the ones that benefited most from the test, as did patients with symptomatic MS and PUV. PMID- 25295133 TI - Cost-effectiveness analysis reveals microsurgical varicocele repair is superior to percutaneous embolization in the treatment of male infertility. AB - INTRODUCTION: Varicoceles are a common cause of male infertility; repair can be accomplished using either surgical or radiological means. We compare the cost effectiveness of the gold standard, the microsurgical varicocele repair (MV), to the options of a nonmicrosurgical approach (NMV) and percutaneous embolization (PE) to manage varicocele-associated infertility. METHODS: A Markov decision analysis model was developed to estimate costs and pregnancy rates. Within the model, recurrences following MV and NMV were re-treated with PE and recurrences following PE were treated with repeat PE, MV or NMV. Pregnancy and recurrence rates were based on the literature, while costs were obtained from institutional and government supplied data. Univariate and probabilistic sensitivity-analyses were performed to determine the effects of the various parameters on model outcomes. RESULTS: Primary treatment with MV was the most cost-effective strategy at $5402 CAD (Canadian)/pregnancy. Primary treatment with NMV was the least costly approach, but it also yielded the fewest pregnancies. Primary treatment with PE was the least cost-effective strategy costing about $7300 CAD/pregnancy. Probabilistic sensitivity analysis reinforced MV as the most cost-effective strategy at a willingness-to-pay threshold of >$4100 CAD/pregnancy. CONCLUSIONS: MV yielded the most pregnancies at acceptable levels of incremental costs. As such, it is the preferred primary treatment strategy for varicocele-associated infertility. Treatment with PE was the least cost-effective approach and, as such, is best used only in cases of surgical failure. PMID- 25295134 TI - Penile injuries: A 10-year experience. AB - We report our 10-year experience with penile injuries. We retrospectively reviewed the records of 156 cases of male external genitalia injuries between May 2002 and December 2012. Of these, only 26 patients presented without urethral injuries and were included in this study. Patients were divided into 4 groups: Group 1 (n = 12) with patients with penile fractures injuries; Group 2 (n = 5) with patients with penile amputation injuries; Group 3 (n = 2) with patients with penile penetrating injuries; and Group 4 (n = 7) with patients with penile soft tissue injuries. Grading of injury was done using the American Association for the Surgery of Trauma (AAST)-Organ injury scale of penile injury. Penile injuries without urethral injuries are urological emergencies which require immediate attention. PMID- 25295135 TI - Management of post-radiation therapy complications among prostate cancer patients: A case series. AB - INTRODUCTION: Treating prostate cancer with radiation therapy (RT) is a viable option, albeit with its own profile of complications. We describe a unique Canadian report of a single surgeon (RJB) experience in the management of complex post-prostate cancer RT complications. METHODS: We retrospectively analyzed patients who had previously received external beam radiation (XRT) or brachytherapy (BT) for prostate cancer referred to a single surgeon for persistent urologic related difficulties between 2005 and 2010. We used the Radiation Therapy Oncology Group (RTOG) morbidity grading system to assign each patient a 1 to 5 grade for their greatest complication. RESULTS: In total, 15 patients were identified with a total of 43 RT-related complications. Of these 43 complications, 19 presented with obstruction, 8 with radiation failure or new bladder cancer, 6 with hematuria, 5 with intractable incontinence, and 5 with urinary tract infections. These patients required several investigations prior to treatment. Treatment of these complications used surgical, local and medical approaches. In the end, 1 patient had total incontinence, 3 improved their incontinence, 3 had self-catheterization and dilation, 1 voided well, 3 underwent cystectomy with ileo-conduits, 2 had chronic hematuria, and 2 passed away. CONCLUSION: These patients are heavily investigated and require significant resources, including patient visits, diagnostics and treatment modalities to optimize their condition. Cure is not always possible, but the aim to improve quality of life should guide management. PMID- 25295136 TI - Pathologic analysis, diagnosis and treatment of adrenal myelolipoma. AB - With the widespread use of non-invasive imaging modalities, the incidental detection of myelolipoma has become more common. We analyze the clinical data of 4 typical cases of unilateral adrenal myelolipomas, including 1 hormonally inactive patient and 3 hormonally active cases with hyperaldosteronemia, hypercortisolism and hyperandrogenemia. Obvious differences were found in the pathological sections. To our knowledge, this is the first article discussing the etiology of adrenal myelolipoma from pathologic analyses. PMID- 25295137 TI - Large bowel infarct following antegrade scrotal sclerotherapy for varicocele: A case report. AB - Varicocele is the main cause of male infertility. Treatment stops continuous damage to spermatogenesis, thereby potentially improving fertility. Among all the available procedures, the ante-grade scrotal sclerotherapy (ASS), a combined radiological-surgical approach first introduced by Tauber, is gaining more popularity due to its minimal invasiveness. We report the case of a 35-year old man who was subjected to a colonic resection after antegrade scrotal sclerotherapy for varicocele. The procedure was necessary due to the embolization of venous anastomosis between the spermatic and mesenteric veins, which were not detectable at the preoperative phlebography. PMID- 25295138 TI - A case with fistula formation between a perinephric retroperitoneal abscess, a ureter and a descending colon: Successful outcome after conservative management. AB - A 72-year-old man diagnosed with hydronephrosis and perinephric abscess because of an impacted urinary stone in the left uretero-pelvic junction was admitted to hospital with high-grade fever. The insertion of a percutaneous drain improved his general condition. Then, imaging from the percutaneous drainage tube revealed a fistula formation between the cavity of the perinephric retroperitoneal abscess, the descending colon, and the left renal pelvis. The patient received conservative management, including insertion of a percutaneous drain, discontinuation of oral intake and antimicrobial chemotherapy. Three days after the percutaneous drainage and discontinuation of oral intake, imaging revealed no apparent fistula. Fistula formation between a perinephric abscess and the descending colon is very rare; this is the first case of a long-term favourable outcome by conservative management. PMID- 25295139 TI - Painful erections secondary to rare epithelioid hemangioma of the penis. AB - Epithelioid hemangioma is a rare benign vascular tumour that atypically involves the penis and usually presents as a painful nodule. A 35-year-old man presented with a 5-month history of painful erections without a clinically apparent lesion or deformity. Magnetic resonance imaging (MRI) with pharmacologically induced erection demonstrated a 1.3-cm nodular lesion deep to the skin at the base of his penis. Following local excision of the lesion, which was diagnosed as an epithelioid hemangioma, the patient was symptom free. This case demonstrates a rare etiology of painful erections with a unique presentation. To the authors' knowledge, it is also the first report of MRI with intracavernosal injection of trimix to assess for a specific cause of painful erections. PMID- 25295140 TI - Embryology and adult urology - Not always mutually exclusive: A case report on true hermaphroditism at an adult urology clinic. AB - True hermaphrodite (TH) is one of the rarest varieties of disorders of sexual differentiation. Most patients present early in the life and are managed by pediatricians. We present a rare case of an adult TH which was first diagnosed by a urologist. We discuss the pathology of TH and its clinical relevance. Knowledge and awareness of embryology are vital to all specialties. PMID- 25295141 TI - First case of invasive squamous cell carcinoma in a stoma of a Monti ileovesicostomy. AB - We report a very rare case of invasive squamous cell carcinoma (SCC) in the abdominal stoma of a Monti ileovesicostomy. Our patient underwent an uncomplicated Monti ileovesicostomy at age 16 for a neurogenic bladder. She presented 10 years later with difficulty catheterizing the stoma. A biopsy of peristomal tissue showed moderately differentiated SCC. A cystoscopy did not reveal any bladder tumours or suspicious lesions. A computed tomography (CT) scan of the abdomen and pelvis did not demonstrate metastasis. The patient underwent a complete en bloc resection of the stomal site, the Monti, a partial cuff of bladder, and 2 loops of bowel that were adherent to the Monti. Final pathology revealed pure invasive SCC arising around the stoma and negative surgical margins. Six months later, a follow-up CT scan showed no evidence of malignancy, while a cystoscopy revealed a small erythematous area in the posterior bladder wall. Urinary cytology was positive for SCC. Transurethral resection of the erythematous lesion with random bladder biopsies showed SCC in situ in the erythematous lesion and right lateral bladder wall. Staging workup was negative. The patient subsequently underwent a radical cystectomy and ileal conduit diversion with bilateral pelvic lymph node dissection. Final pathology on cystectomy specimen was SCC in situ without evidence of invasive carcinoma. The patient has remained in remission at the 3-year follow-up. PMID- 25295142 TI - Renal solitary fibrous tumour: A rare pathological entity. AB - A solitary fibrous tumour (SFT) is a rare mesenchymal cell neoplasm that can develop at any site. SFT of the kidney is extremely rare. Recently, we had a case of solitary fibrous tumour involving the left kidney in a 71-year-old female patient. The SFT was incidentally found by imaging modalities at the time of a physical workup. Computed tomography and retrograde pyelography showed a 4 * 3.5 * 4-cm nodular mass in the middle poles of the left kidney adjacent to the renal pelvis. A laparoscopic radical resection of the left kidney was performed. The tumour was well-circumscribed and composed of a mixture of spindle cells; microscopically, we found dense collagenous bands. Immunohistochemical studies showed strong reactions with CD34, bcl-2 and CD99. A nuclear positivity with Ki 67 was observed in less than 1% of cells. The tumour was negative for desmin, SMA and CD117. Histopathological and immunohistochemical studies confirmed the diagnosis of a solitary fibrous tumour. PMID- 25295143 TI - [Not Available]. PMID- 25295144 TI - [Not Available]. PMID- 25295145 TI - [Not Available]. PMID- 25295146 TI - Withania coagulans fruit extract reduces oxidative stress and inflammation in kidneys of streptozotocin-induced diabetic rats. AB - The present study was carried out to investigate the changes in oxidative and inflammatory status in streptozotocin-induced diabetic rat's kidneys and serum following treatment with Withania coagulans, a popular herb of ethnomedicinal significance. The key markers of oxidative stress and inflammation such as inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) and immunoregulatory cytokines (IL-4 and IFN-gamma) were increased in kidneys along with significant hyperglycemia. However, treatment of four-month diabetic rats with Withania coagulans (10 mg/kg) for 3 weeks significantly attenuated hyperglycemia and reduced the levels of proinflammatory cytokines in kidneys. In addition, Withania coagulans treatment restored the glutathione levels and inhibited lipid peroxidation along with marked reduction in kidney hypertrophy. The present study demonstrates that Withania coagulans corrects hyperglycemia and maintained antioxidant status and reduced the proinflammatory markers in kidneys, which may subsequently reduce the development and progression of renal injury in diabetes. The results of the present study are encouraging for its potential use to delay the onset and progression of diabetic renal complications. However, the translation of therapeutic efficacy in humans requires further studies. PMID- 25295148 TI - Correlation of multiple sclerosis (MS) incidence trends with solar and geomagnetic indices: Time to revise the method of reporting MS epidemiological data. AB - BACKGROUND: Recently, we introduced solar related geomagnetic disturbances (GMD) as a potential environmental risk factor for multiple sclerosis (MS). The aim of this study was to test probable correlation between solar activities and GMD with long-term variations of MS incidence. METHODS: After a systematic review, we studied the association betwee n alterations in the solar wind velocity (VSW) and planetary A index (AP, a GMD index) with MS incidence in Tehran and western Greece, during the 23(rd) solar cycle (1996-2008), by an ecological-correlational study. RESULTS: We found moderate to strong correlations among MS incidence of Tehran with VSW (rS = 0.665, P = 0.013), with 1 year delay, and also with AP (rS = 0.864, P = 0.001) with 2 year delay. There were very strong correlations among MS incidence data of Greece with VSW (r = 0.906, P < 0.001) and with AP (r = 0.844, P = 0.001), both with 1 year lag. CONCLUSION: It is the first time that a hypothesis has introduced an environmental factor that may describe MS incidence alterations; however, it should be reminded that correlation does not mean necessarily the existence of a causal relationship. Important message of these findings for researchers is to provide MS incidence reports with higher resolution for consecutive years, based on the time of disease onset and relapses, not just the time of diagnosis. Then, it would be possible to further investigate the validity of GMD hypothesis or any other probable environmental risk factors. PMID- 25295147 TI - Multiple sclerosis and pregnancy; What a neurologist may be asked for? AB - Multiple sclerosis (MS) is the most common chronic autoimmune demyelinating disorder of the central nervous system (CNS) which preferentially involves young women in early child bearing age. Opposite to traditional view emphasized on discouraging female patients from enduring pregnancy, recent investigations showed that pregnancy-related physiological alterations, especially during the third trimester, reduce the annual relapse rate of multiple sclerosis up to 80% which is comparable with conventional disease modifying drugs. Nowadays, expert's viewpoint is that female patients should not be discouraged from having children. Nonetheless, who and when should be allowed to endure gestational period is a complex decision which should be taken for every patient individually. It necessitates that neurologists be aware of updated information regarding pregnancy-related fetal and maternal considerations in patients with MS. In this brief review, it was tried to discuss this topic according to available data and guideline-based recommendations. PMID- 25295149 TI - Interleukin-6, a reliable prognostic factor for ischemic stroke. AB - BACKGROUND: Interleukin-6 (IL-6) is one of the inflammatory mediators characterized by elevated levels in ischemic stroke (IS) patients. The present study set out to assess the role of IL-6, as a marker for inflammation, in the severity and prognosis of acute IS. METHODS: In a cross-sectional descriptive study, 45 patients with acute IS were selected. Patients with their first day of stroke were included in the study. National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) for stroke severity were evaluated on Days 1, 5, 90, and 365. Serum IL-6 level was measured by enzyme-linked immunosorbent assay (ELISA) on days 1 and 5. RESULTS: In the present study, 45 patients with a mean age of 77.6 +/- 4.9 including 32 (71%) men and 13 (28.9%) women were studied. Death occurred in 2 (4.4%) patients before discharge from the hospital; the others, be that as it may, followed the study until Day 365 with a mortality rate of 6 (13.3%). A positive significant correlation was found between IL-6, and NIHSS and mRS of the patients from the time of admission to the end of the follow-up period (P < 0.001, r = 0.6). Moreover, there was a significant correlation between IL-6 and infarction size in brain magnetic resonance imaging (MRI) scan (P < 0.001, r = 0.7). CONCLUSION: The evidence from the present study suggests that IL-6 contributes to determination of severity of ischemic stroke. In addition, IL-6 concentrations affect clinical outcomes in ischemic stroke. PMID- 25295150 TI - Brain areas impaired in oral and verbal apraxic patients. AB - BACKGROUND: As both oral and verbal apraxia are related to vocal orofacial musculature, this study aimed at identifying brain regions impaired in cases with oral and verbal apraxia. METHODS: In this non-experimental study, 46 left brain damaged subjects (17 females) aged 23-84 years, were examined by oral and verbal apraxia tasks. Impaired and spared Broca's area, insula, and middle frontal gyrus in the left hemisphere were checked from magnetic resonance imaging and computed tomography scans utilizing Talairach Atlas. Data were analyzed using chi-square test. RESULTS: Insula was significantly impaired in both forms of oral and verbal apraxia and different severities and prominent forms of both apraxias (P < 0.05). Broca's area was slightly less involved than insula in two forms of apraxia. CONCLUSION: As the damage of insula was more prominent in both forms of apraxias, it seems that oral and verbal apraxia may have commonalities regarding their underlying brain lesions. PMID- 25295151 TI - The assessment of pragmatics in Iranian patients with right brain damage. AB - BACKGROUND: Pragmatics is appropriate use of language across a variety of social contexts that provides accurate interpretation of intentions. The occurrence of the right hemisphere lesions can interfere with pragmatic abilities, and particularly with the processing of nonliteral speech acts. METHODS: Since the objective of this study was to assess different aspects of pragmatic competence in the right hemisphere damage (RHD) patients, 20 Iranian patients with right hemisphere lesions were examined by adult pragmatic profile (APP) and a novel checklist was introduced for Persian language speaking individuals. Meanwhile, 40 healthy adult individuals, who were age and gender matched with RHD patients, were considered as the control group. After obtaining video records, all subjects were evaluated for 35 pragmatic skills, including 24 verbal, 5 paralinguistic, and 6 nonverbal aspects, by a two-point scale system. RESULTS: Studying RHD patients and their healthy counterparts revealed that the performance by participants with right hemisphere lesions exhibited a high degree of inappropriate pragmatic abilities compared with controls in all domains. Furthermore, RHD patients showed a trend of increasing difficulty in understanding and producing different pragmatic phenomena, including standard communication acts. CONCLUSION: Present results indicated that the right hemisphere lesions significantly affected pragmatic abilities in verbal, paralinguistic and nonverbal aspects. Such a pattern of performance, which is in line with deficits previously reported for RHD, proved the unquestioned role of the right hemisphere in processing nonliteral language. PMID- 25295152 TI - Parkinsonism associated with multiple sclerosis: A report of eight new cases and a review on the literature. AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease that affects the central nervous system. Except tremor, other movement disorders such as Parkinsonism are less frequent in MS. However, some investigations have shown inflammatory and autoimmune aspects of Parkinson's disease. In this study, we report eight new cases of MS who present Parkinson's disease. METHODS: This retrospective population-based study was carried out on Isfahan MS society between April 2003 and July 2012. A total of 3792 patients with MS were surveyed for Parkinson's disease. Parkinson's disease was approved according to "UK Parkinson disease Brain Bank" criteria. Eligible cases were invited to have an interview with a neurologist. MRI was carried out according to the baseline. RESULTS: We identified eight patients (three men and five women) who present MS and Parkinson's disease. The mean (+/-SD) age of onset was 33.3 +/- 6.5 (range: 24-42) years for MS and 39.5 +/- 8.6 (range: 30-55) years for Parkinson's disease patients. In all patients, MS was preceded Parkinson's disease. Parkinson's disease was developed within mean duration of 6.1 +/- 3.4 (range 2-13) years after MS. Focal lesions was shown in six cases, lesions of basal ganglia (BG) in four, lesions of the thalamus in two and lesions of mid-brain in five of cases. In four cases, Parkinsonism occurred before age 40 that is considered as Young Onset Parkinson's disease. CONCLUSION: We reported eight patients with MS and Parkinson's disease. To the best of our knowledge, 34 cases of Parkinsonism associating with MS are reported so far. Parkinsonism is a movement disorder, defines as deep gray matter disorder which lead to dopamine deficiency in BG. Investigations have shown that MS could affect deep gray matter structures. Demyelinated lesions in MS and consequence axonal loss in BG and/or nigrostriatal pathway may be responsible for Parkinsonism manifestations in such cases. PMID- 25295153 TI - Comparison of the health-related quality of life between epileptic patients with partial and generalized seizure. AB - BACKGROUND: Epilepsy is defined as recurrent unprovoked febrile seizures, which cause disability in patients. This study aims to assess the health-related quality-of-life (QOL) in epileptic patients in Fars Province, southern Iran. METHODS: One-hundred epileptic patients, above 18 years, referred to Shiraz University of Medical Sciences affiliated clinics, were included. The QOL of patients with generalized and partial seizure were assessed using the Iranian valid and reliable Sf-36 questionnaire. Patients' socio-demographic and their disease features were also compared with each other using a questionnaire. RESULTS: In partial epilepsy group (n = 24), the married patients in social functioning (SF) aspect of QOL (64.42 +/- 14.29) (P = 0.024), the patients on antiepileptic drugs (AEDs) monotherapy in both physical functioning (PF) (88.75 +/- 11.57) (P = 0.030) and SF (75.00 +/- 6.68) (P = 0.022) aspects, the employed patients in PF aspect of QOL (P = 0.023) (91.87 +/- 8.83) and those with high income in mental health aspect of QOL (P = 0.036 and correlation coefficient = 0.413) got better scores compared with the partial epileptic patients who were single, on polytherapy, unemployed and had low to moderate income. In generalized epilepsy group (n = 76), patients on AEDs monotherapy in PF aspect of QOL (P = 0.025) (78.33 +/- 24.36) and employed patients in vitality aspect (P = 0.023) (57.00 +/- 28.25) had better scores. Data were analyzed using SPSS for windows. CONCLUSION: Epilepsy can affect patient's life in a number of ways such as their lives, marriage, occupation, and education. We can encourage patients to find a partner, continue higher education and try to find a job. PMID- 25295154 TI - Decompressive craniectomy after unsuccessful intravenous thrombolysis of malignant cerebral infarction. AB - BACKGROUND: Intravenous recombinant tissue plasminogen activator (rt-PA) is an approved treatment for acute ischemic stroke within 4.5 h of symptoms onset. Decompressive craniectomy (DC) has been shown as an effective therapeutic modality in malignant middle cerebral artery (MCA) infarction. As rt-PA could result in hemorrhagic complication during or after any surgery DC may be associated with severe bleeding after intravenous thrombolysis. CASE DESCRIPTION: A 57-year-old woman was presented 90 min after the sudden onset of left hemiplegia. Despite intravenous thrombolytic therapy, she lost consciousness within 48 h and brain CT scan showed a right malignant MCA infarction associated with a small bleeding. DC was performed without any complication. The patient improved dramatically. CONCLUSION: DC could be done safety for malignant MCA infarction after unsuccessful intravenous thrombolytic therapy even the later was complicated with intra-infarction hemorrhage. PMID- 25295155 TI - Fatigue, depression, and physical impairment in multiple sclerosis. AB - BACKGROUND: Fatigue, depression, and physical impairment are common among multiple sclerosis (MS) patients. The aim of this study was to determine the relationship between depression, physical impairment, and fatigue in an Iranian MS cohort. METHODS: Fifty consecutive relapsing-remitting MS patients and 50 age- and sex-matched healthy controls (HCs) were recruited from Sina Rehabilitation Clinic, Tehran, Iran. The depression substance of Hospital Anxiety and Depression Scale (HADS), Expended Disability Status Scale, and Fatigue Severity Scale questionnaires were used to assess depression, physical impairment, and fatigue, respectively. RESULTS: This study included 38 (76%) females and 12 (24%) males in both patients and HC groups. The depression substance of the HADS in MS and HCs showed a mean value of 1.92 +/- 0.80 and 1.17 +/- 0.38, respectively (P < 0.001). Pearson's correlation analyses showed that in the MS group depression was associated with fatigue (r = 0.54, P = 0.01), but not with physical impairment (r = 0.16, p = 0.01), while fatigue was associated with both depression (r = 0.54, P = 0.01) and physical impairment (r = 0.36, P = 0.01). Depression in HCs group was also associated with fatigue (r -0.64, P = 0.01). CONCLUSION: Fatigue is associated with both depression and physical impairment, and an intervention in one of these conditions might improve others. PMID- 25295156 TI - Valproate adverse effects on creatine metabolism and transport in a patient under drug therapy. PMID- 25295157 TI - Hot cross bun sign in a case with multisystem atrophy. PMID- 25295159 TI - Structural abnormality of the corticospinal tract in major depressive disorder. AB - BACKGROUND: Scientists are beginning to document abnormalities in white matter connectivity in major depressive disorder (MDD). Recent developments in diffusion weighted image analyses, including tractography clustering methods, may yield improved characterization of these white matter abnormalities in MDD. In this study, we acquired diffusion-weighted imaging data from MDD participants and matched healthy controls. We analyzed these data using two tractography clustering methods: automated fiber quantification (AFQ) and the maximum density path (MDP) procedure. We used AFQ to compare fractional anisotropy (FA; an index of water diffusion) in these two groups across major white matter tracts. Subsequently, we used the MDP procedure to compare FA differences in fiber paths related to the abnormalities in major fiber tracts that were identified using AFQ. RESULTS: FA was higher in the bilateral corticospinal tracts (CSTs) in MDD (p's < 0.002). Secondary analyses using the MDP procedure detected primarily increases in FA in the CST-related fiber paths of the bilateral posterior limbs of the internal capsule, right superior corona radiata, and the left external capsule. CONCLUSIONS: This is the first study to implicate the CST and several related fiber pathways in MDD. These findings suggest important new hypotheses regarding the role of CST abnormalities in MDD, including in relation to explicating CST-related abnormalities to depressive symptoms and RDoC domains and constructs. PMID- 25295160 TI - Lysosomal drug sequestration as a mechanism of drug resistance in vascular sarcoma cells marked by high CSF-1R expression. AB - BACKGROUND: Human angiosarcoma and canine hemangiosarcoma are thought to arise from vascular tissue or vascular forming cells based upon their histological appearance. However, recent evidence indicates a hematopoietic or angioblastic cell of origin for these tumors. In support of this idea, we previously identified an endothelial-myeloid progenitor cell population with high expression of endothelial cell markers and the myeloid cell marker, colony stimulating factor 1 receptor (CSF-1R). Here, we further characterized these cells to better understand how their cellular characteristics may impact current therapeutic applications. METHODS: We performed cell enrichment studies from canine hemangiosarcoma and human angiosarcoma cell lines to generate cell populations with high or low CSF-1R expression. We then utilized flow cytometry, side population and cell viability assays, and fluorescence based approaches to elucidate drug resistance mechanisms and to determine the expression of hematopoietic and endothelial progenitor cell markers. RESULTS: We demonstrated that cells with high CSF-1R expression enriched from hemangiosarcoma and angiosarcoma cell lines are more drug resistant than cells with little or no CSF 1R expression. We determined that the increased drug resistance may be due to increased ABC transporter expression in hemangiosarcoma and increased drug sequestration within cellular lysosomes in both hemangiosarcoma and angiosarcoma. CONCLUSIONS: We identified drug sequestration within cellular lysosomes as a shared drug resistance mechanism in human and canine vascular sarcomas marked by high CSF-1R expression. Taken together, our results demonstrate that studies in highly prevalent canine hemangiosarcoma may be especially relevant to understanding and addressing drug resistance mechanisms in both the canine and human forms of this disease. PMID- 25295161 TI - Ergot alkaloid intoxication in perennial ryegrass (Lolium perenne): an emerging animal health concern in Ireland? AB - Four primary mycotoxicosis have been reported in livestock caused by fungal infections of grasses or cereals by members of the Clavicipitaceae family. Ergotism (generally associated with grasses, rye, triticale and other grains) and fescue toxicosis (associated with tall fescue grass, Festuca arundinacea) are both caused by ergot alkaloids, and referred to as 'ergot alkaloid intoxication'. Ryegrass staggers (associated with perennial ryegrass Lolium perenne) is due to intoxication with an indole-diperpene, Lolitrem B, and metabolites. Fescue associated oedema, recently described in Australia, may be associated with a pyrrolizidine alkaloid, N-acetyl norloline. Ergotism, caused by the fungus Claviceps purpurea, is visible and infects the outside of the plant seed. Fescue toxicosis and ryegrass staggers are caused by Neotyphodium coenophalium and N. lolii, respectively. Fescue-associated oedema has been associated with tall fescue varieties infected with a specific strain of N. coenophialum (AR542, Max P or Max Q). The name Neotyphodium refers to asexual derivatives of Epichloe spp., which have collectively been termed the epichloe fungi. These fungi exist symbiotically within the grass and are invisible to the naked eye. The primary toxicological effect of ergot alkaloid involves vasoconstriction and/or hypoprolactinaemia. Ingestion of ergot alkaloid by livestock can cause a range of effects, including poor weight gain, reduced fertility, hyperthermia, convulsions, gangrene of the extremities, and death. To date there are no published reports, either internationally or nationally, reporting ergot alkaloid intoxication specifically associated with perennial ryegrass endophytes. However, unpublished reports from the Irish Equine Centre have identified a potential emerging problem of ergot alkaloid intoxication with respect to equines and bovines, on primarily perennial ryegrass-based diets. Ergovaline has been isolated in varying concentrations in the herbage of a small number of equine and bovine farms where poor animal health and performance had been reported. Additionally, in some circumstances changes to the diet, where animals were fed primarily herbage, were sufficient to reverse adverse effects. Pending additional information, these results suggest that Irish farm advisors and veterinarians should be aware of the potential adverse role on animal health and performance of ergot alkaloids from perennial ryegrass infected with endophytic fungi. PMID- 25285203 TI - Mutation extraction tools can be combined for robust recognition of genetic variants in the literature. AB - As the cost of genomic sequencing continues to fall, the amount of data being collected and studied for the purpose of understanding the genetic basis of disease is increasing dramatically. Much of the source information relevant to such efforts is available only from unstructured sources such as the scientific literature, and significant resources are expended in manually curating and structuring the information in the literature. As such, there have been a number of systems developed to target automatic extraction of mutations and other genetic variation from the literature using text mining tools. We have performed a broad survey of the existing publicly available tools for extraction of genetic variants from the scientific literature. We consider not just one tool but a number of different tools, individually and in combination, and apply the tools in two scenarios. First, they are compared in an intrinsic evaluation context, where the tools are tested for their ability to identify specific mentions of genetic variants in a corpus of manually annotated papers, the Variome corpus. Second, they are compared in an extrinsic evaluation context based on our previous study of text mining support for curation of the COSMIC and InSiGHT databases. Our results demonstrate that no single tool covers the full range of genetic variants mentioned in the literature. Rather, several tools have complementary coverage and can be used together effectively. In the intrinsic evaluation on the Variome corpus, the combined performance is above 0.95 in F measure, while in the extrinsic evaluation the combined recall performance is above 0.71 for COSMIC and above 0.62 for InSiGHT, a substantial improvement over the performance of any individual tool. Based on the analysis of these results, we suggest several directions for the improvement of text mining tools for genetic variant extraction from the literature. PMID- 25285204 TI - Abnormal hemostatic function one year after orthotopic liver transplantation can be fully attributed to endothelial cell activation. AB - BACKGROUND: The long-term risk of thrombotic and vascular complications is elevated in liver transplant recipients compared to the general population. Patients with cirrhosis are in a hypercoagulable status during and directly after orthotopic liver transplantation, but it is unclear whether this hypercoagulability persists over time. AIM: We aimed to investigate the hemostatic status of liver transplant recipients one year after transplantation. METHODS: We prospectively collected blood samples of 15 patients with a functioning graft one year after orthotopic liver transplantation and compared the hemostatic status of these patients with that of 30 healthy individuals. RESULTS: Patients one year after liver transplantation had significantly elevated plasma levels of von Willebrand factor (VWF). Thrombin generation, as assessed by the endogenous thrombin potential, was decreased in patients, which was associated with increased plasma levels of the natural anticoagulants antithrombin and tissue factor pathway inhibitor. Plasma fibrinolytic potential was significantly decreased in patients and correlated inversely with levels of plasminogen activator inhibitor-1. CONCLUSION: One year after liver transplantation, liver graft recipients have a dysregulated hemostatic system characterised by elevation of plasma levels of endothelial-derived proteins. Increased levels of von Willebrand factor and decreased fibrinolytic potential may (in part) be responsible for the increased risk for vascular disease seen in liver transplant recipients. PMID- 25285207 TI - The effects of extremes of pH on the growth and transcriptomic profiles of three haloarchaea. AB - The halophilic archaea (haloarchaea) live in saline environments, which are found across the globe. In addition to salinity, these niches can be quite dynamic and experience extreme conditions such as low oxygen content, radiation (gamma and UV), pH and temperature. However, of all the naturally occurring stresses faced by the haloarchaea, only one, pH, has not been previously investigated in regard to the changes induced in the transcriptome. Therefore, we endeavored to determine the responses in three haloarchaea: Halorubrum lacusprofundi (Hla), Haloferax volcanii (Hvo), and Halobacterium sp. NRC-1 (NRC-1) to growth under acidic and alkaline pH. Our observations showed that the transcriptomes of Hvo and NRC-1 regulated stress, motility, and ABC transporters in a similar manner, which is in line with previous reports from other prokaryotes when grown in an acidic environment. However, the pattern for Hla was more species specific. For alkaline stress, all three haloarchaea responded in a manner similar to well studied archaea and bacteria showing the haloarchaeal response was general to prokaryotes. Additionally, we performed an analysis on the changes in the transcriptomes of the three haloarchaea when shifting from one pH extreme to the other. The results showed that the transcriptomes of all three haloarchaea respond more similarly when moving from alkaline to acidic conditions compared to a shift in the opposite direction. Interestingly, our studies also showed that individual genes of multiple paralogous gene families ( tbp, tfb, orc/ cdc6, etc.) found in the haloarchaea were regulated under specific stresses thereby providing evidence that they modulate the response to various environmental stresses. The studies described here are the first to catalog the changes in the haloarchaeal transcriptomes under growth in extreme pH and help us understand how life is able to thrive under all conditions present on Earth and, if present, on extraterrestrial bodies as well. PMID- 25285208 TI - shinyMethyl: interactive quality control of Illumina 450k DNA methylation arrays in R. AB - We present shinyMethyl, a Bioconductor package for interactive quality control of DNA methylation data from Illumina 450k arrays. The package summarizes 450k experiments into small exportable R objects from which an interactive interface is launched. Reactive plots allow fast and intuitive quality control assessment of the samples. In addition, exploration of the phenotypic associations is possible through coloring and principal component analysis. Altogether, the package makes it easy to perform quality assessment of large-scale methylation datasets, such as epigenome-wide association studies or the datasets available through The Cancer Genome Atlas portal. The shinyMethyl package is implemented in R and available via Bioconductor. Its development repository is at https://github.com/jfortin1/shinyMethyl. PMID- 25295166 TI - Crystallography and large research infrastructures, a perfect marriage. AB - The role of large-scale neutron and synchrotron facilities in the development of crystallographic research is discussed. PMID- 25295167 TI - Tackling a difficult question: how do crystals of coordination polymers form? AB - Some questions are hard to address, and equally hard to ignore. Recent work by C. Y. Su et al. [Jiang et al. (2014), IUCrJ, 305-317] concerns a highly challenging aspect of crystalline coordination polymers - trying to understand how they form. PMID- 25295168 TI - Accurate H-atom parameters from X-ray diffraction data. AB - The difficulties in defining the positions and thermal parameters for hydrogen atoms using X-ray diffraction data alone are discussed. PMID- 25295170 TI - Electronic materials with a wide band gap: recent developments. AB - The development of semiconductor electronics is reviewed briefly, beginning with the development of germanium devices (band gap E g = 0.66 eV) after World War II. A tendency towards alternative materials with wider band gaps quickly became apparent, starting with silicon (E g = 1.12 eV). This improved the signal-to noise ratio for classical electronic applications. Both semiconductors have a tetrahedral coordination, and by isoelectronic alternative replacement of Ge or Si with carbon or various anions and cations, other semiconductors with wider E g were obtained. These are transparent to visible light and belong to the group of wide band gap semiconductors. Nowadays, some nitrides, especially GaN and AlN, are the most important materials for optical emission in the ultraviolet and blue regions. Oxide crystals, such as ZnO and beta-Ga2O3, offer similarly good electronic properties but still suffer from significant difficulties in obtaining stable and technologically adequate p-type conductivity. PMID- 25295169 TI - Contemporary X-ray electron-density studies using synchrotron radiation. AB - Synchrotron radiation has many compelling advantages over conventional radiation sources in the measurement of accurate Bragg diffraction data. The variable photon energy and much higher flux may help to minimize critical systematic effects such as absorption, extinction and anomalous scattering. Based on a survey of selected published results from the last decade, the benefits of using synchrotron radiation in the determination of X-ray electron densities are discussed, and possible future directions of this field are examined. PMID- 25295171 TI - Application of Patterson-function direct methods to materials characterization. AB - The aim of this article is a general description of the so-called Patterson function direct methods (PFDM), from their origin to their present state. It covers a 20-year period of methodological contributions to crystal structure solution, most of them published in Acta Crystallographica Section A. The common feature of these variants of direct methods is the introduction of the experimental intensities in the form of the Fourier coefficients of origin-free Patterson-type functions, which allows the active use of both strong and weak reflections. The different optimization algorithms are discussed and their performances compared. This review focuses not only on those PFDM applications related to powder diffraction data but also on some recent results obtained with electron diffraction tomography data. PMID- 25295173 TI - Structural disorder and transformation in crystal growth: direct observation of ring-opening isomerization in a metal-organic solid solution. AB - A rare example is reported in which discrete Ag2 L 2 ring and (AgL)infinity chain motifs [L = N,N'-bis(3-imidazol-1-yl-propyl)-pyromellitic diimide] co-crystallize in the same crystal lattice with varying ratios and degrees of disorder. Crystal structures obtained from representative crystals reveal compatible packing arrangements of the cyclic and polymeric isomers within the crystal lattice, which enables them to co-exist within a crystalline solid solution. A feasible pathway for transformation between the isomers is suggested via facile rotation of the coordinating imidazolyl groups. This chemical system could provide a chance for direct observation of ring-opening isomerization at the crystal surface. Mass spectrometry and (1)H NMR titration show a dynamic equilibrium between cyclic and oligomeric species in solution, and a potential crystallization process is suggested involving alignment of precursors directed by aromatic stacking interactions between pyromellitic diimide units, followed by ring-opening isomerization at the interface between the solid and the solution. Both cyclic and oligomeric species can act as precursors, with interconversion between them being facile due to a low energy barrier for rotation of the imidazole rings. Thermogravimetric analysis and variable-temperature powder X-ray diffraction indicate a transition to a different crystalline phase around 120 degrees C, which is associated with loss of solvent from the crystal lattice. PMID- 25295174 TI - Structural basis for the transformation pathways of the sodium naproxen anhydrate hydrate system. AB - Crystal structures are presented for two dihydrate polymorphs (DH-I and DH-II) of the non-steroidal anti-inflammatory drug sodium (S)-naproxen. The structure of DH I is determined from twinned single crystals obtained by solution crystallization. DH-II is obtained by solid-state routes, and its structure is derived using powder X-ray diffraction, solid-state (13)C and (23)Na MAS NMR, and molecular modelling. The validity of both structures is supported by dispersion corrected density functional theory (DFT-D) calculations. The structures of DH-I and DH-II, and in particular their relationships to the monohydrate (MH) and anhydrate (AH) structures, provide a basis to rationalize the observed transformation pathways in the sodium (S)-naproxen anhydrate-hydrate system. All structures contain Na(+)/carboxylate/H2O sections, alternating with sections containing the naproxen molecules. The structure of DH-I is essentially identical to MH in the naproxen region, containing face-to-face arrangements of the naphthalene rings, whereas the structure of DH-II is comparable to AH in the naproxen region, containing edge-to-face arrangements of the naphthalene rings. This structural similarity permits topotactic transformation between AH and DH II, and between MH and DH-I, but requires re-organization of the naproxen molecules for transformation between any other pair of structures. The topotactic pathways dominate at room temperature or below, while the non-topotactic pathways become active at higher temperatures. Thermochemical data for the dehydration processes are rationalized in the light of this new structural information. PMID- 25295172 TI - Expression, purification and crystallization of CTB-MPR, a candidate mucosal vaccine component against HIV-1. AB - CTB-MPR is a fusion protein between the B subunit of cholera toxin (CTB) and the membrane-proximal region of gp41 (MPR), the transmembrane envelope protein of Human immunodeficiency virus 1 (HIV-1), and has previously been shown to induce the production of anti-HIV-1 antibodies with antiviral functions. To further improve the design of this candidate vaccine, X-ray crystallography experiments were performed to obtain structural information about this fusion protein. Several variants of CTB-MPR were designed, constructed and recombinantly expressed in Escherichia coli. The first variant contained a flexible GPGP linker between CTB and MPR, and yielded crystals that diffracted to a resolution of 2.3 A, but only the CTB region was detected in the electron-density map. A second variant, in which the CTB was directly attached to MPR, was shown to destabilize pentamer formation. A third construct containing a polyalanine linker between CTB and MPR proved to stabilize the pentameric form of the protein during purification. The purification procedure was shown to produce a homogeneously pure and monodisperse sample for crystallization. Initial crystallization experiments led to pseudo-crystals which were ordered in only two dimensions and were disordered in the third dimension. Nanocrystals obtained using the same precipitant showed promising X-ray diffraction to 5 A resolution in femtosecond nanocrystallography experiments at the Linac Coherent Light Source at the SLAC National Accelerator Laboratory. The results demonstrate the utility of femtosecond X-ray crystallography to enable structural analysis based on nano/microcrystals of a protein for which no macroscopic crystals ordered in three dimensions have been observed before. PMID- 25295175 TI - New structural forms of a mycobacterial adenylyl cyclase Rv1625c. AB - Rv1625c is one of 16 adenylyl cyclases encoded in the genome of Mycobacterium tuberculosis. In solution Rv1625c exists predominantly as a monomer, with a small amount of dimer. It has been shown previously that the monomer is active and the dimeric fraction is inactive. Both fractions of wild-type Rv1625c crystallized as head-to-head inactive domain-swapped dimers as opposed to the head-to-tail dimer seen in other functional adenylyl cyclases. About half of the molecule is involved in extensive domain swapping. The strain created by a serine residue located on a hinge loop and the crystallization condition might have led to this unusual domain swapping. The inactivity of the dimeric form of Rv1625c could be explained by the absence of the required catalytic site in the swapped dimer. A single mutant of the enzyme was also generated by changing a phenylalanine predicted to occur at the functional dimer interface to an arginine. This single mutant exists as a dimer in solution but crystallized as a monomer. Analysis of the structure showed that a salt bridge formed between a glutamate residue in the N-terminal segment and the mutated arginine residue hinders dimer formation by pulling the N-terminal region towards the dimer interface. Both structures reported here show a change in the dimerization-arm region which is involved in formation of the functional dimer. It is concluded that the dimerization arm along with other structural elements such as the N-terminal region and certain loops are vital for determining the oligomeric nature of the enzyme, which in turn dictates its activity. PMID- 25295176 TI - Room-temperature serial crystallography using a kinetically optimized microfluidic device for protein crystallization and on-chip X-ray diffraction. AB - An emulsion-based serial crystallographic technology has been developed, in which nanolitre-sized droplets of protein solution are encapsulated in oil and stabilized by surfactant. Once the first crystal in a drop is nucleated, the small volume generates a negative feedback mechanism that lowers the supersaturation. This mechanism is exploited to produce one crystal per drop. Diffraction data are measured, one crystal at a time, from a series of room temperature crystals stored on an X-ray semi-transparent microfluidic chip, and a 93% complete data set is obtained by merging single diffraction frames taken from different unoriented crystals. As proof of concept, the structure of glucose isomerase was solved to 2.1 A, demonstrating the feasibility of high-throughput serial X-ray crystallography using synchrotron radiation. PMID- 25295177 TI - Hirshfeld atom refinement. AB - Hirshfeld atom refinement (HAR) is a method which determines structural parameters from single-crystal X-ray diffraction data by using an aspherical atom partitioning of tailor-made ab initio quantum mechanical molecular electron densities without any further approximation. Here the original HAR method is extended by implementing an iterative procedure of successive cycles of electron density calculations, Hirshfeld atom scattering factor calculations and structural least-squares refinements, repeated until convergence. The importance of this iterative procedure is illustrated via the example of crystalline ammonia. The new HAR method is then applied to X-ray diffraction data of the dipeptide Gly-l-Ala measured at 12, 50, 100, 150, 220 and 295 K, using Hartree Fock and BLYP density functional theory electron densities and three different basis sets. All positions and anisotropic displacement parameters (ADPs) are freely refined without constraints or restraints - even those for hydrogen atoms. The results are systematically compared with those from neutron diffraction experiments at the temperatures 12, 50, 150 and 295 K. Although non-hydrogen-atom ADPs differ by up to three combined standard uncertainties (csu's), all other structural parameters agree within less than 2 csu's. Using our best calculations (BLYP/cc-pVTZ, recommended for organic molecules), the accuracy of determining bond lengths involving hydrogen atoms from HAR is better than 0.009 A for temperatures of 150 K or below; for hydrogen-atom ADPs it is better than 0.006 A(2) as judged from the mean absolute X-ray minus neutron differences. These results are among the best ever obtained. Remarkably, the precision of determining bond lengths and ADPs for the hydrogen atoms from the HAR procedure is comparable with that from the neutron measurements - an outcome which is obtained with a routinely achievable resolution of the X-ray data of 0.65 A. PMID- 25295178 TI - Ureteral Stent Placement Increases the Risk for Developing BK Viremia after Kidney Transplantation. AB - The placement of ureteral stent (UrSt) at kidney transplantation reduces major urological complications but increases the risk for developing nephropathy from the BK virus. It is unclear whether UrSt placement increases nephropathy risk by increasing risk of precursor viral replication or by other mechanisms. We retrospectively investigated whether UrSt placement increased the risk for developing BK Viremia (BKVM) in adult and pediatric kidney transplants performed at the University of Florida between July 1, 2007, and December 31, 2010. In this period all recipients underwent prospective BKV PCR monitoring and were maintained on similar immunosuppression. Stent placement or not was based on surgeon preference. In 621 transplants, UrSt were placed in 295 (47.5%). BKVM was seen in 22% versus 16% without UrSt (P = 0.05). In multivariate analyses, adjusting for multiple transplant covariates, only UrSt placement remained significantly associated with BKVM (P = 0.04). UrSt placement significantly increased the risk for BKVM. Routine UrSt placement needs to be revaluated, since benefits may be negated by the need for more BK PCR testing and potential for graft survival-affecting nephritis. PMID- 25295179 TI - Histochemical Study of the Progenetic Trematode Alloglossidium renale. AB - A histochemical study of the progenetic trematode Alloglossidium renale has demonstrated the absence of any secreted material between the adult worm and the host (freshwater shrimp) antennal gland tubules. Host tissue is affected only by the compression, abrasion, and ingestion by the parasite, and host tubule cells near the worm have the same staining patterns as those distant from the parasite. The trematode sometimes dies within the host, leaving a necrotic mass whose histochemical staining differs significantly from the living organism. In the necrotic mass, the only recognizable features were the ova and the vitellarium, which atrophied and resulted in tyrosine-positive staining within the mass. A melanin reaction was not observed in the host using a specialized ferro ferricyanide stain. The only apparent host response to infection was a layer of damaged squamous host cells adhering to the necrotic worm. The results confirm benign host-parasite effects and a highly evolved relationship between the host and parasite, perhaps bordering on commensalism. PMID- 25295181 TI - Moringa oleifera Supplemented Diets Prevented Nickel-Induced Nephrotoxicity in Wistar Rats. AB - Background. The Moringa oleifera plant has been implicated for several therapeutic potentials. Objective. To evaluate whether addition of M. oleifera to diet has protective effect against nickel-induced nephrotoxicity in rats. Methodology. Male Wistar rats were assigned into six groups of five. The rats were given oral exposure to 20 mg/kg nickel sulphate (NiSO4) in normal saline and sustained on either normal diet or diets supplemented with Moringa oleifera at different concentrations for 21 days. 24 hours after cessation of treatments, all animals were sacrificed under slight anesthesia. The blood and kidney samples were collected for biochemical and histopathology analyses, respectively. Results. NiSO4 exposure reduced the kidney-to-body weight ratio in rats and caused significant elevation in the levels of plasma creatinine, urea, and potassium. Also, the plasma level of sodium was decreased by NiSO4 exposure. However, addition of M. oleifera to diets averted the nickel-induced alteration to the level of creatinine and urea. The histopathology revealed damaged renal tubules and glomerular walls caused by NiSO4 exposure. In contrast, the damages were ameliorated by the M. oleifera supplemented diets. Conclusion. The addition of M. oleifera to diet afforded significant protection against nickel-induced nephrotoxicity. PMID- 25295180 TI - Impact of identification and treatment of depression in heart transplant patients. AB - Background. The effects of clinical depression after orthotopic heart transplantation (OHT) are relatively unknown. The purpose of this study was to evaluate the impact of depression on outcomes after OHT. Methods. We performed a single center retrospective review of 102 consecutive patients who underwent OHT at Northwestern Memorial Hospital from June 2005 to October 2009. The diagnosis of depression was obtained from attending physician documentation. The primary endpoints were all-cause mortality (ACM), hospitalizations, and rejection. Results. Of 102 OHT patients, 26 (26%) had depression. Depressed patients were similar in age to nondepressed patients (57.6 years versus 56.9, P = 0.79). There was no statistical difference in survival between groups at 5 years after OHT (P = 0.94). All-cause hospitalizations were higher in depressed versus nondepressed patients (4.3 versus 2.6 hospitalizations P = 0.05). There were no significant differences in hospitalizations between the two groups for the following complications: cardiac (heart failure, edema, arrhythmias, and acute rejection) and infections. There was no significant difference in episodes of 2R and 3R rejection. Conclusion. Early identification and treatment of depression in OHT patients result in outcomes similar to nondepressed patients. PMID- 25295182 TI - HO-1 Upregulation Attenuates Adipocyte Dysfunction, Obesity, and Isoprostane Levels in Mice Fed High Fructose Diets. AB - Background. Fructose metabolism is an unregulated metabolic pathway and excessive fructose consumption is known to activate ROS. HO-1 is a potent antioxidant gene that plays a key role in decreasing ROS and isoprostanes. We examined whether the fructose-mediated increase in adipocyte dysfunction involves an increase in isoprostanes and that pharmacological induction of HO-1 would decrease both isoprostane levels and adipogenesis. Methods and Results. We examined the effect of fructose, on adipogenesis in human MSCs in the presence and absence of CoPP, an inducer of HO-1. Fructose increased adipogenesis and the number of large lipid droplets while decreasing the number of small lipid droplets (P < 0.05). Levels of heme and isoprostane in fructose treated MSC-derived adipocytes were increased. CoPP reversed these effects and markedly increased HO-1 and the Wnt signaling pathway. The high fructose diet increased heme levels in adipose tissue and increased circulating isoprostane levels (P < 0.05 versus control). Fructose diets decreased HO-1 and adiponectin levels in adipose tissue. Induction of HO-1 by CoPP decreased isoprostane synthesis (P < 0.05 versus fructose). Conclusion. Fructose treatment resulted in increased isoprostane production and adipocyte dysfunction, which was reversed by the increased expression of HO-1. PMID- 25295184 TI - Resource utilisation and costs of depressive patients in Germany: results from the primary care monitoring for depressive patients trial. AB - Background. Depression is the most common type of mental disorder in Germany. It is associated with a high level of suffering for individuals and imposes a significant burden on society. The aim of this study was to estimate the depression related costs in Germany taking a societal perspective. Materials and Methods. Data were collected from the primary care monitoring for depressive patients trial (PRoMPT) of patients with major depressive disorder who were treated in a primary care setting. Resource utilisation and days of sick leave were observed and analysed over a 1-year period. Results. Average depression related costs of ?3813 were calculated. Significant differences in total costs due to sex were demonstrated. Male patients had considerable higher total costs than female patients, whereas single cost categories did not differ significantly. Further, differences in costs according to severity of disease and age were observed. The economic burden to society was estimated at ?15.6 billion per year. Conclusion. The study results show that depression poses a significant economic burden to society. There is a high potential for prevention, treatment, and patient management innovations to identify and treat patients at an early stage. PMID- 25295183 TI - Effect of a Mediterranean Diet Intervention on Dietary Glycemic Load and Dietary Glycemic Index: The PREDIMED Study. AB - Objective. To compare the one year effect of two dietary interventions with MeDiet on GL and GI in the PREDIMED trial. Methods. Participants were older subjects at high risk for cardiovascular disease. This analysis included 2866 nondiabetic subjects. Diet was assessed with a validated 137-item food frequency questionnaire (FFQ). The GI of each FFQ item was assigned by a 5-step methodology using the International Tables of GI and GL Values. Generalized linear models were fitted to assess the relationship between the intervention group and dietary GL and GI at one year of follow-up, using control group as reference. Results. Multivariate-adjusted models showed an inverse association between GL and MeDiet + extra virgin olive oil (EVOO) group: beta = -8.52 (95% CI: -10.83 to -6.20) and MeDiet + Nuts group: beta = -10.34 (95% CI: -12.69 to -8.00), when comparing with control group. Regarding GI, beta = -0.93 (95% CI: -1.38 to -0.49) for MeDiet + EVOO, beta = -1.06 (95% CI: -1.51 to -0.62) for MeDiet + Nuts when comparing with control group. Conclusion. Dietary intervention with MeDiet supplemented with EVOO or nuts lowers dietary GL and GI. PMID- 25295185 TI - Serum Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 (ITIH4) in Children with Chronic Hepatitis C: Relation to Liver Fibrosis and Viremia. AB - Liver fibrosis and viremia are determinant factors for the treatment policy and its outcome in chronic hepatitis C virus (HCV) infection. We aimed to investigate serum level of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and its relation to liver fibrosis and viremia in children with chronic HCV. ITIH4 was measured by ELISA in 33 treatment-naive children with proved chronic HCV and compared according to different clinical, laboratory and histopathological parameters. Liver histopathological changes were assessed using Ishak score and compared with aspartate transaminase-to-platelet ratio (APRI) and FIB-4 indices as simple noninvasive markers of fibrosis. ITIH4 was measured in a group of 30 age- and sex-matched healthy controls. ITIH4 was significantly higher in patients than in controls (54.2 +/- 30.78 pg/mL versus 37.21 +/- 5.39 pg/mL; P = 0.021). ITIH4, but not APRI or FIB-4, had a significant direct correlation with fibrosis stage (P = 0.015, 0.961, and 0.389, resp.), whereas, the negative correlation of ITIH4 with HCV viremia was of marginal significance (P = 0.071). In conclusion, ITIH4 significantly correlated with higher stages of fibrosis indicating a possible relation to liver fibrogenesis. The trend of higher ITIH4 with lower viremia points out a potential antiviral properties and further studies in this regard are worthwhile. PMID- 25295186 TI - Timing Matters: HIV Testing Rates in the Emergency Department. AB - Study Objectives. In response to the 2010 New York State HIV testing law, we sought to understand the contextual factors that influence HIV testing rates in the emergency department (ED). Methods. We analyzed electronic health record logs from 97,655 patients seen in three EDs in New York City. We used logistic regression to assess whether time of day, day of the week, and season significantly affected HIV testing rates. Results. During our study period, 97,655 patients were evaluated and offered an HIV test. Of these, 7,763 (7.9%) agreed to be tested. Patients arriving between 6 a.m. and 7:59 p.m. were significantly (P < 0.001) more likely to be tested for HIV, followed by patients arriving between 8:00 p.m. and 9:59 p.m. (P < 0.01) and followed by patients arriving between 5-5:59 a.m. and 10-10:59 p.m. (P < 0.05) compared to patients arriving at midnight. Seasonal variation was also observed, where patients seen in July, August, and September (P < 0.001) were more likely to agree to be tested for HIV compared to patients seen in January, while patients seen in April and May (P < 0.001) were less likely to agree to be tested for HIV. Conclusion. Time of day and season affect HIV testing rates in the ED, along with other factors such as patient acuity and completion of other blood work during the ED visit. These findings provide useful information for improving the implementation of an HIV testing program in the ED. PMID- 25295187 TI - In silico investigation of a surgical interface for remote control of modular miniature robots in minimally invasive surgery. AB - Aim. Modular mini-robots can be used in novel minimally invasive surgery techniques like natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single site (LESS) surgery. The control of these miniature assistants is complicated. The aim of this study is the in silico investigation of a remote controlling interface for modular miniature robots which can be used in minimally invasive surgery. Methods. The conceptual controlling system was developed, programmed, and simulated using professional robotics simulation software. Three different modes of control were programmed. The remote controlling surgical interface was virtually designed as a high scale representation of the respective modular mini-robot, therefore a modular controlling system itself. Results. With the proposed modular controlling system the user could easily identify the conformation of the modular mini-robot and adequately modify it as needed. The arrangement of each module was always known. The in silico investigation gave useful information regarding the controlling mode, the adequate speed of rearrangements, and the number of modules needed for efficient working tasks. Conclusions. The proposed conceptual model may promote the research and development of more sophisticated modular controlling systems. Modular surgical interfaces may improve the handling and the dexterity of modular miniature robots during minimally invasive procedures. PMID- 25295188 TI - Multidetector computer tomography: evaluation of blunt chest trauma in adults. AB - Imaging plays an essential part of chest trauma care. By definition, the employed imaging technique in the emergency setting should reach the correct diagnosis as fast as possible. In severe chest blunt trauma, multidetector computer tomography (MDCT) has become part of the initial workup, mainly due to its high sensitivity and diagnostic accuracy of the technique for the detection and characterization of thoracic injuries and also due to its wide availability in tertiary care centers. The aim of this paper is to review and illustrate a spectrum of characteristic MDCT findings of blunt traumatic injuries of the chest including the lungs, mediastinum, pleural space, and chest wall. PMID- 25295189 TI - Prognostic importance of fibroblast growth factor-23 in dialysis patients. AB - Introduction. In this study, we aimed to demonstrate the correlation of FGF-23 levels with bone-mineral metabolism, anemia, and the treatment in dialysis patients. Methods. Eighty-nine patients with similar age, gender, dialysis duration, and dialysis adequacy who were receiving hemodialysis replacement therapy for at least 6 months were included in the study. Serum iron, iron binding capacity, ferritin, hemoglobin (Hb), hematocrit (Htc), calcium (Ca), phosphorus (P), intact parathormone (iPTH), and FGF-23 levels were studied. In addition, active vitamin D and phosphate binders calcimimetic therapies that patients have received in the last 6 months were recorded. Results. It was determined that there was a positive correlation between serum FGF-23 values and PTH values (P < 0, 01) and Ca*P values (P < 0, 01). A positive correlation was found between serum FGF-23 values and Ca values at a rate of 24,6% (P < 0, 05) and between P values at a rate of 59,1% (P < 0, 01). A positive correlation was determined between serum FGF-23 values and hemoglobin (Hb) values (P < 0, 05) and hematocrit (Htc) values (P < 0, 05). In multivariate analysis, no significant correlation was found between serum FGF-23 levels and Hb and Htc. Conclusion. The effects of high serum FGF-23 levels on different parameters may be correlated with the development of refractory secondary hyperparathyroidism. PMID- 25295190 TI - Dimerization of peptides by calcium ions: investigation of a calcium-binding motif. AB - We investigated calcium-binding motifs of peptides and their recognition of active functionalities for coordination. This investigation generates the fundamentals to design carrier material for calcium-bound peptide-peptide interactions. Interactions of different peptides with active calcium domains were investigated. Evaluation of selectivity was performed by electrospray ionization mass spectrometry by infusing solutions containing two different peptides (P1 and P2) in the presence of calcium ions. In addition to signals for monomer species, intense dimer signals are observed for the heterodimer ions (P1 ? Ca(2+) ? P2) (? represents the noncovalent binding of calcium with the peptide) in the positive ion mode and for ions ([P1-2H](2-) ? Ca(2+) ? [P2-2H](2-)) in the negative ion mode. Monitoring of the dissociation from these mass selected dimer ions via the kinetic method provides information on the calcium affinity order of different peptide sequences. PMID- 25295191 TI - Is the cloze procedure appropriate to evaluate health literacy in older individuals? Age effects in the test of functional health literacy in adults. AB - Health literacy has received increasing attention because of its importance for older individuals' health, as studies have shown a close relation between older individuals' health literacy and their health. Research also suggests that older individuals have low levels of health literacy, but this finding is variable and may depend on which health literacy test is used. Older individuals assessed with the Test of Functional Health Literacy (TOFHLA) score lower than younger individuals, but a previous study suggested that this may result from age-related differential item functioning (DIF) on the TOFHLA. The study reported here assessed age-related DIF in a sample of community-dwelling volunteers. Twenty-two percent of items were differentially more difficult for older individuals independent of their overall ability, and when these items were eliminated from the total score, age differences were no longer found. Performance on a working memory task predicted older but not younger individuals' performance on the age related items. At least part of older individuals' apparent deficits in health literacy when assessed by the TOFHLA may be related to DIF on its items. The TOFHLA, and any measure that employs the cloze procedure to evaluate reading comprehension, should be used cautiously in older individuals. PMID- 25295192 TI - Could some geriatric characteristics hinder the prescription of anticoagulants in atrial fibrillation in the elderly? AB - Several studies have reported underprescription of anticoagulants in atrial fibrillation (AF). We conducted an observational study on 142 out of a total of 995 consecutive >=75 years old patients presenting AF (14%) when admitted in an emergency unit of a general hospital, in search of geriatric characteristics that might be associated with the underprescription of anticoagulation therapy (mostly antivitamin K at the time of the study). The following data was collected from patients presenting AF: medical history including treatment and comorbidities, CHADS2 score, ISAR scale (frailty), Lawton's scale (ADL), GDS scale (mood status), MUST (nutrition), and blood analysis (INR, kidney function, and albumin). Among those patients for who anticoagulation treatment was recommended (73%), only 61% were treated with it. In the group with anticoagulation therapy, the following characteristics were observed more often than in the group without such therapy: a recent (<=6 months) hospitalization and medical treatment including digoxin or based on >3 different drugs. Neither the value of the CHADS2 score, nor the geriatric characteristics could be correlated with the presence or the absence of an anticoagulation therapy. More research is thus required to identify and clarify the relative importance of patient-, physician-, and health care system-related hurdles for the prescription of oral anticoagulation therapy in older patients with AF. PMID- 25295193 TI - Variation in Anatomical Position of Vermiform Appendix among Iranian Population: An Old Issue Which Has Not Lost Its Importance. AB - Vermiform appendix has diverse anatomical positions, lengths, and conditions of mesoappendix. Knowing the exact anatomical position of vermiform appendix is important in view of surgeons for on-time diagnosis and management of acute appendicitis. The aim of present study is determination of these characteristics of vermiform appendix among Iranian population. The present study was conducted on 200 bodies, selected from the dead bodies that had been referred to local bureau of legal medicine, Zenjan province, Iran, for medicolegal autopsy since 21 Mar 2010 to 21 Mar 2011. According to the results, the anatomical positions of the appendix were pelvic, subcecal, retroileal, retrocecal, ectopic, and preileal in 55.8%, 19%, 12.5%, 7%, 4.2%, and 1.5% of the bodies, respectively. The mean length of vermiform appendix was 91.2 mm and 80.3 mm in men and women, respectively. Mesoappendix was complete in 79.5% of the bodies. No association was found between sex and anatomical position of vermiform appendix. Anterior anatomical position was the most common position for vermiform appendix. It is inconsistent with most related reports from western countries. It might be possible that some factors, such as race, geographical changes, and dietary habits, play roles in determining the position of vermiform appendix. PMID- 25295195 TI - Application of experimental design in preparation of nanoliposomes containing hyaluronidase. AB - Hyaluronidase is an enzyme that catalyzes breakdown of hyaluronic acid. This property is utilized for hypodermoclysis and for treating extravasation injury. Hyaluronidase is further studied for possible application as an adjuvant for increasing the efficacy of other drugs. Development of suitable carrier system for hyaluronidase would help in coadministration of other drugs. In the present study, the hyaluronidase was encapsulated in liposomes. The effect of variables, namely, phosphatidylcholine (PC), cholesterol, temperature during film formation (T 1), and speed of rotation of the flask during film formation (SPR) on percentage of protein encapsulation, was first analyzed using factorial design. The study showed that level of phosphatidylcholine had the maximum effect on the outcome. The effect of interaction of PC and SPR required for preparation of nanoliposomes was identified by central composite design (CCD). The dependent variables were percentage protein encapsulation, particle size, and zeta potential. The study showed that ideal conditions for production of hyaluronidase loaded nanoliposomes are PC-140 mg and cholesterol 1/5th of PC when the SPR is 150 rpm and T 1 is 50 degrees C. PMID- 25295194 TI - The RAG Model: A New Paradigm for Genetic Risk Stratification in Multiple Myeloma. AB - Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based "traffic-light" risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient. PMID- 25295196 TI - Effective concentration and detection of cryptosporidium, giardia, and the microsporidia from environmental matrices. AB - Cryptosporidium spp., Giardia spp., and members of Microsporidia are enteropathogenic parasites of humans and animals, producing asymptomatic to severe intestinal infections. To circumvent various impediments associated with current detection methods, we tested a method providing multistage purification and separation in a single, confined step. Standard real-time PCR was used as a detection method. Samples spiked with C. parvum and G. intestinalis were split for comparison to standard Method 1623. Results were equivalent to immunomagnetic procedures for Cryptosporidium, and Giardia. Overall percent recovery for Cryptosporidium with Method 1623 averaged 26.89% (std 21.44%; min = 0%; max = 73%) and was similar but less variable for qPCR method at an estimated average of 27.67 (std 17.65%; min = 5%; max = 63%). For Giardia, Method 1623 had an overall average recovery of 27.11% (std 17.98%; min = 1%; max = 58%), while multistage purification and qPCR had an estimated lower overall recovery at 18.58% (std 13.95%; min = 0%; max = 35%). Microsporidia were also readily detected with an estimated recovery of 46.81% overall (std 17.66%; min = 18%; max = 70%) for E. intestinalis and 38.90% (std 14.36%; min = 13%; max = 62%) for E. bieneusi. PMID- 25295197 TI - A rare presentation of hepatitis a infection with extrahepatic manifestations. AB - Hepatitis A has a variety of associated extrahepatic manifestations that clinicians should be aware of for early diagnosis and treatment. We report a unique case of hepatitis A presenting with multiple extrahepatic manifestations not previously described in a single patient. A 34-year-old male presented with sudden onset of left sided facial pain, swelling, and skin rash, with diffuse body pains and muscle weakness, and was found to be positive for hepatitis A immunoglobulin M (IgM). He was initially started on antibiotics for concerns of bacterial parotitis but did not show any improvement. A punch biopsy of his mandibular rash and swelling was done which showed lymphohistiocytic infiltration with a few eosinophils. A trial of prednisone resulted in improvement of his symptoms. Clinicians should be aware to look for hepatitis A infection in a patient with atypical clinical picture causing a widespread systemic inflammatory response. Treatment with prednisone may result in resolution. PMID- 25295198 TI - An Esophagogastroduodenal Crohn's-Like Disease in a Long-Standing Pan-Ulcerative Colitis Patient. AB - Inflammatory bowel disease (IBD) comprises the principal subtypes Crohn's disease (CD) and ulcerative colitis (UC), with a fraction remaining as IBD unclassified (IBDU). Given the complexity of IBD manifestations in a patient over time and our increasing understanding of IBD biology, a modification in subtype diagnosis can also occur. Herein is a case of a 27-year-old female with well-controlled and long-standing pan-UC, who developed Crohn's-like esophagogastroduodenitis. The difficulty in classifying IBD into a single traditional subtype, and the debated presentation of a coexistent IBD will be discussed. PMID- 25295199 TI - Lupus enteritis as an initial presentation of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder which can affect multiple organs and clinical presentation is often a myriad of symptoms; therefore, the index of suspicion should rise when evaluating patients with multiorgan symptomatology. Lupus enteritis is a distinct subset of SLE, defined as either vasculitis or inflammation of the small bowel, with supportive image and/or biopsy findings. The clinical picture of lupus enteritis is often nonspecific, with mild to severe abdominal pain, diarrhea, and vomiting being the cardinal manifestations. Although considered a form of visceral or serosal vasculitis, lupus enteritis is seldom confirmed on histology, making computerized tomography (CT) the gold standard for diagnosis. Lupus enteritis is generally steroid-responsive, and the route of administration is based on clinical status and organ involvement, with preference for intravenous (IV) route in flares with significant tissue edema. The following case describes a young woman presenting with lupus enteritis and lupus panniculitis as an initial manifestation of SLE, the utilization of abdominal CT in diagnosis, and current treatment protocols used for lupus enteritis. PMID- 25295200 TI - Autoimmune Demyelinating Polyneuropathy as a Manifestation of Chronic Graft versus-Host Disease after Adult Cord Blood Transplantation in a Patient with Chronic Lymphocytic Leukemia. AB - Immune mediated demyelinating disease after allogeneic stem cell transplantation is a rare entity with unclear etiology. Acute inflammatory demyelinating polyneuropathy (AIDP) has been reported after related and adult unrelated allogeneic stem cell transplantation but no such case has been reported after unrelated cord blood transplantation. We hereby present the first case of AIDP after double umbilical cord blood transplantation (DUCBT). A 55-year-old man with chronic lymphocytic leukemia (CLL) received a cord blood transplant for relapsed refractory disease with high risk cytogenetics. On day 221, patient presented with skin rash, tingling in both lower extremites, and ascending paralysis that progressed rapidly over the course of 2 days. The workup resulted in a diagnosis of AIDP and administration of intravenous immunoglobulins plus steroids was initiated. Motor and sensory powers were fully recovered and his chronic GVHD was managed for several months with single agent sirolimus. PMID- 25295201 TI - Hepatitis e infection in a renal transplant recipient. AB - An asymptomatic 35-year-old renal transplant recipient was noted to have deranged liver function tests. Liver biopsy revealed a portal inflammatory process with mild lobular activity and portal fibrous expansion, consistent with a virally mediated process. An extensive viral screen confirmed infection with Hepatitis E virus genotype 3 (HEV-3). There is increased awareness about locally acquired Hepatitis E virus (HEV) infection in the transplant population in the UK. The important implications of this infection are becoming more apparent as progression to liver cirrhosis can occur. However, the incidence, natural history, and treatment of HEV infection in the transplant population are not well established. This report illustrates a case of delayed spontaneous clearance of the HEV infection. PMID- 25295202 TI - Color Doppler score: a new approach for monitoring a large placental chorioangioma. AB - We employed color Doppler score as an innovative approach for the prenatal diagnosis and monitoring of a large placental chorioangioma case diagnosed at 26 weeks and the subjective semiquantitative assessment of the vascularization. The blood flow was assessed by a color Doppler score based on the intensity of the color signal with the following value ranges: (1) no flow, (2) minimal flow, (3) moderate flow, and (4) high vascular flow. Weekly examinations were programmed. Initially, a color Doppler score 3 was assigned, remaining unchanged at the following two exams and decreasing to Score 2 in the following 2 exams and to Score 1 thereafter. The ultrasonographic scan showed an increase of the mass size at the second and third exams and was followed by an arrest of the growth persisting for the rest of the pregnancy. Some hyperechogenic spots inside the mass appeared at the end. Expectant management was opted for, and the delivery was at 39, 2 weeks and maternal and fetal outcomes were favourable. The color Doppler score employed for assessment of vascularization in successive examinations proved to be an important tool for the prediction of the chorioangioma involution, and this new approach of monitoring allowed effective surveillance and successful tailored management. PMID- 25295203 TI - Bilateral choroidal metastasis from non-small cell lung cancer. AB - Breast and lung cancers are the most common primary neoplasms to manifest with choroidal metastases. The incidence of choroidal metastases from metastatic lung cancer was reported to be 2-6.7%. We report a case of bilateral choroidal metastasis from non-small cell lung cancer. A 59-year-old Caucasian female patient, never a smoker, was diagnosed with stage IV lung adenocarcinoma metastatic to the pleura, bones, and the brain. Her initial scan of the chest showed innumerable soft tissue nodules and mediastinal adenopathy compatible with metastatic disease. Her initial brain MRI showed numerous small enhancing lesions consistent with extensive disease. Unfortunately, during her follow-up visits, she presented with bulge on her left eye. Simultaneously, her follow-up chest scan showed increase in the size of the lung nodules. She continued to have a reasonable performance status at that time, except for mild increase in her dyspnea. The choroidal metastases require a multidisciplinary care and should be among the differential patients with malignancy who present with ocular symptoms. PMID- 25295204 TI - Choroidal coloboma in a case of tay-sachs disease. AB - Coloboma as an ocular finding has been documented in various syndromes. Here we have a case of infantile Tay-Sachs disease associated with unilateral choroidal coloboma. To the best of our knowledge, such an association has not been documented in the literature. Whether such an association is a matter of chance or signifies the involvement of ganglioside metabolism in ocular embryogenesis remains to be elucidated. PMID- 25295205 TI - Spontaneous cervical intradural disc herniation associated with ossification of posterior longitudinal ligament. AB - Intradural herniation of a cervical disc is rare; less than 35 cases have been reported to date. A 52-year-old man with preexisting ossification of posterior longitudinal ligament developed severe neck pain with Lt hemiparesis while asleep. Neurological exam was consistent with Brown-Sequard syndrome. Magnetic resonance images showed a C5-6 herniated disc that was adjacent to the ossified ligament and indenting the cord. The mass was surrounded by cerebrospinal fluid signal intensity margin, and caudally the ventral dura line appears divided into two, consistent with the "Y-sign" described by Sasaji et al. Cord edema were noted. Because of preexisting canal stenosis and spinal cord at risk, a laminoplasty was performed, followed by an anterior C6 corpectomy. Spot-weld type adhesions of the posterior longitudinal ligament to the dura was noted, along with a longitudinal tear in the dura. An intradural extra-arachnoid fragment of herniated disc was removed. Clinical exam at 6 months after surgery revealed normal muscle strength but persistent mild paresthesias. It is difficult to make a definite diagnosis of intradural herniation preoperatively; however, the clinical findings and radiographic signs mentioned above are suggestive and should alert the surgeon to look for an intradural fragment. PMID- 25295206 TI - Cervical Bone Graft Candida albicans Osteomyelitis: Management Strategies for an Uncommon Infection. AB - Candida osteomyelitis in the current literature is an emerging infection. The factors contributing to its emergence include a growing population of immunosuppressed patients, invasive surgeries, broad-spectrum antibiotics, injection drug users, and alcohol abuse. The diagnosis requires a high degree of suspicion. The insidious progression of infection and the nonspecificity of laboratory and radiologic findings may contribute to a delay in diagnosis. The current case concerns a 27-year-old man with a spinal cord injury who, after undergoing anterior cervical fixation and fusion surgery, developed postoperative systemic bacterial infection and required long-term antibiotic therapy. After six months, a CT scan demonstrated an almost complete anterior dislocation of the implants caused by massive bone destruction and reabsorption in Candida albicans infection. The patient underwent a second intervention consisting firstly of a posterior approach with C4-C7 fixation and fusion, followed by a second anterior approach with a corpectomy of C5 and C6, a tricortical bone grafting from the iliac crest, and C4-C7 plating. The antifungal therapy with fluconazole was effective without surgical debridement of the bone graft, despite the fact that signs of the bone graft being infected were seen from the first cervical CT scans carried out after one month. PMID- 25295207 TI - Temporal bone fracture causing superior semicircular canal dehiscence. AB - Importance. Superior semicircular canal dehiscence (SCD) is a third window lesion of the inner ear causing symptoms of vertigo, autophony, tinnitus, and hearing loss. A "two-hit" hypothesis has traditionally been proposed, whereby thinly developed bone overlying the superior canal is disrupted by a sudden change in intracranial pressure. Although the symptoms of SCD may be precipitated by head injury, no previous reports have described a temporal bone fracture directly causing SCD. Observations. Two patients sustained temporal bone fractures after closed head trauma, and developed unilateral otologic symptoms consistent with SCD. In each instance, computed tomography imaging revealed fractures extending through the bony roof of the superior semicircular canal. Conclusions and Relevance. Temporal bone fractures, which are largely treated nonoperatively, have not previously been reported to cause SCD. As it is a potentially treatable entity, SCD resulting from temporal bone fracture must be recognized as a possibility and diagnosed promptly if present. PMID- 25295208 TI - Primary squamous cell carcinoma of the thyroid diagnosed as anaplastic carcinoma: failure in fine-needle aspiration cytology? AB - A case of primary squamous-cell carcinoma (SCC) of the thyroid which had been initially diagnosed as an anaplastic carcinoma (ATC) is described: female, 73 years old, with a fast-growing cervical nodule on the left side and hoarseness for 3 months. Ultrasonography showed a 4.5 cm solid nodule. FNA was compatible with poorly differentiated carcinoma with immunoreactivity for AE1/AE3, EMA. Thyroidectomy was performed. Histopathological examination showed a nonencapsulated tumor. Immunohistochemistry disclosed positivity for AE1/AE3, p53,p63, and Ki67. The diagnosis was ATC. A second opinion reported tumor consisting of squamous cells, with intense inflammatory infiltrate both in tumor and in the adjacent thyroid, with final diagnosis of SCC, associated with Hashimoto thyroiditis. No other primary focus of SCC was found. Patient has shown a 48-month survival period. Clinically, primary SCCs of the thyroid and ATCs are similar. The distinction is often difficult particularly when based on the cytological analysis of FNA material. PMID- 25295209 TI - Quality improvement opportunities in caring for patients with nonepileptic seizures. AB - Background. Patients with nonepileptic seizures (NES) are challenging to treat for myriad reasons. Often patients may be misdiagnosed with having epilepsy and then may suffer unintended consequences of treatment side effects with antiepileptic medication. In addition, patients may be maligned by health care providers due to a lack of ownership by both psychiatrists and neurologists and a dearth of dedicated professionals who are able to effectively treat and reduce severity and frequency of symptoms. Aims of Case Report. Many psychiatrists and neurologists are unaware of the extent of the barriers to care faced by patients with NES (PWNES) and the degree of perception of maltreatment or lack of therapeutic alliance at various stages of their care, including medical workup, video-EEG monitoring, and follow-up plans. We present the case of a patient with NES who experienced numerous barriers as well as incoordination to her care despite being offered a breadth of resources and discuss the quality improvement opportunities that may exist to improve care of patients with NES. Conclusion. No known literature has documented the extensive barriers to care of PWNES in parallel to quality improvement opportunities for improving their care. We endeavor to contribute to the overall formulation and development of a clinical care pathway for PWNES. PMID- 25295210 TI - Eradication of Burkholderia cepacia Using Inhaled Aztreonam Lysine in Two Patients with Bronchiectasis. AB - There are not many articles about the chronic bronchial infection/colonization in patients with underlying lung disease other than cystic fibrosis (CF), especially with non-CF bronchiectasis (NCFBQ). The prevalence of B. cepacia complex is not well known in NCFBQ. The vast majority of published clinical data on Burkholderia infection in individuals with CF is comprised of uncontrolled, anecdotal, and/or single center experiences, and no consensus has emerged regarding treatment. We present two cases diagnosed with bronchiectasis (BQ) of different etiology, with early pulmonary infection by B. cepacia complex, which was eradicated with inhaled aztreonam lysine. PMID- 25295211 TI - Primary tubercular chest wall abscess in a young immunocompetent male. AB - Chest wall tuberculosis is a rare entity especially in an immunocompetent patient. Infection may result from direct inoculation of the organisms or hematogenous spread from some underlying pathology. Infected lymph nodes may also transfer the bacilli through lymphatic route. Chest wall tuberculosis may resemble a pyogenic abscess or tumour and entertaining the possibility of tubercular etiology remains a clinical challenge unless there are compelling reasons of suspicion. In tuberculosis endemic countries like India, all the abscesses indolent to routine treatment need investigation to rule out mycobacterial causes. We present here a case of chest wall tuberculosis where infection was localized to skin only and, in the absence of any evidence of specific site, it appears to be a case of primary involvement. PMID- 25295212 TI - Vaginoperineal Fistula as a Complication of Perianal Surgery in a Patient with Sjogren's Syndrome: A Case Report. AB - Forty-seven-year-old woman with Sjogren's syndrome had been operated on because of transsphincteric perianal fistula secondary to perianal abscess. Vaginal wall injury occurred during the course of the operation and injured tissue was repaired primarily. Three months later, patient suffered from the recurrence of perianal fistula symptoms and fistulectomy was performed once again under antibiotic suppression. Several months later, perineal discharge continued, and, therefore, patient was admitted to the hospital for the third time and a fistulotomy was performed. Two months after the third operation, patient was admitted with leukorrhea and a perineovaginal fistula was detected. This time, not only her surgical problem but also her immune system disorder was considered in the preoperative workup. Then, patient was hospitalized for the fourth time and "fistulectomy/perineoplasty" was performed successfully. We believe that patients with autoimmune disorders with or without medical treatment may have healing problems during the course of surgical processes and therefore such medical problems must be taken into consideration by the surgeons. PMID- 25295213 TI - Mean platelet volume in patients with obstructive sleep apnea and its relationship with simpler heart rate derivatives. AB - Some studies show increased mean platelet volume (MPV) in obstructive sleep apnea (OSA). The aim of this study was to evaluate MPV in OSA patients without cardiovascular risk factors and the possible association of heart rate derivatives with MPV. A total of 82 patients (aged 30-70 years) were divided into 2 groups according to the presence of either OSA or non-OSA as the control group. The OSA group consisted of 52 patients and the control group consisted of 30 subjects. Neither group was significantly different in terms of MPV values as well as heart rate (HR) derivatives such as minimum HR, maximum HR, the difference between maximum HR and minimum HR, mean HR, and heart rate performance index (HRPI) [(HR max. - HR min.)/HR mean] (P > 0.05 for all variables). In multivariate analysis, platelet count and percentages of recording time spent at arterial oxygen saturation < 90% significant variables are associated with MPV (beta +/- SE: -0.004 +/- 0.002, 95% CI, -0.008 to -0.001; P = 0.034) and (beta +/ SE: 2.93 +/- 1.93, 95% CI, 0.167 to 5.69; P = 0.038). Consequently, our findings predominantly suggest that there is a casual and reciprocal interaction between MPV and autonomic activation. PMID- 25295215 TI - Papillary thyroid cancer, macrofollicular variant: the follow-up and analysis of prognosis of 5 patients. AB - Objective. The main aim of this study was to comparatively analyze the recurrence and prognosis of this rare variant with the literature by analyzing the follow-up data of 5 patients diagnosed with papillary cancer macrofollicular variant. Methods. The demographic data, radiological and pathological data, and prognostic data of 5 patients who underwent surgery for thyroid cancer and were diagnosed with papillary cancer macrofollicular variant pathologically were retrospectively analyzed. Results. The mean age of patients whose mean follow-up period was determined as 7.2 years was 41, and the male/female ratio was 4/1. All patients underwent total thyroidectomy. The pathology report of 2 patients (40%) revealed macrofollicular variant of papillary microcancer, and 3 patients papillary cancer macrofollicular variant. Central dissection was performed in one patient (20%) due to macroscopic pathologic lymph node and 4 metastatic lymph nodes were reported. Also, locoregional recurrence was present in 3 out of 5 patients (60%). Conclusions. Although an impression of earlier and increased risk of recurrence in papillary carcinoma with macrofollicular variant has been documented, more studies with extensive follow-up times and large populations are required. PMID- 25295214 TI - Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. AB - Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) is a potent inhibitor of VEGF receptors (VEGFR1-3) and other prooncogenic and prooncogenic receptor tyrosine kinases, including fibroblast growth factor receptors (FGFR1-4), platelet derived growth factor receptor alpha (PDGFRalpha), KIT, and RET. We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice. Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer (DTC), 5 anaplastic thyroid cancer (ATC), and 1 medullary thyroid cancer (MTC) xenograft models. Lenvatinib also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts, while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines: that is, RO82-W-1 and TT cells. Western blot analysis showed that cultured RO82-W-1 cells overexpressed FGFR1 and that lenvatinib inhibited the phosphorylation of FGFR1 and its downstream effector FRS2. Lenvatinib also inhibited the phosphorylation of RET with the activated mutation C634W in TT cells. These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and RET signaling pathway in preclinical human thyroid cancer models. PMID- 25295217 TI - Histopathological audit of 373 nononcological hysterectomies in a teaching hospital. AB - Hysterectomy, the most common gynecological surgery, provides a definitive cure to various diseases like DUB (dysfunctional uterine bleeding), leiomyoma, adenomyosis, chronic pelvic pain, prolapse, and malignancy. However, with advent of effective medical and conservative treatment modalities for nononcological causes it is now posing question mark on justification of hysterectomy. Therefore, an audit is required to assess the correlation between preoperative diagnosis and histopathological examination of specimen for justification of the procedure. In this study over period of one year (April 2013 to March 2014) 373 hysterectomies specimens were received in the department of pathology for nononcological causes. The age of patients ranged from 22 to 85 years with mean 45 +/- 9.2 years. All cases were divided into five categories on the basis of age and audit was done. In this study the most common finding was leiomyoma (43.7%) followed by adenomyosis (19.3%). Almost 50% of hysterectomies causes were justified as preoperative diagnosis matched with histopathology. Cohen kappa statistics were used to measure agreement between preoperative and postoperative histopathological diagnosis which was found to be fair with kappa value being 0.36. This study highlights that regular audit of surgeries can help improve quality of health care services and provide safe conservative option to patients. PMID- 25295216 TI - Antirelapse Efficacy of Various Primaquine Regimens for Plasmodium vivax. AB - Background. Efficacy of standard dose of primaquine (PQ) as antirelapse for P. vivax has decreased. We aimed to assess efficacy of different PQ regimens. Methods. It was an open label, randomized, controlled, parallel group, assessor blind study comparing antirelapse efficacy of 3 PQ regimens (B = 15 mg/day * 14 days, C = 30 mg/day * 7 days, and D = 30 mg/day * 14 days) with no PQ group (A) in P. vivax patients. Paired primary and recurrence samples were subjected to 3 methods: (i) month of recurrence and genotyping, (ii) by PCR-RFLP, and (iii) PCR sequencing, to differentiate relapse and reinfection. The rates of recurrence relapse and reinfection were compared. Methods were compared for concordance between them. Results. The recurrence rate was 16.39%, 8.07%, 10.07%, and 6.62% in groups A, B, C, and D, respectively (P = 0.004). The relapse rate was 6.89%, 1.55%, 4%, and 3.85% as per the month of recurrence; 8.2%, 2%, 4.58%, and 3.68% (P = 0.007) as per PCR-RFLP; and 2.73%, 1.47%, 1.55%, and 1.53% as per PCR sequencing for groups A, B, C, and D, respectively. The concordance between methods was low, 45%. Conclusion. The higher recurrence rate in no PQ as compared to PQ groups documents PQ antirelapse activity. Regimens tested were safe. However, probable resistance to PQ warrants continuous monitoring and low concordance and limitations in the methods warrant caution in interpreting. PMID- 25295218 TI - In Vitro Studies on the Antioxidant Property and Inhibition of alpha-Amylase, alpha-Glucosidase, and Angiotensin I-Converting Enzyme by Polyphenol-Rich Extracts from Cocoa (Theobroma cacao) Bean. AB - Background. This study sought to investigate the antidiabetic and antihypertensive mechanisms of cocoa (Theobroma cacao) bean through inhibition of alpha-amylase, alpha-glucosidase, angiotensin-1 converting enzyme, and oxidative stress. Methodology. The total phenol and flavonoid contents of the water extractable phytochemicals from the powdered cocoa bean were determined and the effects of the extract on alpha-amylase, alpha-glucosidase, and angiotensin-1 converting enzyme activities were investigated in vitro. Furthermore, the radicals [1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2..-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) (ABTS), hydroxyl (OH), and nitric oxide (NO)] scavenging ability and ferric reducing antioxidant property of the extract were assessed. Results. The results revealed that the extract inhibited alpha amylase (1.81 +/- 0.22 mg/mL), alpha-glucosidase (1.84 +/- 0.17 mg/mL), and angiotensin-1 converting enzyme (0.674 +/- 0.06 mg/mL [lungs], 1.006 +/- 0.08 mg/mL [heart]) activities in a dose-dependent manner and also showed dose dependent radicals [DPPH (16.94 +/- 1.34 mg/mL), NO (6.98 +/- 0.886 mg/mL), OH (3.72 +/- 0.26 mg/mL), and ABTS (15.7 +/- 1.06 mmol/TEAC.g] scavenging ability. Conclusion. The inhibition of alpha-amylase, alpha-glucosidase, and angiotensin-1 converting enzyme activities by the cocoa bean extract could be part of the possible mechanism by which the extract could manage and/or prevent type-2 diabetes and hypertension. PMID- 25295219 TI - The role of prestroke glycemic control on severity and outcome of acute ischemic stroke. AB - Background/Aim. Relatively few studies have investigated the association of prestroke glycemic control and clinical outcome in acute ischemic stroke (IS) patients, regardless of presence of diabetes mellitus (DM). The aim of this study was to investigate the importance of prestroke glycemic control on survival, stroke severity, and functional outcome of patients with acute IS. Methods. We performed a retrospective survival analysis of 501 patients with IS admitted to Sahlgrenska University Hospital from February 15, 2005, through May 31, 2009. The outcomes of interest were acute and long-term survival; the stroke severity (NIHSS) and the functional outcome, mRS, at 12 months. Results. HbA1c was a good predictor of acute (HR 1.45; CI, 1.09 to 1.93, P = 0.011) and long-term mortality (HR 1.29; CI 1.03 to 1.62; P = 0.029). Furthermore, HbA1c >6% was significantly correlated with acute stroke severity (OR 1.29; CI 1.01 to 1.67; P = 0.042) and predicted worse functional outcome at 12 months (OR 2.68; CI 1.14 to 6.03; P = 0.024). Conclusions. Our study suggests that poor glycemic control (baseline HbA1c) prior to IS is an independent risk factor for poor survival and a marker for increased stroke severity and unfavorable long-term functional outcome. PMID- 25295220 TI - Validated method for the determination of piroxicam by capillary zone electrophoresis and its application to tablets. AB - Simple and rapid capillary zone electrophoretic method was developed and validated in this study for the determination of piroxicam in tablets. The separation of piroxicam was conducted in a fused-silica capillary by using 10 mM borate buffer (pH 9.0) containing 10% (v/v) methanol as background electrolyte. The optimum conditions determined were 25 kV for separation voltage and 1 s for injection time. Analysis was carried out with UV detection at 204 nm. Naproxen sodium was used as an internal standard. The method was linear over the range of 0.23-28.79 ug/mL. The accuracy and precision were found to be satisfied within the acceptable limits (<2%). The LOD and LOQ were found to be 0.07 and 0.19 ug/mL, respectively. The method described here was applied to tablet dosage forms and the content of a tablet was found in the limits of USP-24 suggestions. To compare the results of capillary electrophoretic method, UV spectrophotometric method was developed and the difference between two methods was found to be insignificant. The capillary zone electrophoretic method developed in this study is rapid, simple, and suitable for routine analysis of piroxicam in pharmaceutical tablets. PMID- 25295221 TI - Development and Optimization of an UPLC-QTOF-MS/MS Method Based on an In-Source Collision Induced Dissociation Approach for Comprehensive Discrimination of Chlorogenic Acids Isomers from Momordica Plant Species. AB - Chlorogenic acids (CGA) have been profiled in the leaves of Momordica balsamina, Momordica charantia, and Momordica foetida. All three species were found to contain the trans and cis isomers of 4-acyl para-coumaroylquinic acid (pCoQA), caffeoylquinic acid (CQA), and feruloylquinic acid (FQA). To the best of our knowledge, this is the first report of pCoQA and FQA and their cis isomers in these Momordica species. These profiles were obtained by a newly developed UPLC qTOF-MS method based on the in-source collision induced dissociation (ISCID) method optimized to mimic the MS(2) and MS(3) fragmentation of an ion trap-based MS. The presence of the cis isomers is believed to be due to high UV exposure of these plants. Furthermore, the absence of the 3-acyl and 5-acyl CGA molecules points to a metabolic mark that is unusual and represents a very interesting biochemical phenotype of these species. Our optimized ISCID method was also shown to be able to distinguish between the geometrical isomers of all three forms of CGA, a phenomenon previously deemed impossible with other common mass spectrometry systems used for CGA analyses. PMID- 25295222 TI - Massive transfusion protocol activation does not result in preferential use of older red blood cells. AB - Widespread, anecdotal belief exists that patients receiving massive transfusion, particularly those for whom a massive transfusion protocol (MTP) is activated, are more likely to receive older red blood cells (RBCs). Retrospective review of blood bank records from calendar year 2011 identified 131 patients emergently issued >=10 RBC units (emergency release (ER)) prior to obtaining a type and screen. This cohort was subclassified based on whether there was MTP activation. For comparison, 176 identified patients transfused with >=10 RBC units in a routine fashion over 24 hours represented the nonemergency release (nER) cohort. Though the median age of ER RBCs was 5 days older than nER RBCs (ER 20, nER 15 days, P < 0.001), both fell within the third week of storage. Regardless of MTP activation, transfused ER RBCs had the same median age (MTP 20, no-MTP 20 days, P = 0.069). In the ER cohort, transition to type-specific blood components increased the median age of transfused RBC units from 17 to 36 days (P < 0.001). These data refute the anecdotal belief that MTP activation results in transfusion of older RBCs. However, upon transition to type-specific blood components, the age of RBCs enters a range in which it is hypothesized that there may be a significant effect of storage age on clinical outcomes. PMID- 25295223 TI - Temporal course of the tourette syndrome clinical triad. AB - BACKGROUND: Tourette syndrome (TS) is a disorder characterized by childhood onset of motor and phonic tics, often with improvement of tic symptoms by young adult years. The temporal course of tics and commonly comorbid behavioral symptoms is still not well characterized. METHODS: In order to clarify the time course of tics and comorbid attention deficit hyperactivity disorder (ADHD) or obsessive compulsive disorder (OCD) in TS, we administered a brief survey regarding the course of symptoms at a single point in time to 53 TS patients aged 13-31 years. RESULTS: Mean age (+/-SD) at symptom onset was 7.9 (+/-3.6) years for tics, 7.9 (+/-3.5) for ADHD, and 9.2 (+/-5.0) for OCD. Age at peak symptom severity was 12.3 (+/-4.6) years for tics, 10.8 (+/-3.8) for ADHD, and 12.6 (+/-5.5) for OCD. Tics, ADHD, and OCD were reported to be no longer present in 32.0%, 22.8%, and 21.0% of subjects, respectively. Decline in symptom severity began at age 14.7 (+/-3.7) years for tics, 13.9 (+/-2.9) for ADHD, and 15.1 (+/-5.0) for OCD. Remission of symptoms occurred at age 17.4 (+/-3.8) years for tics, 17.4 (+/-1.3) for ADHD, and 15.6 (+/-2.3) for OCD. DISCUSSION: Our data confirm and expand previously reported TS spectrum symptom milestones and may guide design of future research aimed at improving the course of TS. PMID- 25295224 TI - Texaphyrins and water-soluble zinc(II) ionophores: development, mechanism of anticancer activity, and synergistic effects. AB - Texaphyrins, first prepared by Sessler and coworkers in the 1980s, represent early examples of expanded porphyrins. This class of pentaaza, oligopyrrolic macrocycles demonstrates excellent tumor localization and metal-chelating properties. In biological milieus, texaphyrins act as redox mediators and are able to produce reactive oxygen species. Furthermore, texaphyrins have been shown to upregulate zinc in vivo, an important feature that inspired us to develop new zinc ionophores that might allow the same function to be elicited but via a simpler chemical means. In this review, the basic properties of texaphyrins and the zinc ionophores they helped spawn will be discussed in the cadre of developing an understanding that could lead to the preparation of new, redox active anticancer agents. PMID- 25295226 TI - Optimizing tissue sampling for the diagnosis, subtyping, and molecular analysis of lung cancer. AB - Lung cancer has entered the era of personalized therapy with histologic subclassification and the presence of molecular biomarkers becoming increasingly important in therapeutic algorithms. At the same time, biopsy specimens are becoming increasingly smaller as diagnostic algorithms seek to establish diagnosis and stage with the least invasive techniques. Here, we review techniques used in the diagnosis of lung cancer including bronchoscopy, ultrasound-guided bronchoscopy, transthoracic needle biopsy, and thoracoscopy. In addition to discussing indications and complications, we focus our discussion on diagnostic yields and the feasibility of testing for molecular biomarkers such as epidermal growth factor receptor and anaplastic lymphoma kinase, emphasizing the importance of a sufficient tumor biopsy. PMID- 25295225 TI - The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models. AB - When PI3K (phosphatidylinositol-3 kinase) is activated by receptor tyrosine kinases, it phosphorylates PIP2 to generate PIP3 and activates the signaling pathway. Phosphatase and tensin homolog deleted on chromosome 10 dephosphorylates PIP3 to PIP2, and thus, negatively regulates the pathway. AKT (v-akt murine thymoma viral oncogene homolog; protein kinase B) is activated downstream of PIP3 and mediates physiological processes. Furthermore, substantial crosstalk exists with other signaling networks at all levels of the PI3K pathway. Because of its diverse array, gene mutations, and amplifications and also as a consequence of its central role in several signal transduction pathways, the PI3K-dependent axis is frequently activated in many tumors and is an attractive therapeutic target. The preclinical testing and analysis of these novel therapies requires appropriate and well-tailored systems. Mouse models in which this pathway has been genetically modified have been essential in understanding the role that this pathway plays in the tumorigenesis process. Here, we review cancer mouse models in which the PI3K/AKT pathway has been genetically modified. PMID- 25295228 TI - Economic Impact of Tissue Testing and Treatments of Metastatic NSCLC in the Era of Personalized Medicine. AB - A paradigm-shift in the management of non-small cell lung cancer (NSCLC) has resulted in many new therapies becoming available for patients with advanced disease. Stratification of treatment by histologic and molecular subtype is recommended to obtain the greatest clinical benefit for patients while minimizing adverse effects of treatment. However, these advances in diagnosis and treatment of NSCLC have come at a financial cost. This review highlights the economic impact of screening for molecular abnormalities and targeted treatment for advanced NSCLC. Major determinants of cost are drug acquisition and molecular testing. As technologies advance, molecular testing costs may reduce. However, we must collaborate with payers and manufacturers to ensure that high drug costs do not limit patient accessibility to potentially beneficial treatment. PMID- 25295229 TI - The potential diagnostic role of the number of ultrasonographic characteristics for patients with thyroid nodules evaluated as bethesda I-v. AB - OBJECTIVE: Fine-needle aspiration cytology (FNAC) is considered to be the most reliable method of examination for thyroid nodules. However, when thyroid nodules are evaluated as Bethesda I-V, the role of ultrasonography is considered to be enhanced. We investigated the association between a number of ultrasonographic (US) characteristics and the risk of thyroid malignancy, and assessed the optimal compromise on the number of US characteristics for predicting thyroid malignancy. METHODS: Seventy-three patients, whose thyroid nodules were evaluated as Bethesda I-V by FNAC prior to surgery, were treated surgically. A number of US characteristics, such as microcalcification, irregular margins, hypoechogenicity, a taller-than-wide shape, and the absence of halo sign, were assessed before surgery. The optimal compromise on the number of US characteristics was analyzed using a receiver operating characteristics (ROC) curve. The area under the ROC curve (AUC) represents the overall discriminatory ability of a test. RESULTS: The risk of malignancy was 11.8% in patients without any US characteristics, 44.4% in those with one characteristic, 61.5% in those with two characteristics, 75% in those with three characteristics, 90% in those with four characteristics, and 100% in those with five characteristics. The AUC was favorable (0.81599). At least two US characteristics were revealed to be the optimal compromise on the number of US characteristics based on the ROC curve. CONCLUSION: We proved the role of the number of US characteristics in predicting thyroid malignancy. It was thought that a surgical approach should be considered for patients with at least two US characteristics. PMID- 25295227 TI - Image-guided radiotherapy for cardiac sparing in patients with left-sided breast cancer. AB - Patients with left-sided breast cancer are at risk of cardiac toxicity because of cardiac irradiation during radiotherapy with the conventional 3-dimensional conformal radiotherapy technique. In addition, many patients may receive chemotherapy prior to radiation, which may damage the myocardium and may increase the potential for late cardiac complications. New radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) may decrease the risk of cardiac toxicity because of the steep dose gradient limiting the volume of the heart irradiated to a high dose. Image-guided radiotherapy (IGRT) is a new technique of IMRT delivery with daily imaging, which may further reduce excessive cardiac irradiation. Preliminary results of IGRT for cardiac sparing in patients with left-sided breast cancer are promising and need to be investigated in future prospective clinical studies. PMID- 25295231 TI - PP2A: The Achilles Heal in MDS with 5q Deletion. AB - Myelodysplastic syndromes (MDS) represent a hematologically diverse group of myeloid neoplasms, however, one subtype characterized by an isolated deletion of chromosome 5q [del(5q)] is pathologically and clinically distinct. Patients with del(5q) MDS share biological features that account for the profound hypoplastic anemia and unique sensitivity to treatment with lenalidomide. Ineffective erythropoiesis in del(5q) MDS arises from allelic deletion of the ribosomal processing S-14 (RPS14) gene, which leads to MDM2 sequestration with consequent p53 activation and erythroid cell death. Since its approval in 2005, lenalidomide has changed the natural course of the disease. Patients who achieve transfusion independence and/or a cytogenetic response with lenalidomide have a decreased risk of progression to acute myeloid leukemia and an improved overall survival compared to non-responders. Elucidation of the mechanisms of action of lenalidomide in del(5q) MDS has advanced therapeutic strategies for this disease. The selective cytotoxicity of lenalidomide in del(5q) clones derives from inhibition of a haplodeficient phosphatase whose catalytic domain is encoded within the common deleted region on chromosome 5q, i.e., protein phosphatase 2A (PP2Acalpha). PP2A is a highly conserved, dual specificity phosphatase that plays an essential role in regulation of the G2/M checkpoint. Inhibition of PP2Acalpha results in cell-cycle arrest and apoptosis in del(5q) cells. Targeted knockdown of PP2Acalpha using siRNA is sufficient to sensitize non-del(5q) clones to lenalidomide. Through its inhibitory effect on PP2A, lenalidomide stabilizes MDM2 to restore p53 degradation in erythroid precursors, with subsequent arrest in G2/M. Unfortunately, the majority of patients with del(5q) MDS develop resistance to lenalidomide over time associated with PP2Acalpha over-expression. Targeted inhibition of PP2A with a more potent inhibitor has emerged as an attractive therapeutic approach for patients with del(5q) MDS. PMID- 25295232 TI - Application of Rasch model for evaluating the quality of life in blind war veterans. AB - Background Quality of life evaluates the general well-being of individuals and it can be considered as one of the important aspects in programming and giving service to disabled people. Blindness is one of the most important kinds of physical disability that has a direct effect on quality of life, so this study aimed to explore how war blindness influences the quality of life. METHODS: In this cross-sectional study, data from 71 blind war (Iran-Iraq) veterans in 2010 were collected using the Short Form Health Survey instrument (SF36). Rasch model was fitted by running WINSTEPS software and then item parameter (beta), i.e. difficulty of items, and person parameter ([Formula: see text] ), i.e. the ability or attainment level of respondents, were estimated. RESULTS: In a total of 71 cases, 69 cases (97 %) were male with a mean (+/-SD ) age and blindness duration range of 48.97 (+/-10.655) yrs and 25.74 (+/-3.692) yrs, respectively. Item difficulty ranged from 2.962 to 4.441. Comparison of the SF36 scores and Rasch measurements showed that standard error of Rasch model estimates in physical and total scores are less than SF36 scores. CONCLUSION: Due to the advantages and higher accuracy of the Rasch model, using this model can be a good alternative for the traditional models. With due regard to the relative low quality of life of blind war veterans in this study and other similar study, further investigation are recommended to be carried out to this group of society. PMID- 25295233 TI - Historical trends and projected hospital admissions for chronic hepatitis C infection in Canada: a birth cohort analysis. AB - BACKGROUND: Much of the recent increase in hospital admission rates and mortality associated with hepatitis C in Canada is believed to be because of a higher prevalence of hepatitis C virus infection among those born between 1945 and 1965 (the baby boomer generation). We explored the effects of birth cohort on the rates of and projected trends in hospital admissions associated with hepatitis C. METHODS: The hospital records of 17 344 inpatients with a diagnosis of chronic hepatitis C and liver disease, including liver cancer, were extracted from the Canadian Discharge Abstract Database for April 2004 to March 2011. For each 5 year birth cohort from 1915 to 1984, regression analysis was used to estimate the temporal trends associated with the average age of the cohort during the study period. Future hospital admissions were predicted based on the assumption that past trends would continue. RESULTS: Hospital admissions associated with hepatitis C and liver disease increased an average of 6.0% (95% confidence interval [CI] 4.4%-7.7%) a year over the study period. As of 2010, hospital admission rates were highest for the 1950-1954 and 1955-1959 birth cohorts, at 17.6 (95% CI 13.2-23.5) and 13.7 (95% CI 10.3-18.2) times the rate for the 1970 1974 birth cohort. The corresponding same-age rate ratios predicted under a status quo scenario were 3.6 (95% CI 2.3-4.9) and 3.4 (95% CI 2.1-4.7). Same-age rate ratios were significantly higher for the four 5-year birth cohorts between 1950 and 1969 compared with other birth cohorts. INTERPRETATION: Hospital admissions associated with chronic hepatitis C and liver disease were significantly higher for the 1950-1954 and 1955-1959 birth cohorts than for most other birth cohorts. Without further interventions, the disease burden associated with hepatitis C will continue to increase for most birth cohorts, likely peaking after age 70 years. The substantial disease burden emerging in younger birth cohorts should be monitored. PMID- 25295230 TI - The Biology and Targeting of FLT3 in Pediatric Leukemia. AB - Despite remarkable improvement in treatment outcomes in pediatric leukemia over the past several decades, the prognosis for high-risk groups of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), as well as for relapsed leukemia, remains poor. Intensification of chemotherapy regimens for those at highest risk has improved success rates, but at the cost of significantly increased morbidity and long-term adverse effects. With the success of imatinib in Philadelphia-chromosome-positive leukemia and all-trans retinoic acid in acute promyelocytic leukemia, the quest to find additional molecularly targeted therapies has generated much excitement over recent years. Another such possible target in pediatric acute leukemia is FMS-like tyrosine kinase 3 (FLT3). FLT3 aberrations are among the most frequently identified transforming events in AML, and have significant clinical implications in both high-risk pediatric AML and in certain high-risk groups of pediatric ALL. Therefore, the successful targeting of FLT3 has tremendous potential to improve outcomes in these subsets of patients. This article will give an overview of the molecular function and signaling of the FLT3 receptor, as well as its pathogenic role in leukemia. We review the discovery of targeting FLT3, discuss currently available FLT3 inhibitors in pediatric leukemia and results of clinical trials to date, and finally, consider the future promise and challenges of FLT3 inhibitor therapy. PMID- 25295234 TI - Influence of country of birth and ethnicity on body mass index among Canadian youth: a national survey. AB - BACKGROUND: The body mass index (BMI) of youth often changes when they immigrate to a new country as a result of the adoption of new behaviours, a process called acculturation. We investigated whether BMI differs by country of birth (Canada v. other countries) and ethnicity, both individually and together. We also examined whether time since immigration and health-related behaviour explain any observed BMI differences. METHODS: Data sources were the Canadian Health Behaviour in School-Aged Children study and the Canada Census of Population. Participants were youth in grades 6-10 (weighted sample n = 19 272). A questionnaire was used to assess participants' sociodemographic characteristics, height, weight and health related behaviour. We calculated BMIs from participants' self-reported heights and weights and used World Health Organization growth references to determine BMI percentiles. RESULTS: Based on self-reported heights and weights, BMI percentiles for foreign-born youth were lower than those of youth born in Canada (-4, 95% confidence interval [CI] -6 to -2). This difference did not decrease with time since immigration. Similarly, BMI percentiles were lower among East and Southeast Asian youth than their peers from the Canadian host culture (-4, 95% CI -6 to 2). Finally, BMI percentiles for foreign-born Arab and West Asian youth and East Indian and South Asian youth were lower than their Canadian-born peers of the same ethnicity (-14, 95% CI -22 to -7; -8, 95% CI -14 to -3). INTERPRETATION: Immigrant generation and ethnicity were related to BMI among Canadian youth, both independently and together. Some ethnic groups showed differences by country of birth, i.e., East Indian and South Asian, while others showed no such difference, i.e., East and Southeast Asian. There was no association with time since immigration. Our findings reinforce the need to investigate country of birth and ethnicity when considering the determinants of childhood BMI. PMID- 25295235 TI - A quantitative and qualitative evaluation of the British Columbia Take Home Naloxone program. AB - BACKGROUND: In August 2012, the British Columbia Take Home Naloxone (BCTHN) program was introduced to help to reduce opioid overdose and its consequences. This study evaluates the BCTHN program, identifying the successes and challenges of implementing a provincial program in Canada. METHODS: In this cross-sectional study, we reviewed the records of the BCTHN administrative program to report on program outcomes (participation and overdose reversals). Focus groups and individual interviews were conducted with 40 clients in Vancouver; 12 individual interviews were completed with service providers, police officers and parents of people who use opioids from both the Vancouver and Interior regions of British Columbia. Qualitative data were analyzed using content analysis and a qualitative descriptive approach. RESULTS: As of March 13, 2014, the BCTHN program had been implemented at 40 sites, trained 1318 participants in overdose prevention, recognition and response, distributed 836 kits to clients and received reports of 85 overdose reversals. Stakeholders were supportive of the program, and clients reported greater confidence in response to overdose. Service providers found the program training materials easy to use and that training increased client engagement. Some of the challenges included difficulty in identifying physician willing to prescribe, recruitment of some at-risk populations (e.g., long-term opioid users and patients with chronic pain), and clients' reluctance to call 911. We also found that the police had some misconceptions about BCTHN. INTERPRETATION: The BCTHN program was easy to implement, empowering for clients and was responsible for reversing 85 overdoses in its first 20 months. We suggest communities across Canada should consider implementing take-home naloxone programs and evaluate their findings. PMID- 25295236 TI - Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. AB - BACKGROUND: Guidelines recommend metformin as the first-line oral treatment for type 2 diabetes. We conducted a systematic review to assess whether the use of second- and third-generation sulfonylurea agents is associated with benefits and harms in terms of patient-important outcomes compared with metformin. METHODS: We searched several electronic databases and other sources for randomized clinical trials published to August 2011. We included trials that compared sulfonylurea versus metformin monotherapy among patients 18 years or older with type 2 diabetes and that had an intervention period of at least 24 weeks. We assessed risk of bias and extracted data related to interventions and outcomes. The risk of random errors was assessed by trial sequential analysis. RESULTS: We included 14 trials (4560 participants). All trials were judged to be at high risk of bias. Data on patient-important outcomes were sparse. Compared with metformin, sulfonylurea did not significantly affect all-cause mortality (relative risk [RR] 0.98, 95% confidence interval [CI] 0.61 to 1.58) or cardiovascular mortality (RR 1.47, 95% CI 0.54 to 4.01). Sulfonylurea significantly decreased the risk of nonfatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93). However, the definition of this outcome varied among trials, and trial sequential analysis showed that more trials are needed before reliable conclusions can be drawn. No differences between sulfonylurea and metformin were found for change in fasting blood glucose level or glycosylated hemoglobin concentration in the random effects model. Sulfonylurea resulted in greater weight gain compared with metformin, a finding confirmed in the trial sequential analysis. Significantly more patients in the sulfonylurea arm than in the metformin arm had mild hypoglycemia (RR 2.95, 95% CI 2.13 to 4.07) and severe hypoglycemia (RR 5.64, 95% CI 1.22 to 26.00). INTERPRETATION: Some evidence suggests that, compared with metformin, second- and third-generation sulfonylureas may not affect all-cause or cardiovascular mortality but may decrease the risk of nonfatal macrovascular outcomes among patients with type 2 diabetes. They may also increase the risk of hypoglycemia. In general, the available data were too few and inconsistent to provide firm evidence concerning patient-important outcomes in relation to the benefits and harms of sulfonylurea versus metformin monotherapy. PMID- 25295237 TI - Temporal trends and differences in mortality at trauma centres across Ontario from 2005 to 2011: a retrospective cohort study. AB - BACKGROUND: Care in a trauma centre is associated with significant reductions in mortality after severe injury. However, emerging evidence suggests that outcomes across similarly accredited trauma centres are not equivalent, even after adjusting for case-mix. The primary objective of this analysis was to evaluate secular trends in overall mortality at trauma centres. Secondarily, we explored trauma centre-specific mortality to determine the extent of variation between centres. METHODS: Data on 26 421 adults (>=?18 yr) admitted to a trauma centre between 2005 and 2011 were derived from the Ontario Trauma Registry. We used generalized estimating equations to calculate in-hospital mortality over time and hierarchical models to estimate trauma-centre-specific mortality. To quantify variability between centres, we calculated median odds ratios. Adjusted odds of death were calculated for each trauma centre to identify those with higher than expected, average and lower than expected mortality. RESULTS: Overall mortality at trauma centres decreased from 13.2% in 2005 to 11.2% in 2009. After adjusting for case mix, the odds of death decreased by approximately 3% a year (95% confidence interval 0%-5%). Trauma centre-specific mortality ranged from 11.4% to 13.1%. After adjusting for case mix, differences in trauma centre-specific mortality were observed (median odds ratio = 1.25), suggesting that the odds of dying could be 1.25-fold greater if the same patient was admitted to 1 randomly selected trauma centre as opposed to another. Differences were most pronounced for patients with isolated head injuries and among older patients as evidenced by higher median odds ratios and the number of outliers. INTERPRETATION: We observed a significant improvement over time in the mortality of severely injured patients cared for at Ontario's trauma centres. However, considerable differences in trauma centre-specific mortality were observed. Differences were most pronounced among older injured patients and those with isolated traumatic brain injury. System-wide performance improvement initiatives should target these subgroups. PMID- 25295239 TI - Medical repatriation of migrant farm workers in Ontario: a descriptive analysis. AB - BACKGROUND: Approximately 40 000 migrant farm workers are employed annually in Canada through temporary foreign worker programs. Workers experiencing health conditions that prevent ongoing work are normally repatriated to their home country, which raises concerns about human rights and health equity. In this study, we present data on the reasons for medical repatriation of migrant farm workers in Ontario. METHODS: In this retrospective descriptive study, we examined medical repatriation data from Foreign Agricultural Resource Management Services, a non-profit corporation managing the contracts of more than 15 000 migrant farm workers in Ontario annually. We extracted repatriation and demographic data for workers from 2001-2011. Physician volunteers used a validated system to code the reported reasons for medical repatriation. We conducted descriptive analyses of the dominant reasons for repatriation and rates of repatriation. RESULTS: During 2001-2011, 787 repatriations occurred among 170 315 migrant farm workers arriving in Ontario (4.62 repatriations per 1000 workers). More than two-thirds of repatriated workers were aged 30-49 years. Migrant farm workers were most frequently repatriated for medical or surgical reasons (41.3%) and external injuries including poisoning (25.5%). INTERPRETATION: This study provides quantitative health data related to a unique and vulnerable occupational group. Our findings reinforce existing knowledge regarding occupational hazards and health conditions among migrant farm workers. Medical repatriation of migrant farm workers merits further examination as a global health equity concern. PMID- 25295238 TI - Cardiovascular risk among South Asians living in Canada: a systematic review and meta-analysis. AB - BACKGROUND: South Asians represent about 3% of the Canadian population and have a higher burden of certain cardiovascular risk factors and cardiovascular disease (CVD) compared with white people. The objective of this study was to review the literature to compare cardiovascular risk factors and disease management practices among adult South Asian and white Canadians. METHODS: We searched MEDLINE, Embase, Cochrane and Cumulative Index to Nursing and Allied Health Literature databases from their inception through Feb. 17, 2014 and the reference lists of the selected articles. English-language studies of interventions and observational studies of biological mechanisms underlying CVD risk in South Asians conducted in Canada were eligible for inclusion. Where appropriate, we used random-effects meta-analyses to integrate results comparing the CVD risk profiles of South Asian and white Canadians. RESULTS: We included 50 articles (n = 5 805 313 individuals) in this review. Compared with white Canadians, South Asian Canadians had a higher prevalence and incidence of CVD, an increased prevalence of diabetes (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.81 to 2.80, p < 0.001) and hypertension (OR 1.11, 95% CI 1.02 to 1.22, p = 0.02), lower high-density lipoprotein cholesterol levels (mean difference -0.19 mmol/L, 95% CI -0.25 to -0.13 mmol/L, p < 0.001) and a higher percentage of body fat (men: absolute mean difference 3.23%, 95% CI 0.83% to 5.62%, p = 0.008; women: absolute mean difference 4.09%, 95% CI 3.46% to 4.72%, p < 0.001). South Asian people are also more sedentary, consume higher levels of carbohydrates and are less likely to smoke tobacco (OR 0.38, 95% CI 0.24 to 0.60, p < 0.001]) than white Canadians. No differences in access to diagnostic tests, outcomes following cardiovascular surgery or use of cardiac rehabilitation programs were apparent. INTERPRETATION: Compared with white people, South Asian people living in Canada have a higher prevalence and incidence of CVD and possess a unique cardiovascular risk profile. PMID- 25295240 TI - Performance of the high-sensitivity troponin assay in diagnosing acute myocardial infarction: systematic review and meta-analysis. AB - BACKGROUND: High-sensitivity cardiac troponin assays have been adopted by many clinical centres worldwide; however, clinicians are uncertain how to interpret the results. We sought to assess the utility of these assays in diagnosing acute myocardial infarction (MI). METHODS: We carried out a systematic review and meta analysis of studies comparing high-sensitivity with conventional assays of cardiac troponin levels among adults with suspected acute MI in the emergency department. We searched MEDLINE, EMBASE and Cochrane databases up to April 2013 and used bivariable random-effects modelling to obtain summary parameters for diagnostic accuracy. RESULTS: We identified 9 studies that assessed the use of high-sensitivity troponin T assays (n = 9186 patients). The summary sensitivity of these tests in diagnosing acute MI at presentation to the emergency department was estimated to be 0.94 (95% confidence interval [CI] 0.89-0.97); for conventional tests, it was 0.72 (95% CI 0.63-0.79). The summary specificity was 0.73 (95% CI 0.64-0.81) for the high-sensitivity assay compared with 0.95 (95% CI 0.93-0.97) for the conventional assay. The differences in estimates of the summary sensitivity and specificity between the high-sensitivity and conventional assays were statistically significant (p < 0.01). The area under the curve was similar for both tests carried out 3-6 hours after presentation. Three studies assessed the use of high-sensitivity troponin I assays and showed similar results. INTERPRETATION: Used at presentation to the emergency department, the high-sensitivity cardiac troponin assay has improved sensitivity, but reduced specificity, compared with the conventional troponin assay. With repeated measurements over 6 hours, the area under the curve is similar for both tests, indicating that the major advantage of the high-sensitivity test is early diagnosis. PMID- 25295242 TI - Future directions for public health education reforms in India. AB - Health systems globally are experiencing a shortage of competent public health professionals. Public health education across developing countries is stretched by capacity generation and maintaining an adequate 'standard' and 'quality' of their graduate product. We analyzed the Indian public health education scenario using the institutional and instructional reforms framework advanced by the Lancet Commission report on Education of Health Professionals. The emergence of a new century necessitates a re-visit on the institutional and instructional challenges surrounding public health education. Currently, there is neither an accreditation council nor a formal structure or system of collaboration between academic stakeholders. Health systems have little say in health professional training with limited dialogue between health systems and public health education institutions. Despite a recognized shortfall of public health professionals, there are limited job opportunities for public health graduates within the health system and absence of a structured career pathway for them. Public health institutions need to evolve strategies to prevent faculty attrition. A structured development program in teaching-learning methods and pedagogy is the need of the hour. PMID- 25295241 TI - Endocrinopathies in survivors of childhood neoplasia. AB - Advancements in cancer treatments have increased the number of survivors of childhood cancers. Endocrinopathies are common complications following cancer therapy and may occur decades later. The objective of the current review is to address the main endocrine abnormalities detected in childhood cancer survivors including disorders of the hypothalamic-pituitary axis, thyroid, puberty, gonads, bone, body composition, and glucose metabolism. PMID- 25295243 TI - The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk. AB - The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people. PMID- 25295244 TI - Distance to School is Associated with Sedentary Time in Children: Findings from the URBAN Study. AB - Sedentary behavior is associated with overweight and obesity in children, and distance to school has been negatively associated with active commuting to school. It is not known how distance to school relates to sedentary behavior in children. The aim of this study was to investigate the association between distance to school and children's sedentary behavior during weekdays at times where children interact with the neighborhood environment. Children (5-13 years, n = 295) who participated in the understanding relationships between activity and neighborhoods study (2008-2010) across four New Zealand cities wore a hip-mounted accelerometer for 7 days. Minutes spent sedentary (accelerometer count <100 min( 1)) were derived for the school travel periods (0800-0859 and 1500-1559) and after school discretionary time (1600-1759). Shortest street network distance to school was calculated from residential addresses using geographical information systems and parsed into tertiles for analysis. Children completed a daily travel log including mode of transport to and from school, which was dichotomized into active (walking and cycling) and passive (motorized) modes. Children living in the second tertile of distance from school were the least sedentary during the school traveling periods (42 +/- 10%, mean +/- true between-child SD) compared to those living in the first or third distance tertiles (47 +/- 10 and 49 +/- 10%, respectively); the differences were clear and likely substantial (90% confidence limits +/- 6%). Children who traveled by motorized transport were more sedentary for each of the distance tertiles (50 versus 44%, 46 versus 39%, and 54 versus 27% for first, second, and third tertiles, respectively; 90% confidence limits +/ 7%). In the period of 1600-1759, girls in the third distance tertile were the most sedentary. The combined effects of 1-2 km distance from school and active commuting to school contributed to least sedentary time in children. PMID- 25295246 TI - Physical and dosimetric optimization of laser equipment in dermatology: a preliminary study. AB - The aim of this preliminary study is to investigate the correlation between clinical set-up at present used in the treatment of specific skin conditions and laser beam absorbed power in the tissue. This study focused on the CO2 and Nd-Yag laser equipment used in the daily clinical practice in the Department of Dermatology of San Gallicano Institute in Rome. Different types of tissue equivalent material with various water and haemoglobin concentrations were tested to evaluate laser beam attenuation power. In particular, thinly sliced pork loin, of uniform consistency and without fat, was selected for its high content of haemoglobin to mimic human tissues. An optical power meter was used to measure the power or energy of a laser beam. During measurements, the tissue equivalent phantoms were positioned on the detector head and the laser beam was orthogonally oriented. The results of two experimental set-ups are reported here. The dependence of residual power (W) as a function of ex vivo tissue thickness (mm) for different laser output powers was studied. Data were fitted by a parametric logistic equation. These preliminary data allow for more accurately determining the energy fraction released from lasers to the tissues in order to improve clinical outcomes. PMID- 25295245 TI - Autophagy and non-alcoholic fatty liver disease. AB - Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma. PMID- 25295248 TI - Chronic kidney disease and upper tract urothelial carcinomas. PMID- 25295250 TI - Age dependent differences in collagen alignment of glutaraldehyde fixed bovine pericardium. AB - Bovine pericardium is used for heart valve leaflet replacement where the strength and thinness are critical properties. Pericardium from neonatal animals (4-7 days old) is advantageously thinner and is considered as an alternative to that from adult animals. Here, the structures of adult and neonatal bovine pericardium tissues fixed with glutaraldehyde are characterized by synchrotron-based small angle X-ray scattering (SAXS) and compared with the mechanical properties of these materials. Significant differences are observed between adult and neonatal tissue. The glutaraldehyde fixed neonatal tissue has a higher modulus of elasticity (83.7 MPa) than adult pericardium (33.5 MPa) and a higher normalised ultimate tensile strength (32.9 MPa) than adult pericardium (19.1 MPa). Measured edge on to the tissue, the collagen in neonatal pericardium is significantly more aligned (orientation index (OI) 0.78) than that in adult pericardium (OI 0.62). There is no difference in the fibril diameter between neonatal and adult pericardium. It is shown that high alignment in the plane of the tissue provides the mechanism for the increased strength of the neonatal material. The superior strength of neonatal compared with adult tissue supports the use of neonatal bovine pericardium in heterografts. PMID- 25295249 TI - Interaction analysis through proteomic phage display. AB - Phage display is a powerful technique for profiling specificities of peptide binding domains. The method is suited for the identification of high-affinity ligands with inhibitor potential when using highly diverse combinatorial peptide phage libraries. Such experiments further provide consensus motifs for genome wide scanning of ligands of potential biological relevance. A complementary but considerably less explored approach is to display expression products of genomic DNA, cDNA, open reading frames (ORFs), or oligonucleotide libraries designed to encode defined regions of a target proteome on phage particles. One of the main applications of such proteomic libraries has been the elucidation of antibody epitopes. This review is focused on the use of proteomic phage display to uncover protein-protein interactions of potential relevance for cellular function. The method is particularly suited for the discovery of interactions between peptide binding domains and their targets. We discuss the largely unexplored potential of this method in the discovery of domain-motif interactions of potential biological relevance. PMID- 25295247 TI - Targeting mast cells tryptase in tumor microenvironment: a potential antiangiogenetic strategy. AB - Angiogenesis is a complex process finely regulated by the balance between angiogenesis stimulators and inhibitors. As a result of proangiogenic factors overexpression, it plays a crucial role in cancer development. Although initially mast cells (MCs) role has been defined in hypersensitivity reactions and in immunity, it has been discovered that MCs have a crucial interplay on the regulatory function between inflammatory and tumor cells through the release of classical proangiogenic factors (e.g., vascular endothelial growth factor) and nonclassical proangiogenic mediators granule-associated (mainly tryptase). In fact, in several animal and human malignancies, MCs density is highly correlated with tumor angiogenesis. In particular, tryptase, an agonist of the proteinase activated receptor-2 (PAR-2), represents one of the most powerful angiogenic mediators released by human MCs after c-Kit receptor activation. This protease, acting on PAR-2 by its proteolytic activity, has angiogenic activity stimulating both human vascular endothelial and tumor cell proliferation in paracrine manner, helping tumor cell invasion and metastasis. Based on literature data it is shown that tryptase may represent a promising target in cancer treatment due to its proangiogenic activity. Here we focused on molecular mechanisms of three tryptase inhibitors (gabexate mesylate, nafamostat mesylate, and tranilast) in order to consider their prospective role in cancer therapy. PMID- 25295251 TI - Risk factors for chronic subdural hematoma after a minor head injury in the elderly: a population-based study. AB - Chronic subdural hematoma (CSDH) is one of the major comorbidities in elderly resulting in disability and death. Early recognition of CSDH is important for early management. However, manifestations of CSDH are nonspecific and subtle. Therefore, identification of risk factors of CSDH can offer clinical follow-up strategies for patients after episodes of head injury. The purpose of the study aimed at identifying risk factors of CSDH of Taiwanese. Analysis of data from the National Health Insurance provides important information on predictive factors influencing the early diagnosis of CSDH in elderly patients following minor head injuries. The current study is the first nationwide population-based study in Taiwan, showing that old age (>=75 years), male gender, and coexisting hydrocephalus are significantly predictive factors, irrespective to their medical comorbidities. PMID- 25295252 TI - The role of microRNAs in ovarian cancer. AB - Ovarian cancer is the most lethal of malignant gynecological tumors. Its lethality may be due to difficulties in detecting it at an early stage and lack of effective treatments for patients with an advanced or recurrent status. Therefore, there is a strong need for prognostic and predictive markers to diagnose it early and to help optimize and personalize treatment. MicroRNAs are noncoding RNAs that regulate target genes posttranscriptionally. They are involved in carcinogenesis, cell cycle, apoptosis, proliferation, invasion, metastasis, and chemoresistance. The dysregulation of microRNAs is involved in the initiation and progression of human cancers including ovarian cancer, and strong evidence that microRNAs can act as oncogenes or tumor suppressor genes has emerged. Several microRNA signatures that are unique to ovarian cancer have been proposed, and serum-circulating microRNAs have the potential to be useful diagnostic and prognostic biomarkers. Various microRNAs such as those in the miR 200 family, the miR-199/214 cluster, or the let-7 paralogs have potential as therapeutic targets for disseminated or chemoresistant ovarian tumors. Although many obstacles need to be overcome, microRNA therapy could be a powerful tool for ovarian cancer prevention and treatment. In this review, we discuss the emerging roles of microRNAs in various aspects of ovarian cancer. PMID- 25295253 TI - Optical coherence tomography guided laser cochleostomy: towards the accuracy on tens of micrometer scale. AB - Lasers have been proven to be precise tools for bone ablation. Applying no mechanical stress to the patient, they are potentially very suitable for microsurgery on fragile structures such as the inner ear. However, it remains challenging to control the laser-bone ablation without injuring embedded soft tissue. In this work, we demonstrate a closed-loop control of a short-pulsed CO2 laser to perform laser cochleostomy under the monitoring of an optical coherence tomography (OCT) system. A foresighted detection of the bone-endosteum-perilymph boundary several hundred micrometers before its exposure has been realized. Position and duration of the laser pulses are planned based on the residual bone thickness distribution. OCT itself is also used as a highly accurate tracking system for motion compensation between the target area and the optics. During ex vivo experimental evaluation on fresh porcine cochleae, the ablation process terminated automatically when the thickness of the residual tissue layer uniformly reached a predefined value. The shape of the resulting channel bottom converged to the natural curvature of the endosteal layer without injuring the critical structure. Preliminary measurements in OCT scans indicated that the mean absolute accuracy of the shape approximation was only around 20 MUm. PMID- 25295254 TI - New insights into monoclonal B-cell lymphocytosis. AB - Monoclonal B-cell lymphocytosis (MBL) is a premalignant condition characterized by the presence of less than 5000/MUL circulating clonal B cells in otherwise healthy individuals. Three subcategories have been identified according to the immunophenotypic features: CLL-like, CD5(+) atypical, and CD5(-) MBL. CLL-like MBL is by far the most frequent and best studied category and further divided in low-count [LC] and high-count [HC] MBL, based on a cutoff value of 500/MUL clonal B cells. LC-MBL typically remains stable and probably does not represent a truly premalignant condition, but rather an age-related immune senescence. On the other hand, HC-MBL is closely related to CLL-Rai0, bearing similar immunogenetic profile, and is associated with an annual risk of progression to CLL requiring therapy at a rate of 1.1%. Currently there are no reproducible factors for evaluating the risk of progression to CLL. CD5(-) MBL is characterized by an immunophenotype consistent with marginal zone origin and displays many similarities with marginal zone lymphomas (MZL), mainly the splenic MZL. The cutoff value of 5000/MUL clonal B cells cannot probably be applied in CD5(-) MBL, requiring a new definition to describe those cases. PMID- 25295255 TI - Early onset intrauterine growth restriction in a mouse model of gestational hypercholesterolemia and atherosclerosis. AB - The susceptibility to develop atherosclerosis is increased by intrauterine growth restriction and prenatal exposure to maternal hypercholesterolemia. Here, we studied whether mouse gestational hypercholesterolemia and atherosclerosis affected fetal development and growth at different stages of gestation. Female LDLR KO mice fed a proatherogenic, high cholesterol (HC) diet for 3 weeks before conception and during pregnancy exhibited a significant increase in non-HDL cholesterol and developed atherosclerosis. At embryonic days 12.5 (E12.5), E15.5, and E18.5, maternal gestational hypercholesterolemia and atherosclerosis were associated to a 22-24% reduction in male and female fetal weight without alterations in fetal number/litter or morphology nor placental weight or structure. Feeding the HC diet exclusively at the periconceptional period did not alter fetal growth, suggesting that maternal hypercholesterolemia affected fetal weight only after implantation. Vitamin E supplementation (1,000 UI of alpha tocopherol/kg) of HC-fed females did not change the mean weight of E18.5 fetuses but reduced the percentage of fetuses exhibiting body weights below the 10th percentile of weight (HC: 90% vs. HC/VitE: 68%). In conclusion, our results showed that maternal gestational hypercholesterolemia and atherosclerosis in mice were associated to early onset fetal growth restriction and that dietary vitamin E supplementation had a beneficial impact on this condition. PMID- 25295257 TI - Awareness levels about breast cancer risk factors, early warning signs, and screening and therapeutic approaches among Iranian adult women: a large population based study using latent class analysis. AB - BACKGROUND AND OBJECTIVE: Breast cancer (BC) continues to be a major cause of morbidity and mortality among women throughout the world and in Iran. Lack of awareness and early detection program in developing country is a main reason for escalating the mortality. The present research was conducted to assess the Iranian women's level of knowledge about breast cancer risk factors, early warning signs, and therapeutic and screening approaches, and their correlated determinants. METHODS: In a cross-sectional study, 2250 women before participating at a community based screening and public educational program in an institute of cancer research in Isfahan, Iran, in 2012 were investigated using a self-administered questionnaire about risk factors, early warning signs, and therapeutic and screening approaches of BC. Latent class regression as a comprehensive statistical method was used for evaluating the level of knowledge and its correlated determinants. RESULTS: Only 33.2%, 31.9%, 26.7%, and 35.8% of study participants had high awareness levels about screening approaches, risk factors, early warning signs and therapeutic modalities of breast cancer, respectively, and majority had poor to moderate knowledge levels. Most effective predictors of high level of awareness were higher educational qualifications, attending in screening and public educational programs, personal problem, and family history of BC, respectively. CONCLUSION: Results of current study indicated that the levels of awareness among study population about key elements of BC are low. These findings reenforce the continuing need for more BC education through conducting public and professional programs that are intended to raise awareness among younger, single women and those with low educational attainments and without family history. PMID- 25295256 TI - Subunit composition of neurotransmitter receptors in the immature and in the epileptic brain. AB - Neuronal activity is critical for synaptogenesis and the development of neuronal networks. In the immature brain excitation predominates over inhibition facilitating the development of normal brain circuits, but also rendering it more susceptible to seizures. In this paper, we review the evolution of the subunit composition of neurotransmitter receptors during development, how it promotes excitation in the immature brain, and how this subunit composition of neurotransmission receptors may be also present in the epileptic brain. During normal brain development, excitatory glutamate receptors peak in function and gamma-aminobutiric acid (GABA) receptors are mainly excitatory rather than inhibitory. A growing body of evidence from animal models of epilepsy and status epilepticus has demonstrated that the brain exposed to repeated seizures presents a subunit composition of neurotransmitter receptors that mirrors that of the immature brain and promotes further seizures and epileptogenesis. Studies performed in samples from the epileptic human brain have also found a subunit composition pattern of neurotransmitter receptors similar to the one found in the immature brain. These findings provide a solid rationale for tailoring antiepileptic treatments to the specific subunit composition of neurotransmitter receptors and they provide potential targets for the development of antiepileptogenic treatments. PMID- 25295258 TI - Genetic transformation of Metroxylon sagu (Rottb.) cultures via Agrobacterium mediated and particle bombardment. AB - Sago palm (Metroxylon sagu) is a perennial plant native to Southeast Asia and exploited mainly for the starch content in its trunk. Genetic improvement of sago palm is extremely slow when compared to other annual starch crops. Urgent attention is needed to improve the sago palm planting material and can be achieved through nonconventional methods. We have previously developed a tissue culture method for sago palm, which is used to provide the planting materials and to develop a genetic transformation procedure. Here, we report the genetic transformation of sago embryonic callus derived from suspension culture using Agrobacterium tumefaciens and gene gun systems. The transformed embryoids cells were selected against Basta (concentration 10 to 30 mg/L). Evidence of foreign genes integration and function of the bar and gus genes were verified via gene specific PCR amplification, gus staining, and dot blot analysis. This study showed that the embryogenic callus was the most suitable material for transformation as compared to the fine callus, embryoid stage, and initiated shoots. The gene gun transformation showed higher transformation efficiency than the ones transformed using Agrobacterium when targets were bombarded once or twice using 280 psi of helium pressure at 6 to 8 cm distance. PMID- 25295259 TI - Cholesterol assimilation by Lactobacillus probiotic bacteria: an in vitro investigation. AB - Excess cholesterol is associated with cardiovascular diseases (CVD), an important cause of mortality worldwide. Current CVD therapeutic measures, lifestyle and dietary interventions, and pharmaceutical agents for regulating cholesterol levels are inadequate. Probiotic bacteria have demonstrated potential to lower cholesterol levels by different mechanisms, including bile salt hydrolase activity, production of compounds that inhibit enzymes such as 3-hydroxy-3 methylglutaryl coenzyme A, and cholesterol assimilation. This work investigates 11 Lactobacillus strains for cholesterol assimilation. Probiotic strains for investigation were selected from the literature: Lactobacillus reuteri NCIMB 11951, L. reuteri NCIMB 701359, L. reuteri NCIMB 702655, L. reuteri NCIMB 701089, L. reuteri NCIMB 702656, Lactobacillus fermentum NCIMB 5221, L. fermentum NCIMB 8829, L. fermentum NCIMB 2797, Lactobacillus rhamnosus ATCC 53103 GG, Lactobacillus acidophilus ATCC 314, and Lactobacillus plantarum ATCC 14917. Cholesterol assimilation was investigated in culture media and under simulated intestinal conditions. The best cholesterol assimilator was L. plantarum ATCC 14917 (15.18+/-0.55 mg/10(10) cfu) in MRS broth. L. reuteri NCIMB 701089 assimilated over 67% (2254.70+/-63.33 mg/10(10) cfu) of cholesterol, the most of all the strains, under intestinal conditions. This work demonstrates that probiotic bacteria can assimilate cholesterol under intestinal conditions, with L. reuteri NCIMB 701089 showing great potential as a CVD therapeutic. PMID- 25295260 TI - The longitudinal assessment of osteomyelitis development by molecular imaging in a rabbit model. AB - INTRODUCTION: Osteomyelitis is a severe orthopaedic complication which is difficult to diagnose and treat. Previous experimental studies mainly focussed on evaluating osteomyelitis in the presence of an implant or used a sclerosing agent to promote infection onset. In contrast, we focused on the longitudinal assessment of a nonimplant related osteomyelitis. METHODS: An intramedullary tibial infection with S. aureus was established in NZW rabbits. Clinical and haematological infection status was evaluated weekly, combined with X-ray radiographs, biweekly injections of calcium binding fluorophores, and postmortem micro-CT. The development of the infection was assessed by micro-PET at consecutive time points using 18F-FDG as an infection tracer. RESULTS: The intramedullary contamination of the rabbit tibia resulted in an osteomyelitis. Haematological parameters confirmed infection in mainly the first postoperative weeks (CRP at the first 5 postoperative weeks, leucocyte differentiation at the second and sixth postoperative weeks, and ESR on the second postoperative week only), while micro-PET was able to detect the infection from the first post operative week onward until the end of the study. CONCLUSIONS: This study shows that osteomyelitis in the rabbit can be induced without use of an implant or sclerosing agent. The sequential follow-up indicates that the diagnostic value of each infection parameter is time point dependant. Furthermore, from all parameters used, the diagnostic value of 18F-FDG micro-PET is the most versatile to assess the presence of an orthopaedic infection in this model. PMID- 25295262 TI - Attachment of Asaia bogorensis originating in fruit-flavored water to packaging materials. AB - The objective of this study was to investigate the adhesion of isolated spoilage bacteria to packaging materials used in the food industry. Microorganisms were isolated from commercial fruit-flavored mineral water in plastic bottles with flocks as a visual defect. The Gram-negative rods were identified using the molecular method through the amplification of a partial region of the 16S rRNA gene. Based on the sequence identity (99.6%) between the spoilage organism and a reference strain deposited in GenBank, the spoilage isolate was identified as Asaia bgorensis. Experiments on bacterial adhesion were conducted using plates made of glass and polystyrene (packaging materials commonly used in the beverage industry). Cell adhesion ability was determined using luminometry, plate count, and the microscopic method. The strain of A. bogorensis was characterized by strong adhesion properties which were dependent on the surface type, with the highest cell adhesion detected on polystyrene. PMID- 25295263 TI - Model of break-bone fever via beta-derivatives. AB - Using the new derivative called beta-derivative, we modelled the well-known infectious disease called break-bone fever or the dengue fever. We presented the endemic equilibrium points under certain conditions of the physical parameters included in the model. We made use of an iteration method to solve the extended model. To show the efficiency of the method used, we have presented in detail the stability and the convergence of the method for solving the system (2). We presented the uniqueness of the special solution of system (2) and finally the numerical simulations were presented for various values of beta. PMID- 25295261 TI - The impact of extracellular vesicle-encapsulated circulating microRNAs in lung cancer research. AB - Lung cancer is the leading cause of cancer-related deaths. Biomarkers for lung cancer have raised great expectations in their clinical applications for early diagnosis, survival, and therapeutic responses. MicroRNAs (miRNAs), a family of short endogenous noncoding RNAs, play critical roles in cell growth, differentiation, and the development of various types of cancers. Current studies have shown that miRNAs are present in the extracellular spaces, packaged into various membrane-bound vesicles. Tumor-specific circulating miRNAs have been developed as early diagnostic biomarkers for lung cancer. Remarkably, some studies have succeeded in discovering circulating miRNAs with prognostic or predictive significance. Extracellular vesicles (EVs), such as exosomes and microvesicles, are recognized as novel tools for cell-cell communication and as biomarkers for various diseases. Their vesicle composition and miRNA content have the ability to transfer biological information to recipient cells and play an important role in cancer metastasis and prognosis. This review provides an in depth summary of current findings on circulating miRNAs in lung cancer patients used as diagnostic biomarkers. We also discuss the role of EV miRNAs in cell-cell communication and explore the effectiveness of these contents as predictive biomarkers for cancer malignancy. PMID- 25295264 TI - Can pin-on-disk testing be used to assess the wear performance of retrieved UHMWPE components for total joint arthroplasty? AB - The objective of this study was to assess the suitability of using multidirectional pin-on-disk (POD) testing to characterize wear behavior of retrieved ultrahigh molecular weight polyethylene (UHMWPE). The POD wear behavior of 25 UHMWPE components, retrieved after 10 years in vivo, was compared with 25 that were shelf aged for 10-15 years in their original packaging. Components were gamma sterilized (25-40 kGy) in an air or reduced oxygen (inert) package. 9 mm diameter pins were fabricated from each component and evaluated against CoCr disks using a super-CTPOD with 100 stations under physiologically relevant, multidirectional loading conditions. Bovine serum (20 g/L protein concentration) was used as lubricant. Volumetric wear rates were found to vary based on the aging environment, as well as sterilization environment. Volumetric wear rates were the lowest for the pins in the gamma inert, shelf aged cohort. These results support the utility of using modern, multidirectional POD testing with a physiologic lubricant as a novel method for evaluating wear properties of retrieved UHMWPE components. The data also supported the hypothesis that wear rates of gamma-inert liners were lower than gamma-air liners for both retrieved and shelf aging conditions. However, this difference was not statistically significant for the retrieved condition. PMID- 25295266 TI - A comparison of antegrade percutaneous and laparoscopic approaches in the treatment of proximal ureteral stones. AB - PURPOSE: To compare the effectiveness and safety of retroperitoneal laparoscopic ureterolithotomy (RLU) and percutaneous antegrade ureteroscopy (PAU) in which we use semirigid ureteroscopy in the treatment of proximal ureteral stones. METHODS: Fifty-eight patients with large, impacted stones who had a history of failed shock wave lithotripsy (SWL) and, retrograde ureterorenoscopy (URS) were included in the study between April 2007 and April 2014. Thirty-seven PAU and twenty-one RLU procedures were applied. Stone-free rates, operation times, duration of hospital stay, and follow-up duration were analyzed. RESULTS: Overall stone-free rate was 100% for both groups. There was no significant difference between both groups with respect to postoperative duration of hospital stay and urinary leakage of more than 2 days. PAU group had a greater amount of blood loss (mean hemoglobin drops for PAU group and RLU group were 1.6+/-1.1 g/dL versus 0.5+/-0.3 g/dL, resp.; P=0.022). RLU group had longer operation time (for PAU group and RLU group 80.1+/-44.6 min versus 102.1+/-45.5 min, resp.; P=0.039). CONCLUSIONS: Both PAU and RLU appear to be comparable in the treatment of proximal ureteral stones when the history is notable for a failed retrograde approach or SWL. The decision should be based on surgical expertise and availability of surgical equipment. PMID- 25295265 TI - IGF-1 and ADMA levels are inversely correlated in nondiabetic ankylosing spondylitis patients undergoing anti-TNF-alpha therapy. AB - Like rheumatoid arthritis, ankylosing spondylitis (AS) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome (MeS) features. AS patients often display osteoporosis as well as new bone formation. Insulin-like growth factor 1 (IGF-1) is a protein involved in both inflammation and bone metabolism. In the present study we assessed whether disease activity, systemic inflammation, MeS features, adipokines, and biomarkers of endothelial activation were associated with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in a series of 30 nondiabetic AS patients without CV disease undergoing TNF-alpha antagonist-infliximab therapy. All determinations were made in the fasting state, immediately before an infliximab infusion. Although no association of IGF-1 and IGFBP-3 levels with angiopoietin-2 or osteopontin was found, an inverse correlation between IGF-1 levels and asymmetric dimethylarginine (ADMA), an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction, was found (r=-0.397; P=0.04). However, no significant association was found between IGF-1 and IGFBP-3 levels and disease activity, systemic inflammation, metabolic syndrome features, or adipokines. In conclusion, in nondiabetic patients with AS undergoing periodic anti-TNF-alpha therapy, IGF-1 and ADMA are inversely correlated. PMID- 25295267 TI - Comparison of proton pump inhibitor and histamine-2 receptor antagonist in the prevention of recurrent peptic ulcers/erosions in long-term low-dose aspirin users: a retrospective cohort study. AB - BACKGROUND: Proton pump inhibitor and histamine-2 receptor antagonist can prevent aspirin-related ulcers/erosions but few studies compare the efficacy of these two agents. Aims. We evaluated the efficacy of omeprazole and famotidine in preventing recurrent ulcers/erosions in low-dose aspirin users. METHODS: The 24 week clinical outcomes of the patients using low-dose aspirin for cardiovascular protection with a history of ulcers/erosions and cotherapy of omeprazole or famotidine were retrospectively reviewed. The incidence of gastrointestinal symptoms, recurrent ulcers/erosions, erosive esophagitis, gastrointestinal bleeding, and thromboembolic events was analyzed. RESULTS: A total of 104 patients (famotidine group, 49 patients; omeprazole group, 55 patients) were evaluated. Famotidine group had more gastrointestinal symptoms episodes than omeprazole group (46.9% versus 23.6%, P=0.01). Fifteen famotidine group patients and 5 omeprazole group patients had recurrent ulcers/erosions (30.6% versus 9.1%, P=0.005). Lanza scale was significantly lower in omeprazole group than in famotidine group (1.2+/-0.7 versus 1.7+/-1.1, P=0.008). Only 1 famotidine group patient had ulcer bleeding. The incidences of erosive esophagitis and thromboembolic events were comparable between both groups. CONCLUSIONS: Omeprazole was superior to famotidine with less gastrointestinal symptoms and recurrent ulcers/erosions in patients using 24-week low-dose aspirin. The risk of erosive esophagitis, gastrointestinal bleeding, and thromboembolic events was similar between both groups. PMID- 25295269 TI - Carbon ion therapy for early-stage non-small-cell lung cancer. AB - Carbon ion therapy is a type of radiotherapies that can deliver high-dose radiation to a tumor while minimizing the dose delivered to the organs at risk; this profile differs from that of photon radiotherapy. Moreover, carbon ions are classified as high-linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. Recently, high-precision radiotherapy modalities such as stereotactic body radiotherapy (SBRT), proton therapy, and carbon ion therapy have been used for patients with early-stage non-small-cell lung cancer, and the results are promising, as, for carbon ion therapy, local control and overall survival rates at 5 years are 80-90% and 40-50%, respectively. Carbon ion therapy may be theoretically superior to SBRT and proton therapy, but the literature that is currently available does not show a statistically significant difference among these treatments. Carbon ion therapy demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, carbon ion therapy may be safer for treating patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. Furthermore, carbon ion therapy may also be suitable for dose escalation and hypofractionation. PMID- 25295270 TI - Surface modifications of dental ceramic implants with different glass solder matrices: in vitro analyses with human primary osteoblasts and epithelial cells. AB - Ceramic materials show excellent esthetic behavior, along with an absence of hypersensitivity, making them a possible alternative implant material in dental surgery. However, their surface properties enable only limited osseointegration compared to titanium implants. Within this study, a novel surface coating technique for enhanced osseointegration was investigated biologically and mechanically. Specimens of tetragonal zirconia polycrystal (TZP) and aluminum toughened zirconia (ATZ) were modified with glass solder matrices in two configurations which mainly consisted of SiO2, Al2O3, K2O, and Na2O. The influence on human osteoblastic and epithelial cell viability was examined by means of a WST-1 assay as well as live/dead staining. A C1CP-ELISA was carried out to verify procollagen type I production. Uncoated/sandblasted ceramic specimens and sandblasted titanium surfaces were investigated as a reference. Furthermore, mechanical investigations of bilaterally coated pellets were conducted with respect to surface roughness and adhesive strength of the different coatings. These tests could demonstrate a mechanically stable implant coating with glass solder matrices. The coated ceramic specimens show enhanced osteoblastic and partly epithelial viability and matrix production compared to the titanium control. Hence, the new glass solder matrix coating could improve bone cell growth as a prerequisite for enhanced osseointegration of ceramic implants. PMID- 25295268 TI - Aptamers as both drugs and drug-carriers. AB - Aptamers are short nucleic acid oligos. They may serve as both drugs and drug carriers. Their use as diagnostic tools is also evident. They can be generated using various experimental, theoretical, and computational techniques. The systematic evolution of ligands by exponential enrichment which uses iterative screening of nucleic acid libraries is a popular experimental technique. Theory inspired methodology entropy-based seed-and-grow strategy that designs aptamer templates to bind specifically to targets is another one. Aptamers are predicted to be highly useful in producing general drugs and theranostic drugs occasionally for certain diseases like cancer, Alzheimer's disease, and so on. They bind to various targets like lipids, nucleic acids, proteins, small organic compounds, and even entire organisms. Aptamers may also serve as drug-carriers or nanoparticles helping drugs to get released in specific target regions. Due to better target specific physical binding properties aptamers cause less off-target toxicity effects. Therefore, search for aptamer based drugs, drug-carriers, and even diagnostic tools is expanding fast. The biophysical properties in relation to the target specific binding phenomena of aptamers, energetics behind the aptamer transport of drugs, and the consequent biological implications will be discussed. This review will open up avenues leading to novel drug discovery and drug delivery. PMID- 25295271 TI - KML001, a telomere-targeting drug, sensitizes glioblastoma cells to temozolomide chemotherapy and radiotherapy through DNA damage and apoptosis. AB - Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated gamma-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma. PMID- 25295273 TI - Alterations in red blood cell deformability during storage: a microfluidic approach. AB - Red blood cells (RBCs) undergo extensive deformation when travelling through the microcapillaries. Deformability, the combined result of properties of the membrane-cytoskeleton complex, the surface area-to-volume ratio, and the hemoglobin content, is a critical determinant of capillary blood flow. During blood bank storage and in many pathophysiological conditions, RBC morphology changes, which has been suggested to be associated with decreased deformability and removal of RBC. While various techniques provide information on the rheological properties of stored RBCs, their clinical significance is controversial. We developed a microfluidic approach for evaluating RBC deformability in a physiologically meaningful and clinically significant manner. Unlike other techniques, our method enables a high-throughput determination of changes in deformation capacity to provide statistically significant data, while providing morphological information at the single-cell level. Our data show that, under conditions that closely mimic capillary dimensions and flow, the capacity to deform and the capacity to relax are not affected during storage in the blood bank. Our data also show that altered cell morphology by itself does not necessarily affect deformability. PMID- 25295274 TI - EXIA2: web server of accurate and rapid protein catalytic residue prediction. AB - We propose a method (EXIA2) of catalytic residue prediction based on protein structure without needing homology information. The method is based on the special side chain orientation of catalytic residues. We found that the side chain of catalytic residues usually points to the center of the catalytic site. The special orientation is usually observed in catalytic residues but not in noncatalytic residues, which usually have random side chain orientation. The method is shown to be the most accurate catalytic residue prediction method currently when combined with PSI-Blast sequence conservation. It performs better than other competing methods on several benchmark datasets that include over 1,200 enzyme structures. The areas under the ROC curve (AUC) on these benchmark datasets are in the range from 0.934 to 0.968. PMID- 25295275 TI - Effect of high hydrostatic pressure processing on microbiological shelf-life and quality of fruits pretreated with ascorbic acid or SnCl2. AB - In the current study, the processing conditions required for the inactivation of Paenibacillus polymyxa and relevant spoilage microorganisms by high hydrostatic pressure (HHP) treatment on apricot, peach, and pear pieces in sucrose (22 degrees Brix) solution were assessed. Accordingly, the shelf-life was determined by evaluating both the microbiological quality and the sensory characteristics (taste, odor, color, and texture) during refrigerated storage after HHP treatment. The microbiological shelf-life of apricots, peaches, and pears was prolonged in the HHP-treated products in comparison with the untreated ones. In all HHP-treated packages for apricots, peaches, and pears, all populations were below the detection limit of the method (1 log CFU/g) and no growth of microorganisms was observed until the end of storage. Overall, no differences of the L*, a*, or b* value among the untreated and the HHP-treated fruit products were observed up to the time at which the unpressurized product was characterized as spoiled. HHP treatment had no remarkable effect on the firmness of the apricots, peaches, and pears. With regard to the sensory assessment, the panelists marked better scores to HHP-treated products compared to their respective controls, according to taste and total evaluation during storage of fruit products. PMID- 25295276 TI - Effects of soft denture liners on L929 fibroblasts, HaCaT keratinocytes, and RAW 264.7 macrophages. AB - The effects of six soft liners (Ufi Gel P (UG), Sofreliner S (SR), Durabase Soft (D), Trusoft (T), Coe Comfort (CC), and Softone (ST)) on L929, HaCat, and RAW 264.7 cells were investigated. Eluates (24 and 48 h) from the materials were applied on the cells and the viability, type of cell death, and morphology were evaluated. Cells were also seeded on the specimens' surfaces (direct contact) and incubated (24 or 48 h), and viability was analyzed. Controls were cells in culture medium without eluates or specimens. For cell viability, no significant differences were found among materials or between extraction periods, and the liners were noncytotoxic or slightly cytotoxic. Morphology of RAW 264.7 cells was altered by the 24 h eluates from CC and D and the 48 h eluates from SR, CC, and D. The 24 and 48 h eluates from all materials (except T) increased the percentages of L929 necrotic cells. For direct contact tests, the lowest cytotoxicity was observed for UG and SR. Although eluates did not reduce viability, morphology alterations and increase in necrosis were seen. Moreover, in the direct contact, effects on viability were more pronounced, particularly for D, T, CC and ST. Thus, the use of UG and SR might reduce the risk of adverse effects. PMID- 25295277 TI - Evaluating the bone tissue regeneration capability of the Chinese herbal decoction Danggui Buxue Tang from a molecular biology perspective. AB - Large bone defects are a considerable challenge to reconstructive surgeons. Numerous traditional Chinese herbal medicines have been used to repair and regenerate bone tissue. This study investigated the bone regeneration potential of Danggui Buxue Tang (DBT), a Chinese herbal decoction prepared from Radix Astragali (RA) and Radix Angelicae Sinensis (RAS), from a molecular biology perspective. The optimal ratio of RA and RAS used in DBT for osteoblast culture was obtained by colorimetric and alkaline phosphatase (ALP) activity assays. Moreover, the optimal concentration of DBT for bone cell culture was also determined by colorimetric, ALP activity, nodule formation, Western blotting, wound-healing, and tartrate-resistant acid phosphatase activity assays. Consequently, the most appropriate weight ratio of RA to RAS for the proliferation and differentiation of osteoblasts was 5:1. Moreover, the most effective concentration of DBT was 1,000 MUg/mL, which significantly increased the number of osteoblasts, intracellular ALP levels, and nodule numbers, while inhibiting osteoclast activity. Additionally, 1,000 MUg/mL of DBT was able to stimulate p-ERK and p-JNK signal pathway. Therefore, DBT is highly promising for use in accelerating fracture healing in the middle or late healing periods. PMID- 25295278 TI - Accelerated corneal collagen cross-linking in pediatric patients: two-year follow up results. AB - PURPOSE: To evaluate the effectiveness and safety of accelerated corneal collagen cross-linking (ACXL) in patients below 14 years of age with progressive keratoconus. MATERIALS AND METHODS: Thirty eyes of 18 patients with established progressive keratoconus underwent preoperative and postoperative visual acuity assessment, topography, and specular microscopy prior to ACXL and were followed up for 24 months. RESULTS: Mean age of the patients was 12.7 years with ten males and eight females. There was an improvement in the mean postoperative uncorrected distant visual acuity (from 0.76+/-0.26 to 0.61+/-0.25; P=0.005), mean corrected distant visual acuity (from 0.24+/-0.19 to 0.12+/-0.12; P<0.001), mean spherical refraction (from -3.04 DS+/-3.60 to -2.38 DS+/-3.37; P=0.28), mean cylinder (from -3.63 DC+/-1.82 to -2.80 DC+/-1.48; P=0.008), and spherical equivalent (from 4.70 D+/-3.86 to -3.75 D+/-3.49; P=0.15). Three eyes of two patients with vernal keratoconjunctivitis (VKC) showed progression. There were no intra- or postoperative complications. CONCLUSION: In pediatric patients ACXL is an effective and safe procedure for the management of keratoconus. Optimal management of VKC is important to arrest the progression of keratoconus. PMID- 25295272 TI - Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. AB - Cancer is the most dreadful disease worldwide in terms of morbidity and mortality. The exact cause of cancer development and progression is not fully known. But it is thought that cancer occurs due to the structural and functional changes in the genes. The current approach to cancer treatment based on allopathic is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a safe and effective mode of treatment is needed to control the cancer development and progression. Some medicinal plants provide a safe, effective and affordable remedy to control the progression of malignant cells. The importance of medicinal plants and their constituents has been documented in Ayurveda, Unani medicine, and various religious books. Curcumin, a vital constituent of the spice turmeric, is an alternative approach in the prevention of cancer. Earlier studies have shown the effect of curcumin as an antioxidant, antibacterial, antitumor and it also has a noteworthy role in the control of different diseases. In this review, we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer via the regulation of various cell signaling and genetic pathways. PMID- 25295279 TI - Simultaneous coproduction of hydrogen and ethanol in anaerobic packed-bed reactors. AB - This study evaluated the use of an anaerobic packed-bed reactor for hydrogen production at different hydraulic retention times (HRT) (1-8 h). Two reactors filled with expanded clay and fed with glucose (3136-3875 mg L(-1)) were operated at different total upflow velocities: 0.30 cm s(-1) (R030) and 0.60 cm s(-1) (R060). The effluent pH of the reactors was maintained between 4 and 5 by adding NaHCO3 and HCl solutions. It was observed a maximum hydrogen production rate of 0.92 L H2 h(-1) L(-1) in R030 at HRT of 1 h. Furthermore, the highest hydrogen yield of 2.39 mol H2 mol(-1) glucose was obtained in R060. No clear trend was observed by doubling the upflow velocities at this experiment. High ethanol production was also observed, indicating that the ethanol-pathway prevailed throughout the experiment. PMID- 25295280 TI - Serum samples that have been stored long-term (>10 years) can be used as a suitable data source for developing cardiovascular risk prediction models in large observational rheumatoid arthritis cohorts. AB - OBJECTIVE: There is an unmet need for a specific cardiovascular risk (CV) algorithm for rheumatoid arthritis (RA) patients. Lipoprotein data are often not available in RA cohorts but could be obtained from frozen blood samples. The objective of this study was to estimate the storage effect on lipoproteins in long-term (>10 years) frozen serum samples. METHODS: Data were used from an inception RA cohort. Multiple serum samples from 152 patients were analyzed for lipoproteins, being frozen for 1-26 years at -20 degrees C. Storage effect on lipoproteins was estimated using longitudinal regression analyses and a lipid decay correction factor was developed. Clinical impact of the storage effect on lipoproteins was assessed by calculating the number of patients reclassified to another CV risk group according to the SCORE risk calculator after applying the decay correction factor. RESULTS: There was a significant effect of storage time on total cholesterol (TC) (P<0.001) and high density lipoprotein cholesterol (HDL c) levels (P<0.001), not LDL-c (P=0.83). The lipid decay correction factor was 0.03 mmol/L and 0.024 mmol/L per additional year of storage for TC and HDL-c, respectively. The TC:HDL ratio decreased after correction for storage effect. After correction, only 5% of patients were reclassified to another CV risk group. CONCLUSION: A modest storage decay effect on lipoproteins was found that is unlikely to significantly affect CV risk stratification. Serum samples that have been stored long-term (>10 years) can be used to obtain valid lipid levels for developing CV risk prediction models in RA cohorts, even without applying a decay correction factor. PMID- 25295281 TI - Structural basis of binding and rationale for the potent urease inhibitory activity of biscoumarins. AB - Urease belongs to a family of highly conserved urea-hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and reactive cysteine residue in the active sites. In the current study we examined a series of biscoumarins 1-10 for their mechanisms of inhibition with the nickel containing active sites of Jack bean and Bacillus pasteurii ureases. All these compounds competitively inhibited Jack bean urease through interaction with the nickel metallocentre, as deduced from Michaelis-Menten kinetics, UV-visible absorbance spectroscopic, and molecular docking simulation studies. Some of the compounds behaved differently in case of Bacillus pasteurii urease. We conducted the enzyme kinetics, UV-visible spectroscopy, and molecular docking results in terms of the known protein structure of the enzyme. We also evaluated possible molecular interpretations for the site of biscoumarins binding and found that phenyl ring is the major active pharmacophore. The excellent in vitro potency and selectivity profile of the several compounds described combined with their nontoxicity against the human cells and plants suggest that these compounds may represent a viable lead series for the treatment of urease associated problems. PMID- 25295283 TI - Ocular inflammation in uveal tract in aged obese type 2 diabetic rats (Spontaneously Diabetic Torii fatty rats). AB - We report uveitis observed in an obese type 2 diabetes rat model, Spontaneously Diabetic Torii Lepr(fa) (SDT fatty) rats aged over 50 weeks. The eyes of SDT fatty rats (16 animals: 7 males and 9 females with 50 or 60 weeks of age) were examined histopathologically. Infiltration of inflammatory cells in the uveal tract was observed in 13 of 16 animals. One female showed severe inflammation affecting the entire uveal tract including the iris, ciliary body, and choroid with a variety of inflammatory cells (neutrophils, lymphocytes, and macrophages). Those changes clinically mimic the findings of diabetic iridocyclitis in diabetic patients. Uveitis associated with diabetes can occur in diabetic patients but the pathogenesis still remains unknown. Since increased extramedullary hematopoiesis in the spleen and abscess in the genital and lower urinary tracts were observed in some SDT fatty rats, increased susceptibility to infection, prolongation of inflammatory states, and disorders of the immune system were considered to be possible factors of the uveitis in aged SDT fatty rats. There have been few reports on how diabetes has influence on the development of uveitis associated with bacterial infection. The SDT fatty rat can be an animal model to investigate diabetes-associated uveitis. PMID- 25295282 TI - Bifidobacteria-host interactions--an update on colonisation factors. AB - Bifidobacteria are one of the predominant bacterial groups of the human intestinal microbiota and have important functional properties making them interesting for the food and dairy industries. Numerous in vitro and preclinical studies have shown beneficial effects of particular bifidobacterial strains or strain combinations on various health parameters of their hosts. This indicates the potential of bifidobacteria in alternative or supplementary therapeutic approaches in a number of diseased states. Based on these observations, bifidobacteria have attracted considerable interest by the food, dairy, and pharmaceutical industries and they are widely used as so-called probiotics. As a consequence of the rapidly increasing number of available bifidobacterial genome sequences and their analysis, there has been substantial progress in the identification of bifidobacterial structures involved in colonisation of and interaction with the host. With the present review, we aim to provide an update on the current knowledge on the mechanisms by which bifidobacteria colonise their hosts and exert health promoting effects. PMID- 25295285 TI - The role of inflammatory, anti-inflammatory, and regulatory cytokines in patients infected with cutaneous leishmaniasis in Amazonas State, Brazil. AB - The authors discuss in this paper the role of inflammatory, anti-inflammatory, and regulatory cytokines in patients infected with different species of Leishmania in Amazonas State, Brazil. A comparative analysis was made of serum concentrations of these cytokines in the peripheral blood of 33 patients infected with cutaneous leishmaniasis. The isolates were identified as Leishmania guyanensis, L. naiffi, and L. amazonensis. Most (64%) of the patients were male ranging in age from 18 to 58 years. Protein expression profiles of IL-2, IL-4, IL 6, IL-10, IFN-gamma, TNF-alpha, and IL-17 cytokines were shown to vary significantly between infected and noninfected (control group) individuals and according to the Leishmania species. Infection caused by L. guyanensis accounted for 73% of the cases and patients with this parasite also showed higher concentrations of IL-2, IFN-gamma, IL-4, and IL-17 when compared to infection by L. amazonensis. Patients with infection caused by L. naiffi showed higher concentration of the cytokines analyzed when compared to uninfected patients; however, there was no statistically significant difference with the other species analyzed. PMID- 25295287 TI - Pathophysiological roles of cytokine-chemokine immune network. PMID- 25295284 TI - Cytokine-mediated bone destruction in rheumatoid arthritis. AB - Bone homeostasis, which involves formation and resorption, is an important process for maintaining adequate bone mass in humans. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and bone loss, leading to joint destruction and deformity, and is a representative disease of disrupted bone homeostasis. The bone loss and joint destruction are mediated by immunological insults by proinflammatory cytokines and various immune cells. The connection between bone and immunity has been intensely studied and comprises the emerging field of osteoimmunology. Osteoimmunology is an interdisciplinary science investigating the interplay between the skeletal and the immune systems. The main contributors in osteoimmunology are the bone effector cells, such as osteoclasts or osteoblasts, and the immune cells, particularly lymphocytes and monocytes. Physiologically, osteoclasts originate from immune cells, and immune cells regulate osteoblasts and vice versa. Pathological conditions such as RA might affect these interactions, thereby altering bone homeostasis, resulting in the unfavorable outcome of bone destruction. In this review, we describe the osteoclastogenic roles of the proinflammatory cytokines and immune cells that are important in the pathophysiology of RA. PMID- 25295288 TI - Secure cooperative spectrum sensing for the cognitive radio network using nonuniform reliability. AB - Both reliable detection of the primary signal in a noisy and fading environment and nullifying the effect of unauthorized users are important tasks in cognitive radio networks. To address these issues, we consider a cooperative spectrum sensing approach where each user is assigned nonuniform reliability based on the sensing performance. Users with poor channel or faulty sensor are assigned low reliability. The nonuniform reliabilities serve as identification tags and are used to isolate users with malicious behavior. We consider a link layer attack similar to the Byzantine attack, which falsifies the spectrum sensing data. Three different strategies are presented in this paper to ignore unreliable and malicious users in the network. Considering only reliable users for global decision improves sensing time and decreases collisions in the control channel. The fusion center uses the degree of reliability as a weighting factor to determine the global decision in scheme I. Schemes II and III consider the unreliability of users, which makes the computations even simpler. The proposed schemes reduce the number of sensing reports and increase the inference accuracy. The advantages of our proposed schemes over conventional cooperative spectrum sensing and the Chair-Varshney optimum rule are demonstrated through simulations. PMID- 25295286 TI - Comparisons of CVID and IgGSD: referring physicians, autoimmune conditions, pneumovax reactivity, immunoglobulin levels, blood lymphocyte subsets, and HLA-A and -B typing in 432 adult index patients. AB - Common variable immunodeficiency (CVID) and immunoglobulin (Ig) G subclass deficiency (IgGSD) are heterogeneous disorders characterized by respiratory tract infections, selective Ig isotype deficiencies, and impaired antibody responses to polysaccharide antigens. Using univariable analyses, we compared observations in 34 CVID and 398 IgGSD adult index patients (81.9% women) referred to a hematology/oncology practice. Similarities included specialties of referring physicians, mean ages, proportions of women, reactivity to Pneumovax, median serum IgG3 and IgG4 levels, median blood CD56+/CD16+ lymphocyte levels, positivity for HLA-A and -B types, and frequencies of selected HLA-A, -B haplotypes. Dissimilarities included greater prevalence of autoimmune conditions, lower median IgG, IgA, and IgM, and lower median CD19+, CD3+/CD4+, and CD3+/CD8+ blood lymphocytes in CVID patients. Prevalence of Sjogren's syndrome and hypothyroidism was significantly greater in CVID patients. Combined subnormal IgG1/IgG3 occurred in 59% and 29% of CVID and IgGSD patients, respectively. Isolated subnormal IgG3 occurred in 121 IgGSD patients (88% women). Logistic regression on CVID (versus IgGSD) revealed a significant positive association with autoimmune conditions and significant negative associations with IgG1, IgG3, and IgA and CD56+/CD16+ lymphocyte levels, but the odds ratio was increased for autoimmune conditions alone (6.9 (95% CI 1.3, 35.5)). PMID- 25295289 TI - Modeling and assessment of long afterglow decay curves. AB - Multiple exponential equations have been successfully fitted to experimental long afterglow decay curve data for some phosphor materials by previous researchers. The calculated decay constants in such equations are used to assess the phosphorescence characteristics of an object. This study generates decay constants from experimental test data and from existing literature for comparison. It shows that the decay constants of an object may not be invariant and that they are dependent on phosphor material, temperature, irradiation intensity, sample thickness, and phosphor density for samples. In addition, the use of different numbers of exponential components in interpretation leads to different numerical results for decay constants. The relationship between the calculated decay constants and the afterglow characteristics of an object is studied and discussed in this paper. The appearance of the luminescence intensity is less correlated to the decay constants than to the time-invariant constants in an equation. PMID- 25295290 TI - Plasmonic structure enhanced exciton generation at the interface between the perovskite absorber and copper nanoparticles. AB - The refractive index and extinction coefficient of a triiodide perovskite absorber (TPA) were obtained by fitting the transmittance spectra of TPA/PEDOT:PSS/ITO/glass using the transfer matrix method. Cu nanoplasmonic structures were designed to enhance the exciton generation in the TPA and to simultaneously reduce the film thickness of the TPA. Excitons were effectively generated at the interface between TPA and Cu nanoparticles, as observed through the 3D finite-difference time-domain method. The exciton distribution is advantageous for the exciton dissociation and carrier transport. PMID- 25295291 TI - Performance evaluation of the machine learning algorithms used in inference mechanism of a medical decision support system. AB - The importance of the decision support systems is increasingly supporting the decision making process in cases of uncertainty and the lack of information and they are widely used in various fields like engineering, finance, medicine, and so forth, Medical decision support systems help the healthcare personnel to select optimal method during the treatment of the patients. Decision support systems are intelligent software systems that support decision makers on their decisions. The design of decision support systems consists of four main subjects called inference mechanism, knowledge-base, explanation module, and active memory. Inference mechanism constitutes the basis of decision support systems. There are various methods that can be used in these mechanisms approaches. Some of these methods are decision trees, artificial neural networks, statistical methods, rule-based methods, and so forth. In decision support systems, those methods can be used separately or a hybrid system, and also combination of those methods. In this study, synthetic data with 10, 100, 1000, and 2000 records have been produced to reflect the probabilities on the ALARM network. The accuracy of 11 machine learning methods for the inference mechanism of medical decision support system is compared on various data sets. PMID- 25295292 TI - Generalized synchronization with uncertain parameters of nonlinear dynamic system via adaptive control. AB - An adaptive control scheme is developed to study the generalized adaptive chaos synchronization with uncertain chaotic parameters behavior between two identical chaotic dynamic systems. This generalized adaptive chaos synchronization controller is designed based on Lyapunov stability theory and an analytic expression of the adaptive controller with its update laws of uncertain chaotic parameters is shown. The generalized adaptive synchronization with uncertain parameters between two identical new Lorenz-Stenflo systems is taken as three examples to show the effectiveness of the proposed method. The numerical simulations are shown to verify the results. PMID- 25295293 TI - Certain inequalities involving generalized Erdelyi-Kober fractional q-integral operators. AB - In recent years, a remarkably large number of inequalities involving the fractional q-integral operators have been investigated in the literature by many authors. Here, we aim to present some new fractional integral inequalities involving generalized Erdelyi-Kober fractional q-integral operator due to Gaulue, whose special cases are shown to yield corresponding inequalities associated with Kober type fractional q-integral operators. The cases of synchronous functions as well as of functions bounded by integrable functions are considered. PMID- 25295294 TI - Assessment and classification of service learning: a case study of CS/EE students. AB - This study investigates the undergraduate students in computer science/electric engineering (CS/EE) in Taiwan to measure their perceived benefits from the experiences in service learning coursework. In addition, the confidence of their professional disciplines and its correlation with service learning experiences are examined. The results show that students take positive attitudes toward service learning and their perceived benefits from service learning are correlated with their confidence in professional disciplines. Furthermore, this study designs the knowledge model by Bayesian network (BN) classifiers and term frequency-inverse document frequency (TFIDF) for counseling students on the optimal choice of service learning. PMID- 25295295 TI - Minimizing the total service time of discrete dynamic berth allocation problem by an iterated greedy heuristic. AB - Berth allocation is the forefront operation performed when ships arrive at a port and is a critical task in container port optimization. Minimizing the time ships spend at berths constitutes an important objective of berth allocation problems. This study focuses on the discrete dynamic berth allocation problem (discrete DBAP), which aims to minimize total service time, and proposes an iterated greedy (IG) algorithm to solve it. The proposed IG algorithm is tested on three benchmark problem sets. Experimental results show that the proposed IG algorithm can obtain optimal solutions for all test instances of the first and second problem sets and outperforms the best-known solutions for 35 out of 90 test instances of the third problem set. PMID- 25295296 TI - The assignment of scores procedure for ordinal categorical data. AB - Ordinal data are the most frequently encountered type of data in the social sciences. Many statistical methods can be used to process such data. One common method is to assign scores to the data, convert them into interval data, and further perform statistical analysis. There are several authors who have recently developed assigning score methods to assign scores to ordered categorical data. This paper proposes an approach that defines an assigning score system for an ordinal categorical variable based on underlying continuous latent distribution with interpretation by using three case study examples. The results show that the proposed score system is well for skewed ordinal categorical data. PMID- 25295297 TI - Evaluation of phytoavailability of heavy metals to Chinese cabbage (Brassica chinensis L.) in rural soils. AB - This study compared the extractability of Cd, Cu, Ni, Pb, and Zn by 8 extraction protocols for 22 representative rural soils in Taiwan and correlated the extractable amounts of the metals with their uptake by Chinese cabbage for developing an empirical model to predict metal phytoavailability based on soil properties. Chemical agents in these protocols included dilute acids, neutral salts, and chelating agents, in addition to water and the Rhizon soil solution sampler. The highest concentrations of extractable metals were observed in the HCl extraction and the lowest in the Rhizon sampling method. The linear correlation coefficients between extractable metals in soil pools and metals in shoots were higher than those in roots. Correlations between extractable metal concentrations and soil properties were variable; soil pH, clay content, total metal content, and extractable metal concentration were considered together to simulate their combined effects on crop uptake by an empirical model. This combination improved the correlations to different extents for different extraction methods, particularly for Pb, for which the extractable amounts with any extraction protocol did not correlate with crop uptake by simple correlation analysis. PMID- 25295298 TI - Synthesis of silver nanoparticles dispersed in various aqueous media using laser ablation. AB - The particle size, morphology, and stability of Ag-NPs were investigated in the present study. A Q-Switched Nd: YAG pulsed laser (lambda = 532 nm, 360 mJ/pulse) was used for ablation of a pure Ag plate for 30 min to prepare Ag-NPs in the organic compound such as ethylene glycol (EG) and biopolymer such as chitosan. The media (EG, chitosan) permitted the making of NPs with well dispersed and average size of Ag-NPs in EG is about 22 nm and in chitosan is about 10 nm in spherical form. Particle size, morphology, and stability of NPs were compared with distilled water as a reference. The stability of the samples was studied by measuring UV-visible absorption spectra of samples after one month. The result indicated that the formation efficiency of NPs in chitosan was higher than other media and NPs in chitosan solution were more stable than other media during one month storage. This method for synthesis of silver NPs could be as a green method due to its environmentally friendly nature. PMID- 25295299 TI - Linear and nonlinear schemes applied to pitch control of wind turbines. AB - Linear controllers have been employed in industrial applications for many years, but sometimes they are noneffective on the system with nonlinear characteristics. This paper discusses the structure, performance, implementation cost, advantages, and disadvantages of different linear and nonlinear schemes applied to the pitch control of the wind energy conversion systems (WECSs). The linear controller has the simplest structure and is easily understood by the engineers and thus is widely accepted by the industry. In contrast, nonlinear schemes are more complicated, but they can provide better performance. Although nonlinear algorithms can be implemented in a powerful digital processor nowadays, they need time to be accepted by the industry and their reliability needs to be verified in the commercial products. More information about the system nonlinear feature is helpful to simplify the controller design. However, nonlinear schemes independent of the system model are more robust to the uncertainties or deviations of the system parameters. PMID- 25295300 TI - Heuristic evaluation on mobile interfaces: a new checklist. AB - The rapid evolution and adoption of mobile devices raise new usability challenges, given their limitations (in screen size, battery life, etc.) as well as the specific requirements of this new interaction. Traditional evaluation techniques need to be adapted in order for these requirements to be met. Heuristic evaluation (HE), an Inspection Method based on evaluation conducted by experts over a real system or prototype, is based on checklists which are desktop centred and do not adequately detect mobile-specific usability issues. In this paper, we propose a compilation of heuristic evaluation checklists taken from the existing bibliography but readapted to new mobile interfaces. Selecting and rearranging these heuristic guidelines offer a tool which works well not just for evaluation but also as a best-practices checklist. The result is a comprehensive checklist which is experimentally evaluated as a design tool. This experimental evaluation involved two software engineers without any specific knowledge about usability, a group of ten users who compared the usability of a first prototype designed without our heuristics, and a second one after applying the proposed checklist. The results of this experiment show the usefulness of the proposed checklist for avoiding usability gaps even with nontrained developers. PMID- 25295301 TI - PhysioDroid: combining wearable health sensors and mobile devices for a ubiquitous, continuous, and personal monitoring. AB - Technological advances on the development of mobile devices, medical sensors, and wireless communication systems support a new generation of unobtrusive, portable, and ubiquitous health monitoring systems for continuous patient assessment and more personalized health care. There exist a growing number of mobile apps in the health domain; however, little contribution has been specifically provided, so far, to operate this kind of apps with wearable physiological sensors. The PhysioDroid, presented in this paper, provides a personalized means to remotely monitor and evaluate users' conditions. The PhysioDroid system provides ubiquitous and continuous vital signs analysis, such as electrocardiogram, heart rate, respiration rate, skin temperature, and body motion, intended to help empower patients and improve clinical understanding. The PhysioDroid is composed of a wearable monitoring device and an Android app providing gathering, storage, and processing features for the physiological sensor data. The versatility of the developed app allows its use for both average users and specialists, and the reduced cost of the PhysioDroid puts it at the reach of most people. Two exemplary use cases for health assessment and sports training are presented to illustrate the capabilities of the PhysioDroid. Next technical steps include generalization to other mobile platforms and health monitoring devices. PMID- 25295302 TI - Robust framework to combine diverse classifiers assigning distributed confidence to individual classifiers at class level. AB - We have presented a classification framework that combines multiple heterogeneous classifiers in the presence of class label noise. An extension of m-Mediods based modeling is presented that generates model of various classes whilst identifying and filtering noisy training data. This noise free data is further used to learn model for other classifiers such as GMM and SVM. A weight learning method is then introduced to learn weights on each class for different classifiers to construct an ensemble. For this purpose, we applied genetic algorithm to search for an optimal weight vector on which classifier ensemble is expected to give the best accuracy. The proposed approach is evaluated on variety of real life datasets. It is also compared with existing standard ensemble techniques such as Adaboost, Bagging, and Random Subspace Methods. Experimental results show the superiority of proposed ensemble method as compared to its competitors, especially in the presence of class label noise and imbalance classes. PMID- 25295303 TI - Gene network biological validity based on gene-gene interaction relevance. AB - In recent years, gene networks have become one of the most useful tools for modeling biological processes. Many inference gene network algorithms have been developed as techniques for extracting knowledge from gene expression data. Ensuring the reliability of the inferred gene relationships is a crucial task in any study in order to prove that the algorithms used are precise. Usually, this validation process can be carried out using prior biological knowledge. The metabolic pathways stored in KEGG are one of the most widely used knowledgeable sources for analyzing relationships between genes. This paper introduces a new methodology, GeneNetVal, to assess the biological validity of gene networks based on the relevance of the gene-gene interactions stored in KEGG metabolic pathways. Hence, a complete KEGG pathway conversion into a gene association network and a new matching distance based on gene-gene interaction relevance are proposed. The performance of GeneNetVal was established with three different experiments. Firstly, our proposal is tested in a comparative ROC analysis. Secondly, a randomness study is presented to show the behavior of GeneNetVal when the noise is increased in the input network. Finally, the ability of GeneNetVal to detect biological functionality of the network is shown. PMID- 25295304 TI - Improving RLRN image splicing detection with the Use of PCA and kernel PCA. AB - Digital image forgery is becoming easier to perform because of the rapid development of various manipulation tools. Image splicing is one of the most prevalent techniques. Digital images had lost their trustability, and researches have exerted considerable effort to regain such trustability by focusing mostly on algorithms. However, most of the proposed algorithms are incapable of handling high dimensionality and redundancy in the extracted features. Moreover, existing algorithms are limited by high computational time. This study focuses on improving one of the image splicing detection algorithms, that is, the run length run number algorithm (RLRN), by applying two dimension reduction methods, namely, principal component analysis (PCA) and kernel PCA. Support vector machine is used to distinguish between authentic and spliced images. Results show that kernel PCA is a nonlinear dimension reduction method that has the best effect on R, G, B, and Y channels and gray-scale images. PMID- 25295305 TI - Determination of haloacetic acids in bottled and tap water sources by dispersive liquid-liquid microextraction and GC-MS analysis. AB - Haloacetic acids are toxic organic pollutants that can be formed as by-products of disinfection of water by chlorination. In this study, we developed a fast and efficient method for the determination of six species of these compounds in water using dispersive liquid-liquid microextraction followed by GC-MS analysis. To be suitable for GC analysis, the acidic analytes were derivatized using n-octanol. One-factor-at-a-time optimization was carried out on several factors including temperature, extraction time, amount of catalyst, and dispersive solvent. The optimized conditions were then used to determine calibration parameters. Linearity, as demonstrated by coefficient of determination, ranged between 0.9900 and 0.9966 for the concentration range of 0.05-0.57 ug/L. The proposed method has good repeatability; intraday precision was calculated as %RSD of 2.38-9.34%, while interday precision was 4.69-8.06%. The method was applied to real samples in bottled water and tap water sources. Results indicated that the total concentrations of the analytes in these sources (2.97-5.30 ug/L) were far below the maximum contaminant levels set by both the World Health Organization and the United States Environmental Protection Agency. The proposed method compared favorably with methods reported in the literature. PMID- 25295306 TI - SVM-RFE based feature selection and Taguchi parameters optimization for multiclass SVM classifier. AB - Recently, support vector machine (SVM) has excellent performance on classification and prediction and is widely used on disease diagnosis or medical assistance. However, SVM only functions well on two-group classification problems. This study combines feature selection and SVM recursive feature elimination (SVM-RFE) to investigate the classification accuracy of multiclass problems for Dermatology and Zoo databases. Dermatology dataset contains 33 feature variables, 1 class variable, and 366 testing instances; and the Zoo dataset contains 16 feature variables, 1 class variable, and 101 testing instances. The feature variables in the two datasets were sorted in descending order by explanatory power, and different feature sets were selected by SVM-RFE to explore classification accuracy. Meanwhile, Taguchi method was jointly combined with SVM classifier in order to optimize parameters C and gamma to increase classification accuracy for multiclass classification. The experimental results show that the classification accuracy can be more than 95% after SVM-RFE feature selection and Taguchi parameter optimization for Dermatology and Zoo databases. PMID- 25295307 TI - Advantage management strategy in competition via technological race perspective: empirical evidence from the Taiwanese manufacturing industry. AB - This study investigated the advantage management strategies of a firm regarding the technological race in the manufacturing sector. This is to reveal whether firms adopt a catch-up or leapfrogging strategy in the competition for innovation. The results show that competition is fierce in the Taiwanese manufacturing industry. Taiwanese manufacturing firms (mostly SMEs) tend to adopt the "catch-up" strategy to keep up with their competitors in order to remain in the technological race. The result indicates that, under financial constraints, Taiwanese manufacturing firms attempt to invest in R&D to catch up with their rivals or to avoid being eliminated from the race. PMID- 25295308 TI - Comparative study of human age estimation with or without preclassification of gender and facial expression. AB - Age estimation has many useful applications, such as age-based face classification, finding lost children, surveillance monitoring, and face recognition invariant to age progression. Among many factors affecting age estimation accuracy, gender and facial expression can have negative effects. In our research, the effects of gender and facial expression on age estimation using support vector regression (SVR) method are investigated. Our research is novel in the following four ways. First, the accuracies of age estimation using a single level local binary pattern (LBP) and a multilevel LBP (MLBP) are compared, and MLBP shows better performance as an extractor of texture features globally. Second, we compare the accuracies of age estimation using global features extracted by MLBP, local features extracted by Gabor filtering, and the combination of the two methods. Results show that the third approach is the most accurate. Third, the accuracies of age estimation with and without preclassification of facial expression are compared and analyzed. Fourth, those with and without preclassification of gender are compared and analyzed. The experimental results show the effectiveness of gender preclassification in age estimation. PMID- 25295309 TI - Battery energy storage sizing when time of use pricing is applied. AB - Battery energy storage systems (BESSs) are considered a key device to be introduced to actuate the smart grid paradigm. However, the most critical aspect related to the use of such device is its economic feasibility as it is a still developing technology characterized by high costs and limited life duration. Particularly, the sizing of BESSs must be performed in an optimized way in order to maximize the benefits related to their use. This paper presents a simple and quick closed form procedure for the sizing of BESSs in residential and industrial applications when time-of-use tariff schemes are applied. A sensitivity analysis is also performed to consider different perspectives in terms of life span and future costs. PMID- 25295310 TI - Improving vision-based motor rehabilitation interactive systems for users with disabilities using mirror feedback. AB - Observation is recommended in motor rehabilitation. For this reason, the aim of this study was to experimentally test the feasibility and benefit of including mirror feedback in vision-based rehabilitation systems: we projected the user on the screen. We conducted a user study by using a previously evaluated system that improved the balance and postural control of adults with cerebral palsy. We used a within-subjects design with the two defined feedback conditions (mirror and no mirror) with two different groups of users (8 with disabilities and 32 without disabilities) using usability measures (time-to-start (T(s)) and time-to-complete (T(c))). A two-tailed paired samples t-test confirmed that in case of disabilities the mirror feedback facilitated the interaction in vision-based systems for rehabilitation. The measured times were significantly worse in the absence of the user's own visual feedback (T(s) = 7.09 (P < 0.001) and T(c) = 4.48 (P < 0.005)). In vision-based interaction systems, the input device is the user's own body; therefore, it makes sense that feedback should be related to the body of the user. In case of disabilities the mirror feedback mechanisms facilitated the interaction in vision-based systems for rehabilitation. Results recommends developers and researchers use this improvement in vision-based motor rehabilitation interactive systems. PMID- 25295311 TI - A new sensors-based covert channel on android. AB - Covert channels are not new in computing systems, and have been studied since their first definition four decades ago. New platforms invoke thorough investigations to assess their security. Now is the time for Android platform to analyze its security model, in particular the two key principles: process isolation and the permissions system. Aside from all sorts of malware, one threat proved intractable by current protection solutions, that is, collusion attacks involving two applications communicating over covert channels. Still no universal solution can countermeasure this sort of attack unless the covert channels are known. This paper is an attempt to reveal a new covert channel, not only being specific to smartphones, but also exploiting an unusual resource as a vehicle to carry covert information: sensors data. Accelerometers generate signals that reflect user motions, and malware applications can apparently only read their data. However, if the vibration motor on the device is used properly, programmatically produced vibration patterns can encode stolen data and hence an application can cause discernible effects on acceleration data to be received and decoded by another application. Our evaluations confirmed a real threat where strings of tens of characters could be transmitted errorless if the throughput is reduced to around 2.5-5 bps. The proposed covert channel is very stealthy as no unusual permissions are required and there is no explicit communication between the colluding applications. PMID- 25295312 TI - Soft covering based rough sets and their application. AB - Soft rough sets which are a hybrid model combining rough sets with soft sets are defined by using soft rough approximation operators. Soft rough sets can be seen as a generalized rough set model based on soft sets. The present paper aims to combine the covering soft set with rough set, which gives rise to the new kind of soft rough sets. Based on the covering soft sets, we establish soft covering approximation space and soft covering rough approximation operators and present their basic properties. We show that a new type of the soft covering upper approximation operator is smaller than soft upper approximation operator. Also we present an example in medicine which aims to find the patients with high prostate cancer risk. Our data are 78 patients from Selcuk University Meram Medicine Faculty. PMID- 25295313 TI - Long term impact of balloon post-dilatation on neointimal formation: an experimental comparative study between second-generation self-expanding versus balloon-expandable stent technologies. AB - Background: Self-expanding stents (SES) are reemerging as therapeutic alternatives to treat coronary artery disease. It has been proposed that SES can improve clinical outcomes by inducing less injury at implantation and achieving better vessel wall apposition.To date, little data exists comparing the vascular response to both methods of deployment in a controlled experimental setting. Objective: To quantify differences in vascular injury and healing between second generation SES and balloon-expandable stents (BES) and the effects of balloon post-dilatation in a porcine coronary model. Methods: Seventy-five bare SES (AXXESS or vProtect) and 42 BES (Vision) were implanted in porcine coronaries. A subset of these received balloon post-dilatation(SES 1 D 5 22, BES 1 D 5 20). Follow-up was scheduled at 30 (BES 5 10, BES 1 D 56, SES 5 19, SES 1 D 5 8), 90 (BES 5 6, BES 1 D 5 8, SES 5 19, SES 1 D 5 8), and 180 days (BES 5 6, BES 1 D 5 6, SES 5 15, SES 1 D 5 6). Results: In vivo imaging and histological analysis showed that neointimal formation peaks early (30 days) in BES. Conversely, for SES, the peak occurred later (90 days). However, the neointimal formation achieved in either group equalized at 180 days. For SES, post-dilatation shortened the peak of neointimal formation to 30 days. Conversely, for BES, post dilatation delayed the peak of neointimal formation to 90 days. At 30 days, histology showed that SES had significantly less injury. However, at 90 days, injury scores tended to be higher for SES. By 180 days, injury scores were comparable between both groups. Conclusions: The mechanism of stent expansion influences the degree of vascular injury and healing. The synergistic use of balloon post dilatation changes the dynamics of healing and may impact the potential beneficial effects inherent to SES technologies. PMID- 25295314 TI - Well-trained generalists can help improve surgical capacity at district hospitals. PMID- 25295315 TI - Well-trained generalists can help improve surgical capacity at district hospitals. PMID- 25295316 TI - Parents' perceptions of HIV counselling and testing in schools: study methodology deeply flawed. PMID- 25295317 TI - HIV counselling and testing in schools. PMID- 25295318 TI - Rapid, minimally invasive adult voluntary male circumlcision with the Unicirc, a novel disposable device. PMID- 25295319 TI - Rapid, minimally invasive adult voluntary male circumcision with the Unicirc. PMID- 25295320 TI - It would have been better if I had HIV instead of diabetes. PMID- 25295321 TI - Call for closure of Folateng private wards in public hospitals in southern Gauteng. PMID- 25295323 TI - Lowering private investor risk to build a healthier country. PMID- 25295322 TI - A new horizon for the medical device sector in South Africa. PMID- 25295324 TI - Population-based health funding under attack. PMID- 25295326 TI - Breast cancer. PMID- 25295327 TI - Response to J.W. Pike by C.M. Girgis, N. Mokbel, K.M. Cha, P.J. Houweling, M. Abboud, D.R. Fraser, R.S. Mason, R.J. Clifton-Bligh, and J.E. Gunton. PMID- 25295328 TI - The challenges of managing breast cancer in the developing world - a perspective from sub-Saharan Africa. AB - Communicable diseases are the major cause of mortality in lower-income countries. Consequently, local and international resources are channelled mainly into addressing the impact of these conditions. HIV, however, is being successfully treated, people are living longer,and disease patterns are changing. As populations age, the incidence of cancer inevitably increases. The World Health Organization has predicted a dramatic increase in global cancer cases during the next 15 years, the majority of which will occur in low- and middle-income countries. Cancer treatment is expensive and complex and in the developing world 5% of global cancer funds are spent on 70% of cancer cases. This paper reviews the challenges of managing breast cancer in the developing world, using sub Saharan Africa as a model. PMID- 25295329 TI - Down-staging of breast cancer in the pre-screening era: Experiences from Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. PMID- 25295330 TI - Side-effects of systemic therapy for the management of breast cancer. PMID- 25295331 TI - The management of breast cancer-related lymphoedema. PMID- 25295332 TI - Stigma, survivorship and solutions: Addressing the challenges of living with breast cancer in low-resource areas. PMID- 25295333 TI - An approach to the management of locally advanced breast cancer: part 1. PMID- 25295334 TI - The art of intertwining life and work. PMID- 25295335 TI - Bacillus anthracis. PMID- 25295337 TI - [In memoriam. Ignasi Balaguer-Vintro (25/5/1925-20/3/2014)]. PMID- 25295338 TI - ECG quiz. Ta waves mimicking infero-lateral ST elevation during an exercise stress test. PMID- 25295339 TI - EKG quiz. Pacer talk. PMID- 25295340 TI - ECG quiz. What is causing the finding: the pacemaker, patient or the ECG machine? PMID- 25295341 TI - ECG quiz. Failure to capture? PMID- 25295342 TI - Clinicopathologic conference case 1: incidental finding on left posterior tongue. PMID- 25295343 TI - Clinicopathologic conference case 2: a man with progressive alveolar bone loss and spontaneous tooth exfoliation. PMID- 25295344 TI - Clinicopathologic conference case 3: a 75- year-old man with progressive right sided hearing loss and dizziness. PMID- 25295345 TI - Clinicopathologic conference case 4: painful nonhealing oral ulcerations. PMID- 25295346 TI - Clinicopathologic conference case 5: patient presenting with facial abscess and aggressive osteolysis with prominent periosteal reaction of the mandible. PMID- 25295347 TI - Desmond Alexander McQuillan: MBChB, DA(RCS,RCP), FFARACS, MRCGP, Dip Obst, FANZCA;1925-2014. PMID- 25295348 TI - Professional misconduct (Med10/152P). PMID- 25295349 TI - Professional misconduct (Med10/170D). PMID- 25295350 TI - Extracellular calcium regulates keratinocyte proliferation and HPV 16 E6 RNA expression in vitro. AB - Human papillomaviruses (HPV) are known to immortalize oral keratinocytes in vitro, but the underlying mechanisms causing the following resistance to differentiation remain unclear. We investigated the effect of extracellular calcium on the proliferation of HPV16-positive keratinocytes and on the mRNA expression of the viral E6-oncogene. HPV16-positive hypopharyngeal carcinoma cells (UD-SCC-2), spontaneously immortalized- (HMK) and HPV16 E6/E7-immortalized human gingival keratinocytes (IHGK) were grown for 3, 6 and 9 days in Keratinocyte Serum-free Medium with calcium concentrations ranging from 0 mM to 6 mM. Calcium concentrations up to 0.09 mM increased cellular proliferation, which decreased at higher concentrations. A shift of calcium concentration from 0 to 4 mM increased E6 expression in UD-SCC-2 cells 2.4-fold by day 9. Simultaneously, E2 expression increased. The most significant upregulation of E6 and E2 expressions was observed at day 9, grown in high-calcium media and the increase in E6 expression coincided with an increase in involucrin expression, likely indicating cell differentiation. Despite this, HPV-positive cells continued to proliferate even at high-calcium media in contrast to HPV-negative cells. Overexpression of E6 mRNA may be an important feature of HPV16-positive cells to resist the natural calcium gradient in differentiating keratinocytes allowing cell proliferation. PMID- 25295351 TI - Hypopharyngeal cancer incidence, treatment, and survival: temporal trends in the United States. AB - OBJECTIVES/HYPOTHESIS: The objective was to characterize incidence, treatment, and survival for hypopharyngeal cancer in the United States between 1988 and 2010, and to analyze associations between changes in treatment modality and survival. STUDY DESIGN: Retrospective cohort study. METHODS: A total of 3,958 adult patients with hypopharyngeal cancer were identified in the Surveillance, Epidemiology, and End Results database. Incidence, treatment, and survival, controlling for patient demographics and disease severity, were analyzed using two-tailed t tests, Kaplan-Meier analysis, and univariate and multivariate Cox regression. RESULTS: The incidence of hypopharyngeal cancer decreased from 1973 to 2010 with an average annual percent change (APC) of -2.0% every year (P < .05). Treatment with laryngopharyngectomy decreased (-2.5% APC, P < .001), treatment with radiotherapy without surgery increased (+2.0% APC, P < .001), and treatment with neither surgery nor radiotherapy increased (+0.5% APC, P < .001) between 1988 and 2010. There was a significant increase in the 5-year overall survival between 1988 and 1990 and between 1991 and 1995 (P = .024) with no other significant temporal trends in survival. Multivariate analysis revealed that age (65-74, 75-84, or 85+ relative to 18-54 years old), race (white relative to non African races), T stage (T2, T3, or T4 relative to T1), N stage (N2 or N3 relative to N0), and treatment modality (-surgery/-radiation, surgery/+radiation, and +surgery/-radiation relative to +surgery/+radiation) were all significantly associated with worse survival. CONCLUSIONS: Hypopharyngeal cancer has had a decreasing incidence with little change in patient or tumor characteristics. Treatment has increasingly involved radiation without laryngopharyngectomy. This has not been associated with a decrease in survival. Controlling for patient demographics and disease severity, radiation with laryngopharyngectomy is associated with improved survival. PMID- 25295352 TI - Endoscopic clip for closure of persistent tracheoesophageal fistula in an infant. PMID- 25295353 TI - Response. PMID- 25295354 TI - Response. PMID- 25295356 TI - Psychopharmacological management and treatment of patients. Preface. PMID- 25295357 TI - Patient page. About stroke: types of stroke. PMID- 25295358 TI - Author response. PMID- 25295359 TI - Real-time trafficking of PEGylated liposomes in the rodent focal brain ischemia analyzed by positron emission tomography. AB - Aliposomal drug delivery system was previously applied to ischemic brain model rats for the treatment of brain ischemia, and we observed that 100-nm-sized liposomes could extravasate and accumulate in the ischemic brain region even when cerebral blood flow was markedly reduced in permanent middle cerebral artery occlusion (p-MCAO) model rats. In the present study, we investigated the real time cerebral distribution of polyethylene glycol (PEG)-modified liposomes (PEGliposomes) labeled with 1-[18F]fluoro-3,6-dioxatetracosane in p-MCAO rats by positron emission tomography (PET). [18F]-Labeled PEG-liposomes were intravenously injected into p-MCAO rats 1 h after the onset of occlusion, and then a PET scan was performed for 2 h. The PET scan showed that the signal intensity of [18F] gradually increased in the ischemic region despite the drastic reduction in cerebral perfusion, suggesting that PEG-liposomes had accumulated in and around the ischemic region. Therefore,drug delivery to the ischemic region by use of liposomes would be possible under ischemic conditions, and a liposomal drug delivery system could be a promising strategy for protecting the ischemic brain from damage before recovery from ischemia. PMID- 25295360 TI - Discovery of Australian bat lyssavirus in horses poses further threats to human and animal health. PMID- 25295361 TI - A female veterinarian may also apply. PMID- 25295362 TI - Evolving our thinking on membership. PMID- 25295363 TI - Vet students at risk of a lifetime of debt. PMID- 25295364 TI - Veterinary remuneration - the facts. PMID- 25295365 TI - Celebrating the village vet's lifestyle. PMID- 25295366 TI - Volunteering in Australia's remote indigenous communities. PMID- 25295367 TI - Crisis response for animal welfare situation overview report. PMID- 25295368 TI - Good news on antimicrobial resistance in cattle. PMID- 25295369 TI - Crossbred cats live longer than purebred cats. PMID- 25295370 TI - Nearly 1000 vets attend the World Buiatrics Congress in Cairns. PMID- 25295371 TI - Asking appropriate interview questions: equal opportunity influences. PMID- 25295372 TI - Overcoming anxiety and increasing resilience in pets. PMID- 25295373 TI - Euthanasia of a greyhound. PMID- 25295374 TI - [Environmental health on the neonatal unit: what is the role of routine surface disinfection?]. PMID- 25295375 TI - Rights and wrongs o the HIM front lines. Not all decisions pay off for health information management leaders, but many bring lasting benefits. PMID- 25295376 TI - Methadone maintenance therapy and HIV counseling and testing are associated with lower frequency of risky behaviors among injection drug users in China. AB - Three consecutive cross-sectional surveys were conducted among injection drug users (IDUs). Of 2,530 participants, 47.7% reported ever sharing needles, 78.2% having had unprotected sex in the last month, 34.4% not receiving either methadone maintenance therapy (MMT) or HIV voluntary counseling and testing (VCT), 4.8% ever receiving MMT-only, 36.6% ever receiving VCT-only, and 24.2% ever receiving both MMT and VCT. MMT-only and the combination of MMT and VCT had significant associations with needle sharing and on unprotected sexual behaviors. Effectively integrating VCT into MMT services is a logical way to maximize the impact of both interventions on risky behaviors among IDUs. PMID- 25295377 TI - Structure and topology of soda-lime silicate glasses: implications for window glass. AB - The structural and topological properties of soda-lime silicate glasses of the form (1-2x)SiO2-xNa2O-xCaO are studied from classical molecular dynamics using a Buckingham type potential. Focus is made on three compositions (x = 6%, 12%, and 18%) which are either silica-rich or modifier-rich. We compare the results to available experimental measurements on structural properties and find that the simulated pair correlation function and total structure factor agree very well with available experimental measurements from neutron diffraction. The detail of the structural analysis shows that the Na and Ca coordination numbers tend to evolve with composition, and with increasing modifier content, changing from 5.0 to 5.6 and from 4.0 to 5.0 for Ca and Na, respectively. The analysis from topological constraints shows that the picture derived on a heuristic basis using classical valence rules remains partially valid. Ultimately, typical elastic phases are identified from the application of rigidity theory, and results indicate that the 6% system is stressed-rigid, whereas the modifier-rich composition (18%) is flexible. These results receive support from a full analysis of the vibrational density of states showing the low-energy bands at E < 20 meV increase as the system becomes flexible, providing another indirect signature of the presence of rigid to flexible transitions in this archetypal glass. Consequences for window glass are discussed under this perspective. PMID- 25295378 TI - Increased seroreactivity to human T cell lymphoma/leukemia virus-related endogenous sequence-1 Gag peptides in patients with human T cell lymphoma/leukemia virus myelopathy. AB - Previously, we had shown that although only 8% of patients with large granular lymphocytic leukemia (LGLL) were infected with human T cell lymphoma/leukemia virus (HTLV)-2, almost half had antibodies to HTLV Gag and Env peptides. Herein, we investigated whether this could be due to cross-reactive antibodies to two homologous peptides in the Gag protein of the endogenous retrovirus HTLV-related endogenous sequence-1 (HRES-1). In addition, we had previously shown that patients with HTLV neurodegenerative diseases had increased seroreactivity to homologous HERV-K10 endogenous retrovirus peptides. Hence, in this study we also examined whether these patients had increased seroreactivity to the aforementioned HRES-1 Gag peptides. Sera from 100 volunteer blood donors (VBD), 53 patients with LGLL, 74 subjects with HTLV-1 or 2 infection (58 nonmyelopathy and 16 myelopathy), and 83 patients with multiple sclerosis (MS) were evaluated. The HTLV-positive myelopathy (HAM) patients had a statistically increased prevalence of antibodies to both HRES-1 Gag peptides (81%) vs. the VBD (0%), LGLL patients (13%), and MS patients (1%), and the HTLV-positive nonmyelopathy subjects (21%). The data suggest that cross-reactivity to HRES-1 peptides could be involved in the pathogenesis of HAM. The difference between the VBD and LGLL patients was also statistically significant, also suggesting a possible association in a minority of patients. PMID- 25295379 TI - Cancer patient experience with navigation service in an urban hospital setting: a qualitative study. AB - Cancer patient navigators are increasingly present on the oncology health care team. The positive impact of navigation on cancer care is recognised, yet a clear understanding of what the patient navigator does and how he/she executes the role continues to emerge. This study aimed to understand cancer patients' perceptions of, and experiences with patient navigation, exploring how navigation may enhance the patient experience in an urban hospital setting where patients with varying needs are treated. A qualitative study using a constructionist approach was conducted. Fifteen colorectal cancer patients participated in semi-structured telephone interviews. Data were analyzed inductively and iteratively. Findings provide insight into two central aspects of cancer navigation: navigation as patient-centred coordination and explanation of clinical care, and navigation as individualised, holistic support. Within these themes, the key benefits of navigation from the patients' perspective were demystifying the system; ensuring comprehension, managing expectations; and, delivering patient-centred care. The navigator provided individualised and extended family support; a holistic approach; and, addressed emotional and psychological needs. These findings provide a means to operationalise and validate an emerging role description and competency framework for the cancer navigator who must identify and adapt to patients' varying needs throughout the cancer care continuum. PMID- 25295380 TI - [Gliomas and BRCA genes mutations: fortuitous association or imputability?]. AB - BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future. PMID- 25295381 TI - Automatic commissioning of a GPU-based Monte Carlo radiation dose calculation code for photon radiotherapy. AB - Monte Carlo (MC) simulation is commonly considered as the most accurate method for radiation dose calculations. Commissioning of a beam model in the MC code against a clinical linear accelerator beam is of crucial importance for its clinical implementation. In this paper, we propose an automatic commissioning method for our GPU-based MC dose engine, gDPM. gDPM utilizes a beam model based on a concept of phase-space-let (PSL). A PSL contains a group of particles that are of the same type and close in space and energy. A set of generic PSLs was generated by splitting a reference phase-space file. Each PSL was associated with a weighting factor, and in dose calculations the particle carried a weight corresponding to the PSL where it was from. Dose for each PSL in water was pre computed, and hence the dose in water for a whole beam under a given set of PSL weighting factors was the weighted sum of the PSL doses. At the commissioning stage, an optimization problem was solved to adjust the PSL weights in order to minimize the difference between the calculated dose and measured one. Symmetry and smoothness regularizations were utilized to uniquely determine the solution. An augmented Lagrangian method was employed to solve the optimization problem. To validate our method, a phase-space file of a Varian TrueBeam 6 MV beam was used to generate the PSLs for 6 MV beams. In a simulation study, we commissioned a Siemens 6 MV beam on which a set of field-dependent phase-space files was available. The dose data of this desired beam for different open fields and a small off-axis open field were obtained by calculating doses using these phase space files. The 3D gamma-index test passing rate within the regions with dose above 10% of dmax dose for those open fields tested was improved averagely from 70.56 to 99.36% for 2%/2 mm criteria and from 32.22 to 89.65% for 1%/1 mm criteria. We also tested our commissioning method on a six-field head-and-neck cancer IMRT plan. The passing rate of the gamma-index test within the 10% isodose line of the prescription dose was improved from 92.73 to 99.70% and from 82.16 to 96.73% for 2%/2 mm and 1%/1 mm criteria, respectively. Real clinical data measured from Varian, Siemens, and Elekta linear accelerators were also used to validate our commissioning method and a similar level of accuracy was achieved. PMID- 25295382 TI - The effect of work shift configurations on emergency medical dispatch center response. AB - OBJECTIVE: It has been proved that emergency medical dispatch centers (EMDC) save lives by promoting an appropriate allocation of emergency medical service resources. Indeed, optimal dispatcher call duration is pivotal to reduce the time gap between the time a call is placed and the delivery of medical care. However, little is known about the impact of work shift configurations (i.e., work shift duration and work shift rotation throughout the day) and dispatcher call duration. Thus, the objective of our study was to assess the effect of work shift configurations on dispatcher call duration. METHODS: During a 1-year study period, we analyzed the dispatcher call durations for medical and trauma calls during the 4 different work shift rotations (day, morning, evening, and night) and during the 10-hour work shift of each dispatcher in the EMDC of Nantes. We extracted dispatcher call durations from our advanced telephone system, configured with CC Pulse + (Genesys, Alcatel Lucent), and collected them in a custom designed database (Excel, Microsoft). Afterward, we analyzed these data using linear mixed effects models. RESULTS: During the study period, our EMDC received 408,077 calls. Globally, the mean dispatcher call duration was 107 +/- 45 seconds. Based on multivariate linear mixed effects models, the dispatcher call duration was affected by night work shift and work shift duration greater than 8 hours, increasing it by about 10 +/- 1 seconds and 4 +/- 1 seconds, respectively (both p < 0.001). CONCLUSION: Our study showed that there was a statistically significant difference in dispatcher call duration over work shift rotation and duration, with longer durations seen over night shifts and shifts over 8 hours. While these differences are small and may not have clinical significance, they may have implications for EMDC efficiency. PMID- 25295383 TI - Outcomes of invasive mechanical ventilation in children and adolescents hospitalized due to status asthmaticus in United States: a population based study. AB - OBJECTIVE: Current national estimates of and outcomes of Invasive Mechanical Ventilation (MV) in status asthmaticus (SA) are unclear. The objective of this study is to estimate the incidence and outcomes of MV in hospitalized SA children and adolescents. METHODS: We used the Nationwide Inpatient Sample (NIS, 2009 2010), the largest all-payer hospital discharge database in United States. All hospitalizations (age <=21 years) with a primary diagnosis of SA were selected. MV was identified using ICD-9-CM procedure codes. Multivariable regression analyses were used to examine the association between MV and outcomes (Length of Stay (LOS) and Hospital Charges (HC)). RESULTS: Over the study period, of the 250 718 SA hospitalizations, MV was needed for <96 h in 0.37% hospitalizations and 0.18% had MV for >=96 h. Complications occurred in 12.4% (30 991) of all hospitalizations with pneumonia (10.8%) being the most common. A total of 65 patients died in hospitals (the overall in-hospital mortality [IHM] rate was 0.03%). About 55 of these deaths occurred among those who had MV (4% IHM rate for those receiving MV). The mean LOS and hospital HC included without MV (2.1 d, $11 921) MV < 96 h (4.8 d, $52 201); MV > 96 h (15.6 d, $200 336). After adjustment for patient/hospital level factors, the need for MV was associated with significantly higher LOS and HC (p < 0.0001). Those who had MV<96 h (OR = 2.58, 95% CI = 1.77-3.77) or MV >= 96 h (OR = 6.23, 95% CI = 3.87-10.03) had higher risk of developing pneumonia. CONCLUSIONS: Although MV is infrequently needed in children and adolescents hospitalized for SA (0.55% incidence rate), it is associated with higher IHM rate and significant hospital resource utilization. PMID- 25295384 TI - Genetic variation within the histamine pathway among patients with asthma--a pilot study. AB - OBJECTIVE: Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine-related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway, and determine their association with asthma and HRH1 mRNA expression. METHODS: We enrolled children and adults (n = 93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for nine known SNPs in the HDC, HRH1, HRH4, HNMT and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher's exact test and Chi-square test were used to determine differences in allele, genotype and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p < 0.05. RESULTS: No difference was observed in genotype/allele frequency for the nine SNPs between subjects with and without asthma. The HNMT-1639C/-464C/314C/3'UTRA haplotype was more frequently observed in those without asthma than those with asthma (p = 0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p = 0.04). CONCLUSIONS: Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings. PMID- 25295386 TI - Biofouling and microbial communities in membrane distillation and reverse osmosis. AB - Membrane distillation (MD) is an emerging desalination technology that uses low grade heat to drive water vapor across a microporous hydrophobic membrane. Currently, little is known about the biofilms that grow on MD membranes. In this study, we use estuarine water collected from Long Island Sound in a bench-scale direct contact MD system to investigate the initial stages of biofilm formation. For comparison, we studied biofilm formation in a bench-scale reverse osmosis (RO) system using the same feedwater. These two membrane desalination systems expose the natural microbial community to vastly different environmental conditions: high temperatures with no hydraulic pressure in MD and low temperature with hydraulic pressure in RO. Over the course of 4 days, we observed a steady decline in bacteria concentration (nearly 2 orders of magnitude) in the MD feed reservoir. Even with this drop in planktonic bacteria, significant biofilm formation was observed. Biofilm morphologies on MD and RO membranes were markedly different. MD membrane biofilms were heterogeneous and contained several colonies, while RO membrane biofilms, although thicker, were a homogeneous mat. Phylogenetic analysis using next-generation sequencing of 16S rDNA showed significant shifts in the microbial communities. Bacteria representing the orders Burkholderiales, Rhodobacterales, and Flavobacteriales were most abundant in the MD biofilms. On the basis of the results, we propose two different regimes for microbial community shifts and biofilm development in RO and MD systems. PMID- 25295385 TI - Functional connectivity associated with acoustic stability during vowel production: implications for vocal-motor control. AB - Vowels provide the acoustic foundation of communication through speech and song, but little is known about how the brain orchestrates their production. Positron emission tomography was used to study regional cerebral blood flow (rCBF) during sustained production of the vowel /a/. Acoustic and blood flow data from 13, normal, right-handed, native speakers of American English were analyzed to identify CBF patterns that predicted the stability of the first and second formants of this vowel. Formants are bands of resonance frequencies that provide vowel identity and contribute to voice quality. The results indicated that formant stability was directly associated with blood flow increases and decreases in both left- and right-sided brain regions. Secondary brain regions (those associated with the regions predicting formant stability) were more likely to have an indirect negative relationship with first formant variability, but an indirect positive relationship with second formant variability. These results are not definitive maps of vowel production, but they do suggest that the level of motor control necessary to produce stable vowels is reflected in the complexity of an underlying neural system. These results also extend a systems approach to functional image analysis, previously applied to normal and ataxic speech rate that is solely based on identifying patterns of brain activity associated with specific performance measures. Understanding the complex relationships between multiple brain regions and the acoustic characteristics of vocal stability may provide insight into the pathophysiology of the dysarthrias, vocal disorders, and other speech changes in neurological and psychiatric disorders. PMID- 25295387 TI - Adsorption of lysozyme on hyaluronic acid functionalized SBA-15 mesoporous silica: a possible bioadhesive depot system. AB - Silica-based ordered mesoporous materials are very attractive matrices to prepare smart depot systems for several kinds of therapeutic agents. This work focuses on the well-known SBA-15 mesoporous silica and lysozyme, an antimicrobial protein. In order to improve the bioadhesion properties of SBA-15 particles, the effect of hyaluronic acid (HA) functionalization on lysozyme adsorption was investigated. SBA-15 samples having high (H-SBA) and low (L-SBA) levels of functionalization were analyzed during the three steps of the preparations: (1) introduction of the -NH2 groups to obtain the SBA-NH2 samples; (2) functionalization with HA to obtain the SBA-HA matrices; (3) adsorption of lysozyme. All silica matrices were characterized through N2-adsorption/desorption isotherms, small-angle X-ray scattering, transmission electron microscopy, thermogravimetric analysis, and Fourier transform infrared spectroscopy. The whole of the experimental data suggests that a high level of functionalization of the silica surface allows for a negligible lysozyme adsorption mainly due to unfavorable electrostatic interactions (H-SBA-NH2) or steric hindrance (H-SBA-HA). A low degree of functionalization of the silica surface brings about a very good performance toward lysozyme adsorption, being 71% (L-SBA-NH2) and 63% (L-SBA-HA) respectively, compared to that observed for original SBA-15. Finally, two different kinetic models--a "pseudo-second order" and a "intraparticle diffusion" -were compared to fit lysozyme adsorption data, the latter being more reliable than the former. PMID- 25295388 TI - Enhancing dropwise condensation through bioinspired wettability patterning. AB - Dropwise condensation (DWC) heat transfer depends strongly on the maximum diameter (Dmax) of condensate droplets departing from the condenser surface. This study presents a facile technique implemented to gain control of Dmax in DWC within vapor/air atmospheres. We demonstrate how this approach can enhance the corresponding heat transfer rate by harnessing the capillary forces in the removal of the condensate from the surface. We examine various hydrophilic superhydrophilic patterns, which, respectively, sustain and combine DWC and filmwise condensation on the substrate. The material system uses laser-patterned masking and chemical etching to achieve the desired wettability contrast and does not employ any hydrophobizing agent. By applying alternating straight parallel strips of hydrophilic (contact angle ~78 degrees ) mirror-finish aluminum and superhydrophilic regions (etched aluminum) on the condensing surface, we show that the average maximum droplet size on the less-wettable domains is nearly 42% of the width of the corresponding strips. An overall improvement in the condensate collection rate, up to 19% (as compared to the control case of DWC on mirror-finish aluminum) was achieved by using an interdigitated superhydrophilic track pattern (on the mirror-finish hydrophilic surface) inspired by the vein network of plant leaves. The bioinspired interdigitated pattern is found to outperform the straight hydrophilic-superhydrophilic pattern design, particularly under higher humidity conditions in the presence of noncondensable gases (NCG), a condition that is more challenging for maintaining sustained DWC. PMID- 25295389 TI - Removal of oxalic acid, oxamic acid and aniline by a combined photolysis and ozonation process. AB - Aniline (ANL), an aromatic amine, oxalic acid (OXA) and oxamic acid (OMA), short chain carboxylic acids, were chosen as model organic pollutants for testing the combined effect of neat photolysis and ozonation in the treatment of aqueous effluents. In order to better understand the results, single ozonation and neat photolysis were also carried out. OXA has a high refractory character relatively to single ozonation and neat photolysis only accounted for 26% conversion of OXA after 2 h of reaction. On the other hand, OXA complete degradation was observed in less than an hour when ozone and light were used simultaneously. Despite OMA, a compound never studied before by a combined ozonation and photolysis treatment, being highly refractory to oxidation, more than 50% was removed by photo ozonation after 3 h of reaction. In the case of ANL, both single ozonation and photo-ozonation resulted in 100% removal in a short reaction period due to the high reactivity of ozone to attack this type of molecules; however, only the combined method leads to efficient mineralization (89%) after 3 h of reaction. A significant synergetic effect was observed in the degradation of the selected contaminants by the simultaneous use of ozone and light, since the mineralization rate of combined method is higher than the sum of the mineralization rates of the individual treatments. The promising results observed in the degradation of the selected contaminants are paving the way to the application of photo-ozonation in the treatment of wastewater containing this type of pollutants. PMID- 25295390 TI - Estimation of prenatal aorta intima-media thickness from ultrasound examination. AB - Prenatal events such as intrauterine growth restriction and increased cardiovascular risk in later life have been shown to be associated with an increased intima-media thickness (aIMT) of the abdominal aorta in the fetus. In order to assess and manage atherosclerosis and cardiovascular disease risk in adults and children, in recent years the measurement of abdominal and carotid artery thickness has gained a growing appeal. Nevertheless, no computer aided method has been proposed for the analysis of prenatal vessels from ultrasound data, yet. To date, these measurements are being performed manually on ultrasound fetal images by skilled practitioners. The aim of the presented study is to introduce an automatic algorithm that identifies abdominal aorta and estimates its diameter and aIMT from routine third trimester ultrasonographic fetal data.The algorithm locates the aorta, then segments it and, by modeling the arterial wall longitudinal sections by means of a gaussian mixture, derives a set of measures of the aorta diameter (aDiam) and of the intima-media thickness (aIMT). After estimating the cardiac cycle, the mean diameter and the aIMT at the end-diastole phase are computed.Considering the aIMT value for each subject, the correlation between automatic and manual end-diastolic aIMT measurements is 0.91 in a range of values 0.44-1.10 mm, corresponding to both normal and pathological conditions. The automatic system yields a mean relative error of 19%, that is similar to the intra-observer variability (14%) and much lower that the inter observer variability (42%).The correlation between manual and automatic measurements and the small error confirm the ability of the proposed system to reliably estimate aIMT values in prenatal ultrasound sequences, reducing measurement variability and suggesting that it can be used for an automatic assessment of aIMT. PMID- 25295391 TI - Ionic liquid electrolytes with various sodium solutes for rechargeable Na/NaFePO4 batteries operated at elevated temperatures. AB - NaFePO4 with an olivine structure is synthesized via chemical delithiation of LiFePO4 followed by electrochemical sodiation of FePO4. Butylmethylpyrrolidinium bis(trifluoromethanesulfonyl)imide (BMP-TFSI) ionic liquid (IL) with various sodium solutes, namely NaBF4, NaClO4, NaPF6, and NaN(CN)2, is used as an electrolyte for rechargeable Na/NaFePO4 cells. The IL electrolytes show high thermal stability (>350 degrees C) and nonflammability, and are thus ideal for high-safety applications. The highest conductivity and the lowest viscosity of the electrolyte are obtained with NaBF4. At an elevated temperature (above 50 degrees C), the IL electrolyte is more suitable than a conventional organic electrolyte for the sodium cell. At 75 degrees C, the measured capacity of NaFePO4 in a NaBF4-incorporated IL electrolyte is as high as 152 mAh g(-1) (at 0.05 C), which is near the theoretical value (154 mAh g(-1)). Moreover, 60% of this capacity can be retained when the charge-discharge rate is increased to 1 C. PMID- 25295392 TI - Structure-activity relationship of highly potent galactonoamidine inhibitors toward beta-galactosidase (Aspergillus oryzae). AB - A small library of 22 N-substituted galactonoamidines was synthesized, and their structure-activity relationship for inhibition of the hydrolytic activity of beta galactosidase (Aspergillus oryzae) was evaluated. A fast screening assay in 96 well plate format was used to follow the enzymatic hydrolysis of 2-chloro-4 nitrophenyl-beta-D-galactopyranoside using UV-vis spectroscopy. The aglycon moiety of all compounds was found to have a profound effect on their inhibitory ability. In general, galactonoamidines derived from cyclic aliphatic and linear amines show higher inhibition activity than those derived from benzylamines. Hydrophobic interactions of the methyl group rather than pi-pi stacking interactions of the aromatic ring in p-methylbenzyl-D-galactonoamidine were identified to cause its transition-state-like character and the remarkably high inhibitory ability (K(i) = 8 nM). A flexible 3-carbon methylene spacer between the exo N atom of the sugar moiety and a phenyl group furthermore increased the observed apparent inhibition drastically. PMID- 25295394 TI - Caught in the act: multiple binding sites for memantine. AB - In this issue of Structure, Ulens and colleagues demonstrate how an elegant combination of complementary functional and structural approaches can uncover both binding sites and conformational consequences associated with the Alzheimer's drug memantine binding to an ion channel. PMID- 25295393 TI - Perspectives on HIV prevention among urban black women: a potential role for HIV pre-exposure prophylaxis. AB - Limited data exist regarding attitudes and acceptability of topical and oral HIV pre-exposure prophylaxis (PrEP) among US black women. This investigation explored interest in HIV chemoprophylaxis and modes of use. Five focus groups enrolled 26 black women recruited from an inner-city community health center and affiliated HIV testing sites. Thematic analysis utilized Atlas.ti. Most women expressed interest in PrEP, as many reported condom failure concerns. Most women preferred a pill formulation to intravaginal gel because of greater perceived privacy and concerns about vaginal side effects and gel leakage. Women who had taken pills previously advocated daily dosing and indicated adherence concerns about episodic or post-coital PrEP. Many women desired prophylactic strategies that included partner testing. Urban black women are interested in utilizing PrEP; however, misgivings exist about gel inconvenience and potential side effects for themselves and their partners. Most women preferred oral PrEP, dosed daily. PMID- 25295395 TI - Switch for the necroptotic permeation pore. AB - The helical protein MLKL inserts into cell membranes and forms a permeation pore therein, resulting in cell death. In this issue of Structure, the article by Su and colleagues reports that helix 6 regulates the opening of the pore formed by preceding core helices. PMID- 25295396 TI - Transient dimerization of human MxA promotes GTP hydrolysis, resulting in a mechanical power stroke. AB - Myxovirus resistance (Mx) proteins restrict replication of numerous viruses. They are closely related to membrane-remodeling fission GTPases, such as dynamin. Mx proteins can tubulate lipids and form rings or filaments that may interact directly with viral structures. GTPase domain dimerization is thought to allow crosstalk between the rungs of a tubular or helical assembly, facilitating constriction. We demonstrate that the GTPase domain of MxA dimerizes to facilitate catalysis, in a fashion analogous to dynamin. GTP binding is associated with the lever-like movement of structures adjacent to the GTPase domain, while GTP hydrolysis returns MxA to its resting state. Dimerization is not significantly promoted by substrate binding and occurs only transiently, yet is central to catalytic efficiency. Therefore, we suggest dimerization functions to coordinate the activity of spatially adjacent Mx molecules within an assembly, allowing their mechanical power strokes to be synchronized at key points in the contractile cycle. PMID- 25295397 TI - Structural basis of the activation and degradation mechanisms of the E3 ubiquitin ligase Nedd4L. AB - We investigated the mechanisms of activation and degradation of the E3 ubiquitin ligase Nedd4L combining the available biochemical information with complementary biophysical techniques. Using nuclear magnetic resonance spectroscopy, we identified that the C2 domain binds Ca(2+) and inositol 1,4,5-trisphosphate (IP3) using the same interface that is used to interact with the HECT domain. Thus, we propose that the transition from the closed to the active form is regulated by a competition of IP3 and Ca(2+) with the HECT domain for binding to the C2 domain. We performed relaxation experiments and molecular dynamic simulations to determine the flexibility of the HECT structure and observed that its conserved PY motif can become solvent-exposed when the unfolding process is initiated. The structure of the WW3 domain bound to the HECT-PY site reveals the details of this interaction, suggesting a possible auto-ubquitination mechanism using two molecules, a partially unfolded one and a fully functional Nedd4L counterpart. PMID- 25295399 TI - Simple errors in interpretation and publication can be costly. PMID- 25295398 TI - Multiscale conformational heterogeneity in staphylococcal protein a: possible determinant of functional plasticity. AB - The Staphylococcus aureus virulence factor staphylococcal protein A (SpA) is a major contributor to bacterial evasion of the host immune system, through high affinity binding to host proteins such as antibodies. SpA includes five small three-helix-bundle domains (E-D-A-B-C) separated by conserved flexible linkers. Prior attempts to crystallize individual domains in the absence of a binding partner have apparently been unsuccessful. There have also been no previous structures of tandem domains. Here we report the high-resolution crystal structures of a single C domain, and of two B domains connected by the conserved linker. Both structures exhibit extensive multiscale conformational heterogeneity, which required novel modeling protocols. Comparison of domain structures shows that helix1 orientation is especially heterogeneous, coordinated with changes in side chain conformational networks and contacting protein interfaces. This represents the kind of structural plasticity that could enable SpA to bind multiple partners. PMID- 25295400 TI - Individual treatment effects: implications for research, clinical practice, and policy. AB - Funding for comparative effectiveness research (CER) has focused attention on what treatments work best under what specific clinical circumstances, and for whom. Because not all patients respond in the same way, treatment decisions, clinical guidelines, and coverage policies applied in a "one-size-fits-all" fashion based upon the population "average" response may lead to suboptimal outcomes. Existing frameworks focus on why patients respond differently to treatments. We propose a framework that identifies when these differences are likely to be clinically important. Scenarios are presented in which it may be most critical for clinical decisions and policies to distinguish between the average and the individual patient so that treatment recommendations provide the greatest benefits for the largest number of patients. We provide recommendations for researchers to help identify issues to study, for providers to help assist them in recommending optimal treatment for individual patients, and for payers or public health bodies to help balance societal needs with those of the individual. PMID- 25295401 TI - Managed care patients' preferences, physician recommendations, and colon cancer screening. AB - Objective To evaluate associations between patients' preferences for attributes of different colorectal (CRC) screening modalities, physician CRC screening recommendations during periodic health exams, and subsequent utilization of screening 12 months later in a large health maintenance organization (HMO). Study Design Multi-method study including baseline surveys from average-risk HMO members joined with audio recordings of 415 periodic health exams (PHEs) and electronic medical record (EMR) data. Methods Patient ratings of test attributes were used to create an algorithm reflecting type and strength of CRC screening modality preference at baseline. Physician recommendations were obtained from audio recordings. Attribute-based test preferences and physician recommendations were compared with CRC test use using chisquare tests. Associations between attribute-based preferences and physician recommendations were assessed using logistic regression. Results Based on attribute rankings, most participants had a weak preference for colonoscopy (COL) (41%), an unclear preference (22.4%), or a weak preference for fecal occult blood testing (FOBT) (18.6%). About half (56%) of patients were screened at 12 months and there was no statistical association between attribute preferences and type of test received. Patients were significantly more likely to receive a recommendation including a test other than COL when they had an attribute-based test preference for FOBT (odds ratio [OR]: 2.17; 95% CI, 1.26-3.71; P < .01). Conclusions CRC screening test use in this large HMO was generally low. It was not associated with patients' preferences for different attributes of CRC screening tests but was associated with physician recommendations. Physicians may have better success in getting patients to screen if they consider preferences for test attributes. PMID- 25295402 TI - Drug plan design incentives among Medicare prescription drug plans. AB - OBJECTIVE: Medicare Advantage prescription drug plans (MA-PDs) and standalone prescription drug plans (PDPs) face different incentives for plan design resulting from the scope of covered benefits (only outpatient drugs for PDPs versus all drug and nondrug services for Medicare Advantage [MA]/MA-PDs). The objective is to begin to explore how MA-PDs and PDPs may be responding to their different incentives related to benefit design. STUDY DESIGN: We compared 2012 PDP and MA-PD average formulary coverage, prior authorization (PA) or step therapy use, and copayment requirements for drugs in 6 classes used commonly among Medicare beneficiaries. DATA: We primarily used 2012 Prescription Drug Plan Formulary and Pharmacy Network Files and MA enrollment data. 2011 Truven Health MarketScan claims were used to estimate drug prices and to compute drug market share. Average coverage and PA/step rates, and average copayment requirements, were weighted by plan enrollment and drug market share. RESULTS: MA-PDs are generally more likely to cover and less likely to require PA/step for brand name drugs with generic alternatives than PDPs, and MA-PDs often have lower copayment requirements for these drugs. For brands without generics, we generally found no differences in average rates of coverage or PA/step, but MA-PDs were more likely to cover all brands without generics in a class. CONCLUSIONS: We found modest, confirmatory evidence suggesting that PDPs and MA-PDs respond to different incentives for plan design. Future research is needed to understand the factors that influence Medicare drug plan design decisions. PMID- 25295403 TI - Success of automated algorithmic scheduling in an outpatient setting. AB - OBJECTIVE: To determine if algorithmically generated double-booking recommendations could increase patient volume per clinical session without increasing the burden on physicians. STUDY DESIGN: A randomized controlled trial was conducted with 519 clinical sessions for 13 dermatologists from December 1, 2011, through March 31, 2012. METHODS: Sessions were randomly assigned to "Smart Booking," an algorithm that generates double-booking recommendations using a missed appointment (no-shows + same-day cancella- tions) predictive model (c statistic 0.71), or to a control arm where usual booking rules were applied. The primary outcomes were the average number and variance of arrived patients per session, after controlling by physician. In addition, physicians received a survey after each session to quantify how busy they felt during that session. RESULTS: 257 sessions were randomized to Smart-Booking and 262 sessions were randomized to control booking. Using a generalized multivariate linear model, the average number of arrived patients per session was higher in the Smart-Booking intervention arm than the control (15.7 vs 15.2, difference between groups 4.2; 95% CI, 0.08-0.75; P = .014).The variance was also higher in the intervention than control (3.72 vs 3.33, P = .38).The survey response rate was 92% and the physicians reported being similarly busy in each study arm. CONCLUSIONS: Algorithmically generated double-booking recommendations of dermatology clinical sessions using individual physician assumptions and predictive modeling can increase the number of arrived patients without overburdening physicians, and is likely scalable to other settings. PMID- 25295404 TI - Medicaid prior authorization policies and imprisonment among patients with schizophrenia. AB - OBJECTIVE: To examine the impact of Medicaid prior authorization for atypical antipsychotics on the prevalence of schizophrenia among the prison population. Study DESIGN: We collected drug-level information on prior authorization restrictions from Medicaid programs in 30 states to determine which states had prior authorization requirements before 2004. We linked the regulatory data to a survey of prison inmates conducted in 2004. METHODS: We used a sample of 16,844 inmates from a nationally representative survey and analyzed the data using cross sectional regression. To capture the impact of prior authorization, we estimated 2 models: the first included an indicator variable for states requiring prior authorization, and a second model used per capita atypical usage. RESULTS: Evidence indicated that prior authorization restrictions on atypical antipsychotics are associated with an increase in the odds of a schizophrenic resident being imprisoned in a state. State-level prior authorization requirements for atypical antipsychotics are associated with a 2.7% increase in the likelihood that an imprisoned inmate displays psychotic symptoms, and a 1.25 increase in the likelihood that an inmate was previously diagnosed with schizophrenia by a physician. Higher state-level atypical prescriptions per capita are also associated with lower likelihood of psychotic symptoms and of prior schizophrenia diagnosis among prisoners. CONCLUSIONS: Prior authorization requirements for atypical antipsychotics, which are designed to reduce healthcare costs, are associated with greater prevalence of mental illness within the criminal justice system.This association raises important questions about whether increased costs to the criminal justice system might mitigate or offset prescription drug savings created by prior authorization requirements. PMID- 25295406 TI - Does it make sense to detect Streptococcus pyogenes during tonsillitis in Europe to prevent acute rheumatic fever? PMID- 25295407 TI - Why does infant stepping disappear and can it be stimulated by optic flow? AB - Two independent experiments (n = 22 and n = 22) showed that 2-month-old infants displayed significantly more stepping movements when supported upright in the air than when supported with their feet contacting a surface. Air- and surface stepping kinematics were quite similar (Experiment 2). In addition, when data were collapsed across both experiments, more air steps and more donkey kicks were seen when infants were exposed to optic flows that specified backward compared to forward translation. The findings challenge the currently accepted heavy legs explanation for the disappearance of stepping at 2 months of age and raise new questions about the visual control of stepping. PMID- 25295405 TI - Co-feeding transmission in Lyme disease pathogens. AB - This review examines the phenomenon of co-feeding transmission in tick-borne pathogens. This mode of transmission is critical for the epidemiology of several tick-borne viruses but its importance for Borrelia burgdorferi sensu lato, the causative agents of Lyme borreliosis, is still controversial. The molecular mechanisms and ecological factors that facilitate co-feeding transmission are therefore examined with particular emphasis on Borrelia pathogens. Comparison of climate, tick ecology and experimental infection work suggests that co-feeding transmission is more important in European than North American systems of Lyme borreliosis, which potentially explains why this topic has gained more traction in the former continent than the latter. While new theory shows that co-feeding transmission makes a modest contribution to Borrelia fitness, recent experimental work has revealed new ecological contexts where natural selection might favour co feeding transmission. In particular, co-feeding transmission might confer a fitness advantage in the Darwinian competition among strains in mixed infections. Future studies should investigate the ecological conditions that favour the evolution of this fascinating mode of transmission in tick-borne pathogens. PMID- 25295408 TI - Lactococcus garvieae Endocarditis on a Prosthetic Biological Aortic Valve. AB - Lactococcus garvieae (LG) endocarditis is a rare disease in humans. There are only about 16 reported cases in the world. We report a 76-year-old male patient with LG endocarditis. In depth interview with the patient revealed that 2 weeks prior to admission, he had eaten sushi containing raw fish. Unlike many of the other infections reported, which were on a native mitral valve, our patient's vegetation was on a prosthetic aortic valve. PMID- 25295409 TI - Community pharmacy as a setting for public health nutrition action: Australian nutritionists' perspectives. AB - OBJECTIVE: To explore public health nutritionists' perceptions of nutrition and its place in community pharmacy (CP) presently and into the future; and to explore perceived opportunities, feasibility and scope of public health nutrition (PHN) interventions in CP, with a focus on maternal and infant nutrition. DESIGN: Qualitative data were gathered through semi-structured interviews and drew on hermeneutics as the theoretical framework for analysis and interpretation. SETTING: Queensland, Australia. SUBJECTS: Public health nutritionists, identified through purposive, criterion sampling, were chosen due to (i) their role as potential stakeholders, (ii) their knowledge and emphasis on nutrition and (iii) their practice experience. RESULTS: Opportunities for PHN action focused primarily on actions relating to early nutrient supplementation in pregnancy and breast-feeding protection and promotion. Opportunities in CP were constrained by practitioners' perception of (i) conflict between health care and commercial interests in CP, (ii) problematic practices in CP and (iii) values and motivations of practitioners and other stakeholders in the CP sector. Strategies were suggested to improve practices and enhance the setting from a PHN perspective. Participants suggested both collaborative and regulatory approaches to achieve settings-based changes, identifying the need for these to coexist for effective outcomes. CONCLUSIONS: Public health nutritionists suggest that opportunities for PHN action are constrained by perceived conflicted interests and that consumers need to be adequately protected from the influence of commercial interests. PHN action in this setting needs adequate reflection on evidence as well as ethics ensuring that practices are 'for the good' of mothers and infants. PMID- 25295411 TI - A thermoresponsive biodegradable polymer with intrinsic antioxidant properties. AB - Oxidative stress in tissue can contribute to chronic inflammation that impairs wound healing and the efficacy of cell-based therapies and medical devices. We describe the synthesis and characterization of a biodegradable, thermoresponsive gel with intrinsic antioxidant properties suitable for the delivery of therapeutics. Citric acid, poly(ethylene glycol) (PEG), and poly-N isopropylacrylamide (PNIPAAm) were copolymerized by sequential polycondensation and radical polymerization to produce poly(polyethylene glycol citrate-co-N isopropylacrylamide) (PPCN). PPCN was chemically characterized, and the thermoresponsive behavior, antioxidant properties, morphology, potential for protein and cell delivery, and tissue compatibility in vivo were evaluated. The PPCN gel has a lower critical solution temperature (LCST) of 26 degrees C and exhibits intrinsic antioxidant properties based on its ability to scavenge free radicals, chelate metal ions, and inhibit lipid peroxidation. PPCN displays a hierarchical architecture of micropores and nanofibers, and contrary to typical thermoresponsive polymers, such as PNIPAAm, PPCN gel maintains its volume upon formation. PPCN efficiently entrapped and slowly released the chemokine SDF 1alpha and supported the viability and proliferation of vascular cells. Subcutaneous injections in rats showed that PPCN gels are resorbed over time and new connective tissue formation takes place without signs of significant inflammation. Ultimately, this intrinsically antioxidant, biodegradable, thermoresponsive gel could potentially be used as an injectable biomaterial for applications where oxidative stress in tissue is a concern. PMID- 25295413 TI - Ultraviolet and visible range plasmonics in the topological insulator Bi1.5Sb0.5Te1.8Se1.2. AB - The development of metamaterials, data processing circuits and sensors for the visible and ultraviolet parts of the spectrum is hampered by the lack of low-loss media supporting plasmonic excitations. This has driven the intense search for plasmonic materials beyond noble metals. Here we show that the semiconductor Bi1.5Sb0.5Te1.8Se1.2, also known as a topological insulator, is also a good plasmonic material in the blue-ultraviolet range, in addition to the already investigated terahertz frequency range. Metamaterials fabricated from Bi1.5Sb0.5Te1.8Se1.2 show plasmonic resonances from 350 to 550 nm, while surface gratings exhibit cathodoluminescent peaks from 230 to 1,050 nm. The observed plasmonic response is attributed to the combination of bulk charge carriers from interband transitions and surface charge carriers of the topological insulator. The importance of our result is in the identification of new mechanisms of negative permittivity in semiconductors where visible range plasmonics can be directly integrated with electronics. PMID- 25295412 TI - Occurrence of conjugative IncF-type plasmids harboring the blaCTX-M-15 gene in Enterobacteriaceae isolates from newborns in Tunisia. AB - BACKGROUND: CTX-M-15 is the dominant type of extended-spectrum beta-lactamase in clinical isolates. This enzyme constitutes the most widespread enzymes in Tunisia. In this study, we were interested to understand the causes of the evolutionary success of CTX-M-15 in a Tunisian university hospital. METHODS: A total of of 72 cefotaxime-resistant Enterobacteriaceae were isolated from newborn patients at the hospital Taher sfar Mahdia in Tunisia and characterized their genetic support by means of molecular techniques. RESULTS: Isolates were clustered into various clonal groups, although most isolates belonged to sequence types ST39 (Klebsiella pneumoniae) and ST131 (Escherichia coli). F replicons (FIA, FIB, and FII) were the most frequently detected replicon types in our collection (91.66%). CONCLUSION: This is the first report of QnrB- and CTX-M-15 encoding large IncF-type conjugative plasmids in Tunisia. PMID- 25295414 TI - The usefulness of the leuprolide stimulation test as a diagnostic method of idiopathic central precocious puberty in girls. AB - Central precocious puberty (CPP) diagnosis is based on clinical evaluation, but hormonal evaluation is crucial. The aim of the study was to evaluate the usefulness of the leuprolide stimulation test for diagnosis of idiopathic CPP. Sixty-one girls, aged 5-8 years, were evaluated retrospectively for premature breast development. According to clinical evolution, 28 had progressive puberty and 33 nonprogressive puberty. All underwent a leuprolide stimulation test. Cutoff points, sensitivity, and specificity for gonadotropins and estradiol were determined by receiver operating characteristic (ROC) curves. Cutoff points for CPP were: baseline LH: > 0.1 mUI/l, FSH: > 2.3 mUI/l, LH/FSH ratio: > 0.23, estradiol: > 12 pg/ml; and stimulated LH: > 5.5 mUI/l, LH/FSH ratio: > 0.24, estradiol: > 79.67 pg/ml. The best diagnostic efficiency for progressive puberty were stimulated LH/FSH ratio (sensitivity: 100%, specificity 94%) followed by stimulated LH (sensitivity: 93%, specificity: 100%). Stimulated LH/FSH ratio and LH resulted in the most useful parameters for the diagnosis of CPP. Stimulated estradiol did not add more information. PMID- 25295415 TI - Influence of plasma cortisol and other laboratory parameters on nonalcoholic Fatty liver disease. AB - The objective of the present study was to analyse the association between the plasma cortisol concentration and nonalcoholic fatty liver disease (NAFLD). A total of 1 326 subjects (age 18-65 years) were examined in the context of an epidemiological study of a population-based random sample. Medical history and anthropometric data of 662 women and 664 men were documented. In addition, laboratory examinations were performed and the fat concentration of the liver was estimated by ultrasound examination. Mean cortisol concentration in plasma was 260.4+/-156.8 nmol/l for women and 295.8+/-161.2 nmol/l for men. NAFLD was identified in 17.7% in women and 35.1% in men. Plasma cortisol concentration showed no association with the existence of NAFLD. NAFLD correlated positive with age, body-mass index (BMI), waist-to-hip-ratio (WHR), alanine aminotransferase (ALT), and triglycerides. The present study failed to establish any association of plasma cortisol concentrations and NAFLD. PMID- 25295416 TI - Not all glucocorticoid-induced obesity is the same: differences in adiposity among various diagnostic groups of Cushing syndrome. AB - The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias (BAHs), which are often associated with ACTH-independent Cushing syndrome (CS). Although CS is invariably associated with obesity and is frequently associated with PKA signaling defects, we recently reported that its different forms appear to also present with variable weight gain and adiposity. The present study was aimed at characterizing further the phenotypic and molecular differences in periadrenal adipose tissue (PAT) among patients with subtypes of CS, by anthropometric/biochemical analyses and quantification of PKA expression and activity in BAHs in comparison to a non-CS group with aldosterone producing adenomas (APAs). Glucocorticoid levels, serum parameters, and BMI were analyzed among a larger patient cohort including those with different forms of CS, APAs, and Cushing disease. Abdominal CT scans were available for a small subset of patients examined for fat distribution. PAT collected during adrenalectomy was assayed for PKA activity, cAMP, and PKA expression. BMI and BMI z-score were lower in adults with PPNAD with PRKAR1A mutations and in pediatric patients with PPNAD with and without PRKAR1A mutations, respectively. Patients with PPNAD had higher cAMP levels in PAT and different fat distribution. Thus, PKA activity in PAT differed between CS diagnostic groups. Increased cAMP and PKA activity may have contributed to phenotypic differences among subtypes of CS. In agreement with the known roles of cAMP signaling in the regulation of adiposity, patients with PPNAD were less obese than other patients with CS. PMID- 25295417 TI - The relationship between serum uric acid levels and beta-cell functions in nondiabetic subjects. AB - High serum uric acid (UA) levels are believed to be an independent risk factor for the development of diabetes. We aimed to investigate the relationship between serum UA concentrations and early-phase insulin secretion following a 75 g oral glucose tolerance test (OGTT) in nondiabetic subjects. We enrolled 570 Japanese subjects (354 males and 216 females, aged 50.5 +/- 8.9 years and 52.6 +/- 7.3 years, respectively), who underwent the 75 g OGTT during their annual health examination. The OGTT confirmed their nondiabetic status. Insulin secretion was estimated by the disposition index (DI) [(Delta insulin/Delta glucose (0-30 min) * (1/HOMA-IR)], which is an adjusted measure of beta-cell function relative to variations in insulin sensitivity. Simple linear regression analysis showed negative correlations between serum UA levels and DI, when examined in the whole study population and female subjects only (r = -0.209, p < 0.001 and r = -0.232, p < 0.001, respectively). However, in male subjects, UA levels did not correlate with DI. In females, multivariate linear regression analysis revealed that serum UA levels were the major predictors of DI, explaining 16.4% of its variation (p < 0.001). Serum UA levels significantly correlate with early-phase insulin secretion in nondiabetic Japanese women. It may be an independent risk factor for predicting beta-cell function in women. PMID- 25295410 TI - Pneumothorax risk factors in smokers with and without chronic obstructive pulmonary disease. AB - RATIONALE: The demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined. OBJECTIVES: We evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema. METHODS: The study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report. MEASUREMENTS AND MAIN RESULTS: Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08-2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34-2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03-1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01-1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09-1.33). CONCLUSIONS: Among smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00608764). PMID- 25295418 TI - Leptin is positively associated with blood pressure in african men with a low body mass index: the SAfrEIC study. AB - Severe underweight may be a risk factor for hypertension in developing countries, although the manner whereby this occurs is unknown. Leptin is known to exert both beneficial and detrimental vascular effects, and is predictive of poor cardiovascular outcome at high levels, but also at low levels. We explored the relationship between blood pressure and leptin in black men from South Africa with a body mass index (BMI) in the underweight to normal range. We included 113 African men (BMI<=25 kg/m(2)) and took anthropometric, biochemical and cardiovascular measures. The blood pressure-leptin relationship was then investigated along quintiles of leptin and within BMI stratified median split (20 kg/m(2)) groups. Blood pressure increased across leptin quintiles 1-3 (p for trend<=0.040), whereas no relationship was observed along quintiles 3 to 5 (p for trend>=0.14) (adjusted for age and waist circumference). Blood pressure was similar in the two BMI median split groups (p>=0.083). In the low BMI group only, blood pressure associated positively with leptin following unadjusted, partial, and full adjustment (systolic blood pressure and diastolic blood pressure: R(2)=0.20-0.27, beta=0.32-0.34, p<=0.009). Decreasing leptin levels are not likely to contribute to hypertension prevalence in the underweight. Rather, in African men with a BMI<=20 kg/m(2), low leptin levels are positively and independently associated with elevated blood pressure, which is not seen at higher BMI (20-25 kg/m(2)). Our findings suggest a differential concentration dependent vascular effect of leptin in underweight and normal weight African men. PMID- 25295419 TI - Improving glucose tolerance by reducing weight gain in a polygenic obese mouse model: use of a high protein diet. AB - Diets to decrease body weight have limited success in achieving and importantly maintaining this weight loss long-term. It has recently been suggested that energy intake can be regulated by the amount of protein ingested, termed the protein leverage hypothesis. In this study, we determined whether a high protein diet would be effective in achieving and maintaining weight loss in a genetically obese model, the New Zealand Obese (NZO) mouse. NZO and C57BL/6J (C57) control mice were fed a high protein or chow diet for 5 weeks from weaning (3 weeks of age). Body weight and food intake were determined. Mice on the same diet were bred to produce offspring that were fed either a chow or high protein diet. Body weight, food intake, and glucose tolerance were determined. Feeding NZO and C57 mice a high protein diet for 5 weeks resulted in reduced food intake and consequently energy intake and body weight gain compared with mice on a chow diet. NZO mice fed a high protein diet showed a significant improvement in glucose tolerance compared with their chow-fed counterparts, while no difference was seen in C57 mice fed chow or protein diet. The offspring of NZO mice that were fed a high protein diet during gestation and weaning were also lighter and displayed improved glucose tolerance compared with chow fed animals. We conclude that a high protein diet is a reasonable strategy to reduce body weight gain and improve glucose tolerance in the NZO mouse, a polygenic model of obesity. PMID- 25295420 TI - Mutation in insulin receptor attenuates oxidative stress and apoptosis in pancreatic beta-cells induced by nutrition excess: reduced insulin signaling and ROS. AB - Type 2 diabetes results from the failure of beta-cells to adequately compensate for insulin resistance. Although the reduction of beta-cell mass is because of increased cell death and/or inadequate replication or neogenesis, the mechanism underlying beta-cell mass reduction is not fully understood. Here, we clarify the role of insulin signaling pathway in the beta-cell apoptosis using insulin resistant model mice. Wild-type mice and those carrying a mutation in the insulin receptor (mIR) were fed either regular chow or a high-fat diet for 6 weeks and subsequently investigated for beta-cell apoptosis, endoplasmic reticulum stress, and oxidative stress. Insulin tolerance tests revealed that mIR mice fed a high fat diet (mIRHF) had higher insulin resistance. Beta-cell apoptosis was increased 2-fold in the wild-type mice fed a high-fat diet (wHF) compared with control mice, whereas beta-cell apoptosis in mIRHF mice did not increase compared with that in mIR mice. The expression of endoplasmic reticulum stress markers in isolated islets did not differ between the groups. Staining of 8-hydroxy-2' deoxyguanosine and 4-hydroxy-2-nonenal in islets of wHF mice significantly increased, but the staining in mIRHF mice was not different from that in control group. Gene expression of the antioxidant enzyme MnSOD was significantly higher in mIRHF mice than those in the other 3 groups. A mutation in the insulin receptor attenuated the oxidative stress and apoptosis in beta-cells even though high caloric nutrient was loaded. Our results suggest that reduced insulin signaling protects beta-cells thorough decline of oxidative stress. PMID- 25295421 TI - From beta-catenin to ARM-repeat proteins in adrenocortical disorders. AB - Armadillo-containing proteins (ACPs) are a large family of evolutionary conserved proteins, characterized by the tandem repeat copy of a 42 amino acids motif, which forms a 3 dimensional protein-protein interaction domain. This permits ACPs to interact with plenty of partners and consequently, most of these proteins have several independent cellular roles. Perhaps the most well-known protein of this family is beta-catenin, which is crucial in the regulation of development and adult tissue homeostasis through its 2 independent functions, acting in cellular adhesion in addition to being a transcriptional co-activator. APCs have important functions in many tissues, but here we summarize the adrenocortical role of 2 well-described ACPs, beta-catenin (CTNNB1), Adenomatous Polyposis Coli (APC), and discuss the possible role in the adrenal cortex of the most recently discovered, Armadillo-repeat containing 5 (ARMC5). PMID- 25295422 TI - Antidepressant augmentation with anti-inflammatory agents. AB - Antidepressant augmentation strategies are commonly employed to treat depressed patients who do not respond to antidepressant monotherapy. Neuroinflammatory mechanisms have been implicated in depression, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been found effective in animal models of depression both in monotherapy and when used to augment antidepressant drugs. However, results with NSAIDs have been mixed in human observational studies, with both better and worse depression outcomes reported. Four small (pooled N = 160) randomized controlled trials suggest that celecoxib (200-400 mg/d) augmentation of antidepressant medication improves 4-6 week outcomes in major depressive disorder. There are no data, however, to support the use of celecoxib or other NSAIDs in antidepressant resistant depression. There are also concerns about adverse events associated with NSAID treatment, and about pharmacodynamic drug interactions between these drugs and serotonin reuptake inhibitors. A reasonable conclusion for the present is that NSAID augmentation of antidepressants is, at best, a tentative approach in nonrefractory major depression. PMID- 25295423 TI - Depression: addressing partial response after first-line antidepressant treatment. PMID- 25295424 TI - Postdeployment suicidal ideations and trajectories of posttraumatic stress disorder in Danish soldiers: a 3-year follow-up of the USPER study. AB - OBJECTIVE: Suicidal ideation in veterans is of great concern. The objective of this study is to examine how heterogeneous posttraumatic stress disorder (PTSD) trajectories are associated with postdeployment suicidal ideation in veterans 2.5 years postdeployment to a combat zone in Afghanistan. If PTSD trajectories are associated with postdeployment suicidal ideations, then the accumulative knowledge on what characterizes veterans falling into different PTSD trajectories may provide better opportunities for early identification of suicidal high-risk veterans. METHOD: In this prospective study of 743 Danish soldiers deployed to Afghanistan from February to August in 2009, we collected data at 6 time points from 6 weeks before deployment to 2.5 years after homecoming (total for this study: 456). At all assessments, the soldiers responded to a comprehensive questionnaire including measures of PTSD (measured by the PTSD Checklist, Civilian Version) and other mental and physical health variables, demographics, and social and combat-related factors. Suicidal ideation was measured by an item from the European Parasuicide Study Interview Schedule II. In a previous study based on soldiers from this cohort, we identified 6 PTSD trajectories using latent growth mixture modeling, which we have extracted and applied as independent variables in this study. Adjusted multivariable logistic regression analyses were applied to examine whether deployed soldiers with certain PTSD symptom trajectories were more likely to report suicidal ideation 2.5 years after homecoming. RESULTS: Two PTSD trajectories with high PTSD symptom level 2.5 years after return were significantly associated with suicidal ideation 2.5 years after homecoming. Thus, a relieved-worsening class, described by initial decreasing PTSD symptom levels followed by a steep increase in symptoms had higher risk of suicidal ideation (OR = 7.84; 95% CI, 1.68-36.6), which was also the case for a late-onset class (OR 5.2; 95% CI, 2.21-12.24) when compared to a low-stable class. CONCLUSIONS: Heterogeneous PTSD trajectories are associated with suicidal ideation in veterans 2.5 years after homecoming. PMID- 25295425 TI - JCP early career psychiatrists. Introduction. PMID- 25295426 TI - A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. AB - OBJECTIVE: Prescribers often consider the off-label use of stimulants or stimulant alternatives as adjunctive antidepressants. The authors reviewed the available literature on the efficacy of these agents for treatment of refractory unipolar and bipolar depression. DATA SOURCES: PubMed, MEDLINE, and relevant English-language literature from 1988-2013 were searched. Keywords were dopaminergic, stimulant, augmentation, treatment refractory depression, dextroamphetamine, methylphenidate, modafinil, atomoxetine, and cardiovascular safety. STUDY SELECTION: All randomized controlled trials (RCTs) published during this time period were included. When RCTs were unavailable, open studies were summarized. DATA EXTRACTION: Data on the efficacy of stimulants and stimulant alternatives as treatment augmentation for unipolar and bipolar depression were extracted. RESULTS: Three open studies showed positive findings for dopaminergic stimulants, and, although 2 RCTs showed negative findings, a recent RCT revealed positive results for lisdexamfetamine as an adjunctive agent. To date, dopaminergic stimulants have not been tested in bipolar depression RCTs. Four completed RCTs suggested that modafinil/armodafinil were beneficial as treatment adjuncts for unipolar and bipolar depression, with very low rates of mood switch in bipolar depression. One study was stopped prematurely due to safety concerns of increased suicidality. CONCLUSIONS: Modafinil and armodafinil are recommended treatment adjuncts for refractory unipolar and bipolar depression. Until recently, RCT data on dopaminergic stimulants were too limited to warrant their use as first-line treatment adjuncts. However, the promising results of 1 recent lisdexamfetamine RCT, when considered in the context of the deleterious effect of subsyndromal depression, suggest consideration of dopaminergic medications in treatment-refractory unipolar or bipolar depression when modafinil is cost prohibitive or otherwise contraindicated. PMID- 25295427 TI - Long-term outcome of obsessive-compulsive disorder in adults: a meta-analysis. AB - OBJECTIVE: To study the long-term rate and predictors of remission in adults with obsessive-compulsive disorder (OCD), using meta-analysis. DATA SOURCES: The MEDLINE database was searched to May 2013 using the search terms obsessive compulsive disorder, prospective, outcome study, clinical course, remission, prognosis, follow-up, and long-term and limits for language (English), species (humans), and age (adults). This was supplemented by manual bibliographic cross referencing. STUDY SELECTION: English-language studies from peer-reviewed journals on adults with DSM-III-R, DSM-IV, DSM-IV-TR, ICD-9, or ICD-10 diagnosis of OCD followed up for >= 1 year and treated with serotonin reuptake inhibitors and/or cognitive-behavioral therapy that reported rate of remission (Yale-Brown Obsessive Compulsive Scale [YBOCS] score < 16 at longest follow-up) were included. DATA EXTRACTION: Data were gathered as numbers/means/percentages/categories on sample size, study design, follow-up duration, age at assessment, illness duration, age at illness onset, gender, marital status, inpatient/outpatient status, family history, baseline YBOCS score, comorbidities, and remission. RESULTS: Seventeen studies (pooled N = 1,265) fit the selection criteria and were used for the meta-analysis. The pooled sample had a mean follow-up duration 4.91 years and was predominantly male and outpatient and had onset of illness in the second decade, illness duration more than 10 years, and moderate-to-severe OCD. Pooled remission rate was 53% (95% CI, 42%-65%). Prospective studies showed higher pooled remission rate than retrospective studies (55% [95% CI, 45%-65%] vs 50% [95% CI, 27%-73%], P < .001). Indian studies showed higher pooled remission rate than others (71% [95% CI, 59% 83%] vs 48% [95% CI, 37%-59%], P < .001). Age at onset (t = -7.08, P = .019), illness duration (t = -8.13, P = .015), baseline YBOCS score (t = -6.81,P = .021), and male gender (t = -5.92, P = .027) had significant negative association with remission on meta-regression. CONCLUSION: A high long-term remission rate found in this meta-analysis is contrary to generally held beliefs about poor outcome of individuals with OCD. Multicenter, prospective, long-term studies should systematically examine course and outcome in larger samples, emphasizing symptomatic and functional recovery. PMID- 25295428 TI - Can we bottle psychosocial treatments for addiction? The role of oxytocin. PMID- 25295432 TI - Glucometabolic hormones and cardiovascular risk markers in antipsychotic-treated patients. AB - OBJECTIVE: Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear. METHOD: Fifty nondiabetic (fasting plasma glucose <= 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean +/- SD age = 33.0 +/- 6.7 years; body mass index [BMI; kg/m2] = 26.0 +/- 4.7; waist circumference = 95.9 +/ 13.3 cm; glycated hemoglobin A1c [HbA1c] = 5.7% +/- 0.3%) and 93 age- and waist circumference-matched healthy male controls (age = 33 +/- 7.3 years; BMI = 26.1 +/- 3.9; waist circumference = 94.6 +/- 11.9 cm; HbA1c = 5.7% +/- 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010. RESULTS: Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P <= .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. CONCLUSIONS: Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00627757. PMID- 25295433 TI - Plasma L-tryptophan concentration in major depressive disorder: new data and meta analysis. AB - OBJECTIVE: Tryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta analysis on previous studies and our own data. DATA SOURCES: We searched the PubMed database for case-control studies published until August 31, 2013, using the search terms plasma AND tryptophan AND synonyms for MDD. An additional search was performed for the term amino acid instead of tryptophan. We obtained our own data in 66 patients with MDD (DSM-IV) and 82 controls who were recruited from March 2011 to July 2012. The majority of the patients were medicated (N = 53). Total plasma tryptophan concentrations were measured by the liquid chromatography/mass spectrometry method. STUDY SELECTION: We scrutinized 160 studies for eligibility. Original articles that were written in English and documented plasma tryptophan values in patients and controls were selected. DATA EXTRACTION: We included 24 studies from the literature and our own data in the meta-analysis, which involved a total of 744 patients and 793 controls. Data on unmedicated patients (N = 156) and their comparison subjects (N = 203) were also extracted. To see the possible correlation between tryptophan concentrations and depression severity, meta-regression analysis was performed for 10 studies with the Hamilton Depression Rating Scale 17-item version score. RESULTS: In our case control study, mean (SD) plasma tryptophan level was significantly decreased in the MDD patients versus the controls (53.9 [10.9] vs 57.2 [11.3] MUmol/L; P = .03). The meta-analysis after adjusting for publication bias showed a significant decrease in patients with MDD with a modest effect size (Hedges g, -0.45). However, analysis on unmedicated subjects yielded a large effect (Hedges g, 0.84; P = .00015). We found a weak association with depression severity in the meta-regression analysis (P = .049). CONCLUSIONS: This meta-analysis provides convincing evidence for reduced plasma tryptophan levels in patients with MDD, particularly in unmedicated patients. PMID- 25295434 TI - Personality modulates the efficacy of treatment in patients with major depressive disorder. AB - OBJECTIVE: Effects of depression treatment are obscured by heterogeneity among patients. Personality types could be one source of heterogeneity that explains variability in treatment response. Clinically meaningful variations in personality patterns could be captured with data-driven subgroups. The aim of this study was to identify such personality types and to explore their predictive value for treatment efficacy. METHOD: Participants (N = 146) in the current exploratory study came from a randomized controlled trial in primary care depressed patients, conducted between January 1998 and June 2003, comparing different treatments. All participants were diagnosed with a major depressive disorder (MDD) according to the DSM-IV. Primary (care as usual [CAU] or CAU plus a psychoeducational prevention program [PEP]) and specialized (CAU + PEP + psychiatric consultation or cognitive-behavioral therapy) treatment were compared. Personality was assessed with the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI). Personality classes were identified with latent profile analysis (LPA). During 1 year, weekly depression ratings were obtained by trimonthly assessment with the Composite International Diagnostic Interview. Mixed models were used to analyze the effects of personality on treatment efficacy. RESULTS: A 2-class LPA solution fit best to the NEO-FFI data: Class 1 (vulnerable, n = 94) was characterized by high neuroticism, low extraversion, and low conscientiousness, and Class 2 (resilient, n = 52) by medium neuroticism and extraversion and higher agreeableness and conscientiousness. Recovery was quicker in the resilient class (class * time: P < .001). Importantly, specialized treatment had added value only in the vulnerable class, in which it was associated with quicker recovery than primary treatment (class * time * treatment: P < .001). CONCLUSIONS: Personality profile may predict whether specialized clinical efforts have added value, showing potential implications for planning of treatments. PMID- 25295435 TI - Effectiveness of aripiprazole, olanzapine, quetiapine, and risperidone augmentation treatment for major depressive disorder: a nationwide population based study. AB - OBJECTIVE: Previous studies suggested that antidepressants augmented with second generation antipsychotics (SGAs), including aripiprazole, olanzapine, quetiapine, and risperidone, resulted in better treatment response or higher rates of remission in patients with major depressive disorder (MDD). However, population based study on SGA augmentation for patients with MDD remains limited. The purpose of this study was to investigate the effectiveness of SGA augmentation for treatment of MDD using the National Health Insurance Research Database in Taiwan. METHOD: The subjects were patients with MDD (ICD-9-CM code: 296.2 and 296.3) who were initially admitted to psychiatric inpatient settings for the first time between January 1, 1996, and December 31, 2007, and could be tracked until December 31, 2011. To assess the treatment effect of SGA augmentation, 993 MDD patients who received aripiprazole, olanzapine, quetiapine, or risperidone augmentation treatment for 8 weeks or more were included in this 1-year mirror image study. Outcome measures included length of psychiatric hospitalization and number of psychiatric admissions and emergency room (ER) visits. RESULTS: After patients received SGA augmentation treatment, key psychiatric service use (including length of psychiatric hospitalization [P < .0001], number of psychiatric admissions [P < .0001], and ER visits [P = .0006]) due to MDD diagnosis was significantly reduced. Subgrouping analysis for each SGA drug also showed significant reduction in number of psychiatric admissions for MDD patients who received aripiprazole (P < .0001), olanzapine (P = .003), quetiapine (P < .0001), and risperidone (P < .0001). CONCLUSIONS: The study provides support that aripiprazole, olanzapine, quetiapine, and risperidone augmentation therapy could be effective in reducing psychiatric service utilization among MDD patients. PMID- 25295436 TI - Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. AB - OBJECTIVE: Patients with anxious depression are typically more difficult to treat with monoaminergic antidepressants compared to those with nonanxious depression. Although novel research has shown that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapidly acting, relatively sustained effects in treating depression, we predicted that, consistent with the existent literature on traditional antidepressants, patients with anxious depression would have a poorer antidepressant response. METHOD: Twenty-six inpatients with treatment-resistant major depressive disorder (MDD) (DSM-IV criteria) received a single infusion of ketamine (0.5 mg/kg over 40 minutes) from January 2006-March 2013 and were followed for 28 days. A post hoc analysis compared treatment response and relapse using the Montgomery-Asberg Depression Rating Scale (MADRS) in patients with anxious versus nonanxious depression. Anxious depression was defined as MDD plus a Hamilton Depression Rating Scale anxiety/somatization factor score >= 7. RESULTS: Both anxious and nonanxious depressed patients responded positively to ketamine. A linear mixed model controlling for baseline with the MADRS revealed a significant group main effect (P = .03) and group-by-time interaction (P = .01). Post hoc tests indicated that patients with anxious depression had significantly fewer depression symptoms compared to those with nonanxious depression at days 1 through 5, 9 through 12, 15 through 17, and 25, with no significant group differences in dissociative (P = .62) or psychotic (P = .41) side effects. Regarding responders, patients with anxious depression relapsed significantly later than those with nonanxious depression (median +/- SE = 19.0 +/- 17.9 vs 1.0 +/- 0.0 days to relapse, respectively; chi2 = 9.30; P = .002). CONCLUSIONS: Unexpectedly, patients with anxious depression responded better to ketamine than those with nonanxious depression, with longer time to relapse and no side effect differences. This finding gives promise for the role of novel glutamatergic medications for the treatment of those with anxious depression, a traditionally difficult-to-treat subgroup of depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00088699. PMID- 25295437 TI - Does negative affectivity predict differential response to an SSRI versus a non SSRI antidepressant? AB - OBJECTIVE: This work tested the hypothesis that patients with high negative affectivity (NA) would have a better response to a serotonergic agent (escitalopram) than to one not thought to act directly on serotonin (bupropion). METHOD: Data from a study conducted between August 2007 and July 2011 were reanalyzed retrospectively. Patients (N = 245) meeting criteria for major depressive disorder (MDD), diagnosed with DSM-IV-TR, were randomly assigned to double-blind treatment with bupropion extended-release, escitalopram, or the combination. Negative affectivity score was estimated using the guilt, hostility/irritability, and fear/anxiety items of the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptoms, and the Social Adjustment Scale. We felt that these items captured published descriptions of the NA construct. A Clinical Global Impressions-Severity of Illness (CGI-S) score <= 2 defined response. Because combined treatment addressed both serotonin and non-serotonin systems, patients treated with both medications did not test the hypothesis and so were excluded from the analyses. RESULTS: Analysis of covariance with treatment as a grouping variable, NA as covariate, and CGI-S as dependent variable showed a significant 2 way interaction between treatment and NA (F1,156 = 4.82, P < .03). In the low-NA group, response rates were similar between treatments (escitalopram: 28/42 [67%]; bupropion: 23/40 [58%]; NS), while there was a significant advantage for escitalopram in patients with high NA (escitalopram: 24/40 [60%]; bupropion = 14/41 [34%]; P = .017). CONCLUSIONS: These data suggest that patients with high negative affectivity respond preferentially to antidepressants that selectively enhance serotonin neurotransmission. Although patients with low NA appear to benefit from serotonin enhancement as well, they also improved with bupropion, an antidepressant not thought to directly affect serotonin neurotransmission. These findings come from retrospective analyses using unproven approximation of NA, so no clinical inferences should be made before independent replication utilizing accepted NA measurement. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00519428. PMID- 25295438 TI - Viewing suicide risk through a new lens: the benefits of examining symptom trajectories. PMID- 25295439 TI - Beyond categorical classifications: the importance of identifying posttrauma symptom trajectories and associated negative outcomes. PMID- 25295440 TI - Empirical characterization of heterogeneous posttraumatic stress responses is necessary to improve the science of posttraumatic stress. PMID- 25295441 TI - Trajectories of PTSD symptoms and predictive factors of trajectory membership: a step toward identifying veterans at risk. PMID- 25295442 TI - Resilience and other reactions to military deployment: the complex task of identifying distinct adjustment trajectories. PMID- 25295443 TI - Paying reviewers for scientific papers and ethical committees. PMID- 25295444 TI - Knowledge, perceptions and use of generic drugs: a cross sectional study. AB - OBJECTIVE: To assess the level of knowledge, perceptions and usage profile for generic drugs among laypersons. METHODS: A cross-sectional study was conducted with 278 volunteers (180 women and 98 men, aged 37.1+/-15.8 years). A questionnaire was drawn up with questions on their use, perceptions and knowledge of generic drugs. RESULTS: Most respondents (99.6%) knew that generic drugs exist, but only 48.6% were able to define them correctly, while 78.8% of the respondents had some information about generics. This information was obtained mainly through television (49.3%). In terms of generic drug characteristics, 79.1% stated that they were confident about their efficacy, 74.8% believed that generic drugs have the same effect as branded medications, 88.8% said that generics were priced lower than branded medications, and 80.2% stated that they bought generic drugs because of price. With regard to drugs prescribed by medical practitioners, 17.6% of the participants said that their doctors never prescribed generics and only 7.5% confirmed that their doctors always prescribed generics. CONCLUSION: For the lay public, the sample in this study has sufficient knowledge of generic drugs in terms of definition, efficacy and cost. Consequently, the volunteers interviewed are very likely to use generics. Furthermore, the results of this study indicate that programs should be implemented in order to boost generic drug prescriptions by medical practitioners. PMID- 25295445 TI - Evolution of post-deployment indicators of oral health on the Family Health Strategy. AB - OBJECTIVE: To evaluate the evolution of indicators after the implementation of 21 Oral Healthcare Teams in the Family Health Strategy. METHODS: We used data from outpatient services of Oral Healthcare Teams to evaluate efficiency, access, percentage of absences and emergencies of oral healthcare professionals who worked in the partnership between the Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein and the Secretaria Municipal de Saude de Sao Paulo, during the period 2009-2011. RESULTS: Percentages of emergencies, income, and access showed a significant difference during the period analyzed, but no difference for percentage of absences was found. When monthly analysis was made, it is noteworthy that at the beginning of service implementation a fluctuation occurred, which may indicate that the work was consolidated over the months, becoming capable of receiving new professionals and increasing the population served. Comparison of the indicators in that period with the goals agreed upon between the Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein and the Secretaria Municipal de Saude de Sao Paulo made it possible to notice that the Oral Health Teams had a good performance. CONCLUSION: The results showed that the goals were achieved reflecting the increasing number of professionals, the maturing of work processes in the Oral Health Teams, and optimization of the manpower available to perform the activities. Understanding these results will be important to guide the actions of Oral Health Teams for the following years and to assess the achievement of goals. PMID- 25295446 TI - Nosocomial infections by Klebsiella pneumoniae carbapenemase producing enterobacteria in a teaching hospital. AB - OBJECTIVE: To analyze the profile of patients with microorganisms resistant to carbapenems, and the prevalence of the enzyme Klebsiella pneumoniae carbapenemase in interobacteriaceae. METHODS: Retrospective descriptive study. From the isolation in bacteriological tests ordered by clinicians, we described the clinical and epidemiological characteristics of patients with enterobacteria resistants to carbapenems at a university hospital, between March and October 2013. RESULTS: We included 47 isolated patients in this study, all exhibiting resistance to carbapenems, including 9 patients who were confirmed as infected/colonized with K. pneumoniae carbapenemase. Isolation in tracheal aspirates (12; 25.5%) predominated. The resistance to ertapenem, meropenem, and imipenem was 91.5%, 83.0% and 80.0%, respectively. Aminoglycosides was the class of antimicrobials that showed the highest sensitivity, 91.5% being sensitive to amikacin and 57.4% to gentamicin. CONCLUSION: The K. pneumoniae carbapenemase was an important agent in graun isotaling in hospital intection. The limited therapeutic options emphasize the need for rapid laboratory detection, as well as the implementation of measures to prevent and control the spread of these pathogens. PMID- 25295447 TI - Sleeve gastrectomy with anti-reflux procedures. AB - OBJECTIVE: Sleeve gastrectomy is the fastest growing surgical procedure to treat obesity in the world but it may cause or worsen gastroesophageal reflux disease. This article originally aimed to describe the addition of anti-reflux procedures (removal of periesophageal fats pads, hiatoplasty, a small plication and fixation of the gastric remnant in position) to the usual sleeve gastrectomy and to report early and late results. METHODS: Eighty-eight obese patients that also presented symptoms of gastroesophageal reflux disease were submitted to sleeve gastrectomy with anti-reflux procedures. Fifty of them were also submitted to a transit bipartition. The weight loss of these patients was compared to consecutive 360 patients previously submitted to the usual sleeve gastrectomy and to 1,140 submitted to sleeve gastrectomy + transit bipartition. Gastroesophageal reflux disease symptoms were specifically inquired in all anti-reflux sleeve gastrectomy patients and compared to the results of the same questionnaire applied to 50 sleeve gastrectomy patients and 60 sleeve gastrectomy + transit bipartition patients that also presented preoperative symptoms of gastroesophageal reflux disease. RESULTS: In terms of weight loss, excess of body mass index loss percentage after anti-reflux sleeve gastrectomy is not inferior to the usual sleeve gastrectomy and anti-reflux sleeve gastrectomy + transit bipartition is not inferior to sleeve gastrectomy + transit bipartition. Anti-reflux sleeve gastrectomy did not add morbidity but significantly diminished gastroesophageal reflux disease symptoms and the use of proton pump inhibitors to treat this condition. CONCLUSION: The addition of anti-reflux procedures, such as hiatoplasty and cardioplication, to the usual sleeve gastrectomy did not add morbidity neither worsened the weight loss but significantly reduced the occurrence of gastroesophageal reflux disease symptoms as well as the use of proton pump inhibitors. PMID- 25295448 TI - The use of external event monitoring (web-loop) in the elucidation of symptoms associated with arrhythmias in a general population. AB - OBJECTIVE: To correlate arrhythmic symptoms with the presence of significant arrhythmias through the external event monitoring (web-loop). METHODS: Between January and December 2011, the web-loop was connected to 112 patients (46% of them were women, mean age 52+/-21 years old). Specific arrhythmic symptoms were defined as palpitations, pre-syncope and syncope observed during the monitoring. Supraventricular tachycardia, atrial flutter or fibrillation, ventricular tachycardia, pauses greater than 2 seconds or advanced atrioventricular block were classified as significant arrhythmia. The association between symptoms and significant arrhythmias were analyzed. RESULTS: The web-loop recorded arrhythmic symptoms in 74 (66%) patients. Of these, in only 14 (19%) patients the association between symptoms and significant cardiac arrhythmia was detected. Moreover, significant arrhythmia was found in 11 (9.8%) asymptomatic patients. There was no association between presence of major symptoms and significant cardiac arrhythmia (OR=0.57, CI95%: 0.21-1.57; p=0.23). CONCLUSION: We found no association between major symptoms and significant cardiac arrhythmia in patients submitted to event recorder monitoring. Event loop recorder was useful to elucidate cases of palpitations and syncope in symptomatic patients. PMID- 25295449 TI - Prevalence of renal insufficiency in elderly cancer patients in a tertiary cancer center. AB - OBJECTIVE: To estimate the prevalence of abnormal glomerular filtration rate in elderly patients with solid tumors. METHODS: A retrospective study with patients aged >65 years diagnosed with solid tumors between January 2007 and December 2011 in a cancer center. The following data were collected: sex, age, serum creatinine at the time of diagnosis and type of tumor. Renal function was calculated using abbreviated Modification of Diet in Renal Disease (MDRD) formulae and then staged in accordance with the clinical practice guidelines published by the Working Group of the National Kidney Foundation. RESULTS: A total of 666 patients were included and 60% were male. The median age was 74.2 years (range: 65 to 99 years). The most prevalent diagnosis in the study population were colorectal (24%), prostate (20%), breast (16%) and lung cancer (16%). The prevalence of elevated serum creatinine (>1.0mg/dL) was 30%. However, when patients were assessed using abbreviated MDRD formulae, 66% had abnormal renal function, stratified as follows: 45% with stage 2, 18% with stage 3, 3% with stage 4 and 0.3% with stage 5. CONCLUSION: To the best of our knowledge, this was the first study to estimate the frequency of renal insufficiency in elderly cancer patients in Brazil. The prevalence of abnormal renal function among our cohort was high. As suspected, the absolute creatinine level does underestimate renal function impairment and should not be used as predictor of chemotherapy metabolism, excretion and consequent toxicity. PMID- 25295450 TI - Hematological change parameters in patients with pressure ulcer at long-term care hospital. AB - OBJECTIVE: To assess factors associated with the development of pressure ulcers, and to compare the effectiveness of pharmacological treatments. METHODS: The factors associated with the development of pressure ulcers were compared in lesion-carrying patients (n=14) and non-carriers (n=16). Lesion-carrying patients were treated with 1% silver sulfadiazine or 0.6IU/g collagenase and were observed for 8 weeks. The data collected was analyzed with p<0.05 being statistically relevant. RESULTS: The prevalence of pressure ulcers was about 6%. The comparison of carrier and non-carrier groups of pressure ulcers revealed no statistically significant difference in its occurrence with respect to age, sex, skin color, mobility, or the use of diapers. However, levels of hemoglobin, hematocrit, and red blood cells were found to be statistically different between groups, being lower in lesion-carrying patients. There was no significant difference found in lesion area between patients treated with collagenase or silver sulfadiazine, although both groups showed an overall reduction in lesion area through the treatment course. CONCLUSION: Hematologic parameters showed a statistically significant difference between the two groups. Regarding the treatment of ulcers, there was no difference in the area of the lesion found between the groups treated with collagenase and silver sulfadiazine. PMID- 25295451 TI - Attention deficit and hyperactivity disorder: a therapeutic option. AB - OBJECTIVE: To evaluate the use of a therapeutic regimen to treat attention deficit hyperactivity disorder patients. METHODS: A total of 140 patients initially underwent physical, neurological and laboratory evaluation. Thereafter, treatment was initiated with a compounding product consisting of a tricyclic antidepressant and an anxiolytic. RESULTS: The response was positive in 71.43% of patients in controlling hyperactivity and improving dispersion and attention deficit. CONCLUSION: The therapeutic regimen utilized proved to be an effective therapeutic alternative, especially for patients who do not adapt to psychostimulant drugs. PMID- 25295452 TI - Metric analysis of basal sphenoid angle in adult human skulls. AB - OBJECTIVE: To analyze the variations in the angle basal sphenoid skulls of adult humans and their relationship to sex, age, ethnicity and cranial index. METHODS: The angles were measured in 160 skulls belonging to the Museum of the Universidade Federal de Sao Paulo Department of Morphology. We use two flexible rules and a goniometer, having as reference points for the first rule the posterior end of the ethmoidal crest and dorsum of the sella turcica, and for the second rule the anterior margin of the foramen magnum and clivus, measuring the angle at the intersection of two. RESULTS: The average angle was 115.41 degrees , with no statistical correlation between the value of the angle and sex or age. A statistical correlation was noted between the value of the angle and ethnicity, and between the angle and the horizontal cranial index. CONCLUSION: The distribution of the angle basal sphenoid was the same in sex, and there was correlation between the angle and ethnicity, being the proportion of non-white individuals with an angle >125 degrees significantly higher than that of whites with an angle >125 degrees . There was correlation between the angle and the cranial index, because skulls with higher cranial index tend to have higher basiesfenoidal angle too. PMID- 25295453 TI - Influence of different frequencies of transcutaneous electrical nerve stimulation on the threshold and pain intensity in young subjects. AB - OBJECTIVE: To investigate the effects of different transcutaneous electrical nerve stimulation frequencies in nociception front of a pressure pain threshold and cold in healthy individuals. METHODS: Twenty healthy subjects were divided into four groups, all of which have gone through all forms of electrical stimulation at different weeks. Assessments were pre and post-therapy, 20 and 60 minutes after stimulation. To evaluate the pressure pain threshold, an algometer was used with one tapered tip, pressing the hypothenar region until voluntary report the word "pain". Cold pain intensity was assessed by immersion in water at 5 degrees C for 30 seconds; at the end, the subject was asked to quantify the pain intensity on a Visual Analog Scale for Pain. For electrical stimulation, two electrodes were used near the elbow, for 20 minutes, with an intensity strong, but not painful. The frequency was in accordance with the group: 0Hz (placebo); 7Hz; 100Hz; and 255Hz. RESULTS: Both for the assessment of pressure pain threshold as the cold pain intensity, there was no significant difference (p>0.05). CONCLUSION: We conclude that the use of transcutaneous electrical nerve stimulation on dermatomes C6 to C8 produced no significant change in pressure pain threshold or cold discomfort. PMID- 25295454 TI - Creating and validating an instrument to identify the workload at an oncology and hematology outpatient service. AB - OBJECTIVE: Construct and to validate an instrument for measuring the time spent by nursing staff in the interventions/activities in Outpatient Oncology and Hematology, interventions based on Nursing Interventions Classification (NIC), for key areas of Pediatric Oncology and Oncology Nursing. METHODS: Cross sectional study divided into two steps: (1) construction of an instrument to measure the interventions/Nursing activities and (2) validation of this instrument. RESULTS: We selected 32 essential interventions from NIC for Pediatric Oncology and Oncology Nursing areas. The judges agreed with removing 13 and including 6 interventions in the instrument, beyond personal activity. CONCLUSION: The choice of essential interventions from NIC is justified by the gain time on research. PMID- 25295455 TI - Theoretical and practical knowledge of nursing professionals on indirect blood pressure measurement at a coronary care unit. AB - OBJECTIVE: To determine and to analyze the theoretical and practical knowledge of Nursing professionals on indirect blood pressure measurement. METHODS: This cross sectional study included 31 professionals of a coronary care unit (86% of the Nursing staff in the unit). Of these, 38.7% of professionals were nurses and 61.3% nurse technicians. A validated questionnaire was used to theoretical evaluation and for practice assessment the auscultatory technique was applied in a simulation environment, under a non-participant observation. RESULTS: To the theoretical knowledge of the stages of preparation of patient and environment, 12.9% mentioned 5-minute of rest, 48.4% checked calibration, and 29.0% chose adequate cuff width. A total of 64.5% of professionals avoided rounding values, and 22.6% mentioned the 6-month deadline period for the equipment calibration. On average, in practice assessment, 65% of the steps were followed. Lacks in knowledge were primary concerning lack of checking the device calibration and stethoscope, measurement of arm circumference to choose the cuff size, and the record of arm used in blood pressure measurement. CONCLUSION: Knowledge was poor and had disparities between theory and practice with evidence of steps taken without proper awareness and lack of consideration of important knowledge during implementation of blood pressure measurement. Educational and operational interventions should be applied systematically with institutional involvement to ensure safe care with reliable values. PMID- 25295456 TI - Transcriptional expression study in the central nervous system of rats: what gene should be used as internal control? AB - OBJECTIVE: A growing number of published articles report the expression of specific genes with different behavior patterns in rats. The levels of messenger ribonucleic acid transcripts are usually analyzed by reverse transcription followed by polymerase chain reaction and quantified after normalization with an internal control or reference gene (housekeeping gene). Nevertheless, housekeeping genes exhibit different expression in the central nervous system, depending on the physiological conditions and the area of the brain to be studied. The choice of a good internal control gene is essential for obtaining reliable results. This study evaluated the expression of three housekeeping genes (beta-actin, cyclophilin A, and ubiquitin C) in different areas of the central nervous system in rats (olfactory bulb, hippocampus, striatum, and prefrontal cortex). METHODS: Wistar rats (virgin females, n=6) during the diestrum period were used. Total ribonucleic acid was extracted from each region of the brain; the complementary deoxyribonucleic acid was synthesized by reverse transcription and amplified by real-time quantitative polymerase chain reaction using SYBRTM Green and primers specific for each one of the reference genes. The stability of the expression was determined using NormFinder. RESULTS: Beta-actin was the most stable gene in the hippocampus and striatum, while cyclophilin A and ubiquitin C showed greater stability in the prefrontal cortex and the olfactory bulb, respectively. CONCLUSION: Based on our study, further studies of gene expression using rats as animal models should take into consideration these results when choosing a reliable internal control gene. PMID- 25295457 TI - Public private partnership in vascular surgery. AB - OBJECTIVE: To describe and analyze the results of a public-private partnership between the Ministry of Health and a private hospital in a project of assistance and scientific research in the field of endovascular surgery. METHODS: The flows, costs and clinical outcomes of patients treated in a the public-private partnership between April 2012 and July 2013 were analyzed. All patients underwent surgery and stayed at least one day at the intensive care unit of the private hospital. They also participated in a research protocol to compare two intravenous contrast media used in endovascular surgery (iodinated contrast and carbon dioxide). RESULTS: A total of 62 endovascular procedures were performed in 57 patients from the public healthcare system. Hospital and endovascular supplies expenses were significantly higher as compared to the amount paid by the Unified Health System (SUS - Sistema Unico de Saude) in two out of three disease groups studied. Among outpatients, the average interval between appointment and surgery was 15 days and, in hospitalized patients 7 days. All procedures were successful with no conversion to open surgery. The new contrast medium studied - carbon dioxide - was effective and cheaper. CONCLUSION: The waiting time for patients between indication and accomplishment of surgery was significantly reduced. Public-private partnerships can speed up care of patients from public health services, and generate and improve scientific knowledge. PMID- 25295458 TI - Neuromuscular electrical stimulation in critically ill patients in the intensive care unit: a systematic review. AB - OBJECTIVE: To analyze the outcomes enabled by the neuromuscular electric stimulation in critically ill patients in intensive care unit assisted. METHODS: A systematic review of the literature by means of clinical trials published between 2002 and 2012 in the databases LILACS, SciELO, MEDLINE and PEDro using the descriptors "intensive care unit", "physical therapy", "physiotherapy", "electric stimulation" and "randomized controlled trials". RESULTS: We included four trials. The sample size varied between 8 to 33 individuals of both genders, with ages ranging between 52 and 79 years, undergoing invasive mechanical ventilation. Of the articles analyzed, three showed significant benefits of neuromuscular electrical stimulation in critically ill patients, such as improvement in peripheral muscle strength, exercise capacity, functionality, or loss of thickness of the muscle layer. CONCLUSION: The application of neuromuscular electrical stimulation promotes a beneficial response in critically patients in intensive care. PMID- 25295459 TI - Personalized medicine and the clinical laboratory. AB - Personalized medicine is the use of biomarkers, most of them molecular markers, for detection of specific genetic traits to guide various approaches for preventing and treating different conditions. The identification of several genes related to heredity, oncology and infectious diseases lead to the detection of genetic polymorphisms that are involved not only in different clinical progression of these diseases but also in variations in treatment response. Currently, it is possible to detect these polymorphisms using several methodologies: detection of single nucleotide polymorphisms using polymerase chain reaction methods; nucleic acid microarray detection; and nucleic acid sequencing with automatized DNA sequencers using Sanger-derived methods and new generation sequencing. Personalized medicine assays are directed towards detecting genetic variations that alter interactions of drugs with targets or the metabolic pathways of drugs (upstream and downstream) and can be utilized for the selection of drug formulations and detect different immunogenicities of the drug. Personalized medicine applications have already been described in different areas of Medicine and allow specific treatment approaches to be applied to each patient and pathology according to the results of these assays. The application of such a protocol demands an increasing interaction between the clinical laboratory and the clinical staff. For its implementation, a coordinated team composed of basic researchers and physicians highly specialized in their areas supported by a highly specialized team of clinical analysts particularly trained in molecular biology assays is necessary. PMID- 25295461 TI - Negative association between right bundle branch block and inducibility of ventricular tachyarrhythmias in Chagas disease. PMID- 25295460 TI - Left colectomy with intracorporeal anastomosis: technical aspects. AB - Oncologic laparoscopic colectomy represents a fully validated surgical approach to the management of colorectal cancer. However, laparoscopic surgery for distal transverse and descending colon lesions remains a challenging procedure. A total laparoscopic approach to the left colectomy is an interesting option for critically ill patients although reports in the literature on this subject are scarce and its approach still not standardized because of its selective nature for indication. There are several advantages associated with conduction of totally laparoscopic approach to the left colon. Intracorporeal vessel sealing ensures an adequate lymph node dissection. Moreover, it enables the construction of a well-vascularized anastomosis. Ultimately, the occurrence of late wound complications are possibly reduced for the placement of a low abdominal incision exclusively used for specimen extraction. This paper aimed at describing our technique for a totally laparoscopic left colectomy for distal transverse and descending colon lesions. PMID- 25295462 TI - Inhibition of diacylglycerol acyltransferase by prenylated flavonoids isolated from the stem bark of Maackia amurensis. AB - A new prenylated flavanone, erythraddison Z (1), together with eight known flavonoids (2-9), was isolated from the stem bark of Maackia amurensis. Their structures were elucidated on the basis of spectroscopic methods, including 1D and 2D NMR (COSY, HMQC, and HMBC) techniques. All the isolates, with the exception of 3, 6 and 7, strongly inhibited diacylglycerol acyltransferase activity in an in vitro assay with IC50 values ranging from 96.5 +/- 0.6 to 135.1 +/- 1.4 MUM. PMID- 25295463 TI - Catalyst-free reductive amination of aromatic aldehydes with ammonium formate and Hantzsch ester. AB - The protocol of the reductive amination of aromatic aldehydes using ammonium formate and Hantzsch ester is described. It is a mild, convenient, acid- and catalyst-free system applied for the synthesis of both symmetric and asymmetric aromatic secondary amines. PMID- 25295464 TI - 1H and 13C NMR assignments of three new tricycloalternarenes from endophytic fungus Alternaria tenuissima HS03-07. PMID- 25295465 TI - Transcriptional regulation of the novel monoamine oxidase renalase: Crucial roles of transcription factors Sp1, STAT3, and ZBP89. AB - Renalase, a novel monoamine oxidase, is emerging as an important regulator of cardiovascular, metabolic, and renal diseases. However, the mechanism of transcriptional regulation of this enzyme remains largely unknown. We undertook a systematic analysis of the renalase gene to identify regulatory promoter elements and transcription factors. Computational analysis coupled with transfection of human renalase promoter/luciferase reporter plasmids (5'-promoter-deletion constructs) into various cell types (HEK-293, IMR32, and HepG2) identified two crucial promoter domains at base pairs -485 to -399 and -252 to -150. Electrophoretic mobility shift assays using renalase promoter oligonucleotides with and without potential binding sites for transcription factors Sp1, STAT3, and ZBP89 displayed formation of specific complexes with HEK-293 nuclear proteins. Consistently, overexpression of Sp1, STAT3, and ZBP89 augmented renalase promoter activity; additionally, siRNA-mediated downregulation of Sp1, STAT3, and ZBP89 reduced the level of endogenous renalase transcription as well as the transfected renalase promoter activity. In addition, chromatin immunoprecipitation assays showed in vivo interactions of these transcription factors with renalase promoter. Interestingly, renalase promoter activity was augmented by nicotine and catecholamines; while Sp1 and STAT3 synergistically activated the nicotine-induced effect, Sp1 appeared to enhance epinephrine-evoked renalase transcription. Moreover, renalase transcript levels in mouse models of human essential hypertension were concomitantly associated with endogenous STAT3 and ZBP89 levels, suggesting crucial roles for these transcription factors in regulating renalase gene expression in cardiovascular pathological conditions. PMID- 25295466 TI - Gene therapy for hemophilia B with liver-specific element mediated by Rep-RBE site-specific integration system. AB - Adeno-associated virus (AAV) is a nonpathogenic virus capable of targeting human chromosome 19 for integration at AAVS1 site, and a 16 bp Rep binding element (RBE) sequence of AAV was sufficient for mediating this specific integration in the presence of AAV regulation proteins (Rep). Previously, we cotransduced 2 plasmids, pRBE-CMV-hFIX and pRC, into the AAVS1 transgenic mice by hydrodynamic injection, and a long-term expression of human coagulation Factor IX (hFIX) was observed. The corresponding AAVS1 locus site-specific integrations were verified by nested polymerase chain reaction. In this study, we established a novel hFIX expression plasmid, pRBE-HCR-hAAT-hFIX, driven by a liver-specific promoter by replacing the CMV promoter of pRBE-CMV-hFIX with a humanized promoter consisting of HCR-hAAT. The expression of hFIX in vitro was almost the same in transient transfection of pRBE-CMV-hFIX or pRBE-HCR-hAAT-hFIX. AAVS1-specific integrations were identified both in mice transfected with pRC/pRBE-CMV-hFIX cocktail and pRC/pRBE-HCR-hAAT-hFIX cocktail. However, the expression of hFIX of pRBE-HCR-hAAT hFIX mice was higher and persisted longer. It achieved more than 1% of normal plasma hFIX concentration and maintained for 240 days. The result suggested that RBE-HCR-hAAT element could improve the expression of hFIX and present potential usage of Rep-RBE site-specific integration in gene therapy for hemophilia B. PMID- 25295469 TI - Parallelization strategy for large-scale vibronic coupling calculations. AB - The vibronic coupling model of Koppel, Domcke, and Cederbaum is a powerful means to understand, predict, and analyze electronic spectra of molecules, especially those that exhibit phenomena that involve breakdown of the Born-Oppenheimer approximation. In this work, we describe a new parallel algorithm for carrying out such calculations. The algorithm is conceptually founded upon a "stencil" representation of the required computational steps, which motivates an efficient strategy for coarse-grained parallelization. The equations involved in the direct CI type diagonalization of the model Hamiltonian are presented, the parallelization strategy is discussed in detail, and the method is illustrated by calculations involving direct-product basis sets with as many as 17 vibrational modes and 130 billion basis functions. PMID- 25295470 TI - Football and Sports Medicine: A Special Issue to Celebrate the 2014 FIFA World Cup Brazil. PMID- 25295471 TI - The incidence of injury in a Caribbean amateur women's football league. AB - This prospective study looked at the incidence of injury (IN) sustained by players during a season in an amateur women's football league in Trinidad and Tobago where games were played on grass (GR) and on a new generation artificial turf (AT). The overall incidence of time loss injuries was 27.6/1000 player hours (95% CI: 17.0, 38.2). Most injuries were mild and players returned to play within one week of sustaining an injury. Players who trained predominately on, and played their home games on AT (PAT) sustained significantly fewer injuries when playing games on GR than those sustained while playing on AT (p=0.006). There were no differences in injury rates between games played on AT versus games played on GR (p=0.68). Most injuries were of a non-contact nature and so an injury prevention program should be implemented to reduce the injury rate in this amateur league. PMID- 25295472 TI - Pain, injury and related behaviours among footballers partaking in tournaments. AB - This study sought to determine the prevalence of self-reported pain and/or injury (SRPI) experienced by Caribbean footballers and the associated behaviours associated with SRPI. The prevalence of SRPI among footballers was 46.2%, with 71.5% and 36%, respectively, of players admitting having played one game previously with an injury, and having used a painkiller before playing at least one game previously. Female players were more likely to hide an injury from the coaching staff in order to play a game (OR = 2.9, 95% CI (1.7, 4.8)) and attempt to use a banned substance in order to get fit to play (OR = 4.2, 95% CI (1.2, 14.3)) than males, but males were more likely to use a painkiller before playing games than females (OR = 2.2, 95% CI (1.9, 3.9)). Education of players on analgesics and basic injury management together with the implementation of injury prevention programs are needed for these players. PMID- 25295473 TI - An intensive Winter fixture schedule induces a transient fall in salivary IgA in English premier league soccer players. AB - We examined the effects of an intensive fixture schedule on salivary IgA (SIgA) concentration in professional soccer players from the English Premier League. Salivary samples were obtained from 21 males who participated in seven games over a 30-day period during December 2013 and January 2014 (games 1-5 occurred in a 15 day period). Salivary-IgA decreased (P < 0.05) at 2 days post-game 3 (45 +/- 9 MUg mL(-1)), 4 (52 +/- MUg mL(-1)) and 5 (41 +/- 10 MUg mL(-1)) compared with game 1 (139 +/- 25 MUg mL(-1)). When the normal fixture schedule resumed (i.e. one game per week), SIgA returned towards baseline such that game 6 and 7 values were not different (P > 0.05) from game 1 (91 +/- 18 and 99 +/- 21 MUg mL(-1), respectively). Data demonstrate for the first time that a congested winter fixture schedule induces detectable perturbations to mucosal immunity in professional soccer players. PMID- 25295474 TI - Characterization of static balance abilities in elite soccer players by playing position and age. AB - In this study, we investigated the static balance of adult and adolescent elite soccer players to understand how expertise and playing position influence postural control. Seventy-one national level players were tested using a force platform to acquire Center-of-Pressure (COP) data in uni- and bipedal stance and calculate sway area (SA), COP path length, velocity and displacements. The results show significant differences in postural sway related to age and playing position only for single-limb stance. In particular, midfielders exhibited significantly lower values of SA with respect to defenders (-48%, p = 0.001) and the under-15 players exhibited SA 42-64% higher than all the others (p = 0.001). In the light of planning training or rehabilitation programs specific for each player's role and age, sway measurements may supply useful, objective and reliable information only for the unipedal test as the bipedal standing appears not challenging enough to let differences in balance abilities emerge. PMID- 25295475 TI - Soccer-specific fatigue decreases reactive postural control with implications for ankle sprain injury. AB - To quantify the influence of soccer-specific fatigue on reactive dynamic balance, ten male professional soccer players (age 24.7 +/- 4.4 yr, body mass 77.1 +/- 8.3 kg, VO2max 63.0 +/- 4.8 ml.kg.min(-1)) completed an exercise protocol replicating the activity profile of match-play. Pre-exercise, and at 15 min intervals, players completed three balance tasks requiring response to a system perturbed to induce either plantar flexion of the ankle or inversion of the ankle (by rotation or translation). ANOVA revealed a significant main effect for exercise duration in each task, with both reaction time and total centre of gravity displacement tending to increase during each half. In all three trials there was a significant increase in medio-lateral and anterior-posterior displacement, the planar perturbation of the platform evoking a multi-angular response. Dynamic balance performance decreased as a function of time during each half, suggesting a greater risk of injuries at these specific times, in accord with epidemiological observations of ankle sprain injury. PMID- 25295476 TI - Acute effects of the number of players and scoring method on physiological, physical, and technical performance in small-sided soccer games. AB - This study aims to examine the effect of differences in the number of players and scoring method on heart rate responses, time-motion characteristics, and technical/tactical performance during small-sided soccer games. Ten male amateur soccer players (26.4 +/- 5.3 years old, 8.4 +/- 3.2 years of practice, 179.3 +/- 5.2 cm body height, 71.2 +/- 7.1 kg body weight, 45.8 +/- 2.6 ml.kg(-1)min( 1)VO2max) from the Portuguese regional league played nine different small-sided games (i.e., 3 formats * 3 scoring methods). The study used two-way MANOVA, two away ANOVA, and one-way ANOVA, depending on the specific procedure for the analysis. Compared with other formats, 2v2 induced significantly greater values of technical/tactical indexes (p = 0.001), 3v3 induced significantly higher %HRreserve values (p = 0.001), and 4v4 led to significantly greater distance coverage and speed (p = 0.001). The study provided evidence for coaches to set different small-sided game conditions depending on the training purpose in terms of physiological, physical, and technical performance. PMID- 25295477 TI - The biological age of 14-year-old boys and success in adult soccer: do early maturers predominate in the top-level game? AB - Talent identification and development in soccer is often biased by maturation related differences of young athletes. However, there is no information available about success rates for youth maturing at different tempos to achieve success in elite adult soccer. The purposes of this study were to determine the prevalence of different maturational groups among boys playing soccer, and to track them for competence in adult performance. A prospective cohort study design was used to follow 55, 14-year-old boys playing in Serbian youth soccer Division I over eight years. At the age of 14, biological age using skeletal age rates was determined, and participants were categorized as early maturers (EaM), normal maturers (NoM), and late maturers (LaM). Game competence for adult soccer at age 22 was described as elite if an individual played for clubs competing in top-five international soccer leagues (La Liga, Premier League, Bundesliga, Serie A, and Ligue 1), and/or has become a member of an adult National team. Among boys in our study group, 43.8% were categorized as EaM, 35.4% as NoM, and 20.8% as LaM (P = 0.11). A significant difference in biological age was found among maturational groups at age 14, with EaM > NoM > LaM (P > 0.0001). When assessed for adult soccer competence, 33.3% of participants (16 out of 48 players) succeed in achieving elite level. Elite soccer competence acquired 60.1% players from the group of LaM, 38.1% from NoM, and 11.8% from EaM (P > 0.0001). Our comparative analysis suggests that soccer excludes early maturing boys and favors late maturing boys as level of performance increases. PMID- 25295478 TI - Physical growth and changes in intermittent endurance run performance in young male Basque soccer players. AB - The present 4-year longitudinal study examined physical growth and development of intermittent endurance run performance in young Basque soccer players aged 10-15 years applying multilevel regression modeling. Anthropometry, predicted adult stature and Yo-Yo Intermittent Recovery level 1 test (Yo-Yo IR1) of players from the under-11 teams from the Athletic Club of Bilbao were measured at pre- and end season (two measurements per year of study, n = 33 considered for analysis). A non-linear effect of age on intermittent endurance run was observed, with significantly higher increases in Yo-Yo IR1 between 10-11 year-old and 14-15 year old players. The development of Yo-Yo IR1 performance in all the years of the study was influenced positively by training exposure during the seasons (P < 0.01) and independent of maturity status and body size (P > 0.05). The steady development of intermittent endurance run performance during pubertal years in adolescent Basque soccer players is partially influenced by training exposure. PMID- 25295479 TI - The effect of different environmental conditions on the decision-making performance of soccer goal line officials. AB - Goal line officials (GLO) are exposed to extreme environmental conditions when employed to officiate in professional European soccer cup competitions. The present study aimed to investigate the effect of such environments on GLO decision-making ability. Thirteen male participants were exposed to three conditions: cold (-5 degrees C, 50% relative humidity (RH)); temperate (18 degrees C, 50% RH); and hot (30 degrees C, 50% RH) for 90 min per condition, with a 15 min half-time break after 45 min. Decision-making ability was assessed throughout the 90 min exposure. Core and skin temperatures were recorded throughout. Decision making was improved during exposure to the temperate condition when compared with the cold (mean difference = 12.5%; 95% CI = 1.1%, 23.9%; P = 0.031). Regression analysis indicated that as skin temperature increases so does decision-making ability. Exposure to cold conditions diminished the decision-making ability of GLO. PMID- 25295481 TI - [Management of surgical abdominal emergencies in Kara teaching hospital (Togo): 10-year retrospective study of 594 cases]. AB - PURPOSE: The aim of this study was to describe the epidemiologic, diagnostic, and therapeutic aspects of surgical abdominal emergencies in a teaching hospital in a developing country (Togo). MATERIAL AND METHOD: This retrospective study included the medical files of all patients managed for surgical abdominal emergencies from March 1, 2002, to March 1, 2012. RESULTS: The study included 594 patients, with a mean age of 30.3 years (range: 1 month to 80 years) and a 2.1 male:female sex ratio. The emergencies were acute generalized peritonitis (54.5%), intestinal obstruction (26.6%), acute appendicitis (14.5%), and abdominal trauma (4.4%). Plain abdominal radiographs were taken for 414 patients with acute generalized peritonitis (324 cases) and intestinal obstructions without a strangulated hernia (90 cases). Nine patients had abdominal ultrasounds for abdominal trauma (5 cases) and appendicular abscess (4 cases). No abdominal CT scan was performed. All patients underwent surgery, 316 (53.2%) by physician assistants and 278 (46.8%) by surgeons. Resuscitation and anesthesia were performed by nurse anesthetists. The postoperative course was complicated in 182 cases (30.7%). These complications included parietal suppurations (18.2%), eviscerations (5.1%), ileal fistulas (4.4%), and postoperative peritonitis (3%). The death rate was 11.4%. CONCLUSION: Surgical abdominal emergencies at the Kara teaching hospital were both common and serious. Their particularly high morbidity and mortality might be reduced through the adoption of reasonably practicable measures: paramedical personnel training, public awareness, establishment of management protocols, and improvement of technical equipment (laboratory). PMID- 25295483 TI - Epidemiology of constipation in Sao Paulo, Brazil: a population-based study. AB - OBJECTIVE: Epidemiologic data on constipation in South America are limited. The main objective of this study was to assess the prevalence of self-reported symptoms of constipation in Brazil. METHODS: Telephone and personal surveys were conducted among community-dwelling adults in homes with land-based telephones in Sao Paulo. Data were weighted by numbers of adults, total residents, and telephones in each household. To account for potential nonresponse and noncoverage bias, results were further adjusted according to Brazilian census data. RESULTS: Among 4570 households contacted, 3050 adults (66.7%) participated. Respondents (mean [SE] age: 42.6 [2.7] years) were primarily women (53.1%). A minority of all respondents reported symptoms consistent with constipation, including a perception of incomplete voiding in 8.0%; expending efforts to defecate in 7.6%; <=2 stools weekly in 9.0%; and hard stools in 12.7%. Prevalences of these symptoms and efforts to manage them were more frequent in women (P <= 0.004), but most were not significantly associated with advancing age. With increasing age, proportions of respondents with <=2 stools per week declined (P = 0.001), whereas use of bowel enemas (P = 0.026) and digital maneuvers to disimpact stool increased (P < 0.001). Despite frequent constipation symptoms, the vast majority of respondents did not report using prescription medications, but some used natural remedies (29.5%) and/or laxatives (13.4%). CONCLUSIONS: Symptoms of constipation are prevalent in Sao Paulo, particularly among women. On the other hand, most survey respondents did not use medications or other remedies that manage this condition. These findings may point to an unmet gastrointestinal treatment need. Future research is needed to corroborate our findings in rural settings and to further evaluate potential predictors and consequences of constipation in South America. PMID- 25295484 TI - A universal molecular translator for non-nucleic acid targets that enables dynamic DNA assemblies and logic operations. AB - A universal molecular translator based on the target-triggered DNA strand displacement was developed, which was able to convert various kinds of non nucleic acid targets into a unique output DNA. This translation strategy was successfully applied in directing dynamic DNA assemblies and in realizing three input logic gate operations. PMID- 25295482 TI - Platelets: still a therapeutical target for haemostatic disorders. AB - Platelets are cytoplasmatic fragments from bone marrow megakaryocytes present in blood. In this work, we review the basis of platelet mechanisms, their participation in syndromes and in arterial thrombosis, and their potential as a target for designing new antithrombotic agents. The option of new biotechnological sources is also explored. PMID- 25295485 TI - N-trimethylchitosan/alginate layer-by-layer self assembly coatings act as "fungal repellents" to prevent biofilm formation on healthcare materials. AB - Fungal biofilm formation on healthcare materials is a significant clinical concern, often leading to medical-device-related infections, which are difficult to treat. A novel fungal repellent strategy is developed to control fungal biofilm formation. Methylacrylic acid (MAA) is grated onto poly methyl methacrylate (PMMA)-based biomaterials via plasma-initiated grafting polymerization. A cationic polymer, trimethylchitosan (TMC), is synthesized by reacting chitosan with methyl iodide. Sodium alginate (SA) is used as an anionic polymer. TMC/SA multilayers are coated onto the MAA-grafted PMMA via layer-by layer self-assembly. The TMC/SA multilayer coatings significantly reduce fungal initial adhesion, and effectively prevent fungal biofilm formation. It is concluded that the anti-adhesive property of the surface is due to its hydrophilicity, and that the biofilm-inhibiting action is attributed to the antifungal activity of TMC as well as the chelating function of TMC and SA, which may have acted as fungal repellents. Phosphate buffered saline (PBS)-immersion tests show that the biofilm-modulating effect of the multilayer coatings is stable for more than 4 weeks. Furthermore, the presence of TMC/SA multilayer coatings improves the biocompatibility of the original PMMA, offering a simple, yet effective, strategy for controlling fungal biofilm formation. PMID- 25295491 TI - Anatomical features and clinical correlations in Caucasian patients with definite arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - AIM: Arrhythmogenic right ventrticular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by fibrofatty replacement and a high risk of ventricular arrhythmias (VA) and sudden cardiac death (SCD). The aim of the present investigation is to examine the pathological profile and the clinical correlations in a group of ARVD/C patients. METHODS: We conducted a multicenter study evaluating 47 patients (31 men; mean age 37+/-14 years) with definite ARVD/C. Diagnosis was established according to the actual clinicomorphologic criteria at autopsy or clinically. We divided the study population in 2 different groups. First group included 28 alive patients and the second 19 patients dead suddenly. RESULTS: Age at presentation was different in the two groups (P=0.0015). We observed an important association regarding the risk of sudden death and the history of physical exercise (P=0.0017). Moreover patients with negative outcome (i.e., SCD, cardiac transplantation, congestive heart failure) had a significantly association with biventricular form of ARVD/C (P=0.0034) and age presentation (P=0.003). Left ventricular (LV) involvement was frequently observed in the two groups (17% and 32% respectively). Post-mortem examination revealed frequent inflammatory infiltrates (26%) indicating active myocarditis, which probably justify the fatal arrhythmic events occurred in these patients. CONCLUSION: Frequent LV involvement justifies the recent adoption of the broad term Arrhythmogenic Cardiomyopathy. Early age presentation, sport activity and the biventricular form of ARVD/C represent important predictors of adverse outcome that can be useful to early identify patients at high risk. PMID- 25295492 TI - Optimizing vessel healing following drug eluting stent implantation with biodegradable polymer DES. AB - The introduction of coronary drug eluting stents (DES) more than 10 years ago drastically decreased the occurrence of restenosis, compared with first generation bare metal stents (BMS). However, the optimism created by the first studies was soon shadowed by the demonstration of higher rates of late and very late stent thrombosis (ST). The research performed in this phenomenon highlighted the causative role played by incomplete stent strut coverage, hypersensitivity reactions caused by the drug eluting polymer, and neoatherosclerosis, all markers of an inadequate vascular response to DES implantation. Over the following years, new development in stent and eluting polymer technologies have been incorporated in second generation DES to optimize the process of vessel healing and, thus, to avoid these complications. Furthermore, it is envisaged that adequate vessel healing would be followed by less dependence on double antiplatelet, a limiting aspect for DES use in different clinical scenarios. In this review, we focused on the use of biodegradable eluting polymers to increase DES safety, revisiting the rationale for its use and the synergic action with other changes in stent technology aimed to optimize vessel healing after DES implantation. PMID- 25295493 TI - Polymer-free amphilimus-eluting stents in patients with diabetes mellitus. AB - Despite several improvements in drug-eluting stents design, diabetes mellitus (DM) remains an Achilles' heel for percutaneous coronary revascularization at the present time. The Cre8 stent is a third-generation drug-eluting stent devoid of polymer. The drug, which is formulated with an amphiphilic carrier, is eluted from laser-dug wells on the stent's abluminal surface. The Cre8 stent hat has shown promising preliminary results in patients with DM. This review summarizes the mechanisms of DES failure in patients with DM and the potential role of the Cre8 stent in this high-risk population. PMID- 25295490 TI - Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. AB - Epithelial-to-mesenchymal transition-like (EMT-like) is a critical process allowing initiation of metastases during tumour progression. Here, to investigate its role in intestinal cancer, we combine computational network-based and experimental approaches to create a mouse model with high metastatic potential. Construction and analysis of this network map depicting molecular mechanisms of EMT regulation based on the literature suggests that Notch activation and p53 deletion have a synergistic effect in activating EMT-like processes. To confirm this prediction, we generate transgenic mice by conditionally activating the Notch1 receptor and deleting p53 in the digestive epithelium (NICD/p53(-/-)). These mice develop metastatic tumours with high penetrance. Using GFP lineage tracing, we identify single malignant cells with mesenchymal features in primary and metastatic tumours in vivo. The development of such a model that recapitulates the cellular features observed in invasive human colorectal tumours is appealing for innovative drug discovery. PMID- 25295494 TI - Use of EPC-capturing stent in patient with acute coronary syndrome and high bleeding risk. AB - The case involved a 75-year-old male patient whose risk factors included hypertension, diabetes (on oral treatment) and untreated hypercholesterolaemia. He was previously admitted to the urology department in 2012 due to severe haematuria and was referred to transvesical prostatectomy. His condition became progressively complicated by acute coronary syndrome. PMID- 25295495 TI - Successful ablation of a concealed accessory pathway mediated tachycardia in a patient with Lutembacher syndrome. PMID- 25295496 TI - The functional role of long non-coding RNA in digestive system carcinomas. AB - In recent years, long non-coding RNAs (lncRNAs) are emerging as either oncogenes or tumor suppressor genes. Recent evidences suggest that lncRNAs play a very important role in digestive system carcinomas. However, the biological function of lncRNAs in the vast majority of digestive system carcinomas remains unclear. Recently, increasing studies has begun to explore their molecular mechanisms and regulatory networks that they are implicated in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in digestive system carcinomas. It is becoming clear that lncRNAs will be exciting and potentially useful for diagnosis and treatment of digestive system carcinomas, some of these lncRNAs might function as both diagnostic markers and the treatment targets of digestive system carcinomas. PMID- 25295497 TI - Hybrid biosynthesis of roseobacticides from algal and bacterial precursor molecules. AB - Roseobacticides regulate the symbiotic relationship between a marine bacterium (Phaeobacter inhibens) and a marine microalga (Emiliania huxleyi). This relationship can be mutualistic, when the algal host provides food for the bacteria and the bacteria produce growth hormones and antibiotics for the algae, or parasitic, when the algae senesce and release p-coumaric acid. The released p coumaric acid causes the bacteria to synthesize roseobacticides, which are nM-MUM toxins for the algae. We examined the biosynthesis of roseobacticides and report that all roseobacticide precursors play critical roles during the mutualist phase of the symbiosis. Roseobacticides are biosynthesized from the algal growth promoter, the major food molecule provided by the algal cells, and the algal senescence signal that initiates the mutualist-to-parasite switch. Thus, molecules that are beneficial during mutualism are diverted to the synthesis of toxins during parasitism. A plausible mechanism for assembling roseobacticides from these molecules is proposed. PMID- 25295498 TI - 2009 H1N1 influenza and pregnancy--5 years later. PMID- 25295499 TI - The little things. PMID- 25295502 TI - Physiological approach to assessment of acid-base disturbances. PMID- 25295500 TI - A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. AB - BACKGROUND: In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based gamma retrovirus vector expressing interleukin-2 receptor gamma-chain (gammac) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS: We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self inactivating (SIN) gamma-retrovirus vector containing deletions in viral enhancer sequences expressing gammac (SIN-gammac). RESULTS: All patients received bone marrow-derived CD34+ cells transduced with the SIN-gammac vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS: This modified gamma-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.). PMID- 25295501 TI - Response and acquired resistance to everolimus in anaplastic thyroid cancer. AB - Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18 month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors. PMID- 25295503 TI - Images in clinical medicine. Cutaneous melanosis in peripheral cortisol resistance. PMID- 25295504 TI - Case records of the Massachusetts General Hospital. Case 31-2014. A 50-year-old man with back pain, fatigue, weight loss, and knee swelling. PMID- 25295506 TI - Letrozole or clomiphene for infertility in the polycystic ovary syndrome. PMID- 25295508 TI - Letrozole or clomiphene for infertility in the polycystic ovary syndrome. PMID- 25295507 TI - Letrozole or clomiphene for infertility in the polycystic ovary syndrome. PMID- 25295509 TI - Videos in clinical medicine. Ultrasound-guided insertion of a radial arterial catheter. PMID- 25295510 TI - Images in clinical medicine. Hypoglossal nerve palsy during meningococcal meningitis. PMID- 25295511 TI - Solid-phase synthesis of tetrahydropyridazinedione-constrained peptides. AB - The design and solid-phase synthesis of tetrahydropyridazine-3,6-dione (Tpd) peptidomimetics derived from backbone-aminated peptides is reported. The described protocol features the synthesis of chiral alpha-hydrazino acids suitable for chemoselective incorporation into growing peptide chains. Acid catalyzed cyclization to form the Tpd ring during cleavage affords the target peptidomimetics in good yield and purity. The scope of Tpd incorporation is demonstrated through the synthesis of constrained peptides featuring nucleophilic/electrophilic side chains and sterically encumbered alpha substituted hydrazino acid residues. PMID- 25295512 TI - [Hospital mortality associated with upper gastrointestinal hemorrhage due to ruptured esophageal varices at the Lome Campus Hospital in Togo]. AB - AIM: To study hospital mortality associated with upper gastrointestinal hemorrhages due to variceal bleeding in the department of hepatology and gastroenterology at the Lome Campus University Hospital. PATIENTS AND METHOD: This retrospective cross-sectional and analytic study examined the 55 patients admitted for variceal bleeding on upper endoscopies during the 3-year period from January 1, 2008, through December 31, 2010. RESULTS: These patients accounted for 4.1% of all hospitalizations during the study period in the department. Their average age was 35 years, and their sex-ratio 4. A history of chronic liver disease was found in 65.5%. Liver cirrhosis was the principal cause of the esophageal varices, complicated by hepatocellular carcinoma in 30.9% of them. The mortality rate was 25.5% and was not related to the cause of portal hypertension. All the patients with a recurrence of bleeding died. Mortality was associated with jaundice. Blood transfusion did not significantly improve the prognosis. CONCLUSION: the mortality rate among patients with upper gastrointestinal hemorrhage linked to variceal bleeding is high in our unit. The prevention of hepatitis virus B is important because it is the main cause of chronic liver disease causing portal hypertension in our department. PMID- 25295513 TI - Adhesive proteins of stalked and acorn barnacles display homology with low sequence similarities. AB - Barnacle adhesion underwater is an important phenomenon to understand for the prevention of biofouling and potential biotechnological innovations, yet so far, identifying what makes barnacle glue proteins 'sticky' has proved elusive. Examination of a broad range of species within the barnacles may be instructive to identify conserved adhesive domains. We add to extensive information from the acorn barnacles (order Sessilia) by providing the first protein analysis of a stalked barnacle adhesive, Lepas anatifera (order Lepadiformes). It was possible to separate the L. anatifera adhesive into at least 10 protein bands using SDS PAGE. Intense bands were present at approximately 30, 70, 90 and 110 kilodaltons (kDa). Mass spectrometry for protein identification was followed by de novo sequencing which detected 52 peptides of 7-16 amino acids in length. None of the peptides matched published or unpublished transcriptome sequences, but some amino acid sequence similarity was apparent between L. anatifera and closely-related Dosima fascicularis. Antibodies against two acorn barnacle proteins (ab-cp-52k and ab-cp-68k) showed cross-reactivity in the adhesive glands of L. anatifera. We also analysed the similarity of adhesive proteins across several barnacle taxa, including Pollicipes pollicipes (a stalked barnacle in the order Scalpelliformes). Sequence alignment of published expressed sequence tags clearly indicated that P. pollicipes possesses homologues for the 19 kDa and 100 kDa proteins in acorn barnacles. Homology aside, sequence similarity in amino acid and gene sequences tended to decline as taxonomic distance increased, with minimum similarities of 18-26%, depending on the gene. The results indicate that some adhesive proteins (e.g. 100 kDa) are more conserved within barnacles than others (20 kDa). PMID- 25295514 TI - Amphibian beta diversity in the Brazilian Atlantic Forest: contrasting the roles of historical events and contemporary conditions at different spatial scales. AB - Current patterns of biodiversity distribution result from a combination of historical and contemporary processes. Here, we compiled checklists of amphibian species to assess the roles of long-term climate stability (Quaternary oscillations), contemporary environmental gradients and geographical distance as determinants of change in amphibian taxonomic and phylogenetic composition in the Brazilian Atlantic Forest. We calculated beta diversity as both variation in species composition (CBD) and phylogenetic differentiation (PBD) among the assemblages. In both cases, overall beta diversity was partitioned into two basic components: species replacement and difference in species richness. Our results suggest that the CBD and PBD of amphibians are determined by spatial turnover. Geographical distance, current environmental gradients and long-term climatic conditions were complementary predictors of the variation in CBD and PBD of amphibian species. Furthermore, the turnover components between sites from different regions and between sites within the stable region were greater than between sites within the unstable region. On the other hand, the proportion of beta-diversity due to species richness difference for both CBD and PBD was higher between sites in the unstable region than between sites in the stable region. The high turnover components from CBD and PBD between sites in unstable vs stable regions suggest that these distinct regions have different biogeographic histories. Sites in the stable region shared distinct clades that might have led to greater diversity, whereas sites in the unstable region shared close relatives. Taken together, these results indicate that speciation, environmental filtering and limited dispersal are complementary drivers of beta-diversity of amphibian assemblages in the Brazilian Atlantic Forest. PMID- 25295515 TI - Crystal structures of influenza A virus matrix protein M1: variations on a theme. AB - Matrix protein 1 (M1) of the influenza A virus plays multiple roles in virion assembly and infection. Interest in the pH dependence of M1's multiple functions led us to study the effect of subtle pH changes on M1 structure, resulting in the elucidation of a unique low-pH crystal structure of the N(1-165)-domain of A/WSN/33 (H1N1) M1 that has never been reported. Although the 2.2 A crystal structure of M1 N-terminus shows a dimer with the two monomers interacting in a face-to-face fashion at low pH as observed earlier, a 44 degrees rotation of the second monomer has led to a significantly different dimer interface that possibly affects dimer stability. More importantly, while one of the monomers is fully defined, the N-terminal half of the second monomer shows considerable disorder that appears inherent in the protein and is potentially physiologically relevant. Such disorder has not been observed in any other previously reported structure at either low or high pH conditions, despite similar crystallization pH conditions. By comparing our novel N(1-165)-domain structure with other low-pH or neutral-pH M1 structures, it appears that M1 can energetically access different monomer and dimer conformations, as well as oligomeric states, with varying degree of similarities. The study reported here provides further insights into M1 oligomerization that may be essential for viral propagation and infectivity. PMID- 25295517 TI - Latitudinal environmental niches and riverine barriers shaped the phylogeography of the Central Chilean endemic Dioscorea humilis (Dioscoreaceae). AB - The effects of Pleistocene glaciations and geographical barriers on the phylogeographic patterns of lowland plant species in Mediterranean-climate areas of Central Chile are poorly understood. We used Dioscorea humilis (Dioscoreaceae), a dioecious geophyte extending 530 km from the Valparaiso to the Bio-Bio Regions, as a case study to disentangle the spatio-temporal evolution of populations in conjunction with latitudinal environmental changes since the Last Inter-Glacial (LIG) to the present. We used nuclear microsatellite loci, chloroplast (cpDNA) sequences and environmental niche modelling (ENM) to construct current and past scenarios from bioclimatic and geographical variables and to infer the evolutionary history of the taxa. We found strong genetic differentiation at nuclear microsatellite loci between the two subspecies of D. humilis, probably predating the LIG. Bayesian analyses of population structure revealed strong genetic differentiation of the widespread D. humilis subsp. humilis into northern and southern population groups, separated by the Maipo river. ENM revealed that the ecological niche differentiation of both groups have been maintained up to present times although their respective geographical distributions apparently fluctuated in concert with the climatic oscillations of the Last Glacial Maximum (LGM) and the Holocene. Genetic data revealed signatures of eastern and western postglacial expansion of the northern populations from the central Chilean depression, whereas the southern ones experienced a rapid southward expansion after the LGM. This study describes the complex evolutionary histories of lowland Mediterranean Chilean plants mediated by the summed effects of spatial isolation caused by riverine geographical barriers and the climatic changes of the Quaternary. PMID- 25295518 TI - Understanding side reactions in K-O2 batteries for improved cycle life. AB - Superoxide based metal-air (or metal-oxygen) batteries, including potassium and sodium-oxygen batteries, have emerged as promising alternative chemistries in the metal-air battery family because of much improved round-trip efficiencies (>90%). In order to improve the cycle life of these batteries, it is crucial to understand and control the side reactions between the electrodes and the electrolyte. For potassium-oxygen batteries using ether-based electrolytes, the side reactions on the potassium anode have been identified as the main cause of battery failure. The composition of the side products formed on the anode, including some reaction intermediates, have been identified and quantified. Combined experimental studies and density functional theory (DFT) calculations show the side reactions are likely driven by the interaction of potassium with ether molecules and the crossover of oxygen from the cathode. To inhibit these side reactions, the incorporation of a polymeric potassium ion selective membrane (Nafion-K(+)) as a battery separator is demonstrated that significantly improves the battery cycle life. The K-O2 battery with the Nafion-K(+) separator can be discharged and charged for more than 40 cycles without increases in charging overpotential. PMID- 25295516 TI - Antinematode activity of Violacein and the role of the insulin/IGF-1 pathway in controlling violacein sensitivity in Caenorhabditis elegans. AB - The purple pigment violacein is well known for its numerous biological activities including antibacterial, antiviral, antiprotozoan, and antitumor effects. In the current study we identify violacein as the antinematode agent produced by the marine bacterium Microbulbifer sp. D250, thereby extending the target range of this small molecule. Heterologous expression of the violacein biosynthetic pathway in E. coli and experiments using pure violacein demonstrated that this secondary metabolite facilitates bacterial accumulation in the nematode intestine, which is accompanied by tissue damage and apoptosis. Nematodes such as Caenorhabditis elegans utilise a well-defined innate immune system to defend against pathogens. Using C. elegans as a model we demonstrate the DAF-2/DAF-16 insulin/IGF-1 signalling (IIS) component of the innate immune pathway modulates sensitivity to violacein-mediated killing. Further analysis shows that resistance to violacein can occur due to a loss of DAF-2 function and/or an increased function of DAF-16 controlled genes involved in antimicrobial production (spp-1) and detoxification (sod-3). These data suggest that violacein is a novel candidate antinematode agent and that the IIS pathway is also involved in the defence against metabolites from non-pathogenic bacteria. PMID- 25295519 TI - Intraoperative hyperglycemia during liver resection: predictors and association with the extent of hepatocytes injury. AB - BACKGROUND: Patients undergoing liver resection are at risk for intraoperative hyperglycemia and acute hyperglycemia is known to induce hepatocytes injury. Thus, we aimed to evaluate whether intraoperative hyperglycemia during liver resection is associated with the extent of hepatic injury. METHODS: This 1 year retrospective observation consecutively enrolled 85 patients undergoing liver resection for hepatocellular carcinoma. Blood glucose concentrations were measured at predetermined time points including every start/end of intermittent hepatic inflow occlusion (IHIO) via arterial blood analysis. Postoperative transaminase concentrations were used as surrogate parameters indicating the extent of surgery-related acute hepatocytes injury. RESULTS: Thirty (35.5%) patients developed hyperglycemia (blood glucose > 180 mg/dl) during surgery. Prolonged (>= 3 rounds) IHIO (odds ratio [OR] 7.34, P = 0.004) was determined as a risk factors for hyperglycemia as well as cirrhosis (OR 4.07, P = 0.022), lower prothrombin time (OR 0.01, P = 0.025), and greater total cholesterol level (OR 1.04, P = 0.003). Hyperglycemia was independently associated with perioperative increase in transaminase concentrations (aspartate transaminase, beta 105.1, standard error 41.7, P = 0.014; alanine transaminase, beta 81.6, standard error 38.1, P = 0.035). Of note, blood glucose > 160 or 140 mg/dl was not associated with postoperative transaminase concentrations. CONCLUSIONS: Hyperglycemia during liver resection might be associated with the extent of hepatocytes injury. It would be rational to maintain blood glucose concentration < 180 mg/dl throughout the surgery in consideration of parenchymal disease, coagulation status, lipid profile, and the cumulative hepatic ischemia in patients undergoing liver resection for hepatocellular carcinoma. PMID- 25295521 TI - No evidence of conpopulation sperm precedence between allopatric populations of house mice. AB - Investigations into the evolution of reproductive barriers have traditionally focused on closely related species, and the prevalence of conspecific sperm precedence. The effectiveness of conspecific sperm precedence at limiting gene exchange between species suggests that gametic isolation is an important component of reproductive isolation. However, there is a paucity of tests for evidence of sperm precedence during the earlier stages of divergence, for example among isolated populations. Here, we sourced individuals from two allopatric populations of house mice (Mus domesticus) and performed competitive in vitro fertilisation assays to test for conpopulation sperm precedence specifically at the gametic level. We found that ova population origin did not influence the outcome of the sperm competitions, and thus provide no evidence of conpopulation or heteropopulation sperm precedence. Instead, we found that males from a population that had evolved under a high level of postcopulatory sexual selection consistently outcompeted males from a population that had evolved under a relatively lower level of postcopulatory sexual selection. We standardised the number of motile sperm of each competitor across the replicate assays. Our data therefore show that competitive fertilizing success was directly attributable to differences in sperm fertilizing competence. PMID- 25295520 TI - A validated age-related normative model for male total testosterone shows increasing variance but no decline after age 40 years. AB - The diagnosis of hypogonadism in human males includes identification of low serum testosterone levels, and hence there is an underlying assumption that normal ranges of testosterone for the healthy population are known for all ages. However, to our knowledge, no such reference model exists in the literature, and hence the availability of an applicable biochemical reference range would be helpful for the clinical assessment of hypogonadal men. In this study, using model selection and validation analysis of data identified and extracted from thirteen studies, we derive and validate a normative model of total testosterone across the lifespan in healthy men. We show that total testosterone peaks [mean (2.5-97.5 percentile)] at 15.4 (7.2-31.1) nmol/L at an average age of 19 years, and falls in the average case [mean (2.5-97.5 percentile)] to 13.0 (6.6-25.3) nmol/L by age 40 years, but we find no evidence for a further fall in mean total testosterone with increasing age through to old age. However we do show that there is an increased variation in total testosterone levels with advancing age after age 40 years. This model provides the age related reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism. PMID- 25295522 TI - Regulation of circadian and acute activity levels by the murine suprachiasmatic nuclei. AB - The suprachiasmatic nuclei (SCN) coordinate the daily sleep-wake cycle by generating a circadian rhythm in electrical impulse frequency. While period and phase of the SCN rhythm have been considered as major output parameters, we propose that the waveform of the rhythm of the SCN also has significance. Using implanted micro-electrodes, we recorded SCN impulse frequency in freely moving mice and manipulated its circadian waveform by exposing mice to light-dark (LD) cycle durations ranging from 22 hours (LD 11:11) to 26 hours (LD 13:13). Adaptation to long T-cycles (>24 h) resulted in a trough in electrical activity at the beginning of the night while in short T-cycles (<24 h), SCN activity reached a trough at the end of night. In all T-cycle durations, the intensity of behavioral activity was maximal during the trough of SCN electrical activity and correlated negatively with increasing levels of SCN activity. Interestingly, small changes in T-cycle duration could induce large changes in waveform and in the time of trough (about 3.5 h), and accordingly in the timing of behavioral activity. At a smaller timescale (minutes to hours), we observed a negative correlation between SCN activity and behavioral activity, and acute silencing of SCN neurons by tetrodotoxin (TTX) during the inactive phase of the animal triggered behavioral activity. Thus, the SCN electrical activity levels appear crucially involved in determining the temporal profile of behavioral activity and controls behavior beyond the circadian time domain. PMID- 25295523 TI - The suppressive effect of resveratrol on HIF-1alpha and VEGF expression after warm ischemia and reperfusion in rat liver. AB - BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. The aim of the present study was to investigate the effect of resveratrol (RES) on the expression of ischemic-induced HIF-1alpha and vascular endothelial growth factor (VEGF) in rat liver. METHODS: Twenty-four rats were randomized into Sham, ischemia/reperfusion (I/R), and RES preconditioning groups. I/R was induced by portal pedicle clamping for 60 minutes followed by reperfusion for 60 minutes. The rats in RES group underwent the same surgical procedure as I/R group, and received 20 mg/kg resveratrol intravenously 30 min prior to ischemia. Blood and liver tissue samples were collected and subjected to biochemical assays, RT-PCR, and Western blot assays. RESULTS: I/R resulted in a significant (P<0.05) increase in liver HIF-1alpha and VEGF at both mRNA and protein levels 60 minutes after reperfusion. The mRNA and protein expressions of HIF-1alpha and VEGF decreased significantly in RES group when compared to I/R group (P<0.05). CONCLUSION: The inhibiting effect of RES on the expressions of HIF-1alpha and VEGF induced by I/R in rat liver suggested that HIF-1alpha/VEGF could be a promising drug target for RES in the development of an effective anticancer therapy for the prevention of hepatic tumor growth and metastasis. PMID- 25295524 TI - Data-driven decisions for reducing readmissions for heart failure: general methodology and case study. AB - BACKGROUND: Several studies have focused on stratifying patients according to their level of readmission risk, fueled in part by incentive programs in the U.S. that link readmission rates to the annual payment update by Medicare. Patient specific predictions about readmission have not seen widespread use because of their limited accuracy and questions about the efficacy of using measures of risk to guide clinical decisions. We construct a predictive model for readmissions for congestive heart failure (CHF) and study how its predictions can be used to perform patient-specific interventions. We assess the cost-effectiveness of a methodology that combines prediction and decision making to allocate interventions. The results highlight the importance of combining predictions with decision analysis. METHODS: We construct a statistical classifier from a retrospective database of 793 hospital visits for heart failure that predicts the likelihood that patients will be rehospitalized within 30 days of discharge. We introduce a decision analysis that uses the predictions to guide decisions about post-discharge interventions. We perform a cost-effectiveness analysis of 379 additional hospital visits that were not included in either the formulation of the classifiers or the decision analysis. We report the performance of the methodology and show the overall expected value of employing a real-time decision system. FINDINGS: For the cohort studied, readmissions are associated with a mean cost of $13,679 with a standard error of $1,214. Given a post-discharge plan that costs $1,300 and that reduces 30-day rehospitalizations by 35%, use of the proposed methods would provide an 18.2% reduction in rehospitalizations and save 3.8% of costs. CONCLUSIONS: Classifiers learned automatically from patient data can be joined with decision analysis to guide the allocation of post-discharge support to CHF patients. Such analyses are especially valuable in the common situation where it is not economically feasible to provide programs to all patients. PMID- 25295525 TI - Robust selection of cancer survival signatures from high-throughput genomic data using two-fold subsampling. AB - Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (http://cran.r-project.org). PMID- 25295526 TI - Establishment of Myotis myotis cell lines--model for investigation of host pathogen interaction in a natural host for emerging viruses. AB - Bats are found to be the natural reservoirs for many emerging viruses. In most cases, severe clinical signs caused by such virus infections are normally not seen in bats. This indicates differences in the virus-host interactions and underlines the necessity to develop natural host related models to study these phenomena. Due to the strict protection of European bat species, immortalized cell lines are the only alternative to investigate the innate anti-virus immune mechanisms. Here, we report about the establishment and functional characterization of Myotis myotis derived cell lines from different tissues: brain (MmBr), tonsil (MmTo), peritoneal cavity (MmPca), nasal epithelium (MmNep) and nervus olfactorius (MmNol) after immortalization by SV 40 large T antigen. The usefulness of these cell lines to study antiviral responses has been confirmed by analysis of their susceptibility to lyssavirus infection and the mRNA patterns of immune-relevant genes after poly I:C stimulation. Performed experiments indicated varying susceptibility to lyssavirus infection with MmBr being considerably less susceptible than the other cell lines. Further investigation demonstrated a strong activation of interferon mediated antiviral response in MmBr contributing to its resistance. The pattern recognition receptors: RIG-I and MDA5 were highly up-regulated during rabies virus infection in MmBr, suggesting their involvement in promotion of antiviral responses. The presence of CD14 and CD68 in MmBr suggested MmBr cells are microglia-like cells which play a key role in host defense against infections in the central nervous system (CNS). Thus the expression pattern of MmBr combined with the observed limitation of lyssavirus replication underpin a protective mechanism of the CNS controlling the lyssavirus infection. Overall, the established cell lines are important tools to analyze antiviral innate immunity in M. myotis against neurotropic virus infections and present a valuable tool for a broad spectrum of future investigations in cellular biology of M. myotis. PMID- 25295527 TI - Rubber hand illusion reduces discomfort caused by cold stimulus. AB - There is a growing interest in body-ownership disruptions and their consequences for subjective experiences such as tactile sensations or pain. Here, we investigated the effect of the rubber hand illusion (RHI) on the perceived discomfort caused by cold stimulus applied to the real hand. The results showed reduced discomfort to cold reflected in behavioural and subjective measures. The stronger the illusion, the later the cold temperature became unpleasant and the less intense the experience was rated. We discuss the link between thermoception and body ownership as well as possible theoretical and methodological implications for studies on pain experience under RHI. PMID- 25295528 TI - Entrenched geographical and socioeconomic disparities in child mortality: trends in absolute and relative inequalities in Cambodia. AB - BACKGROUND: Cambodia has made considerable improvements in mortality rates for children under the age of five and neonates. These improvements may, however, mask considerable disparities between subnational populations. In this paper, we examine the extent of the country's child mortality inequalities. METHODS: Mortality rates for children under-five and neonates were directly estimated using the 2000, 2005 and 2010 waves of the Cambodian Demographic Health Survey. Disparities were measured on both absolute and relative scales using rate differences and ratios, and where applicable, slope and relative indices of inequality by levels of rural/urban location, regions and household wealth. FINDINGS: Since 2000, considerable reductions in under-five and to a lesser extent in neonatal mortality rates have been observed. This mortality decline has, however, been accompanied by an increase in relative inequality in both rates of child mortality for geography-related stratifying markers. For absolute inequality amongst regions, most trends are increasing, particularly for neonatal mortality, but are not statistically significant. The only exception to this general pattern is the statistically significant positive trend in absolute inequality for under-five mortality in the Coastal region. For wealth, some evidence for increases in both relative and absolute inequality for neonates is observed. CONCLUSION: Despite considerable gains in reducing under-five and neonatal mortality at a national level, entrenched and increased geographical and wealth-based inequality in mortality, at least on a relative scale, remain. As expected, national progress seems to be associated with the period of political and macroeconomic stability that started in the early 2000s. However, issues of quality of care and potential non-inclusive economic growth might explain remaining disparities, particularly across wealth and geography markers. A focus on further addressing key supply and demand side barriers to accessing maternal and child health care and on the social determinants of health will be essential in narrowing inequalities. PMID- 25295529 TI - The effect of self-efficacy on visual discrimination sensitivity. AB - Can subjective belief about one's own perceptual competence change one's perception? To address this question, we investigated the influence of self efficacy on sensory discrimination in two low-level visual tasks: contrast and orientation discrimination. We utilised a pre-post manipulation approach whereby two experimental groups (high and low self-efficacy) and a control group made objective perceptual judgments on the contrast or the orientation of the visual stimuli. High and low self-efficacy were induced by the provision of fake social comparative performance feedback and fictional research findings. Subsequently, the post-manipulation phase was performed to assess changes in visual discrimination thresholds as a function of the self-efficacy manipulations. The results showed that the high self-efficacy group demonstrated greater improvement in visual discrimination sensitivity compared to both the low self-efficacy and control groups. These findings suggest that subjective beliefs about one's own perceptual competence can affect low-level visual processing. PMID- 25295530 TI - Fractured genetic connectivity threatens a southern california puma (Puma concolor) population. AB - Pumas (Puma concolor; also known as mountain lions and cougars) in southern California live among a burgeoning human population of roughly 20 million people. Yet little is known of the consequences of attendant habitat loss and fragmentation, and human-caused puma mortality to puma population viability and genetic diversity. We examined genetic status of pumas in coastal mountains within the Peninsular Ranges south of Los Angeles, in San Diego, Riverside, and Orange counties. The Santa Ana Mountains are bounded by urbanization to the west, north, and east, and are separated from the eastern Peninsular Ranges to the southeast by a ten lane interstate highway (I-15). We analyzed DNA samples from 97 pumas sampled between 2001 and 2012. Genotypic data for forty-six microsatellite loci revealed that pumas sampled in the Santa Ana Mountains (n = 42) displayed lower genetic diversity than pumas from nearly every other region in California tested (n = 257), including those living in the Peninsular Ranges immediately to the east across I-15 (n = 55). Santa Ana Mountains pumas had high average pairwise relatedness, high individual internal relatedness, a low estimated effective population size, and strong evidence of a bottleneck and isolation from other populations in California. These and ecological findings provide clear evidence that Santa Ana Mountains pumas have been experiencing genetic impacts related to barriers to gene flow, and are a warning signal to wildlife managers and land use planners that mitigation efforts will be needed to stem further genetic and demographic decay in the Santa Ana Mountains puma population. PMID- 25295531 TI - An integrated bioimpedance--ECG gating technique for respiratory and cardiac motion compensation in cardiac PET. AB - Respiratory motion may degrade image quality in cardiac PET imaging. Since cardiac PET studies often involve cardiac gating by ECG, a separate respiratory monitoring system is required increasing the logistic complexity of the examination, in case respiratory gating is also needed. Thus, we investigated the simultaneous acquisition of both respiratory and cardiac gating signals using II limb lead mimicking electrode configuration during cardiac PET scans of 11 patients. In addition to conventional static and ECG-gated images, bioimpedance technique was utilized to generate respiratory- and dual-gated images. The ability of the bioimpedance technique to monitor intrathoracic respiratory motion was assessed estimating cardiac displacement between end-inspiration and expiration. The relevance of dual gating was evaluated in left ventricular volume and myocardial wall thickness measurements. An average 7.6 +/- 3.3 mm respiratory motion was observed in the study population. Dual gating showed a small but significant increase (4 ml, p = 0.042) in left ventricular myocardial volume compared to plain cardiac gating. In addition, a thinner myocardial wall was observed in dual-gated images (9.3 +/- 1.3 mm) compared to cardiac-gated images (11.3 +/- 1.3 mm, p = 0.003). This study shows the feasibility of bioimpedance measurements for dual gating in a clinical setting. The method enables simultaneous acquisition of respiratory and cardiac gating signals using a single device with standard ECG electrodes. PMID- 25295532 TI - [Targeting mTOR and identification of " exceptional responders "]. PMID- 25295533 TI - Efficient low bandgap polymer solar cell with ordered heterojunction defined by nanoimprint lithography. AB - In this work, we demonstrate the feasibility of using nanoimprint lithography (NIL) to make efficient low bandgap polymer solar cells with well-ordered heterojunction. High quality low bandgap conjugated polymer poly[2,6-(4,4-bis(2 ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3 benzothiadiazole)] (PCPDTBT) nanogratings are fabricated using this technique for the first time. The geometry effect of PCPDTBT nanostructures on the solar cell performance is investigated by making PCPDTBT/C70 solar cells with different feature sizes of PCPDTBT nanogratings. It is found that the power conversion efficiency (PCE) increases with increasing nanograting height, PCPDTBT/C70 junction area, and decreasing nanograting width. We also find that NIL makes PCPDTBT chains interact more strongly and form an improved structural ordering. Solar cells made on the highest aspect ratio PCPDTBT nanostructures are among the best reported devices using the same material with a PCE of 5.5%. PMID- 25295534 TI - Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. AB - A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy. PMID- 25295535 TI - Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus. AB - Levels of pituitary growth hormone (GH), a metabolic homeostatic factor with strong lipolytic activity, are decreased in obese individuals. GH declines prior to the onset of weight gain in response to excess caloric intake and hyperinsulinemia; however, the mechanism by which GH is reduced is not clear. We used transgenic mice expressing the human GH (hGH) gene, GH1, to assess the effect of high caloric intake on expression as well as the local chromosome structure of the intact GH1 locus. Animals exposed to 3 days of high caloric intake exhibited hyperinsulinemia without hyperglycemia and a decrease in both hGH synthesis and secretion, but no difference in endogenous production of murine GH. Efficient GH1 expression requires a long-range intrachromosomal interaction between remote enhancer sequences and the proximal promoter region through "looping" of intervening chromatin. High caloric intake disrupted this interaction and decreased both histone H3/H4 hyperacetylation and RNA polymerase II occupancy at the GH1 promoter. Incorporation of physical activity muted the effects of excess caloric intake on insulin levels, GH1 promoter hyperacetylation, chromosomal architecture, and expression. These results indicate that energy homeostasis alters postnatal hGH synthesis through dynamic changes in the 3-dimensional chromatin structure of the GH1 locus, including structures required for cell type specificity during development. PMID- 25295536 TI - TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1. AB - Ischemia is a leading cause of acute kidney injury. Kidney ischemia is associated with loss of cellular ion homeostasis; however, the pathways that underlie ion homeostasis dysfunction are poorly understood. Here, we evaluated the nonselective cation channel transient receptor potential melastatin 2 (TRPM2) in a murine model of kidney ischemia/reperfusion (I/R) injury. TRPM2-deficient mice were resistant to ischemic injury, as reflected by improved kidney function, reduced histologic damage, suppression of proapoptotic pathways, and reduced inflammation. Moreover, pharmacologic TRPM2 inhibition was also protective against I/R injury. TRPM2 was localized mainly in kidney proximal tubule epithelial cells, and studies in chimeric mice indicated that the effects of TRPM2 are due to expression in parenchymal cells rather than hematopoietic cells. TRPM2-deficient mice had less oxidative stress and lower levels of NADPH oxidase activity after ischemia. While RAC1 is a component of the NADPH oxidase complex, its relation to TRPM2 and kidney ischemic injury is unknown. Following kidney ischemia, TRPM2 promoted RAC1 activation, with active RAC1 physically interacting with TRPM2 and increasing TRPM2 expression at the cell membrane. Finally, inhibition of RAC1 reduced oxidant stress and ischemic injury in vivo. These results demonstrate that TRPM2-dependent RAC1 activation increases oxidant stress and suggest that therapeutic approaches targeting TRPM2 and/or RAC1 may be effective in reducing ischemic kidney injury. PMID- 25295537 TI - Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination. AB - The signal-responsive E3 ubiquitin ligase pellino 1 (PELI1) regulates TLR and T cell receptor (TCR) signaling and contributes to the maintenance of autoimmunity; however, little is known about the consequence of mutations that result in upregulation of PELI1. Here, we developed transgenic mice that constitutively express human PELI1 and determined that these mice have a shorter lifespan due to tumor formation. Constitutive expression of PELI1 resulted in ligand-independent hyperactivation of B cells and facilitated the development of a wide range of lymphoid tumors, with prominent B cell infiltration observed across multiple organs. PELI1 directly interacted with the oncoprotein B cell chronic lymphocytic leukemia (BCL6) and induced lysine 63-mediated BCL6 polyubiquitination. In samples from patients with diffuse large B cell lymphomas (DLBCLs), PELI1 expression levels positively correlated with BCL6 expression, and PELI1 overexpression was closely associated with poor prognosis in DLBCLs. Together, these results suggest that increased PELI1 expression and subsequent induction of BCL6 promotes lymphomagenesis and that this pathway may be a potential target for therapeutic strategies to treat B cell lymphomas. PMID- 25295538 TI - PCP4 regulates Purkinje cell excitability and cardiac rhythmicity. AB - Cardiac Purkinje cells are important triggers of ventricular arrhythmias associated with heritable and acquired syndromes; however, the mechanisms responsible for this proarrhythmic behavior are incompletely understood. Here, through transcriptional profiling of genetically labeled cardiomyocytes, we identified expression of Purkinje cell protein-4 (Pcp4), a putative regulator of calmodulin and Ca2+/calmodulin-dependent kinase II (CaMKII) signaling, exclusively within the His-Purkinje network. Using Pcp4-null mice and acquired cardiomyopathy models, we determined that reduced expression of PCP4 is associated with CaMKII activation, abnormal electrophysiology, dysregulated intracellular calcium handling, and proarrhythmic behavior in isolated Purkinje cells. Pcp4-null mice also displayed profound autonomic dysregulation and arrhythmic behavior in vivo. Together, these results demonstrate that PCP4 regulates cardiac excitability through both Purkinje cell-autonomous and central mechanisms and identify this modulator of CaMKII signaling as a potential arrhythmia-susceptibility candidate. PMID- 25295539 TI - Chronic allergic contact dermatitis promotes skin cancer. AB - Allergic contact dermatitis (ACD) is well recognized as an adverse event associated with implantable medical devices that contain allergenic materials like nickel; however, other cutaneous consequences of chronic exposure to allergens in implanted devices are not well understood. Here, we present a clinical case of Marjolin's ulcer, an invasive squamous cell carcinoma (SCC) that developed in response to chronic ACD caused by an orthopedic implant. We used a standard murine model of contact hypersensitivity to determine whether chronic ACD promotes skin carcinogenesis. Chronic application of 1-fluoro-2,4 dinitrobenzene (DNFB) to carcinogen-treated skin led to the development of papillomas and aggressive SCC. DNFB-driven chronic ACD was marked by type 2 inflammation, which mediated skin carcinogenesis, as mice unable to mount an inflammatory response were less likely to develop skin tumors. Importantly, we found similar tumor-promoting inflammation surrounding the SCC in our patient. Our findings demonstrate that chronic ACD caused by constant exposure to an allergen can promote tumorigenesis at skin sites with preexisting cancer initiated cells. Moreover, our results suggest that patients with implantable devices placed in close proximity to the skin should be monitored for ACD and highlight the importance of patch testing prior to the placement of such devices. PMID- 25295540 TI - Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model. AB - The demonstrated ability to differentiate both human embryonic stem cells (hESCs) and patient-derived induced pluripotent stem cells (hiPSCs) into hepatocyte-like cells (HLCs) holds great promise for both regenerative medicine and liver disease research. Here, we determined that, despite an immature phenotype, differentiated HLCs are permissive to hepatitis C virus (HCV) infection and mount an interferon response to HCV infection in vitro. HLCs differentiated from hESCs and hiPSCs could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter. The HLCs were maintained for more than 3 months in the livers of chimeric mice, in which they underwent further maturation and proliferation. These engrafted and expanded human HLCs were permissive to in vivo infection with HCV-positive sera and supported long-term infection of multiple HCV genotypes. Our study demonstrates efficient engraftment and in vivo HCV infection of human stem cell-derived hepatocytes and provides a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection. PMID- 25295543 TI - Characteristics of older adult physical activity program users. AB - OBJECTIVES: Physical activity levels are low among older adults. Many Medicare members have access to low-cost programs including Silver Sneakers (SS) and EnhanceFitness (EF) at no additional cost, however, utilization of these programs is low. We aimed to compare characteristics of people using SS and EF to nonusers of these programs to better understand the characteristics of these 2 populations and to guide future physical activity promotion program design. STUDY DESIGN: Cross-sectional. METHODS: We used 2010 and 2011 electronic health records including demographic, health condition, Charlson comorbidity score, healthcare cost and utilization, and SS and EF program utilization data from 37,492 Medicare members from a large integrated health care system. Models were fit using logistic and negative binomial regression adjusting for age, gender, race, ethnicity, BMI category, and primary care clinic location. RESULTS: Compared with nonusers (N = 30,733; 82%), SS users (N = 6200; 16.5%) were younger and less likely to be male, obese, or have diabetes or cardiovascular disease; they also had lower Charlson scores and fewer hospital admissions than nonusers. EF users (N = 721; 2%) were older, were less likely to be male, had lower Charlson scores, and had fewer hospital admissions compared to nonusers. CONCLUSIONS: Low-cost, evidence-based physical activity programs are vastly underused by Medicare members. Our data suggest that targeting more chronically ill and obese older adults for physical activity programs might help improve the reach of existing evidence-based programs. PMID- 25295541 TI - Skin exposure promotes a Th2-dependent sensitization to peanut allergens. AB - Sensitization to foods often occurs in infancy, without a known prior oral exposure, suggesting that alternative exposure routes contribute to food allergy. Here, we tested the hypothesis that peanut proteins activate innate immune pathways in the skin that promote sensitization. We exposed mice to peanut protein extract on undamaged areas of skin and observed that repeated topical exposure to peanut allergens led to sensitization and anaphylaxis upon rechallenge. In mice, this epicutaneous peanut exposure induced sensitization to the peanut components Ara h 1 and Ara h 2, which is also observed in human peanut allergy. Both crude peanut extract and Ara h 2 alone served as adjuvants, as both induced a bystander sensitization that was similar to that induced by the atopic dermatitis-associated staphylococcal enterotoxin B. In cultured human keratinocytes and in murine skin, peanut extract directly induced cytokine expression. Moreover, topical peanut extract application induced an alteration dependent on the IL-33 receptor ST2 in skin-draining DCs, resulting in Th2 cytokine production from T cells. Together, our data support the hypothesis that peanuts are allergenic due to inherent adjuvant activity and suggest that skin exposure to food allergens contributes to sensitization to foods in early life. PMID- 25295544 TI - The underuse of carotid interventions in veterans with symptomatic carotid stenosis. AB - OBJECTIVES: To examine the receipt of carotid intervention among eligible patients post stroke in the Veterans Health Administration (VA). METHODS: We examined whether veterans admitted to a VA medical center in 2007 with a diagnosis of stroke and who were eligible for intervention, received carotid intervention in a period up to 6 months after their index hospitalization. We also examined whether demographics, comorbid conditions, stroke severity and availability of vascular intervention services were independently associated with receipt of intervention. RESULTS: Among the 5721 patients admitted, 253 ischemic stroke patients had evidence of some carotid stenosis and had data on side of stroke available. Among the 200 patients who had at least 50% to 99% stenosis of the carotid artery, 34 (17%) received intervention (95% confidence interval [CI], 11.79%-22.21%). In a multivariable model, black race and past history of diabetes were significantly associated with carotid intervention: An eligible black patient was 6 times more likely to NOT receive intervention compared to patients of other races (adjusted odds ratio [OR] = 6.54; 95% CI, 1.34-31.9), and a patient with diabetes was 3 times more likely to NOT receive intervention (adjusted OR = 3.38; 95% CI, 1.24- 9.24) compared to non-diabetics. Stroke severity and availability of vascular surgery services was not associated with receipt of intervention. CONCLUSIONS: Few patients with symptomatic carotid stenosis who were admitted with stroke to the VA received carotid intervention. Future research should be directed at improving access to this procedure among eligible patients in the VA. PMID- 25295542 TI - Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation. AB - Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1 deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1-deficient mice. IL-1beta cleavage and secretion were impaired in HO-1-deficient macrophages, and CO-dependent processing of IL-1beta required the presence of bacteria-derived ATP. We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1beta inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes. PMID- 25295545 TI - Evaluating a hepatitis c quality gap: missed opportunities for HCV-related cares. AB - OBJECTIVES: Diagnosis of chronic hepatitis C virus (HCV) is a 2-step process involving hepatitis C antibody (HCVab) testing followed by viral ribonucleic acid (RNA) testing. The HCV status of those with a positive HCVab without viral testing cannot be determined. This study sought to describe the HCV-related care provided to patients in this care gap. STUDY DESIGN: Retrospective cohort study of active patients with a positive HCVab test who did not complete viral testing. METHODS: Electronic medical records (EMRs) were reviewed to determine if each subject's first positive HCVab result was acknowledged by a provider. For results acknowledged, we described provider actions in response to the result. When providers performed specific clinical actions within 1 year of the positive HCVab test, we captured the type of action taken. When the unsubstantiated diagnosis was documented in the EMR, we determined if the diagnosis was mentioned by subsequent providers. RESULTS: Positive HCVab results were not acknowledged in 31% of subjects. In 35%, providers added chronic HCV to the problem list in the EMR, resulting in a higher likelihood of subsequent providers mentioning the diagnosis in their EMR documentation. In 143 subjects whose providers recommended HCV-related clinical actions within 1 year of the positive result, 45% were educated about HCV and 42% had their liver enzymes monitored. CONCLUSIONS: With more widespread testing anticipated and more effective treatments available, health systems should ensure the HCV diagnostic process results in the delivery of an accurate and timely HCV diagnosis, to reduce the risk of harm to patients. PMID- 25295546 TI - Structural capabilities in small and medium-sized patient-centered medical homes. AB - OBJECTIVES: 1) Evaluate structural capabilities associated with the patient centered medical home (PCMH) model in PCMH pilots in Colorado, Ohio, and Rhode Island; 2) evaluate changes in capabilities over 2 years in the Rhode Island pilot; and 3) evaluate facilitators and barriers to the adoption of capabilities. STUDY DESIGN: We assessed structural capabilities in the 30 pilot practices using a cross-sectional study design and examined changes over 2 years in 5 Rhode Island practices using a pre/post design. METHODS: We used National Committee for Quality Assurance's Physician Practice Connections-Patient-Centered Medical Home (PPC/PCMH) accreditation survey data to measure capabilities. We stratified by high and low performance based on total score and by practice size. We analyzed change from baseline to 24 months for the Rhode Island practices. We analyzed qualitative data from interviews with practice leaders to identify facilitators and barriers to building capabilities. RESULTS: On average, practices scored 73 points (out of 100 points) for structural capabilities. High and low performers differed most on electronic prescribing, patient self-management, and care management standards. Rhode Island practices averaged 42 points at baseline, and reached 90 points by the end of year 2. Some of the key facilitators that emerged were payment incentives, "transformation coaches," learning collaboratives, and data availability supporting performance management and quality improvement. Barriers to improvement included the extent of transformation required, technology shortcomings, slow cultural change, change fatigue, and lack of broader payment reform. CONCLUSIONS: For these early adopters, prevalence of structural capabilities was high, and performance was substantially improved for practices with initially lower capabilities. We conclude that building capabilities requires payment reform, attention to implementation, and cultural change. PMID- 25295547 TI - Shifting cardiovascular care to nurses results in structured chronic care. AB - OBJECTIVES: To explore nurse involvement in cardiovascular risk management (CVRM) in primary care and how this involvement was associated with the degree of structured chronic illness care. STUDY DESIGN: A cross-sectional observational study in 7 European countries. METHODS: Five aspects of nurse involvement in CVRM and 35 specific components of structured chronic illness care were documented in 202 primary care practices in Austria, Belgium, Germany, the Netherlands, Slovenia, Spain, and Switzerland. An overall measure for chronic care management, range 0 to 5, was constructed, derived from elements of the Chronic Care Model (CCM). Random coefficient regression modeling was used to explore associations. RESULTS: A majority of practices involved nurses for organization of CVRM in administrative tasks (82.2 %), risk factor monitoring (78.5%) and patient education (57.1%). Fewer practices involved nurses in defining protocol and the organization for CVRM (45%) or diagnosis and treatment (34.6%). With an increasing number of tasks handled by nurses, overall median adoption of CCM increased from 2.7 (95% CI, 1.5-3.6) to 4.2 (95% CI, 3.8-4.1). When the number of nurse tasks increased by 1, the adoption of CCM increased by 0.13 (P <.05; 95% CI, 0.03-0.22). Some practices with low nurse involvement had high adoption of CCM, while variation of adoption of CCM across practices reduced substantially with an increasing level of nurse involvement. CONCLUSIONS: Nurses were involved in the delivery of CVRM in varying degrees. Higher involvement of nurses was associated with higher degree of structured chronic illness care, with less variation. PMID- 25295548 TI - Geographical origin of post-landmine injury malaria infections. AB - OBJECTIVE: In Cambodia, a highly landmine-contaminated country with endemic malaria, symptomatic falciparum malaria has been observed in patients presenting with traumatic landmine injuries. Because a link between recrudescence of symptomatic Plasmodium falciparum malaria and severe trauma is well established, we explored whether a link could be demonstrated between the geolocation of landmine amputations and malaria cases. METHOD: Landmine amputation data in Cambodia (2005-2008) were compared with predicted measures of malaria endemicity. Data of injuries that had resulted in amputation were plotted over a surface of P falciparum parasite rates. RESULTS: No statistically significant correlation was found, possibly because the P falciparum endemicity surface was drawn from a model-based geostatistical prediction of infection prevalence and did not distinguish cases of recrudescence. The implication of this finding is that where symptomatic falciparum malaria has been observed in patients with landmine injuries, the cases were likely to be reactivated falciparum infections and not new cases. CONCLUSIONS: Further research is needed to understand the relationship between P falciparum and trauma. To distinguish P falciparum recrudescence from new cases, a prospective registry is needed. Also, practitioners need to be aware of the possibility of post-injury malaria recrudescence in complex emergencies. PMID- 25295549 TI - Letter to the editor: Suicidal ideation and research ethics committees. PMID- 25295550 TI - Reply to the letter from Grunze and Walden. AB - Professors Grunze and Walden sent a letter associated with our article. In this letter, we reply to their comments. PMID- 25295551 TI - Antipsychotic agents used to augment clozapine during long-term inpatient hospitalizations. AB - INTRODUCTION: Literature assessing effective clozapine augmentation strategies is limited. The aim of this retrospective evaluation was to examine antipsychotics used to augment clozapine and assess whether an augmentation antipsychotic would continue at discharge. METHODS: Demographic, clinical and pharmacy data were collected retrospectively if patients had received clozapine plus an antipsychotic used for augmentation. The dose of the augmentation agent, length of augmentation therapy, and concomitant medications were collected. RESULTS: Of the 49 patients (mean age 45.3+/-12.1 years), 27 (55%) were male. The mean clozapine dose at discharge was 406.1+/-121.8 mg. When a first generation antipsychotic (FGA) was selected initially to augment clozapine there was a greater likelihood it would be continued until discharge compared to a second generation antipsychotic (SGA) (78 vs. 50%, OR=3.6, 95% CI 1.03-12.6). FGAs (3.2%) compared to SGAs (35%) were less likely to be discontinued due to a documented lack of benefit when first selected to augment clozapine (OR=16.2, 95% CI 2-131.3). Electroconvulsive therapy plus clozapine was found to be beneficial in several patients (n=14) who failed at least 1 augmentation strategy. DISCUSSION: This real world data suggests that adding an antipsychotic to clozapine is a reasonable approach to those who do not fully respond to clozapine monotherapy. While comparisons of all agents could not be conducted from this small retrospective study, these data suggest FGAs should be investigated in future studies as potential agents to successfully augment clozapine therapy. PMID- 25295552 TI - SLC6A2 and SLC6A4 variants interact with venlafaxine serum concentrations to influence therapy outcome. AB - OBJECTIVE: The effects of genetic variants in genes encoding the target structures of antidepressants on the therapeutic efficacy of antidepressant drugs have been investigated with unconclusive results. One possible confounding factor in most studies was the fact that drug serum concentrations had not been determined. METHODS: Within a clinical setting, 56 inpatients suffering from depressive episodes in the context of either major depressive disorder or bipolar affective disorder were studied. Response to venlafaxine was assessed after 4 weeks of treatment and correlated to serum concentration and functional variants in genes encoding the norepinephrine (SLC6A2; rs28386840) and the serotonin transporter (SLC6A4; [5-HTTLPR], rs25531). Symptom change was evaluated using the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: No association between therapeutic response, venlafaxine serum concentration (active moiety) and rs28386840 was found. In carriers of the high expressing SLC6A4 genotype (lAlA-), a poor response to venlafaxine was found significantly more often. In subsamples stratified for serum concentration this held true for patients with serum concentrations between 201 and 400 ng/mL (n=21), while in patients with sub- (<= 200 ng/mL; n=12) and supra-recommended (> 400 ng/mL; n=23) concentrations, no significant differences were observed. DISCUSSION: The observed association is consistent with findings of some previous studies, whereas others showed differing results highlighting the need for further investigations. PMID- 25295553 TI - Possible drug-drug interaction between pregabalin and clozapine in patients with schizophrenia: clinical perspectives. AB - INTRODUCTION: Pregabalin is an antiepileptic drug with anti-anxiety properties and is approved for treatment of generalized anxiety disorder. Anxiety is common in patients with schizophrenia and pregabalin has been suggested as an off-label add-on treatment. METHODS: Pregabalin was added to clozapine in 2 patients with schizophrenia, who both suffered from severe anxiety symptoms. RESULTS: Both patients experienced falls and consequently bone fractures. Increased plasma levels of clozapine likely contributed to the outcome. One patient had confirmed seizures whereas the mechanism in the other patient was less clear. DISCUSSION: This short report discusses the possible mechanism of a pregabalin-clozapine interaction. PMID- 25295555 TI - Show your courage. PMID- 25295554 TI - National Association of Clinical Nurse Specialists News: President's Message. PMID- 25295556 TI - Helping patients improve their health through the use of technology. PMID- 25295557 TI - Quality nursing documentation in the medical record. PMID- 25295558 TI - Transitional care: assuring evidence-based practice in skilled nursing facilities. PMID- 25295559 TI - Dietary supplements for preventing postnatal depression. PMID- 25295560 TI - Creating satisfied clients. PMID- 25295561 TI - Capture of knowledge work of clinical nurse specialists using a role tracking tool. AB - PURPOSE: The aim of this study was to quantify clinical nurse specialist (CNS) work and determine if competencies are associated with personal characteristics, priorities, and quality outcomes. BACKGROUND: The work of a CNS is difficult to quantify. Nurse leaders need quantifiable data to understand the impact of CNS work. DESIGN: A prospective, single-center, correlational study with a convenience sample was conducted. SETTING AND SAMPLE: The study was conducted in a 1200-bed quaternary care medical center in Northeast Ohio, using CNSs. METHODS: The investigator-developed Role Tracker Tool (software) and a CNS questionnaire were used to collect baseline and monthly data for 5 months. Characteristics of the CNSs were summarized using descriptive statistics. Correlational statistics were used to measure associations. After mutually exclusive groups were created, tests for differences were completed using a Welch 2-sample t test and analysis of variance. Regression models were used to determine if relationships existed over time between competencies, priority ranking of competencies, and nursing characteristics. FINDINGS: Among 14 CNSs, mean (SD) age was 45 (10.11) years; mean (SD) CNS experience was 5.57 (7.87) years. Of 6 competencies, CNSs ranked quality as most important, followed by clinical work. Research ranked low. Mean (SD) time spent in hours/8.5-hour workday over 5 months was highest for clinical work, at 1.9 (1) hours, and lowest for professional self-development, at 0.4 (0.4) hours. Time spent on specific competencies varied by specialty, years as a CNS and at current employer, and comfort in competencies and spheres after controlling for nurse characteristics and monthly trends. Of 9 quality initiative focuses, mean (SD) time in hours/8.5-hour workday was highest for heart failure, with 0.7(0.8) hours. Time spent on quality initiatives was not associated with changes in quality improvement outcomes. Clinical nurse specialist competency priorities, quality initiative focuses, and quality outcomes varied over time. IMPLICATIONS: The work of CNSs can be captured and analyzed to enhance understanding of unique and varied CNS contributions in the healthcare matrix. PMID- 25295562 TI - Nurse-led clinics for patients with chronic diseases in hospital and transmural care organizations. AB - OBJECTIVES: The objectives of this study were to elucidate the purpose, content, and organization of nurse-led clinics for patients with chronic diseases and to explore whether there are differences in the content and context of the nurse-led clinics and attention for the home situation between a transmural and a hospital setting. SETTINGS: Transmural setting by which nurses work in both primary and secondary care and hospital setting where nurses are employed by a local hospital. Within the transmural setting, 4 nurse-led clinics were studied: heart failure, rheumatoid arthritis, Parkinson disease, and multiple sclerosis. Within the hospital setting, 3 nurse-led clinics were studied: heart failure, rheumatoid arthritis, and Parkinson disease. METHODS: A multiple-case embedded design was used to investigate the content and context of the nurse-led clinics for patients with heart failure, rheumatoid arthritis, Parkinson disease, and multiple sclerosis in the transmural and hospital setting. SAMPLE: One hundred twenty-one patient records, bimonthly telephone interviews with 218 patients, and face-to face interviews with 7 nurses. RESULTS: Nurses focus on disease itself, treatment, and the everyday life of the patient. In addition, nurses maintain contacts with colleagues and other disciplines both inside and outside the hospital. No influence of setting was found on the execution of nurse-led clinics. CONCLUSIONS: Nurse-led clinics for chronically ill patients focus on all aspects of living with a chronic disease. The organizational context does not seem to contribute to the execution of the nurse-led clinics. Instead, this seems to be driven by patient needs, the definition of nursing and nursing competencies, and general developments in the nursing profession. IMPLICATIONS: To improve nursing care for patients with chronic illnesses, changing the organizational context might not be useful. PMID- 25295563 TI - The clinical nurse specialist as resuscitation process manager. AB - PURPOSE/OBJECTIVES: The purpose of this article was to describe the history and leadership dimensions of the role of resuscitation process manager and provide specific examples of how this role is implemented at a Midwest medical center. BACKGROUND: In 1992, a medical center in the Midwest needed a nurse to manage resuscitation care. RATIONALE: This role designation meant that this nurse became central to all quality improvement efforts in resuscitation care. The role expanded as clinical resuscitation guidelines were updated and as the medical center grew. The role became known as the critical care clinical nurse specialist as resuscitation process manager. This clinical care nurse specialist was called a manager, but she had no direct line authority, so she accomplished her objectives by forming a multitude of collaborative networks. DESCRIPTION: Based on a framework by Finkelman, the manager role incorporated specific leadership abilities in quality improvement: (1) coordination of medical center-wide resuscitation, (2) use of interprofessional teams, (3) integration of evidence into practice, and (4) staff coaching to develop leadership. OUTCOME: The manager coordinates resuscitation care with the goals of prevention of arrests if possible, efficient and effective implementation of resuscitation protocols, high quality of patient and family support during and after the resuscitation event, and creation or revision of resuscitation policies for in-hospital and for ambulatory care areas. The manager designs a comprehensive set of meaningful and measurable process and outcome indicators with input from interprofessional teams. The manager engages staff in learning, reflecting on care given, and using the evidence base for resuscitation care. Finally, the manager role is a balance between leading quality improvement efforts and coaching staff to implement and sustain these quality improvement initiatives. CONCLUSION: Revisions to clinical guidelines for resuscitation care since the 1990s have resulted in medical centers developing improved resuscitation processes that require management. The manager enhances collaborative quality improvement efforts that are in line with Institute of Medicine recommendations. IMPLICATIONS: The role of resuscitation process manager may be of interest to medical centers striving for excellence in evidence-based resuscitation care. PMID- 25295564 TI - Healthcare experiences of lesbian, gay, and bisexual college students: recommendations for the clinical nurse specialist. AB - PURPOSE/AIMS: The purpose of this study was to describe the healthcare experiences of lesbian, gay, and bisexual college students (ages 18-24 years) in the local college community. A specific aim of the study was to describe the factors (eg, healthcare system, patient, provider, clinical encounter) that influence this experience. DESIGN: This qualitative descriptive study used a community-based participatory research approach. SETTING: This study was conducted at a local college consortium in New England that consisted of 13 private and public colleges and universities. SAMPLE: A total of 19 college students who self-identified as lesbian (n = 7), gay (n = 7), and female bisexual (n = 4) were included. The mean (SD) age of the sample was 20.7 (1.2) years (range, 19-24 years), and the mean (SD) number of completed college years was 2.4 (1.2) (range, 1-5). METHODS: Three online synchronous focus groups were conducted. RESULTS: Qualitative content analysis revealed 1 overarching theme (not all the same), 1 main theme (comfort during the clinical encounter), and 3 subthemes (personalizing the clinical encounter, deciding to disclose and social stigma, and seeking support of self-identified sexual orientation). CONCLUSIONS: Participants provided recommendations that are helpful to clinical nurse specialists to promote positive clinical encounters. Implications for clinical nurse specialist practice and recommendations for further research are addressed. PMID- 25295565 TI - Clinical nurse specialist profile. PMID- 25295566 TI - With grace: a duet for a dancer, David Leventhal, and a dancer with Parkinson's disease, Pamela Quinn. PMID- 25295570 TI - [Obesity and cardiometabolic risk factors during pregnancy.] AB - PURPOSE: To assess cardiometabolic risk factors during normal pregnancy and the influence of maternal obesity on them. METHODS: This study included 25 healthy pregnant women with a single pregnancy and a gestational age of less than twenty weeks. Longitudinal analysis of blood pressure, body weight, body mass index (BMI), serum concentrations of leptin, adiponectin, cortisol, total cholesterol and fractions, triglycerides, uric acid, fasting glucose, oral glucose tolerance test, HOMA-IR and insulin/glucose ratio was performed each trimester during pregnancy. In order to evaluate the impact of obesity, pregnant women were divided into two groups based on BMI for the first quarter of pregnancy: Gpn for pregnant women with BMI<25 kg/m2 and Gso for BMI>=25 kg/m2. One-Way ANOVA for repeated measurements or Friedman test and Student-t or Mann-Whitney tests for statistical comparisons and Pearson correlations test were used for statistical analysis. RESULTS: The mean values for the first quarter of pregnancy for the following parameters were: age: 22 years; weight: 66.3 kg and BMI 26.4 kg/m2, with 20.2 and 30.7 kg/m2 for the Gpn and Gso groups, respectively. Mean weight gain during pregnancy was +/-12.7 kg with 10.3 kg for the Gso group and 15.2 kg for the Gpn group. Regarding plasma determinations, cortisol, uric acid and lipid profile increased during all trimesters of pregnancy, except for HDL-cholesterol, which did not change. Blood pressure, insulin and HOMA-IR only increased in the third quarter of pregnancy. The Gso group tended to gain more weight and to show higher concentrations of leptin, total cholesterol, LDL-cholesterol, VLDL cholesterol, TG, glucose, insulin, HOMA-IR, besides lower HDL-cholesterol and greater diastolic blood pressure in the 3rd quarter of pregnancy. Three pregnant women developed gestational hypertension, presented prepregnancy obesity, excessive weight gain, hyperleptinemia and an insulin/glucose ratio greater than two. Weight and BMI were positively correlated with total cholesterol and its LDL fraction, TG, uric acid, fasting blood glucose, insulin and HOMA-IR; and were negatively correlated with adiponectin and HDL-cholesterol. Leptin level was positively correlated with blood pressure. CONCLUSIONS: The metabolic changes in pregnancy are more significant in obese women, suggesting, as expected, an increased risk of cardiometabolic complications. During their first visit for prenatal care, obese women should be informed about these risks, have their BMI and insulin/glucose ratio calculated along with their lipid profile to identify pregnant women at higher risk for cardiovascular diseases. PMID- 25295571 TI - Changes in motor behavior during pregnancy in rats: the basis for a possible animal model of restless legs syndrome. AB - PURPOSE: Pregnant women have a 2-3 fold higher probability of developing restless legs syndrome (RLS - sleep-related movement disorders) than general population. This study aims to evaluate the behavior and locomotion of rats during pregnancy in order to verify if part of these animals exhibit some RLS-like features. METHODS: We used 14 female 80-day-old Wistar rats that weighed between 200 and 250 g. The rats were distributed into control (CTRL) and pregnant (PN) groups. After a baseline evaluation of their behavior and locomotor activity in an open field environment, the PN group was inducted into pregnancy, and their behavior and locomotor activity were evaluated on days 3, 10 and 19 of pregnancy and in the post-lactation period in parallel with the CTRL group. The serum iron and transferrin levels in the CTRL and PN groups were analyzed in blood collected after euthanasia by decapitation. RESULTS: There were no significant differences in the total ambulation, grooming events, fecal boli or urine pools between the CTRL and PN groups. However, the PN group exhibited fewer rearing events, increased grooming time and reduced immobilization time than the CTRL group (ANOVA, p<0.05). CONCLUSION: These results suggest that pregnant rats show behavioral and locomotor alterations similar to those observed in animal models of RLS, demonstrating to be a possible animal model of this sleep disorder. PMID- 25295572 TI - [Epidemiology of imported malaria and entomological study of breeding sites of potential risk areas in the province of Khemisset (Morocco)]. AB - No case of autochthonous malaria has been detected in Morocco since 2004. This achievement is due to a national strategy to combat the disease by appropriate and well-organized disease detection and treatment, as well as control of the mosquito vector of the disease, the female Anopheles mosquito. Nonetheless, imported malaria cases have been increasing (75 in 2007), due to the rise in international travel and migration from countries where the disease is endemic. This work is divided into two parts: the first part is a retrospective study of the cases of imported malaria identified by optical microscopy in the Laboratory of Medical Entomology of the Khemisset Provincial Delegation of Health from 2000 to 2010. The second part is an entomological study conducted in 2010 of the Culicidae insect family, especially the Anopheles genus. The results show that of 176,457 requests for parasite testing, 14 were positive. All positive samples came from men older than 23 years. The cases identified are imported from two African countries: the Democratic Republic of Congo (86%) and Ivory Coast (14%). The years of high incidence were 2003 with four cases and 2000, 2004 and 2006 with two cases. The species found are Plasmodium falciparum in 13 cases (93%) and Plasmodium ovale in one case (7%). The vector of autochthonous malaria, which was eliminated in 2004, is Anopheles (Anopheles) labranchiae Fallerouni 1926, and it was the dominant species found in our entomological study (424 larvae). The other species were found in breeding sites in potential at-risk locations in the study area. PMID- 25295573 TI - Few-layer molybdenum disulfide transistors and circuits for high-speed flexible electronics. AB - Two-dimensional layered materials, such as molybdenum disulfide, are emerging as an exciting material system for future electronics due to their unique electronic properties and atomically thin geometry. Here we report a systematic investigation of MoS2 transistors with optimized contact and device geometry, to achieve self-aligned devices with performance including an intrinsic gain over 30, an intrinsic cut-off frequency fT up to 42 GHz and a maximum oscillation frequency fMAX up to 50 GHz, exceeding the reported values for MoS2 transistors to date (fT~0.9 GHz, fMAX~1 GHz). Our results show that logic inverters or radio frequency amplifiers can be formed by integrating multiple MoS2 transistors on quartz or flexible substrates with voltage gain in the gigahertz regime. This study demonstrates the potential of two-dimensional layered semiconductors for high-speed flexible electronics. PMID- 25295574 TI - Quantitative insight in utilizing circulating angiogenic factors as biomarkers for antiangiogenic therapy: systems pharmacology approach. AB - Circulating angiogenic factors (CAF) like vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and sVEGFR2 have potential as biomarkers for antiangiogenic therapy. The interpretation of changes in CAF is complicated by the dynamic nature of the tumor and host cells emanating CAF in response to VEGF pathway inhibition. We developed a systems pharmacology model of anti-VEGF agents to investigate CAF modulation by tumor and host cells, and the relationship between overall CAF changes in response to sunitinib and antitumor efficacy. This model distinguishes between the tumor cells' contributions from tumor-independent response to therapy and total plasma CAF correlating with antitumor activity. Altered VEGF is more likely to serve as a useful biomarker reflecting tumor responses in cancer patients whose pretreatment VEGF is higher than baseline VEGF in healthy subjects. Our findings provide a mechanistic insight into tumor modulation of angiogenic molecules, and may explain the inconsistent results found in previous biomarker studies. PMID- 25295575 TI - Predicting high-throughput screening results with scalable literature-based discovery methods. AB - The identification of new therapeutic uses for existing agents has been proposed as a means to mitigate the escalating cost of drug development. A common approach to such repurposing involves screening libraries of agents for activities against cell lines. In silico methods using knowledge from the biomedical literature have been proposed to constrain the costs of screening by identifying agents that are likely to be effective a priori. However, results obtained with these methods are seldom evaluated empirically. Conversely, screening experiments have been criticized for their inability to reveal the biological basis of their results. In this paper, we evaluate the ability of a scalable literature-based approach, discovery-by-analogy, to identify a small number of active agents within a large library screened for activity against prostate cancer cells. The methods used permit retrieval of the knowledge used to infer their predictions, providing a plausible biological basis for predicted activity. PMID- 25295576 TI - A heterozygous female with Fabry disease due to a novel alpha-galactosidase A mutation exhibits a unique synaptopodin distribution in vacuolated podocytes. AB - We report the case of a 42-yearold woman diagnosed with heterozygous Fabry disease (FD) due to a novel alpha-galactosidase A Pro210Ser mutation and exhibiting a unique distribution of synaptopodin within podocytes. The patient was referred to our hospital with moderate proteinuria, and a renal biopsy was performed. Light microscopic examination of the specimen revealed diffuse global enlargement of podocytes, which also showed foamy changes. Electron microscopy revealed abundant myeloid bodies in podocytes and focal mitochondrial abnormalities within the tubules. The patient exhibited none of the characteristic symptoms of FD except hypohidrosis and had no obvious family history. Genetic analysis revealed a novel missense mutation (Pro210Ser) in the alpha-galactosidase A gene. She was ultimately diagnosed with FD based on immunohistochemical staining indicating large amounts of accumulated globotriaosylceramide in her podocytes, detection of urinary globotriaosylceramide secretion using high-performance thin-layer chromatography/ immunostaining, and structural modeling of the mutated alpha-galactosidase A (Pro210Ser). Immunostaining of the swollen and foamy podocytes using podocyte associated antibodies (against podocalyxin, Wilms tumor-1, vimentin, and synaptopodin) revealed a unique distribution of synaptopodin surrounding globotriaosylceramide. To our knowledge, this is the first report of immunohistologically detected synaptopodin upregulation in foamy podocytes in a patient with FD. PMID- 25295577 TI - Acute kidney injury and hyperbilirubinemia in a young male after ingestion of Tribulus terrestris. AB - Acute tubular necrosis (ATN), especially from toxic injury is frequently accompanied by tubular casts and crystals. Myeloma casts, myoglobin, red blood cell and granular casts are well described. However, bile casts in tubules are rarely seen. We describe a case of Tribulus terrestris toxicity in a young healthy male, presenting with severe hyperbilirubinemia followed by acute renal failure and bile containing casts in the tubules. Tribulus terrestris is an herb often used by athletes as a nutritional supplement for performance enhancement. Although it is thought to be relatively safe, serious side effects have been reported before. Our aim is to increase awareness of the potential toxicities of performance enhancing herbal medications. These are often sold over-the-counter and therefore casually used, especially by young healthy individuals. Beneficial effects are controversial. Under-reporting by patients and infrequent documentation by health-care providers can delay diagnosis. We elaborately describe the kidney biopsy findings in Tribulus terrestris toxicity, and also provide a concise overview of the spectrum of tubular casts and their staining patterns, found in various kidney diseases. PMID- 25295578 TI - Effect of lanthanum carbonate versus calcium-based phosphate binders in dialysis patients: a meta-analysis. AB - BACKGROUND: The effects of lanthanum carbonate (LC) vs. calciumbased phosphate binders in dialysis patients have been a matter of debate. METHODS: We electronically searched PubMed, Embase, CENTRAL, and CBM for all randomized controlled trials comparing LC with calcium-based phosphate binders in adult dialysis patients. Quality assessment was performed using the Cochrane risk of bias tool. Metaanalysis was conducted by RevMan 5.2. RESULTS: Nine studies were eligible for our meta-analysis. There was no significant difference in all-cause mortality (RR 0.84, 95% CI 0.25 - 2.83) and cardiovascular events (RR 0.84, 95% CI 0.55 - 1.29) between LC and calcium-based phosphate binders. LC was associated with similar proportions of phosphate-controlled patients (RR 0.63, 95% CI 0.27 - 1.44) and lower incidence of hypercalcemia (RR 0.13, 95% CI 0.05 - 0.35) in comparison to calcium-based phosphate binders. Compared with calcium salts, LC was associated with significantly lower serum calcium, similar serum Ca x P product and higher serum iPTH. CONCLUSION: Despite the trends observed, we found no statistically significant differences in all-cause mortality and cardiovascular events between LC and calcium-based phosphate binders in dialysis patients. The conclusion was limited by lack of large sample and long-term trials. LC could reduce the incidence of hypercalcemia while comparable with calcium-based phosphate binders in reducing serum phosphorus level. PMID- 25295579 TI - Light chain crystalline kidney disease: diagnostic urine microscopy as the "liquid kidney biopsy". AB - Multiple myeloma (MM) is a plasma cell disorder, which often causes parenchymal kidney disease. Light chain (LC) cast nephropathy represents the most common renal lesion. In some instances, LC crystals precipitate within renal tubular lumens and deposit within proximal tubular cell cytoplasms. Importantly, urine microscopy in such patients can provide insight into the underlying LC-related lesion. Here we present two patients with MM complicated by acute kidney injury (AKI) where LC crystalline casts were observed on urinary sediment analysis. Kidney biopsy revealed acute tubular injury with LC crystal casts within both tubular lumens and renal tubular epithelial cell cytoplasms. These findings suggest that the urinary sediment may be a non-invasive way to diagnose LC crystalline-induced AKI in patients with MM. PMID- 25295580 TI - A novel laparoscopic ureterolithotomy with renal stone removal using a rigid nephroscope and ultrasonic lithotripter through a laparoscopic port in a patient with giant ureteral and renal stones. PMID- 25295581 TI - College of American Pathologists Guidelines for Reporting HER2 Test Results in Gastric Cancer. PMID- 25295582 TI - In reply. PMID- 25295585 TI - Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21(CDKN1A). AB - Endoplasmic reticulum (ER) stress occurs in poorly perfused tissues and activates the p53 isoform p53/47 to promote G2 arrest via 14-3-3sigma. This contrasts with the p21(CDKN1A)-dependent G1 arrest caused by p53 following DNA damage. It is not known how cells respond to conditions when both pathways are activated. Here we show that p53/47 prevents p53-induced p21 transcription during ER stress and that both isoforms repress p21 mRNA translation. This prevents p21 from promoting COP1 mediated 14-3-3sigma degradation and leads to G2 arrest. DNA damage does not result in p53-dependent induction of p21 during ER stress and instead results in an increase in p53-induced apoptosis. This illustrates how p53 isoforms target an intrinsic balance between the G1 and G2 checkpoints for cell cycle coordination and demonstrates an ER stress-dependent p53 pathway that suppresses p21 and lowers the apoptotic threshold to genotoxic drugs. PMID- 25295583 TI - Proteomic analysis of oral cavity squamous cell carcinoma specimens identifies patient outcome-associated proteins. AB - CONTEXT: Global proteomic analysis of oral cavity squamous cell carcinoma was performed to identify changes that reflect patient outcomes. OBJECTIVES: To identify differentially expressed proteins associated with patient outcomes and to explore the use of imaging mass spectrometry as a clinical tool to identify clinically relevant proteins. DESIGN: Two-dimensional separation of digested peptides generated from 43 specimens with high-resolution mass spectrometry identified proteins associated with disease-specific death, distant metastasis, and loco-regional recurrence. RNA expressions had been correlated to protein levels to test transcriptional regulation of clinically relevant proteins. Imaging mass spectrometry explored an alternative platform for assessing clinically relevant proteins that would complement surgical pathologic diagnosis. RESULTS: Seventy-two peptide features were found to be associated with 3 patient outcomes: disease-specific death (9), distant metastasis (16), and loco-regional recurrence (39); 8 of them were associated with multiple outcomes. Functional ontology revealed major changes in cell adhesion and calcium binding. Thirteen RNAs showed strong correlation with their encoded proteins, implying transcriptional control. Reduction of DSP, PKP1, and TRIM29 was associated with significantly shorter time to onset of distant metastasis. Reduction of PKP1 and TRIM29 correlated with poorer disease-specific survival. Additionally, S100A8 and S100A9 reductions were verified for their association with poor prognosis using imaging mass spectrometry, a platform more adaptable for use with surgical pathology. CONCLUSIONS: Using global proteomic analysis, we have identified proteins associated with clinical outcomes. The list of clinically relevant proteins observed will provide a means to develop clinical assays for prognosis and optimizing treatment selection. PMID- 25295586 TI - [The role of surgical treatment in the management of nonparasitic hepatic cysts in Madagascar]. AB - Non-parasitic liver cysts are rare in our country. We report the second case in a 61-year-old woman admitted for a painful epigastric mass. The diagnosis was suggested by ultrasound and confirmed by histological examination of the surgical specimen. Surgical treatment was performed through a right transverse subcostal incision and consisted of a maximal resection of the cystic wall. No complications followed. After 12 months, the patient was asymptomatic, and no recurrence had been observed. PMID- 25295587 TI - Ixeridium calcicola (Compositae), a new limestone endemic from Taiwan, with notes on its atypical basic chromosome number, phylogenetic affinities, and a limestone refugium hypothesis. AB - A new species Ixeridium calcicola (Compositae) endemic to middle altitude (ca 1,000-2,000 m asl) limestone mountains of eastcentral Taiwan is described based on morphological and chromosome cytological observations and molecular phylogenetic analyses. Ixeridium calcicola resembles Ixeridium transnokoense, endemic to upper montane and alpine ranges (2,600-3,500 m asl) of Taiwan, in the dwarf habit, but differs in the oblong to lanceolate leaf blades (vs. linear to linear-lanceolate), the presence of mucronulate teeth on the leaf margin and petiole (vs. smooth to very sparse), the dark purple lower leaf surface (vs. greenish), the capitulum with 10 to 12 florets (vs. 5 to 7) and 8 to 10 inner phyllaries (vs. 5, rarely to 7). The basic chromosome number in Ixeridium was known as X = 7. However, the new species has a basic chromosome number of X = 8, as recorded also in the closely related Ixeris. Molecular phylogenetic analyses with the expanded sampling of Ixeridium and Ixeris including both type species supported the monophyly of each of the genera and the placement of the new species in Ixeridium. The result of the phylogenetic analyses and detailed observation of the chromosome morphology revealed that X = 8 in Ixeridium calcicola is derived from centric fission in an ancestral karyomorphotype with X = 7 in Ixeridium. Ixeridium calcicola and Ixeridium transnokoense formed a Taiwan endemic lineage and their estimated divergence time was in the middle Pleistocene. Their common ancestral lineage may have experienced altitudinal distribution shifts in response to glacial-interglacial temperature fluctuation, and a lineage which had not retreated to alpine ranges in an interglacial period likely survived in a limestone refugium, where ordinary plant species did not grow, leading to allopatric speciation. PMID- 25295588 TI - Biosynthesis of Taxadiene in Saccharomyces cerevisiae : selection of geranylgeranyl diphosphate synthase directed by a computer-aided docking strategy. AB - Identification of efficient key enzymes in biosynthesis pathway and optimization of the fitness between functional modules and chassis are important for improving the production of target compounds. In this study, the taxadiene biosynthesis pathway was firstly constructed in yeast by transforming ts gene and overexpressing erg20 and thmgr. Then, the catalytic capabilities of six different geranylgeranyl diphosphate synthases (GGPPS), the key enzyme in mevalonic acid (MVA) pathway catalyzing famesyl diphosphate (FPP) to geranylgeranyl diphosphate (GGPP), were predicted using enzyme-substrate docking strategy. GGPPSs from Taxus baccata x Taxus cuspidate (GGPPSbc), Erwinia herbicola (GGPPSeh), and S. cerevisiae (GGPPSsc) which ranked 1st, 4th and 6th in docking with FPP were selected for construction. The experimental results were consistent with the computer prediction that the engineered yeast with GGPPSbc exhibited the highest production. In addition, two chassis YSG50 and W303-1A were chosen, and the titer of taxadiene reached 72.8 mg/L in chassis YSG50 with GGPPSbc. Metabolomic study revealed that the contents of tricarboxylic acid cycle (TCA) intermediates and their precursor amino acids in chassis YSG50 was lower than those in W303-1A, indicating less carbon flux was divided into TCA cycle. Furthermore, the levels of TCA intermediates in the taxadiene producing yeasts were lower than those in chassis YSG50. Thus, it may result in more carbon flux in MVA pathway in chassis YSG50, which suggested that YSG50 was more suitable for engineering the taxadiene producing yeast. These results indicated that computer-aided protein modeling directed isoenzyme selection strategy and metabolomic study could guide the rational design of terpenes biosynthetic cells. PMID- 25295589 TI - Postural instability detection: aging and the complexity of spatial-temporal distributional patterns for virtually contacting the stability boundary in human stance. AB - Falls among the older population can severely restrict their functional mobility and even cause death. Therefore, it is crucial to understand the mechanisms and conditions that cause falls, for which it is important to develop a predictive model of falls. One critical quantity for postural instability detection and prediction is the instantaneous stability of quiet upright stance based on motion data. However, well-established measures in the field of motor control that quantify overall postural stability using center-of-pressure (COP) or center-of mass (COM) fluctuations are inadequate predictors of instantaneous stability. For this reason, 2D COP/COM virtual-time-to-contact (VTC) is investigated to detect the postural stability deficits of healthy older people compared to young adults. VTC predicts the temporal safety margin to the functional stability boundary ( = limits of the region of feasible COP or COM displacement) and, therefore, provides an index of the risk of losing postural stability. The spatial directions with increased instability were also determined using quantities of VTC that have not previously been considered. Further, Lempel-Ziv-Complexity (LZC), a measure suitable for on-line monitoring of stability/instability, was applied to explore the temporal structure or complexity of VTC and the predictability of future postural instability based on previous behavior. These features were examined as a function of age, vision and different load weighting on the legs. The primary findings showed that for old adults the stability boundary was contracted and VTC reduced. Furthermore, the complexity decreased with aging and the direction with highest postural instability also changed in aging compared to the young adults. The findings reveal the sensitivity of the time dependent properties of 2D VTC to the detection of postural instability in aging, availability of visual information and postural stance and potential applicability as a predictive model of postural instability during upright stance. PMID- 25295590 TI - The distribution of high-risk human papillomaviruses is different in young and old patients with cervical cancer. AB - Despite numerous human papillomavirus (HPV) frequency studies in women with cervical cancer (CC), little is known of HPV frequency trends according to patient age. In this work, we compare the mean age and frequency distribution by age of CC patients positive for different HPVs. This study included 462 CC patients. HPVs were detected by PCR and typed using DNA sequencing. A total of 456 patients (98.7%) were positive for HPV: 418 (90.5%) had single and 38 (8.2%) had double HPV infections. HPV16 (46.5%), HPV18 (10.4%), HPV45 (6.7%), and HPV31 (4.1%) were the most frequent viral types in single-infected patients. The mean ages of single-infected patients with HPV16 (49.2+/-13.3), HPV18 (47.9+/-12.2), HPV45 (47.9+/-11.7), or HPV39 (42.6+/-8.9) were significantly lower than the mean ages of patients singly (53.9+/-12.7; p<0.001, t-test) or doubly (55.4+/-12.7; p<0.05, t-test) infected with the remaining HPVs. Three different trends were identified: one for HPV16, another for HPVs18/45/39, and a third for the rest of HPVs. The frequency trend of HPV16 shows two peaks. The first (63.2%) was found in the youngest women (<=35 years), followed by a decreasing trend until the age of 55-60 years (31.1%). The second peak arose at 61-65 years (52.5%), followed by a decreasing trend. The trend for HPVs18/45/39 declined from the youngest (19.3%) to the oldest (>70 years; 12.8%) women. In contrast, the trend for the remaining HPVs increased from the youngest (15.8%) to the oldest (46.2%) women. Unlike other life-style factors, low-risk sexual behavior was associated with late onset of CC independent of low-oncogenic HPV types (p<0.05, Wald chi-square statistic). The data indicate that most CCs in young women depend on the presence of high oncogenic HPVs. In contrast, almost half of CCs in older patients had low oncogenic HPVs, suggesting they could depend on the presence of other factors. PMID- 25295591 TI - Role of IL-4 gene polymorphisms in HBV-related hepatocellular carcinoma in a Chinese population. AB - BACKGROUND: Interleukin-4 (IL-4) is best known as an important mediator and modulator of immune and inflammatory responses. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer, and genetic variations in the IL-4 gene may be associated with the risk of hepatitis B virus (HBV)-related HCC. However, few studies have been conducted on their association. OBJECTIVES: To clarify the effects of IL-4 gene polymorphisms on the risk of HBV-related HCC, two common variants, -590C/T (rs2243250) and -33C/T (rs2070874), and their relationship with HBV-related disease risk were investigated in a Chinese population. METHODS: IL-4 -590C/T and -33C/T polymorphisms were examined in 154 patients with HBV-related HCC, 62 patients with HBV-induced liver cirrhosis (LC), 129 patients with chronic hepatitis B (CHB), and 94 healthy controls, using the polymerase chain reaction restriction fragment length polymorphism method and DNA sequencing. RESULTS: Overall, no significant differences were observed regarding the IL-4 -590C/T and 33C/T polymorphism genotypes, alleles, or haplotypes between the patient groups and the healthy controls. However, the CC genotypes of IL-4 -590C/T and -33C/T polymorphisms were observed to be significantly associated with CHB in subgroup analysis in males [CC versus TT (OR: 4.193, 95% CI: 1.094-16.071, P = 0.037; and OR: 3.438, 95% CI: 1.032-11.458, P = 0.044) and CC versus TT+CT (OR: 4.09, 95% CI: 1.08-15.49, P = 0.038; and OR: 3.43, 95% CI: 1.04-11.28, P = 0.042)]. CONCLUSIONS: These findings suggest that genetic variants in IL-4 -590C/T and 33C/T polymorphisms may be a risk factor for CHB in Chinese males but not for HBV related LC or HCC. PMID- 25295592 TI - Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl) phthalate in male Long Evans rats. AB - Early developmental exposure to di(2-ethylhexyl) phthalate (DEHP) has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats. PMID- 25295593 TI - Adjacent habitat influence on stink bug (Hemiptera: Pentatomidae) densities and the associated damage at field corn and soybean edges. AB - The local dispersal of polyphagous, mobile insects within agricultural systems impacts pest management. In the mid-Atlantic region of the United States, stink bugs, especially the invasive Halyomorpha halys (Stal 1855), contribute to economic losses across a range of cropping systems. Here, we characterized the density of stink bugs along the field edges of field corn and soybean at different study sites. Specifically, we examined the influence of adjacent managed and natural habitats on the density of stink bugs in corn and soybean fields at different distances along transects from the field edge. We also quantified damage to corn grain, and to soybean pods and seeds, and measured yield in relation to the observed stink bug densities at different distances from field edge. Highest density of stink bugs was limited to the edge of both corn and soybean fields. Fields adjacent to wooded, crop and building habitats harbored higher densities of stink bugs than those adjacent to open habitats. Damage to corn kernels and to soybean pods and seeds increased with stink bug density in plots and was highest at the field edges. Stink bug density was also negatively associated with yield per plant in soybean. The spatial pattern of stink bugs in both corn and soybeans, with significant edge effects, suggests the use of pest management strategies for crop placement in the landscape, as well as spatially targeted pest suppression within fields. PMID- 25295594 TI - The effect of visual apparent motion on audiovisual simultaneity. AB - Visual motion information from dynamic environments is important in multisensory temporal perception. However, it is unclear how visual motion information influences the integration of multisensory temporal perceptions. We investigated whether visual apparent motion affects audiovisual temporal perception. Visual apparent motion is a phenomenon in which two flashes presented in sequence in different positions are perceived as continuous motion. Across three experiments, participants performed temporal order judgment (TOJ) tasks. Experiment 1 was a TOJ task conducted in order to assess audiovisual simultaneity during perception of apparent motion. The results showed that the point of subjective simultaneity (PSS) was shifted toward a sound-lead stimulus, and the just noticeable difference (JND) was reduced compared with a normal TOJ task with a single flash. This indicates that visual apparent motion affects audiovisual simultaneity and improves temporal discrimination in audiovisual processing. Experiment 2 was a TOJ task conducted in order to remove the influence of the amount of flash stimulation from Experiment 1. The PSS and JND during perception of apparent motion were almost identical to those in Experiment 1, but differed from those for successive perception when long temporal intervals were included between two flashes without motion. This showed that the result obtained under the apparent motion condition was unaffected by the amount of flash stimulation. Because apparent motion was produced by a constant interval between two flashes, the results may be accounted for by specific prediction. In Experiment 3, we eliminated the influence of prediction by randomizing the intervals between the two flashes. However, the PSS and JND did not differ from those in Experiment 1. It became clear that the results obtained for the perception of visual apparent motion were not attributable to prediction. Our findings suggest that visual apparent motion changes temporal simultaneity perception and improves temporal discrimination in audiovisual processing. PMID- 25295595 TI - Alcohol consumption among Arabs in Israel: a qualitative study. AB - BACKGROUND: The Israeli society is a unique setting in which the Arabs are exposed to western alcohol consumption norms while living in Arab communities where alcohol consumption is not accepted. OBJECTIVES: To characterize Arab Muslim, Druze and Christian alcohol consumption behaviors and contingencies while being exposed to western style alcohol consumption. METHODS: This study was a phenomenological qualitative study interviewing six focus groups and 13 individual Arab Muslims, Christians and Druze. Themes and categories were identified using qualitative methodology analysis. RESULTS: Two concurrent contingencies exist for Arab Muslim men: on the one hand they describe pressure to drink because of social norms, and on the other hand they are reprehended for drinking, because of the religious interdiction. Therefore, they hide their drinking in secluded places. In addition, participants reported more heavy drinking among Muslim Men. Arab Christians reported drinking openly especially among men. Women do not drink and are looked down upon if they drink. Drinking may be viewed as a stage in life that a Muslim boy or young man goes through, he is expected to grow out of this stage and stop drinking while becoming religious. Conclusions/importance: Due to Muslim laws prohibiting alcohol consumption, alcohol consumption is not high, however it does exist especially among young men and when they drink they tend to drink heavily, more than the Arab Christians. Therefore, there is a need for interventions targeting younger Muslim men, to establish moderate drinking behaviors, if they chose to drink. PMID- 25295596 TI - Nonmedical prescription drug use (NMPDU) in the Swedish general population- correlates of analgesic and sedative use. AB - BACKGROUND: Nonmedical prescription drug use (NMPDU) is a growing problem in many countries. OBJECTIVES: The aim of the present study was to report correlates of and compare different subtypes of NMPDU in the Swedish general population. METHODS: Data were drawn from a Swedish national household survey conducted in 2008-2009. A stratified sample of 58,000 individuals aged 15 to 64 was randomly selected, with a response rate of 38.3%. Hierarchical logistic regression analysis was used to compare sociodemographic, substance use, and health correlates of nonmedical analgesic use, nonmedical sedative use, and combined nonmedical use of these two types of prescription drugs. RESULTS: In the final logistic regression model, all three patterns of NMPDU were equally associated with female gender, hazardous alcohol use, habitual smoking and cannabis use, but there were several significant differences in other demographic, health, and drug use correlates between the groups. CONCLUSIONS/IMPORTANCE: Nonmedical use of prescription analgesics, prescription sedatives and combined nonmedical use of these drugs might constitute clinically distinct subgroups of NMPDU. This study is one of few to report correlates of NMPDU from a large, national household survey in a country other than the United States. PMID- 25295597 TI - Parental rules, parent and peer attachment, and adolescent drinking behaviors. AB - Family factors have been widely implicated in the development of adolescent drinking behaviors. These include parental attachment and parental rules concerning drinking behaviors. Moreover, throughout adolescence attachment to parents gives way to attachment to peers, and parental rules about alcohol use become less strict. The present study examined the relationship between parental and peer attachment, parental rules on drinking and alcohol use in a large sample (n = 1,724) of adolescents in the United Kingdom. Controlling for school grade (proxy for age), sex and the non-independence of respondents (clustering at school level) results showed that scores on a parental rules on drinking questionnaire were a significant statistical predictor when comparing moderate drinkers and abstainers, as well as moderate drinkers and problematic drinkers. Scores on both attachment scales were also significant, but only in the comparison between moderate and problematic drinkers, with lower attachment to parents and higher attachment to peers associated with problematic drinking. PMID- 25295598 TI - Pretreatment assessment-related reductions in drinking among women with alcohol use disorders. AB - BACKGROUND: Preliminary studies have suggested that patients entering research trials for alcohol use disorders (AUDs) may show substantial reductions in drinking prior to beginning treatment. OBJECTIVES: Determine whether significant pretreatment reductions in drinking are present in a sample of alcohol-dependent women entering a psychotherapy trial for AUDs, and whether such pretreatment drinking reductions predict lower levels of drinking during and posttreatment. METHOD: The study included 136 women with DSM-IV alcohol dependence who participated in a trial of individual or couples-based cognitive behavioral therapy for AUDs. Repeated-measures ANOVAs were used to examine changes in drinking across the pretreatment assessment period, and hierarchical multiple regression was used to test whether pretreatment reductions in drinking predicted continued reduced drinking during treatment and follow-up at 12 months posttreatment. RESULTS: Patients had significant reductions in drinking quantity and frequency throughout the pretreatment period, with one-third of the sample becoming abstinent prior to treatment. Controlling for baseline quantity and frequency of drinking, reductions in pretreatment drinking were predictive of reduced frequency of drinking within- and posttreatment, and lower quantity of drinking per drinking occasion in the within-treatment period but not the posttreatment period. Motivational level and treatment arm did not predict the level of change in drinking across the pretreatment period. CONCLUSIONS: The overall reductions in drinking are consistent with previous findings suggesting that female participants in AUD treatment trials can show a substantial amount of reduction in drinking during the pretreatment assessment phase, before therapy skills are imparted. PMID- 25295600 TI - Development of a likelihood of survival scoring system for hospitalized equine neonates using generalized boosted regression modeling. AB - BACKGROUND: Medical management of critically ill equine neonates (foals) can be expensive and labor intensive. Predicting the odds of foal survival using clinical information could facilitate the decision-making process for owners and clinicians. Numerous prognostic indicators and mathematical models to predict outcome in foals have been published; however, a validated scoring method to predict survival in sick foals has not been reported. The goal of this study was to develop and validate a scoring system that can be used by clinicians to predict likelihood of survival of equine neonates based on clinical data obtained on admission. METHODS AND RESULTS: Data from 339 hospitalized foals of less than four days of age admitted to three equine hospitals were included to develop the model. Thirty seven variables including historical information, physical examination and laboratory findings were analyzed by generalized boosted regression modeling (GBM) to determine which ones would be included in the survival score. Of these, six variables were retained in the final model. The weight for each variable was calculated using a generalized linear model and the probability of survival for each total score was determined. The highest (7) and the lowest (0) scores represented 97% and 3% probability of survival, respectively. Accuracy of this survival score was validated in a prospective study on data from 283 hospitalized foals from the same three hospitals. Sensitivity, specificity, positive and negative predictive values for the survival score in the prospective population were 96%, 71%, 91%, and 85%, respectively. CONCLUSIONS: The survival score developed in our study was validated in a large number of foals with a wide range of diseases and can be easily implemented using data available in most equine hospitals. GBM was a useful tool to develop the survival score. Further evaluations of this scoring system in field conditions are needed. PMID- 25295602 TI - Basic cancer research: why it is essential for the future of cancer therapy. AB - The last decade has witnessed significant progress in cancer understanding and therapy: we can now identify the genetic drivers of individual tumours, and tailor drugs able to specifically intercept the driver mutations. While all agree that personalized cancer medicine is a clear outcome of the resources dedicated to cancer research over the last 50 years, some critics question the necessity for continuous investments in sub-fields other than clinical research and drug development. Herein, scientists from the European Association for Cancer Research (EACR) argue that the new ways to diagnose and treat cancer present important and hitherto unaddressed challenges for fundamental research of cancer. Allocating the resources needed for basic studies will likely fuel the next wave of achievements in the long way to conquer cancer. PMID- 25295599 TI - Soluble heparan sulfate fragments generated by heparanase trigger the release of pro-inflammatory cytokines through TLR-4. AB - Heparanase is a beta-D-endoglucuronidase that cleaves heparan sulfate (HS), facilitating degradation of the extracellular matrix (ECM) and the release of HS bound biomolecules including cytokines. The remodeling of the ECM by heparanase is important for various physiological and pathological processes, including inflammation, wound healing, tumour angiogenesis and metastasis. Although heparanase has been proposed to facilitate leukocyte migration through degradation of the ECM, its role in inflammation by regulating the expression and release of cytokines has not been fully defined. In this study, the role of heparanase in regulating the expression and release of cytokines from human and murine immune cells was examined. Human peripheral blood mononuclear cells treated ex vivo with heparanase resulted in the release of a range of pro inflammatory cytokines including IL-1beta, IL-6, IL-8, IL-10 and TNF. In addition, mouse splenocytes treated ex vivo with heparanase resulted in the release of IL-6, MCP-1 and TNF. A similar pattern of cytokine release was also observed when cells were treated with soluble HS. Furthermore, heparanase-induced cytokine release was abolished by enzymatic-inhibitors of heparanase, suggesting this process is mediated via the enzymatic release of cell surface HS fragments. As soluble HS can signal through the Toll-like receptor (TLR) pathway, heparanase may promote the upregulation of cytokines through the generation of heparanase cleaved fragments of HS. In support of this hypothesis, mouse spleen cells lacking the key TLR adaptor molecule MyD88 demonstrated an abolition of cytokine release after heparanase stimulation. Furthermore, TLR4-deficient spleen cells showed reduced cytokine release in response to heparanase treatment, suggesting that TLR4 is involved in this response. Consistent with these observations, the pathway involved in cytokine upregulation was identified as being NF-kappaB dependent. These data identify a new mechanism for heparanase in promoting the release of pro-inflammatory cytokines that is likely to be important in regulating cell migration and inflammation. PMID- 25295603 TI - John Hatch on community organizing in the Mississippi Delta, 1965. PMID- 25295604 TI - The community part in health center program. PMID- 25295601 TI - Body mass index: accounting for full time sedentary occupation and 24-hr self reported time use. AB - OBJECTIVES: We used linked existing data from the 2006-2008 American Time Use Survey (ATUS), the Current Population Survey (CPS, a federal survey that provides on-going U.S. vital statistics, including employment rates) and self-reported body mass index (BMI) to answer: How does BMI vary across full time occupations dichotomized as sedentary/non-sedentary, accounting for time spent in sleep, other sedentary behaviors, and light, moderate, and vigorous intensity activities? METHODS: We classified time spent engaged at a primary job (sedentary or non-sedentary), sleep, and other non-work, non-sleep intensity-defined behaviors, specifically, sedentary behavior, light, moderate, and vigorous intensity activities. Age groups were defined by 20-29, 30-39, 40-49, and 50-64 years. BMI groups were defined by 18.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9, and >=35.0 kg/m2. Logistic and linear regression were used to examine the association between BMI and employment in a sedentary occupation, considering time spent in sleep, other non-work time spent in sedentary behaviors, and light, moderate, and vigorous intensity activities, sex, age race/ethnicity, and household income. RESULTS: The analysis data set comprised 4,092 non-pregnant, non-underweight individuals 20-64 years of age who also reported working more than 7 hours at their primary jobs on their designated time use reporting day. Logistic and linear regression analyses failed to reveal any associations between BMI and the sedentary/non-sedentary occupation dichotomy considering time spent in sleep, other non-work time spent in sedentary behaviors, and light, moderate, and vigorous intensity activities, sex, age, race/ethnicity, and household income. CONCLUSIONS: We found no evidence of a relationship between self-reported full time sedentary occupation classification and BMI after accounting for sex, age, race/ethnicity, and household income and 24-hours of time use including non-work related physical activity and sedentary behaviors. The various sources of error associated with self-report methods and assignment of generalized activity and occupational intensity categories could compound to obscure any real relationships. PMID- 25295605 TI - Eliminating racial and ethnic disparities in health, SAAPHI action plan. PMID- 25295608 TI - Integrating knowledge for public health action. PMID- 25295606 TI - The Society for the Analysis of African-American Public Health Issues (SAAPHI). PMID- 25295609 TI - Outbreaks of acute gastroenteritis transmitted by person-to-person contact- United States, 2009-2010. PMID- 25295612 TI - Precise Implant Placement With a Computer-Assisted Surgical Guide in Cleft Lip and Palate Patients. AB - It is very common for cleft lip and palate patients to have congenitally missing teeth. Insufficient buccopalatal bone volume, a shallow vestibule, and lack of soft tissue resulting from previous surgical scarring render it difficult for clinicians to place implants in the missing area. This report describes guide surgery that represents a treatment option for cases in which implants need to be placed in tight spaces with minimal bone space, to minimize as far as possible manual placement errors. PMID- 25295610 TI - Phosphodiesterase 8a supports HIV-1 replication in macrophages at the level of reverse transcription. AB - BACKGROUND: HIV-1 infected macrophages play a key role in HIV-1 infection. Even during anti-retroviral treatment, macrophages keep producing virus due to suboptimal tissue penetration and reduced efficacy of antiretrovirals. It is therefore of major importance to understand which host factors are involved in HIV-1 replication in macrophages. Previously, we have shown that genetic polymorphisms in phosphodiesterase 8a (PDE8A) are strongly associated with HIV-1 replication in these cells. Here we analyzed the mechanism and regulation of PDE8A in HIV-1 replication in macrophages. RESULTS: PDE8A mRNA expression strongly increases upon differentiation of monocytes into macrophages, which corresponds to the increased susceptibility of mature macrophages to HIV-1. In parallel, expression of microRNA miR-145-5p, predicted to target PDE8A mRNA, strongly decreased. The interaction of miR-145-5p with the 3' UTR of PDE8A mRNA could be experimentally validated, suggesting that indeed miR-145-5p can regulate PDE8A expression levels. Knockdown of PDE8A in macrophages resulted in a decrease in total HIV-1 replication and proviral DNA levels. These observations confirm that PDE8A regulates HIV-1 replication in macrophages and that this effect is mediated through early steps in the viral replication cycle. CONCLUSIONS: PDE8A is highly expressed in macrophages, and its expression is regulated by miR-145 5p. Our findings strongly suggest that PDE8A supports HIV-1 replication in macrophages and that this effect is mediated at the level of reverse transcription. PMID- 25295611 TI - Involvement of tumor macrophage HIFs in chemotherapy effectiveness: mathematical modeling of oxygen, pH, and glutathione. AB - The four variables, hypoxia, acidity, high glutathione (GSH) concentration and fast reducing rate (redox) are distinct and varied characteristics of solid tumors compared to normal tissue. These parameters are among the most significant factors underlying the metabolism and physiology of solid tumors, regardless of their type or origin. Low oxygen tension contributes to both inhibition of cancer cell proliferation and therapeutic resistance of tumors; low extracellular pH, the reverse of normal cells, mainly enhances tumor invasion; and dysregulated GSH and redox potential within cancer cells favor their proliferation. In fact, cancer cells under these microenvironmental conditions appreciably alter tumor response to cytotoxic anti-cancer treatments. Recent experiments measured the in vivo longitudinal data of these four parameters with tumor development and the corresponding presence and absence of tumor macrophage HIF-1alpha or HIF-2alpha in a mouse model of breast cancer. In the current paper, we present a mathematical model-based system of (ordinary and partial) differential equations to monitor tumor growth and susceptibility to standard chemotherapy with oxygen level, pH, and intracellular GSH concentration. We first show that our model simulations agree with the corresponding experiments, and then we use our model to suggest treatments of tumors by altering these four parameters in tumor microenvironment. For example, the model qualitatively predicts that GSH depletion can raise the level of reactive oxygen species (ROS) above a toxic threshold and result in inhibition of tumor growth. PMID- 25295613 TI - Sentinel hospital-based surveillance for assessment of burden of rotavirus gastroenteritis in children in Pakistan. AB - OBJECTIVES: To determine the burden and molecular epidemiology of rotavirus gastroenteritis in children hospitalized with severe acute watery diarrhea in Pakistan prior to introduction of rotavirus vaccine. METHODS: A cross-sectional study was carried out over a period of two years from 2006 - 2008 at five sentinel hospitals in the cities of Karachi, Lahore, Rawalpindi, and Peshawar. Stool samples collected from children under five years of age hospitalized with severe acute watery diarrhea were tested for rotavirus antigen via enzyme immunoassay (EIA) (IDEA REF K6020 Oxoid Ltd (Ely), Cambridge, United Kingdom). A subset of EIA positive stool samples were further processed for genotyping. RESULTS: 6679 children were enrolled and stool specimens of 2039 (30.5%) were positive for rotavirus. Rotavirus positivity ranged from 16.3% to 39.4% in the 5 hospitals with highest positivity in Lahore. 1241 (61%) of all rotavirus cases were in infants under one year of age. Among the strains examined for G serotypes, the occurrence of G1, G2, G9 and G4 strains was found to be 28%, 24%, 14% and 13%, respectively. Among P-types, the most commonly occurring strains were P6 (31.5%) followed by P8 (20%) and P4 (12%). Prevalent rotavirus genotype in hospitalized children of severe diarrhea were G1P[8] 11.6% (69/593), followed by G2P[4] 10.4% (62/593), and G4P[6] 10.1% (60/593). CONCLUSIONS: Approximately one third of children hospitalized with severe gastroenteritis in urban centers in Pakistan have rotavirus. Introduction of rotavirus vaccine in Pakistan's national immunization program could prevent many severe episodes and diarrheal deaths. PMID- 25295614 TI - Association of Toll-like receptor 10 polymorphisms with autoimmune thyroid disease in Korean children. AB - BACKGROUND: The Toll-like receptors (TLRs) are germline-encoded receptors that play an essential role in initiating the immune response against pathogens. In this study, we assess the association of TLR polymorphism with autoimmune thyroid disease (AITD) in Korean children. METHODS: We investigated three polymorphisms in the TLR10 gene (rs4129009, rs11096956, and rs10004195) in 85 Korean AITD patients (Graves' disease, [GD]=50, Hashimoto's disease [HD]=35; thyroid associated ophthalmopathy [TAO]=23, non-TAO=62; male=16, female=69; mean age=13.4+/-3.1 years) and 279 healthy control subjects. RESULTS: In patients with AITD, the frequencies of the TLR10 rs4129009 A allele (odds raio [OR]=3.9, corrected p=0.04) and rs10004195 T allele (OR=2.8, corrected p=0.02) were higher than in the healthy controls, whereas the TLR10 rs4129009 GG genotype (OR=0.3, corrected p=0.04) and rs10004195 AA genotype (OR=0.4, corrected p=0.02) showed lower frequencies. The TLR10 rs11096956 did not show any significant association. These significant associations were also found in the non-thyroid-associated ophthalmopathy (TAO) group, but not in the TAO group. The haplotype (AGT) frequency of TLR10 rs4129009, rs11096956, and rs10004195 was higher in the AITD group than in healthy controls (OR=2.1, corrected p=0.03). CONCLUSIONS: Our results suggest that TLR10 polymorphisms may contribute to the pathogenesis of AITD. PMID- 25295615 TI - An assessment of the efficiency of methods for measurement of the computed tomography dose index (CTDI) for cone beam (CBCT) dosimetry by Monte Carlo simulation. AB - The IEC has introduced a practical approach to overcome shortcomings of the CTDI100 for measurements on wide beams employed for cone beam (CBCT) scans. This study evaluated the efficiency of this approach (CTDIIEC) for different arrangements using Monte Carlo simulation techniques, and compared CTDIIEC to the efficiency of CTDI100 for CBCT. Monte Carlo EGSnrc/BEAMnrc and EGSnrc/DOSXYZnrc codes were used to simulate the kV imaging system mounted on a Varian TrueBeam linear accelerator. The Monte Carlo model was benchmarked against experimental measurements and good agreement shown. Standard PMMA head and body phantoms with lengths 150, 600, and 900 mm were simulated. Beam widths studied ranged from 20 300 mm, and four scanning protocols using two acquisition modes were utilized. The efficiency values were calculated at the centre (epsilonc) and periphery (epsilonp) of the phantoms and for the weighted CTDI (epsilonw). The efficiency values for CTDI100 were approximately constant for beam widths 20-40 mm, where epsilonc(CTDI100), epsilonp(CTDI100), and epsilonw(CTDI100) were 74.7 +/- 0.6%, 84.6 +/- 0.3%, and 80.9 +/- 0.4%, for the head phantom and 59.7 +/- 0.3%, 82.1 +/- 0.3%, and 74.9 +/- 0.3%, for the body phantom, respectively. When beam width increased beyond 40 mm, epsilon(CTDI100) values fell steadily reaching ~30% at a beam width of 300 mm. In contrast, the efficiency of the CTDIIEC was approximately constant over all beam widths, demonstrating its suitability for assessment of CBCT. epsilonc(CTDIIEC), epsilonp(CTDIIEC), and epsilonw(CTDIIEC) were 76.1 +/- 0.9%, 85.9 +/- 1.0%, and 82.2 +/- 0.9% for the head phantom and 60.6 +/- 0.7%, 82.8 +/- 0.8%, and 75.8 +/- 0.7%, for the body phantom, respectively, within 2% of epsilon(CTDI100) values for narrower beam widths. CTDI100,w and CTDIIEC,w underestimate CTDIinfinity,w by ~55% and ~18% for the head phantom and by ~56% and ~24% for the body phantom, respectively, using a clinical beam width 198 mm. The CTDIIEC approach addresses the dependency of efficiency on beam width successfully and correction factors have been derived to allow calculation of CTDIinfinity. PMID- 25295616 TI - Bioelectrochemical denitrification using carbon felt/multiwall carbon nanotube. AB - The aim of this work was to enhance the efficiency of a bioelectrochemical denitrification process using a biocathode of carbon felt (CF)/multiwall carbon nanotube (MWCNT) composite. The efficiency of the bioelectrochemical denitrification was assessed as the function of various operational parameters, such as ORP, pH, current density, retention time and nitrate concentrations. Scanning electron microscope (SEM) images of the biocathode surfaces revealed a homogeneous distribution of the MWCNT on the CF matrix. Optimum ORP, pH, current density and retention time were -100 mV, 7.0, 15 mA/cm2 and 6 h, respectively. The highest nitrate removal efficiency at the optimum condition was 92.7% for CF/MWCNT. The reduction time for achieving the nitrate standard using CF/MWCNT was 4 h. It is proposed that the prepared nanocomposite will have the best biocathode properties in the bioelectrochemistry denitrification experiments. PMID- 25295617 TI - Two new phenol derivatives from Stereum hirsutum FP-91666. AB - Two new phenol derivatives, 2-(3-methyl-2-buten-1-yl)-4-methoxyethyl-phenol (1) and 5-hydroxy-4-(hydroxymethyl)-2-(3-methylbut-2-en-1-yl)cyclohex-4-en-1-one (2), together with eight known compounds consisting of phenol derivatives (3 and 4), niacinamide (5), and five ergosta type compounds (6-10), were isolated from solid fermentation products of Stereum hirsutum FP-91666. Two new structures were elucidated by extensive spectroscopic methods, including 1D NMR and 2D NMR, and HR-EI-MS experiments. PMID- 25295618 TI - ICln: a new regulator of non-erythroid 4.1R localisation and function. AB - To optimise the efficiency of cell machinery, cells can use the same protein (often called a hub protein) to participate in different cell functions by simply changing its target molecules. There are large data sets describing protein protein interactions ("interactome") but they frequently fail to consider the functional significance of the interactions themselves. We studied the interaction between two potential hub proteins, ICln and 4.1R (in the form of its two splicing variants 4.1R80 and 4.1R135), which are involved in such crucial cell functions as proliferation, RNA processing, cytoskeleton organisation and volume regulation. The sub-cellular localisation and role of native and chimeric 4.1R over-expressed proteins in human embryonic kidney (HEK) 293 cells were examined. ICln interacts with both 4.1R80 and 4.1R135 and its over-expression displaces 4.1R from the membrane regions, thus affecting 4.1R interaction with beta-actin. It was found that 4.1R80 and 4.1R135 are differently involved in regulating the swelling activated anion current (ICl,swell) upon hypotonic shock, a condition under which both isoforms are dislocated from the membrane region and thus contribute to ICl,swell current regulation. Both 4.1R isoforms are also differently involved in regulating cell morphology, and ICln counteracts their effects. The findings of this study confirm that 4.1R plays a role in cell volume regulation and cell morphology and indicate that ICln is a new negative regulator of 4.1R functions. PMID- 25295620 TI - Body mass index and all-cause mortality in a large prospective cohort of white and black U.S. Adults. AB - Remaining controversies on the association between body mass index (BMI) and mortality include the effects of smoking and prevalent disease on the association, whether overweight is associated with higher mortality rates, differences in associations by race and the optimal age at which BMI predicts mortality. To assess the relative risk (RR) of mortality by BMI in Whites and Blacks among subgroups defined by smoking, prevalent disease, and age, 891,572 White and 38,119 Black men and women provided height, weight and other information when enrolled in the Cancer Prevention Study II in 1982. Over 28 years of follow-up, there were 434,400 deaths in Whites and 18,702 deaths in Blacks. Cox proportional-hazards regression was used to estimate multivariable adjusted relative risks (RR) and 95% confidence intervals (CI). Smoking and prevalent disease status significantly modified the BMI-mortality relationship in Whites and Blacks; higher BMI was most strongly associated with higher risk of mortality among never smokers without prevalent disease. All levels of overweight and obesity were associated with a statistically significantly higher risk of mortality compared to the reference category (BMI 22.5-24.9 kg/m2), except among Black women where risk was elevated but not statistically significant in the lower end of overweight. Although absolute mortality rates were higher in Blacks than Whites within each BMI category, relative risks (RRs) were similar between race groups for both men and women (p-heterogeneity by race = 0.20 for men and 0.23 for women). BMI was most strongly associated with mortality when reported before age 70 years. Results from this study demonstrate for the first time that the BMI-mortality relationship differs for men and women who smoke or have prevalent disease compared to healthy never-smokers. These findings further support recommendations for maintaining a BMI between 20-25 kg/m2 for optimal health and longevity. PMID- 25295621 TI - Comparison of vascular cognitive impairment--no dementia by multiple classification methods. AB - AIMS: To compare vascular cognitive impairment-no dementia (VCI-ND) using different classification methods. METHODS: We recruited 56 patients with VCI-ND between April 2012 and March 2013. We used a battery of neuropsychological tests to classify patients with VCI-ND into different subtypes based on memory and executive function as follows: cognitive screening (Mini-Mental State Examination, MMSE), memory (Auditory Verbal Learning Test, AVLT), executive/attention (Shape Trails Test, STT; Stroop Color-Word Test, SCWT; Reading the Mind in the Eyes, RME; Digit Ordering Test-A, DOT-A; Symbol Digit Modalities Test, SDMT), language (Action Naming Test, ANT; Boston Naming Test, BNT; Famous Face Test, FFT; Similarity Test, ST; Verbal Fluency Test, VFT) and visuospatial function (Complex Figure Test, CFT). RESULTS: The two groups had comparable demographic information (P>0.05). Amnestic VCI-ND (aVCI-ND) patients obtained significantly lower scores compared with individuals with nonamnestic VCI-ND (naVCI-ND) on the AVLT memory test, VFT language test and VFT-alternating executive test (P<0.05). Additionally, executive VCI-ND (eVCI-ND) patients performed significantly longer than nonexecutive VCI-ND (neVCI-ND) patients on the SCWT-C timed executive test. Finally, eVCI-ND patients obtained significantly lower scores compared with neVCI-ND patients on the RME, DOT-A and SDMT-correct executive tests and the ANT, BNT and ST language tests (P<0.05). CONCLUSION: aVCI ND patients performed poorly compared with naVCI-ND patients in terms of executive and language functions, while eVCI-ND patients performed poorly compared with neVCI-ND patients in terms of language function. PMID- 25295619 TI - Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4+CD25- T cells in experimental colitis. AB - BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) is based on vagus nerve (VN) activity that regulates macrophage and dendritic cell responses in the spleen through alpha-7 nicotinic acetylcholine receptor (a7nAChR) signaling. Inflammatory bowel disease (IBD) patients present dysautonomia with decreased vagus nerve activity, dendritic cell and T cell over-activation. The aim of this study was to investigate whether central activation of the CAP alters the function of dendritic cells (DCs) and sequential CD4+/CD25-T cell activation in the context of experimental colitis. METHODS: The dinitrobenzene sulfonic acid model of experimental colitis in C57BL/6 mice was used. Central, intracerebroventricular infusion of the M1 muscarinic acetylcholine receptor agonist McN-A-343 was used to activate CAP and vagus nerve and/or splenic nerve transection were performed. In addition, the role of alpha7nAChR signaling and the NF-kB pathway was studied. Serum amyloid protein (SAP)-A, colonic tissue cytokines, IL-12p70 and IL-23 in isolated splenic DCs, and cytokines levels in DC CD4+CD25-T cell co-culture were determined. RESULTS: McN-A-343 treatment reduced colonic inflammation associated with decreased pro-inflammatory Th1/Th17 colonic and splenic cytokine secretion. Splenic DCs cytokine release was modulated through alpha7nAChR and the NF-kB signaling pathways. Cholinergic activation resulted in decreased CD4+CD25-T cell priming. The anti-inflammatory efficacy of central cholinergic activation was abolished in mice with vagotomy or splenic neurectomy. CONCLUSIONS: Suppression of splenic immune cell activation and altered interaction between DCs and T cells are important aspects of the beneficial effect of brain activation of the CAP in experimental colitis. These findings may lead to improved therapeutic strategies in the treatment of IBD. PMID- 25295622 TI - Chemerin as a marker of body fat and insulin resistance in women with polycystic ovary syndrome. AB - Adipocytokines may alter normal metabolic function and play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). We prospectively evaluated a cohort of obese and non-obese women with PCOS and non-PCOS controls for both novel (chemerin and omentin-1) and established (leptin and adiponectin) adipokines. Compared with age-matched controls, non-obese women with PCOS had decreased serum omentin-1 (191.1 ng/ml versus 269.7 ng/ml, p = 0.0001), while serum chemerin was not significantly altered in women with PCOS (53.95 ng/ml versus 48.61 ng/ml, p = 0.11). The findings were similar in the entire group of women with PCOS. However, in women with PCOS, chemerin correlated with leptin (r = 0.508, p = 0.004), adiponectin (r = -0.36, p = 0.014), and the leptin/adiponectin (L/A) ratio (r = 0.605, p < 0.0001), while there were no such correlations with omentin-1. In women with PCOS, chemerin correlated with BMI (r = 0.317, p = 0.034), abdominal subcutaneous fat (r = 0.451, p = 0.0019), and insulin resistance (HOMA-IR, r = 0.428, p = 0.0034), while omentin-1 did not correlate with any parameter. These data suggest that chemerin although not significantly elevated in women with PCOS correlates with adiposity and insulin resistance, and it is the single best adipokine measured in this regard. Chemerin, through its inflammatory role as a chemo-attractant in adipose tissue, may be an important determinant of insulin resistance in PCOS. PMID- 25295623 TI - Role of the X-linked gene GPR174 in autoimmune Addison's disease. AB - CONTEXT: Autoimmune endocrinopathies demonstrate a profound gender bias, but the reasons for this remain obscure. The 1000 genes on the X chromosome are likely to be implicated in this inherent susceptibility; various theories, including skewed X chromosome inactivation and fetal microchimerism, have been proposed. GPR174 is an Xq21 putative purinergic receptor that is widely expressed in lymphoid tissues. A single-nucleotide polymorphism, rs3827440, encoding Ser162Pro, has recently been associated with Graves' disease in Chinese and Polish populations, suggesting a role of this X chromosome gene in autoimmune disease. OBJECTIVE: We investigated the role of rs3827440 in a UK cohort of patients with autoimmune Addison's disease (AAD). Samples from 286 AAD cases and 288 healthy controls were genotyped using TaqMan single-nucleotide polymorphism genotyping assays (C_25954273_10) on the Applied Biosystems 7900HT Fast real-time PCR system. DESIGN: Using a dominant (present/absent) model, the serine-encoding T allele of rs3827440 was present in 189 of 286 AAD patients (66%) compared with 132 of 288 unaffected controls (46%) [P = .010, odds ratio 1.80 (5%-95% confidence interval 1.22-2.67)]. An allele dosage model found a significant excess of the T allele in AAD patients compared with controls [P = .03, odds ratio 1.34 (5%-95% confidence interval 1.07-1.67)]. CONCLUSION: We have demonstrated a significant association of this X chromosome-encoded immunoreceptor with AAD for the first time. This X linked gene could have a more generalized role in autoimmunity pathogenesis: G protein-coupled receptors are promising drugable targets, and further work to elucidate the functional role of GPR174 is now warranted. PMID- 25295625 TI - Combined isometric and vibration training does not enhance strength beyond that of isometric training alone. AB - Research considering combined vibration and strength training is extensive yet results are equivocal. However, to date there appears no research which has considered the combination of both direct vibration and whole---body vibration when used in an isometric deadlift position. The aims of this study were to compare groups performing isometric training with and without direct and whole-- body vibration. Twenty four participants (19---24 years) were randomly divided into: isometric training with vibration (ST+VT: n=8), isometric training without vibration (ST: n=8), and control (CON: n=8). Within the training groups participants trained twice per week, for 6 weeks, performing 6---sets of maximal isometric deadlift contractions, increasing in duration from 30 seconds to 40 seconds (weeks 1---6). Hip and knee angle was maintained at 60 degrees and 110 degrees , respectively for both testing and training. Training sessions for ST+VT were identical to ST with the addition of a direct vibratory stimulus through hand---held straps and whole---body vibration via standing on vibration a platform. The amplitude remained constant (2mm) throughout the intervention whilst the frequency increased from 35Hz to 50Hz. Pre--- and post---test isometric strength was measured using an isometric deadlift dynamometer. Results revealed significant increases in isometric strength for both ST+VT (p < 0.001, 23.8%) and ST (p < 0.001, 32.5%) compared to CON, with no significant differences between ST+VT and ST training groups. The present study provides evidence to suggest that there are no greater gains to be incurred by the addition of a vibratory stimulus to traditional strength training. PMID- 25295624 TI - Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis. AB - CONTEXT: Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available; however, its use is limited by a serious side effect profile, including thyroiditis. The mechanisms underlying AMIO thyroid toxicity have been elusive; thus, identification of novel approaches in order to prevent thyroiditis is essential in patients treated with AMIO. OBJECTIVE: Our aim was to evaluate whether AMIO treatment could induce endoplasmic reticulum (ER) stress in human thyroid cells and the possible implications of this effect in AMIO-induced destructive thyroiditis. RESULTS: Here we report that AMIO, but not iodine, significantly induced the expression of ER stress markers including Ig heavy chain-binding protein (BiP), phosphoeukaryotic translation initiation factor 2alpha (eIF2alpha), CCAAT/enhancer-binding protein homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO down-regulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced down-regulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1 cells and human primary thyrocytes with the chemical chaperone 4-phenylbutyric acid completely prevented the effect of AMIO on both ER stress induction and Tg down-regulation. CONCLUSIONS: We identified ER stress as a novel mechanism contributing to AMIO induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation, providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis. PMID- 25295626 TI - Can practice of Dancesport as physical activity be associated with the concept of "successful aging"? AB - AIM: Regular and structured physical activity is known to be effective in preventing and/or reducing the physical and mental decline associated with aging. Indeed, such usefulness of physical activity has been associated with the concept of "successful aging". The aim of the present study was to evaluate the possible physical and cognitive effects deriving from the practice of Dancesport in comparison with the participation in adapted physical activity (APA) programs and sedentarity. METHODS: A total of 150 healthy older adults were enrolled, consisting of three groups: 1) Dancesport (non-competitive Latin American and Standard dancers); 2) APA (subjects practicing a multicomponent training program adapted to elderly); 3) control (sedentary subjects). All participants were assessed with cognitive computerized tests and underwent motor tests (Tinetti Test [TT] and Sit and Reach [SR] Test), and filled out a questionnaire to evaluate leisure cognitive activities and Short Form-12 (SF-12) questionnaire to assess quality of life. RESULTS: Subjects practicing Dancesport and APA performed significantly better in all proposed tests than sedentary subjects. In particular, dancers reported better scores in both cognitive and motor tests as well as in SF-12 compared to APA. CONCLUSION: Given its peculiar characteristics, Dancesport represents a feasible, attractive and alternative physical activity to preserve cognitive and physical functions during aging. Increased self-esteem, social contact and psychophysical wellness significantly ameliorate the quality of life during aging. PMID- 25295628 TI - Potentialities of a membrane reactor with laccase grafted membranes for the enzymatic degradation of phenolic compounds in water. AB - This paper describes the degradation of phenolic compounds by laccases from Trametes versicolor in an enzymatic membrane reactor (EMR). The enzymatic membranes were prepared by grafting laccase on a gelatine layer previously deposited onto alpha-alumina tubular membranes. The 2,6-dimethoxyphenol (DMP) was selected from among the three different phenolic compounds tested (guaiacol, 4 chlorophenol and DMP) to study the performance of the EMR in dead end configuration. At the lowest feed substrate concentration tested (100 mg.L-1), consumption increased with flux (up to 7.9 * 103 mg.h-1.m-2 at 128 L.h-1.m-2), whereas at the highest substrate concentration (500 mg.L-1), it was shown that the reaction was limited by the oxygen content. PMID- 25295630 TI - Large-angle x-ray scatter in Talbot-Lau interferometry for breast imaging. AB - Monte Carlo simulations were used to investigate large-angle x-ray scatter at design energy of 25 keV during small field of view (9.6 cm * 5 cm) differential phase contrast imaging of the breast using Talbot-Lau interferometry. Homogenous, adipose and fibroglandular breasts of uniform thickness ranging from 2 to 8 cm encompassing the field of view were modeled. Theoretically determined transmission efficiencies of the gratings were used to validate the Monte Carlo simulations, followed by simulations to determine the x-ray scatter reaching the detector. The recorded x-ray scatter was classified into x-ray photons that underwent at least one Compton interaction (incoherent scatter) and Rayleigh interaction alone (coherent scatter) for further analysis. Monte Carlo based estimates of transmission efficiencies showed good correspondence [Formula: see text] with theoretical estimates. Scatter-to-primary ratio increased with increasing breast thickness, ranging from 0.11 to 0.22 for 2-8 cm thick adipose breasts and from 0.12 to 0.28 for 2-8 cm thick fibroglandular breasts. The analyzer grating reduced incoherent scatter by ~18% for 2 cm thick adipose breast and by ~35% for 8 cm thick fibroglandular breast. Coherent scatter was the dominant contributor to the total scatter. Coherent-to-incoherent scatter ratio ranged from 2.2 to 3.1 for 2-8 cm thick adipose breasts and from 2.7 to 3.4 for 2 8 cm thick fibroglandular breasts. PMID- 25295629 TI - Membrane bioprocesses for pharmaceutical micropollutant removal from waters. AB - The purpose of this review work is to give an overview of the research reported on bioprocesses for the treatment of domestic or industrial wastewaters (WW) containing pharmaceuticals. Conventional WW treatment technologies are not efficient enough to completely remove all pharmaceuticals from water. Indeed, these compounds are becoming an actual public health problem, because they are more and more present in underground and even in potable waters. Different types of bioprocesses are described in this work: from classical activated sludge systems, which allow the depletion of pharmaceuticals by bio-degradation and adsorption, to enzymatic reactions, which are more focused on the treatment of WW containing a relatively high content of pharmaceuticals and less organic carbon pollution than classical WW. Different aspects concerning the advantages of membrane bioreactors for pharmaceuticals removal are discussed, as well as the more recent studies on enzymatic membrane reactors to the depletion of these recalcitrant compounds. PMID- 25295627 TI - The role of rab proteins in neuronal cells and in the trafficking of neurotrophin receptors. AB - Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways. PMID- 25295632 TI - [Discovery of a new mutation in MYOD1 characterizes a subset of aggressive embryonal rhabdomyosarcoma partnering with mutations of the PI3K-AKT pathway]. PMID- 25295631 TI - Protein is an important but undervalued macronutrient in the nutritional care of patients with cystic fibrosis. AB - PURPOSE OF REVIEW: Achieving an optimal nutritional status in patients with cystic fibrosis (CF) is important to maintain better pulmonary function, physical performance, and to prolong survival. So far, nutrition care in CF has mainly focused on fat intake and achieving energy balance, but there is increasing information on the clinical importance of muscle maintenance and protein intake in CF. RECENT FINDINGS: Low muscle mass is consistently associated with pulmonary decline, bone mineral loss, and poor survival in CF. High energy and fat intake contributes to an increased prevalence of overweight and obesity in CF. Obesity per se is not related to better lung function in CF and has negative metabolic and clinical consequences, particularly when muscle wasting is present. Protein digestion capacity is severely impaired in CF, but high protein intake is needed and essential amino acid mixtures appear highly anabolic even in those with severe muscle loss. SUMMARY: Body composition assessment and achieving protein balance in the routine care in CF is important to prevent muscle loss and further improve the clinical and overall outcome of these patients. New approaches are needed to optimize the interaction between high essential amino-acid-rich protein intake and pancreatic enzyme regimen in CF. The optimal level of protein intake needs to be assessed in clinically stable CF patients as well as in those recovering from an acute exacerbation. PMID- 25295633 TI - Commentary on "A novel technique to minimize deformation of the stomach in laparoscopic partial gastrectomy for intraluminal gastric GISTs". PMID- 25295634 TI - Intraabdominal partitioning of the laparoscopic sleeve gastrectomy remnant optimizes the specimen extraction ergonomics and postoperative pain and is an attractive technique in teenage patients. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) has become an increasingly popular bariatric procedure in the pediatric population worldwide. The fear of complications, postoperative pain, and recovery remain the reservations for wider application of surgery in morbidly obese children. We present a novel technique for LSG remnant retrieval. MATERIALS AND METHODS: The patient was a 16-year old girl with a body mass index of 55 kg/m(2) and significant comorbidities who underwent LSG and liver biopsy. In the extraction technique, a specimen containing the gastric body and fundus, approximately 80% of the stomach volume, was partitioned longitudinally and intracorporeally with endoshears; subsequently, it was retrieved in one fragment via the lumen of a 15-mm port. RESULTS: The procedure time was 65 minutes (specimen extraction time was 7 minutes). Her recovery was uneventful, and she was discharged home on the second postoperative day. At the 1-, 3-, and 6-month follow-up, she has shown all the benefits of weight loss and associated improvement in metabolic parameters and quality of life, without any complications. CONCLUSIONS: This technique for gastric remnant retrieval results in minimizing postoperative pain, reducing operative costs, and minimizing the likelihood of wound infection. PMID- 25295635 TI - Evaluation of cardiac function during laparoscopic gastrostomy in pediatric patients with hypoplastic left heart syndrome using intraoperative transesophageal echocardiography. AB - INTRODUCTION: Patients with single ventricle physiology (SVP)--specifically, hypoplastic left heart syndrome (HLHS)--frequently need long-term enteral access; however, they are at an extremely high operative risk. Nothing has been published on the physiologic impact on single ventricle function during laparoscopy in this patient population. Therefore, we performed intraoperative transesophageal echocardiography (TEE) to study the physiologic effects of laparoscopic surgery in these patients. PATIENTS AND METHODS: After Internal Review Board approval, patients with SVP undergoing laparoscopic gastrostomy were studied with intraoperative TEE, and fractional shortening was determined. Patients were separated into those with HLHS and others with SVP. Data are reported as mean +/- standard deviation values. Analysis of variance was used for continuous variables. RESULTS: From August 2011 to February 2013, in total, 11 patients with SVP underwent laparoscopic gastrostomy, including 6 with HLHS. One of the 6 HLHS patients and 1 of the SVP patients underwent concurrent fundoplication. All patients were post-first-stage palliation; two had completed post-second stage. Fractional shortening tended to decrease during insufflation and return to baseline after desufflation. There was no 30-day mortality. CONCLUSIONS: Pneumoperitoneum associated with laparoscopic gastrostomy tube placement results in a reversible decrease in fractional shortening in patients with HLHS and SVP. Overall, the children tolerated pneumoperitoneum. TEE allows for real-time assessment of ventricular function and volume and may improve safety during longer procedures. PMID- 25295636 TI - Comparison of minimally invasive and open gastric transposition in children. AB - BACKGROUND: Gastric transposition is an established method of esophageal replacement in children, and the use of minimally invasive techniques avoids the trauma of open access. The objective of this study was to compare outcomes of minimally invasive versus open gastric transposition in children. MATERIALS AND METHODS: All cases of attempted laparoscopic-assisted gastric transposition at Great Ormond Street Hospital (GOSH), London, United Kingdom, between 2003 and 2012 were retrospectively reviewed. A comprehensive literature search was completed on MEDLINE for minimally invasive gastric transposition in children, and postoperative outcomes were collated. The outcomes from the retrospective review (single-center, GOSH) and the literature search (multicenter) were compared with those of the largest study on open gastric transposition consisting of 192 cases performed at GOSH. RESULTS: In this retrospective review of 19 patients (mean age, 3.5 years; range, 0.4-15 years), the indications were long gap esophageal atresia, postoperative, caustic, and idiopathic esophageal stricture, and esophageal dysmotility. Three cases were converted to laparotomy and excluded from subsequent analysis. There were one anastomotic leak, two strictures, and no deaths in this series. The literature search yielded a further 50 cases for comparison. Single-center (n=16) and multicenter (n=66) comparison of minimally invasive versus open technique (n=192) showed no difference in leak (6.3% and 16.7%, respectively, versus 12.0%; P=.701 and P=.398), stricture (12.5% and 15.2% versus 20.8%; P=.535 and P=.370), and mortality rates (0% and 1.5% versus 4.7%; P=1.000 and P=.461). CONCLUSION: Minimally invasive gastric transposition is a safe and acceptable alternative to open surgery in children. PMID- 25295637 TI - Two new compounds from Ganoderma lucidum. AB - Two pairs of new enantiomers, lucidulactones A and B (1 and 2), and two known compounds were isolated from Ganoderma lucidum. Their structures were determined by means of spectroscopic methods. The chiral HPLC was used to separate the ( - ) and (+)-antipodes of the new compounds. PMID- 25295639 TI - Central pain. AB - Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topic addressed in this issue is central pain, a neuropathic pain syndrome caused by a lesion in the brain or spinal cord that sensitizes one's perception of pain. It is a debilitating condition caused by various diseases such as multiple sclerosis, strokes, spinal cord injuries, or brain tumors. Varied symptoms and the use of pharmacological medicines and nonpharmacological therapies will be addressed. PMID- 25295640 TI - Low back pain and yoga. AB - ABSTRACT Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topic addressed in this issue is chronic low back pain, one of the most common reasons to visit one's primary care doctor. Complementary approaches, including yoga, will be addressed. PMID- 25295641 TI - The painful primary hip replacement - review of the literature. AB - Total hip replacement is one of the most successful surgical procedures of the 20th century (World Health Organisation). The success rate is dependent on the chosen endpoint. Evaluation of the outcome in joint replacement surgery has shifted from the revision rate toward patient satisfaction and quality of life. Patient satisfaction is reported to be up to 96% 16 years postoperatively, but the prevalence of groin pain after conventional total hip replacement ranges from 0.4% to 18.3% and activity-limiting thigh pain is still an existing problem linked to the femoral component of uncemented hip replacement in up to 1.9% to 40.9% of cases in some series. The aim of our article is to review the aetiology, diagnostic procedures and treatment of the painful primary total hip replacement. We discuss the most relevant intrinsic and extrinsic aetiological factors responsible for chronic pain after total hip arthroplasty focusing on comparative studies and randomised controlled trials including diagnostics and management. Detailed analysis of history, clinical examination, imaging and laboratory tests are required prior to any revision for painful total hip arthroplasty. Revision surgery without knowing the underlying pathology should be avoided. PMID- 25295643 TI - Is SOD2 Ala16Val polymorphism associated with migraine with aura phenotype? AB - Several studies suggest a role of oxidative stress in the physiopathology of migraine, particularly in the form with aura. In a case-control study, we investigated the association between migraine and superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) genes in a cohort of 490 consecutive unrelated Caucasian migraineurs (migraine with aura [MwA], n=107; migraine without aura [MwoA], n=246; chronic migraine [CM], n=137) and 246 healthy controls recruited at our Headache and Pain Unit and stored in the Interinstitutional Multidisciplinary BioBank (BioBIM). Migraine phenotype was carefully detailed using face-to-face interviews. We examined polymorphisms of SOD1 gene (A/C substitution-rs2234694) and SOD2 gene (C/T transition-rs4880-Ala16Val). The rs4880 TT (Val/Val) genotype was associated (p=0.042) with the presence of unilateral cranial autonomic symptoms (UAs) in MwA patients. We also found a mild correlation between SOD2 rs4880 genotype and the type of acute migraine treatment (p=0.048) in MwA patients. Our findings suggest that SOD2 is a disease-modifier gene influencing oxidative mechanisms in MwA. These observations lead to the hypothesis that SOD2 polymorphism may cause a defective control of the oxidative phenomena linked to cortical spreading depression, the neurophysiological hallmark of migraine aura, causing an overstimulation of trigeminal neurons and UAs triggering. PMID- 25295642 TI - H2 receptor antagonists and right ventricular morphology: the MESA right ventricle study. AB - RATIONALE: H2 receptor antagonist (H2RA) use is common and may act directly on the heart through myocardial H2 receptors or indirectly through changes in pulmonary vascular resistance. OBJECTIVES: To determine the relationship between histamine H2RA use and right ventricular (RV) morphology. METHODS: We studied 4,122 participants in the Multi-Ethnic Study of Atherosclerosis without clinical cardiovascular disease who had magnetic resonance imaging assessment of RV morphology and ascertainment of medication use. Multivariable linear regression estimated cross-sectional associations between H2RA use and RV morphology after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Further adjustments for co-medication use, left ventricular parameters, lung structure and function, renal function, or inflammatory markers were considered in separate models. Analyses in a subcohort restricted to H2RA or proton pump inhibitor users accounted for confounding by the indication of gastroesophageal reflux disease. MEASUREMENTS AND MAIN RESULTS: H2RA use was associated with lower RV mass (-0.7 g; 95% confidence interval, -1.2 to -0.2 g; P = 0.004) and smaller RV end-diastolic volume (-4.2 ml; 95% confidence interval, 7.2 to -1.2 ml; P = 0.006). This relationship was unchanged with adjustment for co-medication use, lung structure and function, renal function, and inflammation. The relationship with RV mass was independent of left ventricular mass. Results were similar in the smaller cohort restricted to proton pump inhibitor and H2RA users. CONCLUSIONS: H2RA use was associated with lower RV mass and smaller RV end diastolic volume. Additional study of histamine and H2 receptors in cardiopulmonary diseases affecting the RV may have direct clinical relevance. PMID- 25295644 TI - Novel directions for G * E analysis in psychiatry. AB - G * E in psychiatry may explain why environmental risk factors have big impact in some individuals but not in others, and conversely why relatives that are genetically at risk for disease do not all develop disease. Here we discuss two novel methods that use an aggregate genome-wide measure of genetic risk to detect G * E and estimate its effect in the population using data currently available and data we anticipate will be available in the near future. The first method exploits summary statistics from large-scale genome-wide association studies ignorant of the environmental conditions and detects G * E in an out-of-sample risk-profiling framework. The second method relies on larger samples and is based on a mixed linear model framework. It estimates variance explained directly from single nucleotide polymorphisms and environmental measures. Both methods have great potential to improve public health interventions focusing on risk-based screening that is informed by both genetic and environmental risk factors. PMID- 25295645 TI - Attention benefits after a single dose of metadoxine extended release in adults with predominantly inattentive ADHD. AB - OBJECTIVE: To assess the first-dose effectiveness and tolerability of metadoxine extended release (MDX) in adults with predominantly inattentive attention deficit/hyperactivity disorder (ADHD-PI). METHODS: In this double-blind, placebo controlled, crossover study, adults with ADHD-PI were randomized 1:1:1 to receive a single dose of MDX 1400 mg, MDX 700 mg, and placebo (ClinicalTrials.gov identifier: NCT01685281). The primary efficacy end point was the mean change in the Test of Variables of Attention (TOVA) ADHD score from baseline to 3 to 5 hours after drug administration. Secondary assessments included TOVA subscores, TOVA response rates (defined as an increase of 0.8 points in the TOVA ADHD score), and the Cambridge Neuropsychological Automated Test Battery. Safety assessments included adverse events and vital signs. RESULTS: The intention-to treat population included 36 patients (52.8% men; mean age, 32 years). The efficacy of MDX 1400 mg was demonstrated by a statistically significant difference in the mean (+/- SD) change in the TOVA ADHD score at baseline to 3 to 5 hours after drug administration compared with placebo (2.0 [4.2]; P = 0.009). The TOVA response time variability subscore was significantly different between MDX 1400 mg and placebo (mean difference, 7.9 [19.2] points; P = 0.022). Significantly more adults responded to single-dose MDX 1400 mg versus placebo (97.1% vs 71.4%, P = 0.006). There were no statistically significant differences between MDX 700 mg and placebo on any measures. Exploratory analyses of the Cambridge Neuropsychological Automated Test Battery did not yield significant findings. Fatigue and headache were the 2 most frequently reported adverse events. There were no clinically significant abnormalities in laboratory values, vital signs measurements, Columbia-Suicide Severity Rating Scale scores, or electrocardiographic parameters. CONCLUSIONS: Single-dose MDX 1400 mg significantly improved sustained and selective attention in adults with ADHD-PI as measured by the TOVA ADHD score 3 to 5 hours after drug administration. Single doses of MDX 700 and 1400 mg were well tolerated. PMID- 25295646 TI - Clinical effects of lisdexamfetamine and mixed amphetamine salts immediate release in adult ADHD: results of a crossover design clinical trial. AB - OBJECTIVES: To examine the clinical effects of equivalent doses of single-blind (SB; patient-blind) lisdexamfetamine (LDX) and mixed amphetamine salts-immediate release (MAS-IR) on adult attention-deficit/hyperactivity disorder (ADHD) in a placebo (PBO)-controlled, crossover design. METHODS: Twenty-four subjects were treated sequentially in a fixed order with (1) SB PBO (matching LDX) for 1 week, (2) SB LDX (up to 70 mg/day) for 5 weeks, (3) SB PBO washout for 3 weeks, and (4) open-label treatment MAS-IR (tid up to 45 mg/day) for 5 weeks. Clinical effects on ADHD and executive function were assessed weekly throughout the trial with the ADHD Rating Scale with adult prompts, the Clinical Global Impression Severity Scale (CGI-S), and the Behavior Rating Inventory of Executive Function (BRIEF). RESULTS: Lisdexamfetamine and MAS-IR were generally well tolerated. Significant and equal reductions on ADHD clinician ratings were seen. Significantly greater reductions in CGI-S and selected BRIEF subsets were observed in LDX over MAS-IR treatment. However, in general, baseline scores for MAS-IR treatment did not fully return to the LDX baseline. Adherence in this structured and monitored clinical trial was good for once daily LDX and 3 times a day MAS-IR. CONCLUSIONS: In this crossover study, both LDX and MAS-IR had significant effects on ADHD clinician ratings and measures of executive function (with response rates of about 80%); patients in this monitored clinical trial were adherent with once daily LDX and 3 times a day MAS-IR, which may not be the case in real-world clinical practice. The findings of some superiority of LDX over MAS-IR on the CGI S and BRIEF ratings may be influenced by the variability in the baselines used, but nevertheless should be further investigated in larger scale, parallel-design clinical trials. PMID- 25295647 TI - Addressing attention-deficit/hyperactivity disorder in the workplace. AB - Although generally considered a childhood disorder, attention deficit/hyperactivity disorder (ADHD) can persist into adulthood and impede achievement in the workplace. Core ADHD symptoms of inattention, hyperactivity, and impulsivity can be associated with poor organization, time management, and interpersonal relationships. Employment levels, earning power, and productivity are reduced among individuals with ADHD compared with those without ADHD. Furthermore, the costs of employing individuals with ADHD are higher because of work absences and lost productivity. The primary care provider plays an integral role in managing ADHD symptoms and providing the necessary resources that will help individuals with ADHD succeed in the workplace. Pharmacotherapy can reduce ADHD symptoms and improve functioning; however, it is also important to consider how positive traits associated with ADHD, such as creative thinking, can be used in the workplace. Workplace accommodations and behavioral therapies, such as coaching, can also enhance time management and organizational skills. This review describes how ADHD symptoms affect workplace behaviors, the effect of ADHD on employment and workplace performance, and the management of ADHD in working adults. PMID- 25295648 TI - Relationship of ADHD symptoms and global illness severity in adults treated with lisdexamfetamine dimesylate. AB - The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and global clinical assessment of functionality is complex. This post-hoc analysis explores this relationship and suggests implications for patient assessment in clinical practice. Adults with ADHD on a stable lisdexamfetamine dimesylate (LDX) dose for >= 6 months were enrolled in a double-blind, placebo controlled, randomized withdrawal study. Participants entered a 3-week open-label phase continuing their prior LDX dose and were then randomized to placebo or the same LDX dose for a 6-week, double-blind, randomized withdrawal phase. ADHD symptom distribution was measured by the ADHD Rating Scale IV (ADHD-RS-IV) with Adult Prompts total score reflecting DSM-IV-TR ADHD symptom criteria and severity by Clinical Global Impressions-Severity (CGI-S) ratings at study entry and at end of study. Of 123 participants enrolled in the open-label phase, 116 were included in the randomized withdrawal phase (placebo, n = 60; LDX, n = 56). As reported in a prior publication, mean (standard deviation) ADHD-RS-IV total score change from baseline (week 3) to end of study (randomized-withdrawal phase) was 16.8 (11.80) for placebo and 1.6 (8.63) for LDX. At end of study, for placebo and LDX, 5.0% and 32.1% of participants, respectively, had a CGI-S = 1, 11.7% and 35.7% had a CGI-S = 2, 11.7% and 17.9% had a CGI-S = 3, 33.3% and 7.1% had a CGI-S = 4, 35.0% and 7.1% had a CGI-S = 5, and 3.3% and 0% had a CGI-S = 6; no participants had a CGI-S = 7 (P < 0.0001). The CGI-S ratings increased (worsened) as ADHD symptom scores worsened. Post-hoc regression analysis between ADHD-RS-IV scores and CGI-S demonstrated shared variance of 47% at week 3 and 69% for both placebo and LDX at end of study. Although ADHD symptom scores demonstrate a linear relationship with global illness severity, the variance suggests that other factors not captured by symptom scales are also important in assessing patient outcomes in clinical practice. ( TRIAL REGISTRATION: ClinicalTrials.gov NCT00877487.). PMID- 25295649 TI - Comorbidities in adult attention-deficit/hyperactivity disorder: a practical guide to diagnosis in primary care. AB - Diagnosis and management of attention-deficit/hyperactivity disorder (ADHD) in adults is complex and challenging because of the frequent comorbidity of other psychiatric disorders that have symptoms overlapping with those of ADHD. The presence of comorbidities can create challenges to making an accurate diagnosis and also impact treatment options and outcomes. This review discusses disorders that may be comorbid with ADHD in adults, including anxiety, mood, substance use disorder, antisocial personality disorder, and borderline personality disorder. Suggestions for recognizing these comorbidities and distinguishing them from ADHD and perspectives on their possible impact on ADHD treatment are included. Adjunctive nonpharmacologic modalities may be especially helpful in the case of comorbid mood, anxiety, substance abuse, or personality disorders. PMID- 25295650 TI - The patient experience with DSM-5-defined binge eating disorder: characteristics, barriers to treatment, and implications for primary care physicians. AB - BACKGROUND: Binge eating disorder (BED) is now a formal diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). However, post-DSM-5 patient profiles and viewpoints on BED diagnosis and treatment remain unclear. This study used a focus group methodology to examine demographic and clinical characteristics, as well as perceptions of diagnosis and treatment from patients with BED symptoms who were either formally diagnosed with BED or undiagnosed. METHODS: Binge eating disorder-diagnosed individuals (n = 11) or those meeting the DSM-5 BED diagnostic criteria but were undiagnosed (n = 14) participated in 6 semistructured focus groups conducted by trained staff at 3 geographic locations in the United States. Patients completed a series of demographic and clinical measures and then engaged in a moderated discussion focused on identifying factors associated with their experiences with BED. RESULTS: Sixty percent of the patients were female, 48% were white and 40% were black, and 76% were employed. The diagnosed group had a slightly higher socioeconomic status; undiagnosed patients had a higher average body mass index. In the overall sample, comorbid anxiety (40%) and depression (40%) were the most common psychiatric comorbidities. Even in the diagnosed group, only half of the patients (54.5%) became aware of BED through their health care provider (HCP; n = 6). Patients perceived that HCPs were focused more on physical ailments, were judgmental about weight, and were unable to distinguish BED from obesity. They also expressed a desire for safe, nonjudgmental interactions with HCPs. CONCLUSIONS: Education and income may be factors affecting access to care and BED diagnosis. Both patient groups reported considerable psychopathology and medical comorbidities. Moreover, the patient groups perceived HCPs as both having inadequate understanding of BED and providing insensitive and ineffective communication regarding eating behaviors. The study findings in diagnosed and undiagnosed patient groups underscore the need for greater BED disease state awareness and patient sensitivity among HCPs. PMID- 25295651 TI - The potential for misuse and abuse of medications in ADHD: a review. AB - This article reviews the literature concerning attention-deficit/hyperactivity disorder (ADHD) medication misuse, abuse, dependence, diversion, and malingering. The review covers nonmedical use (NMU) of both stimulant (methylphenidate and amphetamine) and nonstimulant (alpha-adrenergic agonists and atomoxetine) prescription medications, and provides a discussion on the relevance for ADHD treatment today. The neural basis for ADHD medication mechanisms of action (increased norepinephrine and dopamine signaling) and their neurobiochemical relationship to the abuse potential is explored. Regionally-specific, stimulant induced elevations in brain dopamine appear to be integral to both efficacy in ADHD and potential for abuse. In addition to the prevalence of misuse and diversion, additional topics discussed include the potential safety concerns associated with NMU of prescription ADHD medications and the cost to payers of prescription drug diversion (eg, increased emergency department visits associated with misuse). The evidence describing the difficulty in detecting malingering for the purpose of illicit access to ADHD medications for subsequent misuse or diversion is also summarized. Moreover, the effect of ADHD medications in patients with comorbid substance use disorder and the controversial potential linkage of stimulant prescription use with subsequent substance use disorder are explored. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study. Stimulant effectiveness and speed of action are deemed desirable to enhance attention and focus performance for activities like studying, but stimulants are also misused recreationally. Conversely, the data suggest a lack of abuse potential and lack of actual medication misuse for the nonstimulant medications. Although they can be efficacious for the treatment of ADHD, the nonstimulants lack a mechanism of action linked to the abuse potential and they lack the desirable effects (speed of action, stimulant feel) that make stimulants susceptible to NMU. In light of these findings, the data suggest a need for close screening and therapeutic monitoring of ADHD medication use. In addition, nonstimulants might be an appropriate alternative for patients with concern about abuse and physicians concerned with general misuse and diversion. PMID- 25295652 TI - Integrating modern concepts of insomnia and its contemporary treatment into primary care. AB - Insomnia affects one-third of the adult population. Ten percent of adults surveyed in America consider it a serious problem. Chronic insomnia is associated with poor quality of life and the potential for various psychiatric and medical conditions, notably depression and cardiovascular disease. Since most patients with insomnia are unlikely to disclose obvious sleeping difficulties, the first step in diagnosing and managing patients is having a high index of suspicion in patients with specific complaints, comorbidities, and risk factors. This is followed by a complete evaluation of the patient's medical and physical history to determine if the insomnia is primary or comorbid with another disease. The management of insomnia should consider the extent of impairment associated with the disorder, as well as duration, causes, and comorbidities. In some cases, referral to a specialist is warranted. Recently, there have been new definitions of insomnia proposed; elucidation of the role of orexin-mediated hyperarousal brain neural pathway in the sleep-wake cycle; and new drugs available that target this system. Thus, a review and update for today's primary care physician is warranted. PMID- 25295653 TI - Assessment of upper extremity function in multiple sclerosis: review and opinion. AB - Upper extremity (UE) dysfunction may be present in up to ~80% of individuals with multiple sclerosis (MS), although its importance may be under-recognized relative to walking impairment, which is the hallmark symptom of MS. Upper extremity dysfunction affects independence and can impact the ability to use walking aids. Under-recognition of UE dysfunction may result in part from limited availability of performance-based and patient self-report measures that are validated for use in MS and that can be readily incorporated into clinical practice for screening and regularly scheduled assessments. In addition to the 9-Hole Peg Test, which is part of the Multiple Sclerosis Functional Composite, there are several performance-based measures that are generally used in the rehabilitation setting. These measures include the Box and Block Test, the Action Research Arm Test, the Test d'Evaluation de la performance des Membres Superieurs des Personnes Agees, and the Jebsen-Taylor Test of Hand Function. Several of these measures were developed for use in stroke, although in contrast to stroke, which is characterized by unilateral dysfunction, UE impairment in MS is generally bilateral, and should be assessed as such. Similarly, patient-reported UE measures are available, including Disabilities of the Arm, Shoulder, and Hand (DASH) and its shorter version, QuickDASH, the Manual Ability Measure, and ABILHAND, although none has been psychometrically validated for MS. Recently, item response theory was used to develop a Neuro-QOL (Quality of Life) UE measure and a Patient-Reported Outcomes Measurement Information System UE measure; neither of these have demonstrated sensitivity to change, limiting their use for longitudinal assessment. Consequently, although work is still needed to develop and validate performance-based and patient-reported measures of UE function that are suitable for use in daily MS clinical practice, currently available UE measures can be recommended for incorporation into MS management, albeit with an understanding of their limitations. PMID- 25295654 TI - Dementia subtypes in Antalya, Turkey: a retrospective study. AB - The frequency of dementia is increasing steadily, and it is currently estimated that 60% of patients suffering from this disease reside in developing countries. An improvement in health care services for this elderly patients must be anticipated to assist in reducing the patient burden to their communities, families, and health systems; alternately, contributions made by hospitals through their diagnostic efforts and treatment of patients are of great importance. The purpose of this study was to evaluate the health records (n = 246) of patients in a dementia clinic for data regarding age, sex, occupation, reason for presentation, laboratory findings, neuropsychological tests, diagnoses made at presentation, and follow-up visits. Patients aged >= 60 years with cognitive symptoms were included in the study; mean age was 74.4 (SD, 7.58) years, with a predominantly female population (n = 142; 57.7%). The main reason for patient presentation was memory problems (n = 238; 96.7%). Administration of the Mini-Mental State Examination (MMSE) revealed a mean score of 19.14 (SD, 8.24) across the patient population; Montreal Cognitive Assessment mean test scores were 20.9 (SD, 5.31); and Clock Drawing Test median score was 2 points (min-max, 0-4). The most common diagnoses were Alzheimer-type dementia (n = 167; 67.9%) and mild cognitive impairment (n = 49; 19.9%). During a 31-month period, the dementia outpatient clinic was visited an average of 2.79 (SD, 2.32) times. Findings indicated that women had higher vitamin B12 levels (P = 0.001), lower MMSE scores (P = 0.022), fewer follow-up visits (P = 0.006), and higher low density lipoprotein cholesterol levels (P = 0.02). PMID- 25295655 TI - Analysis of buprenorphine/naloxone dosing impact on treatment duration, resource use and costs in the treatment of opioid-dependent adults: a retrospective study of US public and private health care claims. AB - OBJECTIVES: The buprenorphine/naloxone combination is used to treat the chronic relapsing disorder of opioid dependence. Adequate dosing levels are important to control cravings, prevent withdrawal syndrome, and maintain patients in treatment. The objective of this study was to estimate the impact of dosing on treatment persistence, resource utilization, and total direct health care costs. METHODS: A retrospective cohort analysis was performed using administrative claims extracted from the MarketScan and Clinformatics databases from January 2007 to June and November 2012. Patients initiating treatment with buprenorphine/naloxone were classified into 2 groups based on the prescribed average dose over the entire treatment period and matched by multiple criteria. The threshold for differentiating the dosing groups was set at 15 and 15.7 mg/day for publicly and privately insured patients, respectively. Resource utilization and related costs were calculated over the 12-month period after the treatment initiation. RESULTS: Patient characteristics at baseline were considerably different between the privately and publicly insured patients. Publicly insured patients were slightly younger (33.1 vs 34.3 years old for privately insured) and had a higher prevalence of mental disorders (70.9% vs 64.9%). In both groups, patients treated with higher doses (> 15 mg and > 15.7 mg per day for publicly and privately insured patients, respectively) had lower risk of discontinuation (public: 11% lower; private: 9% lower) and lower probability of a psychiatric hospitalization than patients treated with lower doses (public: 17% lower; private: 41% lower). Total costs were comparable between the 2 groups (public: $14 600; private: $21 000) despite the expected higher cost of pharmacy in the higher-dose group. CONCLUSIONS: Treatment with higher doses of buprenorphine/naloxone was associated with a longer time to treatment discontinuation, less resource use, and lower total medical costs despite higher pharmacy acquisition cost. PMID- 25295656 TI - Risk factors associated with hypogonadism in beta-thalassemia major patients: predictors for a frequent complication of a rare disease. AB - BACKGROUND: beta-Thalassemia major (BTM) is a rare disease that challenges clinicians because of the high prevalence of complications despite progress in the development of new therapeutic methods. The aim of this study was to identify clinical and hematological parameters associated with hypogonadism, the most frequent iron overload-related complication found in Romanian patients. METHODS: Patients with BTM were evaluated in the Endocrinology Department of Elias Hospital between February 2004 and December 2013. Only patients who provided written informed consent were included in the study. A complete physical and hormonal evaluation was performed on all patients, and data regarding treatment of the hematological disease were collected. RESULTS: Of the evaluable patients, 85 were included in the study (median age, 21[10] years; range, 13-36 years). We found that 30.6% of the study participants (26 of 85) had normal gonadal status, 54.1% (46 of 85) had early forms of hypogonadism (delayed or arrested puberty), and 15.3% (n = 13) developed hypogonadism after complete sexual maturation. Patients with any form of hypogonadism were older (median age 22 vs 16.5 years, P = 0.047), had significantly lower average hemoglobin levels (P = 0.003), and had higher levels of serum ferritin (P = 0.006) versus patients without hypogonadism. Patients with delayed puberty were associated with increased average serum ferritin levels (P = 0.007), decreased hemoglobin levels (P = 0.001), and increased age at initiation of iron chelation therapy (P < 0.01). We found no significant differences between patients with early forms of hypogonadism and those with hypogonadism after complete sexual maturation, with respect to the analyzed parameters. Patients with adult hypogonadism were significantly older (median age 26 vs 16.5 years, P = 0.007) and tended to have higher serum ferritin levels (P = 0.056) compared with patients without hypogonadism. CONCLUSION: Our data show that hypogonadism is highly prevalent among Romanian patients with BTM, its presence being associated with higher iron overload and lower hemoglobin values. The late start of iron chelation therapy was particularly associated with pubertal abnormalities. PMID- 25295657 TI - Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections in obese patients. AB - BACKGROUND: Ceftaroline fosamil is a broad-spectrum antibiotic approved by the US Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia. The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a multicenter registry study of patients treated with ceftaroline fosamil in the United States for ABSSSI or community-acquired bacterial pneumonia. OBJECTIVE: To describe the clinical effectiveness of ceftaroline fosamil in the treatment of ABSSSI in obese patients [body mass index (BMI) >= 30] compared with patients with a normal BMI (18.5 to <= 24.9). METHODS: Data were collected at US study centers by randomly ordered chart review. RESULTS: Data from 261 patients with a normal BMI and 690 patients with an obese BMI were collected. The percentage of males was higher in the normal BMI than in the obese category (58.2% and 49.0%, respectively). The mean and median ages at baseline were similar. Most patients (91%) were treated on a general hospital ward, and the mean and median lengths of stay were similar between the 2 groups (approximately 11 days and 7 days, respectively). A total of 73.2% of normal BMI patients and 77.5% of obese patients were discharged to home. Rates of diabetes mellitus were 26.4% in the normal BMI group and 55.1% in the obese group. Methicillin-resistant Staphylococcus aureus was isolated from 26.1% of normal BMI patients and 20.5% of obese patients (16.4% morbidly obese subset). Mean treatment duration for all patients was 5.9 days. Of patients with a normal BMI, 57.5% received ceftaroline fosamil as monotherapy as did 63.3% of obese patients. Clinical success was high in both the normal BMI (85.1%) and the obese (89.0%) groups. CONCLUSION: Ceftaroline fosamil is an effective treatment option for obese patients with ABSSSI with a similar clinical success rate, mean and median length of stay, and discharge destination to home when compared with normal BMI patients. PMID- 25295658 TI - Examining the role of activity, exercise, and pharmacology in mild COPD. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and, although it is a preventable and treatable disease, it often remains undiagnosed in patients with mild disease. It is now evident that pathologic changes and physiologic impairment start early in disease progression, and even patients with mild airflow limitation have impairment in the form of exertional dyspnea, general fatigue, and exercise intolerance. Primary care physicians are optimally positioned to recognize these progressive activity restrictions in their patients, usually involving little more than a detailed patient history and a simple symptom questionnaire. Once a patient with persistent activity-related dyspnea has been diagnosed with COPD, bronchodilators can effectively address expiratory airflow limitation and lung hyperinflation that underlie symptoms. These pharmacologic interventions work in conjunction with nonpharmacologic interventions, including smoking cessation, exercise training, and pulmonary rehabilitation. Although the benefits of exercise intervention are well established in patients with more severe COPD, a small amount of new data is emerging that supports the benefits of both pharmacologic treatment and exercise training for improving exercise endurance in patients with mild-to-moderate COPD. This review examines the growing body of data that suggests that early identification-most likely by primary care physicians-and appropriate intervention can favorably impact the symptoms, exercise tolerance, health status, quality of life, hospitalizations, and economic costs of COPD. PMID- 25295659 TI - Eye movement during reading in young adults with cerebral palsy measured with eye tracking. AB - BACKGROUND: Cerebral palsy is a nonprogressive brain disorder associated with lifelong motor impairments and often with cognitive deficits, impaired communication, and impaired sensory perception. Vision deficits, in particular, occur frequently in cerebral palsy and can lead to reading difficulties. OBJECTIVE: Investigate the extent to which the motor impairments in this clinical group affect patients' ability to read. METHODS: An eye-tracking system was used to record the eye movements during a reading task in 31 adults diagnosed with cerebral palsy and in 10 healthy controls. Participants were asked to read out loud 1 to 5 excerpts from children's books. RESULTS: In comparison to the healthy readers, cerebral palsy patients took longer to read the excerpts; made more saccades, fixations, and regressions; and made shorter saccades. Average fixation times were similar between the 2 groups, but the average saccade duration was significantly longer for the cerebral palsy group, as a function of the degree of severity of motor impairment. The latter was not a determinant of the level of text comprehension achieved by these patients. CONCLUSIONS: OBJECTIVE measures of eye movement during a reading task can be obtained in cerebral palsy patients using eye-tracking techniques. RESULTS suggest that cerebral palsied patients may experience difficulties in searching for words during reading. PMID- 25295660 TI - Prescribing opioids for chronic noncancer pain in primary care: risk assessment. AB - The use of opioids for patients with chronic noncancer pain has increased dramatically, and with increasing use there is increasing concern about the potential for abuse and addiction during long-term treatment. Clinicians should avoid viewing formal or subjective risk assessment as a means of classifying patients into 2 distinct categories: compliant patients and substance abusers. The provider who perceives a patient as compliant may have a complacent attitude toward aberrant drug-related behavior, presuming that these signs reflect inadequately controlled pain, to be addressed by dose escalation. The provider who perceives a patient as a substance abuser may refuse to provide treatment for pain, leaving the patient to seek either illicit drugs or prescribed treatment from another provider. In fact, in seemingly compliant patients, any noncompliant use of opioids presents a safety risk regardless of the explanations offered. Even in known or suspected drug abusers, chronic pain warrants the use of adequate pharmacotherapy, although treatment in such cases may exclude drugs with high abuse potential. Thus, all aberrant drug-related behavior should be addressed within a treatment plan that combines adequate pain care with suitable interventions for the aberrant behavior, following current best practice strategies. This approach is consistent with the approach taken with other health conditions, such as diabetes or hypertension, for which it is understood that noncompliance with therapy presents a risk of harm. PMID- 25295661 TI - Staphylococcus aureus bacteremia: targeting the source. AB - Bacteremia due to Staphylococcus aureus is one of the major causes of morbidity and mortality in India, but studies targeting the source of Staphylococcus aureus bacteremia are lacking. S. aureus has a vivid armamentarium consisting of toxins, adhesins, and other virulence factors by virtue of which it can cause varied types of infections, sometimes of a serious nature. This review highlights the possible causes of S. aureus bacteremia, and discusses the necessity of tracing its source and eliminating it with proper antibiotic therapy to avoid recurrences or relapses. PMID- 25295662 TI - Outcome comparison of 600 mg versus 300 mg loading dose of clopidogrel for patients with ST-elevation myocardial infarction: a meta-analysis. AB - BACKGROUND: A 600-mg loading dose (LD) of clopidogrel has been shown to be superior to a 300-mg LD in inhibiting platelet function. However, data for clinical superiority are limited, and there is a paucity of adequately powered randomized trials investigating this issue. This meta-analysis was performed to determine the optimal LD of clopidogrel in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention. METHODS: A meta analysis of controlled trials and observational studies was performed comparing 600-mg with 300-mg LDs of clopidogrel. The primary efficacy end point was a major adverse cardiac event (MACE), and the primary safety end point was major bleeding. Data were extracted on an intention to treat basis. The X2 test was used to evaluate heterogeneity. A random effects model was used, and odds ratios (OR) were calculated using the Mantel-Haenszel method. RESULTS: Nine studies involving 18 623 patients were included in the efficacy analysis. Mean duration of follow-up was 8 months. Four studies were eligible for the safety analysis. The MACE risk was lower with a 600-mg LD (7.0% [650/9231]) than with a 300-mg LD (9.2% [867/9392]; OR, 0.75; 95% CI, 0.63-0.91). On the other hand, there was no significant difference in the major bleeding events between the 2 groups (2.5% [89/3551] with 600 mg vs 2.3% [63/2796] with 300 mg; OR, 0.84; 95% CI, (0.60 1.16). CONCLUSIONS: In ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention, administration of a 600-mg LD of clopidogrel is associated with a lower risk of MACE than is administration of a 300-mg LD, without increasing the risk of major bleeding. PMID- 25295663 TI - Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. AB - BACKGROUND: Because hydrogen therapy has been found beneficial for the treatment of inflammation, ischemia-reperfusion injury, and oxidative stress in humans, it seems useful to evaluate the effects of exogenously administered hydrogen as an element in the immediate management of sports-related soft tissue injuries. The main aim of this pilot study was to examine the effects of 2-week administration of hydrogen on the biochemical markers of inflammation and functional recovery in male professional athletes after acute soft tissue injury. METHOD: During the 2013 season (from March to May), 36 professional athletes were recruited as participants and examined by a certified sports medicine specialist in the first 24 hours after an injury was sustained. Subjects were allocated to 3 randomly assigned trials in a single-blind design. Those in the control group received a traditional treatment protocol for soft tissue injury. Subjects in the first experimental group followed the same procedures as the control group but with additional administration throughout the study of oral hydrogen-rich tablets (2 g per day). Subjects in the second experimental group also followed the procedures of the control group, with additional administration throughout the study of both oral hydrogen-rich tablets (2 g per day) and topical hydrogen-rich packs (6 times per day for 20 minutes). Participants were evaluated at the time of the injury report and at 7 and 14 days after baseline testing. RESULTS: Oral and topical hydrogen intervention was found to augment plasma viscosity decrease as compared with the control group (P = 0.04). Differences were found for range-of-motion recovery between the 3 groups; oral and topical hydrogen intervention resulted in a faster return to normal joint range of motion for both flexion and extension of the injured limb as compared with the control intervention (P < 0.05). CONCLUSION: These preliminary results support the hypothesis that the addition of hydrogen to traditional treatment protocols is potentially effective in the treatment of soft tissue injuries in male professional athletes. Trial identification: Clinicaltrials.gov number NCT01759498. PMID- 25295666 TI - Letter to the editor: Suicidal ideation and research ethics committees: a reply. PMID- 25295667 TI - A comparison between phone-based psychotherapy with and without text messaging support in between sessions for crisis patients. AB - BACKGROUND: Few studies have tested whether individually tailored text messaging interventions have an effect on clinical outcomes when used to supplement traditional psychotherapy. This is despite the potential to improve outcomes through symptom monitoring, prompts for between-session activities, and psychoeducation. OBJECTIVE: The intent of the study was to explore the use of individually tailored between-session text messaging, or short message service (SMS), as an adjunct to telephone-based psychotherapy for consumers who present to the Emergency Department (ED) in situational and/or emotional crises. METHODS: Over a 4-month period, two therapists offered 68 prospective consumers of a telephone-based psychotherapy service individually tailored between-session text messaging alongside their telephone-based psychotherapy. Attendance and clinical outcomes (depression, anxiety, functional impairment) of those receiving messages were compared against a historical control group (n=157) who received telephone psychotherapy only. RESULTS: A total of 66% (45/68) of the consumers offered SMS accepted the intervention. A total of 432 messages were sent over the course of the trial, the majority involving some kind of psychoeducation or reminders to engage in therapy goals. There were no significant differences in clinical outcomes between consumers who received the SMS and those in the control group. There was a trend for participants in the intervention group to attend fewer sessions than those in the control group (mean 3.7, SD 1.9 vs mean 4.4, SD 2.3). CONCLUSIONS: Both groups showed significant improvement over time. Individually tailored SMS were not found to improve clinical outcomes in consumers receiving telephone-based psychotherapy, but the study was underpowered, given the effect sizes noted and the significance level chosen. Given the ease of implementation and positive feedback from therapists and clients, individually tailored text messages should be explored further in future trials with a focus on enhancing the clinical impact of the tailored text messages, and utilizing designs with additional power to test for between-group effects. PMID- 25295668 TI - The influence of the aromatic aglycon of galactoclusters on the binding of LecA: a case study with O-phenyl, S-phenyl, O-benzyl, S-benzyl, O-biphenyl and O naphthyl aglycons. AB - A library of 24 new mannose-centered tetragalactoclusters with four different linkers (di- and triethyleneglycol with phosphodiester or phosphorothioate linkages) and six different aromatic aglycons (O-phenyl, S-phenyl, O-benzyl, S benzyl, O-biphenyl and O-naphthyl) was synthesized. Their interactions with LecA were evaluated on a DNA Directed Immobilization (DDI) based glycocluster array allowing the determination of their IC50 against lactose and the evaluation of their dissociation constant (Kd). Finally, the docking simulations confirm the experimental results and demonstrated that the better affinity of O-biphenyl- and O-naphthyl-galactoside is due to a double interaction between the aromatic ring and the histidine 50 and proline 51 of LecA. PMID- 25295669 TI - Antihypertensive effect of Carica papaya via a reduction in ACE activity and improved baroreflex. AB - The aims of this study were to evaluate the antihypertensive effects of the standardised methanolic extract of Carica papaya, its angiotensin converting enzyme inhibitory effects in vivo, its effect on the baroreflex and serum angiotensin converting enzyme activity, and its chemical composition. The chemical composition of the methanolic extract of C. papaya was evaluated by liquid chromatography-mass/mass and mass/mass spectrometry. The angiotensin converting enzyme inhibitory effect was evaluated in vivo by Ang I administration. The antihypertensive assay was performed in spontaneously hypertensive rats and Wistar rats that were treated with enalapril (10 mg/kg), the methanolic extract of C. papaya (100 mg/kg; twice a day), or vehicle for 30 days. The baroreflex was evaluated through the use of sodium nitroprusside and phenylephrine. Angiotensin converting enzyme activity was measured by ELISA, and cardiac hypertrophy was evaluated by morphometric analysis. The methanolic extract of C. papaya was standardised in ferulic acid (203.41 +/- 0.02 ug/g), caffeic acid (172.60 +/- 0.02 ug/g), gallic acid (145.70 +/- 0.02 ug/g), and quercetin (47.11 +/- 0.03 ug/g). The flavonoids quercetin, rutin, nicotiflorin, clitorin, and manghaslin were identified in a fraction of the extract. The methanolic extract of C. papaya elicited angiotensin converting enzyme inhibitory activity. The antihypertensive effects elicited by the methanolic extract of C. papaya were similar to those of enalapril, and the baroreflex sensitivity was normalised in treated spontaneously hypertensive rats. Plasma angiotensin converting enzyme activity and cardiac hypertrophy were also reduced to levels comparable to the enalapril-treated group. These results may be associated with the chemical composition of the methanolic extract of C. papaya, and are the first step into the development of a new phytotherapic product which could be used in the treatment of hypertension. PMID- 25295670 TI - Essential oil from Myrcia ovata: chemical composition, antinociceptive and anti inflammatory properties in mice. AB - The leaves of Myrcia ovata, popularly known as "laranjinha do mato", are frequently used as an infusion in folk medicine. The essential oil obtained from these leaves is rich in citral, a mixture of neral and geranial isomers, known for its analgesic effect. Male Swiss mice (20-22 g) were tested in models of acute pain (acetic acid-induced abdominal writhing, tail flick, and formalin tests) and acute inflammation (paw oedema and air pouch tests) as well as in a model for evaluation of spontaneous motor performance (open-field test). The essential oil from M. ovata was administered orally at doses of 50-300 mg/kg. In addition, water, vehicle, morphine (5.01 mg/kg for evaluation of pain and motor performance), acetyl salicylic acid (200 mg/kg in the formalin test), and dexamethasone (2.25 mg/kg for evaluation of oedema formation, leukocyte extravasation, and quantification of cytokines) were administered. The essential oil showed a significant effect at doses of 200 and 300 mg/kg in the acute pain and acute inflammation tests. The effect of the essential oil was reduced by pretreatment with naloxone. The essential oil did not induce motor impairment. The extract was not toxic after oral administration (LD50 > 3000 mg/kg). These data provide initial evidence that the traditional use of M. ovata can be effective in reducing pain and inflammation. PMID- 25295671 TI - Antiproliferative activity of Artemisia asiatica extract and its constituents on human tumor cell lines. AB - The extract of Artemisia asiatica herb with antiproliferative activity against four human tumor cell lines (A2780, A431, HeLa, and MCF7) was analyzed by the MTT assay, and bioassay-directed fractionation was carried out in order to identify the compounds responsible for the cytotoxic activity. Guaianolide (1-4), seco guianolide (5), germacranolide (6) and eudesmanolide sesquiterpenes (7), monoterpenes (8, 9), including the new compound artemisia alcohol glucoside (8), and flavonoids (10-16) were isolated as a result of a multistep chromatographic procedure (CC, CPC, PLC, and gel filtration). The compounds were identified by means of UV, MS, and NMR spectroscopy, including (1)H-and (13)C-NMR, (1)H-(1)H COSY, NOESY, HSQC, and HMBC experiments. The isolated compounds 1-16 were evaluated for their tumor cell growth-inhibitory activities on a panel of four adherent cancer cell lines, and different types of secondary metabolites were found to be responsible for the cytotoxic effects of the extract. Especially cirsilineol (13), 3beta-chloro-4alpha,10alpha-dihydroxy-1alpha,2alpha-epoxy 5alpha,7alphaH-guai-11(13)-en-12,6alpha-olide (3), and iso-seco-tanapartholide 3 O-methyl ester (5) exerted marked cytotoxic effects against the investigated cell lines, while jaceosidin (12), 6-methoxytricin (15), artecanin (2), and 5,7,4',5' tetrahydroxy-6,3'-dimethoxyflavone (14) were moderately active. All the sesquiterpenes and monoterpenes are reported here for the first time from this species, and in the case of artecanin (2), 3alpha-chloro-4beta,10alpha-dihydroxy 1beta,2beta-epoxy-5alpha,7alphaH-guai-11(13)-en-12,6alpha-olide (4), ridentin (6), and ridentin B (7), previously unreported NMR spectroscopic data were determined. PMID- 25295672 TI - Recovery of polyphenols from rose oil distillation wastewater using adsorption resins--a pilot study. AB - The production of rose oil from rose flowers by water steam distillation leaves a water fraction of the distillate as main part of the waste. Therefore, the rose oil distillation wastewater represents a serious environmental problem due to the high content of polyphenols which are difficult to decompose and have to be considered as biopollutants when discarded into the drainage system and rivers. On the other hand, natural polyphenols are valuable compounds with useful properties as bioactive substances. Until now there is no established practice for processing of rose oil distillation wastewater and utilization of contained substances. Thus, it was the aim of this study to develop a strategy to separate this wastewater into a polyphenol depleted water fraction and a polyphenol enriched fraction which could be developed into innovative value-added products. In a first step, the phytochemical profile of rose oil distillation wastewater was determined. Its HPLC-PDA-MS analysis revealed the presence of flavan-3-ols, flavanones, flavonols and flavones. In a second step, the development of a stepwise concentration of rose oil distillation wastewater was performed. The concentration process includes a filtration process to eliminate suspended solids in the wastewater, followed by adsorption of the contained phenolic compounds onto adsorption resins (XAD and SP). Finally, desorption of the polyphenol fraction from the resin matrix was achieved using ethanol and/or aqueous ethanol. The result of the process was a wastewater low in soluble organic compounds and an enriched polyphenol fraction (RF20 SP-207). The profile of this fraction was similar to that of rose oil distillation wastewater and showed the presence of flavonols such as quercetin and kaempferol glycosides as major metabolites. These compounds were isolated from the enriched polyphenol fraction and their structures confirmed by NMR. In summary, a pilot medium scale system was developed using adsorption resins for the recovery of polyphenols from rose oil distillation wastewater suggesting an industrial scalability of the process. PMID- 25295673 TI - Attenuation of cisplatin-induced emetogenesis by standardized Bacopa monnieri extracts in the pigeon: behavioral and neurochemical correlations. AB - Nausea and vomiting are the most distressing and common side effects of cancer chemotherapy which often result in patient noncompliance. In the present study, standardized methanolic and n-butanolic fractions of Bacopa monnieri were evaluated against cisplatin-induced emesis in the pigeon in relation to their activity on central and intestinal neurotransmitters levels. Cisplatin (7.0 mg/kg, i. v.) induced reproducible emesis without lethality in healthy pigeons. The methanolic (10-40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5-20 mg/kg), as well as the antioxidant N-(2-mercaptopropionyl) glycine (10 mg/kg), attenuated cisplatin-induced emesis by 66.3% (p < 0.05), 71.6% (p < 0.001), and 76.5% (p < 0.001), respectively, where the standard antiemetic metoclopramide (30 mg/kg) produced a 48.9% reduction (p < 0.01). The methanolic and n-butanolic fractions of B. monnieri at all of the doses tested significantly reduced the serotonin concentration (p < 0.001) in the brain stem and intestine 3 h after cisplatin administration, while at the 18th h, B. monnieri treatments attenuated not only the dopamine upsurge in the area postrema and brain stem (p < 0.05-0.001), but also the intestinal 5-HT concentration (p < 0.01-0.001). B. monnieri treatments alone did not alter the basal neurotransmitters or their metabolites in the brain areas and intestine. The prolonged suppressive effect of B. monnieri treatments on the behavioral signs of cisplatin-induced emesis, the subsequent supportive neural evidence, and the safety and tolerability profile suggest that B. monnieri methanolic and bacoside-rich n-butanolic fractions might be a valuable adjunct in the treatment of emetogenic chemotherapy, and this warrants further study in other models of emesis. PMID- 25295674 TI - Suppressing qubit dephasing using real-time Hamiltonian estimation. AB - Unwanted interaction between a quantum system and its fluctuating environment leads to decoherence and is the primary obstacle to establishing a scalable quantum information processing architecture. Strategies such as environmental and materials engineering, quantum error correction and dynamical decoupling can mitigate decoherence, but generally increase experimental complexity. Here we improve coherence in a qubit using real-time Hamiltonian parameter estimation. Using a rapidly converging Bayesian approach, we precisely measure the splitting in a singlet-triplet spin qubit faster than the surrounding nuclear bath fluctuates. We continuously adjust qubit control parameters based on this information, thereby improving the inhomogenously broadened coherence time (T2*) from tens of nanoseconds to >2 MUs. Because the technique demonstrated here is compatible with arbitrary qubit operations, it is a natural complement to quantum error correction and can be used to improve the performance of a wide variety of qubits in both meteorological and quantum information processing applications. PMID- 25295675 TI - Personalized preventive care reduces healthcare expenditures among Medicare Advantage beneficiaries. AB - OBJECTIVES: To investigate the impact on healthcare expenditure and utilization trends of a personalized preventive care program designed to deliver individualized care focused on disease preventionamong Medicare Advantage beneficiaries. STUDY DESIGN: MD-Value in Prevention (MDVIP) consists of a network of affiliated primary care physicians who utilize a model of healthcare delivery based on an augmented physician-patient relationship and focused on personalized preventive healthcare. The cost-effectiveness of the program was estimated using medical and pharmacy claims data relative to nonmembers. METHODS: Multivariate modeling was used to control for demographic, socioeconomic, supply of healthcare services, and health status differences between members and nonmembers. Healthcare expenditure and utilization trends for members and nonmembers were tracked from the pre-period prior to member enrollment for a period of 2 years post enrollment. RESULTS: MDVIP members experienced significantly reduced utilization rates for emergency department visits and inpatient admissions. Reduced medical utilization resulted in program savings of $86.68 per member per month (PMPM) in year 1 and $47.03 PMPM in year 2 compared with nonmembers. CONCLUSIONS: A primary care model based on an augmented physician-patient relationship and focused on personalized preventive medicine can reduce Medicare Advantage healthcare spending. PMID- 25295676 TI - Impact of hypertension on healthcare costs among children. AB - OBJECTIVES: Despite the significant prevalence of elevated blood pressure (BP) and body mass index (BMI) in children, few studies have assessed their combined impact on healthcare costs. This study estimates healthcare costs related to BP and BMI in children and adolescents. STUDY DESIGN: Prospective dynamic cohort study of 71,617 children aged 3 to 17 years with 208,800 child years of enrollment in integrated health systems in Colorado or Minnesota between January 1, 2007, and December 31, 2011. METHODS: Generalized linear models were used to calculate standardized annual estimates of total, inpatient, outpatient, and pharmacy costs, outpatient utilization, and receipt of diagnostic and evaluation tests associated with BP status and BMI status. Results: Total annual costs were significantly lower in children with normal BP ($736, SE = $15) and prehypertension ($945, SE = $10) than children with hypertension ($1972, SE = $74) (P <.001, each comparison), adjusting for BMI. Total annual cost for children below the 85th percentile of BMI ($822, SE = $8) was significantly lower than for children between the 85th and 95th percentiles ($954, SE = $45) and for children at or above the 95th percentile ($937, SE = $13) (P <.001, each), adjusting for HT. CONCLUSIONS: This study shows strong associations of prehypertension and hypertension, independent of BMI, with healthcare costs in children. Although BMI status was also statistically significantly associated with costs, the major influence on cost in this large cohort of children and adolescents was BP status. Costs related to elevated BMI may be systematically overestimated in studies that do not adjust for BP status. PMID- 25295677 TI - Massachusetts health reform and Veterans Affairs health system enrollment. AB - OBJECTIVES: Veterans Health Administration (VA) operates the largest integrated health system in the nation. The Affordable Care Act (ACA) does not require any changes to VA, but the individual mandate and expanded health insurance options may change veterans' preferences for coverage. We examined the impact of healthcare reform in Massachusetts, which also included these policy changes, on veterans' enrollment in VA, private insurance, and Medicaid. STUDY DESIGN: Massachusetts' healthcare reform in June 2006 served as a natural experiment. Using data from the 2004-2013 Current Population Surveys, we examined enrollment in VA, private insurance, and Medicaid, comparing veterans residing in Massachusetts with veterans residing in neighboring New England states that did not undergo health reform. METHODS: We estimated the probability of being enrolled in VA, private insurance, and Medicaid before and after healthcare reform, using multivariate probit models while adjusting for individual characteristics. Using a difference-in-difference approach, we compared pre-post changes in enrollment probability among Massachusetts and non-Massachusetts veterans, respectively. RESULTS: Compared with other New England veterans, Massachusetts veterans decreased their enrollment in VA and private insurance by 0.2 (P = .857) and 0.9 (P = .666) percentage points, respectively, following health reform. In contrast, Medicaid enrollment increased by 2.5 percentage points (P = .038). CONCLUSIONS: Healthcare reform in Massachusetts was associated with greater Medicaid enrollment, but was not significantly associated with VA and private insurance enrollment. Our results are significant for informing VA fiscal planning in the post ACA era. PMID- 25295678 TI - Potential role of network meta-analysis in value-based insurance design. AB - OBJECTIVES: Value-based insurance design (V-BID) has emerged as an approach to improve health outcomes and contain healthcare costs by encouraging use of high value care. We estimated the impact of a V-BID for osteoporosis treatments using comparative effectiveness evidence and real-world data from a California health insurance plan to estimate the benefits of the design's implementation. METHODS: This study consisted of 4 steps. First, we reviewed randomized clinical trials including osteoporosis treatments-alendronate, ibandronate, risedronate, raloxifene, and teriparatide-reported in a recent Agency for Health Research Quality systematic review. Second, we performed a network meta-analysis to synthesize data from the clinical trials and estimate the comparative effectiveness of included treatments. Third, we implemented a V-BID by removing co-payments for the most effective treatments. Fourth, using a Monte Carlo simulation, we estimated the impact of the V-BID in terms of fracture reduction and cost-savings. RESULTS: Thirty-two randomized controlled trials were included in the network meta-analysis. We estimated that alendronate, risedronate, and teriparatide have the highest probability of being most effective across each fracture type-vertebral, hip, and nonvertebral/ nonhip. After eliminating co payments, (ie, reducing them to zero), for these treatments, we estimated the health plan would experience a 7% (n = 287) decrease in fractures and an 8% ($6.8 million) decrease in costs. CONCLUSIONS: Our study illustrates the benefits of comparative effectiveness evidence in V-BID development. We show that where clinical trials are lacking, network meta-analysis can provide valuable insights into the potential clinical and economic benefits of V-BID. PMID- 25295679 TI - Tracking spending among commercially insured beneficiaries using a distributed data model. AB - OBJECTIVES: To explore the feasibility of using a distributed data model for ongoing reporting of local healthcare spending, specifically to investigate the contribution of utilization and pricing to geographic variation and trends in reimbursements for commercially insured beneficiaries younger than 65 years. STUDY DESIGN: Retrospective descriptive analysis. METHODS: Commercial claims were obtained for beneficiaries in 5 states for the years 2008 to 2010 using a distributed data model. Claims were aggregated to the hospital service area (HSA) level and healthcare utilization was quantified using a novel, National Quality Forum-endorsed measure that is independent of price and allows for the calculation of resource use across all services in standardized units. We examined trends in utilization, prices, and reimbursements over time. To examine geographic variation, we mapped resource use by HSA in the 3 states from which we had data from multiple insurers. We calculated the correlation between commercial and Medicare reimbursements and utilization. Medicare claims were obtained from the Dartmouth Atlas. RESULTS: We found that much of the recent growth in reimbursements for the commercially insured from 2008 to 2010 was due to increases in prices, particularly for outpatient services. As in the Medicare population, resource use by this population varied by HSA. While overall resource use patterns in the commercially insured did not mirror those among Medicare beneficiaries, we observed a strong correlation in inpatient hospital use. CONCLUSIONS: This research demonstrates the feasibility and value of public reporting of standardized area-level utilization and price data using a distributed data model to understand variation and trends in reimbursements. PMID- 25295680 TI - Contemporary use of dual antiplatelet therapy for preventing cardiovascular events. AB - OBJECTIVES: CHARISMA was a landmark randomized clinical trial that failed to demonstrate a benefit of dual antiplatelet therapy (DAPT) over aspirin alone for preventing cardiovascular events. However, subgroup analyses of the trial found fewer major adverse cardiovascular events (MACEs) for patients with established cardiovascular disease but more MACEs for patients with multiple risk factors without established cardiovascular disease. Our objective was to examine DAPT use in contemporary clinical practice after publication of CHARISMA results. STUDY DESIGN: Retrospective analysis of a large clinical registry of outpatient cardiovascular visits to over 1000 physicians that collected data on patient clinical history, symptoms, vital signs, and medications. METHODS: Clinical characteristics and prescription rates of aspirin and clopidogrel were compared for patients with established cardiovascular disease and for patients with only multiple cardiovascular risk factors. Prescription of DAPT by calendar quarter was evaluated from 2008 to 2011 using multivariable Poisson regression models. RESULTS: Of 167,839 patients with established cardiovascular disease, 20.5% were prescribed both aspirin and clopidogrel. Of 20,478 patients with multiple risk factors but no known cardiovascular disease, 3.5% were prescribed both aspirin and clopidogrel. Across 14 calendar quarters, prescription rates of DAPT did not change significantly for patients with established CVD but decreased for patients with multiple risk factors with an incidence rate ratio of 0.77. CONCLUSIONS: Use of DAPT is modest in patients with established cardiovascular disease, for whom the CHARISMA trial suggested decreased MACEs, and prescription rates have remained stable over time. Use of DAPT in patients with multiple risk factors only, for whom CHARISMA suggested that DAPT may lead to increased MACE, was low and decreased over time. PMID- 25295681 TI - Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. AB - OBJECTIVE: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. METHODS: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. RESULTS: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. CONCLUSION: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12612000830897. PMID- 25295682 TI - Perimetry, retinal nerve fiber layer thickness and papilledema grade after cerebrospinal fluid shunting in patients with idiopathic intracranial hypertension. AB - BACKGROUND: To investigate the effect of cerebrospinal fluid (CSF) shunting on quantitative perimetry and papilledema in patients with uncontrolled idiopathic intracranial hypertension (IIH). METHODS: We retrospectively reviewed all cases of IIH with CSF shunting at our institution between 2004 and 2011. Perimetry was performed before and after surgery in 15 patients, and the mean deviation (MD) was compared before and after surgery to assess the effect of the intervention. RESULTS: Fourteen of the IIH patients were female and 1 was male. The average age was 34 years. CSF shunting resulted in significant improvement in the perimetric results with an increase in the MD of 5.63 +/- 1.19 dB (P < 0.0001). Additionally, average retinal nerve fiber layer (RNFL) thickness measurement by optical coherence tomography decreased by 87.27 +/- 16.65 MUm (P < 0.0001), and Frisen papilledema grade decreased by 2.19 +/- 0.71 (P < 0.0001). CONCLUSIONS: Our results suggest that CSF shunting results in improvement in perimetry, RNFL swelling, and papilledema grade in patients with IIH. PMID- 25295683 TI - Association between phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. AB - BACKGROUND: Use of phosphodiesterase-5 (PDE-5) inhibitors has been reported to be a risk factor for development of nonarteritic anterior ischemic optic neuropathy (NAION) in males, based largely on a number of case reports. The objective of our study was to determine whether men who use this class of medications are more likely than a matched control group to develop NAION. METHODS: A pharmacoepidemiological nested case-control study was used to examine the above association in a health claims database of physician diagnoses and prescription medication dispensing. Cases of NAION were matched with corresponding controls and correlated with the use of PDE-5 inhibitors. A conditional logistic regression model was used to estimate rate ratios for development of NAION with use of PDE-5 inhibitors. RESULTS: A total of 1,109 cases of NAION were found and matched to 1,237,290 controls identified within the database. Cases were more likely to have hyperlipidemia, diabetes, hypertension, myocardial infarction, and cerebrovascular accident in the year preceding their NAION. The adjusted rate ratio for any use of PDE-5 inhibitor in the year before the NAION was 1.01 (95% confidence interval [CI], 0.79-1.28); recent use of a PDE-5 inhibitor in the 30 days before the NAION also had no significant association, with an adjusted rate ratio of 0.96 (95% CI, 0.75-1.23). Results for individual PDE-5 inhibitors did not achieve statistical significance. CONCLUSIONS: Our results do not suggest any association between having a prescription filled for PDE-5 inhibitor medication and receiving a diagnosis code for NAION. This is consistent with other studies in the literature that have failed to elucidate a plausible mechanism by which these drugs might compromise circulation at the optic nerve head. PMID- 25295684 TI - Renal cell carcinoma metastatic to the orbit in a patient with Wegener granulomatosis. PMID- 25295685 TI - Progressive MRI findings in Creutzfeldt-Jakob disease. PMID- 25295687 TI - A fast, efficient and simple method for the synthesis of cyclic alkenyl fluorides by a fluorinative carbocyclization reaction. AB - A simple transformation of alkynol or enyne derivatives into cyclic alkenyl fluorides by using tetrafluoroboric acid as the proton and fluoride source is reported. This study includes the first biomimetic cationic cyclization/nucleophilic fluorination reaction of polyenyne derivatives to give terpenoid derivatives. PMID- 25295686 TI - Chiasmatic and achiasmatic inverted meiosis of plants with holocentric chromosomes. AB - Meiosis is a specialized cell division in sexually reproducing organisms before gamete formation. Following DNA replication, the canonical sequence in species with monocentric chromosomes is characterized by reductional segregation of homologous chromosomes during the first and equational segregation of sister chromatids during the second meiotic division. Species with holocentric chromosomes employ specific adaptations to ensure regular disjunction during meiosis. Here we present the analysis of two closely related plant species with holocentric chromosomes that display an inversion of the canonical meiotic sequence, with the equational division preceding the reductional. In-depth analysis of the meiotic divisions of Rhynchospora pubera and R. tenuis reveals that during meiosis I sister chromatids are bi-oriented, display amphitelic attachment to the spindle and are subsequently separated. During prophase II, chromatids are connected by thin chromatin threads that appear instrumental for the regular disjunction of homologous non-sister chromatids in meiosis II. PMID- 25295691 TI - [Severe acute colitis: two fatal cases in Dakar]. AB - OBJECTIVE: Severe acute colitis (SAC) is one of the major complications of inflammatory bowel disease (IBD), especially ulcerative colitis, and it is life threatening. Although IBD is considered rare in sub-Saharan Africa, we report 2 fatal cases of SAC in Senegalese patients with ulcerative colitis in Dakar. CASES: One patient was a 73-year-old man and the other a 35-year-old woman. In both cases, the diagnosis was preceded by a chronic dysenteric syndrome (febrile in the woman). Despite antibiotic treatment for potential infectious colitis, both patients' condition worsened. Second-line treatment of parenteral corticosteroids did not prevent the occurrence of intestinal perforation for the man, who developed multiorgan failure. The woman developed toxic megacolon during antibiotic treatment, and it was fatal despite bolus corticosteroids: cardiovascular collapse with shock (case 2) occurred before emergency surgery could begin. Conclusion: in subtropical zones where infectious colitis predominates, it is important to consider the diagnosis of SAC in patients with ulcerative colitis and to begin appropriate treatment despite the fear of infection and the difficulty of accessibility to endoscopic exploration. PMID- 25295692 TI - Testing primary-school children's understanding of the nature of science. AB - Understanding the nature of science (NOS) is a critical aspect of scientific reasoning, yet few studies have investigated its developmental beginnings and initial structure. One contributing reason is the lack of an adequate instrument. Two studies assessed NOS understanding among third graders using a multiple select (MS) paper-and-pencil test. Study 1 investigated the validity of the MS test by presenting the items to 68 third graders (9-year-olds) and subsequently interviewing them on their underlying NOS conception of the items. All items were significantly related between formats, indicating that the test was valid. Study 2 applied the same instrument to a larger sample of 243 third graders, and their performance was compared to a multiple-choice (MC) version of the test. Although the MC format inflated the guessing probability, there was a significant relation between the two formats. In summary, the MS format was a valid method revealing third graders' NOS understanding, thereby representing an economical test instrument. A latent class analysis identified three groups of children with expertise in qualitatively different aspects of NOS, suggesting that there is not a single common starting point for the development of NOS understanding; instead, multiple developmental pathways may exist. PMID- 25295693 TI - Gigaseal mechanics: creep of the gigaseal under the action of pressure, adhesion, and voltage. AB - Patch clamping depends on a tight seal between the cell membrane and the glass of the pipet. Why does the seal have such high electric resistance? Why does the patch adhere so strongly to the glass? Even under the action of strong hydrostatic, adhesion, and electrical forces, it creeps at a very low velocity. To explore possible explanations, we examined two physical models for the structure of the seal zone and the adhesion forces and two respective mechanisms of patch creep and electric conductivity. There is saline between the membrane and glass in the seal, and the flow of this solution under hydrostatic pressure or electroosmosis should drag a patch. There is a second possibility: the lipid core of the membrane is liquid and should be able to flow, with the inner monolayer slipping over the outer one. Both mechanisms predict the creep velocity as a function of the properties of the seal and the membrane, the pipet geometry, and the driving force. These model predictions are compared with experimental data for azolectin liposomes with added cholesterol or proteins. It turns out that to obtain experimentally observed creep velocities, a simple viscous flow in the seal zone requires ~10 Pa.s viscosity; it is unclear what structure might provide that because that viscosity alone severely constrains the electric resistance of the gigaseal. Possibly, it is the fluid bilayer that allows the motion. The two models provide an estimate of the adhesion energy of the membrane to the glass and membrane's electric characteristics through the comparison between the velocities of pressure-, adhesion-, and voltage-driven creep. PMID- 25295694 TI - Identification and characterization of arsenite methyltransferase from an archaeon, Methanosarcina acetivorans C2A. AB - Arsenic is a ubiquitous toxic contaminant in the environment. The methylation of arsenic can affect its toxicity and is primarily mediated by biological processes. Few studies have focused on the mechanism of arsenic methylation in archaea although archaea are widespread in the environment. Here, an arsenite [As(III)] methyltransferase (ArsM) was identified and characterized from an archaeon Methanosarcina acetivorans C2A. Heterologous expression of MaarsM was shown to confer As(III) resistance to an arsenic-sensitive strain of E. coli through arsenic methylation and subsequent volatilization. Purified MaArsM protein was further identified the function in catalyzing the formation of various methylated products from As(III) in vitro. Methylation of As(III) by MaArsM is highly dependent on the characteristics of the thiol cofactors used, with some of them (coenzyme M, homocysteine, and dithiothreitol) more efficient than GSH. Site-directed mutagenesis demonstrated that three conserved cysteine (Cys) residues (Cys62, Cys150, and Cys200) in MaArsM were necessary for As(III) methylation, of which only Cys150 and Cys200 were required for the methylation of monomethylarsenic. These results present a molecular pathway for arsenic methylation in archaea and provide some insight into the role of archaea in As biogeochemistry. PMID- 25295695 TI - The influence of psychological factors on post-partum weight retention at 9 months. AB - OBJECTIVES: Post-partum weight retention (PWR) has been identified as a critical pathway for long-term overweight and obesity. In recent years, psychological factors have been demonstrated to play a key role in contributing to and maintaining PWR. DESIGN: Therefore, the aim of this study was to explore the relationship between post-partum psychological distress and PWR at 9 months, after controlling for maternal weight factors, sleep quality, sociocontextual influences, and maternal behaviours. METHOD: Pregnant women (N = 126) completed a series of questionnaires at multiple time points from early pregnancy until 9 months post-partum. RESULTS: Hierarchical regression indicated that gestational weight gain, shorter duration (6 months or less) of breastfeeding, and post partum body dissatisfaction at 3 and 6 months are associated with higher PWR at 9 months; stress, depression, and anxiety had minimal influence. CONCLUSION: Interventions aimed at preventing excessive PWR should specifically target the prevention of body dissatisfaction and excessive weight gain during pregnancy. STATEMENT OF CONTRIBUTION: What is already known on this subject? Post-partum weight retention (PWR) is a critical pathway for long-term overweight and obesity. Causes of PWR are complex and multifactorial. There is increasing evidence that psychological factors play a key role in predicting high PWR. What does this study add? Post-partum body dissatisfaction at 3 and 6 months is associated with PWR at 9 months post-birth. Post-partum depression, stress and anxiety have less influence on PWR at 9 months. Interventions aimed at preventing excessive PWR should target body dissatisfaction. PMID- 25295696 TI - The impact of diagnosis and trait anxiety on psychological distress in women with early stage breast cancer: a prospective study. AB - OBJECTIVES: High trait anxiety (HTA) determines depressive symptoms and state anxiety in women with breast cancer (BC) or benign breast disease (BBD). Before implementing screening for psychological counselling in these women, it is important to evaluate whether high state anxiety and depressive symptoms are determined by (the threat of) having BC or solely by HTA. Therefore, we compared women with a lump in the breast with women with gallstone disease (GD). METHODS: Women diagnosed with BC (n = 152), BBD (n = 205), and GD (n = 128) were included in a prospective longitudinal study. Questionnaires concerning trait anxiety (baseline), state anxiety, and depressive symptoms were completed before diagnosis was known (BC and BBD) or the laparoscopic cholecystectomy and 6 months later. RESULTS: Pre-diagnosis BC patients scored higher on state anxiety (p = .001) and depressive symptoms (p < .001) compared with GD. At 6 months, scores on depressive symptoms in BC remained higher than GD (p = .005). In women with HTA, before being diagnosed with BC or BBD, scores on state anxiety were higher compared with HTA women with GD (p < .001, p = .040). State anxiety and depressive symptoms at 6 months were predicted by baseline depressive symptoms in women with BC. CONCLUSIONS: The severity of diagnosis (BC) in combination with HTA determined the level of state anxiety and depressive symptoms. Therefore, we recommend identifying women with HTA and offering them a tailor-made follow-up protocol during and after the diagnostic process for BBD or BC. STATEMENT OF CONTRIBUTION: What is already known on this subject? Women diagnosed with BC or BBD experience high levels of anxiety and distress during the diagnostic process. These adverse psychological effects are strengthened by the personality characteristic trait anxiety. Before implementing screening for psychological counselling in women with high trait anixety, it is important to evaluate whether high state anxiety and depressive symptoms are determined by (the threat of) having BC or solely by HTA. What does this study add? To our knowledge, this is the first study comparing women who are confronted with the possibility of having a life-threatening disease, that is, BC, with women who were not suspected of having a life-threatening disease, that is, GD. This study reveals that the severity of diagnosis (BC) in combination with HTA determined the level of state anxiety and depressive symptoms. Therefore, we recommend identifying women with HTA and offering them a tailor-made follow-up protocol during and after the diagnostic process for BC or BBD. PMID- 25295697 TI - Morphological transformations in polymer brushes in binary mixtures: DPD study. AB - Morphological transformations in polymer brushes in a binary mixture of good and bad solvents are studied using dissipative particle dynamics simulations drawing on a characteristic example of polyisoprene natural rubber in an acetone-benzene mixture. A coarse-grained DPD model of this system is built based on the experimental data in the literature. We focus on the transformation of dense, collapsed brush in bad solvent (acetone) to expanded brush solvated in good solvent (benzene) as the concentration of benzene increases. Compared to a sharp globule-to-coil transition observed in individual tethered chains, the collapsed to-expanded transformation in brushes is found to be gradual without a prominent transition point. The transformation becomes more leveled as the brush density increases. At low densities, the collapsed brush is highly inhomogeneous and patterned into bunches composed of neighboring chains due to favorable polymer polymer interaction. At high densities, the brush is expanded even in bad solvent due to steric restrictions. In addition, we considered a model system similar to the PINR-acetone-benzene system, but with the interactions between the solvent components worsened to the limit of miscibility. Enhanced contrast between good and bad solvents facilitates absorption of the good solvent by the brush, shifting the collapsed-to-expanded transformation to lower concentrations of good solvent. This effect is especially pronounced for higher brush densities. PMID- 25295698 TI - Ca2Mn2O5 as oxygen-deficient perovskite electrocatalyst for oxygen evolution reaction. AB - This paper presents the use of Ca2Mn2O5 as an oxygen-deficient perovskite electrocatalyst for oxygen evolution reaction (OER) in alkaline media. Phase-pure Ca2Mn2O5 was made under mild reaction temperatures through a reductive annealing method. This oxygen deficient perovskite can catalyze the generation of oxygen at ~1.50 V versus (vs) reversible hydrogen electrode (RHE) electrochemically, and reach an OER mass activity of 30.1 A/g at 1.70 V (vs RHE). In comparison to the perovskite CaMnO3, Ca2Mn2O5 shows higher OER activities. The molecular level oxygen vacancies and high spin electron configuration on manganese in the crystal structures are likely the contributing factors for the enhanced performance. This work demonstrates that oxygen-deficient perovskite, A2B2O5, is a new class of high performance electrocatalyst for those reactions that involve active oxygen intermediates, such as reduction of oxygen and OER in water splitting. PMID- 25295699 TI - Development of a straightforward and robust technique to implement hadamard encoded multiplexing to high-performance liquid chromatography. AB - High-performance liquid chromatography (HPLC) is an indispensable technique to separate, quantify, and identify a broad range of compounds. Recent advances in HPLC technology led to the development of ultrahigh-performance instruments that allow rapid sample analysis with high efficiency. Nevertheless, there is still the opportunity to increase the sample throughput and to improve the signal-to noise ratio by the application of multiplexing, where the injected samples are encoded with defined sequences. The obtained signal is then deconvoluted to give conventional chromatograms. In this work we present a method and technique which can be easily implemented in commercially available HPLC instruments to perform multiplexing analysis. Using our approach, multiplexing can be performed on standard laboratory equipment by software control and offers an inherent advantage in sensitivity and minimization of analysis time, demonstrated for the analysis of highly diluted polynuclear aromatic hydrocarbon (PAH) samples in water. PMID- 25295700 TI - Proton enhancement in an extended nanochannel. AB - Proton enhancement in an extended nanochannel is investigated by a continuum model consisting of three-dimensional Poisson-Nernst-Planck equations for the ionic mass transport of multiple ionic species with the consideration of surface chemistry on the nanochannel wall. The model is validated by the existing experimental data of the proton distribution inside an extended silica nanochannel. The proton enhancement behavior depends substantially on the background salt concentration, pH, and dimensions of the nanochannel. The proton enrichment at the center of the nanochannel is significant when the bulk pH is medium high (ca. 8) and the salt concentration is relatively low. The results gathered are informative for the development of biomimetic nanofluidic apparatuses and the interpretation of relevant experimental data. PMID- 25295701 TI - Nanoscale electrical and mechanical characteristics of conductive polyaniline network in polymer composite films. AB - The presence and characteristics of a connected network of polyaniline (PANI) within a composite coating based on polyester acrylate (PEA) has been investigated. The bulk electrical conductivity of the composite was measured by impedance spectroscopy. It was found that the composite films containing PANI have an electrical conductivity level in the range of semiconductors (order of 10(-3) S cm(-1)), which suggests the presence of a connected network of the conductive phase. The nanoscopic distribution of such a network within the cured film was characterized by PeakForce tunneling atomic force microscopy (AFM). This method simultaneously provides local information about surface topography and nanomechanical properties, together with electrical conductivity arising from conductive paths connecting the metallic substrate to the surface of the coating. The data demonstrates that a PEA-rich layer exists at the composite-air interface, which hinders the conductive phase to be fully detected at the surface layer. However, by exposing the internal structure of the composites using a microtome, a much higher population of a conductive network of PANI, with higher elastic modulus than the PEA matrix, was observed and characterized. Local current-voltage (I-V) spectroscopy was utilized to investigate the conduction mechanism within the nanocomposite films, and revealed non-Ohmic characteristics of the conductive network. PMID- 25295702 TI - Identification of a new reactive metabolite of pyrrolizidine alkaloid retrorsine: (3H-pyrrolizin-7-yl)methanol. AB - Pyrrolizidine alkaloids (PAs) such as retrorsine are common food contaminants that are known to be bioactivated by cytochrome P450 enzymes to putative hepatotoxic, genotoxic, and carcinogenic metabolites known as dehydropyrrolizidine alkaloids (DHPs). We compared how both electrochemical (EC) and human liver microsomal (HLM) oxidation of retrorsine could produce short lived intermediate metabolites; we also characterized a toxicologically important metabolite, (3H-pyrrolizin-7-yl)methanol. The EC cell was coupled online or offline to a liquid chromatograph/mass spectrometer (LC/MS), whereas the HLM oxidation was performed in 100 mM potassium phosphate (pH 7.4) in the presence of NADPH at 37 degrees C. The EC cell oxidation of retrorsine produced 12 metabolites, including dehydroretrorsine (m/z 350, [M + H(+)]), which was degraded to a new reactive metabolite at m/z 136 ([M + H(+)]). The molecular structure of this small metabolite was determined using high-resolution mass spectrometry and NMR spectroscopy followed by chemical synthesis. In addition, we also identified another minor but reactive metabolite at m/z 136, an isomer of (3H-pyrrolizin-7-yl)methanol. Both (3H-pyrrolizin-7-yl)methanol and its minor isomer were also observed after HLM oxidation of retrorsine and other hepatotoxic PAs such as lasiocarpine and senkirkin. In the presence of reduced glutathione (GSH), each isomer formed identical GSH conjugates at m/z 441 and m/z 730 in the negative ESI-MS. Because (3H-pyrrolizine-7-yl)methanol) and its minor isomer subsequently reacted with GSH, it is concluded that (3H-pyrrolizin-7-yl)methanol may be a common toxic metabolite arising from PAs. PMID- 25295703 TI - Gallium-catalyzed reductive chlorination of carboxylic acids with copper(II) chloride. AB - Described herein is the direct chlorination of carboxylic acids using copper(II) chloride via a gallium(III)-catalyzed reduction in the presence of a hydrosiloxane. During this reductive chlorination, the counteranions of CuCl2 functioned as a chloride source. PMID- 25295704 TI - Compact non-rock-salt structures in sodium fluoride cluster ions at specific sizes revealed by ion mobility mass spectrometry. AB - Structures of small sodium fluoride cluster cations, Na(n)F(n-1)(+), have been determined for n = 5-23 by ion mobility mass spectrometry. In the mass spectrum of Na(n)F(n-1)(+) cluster ions measured after collisions in the ion-drift cell, cuboid ions with near-regular hexahedron such as n = 14 (3 * 3 * 3), 23 (3 * 3 * 5), 38 (3 * 5 * 5), 63 (5 * 5 * 5), and 88 (5 * 5 * 7) were predominantly observed as magic numbers. By comparison of the collision cross sections obtained from the ion mobility measurements with theoretical ones, we have experimentally shown that the ions of n = 7 and 10 have stable non-rock-salt type structures in which one sodium atom is encapsulated into the sodium fluoride cuboid lattice. The collision cross sections of n = 12 and 13 are almost equal to that of the n = 14 cuboid. A similar feature was also observed in collision cross sections of n = 21 and 22, which are equal to that of the n = 23 cuboid. These features indicate that the cluster ions of n = 12, 13, 21, and 22 have near-cuboid structures with some surface defects. PMID- 25295706 TI - Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity. AB - Botulinum neurotoxin serotype A (BoNT/A) is one of the most lethal toxins known. Its extreme toxicity is due to its light chain (LC), a zinc protease that cleaves SNAP-25, a synaptosome-associated protein, leading to the inhibition of neuronal activity. Studies on BoNT/A LC have revealed that two regions, termed exosites, can play an important role in BoNT catalytic activity. A clear understanding of how these exosites influence neurotoxin catalytic activity would provide a critical framework for deciphering the mechanism of SNAP-25 cleavage and the design of inhibitors. Herein, based on the crystallographic structure of BoNT/A LC complexed with its substrate, we designed an alpha-exosite binding probe. Experiments with this unique probe demonstrated that alpha-exosite binding enhanced both catalytic activity and stability of the LC. These data help delineate why alpha-exosite binding is needed for SNAP-25 cleavage and also provide new insights into the extended lifetime observed for BoNT/A LC in vivo. PMID- 25295707 TI - Labeling milk along its production chain with DNA encapsulated in silica. AB - The capability of tracing a food product along its production chain is important to ensure food safety and product authenticity. For this purpose and as an application example, recently developed Silica Particles with Encapsulated DNA (SPED) were added to milk at concentrations ranging from 0.1 to 100 ppb (MUg per kg milk). Thereby the milk, as well as the milk-derived products yoghurt and cheese, could be uniquely labeled with a DNA tag. Procedures for the extraction of the DNA tags from the food matrixes were elaborated and allowed identification and quantification of previously marked products by quantitative polymerase chain reaction (qPCR) with detection limits below 1 ppb of added particles. The applicability of synthetic as well as naturally occurring DNA sequences was shown. The usage of approved food additives as DNA carrier (silica = E551) and the low cost of the technology (<0.1 USD per ton of milk labeled with 10 ppb of SPED) display the technical applicability of this food labeling technology. PMID- 25295708 TI - Sc(OTf)3-catalyzed transfer diazenylation of 1,3-dicarbonyls with triazenes via N N bond cleavage. AB - A new and efficient method for diazenylation reactions was developed with a Sc(OTf)3-catalyzed nitrogen-nitrogen bond cleavage process with triazenes. The transfer diazenylation reactions accommodate a diverse range of active methylene substrates including simple ketones to give aliphatic azo compounds that are of significant potential as azo prodrugs in high yields under mild conditions. PMID- 25295710 TI - Informing pre-registration nurse education: a proposal outline on the value, methods and ethical considerations of involving children in doctoral research. AB - As pre-registration nurse education programmes evolve within the United Kingdom, it is imperative to involve patient/client groups within the research process, as the outcome may invoke a change in the care delivery of the registered nurse (RN). This paper focuses upon children and how children might hypothetically contribute to informing a generic nursing programme in their capacity as a rights holder and expert in their own lives. Even though their contribution and value has been debated around their capacity as research advisor, research participant and co researcher, this paper explores how the child's view of their experience of hospital and of the good nurse could be best captured. Research is a powerful vehicle that can enable their voice to equally inform UK nurse educators and policy makers so that the child's health care needs are effectively met in hospital by RN's who complete a generic programme. PMID- 25295711 TI - [Minutes of the 33rd Congress of ESTRO held in Vienna (Austria), 4-8 April 2014]. PMID- 25295709 TI - Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. AB - RATIONALE: The role of procalcitonin (PCT), a widely used sepsis biomarker, in critically ill patients with sepsis is undetermined. OBJECTIVES: To investigate the effect of a low PCT cut-off on antibiotic prescription and to describe the relationships between PCT plasma concentration and sepsis severity and mortality. METHODS: This was a multicenter (11 Australian intensive care units [ICUs]), prospective, single-blind, randomized controlled trial involving 400 patients with suspected bacterial infection/sepsis and expected to receive antibiotics and stay in ICU longer than 24 hours. The primary outcome was the cumulative number of antibiotics treatment days at Day 28. MEASUREMENTS AND MAIN RESULTS: PCT was measured daily while in the ICU. A PCT algorithm, including 0.1 ng/ml cut-off, determined antibiotic cessation. Published guidelines and antimicrobial stewardship were used in all patients. Primary analysis included 196 (PCT) versus 198 standard care patients. Ninety-three patients in each group had septic shock. The overall median (interquartile range) number of antibiotic treatment days were 9 (6-21) versus 11 (6-22), P = 0.58; in patients with positive pulmonary culture, 11 (7-27) versus 15 (8-27), P = 0.33; and in patients with septic shock, 9 (6-22) versus 11 (6-24), P = 0.64; with an overall 90-day all-cause mortality of 35 (18%) versus 31 (16%), P = 0.54 in the PCT versus standard care, respectively. Using logistic regression, adjusted for age, ventilation status, and positive culture, the decline rate in log(PCT) over the first 72 hours independently predicted hospital and 90-day mortality (odds ratio [95% confidence interval], 2.76 [1.10-6.96], P = 0.03; 3.20 [1.30-7.89], P = 0.01, respectively). CONCLUSIONS: In critically ill adults with undifferentiated infections, a PCT algorithm including 0.1 ng/ml cut-off did not achieve 25% reduction in duration of antibiotic treatment. Clinical trial registered with http://www.anzctr.org.au (ACTRN12610000809033). PMID- 25295712 TI - HF-free synthesis of anatase TiO2 nanosheets with largely exposed and clean {001} facets and their enhanced rate performance as anodes of lithium-ion battery. AB - An interface between toluene and water was utilized to synthesize ca. 10 nm thick of anatase TiO2 nanosheets (NSs) with 82% exposure of {001} facets. In this procedure, highly corrosive and toxic HF, which was generally used to prepare TiO2 NSs with largely exposed high energy facets, was avoided. Furthermore, the surfaces of the NSs were quite clean as suggested by XPS analysis. Serving as anode materials in lithium-ion batteries, these as-prepared anatase TiO2 NSs manifested a low initial irreversible capacity loss (12.5% at 1 C), an excellent capacity retention at 10 C charge-discharge rate (101.9 mA h g(-1) after 100 cycles), and enhanced rate performance at 0.5-10 C current rates in compared with Degussa P25 TiO2 nanoparticles (NPs). Their excellent electrochemical performances were mainly derived from the large proportion of {001} exposed facets and a very short diffusion pathway, which allowed fast and efficient Li(+) transportation in the electrodes. PMID- 25295714 TI - CBCT volumetric coverage extension using a pair of complementary circular scans with complementary kV detector lateral and longitudinal offsets. AB - Onboard cone-beam CT (CBCT) has been widely used in image guided radiation therapy. However, the longitudinal coverage is only 15.5 cm in the pelvis scan mode. As a result, a single CBCT scan cannot cover the planning target volume in the longitudinal direction for over 80% of the patients. The common approach is to use double- or multiple-circular scans and then combine multiple CBCT volumes after reconstruction. However it raises concerns regarding doubled imaging dose at the imaging beam junctions due to beam divergence. In this work, we present a new method, DSCS (Dual Scan with Complementary Shifts), to address the CBCT coverage problem using a pair of complementary circular scans. In DSCS, two circular scans were performed at 39.5 cm apart longitudinally. In the superior scan, the detector panel was offset by 16 cm to the left, 15 cm to the inferior. In the inferior scan, the detector panel was shifted 16 cm to the right and 15 cm to the superior. The effective imaging volume is 39.5 cm longitudinally with a 45 cm lateral field-of-view (FOV). Half beam blocks were used to confine the imaging radiation inside the volume of interest. A new image reconstruction algorithm was developed, based on the Feldkamp-Davis-Kress cone-beam CT reconstruction algorithm, to support the DSCS scanning geometry. Digital phantom simulations were performed to demonstrate the feasibility of DSCS. Physical phantom studies were performed using an anthropomorphic phantom on a commercial onboard CBCT system. With basic scattering corrections, the reconstruction results were acceptable. Other issues, including the discrepancy in couch vertical at different couch longitudinal positions, and the inaccuracy in couch table longitudinal movement, were manually corrected during the reconstruction process. In conclusion, the phantom studies showed that, using DSCS, a 39.5 cm longitudinal coverage with a 45 cm FOV was accomplished. The efficiency of imaging dose usage was near 100%. This proposed method could be potentially useful for image guidance and subsequent treatment plan adaptation. PMID- 25295713 TI - The epidemiology of Mycobacterium bovis in wild deer and feral pigs and their roles in the establishment and spread of bovine tuberculosis in New Zealand wildlife. AB - In New Zealand, wild deer and feral pigs are assumed to be spillover hosts for Mycobacterium bovis, and so are not targeted in efforts aimed at locally eradicating bovine tuberculosis (TB) from possums (Trichosurus vulpecula), the main wildlife host. Here we review the epidemiology of TB in deer and pigs, and assess whether New Zealand's TB management programme could be undermined if these species sometimes achieve maintenance host status. In New Zealand, TB prevalences of up to 47% have been recorded in wild deer sympatric with tuberculous possums. Patterns of lesion distribution, age-specific prevalences and behavioural observations suggest that deer become infected mainly through exposure to dead or moribund possums. TB can progress rapidly in some deer (<10%), but generalised disease is uncommon in wild deer; conversely some infected animals can survive for many years. Deer-to-deer transmission of M. bovis is rare, but transmission from tuberculous deer carcasses to scavengers, including possums, is likely. That creates a small spillback risk that could persist for a decade after transmission of new infection to wild deer has been halted. Tuberculosis prevalence in New Zealand feral pigs can reach 100%. Infections in lymph nodes of the head and alimentary tract predominate, indicating that TB is mostly acquired through scavenging tuberculous carrion, particularly possums. Infection is usually well contained, and transmission between pigs is rare. Large reductions in local possum density result in gradual declines (over 10 years) in TB prevalence among sympatric wild deer, and faster declines in feral pigs. Elimination of TB from possums (and livestock) therefore results in eventual disappearance of TB from feral pigs and wild deer. However, the risk of spillback infection from deer to possums substantially extends the time needed to locally eradicate TB from all wildlife (compared to that which would be required to eradicate disease from possums alone), while dispersal or translocation of pigs (e.g. by hunters) creates a risk of long-distance spread of disease. The high rate at which pigs acquire M. bovis infection from dead possums makes them useful as sentinels for detecting TB in wildlife. It is unlikely that wild deer and feral pigs act as maintenance hosts anywhere in New Zealand, because unrestricted year-round hunting keeps densities low, with far less aggregation than on New Zealand farms. We conclude that active management of wild deer or feral pigs is not required for local TB eradication in New Zealand. PMID- 25295715 TI - Effect of acute, slightly increased intra-abdominal pressure on intestinal permeability and oxidative stress in a rat model. AB - INTRODUCTION: Intra-abdominal hypertension (IAH) is known as a common, serious complication in critically ill patients. Bacterial translocation and permeability changes are considered the pathophysiological bases for IAH-induced enterogenic endotoxemia and subsequent multiorgan failure. Nevertheless, the effects of slightly elevated intra-abdominal pressures (IAPs) on the intestinal mucosa and the associated mechanisms remain unclear. METHODS: To investigate the acute effects of different nitrogen pneumoperitoneum grades on colonic mucosa, male Sprague-Dawley rats were assigned to six groups with different IAPs (0 [control], 4, 8, 12, 16, and 20 mmHg, n = 6/group). During 90 min of exposure, we dynamically monitored the heart rate and noninvasive hemodynamic parameters. After gradual decompression, arterial blood gas analyses were conducted. Thereafter, structural injuries to the colonic mucosa were identified using light microscopy. Colon permeability was determined using the expression of tight junction proteins, combined with fluorescein isothiocyanate dextran (FD-4) absorption. The pro-oxidant-antioxidant balance was determined based on the levels of malondialdehyde (MDA) and antioxidant enzymes. RESULTS: IAH significantly affected the histological scores of the colonic mucosa, tight junction protein expression, mucosal permeability, and pro-oxidant-antioxidant balance. Interestingly, elevations of IAP that were lower than the threshold for IAH also showed a similar, undesirable effect. In the 8 mmHg group, mild hyponatremia, hypocalcemia, and hypoxemia occurred, accompanied by reduced blood and abdominal perfusion pressures. Mild microscopic inflammatory infiltration and increased MDA levels were also detected. Moreover, an 8-mm Hg IAP markedly inhibited the expression of tight junction proteins, although no significant differences in FD-4 permeability were observed between the 0- and 8-mmHg groups. CONCLUSIONS: Acute exposure to slightly elevated IAP may result in adverse effects on intestinal permeability and the pro-oxidant-antioxidant balance. Therefore, in patients with critical illnesses, IAP should be dynamically monitored and corrected, as soon as possible, to prevent intestinal mucosal injury and subsequent gut-derived sepsis. PMID- 25295716 TI - Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive. AB - OBJECTIVE: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). MATERIALS: Participants were healthy, nonobese women aged 18 - 45 years (study 1) or 18 - 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). METHODS: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P-M-E (EE/GSD patch (P) every 7 days for 28 days -> COC (M) once-daily for 21 days -> two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M-P-E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7 day patch-free interval). RESULTS: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 - 1.16), indicating average daily delivery similar to oral administration of 0.019 - 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 - 0.885), indicating average daily delivery from the patch of 0.057 - 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0-168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 - 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. CONCLUSIONS: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives. PMID- 25295717 TI - Switching between phenytoin generics in patients with epilepsy may lead to increased risk of breakthrough seizure: chart analysis and practice recommendations. AB - OBJECTIVE: The Food and Drug Administration (FDA) only requires bioequivalence testing of generic substitutions in order for them to be deemed equivalen to the original product. There may be a large difference of bioavailability among the generic drugs that especially have a narrow therapeutic index, and this may affect clinical outcomes. We aimed to determine whether switching from generic-to generic equivalent anti-epileptic drugs (AEDs) in patients with epilepsy is associated with clinical outcomes. METHODS: We performed a retrospective study using the electronic medical records of a tertiary hospital. Adults with a history of epilepsy who used a generic phenytoin and whose therapy was switched to another generic phenytoin between January 2012 and June 2013 were included (n = 80). We compared the drug concentration of phenytoin and seizure events before and after the switch. RESULTS: After switching their generic phenytoin, 33 out of 80 patients (41%) suffered from increasing seizure events (pre-interchange period, 0.44 +/- 0.97; post-interchange period, 1.24 +/- 2.05; p < 0.0001). The number of medical visits for acute seizure significantly increased in the post interchange period. The phenytoin serum concentration of all the patients was lesser in the post-interchange period than in the pre-interchange period. (pre interchange period, 12.79 MUg/mL; post-interchange period, 6.36 MUg/mL; p < 0.0001). Among the patients with drug resistant epilepsy (DRE), 17 patients (84.2%) had increasing seizure events in the post-interchange period. CONCLUSIONS: We confirmed that there was a significant difference in bioavailability between generic phenytoin. Therefore, when using or switching generic anti-epileptic drugs, therapeutic drug monitoring must be done, and the patients' condition must be considered. PMID- 25295718 TI - Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopedic surgery and for prevention of stroke in atrial fibrillation. AB - BACKGROUND: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. OBJECTIVES: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. METHODS: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. RESULTS: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. CONCLUSIONS: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings. PMID- 25295720 TI - Reporting problems related to medications in Spain. The yonotifico (I report) project, an option for citizens. PMID- 25295719 TI - Effects of postoperative analgesia with the combination of tramadol and lornoxicam on serum inflammatory cytokines in patients with gastric cancer. AB - OBJECTIVE: To compare the effects of postoperative patient-controlled intravenous analgesia (PCIA) with morphine, tramadol, or tramadol combined with lornoxicam on serum inflammatory cytokine production. METHODS: 60 patients with an American Society of Anesthesiologists (ASA) physical status of I or II, undergoing radical correction of gastric cancer, were equally randomized to receive PCIA with morphine (M group), tramadol (T group), or tramadol combined with lornoxicam (L group). The visual analog scale (VAS) and Bruggemann comfort scale (BCS) scores were used to evaluate the postoperative analgesic efficacy. Serum levels of the interleukins (IL) IL-2, IL-6, and IL-10, and soluble IL-2 receptor (sIL-2R) were measured before anesthesia, 90 min after incision, and 24, 48, and 72 h after surgery. RESULTS: No significant difference was found in the VAS, BCS, or baseline serum IL-2, IL-6, IL-10, or sIL-2R between the groups. At 90 min after incision, only the IL-6 levels increased (p < 0.05). At 24 h after surgery, the IL-2 levels decreased, with the M group having the lowest levels, while IL-6, IL 10, and sIL-2R levels increased, with the M group having the highest level and the L group having the lowest level (p < 0.05). At 48 h after surgery, the cytokine levels were starting to return to the baselines but still had statistical significance (p < 0.05). At 72 h after surgery, only the IL-6 levels had returned to their baseline. CONCLUSION: PCIA using tramadol combined with lornoxicam has less influence on inflammatory cytokines than morphine or tramadol alone in patients undergoing gastric cancer surgery. PMID- 25295721 TI - Bioactive constituents of oleanane-type triterpene saponins from the roots of Glycyrrhiza glabra. AB - Three new oleanane-type triterpene saponins, namely licorice-saponin M3 (1), licorice-saponin N4 (2), and licorice-saponin O4 (3), an artificial product (4), as well as five known triterpene glucuronides (5-9), were isolated from the roots of Glycyrrhiza glabra L. Their structures were established using 1D and 2D NMR spectroscopy, mass spectrometry, and by comparison with spectroscopic data reported in the literature. The inhibitory effects of the selected compounds on neuraminidase were evaluated, and the preliminary structure-activity relationship was also predicted. PMID- 25295722 TI - Fabrication of an inexpensive and high efficiency microphotoreactor using CO2 laser technique for photocatalytic water treatment applications. AB - In this study, a micro-photoreactor with catalyst-immobilized micro-channels was designed and fabricated using CO2 laser as a simple and inexpensive technique. The micro-photoreactor is composed of an array of micro-channels, a quartz plate, and an array of UV-LEDs. The micro-channels with the dimension of 400 um width, 50 um depth, and 80 cm length were inscribed on a flat plate of poly(methyl methacrylate) (PMMA). The illuminated specific surface area for the designed micro-reactor was calculated to be 25000 m(-1). To examine the performance of miniaturized photoreactor, the photocatalytic degradation of 4-Nitrophenol as a refractory pollutant was investigated. The effects of operational variables on the performance of micro-photoreactor were studied. Higher photocatalytic degradation is obtained for low flow rates, high light intensities, long micro channels lengths, and low inlet concentrations. Also, the performance of micro photoreactor was examined in the presence of different types of TiO2 catalysts with an average particle size between 5 and 27 nm (such as P25, PC500, Merck, and UV100) and textile dyes with different chemical structures (such as Acid Orange 7, Acid Violet 19, Basic Red 46, Methyl Orange, and Malachite Green). Finally, the reusability of miniaturized photoreactor was evaluated and the results showed satisfactory stability and reusability for the designed micro-reactor in the photocatalytic degradation of organic pollutants. PMID- 25295723 TI - Maternal parity and the risk of congenital heart defects in offspring: a dose response meta-analysis of epidemiological observational studies. AB - BACKGROUND: Epidemiological studies have reported conflicting results regarding maternal parity and the risk of congenital heart defects (CHDs). However, a meta analysis of the association between maternal parity and CHDs in offspring has not been conducted. METHODS: We searched MEDLINE and EMBASE for articles catalogued between their inception and March 8, 2014; we identified relevant published studies that assessed the association between maternal parity and CHD risk. Two authors independently assessed the eligibility of the retrieved articles and extracted data from them. Study-specific relative risk estimates were pooled by random-effects or fixed-effects models. From the 11272 references, a total of 16 case-control studies and 3 cohort studies were enrolled in this meta-analysis. RESULTS: The overall relative risk of CHD in parous versus nulliparous women was 1.01 (95% CI, 0.97-1.06; Q = 32.34; P = 0.006; I2 = 53.6%). Furthermore, we observed a significant association between the highest versus lowest parity number, with an overall RR = 1.20 (95% CI, 1.10-1.31; (Q = 74.61, P<0.001, I2 = 82.6%). A dose-response analysis also indicated a positive effect of maternal parity on CHD risk, and the overall increase in relative risk per one live birth was 1.06 (95% CI, 1.02-1.09); Q = 68.09; P<0.001; I2 = 80.9%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among studies. A Galbraith plot was created to graphically assess the sources of heterogeneity. CONCLUSION: In summary, this meta-analysis provided a robust estimate of the positive association between maternal parity and risk of CHD. PMID- 25295724 TI - Are flying-foxes coming to town? Urbanisation of the spectacled flying-fox (Pteropus conspicillatus) in Australia. AB - Urbanisation of wildlife populations is a process with significant conservation and management implications. While urban areas can provide habitat for wildlife, some urbanised species eventually come into conflict with humans. Understanding the process and drivers of wildlife urbanisation is fundamental to developing effective management responses to this phenomenon. In Australia, flying-foxes (Pteropodidae) are a common feature of urban environments, sometimes roosting in groups of tens of thousands of individuals. Flying-foxes appear to be becoming increasingly urbanised and are coming into increased contact and conflict with humans. Flying-fox management is now a highly contentious issue. In this study we used monitoring data collected over a 15 year period (1998-2012) to examine the spatial and temporal patterns of association of spectacled flying-fox (Pteropus conspicillatus) roost sites (camps) with urban areas. We asked whether spectacled flying-foxes are becoming more urbanised and test the hypothesis that such changes are associated with anthropogenic changes to landscape structure. Our results indicate that spectacled flying-foxes were more likely to roost near humans than might be expected by chance, that over the period of the study the proportion of the flying-foxes in urban-associated camps increased, as did the number of urban camps. Increased urbanisation of spectacled flying-foxes was not related to changes in landscape structure or to the encroachment of urban areas on camps. Overall, camps tended to be found in areas that were more fragmented, closer to human habitation and with more urban land cover than the surrounding landscape. This suggests that urbanisation is a behavioural response rather than driven by habitat loss. PMID- 25295726 TI - Soft Tissue Response and Survival of Extraoral Implants: A Long-Term Follow-up. AB - Maxillofacial defects may be reconstructed by plastic surgery or treated by prosthetic mean rehabilitation. In case of large defects, prosthetic rehabilitation rather than surgical reconstruction is preferred due to the insufficient esthetic results of surgical interventions. However, retention of the craniofacial prosthesis is a great problem despite the satisfactory esthetic results. With the presentation of extraoral implants, the retention of maxillofacial prostheses was improved, and osseointegrated craniofacial implants have become indispensable for retention and stability. However, there are conflicting results regarding the success rates of osseointegrated implants used at the craniofacial region. A total of 24 patients with 64 implants (30 in auricular region of 13 patients, 24 in nasal region of 8 patients, and 10 in orbital region of 3 patients) ranging in age from 16 to 83 years (mean age = 45.45 years) were evaluated. One patient among 13 patients (1/13) has lost his implants in the auricular area, 1 patient among 8 patients (1/8) lost his implants, and 1 patient among 3 patients (1/3) has lost all of her implants. Peri implant soft tissue response was evaluated for a 60-month period and a total of 654 visits/sites recorded. Grade 0 (no irritation) was present in 72.8% (476/654) of the visits/sites. Grade 1 (slight redness) was observed for 18.8% (123/654). Grade 2 (red and slightly moist tissue) was scored in 6.9% (45/654). Grade 3 (red and slightly moist tissue with granulation) was noted in 1.5% (10/654) and grade 4 (infection) could not be found. Ossseointegrated implants provide reasonable support and show successful results when used with maxillofacial prostheses. PMID- 25295725 TI - A significant reduction in the frequency of HIV-1 drug resistance in Quebec from 2001 to 2011 is associated with a decrease in the monitored viral load. AB - BACKGROUND: HIV drug resistance represents a major threat for effective treatment. We assessed the trends in the frequency of drug resistance mutations and the monitored viral load (VL) in treatment-naive (TN) and treatment experienced (TE) individuals infected with HIV-1 in Quebec, Canada, between 2001 and 2011. METHODS AND FINDINGS: Resistance data were obtained from 4,105 and 5,086 genotypic tests performed on TN and TE patients, respectively. Concomitantly, 274,161 VL tests were carried out in the Province. Changes over time in drug resistance frequency and in different categories of VL were assessed using univariate logistic regression. Multiple logistic regression was used to evaluate associations between the rates of certain mutations and antiretroviral prescriptions. From 2001 to 2011, the proportion of undetectable VL test results continually increased, from 42.1% to 75.9%, while a significant decrease in the frequency of resistance mutations associated with protease inhibitors [PI (from 54% to 16%)], nucleoside [NRTI (from 78% to 37%) and non-nucleoside reverse transcriptase inhibitors [NNRTI (from 44% to 31%)] was observed in TE patients. In TN individuals, the overall frequency of transmitted drug resistance was 13.1%. A multiple logistic regression analysis indicated that the introduction of co-formulated emtricitabine/tenofovir or emtricitabine/tenofovir/efavirenz was positively associated with the decrease of the frequency of the M184I/V mutations observed overtime (p = 0.0004). CONCLUSIONS: We observed a significant decrease in the frequency of drug resistance mutations in TE patients, concomitant with a decrease in the proportion of patients with detectable viremia. These findings may be related to both the increased potencies and adherence to therapy associated with newer antiretroviral regimens. Nevertheless, our data demonstrate that broad use of antiretrovirals does not increase the level of circulating drug resistant variants. PMID- 25295727 TI - Cotton rat (Sigmodon hispidus) signaling lymphocyte activation molecule (CD150) is an entry receptor for measles virus. AB - Cotton rats (Sigmodon hispidus) replicate measles virus (MV) after intranasal infection in the respiratory tract and lymphoid tissue. We have cloned the cotton rat signaling lymphocytic activation molecule (CD150, SLAM) in order to investigate its role as a potential receptor for MV. Cotton rat CD150 displays 58% and 78% amino acid homology with human and mouse CD150, respectively. By staining with a newly generated cotton rat CD150 specific monoclonal antibody expression of CD150 was confirmed in cotton rat lymphoid cells and in tissues with a pattern of expression similar to mouse and humans. Previously, binding of MV hemagglutinin has been shown to be dependent on amino acids 60, 61 and 63 in the V region of CD150. The human molecule contains isoleucine, histidine and valine at these positions and binds to MV-H whereas the mouse molecule contains valine, arginine and leucine and does not function as a receptor for MV. In the cotton rat molecule, amino acids 61 and 63 are identical with the mouse molecule and amino acid 60 with the human molecule. After transfection with cotton rat CD150 HEK 293 T cells became susceptible to infection with single cycle VSV pseudotype virus expressing wild type MV glycoproteins and with a MV wildtype virus. After infection, cells expressing cotton rat CD150 replicated virus to lower levels than cells expressing the human molecule and formed smaller plaques. These data might explain why the cotton rat is a semipermissive model for measles virus infection. PMID- 25295730 TI - Recent warming of lake Kivu. AB - Lake Kivu in East Africa has gained notoriety for its prodigious amounts of dissolved methane and dangers of limnic eruption. Being meromictic, it is also expected to accumulate heat due to rising regional air temperatures. To investigate the warming trend and distinguish between atmospheric and geothermal heating sources, we compiled historical temperature data, performed measurements with logging instruments, and simulated heat propagation. We also performed isotopic analyses of water from the lake's main basin and isolated Kabuno Bay. The results reveal that the lake surface is warming at the rate of 0.12 degrees C per decade, which matches the warming rates in other East African lakes. Temperatures increase throughout the entire water column. Though warming is strongest near the surface, warming rates in the deep waters cannot be accounted for solely by propagation of atmospheric heat at presently assumed rates of vertical mixing. Unless the transport rates are significantly higher than presently believed, this indicates significant contributions from subterranean heat sources. Temperature time series in the deep monimolimnion suggest evidence of convection. The progressive deepening of the depth of temperature minimum in the water column is expected to accelerate the warming in deeper waters. The warming trend, however, is unlikely to strongly affect the physical stability of the lake, which depends primarily on salinity gradient. PMID- 25295729 TI - Differential expression of microRNAs in Francisella tularensis-infected human macrophages: miR-155-dependent downregulation of MyD88 inhibits the inflammatory response. AB - Francisella tularensis is a Gram-negative, facultative intracellular pathogen that replicates in the cytosol of macrophages and is the causative agent of the potentially fatal disease tularemia. A characteristic feature of F. tularensis is its limited proinflammatory capacity, but the mechanisms that underlie the diminished host response to this organism are only partially defined. Recently, microRNAs have emerged as important regulators of immunity and inflammation. In the present study we investigated the microRNA response of primary human monocyte derived macrophages (MDMs) to F. tularensis and identified 10 microRNAs that were significantly differentially expressed after infection with the live vaccine strain (LVS), as judged by Taqman Low Density Array profiling. Among the microRNAs identified, miR-155 is of particular interest as its established direct targets include components of the Toll-like receptor (TLR) pathway, which is essential for innate defense and proinflammatory cytokine production. Additional studies demonstrated that miR-155 acted by translational repression to downregulate the TLR adapter protein MyD88 and the inositol 5'-phosphatase SHIP-1 in MDMs infected with F. tularensis LVS or the fully virulent strain Schu S4. Kinetic analyses indicated that miR-155 increased progressively 3-18 hours after infection with LVS or Schu S4, and target proteins disappeared after 12-18 hours. Dynamic modulation of MyD88 and SHIP-1 was confirmed using specific pre-miRs and anti-miRs to increase and decrease miR-155 levels, respectively. Of note, miR-155 did not contribute to the attenuated cytokine response triggered by F. tularensis phagocytosis. Instead, this microRNA was required for the ability of LVS-infected cells to inhibit endotoxin-stimulated TNFalpha secretion 18-24 hours after infection. Thus, our data are consistent with the ability of miR-155 to act as a global negative regulator of the inflammatory response in F. tularensis-infected human macrophages. PMID- 25295731 TI - Acylation of Glucagon-like peptide-2: interaction with lipid membranes and in vitro intestinal permeability. AB - BACKGROUND: Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation as well as increasing enzymatic stability without disrupting biological potency. Acylation has furthermore been shown to increase interactions with the lipid membranes of mammalian cells. The extent to which such interactions hinder or benefit delivery of acylated peptide drugs across cellular barriers such as the intestinal epithelia is currently unknown. The present study investigates the effect of acylating peptide drugs from a drug delivery perspective. PURPOSE: We hypothesize that the membrane interaction is an important parameter for intestinal translocation, which may be used to optimize the acylation chain length for intestinal permeation. This work aims to characterize acylated analogues of the intestinotrophic Glucagon-like peptide-2 by systematically increasing acyl chain length, in order to elucidate its influence on membrane interaction and intestinal cell translocation in vitro. RESULTS: Peptide self-association and binding to both model lipid and cell membranes was found to increase gradually with acyl chain length, whereas translocation across Caco-2 cells depended non-linearly on chain length. Short and medium acyl chains increased translocation compared to the native peptide, but long chain acylation displayed no improvement in translocation. Co administration of a paracellular absorption enhancer was found to increase translocation irrespective of acyl chain length, whereas a transcellular enhancer displayed increased synergy with the long chain acylation. CONCLUSIONS: These results show that membrane interactions play a prominent role during intestinal translocation of an acylated peptide. Acylation benefits permeation for shorter and medium chains due to increased membrane interactions, however, for longer chains insertion in the membrane becomes dominant and hinders translocation, i.e. the peptides get 'stuck' in the cell membrane. Applying a transcellular absorption enhancer increases the dynamics of membrane insertion and detachment by fluidizing the membrane, thus facilitating its effects primarily on membrane associated peptides. PMID- 25295732 TI - REG4 independently predicts better prognosis in non-mucinous colorectal cancer. AB - INTRODUCTION: Colorectal cancer (CRC) is one of the world's three most common cancers and its incidence is rising. To identify patients who benefit from adjuvant therapy requires novel biomarkers. The regenerating islet-derived gene (REG) 4 belongs to a group of small secretory proteins involved in cell proliferation and regeneration. Its up-regulated expression occurs in inflammatory bowel diseases also in gastrointestinal cancers. Reports on the association of REG4 expression with CRC prognosis have been mixed. Our aim was to investigate tumor REG4 expression in CRC patients and its coexpression with other intestinal markers. METHODS: Tumor expression of REG4 was evaluated by immunohistochemistry in 840 consecutive surgically treated CRC patients at Helsinki University Central Hospital. Expression of MUC1, MUC2, MUC5AC, synapthophysin, and chromogranin was evaluated in a subgroup of 220 consecutively operated CRC patients. REG4 expression with clinicopathological parameters, other intestinal markers, and the impact of REG4 expression on survival were assessed. RESULTS: REG4 expression associated with favorable clinicopathological parameters and with higher overall survival from non-mucinous CRC (p = 0.019). For such patients under 65, its expression was an independent marker of lower risk of death within 5 years that cancer; univariable hazard ratio (HR) = 0.57; 95% confidence interval (CI) (0.34-0.94); multivariable HR = 0.55; 95% CI (0.33 0.92). In non-mucinous CRC, REG4 associated with positive MUC2, MUC4, and MUC5AC expression. CONCLUSION: We show, to our knowledge for the first time, that REG4 IHC expression to be an independent marker of favorable prognosis in non-mucinous CRC. Our results contradict those from studies based on quantification of REG4 mRNA levels, a discrepancy warranting further studies. PMID- 25295734 TI - Imitation, genetic lineages, and time influenced the morphological evolution of the violin. AB - Violin design has been in flux since the production of the first instruments in 16th century Italy. Numerous innovations have improved the acoustical properties and playability of violins. Yet, other attributes of the violin affect its performance less, and with fewer constraints, are potentially more sensitive to historical vagaries unrelated to quality. Although the coarse shape of violins is integral to their design, details of the body outline can vary without significantly compromising sound quality. What can violin shapes tell us about their makers and history, including the degree that luthiers have influenced each other and the evolution of complex morphologies over time? Here, I provide an analysis of morphological evolution in the violin family, sampling the body shapes of over 9,000 instruments over 400 years of history. Specific shape attributes, which discriminate instruments produced by different luthiers, strongly correlate with historical time. Linear discriminant analysis reveals luthiers who likely copied the outlines of their instruments from others, which historical accounts corroborate. Clustering of averaged violin shapes places luthiers into four major groups, demonstrating a handful of discrete shapes predominate in most instruments. Violin shapes originating from multi generational luthier families tend to cluster together, and familial origin is a significant explanatory factor of violin shape. Together, the analysis of four centuries of violin shapes demonstrates not only the influence of history and time leading to the modern violin, but widespread imitation and the transmission of design by human relatedness. PMID- 25295735 TI - Interprofessional education for first year psychology students: career plans, perceived relevance and attitudes. AB - Undergraduate psychology students have been largely excluded from interprofessional education (IPE) initiatives. In contrast to many health professions, undergraduate psychology students do not engage in work placements as part of their degree, and many enter careers outside the health care context. However, the collaborative skills gained through an IPE experience may well be beneficial to students who work in this wider context. This research examines whether undergraduate psychology students' views of IPE vary according to their planned career directions, and if so, whether the perceived relevance of IPE mediates the relationships. A sample of 188 Australian university undergraduate psychology students completed an online questionnaire following completion of a first-year IPE health sciences program. Path analysis indicated that psychology students' attitudes towards IPE are associated with both professional identification and practitioner orientation, fully mediated through the perceived relevance of IPE to future career and study plans. Stronger professional identification and practitioner orientation were associated with greater perceived relevance and more positive and less negative attitudes towards IPE. Placing a stronger emphasis on the generalizability of IP skills taught may increase students' awareness of the relevance outside of the health context, reducing disengagement of students planning alternative careers. PMID- 25295736 TI - Leukoaraiosis significantly worsens driving performance of ordinary older drivers. AB - BACKGROUND: Leukoaraiosis is defined as extracellular space caused mainly by atherosclerotic or demyelinated changes in the brain tissue and is commonly found in the brains of healthy older people. A significant association between leukoaraiosis and traffic crashes was reported in our previous study; however, the reason for this is still unclear. METHOD: This paper presents a comprehensive evaluation of driving performance in ordinary older drivers with leukoaraiosis. First, the degree of leukoaraiosis was examined in 33 participants, who underwent an actual-vehicle driving examination on a standard driving course, and a driver skill rating was also collected while the driver carried out a paced auditory serial addition test, which is a calculating task given verbally. At the same time, a steering entropy method was used to estimate steering operation performance. RESULTS: The experimental results indicated that a normal older driver with leukoaraiosis was readily affected by external disturbances and made more operation errors and steered less smoothly than one without leukoaraiosis during driving; at the same time, their steering skill significantly deteriorated. CONCLUSIONS: Leukoaraiosis worsens the driving performance of older drivers because of their increased vulnerability to distraction. PMID- 25295733 TI - The effect of morphine on regional cerebral blood flow measured by 99mTc-ECD SPECT in dogs. AB - To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with 99mTc Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points. PMID- 25295737 TI - [Bevacizumab and taxanes in the first-line treatment of metastatic breast cancer : overall survival and subgroup analyses of the ATHENA study in France]. AB - The international phase IIIb study, ATHENA assessed the combination of bevacizumab/taxane-based chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer (mBC) in real-life setting. Among the 365 patients included in France, median overall survival (OS) is 28.4 months (CI95% 24.8-33.0), with a median time from treatment start to end of study of 36,5 months (25,1-45,4). Exploratory analyses in three sub-groups show that the median OS in long responder patients (not progressing for at least one year; n = 116) is not reached. In responder patients (n = 308), median OS is 33.0 months (CI95% 28.6-37.4) and 12.4 months (CI95% 11.2-17.4) in non-responders (n = 41). In patients with mBC expressing hormone receptors (HR+), treated with first-line hormone therapy before inclusion (n = 87) median OS in is 23.2 months (CI95% 19.6 28.6), and 35.3 months (CI95% 32.2-not reached); P = 0.004 in patients treated first with chemotherapy + bevacizumab (n = 179). The safety analysis in the various sub-groups of grade 3-5 adverse events of particular interest to bevacizumab of this study was comparable to the safety data of randomized phase III studies. PMID- 25295740 TI - Upregulation of microRNA processing enzymes Drosha and Dicer in gestational diabetes mellitus. AB - MicroRNAs (miRNAs) have been shown to play important roles in diverse cellular processes and linked to variety of disorders. Dicer and Drosha are two major enzymes in the miRNA biogenesis process. DGCR8 is the assistant of Drosha in the microprocessor complex. In this study, we evaluated the mRNA expression profiles of major miRNA processing machinery Drosha, Dicer, and DGCR8 in gestational diabetes mellitus (GDM), pregnant and healthy women. Our findings indicate that the expression levels of Drosha, Dicer and DGCR8 were upregulated in both pregnant and GDM patients compared to the control group. However, Drosha and Dicer were upregulated more than pregnant group. In conclusion, we detected dysregulation of Drosha, Dicer and DGCR8 expression in pregnant and GDM patients when compared to healthy control participants. Therefore, we favor the hypothesis that miRNAs are involved in the development of GDM. PMID- 25295741 TI - A dose error evaluation study for 4D dose calculations. AB - Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms.The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms.The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm; 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex programming structure. The study discloses disadvantages for the bETM and for the DIM. DIM yielded insufficient results for large voxel sizes, while bETM is prone to errors for small voxel sizes. PMID- 25295742 TI - Bacterial infections in hematopoietic stem cell transplantation recipients. AB - PURPOSE OF REVIEW: Bacterial infections are among the most frequent complications of hematopoietic stem cell transplant (HSCT). This review describes current epidemiology and management of bacterial infections. RECENT FINDINGS: Multidrug resistant (MDR) bacteria are increasingly frequent in HSCT recipients, but significant differences in etiology of bacterial infections and prevalence of resistant strains exist between different transplant centers. Methicillin resistant coagulase-negative staphylococci, extended-spectrum beta-lactamase producing Enterobacteriaceae, vancomycin-resistant enterococci and MDR Pseudomonas aeruginosa are the most relevant examples. Infection control measures are mandatory to limit the spread of resistant strains. Selective digestive decontamination is controversial and potentially associated with inducing resistance to antibiotics that might be the last treatment option, such as colistin or aminoglycosides. Empirical therapy should be individualized, and an escalation or de-escalation approach should be chosen depending on local epidemiology, colonization and clinical presentation. Antimicrobial stewardship, with the aim of improving management of bacterial infections, should be put in place in transplant units. SUMMARY: Bacterial infections in the transplant population warrant currently particular attention to limit the negative impact of infections caused by resistant strains. PMID- 25295743 TI - Epidemiology and risk factors for invasive fungal diseases in hematopoietic stem cell transplantation. AB - PURPOSE OF REVIEW: Knowledge of the epidemiology and the risk factors of invasive fungal diseases (IFDs) in hematopoietic stem cell transplant (HSCT) recipients is a critical determinant of the prevention, diagnosis and therapeutic antifungal strategy. Transplant procedures are characterized by a continuous evolution; therefore, an update of the epidemiological findings of IFDs in HSCT populations is needed. RECENT FINDINGS: In the last few years, the incidence and the clinical risk factors of IFD, mainly in allogeneic HSCT populations, have been investigated in prospective, multicenter studies. New findings in the different types and phases of transplant may be considered for a redefinition of the level of risk of IFD after HSCT. Furthermore, recent studies have uncovered associations between host's and/or donor's genetic variants and immunological risk for IFDs, in particular invasive aspergillosis. SUMMARY: Evolution of the transplant procedures was followed by an important change in the epidemiology and clinical risk of IFD after allogeneic HSCT. A new stratification of subpopulations according to different clinical infectious risk and genetic susceptibility may be considered to predict those patients most vulnerable to IFD and update tailored antifungal strategies. PMID- 25295744 TI - Diagnosis and treatment of cytomegalovirus 2013. AB - PURPOSE OF REVIEW: Despite significant improvements in the management of patients undergoing allogeneic stem cell transplantation, including anticytomegalovirus (CMV) prophylaxis and treatment, clinical handling of CMV infection remains challenging in the light of high morbidity and mortality rates. Thus, novel strategies and agents to control CMV infection and disease will be discussed. RECENT FINDINGS: Novel assays to quantify viral load and detect antiviral resistance mechanisms on the basis of next-generation sequencing have been described and will help to earlier and more effectively control CMV infection. In addition, safer and more effective antiviral agents are now available and strategies to boost the CMV-directed immune responses are being explored in the clinic. SUMMARY: Novel diagnostic tests, novel agents and the increased understanding of the immune response to CMV have and will have a major impact on improving the management of CMV infection in hematological patients. PMID- 25295745 TI - Mucormycosis: a new concern in the transplant ward? AB - PURPOSE OF REVIEW: This study focuses on the epidemiology and management of mucormycosis in hematopoietic stem cell transplant patients, a life-threatening mold infection whose incidence has increased over the past decades. RECENT FINDINGS: Mucormycosis may occur in hematopoietic stem cell transplant recipients with severe graft-versus-host disease, steroids, neutropenia, iron overload, diabetes, and malnutrition, or those who received antifungals not active against Mucorales. Its incidence in allogeneic hematopoietic stem cell transplant is around 0.3%. As Mucorales are not susceptible to voriconazole and candins, and as mucormycosis often mimics aspergillosis, it is extremely important to have a precise diagnostic to correctly manage the patient. The reversed halo sign on chest computed tomography has been associated to mucormycosis in neutropenic patients, but is not pathognomonic. Direct fungal identification is crucial. Molecular approaches are developed that may be extremely useful for early diagnosis. SUMMARY: Although randomized trials are quite impossible to run, due to the rarity of the disease, the recent numerous data have allowed the elaboration of European guidelines for the management of mucormycosis. Lipid formulations of amphotericin B, and especially liposomal amphotericin B at high doses (5-10 mg/kg/day), are the standard treatment, combined with surgery and control of favoring factors. The prognosis is poor, and any delay in the initiation of therapy may impact on outcome. PMID- 25295746 TI - Hardwiring patient blood management: harnessing information technology to optimize transfusion practice. AB - PURPOSE OF REVIEW: This review will describe recent applications of computerized provider order entry (CPOE) with clinical decision support systems (CDSS) in transfusion medicine and other novel ways information technology is being applied to support patient blood management (PBM) efforts. RECENT FINDINGS: CPOE with CDSS can be used to encourage appropriate transfusion practices as part of an institutional PBM program. The impact of CPOE with CDSS is enhanced when the laboratory information system (LIS) can be linked to the electronic medical record (EMR) to enable adaptive alerts that query transfusion orders against current laboratory and/or clinical data to ensure provider ordering practice is consistent with institutional guidelines. Additional current applications of healthcare information technology to transfusion medicine include creation of electronic reports to support order auditing, assessment of blood product utilization and compliance monitoring. SUMMARY: Application of healthcare information technology to transfusion medicine will expand, as more institutions embrace PBM and utilize their EMR and LIS to 'hardwire' appropriate transfusion practice. The impact of implementation of CPOE with CDSS is variable and influenced by multiple factors including existing practice patterns, provider receptiveness and system configuration. PMID- 25295747 TI - The screening of RNA aptamers specific for carbonic anhydrase I using the Systematic Evolution of Ligands by an Exponential Enrichment Method (SELEX). AB - Carbonic anhydrases (CA) or carbonate dehydratases are a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate. CA I is the most abundant protein in the cytosol and has been reported to the partially associated with a number of fatal diseases. A newly established Systematic Evolution of Ligands by EXponential enrichment (SELEX) method referred to as Protein-SELEX was used to select RNA aptamers against the human erythrocyte CA I (CA I) protein. After five rounds of selection and counter selection the specific binding of the 6th cycle in vitro transcribed RNA library to CA I was detected by an Electrophoretic Mobility Shift Assay (EMSA). Three Specific sequences were identified as binding candidates after cloning and sequence analysis and one of the selected CA I specific RNA aptamers, CAapt1, was used to confirm specific binding and the Kd values were determined using an EMSA. The CAapt1 RNA aptamer showed no affinity towards any other protein and in comparison to the "0" cycle library, a significant enrichment was obtained. This methodology permitted us to successfully investigate the ssRNA aptamer CAapt1 for CA I protein. PMID- 25295748 TI - Synthesis and general biological activity of a small adenosine-5'-(carboxamide and sulfanilamide) library. AB - A small library of fifty-five adenosine peptide analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from 2',3'-O isopropylideneadenosine-5'-carboxylic acid 2. The coupling of amine or sulfanilamide reactants to the free 5'-carboxylic acid moiety of 2, in automated solution-phase fashion, led after acid-mediated hydrolysis to target compounds 3 57 in good yields and high purity. No marked anticancer or antimalarial activity was noted on preliminary cellular testing. Initial screening through the MLPCN program, however, indicates that these analogs may show diverse and interesting biological activities. PMID- 25295749 TI - DNA binding studies of hematoxylin-Dy(sh) complex by spectrometry using acridine orange as a probe. AB - The interaction of a hematoxylin(HE)-Dy(SH) complex with herring sperm DNA(hsDNA) was studied using acridine orange(AO) as a probe by UV-vis absorption, circular dichroism(CD), fluorescence spectroscopy and viscosity measurements. From the results of the probe experiment, we found that the HE-Dy(SH) complex could compete with AO for intercalating into hsDNA. The binding constants of the HE Dy(SH) complex to hsDNA was obtained by the double reciprocal method and indicated that the affinity between hsDNA and the complex is weaker than that between hsDNA and classical intercalators. The thermodynamic parameters(DeltaH degrees , DeltaG degrees , DeltaS degrees ) were calculated from the UV-vis absorption data measured at two different temperatures. Further experimental results suggested that there exist groove binding and partial intercalation binding between hsDNA and HE-Dy(SH) complex. PMID- 25295751 TI - Synthesis of new perhydropyrrolo[1,2-a]pyrazine derivatives and their evaluation in animal models of epilepsy. AB - A series of novel stereochemically pure derivatives of the investigative broad spectrum anticonvulsant ADD408003 was designed and synthesized. Five-center four component (U-5C-4CR) and four-center three-component (U-4C-3CR) variants of Ugi reaction were used in the key step of the synthetic pathways. The compounds obtained were evaluated for the anticonvulsant activitiy in the maximal electroshock seizure (MES), subcutaneous Metrazole (scMET) and minimal clonic seizure (6 Hz) animal models of epilepsy. The efficacies of most derivatives in the 6 Hz model of pharmacoresistant partial seizures were markedly higher than in the 'classical' MES and scMET models. The most active compounds, (4R,8aR)-3a, and (4S,8aS)-6 displayed median effective doses (ED50) of 47.90 and 126.19 mg/kg, respectively, for the 6 Hz test. PMID- 25295750 TI - Right place, wrong species: a 20-year review of rabies virus cross species transmission among terrestrial mammals in the United States. AB - INTRODUCTION: In the continental US, four terrestrial mammalian species are reservoirs for seven antigenic rabies virus variants. Cross species transmission (CST) occurs when a rabies virus variant causes disease in non-reservoir species. METHODS: This study analyzed national surveillance data for rabies in terrestrial mammals. The CST rate was defined as: number of rabid non-reservoir animals/number of rabid reservoir animals. CST rates were analyzed for trend. Clusters of high CST rate counties were evaluated using space-time scanning statistics. RESULTS: The number of counties reporting a raccoon variant CST rate >1.0 increased from 75 in 1992 to 187 in 2011; counties with skunk variant CST rates >1.0 remained unchanged during the same period. As of 2011, for every rabid raccoon reported within the raccoon variant region, there were 0.73 cases of this variant reported in non-reservoir animals. Skunks were the most common non reservoir animal reported with the raccoon rabies variant. Domestic animals were the most common non-reservoir animal diagnosed with a skunk rabies virus variant (n = 1,601). Cross species transmission rates increased fastest among domestic animals. CONCLUSIONS: Cross species transmission of rabies virus variants into non-reservoir animals increases the risk of human exposures and threatens current advances toward rabies control. Cross species transmission in raccoon rabies enzootic regions increased dramatically during the study period. Pet owners should vaccinate their dogs and cats to ensure against CST, particularly in regions with active foci of rabies circulation. Clusters of high CST activity represent areas for further study to better understand interspecies disease transmission dynamics. Each CST event has the potential to result in a rabies virus adapted for sustained transmission in a new species; therefore further understanding of the dynamics of CST may help in early detection or prevention of the emergence of new terrestrial rabies virus variants. PMID- 25295752 TI - Exploring the breadth of the top-down representations that control attentional disengagement. AB - Recent studies attribute top-down control as the primary determinant of the speed with which attention can be disengaged from an object, and disengagement has received increased interest as a means to distinguish between top-down and bottom up accounts of attention capture. We present the results of three experiments exploring the breadth of the representations that delay attentional disengagement based on top-down goals. Experiments 1 and 2 examined whether objects similar to an observers' search target, but differing in luminance and hue, delayed the reallocation of attention in a search paradigm designed to isolate disengagement time. Experiment 3 explored whether the representations that delay disengagement are based on absolute similarity with the search target, or are tuned based on target/nontarget relationships. These three studies confirmed the role of top down goals in automatically contributing to dwell times and revealed that the representations that underlie disengagement effects are broad (automatically delaying disengagement for items similar, but not identical to, the search target). In some cases, attention sets appeared to be graded in nature, but in others target-distractor relationships influenced the degree to which an irrelevant item held attention. Implications for theories of attention capture and potential functional significance of these automatic effects are discussed. PMID- 25295753 TI - Phenotypic, ultra-structural, and functional characterization of bovine peripheral blood dendritic cell subsets. AB - Dendritic cells (DC) are multi-functional cells that bridge the gap between innate and adaptive immune systems. In bovine, significant information is lacking on the precise identity and role of peripheral blood DC subsets. In this study, we identify and characterize bovine peripheral blood DC subsets directly ex vivo, without further in vitro manipulation. Multi-color flow cytometric analysis revealed that three DC subsets could be identified. Bovine plasmacytoid DC were phenotypically identified by a unique pattern of cell surface protein expression including CD4, exhibited an extensive endoplasmic reticulum and Golgi apparatus, efficiently internalized and degraded exogenous antigen, and were the only peripheral blood cells specialized in the production of type I IFN following activation with Toll-like receptor (TLR) agonists. Conventional DC were identified by expression of a different pattern of cell surface proteins including CD11c, MHC class II, and CD80, among others, the display of extensive dendritic protrusions on their plasma membrane, expression of very high levels of MHC class II and co-stimulatory molecules, efficient internalization and degradation of exogenous antigen, and ready production of detectable levels of TNF-alpha in response to TLR activation. Our investigations also revealed a third novel DC subset that may be a precursor of conventional DC that were MHC class II+ and CD11c-. These cells exhibited a smooth plasma membrane with a rounded nucleus, produced TNF-alpha in response to TLR-activation (albeit lower than CD11c+ DC), and were the least efficient in internalization/degradation of exogenous antigen. These studies define three bovine blood DC subsets with distinct phenotypic and functional characteristics which can be analyzed during immune responses to pathogens and vaccinations of cattle. PMID- 25295755 TI - Residency time as an indicator of reproductive restraint in male burying beetles. AB - The cost of reproduction theory posits that there are trade-offs between current and future reproduction because resources that are allocated to current offspring cannot be used for future reproductive opportunities. Two adaptive reproductive strategies have been hypothesized to offset the costs of reproduction and maximize lifetime fitness. The terminal investment hypothesis predicts that as individuals age they will allocate more resources to current reproduction as a response to decreasing residual reproductive value. The reproductive restraint hypotheses predicts that as individuals age they will allocate fewer resources to current reproduction to increase the chance of surviving for an additional reproductive opportunity. In this study, we test for adaptive responses to advancing age in male burying beetles, Nicrophorus orbicollis. Burying beetles use facultative biparental care, but the male typically abandons the brood before the female. Previous work in male burying beetles has suggested several factors to explain variation in male residency time, but no study has observed male behavior throughout their entire reproductive lifetimes to determine whether males change residency time in an adaptive way with age. We compared residency time of males that reproduced biparentally, uniparentally, and on different-sized carcasses to determine if they used an adaptive reproductive strategy. Males did not increase residency time as they aged when reproducing biparentally, but decreased residency time with age when reproducing uniparentally. A decrease in parental care with age is consistent with a reproductive restraint strategy. When female age increased over time, males did not increase their residency time to compensate for deteriorating female condition. To our knowledge, this is the first test of adaptive reproductive allocation strategies in male burying beetles. PMID- 25295754 TI - Identification and characterization of Wilt and salt stress-responsive microRNAs in chickpea through high-throughput sequencing. AB - Chickpea (Cicer arietinum) is the second most widely grown legume worldwide and is the most important pulse crop in the Indian subcontinent. Chickpea productivity is adversely affected by a large number of biotic and abiotic stresses. MicroRNAs (miRNAs) have been implicated in the regulation of plant responses to several biotic and abiotic stresses. This study is the first attempt to identify chickpea miRNAs that are associated with biotic and abiotic stresses. The wilt infection that is caused by the fungus Fusarium oxysporum f.sp. ciceris is one of the major diseases severely affecting chickpea yields. Of late, increasing soil salinization has become a major problem in realizing these potential yields. Three chickpea libraries using fungal-infected, salt-treated and untreated seedlings were constructed and sequenced using next-generation sequencing technology. A total of 12,135,571 unique reads were obtained. In addition to 122 conserved miRNAs belonging to 25 different families, 59 novel miRNAs along with their star sequences were identified. Four legume-specific miRNAs, including miR5213, miR5232, miR2111 and miR2118, were found in all of the libraries. Poly(A)-based qRT-PCR (Quantitative real-time PCR) was used to validate eleven conserved and five novel miRNAs. miR530 was highly up regulated in response to fungal infection, which targets genes encoding zinc knuckle- and microtubule-associated proteins. Many miRNAs responded in a similar fashion under both biotic and abiotic stresses, indicating the existence of cross talk between the pathways that are involved in regulating these stresses. The potential target genes for the conserved and novel miRNAs were predicted based on sequence homologies. miR166 targets a HD-ZIPIII transcription factor and was validated by 5' RLM-RACE. This study has identified several conserved and novel miRNAs in the chickpea that are associated with gene regulation following exposure to wilt and salt stress. PMID- 25295756 TI - Early changes in clinical, functional, and laboratory biomarkers in workers at risk of indium lung disease. AB - RATIONALE: Occupational exposure to indium compounds, including indium-tin oxide, can result in potentially fatal indium lung disease. However, the early effects of exposure on the lungs are not well understood. OBJECTIVES: To determine the relationship between short-term occupational exposures to indium compounds and the development of early lung abnormalities. METHODS: Among indium-tin oxide production and reclamation facility workers, we measured plasma indium, respiratory symptoms, pulmonary function, chest computed tomography, and serum biomarkers of lung disease. Relationships between plasma indium concentration and health outcome variables were evaluated using restricted cubic spline and linear regression models. MEASUREMENTS AND MAIN RESULTS: Eighty-seven (93%) of 94 indium tin oxide facility workers (median tenure, 2 yr; median plasma indium, 1.0 MUg/l) participated in the study. Spirometric abnormalities were not increased compared with the general population, and few subjects had radiographic evidence of alveolar proteinosis (n = 0), fibrosis (n = 2), or emphysema (n = 4). However, in internal comparisons, participants with plasma indium concentrations >= 1.0 MUg/l had more dyspnea, lower mean FEV1 and FVC, and higher median serum Krebs von den Lungen-6 and surfactant protein-D levels. Spline regression demonstrated nonlinear exposure response, with significant differences occurring at plasma indium concentrations as low as 1.0 MUg/l compared with the reference. Associations between health outcomes and the natural log of plasma indium concentration were evident in linear regression models. Associations were not explained by age, smoking status, facility tenure, or prior occupational exposures. CONCLUSIONS: In indium-tin oxide facility workers with short-term, low level exposure, plasma indium concentrations lower than previously reported were associated with lung symptoms, decreased spirometric parameters, and increased serum biomarkers of lung disease. PMID- 25295757 TI - Associations between Klinefelter's syndrome and autoimmune diseases: English national record linkage studies. AB - There are reports suggesting that people with Klinefelter's syndrome (KS) may be at increased risk of some autoimmune diseases, but the evidence is not substantial. We wanted to add to the evidence by systematically assessing the risk of autoimmune diseases in a national cohort of people with KS. We selected records of all people with KS in a record-linked dataset of all hospital day cases and inpatient admissions in England, 1999-2011; and we followed them up by electronic record linkage to identify the occurrence of autoimmune diseases. We compared their occurrence in the KS cohort with a control cohort, studied in the same way, and expressed the results as rate ratios (RR). Of 30 autoimmune diseases studied in people with KS, there were significantly increased risks of seven-Addison's disease (RR 11.7, 95% confidence interval 2.4-34.4), diabetes mellitus type 1 (6.1, 4.4-8.3), multiple sclerosis (4.3, 1.2-11.0), acquired hypothyroidism (2.7, 1.8-4.0), rheumatoid arthritis (3.3, 2.0-5.2), Sjogren's syndrome (19.3, 4.0-57.0) and systemic lupus erythematosus (18.1, 2.2-65.6). We concluded that people with KS have increased risk of some autoimmune diseases, particularly those that are female-predominant. The increased risk of autoimmune diseases associated with the XXY karyotype may hold clues to the pathogenesis of some aspects of autoimmunity. PMID- 25295759 TI - Risky single occasion drinking frequency and alcohol-related consequences: can abstinence during early adulthood lead to alcohol problems? AB - QUESTIONS UNDER STUDY: the main purpose of this longitudinal study was to determine the impact of risky single occasion drinking (RSOD) frequency on alcohol dependence and drinking consequences reported 15 months later. METHODS: As a baseline sample, 5,990 young men were assessed on their drinking habits including the frequency of RSOD. Of them, 5,196 were reassessed at follow-up 15 months later on RSOD frequency, alcohol dependence and alcohol related consequences in thze interceding year. Drop out biases were investigated. RESULTS: Around 45% of the baseline participants reported regular RSOD (every month or more frequently). Despite the fact that RSOD distribution was generally stable during the initial sample, 47.4% reported a variation of their RSOD frequency 15 months later. Around 25% of the sample reported reduced RSOD frequency. Nonetheless, occasional RS drinkers were more likely to become regular (monthly) RSO drinkers at follow up. Daily and weekly RSOD were associated with high proportions of alcohol dependence and detrimental consequences of drinking. Surprisingly, abstainers at baseline were more likely to be at risk of alcohol dependence and consequences at follow up than non-RSO drinkers. CONCLUSIONS: Despite the fact that alcohol abstinence is logically the best way to avoid the detrimental consequences of alcohol drinking, abstainers at baseline reported as many problems due to alcohol use at follow up as occasional or monthly RSO drinkers. The few participants who had become RSO drinkers during the follow up period were indeed likely to engage in detrimental behaviour. Non-RSO drinkers had the fewest problems due to alcohol use. This substantiates the early occurrence of drinking consequences among inexperienced RSO drinkers. PMID- 25295761 TI - Return-to-play guidelines in concussion: revisiting the literature. AB - Return-to-play (RTP) guidelines in concussion management and treatment continue to challenge clinicians, despite recent updates to the protocols and the ongoing media attention. The current guidelines address individualized treatment planning but are difficult to apply to athletes who experience prolonged symptoms, are younger, or have sustained multiple concussions. Recent literature findings have contributed to an improved understanding and applicability of the guidelines while emphasizing a multidisciplinary paradigm in formulating an individualized RTP decision. Successful implementation of the RTP guidelines will ensure that athletes are protected from further injury and return to their baseline functional status. PMID- 25295760 TI - Polymer micronetworks with shape-memory as future platform to explore shape dependent biological effects. AB - Polymer micronetworks allowing stimuli-induced, predefined, and spatially directed shape shifts. The temperature-induced on-demand switching of shape is introduced as a function of polyester carriers. With their adjustable -switching temperature, micronetworks may serve as a model system to explore static and dynamic shape effects in biological systems. PMID- 25295758 TI - CEST signal at 2ppm (CEST@2ppm) from Z-spectral fitting correlates with creatine distribution in brain tumor. AB - In general, multiple components such as water direct saturation, magnetization transfer (MT), chemical exchange saturation transfer (CEST) and aliphatic nuclear Overhauser effect (NOE) contribute to the Z-spectrum. The conventional CEST quantification method based on asymmetrical analysis may lead to quantification errors due to the semi-solid MT asymmetry and the aliphatic NOE located on a single side of the Z-spectrum. Fitting individual contributors to the Z-spectrum may improve the quantification of each component. In this study, we aim to characterize the multiple exchangeable components from an intracranial tumor model using a simplified Z-spectral fitting method. In this method, the Z spectrum acquired at low saturation RF amplitude (50 Hz) was modeled as the summation of five Lorentzian functions that correspond to NOE, MT effect, bulk water, amide proton transfer (APT) effect and a CEST peak located at +2 ppm, called CEST@2ppm. With the pixel-wise fitting, the regional variations of these five components in the brain tumor and the normal brain tissue were quantified and summarized. Increased APT effect, decreased NOE and reduced CEST@2ppm were observed in the brain tumor compared with the normal brain tissue. Additionally, CEST@2ppm decreased with tumor progression. CEST@2ppm was found to correlate with the creatine concentration quantified with proton MRS. Based on the correlation curve, the creatine contribution to CEST@2ppm was quantified. The CEST@2ppm signal could be a novel imaging surrogate for in vivo creatine, the important bioenergetics marker. Given its noninvasive nature, this CEST MRI method may have broad applications in cancer bioenergetics. PMID- 25295762 TI - Modifying factors in sports-related concussion: dangerous style of play. AB - In its third iteration, the Concussion in Sport Group identified 10 modifying factors that were presumed clinically to influence the investigation and management of concussions in sports. "Dangerous style of play" was delineated as one of these factors, most likely based on clinical lore. These modifying factors were retained in a more recent Concussion in Sport Group statement. To date, there has been no concerted effort to support or refute the inclusion of this constellation of behaviors as a modifying factor in sports-related concussion. This article reviews and summarizes the limited evidence related to a dangerous style of play in sports-related concussion, offers a preliminary assessment of its relevance as a modifying factor, and provides additional information on other aspects of player, coach, and governing body behavior and their potential effect(s) on reducing concussive injuries. PMID- 25295763 TI - Chronic traumatic encephalopathy and the availability cascade. AB - Chronic traumatic encephalopathy (CTE) in sports has been known for > 85 years, and has experienced a resurgence of interest over the past decade, both in the media and in the scientific community. However, there appears to be a disconnection between the public's perception of CTE and the currently available scientific data. The cognitive bias known as the "availability cascade" has been suggested as a reason to explain this rift in knowledge. This review summarizes and updates the history of CTE in sports, discusses recent epidemiological and autopsy studies, summarizes the evidence base related to CTE in sports, and offers recommendations for future directions. PMID- 25295765 TI - Evaluation of the Zachery Lystedt Law among female youth soccer players. AB - BACKGROUND: Despite recent increased awareness about sports concussions, few studies have evaluated the effect of concussion laws on concussion outcomes among young athletes. The purpose of our study was to evaluate the effect of the Washington State Zachery Lystedt Concussion Law on playing with concussion symptoms and being evaluated by a health care provider. METHODS: We performed a prospective cohort study of 351 elite female soccer players, aged 12 to 15 years, from 33 randomly selected youth soccer teams in the Puget Sound region of Washington State from 2008 to 2012. The Washington State Zachery Lystedt Concussion Law went into effect on July 1, 2009. Among concussed players (N = 59), we assessed the risk of playing with symptoms, the evaluation by a health care professional, and receiving a concussion diagnosis before and after the law was passed using logistic regression to estimate odds ratios and 95% CIs. RESULTS: The majority of concussed players (59.3%) continued to play with symptoms, and we found no statistically significant difference in the proportion of players who played with symptoms before and after the law was passed. Only 44.1% of concussed players were evaluated by a health care provider, with no difference before and after the law was passed. Among those evaluated by a health care professional, players were 2.1-fold (95% CI, 1.0-10.1) more likely to receive a concussion diagnosis after the law was passed. CONCLUSION: The majority of concussed female youth soccer players report playing with symptoms. Legislation mandating concussion education and evaluation prior to returning to play was not associated with an increase in concussion evaluations by health care providers. PMID- 25295766 TI - Validation of musculoskeletal ultrasound to assess and quantify muscle glycogen content. A novel approach. AB - Glycogen storage is essential for exercise performance. The ability to assess muscle glycogen levels should be an important advantage for performance. However, skeletal muscle glycogen assessment has only been available and validated through muscle biopsy. We have developed a new methodology using high-frequency ultrasound to assess skeletal muscle glycogen content in a rapid, portable, and noninvasive way using MuscleSound (MuscleSound, LCC, Denver, CO) technology. PURPOSE: To validate the utilization of high-frequency musculoskeletal ultrasound for muscle glycogen assessment and correlate it with histochemical glycogen quantification through muscle biopsy. METHODS: Twenty-two male competitive cyclists (categories: Pro, 1-4; average height, 183.7 +/- 4.9 cm; average weight, 76.8 +/- 7.8 kg) performed a steady-state test on a cyclergometer for 90 minutes at a moderate to high exercise intensity, eliciting a carbohydrate oxidation of 2 3 g.min-1 and a blood lactate concentration of 2 to 3 mM. Pre- and post-exercise glycogen content from rectus femoris muscle was measured using histochemical analysis through muscle biopsy and through high-frequency ultrasound scans using MuscleSound technology. RESULTS: Correlations between muscle biopsy glycogen histochemical quantification (mmol.kg-1) and high-frequency ultrasound methodology through MuscleSound technology were r = 0.93 (P < 0.0001) pre exercise and r = 0.94 (P < 0.0001) post-exercise. The correlation between muscle biopsy glycogen quantification and high-frequency ultrasound methodology for the change in glycogen from pre- and post-exercise was r = 0.81 (P < 0.0001). CONCLUSION: These results demonstrate that skeletal muscle glycogen can be measured quickly and noninvasively through high-frequency ultrasound using MuscleSound technology. PMID- 25295764 TI - The utility of the balance error scoring system for mild brain injury assessments in children and adolescents. AB - The Balance Error Scoring System (BESS) is widely recognized as an acceptable assessment of postural control for adult patients following a mild traumatic brain injury (mTBI) or concussion. However, the measurement properties of the BESS as a post-mTBI assessment test for younger patients are not well understood. The purpose of this study was to evaluate the utility of the BESS as a post-mTBI assessment test for children and adolescents aged 8 to 18 years through 2 investigations: (1) a retrospective medical records review of the relationship among age, BESS scores, and other common post-mTBI assessment tests; and (2) a prospective study comparing BESS scores for a cohort of children with a recent mTBI and BESS scores for a cohort of matched healthy peers. Age was found to be significantly correlated with several of the BESS measures and the total BESS score (P < 0.05). Significant differences were observed between the injured and healthy cohorts for 3 of the BESS measures and the total BESS score. However, the observed differences were not likely to be clinically meaningful. Cumulatively, evidence from the literature and the results of these studies indicate that the BESS may be limited for producing accurate assessments of younger athletes' post mTBI postural control abilities. Future research recommendations include testing of modified versions of the BESS or other alternatives for post-mTBI postural control assessments with younger individuals. PMID- 25295767 TI - The use of platelet-rich plasma for the treatment of osteoarthritis. AB - Osteoarthritis (OA) is the most common cause of disability in the United States. With an aging population, its incidence is only likely to rise. Articular cartilage has a poor capacity to heal. The advent of regenerative medicine has heralded a new approach to early treatment of degenerative conditions such as osteoarthritis by focusing on regenerating damaged tissue rather than focusing on replacement. Platelet-rich plasma (PRP) is one such treatment that has received much recent attention and has been used particularly for tendon healing. Recent studies have focused on assessing its use on degenerative conditions such as OA. In this article, we review the evidence for the pathologic basis for the use of PRP in OA and also the clinical outcomes pertaining to its use. Finally, we also consider reasons for the inconsistent clinical success pertaining to its use. PMID- 25295768 TI - Managing the pain of knee osteoarthritis. AB - Pain from knee osteoarthritis creates a significant burden for symptomatic patients, who are often forced to change their lifestyle because of their symptoms. Activity modification, therapy, weight loss, nonsteroidal anti inflammatory drugs, shoe orthotics, bracing, and injections are the nonoperative options available. New technologies are also emerging in the treatment of knee osteoarthritis. Ultimately, these therapeutic modalities should reduce pain and increase the overall functioning of patients. These nonoperative modalities give the clinician several effective options before surgical management is considered. PMID- 25295769 TI - Medical expenditures in division I collegiate athletics: an analysis by sport and gender. AB - OBJECTIVE: Medical expenses for collegiate athletics include providing a training room with its supplies, equipment, personnel costs, and insurance coverage. Additional expenses beyond the training room include imaging, diagnostic testing, specialty consultations, and surgeries. We hypothesized that there would be no difference in average expenses or number of claims between male and female athletes over a 5-year period. DESIGN: Prospective patient cohort. SETTING: A sports medicine center serving athletes in Big 10 Conference intercollegiate sports. ASSESSMENT OF RISK FACTORS: All medical claims and charges for 36 varsity teams were analyzed from 2005 to 2010. The teams were categorized into 3 groups: female-only teams, male-only teams, and coed teams. Analysis of sports with corresponding male and female teams was also performed. MAIN OUTCOME MEASUREMENTS: Claims and charges for medical care for 36 intercollegiate athletic teams over 5 years. RESULTS: Individual team claims and charges were stable over the study period. In 11 of the 14 sex-matched sports, the female teams had higher average annual charges. After normalizing for roster size in the sex-matched sports, females had 0.97 more average annual claims (P < 0.01) and $1459 higher annual charges (P = 0.001) than their male counterparts. The charges per claim were similar between the sexes. The 5 teams with the highest average annual charges were football, wrestling, softball, women's crew, and men's lacrosse. When normalized for roster size, the 5 sports with the highest average annual charges per athlete were softball, women's diving, men's basketball, wrestling, and men's gymnastics. CONCLUSION: Charges per claim were similar between the sex matched sports, but the female sports had a higher number of annual claims per athlete and thus higher total charges per athlete/year. Football had the highest average annual total charges as a team, but when normalized for roster size football charges per athlete/year were similar to those of other sports. PMID- 25295770 TI - Prescribing physical activity through primary care: does activity intensity matter? AB - BACKGROUND: Physical activity guidelines recommend engaging in moderate- and vigorous-intensity physical activity to elicit health benefits. Similarly, these higher intensity ranges for activity are typically targeted in healthy living interventions (ie, exercise prescription). Comparatively less attention has been focused on changing lower intensity physical activity (ie, sedentary activity) behaviors. The purpose of this study was to explore the effects of prescribing changes to physical activity of various intensities (ie, sedentary through exercise) through the primary care setting. METHODS: Sixty older adults (aged 55 75 years; mean age 63 = 5 years) volunteered to participate, and were randomly assigned to 4 groups: 3 receiving an activity prescription intervention targeting a specific intensity of physical activity (exercise, sedentary, or both), and 1 control group. During the 12-week intervention period participants followed personalized activity programs at home. Basic clinical measures (anthropometrics, blood pressure, aerobic fitness) and blood panel for assessing cardiometabolic risk (glucose, lipid profile) were conducted at baseline (week 0) and follow-up (week 12) in a primary care office. RESULTS: There were no differences between groups at baseline (P > 0.05). The intervention changed clinical (F5,50 = 20.458, P = 0.000, etaP2 = 0.672) and blood panel measures (F5,50 = 4.576, P = 0.002, etaP2 = 0.314) of cardiometabolic health. Post hoc analyses indicted no differences between groups (P > 0.05). CONCLUSION: Physical activity prescription of various intensities through the primary care setting improved cardiometabolic health status. To our knowledge, this is the first report of sedentary behavior prescription (alone, or combined with exercise) in primary care. The findings support the ongoing practice of fitness assessment and physical activity prescription for chronic disease management and prevention. PMID- 25295771 TI - Health promotion through primary care: enhancing self-management with activity prescription and mHealth. AB - BACKGROUND: It is well established in the literature that regular participation in physical activity is effective for chronic disease management and prevention. Remote monitoring technologies (ie, mHealth) hold promise for engaging patients in self-management of many chronic diseases. The purpose of this study was to test the effectiveness of an mHealth study with tailored physical activity prescription targeting changes in various intensities of physical activity (eg, exercise, sedentary behavior, or both) for improving physiological and behavioral markers of lifestyle-related disease risk. METHODS: Forty-five older adults (aged 55-75 years; mean age 63 +/- 5 years) were randomly assigned to receive a personal activity program targeting changes to either daily exercise, sedentary behavior, or both. All participants received an mHealth technology kit including smartphone, blood pressure monitor, glucometer, and pedometer. Participants engaged in physical activity programming at home during the 12-week intervention period and submitted physical activity (steps/day), blood pressure (mm Hg), body weight (kg), and blood glucose (mmol/L) measures remotely using study-provided devices. RESULTS: There were no differences between groups at baseline (P > 0.05). The intervention had a significant effect (F(10 488) = 2.947, P = 0.001, etaP2 = 0.057), with similar changes across all groups for physical activity, body weight, and blood pressure (P > 0.05). Changes in blood glucose were significantly different between groups, with groups prescribed high-intensity activity (ie, exercise) demonstrating greater reductions in blood glucose than the group prescribed changes to sedentary behavior alone (P < 0.05). CONCLUSIONS: Findings demonstrate the utility of pairing mHealth technologies with activity prescription for prevention of lifestyle-related chronic diseases among an at risk group of older men and women. RESULTS support the novel approach of prescribing changes to sedentary behaviors (alone, and in conjunction with exercise) to reduce risk of developing lifestyle-related chronic conditions. PMID- 25295772 TI - Upper extremity physeal injury in young baseball pitchers. AB - Adolescent baseball players, especially pitchers, are at increased risk for shoulder and elbow injuries as their level of competition increases. The intersection of the adolescent growth spurt with the high levels of elbow valgus and shoulder rotational torques placed upon the arm during overhand pitching predisposes the shoulder and elbow to physeal injuries. Little League shoulder and Little League elbow syndromes most commonly represent pathology at the physeal regions of the proximal and distal humerus and proximal ulna sustained from repetitive loads caused by overhead throwing. There is a growing understanding that these injuries occur on a wide spectrum from delayed physeal closure and physeal widening to acute transphyseal fracture. Although operative intervention is infrequently required, patient and parent counseling can be complex. Health care professionals who care for adolescent baseball players also can play an important role in prevention. Appropriate counseling requires a comprehensive understanding of the clinical, radiographic, and biomechanical aspects of these injuries. This review summarizes these major concepts, focusing on the best available evidence from recent biomechanical and clinical studies on shoulder and elbow injuries in adolescent baseball pitchers. PMID- 25295773 TI - Operative treatment of femoroacetabular impingement. AB - Femoroacetabular impingement is a common pathologic disorder of the hip that causes pain and has been implicated in the development of early osteoarthritis in young adults. This disorder includes 2 different subtypes: cam impingement and pincer impingement. When nonsurgical treatment methods fail, surgical options are indicated. These options have been increasingly investigated over recent years and show promising results. Several surgical techniques have been described, including surgical dislocation of the hip, mini-open procedures, hip arthroscopy, and periacetabular osteotomies. Nevertheless, the preferred mode of surgical management of femoroacetabular impingement remains a source of controversy. Only short-term and midterm outcome data are available regarding the efficacy of these surgical techniques. This review details 5 approaches for surgical management of femoroacetabular impingement: open surgical dislocation, a combined arthroscopic and open approach, hip arthroscopy, a mini-open anterior approach, and periacetabular osteotomy. It focuses specifically on surgical technique, outcomes, and their efficacy in treatment of femoroacetabular impingement. PMID- 25295774 TI - General and disease-specific use of outcomes scores for the shoulder: a survey of AOSSM, AANA, and ISAKOS members. AB - OBJECTIVE: To report on the knowledge and use of both general and disease specific shoulder outcomes scores among orthopedic surgeons. METHODS: A 22 question Internet survey was administered to members of the American Orthopaedic Society for Sports Medicine, the Arthroscopy Association of North American, and the International Society of Arthroscopy, Knee Surgery, and Orthopedic Sports Medicine via voluntary e-mail participation. Questions targeted demographic information, preferred surgical management of shoulder conditions, and the preferred use of shoulder outcomes instruments in clinical practice. RESULTS: Excluding defunct and duplicate e-mails among membership societies, a total of 3892 unique e-mails were sent, from which 1129 surveys were returned and were fully completed (29%). The largest number of respondents were in private practice (52%); 21% were in academia; and 26% were in a mix of settings. As for location, 74% practiced in the United States, 10% in Europe, 8% in Mexico/South America, and 6% in Asia. A total of 31% total respondents used scores all or most of the time, and 30% used scores at least some of the time. Respondents felt that the 3 most commonly utilized shoulder scores were the American Shoulder and Elbow Surgeons (ASES) score, the University of California at Los Angeles (UCLA) score, and the Constant score. The majority of respondents (76%) performed all arthroscopic instability repairs. The ASES and Western Ontario Shoulder Instability Index (WOSI) scores were the most preferred measures to monitor instability patients, whether or not the scores were actually implemented in their practice. Most perform between 10 and 25 superior labrum anterior-posterior repairs per year and preferred the ASES, UCLA, and Constant scores for these repairs; rotator cuff repair preferred outcomes instruments were similar. When asked to choose 1 score for all shoulder conditions, the ASES was the clear favorite. CONCLUSIONS: This study reports the knowledge and utilization of shoulder scores for both general and disease-specific conditions. Most respondents preferred the ASES score for most shoulder conditions; however, other scores, such as the WOSI, the Constant, and the Short-Form (SF)-36/12, were popular. This information offers insight into the current and future use of shoulder outcomes both for general and disease-specific use. PMID- 25295775 TI - Pectoralis major ruptures in professional American football players. AB - BACKGROUND: Pectoralis major injuries are an infrequent shoulder injury that can result in pain, weakness, and deformity. These injuries may occur during the course of an athletic competition, including football. The purpose of this study was to determine the incidence of pectoralis major ruptures in professional football players and time lost from the sport following injury. We hypothesized that ruptures most frequently occur during bench-press strength training. METHODS: The National Football League Injury Surveillance System was reviewed for all pectoralis major injuries in all players from 2000 to 2010. Details regarding injury setting, player demographics, method of treatment, and time lost were recorded. RESULTS: A total of 10 injuries-complete ruptures-were identified during this period. Five of the 10 were sustained in defensive players, generally while tackling. Nine occurred during game situations, and 1 occurred during practice. Specific data pertinent to the practice injury was not available. No rupture occurred during weight lifting. Eight ruptures were treated operatively, and 2 cases did not report the method of definitive treatment. The average days lost was 111 days (range, 42-189). The incidence was 0.004 pectoralis major ruptures during the 11-year study period. CONCLUSIONS: Pectoralis major injuries are uncommon while playing football. In the National Football League, these injuries primarily occur not during practice or while bench pressing but rather during games. When pectoralis major ruptures do occur, they are successfully treated operatively. Surgery may allow for return to full sports participation. LEVEL OF EVIDENCE: IV, case series. PMID- 25295776 TI - The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells. AB - Saponins, amphiphiles of natural origin with numerous biological activities, are widely used in the cosmetic and pharmaceutical industry. Some saponins exhibit relatively selective cytotoxic effects on cancer cells but the tendency of saponins to induce hemolysis limits their anticancer potential. This review focused on the effects of saponin activity on membranes and consequent implications for red blood and cancer cells. This activity seems to be strongly related to the amphiphilic character of saponins that gives them the ability to self-aggregate and interact with membrane components such as cholesterol and phospholipids. Membrane interactions of saponins with artificial membrane models, red blood and cancer cells are reviewed with respect to their molecular structures. The review considered the mechanisms of these membrane interactions and their consequences including the modulation of membrane dynamics, interaction with membrane rafts, and membrane lysis. We summarized current knowledge concerning the mechanisms involved in the interactions of saponins with membrane lipids and examined the structure activity relationship of saponins regarding hemolysis and cancer cell death. A critical analysis of these findings speculates on their potential to further develop new anticancer compounds. PMID- 25295777 TI - [Reference values for arterial oxygen content]. AB - BACKGROUND: In clinical practice, oxygen saturation as measured by photoplethysmography and arterial oxygen tension as determined by blood gas analysis are the parameters used frequently to estimate the oxygen status of a patient. Additionally, the cardiac output CO and the arterial oxygen content CaO2 are critical for the delivery of oxygen DO2 to organs and tissues. So far, CaO2 reference values published by Mertzlufft and Zander (1984) and Siggaard-Andersen (1990) are widely used. The aim of the present study was to reevaluate previously published results using the results of a population-based study. Furthermore, the impact of smoking on CaO2 will be assessed. PATIENTS AND METHODS: Data of 1018 volunteers from the Study of Health in Pomerania (SHIP) were analyzed. CaO2 was calculated from blood gas analysis of capillary blood obtained from a hyperemised ear lobe. Reference value equations controlled for sex, age and smoking were derived with quantile regression analysis and fractional polynomials. RESULTS: Lower limits of normal (LLN) decline with age. Current smoking has no significant influence on LLN for CaO2. CONCLUSION: Sex, age and smoking-specific normal values can be calculated using the current equations. PMID- 25295778 TI - [WeanNet: a network of weaning units headed by pneumologists]. AB - There is an increase of both prolonged mechanical ventilation (MV) and prolonged weaning from the respirator in the last decade in Germany. Prolonged MV is associated with an increase of morbidity, mortality and costs.The network "WeanNet", which has been founded by the "Deutsche Gesellschaft fur Pneumologie und Beatmungsmedizin e. V. (DGP, German Respiratory Society) connects weaning units headed by pneumologists with special experience in intensive care medicine.The certification of a weaning unit within WeanNet aims at the improvement of treatment quality, outcome and reduction of costs by well defined structures and processes.Based on growing experience the criteria and procedures of the certification process were adjusted in the last years, leading to a higher transparency and acceleration of the process. On this background WeanNet is necessary to improve the communication about prolonged weaning in public health, with insurance companies and associated scientific societies. PMID- 25295779 TI - SNX13 reduction mediates heart failure through degradative sorting of apoptosis repressor with caspase recruitment domain. AB - Heart failure (HF) is associated with complicated molecular remodelling within cardiomyocytes; however, the mechanisms underlying this process remain unclear. Here we show that sorting nexin-13 (SNX13), a member of both the sorting nexin and the regulator of G protein signalling (RGS) protein families, is a potent mediator of HF. Decreased levels of SNX13 are observed in failing hearts of humans and of experimental animals. SNX13-deficient zebrafish recapitulate HF with striking cardiomyocyte apoptosis. Mechanistically, a reduction in SNX13 expression facilitates the degradative sorting of apoptosis repressor with caspase recruitment domain (ARC), which is a multifunctional inhibitor of apoptosis. Consequently, the apoptotic pathway is activated, resulting in the loss of cardiac cells and the dampening of cardiac function. The N-terminal PXA structure of SNX13 is responsible for mediating the endosomal trafficking of ARC. Thus, this study reveals that SNX13 profoundly affects cardiac performance through the SNX13-PXA-ARC-caspase signalling pathway. PMID- 25295781 TI - Break on through to the other 1. AB - Although discovered in 1974, FGF1 was previously unrealized to have a role in metabolism. Suh et al. (2014) now report impressive pharmacological outcomes of FGF1 therapy in mice that imply this protein is an important metabolic regulator with therapeutic potential in the treatment of insulin resistance and type 2 diabetes. PMID- 25295782 TI - An epigenetic "LINK(RNA)" to pathological cardiac hypertrophy. AB - Reinduction of fetal gene expression is characteristic of the failing adult heart. Han et al. (2014) demonstrate that a novel cluster of long noncoding RNAs, Myheart, protects the heart from pathological hypertrophy, involving a negative feedback molecular circuit with the epigenetic Brg1 complex to inhibit fetal-gene reactivation. PMID- 25295783 TI - SUMOylation places LRH-1 in PROXimity to lipid metabolism. AB - The development of atherosclerosis is countered by the reverse transport of cholesterol from peripheral tissues to the liver for excretion. In this issue of Cell Metabolism, Stein et al. (2014) establish LRH-1 as an important regulator of reverse cholesterol transport and identify SUMOylation as a primary mode of LRH-1 regulation. PMID- 25295784 TI - Muscle over mind. AB - Depression is associated with elevated kynurenine levels, a tryptophan metabolite generated under stress and inflammatory conditions. Agudelo et al. (2014) now reveal how PGC-1alpha1 overexpression in muscle mimics anti-depressant effects of exercise by promoting kynurenine aminotransferase expression, likely preventing kynurenine from crossing the blood brain barrier to disrupt neural plasticity. PMID- 25295785 TI - Periostin: a new extracellular regulator of obesity-induced hepatosteatosis. AB - Periostin is a crucial extracellular remodeling factor in the inflammatory and tumor microenvironments, but its function in nonalcoholic fatty liver disease remains unclear. Lu et al. (2014) now demonstrate that periostin is a critical player in the regulation of hepatic triglyceride homeostasis and the development of obesity-induced hepatosteatosis. PMID- 25295786 TI - A missing link in body weight homeostasis: the catabolic signal of the overfed state. AB - Mammals regulate fat mass so that increases or reductions in adipose tissue mass activate responses that favor return to one's previous weight. A reduction in fat mass activates a system that increases food intake and reduces energy expenditure; conversely, overfeeding and rapid adipose tissue expansion reduces food intake and increases energy expenditure. With the identification of leptin nearly two decades ago, the central circuit that defends against reductions in body fat was revealed. However, the systems that defend against rapid expansion of fat mass remain largely unknown. Here we review the physiology of the overfed state and evidence for a distinct regulatory system, which unlike the leptin mediated system, we propose primarily measures a functional aspect of adipose tissue and not total mass per se. PMID- 25295787 TI - Let-7 coordinately suppresses components of the amino acid sensing pathway to repress mTORC1 and induce autophagy. AB - Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 microRNA as capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately downregulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain to eliminate protein aggregates, establishing its physiological relevance for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms. PMID- 25295788 TI - Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. AB - Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6(Delta/Delta)) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6(Delta/Delta) mice, but also in brown adipose tissue- (CerS6(DeltaBAT)) and liver-specific (CerS6(DeltaLIVER)) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition. PMID- 25295790 TI - Characteristics of institutionalized young onset dementia patients--the BEYOnD study. AB - BACKGROUND: People with Young Onset Dementia (YOD) have specific needs for care. These people eventually require institutional care, usually delivered by institutions designed for the elderly. The Dutch network of care organizations delivering specialized YOD care offers a unique opportunity to obtain more knowledge of this special population. METHODS: Our cross-sectional study collected data from 230 people with YOD in eight care homes providing YOD specialized care. Data collected: demographic data, disease duration, dementia subtype, comorbidity, dementia severity (Global Deterioration Scale - GDS), neuropsychiatric symptoms (NPS; Neuropsychiatric Inventory - NPI, Cohen Mansfield Agitation Inventory - CMAI), disease awareness (Guidelines for the Rating of Awareness Deficits - GRAD), need for assistance (hierarchic Activities of Daily Living (ADL) scale - Resident Assessment Instrument - Minimum Data Set (RAI MDS)). RESULTS: The mean age of the residents with YOD in care homes was 60 years and 53% of them were men. There is a large variety of etiologic diagnoses underlying the dementia. Dementia severity was very mild to mild in 18%, moderate in 25%, and severe or very severe in 58% of the participants. The prevalence of NPS was high with 90% exhibiting one or more clinically relevant NPS. Comorbidity was present in more than three quarters of the participants, most frequently psychiatric disorders. CONCLUSIONS: The institutionalized YOD population is heterogeneous. NPS occur in almost all institutionalized people with YOD, and frequency and severity of NPS are higher than in late onset dementia (LOD) and community-dwelling YOD patients. Care should be delivered in settings accommodating a mixed male and female population, with appropriate, meaningful activities for all individuals. Further research is needed on NPS in YOD, to enhance quality of life and work in specialized YOD-care. PMID- 25295789 TI - CerS2 haploinsufficiency inhibits beta-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. AB - Inhibition of ceramide synthesis prevents diabetes, steatosis, and cardiovascular disease in rodents. Six different ceramide synthases (CerS) that differ in tissue distribution and substrate specificity account for the diversity in acyl-chain composition of distinct ceramide species. Haploinsufficiency for ceramide synthase 2 (CerS2), the dominant isoform in the liver that preferentially makes very-long-chain (C22/C24/C24:1) ceramides, led to compensatory increases in long chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance. Mechanistic studies revealed that these metabolic effects were likely due to impaired beta-oxidation resulting from inactivation of electron transport chain components. Inhibiting global ceramide synthesis negated the effects of CerS2 haploinsufficiency in vivo, and increasing C16-ceramides by overexpressing CerS6 recapitulated the phenotype in isolated, primary hepatocytes. Collectively, these studies reveal that altering sphingolipid acylation patterns impacts hepatic steatosis and insulin sensitivity and identify CerS6 as a possible therapeutic target for treating metabolic diseases associated with obesity. PMID- 25295791 TI - Synchronization of coverage, benefits, and payment to drive innovation. AB - More than 35% of Medicare beneficiaries receive care from providers operating under some form of shared savings/risk type of pay-for-performance incentive. Implementation of payment reform without a corresponding change to coverage, benefit, and other payment requirements, however, creates conflicting incentives that may nullify the intended aim of payment reform: to improve health outcomes, while saving costs. If related policies do not evolve to align with payment reform, those entities contracted to receive new bundled payments, such as hospitals or physician groups, will only be able to redesign care to the extent that care meets the myriad of related payment policy requirements. Shifting greater medical management authority from payers to entities managing the payment bundles is a gradual process, as the experience of commercial payers proves. Transitioning the responsibility for modifying coverage, benefit, and payment requirements from CMS to principal accountable bundlers (PABs) will depend on the PAB's degree of financial risk sharing as well as scope of the episode. PMID- 25295792 TI - The effect of depression treatment on work productivity. AB - OBJECTIVES: Depression is associated with lowered work functioning, including absence, productivity impairment at work, and decreased job retention. Although high-quality depression treatment provided in clinical trials has been found to reduce symptoms and improve work function, the effectiveness of routine treatment for depression in primary care has received less attention. STUDY DESIGN: This prospective cohort study investigated the relationship between improvements in both depression symptoms and productivity in outpatients from 77 clinics in Minnesota following routine depression treatment. METHODS: Data were obtained from patients receiving usual care for depression prior to initiation of a statewide quality improvement collaborative called DIAMOND (Depression Improvement Across Minnesota: Offering a New Direction). Patients started on antidepressants were surveyed on depression symptom severity (Patient Health Questionnaire [PHQ-9]), productivity loss (Work Productivity and Activity Impairment questionnaire [WPAI]), health status, and demographics. Data were collected again 6 months later to assess changes in depression symptoms and productivity. RESULTS: Data from 432 employed patients with complete baseline and outcome data showed significant reductions in depression symptoms and increases in productivity (P < .0001) over 6 months. Greater improvements in productivity at 6 months were associated with greater improvement in depression symptoms as well as with greater depression severity (P < .0001) and poorer productivity (P < .0001) at baseline. CONCLUSIONS: This study demonstrated a significant relationship betweenimprovement in depression symptoms and improvements in productivity following routine primary care depression treatment. These findings underscore the benefit of depression care to improve work outcomes and to yield a potential return on healthcare investment to employers. PMID- 25295793 TI - Health economic analysis of Breast Cancer Index in patients with ER+, LN- breast cancer. AB - OBJECTIVES: Breast Cancer Index (BCI) is a novel gene expression-based test for patients with estrogen receptor positive (ER+), lymph node negative (LN-) breast cancer that predicts risk of recurrence over 10 years, and also specifically predicts risk of late (>=5 y) recurrences and likelihood of benefit from extended (>=5 y) endocrine therapy. The objective of this study was to evaluate cost utility of BCI from a US third-party payer perspective. STUDY DESIGN: Two fact based economic models were developed to project the cost and effectiveness of BCI in a hypothetical population of patients with ER+, LN- breast cancer compared with standard clinicopathologic diagnostic modalities. METHODS: Costs associated with adjuvant chemotherapy, toxicity, followup, endocrine therapy, and recurrence were modeled over 10 years. The models examined cost utility compared with standard practice when used at diagnosis and in patients disease-free at 5 years post diagnosis. RESULTS: Use of BCI was projected to be cost saving in both models. In the newly diagnosed population, net cost savings were $3803 per patient tested. In the 5 years post diagnosis population, BCI was projected to yield a net cost savings of $1803 per patient tested. Sensitivity analyses demonstrated that BCI was cost saving across a wide range of clinically relevant input assumptions. CONCLUSIONS: BCI was projected to be cost saving when used either at diagnosis or at 5 years post diagnosis. Cost savings are achieved through projected impact on adjuvant chemotherapy use, extended endocrine therapy use, and endocrine therapy compliance. These findings require validation in additional cohorts, including studies of real-world clinical practice. PMID- 25295794 TI - Optimizing enrollment in employer health programs: a comparison of enrollment strategies in the Diabetes Health Plan. AB - BACKGROUND: Many health programs struggle with low enrollment rates. OBJECTIVES: To compare the characteristics of populations enrolled in a new health plan when employer groups implement voluntary versus automatic enrollment approaches. STUDY DESIGN: We analyzed enrollment rates resulting from 2 different strategies: voluntary and automatic enrollment. We used regression modeling to estimate the associations of patient characteristics with the probability of enrolling within each strategy. The subjects were 5014 eligible employees from 11 self-insured employers who had purchased the Diabetes Health Plan (DHP), which offers free or discounted copayments for diabetes related medications, testing supplies, and physician visits. Six employers used voluntary enrollment while 5 used automatic enrollment. The main outcome of interest was enrollment into the DHP. Predictors were gender, age, race/ethnicity, dependent status, household income, education level, number of comorbidities, and employer group. RESULTS: Overall, the proportion of eligible members who were enrolled within the automatic enrollment strategy was 91%, compared with 35% for voluntary enrollment. Income was a significant predictor for voluntary enrollment but not for automatic enrollment. Within automatic enrollment, covered dependents, Hispanics, and persons with 1 nondiabetes comorbidity were more likely to enroll than other subgroups. Employer group was also a significant correlate of enrollment. Notably, all demographic groups had higher DHP enrollment rates under automatic enrollment than under voluntary enrollment. CONCLUSIONS: For employer-based programs that struggle with low enrollment rates, especially among certain employee subgroups, an automatic enrollment strategy may not only increase the total number of enrollees but may also decrease some enrollment disparities. PMID- 25295795 TI - Economic implications of weight change in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Assess the impact of weight change on costs, resource use, and treatment discontinuation among metformin-treated patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: Observational, retrospective cohort. METHODS: Adults with T2DM who were pre existing metformin-treated patients were included. Insulin users were excluded. Administrative data from January 1, 2000, to December 31, 2010, were linked to clinical data, and patients were placed into cohorts based on relative change in body weight. Three cohorts were created: weight loss (decrease >3%), and weight neutral (change <=3%), weight gain (increase > 3%). Inter-cohort differences in resource utilization, costs (2010 US$), and treatment discontinuation were evaluated using statistical models that adjusted for baseline characteristics. RESULTS: A total of 2110 patients (weight loss = 967; weight neutral = 970; weight gain = 173) were included; mean age was 59.6 years, 52.2% were women, 64.1% were Caucasian, and average baseline weight was 98.7 kg. The weight-loss cohort incurred significantly lower costs per year compared with the weight-neutral cohort, driven mainly by lower medical costs from reduced utilization. Weight reduction was associated with approximately $2200 and approximately $440 lower annual all-cause and T2DM-specific costs (P < .05), respectively. Patients who lost weight were 21% less likely to discontinue therapy. Weight gain was associated with a significant increase in all-cause costs of $3400 per year compared with the weight-neutral cohort; however, differences in T2DM-specific costs and discontinuation rates did not reach significance levels. CONCLUSIONS: Weight loss (> 3%) among patients with T2DM was associated with decreased costs and lower rates of treatment discontinuation. Hence weight-focused treatment approaches can help reduce the economic burden for patients with T2DM. PMID- 25295796 TI - Does CAC testing alter downstream treatment patterns for cardiovascular disease? AB - OBJECTIVES: To assess if coronary artery calcium (CAC) scans influence treatment patterns as reflected by subsequent rates of cardiac imaging and therapeutic interventions, and their effect on ischemic events downstream. STUDY DESIGN: Longitudinal observational study from January 1, 2005, through August 31, 2011, using a large managed-care medical and pharmacy claims database. METHODS: Two cohorts were evaluated: CAC patients who received CAC testing, and Reference patients, subject to preauthorization, who were denied CAC scans. Patients were adults less than 65 years old. Index date was CAC scan date for CAC and pre authorization request date for Reference. Patients were stratified into high-risk and non-high-risk categories; outcomes were analyzed only for non-high-risk where CAC scores could potentially modify risk classification. Cardiac imaging, coronary revascularizations, and pharmaceutical interventions were evaluated for 6 months post index and adverse ischemic events were assessed using all available follow-up time. RESULTS: The study included 2679 CAC and 1135 Reference patients. Among non-high-risk patients, similar proportions of both groups received an imaging test within 6 months (23.2% vs 23.8%, respectively; P = .5); revascularization rates and pharmaceutical utilization were similar. Adverse events were rare. Age-sex adjusted incidence rate ratio for adverse events was 1.1 (95% CI, 0.36-3.38) among CAC relative to Reference. High-risk patients, considered inappropriate for CAC testing, represented 20.2% and 23.5% of CAC and Reference, respectively (P <.05). CONCLUSIONS: Patients having CAC scans were not associated with fewer downstream ischemic events nor with reduced subsequent imaging and therapeutic interventions among non-high-risk patients. Results also indicated inappropriate testing of high-risk patients. PMID- 25295797 TI - Potential benefits of increased access to doula support during childbirth. AB - OBJECTIVES: The annual costs of US maternity-related hospitalizations exceed $27 billion. Continuous labor support from a trained doula is associated with improved outcomes and potential cost savings. This study aimed to document the relationship between doula support, desire for doula support, and cesarean delivery, distinguishing cesarean deliveries without a definitive medical indication. STUDY DESIGN: Retrospective analysis of a nationally representative survey of women who delivered a singleton baby in a US hospital in 2011- 2012 (N = 2400). METHODS: Multivariable logistic regression analysis of characteristics associated with doula support and desire for doula support; similar models examine the relationship between doula support, desire for doula support, and 1) any cesarean or 2) nonindicated cesarean. RESULTS: Six percent of women reported doula care during childbirth. Characteristics associated with desiring but not having doula support were black race (vs white; adjusted odds ratio [AOR] = 1.77; 95% CI,1.03-3.03), and publicly insured or uninsured (vs privately insured; AOR = 1.83, CI, 1.17-2.85; AOR = 2.01, CI, 1.07-3.77, respectively). Doula-supported women had lower odds of cesarean compared without doula support and those who desired but did not have doula support (AOR = 0.41, CI, 0.18-0.96; and AOR = 0.31, CI, 0.13-0.74). The odds of nonindicated cesarean were 80-90% lower among doula-supported women (AOR= 0.17, CI, 0.07-0.39; and AOR= 0.11, CI, 0.03-0.36). CONCLUSIONS: Women with doula support have lower odds of nonindicated cesareans than those who did not have a doula as well as those who desired but did not have doula support. Increasing awareness of doula care and access to support from a doula may facilitate decreases in nonindicated cesarean rates. PMID- 25295798 TI - Effects of multidisciplinary team care on utilization of emergency care for patients with lung cancer. AB - OBJECTIVES: To improve the quality of care, multidisciplinary team (MDT) care was implemented in Taiwan. This study examined the relationship between MDT care and emergency department visits for lung cancer patients. STUDY DESIGN: A retrospective cohort study with MDT care participants and matched a double number of control group of non-participants was followed. METHODS: In this study, 22,817 patients with newly diagnosed lung cancer were recruited from 2005 to 2007 in Taiwan. Matching based on the propensity of receiving MDT care was used. A total of 8172 patients were observed in this study. A c2, ANOVA, logistic regression, and Poisson regression were used to elucidate the effects of MDT care. RESULTS: The lung cancer patients participating in MDT had lower risk to visit an emergency department (ED) (OR = 0.89; 95% CI, 0.80-0.98), and the incidence rate ratio decreased by 11% (95% CI, -0.15 to -0.07). Gender, monthly salary, urbanization of the residence area, comorbid conditions, catastrophic illness/injury, treatment method, number of outpatient visits, length of stay, hospital ownership, level of hospital, and the age of the patient's physician were all significantly related to the frequency of ED visits (P < .05). CONCLUSIONS: The frequency of emergency department visits of patients with MDT care was lower than that of those without it. The patients with MDT received enhanced care. PMID- 25295799 TI - Risk factors associated with irreversible airway obstruction in nonsmoking adult patients with severe asthma. AB - Persistent airways obstruction (PAO) may affect some patients with severe asthma and may significantly worsen the prognosis. This study was designed to detect risk factors associated with persistent airflow limitation in nonsmoking adult patients with severe asthma. A total of 68 adults with severe asthma were recruited and followed prospectively for four to six weeks during the stable phase of disease. For all patients, at every visit spirometry with reversibility test was performed. Based on the results, patients were stratified into group 1 (reversible obstruction) or group 2 (PAO). In both cohorts, associations of postbronchodilatator forced expiratory volume in one second/forced vital capacity ratio (FEV1/FVC) with patients' age, gender, asthma duration, history of atopy and allergy, family history, medications, frequency of previous exacerbations, infections, hospitalizations, and artificial ventilation due to the asthma attack related respiratory failure were investigated. Using a univariate logistic regression analysis, we have shown that older age, more than six exacerbations per year, artificial ventilation in the past, at least one hospitalization per year, the presence of atopic dermatitis, and exposure to domestic visible mold were all independent risk factors of PAO. Furthermore, multivariate regression analysis demonstrated that especially those with domestic exposure to visible molds, with very frequent exacerbations and with at least one hospitalization throughout the last year, were at risk for developing PAO. Domestic exposure to molds, hospitalization during the last year, and very frequent exacerbations were associated with PAO in patients with severe asthma. These factors may help in predicting fixed airflow limitation in nonsmoking patients with severe asthma. PMID- 25295800 TI - Altered L-arginine metabolism in children with controlled asthma. AB - Decreased level of L-arginine may lead to airway hyperresponsiveness, inflammation, and airway remodeling. Changes in L-arginine metabolism were observed earlier in adult asthmatic patients. Studies on L-arginine metabolism in children with bronchial asthma are limited. Because biosynthesis of L-arginine is insufficient in growing children, its potential metabolic alterations may have important clinical implications. This study was designed to evaluate L-arginine metabolism in children with well-controlled asthma. The studies were conducted on blood serum of 30 asthmatic and 20 healthy children (control group). Levels of L arginine and its metabolic products, L-citrulline and L-ornithine, were measured by HPLC. Arginase activity was determined spectrophotometrically. Disease severity was evaluated by the asthma control test (ACT) and the level of nitric oxide (NO) in exhaled air. In asthmatic children L-arginine concentration was significantly lowered, whereas arginase activity was unchanged when compared with the healthy group. However, L-ornithine and L-citrulline levels were significantly increased. There was no correlation between arginase activity, amino acids levels, ACT scores, and exhaled NO. In children with chronic, well controlled asthma L-arginine metabolism is altered. Given that L-arginine is absolutely essential for children, our findings may be of particular importance for the management of children with non-exacerbated asthma. They may also help to develop new therapeutic strategies targeted at L-arginine metabolism in the future. PMID- 25295801 TI - United airway disease. PMID- 25295802 TI - Allergic rhinitis and asthma: epidemiology and common pathophysiology. AB - Allergic rhinitis and asthma are common diseases that frequently occur together. This concept has been referred to in the literature as united airway disease. Epidemiological studies have shown that the majority of patients with asthma have concomitant rhinitis and the presence of rhinitis is an increased risk factor for development of asthma. Patients with asthma and rhinitis share common physiology including heightened bronchial hyperresponsiveness and heightened reactivity to a variety of stimuli. Immunopathology of allergic rhinitis is also similar with the predominance of T-helper type 2 inflammation and tissue eosinophilia. Although several mechanisms have been proposed to explain the united airway theory, some of the best lines of evidence suggest that local airway inflammation can result in a systemic inflammatory response. Pharmacotherapeutic studies have shown that the treatment of rhinitis can improve asthma and vice versa. Nevertheless, systemic approaches such as immunotherapy lead to better outcomes for treating both disease states simultaneously. This article will focus on the data supporting the common epidemiology, shared pathophysiology, and therapeutic interventions aimed at allergic rhinitis and asthma as united airway diseases. PMID- 25295803 TI - Prognostic factors in outcome of angioedema in the emergency department. AB - Angioedema is a transient, localized swelling caused by two distinct mechanisms, mediated by histamine and bradykinin, respectively, although a proportion of cases remain idiopathic. Studies that characterize undifferentiated angioedema presenting in emergency departments (EDs) are limited. This study investigates the presentation patterns of undifferentiated angioedema in the ED based on the presumed mechanism of swelling. Medical records from all ED visits to two tertiary care hospitals from July 2007 to March 2012 were electronically reviewed. Records with documented visible swelling on general inspection and/or fiberoptic laryngoscopy and a diagnostic code for anaphylactic shock, angioneurotic edema, allergy unspecified, defects in the complement system, or unspecified drug adverse effects were included. Demographic, clinical, and outcome data were collected via a standardized form. Data were analyzed descriptively, including frequencies and percentages for categorical data and means and SDs for continuous data. Predictors for admission were identified using multivariate logistic regression models. ED records from 527 visits for angioedema by 455 patients were included in the study. Annual rate of angioedema was 1 per 1000 ED visits. Urticaria was associated with peripheral (p = 0.008) and lip angioedema (p = 0.001), and the absence of urticaria correlated with tongue angioedema (p = 0.001) and trended toward correlation with pharyngeal angioedema (p = 0.056). Significant predictors of admission included nonsteroidal anti-inflammatory drug-induced angioedema (odds ratio [OR], 15.3), epinephrine treatment (OR, 8.34), hypotension (OR, 15.7), multiple-site angioedema (OR, 4.25), and pharyngeal (OR, 1.23) and tongue angioedema (OR, 4.62). Concomitant urticaria was associated with a significant longer stay in the ED (p < 0.001). The presence of urticaria correlated with the location of angioedema, need for airway management, length of ED visit, and recurrence. A detailed drug and family history, screening blood work for C1 esterase inhibitor deficiency when indicated, and prompt management of angioedema based on presumed mechanism of swelling are crucial steps in managing undifferentiated angioedema in ED. PMID- 25295804 TI - Quality of life in patients with hereditary angioedema receiving therapy for routine prevention of attacks. AB - Patients with hereditary angioedema (HAE) have impaired health-related quality of life (HRQoL), but the effect of preventative treatment strategies on HRQoL has not been evaluated. This study was designed to evaluate the effect of routine prevention therapy with nanofiltered C1 inhibitor (C1 INH-nf; human) on the HRQoL of patients with HAE. Thiry-six-item Short Form (SF-36) Version 1.0 questionnaires were administered at the beginning and end of two 12-week treatment periods in this multicenter, randomized, placebo-controlled, crossover study. Patients (n = 22) received intravenous injections of 1000 U of C1 INH-nf or placebo every 3-4 days for 12 weeks and then crossed over to the other treatment arm for a second 12-week period. Patients could receive open-label C1 INH-nf (1000 U) for the acute treatment of angioedema attacks in either arm of the study. Sixteen patients had evaluable SF-36 data. Mean physical component summary scores (PCSs) were 36.41 at baseline, 37.06 at the end of the placebo period, and 43.92 at the end of the C1 INH-nf period. Mean mental component summary scores (MCSs) were 49.90, 44.98, and 54.00, respectively. Least square mean differences (95% confidence intervals) between C1 INH-nf and placebo in norm based SF-36 scores at the end of each treatment period were 6.55 (1.48, 11.62; p = 0.015) for PCS and 8.70 (1.67, 15.72; p = 0.019) for MCS. In a clinical trial setting, patients with HAE had significantly better HRQoL after 12 weeks of C1 INH-nf for routine prevention compared with acute treatment of individual angioedema attacks in the absence of routine prevention while on placebo. This study was a part of the clinical trial NCT01005888 registered in www.clinicaltrials.gov. PMID- 25295805 TI - Risk factors for the development of atopic dermatitis and early wheeze. AB - A global assessment of allergic diseases and prenatal and postnatal exposure to various environmental risk factors is needed to enable early prevention of allergic diseases. This study was designed to evaluate an inner-city urban birth cohort to identify early environmental factors associated with atopic dermatitis and food allergy, as well as the incidence of wheezing during the 1st year of life. We evaluated 501 children from the Polish Mother and Child Cohort Study (2007-2011). The children's health, socioeconomic status, and housing conditions were assessed using a questionnaire. Exposure to tobacco was assessed based on questionnaire data and cotinine measurements. Multiple regression analysis showed that parental atopy, higher paternal education, and more frequent house cleaning significantly predicted atopic dermatitis in the 1st year of life; odds ratio (OR) for the variables was 2.7 (95% CI, 1.3-1.57), 2.8 (95% CI, 1.5-5.0), and 1.8 (95% CI, 1.1-2.9), respectively. Keeping a pet at home during pregnancy increased the risk of food allergy (OR, 1.48; 95% CI, 1.02-2.16). Longer breast-feeding decreased the risk of both food allergy (OR, 0.88; 95% CI, 0.82-0.95) and atopic dermatitis (OR, 0.9; 95% CI, 0.8-0.95) in the 1st year of life. Positive association between maternal exposure to increased concentrations of particulate matter 10 and atopic dermatitis in univariate analyses was found. Atopic dermatitis/food allergy and wheezing/inhaled corticosteroid use had distinct risk factors. The risk factor profile of atopic dermatitis/food allergy in early childhood that is defined in this study support the following recommendations: (i) longer breast-feeding, (ii) avoid pets during gestation, (iii) avoid too frequent house cleaning, and (iv) living in an area with decreased traffic density. This study was a part of the clinical trial NCT01861548 registered in www.clinicaltrials.gov. PMID- 25295806 TI - Predicting asthma control: the role of psychological triggers. AB - Asthma triggers have been linked to adverse health outcomes in asthma, but little is known about their association with asthma control. Because trigger avoidance is an integral part of successful asthma management, psychological triggers in particular may be associated with suboptimal asthma control, given the difficulty of controlling them. We examined cross-sectional and longitudinal associations of perceived asthma triggers with self-report of asthma control impairment, symptoms, and spirometric lung function (forced expiratory volume in the 1st second, [FEV1]) in 179 adult primary care asthma patients. Perceived asthma triggers explained up to 42.5% of the variance in asthma control and symptoms, but not in FEV1 alone. Allergic triggers explained up to 12.1% of the asthma control and symptom variance, three nonallergic trigger types, air pollution/irritants, physical activity, and infection, explained up to 26.2% over and above allergic triggers, and psychological triggers up to 9.5% over and above all other triggers. Psychological triggers alone explained up to 33.9% of the variance and were the only trigger class that was consistently significant in all final multiple regression models predicting control and symptoms. Psychological triggers also predicted lower asthma control 3-6 months later, although controlling for initial asthma control eliminated this association. In free reports of individually relevant triggers, only psychological triggers were associated with suboptimal asthma control. Trigger factors are important predictors of self-reported asthma control and symptoms but not actual lung function. Particular attention should be directed to psychological triggers as indicators of patients' perceptions of suboptimal asthma control. PMID- 25295807 TI - Perceived stress and severity of chronic rhinosinusitis in allergic and nonallergic patients. AB - Chronic stress exposure carries greater risk of onset of atopic respiratory disorders such as rhinitis and asthma. The interaction between depression, anxiety, and severity of chronic rhinosinusitis (CRS) has been suggested. We aimed to access the relationship between psychological stress, severity of CRS, and atopy. Sixty-three consecutive patients referred with CRS were asked to score the severity of rhinosinusitis symptoms on a visual analog scale and to fill in questionnaires on the disease-specific quality of life and perceived stress-22 item Sino-Nasal Outcome Test (SNOT-22) and measure of perceived stress (MPS) scale, respectively. Inclusion criteria for the study were a reliable allergy evaluation and a recent computerized tomography (CT) scan of the sinuses. Patients with nasal polyps (NPs), asthma, and previous surgery were excluded. The study group consisted of 14 allergic and 18 nonallergic patients with CRS without NPs (CRSsNPs). Correlation between MPS and SNOT-22 scores in the study group was highly significant (Pearson r = 0.61; p = 0.001). Patients with higher stress scores had significantly stronger postnasal discharge, thick discharge, cough, disturbed sleep, fatigue, and sadness. Postnasal drip was significantly stronger in patients with allergy. The correlation between SNOT-22 and CT scores was insignificant. The correlation between MPS and SNOT-22 scores suggests an interaction between severity of CRS and chronic stress, but not with the extent of the disease on CT in CRSsNPs. Chronic psychological stress might be one of the factors that modifies the disease severity and may lead to uncontrolled disease in CRS patients. PMID- 25295808 TI - Serum basal tryptase levels in healthy children: correlation between age and gender. AB - Tryptase is used as a marker in many clinical conditions such as mast cell activation and systemic anaphylaxis. Normal levels of the serum basal tryptase (sBT) are determined in adulthood; however, data about nonallergic healthy children is limited. This study was designed to determine the normal sBT levels in healthy children. Total sBT levels were measured in 113 sera from healthy nonallergic children, for routine follow-up or diagnosis of illnesses that are not known to induce changes in serum tryptase levels. One hundred thirteen children aged 0.16-9.91 years (male/female subjects, 68/45 [60%/40%]) with a median (interquartile) age of 3.36 years (1.94-5.68 years) were evaluated. The sBT level was determined to be 3.30 ng/mL (2.38-4.36) median (interquartile) for the whole group. There was a tendency of higher sBT levels for boys than girls (3.49 [2.56-4.64 ng/mL] and 2.91 ng/mL [2.16-4.16 ng/mL], respectively); however, these findings were not significant (p = 0.12). The analysis of the whole group revealed that sBT levels were inversely related with age (r = -0.259; p = 0.006); and the decrease of sBT with age was more prominent in girls (r = -0.282; p = 0.02) than in boys. The highest sBT levels were found in the 0- to 1-year age group (all, 4.67 ng/mL [4.04-6.39 ng/mL]; boys, 5.34 ng/mL [4.04-6.39 ng/mL]; girls, 4.48 ng/mL [3.23-16.26 ng/mL]). The sBT levels in healthy children are similar to those in adults except in infancy. Interestingly, sBT levels tend to decrease slightly with age. Although they did not reach significance, sBT levels were found to be higher in boys compared with the girls. PMID- 25295809 TI - Comparison of atopic features between children and adults with eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a clinicopathological diagnosis seen in children as well as adults. Growing evidence suggests that EoE is strongly associated with atopic disorders. Presenting symptoms differ in children and adults and it is not known whether atopic features vary by age. This study was designed to compare atopic features and allergic sensitization between children and adults with EoE. We conducted a retrospective analysis of demographic and clinical data from 50 children (aged 2-18 years) and 50 adults (aged 21-75 years) with a biopsy-proven diagnosis of EoE referred to our allergy clinic. Data regarding patient characteristics, history of atopic diseases, and allergy test results were collected for analysis. The majority of children and adults were white and male patients. When compared with adults, a higher percentage of children had a history of asthma (52% versus 24%; p < 0.05). There was no statistically significant difference between adults and children regarding history of allergic rhinitis, atopic dermatitis, immunoglobulin E-mediated food allergy, and family history of atopy. There was no statistically significant difference between children and adults regarding immediate-type sensitization to foods and aeroallergens. Compared with adults, a higher percentage of children showed a positive reaction to one or more foods on patch testing (62% versus 31%; p = 0.01). A high prevalence of comorbid atopic diseases and sensitizations to food and environmental allergens was seen in both children and adults. Children had a significantly higher rate of asthma and positive patch test to foods compared with adults. PMID- 25295811 TI - For the patient. Risk factors for the development of atopic dermatitis and early wheeze. PMID- 25295810 TI - Fifty-five-year-old man with chronic yeast infections. AB - As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward. PMID- 25295812 TI - Critical care medicine: extracorporeal oxygenation is feasible in Brazil? PMID- 25295813 TI - Awaking, exercising, sitting, walking and extubating: moving on the paradigms for mechanically ventilated patients. PMID- 25295814 TI - Intensive care unit staffing and quality of care: challenges in times of an intensivist shortage. PMID- 25295815 TI - Nosocomial pneumonia in the intensive care unit: how should treatment failure be predicted? PMID- 25295816 TI - Ventilator-associated tracheobronchitis: where are we now? PMID- 25295818 TI - Latin American consensus on the use of transcranial Doppler in the diagnosis of brain death. AB - Transcranial Doppler evaluates cerebral hemodynamics in patients with brain injury and is a useful technical tool in diagnosing cerebral circulatory arrest, usually present in the brain-dead patient. This Latin American Consensus was formed by a group of 26 physicians experienced in the use of transcranial Doppler in the context of brain death. The purpose of this agreement was to make recommendations regarding the indications, technique, and interpretation of the study of transcranial ultrasonography in patients with a clinical diagnosis of brain death or in the patient whose clinical diagnosis presents difficulties; a working group was formed to enable further knowledge and to strengthen ties between Latin American physicians working on the same topic. A review of the literature, concepts,and experiences were exchanged in two meetings and via the Internet. Questions about pathophysiology, equipment, techniques, findings, common problems, and the interpretation of transcranial Doppler in the context of brain death were answered. The basic consensus statements are the following: cerebral circulatory arrest is the final stage in the evolution of progressive intracranial hypertension, which is visualized with transcranial Doppler as a "pattern of cerebral circulatory arrest". The following are accepted as the standard of cerebral circulatory arrest: reverberant pattern, systolic spikes, and absence of previously demonstrated flow. Ultrasonography should be used - in acceptable hemodynamic conditions - in the anterior circulation bilaterally (middle cerebral artery) and in the posterior (basilar artery) territory. If no ultrasonographic images are found in any or all of these vessels, their proximal arteries are acceptable to be studied to look for a a pattern of cerebral circulatory arrest. PMID- 25295820 TI - Out-of-bed extubation: a feasibility study. AB - OBJECTIVE: In clinical intensive care practice, weaning from mechanical ventilation is accompanied by concurrent early patient mobilization. The aim of this study was to compare the success of extubation performed with patients seated in an armchair compared to extubation with patients in a supine position. METHODS: A retrospective study, observational and non-randomized was conducted in a mixed-gender, 23-bed intensive care unit. The primary study outcome was success of extubation, which was defined as the patient tolerating the removal of the endotracheal tube for at least 48 hours. The differences between the study groups were assessed using Student's t-test and chi-squared analysis. RESULTS: Ninety one patients were included from December 2010 and June 2011. The study population had a mean age of 71 years +/- 12 months, a mean APACHE II score of 21+/-7.6, and a mean length of mechanical ventilation of 2.6+/-2 days. Extubation was performed in 33 patients who were seated in an armchair (36%) and in 58 patients in a supine position (64%). There were no significant differences in age, mean APACHE II score or length of mechanical ventilation between the two groups, and a similar extubation success rate was observed (82%, seated group versus 85%, supine group, p>0.05). Furthermore, no significant differences were found between the two groups in terms of post-extubation distress, need for tracheostomy, duration of mechanical ventilation weaning, or intensive care unit stay. CONCLUSION: Our results suggest that the clinical outcomes of patients extubated in a seated position are similar to those of patients extubated in a supine position. This new practice of seated extubation was not associated with adverse events and allowed extubation to occur simultaneously with early mobilization. PMID- 25295817 TI - Brazilian recommendations of mechanical ventilation 2013. Part 2. AB - Perspectives on invasive and noninvasive ventilatory support for critically ill patients are evolving, as much evidence indicates that ventilation may have positive effects on patient survival and the quality of the care provided in intensive care units in Brazil. For those reasons, the Brazilian Association of Intensive Care Medicine (Associacao de Medicina Intensiva Brasileira - AMIB) and the Brazilian Thoracic Society (Sociedade Brasileira de Pneumologia e Tisiologia SBPT), represented by the Mechanical Ventilation Committee and the Commission of Intensive Therapy, respectively, decided to review the literature and draft recommendations for mechanical ventilation with the goal of creating a document for bedside guidance as to the best practices on mechanical ventilation available to their members. The document was based on the available evidence regarding 29 subtopics selected as the most relevant for the subject of interest. The project was developed in several stages, during which the selected topics were distributed among experts recommended by both societies with recent publications on the subject of interest and/or significant teaching and research activity in the field of mechanical ventilation in Brazil. The experts were divided into pairs that were charged with performing a thorough review of the international literature on each topic. All the experts met at the Forum on Mechanical Ventilation, which was held at the headquarters of AMIB in Sao Paulo on August 3 and 4, 2013, to collaboratively draft the final text corresponding to each sub topic, which was presented to, appraised, discussed and approved in a plenary session that included all 58 participants and aimed to create the final document. PMID- 25295821 TI - Lack of agreement between different observers and methods in the measurement of capillary refill time in healthy volunteers: an observational study. AB - OBJECTIVE: Peripheral perfusion abnormalities are relevant manifestations of shock. Capillary refill time is commonly used for their evaluation. However, the reproducibility of capillary refill time measurements and their correlation with other variables of peripheral perfusion, have not been comprehensively evaluated. Our goal was to determine, in healthy volunteers, the agreement between different methods of capillary refill time quantification and different observers, as well as their correlation with other markers of peripheral perfusion. Methods: We studied 63 healthy volunteers. Two observers measured capillary refill time by means of two methods, direct view (CRTchronome ter) and video analysis (CRTvideo). We also measured perfusion index (PI) derived from pulse plethysmography and finger pad temperature (T degrees peripheral). The agreement between observers and methods was assessed using the Bland and Altman method. Correlations were calculated using Pearson's correlation. A p-value<0.05 was considered significant. RESULTS: The 95% limits of agreement between the two observers were 1.9 sec for CRTchronometer and 1.7 sec for CRTvideo. The 95% limits of agreement between CRTchronometer and CRTvideo were 1.7 sec for observer 1 and 2.3 sec for observer 2. Measurements of CRTchronometer performed by the two observers were correlated with T degrees peripheral. Measurements of CRTvideo performed by the two observers were correlated with T degrees peripheral and perfusion index. CONCLUSION: In healthy volunteers, measurements of capillary refill time performed by either different observers or different methods showed poor agreement. Nevertheless, capillary refill time still reflected peripheral perfusion as shown by its correlation with objective variables of peripheral perfusion. PMID- 25295822 TI - The impact of hypertonic and normal saline in gut reperfusion after ischemia in rats. AB - OBJECTIVE: We investigated the effect of two different saline solutions on the mechanisms of injury after intestinal ischemia: oxidative stress and inflammatory responses. METHODS: Wistar rats underwent transient superior mesenteric artery occlusion and were studied for 6 hours after reperfusion. After randomization, the animals were divided into four groups: Sham; Hypertonic Saline, in which they received infusion of 4 mL/kg body weight of 7.5% hypertonic saline; Saline, in which they received infusion of 33 mL/kg body weight of 0.9% saline; and Non Treatment. The infusion was performed immediately prior to the reperfusion. The plasma concentrations of interleukin 6 and interleukin 10 were measured. Tissue samples (lung, liver, and intestine) were collected for malondialdehyde, myeloperoxidase, and interleukin measurements. RESULTS: The animals that received infusions (Hypertonic Saline and Saline) showed lower levels of tissue malondialdehyde, myeloperoxidase, interleukin 6, and interleukin 10 compared with the Non Treatment group. The plasma concentrations of interleukin 6 and interleukin 10 were higher in the animals treated with 7.5% hypertonic saline compared with Saline and Non Treatment groups. CONCLUSION: In this model of transient intestinal ischemia, the adequate maintenance of intravascular volume decreased oxidative stress and the synthesis of inflammatory markers. Both 7.5% Hypertonic Saline and Saline attenuated the deleterious effects observed after intestinal ischemia. PMID- 25295819 TI - The economic effect of extracorporeal membrane oxygenation to support adults with severe respiratory failure in Brazil: a hypothetical analysis. AB - OBJECTIVE: To analyze the cost-utility of using extracorporeal oxygenation for patients with severe acute respiratory distress syndrome in Brazil. METHODS: A decision tree was constructed using databases from previously published studies. Costs were taken from the average price paid by the Brazilian Unified Health System (Sistema Unico de Saude; SUS) over three months in 2011. Using the data of 10,000,000 simulated patients with predetermined outcomes and costs, an analysis was performed of the ratio between cost increase and years of life gained, adjusted for quality (cost-utility), with survival rates of 40 and 60% for patients using extracorporeal membrane oxygenation. RESULTS: The decision tree resulted in 16 outcomes with different life support techniques. With survival rates of 40 and 60%, respectively, the increased costs were R$=-301.00/-14.00, with a cost of R$=-30,913.00/-1,752.00 paid per six-month quality-adjusted life year gained and R$=-2,386.00/-90.00 per quality-adjusted life-year gained until the end of life, when all patients with severe ARDS were analyzed. Analyzing only patients with severe hypoxemia (i.e., a ratio of partial oxygen pressure in the blood to the fraction of inspired oxygen <100 mmHg), the increased cost was R$= 5,714.00/272.00, with a cost per six-month quality-adjusted life-year gained of R$=-9,521.00/293.00 and a cost of R$=-280.00/7.00 per quality-adjusted life-year gained. CONCLUSION: The cost-utility ratio associated with the use of extracorporeal membrane oxygenation in Brazil is potentially acceptable according to this hypothetical study. PMID- 25295823 TI - In vitro and in vivo validation of stored swine erythrocyte viability to establish an experimental model of homologous red blood cell transfusion: a pilot study. AB - OBJECTIVE: To develop experimental models of erythrocyte transfusion, the first step is to ensure the viability of the red blood cells transfused. In this pilot study, we assessed the viability of transfused red blood cells with validation in vitro and in vivo of homologous swine erythrocytes stored for 14 days. METHODS: Blood collected from one Agroceres swine was stored in two red blood cell units. In vivo validation was performed by labeling the red blood cells with Na251CrO4 and recovering the viable erythrocytes after 24 hours of infusion in one autologous and four homologous animals. In vitro validation was performed at baseline and after 14 days in sixteen red blood cell units by measuring hemoglobin, hematocrit, hemolysis index and free hemoglobin. A post-mortem splenectomy was performed to evaluate the splenic sequestration of erythrocytes, and the radioactivity of the supernatant samples was counted to evaluate intravascular hemolysis. RESULTS: After 14 days of storage, the red blood cell units had lower volumes and equivalent total concentrations of hemoglobin and hematocrit compared to human standards. The free hemoglobin concentration increased from 31.0+/-9.3 to 112.4+/-31.4 mg/dL (p<0.001), and the hemolysis index increased from 0.1+/-0.1 to 0.5+/-0.1% (p<0.001). However, these tests were within the acceptable range for human standards. The percentage of radioactivity in supernatant samples was similar at baseline and after 24 hours, thus excluding significant hemolysis. No evidence of splenic sequestration of radioactive erythrocytes was found. CONCLUSION: Swine red blood cells stored for 14 days are viable and can be used in experimental studies of transfusion. These validation experiments are important to aid investigators in establishing experimental models of transfusion. PMID- 25295824 TI - Nursing Activities Score and workload in the intensive care unit of a university hospital. AB - OBJECTIVE: The nursing workload consists of the time spent by the nursing staff to perform the activities for which they are responsible, whether directly or indirectly related to patient care. The aim of this study was to evaluate the nursing workload in an adult intensive care unit at a university hospital using the Nursing Activities Score (NAS) instrument. METHODS: A longitudinal, prospective study that involved the patients admitted to the intensive care unit of a university hospital between March and December 2008. The data were collected daily to calculate the NAS, the Acute Physiology and Chronic Health Evaluation (APACHE II), the Sequential Organ Failure Assessment (SOFA) and the Therapeutic Intervention Scoring System (TISS-28) of patients until they left the adult intensive care unit or after 90 days of hospitalization. The level of significance was set at 5%. RESULTS: In total, 437 patients were evaluated, which resulted in an NAS of 74.4%. The type of admission, length of stay in the intensive care unit and the patients' condition when leaving the intensive care unit and hospital were variables associated with differences in the nursing workload. There was a moderate correlation between the mean NAS and APACHE II severity score (r=0.329), the mean organic dysfunction SOFA score (r=0.506) and the mean TISS-28 score (r=0.600). CONCLUSION: We observed a high nursing workload in this study. These results can assist in planning the size of the staff required. The workload was influenced by clinical characteristics, including an increased workload required for emergency surgical patients and patients who died. PMID- 25295825 TI - The knowledge of intensive care professionals about diarrhea. AB - OBJECTIVE: To assess the opinions and practices of intensive care professionals with regard to diarrhea in critically ill patients. METHODS: A multicenter cross sectional study was conducted among health care professionals working at three adult intensive care units.Participants responded individually to a self administered questionnaire about their length of work experience in intensive care; the definition,characterization, and causes of diarrhea;types of records in the patient's medical record; and training received. RESULTS: A total of 78 professionals participated in this study, of whom 59.0% were nurse technicians, 25.7%were nurses, and 15.3% were physicians;77.0% of them had worked in intensive care for over 1 year. Only 37.2% had received training on this topic. Half of the interviewees defined diarrhea as "liquid and/or pasty stools" regardless of frequency, while the other 50.0% defined diarrhea based on the increased number of daily bowel movements. The majority of them mentioned diet as the main cause of diarrhea, followed by "use of medications" (p<0.001). Distinct nutritional practices were observed among the analyzed professionals regarding episodes of diarrhea, such as discontinuing, maintaining, or reducing the volume of enteral nutrition; physicians reported that they do not routinely communicate the problem to other professionals (for example, to a nutritionist) and do not routinely record and quantify diarrhea events in patients' medical records. CONCLUSION: Different opinions and practices were observed in intensive care professionals with regard to diarrhea. PMID- 25295827 TI - Platypnea-orthodeoxia syndrome in patients presenting enlarged aortic root: case report and literature review. AB - We describe herein a case of a patient who, when in orthostatic positions, had severe hypoxemia and ventilatory dysfunction. Although the severity of symptoms required hospitalization in an intensive care setting, the initial tests only identified the presence of enlarged aortic root, which did not explain the condition. The association of these events with an unusual etiology, namely intracardiac shunt, characterized the diagnosis of platypnea-orthodeoxia syndrome. The literature review shows that, with advancing research methods, there was a progressive increase in the identification of this condition, and this association should be part of the differential diagnosis of dyspnea in patients with enlarged aortic root. PMID- 25295826 TI - Prognostic value of circulating DNA levels in critically ill and trauma patients. AB - The number of studies investigating circulating nucleic acids as potential biomarkers has increased in recent years. The detection of such biomarkers is a minimally invasive alternative for the diagnosis and prognosis of various clinical conditions. The value of circulating DNA levels as a predictive biomarker has been demonstrated in patients suffering from numerous acute pathologies that have a high risk of intensive care needs and in-hospital deaths. The mechanism by which circulating DNA levels increase in patients with these conditions remains unclear. In this review, we focused on the potential use of this biomarker for prognosis prediction in critically ill and trauma patients. The literature review was performed by searching MedLine using PubMed in the English language. PMID- 25295828 TI - Post-extubation atelectasis in newborns with surgical diseases: a report of two cases involving the use of a high-flow nasal cannula. AB - Atelectasis is a pulmonary disorder that lengthens the hospitalization time of newborns in intensive care units, resulting in increased morbidity among these infants. High-flow nasal cannulae have been used in newborns to prevent atelectasis and/or expand pulmonary regions affected by atelectasis; however, to date, no evidence-based data regarding this approach have been reported. In this paper, we report on the cases of two male newborn patients. The first and second patients described in this report were hospitalized for a neurosurgical procedure and the treatment of abdominal disease, respectively, and were subjected to invasive mechanical ventilation for 4 and 36 days, respectively. After extubation, these patients continued receiving oxygen therapy but experienced clinical and radiological worsening typical of atelectasis. In both cases, by 24 hours after the implantation of an high-flow nasal cannulae to provide noninvasive support, radiological examinations revealed the complete resolution of atelectasis. In these cases, the use of an high-flow nasal cannulae was effective in reversing atelectasis. Thus, this approach may be utilized as a supplemental noninvasive ventilatory therapy to avoid unnecessary intubation. PMID- 25295829 TI - Fulminant myocarditis associated with the H1N1 influenza virus: case report and literature review. AB - A case of fulminant myocarditis associated with the H1N1 influenza virus. This case report describes the patient's clinical course and emphasizes the importance of bedside echocardiography as an aid in the early diagnosis and management of children with severe myocardial dysfunction. It also discusses aspects relevant to the treatment and prognosis of fulminant myocarditis. The patient was a female, 4 years and 8 months old, previously healthy and with a history of flu symptoms in the past two weeks. The patient was admitted to the emergency room with signs of hemodynamic instability, requiring ventilatory support and vasoactive drugs. The laboratory tests, chest X-ray and echocardiogram suggested the presence of myocarditis. The test for H1N1 in nasopharyngeal secretions was positive. The patient evolved to refractory cardiogenic shock despite the clinical measures applied and died 48 hours after admission to the intensive care unit. The H1N1 influenza virus is an etiological agent associated with acute myocarditis, but there are few reported cases of fulminant myocarditis caused by the H1N1 virus. The identification of signs and symptoms suggestive of fulminant progression should be immediate, and bedside echocardiography is a useful tool for the early detection of myocardial dysfunction and for therapeutic guidance. The use of immunosuppressive therapy and antiviral therapy in acute myocarditis of viral etiology is controversial; hence,the treatment is based on hemodynamic and ventilatory support. The use of hemodynamic support by extracorporeal membrane oxygenation emerges as a promising treatment. PMID- 25295831 TI - Dynamic scaling of morphogen gradients on growing domains. AB - Developmental mechanisms are highly conserved, yet act in embryos of very different sizes. How scaling is achieved has remained elusive. Here we identify a generally applicable mechanism for dynamic scaling on growing domains and show that it quantitatively agrees with data from the Drosophila wing imaginal disc. We show that for the measured parameter ranges, the Dpp gradient does not reach steady state during Drosophila wing development. We further show that both, pre steady-state dynamics and advection of cell-bound ligand in a growing tissue can, in principle, enable scaling, even for non-uniform tissue growth. For the parameter values that have been established for the Dpp morphogen in the Drosophila wing imaginal disc, we show that scaling is mainly a result of the pre steady-state dynamics. Pre-steady-state dynamics are pervasive in morphogen controlled systems, thus making this a probable general mechanism for dynamic scaling of morphogen gradients in growing developmental systems. PMID- 25295833 TI - [The disease called "Barbiers" in the 19th century]. AB - Described by French, English, and Dutch physicians, the disease known as Barbiers struck the island of Reunion in 1805, 1821, 1838 and 1847. It also ravaged India and other parts of the world during the 19(th) century. The origin of the name Barbiers nonetheless remains unknown. Because no diagnostic tests existed at the time, Barbiers has been thought to refer to several clinical entities, and has been the topic of passionate debates among French doctors, including Auguste Vinson and Le Roy De Mericourt, as well as among their British colleagues. This article reviews its history and tries to understand its true nature in 2014, but cannot reach a firm conclusion. PMID- 25295834 TI - Economic evaluation of a randomized controlled trial of pharmacist-supervized patient self-testing of warfarin therapy. AB - WHAT IS KNOWN AND OBJECTIVE: The increase in numbers of patients requiring oral anti-coagulation testing in outpatient clinics has focused attention on alternative flexible systems of anti-coagulation management. One option is pharmacist led patient self-testing (PST) of international normalised ratio (INR) levels. PST has demonstrated improvements in anti-coagulation control, but its cost-effectiveness is inconclusive. This study reports the first cost effectiveness evaluation of a randomized controlled trial of an automated direct to-patient expert system, enabling remote and effective management of patients on oral anti-coagulation therapy. METHODS: We conducted an economic evaluation alongside a randomised controlled trial investigating a pharmacist led PST method. The primary outcome was to determine the cost effectiveness of PST in comparison with usual care (management in a hospital based anti-coagulation clinic). Long term anti-coagulation patients were recruited to a 6 month cross over study between PST and routine care in an anti-coagulation clinic. Economic evaluation was from the healthcare payer perspective. RESULTS AND DISCUSSION: On a per patient basis over a 6 month period, PST resulted in an incremental cost of ?59.08 in comparison with routine care. Patients achieved a significantly higher time in therapeutic range (TTR) during the PST arm in comparison with routine care, (72 +/- 19.7% vs. 59 +/- 13.5%). Overall cost of managing a patient through pharmacist supervised PST for a 6 month period is ?226.45. Additional analysis of strategies from a societal perspective indicated that PST was the dominant strategy. WHAT IS NEW AND CONCLUSION: Pharmacist led patient self-testing is a viable method of management. It provides significant increases in anti coagulation control for a minimal increase in cost. PMID- 25295835 TI - Thermodynamic Driving Forces for Dye Molecule Position and Orientation in Nanoconfined Solvents. AB - The results of replica exchange molecular dynamics simulations of a coumarin 153 (C153) dye molecule dissolved in ethanol confined within a 2.4 nm hydrophilic amorphous silica pore are presented. The C153 dye position and orientation distributions provide insight into time-dependent fluorescence measurements in nanoconfined solvents as well as general features of chemistry in mesoporous materials. In addition to the distributions themselves, the free energy, internal energy, and entropic contributions have been calculated to explore the factors determining the distributions. The most likely location of C153 is found to be near the pore surface, but two possible hydrogen-bonding structures lead to differing orientations. Internal energy and entropy are found to be competing forces within the pore, with entropy playing a significant role with unexpected consequences. These results represent a crucial step in determining how the nanoconfining framework can affect measurements of solvation dynamics. PMID- 25295836 TI - Influence of extracellular polymeric substances on the long-term fate, dissolution, and speciation of copper-based nanoparticles. AB - The influence of phytoplankton-derived soluble extracellular polymeric substances (EPS), pH, and ionic strength (IS) on the dissolution, speciation, and stability of nano-CuO, nano-Cu, and Kocide (a micron sized Cu(OH)2-based fungicide) was investigated over 90 days. EPS improved the stability of commercial copper-based nanoparticles (CBNPs) in most conditions, in addition to influencing their dissolution. The dissolution rate was pH 4?pH 7>pH 11. The presence of EPS correlated with higher dissolved Cu at pH 7 and 11, and lower dissolved Cu at pH 4. More dissolution was observed at higher IS (NaCl) due to complexation with Cl . Dissolution of nano-CuO at pH 7 increased from 0.93% after 90 days (without EPS) to 2.01% (with 5 mg-C EPS/L) at 10 mM IS. Nano-CuO dissolved even more (2.42%) when IS was increased to 100 mM NaCl (with EPS). The ratio of free Cu2+/total dissolved Cu decreased in the presence of EPS, or as pH and/or IS increased. On a Cu mass basis, Kocide had the highest dissolved and suspended Cu at pH 7. However, dissolution of nano-Cu resulted in a higher fraction of free Cu2+, which may make nano-Cu more toxic to pelagic organisms. PMID- 25295838 TI - Systematical characterization of phase behaviors and membrane properties of fatty acid/didecyldimethylammonium bromide vesicles. AB - Fatty acids (FAs) are known to form vesicle structures, depending on the surrounding pH conditions. In this study, we prepared vesicles by mixing FAs and a cationic surfactant, and then investigated their physicochemical properties using fluorescence spectroscopy and dielectric dispersion analysis (DDA). The assemblies formed from oleic acid (OA) and linoleic acid (LA) were modified by adding didecyldimethylammonium bromide (DDAB). The phase state of FA/DDAB mixtures was investigated with pH titration curves and turbidity measurements. The trigonal diagram of FA/ionized FA/DDAB was successfully drawn to understand the phase behaviors of FA/DDAB systems. The analysis of fluidities in the interior of the membrane with use of 1,6-diphenyl-1,3,5-hexatriene (DPH) indicated that the membrane fluidities of OA/DDAB and LA/DDAB at pH 8.5 slightly decreased in proportion to the molar ratio of DDAB in FA/DDAB systems. The fluorescent probe 6-lauroyl-2-dimethylamino naphthalene (Laurdan) indicated that the LA vesicle possessed a dehydrated surface, while the OA vesicle surface was hydrated. Modification of LA vesicles with DDAB induced the hydration of membrane surfaces, whereas modification of OA vesicles by DDAB had the opposite effect. DDA analysis indicated that the membrane surfaces were hydrated in the presence of DDAB, suggesting that the surface properties of FA vesicles are tunable by DDAB modification. PMID- 25295837 TI - Clozapine use reduced psychiatric hospitalization and emergency room visits in patients with bipolar disorder independent of improved treatment regularity in a three-year follow-up period. AB - OBJECTIVES: The efficacy of clozapine in bipolar disorder remains to be systemically examined. In the current study, we sought to disentangle the effect of clozapine from that of improved treatment regularity and to compare the effect of clozapine with the effect of regular treatment for bipolar disorder by exploring the complete 10-year clozapine prescription data from a Taiwanese total population health claims database. METHODS: In the period between 2000 and 2009, 3,874 (3.3%) out of the 117,785 patients identified as having bipolar disorder in a Taiwanese total population health claims database were ever prescribed clozapine. Among them, 920 patients with bipolar disorder who had good pre clozapine medication compliance and received at least two clozapine prescriptions were further categorized according to their clozapine medication possession ratio (MPR) as regular users (MPR >= 0.8; n = 476) and irregular users (MPR < 0.8; n = 444). Using a mirror-image design, we compared the numbers of emergency room (ER) visits, hospitalizations and hospital days, and the average durations of a single hospitalization during the pre- and post-clozapine mirror periods with a follow up time of up to three years, controlling for time-variant course confounders. RESULTS: The patterns of change in outcome indices from the pre-clozapine period to the post-clozapine period differed significantly between the two clozapine user groups. Clinical outcome indices improved only in regular users, while they deteriorated in irregular users. Over the three-year follow-up period, the irregular users consistently had a higher adjusted risk for increased numbers of ER visits [odds ratio (OR): 2.06-2.43], hospitalizations (OR: 2.52-3.22), and total hospital days (OR: 2.42-2.91) when compared to the regular users. Thus, effects of clozapine were consistently demonstrated in one- to three-year mirror comparison periods. CONCLUSIONS: Clozapine, when used with high treatment regularity (MPR > 0.8), was effective in reducing the numbers of ER visits, hospitalizations, and total hospital days in patients with bipolar disorder with previous frequent hospitalizations and ER visits despite regular pre-clozapine treatment for bipolar disorder. However, high early attrition and suboptimal treatment compliance need to be rectified in order to optimize the outcome of clozapine treatment in bipolar disorders. PMID- 25295839 TI - A tribute to a friend: Dr. Connie L. Drisko. PMID- 25295840 TI - HPV-positive head and neck cancers: a review of the literature. AB - PURPOSE: The human papillomavirus (HPV) is a sexually transmitted disease (STD) that is rampant among young adults and is linked with cervical and oropharyngeal cancers (OPC). As the preventive arm of oral health care, dental hygienists can take the lead in educating the young adult population about risk factors for HPV and OPC. Dental hygienists' active involvement in educational initiatives may help minimize the spread of HPV associated STDs, prevent transmission of HPV to the head and neck region, and decrease the development of OPC. PMID- 25295841 TI - Addressing early preventive oral health care among young children: a pilot evaluation of the Baby Oral Health Program (bOHP) among dental professionals. AB - PURPOSE: Many communities lack dental professionals with the knowledge and behavioral skills needed to deliver care to young children (<3 years). This study aimed to examine the impact of an intervention (the Baby Oral Health Program (bHOP)) on dental providers' knowledge, values, confidence and practice behaviors regarding preventive oral health care to young children (<3 years), and assess the feasibility and satisfaction of the bOHP among dental providers in a Canadian community setting. METHODS: A quasi-experimental design was employed, with 24 intervention (4.5 hour workshop, and booster session 1 month following) and 18 control group participants completing pre- and post-surveys. RESULTS: A significant group interaction effect emerged for value and knowledge (p<0.05), with participants in the intervention group demonstrating significantly higher baseline to post-intervention change scores. No significant group differences were found for confidence and practice behaviors (p>0.05). Mean scores for perceived workshop usefulness and perceived influence on practice were high. CONCLUSION: Findings suggest that bOHP is effective in increasing dental professionals' knowledge and values about the importance of preventive oral health among young children. However, consideration to provider's stage of readiness to change and more systems-based approaches to enhancing early oral health interventions should be assessed. PMID- 25295842 TI - Building online learning communities in a graduate dental hygiene program. AB - PURPOSE: The literature abounds with research related to building online communities in a single course; however, limited evidence is available on this phenomenon from a program perspective. The intent of this qualitative case study inquiry was to explore student experiences in a graduate dental hygiene program contributing or impeding the development and sustainability of online learning communities. METHODS: Approval from the IRB was received. A purposive sampling technique was used to recruit participants from a stratification of students and graduates. A total of 17 participants completed semi-structured interviews. Data analysis was completed through 2 rounds - 1 for coding responses and 1 to construct categories of experiences. RESULTS: The participants' collective definition of an online learning community was a complex synergistic network of interconnected people who create positive energy. The findings indicated the development of this network began during the program orientation and was beneficial for building a foundation for the community. Students felt socially connected and supported by the network. Course design was another important category for participation in weekly discussions and group activities. Instructors were viewed as active participants in the community, offering helpful feedback and being a facilitator in discussions. Experiences impeding the development of online learning communities related to the poor performance of peers and instructors. CONCLUSION: Specific categories of experiences supported and impeded the development of online learning communities related to the program itself, course design, students and faculty. These factors are important to consider in order to maximize student learning potential in this environment. PMID- 25295843 TI - Endoscopic vs. tactile evaluation of subgingival calculus. AB - PURPOSE: Endoscopic technology has been developed to facilitate imagery for use during diagnostic and therapeutic phases of periodontal care. The purpose of this study was to compare the level of subgingival calculus detection using a periodontal endoscope with that of conventional tactile explorer in periodontitis subjects. METHODS: A convenience sample of 26 subjects with moderate periodontitis in at least 2 quadrants was recruited from the University of Minnesota School of Dentistry to undergo quadrant scaling and root planing. One quadrant from each subject was randomized for tactile calculus detection alone and the other quadrant for tactile detection plus the Perioscope TM (Perioscopy Inc., Oakland, Cali). A calculus index on a 0 to 3 score was performed at baseline and at 2 post-scaling and root planing visits. Sites where calculus was detected at visit 1 were retreated. T-tests were used to determine within-subject differences between PerioscopeTM and tactile measures, and changes in measures between visits. RESULTS: Significantly more calculus was detected using the PerioscopeTM vs. tactile explorer for all 3 subject visits (p<0.005). Mean changes (reduction) in calculus detection from baseline to visit 1 were statistically significant for both the PerioscopeTM and tactile quadrants (p<0.0001). However, further reductions in calculus detection from visit 1 to visit 2 was only significant for the PerioscopeTM quadrant (p<0.025), indicating that this methodology was able to more precisely detect calculus at this visit. CONCLUSION: It was concluded that the addition of a visual component to calculus detection via the PerioscopeTM was most helpful in the re-evaluation phase of periodontal therapy. PMID- 25295844 TI - A persistent diazaheptacene derivative. AB - We describe the synthesis of characterizable diazaheptacene derivatives. Diazaheptacenes need four silylethynyl protecting groups to be isolable. TIPS ethynyl groups are not bulky enough to allow stabilization. Four Si(sec-Bu)3 ethynyl groups symmetrically attached to the acene core sufficiently protect the formed diazaheptacene from dimerization through Diels-Alder reaction. It was characterized by NMR and UV-vis spectroscopies and cyclic voltammetry. PMID- 25295845 TI - The use of ion mobility mass spectrometry for isomer composition determination extracted from Se-rich yeast. AB - The isomer ratio determination of a selenium-containing metabolite produced by Se rich yeast was performed. Electrospray ionization and ion mobility mass spectrometry (IM-MS) were unsuccessfully used in order to resolve the isomers according to their collisional cross section (CCS) difference. The isomer ratio determination of 2,3-dihydroxypropionylselenocystathionine was performed after multidimensional liquid chromatography preconcentration from a water extract of Se-rich yeast using preparative size exclusion, anion exchange, and capillary reverse phase columns coupled to IM-MS. 4'-nitrobenzo-15-crown-5 ether, a selective shift reagent (SSR), was added after the last chromatographic dimension in order to specifically increase the CCS of one of the isomers by the formation of a stable host-guest system with the crown ether. Both isomers were consequently fully resolved by IM-MS, and the relative ratio of the isomers was determined to be 11-13% and 87-89%. The present data compared favorably with the literature to support the analytical strategy despite the lack of an authentic standard for method validation. In addition, computational chemistry methods were successfully applied to design the SSR and to support the experimental data. PMID- 25295846 TI - Influence of copolymer composition on the phase behavior of solid dispersions. AB - The incorporation of poorly soluble active pharmaceutical ingredients (APIs) into excipients (e.g., polymers) to formulate an amorphous solid dispersion is a promising strategy to improve the oral bioavailability of the API. The application of copolymer excipients allows access to combinations of different monomers and thus to the design of excipients to improve solid-dispersion properties. In this work, the thermodynamic phase behavior of solid dispersions was investigated as a function of the API, type of monomer, and copolymer composition. The glass-transition temperatures and API solubilities in the solid dispersions of naproxen and indomethacin in polyvinylpyrrolidone, polyvinyl acetate, and copolymers with different weight fractions of vinylpyrrolidone and vinyl actetate were investigated. It is shown that the thermodynamic phase behavior of API/copolymer solid dispersions is a function of monomer type and copolymer composition. This effect was also predicted by using the perturbed chain statistical associating fluid theory (PC-SAFT). The glass-transition temperature of the solid dispersions was calculated with the Gordon-Taylor equation. PMID- 25295848 TI - Metal cation cross-linked nanocellulose hydrogels as tissue engineering substrates. AB - The use of cellulose materials for biomedical applications is attractive due to their low cost, biocompatibility, and biodegradability. Specific processing of cellulose to yield nanofibrils further improves mechanical properties and suitability as a tissue engineering substrate due to the similarity to the fibrous structure, porosity, and size-scale of the native extracellular matrix. In order to generate the substrate, nanocellulose hydrogels were fabricated from carboxylated cellulose nanofibrils via hydrogelation using metal salts. Hydrogels cross-linked with Ca(2+) and Fe(3+) were investigated as tissue culture substrates for C3H10T1/2 fibroblast cells. Control substrates as well as those with physically adsorbed and covalently attached fibronectin protein were evaluated with X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR), and enzyme linked immunosorbent assay (ELISA). Significantly more cells were attached to surfaces modified with protein, with the highest number of cells adhered to the calcium cross-linked hydrogels with covalently attached protein. PMID- 25295847 TI - Anti-heparanase aptamers as potential diagnostic and therapeutic agents for oral cancer. AB - Heparanase is an endoglycosidase enzyme present in activated leucocytes, mast cells, placental tissue, neutrophils and macrophages, and is involved in tumour metastasis and tissue invasion. It presents a potential target for cancer therapies and various molecules have been developed in an attempt to inhibit the enzymatic action of heparanase. In an attempt to develop a novel therapeutic with an associated diagnostic assay, we have previously described high affinity aptamers selected against heparanase. In this work, we demonstrated that these anti-heparanase aptamers are capable of inhibiting tissue invasion of tumour cells associated with oral cancer and verified that such inhibition is due to inhibition of the enzyme and not due to other potentially cytotoxic effects of the aptamers. Furthermore, we have identified a short 30 bases aptamer as a potential candidate for further studies, as this showed a higher ability to inhibit tissue invasion than its longer counterpart, as well as a reduced potential for complex formation with other non-specific serum proteins. Finally, the aptamer was found to be stable and therefore suitable for use in human models, as it showed no degradation in the presence of human serum, making it a potential candidate for both diagnostic and therapeutic use. PMID- 25295849 TI - Palladium(II)-catalyzed desulfitative synthesis of aryl ketones from sodium arylsulfinates and nitriles: scope, limitations, and mechanistic studies. AB - A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle. PMID- 25295850 TI - Interstrand cross-link and bioconjugate formation in RNA from a modified nucleotide. AB - RNA oligonucleotides containing a phenyl selenide derivative of 5-methyluridine were chemically synthesized by solid-phase synthesis. The phenyl selenide is rapidly converted to an electrophilic, allylic phenyl seleneate under mild oxidative conditions. The phenyl seleneate yields interstrand cross-links when part of a duplex and is useful for synthesizing oligonucleotide conjugates. Formation of the latter is illustrated by reaction of an oligonucleotide containing the phenyl selenide with amino acids in the presence of mild oxidant. The products formed are analogous to those observed in tRNA that are believed to be formed posttranslationally via a biosynthetic intermediate that is chemically homologous to the phenyl seleneate. PMID- 25295851 TI - Growth and Raman spectra of single-crystal trilayer graphene with different stacking orientations. AB - Understanding the growth mechanism of graphene layers in chemical vapor deposition (CVD) and their corresponding Raman properties is technologically relevant and of importance for the application of graphene in electronic and optoelectronic devices. Here, we report CVD growth of single-crystal trilayer graphene (TLG) grains on Cu and show that lattice defects at the center of each grain persist throughout the growth, indicating that the adlayers share the same nucleation site with the upper layers and these central defects could also act as a carbon pathway for the growth of a new layer. Statistics shows that ABA, 30-30, 30-AB, and AB-30 make up the major stacking orientations in the CVD-grown TLG, with distinctive Raman 2D characteristics. Surprisingly, a high level of lattice defects results whenever a layer with a twist angle of theta = 30 degrees is found in the multiple stacks of graphene layers. PMID- 25295852 TI - Importance of purity evaluation and the potential of quantitative 1H NMR as a purity assay. AB - In any biomedical and chemical context, a truthful description of chemical constitution requires coverage of both structure and purity. This qualification affects all drug molecules, regardless of development stage (early discovery to approved drug) and source (natural product or synthetic). Purity assessment is particularly critical in discovery programs and whenever chemistry is linked with biological and/or therapeutic outcome. Compared with chromatography and elemental analysis, quantitative NMR (qNMR) uses nearly universal detection and provides a versatile and orthogonal means of purity evaluation. Absolute qNMR with flexible calibration captures analytes that frequently escape detection (water, sorbents). Widely accepted structural NMR workflows require minimal or no adjustments to become practical 1H qNMR (qHNMR) procedures with simultaneous qualitative and (absolute) quantitative capability. This study reviews underlying concepts, provides a framework for standard qHNMR purity assays, and shows how adequate accuracy and precision are achieved for the intended use of the material. PMID- 25295853 TI - A conserved acidic residue in phenylalanine hydroxylase contributes to cofactor affinity and catalysis. AB - The catalytic domains of aromatic amino acid hydroxylases (AAAHs) contain a non heme iron coordinated to a 2-His-1-carboxylate facial triad and two water molecules. Asp139 from Chromobacterium violaceum PAH (cPAH) resides within the second coordination sphere and contributes key hydrogen bonds with three active site waters that mediate its interaction with an oxidized form of the cofactor, 7,8-dihydro-l-biopterin, in crystal structures. To determine the catalytic role of this residue, various point mutants were prepared and characterized. Our isothermal titration calorimetry (ITC) analysis of iron binding implies that polarity at position 139 is not the sole criterion for metal affinity, as binding studies with D139E suggest that the size of the amino acid side chain also appears to be important. High-resolution crystal structures of the mutants reveal that Asp139 may not be essential for holding the bridging water molecules together, because many of these waters are retained even in the Ala mutant. However, interactions via the bridging waters contribute to cofactor binding at the active site, interactions for which charge of the residue is important, as the D139N mutant shows a 5-fold decrease in its affinity for pterin as revealed by ITC (compared to a 16-fold loss of affinity in the case of the Ala mutant). The Asn and Ala mutants show a much more pronounced defect in their kcat values, with nearly 16- and 100-fold changes relative to that of the wild type, respectively, indicating a substantial role of this residue in stabilization of the transition state by aligning the cofactor in a productive orientation, most likely through direct binding with the cofactor, supported by data from molecular dynamics simulations of the complexes. Our results indicate that the intervening water structure between the cofactor and the acidic residue masks direct interaction between the two, possibly to prevent uncoupled hydroxylation of the cofactor before the arrival of phenylalanine. It thus appears that the second coordination sphere Asp residue in cPAH, and, by extrapolation, the equivalent residue in other AAAHs, plays a role in fine-tuning pterin affinity in the ground state via deformable interactions with bridging waters and assumes a more significant role in the transition state by aligning the cofactor through direct hydrogen bonding. PMID- 25295854 TI - Obstructive sleep apnea during REM sleep and hypertension. results of the Wisconsin Sleep Cohort. AB - RATIONALE: Obstructive sleep apnea (OSA) is associated with hypertension. OBJECTIVES: We aimed to quantify the independent association of OSA during REM sleep with prevalent and incident hypertension. METHODS: We included adults enrolled in the longitudinal community-based Wisconsin Sleep Cohort Study with at least 30 minutes of REM sleep obtained from overnight in-laboratory polysomnography. Studies were repeated at 4-year intervals to quantify OSA. Repeated measures logistic regression models were fitted to explore the association between REM sleep OSA and prevalent hypertension in the entire cohort (n = 4,385 sleep studies on 1,451 individuals) and additionally in a subset with ambulatory blood pressure data (n = 1,085 sleep studies on 742 individuals). Conditional logistic regression models were fitted to longitudinally explore the association between REM OSA and development of hypertension. All models controlled for OSA events during non-REM sleep, either by statistical adjustment or by stratification. MEASUREMENTS AND MAIN RESULTS: Fully adjusted models demonstrated significant dose-relationships between REM apnea-hypopnea index (AHI) and prevalent hypertension. The higher relative odds of prevalent hypertension were most evident with REM AHI greater than or equal to 15. In individuals with non-REM AHI less than or equal to 5, a twofold increase in REM AHI was associated with 24% higher odds of hypertension (odds ratio, 1.24; 95% confidence interval, 1.08-1.41). Longitudinal analysis revealed a significant association between REM AHI categories and the development of hypertension (P trend = 0.017). Non-REM AHI was not a significant predictor of hypertension in any of the models. CONCLUSIONS: Our findings indicate that REM OSA is cross sectionally and longitudinally associated with hypertension. This is clinically relevant because treatment of OSA is often limited to the first half of the sleep period leaving most of REM sleep untreated. PMID- 25295855 TI - Intraocular pressure and associations in children. The Gobi Desert Children Eye Study. AB - PURPOSE: To assess the intraocular pressure (IOP) and its association in children in a population living in an oasis in the Gobi Desert. METHODS: The cross sectional school-based study included all schools in the Ejina region. The children underwent an ophthalmic examination, non-contact tonometry and measurement of blood pressure and body height and weight. RESULTS: Out of eligible 1911 children, 1565 (81.9%) children with a mean age of 11.9+/-3.5 years (range: 6-21 years) participated. Mean spherical refractive error was -1.58+/ 2.00 diopters. In multivariate analysis, higher IOP (right eye) was associated with younger age (P<0.001; standardized coefficient beta: -0.13; regression coefficient B: -0.13; 95% Confidence interval (CI):-0.18, -0.07), higher diastolic blood pressure (P<0.001;beta:0.13;B:0.05;95%CI:0.03,0.07), higher corneal refractive power (P<0.001;beta:0.11;B:0.23;95%CI:0.12,0.34), more myopic refractive error (P = 0.035;beta: -0.06;B: -0.10;95%CI: -0.19, -0.001), and Han Chinese ethnicity of the father (P = 0.03;beta:0.06;B:0.42;95%CI:0.04,0.89). If age and diastolic blood pressure were dropped, higher IOP was associated with higher estimated cerebrospinal fluid pressure (CSFP) (P<0.001;beta:0.09; B:0.13;95%CI:0.06,0.21) after adjusting for higher corneal refractive power (P<0.001) and Han Chinese ethnicity of the father (P = 0.04). Correspondingly, higher IOP of the left eye was associated with younger age (P<0.001;beta: 0.15;B: -0.16;95%CI: -0.21, -0.10), female gender (P<0.001;beta:0.09;B:0.65;95%CI:0.30,1.01), higher corneal refractive power (P<0.001;beta:0.08;B:0.19;95%CI:0.06,0.32), more myopic refractive error (P = 0.03;beta: -0.06;B: -0.12;95%CI: -0.22, -0.01), and higher estimated CSFP (P<0.001;beta:0.11;B:0.17;95%CI:0.09,0.24). CONCLUSIONS: In school children, higher IOP was associated with steeper corneal curvature and with younger age and higher blood pressure, or alternatively, with higher estimated CSFP. Corneal curvature radius should be included in the correction of IOP measurements. The potential association between IOP and CSFP as also assumed in adults may warrant further research. PMID- 25295856 TI - Antioxidant activity, delayed aging, and reduced amyloid-beta toxicity of methanol extracts of tea seed pomace from Camellia tenuifolia. AB - There is a growing interest in the exploitation of the residues generated by plants. This study explored the potential beneficial health effects from the main biowaste, tea seed pomace, produced when tea seed is processed. DPPH radical scavenging and total phenolic content assays were performed to evaluate the in vitro activities of the extracts. Caenorhabditis elegans was used as in vivo model to evaluate the beneficial health effects, including antioxidant activity, delayed aging, and reduced amyloid-beta toxicity. Among all soluble fractions obtained from the extracts of tea seed pomace from Camellia tenuifolia, the methanol (MeOH)-soluble fraction has the best in vivo antioxidant activities. The MeOH-soluble extraction was further divided into six fractions by chromatography with a Diaion HP-20 column eluted with water/MeOH, and fraction 3 showed the best in vitro and in vivo antioxidant activities. Further analysis in C. elegans showed that the MeOH extract (fraction 3) of tea seed pomace significantly decreased intracellular reactive oxygen species, prolonged C. elegans lifespan, and reduced amyloid-beta (Abeta) toxicity in transgenic C. elegans expressing human Abeta. Moreover, bioactivity-guided fractionation yielded two potent constituents from fraction 3 of the MeOH extract, namely, kaempferol 3-O-(2" glucopyranosyl)-rutinoside and kaempferol 3-O-(2"-xylopyranosyl)-rutinoside, and both compounds exhibited excellent in vivo antioxidant activity. Taken together, MeOH extracts of tea seed pomace from C. tenuifolia have multiple beneficial health effects, suggesting that biowaste might be valuable to be explored for further development as nutraceutical products. Furthermore, the reuse of agricultural byproduct tea seed pomace also fulfills the environmental perspective. PMID- 25295857 TI - Pilocytic astrocytoma with IDH1 mutation in the cerebellum of an elderly patient. PMID- 25295858 TI - Chemoproteomics demonstrates target engagement and exquisite selectivity of the clinical phosphodiesterase 10A inhibitor MP-10 in its native environment. AB - Phosphodiesterases (PDEs) regulate the levels of the second messengers cAMP and cGMP and are important drug targets. PDE10A is highly enriched in medium spiny neurons of the striatum and is an attractive drug target for the treatment of basal ganglia diseases like schizophrenia, Parkinson's disease, or Huntington's disease. Here we describe the design, synthesis, and application of a variety of chemical biology probes, based on the first clinically tested PDE10A inhibitor MP 10, which were used to characterize the chemoproteomic profile of the clinical candidate in its native environment. A clickable photoaffinity probe was used to measure target engagement of MP-10 and revealed differences between whole cell and membrane preparations. Moreover, our results illustrate the importance of the linker design in the creation of functional probes. Biotinylated affinity probes allowed identification of drug-interaction partners in rodent and human tissue and quantitative mass spectrometry analysis revealed highly specific binding of MP-10 to PDE10A with virtually no off-target binding. The profiling of PDE10A chemical biology probes described herein illustrates a strategy by which high affinity inhibitors can be converted into probes for determining selectivity and target engagement of drug candidates in complex biological matrices from native sources. PMID- 25295859 TI - Fitness of crop-wild hybrid sunflower under competitive conditions: implications for crop-to-wild introgression. AB - Understanding the likelihood and extent of introgression of novel alleles in hybrid zones requires comparison of lifetime fitness of parents and hybrid progeny. However, fitness differences among cross types can vary depending on biotic conditions, thereby influencing introgression patterns. Based on past work, we predicted that increased competition would enhance introgression between cultivated and wild sunflower (Helianthus annuus) by reducing fitness advantages of wild plants. To test this prediction, we established a factorial field experiment in Kansas, USA where we monitored the fitness of four cross types (Wild, F1, F2, and BCw hybrids) under different levels of interspecific and intraspecific competition. Intraspecific manipulations consisted both of density of competitors and of frequency of crop-wild hybrids. We recorded emergence of overwintered seeds, survival to reproduction, and numbers of seeds produced per reproductive plant. We also calculated two compound fitness measures: seeds produced per emerged seedling and seeds produced per planted seed. Cross type and intraspecific competition affected emergence and survival to reproduction, respectively. Further, cross type interacted with competitive treatments to influence all other fitness traits. More intense competition treatments, especially related to density of intraspecific competitors, repeatedly reduced the fitness advantage of wild plants when considering seeds produced per reproductive plant and per emerged seedling, and F2 plants often became indistinguishable from the wilds. Wild fitness remained superior when seedling emergence was also considered as part of fitness, but the fitness of F2 hybrids relative to wild plants more than quadrupled with the addition of interspecific competitors and high densities of intraspecific competitors. Meanwhile, contrary to prediction, lower hybrid frequency reduced wild fitness advantage. These results emphasize the importance of taking a full life cycle perspective. Additionally, due to effects of exogenous selection, a given hybrid generation may be especially well-suited to hastening introgression under particular environmental conditions. PMID- 25295861 TI - Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene. AB - Congenital hepatic fibrosis has been described as a lethal disease with monogenic autosomal recessive inheritance in the Swiss Franches-Montagnes horse breed. We performed a genome-wide association study with 5 cases and 12 controls and detected an association on chromosome 20. Subsequent homozygosity mapping defined a critical interval of 952 kb harboring 10 annotated genes and loci including the polycystic kidney and hepatic disease 1 (autosomal recessive) gene (PKHD1). PKHD1 represents an excellent functional candidate as variants in this gene were identified in human patients with autosomal recessive polycystic kidney and hepatic disease (ARPKD) as well as several mouse and rat mutants. Whereas most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, a small subset of the human ARPKD patients have only liver symptoms, similar to our horses with congenital hepatic fibrosis. The PKHD1 gene is one of the largest genes in the genome with multiple alternative transcripts that have not yet been fully characterized. We sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants in the critical interval. We identified two missense variants in the PKHD1 gene which were strongly, but not perfectly associated with congenital hepatic fibrosis. We speculate that reduced penetrance and/or potential epistatic interactions with hypothetical modifier genes may explain the imperfect association of the detected PKHD1 variants. Our data thus indicate that horses with congenital hepatic fibrosis represent an interesting large animal model for the liver-restricted subtype of human ARPKD. PMID- 25295862 TI - Enhancement of synthetic Trichoderma-based enzyme mixtures for biomass conversion with an alternative family 5 glycosyl hydrolase from Sporotrichum thermophile. AB - Enzymatic conversion of lignocellulosic materials to fermentable sugars is a limiting step in the production of biofuels from biomass. We show here that combining enzymes from different microbial sources is one way to identify superior enzymes. Extracts of the thermophilic fungus Sporotrichum thermophile (synonym Myceliophthora thermophila) gave synergistic release of glucose (Glc) and xylose (Xyl) from pretreated corn stover when combined with an 8-component synthetic cocktail of enzymes from Trichoderma reesei. The S. thermophile extracts were fractionated and an enhancing factor identified as endo-beta1,4 glucanase (StCel5A or EG2) of subfamily 5 of Glycosyl Hydrolase family 5 (GH5_5). In multi-component optimization experiments using a standard set of enzymes and either StCel5A or the ortholog from T. reesei (TrCel5A), reactions containing StCel5A yielded more Glc and Xyl. In a five-component optimization experiment (i.e., varying four core enzymes and the source of Cel5A), the optimal proportions for TrCel5A vs. StCel5A were similar for Glc yields, but markedly different for Xyl yields. Both enzymes were active on lichenan, glucomannan, and oat beta-glucan; however, StCel5A but not TrCel5A was also active on beta1,4 mannan, two types of galactomannan, and beta1,4-xylan. Phylogenetically, fungal enzymes in GH5_5 sorted into two clades, with StCel5A and TrCel5A belonging to different clades. Structural differences with the potential to account for the differences in performance were deduced based on the known structure of TrCel5A and a homology-based model of StCel5A, including a loop near the active site of TrCel5A and the presence of four additional Trp residues in the active cleft of StCel5A. The results indicate that superior biomass-degrading enzymes can be identified by exploring taxonomic diversity combined with assays in the context of realistic enzyme combinations and realistic substrates. Substrate range may be a key factor contributing to superior performance within GH5_5. PMID- 25295863 TI - Loss of infectivity of HIV-1 particles produced by mobile lymphocytes. AB - HIV-1 spreads by cell-free particles and through direct cell contacts. To discriminate between these two modes of dissemination, an assay in which the cells are cultured under shaking conditions impairing cell-to-cell transmission has been described. We addressed the impact of shaking on HIV-1 particle infectivity. Kinetics of HIV-1 infection in static or shaking conditions confirmed that HIV-1 replication is reduced in mobile lymphocyte T cells. Strikingly, the infectivity of viruses produced by mobile lymphocytes was dramatically reduced. In parallel, the amount of envelope protein present on these particles showed a continuous decrease over time. We conclude that inefficient HIV-1 replication in mobile lymphocytes in this experimental system is not only due to avoidance of viral cell-to-cell transfer but also to the loss of infectivity of the viral particles due to the alteration of the composition and functionality of the particles produced by these lymphocytes. It is important to take these observations into account when studying viral transmission under shaking conditions. PMID- 25295864 TI - Coral reefs on the edge? Carbon chemistry on inshore reefs of the great barrier reef. AB - While increasing atmospheric carbon dioxide (CO2) concentration alters global water chemistry (Ocean Acidification; OA), the degree of changes vary on local and regional spatial scales. Inshore fringing coral reefs of the Great Barrier Reef (GBR) are subjected to a variety of local pressures, and some sites may already be marginal habitats for corals. The spatial and temporal variation in directly measured parameters: Total Alkalinity (TA) and dissolved inorganic carbon (DIC) concentration, and derived parameters: partial pressure of CO2 (pCO2); pH and aragonite saturation state (Omegaar) were measured at 14 inshore reefs over a two year period in the GBR region. Total Alkalinity varied between 2069 and 2364 umol kg-1 and DIC concentrations ranged from 1846 to 2099 umol kg 1. This resulted in pCO2 concentrations from 340 to 554 uatm, with higher values during the wet seasons and pCO2 on inshore reefs distinctly above atmospheric values. However, due to temperature effects, Omegaar was not further reduced in the wet season. Aragonite saturation on inshore reefs was consistently lower and pCO2 higher than on GBR reefs further offshore. Thermodynamic effects contribute to this, and anthropogenic runoff may also contribute by altering productivity (P), respiration (R) and P/R ratios. Compared to surveys 18 and 30 years ago, pCO2 on GBR mid- and outer-shelf reefs has risen at the same rate as atmospheric values (~1.7 uatm yr-1) over 30 years. By contrast, values on inshore reefs have increased at 2.5 to 3 times higher rates. Thus, pCO2 levels on inshore reefs have disproportionately increased compared to atmospheric levels. Our study suggests that inshore GBR reefs are more vulnerable to OA and have less buffering capacity compared to offshore reefs. This may be caused by anthropogenically induced trophic changes in the water column and benthos of inshore reefs subjected to land runoff. PMID- 25295866 TI - Lake level fluctuations boost toxic cyanobacterial "oligotrophic blooms". AB - Global warming has been shown to strongly influence inland water systems, producing noticeable increases in water temperatures. Rising temperatures, especially when combined with widespread nutrient pollution, directly favour the growth of toxic cyanobacteria. Climate changes have also altered natural water level fluctuations increasing the probability of extreme events as dry periods followed by heavy rains. The massive appearance of Dolichospermum lemmermannii ( = planktonic Anabaena), a toxic species absent from the pelagic zone of the subalpine oligotrophic Lake Maggiore before 2005, could be a consequence of the unusual fluctuations of lake level in recent years. We hypothesized that these fluctuations may favour the cyanobacterium as result of nutrient pulses from the biofilms formed in the littoral zone when the lake level is high. To help verify this, we exposed artificial substrates in the lake, and evaluated their nutrient enrichment and release after desiccation, together with measurements of fluctuations in lake level, precipitation and D. lemmermannii population. The highest percentage of P release and the lowest C:P molar ratio of released nutrients coincided with the summer appearance of the D. lemmermannii bloom. The P pulse indicates that fluctuations in level counteract nutrient limitation in this lake and it is suggested that this may apply more widely to other oligotrophic lakes. In view of the predicted increase in water level fluctuations due to climate change, it is important to try to minimize such fluctuations in order to mitigate the occurrence of cyanobacterial blooms. PMID- 25295867 TI - Computational and experimental studies on the mechanism of formation of poly(hexahydrotriazine)s and poly(hemiaminal)s from the reactions of amines with formaldehyde. AB - Combined experimental and computational studies have been performed on the mechanism of formation of poly(hexahydrotriazine) and hemiaminal dynamic covalent network (PHT and HDCN) thermosetting polymers from the reactions of diamines with formaldehyde (Science 2014, 344, 732-735). Results suggest that these polymers are formed by a mechanism involving the water promoted stepwise addition of amines with formaldehyde in preference to dimerization or cyclotrimerization of imine intermediates or self-catalysis by the amine reagents. The predicted mechanism also explains experimentally observed electronic effects for hexahydrotriazine formation. PMID- 25295865 TI - A rare HBV subgenotype D4 with unique genomic signatures identified in north eastern India--an emerging clinical challenge? AB - BACKGROUND/AIMS: HBV has been classified into ten genotypes (A-J) and multiple subgenotypes, some of which strongly influence disease outcome and their distribution also correlate with human migration. HBV infection is highly prevalent in India and its diverse population provides an excellent opportunity to study the distinctiveness of HBV, its evolution and disease biology in variegated ethnic groups. The North-East India, having international frontiers on three sides, is one of the most ethnically and linguistically diverse region of the country. Given the paucity of information on molecular epidemiology of HBV in this region, the study aimed to carry out an in-depth genetic characterization of HBV prevailing in North-East state of Tripura. METHODS: From sera of chronically HBV infected patients biochemical/serological tests, HBV DNA quantification, PCR amplification, sequencing of PreS/S or full-length HBV genomes were done. HBV genotype/subgenotype determination and sequence variability were assessed by MEGA5-software. The evolutionary divergence times of different HBV subgenotypes were estimated by DNAMLK/PHYLIP program while jpHMM method was used to detect any recombination event in HBV genomes. RESULTS: HBV genotypes D (89.5%), C (6.6%) and A (3.9%) were detected among chronic carriers. While all HBV/A and HBV/C isolates belonged to subgenotype-A1 and C1 respectively, five subgenotypes of HBV/D (D1-D5) were identified including the first detection of rare D4. These non recombinant Indian D4 (IndD4) formed a distinct phylogenetic clade, had 2.7% nucleotide divergence and recent evolutionary radiation than other global D4. Ten unique amino acids and 9 novel nucleotide substitutions were identified as IndD4 signatures. All IndD4 carried T120 and R129 in ORF-S that may cause immune/vaccine/diagnostic escape and N128 in ORF-P, implicated as compensatory Lamivudine resistance mutation. CONCLUSIONS: IndD4 has potential to undermine vaccination programs or anti-viral therapy and its introduction to North-East India is believed to be linked with the settlement of ancient Tibeto-Burman migrants from East-Asia. PMID- 25295868 TI - Injection of crushed tablets--a prospective observational study. PMID- 25295869 TI - Profibrinolytic effect of the epigenetic modifier valproic acid in man. AB - AIMS: The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro. METHODS AND RESULTS: The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns). CONCLUSION: Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies. TRIAL REGISTRATION: The EU Clinical Trials Register 2009-011723-31. PMID- 25295871 TI - Waist circumference and risk of lower urinary tract symptoms: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: Epidemiological studies have reported conflicting results concerning the role of central obesity in lower urinary tract symptoms. We performed a meta-analysis to determine whether larger waist circumference (WC) is a predicted signal for Lower Urinary Tract Symptoms (LUT). Data resource: Eligible studies were retrieved by searching PubMed, Web of science, and the Cochrane Library database up to January 2014. STUDY ELIGIBILITY CRITERIA: Prospective and retrospective cohort, case-controlled trials and observational studies. DATA EXTRACTION: Data were extracted and analyzed using random effect models to reveal an array of risk factors. Dose-response meta-analysis was performed for studies reporting categorical risk estimates at multiple exposure levels. Study heterogeneity and publication biases were assessed. DATA SYNTHESIS: A total of 12 studies met the inclusion criteria of the meta-analysis. A positive association with waist circumference (WC) was observed between WC and LUTS at an odds ratio of 1.49, (95% confidence intervals 1.34-1.64). In subgroup analysis, WC exhibited a positive dose-dependent relationship with LUTS in mostly study design, region and primary outcomes. LIMITATION: Potential biases from preferential publication and selective reporting. CONCLUSION: Large WC is associated with increased risk of LUTS. Further studies are needed to confirm this finding and to define related biological mechanisms. PMID- 25295870 TI - Importance of reciprocal balance of T cell immunity in Mycobacterium abscessus complex lung disease. AB - BACKGROUND: Little is known about the nature of the host immune response to Mycobacterium abscessus complex (MABC) infection. The aim of the present study was to investigate whether alterations in serum immunomolecule levels after treating MABC lung disease patients with antibiotics can reflect the disease associated characteristics. METHODS: A total of 22 immunomolecules in 24 MABC lung disease patients before and after antibiotic therapy were quantitatively analyzed using a multiplex bead-based system. RESULTS: In general, the pre treatment levels of T helper type 1 (Th1)-related cytokines, i.e., interferon (IFN)-gamma and interleukin (IL)-12, and Th2-related cytokines, i.e., IL-4 and IL 13, were significantly decreased in patients compared with control subjects. In contrast, the pre-treatment levels of Th17-related cytokines, i.e., IL-17 and IL 23, were significantly increased in MABC patients. Interestingly, significantly higher levels of IFN-gamma-induced protein (IP)-10 and monokine induced by IFN gamma protein (MIG) were detected in patients with failure of sputum conversion at post-treatment compared to patients with successful sputum conversion. CONCLUSION: Reduced Th1 and Th2 responses and enhanced Th17 responses in patients may perpetuate MABC lung disease, and the immunomolecules IP-10 and MIG, induced through IFN-gamma, may serve as key markers for indicating the treatment outcome. PMID- 25295872 TI - The impact of the bladder wall thickness on the outcome of the medical treatment using alpha-blocker of BPH patients with LUTS. AB - OBJECTIVES: To evaluate whether the outcome of medical treatment with alpha 1 receptor blocker in Benign prostatic hyperplasia (BPH) patients with lower urinary tract symptoms (LUTS) is affected by the bladder wall thickness (BWT) Methods: A total of 125 male BPH patients with LUTS were enrolled. All patients were assessed using The International Prostatic Symptom Score (IPSS), prostate specific antigen (PSA), prostate volume, uroflowmetry, post voiding residual (PVR). BWT was measured by Trans-abdominal ultrasound, and patients were divided into two groups group 1 (patients with BWT <5 mm) and group 2 (patients with BWT >=5 mm). The patients were reassessed after 2 months of treatment with alpha 1 receptor blocker (alfuzosin 10 mg). Clinical parameters were analyzed and compared between groups. RESULTS: There were significant difference between both groups as regard IPSS, voiding symptoms, and storage symptoms (p = 0.005), (p = 0.010) and (p = 0.041) respectively. After medication, there were improvements in the total IPSS, voiding symptoms, storage symptoms, Qmax, PVR and Qol in both groups and these improvements were more effectively in (group 1) than (group 2) with statistically significant differences (p < 0.05). CONCLUSION: BWT has positive correlation with the total IPSS, voiding symptoms subscores and storage symptoms subscores. The response to medical treatment is found statistically less in patients with BWT greater than 5 mm. PMID- 25295874 TI - Sensitivity and tolerance of Riparian arthropod communities to altered water resources along a drying river. AB - BACKGROUND: Rivers around the world are drying with increasing frequency, but little is known about effects on terrestrial animal communities. Previous research along the San Pedro River in southeastern AZ, USA, suggests that changes in the availability of water resources associated with river drying lead to changes in predator abundance, community composition, diversity, and abundance of particular taxa of arthropods, but these observations have not yet been tested manipulatively. METHODS AND RESULTS: In this study, we constructed artificial pools in the stream bed adjacent to a drying section of the San Pedro River and maintained them as the river dried. We compared pitfall trapped arthropods near artificial pools to adjacent control sites where surface waters temporarily dried. Assemblage composition changed differentially at multiple taxonomic levels, resulting in different assemblages at pools than at control sites, with multiple taxa and richness of carabid beetle genera increasing at pools but not at controls that dried. On the other hand, predator biomass, particularly wolf spiders, and diversity of orders and families were consistently higher at control sites that dried. These results suggest an important role for colonization dynamics of pools, as well as the ability of certain taxa, particularly burrowing wolf spiders, to withstand periods of temporary drying. CONCLUSIONS: Overall, we found some agreement between this manipulative study of water resources and a previous analysis of river drying that showed shifts in composition, changes in diversity, and declines in abundance of certain taxa (e.g. carabid beetles). However, colonization dynamics of pools, as well as compensatory strategies of predatory wolf spiders seem to have led to patterns that do not match previous research, with control sites maintaining high diversity, despite drying. Tolerance of river drying by some species may allow persistence of substantial diversity in the face of short-term drying. The long-term effects of drying remain to be investigated. PMID- 25295873 TI - The peptide microarray "ChloroPhos1.0" identifies new phosphorylation targets of plastid casein kinase II (pCKII) in Arabidopsis thaliana. AB - We report the development of a peptide microarray based on previously determined phosphorylation sites in chloroplast proteins. Altogether, 905 peptides were spotted as 15mers in nine replicates onto glass slides. We used the microarray for in vitro phosphorylation experiments and specifically assessed the peptide substrate spectrum of chloroplast casein kinase II (pCKII). To this end, native pCKII from Arabidopsis thaliana and Sinapis alba chloroplasts was enriched by Heparin-Sepharose chromatography and its activity on the microarray was compared to the activity of a recombinant Arabidopsis pCKII. All three kinase preparations phosphorylated a similar set of peptides that were clearly distinct from those phosphorylated by bovine heart protein kinase A (PKA) in control experiments. The majority of the pCKII phosphorylation targets are involved in plastid gene expression, supporting the earlier denomination of pCKII as plastid transcription kinase (PTK). In addition we identified Alb3 as pCKII substrate that is essential for the integration of light-harvesting complex subunits (LHC) into the thylakoid membrane. Plastid CKII phosphorylation activity was characterized in greater detail in vitro with recombinant wildtype Alb3 and phosphorylation site mutants as substrates, establishing S424 as the pCKII phosphorylation site. Our data show that the peptide microarray ChloroPhos1.0 is a suitable tool for the identification of new kinase downstream targets in vitro that can be validated subsequently by in vivo experiments. PMID- 25295875 TI - Anthracobunids from the middle eocene of India and pakistan are stem perissodactyls. AB - Anthracobunidae is an Eocene family of large mammals from south Asia that is commonly considered to be part of the radiation that gave rise to elephants (proboscideans) and sea cows (sirenians). We describe a new collection of anthracobunid fossils from Middle Eocene rocks of Indo-Pakistan that more than doubles the number of known anthracobunid fossils and challenges their putative relationships, instead implying that they are stem perissodactyls. Cranial, dental, and postcranial elements allow a revision of species and the recognition of a new anthracobunid genus. Analyses of stable isotopes and long bone geometry together suggest that most anthracobunids fed on land, but spent a considerable amount of time near water. This new evidence expands our understanding of stem perissodactyl diversity and sheds new light on perissodactyl origins. PMID- 25295877 TI - Measuring long-term impact based on network centrality: unraveling cinematic citations. AB - Traditional measures of success for film, such as box-office revenue and critical acclaim, lack the ability to quantify long-lasting impact and depend on factors that are largely external to the craft itself. With the growing number of films that are being created and large-scale data becoming available through crowd sourced online platforms, an endogenous measure of success that is not reliant on manual appraisal is of increasing importance. In this article we propose such a ranking method based on a combination of centrality indices. We apply the method to a network that contains several types of citations between more than 40,000 international feature films. From this network we derive a list of milestone films, which can be considered to constitute the foundations of cinema. In a comparison to various existing lists of 'greatest' films, such as personal favourite lists, voting lists, lists of individual experts, and lists deduced from expert polls, the selection of milestone films is more diverse in terms of genres, actors, and main creators. Our results shed light on the potential of a systematic quantitative investigation based on cinematic influences in identifying the most inspiring creations in world cinema. In a broader perspective, we introduce a novel research question to large-scale citation analysis, one of the most intriguing topics that have been at the forefront of scientific enquiries for the past fifty years and have led to the development of various network analytic methods. In doing so, we transfer widely studied approaches from citation analysis to the the newly emerging field of quantification efforts in the arts. The specific contribution of this paper consists in modelling the multidimensional cinematic references as a growing multiplex network and in developing a methodology for the identification of central films in this network. PMID- 25295876 TI - Assessment of choroidal thickness in healthy and glaucomatous eyes using swept source optical coherence tomography. AB - PURPOSE: To evaluate choroidal thickness (CT) in healthy and glaucomatous eyes using Swept Source Optical Coherence Tomography (SS-OCT). METHODS: A cross sectional observational study of 216 eyes of 140 subjects with glaucoma and 106 eyes of 67 healthy subjects enrolled in the Diagnostic Innovations in Glaucoma Study. CT was assessed from wide-field (12*9 mm) SS-OCT scans. The association between CT and potential confounding variables including age, gender, axial length, intraocular pressure, central corneal thickness and ocular perfusion pressure was examined using univariable and multivariable regression analyses. RESULTS: Overall CT was thinner in glaucomatous eyes with a mean (+/- standard deviation) of 157.7+/-48.5 um in glaucoma compared to 179.9+/-36.1 um in healthy eyes (P<0.001). The choroid was thinner in both the peripapillary and macular regions in glaucoma compared to controls. Mean peripapillary CT was 154.1+/-44.1 um and 134.0+/-56.9 um (P<0.001) and macular CT 199.3+/-46.1 um and 176.2+/-57.5 um (P<0.001) for healthy and glaucomatous eyes respectively. However, older age (P<0.001) and longer axial length (P<0.001) were also associated with thinner choroid and when differences in age and axial length between glaucomatous and healthy subjects were accounted for, glaucoma was not significantly associated with CT. There was also no association between glaucoma severity and CT. CONCLUSIONS: Glaucoma was not associated with CT measured using SS-OCT; however, older age and longer axial length were associated with thinner choroid so should be considered when interpreting CT measurements. PMID- 25295878 TI - Effect of elevated pCO2 on metabolic responses of porcelain crab (Petrolisthes cinctipes) Larvae exposed to subsequent salinity stress. AB - Future climate change is predicted to alter the physical characteristics of oceans and estuaries, including pH, temperature, oxygen, and salinity. Investigating how species react to the influence of such multiple stressors is crucial for assessing how future environmental change will alter marine ecosystems. The timing of multiple stressors can also be important, since in some cases stressors arise simultaneously, while in others they occur in rapid succession. In this study, we investigated the effects of elevated pCO2 on oxygen consumption by larvae of the intertidal porcelain crab Petrolisthes cinctipes when exposed to subsequent salinity stress. Such an exposure mimics how larvae under future acidified conditions will likely experience sudden runoff events such as those that occur seasonally along portions of the west coast of the U.S. and in other temperate systems, or how larvae encounter hypersaline waters when crossing density gradients via directed swimming. We raised larvae in the laboratory under ambient and predicted future pCO2 levels (385 and 1000 uatm) for 10 days, and then moved them to seawater at ambient pCO2 but with decreased, ambient, or elevated salinity, to monitor their respiration. While larvae raised under elevated pCO2 or exposed to stressful salinity conditions alone did not exhibit higher respiration rates than larvae held in ambient conditions, larvae exposed to elevated pCO2 followed by stressful salinity conditions consumed more oxygen. These results show that even when multiple stressors act sequentially rather than simultaneously, they can retain their capacity to detrimentally affect organisms. PMID- 25295879 TI - Clinical NECR in 18F-FDG PET scans: optimization of injected activity and variable acquisition time. Relationship with SNR. AB - The injected activity and the acquisition time per bed position for 18F-FDG PET scans are usually optimized by using metrics obtained from phantom experiments. However, optimal activity and time duration can significantly vary from a phantom set-up and from patient to patient. An approach using a patient-specific noise equivalent count rate (NECR) modelling has been previously proposed for optimizing clinical scanning protocols. We propose using the clinical NECR on a large population as a function of the body mass index (BMI) for deriving the optimal injected activity and acquisition duration per bed position. The relationship between the NEC and the signal-to-noise ratio (SNR) was assessed both in a phantom and in a clinical setting. 491 consecutive patients were retrospectively evaluated and divided into 4 BMI subgroups. Two criteria were used to optimize the injected activity and the time per bed position was adjusted using the NECR value while keeping the total acquisition time constant. Finally, the relationship between NEC and SNR was investigated using an anthropomorphic phantom and a population of 507 other patients. While the first dose regimen suggested a unique injected activity (665 MBq) regardless of the BMI, the second dose regimen proposed a variable activity and a total acquisition time according to the BMI. The NEC improvement was around 35% as compared with the local current injection rule. Variable time per bed position was derived according to BMI and anatomical region. NEC and number of true events were found to be highly correlated with SNR for the phantom set-up and partially confirmed in the patient study for the BMI subgroup under 28 kg m(-2) suggesting that for the scanner, the nonlinear reconstruction algorithm used in this study and BMI < 28 kg m(-2), NEC, or the number of true events linearly correlated with SNR(2). PMID- 25295880 TI - A novel oxybis cresol verticilatin with highly varying degrees of biological activities from the insect pathogenic fungus Paecilomyces verticillatus. AB - A novel oxybis cresol compound named verticilatin (1), together with two known compounds, 5-methylresorcinol (2) and 2,4-dihydroxy-3,6-dimethylbenzaldehyde (3), was isolated from cultures of the insect pathogenic fungi Paecilomyces verticillatus. The structures of compounds were determined by extensive spectroscopic analysis of HR-ESI-MS and 1D and 2D NMR including HSQC, HMBC, COSY, and ROESY. Fortunately, compound 1 exhibited significant inhibitory activities against CDC25B, cathepsin B, MEG2, and SHP2 enzyme, with IC50 values of 11.5, 3.5, 7.8, and 15 MUg/ml, respectively. PMID- 25295881 TI - Proton energy optimization and reduction for intensity-modulated proton therapy. AB - Intensity-modulated proton therapy (IMPT) is commonly delivered via the spot scanning technique. To 'scan' the target volume, the proton beam is controlled by varying its energy to penetrate the patient's body at different depths. Although scanning the proton beamlets or spots with the same energy can be as fast as 10 20 m s(-1), changing from one proton energy to another requires approximately two additional seconds. The total IMPT delivery time thus depends mainly on the number of proton energies used in a treatment. Current treatment planning systems typically use all proton energies that are required for the proton beam to penetrate in a range from the distal edge to the proximal edge of the target. The optimal selection of proton energies has not been well studied. In this study, we sought to determine the feasibility of optimizing and reducing the number of proton energies in IMPT planning. We proposed an iterative mixed-integer programming optimization method to select a subset of all available proton energies while satisfying dosimetric criteria. We applied our proposed method to six patient datasets: four cases of prostate cancer, one case of lung cancer, and one case of mesothelioma. The numbers of energies were reduced by 14.3%-18.9% for the prostate cancer cases, 11.0% for the lung cancer cases and 26.5% for the mesothelioma case. The results indicate that the number of proton energies used in conventionally designed IMPT plans can be reduced without degrading dosimetric performance. The IMPT delivery efficiency could be improved by energy layer optimization leading to increased throughput for a busy proton center in which a delivery system with slow energy switch is employed. PMID- 25295882 TI - Exogenous bacterial osteomyelitis in 52 dogs: a retrospective study of etiology and in vitro antimicrobial susceptibility profile (2000-2013). AB - BACKGROUND: Most clinical cases of osteomyelitis in dogs involve infectious agents, especially bacteria and fungi. The characterization of these microorganisms may aid in the prevention and treatment of disease. OBJECTIVE: The aim of this study was to evaluate retrospectively microbiological cultures and in vitro antimicrobial susceptibility profile of isolates from 52 cases of bacterial osteomyelitis in long bones of dogs over 2000-2013. In 78% of the cases injuries were caused by a motor vehicle accident, but there were a few cases of dog bites (17%) and ascending infection due to pododermatitis (5%). ANIMALS AND METHODS: The isolated microorganisms were identified based on conventional phenotypic methods. In vitro disk diffusion test was performed using 30 different antimicrobials. RESULTS: The isolates were obtained from femur (28%), humerus (16%), tibia (31%), and radius/ulna (25%). Among 52 cases, culture was positive in 88% of cases. Thirteen genus of different species of microorganisms were isolated. The most common microorganisms isolated were Staphylococcus spp. and Escherichia coli followed by Streptococcus spp., enteric bacteria, Corynebacterium sp. and anaerobic bacteria. In 42% of cases cultures were mixed. The most effective drugs against isolated bacteria were amoxicillin and clavulanate potassium (79%) followed by ceftriaxone (69%). High-resistance rates were documented against azithromycin (80%), penicillin (59%), and clindamycin (59%). CONCLUSIONS: The present study highlights diverse etiologic agents in cases of infectious bacterial osteomyelitis, with predominance of Staphylococcus genus, and reinforces the importance of obtaining cultures and susceptibility profiles given the high rates of antimicrobial resistance. PMID- 25295884 TI - New AAIP affiliates increase JOI readership. PMID- 25295883 TI - [Management of suspected cases of malaria before admission to a district hospital in Burkina Faso]. AB - After widespread use and misuse of antimalarial drugs led to the emergence of resistance, new guidelines for malaria treatment with artemisinine-based combination therapy (ACT) were introduced in Burkina Faso in 2005. To describe the management (drug therapy and other practices) of patients with suspected malaria before their admission to the district hospital of Do, seven years later. This cross-sectional study was conducted during admission to the district hospital, during the low season for malaria, from December 2010 to May 2011. It included all patients aged 6 months or older diagnosed with suspected malaria according to the criteria of the national malaria control program, excluding those with severe comorbidities. The study included 476 suspected cases, 422 (88.7%) uncomplicated and 54 (11.3%) complicated. They accounted for 7.9% of all admissions. Their mean age was 14.4 years, and 35.3% (n = 168) were younger than 5 years. Only 23 (4.8%) had first consulted in a primary health care facility; 346 (72.7%) had used initial self-medication (or, more precisely in some cases, parental administration of medication without medical consultation). Overall, 435 (91.4%) came directly to the district hospital, 331 (76.1%) of them after self medication; 10 (2.1%) had first consulted a traditional healer. The practice of self-medication did not differ according to age, gender, or complications (p>0.05). The drugs used for self-medication were mainly antipyretics (94.5%) and antimalarials (16.8%); the latter included ACT (39.6%), quinine (19.0%), and non recommended antimalarial agents (41.4%). During the malaria low season, the treatment itinerary of suspected malaria cases is marked by equal use of ACT and non-recommended antimalarials for self-medication and minimal use of the primary level of care. A study underway of this management and these itineraries during the epidemic season may provide more data about use of ACT, the last armament against malaria in drug-resistant areas such as Burkina Faso. PMID- 25295885 TI - Effect of platelet-rich plasma on the healing of mandibular defects treated with fresh frozen bone allograft: a radiographic study in dogs. AB - The purpose of this study was to radiographically analyze the effect of autologous platelet rich plasma (PRP) on the healing of fresh frozen bone allograft (FFBA) placed in surgically created resection defects in mandibles of dogs. Bilateral resection defects measuring 1.5 cm * 1 cm were surgically created on the inferior border of the mandible in 10 adult male dogs. The defects were randomly divided into three groups: C, FFBA, and FFBA/PRP. In Group C, the defect was filled by blood clot only. In Group FFBA, the defect was filled with particulate fresh frozen bone allograft. In Group FFBA/PRP, it was filled with particulate fresh frozen bone allograft combined with PRP. At 90 days postoperative, standardized radiographs of the mandibles were obtained and results were quantitatively evaluated. Analysis of digitized radiographs indicated that non-PRP grafts were significantly less dense than the PRP grafts. Group FFBA/PRP also presented a statistically greater mineralized tissue area than Groups C and FFBA. Within the limits of this study, it can be concluded that PRP enhanced the healing of FFBA in resection defects in mandibles of dogs. PMID- 25295886 TI - Assessment of Candida species colonization and denture-related stomatitis in bar- and locator-retained overdentures. AB - The aim of this study was to assess the prevalence of denture-related stomatitis (DRS) in different attachment-retained overdenture wearers and its association with particular colonizing Candida species. Thirty-seven edentulous patients with implant-supported maxillary or mandibular overdentures were enrolled. A full clinical history was obtained, including details of patients' oral hygiene practices and the levels of erythema based on Newton's classification scale. Swabs were taken from the palate and investigated mycologically to identify the yeast colonies. Quantitative and qualitative microbiological assessments were performed, which included recording the total numbers of colonies (cfu), their color, and their morphological characteristics. Significant differences were found in cfu values between the attachment and inner surfaces of locator- and bar retained overdentures (P < .05). Candida albicans was the most common species in both evaluations, being isolated from 81.3% of bar-retained overdentures and 38.1% of locator-retained overdentures. DRS developed in all patients using bar retained overdentures but in only 71.4% of those using locator-retained overdentures. No statistically significant relationship was found between bar and locator attachments according to smoking habit, overnight removal, or plaque and gingival indices (P > .05). PMID- 25295887 TI - A simple solution for vector control in vertical alveolar distraction osteogenesis. AB - One of the important and frequent complications in alveolar distraction osteogenesis is vectorial change of the transport segment. This report presents a simple solution for vector angulation control by placing intermaxillary fixation screws intraoperatively. Advantages of the technique are also discussed. PMID- 25295888 TI - A retrospective 3- to 5-year study of the reconstruction of oral function using implant-supported prostheses in patients with hypohidrotic ectodermal dysplasia. AB - The aim of this study was to evaluate oral function rehabilitation in patients with hypohidrotic ectodermal dysplasia (HED) using implant-supported prostheses based on bone augmentation. From September 2005 and March 2009, 25 HED patients were chosen for clinical data analysis in this study. The criteria for patient selection included the following: the display of clinical features of HED, the number of congenitally missing teeth (>5), the patient age (>16 years), the patient's willingness, and the patient's tolerance for bone graft surgery and implant placement. Follow-up evaluations were initiated from the time of implant prosthetic placement and scheduled annually for 3-5 years. The effects of oral function reconstruction were assessed based on the cumulative survival and success rates of implants, the health of the peri-implant area, and the degree of patient satisfaction. Twenty-five HED patients received 169 conventional implants and 10 zygomatic implants (179 total implants). During 3-5 years of post-loading evaluations, 5 of the 179 implants failed and 3 implants were removed. The 3-year success and cumulative survival rates were 97.2% and 98.3%, respectively. Furthermore, periodontal probing and radiographic assessments showed that the 3 year incidence of peri-implantitis was 4.5%. Finally, HED patients expressed high degrees of satisfaction with their facial contours, masticatory function, pronunciation ability, and comfort with the implant-supported prostheses. The results of this 3- to 5-year retrospective study indicate that the oral function of HED patients can be effectively reconstructed using bone augmentation and implant-supported prostheses; however, longer term results are warranted in the future. PMID- 25295889 TI - Repair technique for fractured implant-supported metal-ceramic restorations: a clinical report. AB - The fracture of porcelain structures have been related in either natural dentition or implant-supported restorations. Techniques using a composite resin or indirect methods can be used. This article presents a porcelain fracture on implant-supported metal-ceramic restoration. IPS Empress e.max laminate veneer restoration was used to repair the fracture. With this technique, it was possible to restore aesthetics and function, combined with low cost and patient satisfaction. PMID- 25295890 TI - New method to increase inter-alveolar height with preservation of crestal cortical bone for implant treatment. AB - The aim of this technique is to provide adequate interocclusal distance (3 mm) allowing preprosthetic management. A bone block was cut with piezosurgery and extracted, leaving the crestal cortical bone intact. The free crestal alveolar bone was fixed to the maxilla with 2 dental implants. After 3 months of follow up, abutment surgery was performed and osseointegration was evident with adequate interocclusal height (7 mm) allowing prosthetic management. PMID- 25295891 TI - Implant placement with a guided surgery system based on stress analyses utilizing the bone density: a clinical case report. PMID- 25295892 TI - Maxillary sinus augmentation and implant placement using venous blood without graft material: a case letter. PMID- 25295893 TI - Modification of maxillary sinus floor with orthodontic treatment and implant therapy: a case letter. PMID- 25295894 TI - A surgical guide for optimal placement and immediate restoration of implant. PMID- 25295895 TI - Transition metal ion induced hydrogelation by amino-terpyridine ligands. AB - Hydrogelation behavior of two amino-terpyridine ligands in the presence of divalent metal ions in water was studied in detail. The effect of ligand structure and different counter anions on the gel morphologies was also explored. PMID- 25295896 TI - Open-angle glaucoma surgery: the current standing. PMID- 25295897 TI - Fundus autofluorescence in blunt ocular trauma. AB - PURPOSE: To describe the findings of fundus autofluorescence (FAF) imaging in patients with blunt ocular trauma. METHODS: In this non-interventional retrospective study, we reviewed medical records and imaging examination results. The data analyzed included gender, age, laterality, trauma etiology, time between trauma and imaging, visual acuity, changes in the retinal periphery, fundus examination results, and FAF imaging findings. FAF imaging was performed using a Topcon TRC-50DX Retinal Camera (Tokyo, Japan). RESULTS: Eight eyes from 8 patients were studied. The mean age was 27.6 years (range, 19-43 years). Men (n=7) were more frequently affected by blunt ocular trauma than women (n=1). Physical aggression was the most common trauma etiology (n=3), followed by accidents with fireworks (n=2). Other causes were car accidents (n=1), occupational trauma caused by a grinder (n=1), or being hit by a stone (n=1). Visual acuity ranged from 20/80 to light perception. Traumatic pigment epitheliopathy (TPE) was identified in 5 cases, choroidal rupture in 3 cases, subretinal hemorrhage in 3 cases, and Purtscher's retinopathy in 1 case. Hypoautofluorescence was observed in cases of choroidal rupture, recent subretinal hemorrhage, and intraretinal hemorrhage, and in two cases of TPE. Hyperautofluorescence was observed in cases of old subretinal hemorrhage and at the edge of the lesion in two cases of choroidal rupture. Mild hyperautofluorescence was observed in the posterior pole in Purtscher's retinopathy. Three cases of TPE exhibited hypoautofluorescence with diffuse hyperautofluorescent areas. CONCLUSION: FAF imaging is a non-invasive method for assessing changes in the posterior segment of the eye resulting from blunt ocular trauma. Furthermore, this technique provides valuable information. We described the findings of FAF imaging in cases of TPE, choroidal rupture, subretinal hemorrhage, and Purtscher's retinopathy. PMID- 25295898 TI - Pediatric cataracts: clinical aspects, frequency of strabismus and chronological, etiological, and morphological features. AB - PURPOSE: This study aimed to evaluate the frequency of strabismus and chronological, etiological, and morphological features in patients with pediatric cataracts. METHODS: Medical records of pediatric patients were evaluated at the Congenital Cataract Section, Department of Ophthalmology, Federal University of Sao Paulo, from 2001 to 2011. Patients with congenital cataract or developmental cataract were included. The patients with traumatic cataract, cataract secondary to uveitis, radiation or drugs, aphakic or pseudophakic patients who underwent surgery in another hospital, patients with glaucoma, non-lenticular leukocorias (retinoblastoma, retinopathy of prematurity, prelenticular leukocorias), and lens subluxation were excluded from the study. The following outcomes were evaluated: frequency of chronological, etiological, and morphological features, laterality, and occurrence of associated strabismus. RESULTS: A total of 207 patients were included. One hundred and seventeen patients (56.5%) had congenital cataract and 90 patients (43.5%) had developmental cataract. One hundred and nine patients (52.6%) had unilateral cataract. In terms of morphology, 72 children (33.8%) had zonular cataract and 66 (31.9%) had total cataract. Idiopathic cataract affected 150 patients (72.5%). There were 108 patients (52.2%) with strabismus, mainly secondary esotropia. CONCLUSION: Idiopathic etiology was the most frequent cause in this group of patients. Zonular cataract was the main morphological type of cataract in the study. Unilateral cataract occurred more frequently in patients with persistent fetal vasculature (PFV). Strabismus presented in 52% of the patients. The current analysis may help establish an earlier and more accurate diagnosis of pediatric cataracts. PMID- 25295899 TI - Measurement of choroid thickness in pregnant women using enhanced depth imaging optical coherence tomography. AB - PURPOSE: To investigate choroidal thickness in healthy pregnant women during different trimesters using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: This prospective study included 90 healthy pregnant women in their first, second, or third trimester (groups 1, 2, and 3, respectively) and 30 non-pregnant healthy women (group 4). The age range for all groups was 18-40 years. Spectral domain optical coherence tomography scans were obtained to estimate the average choroidal thickness. Using EDI-OCT, we measured choroidal thickness manually from the outer border of the retinal pigment epithelium to the inner scleral border at the subfovea, 3 mm temporal, and 3 mm nasal to the fovea. Differences among groups were analyzed by one-way ANOVA. RESULTS: We found a statistically significant difference between groups 2 and group 4 for subfoveal, temporal, and nasal mean choroidal thickness (p=0.007, p<0.001, p=0.026, respectively). The mean choroidal thickness for group 2 was 395 +/- 80 MUm, 338 +/- 74 MUm, and 233 +/- 61 MUm at the regions subfoveal, temporal, and nasal to the fovea, respectively. In comparison, the mean choroidal thickness for group 4 was 335 +/- 86 MUm, 274 +/- 54 MUm, and 200 +/- 53 MUm at the regions subfoveal, temporal, and nasal to the fovea, respectively. No statistically significant differences were found for choroidal thickness among groups 1-4 (p=0.214, p=0.177, p=0.094, respectively) and between groups 3-4 (p=0.105, p=0.261, p=0.695, respectively) for all measured points. CONCLUSION: Our results suggest that choroidal thickening can occur at the regions subfoveal, temporal, and nasal to the fovea in the second trimester. PMID- 25295901 TI - Conjunctival melanoma: survival analysis in twenty-two Mexican patients. AB - PURPOSE: To describe the cases of conjunctival melanoma (CM) and report the disease-free interval (DFI) and overall survival (OS). METHODS: The charts of 22 patients who were admitted to two hospitals between 1985 and 2006 were reviewed for pertinent data, including demographics, site of involvement in the conjunctiva and sub-sites, surgical treatment, and adjuvant treatment. RESULTS: There were 10 (45.45%) males and 12 (54.55%) females. Mean age was 52.3 years. In this group, 15 patients (68.1%) involved the bulbar conjunctiva, and 7 (31.9%) involved the palpebral conjunctiva. Of the 22 patients, 72.72% had a history of conjunctival melanosis. The average tumor size was 20.4 mm. Eight (36.36%) patients underwent orbital exenteration, 2 (9.06%) had enucleation, 5 (22.72%) had wide excision of the lesion followed by radiotherapy, 2 (9.06%) had orbital exenteration with neck dissection, and the remaining 5 patients (22.72%) were considered adequately treated only with wide excision. Eight (36.36%) patients received adjuvant treatment. Disease-free survival at 5 years was 51% and the overall survival at 5 and 10 years was 50% and 37%, respectively. CONCLUSION: Conjunctival melanoma is a rare entity. Tumor behavior is aggressive, and the optimal treatment is surgery with adjuvant therapy. PMID- 25295900 TI - Ocular biometry and central corneal thickness in children: a hospital-based study. AB - PURPOSE: To investigate the distribution of axial length, anterior chamber depth, lens thickness, vitreous chamber depth, and central corneal thickness in children at different age groups. METHODS: We studied 364 eyes in 182 children with ages between 1 and 12 years. Axial length, anterior chamber depth, lens thickness, and vitreous chamber depth were measured by ultrasound biometry. Central corneal thickness was measured by ultrasound pachymetry in all children. RESULTS: The mean age was 6.54 ?} 3.42 years. The axial length was 20.95 mm in 1-2 years old and 22.95 mm in 11-12 years old. The central corneal thickness was 556 MUm in 1-2 years old and 555 MUm in 11-12 years old. The mean anterior chamber depth and vitreous chamber depth increased with age (3.06 mm to 3.44 mm in anterior chamber depth, 13.75 mm to 15.99 mm in vitreous chamber depth), and the lens thickness decreased as age increased (3.67-3.51 mm). CONCLUSION: The axial length increased with age and reached adult levels by the age of 9-10 years. The lens thickness gradually decreased until 12 years. The central corneal thickness measurements did not yield a linear algorithm. PMID- 25295902 TI - Static cyclotorsion measurements using the Schwind Amaris laser. AB - PURPOSE: To assess the reliability and reproducibility of static cyclotorsion correction (SCC) measurements made using the Schwind Amaris Excimer laser in patients undergoing LASIK or PRK, and compare the outcomes of treating astigmatism with and without SCC. METHODS: Eighty eyes of 40 patients were included in this study. All eyes underwent 2 or 3 sets of five measurements: before and after speculum placement, and after flap-lift (in LASIK cases). We assessed the reproducibility, accuracy, and the percentage of "no catch" measurements. The astigmatism was calculated pre-and 3-months-postoperatively by vector analysis. RESULTS: The mean age of the patients was 23.67 ?} 4.19 years. Preoperative spherical equivalent and astigmatism were -2.56 ?} 2.86 D and +1.36 ?} 0.98 D, respectively. The mean measurement time was 15.1 seconds per measurement. The percentages of "no catch" were: 63.8%, 14.9%, and 26.9%; pre speculum, post-speculum, and post flap-lift, respectively. Cyclotorsion of >=}2 degrees was seen in 41.25% and 66% of the cases before and after the flap-lift, respectively. Significant cyclotorsion (>=}5 degrees ) was seen in 12.50% and 18% of the eyes pre and post flap-lift. The mean astigmatism dropped from +1.53 D@1 degrees to +0.34D@3 degrees when SCC was used and from +1.86D@1 degrees to +0.23D@7 degrees when SCC was not used. No statistical difference was noticed between the groups (p>0.05) in the postoperative residual astigmatism. A postoperative astigmatism of >= D was seen in 10% and 20% of eyes with and without SCC, respectively (p<0.01). CONCLUSION: Although not always feasible, the SCC measurement is a simple and useful tool. Postoperative astigmatism showed less variability when SCC was used. PMID- 25295903 TI - Is the cost the primary barrier for cataract surgery in Paraguay? AB - PURPOSE: To determine if the cost was the main barrier to undergo cataract surgery in Paraguay. METHODS: We conducted a cohort study with patients screened in the 2011 Rapid Assessment of Avoidable Blindness (RAAB) who had reported that the cost was the main barrier to undergo cataract surgery in Paraguay. All patients with operable cataract from the RAAB study and with registered telephone numbers were interviewed by telephone and were offered free surgery services. The patients who did not come for surgery were re-interviewed by telephone to analyze the reasons for not undergoing the operation. RESULTS: Out of 122 patients identified in the RAAB study with barriers for cataract surgery, 69 (56.6%) reported that the surgical fee was the main barrier; 52 (75.4%) of them had their telephone numbers registered. Thirty-six (69.2%) patients did not reside in the metropolitan area of Asuncion. Six patients (12%), all from Asuncion, agreed to undergo free surgery. Forty-six patients did not agree the free surgery mainly due to the costs associated with their transportation (n=31, 67%) and the travel costs of their companion (n=6, 13%). CONCLUSION: Surgery fee alone was not the major contributing factor for not undergoing cataract surgery. Place of residence and other indirect out-of-pocket expenses, such as transportation and companion related costs appear to be more relevant. While further investigation is needed to assess if reducing the cost of transport will improve the uptake, the findings in this study suggest that a surgical package with all costs should be offered to patients of cataract surgical programs to increase cataract surgical coverage in Paraguay. PMID- 25295904 TI - Expression of TNF-alpha and IL-6 cytokines in the choroid and sclera of hypercholesterolemic rabbits. AB - PURPOSE: This study aimed to evaluate the expression of the inflammatory cytokines TNF-alpha and IL-6 in the sclera and choroid of hypercholesterolemic rabbits. METHOD: Twenty-one New Zealand male albino rabbits were divided into two groups: NG and HG. The NG group was fed a standard rabbit diet and the HG group was fed a cholesterol-enriched diet (1%). The serum total cholesterol, triglyceride, HDL cholesterol, and fasting blood glucose levels were determined at the beginning of the experiment and on the day of euthanasia. Euthanasia of animals in the NG and HG groups was performed at the end of the 4th and 8th week, respectively. The eyes were analyzed immunohistochemically using TNF-alpha and IL 6 antibodies. RESULTS: At the time of euthanasia, the HG group showed a significant increase in total cholesterol and triglyceride when compared with the NG group (p<0.001). When compared with the NG group, there was a significant increase in the expression of TNF-alpha (p<0.001) and IL-6 (p=0.002) in the choroid and sclera of animals in the HG group. CONCLUSION: This study demonstrates that the hypercholesterolemic diet induces expression of TNF-alpha and IL-6 in the choroid and sclera of rabbits. PMID- 25295905 TI - Efficacy of a lutein-based dye (PhacodyneTM) for visualizing anterior capsulorhexis during cataract surgery by phacoemulsification. AB - PURPOSE: To evaluate the efficacy and safety of a novel lutein-based dye for the anterior capsulorhexis during phacoemulsification in cataract surgery in humans. METHODS: Twenty-five eyes from 25 patients were operated by 25 different surgeons who performed continuous circular capsulorhexis (CCC) guided by a lutein-based dye (PhacodyneTM) during cataract surgery by phacoemulsification. A questionnaire assessed the surgeon's opinion regarding the efficacy of the dye. Follow-up examinations were performed at 1, 7, and 30 days post-surgery. Eyes were evaluated by full ophthalmic examination, corneal topography/pachymetry, and corneal endothelial cell count. RESULTS: As revealed by the answers to the questionnaire, the dye facilitated the CCC procedure in all eyes. Baseline nuclear cataract classification (according to the Lens Opacities Classification System III; LOCS III) was 3.24 (+/- 1.12). Preoperative BCVA (logMAR) was 0.89 +/ 0.59 and improved to 0.23 +/- 0.22 on day 30 after surgery. The intraocular pressure (IOP) remained stable and the inflammatory reaction subsided in all cases within the first 7 days after surgery. The pre-operative values of corneal pachymetry and IOP were similar to those found on follow-up day 30. Loss in endothelial cell number was similar to earlier reports. CONCLUSION: PhacodyneTM was efficient when used for anterior capsulorhexis during cataract surgery by phacoemulsification and PMID- 25295906 TI - Ophthalmologic findings in hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin. AB - PURPOSE: To identify the effect of pegylated interferon f?-2b and ribavirin treatment in the ocular fundus examination, visual acuity, and visual field. METHODS: Prospective observational study was performed at the Hepatology Clinic of Sao Jose Regional Hospital and at the Vitreoretinal Department at the Sadalla Amin Ghanem Eye Hospital in patients with chronic hepatitis C before and during treatment with pegylated interferon f?-2b together with ribavirin. RESULTS: Six (37.5%) of 16 patients developed retinopathy during the treatment, two of which (12.5%) presented retinal hemorrhage, and four patients (6 eyes) presented cotton wool spots (25%) that regressed during the treatment. One patient (6.25%) presented transient decrease in visual acuity during the treatment and recovered spontaneously without specific therapy. CONCLUSION: Recommended treatment methods for hepatitis C may cause transient retinopathy, commonly without any damage to visual function in most patients. Although ocular involvement is rare, follow-up with an ophthalmologist is recommended during the course of the hepatitis C medication. PMID- 25295907 TI - Severe scleral dellen as an early complication of pterygium excision with simple conjunctival closure and review of the literature. AB - We describe a patient with acute scleral dellen (SD) after pterygium excision with simple conjunctival closure. In addition, we present a PUBMED review on the medical literature on early SD after pterygium surgery. This case describes a 45 year-old man who presented with severe SD, 7 days after pterygium surgery with minimal cauterization of episcleral vessels and simple conjunctival closure.No other adjunctive therapy was used intraoperatively. The patient refused conjunctival flap coverage of the lesion. Therefore, medical treatment consisted of antibiotic ointment, patching, and daily follow-up. After 7 days, the patching was changed for intensive ocular lubrication. Five weeks later, the surrounding conjunctive had completely covered the affected sclera. To the best of our knowledge, this is the first report of early SD following pterygium excision and simple conjunctival closure with no other adjunctive therapy. When performing pterygium excision with conjunctival coverage of the sclera, a close follow-upis recommended to rule out wound dehiscence and SD, even when surgical wound closure is considered to prevent PMID- 25295908 TI - Transient spectral domain optical coherence tomography findings in classic MEWDS: a case report. AB - The purpose of this study was to describe a patient with multiple evanescent white dot syndrome (MEWDS) who presented with classic retinal findings and transient changes in outer retinal anatomy. A 20-year-old man presented with mild blurred vision in the left eye, reporting flu-like symptoms 1 week before the visual symptoms started. Fundus examination of the left eye revealed foveal granularity and multiple scattered spots deep to the retina in the posterior pole. Fluorescein angiography and indocyanine green angiography showed typical MEWDS findings. Spectral Domain Optical Coherence Tomography has shown transient changes in outer retinal anatomy with disappearance of inner segment-outer segment junction and mild attenuation of external limiting membrane. Six months later, Spectral Domain Optical Coherence Tomography has shown complete resolution with recovery of normal outer retinal aspect. PMID- 25295909 TI - Susac syndrome: diverse clinical findings and treatment. AB - We report a case of a 19-year-old woman presenting bilateral neurosensorial hearing loss, mental abnormalities, and loss of visual field in the left eye. Visual acuity was 20/20 in OD and 20/25 in OS. Patient was examined systemically. Audiometry showed sensorineural hearing loss in both ears. The magnetic resonance imaging (MRI) of brain revealed multiple small lesions in the white matter in both cerebral hemispheres and at the corpus callosum. Fundoscopy showed bilateral normal optic disc and sheathing of the arterioles in the middle periphery of OD. Retinal edema and cotton-wool spots were observed. Fluorescein angiography showed bilateral peripheral occlusive arterial vasculopathy. The patient was diagnosed with Susac syndrome and treated with quetiapine fumarate, flunitrazepam, and prednisone, which resulted in stabile outcome. This case shows that a high index of suspicion leading to early recognition and treatment is important to avoid irreversible damage. PMID- 25295910 TI - Intrastromal crosslinking in post-LASIK ectasia. AB - We describe a case of early post-LASIK ectasia detected in the first 6 months after surgery. The patient was treated by means of intrastromal corneal crosslinking under the flap, without de-epithelialization, which resulted in a positive outcome. At the time of writing, 2 years after the procedure, the patient remained free of progression. PMID- 25295911 TI - Is dry eye an environmental disease? AB - Previous studies have revealed that eye contact with either air pollutants or adverse indoor and/or outdoor environmental conditions can affect tear film composition and ocular surface components. These effects are mediated by selective binding of the environmental agents to ocular surface membrane receptors, leading to activation of pro inflammatory signaling pathways. The aim of the current review was to examine the published evidence associated with environmental factors and ocular surface disease and dry eye. Specifically, the reader will appreciate why it is possible to refer to them as mediators of Environmental Dry Eye Disease (EDED), a singular clinical entity inside DED context, directly caused by pollutants and/ or adverse climatic conditions. The indicators and clinical findings are described along with EDE differential diagnosis in its acute and the chronic phases. Based on strong existing evidence of clinical reports and epidemiological observations regarding DED and environmental factors we conclude that there is a straight cause-and-effect relationship between ambient stresses and DED. International standards and web based tools are described for monitoring worldwide environmental conditions referring localities and populations susceptible to EDED. This information is beneficial to health providers to pinpoint the individuals and predisposed groups afflicted with DED. Such insights may not only improve the understanding and treatment of DED but also help to identify the contributing factors and lower the frequency and progression of EDED. PMID- 25295912 TI - Bilateral acute depigmentation of the iris (BADI): first reported case in Brazil. PMID- 25295913 TI - Refractive error in school children in Campinas, Brazil. PMID- 25295914 TI - Natamycin content and quality evaluation of yoghurt from small- and large-scale brands in Turkey. AB - In this study, the presence of natamycin and quality parameters of yoghurt samples manufactured by small- and large-scale dairy firms in Turkey were investigated. Physicochemical and microbiological results revealed that, except Lactobacillus bulgaricus and Streptococcus thermophilus counts, the majority of the yoghurts manufactured by small-scale dairy firms were found to be out of the limits. Natamycin was detected in 31 and 2 yoghurt samples from small- and large scale brands, respectively. The levels of natamycin in small-scale brand yoghurts were higher than those in large-scale brand yoghurts. Of the analysed samples, 42.3% did not comply with the Turkish Food Codex. PMID- 25295915 TI - On the biological plausibility of Wind Turbine Syndrome. AB - An emerging environmental health issue relates to potential ill-effects of wind turbine noise. There have been numerous suggestions that the low-frequency acoustic components in wind turbine signals can cause symptoms associated with vestibular system disorders, namely vertigo, nausea, and nystagmus. This constellation of symptoms has been labeled as Wind Turbine Syndrome, and has been identified in case studies of individuals living close to wind farms. This review discusses whether it is biologically plausible for the turbine noise to stimulate the vestibular parts of the inner ear and, by extension, cause Wind Turbine Syndrome. We consider the sound levels that can activate the semicircular canals or otolith end organs in normal subjects, as well as in those with preexisting conditions known to lower vestibular threshold to sound stimulation. PMID- 25295916 TI - Prevalence and severity of depression and anxiety in patients with systemic lupus erythematosus: An epidemiologic study in Iranian patients. AB - OBJECTIVES: We aimed to evaluate the prevalence of depression and anxiety in patients with systemic lupus erythematosus (SLE) and explore their association with demographic and clinical features. METHODS: In this cross-sectional study, 166 SLE patients in rheumatology center of Shariati hospital, Tehran University of Medical Sciences were enrolled. SLE disease activity index (SLEDAI) and Beck and Cattell inventories for evaluation of depression and anxiety were completed for each patient. RESULTS: The mean age of patients was 33.1 +/- 11.1 years and 92.2% of them were female. Two patients (1.2%) had only depression (without anxiety), while 36 patients (21.6%) had only anxiety (without depression). Meanwhile, 105 patients (63.3%) had mixed depression-anxiety and 23 patients (13.8%) did not have either depression or anxiety. Mean daily dose of prednisolone and number of administered drugs did not show significant difference between different subgroups of patients. In assessment of clinical and therapeutic items, no significant correlation between severity of depression (P = 0.65) and anxiety (P = 0.36) with daily dose of prednisolone in SLE patients was observed. There was no significant association between SLEDAI and severity of depression or anxiety. Occupational status had significant correlation with severity of depression and anxiety (P = 0.005).On the contrary, no significant correlation between number of administered drugs and severity of depression and anxiety was present. CONCLUSION: This study indicated the high prevalence of depression and anxiety among SLE patients and reinforced the need of a comprehensive psychiatric work-up in SLE. PMID- 25295917 TI - Usefulness of MR imaging of the parotid glands in patients with secondary Sjogren's syndrome associated with rheumatoid arthritis. AB - OBJECTIVE: To assess the correlation between MR imaging (MRI) of parotid glands with X-ray sialography, histopathology of the labial salivary glands, and salivary secretion, in patients with secondary Sjogren's syndrome (SS) associated with rheumatoid arthritis (RA). METHODS: Non-contrast MRI of the parotid glands was performed in 13 secondary SS patients associated with RA who satisfied the revised Japanese diagnostic criteria for SS (1999), and the ACR/EULAR classification criteria for RA (2010). The MRI findings were classified according to the degree of high-intensity signal on T1-weighted images (T1WI) and short inversion time inversion recovery (STIR) images into five grades (0-4), using the modified Nagasaki University grading method. The results of MRI grading were compared with the Rubin and Holt staging of X-ray sialography (0-4), the Greenspan grading of labial salivary gland histopathology (0-4), and salivary secretion by the gum test (ml/10 min). RESULTS: All 13 patients were females, with a mean age of 50.2 +/- 11.3 years. According to the MRI grading, 3 patients were Grade 1, 5 were Grade 2, 5 were Grade 3, and none was Grade 0 or Grade 4. The mean stage by X-ray sialography was 1.7 +/- 1.0, the mean grade by histopathology was 2.4 +/- 1.2, and the mean volume of salivary secretion was 9.7 +/- 3.9 ml. The MRI grading correlated significantly with the Rubin and Holt staging and Greenspan grading (P < 0.01 each, Spearman's rank correlation), and significantly and inversely with the results of the gum test (P < 0.05). CONCLUSION: The results suggest that MRI of the parotid glands is a useful noninvasive tool for evaluating destruction and inflammation in the salivary glands. PMID- 25295918 TI - A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. AB - OBJECTIVES: To assess the ability of a multi-biomarker disease activity (MBDA) score to track clinical response in patients with rheumatoid arthritis (RA) treated with different TNF inhibitors. METHODS: The study included 147 patients who had received adalimumab, etanercept, or infliximab for a year or more, during routine clinical care at the University Hospital of Occupational and Environmental Health, Japan. MBDA scores and clinical measures of disease activity were evaluated at baseline and, after 24 weeks (N = 84) and 52 weeks of treatment. Relationships between the changes (?) in MBDA score and changes in clinical measures or EULAR response categories were evaluated. RESULTS: The median disease activity was 5.7 by DAS28-ESR and 64 by MBDA score at baseline, and decreased significantly with treatment. ?MBDA scores over 1 year correlated with ?DAS28-ESR (r = 0.48) and ?DAS28-CRP (r = 0.46). Linear relationships between ?MBDA scores and ?DAS28-ESR or ?DAS28-CRP were not significantly different between TNF inhibitors. The MBDA scores declined significantly more in good responders (median change: -29) than moderate (-21), and more in moderate than in non-responders (+ 2), by the EULAR criteria. CONCLUSIONS: MBDA scores tracked disease activity and treatment response in patients with RA treated with three TNF inhibitors. The relationships between ?MBDA scores and ?DAS28-ESR or ?DAS28-CRP were consistent across the three TNF inhibitor groups. PMID- 25295919 TI - Efficacy of methotrexate and tumor necrosis factor inhibitors in Japanese patients with active psoriatic arthritis. AB - OBJECTIVE: The aim of this study was to assess the efficacy of oral methotrexate and tumor necrosis factor inhibitors in Japanese patients with active psoriatic arthritis. METHODS: We retrospectively investigated 51 patients who fulfilled the ClASsification criteria for Psoriatic ARthritis (CASPAR) criteria for the efficacy of tumor necrosis factor inhibitors and methotrexate. We assessed the visual analog scale score, psoriasis area and severity index score, C-reactive protein-based disease activity score in 28 joints (DAS28), swollen joint count (0 66), tender joint count (0-68), health assessment questionnaire score, C-reactive protein level, erythrocyte sedimentation rate, and matrix metalloproteinase 3, at both baseline and week 24. RESULTS: Of the 51 patients, 34 were male and 17 were female, with a mean age of 50.3 +/- 13.2 years. The duration of psoriasis to onset of arthritis was 10.2 +/- 9.1 years. At week 24, in the group treated with the tumor necrosis factor inhibitor plus methotrexate, the tender joint count declined from 6.05 +/- 5.84 to 0.43 +/- 1.03, the swollen joint count declined from 6.42 +/- 4.36 to 0.00 +/- 0.00, and the DAS28 declined from 4.35 +/- 0.82 to 2.04 +/- 0.68. In the group treated with methotrexate alone, the tender joint count declined from 3.70 +/- 1.76 to 0.60 +/- 0.86, the swollen joint count declined from 5.26 +/- 4.00 to 0.27 +/- 0.70, and the DAS28 declined from 3.91 +/ 0.82 to 1.94 +/- 0.53. There were no significant differences in the mean reduction in clinical measurements between the two groups. CONCLUSION: Our study demonstrated that methotrexate and tumor necrosis factor inhibitors are effective for the treatment of active psoriatic arthritis in Japanese patients. PMID- 25295920 TI - Validity and responsiveness of a self-administered foot evaluation questionnaire in rheumatoid arthritis. AB - OBJECTIVES: A self-administered foot evaluation questionnaire (SAFE-Q) was developed by the Japanese Society for Surgery of the Foot (JSSF). The aim of this study is to evaluate the validity and responsiveness of the SAFE-Q in patients with rheumatoid arthritis (RA). METHODS: In total, 180 patients with RA answered the SAFE-Q. Of 180 patients, 34 answered the SAFE-Q twice, preoperatively and postoperatively, to assess responsiveness. Construct validity was tested by comparing the 5 SAFE-Q subscales and the JSSF standard rating system for the RA foot and ankle scale (JSSF-RA), a Japanese version of the Health Assessment Questionnaire (JHAQ), disease activity score in 28 joints (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI). Responsiveness was examined by calculating the standardized response mean (SRM) and effect size (ES) 3 months after surgery. RESULTS: There were moderate correlations between the SAFE-Q and the JSSF-RA and JHAQ. Conversely, a low correlation was observed between the SAFE-Q and DAS28, SDAI, and CDAI. The responsiveness was high, with an SRM of 0.9 and ES of 0.7 for pain subscales. CONCLUSION: SAFE-Q is a useful tool for assessing the foot and ankle in RA patients. PMID- 25295921 TI - Preference of surgical procedure for the forefoot deformity in the rheumatoid arthritis patients--A prospective, randomized, internal controlled study. AB - OBJECTIVES: The deformed rheumatoid forefoot may be treated with resection of lesser metatarsal heads combined with arthrodesis or resection of the first metatarsophalangeal joint. Recurrent hallux valgus deformity has been reported by resection. We performed a prospective, randomized, internal-controlled study to compare results between arthrodesis and resection. METHODS: We resected the lesser metatarsal heads bilaterally and performed arthrodesis of the first metatarsophalangeal joint on one side and resection on the opposite side. We investigated 26 patients (52 feet) who were followed at least one year. Patients were assessed for clinical score, hallux valgus angle (HVA), angle between first and second metatarsals, and angle between first and fifth metatarsals preoperatively, postoperatively and at final follow-up. We evaluated callosities, claw toes, recurrences, and procedure preferences. RESULTS: The mean follow-up period was 4.1 years. No significant differences between arthrodesis and resection were seen, with the exception of HVA. That was significantly less on arthrodesis side (11.5 degrees ) than on resection side (17.0 degrees , p < 0.05). Seven callosities on resection side and four on arthrodesis side were observed. On resection side, hallux valgus deformity often recurred (15.3%). Patients expressed a significant preference for arthrodesis over resection (p = 0.008). CONCLUSIONS: Arthrodesis provides better results for maintaining HVA. PMID- 25295922 TI - Optimization of magnetic field-assisted synthesis of carbon nanotubes for sensing applications. AB - One of the most effective ways of synthesizing carbon nanotubes is the arc discharge method. This paper describes a system supported by a magnetic field which can be generated by an external coil. An electric arc between two electrodes is stabilized by the magnetic field following mass flux stabilization from the anode to the cathode. In this work four constructions are compared. Different configurations of cathode and coils are calculated and presented. Exemplary results are discussed. The paper describes attempts of magnetic field optimization for different configurations of electrodes. PMID- 25295923 TI - Take the plunge (for charity). AB - The Ice Bucket Challenge, a social media-driven fundraiser for the Amyotrophic Lateral Sclerosis (ALS) Association, has raised over $100 million to date. Despite criticisms of this fundraiser, efforts to understand why it has been so successful and how to sustain its momentum would benefit its cause--research funding--and may inform future charitable campaigns. PMID- 25295924 TI - Ice bucket challenge cash may help derisk ALS drug research. PMID- 25295925 TI - Arrests reveal debate about costs and benefits of proton therapy. PMID- 25295926 TI - New platform for cataloging hundreds of proteins gets test drive. PMID- 25295927 TI - Connectivity webs from HIV sequences could inform counseling. PMID- 25295930 TI - Hopeful act: a rebel transplants organs from HIV-positive donors. PMID- 25295932 TI - The BIM deletion polymorphism cannot account for intrinsic TKI resistance of Chinese individuals with chronic myeloid leukemia. PMID- 25295933 TI - Reply: the BIM deletion polymorphism cannot account for intrinsic TKI resistance of Chinese individuals with chronic myeloid leukemia. PMID- 25295934 TI - Astrocyte-derived lactosylceramide implicated in multiple sclerosis. PMID- 25295935 TI - The impact of JAK-STAT signaling on muscle regeneration. PMID- 25295936 TI - Thymocyte transformation enhanced. PMID- 25295937 TI - Protein breakdown precedes pancreatic tumor development. PMID- 25295938 TI - Understanding the role of progranulin in Alzheimer's disease. PMID- 25295939 TI - Genome editing: a tool for research and therapy: targeted genome editing hits the clinic. PMID- 25295940 TI - Genome editing: a tool for research and therapy: towards a functional understanding of variants for molecular diagnostics using genome editing. PMID- 25295945 TI - Balzac's Unknown Masterpiece: spotting the next big thing in art and science. PMID- 25295946 TI - Lasker Award winner Peter Walter. PMID- 25295947 TI - Lasker Award winner Kazutoshi Mori. PMID- 25295948 TI - Lasker Award winner Mahlon DeLong. PMID- 25295949 TI - Lasker Award winner Alim Louis Benabid. PMID- 25295950 TI - Lasker Award winner Mary-Claire King. PMID- 25295955 TI - [Alternative prescription schedules of sunitinib in metastatic kidney cancer: from the underground to the light?]. AB - Sunitinib was the first targeted therapy improving progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) in the first line of treatment. Classically, sunitinib is administered at a dose of 50 mg/day during four weeks followed by two weeks off (schedule 4/6). This schedule has two pitfalls: intermittent exposure with two weeks "off" and the increase in toxicity during the fourth week. Several alternative prescription schedules were studied with the aim of limiting the intensity of toxicity while maintaining efficacy. This review summarizes the published data on alternative schedules of sunitinib in terms of safety and efficacy. All articles and abstracts on alternative schedule of sunitinib in the mRCC were reviewed. Clinical trials were also searched. Studies evaluating the continuous schedule have not provided evidence of its superiority compared to the 4/6 schedules in terms of activity, tolerance or dose-intensity. Retrospective data of patients treated in a schedule two weeks of treatment "on" one week "off" (schedule 2/3) with sunitinib 50 mg/day show PFS that seem superior to those obtained with a schedule 4/ 6, while having a better safety profile. The alternating schedule of sunitinib 2/3 (50 mg/day) may be a better alternative to schedule 4/6 in terms of tolerance. If toxicity occurs with 50 mg/day on a schedule 4/6, it would probably offer a better alternative in terms of efficiency than dose reduction. The results of ongoing and future studies are expected to prospectively validate the concept. PMID- 25295958 TI - Optimal targets for blood pressure control in chronic kidney disease: the debate continues. AB - PURPOSE OF REVIEW: Because advanced chronic kidney disease (CKD) is often an exclusion criterion for large randomized trials of the management of hypertension, clinical decision making for these patients has relied on a few small, specific studies and much extrapolation. Several blood pressure treatment guidelines have recently been reissued. This review explores the applicability of the revised recommendations to CKD. RECENT FINDINGS: Many new publications are meta-analyses, guidelines and debates about guidelines. New data from trials are scant. Three revised guidelines (KDIGO, JNC8, KHA-CARI) recommend a target of less than 140/90. Most antihypertensive drugs are equally effective - but this rule may not apply to advanced CKD. Proteinuric renal disease is seen as an exception; all three guidelines set a target of 130/80 and the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker (but not both) is preferred. SUMMARY: There is no shortage of new commentary and advice, but evidence strength and generalizability diminish as the kidneys fail and the impact of calcified vessels and salt and water overload increases. A risk-based approach to intervention may be no less valuable than targets. Clinical trials of individuals with advanced CKD will be needed to identify effective treatments and may see a resurgence of the role of spironolactone. PMID- 25295956 TI - Middle pleistocene human remains from Tourville-la-Riviere (Normandy, France) and their archaeological context. AB - Despite numerous sites of great antiquity having been excavated since the end of the 19th century, Middle Pleistocene human fossils are still extremely rare in northwestern Europe. Apart from the two partial crania from Biache-Saint-Vaast in northern France, all known human fossils from this period have been found from ten sites in either Germany or England. Here we report the discovery of three long bones from the same left upper limb discovered at the open-air site of Tourville-la-Riviere in the Seine Valley of northern France. New U-series and combined US-ESR dating on animal teeth produced an age range for the site of 183 to 236 ka. In combination with paleoecological indicators, they indicate an age toward the end of MIS 7. The human remains from Tourville-la-Riviere are attributable to the Neandertal lineage based on morphological and metric analyses. An abnormal crest on the left humerus represents a deltoid muscle enthesis. Micro- and or macro-traumas connected to repetitive movements similar to those documented for professional throwing athletes could be origin of abnormality. PMID- 25295960 TI - New insights regarding chronic antibody-mediated rejection and its progression to transplant glomerulopathy. AB - PURPOSE OF THIS REVIEW: To discuss new insights regarding chronic antibody mediated rejection (CAMR) and its progression to transplant glomerulopathy. We will describe the progression to transplant glomerulopathy from a histologic perspective and provide updates on what is known about its pathophysiology, prognosis, and potential therapy. RECENT FINDINGS: Transplant glomerulopathy is a major contributor to long-term renal allograft loss and is most often associated with CAMR. On the basis of protocol biopsies, we have found that 3.5% of conventional transplants and 27.5% of positive crossmatch kidney transplants have transplant glomerulopathy at 1 year. The pathophysiology of the process is largely unknown, but complement activation was previously thought to be essential. However, CAMR appears to develop despite terminal complement blockade and many C4d negative cases of CAMR have been identified. Thus, complement independent mechanisms, such as direct endothelial cell activation and the infiltration of natural killer cells and monocytes, are likely key to the development of transplant glomerulopathy. SUMMARY: Transplant glomerulopathy is often the result of CAMR and leads to allograft loss. It is characterized by distinctive histologic changes, and its pathophysiology is a multifaceted process involving both innate and adaptive immunity. Despite advances in the understanding of this condition, no effective therapy exists. PMID- 25295959 TI - Is left ventricular hypertrophy a modifiable risk factor in end-stage renal disease. AB - PURPOSE OF REVIEW: Left ventricular hypertrophy (LVH) is common in end-stage renal disease (ESRD) and has been advocated as a therapeutic target. We review the considerations for targeting LVH as a modifiable risk factor in ESRD. RECENT FINDINGS: Pathologic myocardial changes underlying LVH provide an ideal substrate for the spread of arrhythmia and may be key contributors to the occurrence of sudden death in ESRD. LVH is present in 68-89% of incident hemodialysis patients and is frequently progressive, although regression is observed in a minority of patients. Higher degrees of baseline LVH, as well as greater increases in left ventricular mass index over time, are associated with decreased survival, but whether these associations are causal remains uncertain. Several interventions, including angiotensin blockade and frequent dialysis, can reduce the left ventricular mass index, but whether this is associated with improved survival has not been definitively demonstrated. SUMMARY: LVH is a highly prevalent and reversible risk factor, which holds promise as a novel therapeutic target in ESRD. Interventional trials are needed to provide additional evidence that LVH regression improves survival before prevention and reversal of LVH can be definitively adopted as a therapeutic paradigm in ESRD. PMID- 25295961 TI - Current status of kidney transplantation in HIV-infected patients. AB - PURPOSE OF REVIEW: To summarize the most current literature on transplant outcomes in HIV-infected kidney recipients. RECENT FINDINGS: HIV-infected recipients overall have excellent patient and allograft outcomes. Acute rejection, delayed graft function, drug-drug interactions and limited access to organs have emerged as important issues for HIV-infected kidney transplant patients. The subset of patients who are coinfected with hepatitis C virus do not fare as well and improving their outcomes should be a focus of future research in the field. SUMMARY: Renal transplantation remains the optimal treatment for end stage renal disease in the HIV-infected patient. PMID- 25295962 TI - Quality improvement initiative to reduce deep vein thrombosis associated with peripherally inserted central catheters in adults with cystic fibrosis. AB - RATIONALE: Peripherally inserted central catheters (PICCs) are common in the treatment of patients with cystic fibrosis (CF). Previous reports suggest that patients with CF are at increased risk for PICC-associated deep vein thrombosis (DVT). OBJECTIVES: We assessed potential risk factors for symptomatic PICC associated DVT with subsequent implementation of a quality improvement (QI) initiative to reduce PICC-associated DVT in patients with CF. METHODS: This was a 5-year retrospective cohort study with subsequent 21-month prospective observation following implementation of a QI intervention in adults (aged 18 yr or older) with CF. All patients with a PICC inserted from July 2006 to March 2013 at our CF Foundation-accredited center were included. Symptomatic DVT was diagnosed by Doppler ultrasound. PICC insertions were analyzed, and nine risk factors for DVT were analyzed to formulate a QI initiative to reduce risk of PICC associated DVT. The QI program focused on staff education and included modification to PICC order entry with a 4 French (F) single-lumen (SL) catheter as standard for all patients with CF. MEASUREMENTS AND MAIN RESULTS: A total of 369 PICCs were analyzed in 117 unique patients for a total of 5,437 PICC-days of placement. Symptomatic DVT was diagnosed in 28 (7.6%) of the 369 PICCs analyzed. Using regression analysis, the strongest predictors for DVT occurrence were warfarin use (odds ratio [OR] = 9.2, P = 0.006) and history of PICC-associated DVT (OR = 2.97, P = 0.08). Insertion of a 4F SL PICC resulted in zero symptomatic DVT. Zero episodes of DVT associated with 4F PICC insertion prevented use of PICC size in regression analysis. However, univariate analysis revealed that insertion of a 4F SL PICC instead of either 5F double lumen or 6F triple lumen was associated with a reduction in PICC-associated DVT (P = 0.001). After the QI intervention, 4F SL catheter insertion substantially increased to 65.8% of all PICCs inserted, whereas 6F triple-lumen catheter insertion declined to 6.8% of PICCs inserted. The QI initiative resulted in an absolute risk reduction in DVT per PICC placed of 6.1% (P = 0.055). CONCLUSIONS: To reduce risk of PICC associated DVT in patients with CF, QI strategies should focus on insertion of smaller-diameter 4F PICCs and reduction in PICC use in high-risk patients when possible. PMID- 25295963 TI - Gathering and learning from relevant clinical data: a new framework. AB - Given the rising costs of health care in today's economic environment, the need for effective, value-driven care has never been more pressing. While the U.S. health care system strives continually to improve patient outcomes, it struggles with the inadequacies due to variation in care and the inefficiencies of unnecessary resource utilization. The tools traditionally used to study care, from retrospective studies to randomized controlled trials, may be inadequate to address the complicated, interdependent questions related to defining effective care. To overcome the deficiencies of these traditional tools and better optimize our health care system, a new kind of methodology is required--one that integrates the functionality of previously existing tools in a novel way. Standardized Clinical Assessment and Management Plans (SCAMPs) were designed to accomplish this goal. A SCAMP is a care pathway, designed by clinicians, to guide medical decision making around a particular disorder. SCAMPs are unique in that they invite knowledge-based diversions from their recommendations and are accompanied by data collection and continuous improvement processes. Through these mechanisms, SCAMPs successfully reduce practice variation, optimize resource use, and create an integrated medical learning system which overcomes many of the inadequacies of traditional research tools. As such, the SCAMP paradigm may represent an important breakthrough in the effort to define and implement effective health care. PMID- 25295964 TI - Efficacy of an internet-based learning module and small-group debriefing on trainees' attitudes and communication skills toward patients with substance use disorders: results of a cluster randomized controlled trial. AB - PURPOSE: To examine whether an Internet-based learning module and small-group debriefing can improve medical trainees' attitudes and communication skills toward patients with substance use disorders (SUDs). METHOD: In 2011-2012, 129 internal and family medicine residents and 370 medical students at two medical schools participated in a cluster randomized controlled trial, which assessed the effect of adding a two-part intervention to the SUDs curricula. The intervention included a self-directed, media-rich Internet-based learning module and a small group, faculty-led debriefing. Primary study outcomes were changes in self assessed attitudes in the intervention group (I-group) compared with those in the control group (C-group) (i.e., a difference of differences). For residents, the authors used real-time, Web-based interviews of standardized patients to assess changes in communication skills. Statistical analyses, conducted separately for residents and students, included hierarchical linear modeling, adjusted for site, participant type, cluster, and individual scores at baseline. RESULTS: The authors found no significant differences between the I- and C-groups in attitudes for residents or students at baseline. Compared with those in the C-group, residents, but not students, in the I-group had more positive attitudes toward treatment efficacy and self-efficacy at follow-up (P<.006). Likewise, compared with residents in the C-group, residents in the I-group received higher scores on screening and counseling skills during the standardized patient interview at follow-up (P=.0009). CONCLUSIONS: This intervention produced improved attitudes and communication skills toward patients with SUDs among residents. Enhanced attitudes and skills may result in improved care for these patients. PMID- 25295965 TI - Placing constraints on the use of the ACGME milestones: a commentary on the limitations of global performance ratings. AB - As part of the outcomes-based accreditation process, the Accreditation Council for Graduate Medical Education (ACGME) now requires that medical specialties formulate and use educational milestones to assess residents' performance. These milestones are specialty-specific achievements that residents are expected to demonstrate at established intervals in their training. In this Commentary, the authors argue that the pressure to efficiently use program directors' and faculty members' time, particularly in the increasingly clinical-revenue-dependent model of the academic medical center, will lead program directors to meet these new accreditation expectations solely by adding items that assess these competencies to global end-of-rotation rating forms. This approach will increase the workload of faculty but will not provide new and useful information about residents' competence. These same concerns could apply if assessment committees attempt to measure these new performance dimensions without using direct observation to evaluate residents' performance. In these circumstances, the milestones movement will fall short of its intention and potential. In this Commentary, the authors outline and provide evidence from the literature for their concerns. They discuss the role that human judges play in measuring performance, the measurement characteristics of global performance ratings, and the problems associated with simply adding items to existing global rating forms. PMID- 25295966 TI - Algorithms, clinical practice guidelines, and standardized clinical assessment and management plans: evidence-based patient management standards in evolution. AB - In this issue, Farias and colleagues describe how to develop a clinical care pathway by using a structured, continuous learning process embedded within the day-to-day delivery of care. Their method is called Standardized Clinical Assessment and Management Plans (SCAMPs). A care pathway, such as a SCAMP, includes multiple decision points and related recommendations. The SCAMP process can test the validity of each decision point if clinicians document patient data and record their reasoning when they deviate from the recommended action at a decision point. The unique feature of SCAMPs is that they encourage dissent, unlike clinical practice guidelines (CPGs), algorithms, and bundled electronic health record protocols, which are designed to be followed. If a clinician deviates from the recommended action at a decision point, an explanation is required. This feedback, which should explain why a patient does not precisely "fit" the logic of the care pathway, may lead the SCAMP developers to modify the decision point. The authors of this Commentary argue that SCAMPs and CPGs, two approaches to developing clinical standards of care, are fundamentally equivalent. The key link between them is the recently described process of deconstructing a CPG into the many steps that are necessary to consistently apply it to clinical practice. The SCAMP process puts these steps to the test of daily practice. The Commentary ends with a list of foundational principles for developing standards of clinical care. These principles should apply to care pathways, algorithms, practice guidelines, or SCAMPs. PMID- 25295967 TI - Realizing the promise of competency-based medical education. AB - Competency-based medical education (CBME) places a premium on both educational and clinical outcomes. The Milestones component of the Next Accreditation System represents a fundamental change in medical education in the United States and is part of the drive to realize the full promise of CBME. The Milestones framework provides a descriptive blueprint in each specialty to guide curriculum development and assessment practices. From the beginning of the Outcomes project in 1999, the Accreditation Council for Graduate Medical Education and the larger medical education community recognized the importance of improving their approach to assessment. Work-based assessments, which rely heavily on the observations and judgments of clinical faculty, are central to a competency-based approach. The direct observation of learners and the provision of robust feedback have always been recognized as critical components of medical education, but CBME systems further elevate their importance. Without effective and frequent direct observation, coaching, and feedback, the full potential of CBME and the Milestones cannot be achieved. Furthermore, simply using the Milestones as end-of rotation evaluations to "check the box" to meet requirements undermines the intent of an outcomes-based accreditation system. In this Commentary, the author explores these challenges, addressing the concerns raised by Williams and colleagues in their Commentary. Meeting the assessment challenges of the Milestones will require a renewed commitment from institutions to meet the profession's "special obligations" to patients and learners. All stakeholders in graduate medical education must commit to a professional system of self regulation to prepare highly competent physicians to fulfill this social contract. PMID- 25295969 TI - Surface structures of poly(methyl methacrylate) films influenced by chain entanglement in the corresponding film-formation solution. AB - The effects of the properties of casting solution on the surface structure of poly(methyl methacrylate) (PMMA) films were systematically investigated. It was observed that the hydrophobicity of PMMA films increased with increasing viscosity of the corresponding polymer solution regardless of the film-formation techniques that were utilized. The ratio of the C-H symmetric stretching vibrations of methylene groups (hydrophobic components, with a peak at 2910 cm( 1)) to those of the ester methyl groups (relative hydrophilic components, with a peak at 2955 cm(-1)) from sum frequency generation (SFG) vibrational spectra, A2910/A2955, was used as a parameter to evaluate the structure on the film surface, which was related to the surface wettability of the films. The results showed that A2910/A2955 of cast PMMA films increased linearly with etasp(0.3) (etasp, the specific viscosity of the casting solution), whereas that of the corresponding spin-coated films showed a linear relationship defined as etasp(0.3)E(0.26), where E is the average number of entanglement points per molecule (E = Mw/Me). These results indicate that a relative equilibrium conformation on the PMMA film surface, adopted from the perspective of thermodynamics, was easily achieved during film formation, when the conformation of the polymer chains in the corresponding casting solution was close to that in the bulk. For the spin-coated films, the chain entanglement structure in the casting solution was a more important factor for the resulting film to reach a relative equilibrium state, since this structure was in favor of maintaining the pristine conformation in casting solution under centrifugal force during spin coating. This work may help to enhance the fundamental understanding of the formation of the film surface structure from polymer solution to the resulting solid film, which will affect not only the corresponding surface properties, but also the dynamics of the resulting thin films. PMID- 25295968 TI - Association of smoking and nicotine dependence with pre-diabetes in young and healthy adults. AB - INTRODUCTION: Several studies have shown an increased risk of type 2 diabetes among smokers. Therefore, the aim of this analysis was to assess the relationship between smoking, cumulative smoking exposure and nicotine dependence with pre diabetes. METHODS: We performed a cross-sectional analysis of healthy adults aged 25-41 in the Principality of Liechtenstein. Individuals with known diabetes, Body Mass Index (BMI) >35 kg/m2 and prevalent cardiovascular disease were excluded. Smoking behaviour was assessed by self-report. Pre-diabetes was defined as glycosylated haemoglobin between 5.7% and 6.4%. Multivariable logistic regression models were done. RESULTS: Of the 2142 participants (median age 37 years), 499 (23.3%) had pre-diabetes. There were 1,168 (55%) never smokers, 503 (23%) past smokers and 471 (22%) current smokers, with a prevalence of pre-diabetes of 21.2%, 20.9% and 31.2%, respectively (p <0.0001). In multivariable regression models, current smokers had an odds ratio (OR) of pre-diabetes of 1.82 (95% confidential interval (CI) 1.39; 2.38, p <0.0001). Individuals with a smoking exposure of <5, 5-10 and >10 pack-years had an OR (95% CI) for pre-diabetes of 1.34 (0.90; 2.00), 1.80 (1.07; 3.01) and 2.51 (1.80; 3.59) (p linear trend <0.0001) compared with never smokers. A Fagerstrom score of 2, 3-5 and >5 among current smokers was associated with an OR (95% CI) for pre-diabetes of 1.27 (0.89; 1.82), 2.15 (1.48; 3.13) and 3.35 (1.73; 6.48) (p linear trend <0.0001). DISCUSSION: Smoking is strongly associated with pre-diabetes in young adults with a low burden of smoking exposure. Nicotine dependence could be a potential mechanism of this relationship. PMID- 25295970 TI - Role of adiponectin in delayed embryonic development of the short-nosed fruit bat, Cynopterus sphinx. AB - The aim of this study was to evaluate the role of adiponectin in the delayed embryonic development of Cynopterus sphinx. Adiponectin receptor (ADIPOR1) abundance was first observed to be lower during the delayed versus non-delayed periods of utero-embryonic unit development. The effects of adiponectin treatment on embryonic development were then evaluated during the period of delayed development. Exogenous treatment increased the in vivo rate of embryonic development, as indicated by an increase in weight, ADIPOR1 levels in the utero embryonic unit, and histological changes in embryonic development. Treatment with adiponectin during embryonic diapause showed a significant increase in circulating progesterone and estradiol concentrations, and in production of their receptors in the utero-embryonic unit. The adiponectin-induced increase in estradiol synthesis was correlated with increased cell survival (BCL2 protein levels) and cell proliferation (PCNA protein levels) in the utero-embryonic unit, suggesting an indirect effect of adiponectin via estradiol synthesis by the ovary. An in vitro study further confirmed the in vivo findings that adiponectin treatment increases PCNA levels together with increased uptake of glucose by increasing the abundance of glucose transporter 8 (GLUT8) in the utero-embryonic unit. The in vitro study also revealed that adiponectin, together with estradiol but not alone, significantly increased ADIPOR1 protein levels. Thus, adiponectin works in concert with estradiol to increase glucose transport to the utero embryonic unit and promote cell proliferation, which together accelerate embryonic development. PMID- 25295971 TI - Chemo-, regio-, and stereoselective trifluoromethylation of styrenes via visible light-driven single-electron transfer (SET) and triplet-triplet energy transfer (TTET) processes. AB - A process for tunable and chemo-, regio-, and stereoselective photocatalytic trifluoromethylation of styrenes was developed. Thermodynamically stable E trifluoromethylated alkenes were prepared using Togni's reagent in the presence of Ru(bpy)3Cl2.6H2O under visible light irradiation, whereas less thermodynamically stable Z-trifluoromethylated alkenes were obtained by employing Umemoto's reagent and photocatalyst Ir(ppy)3. PMID- 25295972 TI - Residency patterns and migration dynamics of adult bull sharks (Carcharhinus leucas) on the east coast of southern Africa. AB - Bull sharks (Carcharhinus leucas) are globally distributed top predators that play an important ecological role within coastal marine communities. However, little is known about the spatial and temporal scales of their habitat use and associated ecological role. In this study, we employed passive acoustic telemetry to investigate the residency patterns and migration dynamics of 18 adult bull sharks (195-283 cm total length) tagged in southern Mozambique for a period of between 10 and 22 months. The majority of sharks (n = 16) exhibited temporally and spatially variable residency patterns interspersed with migration events. Ten individuals undertook coastal migrations that ranged between 433 and 709 km (mean = 533 km) with eight of these sharks returning to the study site. During migration, individuals exhibited rates of movement between 2 and 59 km x d(-1) (mean = 17.58 km x d(-1)) and were recorded travelling annual distances of between 450 and 3760 km (mean = 1163 km). Migration towards lower latitudes primarily took place in austral spring and winter and there was a significant negative correlation between residency and mean monthly sea temperature at the study site. This suggested that seasonal change is the primary driver behind migration events but further investigation is required to assess how foraging and reproductive activity may influence residency patterns and migration. Results from this study highlight the need for further understanding of bull shark migration dynamics and suggest that effective conservation strategies for this vulnerable species necessitate the incorporation of congruent trans-boundary policies over large spatial scales. PMID- 25295973 TI - Droplet microfluidics in (bio)chemical analysis. AB - Droplet microfluidics may soon change the paradigm of performing chemical analyses and related instrumentation. It can improve not only the analysis scale, possibility for sensitivity improvement, and reduced consumption of chemical and biological reagents, but also the speed of performing a variety of unit operations. At present, microfluidic platforms can reproducibly generate monodisperse droplet populations at kHz or higher rates with droplet sizes suitable for high-throughput experiments, single-cell detection or even single molecule analysis. In addition to being used as microreactors with volume in the micro- to femtoliter range, droplet based systems have also been used to directly synthesize particles and encapsulate biological entities for biomedicine and biotechnology applications. This minireview summarizes various droplet microfluidics operations and applications for (bio)chemical assays described in the literature during the past few years. PMID- 25295974 TI - [Clinical ethics support in psychiatry: topics--concepts--experiences]. PMID- 25295975 TI - [Preventive detention is a psychiatric issue--pro]. PMID- 25295976 TI - [Preventive detention is a psychiatric issue--contra]. PMID- 25295977 TI - [Moral case deliberation about coercion in psychiatry. Dilemmas, value and implementation]. AB - OBJECTIVE: To identify moral dilemmas regarding coercion and restraint among professionals working at a psychiatric ward, to get insight in the value of Moral Case Deliberation meetings about these dilemmas, and in the implementation of such meetings. METHODS: Qualitative explorative study with interviews, focus group and participant observation. RESULTS: Professionals experience dilemmas related to closing the ward (freedom versus safety), coercive treatment (freedom versus health), and camera surveillance (privacy versus safety). The introduction of Moral Case Deliberation contributes to changes concerning quality of treatment, professionalism of healthcare providers, and cooperation in the treatment team. The implementation of Moral Case Deliberation depends on an atmosphere of trust, expertise of the facilitator, and active involvement of a local coordinator. Bottlenecks for implementation include the availability of physicians, time-pressure and intervals between meetings. CONCLUSION: Moral Case Deliberation fosters quality of treatment and moral competence of professionals in dealing with ethical dilemmas in psychiatric practice. Continuity of Moral Case Deliberation meetings motivates the participants and provides the opportunity to learn and practice ethical skills. PMID- 25295978 TI - [People living with dementia until their natural end of life: an alternative to (medically) assisted suicide]. PMID- 25295979 TI - [Dementia stigma and sequelae - risks and side effects of psychiatric diagnoses]. PMID- 25295981 TI - Trauma and emergency: is the unified health system (SUS) the solution in Brazil? PMID- 25295982 TI - Ethics in the digital age. PMID- 25295980 TI - Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice. AB - Even as the study of plant genomics rapidly develops through the use of high throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits. PMID- 25295983 TI - Helicopter emergency medical rescue for the traumatized: experience in the metropolitan region of Campinas, Brazil. AB - OBJECTIVE: To analyze the profile of patients served by the air medical rescue system in the Metropolitan Region of Campinas, evaluating: triage and mobilization criteria; response time; on-site care and transport time; invasive procedures performed in the Pre-Hospital Care (PHC); severity of patients; morbidity and mortality. METHODS: We conducted a prospective, descriptive study in which we analyzed medical records of patients rescued between July 2010 and December 2012. During this period, 242 victims were taken to the HC-Unicamp. Of the 242 patients, 22 were excluded from the study. RESULTS: of the 220 cases evaluated, 173 (78.6%) were male, with a mean age of 32 years. Blunt trauma was the most prevalent (207 cases - 94.1%), motorcycle accidents being the most common mechanisms of injury (66 cases - 30%), followed by motor vehicle collisions (51 cases - 23.2%). The average response time was 10 +/- 4 minutes and the averaged total pre-hospital time was 42 +/- 11 minutes. The mean values of the trauma indices were: RTS = 6.2 +/- 2.2; ISS = 19.2 +/- 12.6; and TRISS = 0.78 +/- 0.3. Tracheal intubation in the pre-hospital environment was performed in 77 cases (35%); 43 patients (19.5%) had RTS of 7.84 and ISSd"9, being classified as over-triaged. Of all patients admitted, the mortality was 15.9% (35 cases). CONCLUSION: studies of air medical rescue in Brazil are required due to the investments made in the pre-hospital care in a country without an organized trauma system. The high rate of over-triage found highlights the need to improve the triage and mobilization criteria. PMID- 25295984 TI - Importance of multidisciplinary trauma prevention program for youth. AB - OBJECTIVE: present the experience of the P.A.R.T.Y. program in Campinas, thereby changing the habits of young people. METHODS: The organizers visited the participating schools talking to the students, who are aged between 14-18 years. These students spent an afternoon at the Clinics Hospital of Unicamp, where, for four hours, they attended lectures of the organizers, partners and municipal sectors, and also visited the hospital, talking with trauma victims. Questionnaires were evaluated between 2010-2012, being applied before and after the project. RESULTS: 2,450 high school students attended the program. The mean age is 16 +/- 0,99 years and 37.6% were male. 3.6% of males already drive while drunk versus 0.8% of women. Before the project 116 (11.3%) thought that drunk driving wasn't a risk, and only 37 (3.6%) knew the alcohol effects. After the project, 441 (43%) began to consider drunk driving a risk and 193 (18.8%) know the alcohol effects when driving. 956 (93.3%) considered that prevention projects have a huge impact on their formation. CONCLUSION: It's expected that the attendees will act as multipliers of information, conveying the message of prevention to their entire social circles resulting in reduction in the number of trauma events involving the young, in the long term. PMID- 25295985 TI - Implementation of a trauma registry in a Brazilian public hospital: the first 1,000 patients. AB - OBJECTIVE: Show the steps of a Trauma Registry (TR) implementation in a Brazilian public hospital and evaluate the initial data from the database. METHODS: Descriptive study of the a TR implementation in Joao XXIII Hospital (Hospital Foundation of the state of Minas Gerais) and analysis of the initial results of the first 1,000 patients. RESULTS: The project was initiated in 2011 and from January 2013 we began collecting data for the TR. In January 2014 the registration of the first 1000 patients was completed. The greatest difficulties in the TR implementation were obtaining funds to finance the project and the lack of information within the medical records. The variables with the lowest completion percentage on the physiological conditions were: pulse, blood pressure, respiratory rate and Glasgow coma scale. Consequently, the Revised Trauma Score (RTS) could be calculated in only 31% of cases and the TRISS methodology applied to 30.3% of patients. The main epidemiological characteristics showed a predominance of young male victims (84.7%) and the importance of aggression as a cause of injuries in our environment (47.5%), surpassing traffic accidents. The average length of stay was 6 days, and mortality 13.7%. CONCLUSION: Trauma registries are invaluable tools in improving the care of trauma victims. It is necessary to improve the quality of data recorded in medical records. The involvement of public authorities is critical for the successful implementation and maintenance of trauma registries in Brazilian hospitals. PMID- 25295986 TI - Evaluation of prognostic factors of decompressive craniectomy in the treatment of severe traumatic brain injury. AB - OBJECTIVE: to determine predictive factors for prognosis of decompressive craniectomy in patients with severe traumatic brain injury (TBI), describing epidemiological findings and the major complications of this procedure. METHODS: we conducted a retrospective study based on analysis of clinical and neurological outcome, using the extended Glasgow outcome in 56 consecutive patients diagnosed with severe TBI scale treated in the emergency department from February 2004 to July 2012. The variables assessed were age, mechanism of injury, presence of pupillary changes, Glasgow coma scale (GCS) score on admission, CT scan findings (volume, type and association of intracranial lesions, deviation from the midline structures and classification in the scale of Marshall and Rotterdam). RESULTS: we observed that 96.4% of patients underwent unilateral decompressive craniectomy (DC) with expansion duraplasty, and the remainder to bilateral DC, 53.6% of cases being on the right 42.9% on the left, and 3.6% bilaterally, with predominance of the fourth decade of life and males (83.9%). Complications were described as transcalvarial herniation (17.9%), increased volume of brain contusions (16.1%) higroma (16.1%), hydrocephalus (10.7%), swelling of the contralateral lesions (5.3%) and CSF leak (3.6%). CONCLUSION: among the factors studied, only the presence of mydriasis with absence of pupillary reflex, scoring 4 and 5 in the Glasgow Coma Scale, association of intracranial lesions and diversion of midline structures (DML) exceeding 15 mm correlated statistically as predictors of poor prognosis. PMID- 25295987 TI - Critical analysis of thoracotomies performed in the emergency room in 10 years. AB - OBJECTIVE: To conduct a critical analysis of thoracotomies performed in the emergency rooms. METHODS: We analyzed mortality rates and survival as outcome variables, mechanism of injury, site of injury and anatomic injury as clinical variables, and gender and age as demographic variables of patients undergoing thoracotomy in the emergency room after traumatic injury. RESULTS: Of the 105 patients, 89.5% were male. The average age was 29.2 years. Penetrating trauma accounted for 81% of cases. The most common mechanism of trauma was wound by a firearm projectile (gunshot), in 64.7% of cases. Patients with stab wounds (SW) accounted for 16.2% of cases. Overall survival was 4.7%. Survival by gunshot was 1.4%, and by SW, 23.5%. The ERT following blunt trauma showed a 100%mortality. CONCLUSION: The results obtained in the Emergency Hospital of Porto Alegre POA HPS are similar to those reported in the world literature. PMID- 25295988 TI - Natural history of extensive diaphragmatic injury on the right side: experimental study in rats. AB - OBJECTIVE: To evaluate the natural healing of the rat diaphragm that suffered an extensive right penetrating injury. METHODS: Animals were submitted to an extensive penetrating injury in right diaphragm. The sample consisted of 40 animals. The variables studied were initial weight, weight 21 days after surgery; healing of the diaphragm, non-healing of the diaphragm, and herniated abdominal contents into the chest. RESULTS: Ten animals were used as controls for weight and 30 animals were operated. Two animals died during the experiment, so 28 animals formed the operated group; healing of the diaphragm occurred in 15 animals (54%), 11 other animals showed diaphragmatic hernia (39%) and in two we observed only diaphragmatic injury without hernia (7%). Among the herniated organs, the liver was found in 100% of animals, followed by the omentum in 77%, small bowel in 62%, colon in 46%, stomach in 31% and spleen in 15%. The control group and the diaphragmatic healing subgroup showed increased weight since the beginning of the study and the 21 days after surgery (p <0.001). The unhealed group showed no change in weight (p = 0.228). CONCLUSION: there is a predominance of spontaneous healing in the right diaphragm; animals in which there was no healing of the diaphragm did not gain weight, and the liver was the organ present in 100% the diaphragmatic surface in all rats with healed diaphragm or not. PMID- 25295989 TI - Comparative analysis between identified injuries of victims of fall from height and other mechanisms of closed trauma. AB - OBJECTIVE: To analyze the lesions diagnosed in victims of falls, comparing them with those diagnosed in other mechanisms of blunt trauma. METHODS: We conducted a retrospective study of trauma protocol charts (prospectively collected) from 2008 to 2010, including victims of trauma over 13 years of age admitted to the emergency room. The severity of injuries was stratified by the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). Variables were compared between the group of victims of falls from height (Group 1) and the other victims of blunt trauma (Group 2). We used the Student t, chi-square and Fisher tests for comparison between groups, considering the value of p <0.05 as significant. RESULTS: The series comprised 4,532 cases of blunt trauma, of which 555 (12.2%) were victims of falls from height. Severe lesions (AISe"3) were observed in the extremities (17.5%), in the cephalic segment (8.4%), chest (5.5%) and the abdomen (2.9%). Victims of Group 1 had significantly higher mean age, AIS in extremities / pelvis, AIS in the thoracic segment and ISS (p <0.05). The group 1 had significantly (p <0.05) higher incidence of tracheal intubation on admission, pneumothorax, hemothorax, rib fractures, chest drainage, spinal trauma, pelvic fractures, complex pelvic fractures and fractures to the upper limbs. CONCLUSION: Victims of fall from height had greater anatomic injury severity, greater frequency and severity of lesions in the thoracic segment and extremities. PMID- 25295990 TI - Jejunum and ileum blunt trauma: what has changed with the implementation of multislice computed tomography? AB - OBJECTIVE: to evaluate the impact of the new technology of multidetector computed tomography (MDCT) in improving the accuracy and early diagnosis of BSBI. METHODS: patients with blunt small bowel injuries (BSBI) grade> I were identified retrospectively and their CT scans reviewed by an experienced radiologist. Clinical and tomographic findings were analyzed and patients grouped as "pre MDCT" and "post-MDCT", according to the time of implementation of a 64-slice MDCT. RESULTS: of the 26 patients with BSBI 16 had CT scans. Motor vehicle collision (62.5%) was the most frequent mechanism of injury. In the pre-MDCT period, five of the 13 patients (38.5%) had abdominal CT, and in the post-MDCT, 11 of 13 patients (84.6%) had the exam. During pre-MDCT, all CT scans were abnormal with findings of pneumoperitoneum (60%), free fluid (40%) and bowel wall enhancement (20%). In the post-MDCT group, all exams but one were abnormal and the most frequent findings were free fluid (90.9%), bowel wall enhancement (72.7%), and pneumoperitoneum (54.5%). However, the rate of delayed laparotomy did not change. The mortality rate in both groups were similar, with 20% during pre-MDCT and 18.2% during post-MDCT. CONCLUSION: the use of MDCT in abdominal trauma in our service has increased the sensibility of the diagnosis, but has had no impact on outcome so far. PMID- 25295991 TI - Comparative analysis between identified injuries of victims of fall from height and other mechanisms of closed trauma. AB - OBJECTIVE: to identify predictors of death in blunt trauma patients sustaining pelvic fractures and, posteriorly, compare them to a previously reported series from the same center. METHOD: Retrospective analysis of trauma registry data, including blunt trauma patients older than 14 y.o. sustaining pelvic fractures admitted from 2008 to 2010. Patients were assigned into group 1 (dead) or 2 (survivors). We used Student's t, qui square and Fisher's tests for statistical analysis, considering p<0.05 as significant. Posteriorly, we compared predictors of death between both periods. RESULTS: Seventy-nine cases were included. Mean RTS, ISS and TRISS were, respectively, 6.44 + 2.22, 28.0 + 15.2 e 0.74 + 0.33. Nineteen patients died (24,0%). Main cause of death was hemorrhage (42,1%). Group 1 was characterized by (p<0.05) lower systolic blood pressure and Glasgow coma scale means on admission, higher heart rate, head AIS, extremity AIS and ISS means, as well as, higher frequency of severe head injuries and complex pelvic fractures. Comparing both periods, we notice that the anatomic and physiologic severity of injury increased (RTS and ISS means). Furthermore, there was a decrease in the impact of associated thoracic and abdominal injuries on the prognosis and an association of lethality with the presence of complex pelvic fractures. CONCLUSION: There were significant changes in the predictors of death between these two periods. The impact of thoracic and abdominal associated injures decreased while the importance of severe retroperitoneal hemorrhage increased. There was also an increase in trauma severity, which accounted for high lethality. PMID- 25295992 TI - Transoperative refusion: a simple and safe method in emergency surgery. AB - The objective is to reinforce the importance of blood reinfusion as a cheap, safe and simple method, which can be used in small hospitals, especially those in which there is no blood bank. Moreover, even with the use of devices that perform the collection and filtration of blood, more recent studies show that the cost benefit ratio is much better when autologous transfusion is compared with blood transfusions, even when there is injury to hollow viscera and blood contamination. It is known that the allogeneic blood transfusion carries a number of risks to patients, among them are the coagulation disorders mediated by excess enzymes in the conserved blood, and deficiency in clotting factors, mainly the Factor V, the proacelerin. Another factor would be the risk of contamination with still unknown pathogens or that are not investigated during screening for selection of donors, such as the West Nile Fever and Creutzfeldt-Jacob, better known as "Mad Cow" disease. Comparing both methods, we conclude that blood autotransfusion has numerous advantages over heterologous transfusion, even in large hospitals. We are not against blood transfusions, just do not agree that the patient's own blood is discarded without making sure there will be enough blood in stock to get him out of the hemorrhagic shock. PMID- 25295993 TI - Trauma leagues: an alternative way to teach trauma surgery to medical students. AB - OBJECTIVE: to compare the knowledge of medical students between those who are members of the Trauma League (TL) and those from a non-Trauma League (NTL) group of the Federal University of Espirito Santo (UFES). METHODS: cross-sectional, analytical and descriptive study. Two knowledge tests, with 30 questions each, were applied to students from 3rd to 12th period, randomly selecting five students per period, with 50 students in the TL group and 50 in NTL. The questionnaire topics were: pre-hospital care, the mnemonic ABCDE trauma sequence, advanced trauma and imaging. The students' performances were evaluated by graduation-period group: basic (3rd-5th period), intermediary/clinical (6th-8th) and internship (9th-12th). RESULTS: in the first test the average accuracy of the TL group was 20.64 +/- 3.17, while for the NTL group, it was 14.76 +/- 5.28 (p<0.005). In the second test the average accuracy for the TL group was 21.52 +/- 3.64, while for the NTL group, the average was 15.36 +/- 29.5 (p<0.005). When divided into graduation periods, it was observed that the TL group showed a higher average across all three groups (p<0.05) in both tests. CONCLUSION: the students who attended the academic league activities have greater knowledge of the issues that are considered relevant to patient trauma care. In all periods of undergraduate academic training, the TL group had greater knowledge of the subject than the NTL group. PMID- 25295994 TI - Plant sunscreens in the UV-B: ultraviolet spectroscopy of jet-cooled sinapoyl malate, sinapic acid, and sinapate ester derivatives. AB - Ultraviolet spectroscopy of sinapoyl malate, an essential UV-B screening agent in plants, was carried out in the cold, isolated environment of a supersonic expansion to explore its intrinsic UV spectral properties in detail. Despite these conditions, sinapoyl malate displays anomalous spectral broadening extending well over 1000 cm(-1) in the UV-B region, presenting the tantalizing prospect that nature's selection of UV-B sunscreen is based in part on the inherent quantum mechanical features of its excited states. Jet-cooling provides an ideal setting in which to explore this topic, where complications from intermolecular interactions are eliminated. In order to better understand the structural causes of this behavior, the UV spectroscopy of a series of sinapate esters was undertaken and compared with ab initio calculations, starting with the simplest sinapate chromophore sinapic acid, and building up the ester side chain to sinapoyl malate. This "deconstruction" approach provided insight into the active mechanism intrinsic to sinapoyl malate, which is tentatively attributed to mixing of the bright V ((1)pipi*) state with an adiabatically lower (1)npi* state which, according to calculations, shows unique charge-transfer characteristics brought on by the electron-rich malate side chain. All members of the series absorb strongly in the UV-B region, but significant differences emerge in the appearance of the spectrum among the series, with derivatives most closely associated with sinapoyl malate showing characteristic broadening even under jet cooled conditions. The long vibronic progressions, conformational distribution, and large oscillator strength of the V (pipi*) transition in sinapates makes them ideal candidates for their role as UV-B screening agents in plants. PMID- 25295996 TI - Cyclic GMP-AMP displays mucosal adjuvant activity in mice. AB - The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP) after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice. A characteristic of the cGAMP-induced immune response is the slightly reduced induction of interleukin-17 as a hallmark of Th17 activity--a distinct feature that is not observed with other cyclic di-nucleotide adjuvants. We further characterize the innate immune stimulation activity in vitro on murine bone marrow-derived dendritic cells and human dendritic cells. The observed results suggest the consideration of cGAMP as a candidate mucosal adjuvant for human vaccines. PMID- 25295997 TI - Comorbidity of ADHD and subsequent bipolar disorder among adolescents and young adults with major depression: a nationwide longitudinal study. AB - OBJECTIVES: Previous studies have found that attention-deficit hyperactivity disorder (ADHD) in childhood and adolescence is associated with an increased risk of major depression and bipolar disorder in later life. However, the effect of ADHD comorbidity on the diagnostic conversion to bipolar disorder among patients with major depression is still uncertain. METHODS: Using the Taiwan National Health Insurance Research Database, 58,023 subjects < 30 years of age who had major depression with (n = 1,193) or without (n = 56,830) ADHD comorbidity between the years 2000 and 2008 were enrolled in our study. Subjects who developed bipolar disorder during the follow-up to the end of 2011 were identified. RESULTS: Adolescents and young adults who had major depression with ADHD comorbidity had an increased incidence of subsequent bipolar disorder (18.9% versus 11.2%, p < 0.001) compared to those without ADHD. Cox regression analysis showed that ADHD comorbidity was an independent risk factor (hazard ratio = 1.50, 95% confidence interval 1.30-1.72) predicting subsequent bipolar disorder among those with major depression, adjusting for demographic data and psychiatric comorbidities. CONCLUSIONS: Patients with comorbid diagnoses of major depression and ADHD had an increased risk of diagnostic conversion to bipolar disorder compared to those who had major depression alone. Further studies would be required to validate this finding and to investigate the possible underlying mechanisms. PMID- 25295998 TI - Thymoma-associated lymphocytosis in a dog. AB - A 9-year-old female spayed English Springer Spaniel was evaluated for a cranial mediastinal mass and lymphocytosis. Flow cytometric immunophenotyping of peripheral blood lymphocytes revealed 97% as CD3 positive, confirming a T-cell lineage. Additionally, T-cell subset assessment showed 53.2% to be double negative T-lymphocytes, expressing neither CD4 nor CD8 surface markers. The number of double-negative lymphocytes in circulation coincided with the number of T-cell receptor (TCR) gammadelta-expressing T-cells in circulation. Molecular T cell clonality analysis of TCR Gamma (TCRG) gene rearrangement showed a polyclonal expansion of T-lymphocytes. Histopathology confirmed the mass to be a thymoma, supporting the diagnosis of thymoma-associated T-cell lymphocytosis. Resolution of the lymphocytosis after removal of the thymoma provided further evidence for this diagnosis. To the authors' knowledge, this case is only the second report of thymoma-associated peripheral lymphocytosis in the veterinary literature, and is the first to report a confirmed thymoma-associated peripheral gammadelta T-cell lymphocytosis in a dog. PMID- 25296000 TI - Direct quantification of loop interaction and pi-pi stacking for G-quadruplex stability at the submolecular level. AB - The well-demonstrated biological functions of DNA G-quadruplex inside cells call for small molecules that can modulate these activities by interacting with G quadruplexes. However, the paucity of the understanding of the G-quadruplex stability contributed from submolecular elements, such as loops and tetraguanine (G) planes (or G-quartets), has hindered the development of small-molecule binders. Assisted by click chemistry, herein, we attached pulling handles via two modified guanines in each of the three G-quartets in human telomeric G quadruplex. Mechanical unfolding using these handles revealed that the loop interaction contributed more to the G-quadruplex stability than the stacking of G quartets. This result was further confirmed by the binding of stacking ligands, such as telomestatin derivatives, which led to similar mechanical stability for all three G-quartets by significant reduction of loop interactions for the top and bottom G-quartets. The direct comparison of loop interaction and G-quartet stacking in G-quadruplex provides unprecedented insights for the design of more efficient G-quadruplex-interacting molecules. Compared to traditional experiments, in which mutations are employed to elucidate the roles of specific residues in a biological molecule, our submolecular dissection offers a complementary approach to evaluate individual domains inside a molecule with fewer disturbances to the native structure. PMID- 25295995 TI - Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation. AB - Acute respiratory distress syndrome (ARDS) is a common and often fatal inflammatory lung condition without effective targeted therapies. Regulatory T cells (Tregs) resolve lung inflammation, but mechanisms that enhance Tregs to promote resolution of established damage remain unknown. DNA demethylation at the forkhead box protein 3 (Foxp3) locus and other key Treg loci typify the Treg lineage. To test how dynamic DNA demethylation affects lung injury resolution, we administered the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) to wild-type (WT) mice beginning 24 hours after intratracheal LPS-induced lung injury. Mice that received DAC exhibited accelerated resolution of their injury. Lung CD4(+)CD25(hi)Foxp3(+) Tregs from DAC-treated WT mice increased in number and displayed enhanced Foxp3 expression, activation state, suppressive phenotype, and proliferative capacity. Lymphocyte-deficient recombinase activating gene-1 null mice and Treg-depleted (diphtheria toxin-treated Foxp3(DTR)) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 * 10(5) DAC treated, but not vehicle-treated, exogenous Tregs rescued Treg-deficient mice from ongoing lung inflammation. In addition, in WT mice with influenza-induced lung inflammation, DAC rescue treatment facilitated recovery of their injury and promoted an increase in lung Treg number. Thus, DNA methyltransferase inhibition, at least in part, augments Treg number and function to accelerate repair of experimental lung injury. Epigenetic pathways represent novel manipulable targets for the treatment of ARDS. PMID- 25296001 TI - Theoretical study of solvent effects on the ground and low-lying excited free energy surfaces of a push-pull substituted azobenzene. AB - The ground and low-lying excited free energy surfaces of 4-amino-4'-cyano azobenzene, a molecule that has been proposed as building block for chiroptical switches, are studied in gas phase and a variety of solvents (benzene, chloroform, acetone, and water). Solvent effects on the absorption and emission spectra and on the cis-trans thermal and photo isomerizations are analyzed using two levels of calculation: TD-DFT and CASPT2/CASSCF. The solvent effects are introduced using a polarizable continuum model and a QM/MM method, which permits one to highlight the role played by specific interactions. We found that, in gas phase and in agreement with the results found for other azobenzenes, the thermal cis-trans isomerization follows a rotation-assisted inversion mechanism where the inversion angle must reach values close to 180 degrees but where the rotation angle can take almost any value. On the contrary, in polar solvents the mechanism is controlled by the rotation of the CN?NC angle. The change in the mechanism is mainly related to a better solvation of the nitrogen atoms of the azo group in the rotational transition state. The photoisomerization follows a rotational pathway both in gas phase and in polar and nonpolar solvents. The solvent introduces only small modifications in the npi* free energy surface (S1), but it has a larger effect on the pipi* surface (S2) that, in polar solvents, gets closer to S1. In fact, the S2 band of the absorption spectrum is red-shifted 0.27 eV for the trans isomer and 0.17 eV for the cis. In the emission spectrum the trend is similar: only S2 is appreciably affected by the solvent, but in this case a blue shift is found. PMID- 25296002 TI - Cr(VI) reduction and Cr(III) immobilization by Acinetobacter sp. HK-1 with the assistance of a novel quinone/graphene oxide composite. AB - Cr(VI) biotreatment has attracted a substantial amount of interest due to its cost effectiveness and environmental friendliness. However, the slow Cr(VI) bioreduction rate and the formed organo-Cr(III) in solution are bottlenecks for biotechnology application. In this study, a novel strain, Acinetobacter sp. HK-1, capable of reducing Cr(VI) and immobilizing Cr(III) was isolated. Under optimal conditions, the Cr(VI) reduction rate could reach 3.82 mg h(-1) g cell(-1). To improve the Cr(VI) reduction rate, two quinone/graphene oxide composites (Q-GOs) were first prepared via a one-step covalent chemical reaction. The results showed that 2-amino-3-chloro-1,4-naphthoquinone-GO (NQ-GO) exhibited a better catalytic performance in Cr(VI) reduction compared to 2-aminoanthraquinone-GO. Specifically, in the presence of 50 mg L(-1) NQ-GO, a Cr(VI) removal rate of 190 mg h(-1) g cell(-1), which was the highest rate obtained, was achieved. The increased Cr(VI) reduction rate is mainly the result of NQ-GO significantly increasing the Cr(VI) reduction activity of cell membrane proteins containing dominant Cr(VI) reductases. X-ray photoelectron spectroscopy analysis found that Cr(VI) was reduced to insoluble Cr(III), which was immobilized by glycolipids secreted by strain HK-1. These findings indicate that the application of strain HK-1 and NQ-GO is a promising strategy for enhancing the treatment of Cr(VI) containing wastewater. PMID- 25296004 TI - Diversity in older people's mental health services: black and minority ethnic groups or the universality of the rainbow? PMID- 25296003 TI - Spectroscopic and atomic force studies of the functionalisation of carbon surfaces: new insights into the role of the surface topography and specific chemical states. AB - The utility of carbon materials in applications as diverse as drug delivery and photocatalysis is often undermined by the complexity of their surface chemistry; different sources of carbon give rise to a varied mixture of functional groups and hence different properties. Considerable efforts have been made to identify specific groups at these surfaces and elucidate the complex interactions that take place but even on materials such as graphene and carbon nanotubes there remains uncertainty about the nature of the components present and their role in the nucleation of other functional materials at the surface. The present study uses highly ordered pyrolytic graphite (HOPG) as a model on which the fundamental properties of specific functional groups and their interactions with deposited nanoparticles can be characterised. We have shown that treatment of HOPG surfaces with low concentrations of hydrochloric acid results in significant topographic changes to the surface and a low concentration of oxygen containing species. From selective derivatization and a comparison of their XP spectra, the latter can be unambiguously identified as surface hydroxyls. DFT calculations have shown that these groups are stable in close proximity to each other. Heating to 573 K leads to conversion of the hydroxyls to mixture of two states, one of which is identified as a ketone whilst the other is proposed to be an ether. Gold deposition on the surface from aqueous solutions of chloroauric acid is shown to be strongly influenced by the nature of the oxygen species present. PMID- 25296005 TI - [Epidemiology of cysticercosis and neurocysticercosis]. AB - Within the genus Taenia, three species are human parasites: T. solium, T. saginata and a new uncommon species, T. asiatica, described recently in Asia. T. saginata and T. solium live as adult tapeworms in human intestines, where they cause taeniasis. T. saginata is widely present worldwide, in all regions where cattle are bred. T. solium is endemic in many countries where livestock and consumption of pigs are common. Cattle and pigs become infected by ingesting eggs emitted by humans into the environment and serve as the respective intermediate hosts of these helminths and host larval forms, or metacestodes or cysticerci. Cysticerci develop into adult worms in the human intestines after a person has eaten contaminated raw or undercooked meat. In the T. solium, eggs are also human contaminants. Humans, like swine, can develop cysticercosis after ingesting eggs with water or contaminated food, or via dirty hands. The clinical manifestations of cysticercosis are highly variable both in kind and in severity. The period between initial infection and the onset of symptoms can also vary. The clinical expression of cysticercosis is generally dependent on the number, size and location of the cysts, as well as the host immune response to the parasite. The preferred locations are the muscles, subcutaneous tissues, central nervous system (CNS), and eyes. Subcutaneous and muscular forms are often asymptomatic. Severe cysticercosis is due to larvae located in human CNS - neurocysticercosis. The World Health Organization (WHO) lists neurocysticercosis as a neglected tropical disease. It estimates that about 50 million people worldwide have neurocysticercosis in the world and that it causes about 50,000 deaths each year. Its most frequent clinical manifestations are seizures, intracranial hypertension, neurological deficits, and sometimes psychiatric manifestations. It is also responsible for more than 50% of the cases of late-onset epilepsy in developing countries. The T. solium taeniasis/cysticercosis complex is endemic in many developing countries in sub-Saharan Africa, Latin America, and Asia. Although T. solium had virtually disappeared in developed countries due to industrialization, improved methods of husbandry, and health checks, cysticercosis and neurocysticercosis are diagnosed anew in North America, Europe and Australia due to increased immigration from endemic areas. Cysticercosis is considered an eradicable disease. Although theoretically feasible, this concept has been replaced by projects to control and reduce the impact of cysticercosis on human health (through mass treatment of people, veterinary control of pigs, improved farming techniques, and health education). PMID- 25296007 TI - Trichiconins A-C, limonoids with new carbon skeletons from Trichilia connaroides. AB - Three limonoids, trichiconin A (1) possessing a new carbon skeleton of a rearranged A,B-ring system and trichiconins B (2) and C (3) featuring an unprecedented A,B,D-seco skeleton, were isolated from the twigs of Trichilia connaroides. The carbon scaffold of trichiconin A is designated as trichiconane. Their structures with absolute stereochemistry were determined by spectroscopic data, X-ray crystallography, and CD analysis. Compounds 2 and 3 showed modest anti-HIV activities. PMID- 25296008 TI - Free-standing magnetic nanopillars for 3D nanomagnet logic. AB - Nanomagnet logic (NML) is a relatively new computation technology that uses arrays of shape-controlled nanomagnets to enable digital processing. Currently, conventional resist-based lithographic processes limit the design of NML circuitry to planar nanostructures with homogeneous thicknesses. Here, we demonstrate the focused electron beam induced deposition of Fe-based nanomaterial for magnetic in-plane nanowires and out-of-plane nanopillars. Three-dimensional (3D) NML was achieved based on the magnetic coupling between nanowires and nanopillars in a 3D array. Additionally, the same Fe-based nanomaterial was used to produce tilt-corrected high-aspect-ratio probes for the accurate magnetic force microscopy (MFM) analysis of the fabricated 3D NML gate arrays. The interpretation of the MFM measurements was supported by magnetic simulations using the Object Oriented MicroMagnetic Framework. Introducing vertical out-of plane nanopillars not only increases the packing density of 3D NML but also introduces an extra magnetic degree of freedom, offering a new approach to input/output and processing functionalities in nanomagnetic computing. PMID- 25296009 TI - Photocurrent induced by conducting channels of hole transporting layer to adjacent photoactive perovskite sensitized TiO2 thin film: solar cell paradigm. AB - A high performance perovskite solar cell was fabricated using the distinguished morphology of polyaniline nanoparticles (PANI-NPs) as an efficient hole transporting layer (HTL) with methylammonium lead iodide perovskite (CH3NH3PbI3) as sensitizer. PANI-NPs were simply synthesized by the oxidative chemical polymerization of aniline monomer at 0-5 degrees C. A reasonable solar-to electricity conversion efficiency of ~6.29% with a high short circuit current (JSC) of ~17.97 mA/cm(2) and open circuit voltage (VOC) of ~0.877 V were accomplished by Ag/PANI-NPs/CH3NH3PbI3/mp-anatase-TiO2/bl-TiO2/FTO perovskite solar cell. The transient photocurrent and photovoltage studies revealed that the fabricated solar cell showed better charge transport time, diffusion coefficient, diffusion length, and charge collection efficiency. Herein, the use of PANI-NPs as the HTL improved the charge carrier generation and the charge collection efficiency of the fabricated solar cell. PMID- 25296010 TI - Allometric modelling of peak oxygen uptake in male soccer players of 8-18 years of age. AB - BACKGROUND: Peak oxygen uptake (VO2peak) is routinely scaled as mL O2 per kilogram body mass despite theoretical and statistical limitations of using ratios. AIM: To examine the contribution of maturity status and body size descriptors to age-associated inter-individual variability in VO2peak and to present static allometric models to normalize VO2peak in male youth soccer players. SUBJECTS AND METHODS: Total body and estimates of total and regional lean mass were measured with dual energy X-ray absorptiometry in a cross sectional sample of Portuguese male soccer players. The sample was divided into three age groups for analysis: 8-12 years, 13-15 years and 16-18 years. VO2peak was estimated using an incremental maximal exercise test on a motorized treadmill. Static allometric models were used to normalize VO2peak. RESULTS: The independent variables with the best statistical fit explained 72% in the younger group (lean body mass: k = 1.07), 52% in mid-adolescent players (lean body mass: k = 0.93) and 31% in the older group (body mass: k = 0.51) of variance in VO2peak. The inclusion of the exponential term pubertal status marginally increased the explained variance in VO2peak (adjusted R(2 )= 36-75%) and provided statistical adjustments to the size descriptors coefficients. CONCLUSION: The allometric coefficients and exponents evidenced the varying inter-relationship among size descriptors and maturity status with aerobic fitness from early to late-adolescence. Lean body mass, lean lower limbs mass and body mass combined with pubertal status explain most of the inter-individual variability in VO2peak among youth soccer players. PMID- 25296012 TI - Infection with murine norovirus 4 does not alter Helicobacter-induced inflammatory bowel disease in Il10(-/-) mice. AB - Infection of laboratory mice with murine noroviruses (MNV) is widely prevalent. MNV alters various mouse models of disease, including the Helicobacter bilis induced mouse model of inflammatory bowel disease (IBD) in Mdr1a(--) mice. To further characterize the effect of MNV on IBD, we used mice deficient in the immunoregulatory cytokine IL10 (Il10(-/-) mice). In vitro infection of Il10(-/-) bone marrow-derived macrophages (BMDM) with MNV4 cocultured with H. bilis antigens increased the gene expression of the proinflammatory cytokines IL1beta, IL6, and TNFalpha as compared with that of BMDM cultured with H. bilis antigens only. Therefore, to test the hypothesis that MNV4 infection increases inflammation and alters disease phenotype in H. bilis-infected Il10(-/-) mice, we compared the amount and extent of inflammation in Il10(-/-) mice coinfected with H. bilis and MNV4 with those of mice singly infected with H. bilis. IBD scores, incidence of IBD, or frequency of severe IBD did not differ between mice coinfected with H. bilis and MNV4 and those singly infected with H. bilis. Mice infected with MNV4 only had no appreciable IBD, comparable to uninfected mice. Our findings suggest that, unlike in Mdr1a(-/-) mice, the presence of MNV4 in Il10(-/-) mouse colonies is unlikely to affect the IBD phenotype in a Helicobacter-induced model. However, because MNV4 altered cytokine expression in vitro, our results highlight the importance of determining the potential influence of MNV on mouse models of inflammatory disease, given that MNV has a tropism for macrophages and dendritic cells and that infection is widely prevalent. PMID- 25296011 TI - Electrochemical techniques for subsecond neurotransmitter detection in live rodents. AB - Alterations in neurotransmission have been implicated in numerous neurodegenerative and neuropsychiatric disorders, including Alzheimer disease, Parkinson disease, epilepsy, and schizophrenia. Unfortunately, few techniques support the measurement of real-time changes in neurotransmitter levels over multiple days, as is essential for ethologic and pharmacodynamic testing. Microdialysis is commonly used for these research paradigms, but its poor temporal and spatial resolution make this technique inadequate for measuring the rapid dynamics (milliseconds to seconds) of fast signaling neurotransmitters, such as glutamate and acetylcholine. Enzymatic microelectrode arrays (biosensors) coupled with electrochemical recording techniques have demonstrated fast temporal resolution (less than 1 s), excellent spatial resolution (micron-scale), low detection limits (<=200 nM), and minimal damage (50 to 100 MUm) to surrounding brain tissue. Here we discuss the benefits, methods, and animal welfare considerations of using platinum microelectrodes on a ceramic substrate for enzyme-based electrochemical recording techniques for real-time in vivo neurotransmitter recordings in both anesthetized and awake, freely moving rodents. PMID- 25296013 TI - Use of in ovo chorioallantoic membrane engraftment to culture testes from neonatal mice. AB - Many attempts have been made to culture germ cells in vitro by mimicking their development in vivo. The objective of this study was to establish an alternative method of xenotransplantation by developing a new approach for the rapid induction of spermatogenesis by using the chorioallantoic membrane of developing chicken embryos. Fertilized chicken eggs were incubated for 7 d, after which a small window was cut into the shell of the egg. We then transplanted testes from 7- to 8-d-old B6D2F1 mice onto the vessels of the chorioallantoic membrane and incubated them at 35.0 degrees C for 14 d or 37.5 degrees C for 12 d. After this in ovo CAM (iCAM) culture, the survival rates of the eggs and testes were assessed histologically and immunohistologically. The transplanted testes in the chicken embryos that survived were supported by the CAM, with an associated chronic vascularization response. The testes cultured at 35.0 degrees C had lower rates of generation and higher rates of death than did those cultured at 37.5 degrees C. Histologic examination of the testes cultured at 37.5 degrees C revealed the presence of spermatogonia and primary spermatocyte-like germ cells in the seminiferous tubules. The number of cells positive for synaptonemal complex protein 3 in the seminiferous tubules was significantly higher than that in the noniCAM-cultured testes from control mice. These results suggest that iCAM culturing of neonatal donor testis induces androcyte development. This method could be the foundation for a method that would enable in vitro spermatogenesis. PMID- 25296014 TI - Effects of buprenorphine and estrous cycle in a murine model of cecal ligation and puncture. AB - The effect of opioids on the immunopathology of sepsis models in mice has been controversial. In previous work, we showed that mortality and various inflammatory parameters did not differ between female mice given saline or buprenorphine after cecal ligation and puncture. To investigate further, we hypothesized that buprenorphine would not affect outcomes of sepsis at any stage of estrous. Female mice were allocated into 4 groups (n = 20 per group) according to stage of estrous. Mice then underwent cecal ligation and puncture and received either buprenorphine or saline. In 3-wk survival studies, overall survival did not differ between buprenorphine- and saline-treated mice. When mice were stratified according to stage of estrous, survival did not vary among saline treated groups but was lower in buprenorphine-treated mice in metestrus compared with proestrus. To investigate inflammation as a potential mechanism for survival, we measured cell counts and cytokine levels in the peripheral blood and peritoneal lavage fluid at 12 and 24 h after cecal ligation and puncture. At 24 h, buprenorphine-treated mice in proestrus had more circulating neutrophils and monocytes than did saline-treated mice in proestrus and more circulating WBC than did mice in any other stage with or without buprenorphine. Our current results suggest that the effects of buprenorphine on a 50% survival model of sepsis in BALB/c female mice are minimal overall but that the stage of estrous has various effects in this model. Investigators should consider the effects of buprenorphine and estrous cycle when using female mice in sepsis research. PMID- 25296015 TI - Behavioral perturbation and sleep in healthy and virus-infected inbred mice. AB - Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that has been studied extensively in terms of host immune responses to herpesviruses during acute infection, latency, and reactivation from latency. Although herpesvirus infections in people can be associated with fatigue and excessive sleepiness during both acute and latent infection, MuGHV has not been assessed extensively as a model for studying the behavioral consequences of chronic latent herpesvirus infections. To assess MuGHV infection as a model for evaluating fatigue and assessing potential mechanisms that underlie the exacerbation of fatigue during chronic viral disease, we evaluated sleep, temperature, and activity after exposure of healthy and latently MuGHV-infected mice to sleep fragmentation and social interaction. Neither treatment nor infection significantly affected temperature. However, at some time points, latently infected mice that underwent sleep fragmentation had less locomotor activity and more slow-wave sleep than did mice exposed to social interaction. In addition, delta-wave amplitude during slow-wave sleep was lower in infected mice exposed to sleep fragmentation compared with uninfected mice exposed to the same treatment. Both reduced locomotor activity and increased time asleep could indicate fatigue in infected mice after sleep fragmentation; reduced delta-wave amplitude during slow-wave sleep indicates a light plane of sleep from which subjects would be aroused easily. Identifying the mechanisms that underlie sleep responses of mice with chronic latent MuGHV infection may increase our understanding of fatigue during infec- tions and eventually contribute to improving the quality of life for people with chronic viral infections. PMID- 25296016 TI - Novel cuff design to facilitate anastomosis of small vessels during cervical heterotopic heart transplantation in rats. AB - Cervical heterotopic heart transplantation in rodents is a useful tool for studying transplantation immunology. However, end-to-end anastomosis of small diameter vessels by using standard microsurgical technique is technically difficult and can require prolonged graft ischemia. A novel cuff system was designed from polyethylene tubing to allow anastomosis of vessels with internal luminal diameters of 0.3 to 0.9 mm. Key features include a spring-like adjustable lumen to facilitate vessel eversion, a barb to hold vessel ends in place after eversion, and a handling system that allows easy manipulation and stabilization of cuffs by a single operator. After a training period, a single operator performed a series of 8 transplants in which the mean warm ischemic time of grafts was 8.5 +/- 2.9 min. Here we provide a detailed description of how to construct and perform end-to-end vessel anastomosis by using our novel cuff system. The discussion of the technique is supplemented with tips learned during the process of developing a reliable experimental model. PMID- 25296017 TI - Spontaneous epithelioid hemangiosarcoma in a rhesus monkey (Macaca mulatta). AB - Epithelioid hemangiosarcoma is a rare malignant endothelial neoplasia with a unique, predominantly epithelioid morphology. A 4-y-old rhesus monkey from our laboratory had multiple neoplastic nodules in a digit, limb skin, hindlimb muscle, and visceral organs including lung, heart, and brain. The nodules were composed of pleomorphic, polygonal, epithelioid, neoplastic cells that were arranged in sheets, nests, and cords and supported by variably dense fibrovascular connective tissue. The morphologic features of this tumor were predominantly epithelioid. However, some regions contained cystic spaces, clefts, and channel-like structures, all of which were lined with morphologically distinct neoplastic endothelial cells. These neoplastic cells, with or without epithelioid morphology, were positive immunohistochemically for CD31, factor VIII related antigen, and vimentin. The presence of multiple metastatic nodules, high mitotic rate, and extensive Ki67-positive staining were consistent with malignancy. This report is the first description of epithelioid hemangiosarcoma in a rhesus monkey. PMID- 25296018 TI - Invasive ductular carcinoma in 2 rhesus macaques (Macaca mulatta). AB - In the United States, breast cancer is the most common malignancy among women, with an estimated lifetime incidence of approximately 12% in American women. Invasive ductal carcinoma is the most common form of breast cancer in women, accounting for approximately 60% of all breast carcinomas. Prognostic markers are used to assess aggressiveness, invasiveness, and extent of spread of a neoplasm and thus may be correlated with patient survival. Immunohistochemistry is currently widely used for this purpose, with a variety of prognostication markers available. Classic markers for breast cancer in women include estrogen and progesterone receptor steroid hormone proteins and human epidermal growth factor receptor 2. Many additional markers have been used in diagnosis and prognostication, including p53, p63, and E-cadherin and cell proliferation markers such as Ki67. Despite an estimated lifetime incidence of approximately 6.1%, naturally occurring mammary neoplasms in nonhuman primates are uncommonly reported, with only sporadic references over the past 75 y. The majority of reported tumors occur in rhesus macaques, although this prevalence has been suggested to be a consequence of their high frequency of usage in biomedical research. Here we present 2 cases of mammary carcinoma in adult female intact rhesus macaques, with cytology, histopathology, and extensive immunohistochemical analysis. According to current classifications for human breast tumors, both tumors were classified as invasive ductal carcinoma. The prognostic value of immunohistochemical markers in human breast cancer and in reported cases in nonhuman primates is discussed. PMID- 25296019 TI - Chagas disease in 2 geriatric rhesus macaques (Macaca mulatta) housed in the Pacific Northwest. AB - Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in Latin America but also is found in the southern United States, particularly Texas and along the Gulf Coast. Typical clinical manifestations of Chagas disease are not well-characterized in rhesus macaques, but conduction abnormalities, myocarditis, and encephalitis and megaesophagus have been described. Here we report 2 cases of Chagas disease in rhesus macaques housed in the northwestern United States. The first case involved a geriatric male macaque with cardiomegaly, diagnosed as dilated cardiomyopathy on ultrasonographic examination. Postmortem findings included myocarditis as well as ganglioneuritis in the esophagus, stomach, and colon. The second case affected a geriatric female macaque experimentally infected with SIV. She was euthanized for a protocol-related time point. Microscopic examination revealed chronic myocarditis with amastigotes present in the cardiomyocytes, ganglioneuritis, and opportunistic infections attributed to her immunocompromised status. Banked serum samples from both macaques had positive titers for T. cruzi. T. cruzi DNA was amplified by conventional PCR from multiple tissues from both animals. Review of their histories revealed that both animals had been obtained from facilities in South Texas more than 12 y earlier. Given the long period of clinical latency, Chagas disease may be more prevalent in rhesus macaques than typically has been reported. T. cruzi infection should be considered for animals with unexplained cardiac or gastrointestinal pathology and that originated from areas known to have a high risk for disease transmission. PMID- 25296020 TI - Systematic review of the efficacy of cognitive-behavior therapy related treatments for victims of natural disasters: a worldwide problem. AB - Natural disasters can have devastating consequences. Each year, about 225 million people are victims of natural disasters worldwide, and up to 13,5 million of these people can develop post-traumatic stress disorder (PTSD) in the first or second year following the disaster. Cognitive-behavior therapy (CBT) is the first choice treatment for this disorder. In order to evaluate the efficacy of psychotherapeutic treatment based on cognitive-behavior therapy for people who developed post traumatic stress disorder after natural disasters we conducted a systematic search of published studies. We used the terms reported below in the electronic databases ISI Web of Science, PsycINFO, PubMed, PILOTS and Scopus with no restrictions of language or publication date. Articles that described randomized controlled, non-randomized controlled and non controlled studies on the efficacy of cognitive-behavior therapy for individuals diagnosed with post traumatic stress disorder after exposure to a natural disaster were eligible for inclusion. The studies were required to use a standardized measure of effectiveness before and after the intervention and have a group of patients who had used cognitive-behavior therapy as the only intervention. Our search identified 820 studies, and 11 were selected for this review. These 11 studies involved 742 subjects, 10 related to earthquakes and 1 to a hurricane. The cognitive-behavior therapy techniques used were various: 7 studies used exposure therapy, 2 studies used problem solving, and the only 2 studies with adolescents used techniques including reconstructions and reprocessing of the traumatic experience. As limitations, the search involved only five electronic databases, no experts in the field were consulted, and the heterogeneity of the findings made it impossible to perform a meta-analysis. The results suggest the efficacy of cognitive-behavior therapy, particularly exposure techniques, for the treatment of post-traumatic stress disorder after earthquakes. However, further studies with stronger methodologies, i.e. randomized-control trials and non randomized controlled trials, are needed. PMID- 25296021 TI - Nicotine stimulates nerve growth factor in lung fibroblasts through an NFkappaB dependent mechanism. AB - RATIONALE: Airway hyperresponsiveness (AHR) is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM) cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF) secretion into the environment. METHODS: Primary lung fibroblasts isolated from wild type and alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) deficient mice were treated with nicotine (50 ug/ml) in vitro for 72 hours. NGF levels were measured in culture media and in bronchoalveolar lavage (BAL) fluid from asthmatic, smoking and non-smoking subjects by ELISA. The role of the NFkappaB pathway in nicotine-induced NGF expression was investigated by measuring NFkappaB nuclear translocation, transcriptional activity, chromatin immunoprecipitation assays, and si-p65 NFkappaB knockdown. The ability of nicotine to stimulate a fibroblast-mediated, contractile ASM cell phenotype was confirmed by examining expression of contractile proteins in ASM cells cultured with fibroblast-conditioned media or BAL fluid. RESULTS: NGF levels were elevated in the bronchoalveolar lavage fluid of nicotine-exposed mice, current smokers, and asthmatic children. Nicotine increased NGF secretion in lung fibroblasts in vitro in a dose-dependent manner and stimulated NFkappaB nuclear translocation, p65 binding to the NGF promoter, and NFkappaB transcriptional activity. These responses were attenuated in alpha7 nAChR deficient fibroblasts and in wild type fibroblasts following NFkappaB inhibition. Nicotine-treated, fibroblast-conditioned media increased expression of contractile proteins in ASM cells. CONCLUSION: Nicotine stimulates NGF release by lung fibroblasts through alpha7 nAChR and NFkappaB dependent pathways. These novel findings suggest that the nicotine-alpha7 nAChR-NFkappaB- NGF axis may provide novel therapeutic targets to attenuate tobacco smoke-induced AHR. PMID- 25296022 TI - Flattop regulates basal body docking and positioning in mono- and multiciliated cells. AB - Planar cell polarity (PCP) regulates basal body (BB) docking and positioning during cilia formation, but the underlying mechanisms remain elusive. In this study, we investigate the uncharacterized gene Flattop (Fltp) that is transcriptionally activated during PCP acquisition in ciliated tissues. Fltp knock-out mice show BB docking and ciliogenesis defects in multiciliated lung cells. Furthermore, Fltp is necessary for kinocilium positioning in monociliated inner ear hair cells. In these cells, the core PCP molecule Dishevelled 2, the BB/spindle positioning protein Dlg3, and Fltp localize directly adjacent to the apical plasma membrane, physically interact and surround the BB at the interface of the microtubule and actin cytoskeleton. Dlg3 and Fltp knock-outs suggest that both cooperatively translate PCP cues for BB positioning in the inner ear. Taken together, the identification of novel BB/spindle positioning components as potential mediators of PCP signaling might have broader implications for other cell types, ciliary disease, and asymmetric cell division. PMID- 25296023 TI - Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes. PMID- 25296024 TI - Early patterning and specification of cardiac progenitors in gastrulating mesoderm. AB - Mammalian heart development requires precise allocation of cardiac progenitors. The existence of a multipotent progenitor for all anatomic and cellular components of the heart has been predicted but its identity and contribution to the two cardiac progenitor 'fields' has remained undefined. Here we show, using clonal genetic fate mapping, that Mesp1+ cells in gastrulating mesoderm are rapidly specified into committed cardiac precursors fated for distinct anatomic regions of the heart. We identify Smarcd3 as a marker of early specified cardiac precursors and identify within these precursors a compartment boundary at the future junction of the left and right ventricles that arises prior to morphogenesis. Our studies define the timing and hierarchy of cardiac progenitor specification and demonstrate that the cellular and anatomical fate of mesoderm derived cardiac cells is specified very early. These findings will be important to understand the basis of congenital heart defects and to derive cardiac regeneration strategies. PMID- 25296025 TI - Reduced mucosal associated invariant T-cells are associated with increased disease severity and Pseudomonas aeruginosa infection in cystic fibrosis. AB - BACKGROUND: Primary defects in host immune responses have been hypothesised to contribute towards an inability of subjects with cystic fibrosis (CF) to effectively clear pulmonary infections. Innate T-lymphocytes provide rapid pathogen-specific responses prior to the development of classical MHC class I and II restricted T-cell responses and are essential to the initial control of pulmonary infection. We aimed to examine the relationship between peripheral blood lymphocyte phenotype and clinical outcomes in adults with CF. METHODS: We studied 41 subjects with CF and 22, age matched, non-smoking healthy control subjects. Lymphocytes were extracted from peripheral blood samples and phenotyped by flow-cytometry. Lymphocyte phenotype was correlated with sputum microbiology and clinical parameters. RESULTS: In comparison to healthy control subjects, mucosal associated invariant T (MAIT)-lymphocytes were significantly reduced in the peripheral blood of subjects with CF (1.1% versus 2.0% of T-lymphocytes, P = 0.002). MAIT cell concentration was lowest in CF subjects infected with P. aeruginosa and in subjects receiving treatment for a pulmonary exacerbation. Furthermore a reduced MAIT cell concentration correlated with severity of lung disease. CONCLUSION: Reduced numbers of MAIT cells in subjects with CF were associated with P. aeruginosa pulmonary infection, pulmonary exacerbations and more severe lung disease. These findings provide the impetus for future studies examining the utility of MAIT cells in immunotherapies and vaccine development. Longitudinal studies of MAIT cells as biomarkers of CF pulmonary infection are awaited. PMID- 25296027 TI - Investigation of gold nanoparticle radiosensitization mechanisms using a free radical scavenger and protons of different energies. AB - Gold nanoparticles (GNPs) have been shown to sensitize cancer cells to x-ray radiation, particularly at kV energies where photoelectric interactions dominate and the high atomic number of gold makes a large difference to x-ray absorption. Protons have a high cross-section for gold at a large range of relevant clinical energies, and so potentially could be used with GNPs for increased therapeutic effect.Here, we investigate the contribution of secondary electron emission to cancer cell radiosensitization and investigate how this parameter is affected by proton energy and a free radical scavenger. We simulate the emission from a realistic cell phantom containing GNPs after traversal by protons and x-rays with different energies. We find that with a range of proton energies (1-250 MeV) there is a small increase in secondaries compared to a much larger increase with x-rays. Secondary electrons are known to produce toxic free radicals. Using a cancer cell line in vitro we find that a free radical scavenger has no protective effect on cells containing GNPs irradiated with 3 MeV protons, while it does protect against cells irradiated with x-rays. We conclude that GNP generated free radicals are a major cause of radiosensitization and that there is likely to be much less dose enhancement effect with clinical proton beams compared to x-rays. PMID- 25296026 TI - Self DNA from lymphocytes that have undergone activation-induced cell death enhances murine B cell proliferation and antibody production. AB - Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naive B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naive B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naive B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naive B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases. PMID- 25296028 TI - A new phenylpropanoid and a new isoflavone glycoside from Shenqi Fuzheng Injection. AB - A new phenylpropanoid and a new isoflavone glycoside were isolated from Shenqi Fuzheng Injection. Their structures were elucidated as (alphaS)-alpha-ethenyl-4 hydroxy-3-methoxy-benzenemethanol (1) and calycosin 7-O-[alpha-d-glucopyranosyl (1 -> 4)]-beta-d-glucopyranoside (2) by means of spectroscopic methods including UV, IR, HR-ESI-MS, and NMR. The absolute configurations of 1 and 2 were confirmed by quantum chemical calculation and acid hydrolysis. PMID- 25296029 TI - The role of the sedimentary regime in shaping the distribution of subtidal sandbank environments and the associated meiofaunal nematode communities: an example from the southern North Sea. AB - We combined sediment and faunal data to explore the role of the sedimentary regime in shaping the distribution of subtidal sandbank environments and the associated meiofaunal nematode communities at Broken Bank and Swarte Bank, in the southern North Sea. A variety of sediment transport processes occur in the area, differing in the frequency and magnitude of sediment mobility, and the continuum between erosion, translation and sediment accumulation. The seabed contained a variety of bedforms, including longitudinal furrows, and small to very large sandwaves. The bed sediments were dominated by fine and medium sands, with admixtures of silt and gravel. Based on sedimentary bedforms and grain size analysis, a total of 11 sedimentary facies were delineated, of which 8 were analysed in detail for their relationships with the meiofauna. The sedimentary facies fell clearly into groups of facies, respectively representing high, high moderate and moderate, and episodic sediment mobility. For those sedimentary facies where daily movement of sediments and bedforms occurred ('high' sediment mobility), the resulting spatially homogeneous environments were dominated by an impoverished nematode community comprising small deposit feeders and large predators. Resistance to sediment movement and the ability to exploit alternative food sources were prominent functional features of the successful colonisers. Those facies characterised by relatively infrequent sediment mobility ('episodic' and 'high-moderate and moderate' sediment mobility) comprised a heterogeneous suite of benthic habitats, containing taxonomically and functionally diverse assemblages of nematodes of various sizes, feeding types and reproductive potential. Faunal distribution patterns here indicated trade-offs between the resistance to sediment movement, environmental tolerance and competitive abilities. Our focus on diverse assemblages of organisms with high turnover times, inhabiting highly dynamic sedimentary environments, has revealed new animal-sediment relationships of relevance to pure and applied science. PMID- 25296030 TI - Novel nano-sized MR contrast agent mediates strong tumor contrast enhancement in an oncogene-driven breast cancer model. AB - The current study was carried out to test the potential of a new nanomaterial (Spago Pix) as a macromolecular magnetic MR contrast agent for tumor detection and to verify the presence of nanomaterial in tumor tissue. Spago Pix, synthesized by Spago Nanomedical AB, is a nanomaterial with a globular shape, an average hydrodynamic diameter of 5 nm, and a relaxivity (r1) of approximately 30 (mM Mn)-1 s-1 (60 MHz). The material consists of an organophosphosilane hydrogel with strongly chelated manganese (II) ions and a covalently attached PEG surface layer. In vivo MRI of the MMTV-PyMT breast cancer model was performed on a 3 T clinical scanner. Tissues were thereafter analyzed for manganese and silicon content using inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The presence of nanomaterial in tumor and muscle tissue was assessed using an anti-PEG monoclonal antibody. MR imaging of tumor-bearing mice (n = 7) showed a contrast enhancement factor of 1.8 (tumor versus muscle) at 30 minutes post administration. Contrast was retained and further increased 2-4 hours after administration. ICP-AES and immunohistochemistry confirmed selective accumulation of nanomaterial in tumor tissue. A blood pharmacokinetics analysis showed that the concentration of Spago Pix gradually decreased over the first hour, which was in good agreement with the time frame in which the accumulation in tumor occurred. In summary, we demonstrate that Spago Pix selectively enhances MR tumor contrast in a clinically relevant animal model. Based on the generally higher vascular leakiness in malignant compared to benign tissue lesions, Spago Pix has the potential to significantly improve cancer diagnosis and characterization by MRI. PMID- 25296031 TI - [Treatment of imported Plasmodium falciparum malaria: role of the combination of dihydroartemisinin and piperaquine]. AB - The dihydroartemisinin-piperaquine combination is an antimalarial agent newly available in Europe. It is an artemisinin-combined therapy (ACT) that has been used for more than 10 years in malaria-endemic areas and is recommended since 2010 by the WHO as a first-line treatment of uncomplicated Plasmodium falciparum malaria. In Europe, it has recently been authorized for the treatment of uncomplicated P. falciparum malaria in adults, children, and infants aged 6 months or older and weighing at least 5 kg. Its efficacy is similar to the combination of artemether and lumefantrine, and the regimen is easier. The tolerability profile is nearly the same as the other ACTs. Prolongation of the QT interval appears to be greater than with the artemether-lumefantrine combination in the first 48 hours of treatment, although no clinical consequences have been described. This side effect requires the use of electrocardiographic monitoring in some patients. A risk management plan has been set up by the manufacturer. PMID- 25296032 TI - Remembering the object you fear: brain potentials during recognition of spiders in spider-fearful individuals. AB - In the present study we investigated long-term memory for unpleasant, neutral and spider pictures in 15 spider-fearful and 15 non-fearful control individuals using behavioral and electrophysiological measures. During the initial (incidental) encoding, pictures were passively viewed in three separate blocks and were subsequently rated for valence and arousal. A recognition memory task was performed one week later in which old and new unpleasant, neutral and spider pictures were presented. Replicating previous results, we found enhanced memory performance and higher confidence ratings for unpleasant when compared to neutral materials in both animal fearful individuals and controls. When compared to controls high animal fearful individuals also showed a tendency towards better memory accuracy and significantly higher confidence during recognition of spider pictures, suggesting that memory of objects prompting specific fear is also facilitated in fearful individuals. In line, spider-fearful but not control participants responded with larger ERP positivity for correctly recognized old when compared to correctly rejected new spider pictures, thus showing the same effects in the neural signature of emotional memory for feared objects that were already discovered for other emotional materials. The increased fear memory for phobic materials observed in the present study in spider-fearful individuals might result in an enhanced fear response and reinforce negative beliefs aggravating anxiety symptomatology and hindering recovery. PMID- 25296033 TI - Mediastinal lymph node dissection versus mediastinal lymph node sampling for early stage non-small cell lung cancer: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the overall survival, local recurrence, distant metastasis, and complications of mediastinal lymph node dissection (MLND) versus mediastinal lymph node sampling (MLNS) in stage I-IIIA non-small cell lung cancer (NSCLC) patients. METHODS: A systematic search of published literature was conducted using the main databases (MEDLINE, PubMed, EMBASE, and Cochrane databases) to identify relevant randomized controlled trials that compared MLND vs. MLNS in NSCLC patients. Methodological quality of included randomized controlled trials was assessed according to the criteria from the Cochrane Handbook for Systematic Review of Interventions (Version 5.1.0). Meta-analysis was performed using The Cochrane Collaboration's Review Manager 5.3. The results of the meta-analysis were expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence interval (CI). RESULTS: We included results reported from six randomized controlled trials, with a total of 1,791 patients included in the primary meta-analysis. Compared to MLNS in NSCLC patients, there was no statistically significant difference in MLND on overall survival (HR = 0.77, 95% CI 0.55 to 1.08; P = 0.13). In addition, the results indicated that local recurrence rate (RR = 0.93, 95% CI 0.68 to 1.28; P = 0.67), distant metastasis rate (RR = 0.88, 95% CI 0.74 to 1.04; P = 0.15), and total complications rate (RR = 1.10, 95% CI 0.67 to 1.79; P = 0.72) were similar, no significant difference found between the two groups. CONCLUSIONS: Results for overall survival, local recurrence rate, and distant metastasis rate were similar between MLND and MLNS in early stage NSCLC patients. There was no evidence that MLND increased complications compared with MLNS. Whether or not MLND is superior to MLNS for stage II-IIIA remains to be determined. PMID- 25296034 TI - Factors influencing drug uptake during mass drug administration for control of lymphatic filariasis in rural and urban Tanzania. AB - BACKGROUND: In most countries of Sub-Saharan Africa, control of lymphatic filariasis (LF) is based on annual mass drug administration (MDA) with a combination of ivermectin and albendazole. Treatment coverages are however often suboptimal for programmes to reach the goal of transmission interruption within reasonable time. The present study aimed to identify predictors and barriers to individual drug uptake during MDA implementation by the National LF Elimination Programme in Tanzania. METHODS: A questionnaire based cross sectional household survey was carried out in two rural and two urban districts in Lindi and Morogoro regions shortly after the 2011 MDA. 3279 adults (>=15 years) were interviewed about personal characteristics, socio-economic status, MDA drug uptake among themselves and their children, reasons for taking/not taking drugs, and participation in previous MDA activities for LF control. FINDINGS: The overall drug uptake rate was 55.1% (range of 44.5-75.6% between districts). There was no overall major difference between children (54.8%) and adults (55.2%) or between females (54.9%) and males (55.8%), but the role of these and other predictors varied to some extent between study sites. Major overall predictors of drug uptake among the interviewed adults were increasing age and history of previous drug uptake. Being absent from home during drug distribution was the main reason for not taking the drugs (50.2%) followed by clinical contraindications to treatment (10.8%), missing household visits of drug distributors (10.6%), and households not being informed about the distribution (9.0%). CONCLUSION: Drug uptake relied more on easily modifiable provider-related factors than on individual perceptions and practices in the target population. Limited investments in appropriate timing, dissemination of accurate timing information to recipients and motivation of drug distributors to visit all households (repeatedly when residents are absent) are likely to have considerable potential for increasing drug uptake, in support of successful LF transmission elimination. PMID- 25296035 TI - Consumption of clarified grapefruit juice ameliorates high-fat diet induced insulin resistance and weight gain in mice. AB - To determine the metabolic effects of grapefruit juice consumption we established a model in which C57Bl/6 mice drank 25-50% sweetened GFJ, clarified of larger insoluble particles by centrifugation (cGFJ), ad libitum as their sole source of liquid or isocaloric and sweetened water. cGFJ and control groups consumed similar amounts of liquids and calories. Mice fed a high-fat diet and cGFJ experienced a 18.4% decrease in weight, a 13-17% decrease in fasting blood glucose, a three-fold decrease in fasting serum insulin, and a 38% decrease in liver triacylglycerol values, compared to controls. Mice fed a low-fat diet that drank cGFJ experienced a two-fold decrease in fasting insulin, but not the other outcomes observed with the high-fat diet. cGFJ consumption decreased blood glucose to a similar extent as the commonly used anti-diabetic drug metformin. Introduction of cGFJ after onset of diet-induced obesity also reduced weight and blood glucose. A bioactive compound in cGFJ, naringin, reduced blood glucose and improved insulin tolerance, but did not ameliorate weight gain. These data from a well-controlled animal study indicate that GFJ contains more than one health promoting neutraceutical, and warrant further studies of GFJ effects in the context of obesity and/or the western diet. PMID- 25296037 TI - The role of dark septate endophytic fungal isolates in the accumulation of cesium by chinese cabbage and tomato plants under contaminated environments. AB - Following the 2011 Fukushima Daiichi Nuclear Power Plant accident, the preservation of the food chain from radionuclides contamination has become of crucial importance. The potential of Dark septate endophytic fungi in the management of Cs accumulation in plants under contaminated environments was investigated using Chinese cabbage and tomato plants. Four endophytic fungal isolates of different species, i.e. Pseudosigmoidea ibarakiensis I.4-2-1, Veronaeopsis simplex Y34, Helminthosporium velutinum 41-1, and as yet unidentified taxon 312-6 were tested In Vitro in two levels of Cs (5ppm and 10ppm). On the plant growth, the inoculation of the selected DSEs to both Chinese cabbage and tomato resulted in an increased biomass of up to 82% and 122%, respectively compared to control (non-inoculated) plants. With regards to the Cs accumulation, it varied with the host plant considered. In Chinese cabbage, DSEs inoculation caused higher Cs accumulation in above ground plant parts, whereas in tomato, Cs accumulation decreased significantly with three of the isolates tested, i.e., V. simplex Y34, P. ibarakiensis I.4-2-1, and the as yet unidentified taxon 312-6 suggesting low-risk transfer on the above ground plants parts as a result of high and negative plant reactions rather than high and positive reactions as it is the case with Chinese cabbage. These results suggested that DSEs can be recommended for use with Chinese cabbage to enhance phytoremediation of Cs in surrounding contaminated areas. With tomato, DSEs can be recommended for decreasing the accumulation of Cs in plants under contaminated environments. PMID- 25296036 TI - Health risk assessment for air pollutants: alterations in lung and cardiac gene expression in mice exposed to Milano winter fine particulate matter (PM2.5). AB - Oxidative stress, pulmonary and systemic inflammation, endothelial cell dysfunction, atherosclerosis and cardiac autonomic dysfunction have been linked to urban particulate matter exposure. The chemical composition of airborne pollutants in Milano is similar to those of other European cities though with a higher PM2.5 fraction. Milano winter fine particles (PM2.5win) are characterized by the presence of nitrate, organic carbon fraction, with high amount of polycyclic aromatic hydrocarbons and elements such as Pb, Al, Zn, V, Fe, Cr and others, with a negligible endotoxin presence. In BALB/c mice, we examined, at biochemical and transcriptomic levels, the adverse effects of repeated Milano PM2.5win exposure in lung and heart. We found that ET-1, Hsp70, Cyp1A1, Cyp1B1 and Hsp-70, HO-1, MPO respectively increased within lung and heart of PM2.5win treated mice. The PM2.5win exposure had a strong impact on global gene expression of heart tissue (181 up-regulated and 178 down-regulated genes) but a lesser impact on lung tissue (14 up-regulated genes and 43 down-regulated genes). Focusing on modulated genes, in lung we found two- to three-fold changes of those genes related to polycyclic aromatic hydrocarbons exposure and calcium signalling. Within heart the most striking aspect is the twofold to threefold increase in collagen and laminin related genes as well as in genes involved in calcium signaling. The current study extends our previous findings, showing that repeated instillations of PM2.5win trigger systemic adverse effects. PM2.5win thus likely poses an acute threat primarily to susceptible people, such as the elderly and those with unrecognized coronary artery or structural heart disease. The study of genomic responses will improve understanding of disease mechanisms and enable future clinical testing of interventions against the toxic effects of air pollutant. PMID- 25296039 TI - The scientific impact of nations: journal placement and citation performance. AB - International collaboration is becoming increasingly important for the advancement of science. To gain a more precise understanding of how factors such as international collaboration influence publication success, we divide publication success into two categories: journal placement and citation performance. Analyzing all papers published between 1996 and 2012 in eight disciplines, we find that those with more countries in their affiliations performed better in both categories. Furthermore, specific countries vary in their effects both individually and in combination. Finally, we look at the relationship between national output (in papers published) and input (in citations received) over the 17 years, expanding upon prior depictions by also plotting an expected proportion of citations based on Journal Placement. Discrepancies between this expectation and the realized proportion of citations illuminate trends in performance, such as the decline of the Global North in response to rapidly developing countries, especially China. Yet, most countries' show little to no discrepancy, meaning that, in most cases, citation proportion can be predicted by Journal Placement alone. This reveals an extreme asymmetry between the opinions of a few reviewers and the degree to which paper acceptance and citation rates influence career advancement. PMID- 25296038 TI - SERPINA3K plays antioxidant roles in cultured pterygial epithelial cells through regulating ROS system. AB - We recently demonstrated that SERPINA3K, a serine proteinase inhibitor, has antioxidant activity in the cornea. Here we investigated the antioxidant effects of SERPINA3K on the pterygial, which is partially caused by oxidative stress in pathogenesis. The head part of primary pterygial tissue was dissected and then cultured in keratinocyte serum-free defined medium (KSFM). The cultured pterygial epithelial cells (PECs) were treated with SERPINA3K. The cell proliferation and migration of PECs were measured and analyzed. Western blot and quantitative real time polymerase chain reaction (PCR) assay were performed. It showed that SERPINA3K significantly suppressed the cell proliferation of PECs in a concentration-dependent manner, compared with cultured human conjunctival epithelial cells. SERPINA3K also inhibited the cell migration of PECs. Towards its underlying mechanism, SERPINA3K had antioxidant activities on the PECs by significantly inhibiting NADPH oxidase 4 (NOX4), which is an important enzyme of ROS generation, and by elevating the levels of key antioxidant factors of ROS: such as NAD(P)H dehydrogenase (quinone 1) (NQO1), NF-E2-related factor-2 (NRF2) and superoxide dismutases (SOD2). Meanwhile, SERPINA3K down-regulated the key effectors of Wnt signaling pathway: beta-catenin, nonphospho-beta-catenin, and low-density lipoprotein receptor-related protein 6 (LRP6). We provided novel evidence that SERPINA3K had inhibitory effects on pterygium and SERPINA3K played antioxidant role via regulating the ROS system and antioxidants. PMID- 25296040 TI - A theoretical study of ternary indole-cation-anion complexes. AB - The simultaneous interactions of an anion and a cation with a pi system were investigated by MP2 and M06-2X theoretical calculations. Indole was chosen as a model pi system for its relevance in biological environments. Two different orientations of the anion, interacting with the N-H and with the C-H groups of indole, were considered. The four cations (Na(+), NH4(+), C(NH2)3(+) and N(CH3)4(+)) and the four anions (Cl(-), NO3(-), HCOO(-) and BF4(-)) included in the study are of biological interest. The total interaction energy of the ternary complexes was calculated and separated into its two- and three-body components and all of them are further divided into their electrostatic, exchange, repulsion, polarization and dispersion contributions using the local molecular orbital-energy decomposition analysis (LMO-EDA) methodology. The binding energy of the indole-cation-anion complexes depends on both ions, with the cation having the strongest effect. The intense cation-anion attraction determines the geometric and energetic features in all ternary complexes. These structures, with both ions on the same side of the pi system, show an anti-cooperative interaction. However, the interaction is not only determined by electrostatics, but also the polarization contribution is important. Specific interactions like the one established between the anion and the N-H group of indole or the proton transfer between an acidic cation and a basic anion play a significant role in the energetics and the structure of particular complexes. The presence of the polar solvent as modelled with the polarizable continuum model (PCM) does not seem to have a significant effect on the geometry of the ternary complexes, but drastically weakens the interaction energy. Also, the strength of the interaction is reduced at a faster rate when the anion is pushed away, compared to the results obtained in the gas phase. The combination of PCM with the addition of one water molecule indicates that the PCM method properly reproduces the main energetic and geometrical changes, even at the quantitative level, but the explicit hydration allows refining the solvent effect and detecting cases that do not follow the general trend. PMID- 25296043 TI - A stitch (of primary care) in time. PMID- 25296044 TI - Hip fracture: the case for a funded national registry. PMID- 25296041 TI - Selective in vivo targeting of human liver tumors by optimized AAV3 vectors in a murine xenograft model. AB - Current challenges for recombinant adeno-associated virus (rAAV) vector-based cancer treatment include the low efficiency and the lack of specificity in vivo. rAAV serotype 3 (rAAV3) vectors have previously been shown to be ineffective in normal mouse tissues following systemic administration. In the present study, we report that rAAV3 vectors can efficiently target and transduce various human liver cancer cells in vivo. Elimination of specific surface-exposed serine and threonine residues on rAAV3 capsids results in further augmentation in the transduction efficiency of these vectors, without any change in the viral tropism and cellular receptor interactions. In addition, we have identified a potential chemotherapy drug, shikonin, as a multifunctional compound to inhibit liver tumor growth as well as to significantly enhance the efficacy of rAAV vector-based gene therapy in vivo. Furthermore, we also document that suppression of tumorigenesis in a human liver cancer xenograft model can be achieved through systemic administration of the optimized rAAV3 vectors carrying a therapeutic gene, and shikonin at a dose that does not lead to liver damage. Our research provides a novel means to achieve not only targeted delivery but also the potential for gene therapy of human liver cancer. PMID- 25296045 TI - Prevention and early detection in young children: challenges for policy and practice. PMID- 25296048 TI - Mental health reform: increased resources but limited gains. PMID- 25296049 TI - Ethical challenges for doctors working in immigration detention. PMID- 25296050 TI - Unrelieved pain: are we making progress? Shared education for general practitioners and specialists is the best way forward. PMID- 25296051 TI - Abortion and breast cancer risk for Australian women. PMID- 25296052 TI - New TGA warning label for use of NSAIDs in fluid-depleted children. PMID- 25296053 TI - Will current health reforms in south and east Asia improve equity? PMID- 25296054 TI - Will current health reforms in south and east Asia improve equity? In reply. PMID- 25296055 TI - Inappropriate use of dual energy absorptiometry body composition estimation. PMID- 25296056 TI - Multiple mini interview performance of repeat applicants to medical school admission. PMID- 25296057 TI - Time to end the ban on HIV-positive proceduralists and dentists. PMID- 25296058 TI - The benefits and harms of deprescribing. AB - Deprescribing is the process of trial withdrawal of inappropriate medications. Currently, the strongest evidence for benefit of deprescribing is from cohort and observational studies of withdrawal of specific medication classes that have shown better patient outcomes, mainly through resolution of adverse drug reactions. Additional potential benefits of deprescribing include reduced financial costs and improved adherence with other medications. The harms of ceasing medication use include adverse drug withdrawal reactions, pharmacokinetic and pharmacodynamic changes and return of the medical condition. These can be minimised with proper planning (ie, tapering), monitoring after withdrawal, and reinitiation of the medication if the condition returns. More evidence is needed regarding negative, non-reversible effects of ceasing use of certain classes of medication, such as acetylcholinesterase inhibitors. Cessation of use has not been studied for many medication classes, and large-scale randomised controlled trials of systematic deprescribing are required before the true benefits and harms can be known. PMID- 25296059 TI - First do no harm: a real need to deprescribe in older patients. AB - Inappropriate polypharmacy in older patients imposes a significant burden of decreased physical functioning, increased risk of falls, delirium and other geriatric syndromes, hospital admissions and death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed medications. Deprescribing is the process of tapering or stopping drugs, with the goal of minimising polypharmacy and improving outcomes. Barriers to deprescribing include underappreciation of the scale of polypharmacy-related harm by both patients and prescribers; multiple incentives to overprescribe; a narrow focus on lists of potentially inappropriate medications; reluctance of prescribers and patients to discontinue medication for fear of unfavourable sequelae; and uncertainty about effectiveness of strategies to reduce polypharmacy. Ways of countering such barriers comprise reframing the issue to one of highest quality patient-centred care; openly discussing benefit harm trade-offs with patients and assessing their willingness to consider deprescribing; targeting patients according to highest risk of adverse drug events; targeting drugs more likely to be non-beneficial; accessing field-tested discontinuation regimens for specific drugs; fostering shared education and training in deprescribing among all members of the health care team; and undertaking deprescribing over an extended time frame under the supervision of a single generalist clinician. PMID- 25296060 TI - Australia's treatment of refugee and asylum seeker children: the views of Australian paediatricians. AB - OBJECTIVE: Australia's response to refugees and people seeking asylum is a matter of national debate. We sought to determine the knowledge and attitudes of paediatricians about refugee and asylum seeker issues (both onshore and offshore). DESIGN, SETTING AND PARTICIPANTS: In November 2013, we emailed a questionnaire web link to all Australian general and community paediatricians registered with the Royal Australasian College of Physicians. MAIN OUTCOME MEASURES: Proportion of respondents by demographic characteristics using chi(2) and Fisher exact test (alpha = 0.05). RESULTS: There were 139 respondents (response rate, 40.5%). Respondents' characteristics were broadly representative of all Australian general paediatricians. Over 80% correctly used the term "asylum seeker" rather than "boat person" or "illegal immigrant" for children applying for protection. Over 80% agreed with the Australian Medical Association assertion that mandatory detention of children constitutes child abuse, and disagreed with offshore processing. Less than half knew which subgroups were eligible for Medicare or had had pre-departure HIV and tuberculosis screening tests; or that the average stay in refugee camps before settlement in Australia was more than 10 years. Only about 60% knew that the Minister for Immigration and Citizenship was the legal guardian of detained unaccompanied minors. One in eight knew about the Medicare eligibility hotline. Respondents' sex, where their medical degree was obtained, frequency of seeing refugees and asylum seekers and years of experience had little association with responses. CONCLUSIONS: Australian paediatricians considered mandatory detention a form of child abuse and strongly disagreed with offshore processing. There is a clear need for education about practical issues such as current health screening practices and Medicare eligibility. PMID- 25296061 TI - Mandatory reports of concerns about the health, performance and conduct of health practitioners. AB - OBJECTIVE: To describe the frequency and characteristics of mandatory reports about the health, competence and conduct of registered health practitioners in Australia. DESIGN AND SETTING: Retrospective review and multivariate analysis of allegations of "notifiable conduct" involving health practitioners received by the Australian Health Practitioner Regulation Agency (AHPRA) between 1 November 2011 and 31 December 2012. MAIN OUTCOME MEASURES: Statutory grounds for reports, types of behaviour reported, and incidence of notifications by profession, sex, age, jurisdiction and geographic area. RESULTS: Of 819 mandatory notifications made during the study period, 501 (62%) related to perceived departures from accepted professional standards, mostly standards of clinical care. Nurses and doctors dominated notifications: 89% (727/819) involved a doctor or nurse in the role of notifier and/or respondent. Health professionals other than the respondents' treating practitioners made 46% of notifications (335/731), and the profession of the notifier and respondent was the same in 80% of cases (557/697). Employers made 46% of notifications (333/731). Psychologists had the highest rate of notifications, followed by medical practitioners, and then nurses and midwives (47, 41 and 40 reports per 10 000 practitioners per year, respectively). Incidence of notifications against men was more than two-and-a-half times that for women (46 v 17 reports per 10 000 practitioners per year; P < 0.001) and there was fivefold variation in incidence across states and territories. CONCLUSIONS: Although Australia's mandatory reporting regime is in its infancy, our data suggest that some of the adverse effects and manifest benefits forecast by critics and supporters, respectively, have not materialised. Further research should explore the variation in notification rates observed, evaluate the outcomes of reports, and test the effects of the mandatory reporting law on whistleblowing and help-seeking behaviour. PMID- 25296062 TI - Identified health concerns and changes in management resulting from the Healthy Kids Check in two Queensland practices. AB - OBJECTIVES: To determine how many children had health problems identified by the Healthy Kids Check (HKC) and whether this resulted in changes to clinical management. DESIGN, SETTING AND PARTICIPANTS: A medical records audit from two Queensland general practices, identifying 557 files of children who undertook an HKC between January 2010 and May 2013. MAIN OUTCOME MEASURES: Child health problems identified in the medical records before, during and after the HKC. RESULTS: Most children in our sample had no problems detected in their medical record (56%), 21% had problems detected during the HKC assessment, 19% had problems detected before, and 4% after. Most frequent health concerns detected during the HKC were speech and language (20%), toileting, hearing and vision (15% each), and behavioural problems (9%). Of the 116 children with problems detected during the HKC, 19 (3% of the total sample) had these confirmed, which resulted in a change of management. No further action was recorded for 9% of children. Missing data from reviews or referral outcomes for 8% precluded analyses of these outcomes. We estimated that the change in clinical management to children with health concerns directly relating to the HKC ranged between 3% and 11%. CONCLUSIONS: Overall, data suggest that general practitioners are diligent in detecting and managing child health problems. Some of these problems were detected only during the HKC appointment, resulting in change of management for some children. Further studies are required to estimate the full benefits and harms, and particularly the false negatives and true positives, of the HKC. PMID- 25296064 TI - Orthogeriatric services associated with lower 30-day mortality for older patients who undergo surgery for hip fracture. AB - OBJECTIVE: To examine the impact of orthogeriatric services on 30-day mortality and length of stay (LOS) for hip fracture patients undergoing surgery in public hospitals in New South Wales. DESIGN, SETTING AND PATIENTS: A retrospective analysis of patients aged 65 years and older who had a fractured hip and received surgical intervention between 1 July 2009 and 30 June 2011 at one of the 37 NSW public hospitals operating on hip fracture patients. MAIN OUTCOME MEASURES: 30 day mortality and LOS. RESULTS: During the study period, there were 9601 hip fracture cases for which surgery was done. Mean age, sex and comorbidity distribution were similar for hip fracture patients treated in hospitals with an orthogeriatric service compared with those treated in hospitals without an orthogeriatric service. There were 706 deaths within 30 days of hip fracture surgery, and the overall unadjusted 30-day mortality rate was 7.4%. The median adjusted 30-day mortality rate for hospitals with an orthogeriatric service was significantly lower than that for hospitals without an orthogeriatric service (6.2% v 8.4%; P < 0.002). Median total LOS was longer at hospitals with an orthogeriatric service compared with hospitals that did not have an orthogeriatric service (26 days v 22 days; P < 0.001). CONCLUSIONS: The presence of an orthogeriatric service was associated with a reduction in 30-day mortality but a longer LOS. More research is required to understand the key aspects of care that determine health outcomes. The recently launched Australian and New Zealand Hip Fracture Registry will provide data that will enable improvements in care. PMID- 25296065 TI - Factors predicting uptake of long-acting reversible methods of contraception among women presenting for abortion. AB - OBJECTIVE: To examine the uptake of long-acting reversible contraceptive (LARC) methods after abortion among women seeking abortions through a major Australian abortion provider. DESIGN AND SETTING: Cross-sectional study of women's post abortion contraceptive choices, conducted at Marie Stopes International clinics across Australia between 1 September and 31 December 2012. PARTICIPANTS: 7267 of 9477 women (76.7%) presenting during the study period had data collection forms completed. Analysis was based on the 6348 women with completed demographic details. MAIN OUTCOME MEASURES: Uptake and immediate provision of LARC contraception after abortion. RESULTS: Just over a quarter of women (1742; 27.4%) chose a LARC method for use after abortion. Of those choosing a LARC, immediate provision occurred in 71.1%. Compared with women aged 20-24 years, those aged 16 19 years were less likely to have immediate LARC insertion and those over 30 more likely. Women in the lowest socioeconomic quintile were the least likely to leave the service with their chosen LARC in place compared with those in higher quintiles. Immediate LARC provision occurred more often after surgical abortion compared with medical abortion (1034 [74.4%] v 204 [60.0%]; P < 0.001). CONCLUSION: Among women who opted for a LARC method after abortion, immediate provision was less likely to occur in women aged under 30 years, less likely as their level of disadvantage increased and more likely after surgical abortion compared with medical abortion. Public health policy needs to facilitate access to LARC methods after abortion so that more women are able to avoid a further unintended pregnancy. PMID- 25296066 TI - Occupational impact of internet-delivered cognitive behaviour therapy for depression and anxiety: reanalysis of data from five Australian randomised controlled trials. AB - OBJECTIVE: To determine whether internet-delivered cognitive behaviour therapy (iCBT) for depression and anxiety reduces self-reported absenteeism in employed individuals. DESIGN, PARTICIPANTS AND SETTING: We reanalysed data from five randomised controlled trials of iCBT: two for depression (conducted from September 2008 to February 2009 and from June 2009 to January 2010), two for generalised anxiety disorder (conducted from March 2009 to June 2009 and from July 2009 to January 2010) and one for social phobia (conducted from May 2008 to July 2008). Participants across Australia were recruited via a website. The inclusion criteria were: (i) meets criteria for the disorder of interest; (ii) aged 18 years or over; (iii) no previous history of a psychotic disorder or drug or alcohol misuse; (iv) not actively suicidal. The iCBT courses each consisted of six online lessons (to be completed within 11 weeks), homework assignments, automatic emails and resource documents. MAIN OUTCOME MEASURE: The number of days absent (self-reported absenteeism) in the previous week. RESULTS: We included 284 participants in our analysis. When data for the three disorders were combined, participants who received iCBT had significant reductions in self-reported absenteeism compared with those in the control groups (who were on a waitlist) (P = 0.03). When data for the three disorders were analysed separately, reductions in self-reported absenteeism for participants who received iCBT were not significantly different to those for participants in the control groups. CONCLUSION: Using data from five RCTs, we showed that iCBT was associated with reductions in self-reported absenteeism. Future research should focus on replicating these findings in other contexts, such as other disorders and other iCBT courses. PMID- 25296068 TI - How do you keep them down on the farm? PMID- 25296067 TI - First Australian report of vitamin D-dependent rickets type I. PMID- 25296070 TI - The importance of effectively combating HIV/AIDS through tackling the social aspects of the pandemic post-2015. PMID- 25296071 TI - Molecular and morphological differentiation of two similar species of Accacoeliidae (Digenea): Accacladocoelium macrocotyle and A. nigroflavum from sunfish, Mola mola. AB - In a study of 106 sunfish, Mola mola (L.), from Mediterranean waters, 2,731 worms, belonging to 2 congeneric species of accacoeliids, Accacladocoelium macrocotyle (Diesing, 1858) Robinson, 1934 and Accacladocoelium nigroflavum (Rudolphi, 1819) Robinson, 1934 , were collected from the digestive system. It is often difficult to differentiate between these 2 species as they are sympatric and very similar; in fact, according to previous descriptions, the extent of the vitellarium is the only interspecific difference, described as extending posteriorly to the ovary in A. macrocotyle and as anterior to the anterior testis in A. nigroflavum. However, this diagnostic trait is not always valid; moreover, it is often indistinguishable because it is masked by the uterine eggs. Here, the morphology of new specimens of both species has been studied in detail and combined with molecular analysis. This study shows that the extension of the vitellarium is very similar in both species, but the degree of ramification differs. Furthermore, although the morphological differences are very slight, both species seemed genetically different: intraspecific differences ranged between 0.8 and 1.5% in internal transcribed spacer (ITS)-2 rRNA gene (ITS2) and between 0.5 and 1.6% in cytochrome c oxidase subunit 1 (COI) and interspecific differences ranged between 2 and 3.2% in ITS2 and between 9.6 and 10.6% in COI. In addition, we observed previously undescribed morphological differences, which help to differentiate these 2 species: the oral sucker is relatively smaller in A. nigroflavum than in A. macrocotyle and the ovary is usually relatively longer in A. nigroflavum than in A. macrocotyle. PMID- 25296072 TI - [Nodular lymphocyte-predominant Hodgkin lymphoma in children: clinical course, biology, and management]. AB - Nodular lymphocyte predominant Hodgkin disease (NLPHL) differs clearly from classical Hodgkin lymphoma (cHL) by clinical presentation and more favorable outcome. Patients often present with early stage IA or IIA. Extranodal disease and B-symptoms are uncommon. Histologically, NLPHL is characterized by the presence of atypical "lymphocyte predominant cells" (LP cells) or "pop-corn" cells in a non-neoplastic and reactionnal nodular background of small mature B lymphocytes. LP cells are negative for CD30 and positive for CD20, BCL6 and EMA (in half of the cases). FDG-PET plays an important role in evaluation of cHL and NLPHL for staging, therapy assessment and relapse. Historically, patients with NLPHL have been treated like patients with cHL, but their very favorable prognosis and the risk of late complications of chemotherapy and/or radiotherapy have led to a de-escalation in recent years. Patients with early stage could be treated by surgical adenectomy alone or associated with not intensive chemotherapy. Currently, there is no consensus regarding to the optimal treatment of patients with advanced stage. Rituximab used as monotherapy or in association with chemotherapy has achieved complete or partial responses. The outcome of NLPHL is singular by the frequent occurrence of late relapses and the risk of transformation into aggressive B lymphoma justifying an extended follow-up. Further prospective studies are needed to optimize treatment of these advanced and recurrent forms. PMID- 25296073 TI - Quality of life after bariatric surgery. PMID- 25296074 TI - Outcomes on quality of life, weight loss, and comorbidities after Roux-en-Y gastric bypass. AB - CONTEXT: Bariatric surgery has become the most effective method for producing weight loss in obese patients. The evaluation of improvement of comorbidities and changes in the quality of life are important outcome factors; however, it is necessary to investigate whether they persist over the long term. METHODS: A cross-sectional study was conducted on 143 obese patients from our institution from February 2007 to February 2008. These patients were divided into five independent groups, one being a control group, plus four other groups with 1, 2, 3, 4 or more years following surgical Roux-en-Y gastric bypass with a silicon ring banded. quality of life forms and anthropometric measurements were performed and its scores correlated with social factors, weight loss success, and status of obesity-related conditions. RESULTS: For the group that was 1 year postoperative, a significant percentage of excess body weight loss (EBWL%) of 81.7% was observed. The groups with 2, 3, 4 or more years of post-surgical follow-up showed a EBWL decline, but without significant difference. The main comorbidity percentages in all patients who had the surgery was as follows: 69.7% for hypertension; 88.2% for diabetes mellitus; and 27.5% for arthropathy. There was a significant decrease in the rate for diabetes resolution (P = 0.035) observed by evolutionary assessment of the comorbidity resolution. The results obtained by BAROS were good, very good, or excellent in more than 96% of patients in all evaluations that were performed. The use of the Moorehead-Ardelt Questionnaire (M/A) demonstrated improvement in the quality of life. Moreover, the quality of life, when evaluated through SF-36, also showed improvement in all related areas after 1 year; however, after 4 years, improvement remained elevated only in the areas of general state of health and functional capacity. CONCLUSIONS: The Roux en-Y gastric bypass procedure was able to achieve EBWL of 81.7% after 1 year following surgery, remaining steady with little decline after this period. Important resolution of comorbidities, such as hypertension and diabetes, was also seen. Immediate surgical outcomes assessed by SF-36 and M/A in the area of quality of life were satisfactory, but the general state of health and functional capacity areas were sustained satisfactory at a later time only. PMID- 25296075 TI - Age and gender may influence the results of Roux-en-Y gastric bypass? Metabolic syndrome parameters. AB - CONTEXT: Severe obesity affects the body favoring the development of serious diseases, including hypertension, diabetes mellitus, atherosclerosis and non alcoholic fatty liver disease. Bariatric procedures increased in Brazil in the last decade. OBJECTIVES: The purpose of this study was to verify if gender and age in date of procedure resulted significant differences in metabolic syndrome parameters after surgery. METHODS: The study involved 205 medical records of adult patients undergoing Roux-en-Y gastric bypass, stratified by gender and age groups and followed one year by a multidisciplinary team. RESULTS: It was observed significant decrease in body mass index, fasting glucose and insulin at all ages and both genders. Lipid profile showed significant improvements except high density lipoprotein cholesterol. Ectopic fat in the liver has decreased after 6 months in patients classified with steatosis at baseline. Patients classified as hypertensive blood pressure levels decreased 6 months after surgical intervention. CONCLUSIONS: Roux-en-Y gastric bypass proved to be an important tool in remission of metabolic syndrome parameters. The reduction of body mass accompanied to decrease in insulin resistance resulted in lower prevalence of comorbidities associated with obesity. The benefits were similar and extended both genders and all age groups between 18 and 65 years old. PMID- 25296076 TI - Prevalence of infection with cagA-positive Helicobacter pylori strains among children and adolescents in southern Brazil. AB - CONTEXT: Helicobacter pylori (H. pylori) has a worldwide distribution, but the prevalence of infection, virulence factors, and clinical presentation vary widely according to the studied population. In Brazil, a continental country composed of several ethnicities and cultural habits, the behavior of infection also appears to vary, as many other studies have shown. OBJECTIVES: Describe the prevalence of infection with cagA-positive H. pylori strains in a group of children and adolescents who underwent esophagogastroduodenoscopy in Porto Alegre, Rio Grande do Sul. METHODS: Fifty-four gastric biopsy specimens of children and adolescents with H. pylori infection demonstrated by histology, urease test and molecular analysis were tested for the presence of cagA positive H. pylori strains by the polymerase chain reaction method. RESULTS: The prevalence of cagA-positive H. pylori was 29.6% (95% confidence interval, 18 to 43.6%). There were no statistically significant differences in clinical or demographic characteristics or in the endoscopic and histological features of patients infected with cagA positive strains as compared with those infected by cagA-negative strains. CONCLUSIONS: he study showed a low prevalence of infection with cagA-positive H. pylori strains among children and adolescents who underwent EGD in southern Brazil, in comparison to studies conducted with children from other regions of Brazil. There was no association between the presence of cagA-positive strains and more severe clinical presentations in the studied sample. PMID- 25296077 TI - Study on adherence to capecitabine among patients with colorectal cancer and metastatic breast cancer. AB - CONTEXT: Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. OBJECTIVES: To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient's quality of life. METHODS: Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. RESULTS: Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. CONCLUSIONS: Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance. PMID- 25296078 TI - Quality of life in patients with inflammatory bowel disease: importance of clinical, demographic and psychosocial factors. AB - CONTEXT: Inflammatory bowel disease causes physical and psychosocial consequences that can affect the health related quality of life. OBJECTIVES: To analyze the relationship between clinical and sociodemographic factors and quality of life in inflammatory bowel disease patients. METHODS: Ninety two patients with Crohn's disease and 58 with ulcerative colitis, filled in the inflammatory bowel disease questionnaire (IBDQ-32) and a questionnaire to collect sociodemographic and clinical data. The association between categorical variables and IBDQ-32 scores was determined using Student t test. Factors statistically significant in the univariate analysis were included in a multivariate regression model. RESULTS: IBDQ-32 scores were significantly lower in female patients (P<0.001), patients with an individual perception of a lower co-workers support (P<0.001) and career fulfillment (P<0.001), patients requiring psychological support (P = 0.010) and pharmacological treatment for anxiety or depression (P = 0.002). A multivariate regression analysis identified as predictors of impaired HRQOL the female gender (P<0.001) and the perception of a lower co-workers support (P = 0.025) and career fulfillment (P = 0.001). CONCLUSIONS: The decrease in HRQQL was significantly related with female gender and personal perception of disease impact in success and social relations. These factors deserve a special attention, so timely measures can be implemented to improve the quality of life of patients. PMID- 25296079 TI - Do changes in anal sphincter anatomy correlate with anal function in women with a history of vaginal delivery? AB - OBJECTIVES: To evaluate anal sphincter anatomy using three-dimensional ultrasonography (3-DAUS) in incontinent women with vaginal delivery, correlate anatomical findings with symptoms of fecal incontinence and determine the effect of vaginal delivery on anal canal anatomy and function. METHODS: Female with fecal incontinence and vaginal delivery were assessed with Wexner's score, manometry, and 3DAUS. A control group comprising asymptomatic nulliparous was included. Anal pressure, the angle of the defect and length of the external anal sphincter (EAS), the anterior and posterior internal anal sphincter (IAS), the EAS + puborectal and the gap were measured and correlated with score. RESULTS: Of the 62, 49 had fecal incontinence and 13 were asymptomatic. Twenty five had EAS defects, 8 had combined EAS+IAS defects, 16 had intact sphincters and continence scores were similar. Subjects with sphincter defects had a shorter anterior EAS, IAS and longer gap than women without defects. Those with a vaginal delivery and intact sphincters had a shorter anterior EAS and longer gap than nulliparous. We found correlations between resting pressure and anterior EAS and IAS length in patients with defects. CONCLUSIONS: Fecal incontinence symptoms did not correlate with anal pressures and anal sphincter anatomy changes, but women with sphincter defects have shorter anterior EAS and IAS and a longer gap. PMID- 25296080 TI - Laparoscopy versus laparotomy in the repair of ventral hernias: systematic review and meta-analysis. AB - OBJECTIVE: To compare the laparotomy and laparoscopy techniques for correction of ventral hernia when related to perioperative complications, length of hospitalization, surgical time, and recurrence of hernia. METHODS: This was a systematic review of randomized controlled trials, which included studies retrieved from four databases (MEDLINE, Embase, Cochrane and LILACS), using a combination of the terms (Hernia, Ventral) and (Laparoscopy) and (Laparotomy). RESULTS: Six randomized trials were included, totaling 566 patients, 283 in the Laparoscopy group and 283 in the Laparotomy group. Laparoscopy reduced the risk of infection of the surgical wound (NNT = 5) and seroma formation (NNT = 13) and less length hospitalization (P = 0.02) compared to laparotomy in the correction of ventral hernias. Furthermore, laparoscopy increased the incidence of enterotomy (NNH = 25) and post operative pain (NNH = 8) and longer surgical time (P = 0.0009) when compared with laparotomy. There was no difference related to abscess (P = 0.79), hematoma (P = 0.43) and recurrency of ventral hernias (P = 0.25). CONCLUSIONS: In the correction of ventral hernias, the use of laparoscopic technique is effective to reduce infections of the surgical wound and seroma formation, as well as, decrease the length hospitalization. PMID- 25296081 TI - Improvement in quality-of-life after laparoscopic Nissen fundoplication. AB - CONTEXT: Evaluating quality of life after surgery for gastroesophageal reflux is fundamental, since improvement of symptoms is the main goal of treatment. OBJECTIVE: To compare the satisfaction of patients operated for GERD, interviewed at the office, with patients interviewed by telephone. METHODS: One hundred and seventy-eight patients were submitted to laparoscopic Nissen fundoplication. Ninety patients were found, and 45 agreed to come to the hospital's office. The other 45 patients were interviewed by telephone. Quality of life was evaluated using three methods: The GERD-HRQL questionnaire, translated to Portuguese; question "If you could choose it today, would you do surgery again?"; and question "If you could classify your symptom improvement between 0 and 10, which grade would you give?" Patients were divided in group A (office interview) and B (telephone interview). Statistical analysis was performed. RESULTS: The average GERD-HRQL score in group A was 6.29, while in group B was 14.09(P = 0.002). There was no statistical difference between groups A and B regarding patients choice of doing the surgery again(P = 0.714) and their grade of postoperative symptom improvement (P = 0.642). CONCLUSION: The overall postoperative satisfaction was high. The GERD-HRQL questionnaire might not be suitable for application by telephone in our population, and based on other analyzes, the satisfaction and quality of life of patients interviewed at the office or by telephone was similar. PMID- 25296082 TI - Acidic and neutral liquid ingestion in patients with gastroesophageal reflux disease. AB - CONTEXT: Sour acidic liquid has a slower distal esophageal transit than a neutral liquid. Our hypothesis was that an acidic sour bolus has a different ingestion dynamic than a neutral bolus. METHOD: In 50 healthy volunteers and 29 patients with gastroesophageal reflux disease (GERD), we evaluated the ingestion dynamics of 100 mL of acidic sour liquid (concentrated lemon juice, pH: 3.0) and 100 mL of water (pH: 6.8). The time to ingest the total volume, the number of swallows to ingest the volume, the interval between swallows, the flux of ingestion and the volume ingested in each swallow was measured. RESULTS: In both groups, healthy volunteers and patients in treatment for GERD, the acidic liquid took longer to be ingested, a higher number of swallows, a slower flux of ingestion and a smaller volume in each swallow than the neutral bolus. There was no difference between healthy volunteers and patients with GERD. The ingestion in women was longer than in men for acidic and neutral liquids. CONCLUSION: Acidic liquid has a different dynamic of ingestion than the neutral liquid, which may be consequence of the slower transit through the distal esophageal body or an anticipation to drink a sour bolus. Patients with GERD have the same prolonged ingestion of the acidic liquid bolus as seen in healthy volunteers. PMID- 25296083 TI - Videofluoroscopic swallowing study: esophageal alterations in patients with dysphagia. AB - CONTEXT: Videofluoroscopic swallowing study is a dynamic exam and allows the evaluation of the complete swallowing process. However, most published studies have only reported alterations in the oropharynx and pharyngoesophageal transition, leaving the analysis of the esophagus as a secondary goal. OBJECTIVES: The goal of this study was to investigate the prevalence of alterations in the esophageal phase thorough videofluoroscopic swallowing study in patients with dysphagia. METHODS: Consecutive patients with dysphagia who underwent videofluoroscopic swallowing study including esophageal analysis between May 2010 and May 2012 had their exams retrospectively reviewed. Patients were classified into two groups: Group I - without a pre-established etiological diagnosis and Group II - with neurological disease. During the exam, the patients ingested three different consistencies of food (liquid, pasty and solid) contrasted with barium sulfate and 19 items were analyzed according to a protocol. The esophageal phase was considered abnormal when one of the evaluated items was compromised. RESULTS: Three hundred and thirty-three (n = 333) consecutive patients were studied - 213 (64%) in Group I and 120 (36%) in Group II. Esophageal alterations were found in 104 (31%) patients, with a higher prevalence in Group I (36.2%), especially on the items esophageal clearance (16.9%) and tertiary contractions (16.4%). It was observed that 12% of individuals in Group I only presented alterations on the esophageal phase. CONCLUSION: Evaluation of the esophageal phase of swallowing during videofluoroscopic swallowing study detects abnormalities in patients with cervical dysphagia, especially in the group without pre-established etiological diagnosis. PMID- 25296084 TI - Comparison of selective and non selective cyclo-oxygenase 2 inhibitors in experimental colitis exacerbation: role of leukotriene B4 and superoxide dismutase. AB - CONTEXT: Nonsteroidal anti-inflammatory drugs are considered one of the most important causes of reactivation of inflammatory bowel disease. With regard to selective cyclo-oxygenase 2 inhibitors, the results are controversial in experimental colitis as well as in human studies. OBJECTIVES: The aim this study is to compare nonsteroidal anti-inflammatory drugs effects, selective and non selective cyclo-oxygenase 2 inhibitors, in experimental colitis and contribute to the understanding of the mechanisms which nonsteroidal anti-inflammatory drugs provoke colitis exacerbation. METHODS: Six groups of rats: without colitis, with colitis, and colitis treated with celecoxib, ketoprofen, indometacin or diclofenac. Survival rates, hemoglobin, plasmatic albumin, colonic tissue of interleukin-1beta, interleukin-6, tumor necrosis factor alpha, prostaglandin E2, catalase, superoxide dismutase, thiobarbituric acid-reactive substances, chemiluminescence induced by tert-butil hydroperoxides, and tissue and plasmatic leukotriene B4 were determined. RESULTS: The groups treated with diclofenac or indometacin presented lower survival rates, hemoglobin and albumin, higher tissue and plasmatic leukotriene B4 and tissue superoxide dismutase than the group treated with celecoxib. Ketoprofen presented an intermediary behavior between diclofenac/indometacin and celecoxib, concerning to survival rate and albumin. The groups without colitis, with colitis and with colitis treated with celecoxib showed leukotriene B4 and superoxide dismutase lower levels than the groups treated with nonselective cyclo-oxygenase 2 inhibitors. CONCLUSIONS: Diclofenac and indometacin presented the highest degree of induced colitis exacerbation with nonsteroidal anti-inflammatory drugs, celecoxib did not show colitis exacerbation, and ketoprofen presented an intermediary behavior between diclofenac/indometacin and celecoxib. These results suggest that leukotriene B4 and superoxide dismutase can be involved in the exacerbation of experimental colitis by nonselective nonsteroidal anti-inflammatory drugs. PMID- 25296085 TI - Malignancy in large colorectal lesions. AB - CONTEXT: The size of colorectal lesions, besides a risk factor for malignancy, is a predictor for deeper invasion objectives: To evaluate the malignancy of colorectal lesions >=20 mm. METHODS: Between 2007 and 2011, 76 neoplasms >=20 mm in 70 patients were analyzed. RESULTS: The mean age of the patients was 67.4 years, and 41 were women. Mean lesion size was 24.7 mm +/- 6.2 mm (range: 20 to 50 mm). Half of the neoplasms were polypoid and the other half were non-polypoid. Forty-two (55.3%) lesions were located in the left colon, and 34 in the right colon. There was a high prevalence of III L (39.5%) and IV (53.9%) pit patterns. There were 72 adenomas and 4 adenocarcinomas. Malignancy was observed in 5.3% of the lesions. Thirty-three lesions presented advanced histology (adenomas with high-grade dysplasia or early adenocarcinoma), with no difference in morphology and site. Only one lesion (1.3%) invaded the submucosa. Lesions larger than 30 mm had advanced histology (P = 0.001). The primary treatment was endoscopic resection, and invasive carcinoma was referred to surgery. Recurrence rate was 10.6%. CONCLUSIONS: Large colorectal neoplasms showed a low rate of malignancy. Endoscopic treatment is an effective therapy for these lesions. PMID- 25296086 TI - Endoscopic treatment of post-liver transplantation anastomotic biliary stricture: systematic review and meta-analysis. AB - CONTEXT: Biliary strictures after liver transplantation are recognized as its Achilles' heel. The strictures are classified in anastomotic and ischemic or non anastomotic biliary strictures, and they figure among the most common complications after liver transplantation. There are some treatment options including balloon dilation, the placement of multiple plastic stents and the placement of self-expandable metal stents and all of them seem to have good results. OBJECTIVES: The aim of this study was to systematically review the literature concerning the results of the endoscopic treatment of anastomotic biliary strictures after liver transplantation. METHODS: A systematic review of the literature was performed on the management of anastomotic biliary strictures post- orthotopic liver transplantation. The Medline-PubMed, EMBASE, Scielo LILACS, and Cochrane Databases were electronically searched from January 1966 to April 2013. RESULTS: No well-designed randomized controlled trial was found. Most studies were retrospective or prospective comparisons in design. One study (86 patients) compared the endoscopic and the percutaneous accesses. The sustained clinical success rates were similar but the treatment duration was longer in the percutaneous group access. Two studies (56 patients) compared balloon dilation with balloon dilation and multiple plastic stents. There were no differences concerning sustained clinical success and complication rates. CONCLUSIONS: Balloon dilation is as effective as balloon dilation plus multiple plastic stenting for the resolution of the anastomotic biliary strictures. Well-designed randomized trials are still needed to compare balloon dilation versus multiple plastic stenting versus metallic stenting. PMID- 25296087 TI - Cholangioscopy in bile duct disease: a case series. AB - CONTEXT: Direct endoscopic visualization of biliopancreatic duct is certainly one of the greatest advances of therapeutic endoscopy. The use of a single-operator cholangioscopy platform (SpyGlass) is a promising technique in the evaluation of diseases such as indeterminate biliary stricture and giant choledocholitiasis. This is the first Brazilian case series using this technology. METHODS: We report a case series of 20 patients in whom SpyGlass was used with diagnostic and therapeutic intention. RESULTS: Most patients were female (60%) and the median age was 48 years (ranging from 14 to 94). Choledocholitiasis was the most common indication (12/20), and electrohydraulic lithotripsy was applied in eight (66%). Electrohydraulic lithotripsy was successful in seven (87.5%) patients. Partial stone fragmentation occurred in one patient with large stone causing stone choledochal disproportion, which was conducted with biliary plastic stent placement and a second scheduled endoscopic approach in 3 months. In cases of undefined etiology of biliary strictures, it was possible to exclude malignancy due to direct visualization (7/8) or biopsy (1/8). One complication occurred (duodenal perforation) after papillary balloon dilation. CONCLUSION: The use of SpyGlass demonstrated the benefits, especially in cases of large bile duct stones and indeterminate biliary strictures. Other potencial improvements such as reduction on radiation exposure should be confirmed in prospective studies. PMID- 25296088 TI - Ginseng, green tea or fibrate: valid options for nonalcoholic steatohepatitis prevention? AB - OBJECTIVES: Panax ginseng, Camellia sinensis and bezafibrate were compared for their lipid-lowering, antioxidant and anti-inflammatory properties as potential agents to prevent nonalcoholic fatty liver disease and its progression to nonalcoholic steatohepatitis. METHODS: Fifty Wistar rats were randomized into five groups: G1 (feed with standard diet); G2 (feed with high-fat diet with 58% of energy from fat); G3 (high-fat diet + standardized Panax ginseng extract at 100 mg/kg/day); G4 (high-fat diet + standardized Camellia sinensis extract at 100 mg/kg/day); and G5 (high-fat diet + bezafibrate at 100 mg/kg/day), given by gavage. The animals were sacrificed eight weeks later and blood was collected for glucose, insulin, cholesterol, triglycerides, AST, ALT, alkaline phosphatase and gamma-glutamyl transferase determinations. The score system for nonalcoholic fatty liver disease was used to analyse the liver samples. RESULTS AND CONCLUSIONS: High-fat diet resulted in a significant increase in animal body weight, biochemical changes and enzymatic elevations. Steatosis, inflammation and hepatocellular ballooning scores were significant high in this group. The biochemical and histological variables were statistically similar in the bezafibrate group and control group. Treatment with Panax ginseng extract prevented obesity and histological features of nonalcoholic steatohepatitis (steatosis and inflammation) compared to high-fat diet. Camellia sinensis showed a less effective biochemical response, with small reduction in steatosis and inflammation but lower ballooning scores. PMID- 25296089 TI - Effect of Helicobacter pylori eradication on hepatic steatosis, NAFLD fibrosis score and HSENSI in patients with nonalcoholic steatohepatitis: a MR imaging based pilot open-label study. AB - CONTEXT: Limited clinical data suggest Helicobacter pylori (Hp) infection may contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. OBJECTIVES: The effect of Hp eradication on hepatic steatosis (magnetic resonance imaging), nonalcoholic fatty liver disease fibrosis score and HSENSI (Homocysteine, serum glutamic oxaloacetic transaminase, Erythrocyte sedimentation rate, nonalcoholic steatohepatitis Index) in nonalcoholic steatohepatitis patients. METHODS: Thirteen adult patients with biopsy-proven nonalcoholic steatohepatitis, asymptomatic for gastrointestinal disease, underwent 13C urea breath test; Hp positive patients received eradication therapy until repeat test become negative. Hepatic fat fraction, standard biochemical tests and calculation of nonalcoholic fatty liver disease fibrosis score and HSENSI were performed at baseline and month 12. RESULTS: Hepatic fat fraction was similar for between and within group comparisons. Nonalcoholic fatty liver disease fibrosis score showed a non significant trend towards decrease in Hp(+) [-0.34 (-1.39-0.29) at baseline and 0.24 (-0.99-0.71) at month 12; P = 0.116], whereas increase in Hp(-) group [-0.38 (-1.72-0.11) and -0.56 (-1.43-0.46), respectively; P = 0.249]. HSENSI was significantly decreased only in Hp(+) group [1.0 (1.0-2.0) at baseline and 1.0 (0 1.0) at month 12; P = 0.048]. CONCLUSIONS: Hp eradication had no long-term effect on hepatic steatosis, but showed a trend towards improvement in nonalcoholic fatty liver disease fibrosis score and HSENSI. These results warrant larger studies with paired biopsies. PMID- 25296090 TI - Intensive care without walls - introduction of a Medical Emergency Team system in a Swiss tertiary care centre. AB - QUESTIONS UNDER STUDY: To improve the response of deteriorating patients during their hospital stay, the University Hospital Bern has introduced a Medical Emergency Team (MET). Aim of this retrospective cohort study is to review the preceding factors, patient characteristics, process parameters and their correlation to patient outcomes of MET calls since the introduction of the team. METHODS: Data on patient characteristics, parameters related to MET activation and intervention and patient outcomes were evaluated. A Vital Sign Score (VSS), which is defined as the sum of the occurrence of each vital sign abnormalities, was calculated for all physiological parameters pre MET event, during event and correlation with hospital outcomes. RESULTS: A total of 1,628 MET calls in 1,317 patients occurred; 262 (19.9%) of patients with MET calls during their hospital stay died. The VSS pre MET event (odds ratio [OR] 1.78, 95% confidence interval [CI] 1.50-2.13; AUROC 0.63; all p <0.0001) and during the MET call (OR 1.60, 95% CI 1.41-1.83; AUROC 0.62; all p <0.0001) were significantly correlated to patient outcomes. A significant increase in MET calls from 5.2 to 16.5 per 1000 hospital admissions (p <0.0001) and a decrease in cardiac arrest calls in the MET perimeter from 1.6 in 2008 to 0.8 per 1000 admissions was observed during the study period (p = 0.014). CONCLUSIONS: The VSS is a significant predictor of mortality in patients assessed by the MET. Increasing MET utilisation coincided with a decrease in cardiac arrest calls in the MET perimeter. PMID- 25296091 TI - Live to work or love to work: work craving and work engagement. AB - OBJECTIVE: According to the theory of work craving, a workaholic has a craving for self-worth compensatory incentives and an expectation of relief from negative affect experienced through neurotic perfectionism and an obsessive-compulsive style of working. Research has shown that workaholism and work engagement should be considered as two distinct work styles with different health consequences. However, the mechanisms underlying the adoption of these work styles have been neglected. The present study proposes that work craving and work engagement are differentially associated with self-regulatory competencies and health. In particular, we expected that the working styles mediate the relationships between emotional self-regulation and health. METHODS: In the cross-sectional study, 469 teachers from German schools completed online administered questionnaires. By means of structural equation modeling, we tested two indirect paths: a) from self relaxation deficits via work craving to poor health and b) from self-motivation competencies via work engagement to good health. RESULTS: As expected, we found evidence that a) the negative relationship of self-relaxation deficits on health was partially mediated by work craving and b) the positive relationship of self motivation competencies on health was partially mediated by work engagement. CONCLUSIONS: The present study emphasizes the importance of self-regulation competencies for healthy or unhealthy work styles. Whereas work craving was associated with a low ability to down-regulate negative emotions and poor health, work engagement was associated with a high ability to up-regulate positive emotions and good health. PMID- 25296093 TI - Cardiovascular risk assessment in kidney transplantation. AB - Cardiovascular disease (CVD) remains the most common cause of death after kidney transplantation worldwide, with the highest event rate in the early postoperative period. In an attempt to address this issue, screening for CVD prior to transplant is common, but the clinical utility of screening asymptomatic transplant candidates remains unclear. A large degree of variation exists among both transplant center practice patterns and clinical practice guidelines regarding who should be screened, and opinions are based on mixed observational data with great potential for bias. In this review, we discuss the potential risks, benefits, and evidence for screening for CVD in kidney transplant candidates, and also the next steps to better evaluate and treat asymptomatic kidney transplant candidates. PMID- 25296092 TI - Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. AB - The short-term mortality of cirrhotic patients who develop renal dysfunction remains unacceptably high, and as such the treatment of this condition is an unmet need. Although features of kidney injury are well recognized in these patients, the pathophysiology is complex and not completely understood. Improved understanding of the pathophysiological mechanisms involved in renal dysfunction occurring on a background of cirrhosis is key to developing effective treatment strategies to improve survival. Renal dysfunction due to hepatorenal syndrome (HRS) is characteristic of cirrhosis. Our current understanding is that HRS is functional in nature and occurs as a consequence of hemodynamic changes associated with portal hypertension. However, there is evidence in the literature suggesting that, histologically, the kidneys are not always normal in the vast majority of patients who present with renal dysfunction on the background of cirrhosis. Furthermore, there is emerging data implicating nonvasomotor mechanisms in the pathophysiology of renal dysfunction in cirrhosis. This mini review aims to present the evidence suggesting that factors other than hemodynamic dysregulation have an important role in the development of this major complication for patients with progressive cirrhosis. PMID- 25296094 TI - The use of immunoglobulin light chain assays in the diagnosis of paraprotein related kidney disease. AB - Kidney involvement is common in paraprotein-related diseases. A diversity of clinical presentations and histopathological features can occur secondary to tissue injury caused by precipitation or deposition of a clonal immunoglobulin, usually an immunoglobulin light chain. The paraprotein is either produced by multiple myeloma or by a clone of B-cell lineage that does not fulfill diagnostic criteria for multiple myeloma. The recent introduction of serum immunoglobulin free light chain assays, which accurately quantify both light chain isotypes to produce a ratio that indicates the presence or absence of a light chain paraprotein, is a major clinical development. However, as the interpretation of the assay can be challenging, the aim of this review is to clarify the role of serum and urinary light chain assays in the screening and diagnosis of paraprotein-related kidney disease. PMID- 25296095 TI - Early HIV-1 infection is associated with reduced frequencies of cervical Th17 cells. AB - BACKGROUND: The hallmark of HIV infection is progressive but variable rates of systemic and mucosal CD4 depletion, leading to immunodeficiency. The impact of early HIV infection on cervical CD4 T-cell populations in humans remains poorly described. METHODS: We analyzed cytobrush-derived immune cells by flow cytometry and cytokines in cervicovaginal lavage from participants in early HIV (<6 months postinfection), chronic HIV, and HIV-uninfected controls. RESULTS: CD4:CD8 ratios declined rapidly in both the cervix and the blood following HIV infection. In contrast, absolute cervical CD4 T-cell counts in early HIV were comparable to HIV uninfected participants, declining only in chronic infection. Early HIV infection was associated with increases in RANTES and MIP3a in cervicovaginal fluids. Concurrently, slight increases in activated cells (CD38HLA-DR) and higher levels of CTLA4 expression on Tregs in the cervix were observed. Although study groups did not differ with respect to levels of CCR5, integrin B7, or CD69, the frequencies of Th17 cells (defined as CCR6CCR10) was reduced by >10-fold in early HIV infection and Th1 cells (defined as CCR6CXCR3) were reduced by >2-fold. Although CCR6CCR10 cells did not differ in HIV receptor expression, these cells produced higher levels of interferon gamma and interleukin 17. CONCLUSIONS: These data support the model of initial CD4 T-cell depletion followed by overall T-cell influx in response to infection and concomitant increases in immune activation, inflammation, and regulatory markers. These data are among the earliest characterization of the cellular milieu in the female genital tract following male-to-female HIV transmission. PMID- 25296097 TI - Changes in bone mineral density after 96 weeks of treatment with atazanavir/ritonavir or lopinavir/ritonavir plus tenofovir DF/emtricitabine in treatment-naive patients with HIV-1 infection: the CASTLE body composition substudy. AB - : Antiretroviral therapy initiation is associated with declines in bone mineral density (BMD), which seem greatest with tenofovir disoproxil fumarate (DF) containing regimens. Data comparing protease inhibitors are limited. This CASTLE substudy compared paired baseline with week 96 BMD in patients initiating tenofovir DF/emtricitabine plus atazanavir/ritonavir (n = 106) vs lopinavir/ritonavir (n = 70). In both groups, week 96 BMD declined significantly in arm, leg, trunk, and total body regions. Atazanavir/ritonavir was associated with smaller 96-week trunk and total body BMD declines compared with lopinavir/ritonavir [multivariate-adjusted least squares mean difference +2.00% (95% confidence interval: 0.52 to 3.45; P = 0.008) and +1.24% (95% confidence interval: 0.13 to 2.35; P = 0.029), respectively]. In addition, low baseline CD4 cell count (<50 cells per microliter) and increasing age were associated with larger declines in BMD. PMID- 25296096 TI - "If I take my medicine, I will be strong: " evaluation of a pediatric HIV disclosure intervention in Namibia. AB - BACKGROUND: Despite known benefits, only a small proportion of HIV-infected children in sub-Saharan Africa know their status and limited disclosure interventions exist. Namibia's Ministry of Health and Social Services developed and implemented a multipronged intervention to support health care workers (HCWs) and caregivers in the disclosure process. METHODS: The intervention included a staged disclosure cartoon book, child and caregiver readiness assessment tools, a monitoring form to track progress over visits, and HCW training curriculum. We conducted qualitative interviews with 35 HCWs and 46 caregivers of HIV-positive children at 4 high volume HIV clinics. Interviews elicited detailed information about intervention uptake and impact. HCWs also participated in a self-efficacy survey. RESULTS: The intervention improved HCW and caregiver confidence and communication skills in pediatric disclosure. The most valuable intervention component was the disclosure cartoon book, which provided structure, language, and guidance for a gradual disclosure process. HCWs reported it greatly reduced caregiver resistance to disclosure. Both caregivers and HCWs reported improved knowledge and ability to support the pediatric patient, improved child understanding of how HIV medications work, increased child hopefulness for their future, and improved child adherence to care and treatment. HCW self-efficacy surveys found that HCWs who received training felt more confident in their ability to engage in the disclosure process. CONCLUSIONS: HCWs and caregivers highly endorsed the intervention. Given the urgency to address pediatric HIV disclosure in Africa, and the utility and low cost of the locally-produced disclosure tool, this approach may be useful in other similar settings. PMID- 25296099 TI - Association between latent toxoplasmosis and psychiatric disorders in HIV infected subjects. PMID- 25296098 TI - Comparing the novel method of assessing PrEP adherence/exposure using hair samples to other pharmacologic and traditional measures. AB - OBJECTIVE: The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. DESIGN: Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. METHODS: At weeks 8 and 16, self-reported pill taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). RESULTS: Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41-0.86, all P < 0.001). CONCLUSIONS: Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted. PMID- 25296100 TI - Test, treat, and cure. PMID- 25296101 TI - Potential for conceptual bias in studies of racial disparities in HIV infection. PMID- 25296102 TI - The impact of alpha-lipoic acid on amikacin-induced nephrotoxicity. AB - Amikacin (AK) is an antibacterial drug, but it has remarkable nephrotoxic and ototoxic side effects due to increase in reactive oxygen radicals. This study was established to determine the possible protective effects of alpha-lipoic acid (ALA), a powerful antioxidant, on AK-induced nephrotoxicity. Three different groups of rats (n = 6) were administered saline (control), AK (1.2 g/kg, intraperitoneally), ALA (100 mg/kg, p.o.) and AK combination (ALA one day before the AK for five days). Renal function, oxidative stress markers and histological changes were evaluated at the end of the experiment. Malondialdehyde was increased as an indicator of free radical formation in AK-induced group and decreased with ALA treatment. While catalase activity was increased significantly, superoxide dismutase and glutathione peroxidase activities were not statistically significant increased with ALA treatment. The result showed that AK enhanced levels of urea, creatinine and blood urea nitrogen in serum significantly. Administration of ALA reduced these levels of biochemical markers. Histopathological observations were confirmed by biochemical findings. In conclusion, ALA is suggested to be a potential candidate to ameliorate AK-induced nephrotoxicity. PMID- 25296103 TI - A meta-analysis on the relationship of eNOS 4b/a polymorphism and diabetic nephropathy susceptibility. AB - To clarify the effect of nitric oxide synthase (NOS) type III 4b/a polymorphism on the susceptibility to diabetic nephropathy (DN) by meta-analysis, we performed a computerized search of PubMed, EMBASE, Chinese BioMedical Literature Database, China Science and Technology Journal Database, Chinese Journal Full-text Database and WanFang to identity case-control studies on relationship between NOS type III 4b/a polymorphism and the susceptibility to DN. Statistic analysis and heterogeneity test were conducted by StataSE12. The meta-analysis involved 26 studies for DN comparing with diabetes mellitus (DM) and 15 studies for DN comparing with healthy persons, which provided 6144/4900 cases/controls and 2134/2348 cases/controls, respectively. Moderate heterogeneity was found among including studies. The qualities of half studies are low. Meta-analysis derived a significant association between the NOS type III 4b/a and the risk of developing DN in Asian population. The sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) produced non-significant changes. Compared with diabetes patients, the pre-allele model produced certain association in global populations [odds ratio (OR) = 1.26, 95% confidence interval (95% CI): 1.10 1.45], significant association in Asian population (OR = 1.51, 95% CI: 1.13-2.01) and certain association in type 2 DM patients (OR = 1.29, 95% CI: 1.09-1.54). Only in the dominant model, the funnel plot and Egger's test provided evidence of publication bias (p = 0.024). Overall, although there is some evidence of association between NOS type III 4b/a polymorphism and DN in Asian population, the more reliable findings need further and more rigorous, prospective and high quality studies. PMID- 25296104 TI - Association of malnutrition-inflammation score, dialysis-malnutrition score and serum albumin with novel risk factors for cardiovascular diseases in hemodialysis patients. AB - BACKGROUND: This study was designed to investigate the associations between malnutrition-inflammation score (MIS), dialysis-malnutrition score (DMS) and serum albumin with novel risk factors for cardiovascular diseases (CVD) in hemodialysis (HD) patients. METHODS: In this cross-sectional study, 291 HD patients were randomly selected from among 2302 adult HD patients in Tehran HD centers. The MIS and DMS were determined during one of the dialysis sessions in these patients. In addition, 4 mL blood was obtained before dialysis and analyzed for serum albumin and novel risk factors for CVD, including C-reactive protein (CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, malondialdehyde (MDA), nitric oxide (NO), endothelin-1 and lipoprotein (a) [Lp (a)]. RESULTS: MIS and DMS were significantly positively correlated with serum CRP (p < 0.01) and sICAM 1 (p < 0.01), whereas serum albumin concentration was significantly negatively correlated with serum CRP (p < 0.01) and sICAM-1 (p < 0.01). There were no significant correlations between MIS, DMS and serum albumin with serum concentrations of sVCAM-1, sE-selectin, MDA, NO, endothelin-1 and Lp (a). CONCLUSION: This study indicates that protein-energy wasting indicators in HD patients are associated with serum CRP and sICAM-1, as two CVD risk factors. PMID- 25296105 TI - Connective tissue growth factor induces tubular epithelial to mesenchymal transition through the activation of canonical Wnt signaling in vitro. AB - BACKGROUND: Overwhelming evidences suggest epithelial to mesenchymal transition (EMT) of tubular epithelial cells contributes to renal fibrosis of chronic kidney disease (CKD). Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of EMT. However, the molecular mechanisms that regulate cell behaviors are not clear. OBJECTIVE: The purpose of this study was to investigate whether CTGF induces EMT via activation of canonical Wnt signaling in renal tubular epithelial cells. METHODS: Human renal proximal tubular epithelial cells (HK-2) were divided into control group, CTGF group and dickkopf (Dkk)-1 plus CTGF group. We assessed the biological changes of canonical Wnt signaling, including phosphorylation of low-density lipoprotein receptor-related protein (LRP6) and glycogen synthase kinase-3beta (GSK-3beta) and accumulation and nuclear localization of beta-catenin. Meanwhile, morphological changes of the three groups were observed and tubular EMT was further confirmed by detecting the expression of alpha-SMA and E-cadherin. RESULTS: The phosphorylation levels of LRP6 and GSK-3beta and the expression of beta-catenin in CTGF group were higher than control group (p < 0.05). The accumulation and nuclear localization of beta catenin was induced in CTGF group. Meanwhile, CTGF group cells showed a mesenchymal morphological phenotype and exhibited increased expressions of E cadherin and decreased expressions of alpha-SMA compared to control group (p < 0.05), suggesting tubular EMT. Furthermore, we also found that Dkk-1 blocked the above CTGF's effects by binding with LRP6. CONCLUSION: CTGF induces EMT via activation of canonical Wnt signaling in HK-2 cells in vitro, which may play an important role in the renal fibrosis of CKD. PMID- 25296107 TI - Possible pathogenic mechanism of propofol infusion syndrome involves coenzyme q. AB - BACKGROUND: Propofol is a short-acting intravenous anesthetic agent. In rare conditions, a life-threatening complication known as propofol infusion syndrome can occur. The pathophysiologic mechanism is still unknown. Some studies suggested that propofol acts as uncoupling agent, others suggested that it inhibits complex I or complex IV, or causes increased oxidation of cytochrome c and cytochrome aa3, or inhibits mitochondrial fatty acid metabolism. Although the exact site of interaction is not known, most hypotheses point to the direction of the mitochondria. METHODS: Eight rats were ventilated and sedated with propofol up to 20 h. Sequential biopsy specimens were taken from liver and skeletal muscle and used for determination of respiratory chain activities and propofol concentration. Activities were also measured in skeletal muscle from a patient who died of propofol infusion syndrome. RESULTS: In rats, authors detected a decrease in complex II+III activity starting at low tissue concentration of propofol (20 to 25 uM), further declining at higher concentrations. Before starting anesthesia, the complex II+III/citrate synthase activity ratio in liver was 0.46 (0.25) and in skeletal muscle 0.23 (0.05) (mean [SD]). After 20 h of anesthesia, the ratios declined to 0.17 (0.03) and 0.12 (0.02), respectively. When measured individually, the activities of complexes II and III remained normal. Skeletal muscle from one patient taken in the acute phase of propofol infusion syndrome also shows a selective decrease in complex II+III activity (z score: -2.96). CONCLUSION: Propofol impedes the electron flow through the respiratory chain and coenzyme Q is the main site of interaction with propofol. PMID- 25296109 TI - Improving the management of hip fractures in the elderly: a role for the perioperative surgical home? PMID- 25296108 TI - Neurophysiological correlates of sevoflurane-induced unconsciousness. AB - BACKGROUND: Recent studies of anesthetic-induced unconsciousness in humans have focused predominantly on the intravenous drug propofol and have identified anterior dominance of alpha rhythms and frontal phase-amplitude coupling patterns as neurophysiological markers. However, it is unclear whether the correlates of propofol-induced unconsciousness are generalizable to inhaled anesthetics, which have distinct molecular targets and which are used more commonly in clinical practice. METHODS: The authors recorded 64-channel electroencephalograms in healthy human participants during consciousness, sevoflurane-induced unconsciousness, and recovery (n = 10; n = 7 suitable for analysis). Spectrograms and scalp distributions of low-frequency (1 Hz) and alpha (10 Hz) power were analyzed, and phase-amplitude modulation between these two frequencies was calculated in frontal and parietal regions. Phase lag index was used to assess phase relationships across the cortex. RESULTS: At concentrations sufficient for unconsciousness, sevoflurane did not result in a consistent anteriorization of alpha power; the relationship between low-frequency phase and alpha amplitude in the frontal cortex did not undergo characteristic transitions. By contrast, there was significant cross-frequency coupling in the parietal region during consciousness that was not observed after loss of consciousness. Furthermore, a reversible disruption of anterior-posterior phase relationships in the alpha bandwidth was identified as a correlate of sevoflurane-induced unconsciousness. CONCLUSION: In humans, sevoflurane-induced unconsciousness is not correlated with anteriorization of alpha and related cross-frequency patterns, but rather by a disruption of phase-amplitude coupling in the parietal region and phase-phase relationships across the cortex. PMID- 25296110 TI - From Park Ridge to Schaumburg to the World Wide Web: the Wood Library-Museum of Anesthesiology. PMID- 25296111 TI - Early warning system scores for clinical deterioration in hospitalized patients: a systematic review. AB - RATIONALE: Early warning system (EWS) scores are used by hospital care teams to recognize early signs of clinical deterioration and trigger more intensive care. OBJECTIVE: To systematically review the evidence on the ability of early warning system scores to predict a patient's risk of clinical deterioration and the impact of early warning system implementation on health outcomes and resource utilization. METHODS: We searched the MEDLINE, CINAHL, and Cochrane Central Register of Controlled Trials databases through May 2014. We included English language studies of early warning system scores used with adults admitted to medical or surgical wards. We abstracted study characteristics, including population, setting, sample size, duration, and criteria used for early warning system scoring. For predictive ability, the primary outcomes were modeled for discrimination on 48-hour mortality, cardiac arrest, or pulmonary arrest. Outcomes for the impact of early warning system implementation included 30-day mortality, cardiovascular events, use of vasopressors, respiratory failure, days on ventilator, and resource utilization. We assessed study quality using a modified Quality in Prognosis Studies assessment tool where applicable. MEASUREMENTS AND MAIN RESULTS: Of 11,183 citations studies reviewed, one controlled trial and 20 observational studies of 13 unique models met our inclusion criteria. In eight studies, researchers addressed the predictive ability of early warning system tools and found a strong predictive value for death (area under the receiver operating characteristic curve [AUROC], 0.88-0.93) and cardiac arrest (AUROC, 0.74-0.86) within 48 hours. In 13 studies (one controlled trial and 12 pre-post observational studies), researchers addressed the impact on health outcomes and resource utilization and had mixed results. The one controlled trial was of good quality, and the researchers found no difference in mortality, transfers to the ICU, or length of hospital stay. The pre-post designs of the remaining studies have significant methodological limitations, resulting in insufficient evidence to draw conclusions. CONCLUSIONS: Early warning system scores perform well for prediction of cardiac arrest and death within 48 hours, although the impact on health outcomes and resource utilization remains uncertain, owing to methodological limitations. Efforts to assess performance and effectiveness more rigorously will be needed as early warning system use becomes more widespread. PMID- 25296112 TI - From crescent to mature virion: vaccinia virus assembly and maturation. AB - Vaccinia virus (VACV) has achieved unprecedented success as a live viral vaccine for smallpox which mitigated eradication of the disease. Vaccinia virus has a complex virion morphology and recent advances have been made to answer some of the key outstanding questions, in particular, the origin and biogenesis of the virion membrane, the transformation from immature virion (IV) to mature virus (MV), and the role of several novel genes, which were previously uncharacterized, but have now been shown to be essential for VACV virion formation. This new knowledge will undoubtedly contribute to the rational design of safe, immunogenic vaccine candidates, or effective antivirals in the future. This review endeavors to provide an update on our current knowledge of the VACV maturation processes with a specific focus on the initiation of VACV replication through to the formation of mature virions. PMID- 25296113 TI - Constitutive phospholipid scramblase activity of a G protein-coupled receptor. AB - Opsin, the rhodopsin apoprotein, was recently shown to be an ATP-independent flippase (or scramblase) that equilibrates phospholipids across photoreceptor disc membranes in mammalian retina, a process required for disc homoeostasis. Here we show that scrambling is a constitutive activity of rhodopsin, distinct from its light-sensing function. Upon reconstitution into vesicles, discrete conformational states of the protein (rhodopsin, a metarhodopsin II-mimic, and two forms of opsin) facilitated rapid (>10,000 phospholipids per protein per second) scrambling of phospholipid probes. Our results indicate that the large conformational changes involved in converting rhodopsin to metarhodopsin II are not required for scrambling, and that the lipid translocation pathway either lies near the protein surface or involves membrane packing defects in the vicinity of the protein. In addition, we demonstrate that beta2-adrenergic and adenosine A2A receptors scramble lipids, suggesting that rhodopsin-like G protein-coupled receptors may play an unexpected moonlighting role in re-modelling cell membranes. PMID- 25296115 TI - Comparative analysis of antiviral responses in Brachypodium distachyon and Setaria viridis reveals conserved and unique outcomes among C3 and C4 plant defenses. AB - Viral diseases cause significant losses in global agricultural production, yet little is known about grass antiviral defense mechanisms. We previously reported on host immune responses triggered by Panicum mosaic virus (PMV) and its satellite virus (SPMV) in the model C3 grass Brachypodium distachyon. To aid comparative analyses of C3 and C4 grass antiviral defenses, here, we establish B. distachyon and Setaria viridis (a C4 grass) as compatible hosts for seven grass infecting viruses, including PMV and SPMV, Brome mosaic virus, Barley stripe mosaic virus, Maize mild mottle virus, Sorghum yellow banding virus, Wheat streak mosaic virus (WSMV), and Foxtail mosaic virus (FoMV). Etiological and molecular characterization of the fourteen grass-virus pathosystems showed evidence for conserved crosstalk among salicylic acid (SA), jasmonic acid, and ethylene pathways in B. distachyon and S. viridis. Strikingly, expression of PHYTOALEXIN DEFICIENT4, an upstream modulator of SA signaling, was consistently suppressed during most virus infections in B. distachyon and S. viridis. Hierarchical clustering analyses further identified unique antiviral responses triggered by two morphologically similar viruses, FoMV and WSMV, and uncovered other host dependent effects. Together, the results of this study establish B. distachyon and S. viridis as models for the analysis of plant-virus interactions and provide the first framework for conserved and unique features of C3 and C4 grass antiviral defenses. PMID- 25296116 TI - Resistance to Plum pox virus strain C in Arabidopsis thaliana and Chenopodium foetidum involves genome-linked viral protein and other viral determinants and might depend on compatibility with host translation initiation factors. AB - Research performed on model herbaceous hosts has been useful to unravel the molecular mechanisms that control viral infections. The most common Plum pox virus (PPV) strains are able to infect Nicotiana species as well as Chenopodium and Arabidopsis species. However, isolates belonging to strain C (PPV-C) that have been adapted to Nicotiana spp. are not infectious either in Chenopodium foetidum or in Arabidopsis thaliana. In order to determine the mechanism underlying this interesting host-specific behavior, we have constructed chimerical clones derived from Nicotiana-adapted PPV isolates from the D and C strains, which differ in their capacity to infect A. thaliana and C. foetidum. With this approach, we have identified the nuclear inclusion a protein (VPg+Pro) as the major pathogenicity determinant that conditions resistance in the presence of additional secondary determinants, different for each host. Genome-linked viral protein (VPg) mutations similar to those involved in the breakdown of eIF4E mediated resistance to other potyviruses allow some PPV chimeras to infect A. thaliana. These results point to defective interactions between a translation initiation factor and the viral VPg as the most probable cause of host-specific incompatibility, in which other viral factors also participate, and suggest that complex interactions between multiple viral proteins and translation initiation factors not only define resistance to potyviruses in particular varieties of susceptible hosts but also contribute to establish nonhost resistance. PMID- 25296114 TI - A DNA barcoding approach to characterize pollen collected by honeybees. AB - In the present study, we investigated DNA barcoding effectiveness to characterize honeybee pollen pellets, a food supplement largely used for human nutrition due to its therapeutic properties. We collected pollen pellets using modified beehives placed in three zones within an alpine protected area (Grigna Settentrionale Regional Park, Italy). A DNA barcoding reference database, including rbcL and trnH-psbA sequences from 693 plant species (104 sequenced in this study) was assembled. The database was used to identify pollen collected from the hives. Fifty-two plant species were identified at the molecular level. Results suggested rbcL alone could not distinguish among congeneric plants; however, psbA-trnH identified most of the pollen samples at the species level. Substantial variability in pollen composition was observed between the highest elevation locality (Alpe Moconodeno), characterized by arid grasslands and a rocky substrate, and the other two sites (Cornisella and Ortanella) at lower altitudes. Pollen from Ortanella and Cornisella showed the presence of typical deciduous forest species; however in samples collected at Ortanella, pollen of the invasive Lonicera japonica, and the ornamental Pelargonium x hortorum were observed. Our results indicated pollen composition was largely influenced by floristic local biodiversity, plant phenology, and the presence of alien flowering species. Therefore, pollen molecular characterization based on DNA barcoding might serve useful to beekeepers in obtaining honeybee products with specific nutritional or therapeutic characteristics desired by food market demands. PMID- 25296117 TI - Palladium-catalyzed direct regioselective ortho-phosphonation of aromatic azo compounds with dialkyl phosphites. AB - An efficient palladium-catalyzed regioselective C-P bond formation of azo compounds through C-H bond functionalization using dialkyl phosphites as phosphorus source under mild conditions was developed. A series of both symmetrical and unsymmetrical azoarenes were successfully phosphonylated through this procedure with tolerance of a broad range of functional groups. PMID- 25296118 TI - [Sport with defibrillator -- is that possible?]. PMID- 25296119 TI - [Implants in sports -- exercise is good]. PMID- 25296120 TI - [Health -- men need to exercise more, please!]. PMID- 25296121 TI - [Dear readers]. PMID- 25296126 TI - Visual outcome in early vitrectomy for posterior persistent fetal vasculature associated with traction retinal detachment. AB - PURPOSE: This study investigates the anatomical and visual outcome of vitrectomy for the treatment of unilateral posterior persistent fetal vasculature with associated traction retinal detachment in very young patients. METHODS: A retrospective case series study from 1998 through 2010 of 11 eyes in 11 patients who underwent pars plana vitrectomy with or without lensectomy for unilateral posterior persistent fetal vasculature with traction retinal detachment affecting the macula. RESULTS: Ten of the 11 patients (91%) received surgical intervention when 13 months old or younger (average age, 4 months). Postoperatively, 6 of 10 eyes (60%) had 20/800 or better vision, 2 of which had 20/60 vision. All 10 patients in this group had their retinas reattached postoperatively with significant reversal of retinal dragging. One of the 11 patients (9%) received surgical intervention for posterior persistent fetal vasculature at 33 months of age. This patient had persistent traction retinal detachment and a postoperative visual acuity of hand motion. Postoperative glaucoma was detected in 4 patients (36%). CONCLUSION: This study suggests that early intervention in patients with unilateral posterior persistent fetal vasculature with associated macula affecting traction retinal detachment may provide a better visual and anatomical outcome when vitrectomy and retinal reattachment are performed at a very early age. PMID- 25296127 TI - Choroidal osteoma shows bone lamella and vascular channels on enhanced depth imaging optical coherence tomography in 15 eyes. AB - PURPOSE: To describe enhanced depth imaging optical coherence tomography findings of choroidal osteoma. METHODS: Retrospective, observational case series of 15 eyes with choroidal osteoma imaged with EDI-OCT. RESULTS: The mean age at presentation was 27 years. There were 10 women and 3 men. The visual acuity ranged from 20/20 to hand motion, with reduced visual acuity secondary to photoreceptor loss in the foveola (n = 5) or subfoveal fluid (n = 1), and additional choroidal neovascular membrane (n = 3). The mean basal tumor diameter was 8.0 mm, and ultrasonographic thickness was 1.5 mm. Using enhanced depth imaging optical coherence tomography, the mean tumor thickness was 589 MUm when compared with a matched choroidal region in the unaffected eye of 247 MUm (138% increased thickness) (P = 0.009). The tumor surface topography was classified (ultrasonography vs. enhanced depth imaging optical coherence tomography) as flat (87 vs. 13%), dome (13 vs. 40%), or undulating (0 vs. 47%). On enhanced depth imaging optical coherence tomography, unique features included horizontal lamellar lines (presumed bone lamella) (n = 15, 100%) and hyperreflective horizontal lines (presumed cement lines) (n = 8, 53%). Other features included horizontal tubular lamella with optically empty center (presumed Haversian canals or vascular channels) (n = 9, 60%), vertical tubular lamella (presumed Volkmann canals or vascular channels) (n = 2, 13%), and speckled regions (presumed compact or small trabecular bone) (n = 6, 40%). Of the nine eyes with subfoveolar osteoma, the tumor was completely ossified (n = 4), partially deossified (n = 2), or completely deossified (n = 3). Photoreceptor thinning/atrophy was found in all five eyes with deossified osteoma, whereas intact photoreceptor appearance was noted in the four eyes with ossified subfoveal osteoma. CONCLUSION: Enhanced depth imaging optical coherence tomography reveals characteristic surface topography of choroidal osteoma as dome or undulating (87%) with unique intrinsic features of horizontal lamellar lines (100%), horizontal (60%) or vertical (13%) tubules, and speckled regions (40%). Photoreceptor loss was evident in every case of tumor deossification. PMID- 25296128 TI - Identification of unknown microcontaminants in Dutch river water by liquid chromatography-high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. AB - In the past decade during automated surface water monitoring in the river Meuse at border station Eijsden in The Netherlands, a set of unknown compounds were repeatedly detected by online liquid chromatography-diode-array detection in a relatively high signal intensity. Because of the unknown nature of the compounds, the consequently unknown fate of this mixture in water treatment processes, the location being close to the water inlet of a drinking water supply company and their possible adverse public health effects, it was deemed necessary to elucidate the identity of the compounds. No data are available for the occurrence of these unknowns at downstream locations. After concentration and fractionation of a sample by preparative Liquid Chromatography, identification experiments were performed using Liquid Chromatography-High Resolution Mass Spectrometry (LC-HR MS) combined with High Resolution Nuclear Magnetic Resonance Spectroscopy (HR NMR). Accurate mass determination of the unknown parent compound and its fragments obtained in MS/MS provided relevant information on the elemental composition of the unknown compounds. With the use of NMR techniques and the information about the elemental composition, the identity of the compounds in the different sample fractions was determined. Beside some regularly detected compounds in surface water, like caffeine and bisphenol-S, five dihydroxydiphenylmethane isomers were identified. The major unknown compound was identified as 4,4'-dihydroxy-3,5,3',5'-tetra(hydroxymethyl)diphenylmethane. This compound was confirmed by analysis of the pure reference compound. This is one of the first studies that employs the combination of high resolution MS with NMR for identification of truly unknown compounds in surface waters at the MUg/L level. Five of the seven identified compounds are unexpected and not contained in the CAS database, while they can be presumed to be products generated during the production of resins. PMID- 25296129 TI - New methods and applications in solid-state NMR spectroscopy of quadrupolar nuclei. AB - Solid-state nuclear magnetic resonance (NMR) spectroscopy has long been established as offering unique atomic-scale and element-specific insight into the structure, disorder, and dynamics of materials. NMR spectra of quadrupolar nuclei (I > (1)/2) are often perceived as being challenging to acquire and to interpret because of the presence of anisotropic broadening arising from the interaction of the electric field gradient and the nuclear electric quadrupole moment, which broadens the spectral lines, often over several megahertz. Despite the vast amount of information contained in the spectral line shapes, the problems with sensitivity and resolution have, until very recently, limited the application of NMR spectroscopy of quadrupolar nuclei in the solid state. In this Perspective, we provide a brief overview of the quadrupolar interaction, describe some of the basic experimental approaches used for acquiring high-resolution NMR spectra, and discuss the information that these spectra can provide. We then describe some interesting recent examples to showcase some of the more exciting and challenging new applications of NMR spectra of quadrupolar nuclei in the fields of energy materials, microporous materials, Earth sciences, and biomaterials. Finally, we consider the possible directions that this highly informative technique may take in the future. PMID- 25296130 TI - [Laboratory test features of newly diagnosed adult HIV-infected patients in Ouagadougou (Burkina Faso)]. AB - In a sub-Saharan African population of adults beginning care for HIV infection, we sought to describe some laboratory features and their correlation with disease progression. We retrospectively reviewed pretreatment laboratory records of recently diagnosed adults (Elisa test) beginning care at the Internal Medicine department of Yalgado Ouedraogo University Hospital between June 2009 and August 2010. The values have been classified according to WHO standards. During the study period, 177 patients were newly diagnosed as HIV-positive. Among them, 144 (81.4%) had CD4 counts below 350 cells/MUL. The mean hemoglobin level was 10.3 +/ 2.1 g/dL for women (n = 94) and 11.2 +/- 2.8 g/dL for men (n = 67, p = 0.028), and 113 (71.1%) had anemia, 12 of them severe (7.5%). Anemia and lymphopenia were significantly correlated with a low CD4 count (p = 0.001 and 0.003 respectively). Six patients (3.4%) also had type 2 diabetes. Total cholesterol was normal in all patients, and 8 (10.4%) had hypertriglyceridemia. Hematopoietic, glycemic and lipid disorders seem relatively common in untreated black patients with HIV infection. A low CD4 count appears to predict hematopoietic cell deficits. PMID- 25296131 TI - Study of the formation and solution properties of worm-like micelles formed using both N-hexadecyl-N-methylpiperidinium bromide-based cationic surfactant and anionic surfactant. AB - The viscoelastic properties of worm-like micelles formed by mixing the cationic surfactant N-hexadecyl-N-methylpiperidinium bromide (C16MDB) with the anionic surfactant sodium laurate (SL) in aqueous solutions were investigated using rheological measurements. The effects of sodium laurate and temperature on the worm-like micelles and the mechanism of the observed shear thinning phenomenon and pseudoplastic behavior were systematically investigated. Additionally, cryogenic transmission electron microscopy images further ascertained existence of entangled worm-like micelles. PMID- 25296132 TI - Inhibitors of Phosphodiesterase 4, but Not Phosphodiesterase 3, Increase beta2 Agonist-Induced Expression of Antiinflammatory Mitogen-Activated Protein Kinase Phosphatase 1 in Airway Smooth Muscle Cells. AB - beta2-agonists are principally used in asthma to provide bronchodilation; however, they also have antiinflammatory properties, due, in part, to their ability to up-regulate mitogen-activated protein kinase phosphatase (MKP) 1 in a cAMP-dependent manner. Phosphodiesterases (PDEs) are attractive targets for potentiating the antiinflammatory response. There are 11 subfamilies of PDE enzymes; among these, inhibition of PDE3 and PDE4 are the main targets for airway smooth muscle (ASM). PDE enzymes are important intracellular regulators that catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and/or 3',5' cyclic guanosine monophosphate to their inactive forms. Given that MKP-1 is cAMP dependent, and inhibition of PDE acts to increase beta2-agonist-induced cAMP, it is possible that the presence of PDE inhibitors may enhance beta2-adrenoceptor mediated responses. We address this herein by comparing the ability of a panel of inhibitors against PDE3 (cilostamide, cilostazol, milrinone) or PDE4 (cilomilast, piclamilast, rolipram) to increase cAMP, MKP-1 mRNA expression, and protein up regulation in ASM cells induced in response to the beta2-agonist formoterol. Our data show that inhibitors of PDE4, but not PDE3, increase beta2-agonist-induced cAMP and induce MKP-1 mRNA expression and protein up-regulation. When cAMP was increased, there was a concomitant increase in MKP-1 levels and significant inhibition of TNF-alpha-induced CXCL8 (IL-8). This result was consistent with all PDE4 inhibitors examined but not for the PDE3 inhibitors. These findings reinforce cAMP-dependent control of MKP-1 expression, and suggest that PDE4 is the predominant PDE isoform responsible for formoterol-induced cAMP breakdown in ASM cells. Our study is the first to demonstrate that PDE4 inhibitors augment antiinflammatory effects of beta2-agonists via increased MKP-1 expression in ASM cells. PMID- 25296133 TI - Low-temperature molecular motions in lipid bilayers in the presence of sugars: insights into cryoprotective mechanisms. AB - Sugars and sugar alcohols can stabilize biological systems under extreme conditions of desiccation and freezing. Phospholipid bilayers solvated by aqueous solutions of sucrose, trehalose, and sorbitol at concentrations of 0.2 and 1 M and containing incorporated spin-labeled stearic acids were studied by electron spin echo (ESE) spectroscopy, a pulsed version of electron paramagnetic resonance (EPR). The phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and the stearic acids were labeled with nitroxide 4,4-dimethyl-oxazolidine-1-oxyl (DOXYL) attached rigidly at either the 5th or 16th carbon positions. The ratio of the echo time traces for the two field positions in the EPR spectrum possessing the largest and smallest anisotropies gave the anisotropic contribution to the echo decay, which obeys exponential time dependence with good accuracy. At low temperatures, the anisotropic contribution is induced by stochastic (or diffusive) orientational vibrations of the molecule as a whole (i.e., stochastic molecular librations), with the exponential decay rate Wanis proportional to tauc, where is the mean angular amplitude of the motion and tauc is the correlation time. In all cases, it was found that Wanis begins to increase sharply above 170-200 K, which was ascribed to the dynamical transition known for biological systems at these temperatures. For hydration by the sucrose and trehalose solutions, Wanis was found to increase noticeably also above ~120 K, which was explained by bilayer expansion due to direct bonding of sugar molecules to the bilayer surface. The Wanis temperature dependencies were found to be close to those obtained for the simple systems of the nitroxide spin probe TEMPONE in aqueous sorbitol and sugar 1 M solutions. This correlation suggests a possible mechanism of cryoprotective action of sorbitol and sugars due to the similarity of low-temperature motions in the membrane and in the cryoprotectant containing surrounding liquid. PMID- 25296134 TI - Planning and evaluating health programs: contributions of the RE-AIM framework to nursing. PMID- 25296135 TI - Beliefs related to adherence to oral antidiabetic treatment according to the Theory of Planned Behavior. AB - OBJECTIVE: to identify salient behavioral, normative, control and self-efficacy beliefs related to the behavior of adherence to oral antidiabetic agents, using the Theory of Planned Behavior. METHOD: cross-sectional, exploratory study with 17 diabetic patients in chronic use of oral antidiabetic medication and in outpatient follow-up. Individual interviews were recorded, transcribed and content-analyzed using pre-established categories. RESULTS: behavioral beliefs concerning advantages and disadvantages of adhering to medication emerged, such as the possibility of avoiding complications from diabetes, preventing or delaying the use of insulin, and a perception of side effects. The children of patients and physicians are seen as important social references who influence medication adherence. The factors that facilitate adherence include access to free-of-cost medication and taking medications associated with temporal markers. On the other hand, a complex therapeutic regimen was considered a factor that hinders adherence. Understanding how to use medication and forgetfulness impact the perception of patients regarding their ability to adhere to oral antidiabetic agents. CONCLUSION: medication adherence is a complex behavior permeated by behavioral, normative, control and self-efficacy beliefs that should be taken into account when assessing determinants of behavior. PMID- 25296136 TI - Association of cardiovascular risk factors with the different presentations of acute coronary syndrome. AB - OBJECTIVE: to identify the relationship between different presentations of acute coronary syndrome and cardiovascular risk factors among hospitalized individuals. METHOD: cross-sectional study performed in a teaching hospital in Sao Paulo, in the State of Sao Paulo (SP). Socio-demographic, clinical and anthropometric data of 150 individuals hospitalized due to acute coronary syndrome were collected through interviews and review of clinical charts. Association between these data and the presentation of the syndrome were investigated. RESULTS: there was a predominance of ST segment elevation acute myocardial infarction. There was significant association of systemic hypertension with unstable angina and high values of low density lipoprotein with infarction, without influence from socio demographic characteristics. CONCLUSION: arterial hypertension and high levels of low-density lipoprotein were associated with different presentations of coronary syndrome. The results can provide support for health professionals for secondary prevention programs aimed at behavioural changing. PMID- 25296137 TI - Arterial hypertension and other risk factors associated with cardiovascular diseases among adults. AB - OBJECTIVE: to identify the prevalence of arterial hypertension and its association with cardiovascular risk factors among adults. METHOD: cross sectional, population-based, descriptive study conducted with 408 adult individuals. Data were collected through a questionnaire and measurements of weight, height and waist circumference. Person's Chi-square and multiple logistic regression were used in the data analysis. RESULTS: 23.03% of the individuals reported hypertension with a higher prevalence among women. Odds Ratio indicated that smoking, body mass index, waist circumference, diabetes mellitus and dyslipidemia were positively associated with arterial hypertension. CONCLUSION: high self-reported hypertension and its association with other cardiovascular risk factors such as diabetes, obesity and dyslipidemia show the need for specific nursing interventions and the implementation of protocols focused on minimizing complications arising from hypertension, as well as to prevent the emergence of other cardiovascular diseases. PMID- 25296138 TI - Out-of-hospital cardiac arrest: determinant factors for immediate survival after cardiopulmonary resuscitation. AB - OBJECTIVE: to analyze determinant factors for the immediate survival of persons who receive cardiopulmonary resuscitation from the advanced support units of the Mobile Emergency Medical Services (SAMU) of Belo Horizonte. METHOD: this is a retrospective, epidemiological study which analyzed 1,165 assistance forms, from the period 2008 - 2010. The collected data followed the Utstein style, being submitted to descriptive and analytical statistics with tests with levels of significance of 5%. RESULTS: the majority were male, the median age was 64 years, and the ambulance response time, nine minutes. Immediate survival was observed in 239 persons. An association was ascertained of this outcome with "cardiac arrest witnessed by persons trained in basic life support" (OR=3.49; p<0.05; CI 95%), "cardiac arrest witnessed by Mobile Emergency Medical Services teams" (OR=2.99; p<0.05; CI95%), "only the carry out of basic life support" (OR=0.142; p<0.05; CI95%), and "initial cardiac rhythm of asystole" (OR=0.33; p<0.05; CI 95%). CONCLUSION: early access to cardiopulmonary resuscitation was related to a favorable outcome, and the non-undertaking of advanced support, and asystole, were associated with worse outcomes. Basic and advanced life support techniques can alter survival in the event of cardiac arrest. PMID- 25296139 TI - Pain intensity, disability and depression in individuals with chronic back pain. AB - OBJECTIVES: to measure the pain intensity, identify the disability and depression levels in people with chronic back pain and to correlate these variables. A cross sectional, descriptive and exploratory study was undertaken at the Pain Treatment Clinic of the University of Sao Paulo at Ribeirao Preto Hospital das Clinicas, between February and June 2012, after receiving approval from the Ethics Committee at the University of Sao Paulo at Ribeirao Preto College of Nursing. METHOD: sixty subjects with chronic back pain participated. The instruments used were: the 11-point Numerical Category Scale, the Roland-Morris Disability Questionnaire and the Beck Depression Inventory. To analyze the data, the arithmetic means, standard deviations and Spearman's correlation coefficient were calculated. RESULTS: the findings show that the participants presented high pain, disability and depression levels. The correlation between pain intensity and disability and between pain intensity and depression was positive and weak and, between disability and depression, positive and moderate. CONCLUSION: the study variables showed moderate and weak indices and the mutual correlations were positive. PMID- 25296140 TI - Quality of life assessment of patients with and without venous ulcer. AB - OBJECTIVES: to compare the quality of life of patients with chronic venous disease with and without ulcer and to identify the most affected aspects. METHOD: cross-sectional study with a sample of 204 patients with chronic venous disease. The quality of life was assessed with the help of the SF-36 questionnaire. To compare the scores between the groups, the Mann-Whitney test was used, considering a statistically significant difference when p<0.05. RESULTS: the quality of life score of patients with ulcer was lower when compared to that of patients without ulcer, in all domains and dimensions of the SF-36, particularly in the domains physical aspect and functional capacity, with very low scores. CONCLUSION: all aspects of quality of life were more compromised in people with ulcers. These findings can contribute towards a better understanding of the effects of chronic venous disease on the quality of life and towards a better orientation of therapeutic interventions in this population. PMID- 25296141 TI - Quality of life and people living with AIDS: relationship with sociodemographic and health aspects. AB - OBJECTIVE: to analyze the relationship of sociodemographic and health dimensions with the quality of life of people living with the human immunodeficiency virus. METHOD: descriptive and quantitative study. The subjects were 131 seropositive people treated in a specialized center of the Norte-Fluminense municipality, Brazil. A form with sociodemographic and health data was applied, as well as the World Health Organization instrument for the assessment of the quality of life of people with the human immunodeficiency virus. RESULTS: the statistical analysis revealed a significant difference in the assessment of the various dimensions of quality of life by the subjects for gender, education, employment, personal income, medical condition, self-perception of sickness, history of hospitalizations, and bodily alterations due to the antiretroviral drugs. CONCLUSION: professional nursing and health care, as well as public policies in the area, should valorize the quality of life approach, considering the conditions related to its configuration. PMID- 25296142 TI - Cultural adaptation to Brazil of the questionnaire Costs of caring for children with cancer. AB - OBJECTIVE: to present the cultural adaptation of the questionnaire Costs of caring for children with cancer, offering a valid and reliable tool to assess the economic repercussions of childhood cancer for Brazilian families. METHOD: it is a methodological research with a cross-sectional design. The methodological framework to validate the questionnaire was a combined process that included seven steps: translation to Portuguese; first translated consensus version; evaluation by Expert Committee; consensus on the Expert Committee version; back translation; consensus of back-translated versions; semantic validation. The study was conducted in two phases: phase one was the translation and back translations process, with five expert committee members. Phase two was the semantic validation, with 24 participants, who answered an instrument about their impressions of the questionnaire and suggested modifications. RESULTS: in phase one, items were included, excluded, and replaced to make the content equivalent and valid for use with Brazilian context. In phase two, the majority of the participants were mothers, who made suggestions about the relevance and clarity of the items in the questionnaire. CONCLUSIONS: the authors discussed these recommendations and made adaptations, turning the questionnaire into a valid and reliable tool for application. PMID- 25296143 TI - Validity and reliability of a pediatric patient classification instrument. AB - OBJECTIVES: to assess the construct validity and reliability of the Pediatric Patient Classification Instrument. METHODS: correlation study developed at a teaching hospital. The classification involved 227 patients, using the pediatric patient classification instrument. The construct validity was assessed through the factor analysis approach and reliability through internal consistency. RESULTS: the Exploratory Factor Analysis identified three constructs with 67.5% of variance explanation and, in the reliability assessment, the following Cronbach's alpha coefficients were found: 0.92 for the instrument as a whole; 0.88 for the Patient domain; 0.81 for the Family domain; 0.44 for the Therapeutic procedures domain. CONCLUSIONS: the instrument evidenced its construct validity and reliability, and these analyses indicate the feasibility of the instrument. The validation of the Pediatric Patient Classification Instrument still represents a challenge, due to its relevance for a closer look at pediatric nursing care and management. Further research should be considered to explore its dimensionality and content validity. PMID- 25296144 TI - Child safety from the perspective of essential needs. AB - OBJECTIVE: to characterize the maternal care for children under one year of age with a view to child health promotion at home. METHOD: exploratory study with qualitative data analysis, thematic mode, based on the conceptual framework of the essential needs of children, based on interviews recorded with 16 mothers. RESULTS: the analysis of the maternal narratives showed elements that facilitate the promotion of child safety: presence and involvement of the parents, constant surveillance for physical and emotional protection, experiences to stimulate child development, support networks for childcare at home; and inhibiting elements of child safety: limited perception of characteristics of child development and of children's singularities, overprotection and difficulties to set limits. CONCLUSION: the study enhances the understanding of home care in child health promotion, directing professional actions to guarantee ongoing nurturing relationships, protection, respect for individual differences, experiences appropriate to child development, limit setting and construction of stable and supportive social networks. In addition, the relevance of considering the maternal perspective in child health care is considered, as a strategy to apprehend aspects related to the attendance of the growth and development needs, particularly for child health promotion at home. PMID- 25296145 TI - Development and validation of an educational booklet for healthy eating during pregnancy. AB - OBJECTIVE: to describe the validation process of an educational booklet for healthy eating in pregnancy using local and regional food. METHODS: methodological study, developed in three steps: construction of the educational booklet, validation of the educational material by judges, and by pregnant women. The validation process was conducted by 22 judges and 20 pregnant women, by convenience selection. We considered a p-value<0.85 to validate the booklet compliance and relevance, according to the six items of the instrument. As for content validation, the item-level Content Validity Index (I-CVI) was considered when a minimum score of at least 0.80 was obtained. RESULTS: five items were considered relevant by the judges. The mean I-CVI was 0.91. The pregnant women evaluated positively the booklet. The suggestions were accepted and included in the final version of the material. CONCLUSION: the booklet was validated in terms of content and relevance, and should be used by nurses for advice on healthy eating during pregnancy. PMID- 25296146 TI - Activities of the healthcare team for women who smoke during pregnancy and the puerperium. AB - OBJECTIVE: to identify activities developed by the healthcare team for pregnant and postpartum women who smoke. METHOD: cross-sectional study with a sample of 135 healthcare team members who assist pregnant and postpartum women in a university hospital located in southern Brazil. The data was collected using questionnaires and analyzed using the Statistical Package for Social Sciences software. RESULTS: 76 (56.3%) staff members reported that they always addressed smoking cessation; however, the approach occurred in only two periods of the hospitalization and/or prenatal consultations, not including family members. In regard to the effectiveness of their actions, the health team assessed it as fair or poor, and mentioned the need for updating knowledge regarding this issue. CONCLUSIONS: the health team did not perform the approach as recommended by the tobacco control guidelines, requiring training to offer a qualified and efficient intervention. PMID- 25296147 TI - The effects of compensatory workplace exercises to reduce work-related stress and musculoskeletal pain. AB - OBJECTIVES: to assess the effect of a compensatory workplace exercise program on workers with the purpose of reducing work-related stress and musculoskeletal pain. METHOD: quasi-experimental research with quantitative analysis of the data, involving 30 administrative workers from a Higher Education Public Institution. For data collection, questionnaires were used to characterize the workers, as well as the Workplace Stress Scale and the Corlett Diagram. The research took place in three stages: first: pre-test with the application of the questionnaires to the subjects; second: Workplace Exercise taking place twice a week, for 15 minutes, during a period of 10 weeks; third: post-test in which the subjects answered the questionnaires again. For data analysis, the descriptive statistics and non-parametric statistics were used through the Wilcoxon Test. RESULTS: work related stress was present in the assessed workers, but there was no statistically significant reduction in the scores after undergoing Workplace Exercise. However, there was a statistically significant pain reduction in the neck, cervical, upper, middle and lower back, right thigh, left leg, right ankle and feet. CONCLUSION: the Workplace Exercise promoted a significant pain reduction in the spine, but did not result in a significant reduction in the levels of work-related stress. PMID- 25296148 TI - Acute kidney injury after contrast-enhanced examination among elderly. AB - OBJECTIVES: to assess renal function in elderly patients undergoing contrast enhanced computed tomography and identify the preventive measures of acute kidney injury in the period before and after the examination. METHOD: longitudinal cohort study conducted at the Federal University of Sao Paulo Hospital, from March 2011 to March 2013. All hospitalized elderly, of both sexes, aged 60 years and above, who performed the examination, were included (n=93). We collected sociodemographic data, data related to the examination and to the care provided, and creatinine values prior and post exam. RESULTS: an alteration in renal function was observed in 51 patients (54%) with a statistically significant increase of creatinine values (p<0.04), and two patients (4.0%) required hemodialysis. CONCLUSION: There is an urgent need for protocols prior to and post contrast-enhanced examination in the elderly, and other studies to verify the prognosis of this population. PMID- 25296149 TI - Influence of the length of institutionalization on older adults' postural balance and risk of falls: a transversal study. AB - OBJECTIVE: to ascertain the influence of the length of institutionalization on older adults' balance and risk of falls. METHOD: to evaluate the risk of falls, the Berg Balance Scale and the Timed Get Up and Go test were used; and for measuring postural balance, static stabilometry was used, with acquisition of the elliptical area of 95% and mean velocities on the x and y axes of center of pressure displacement. Parametric and nonparametric measures of association and comparison (alpha<0.05) were used. RESULTS: there was no significant correlation between the length of institutionalization and the tests for evaluation of risk of falling, neither was there difference between groups and within subgroups, stratified by length of institutionalization and age. In the stabilometric measurements, there was a negative correlation between the parameters analyzed and the length of institutionalization, and difference between groups and within subgroups. CONCLUSION: this study's results point to the difficulty of undertaking postural control tasks, showing a leveling below the clinical tests' reference scores. In the stabilometric behavior, one should note the reduction of the parameters as the length of institutionalization increases, contradicting the assumptions. This study's results offer support for the development of a multi professional model for intervention with the postural control and balance of older adults living in homes for the aged. PMID- 25296150 TI - Pre-frailty and frailty of elderly residents in a municipality with a low Human Development Index. AB - OBJECTIVE: to identify the prevalence of the factors associated with pre-frailty and frailty of elderly residents in a municipality with a low Human Development Index METHOD: Cross-sectional study with a populational and household framework conducted with 316 elderly people. Frailty was determined from the presence of three or more of the following factors: (i) self-reported unintentional weight loss; (ii) lack of strength and energy; (iii) weakness; (iv) slowness; (v) low level of physical activity. The association between frailty and socio demographic, behavioral and health factors was measured using the multinomial logistic regression technique. RESULTS: The prevalence of pre-frailty and frailty was 58.7% and 23.8%, respectively. The adjusted regression model showed that the state of pre-frailty was associated with gender, age group and BMI, and frailty was associated with gender, age group, hospitalization, functional capacity, and self-perceived health. CONCLUSION: The evidence presented in this study demonstrates more variables associated with the frailty condition, reinforcing the concept of a multifactorial clinical syndrome that may result in the loss of functionality. PMID- 25296151 TI - Prevalence and intensity of chronic pain and self-perceived health among elderly people: a population-based study. AB - OBJECTIVE: to identify the prevalence and intensity of chronic pain among elderly people of the community and to analyze associations with the self-perceived health status. METHOD: cross-sectional study with a populational sample (n=934), conducted through household interviews in the city of Goiania, Brazil. The intensity of chronic pain (existing for 6 months or more) was measured using a numerical scale (0-10) and the self-perceived health through a verbal scale (very good, good, fair, poor, very poor). For the statistical analysis, the absolute frequency and percentage, CI (95%), Chi-square test, Odds ratio, and regression analysis were used. Significance of 5%. RESULTS: The prevalence of chronic pain was 52.8% [CI (95%):49.4-56.1]; most frequently located in the lower limbs (34.5%) and lumbar region (29.5%); with high or the worst possible intensity for 54.6% of the elderly people. The occurrence of chronic pain was associated with (p<0.0001) a worse self-perception of health (OR=4.2:2.5-7.0), a greater number of chronic diseases (OR=1.8:1.2-2.7), joint disease (OR=3.5:2.4-5.1) and the female gender (OR=2.3:1.7-3.0). A lower intensity of chronic pain was associated with a better self-perception of health (p<0.0001). CONCLUSION: the majority of the elderly people of the community reported chronic pain, of a severe intensity, and located in areas related to movement activities, thus influencing the morbidity and mortality of this population. PMID- 25296152 TI - The meaning of pharmacological treatment for schizophrenic patients. AB - OBJECTIVE: to understand the meaning of medication therapy for schizophrenic patients and formulate a theoretical model about the study phenomenon. METHOD: a qualitative approach was employed, using Symbolic Interactionism as the theoretical and Grounded Theory as the methodological framework. The research was developed between 2008 and 2010 at three community mental health services in the interior of the State of Sao Paulo - Brazil. Thirty-six patients and thirty-six family members were selected through theoretical sampling. The data were mainly collected through open interviews and observation and simultaneously analyzed through open, axial and selective coding. RESULTS: the meaning of the pharmacotherapy is centered on the phenomenon "Living with a help that bothers", which expresses the patients' ambivalence towards the medication and determines their decision making. The insight, access, limitations for self-administration of the drugs and interactions with family members and the health team influenced the patient's medication-related behavior. CONCLUSION: the theory presented in this study provides a comprehensive, contextualized, motivational and dynamic understanding of the relation the patient experiences and indicates potentials and barriers to follow the medication treatment. PMID- 25296153 TI - Impact of "+Contigo" training on the knowledge and attitudes of health care professionals about suicide. AB - OBJECTIVES: to evaluate the results of "+Contigo" training, developed by nurses and directed at 66 health professionals of integrated school health teams in Primary Health Care. METHOD: quantitative with data collection through the Suicide Behavior Attitude Questionnaire, administered before and after the training. RESULTS: significant increases were observed in suicide prevention knowledge and in changing attitudes of health professionals towards individuals with suicidal behavior. CONCLUSION: these results allow us to affirm that nurses hold scientific and pedagogical knowledge that grant them a privileged position in the health teams, to develop training aimed at health professionals involved in suicide prevention. PMID- 25296154 TI - Nicotine dependence in the mental disorders, relationship with clinical indicators, and the meaning for the user. AB - OBJECTIVE: to identify the degree of nicotine dependence among patients with schizophrenia and other mental disorders hospitalized in a general hospital, correlating these indices with clinical indicators and the meaning for the user. METHOD: the study was performed in the psychiatric unit of a general hospital, interviewing 270 patients with mental disorders using a questionnaire and the application of the Fagerstrom test. A descriptive statistical analysis of the data and thematic analysis of the content were performed. RESULTS: among the 270 patients with mental disorders, 35.6% were smokers; of whom, 53.2% presented high or very high nicotine dependence. Of the 96 smokers, 32 (33.3%) were schizophrenic, among whom, 59.4% presented high or very high dependence. Higher levels of dependence were also found among the 59 elderly people (61.5%) and 60 subjects with somatic comorbidities (62.5%). Meanings of smoking for the subjects: helps to forget problems and face daily conflicts; alleviates side effects of the medications; self-control; distraction; part of life. CONCLUSION: more intense tobacco dependence among schizophrenic patients is justified due to it helping them to cope with the difficulties of the disease. Nurses occupy a strategic position in the care. PMID- 25296155 TI - BMI gain and insulin resistance among school-aged children: a population-based longitudinal study in the Brazilian Amazon. AB - Investigation of the determinants of metabolic outcomes associated with non communicable diseases is increasingly important in developing countries, but such parameters have not been explored extensively during childhood. The present study assessed the impact of weight gain, measured as BMI-for-age Z-scores, on glucose and insulin concentrations, homeostasis model assessment index of insulin resistance (HOMA-IR) values, and systolic and diastolic blood pressure during school years among Amazonian children. A population-based prospective study of 696 children aged >4 to <= 10 years with complete anthropometric information at baseline (51% females and 86% of mixed race) was carried out; 411 children had data on metabolic parameters after a median follow-up period of 2.0 years (range 1.7-2.6 years). During follow-up, there was a significant increase in the proportion of overweight children (BMI-for-age Z-score >1) from 10.1 to 15.8% (P= 0.003). In linear regression models adjusted for the child's sex, age, race/ethnicity, baseline household wealth, birth weight and pubertal development stage, for each unit of BMI-for-age Z-score variation during follow-up, an increase of 8.58 (95% CI 7.68, 9.60) pmol/l in fasting plasma insulin concentrations and 1.47 (95% CI 1.30, 1.66) in HOMA-IR values was observed. There was no significant impact of weight gain on glucose concentrations and systolic and diastolic blood pressure. In conclusion, we found evidence that an increase in BMI during a 2-year period affected insulin resistance during school years. Considering the significant increase in overweight in this age group, special attention should be paid to monitoring increases in BMI in children from the Brazilian Amazon. PMID- 25296156 TI - Regioselective thiolation of arenes and heteroarenes: C-H functionalization strategy for C-S bond formation. AB - A facile transition-metal-free oxidative cross-dehydrogenative coupling reaction involving selective formation of a C-S bond leading to the synthesis of arylthiobenzoxazoles, heteroarylthiobenzoxazoles, and arylthiobenzothiazoles has been described. This highly regioselective C-H functionalization reaction with electron-rich aromatic systems including heteroaromatics is achieved by reversing the reactivity of sulfur in the presence of a suitable oxidant and strong acid. PMID- 25296157 TI - Comparative pathogenicity in Swiss mice of Trypanosoma cruzi IV from northern Brazil and Trypanosoma cruzi II from southern Brazil. AB - The geographical heterogeneity of Chagas disease (ChD) is mainly caused by genetic variability of the etiological agent Trypanosoma cruzi. Our hypothesis was that the pathogenicity for mice may vary with the genetic lineage (or Discrete Typing Unit - DTU) of the parasite. To test this hypothesis, parasitological and histopathological evaluations were performed in mice inoculated with strains belonging to the DTU T. cruzi IV (TcIV) from the State of Amazonas (northern Brazil), or the DTU T. cruzi II (TcII) from the State of Parana (southern Brazil). Groups of 10 Swiss mice were inoculated with eight strains of TcIV obtained from acute cases (7) from two outbreaks of orally acquired ChD, and from the triatomine Rhodnius robustus (1) from Amazonas; and three strains of TcII obtained from chronic patients in Parana. We evaluated the pre-patent period, patent period, maximum peak of parasitemia, day of maximum peak of parasitemia, area under the parasitemia curve, inflammatory process, and tissue parasitism in the acute phase. TcIV was less virulent than TcII, and showed significantly (p < 0.005) lower parasitemia levels. Although the levels of tissue parasitism did not differ statistically, mice infected with TcIV displayed significantly (p < 0.001) fewer inflammatory processes than mice infected with TcII. This supported the working hypothesis, since TcIV from Amazonas was less pathogenic than TcII from Parana; and agreed with the lower severity of human cases of ChD in the Amazon region. PMID- 25296159 TI - The N-pact factor: evaluating the quality of empirical journals with respect to sample size and statistical power. AB - The authors evaluate the quality of research reported in major journals in social personality psychology by ranking those journals with respect to their N-pact Factors (NF)-the statistical power of the empirical studies they publish to detect typical effect sizes. Power is a particularly important attribute for evaluating research quality because, relative to studies that have low power, studies that have high power are more likely to (a) to provide accurate estimates of effects, (b) to produce literatures with low false positive rates, and (c) to lead to replicable findings. The authors show that the average sample size in social-personality research is 104 and that the power to detect the typical effect size in the field is approximately 50%. Moreover, they show that there is considerable variation among journals in sample sizes and power of the studies they publish, with some journals consistently publishing higher power studies than others. The authors hope that these rankings will be of use to authors who are choosing where to submit their best work, provide hiring and promotion committees with a superior way of quantifying journal quality, and encourage competition among journals to improve their NF rankings. PMID- 25296160 TI - Chemoselective synthesis of trifluoromethylated gamma-butenolide derivatives via phosphine-promoted tandem reaction of allylic carbonates and trifluoromethyl ketones. AB - A novel chemoselective phosphine-mediated tandem reaction between nonsubstituted MBH carbonates and aryl trifluoromethyl ketones is described. The product selectivity of the reaction is easily tunable by changing the ratios of the two reactants, and mono- or bicyclic bistrifluoromethylated vinyl gamma-butenolide products can be prepared with good chemoselectivity in modest-to-good yields and diastereoselectivities. The formation of the bicyclic gamma-butenolide structures via a one-pot four-step sequence under phosphine catalysis is unprecedented. PMID- 25296161 TI - IL-23 p19 knockout mice exhibit minimal defects in responses to primary and secondary infection with Francisella tularensis LVS. AB - Our laboratory's investigations into mechanisms of protective immunity against Francisella tularensis Live Vaccine Strain (LVS) have uncovered mediators important in host defense against primary infection, as well as those correlated with successful vaccination. One such potential correlate was IL-12p40, a pleiotropic cytokine that promotes Th1 T cell function as part of IL-12p70. LVS infected IL-12p40 deficient knockout (KO) mice maintain a chronic infection, but IL-12p35 KO mice clear LVS infection; thus the role that IL-12p40 plays in immunity to LVS is independent of the IL-12p70 heterodimer. IL-12p40 can also partner with IL-23p19 to create the heterodimeric cytokine IL-23. Here, we directly tested the role of IL-23 in LVS resistance, and found IL-23 to be largely dispensable for immunity to LVS following intradermal or intranasal infection. IL-23p19 KO splenocytes were fully competent in controlling intramacrophage LVS replication in an in vitro overlay assay. Further, antibody responses in IL-23p19 KO mice were similar to those of normal wild type mice after LVS infection. IL-23p19 KO mice or normal wild type mice that survived primary LVS infection survived maximal doses of LVS secondary challenge. Thus p40 has a novel role in clearance of LVS infection that is unrelated to either IL-12 or IL-23. PMID- 25296162 TI - Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. AB - Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention. PMID- 25296163 TI - Accidental genetic engineers: horizontal sequence transfer from parasitoid wasps to their Lepidopteran hosts. AB - We show here that 105 regions in two Lepidoptera genomes appear to derive from horizontally transferred wasp DNA. We experimentally verified the presence of two of these sequences in a diverse set of silkworm (Bombyx mori) genomes. We hypothesize that these horizontal transfers are made possible by the unusual strategy many parasitoid wasps employ of injecting hosts with endosymbiotic polydnaviruses to minimize the host's defense response. Because these virus-like particles deliver wasp DNA to the cells of the host, there has been much interest in whether genetic information can be permanently transferred from the wasp to the host. Two transferred sequences code for a BEN domain, known to be associated with polydnaviruses and transcriptional regulation. These findings represent the first documented cases of horizontal transfer of genes between two organisms by a polydnavirus. This presents an interesting evolutionary paradigm in which host species can acquire new sequences from parasitoid wasps that attack them. Hymenoptera and Lepidoptera diverged ~300 MYA, making this type of event a source of novel sequences for recipient species. Unlike many other cases of horizontal transfer between two eukaryote species, these sequence transfers can be explained without the need to invoke the sequences 'hitchhiking' on a third organism (e.g. retrovirus) capable of independent reproduction. The cellular machinery necessary for the transfer is contained entirely in the wasp genome. The work presented here is the first such discovery of what is likely to be a broader phenomenon among species affected by these wasps. PMID- 25296165 TI - Frequency and zero-point vibrational energy scale factors for double-hybrid density functionals (and other selected methods): can anharmonic force fields be avoided? AB - We have obtained uniform frequency scaling factors lambda(harm) (for harmonic frequencies), lambda(fund) (for fundamentals), and lambda(ZPVE) (for zero-point vibrational energies (ZPVEs)) for the Weigend-Ahlrichs and other selected basis sets for MP2, SCS-MP2, and a variety of DFT functionals including double hybrids. For selected levels of theory, we have also obtained scaling factors for true anharmonic fundamentals and ZPVEs obtained from quartic force fields. For harmonic frequencies, the double hybrids B2PLYP, B2GP-PLYP, and DSD-PBEP86 clearly yield the best performance at RMSD = 10-12 cm(-1) for def2-TZVP and larger basis sets, compared to 5 cm(-1) at the CCSD(T) basis set limit. For ZPVEs, again, the double hybrids are the best performers, reaching root-mean square deviations (RMSDs) as low as 0.05 kcal/mol, but even mainstream functionals like B3LYP can get down to 0.10 kcal/mol. Explicitly anharmonic ZPVEs only are marginally more accurate. For fundamentals, however, simple uniform scaling is clearly inadequate. PMID- 25296164 TI - Operator dependent choice of prostate cancer biopsy has limited impact on a gene signature analysis for the highly expressed genes IGFBP3 and F3 in prostate cancer epithelial cells. AB - BACKGROUND: Predicting the prognosis of prostate cancer disease through gene expression analysis is receiving increasing interest. In many cases, such analyses are based on formalin-fixed, paraffin embedded (FFPE) core needle biopsy material on which Gleason grading for diagnosis has been conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator's choice of biopsy was evaluated. METHODS: Multiple biopsy samples from 43 patients were evaluated using a previously reported gene signature of IGFBP3, F3 and VGLL3 with potential prognostic value in estimating overall survival at diagnosis of prostate cancer. A four multiplex one-step qRT-PCR test kit, designed and optimized for measuring the signature in FFPE core needle biopsy samples was used. Concordance of gene expression levels between primary and secondary Gleason tumor patterns, as well as benign tissue specimens, was analyzed. RESULTS: The gene expression levels of IGFBP3 and F3 in prostate cancer epithelial cell containing tissue representing the primary and secondary Gleason patterns were high and consistent, while the low expressed VGLL3 showed more variation in its expression levels. CONCLUSION: The assessment of IGFBP3 and F3 gene expression levels in prostate cancer tissue is independent of Gleason patterns, meaning that the impact of operator's choice of biopsy is low. PMID- 25296166 TI - Electrical stimulation using conductive polymer polypyrrole promotes differentiation of human neural stem cells: a biocompatible platform for translational neural tissue engineering. AB - Conductive polymers (CPs) are organic materials that hold great promise for biomedicine. Potential applications include in vitro or implantable electrodes for excitable cell recording and stimulation and conductive scaffolds for cell support and tissue engineering. In this study, we demonstrate the utility of electroactive CP polypyrrole (PPy) containing the anionic dopant dodecylbenzenesulfonate (DBS) to differentiate novel clinically relevant human neural stem cells (hNSCs). Electrical stimulation of PPy(DBS) induced hNSCs to predominantly beta-III Tubulin (Tuj1) expressing neurons, with lower induction of glial fibrillary acidic protein (GFAP) expressing glial cells. In addition, stimulated cultures comprised nodes or clusters of neurons with longer neurites and greater branching than unstimulated cultures. Cell clusters showed a similar spatial distribution to regions of higher conductivity on the film surface. Our findings support the use of electrical stimulation to promote neuronal induction and the biocompatibility of PPy(DBS) with hNSCs and opens up the possibility of identifying novel mechanisms of fate determination of differentiating human stem cells for advanced in vitro modeling, translational drug discovery, and regenerative medicine. PMID- 25296167 TI - Self-assembled multiwalled carbon nanotube films assisted by ureidopyrimidinone based multiple hydrogen bonds. AB - Self-assembled functionalized multiwalled carbon nanotube (MWNT) films were successfully constructed, linked by a kind of strong binding strength from the self-complementary hydrogen-bonding array of ureidopyrimidinone-based modules (UPM) attached. Employing the feasible reaction of isocyanate containing ureidopyrimidinone with amine modified MWNTs, the UPMs composed of ureidopyrimidinone and ureido were attached to MWNTs with the content as low as 0.6 mmol/g MWNTs. Upon multiple hydrogen-bonding interactions from incorporation of the AADD (A, hydrogen-bonding acceptor; D, hydrogen-bonding donor) quadruple hydrogen bonds of ureidopyrimidinone and the double hydrogen bonds of ureido group, UPM functionalized MWNTs (MWNT-UPM) can be well dispersed in the polar solvent of N,N-dimethylformamide (DMF), while they tend to self-assemble to give a self-supported film in the apolar solvent of CHCl3. In addition, by using the multiple hydrogen-bonding interactions as the driving force, the layer-by-layer (LBL) MWNT-UPM films with high coverage on solid slides can be processed. Because of the self-association of MWNT-UPM in apolar solvent, it was found that the LBL assembly of MWNT-UPM was more favorable in the polar solvent of DMF than in the apolar solvent of CHCl3. Moreover, the hydrogen-bonding linked MWNT-UPM films showed good stability upon soaking in different solvents. Furthermore, the as prepared LBL films showed electrochemical active behaviors, exhibiting a remarkable catalytic effect on the reduction of nifedipine. PMID- 25296168 TI - DMG-alpha--a computational geometry library for multimolecular systems. AB - The DMG-alpha library grants researchers in the field of computational biology, chemistry, and biophysics access to an open-sourced, easy to use, and intuitive software for performing fine-grained geometric analysis of molecular systems. The library is capable of computing power diagrams (weighted Voronoi diagrams) in three dimensions with 3D periodic boundary conditions, computing approximate projective 2D Voronoi diagrams on arbitrarily defined surfaces, performing shape properties recognition using alpha-shape theory and can do exact Solvent Accessible Surface Area (SASA) computation. The software is written mainly as a template-based C++ library for greater performance, but a rich Python interface (pydmga) is provided as a convenient way to manipulate the DMG-alpha routines. To illustrate possible applications of the DMG-alpha library, we present results of sample analyses which allowed to determine nontrivial geometric properties of two Escherichia coli-specific lipids as emerging from molecular dynamics simulations of relevant model bilayers. PMID- 25296169 TI - Transparent conducting aerogels of antimony-doped tin oxide. AB - Bulk antimony-doped tin oxide aerogels are prepared by epoxide-initiated sol-gel processing. Tin and antimony precursors are dissolved in ethanol and water, respectively, and propylene oxide is added to cause rapid gelation of the sol, which is then dried supercritically. The Sb:Sn precursor mole ratio is varied from 0 to 30% to optimize the material conductivity and absorbance. The materials are characterized by electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy (XPS), nitrogen physisorption analysis, a four-point probe resistivity measurement, and UV-vis diffuse reflectance spectroscopy. The samples possess morphology typical of aerogels without significant change with the amount of doping. Calcination at 450 degrees C produces a cassiterite crystal structure in all aerogel samples. Introduction of Sb at 15% in the precursor (7.6% Sb by XPS) yields a resistivity more than 3 orders of magnitude lower than an undoped SnO2 aerogel. Calcination at 800 degrees C reduces the resistivity by an additional 2 orders of magnitude to 30 Omega.cm, but results in a significant decrease in surface area and pore volume. PMID- 25296170 TI - Array comparative genomic hybridisation testing in CHD. AB - BACKGROUND: CHD is the leading cause of mortality due to birth defects. Array comparative genomic hybridisation (aCGH) detects submicroscopic copy number changes and may improve identification of the genetic basis of CHD. METHODS: This is a retrospective analysis of 1252 patients from a regional referral centre who had undergone aCGH. Of the patients, 173 had CHD. A whole-genome custom-designed oligonucleotide array with >44,000 probes was used to detect copy number changes. RESULTS: Of the 1252 patients, 335 (26.76%) had abnormal aCGH results. Of the 173 patients with CHD, 50 (28.9%) had abnormal aCGH results versus 284 (26.3%) of 1079 non-cardiac patients. There were six patients with CHD who had well described syndromes such as Wolf-Hirschhorn, trisomy 13, DiGeorge, and Williams. Of the patients with CHD, those with left-sided heart disease had the highest proportion (14/31; 45.13%) of abnormal aCGH results, followed by those with conotruncal heart disease (10/29; 34.48%), endocardial cushion defects (13/50; 26%), complex/other heart disease (12/52; 23.08%), and patent ductus arteriosus (1/11; 9.09%). CONCLUSIONS: Patients with CHD are at a substantial risk of having microdeletions and microduplications. The incidence of abnormalities on aCGH analysis is higher than identified with karyotype, and identification of copy number changes may help identify the genetic basis of the specific heart defects. However, aCGH may not have a significant diagnostic yield in those with isolated CHD. Further research using larger data sets may help identify candidate genes associated with CHD. PMID- 25296171 TI - Statistical analysis of long-term monitoring data for persistent organic pollutants in the atmosphere at 20 monitoring stations broadly indicates declining concentrations. AB - During recent decades concentrations of persistent organic pollutants (POPs) in the atmosphere have been monitored at multiple stations worldwide. We used three statistical methods to analyze a total of 748 time series of selected POPs in the atmosphere to determine if there are statistically significant reductions in levels of POPs that have had control actions enacted to restrict or eliminate manufacture, use and emissions. Significant decreasing trends were identified in 560 (75%) of the 748 time series collected from the Arctic, North America, and Europe, indicating that the atmospheric concentrations of these POPs are generally decreasing, consistent with the overall effectiveness of emission control actions. Statistically significant trends in synthetic time series could be reliably identified with the improved Mann-Kendall (iMK) test and the digital filtration (DF) technique in time series longer than 5 years. The temporal trends of new (or emerging) POPs in the atmosphere are often unclear because time series are too short. A statistical detrending method based on the iMK test was not able to identify abrupt changes in the rates of decline of atmospheric POP concentrations encoded into synthetic time series. PMID- 25296172 TI - Natural aminoacyl tRNA synthetase fragment enhances cardiac function after myocardial infarction. AB - A naturally-occurring fragment of tyrosyl-tRNA synthetase (TyrRS) has been shown in higher eukaryotes to 'moonlight' as a pro-angiogenic cytokine in addition to its primary role in protein translation. Pro-angiogenic cytokines have previously been proposed to be promising therapeutic mechanisms for the treatment of myocardial infarction. Here, we show that systemic delivery of the natural fragment of TyRS, mini-TyrRS, improves heart function in mice after myocardial infarction. This improvement is associated with reduced formation of scar tissue, increased angiogenesis of cardiac capillaries, recruitment of c-kitpos cells and proliferation of myocardial fibroblasts. This work demonstrates that mini-TyrRS has beneficial effects on cardiac repair and regeneration and offers support for the notion that elucidation of the ever expanding repertoire of noncanonical functions of aminoacyl tRNA synthetases offers unique opportunities for development of novel therapeutics. PMID- 25296173 TI - Spectral diffusion: an algorithm for robust material decomposition of spectral CT data. AB - Clinical successes with dual energy CT, aggressive development of energy discriminating x-ray detectors, and novel, target-specific, nanoparticle contrast agents promise to establish spectral CT as a powerful functional imaging modality. Common to all of these applications is the need for a material decomposition algorithm which is robust in the presence of noise. Here, we develop such an algorithm which uses spectrally joint, piecewise constant kernel regression and the split Bregman method to iteratively solve for a material decomposition which is gradient sparse, quantitatively accurate, and minimally biased. We call this algorithm spectral diffusion because it integrates structural information from multiple spectral channels and their corresponding material decompositions within the framework of diffusion-like denoising algorithms (e.g. anisotropic diffusion, total variation, bilateral filtration). Using a 3D, digital bar phantom and a material sensitivity matrix calibrated for use with a polychromatic x-ray source, we quantify the limits of detectability (CNR = 5) afforded by spectral diffusion in the triple-energy material decomposition of iodine (3.1 mg mL(-1)), gold (0.9 mg mL(-1)), and gadolinium (2.9 mg mL(-1)) concentrations. We then apply spectral diffusion to the in vivo separation of these three materials in the mouse kidneys, liver, and spleen. PMID- 25296174 TI - Phylogenetic relationships of the triassic archaeosemionotus deecke (halecomorphi, ionoscopiformes) from the 'perledo fauna'. AB - The lagerstatten in the Monte San Giorgio have provided excellent fossils representing one of the most important windows to the marine life during the Triassic. Among these fossils, fishes are abundant and extraordinarily well preserved. Most of these fishes represent extinct lineages and were difficult to understand and classify during the early years after discovery. These difficulties usually led to a mixture of species under the same taxonomic name. This is the case of fishes referred to the genus Archaeosemionotus. The name bearing type of A. connectens, the type species of this genus, represents a basal halecomorph, but most other fishes referred to this genus represent basal ginglymodians. Therefore, we conducted this study to clarify the taxonomic status and phylogenetic relationships of A. connectens, which is a member of the family Furidae (Halecomorphi, Ionoscopiformes) representing the second cladistically supported evidence of ionoscopiforms in the Triassic and it is thus one of the two oldest reliable records of this group. Ionoscopiforms have a long stratigraphic range, though their fossil record is rather patchy. In our analysis, the sister taxon of Archaeosemionotus is Robustichthys from the Anisian of China, and they together form a clade with Furo, which is known from several localities ranging from the Early to the Late Jurassic. Other ionoscopiforms are so far known from the Kimmeridgian to the Albian and it is thus evident that recent efforts have concentrated on the later history of the group (Late Jurassic to Cretaceous). The phylogenetic relationships obtained for the Ionoscopiformes do not show a clear palaeobiogeographic pattern, but give important new insights into the origin, divergence date and early history of this clade. PMID- 25296176 TI - Combinatorial pulsed laser deposition of magnetic and magneto-optical Sr(GaxTiyFe0.34-0.40)O3-delta perovskite films. AB - Ferromagnetic Sr(GaxTiyFe0.34-0.40)O3-delta (0.1 <= x, y <= 0.5) films with single-crystal perovskite structure were epitaxially grown on (001) (LaAlO3)0.3(Sr2AlTaO6)0.7 substrates by combinatorial pulsed laser deposition (CPLD) and compared with previous results from films grown from single targets. In CPLD films the Fe was present as both Fe(2+) and Fe(3+). The distribution of Sr, Ga, Ti, and O was homogeneous, but Fe-rich nanowires with diameter of 3 nm were present perpendicular to the film plane. The unit cell was tetragonally distorted with the ratio of out-of-plane to in-plane lattice parameter decreasing from 1.06 to 1.02 as the Ga content increased. The magnetic easy axis of the films changed from out-of-plane when Ti content y > 0.3 to isotropic as the Ga content increased, consistent with a reduction in magnetoelastic anisotropy. The Ga lowered the Faraday rotation and the magnetization but increased the optical transmittance. PMID- 25296175 TI - Comparison of amino acids physico-chemical properties and usage of late embryogenesis abundant proteins, hydrophilins and WHy domain. AB - Late Embryogenesis Abundant proteins (LEAPs) comprise several diverse protein families and are mostly involved in stress tolerance. Most of LEAPs are intrinsically disordered and thus poorly functionally characterized. LEAPs have been classified and a large number of their physico-chemical properties have been statistically analyzed. LEAPs were previously proposed to be a subset of a very wide family of proteins called hydrophilins, while a domain called WHy (Water stress and Hypersensitive response) was found in LEAP class 8 (according to our previous classification). Since little is known about hydrophilins and WHy domain, the cross-analysis of their amino acids physico-chemical properties and amino acids usage together with those of LEAPs helps to describe some of their structural features and to make hypothesis about their function. Physico-chemical properties of hydrophilins and WHy domain strongly suggest their role in dehydration tolerance, probably by interacting with water and small polar molecules. The computational analysis reveals that LEAP class 8 and hydrophilins are distinct protein families and that not all LEAPs are a protein subset of hydrophilins family as proposed earlier. Hydrophilins seem related to LEAP class 2 (also called dehydrins) and to Heat Shock Proteins 12 (HSP12). Hydrophilins are likely unstructured proteins while WHy domain is structured. LEAP class 2, hydrophilins and WHy domain are thus proposed to share a common physiological role by interacting with water or other polar/charged small molecules, hence contributing to dehydration tolerance. PMID- 25296177 TI - Induction of the viable but nonculturable state of Ralstonia solanacearum by low temperature in the soil microcosm and its resuscitation by catalase. AB - Ralstonia solanacearum is the causal agent of bacterial wilt on a wide variety of plants, and enters a viable but nonculturable (VBNC) state under stress conditions in soil and water. Here, we adopted an artificial soil microcosm (ASM) to investigate the VBNC state of R. solanacearum induced by low temperature. The culturability of R. solanacearum strains SL341 and GMI1000 rapidly decreased at 4 degrees C in modified ASM (mASM), while it was stably maintained at 25 degrees C in mASM. We hypothesized that bacterial cells at 4 degrees C in mASM are viable but nonculturable. Total protein profiles of SL341 cells at 4 degrees C in mASM did not differ from those of SL341 culturable cells at 25 degrees C in mASM. Moreover, the VBNC cells maintained in the mASM retained respiration activity. Catalase treatment effectively restored the culturability of nonculturable cells in mASM, while temperature increase or other treatments used for resuscitation of other bacteria were not effective. The resuscitated R. solanacearum from VBNC state displayed normal level of bacterial virulence on tomato plants compared with its original culturable bacteria. Expression of omp, oxyR, rpoS, dps, and the 16S rRNA gene quantified by RT-qPCR did not differ significantly between the culturable and VBNC states of R. solanacearum. Our results suggested that the VBNC bacterial cells in mASM induced by low temperature exist in a physiologically unique state. PMID- 25296181 TI - Mortality in the United States, 2012. AB - KEY FINDINGS: Data from the National Vital Statistics System, Mortality. Life expectancy at birth for the U.S. population reached a record high of 78.8 years in 2012. The age-adjusted death rate for the United States decreased 1.1% from 2011 to 2012 to a record low of 732.8 per 100,000 standard population. The 10 leading causes of death in 2012 remained the same as in 2011. Age-adjusted death rates decreased significantly from 2011 to 2012 for 8 of the 10 leading causes and increased significantly for one leading cause (suicide). The infant mortality rate decreased 1.5% from 2011 to 2012 to a historic low of 597.8 infant deaths per 100,000 live births. The 10 leading causes of infant death in 2012 remained the same as in 2011. This report presents 2012 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among residents of the United States by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population (1). Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, 10 leading causes of death, and 10 leading causes of infant death were analyzed by comparing 2012 final data with 2011 final data. PMID- 25296178 TI - Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat. AB - The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8-13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains. PMID- 25296179 TI - A novel role for D-alanylation of lipoteichoic acid of enterococcus faecalis in urinary tract infection. AB - BACKGROUND: Enterococci are the third most common cause of healthcare-associated infections, which include urinary tract infections, bacteremia and endocarditis. Cell-surface structures such as lipoteichoic acid (LTA) have been poorly examined in E. faecalis, especially with respect to urinary tract infections (UTIs). The dlt operon is responsible for the D-alanylation of LTA and includes the gene dltA, which encodes the D-alanyl carrier protein ligase (Dcl). The involvement of LTA in UTI infection by E. faecalis has not been studied so far. Here, we examined the role of teichoic acid alanylation in the adhesion of enterococci to uroepithelial cells. RESULTS: In a mouse model of urinary tract infection, we showed that E. faecalis 12030DeltadltA mutant colonizes uroepithelial surfaces more efficiently than wild type bacteria. We also demonstrated that this mutant adhered four fold better to human bladder carcinoma cell line T24 compared to the wild type strain. Bacterial adherence could be significantly inhibited by purified lipoteichoic acid (LTA) and inhibition was specific. CONCLUSION: In contrast to bacteraemia model and adherence to colon surfaces, E. faecalis 12030DeltadltA mutant colonized uroepithelial surfaces more efficiently than wild type bacteria. In the case of the uroepithelial surface the adherence to specific host cells could be prevented by purified LTA. Our results therefore suggest a novel function of alanylation of LTA in E. faecalis. PMID- 25296182 TI - Hierarchical nanocomposites of vanadium oxide thin film anchored on graphene as high-performance cathodes in li-ion batteries. AB - Hierarchical nanocomposites of V2O5 thin film anchored on graphene sheets were prepared by slow hydrolysis of vanadyl triisobutoxide on graphene oxide followed by thermal treatment. The nanocomposite possessed a hierarchical structure of thin V2O5 film uniformly grown on graphene, leading to a high specific surface area and a good electronic/ionic conducting path. When used as the cathode material, the graphene/V2O5 nanosheet nanocomposites exhibit higher specific capacity, better rate performance, and longer cycle life, as compared to the pure V2O5. The nanocomposite cathode was able to deliver a specific capacity of 243 mAh/g, 191 mAh/g, and 86 mAh/g at a current density of 50 mA/g, 500 mA/g, and 15 A/g, respectively. Even after 300 cycles at 500 mA/g, the composite electrode still exhibited a specific capacity of ~ 122 mAh/g, which corresponds to ~ 64% of its initial capacity. This enhanced electrochemical performance can be attributed to facile electron transport between graphene and V2O5, fast Li-ion diffusion within the electrode, the high surface area of the composites, and a pore structure that can accommodate the volume change during lithiation/delithiation, which results from the unique hierarchical nanostructure of the V2O5 anchored on graphene. PMID- 25296183 TI - Evaluation of intereye corneal asymmetry in patients with keratoconus. A scheimpflug imaging study. AB - PURPOSE: To assess the correlation between keratoconus severity and intereye asymmetry of pachymetric data and posterior elevation values and to evaluate their combined accuracy in discriminating normal corneas from those with keratoconus. METHODS: This study included 97 patients: 65 subjects with bilateral normal corneas (NC) and 32 with keratoconus (KC). Central corneal thickness (CCT), thinnest corneal thickness (ThCT) and posterior elevation (PE) at the thinnest point of the cornea were measured in both eyes using Scheimpflug imaging. Intereye asymmetry and its correlation with keratoconus severity were calculated for each variable. The area under the receiver operating characteristic curve (AUROC) was used to compare predictive accuracy of different variables for keratoconus. RESULTS: In normal eyes, intereye differences were significantly lower compared with the keratoconus eyes (p<0.001, for CCT, ThCT and PE). There was a significant exponential correlation between disease severity and intereye asymmetry of steep keratometry (r2 = 0.55, p<0.001), CCT (r2 = 0.39, p<0.001), ThCT (r2 = 0.48, p<0.001) and PE (r2 = 0.64, p<0.001). After adjustment for keratoconus severity, asymmetry in thinnest pachymetry proved to be the best parameter to characterize intereye corneal asymmetry in keratoconus. This variable had high accuracy and significantly better discriminating ability (AUROC: 0.99) for KC than posterior elevation (AUROC: 0.96), ThCT (AUROC: 0.94) or CCT (AUROC: 0.92) alone. CONCLUSIONS: There is an increased intereye asymmetry in keratometry, pachymetry and posterior corneal elevation values in keratoconic patients compared to subjects with normal corneas. Keratoconus patients with more severe disease are also more asymmetric in their disease status which should be taken into account during clinical care. PMID- 25296184 TI - Time devours things: how impulsivity and time affect temporal decisions in pathological gamblers. AB - Impulsivity is associated with several psychiatric disorders in which the loss of control of a specific behavior determines the syndrome itself. One particularly interesting population characterized by reported high impulsivity and problematic decision-making are those diagnosed with pathological gambling. However the association between impulsivity and decision making in pathological gambling has been only partially confirmed until now. We tested 23 normal controls and 23 diagnosed pathological gamblers in an intertemporal choice task, as well as other personality trait measurements. Results showed that gamblers scored higher on impulsivity questionnaires, and selected a higher percentage of impatient choices (higher percentage of smaller, sooner rewards), when compared to normal controls. Moreover, gamblers were faster in terms of reaction times at selecting the smaller, sooner options and discounted rewards more rapidly over time. Importantly, regression analyses clarified that self-reported measures of impulsivity played a significant role in biasing decisions towards small but more rapidly available rewards. In the present study we found evidence for impulsivity in personality traits and decisions in pathological gamblers relative to controls. We conclude by speculating on the need to incorporate impulsivity and decision biases in the conceptualization of pathological gambling for a better understanding and treatment of this pathology. PMID- 25296186 TI - [Neurologic diseases in a rural tropical area: experience at a primary health care center in the Boeny region of Madagascar]. AB - There is, to our knowledge, no study reporting the demand for health care related to neurological diseases in rural tropical areas of developing countries. Neurology is nonetheless more or less closely related to the priority health issues in these countries. Over a 6-week period, 626 patients were seen at the primary health center in the town of Madirovalo, Madagascar. Neurological disorders accounted for 11.1% of the consultations. The neurological disorders most frequently leading to consultations were headaches (42.7%), with primary headaches accounting for 16%; next came leprosy neuropathy (14.7%), with a worrisome total of 8 new cases; other peripheral neuropathies (13.3%), and epilepsy (12%). The relatively low share of the latter seems likely related to families' frequent use of traditional healers rather than Western medicine. Neurological diseases appears to represent a significant part of the health-care demand of people living in rural tropical areas of developing countries, and specific support in this specialization is essential. PMID- 25296185 TI - Quantitative Analysis of Myelin and Axonal Remodeling in the Uninjured Motor Network After Stroke. AB - Contralesional brain connectivity plasticity was previously reported after stroke. This study aims at disentangling the biological mechanisms underlying connectivity plasticity in the uninjured motor network after an ischemic lesion. In particular, we measured generalized fractional anisotropy (GFA) and magnetization transfer ratio (MTR) to assess whether poststroke connectivity remodeling depends on axonal and/or myelin changes. Diffusion-spectrum imaging and magnetization transfer MRI at 3T were performed in 10 patients in acute phase, at 1 and 6 months after stroke, which was affecting motor cortical and/or subcortical areas. Ten age- and gender-matched healthy volunteers were scanned 1 month apart for longitudinal comparison. Clinical assessment was also performed in patients prior to magnetic resonance imaging (MRI). In the contralesional hemisphere, average measures and tract-based quantitative analysis of GFA and MTR were performed to assess axonal integrity and myelination along motor connections as well as their variations in time. Mean and tract-based measures of MTR and GFA showed significant changes in a number of contralesional motor connections, confirming both axonal and myelin plasticity in our cohort of patients. Moreover, density-derived features (peak height, standard deviation, and skewness) of GFA and MTR along the tracts showed additional correlation with clinical scores than mean values. These findings reveal the interplay between contralateral myelin and axonal remodeling after stroke. PMID- 25296187 TI - The impact of tension-free vaginal tape on the urethral closure function: mechanism of action. AB - AIM: To investigate if the tension-free vaginal tape (TVT) works by increasing the abdominal to urethral pressure impact ratio (APIR). METHODS: Twenty one women with urodynamically proven stress urinary incontinence (SUI) were assessed by ICIQ-SF, pad-weighing test, incontinence diary and Urethral Pressure Reflectometry (UPR) before and after TVT. UPR was conducted during resting and increased intra-abdominal pressure (P(Abd)) by straining. Related values of P(Abd) and urethral opening pressure (P(o)) were plotted into an abdomino urethral pressuregram. Linear regression of the values was conducted, and the slope of the line was found. The slope expresses the ratio of pressure increase in the urethra compared to the pressure increase in the abdomen and was called APIR. RESULTS: The urethral opening pressure at rest (P(o-rest)) was unchanged after TVT, while APIR increased in all women (from 0.7 to 1.4, P < 0.0001). CONCLUSIONS: The TVT seems to strengthen the urethral closure function by increasing the APIR while P(o-rest) is unchanged regardless of the type of pre operative dysfunction. This confirms the theory of TVT's mechanism of action being mid-urethral support. PMID- 25296189 TI - Patient satisfaction with video teleconsultation in a virtual diabetes outreach clinic. AB - OBJECTIVE: This study assessed the level of patient satisfaction with diabetes remote consultations via videoconferencing in a virtual outreach clinic. MATERIALS AND METHODS: A cross-sectional observational survey was conducted of people with diabetes who were living in regional cities of Queensland, Australia, and remotely consulted by endocrinologists at the Princess Alexandra Hospital tele-endocrinology clinic in Brisbane during autumn 2013. A questionnaire with 15 multiple-choice questions and one open-ended question was developed for assessing patient satisfaction with videoconferencing for specialty consultation. The questionnaire items showed strong internal consistency (Cronbach's alpha = 0.90). Patient satisfaction was assessed by this 16-item questionnaire exploring four dimensions: equipment/technical issues; communication and rapport; clinical assessment; and program evaluation. RESULTS: In total, 62 questionnaires were mailed to the patients, with 24 (39%) surveys completed and returned. The quality of video had the highest satisfaction rate (100%). The lowest satisfaction scores were reported in the "Clinical Assessment" dimension, in which 21% of respondents (five of 24) were concerned that the lack of physical contact could be a problem for managing their diabetes. The patients did not report any problem with building rapport with their consultant over the videoconference. CONCLUSIONS: The patients with diabetes who were seen remotely by endocrinologists via videoconferencing were generally satisfied with remote consultation. The questionnaire developed specifically for diabetes video teleconsultation in this study is useful for the measurement of patient satisfaction, and a modified version may be used in other clinical specialties. PMID- 25296188 TI - Engineering pyranose 2-oxidase for modified oxygen reactivity. AB - Pyranose 2-oxidase (POx), a member of the GMC family of flavoproteins, catalyzes the regioselective oxidation of aldopyranoses at position C2 to the corresponding 2-ketoaldoses. During the first half-reaction, FAD is reduced to FADH2 and reoxidized in the second half-reaction by reducing molecular oxygen to H2O2. Alternative electron acceptors including quinones, radicals or chelated metal ions show significant and in some cases even higher activity. While oxygen as cheap and abundantly available electron acceptor is favored for many processes, reduced oxygen reactivity is desirable for some applications such as in biosensors/biofuel cells because of reduced oxidative damages to the biocatalyst from concomitant H2O2 production as well as reduced electron "leakage" to oxygen. The reactivity of flavoproteins with oxygen is of considerable scientific interest, and the determinants of oxygen activation and reactivity are the subject of numerous studies. We applied site-saturation mutagenesis on a set of eleven amino acids around the active site based on the crystal structure of the enzyme. Using microtiter plate screening assays with peroxidase/2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) and 2,6-dichlorophenolindophenol, variants of POx with decreased oxidase activity and maintained dehydrogenase activity were identified. Variants T166R, Q448H, L545C, L547R and N593C were characterized with respect to their apparent steady-state constants with oxygen and the alternative electron acceptors DCPIP, 1,4-benzoquinone and ferricenium ion, and the effect of the mutations was rationalized based on structural properties. PMID- 25296190 TI - Hepatic metabolism: a key component of herbal drugs research. AB - Liver is the largest metabolic organ for a wide range of endogenous and exogenous compounds and plays a crucial part in the pharmacokinetics and pharmacodynamics through various metabolic reactions. This review provides a progressive description of hepatic metabolism of herbal drugs with respect to metabolic types and investigational methods. In addition, the problems encountered during the research process are discussed. PMID- 25296191 TI - Children's safety initiative: a national assessment of pediatric educational needs among emergency medical services providers. AB - OBJECTIVE: Emergency medical services (EMS) providers may have critical knowledge gaps in pediatric care due to lack of exposure and training. There is currently little evidence to guide educators to the knowledge gaps that most need to be addressed to improve patient safety. The objective of this study was to identify educational needs of EMS providers related to pediatric care in various domains in order to inform development of curricula. METHODS: The Children's Safety Initiative-EMS performed a three-phase Delphi survey on patient safety in pediatric emergencies among providers and content experts in pediatric emergency care, including physicians, nurses, and prehospital providers of all levels. Each round included questions related to educational needs of providers or the effect of training on patient safety events. We identified knowledge gaps in the following domains: case exposure, competency and knowledge, assessment and decision making, and critical thinking and proficiency. Individual knowledge gaps were ranked by portion of respondents who ranked them "highly likely" (Likert type score 7-10 out of 10) to contribute to safety events. RESULTS: There were 737 respondents who were included in analysis of the first phase of the survey. Paramedics were 50.8% of respondents, EMT-basics/first responders were 22%, and physicians 11.4%. The top educational priorities identified in the final round of the survey include pediatric airway management, responder anxiety when working with children, and general pediatric skills among providers. The top three needs in decision-making include knowing when to alter plans mid-course, knowing when to perform an advanced airway, and assessing pain in children. The top 3 technical or procedural skills needs were pediatric advanced airway, neonatal resuscitation, and intravenous/intraosseous access. For neonates, specific educational needs identified included knowing appropriate vital signs and preventing hypothermia. CONCLUSIONS: This is the first large-scale Delphi survey related to pediatric prehospital education. Our results provide foundational information related to the educational needs of prehospital providers. Medical directors and educators can use the results to shape future curricular development. PMID- 25296193 TI - [Vandetanib, in the management of patients with locally advanced or metastatic medullary thyroid carcinomas]. AB - Medullary thyroid cancer (MTC) is a rare cancer. Vandetanib, a RET tyrosine kinase inhibitor, significantly increased progression free survival and is the first treatment approved in France for unresectable, locally advanced or metastatic MTC that is symptomatic or progressive. Most frequents adverse events are diarrhea, folliculitis and asthenia. The prolongation of the QT interval on electrocardiogram is frequent but in the most of cases not clinically relevant. A good selection of the patients who could benefit from this treatment and management of side effect are important for the risk-benefit assessment. PMID- 25296192 TI - GPKOW is essential for pre-mRNA splicing in vitro and suppresses splicing defect caused by dominant-negative DHX16 mutation in vivo. AB - Human GPKOW [G-patch (glycine-rich) domain and KOW (Kyrpides, Ouzounis and Woese) domain] protein contains a G-patch domain and two KOW domains, and is a homologue of Arabidopsis MOS2 and Saccharomyces Spp2 protein. GPKOW is found in the human spliceosome, but its role in pre-mRNA splicing remains to be elucidated. In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. Adding back recombinant GPKOW restored splicing to the depleted extract. In vivo, overexpression of GPKOW partially suppressed the splicing defect observed in dominant-negative DHX16 mutant expressing cells. Mutations at the G-patch domain greatly diminished the GPKOW DHX16 interaction; however, the mutant was active in splicing and was able to suppress splicing defect. Mutations at the KOW1 domain slightly altered the GPKOW RNA interaction, but the mutant was less functional in vitro and in vivo. Our results indicated that GPKOW can functionally impact DHX16 but that interaction between the proteins is not required for this activity. PMID- 25296194 TI - Effect of embryo culture media on birthweight and length in singleton term infants after IVF-ICSI. AB - QUESTIONS UNDER STUDY: To investigate if two distinct, commercially available embryo culture media have a different effect on birthweight and length of singleton term infants conceived after IVF-ICSI. METHODS: University hospital based cohort study. Between 1 January 2000 and 31 December 2004, patients conceiving through IVF-ICSI at the University Hospital, Lausanne have been allocated to two distinct embryo culture media. Only term singleton pregnancies were analysed (n = 525). Data analysis was performed according to two commercially available culture media: Vitrolife (n = 352) versus Cook (n = 173). Analysis was performed through linear regression adjusted for confounders. Media were considered equivalent if the 95% confidence interval lay between -150 g/+150 g. RESULTS: Length, gestational age and distribution of birthweight percentiles did not differ between groups (for both genders). Analysis of the whole cohort, adjusted for a subset of confounders, resulted in a statistically not different mean birthweight between the two groups (Vitrolife +37 g vs Cook, 95%CI: -46 g to 119 g) suggesting equivalence. Adjustment for an enlarged number of confounders in a subsample of patients (n = 258) also revealed no relevant mean birthweight difference of +71 g (95%CI: -45 g to 187 g) in favour of Vitrolife; however, lacking power to prove equivalence. CONCLUSIONS: Our data suggest that significant differences in birthweight due to these two distinct, commercially available embryo culture media are unlikely. PMID- 25296198 TI - The importance of remnant native vegetation of Amazonian submontane forest for the conservation of lizards. AB - Forest fragmentation affects animal population dynamics mainly by loss of habitat and disruption of animal movement. Lizard assemblages are affected by environmental changes, but, depending on their ecological needs, some species might be more vulnerable than others. The southern Amazon suffers accelerated anthropic actions replacing natural environments by farmland (crops and pasture). This region is considerably drier than most of the northern Amazon, with stational semi-deciduous forests fragmented and isolated by pasture, and crops to a lesser extent. Here we report data on lizard assemblages using semi-deciduous forests, forest edge and the surrounding pasture in the southern Amazon in Mato Grosso, Brazil. Lizards were collected in 21 forest fragments (41 to 7,035 ha) surrounded by pasture; using pitfall traps placed on a degradation gradient - from pasture inwards forest fragment (up to 200 m). We collected 242 individuals (14 species, seven families) in 6,300 trap-days. The pattern of species occurrence was largely nested and this nesting was associated with three habitat guilds (generalist, edge-tolerant, and forest species). Although there was no obvious fragmentation effect on lizards diversity community-wise, Hoplocercus spinosus, Bachia dorbignyi, Micrablepharus maximiliani and Kentropyx calcarta were more vulnerable to such effects than all other ten species collected. We verified that assemblages inhabiting pasture and forest edge are a nested subset of assemblages from the forest core. The remnant native vegetation is not distributed homogeneously and lizards species can persist in different parts of the landscape, therefore we recommend the protection of forest remnants as an important conservation action for lizards of the southern Amazon. PMID- 25296195 TI - Novel vaccine vectors for HIV-1. AB - The ultimate solution to the global HIV-1 epidemic will probably require the development of a safe and effective vaccine. Multiple vaccine platforms have been evaluated in preclinical and clinical trials, but given the disappointing results of clinical efficacy studies so far, novel vaccine approaches are needed. In this Opinion article, we discuss the scientific basis and clinical potential of novel adenovirus and cytomegalovirus vaccine vectors for HIV-1 as two contrasting but potentially complementary vector approaches. Both of these vector platforms have demonstrated partial protection against stringent simian immunodeficiency virus challenges in rhesus monkeys using different immunological mechanisms. PMID- 25296196 TI - Caenorhabditis elegans bacterial pathogen resistant bus-4 mutants produce altered mucins. AB - Caenorabditis elegans bus-4 glycosyltransferase mutants are resistant to infection by Microbacterium nematophilum, Yersinia pestis and Yersinia pseudotuberculosis and have altered susceptibility to two Leucobacter species Verde1 and Verde2. Our objective in this study was to define the glycosylation changes leading to this phenotype to better understand how these changes lead to pathogen resistance. We performed MALDI-TOF MS, tandem MS and GC/MS experiments to reveal fine structural detail for the bus-4 N- and O-glycan pools. We observed dramatic changes in O-glycans and moderate ones in N-glycan pools compared to the parent strain. Ce core-I glycans, the nematode's mucin glycan equivalent, were doubled in abundance, halved in charge and bore shifts in terminal substitutions. The fucosyl O-glycans, Ce core-II and neutral fucosyl forms, were also increased in abundance as were fucosyl N-glycans. Quantitative expression analysis revealed that two mucins, let-653 and osm-8, were upregulated nearly 40 fold and also revealed was a dramatic increase in GDP-Man 4,6 dehydratease expression. We performed detailed lectin binding studies that showed changes in glycoconjugates in the surface coat, cuticle surface and intestine. The combined changes in cell surface glycoconjugate distribution, increased abundance and altered properties of mucin provide an environment where likely the above pathogens are not exposed to normal glycoconjugate dependent cues leading to barriers to these bacterial infections. PMID- 25296199 TI - Recurrent blooms of Heterosigma akashiwo (Raphidophyceae) in the Piraque Channel, Rodrigo de Freitas Lagoon, southeast Brazil. AB - Six blooms of Heterosigma akashiwo (Raphidophyceae) were observed from March 2007 through March 2008 in the Rodrigo de Freitas Lagoon, a semi-confined eutrophic system located in Rio de Janeiro state, southeast Brazil. Vegetative cells of H. akashiwo analysed by optical and electron microscopy showed morphology as described in the literature. The blooms (2.8 * 10(4) to 4 * 10(8) cell.L(-1)) were restricted to the middle section of the Piraque Channel, which is situated in the northeastern part of the lagoon and receives freshwater inflow. The salinity of subsurface water and the channel depth showed significant negative correlations with H. akashiwo abundances, and appeared to restrict the blooms to this compartment of the lagoon. No fish mortality was associated with the H. akashiwo blooms, nor were brevetoxins detected in a cell extract obtained from the bloom observed on 19 March 2007. PMID- 25296200 TI - Efficiency of small mammal trapping in an Atlantic Forest fragmented landscape: the effects of trap type and position, seasonality and habitat. AB - Trapping methods can strongly influence the sampling of mammal communities. This study compared the efficiency of the capture of small mammals in Sherman traps in two positions (at ground level and in trees) and pitfall traps in a fragmented landscape. Trapping sessions were carried out between October 2008 and October 2009 at two fragments (8 and 17 ha), an agroforest corridor between them, and the adjacent pasture. A total effort of 4622 trap-nights resulted in 155 captures of 137 individuals from six species. Pitfalls had greater success (4.03%), followed by Shermans on the ground (2.98%) and on trees (2.37%; chi2 = 6.50, p = 0.04). Five species were caught in Sherman ground traps, four in pitfalls and just two on trees. There was no difference among trap types for marsupials (chi2 = 4.75; p = 0.09), while for rodents, pitfalls were more efficient than Shermans on the ground (Fisher's exact test, p = 0.02). As a result, the efficiency of each trap type differed among habitats, due to differences in their species composition. Pitfalls were more efficient in the rainy season (Fisher's exact test, p <0.0001) while Shermans on trees were more efficient in the dry season (Fisher's exact test, p = 0.009). There was no difference between seasons for Shermans on the ground (Fisher's exact test, p = 0.76). Considering the results found, we recommend that future studies of forest mammal communities, particularly those designed to test the effects of forest fragmentation, include combinations of different trap types. PMID- 25296201 TI - Chemical defense in the red seaweed Plocamium brasiliense: spatial variability and differential action on herbivores. AB - Species of Plocamium are known as prolific sources of halogenated secondary metabolites exhibiting few explored ecological roles. In this study the crude extracts from specimens of P. brasiliense collected in two distinct places, Enseada do Forno and Praia Rasa, Buzios, Estado do Rio de Janeiro, were evaluated as defense against the sea urchin Lytechinus variegatus and the crab Acanthonyx scutiformis. These specimens produce a similar amount of crude extract and also halogenated monoterpene compound-types, but individuals of P. brasiliense from Praia Rasa exhibit a major compound representing about 59% of the total chemicals. Natural concentrations of the crude extracts obtained from both specimens of P. brasiliense significantly inhibited the herbivory by the sea urchin L. variegatus, but had no significant effect on the feeding by A. scutiformis, a crab commonly associated to chemically defended host. Crude extract from P. brasiliense collected at Praia Rasa was more efficient as defense against L. variegatus than that crude extract from populations of this alga from Enseada do Forno, probably due to presence of a major secondary metabolite. These two studied population live under different environmental conditions, but they are only about 30 Km apart. However, it is impossible to affirm that environmental characteristics (abiotic or biotic) would be responsible for the difference of defensive potential found in the two populations of P. brasiliense studied here. Further genetic studies will be necessary to clarify this question and to explain why populations of a single species living in different but close locations can exhibit distinct chemicals. PMID- 25296202 TI - Evaluation of abundance indexes in open population studies: a comparison in populations of small mammals in southern Brazil. AB - Many manuscripts comparing populations and/or analysing the structure of animal communities use indexes of captures as synonymous of abundance. However, the basic methods more suitable to this assumption - probabilistic estimates based on equal capture probability - have not been considered. In this study, the deviations caused by different types of capture indexes are compared with a common probabilistic population estimator (Cormack-Jolly-Seber). The analyses showed that Minimum Number Known Alive (MNKA) and the number of individuals showed greater association with the population estimator than with non probabilistic indexes based on recaptures. Therefore, none of the indexes presented the same performance to estimate population size estimation which can lead to ecological misinterpretation. Some recommendations were also described. PMID- 25296203 TI - Subsistence hunting of Cuniculus paca in the middle of the Solimoes River, Amazonas, Brazil. AB - Ungulates, large primates and caviomorfs are cited by Amazonian hunters as preferred species. In this research, paca (Cuniculus paca) hunting was investigated in relation to water levels and the lunar cycle. In eight years of monitoring in the Amana Sustainable Development Reserve, the killing of 625 pacas was registered in five monitored communities. Paca hunting took place mainly at night and the most commonly used method is "spotlighting". A positive correlation between the number of pacas killed and water level (rs=0.890; p<0.0001) was found. At least 37% of the pacas were hunted when moon illumination level was less than 10%, before moonrise or after moonset. In the Boa Esperanca community, capture of paca tended to decrease on nights with high moon illumination (rs= 0.663; p=0.067). At the same time, an expressive catch-per-unity-effort decrease was also observed in this community (r2= -0.881; p<0.001), allowing us to predict unsustainable hunting levels for the next decade. The stock of animals in these areas could be continuously replaced if surrounding areas consisted of continuous forests. However, continuous hunting and deforestation force local hunters to travel longer distances to kill prey such as pacas. The confirmation of the relation between paca habits and lunar illumination and water level, a pattern described by local hunters, demonstrates the potential value of participatory research and the possibility of integrating traditional knowledge into scientific knowledge. PMID- 25296204 TI - The importance of protozoan bacterivory in a subtropical environment (Lobo-Broa Reservoir, SP, Brazil). AB - This study evaluated the importance of heterotrophic nanoflagellates (HNF) and ciliates bacterivory in a mesotrophic subtropical environment (Lobo-Broa Reservoir, Brazil) by the quantification of their ingestion rates. The in situ experiments using fluorescently labelled bacteria (FLB) were carried out bimonthly over one year (three surveys in the dry season and three in the rainy one) at the sub-surface of two sampling points that have different trophic degrees. The ingestion rates for both ciliates and HNF were higher in the meso eutrophic region (point 2) due to the higher water temperatures, which accelerate the metabolism of protozoans and the higher bacteria densities. Concerning total protozoan bacterivory, the HNF had the greatest grazing impact on bacterial community, especially the HNF <5 um. The data showed that HNF grazing, in addition to regulating the bacteria abundance, also induced changes to the bacterial community structure, such as increasing size and numbers of bacterial filaments. The ciliates were also important to the system bacterivory, especially in point 2, where there were high densities and ingestion rates. The protozoan bottom-up control was more important in the dry season and the top-down control was more important in the rainy season, so, these two forces are equally important to the bacterial abundance regulation in this reservoir in an annual basis. PMID- 25296205 TI - Preferential prey selection by Desmodus rotundus (E. Geoffroy, 1810, Chiroptera, Phyllostomidae) feeding on domestic herbivores in the municipality of Sao Pedro- SP. AB - In order to verify possible preferential prey selection by Desmodus rotundus feeding on domestic herbivores in the Municipality of Sao Pedro (Sao Paulo, Brazil), vampire bat attacks were surveyed at rural properties where domestic herbivores were being raised and attack frequencies of D. rotundus on the total herd and on different species were calculated. The analysis found that the most frequently attacked herbivores were cattle and horses. The chi-square test (chi2), with a significance level of 5% corroborated the comparative analysis of attack frequency in properties that had these two species. Of the two, horses were attacked more frequently, which could be a sign that D. rotundus exhibits preferential prey selection when attacking domestic herbivores. This evidence is also supported by the Optimal Foraging Theory, in which the net rate of energy consumed is higher for horses than it is for cattle. Additionally, we propose that the thinner integument of horses (relative to that of cattle) may facilitate bites by D. rotundus and thus contribute to the observed prey preference. PMID- 25296206 TI - Carrion consumption by Dasyprocta leporina (Rodentia: Dasyproctidae) and a review of meat use by agoutis. AB - The consumption of the carrion of a tapiti by a reintroduced female Dasyprocta leporina was observed in the wild. Herein, besides describing this event, we reviewed other evidence of vertebrate consumption by agoutis. Most of the studies describing this behaviour have been carried out in captivity. The preyed animals included birds and small rodents, which were sometimes killed by agoutis. This pattern suggests that this is not an anomalous behaviour for the genus, reflecting its omnivorous habits. This behaviour can be a physiologically sound feeding strategy, so new studies should focus on the temporal variation in the consumption of this resource, possibly related to food scarcity periods or to reproductive seasons, when the need for high-quality food tends to increase. PMID- 25296207 TI - Evidence for herbaceous seed dispersal by small-bodied fishes in a Pantanal seasonal wetland. AB - We analysed the germination of seeds after their passage through the digestive tract of small floodplain fishes. Samples were collected in five open flooded fields of the northern Pantanal in March 2011. All fishes were sacrificed and their intestinal contents were removed. The fecal material was weighed and stored at 4 degrees C in a GF/C filter wrapped in aluminum foil. The material was then transferred to a receptacle containing sterilised soil from the sampling area. The fecal samples were kept in a germination chamber for 68 days and then transferred to a greenhouse for another 67 days. We collected a total of 45 fish species and 1014 individuals which produced a total amount of 32 g of fresh fecal mass and 11 seedlings. We were able to identify six seedlings: two Banara arguta, two Steinchisma laxa, one Hymenachne amplexicaulis and one Luziola sp.. The fish species that produced samples with seedlings were Astyanax assuncionensis, Metynnis mola, Plesiolebias glaucopterus, Acestrorhyncus pantaneiro and Anadoras wendelli. With the exception of B. arguta the remaining plant species and all fish species were not known to be associated with the seed dispersal process of these plants. We found a ratio of 0.435 seedlings.g-1 of fresh fecal material, which is 100 times higher than the amount of seedlings encountered in fresh soil mass (92,974 grams) in seed bank studies conducted in the same study area. In particular, Astyanax assuncionensis and Metynnis mola were among the most frequent and most abundant fish taxa in the area. Together with the high seed concentration in the fish fecal material, this evidence allows us to conclude that such fish species may play an important role in seed dispersal in the herbaceous plants of the Pantanal. PMID- 25296208 TI - Differential habitat use by demographic groups of the redfinger rubble crab Eriphia gonagra (Fabricius, 1781). AB - The structurally diverse rocky shores along the northern coast of the state of Sao Paulo, Brazil, support a varied fauna and provide refuges for many organisms. Some of these environments allow for extensive microhabitats, among them the sand reefs formed by the polychaete Phragmatopoma lapidosa, which occupy much of this area. The beauty of the landscape attracts large numbers of tourists, who contribute to the damage to the sand reef colonies, causing an imbalance in the patterns of population distribution and of this ecosystem. We describe the structure and population biology of the redfinger rubble crab Eriphia gonagra, and investigated the differential occupation of the habitat by each demographic category of this species. Crabs were sampled monthly for two consecutive years on the rocky coast of Grande Beach, Ubatuba, Sao Paulo, during spring low tides. Sampling was carried out over an area of approximately 1200 m2, during two hours on the rock surface and another two hours on the sand reefs. A total of 1407 crabs were collected; 776 on the sand reef (SR) and 631 on the rocky shore (RO). The majority of juvenile crabs inhabited the SR, while adult crabs were equally distributed in both microhabitats. This study showed that the SR is a natural nursery ground for the establishment of the early juvenile stages of E. gonagra, which use the reefs as a refuge and food resource. Many other organisms (mollusks, echinoderms, polychaetes etc.) settle on the reefs, and these areas may be among the most important in maintaining benthic diversity in the region. PMID- 25296209 TI - Reporting social behaviours of mixed-species troops formed by Callithrix jacchus and Callithrix penicillata (Primate, Callitrichidae). AB - In New World primates, mixed-species troops have been reported. Here, we analysed the performance of affiliative and agonistic behaviours of Callithrix jacchus and Callithrix penicillata living in mixed groups. For this purpose, we recorded the interaction of the individuals from two groups located in Bauru city, in the state of Sao Paulo (Brazil). Our data show that in both groups, affiliative behaviours appeared more frequently than agonistic ones. We concluded that there is cohesion inside the mixed-species troops observed. We suggest that a deeper knowledge about the social behaviour of mixed-species troop species certainly may be useful in projects linked with the management of the impact caused by them. PMID- 25296210 TI - Characterization of the microbial community in a lotic environment to assess the effect of pollution on nitrifying and potentially pathogenic bacteria. AB - This study aimed to investigate microbes involved in the nitrogen cycle and potentially pathogenic bacteria from urban and rural sites of the Sao Pedro stream. Water samples were collected from two sites. A seasonal survey of bacterial abundance was conducted. The dissolved nutrient content was analysed. PCR and FISH analysis were performed to identify and quantify microbes involved in the nitrogen cycle and potentially pathogenic bacteria. The seasonal survey revealed that the bacterial abundance was similar along the year on the rural area but varied on the urban site. Higher concentration of dissolved nutrients in the urban area indicated a eutrophic system. Considering the nitrifying microbes, the genus Nitrobacter was found, especially in the urban area, and may act as the principal bacteria in converting nitrite into nitrate at this site. The molecular markers napA, amoA, and nfrA were more accumulated at the urban site, justifying the higher content of nutrients metabolised by these enzymes. Finally, high intensity of amplicons from Enterococcus, Streptococcus, Bacteroides/Prevotella/Porphyromonas, Salmonella, S. aureus, P. aeruginosa and the diarrheagenic lineages of E. coli were observed at the urban site. These results indicate a change in the structure of the microbial community imposed by anthrophic actions. The incidence of pathogenic bacteria in aquatic environments is of particular importance to public health, emphasising the need for sewage treatment to minimise the environmental impacts associated with urbanisation. PMID- 25296211 TI - Insect herbivores associated with an evergreen tree Goniorrhachis marginata Taub. (Leguminosae: Caesalpinioideae) in a tropical dry forest. AB - Goniorrhachis marginata Taub. (Leguminosae: Caesalpinioideae) is a tree species found in Brazilian tropical dry forests that retain their leaves during the dry season. That being, we addressed the following question: i) How do insect diversity (sap-sucking and chewing), leaf herbivory and defensive traits (tannin and leaf sclerophylly) vary on the evergreen tree species G. marginata between seasons? The abundance of sap-sucking insects was higher in the dry season than in the rainy season. However, we did not verify any difference in the species richness and abundance of chewing insects between seasons. Leaf herbivory was higher in the rainy season, whereas leaf sclerophylly was higher in the dry season. However, herbivory was not related to sclerophylly. Insect herbivores likely decrease their folivory activity during the dry season due to life history patterns or changes in behaviour, possibly entering diapause or inactivity during this period. Therefore, G. marginata acts as a likely keystone species, serving as a moist refuge for the insect fauna during the dry season in tropical dry forest, and the presence of this evergreen species is crucial to conservation strategies of this threatened ecosystem. PMID- 25296212 TI - High consumption of primates by pumas and ocelots in a remnant of the Brazilian Atlantic Forest. AB - We studied the diet of the ocelot and puma during the years 2007 and 2008 at the Feliciano Miguel Abdala Reserve, in Minas Gerais, south-eastern Brazil. We collected 49 faecal samples (scats) from cats, and identified the species of cat from 23 of them by the analysis of the microstructure patterns of hairs found in their faeces: 17 scats of the puma (Puma concolor) and six of the ocelot (Leopardus pardalis). In the puma scats, we identified three species of primates (Brachyteles hypoxanthus, Alouatta guariba and Sapajus nigritus), the remains of which were found in eight of 17 collected (47.1%), representing 26.7% of items consumed. For the ocelot, we detected capuchin monkey (S. nigritus) remains in three of the six scats (50%), accounting for 18.7% of items consumed by ocelot. We were unable to identify the cat species in the remaining 26 faecal samples, but we were able to analyse the food items present. Primates were found in five of these 26 faeces (19.2%) and represented 10.2% of the items found. Although the sample size is limited, our results indicate a relatively high consumption of primates by felines. We believe that this high predation may be the result of the high local density of primates as well as the greater exposure to the risks of predation in fragmented landscapes, which tends to increase the incidence of the primates using the ground. PMID- 25296213 TI - Seasonal dynamics of Daphnia laevis Birge, 1878 ephippia in a tropical lake with a description of a new methodology for in situ evaluation. AB - The effect of dormancy in zooplankton populations is still unknown, largely because of the lack of methods to estimate hatching and production of the dormant stages. This study aimed to compare the production and hatching rates of ephippia of Daphnia laevis between thermal stratification and mixing periods in Jacare Lake (Middle Rio Doce, Minas Gerais, Brazil). For this, we collected ephippia on the sediment with core sampler and we created a device called the "Ephippial Collector". There was a significant difference in ephippia hatching in situ between stratification and mixing periods (Pearson's Chi-squared test p <0.001), being higher in the second one. Significant differences in the hatching rates between periods was observed in the laboratory only for ephippia collected with Ephippial Collectors (Pearson's Chi-squared test p <0.001), being higher during the mixing period (~ 8%). The core sample allows the collection of a certain fraction of the sediment that may contain a mixture of ephippia produced in different periods, i.e., may contain old and not viable ephippia, which masks the hatching rate. Thus, seasonality in hatching rates of ephippia was reported only by Ephippial Collectors. The higher hatching rate observed during the mixing period in the lake suggests that individuals hatched from ephippia may contribute to the increase in the population of D. laevis in the water column at this time. PMID- 25296214 TI - Beetles (Insecta, Coleoptera) associated with pig carcasses exposed in a Caatinga area, Northeastern Brazil. AB - The species richness, abundance and seasonality of Coleoptera fauna associated with pig carcasses exposed in a Caatinga area were examined. Tray, pitfall and modified Shannon traps were settled together to collect these insects during two seasons (dry and rainy). 4,851 beetles were collected, belonging to 19 families and 88 species. Staphylinidae (2,184) and Histeridae (1,264) were the most abundant families and accounted for 71.1% of the specimens collected. Scarabaeidae (15) showed the highest species richness. The most abundant species were Atheta iheringi Bernhauer, 1908 (Staphylinidae) (1,685), Euspilotus sp. (Histeridae) (461), Stelidota geminata (Say, 1825) (Nitidulidae) (394), Xerosaprinus diptychus (Marseul, 1855) (Histeridae) (331) and Dermestes maculatus De Geer, 1774 (Dermestidae). Amongst these species, X. diptychus showed to be strongly influenced by seasonality, since 96.1% of the specimens were collected during the dry season. PMID- 25296215 TI - Toxomerus duplicatus Wiedemann, 1830 (Diptera: Syrphidae) preying on Microtheca spp. (Coleoptera: Chrysomelidae) larvae. AB - Microtheca spp. (Coleoptera: Chrysomelidae) are insect pests primarily related to Brassicaceae crops. In the State of Rio Grande do Sul (RS), southern Brazil, they are found on forage turnip, Raphanus sativus L. var. oleiferus Metzg., which is commonly grown during fall/winter seasons. This work reports the predation of Microtheca spp. larvae by Toxomerus duplicatus Wiedemann, 1830 (Diptera: Syrphidae) larvae, on forage turnip crop, in Santa Maria, RS. This register provides new information about Microtheca spp. natural enemies in Brazil, which might be a new option for integrate pest management of these species. PMID- 25296216 TI - Flowers visited by hummingbirds in the open habitats of the southeastern Brazilian mountaintops: species composition and seasonality. AB - The hummingbird-visited plant community located on the open-habitat mountaintop of the Espinhaco Range was studied for two years (from August 2007 to July 2009) in Serra do Cipo National Park, Southeastern Brazil (19 degrees 15' S and 43 degrees 31' W). The floral characteristics and flowering period of the hummingbird-visited plants was monthly recorded along trails located in three vegetation types: (1) typical campos rupestres (TCR), (2) open fields (OPF), and (3) capoes de mata (CAM). Hummingbird visitation was observed in 51 plant species, 22 ornithophilous and 29 non-ornithophilous species. The TCR showed the greatest number of species visited (N = 38), followed by the OPF (N = 18) and CAM (N = 17). Six species of hummingbirds were recorded visiting flowers: Augastes scutatus, Campylopterus largipennis, Colibri serrirostris, Chlorostilbon lucidus, Eupetomena macroura and Phaethornis pretrei. This study demonstrates that the species richness and the number of ornithophilous species visited by the hummingbirds at the study site are more similar to hummingbird-plant communities of the Atlantic Forest than to those of the Cerrado communities and other Brazilian highland open-habitat communities. The plant families most visited by hummingbirds were Bromeliaceae and Asteraceae. Although the Asteraceae family is rarely used as a food resource for hummingbirds in other high and lowland communities, in the study site this family is used mainly by the endemic hummingbird Augastes scutatus. We found a large overlap of flowering throughout the year among the species visited by the hummingbirds. Thus, the nectar availability supports these resident hummingbirds. The present study also showed that the studied hummingbird-plant community is composed of many species endemic to the campos rupestres of the Espinhaco Range, some of which are considered to be in danger of extinction, thus constituting a unique and threatened community. Thus, understanding hummingbird-plant pollination dynamics becomes fundamental to the conservation of the campos rupestres. PMID- 25296217 TI - Economic assessment of urban watersheds: developing mechanisms for environmental protection of the Feijao river, Sao Carlos--SP, Brazil. AB - In order to determine the willingness of the population of Sao Carlos (a city in the state of Sao Paulo, Brazil) to pay for the environmental protection (WTP) of the Feijao River's watershed, the Contingent Valuation Method (CVM), as well as the bidding-games technique, were used. In October 2010, 280 questionnaires were applied to a probabilistic sample of the population. A multivariate logistic regression model was built, creating five scenarios adjusted to the age and probability to pay according to the significant variables found. Concerning the WTP, 56% of the interviewees showed willingness to pay a monthly amount using the water bill as a vehicle for this. The WTP average was 1.94 US Dollar (USD), with a standard deviation of 1.91 USD. The total annual amount for the scenario that considers the whole population over 18 years old was of USD 3,930,616.80. The main argument for the negative WTP was that the interviewees could not afford it (14%). PMID- 25296218 TI - The predatory mite Phytoseiulus macropilis (Acari: Phytoseiidae) occurring on sweet potato (Ipomoea batatas) plants in Diamantina, Minas Gerais State, Brazil. PMID- 25296219 TI - Confirmation of sexual dimorphism in Hoplias aimara (Valenciennes, 1847) (Erythrinidae: Characiformes) proposed by local expertise in Amapa, Brazil. AB - Fishes may show sexual dimorphism according to their reproductive strategies. In some species, this differentiation is already well known. However, with the findings obtained from recent studies, the number of species for which sex can be determined without dissection has increased. Thus far, the presence of external secondary sexual characteristics in Hoplias aimara, a very well-studied species, has not been reported. Traditional knowledge evidenced through riparian people observations indicated the possibility of sexual dimorphism in this species, which was studied in 2 conservation units, Sustainable Development Reserve of Iratapuru River and Tumucumaque Mountains National Park, in the state of Amapa, Brazil. Fishes were captured, and their anal fins were examined when they were still fresh; the sex of the fishes was confirmed by dissection. The same procedure was used for formalin-fixed fishes. By assessing the shape of the anal fin in fresh or fixed fishes, it was possible to determine the sex of the fish, which was then confirmed by dissection. H. aimara shows sexual dimorphism expressed in the morphology of their anal fin. Thus, the sex of fishes deposited in collections can be identified without any dissection, thereby providing important biological information about the specimens. PMID- 25296220 TI - Life history of Neoseiulus californicus (McGregor, 1954) (Acari: Phytoseiidae) fed with castor bean (Ricinus communis L.) pollen in laboratory conditions. AB - The predatory mite, Neoseiulus californicus (McGregor, 1954) (Acari: Phytoseiidae) is one of the principal natural enemies of tetranychid mites in several countries, promoting efficient control of those mites in several food and ornamental crops. Pest attacks such as that of the spider mite, Tetranychus urticae Koch, 1836 (Acari: Tetranychidae), is one of the problems faced by farmers, especially in the greenhouse, due to the difficulty of its control with the use of chemicals because of the development of fast resistance making it hard to control it. The objective of this work was to study the life history of the predatory mite N. californicus as a contribution to its mass laboratory rearing, having castor bean plant [Ricinus communis L. (Euphorbiaceae)] pollen as food, for its subsequent use as a natural enemy of T. urticae on a cultivation of greenhouse rosebushes. The studies were carried out in the laboratory, at 25 +/- 2 degrees C of temperature, 70 +/- 10% RH and a 14 hour photophase. The biological aspects and the fertility life table were appraised. Longevity of 32.9 days was verified for adult females and 40.4 days for males. The intrinsic rate of increase (rm) was 0.2 and the mean generation time (T) was 17.2 days. The population doubled every 4.1 days. The results obtained were similar to those in which the predatory mite N. californicus fed on T. urticae. PMID- 25296221 TI - Disease resistance of pacu Piaractus mesopotamicus (Holmberg, 1887) fed with beta glucan. AB - Effects of beta-glucan on innate immune responses and survival were studied in pacu experimentally infected with Aeromonas hydrophila. Fish fed diets containing 0, 0.1% and 1% beta-glucan were injected with A. hydrophila. beta-glucan enhanced fish survival in both treated groups (26.7% and 21.2% of the control, respectively). Leukocyte respiratory burst and alternative complement pathway activities were elevated after bacterial challenge regardless the beta-glucan concentration. Lysozyme activity was higher after infection and showed a gradual increase as beta-glucan concentration increased. A significant elevation in WBC count was observed either after bacterial challenge or by influence of beta glucan separately. The same response was observed in the number of thrombocytes, lymphocytes, eosinophils, LG-PAS positive cell and monocytes. It can be concluded that feeding pacu with beta-glucan can increase protection against A. hydrophila, due to changes in non-specific immune responses. PMID- 25296222 TI - Comparison between Oligoryzomys nigripes and O. flavescens by RAPD and genetic diversity in O. nigripes (Rodentia, Cricetidae). AB - The genus of Oligoryzomys includes species of small size, morphologically similar, which may impede taxonomic identification, mainly between O. flavescens (Waterhouse, 1837) and O. nigripes (Olfers, 1818). The main objective of this work was to investigate whether the RAPD markers are capable of genetically differentiating the specimens O. nigripes and O. flavescens, coming from Rio Grande do Sul (RS) and Santa Catarina (SC) states, and also to estimate the genetic variability among populations of O. nigripes, with the Uruguay River as a geographical barrier. For this purpose, samples were collected in fragments of forests situated in the North of RS, at FLONA (Floresta Nacional de Passo Fundo) and in fragments from SC, close to the Uruguay River. The karyotyping of two samples for each species was carried out and compared using the RAPD technique together with non- karyotyped individuals. Samples of O. nigripes presented 2n = 62; NA = 82, with submetacentric arms on the largest chromosomes, while samples of O. flavescens showed 2n = 64; NA = 66, with the largest chromosomes presenting acrocentric morphology, making such a result the main difference between the species. The analysis was able to detect two distinct groups, being the first one with karyotyped O. flavescens and the second with karyotyped O. nigripes. Identification afforded 211 loci, among them 181 (85.78%) polymorphic. The Jaccard similarity coefficient was in the range of 0.45 to 0.87. The UPGMA and Main Coordinate Analysis techniques demonstrated the existence of heterogeneous genetics among populations, but did not separate them completely in terms of geographical standards, and they are not influenced by the Uruguay River, which did not act as an efficient barrier. PMID- 25296223 TI - Reproduction, development and habits of the large turkey louse Chelopistes meleagridis (Phthiraptera: Ischnocera) under laboratory conditions. AB - The bionomy of Chelopistes meleagridis off the host was observed with the aim of better understanding the aspects of this species' life cycle. For this purpose, C. meleagridis adults were collected and maintained under controlled conditions to reproduce (35 degrees C and RH > 80%), with turkey feathers as the food source. From the offspring of these lice, the development of 150 individuals was observed from the egg to the adult phase. These eggs were divided into two groups of 75 each. After hatching, one group was given a diet composed of feathers while the other received feathers plus skin of the host turkey (Meleagris gallopavo). The "feather + skin" diet resulted in the greatest number of adults, so this diet was given to the next generation of lice reared in vitro, starting from the first instar, to observe their fertility, fecundity and longevity. High reproduction rates were found in relation to other lice of the Ischnocera sub-order, particularly the number of eggs per day and number of eggs produced per female over the lifetime (means of 2.54 and 26.61 eggs, respectively, for wild females and 2.11 and 29.33 eggs for laboratory-reared females). The inclusion of skin in the diet was a determining factor for development to the adult stage, since 48% of the lice fed this diet reached that stage, versus 1.3% that reached maturity fed only with feathers. The development time of the males and females was similar (mean of 29.38 days), without any difference in the sexual proportion of the adults. PMID- 25296224 TI - Response of frugivorous primates to changes in fruit supply in a northern Amazonian forest. AB - Few attempts have been made to understand how spatiotemporal changes in fruit supply influence frugivores in tropical forests. The marked spatiotemporal variation in fruit supply can affect frugivore abundance and distribution, but studies addressing the effects of this variation on primates are scarce. The present study aimed to investigate how the spatiotemporal distribution of fruits influences the local distribution of three frugivorous primates in the eastern part of the Maraca Ecological Station, a highly seasonal Amazonian rainforest. Specifically, it was hypothesised that primate distribution will track changes in fruit supply, resulting that sites with high fruit availability should be heavily used by primates. During a 1-year study, fruit supply (ground fruit surveys) and primate density (line-transects) were monitored in twelve 2 km-long transects at monthly intervals. Fruit supply varied seasonally, being low during the dry season. The density of Ateles belzebuth was positively related to fruit supply during fruit shortage, but Cebus olivaceus and Alouatta macconnelli did not follow the same pattern. The supply of Sapotaceae fruit was an important component determining local distribution of A. belzebuth during the overall fruit shortage. Highly frugivorous primates such as A. belzebuth respond to seasonal decline in fruit supply by congregating at places with high fruit supply in this forest, particularly, those with many individuals of species of Sapotaceae. This study underscores the importance of small-scale spatiotemporal changes of fruit supply as a key component of frugivorous primate ecology in highly seasonal environments. PMID- 25296225 TI - A morphological anomaly in Clausocalanus mastigophorus (Claus, 1863) (Copepoda, Calanoida) from St. Peter and St. Paul Archipelago. PMID- 25296226 TI - Morphometry of Cornops aquaticum (Orthoptera: Acrididae: Leptysminae) in the Pantanal of Mato Grosso, Brazil. AB - Insects show morphometric variations associated with the environment that may be the result of phenotypic response or genetic inheritance, or both. Thereby, studies that emphasise the variability in body size are very useful for understanding the dynamics and the stability of ecological systems. Cornops aquaticum (Bruner, 1906) (Acrididae) is a semi-aquatic grasshopper, distributed from the southeast of Mexico to the south of Buenos Aires Province, Argentina, and is intimately associated with the aquatic macrophytes Eichhornia spp. and Pontederia spp. In its wide habitat distribution, C. aquaticum shows variations in its life cycle and morphometric differences that were observed suggesting geographic and host plant influence. Considering these findings, this study aimed to find out the morphometric characteristics of this species at the Pantanal of Pocone - MT, using the protocol of the project "HICWA - Host-Insect Coevolution on Waterhyacinth", as well as to assess possible differences in each stage of development between the sexes and among seasonal periods (flood, high water, low water and dry). During 12 months a total of 600 individuals were collected in monthly collections of 50 grasshoppers, and of this total, 261 were adults and 339 nymphs. The following measurements were taken: total length (A); body length (B); wing length (I) and measurement of the hind femur (H). The results showed that both male and female have different measurements but not correlated with seasonal periods. The average obtained for each character and the seasonality showed the highest values during the flood period. In nymphs, the measurement of the posterior femur presented the lower variation between individuals and characters. PMID- 25296227 TI - Vascular function in arteries of intertidal fish Girella laevifrons (Kyphosidae). AB - Preliminary studies showed that dorsal artery contraction mediated by acetylcholine (ACh) is blocked with indomethacin in intertidal fish (Girella laevifrons). Our objective was to characterise the cholinergic pathway in several artery vessels of the G. laevifrons. Afferent and efferent branchial, dorsal and mesenteric arteries were dissected of 6 juvenile specimens, isometric tension studies were done using dose response curves (DRC) for Ach (10(-13) to 10(-3) M), and cholinergic pathways were obtained by blocking with atropine or indomethacin. CRC to ACh showed a pattern of high and low sensitivity. Furthermore, these contractions were blocked in the presence of atropine and indomethacin in all vessels. Our results suggest that contraction observed with acetylcholine is mediated by receptors that activate a cyclooxygenase contraction pathway. PMID- 25296228 TI - Body size and clonality consequences for sexual reproduction in a perennial herb of Brazilian rupestrian grasslands. AB - Body size is one of the most important factors regarding herbaceous perennial plants life-histories, and several fitness components of these organisms are related to size. Clonal plants show distinct kinds of reproduction and can develop offspring by sexual or asexual ways. We aimed to understand how body size affects Comanthera nivea (Eriocaulaceae) sexual reproduction and to verify how clonal growth is related to flower head production in this species. We sampled 600 rosettes in rupestrian grasslands and performed linear regression analysis between body size and number of produced flower heads. We also compared the flower head production between isolated rosettes and rosettes within clones. Our results showed that body size was significantly related, but explained only a small part of flower head production. The flower head production was higher in rosettes within clones than in isolated ones. The clones presented a rosette or a small group of rosettes that concentrated the sexual reproduction. Clonality was positively associated with sexual reproduction. Clonality can represent an important way of allowing the persistence of plants by sexual reproduction in markedly seasonal stressful environments. The cases of clonality enhancing the sexual reproduction must be considered and put in focus on reproductive biology research. PMID- 25296230 TI - Letter from the editor: immunological Investigations. PMID- 25296231 TI - Current advances and remaining challenges in human transplant immunology. PMID- 25296233 TI - The increasing clinical importance of alloantibodies in kidney transplantation. AB - Historically, cellular rather than humoral immunity has gathered the most attention in kidney transplantation. As the specter of cellular acute rejection and early graft loss has faded due to the availability of highly effective immunosuppressive therapy, scientific and clinical studies now focus on improving long-term graft survival. It is increasingly appreciated that alloantibodies directed against HLA and non-HLA antigens are key factors in determining graft longevity. Significant efforts are now being made to better understand the critical impact that B cells and alloantibodies make on organ allocation and graft survival. Future therapies directed specific for the humoral alloresponse will undoubtedly lead to improved outcomes after kidney transplantation. This review will cover some of the advances in the understanding and management of the continuum of humoral immunity in renal transplantation in the pre, peri and post transplant periods. PMID- 25296234 TI - Induction therapy in renal transplant recipients: a review. AB - Transplant science has improved significantly over the last decade. Influenced by novel advancements, rejection rates and short-term graft losses diminished substantially. Induction therapy was shown to reduce rejection rates and improve short-term graft survival. In this article, we discuss the most commonly used induction agents and the choice of induction therapy in different renal transplant recipient subgroups. The medical literature as well as our own experience was used to prepare this review. At this time, induction therapy is commonly used in upwards of 80%, of renal transplant recipients. Depleting agents are the most frequently used agents and they account for more than 75% of all induction therapies in the United States. Currently, there is no consensus regarding the choice of induction therapy. The type of induction therapy is generally selected based on a comprehensive evaluation of the recipient and the donor's immunological risks, the risk of developing opportunistic infection and malignancy, recipient comorbidities, financial burden and the choice of maintenance immunosuppressive regimen. PMID- 25296232 TI - Flow cytometry and solid organ transplantation: a perfect match. AB - In the field of transplantation, flow cytometry serves a well-established role in pre-transplant crossmatching and monitoring immune reconstitution following hematopoietic stem cell transplantation. The capabilities of flow cytometers have continuously expanded and this combined with more detailed knowledge of the constituents of the immune system, their function and interaction and newly developed reagents to study these parameters have led to additional utility of flow cytometry-based analyses, particularly in the post-transplant setting. This review discusses the impact of flow cytometry on managing alloantigen reactions, monitoring opportunistic infections and graft rejection and gauging immunosuppression in the context of solid organ transplantation. PMID- 25296235 TI - Immune minimization strategies in renal transplantation. AB - Very low early rejection rates and excellent short-term kidney allograft outcomes have been the mainstay of forwarding the field of Kidney Transplantation in the last few decades. This progress is mainly achieved by using the current armamentarium of maintenance immunosuppression in different combinations and dosages of calcineurin inhibitors (CNI), corticosteroids and antiproliferative drugs. Metabolic risks and nephrotoxicity of CNIs has led to a search for strategies to minimize their use. Similarly, metabolic risks, mood abnormalities and Cushing-like side effects of steroids have forced physicians and patients alike to try to minimize their use in transplantation. Here, we review the most recent randomized controlled trials of minimization of CNI/steroids in a manner (with incident immunologic risks, state of net immunosuppression and side- effects) that may be helpful to choose the best strategy for the individual patient. New trials testing minimization strategies should include in their design, an assessment of the impact of minimization on development of donor specific antibodies and antibody-mediated rejection as well as long-term outcomes. PMID- 25296236 TI - Long-term outcomes following sirolimus conversion after renal transplantation. AB - Long-term outcomes following renal transplantation remain limited due to chronic progressive injury partly as a result of calcineurin inhibitor (CNI) toxicity. Thus, patients have been converted to non-CNI immunosuppressives despite the lack of evidence of long-term benefits from CNI free therapy. We now report our 10 year experience converting patients with well functioning transplants from CNI to sirolimus. We retrospectively analyzed outcomes of patients receiving continuous CNI based therapy (CNI, n = 309) or who were switched to sirolimus within the first year of post-transplantation (CONV, n = 54). The groups were similar for most recipient, graft and donor characteristics, however, diabetes was more common in the CNI group and statin use was more frequent in the CONV group. The average time to conversion was 7.2 months and the creatinine level at the time of switching was 1.4 mg/dl. Ten year graft and patient survival rates were equivalent in both groups. There were no differences in the causes of death or graft loss in both groups. Renal function was available for 5 years posttransplant and was no different between groups. Thus, there is no evidence that routinely switching patients with well functioning renal allografts to sirolimus from CNI based immunosuppression provides long-term benefit. PMID- 25296238 TI - Etiology of GVHD: alloreactivity or impaired cellular adaptation? AB - According to the self-nonself model of immunity, allogeneic T cells are considered as major cause of graft versus host disease (GVHD) following allogeneic stem cell transplantation (SCT). On the other hand, the danger model of immunity suggests that transplant-associated recipient tissue injury rather than donor-derived alloreactive T cells is the main cause of GVHD. What has been less appreciated are the early, both conditioning-dependent and conditioning independent, events that impair homeostatic cellular adaptations and host protective immune responses leading to the development of tissue-specific GVHD. The notion of gut injury precipitating in GVHD has been acknowledged by clinicians, with the shift to reduced intensity-conditioning regimens that prevent acute tissue injury and are less disruptive of tissue adaptation to T cell attack. Also, the role of host-protective immune response against pathogens in preventing GVHD has been shown by the lack of severe GVHD in germ free mice as well as an impaired anti-viral immune response during chronic GVHD. This article provides a brief review of the literature on GVHD and suggests that transplant induced dysregulation of the protective immune response in the recipient of SCT is more important than allogeneic T cells in causing GVHD. PMID- 25296237 TI - Recent immunomodulatory strategies in transplantation. AB - Despite preservation methods, surgical procedures, current immunosuppressive therapy regimens advances, organ transplantation is accompanied with a poor long term survival and significant mortality. This has led to an increased interest to optimize outcomes while minimizing associated toxicity by using alternative methods for maintenance immunosuppression, organ rejection treatment, and monitoring of immunosuppression. Advance in long-standing allograft outcomes may depend on new drugs with novel mechanisms of action with minimal toxicity. Newer treatment techniques have been developed, including using novel stem cell-based therapies such as mesenchymal stem cells, phagosomes and exosomes. Immunoisolation techniques and salvage therapies, including photopheresis and total lymphoid irradiation have emerged as alternate therapeutic choices. The present review evaluates the recent clinical advances in immunosuppressive therapies for organ transplantation. PMID- 25296239 TI - Immunology of hematopoietic stem cell transplant. AB - Hematopoietic stem cell transplantation (HSCT) is a procedure in which infusion of hematopoietic stem cells is used to reestablish hematopoietic function in patients with damaged or defective bone marrow or immune systems. Early and late complications following allogeneic HSCT include acute and chronic graft-versus host disease (GVHD), donor rejection, graft failure, relapse of primary malignancy, conditioning-related toxicity, immunodeficiency and infections. Immunology has a central role in allogeneic hematopoietic cell transplantation. Any appreciation of the immunological mechanism involved in engraftment, GVHD, the development of tolerance, immune reconstitution, and the control of malignancy requires some understanding of the immunologic basis for immune reactions provoked by grafting tissue from one individual to another. In the future it should be possible to learn what gene(s) must be activated and which must be repressed to force stem cells into division without maturation; to engineer a mechanism into the cells that stops proliferation and sets the stage for amplification; to search if there could be a universal donor cell line, neatly packaged and stabilized in sealed vials and distributed by the pharmaceutical industry; to modify the transplanted cells in such a way that they have a proliferative advantage over those of the host and to deliver the lethal blow against the neoplasm, perhaps the cells that are infused will be engineered in such a way as to be able to distinguish between normal host cells and tumor. PMID- 25296240 TI - Immunological aspects of corneal transplant. AB - Corneal transplant is the most common solid tissue transplant in humans. Advances in microsurgical techniques, eye banking and the use of corticosteroids have improved the success of corneal transplants. Over 65,000 corneal transplants are being performed worldwide annually. Most of these transplants are performed in developed countries. Cornea is considered an immune privileged site. Despite this, immune mediated graft rejection is the most single cause of cornea graft failure and is one of the major postoperative complications. Incidences from as low as 2% to as high as 50% have been reported depending upon the degree of vascularization. Rejection involves donor tissue recognition and various factors may influence this rejection. Major factors include the antigenic load of the donor tissue; other factors include death to enucleation time, methods and temperature of preserving the tissue. Host factors that may impact the graft include ocular surface diseases such as dry eye, chemical burns and autoimmune diseases such as mucous membrane pemphigoid. Following infection, surgery or trauma, cells of the innate immune system invade the cornea as a result of up regulation of cytokines, cellular adhesion molecules and growth and angiogenic factors. These factors results in neoangiogenesis and lymphoangiogenesis, leading to immune activation and graft rejection. The various immunological mechanisms that may play a role in the corneal transplant are discussed. PMID- 25296241 TI - Intrapleural tissue plasminogen activator and deoxyribonuclease for pleural infection. An effective and safe alternative to surgery. AB - RATIONALE: Intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) therapy for pleural infection given at the time of diagnosis has been shown to significantly improve radiological outcomes. Published cases are limited to only a single randomized controlled trial and a few case reports. OBJECTIVES: Multinational observation series to evaluate the pragmatic "real-life" application of tPA/DNase treatment for pleural infection in a large cohort of unselected patients. METHODS: All patients from eight centers who received intrapleural tPA/DNase for pleural infection between January 2010 and September 2013 were included. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity and inflammatory markers, need for surgery, and adverse events. MEASUREMENTS AND MAIN RESULTS: Of 107 patients treated, the majority (92.3%) were successfully managed without the need for surgical intervention. No patients died as a result of pleural infection. Most patients (84%) received tPA/DNase more than 24 hours after failing to respond to initial conservative management with antibiotics and thoracostomy. tPA/DNase increased fluid drained from a median of 250 ml (interquartile range [IQR], 100-654) in the 24 hours preceding commencement of intrapleural therapy to 2,475 ml (IQR 1,800-3,585) in the 72 hours following treatment initiation (P < 0.05). We observed a corresponding clearance of pleural opacity on chest radiographs from a median of 35% (IQR 25-31) to 14% (7-28) of the hemithorax (P < 0.001), as well as significant reduction in C-reactive protein (P < 0.05). Pain necessitating escalation of analgesia occurred in 19.6% patients, and nonfatal bleeding occurred in 1.8%. CONCLUSIONS: This large series of patients who received intrapleural tPA/DNase therapy provides important evidence that the treatment is effective and safe, especially as a "rescue therapy" in patients who do not initially respond to antibiotics and thoracostomy drainage. PMID- 25296242 TI - Metabolomic fingerprint classification of Brachychiton acerifolius organs via UPLC-qTOF-PDA-MS analysis and chemometrics. AB - Brachychiton acerifolius, or Sterculia acerifolia as formerly known, is a member of a genus reported for a myriad of bioactive compounds. Metabolome analysis of B. acerifolius--leaves, flowers and seeds--and quantification of its major compounds are demonstrated in this study. Metabolites were analysed via UPLC-PDA qTOF-(+/-) ESI-MS and UPLC/ITMS, with a total of 56 metabolites characterised including 30 flavonoids, 2 anthocyanins, 6 phenolic acids (i.e. citric and hydroxycitric acid conjugates) and 8 fatty acids (FAs). Multivariate data analyses (i.e. principle component analysis and orthogonal partial least square discriminate analysis) were applied to identify metabolite markers for each organ. Pelargonidin-O-glucoside and naringenin-O-glucuronide were found exclusively in flowers versus flavone enrichment in leaves (i.e. luteolin-O glucuronide and apigenin-O-rhamnosyl glucuronide). Gas chromatography/mass spectrometry analysis revealed the presence of toxic cyclopropene FAs in seeds which may restrict its use. Antioxidant activity assessment for the three organs was performed in comparison with vitamin C as positive control. Leaves showed the highest activity (IC50 0.015 mg/mL). PMID- 25296243 TI - A randomized controlled trial comparing a low-residue diet versus clear liquids for colonoscopy preparation: impact on tolerance, procedure time, and adenoma detection rate. AB - OBJECTIVE: To achieve an excellent bowel preparation, it is routine to require a clear liquid diet on the day before the procedure. Unfortunately, this dietary modification may be poorly tolerated. We examine whether a change in precolonoscopy dietary restriction can lead to better patient tolerance without compromising examination quality. METHODS: This is a prospective, blinded, randomized controlled trial of patients undergoing screening or surveillance colonoscopy. The primary objective measures the effect of dietary modification on bowel prep quality. Secondary endpoints include polyp detection, patient tolerance, withdrawal time, and patient acceptance. A total of 200 patients were randomized to either (a) a low-residue diet for breakfast and lunch the day before the procedure or (b) clear liquids all day before the procedure. All patients underwent an identical low-volume sodium sulfate split prep. Bowel prep quality was scored using the Boston Bowel Preparation Scale (BBPS). A t test with TOST was used for noninferiority. Secondary endpoints were compared using chi analysis. RESULTS: Overall, 96.5% of patients had a good or excellent bowel prep (BBPS=6, 7, 8, or 9). LRD prep quality was noninferior to CLD prep quality (LRD 7.8 vs. CLD 8.1). Polyp detection rates were similar (68% vs. 65.4%, P=0.6899). Patient tolerance and acceptance did not differ. Withdrawal times were equivalent between both groups (16.2 vs. 16.5 min, P=NS). CONCLUSIONS: Patients allowed to have a limited low-residue diet before colonoscopy achieve a bowel prep quality that is noninferior to patients on a strict clear liquid diet limitation. Furthermore, polyp detection rates, patient tolerance, and patient acceptance were similar between the 2 groups. PMID- 25296244 TI - A fractal nature for polymerized laminin. AB - Polylaminin (polyLM) is a non-covalent acid-induced nano- and micro-structured polymer of the protein laminin displaying distinguished biological properties. Polylaminin stimulates neuritogenesis beyond the levels achieved by ordinary laminin and has been shown to promote axonal regeneration in animal models of spinal cord injury. Here we used confocal fluorescence microscopy (CFM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) to characterize its three-dimensional structure. Renderization of confocal optical slices of immunostained polyLM revealed the aspect of a loose flocculated meshwork, which was homogeneously stained by the antibody. On the other hand, an ordinary matrix obtained upon adsorption of laminin in neutral pH (LM) was constituted of bulky protein aggregates whose interior was not accessible to the same anti-laminin antibody. SEM and AFM analyses revealed that the seed unit of polyLM was a flat polygon formed in solution whereas the seed structure of LM was highly heterogeneous, intercalating rod-like, spherical and thin spread lamellar deposits. As polyLM was visualized at progressively increasing magnifications, we observed that the morphology of the polymer was alike independently of the magnification used for the observation. A search for the Hausdorff dimension in images of the two matrices showed that polyLM, but not LM, presented fractal dimensions of 1.55, 1.62 and 1.70 after 1, 8 and 12 hours of adsorption, respectively. Data in the present work suggest that the intrinsic fractal nature of polymerized laminin can be the structural basis for the fractal-like organization of basement membranes in the neurogenic niches of the central nervous system. PMID- 25296245 TI - Effects of stimulating surface during static upright posture in the elderly. AB - This study aimed to investigate the influence of three stimulating surfaces based on center of pressure (CoP), anteroposterior sway velocity (V(A/P)), and medio lateral sway velocity (V(M/L)) of 40 elderly subjects. CoP and V(M/L) showed a significant decrease in all visual conditions only in the stimulating surface whereas V(A/P) showed a significant decrease only on the same surface with eyes open. Results confirm the importance of multisensory stimulation in postural control in the elderly. PMID- 25296246 TI - Extremely stretchable thermosensitive hydrogels by introducing slide-ring polyrotaxane cross-linkers and ionic groups into the polymer network. AB - Stimuli-sensitive hydrogels changing their volumes and shapes in response to various stimulations have potential applications in multiple fields. However, these hydrogels have not yet been commercialized due to some problems that need to be overcome. One of the most significant problems is that conventional stimuli sensitive hydrogels are usually brittle. Here we prepare extremely stretchable thermosensitive hydrogels with good toughness by using polyrotaxane derivatives composed of alpha-cyclodextrin and polyethylene glycol as cross-linkers and introducing ionic groups into the polymer network. The ionic groups help the polyrotaxane cross-linkers to become well extended in the polymer network. The resulting hydrogels are surprisingly stretchable and tough because the cross linked alpha-cyclodextrin molecules can move along the polyethylene glycol chains. In addition, the polyrotaxane cross-linkers can be used with a variety of vinyl monomers; the mechanical properties of the wide variety of polymer gels can be improved by using these cross-linkers. PMID- 25296247 TI - Nicardipine is superior to esmolol for the management of postcraniotomy emergence hypertension: a randomized open-label study. AB - BACKGROUND: Emergence hypertension after craniotomy is a well-documented phenomenon for which natural history is poorly understood. Most clinicians attribute this phenomenon to an acute and transient increase in catecholamine release, but other mechanisms such as neurogenic hypertension or activation of the renin-angiotensin-aldosterone system have also been proposed. In this open label study, we compared the monotherapeutic antihypertensive efficacy of the 2 most titratable drugs used to treat postcraniotomy emergence hypertension: nicardipine and esmolol. We also investigated the effect of preoperative hypertension on postcraniotomy hypertension and the natural history of postcraniotomy hypertension in the early postoperative period. METHODS: Fifty-two subjects were prospectively randomized to receive either nicardipine or esmolol as the sole drug for treatment of emergence hypertension at the conclusion of brain tumor resection (40 subjects finally analyzed). After a uniform anesthetic, standardized protocols of these antihypertensive medications were administered for the treatment of systolic blood pressure (SBP) >130, with the goal of maintaining SBP <140 throughout the first postoperative day. In the event of study medication "failure," a "rescue" antihypertensive (labetalol or hydralazine) was used. The O'Brien-Fleming Spending Function was used to calculate the appropriate alpha value for each interim analysis of the primary outcome; univariate analysis was performed otherwise, with a 2-sided P<0.05 considered statistically significant. RESULTS: The incidence of nicardipine failure (5%, 95% confidence interval [CI] 0.1%-24.9%) was significantly less than that of esmolol (55%, 95% CI 31.5%-76.9%) as a sole drug in controlling SBP after brain tumor resection (difference 99% CI 13.8%-75.7%, P = 0.0012). The presence of preoperative hypertension or the approach to surgery (open craniotomy versus endonasal transsphenoidal) had no significant effect on the incidence of failure of the antihypertensive regimen used. We did not observe a difference in the need for opioid therapy for postcraniotomy pain between drug groups (99% CI difference -39.2%-30.2%). Failure of the study drug predicted the need for rescue drug therapy in the initial 12 hours after discharge from the recovery room (difference success versus failure = -41.7%, 99% CI difference -72.3% to -1.8%, P = 0.0336) but not during the period 12 to 24 hours after discharge from the recovery room (difference success versus failure = -27.4%, 99% CI difference 63.8%-9.2%, P = 0.143). However, in those patients carrying a preoperative diagnosis of hypertension, the need for rescue medication was only different during the period 12 to 24 hours after discharge from the recovery room (difference normotensive versus hypertensive = -35.4%, 99% CI difference -66.9% to -0.3%, P = 0.0254). CONCLUSIONS: Nicardipine is superior to esmolol for the treatment of postcraniotomy emergence hypertension. This type of hypertension is thought to be a transient phenomenon not solely related to sympathetic activation and catecholamine surge but also possibly encompassing other physiologic factors. For treating postcraniotomy emergence hypertension, nicardipine is a relatively effective sole drug, whereas if esmolol is used, rescue antihypertensive medications should be readily available. PMID- 25296248 TI - Assessment and characterisation of yeast-based products intended to mitigate ochratoxin exposure using in vitro and in vivo models. AB - The aim of this paper was to evaluate the capacity of several yeast-based products, derived from baker's and brewer's yeasts, to sequester the mycotoxin ochratoxin A (OTA) and to decrease its rate of absorption and DNA adduct formation in vivo. The experimental protocol included in vitro binding studies using isotherm models, in vivo chicken experiments, in which the serum and tissue concentrations of OTA were analysed in the absence and presence of the test compounds, and the profile of OTA-derived metabolites and their associated DNA adducts were determined. Additionally in vitro cell culture studies (HK2 cells) were applied to assess further the effects for yeast cell product enriched with glutathione (GSH) or selenium. Results of the in vitro binding assay in a buffer system indicated the ability of the yeast-based products, as sequester of OTA, albeit at a different level. In the in vitro experiments in chickens, decreased serum and tissue concentrations of treated animals confirmed that yeast-based products are able to prevent the absorption of OTA. A comparison of the binding affinity in a standard in vitro binding assay with the results obtained in an in vivo chicken experiment, however, showed a poor correlation and resulted in a different ranking of the products. More importantly, we could show that yeast based products actively modulate the biotransformation of OTA in vivo as well as in vitro in a cell culture model. This effect seems to be attributable to residual enzymatic activities in the yeast-based products. An enrichment of yeast cell wall products with GSH or selenium further modulated the profile of the generated OTA metabolites and the associated pattern of OTA-induced DNA adducts by increasing the conversion of OTA into less toxic metabolites such as OTA, OTB and 4-OH-OTA. A reduced absorption and DNA adduct formation was particularly observed with GSH-enriched yeast, whereas selenium-enriched yeasts could counteract the OTA-induced decrease in cell viability, but at the same time increased the OTA-DNA adducts formation. These findings indicate the need for an in-depth characterisation of yeast-based products used as mycotoxin-mitigating feed additives, in in vivo models with target animal species taking into account not only their ability to sequester toxins in the gastrointestinal tract but also their potential effects on the biotransformation of mycotoxins. PMID- 25296250 TI - Binary orbits as the driver of gamma-ray emission and mass ejection in classical novae. AB - Classical novae are the most common astrophysical thermonuclear explosions, occurring on the surfaces of white dwarf stars accreting gas from companions in binary star systems. Novae typically expel about 10(-4) solar masses of material at velocities exceeding 1,000 kilometres per second. However, the mechanism of mass ejection in novae is poorly understood, and could be dominated by the impulsive flash of thermonuclear energy, prolonged optically thick winds or binary interaction with the nova envelope. Classical novae are now routinely detected at gigaelectronvolt gamma-ray wavelengths, suggesting that relativistic particles are accelerated by strong shocks in the ejecta. Here we report high resolution radio imaging of the gamma-ray-emitting nova V959 Mon. We find that its ejecta were shaped by the motion of the binary system: some gas was expelled rapidly along the poles as a wind from the white dwarf, while denser material drifted out along the equatorial plane, propelled by orbital motion. At the interface between the equatorial and polar regions, we observe synchrotron emission indicative of shocks and relativistic particle acceleration, thereby pinpointing the location of gamma-ray production. Binary shaping of the nova ejecta and associated internal shocks are expected to be widespread among novae, explaining why many novae are gamma-ray emitters. PMID- 25296249 TI - Clathrin regenerates synaptic vesicles from endosomes. AB - Ultrafast endocytosis can retrieve a single, large endocytic vesicle as fast as 50-100 ms after synaptic vesicle fusion. However, the fate of the large endocytic vesicles is not known. Here we demonstrate that these vesicles transition to a synaptic endosome about one second after stimulation. The endosome is resolved into coated vesicles after 3 s, which in turn become small-diameter synaptic vesicles 5-6 s after stimulation. We disrupted clathrin function using RNA interference (RNAi) and found that clathrin is not required for ultrafast endocytosis but is required to generate synaptic vesicles from the endosome. Ultrafast endocytosis fails when actin polymerization is disrupted, or when neurons are stimulated at room temperature instead of physiological temperature. In the absence of ultrafast endocytosis, synaptic vesicles are retrieved directly from the plasma membrane by clathrin-mediated endocytosis. These results may explain discrepancies among published experiments concerning the role of clathrin in synaptic vesicle endocytosis. PMID- 25296251 TI - HIV: A stamp on the envelope. PMID- 25296252 TI - Neuroscience: towards unified vesicle endocytosis. PMID- 25296253 TI - Rapid development of broadly influenza neutralizing antibodies through redundant mutations. AB - The neutralizing antibody response to influenza virus is dominated by antibodies that bind to the globular head of haemagglutinin, which undergoes a continuous antigenic drift, necessitating the re-formulation of influenza vaccines on an annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region (HCDR) residues. However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals, suggesting that several somatic mutations may be required for their development. To address this, here we characterize 197 anti stem antibodies from a single donor, reconstruct the developmental pathways of several VH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 in HCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity and making both the initial mutations and phenylalanine at position 54 functionally redundant. These results define VH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process. PMID- 25296254 TI - R-loops induce repressive chromatin marks over mammalian gene terminators. AB - The formation of R-loops is a natural consequence of the transcription process, caused by invasion of the DNA duplex by nascent transcripts. These structures have been considered rare transcriptional by-products with potentially harmful effects on genome integrity owing to the fragility of the displaced DNA coding strand. However, R-loops may also possess beneficial effects, as their widespread formation has been detected over CpG island promoters in human genes. Furthermore, we have previously shown that R-loops are particularly enriched over G-rich terminator elements. These facilitate RNA polymerase II (Pol II) pausing before efficient termination. Here we reveal an unanticipated link between R loops and RNA-interference-dependent H3K9me2 formation over pause-site termination regions in mammalian protein-coding genes. We show that R-loops induce antisense transcription over these pause elements, which in turn leads to the generation of double-stranded RNA and the recruitment of DICER, AGO1, AGO2 and the G9a histone lysine methyltransferase. Consequently, an H3K9me2 repressive mark is formed and heterochromatin protein 1gamma (HP1gamma) is recruited, which reinforces Pol II pausing before efficient transcriptional termination. We predict that R-loops promote a chromatin architecture that defines the termination region for a substantial subset of mammalian genes. PMID- 25296257 TI - Influenza vaccine for 2014-2015. PMID- 25296256 TI - Clonal dynamics of native haematopoiesis. AB - It is currently thought that life-long blood cell production is driven by the action of a small number of multipotent haematopoietic stem cells. Evidence supporting this view has been largely acquired through the use of functional assays involving transplantation. However, whether these mechanisms also govern native non-transplant haematopoiesis is entirely unclear. Here we have established a novel experimental model in mice where cells can be uniquely and genetically labelled in situ to address this question. Using this approach, we have performed longitudinal analyses of clonal dynamics in adult mice that reveal unprecedented features of native haematopoiesis. In contrast to what occurs following transplantation, steady-state blood production is maintained by the successive recruitment of thousands of clones, each with a minimal contribution to mature progeny. Our results demonstrate that a large number of long-lived progenitors, rather than classically defined haematopoietic stem cells, are the main drivers of steady-state haematopoiesis during most of adulthood. Our results also have implications for understanding the cellular origin of haematopoietic disease. PMID- 25296258 TI - Empagliflozin (Jardiance) for diabetes. PMID- 25296259 TI - A stool DNA test (Cologuard) for colorectal cancer screening. PMID- 25296260 TI - Rescheduling of hydrocodone combination products. PMID- 25296261 TI - In brief: PCV13 for adults 65 years and older. PMID- 25296255 TI - Structure and immune recognition of trimeric pre-fusion HIV-1 Env. AB - The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation. PMID- 25296263 TI - Direct carboxylation of simple arenes with CO2 through a rhodium-catalyzed C-H bond activation. AB - Direct carboxylation of simple arenes under atmospheric pressure of CO2 is achieved through a rhodium-catalyzed C-H bond activation without the assistance of a directing group. Various arenes such as benzene, toluene, xylene, electron rich or electron-deficient benzene derivatives, and heteroaromatics are directly carboxylated with high TONs. PMID- 25296262 TI - One-electron oxidation of gemcitabine and analogs: mechanism of formation of C3' and C2' sugar radicals. AB - Gemcitabine is a modified cytidine analog having two fluorine atoms at the 2' position of the ribose ring. It has been proposed that gemcitabine inhibits RNR activity by producing a C3'* intermediate via direct H3'-atom abstraction followed by loss of HF to yield a C2'* with 3'-keto moiety. Direct detection of C3'* and C2'* during RNR inactivation by gemcitabine still remains elusive. To test the influence of 2'- substitution on radical site formation, electron spin resonance (ESR) studies are carried out on one-electron oxidized gemcitabine and other 2'-modified analogs, i.e., 2'-deoxy-2'-fluoro-2'-C-methylcytidine (MeFdC) and 2'-fluoro-2'-deoxycytidine (2'-FdC). ESR line components from two anisotropic beta-2'-F-atom hyperfine couplings identify the C3'* formation in one-electron oxidized gemcitabine, but no further reaction to C2'* is found. One-electron oxidized 2'-FdC is unreactive toward C3'* or C2'* formation. In one-electron oxidized MeFdC, ESR studies show C2'* production presumably from a very unstable C3'* precursor. The experimentally observed hyperfine couplings for C2'* and C3'* match well with the theoretically predicted ones. C3'* to C2'* conversion in one electron oxidized gemcitabine and MeFdC has theoretically been modeled by first considering the C3'* and H3O(+) formation via H3'-proton deprotonation and the subsequent C2'* formation via HF loss induced by this proximate H3O(+). Theoretical calculations show that in gemcitabine, C3'* to C2'* conversion in the presence of a proximate H3O(+) has a barrier in agreement with the experimentally observed lack of C3'* to C2'* conversion. In contrast, in MeFdC, the loss of HF from C3'* in the presence of a proximate H3O(+) is barrierless resulting in C2'* formation which agrees with the experimentally observed rapid C2'* formation. PMID- 25296264 TI - Control of the dual reactivity (iminium-dienamine) of beta-arylmethyl alpha,beta unsaturated aldehydes in organocatalytic 1,3-dipolar cycloadditions with N benzoyl C,N-cyclic azomethine imines. AB - 1,3-Dipolar cycloadditions of C,N-cyclic azomethine imines with alpha,beta unsaturated aldehydes can be performed with complete control of the regio-, exo-, and enantioselectivity under aminocatalytic conditions. The so far never studied competence of the iminium-dienamine reactivity inherent to beta-alkyl alpha,beta unsaturated aldehydes was studied, which was possible by allowing achievement of complete control of the chemoselectivity in reactions of the beta-arylmethyl derivatives with azomethine imines by using different additives and organocatalysts, whose role has been rationalized by DFT calculations and chemical proofs. Thus, it has been possible to selectively obtain the pyrazolidines resulting from both the attack to the C2-C3 (via iminium) and the C3-C4 (via dienamine) bonds at the starting enals, which can be used as precursors of interesting tetrahydroisoquinolinic compounds. PMID- 25296265 TI - Aptamers as promising molecular recognition elements for diagnostics and therapeutics in the central nervous system. AB - Oligonucleotide aptamers are short, synthetic, single-stranded DNA or RNA able to recognize and bind to a multitude of targets ranging from small molecules to cells. Aptamers have emerged as valuable tools for fundamental research, clinical diagnosis, and therapy. Due to their small size, strong target affinity, lack of immunogenicity, and ease of chemical modification, aptamers are an attractive alternative to other molecular recognition elements, such as antibodies. Although it is a challenging environment, the central nervous system and related molecular targets present an exciting potential area for aptamer research. Aptamers hold promise for targeted drug delivery, diagnostics, and therapeutics. Here we review recent advances in aptamer research for neurotransmitter and neurotoxin targets, demyelinating disease and spinal cord injury, cerebrovascular disorders, pathologies related to protein aggregation (Alzheimer's, Parkinson's, and prions), brain cancer (glioblastomas and gliomas), and regulation of receptor function. Challenges and limitations posed by the blood brain barrier are described. Future perspectives for the application of aptamers to the central nervous system are also discussed. PMID- 25296267 TI - Cooperative effects of cation size and variable coordination modes of Te(4+) on the frameworks of new alkali metal indium tellurites, NaIn(TeO3)2, KIn(TeO3)2, RbInTe3O8, and CsInTe3O8. AB - Four new alkali metal indium tellurites, NaIn(TeO3)2, KIn(TeO3)2, RbInTe3O8, and CsInTe3O8, have been prepared through hydrothermal and solid state synthesis reactions using corresponding alkali metal carbonates, In2O3 [or In(NO3)3.xH2O], and TeO2. The structures of the reported materials have been determined by powder and single crystal X-ray diffraction. The mixed indium tellurites reveal a rich structural chemistry with different channel structures. NaIn(TeO3)2 shows 8 membered rings, whereas stoichiometrically similar KIn(TeO3)2 exhibits both 8- and 12-membered rings in the frameworks. Isostructural RbInTe3O8 and CsInTe3O8 reveal three-dimensional frameworks consisting of InO6, TeO3, and TeO4 groups. Close structural examination suggests that the alkali metal cation size and variable coordination modes of Te(4+) cations cooperatively influence the framework geometries of the new mixed metal tellurites. Detailed characterizations including spectroscopic, elemental, and thermal analyses are introduced. Local dipole moments and out-of-center distortions for the constituent polyhedra are also reported. PMID- 25296266 TI - [Semiological features and risk factors associated with osteoarthritis of the hip in Ouagadougou (Burkina Faso)]. AB - OBJECTIVE: To study the epidemiological and clinical aspects of osteoarthritis (OA) of the hip in Ouagadougou, as well as its risk factors. PATIENTS AND METHODS: This retrospective study covered cases treated over a 3-year period (February 2006 through January 2009) in the internal medicine department of the Yalgado Ouedraogo Teaching Hospital of Ouagadougou (Burkina Faso) and the surgery department of the private hospital Notre-Dame-de la Paix of Ouagadougou. All patients included had OA of the hip that met the Kellgren and Lawrence criteria. RESULTS: There were 46 patients who met the study criteria, but only 40 files could be used. The patients' mean age was 46.4 years +/- 15.2 years (range 25-80 years; 10 patients were older than 56 years). Men accounted for more than half (n=23, 57.5%). The mean duration of disease was 6.2 years +/- 4.5 years (range: 1 19 years). The right hip alone was concerned in 20 patients (50%), the left hip in 16 (40%), and the OA was bilateral in four (10%). Seventeen patients had sickle cell disease (42.5%), 11 SC and 6 SS. The risk factors included necrosis of the femoral head in 19 cases (59.37%), hip dysplasia in 6 (18.74%), hip trauma in 3 (9.37%), inflammatory arthropathy in 3 more (9.37%), and epiphysitis in one (3.13%). The OA of the hip was primary in 8 cases (20%). Three patients were at stage 1, 9 at stage 2, 15 at stage 3, and 13 at stage 4 according to the Arlet Ficat classification. CONCLUSION: OA of the hip arises in a young population and is dominated by secondary OA. The dominant risk factor was aseptic necrosis of the femoral head associated with sickle cell disease. In view of the small number of patients with primary OA, no definitive conclusions can be drawn about it. PMID- 25296272 TI - Individual differences in susceptibility to the McGurk effect: links with lipreading and detecting audiovisual incongruity. AB - PURPOSE: Prior studies (e.g., Nath & Beauchamp, 2012) report large individual variability in the extent to which participants are susceptible to the McGurk effect, a prominent audiovisual (AV) speech illusion. The current study evaluated whether susceptibility to the McGurk effect (MGS) is related to lipreading skill and whether multiple measures of MGS that have been used previously are correlated. In addition, it evaluated the test-retest reliability of individual differences in MGS. METHOD: Seventy-three college-age participants completed 2 tasks measuring MGS and 3 measures of lipreading skill. Fifty-eight participants returned for a 2nd session (approximately 2 months later) in which MGS was tested again. RESULTS: The current study demonstrated that MGS shows high test-retest reliability and is correlated with some measures of lipreading skill. In addition, susceptibility measures derived from identification tasks were moderately related to the ability to detect instances of AV incongruity. CONCLUSIONS: Although MGS is often cited as a demonstration of AV integration, the results suggest that perceiving the illusion depends in part on individual differences in lipreading skill and detecting AV incongruity. Therefore, individual differences in susceptibility to the illusion are not solely attributable to individual differences in AV integration ability. PMID- 25296273 TI - Imaging of the brain in patients with human immunodeficiency virus infection. AB - Neurologic disease in acquired immunodeficiency syndrome (AIDS) patients is related either to opportunistic pathogens or to direct central nervous system (CNS) invasion by the human immunodeficiency virus. Despite the increasing availability of antiretroviral therapy, opportunistic infections continue to afflict patients in the developing world and in other populations with limited access to appropriate treatment. Classic CNS infections in the setting of AIDS include toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and cytomegalovirus encephalitis. Additionally, AIDS patients are far more susceptible to acquiring CNS tuberculosis and neurosyphilis, both of which exhibit altered disease characteristics in the setting of immunosuppression. Neuroimaging is a crucial component of the diagnostic work-up of these conditions, and findings include, but are not limited to, intracranial mass lesions, white matter disease, meningoencephalitis, vascular complications, and hydrocephalus. Though various disease processes can produce imaging findings that overlap with one another, certain characteristic patterns may suggest a particular pathogen, and advanced imaging techniques and laboratory tests allow for definitive diagnosis. Knowledge of the imaging patterns seen in the setting of AIDS-related CNS disease is vital to the neuroradiologist, whose interpretation may guide decisions related to treatment and further work-up. PMID- 25296268 TI - Childhood-onset asthma in smokers. association between CT measures of airway size, lung function, and chronic airflow obstruction. AB - RATIONALE AND OBJECTIVES: Asthma is associated with chronic airflow obstruction. Our goal was to assess the association of computed tomographic measures of airway wall volume and lumen volume with the FEV1 and chronic airflow obstruction in smokers with childhood-onset asthma. METHODS: We analyzed clinical, lung function, and volumetric computed tomographic airway volume data from 7,266 smokers, including 590 with childhood-onset asthma. Small wall volume and small lumen volume of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small wall volume, small lumen volume, FEV1, and chronic airflow obstruction (post-bronchodilator FEV1/FVC ratio < 0.7) using linear and logistic models. MEASUREMENTS AND MAIN RESULTS: Compared with subjects without childhood-onset asthma, those with childhood-onset asthma had smaller wall volume and lumen volume (P < 0.0001) of segmental airways. Among subjects with childhood-onset asthma, those with the smallest wall volume and lumen volume had the lowest FEV1 and greatest odds of chronic airflow obstruction. A similar tendency was seen in those without childhood-onset asthma. When comparing these two groups, both small wall volume and small lumen volume were more strongly associated with FEV1 and chronic airflow obstruction among subjects with childhood-asthma in multivariate models. CONCLUSION: In smokers with childhood onset asthma, smaller airways are associated with reduced lung function and chronic airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT00608764). PMID- 25296274 TI - Magnetic resonance imaging in viral and prion diseases of the central nervous system. AB - The early detection and specific diagnosis of viral infections of the central nervous system are important because many of these diseases are potentially treatable. However, clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some, but not all, viruses. Neuroimaging, in conjunction with clinical history and laboratory tests, plays an important role in narrowing the differential diagnoses. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections and prions that involve the central nervous system. PMID- 25296275 TI - Spinal infections: clinical and imaging features. AB - Spinal infections represent a group of rare conditions affecting vertebral bodies, intervertebral discs, paraspinal soft tissues, epidural space, meninges, and spinal cord. The causal factors, clinical presentations, and imaging features are a challenge because the difficulty to differentiate them from other conditions, such as degenerative and inflammatory disorders and spinal neoplasm. They require early recognition because delay diagnosis, imaging, and intervention may have devastating consequences especially in children and the elderly. This article reviews the most common spinal infections, their pathophysiologic, clinical manifestation, and their imaging findings. PMID- 25296276 TI - Magnetic resonance imaging of infectious meningitis and ventriculitis in adults. AB - Magnetic resonance imaging findings of meningitis are usually nonspecific with respect to the causative pathogen because the brain response to these insults is similar in most cases. In this article, we will use a few representative cases to describe the characteristic magnetic resonance findings of meningitis and its complications, including ventriculitis. PMID- 25296278 TI - Hydrazine-mediated construction of nanocrystal self-assembly materials. AB - Self-assembly is the basic feature of supramolecular chemistry, which permits to integrate and enhance the functionalities of nano-objects. However, the conversion of self-assembled structures to practical materials is still laborious. In this work, on the basis of studying one-pot synthesis, spontaneous assembly, and in situ polymerization of aqueous semiconductor nanocrystals (NCs), NC self-assembly materials are produced and applied to design high performance white light-emitting diode (WLED). In producing self-assembly materials, the additive hydrazine (N2H4) is curial, which acts as the promoter to achieve room temperature synthesis of aqueous NCs by favoring a reaction-controlled growth, as the polyelectrolyte to weaken inter-NC electrostatic repulsion and therewith facilitate the one-dimensional self-assembly, and in particular as the bifunctional monomers to polymerize with mercapto carboxylic acid-modified NCs via in situ amidation reaction. This strategy is versatile for mercapto carboxylic acid-modified aqueous NCs, for example CdS, CdSe, CdTe, CdSe(x)Te(1 x), and Cd(y)Hg(1-y)Te. Because of the multisite modification with carboxyl, the NCs act as macromonomers, thus producing cross-linked self-assembly materials with excellent thermal, solvent, and photostability. The assembled NCs preserve strong luminescence and avoid unpredictable fluorescent resonance energy transfer, the main problem in design WLED from multiple NC components. These advantages allow the fabrication of NC-based WLED with high color rendering index (86), high luminous efficacy (41 lm/W), and controllable color temperature. PMID- 25296277 TI - The direction of the difference between Canadian and American erythrocyte folate concentrations is dependent on the assay method employed: a comparison of the Canadian Health Measures Survey and National Health and Nutrition Examination Survey. AB - Fortification of select grain products with folic acid and periconceptional supplementation recommendations in Canada and the USA have improved folate status, and have been associated with a reduced risk of neural tube defects. In the present study, we aimed to conduct a comparison of erythrocyte folate concentrations from the 2007-9 Canadian Health Measures Survey (CHMS) and the 2007-8 US National Health and Nutrition Examination Survey (NHANES). Erythrocyte folate concentration was assessed in participants aged 6-79 years (CHMS, n 5248; NHANES, n 7070). To account for different folate assays employed - Immulite 2000 immunoassay (CHMS) and microbiological assay (NHANES) - a conversion equation was generated (n 152 adults) to adjust the CHMS data. t Tests were used to examine country differences. Median Canadian erythrocyte folate concentrations (method adjusted) were lower than those of Americans (988 and 1100 nmol/l, respectively), but unadjusted median Canadian erythrocyte folate concentrations were higher (1250 nmol/l). The upper 95% CI boundary of the method-adjusted Canadian erythrocyte folate distribution overlapped that of the American erythrocyte folate concentrations, while the lower 95% CI boundary of the method-adjusted Canadian erythrocyte folate data was below the American distribution. In summary, the fact that erythrocyte folate concentrations were either higher or lower in Canadians compared with Americans, depending on whether an adjustment was made to account for assay differences, suggests that caution must be exercised in evaluating erythrocyte folate data from different countries because analytical methods are not readily comparable. Furthermore, we cannot unequivocally conclude that there are true differences in erythrocyte folate concentrations between the Canadian and American populations in the post-fortification era. PMID- 25296279 TI - Optimal Dimensionality Reduction of Multistate Kinetic and Markov-State Models. AB - We develop a systematic procedure for obtaining rate and transition matrices that optimally describe the dynamics of aggregated superstates formed by combining (clustering or lumping) microstates. These reduced dynamical models are constructed by matching the time-dependent occupancy-number correlation functions of the superstates in the full and aggregated systems. Identical results are obtained by using a projection operator formalism. The reduced dynamic models are exact for all times in their full non-Markovian formulation. In the approximate Markovian limit, we derive simple analytic expressions for the reduced rate or Markov transition matrices that lead to exact auto- and cross-relaxation times. These reduced Markovian models strike an optimal balance between matching the dynamics at short and long times. We also discuss how this approach can be used in a hierarchical procedure of constructing optimal superstates through aggregation of microstates. The results of the general reduced-matrix theory are illustrated with applications to simple model systems and a more complex master equation model of peptide folding derived previously from atomistic molecular dynamics simulations. We find that the reduced models faithfully capture the dynamics of the full systems, producing substantial improvements over the common local-equilibrium approximation. PMID- 25296280 TI - The difference in pharmacists' interventions across the diverse settings in a children's hospital. AB - AIMS: This study aimed to document and compare the nature of clinical pharmacists' interventions made in different practice settings within a children's hospital. METHODS: The primary investigator observed and documented all clinical interventions performed by clinical pharmacists for between 35-37 days on each of the five study wards from the three practice settings, namely general medical, general surgical and hematology-oncology. The rates, types and significance of the pharmacists' interventions in the different settings were compared. RESULTS: A total of 982 interventions were documented, related to the 16,700 medication orders reviewed on the five wards in the three practice settings over the duration of the study. Taking medication histories and/or patient counselling were the most common pharmacists' interventions in the general settings; constituting more than half of all interventions. On the Hematology-Oncology Ward the pattern was different with drug therapy changes being the most common interventions (n = 73/195, 37.4% of all interventions). Active interventions (pharmacists' activities leading to a change in drug therapy) constituted less than a quarter of all interventions on the general medical and surgical wards compared to nearly half on the specialty Hematology Oncology Ward. The majority (n = 37/42, 88.1%) of a random sample of the active interventions reviewed were rated as clinically significant. Dose adjustment was the most frequent active interventions in the general settings, whilst drug addition constituted the most common active interventions on the Hematology Oncology Ward. The degree of acceptance of pharmacists' active interventions by prescribers was high (n = 223/244, 91.4%). CONCLUSIONS: The rate of pharmacists' active interventions differed across different practice settings, being most frequent in the specialty hematology-oncology setting. The nature and type of the interventions documented in the hematology-oncology were also different compared to those in the general medical and surgical settings. PMID- 25296281 TI - Toxicity induced by F. poae-contaminated feed and the protective effect of Montmorillonite supplementation in broilers. AB - The T-2 and HT-2 toxins, the main metabolites of Fusarium poae, induce toxicity in broilers and accumulate in tissues. Consequently, during the breeding process of broilers, diets are frequently supplemented with physical adsorbents to protect birds against the toxicity induced by mycotoxins. In the present research, T-2 and HT-2 were produced in maize inoculated with F. poae. Mont, the strongest adsorbent based on in vitro adsorption ratios, was added to the contaminated diet. One-day-old chickens were randomly and equally divided into the following four groups: control diet group, Mont supplemented diet group, contaminated diet group and detoxification diet group. The experiment lasted for 42 days. Compared to the control group, the contaminated group showed significant decrease in body weight, feed intake and TP (P < 0.05), and marked increase in FCR, ALP, AST and ALT activity, T-2/HT-2 residues in the tissues and the relative expressions of apoptosis-related mRNAs (P < 0.05). Mont supplementation provided protection for the treated broilers in terms of performance, blood biochemistry, hepatic function, T-2/HT-2 residue of tissues and apoptosis. Therefore, Mont may be suitable as a detoxification agent for T-2/HT-2 in feed for broilers. PMID- 25296282 TI - Materials processing routes to trap-free halide perovskites. AB - Photovoltaic devices based on lead iodide perovskite films have seen rapid advancements, recently achieving an impressive 17.9% certified solar power conversion efficiency. Reports have consistently emphasized that the specific choice of growth conditions and chemical precursors is central to achieving superior performance from these materials; yet the roles and mechanisms underlying the selection of materials processing route is poorly understood. Here we show that films grown under iodine-rich conditions are prone to a high density of deep electronic traps (recombination centers), while the use of a chloride precursor avoids the formation of key defects (Pb atom substituted by I) responsible for short diffusion lengths and poor photovoltaic performance. Furthermore, the lowest-energy surfaces of perovskite crystals are found to be entirely trap-free, preserving both electron and hole delocalization to a remarkable degree, helping to account for explaining the success of polycrystalline perovskite films. We construct perovskite films from I-poor conditions using a lead acetate precursor, and our measurement of a long (600 +/- 40 nm) diffusion length confirms this new picture of the importance of growth conditions. PMID- 25296283 TI - A straightforward modification in the thrombin binding aptamer improving the stability, affinity to thrombin and nuclease resistance. AB - Degradation of nucleic acids in biological environments is the major drawback of the therapeutic use of aptamers. Among the approaches used to circumvent this negative aspect, the introduction of 3'-3' inversion of polarity sites at the sequence 3'-end has successfully been proposed. However, the introduction of inversion of polarity at the ends of the sequence has never been exploited for G quadruplex forming aptamers. In this communication we describe CD, UV, electrophoretic and biochemical investigations concerning thrombin binding aptamer analogues containing one or two inversions of polarity sites at the oligonucleotide ends. Data indicate that, in some cases, this straightforward chemical modification is able to improve, at the same time, the thermal stability, affinity to thrombin and nuclease resistance in biological environments, thus suggesting its general application as a post-SELEX modification also for other therapeutically promising aptamers adopting G quadruplex structures. PMID- 25296285 TI - Nothing special in the specialist? Draft genome sequence of Cryomyces antarcticus, the most extremophilic fungus from Antarctica. AB - The draft genome of the Antarctic endemic fungus Cryomyces antarcticus is presented. This rock inhabiting, microcolonial fungus is extremely stress tolerant and it is a model organism for exobiology and studies on stress resistance in Eukaryots. Since this fungus is a specialist in the most extreme environment of the Earth, the analysis of its genome is of important value for the understanding of fungal genome evolution and stress adaptation. A comparison with Neurospora crassa as well as with other microcolonial fungi shows that the fungus has a genome size of 24 Mbp, which is the average in the fungal kingdom. Although sexual reproduction was never observed in this fungus, 34 mating genes are present with protein homologs in the classes Eurotiomycetes, Sordariomycetes and Dothideomycetes. The first analysis of the draft genome did not reveal any significant deviations of this genome from comparative species and mesophilic hyphomycetes. PMID- 25296284 TI - Association between maternal exposure to di(2-ethylhexyl) phthalate and reproductive hormone levels in fetal blood: the Hokkaido study on environment and children's health. AB - Prenatal di(2-ethylhexyl) phthalate (DEHP) exposure can produce reproductive toxicity in animal models. Only limited data exist from human studies on maternal DEHP exposure and its effects on infants. We aimed to examine the associations between DEHP exposure in utero and reproductive hormone levels in cord blood. Between 2002 and 2005, 514 pregnant women agreed to participate in the Hokkaido Study Sapporo Cohort. Maternal blood samples were taken from 23-35 weeks of gestation and the concentration of the primary metabolite of DEHP, mono(2 ethylhexyl) phthalate (MEHP), was measured. Concentrations of infant reproductive hormones including estradiol (E2), total testosterone (T), and progesterone (P4), inhibin B, insulin-like factor 3 (INSL3), steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone were measured from cord blood. Two hundred and two samples with both MEHP and hormones' data were included in statistical analysis. The participants completed a self-administered questionnaire regarding information on maternal characteristics. Gestational age, birth weight and infant sex were obtained from birth records. In an adjusted linear regression analysis fit to all study participants, maternal MEHP levels were found to be associated with reduced levels of T/E2, P4, and inhibin B. For the stratified analyses for sex, inverse associations between maternal MEHP levels T/E2, P4, inhibin B, and INSL3 were statistically significant for males only. In addition, the MEHP quartile model showed a significant p-value trend for P4, inhibin B, and INSL3 decrease in males. Since inhibin B and INSL3 are major secretory products of Sertoli and Leydig cell, respectively, the results of this study suggest that DEHP exposure in utero may have adverse effects on both Sertoli and Leydig cell development in males, which agrees with the results obtained from animal studies. Comprehensive studies investigating phthalates' exposure in humans, as well as their long-term effects on reproductive development are needed. PMID- 25296286 TI - Assessment of intraocular measurements in neonatal foals and association with gender, laterality, and body weight: a clinical study. AB - Objective of this study was to describe intraocular measurements in newly born foals (1-7 days of age) and assess the association between globe measurements and gender, laterality, and body weight. B-scan ultrasonographic biometry was performed on both eyes of 22 healthy foals (44 eyes) ages 1-7 days using a 10-MHz transducer. Intraocular measurements (anterior chamber depth, central lens thickness, vitreous chamber depth, axial globe length, longitudinal globe length, lens poles distance) were carried out using the ultrasound internal calipers. The influence of gender (male or female), laterality (right or left eye), and body weight ("light" <48 kg; "heavy" >=48 kg) on ocular measurements was analysed by the Student t test. Values of P<0.05 were accepted as significant for all analyses. Mean anterior chamber depth was 2.2+/-0.5 mm (Standard Deviation); central lens thickness was 9.9+/-0.8 mm; vitreous chamber depth was 15.5+/-1.1 mm; axial globe length was 27.6+/-1.6 mm; longitudinal globe length was 35.8+/ 1.2 mm, and lens poles distance was 16.4+/-1.0 mm. Intraocular measurements were not influenced by gender, laterality nor body weight. This study provides reference values for intraocular measurements in neonatal foals and may be useful in the diagnosis and treatment of congenital and acquired pathologies involving the globe. PMID- 25296288 TI - Experimental Mycobacterium tuberculosis infection in the Chinese tree shrew. AB - In recent years, the Chinese tree shrew has been considered to be a promising experimental animal for numerous diseases. Yet the susceptibility of Mycobacterium tuberculosis (MTB) in Chinese tree shrew is still unknown. We infected Chinese tree shrews with a high dose (2.5 * 10(6) CFU) or a low dose (2.5 * 10(3) CFU) of the H37Rv strain via the femoral vein to cause severe or mild disease. Disease severity was determined by clinical signs, pathologic changes and bacteria distribution in organs. Furthermore, among lung samples of the uninfected, mildly and seriously ill Chinese tree shrews, differentially expressed protein profiles were analyzed through iTRAQ and validated by qPCR. Tuberculous nodules, skin ulceration, pleural effusion and cerebellum necrosis could be observed in seriously ill animals. Regulation of the actin cytoskeleton was newly defined as a possible MTB-related pathway correlated with disease progression. This comprehensive analysis of the experimental infection and the depiction of the proteomics profiles in the Chinese tree shrew provide a foundation for the establishment of a new animal model of tuberculosis and provide a better understanding of the mechanism of tuberculosis. PMID- 25296289 TI - Evidence for the cyclic CN2 carbene in the gas phase. AB - 3-Halodiazirine-3-carboxylic acids (c-CN2XCOOH, X = Cl or Br) were prepared from their esters and converted to the corresponding sodium salts. Collision-induced dissociation (CID) of the carboxylate ions led exclusively to the loss of CO2 and the resulting c-CN2X(-) ions dissociated to c-CN2 carbene at low energies. The bond dissociation energy (BDE) for c-CN2Br(-) was found to be less than 8 kcal/mol using CID of the anion generated by electrospray ionization of the carboxylate. The analogous difluoro system (CF2XCOOH/CF2X(-)/CF2) exhibits similar dissociative behavior. All experimental BDEs are in very good agreement with MP4/aug-cc-pVTZ calculations. PMID- 25296291 TI - First steps in photophysics. I. Fluorescence yield and radiative rate coefficient of 9,10-bis(phenylethynyl)anthracene in paraffins. AB - The fluorescence quantum yield of 9,10-bis(phenylethynyl)anthracene (BPEA) is almost unity in every examined solvent. Using different hydrocarbons, one can make a convenient and sufficiently accurate experimental test for determination of the extent of the refractive index correction needed in fluorescence quantum yield determination on a given fluorometer. By comparison of the measurements in n-pentane-cis-decaline or n-hexane-toluene solvent pairs, the requirement of the n(2) correction is confirmed for most of the fluorometers; however, for one of the examined pieces of equipment the necessary correction proved to be slightly lower. By excited state's lifetime measurements, the refractive index dependence of the fluorescence rate coefficient was reexamined. At 25 degrees C for BPEA the relationship is in agreement with Bakhshiev's prediction: the experimentally determined exponent of n in the rate coefficient deriving equation is around 1.32 using different paraffins as solvents. The negative temperature coefficient of the radiative rate in part originates from the temperature dependence of the refractive index, while also a small intrinsic contribution has been found. PMID- 25296290 TI - Turn-on detection of a cancer marker based on near-infrared luminescence energy transfer from NaYF4:Yb,Tm/NaGdF4 core-shell upconverting nanoparticles to gold nanorods. AB - A homogeneous immunoassay for the sensitive and selective determination of trace amounts of alpha-fetoprotein (AFP, a cancer marker) by detection in the near infrared (NIR) region based on luminescence energy transfer (LET) from NaYF4:Yb,Tm/NaGdF4 core-shell upconverting nanoparticles to gold nanorods (GNRs) is presented. The carboxyl-functionalized NaYF4:Yb,Tm/NaGdF4 core-shell upconverting nanoparticles (UCNPs) were excited by a 980 nm continuous wavelength laser, and its emission peak appeared at a near-infrared wavelength (~804 nm). The carboxyl-functionalized upconverting nanoparticles were conjugated with the anti-AFP (Ab1) and acted as donor. GNRs with a high absorption band around 790 nm, which was overlapped the UCNPs emission, were synthesized and acted as the acceptor. The donor (negatively charged) interacted with the acceptor (positively charged) via electrostatic interactions to bring them into close proximity. LET could occur, producing a quenching phenomenon. When the AFP antigens were added into the system, the binding affinity between AFP and Ab1 was stronger than the electrostatic interactions, which released the energy acceptors from the energy donors, interrupting luminescence energy transfer, and therefore, the luminescence was recovered. On the basis of the restored luminescence, a turn-on optical immunosening system was developed. Under the optimal conditions, the linear range of detection was from 0.18 to 11.44 ng/mL for AFP (R = 0.99), with a detection limit as low as 0.16 ng/mL. The proposed method has also been used to monitor AFP in human serum samples. Therefore, further study based on the NaYF4:Yb,Tm/NaGdF4 core-shell nanoparticles-GNRs construction may open the way for a new class of NIR-LET biosensors with wide applications. PMID- 25296292 TI - Balloon angioplasty of the bilateral renal arteries by Takayasu arteritis with a paclitaxel-eluting balloon. AB - We report about a 12-year-old girl who presented with a blood pressure difference between the extremities with the suspicion of an aortic coarctation. After imaging and laboratory tests, the diagnosis of Takayasu arteritis was made. Owing to persistent arterial hypertension despite medical treatment, we initiated a treatment with a balloon angioplasty of the renal arteries with an eluting balloon. PMID- 25296294 TI - A probabilistic model for analysing the effect of performance levels on visual behaviour patterns of young sailors in simulated navigation. AB - The visual behaviour is a determining factor in sailing due to the influence of the environmental conditions. The aim of this research was to determine the visual behaviour pattern in sailors with different practice time in one star race, applying a probabilistic model based on Markov chains. The sample of this study consisted of 20 sailors, distributed in two groups, top ranking (n = 10) and bottom ranking (n = 10), all of them competed in the Optimist Class. An automated system of measurement, which integrates the VSail-Trainer sail simulator and the Eye Tracking System(TM) was used. The variables under consideration were the sequence of fixations and the fixation recurrence time performed on each location by the sailors. The event consisted of one of simulated regatta start, with stable conditions of wind, competitor and sea. Results show that top ranking sailors perform a low recurrence time on relevant locations and higher on irrelevant locations while bottom ranking sailors make a low recurrence time in most of the locations. The visual pattern performed by bottom ranking sailors is focused around two visual pivots, which does not happen in the top ranking sailor's pattern. In conclusion, the Markov chains analysis has allowed knowing the visual behaviour pattern of the top and bottom ranking sailors and its comparison. PMID- 25296293 TI - Preparation of plasmonic platforms of silver wires on gold mirrors and their application to surface enhanced fluorescence. AB - In this report we describe a preparation of silver wires (SWs) on gold mirrors and its application to surface enhanced fluorescence (SEF) using a new methodology. Silica protected gold mirrors were drop-coated with a solution of silver triangular nanoprisms. The triangular nanoprisms were slowly air-dried to get silver wires that self-assembled on the gold mirrors. Fluorescence enhancement was studied using methyl azadioxatriangulenium chloride (Me-ADOTA . Cl) dye in PVA spin-coated on a clean glass coverslip. New Plasmonic Platforms (PPs) were assembled by placing a mirror with SWs in contact with a glass coverslip spin-coated with a uniform Me-ADOTA . Cl film. It was shown that surface enhanced fluorescence is a real phenomenon, not just an enhancement of the fluorescence signal due to an accumulation of the fluorophore on rough nanostructure surfaces. The average fluorescence enhancement was found to be about 15-fold. The lifetime of Me-ADOTA . Cl dye was significantly reduced (~ 4 times) in the presence of SWs. Moreover, fluorescence enhancement and lifetime did not show any dependence on the excitation light polarization. PMID- 25296295 TI - Low carbon technology performance vs infrastructure vulnerability: analysis through the local and global properties space. AB - Renewable energy technologies, necessary for low-carbon infrastructure networks, are being adopted to help reduce fossil fuel dependence and meet carbon mitigation targets. The evolution of these technologies has progressed based on the enhancement of technology-specific performance criteria, without explicitly considering the wider system (global) impacts. This paper presents a methodology for simultaneously assessing local (technology) and global (infrastructure) performance, allowing key technological interventions to be evaluated with respect to their effect on the vulnerability of wider infrastructure systems. We use exposure of low carbon infrastructure to critical material supply disruption (criticality) to demonstrate the methodology. A series of local performance changes are analyzed; and by extension of this approach, a method for assessing the combined criticality of multiple materials for one specific technology is proposed. Via a case study of wind turbines at both the material (magnets) and technology (turbine generators) levels, we demonstrate that analysis of a given intervention at different levels can lead to differing conclusions regarding the effect on vulnerability. Infrastructure design decisions should take a systemic approach; without these multilevel considerations, strategic goals aimed to help meet low-carbon targets, that is, through long-term infrastructure transitions, could be significantly jeopardized. PMID- 25296296 TI - Deficits in tactile learning in a mouse model of fragile X syndrome. AB - The fragile X mental retardation 1 mutant mouse (Fmr1 KO) recapitulates several of the neurologic deficits associated with Fragile X syndrome (FXS). As tactile hypersensitivity is a hallmark of FXS, we examined the sensory representation of individual whiskers in somatosensory barrel cortex of Fmr1 KO and wild-type (WT) mice and compared their performance in a whisker-dependent learning paradigm, the gap cross assay. Fmr1 KO mice exhibited elevated responses to stimulation of individual whiskers as measured by optical imaging of intrinsic signals. In the gap cross task, initial performance of Fmr1 KO mice was indistinguishable from WT controls. However, while WT mice improved significantly with experience at all gap distances, Fmr1 KO mice displayed significant and specific deficits in improvement at longer distances which rely solely on tactile information from whiskers. Thus, Fmr1 KO mice possess altered cortical responses to sensory input that correlates with a deficit in tactile learning. PMID- 25296298 TI - Engaging the "clutch" to move forward. PMID- 25296297 TI - The usefulness of standardized uptake value in differentiation between benign and malignant thyroid lesions detected incidentally in 18F-FDG PET/CT examination. AB - INTRODUCTION: In the last decade, (18)F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET and PET/CT) has become one of the major diagnostic tools used in oncology. A significant number of patients who undergo this procedure, due to non-thyroidal reasons, present incidental uptake of (18F-FDG) in the thyroid. The aim of the study was to compare the SUVmax (standardized uptake value) of thyroid focal lesions, which were incidentally found on PET/CT, in relation to the results of thyroid fine-needle aspiration biopsy (FNAB) and/or histopathological evaluation. MATERIALS AND METHODS: Patients referred for PET/CT examination, due to non-thyroidal illness, presented focal 18F-FDG uptake in the thyroid and were advised to undergo ultrasonography (US), hormonal evaluation, FNAB and/or total thyroidectomy at our institution. RESULTS: 6614 PET/CT examinations performed in 5520 patients were analyzed. Of the 122 patients with focal thyroid 18F-FDG activity, 82 patients (67.2%) underwent further thyroid evaluation using FNAB. Benign lesions were diagnosed in 46 patients, malignant - in 19 patients (confirmed by post-surgical histopathology), while 17 patients had inconclusive results of cytological assessment. Mean SUVmax of benign lesions was 3.2+/-2.8 (median = 2.4), while the mean SUVmax value for malignant lesions was 7.1+/-8.2 (median = 3.5). The risk of malignancy was 16.7% for lesions with a SUVmax under 3, 43.8% for lesions with a SUVmax between 3 and 6, and 54.6% for lesions with a SUVmax over 6. In the group of malignant lesions, a positive correlation between the lesion's diameter and SUVmax was observed (p = 0.03, r = 0.57). CONCLUSIONS: Subjects with incidental focal uptake of 18F-FDG in thyroid are at a high risk of thyroid malignancy. A high value of SUVmax further increases the risk of malignancy, indicating the necessity for further cytological or histological evaluation. However, as SUVmax correlated with the diameter of malignant lesions, small lesions with focal uptake of 18F-FDG should be interpreted cautiously. PMID- 25296299 TI - Channelrhodopsin photochromic reactions provide multicolor optogenetic control. PMID- 25296300 TI - Monitoring of single vesicle cytochrome-c release illuminates BAK as a novel target of Abeta oligomers. PMID- 25296301 TI - Hugh E. Huxley: the compleat biophysicist. AB - The sliding filament model of muscle contraction, put forward by Hugh Huxley and Jean Hanson in 1954, is 60 years old in 2014. Formulation of the model and subsequent proof was driven by the pioneering work of Hugh Huxley (1924-2013). We celebrate Huxley's integrative approach to the study of muscle contraction; how he persevered throughout his career, to the end of his life at 89 years, to understand at the molecular level how muscle contracts and develops force. Here we show how his life and work, with its focus on a single scientific problem, had impact far beyond the field of muscle contraction to the benefit of multiple fields of cellular and structural biology. Huxley introduced the use of x-ray diffraction to study the contraction in living striated muscle, taking advantage of the paracrystalline lattice that would ultimately allow understanding contraction in terms of single molecules. Progress required design of instrumentation with ever-increasing spatial and temporal resolution, providing the impetus for the development of synchrotron facilities used for most protein crystallography and muscle studies today. From the time of his early work, Huxley combined electron microscopy and biochemistry to understand and interpret the changes in x-ray patterns. He developed improved electron-microscopy techniques, thin sections and negative staining, that enabled answering major questions relating to the structure and organization of thick and thin filaments in muscle and the interaction of myosin with actin and its regulation. Huxley established that the ATPase domain of myosin forms the crossbridges of thick filaments that bind actin, and introduced the idea that myosin makes discrete steps on actin. These concepts form the underpinning of cellular motility, in particular the study of how myosin, kinesin, and dynein motors move on their actin and tubulin tracks, making Huxley a founder of the field of cellular motility. PMID- 25296302 TI - Combining AFM and acoustic probes to reveal changes in the elastic stiffness tensor of living cells. AB - Knowledge of how the elastic stiffness of a cell affects its communication with its environment is of fundamental importance for the understanding of tissue integrity in health and disease. For stiffness measurements, it has been customary to quote a single parameter quantity, e.g., Young's modulus, rather than the minimum of two terms of the stiffness tensor required by elasticity theory. In this study, we use two independent methods (acoustic microscopy and atomic force microscopy nanoindentation) to characterize the elastic properties of a cell and thus determine two independent elastic constants. This allows us to explore in detail how the mechanical properties of cells change in response to signaling pathways that are known to regulate the cell's cytoskeleton. In particular, we demonstrate that altering the tensioning of actin filaments in NIH3T3 cells has a strong influence on the cell's shear modulus but leaves its bulk modulus unchanged. In contrast, altering the polymerization state of actin filaments influences bulk and shear modulus in a similar manner. In addition, we can use the data to directly determine the Poisson ratio of a cell and show that in all cases studied, it is less than, but very close to, 0.5 in value. PMID- 25296303 TI - Cells as active particles in asymmetric potentials: motility under external gradients. AB - Cell migration is a crucial event during development and in disease. Mechanical constraints and chemical gradients can contribute to the establishment of cell direction, but their respective roles remain poorly understood. Using a microfabricated topographical ratchet, we show that the nucleus dictates the direction of cell movement through mechanical guidance by its environment. We demonstrate that this direction can be tuned by combining the topographical ratchet with a biochemical gradient of fibronectin adhesion. We report competition and cooperation between the two external cues. We also quantitatively compare the measurements associated with the trajectory of a model that treats cells as fluctuating particles trapped in a periodic asymmetric potential. We show that the cell nucleus contributes to the strength of the trap, whereas cell protrusions guided by the adhesive gradients add a constant tunable bias to the direction of cell motion. PMID- 25296304 TI - Uncovering the mechanism of trapping and cell orientation during Neisseria gonorrhoeae twitching motility. AB - Neisseria gonorrheae bacteria are the causative agent of the second most common sexually transmitted infection in the world. The bacteria move on a surface by means of twitching motility. Their movement is mediated by multiple long and flexible filaments, called type IV pili, that extend from the cell body, attach to the surface, and retract, thus generating a pulling force. Moving cells also use pili to aggregate and form microcolonies. However, the mechanism by which the pili surrounding the cell body work together to propel bacteria remains unclear. Understanding this process will help describe the motility of N. gonorrheae bacteria, and thus the dissemination of the disease which they cause. In this article we track individual twitching cells and observe that their trajectories consist of alternating moving and pausing intervals, while the cell body is preferably oriented with its wide side toward the direction of motion. Based on these data, we propose a model for the collective pili operation of N. gonorrheae bacteria that explains the experimentally observed behavior. Individual pili function independently but can lead to coordinated motion or pausing via the force balance. The geometry of the cell defines its orientation during motion. We show that by changing pili substrate interactions, the motility pattern can be altered in a predictable way. Although the model proposed is tangibly simple, it still has sufficient robustness to incorporate further advanced pili features and various cell geometries to describe other bacteria that employ pili to move on surfaces. PMID- 25296305 TI - Coherent motions in confluent cell monolayer sheets. AB - Cell migration plays a pivotal role in many physiologically important processes such as embryogenesis, wound-healing, immune defense, and cancer metastasis. Although much effort has been directed toward motility of individual cells, the mechanisms underpinning collective cell migration remain poorly understood. Here we develop a collective motility model that incorporates cell mechanics and persistent random motions of individual cells to study coherent migratory motions in epithelial-like monolayers. This model, in absence of any external chemical signals, is able to explain coordinate rotational motion seen in systems ranging from two adherent cells to multicellular assemblies. We show that the competition between the active persistent force and random polarization fluctuation is responsible for the robust rotation. Passive mechanical coupling between cells is necessary but active chemical signaling between cells is not. The predicted angular motions also depend on the geometrical shape of the underlying substrate: cells exhibit collective rotation on circular substrates, but display linear back and-forth motion on long and narrow substrates. PMID- 25296306 TI - The mechanism of phagocytosis: two stages of engulfment. AB - Despite being of vital importance to the immune system, the mechanism by which cells engulf relatively large solid particles during phagocytosis is still poorly understood. From movies of neutrophil phagocytosis of polystyrene beads, we measure the fractional engulfment as a function of time and demonstrate that phagocytosis occurs in two distinct stages. During the first stage, engulfment is relatively slow and progressively slows down as phagocytosis proceeds. However, at approximately half-engulfment, the rate of engulfment increases dramatically, with complete engulfment attained soon afterwards. By studying simple mathematical models of phagocytosis, we suggest that the first stage is due to a passive mechanism, determined by receptor diffusion and capture, whereas the second stage is more actively controlled, perhaps with receptors being driven toward the site of engulfment. We then consider a more advanced model that includes signaling and captures both stages of engulfment. This model predicts that there is an optimum ligand density for quick engulfment. Further, we show how this model explains why nonspherical particles engulf quickest when presented tip-first. Our findings suggest that active regulation may be a later evolutionary innovation, allowing fast and robust engulfment even for large particles. PMID- 25296307 TI - Imaging GFP-based reporters in neurons with multiwavelength optogenetic control. AB - To study the impact of neural activity on cellular physiology, one would like to combine precise control of firing patterns with highly sensitive probes of cellular physiology. Light-gated ion channels, e.g., Channelrhodopsin-2, enable precise control of firing patterns; green fluorescent protein-based reporters, e.g., the GCaMP6f Ca(2+) reporter, enable highly sensitive probing of cellular physiology. However, for most actuator-reporter combinations, spectral overlap prevents straightforward combination within a single cell. Here we explore multiwavelength control of channelrhodopsins to circumvent this limitation. The "stoplight" technique described in this article uses channelrhodopsin variants that are opened by blue light and closed by orange light. Cells are illuminated with constant blue light to excite fluorescence of a green fluorescent protein based reporter. Modulated illumination with orange light negatively regulates activation of the channelrhodopsin. We performed detailed photophysical characterization and kinetic modeling of four candidate stoplight channelrhodopsins. The variant with the highest contrast, sdChR(C138S,E154A), enabled all-optical measurements of activity-induced calcium transients in cultured rat hippocampal neurons, although cell-to-cell variation in expression levels presents a challenge for quantification. PMID- 25296308 TI - Hv1 proton channel opening is preceded by a voltage-independent transition. AB - The voltage sensing domain (VSD) of the voltage-gated proton channel Hv1 mediates a H(+)-selective conductance that is coordinately controlled by the membrane potential (V) and the transmembrane pH gradient (DeltapH). Allosteric control of Hv1 channel opening by DeltapH (V-DeltapH coupling) is manifested by a characteristic shift of approximately 40 mV per DeltapH unit in the activation. To further understand the mechanism for V-DeltapH coupling in Hv1, H(+) current kinetics of activation and deactivation in excised membrane patches were analyzed as a function of the membrane potential and the pH in the intracellular side of the membrane (pHI). In this study, it is shown for the first time to our knowledge that the opening of Hv1 is preceded by a voltage-independent transition. A similar process has been proposed to constitute the step involving coupling between the voltage-sensing and pore domains in tetrameric voltage-gated channels. However, for Hv1, the VSD functions as both the voltage sensor and the conduction pathway, suggesting that the voltage independent transition is intrinsic to the voltage-sensing domain. Therefore, this article proposes that the underlying mechanism for the activation of Hv1 involves a process similar to VSD relaxation, a process previously described for voltage-gated channels and voltage-controlled enzymes. Finally, deactivation seemingly occurs as a strictly voltage dependent process, implying that the kinetic event leading to opening of the proton conductance are different than those involved in the closing. Thus, from this work it is proposed that Hv1 activity displays hysteresis. PMID- 25296309 TI - Investigating the effect of particle size on pulmonary surfactant phase behavior. AB - We study the impact of the addition of particles of a range of sizes on the phase transition behavior of lung surfactant under compression. Charged particles ranging from micro- to nanoscale are deposited on lung surfactant films in a Langmuir trough. Surface area versus surface pressure isotherms and fluorescent microscope observations are utilized to determine changes in the phase transition behavior. We find that the deposition of particles close to 20 nm in diameter significantly impacts the coexistence of the liquid-condensed phase and liquid expanded phase. This includes morphological changes of the liquid-condensed domains and the elimination of the squeeze-out phase in isotherms. Finally, a drastic increase of the domain fraction of the liquid-condensed phase can be observed for the deposition of 20-nm particles. As the particle size is increased, we observe a return to normal phase behavior. The net result is the observation of a critical particle size that may impact the functionality of the lung surfactant during respiration. PMID- 25296310 TI - Chain-length heterogeneity allows for the assembly of fatty acid vesicles in dilute solutions. AB - A requirement for concentrated and chemically homogeneous pools of molecular building blocks would severely restrict plausible scenarios for the origin of life. In the case of membrane self-assembly, models of prebiotic lipid synthesis yield primarily short, single-chain amphiphiles that can form bilayer vesicles only at very high concentrations. These high critical aggregation concentrations (cacs) pose significant obstacles for the self-assembly of single-chain lipid membranes. Here, we examine membrane self-assembly in mixtures of fatty acids with varying chain lengths, an expected feature of any abiotic lipid synthesis. We derive theoretical predictions for the cac of mixtures by adapting thermodynamic models developed for the analogous phenomenon of mixed micelle self assembly. We then use several complementary methods to characterize aggregation experimentally, and find cac values in close agreement with our theoretical predictions. These measurements establish that the cac of fatty acid mixtures is dramatically lowered by minor fractions of long-chain species, thereby providing a plausible route for protocell membrane assembly. Using an NMR-based approach to monitor aggregation of isotopically labeled samples, we demonstrate the incorporation of individual components into mixed vesicles. These experiments suggest that vesicles assembled in dilute, mixed solutions are depleted of the shorter-chain-length lipid species, a finding that carries implications for the composition of primitive cell membranes. PMID- 25296311 TI - Raft formation in lipid bilayers coupled to curvature. AB - We present computer simulations of a membrane in which the local composition is coupled to the local membrane curvature. At high temperatures (i.e., above the temperature of macroscopic phase separation), finite-sized transient domains are observed, reminiscent of lipid rafts. The domain size is in the range of hundred nanometers, and set by the membrane elastic properties. These findings are in line with the notion of the membrane as a curvature-induced microemulsion. At low temperature, the membrane phase separates. The transition to the phase-separated regime is continuous and belongs to the two-dimensional Ising universality class when the coupling to curvature is weak, but becomes first-order for strong curvature-composition coupling. PMID- 25296312 TI - Beta-amyloid oligomers activate apoptotic BAK pore for cytochrome c release. AB - In Alzheimer's disease, cytochrome c-dependent apoptosis is a crucial pathway in neuronal cell death. Although beta-amyloid (Abeta) oligomers are known to be the neurotoxins responsible for neuronal cell death, the underlying mechanisms remain largely elusive. Here, we report that the oligomeric form of synthetic Abeta of 42 amino acids elicits death of HT-22 cells. But, when expression of a bcl-2 family protein BAK is suppressed by siRNA, Abeta oligomer-induced cell death was reduced. Furthermore, significant reduction of cytochrome c release was observed with mitochondria isolated from BAK siRNA-treated HT-22 cells. Our in vitro experiments demonstrate that Abeta oligomers bind to BAK on the membrane and induce apoptotic BAK pores and cytochrome c release. Thus, the results suggest that Abeta oligomers function as apoptotic ligands and hijack the intrinsic apoptotic pathway to cause unintended neuronal cell death. PMID- 25296313 TI - Giant unilamellar vesicles formed by hybrid films of agarose and lipids display altered mechanical properties. AB - Giant unilamellar vesicles (GUVs) are presumably the current most popular biomimetic membrane model. Preparation of GUVs in physiological conditions using the classical electroformation method is challenging. To circumvent these difficulties, a new method was recently reported, by which GUVs spontaneously swell from hybrid films of agarose and lipids. However, agarose is left encapsulated in the vesicles in different amounts. In this work, we thoroughly characterize the mechanical properties of these agarose-GUVs in response to electric pulses, which induce vesicle deformation and can lead to membrane poration. We show that the relaxation dynamics of deformed vesicles, both in the presence and absence of poration, is significantly slowed down for agarose-GUVs when compared to agarose-free GUVs. In the presence of poration, agarose polymers prevent complete pore closure and lead to high membrane permeability. A fraction of the vesicles were found to encapsulate agarose in the form of a gel-like meshwork. These vesicles rupture and open up after electroporation and the meshwork is expelled through a macropore. When the agarose-GUVs are heated above the melting temperature of agarose for 2 h before use, vesicle response is (partially) recovered due to substantial release of encapsulated agarose during temperature treatment. Our findings reveal potential artifactual behavior of agarose-GUVs in processes involving morphological changes in the membrane as well as poration. PMID- 25296314 TI - Traffic within the cytochrome b6f lipoprotein complex: gating of the quinone portal. AB - The cytochrome bc complexes b6f and bc1 catalyze proton-coupled quinol/quinone redox reactions to generate a transmembrane proton electrochemical gradient. Quinol oxidation on the electrochemically positive (p) interface of the complex occurs at the end of a narrow quinol/quinone entry/exit Qp portal, 11 A long in bc complexes. Superoxide, which has multiple signaling functions, is a by-product of the p-side quinol oxidation. Although the transmembrane core and the chemistry of quinone redox reactions are conserved in bc complexes, the rate of superoxide generation is an order of magnitude greater in the b6f complex, implying that functionally significant differences in structure exist between the b6f and bc1 complexes on the p-side. A unique structure feature of the b6f p-side quinol oxidation site is the presence of a single chlorophyll-a molecule whose function is unrelated to light harvesting. This study describes a cocrystal structure of the cytochrome b6f complex with the quinol analog stigmatellin, which partitions in the Qp portal of the bc1 complex, but not effectively in b6f. It is inferred that the Qp portal is partially occluded in the b6f complex relative to bc1. Based on a discrete molecular-dynamics analysis, occlusion of the Qp portal is attributed to the presence of the chlorophyll phytyl tail, which increases the quinone residence time within the Qp portal and is inferred to be a cause of enhanced superoxide production. This study attributes a novel (to our knowledge), structure-linked function to the otherwise enigmatic chlorophyll-a in the b6f complex, which may also be relevant to intracellular redox signaling. PMID- 25296315 TI - DNA methylation effects on tetra-nucleosome compaction and aggregation. AB - DNA CpG methylation has been associated with chromatin compaction and gene silencing. Whether DNA methylation directly contributes to chromatin compaction remains an open question. In this study, we used fluorescence fluctuation spectroscopy (FFS) to evaluate the compaction and aggregation of tetra nucleosomes containing specific CpG patterns and methylation levels. The compactness of both unmethylated and methylated tetra-nucleosomes is dependent on DNA sequences. Specifically, methylation of the CpG sites located in the central dyad and the major grooves of DNA seem to have opposite effects on modulating the compactness of tetra-nucleosomes. The interactions among tetra-nucleosomes, however, seem to be enhanced because of DNA methylation independent of sequence contexts. Our finding can shed light on understanding the role of DNA methylation in determining nucleosome positioning pattern and chromatin compactness. PMID- 25296316 TI - The myosin inhibitor blebbistatin stabilizes the super-relaxed state in skeletal muscle. AB - The super-relaxed state of myosin (SRX), in which the myosin ATPase activity is strongly inhibited, has been observed in a variety of muscle types. It has been proposed that myosin heads in this state are inhibited by binding to the core of the thick filament in a structure known as the interacting-heads motif. The myosin inhibitor blebbistatin has been shown in structural studies to stabilize the binding of myosin heads to the thick filament, and here we have utilized measurements of single ATP turnovers to show that blebbistatin also stabilizes the SRX in both fast and slow skeletal muscle, providing further support for the proposal that myosin heads in the SRX are also in the interacting-heads motif. We find that the SRX is stabilized using blebbistatin even in conditions that normally destabilize it, e.g., rigor ADP. Using blebbistatin we show that spin labeled nucleotides bound to myosin have an oriented spectrum in the SRX in both slow and fast skeletal muscle. This is to our knowledge the first observation of oriented spin probes on the myosin motor domain in relaxed skeletal muscle fibers. The spectra for skeletal muscle with blebbistatin are similar to those observed in relaxed tarantula fibers in the absence of blebbistatin, demonstrating that the structure of the SRX is similar in different muscle types and in the presence and absence of blebbistatin. The mobility of spin probes attached to nucleotides bound to myosin shows that the conformation of the nucleotide site is closed in the SRX. PMID- 25296317 TI - Determining intrachain diffusion coefficients for biopolymer dynamics from single molecule force spectroscopy measurements. AB - The conformational diffusion coefficient for intrachain motions in biopolymers, D, sets the timescale for structural dynamics. Recently, force spectroscopy has been applied to determine D both for unfolded proteins and for the folding transitions in proteins and nucleic acids. However, interpretation of the results remains unsettled. We investigated how instrumental effects arising from the force probes used in the measurement can affect the value of D recovered via force spectroscopy. We compared estimates of D for the folding of DNA hairpins found from measurements of rates and energy landscapes made using optical tweezers with estimates obtained from the same single-molecule trajectories via the transition path time. The apparent D obtained from the rates was much lower than the result found from the same data using transition time analysis, reflecting the effects of the mechanical properties of the force probe. Deconvolution of the finite compliance effects on the measurement allowed the intrinsic value to be recovered. These results were supported by Brownian dynamics simulations of the effects of force-probe compliance and bead size. PMID- 25296318 TI - Modest influence of FRET chromophores on the properties of unfolded proteins. AB - Single-molecule Forster resonance energy transfer (FRET) experiments are often used to study the properties of unfolded and intrinsically disordered proteins. Because of their large extinction coefficients and quantum yields, synthetic heteroaromatic chromophores covalently linked to the protein are often used as donor and acceptor fluorophores. A key issue in the interpretation of such experiments is the extent to which the properties of the unfolded chain may be affected by the presence of these chromophores. In this article, we investigate this question using all-atom explicit solvent replica exchange molecular dynamics simulations of three different unfolded or intrinsically disordered proteins. We find that the secondary structure and long-range contacts are largely the same in the presence or absence of the fluorophores, and that the dimensions of the chain with and without chromophores are similar. This suggests that, at least in the cases studied, extrinsic fluorophores have little effect on the structural properties of unfolded or disordered proteins. We also find that the critical FRET orientational factor kappa(2), has an average value and equilibrium distribution very close to that expected for isotropic orientations, which supports one of the assumptions frequently made when interpreting FRET efficiency in terms of distances. PMID- 25296319 TI - Protein unfolding by biological unfoldases: insights from modeling. AB - The molecular determinants of the high efficiency of biological machines like unfoldases (e.g., the proteasome) are not well understood. We propose a model to study protein translocation into the chamber of biological unfoldases represented as a funnel. It is argued that translocation is a much faster way of unfolding a protein than end-to-end stretching, especially in a low-force regime, because it allows for a conformational freedom while concentrating local tension on consecutive regions of a protein chain and preventing refolding. This results in a serial unfolding of the protein structures dominated by unzipping. Thus, pulling against the unfoldase pore is an efficient catalyst of the unfolding reaction. We also show that the presence of the funnel makes the tension along the backbone of the substrate protein nonuniform even when the protein gets unfolded. Hence, the stalling force measured by single-molecule force spectroscopy techniques may be smaller than the traction force of the unfoldase motor. PMID- 25296320 TI - Copper-based pulsed dipolar ESR spectroscopy as a probe of protein conformation linked to disease states. AB - We demonstrate the ability of pulsed dipolar electron spin resonance (ESR) spectroscopy (PDS) to report on the conformation of Cu-Zn superoxide dismutase (SOD1) through the sensitive measurement of dipolar interactions between inherent Cu(2+) ions. Although the extent and the anisotropy of the Cu ESR spectrum provides challenges for PDS, Ku-band (17.3 GHz) double electron-electron resonance and double-quantum coherence variants of PDS coupled with distance reconstruction methods recover Cu-Cu distances in good agreement with crystal structures. Moreover, Cu-PDS measurements expose distinct differences between the conformational properties of wild-type SOD1 and a single-residue variant (I149T) that leads to the disease amyotrophic lateral sclerosis (ALS). The I149T protein displays a broader Cu-Cu distance distribution within the SOD1 dimer compared to wild-type. In a nitroxide (NO)-labeled sample, distance distributions obtained from Cu-Cu, Cu-NO, and NO-NO separations reveal increased structural heterogeneity within the protein and a tendency for mutant dimers to associate. In contrast, perturbations caused by the ALS mutation are completely masked in the crystal structure of I149T. Thus, PDS readily detects alterations in metalloenzyme solution properties not easily deciphered by other methods and in doing so supports the notion that increased range of motion and associations of SOD1 ALS variants contribute to disease progression. PMID- 25296322 TI - Evolution of specificity in protein-protein interactions. AB - Hub proteins are proteins that maintain promiscuous molecular recognition. Because they are reported to play essential roles in cellular control, there has been a special interest in the study of their structural and functional properties, yet the mechanisms by which they evolve to maintain functional interactions are poorly understood. By combining biophysical simulations of coarse-grained proteins and analysis of proteins-complex crystallographic structures, we seek to elucidate those mechanisms. We focus on two types of hub proteins: Multi hubs, which interact with their partners through different interfaces, and Singlish hubs, which do so through a single interface. We show that loss of structural stability is required for the evolution of protein protein-interaction (PPI) networks, and it is more profound in Singlish hub systems. In addition, different ratios of hydrophobic to electrostatic interfacial amino acids are shown to support distinct network topologies (i.e., Singlish and Multi systems), and therefore underlie a fundamental design principle of PPI in a crowded environment. We argue that the physical nature of hydrophobic and electrostatic interactions, in particular, their favoring of either same-type interactions (hydrophobic-hydrophobic), or opposite-type interactions (negatively-positively charged) plays a key role in maintaining the network topology while allowing the protein amino acid sequence to evolve. PMID- 25296321 TI - Computational studies of the effect of the S23D/S24D troponin I mutation on cardiac troponin structural dynamics. AB - During beta-adrenergic stimulation, cardiac troponin I (cTnI) is phosphorylated by protein kinase A (PKA) at sites S23/S24, located at the N-terminus of cTnI. This phosphorylation has been shown to decrease KCa and pCa50, and weaken the cTnC-cTnI (C-I) interaction. We recently reported that phosphorylation results in an increase in the rate of early, slow phase of relaxation (kREL,slow) and a decrease in its duration (tREL,slow), which speeds up the overall relaxation. However, as the N-terminus of cTnI (residues 1-40) has not been resolved in the whole cardiac troponin (cTn) structure, little is known about the molecular-level behavior within the whole cTn complex upon phosphorylation of the S23/S24 residues of cTnI that results in these changes in function. In this study, we built up the cTn complex structure (including residues cTnC 1-161, cTnI 1-172, and cTnT 236-285) with the N-terminus of cTnI. We performed molecular-dynamics (MD) simulations to elucidate the structural basis of PKA phosphorylation-induced changes in cTn structure and Ca(2+) binding. We found that introducing two phosphomimic mutations into sites S23/S24 had no significant effect on the coordinating residues of Ca(2+) binding site II. However, the overall fluctuation of cTn was increased and the C-I interaction was altered relative to the wild type model. The most significant changes involved interactions with the N terminus of cTnI. Interestingly, the phosphomimic mutations led to the formation of intrasubunit interactions between the N-terminus and the inhibitory peptide of cTnI. This may result in altered interactions with cTnC and could explain the increased rate and decreased duration of slow-phase relaxation seen in myofibrils. PMID- 25296323 TI - Mapping membrane protein backbone dynamics: a comparison of site-directed spin labeling with NMR 15N-relaxation measurements. AB - The ability to detect nanosecond backbone dynamics with site-directed spin labeling (SDSL) in soluble proteins has been well established. However, for membrane proteins, the nitroxide appears to have more interactions with the protein surface, potentially hindering the sensitivity to backbone motions. To determine whether membrane protein backbone dynamics could be mapped with SDSL, a nitroxide was introduced at 55 independent sites in a model polytopic membrane protein, TM0026. Electron paramagnetic resonance spectral parameters were compared with NMR (15)N-relaxation data. Sequential scans revealed backbone dynamics with the same trends observed for the R1 relaxation rate, suggesting that nitroxide dynamics remain coupled to the backbone on membrane proteins. PMID- 25296324 TI - Folding and hydrodynamics of a DNA i-motif from the c-MYC promoter determined by fluorescent cytidine analogs. AB - The four-stranded i-motif (iM) conformation of cytosine-rich DNA has importance to a wide variety of biochemical systems that range from their use in nanomaterials to potential roles in oncogene regulation. The iM structure is formed at slightly acidic pH, where hemiprotonation of cytosine results in a stable C-C(+) basepair. Here, we performed fundamental studies to examine iM formation from a C-rich strand from the promoter of the human c-MYC gene. We used a number of biophysical techniques to characterize both the hydrodynamic properties and folding kinetics of a folded iM. Our hydrodynamic studies using fluorescence anisotropy decay and analytical ultracentrifugation show that the iM structure has a compact size in solution and displays the rigidity of a double strand. By studying the rates of circular dichroism spectral changes and quenching of fluorescent cytidine analogs, we also established a mechanism for the folding of a random coil oligo into the iM. In the course of determining this folding pathway, we established that the fluorescent dC analogs tC degrees and PdC can be used to monitor individual residues of an iM structure and to determine the pKa of an iM. We established that the C-C(+) hydrogen bonding of certain bases initiates the folding of the iM structure. We also showed that substitutions in the loop regions of iMs give a distinctly different kinetic signature during folding compared with bases that are intercalated. Our data reveal that the iM passes through a distinct intermediate form between the unfolded and folded forms. Taken together, our results lay the foundation for using fluorescent dC analogs to follow structural changes during iM formation. Our technique may also be useful for examining folding and structural changes in more complex iMs. PMID- 25296325 TI - Bacterial motility patterns reveal importance of exploitation over exploration in marine microhabitats. Part I: theory. AB - Bacteria use different motility patterns to navigate and explore natural habitats. However, how these motility patterns are selected, and what their benefits may be, are not understood. In this article, we analyze the effect of motility patterns on a cell's ability to migrate in a chemical gradient and to localize at the top of the gradient, the two most important characteristics of bacterial chemotaxis. We will focus on two motility patterns, run-tumble and run reverse-flick, that are observed and characterized in enteric bacterium Escherichia coli and marine bacterium Vibrio alginolyticus, respectively. To make an objective comparison, master equations are developed on the basis of microscopic motions of the bacteria. An unexpected yet significant result is that by adopting the run-reverse-flick motility pattern, a bacterium can reduce its diffusivity without compromising its drift in the chemical gradient. This finding is biologically important as it suggests that the motility pattern can improve a microorganism's ability to sequester nutrients in a competitive environment. PMID- 25296326 TI - Structure-function relations and rigidity percolation in the shear properties of articular cartilage. AB - Among mammalian soft tissues, articular cartilage is particularly interesting because it can endure a lifetime of daily mechanical loading despite having minimal regenerative capacity. This remarkable resilience may be due to the depth dependent mechanical properties, which have been shown to localize strain and energy dissipation. This paradigm proposes that these properties arise from the depth-dependent collagen fiber orientation. Nevertheless, this structure-function relationship has not yet been quantified. Here, we use confocal elastography, quantitative polarized light microscopy, and Fourier-transform infrared imaging to make same-sample measurements of the depth-dependent shear modulus, collagen fiber organization, and extracellular matrix concentration in neonatal bovine articular cartilage. We find weak correlations between the shear modulus |G(*)| and both the collagen fiber orientation and polarization. We find a much stronger correlation between |G(*)| and the concentration of collagen fibers. Interestingly, very small changes in collagen volume fraction vc lead to orders of-magnitude changes in the modulus with |G(*)| scaling as (vc - v0)(xi). Such dependencies are observed in the rheology of other biopolymer networks whose structure exhibits rigidity percolation phase transitions. Along these lines, we propose that the collagen network in articular cartilage is near a percolation threshold that gives rise to these large mechanical variations and localization of strain at the tissue's surface. PMID- 25296327 TI - Sequence-dependent biophysical modeling of DNA amplification. AB - A theoretical framework for prediction of the dynamic evolution of chemical species in DNA amplification reactions, for any specified sequence and operating conditions, is reported. Using the polymerase chain reaction (PCR) as an example, we developed a sequence- and temperature-dependent kinetic model for DNA amplification using first-principles biophysical modeling of DNA hybridization and polymerization. We compare this kinetic model with prior PCR models and discuss the features of our model that are essential for quantitative prediction of DNA amplification efficiency for arbitrary sequences and operating conditions. Using this model, the kinetics of PCR is analyzed. The ability of the model to distinguish between the dynamic evolution of distinct DNA sequences in DNA amplification reactions is demonstrated. The kinetic model is solved for a typical PCR temperature protocol to motivate the need for optimization of the dynamic operating conditions of DNA amplification reactions. It is shown that amplification efficiency is affected by dynamic processes that are not accurately represented in the simplified models of DNA amplification that form the basis of conventional temperature cycling protocols. Based on this analysis, a modified temperature protocol that improves PCR efficiency is suggested. Use of this sequence-dependent kinetic model in a control theoretic framework to determine the optimal dynamic operating conditions of DNA amplification reactions, for any specified amplification objective, is discussed. PMID- 25296328 TI - An energy-optimal approach for entrainment of uncertain circadian oscillators. AB - We develop an approach to find an energy-optimal stimulus that entrains an ensemble of uncertain, uncoupled limit cycle oscillators. Furthermore, when entrainment occurs, the phase shift between oscillators is constrained to be less than a predetermined amount. This approach is illustrated for a model of Drosophila circadian activity, for which it performs better than a standard 24-h light-dark cycle. Because this method explicitly accounts for uncertainty in a given system and only requires information that is experimentally obtainable, it is well suited for experimental implementation and could ultimately represent what is believed to be a novel treatment for patients suffering from advanced/delayed sleep-phase syndrome. PMID- 25296330 TI - Human T-lymphotropic virus 1, breastfeeding, and antiretroviral therapy. PMID- 25296329 TI - Equations of interdoublet separation during flagella motion reveal mechanisms of wave propagation and instability. AB - The motion of flagella and cilia arises from the coordinated activity of dynein motor protein molecules arrayed along microtubule doublets that span the length of axoneme (the flagellar cytoskeleton). Dynein activity causes relative sliding between the doublets, which generates propulsive bending of the flagellum. The mechanism of dynein coordination remains incompletely understood, although it has been the focus of many studies, both theoretical and experimental. In one leading hypothesis, known as the geometric clutch (GC) model, local dynein activity is thought to be controlled by interdoublet separation. The GC model has been implemented as a numerical simulation in which the behavior of a discrete set of rigid links in viscous fluid, driven by active elements, was approximated using a simplified time-marching scheme. A continuum mechanical model and associated partial differential equations of the GC model have remained lacking. Such equations would provide insight into the underlying biophysics, enable mathematical analysis of the behavior, and facilitate rigorous comparison to other models. In this article, the equations of motion for the flagellum and its doublets are derived from mechanical equilibrium principles and simple constitutive models. These equations are analyzed to reveal mechanisms of wave propagation and instability in the GC model. With parameter values in the range expected for Chlamydomonas flagella, solutions to the fully nonlinear equations closely resemble observed waveforms. These results support the ability of the GC hypothesis to explain dynein coordination in flagella and provide a mathematical foundation for comparison to other leading models. PMID- 25296331 TI - Reproducibility and absolute quantification of muscle glycogen in patients with glycogen storage disease by 13C NMR spectroscopy at 7 Tesla. AB - Carbon-13 magnetic resonance spectroscopy (13C MRS) offers a noninvasive method to assess glycogen levels in skeletal muscle and to identify excess glycogen accumulation in patients with glycogen storage disease (GSD). Despite the clinical potential of the method, it is currently not widely used for diagnosis or for follow-up of treatment. While it is possible to perform acceptable 13C MRS at lower fields, the low natural abundance of 13C and the inherently low signal to-noise ratio of 13C MRS makes it desirable to utilize the advantage of increased signal strength offered by ultra-high fields for more accurate measurements. Concomitant with this advantage, however, ultra-high fields present unique technical challenges that need to be addressed when studying glycogen. In particular, the question of measurement reproducibility needs to be answered so as to give investigators insight into meaningful inter-subject glycogen differences. We measured muscle glycogen levels in vivo in the calf muscle in three patients with McArdle disease (MD), one patient with phosphofructokinase deficiency (PFKD) and four healthy controls by performing 13C MRS at 7T. Absolute quantification of the MRS signal was achieved by using a reference phantom with known concentration of metabolites. Muscle glycogen concentration was increased in GSD patients (31.5+/-2.9 g/kg w. w.) compared with controls (12.4+/-2.2 g/kg w. w.). In three GSD patients glycogen was also determined biochemically in muscle homogenates from needle biopsies and showed a similar 2.5-fold increase in muscle glycogen concentration in GSD patients compared with controls. Repeated inter-subject glycogen measurements yield a coefficient of variability of 5.18%, while repeated phantom measurements yield a lower 3.2% system variability. We conclude that noninvasive ultra-high field 13C MRS provides a valuable, highly reproducible tool for quantitative assessment of glycogen levels in health and disease. PMID- 25296332 TI - The growing price gap between more and less healthy foods: analysis of a novel longitudinal UK dataset. AB - OBJECTIVES: The UK government has noted the public health importance of food prices and the affordability of a healthy diet. Yet, methods for tracking change over time have not been established. We aimed to investigate the prices of more and less healthy foods over time using existing government data on national food prices and nutrition content. METHODS: We linked economic data for 94 foods and beverages in the UK Consumer Price Index to food and nutrient data from the UK Department of Health's National Diet and Nutrition Survey, producing a novel dataset across the period 2002-2012. Each item was assigned to a food group and also categorised as either "more healthy" or "less healthy" using a nutrient profiling model developed by the Food Standards Agency. We tested statistical significance using a t-test and repeated measures ANOVA. RESULTS: The mean (standard deviation) 2012 price/1000 kcal was L2.50 (0.29) for less healthy items and L7.49 (1.27) for more healthy items. The ANOVA results confirmed that all prices had risen over the period 2002-2012, but more healthy items rose faster than less healthy ones in absolute terms:L0.17 compared to L0.07/1000 kcal per year on average for more and less healthy items, respectively (p<0.001). CONCLUSIONS: Since 2002, more healthy foods and beverages have been consistently more expensive than less healthy ones, with a growing gap between them. This trend is likely to make healthier diets less affordable over time, which may have implications for individual food security and population health, and it may exacerbate social inequalities in health. The novel data linkage employed here could be used as the basis for routine food price monitoring to inform public health policy. PMID- 25296333 TI - The kill date as a management tool for cover cropping success. AB - Integrating cover crops (CC) in rotations provides multiple ecological services, but it must be ensured that management does not increase pre-emptive competition with the subsequent crop. This experiment was conducted to study the effect of kill date on: (i) CC growth and N content; (ii) the chemical composition of residues; (iii) soil inorganic N and potentially mineralizable N; and (iv) soil water content. Treatments were fallow and a CC mixture of barley (Hordeum vulgare L.) and vetch (Vicia sativa L.) sown in October and killed on two different dates in spring. Above-ground biomass and chemical composition of CC were determined at harvest, and ground cover was monitored based on digital image analysis. Soil mineral N was determined before sowing and after killing the CC, and potentially mineralizable N was measured by aerobic incubation at the end of the experiment. Soil water content was monitored daily to a depth of 1.1 m using capacitance sensors. Under the present conditions of high N availability, delaying kill date increased barley above-ground biomass and N uptake from deep soil layers; little differences were observed in vetch. Postponing kill date increased the C/N ratio and the fiber content of plant residues. Ground cover reached >80% by the first kill date (~1250 degrees C days). Kill date was a means to control soil inorganic N by balancing the N retained in the residue and soil, and showed promise for mitigating N losses. The early kill date decreased the risk of water and N pre emptive competition by reducing soil depletion, preserving rain harvested between kill dates and allowing more time for N release in spring. The soil potentially mineralizable N was enhanced by the CC and kill date delay. Therefore kill date is a crucial management variable for maximizing the CC benefits in agricultural systems. PMID- 25296334 TI - Effect of cholecalciferol supplementation on inflammation and cellular alloimmunity in hemodialysis patients: data from a randomized controlled pilot trial. AB - BACKGROUND: Memory T-cells are mediators of transplant injury, and no therapy is known to prevent the development of cross-reactive memory alloimmunity. Activated vitamin D is immunomodulatory, and vitamin D deficiency, common in hemodialysis patients awaiting transplantation, is associated with a heightened alloimmune response. Thus, we tested the hypothesis that vitamin D3 supplementation would prevent alloreactive T-cell memory formation in vitamin D-deficient hemodialysis patients. METHODS AND FINDINGS: We performed a 12-month single-center pilot randomized, controlled trial of 50,000 IU/week of cholecalciferol (D3) versus no supplementation in 96 hemodialysis patients with serum 25(OH)D<25 ng/mL, measuring effects on serum 25(OH)D and phenotypic and functional properties of T cells. Participants were randomized 2:1 to active treatment versus control. D3 supplementation increased serum 25(OH)D at 6 weeks (13.5 [11.2] ng/mL to 42.5 [18.5] ng/mL, p<0.001) and for the duration of the study. No episodes of sustained hypercalcemia occurred in either group. Results of IFNgamma ELISPOT based panel of reactive T-cell assays (PRT), quantifying alloreactive memory, demonstrated greater increases in the controls over 1 year compared to the treatment group (delta PRT in treatment 104.8+/-330.8 vs 252.9+/-431.3 in control), but these changes in PRT between groups did not reach statistical significance (p = 0.25). CONCLUSIONS: D3 supplements are safe, effective at treating vitamin D deficiency, and may prevent time-dependent increases in T-cell alloimmunity in hemodialysis patients, but their effects on alloimmunity need to be confirmed in larger studies. These findings support the routine supplementation of vitamin D-deficient transplant candidates on hemodialysis and highlight the need for large-scale prospective studies of vitamin D supplementation in transplant candidates and recipients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01175798. PMID- 25296336 TI - Enhanced photovoltaic properties and long-term stability in plasmonic dye sensitized solar cells via noncorrosive redox mediator. AB - We demonstrate the localized surface plasmon resonance (LSPR) effect, which can enhance the photovoltaic properties of dye-sensitized solar cells (DSSCs), and the long-term stability of size-controlled plasmonic structures using a noncorrosive redox mediator. Gold nanoparticles (Au NPs) were synthesized with a phase transfer method based on ligand exchange. This synthetic method is advantageous because the uniformly sized Au NPs, can be mass produced and easily applied to DSSC photoanodes. The plasmonic DSSCs showed an 11% improvement of power conversion efficiency due to the incorporation of 0.07 wt % Au NPs, compared to the reference DSSCs without Au NPs. The improved efficiency was primarily due to the enhanced photocurrent generation by LSPR effect. With the cobalt redox mediator, the long-term stability of the plasmonic structures also significantly increased. The plasmonic DSSCs with cobalt(II/III) tris(2,2' bipyridine) ([Co(bpy)3](2+/3+)) redox mediator maintained the LSPR effect with stable photovoltaic performance for 1000 h. This is, to our knowledge, the first demonstration of the long-term stability of plasmonic nanostructures in plasmonic DSSCs based on liquid electrolytes. As a result, the enhanced long-term stability of plasmonic NPs via a noncorrosive redox mediator will increase the feasibility of plasmonic DSSCs. PMID- 25296337 TI - Prevalence of intestinal parasitic infections among children under five years of age with emphasis on Schistosoma mansoni in Wonji Shoa Sugar Estate, Ethiopia. AB - Intestinal parasite infections are major public health problems of children in developing countries causing undernutrition, anemia, intestinal obstruction and mental and physical growth retardation. This study was conducted to assess the prevalence of intestinal helminthic infections among children under five years of age with emphasis on Schistosoma mansoni in Wonji Shoa Sugar Estate, Ethiopia. A cross-sectional parasitological survey was conducted in under-five children living in Wonji Shoa Sugar Estate Ethiopia, April, 2013. Stool samples were collected and examined for intestinal parasites using single Kato-Katz and single Sodium acetate-acetic acid-formalin (SAF) solution concentration methods. Out of 374 children examined using single Kato-Katz and single SAF-concentration methods, 24.3% were infected with at least one intestinal parasite species. About 10.4%, 8.8%, 4.6%, 2.9%, 1.6% and 0.8% of the children were infected with Hymenolepis nana, Schistosoma mansoni, Ascaris lumbricoides, Trichuris trichiura, Enterobius vermicularis and hookworm, respectively. Prevalence of double, triple and quadruple intestinal helminthic infection was 6.4%, 0.54% and 1.1%, respectively. A significant increase in prevalence of S. mansoni (8.3% versus 3.2%) and T. trichiura (2.7% versus 0.5%) infection was observed when determined via the single Kato-Katz method compared to the prevalence of the parasites determined via the single SAF-concentration method. On the other hand, the single SAF-concentration method (9.1%) revealed a significantly higher prevalence of H. nana infection than the single Kato-Katz (1.6%) does. In conclusion, intestinal helminths infections particularly S. mansoni and H. nana were prevalent in under five children of Wonji Shoa Sugar Estate. Including praziquantel treatment in the deworming program as per the World Health Organization guidelines would be vital to reduce the burden of these diseases in areas where S. mansoni and H. nana infections are prevalent among under-fives. Kato-Katz can be used in estimating the prevalence of S. mansoni and other helminth infections. PMID- 25296335 TI - Factors that drive dentists towards or away from dental caries preventive measures: systematic review and metasummary. AB - BACKGROUND: Dental caries is a serious public health concern. The high cost of dental treatment can be avoided by effective preventive measures, which are dependent on dentists' adherence. This study aimed to evaluate the factors that drive dentists towards or away from dental caries preventive measures. METHODS AND FINDINGS: This systematic review was registered in PROSPERO (CRD42012002235). Several databases as well as the reference lists and citations of the included publications were searched according to PRISMA guidelines, yielding 18,276 titles and abstracts, which were assessed to determine study eligibility. Seven qualitative studies and 41 surveys (36,501 participants) remained after data extraction and interpretation. A total of 43 findings were abstracted from the reports and were grouped together into 6 categories that were judged to be topically similar: education and training, personal beliefs, work conditions, remuneration, gender, place of residence and patients. The main findings for adherence based on their calculated frequency effect sizes (ES) were teamwork (21%) and post-graduation (12%), while for non-adherence were biologicism (27%), and remuneration for preventive procedures (25%). Intensity ES were also calculated and demonstrated low prevalence of the findings. Quality assessment of the studies demonstrated that the methodological quality, particularly of surveys, varied widely among studies. CONCLUSIONS: Despite the questionable quality of the included reports, the evidence that emerged seems to indicate that further education and training coupled with a fairer pay scheme would be a reasonable approach to change the balance in favor of the provision of dental caries preventive measures by dentists. The results of this review could be of value in the planning and decision making processes aimed at encouraging changes in professional dental practice that could result in the improvement of the oral health care provided to the population in general. PMID- 25296338 TI - [Prevalence of decreasing vitamin D reserves in black patients undergoing intermittent hemodialysis in Dakar (Senegal): 37 cases]. AB - It is now established that vitamin D acts as a steroid hormone via a nuclear receptor to perform its varied functions in mineral metabolism. Very few studies in sub-Saharan Africa, and in Senegal in particular, have focused on the prevalence of low vitamin D reserves in black individuals living in this sunny region. We conducted this study to assess the prevalence of a drop in vitamin D reserves in a population of blacks undergoing intermittent hemodialysis. This descriptive study took place at three hemodialysis centers in Dakar and included 37 patients whose 25-hydroxyvitamin D (25-OH-D) levels had been assayed. The patients' mean age was 51 years, and their sex ratio 1.49. The average concentration of 25-OH-D was 70 nmol/L. Below-normal reserves were found in 23 patients (62.2%), especially among those aged 50-75 years. All patients with low 25-OH-D reserves received vitamin D3 supplementation at a dose of 100,000 IU of cholecalciferol per month. This supplementation normalized 25-OH-D levels in the 10 patients subsequently tested. Given the small sample size, a study with a larger number of patients is needed to reach a conclusion about the exact prevalence of low vitamin D reserves in this population and to investigate possible associated factors. PMID- 25296339 TI - Attentional bias in snus users: an experimental study. AB - The use of nicotine in the form of "snus" is substantial and increasing in some geographic areas, in particular among young people. It has previously been suggested that addictions may operate through a mechanism of attentional bias, in which stimuli representative of the dependent substance increase in salience, thus increasing the addictive behavior. However, this hypothesis has not been tested for the case of snus. The current experiment used a modified Stroop task and a dot-probe task to investigate whether 40 snus users show an attentional bias towards snus-relevant stimuli, compared to 40 non-snus users. There were no significant differences between the two groups on reaction times or accuracy on either Stroop or dot-probe task, thus failing to show an attentional bias towards snus-relevant stimuli for snus users. This could imply that other mechanisms may contribute to maintenance of snus use than for other addictions. However, this is the first experimental study investigating attentional bias in snus users, and more research is warranted. PMID- 25296340 TI - Towards the generation of B-cell receptor retrogenic mice. AB - Transgenic expression of B- and T-cell receptors (BCRs and TCRs, respectively) has been a standard tool to study lymphocyte development and function in vivo. The generation of transgenic mice is time-consuming and, therefore, a faster method to study the biology of defined lymphocyte receptors in vivo would be highly welcome. Using 2A peptide-linked multicistronic retroviral vectors to transduce stem cells, TCRs can be expressed rapidly in mice of any background. We aimed at adopting this retrogenic technology to the in vivo expression of BCRs. Using a well characterised BCR specific for hen egg lysozyme (HEL), we achieved surface expression of the retrogenically encoded BCR in a Rag-deficient pro B cell line in vitro. In vivo, retrogenic BCRs were detectable only intracellularly but not on the surface of B cells from wild type or Rag2-deficient mice. This data, together with the fact that no BCR retrogenic mouse model has been published in the 7 years since the method was originally published for TCRs, strongly suggests that achieving BCR-expression in vivo with retrogenic technology is highly challenging if not impossible. PMID- 25296341 TI - The paleoecology, habitats, and stratigraphic range of the enigmatic cretaceous brachiopod peregrinella. AB - Modern and Cenozoic deep-sea hydrothermal-vent and methane-seep communities are dominated by large tubeworms, bivalves and gastropods. In contrast, many Early Cretaceous seep communities were dominated by the largest Mesozoic rhynchonellid brachiopod, the dimerelloid Peregrinella, the paleoecologic and evolutionary traits of which are still poorly understood. We investigated the nature of Peregrinella based on 11 occurrences world wide and a literature survey. All in situ occurrences of Peregrinella were confirmed as methane-seep deposits, supporting the view that Peregrinella lived exclusively at methane seeps. Strontium isotope stratigraphy indicates that Peregrinella originated in the late Berriasian and disappeared after the early Hauterivian, giving it a geologic range of ca. 9.0 (+1.45/-0.85) million years. This range is similar to that of rhynchonellid brachiopod genera in general, and in this respect Peregrinella differs from seep-inhabiting mollusks, which have, on average, longer geologic ranges than marine mollusks in general. Furthermore, we found that (1) Peregrinella grew to larger sizes at passive continental margins than at active margins; (2) it grew to larger sizes at sites with diffusive seepage than at sites with advective fluid flow; (3) despite its commonly huge numerical abundance, its presence had no discernible impact on the diversity of other taxa at seep sites, including infaunal chemosymbiotic bivalves; and (4) neither its appearance nor its extinction coincides with those of other seep-restricted taxa or with global extinction events during the late Mesozoic. A preference of Peregrinella for diffusive seepage is inferred from the larger average sizes of Peregrinella at sites with more microcrystalline carbonate (micrite) and less seep cements. Because other seep-inhabiting brachiopods occur at sites where such cements are very abundant, we speculate that the various vent- and seep inhabiting dimerelloid brachiopods since Devonian time may have adapted to these environments in more than one way. PMID- 25296342 TI - Assessment of the safety and effectiveness of emergency department STEMI bypass by defibrillation-only emergency medical technicians/primary care paramedics. AB - INTRODUCTION: The American Heart Association (AHA) suggests emergency medical service (EMS) providers transporting ST-segment elevation myocardial infarction (STEMI) patients to a percutaneous coronary intervention (PCI) center require advanced life support (ALS) skills. OBJECTIVES: To evaluate the potential safety and time savings effectiveness of defibrillation-only emergency medical technician/primary care paramedic (EMT-D/PCP) EMS transport to a PCI center in a system where only emergency medical technician-paramedics/advanced care paramedics (EMT-Ps/ACPs) are authorized to bypass non-PCI hospitals. METHODS: We reviewed 89 consecutive patients meeting STEMI criteria transported by EMT Ds/PCPs per protocol by one of three paths: 1) closest non-PCI center emergency department (ED) with secondary transfer by EMT-Ps/ACPs to a PCI lab, 2) rendezvous with EMT-Ps/ACPs and diversion to a PCI lab, and 3) PCI center ED if it was closest. Actual transport times to the PCI center ED were compared to predicted transport times determined by mapping software had EMT-Ds/PCPs followed a direct path. Lastly, we recorded predefined clinically important events and advanced care interventions. RESULTS: Twenty-seven, 51, and 11 patients followed paths 1, 2, and 3 respectively. Median transport times for path 1 were 6 (IQR 5) minutes to reach the nearest non-PCI center ED and 66 (IQR 45) minutes to the PCI center ED compared to a median predicted 13 (IQR 7) minutes to a PCI center ED had EMT-Ds/PCPs followed a direct path. Median transport time for path 2 was 12 (IQR 8) minutes compared to a median predicted time of 11 (IQR 6) minutes had no EMT-P/ACP rendezvous occurred. Median transport time for path 3 was 7 minutes (IQR 5). Three patients experienced prehospital cardiac arrest; 1 required dopamine, and 4 others received a saline bolus for hypotension. CONCLUSIONS: Substantial time savings may occur if EMT-Ds/PCPs bypass non-PCI center EDs with only a small predicted increase (about 7 minutes) in the transport time to the PCI center ED. EMT-P/ACP rendezvous does not appear to substantially increase transport time. Given the relatively low occurrence of clinically important events, our findings suggest that EMT-D/PCP bypass to a PCI center ED may be safe and effective for selected STEMI patients. PMID- 25296343 TI - Racemosin C, a novel minor bisindole alkaloid with protein tyrosine phosphatase 1B inhibitory activity from the green alga Caulerpa racemosa. AB - A novel minor bisindole alkaloid, racemosin C (1), characterized by a naturally unprecedented 8-hydroxy-2,4,6-cyclooctatrienone ring fused with two indole systems, was isolated from the green alga Caulerpa racemosa, together with one known related metabolite, caulersin (2). The structure of 1 was elucidated on the basis of extensive spectroscopic analysis, and by comparison with the data of related known compounds. A plausible biosynthetic pathway of 1 was proposed. Compounds 1 and 2 exhibited significant PTP1B inhibitory activity with IC50 values of 5.86 +/- 0.57 and 7.14 +/- 1.00 MUM, respectively, compared with the positive control oleanolic acid (IC50 = 3.03 +/- 0.20 MUM). On the basis of the data obtained, the Caulerpa bisindole alkaloids may be considered as a new class of PTP1B inhibitors. PMID- 25296346 TI - A new chapter for the Lindsay Leg Clubs. PMID- 25296344 TI - Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients. AB - Fully sedated patients, being treated in the intensive care unit (ICU), experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully sedated ICU patients admitted for acute critical illness [n=3 males, n=3 females; age 63 +/- 6 y; APACHE II (Acute Physiology and Chronic Health Evaluation II) disease-severity-score: 29 +/- 2]. One leg was subjected to twice daily NMES of the quadriceps muscle for a period of 7 +/- 1 day whereas the other leg acted as a non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fibre-type-specific cross-sectional area (CSA). Furthermore, phosphorylation status of the key proteins involved in the regulation of muscle protein synthesis was assessed and mRNA expression of selected genes was measured. In the CON leg, type 1 and type 2 muscle-fibre-CSA decreased by 16 +/- 9% and 24 +/- 7% respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mammalian target of rapamycin (mTOR) phosphorylation by 19 +/- 5% when compared with baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined [forkhead box protein O1 (FOXO1); P<0.05] or remained unchanged [muscle atrophy F-box (MAFBx) and muscle RING finger protein-1 (MuRF1)], with no differences between the legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill comatose patients. PMID- 25296345 TI - Characteristics of patients with pulmonary venoocclusive disease awaiting transplantation. AB - RATIONALE: Pulmonary venoocclusive disease (PVOD) is an uncommon cause of pulmonary arterial hypertension (PAH). However, unlike PAH, treatment options for PVOD are usually quite limited. The impact of the lung allocation score on access to transplantation for patients with PVOD and the clinical course of these patients have not been well-described. OBJECTIVES: To examine the association between the diagnosis of PVOD and lung transplantation for patients on the transplant waiting list. METHODS: Patients with a diagnosis of PVOD and PAH registered on the United Network for Organ Sharing wait list for transplantation from May 4, 2005 to May 3, 2013 were included. Lung transplantation was the primary outcome measure. Multivariable analyses were performed to determine the odds of dying or receiving a lung transplant after listing. Survival was compared using Kaplan-Meier and competing risks methods. RESULTS: Of 12,251 patients listed for lung transplantation, 49 with PVOD and 647 with PAH were identified. There were no significant differences in the lung allocation score between patients with PVOD and PAH at listing, transplant, or wait list removal for death/too sick for transplant. By 6 months, 22.6% of patients with PVOD had been removed from the wait list due to death, compared with 11.0% of patients with PAH (Chi-square P = 0.03). Patients with PVOD who died or were considered too sick for transplant were removed from the waiting list sooner after listing (22 vs. 105 d, P = 0.08). There was no difference in the proportion of patients with PVOD and PAH transplanted (50.0 vs. 47.6%, P = 0.60). CONCLUSIONS: In the lung allocation score era, patients with PVOD may be at higher risk for death while on the transplant waiting list. After wait list registration, close monitoring for disease progression is advised. PMID- 25296347 TI - Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. AB - OBJECTIVE: To evaluate how the different processing methods cryopreservation and dehydration affect the structural integrity and biological composition of key signalling molecules within amniotic membrane and umbilical cord tissues. METHOD: We directly compared cryopreserved amniotic membrane (AM) and umbilical cord (UC) tissues with dehydrated amniotic membrane/chorion (dHACM) tissue using biochemical and functional assays including histological and histochemical staining, BCA, agarose gel electrophoresis, western blot, ELISA, and proliferation and cell death assays. RESULTS: Cryopreservation retains the native architecture of the AM/UC extracellular matrix and maintains the quantity and activity of key biological signals present in fresh AM/UC, including high molecular weight hyaluronic acid, heavy chain-HA complex, and pentraxin 3. In contrast, dehydrated tissues were structurally compromised and almost completely lacked these crucial components. CONCLUSION: The results presented here indicate that cryopreservation better preserves the structural and biological signaling molecules of foetal tissues. PMID- 25296348 TI - Antimicrobials and Non-Healing Wounds. Evidence, controversies and suggestions key messages. AB - This article constitutes an extraction of key messages originally presented in the Document: Antimicrobials and Non-Healing Wounds. Evidence, controversies and suggestions written by the European Wound Management Association (EWMA), and originally published by the Journal of Wound Care in 2013. All sections are shortened and some not included. For further details please refer to in the original document which can be downloaded via www.ewma.org . PMID- 25296349 TI - Adhesion of meticillin-resistant Staphylococcus aureus to DACC-coated dressings. AB - OBJECTIVE: The aim of this in vitro study was to demonstrate the binding capacity of multiple meticillin-resistant Staphylococcus aureus (MRSA) strains and compare the binding capacity to meticillin-sensitive Staphylococcus aureus. METHOD: The binding of Staphylococcus aureus to a surface was assessed by bioluminescent monitoring of the bacterial ATP levels. This assay can be used as an in vitro diagnostic model for bacteria binding in a critically colonised wound. RESULTS: Eleven strains of Staphylococcus aureus were examined including MRSA, all of which efficiently and equally adhered to the dialkyl carbamoyl chloride (DACC) coated dressing (Sorbact; Abigo Medical AB). The binding capacity was all in the same range 0.7-2.9 * 106 CFU/cm2. regardless of the antibiotic resistance properties of the specific strain. CONCLUSION: The decrease of wound bioburden of Staphylococcus aureus including MRSA is the result of the high binding capacity shown in this study and by earlier data. The findings in this study strengthen the held view that development of antibiotic resistance has minimal impact on the surface structures of the microorganisms in wounds. PMID- 25296350 TI - Dehydrated human amnion/chorion membrane for the treatment of severe skin and tissue loss in an preterm infant: a case report. AB - Extreme prematurity complicated with severe congenital cutaneous candidiasis (CCC) is rare and clinically challenging. We present the case of a 615g dizygotic twin delivered at 24 weeks gestation with congenital candidiasis, who developed severe skin and tissue loss, successfully treated with dehydrated human amnion/chorion membrane (dHACM). The infant had a complicated medical course, including treatment for patent ductus arteriosus (PDA), necrotising enterocolitis (NEC), and neonatal abstinence syndrome (NAS). In the operating room after debridement, dHACM was placed over all abdominal and back areas of skin loss and covered with a non-occlusive, non-adherent silver dressing. This dressing regimen was chosen in an effort to provide not only topical antimicrobial coverage, but also to maintain a non-shear, moist wound healing environment, which was so important in the dry incubator environment of the neonatal intensive care centre. Over the next four weeks, the baby was medically managed, and the wounds healed on their own with only weekly bedside dressing changes. This case report provides the first example of successful complex management of extensive life-threatening wounds in a premature infant using dHACM. PMID- 25296351 TI - The perspectives of adults with venous leg ulcers on exercise: an exploratory study. AB - OBJECTIVE: Exercise has the potential to offer a range of health benefits in addition to improving healing outcomes for people with venous leg ulcers (VLUs). However, despite evidence-based recommendations, most of these individuals do not engage in regular exercise. The aim of this study was to gain an understanding of the perspectives of adults with VLUs, in relation to exercise. METHOD: This was a qualitative design using semi-structured interviews and discussions. Ten participants with venous leg ulceration volunteered to participate. Recruitment was through a specialist wound clinic. Verbatim data were collected by an experienced moderator using a semi-structured guide. Data saturation was reached after three group discussions and two interviews. A random selection of transcripts was sent back to the participants for verification. Thematic content analysis was used to determine major themes and categories. Two transcripts were independently analysed, categories and themes independently developed, cross checked and found comparable. Remaining transcripts were analysed using the developed categories and codes. RESULTS: Regardless of their current exercise routine, participants reported exercising before venous leg ulceration and expressed an interest in either becoming active or maintaining an active lifestyle. Overall, four themes emerged from the findings: i) participant understanding of the relationship between chronic venous insufficiency and exercise patterns; ii) fear of harm impacts upon positive beliefs and attitudes to exercise; iii) perceived factors limit exercise; and iv) structured management facilitates exercise. CONCLUSION: The value of exercise in improving outcomes in VLUs lies in its capacity to promote venous return and reduce the risk of secondary conditions in this population. Despite motivation and interest in being exercise active, people with VLUs report many obstacles. Further exploration of mechanisms that assist this patient population and promote understanding about management of barriers, coupled with promotion of enabling factors, is vital for improving their exercise participation. PMID- 25296352 TI - Scleroderma and evidence based non-pharmaceutical treatment modalities for digital ulcers: a systematic review. AB - OBJECTIVE: Digital ulcers are difficult to heal, increasing the chance of infection, gangrene, amputation and limited functional use of hands. They are a complication in scleroderma or systematic sclerosis (SSc) and occur in approximately 50% of patients. This is a systematic review of the evidence supporting the use of non-pharmaceutical therapeutic modalities and their effectiveness to facilitate the healing of chronic digital ulcers in patients with scleroderma. METHOD: A comprehensive review of computerised databases from 2000-2013: PubMed/MEDLINE, CINAHL, Pedro, OT Seeker, OT Search, OVID, and Proquest as well as manual review of other resources was completed using the following search terms scleroderma or systemic sclerosis and/or digital ulcers, specific modalities (low level laser therapy, electrical stimulation, intermittent compression, ultrasound, vitamin E, myofascial release, wound dressings, iontophoresis, negative pressure therapy, and exercise), chronic wounds, and wound care. English language studies, from 2000 to January 2013, which used therapeutic modalities to facilitate healing of digital ulcers and use healing of the digital ulcer as an outcome measure were reviewed. RESULTS: Of the 403 identified articles, only 11 studies addressed non-pharmaceutical treatment modalities to facilitate healing for digital ulcers. Exercise had no direct effect on healing ulcers. The following studies were positive but have limitations in design and sample size:: hyperbaric oxygen therapy (n=2), negative pressure therapy (n=1), intermittent compression (n=27) and acoustic pressure wound healing (n=1). Vitamin E gel showed a significant difference compared to a control group (n=27). Iontophoresis studies have shown that the modality increases blood flow but the results in five different studies are mixed and the application and intensity were inconsistent. CONCLUSION: No one modality was proven to be the most effective. Larger efficacy studies on treating digital ulcers are needed in order to develop appropriate care guidelines to improve outcomes, promote function and lower health-care costs. PMID- 25296353 TI - Chronic granulomatous disease: why an inflammatory disease? AB - Chronic granulomatous disease is a primary immunodeficiency caused by mutations in the genes encoding subunits of the phagocytic NADPH oxidase system. Patients can present with severe, recurrent infections and noninfectious conditions. Among the latter, inflammatory manifestations are predominant, especially granulomas and colitis. In this article, we systematically review the possible mechanisms of hyperinflammation in this rare primary immunodeficiency condition and their correlations with clinical aspects. PMID- 25296354 TI - Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data. AB - Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC. PMID- 25296355 TI - Hepatic inducible nitric oxide synthase expression increases upon exposure to hypergravity. AB - Stimulation by a number of conditions, including infection, cytokines, mechanical injury, and hypoxia, can upregulate inducible nitric oxide synthase (iNOS) in hepatocytes. We observed that exposure to hypergravity significantly upregulated the transcription of the hepatic iNOS gene. The aim of this study was to confirm our preliminary data, and to further investigate the distribution of the iNOS protein in the livers of mice exposed to hypergravity. ICR mice were exposed to +3 Gz for 1 h. We investigated the time course of change in the iNOS expression. Hepatic iNOS mRNA expression progressively increased in centrifuged mice from 0 to 12 h, and then decreased rapidly by 18 h. iNOS mRNA levels in the livers of centrifuged mice was significantly higher at 3, 6, and 12 h than in uncentrifuged control mice. The pattern of iNOS protein expression paralleled that of the mRNA expression. At 0 and 1 h, weak cytoplasmic iNOS immunoreactivity was found in some hepatocytes surrounding terminal hepatic venules. It was noted that at 6 h there was an increase in the number of perivenular hepatocytes with moderate to strong cytoplasmic immunoreactivity. The number of iNOS-positive hepatocytes was maximally increased at 12 h. The majority of positively stained cells showed a strong intensity of iNOS expression. The expression levels of iNOS mRNA and protein were significantly increased in the livers of mice exposed to hypergravity. These results suggest that exposure to hypergravity significantly upregulates iNOS at both transcriptional and translational levels. PMID- 25296356 TI - Therapeutic mechanism of treating SMMC-7721 liver cancer cells with magnetic fluid hyperthermia using Fe2O3 nanoparticles. AB - This study aimed to investigate the therapeutic mechanism of treating SMMC-7721 liver cancer cells with magnetic fluid hyperthermia (MFH) using Fe2O3 nanoparticles. Hepatocarcinoma SMMC-7721 cells cultured in vitro were treated with ferrofluid containing Fe2O3 nanoparticles and irradiated with an alternating radio frequency magnetic field. The influence of the treatment on the cells was examined by inverted microscopy, MTT and flow cytometry. To study the therapeutic mechanism of the Fe2O3 MFH, Hsp70, Bax, Bcl-2 and p53 were detected by immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). It was shown that Fe2O3 MFH could cause cellular necrosis, induce cellular apoptosis, and significantly inhibit cellular growth, all of which appeared to be dependent on the concentration of the Fe2O3nanoparticles. Immunocytochemistry results showed that MFH could induce high expression of Hsp70 and Bax, decrease the expression of mutant p53, and had little effect on Bcl-2. RT-PCR indicated that Hsp70 expression was high in the early stage of MFH (<24 h) and became low or absent after 24 h of MFH treatment. It can be concluded that Fe2O3MFH significantly inhibited the proliferation of in vitro cultured liver cancer cells (SMMC-7721), induced cell apoptosis and arrested the cell cycle at the G2/M phase. Fe2O3 MFH can induce high Hsp70 expression at an early stage, enhance the expression of Bax, and decrease the expression of mutant p53, which promotes the apoptosis of tumor cells. PMID- 25296357 TI - Effect of exercise training on Ca2+ release units of left ventricular myocytes of spontaneously hypertensive rats. AB - In cardiomyocytes, calcium (Ca2+) release units comprise clusters of intracellular Ca2+ release channels located on the sarcoplasmic reticulum, and hypertension is well established as a cause of defects in calcium release unit function. Our objective was to determine whether endurance exercise training could attenuate the deleterious effects of hypertension on calcium release unit components and Ca2+ sparks in left ventricular myocytes of spontaneously hypertensive rats. Male Wistar and spontaneously hypertensive rats (4 months of age) were divided into 4 groups: normotensive (NC) and hypertensive control (HC), and normotensive (NT) and hypertensive trained (HT) animals (7 rats per group). NC and HC rats were submitted to a low-intensity treadmill running protocol (5 days/week, 1 h/day, 0% grade, and 50-60% of maximal running speed) for 8 weeks. Gene expression of the ryanodine receptor type 2 (RyR2) and FK506 binding protein (FKBP12.6) increased (270%) and decreased (88%), respectively, in HC compared to NC rats. Endurance exercise training reversed these changes by reducing RyR2 (230%) and normalizing FKBP12.6 gene expression (112%). Hypertension also increased the frequency of Ca2+ sparks (HC=7.61 +/- 0.26 vs NC=4.79 +/- 0.19 per 100 um/s) and decreased its amplitude (HC=0.260 +/- 0.08 vs NC=0.324 +/- 0.10 DeltaF/F0), full width at half-maximum amplitude (HC=1.05 +/- 0.08 vs NC=1.26 +/- 0.01 um), total duration (HC=11.51 +/- 0.12 vs NC=14.97 +/- 0.24 ms), time to peak (HC=4.84 +/- 0.06 vs NC=6.31 +/- 0.14 ms), and time constant of decay (HC=8.68 +/- 0.12 vs NC=10.21 +/- 0.22 ms). These changes were partially reversed in HT rats (frequency of Ca2+ sparks=6.26 +/- 0.19 um/s, amplitude=0.282 +/- 0.10 DeltaF/F0, full width at half-maximum amplitude=1.14 +/- 0.01 um, total duration=13.34 +/- 0.17 ms, time to peak=5.43 +/- 0.08 ms, and time constant of decay=9.43 +/- 0.15 ms). Endurance exercise training attenuated the deleterious effects of hypertension on calcium release units of left ventricular myocytes. PMID- 25296359 TI - Intercostal and forearm muscle deoxygenation during respiratory fatigue in patients with heart failure: potential role of a respiratory muscle metaboreflex. AB - The purpose of this study was to determine the effect of respiratory muscle fatigue on intercostal and forearm muscle perfusion and oxygenation in patients with heart failure. Five clinically stable heart failure patients with respiratory muscle weakness (age, 66 +/- 12 years; left ventricle ejection fraction, 34 +/- 3%) and nine matched healthy controls underwent a respiratory muscle fatigue protocol, breathing against a fixed resistance at 60% of their maximal inspiratory pressure for as long as they could sustain the predetermined inspiratory pressure. Intercostal and forearm muscle blood volume and oxygenation were continuously monitored by near-infrared spectroscopy with transducers placed on the seventh left intercostal space and the left forearm. Data were compared by two-way ANOVA and Bonferroni correction. Respiratory fatigue occurred at 5.1 +/- 1.3 min in heart failure patients and at 9.3 +/- 1.4 min in controls (P<0.05), but perceived effort, changes in heart rate, and in systolic blood pressure were similar between groups (P>0.05). Respiratory fatigue in heart failure reduced intercostal and forearm muscle blood volume (P<0.05) along with decreased tissue oxygenation both in intercostal (heart failure, -2.6 +/- 1.6%; controls, +1.6 +/- 0.5%; P<0.05) and in forearm muscles (heart failure, -4.5 +/- 0.5%; controls, +0.5 +/- 0.8%; P<0.05). These results suggest that respiratory fatigue in patients with heart failure causes an oxygen demand/delivery mismatch in respiratory muscles, probably leading to a reflex reduction in peripheral limb muscle perfusion, featuring a respiratory metaboreflex. PMID- 25296358 TI - Erythropoietin reduces the expression of myostatin in mdx dystrophic mice. AB - Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-beta1 (TGF beta1), and tumor necrosis factor-alpha (TNF-alpha) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO = 0.60 +/- 0.11, control = 1.07 +/- 0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-beta1 (rhEPO = 0.95 +/- 0.14, control = 1.05 +/- 0.16) and TNF-alpha (rhEPO = 0.73 +/- 0.20, control = 1.01 +/- 0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle. PMID- 25296360 TI - Estimating the average length of hospitalization due to pneumonia: a fuzzy approach. AB - Exposure to air pollutants is associated with hospitalizations due to pneumonia in children. We hypothesized the length of hospitalization due to pneumonia may be dependent on air pollutant concentrations. Therefore, we built a computational model using fuzzy logic tools to predict the mean time of hospitalization due to pneumonia in children living in Sao Jose dos Campos, SP, Brazil. The model was built with four inputs related to pollutant concentrations and effective temperature, and the output was related to the mean length of hospitalization. Each input had two membership functions and the output had four membership functions, generating 16 rules. The model was validated against real data, and a receiver operating characteristic (ROC) curve was constructed to evaluate model performance. The values predicted by the model were significantly correlated with real data. Sulfur dioxide and particulate matter significantly predicted the mean length of hospitalization in lags 0, 1, and 2. This model can contribute to the care provided to children with pneumonia. PMID- 25296361 TI - Relationship between pulmonary function and indoor air pollution from coal combustion among adult residents in an inner-city area of southwest China. AB - Few studies evaluate the amount of particulate matter less than 2.5 mm in diameter (PM2.5) in relation to a change in lung function among adults in a population. The aim of this study was to assess the association of coal as a domestic energy source to pulmonary function in an adult population in inner-city areas of Zunyi city in China where coal use is common. In a cross-sectional study of 104 households, pulmonary function measurements were assessed and compared in 110 coal users and 121 non-coal users (>=18 years old) who were all nonsmokers. Several sociodemographic factors were assessed by questionnaire, and ventilatory function measurements including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), the FEV1/FVC ratio, and peak expiratory flow rate (PEFR) were compared between the 2 groups. The amount of PM2.5 was also measured in all residences. There was a significant increase in the relative concentration of PM2.5 in the indoor kitchens and living rooms of the coal-exposed group compared to the non-coal-exposed group. In multivariate analysis, current exposure to coal smoke was associated with a 31.7% decrease in FVC, a 42.0% decrease in FEV1, a 7.46% decrease in the FEV1/FVC ratio, and a 23.1% decrease in PEFR in adult residents. The slope of lung function decrease for Chinese adults is approximately a 2-L decrease in FVC, a 3-L decrease in FEV1, and an 8 L/s decrease in PEFR per count per minute of PM2.5 exposure. These results demonstrate the harmful effects of indoor air pollution from coal smoke on the lung function of adult residents and emphasize the need for public health efforts to decrease exposure to coal smoke. PMID- 25296362 TI - Occult hepatitis B virus infection in liver transplant patients in a Brazilian referral center. AB - Estimates of occult hepatitis B virus (HBV) infection prevalence varies among different studies depending on the prevalence of HBV infection in the study population and on the sensitivity of the assay used to detect HBV DNA. We investigated the prevalence of occult HBV infection in cirrhotic patients undergoing liver transplantation in a Brazilian referral center. Frozen liver samples from 68 adults were analyzed using a nested polymerase chain reaction assay for HBV DNA. The specificity of the amplified HBV sequences was confirmed by direct sequencing of the amplicons. The patient population comprised 49 (72.1%) males and 19 (27.9%) females with a median age of 53 years (range=18-67 years). Occult HBV infection was diagnosed in three (4.4%) patients. The etiologies of the underlying chronic liver disease in these cases were alcohol abuse, HBV infection, and cryptogenic cirrhosis. Two of the patients with cryptic HBV infection also presented hepatocellular carcinoma. Markers of previous HBV infection were available in two patients with occult HBV infection and were negative in both. In conclusion, using a sensitive nested polymerase chain reaction assay to detect HBV DNA in frozen liver tissue, we found a low prevalence of occult HBV infection in cirrhotic patients undergoing liver transplant, probably due to the low prevalence of HBV infection in our population. PMID- 25296363 TI - Elevated levels of plasma osteoprotegerin are associated with all-cause mortality risk and atherosclerosis in patients with stages 3 to 5 chronic kidney disease. AB - Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and plays a role in vascular calcification. We evaluated the relationship between osteoprotegerin levels and inflammatory markers, atherosclerosis, and mortality in patients with stages 3-5 chronic kidney disease. A total of 145 subjects (median age 61 years, 61% men; 36 patients on hemodialysis, 55 patients on peritoneal dialysis, and 54 patients with stages 3-5 chronic kidney disease) were studied. Clinical characteristics, markers of mineral metabolism (including fibroblast growth factor-23 [FGF-23]) and inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]), and the intima-media thickness (IMT) in the common carotid arteries were measured at baseline. Cardiac function was assessed by color tissue Doppler echocardiography. After 36 months follow-up, the survival rate by Kaplan-Meier analysis was significantly different according to OPG levels (chi 2 =14.33; P=0.002). Increased OPG levels were positively associated with IL-6 (r=0.38, P<0.001), FGF-23 (r=0.26, P<0.001) and hsCRP (r=0.0.24, P=0.003). In addition, OPG was positively associated with troponin I (r=0.54, P<0.001) and IMT (r=0.39, P<0.0001). Finally, in Cox analysis, only OPG (HR=1.07, 95%CI=1.02-1.13) and hsCRP (HR=1.02, 95%CI=1.01-1.04) were independently associated with increased risk of death. These results suggested that elevated levels of serum OPG might be associated with atherosclerosis and all-cause mortality in patients with chronic kidney disease. PMID- 25296364 TI - Relationship between deep venous thrombosis and inflammatory cytokines in postoperative patients with malignant abdominal tumors. AB - Deep venous thrombosis (DVT) is a common surgical complication in cancer patients and evidence that inflammation plays a role in the occurrence of DVT is increasing. We studied a population of cancer patients with abdominal malignancies with the aim of investigating whether the levels of circulating inflammatory cytokines were associated with postoperative DVT, and to determine the levels in DVT diagnoses. The serum levels of C-reactive protein (CRP), interleukins (IL)-6 and IL-10, nuclear transcription factor-kappaB (NF-kappaB) and E-selectin (E-Sel) were determined in 120 individuals, who were divided into 3 groups: healthy controls, patients with and patients without DVT after surgery for an abdominal malignancy. Data were analyzed by ANOVA, Dunnet's T3 test, chi square test, and univariate and multivariate logistic regression as needed. The CRP, IL-6, NF-kappaB, and E-Sel levels in patients with DVT were significantly higher than those in the other groups (P<0.05). The IL-10 level was higher in patients with DVT than in controls but lower than in patients without DVT. Univariate analysis revealed that CRP, IL-6, NF-kappaB, and E-Sel were statistically associated with the risk of DVT (OR=1.98, P=0.002; OR=1.17, P=0.000; OR=1.03, P=0.042; and OR=1.38, P=0.003; respectively), whereas IL-10 had a protective effect (OR=0.94, P=0.011). Multivariate analysis showed that E-Sel was an independent risk factor (OR=1.41, P=0.000). Thus, this study indicated that an increased serum level of E-Sel was associated with increased DVT risk in postoperative patients with abdominal malignancy, indicating that E-Sel may be a useful predictor of diagnosis of DVT. PMID- 25296366 TI - Poly(epsilon-caprolactone) nanowebs functionalized with alpha- and gamma cyclodextrins. AB - The effects of alpha- and gamma-cyclodextrins (alpha- and gamma-CDs) on the thermal and crystal nucleation behavior of electrospun poly(epsilon-caprolactone) (PCL) nanofibers have been investigated. PCL/CD composite nanofibers were obtained for the first time by electrospinning the mixture from chloroform/N,N dimethylformamide (60:40). Scanning electron microscopy analyses indicated that neat PCL nanofibers have an average diameter of 400 nm, which increases with the addition of CDs. The presence of CDs on or in the electrospun PCL fibers in the electrospun mats was investigated using Fourier transform infrared spectroscopy, thermogravimetric analysis, and wide-angle X-ray diffraction analysis. Differential scanning calorimetry showed that the PCL/CD composite fibers exhibit higher crystallization temperatures and sharper crystallization exotherms with increased CD loading, indicating the ability of CDs to nucleate PCL crystallization. Water contact angle (WCA) measurements indicate an inverse relationship between WCA and alpha- or gamma-CD concentration up to 30% loading. Phenolphthalein absorption tests were performed to study the kinetics of their inclusion complex (IC) formation with CDs. Unexpectedly, gamma-CD-functionalized nanowebs performed better than alpha-CD. This might be because at elevated loadings some alpha-CDs may have threaded over PCL chains and formed ICs, whereas gamma-CD did not. With their encapsulation capabilities and their lowered hydrophobicity, PCL/CD composite fibers might have potential uses in medical applications, in particular as wound odor absorbants in dressings, because it is well known that CDs can form ICs with these odorants, thereby effectively removing them. PMID- 25296365 TI - Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in Sao Luis, Brazil, and its association with prognostic factors and disease-free survival. AB - The CYP2D6 enzyme is crucial for the metabolism of tamoxifen. The CYP2D6 gene is highly polymorphic, and individuals can be extensive, intermediate, or poor tamoxifen metabolizers. The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival. We observed a high frequency of CYP2D6 *10, with an allelic frequency of 0.14 (14.4%). The *3 allele was not present in the studied population, and *4 had an allelic frequency of 0.13 (13.8%). We conclude that patients with reduced CYP2D6 activity did not present worse tumor characteristics or decreased disease-free survival than women with normal enzyme activity, as the difference was not statistically significant. We also observed a high frequency of CYP2D6 *10, which had not been previously described in this specific population. This study is the first in north-northeastern Brazil that aimed to contribute to the knowledge of the Brazilian regional profile for CYP2D6 polymorphisms and their phenotypes. These findings add to the knowledge of the distribution of different polymorphic CYP2D6 alleles and the potential role of CYP2D6 genotyping in clinical practice prior to choosing therapeutic protocols. PMID- 25296367 TI - The reliability of a novel magnetic resonance compatible electro-pneumatic device for delivering a painful pressure stimulus over the lumbar spine. AB - BACKGROUND: Chronic lower back pain (CLBP) is a significant public health problem in the USA. The complexity of CLBP necessitates an assessment tool that can objectively evaluate the aspects of CLBP that lead to disability. Here we present a novel means by which to provide pressure stimuli to the lumbar spine through the use of an electro-pneumatic circuit that can be used in conjunction with functional magnetic resonance imaging (fMRI) technology to assess the cortical activity changes associated with CLBP. METHODS: A test-retest experimental design was used to objectively quantify pressure pain sensitivity of the lumbar spine. Sensitivity was investigated through the identification of pressure pain thresholds of the lumbar spine using a multiple random staircase method (5-s stimuli) and continuous pain intensity rating (25-s stimuli). RESULTS: Data presented here were consistent and reliable from day to day with an interclass correlation coefficient (ICC) value of 0.913 for threshold values overall and individual ICC values of 0.652, 0.818, and 0.851 for mild, moderate, and intense thresholds, respectively. Linear regression analysis for longer trials indicated a large variation on day 1, R(2) values ranged from 0.222 to 0.882, however, the number of low correlation values decreased with only three subjects having R(2) < 0.6 for trial 2 on day 2. CONCLUSION: This project has successfully developed a device that can deliver a reliable and reproducible stimulus over the lumbar spine that mimics the palpatory technique used in clinical practice, and can be used in conjunction with fMRI to assess cortical response. PMID- 25296368 TI - What the future holds: in response to global health care challenges, innovation has become the new "way of life". PMID- 25296369 TI - Forecast 2014: this year will be a good one for biomedical engineering--thanks to breakthrough technologies and unprecedented funding opportunities. PMID- 25296370 TI - Seven steps to innovation: insights from experts on where it's needed and how it's done. PMID- 25296371 TI - Waking up to innovation: a tighter economic climate has the U.K.'s National Health Service looking for radical transformation. PMID- 25296372 TI - Barriers to health care innovation: Regina Herzlinger warns that innovators need to know what obstacles they face and how to overcome them. PMID- 25296373 TI - Accelerating the innovation cycle: a Boston model seeks solutions for lagging ingenuity in health care. PMID- 25296374 TI - Bridging the gap from bench to bedside: China takes a new look at moving innovative health care ideas into the marketplace. PMID- 25296375 TI - Science by the masses: is crowdfunding the future for biotech start-ups? PMID- 25296376 TI - Innovating openly: researchers and patients turn to crowdsourcing to collaborate on clinical trials, drug discovery, and more. PMID- 25296377 TI - Spirometry: a historical gallery up to 1905. PMID- 25296378 TI - Pioglitazone improves potassium channel remodeling induced by angiotensin II in atrial myocytes. AB - BACKGROUND: It has been demonstrated that atrial electrical remodeling contributes toward atrial fibrillation (AF) maintenance, and that angiotensin II (AngII) is involved in the pathogenesis of atrial electrical remodeling. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists have been shown to inhibit atrial electrical remodeling, but the underlying mechanisms are poorly understood. In the present study we investigated the regulating effects of PPAR-g agonist on AngII-induced potassium channel remodeling in atrial myocytes. MATERIAL/METHODS: Whole-cell patch-clamp technique was used to record transient outward potassium current (Ito), ultra-rapid delayed rectifier potassium (Ikur), and inward rectifier potassium current (Ik1). Real-time PCR was used to assess potassium channel subunit mRNA expression. RESULTS: Compared with the control group, AngII reduced Ito and Ikur current density as well as amplified Ik1 current density, which were partially prevented by pioglitazone. Furthermore, pioglitazone alleviated the downregulation of Ito subunit (Kv 4.2) and Ikur subunit (Kv 1.5), as well as the upregulation of Ik1 subunit (Kir 2.1 and Kir 2.2) mRNA expression stimulated by AngII. CONCLUSIONS: These results suggest that pioglitazone exhibits a beneficial effect on AngII-induced potassium channel remodeling. PPAR-gamma agonists may be potentially effective up-stream therapies for AF. PMID- 25296380 TI - Controllably interfacing with metal: a strategy for enhancing CO oxidation on oxide catalysts by surface polarization. AB - Heterogeneous catalysis often involves charge transfer from catalyst surface to adsorbed molecules, whose activity thus depends on the surface charge density of catalysts. Here, we demonstrate a unique solution-phase approach to achieve controllable interfacial lengths in oxide-metal hybrid structures. Resulting from their different work functions, surface polarization is induced by the Ag-CuO interface and acts to tailor the surface charge state of CuO. As a result, the designed hybrid catalysts exhibit enhanced intrinsic activities in catalyzing CO oxidation in terms of apparent activation energy, as compared with their counterparts. Moreover, the CO conversion rate can be enhanced by maximizing the Ag-CuO interfacial length and thus the number of active sites on the CuO. This work provides a new strategy for tuning catalytic performance by controlling interface in hybrid catalysts. PMID- 25296379 TI - Alternative meiotic chromatid segregation in the holocentric plant Luzula elegans. AB - Holocentric chromosomes occur in a number of independent eukaryotic lineages. They form holokinetic kinetochores along the entire poleward chromatid surfaces, and owing to this alternative chromosome structure, species with holocentric chromosomes cannot use the two-step loss of cohesion during meiosis typical for monocentric chromosomes. Here we show that the plant Luzula elegans maintains a holocentric chromosome architecture and behaviour throughout meiosis, and in contrast to monopolar sister centromere orientation, the unfused holokinetic sister centromeres behave as two distinct functional units during meiosis I, resulting in sister chromatid separation. Homologous non-sister chromatids remain terminally linked after metaphase I, by satellite DNA-enriched chromatin threads, until metaphase II. They then separate at anaphase II. Thus, an inverted sequence of meiotic sister chromatid segregation occurs. This alternative meiotic process is most likely one possible adaptation to handle a holocentric chromosome architecture and behaviour during meiosis. PMID- 25296381 TI - National health spending in 2014--acceleration delayed. PMID- 25296382 TI - A short-wavelength infrared emitting multimodal probe for non-invasive visualization of phagocyte cell migration in living mice. AB - For the non-invasive visualization of cell migration in deep tissues, we synthesized a short-wavelength infrared (SWIR) emitting multimodal probe that contains PbS/CdS quantum dots, rhodamine 6G and iron oxide nanoparticles. This probe enables multimodal (SWIR fluorescence/magnetic resonance) imaging of phagocyte cell migration in living mice. PMID- 25296383 TI - Divergent total synthesis of triptolide, triptonide, tripdiolide, 16 hydroxytriptolide, and their analogues. AB - A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation-lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity. PMID- 25296384 TI - Dependence, misuse, and beliefs regarding use of hypnotics by elderly psychiatric patients taking zolpidem, estazolam, or flunitrazepam. AB - INTRODUCTION: To examine the prevalence rates and correlates of dependence on, misuse of, and beliefs regarding use of hypnotics in elderly psychiatric patients with long-term use of zolpidem, estazolam, or flunitrazepam. METHODS: A total of 139 psychiatric outpatients 65 or more years of age who used zolpidem, estazolam, or flunitrazepam for at least 3 months were studied. The levels of hypnotic dependence and beliefs regarding hypnotic use (necessity and concern) were assessed. Three patterns of hypnotic misuse in the past 1 month were also explored. The correlates of high dependence, misuse, and unfavorable attitude and high concern toward hypnotic use were examined using logistic regression analyses. RESULTS: A total of 28.8%, 7.9%, 12.2%, and 22.3% of participants reported high dependence on, misuse of, unfavorable attitude toward, and high concern toward hypnotic use, respectively. Males were more likely to report unfavorable attitude toward hypnotic use than females. Elders with significant depression were more likely to report high concern toward hypnotic use than those without significant depression. Elders with high concern toward hypnotic use were more likely to report high dependence on hypnotics than those with low concern. Elders with significant depression and taking zolpidem were more likely to misuse hypnotics than those without significant depression and taking estazolam or flunitrazepam, respectively. DISCUSSION: Clinicians should monitor the possibility of dependence on and misuse of hypnotics among elderly psychiatric patients who had the correlates identified in this study. PMID- 25296386 TI - Molecular origin of the self-assembled morphological difference caused by varying the order of charged residues in short peptides. AB - In order to understand how microscopic molecular interactions between short peptides determine their mesoscopic self-assembled morphology, we studied the microscopic assembled structures of the short peptides I4K2 and KI4K, which have the same amino acid composition but different sequences, by using all-atom replica exchange molecular dynamics simulation. We found that, at room temperature, the difference in amino acid sequence does not apparently alter their strong propensity of forming beta-sheets but does strongly affect their assembled stable structures and their appearance probabilities. These differences result from the competition between the electrostatic and hydrophobic interactions among the side chains of the molecules, which are linked up by hydrogen bonds formed between neighboring peptide backbones. Our simulation results not only reveal the molecular origin of the self-assembled morphological difference between I4K2 and KI4K but also demonstrate in general the subtle balance between electrostatic, hydrophobic, and hydrogen bonding interactions in short-peptide self-assembly. PMID- 25296387 TI - The need of MMP-2 on the sperm surface for Xenopus fertilization: its role in a fast electrical block to polyspermy. AB - Monospermic fertilization in the frog, Xenopus laevis, is ensured by a fast rising, positive fertilization potential to prevent polyspermy on the fertilized egg, followed by a slow block with the formation of a fertilization envelope over the egg surface. In this paper, we found that not only the enzymatic activity of sperm matrix metalloproteinase-2 (MMP-2) was necessary for a sperm to bind and/or pass through the extracellular coat of vitelline envelope, but also the hemopexin (HPX) domain of MMP-2 on the sperm surface was involved in binding and membrane fusion between the sperm and eggs. A peptide with a partial amino acid sequence of the HPX domain caused egg activation accompanied by an increase in [Ca(2+)]i in a voltage-dependent manner, similar to that in fertilization. The membrane microdomain (MD) of unfertilized eggs bound the HPX peptide, and this was inhibited by ganglioside GM1 distributed in the MD. The treatment of sperm with GM1 or anti-MMP-2 HPX antibody allows the sperm to fertilize an egg clamped at 0 mV, which untreated sperm cannot achieve. We propose a model accounting for the mechanism of voltage-dependent fertilization based on an interaction between the positively charged HPX domain in the sperm membrane and negatively-charged GM1 in the egg plasma membrane. PMID- 25296388 TI - Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3Kalpha: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives. AB - A series of novel 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives were synthesized and evaluated for their biological activities as PI3K inhibitors. In vitro biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 4l exhibited the most potent and selective activity for PI3Kalpha, with the value of 0.014 MUM, an approximately 30-fold increase in comparison with LY294002. Docking simulation was performed to position compound 4l into the PI3Kalpha active site and the result showed that compound 4l could bind well at the PI3Kalpha active site and it indicated that compound 4l could be a potential inhibitor of PI3Kalpha. PMID- 25296390 TI - Rapid chemical reaction workup based on a rigid solvent extraction. AB - The conventional chemical reaction workup based on liquid-liquid extraction is a time- and labor-consuming practice. We have developed a substantially faster technique for the routine workup that relies on a porous organic polymer (Porelite) supported solvent phase to extract organic products from an aqueous reaction mixture. We call this process rigid solvent extraction. Using this technique, the tedious liquid-liquid extraction can be replaced by a simple filtration, making parallel operation and automation feasible. PMID- 25296389 TI - Treatment-related problems experienced by cancer patients undergoing chemotherapy: a scoping review. AB - Cancer patients undergoing chemotherapy experience a range of treatment-related problems, and variations in prevalence exist between treatment centres. A scoping review was undertaken to map reported rates of problem prevalence in the literature. This will inform development of a patient-reported outcome measure (PROM) to monitor prevalence and severity of problems over time and assist service providers optimise supportive care provision. Two databases (Embase and Medline) were searched from 2002 to 2013. Fifty one published papers and conference abstracts reporting problem prevalence rates were identified. The papers reported 98 different problems, from which a typology of 27 problem domains was developed, including both physical symptoms and psychosocial issues. The problem domains most often studied were nausea, vomiting and fatigue. This review reflects the chemotherapy-associated problems to which researchers attach the most importance. The range in reported prevalence across studies was very broad (e.g. nausea: 9-74%), with even less frequently studied problems showing high prevalence in some studies (e.g. gynaecological problems: up to 94%). The wide variation in prevalence and range of problems experienced raises challenges for PROM development. Patients should therefore be involved in consensus exercises to assist selection of items to ensure any instrument is complete and robust. PMID- 25296391 TI - Injectable scaffolds for bone regeneration. AB - Clinical treatments of significant bone defects involve invasive procedures such as the application of auto- and allografts. These procedures present many limitations including the potential for infection and rejection. There is therefore a need to develop novel therapeutic strategies able to exploit the natural regenerative potential of bone and that can be delivered in a less invasive manner. Among the materials studied for the development of novel scaffolds, stimuli-responsive gels containing hydroxyapatite and carbon nanotubes as nanofillers have generated great interest. In the present work, chitosan gels containing chitosan grafted CNTs and chitosan-hydroxyapatite complex have been formed by cross-linking with glycerol phosphate. The addition of the nanofillers afforded hydrogels with a faster sol/gel transition at 37 degrees C and enhanced mechanical properties. The thermosensitive composite gels also showed a good bioactivity profile associated with potential for the prolonged delivery of protein drugs. The inclusion of chemically cross-linked CNTs and HA in thermosensitive gels afforded injectable composite materials with enhanced properties, including reduction of gelation time, improved mechanical properties, good bioactivity, and prolonged drug release. PMID- 25296392 TI - On the participation of photoinduced N-H bond fission in aqueous adenine at 266 and 220 nm: a combined ultrafast transient electronic and vibrational absorption spectroscopy study. AB - A combination of ultrafast transient electronic absorption spectroscopy (TEAS) and transient vibrational absorption spectroscopy (TVAS) is used to investigate whether photoinduced N-H bond fission, mediated by a dissociative 1pisigma(*) state, is active in aqueous adenine (Ade) at 266 and 220 nm. In order to isolate UV/visible and IR spectral signatures of the adeninyl radical (Ade[-H]), formed as a result of N-H bond fission, TEAS and TVAS are performed on Ade in D2O under basic conditions (pD = 12.5), which forms Ade[-H](-) anions via deprotonation at the N7 or N9 sites of Ade's 7H and 9H tautomers. At 220 nm we observe one-photon detachment of an electron from Ade[-H](-), which generates solvated electrons (eaq(-)) together with Ade[-H] radicals, with clear signatures in both TEAS and TVAS. Additional wavelength dependent TEAS measurements between 240-260 nm identify a threshold of 4.9 +/- 0.1 eV (~250 nm) for this photodetachment process in D2O. Analogous TEAS experiments on aqueous Ade at pD = 7.4 generate a similar photoproduct signal together with eaq(-) after excitation at 266 and 220 nm. These eaq(-) are born from ionization of Ade, together with Ade(+) cations, which are indistinguishable from Ade[-H] radicals in TEAS. Ade(+) and Ade[-H] are found to have different signatures in TVAS and we verify that the pD = 7.4 photoproduct signal observed in TEAS following 220 nm excitation is solely due to Ade(+) cations. Based on these observations, we conclude that: (i) N-H bond fission in aqueous Ade is inactive at wavelengths >=220 nm; and (ii) if such a channel exists in aqueous solution, its threshold is strongly blue-shifted relative to the onset of the same process in gas phase 9H-Ade (<=233 nm). In addition, we extract excited state lifetimes and vibrational cooling dynamics for 9H-Ade and Ade[-H](-). In both cases, excited state lifetimes of <500 fs are identified, while vibrational cooling occurs within a time frame of 4-5 ps. In contrast, 7H Ade is confirmed to have a longer excited state lifetime of ~5-10 ps through both TEAS and TVAS. PMID- 25296393 TI - Reduced graphene oxide-silver nanoparticle composite as visible light photocatalyst for degradation of colorless endocrine disruptors. AB - Sunlight-induced degradation of organic pollutants is an ideal approach for environmental pollution control and wastewater treatment. Although a variety of photocatalysts have been designed toward this goal, efficient degradation of colorless organic pollutants by visible light is a challenging issue. Here, we show that a reduced graphene oxide (rGO)-based composite with silver nanoparticle (rGO-Ag) can act as an efficient visible-light photocatalyst for the degradation of colorless organic pollutants. We have developed a simple, large-scale synthesis method for rGO-Ag and used it for the degradation of three well-known endocrine disruptors (phenol, bisphenol A, and atrazine) under UV and visible light. It is found that photocatalytic efficiency by rGO-Ag under visible light is significantly higher compared to that of rGO or silver nanoparticles. It is proposed that Ag nanoparticles offer visible-light-induced excitation of silver plasmons, and conductive rGO offers efficient charge separation and thus induces oxidative degradation of the organic pollutant. This approach can be extended for sunlight-induced degradation of different organic pollutants. PMID- 25296394 TI - Investigating the biodegradability of a fluorotelomer-based acrylate polymer in a soil-plant microcosm by indirect and direct analysis. AB - Fluorotelomer-based acrylate polymers (FTACPs) are a class of side-chain fluorinated polymers used for a variety of commercial applications. The degradation of FTACPs through ester hydrolysis, cleavage of the polymer backbone, or both could serve as a significant source of perfluoroalkyl carboxylates (PFCAs). The biodegradation of FTACPs was evaluated in a soil-plant microcosm over 5.5 months in the absence/presence of wastewater treatment plant (WWTP) biosolids using a unique FTACP determined to be a homopolymer of 8:2 fluorotelomer acrylate (8:2 FTAC). Although structurally different from commercial FTACPs, the unique FTACP possesses 8:2 fluorotelomer side chain appendages bound to the polymer backbone via ester moieties. Liberation and subsequent biodegradation of the 8:2 fluorotelomer appendages was indirectly determined by monitoring for PFCAs of varying chain lengths (C6-C9) and known fluorotelomer intermediates by liquid chromatography tandem mass spectrometry (LC MS/MS). A FTACP biodegradation half-life range of 8-111 years was inferred from the 8:2 fluorotelomer alcohol (8:2 FTOH) equivalent of the unique FTACP and the increase of degradation products. The progress of FTACP biodegradation was also directly monitored qualitatively using matrix-assisted laser desorption/ionization (MALDI-TOF) time-of-flight mass spectrometry. The combination of indirect and direct analysis indicated that the model FTACP biodegraded predominantly to perfluorooctanoate (PFOA) in soils and at a significantly higher rate in the presence of a plant and WWTP biosolids. PMID- 25296395 TI - Transparent and robust siloxane-based hybrid lamella film as a water vapor barrier coating. AB - Water vapor barriers are important in various application fields, such as food packaging and sealants in electronic devices. Polymer/clay composites are well studied water vapor barrier materials, but their transparency and mechanical strength degrade with increasing clay loading. Herein, we demonstrate films with good water vapor barrier properties, high transparency, and mechanical/thermal stability. Water vapor barrier films were prepared by the solution crystallization of siloxane hybrid lamellae. The films consist of highly crystallized organic/inorganic hybrid lamellae, which provide high transparency, hardness, and thermal stability and inhibit the permeation of water vapor. The water permeability of a 6 MUm thick hybrid film is comparable to that of a 200 MUm thick silicon rubber film. PMID- 25296397 TI - Reduction sensitive Poly(l-glutamic acid) (PGA)-protein conjugates designed for polymer masked-unmasked protein therapy. AB - Protein therapeutics have become an important class of medicines for a large variety of diseases. However, they have disadvantages such as rapid elimination/metabolism leading to the need for repeated doses, immunogenicity/antigenicity, and aggregation/degradation during formulation and storage. The concept of polymer masked-unmasked protein therapy (PUMPT) makes use of polymer-protein multivalent conjugation with biodegradable carriers, which mask the protein activity during transport and increase its stability, but is capable of specifically triggering an unmasking effect at the disease site, allowing its therapeutic action. The aim of this study was to widen the PUMPT concept by designing reduction sensitive poly-l-glutamic acid (PGA)-based conjugates, in which the protein release and unmasking effect takes place in the reducing environments found intracellularly as well as in the tumor microenvironment. Lysozyme was used as the model protein to achieve proof of concept. Overall, the synthesized platform showed to be promising for the delivery of anticancer proteins as well as for enzyme replacement therapeutic approaches aiming to treat lysosomal storage disorders. PMID- 25296399 TI - Brooding rumination as a mediator in the relation between early maladaptive schemas and symptoms of depression and social anxiety in adolescents. AB - Theory states that different cognitive constructs can be included in an integrated sequential model. This 3-wave longitudinal study assessed whether schema domains predict brooding rumination and brooding in turn predict depression and social anxiety symptoms among adolescents. A total of 1170 adolescents (M(age) = 13.44 years old, SD(age) = 1.30) completed measures of schema domains, brooding rumination, depression and social anxiety symptoms at baseline, 6- and 12-month follow-up (T1, T2, T3, respectively). Results revealed that the Disconnection and Rejection schema domain at T1 predicted prospective depression symptoms at T3 directly but not through brooding rumination. However, this schema domain did not predict social anxiety symptoms. The Other Directedness schema domain at T1 predicted social anxiety symptoms at T3 both directly and through brooding at T2. Furthermore, this schema domain also predicted depression symptoms at T3 through brooding at T2. Identifying specific schema domains and the mechanisms through which these domains predict psychological symptoms has implications for interventions with adolescents. PMID- 25296396 TI - Nutrition and health in amphibian husbandry. AB - Amphibian biology is intricate, and there are many inter-related factors that need to be understood before establishing successful Conservation Breeding Programs (CBPs). Nutritional needs of amphibians are highly integrated with disease and their husbandry needs, and the diversity of developmental stages, natural habitats, and feeding strategies result in many different recommendations for proper care and feeding. This review identifies several areas where there is substantial room for improvement in maintaining healthy ex situ amphibian populations specifically in the areas of obtaining and utilizing natural history data for both amphibians and their dietary items, achieving more appropriate environmental parameters, understanding stress and hormone production, and promoting better physical and population health. Using a scientific or research framework to answer questions about disease, nutrition, husbandry, genetics, and endocrinology of ex situ amphibians will improve specialists' understanding of the needs of these species. In general, there is a lack of baseline data and comparative information for most basic aspects of amphibian biology as well as standardized laboratory approaches. Instituting a formalized research approach in multiple scientific disciplines will be beneficial not only to the management of current ex situ populations, but also in moving forward with future conservation and reintroduction projects. This overview of gaps in knowledge concerning ex situ amphibian care should serve as a foundation for much needed future research in these areas. PMID- 25296398 TI - An enzyme-sensitive PEG hydrogel based on aggrecan catabolism for cartilage tissue engineering. AB - A new cartilage-specific degradable hydrogel based on photoclickable thiol-ene poly(ethylene glycol) (PEG) hydrogels is presented. The hydrogel crosslinks are composed of the peptide, CRDTEGE-ARGSVIDRC, derived from the aggrecanase cleavable site in aggrecan. This new hydrogel is evaluated for use in cartilage tissue engineering by encapsulating bovine chondrocytes from different cell sources (skeletally immature (juvenile) and mature (adult) donors and adult cells stimulated with proinflammatory lipopolysaccharide (LPS)) and culturing for 12 weeks. Regardless of cell source, a twofold decrease in compressive modulus is observed by 12 weeks, but without significant hydrogel swelling indicating limited bulk degradation. For juvenile cells, a connected matrix rich in aggrecan and collagen II, but minimal collagens I and X is observed. For adult cells, less matrix, but similar quality, is deposited. Aggrecanase activity is elevated, although without accelerating bulk hydrogel degradation. LPS further decreases matrix production, but does not affect aggrecanase activity. In contrast, matrix deposition in the nondegradable hydrogels consists of aggrecan and collagens I, II, and X, indicative of hypertrophic cartilage. Lastly, no inflammatory response in chondrocytes is observed by the aggrecanase-sensitive hydrogels. Overall, it is demonstrated that this new aggrecanase-sensitive hydrogel, which is degradable by chondrocytes and promotes a hyaline-like engineered cartilage, is promising for cartilage regeneration. PMID- 25296400 TI - In vivo NMR spectroscopy: toward real time monitoring of environmental stress. PMID- 25296401 TI - EMG and kinematic responses to unexpected slips after slip training in virtual reality. AB - The objective of the study was to design a virtual reality (VR) training to induce perturbation in older adults similar to a slip and examine the effect of the training on kinematic and muscular responses in older adults. Twenty-four older adults were involved in a laboratory study and randomly assigned to two groups (VR training and control). Both groups went through three sessions including baseline slip, training, and transfer of training on slippery surface. The training group experienced 12 simulated slips using a visual perturbation induced by tilting a VR scene while walking on the treadmill and the control group completed normal walking during the training session. Kinematic, kinetic, and electromyography data were collected during all the sessions. Results demonstrated the proactive adjustments such as increased trunk flexion at heel contact after training. Reactive adjustments included reduced time to peak activations of knee flexors, reduced knee coactivation, reduced time to trunk flexion, and reduced trunk angular velocity after training. In conclusion, the study findings indicate that the VR training was able to generate a perturbation in older adults that evoked recovery reactions and such motor skill can be transferred to the actual slip trials. PMID- 25296402 TI - Uniformization method for solving cardiac electrophysiology models based on the Markov-chain formulation. AB - This paper compares different numerical methods for the solution of myocyte models of cardiac electrophysiology. In particular, it presents how the technique called uniformization method substantially increases the stability of simple first-order methods such as Euler explicit method and Rush-Larsen (RL) method, for the solution of modern electrophysiology models that are based on continuous time Markov chains (MCs) for the description of subcellular structures, such as ion channels. The MCs are often associated with stiff ordinary differential equations that severely limit the time step used by these traditional methods. By using the uniformization method, we could significantly increase the time steps for the solution of different cardiac electrophysiology models and improve the computational performance up to 150 times compared to the performance of Euler's and RL's methods. PMID- 25296403 TI - Multi-modal intra-operative navigation during distal locking of intramedullary nails. AB - The interlocking of intramedullary nails is a technically demanding procedure which involves a considerable amount of X-ray acquisitions; one study lists as many as 48 to successfully complete the procedure and fix screws into 4-6 mm distal holes of the nail. We propose to design an augmented radiolucent drill to assist surgeons in completing the distal locking procedure without any additional X-ray acquisitions. Using an augmented reality fluoroscope that coregisters optical and X-ray images, we exploit solely the optical images to detect the augmented radiolucent drill and estimate its tip position in real-time. Consequently, the surgeons will be able to maintain the down the beam positioning required to drill the screws into the nail holes successfully. To evaluate the accuracy of the proposed augmented drill, we perform a preclinical study involving six surgeons and ask them to perform distal locking on dry bone phantoms. Surgeons completed distal locking 98.3% of the time using only a single X-ray image with an average navigation time of 1.4 +/- 0.9 min per hole. PMID- 25296404 TI - Robust 3D face landmark localization based on local coordinate coding. AB - In the 3D facial animation and synthesis community, input faces are usually required to be labeled by a set of landmarks for parameterization. Because of the variations in pose, expression and resolution, automatic 3D face landmark localization remains a challenge. In this paper, a novel landmark localization approach is presented. The approach is based on local coordinate coding (LCC) and consists of two stages. In the first stage, we perform nose detection, relying on the fact that the nose shape is usually invariant under the variations in the pose, expression, and resolution. Then, we use the iterative closest points algorithm to find a 3D affine transformation that aligns the input face to a reference face. In the second stage, we perform resampling to build correspondences between the input 3D face and the training faces. Then, an LCC based localization algorithm is proposed to obtain the positions of the landmarks in the input face. Experimental results show that the proposed method is comparable to state of the art methods in terms of its robustness, flexibility, and accuracy. PMID- 25296405 TI - Ocular biometrics by score-level fusion of disparate experts. AB - The concept of periocular biometrics emerged to improve the robustness of iris recognition to degraded data. Being a relatively recent topic, most of the periocular recognition algorithms work in a holistic way and apply a feature encoding/matching strategy without considering each biological component in the periocular area. This not only augments the correlation between the components in the resulting biometric signature, but also increases the sensitivity to particular data covariates. The main novelty in this paper is to propose a periocular recognition ensemble made of two disparate components: 1) one expert analyses the iris texture and exhaustively exploits the multispectral information in visible-light data and 2) another expert parameterizes the shape of eyelids and defines a surrounding dimensionless region-of-interest, from where statistics of the eyelids, eyelashes, and skin wrinkles/furrows are encoded. Both experts work on disjoint regions of the periocular area and meet three important properties. First, they produce practically independent responses, which is behind the better performance of the ensemble when compared to the best individual recognizer. Second, they do not share particularly sensitivity to any image covariate, which accounts for augmenting the robustness against degraded data. Finally, it should be stressed that we disregard information in the periocular region that can be easily forged (e.g., shape of eyebrows), which constitutes an active anticounterfeit measure. An empirical evaluation was conducted on two public data sets (FRGC and UBIRIS.v2), and points for consistent improvements in performance of the proposed ensemble over the state-of-the-art periocular recognition algorithms. PMID- 25296406 TI - A Multi-Class Proportional Myocontrol Algorithm for Upper Limb Prosthesis Control: Validation in Real-Life Scenarios on Amputees. AB - Functional replacement of upper limbs by means of dexterous prosthetic devices remains a technological challenge. While the mechanical design of prosthetic hands has advanced rapidly, the human-machine interfacing and the control strategies needed for the activation of multiple degrees of freedom are not reliable enough for restoring hand function successfully. Machine learning methods capable of inferring the user intent from EMG signals generated by the activation of the remnant muscles are regarded as a promising solution to this problem. However, the lack of robustness of the current methods impedes their routine clinical application. In this study, we propose a novel algorithm for controlling multiple degrees of freedom sequentially, inherently proportionally and with high robustness, allowing a good level of prosthetic hand function. The control algorithm is based on the spatial linear combinations of amplitude related EMG signal features. The weighting coefficients in this combination are derived from the optimization criterion of the common spatial patterns filters which allow for maximal discriminability between movements. An important component of the study is the validation of the method which was performed on both able-bodied and amputee subjects who used physical prostheses with customized sockets and performed three standardized functional tests mimicking daily-life activities of varying difficulty. Moreover, the new method was compared in the same conditions with one clinical/industrial and one academic state-of-the-art method. The novel algorithm outperformed significantly the state of-the-art techniques in both subject groups for tests that required the activation of more than one degree of freedom. Because of the evaluation in real time control on both able-bodied subjects and final users (amputees) wearing physical prostheses, the results obtained allow for the direct extrapolation of the benefits of the proposed method for the end users. In conclusion, the method proposed and validated in real-life use scenarios, allows the practical usability of multifunctional hand prostheses in an intuitive way, with significant advantages with respect to previous systems. PMID- 25296407 TI - Force control tasks with pure haptic feedback promote short-term focused attention. AB - Focused attention has great impact on our quality of life. Our learning, social skills and even happiness are closely intertwined with our capacity for focused attention. Attention promotion is replete with examples of training-induced increases in attention capability, most of which rely on visual and auditory stimulation. Pure haptic stimulation to increase attention capability is rarely found. We show that accurate force control tasks with pure haptic feedback enhance short-term focused attention. Participants were trained by a force control task in which information from visual and auditory channels was blocked, and only haptic feedback was provided. The trainees were asked to exert a target force within a pre-defined force tolerance for a specific duration. The tolerance was adaptively modified to different levels of difficulty to elicit full participant engagement. Three attention tests showed significant changes in different aspects of focused attention in participants who had been trained as compared with those who had not, thereby illustrating the role of haptic-based sensory-motor tasks in the promotion of short-term focused attention. The findings highlight the potential value of haptic stimuli in brain plasticity and serve as a new tool to extend existing computer games for cognitive enhancement. PMID- 25296408 TI - A Methodology for the Analysis of Spontaneous Reactions in Automated Hearing Assessment. AB - Audiology is the science of hearing and auditory processes study. The evaluation of hearing capacity is commonly performed by an audiologist using an audiometer, where the patient is asked to show some kind of sign when he or she recognizes the stimulus. This evaluation becomes much more complicated when the patient suffers some type of cognitive decline that hinders the emission of visible signs of recognition. With this group of patients, a typical question-answer interaction is not applicable, so the audiologist must focus his attention on the patient's spontaneous gestural reactions. This manual evaluation entails a number of problems: it is highly subjective, difficult to determine in real time (since the expert must pay attention simultaneously to the audiological process and the patient's reactions), etc. Considering this, in this paper, we present an automatic methodology for processing video sequences recorded during the performance of the hearing test in order to assist the audiologist in the detection of these spontaneous reactions. This screening method analyzes the movements that occur within the eye area, which has been pointed out by the audiologists as the most representative for these patients. By the analysis of these movements, the system helps the audiologist to determine when a positive gestural reaction has taken place increasing the objectivity and reproducibility. PMID- 25296410 TI - A multiobjective evolutionary algorithm based on similarity for community detection from signed social networks. AB - Various types of social relationships, such as friends and foes, can be represented as signed social networks (SNs) that contain both positive and negative links. Although many community detection (CD) algorithms have been proposed, most of them were designed primarily for networks containing only positive links. Thus, it is important to design CD algorithms which can handle large-scale SNs. To this purpose, we first extend the original similarity to the signed similarity based on the social balance theory. Then, based on the signed similarity and the natural contradiction between positive and negative links, two objective functions are designed to model the problem of detecting communities in SNs as a multiobjective problem. Afterward, we propose a multiobjective evolutionary algorithm, called MEAs-SN. In MEAs-SN, to overcome the defects of direct and indirect representations for communities, a direct and indirect combined representation is designed. Attributing to this representation, MEAs-SN can switch between different representations during the evolutionary process. As a result, MEAs-SN can benefit from both representations. Moreover, owing to this representation, MEAs-SN can also detect overlapping communities directly. In the experiments, both benchmark problems and large-scale synthetic networks generated by various parameter settings are used to validate the performance of MEAs-SN. The experimental results show the effectiveness and efficacy of MEAs-SN on networks with 1000, 5000, and 10,000 nodes and also in various noisy situations. A thorough comparison is also made between MEAs-SN and three existing algorithms, and the results show that MEAs-SN outperforms other algorithms. PMID- 25296409 TI - A Visual Analytics Approach Using the Exploration of Multidimensional Feature Spaces for Content-Based Medical Image Retrieval. AB - Content-based image retrieval (CBIR) is a search technique based on the similarity of visual features and has demonstrated potential benefits for medical diagnosis, education, and research. However, clinical adoption of CBIR is partially hindered by the difference between the computed image similarity and the user's search intent, the semantic gap, with the end result that relevant images with outlier features may not be retrieved. Furthermore, most CBIR algorithms do not provide intuitive explanations as to why the retrieved images were considered similar to the query (e.g., which subset of features were similar), hence, it is difficult for users to verify if relevant images, with a small subset of outlier features, were missed. Users, therefore, resort to examining irrelevant images and there are limited opportunities to discover these "missed" images. In this paper, we propose a new approach to medical CBIR by enabling a guided visual exploration of the search space through a tool, called visual analytics for medical image retrieval (VAMIR). The visual analytics approach facilitates interactive exploration of the entire dataset using the query image as a point-of-reference. We conducted a user study and several case studies to demonstrate the capabilities of VAMIR in the retrieval of computed tomography images and multimodality positron emission tomography and computed tomography images. PMID- 25296411 TI - Metastasis mechanism and gene/protein expression in gastric cancer with distant organs metastasis. AB - Metastasis is the most fatal characteristics of malignancy tumor, which accounted for more than 90% of tumor-related mortality. Distant organ or tissue metastasis is a sign of poor prognosis in patients with gastric cancer. Tumor cells metastasis is a very complex process including tumor cell transformation, growth, angiogenesis, invasion, dissemination and survival in the circulation, and subsequent adhesion and colonization the secondary organ or tissue. The origin of tumor cell, genetic variation, the circulatory mode and the physiological structure of the metastatic organ determines the specific sites of distant metastasis. In theory, the metastatic lesion is originated from their primary tumor, so they should have the same molecular profile with the primary tumor. But this view has been confirmed to be wrong in various tumors, including gastric cancer. The gene expression of primary gastric cancer and its metastasis have differences, which may contribute to the early diagnosis and individualized treatment of metastasis. However, the heterogeneity of tumor cells is still unclear in different metastasis lesion of gastric cancer, which will be a major focus of future research. In this review, we discuss the basic principles of cancer metastasis, the unique physiological characteristics of the various metastasis organs and the expression of different functions of gene/protein in primary and metastasis of gastric cancer. In addition, we also discuss the diagnosis, prognosis and treatment in various organ metastasis of gastric cancer. PMID- 25296412 TI - [FRancilian Oncogeriatric Group (FROG)'s focus on management of elderly patients with bladder cancer]. AB - Bladder cancer is diagnosed more often in the elderly. The most effective treatment strategies are mostly very aggressive and are not applicable to all patients in a very heterogeneous population. However, effective options exist to treat the most vulnerable subjects. A multidisciplinary approach including a geriatric assessment is essential for optimal adaptation of treatment. The FRancilian Oncogeriatric Group (FROG) conducted a comprehensive literature search in order to review the applicable therapeutic options according to oncological and geriatric settings. International recommendations are essential to harmonize the management of elderly patients with bladder cancer. PMID- 25296413 TI - [Current indications of allogeneic stem cell transplant in adults with acute myeloid leukemia]. AB - Allogeneic stem cell transplantation (SCT) is an increasingly important therapeutic option for the treatment of adult patients with acute myeloid leukemia. Here we review the current indications of SCT in this disease. While patients with favorable cytogenetics should receive consolidation chemotherapy, patients with unfavorable karyotype are prime candidates for SCT or new approaches to SCT (which should be done in first complete remission). Patients with intermediate prognoses should also receive SCT in first complete remission. In the absence of a suitable matched related donor, most patients will be able to find an alternative donor to proceed to a potentially curative allogeneic transplantation. The use of reduced-intensity conditioning regimens before SCT has allowed patients in the sixth or seventh decades of life to be routinely transplanted. Despite major differences among transplant centers in the intensity and composition of the conditioning regimen and immunosuppression, choice of graft source, postgraft immune-modulation, and supportive care, there has been a dramatic improvement in terms of tolerance. Although it is presumed to be a curative strategy, major complications of SCT remain graft-versus-host disease, delayed immune recovery, multiple comorbidities, and relapse after transplant. PMID- 25296415 TI - Mammalian transient receptor potential (TRP) cation channels. Preface. PMID- 25296414 TI - [Radiation-induces increased tumor cell aggressiveness of tumors of the glioblastomas?]. AB - Glioblastoma multiform is the most common and aggressive brain tumor with a worse prognostic. Ionizing radiation is a cornerstone in the treatment of glioblastome with chemo-radiation association being the actual standard. As a paradoxal effect, it has been suggested that radiotherapy could have a deleterious effect on local recurrence of cancer. In vivo studies have studied the effect of radiotherapy on biological modification and pathogenous effect of cancer cells. It seems that ionizing radiations with photon could activate oncogenic pathways in glioblastoma cell lines. We realized a review of the literature of photon enhanced effect on invasion and migration of glioblastoma cells by radiotherapy. PMID- 25296416 TI - Albrecht Scholz (1940-2013): German dermatologist and historian of dermatology. AB - Albrecht Scholz (Figure 1) was born in Gorlitz (now Zgorzelec, a city located at the Polish-German border, covering both sides of the River Nysa) on September 6, 1940, the youngest of three children. His father was a laryngologist, specializing in voice and hearing impairment. Scholz attended school in his hometown and in 1958 passed his Matura examination, after which he studied medicine at both Humboldt University in Berlin and the "Carl Gustav Carus" Medical Academy in Dresden. Following successful completion of the state examination in 1964 and an internship at the Reichenbach Hospital the following year, he was granted the right to practice medicine. His 1964 doctoral dissertation was titled, "Evaluation of Astrand's Steps in Elderly Patients." PMID- 25296417 TI - [Global eradication of dracunculiasis is a reality nowadays]. AB - Global efforts to eradicate dracunculiasis have continued to progress with only 542 cases reported in 2012 versus almost 1 million cases in the 1980s when the initiative was launched. The disease is still endemic, but in only four countries: South Sudan (541 cases), Chad (10 cases), Mali (4 cases), and Ethiopia (4 cases). The International Commission for the Certification of Dracunculiasis Eradication declared that 180 countries were free of the disease by 2013. Dracunculiasis was first eradicated in the former USSR in 1931 when its last case was registered due to the successful implementation of a package of appropriate measures (case detection and management, vector control, and health education, including water filtration from open water sources and behavioral changes). These approaches were actively taken into account when developing the global strategy for dracunculiasis. The World Health Organization has set a goal to eradicate the disease by 2015. However, despite the fact that the global situation looks very optimistic, the time for completing the program will be most likely postponed due to a few operational challenges remaining in the still endemic countries, in South Sudan in particular. PMID- 25296418 TI - [Extraenteric infection caused by Blastocystis spp. in a female patient with liver abscess]. AB - The cases associated with the development of liver abscesses in a 64-year-old female patient after elective surgery for colon polyposis could form an opinion that extraenteric infection caused by Blastocystis spp. might develop in the immunocompromised host. The development of Blastocystis spp. in the presence of disintegrated liver tissue and inflammatory cells was verified by microscopic examination of liver abscess aspirates. The Romanovsky-Giemsa stained specimens exhibited typical amoeboid, vacuolar and, what is particularly important, dividing forms of Blastocystis spp. The patients full recovery after timely combination therapy with broad-spectrum antibiotics and imidazole group preparations also indirectly argues for the etiological role of Blastocystis spp. in the development of liver abscess with the signs of changes in both lungs (the signs of right lung compression and bilateral hydrothorax). Physicians' awareness of the potential clinical significance of Blastocystis spp. in immunodeficient patients is sure to expand the range of differential diagnostic studies of patients infected with Blastocystis spp.. particularly in case of gastrointestinal tract diseases of unknown etiology. PMID- 25296419 TI - [Serological verification of tick-borne encephalitis cases in the Altai Republic]. AB - Serologic testing of Lyme disease, human granulocytic anaplasmosis and human monocytotopic ehrlichiosis, showed the prevalence of these infections and the risk of mixed infection. The patients with tick-borne encephalitis were found to have its monoinfection and mixed infection in 66.1% and 33.9% of cases, respectively. PMID- 25296420 TI - [Human dirofilariasis: clinical and diagnostic signs and diagnostic methods]. AB - The clinical and diagnostic signs caused by the tissue location and migration of adult Dirofilaria in the human body determine the use of different methods for the diagnosis of dirofilariasis. During their investigations, the authors modified polymerase chain reaction (PCR): they chose and synthesized primers and selected amplification regimens for them and obtained agarose gel bands that corresponded to PCR fragment length nucleotide sequences that were equal to 245 bp for D. (N.) repens and 656 bp for D. immitis. There was 100% agreement in the results of PCR and microscopic examination of sera from 32 dogs and 1 female patient with low parasitemia and in the blood nucleotide sequence characteristic of D. repens. PMID- 25296421 TI - [The diphyllobotriasis epidemiological situation in the Baikal Region]. PMID- 25296422 TI - [Ethological competence of Perm Territory dwellers in the assurance of personal infection safety]. AB - The authors attempted to analyze preventive measures against infectious and parasitic diseases, which were used domestically by the Perm Territory population, their conjugacy with the stereotypes of attitude towards domestic animals, as well as behavioral features of compliance andcompetence in the assurance of infection safety. The found gaps in the assurance of personal infection safety (drinking unboiled water, unprotected sex, disregard of helminth prevention in domestic animals, and unwillingness to go in for sports) are coherent with the epidemiological situation in the Perm Territory and to our clinical and laboratory study of the patients of the Perm Territory Children's Clinical Hospital in 2011. Enzyme immunoassay (EIA) was used to examine 10075 patients for helminths and protozoa; parasitic diseases were detected in 2047 (20.3%) persons. The diagnostic titer of antibodies to Toxocara antigens was revealed in 677 (11.8%) children of 5700 patients examined for toxocariasis; that for Opisthorchis antigens was in 595 (37.7%) of 1578 examined for Opisthorchis infestation. The diagnostic titers for echinococcosis was found in 9 (0.75%) of 1198 patients; later on the diagnosis of hydatid disease was verified by epidemiological, clinical, and laboratory studies. Despite the inadequate informative value of EIA for the diagnosis of giardiasis, high antibody titers to Lamblia antigens were detected in 766 (47.9%) of 1599 children. PMID- 25296423 TI - [Diagnostic value of determination of the blood concentrations of serotonin and high-sensitivity C-reactive protein in patients with tick-borne encephalitis]. AB - The paper shows the informative value of changes in the serum levels of serotonin and high-sensitivity C-reactive protein in 44 patients in the acute period of tickborne encephalitis. Group 1 included 35 patients with non-paralytic neuroinfection; Group 2 comprised 9 patients with paralytic neuroinfection. The serum level of high-sensitivity C-reactive protein increased and that of serotonin decreased in relation to the form and severity of the disease at its height. The elevated level of the former and the low concentration of the latter may serve as an early predictor of the development of a severe paralytic form. Investigating their serum concentrations should be included into an examination plan for patients with acute tick-borne encephalitis. PMID- 25296424 TI - [The species and karyotype composition of malaria mosquito larvae in different water reservoirs of the city of Moscow]. AB - The species and karyotype composition of malaria mosquito larvae was investigated in different water reservoirs of the city of Moscow. Cytogenetic analysis identified 2 malaria mosquito species: An. maculipennis Mg and An. messeae Fall. An. messeae was predominant in all the biotopes studied. The proportion of An. maculipennis varied from 0 to 23.8% and averaged 6.27%. An. messeae larvae were found to have chromosomal polymorphism. Individual local An. messeae populations having a definite, historically established, time and space resistant karyotype structure were shown to form in Moscow. The resistance of the karyotype structure of the populations was provided by reversible fluctuations in the rate of chromosomal inversions. PMID- 25296425 TI - [The patterns of immune and behavioral disorders in Toxoplasma gondii antigen sensitized rat posterity in the postnatal period]. PMID- 25296426 TI - [Peculicidal activity of plant essential oils and their based preparations]. AB - The peculicidal activity of eight plant essential oils in 75% isopropyl alcohol was in vitro investigated. Of them, the substances that were most active against lice were tea tree (Melaleuca), eucalyptus, neem, citronella (Cymbopogon nardus), and clove (Syzygium aromaticum) oils; KT50 was not more than 3 minutes on average; KT95 was 4 minutes. After evaporating the solvent, only five (tea tree, cassia, clove, anise (Anisum vulgare), and Japanese star anise (Illicium anisatum) oils) of the eight test botanical substances were active against lice. At the same time, KT50 and KT95 showed 1.5-5-fold increases. Citronella and anise oils had incomplete ovicidal activity. Since the lice were permethrin-resistant, the efficacy of preparations based on essential oils was much higher than permethrin. PMID- 25296427 TI - [Efficacy of nocodazole et experimental invasion Echinococcus granulosus of white mice]. AB - The therapeutic activity of subcutaneous and intraperitoneal nocodazole injections was studied in albino mice with experimental E. granulosus invasion. The animals were intraperitoneally infected with Echinococcus larval cysts (ELC) from a spontaneously inoculated sheep. Nocodazole aqueous suspension (NAS) was administered at the late stage of invasion in two experiments. In one experiment, the treatment was initiated 7.5 months after inoculation. The animals were given daily subcutaneous injections of gradually increasing daily doses (n = 32) from 5 to 20 mg/kg twice weekly for 4 months (the total active ingredient dose was 400 mg/kg). The mice were dissected 3 months after treatment termination. Their autopsy showed that all ELCs or their vast majority were dead in 17 (70.8%) of 24 NAS-treated mice. Among the completely cured mice, there were animals having dead ELCs amounting to 36.9% of the host's weight. In the other experiment, the mice received intraperitoneal treatment 11.5 months after inoculation. They were given NAS injections (n = 2-8) in the total active ingredient dose of 14-126 mg/kg for 4-32 days. The animals were dissected 12-14 months after inoculation. All the detected ELCs were ascertained to be dead in the mice that had received NAS in an active ingredient dose of 87-126 mg/kg and had been dissected 33-81 days after initiation of treatment. The damaging effect of NAS was accompanied by obvious ELC collapse (the ELC collapse index was 57.5-75.9% for all the cured animals). PMID- 25296428 TI - [Antihelminthic efficacy and therapeutic doses of the Russian innovation anthelmintic nadinate against moniesiasis and nematodiasis in sheep]. PMID- 25296429 TI - [Academician Petr Grigoryevich Sergiev (on the occasion of the 120th anniversary of his birth)]. PMID- 25296430 TI - [Leading figures of Russian medical parasitology]. PMID- 25296431 TI - [Study of helminthiasis caused by nematodes of the suborder Ascaridata]. PMID- 25296432 TI - [Neglected tropical diseases: a New World Health Organization program]. PMID- 25296433 TI - The intersectionality of postsecondary pathways: the case of high school students with special education needs. AB - Using data from the Toronto District School Board, we examine the postsecondary pathways of students with special education needs (SEN). We consider both university and college pathways, employing multilevel multinomial logistic regressions, conceptualizing our findings within a life course and intersectionality framework. Our findings reveal that having SEN reduces the likelihood of confirming university, but increases the likelihood of college confirmation. We examine a set of known determinants of postsecondary education (PSE) pathways that were derived from the literature and employ exploratory statistical interactions to examine if the intersection of various traits differentially impacts upon the PSE trajectories of students with SEN. Our findings reveal that parental education, neighborhood wealth, race, and streaming impact on the postsecondary pathways of students with SEN in Toronto. PMID- 25296434 TI - Social and political convergence on environmental events: the roles of simplicity and visuality in the BP Oil Spill. AB - This paper examines how and when newspapers, environmental nongovernmental organizations, businesses, and the government converge on environmental events. Using data on the 2010 BP Oil Spill from newspaper articles in the United States, Canada, and the United Kingdom, press releases by Greenpeace and Sierra Club, press releases by BP, Halliburton, Transocean, ExxonMobil, and Shell, and press statements by the White House Press Secretary, we examine an event's potential to trigger convergence of social and political action. By treating events as political actants, we examine arguments from the agenda-setting and social movement literatures on timing, simplicity, and visuality to understand when political actors converge. We find that convergence is related to temporal cycles but not simplicity or visuality. PMID- 25296435 TI - Assessing variation in tolerance in 23 Muslim-majority and Western countries. AB - Scholars disagree over whether Islam hinders the development of liberal democracy in Muslim-majority countries. We contribute to this debate by assessing the influence of Islam at the individual and national levels on ethnic, racial, and religious tolerance in 23 countries. Our analyses are based on a set of multilevel models fitted to World Values Survey data and national-level contextual information from various sources. Our findings suggest that people living in Muslim-majority countries tend to be less tolerant than are those living in Western countries. Although a significant part of this difference is attributable to variation in level of economic development and income inequality, Muslim countries remain less tolerant even after controlling for these factors. On the other hand, controlling for other individual-level factors, nonpracticing Muslims in Western countries are more tolerant than are all others in both Muslim majority and Western countries. This finding challenges common claims about the effects of Islam as a religion on tolerance, suggesting that it is Islamic political regimes--not Islam itself--that pose problems for social tolerance. PMID- 25296436 TI - Diversity in midwifery care: working toward social justice. AB - As midwifery moved from lay practice to a regulated health-care profession in Ontario toward the end of the twentieth century, it brought with it many of its social movement goals and aspirations. Among these was the desire to attend to diversity and equity in the provision of birthing care. Drawing on interviews with currently practicing Ontario midwives, this paper focuses on midwives' conceptualizations of diversity and explores their everyday work to support and strengthen diversity among those using and those providing midwifery care. We argue that midwifery's recent relocation within state structured health care means neither that the social change projects of midwifery are complete nor that midwifery has abandoned its movement-based commitment to social change. Responses to social diversity in health care range from efforts to simply improve access to care to analyses of the role of social justice in recognizing the needs of diverse populations. The social justice aspiration to "create a better world" continues to animate the work of midwives postregulation. This paper explores the legacy of midwifery as a social movement, addressing the connections between diversity, social justice and midwifery care. PMID- 25296437 TI - Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. PMID- 25296438 TI - A colorful history: the evolution of indigoids. PMID- 25296439 TI - Bioactive heterocyclic natural products from actinomycetes having effects on cancer-related signaling pathways. PMID- 25296440 TI - Genome mining: concept and strategies for natural product discovery. PMID- 25296441 TI - A polyphasic approach to study the dynamics of microbial population of an organic wheat sourdough during its conversion to gluten-free sourdough. AB - To develop a method for organic gluten-free (GF) sourdough bread production, a long-term and original wheat sourdough was refreshed with GF flours. The dynamics of the sourdough microbiota during five months of back-slopping were analyzed by classical enumeration and molecular methods, including PCR-temporal temperature gel electrophoresis (PCR-TTGE), multiplex PCR, and pulsed field gel electrophoresis (PFGE). The results showed that the yeast counts remained constant, although Saccharomyces cerevisiae, present in the initial wheat sourdough, was no longer detected in the GF sourdough, while lactic acid bacteria (LAB) counts increased consistently. In the first phase, which was aimed at obtaining a GF sourdough from wheat sourdough, Lactobacillus sanfranciscensis, L. plantarum, and L. spicheri were the main LAB species detected. During the second phase, aimed at maintaining the GF sourdough, the L. plantarum and L. spicheri populations decreased whereas L. sanfranciscensis persisted and L. sakei became the predominant species. Multiplex PCRs also revealed the presence of several L. sakei strains in the GF sourdough. In a search for the origin of the LAB species, PCR-TTGE was performed on the flour samples but only L. sanfranciscensis was detected, suggesting a flour origin for this typical sourdough species. Thus, while replacement of the wheat flour by GF flour influenced the sourdough microbiota, some of the original sourdough LAB and yeast species remained in the GF sourdough. PMID- 25296442 TI - Relating the outcome of HCV infection and different host SNP polymorphisms in a Majorcan population coinfected with HCV-HIV and treated with pegIFN-RBV. AB - Hepatitis C virus (HCV) is one of the major causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and the development of HCV-related disease is accelerated in individuals coinfected with human immunodeficiency-1 virus (HIV). In the present study, we correlated different host single-nucleotide polymorphisms (SNPs) in the IL28B, CTLA4, LDLr, and HFE genes and mitochondrial DNA (mtDNA) haplogroups with the outcome of HCV infection and the response to pegylated-interferon plus ribavirin (pegIFN-RBV) treatment. Our study population consisted of 63 Majorcan patients coinfected with HCV and HIV and 59 anonymous unrelated controls. Whereas the population frequency of IL28B alleles was similar to that found in a North-American cohort of European descent, the frequency of the rs12979860 C allele was lower than that determined in other cohorts from Spain. The frequencies of CTLA4 and LDLr polymorphisms were comparable to those reported in other populations. Significant differences between cases and control cohorts occurred only for the H63D mutation of the HFE gene. There were no other differences in the frequencies of other polymorphisms or mtDNA haplogroups. The IL28B rs12979860 CC genotype was shown to be associated with a rapid virological response, and the spontaneous viral clearance rate for HCV was higher in patients with the CTLA4+49 G allele. There was no relationship between SNPs in the LDLr and HFE genes and mtDNA haplogroups and the response to treatment. Our results suggest that the host genetic background plays a significant role in the pegIFN RBV response of patients coinfected with HCV and HIV. PMID- 25296443 TI - Identification of superficial Candida albicans germ tube antigens in a rabbit model of disseminated candidiasis. A proteomic approach. AB - The diagnosis of invasive candidiasis remains a clinical challenge. The detection by indirect immunofluorescence of Candida albicans germ-tube-specific antibodies (CAGTA), directed against germ-tube surface antigens, is a useful diagnostic tool that discriminates between colonization and invasion. However, the standardization of this technique is complicated by its reliance on subjective interpretation. In this study, the antigenic recognition pattern of CAGTA throughout experimental invasive candidiasis in a rabbit animal model was determined by means of 2D-PAGE, Western blotting, and tandem mass spectrometry (MS/MS). Seven proteins detected by CAGTA were identified as methionine synthase, inositol-3-phosphate synthase, enolase 1, alcohol dehydrogenase 1,3 phosphoglycerate kinase, 14-3-3 (Bmhl), and Egd2. To our knowledge, this is the first report of antibodies reacting with Bmhl and Egd2 proteins in an animal model of invasive candidiasis. Although all of the antigens were recognized by CAGTA in cell-wall dithiothreitol extracts of both germ tubes and blastospores of C. albicans, immunoelectron microscopy study revealed their differential location, as the antigens were exposed on the germ-tube cell-wall surface but hidden in the inner layers of the blastospore cell wall. These findings will contribute to developing more sensitive diagnostic methods that enable the earlier detection of invasive candidiasis. PMID- 25296444 TI - Local ciliate communities associated with aquatic macrophytes. AB - This study, based within the catchment area of the River Frome, an important chalk stream in the south of England, compared ciliated protozoan communities associated with three species of aquatic macrophyte common to lotic habitats: Ranunculus penicillatus subsp. pseudofluitans, Nasturtium officinale and Sparganium emersum. A total of 77 ciliate species were counted. No species specific ciliate assemblage was found to be typical of any one plant species. Ciliate abundance between plant species was determined to be significantly different. The ciliate communities from each plant species were unique in that the number of species increased with ciliate abundance. The community associated with R. penicillatus subsp. pseudofluitans showed the highest consistency and species richness whereas S. emersum ciliate communities were unstable. Most notably, N. officinale was associated with low ciliate abundances and an apparent reduction in biofilm formation, discussed herein in relation to the plant's production of the microbial toxin phenethyl isothiocyanate. We propose that the results reflect differences in the quantity and quality of biofilm present on the plants, which could be determined by the different plant morphologies, patterns of plant decay and herbivore defense systems, all of which suppress or promote the various conditions for biofilm growth. PMID- 25296445 TI - Screening, isolation, and characterization of glycosyl-hydrolase-producing fungi from desert halophyte plants. AB - Fungal strains naturally occurring on the wood and leaves of the salt-excreting desert tree Tamarix were isolated and characterized for their ability to produce cellulose- and starch-degrading enzymes. Of the 100 isolates, six fungal species were identified by ITS1 sequence analysis. No significant differences were observed among taxa isolated from wood samples of different Tamarix species, while highly salt-tolerant forms related to the genus Scopulariopsis (an anamorphic ascomycete) occurred only on the phylloplane of T. aphylla. All strains had cellulase and amylase activities, but the production of these enzymes was highest in strain D, a Schizophyllum-commune-related form. This strain, when grown on pretreated Tamarix biomass, produced an enzymatic complex containing levels of filter paperase (414 +/- 16 IU/ml) that were higher than those of other S. commune strains. The enzyme complex was used to hydrolyze different lignocellulosic substrates, resulting in a saccharification rate ofpretreated milk thistle (73.5 +/- 1.2%) that was only 10% lower than that obtained with commercial cellulases. Our results support the use of Tamarix biomass as a useful source of cellulolytic and amylolytic fungi and as a good feedstock for the economical production of commercially relevant cellulases and amylases. PMID- 25296446 TI - Tetracycline-resistance encoding plasmids from Paenibacillus larvae, the causal agent of American foulbrood disease, isolated from commercial honeys. AB - Paenibacillus larvae, the causal agent of American foulbrood disease in honeybees, acquires tetracycline-resistance via native plasmids carrying known tetracycline-resistance determinants. From three P. larvae tetracycline-resistant strains isolated from honeys, 5-kb-circular plasmids with almost identical sequences, designated pPL373 in strain PL373, pPL374 in strain PL374, and pPL395 in strain PL395, were isolated. These plasmids were highly similar (99%) to small tetracycline-encoding plasmids (pMA67, pBHS24, pBSDMV46A, pDMV2, pSU1, pAST4, and pLS55) that replicate by the rolling circle mechanism. Nucleotide sequences comparisons showed that pPL373, pPL374, and pPL395 mainly differed from the previously reported P. larvae plasmid pMA67 in the oriT region and mob genes. These differences suggest alternative mobilization and/or conjugation capacities. Plasmids pPL373, pPL374, and pPL395 were individually transferred by electroporation and stably maintained in tetracycline-susceptible P. larvae NRRL B-14154, in which they autonomously replicated. The presence of nearly identical plasmids in five different genera of gram-positive bacteria, i.e., Bhargavaea, Bacillus, Lactobacillus, Paenibacillus, and Sporosarcina, inhabiting diverse ecological niches provides further evidence of the genetic transfer of tetracycline resistance among environmental bacteria from soils, food, and marine habitats and from pathogenic bacteria such as P. larvae. PMID- 25296447 TI - Calcium and phosphorus concentrations in native and decellularized semilunar valve tissues. AB - BACKGROUND AND AIM OF THE STUDY: Native, allograft, xenograft and bioprosthetic semilunar valves are all susceptible to calcific degeneration. However, intrinsic differences in baseline calcium and phosphorus tissue concentrations within mammalian normal valve structural components (e.g., cusps, sinus, vessel wall) additionally subdivided by tripartite regions (e.g., right-, left- and non coronary leaflets) have never been systematically measured and reported. It was originally hypothesized that variations in normative tissue concentrations of calcium and phosphorus may correspond to subsequent clinical patterns of acquired dystrophic calcification; decellularization was also expected to reduce the tissue concentrations of these elements. METHODS: Native semilunar valves were freshly harvested from 12 juvenile sheep. Half of the valves were decellularized (six aortic and six pulmonary), while the other valves were flash-frozen at -80 degrees C within minutes of euthanasia as native valves. Elemental calcium and phosphorus concentrations were measured in the great vessels, sinus walls and cusps using inductively coupled plasma optical emission spectrometry (ICP-OES), and analyzed with non-parametric statistical tests. RESULTS: Calcium concentrations (microg/mg tissue; median (range) were similar in aortic native cusps (0.37 (0.21)), sinus walls (0.37 (0.09)) and aorta (0.37 (0.08)) (p = 0.8298). Pulmonary calcium concentrations were similar in cusps, but 10-25% higher in the native sinus (p = 0.0018) and pulmonary artery (p < 0.0001) compared to analogous aortic structures. All cusps had higher phosphorus concentrations than their respective conduit tissues. No tripartite regional variations were observed. Decellularization did not reduce the calcium content of cusps, but removed 50-55% of vessel and sinus wall calcium. However, up to 85% of phosphorus was removed from all valve tissues (p < 0.001). CONCLUSION: There were no significant differences in normal tissue concentrations of calcium between aortic valve functional structures, and no semilunar tripartite regional differences in either semilunar valve complex. Thus, the distribution of baseline tissue calcium content of healthy young valves is not inherently predictive of selective or asymmetric anatomical patterns of valve degenerative calcification. Native semilunar cusps contain the highest phosphorus concentrations. Decellularization reduces all elemental concentrations except for cuspal calcium. PMID- 25296448 TI - Quantification of low-gradient severe aortic stenosis using a hybrid approach combining Doppler echocardiography and thermodilution. AB - BACKGROUND AND AIM OF THE STUDY: Estimation of stroke volume in the left ventricular outflow tract (LVOT) is a main limitation to aortic valve area (AVA) calculation by echocardiography when using the continuity equation. In this study, the hypothesis was tested that a hybrid method using thermodilution derived cardiac output measurement and simultaneous Doppler estimation of the systolic ejection period and transvalvular aortic velocities could be used to accurately assess AVA in patients with low-gradient severe aortic stenosis (AS). METHODS: Eighteen patients with low mean gradient (< 40 mmHg) and nine patients with conventionally defined (> or = 40 mmHg) severe AS (< 1 cm2), as assessed by the echocardiographic continuity equation (baseline echocardiography), underwent catheterization and simultaneous Doppler recording of trans-aortic velocities. RESULTS: The mean pressure gradient was slightly lower by Doppler in the catheterization laboratory (35.8 +/-15.7 mmHg) compared to baseline echocardiography (37.4 +/- 15.2 mmHg) and invasive (38.5 +/- 16.6 mmHg) measurements (both p < 0.05). The AVA values were 0.72 +/- 0.12 cm2 during baseline echocardiography, 0.74 +/- 0.14 cm2 by catheterization, and 0.71 +/- 0.14 cm2 by the hybrid method (bias -0.01 +/- 0.11 cm2 and -0.02 +/- 0.08 cm2, versus echocardiography and catheterization, respectively; both p = NS). CONCLUSION: The hybrid method is reasonably accurate in assessing AVA in patients with low-gradient severe AS. Although the continuity equation should be used in routine clinical practice in most patients, this method could serve as an alternative when the LVOT diameter and/or velocities seem questionable. PMID- 25296449 TI - Relationship between left ventricular diastolic function and arterial stiffness in patients with bicuspid aortic valve. AB - BACKGROUND AND AIM OF THE STUDY: Bicuspid aortic valve (BAV), one of the most common congenital cardiac abnormalities, is the result of abnormal aortic leaflet formation during valvulogenesis. Recent studies have reported BAV to be associated with abnormal aortic stiffness, which has a negative impact on left ventricular (LV) diastolic function. The study aim was to investigate the relationship between LV diastolic function, as measured with two-dimensional speckle tracking echocardiography (2D-STE), and arterial stiffness. METHODS: A total of 38 patients with isolated BAV, and 18 age- and gender-matched healthy controls were enrolled prospectively. Patients with aortic valve velocity > 1.7 m/s, more than mild aortic regurgitation (AR) and ascending aorta diameter > 3.6 cm (indexed diameter > 2.1 cm/m2) were excluded. BAV was classified as either anterior-posterior (AP) orientation or right-left (RL) orientation. The LV diastolic function (E/A and E/Em ratio), left atrial (LA) volume index (LAVI), LA systolic strain and strain rate (SR) was assessed using echocardiography. Strain measurements were reported as longitudinal LA strain during ventricular systole (LA-Res), strain during late diastole (LA-Pump), and also as SR during ventricular contraction (LA-SR(s)), during passive ventricular filling (LA SR(E)), and during active atrial contraction (LA-SR(A)) from four-chamber views. Arterial stiffness was evaluated by measuring the aortic pulse wave velocity (PWV), wave reflection was assessed by measuring the central systolic blood pressure (cSBP), central pulse pressure (cPP) and augmentation index (AIx) with applanation tonometry. RESULTS: The aortic diameter at the proximal ascending aorta was larger in patients with BAV than in controls. Compared to controls, the E/Em ratio and LAVI were significantly higher in BAV patients. Although PWV was higher in BAV patients than in controls, no differences were found between the groups in terms of cSBP, cPP and AIx. The BAV group was observed to have significant lower LA-Res and LA-Pump strain values compared to controls. Significant correlations were identified between the PWV and echocardiographic parameters of LV diastolic function determinants, such as LA-Res and LA-Pump. However, there were no significant differences between BAV subgroups in terms of LV diastolic parameters and PWV. CONCLUSION: Patients with isolated BAV have early features of subclinical LV diastolic dysfunction, as measured with 2D-STE. In addition, aortic stiffness assessed by PWV was impaired. The LV diastolic parameters were related to aortic stiffness. PMID- 25296450 TI - Repositioning of an intraventricular dislocated aortic valve during transcatheter aortic valve implantation. AB - The case is presented of a 75-year-old man referred for transcatheter aortic valve implantation. During the procedure the prosthetic aortic valve became dislocated into the left ventricle shortly after expansion. The subsequent steps taken to reposition the valve using only materials at hand are described. PMID- 25296452 TI - Mitral valvuloplasty: when the art of repair meets the biological science. AB - The majority of approaches currently described and practiced in mitral repair surgery result in the vertical immobilization of the posterior leaflet, with the anterior leaflet striving to produce an adequate coaptation. Despite the satisfactory hemodynamic outcome and disappearance of mitral regurgitation, this non-physiological situation results in a redistribution of forces within the mitral apparatus with an increased stress on the leaflets. Biological evidences are pointing at the ability of the valvular interstitial cells to actively respond to biomechanical changes, switching their phenotype and producing different patterns of extracellular matrix proteins. This biological event translates to changes in the anatomical and mechanical properties of the leaflets, leading to an increased stiffening and a susceptibility to develop calcification. These concepts find a clinical reflex in reports on the long-term thickening and calcification of the leaflets after mitral repair, and in the leaflets remodeling phenomena described in chronically dilated ventricles. The importance of respecting the physiological movement and dynamics of the leaflets when performing a valvuloplasty is underlined, and a potential pharmacological modulation of the aforementioned biological processes to ameliorate long-term results of the repair is hypothesized. PMID- 25296451 TI - Valve-sparing aortic root replacement in patients with Marfan syndrome enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. AB - BACKGROUND AND AIM OF THE STUDY: The long-term outcomes of aortic valve-sparing (AVS) root replacement in Marfan syndrome (MFS) patients remain uncertain. The study aim was to determine the utilization and outcomes of AVS root replacement in MFS patients enrolled in the Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). METHODS: At the time of this analysis, 788 patients with MFS were enrolled in the GenTAC Registry, of whom 288 had undergone aortic root replacement. Patients who had undergone AVS procedures were compared to those who had undergone aortic valve replacement (AVR). RESULTS: AVS root replacement was performed in 43.5% of MFS patients, and the frequency of AVS was increased over the past five years. AVS patients were younger at the time of surgery (31.0 versus 36.3 years, p = 0.006) and more likely to have had elective rather than emergency surgery compared to AVR patients, in whom aortic valve dysfunction and aortic dissection was the more likely primary indication for surgery. After a mean follow up of 6.2 +/- 3.6 years, none of the 87 AVS patients had required reoperation; in contrast, after a mean follow up of 10.5 +/ 7.6 years, 11.5% of AVR patients required aortic root reoperation. Aortic valve function has been durable, with 95.8% of AVS patients having aortic insufficiency that was graded as mild or less. CONCLUSION: AVS root replacement is performed commonly among the MFS population, and the durability of the aortic repair and aortic valve function have been excellent to date. These results justify a continued use of the procedure in an elective setting. The GenTAC Registry will be a useful resource to assess the long-term durability of AVS root replacement in the future. PMID- 25296453 TI - Mid-term results of mitral valve repair with autologous pericardium in pediatric patients. AB - BACKGROUND AND AIM OF THE STUDY: Mitral valve repair to treat mitral regurgitation (MR) in pediatric patients remains challenging because of the complex morphology and fragility of the leaflets. The study aim was to review retrospectively the authors' experience with mitral valve repair using autologous pericardium. METHODS: Between April 2004 and November 2011, nine pediatric patients (six males, three females; mean age 2.4 +/- 4.5 years) underwent mitral valve repair with an autologous fresh (n = 5) or glutaraldehyde-treated pericardium (n = 4) to treat severe MR. The etiology of the MR was acute endocarditis, acute chordal rupture and congenital disease in three, two, and four patients, respectively. Autologous pericardium was used for valvuloplasty, leaflet extension plasty and commissuroplasty in two, five, and two patients, respectively. Artificial chordal replacement was performed in three patients. RESULTS: No operative deaths or postoperative endocarditis occurred. One patient required mitral valve replacement at three days after the initial mitral repair. The most recent echocardiography findings of the remaining patients after a mean of 6.3 years (range: 1.3-9.0 years) showed that the severity of mitral insufficiency, left ventricular diastolic diameter and fractional shortening were 1.8 +/- 0.6 (grades 0-4), 40.4 +/- 8.4 mm (114.2 +/- 15.8% of normal) and 35.0 +/ 5.0%, respectively. CONCLUSION: Mitral valve repair using autologous fresh pericardium is associated with mid-term durability and resistance to infection when used for mitral valve repair of active endocarditis in pediatric patients. Augmentation with autologous pericardium could become an alternative to current surgical options. PMID- 25296454 TI - Mitral valve regurgitation after atrial septal defect repair in adults. AB - BACKGROUND AND AIM OF THE STUDY: Mitral valve regurgitation (MR) is known to deteriorate following adult atrial septal defect (ASD) repair in the mid to long term. The study aim was to identify the risk factors for this deterioration. METHODS: Between 1995 and 2011, a total of 93 consecutive patients (aged > or = 18 years) underwent ASD repair at the authors' institution. Patients who underwent concomitant procedures, other than tricuspid annuloplasty or maze procedure, were excluded; hence, 74 patients were enrolled in the study. MR was evaluated by transthoracic echocardiography shortly after surgery and subsequently on a regular basis in the outpatient clinic. Risk factors for the deterioration of MR were estimated using Cox proportional hazards regression. RESULTS: The mean patient age at surgery was 48.0 +/- 17.1 years, and 20 patients (27%) had atrial fibrillation (AF) preoperatively. The mean follow up was 6.9 +/- 5.5 years. The degree of MR was not unchanged or not improved in 54 patients (73.0%) (group 1), but was increased by one grade in 12 patients (16.2%) (group 2), and by two or more grades in eight patients (10.8%) (group 3). At surgery, all patients in group 3 were aged > 50 years. In group 3, on echocardiography, the average end-diastolic left ventricular dimension was increased from 41.8 mm to 51.8 mm (p = 0.027), and enlargement of the mitral annulus was noted in seven patients. Four of the group 3 patients required reoperation for MR after ASD repair. The Cox proportional hazards model revealed preoperative AF (p = 0.045, hazard ratio (HR): 11.68, 95% confidence interval (95% CI): 1.05-129.48) and Qp/Qs > or = 2.8 (p = 0.015, HR: 9.19, 95% CI :1.53-55.04) to be independent risk factors of new-onset or aggravated MR (by two or more grades) after ASD repair. CONCLUSION: An earlier repair of ASD would be preferable in terms of MR aggravated after ASD repair. For elderly patients with a preoperative high Qp/Qs and AF, mitral valve annuloplasty with ASD repair should considered. PMID- 25296455 TI - Textile heart valve: first in-vivo experiment in the aortic position. AB - Non-invasive aortic valve implantation has become an alternative technique to surgical valve replacement in patients at high risk for open-chest surgery. With over 100,000 procedures already performed clinically, the technology is expected to involve less-critical patients in future. Whereas, biological valve tissue is a fragile material when folded for low-diameter catheter insertion purposes, textile polyester is a less-fragile material and may offer an alternative material to replace valve leaflets. One issue related to textile is the porosity of the material, which may induce exaggerated tissue ingrowth. Today, data relating to interactions between living tissues and fabrics used as valve materials are available only in the mitral position. Hence, the study aim was to observe the interaction pattern when the valve is implanted in the aortic position, and to assess the influence of sinus whirls on this pattern. PMID- 25296456 TI - Postoperative conduction disorders after implantation of the self-expandable sutureless Perceval S bioprosthesis. AB - BACKGROUND AND AIM OF THE STUDY: Minimally invasive techniques for aortic valve replacement (AVR) have been developed as an alternative to conventional AVR for patients with high operative risk. Yet, these techniques are still associated with an increased risk of postoperative conduction disorders. The study aim was to identify the incidence and fate of postoperative conduction disorders in patients undergoing sutureless (SU) AVR with the Perceval S bioprosthesis. METHODS: In this observational study, patients who underwent SU AVR with the Perceval S prosthesis at the Catharina Hospital, Eindhoven, were analyzed. Electrocardiograms (ECGs) recorded at baseline, within 24 h postoperatively, before hospital discharge and at follow up were collected by reviewing patients' records. The ECGs were analyzed by two independent investigators to record QRS duration and conduction disorders. RESULTS: All patients (n = 31) who underwent implantation of the Perceval S bioprosthesis between September 2010 and September 2012 were included. At baseline, three patients (9.7%) had preexisting left bundle branch block (LBBB), and one patient (3.2%) had a permanent pacemaker (PPM). New-onset LBBB developed in 11 patients (39.3%), and was transient in three patients (10.7%). Postoperatively, four patients (13.3%) required PPM implantation because of total atrioventricular block; all of these patients had either pre-existing LBBB (n = 1) or new LBBB (n = 3). CONCLUSION: Sutureless AVR with the Perceval S bioprosthesis was frequently complicated by new LBBB, which was persistent in the majority of patients. A relatively high incidence of postoperative PPM implantation was also observed. PMID- 25296457 TI - Early in-vivo hemodynamic comparison of supra-annular aortic bioprostheses: Trifecta versus Perimount Magna Ease. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to compare early postoperative hemodynamic gradients after supra-annular implantation of the Trifecta and Perimount Magna Ease aortic bioprostheses. METHODS: Between January 2010 and December 2011, a total of 235 patients (105 males, 130 females; mean age at surgery 73.8 +/- 10.2 years) underwent supra-annular aortic valve replacement (AVR), with or without concomitant procedures. The patients were divided into 2 groups receiving either the Perimount Magna Ease (n = 117) or Trifecta (n = 118). Concomitant procedures were performed in 133 patients (56.6%), and 25 procedures (10.6%) were redos. Patients with postoperative severe left ventricular dysfunction and moderate to severe mitral regurgitation were excluded. Gradients were calculated pre-discharge using transthoracic echocardiography. Effective orifice area calculations were not performed. Data were collected retrospectively from hospital databases and analyzed using SPSS 17. RESULTS: Both groups compared well for 14 variables. Group A had a higher number of redo operations and the patients were younger. Postoperative peak and mean gradients (in mmHg) for the Magna Ease group versus Trifecta group were: 19 mm valves, 33.5 +/- 16 versus 24.7 +/- 10 (p = 0.11) and 17.4 +/- 6.5 versus 12.7 +/- 4.4 (p = 0.05); 21 mm, 27.2 +/- 9.1 versus 21.8 +/- 7.2 (p = 0.001) and 13.8 +/- 4.7 versus 10.7 +/- 3.4 (p = 0.001); 23 mm, 25.6 +/- 7.8 versus 20.1 +/- 7.9 (p = 0.005) and 13 +/- 4 versus 10.1 +/- 4.3 (p = 0.002); 25 mm, 22.3 +/- 7.8 versus 15.6 +/- 5.1 (p = 0.01) and 12.8 +/- 4.1 versus 8 +/- 2.8 (p = 0.02). The overall mortality was 3.4%. The median hospital stay was nine days in both groups (p = 0.13). Mortality (p = 0.5), and incidences of perioperative stroke (p = 0.45), postoperative new onset atrial fibrillation (p = 0.26) and permanent pacemaker implantation (p = 0.8) were similar in both groups. CONCLUSION: Early postoperative gradients were significantly lower in patients receiving Trifecta valves, although the long-term clinical outcome and durability of the valve will require further evaluation. PMID- 25296458 TI - Excellent mid-term durability of the On-X mechanical aortic valve in the pulmonary position with a low international normalized ratio. AB - BACKGROUND AND AIM OF THE STUDY: Although the pulmonary position has been preferred for the placement of homografts or bioprosthetic valves, the limited longevity of these implants makes reoperation almost unavoidable. Good durability of mechanical valves in the pulmonary position has been reported. The mid-term outcomes were analyzed of patients who received an On-X mechanical heart valve for pulmonary valve replacement (PVR) with a relatively low International Normalized Ratio (INR). METHODS: Between February 2008 and February 2011, mechanical On-X valves (size range: 19 to 25 mm) were implanted for PVR in six patients. Tetralogy of Fallot (ToF) was the most common diagnosis (n = 6). Postoperatively, warfarin was used to maintain the INR at 1.5-2.0. The surgical results and follow up were reviewed retrospectively, with valve failure, thrombosis, embolism, bleeding, reoperation and death being defined as end points. RESULTS: There was no intraoperative or in-hospital mortality. The mean age of patients at the time of PVR was 31 +/- 19.7 years (range: 16-61 years). In patients who underwent repair of ToF (n = 4) the average duration between PVR and previous right ventricular outflow tract (RVOT) reconstruction was 8.75 +/- 3.3 years (range: 5-12 years). The mean follow up period was 3.13 +/- 1.31 years (range: 2-5 years). There was no 30-day mortality, late death, thromboembolism, major bleeding event or valve dysfunction, and no patient needed reoperation. All survivors were categorized as NYHA class I or II. CONCLUSION: A three-year experience with the On-X bileaflet mechanical valve in the pulmonary position demonstrated excellent mid-term durability, with no thromboembolisms or bleeding events when the INR was maintained at 1.5-2.0. For patients who require PVR, either as primary procedure or reoperation, the On-X mechanical heart valve might represent an appropriate option. PMID- 25296459 TI - A single-center experience with the Sorin Mitroflow pericardial aortic valve: hemodynamics up to five years. AB - BACKGROUND AND AIM OF THE STUDY: The authors' institution participated in a 28 center FDA Investigational Device Exemption study to evaluate the Sorin Mitroflow pericardial aortic bioprosthesis. Six high-enrolling sites evaluated patients on an annual basis as part of an ongoing hemodynamic study. These data represent patients followed for an average of five years after implant, with annual echocardiography. METHODS: Seventy-one patients were entered into the study and constitute the basis of this review. Mean follow up was 3.3 +/- 2.0 years (range: 0-5.5 years), with a cumulative follow up of 233 patient-years. The mean patient age was 73.8 years (range: 45-89 years), and 52% were males. The majority of aortic valve lesions were stenosis (63%) or mixed (30%), and nine patients (12.7%) were reoperations. Sixty-one patients (86%) had concomitant procedures, the most common being coronary artery bypass grafting (70%). RESULTS: A total of 281 echocardiograms was obtained from the patients over a five-year period. The largest number of echocardiograms was obtained with 23-mm valve implants (n = 122), followed by 25 mm valve implants (n = 87). The early baseline (30-day) mean gradient was < or = 10 mm in all patients. The mean gradient decreased as the valve size increased (21 mm valve gradient = 10.0 +/- 5.6 mmHg; 27 mm valve gradient = 6.2 +/- 2.2 mmHg). The mean increase in gradient at five years was < 7 mmHg, with a trend towards increased gradients at smaller valve sizes. The effective orifice area (EOA) showed a trend to decline slightly with 21 mm valves (from 1.5 to 1.2 cm2) and 23 mm valves (1.4 to 1.2 cm2), but there was either no change or a slight increase in larger-size valves. Left ventricular mass regression occurred mainly within the first year (18.9%), but then remained stable throughout the study period. No greater than mild prosthetic aortic valve regurgitation was observed over the study period. CONCLUSION: The Sorin Mitroflow aortic valve provides excellent hemodynamic results up to five years, with minimal increase in mean gradients, acceptable peak gradients, and good EOAs with all valves sizes. PMID- 25296460 TI - Right anterior minithoracotomy versus median sternotomy surgery for native mitral valve infective endocarditis. AB - BACKGROUND AND AIM OF THE STUDY: While concomitant medical and surgical therapy has improved the treatment of infective endocarditis (IE), mortality and postoperative complications remain high. A minimally invasive approach to mitral valve surgery has been associated with decreased morbidity and mortality in high risk populations. The study aim was to analyze the feasibility of a minimally invasive approach to valve surgery for native mitral valve IE. METHODS: All heart operations performed between January 2008 and April 2013 at the authors' institution were reviewed retrospectively. The operative times, intensive care unit (ICU) and hospital lengths of stay, postoperative complications, and in hospital mortality of patients who underwent minimally invasive surgery via a right anterior minithoracotomy for native mitral valve IE were compared to those of a cohort which underwent median sternotomy. A Kaplan-Meier analysis was performed to compare long-term survival between the cohorts. RESULTS: A total of 50 patients was identified (22 minithoracotomy, 28 median sternotomy). The baseline characteristics, mitral valve pathology and disease burden (annular abscess, cusp perforation, vegetation size, chordal rupture) were similar between the groups. There was no difference in the rate of active versus healed disease. Patients who underwent a minithoracotomy had fewer postoperative composite complications (41% versus 75%, p = 0.02), mainly driven by a decreased incidence of sepsis (0% versus 21%, p = 0.02), as well as less use of intraoperative blood products (59% versus 93%, p = 0.004), higher rates of mitral valve repair (55% versus 25%, p = 0.03), and a shorter ICU length of stay (56 versus 114 h, p = 0.009). Repair of the mitral valve was associated with a decreased risk of postoperative composite complications (OR 0.16, 95% CI 0.04-0.71, p = 0.02). At 2.5 years postoperatively, survival was estimated at 80% and 68% in the minithoracotomy and median sternotomy groups, respectively (p = 0.33). CONCLUSION: A right anterior minithoracotomy approach for native mitral valve IE provides a safe and feasible alternative to conventional median sternotomy surgery, with improved outcomes conferred by valve repair compared to replacement. PMID- 25296461 TI - Role of mitral valve repair in infective endocarditis. AB - BACKGROUND AND AIM OF THE STUDY: Mitral valve reconstruction (MVP) is currently the standard treatment for degenerative mitral regurgitation (MR). However, when MR is due to infective endocarditis (IE) the range of pathophysiology present often makes any repair challenging. Hence, the authors' clinical experience of MVP to treat MR caused by IE was analyzed. METHODS: Between September 2004 and March 2011, a total of 26 patients (20 males, six females) who had been diagnosed with MR due to IE (single surgeon, retrospective review) were operated on. Among the 26 patients (17 active, nine healed; six Carpentier type I, 20 Carpentier type II), MVP was performed in 11 patients (42.3%), of which six were active cases and five were healed. All MVP procedures included ring annuloplasty. A variety of repair techniques was used, including triangular resection (n = 3), pericardial patch reconstruction (n = 4), commissuroplasty (n = 4), artificial chordoplasty (n = 1), chordae transfer (n = 2), and secondary chordae resection (n = 1). Six of 17 patients who had a pathology favorable for repair underwent valve replacement; the etiologies were underlying valvular disease (n = 2, rheumatic pathology), Child's group C liver cirrhosis (n = 1), second redo sternotomy (n = 1), multivalvular disease (n = 1), and critical medical condition (n = 1, septic shock). RESULTS: The mean follow up duration was 35.7 months (range: 0.1-84.9 months). Among the repair group, none of the patients showed residual MR on postoperative echocardiography. There were no early or late deaths, and no patient showed newly developed MR during the follow up. Among the replacement group, three patients died of noncardiac causes during the follow up (two early deaths and one late death). CONCLUSION: MVP for MR due to IE showed successful clinical outcomes. Valve replacement was performed in some patients with a repair-favorable pathology, after taking into consideration any comorbidities. Whilst standard repair techniques were sufficient, careful decision-making was the key to achieving excellent results for MVP. PMID- 25296462 TI - Pulmonary homograft endocarditis and aortic autograft failure after Ross procedure: a double stentless bioprosthesis approach. AB - The case is reported of a 38-year-old male patient with pulmonary homograft acute infective endocarditis and aortic root dilation that occurred 13 years after a Ross procedure for bicuspid aortic valve regurgitation. Aortic and pulmonary root replacements were performed, using a Freestyle stentless aortic root bioprosthesis in both cases, with excellent hemodynamics on postoperative echocardiography. In addition, preoperative systemic septic embolization had occurred despite an absence of left-sided endocarditis, presumably due to an intrapulmonary shunt. This case report demonstrates the feasibility of a double stentless bioprosthesis approach, and stresses the need to remain vigilant for septic embolization even in isolated right-sided endocarditis. PMID- 25296463 TI - Six-year outcomes after non-resective mitral valve repair with artificial chordae using removable clips. AB - BACKGROUND AND AIM OF THE STUDY: The results were evaluated of a non-resective technique for mitral valve repair with artificial chordae implantation that allows modification of the length of the chordae as many times as necessary, and avoids inadvertent alteration of chordal length during fixation by using removable clips. METHODS: After having determined the length of the artificial chordae, a removable clip was tied on the two thread ends to prevent sliding when performing the competence test. The length of the artificial chordae could be modified by opening the clip and closing it elsewhere along the chordae length. When the competence test was satisfactory, the threads were knotted on the clips. Long-term follow up was completed between January and May 2012, by echocardiography plus consultation with a cardiologist at the authors' institution. RESULTS: A total of 47 patients underwent repair with this technique. Follow up was complete at a median of 6.0 years. There were no in hospital deaths, but four deaths occurred during the follow up period (8.5%). The survival rate at six years was 91.5 +/- 2.1%. One patient (2.1%) had recurrent mitral regurgitation (MR) and required reoperation within two years after the initial surgery. The event-free survival rate, defined as survival free from death, reoperation or cardiovascular adverse events, was 87.2 +/- 5.2% at six years. At the time of follow up, echocardiography identified a fully competent valve or minimal MR in 45 patients (96%), mild MR in one patient (2.1%), and significant MR in one patient (2.1%). CONCLUSION: A satisfactory six-year outcome is reported for this method, whereby removable clips were used to determine the correct length of the artificial chordae, and for accurate tying of the knots. PMID- 25296464 TI - An alternative intraoperative method based on annular circumference for the decision-making of prophylactic tricuspid annuloplasty. AB - BACKGROUND AND AIM OF THE STUDY: Tricuspid valve exploration during surgery plays an important role in the decision-making of concomitant tricuspid annuloplasty at the time of left-sided valve surgery. However, at present a good standard to define tricuspid annular dilatation is not available. The study aim was to introduce an alternative method based on annular circumference to judge the extent of annular dilatation, and investigate its predictive ability for the postoperative progression of tricuspid regurgitation (TR). METHODS: A total of 127 patients with non-significant TR who underwent isolated left-sided valve surgery at the authors' institution between October 2010 and October 2011 were enrolled prospectively in the study. Intraoperative measurements of the tricuspid annular circumference (TAC) were made for each patient and adjusted to the patient's body surface area to give the TAC index (TACI). The primary end-point was defined as the progression of TR by more than two grades, or a final TR grade > or = 3+ at follow up echocardiography. RESULTS: The mean follow up period was 30.2 months (range: 24-37 months). Three variables were found to be associated with postoperative TR progression, including atrial fibrillation, left atrial diameter, and the intraoperatively measured TACI (p = -0.1 in univariate analysis). However, on multiple regression analysis only the TACI (OR 1.586; 95% CI 1.303-1.929; p < 0.001) was significantly associated with TR progression. Based on the receiver-operator characteristic curve, it was possible to derive an optimal cut-off value (83 mm/m2) to predict the postoperative development of TR with higher sensitivity and specificity. CONCLUSION: Among a patient population with predominantly rheumatic left-sided valve disease, the tricuspid annular circumference, when assessed with special sizers, proved to be an ideal method to judge if the annulus would dilate, or not, during surgery. A deduced TACI threshold of 83 mm/m2 was recommended as an indication for prophylactic tricuspid repair. PMID- 25296465 TI - Human pulmonary autograft wall stress at systemic pressures prior to remodeling after the Ross procedure. AB - BACKGROUND AND AIM OF THE STUDY: Remodeling of the pulmonary autograft upon exposure to systemic pressure can lead to progressive dilatation and aneurysmal pathology. Remodeling is driven by changes in autograft wall stress upon exposure to systemic pressure; however, the magnitude of these changes is unknown. Previously, a porcine autograft finite element model was developed to determine wall stress, but the porcine and human material properties differed significantly. Hence, the study aim was to understand human pulmonary autograft biomechanics that lead to remodeling by determining wall stress magnitudes immediately after the Ross procedure using finite element analysis (FEA). METHODS: Human pulmonary root was scanned by high-resolution microcomputed tomography to construct a realistic three-dimensional geometric mesh. Stress strain data from biaxial stretch testing was incorporated into an Ogden hyperelastic model to describe autograft mechanical properties for an adult Ross patient. Autograft dilatation and wall stress distribution during pulmonic and systemic pressures prior to remodeling were determined using explicit FEA in LS DYNA. RESULTS: Human pulmonary autograft demonstrated non-linear material properties, being highly compliant in the low-strain region, and stiffening at high strain. The majority of dilatation occurred with < 20 mmHg pressurization. From pulmonary to systemic pressures, the increases in autograft diameter were up to 17%. Likewise, the maximal wall stress increased approximately 14.6-fold compared to diastolic pressures (from 13.0 to 190.1kPa), and six-fold compared to systolic pressures (from 48.6 to 289.6kPa). CONCLUSION: The first finite element model of the human pulmonary autograft was developed and used to demonstrate how autograft material properties prevent significant dilatation upon initial exposure to systemic pressure. Mild dilatation was noted in the sinuses and sinotubular junction. Autograft wall stress was increased greatly when subjected to systemic pressures, and may trigger biomechanical remodeling of the autograft. Sustained exposure to higher wall stresses, coupled with inadequate remodeling, may lead to future autograft dilatation. PMID- 25296466 TI - Does left atrial enlargement contribute to mitral leaflet tethering in patients with functional mitral regurgitation? Proposed role of atriogenic leaflet tethering. PMID- 25296467 TI - [Unrest within the Universities]. PMID- 25296468 TI - [Treatment of periodontitis in cases of diabetes mellitus is always worthwhile!]. AB - In the May edition of The Nederlands Tijdschrift voor Tandheelkunde the editorial commentary was devoted to the question to what extent the treatment of periodontitis in patients with diabetes mellitus is worthwhile. B.G. Loos, W.J. Teeuw, V. Gerdes and F. Abbas offer a response to this commentary and argue that the treatment of periodontitis in patients with diabetes mellitus is always worthwhile. PMID- 25296469 TI - [A patient with an acute naso-labial swelling]. AB - A patient presented herself with a painful swelling in the left nostril and next to the nose. It appeared to be a rarely occurring naso-labial cyst. This has to do with a developmental disorder resulting from a persistent embryonic glandular duct epithelium. The cyst was drained under local anaesthetic and was removed 3 months later, under general anaesthetics, by an oral and maxillofacial surgeon and an ENT-specialist working together. PMID- 25296470 TI - [Solitary median maxillary central incisor syndrome]. AB - Solitary Median Maxillary Central Incisor syndrome is a rare condition (prevalence 1:50,000), with the characteristic dental feature of a solitary central incisor in the maxilla, positioned exactly in the midline. This single incisor is symmetrical and can be present in the deciduous as well as in the permanent dentition. The syndrome can occur as a mild form of the broad holoprosencephaly-spectrum, but can also be associated with other characteristics. The etiology is still largely unknown, but the syndrome is probably based especially on genetic causes. Early recognition of the syndrome is of great importance for establishing the diagnosis, for additional investigation, for possible treatment of associated anomalies and for the correct advice concerning the risk of inheritance of severe congenital birth defects, related to holoprosencephaly. Dentists and orthodontists can play an important role in this regard and should therefore be able to recognise the clinical features of this condition and know how to refer a patient for further diagnostic counselling. PMID- 25296471 TI - [Psychological aspects of orthognathic surgery]. AB - Corrective jaw surgery, for patients with malocclusion and dysgnathia, is primarily performed to rehabilitate oral functions. However, the patients' motivation for orthognathic surgery often seems to be influenced as well by the desire for aesthetic correction of a facial anomaly. Preoperative screening for psychiatric problems such as body dysmorphic disorder is requisite. The majority of orthognathic patients experience a negative influence of their appearance on their psychosocial well-being. In addition, the hope for aesthetic improvement is not seldom an important incentive for visiting an oral and maxillofacial surgeon. In the literature, in addition to a positive effect of corrective jaw surgery on the patient's perceived appearance, an associated improvement in quality of life is described. Correction of a disharmonious face is at least as important to patients as oral function recovery. PMID- 25296472 TI - [Dentistry and healthcare legislation 11. The dentist and the civil law judge: claims]. AB - In contrast to the law governing complaints and to disciplinary law, a civil law judge can sentence dentists to the restoration of all damages to patients. For this to happen, there has to be evidence of damage, responsibility and a causal connection. For the assumption of responsibility as well as a causal connection, an important question is whether a dentist has violated a relevant guideline or protocol. Moreover, dentists are not only responsible for their own mistakes, but also, in principle, for those of their employees. Depending on the situation, dentists can also be held accountable for the mistakes of a dentist who is working in their practice on a self-employed basis. Dutch dentists do not yet have to fear American situations', because damages awarded in The Netherlands are still relatively low. PMID- 25296473 TI - Divided multimodal attention sensory trace and context coding strategies in spatially congruent auditory and visual presentation. AB - Previous research involving both unimodal and multimodal studies suggests that single-response change detection is a capacity-free process while a discriminatory up or down identification is capacity-limited. The trace/context model assumes that this reflects different memory strategies rather than inherent differences between identification and detection. To perform such tasks, one of two strategies is used, a sensory trace or a context coding strategy, and if one is blocked, people will automatically use the other. A drawback to most preceding studies is that stimuli are presented at separate locations, creating the possibility of a spatial confound, which invites alternative interpretations of the results. We describe a series of experiments, investigating divided multimodal attention, without the spatial confound. The results challenge the trace/context model. Our critical experiment involved a gap before a change in volume and brightness, which according to the trace/context model blocks the sensory trace strategy, simultaneously with a roaming pedestal, which should block the context coding strategy. The results clearly show that people can use strategies other than sensory trace and context coding in the tasks and conditions of these experiments, necessitating changes to the trace/context model. PMID- 25296474 TI - Perception of tactile graphics: embossings versus cutouts. AB - Graphical information, such as illustrations, graphs, and diagrams, are an essential complement to text for conveying knowledge about the world. Although graphics can be communicated well via the visual modality, conveying this information via touch has proven to be challenging. The lack of easily comprehensible tactile graphics poses a problem for the blind. In this paper, we advance a hypothesis for the limited effectiveness of tactile graphics. The hypothesis contends that conventional graphics that rely upon embossings on two dimensional surfaces do not allow the deployment of tactile exploratory procedures that are crucial for assessing global shape. Besides potentially accounting for some of the shortcomings of current approaches, this hypothesis also serves a prescriptive purpose by suggesting a different strategy for conveying graphical information via touch, one based on cutouts. We describe experiments demonstrating the greater effectiveness of this approach for conveying shape and identity information. These results hold the potential for creating more comprehensible tactile drawings for the visually impaired while also providing insights into shape estimation processes in the tactile modality. PMID- 25296475 TI - Retinotopy of facial expression adaptation. AB - The face aftereffect (FAE; the illusion of faces after adaptation to a face) has been reported to occur without retinal overlap between adaptor and test, but recent studies revealed that the FAE is not constant across all test locations, which suggests that the FAE is also retinotopic. However, it remains unclear whether the characteristic of the retinotopy of the FAE for one facial aspect is the same as that of the FAE for another facial aspect. In the research reported here, an examination of the retinotopy of the FAE for facial expression indicated that the facial expression aftereffect occurs without retinal overlap between adaptor and test, and depends on the retinal distance between them. Furthermore, the results indicate that, although dependence of the FAE on adaptation-test distance is similar between facial expression and facial identity, the FAE for facial identity is larger than that for facial expression when a test face is presented in the opposite hemifield. On the basis of these results, I discuss adaptation mechanisms underlying facial expression processing and facial identity processing for the retinotopy of the FAE. PMID- 25296476 TI - Dissociating effects of movement preparation and spatial attention on visual processing: evidence from event-related potentials. AB - The present study investigated whether effects of movement preparation and visual spatial attention on visual processing can be dissociated. Movement preparation and visual spatial attention were manipulated orthogonally in a dual-task design. Ten participants covertly prepared unimanual lateral arm movements to one hemifield, while attending to visual stimuli presented either in the same or in the hemifield opposite to the movement goal. Event-related potentials to task irrelevant visual stimuli were analysed. Both joint and distinct modulations of visual ERPs by visual spatial attention and movement preparation were observed: The latencies of all analysed peaks (P1, N1, P2) were shorter for matching (in terms of direction of attention and movement) versus non-matching sensory-motor conditions. The P1 amplitude, as well, depended on the sensory-motor matching: The P1 was larger for non-matching compared to matching conditions. By contrast, the N1 amplitude showed additive effects of sensory attention and movement preparation: with attention and movement preparation directed towards the visual stimulus the N1 was largest, with both directed opposite to the stimulus the N1 was smallest. P2 amplitudes, instead, were only modulated by sensory attention. The present data show that movement preparation and sensory spatial attention are tightly linked and interrelated, showing joint modulations throughout stimulus processing. At the same time, however, our data argue against the idea of identity of the two systems. Instead, sensory spatial attention and movement preparation seem to be processed at least partially independently, though still exerting a combined influence on visual stimulus processing. PMID- 25296477 TI - The role of the parietal cortex in multisensory and response integration: evidence from transcranial direct current stimulation (tDCS). AB - The question of how the brain forms unified representations from multisensory data that are processed in distinct cortical regions is known in the literature as 'the binding problem'. In the last decade, several studies have suggested possible neural mechanisms and brain regions that might be involved in integration processes. One of the brain regions that is implicated with multisensory perception is the posterior parietal cortex (PPC). Evidence from patients with parietal lesions suggests the involvement of the PPC in coherent perception. Here, we investigated the role of the PPC in multisensory feature integration through experimental manipulation of non-invasive brain stimulation with healthy participants using transcranial direct current stimulation (tDCS). In different sessions, healthy participants received anodal, cathodal, or sham stimulation (2 mA, 20 min) over the right PPC while performing an audio-visual event-file task. The results underscore two interesting observations. Firstly, there was a significant difference in integration effects between features from different modalities in the anodal stimulation compared to sham, suggesting interference of the multisensory integration processes during the brain stimulation. And secondly, after anodal stimulation, the unattended feature became more likely to be integrated with the response feature compared to the other conditions, presumably through an interference of attentional processes. Hence, these findings emphasize the role of the right PPC in multisensory integration. Furthermore, from a methodological perspective, tDCS can be used as an experimental tool by creating a temporary, reversible disruption in cognitive processes in order to explore the mechanisms underlying cognitive functions. PMID- 25296478 TI - JCN articles hit home. PMID- 25296479 TI - Valued tool. PMID- 25296480 TI - Forgiveness gives freedom. PMID- 25296481 TI - When hope is lost: Part 2. PMID- 25296482 TI - Insights. PMID- 25296483 TI - God can use us! PMID- 25296484 TI - Noncompliant patients ... and healthcare systems. PMID- 25296485 TI - Advance directives education: a critical need. AB - Despite increasing age, most older Americans do not have Advance Health Care Directives (AHCDs) while healthcare providers report limited knowledge for teaching about AHCDs. This article offers a history of AHCDs, explores one method for assessing AHCD knowledge using the Knowledge-Attitudinal-Experimental Survey on Advance Directives (KAESAD), and utilizes adult learning theory to develop an AHCD educational in-service for nurses. AHCD information and resources are provided. PMID- 25296486 TI - Faith community nursing: Supporting Healthy People 2020 initiatives. AB - One innovative community-based setting to promote health is the faith community, where care is provided by a faith community nurse (FCN). This descriptive study describes the practice of FCNs, FCN functions and standards, identifies Healthy People 220 Leading Health Indicators being addressed by FCNs, and explores how the FCN model of community-based practice can support implementation of Healthy People 2020. PMID- 25296487 TI - Discovering determinants influencing faith community nursing practice. AB - Faith community nursing (FCN) is an important healthcare delivery system for individuals, families, and communities. Determinants are factors that might influence FCN care. A literature review isolated eight determinants that influence practice; however, there are no clear causal relationships linking specific determinants to specific practice changes. Research is needed to assess how determinants influence practice and outcomes, and provide evidence-based solutions to isolate and manage determinants. A Conceptual Model of FCN, Theoretical Definitions and a Diagram of Determinants of FCN Practice are provided. PMID- 25296488 TI - Palliative Care Doula: an innovative model. AB - Walking the journey of serious illness is very difficult and stressful for patients and families. A universal principle of palliative care is caring for the patient/ family unit. This article introduces a model for the Palliative Care Doula for experienced and advanced practice palliative care nurses to support patients and families during the traumatic and vulnerable period of end-of-life care. PMID- 25296489 TI - Nursing students' perceptions of adoption: educational preparation needed. AB - Adoption is a worldwide practice; most know someone who has been adopted, has adopted a child, or has relinquished a child for adoption. Healthcare professionals will have contact with patients who have a connection to adoption. This study examined the overall perceptions, current knowledge, and gaps in a nursing curriculum as reported by undergraduate nursing students and offers insight into caring for those impacted by adoption. PMID- 25296490 TI - I choose health (Elijo Salud: impacting youth through parish nursing. AB - The 2009-2010 National Health and Nutritional Examination Survey (NHANES) found that 34% of adolescents are overweight and 18% obese. The chance of an overweight/obese adolescent becoming an overweight/obese adult by age 35 is 60%. Hispanic youth are at risk for becoming obese related to eating habits. This paper describes an intervention, I Choose Health (Elijo Salud), with Hispanic church youth. PMID- 25296491 TI - Classroom to clinic: incorporating adolescent spiritual/faith assessment into nurse practitioner education & practice. AB - Although nursing is well grounded in the conceptualization of person as body-mind spirit, there is little evidence that advanced practice nurses routinely address the spirit in giving patient care, especially with adolescents in the outpatient setting. The neglect of spiritual aspects of care may be related to lack of a framework, or education/incorporation into nurse practitioner preparation. This article describes one method of integrating adolescent spiritual/faith assessment into a nurse practitioner clinical course. Readings, assignments, and a grading rubric are offered. PMID- 25296492 TI - Is spiritual care impacted by joy? PMID- 25296493 TI - West sub lassies: deep relationships fueled faith. PMID- 25296494 TI - Facing the giant--tenure! PMID- 25296495 TI - Temptations after a medication error. PMID- 25296496 TI - Amyloid beta lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity. AB - Obesity arising due to the dietary and life style changes is fast reaching epidemic proportions all over the world. There is increasing evidence that the incidence of Alzheimer disease (AD) is significantly influenced by a cluster of metabolic diseases, including diabetes and obesity. This study was aimed to test the suitability of experimentally-induced obesity in rats as an experimental animal model of AD. We used the procedure of neonatal administration of rats with monosodium L-glutamate (MSG), which generates adult obese animals as our study design and assessed the AD-like changes by measuring amyloid beta (1-42) and acetylcholinesterase (AChE) levels in the hippocampal extracts and cognitive impairments by Barnes maze task. Further, we investigated the influence of anti obesity substance [D-Lys (3)] GHRP-6 on blood glucose, hippocampal Abeta, AChE levels and restoration of cognitive deficits. Results revealed that administration of MSG to neonatal rats exhibited increased body mass index and serum glucose levels over the controls. Measurement of markers for AD-like molecular changes i.e. amyloid beta (Abeta) and AChE levels showed marked elevation in these two parameters in the hippocampus of MSG-treated rats. Assessment of cognitive abilities by Barnes maze revealed spatial disorientation characteristic of AD. Administration of ghrelin receptor analog [D-Lys (3)] GHRP 6 to obese rats resulted in significant restoration of serum cholesterol, glucose, leptin and ghrelin levels to that of control with concomitant reduction in hippocampal Abeta and AChE levels. In addition, the treated animals exhibited marked improvement in Barne's maze task. These findings suggest that MSG-induced obese rats may serve as non-transgenic animal model for AD research. Further, the results indicate the potential of [D-Lys (3)] GHRP-6 as a promising anti Alzheimer candidate. PMID- 25296497 TI - Increased activity of goat liver plasma membrane alkaline phosphatase upon release by phosphatidylinositol-specific phospholipase C. AB - Mammalian alkaline phosphatase (ALP) is attached to the plasma membrane by a unique glycosylphosphatidylinositol (GPI) anchor. The influence of such a complex anchoring device on the enzyme function is not fully understood. Here, we report the effect of cleavage of the GPI anchor on the activity of goat liver plasma membrane ALP (GLPM-ALP). Phosphatidylinositol-specific phospholipase C (PI-PLC) purified from Bacillus cereus was used for the cleavage of the GPI anchor (delipidation) and hence for release of ALP from the membrane. Detergents--octyl beta-D-glucopyranoside (OG) and triton X100 (TX100) were also used for solubilization of ALP from the membrane. Resistance to solubilization by TX100 suggested the association of GPI-ALP with lipid rafts. Solubilization of GLPM-ALP with OG had no effect on the enzyme activity; however, delipidation with PI-PLC resulted in enhanced ALP activity. Kinetic analysis showed catalytic activation of PI-PLC-treated GLPM-ALP with an increase in V(max) (35%) without a significant change in K(m). Moreover, this change in Vmax was observed to be independent of pH and buffer. The results suggested the implication of GPI anchor in modulating the catalytic property of GLPM-ALP, thus indicating the role of this special anchoring structure in the enzyme regulation. PMID- 25296498 TI - Molecular cloning and expression pattern of duck Six1 and its preliminary functional analysis in myoblasts transfected with eukaryotic expression vector. AB - Skeletal muscle development is regulated by Six1, an important myogenic transcription factor. However, the functional analysis of duck Six1 has not been reported. Here, we cloned the coding domain sequence (CDS) region of the duck Six1 gene using RT-PCR and RACE methods. Bioinformatics analysis revealed that duck Six1 CDS region comprised of 849 bp and encoded 282 amino acids and had a high degree of homology with other species, suggesting that the functions of duck Six1 gene are conserved among other animals. Real-time PCR used to determine the mRNA expression profiles of duck Six1 in different tissues and different developmental stages showed that Six1 was highly expressed in skeletal muscle and the embryonic stage. Furthermore, the eukaryotic expression vector pEGFP-duSix1 was constructed and transfected into the duck myoblasts; the MTT assay revealed an obvious increase of cell proliferation after transfection. The expression profiles of Six1, Myf5 and MyoD showed that their expression levels were significantly increased. These results together suggested that pEGFP-duSix1 vector was constructed successfully and overexpression of duck Six1 in the myoblasts could promote cell proliferation activity and significant up-regulate expression of Myf5 and MyoD. PMID- 25296499 TI - Association of polymorphisms G(-174)C in IL-6 gene and G(-1082)A in IL-10 gene with traditional cardiovascular risk factors in patients with coronary artery disease. AB - Interleukin-6 (IL-6) polymorphism has been associated with the genetic susceptibility to coronary artery disease (CAD) and also with the lipid profile in different populations. The present work aimed at studying the association, if any between the IL-6 (174) G/C and IL-10 (1082) G/A genes with hypertension or hyperlipidimia in Egyptian patients with CAD and the association of the IL-6 -174 G/C polymorphism with serum IL-6 levels. 108 Egyptian patients with CAD and 143 unrelated healthy subjects were included in the study. The different genotypes of IL-6 and IL-10 were detected by polymerase chain reaction. Serum levels of lipoprotein(a) [Lp(a)] and IL-6 were estimated in the patients, as well as in the healthy subjects. Increased frequency of G allele, GG and GC genotypes in IL-6, as well as decreased frequency of C allele and CC genotype were found in CAD patients, compared to healthy subjects [P = < 0.0001, OR = 3.95, 95% CI (2.16 7.22) for GG and GC vs CC genotype], [P = < 0.0001, OR = 3.44, 95% CI (2.26-5.23) for G allele]. There was an increased frequency of G allele vs A allele in IL-10 genotype in CAD patients, compared to healthy subjects [P = 0.005, OR = 1.866, 95% CI (1.2-2.9]. Higher levels of both Lp(a) and IL-6 were observed in CAD patients, compared to control subjects (P = 0.0012, P = 0.0346, respectively). Increased frequency of IL-6 -174 G-allele was implicated in a greater cardiovascular risk and the presence of G allele or homozygosity for G allele of IL-10 G/A (1082) was associated with an increased prevalence of CAD. The GC genotype and G allele in IL-6 had significant correlation with hyperlipidimic CAD patients; however, G allele in IL-6 and IL-10 showed significant association with hypertension. Thus, G allele in IL-6 and IL-10 was considered as an independent risk factor in hypertensive CAD patients. PMID- 25296500 TI - Fenthion, an organophosphorus pesticide, induces alterations in oxidant/antioxidant status and histopathological disorders in cerebrum and cerebellum of suckling rats. AB - Fenthion (FEN) is an organophosphorus pesticide known for its wide toxic manifestations. In this study, the effects of FEN were evaluated on the cerebrum and cerebellum oxidant/antioxidant status and histopathological disorders in the suckling rats. Pregnant rats were divided into two groups: control group received pure water, while FEN group received daily by their drinking water 551 ppm of FEN from the 14th day of pregnancy until day 14 after delivery. Acetylcholine esterase (AChE) activity was inhibited in both the cerebrum and cerebellum of suckling rats whose mothers were treated with FEN. The cerebrum and cerebellum oxidative damage was demonstrated by a significant increase of malondialdehyde (MDA), advanced oxidation protein product and glutathione (GSH) levels and disturbance in the antioxidant enzyme activities. A significant decline of non protein thiol and vitamin C levels was also observed. These changes were confirmed by histopathological observations which were marked by pyknotic neurons in the cerebrum and apoptotic cells in the cerebellum of FEN-treated rats. In the cerebellum of FEN-treated rats, the most conspicuous damage was the absence of external granular layer, indicating growth retardation. These data suggested that exposure of pregnant and lactating rats to FEN induced oxidative stress and histopathological disorders in the cerebrum and cerebellum of their pups. Thus, the use of FEN must be under strict control, especially for pregnant and lactating mothers. PMID- 25296501 TI - Construction of cDNA expression library of watermelon for isolation of ClWRKY1 transcription factors gene involved in resistance to Fusarium wilt. AB - Full-length cDNAs are very important for genome annotation and functional analysis of genes. The number of full-length cDNAs from watermelon remains limited. Here we report first the construction of a full-length enriched cDNA library from Fusarium wilt stressed watermelon (Citrullus lanatus Thunb.) cultivar PI296341 root tissues using the SMART method. The titer of primary cDNA library and amplified library was 2.21 x 10(6) and 2.0 x 10(10) pfu/ml, respectively and the rate of recombinant was above 85%. The size of insert fragment ranged from 0.3 to 2.0 kb. In this study, we first cloned a gene named ClWRKY1, which was 1981 bp long and encoded a protein consisting of 394 amino acids. It contained two characteristic WRKY domains and two zinc finger motifs. Quantitative real-time PCR showed that ClWRKY1 expression levels reached maximum level at 12 h after inoculation with Fusarium oxysporum f. sp. niveum. The full length cDNA library of watermelon root tissues is not only essential for the cloning of genes which are known, but also an initial key for the screening and cloning of new genes that might be involved in resistance to Fusarium wilt. PMID- 25296502 TI - Molecular mechanism of interaction of mitocurcumin-1 with Akt1 and STAT3: an in silico approach. AB - The bioavailability of curcumin is the limiting factor for its effective use in anti-cancer therapy. Recently, we reported a novel approach to enhance the cellular uptake by conjugating curcumin with triphenyl phosphonium, named mitocurcumin-1. We found that such conjugation significantly increased the uptake of curcumin in various cancer cells and caused cancer cell death by inducing apoptosis by decreasing the phosphorylation of Akt1 (Thr308) and STAT3 (Tyr705). In this study, a molecular mechanistic model deciphering the regulation of phosphorylation of Akt1 and STAT3 by mitocurcumin-1 was investigated and compared with curcumin. The protein structures were obtained from protein data bank data base and protein-ligand interaction studies were performed with mitocurcumin-1 and curcumin. Docking interaction studies of mitocurcumin-1 with Akt1 and STAT3 active sites showed a strong binding affinity of -60.4107 Kcal/mol and -51.1734 Kcal/mol respectively, suggesting mitocurcumin-1 interacted with the residues at the active sites of phosphorylation of these molecules. Further, a Chi rotationary root mean square deviation of 1.468 angstroms and 3.965 angstroms at the active sites in Akt1 and STAT3, respectively indicated that changes in the conformation of protein structure at the active site resulted in the inhibition of phosphorylation of these molecules. To conclude, by using molecular modeling approaches for the first time, we demonstrated the inhibition of Akt1 and STAT3 phosphorylation by mitocurcumin-1. PMID- 25296503 TI - Immobilization of cellulase on TiO2 nanoparticles by physical and covalent methods: a comparative study. AB - Immobilization of cellulase from Aspergillus niger on TiO2 nanoparticles was studied by two different approaches--physical adsorption and covalent coupling. A. niger was selected, as it is generally non-pathogenic, is found in nature in the broad range of habitats and produces cellulase extracellulary. For covalent method, TiO2 nanoparticles were modified with aminopropyltriethoxysilane (APTS). The adsorbed and covalently immobilized enzymes showed 76% and 93% activity, respectively, as compared to the free enzyme. The catalytic efficiency V(max)/K(m) increased from 0.4 to 4.0 after covalent attachment, whereas in adsorption method, it increased slightly from 0.4 to 1.2. The covalently immobilized and adsorbed cellulase lost only 25% and 50% of their activity, respectively after 60 min of incubation at 75 degrees C. The reusability and operational stability data also showed that covalent coupling increased the stability of the enzyme. The presence of enzyme on TiO2 nanoparticles was confirmed by Fourier-transform infrared spectroscopy. The high-resolution transmission electron microscopy (HR-TEM) and atomic force microscopy (AFM) studies indicated aggregation of enzyme when adsorbed on TiO2 surface and a monolayer of enzyme in covalent attachment. In conclusion, covalently attached cellulase retained good activity and thermal stability, as compared to physically adsorbed enzyme. The lower amount of enzyme activity and thermal stability in case of physically adsorbed immobilized enzyme was due to aggregation of the enzyme after adsorption on TiO2 nanoparticles, as revealed by HR-TEM and AFM. Thus, TiO2 nanoparticles could be suitable candidates for immobilization of cellulase for industrial applications like paper, textile, detergent and food industries. PMID- 25296504 TI - Anti-fatigue effects of polysaccharides extracted from Portulaca oleracea L. in mice. AB - Portulaca oleracea L. has been used as a food and medicinal plant for thousands of years in China. Polysaccharides extracted from P. oleracea L. (POP) are its main bioactive compound and have multiple pharmacological activities. However, anti-fatigue effects of POP have not yet been tested. This study was designed to investigate the anti-fatigue effects of POP in mice using the rotarod and forced swimming tests. The mice were randomly divided into four groups, namely normal control group, low-dose POP supplementation group, medium-dose POP supplementation group and high-dose POP supplementation group. The normal control group received distilled water and the supplementation groups received different doses of POP (75, 150 and 300 mg/kg, respectively). The POP or distilled water was administered orally and daily for 30 day. After 30 days, the rotarod and forced swimming tests were performed and then several biochemical parameters related to fatigue were determined. The data showed that POP prolonged the riding times and exhaustive swimming times of mice, decreasing blood lactic acid and serum urea nitrogen levels, as well as increasing the liver and muscle glycogen contents. These results indicated that POP had the anti-fatigue effects. PMID- 25296506 TI - [Gender dysphoria in children and adolescents]. AB - Despite rising demand for treatment, far too few specialist services for gender dysphoric children and adolescents exist. Due to complex issues related to indication of physical treatment with lifelong consequences a thorough interdisciplinary treatment service with development-related evaluation is necessary. The aim of this paper is to outline the professional and social tension, in which the practitioner works, as well as to provide insight into the diversity of developmental trajectories and difficult decisions or dilemmas. PMID- 25296505 TI - Identification of pregnancy-associated glycoproteins by peptide mass fingerprinting in water buffalo (Bubalus bubalis). AB - Ruminant placentas synthesize pregnancy-associated glycoproteins (PAGs) during pregnancy, which serve as biomarkers of pregnancy. The present study was conducted to verify, whether PAGs are expressed in buffalo placenta by using lectin-based affinity chromatography and peptide mass finger printing (PMF). Fetal cotyledonary tissues were collected from gravid uteri procured from slaughtered house. Proteins were extracted and subjected to wheat germ agglutinin (WGA) lectin affinity chromatography to isolate the PAGs. The isolated glycoproteins were separated by one-dimensional SDS-PAGE. PMF results of the 75 kDa protein revealed presence of two PAGs (PAG-7 and -11). The PAG-7 consisted of about 170 mass signals, of which 16 were assigned to corresponding/translated cDNA sequences of buffalo PAG-7, leading to sequence coverage of 40%. PMF result of PAG-11 showed 170 mass signals, of which 15 were assigned to buffalo PAG-11, leading to sequence coverage of 34%. In conclusion, the glycoprotein isolated from placental extract corresponding to 75 kDa band on SDS PAGE gel was a mixture of PAG-7 and -11, which may help in development of suitable diagnostics for pregnancy in buffalo. PMID- 25296507 TI - [The development of gender identity beyond rigid dichotomy]. AB - The conflicts individuals with ambiguous sexual characteristics suffer from are not the result of genetic features but of the rigid and dichotomous gender order, which is currently undergoing a renaissance. This also applies to individuals with an uncertain gender identity. In the best interests of the child a concept of gender seems necessary, that goes beyond a binary separation and allows gender specific intermediary stages in the personal development of identity. Such a gender concept can be developed following psychoanalytic theories. The present discourse contains a scale of connecting factors for a differentiated and less normative conceptualization of gender development. Starting from Freud's concept of constitutional bisexuality, Robert Stoller's theory, which has been firmly rooted in the mainstream of psychoanalysis for more than 40 years, will be critically reviewed. By involving Reimut Reiche's and Jean Laplanche's arguments, a continuative psychological gender theory will be drafted, which does not normatively and reductively claim the demarcation of gender, but rather opens up a space for gender diversity. PMID- 25296508 TI - [Clinical treatment of children and adolescents with gender dysphoria from international experts' point of view]. AB - The clinical treatment of children and adolescents with gender dysphoria is still a controversial issue. The aim of this study was to get an overview of the knowledge and experience of international experts and to highlight shared views as well as differences in theoretical convictions and treatment approaches. Half structured, guide-line based interviews were carried out with international experts in the field. The interviews were analyzed using qualitative content analysis (Mayring, 2010). PMID- 25296509 TI - [Care of children and adolescents with gender dysphoria in the context of an interdisciplinary special consultation service]. AB - In Germany, the situation of health care services for children and adolescents with gender dysphoria is insufficient. In 2006 a specialized multiprofessional outpatient clinic was founded at the University Medical Center Hamburg-Eppendorf. Goals were improvement of health services for gender dysphoric children, development of treatment concepts, and gain of knowledge through research. After finishing a thorough interdisciplinary assessment an individualized, case-by-case treatment starts. Besides psychotherapy an interdisciplinary treatment (e. g. puberty suppression and cross-sex hormones) is provided if indicated. During childhood a watchful waiting and carefully observing attitude is necessary. If a marked increase of gender dysphoria occurs during the first phases of puberty development, puberty suppression and later cross sex-hormones might be indicated. PMID- 25296510 TI - [Characteristics of children and adolescents with gender dysphoria referred to the Hamburg Gender Identity Clinic]. AB - Given the increasing demand for counselling in gender dysphoria in childhood in Germany, there is a definite need for empirical data on characteristics and developmental trajectories of this clinical group. This study aimed to provide a first overview by assessing demographic characteristics and developmental trajectories of a group of gender variant boys and girls referred to the specialised Gender Identity Clinic in Hamburg. Data were extracted from medical charts, transcribed and analysed using qualitative content analysis methods. Categories were set up by inductive-deductive reasoning based on the patients' parents' and clinicians' information in the files. Between 2006 and 2010, 45 gender variant children and adolescents were seen by clinicians; 88.9% (n = 40) of these were diagnosed with gender identity disorder (ICD-10). Within this group, the referral rates for girls were higher than for boys (1:1.5). Gender dysphoric girls were on average older than the boys and a higher percentage of girls was referred to the clinic at the beginning of adolescence (> 12 years of age). At the same time, more girls reported an early onset age. More girls made statements about their (same-sex) sexual orientation during adolescence and wishes for gender confirming medical interventions. More girls than boys revealed self-mutilation in the past or present as well as suicidal thoughts and/or attempts. Results indicate that the presentation of clinically referred gender dysphoric girls differs from the characteristics boys present in Germany; especially with respect to the most salient age differences. Therefore, these two groups require different awareness and individual treatment approaches. PMID- 25296511 TI - [Gender dysphoria in adolescents: difficulties in treatment]. AB - In many children and adolescents with gender dysphoria only minor or no psychopathology is found. 43% of patients seen in the Frankfurt University Gender Identity Clinic for children and adolescents suffer from major psychopathology. To demonstrate difficulties in treatment of these patients courses of treatment in four such patients are presented. In two natal females major psychopathology made decision for reassignment very difficult. Two natal males were in addition not able to follow recommended treatment steps, in these patients diagnostic doubts arose. PMID- 25296512 TI - [About the heterogeneity in adolescents with gender identity disorder: differential importance of psychiatric comorbidity and considerations of individual psychodynamics]. AB - Gender identity disorder (GID), gender dysphoria (GD) respectively, is considered a multifactorial disease whose etiology is subject to complex bio-psycho-social conditions, each with different weighting. As a result, therapists, who treat children and adolescents with GID/GD, have to deal with a very heterogeneous group with individually varying causes, differing psychopathology and varying disease progression. In addition to general psychiatric aspects of development, particularly psychiatric comorbidity, but also the different individual psychodynamics--i. e. the specific constellation of conflicts and possible ego deficits and structural deficits in the learning history of the person are of differential importance. In regard to the indication for gender reassignment measures this sometimes is relevant for the decision. The difficulties arising for decision making and the usefulness of a systematic evaluation of case reports as a basis for further optimization of the treatment recommendations are illustrated by two case reports. In the course of this, also the disadvantages and potential dangers of too early diagnostic definition and introduction of gender somato-medical and legal measures are shown exemplarily. PMID- 25296513 TI - [Gender identity disorders in childhood and adolescence (F64)]. PMID- 25296514 TI - [History of science and technology: its present, past, and future]. PMID- 25296515 TI - [Stocking with bluegill sunfish, Lepomis macrochirus, by fisheries experimental stations, fishing tackle makers, and anglers in Japan, 1960-1975]. AB - This paper discusses some facts that were pivotal in the process of the introduction of Bluegill Sunfish, Lepomis macrochirus, into various places in Japan, however have not been considered in the existing literature. This paper points out that L. macrochirus escaped, and also was stocked, to the open water in Osaka as a result of experiments by a fisheries experimental station in the 1960s and early 1970s. In Shiga Prefecture too, the fish escaped into Lake Biwa as a result of experiments by a fisheries experimental station in about 1969. Neither Osaka nor Shiga are mentioned, by previous studies based on questionnaire research, as the prefectures in which L. macrochirus inhabited in the years between 1960, when the fish was first introduced into Japan, and 1979. In addition, anglers, who considered L. macrochirus an ideal game fish, stocked ponds and lakes in some prefectures with L. macrochirus in around 1970 on purpose to multiply the species. During this process, a network among not only local governments, fisheries experimental stations, and fish farmers, but also industries targeting anglers, such as fishing tackle makers and a magazine for anglers, was being formed, which however did not get established after all. These findings will contribute to enrich the basis of today's genetic research on the distribution of L. macrochirus in Japan. PMID- 25296516 TI - [Engineering education reform plan created by Prof. Dr. Shimizu and establishment of Nagoya Municipal Science Museum--regarding cooperative education between universities and industries in Japan after the Second World War]. AB - This paper gives an account of Prof. Dr. Kinji Shimizu, the first president of Nagoya Institute of Technology, and his establishment of Nagoya Municipal Science Museum. After graduating from the Electrical Engineering Department of Kyoto Imperial University in 1923, Shimizu was impressed by the German Museum in Munich during his stay there as a student in 1932. It's the first time that he learned the education in cooperation with industries. Just after the Second World War, he became director general of the Ministry of Education. However, new education system given by the United States focused not on developing practical ability but on gaining the basic knowledge, which is contrary to what he expected. Then, he contributed to the establishment of the Japanese Society for Engineering Education, besides working as the president of Nagoya Institute of Technology in the earlier 1950s. His idea was supported by industries for the economic growth. Throughout his career, Prof. Dr. Shimizu was convinced that practical engineering education would benefit Japan, and wanted to introduce cooperative education between universities and industries, along the lines of the same system in Germany and the United States. With this vision he founded Nagoya Municipal Science Museum in cooperation with local industries and local government as his final achievement. The museum was completed in 1964. PMID- 25296517 TI - [The Chinese nuclear test and 'atoms for peace' as a measure for preventing nuclear armament of Japan: the nuclear non-proliferation policy of the United States and the introduction of light water reactors into Japan, 1964-1968]. AB - Japan and the United States signed in 1968 a new atomic energy agreement through which US light-water nuclear reactors, including those of the Fukushima Daiichi Nuclear Power Plant of Tokyo Electric Power Company, were to be introduced into Japan. This paper studies the history of negotiations for the 1968 agreement using documents declassified in the 1990s in the US and Japan. After the success of the Chinese nuclear test in October 1964, the United States became seriously concerned about nuclear armament of other countries in Asia including Japan. Expecting that Japan would not have its own nuclear weapons, the US offered to help the country to demonstrate its superiority in some fields of science including peaceful nuclear energy to counter the psychological effect of the Chinese nuclear armament. Driven by his own political agenda, the newly appointed Prime Minister Eisaku Sato responded to the US expectation favorably. When he met in January 1965 with President Johnson, Sato made it clear that Japan would not pursue nuclear weapons. Although the US continued its support after this visit, it nevertheless gave priority to the control of nuclear technology in Japan through the bilateral peaceful nuclear agreement. This paper argues that the 1968 agreement implicitly meant a strategic measure to prevent Japan from going nuclear and also a tactic to persuade Japan to join the Nuclear Non Proliferation Treaty. PMID- 25296518 TI - An evidence-based approach to the management of hematuria in children in the emergency department. AB - Hematuria is defined as an abnormal number of red blood cells in urine. Even a tiny amount of blood (1 mL in 1000 mL of urine) is sufficient to make urine appear pink or red. In the pediatric population, the majority of etiologies are benign and often asymptomatic. However, hematuria may also be a sign of renal pathology, local infection, or systemic disease. Hematuria can be differentiated into 2 categories: macroscopic hematuria (visible to the naked eye) and microscopic hematuria (> 5 red blood cells/high-powered field on urinalysis). This review will outline the current literature regarding evaluation and management of pediatric patients who present to the emergency department with hematuria. Obtaining a thorough history and the appropriate diagnostic tests will be discussed in depth. PMID- 25296519 TI - Lights out. PMID- 25296520 TI - Your PDA is moving forward. PMID- 25296521 TI - Clinicopathologic review: non-healing ulcer of the tongue. Traumatic ulcerative granuloma with stromal eosinophilia. PMID- 25296522 TI - Good grief: why it's always mourning in long term care (and why that's okay). PMID- 25296523 TI - Seize the day, bankers say: the time to finance expansion upgrades is now. PMID- 25296524 TI - Clinical decision meets EHRs. PMID- 25296525 TI - Tech boosts quality, improves marketability. PMID- 25296526 TI - [Behring's personal papers--Behring's lives]. AB - The article wants to show the connection between the enriched personal papers of Emil von Behring (1854-1917) in the Behring archives in Marburg (established in 1927) and the history of the first biography of the scientist, which was published by Heinz Zeiss and Richard Bieling during Nazi era in 1940. One focus is placed on Behring's widow Else von Behring (1876-1936), who was active in arranging Behring's papers in proper order and in searching a biographer of her husband's life. The paper also presents new discoveries from the Behring Works archives in Marburg which show Behring--founder of the serum therapy and first winner of the Nobel Prize for medicine in 1901--as an entrepreneur who was fighting for control and influence in the field of science and of business: maybe another narration of Behring's life. PMID- 25296527 TI - [What remains is what should remain: using estates to construct biographies]. AB - Estates play a major role in historical research, especially biographic research, for they supplement the official writings surrounding the individual view of a historical figure. But they nonetheless reflect only a small part of the scientific and private activities of a researcher. Moreover, before being handed over to an archive, they are also often filtered by the researchers themselves, by family members, and/or by successors to the historical figure's post. The history of an estate is thus of great importance to research. With an eye to the estates of natural scientists, the present text uses a concept of estates that includes not only the surviving texts but also artifacts with which the scientists worked. The focus will be on three physicists--Ernst Mach, Walther Gerlach, and Philipp Lenard--in order to investigate the significance of these objects for their respective biographies and for the history of physics. PMID- 25296528 TI - [Systems, boundaries and resources: the lexicographer Gerhard Wahrig (1923-1978) and the genesis of his project "dictionary as database"]. AB - Gerhard Wahrig's private archive has recently been retrieved by the authors and their siblings. We undertake a first survey of the unpublished material and concentrate on those aspects of Wahrig's bio-ergography which stand in relation to his life project "dictionary as database", realised shortly before his death. We argue that this project was conceived in the 1950s, while Wahrig was writing and editing dictionaries and encyclopedias for the Bibliographisches Institut in Leipzig. Wahrig, who had been a wireless operator in WWII, was well informed about the development of computers in West Germany. He was influenced both by Ferdinand de Saussure and by the discussion on language and structure in the Soviet Union. When he crossed the German/German border in 1959, he experienced mechanisms of exclusion before he could establish himself in the West as a lexicographer. We argue that the transfer of symbolic and human capital was problematic due to the cultural differences between the two Germanies. In the 1970s, he became a professor of General and Applied Linguistics. The project of a "dictionary as database" was intended both as a basis for extensive empirical research on the semantic structure of natural languages and as a working tool for the average user of the German language. Due to his untimely death, he could not pursue his idea of exploring semantic networks. PMID- 25296529 TI - Bacteremia due to Campylobacter in renal transplantation: a case report and review of literature. AB - Campylobacter species are the leading cause of acute bacterial diarrhea in industrialized countries. However, bacteremia is detected in <1% of patients with Campylobacter enteritis and is most likely to occur in patients who are immunocompromised or of older age. To our knowledge, only 2 cases of Campylobacter jejuni bacteremia have been reported in renal transplant recipients (RTRs). We present a case of an RTR with C. jejuni bacteremia presenting as self limiting diarrhea followed by fever and cellulitis. The patient was successfully treated with a 2-week course of imipenem and developed no other complications. We review all cases of Campylobacter bacteremia in RTRs, and discuss clinical presentation and treatment of this potentially fatal disease. PMID- 25296530 TI - Longitudinal changes in maternal corin and mid-regional proatrial natriuretic peptide in women at risk of pre-eclampsia. AB - OBJECTIVE: Corin, an atrial natriuretic peptide-converting enzyme, has been found to promote trophoblast invasion and spiral artery remodeling. Yet, elevated maternal plasma atrial natriuretic peptide (ANP) and corin levels have been reported in pregnancies complicated by pre-eclampsia (PE). The aim of this study was to investigate longitudinal changes in maternal plasma levels of corin and mid-regional proatrial natriuretic peptide (MR-PANP) in pregnancies that develop PE and gestational hypertension (GH). METHODS: This was a nested case-control study drawn from a larger prospective longitudinal study in singleton pregnancies identified as being at high risk for PE by screening at 11 + 0 to 13 + 6 weeks' gestation. Blood samples were taken every 4 weeks until delivery. Values were compared in pregnancies that developed preterm PE (requiring delivery before 37 weeks' gestation), term PE, GH and those that remained normotensive. RESULTS: A total of 471 samples were analyzed from 122 women, including 85 that remained normotensive, 12 that developed GH, 13 term PE and 12 preterm PE. In the normotensive group, log10 corin levels were associated with gestational age (P < 0.01), whereas log10 MR-PANP levels were not. In the preterm-PE group, compared with the normotensive group, corin was significantly lower until 20 weeks' gestation (P = 0.001). In the GH and term-PE groups, corin did not differ significantly from the normotensive group (P = 0.637 and P = 0.161, respectively). Compared with the normotensive group, MR-PANP levels were significantly higher in the pregnancies that developed preterm PE and GH (P = 0.046 and P = 0.019, respectively), but not term PE (P = 0.467). CONCLUSION: Maternal-plasma corin and MR-PANP could potentially be useful biomarkers for the prediction of preterm PE. PMID- 25296531 TI - Novel benzimidazole derivatives as electron-transporting type host to achieve highly efficient sky-blue phosphorescent organic light-emitting diode (PHOLED) device. AB - The development of benzimidazole substituted biphenyls as electron-transporting hosts for bis[2-(4,6-difluorophenyl)pyridinato-C(2),N](picolinato)iridium(III) is reported. Under the optimized conditions, the organic light-emitting diode (OLED) achieves the maximum current efficiency of 57.2 cd/A, power efficiency of 50.4 lm/W, and external quantum efficiency 25.7%. PMID- 25296532 TI - Exclusive periductal/pericystic growth pattern in a case of long-standing monophasic synovial sarcoma of the parotid gland. PMID- 25296533 TI - Long-term safety and efficacy of bimatoprost solution 0.03% application to the eyelid margin for the treatment of idiopathic and chemotherapy-induced eyelash hypotrichosis: a randomized controlled trial. AB - BACKGROUND: Bimatoprost ophthalmic solution 0.03% is approved in several countries for the treatment of eyelash hypotrichosis. Previous trials were limited to 4 months of treatment and primarily idiopathic hypotrichosis. OBJECTIVES: To evaluate the long-term safety and efficacy of bimatoprost in patients with idiopathic or chemotherapy-induced hypotrichosis. METHODS: This multicentre, double-masked, randomized, parallel-group study included two 6-month treatment periods [treatment period 1 (TP1) and treatment period 2 (TP2)]. Patients with idiopathic hypotrichosis were randomized to three treatment groups: (i) bimatoprost (TP1 and TP2); (ii) bimatoprost (TP1) and vehicle (TP2); and (iii) vehicle (TP1) and bimatoprost (TP2). Patients with chemotherapy-induced hypotrichosis were randomized to two treatment groups: (i) bimatoprost or vehicle (TP1) and (ii) bimatoprost (TP2). Primary end point was a composite of at least a one-grade improvement in investigator-assessed Global Eyelash Assessment and at least a three-point improvement in patient-reported Eyelash Satisfaction Questionnaire Domain 2 at month 4. Secondary measures included digitally assessed eyelash characteristics. RESULTS: The primary efficacy end point was met in both populations (idiopathic responder rate was 40.2% for bimatoprost vs. 6.8% for vehicle; postchemotherapy responder rate was 37.5% for bimatoprost vs. 18.2% for vehicle). Efficacy by month 6 was maintained (idiopathic) or enhanced (postchemotherapy) at 12 months. Treatment effects were maintained for approximately 2 months but markedly diminished 4-6 months following treatment cessation in patients with idiopathic hypotrichosis. No drug-related serious adverse events were reported. CONCLUSIONS: Daily treatment with bimatoprost ophthalmic solution 0.03% for 1 year was effective and well tolerated in patients with idiopathic and chemotherapy-induced hypotrichosis. PMID- 25296534 TI - Modelling sustainable salt water management under deficit irrigation conditions for melon in Spain and Brazil. AB - BACKGROUND: In water scarcity areas the use of saline water for irrigation is a common practice. In this study, experimental data from two two-year melon tests were collected for the calibration (2004 'Yellow Melon' (YeMe) type) and validation (2002 YeMe, 2005 and 2006 'Piel de Sapo' (PiSa) type) processes in melon crop simulation under deficit irrigation conditions using salt water. The simulations were carried out for Castilla-La Mancha (Spain) and Ceara (Brazil) using the MOPECO model, which includes optimized regulated deficit irrigation (ORDI) methodology. The objective was to determine the most suitable irrigation strategy for both areas. RESULTS: Under fresh water conditions, ORDI may increase yield by up to 20% (PiSa) and 7% (YeMe) compared with constant deficit irrigation. Higher water deficit should be induced during the vegetative development and ripening stages. The rainfall between irrigation periods is able to leach the salts supplied by the irrigation water. CONCLUSION: The combination of ORDI with different strategies for managing saline water may increase water use efficiency. In these areas it may be of interest not to apply the leaching fraction (saving up to 67% of irrigation water). However, leaching of the soluble salts accumulated before starting the most sensitive periods may be suitable. PMID- 25296535 TI - Gamma-tocopherol enhances apoptotic effects of lovastatin in human colorectal carcinoma cell line (HT29). AB - Recently, we found that lovastatin, a HMG-CoA reductase inhibitor, and gamma tocopherol, one of the significant types of vitamin E in diet, additively induced apoptosis in a colorectal carcinoma cell line. In this study we mechanistically monitored the loss of mitochondrial membrane potential, amount of cytosolic cytochrome c and caspase 3 activity after treatment by lovastatin and gamma tocopherol. HT29 cells were treated with different doses of lovastatin and gamma tocopherol for 48 and 72 h. Lovastatin and gamma-tocopherol in combination induced the release of cytochrome c, caspase 3 activation, and loss of mitochondrial membrane potential more significantly compared to their controls. Our data showed that lovastatin plus gamma tocopherol potently induced mitochondrial membrane potential collapse, cytochrome c release along with caspase 3 activation that reveals the importance of targeting programmed cell death signaling at different points of its signaling pathway for cancer therapy. PMID- 25296536 TI - Linking chemical parameters to sensory panel results through neural networks to distinguish olive oil quality. AB - A wide variety of olive oil samples from different origins and olive types has been chemically analyzed as well as evaluated by trained sensory panelists. Six chemical parameters have been obtained for each sample (free fatty acids, peroxide value, two UV absorption parameters (K232 and K268), 1,2-diacylglycerol content, and pyropheophytins) and linked to their quality using an artificial neural network-based model. Herein, the nonlinear algorithms were used to distinguish olive oil quality. Two different methods were defined to assess the statistical performance of the model (a K-fold cross-validation (K = 6) and three different blind tests), and both of them showed around a 95-96% correct classification rate. These results support that a relationship between the chemical and the sensory analyses exists and that the mathematical tool can potentially be implemented into a device that could be employed for various useful applications. PMID- 25296537 TI - Professor Kyu-Chang Wang: President of the ISPN, 2012-2013. PMID- 25296538 TI - Contribution to the world: a lesson from Dr. Lee Jong-Wook. PMID- 25296540 TI - Cortical dysplasia in children. PMID- 25296539 TI - Management of postoperative pseudomeningoceles: an international survey study. AB - BACKGROUND: Pseudomeningoceles are common complications after posterior fossa and intradural spinal surgery and are often asymptomatic. Management guidelines are lacking, and anecdotally, we have encountered radically different suggested treatments varying from observation to immediate surgical intervention. The goal of this study was to determine the prevailing opinions among neurosurgeons on the management of this condition. METHODS: Neurosurgeons from around the world were invited via an International Society for Pediatric Neurosurgery (ISPN) and Neurosurgery ListServ e-blast to participate in a 33-question survey on the management of pseudomeningoceles, presented as simulated scenarios after posterior fossa and spinal intradural surgery. RESULTS: Two hundred forty-one responses were obtained. Pseudomeningoceles after posterior fossa tumor resection, in the absence of hydrocephalus, were typically managed nonoperatively for 7 to 14 days before re-exploration. Only 0.5 % of the surgeons would offer upfront repair of the pseudomeningocele. In the presence of hydrocephalus, 48 % of the neurosurgeons intervene initially with cerebrospinal fluid (CSF) diversion and would change therapy if the lesion did not resolve in 2 to 4 days. Ninety percent of the surgeons manage spinal pseudomeningoceles nonoperatively for 7-14 days before re-exploration is considered. The most common steps taken to prevent pseudomeningoceles are watertight closure, tissue glues, and duroplasty. CONCLUSION: The present zeitgeist suggests that, in the absence of hydrocephalus, initial observation is appropriate for cranial and spinal pseudomeningoceles. Operative revision should be reserved for failure of conservative treatment. If hydrocephalus is present, consideration should be made for CSF diversion. This study may serve as a guideline regarding acceptable management. PMID- 25296541 TI - Classification and pathological characteristics of the cortical dysplasias. AB - BACKGROUND: Focal cortical dysplasias (FCD) are a well-recognized cause of medically intractable epilepsy. They are defined as malformations of cortical development and are marked by abnormalities of cortical layering and neuronal differentiation and maturation. A number of classification approaches have been devised over the last four decades, indicating controversies surrounding issues of recognition, definition, and philosophical approach. More recent attempts have attempted to correlate morphologic phenotype with clinical or developmental parameters in order to provide a clinical relevance. DISCUSSION: This short review provides an overview of the issues which account for the varied historical approaches to FCD classification and descriptions of gross pathologic findings associated with FCD and an overview of two more recently developed and widely used schema, the Palmini et al. (Neurology 62: S2-8, 2004) and the International League Against Epilepsy (ILAE) classifications Blumcke et al. Epilepsia 52: 158 174, 2011. The pathologic features of these two approaches will be reviewed and compared, including discussion of their limitations. PMID- 25296542 TI - Hemispheric dysplasia and hemimegalencephaly: imaging definitions. AB - BACKGROUND AND PURPOSE: Hemispheric dysplasia (HD) and hemimegalencephaly (HME) are both brain malformations with early clinical manifestation including developmental delay and intractable epilepsy. Sometimes the differentiation of these conditions is not simple. HME is an anomaly of cortical development caused by a combination of neural proliferation and cell migration dysfunction, showing lobar or hemispheric enlargement. On the other hand, HD shows no brain hypertrophy, and even brain atrophy, eventually. PATIENTS AND METHODS: To compare both conditions, we reviewed clinical, MRI, and histopathology of 23 patients with developmental delay and refractory epilepsy treated with hemispheric surgery. RESULTS: Histologically, both groups presented polymicrogyria, focal cortical dysplasia, gray matter (GM) heterotopia, pachygyria, and agyria. The white matter (WM) showed different degrees of gliosis and myelin impairment. Even though with no specificity in histopathology, the degree of lesion was more impressive on HME. The combination of WM dysmyelination and hypertrophy leads to the so called hamartomatous appearing. Although not all HME showed brain enlargement and some HD might show no size changes or atrophy, the size of affected hemisphere and the hamartomatous appearance of the WM were the more relevant signs to differentiate both conditions. CONCLUSION: Brain MRI was the best diagnostic tolls because it allowed together high contrast resolution, whole brain coverage and spatial distribution analysis. HD and HMD showed brain asymmetry tendency, but in opposite directions. The size of affected hemisphere and the hamartomatous appearance of the WM were the more relevant signs to differentiate both conditions. PMID- 25296543 TI - Indications and selection criteria for invasive monitoring in children with cortical dysplasia. AB - PURPOSE: In order to presurgically define the anatomical location of the epileptogenic zone (EZ) and its proximity to possible cortical and subcortical eloquent areas in pediatric patients with medically intractable focal epilepsy, an array of noninvasive tools are available: recorded seizure semiology, scalp electroencephalographic (EEG) recordings (ictal and interictal epileptic patterns), magnetic resonance imaging (MRI), positron emission tomography (PET), ictal single-photon emission computed tomography (SPECT), neuropsychological testing, and/or magnetoencephalography. When the noninvasive tools fail or are insufficient in precisely localizing the EZ and its functional and anatomical interphase with potential eloquent cortical areas, invasive extra-operative monitoring procedures might be needed. DISCUSSION: In this chapter, we will discuss the main goals of extra-operative invasive evaluation for children with medically intractable epilepsy in whom cortical dysplasia is a possible etiology. We will specifically discuss the possible indications, surgical strategies, results, and morbidity associated with the placement of subdural and stereoelectroencephalography (SEEG) electrodes. The rationale behind the choice of each one of the above techniques will also be discussed. PMID- 25296544 TI - Hemispheric malformations of cortical development: surgical indications and approach. AB - INTRODUCTION: The term "hemispheric malformation of cortical development" (MCD) has come into the medical lexicon in the past 20 years as improvements and availability of advanced imaging techniques have permitted more precise diagnosis of a variety of brain developmental disorders that affect large regions of brain. These conditions are united by their propensity to elicit seizures that are difficult to control with medication in the children who suffer them. PURPOSE: The goal of surgical intervention is always to achieve seizure freedom and thereby give the affected child the best possible hope for neurological development. Even when seizure freedom cannot be achieved, a reduction in seizure burden is necessary to permit the survival of the child in many cases of MCD. EVALUATION: A presurgical evaluation of a patient presenting with severe epilepsy and a possible hemispheric malformation can be divided into three stages. The first includes an evaluation of available imaging, clinical, and genetic data to accurately diagnose the child and help determine if surgical intervention is an option. The next includes an evaluation of EEG and neurological data, although this has limited utility in many clinical circumstances. Finally, a clinical team must decide upon an appropriate surgical strategy among a variety of options. CONCLUSIONS: In this review, we will examine the set of diagnoses and associated imaging characteristics that describe the set of conditions for which surgical intervention is a possibility. We include a discussion of available surgical options, describing our own experience with surgery for MCD and the associated postoperative considerations including rates of seizure freedom, considerations for reoperation, and hydrocephalus. PMID- 25296546 TI - Stereoelectroencephalography in children with cortical dysplasia: technique and results. AB - The stereoelectroencephalophraphy (SEEG) method was developed in France by Jean Tailarach and Jean Bancaud during the 50s and has been mostly used in France and Italy, as the method of choice for extraoperative invasive mapping in refractory focal epilepsy. Subsequently, for more than 60 years, SEEG has shown to be a valuable tool for preoperative decision-making in focal epilepsy. Nevertheless, there are few reports addressing the utility and safety of the SEEG methodology applied to children and adolescents. In this chapter, we will discuss the current results of SEEG in pediatric patients with difficult to localize epilepsy. Details regarding surgical technique and clinical results will be presented. PMID- 25296545 TI - Surgery for focal cortical dysplasia in children using intraoperative mapping. AB - OBJECTIVE: Children with malformation of cortical development represent a significant proportion of pediatric epilepsy surgery candidates. Here, we describe a single-center experience with pediatric patients who underwent surgery for intractable epilepsy due to focal cortical dysplasia (FCD). METHODS: Clinical data of 78 patients under 18 years of age with diagnosis of intractable epilepsy due to FCD who underwent surgery from January 1996 to January 2012 were reviewed comparing data of patients submitted to electrocorticography (ECoG) with those without ECoG. RESULTS: Patients' mean age at surgery was 8.52 +/- 4.99 years; mean age at epilepsy onset was 2.55 +/- 3.01 years. Almost 80 % of the patients underwent ECoG register that was essential for delimitation of surgical resection in 66 out of 78 patients. ECoG was performed in all patients with extratemporal lesions, and the most common FCD found was type II. Seizure outcome was similar in groups with or without ECoG. CONCLUSIONS: Tailored resection of FCD lesions for intractable epilepsy can be safely performed in children with a good seizure outcome and low complication rate. Epilepsy surgery should be considered for all patients with FCD and refractory epilepsy. PMID- 25296547 TI - Surgery for posterior quadrantic cortical dysplasia. A review. AB - BACKGROUND: Posterior quadrant dysplastic lesions represent 3-15 % of multilobar cortical developmental pathologies, 3-5 % of all the indications to surgery for epilepsy resistant to medical treatment. OBJECTIVE AND METHODS: The objective of this study is to review the pertinent literature related to the presurgical clinical, neurophysiological, and neuroradiological evaluation of children affected by posterior quadrant dysplasia in order to discuss the intraoperative management and the different surgical techniques that have been proposed to treat this condition as well as factors related with postsurgical seizure outcome. RESULTS AND CONCLUSIONS: Seizures appear most commonly in infants and rapidly progress to a catastrophic course. They are mostly represented by focal seizures and spasms. Surface interictal video-EEG is characterized by background flattening and paroxysmal discharges prevalent on the affected side but not unusually extending to the controlateral hemisphere. The last occasionally shows an independent irritative activity in spite of the absence of further visible structural abnormalities. Most of the patients have visual field or visual attention deficits at diagnosis. Resective as well as disconnective surgical procedures have been proposed for the management of this condition, none of them having shown clear advantages in terms of seizure outcome and complications. Intraoperative electrocorticography (EcoG) and sensorimotor monitoring have been successfully used to improve the localization of the epileptic focus and reduce surgical complication rates. Undistincted lesion borders, independent controlateral ictal or/and interictal EEG activity, and incomplete resections/disconnections are among the main factors that have resulted to be associated with a worse seizure outcome. PMID- 25296548 TI - Approach to cortical dysplasia associated with glial and glioneuronal tumors (FCD type IIIb). AB - INTRODUCTION: Brain tumors are a frequent cause of epilepsy in the pediatric population. The last International League Against Epilepsy (ILAE) classification of focal cortical dysplasias (FCDs) includes a subgroup consisting of tumors with surrounding dysplastic abnormalities (FCD type IIIb). Although its pathogenesis is still unclear, it has several clinical and therapeutic (surgical) implications. BACKGROUND: A number of benign tumors (such as dysembryoplastic neuroepithelial tumors and gangliogliomas) frequently present with medically refractory epilepsy associated with cortical dysplasia. In such cases, planning of surgical resection needs to take into consideration not only the tumor but also the whole area of epileptogenicity. The use of intraoperative electrocorticography recordings is reported to result in better postoperative outcomes, since they help delineate the abnormal cerebral cortex that needs to be resected to provide seizure freedom to patients. Clinical, radiological, and pathological features are also discussed herein. PMID- 25296549 TI - Outcome of surgery in children with focal cortical dysplasia younger than 5 years explored by stereo-electroencephalography. AB - PURPOSE: Focal cortical dysplasia (FCD) is the most frequent etiology for drug resistant epilepsy in young children. Complete removal of the lesion is mandatory to cure the epilepsy. Stereo-EEG (SEEG) is an excellent method to delimitate the zone to be resected in older children and adults. We studied its feasibility in younger children. METHODS: We retrospectively studied 19 children under 5 years of age who underwent SEEG between January 2009 and December 2012 and were subsequently operated on. FCD was diagnosed in all. We reviewed magnetic resonance imaging (MRI), electrophysiological and clinical data, as well as postoperative seizure outcome. We also included fluoro-deoxyglucose positron emission tomography (FDG-PET) studies, which had been systematically performed before invasive recording in 16 of the 19 children. RESULTS: The mean patient's age at the time of SEEG was 38.6 months, and the mean age at seizure onset was 8 months. Three patients had normal MRI. No SEEG-associated complications occurred. We were able to delineate the epileptogenic zone in all children, and electrode stimulation localized the motor area when necessary (12 patients). Hypometabolic areas on FDG-PET included the epileptogenic zone in 13 of the 16 children, with a lobar concordance in 9 (56 %) and the same anatomical extent in 6 (38 %). Twelve children subsequently underwent focal or sublobar resection, six had multilobar resection, and one had hemispherotomy. The etiology was FCD type 2 in 15 and FCD type 1 or type 3 in three children. Eighty-four percent of our population have remained seizure-free at a mean follow-up of 29 months (12-48 months). CONCLUSION: Although children with FCD can successfully undergo resective surgery without invasive EEG, poor seizure semiology at this age inclines to perform SEEG when the dysplastic lesion is ill-defined and/or the electroclinical correlation is unclear. In cases with normal imaging as well as with suspected huge malformations, as was the case in 52 % of our patients, we consider it to be indispensable. PMID- 25296550 TI - Cognitive and epilepsy outcomes after epilepsy surgery caused by focal cortical dysplasia in children: early intervention maybe better. AB - BACKGROUND: Focal cortical dysplasia (FCD) is a specific malformation of cortical development harboring intrinsic epileptogenicity, and most of the patients develop drug-resistant epilepsy in early childhood. The detrimental effects of early and frequent seizures on cognitive function in children are significant clinical issues. In this study, we evaluate the effects of early surgical intervention of FCD on epilepsy outcome and cognitive development. METHODS: From 2006 to 2013, 30 children younger than 18 years old underwent resective surgery for FCDs at Taipei Veterans General Hospital. The mean age at surgery was 10.0 years (range 1.7 to 17.6 years). There were 21 boys and 9 girls. In this retrospective clinical study, seizure outcome, cognitive function, and quality of life were evaluated. To evaluate the effects to outcomes on early interventions, the patients were categorized into four groups according to age of seizure onset, duration of seizure before surgery, and severity of cognitive deficits. RESULTS: Eleven of 22 (50 %) patients demonstrated developmental delay preoperatively. The Engel seizure outcome achievements were class I in 21 (70 %), class II in 2 (7 %), class III in 6 (20 %), and class IV in 1 (3 %) patients. The locations of FCDs resected were in the frontal lobe in 18 cases, temporal lobe in 7, parietal lobe in 2, and in bilobes including frontoparietal lobe in 2 and parieto occipital lobes in 1. Eight cases that had FCDs involved in the rolandic cortex presented hemiparesis before surgical resection. Motor function in four of them improved after operation. The histopathological types of FCDs were type Ia in 1, type Ib in 7, type IIa in 7, type IIb in 12, and type III in 3 patients. FCDs were completely resected in 20 patients. Eighteen (90 %) of them were seizure free (p < 0.001) with three patients that received more than one surgery to accomplish complete resection. The patients who had early seizure onset, no significant cognitive function deficit, and early surgical intervention with complete resection in less than 2 years of seizure duration showed best outcomes on seizure control, cognitive function, and quality of life. CONCLUSION: Delay in cognitive development and poor quality of life is common in children treated for FCDs. Early surgical intervention and complete resection of the lesion help for a better seizure control, cognitive function development, and quality of life. FCDs involved eloquent cortex may not prohibit complete resection for better outcomes. PMID- 25296551 TI - Placement of subdural grids in pediatric patients: technique and results. AB - PURPOSE: The purpose of this study is to describe common indications and technique for the application of chronic invasive electrodes in the pediatric patient suffering from medically intractable epilepsy. METHODS: This chapter was prepared based on a retrospective review of the literature and personal experience based from a large tertiary epilepsy center. CONCLUSIONS: Invasive subdural recordings are a safe and efficacious tool to identify the epileptogenic zone and its relationship to functional cortex in highly selected patients with medically refractory epilepsy. The ability to localize the EZ approaches 90 to 100 %, but seizure-free outcome is more complex depending greatly on the experience of the surgical team and the extent of resection. PMID- 25296552 TI - Outcome after epilepsy surgery for cortical dysplasia in children. AB - BACKGROUND AND PURPOSE: Epilepsy surgery for medically refractory epilepsy secondary to cortical dysplasia in children poses special challenges. We aim to review the current available literature on the outcome after epilepsy surgery for cortical dysplasia in children and critically evaluate the prognostic predictors of outcome. METHODS: A comprehensive review of the literature was performed focusing on the outcome after epilepsy surgery for cortical dysplasia in children. Two large recent meta-analyses that included children and adults and several pediatric series of cortical dysplasia in children were reviewed. RESULTS AND CONCLUSIONS: The overall seizure freedom rates range from 40 to 73 %, at about 2 years after surgery; most studies report 50-55% success rate. Complete resection of the epileptogenic lesion/zone remains the most important variable predictive of postoperative seizure freedom. Features unique to cortical dysplasia that limits our ability to ensure complete resection of the epileptogenic zone are reviewed. PMID- 25296554 TI - Visual analysis of the quantitative composition of metagenomic communities: the AmphoraVizu webserver. AB - Low-cost DNA sequencing methods have given rise to an enormous development of metagenomics in the past few years. One basic--and difficult--task is the phylogenetic annotation of the metagenomic samples studied. The difficulty comes from the fact that the typical environmental sample contains hundreds of unknown and still uncharacterized microorganisms. There are several possible methods to assign at least partial phylogenetic information to these uncharacterized data. Originally, the 16S ribosomal RNA was used as phylogenetic marker, then genome sequence alignments and similarity measures between the unknown genome and the reference genomes were applied (e.g., in the MEGAN software), and more recently, phylogeny-based methods applying suitable sets of marker genes were suggested (AMPHORA, AMPHORA2, and the webserver implementation AmphoraNet). Here, we present a visual analysis tool that is capable of demonstrating the quantitative relations gained from the output of the AMPHORA2 program or the easy-to-use AmphoraNet webserver. Our web-based tool, the AmphoraVizu webserver, makes the phylogenetic distribution of the metagenomic sample clearly visible by using the native output format of AMPHORA2 or AmphoraNet. The user may set the phylogenetic resolution (i.e., superkingdom, phylum, class, order, family, genus, and species) along with the chart type and will receive the distribution data detailed for all relevant marker genes in the sample. For publication quality results, the chart labels can be customized by the user. The visualization webserver is available at the address http://amphoravizu.pitgroup.org. The AmphoraNet webserver is available at http://amphoranet.pitgroup.org. The open-source version of the AmphoraVizu program is available for download at http://pitgroup.org/apps/amphoravizu/AmphoraVizu.pl. PMID- 25296555 TI - Endometrial thickness affects the outcome of in vitro fertilization and embryo transfer in normal responders after GnRH antagonist administration. AB - BACKGROUND: The goal of this study was to assess the association between endometrial thickness on the chorionic gonadotropin (hCG) day and in vitro fertilization and embryo transfer (IVF-ET) outcome in normal responders after GnRH antagonist administration. METHODS: A retrospective cohort study was performed in normal responders with GnRH antagonist administration from January 2011-December 2013. Patients were divided into four groups according to endometrial thickness, as follows: <7 mm (group 1), > = 7- < 8 mm (group 2), > = 8- < 14 mm (group 3), and > =14 mm (group 4). RESULTS: A total of 2106 embryo transfer cycles were analyzed. The pregnancy rate (PR) was 44.87%.The clinical pregnancy rate, ongoing pregnancy rate and the implantation rate (17.28%, 13.79%, 10.17%, respectively) were significantly lower in group 1 compared to the other three groups (p < 0.05). The miscarriage rate was higher in patients with endometrial thickness less than 7 mm. The clinical pregnancy rate, ongoing pregnancy rate and implantation rate were highest in patients with endometrial thickness higher than 14 mm, but showed no difference in patients with those of endometrial thickness between 8-14 mm. CONCLUSIONS: There is a correlation between endometrial thickness measured on hCG day and clinical outcome in normal responders with GnRH antagonist administration. The pregnancy rate was lower in patients with endometrial thickness less than 7 mm compared with patients with endometrial thickness more than 7 mm. PMID- 25296558 TI - Human papillomavirus detection in paraffin-embedded colorectal cancer tissues. AB - Human papillomavirus (HPV) has a well-recognized aetiological role in the development of cervical cancer and other anogenital tumours. Recently, an association between colorectal cancer and HPV infection has been suggested, although this is still controversial. This study aimed at detecting and characterizing HPV infection in 57 paired biopsies from colorectal cancers and adjacent intact tissues using a degenerate PCR approach. All amplified fragments were genotyped by means of sequencing. Overall, HPV prevalence was 12.3 %. In particular, 15.8 % of tumour tissues and 8.8 % of non-cancerous tissue samples were HPV DNA-positive. Of these samples, 85.7 % were genotyped successfully, with 41.7 % of sequences identifying four genotypes of the HR (high oncogenic risk) clade Group 1; the remaining 58.3 % of HPV-genotyped specimens had an unclassified beta-HPV. Examining additional cases and analysing whole genomes will help to outline the significance of these findings. PMID- 25296556 TI - RS11212617 is associated with metformin treatment response in type 2 diabetes in Shanghai local Chinese population. AB - OBJECTIVE: This study was designed to examine the relevance of single-nucleotide polymorphism (SNP) rs11212617 with treatment success in type 2 diabetes patients from Shanghai local Chinese Han population. METHODS: We genotyped rs11212617 in incident metformin users of type 2 diabetes patients from Shanghai local Chinese Han population. Association between rs11212617 and changes in HbA1c, fasting plasma glucose and postprandial glucose level were analysed. RESULTS: Two hundred and seventy-four incident metformin users were included in the study sample. The SNP rs11212617 was significantly associated with metformin response in Shanghai local Chinese Han population. CONCLUSION: The rs11212617 is associated with a reduction in HbA1c, fasting plasma glucose and postprandial glucose level. These results suggest that metformin treatment may be more efficacious in Shanghai and valuable for Chinese daily clinical practice. PMID- 25296559 TI - A hybrid absorption-adsorption method to efficiently capture carbon. AB - Removal of carbon dioxide is an essential step in many energy-related processes. Here we report a novel slurry concept that combines specific advantages of metal organic frameworks, ion liquids, amines and membranes by suspending zeolitic imidazolate framework-8 in glycol-2-methylimidazole solution. We show that this approach may give a more efficient technology to capture carbon dioxide compared to conventional technologies. The carbon dioxide sorption capacity of our slurry reaches 1.25 mol l(-1) at 1 bar and the selectivity of carbon dioxide/hydrogen, carbon dioxide/nitrogen and carbon dioxide/methane achieves 951, 394 and 144, respectively. We demonstrate that the slurry can efficiently remove carbon dioxide from gas mixtures at normal pressure/temperature through breakthrough experiments. Most importantly, the sorption enthalpy is only -29 kJ mol(-1), indicating that significantly less energy is required for sorbent regeneration. In addition, from a technological point of view, unlike solid adsorbents slurries can flow and be pumped. This allows us to use a continuous separation process with heat integration. PMID- 25296560 TI - Tailored selection of the interval between neoadjuvant chemoradiotherapy and surgery for locally advanced rectal cancer: analysis based on the pathologic stage or chemoradiation response. AB - BACKGROUND: The optimal interval between neoadjuvant chemoradiotherapy (CRT) and surgery has yet to be established. Additionally, it is unknown whether patients with different pathologic stages or chemoradiation responses should undergo different intervals between CRT and surgery. Therefore, the purpose of this study was to evaluate whether this interval has a differential effect on the oncologic outcome of patients with different chemoradiation responses or pathologic stages. METHODS: We performed a retrospective study of 291 rectal cancer patients who were treated with preoperative chemoradiation and surgery between March 2004 and November 2012. All patients were separated into two groups according to a 7-week treatment interval. Overall survival (OS) and disease-free survival (DFS) were compared between patients undergoing intervals that were shorter and longer than 7 weeks in the entire group and in subgroups of ypT0-2N0, ypT3-4N0 and ypT0-4N+. The recurrence patterns were also analysed in all of the subgroups. Multivariate analysis was performed to explore the clinical factors that were significantly associated with DFS, local recurrence-free survival (LRFS) and distant metastasis free survival among patients exhibiting ypT3-4N0 and ypT0-4N+. RESULTS: For the ypT0-2N0 patients, the 5-year OS and DFS and the rates of local and distant recurrence were similar between the short and long interval groups. For the patients exhibiting ypT3-4N0, although no significant difference was found in OS or DFS between the short and long interval groups, the rate of local recurrence was higher in the long interval group, which was further confirmed by multivariate analysis. In the patients exhibiting ypT0-4N+, both OS and DFS were lower in the long interval group than in the short interval group. Furthermore, multivariate analysis indicated that the interval was significantly associated with DFS, especially LRFS. CONCLUSIONS: The interval between CRT and surgery may exert a differential effect on the prognosis of patients exhibiting different pathologic stages or chemoradiation responses. Therefore, we strongly suggest tailoring the interval between CRT and surgery in locally advanced rectal cancer. PMID- 25296562 TI - Carbohydrate-based N-heterocyclic carbenes for enantioselective catalysis. AB - Versatile syntheses of C2-linked and C2-symmetric carbohydrate-based imidazol(in)ium salts from functionalised amino-carbohydrate derivatives are reported. The novel NHCs were ligated to [Rh(COD)Cl]2 and evaluated in Rh catalysed asymmetric hydrosilylation of ketones with good yields and promising enantioselectivities. PMID- 25296561 TI - Subchondral bone influences chondrogenic differentiation and collagen production of human bone marrow-derived mesenchymal stem cells and articular chondrocytes. AB - INTRODUCTION: Osteoarthritis (OA) is characterized by an imbalance in cartilage and underlying subchondral bone homeostasis. We hypothesized that signals from the subchondral bone may modulate production of matrix components, alter chondrogenic differentiation potential of cocultured bone marrow-derived mesenchymal stem cells (BMSC) and induce a phenotypic shift in differentiated OA chondrocytes. METHODS: We established a novel coculture model between BMSC, mixed cultures (BMSC and chondrocytes) and chondrocytes embedded in fibrin gel with OA and normal subchondral bone explants (OAB and NB). Tissues and cells were either derived from OA or trauma patients. In addition, we used adipose-derived stem cells (ASC) from liposuction. With gene expression analysis, biochemical assays, immunofluorescence and biomechanical tests we characterized the properties of newly generated extracellular matrix (ECM) from chondrocytes and chondrogenically differentiating BMSC cocultured with OAB or NB in comparison with monocultures (cultures without bone explants). RESULTS: Overall, gene expression of collagens of OAB and NB cocultured cells was reduced compared to monocultures. Concomitantly, we observed significantly lower collagen I, II and III and glycosaminoglycan (GAG) production in OAB cocultured cell lysates. In parallel, we detected increased concentrations of soluble GAGs and basic fibroblast growth factor (bFGF), interleukin (IL)-6 and IL-8 in supernatants of OAB and NB cocultures mainly at early time points. IL-1beta concentration was increased in supernatants of OAB cocultures, but not in NB cocultures. Cell-free NB or OAB explants released different amounts of IL-1beta, bFGF and soluble GAG into cell culture supernatants. In comparison to cocultures, monocultures exhibited higher Young's modulus and equilibrium modulus. Stimulation of monocultures with IL 1beta led to a downregulation of aggrecan (ACAN) gene expression and in general to induced matrix metalloprotease (MMP)2, MMP3 and MMP-13 gene expression while IL-6 and IL-8 stimulation partly reduced ACAN, MMP3 and MMP-13 gene expression. CONCLUSIONS: Our results suggest an alteration of molecular composition and mechanical properties of the newly formed ECM in subchondral bone cocultures. We suggest that soluble factors, that is interleukins and bFGF, released in cocultures exert inhibitory effects on collagen and temporary effects on proteoglycan production, which finally results in a reduction of mechanical strength of newly formed fibrillar networks. PMID- 25296563 TI - Early-onset restrictive eating disturbances in primary school boys and girls. AB - This study sought to determine the distribution of early-onset restrictive eating disturbances characteristic of the new DSM-5 diagnosis, avoidant/restrictive food intake disorder (ARFID) in middle childhood, as well as to evaluate the screening instrument, Eating Disturbances in Youth-Questionnaire (EDY-Q). A total of 1,444 8- to 13-year-old children were screened in regular schools (3rd to 6th grade) in Switzerland using the self-report measure EDY-Q, consisting of 12 items based on the DSM-5 criteria for ARFID. 46 children (3.2%) reported features of ARFID in the self-rating. Group differences were found for body mass index, with underweight children reporting features of ARFID more often than normal and overweight children. The EDY-Q revealed good psychometric properties, including adequate discriminant and convergent validity. Early-onset restrictive eating disturbances are commonly reported in middle childhood. Because of possible negative short- and long-term impact, early detection is essential. Further studies with structured interviews and parent reports are needed to confirm this study's findings. PMID- 25296564 TI - Relationship between renal function and extracorporeal membrane oxygenation use: a single-center experience. AB - The effects of extracorporeal membrane oxygenation (ECMO) support on renal function in children with critical illness are unknown. The objective of this study was to investigate the impact of ECMO on renal function among children in different age groups. We performed a single-center retrospective observational study in critically ill children <= 18 years supported on ECMO for refractory cardiac or pulmonary failure (2006-2012). The patient population was divided into four age groups for the purpose of comparisons. The Acute Kidney Injury Network's (AKIN's) validated, three-tiered staging system for acute kidney injury was used to categorize the degree of worsening renal function. Data on patient demographics, baseline characteristics, renal function parameters, dialysis, ultrafiltration, duration of mechanical cardiac support, and mortality were collected. Comparisons of baseline characteristics, duration of mechanical cardiac support, and renal function were made between the four age groups. During the study period, 311 patients qualified for inclusion, of whom 289 patients (94%) received venoarterial (VA) ECMO, 12 (4%) received venovenous (VV) ECMO, and 8 (3%) received both VV and VA ECMO. A total of 109 patients (36%) received ultrafiltration on ECMO, 58 (19%) received hemodialysis, and 51 (16%) received peritoneal dialysis. There was a steady and sustained improvement in renal function in all age groups during the ECMO run, with the maximum and longest sustained improvement occurring in the oldest age group. Proportions of patients in different AKIN stages remained similar in the first 7 days after ECMO initiation. We demonstrate that renal dysfunction improves early after ECMO support. Irrespective of the underlying disease process or patient age, renal function improves in children with pulmonary or cardiac failure who are placed on ECMO. PMID- 25296565 TI - Experimental evaluation of myocardial fibrosis in a rapid atrial pacing model in New Zealand rabbits using quantitative analysis of ultrasonic backscatter. AB - BACKGROUND: The aim of this study was the establishment of a rapid atrial pacing (RAP)-induced atrial fibrillation (AF) model with electrophotoluminescence and the application of ultrasonic backscatter quantitative analysis of the degree of myocardial fibrosis in New Zealand white rabbits. MATERIAL AND METHODS: Sixteen New Zealand white rabbits were randomly divided into 2 groups: 1) a sham operation group (n=8) with implanted electrodes and no rapid pacing and 2) a pacing group (n=8) with an AF model induced by short-term rapid right atrial pacing for 12 h. Establishment of an AF model, atrial myocardium of myocardial fibrosis was tested by Masson staining and expression of collagen I and collagen III protein was detected with pathologic immunohistochemistry integrated back scatter (IBS). Back scattering integral cycle variation (CVIB) were detected in atrial septal and posterior wall of the right atrium. RESULTS: Rapid atrial pacing successfully induced the atrial fibrillation model in rabbits. Masson staining showed myocardial fibrosis significantly increased in the pacing group. Expression of collagen I and collagen III protein was strongly positive in the pacing group, and expression of collagen I and collagen III protein were weakly positive in the sham operation group. Compared with the sham operation group, AII was increased (8.24+/-0.85 vs. 15.56+/-1.30, P<0.05) and (7.58+/-0.56 vs. 16.60+/ 2.45, P<0.05). CVIB was significantly decreased (2.78+/-0.86 vs. 1.08+/-0.13, P<0.05) and (3.12+/-0.65 vs. 1.56+/-0.15, P<0.05) in septal and posterior wall of the right atrium of the pacing group. CONCLUSIONS: Ultrasonic backscatter measurement technique can be used to evaluate degree of myocardial fibrosis in a right atrial pacing-induced atrial arrhythmia model. PMID- 25296566 TI - Contrasting within- and between-host immune selection shapes Neisseria Opa repertoires. AB - Pathogen evolution is influenced strongly by the host immune response. Previous studies of the effects of herd immunity on the population structure of directly transmitted, short-lived pathogens have primarily focused on the impact of competition for hosts. In contrast, for long-lived infections like HIV, theoretical work has focused on the mechanisms promoting antigenic variation within the host. In reality, successful transmission requires that pathogens balance both within- and between-host immune selection. The Opa adhesins in the bacterial Neisseria genus provide a unique system to study the evolution of the same antigens across two major pathogens: while N. meningitidis is an airborne, respiratory pathogen colonising the nasopharynx relatively transiently, N. gonorrhoeae can cause sexually transmitted, long-lived infections. We use a simple mathematical model and genomic data to show that trade-offs between immune selection pressures within- and between-hosts can explain the contrasting Opa repertoires observed in meningococci and gonococci. PMID- 25296568 TI - Electronic Interactions of Michler's Ketone with DNA Bases in Synthetic Hairpins. AB - The mechanism and dynamics of photoinduced electron transfer in two families of DNA hairpins possessing Michler's ketone linkers have been investigated by means of steady state and time-resolved transient absorption and emission spectroscopies. The excited state behavior of the diol linker employed in hairpin synthesis is similar to that of Michler's ketone in methanol solution. Hairpins possessing only a Michler's ketone linker undergo fast singlet state charge separation and charge recombination with an adjacent purine base, attributed to well-stacked ground state conformations, and intersystem crossing to the triplet state, attributed to poorly stacked ground state conformations. The failure of the triplet to undergo electron transfer reactions on the 7 ns time scale of our measurements is attributed to the low triplet energy and reduction potential of the twisted triplet state. Hairpins possessing both a Michler's ketone linker and a perylenediimide base surrogate separated by four base pairs undergo photoinduced hole transport from the diimide to Michler's ketone upon excitation of the diimide. The efficiency of hole transport is dependent upon the sequence of the intervening purine bases. PMID- 25296567 TI - The EMT (epithelial-mesenchymal-transition)-related protein expression indicates the metastatic status and prognosis in patients with ovarian cancer. AB - OBJECTIVES: The epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of the E-cadherin expression, which is primarily controlled by Snail-related zinc-finger transcription factors. The aim of this study was to evaluate the prognostic impact of the expression of EMT-related proteins (E-cadherin and Snail) in patients with ovarian cancer. METHODS: An immunohistochemical analysis was conducted using tissue microarray samples of 174 primary tumors and 34 metastases of ovarian carcinoma, and the relationships between the protein expression, clinicopathological features and outcomes were investigated. RESULTS: A reduced E-cadherin expression was observed in 36.8% of the primary tumors and 30.4%, 35.7%, 37.7% and 52.7% of the stage I, II, III and IV tumors, respectively. The nuclear expression of Snail was positive in 33.9% of the primary tumors. The rate of an EMT-positive status, as represented by both a reduced E-cadherin expression and a nuclear expression of Snail, was significantly higher in the patients with peritoneal dissemination than in those without (p < 0.05). The EMT status was significantly associated with both the progression-free survival and overall survival (p <0.01). A multivariate analysis showed an EMT-positive status to be a significant predictor of both the progression-free survival (p < 0.05) and overall survival (P < 0.01). CONCLUSIONS: These data indicate that the EMT status is significantly associated with peritoneal metastasis and both the progression-free survival and overall survival in patients with ovarian cancer. Therefore, clarifying and controlling EMT signaling is a promising approach to molecular targeted therapy for ovarian cancer. PMID- 25296569 TI - Management of atrial fibrillation in people with haemophilia--a consensus view by the ADVANCE Working Group. PMID- 25296570 TI - Continuous performance test in pediatric obsessive-compulsive disorder and tic disorders: the role of sustained attention. AB - OBJECTIVE: Pediatric obsessive-compulsive disorder (OCD) and tic disorders (TD) are often associated with attention-deficit hyperactivity disorder (ADHD). In order to clarify the role of attention and inhibitory control in pediatric OCD and TD, a continuous performance test (CPT) was administered to a cohort of children and adolescents with OCD alone, TD alone, and OCD+TD. METHODS: A clinical cohort of 48 children and adolescents with OCD alone (n=20), TD alone (n=15), or OCD+TD (n=13) was interviewed clinically and administered the Conners Continuous Performance Test II (CPT-II). The Conners CPT-II is a 14-minute normed computerized test consisting of 6 blocks. It taps into attention, inhibitory control, and sustained attention cognitive domains. Key parameters include errors of omission (distractability), commission (inhibitory control), and variable responding over time (sustained attention). Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria were applied in a best-estimate process to diagnose OCD, TD, ADHD, and anxiety disorders. RESULTS: Children with OCD+TD had more errors of omission (p=0.03), and more hit RT block change (p=0.003) and hit SE block change (p=0.02) than subjects with OCD alone and TD alone. These deficits in sustained attention were associated with younger age and hoarding tendencies. A clinical diagnosis of ADHD in the OCD+TD group also determined worse sustained attention. CONCLUSIONS: A deficit in sustained attention, a core marker of ADHD, is also a marker of OCD+TD, compared to OCD alone and TD alone. Biological correlates of sustained attention may serve to uncover the pathophysiology of OCD and TD through genetic and imaging studies. PMID- 25296571 TI - Soft liquid phase adsorption for fabrication of organic semiconductor films on wettability patterned surfaces. AB - We report a soft liquid-phase adsorption (SLPA) technique for the fabrication of organic semiconductor films on wettability-patterned substrates using toluene/water emulsions. Wettability-patterned substrates were obtained by the UV ozone treatment of self-assembled monolayers of silane coupling agents on glass plates using a metal mask. Organic semiconductor polymer films were formed selectively on the hydrophobic part of the wettability-patterned substrates. The thickness of the films fabricated by the SLPA technique is significantly larger than that of the films fabricated by dip-coating and spin-coating techniques. The film thickness can be controlled by adjusting the volume ratio of toluene to water, immersion angle, immersion temperature, and immersion time. The SLPA technique allows for the direct production of organic semiconductor films on wettability-patterned substrates with minimized material consumption and reduced number of fabrication steps. PMID- 25296572 TI - Preparation of D-limonene oil-in-water nanoemulsion from an optimum formulation. AB - D-limonene in water nanoemulsion is prepared from an optimum formulation by low energy process at room temperature. The phase behavior of d limonene/isotridecanol ethoxylate-6/ isopropyl alcohol /water system is systematically investigated to identify the optimum formulation. The microstructure of intermediate phases has been characterized by optical microscope and small angle X-ray diffraction. The microstructure of formulation concentrate has been further determined by means of electrical conductivity. The droplet size of nanoemulsion has been determined by light scattering and correlated with their microstructure. The results show that d-limonene nanoemulsion with droplet size of ca. 40 nm is obtained via the addition of the optimum formulation, which is a microemulsion, directly into water. This process involves composition change from a bicontinuous structure. PMID- 25296573 TI - Effects of surfactants and aging time on solidification of rice bran oil at room temperature. AB - This study investigated the roles of rice mono- and diacylglycerol (rice MDG) and commercial MDG on solid structure formation of rice bran oil (RBO) and RBO anhydrous milk fat (AMF) blends after the crystallized blends were aged at 5 degrees C for 12 or 24 h and stored at 30 degrees C for 12 or 24 h. The rice MDG was prepared using a pilot-scale molecular distillation (MD) unit to evaporate out the free fatty acids from deodorizer distillate (DD) at 120, 140 and 160 degrees C at 0.1 Pa. It was found that increasing the distillation temperature during MD process from 120 degrees C to 140 degrees C resulted in higher contents of rice MDG and gamma-oryzanol in the unevaporated fraction (UMD) compared to those in DD. Although UMD increased solid fat content in RBO-UMD blend, it could not stabilize the solid fat phase in the RBO-UMD or RBO-AMFUMD oleogel at 30 degrees C storage. In the presence of UMD, RBO-AMF-UMD blends remained in a liquid state although it contained a high content (38.54%) of saturated fatty acids. On the other hand, with the addition of commercial MDG rich in palmitic acid, RBO-MDG and RBO-AMF-MDG blends were able to retain the volume of solid fat phase in the oleogels provided that the RBO-MDG and RBO-AMF-MDG oleogels were aged at 5 degrees C for at least 12 h. This study implicated that the presence of 1% MDG surfactant having different acyl chains from the major fatty acids in the bulk oil phase, as well as aging regime, could be used to assist solid structure forming process of RBO and RBO-AMF oleogels. PMID- 25296574 TI - Interfacial behavior of pulmonary surfactant preparations containing egg yolk lecithin. AB - Mammalian lungs are covered with lipid-protein complexes or pulmonary surfactants. In this work, which aimed towards the less expensive production of artificial pulmonary surfactants, we produced surfactants composed of egg yolk lecithin (eggPC), palmitic acid, and hexadecanol (= 0.30/0.35/0.35, mol/mol/mol ) containing different amounts of Hel 13-5 (NH2-KLLKLLLKLWLKLLKLLL-COOH) as a substitute for the proteins in native pulmonary surfactants. Surface pressure (pi)-molecular area (A) and surface potential (DV)-A isotherms of the mixtures were measured via the Wilhelmy and ionizing (241)Am electrode methods, respectively. The interactions between the lipid components and Hel 13-5 led to variations in the surface pressure caused by the expulsion of fluid components from the surface. Furthermore, the pi-A and DV-A isotherms featured large hysteresis loops for the surfactant that contained a small amount of Hel 13-5 during compression and successive expansion cycling. To elucidate the morphology, the phase behavior was visualized in situ at the air-water interface by means of fluorescence microscopy; the images suggested less effective interactions between Hel 13-5 and the unsaturated PC in eggPC despite the similarity of their monolayer properties. PMID- 25296575 TI - Uptake of sevoflurane limited by the presence of cholesterol in the lipid bilayer membrane: a multinuclear nuclear magnetic resonance study. AB - The effect of cholesterol on the uptake of a fluorinated general anesthetic, sevoflurane (SF, fluoromethyl 2,2,2-trifluoro-1-[trifluoromethyl]ethyl ether) was studied by multinuclear, high-resolution nuclear magnetic resonance (NMR) spectroscopy in combination with a pulsed-field gradient technique. Using large unilamellar vesicles of egg phosphatidylcholine/egg phosphatidylglycerol/cholesterol as model fluid cell membranes, the (19)F and (1)H NMR chemical shifts, longitudinal relaxation times (T1), and diffusion coefficients (D(eff)) were systematically analyzed to quantify the modulation of SF uptake to the lipid membrane by cholesterol. All NMR parameters (chemical shift, T1, and D(eff)) showed that SF uptake is limited by the presence of cholesterol in the membrane. It was found that SF uptake at 40 mol% cholesterol is limited to 50%-60% of the partitioning fraction in the absence of cholesterol in the membrane. This finding is attributed to the loss of motional freedom in the rigid membrane environment, as demonstrated by the gradual slowdown of lipid mobility D(eff) with increase in cholesterol concentration from 0 mol% to 40 mol%. PMID- 25296576 TI - Effect of talc addition on the extraction yield and quality of extra virgin olive oils from Coratina cultivar after production and during storage. AB - An experimental investigation was carried out with the aim to evaluate the effect of talc on the extraction yield and quality of extra virgin olive oils from Coratina olives after production and during storage. A significant effect of talc, added in the malaxer, on both yield and oil quality was observed. The addition of 1% talc lead to a 15% decrease of the residual oil in the olive pomace, while higher amounts of talc did not determine further significant variations. The use of talc caused also a significant decrease of the peroxide value and tocopherols and a significant increase of carotenoids, chlorophylls, phenols, antioxidant activity and K270, while no influence was detected on free fatty acids and K232. Finally, during storage the differences among the oils were maintained as immediately after their production, with the exception of chlorophylls. PMID- 25296577 TI - Are bilateral breast cancers and breast cancers coexisting with ovarian cancer different from solitary tumors? A pair-matched immunohistochemical analysis aimed at intrinsic tumor phenotype. AB - Patients with bilateral breast cancer (BBC) and breast-ovarian cancer syndrome (BOCS) constitute populations potentially enriched for molecular defects involved in the pathomechanisms of these malignancies. The aim of our study was to compare tumor morphology and expression of estrogen and progesterone receptor, HER2, Ki67, cytokeratin 5/6, E-cadherin, vimentin and epidermal growth factor receptor in tissue microarrays from 199 tumors from BBC or BOCS patients and 199 age matched solitary tumors. Compared to controls, BBC and BOCS considered jointly had lower incidence of DCIS, lower expression of PgR and HER2, and higher expression of Ki67 and vimentin. BOCS tumors were of higher grade, had lower expression of ER and PgR and higher expression of Ki67, CK5/6, vimentin and EGFR. BBC had less DCIS component, lower HER2 expression and higher Ki67 expression. Metachronous BBC (mBBC) had lower expression of ER, PgR and HER2, and higher expression of Ki67 and vimentin. Synchronous BBC (sBBC) had less DCIS component, higher expression of ER, and lower expression of CK5/6, EGFR and E-cadherin. BBC and breast cancers in BOCS differ in many aspects from solitary tumors. BBC are a heterogeneous group of tumors, differing between sBBC and mBBC. mBBC phenotype shares many features with BOCS tumors. PMID- 25296578 TI - Precise detection of chromosomal translocation or inversion breakpoints by whole genome sequencing. AB - Structural variations (SVs), including translocations, inversions, deletions and duplications, are potentially associated with Mendelian diseases and contiguous gene syndromes. Determination of SV-related breakpoints at the nucleotide level is important to reveal the genetic causes for diseases. Whole-genome sequencing (WGS) by next-generation sequencers is expected to determine structural abnormalities more directly and efficiently than conventional methods. In this study, 14 SVs (9 balanced translocations, 1 inversion and 4 microdeletions) in 9 patients were analyzed by WGS with a shallow (5 * ) to moderate read coverage (20 * ). Among 28 breakpoints (as each SV has two breakpoints), 19 SV breakpoints had been determined previously at the nucleotide level by any other methods and 9 were uncharacterized. BreakDancer and Integrative Genomics Viewer determined 20 breakpoints (16 translocation, 2 inversion and 2 deletion breakpoints), but did not detect 8 breakpoints (2 translocation and 6 deletion breakpoints). These data indicate the efficacy of WGS for the precise determination of translocation and inversion breakpoints. PMID- 25296579 TI - The phenotypic and molecular genetic spectrum of Alstrom syndrome in 44 Turkish kindreds and a literature review of Alstrom syndrome in Turkey. AB - Alstrom syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alstrom Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alstrom Syndrome and contribute to genotype-phenotype correlation studies. PMID- 25296581 TI - A canonical splice site mutation in GIPC3 causes sensorineural hearing loss in a large Pakistani family. AB - With homozygosity mapping we have identified two large homozygous regions on chromosome 3q13.11-q13.31 and chromosome 19p13.3-q31.32 in a large Pakistani family suffering from autosomal recessive nonsyndromic hearing impairment (arNSHI). The region on chromosome 19 overlaps with the previously described deafness loci DFNB15, DFNB72 and DFNB95. Mutations in GIPC3 have been shown to underlie the nonsyndromic hearing impairment linked to these loci. Sequence analysis of all exons and exon-intron boundaries of GIPC3 revealed a homozygous canonical splice site mutation, c.226-1G>T, in GIPC3. This is the first mutation described in GIPC3 that affects splicing. The c.226-1G>T mutation is located in the acceptor splice site of intron 1 and is predicted to affect the normal splicing of exon 2. With a minigene assay it was shown to result in the use of an alternative acceptor site in exon 2, resulting in a frameshift and a premature stop codon. This study expands the mutational spectrum of GIPC3 in arNSHI. PMID- 25296580 TI - Novel locus for fibrinogen in 3' region of LEPR gene in island population of Vis (Croatia). AB - Leptin, a possible mediator between energy homeostasis, inflammation and cardiovascular disease (CVD), acts via leptin receptors. We investigated association of single-nucleotide polymorphisms (SNPs) and haplotypes of the leptin receptor gene (LEPR) with several CVD risk factors: body mass index, waist circumference (WC), serum lipids, fibrinogen and C-reactive protein levels. Thirty-one SNPs in and near LEPR gene were analyzed in 986 inhabitants of the island of Vis, Croatia and 29 SNPs in the inland sample (N=499). We assessed linkage disequilibrium (LD), SNP and haplotype associations with the selected phenotypes. rs4291477 significantly associated with fibrinogen (P=0.003) and rs7539471 marginally significantly with high-density lipoprotein (P=0.004), but only in the Vis sample, while rs10493384 marginally significantly associated with triglyceride levels (P=0.006) in the inland sample. SNPs were grouped into eight LD blocks in Vis and in seven blocks in the inland population. Haplotype A-C-A-A G-A in block 5 in Vis (rs1782754, rs1171269, rs1022981, rs6673324, rs3790426, rs10493380) and haplotype A-A-A-A in block 4 in the inland data (rs1782754, rs1022981, rs6673324, rs1137100) were nominally associated with WC, P=7.085 * 10( 22) (adjusted P=0.0979) and P=5.496 * 10(-144) (adjusted P=0.1062), respectively. PMID- 25296582 TI - Study of structural chromosome abnormalities to increase the understanding of human genetic diversity: a commentary on signature of backward replication slippage at the copy number variation junction. PMID- 25296583 TI - Identification of the rare compound heterozygous variants in the NEB gene in a Korean family with intellectual disability, epilepsy and early-childhood-onset generalized muscle weakness. AB - We examined a Korean family with complex phenotypes characterized by intellectual disability, epilepsy and early-childhood-onset generalized muscle weakness. Since we did not find any abnormality using several conventional genetic tests for detection of chromosomal aberrations, gene copy number variations and mitochondrial gene mutations, we aimed to identify disease-causing genetic alteration(s) in this family. We conducted whole-exome sequencing (WES) in this family. After filtering the WES data, we compared five exome sequences of two affected siblings, one unaffected sibling and the unaffected parents, and we determined the allele frequency of the identified variants in an Asian population. Finally, we selected one candidate variant pair which is unique in the patients and corresponds to an autosomal recessive genetic model. The two affected siblings had the same compound heterozygous variation in the NEB gene encoding nebulin, which was composed of two different missense variants: c.2603T>C (p.L868P) in exon 27 and c.21340C>T (p.R7114W) in exon 143. We confirmed these variations by Sanger sequencing. On the basis of the fundamental role of nebulin in the brain and skeletal muscles, we concluded that this compound heterozygous NEB variation may be a sound candidate for the disease causing mutation in this family. Since the patients are characterized by generalized muscle weakness together with neurodevelopmental phenotypes, it is suggested that NEB mutations could manifest more diverse phenotypes than those previously described. PMID- 25296584 TI - Breast cancer and cancer stem cells: a mini-review. AB - Breast cancer is the most common type of malignant disease in women worldwide. In developing countries the past few years have sustained an increasing incidence of this type of cancer. Currently, breast cancer is the second leading cause of death due to cancer in women. In 2008 alone it was diagnosed in more than 1 million patients and each year the number of breast cancer-related deaths is estimated to be ~450,000. The mortality rate in breast cancer patients has been decreasing over the years thanks to the development of early diagnostic methods and more effective treatments. But despite the new advances in cancer diagnosis and treatment, the risk of recurrence and metastasis is ever present. It has been theorized that cancer stem cells are involved in the process of tumor growth and metastases. Due to their self-renewing and differentiation capabilities, they are now considered the underlying factor in tumor recurrence and the main reason for therapy resistance. Therefore, the characterization of cancer stem cells may contribute to the development of more effective treatment strategies that should make it possible to eliminate cancer stem cells in order to prevent tumor relapse and metastasis in diagnosed patients. PMID- 25296585 TI - Markers to predict the efficacy of bevacizumab in the treatment of metastatic colorectal cancer. AB - The identification of clinical, biochemical and molecular markers to predict or monitor the efficacy of bevacizumab represents a major point in the treatment of patients with metastatic colorectal cancer. Studies and genetic analyses have been conducted to identify a predictive biomarker of bevacizumab efficacy. However, genes of the angiogenic pathway and angiogenic biomarkers vary substantially, thereby causing interindividual differences that complicate the identification of predictors for anti-vascular endothelial growth factor drugs like bevacizumab. So, the current challenge in bevacizumab treatment is to find predictive markers and implement them in clinical practice. In this review we have summarized the potential candidate biomarkers that may have a role in identifying patients who benefit most from bevacizumab treatment. PMID- 25296586 TI - The DAMA trial: a diet and physical activity intervention trial to reduce mammographic breast density in postmenopausal women in Tuscany, Italy. Study protocol and baseline characteristics. AB - Aims and background. High mammographic breast density (MBD) is an established risk factor for breast cancer (BC). The influence of diet and physical activity (PA) on MBD has long been investigated. In an observational study of a cohort in Florence, we observed inverse associations between consumption of vegetables and olive oil and moderate leisure-time PA and MBD, while high alcohol intake and high glycemic load diets were positively associated with MBD. We set out to investigate whether dietary and PA interventions were able to reduce MBD in postmenopausal women with high MBD (>50%). Methods and study design. The DAMA (Diet, physical Activity and MAmmography) trial, a factorial randomized trial involving healthy nonsmoking postmenopausal women not using hormone replacement therapy and having MBD >50%, is aimed at evaluating the ability of a 24-month intervention based on moderate-intensity PA and/or dietary modification focused on plant foods with a low glycemic load, low in saturated fats and alcohol, and rich in antioxidants and fiber, to reduce the percent MBD. Participants have been randomized to 1 of 4 study arms (diet, PA, diet + PA, control). Dietary and PA habits and anthropometry are collected at baseline and at the end of the intervention phase together with repeated blood and urine samples. The primary outcome of the study is the absolute change in percent MBD as assessed on baseline and follow-up digital mammograms performed in the framework of the local screening program. Results. Of 728 eligible women, 234 (32.1%) agreed to participate. We did not observe any difference across study arms in the baseline distribution of variables of interest related to diet and lifestyle. Conclusions. The DAMA trial may contribute to a better understanding of MBD determinants. This will provide insight into the pathogenesis of BC and may allow the development of strategies for primary prevention focused on high-MBD groups that are easily identifiable in large-scale BC screening programs. TRIAL REGISTRATION NUMBER: ISRCTN28492718. PMID- 25296587 TI - Italian regional health system structure and expected cancer survival. AB - BACKGROUND AND AIMS: Few studies deal with the association of socioeconomic and health system resource variables with cancer survival at the Italian regional level, where the greatest number of decisions about social and health policies and resource allocations are taken. The present study aimed to describe the causal relationships between socioeconomic and health system resource factors and regional cancer survival and to compute the expected cancer survival at provincial, regional and area levels. METHODS AND STUDY DESIGN: Age-standardized relative survival at 5 years from diagnosis of cases incident in 1995-1998 and followed up to 2004 were derived by gender for 11 sites from the Italian Association of Cancer Registries data bank. The socioeconomic and health system resource variables, describing at a regional level the macro-economy, demography, labor market, and health resources for 1995-2005, came from the Health for All database. A principal components factor analysis was applied to the socioeconomic and health system resource variables. For every site, linear regression models were computed considering the relative survival at 5 years as a dependent variable and the principal components factor analysis factors as independent variables. RESULTS: The factors described the socioeconomic and health-related features of the regional systems and were causally related to the characteristics of the patient taken in charge. The models built by the factors allowed computation of the expected relative survival at 5 years with very good concordance with those observed at regional, macro-regional and national levels. In the regions without any cancer registry, survival was coherent with that of neighboring regions with similar socioeconomic and health system resources characteristics. CONCLUSIONS: The models highlighted the causal correlations between socioeconomic and health system resources and cancer survival, suggesting that they could be good evaluation tools for the efficiency of the resources allocation and use. PMID- 25296588 TI - Recent trends in cancer incidence: impact of risk factors, diagnostic activities and data quality of registration. AB - Aims and background. Cancer incidence variations are influenced by different factors including socioeconomic status, risk factors and use of screening. The purpose of this study was to examine trends in cancer incidence in two urban areas in Europe showing differences in influencing factors but also some common characteristics in the context of data quality of the corresponding cancer registries.Methods. Age-standardized incidence rates (world standard - ASRW) for cases diagnosed in 2000-2009 for Sofia (Bulgaria) and the Canton of Zurich (Switzerland) were calculated using data from the corresponding cancer registries. Average annual percent change (AAPC) was estimated with Joinpoint regression analysis. Data quality was estimated in terms of proportions of microscopically verified (MV%) and death-certificate-only (DCO%) cases. Results. ASRWs for all sites were higher in Zurich for men (311 vs 262 per 100,000) and women (241 vs 231 per 100,000) than in Sofia. Colorectal (both sexes), lung (men), cervical and corpus uteri cancer had a higher incidence in Sofia. Prostate, breast and lung (women) cancer were more often diagnosed in Zurich. A significant increase in female lung cancer incidence was observed in both areas. Overall incidence decreased in Zurich, while it did not significantly change in Sofia. MV% was lower in Sofia than in the Canton of Zurich but increased steadily up to 85% in 2009, whereas in the Canton of Zurich MV% was more or less stable around 95%. The DCO% of Sofia was 19% in 2000 and steadily decreased to 8% in 2009. In the Canton of Zurich, the DCO% decreased from 5% in 2000 but increased again from 2006 onwards, up to 3% in 2009. Conclusions. Cancer incidence rates differ between Sofia and Zurich. Differences concerning socioeconomic status, risk factors, use of cancer screening but also data quality may influence these results. PMID- 25296589 TI - Is breast cancer curable: a study of long-term crude cumulative incidence. AB - AIMS AND BACKGROUND: The problem of the search for a proportion of cured patients of breast cancer and the relative time to cure breast cancer has been known since the 1950s. The literature on this topic has developed during the last decades thanks to the availability of studies with long follow-up times, which was required by the type of disease in question. The aim of this study is to estimate, if it exists, the proportion of cured breast cancer patients with a parametric method accounting for competing causes of death. METHODS: In this work we used data from a two-group randomized controlled trial. From 1973 to 1980, 701 women were recruited with breast cancer measuring no more than 2 cm in diameter. They were randomly assigned to radical mastectomy (349 patients) or breast conserving surgery followed by radiotherapy to the ipsilateral mammary tissue (352 patients). Thanks to a reliable classification of the causes of death, it was possible to analyze data using cause-specific mortality. RESULTS: The parametric crude cumulative incidence estimates by the Gompertz distribution accorded closely with the non-parametric estimates. The analysis was also performed for subsets of patients based on menopausal status and number of positive lymph nodes. Statistical evidence for the existence of a cure fraction ranging from 0.48 to 0.71, depending on the subset, was found. However, the estimated proportion of cured patients has not been reached after 30 years' follow-up for most of the subsets. CONCLUSIONS: Although statistical evidence has been found for the presence of a cure fraction, in practical terms it seems that 30 years after a breast cancer diagnosis cure cannot yet be claimed. PMID- 25296590 TI - Comparison of different predictive tools of axillary status in breast cancer with micrometastatic sentinel node. AB - AIM: To compare the performance of six different nomograms and one score in the prediction of non-sentinel lymph node status in a subset of women with breast cancer and micrometastatic sentinel nodes (SN). MATERIAL AND METHODS: Twenty-five patients were included in the study. Five different nomograms not specifically designed for micrometastatic SN, one recently published nomogram specially developed for this type of patients and one score were analyzed, and the corresponding receiver operating characteristic curves were obtained. The area under the curve (AUC) was calculated, as well as the false negative and false positive results and their corresponding rates (FNR and FPR) for a cutoff of <=10% or <=4 points. RESULTS: The Memorial Sloan Kettering Cancer Center (MSKCC) nomogram showed the best performance in this low-risk group of patients (AUC 0.900, FPR 64%, FNR 0%), followed by the French nomogram. CONCLUSIONS: The MSKCC nomogram seems to have the highest accuracy in the identification of patients with low risk of further axillary disease in the subgroup of women with micrometastatic SN. PMID- 25296591 TI - Positive margins following breast cancer tumorectomy. Can we predict the occurrence of residual disease? AB - AIMS AND BACKGROUND: In conservative early stage breast cancer surgery, the sample's margins are directly related to relapse, and positive or close margins indicate the need for additional surgery. Since the range of residual disease in secondary surgeries and the related pathological factors are highly variable, we intended to evaluate the number of additional surgeries due to compromised margins and identify the percentage of residual disease and factors related to it. METHODS: We retrospectively analyzed the clinical records of 659 tumorectomy or needle localization surgery patients with breast carcinoma at the Hospital Universitario Austral in Buenos Aires, Argentina, between December 2000 and December 2012. The variables considered were age, type of surgery, type of margin, tumor size, histological grade, extensive intraductal component and immunohistochemical profile. We investigated how they related to the presence of residual disease. RESULTS: We identified 68 patients (10%) who were reoperated because of positive (75%) or close (25%) margins. Residual disease was identified in 68% of them; the positive (66%) and close (70%) margin ratio was similar. The individual analysis of variables was statistically significant only for tumors larger than 3 cm (Pearson's chi square [1] = 6.7194; P = 0.0095; relative risk = 1.56 [95% CI 1.09-2.21]) with an association between age and tumor size: Pearson's chi square (1) = 3.8984; P = 0.0483; relative risk = 1.56 (95% CI 1.09 2.21). CONCLUSIONS: The need for second surgery due to compromised margins is not common, with variable residual tumor identifying ranges. Some pathological factors can predict the persistence of residual disease. In our series, tumor size >3 cm was the variable identified as an independent predictor. PMID- 25296592 TI - Efficacy of trastuzumab in unselected patients with HER2-positive metastatic breast cancer: a retrospective analysis. AB - AIMS AND BACKGROUND: The addition of trastuzumab to chemotherapy for HER2 positive metastatic breast cancer has significantly improved progression-free survival and overall survival, although most patients develop resistance or have a primarily resistant disease. The aim of the study was to describe the efficacy and safety of a first-line treatment in unselected metastatic HER2-positive breast cancer patients, treated according to clinical practice. METHODS: From 2000 to 2009, we conducted a retrospective multi-institutional analysis of 182 consecutive patients with HER2-positive metastatic breast cancer who underwent first-line treatment with trastuzumab. The primary end points were progression free survival and overall survival; the secondary end points were survival after progression in patients treated with second-line chemotherapy with or without trastuzumab and safety. A total of 172 patients were analyzed. RESULTS: Median progression-free survival and overall survival were 1.2 (95% CI, 1.1-1.4) and 4.4 years (95% CI, 3.6-5.4), respectively. For 100 patients who received second-line chemotherapy, median survival after progression was significantly longer in those who also received trastuzumab: 2.8 (95% CI, 2.1-4.0) versus 1.2 years (95% CI, 0.6-1.9). CONCLUSIONS: Although based on retrospective data, the study confirms the role of trastuzumab as first-line treatment in metastatic breast cancer outside of a controlled trial. Moreover, information obtained on the use of trastuzumab beyond disease progression supports its use in this setting. PMID- 25296593 TI - Safety and efficacy of bevacizumab in combination with first-line chemotherapy in advanced breast cancer: data from the Italian cohort of the ATHENA trial. AB - AIMS AND BACKGROUND: The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study. METHODS: A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers. RESULTS: A total of 278 patients were included. Median age was 57 years (range, 26-85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade >=3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease. CONCLUSIONS: Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy. PMID- 25296594 TI - Salvage treatment with low-dose weekly paclitaxel in elderly or poor performance status patients with metastatic urothelial carcinoma. AB - AIMS AND BACKGROUND: To evaluate the efficacy of weekly, low-dose paclitaxel chemotherapy after the failure of platinum-based combination chemotherapy in elderly or poor performance status patients with metastatic urothelial carcinoma. METHODS: We retrospectively reviewed the medical records of 25 patients. The regimen consisted of paclitaxel, 60 mg/m2 on days 1, 8 and 15, with or without carboplatin (AUC 2). Treatment was repeated every 4 weeks until disease progression. RESULTS: Of 25 patients, the median age was 68 years (range, 47-82), 4 (16%) were female, and 15 (60%) had an ECOG performance status of 2. All patients were >=65 years or had a performance status of 2 in the cases aged <65 years. Six patients received paclitaxel in combination with carboplatin. The overall response rate was 24% (95% CI, 7.3-40.7) with 6 partial responses. Eight patients (32%) achieved stable disease and 5 (20%) had progressive disease. The median time to progression was 4.0 months (95% CI, 2.9-5.1), and median overall survival was 5.5 months (95% CI, 3.7-7.3). Grade 3-4 toxicities were as follows: neutropenia in 9 patients (36%), anemia in 11 (44%), thrombocytopenia in 2 (8%), neutropenic fever in 2 (8%), asthenia in 4 (16%), anorexia in 2 (8%), nausea in 2 (8%), and peripheral neuropathy in 1 (4%). ECOG performance status (0-1 vs 2) was a significant prognostic factor in multivariate analysis. CONCLUSIONS: Low-dose weekly paclitaxel seems to be a meaningful salvage treatment with moderate activity and acceptable toxicity in elderly or poor performance status patients with metastatic urothelial carcinoma. Oncologists should carefully consider the opportunity of chemotherapy versus best supportive care in these patients. PMID- 25296595 TI - The role of tiopronin for the prevention of chemotherapy-related liver toxicity in advanced colorectal cancer patients treated with mFOLFOX7: a prospective analysis. AB - AIMS AND BACKGROUND: Chemotherapy-related hepatotoxicity is a limitation for the continuation of chemotherapy in patients with advanced colorectal cancer (CRC). This prospective study determined the efficacy of tiopronin infusion in chemotherapy-induced hepatoxicity. METHODS AND STUDY DESIGN: One hundred and fifty patients having advanced CRC treated with first-line palliative chemotherapy were included, of whom 86 were treated with mFOLFOX7 plus supplementation of tiopronin and 64 were treated with the same regimen without tiopronin. Aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), total bilirubin (TBIL), gamma-glutamyl transferase (gamma GT), alkaline phosphatase (ALP), and albumin (ALB) were recorded before treatment and during every therapy cycle. In addition, course discontinuations, dose reductions, and chemotherapy efficacy were evaluated. RESULTS: The age and gender of the two groups were comparable (P >0.05). The proportions of abnormal mean ALT (P = 0.042), AST (P = 0.045), TBIL (P = 0.044) and ALB (P = 0.043) were significantly lower in the tiopronin group than the control group. Course discontinuations (P = 0.002), dose reductions (P = 0.005) and efficacy (P = 0.012) were significantly different between the two groups. Multivariate logistic regression analysis showed that the hepatoprotective drug played an important role in clinical outcome (OR = 6.837; 95% CI, 1.845 to 25.333; P = 0.004). CONCLUSIONS: Tiopronin tends to decrease the incidence of chemotherapy-induced hepatoxicity, enhance patients' tolerance to mFOLFOX7 treatment, and even benefit the efficacy of chemotherapy. PMID- 25296596 TI - Non-metastatic Ewing's sarcoma family of tumors of bone in adolescents and adults: prognostic factors and clinical outcome-single institution results. AB - AIMS AND BACKGROUND: There is limited data regarding outcomes of Ewing's sarcoma family of tumors in adolescents and adults compared with the same tumors in childhood. The aim of the study was to analyze prognostic factors and treatment results in a cohort of adolescents and adults with non-metastatic skeletal Ewing's sarcoma family of tumors. METHODS AND STUDY DESIGN: From 1992-2008, 90 adolescents and adults with Ewing's sarcoma family of tumors of the bone were referred to our institution. Sixty-five (72%) non-metastatic patients with analyzable data and treated in our institution were retrospectively evaluated. All patients were treated with alternated chemotherapy regimens administered every 3 weeks. The local treatment modality was selected according to tumor and patient characteristics. RESULTS: The median age was 21 years (range, 13-50). Most patients (74%) were >17 years of age. Forty-six percent of the tumors were located in the extremities. Local therapy was surgery in 45 patients and radiotherapy alone in 19 patients. Twenty-one patients received preoperative and 13 patients postoperative radiotherapy. Median follow-up was 43 months (range, 7 167). The 5-year event-free and overall survival rates for all patients were 44% and 49%, respectively. On univariate survival analysis, event-free and overall survival were worse for patients >17 years of age, tumor size >8 cm in diameter, an axial location, positive surgical margins, and poor histopathological response (<90% necrosis). Age, tumor site and tumor size on event-free and overall survival remained significant on multivariate analysis. CONCLUSIONS: We identified age, tumor size, and tumor site as independent prognostic factors, in accord with the Western literature. These patients require novel treatment modalities. PMID- 25296597 TI - Radiosurgical options in neuro-oncology: a review on current tenets and future opportunities. Part I: therapeutic strategies. AB - Stereotactic radiosurgery can nowadays be considered not only as a potential adjuvant to surgical treatment of several neuro-oncological pathologies, including primary tumors and metastatic lesions, but in some cases also as a valuable alternative tailored option. In Part I of the review, we propose a dissertation focused on the different irradiation stereotactic radiosurgery techniques to date available for clinical indications more relevant to oncologists and oncologic surgeons, such as high-grade and low-grade gliomas, metastases and meningiomas. It is noteworthy that the most recent body of literature correlated with this topic shows that the therapeutic results presently achievable are revolutionizing the way patients are diagnosed and managed worldwide. As we sought to shed light on the current potentialities of stereotactic radiosurgery, we must consider that to exploit all the benefits provided by this shift in clinical practice, a profound awareness by all practitioners involved in the care of neoplastic patients is certainly warranted. PMID- 25296598 TI - Feasibility of tomotherapy for postoperative irradiation of lower extremity sarcomas. AB - AIMS AND BACKGROUND: To evaluate the effectiveness of helical tomotherapy-based image-guided radiotherapy (IGRT) following surgery for lower extremity sarcoma. METHODS AND STUDY DESIGN: A retrospective review of three patients undergoing postoperative irradiation with tomotherapy for lower extremity sarcoma was conducted. Planning target volume (PTV) coverage, acute side effects, long-term complications and functional results were assessed. RESULTS: Tomotherapy allows adequate coverage of the PTV without an excessive radiation dose to the normal adjacent structures. Radiotherapy side effects were acceptable with no treatment breaks. All patients were disease free with no complications and no impairment of their daily activity at the last follow-up. CONCLUSION: IGRT delivered by tomotherapy may be ideally suited for sarcoma of the extremities because of its ability to achieve a high radiation dose along with excellent normal tissue sparing. Further prospective studies should be conducted to confirm this hypothesis. PMID- 25296599 TI - Combined neutron brachytherapy with external beam radiation in patients with inoperable gastroesophageal junction adenocarcinoma. AB - AIMS AND BACKGROUND: To assess the safety and feasibility of neutron brachytherapy (NBT) combined with external beam radiation (EBRT) in the treatment of patients with inoperable gastroesophageal junction adenocarcinoma (GEJAC). METHODS AND STUDY DESIGN: From January 2001 until November 2011, 67 patients with inoperable GEJAC received EBRT combined with NBT. Radiotherapy consisted of EBRT up to a total dose of 40 to 54 Gy in 20 to 27 fractions and NBT up to 12 to 25 Gy in 3 to 5 fractions. The patients were divided into 2 total-dose groups: a low dose group (28 patients, 52 to 57 Gy) and a high-dose group (39 patients, 58 to 69 Gy). RESULTS: The duration of follow-up ranged from 16 to 106 months. The median survival time for the 67 patients was 15.7 months, and the 1-, 2-, 3- and 5-year rates for overall survival (OS) were 56.7%, 37.2%, 30.8% and 12.7%, respectively. The corresponding local-regional control (LRC) rates were 72.4%, 59.1%, 51.2% and 42.0%, respectively. In univariate analysis, the 5-year OS rates were 7.1% and 16.5% for patients of the low-dose and high-dose groups, respectively (P = 0.024). The incidence of acute esophagitis (grade >=2) was significantly higher in the high-dose group (56.4%) than the low-dose group (32.1%) (P = 0.049). No fistulas or massive bleeding were observed during treatment. Six of the 67 patients (9.0%) experienced late toxicity: fistulas developed in 3 patients and massive bleeding occurred in 3 patients. Of these 6 patients, 4 had persistent or locally recurrent tumors, and 2 displayed no evidence of tumors. Three patients each were in the low-dose and high-dose groups. CONCLUSIONS: The combination of EBRT and NBT was safe and effective in patients with GEJAC. The high-dose group achieved better LRC and OS but had a higher rate of acute esophagitis. PMID- 25296600 TI - Serum receptor-binding cancer antigen expressed on SiSo cells (RCAS1) as a diagnostic and prognostic marker for non-small cell lung cancer. AB - BACKGROUND: Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that induces cell-cycle arrest and apoptosis in cells bearing the RCAS1 receptor. The aim of the study was to elucidate the diagnostic and prognostic value of RCAS1 levels in patients with non-small cell lung cancer. METHODS: Sera collected from 30 healthy volunteers, 40 patients with benign lung diseases and 97 non-small cell lung cancer cases were subjected to RCAS1 ELISA, and relationships between serum RCAS1 and clinical characteristics were evaluated. RESULTS: Serum RCAS1 levels were higher in the non-small cell lung cancer group than in the healthy volunteers and benign lung disease groups (P <0.001). With a cutoff level 19.8 U/ml, RCAS1 had a sensitivity of 87.6%, a specificity of 82.5% and an accuracy of 86.1% for non-small cell lung cancer. Univariate analysis revealed that non-small cell lung cancer patients with elevated RCAS1 levels had significantly shorter overall survival (P = 0.042) than the other two groups. By multivariate analysis, serum RCAS1 was identified as an independent prognostic factor (P = 0.003). CONCLUSIONS: Assessment of serum RCAS1 levels could be considered as a diagnostic and prognostic marker in non-small cell lung cancer. PMID- 25296601 TI - Expression of DNA cytosine deaminase APOBEC3 proteins, a potential source for producing mutations, in gastric, colorectal and prostate cancers. AB - AIMS AND BACKGROUND: APOBEC3B is a deaminase that possesses DNA C-to-T editing activity. A recent report showed that APOBEC3B mRNA was overexpressed in breast cancer and that its expression was responsible for the high C-to-T mutation spectrum in breast cancer, suggesting that APOBEC3B could serve as a source for producing mutations. To see whether APOBEC3B is overexpressed in other common cancers at the protein level, we investigated APOBEC3 protein expression in 100 gastric, 103 colorectal and 107 prostate cancer tissues as well as in 10 breast cancers by immunohistochemistry using antibody that could detect APOBEC3B, APOBEC3F and APOBEC3D proteins. RESULTS: In the cancers, APOBEC3 expression was detected in 100% of breast cancers, 67% of gastric, 84% of colorectal and 67% of prostate cancer. Also, it was expressed in 100% of normal breast, 90% of normal stomach, 82% of normal colon and 93% of normal prostate tissues. In contrast to earlier data that showed an increased APOBEC3B expression in breast cancer cells compared to normal breast cells, APOBEC3 expression in cancers was lower than in normal tissues (gastric and prostate cancer) or was not different from normal tissues (colorectal and breast cancer). There was no significant association of APOBEC3 expression with clinocopathological parameters, including histology, metastasis and stage. CONCLUSIONS: Our data indicate that APOBEC3 overexpression might not be restricted to specific cancer types. Also, APOBEC3 expression in many normal epithelial cells suggests that there might be a mutation unrelated function of APOBEC3 in the normal cells. PMID- 25296602 TI - Autophagy and redox status in carcinoma of an unknown primary. AB - AIM AND BACKGROUND: The purpose of the study was to investigate the role and clinical implications of autophagy and reactive oxygen species-related proteins in carcinoma of an unknown primary (CUP). METHODS AND STUDY DESIGN: Tissue microarray was constructed for a total of 77 CUP cases. Immunohistochemical stains conducted were as follows: autophagy-related beclin-1, LC3A, LC3B, and p62; redox-related catalase, thioredoxin reductase, glutathione S-transferase pi, thioredoxin-interacting protein, and manganese superoxide dismutase. Immunohistochemical results were then related to their clinicopathologic parameters. RESULTS: The degree of LC3A expression showed a difference according to histologic subtype. In undifferentiated carcinoma, LC3A had the highest expression and adenocarcinoma had the lowest expression (P = 0.021). According to clinical subtype, there was a significant difference between LC3A and glutathione S-transferase pi in expression. LC3A had the highest expression in single-organ types and the lowest in intermediate and carcinomatosis types (P = 0.003). Glutathione S-transferase pi showed the highest expression in nodal-type tumors and the lowest in carcinomatosis types (P = 0.010). In univariate analysis, shorter overall survival was related to tumor glutathione S-transferase pi negativity (P = 0.030). CONCLUSIONS: Different expression levels of the autophagy and reactive oxygen species-related proteins, LC3A and glutathione S-transferase pi, were observed according to histologic and/or clinical subtype of carcinoma of an unknown primary. PMID- 25296603 TI - Spiritual aspects of care for adolescents with cancer. AB - AIMS AND BACKGROUND: Adolescents with cancer have psychosocial issues that need to be adequately addressed. Spirituality is a fundamental aspect of their psychological well-being. METHODS: A chaplain is a daily presence in the Youth Project ward for adolescents at the Pediatric Oncology Unit of the Istituto Nazionale Tumori, Milan. The chaplain conducts daily visits to the ward and the outpatient clinic/day hospital, holds daily meetings with the psychologists on staff, and attends biweekly meetings with doctors and/or nurses. The cases of patients referred for spiritual assistance between January and December 2012 were analyzed by patient age and reasons for consultation, and were compared with cases referred for psychological consultation. RESULTS: A psychological consultation was offered to 84% of patients/families, and further support was needed for 23% of children and 45% of teenagers. Spiritual support was provided for 2 children and 20 adolescents (24% of the sample considered). CONCLUSIONS: Acknowledgment of their spiritual needs helps patients to battle with their disease. The reasons patients and parents ask for spiritual assistance only partially overlap with the motives behind requests to see a psychologist. The care of adolescents with cancer should include catering for their spiritual needs by assuring the constant presence of a chaplain on hospital wards. PMID- 25296605 TI - Small bowel perforation caused by advanced melanoma. AB - The incidence of melanoma has been increasing over the years and it remains, despite the heterogeneous survival for different stages, a disease with high mortality. Dissemination occurs primarily by the lymphatic route, followed by the hematogenous route. Gastrointestinal metastases do occur, but they are mainly intraluminal mucosal melanomas. Peritoneal or primary mucosal melanomas are rare. Only a few cases have been described of patients presenting with acute abdominal pain due to a melanoma. In this report we present a young patient with no prior health problems. Due to silent progression of disease at first, and secondarily avoidance of medical consultation, she finally presented to our emergency department with signs of intestinal perforation. In the operating theater a massive metastasis in the intestines with perforation was seen, as well as many smaller intra-abdominal and cutaneous lesions. Approximately 35 cm of jejunum had to be resected. Furthermore, the primary melanoma on the left forearm was excised and turned out to be in almost complete regression. Although initial recovery after surgery was good, the patient died only one month after presentation due to the advanced nature of her disease, which points to the devastating effect of undiagnosed melanoma and gastrointestinal metastasis. Since the melanoma incidence is rising, similar cases may present in the near future. This emphasizes the importance of proper full physical examination in patients with atypical abdominal symptoms. PMID- 25296604 TI - Simultaneous breast and axillary recurrence in a patient with a history of breast cancer and ipsilateral upper extremity melanoma: challenges in diagnosis and management. AB - BACKGROUND: Nodal patterns of spread for breast cancer and melanoma have been extensively studied in the literature. The phenomenon of upper extremity melanoma and ipsilateral breast cancer has been previously reported. We describe a rare case of a simultaneous locoregional recurrence of both malignancies. CASE REPORT: A patient with a previous diagnosis of stage 1A melanoma of the left upper extremity at age 29 developed left breast invasive ductal carcinoma 1 year later. The patient underwent a wide local excision with negative margins for the melanoma and a partial mastectomy with axillary dissection followed by chemotherapy and radiation therapy for her breast cancer. Five years later she was diagnosed with a dual recurrence while 36 weeks pregnant. CONCLUSIONS: Regular follow-up according to the NCCN guidelines is critical in diagnosing a recurrence of malignancy. Pathologic analysis is paramount in dictating management strategies in rare cases of dual recurrence. PMID- 25296606 TI - Metastatic melanoma with spontaneous regression, psoriasis and HLA-Cw6: case report and a hypothesis to explore. AB - Spontaneous regressions of metastatic melanoma are rare, but several cases have been described in the literature. Although the mechanism of the phenomenon is not well understood, it is postulated that an activation of the immune system is behind it. Here we report the case of a patient with metastatic melanoma that, without any treatment, regressed spontaneously. The patient presented psoriasis (a disease of the skin related with autoimmunity) linked with HLA-Cw6. We review the literature and hypothesize with the possible relationship between psoriasis, HLA-Cw6 and the spontaneous regression. PMID- 25296607 TI - A rare case of male breast cavernous-type angioleiomyoma. AB - Cutaneous leiomyomas of the breast are extremely rare, particularly in men. Leiomyomas are categorized into three groups: angioleiomyomas, pilar leiomyomas and genital leiomyomas. Angioleiomyomas, or vascular leiomyomas, are benign tumors arising from smooth muscle cells of arterial or venous walls. We report the case of a 70-year-old man who was admitted to the surgery unit because of a painful lump in the left periareolar region. Ultrasound investigation showed a well-delimited, hyperechogenic, inhomogeneous nodular lesion. The final diagnosis was made after surgical excision and pathological evaluation of the mass. The histological features and immunohistochemical profile, characterized by positive expression of the spindle-shaped tumor cells for desmin and smooth muscle actin and by positive expression of the endothelial cells of the vascular channels for pan-endothelial markers CD34 and CD31, confirmed the diagnosis of a cavernous type angioleiomyoma. PMID- 25296608 TI - Case report of multimodality treatment for metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour. AB - AIMS AND BACKGROUND: Hypercalcaemia due to metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour is challenging to manage and requires a multimodality approach. METHODS: We present a case of a woman undergoing liver transplantation for metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour. RESULTS: A young woman with a history of parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour (Ki-67 5%) removed in 1998 developed bilobar liver metastases in 2004 and underwent repeated transarterial embolisations of liver tumour and therapy with somatostatin analogue. In view of symptomatic hypercalcaemia refractory to medical therapy, she underwent liver transplantation in 2006. In 2012, follow-up imaging showed a 3-cm hypervascular lesion in the posterior wall of the stomach, which was confirmed on endoscopic ultrasound and on gallium-68-octreotate positron emission tomography scan. A gastric wall resection was performed in February 2013, and biopsies showed a neuroendocrine tumour of intermediate grade (Ki-67 15%). In June 2013, a restaging imaging showed a 2.4 cm lesion in the left breast, which was reported as a primary breast cancer on biopsies, and a 14-mm tissue lesion anterior to the gastric antrum. The patient underwent surgical excision of the breast cancer followed by hormone treatment and radiotherapy. She had surgical removal of the gastric recurrence with adjuvant chemotherapy postoperatively. CONCLUSIONS: Hypercalcaemia related to parathyroid hormone-related peptide-secreting neuroendocrine tumour can be life-threatening, and liver transplantation may be a viable option in case of liver only diffuse neuroendocrine metastases refractory to other therapies. The risk of tumour recurrence remains a significant clinical problem after liver transplantation, and only a few patients might be considered tumour-free 5 years after liver transplantation. PMID- 25296609 TI - Tailored stent for bronchial stump fistula closure and omentoplasty for infection control: a combined approach with low morbidity. AB - Bronchopleural fistula (BPF) after pneumonectomy remains a dangerous complication with high mortality and morbidity. Primary closure of the fistula with muscle flaps and a thoracic window is generally used to treat BPF. New techniques for secondary stump closure including glues, stents and coils have been introduced recently. We report the use of a J-shaped tracheal stent device placed during bronchoscopy combined with omentoplasty to control the symptoms related to BPF and pleural space infection, respectively. PMID- 25296610 TI - Granular cell tumor of the neurohypophysis: a single-institution experience. AB - Granular cell tumor (GCT) is a rare neoplasm occurring in the sellar and suprasellar spaces. It is a primary tumor of the neurohypophysis, presumably arising from the pituicytes, a distinctive glial cell of the neurohypophysis. GCTs in most reported cases show biologically benign behavior with slow growth. Only 70 cases of hypophyseal GCTs have been reported in the literature. We report a case of GCT in the neurohypophysis of a 46-year-old woman and discuss the histological and clinical features of this neoplasm together with the treatment modalities, reviewing the pertinent literature. PMID- 25296611 TI - Experience with pazopanib in the treatment of metastatic renal cell carcinoma: a monocentric experience. AB - AIM AND BACKGROUND: The aim of the study was to assess the activity and the safety of pazopanib as first-line therapy in patients with metastatic renal cell carcinoma. METHODS AND STUDY DESIGN: Between September 2011 and April 2014, 15 patients (8 females and 7 males) with metastatic renal cell carcinoma, referred to the Medical Oncology Unit of Policlinico-Bari, were treated with pazopanib, administered orally at the dose of 800 mg daily. Patients were assessed for activity every three months by computed tomography. The primary endpoint was response rate evaluated by RECIST criteria and progression-free survival. RESULTS: To date, 15 patients have been evaluated for response: 11 (73.4%) achieved a partial response after 3 months of therapy with a median duration of 11.6 months (range, 5-31); 3 (20%) had stable disease with a median of 6 months (range, 4-7). No complete response has been observed. One patient progressed, and the median time to disease progression was 11 months. At a median time of 21 months, 14 patients are continuing therapy with pazopanib, and the benefit achieved has remained unchanged in all of them. The median progression-free survival was 10.52 months. Grade 3-4 toxicity was hypertension in 2 patients. CONCLUSIONS: The data confirm other experiences showing the efficacy of pazopanib as first-line therapy in metastatic renal cell carcinoma. The overall clinical benefit rate (partial response + stable disease) was particularly high (>90). There is strong evidence of a long-lasting disease control both for patients achieving partial response and for those with stable disease. PMID- 25296612 TI - Clinical features of male breast cancer and multimodal treatment: a comment to retrospective survey analysis at Italian centers. PMID- 25296613 TI - Potential diagnostic biomarkers: differential expression of LMP2/beta1i and cyclin B1 in human uterine leiomyosarcoma. AB - AIMS AND BACKGROUND: Whilst most uterine smooth muscle neoplasms are benign, uterine leiomyosarcoma (Ut-LMS) is extremely malignant with a high incidence of metastasis and recurrence. Gynecological tumors are often associated with female hormone secretion, but no strong link has been detected between human Ut-LMS and the hormonal environment. In fact, the risk factors for Ut-LMS are poorly understood. In addition, no diagnostic biomarkers for differentiating between leiomyoma, a benign tumor, and malignant Ut-LMS have been found. Interestingly, mice that were homozygously deficient for LMP2/beta1i were found to spontaneously develop Ut-LMS and exhibited a Ut-LMS prevalence of ~40% by 14 months of age. Thus, analyzing potential risk factors for Ut-LMS (such as LMP2/beta1i) might aid the development of diagnostic biomarkers and clinical treatments for the condition. METHODS AND STUDY DESIGN: Fifty-seven patients (age range: 32-83 years) who had been diagnosed with uterine mesenchymal tumors were chosen from a pathological archive. Tissue samples from these patients were fixed in 10% buffered formalin, incubated in 4% paraformaldehyde for 8 hours, and embedded in paraffin. Tissue sections were stained with hematoxylin and eosin for standard histological examination or were subjected to further processing for immunohistochemical (IHC) examination. Serial Ut-LMS, bizarre leiomyoma, leiomyoma, and myometrium sections were subjected to IHC staining of beta-smooth muscle actin, estrogen receptor, cyclin B1, LMP2/beta1i, calponin h1, ki-67, tumor protein p53, and progesterone receptor. RESULTS: The Ut-LMS samples were positive for cyclin B1 and negative for LMP2/beta1i, while the opposite result was obtained for bizarre leiomyoma, leiomyoma, and myometrium samples. CONCLUSIONS: The expression pattern of LMP2/beta1i and cyclin B1 might be a diagnostic biomarker for human Ut-LMS. Studies of the biological roles of LMP2/beta1i and/or cyclin B1 could lead to the elucidation of new targets for therapies against Ut-LMS. PMID- 25296614 TI - Differences between MEG and high-density EEG source localizations using a distributed source model in comparison to fMRI. AB - Electroencephalography (EEG) and magnetoencephalography (MEG) are widely used to localize brain activity and their spatial resolutions have been compared in several publications. While most clinical studies demonstrated higher accuracy of MEG source localization, simulation studies suggested a more accurate EEG than MEG localization for the same number of channels. However, studies comparing real MEG and EEG data with equivalent number of channels are scarce. We investigated 14 right-handed healthy subjects performing a motor task in MEG, high-density-(hd ) EEG and fMRI as well as a somatosensory task in MEG and hd-EEG and compared source analysis results of the evoked brain activity between modalities with different head models. Using individual head models, hd-EEG localized significantly closer to the anatomical reference point obtained by fMRI than MEG. Source analysis results were least accurate for hd-EEG based on a standard head model. Further, hd-EEG and MEG localized more medially than fMRI. Localization accuracy of electric source imaging is dependent on the head model used with more accurate results obtained with individual head models. If this is taken into account, EEG localization can be more accurate than MEG localization for the same number of channels. PMID- 25296615 TI - Ovarian tissue cryopreservation followed by controlled ovarian stimulation and pick-up of mature oocytes does not impair the number or quality of retrieved oocytes. AB - BACKGROUND: The objective of this study was to evaluate the feasibility of fertility preservation in cancer patients by combined bilateral ovarian cortex cryopreservation and embryo freezing. METHODS: This was a cohort-controlled study in a university hospital center. Sixteen patients with a recent cancer diagnosis were included in the study. They all consented to fertility preservation by a combined technique: ovarian tissue cryopreservation (OTC) followed by ovarian stimulation for in vitro fertilization (IVF) and embryo freezing. The control group included 100 women of the same age undergoing IVF for male factor infertility. RESULTS: The mean number of metaphase II oocytes was 8.3 per patient (+/-7.7) and was not statistically different from the control group (8.1 +/- 5.6). The mean number of good quality embryos obtained was not statistically different in the 2 groups (4.2 versus 4.4). CONCLUSION: OTC before embryo freezing does not impair the number or quality of cryopreserved embryos, but increases fertility preservation potential. PMID- 25296616 TI - A seco-catechin cyclization approach to 4->6-linked catechin dimers. AB - A viable route has been developed for the selective synthesis of the 4->6-linked catechin dimers, scarcely accessible from Nature and/or through synthesis. An acyclic nucleophilic catechin precursor (seco-catechin) was used for the regioselective union with an electrophilic catechin unit, and subsequent pyran cyclization gave the desired 4->6-linked dimers, i.e., procyanidin B6 and catechin-(4alpha->6)-gallocatechin. PMID- 25296618 TI - HDL particles--more complex than we thought. PMID- 25296617 TI - Kv 11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv 11.1 (hERG) inhibitors. AB - BACKGROUND AND PURPOSE: Drug-induced arrhythmia due to blockade of the Kv 11.1 channel (also known as the hERG K(+) channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv 11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds. EXPERIMENTAL APPROACH: The affinity and kinetic parameters of 15 prototypical Kv 11.1 inhibitors were evaluated in a number of [(3) H]-dofetilide binding assays. The lipophilicity (logKW - C8 ) and membrane partitioning (logKW - IAM ) of these compounds were determined by means of HPLC analysis. KEY RESULTS: A novel [(3) H]-dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv 11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel. CONCLUSIONS AND IMPLICATIONS: A compound's affinity for the Kv 11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv 11.1 channel. This may help to elucidate how Kv 11.1-induced cardiotoxicity is governed and how it can be circumvented in the future. PMID- 25296619 TI - Imaging adults on extracorporeal membrane oxygenation (ECMO). AB - Extracorporeal membrane oxygenation (ECMO) is increasingly being used in adults following failure to wean from cardiopulmonary bypass, after cardiac surgery or in cases of severe respiratory failure. Knowledge of the different types of ECMO circuits, expected locations of cannulas and imaging appearance of complications is essential for accurate imaging interpretation and diagnosis. Commonly encountered complications are malposition of cannulas, adjacent or distal haemorrhage, stroke, stasis thrombus in access vessels, and distal emboli. This article will describe the imaging appearance of different ECMO circuits in adults as well as commonly encountered complications. If a CT (computed tomography) angiogram is being performed on these patients to evaluate for pulmonary embolism, the scan may be suboptimal from siphoning off of the contrast by the ECMO. In such cases, an optimal image can be obtained by lowering the flow rate of the ECMO circuit or by disabling the circuit for the duration of image acquisition. Key Points * Femoroatrial VV ECMO: femoral vein drainage cannula and right atrial return cannula. * Femorofemoral VV ECMO: return and drainage cannulas placed in femoral veins. * Dual-lumen single cannula VV ECMO: via the right IJ/Femoral vein with the tip in the IVC/SVC. * Peripheral VA ECMO: peripheral venous drainage cannula and peripheral arterial return cannula. * Central VA ECMO: direct right atrial drainage cannula and aortic return cannula. PMID- 25296620 TI - Ovariectomy-induced osteopenia influences the middle and late periods of bone healing in a mouse femoral osteotomy model. AB - Objective It is known that bone healing was delayed in the presence of osteoporosis in humans. However, due to the complexities of the healing of osteoporotic fractures, animal models may be more appropriate to study the effects of osteoporosis in more details and to test drugs on the fracture repair process. The purpose of this study was to investigate the influence of ovariectomy-induced osteopenia in bone healing in an open femoral osteotomy model, and to test the feasibility of this model for evaluating the healing process under osteopenic conditions. Methods In assessing the effects of osteopenia on fracture healing, ovariectomized mouse models were employed. A mid shaft femur osteotomy model was also established 3 weeks after ovariectomy as an osteopenic fracture group (OVX group). Femurs were then harvested at 2 weeks and 6 weeks after fracture for X-ray radiography, micro-computed tomography (micro CT), histology and biomechanical analysis. A sham-operated group (Sham group) was used for comparison. Results The OVX mice had significantly lower BVF, vBMD and TMD in the fracture calluses at 6 weeks (P < 0.05), and similar trend was observed in 2 weeks. Additionally, larger calluses in OVX animals were observed via micro-CT and X-ray, but these did not result in better healing outcomes as determined by biomechanical test at 6 weeks. Histological images of the healing fractures in the OVX mice found forward of broken end resorption and delay of hard callus remodeling. The impaired biomechanical measurements in the OVX group (P < 0.05) were consistent with micro-CT measurements and radiographic scoring, which also indicated delay in fracture healing of the OVX group. Conclusions This study provided evidences that ovariectomy-induced osteopenia impair the middle and late bone healing process once more. These data also supported the validity of the mouse femoral osteotomy model in evaluating the process of bone healing under osteopenic conditions. PMID- 25296621 TI - Resistance to lambda-cyhalothrin in Spanish field populations of Ceratitis capitata and metabolic resistance mediated by P450 in a resistant strain. AB - BACKGROUND: The withdrawal of malathion in the European Union in 2009 resulted in a large increase in lambda-cyhalothrin applications for the control of the Mediterranean fruit fly, Ceratitis capitata, in Spanish citrus crops. RESULTS: Spanish field populations of C. capitata have developed resistance to lambda cyhalothrin (6-14-fold), achieving LC50 values (129-287 ppm) higher than the recommended concentration for field treatments (125 ppm). These results contrast with the high susceptibility to lambda-cyhalothrin found in three Tunisian field populations. We have studied the mechanism of resistance in the laboratory selected resistant strain W-1Klambda (205-fold resistance). Bioassays with synergists showed that resistance was almost completely suppressed by the P450 inhibitor PBO. The study of the expression of 53 P450 genes belonging to the CYP4, CYP6, CYP9 and CYP12 families in C. capitata revealed that CYP6A51 was overexpressed (13-18-fold) in the resistant strain. The W-1Klambda strain also showed high levels of cross-resistance to etofenprox (240-fold) and deltamethrin (150-fold). CONCLUSION: Field-evolved resistance to lambda-cyhalothrin has been found in C. capitata. Metabolic resistance mediated by P450 appears to be the main resistance mechanism in the resistant strain W-1Klambda. The levels of cross resistance found may compromise the effectiveness of other pyrethroids for the control of this species. (c) 2014 Society of Chemical Industry. PMID- 25296622 TI - Evaluation of gardenia yellow using crocetin from alkaline hydrolysis based on ultra high performance liquid chromatography and high-speed countercurrent chromatography. AB - Gardenia yellow is globally the most valuable spice and food color. It is generally a mixture of water-soluble carotenoid glycosyl esters which consist of crocetin bis(gentiobiosyl) ester as the main component. Crocetin is a natural carotenoid dicarboxylic acid that may be a candidate drug for pharmaceutical development, however, it is either present in trace amounts or is absent in natural gardenia yellow products. We here propose that crocetin produced by alkaline hydrolysis can be used to qualitatively evaluate gardenia yellow products using an ultra high performance liquid chromatographic assay. A useful and efficient isolation technique for isolating high-purity crocetin from gardenia yellow using high-speed countercurrent chromatography is described. High speed countercurrent chromatographic fractionation followed by an ultra high performance liquid chromatographic assay showed that trans-crocetin is easily converted to about 15% cis-crocetin (85% trans-crocetin). Crocetin in gardenia yellow was quantitatively evaluated. Our approach is based on the hydrolysis process for converting crocetin glycosyl esters to crocetin before evaluation and isolation using the ultra high performance liquid chromatographic and high-speed countercurrent chromatographic methods. The combination of hydrolysis and chromatographic methods allows evaluation of the purity and quantity of crocetin in gardenia yellow. PMID- 25296623 TI - Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation. AB - BACKGROUND: Some smokers may benefit from a therapy that combines different nicotine replacement therapies (NRT) or drugs with different mechanisms of action.The aim of this study was to determine the efficacy of the combined therapy of varenicline and nicotine patches versus varenicline monotherapy. METHODS: Three hundred forty-one smokers who smoked 20 or more cigarettes per day were recruited from a smoking cessation clinic between February 2012 and June 2013. The participants were randomized to receive a varenicline plus nicotine patch of 21 mg every 24 hours (170) or varenicline plus a placebo patch (171). All of the smokers received a standard 12-week course of varenicline and an 11 week course of either the placebo patch or the active patch after the target quit day. Both groups received behavioral support. The primary outcome was continuous abstinence for weeks 2 through 12 confirmed by exhaled levels of carbon monoxide. Post hoc subgroup analyses were performed to evaluate the treatment effects for a specific endpoint in subgroups of smokers. RESULTS: The combination of the nicotine patch with varenicline was not associated with higher rates of continuous abstinence at 12 weeks (39.1% versus 31.8%; odds ratio (OR) 1.24; 95% confidence interval (CI) 0.8 to 2.6) and 24 weeks (32.8% versus 28.2%; OR 1.17; 95% CI 0.4 to 1.9). When participants were analyzed by subgroups according to cigarette consumption, the abstinence rates among smokers who smoked more than 29 cigarettes per day at 12 weeks (OR 1.39; 95% CI 1.2 to 2.5) and 24 weeks (OR 1.46; 95% CI 1.2 to 2.8) were significantly higher in the combination group. Other post hoc analyses based on level of dependence and previous quit attempts did not show subgroup differences. No differences between the groups for the reported adverse events were observed (chi2 value 0.07; P 0.79). CONCLUSIONS: The combination of varenicline with the nicotine patch does not improve abstinence rates at 12 and 24 weeks compared with varenicline used as monotherapy when all smokers were analyzed as a whole, independent of consumption level. TRIAL REGISTRATION: This study is registered at clinicaltrial.gov (NCT01538394). PMID- 25296624 TI - Production of volatiles in fresh-cut apple: effect of applying alginate coatings containing linoleic acid or isoleucine. AB - One of the main quality parameters in apples is aroma, its main precursors are fatty acids (FA) and amino acids (AA). In this study, alginate edible coatings were used as carriers of linoleic acid or isoleucine to serve as precursors for the production of aroma in cut apples. Apple wedges were immersed in a CaCl2 solution and coated with one of the following formulations: alginate solution (Alg-Ca), Alg-Ca-low-level linoleic acid (0.61 g/Lt), (LFA), Alg-Ca-high-level linoleic acid (2.44 g/L; HFA), Alg-Ca-low-level isoleucine (0.61 g/L; LAA), and Alg-Ca-high-level isoleucine (2.44 g/L; HAA). Apple wedges were stored at 3 degrees C and 85% relative humidity for 21 d and key volatiles were studied during storage. Addition of precursors, mainly isoleucine, showed to increase the production of some key volatiles on coated fresh-cut apples during storage. The concentration of 2-methyl-1-butanol was 4 times higher from day 12 to day 21 in HAA, while 2-methyl butyl acetate increased from day 12 to day 21 in HAA. After 21 d, HAA-apples presented a 40-fold value of 2-methyl-butyl acetate, compared to Alg-Ca cut apples. Values of hexanal increased during cut apple storage when the coating carried linoleic acid, mainly on HFA, from 3 to 12 d. The ability of apples to metabolize AA and FA depends on the concentration of precursors, but also depends on key enzymes, previous apple storage, among others. Further studies should be done to better clarify the behavior of fresh-cut apples as living tissue to metabolize precursors contained in edible coatings for the production of volatiles. PMID- 25296625 TI - Effects of trimester-specific and total gestational weight gain on children's anthropometrics. AB - BACKGROUND: Gestational weight gain (GWG) has been shown to be a risk factor for overweight in offspring.Aim of this study was to quantify the contributions of trimester-specific and total GWG on offspring's BMI and waist circumference (WC). This is of interest for the design of interventions targeted at women showing a high GWG in early pregnancy. METHODS: In a retrospective cohort study data on GWG (total and by trimester, exposure), a number of potential confounders, and children's BMI z-scores and WC (outcomes) were analyzed using structural equation models to disentangle the trimester-specific direct effects of GWG and indirect effects mediated via total GWG. RESULTS: 7313 mother child pairs with a children's mean age of 5.81 years were analyzed. Total effects (indirect + direct) of GWG (kg/week) on children's BMI z-score and WC (cm) were observed in all trimesters, most prominently in the second. The longitudinal effect of GWG is a composite of trimester-specific direct effects (on BMI: 0.105, 0.255, 0.002, on WC: 0.538, 1.64, 0.308) and total GWG (on BMI 0.608, on WC: 1.03) at the end of pregnancy. CONCLUSIONS: Both trimester-specific priming and total GWG explained offspring's anthropometrics. The results indicate, that reversal from additional weight gain attained early in pregnancy resulting in normal total GWG at the end of pregnancy might still contribute to a substantial reduction of offspring's BMI and WC. PMID- 25296626 TI - Factors affecting susceptibility to Mycobacterium tuberculosis: a close view of immunological defence mechanism. AB - Tuberculosis is the most deadly infectious disease. In particular, pulmonary tuberculosis, being the predominant one, is highly contagious. In past the 200 years, one billion tuberculosis (TB) deaths had occurred, and it is anticipated that in the next 25 years, more than 40 million people may be killed by TB unless control measures are implemented. There are various causes which increase the susceptibility to Mycobacterium tuberculosis infection; these include weakened immune system which occurs through various diseases and medications like human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), type II diabetes, end-stage kidney disease, alcoholism and intravenous drug use, certain cancers, cancer treatment such as chemotherapy, malnutrition and very young or advanced age. Some other factors include tobacco use, which increases the risk of getting TB and dying from it. In this manuscript, the authors tried to summarize all the alterations occurring in immune system at cellular and molecular level which occur due to infection, metabolic changes and chemical exposure, which increase susceptibility to mycobacterial infection. PMID- 25296627 TI - Primary corneal melanocytoma in a Collie. AB - A 6-year-old female, spayed Collie was referred to the Western College of Veterinary Medicine for a 12-month history of a progressive right corneal mass. A superficial keratectomy was performed and histopathology revealed a corneal melanocytoma with complete excision. There has been no recurrence of the neoplasm to date (12 months). This is the first known report of an isolated corneal melanocytoma in a canine. PMID- 25296629 TI - Formation of dianions in helium nanodroplets. AB - The formation of dianions in helium nanodroplets is reported for the first time. The fullerene cluster dianions (C60)n(2-) and (C70)n(2-) were observed by mass spectrometry for n>=5 when helium droplets containing the appropriate fullerene were subjected to electron impact at approximately 22 eV. A new mechanism for dianion formation is described, which involves a two-electron transfer from the metastable He(-) ion. As well as the prospect of studying other dianions at low temperature using helium nanodroplets, this work opens up the possibility of a wider investigation of the chemistry of He(-), a new electron-donating reagent. PMID- 25296628 TI - A retrospective analysis of cross-reacting cetuximab IgE antibody and its association with severe infusion reactions. AB - Severe infusion reactions (SIRs) at rates of 5% or less are known side effects of biological agents, including mAbs such as cetuximab. There are currently no prospectively validated risk factors to aid physicians in identifying patients who may be at risk of experiencing an SIR following administration of any of these drugs. A retrospective analysis of 545 banked serum or plasma samples from cancer patients participating in clinical trials of cetuximab was designed to evaluate whether the presence of pretreatment IgE antibodies against cetuximab, as determined by a commercially available assay system, is associated with SIRs during the initial cetuximab infusion. Patients with a positive test indicating the presence of pretreatment antibodies had a higher risk of experiencing an SIR; however, at the prespecified cutoff utilized in this analysis, the test has a relatively low-positive predictive value (0.577 [0.369-0.766]) and a negative predictive value of 0.961 (0.912-0.987) in an unselected patient population. Data collected in this large retrospective validation study support prior observations of an association between the presence of pretreatment IgE antibodies cross reactive with cetuximab and SIRs. Further analysis of the test's ability to predict patients at risk of an SIR would be required before this assay could be used reliably in this patient population. PMID- 25296630 TI - Clozapine-induced myocarditis: separating the wheat from the chaff. PMID- 25296631 TI - Inadequate fruit and vegetable intake in people with psychosis. AB - OBJECTIVE: The objective of this study was to identify factors associated with poor dietary intake (less than four servings of fruit and vegetables daily) in a large nationally representative sample of adults with psychotic disorders. METHODS: The sample comprised 1286 adults aged 18-64 years who took part in the second Australian national survey of psychosis. Dietary information was obtained using a standardised questionnaire; all participants provided fasting blood samples. Variables that may be related to diet and nutritional intake were investigated; these included demographics, physical health outcomes, physical activity, substance use, symptom severity and financial difficulty. Dietary status was explored by sex, age and body mass index using univariate analyses, while a multivariate analysis was performed to identify predictors of low nutritional intake. RESULTS: Approximately 74% of participants ate less than four servings of fruit and vegetables daily. This was associated with a lower body mass index (p<0.05), lower levels of physical activity (p<0.05), sedentary behaviour (p<0.05), substance use (p<0.001), more negative symptoms (p<0.05), eating less frequently (p<0.001), consuming whole fat milk compared to low fat milk (p<0.05), adding salt to food (p<0.05) and financial difficulty (p<0.05). Male sex and younger age (18-34 years) were also associated with lower fruit and vegetable intake (p<0.001). A multivariate regression analysis showed that current smoking (p<0.001) and alcohol (p<0.01) and cannabis abuse (p<0.05) were risk factors for lower fruit and vegetable intake. CONCLUSION: The findings suggest that poor diet in people with psychosis, as reflected by less than four servings of fruit and vegetables daily, is accompanied by other unhealthy behaviours, which has important implications for the development of effective interventions. Importantly, current smoking is a significant predictor of dietary inadequacy. PMID- 25296634 TI - Systolic blood pressure and mortality in patients with atrial fibrillation and heart failure: insights from the AFFIRM and AF-CHF studies. AB - AIMS: To investigate the association between baseline systolic blood pressure levels and mortality in patients with AF with or without LV dysfunction. Hypertension leads to cardiovascular disease but, in specific groups, low blood pressure has been associated with a paradoxical increase in mortality. In patients with AF and heart failure, the relationship between blood pressure and death remains largely unknown. METHODS AND RESULTS: We conducted a post-hoc combined analysis on pooled data from AFFIRM and AF-CHF trials and assessed the relationship between baseline systolic blood pressure (SBP) and mortality and hospitalizations. Patients were classified according to LVEF (>40%, <=40%) and baseline SBP (<120 mmHg, 120-140 mmHg, >140 mmHg). A total of 5436 patients with non-permanent AF were followed for 41 +/- 16 months. In patients with LVEF >40%, baseline SBP was not related to mortality using multivariate Cox regression analyses to adjust for baseline differences (P = 0.563). In contrast, in patients with LVEF <=40% (n = 1980), SBP <120 mmHg and SBP >140 mmHg were both associated with a significant increase in total mortality compared with SBP 120-140 mmHg [hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.41-2.17; and HR 1.40, 95% CI 1.04-1.90, respectively]. Hospitalizations were unrelated to SBP regardless of LVEF. CONCLUSIONS: Mortality is modulated by baseline SBP levels in patients with AF and depressed EF but not in patients with normal EF. Targeted therapy of AF patients based on SBP merits further prospective investigation. PMID- 25296635 TI - HIV infection duration, social support and the level of trauma symptoms in a sample of HIV-positive Polish individuals. AB - The aim of this study was to investigate the relationship between the average HIV infection duration and the level of quantitatively rated post-traumatic stress disorder (PTSD) symptoms and social support dimensions in a sample of 562 Polish HIV+ adults. Possible moderating effects of social support on the relationship between the average HIV infection duration and the level of PTSD symptoms were also analysed. The results of this study suggest that the average HIV infection duration may intensify PTSD symptoms and deteriorate the perceived availability of social support in HIV+ individuals. However, a positive relationship between HIV infection duration and the level of trauma symptoms was observed only in the group of HIV+ individuals with low perceived available social support, but not in the group of HIV-infected individuals with high perceived available social support. This research provided some new insight into the psychological and social aspects of living with HIV. In particular, our results suggest that although HIV infection duration may intensify trauma symptoms and deteriorate social support, perceived available social support may act as a buffer against HIV-related trauma symptoms. PMID- 25296636 TI - Novel nonsense mutation of the EDA gene in a Chinese family with X-linked hypohidrotic ectodermal dysplasia. PMID- 25296637 TI - Validation of HPLC-UV method for determination of minor glycosides contained in Stevia rebaudiana Bertoni leaves. AB - Leaves of Stevia rebaudiana contain glycosides with sweetness and biological activity. However besides the major glycosides, there are other glycosides within extracts that may contribute to its activity, and therefore it is important to quantify them. In this work, an isocratic HPLC method was validated for determination of dulcoside A, steviolbioside, rebaudioside C and rebaudioside B. An HPLC method was performed using a C18 column (250 * 4.6 mm, particle size 5 um) and a UV detector set at 210 nm. The mobile phase consisted of a 32:68 (v/v) mixture of acetonitrile and sodium phosphate buffer (10 mmol/L, pH 2.6), set to a flow rate of 1.0 mL/min. The calculated parameters were: sensitivity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy and precision. The calibration curves were linear over the working range 25-150 ug/mL, with coefficient of correlation of >=0.99 and coefficient of determination of >=0.98. The LOD was 5.68-8.81 ug/mL, while the LOQ was 17.21-26.69 ug/mL. The percentage recoveries of fortified samples were 100 +/- 10% and precision, relative standard deviation, was <10%. The method validation showed accuracy, linearity and precision; therefore this method can be applied for quantitative analysis of minor steviol glycosides in S. rebaudiana leaves. PMID- 25296638 TI - Dermatological consultations in an observation unit of an emergency department in Italy. AB - BACKGROUND: Dermatological emergencies exist and should not be underestimated. On the other hand, many accesses to the emergency department (ED) of patients with dermatological conditions are unjustified. OBJECTIVE: Our main objective is to describe dermatological conditions seen in an ED observation unit (EDOU). Secondly, our aim is to identify alarm symptoms and signs of 'true emergencies'. METHODS: We conducted a prospective study, including dermatological patients admitted to EDOU of the University Hospital of San Martino, Genoa, Italy, in 3 years. RESULTS: Overall 372 patients were studied. The most common condition seen was infection (41.67%) (mainly bacterial), followed by atypical exanthem (13.98%) and vasculitis (11.29%). The highest rate of cases peaked in May (13%); infectious diseases showed two peaks (spring and autumn). CONCLUSION: Given constraints involved in health care today, it is crucial to understand which dermatological presentations are 'true emergencies'. In such a scenario knowing the epidemiology of dermatological emergencies and the alarming skin signs and symptoms might be useful. PMID- 25296640 TI - Conformationally restricted isoindoline-derived spin labels in duplex DNA: distances and rotational flexibility by pulsed electron-electron double resonance spectroscopy. AB - Three structurally related isoindoline-derived spin labels that have different mobilities were incorporated into duplex DNA to systematically study the effect of motion on orientation-dependent pulsed electron-electron double resonance (PELDOR) measurements. To that end, a new nitroxide spin label, (ExIm)U, was synthesized and incorporated into DNA oligonucleotides. (ExIm)U is the first example of a conformationally unambiguous spin label for nucleic acids, in which the nitroxide N-O bond lies on the same axis as the three single bonds used to attach the otherwise rigid isoindoline-based spin label to a uridine base. Continuous-wave (CW) EPR measurements of (ExIm)U confirm a very high rotational mobility of the spin label in duplex DNA relative to the structurally related spin label (Im)U, which has restricted mobility due to an intramolecular hydrogen bond. The X-band CW-EPR spectra of (ExIm)U can be used to identify mismatches in duplex DNA. PELDOR distance measurements between pairs of the spin labels (Im)U, (Ox)U, and (ExIm)U in duplex DNA showed a strong angular dependence for (Im)U, a medium dependence for (Ox)U, and no orientation effect for (ExIm)U. Thus, precise distances can be extracted from (ExIm)U without having to take orientational effects into account. PMID- 25296639 TI - Long-term outcomes following microwave ablation for liver malignancies. AB - BACKGROUND: Microwave ablation has emerged as a promising treatment for liver malignancies, but there are scant long-term follow-up data. This study evaluated long-term outcomes, with a comparison of 915-MHz and 2.4-GHz ablation systems. METHODS: This was a retrospective review of patients with malignant liver tumours undergoing operative microwave ablation with or without liver resection between 2008 and 2013. Regional or systemic (neo)adjuvant therapy was given selectively. Local recurrence was analysed using competing-risk methods with clustering, and overall survival was determined from Kaplan-Meier curves. RESULTS: A total of 176 patients with 416 tumours were analysed. Colorectal liver metastases (CRLM) comprised 81.0 per cent of tumours, hepatocellular carcinoma 8.4 per cent, primary biliary cancer 1.7 per cent and non-CRLM 8.9 per cent. Median follow-up was 20.5 months. Local recurrence developed after treatment of 33 tumours (7.9 per cent) in 31 patients (17.6 per cent). Recurrence rates increased with tumour size, and were 1.0, 9.3 and 33 per cent for lesions smaller than 1 cm, 1-3 cm and larger than 3 cm respectively. On univariable analysis, the local recurrence rate was higher after ablation of larger tumours (hazard ratio (HR) 2.05 per cm; P < 0.001), in those with a perivascular (HR 3.71; P = 0.001) or subcapsular (HR 2.71; P = 0.008) location, or biliary or non-CRLM histology (HR 2.47; P = 0.036), and with use of the 2.4-GHz ablation system (HR 3.79; P = 0.001). Tumour size (P < 0.001) and perivascular position (P = 0.045) remained significant independent predictors on multivariable analysis. Regional chemotherapy was associated with decreased local recurrence (HR 0.49; P = 0.049). Overall survival at 4 years was 58.3 per cent for CRLM and 79.4 per cent for other pathology (P = 0.360). CONCLUSION: Microwave ablation of liver malignancies, either combined or not combined with liver resection, and selective regional and systemic therapy resulted in good long-term survival. Local recurrence rates were low after treatment of tumours smaller than 3 cm in diameter, and those remote from vessels. PMID- 25296642 TI - Is diabetes and hypertension screening worthwhile in resource-limited settings? An economic evaluation based on a pilot of a Package of Essential Non communicable disease interventions in Bhutan. AB - In response to a lack of cost-effective data on screening and early treatment of diabetes and hypertension in resource-limited settings, a model-based economic evaluation was performed on the World Health Organization (WHO)'s Package of Essential Non-communicable (PEN) disease interventions for primary health care in Bhutan. Both local and international data were applied in the model in order to derive lifetime costs and outcomes resulting from the early treatment of diabetes and hypertension. The results indicate that the current screening option (where people who are overweight, obese or aged 40 years or older who visit primary care facilities are screened for diabetes and hypertension) represents good value for money compared to 'no screening'. The study findings also indicate that expanding opportunistic screening (70% coverage of the target population) to universal screening (where 100% of the target population are screened), is likely to be even more cost-effective. From the sensitivity analysis, the value of the screening options remains the same when disease prevalence varies. Therefore, applying this model to other healthcare settings is warranted, since disease prevalence is one of the major factors in affecting the cost-effectiveness results of screening programs. PMID- 25296643 TI - The steps from translatable to translational research. PMID- 25296641 TI - The Thoc1 ribonucleoprotein and prostate cancer progression. AB - BACKGROUND: The majority of newly diagnosed prostate cancers will remain indolent, but distinguishing between aggressive and indolent disease is imprecise. This has led to the important clinical problem of overtreatment. THOC1 encodes a nuclear ribonucleoprotein whose expression is higher in some cancers than in normal tissue. The hypothesis that THOC1 may be a functionally relevant biomarker that can improve the identification of aggressive prostate cancer has not been tested. METHODS: THOC1 protein immunostaining was evaluated in a retrospective collection of more than 700 human prostate cancer specimens and the results associated with clinical variables and outcome. Thoc1 was conditionally deleted in an autochthonous mouse model (n = 22 or 23 per genotype) to test whether it is required for prostate cancer progression. All statistical tests were two-sided. RESULTS: THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth. CONCLUSIONS: Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment. PMID- 25296644 TI - Iro/IRX transcription factors negatively regulate Dpp/TGF-beta pathway activity during intestinal tumorigenesis. AB - Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co-activation of these pathways in the adult Drosophila midgut induces "tumor-like" overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF-beta acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX-family-protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF-beta. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF-beta. In addition, Irx5 expression confers a growth advantage in the presence of TGF beta, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF-beta activity. We propose that during the characteristic adenoma-to-carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF-beta, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF-beta pathway components. PMID- 25296645 TI - Cytotoxic effects of ropivacaine, bupivacaine, and lidocaine on rotator cuff tenofibroblasts. AB - BACKGROUND: Concern has recently arisen over the safety of local anesthetics used on human tissues. HYPOTHESIS: Aminoamide local anesthetics have cytotoxic effects on human rotator cuff tenofibroblasts. STUDY DESIGN: Controlled laboratory study. METHODS: Cultured human rotator cuff tenofibroblasts were divided into control, phosphate buffered saline (PBS), and local anesthetic study groups; the PBS study group was further subdivided by pH level (pH 7.4, 6.0, and 4.4). The 6 local anesthetic subgroups (0.2% and 0.75% ropivacaine, 0.25% and 0.5% bupivacaine, and 1% and 2% lidocaine) were also studied at 10% dilutions of their original concentrations. Exposure times were 5, 10, 20, 40, or 60 minutes for the higher concentrations and 2, 6, 12, 24, 48, or 72 hours for the lower concentrations. Cell viability was evaluated through live, apoptotic, and necrotic cell rates using the annexin V-propidium iodide double-staining method. Intracellular reactive oxygen species (ROS) and the activity of mitogen-activated protein kinases (MAPKs) and caspase-3/7 were investigated. RESULTS: The control and PBS groups showed no significant differences in cell viability (P > .999). In the local anesthetic study groups, cell viability decreased significantly with increases in anesthetic concentrations (P < .001) and exposure times (P < .001), with the exception of the lidocaine subgroups, where this effect was masked by the very high cytotoxicity of even low concentrations. Among the studied local anesthetic subgroups, 0.2% ropivacaine was the least toxic. The levels of intracellular ROS of each local anesthetic subgroup also increased significantly (P < .05). The studied local anesthetics showed increases in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 as well as in levels of caspase-3/7 activity (P < .001). CONCLUSION: The cytotoxicity of the anesthetics studied to tenofibroblasts is dependent on exposure time and concentration. Of the evaluated anesthetics, ropivacaine is the least toxic in the clinically used concentration. The studied anesthetics induce tenofibroblast cell death, mediated by the increased production of ROS, by the increased activation of ERK1/2, JNK, and p38 and by the activation of caspase-3/7. CLINICAL RELEVANCE: This study identified the cytotoxic mechanisms of aminoamide local anesthetics acting on rotator cuff tenofibroblasts. The greatest margin of safety was found in lower anesthetic concentrations in general and more specifically in the use of ropivacaine. PMID- 25296646 TI - Early Versus Delayed Passive Range of Motion After Rotator Cuff Repair: A Systematic Review and Meta-analysis. AB - BACKGROUND: Postoperative rehabilitation has been shown to affect healing of the rotator cuff after surgical repair. However, it is unknown whether an early or delayed rehabilitation protocol is most beneficial for healing. PURPOSE: To determine whether early versus delayed passive range of motion (PROM) affects rotator cuff (RC) retear rates after surgery. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of the literature published between January 2003 and February 2014 was conducted. Retear rates were compared for early (within 1 week after surgery) versus delayed (3-6 weeks after surgery) PROM using chi(2) or Fisher exact tests as well as relative risks (RR) and 95% CIs. In the first analysis, data from evidence level 1 studies that directly compared early versus delayed PROM were pooled; and in the second analysis, data from level 1 to 4 studies that did not directly compare early versus delayed PROM were pooled. The second analysis was stratified by tear size and repair method. RESULTS: Twenty-eight studies (1729 repairs) were included. The first analysis of level 1 studies did not reveal a significant difference in retear rates for early (13.7%) versus delayed (10.5%) PROM (P = .36; RR = 1.30 [95% CI, 0.74-2.30]). The second analysis revealed that for <=3 cm tears, the risk of retear was lower for early versus delayed PROM for transosseous (TO) plus single-row anchor (SA) repairs (18.7% vs 28.2%, P = .02; RR = 0.66 [95% CI, 0.47-0.95]). For >5 cm tears, the risk of retear was greater for early versus delayed PROM for double row anchor (DA) repairs (56.4% vs 20%, P = .002; RR = 2.82 [95% CI, 1.31-6.07]) and for all repair methods combined (52.2% vs 22.6%, P = .01; RR = 2.31 [95% CI, 1.16-4.61]). There were no statistically significant associations for tears measuring <1 cm, 1 to 3 cm, 3 to 5 cm, and >3 cm. CONCLUSION: Evidence is lacking with regard to the optimal timing of PROM after RC repair; however, this study suggests that tear size may be influential. PMID- 25296647 TI - Prophylactic dressing to minimize sacral pressure injuries in high-risk hospitalized patients: a pilot study. AB - AIM: In this paper, we describe a trial protocol used to assess feasibility related to: study administration (recruitment, randomization, retention, compliance, eligibility criteria, suitability of protocol instructions and data collection questionnaires); resource and data management (suitability of site, time and budget allocation, management of personnel and data); intervention fidelity (treatment dose, violations); and effect size. BACKGROUND: Pressure injury can lead to increases in hospital length of stay and cost. The sacrum is identified as one of the most common anatomical pressure injury sites for hospitalized patients. Silicone foam border dressings have been proposed as one strategy to reduce pressure injury incidence; however, rigorous testing of benefit in a general medical-surgical population is required. DESIGN: Randomized controlled trial. METHODS: Eighty patients will be recruited after assessment of high risk of pressure injury in a large tertiary hospital in south-east Queensland, Australia. Eligible, consenting participants will be randomly allocated to either a control group (routine care) or an intervention group (routine care and a sacral prophylactic dressing). The primary outcomes comprise feasibility criteria as identified above. The secondary measure is the presence and severity of sacral pressure injury via blind assessment of digital photographs. Research ethics approval was received in October 2013. DISCUSSION: Prophylactic dressings applied to the sacrum may be an effective method for reducing pressure injury in high-risk general medical-surgical patients. However, more rigorous studies to confirm benefit are required. This pilot study will determine the feasibility and effect size to inform a larger randomized controlled trial. PMID- 25296648 TI - Plasmodesmata-located protein overexpression negatively impacts the manifestation of systemic acquired resistance and the long-distance movement of Defective in Induced Resistance1 in Arabidopsis. AB - Systemic acquired resistance (SAR) is a plant defence response that provides immunity to distant uninfected leaves after an initial localised infection. The lipid transfer protein (LTP) Defective in Induced Resistance1 (DIR1) is an essential component of SAR that moves from induced to distant leaves following a SAR-inducing local infection. To understand how DIR1 is transported to distant leaves during SAR, we analysed DIR1 movement in transgenic Arabidopsis lines with reduced cell-to-cell movement caused by the overexpression of Plasmodesmata Located Proteins PDLP1 and PDLP5. These PDLP-overexpressing lines were defective for SAR, and DIR1 antibody signals were not observed in phloem sap-enriched petiole exudates collected from distant leaves. Our data support the idea that cell-to-cell movement of DIR1 through plasmodesmata is important during long distance SAR signalling in Arabidopsis. PMID- 25296649 TI - Recent advances and future directions in targeting the secretory apparatus in multiple myeloma. AB - Multiple myeloma is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage specialized in producing large amounts of immunoglobulins. The uniquely well-developed secretory apparatus that equips normal and transformed plasma cells with the capacity for high-level protein secretion constitutes a distinctive therapeutic target. In this review we discuss how fundamental cellular processes, such as the unfolded protein response (UPR), endoplasmic reticulum (ER)-associated degradation and autophagy, maintain intracellular protein homeostasis (proteostasis) and regulate plasma cell ontogeny and malignancy. We summarize our current understanding of the cellular effects of proteasome inhibitors and the molecular bases of resistance to them. Furthermore, we discuss how improvements in our understanding of the secretory apparatus and of the complex interactions between intracellular protein synthesis and degradation pathways can disclose novel drug targets for multiple myeloma, defining a paradigm of general interest for cancer biology and disorders of altered proteostasis. PMID- 25296651 TI - Barriers to qualitative dementia research: the elephant in the room. AB - As our population is aging, the global prevalence of dementia is rising. Recent extensive reviews of the dementia literature highlight a clear need for additional qualitative research to address the experiences of people with dementia and their carers. To date, the vast majority of published dementia research is quantitative in nature and, perhaps not surprisingly, attracts the bulk of government funding. In contrast, qualitative dementia research is poorly resourced and less frequently published. Although a myriad of factors are responsible for this dichotomy, we propose that inadequate funding represents the "elephant in the room" of dementia research. In this article, we describe and emphasize the need for qualitative dementia research, highlight existing barriers, and outline potential solutions. Examples of barriers are provided and theoretical underpinnings are proposed. PMID- 25296650 TI - Molecular annotation of ketol-acid reductoisomerases from Streptomyces reveals a novel amino acid biosynthesis interlock mediated by enzyme promiscuity. AB - The 6-phosphogluconate dehydrogenase superfamily oxidize and reduce a wide range of substrates, making their functional annotation challenging. Ketol-acid reductoisomerase (KARI), encoded by the ilvC gene in branched-chain amino acids biosynthesis, is a promiscuous reductase enzyme within this superfamily. Here, we obtain steady-state enzyme kinetic parameters for 10 IlvC homologues from the genera Streptomyces and Corynebacterium, upon eight selected chemically diverse substrates, including some not normally recognized by enzymes of this superfamily. This biochemical data suggested a Streptomyces biosynthetic interlock between proline and the branched-chain amino acids, mediated by enzyme substrate promiscuity, which was confirmed via mutagenesis and complementation analyses of the proC, ilvC1 and ilvC2 genes in Streptomyces coelicolor. Moreover, both ilvC orthologues and paralogues were analysed, such that the relationship between gene duplication and functional diversification could be explored. The KARI paralogues present in S. coelicolor and Streptomyces lividans, despite their conserved high sequence identity (97%), were shown to be more promiscuous, suggesting a recent functional diversification. In contrast, the KARI paralogue from Streptomyces viridifaciens showed selectivity towards the synthesis of valine precursors, explaining its recruitment within the biosynthetic gene cluster of valanimycin. These results allowed us to assess substrate promiscuity indices as a tool to annotate new molecular functions with metabolic implications. PMID- 25296652 TI - The ethics of an ordinary medical technology. AB - Some routinely applied hospital technologies may have unintended consequences for patients and their families. The neonatal cardiorespiratory monitor, a computer like display used to show an infant's vital functions, is one such technology that may become part of a parent's day-to-day being with his or her hospitalized child. In this phenomenological study, I explored how the monitor may mediate parental sensibilities, reshaping the contact of parent and child. This exploration speaks to understanding the relational ethics of even the seemingly most ordinary of medical technologies in clinical contexts. PMID- 25296653 TI - 'Conditional candour' and 'knowing me': an interpretive description study on patient preferences for physician behaviours during end-of-life communication. AB - OBJECTIVE: To understand patients' preferences for physician behaviours during end-of-life communication. METHODS: We used interpretive description methods to analyse data from semistructured, one-on-one interviews with patients admitted to general medical wards at three Canadian tertiary care hospitals. Study recruitment took place from October 2012 to August 2013. We used a purposive, maximum variation sampling approach to recruit hospitalised patients aged >=55 years with a high risk of mortality within 6-12 months, and with different combinations of the following demographic variables: race (Caucasian vs non Caucasian), gender and diagnosis (cancer vs non-cancer). RESULTS: A total of 16 participants were recruited, most of whom (69%) were women and 70% had a non cancer diagnosis. Two major concepts regarding helpful physician behaviour during end-of-life conversations emerged: (1) 'knowing me', which reflects the importance of acknowledging the influence of family roles and life history on values and priorities expressed during end-of-life communication, and (2) 'conditional candour', which describes a process of information exchange that includes an assessment of patients' readiness, being invited to the conversation, and sensitive delivery of information. CONCLUSIONS: Our findings suggest that patients prefer a nuanced approach to truth telling when having end-of-life discussions with their physician. This may have important implications for clinical practice and end-of-life communication training initiatives. PMID- 25296654 TI - Efficacy of dehydroepiandrosterone to overcome the effect of ovarian ageing (DITTO): a proof of principle randomised controlled trial protocol. AB - INTRODUCTION: Dehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a limited number of randomised controlled trials (RCTs). This double blinded RCT aims to measure the effect of DHEA supplementation prior to and during controlled ovarian hyperstimulation on ovarian response prior to IVF treatment in women predicted to have poor ovarian reserve. METHODS AND ANALYSIS: Sixty women with ovarian antral follicle count <=10 and serum anti-Mullerian hormone <=5 pmol/L undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment at the Nurture fertility clinic, Nottingham will be recruited. They will be randomised to either receive DHEA capsule 75 mg/day or placebo for at least 12 weeks before egg collection. All participants will undergo standard long down regulation protocol using human menopausal gonadotropin 300 IU/day. Serum samples and follicular fluids at the time of egg collection will be collected for hormonal immunoassays. For ICSI participants, cumulus cells stripped from oocyte will be collected for cumulus gene expression analyses regarding oocyte competence. Microdrops of oocyte culture media before the time of ICSI will be assessed for glucose, pyruvate and lactate utilisation. Embryo transfer will be performed on day 2, 3 or 5 based on the number and quality of the embryos available. Pregnancy will be defined as urine pregnancy test positive (biochemical pregnancy) and 6-8 weeks ultrasound scan with fetal heart beat (clinical pregnancy) and live birth. It is planned to perform the molecular and nutritional fingerprint analyses in batches after finishing the clinical phase of the study. ETHICS AND DISSEMINATION: The approval of the study was granted by the NHS Research Ethics Committee (Ref number NRES 12/EM/0002), the Medicines and Healthcare products Regulatory Agency (MHRA), and the Nottingham University Hospitals Trust Research and Development department. All participants shall provide written informed consent before being randomised into allocated treatment groups. TRIAL REGISTRATION NUMBER: Protocol V.2.0; EudraCT number: 2011-002425 21; http://www.clinicaltrials.gov; NCT01572025; CTA reference: 03057/0053/001 0002. PMID- 25296655 TI - Discontinuing inappropriate medication in nursing home residents (DIM-NHR Study): protocol of a cluster randomised controlled trial. AB - INTRODUCTION: Nursing home residents often have a high number of comorbidities resulting in polypharmacy. Inappropriate prescribing is therefore likely to occur, which in turn is expected to worsen cognitive impairment, to increase the fall risk and to decrease residents' quality of life. The objective of the 'Discontinuing Inappropriate Medication in Nursing Home Residents' (DIM-NHR) study is to examine the efficacy and cost-effectiveness of the Multidisciplinary Multistep Medication Review (3MR) that is aimed at optimising prescribing and discontinuing inappropriate medication. METHODS: A cluster randomised controlled trial will be conducted. Elderly care physicians and their wards (clusters) will be randomised. Data will be collected at baseline and 4 months after the 3MR has taken place. Six hundred nursing home residents will be recruited of whom more than half are expected to suffer from dementia. The 3MR will be based on consensus criteria and the relevant literature and will be performed by the patient's elderly care physician in collaboration with a pharmacist. ANALYSIS: Primary outcomes-the difference in proportion of residents who successfully discontinued inappropriate medication between the intervention and control group at follow-up. Secondary outcomes-undertreatment, exposure to anticholinergic and sedative medicines, neuropsychiatric symptoms, cognitive function, falls, hospital admission, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Participant burden will be kept at a minimum. The elderly care physician will remain free to adjust medication when symptoms relapse or adverse events occur, rendering serious adverse events highly unlikely. Study findings will be published in peer-reviewed journals and a 3MR toolkit will be developed. TRIAL REGISTRATION NUMBER: This study has been registered at http://www.ClinicalTrials.gov (trial registration number: NCT01876095). PMID- 25296656 TI - A comparison of the force applied on oral structures during intubation attempts between the Pentax-AWS airwayscope and the Macintosh laryngoscope: a high fidelity simulator-based study. AB - OBJECTIVE: We sought to determine whether the use of Pentax-AWS Airwayscope (AWS) applied less force on oral structures during intubation attempts than a conventional direct laryngoscope (DL). DESIGN: Prospective cross-over study. PARTICIPANTS: A total of 37 physicians (9 transitional-year residents, 20 emergency medicine residents and 8 emergency physicians) were enrolled. INTERVENTIONS: We used four simulation scenarios according to the difficulty of intubation and devices and used a high-fidelity simulator to quantify the forces applied on the oral structures. OUTCOME MEASURES: Primary outcomes were the maximum force applied on the maxillary incisors and tongue. Other outcomes of interest were time to intubation and glottic view during intubation attempts. RESULTS: The maximum force applied on the maxillary incisors in the normal airway scenario was higher with the use of AWS than that with DL (107 newton (N) vs 77 N, p=0.02). By contrast, the force in the difficult airway scenario was significantly lower with the use of AWS than that of the DL (89 N vs 183 N, p<0.01). Likewise, the force applied on the tongue was significantly lower with the use of AWS than the use of DL in both airway scenarios (11 N vs 27 N, p<0.001 in the normal airway scenario; 12 N vs 40 N, p<0.01 in the difficult airway scenario). CONCLUSIONS: The use of AWS during intubation attempts was associated with decreased forces applied to oral structures in the simulated difficult airway scenario. PMID- 25296657 TI - A new experimental model for assessing drug efficacy against Trypanosoma cruzi infection based on highly sensitive in vivo imaging. AB - The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, one of the world's major neglected infections. Although development of improved antiparasitic drugs is considered a priority, there have been no significant treatment advances in the past 40 years. Factors that have limited progress include an incomplete understanding of pathogenesis, tissue tropism, and disease progression. In addition, in vivo models, which allow parasite burdens to be tracked throughout the chronic stage of infection, have been lacking. To address these issues, we have developed a highly sensitive in vivo imaging system based on bioluminescent T. cruzi, which express a red-shifted luciferase that emits light in the tissue-penetrating orange-red region of the spectrum. The exquisite sensitivity of this noninvasive murine model has been exploited to monitor parasite burden in real time throughout the chronic stage, has allowed the identification of the gastrointestinal tract as the major niche of long-term infection, and has demonstrated that chagasic heart disease can develop in the absence of locally persistent parasites. Here, we review the parameters of the imaging system and describe how this experimental model can be incorporated into drug development programs as a valuable tool for assessing efficacy against both acute and chronic T. cruzi infections. PMID- 25296658 TI - Labware additives identified to be selective monoamine oxidase-B inhibitors. AB - Plastic labware is used in all processes of modern pharmaceutical research, including compound storage and biological assays. The use of these plastics has created vast increases in productivity and cost savings as experiments moved from glass test tubes and capillary pipettes to plastic microplates and multichannel liquid handlers. One consequence of the use of plastic labware, however, is the potential release of contaminants and their resultant effects on biological assays. We report herein the identification of biologically active substances released from a commonly used plastic microplate. The active contaminants were identified by gas chromatography-mass spectroscopy as dodecan-1-ol, dodecyl 3-(3 dodecoxy-3-oxopropyl)sulfanylpropanoate, and dodecanoic acid, and they were found to be selective monoamine oxidase-B inhibitors. PMID- 25296659 TI - A novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition and kinetic aqueous solubility. AB - In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug-drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug-drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data. PMID- 25296660 TI - A magnetic bead-based ligand binding assay to facilitate human kynurenine 3 monooxygenase drug discovery. AB - Human kynurenine 3-monooxygenase (KMO) is emerging as an important drug target enzyme in a number of inflammatory and neurodegenerative disease states. Recombinant protein production of KMO, and therefore discovery of KMO ligands, is challenging due to a large membrane targeting domain at the C-terminus of the enzyme that causes stability, solubility, and purification difficulties. The purpose of our investigation was to develop a suitable screening method for targeting human KMO and other similarly challenging drug targets. Here, we report the development of a magnetic bead-based binding assay using mass spectrometry detection for human KMO protein. The assay incorporates isolation of FLAG-tagged KMO enzyme on protein A magnetic beads. The protein-bound beads are incubated with potential binding compounds before specific cleavage of the protein-compound complexes from the beads. Mass spectrometry analysis is used to identify the compounds that demonstrate specific binding affinity for the target protein. The technique was validated using known inhibitors of KMO. This assay is a robust alternative to traditional ligand-binding assays for challenging protein targets, and it overcomes specific difficulties associated with isolating human KMO. PMID- 25296661 TI - Randomised, double-blind, placebo-controlled studies on flurbiprofen 8.75 mg lozenges in patients with/without group A or C streptococcal throat infection, with an assessment of clinicians' prediction of 'strep throat'. AB - BACKGROUND: Diagnosing group A streptococcus (Strep A) throat infection by clinical examination is difficult, and misdiagnosis may lead to inappropriate antibiotic use. Most patients with sore throat seek symptom relief rather than antibiotics, therefore, therapies that relieve symptoms should be recommended to patients. We report two clinical trials on the efficacy and safety of flurbiprofen 8.75 mg lozenge in patients with and without streptococcal sore throat. METHODS: The studies enrolled adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and a diagnosis of pharyngitis. The practitioner assessed the likelihood of Strep A infection based on historical and clinical findings. Patients were randomised to flurbiprofen 8.75 mg or placebo lozenges under double-blind conditions and reported the three throat symptoms at baseline and at regular intervals over 24 h. RESULTS: A total of 402 patients received study medication (n = 203 flurbiprofen, n = 199 placebo). Throat culture identified Strep A in 10.0% of patients and group C streptococcus (Strep C) in a further 14.0%. The practitioners' assessments correctly diagnosed Strep A in 11/40 cases (sensitivity 27.5%, and specificity 79.7%). A single flurbiprofen lozenge provided significantly greater relief than placebo for all three throat symptoms, lasting 3-4 h for patients with and without Strep A/C. Multiple doses of flurbiprofen lozenges over 24 h also led to symptom relief, although not statistically significant in the Strep A/C group. There were no serious adverse events. CONCLUSIONS: The results highlight the challenge of identifying Strep A based on clinical features. With the growing problem of antibiotic resistance, non-antibiotic treatments should be considered. As demonstrated here, flurbiprofen 8.75 mg lozenges are an effective therapeutic option, providing immediate and long-lasting symptom relief in patients with and without Strep A/C infection. PMID- 25296662 TI - Skin and soft tissue infections. PMID- 25296663 TI - Reply to Gonzalez del Castillo et al and Rashid and Kravitz. PMID- 25296664 TI - Approach for initial treatment of skin and soft tissue infection. PMID- 25296665 TI - Gaitedness is associated with the DMRT3 'Gait keeper' mutation in Morgan and American Curly horses. PMID- 25296666 TI - Treatment decision-making among Canadian youth with severe haemophilia: a qualitative approach. AB - The first generation of young men using primary prophylaxis is coming of age. Important questions regarding the management of severe haemophilia with prophylaxis persist: Can prophylaxis be stopped? At what age? To what effect? Can the regimen be individualized? The reasons why some individuals discontinue or poorly comply with prophylaxis are not well understood. These issues have been explored using predominantly quantitative research approaches, yielding little insight into treatment decision-making from the perspectives of persons with haemophilia (PWH). Positioning the PWH as a source of expertise about their condition and its management, we undertook a qualitative study: (i) to explore and understand the lived experience of young men with severe haemophilia A or B and (ii) to identify the factors and inter-relationships between factors that affect young men's treatment decision-making. This manuscript reports primarily on the second objective. A modified Straussian, grounded theory methodology was used for data collection (interviews) and preliminary analysis. The study sample, youth aged 15-29, with severe haemophilia A or B, was chosen selectively and recruited through three Canadian Haemophilia Treatment Centres. We found treatment decision-making to be multi-factorial and used the Framework method to analyze the inter-relationships between factors. A typology of four distinct approaches to treatment was identified: lifestyle routine prophylaxis, situational prophylaxis, strict routine prophylaxis and no prophylaxis. Standardized treatment definitions (i.e.: 'primary' and 'secondary', 'prophylaxis') do not adequately describe the ways participants treat. Naming the variation of approaches documented in this study can improve PWH/provider communication, treatment planning and education. PMID- 25296667 TI - The relationship between platelet endothelial cell adhesion molecule-1 and paraquat-induced lung injury in rabbits. AB - BACKGROUND: Platelet endothelial cell adhesion molecule-1 (PECAM-1), also known as CD31, is mainly distributed in vascular endothelial cells. Studies have shown that PECAM-1 is a very significant indicator of angiogenesis, and has been used as an indicator for vascular endothelial cells. The present study aimed to explore the relationship between the expression of PECAM-1 and the degree of acute lung injury (ALI) and fibrosis in paraquat (PQ) induced lung injury in rabbits. METHODS: Thirty-six adult New Zealand rabbits were randomly divided into three groups (12 rabbits in each group) according to PQ dosage: 8 mg/kg (group A), 16 mg/kg (group B), and 32 mg/kg (group C). After PQ infusion, the rabbits were monitored for 7 days and then euthanized. The lungs were removed for histological evaluation. Masson staining was used to determine the degree of lung fibrosis (LF), and semi-quantitative immune-histochemistry analysis to determine the expression of PECAM-1. Pearson's product-moment correlation analysis was performed to evaluate the relationship between the expression of PECAM-1 and the extent of lung injuries expressed by ALI score and degree of LF. RESULTS: Rabbits in the three groups showed apparent poisoning. The rabbits survived longer in group A than in groups B and C (6.47+/-0.99 days vs. 6.09+/-1.04 days vs. 4.77+/ 2.04 days) (P<0.05). ALI score was lower in group A than in groups B and C (8.33+/-1.03 vs. 9.83+/-1.17 vs. 11.50+/-1.38) (P<0.05), and there was statistically significant difference between group B and group C (P=0.03). LF was slighter in group A than in groups B and C (31.09%+/-2.05 % vs. 34.37%+/-1.62 % vs. 36.54%+/-0.44%) (P<0.05), and there was statistically significant difference between group B and group C (P=0.026). The PEACAM-1 expression was higher in group A than in groups B and C (20.31%+/-0.70% vs. 19.34%+/-0.68% vs. 18.37%+/ 0.46%) (P<0.05), and there was statistically significant difference between group B and group C (P=0.017). Pearson's correlation analysis showed that the expression of PECAM-1 was negatively correlated to both ALI score (Coe=-0.732, P=0.001) and degree of LF (Coe=-0.779, P<0.001). CONCLUSIONS: The PECAM-1 expression significantly decreases in New Zealand rabbits after PQ poisoning, and the decrease is dose-dependent. The PECAM-1 expression is negatively correlated with ALI score and LF, showing a significant role in the development of lung injuries induced by PQ. PMID- 25296668 TI - Lifestyle health behaviors of Hong Kong Chinese: results of a cluster analysis. AB - Sociodemographics affect health through pathways of lifestyle choices. Using data from a survey of 467 Hong Kong Chinese, this study aims to examine the prevalence of their lifestyle behaviors, identify profiles based on their sociodemographic and lifestyle variables, and compare differences among the profile groups. Two step cluster analysis was used to identify natural profile groups within the data set: only 37% of the participants engaged in regular physical exercises, and less than 50% monitored their dietary intake carefully. The analysis yields 2 clusters, representing a "healthy" and a "less-healthy" lifestyle group. The "less-healthy" group was predominantly male, younger, employed, and had high-to middle levels of education. The findings reveal the lifestyle behavior patterns and sociodemographic characteristics of a high-risk group, which are essential to provide knowledge for the planning of health promotion activities. PMID- 25296669 TI - Measuring facial symmetry: a perception-based approach using 3D shape and color. AB - OBJECTIVE: Facial symmetry is an important factor affecting esthetics. Thus, its restoration is an essential task in maxillofacial surgery. The aim of this study is to develop an objective measure of facial asymmetry by a novel approach where both the shape and the color are taken into account and to validate its correlation with perception. METHODS: Optical three-dimensional (3D) face scans of 30 healthy adults are performed. Face-specific asymmetry indices are calculated by quantifying color differences as well as spatial distances between 3D data of a face and its mirrored copy. Subjective ratings of symmetry and attractiveness of the faces by 100 subjects are used to validate these indices. RESULTS: The symmetry ratings show significant correlations with color and geometric asymmetry indices. The attractiveness ratings correlate only weakly with both indices. However, the product of the indices exhibits significant correlations with both attractiveness and symmetry ratings. CONCLUSION: The presented combined asymmetry index comprising shape and coloring turned out to reflect subjective perception of both facial symmetry and attractiveness. It thus promises to be a valid objective measure for facial esthetics, which could contribute, e.g., to the evaluation of surgical methods as well as to the design of craniofacial prostheses. PMID- 25296670 TI - Thermal, spectral, and surface properties of LED light-polymerized bulk fill resin composites. AB - The aim of this study was to evaluate the thermal, spectral, and surface properties of four different bulk fill materials - SureFil SDR (SDR, Dentsplay DETREY), QuixFil (QF, Dentsplay DETREY), X-tra base (XB, Voco) X-tra fil (XF, Voco) - polymerized by light-emitting diode (LED). Resin matrix, filler type, size and amount, and photoinitiator types influence the degree of conversion. LED cured bulk fill composites achieved sufficient polymerization. Scanning electron microscope (SEM) analysis revealed different patterns of surface roughness, depending on the composite material. Bulk fill materials showed surface characteristics similar to those of nanohybrid composites. Based on the thermal analysis results, glass transition (T(g)) and initial degradation (T(i)) temperatures changed depending on the bulk fill resin composites. PMID- 25296671 TI - Delivery outcomes after day and night onset of labour. AB - OBJECTIVE: To describe the outcome of night onset of labour as compared with the day onset of labour to investigate if labour that begins at night is more efficient. DESIGN: Retrospective review of labour and delivery data. SETTING: A large United Kingdom maternity service. POPULATION: Over the period of 10 years, there were 30,022 deliveries, of which 19,842 were studied. METHODS: A United Kingdom maternity department database was used to identify deliveries over a 10 year period, and the delivery outcomes were retrieved from these records. The 19,842 labours were divided into two categories: night onset (22.00-06.00 h) and day onset (10.00-18.00 h). MAIN OUTCOME MEASURES: Rates of operative intervention, augmentation, epidural usage and labour duration. RESULTS: A significant difference in delivery outcome was noted (P=0.004) with the night onset labours having more normal deliveries (83.6% vs. 82.5%), fewer caesarean sections (8.7% vs. 10.1%), fewer labour augmentations with syntocinon (14.9% vs. 19.5%, P<0.001), fewer artificial rupture of membranes (14.1% vs. 15.6% P<0.001) and a significantly shorter mean first stage duration (4 h 58 min vs. 5 h 7 min, P<0.05). The proportion of women from each group who delivered between 09.00 and 17.00 h was 3660 (31.1%) in the night-onset group and 2414 (30%) in the day-onset group (chi2=1.3, P=NS) Conclusions: Labours that start at night appear to be more efficient than labours that start during the day. PMID- 25296672 TI - When two turn into one: evolution of membrane transporters from half modules. AB - The recently increasing number of atomic structures for active transporters has not only revealed strong conservation in the architecture of sequence-unrelated transporter families, but also identified a unifying element called the 'inverted repeat topology,' which is found in nearly all transporter folds to date. Indeed, most membrane transporters consist of two or more domains with similar structure, so-called repeats. It is tempting to speculate that transporters have evolved by duplication of one repeat followed by gene fusion and modification events. An intriguing question is, whether recent genes encoding such a 'half-transporter' still exist as independent folding units. Although it seems likely that the evolution of membrane transport proteins, which harbor internal repeats, is linked to these minimal structural building blocks, their identification in the absence of structural data represents a major challenge, as sequence homology is not an issue. In this review we discuss two protein families, the DedA family and the SWEET family, being potential half-transporters and putative ancestors for two of the most abundant secondary transporter families, the MFS family and the LeuT-fold family. PMID- 25296673 TI - Meeting report: present state of molecular genetics in clinical laboratories. Report on the VII European Symposium on Clinical Laboratory and In Vitro Diagnostic Industry in Barcelona. AB - The VII European Symposium of the Clinical Laboratory and In Vitro Diagnostic Industry, co-organized between the Catalan Association for Clinical Laboratory Sciences (ACCLC) and the Catalan Society of Biology, was held on May 28th-29th, 2013 in Barcelona (Catalonia, Spain) under the IFCC auspices and the IUPAC sponsorship. The subject of the present Symposium was "Molecular Genetics in the Clinical Laboratory" and began with an opening conference that was a stroll through the history of molecular genetics in the context of the clinical laboratory. The scientific program was structured in several 2-h length roundtables that dealt with the following topics: recent advances in molecular genetics for clinical microbiology, latest evidences and real applicability of pharmacogenetics in the clinical practice, quality assurance of a molecular genetics laboratory, and latest trends in prenatal genetic diagnosis. The aim of the Symposium was the discussion of the transformation that molecular genetics has generated on clinical laboratories in terms of organization, specialization, interpretation of results and fast technical and knowledge evolution. High qualified professionals from several countries together with in-country experts formed the roundtables. Attendants participated actively in the debates, increasing the overall interest. PMID- 25296674 TI - Design, synthesis and pharmacological screening of beta-amino-, thiadiazole/thiadiazine-phosphonate based triazole motifs as antimicrobial/cytotoxic agents. AB - Three different series of phosphonate derivatives, beta-amino- and fused thiadiazolo/thiadiazine-phosphonates have been synthesized using the addition and/or addition-cyclization protocol of Horner-Wadsworth-Emmons (HWE) reagents to 1,2,4-triazole-3-thiols. The design of potentially antimicrobial and anticancer phosphor esters relied on the results of computer-assisted molecular modeling. All synthesized phosphonates were evaluated for their in vitro antimicrobial activities while anticancer properties were determined for eight out of twenty new phosphonates. The tested phosphonates, except for compounds that have a nitrile moiety, exhibited moderate to significant antimicrobial activity. Nevertheless, the most active compounds were fused thiadiazole-phosphonates, which inhibited the growth of both Gram-negative and Gram-positive bacteria better than beta-aminophosphonates and fused thiadiazolophosphonates. In parallel, the antitumor activity screenings of selected phosphonates from each series and substrate 1 were also done. Their antitumor properties against ten carcinoma cell lines, including breast (MCF7, MDA-MB- 231/ ATCC, MDA-MB-435, BT 549), ovarian (IGROVI, OVCAR-3, SK-OV-3), prostate (PX-3, PU-145), and liver (HEPG2), were investigated. The results showed that all synthesized compounds reflected remarkable antitumor activity against breast (especially MDA-MB 231/ATCC and BT-549), and prostate carcinoma cell lines (PC-3 and DU-145), whereas a moderate to good effect on ovarian and liver cancer cells was observed. PMID- 25296675 TI - Design, synthesis and potential anti-proliferative activity of some novel 4 aminoquinoline derivatives. AB - Novel nineteen compounds based on a 4-aminoquinoline scaffold were designed and synthesized as potential antiproliferative agents. The new compounds were N substituted at the 4-position by aryl or heteroaryl (1-9), quinolin- 3-yl (10), 2 methylquinolin-3-yl (11), thiazol-2-yl (12), and dapsone moieties (13, 14 and 18). Bis-compounds 15, 16 and 19 were also synthesized to assess their biological activity. All the newly synthesized comounds were tested for in vitro antiproliferative activity against the MCF-7 breast cancer cell line. Seventeen of the novel compounds showed higher activity than the reference drug doxorubicin. The corresponding 7-(trifluoromethyl)-N-(3,4,5 trimethoxyphenyl)quinolin-4- amine 1, N-(7-(trifluoromethyl)quinolin-4 yl)quinolin- 3- amine (10), 2-methyl-N-(7-trifluorome-thyl)quinolin-4-yl) quinolin-3-amine (11) and N-(4-(4-aminophenylsulfonyl) phenyl)-7-chloroquinolin-4 amine (13) were almost twice to thrice as potent as doxorubicin. Biological screening of the tested compounds could offer an encouraging framework in this field that may lead to the discovery of potent anticancer agents. PMID- 25296676 TI - Development of novel formulations to enhance in vivo transdermal permeation of tocopherol. AB - Tocopherol represents a big challenge for transdermal permeation owing to its extreme hydrophobicity and large molecular mass. The aim of the present study was to develop alpha-tocopherol (T) topical formulations and evaluate their ex vivo and in vivo permeation. Franz diffusion cells were used for ex vivo permeation, and neonatal rats were used for in vivo permeation. Seven gel formulations and 21 liquid formulations were investigated for physical stability, viscosity and permeation of T. Analysis of T was performed by a validated HPLC method using a UV detector. The ex vivo permeation from gel and emulsion formulations was very poor (0.001-0.015%). Highest permeation was observed from monophasic liquid formulations containing dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycols (TPGs), propylene glycol, ethanol and 9.5% T. The in vivo results demonstrated higher retention in the epidermis compared to subcutaneous tissues, 1377 and 1.13 MUg g-1, respectively. Increasing T concentration from 4.8 to 9.5% did not increase the amount permeated or % of T retained. It was concluded that simple solutions of T in the presence of DMSO and TPGs were more promising systems for effective transdermal permeation compared to gel, emulsion or oleaginous systems. PMID- 25296677 TI - Antioxidative activity and inhibition of key enzymes linked to type-2 diabetes (alpha-glucosidase and alpha-amylase) by Khaya senegalensis. AB - This study evaluated the in vitro antioxidative activity of Khaya senegalensis extracts and inhibitory effects of some solvent fractions on alpha-glucosidase and alpha-amylase activities. The stem bark, root and leaf samples of the plant were sequentially extracted with ethyl acetate, ethanol and water and then tested for antioxidative activity. Our findings revealed that the ethanolic extract of the root had the highest antioxidative activity. Solvent-solvent fractionation of the root ethanolic extract yielded a butanol fraction that showed higher antioxidative activity than other fractions. Furthermore, the butanol fraction had significantly higher (p < 0.05) alpha-glucosidase and alpha-amylase inhibitory activities with IC50 values of 2.89 +/- 0.46 and 97.51 +/- 5.72 MUg mL 1, respectively. Enzyme kinetic studies indicated that the butanol fraction is a non-competitive inhibitor for alpha-glucosidase with an inhibition binding constant K(i) of 1.30 MUg mL-1 and a competitive inhibitor of alpha-amylase with a K(i) of 7.50 MUg mL-1. GC-MS analysis revealed that the butanol fraction contained two chromones, p-anilinophenol and 3-ethyl-5-(3-ethyl-(3H)-benzothiazol 2-ylidene)-2-(p-tolylvinylamino)-4-thiazolidinone. Data obtained in the study suggest that the butanol fraction derived from the ethanolic extract of K. senegalensis root possessed excellent antioxidative as well as alpha-glucosidase and a-amylase inhibitory activities while chromones and/or p-anilinophenol could be the main bioactive compounds responsible for the observed activities. PMID- 25296678 TI - Analysis of active components in Salvia miltiorrhiza injection based on vascular endothelial cell protection. AB - Correlation analysis based on chromatograms and pharmacological activities is essential for understanding the effective components in complex herbal medicines. In this report, HPLC and measurement of antioxidant properties were used to describe the active ingredients of Salvia miltiorrhiza injection (SMI). HPLC results showed that tanshinol, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B, protocatechuic acid and their metabolites in rat serum may contribute to the efficacy of SMI. Assessment of antioxidant properties indicated that differences in the composition of serum powder of SMI caused differences in vascular endothelial cell protection. When bivariate correlation was carried out it was found that salvianolic acid B, tanshinol and protocatechuic aldehyde were active components of SMI because they were correlated to antioxidant properties. PMID- 25296679 TI - Novel ethyl 1,5-disubstituted-1H-pyrazole-3-carboxylates as a new class of antimicrobial agents. AB - A series of pyrazole derivatives 9-22 were designed and synthesized. All the newly synthesized compounds were assayed for their antimicrobial activity against the Grampositive bacteria Staphyllococcus aureus and Bacillius subtilis and the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, in addition to the fungi organisms, Candida albicans, C. parapsilosis and C. tropicalis. Ethyl 5 (2,5-dimethylthiophen-3-yl)-1-phenyl-1H-pyrazole-3-carboxylate (21) (MIC(E.coli) = 0.038 MUmol mL-1, MIC(P. aerug.) = 0.067 MUmol mL-1) is nearly as active as ampicillin (MIC = 0.033 and 0.067 MUmol mL-1), respectively. Ethyl 5-(4-bromo-2 chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (16) (MIC = 0.015 MUmol mL-1) is more active than fluconazole (0.020 MUmol mL-1) as a reference drug against C. parapsilosis. PMID- 25296680 TI - Rosuvastatin, sildenafil and their combination in monocrotaline-induced pulmonary hypertension in rat. AB - There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development. PMID- 25296681 TI - Influence of process parameters on content uniformity of a low dose active pharmaceutical ingredient in a tablet formulation according to GMP. AB - The article describes the development and production of tablets using direct compression of powder mixtures. The aim was to describe the impact of filler particle size and the time of lubricant addition during mixing on content uniformity according to the Good Manufacturing Practice (GMP) process validation requirements. Processes are regulated by complex directives, forcing the producers to validate, using sophisticated methods, the content uniformity of intermediates as well as final products. Cutting down of production time and material, shortening of analyses, and fast and reliable statistic evaluation of results can reduce the final price without affecting product quality. The manufacturing process of directly compressed tablets containing the low dose active pharmaceutical ingredient (API) warfarin, with content uniformity passing validation criteria, is used as a model example. Statistic methods have proved that the manufacturing process is reproducible. Methods suitable for elucidation of various properties of the final blend, e.g., measurement of electrostatic charge by Faraday pail and evaluation of mutual influences of researched variables by partial least square (PLS) regression, were used. Using these methods, it was proved that the filler with higher particle size increased the content uniformity of both blends and the ensuing tablets. Addition of the lubricant, magnesium stearate, during the blending process improved the content uniformity of blends containing the filler with larger particles. This seems to be caused by reduced sampling error due to the suppression of electrostatic charge. PMID- 25296682 TI - Evaluation of the antioxidant activity of Coreopsis tinctoria Nuff. and optimisation of isolation by response surface methodology. AB - The aim of the present study was to determine the antioxidant activity of Coreopsis tinctoria flowering tops (CTFT). Studies were conducted to obtain suitable extraction conditions for chlorogenic acid, quercetin, luteolin, apigenin and kaempferol, which were identified and quantified by HPLC. Response surface methodology was employed to optimise the ultrasound-assisted extraction conditions including extraction time, ethanol concentration and liquid-solid ratio. The antioxidant activity of the extracts was analysed using various antioxidant models, such as DPPH, ABTS and hydroxyl radical scavenging assay. CTFT extracted for 15.0 min with ethanol at a concentration of 60.4% and with liquidsolid ratio 27.5:1 possessed a considerable amounts of total flavonoids and polyphenols (18.9%). This extract showed higher scavenging activity of ABTS and hydroxyl radical activity than rutin, however not in the DPPH test. We may assume that CTFT possess antioxidant and free radical scavenging potentials. PMID- 25296683 TI - Potential of the essential oil from Pimenta pseudocaryophyllus as an antimicrobial agent. AB - This study evaluated the effectiveness of the essential oil of Pimenta pseudocaryophyllus in inhibiting the growth of the main bacteria responsible for bad perspiration odor (Staphylococcus epidermidis, Proteus hauseri, Micrococcus yunnanensis and Corynebacterium xerosis). The chemical profile of the essential oil was evaluated by high-resolution gas chromatography (HR-GC) and four constituents were identified, eugenol being the major component (88.6%). The antimicrobial activity was evaluated by means of the turbidimetric method, using the microdilution assay. The minimum inhibitory concentration (MIC) values of the essential oil ranged from 500 to 1,000 MUg mL-1. Scanning electron microscope (SEM) observations confirmed the physical damage and morphological alteration of the test bacteria treated with the essential oil, reference drugs and eugenol. The findings of the study demonstrated that this essential oil can be used in the formulation of personal care products. PMID- 25296684 TI - Elemental sulfur disproportionation in the redox condensation reaction between o halonitrobenzenes and benzylamines. AB - The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states: S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal free aromatic halogen substitution, and condensation finally led to 2 arylbenzothiazoles 3. PMID- 25296685 TI - Rash and fever after sulfasalazine use. PMID- 25296687 TI - Healthcare providers' views on the acceptability of financial incentives for breastfeeding: a qualitative study. AB - BACKGROUND: Despite a gradual increase in breastfeeding rates, overall in the UK there are wide variations, with a trend towards breastfeeding rates at 6-8 weeks remaining below 40% in less affluent areas. While financial incentives have been used with varying success to encourage positive health related behaviour change, there is little research on their use in encouraging breastfeeding. In this paper, we report on healthcare providers' views around whether using financial incentives in areas with low breastfeeding rates would be acceptable in principle. This research was part of a larger project looking at the development and feasibility testing of a financial incentive scheme for breastfeeding in preparation for a cluster randomised controlled trial. METHODS: Fifty-three healthcare providers were interviewed about their views on financial incentives for breastfeeding. Participants were purposively sampled to include a wide range of experience and roles associated with supporting mothers with infant feeding. Semi-structured individual and group interviews were conducted. Data were analysed thematically drawing on the principles of Framework Analysis. RESULTS: The key theme emerging from healthcare providers' views on the acceptability of financial incentives for breastfeeding was their possible impact on 'facilitating or impeding relationships'. Within this theme several additional aspects were discussed: the mother's relationship with her healthcare provider and services, with her baby and her family, and with the wider community. In addition, a key priority for healthcare providers was that an incentive scheme should not impact negatively on their professional integrity and responsibility towards women. CONCLUSION: Healthcare providers believe that financial incentives could have both positive and negative impacts on a mother's relationship with her family, baby and healthcare provider. When designing a financial incentive scheme we must take care to minimise the potential negative impacts that have been highlighted, while at the same time recognising the potential positive impacts for women in areas where breastfeeding rates are low. PMID- 25296688 TI - Kinetics of conformational changes revealed by voltage-clamp fluorometry give insight to desensitization at ATP-gated human P2X1 receptors. AB - ATP acts as an extracellular signaling molecule at cell-surface P2X receptors, mediating a variety of important physiologic and pathophysiologic roles. Homomeric P2X1 receptors open on binding ATP and then transition to an ATP-bound closed, desensitized state that requires an agonist-free washout period to recover. Voltage-clamp fluorometry was used to record ion channel activity and conformational changes simultaneously at defined positions in the extracellular loop of the human P2X1 receptor during not only agonist binding and desensitization but also during recovery. ATP evoked distinct conformational changes adjacent to the agonist binding pocket in response to channel activation and desensitization. The speed of recovery of the conformational change on agonist washout was state-dependent, with a faster time constant from the open (5 seconds) compared with the desensitized (75 seconds) form of the channel. The ability of ATP to evoke channel activity on washout after desensitization was not dependent on the degree of conformational rearrangement in the extracellular loop, and desensitization was faster from the partially recovered state. An intracellular mutation in the carboxyl terminus that slowed recovery of P2X1 receptor currents (7-fold less recovery at 30 seconds) had no effect on the time course of the extracellular conformational rearrangements. This study highlights that the intracellular portion of the receptor can regulate recovery and shows for the first time that this is by a mechanism independent of changes in the extracellular domain, suggesting the existence of a distinct desensitization gate in this novel class of ligand gated ion channels. PMID- 25296689 TI - How to address smoking cessation in HIV patients. AB - Tobacco consumption is the modifiable risk factor contributing most to the development of non-AIDS-defining events among persons living with HIV/AIDS (PLWHA). Clinicians' awareness of this problem is critical and not yet adequate. Practical information issued by public health authorities or contained in experts' clinical guidelines regarding how to address smoking cessation in PLWHA is scarce. The aim of this review is to provide physicians with comprehensive and practical information regarding how to identify HIV-positive patients willing to stop smoking and those more likely to succeed, how to choose the most suitable strategy for an individual patient, and how to help the patient during the process. In the light of current evidence on the efficacy and benefits of stopping smoking in PLWHA, physicians must actively pursue smoking cessation as a major objective in the clinical care of PLWHA. PMID- 25296691 TI - Sanctacaris uncata: the oldest chelicerate (Arthropoda). AB - The morphology of the arthropod Sanctacaris uncata, from the Middle Cambrian Burgess Shale of Canada, is reinterpreted based on a restudy of previously described material. Although originally considered a chelicerate-like arthropod, these affinities were dismissed based primarily on interpretations of the anterior appendages and hypotheses which considered the megacheirans ('great appendage' arthropods) as putative ancestors of chelicerates. The similarities between megacheirans and chelicerates appear to be overstated however, and this study instead reaffirms the identity of putative chelicerate feature in S. uncata and similar arthropods such as Sidneyia and Emeraldella, both also from the Middle Cambrian Burgess Shale. Newly interpreted features, including the presence of pediform exites, multi-partite trunk exopods, and a trunk differentiated into an anterior limb-bearing area and a differentiated posterior limbless abdomen, were coded into an extensive phylogenetic data set of fossil and recent arthropods. In all analyses, Sanctacaris resolved as the basal-most member of total-group Euchelicerata (the least inclusive group including horseshoe crabs and arachnids but not pycnogonids), thus making it the oldest chelicerate in the fossil record. The vicissicaudates (including Sidneyia, Emeraldella, aglaspidids, and cheloniellids--all of which have previously been allied to chelicerates) resolved as sister-taxon to crown-group Chelicerata. This topology indicates that many purported chelicerate features, such as lamellar gills, and a differentiated posterior abdomen evolved sequentially in the chelicerate stem-lineage. PMID- 25296690 TI - Mesothelioma in a wine cellar man: detailed description of working procedures and past asbestos exposure estimation. AB - A pleural mesothelioma arose in an employee of a wine farm whose work history shows an unusual occupational exposure to asbestos. The information, gathered directly from the case and from a work colleague, clarifies some aspects of the use of asbestos in the process of winemaking which has not been previously reported in such details. The man had worked as a winemaker from 1960 to 1988 in a farm, which in those years produced around 2500 hectoliters of wine per year, mostly white. The wine was filtered to remove impurities; the filter was created by dispersing in the wine asbestos fibers followed by diatomite while the wine was circulating several times and clogging a prefilter made of a dense stainless steel net. Chrysotile asbestos was the sole asbestos mineralogical variety used in these filters and exposure could occur during the phase of mixing dry fibers in the wine and during the filter replacement. A daily and annual time weighted average level of exposure and cumulative dose have been estimated in the absence of airborne asbestos fiber monitoring performed in that workplace. Since 1993, the Italian National Mesothelioma Register, an epidemiological surveillance system, has recorded eight cases with at least one work period spent as winemaker. Four of them never used asbestos filters and presented exposures during other work periods, the other four used asbestos filters but had also other exposures in other industrial divisions. For the information hitherto available, this is the first mesothelioma case with exclusive exposure in the job of winemaking. PMID- 25296686 TI - The evolution of cichlid fish egg-spots is linked with a cis-regulatory change. AB - The origin of novel phenotypic characters is a key component in organismal diversification; yet, the mechanisms underlying the emergence of such evolutionary novelties are largely unknown. Here we examine the origin of egg spots, an evolutionary innovation of the most species-rich group of cichlids, the haplochromines, where these conspicuous male fin colour markings are involved in mating. Applying a combination of RNAseq, comparative genomics and functional experiments, we identify two novel pigmentation genes, fhl2a and fhl2b, and show that especially the more rapidly evolving b-paralog is associated with egg-spot formation. We further find that egg-spot bearing haplochromines, but not other cichlids, feature a transposable element in the cis-regulatory region of fhl2b. Using transgenic zebrafish, we finally demonstrate that this region shows specific enhancer activities in iridophores, a type of pigment cells found in egg spots, suggesting that a cis-regulatory change is causally linked to the gain of expression in egg-spot bearing haplochromines. PMID- 25296692 TI - A note regarding meta-analysis of sequential trials with stopping for efficacy. AB - It is shown that fixed-effect meta-analyses of naive treatment estimates from sequentially run trials with the possibility of stopping for efficacy based on a single interim look are unbiassed (or at the very least consistent, depending on the point of view) provided that the trials are weighted by information provided. A simple proof of this is given. An argument is given suggesting that this also applies in the case of multiple looks. The implications for this are discussed. PMID- 25296693 TI - A case of oculocutaneous albinism type 4: aberrant expression of SLC45A2 transcript with exon skipping. PMID- 25296694 TI - Improving the power to detect risk variants for allergic disease by defining case control status based on both asthma and hay fever. AB - Asthma and hay fever are likely to share hundreds if not thousands of genetic risk variants. Despite this, the extent to which the power to identify shared risk variants could be improved by considering information from both diseases when designing or analyzing genetic studies has not been studied in detail. Simulations were performed to quantify the power to detect an association between case-control status and a bi-allelic risk variant shared between asthma and hay fever across a range of disease and genetic models, as well as different ascertainment and analytical strategies. For a fixed sample size, when designing a new genome-wide association study (GWAS), selecting for genotyping cases with both asthma and hay fever (A+H+), and controls with neither disease (A-H-) was the study design that provided the greatest power to identify a shared risk variant. On the other hand, when analyzing an existing GWAS, power was greatest across a wide range of scenarios, when cases were defined as individuals who suffered from either disease (A+ or H+) and controls as those who suffered from neither (A-H-). Bivariate analysis of asthma and hay fever provided comparable but slightly decreased power. In conclusion, new GWAS can be designed and existing GWAS reanalyzed more efficiently to identify risk variants for allergic disease by using ascertainment or analytical strategies that consider both asthma and hay fever information. PMID- 25296695 TI - Diagnostic accuracy of urinary cytokeratin 19 fragment for endometriosis. AB - Endometriosis affects up to 10% of women of reproductive age and 176 million women worldwide. The prevalence in women with infertility is between 30% and 50% but may be higher in women with pelvic pain, interstitial cystitis, or irritable bowel syndrome. Cytokeratin 19 has been suggested as a potential biomarker in urine for the diagnosis of this condition. The objective of this study was to prospectively determine the accuracy and the performance of a urinary cytokeratin 19 (uCYFRA 21-1) test for diagnosing endometriosis. Ninety-eight consecutive women who underwent laparoscopy had a urinary sample obtained before surgery and were included in the study. Endometriosis was diagnosed by laparoscopy and pathology in 64.3% (63 of 98 women). The estimates and 95% confidence intervals for sensitivity, specificity, positive and negative predictive values, and likelihood ratios were 11.1% (4.5%-21.5%), 94.3% (80.8%-99.3%), 77.7% (39.9 97.1), 37% (27-47.9), 1.94 (0.43-8.86), and 0.94 (0.84-1.06), respectively. Despite the high specificity, the uCYFRA 21-1 test has limited value for clinical practice to discriminate between women with and without endometriosis. PMID- 25296696 TI - Co-administration of GnRH-agonist and hCG for final oocyte maturation (double trigger) in patients with low number of oocytes retrieved per number of preovulatory follicles--a preliminary report. AB - BACKGROUND: Recently, the co-administration of GnRH agonist and hCG for final oocyte maturation- 40 and 34 hours prior to OPU, respectively (double trigger) was suggested as the treatment of genuine empty follicle syndrome. In the present study, we aim to evaluate whether the double trigger improves the number of oocytes retrieved in patients with low (<50%) number of oocytes retrieved per number of preovulatory follicles. METHODS: In this proof of concept cohort historical study, we compared the stimulation characteristics of 8 IVF cycles, which include the double trigger to the patients' previous IVF attempt, triggered with hCG-only. RESULTS: Patients who received the double trigger (study group) had a significantly higher number of oocytes retrieved, number of 2PN, number of embryos transferred and significantly higher proportions of the number of oocytes retrieved to the number of follicles >10 mm and >14 mm in diameter on day of hCG administration, with a tendency toward a higher number of TQE, as compared to their previous cycles (hCG-only trigger). Three ongoing clinical pregnancies were recorded in the study group and none in the hCG-only trigger group. CONCLUSIONS: Co-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 hours prior to OPU, respectively (double trigger), is suggested as a valuable new tool in the armamentarium for treating patients with low/poor oocytes yield despite an apparently normal follicular development and E2 levels and in the presence of optimal hCG levels on the day of OPU. PMID- 25296697 TI - Structural changes of 6a-hydroxy-pterocarpans upon heating modulate their estrogenicity. AB - The isoflavonoid composition of an ethanolic extract of fungus-treated soybean sprouts was strongly altered by a combined acid/heat treatment. UHPLC-MS analysis showed that 6a-hydroxy-pterocarpans were completely converted to their respective, more stable, 6a,11a-pterocarpenes, whereas other isoflavonoids, from the isoflavone and coumestan subclasses, were affected to a much lesser extent (loss of ~15%). Subsequently, mixtures enriched in prenylated 6a-hydroxy pterocarpans (pools of glyceollin I/II/III and glyceollin IV/VI) or prenylated 6a,11a-pterocarpenes (pools of dehydroglyceollin I/II/III and dehydroglyceollin IV/VI) were purified, and tested for activity on both human estrogen receptors (ERalpha and ERbeta). In particular, the response toward ERalpha changed, from agonistic for glyceollins to antagonistic for dehydroglyceollins. Toward ERbeta a decrease in agonistic activity was observed. These results indicate that the introduction of a double bond with the concomitant loss of a hydroxyl group in 6a hydroxy-pterocarpans extensively modulates their estrogenic activity. PMID- 25296698 TI - Mesoporous silica particles as topologically crosslinking fillers for poly(N isopropylacrylamide) hydrogels. AB - Here it is demonstrated that mesoporous silicas (MPSs) can be used as effective "topological crosslinkers" for poly(N-isopropylacrylamide) (PNIPA) hydrogels to improve the mechanical property. Three-dimensional bicontinuous mesporous silica is found to effectively reinforce the PNIPA hydrogels, as compared to nonporous silica and two-dimensional hexagonally ordered mesoporous silica. PMID- 25296699 TI - Between invisible defects and visible impact: the life experiences of adolescents and young adults with congenital heart disease. AB - AIM: To describe the life experiences of adolescents and young adults with congenital heart disease. BACKGROUND: Owing to medical advances, most children with congenital heart disease are expected to survive into adulthood. The transitional development from adolescence to adult is the critical period for fostering self-care. DESIGN: Descriptive phenomenological study. METHODS: Thirty five patients of 15-24 years old with congenital heart disease were recruited from paediatric cardiology clinics by purposive sampling. They were individually interviewed between October 2012-February 2013 using a semi-structured interview guideline and joined adult congenital heart disease clinics at two medical centres in northern Taiwan. The data were analysed using descriptive phenomenological method developed by Giorgi. FINDINGS: The essence of the life experience of adolescents and young adults with congenital heart disease involves a dynamic process of moving between invisible defects and coexistence with the disease. Six themes emerged: (1) invisible defects: the existence of imperfect understanding; (2) conflict: interpersonal frustrations; (3) imbalance: the loss of self-balance; (4) suffering: increasing anxiety; (5) encounters: meeting needs; and (6) coexistence: positive coping strategies. CONCLUSION: As patients with congenital heart disease transition from adolescence into adulthood, they must learn about their disease, overcome frustration and anxiety and develop self care strategies for coexisting with congenital heart disease. Results of this study may serve as clinical care guidelines for adolescents and young adults with congenital heart disease and give a reference for developing transitional intervention strategies. PMID- 25296701 TI - Breaking the taboo: an interpretative phenomenological analysis of healthcare professionals' experience of caring for palliative patients with disgusting symptoms. AB - OBJECTIVES: Disgusting symptoms are common in healthcare settings. Previous research has identified that healthcare professionals systematically avoid contact with patients with disgusting symptoms, potentially compromising patient care. Furthermore, research has highlighted disgust in healthcare professionals as a possible contributory factor to dehumanisation and abuse of patients. Given that healthcare professionals often feel that disgust is unprofessional, they may also feel unable to express or process disgust in their work, potentially impacting their emotional health, and contributing to burning out. Given the ubiquity of disgust in palliative care, we investigated how palliative healthcare professionals' experience and cope with disgust in their work, and how they are supported in doing so. METHODS AND RESULTS: We interviewed six palliative healthcare professionals and analysed their transcripts using Interpretative Phenomenological Analysis, from which four themes are discussed. CONCLUSIONS: Three key findings emerged. Firstly, participants were uncomfortable talking about disgust at work, reducing their access to support for disgust. Secondly, participants often neglected their own emotional needs, and as a result, sometimes become emotionally entangled with patients. Finally, participants were at risk of reducing vital socio-emotional support for patients with disgusting symptoms. Based on our analysis, we suggest interventions to counteract these effects. PMID- 25296702 TI - WebRehab: a Swedish database for quality control in rehabilitation. AB - BACKGROUND: The healthcare sector needs to deliver evidence-based care and be cost-effective. This can be monitored in part via a national quality registry containing individualized data concerning patient problems, medical interventions, outcomes of treatment, and patient-reported outcomes. With this aim, WebRehab Sweden was launched in 1997 and has been available online since 2007. The aim of this paper is to discuss the design, some results, and possible use of such a registry. METHODS: Data entered into the registry online since 2007 were used in this paper. The registry contains information from 7,458 patients. Data from the first 3 years were used to show differences between genders and among diagnostic groups. Non-parametric statistics were used to analyse the differences between groups. RESULTS: The registry coverage of the country is 95%, and completeness is 81%. Data from hospitals/units have been accessible to the general public since 2009, but no data from individuals can be accessed. Length of stay has varied over the years, becoming significantly shorter between 2007 and 2012. CONCLUSION: A quality registry presents an opportunity to improve rehabilitation processes at participating units, provides data for use in benchmarking between units, and enables hospital management to utilize resources wisely. PMID- 25296703 TI - Diversity oriented convergent access for collective total synthesis of bioactive multifunctional carbazole alkaloids: synthesis of carbazomycin A, carbazomycin B, hyellazole, chlorohyellazole, and clausenaline D. AB - Facile syntheses of imperative carbazole alkaloids carbazomycin A, carbazomycin B, hyellazole, chlorohyellazole, and clausenaline D have been demonstrated starting from readily available Boc-protected 3-formylindole and dimethyl maleate. The suitably substituted aromatic rings have been designed comprising three/four significant C-C bond forming reactions. The competent Wittig reaction, selective monoalkylations, one-pot regioselective Weinreb amide formation and Boc deprotection, well designed Grignard reactions, dehydrative intramolecular cyclizations, and Baeyer-Villiger rearrangement of aromatic aldehydes were the main features. PMID- 25296704 TI - Encapsulation of iron in liposomes significantly improved the efficiency of iron supplementation in strenuously exercised rats. AB - To investigate the effect of iron liposome supplementation, a rat model of exercise-associated anemia was established by subjecting the animals to high intensity running exercises for 4 weeks. Rats with confirmed anemia were strenuously exercised for another 2 weeks while receiving iron supplements by intragastric administration of ferric ammonium citrate (FAC) liposomes or heme iron liposomes. Control groups were administered equivalent amounts of FAC, heme iron, or blank liposomes. Subsequently, complete blood count (CBC), serum iron, and liver iron levels were tested to determine the efficiency of iron liposomes in relieving anemia. Superoxide dismutase (SOD) and malonyldialdehyde (MDA) were also detected to determine potential side effects of iron supplementation. The CBC, as well as serum iron and liver iron contents, significantly increased and reached much higher levels in anemic rats treated with iron liposomes, compared with those of control groups. The increase of SOD and decrease of MDA levels were also observed after supplementation with iron liposomes. These results demonstrate that iron liposomes can efficiently relieve the iron deficiency in strenuously exercised rats and may potentially be used as a supplement for the treatment of exercise-associated iron deficiency anemia with minimal side effects. PMID- 25296705 TI - A simulator for percutaneous hepatic microwave thermal ablation under ultrasound guidance. AB - The purpose of this study was to provide a simulation therapy environment for microwave thermal ablation (MWA) under the guidance of ultrasound, and to present an inexpensive and portable simulator built on real patient-based pre-operative computed tomography (CT) data. We established an experimental simulation system for teaching MWA and present the results of a preliminary evaluation of the simulator's realism and utility for training. The system comprises physical elements of an electromagnetic tracking device and an abdominal phantom, and software elements providing three-dimensional (3D) image processing tools, real time navigation functions and objective evaluation function module. Details of the novel aspects of this system are presented, including a portable electromagnetic tracking device, adoption of real patient-based pre-operative CT data of liver, operation simulation of MWA, and recording and playback of the operation simulation. Patients with liver cancer were selected for evaluation of the clinical application value of the experimental simulation system. A total of 50 consultant interventional radiologists and 20 specialist registrars in radiology rated the simulator's hardware reality and overall ergonomics. Results show that the simulator system we describe can be used as a training tool for MWA. It enables training with real patient cases prior to surgery, and it can provide a realistic simulation of the actual procedure. PMID- 25296706 TI - Ceramic barrier layers for flexible thin film solar cells on metallic substrates: a laboratory scale study for process optimization and barrier layer properties. AB - Flexible thin film solar cells are an alternative to both utility-scale and building integrated photovoltaic installations. The fabrication of these devices over electrically conducting low-cost foils requires the deposition of dielectric barrier layers to flatten the substrate surface, provide electrical isolation between the substrate and the device, and avoid the diffusion of metal impurities during the relatively high temperatures required to deposit the rest of the solar cell device layers. The typical roughness of low-cost stainless-steel foils is in the hundred-nanometer range, which is comparable or larger than the thin film layers comprising the device and this may result in electrical shunts that decrease solar cell performance. This manuscript assesses the properties of different single-layer and bilayer structures containing ceramics inks formulations based on Al2O3, AlN, or Si3N4 nanoparticles and deposited over stainless-steel foils using a rotogravure printing process. The best control of the substrate roughness was achieved for bilayers of Al2O3 or AlN with mixed particle size, which reduced the roughness and prevented the diffusion of metals impurities but AlN bilayers exhibited as well the best electrical insulation properties. PMID- 25296707 TI - Fecal continence can be restored by sacral neurostimulation after traumatic unilateral pudendal neuropathy: a case report. PMID- 25296708 TI - Rectal leiomyosarcoma, late complication of pelvic radiotherapy. PMID- 25296709 TI - In vivo fate mapping of cryopreserved murine ovarian grafts. AB - BACKGROUND: Cryopreservation of ovarian tissue has been suggested as an alternative to restore fertility for ovarian failure before chemotherapy. METHODS: Ovaries of donor FVB/N-Tg (PolII-Luc) Ltc transgenic mice (n = 5) were cryopreserved and transplanted to the back muscles of recipient FVB/NJNarl wild type mice that had undergone bilateral oophorectomy. We evaluated the fate of cryopreserved murine ovarian grafts by in vivo bioluminescent imaging (BLI), AMH mRNA expression and follicle counts. RESULTS: There were significantly stronger BLI signals in the fresh ovaries than in the frozen-thawed ones. The number of primordial follicles was significantly lower in frozen-thawed ovaries at 10 days after transplantation (P < 0.001). The AMH mRNA expression was significantly lower in the frozen-thawed ovaries (P < 0.001), showing that unavoidable harm occurs after transplantation. CONCLUSIONS: Ovarian cryopreservation by slow freezing compromises ovarian reserve by cryoinjury and ischemia, evident at an early stage after transplantation. PMID- 25296710 TI - Multiple human papillomavirus infection with or without type 16 and risk of cervical intraepithelial neoplasia among women with cervical cytological abnormalities. AB - PURPOSE: To evaluate the impact of multiple human papillomavirus (HPV) infections on the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in subjects with cervical cytological abnormalities. METHODS: A cross-sectional study of 3,842 women attending a colposcopy service was carried out. Genotyping of 18 high-risk, seven low-risk, and two undefined-risk HPVs was carried out by the INNO-LiPA genotyping system. RESULTS: The final colposcopic/pathological diagnoses were as follows: 1,933 (50.3 %) subjects were negative; 1,041 (27.1 %) CIN1; 280 (7.3 %) CIN2; 520 (13.5 %) CIN3; and 68 (1.8 %) invasive cervical cancer. The prevalence of HPV infection was 75.8 % (2,911/3,842), whereas multiple HPVs were detected in 34.5 % of HPV-positive subjects (2,255/3,842). The adjusted risks of CIN3+ in the group with multiple compared to the group with single infection were 2.31 (95 % CI = 1.54-3.47), among HPV16-positive women, and 3.25 (95 % CI = 2.29-4.61, p = 0.21 compared with HPV16-positive subjects), in HPV16-negative subjects. Out of a total of 1,285 subjects with mild lesions, followed up for a median of 16.1 months (interquartile range = 8.9-36.8), the rate of progression to CIN2-3 was 0.6 % (5/541) among subjects negative or with low-risk HPVs, 1.7 % (8/463) among those with single high-risk HPV, and 5 % (14/281, p < 0.001 compared with HPV-negative/low-risk HPV and p = 0.038 compared with single high-risk HPV) among those with multiple high-risk HPVs. CONCLUSIONS: Among women with cervical cytological abnormalities, infection by multiple high risk HPVs increased the risk of CIN3+ in both HPV16-positive and HPV16-negative subjects. These findings suggest a potential synergistic interaction between high risk HPVs, favoring the progression of CIN lesions. PMID- 25296711 TI - Reduction of methanol in brewed wine by the use of atmospheric and room temperature plasma method and the combination optimization of malt with different adjuncts. AB - Methanol, often generated in brewed wine, is highly toxic for human health. To decrease the methanol content of the brewed wine, atmospheric and room temperature plasma (ARTP) was used as a new mutagenesis tool to generate a mutant of Saccharomyces cerevisiae with lower methanol content. Headspace gas chromatography was used to determine the identity and concentration of methanol with butyl acetate as internal standard in brewed wine. With 47.4% higher and 26.3% positive mutation rates were obtained, the ARTP jet exhibited a strong effect on mutation breeding of S. cerevisiae. The mutant S. cerevisiae S12 exhibited the lowest methanol content, which was decreased by 72.54% compared with that of the wild-type strain. Subsequently, the mutant S. cerevisiae S12 was used to ferment different combinations of malt and adjuncts for lower methanol content and higher alcoholic content. It was shown that the culture 6#, which was 60% malt, 20% wheat, and 20% corn, was the best combinations of malt and adjuncts, with the lowest methanol content (104.8 mg/L), and a relatively higher alcoholic content (15.3%, v/v). The optimal malt-adjunct culture 6#, treated with the glucoamylase dose of 0.04 U/mg of grain released the highest reducing sugars (201.6 mg/mL). It was indicated that the variation in reducing sugars among the combinations of malt and different adjuncts could be due to the dose of exogenous enzymes. PMID- 25296713 TI - The paradoxes of gender mainstreaming in developing countries: The case of health care in Papua New Guinea. AB - Gender mainstreaming developed as the global strategy for gender equality nearly two decades ago. Since then it has faced criticism for its technocratic application, and its role in the de-politicisation and neutralisation of the women's movement in gender policy-making. In the health sector, this incongruity is exacerbated by a traditional bio-medical approach to women's issues. In this paper, we ask whether gender mainstreaming can be made to work in the health sectors of developing countries where these challenges, as well as women's poor health status, are further complicated by a raft of local traditional, cultural, political and socioeconomic barriers. To answer these questions, we present a case study of Papua New Guinea (PNG), one of the world's most disadvantaged and politically challenging countries. We review data on women's health in PNG and analyse PNG's aspirational and actual performance on gender mainstreaming, looking at: international commitments; political will and capacity; national policies and programmes; and the women's movement along with civil society's participation. We find numerous paradoxes between the aims of gender mainstreaming and the necessary conditions for its success. PMID- 25296712 TI - Apoptotic events induced by high glucose in human hepatoma HepG2 cells involve endoplasmic reticulum stress and MAPK's activation. AB - To investigate whether endoplasmic reticulum (ER) stress participates in the induction of apoptosis in HepG2 cells exposed to high glucose and explore its probable mechanism. A series of experiments were performed following HepG2 cells treated with different concentrations of glucose for 48 h. The apoptosis was detected by means of Hoechst staining and flow cytometry. Caspase-3 activity assay was performed by measuring the pNA (p-nitroaniline) to indirectly reveal the catalytic activity of caspase-3. The expression levels of apoptosis-, ER stress-associated proteins and MAPKs were analyzed by western blot. To further characterize the molecular mechanisms, the effects of antioxidant alpha-lipoic acid (ALA) and specific inhibitors for JNK and p38 (SP600125 and SB203580, respectively) were examined by Hoechst staining, immunofluorescence, and western blot. After HepG2 cells were incubated with high glucose for 48 h, both Hoechst staining and flow cytometry analyses unveiled the apoptosis of HepG2 cells. Caspase-3 activity assay revealed that the activity of caspase-3 was enhanced. Western blot showed an enhancement of pro-caspase-9 degradation, a reduction of Bcl-2/Bax ratio, a decrease in GRP78 expression, and increases in CHOP and p47/phox levels. In addition, western blot analysis presented that phosphorylation of p38 and JNK was triggered and that the expression of ASK1 was elevated. In the case of the contributions of oxidative stress and the MAPK signaling pathways, all ALA, SP600125 and SB203580 were able to largely rescue high glucose-induced apoptosis. High glucose induced the apoptosis in HepG2 cells through the activation of ASK1-p38/JNK pathway mediated by ER stress and oxidative stress. PMID- 25296714 TI - A general purification platform for toxic proteins based on intein trans splicing. AB - Many important functional proteins often exhibit toxicity when overexpressed in heterologous hosts. Unfortunately, this toxicity can complicate the production of these proteins in recombinant systems, which can slow their characterization. Although a number of engineered expression strains and plasmids have been developed to optimize toxic protein expression, many targets remain recalcitrant in these systems due to extreme toxicity to the expression host. In this work, we have developed a novel protein purification platform based on intein trans splicing, with special relevance for proteins that are extremely toxic to recombinant host cells. The toxic protein is split into two inactive fragments, which are separately expressed in fusion to the segments of a split intein. The N terminal intein segment is first immobilized onto an affinity column and washed, followed by addition of the C-terminal segment and purification of the complex. The assembled intein controllably splices to deliver the mature target protein, simultaneously releasing the purified target from the affinity column. To optimize this method, we generated a hybrid split intein consisting of the N terminus of the Npu DnaE intein and the C-terminus of the Ssp DnaE intein. This hybrid intein tolerates a wider range of amino acids at the +2 site of the C terminal splicing junction than the Npu intein alone. In the production of the highly toxic homing endonuclease I-TevI, the yield from the hybrid intein is 50 % higher than the native Npu DnaE intein, while the I-TevI protein purified from both inteins showed native activity. PMID- 25296715 TI - Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial mesenchymal transition and stem cell properties in prostate cancer cells. AB - The invasion and metastasis of tumors are triggered by an epithelial to mesenchymal transition (EMT), which is regulated by microRNAs (miRNAs). EMT also promotes malignant tumor progression and the maintenance of the stem cell property, which endows cancer cells with the capabilities of self-renewal and immortalized proliferation. The transcriptional repressor zinc-finger E-box binding homeobox 2 (ZEB2), as an EMT activator, might be an important promoter of metastasis in some tumors. Here, we report that ZEB2 directly represses the transcription of miR-145, which is a strong repressor of EMT. In turn, ZEB2 is also a direct target of miR-145. Further, our findings show that the downregulation of ZEB2 not only represses invasion, migration, EMT, and the stemness of prostate cancer (PCa) cells, but also suppresses the capability of PC 3 cells to invade bone in vivo. Importantly, the expression level of ZEB2 as revealed by immunohistochemical analysis is positively correlated to bone metastasis, the serum free PSA level, the total PSA level, and the Gleason score in PCa patients and is negatively correlated with miR-145 expression in primary PCa specimens. Thus, our findings demonstrate a double-negative feedback loop between ZEB2 and miR-145 and indicate that the ZEB2/miR-145 double-negative feedback loop plays a significant role in the control of EMT and stem cell properties during the bone metastasis of PCa cells. These results suggest that the double-negative feedback loop between ZEB2 and miR-145 contributes to PCa progression and metastasis and might have therapeutic relevance for the bone metastasis of PCa. PMID- 25296716 TI - Spontaneous activity in the developing auditory system. AB - Spontaneous electrical activity is a common feature of sensory systems during early development. This sensory-independent neuronal activity has been implicated in promoting their survival and maturation, as well as growth and refinement of their projections to yield circuits that can rapidly extract information about the external world. Periodic bursts of action potentials occur in auditory neurons of mammals before hearing onset. This activity is induced by inner hair cells (IHCs) within the developing cochlea, which establish functional connections with spiral ganglion neurons (SGNs) several weeks before they are capable of detecting external sounds. During this pre-hearing period, IHCs fire periodic bursts of Ca(2+) action potentials that excite SGNs, triggering brief but intense periods of activity that pass through auditory centers of the brain. Although spontaneous activity requires input from IHCs, there is ongoing debate about whether IHCs are intrinsically active and their firing periodically interrupted by external inhibitory input (IHC-inhibition model), or are intrinsically silent and their firing periodically promoted by an external excitatory stimulus (IHC-excitation model). There is accumulating evidence that inner supporting cells in Kolliker's organ spontaneously release ATP during this time, which can induce bursts of Ca(2+) spikes in IHCs that recapitulate many features of auditory neuron activity observed in vivo. Nevertheless, the role of supporting cells in this process remains to be established in vivo. A greater understanding of the molecular mechanisms responsible for generating IHC activity in the developing cochlea will help reveal how these events contribute to the maturation of nascent auditory circuits. PMID- 25296718 TI - Retraction: Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART. PMID- 25296717 TI - Quantitative and functional characteristics of endothelial progenitor cells in newly diagnosed hypertensive patients. AB - Populations of peripheral blood CD34(+) cells comprise precursors of endothelial cells. These precursors are crucial to cardiovascular homeostasis. Hypertension, as one of the main risk factors for cardiovascular disease, is associated with the loss of endothelium structural integrity and its functional impairment. The aim of our study was to evaluate the subsets of endothelial precursor cells in patients with newly diagnosed arterial hypertension. Twenty-four newly diagnosed, previously untreated hypertensive patients aged 59.5 +/- 12.5 years, were enrolled into the study group, whereas the control group comprised 45 healthy subjects, 55.5+/-10.0 years old. Endothelial progenitor cells (EPCs) were analysed by flow cytometry. The results showed that hypertensive patients were characterized by a significantly higher percentage and number of the CD34(+) cells and simultaneously less differentiated CD34(+)CD45(dim/neg)CD133(+) progenitors. The percentage and number of CD34(+)CD45(neg)VEGFR2(+) and CD34(+)CD45(neg)CD133(+)VEGFR2(+) cells were not different from the control group. Moreover, patients had a significantly lower percentage and number of the CD34(+)CD45(neg)VEGFR2(+)CXCR4(+) and CD34(+)CD45(neg)VEGFR2(+)ICAM-1(+) cells than healthy individuals. These changes were paralleled by early symptoms of nephropathy, that is, lower glomerular filtration rate (GFR) values and borderline micro albuminuria. Our results indicate that an elevation in the number of less differentiated progenitors may be a mechanism compensating for defects of migration and adhesion, present in a more differentiated subset. PMID- 25296719 TI - Macroporous cryogel based spin column with immobilized concanavalin A for isolation of glycoproteins. AB - In this work we have developed a hydrophilic poly(hydroxyethyl methacrylate-co poly(ethylene glycol) diacrylate) cryogel placed in the centrifugal filter device. The composition of the polymerization mixture as well as the polymerization conditions were optimized in order to prepare a material with bimodal pore size distribution with 20-50 MUm flow through macropores and submicrometer pores in the polymer walls. The optimized, mechanically stable, highly porous, material was used for spin column lectin chromatography. The surface of the monolithic scaffold was activated by epichlorohydrin and used for immobilization of concanavalin A to provide the affinity supports for selective isolation of glycoproteins containing high mannose glycan structures. The performance of the developed lectin modified cryogels was evaluated by analyses of glycoprotein mixtures. The efficiency and selectivity of the affinity supports were confirmed by MALDI-MS analysis. PMID- 25296720 TI - The search for monogenic causes of kidney stones. PMID- 25296722 TI - Simultaneous determination of erlotinib and its isomeric major metabolites in human plasma using isocratic liquid chromatography-tandem mass spectrometry and its clinical application. AB - This study developed a method for the simultaneous determination of erlotinib and its isomeric major metabolites, OSI-413 and OSI-420, in human plasma using an isocratic liquid chromatography-tandem mass spectrometry. Plasma specimens deproteinized with acetonitrile were separated using a 3-um particle size octadecylsilyl column. The m/z values of the precursor and product ions for the analytes were as follows: erlotinib, 394.2/278.2; and OSI-413 and OSI-420, 380.2/278.2. The total run time was 21 min and no peaks interfering with the analytes and internal standard (d6 -erlotinib) in human plasma were observed. The calibration curves of erlotinib, OSI-413 and OSI-420 were linear over the concentration ranges of 10-3000, 2-500 and 2-100 ng/mL, respectively. The pretreatment recovery ratios were >86.1%. The intra- and inter-assay precisions and accuracies were <12.7 and 89.0-108.9% for all analytes. This validated method was applied to the determination of plasma samples in lung cancer patients receiving 150 mg of oral erlotinib. The plasma concentration ranges of erlotinib, OSI-413 and OSI-420 were 373-2354, 15.7-379 and 2.5-43.6 ng/mL, respectively. In conclusion, the present method can be helpful for evaluating the plasma exposures of erlotinib and its major isomeric metabolites in clinical settings. PMID- 25296721 TI - Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. AB - Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment. PMID- 25296723 TI - Demonstration of the cause of acute renal failure in a case of IgD multiple myeloma. PMID- 25296725 TI - Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients. AB - LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp(r)) were conducted. An open-label, two-period, fixed sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration-time curve from time zero to tlast (AUC[0-tlast]) and to infinity (AUC[0-infinity]) and maximum plasma concentration (Cmax) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients. PMID- 25296726 TI - Knowledge and practices of pre-school teachers on growth monitoring program- South Africa. AB - The aim of this study was to determine knowledge and practices of pre-school teachers on growth monitoring. A quasi-experimental, one-group pre- and post-test intervention study was conducted in eight conveniently selected government subsidized pre-schools in Vhembe and Mopani districts of Limpopo Province, South Africa. Fifteen pre-school teachers participated in the study. An intervention in a form of nutrition education lessons on growth monitoring was developed and implemented. Pre-school teachers completed a knowledge test questionnaire prior to the lessons. The intervention also included the following training skills: procedure to take anthropometric measurements and plotting the Road to Health Chart. About 67% teachers understood the importance of growth monitoring at baseline. The results also showed an improvement 6 months after intervention. All (100%) teachers knew that growth monitoring can be used for diagnosing undernutrition. The results also showed an improvement in skills, such as the procedure to take anthropometric measurements. Knowledge and practices of teachers on growth monitoring were improved by nutrition education 6 months after intervention. PMID- 25296727 TI - Intervention fidelity and effectiveness of a UK worksite physical activity intervention funded by the BUPA Foundation, UK. AB - The main aim of this study was to test whether the effectiveness of a worksite physical activity intervention delivered in five work organizations varied as a function of intervention fidelity. We conducted a fidelity analysis as part of a large matched-pair cluster randomized controlled trial of a worksite physical activity intervention (AME for Activity). Participants (N = 1260) were employees from five organizations in the UK. The primary trial outcome was physical activity at 9 months post intervention. Adherence, exposure, quality of delivery and participant responsiveness/engagement were measured to assess fidelity. Qualitative data about the context in which the intervention was delivered were collected via focus groups, interviews and field notes. Multi-level modelling was used to provide a comparison of the effect of the intervention on increases in physical activity for worksites where intervention fidelity was good, compared with those where intervention fidelity was poor or moderate. Intervention fidelity was poor in two organizations, moderate in two organizations and good in one organization (local council). Re-analysis of the trial data comparing employees in the local council (N = 443) with employees in all other worksites (N = 611) revealed a significant effect of the intervention on physical activity levels among council employees only. These findings suggest that the measurement of fidelity and the testing of the effects of intervention fidelity on outcomes, as part of the evaluation of complex interventions, are essential to understand the context and conditions in which interventions are most effective. PMID- 25296728 TI - Strain of bone-implant interface and insertion torque regarding different miniscrew thread designs using an artificial bone model. AB - OBJECTIVES: To evaluate the initial stability of dual-thread miniscrews by analyzing the strain at the bone-implant interface and insertion torque during implantation in artificial bone models with different cortical bone thicknesses. MATERIALS AND METHODS: Insertion torque, and strain, measured with a five-element strain gauge in 1.0, 1.5, and 2.0-mm artificial cortical bone, during insertion of single- (OAS-T1507) and dual-thread (MPlant-U3) type self-drilling miniscrews were assessed. RESULTS: Both dual- and single-thread miniscrews showed greater than 7790 MUstrain for all cortical bone thicknesses, and dual-thread miniscrews reached up to 19580 MUstrain in 2.00 m m cortical bone. The strain of dual-thread miniscrews increased with increasing cortical bone thicknesses of 1.0-2.0mm. For single-thread miniscrews, the maximum insertion torque was relatively constant, but maximum insertion torque increased significantly in dual-thread groups with increasing cortical bone thicknesses (P < 0.0001). The maximum insertion torque with all cortical bone thicknesses was significantly lower with single- than dual thread types (P < 0.0001). CONCLUSIONS: Self-drilling dual-thread miniscrews provide better initial mechanical stability, but may cause strain over the physiological bone remodelling limit at the bone-implant interface in thick cortical bone layers. PMID- 25296724 TI - The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs. AB - The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non-coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high-throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine. PMID- 25296729 TI - Dentoskeletal effects of the Bite-Jumping Appliance and the Twin-Block Appliance in the treatment of skeletal Class II malocclusion: a randomized controlled trial. AB - OBJECTIVES: The current parallel group, randomized controlled trial aimed to compare the dentoalveolar and skeletal changes resulting from treatment using two popular functional appliances: the Bite-Jumping Appliance (BJA) and the Twin Block Appliance (TBA). STUDY DESIGN: This study is designed as a parallel-group, randomized controlled trial. MATERIALS AND METHODS: Patients were screened from the patients who were seeking treatment at the Department of Orthodontics, Al Baath University. Eligibility criteria included skeletal Class II division 1 malocclusion resulting from the retrusion of the mandible. A computer-generated randomization list was used to randomly divide the patients into two equal groups to be treated with either the BJA or the TBA. Blinding was applicable for outcome assessment only. Forty-four patients (22 male and 22 female) aged 10.2-13.5 years were randomized in a 1:1 ratio to either the BJA or the TBA groups, and four patients were lost to follow-up (two from each group). Lateral cephalometric radiographs were obtained before treatment and after 12 months of active appliance therapy. Inter-group differences were evaluated with two-sample t tests, and intra-group differences were assessed with paired-sample t-tests at the P <0.05 level. RESULTS: Forty patients (20 in each group) were available for the statistical analysis. Baseline characteristics were similar between groups. Similar changes were observed in the sagittal plane, including a significant increase in the SNB angle. No significant changes were observed in the maxilla. The lower incisors were significantly proclined, and the upper incisors significantly retruded. In the vertical plane, BJA induced mandibular clockwise rotation, and the SN:MP angle increased by 2.14 +/- 2.97 degrees (P = 0.002). Conversely, no significant changes took place in this angle in the TBA group 0.75 +/- 2.37 degrees (P = 0.096). Similarly, Jarabak ratio decreased significantly in the BJA group by -1.78 +/- 0.85% (P = 0.002) and increased significantly in the TBA group by 1.26 +/- 0.76% (P = 0.032), with significant differences between the two groups (P <= 0.001). No serious harm was observed. LIMITATIONS: A limitation of this research is a lack of an untreated control group. However, the resulting differences between the two groups can be attributed to the appliance differences, which fulfil the aim of the current research. CONCLUSIONS: Each of the two appliances is recommended for the functional treatment of skeletal Class II malocclusion resulting from the retrusion of the mandible. The BJA is recommended when clockwise rotation is desired, whereas the TBA is recommended to inhibit vertical development. REGISTRATION: This trial was registered at the Department of Orthodontics, Al-Baath University, Number 16, on 6/25/2012. PROTOCOL: The protocol was not published before trial commencement. FUNDING: No funding or conflict of interest to be declared. PMID- 25296730 TI - Correlation of IL-1F genetic polymorphisms with the risk of colorectal cancer among Chinese populations. AB - Inflammatory/immune cells have the power of infiltrating almost all human solid tumors and influencing all stages of carcinogenesis because of their stimulation of various cytokine subsets. This study aims to determine the correlation of single nucleotide polymorphisms in the IL-17F gene and the risk of colorectal cancer (CRC). One thousand patients diagnosed with CRC and a control group of 354 healthy controls were involved. Peripheral blood samples were collected. The PCR RFLP method was used to detect the 7383A>G (rs2397084) and 7488T>C (rs763780) in the IL-17F gene. Statistical analyses were conducted with version 12.0 STATA statistical software. We found that the allele model suggested that patients carrying C allele were 1.67 times more likely to develop CRC than healthy controls (odds ratio (OR) = 1.67, 95% confidence interval (CI) = 1.22-2.27, P = 0.001). Similarly, the homozygous and dominant models also revealed that the minor IL-17F 7488C allele conferred an increased CRC risk compared to the major T allele among our study participants (CC vs. TT: OR = 4.15, 95% CI = 1.26-13.36, P = 0.011; TC+CC vs. TT: OR = 1.46, 95% CI = 1.04-2.05, P = 0.027). However, all genetic models indicated that the IL-17F 7383A>G (rs2397084) polymorphism was not associated with CRC risk (all P > 0.05). The results of this study indicate that the 7488T>C (rs763780) in the IL-17F gene may be correlated with increased risk of CRC. PMID- 25296731 TI - Genetic determinants of uveal melanoma. AB - Melanoma of the uveal tract is the most common primary intraocular tumor in adults. With advances in genetic research and the open source access of genetic databases, new insights are emerging into the molecular changes of this cancer. As with most other tumors, the driving force behind such research is the hope of finding and developing new modalities for therapeutic purposes, prognosticating disease and understanding risk factors for metastasis. With advances in proteomics, cytogenetics and gene profiling, the stage is set to unearth the underlying genetic basis which can in the future be a target of therapeutic modalities. This article describes the cytogenetic, molecular pathogenesis, and prognostic factors along with the most important findings and their attribution to current and future management of uveal melanoma. PMID- 25296732 TI - TERT polymorphisms rs2853669 and rs7726159 influence on prostate cancer risk in Russian population. AB - Telomere length and telomerase activity have been hypothesized to play a role in cancer development. The aim of our study was to investigate the association of allelic variants of three functional polymorphisms rs2853669, rs2736100, and rs7726159 in the telomerase reverse transcriptase (TERT) gene with the risk of the breast cancer and prostate cancer in Russian population. Six hundred sixty women with breast cancer, 372 men with prostate cancer, and corresponding control groups of 523 women and 363 men were included in the present case-control study. We observed an association of allele rs2853669 C with increased risk of prostate cancer (co-dominant model TC vs. TT OR = 1.65, P = 0.002; additive model OR = 1.42, P = 0.005; dominant model: OR = 1.64, P = 0.001) and allele rs7726159 A with reduced risk of this malignancy (so-dominant model: AA vs. CC OR = 0.42, P = 0.002; additive model: OR = 0.69, P = 0.002; dominant model: OR = 0.67, P = 0.01; recessive model: OR = 0.48, P = 0.005). None of the studied polymorphisms showed an association with the risk of breast cancer. Our results provide evidence that the TERT gene variability modulate prostate cancer predisposition in ethnical Russians. PMID- 25296733 TI - Clinical utility of certain biomarkers as predictors of breast cancer with or without metastasis among Egyptian females. AB - The objective of this study is to explore and correlate the value of certain biomarkers in breast cancer (BC) females with and without metastasis after undergoing the surgical treatment protocol in the National Cancer Institute in Egypt. Thirty females (33-69 years), diagnosed as early breast cancer patients with or without metastasis, and 20 healthy individuals were selected for this study. The biomarkers under investigation were vascular endothelial growth factor (VEGF), C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-8 (IL-8). The correlation between these markers and the tumor grade was also evaluated. The results revealed a significant increase (p < 0.0001) in VEGF, CRP, IL-6, and IL-8 in breast cancer patients with or without metastasis as compared to the healthy group. Surgical treatment of metastatic BC females showed a significant reduction of those parameters by variable degrees, whereas BC females without metastasis recorded the most inhibition levels. Also, there was positive correlation (p < 0.0001) between those biomarkers and the tumor grades. We also noticed an association between VEGF and IL-8 as well as CRP and IL-6. In conclusion, the selected biomarkers may be beneficial for the prognosis of breast cancer and seem to be a diagnostic tool to differentiate between BC with or without metastasis. The descried surgical treatment protocol succeeded to attenuate the elevated biomarker levels and improve patient survival which deserves more extensive studies. PMID- 25296734 TI - Secreted cyclophilin A mediates G1/S phase transition of cholangiocarcinoma cells via CD147/ERK1/2 pathway. AB - Cyclophilin A (CypA) was shown to be upregulated in human cholangiocarcinoma (CCA) tissues. Suppression of intracellular CypA (inCypA) significantly reduces cell proliferation in vitro and tumor growth in nude mice. In the present study, the effect and potential mechanism of secreted CypA (sCypA) on cell proliferation of CCA cell lines were further investigated. CCA cells were treated with sCypA containing conditioned media (CM) or with purified recombinant human CypA (rhCypA). Cell proliferation, cell cycle, ERK1/2, p38 MAPK, NF-kappaB, and STAT3 activities were examined by MTS assay, flow cytometry, and Western blot. sCypA was detected in CM from MMNK1 (an immortalized human cholangiocyte cell line) and six CCA cell lines. The sCypA levels corresponded to the inCypA levels indicating the intracellular origin of sCypA. Both sCypA-containing CM and rhCypA significantly increased proliferation of CCA cells. CD147 depletion by shRNA knockdown or neutralizing with a CD147-monoclonal antibody significantly reduced sCypA-, and rhCypA-mediated cell proliferation. Upon rhCypA treatment, ERK1/2 was rapidly phosphorylated; whereas neutralizing CD147 inhibited ERK1/2 phosphorylation. Cell cycle analysis showed a significant increase in S phase and decrease in G1 population in rhCypA-treated cells. The expression levels of cyclin D1 and phosphorylated-retinoblastoma protein in the rhCypA-treated cells were increased compared with those in the non-treated control cells. p38 MAPK pathway was shown to be suppressed in siCypA-treated cells. In summary, CypA is secreted from CCA cells and enhances cell proliferation in an autocrine/paracrine manner, at least via direct binding with CD147, which may activate the ERK1/2 and p38 MAPK signaling pathways. PMID- 25296735 TI - Diagnostic value of circulating microRNAs as biomarkers for breast cancer: a meta analysis study. AB - Recent studies have provided new insights into the diagnostic value of circulating microRNAs (miRNAs) for breast cancer (BCa). However, the inconsistent results between studies have prevented the widespread usage of miRNAs in clinics. To systematically assess the potential diagnostic value of circulating miRNAs in BCa, we performed a comprehensive meta-analysis. Eligible studies were retrieved by searching electronic databases. The quality of the studies was assessed on the basis of quality assessment for studies of diagnostic accuracy (QUADAS) criteria. The bivariate meta-analysis model was employed to summarize the diagnostic indices and plot the summary receiver operator characteristic (SROC) curve. A total of 15 studies were included in this meta-analysis, involving 1368 BCa patients and 849 healthy controls. Our bivariate random effects meta-analysis yielded an area under curve (AUC) value of 0.9217, with a sensitivity of 0.82 (95 % confidence interval (CI) 0.80-0.83) and specificity of 0.82 (95% CI 0.80-0.85) for the use of miRNAs in differentiating BCa patients from healthy controls. Notably, our subgroup analysis suggested that a combination of multiple miRNAs (AUC, sensitivity, and specificity of 0.9518, 0.87, and 0.88, respectively) seemed to harbor higher accuracy than single miRNA-based assays (AUC, sensitivity, and specificity of 0.8923, 0.79, and 0.77, respectively). Altogether, our data indicate that circulating miRNA profiling has a potential to be used as a screening test for BCa, among which, the detection of a combined multiple miRNAs may be a more comprehensive indicator than individual miRNA. PMID- 25296736 TI - Decreased expression of EFS is correlated with the advanced prostate cancer. AB - Prostate cancer is the most frequently diagnosed malignant neoplasm in men in the developed countries. Although the progression of prostate cancer and the processes of invasion and metastasis by tumor cells are comparatively well understood, the genes involved in these processes are not fully determined. Therefore, a common area of research interest is the identification of novel molecules that are involved in these processes. In the present study, we have used in silico and experimental approaches to compare the expression of embryonal Fyn-associated substrate (EFS) between normal prostate and prostate cancer. We showed that EFS expression is remarkably downregulated in prostate cancer cells, compared to normal prostate cells. We also found that decreased expression of EFS in prostate cancer cells is due to DNA methylation. In addition, we showed that high EFS expression is important to suppress a malignant behavior of prostate cancer cells. Therefore, we suggest that EFS should be considered as a novel tumor suppressor gene in prostate cancer. PMID- 25296737 TI - The changing of serum vitamin B12 and homocysteine levels after gastrectomy in patients with gastric cancer: do they associate with clinicopathological factors? AB - After total (TG) or distal subtotal gastrectomy (DG), patients are at high risk of vitamin B12 (vit-B12) deficiency, which results in elevation of homocysteine levels. The changing of serum vit-B12 and homocysteine levels in patients with gastric cancer is not well known. Seventy-two patients with gastric cancer who had undergone currative gastrectomy and 50 healthy controls were included. Serum vit-B12 and homocysteine levels were analyzed in gastric cancer patients. In addition, these parameters were compared with those of healthy control subjects. While serum vit-B12 levels in gastrectomized patients were significantly lower than that of healthy controls (221.8 +/- 125.6 pg/mL vs. 309.9 +/- 174.3 pg/mL, p = 0.002), homocysteine levels were significantly higher in patients with gastric cancer (14.2 +/- 6.7 MUmol/L vs. 12.5 +/- 6.1 MUmol/L, p = 0.016). Mean serum folate level was found to be high in healthy controls (7.3 ng/mL) compared to patients (9.2 ng/mL, p = 0.027). Out of 72 patients, 40 patients (55.6 %) with gastric cancer developed vit-B12 deficiency after gastrectomy. Vit-B12 deficiency was found to be related with gastrectomy type (p = 0.02) and homocysteine levels (p = 0.014). In patients who underwent TG, the incidence of vit-B12 deficiency was significantly higher compared with those with DG (67.5 vs. 32.5 %). In addition, serum vit-B12 level in patients with DG was significantly higher than that of patients with TG (248.3 +/- 122.0 pg/mL vs. 200.8 +/- 126.7 pg/mL, p = 0.041), whereas homocysteine levels were significantly lower in DG group compared with TG group (12.1 +/- 6.1 MUmol/L vs. 15.8 +/- 6.9 MUmol/L, p = 0.014). A logistic regression analysis showed that the extent of gastrectomy was found to be an independent factor for predicting the occurrence of vit-B12 deficiency (p < 0.001, odds ratio 1.38). Our results showed that cumulative vit-B12 deficiency rate was significantly higher after TG compared with that after DG, while homocysteine levels were significantly higher in TG group compared with DG group. The extent of gastrectomy was found to be an independent factor for predicting the occurrence of vit-B12 deficiency. Vit-B12 deficiency and hyperhomocysteinemia are imperious clinical situation for patients with gastric cancer after surgery. Hence, both preoperative and regular postoperative monitoring of vit-B12 and homocysteine levels for all gastrectomized patients with gastric cancer are important and necessary for early detection and prevention of vit-B12 deficiency and hyperhomocysteinemia as a risk factor for cardiovascular diseases. PMID- 25296738 TI - Screening for medullary carcinoma of the thyroid. PMID- 25296740 TI - Effects of whole body cryo-chamber therapy on pain in patients with chronic low back pain: a prospective double blind randomised controlled trial. AB - BACKGROUND: It is believed that treatment with low temperature can reduce pain perception in chronic pain patients, including chronic low back pain patients. AIM: To evaluate the effects of a two-week repeated intervention of -67 degrees C cryo-chamber in patients with chronic low back pain. DESIGN: A prospective randomized double blind study design. SETTING: Hospital-based outpatients department POPULATION: Outpatients with chronic low back pain. METHODS: Comparing intervention group (-67 degrees C) with higher temperature (-5 degrees C) which was supposed as a control group in a cryo-chamber. RESULTS: Similar effectiveness in pain reduction in both intervention and control groups CONCLUSION: Cryochamber therapy with -67 degrees C is not superior to (sham cryo chamber) with -5 degrees C. CLINICAL REHABILITATION IMPACT: Cryo chambers therapy show positive effect by improving pain. For the treatment, -5 degrees C seems to be sufficient for these patients. PMID- 25296739 TI - Large-scale international study enhances understanding of an emerging acne population: adult females. AB - BACKGROUND: Acne vulgaris is increasingly recognized in adult women; however, few studies have formally evaluated the clinical presentation and factors associated with acne in this population. METHODS: This prospective, observational international study evaluated the clinical characteristics and lifestyle correlates of acne in adults (>=25 years) at a dermatology visit for acne. Investigators conducted a detailed clinical examination and administered a validated questionnaire that covered medical history, disease evolution, lifestyle habits, previous treatments, skin care and quality of life. RESULTS: In this study (n = 374), acne was mild or clear/almost clear in 47.3% of subjects; however, the study visit was not required to be an initial consultation for acne and as such, many patients were already on treatment. Most women (89.8%) had acne involving multiple facial zones (cheeks, forehead, mandibular area, temples) with a spectrum of facial acne severity similar to adolescents. Mixed facial acne (both inflammatory and non-inflammatory lesions present) was the most common presentation; 6.4% of women had inflammatory acne only (no non-inflammatory lesions reported) and 17.1% had comedonal acne with no inflammatory lesions. Truncal acne was present in 48.4% of patients. A small subset (11.2%) had acne localized only to the mandibular area. Compared to the women without localized acne, those with mandibular acne were more likely to be employed (90.5% vs. 78.6%), reported greater daily stress levels (5.8 vs. 5.1), and were more likely to say their jobs were psychologically stressful (71.4% vs. 57.5%). Women with mandibular acne alone were significantly less likely to have a global acne severity rating of moderate or higher (7.1% vs. 50.1%), truncal acne (19.0% vs. 51.9%), post-inflammatory hyperpigmentation (23.8% vs. 51.9%) and erythema (19.0% vs. 48.4%). At the completion of the study visit, this group was also more likely to receive a prescription for an anti-androgen (16.7% vs. 7.7%). CONCLUSIONS: This study represents the first objective assessment of the facial distribution of acne lesions in adult women presenting to the dermatology office. The data surprisingly indicate that the acne distribution in almost 90% of cases is similar to that seen in adolescent acne. The stereotype of adult female acne being due to hormonal disturbances presenting as inflammatory acne localized only to the mandibular area was not found in the majority of this large group. The large majority (93.7%) of women had facial comedones. We recommend that the general treatment approach for adult acne should include agents that target each of the acne lesion subtypes. Subgroup analyses of recent large-scale controlled clinical trials have shown that many adult women respond well to standard first line acne therapy. PMID- 25296741 TI - Mobilization versus manipulations versus sustain apophyseal natural glide techniques and interaction with psychological factors for patients with chronic neck pain: randomized controlled trial. AB - BACKGROUND: Three different types of manual therapy techniques for patients with neck pain and relationship with psychological factors has not been evaluated. AIM: To compare the effectiveness high velocity and low amplitude (HVLA) manipulation vs. posteroanterior mobilization (PA mob) vs. sustain appophyseal natural glide (SNAG) in the management of patients with neck pain and to evaluate the interaction with psychological factors. STUDY DESING: Randomized clinical trial. SETTING: Primary Health Care Center. POPULATION: Patients with history of chronic neck pain over the last 3 months were recruited. METHODS: Patients were randomly assigned to receive treatment with HVLA (N.=15), with PA mob (N.=16) or with SNAG (N.=17). One session was applied. Pain intensity of neck pain, pressure pain threshold over processus spinosus of C2 (PPT_C2) and cervical range of motion (CROM) were measured pre- and post-intervention. Pain catastrophizing, depression, anxiety and kinesiophobia were assessed in baseline. ANOVAs were performed, with main effects, two-way (treatment x time) and three-way interactions (treatment x psychological variable x time) were examined. RESULTS: Fourthy-eight patients (mean+/-SD age, 36.5+/-8.7 years; 87.5% female). A significant interaction treatment x time was observed for VAS-rest in HVLA and AP mob groups (P<0.05). With more pain relief to HVLA and AP mob groups than SNAG groups but all groups improve the same in CROM. Also, a significant three-way treatment x anxiety x time interaction for VAS in Flexion/Extension was identified (P<0.01), and a trend toward significance was observed for the three way treatment x anxiety x time interaction, with respect to CROM in Lateral Flexion movement (P<0.05). CONCLUSION: The results suggest that an HVLA and PA mob groups relieved pain at rest more than SNAG in patients with Neck pain. Among psychological factors, only trait anxiety seems interact with Manual therapy, mainly high anxiety conditions interact with the Mobilization and SNAG effects but under low anxiety conditions interact with the HVLA effects. Significant mean differences can be observed both in VAS in Flexion/Extension and in CROM in lateral-flexion movement when using mobilization under high anxiety conditions CLINICAL REHABILITATION IMPACT: The findings provide preliminary evidence to support that three different techniques have similar immediate effects over neck pain and while under high anxiety levels a better outcome is expected after mobilization intervention, under low anxiety levels a better prognosis is expected after manipulation and SNAG intervention. PMID- 25296742 TI - Treatment outcome of visual feedback training in an adult patient with habitual toe walking. AB - BACKGROUND: Habitual (idiopathic) toe walking (HTW) is not a rare diagnosis in pediatric orthopedic patients, but a relative rare pathology in adults. There are no standard recommendations for treating HTW in adult patients. AIM: To investigate the effects of visual feedback training in an adult patient with habitual toe walking HTW. DESIGN: case report. SETTING: Outpatient rehabilitation department. POPULATION: The 52--year--old woman with HTW. METHODS: The patient participated in visual feedback training on a treadmill with integrated force plates. A display in front of the patient showed her footprints in synchrony with the treadmill speed so that the patient got dynamic feedback about the pressure of the feet on the ground in real--time on the screen. The training was conducted in 10 sessions of about 40 min within three weeks. Gait analysis (30 sec) and a measurement of the active range of joint motion of the ankle were performed before and after the 3--week treatment period and at follow--up after 3 weeks. RESULTS: For both feet, contact time of the heel was increased after the training period, whereas contact time of the forefeet decrease. Also positive changes in the active range of joint motion of the ankle (dorsal extension) were observed in both feet. These positive effects were visible also in the follow--up assessment. CONCLUSIONS: It was shown that providing visual feedback about foot pressure patterns is a promising treatment strategy for adult patients with HTW. PMID- 25296743 TI - Nailfold videocapillaroscopy micro-haemorrhage and giant capillary counting as an accurate approach for a steady state definition of disease activity in systemic sclerosis. AB - INTRODUCTION: Nailfold videocapillaroscopy (NVC) in systemic sclerosis (SSc) is a procedure commonly used for patient classification and subsetting, but not to define disease activity (DA). This study aimed to evaluate whether the number of micro-haemorrhages (MHE), micro-thrombosis (MT), giant capillaries (GC), and normal/dilated capillaries (Cs) in NVC could predict DA in SSc. METHODS: Eight finger NVC was performed in 107 patients with SSc, and the total number of MHE/MT, GC, and the mean number of Cs were counted and defined as number of micro haemorrhages (NEMO), GC and Cs scores, respectively. The European Scleroderma Study Group (ESSG) index constituted the gold standard for DA assessment, and scores >= 3.5 and = 3 were considered indicative of high and moderate activity, respectively. RESULTS: NEMO and GC scores were positively correlated with ESSG index (R = 0.65, P < 0.0001, and R = 0.47, P <0.0001, respectively), whilst Cs score showed a negative correlation with that DA index (R = -0.30, P <0.001). The area under the curve (AUC) of receiver operating characteristic plots, obtained by NEMO score sensitivity and specificity values in classifying patients with ESSG index >= 3.5, was significantly higher than the corresponding AUC derived from either GC or Cs scores (P <0.03 and P <0.0006, respectively). A modified score, defined by the presence of a given number of MHE/MT and GC, had a good performance in classifying active patients (ESSG index >= 3, sensitivity 95.1%, specificity 84.8%, accuracy 88.7%). CONCLUSIONS: MHE/MT and GC appear to be good indicators of DA in SSc, and enhances the role of NVC as an easy technique to identify active patients. PMID- 25296744 TI - A new Rhnull allele in francophone Quebecers. PMID- 25296745 TI - Self-cleaning Metal Organic Framework (MOF) based ultra filtration membranes--a solution to bio-fouling in membrane separation processes. AB - Bio-fouling is a serious problem in many membrane-based separation processes for water and wastewater treatment. Current state of the art methods to overcome this are to modify the membranes with either hydrophilic additives or with an antibacterial compound. In this study, we propose and practise a novel concept to prevent bio-fouling by developing a killing and self-cleaning membrane surface incorporating antibacterial silver nanoparticles and highly hydrophilic negatively charged carboxylic and amine functional groups. The innovative surface chemistry helps to reduce the contact angle of the novel membrane by at least a 48% and increase the pure water flux by 39.4% compared to the control membrane. The flux drop for the novel membrane is also lower (16.3% of the initial flux) than the control membrane (55.3% of the initial flux) during the long term experiments with protein solution. Moreover, the novel membrane continues to exhibit inhibition to microbes even after 1320 min of protein filtration. Synthesis of self-cleaning ultrafiltration membrane with long lasting properties opens up a viable solution for bio-fouling in ultrafiltration application for wastewater purification. PMID- 25296746 TI - Effective PHIP labeling of bioactive peptides boosts the intensity of the NMR signal. AB - A series of novel bioactive derivatives of the sunflower trypsin inhibitor-1 (SFTI-1) suitable for hyperpolarization by parahydrogen-induced polarization (PHIP) was developed. The PHIP activity was achieved by labeling with L propargylglycine, O-propargyl-L-tyrosine, or 4-pentynoic acid. (1) H NMR signal enhancements (SE) of up to a factor of 70 were achieved in aqueous solution. We found that an isolated spatial location of the triple bond within the respective label and its accessibility for the hydrogenation catalyst are essential factors for the degree of signal enhancement. PMID- 25296747 TI - Can we use enthesis ultrasound as an outcome measure of disease activity in spondyloarthritis? A study at the Achilles level. AB - OBJECTIVE: The aim of this study was to evaluate the construct validity of enthesis US in the assessment of disease activity in SpA. METHODS: A longitudinal Achilles enthesis US study in patients with early SpA was undertaken. Achilles US examinations were performed at baseline, 6 and 12 months and compared with clinical outcome measures collected at the baseline visit. RESULTS: Bilateral Achilles enthesis of 146 early SpA patients (68 women) were analysed. Basal mean BASFI, BASRI-spine, BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS) were 2.44 (s.d. 2.05, range 0-8), 0.67 (s.d. 0.74, range 0-3), 4.60 (s.d. 2.07, range 0-9.5) and 2.51 (s.d. 1.16, range 0-5), respectively. The mean ESR was 15.0 mm/h (s.d. 16.99, range 0-109) and the mean CRP was 8.67 mg/l (s.d. 16.98, range 1-90). At baseline, the Achilles Doppler signal and US structure alteration were significantly associated with higher CRP and ESR levels. Patients who had very high disease activity at baseline, as assessed by the ASDAS (>3.5), had a significantly higher Achilles total US score at baseline (P = 0.04), and ASDAS <1.3 predicted no Doppler signal at 6 and 12 months. Overall, the Achilles total US score was significantly higher in patients with higher levels of CRP (baseline P = 0.04, 6 months P = 0.006, 12 months P = 0.03) and ESR (baseline P = 0.02, 6 months P = 0.04, 12 months P = 0.005) at baseline. The Doppler signal at the baseline visit predicted a higher total US score at 6 and 12 months. CONCLUSION: Doppler US has significant associations with other commonly accepted disease activity measures, such as ESR, CRP and ASDAS, and seems to be an objective outcome measure for enthesitis. PMID- 25296748 TI - Structural and functional outcomes of a therapeutic strategy targeting low disease activity in patients with elderly-onset rheumatoid arthritis: a prospective cohort study (CRANE). AB - OBJECTIVE: The aim of this study was to evaluate structural damage and physical disability in patients with elderly-onset RA (EORA) who were treated in clinical practice with a therapeutic strategy targeting low disease activity (LDA). METHODS: Data from 151 MTX-naive patients (mean age 74.9 years) with EORA from a prospective, monocentric registry were analysed. Treatment was adjusted every 3 months targeting LDA [28-joint DAS using ESR (DAS28-ESR) <3.2]. Treatment was initiated with non-biologic DMARDs (nbDMARDs), followed by TNF inhibitors (TNFis) or tocilizumab. The primary outcome was change from week 0 to week 52 in the modified total Sharp score (DeltamTSS). Secondary outcomes were derived from the HAQ Disability Index (HAQ-DI) and DAS28 at week 52. Predictors of clinically relevant radiographic progression [CRRP; DeltamTSS/year more than the smallest detectable change (2.1 points)] were examined using multivariate logistic regression models. RESULTS: Adherence to the treat-to-target strategy was observed in 83.4% of the 151 patients at week 24 and in 75.5% at week 52. At week 52, 67.6% of the patients were receiving a nbDMARD alone, 31.0% a TNFi with or without MTX and 1.4% tocilizumab. At week 52, structural remission (DeltamTSS/yr <=0.5) was achieved in 49.7% of the patients, functional remission (HAQ-DI <=0.5) in 63.4% and LDA in 51.0%. Clinical responses at weeks 12 and 24 were significant independent predictors of CRRP. Cumulative disease activity during the first 12 weeks predicted CRRP with a C-statistic of 0.888. CONCLUSION: Achieving structural remission, functional remission and LDA in clinical practice in EORA patients are realistic goals. Our results indicate significant benefits for a therapeutic strategy targeting LDA for EORA patients in clinical practice. PMID- 25296749 TI - The type of competition modulates the ecophysiological response of grassland species to elevated CO2 and drought. AB - The effects of elevated CO2 and drought on ecophysiological parameters in grassland species have been examined, but few studies have investigated the effect of competition on those parameters under climate change conditions. The objective of this study was to determine the effect of elevated CO2 and drought on the response of plant water relations, gas exchange, chlorophyll a fluorescence and aboveground biomass in four grassland species, as well as to assess whether the type of competition modulates that response. Elevated CO2 in well-watered conditions increased aboveground biomass by augmenting CO2 assimilation. Drought reduced biomass by reducing CO2 assimilation rate via stomatal limitation and, when drought was more severe, also non-stomatal limitation. When plants were grown under the combined conditions of elevated CO2 and drought, drought limitation observed under ambient CO2 was reduced, permitting higher CO2 assimilation and consequently reducing the observed decrease in aboveground biomass. The response to climate change was species specific and dependent on the type of competition. Thus, the response to elevated CO2 in well-watered grasses was higher in monoculture than in mixture, while it was higher in mixture compared to monoculture for forbs. On the other hand, forbs were more affected than grasses by drought in monoculture, while in mixture the negative effect of drought was higher in grasses than in forbs, due to a lower capacity to acquire water and mineral nutrients. These differences in species level growth responses to CO2 and drought may lead to changes in the composition and biodiversity of the grassland plant community in future climate conditions. PMID- 25296750 TI - alpha-Actinin-4 is required for amoeboid-type invasiveness of melanoma cells. AB - alpha-Actinin-4 (ACTN4), a key regulator of the actin cytoskeleton, is up regulated in melanoma, though its role in melanoma remains speculative. We have discovered that in WM1158, a highly aggressive melanoma cell line, down regulation of ACTN4 by shRNA induces a collagen I-dependent amoeboidal-to mesenchymal transition. Re-expression of low levels of WT ACTN4 but not similar expression levels of ACTN1 successfully restores the amoeboidal morphology and limits collagen I gel compaction. A truncated ACTN4 mutant 1-890, which lacks the C-terminal tail, fails to rescue the amoeboidal morphology and to compact collagen I gel. Interestingly, in three-dimensional collagen I gels, ACTN4 KD cells are more polarized compared with cells in which scrambled shRNA is expressed. Surprisingly, ACTN4 KD cells migrate faster than the ones expressing the scrambled shRNA on a collagen I gel (two-dimensional) although these two cell lines migrate similarly on tissue culture. Most importantly, down-regulation of ACTN4 significantly reduced invasion of WM1158 cells into the three-dimensional collagen I gel, a representative of the dermis. Taken together, these findings suggest that ACTN4 plays an important role in maintaining the amoeboidal morphology of invasive melanoma and thus promoting dissemination through collagen rich matrices. PMID- 25296751 TI - Insights into the inhibitory mechanisms of the regulatory protein IIA(Glc) on melibiose permease activity. AB - The phosphotransfer protein IIA(Glc) of the bacterial phosphoenolpyruvate:carbohydrate phosphotransferase system plays a key role in the regulation of carbohydrate metabolism. Melibiose permease (MelB) is one among several permeases subject to IIA(Glc) regulation. The regulatory mechanisms are poorly understood; in addition, thermodynamic features of IIA(Glc) binding to other proteins are also unknown. Applying isothermal titration calorimetry and amine-specific cross-linking, we show that IIA(Glc) directly binds to MelB of Salmonella typhimurium (MelB(St)) and Escherichia coli MelB (MelB(Ec)) at a stoichiometry of unity in the absence or presence of melibiose. The dissociation constant values are 3-10 MUM for MelB(St) and 25 MUM for MelB(Ec). All of the binding is solely driven by favorable enthalpy forces. IIA(Glc) binding to MelB(St) in the absence or presence of melibiose yields a large negative heat capacity change; in addition, the conformational entropy is constrained upon the binding. We further found that the IIA(Glc)-bound MelB(St) exhibits a decreased binding affinity for melibiose or nitrophenyl-alpha-galactoside. It is believed that sugar binding to the permease is involved in an induced fit mechanism, and the transport process requires conformational cycling between different states. Thus, the thermodynamic data are consistent with the interpretation that IIA(Glc) inhibits the induced fit process and restricts the conformational dynamics of MelB(St). PMID- 25296752 TI - Feedback induction of a photoreceptor-specific isoform of retinoid-related orphan nuclear receptor beta by the rod transcription factor NRL. AB - Vision requires the generation of cone and rod photoreceptors that function in daylight and dim light, respectively. The neural retina leucine zipper factor (NRL) transcription factor critically controls photoreceptor fates as it stimulates rod differentiation and suppresses cone differentiation. However, the controls over NRL induction that balance rod and cone fates remain unclear. We have reported previously that the retinoid-related orphan receptor beta gene (Rorb) is required for Nrl expression and other retinal functions. We show that Rorb differentially expresses two isoforms: RORbeta2 in photoreceptors and RORbeta1 in photoreceptors, progenitor cells, and other cell types. Deletion of RORbeta2 or RORbeta1 increased the cone:rod ratio ~2-fold, whereas deletion of both isoforms in Rorb(-/-) mice produced almost exclusively cone-like cells at the expense of rods, suggesting that both isoforms induce Nrl. Electroporation of either RORbeta isoform into retinal explants from Rorb(-/-) neonates reactivated Nrl and rod genes but, in Nrl(-/-) explants, failed to reactivate rod genes, indicating that NRL is the effector for both RORbeta isoforms in rod differentiation. Unexpectedly, RORbeta2 expression was lost in Nrl(-/-) mice. Moreover, NRL activated the RORbeta2-specific promoter of Rorb, indicating that NRL activates Rorb, its own inducer gene. We suggest that feedback activation between Nrl and Rorb genes reinforces the commitment to rod differentiation. PMID- 25296753 TI - A PTCH1 homolog transcriptionally activated by p53 suppresses Hedgehog signaling. AB - The p53-mediated responses to DNA damage and the Hedgehog (Hh) signaling pathway are each recurrently dysregulated in many types of human cancer. Here we describe PTCH53, a p53 target gene that is homologous to the tumor suppressor gene PTCH1 and can function as a repressor of Hh pathway activation. PTCH53 (previously designated PTCHD4) was highly responsive to p53 in vitro and was among a small number of genes that were consistently expressed at reduced levels in diverse TP53 mutant cell lines and human tumors. Increased expression of PTCH53 inhibited canonical Hh signaling by the G protein-coupled receptor SMO. PTCH53 thus delineates a novel, inducible pathway by which p53 can repress tumorigenic Hh signals. PMID- 25296754 TI - ESCRT-0 protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is targeted to endosomes independently of signal-transducing adaptor molecule (STAM) and the complex formation with STAM promotes its endosomal dissociation. AB - The ESCRT-0 complex, consisting of the hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and the signal-transducing adaptor molecule (STAM) proteins, recognizes ubiquitylated cargo during the initial step of endosomal sorting. The endosomal accumulation of overexpressed Hrs has been reported previously to be associated with endosome enlargement. In this study, we have found that co-expressing exogenous STAM1 in Hrs-overexpressing cells leads to a diffuse localization for a large part of the Hrs accumulated on endosomes and a recovery of the impaired cargo protein degradation process, thus suggesting that exogenous STAM abrogates the abnormalities of the Hrs-positive endosomes. A fluorescently labeled Hrs, introduced into the cells by membrane permeabilization, exhibited endosomal localization in the absence of STAM1 and gradually dissociated from the endosomes upon the sequential addition of recombinant STAM1. Furthermore, when microinjected into cells, the fluorescently labeled Hrs also showed endosomal accumulation; however, ESCRT-0 complexes formed prior to the microinjection did not. Analysis of the state of the complex in HeLa cells using blue-native PAGE revealed that the membrane-associated Hrs exists partly as a monomer and not only in the STAM1-bound form. Thus, our data suggest that the membrane binding and dissociation cycle of the ESCRT-0 proteins on the endosomal membrane is a critical step during the cargo sorting process. PMID- 25296755 TI - cAMP-responsive element-binding protein (CREB) and cAMP co-regulate activator protein 1 (AP1)-dependent regeneration-associated gene expression and neurite growth. AB - To regenerate damaged axons, neurons must express a cassette of regeneration associated genes (RAGs) that increases intrinsic growth capacity and confers resistance to extrinsic inhibitory cues. Here we show that dibutyrl-cAMP or forskolin combined with constitutive-active CREB are superior to either agent alone in driving neurite growth on permissive and inhibitory substrates. Of the RAGs examined, only arginase 1 (Arg1) expression correlated with the increased neurite growth induced by the cAMP/CREB combination, both of which were AP1 dependent. This suggests that cAMP-induced AP1 activity is necessary and interacts with CREB to drive expression of RAGs relevant for regeneration and demonstrates that combining a small molecule (cAMP) with an activated transcription factor (CREB) stimulates the gene expression necessary to enhance axonal regeneration. PMID- 25296756 TI - Plasminogen kringle 5 induces endothelial cell apoptosis by triggering a voltage dependent anion channel 1 (VDAC1) positive feedback loop. AB - Human plasminogen kringle 5 (K5) is known to display its potent anti-angiogenesis effect through inducing endothelial cell (EC) apoptosis, and the voltage dependent anion channel 1 (VDAC1) has been identified as a receptor of K5. However, the exact role and underlying mechanisms of VDAC1 in K5-induced EC apoptosis remain elusive. In the current study, we showed that K5 increased the protein level of VDAC1, which initiated the mitochondrial apoptosis pathway of ECs. Our findings also showed that K5 inhibited the ubiquitin-dependent degradation of VDAC1 by promoting the phosphorylation of VDAC1, possibly at Ser 12 and Thr-107. The phosphorylated VDAC1 was attenuated by the AKT agonist, glycogen synthase kinase (GSK) 3beta inhibitor, and siRNA, suggesting that K5 increased VDAC1 phosphorylation via the AKT-GSK3beta pathway. Furthermore, K5 promoted cell surface translocation of VDAC1, and binding between K5 and VDAC1 was observed on the plasma membrane. HKI protein blocked the impact of K5 on the AKT-GSK3beta pathway by competitively inhibiting the interaction of K5 and cell surface VDAC1. Moreover, K5-induced EC apoptosis was suppressed by VDAC1 antibody. These data show for the first time that K5-induced EC apoptosis is mediated by the positive feedback loop of "VDAC1-AKT-GSK3beta-VDAC1," which may provide new perspectives on the mechanisms of K5-induced apoptosis. PMID- 25296757 TI - Investigation of phycobilisome subunit interaction interfaces by coupled cross linking and mass spectrometry. AB - The phycobilisome (PBS) is an extremely large light-harvesting complex, common in cyanobacteria and red algae, composed of rods and core substructures. These substructures are assembled from chromophore-bearing phycocyanin and allophycocyanin subunits, nonpigmented linker proteins and in some cases additional subunits. To date, despite the determination of crystal structures of isolated PBS components, critical questions regarding the interaction and energy flow between rods and core are still unresolved. Additionally, the arrangement of minor PBS components located inside the core cylinders is unknown. Different models of the general architecture of the PBS have been proposed, based on low resolution images from electron microscopy or high resolution crystal structures of isolated components. This work presents a model of the assembly of the rods onto the core arrangement and for the positions of inner core components, based on cross-linking and mass spectrometry analysis of isolated, functional intact Thermosynechococcus vulcanus PBS, as well as functional cross-linked adducts. The experimental results were utilized to predict potential docking interactions of different protein pairs. Combining modeling and cross-linking results, we identify specific interactions within the PBS subcomponents that enable us to suggest possible functional interactions between the chromophores of the rods and the core and improve our understanding of the assembly, structure, and function of PBS. PMID- 25296758 TI - Exchange factor EFA6R requires C-terminal targeting to the plasma membrane to promote cytoskeletal rearrangement through the activation of ADP-ribosylation factor 6 (ARF6). AB - ADP-ribosylation factor 6 (ARF6) small GTPase regulates membrane trafficking and cytoskeleton rearrangements at the plasma membrane (PM) by cycling between the GTP-bound active and GDP-bound inactive conformations. Guanine nucleotide exchange factors (GEFs) activate ARF6. The exchange factor for ARF6 (EFA6) R has been identified as a biomarker for ovarian cancer. EFA6R shares the catalytic Sec7, pleckstrin homology (PH), and coiled coil (CC) domains of the other EFA6 family GEFs. Here we report the functional characterization of EFA6R. Endogenous EFA6R was present in the plasma membrane fraction. The exogenously expressed FLAG and GFP-tagged EFA6R were targeted to the PM. In vitro, GFP-EFA6R associated weakly but preferentially with phosphatidylinositol 4,5-bisphosphate (PIP2) through the PH domain. EFA6R required both its PH and CC domains localized at the C terminus to target the PM. Consistent with this, EFA6R lacking the CC domain (EFA6RDeltaCC) was released from the PM into the cytosol upon PIP2 depletion, whereas EFA6R release from the PM required both PIP2 depletion and actin destabilization. These results suggest that the dual targeting via the PH and CC domains is important for the PM localization of EFA6R. EFA6R specifically catalyzed the GTP loading of ARF6 in mammalian cells. Moreover, EFA6R regulated ARF6 localization and thereby actin stress fiber loss. The GEF activity of EFA6R was dependent on the presence of the Sec7 domain. The PH and CC domains were also required for the in vivo GEF activity of EFA6R but could be functionally replaced by the CAAX motif of K-Ras, suggesting a role for these domains in the membrane targeting of EFA6R. PMID- 25296759 TI - Long term expression of Drosophila melanogaster nucleoside kinase in thymidine kinase 2-deficient mice with no lethal effects caused by nucleotide pool imbalances. AB - Mitochondrial DNA depletion caused by thymidine kinase 2 (TK2) deficiency can be compensated by a nucleoside kinase from Drosophila melanogaster (Dm-dNK) in mice. We show that transgene expression of Dm-dNK in Tk2 knock-out (Tk2(-/-)) mice extended the life span of Tk2(-/-) mice from 3 weeks to at least 20 months. The Dm-dNK(+/-)Tk2(-/-) mice maintained normal mitochondrial DNA levels throughout the observation time. A significant difference in total body weight due to the reduction of subcutaneous and visceral fat in the Dm-dNK(+/-)Tk2(-/-) mice was the only visible difference compared with control mice. This indicates an effect on fat metabolism mediated through residual Tk2 deficiency because Dm-dNK expression was low in both liver and fat tissues. Dm-dNK expression led to increased dNTP pools and an increase in the catabolism of purine and pyrimidine nucleotides but these alterations did not apparently affect the mice during the 20 months of observation. In conclusion, Dm-dNK expression in the cell nucleus expanded the total dNTP pools to levels required for efficient mitochondrial DNA synthesis, thereby compensated the Tk2 deficiency, during a normal life span of the mice. The Dm-dNK(+/-) mouse serves as a model for nucleoside gene or enzyme substitutions, nucleotide imbalances, and dNTP alterations in different tissues. PMID- 25296761 TI - Implications of the Implicit Association Test D-Transformation for Psychological Assessment. AB - Psychometricians strive to eliminate random error from their psychological inventories. When random error affecting tests is diminished, tests more accurately characterize people on the psychological dimension of interest. We document an unusual property of the scoring algorithm for a measure used to assess a wide range of psychological states. The "D-score" algorithm for coding the Implicit Association Test (IAT) requires the presence of random noise in order to obtain variability. Without consequential degrees of random noise, all individuals receive extreme scores. We present results from an algebraic proof, a computer simulation, and an online survey of implicit racial attitudes to show how trial error can bias IAT assessments. We argue as a result that the D-score algorithm should not be used for formal assessment purposes, and we offer an alternative to this approach based on multiple regression. Our critique focuses primarily on the IAT designed to measure unconscious racial attitudes, but it applies to any IAT developed to provide psychological assessments within clinical, organizational, and developmental branches of psychology-and in any other field where the IAT might be used. PMID- 25296760 TI - Covalent modification of the NF-kappaB essential modulator (NEMO) by a chemical compound can regulate its ubiquitin binding properties in vitro. AB - Post-translational modification by ubiquitin plays important roles in multiple physiological and pathological processes. Ubiquitin-binding proteins play a critical role in recognizing and relaying polyubiquitin-based signaling. NEMO (NF kappaB Essential Modulator) is a central player in canonical NF-kappaB signaling whose major function is to bind to Lys-63- and/or M1- (or linear) linked polyubiquitin chains generated in response to cell stimulation. Here we show that Withaferin A (WA), a steroidal lactone, causes a change in NEMO's interaction with specific types of polyubiquitin chains in vitro. WA induces full-length recombinant NEMO to bind to long Lys-48-linked polyubiquitin chains but not tetra ubiquitin species. Significantly, the UBAN (ubiquitin binding in ABIN and NEMO) domain, essential for the ability of NEMO to bind M1/Lys-63-linked polyubiquitin, is dispensable for the WA-induced gain-of-function activity. Mass spectrometric analysis demonstrated that WA covalently modifies NEMO on a cysteine residue within the C-terminal zinc finger (ZF) domain. Point mutations to the ZF can reverse the WA-induced Lys-48-polyubiquitin binding phenotype. Our study demonstrates the feasibility of directly altering the ubiquitin interaction properties of an ubiquitin-binding protein by a chemical compound, thereby shedding light on a novel drug class to potentially alter polyubiquitin-based cellular processes. PMID- 25296762 TI - Reduction in saturated fat intake improves cardiovascular risks in obese adolescents during interdisciplinary therapy. AB - BACKGROUND/OBJECTIVES: Obesity is related to inflammation and cardiovascular disease. The increase in saturated fatty acid intake (SFA) can potentiate cardiovascular risks. The aim of this study was to assess the influence of change in SFA on carotid intima-media thickness (cIMT), metabolic profile and anti/pro inflammatory adipokines in obese adolescents. METHODS: Sixty obese adolescents were subjected to 1 year of interdisciplinary intervention (nutrition, psychology, physical exercise and clinical therapy). Blood glucose, insulin, lipid profile, leptin and adiponectin were analysed. Insulin resistance was estimated by HOMA-IR and HOMA-AD. cIMT was measured by ultrasonography. Dietetic intake was calculated by 3-day dietary record. Volunteers were analysed according to tertiles of change (Delta) in SFA intake: Low-SFA reduction<3.68 g; Moderate SFA reduction 3.68-13.67 g; and High-SFA reduction>13.67 g. RESULTS: Moderate and High-SFA tertiles presented reduction in insulin, leptin/adiponectin ratio, cIMT and increase in adiponectin and adiponectin/leptin ratio. Adiponectin/leptin ratio was predictor of cIMT. HOMA-IR, total cholesterol and LDL-cholesterol reduced only in High-SFA tertile, and was associated with SFA independent of visceral fat. Negative correlations between Delta of SFA and adiponectin and adiponectin/leptin ratio were observed. CONCLUSION: Obese adolescents with moderate and high reduction in SFA presented improvements on pro/anti inflammatory biomarkers and cIMT, leading to reduction in cardiovascular risks. PMID- 25296763 TI - Developing allied health professional support policy in Queensland: a case study. AB - INTRODUCTION: Evidence suggests that professional support for allied health professionals contributes to improved clinical practice, better client outcomes, enhanced workplace satisfaction, increased workplace morale and better clinical governance within organizations. Despite these benefits, the uptake of formal professional support is surprisingly low and implementation often ad hoc. Further, research investigating the development, evaluation and outcomes of implementing policy to establish such support is limited. CASE DESCRIPTION: Queensland Health has developed an organization-wide approach to supporting allied health professionals through a Professional Support Policy and guidelines. The processes of development, implementation and the evaluation framework of this State-wide Professional Support Policy are described. An evidence-based Professional Support Policy that is structured, collaborative and well evaluated will have benefits for allied health professions. However, policy introduction cannot occur in isolation. Current practice does not follow current evidence in the area of professional support implementation. This study describes a current practice baseline for participation prior to the mandating of such a policy. There is a need for improvements in participation rates, documentation and capacity building. CONCLUSIONS: A workforce policy with broad scope should increase the access to, and consistency of, professional support to allied health practitioners. Such policy should facilitate a higher quality clinical practice, better client outcomes, enhanced workplace satisfaction and morale. It may also maximize the recruitment and retention of allied health professionals. Mandating policy should see participation commensurate with that policy. A future step will be a Post Policy Implementation Review to determine the success and effectiveness of the Professional Support Framework within Queensland Health. PMID- 25296764 TI - Diagnosing and managing acute heart failure in adults: summary of NICE guidance. PMID- 25296768 TI - Syncope caused by congenital anomaly at the craniovertebral junction: a case report. AB - INTRODUCTION: Anomalies in the craniovertebral junction may be a rare cause of syncope. The mechanisms of syncope related to craniovertebral junction anomaly remain unknown.We present an extremely rare case with anomaly in the craniovertebral junction and syncope, and discuss the mechanism of the syncope. CASE PRESENTATION: A 10-year-old Japanese boy with a congenital anomaly in the craniovertebral junction presented with recurrent syncope. A physical examination showed generalized hyperreflexia, but motor and sensory examinations were normal. Computed tomography and magnetic resonance imaging showed basilar invagination and spinal cord compression at his craniovertebral junction. Three-dimensional computed tomography angiography revealed an anomalous course of his bilateral vertebral arteries, both of which showed a persistent first intersegmental artery that entered the spinal canal at the caudal portion of the C1 posterior arch. In this case, the arteries were nearly pinched between the C1 posterior arch and the pars interarticularis of the C2. C1 laminectomy and occiput-cervical fusion (O C2) was performed using an instrumentation system. After surgery, the syncope was not observed. CONCLUSIONS: Syncope can be related to compression of extracranial arteries within the neck. In this case, transient brain ischemia caused by the anomalous course of vertebral arteries that were pinched between the C1 posterior arch and the pars interarticularis of C2 in cervical motion was the suspected cause of the syncope. PMID- 25296769 TI - The 2nd Bio-Rheumatology International Congress (BRIC)/The 9th Global Arthritis Research Network (GARN) 2014, Meeting in Moscow, 5-7 June 2014, Moscow, Russian Federation. PMID- 25296765 TI - Quantitative Multi-modal Brain Autoradiography of Glutamatergic, Dopaminergic, Cannabinoid, and Nicotinic Receptors in Mutant Disrupted-In-Schizophrenia-1 (DISC1) Mice. AB - PURPOSE: Disrupted-in-schizophrenia-1 (DISC1) is a promising genetic susceptibility factor for major psychiatric conditions, such as schizophrenia. We hypothesized that the mutant DISC1 alters the homeostasis of multi-receptor interactions between dopaminergic [dopamine 2/3 (D(2/3)R)], glutamatergic [metabotropic glutamate 5 (mGluR5)], cannabinoid 1 (CB(1)R), and nicotinic acetylcholine (alpha4beta2-nAChR) receptors in the brains of mice with inducible forebrain neuronal expression of dominant-negative mutant DISC1. PROCEDURES: The quantitative in vitro autoradiography was performed with positron emission tomography (PET) ligands using [(11)C]raclopride (D2/3R), [(11)C]ABP688 (mGluR5), [(11)C]OMAR (CB(1)R), and [(18)F]AZAN (nAChR). Total binding (pmol/cc) from standard and binding index, defined as [(region of interest - reference) / reference], was analyzed in the parasagittal sections. The cerebellum was used as a reference for D(2/3)R, mGluR5, and alpha4beta2-nAChR, while the midbrain was the reference tissue for CB(1)R, because of the high density of CB(1)R in the cerebellum. RESULTS: We observed a significant positive correlation between mGluR5 and D2/3R in the nucleus accumbens (NAc) in mutant DISC1 (rho = 0.6, p = 0.04; y = 0.02 x + 6.7) and a trend of negative correlation between those receptors in the dorsal striatum (DS) in control animals (rho = -0.5, p = 0.09; y = -0.03 x + 23), suggesting a co-release of dopamine (DA) and glutamate (Glu) in the NAc, but not in the DS. There were trends of an inverse relationship between striatal CB(1)R and D(2/3)R (rho = -0.7, p = 0.07) as well as between dorsal thalamic nAChR and striatal D2/3R (rho = -0.5, p = 0.08). There was no statistically significant difference of the individual receptor density in the majority of brain regions. CONCLUSIONS: The mutant DISC1 altered the homeostasis of multi-receptor interactions of coincident signaling of DA and Glu in the NAc, but not in the DS, and mutually negative control of striatal CB(1)R and D2/3R. Multi-receptor mapping with PET ligands in relevant animal models could be a valuable translational approach for psychiatric drug development. PMID- 25296770 TI - Comparative analysis of methods for genome-wide nucleosome cartography. AB - Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use. PMID- 25296772 TI - Thrombophilia in patients with chronic immune thrombocytopenia. AB - An increased risk of thromboembolic events among patients with chronic immune thrombocytopenia has been reported but is still not fully understood. A thrombophilia panel (factors suspected/known to denote a thrombophilic state or indicate activation of the clotting cascade) was measured in previously treated patients with chronic immune thrombocytopenia enrolled in an eltrombopag trial to assess potential thrombophilia risk markers. Of 167 patients, 136 (81%) had abnormal levels of at least 1 known or suspected thrombosis risk marker or coagulation cascade activation marker. Six patients reported thromboembolic events, and all of these patients had at least two abnormal analytes in the thrombophilia panel. The presence of multiple baseline thrombophilia risk markers support the theory that chronic immune thrombocytopenia is a pro-thrombotic disease. PMID- 25296773 TI - Association of autism tendency and hemodynamic changes in the prefrontal cortex during facial expression stimuli measured by multi-channel near-infrared spectroscopy. AB - AIM: The aim of this study is to examine the hemodynamic changes induced by the cognitive process of facial expression by using multi-channel near-infrared spectroscopy in healthy subjects with varying degrees of autism tendency. METHODS: Subjects were 38 volunteers, 20 men and 18 women. Autism tendency was measured by the Autism Spectrum Quotient. The hemodynamic changes in the prefrontal cortex were measured by 24-channel near-infrared spectroscopy system, while subjects were asked to judge their own emotional response to standardized pictures of eight kinds of facial expressions on a computer screen. RESULTS: There were significant negative correlations between Autism Spectrum Quotient scores and accuracy of fearful expression recognition as well as increases in the concentration of oxygenated hemoglobin in response to four kinds of emotional faces (fear, contempt, sadness and disgust). CONCLUSION: Our findings suggest that the greater tendency to autism that subjects have, the more difficulty they have in recognizing a fearful expression and the less hemodynamic change in the prefrontal cortex they show in response to negative facial expressions. PMID- 25296774 TI - Communication: identification of daughter ions through their electronic spectroscopy at low temperature. AB - We present experimental results on photofragmentation of cooled fragments issued from the photofragmentation of cold parent ions. The cooling of the daughter ions at a few K allows its characterization not only through its fragmentation pattern but also through its well resolved electronic spectroscopy. The proof of principle of the method is demonstrated on the photofragment resulting from Calpha-Cbeta bond rupture in protonated tyrosine (TyrH(+)). The analysis of the daughter ion (m/z 108) photofragmentation spectrum is in agreement with the proposed mechanism implying a proton transfer to the phenyl ring as the first step of the fragmentation mechanism of TyrH(+). PMID- 25296775 TI - Communication: a density functional investigation of structure-property evolution in the tetrakis hexahedral C4Al14 nanocluster. AB - Nanoclusters are prime objects of study in modern nanotechnology and offer a variety of applications promoted by their properties tunable by size, shape, and composition. DFT calculations are employed to analyze structure, stability, and selected electronic properties of a core-shell C4Al14 species. With insertion of the carbon core, the original low-symmetry aluminum cluster is predicted to undergo a considerable reshaping and acquire a striking D4h tetrakis-hexahedral geometry, with proportions controlled by a near-degenerate spin state or charge. The system also becomes more stable to dissociation. Surprisingly, other properties such as ionisation energy and electron affinity do not change significantly, although still exhibit some interesting features including opposite variations for vertical and adiabatic values. The stability and property evolutions are analyzed in terms of contributions from reshaping of the shell and its further interaction with the core. The system thus has potential applications as a symmetric building unit and a molecular device for nano electronics/spintronics. PMID- 25296777 TI - Communication: energy-dependent resonance broadening in symmetric and asymmetric molecular junctions from an ab initio non-equilibrium Green's function approach. AB - The electronic structure of organic-inorganic interfaces often features resonances originating from discrete molecular orbitals coupled to continuum lead states. An example is molecular junction, individual molecules bridging electrodes, where the shape and peak energy of such resonances dictate junction conductance, thermopower, I-V characteristics, and related transport properties. In molecular junctions where off-resonance coherent tunneling dominates transport, resonance peaks in the transmission function are often assumed to be Lorentzian functions with an energy-independent broadening parameter Gamma. Here we define a new energy-dependent resonance broadening function, Gamma(E), based on diagonalization of non-Hermitian matrices, which can describe resonances of a more complex, non-Lorentzian nature and can be decomposed into components associated with the left and right leads, respectively. We compute this quantity via an ab initio non-equilibrium Green's function (NEGF) approach based on density functional theory (DFT) for both symmetric and asymmetric molecular junctions, and show that our definition of Gamma(E), when combined with Breit Wigner formula, reproduces the transmission calculated from DFT-NEGF. Through a series of examples, we illustrate how this approach can shed new light on experiments and understanding of junction transport properties in terms of molecular orbitals. PMID- 25296776 TI - Communication: modeling charge-sign asymmetric solvation free energies with nonlinear boundary conditions. AB - We show that charge-sign-dependent asymmetric hydration can be modeled accurately using linear Poisson theory after replacing the standard electric-displacement boundary condition with a simple nonlinear boundary condition. Using a single multiplicative scaling factor to determine atomic radii from molecular dynamics Lennard-Jones parameters, the new model accurately reproduces MD free-energy calculations of hydration asymmetries for: (i) monatomic ions, (ii) titratable amino acids in both their protonated and unprotonated states, and (iii) the Mobley "bracelet" and "rod" test problems [D. L. Mobley, A. E. Barber II, C. J. Fennell, and K. A. Dill, "Charge asymmetries in hydration of polar solutes," J. Phys. Chem. B 112, 2405-2414 (2008)]. Remarkably, the model also justifies the use of linear response expressions for charging free energies. Our boundary element method implementation demonstrates the ease with which other continuum electrostatic solvers can be extended to include asymmetry. PMID- 25296778 TI - Transport properties of carbon dioxide and methane from molecular dynamics simulations. AB - Transport properties of carbon dioxide and methane are predicted for temperatures between (273.15 and 573.15) K and pressures up to 800 MPa by molecular dynamics simulations. Viscosities and thermal conductivities were obtained through the Green-Kubo formalism, whereas the Einstein relation was used to provide self diffusion coefficient estimates. The differences in property predictions due to the force field nature and parametrization were investigated by the comparison of seven different CO2 models (two single-site models, three rigid three-site models, and two fully flexible three-site models) and three different CH4 models (two single-site models and one fully flexible five-site model). The simulation results show good agreement with experimental data, except for thermal conductivities at low densities. The molecular structure and force field parameters play an important role in the accuracy of the simulations, which is within the experimental deviations reported for viscosities and self-diffusion coefficients considering the most accurate CO2 and CH4 models studied. On the other hand, the molecular flexibility does not seem to improve accuracy, since the explicit account of vibrational and bending degrees of freedom in the CO2 flexible models leads to slightly less accurate results. Nonetheless, the use of a correctional term to account for vibrational modes in rigid models generally improves estimations of thermal conductivity values. At extreme densities, the caging effect observed with single-site representations of the molecules restrains mobility and leads to an unphysical overestimation of viscosities and, conversely, to the underestimation of self-diffusion coefficients. This result may help to better understand the limits of applicability of such force fields concerning structural and transport properties of dense systems. PMID- 25296779 TI - Efficient on-the-fly ab initio semiclassical method for computing time-resolved nonadiabatic electronic spectra with surface hopping or Ehrenfest dynamics. AB - We derive a somewhat crude, yet very efficient semiclassical approximation for computing nonadiabatic spectra. The resulting method, which is a generalization of the multiple-surface dephasing representation, includes quantum effects through interference of mixed quantum-classical trajectories and through quantum treatment of the collective electronic degree of freedom. The method requires very little computational effort beyond the fewest-switches surface hopping or Ehrenfest locally mean-field dynamics and is very easy to implement. The proposed approximation is tested by computing the absorption and time-resolved stimulated emission spectra of pyrazine using the four-dimensional three-surface model which allows for comparison with the numerically exact quantum spectra. As expected, the multiple-surface dephasing representation is not suitable for high-resolution linear spectra, yet it seems to capture all the important features of pump-probe spectra. Finally, the method is combined with on-the-fly ab initio evaluation of the electronic structure (i.e., energies, forces, electric-dipole, and nonadiabatic couplings) in order to compute fully dimensional nonadiabatic spectra of pyrazine without approximations inherent to analytical, including vibronic-coupling models. The Appendix provides derivations of perturbative expressions for linear and pump-probe spectra of arbitrary mixed states and for arbitrary laser pulse shapes. PMID- 25296780 TI - Extending DFT-based genetic algorithms by atom-to-place re-assignment via perturbation theory: a systematic and unbiased approach to structures of mixed metallic clusters. AB - Energy surfaces of metal clusters usually show a large variety of local minima. For homo-metallic species the energetically lowest can be found reliably with genetic algorithms, in combination with density functional theory without system specific parameters. For mixed-metallic clusters this is much more difficult, as for a given arrangement of nuclei one has to find additionally the best of many possibilities of assigning different metal types to the individual positions. In the framework of electronic structure methods this second issue is treatable at comparably low cost at least for elements with similar atomic number by means of first-order perturbation theory, as shown previously [F. Weigend, C. Schrodt, and R. Ahlrichs, J. Chem. Phys. 121, 10380 (2004)]. In the present contribution the extension of a genetic algorithm with the re-assignment of atom types to atom sites is proposed and tested for the search of the global minima of PtHf12 and [LaPb7Bi7](4-). For both cases the (putative) global minimum is reliably found with the extended technique, which is not the case for the "pure" genetic algorithm. PMID- 25296781 TI - A molecular Debye-Huckel approach to the reorganization energy of electron transfer reactions in an electric cell. AB - Electron transfer near an electrode immersed in ionic fluids is studied using the linear response approximation, namely, mean value of the vertical energy gap can be used to evaluate the reorganization energy, and hence any linear response model that can treat Coulomb interactions successfully can be used for the reorganization energy calculation. Specifically, a molecular Debye-Huckel theory is used to calculate the reorganization energy of electron transfer reactions in an electric cell. Applications to electron transfer near an electrode in molten salts show that the reorganization energies from our molecular Debye-Huckel theory agree well with the results from MD simulations. PMID- 25296782 TI - Weighted-density functionals for cavity formation and dispersion energies in continuum solvation models. AB - Continuum solvation models enable efficient first principles calculations of chemical reactions in solution, but require extensive parametrization and fitting for each solvent and class of solute systems. Here, we examine the assumptions of continuum solvation models in detail and replace empirical terms with physical models in order to construct a minimally-empirical solvation model. Specifically, we derive solvent radii from the nonlocal dielectric response of the solvent from ab initio calculations, construct a closed-form and parameter-free weighted density approximation for the free energy of the cavity formation, and employ a pair-potential approximation for the dispersion energy. We show that the resulting model with a single solvent-independent parameter: the electron density threshold (nc), and a single solvent-dependent parameter: the dispersion scale factor (s6), reproduces solvation energies of organic molecules in water, chloroform, and carbon tetrachloride with RMS errors of 1.1, 0.6 and 0.5 kcal/mol, respectively. We additionally show that fitting the solvent-dependent s6 parameter to the solvation energy of a single non-polar molecule does not substantially increase these errors. Parametrization of this model for other solvents, therefore, requires minimal effort and is possible without extensive databases of experimental solvation free energies. PMID- 25296783 TI - The static response function in Kohn-Sham theory: an appropriate basis for its matrix representation in case of finite AO basis sets. AB - The role of the static Kohn-Sham (KS) response function describing the response of the electron density to a change of the local KS potential is discussed in both the theory of the optimized effective potential (OEP) and the so-called inverse Kohn-Sham problem involving the task to find the local KS potential for a given electron density. In a general discussion of the integral equation to be solved in both cases, it is argued that a unique solution of this equation can be found even in case of finite atomic orbital basis sets. It is shown how a matrix representation of the response function can be obtained if the exchange correlation potential is expanded in terms of a Schmidt-orthogonalized basis comprising orbitals products of occupied and virtual orbitals. The viability of this approach in both OEP theory and the inverse KS problem is illustrated by numerical examples. PMID- 25296784 TI - Analytic calculations of hyper-Raman spectra from density functional theory hyperpolarizability gradients. AB - We present the first analytic calculations of the geometrical gradients of the first hyperpolarizability tensors at the density-functional theory (DFT) level. We use the analytically calculated hyperpolarizability gradients to explore the importance of electron correlation effects, as described by DFT, on hyper-Raman spectra. In particular, we calculate the hyper-Raman spectra of the all-trans and 11-cis isomers of retinal at the Hartree-Fock (HF) and density-functional levels of theory, also allowing us to explore the sensitivity of the hyper-Raman spectra on the geometrical characteristics of these structurally related molecules. We show that the HF results, using B3LYP-calculated vibrational frequencies and force fields, reproduce the experimental data for all-trans-retinal well, and that electron correlation effects are of minor importance for the hyper-Raman intensities. PMID- 25296785 TI - Theoretical study of the ammonia nitridation rate on an Fe (100) surface: a combined density functional theory and kinetic Monte Carlo study. AB - Ammonia (NH3) nitridation on an Fe surface was studied by combining density functional theory (DFT) and kinetic Monte Carlo (kMC) calculations. A DFT calculation was performed to obtain the energy barriers (Eb) of the relevant elementary processes. The full mechanism of the exact reaction path was divided into five steps (adsorption, dissociation, surface migration, penetration, and diffusion) on an Fe (100) surface pre-covered with nitrogen. The energy barrier (Eb) depended on the N surface coverage. The DFT results were subsequently employed as a database for the kMC simulations. We then evaluated the NH3 nitridation rate on the N pre-covered Fe surface. To determine the conditions necessary for a rapid NH3 nitridation rate, the eight reaction events were considered in the kMC simulations: adsorption, desorption, dissociation, reverse dissociation, surface migration, penetration, reverse penetration, and diffusion. This study provides a real-time-scale simulation of NH3 nitridation influenced by nitrogen surface coverage that allowed us to theoretically determine a nitrogen coverage (0.56 ML) suitable for rapid NH3 nitridation. In this way, we were able to reveal the coverage dependence of the nitridation reaction using the combined DFT and kMC simulations. PMID- 25296786 TI - Real space electrostatics for multipoles. I. Development of methods. AB - We have extended the original damped-shifted force (DSF) electrostatic kernel and have been able to derive three new electrostatic potentials for higher-order multipoles that are based on truncated Taylor expansions around the cutoff radius. These include a shifted potential (SP) that generalizes the Wolf method for point multipoles, and Taylor-shifted force (TSF) and gradient-shifted force (GSF) potentials that are both generalizations of DSF electrostatics for multipoles. We find that each of the distinct orientational contributions requires a separate radial function to ensure that pairwise energies, forces, and torques all vanish at the cutoff radius. In this paper, we present energy, force, and torque expressions for the new models, and compare these real-space interaction models to exact results for ordered arrays of multipoles. We find that the GSF and SP methods converge rapidly to the correct lattice energies for ordered dipolar and quadrupolar arrays, while the TSF is too severe an approximation to provide accurate convergence to lattice energies. Because real space methods can be made to scale linearly with system size, SP and GSF are attractive options for large Monte Carlo and molecular dynamics simulations, respectively. PMID- 25296787 TI - Real space electrostatics for multipoles. II. Comparisons with the Ewald sum. AB - We report on tests of the shifted potential (SP), gradient shifted force (GSF), and Taylor shifted force (TSF) real-space methods for multipole interactions developed in Paper I of this series, using the multipolar Ewald sum as a reference method. The tests were carried out in a variety of condensed-phase environments designed to test up to quadrupole-quadrupole interactions. Comparisons of the energy differences between configurations, molecular forces, and torques were used to analyze how well the real-space models perform relative to the more computationally expensive Ewald treatment. We have also investigated the energy conservation, structural, and dynamical properties of the new methods in molecular dynamics simulations. The SP method shows excellent agreement with configurational energy differences, forces, and torques, and would be suitable for use in Monte Carlo calculations. Of the two new shifted-force methods, the GSF approach shows the best agreement with Ewald-derived energies, forces, and torques and also exhibits energy conservation properties that make it an excellent choice for efficient computation of electrostatic interactions in molecular dynamics simulations. Both SP and GSF are able to reproduce structural and dynamical properties in the liquid models with excellent fidelity. PMID- 25296788 TI - Computational quantum chemistry for single Heisenberg spin couplings made simple: just one spin flip required. AB - We highlight a simple strategy for computing the magnetic coupling constants, J, for a complex containing two multiradical centers. On the assumption that the system follows Heisenberg Hamiltonian physics, J is obtained from a spin-flip electronic structure calculation where only a single electron is excited (and spin-flipped), from the single reference with maximum Sz, M, to the M - 1 manifold, regardless of the number of unpaired electrons, 2M, on the radical centers. In an active space picture involving 2M orbitals, only one beta electron is required, together with only one alpha hole. While this observation is extremely simple, the reduction in the number of essential configurations from exponential in M to only linear provides dramatic computational benefits. This (M, M - 1) strategy for evaluating J is an unambiguous, spin-pure, wave function theory counterpart of the various projected broken symmetry density functional theory schemes, and likewise gives explicit energies for each possible spin-state that enable evaluation of properties. The approach is illustrated on five complexes with varying numbers of unpaired electrons, for which one spin-flip calculations are used to compute J. Some implications for further development of spin-flip methods are discussed. PMID- 25296789 TI - A quasiparticle-based multi-reference coupled-cluster method. AB - The purpose of this paper is to introduce a quasiparticle-based multi-reference coupled-cluster (MRCC) approach. The quasiparticles are introduced via a unitary transformation which allows us to represent a complete active space reference function and other elements of an orthonormal multi-reference (MR) basis in a determinant-like form. The quasiparticle creation and annihilation operators satisfy the fermion anti-commutation relations. On the basis of these quasiparticles, a generalization of the normal-ordered operator products for the MR case can be introduced as an alternative to the approach of Mukherjee and Kutzelnigg [Recent Prog. Many-Body Theor. 4, 127 (1995); Mukherjee and Kutzelnigg, J. Chem. Phys. 107, 432 (1997)]. Based on the new normal ordering any quasiparticle-based theory can be formulated using the well-known diagram techniques. Beyond the general quasiparticle framework we also present a possible realization of the unitary transformation. The suggested transformation has an exponential form where the parameters, holding exclusively active indices, are defined in a form similar to the wave operator of the unitary coupled-cluster approach. The definition of our quasiparticle-based MRCC approach strictly follows the form of the single-reference coupled-cluster method and retains several of its beneficial properties. Test results for small systems are presented using a pilot implementation of the new approach and compared to those obtained by other MR methods. PMID- 25296790 TI - Temperature effects in first-principles solid state calculations of the chemical shielding tensor made simple. AB - We study the effects of atomic vibrations on the solid-state chemical shielding tensor using first principles density functional theory calculations. At the harmonic level, we use a Monte Carlo method and a perturbative expansion. The Monte Carlo method is accurate but computationally expensive, while the perturbative method is computationally more efficient, but approximate. We find excellent agreement between the two methods for both the isotropic shift and the shielding anisotropy. The effects of zero-point quantum mechanical nuclear motion are important up to relatively high temperatures: at 500 K they still represent about half of the overall vibrational contribution. We also investigate the effects of anharmonic vibrations, finding that their contribution to the zero point correction to the chemical shielding tensor is small. We exemplify these ideas using magnesium oxide and the molecular crystals L-alanine and beta aspartyl-L-alanine. We therefore propose as the method of choice to incorporate the effects of temperature in solid state chemical shielding tensor calculations using the perturbative expansion within the harmonic approximation. This approach is accurate and requires a computational effort that is about an order of magnitude smaller than that of dynamical or Monte Carlo approaches, so these effects might be routinely accounted for. PMID- 25296791 TI - Full-dimensional control of the radiationless decay in pyrazine using the dynamic Stark effect. AB - We present a full quantum-mechanical study of the laser control of the radiationless decay between the B3u(npi(*)) and B2u(pipi(*)) states of pyrazine using the dynamic Stark effect. In contrast to our previous study [Sala et al., J. Chem. Phys. 140, 194309 (2014)], where a four-dimensional model was used, all the 24 degrees of freedom are now included in order to test the robustness of the strategy of control. Using a vibronic coupling Hamiltonian model in a diabatic representation, the multi-layer version of the multi-configuration time-dependent Hartree method is exploited to propagate the corresponding wave packets. We still observe a trapping of the wavepacket on the B2u(pipi(*)) potential energy surface due to the Stark effect for a longer time than the "non-resonant field-free" B2u(pipi(*)) lifetime. PMID- 25296792 TI - On the calculation of internal forces in mechanically stressed polyatomic molecules. AB - We discuss how to define and to compute internal forces in a molecule subjected to mechanical stress. Because of the inherently many-body character of intramolecular interactions, internal forces cannot be uniquely defined without specifying a set of internal coordinates used to describe the molecular structure. When such a set is comprised of 3N - 6 interactomic distances (N being the number of atoms) and includes the bond lengths of interest, we show that the associated forces, while satisfying the equation F = ?V/?R (where R is the bond length, F is the internal force in this bond, and V is the potential energy of the molecule), can be determined from the molecular geometry alone. We illustrate these ideas using several toy models ranging from small molecules to a graphene sheet and show that the magnitude of the internal force in a bond is not necessarily a good predictor of its strength in response to mechanical loading. At the same time, analysis of internal forces reveals interesting phenomena such as the force multiplication effect, where weak external forces may, e.g., be used to break strong bonds, and offers insight into the catch-bond phenomenon where chemical reactivity is suppressed through application of a force. PMID- 25296793 TI - Efficient rejection-based simulation of biochemical reactions with stochastic noise and delays. AB - We propose a new exact stochastic rejection-based simulation algorithm for biochemical reactions and extend it to systems with delays. Our algorithm accelerates the simulation by pre-computing reaction propensity bounds to select the next reaction to perform. Exploiting such bounds, we are able to avoid recomputing propensities every time a (delayed) reaction is initiated or finished, as is typically necessary in standard approaches. Propensity updates in our approach are still performed, but only infrequently and limited for a small number of reactions, saving computation time and without sacrificing exactness. We evaluate the performance improvement of our algorithm by experimenting with concrete biological models. PMID- 25296794 TI - Blip decomposition of the path integral: exponential acceleration of real-time calculations on quantum dissipative systems. AB - The real-time path integral representation of the reduced density matrix for a discrete system in contact with a dissipative medium is rewritten in terms of the number of blips, i.e., elementary time intervals over which the forward and backward paths are not identical. For a given set of blips, it is shown that the path sum with respect to the coordinates of all remaining time points is isomorphic to that for the wavefunction of a system subject to an external driving term and thus can be summed by an inexpensive iterative procedure. This exact decomposition reduces the number of terms by a factor that increases exponentially with propagation time. Further, under conditions (moderately high temperature and/or dissipation strength) that lead primarily to incoherent dynamics, the "fully incoherent limit" zero-blip term of the series provides a reasonable approximation to the dynamics, and the blip series converges rapidly to the exact result. Retention of only the blips required for satisfactory convergence leads to speedup of full-memory path integral calculations by many orders of magnitude. PMID- 25296795 TI - Nonorthogonal orbital based n-body reduced density matrices and their applications to valence bond theory. III. Second-order perturbation theory using valence bond self-consistent field function as reference. AB - Using the formulas and techniques developed in Papers I and II of this series, the recently developed second-order perturbation theory based on a valence bond self-consistent field reference function (VBPT2) has been extended by using the internally contracted correction wave function. This ansatz strongly reduces the size of the interaction space compared to the uncontracted wave function and thus improves the capability of the VBPT2 method dramatically. Test calculations show that internally contracted VBPT2 using only a small number of reference valence bond functions, can give results as accuracy as the VBPT2 method and other more sophisticated methods such as full configuration interaction and multireference configuration interaction. PMID- 25296796 TI - Vibronic coupling in asymmetric bichromophores: theory and application to diphenylmethane-d(5). AB - A theoretical model based on Fulton and Gouterman dimer Hamiltonian [J. Chem. Phys. 35, 1059 (1961)] is used to understand the jet cooled spectra of partly deuterated diphenylmethane (DPM-d5), reported in adjoining paper by Zwier and co workers ["Vibronic coupling in asymmetric bichromophores: Experimental investigation of diphenylmethane-d5," J. Chem. Phys. 141, 064316 (2014)]. The model is extended to include multiple vibrational modes, vibrational asymmetries between the monomers, and inter-monomer modes. Time dependent density functional theory and equation of motion coupled cluster electronic structure calculations are used to obtain parameters for the model Hamiltonian. The monomer units for DPM-d5 are toluene and partially deuterated toluene-d5. The comparisons of modeled and experimental spectra show that the model captures the vibronic effects on a multitude of observables, including anomalously intense vibrational states, transition dipole moment directions, and localization/delocalization phenomena of both the vibronic and electronic wavefunctions. Following the success of the model, a qualitative picture of vibronic coupling in DPM-d5 is built using only three active vibrations. This illustrates the ability of the model to not just qualitatively predict but also phenomenologically explain the vibronic effects observed in spectra of complex bichromophores. PMID- 25296797 TI - Tuned range-separated hybrid functionals in the symmetry-adapted perturbation theory. AB - The aim of this study is to present a performance test of optimally tuned long range corrected (LRC) functionals applied to the symmetry-adapted perturbation theory (SAPT). In the present variant, the second-order energy components are evaluated at the coupled level of theory. We demonstrate that the generalized Kohn-Sham (GKS) description of monomers with optimally tuned LRC functionals may be essential for the quality of SAPT interaction energy components. This is connected to the minimization of a many-electron self-interaction error and exemplified by two model systems: polyacetylenes of increasing length and stretching of He 3 (+). Next we provide a comparison of SAPT approaches based on Kohn-Sham and GKS description of the monomers. We show that LRC leads to results better or comparable with the hitherto prevailing asymptotically corrected functionals. Finally, we discuss the advantages and possible limitations of SAPT based on LRC functionals. PMID- 25296798 TI - Sum frequency generation image reconstruction: aliphatic membrane under spherical cap geometry. AB - The article explores an opportunity to approach structural properties of phospholipid membranes using Sum Frequency Generation microscopy. To establish the principles of sum frequency generation image reconstruction in such systems, at first approach, we may adopt an idealistic spherical cap uniform assembly of hydrocarbon molecules. Quantum mechanical studies for decanoic acid (used here as a representative molecular system) provide necessary information on transition dipole moments and Raman tensors of the normal modes specific to methyl terminal a typical moiety in aliphatic (and phospholipid) membranes. Relative degree of localization and frequencies of the normal modes of methyl terminals make nonlinearities of this moiety to be promising in structural analysis using Sum Frequency Generation imaging. Accordingly, the article describes derivations of relevant macroscopic nonlinearities and suggests a mapping procedure to translate amplitudes of the nonlinearities onto microscopy image plane according to geometry of spherical assembly, local molecular orientation, and optical geometry. Reconstructed images indicate a possibility to extract local curvature of bilayer envelopes of spherical character. This may have practical implications for structural extractions in membrane systems of practical relevance. PMID- 25296799 TI - Light desorption from an yttrium neutralizer for Rb and Fr magneto-optical trap loading. AB - We present here the first evidence of photodesorption induced by low-intensity non-resonant light from an yttrium thin foil, which works as a neutralizer for Rb and Fr ions beam. Neutral atoms are suddenly ejected from the metal surface in a pulsed regime upon illumination with a broadband flash light and then released in the free volume of a pyrex cells. Here atoms are captured by a Magneto-Optical Trap (MOT), which is effectively loaded by the photodesorption. Loading times of the order of the flash rise time are measured. Desorption is also obtained in the continuous regime, by exploiting CW visible illumination of the metallic neutralizer surface. We demonstrate that at lower CW light intensities vacuum conditions are not perturbed by the photodesorption and hence the MOT dynamics remains unaffected, while the trap population increases thanks to the incoming desorbed atoms flux. Even with the Y foil at room temperature and hence with no trapped atoms, upon visible illumination, the number of trapped atoms reaches 10(5). The experimental data are then analyzed by means of an analytical rate equation model, which allows the analysis of this phenomenon and its dynamics and allows the determination of critical experimental parameters and the test of the procedure in the framework of radioactive Francium trapping. In this view, together with an extensive investigation of the phenomenon with (85)Rb, the first demonstration of the photodesorption-aided loading of a (210)Fr MOT is shown. PMID- 25296800 TI - A new feature in the internal heavy isotope distribution in ozone. AB - Ozone produced by discharge or photolysis of oxygen has unusually heavy isotopic composition ((18)O/(16)O and (17)O/(16)O ratio) which does not follow normal mass fractionation rule: delta(17)O ~ 0.52(*)delta(18)O, expressed as an anomaly Delta(17)O = delta(17)O - 0.52(*)delta(18)O. Ozone molecule being an open isosceles triangle can have the heavy isotope located either in its apex or symmetric (s) position or the base or asymmetric (as) position. Correspondingly, one can define positional isotopic enrichment, written as delta(18)O (s) or delta(18)O (as) (and similarly for delta(17)O) as well as position dependent isotope anomaly Delta(17)O (s) and Delta(17)O (as). Marcus and co-workers have proposed a semi-empirical model based in principle on the RRKM model of uni molecular dissociation but with slight modification (departure from statistical randomness assumption for symmetrical molecules) which explains many features of ozone isotopic enrichment. This model predicts that the bulk isotope anomaly is contained wholly in the asymmetric position and the Delta(17)O (s) is zero. Consequently, Delta(17)O (as) = 1.5 (*) Delta(17)O (bulk) (named here simply as the "1.5 rule") which has been experimentally confirmed over a range of isotopic enrichment. We now show that a critical re-analysis of the earlier experimental data demonstrates a small but significant departure from this 1.5 rule at the highest and lowest levels of enrichments. This departure provides the first experimental proof that the dynamics of ozone formation differs from a statistical model constrained only by restriction of symmetry. We speculate over some possible causes for the departure. PMID- 25296801 TI - First principles transport coefficients and reaction rates of Ar2(+) ions in argon for cold plasma jet modeling. AB - Momentum-transfer collision cross-sections and integral collision cross-sections for the collision-induced dissociation are calculated for collisions of ionized argon dimers with argon atoms using a nonadiabatic semiclassical method with the electronic Hamiltonian calculated on the fly via a diatomics-in-molecules semiempirical model as well as inverse-method modeling based on simple isotropic rigid-core potential. The collision cross-sections are then used in an optimized Monte Carlo code for evaluations of the Ar 2 (+) mobility in argon gas, longitudinal diffusion coefficient, and collision-induced dissociation rates. A thorough comparison of various theoretical calculations as well as with available experimental data on the Ar 2 (+) mobility and collision cross-sections is performed. Good agreement is found between both theoretical approaches and the experiment. Analysis of the role of inelastic processes in Ar 2 (+)/Ar collisions is also provided. PMID- 25296803 TI - Full dimensional Franck-Condon factors for the acetylene A (1)A(u)-X (1)Sigma(g)(+) transition. I. Method for calculating polyatomic linear-bent vibrational intensity factors and evaluation of calculated intensities for the gerade vibrational modes in acetylene. AB - Franck-Condon vibrational overlap integrals for the A Au1-X 1Sigmag+ transition in acetylene have been calculated in full dimension in the harmonic normal mode basis. The calculation uses the method of generating functions first developed for polyatomic Franck-Condon factors by Sharp and Rosenstock [J. Chem. Phys. 41(11), 3453-3463 (1964)], and previously applied to acetylene by Watson [J. Mol. Spectrosc. 207(2), 276-284 (2001)] in a reduced-dimension calculation. Because the transition involves a large change in the equilibrium geometry of the electronic states, two different types of corrections to the coordinate transformation are considered to first order: corrections for axis-switching between the Cartesian molecular frames and corrections for the curvilinear nature of the normal modes at large amplitude. The angular factor in the wavefunction for the out-of-plane component of the trans bending mode, nu4("), is treated as a rotation, which results in an Eckart constraint on the polar coordinates of the bending modes. To simplify the calculation, the other degenerate bending mode, nu5("), is integrated in the Cartesian basis and later transformed to the constrained polar coordinate basis, restoring the conventional v and l quantum numbers. An updated A-state harmonic force field obtained recently in the R. W. Field research group is evaluated. The results for transitions involving the gerade vibrational modes are in qualitative agreement with experiment. Calculated results for transitions involving ungerade modes are presented in Paper II of this series [G. B. Park, J. H. Baraban, and R. W. Field, "Full dimensional Franck Condon factors for the acetylene A Au1-X 1Sigmag+ transition. II. Vibrational overlap factors for levels involving excitation in ungerade modes," J. Chem. Phys. 141, 134305 (2014)]. PMID- 25296802 TI - Quantum dynamical investigation of the simplest Criegee intermediate CH2OO and its O-O photodissociation channels. AB - The singlet electronic potential energy surfaces for the simplest Criegee intermediate CH2OO are computed over a two-dimensional reduced subspace of coordinates, and utilized to simulate the photo-initiated dynamics on the S2 (B) state leading to dissociation on multiple coupled excited electronic states. The adiabatic electronic potentials are evaluated using dynamically weighted state averaged complete active space self-consistent field theory. Quasi-diabatic states are constructed from the adiabatic states by maximizing the charge separation between the states. The dissociation dynamics are then simulated on the diabatically coupled excited electronic states. The B <- X electronic transition with large oscillator strength was used to initiate dynamics on the S2 (B) excited singlet state. Diabatic coupling of the B state with other dissociative singlet states results in about 5% of the population evolving to the lowest spin-allowed asymptote, generating H2CO (X (1)A1) and O ((1)D) fragments. The remaining ~95% of the population remains on repulsive B state and dissociates to H2CO (a (3)A") and O ((3)P) products associated with a higher asymptotic limit. Due to the dissociative nature of the B state, the simulated electronic absorption spectrum is found to be broad and devoid of any vibrational structure. PMID- 25296804 TI - Full dimensional Franck-Condon factors for the acetylene A (1)Au-X (1)Sigma(g)(+) transition. II. Vibrational overlap factors for levels involving excitation in ungerade modes. AB - A full-dimensional Franck-Condon calculation has been applied to the A (1)Au-X 1Sigmag+ transition in acetylene in the harmonic normal mode basis. Details of the calculation are discussed in Part I of this series. To our knowledge, this is the first full-dimensional Franck-Condon calculation on a tetra-atomic molecule undergoing a linear-to-bent geometry change. In the current work, the vibrational intensity factors for levels involving excitation in ungerade vibrational modes are evaluated. Because the Franck-Condon integral accumulates away from the linear geometry, we have been able to treat the out-of-plane component of trans bend (nu4('')) in the linear X state in the rotational part of the problem, restoring the chi Euler angle and the a-axis Eckart conditions. A consequence of the Eckart conditions is that the out-of-plane component of nu4('') does not participate in the vibrational overlap integral. This affects the structure of the coordinate transformation and the symmetry of the vibrational wavefunctions used in the overlap integral, and results in propensity rules involving the bending modes of the X state that were not previously understood. We explain the origin of some of the unexpected propensities observed in IR-UV laser-induced fluorescence spectra, and we calculate emission intensities from bending levels of the A state into bending levels of the X state, using normal bending mode and local bending mode basis sets. Our calculations also reveal Franck-Condon propensities for the Cartesian components of the cis bend (nu5('')), and we predict that the best A-state vibrational levels for populating X-state levels with large amplitude bending motion localized in a single C-H bond (the acetylene<->vinylidene isomerization coordinate) involve a high degree of excitation in nu6(') (cis-bend). Mode nu4(') (torsion) populates levels with large amplitude counter-rotational motion of the two hydrogen atoms. PMID- 25296805 TI - Quantum diffusion wave-function approach to two-dimensional vibronic spectroscopy. AB - We apply the quantum diffusion wavefunction approach to calculate vibronic two dimensional (2D) spectra. As an example, we use a system consisting of two electronic states with harmonic oscillator potentials which are coupled to a bath and interact with three time-delayed laser pulses. The first- and second-order perturbative wave functions which enter into the expression for the third-order polarization are determined for a sufficient number of stochastic runs. The wave packet approach, besides being an alternative technique to calculate the spectra, offers an intuitive insight into the dissipation dynamics and its relation to the 2D vibronic spectra. PMID- 25296806 TI - Long-lived polarization protected by symmetry. AB - In this paper we elucidate, theoretically and experimentally, molecular motifs which permit Long-Lived Polarization Protected by Symmetry (LOLIPOPS). The basic assembly principle starts from a pair of chemically equivalent nuclei supporting a long-lived singlet state and is completed by coupling to additional pairs of spins. LOLIPOPS can be created in various sizes; here we review four-spin systems, introduce a group theory analysis of six-spin systems, and explore eight spin systems by simulation. The focus is on AA'XnX'n spin systems, where typically the A spins are (15)N or (13)C and X spins are protons. We describe the symmetry of the accessed states, we detail the pulse sequences used to access these states, we quantify the fraction of polarization that can be stored as LOLIPOPS, we elucidate how to access the protected states from A or from X polarization and we examine the behavior of these spin systems upon introduction of a small chemical shift difference. PMID- 25296807 TI - Intermolecular interactions of trifluorohalomethanes with Lewis bases in the gas phase: an ab initio study. AB - We perform an ab initio computational study of molecular complexes with the general formula CF3X-B that involve one trifluorohalomethane CF3X (X = Cl or Br) and one of a series of Lewis bases B in the gas phase. The Lewis bases are so chosen that they provide a range of electron-donating abilities for comparison. Based on the characteristics of their electron pairs, we consider the Lewis bases with a single n-pair (NH3 and PH3), two n-pairs (H2O and H2S), two n-pairs with an unsaturated bond (H2CO and H2CS), and a single pi-pair (C2H4) and two pi-pairs (C2H2). The aim is to systematically investigate the influence of the electron pair characteristics and the central atom substitution effects on the geometries and energetics of the formed complexes. The counterpoise-corrected supermolecule MP2 and coupled-cluster single double with perturbative triple [CCSD(T)] levels of theory have been employed, together with a series of basis sets up to aug-cc pVTZ. The angular and radial configurations, the binding energies, and the electrostatic potentials of the stable complexes have been compared and discussed as the Lewis base varies. For those complexes where halogen bonding plays a significant role, the calculated geometries and energetics are consistent with the sigma-hole model. Upon formation of stable complexes, the C-X bond lengths shorten, while the C-X vibrational frequencies increase, thus rendering blueshifting halogen bonds. The central atom substitution usually enlarges the intermolecular bond distances while it reduces the net charge transfers, thus weakening the bond strengths. The analysis based on the sigma-hole model is grossly reliable but requires suitable modifications incorporating the central atom substitution effects, in particular, when interaction components other than electrostatic contributions are involved. PMID- 25296808 TI - Chirality of weakly bound complexes: the potential energy surfaces for the hydrogen-peroxide-noble-gas interactions. AB - We consider the analytical representation of the potential energy surfaces of relevance for the intermolecular dynamics of weakly bound complexes of chiral molecules. In this paper we study the H2O2-Ng (Ng=He, Ne, Ar, Kr, and Xe) systems providing the radial and the angular dependence of the potential energy surface on the relative position of the Ng atom. We accomplish this by introducing an analytical representation which is able to fit the ab initio energies of these complexes in a wide range of geometries. Our analysis sheds light on the role that the enantiomeric forms and the symmetry of the H2O2 molecule play on the resulting barriers and equilibrium geometries. The proposed theoretical framework is useful to study the dynamics of the H2O2 molecule, or other systems involving O-O and S-S bonds, interacting by non-covalent forces with atoms or molecules and to understand how the relative orientation of the O-H bonds changes along collisional events that may lead to a hydrogen bond formation or even to selectivity in chemical reactions. PMID- 25296809 TI - Analysis of a new MoO transition in the near-IR: a combined theoretical and experimental study. AB - The near-infrared electronic spectrum of MoO has been recorded in emission using the Fourier transform spectrometer associated with the National Solar Observatory at Kitt Peak, AZ. The gas phase MoO molecules were produced in a neon-based electric discharge using a molybdenum hollow cathode and a trace amount of oxygen. One MoO molecular band was observed in the spectrum with a red-degraded bandhead at 6735 cm(-1) and is assigned as the (0,0) band of the c (3)Pi1 - a (3)Sigma(-) 0+ transition. The assignment is based upon isotopologue shifts and ab initio calculations. Results from the ab initio calculations and analysis are presented. The new calculations support the assignment of the observed transition and have led to reassignment of several electronic states from previous work. PMID- 25296810 TI - VUV photoionization and dissociative photoionization of the prebiotic molecule acetyl cyanide: theory and experiment. AB - The present combined theoretical and experimental investigation concerns the single photoionization of gas-phase acetyl cyanide and the fragmentation pathways of the resulting cation. Acetyl cyanide (AC) is inspired from both the chemistry of cyanoacetylene and the Strecker reaction which are thought to be at the origin of medium sized prebiotic molecules in the interstellar medium. AC can be formed by reaction from cyanoacetylene and water but also from acetaldehyde and HCN or the corresponding radicals. In view of the interpretation of vacuum ultraviolet (VUV) experimental data obtained using synchrotron radiation, we explored the ground potential energy surface (PES) of acetyl cyanide and of its cation using standard and recently implemented explicitly correlated methodologies. Our PES covers the regions of tautomerism (between keto and enol forms) and of the lowest fragmentation channels. This allowed us to deduce accurate thermochemical data for this astrobiologically relevant molecule. Unimolecular decomposition of the AC cation turns out to be very complex. The implications for the evolution of prebiotic molecules under VUV irradiation are discussed. PMID- 25296811 TI - Decay dynamics of alpha,beta-carboxylic methyl esters (CH3OCOCH:CHR) in the lower lying excited states--resonance Raman and complete active space self-consistent field calculation study. AB - The photophysics of two alpha,beta-carboxylic methyl esters after excitation to the light absorbing S2(pipi(*)) state were studied by using the resonance Raman spectroscopy and complete active space self-consistent field (CASSCF) method calculations. The vibrational spectra were assigned on the basis of the experimental measurements and the B3LYP/6-31G(d) computations, as well as the normal mode analysis. The A-band resonance Raman spectra of methyl 2,4 pentadienoate (M24PDA) and methyl trans cronoate (MTCA) were measured to probe the structural dynamics in Franck-Condon region. CASSCF calculations were done to obtain the minimal excitation energies and geometric structures of the lower lying singlet and triplet excited states, and the curve-crossing points. It was revealed that the short-time structural dynamics of M24PDA was dominated by the Calpha=Cbeta-C4=C5 stretch coordinate, while that of MTCA was mostly along the Calpha=Cbeta and the C=O stretch motion. Comparison of the structural dynamics of M24PDA and MTCA with that of 3-methyl-3-pentene-2-one (3M3P2O) indicated that the structural dynamics of MTCA is similar to that of 3M3P2O but different than that of M24PDA in that the variation of the Raman intensity ratios for nu7/nu8, (nu7+nu8)/2nu8, (nu7+2nu8)/3nu8, (nu7+3nu8)/4nu8 of MTCA is similar to that of 3M3P2O but different from that of M24PDA. It is found that the substitution of methyl group in the alpha(')-position of alpha,beta-enones by methoxyl group does not substantially affect the short-time structural dynamics, while the substitution of vinyl group in the beta-position changes significantly the short time structural dynamics and the subsequent decay processes. A detailed decay mechanism is proposed. Two sub-processes which consider the reconjugation and the subsequent charge-transfer reaction of O=C-Calpha=Cbeta chromophore were postulated to describe the variation of short-time structural dynamics with the different substitution. PMID- 25296812 TI - Monitoring equilibrium reaction dynamics of a nearly barrierless molecular rotor using ultrafast vibrational echoes. AB - Using rapidly acquired spectral diffusion, a recently developed variation of heterodyne detected infrared photon echo spectroscopy, we observe ~3 ps solvent independent spectral diffusion of benzene chromium tricarbonyl (C6H6Cr(CO)3, BCT) in a series of nonpolar linear alkane solvents. The spectral dynamics is attributed to low-barrier internal torsional motion. This tripod complex has two stable minima corresponding to staggered and eclipsed conformations, which differ in energy by roughly half of kBT. The solvent independence is due to the relative size of the rotor compared with the solvent molecules, which create a solvent cage in which torsional motion occurs largely free from solvent damping. Since the one-dimensional transition state is computed to be only 0.03 kBT above the higher energy eclipsed conformation, this model system offers an unusual, nearly barrierless reaction, which nevertheless is characterized by torsional coordinate dependent vibrational frequencies. Hence, by studying the spectral diffusion of the tripod carbonyls, it is possible to gain insight into the fundamental dynamics of internal rotational motion, and we find some evidence for the importance of non-diffusive ballistic motion even in the room-temperature liquid environment. Using several different approaches to describe equilibrium kinetics, as well as the influence of reactive dynamics on spectroscopic observables, we provide evidence that the low-barrier torsional motion of BCT provides an excellent test case for detailed studies of the links between chemical exchange and linear and nonlinear vibrational spectroscopy. PMID- 25296813 TI - An (e, 2e + ion) study of low-energy electron-impact ionization and fragmentation of tetrahydrofuran with high mass and energy resolutions. AB - We study the low-energy (E0 = 26 eV) electron-impact induced ionization and fragmentation of tetrahydrofuran using a reaction microscope. All three final state charged particles, i.e., two outgoing electrons and one fragment ion, are detected in triple coincidence such that the momentum vectors and, consequently, the kinetic energies for charged reaction products are determined. The ionic fragments are clearly identified in the experiment with a mass resolution of 1 amu. The fragmentation pathways of tetrahydrofuran are investigated by measuring the ion kinetic energy spectra and the binding energy spectra where an energy resolution of 1.5 eV has been achieved using the recently developed photoemission electron source. Here, we will discuss the fragmentation reactions for the cations C4H8O(+), C4H7O(+), C2H3O(+), C3H6(+), C3H5(+), C3H3(+), CH3O(+), CHO(+), and C2H3(+). PMID- 25296814 TI - Thermal decomposition pathways for 1,1-diamino-2,2-dinitroethene (FOX-7). AB - In this study, we computationally investigate the initial and subsequent steps in the chemical mechanism for the gas-phase thermal decomposition of 1,1-diamino-2,2 dinitroethene (FOX-7). We determine the key exothermic step in the gas-phase thermal decomposition of FOX-7 and explore the similarities and differences between FOX-7 and other geminal dinitro energetic materials. The calculations reveal a mechanism for NO loss involving a 3-member cyclic intermediate, rather than a nitro-nitrite isomerization, that occurs in the radical intermediates formed throughout the decomposition mechanism. PMID- 25296815 TI - The HD molecule in small and medium cages of clathrate hydrates: quantum dynamics studied by neutron scattering measurements and computation. AB - We report inelastic neutron scattering (INS) measurements on molecular hydrogen deuteride (HD) trapped in binary cubic (sII) and hexagonal (sH) clathrate hydrates, performed at low temperature using two different neutron spectrometers in order to probe both energy and momentum transfer. The INS spectra of binary clathrate samples exhibit a rich structure containing sharp bands arising from both the rotational transitions and the rattling modes of the guest molecule. For the clathrates with sII structure, there is a very good agreement with the rigorous fully quantum simulations which account for the subtle effects of the anisotropy, angular and radial, of the host cage on the HD microscopic dynamics. The sH clathrate sample presents a much greater challenge, due to the uncertainties regarding the crystal structure, which is known only for similar crystals with different promoter, but nor for HD (or H2) plus methyl tert-butyl ether (MTBE-d12). PMID- 25296816 TI - Vapor pressures of 1,3-dialkylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquids with long alkyl chains. AB - This work presents the vapor pressure at several temperatures for the 1,3 dialkylimidazolium bis(trifluoromethylsulfonyl)imide series, [CN/2CN/2im][NTf2] (N = 14, 16, 18, and 20), measured by a Knudsen effusion method combined with a quartz crystal microbalance. The thermodynamic properties of vaporization of the ionic liquids under study are analysed together with the results obtained previously for the shorter alkyl chain length [CN/2CN/2im][NTf2] (N = 2, 4, 6, 8, 10, and 12), in order to evaluate the effect of the alkyl side chains of the cation and to get additional insights concerning the nanostructuration of ionic liquids. The symmetry effect is explored, based on the comparison with the asymmetric imidazolium based ionic liquids, [CN-1C1im][NTf2]. A trend shift on the thermodynamic properties of vaporization along the alkyl side chains of the extended symmetric ionic liquids, around [C6C6im][NTf2], was detected. An intensification of the odd-even effect was observed starting from [C6C6im][NTf2], with higher enthalpies and entropies of vaporization for the odd numbered ionic liquids, [C7C7im][NTf2] and [C9C9im][NTf2]. Similar, but less pronounced, odd even effect was found for the symmetric ionic liquids with lower alkyl side chains length, [CN/2CN/2im][NTf2] (with N = 4, 6, 8, 10, and 12). This effect is related with the predominant orientation of the terminal methyl group of the alkyl chain to the imidazolium ring and their influence in the cation-anion interaction. The same Critical Alkyl length at the hexyl, (C6C1and C6C6) was found for both asymmetric and symmetric series indicating that the nanostructuration of the ionic liquids is related with alkyl chain length. PMID- 25296817 TI - Thermophobicity of liquids: heats of transport in mixtures as pure component properties--the case of arbitrary concentration. AB - We have measured Soret coefficients of a large number of binary mixtures of 23 different organic solvents. The present analysis is based on 77 equimolar mixtures and strongly supports the thermophobicity concept previously developed for the heats of transport of originally 10 different substances [S. Hartmann, G. Wittko, W. Kohler, K. I. Morozov, K. Albers, and G. Sadowski, Phys. Rev. Lett. 109, 065901 (2012)]. Among the investigated compounds, cis-decalin is the most thermophobic, hexane the most thermophilic one. In addition to the equimolar mixtures, we have also analyzed the composition dependence of the Soret coefficients and the heats of transport for 22 selected binary mixtures. Both the interpretation of the heats of transport in equimolar mixtures as pure component thermophobicities and the composition dependence of the Soret coefficient can be understood on the basis of the thermodiffusion theory developed by Morozov [Phys. Rev. E 79, 031204 (2009)], according to which the composition dependence is determined by the excess volume of mixing. PMID- 25296818 TI - Thermal conductivity of carbon dioxide from non-equilibrium molecular dynamics: a systematic study of several common force fields. AB - We report a systematic investigation of the thermal conductivity of various three site models of carbon dioxide (CO2) using nonequilibrium molecular dynamics in the temperature range 300-1000 K and for pressures up to 200 MPa. A direct comparison with experimental data is made. Three popular CO2 force fields (MSM, EPM2, and TraPPE) and two flexible models (based on EPM2) were investigated. All rigid force fields accurately predict the equation of state for carbon dioxide for the given range of variables. They can also reproduce the thermal conductivity of CO2 at room temperature and predict a decrease of the thermal conductivity with increasing temperature. At high temperatures, the rigid models underestimate the thermal conductivity. PMID- 25296819 TI - Exploring two-dimensional electron gases with two-dimensional Fourier transform spectroscopy. AB - The dephasing of the Fermi edge singularity excitations in two modulation doped single quantum wells of 12 nm and 18 nm thickness and in-well carrier concentration of ~4 * 10(11) cm(-2) was carefully measured using spectrally resolved four-wave mixing (FWM) and two-dimensional Fourier transform (2DFT) spectroscopy. Although the absorption at the Fermi edge is broad at this doping level, the spectrally resolved FWM shows narrow resonances. Two peaks are observed separated by the heavy hole/light hole energy splitting. Temperature dependent "rephasing" (S1) 2DFT spectra show a rapid linear increase of the homogeneous linewidth with temperature. The dephasing rate increases faster with temperature in the narrower 12 nm quantum well, likely due to an increased carrier-phonon scattering rate. The S1 2DFT spectra were measured using co linear, cross-linear, and co-circular polarizations. Distinct 2DFT lineshapes were observed for co-linear and cross-linear polarizations, suggesting the existence of polarization dependent contributions. The "two-quantum coherence" (S3) 2DFT spectra for the 12 nm quantum well show a single peak for both co linear and co-circular polarizations. PMID- 25296820 TI - Low-frequency collective dynamics in deep eutectic solvents of acetamide and electrolytes: a femtosecond Raman-induced Kerr effect spectroscopic study. AB - In this study, we have investigated the ion concentration dependent collective dynamics in two series of deep eutectic solvent (DES) systems by femtosecond Raman-induced Kerr effect spectroscopy, as well as some physical properties, e.g., shear viscosity (eta), density (rho), and surface tension (gamma). The DES systems studied here are [0.75CH3CONH2 + 0.25{f KSCN + (1 - f )NaSCN}] and [0.78CH3CONH2 + 0.22{f LiBr + (1 - f )LiNO3}] with f = 0, 0.2, 0.4, 0.6, 0.8, and 1.0. gamma of these DES systems shows near insensitivity to f, while rho shows a moderate dependence on f. Interestingly, eta exhibits a strong dependence on f. In the low-frequency Kerr spectra, obtained via the Fourier transform of the collected Kerr transients, a characteristic band at ~70 cm(-1) is clear in [0.78CH3CONH2 + 0.22{f LiBr + (1 - f )LiNO3}] DES especially at the larger f. The band is attributed to the intermolecular hydrogen bond of acetamide. Because of less depolarized Raman activities of intermolecular/interionic vibrational motions, which are mostly translational (collision-induced or interaction induced) motions, of spherical ions, the intermolecular hydrogen-bonding band is clearly observed. In contrast, the intermolecular hydrogen-bonding band is buried in the other intermolecular/interionic vibrational motions, which includes translational and reorientational (librational) motions and their cross-terms, in [0.75CH3CONH2 + 0.25{f KSCN + (1 - f )NaSCN}] system. The first moment (M1) of the intermolecular/interionic vibrational band in these DES systems is much higher than that in typical neutral molecular liquids and shows a weak but contrasting dependence on the bulk parameter ?gamma/rho. The time constants for picosecond overdamped Kerr transients in both the DES systems, which are obtained on the basis of the analysis fitted by a triexponential function, are rather insensitive to f for both the DES systems, but all the three time constants (fast: ~1-3 ps; intermediate: ~7-20 ps; and slow: ~100 ps) are different between the [0.78CH3CONH2 + 0.22{f LiBr + (1 - f )LiNO3}] and [0.75CH3CONH2 + 0.25{f KSCN + (1 - f )NaSCN}] systems. These results indicate that the intermolecular/interionic interactions in DES systems is strongly influenced by the ionic species present in these DES systems. PMID- 25296821 TI - General rules prospected for the liquid fragility in various material groups and different thermodynamic conditions. AB - The fragility parameter has been acknowledged as one of the most important characteristics of glass-forming liquids. We show that the mystery of the dramatic change in molecular dynamics of systems approaching the glass transition can be better understood by the high pressure study of fragility parameters defined in different thermodynamic conditions. We formulate and experimentally confirm a few rules obeyed by the fragility parameters, which are also rationalized by the density scaling law and its modification suggested for associated liquids. In this way, we successfully explore and gain a new insight into the pressure effect on molecular dynamics of van der Waals liquids, polymer melts, ionic liquids, and hydrogen-bonded systems near the glass transition. PMID- 25296822 TI - The mechanism of chemisorption of hydrogen atom on graphene: insights from the reaction force and reaction electronic flux. AB - At the PBE-D3/cc-pVDZ level of theory, the hydrogen chemisorption on graphene was analyzed using the reaction force and reaction electronic flux (REF) theories in combination with electron population analysis. It was found that chemisorption energy barrier is mainly dominated by structural work (~73%) associated to the substrate reconstruction whereas the electronic work is the greatest contribution of the reverse energy barrier (~67%) in the desorption process. Moreover, REF shows that hydrogen chemisorption is driven by charge transfer processes through four electronic events taking place as H approaches the adsorbent surface: (a) intramolecular charge transfer in the adsorbent surface; (b) surface reconstruction; (c) substrate magnetization and adsorbent carbon atom develops a sp(3) hybridization to form the sigmaC-H bond; and (d) spontaneous intermolecular charge transfer to reach the final chemisorbed state. PMID- 25296823 TI - A unified mechanism for the stability of surface nanobubbles: contact line pinning and supersaturation. AB - In this paper, we apply the molecular dynamics simulation method to study the stability of surface nanobubbles in both pure fluids and gas-liquid mixtures. First, we demonstrate with molecular simulations, for the first time, that surface nanobubbles can be stabilized in superheated or gas supersaturated liquid by the contact line pinning caused by the surface heterogeneity. Then, a unified mechanism for nanobubble stability is put forward here that stabilizing nanobubbles require both the contact line pinning and supersaturation. In the mechanism, the supersaturation refers to superheating for pure fluids and gas supersaturation or superheating for the gas-liquid mixtures, both of which exert the same effect on nanobubble stability. As the level of supersaturation increases, we found a Wenzel or Cassie wetting state for undersaturated and saturated fluids, stable nanobubbles at moderate supersaturation with decreasing curvature radius and contact angle, and finally the liquid-to-vapor phase transition at high supersaturation. PMID- 25296825 TI - Effective interaction between a colloid and a soft interface near criticality. AB - Within mean-field theory we determine the universal scaling function for the effective force acting on a single colloid located near the interface between two coexisting liquid phases of a binary liquid mixture close to its critical consolute point. This is the first study of critical Casimir forces emerging from the confinement of a fluctuating medium by at least one shape responsive, soft interface, instead of by rigid walls only as studied previously. For this specific system, our semi-analytical calculation illustrates that knowledge of the colloid-induced, deformed shape of the interface allows one to accurately describe the effective interaction potential between the colloid and the interface. Moreover, our analysis demonstrates that the critical Casimir force involving a deformable interface is accurately described by a universal scaling function, the shape of which differs from that one for rigid walls. PMID- 25296824 TI - Hydrogen bonded structure, polarity, molecular motion and frequency fluctuations at liquid-vapor interface of a water-methanol mixture: an ab initio molecular dynamics study. AB - We have performed ab initio molecular dynamics simulations of a liquid-vapor interfacial system consisting of a mixture of water and methanol molecules. Detailed results are obtained for the structural and dynamical properties of the bulk and interfacial regions of the mixture. Among structural properties, we have looked at the inhomogeneous density profiles of water and methanol molecules, hydrogen bond distributions and also the orientational profiles of bulk and interfacial molecules. The methanol molecules are found to have a higher propensity to be at the interface than water molecules. It is found that the interfacial molecules show preference for specific orientations so as to form water-methanol hydrogen bonds at the interface with the hydrophobic methyl group pointing towards the vapor side. It is also found that for both types of molecules, the dipole moment decreases at the interface. It is also found that the local electric field of water influences the dipole moment of methanol molecules. Among the dynamical properties, we have calculated the diffusion, orientational relaxation, hydrogen bond dynamics, and vibrational frequency fluctuations in bulk and interfacial regions. It is found that the diffusion and orientation relaxation of the interfacial molecules are faster than those of the bulk. However, the hydrogen bond lifetimes are longer at the interface which can be correlated with the time scales found from the decay of frequency time correlations. The slower hydrogen bond dynamics for the interfacial molecules with respect to bulk can be attributed to diminished cooperative effects at the interface due to reduced density and number of hydrogen bonds. PMID- 25296826 TI - Formation of unique trimer of nitric oxide on Cu(111). AB - We report that NO molecules unexpectedly prefer a trimeric configuration on Cu(111). We used scanning tunneling microscopy (STM) at 6 K, and confirmed that the NO molecule is bonded to the face-centered-cubic hollow site in an upright configuration. The individual NO molecule is imaged as a ring protrusion, which is characteristic of the doubly degenerate 2pi(*) orbital. A triangular trimer is thermodynamically more favorable than the monomer and dimer, and its bonding structure was characterized by STM manipulation. This unique behavior of NO on Cu(111) is ascribed to the threefold symmetry of the surface, facilitating effective mixing of the 2pi(*) orbitals in a triangular configuration. PMID- 25296827 TI - Effective and accurate approach for modeling of commensurate-incommensurate transition in krypton monolayer on graphite. AB - Commensurate-incommensurate (C-IC) transition of krypton molecular layer on graphite received much attention in recent decades in theoretical and experimental researches. However, there still exists a possibility of generalization of the phenomenon from thermodynamic viewpoint on the basis of accurate molecular simulation. Recently, a new technique was developed for analysis of two-dimensional (2D) phase transitions in systems involving a crystalline phase, which is based on accounting for the effect of temperature and the chemical potential on the lattice constant of the 2D layer using the Gibbs Duhem equation [E. A. Ustinov, J. Chem. Phys. 140, 074706 (2014)]. The technique has allowed for determination of phase diagrams of 2D argon layers on the uniform surface and in slit pores. This paper extends the developed methodology on systems accounting for the periodic modulation of the substrate potential. The main advantage of the developed approach is that it provides highly accurate evaluation of the chemical potential of crystalline layers, which allows reliable determination of temperature and other parameters of various 2D phase transitions. Applicability of the methodology is demonstrated on the krypton graphite system. Analysis of phase diagram of the krypton molecular layer, thermodynamic functions of coexisting phases, and a method of prediction of adsorption isotherms is considered accounting for a compression of the graphite due to the krypton-carbon interaction. The temperature and heat of C-IC transition has been reliably determined for the gas-solid and solid-solid system. PMID- 25296828 TI - Fe adsorption on hematite (alpha-Fe2O3) (0001) and magnetite (Fe3O4) (111) surfaces. AB - The structure and electronic properties of different terminations of hematite (0001) and magnetite (111) surfaces upon submonolayer Fe adsorption were studied using the spin-polarized density functional theory (DFT) including the Hubbard correction term U (DFT+U). On both oxides the Fe atoms were adsorbed on the most stable iron and oxygen terminated surfaces. The results show that Fe atoms bind strongly both to hematite and magnetite surfaces, however, the binding is distinctly stronger at the oxygen than at the iron terminated surfaces. For both oxides and surface terminations the binding energy of the Fe decreases with increasing coverage, which indicates substantial repulsive interactions between Fe adatoms. On the hematite surface, the most stable sites for Fe adsorption are bulk continuation sites which result in formation of the Fe-rich terminations. On the magnetite surface, the bulk continuation site is favored only for Fe adsorption on the oxygen terminated surface while on the iron terminated one Fe adsorbs in a position closer to the surface iron layer. Submonolayer coverages of Fe modify substantially the surface electronic structure of the oxides and, depending on the termination, can change its character from half-metallic to insulating one, and vice versa. PMID- 25296829 TI - Theoretical study of stability and charge-transport properties of coronene molecule and some of its halogenated derivatives: a path to ambipolar organic based materials? AB - We have carefully investigated the structural and electronic properties of coronene and some of its fluorinated and chlorinated derivatives, including full periphery substitution, as well as the preferred orientation of the non-covalent dimer structures subsequently formed. We have paid particular attention to a set of methodological details, to first obtain single-molecule magnitudes as accurately as possible, including next the use of modern dispersion-corrected methods to tackle the corresponding non-covalently bound dimers. Generally speaking, this class of compounds is expected to self-assembly in neighboring pi stacks with dimer stabilization energies ranging from -20 to -30 kcal mol(-1) at close distances around 3.0-3.3 A. Then, in a further step, we have also calculated hole and electron transfer rates of some suitable candidates for ambipolar materials, and corresponding charge mobility values, which are known to critically depend on the supramolecular organization of the samples. For coronene and per-fluorinated coronene, we have found high values for their hopping rates, although slightly smaller for the latter due to an increase (decrease) of the reorganization energies (electronic couplings). PMID- 25296830 TI - The mold integration method for the calculation of the crystal-fluid interfacial free energy from simulations. AB - The interfacial free energy between a crystal and a fluid, gammacf, is a highly relevant parameter in phenomena such as wetting or crystal nucleation and growth. Due to the difficulty of measuring gammacf experimentally, computer simulations are often used to study the crystal-fluid interface. Here, we present a novel simulation methodology for the calculation of gammacf. The methodology consists in using a mold composed of potential energy wells to induce the formation of a crystal slab in the fluid at coexistence conditions. This induction is done along a reversible pathway along which the free energy difference between the initial and the final states is obtained by means of thermodynamic integration. The structure of the mold is given by that of the crystal lattice planes, which allows to easily obtain the free energy for different crystal orientations. The method is validated by calculating gammacf for previously studied systems, namely, the hard spheres and the Lennard-Jones systems. Our results for the latter show that the method is accurate enough to deal with the anisotropy of gammacf with respect to the crystal orientation. We also calculate gammacf for a recently proposed continuous version of the hard sphere potential and obtain the same gammacf as for the pure hard sphere system. The method can be implemented both in Monte Carlo and Molecular Dynamics. In fact, we show that it can be easily used in combination with the popular Molecular Dynamics package GROMACS. PMID- 25296831 TI - Folding mechanism of a polymer chain with short-range attractions. AB - We investigate the crystallization of a single, flexible homopolymer chain using transition path sampling. The chain consists of N identical spherical monomers evolved according to Langevin dynamics. While neighboring monomers are coupled via harmonic springs, the non-neighboring monomers interact via a hard core and a short-ranged attractive potential. For a sufficiently small interaction range lambda, the system undergoes a first-order freezing transition from an expanded, disordered phase to a compact crystalline state. Using a new shooting move tailored to polymers combined with a committor analysis, we study the transition state ensemble of an N = 128 chain and search for possible reaction coordinates based on likelihood maximization. We find that typical transition states consist of a crystalline nucleus with one or more chain fragments attached to it. Furthermore, we show that the number of particles in the crystalline core is not well suited as a reaction coordinate. We then present an improved reaction coordinate, which includes information from the potential energy and the overall crystallinity of the polymer. PMID- 25296832 TI - Discotic columnar liquid crystal studied in the bulk and nanoconfined states by molecular dynamics simulation. AB - A prototypical Gay Berne discotic liquid crystal was studied by means of molecular dynamics simulations both in the bulk state and under confinement in a nanoporous channel. The phase behavior of the confined system strongly differs from its bulk counterpart: the bulk isotropic-to-columnar transition is replaced by a continuous ordering from a paranematic to a columnar phase. Moreover, a new transition is observed at a lower temperature in the confined state, which corresponds to a reorganization of the intercolumnar order. It reflects the competing effects of pore surface interaction and genuine hexagonal packing of the columns. The translational molecular dynamics in the different phases has been thoroughly studied and discussed in terms of collective relaxation modes, non-Gaussian behavior, and hopping processes. PMID- 25296833 TI - Crumpled globule formation during collapse of a long flexible and semiflexible polymer in poor solvent. AB - By introducing explicit solvent particles and hydrodynamic interactions we demonstrate that crumpled globules are formed after the collapse of long polymer chains (N = 10(4)) in a poor solvent. During the collapse crumples of all sizes form sequentially, but small crumples are not stable and convert to blobs with Gaussian statistics. The observed effective mean squared distance R(2)(n) ~ n(0.38) at n > Ne and contact probability index p(n) ~ n(-0.5) at n ? Ne, which is not following either the model of a fractal globule, or the predictions for an equilibrium globule. Polymer chain stiffness pushes the system to form globular crystallite, and this freezes crumpled structure with R(2)(n) ~ n(0.33) at n > Ne as a stable state. We note that there is some similarity to crumple globule formation and crystallization of polymer melt. PMID- 25296834 TI - Rate effect in the fracture of rubbers and chemically cross-linked gels. AB - Stationary crack propagation in rubbers and chemically cross-linked gels is studied by a new molecular theory of fracture in polymer networks. The fracture energy G (energy required to create a unit free surface by fracture) as a function of the crack velocity V is shown to obey, when measured in the unit of nulkBT, a master curve as a function of the dimensionless velocity 2tan thetaV/lbeta0(T), where nu is the number density of the network chains, T is absolute temperature, theta is the angle of the crack tip, l is the mean distance between the adjacent cross-links, and beta0(T) is the scission rate of the chains. The slope of the master curve in logarithmic scale depends on the nature of chain rupture; it takes a small value 0.16-0.2 in the low velocity region, and exhibits a crossover to the three times larger value 0.5-0.6 in the high velocity region. The ultimate strength G0 as defined by the fracture energy in the limit of zero crack velocity is obtained as a function of the molecular weight of the network chain, the bond energy, and temperature. The theoretical model is applied specifically to peeling and tearing experiments of rubbers and gels to study how the velocity affects the fracture energy in different geometry of network breakage. All results are qualitatively compared with the data reported in the literature. PMID- 25296835 TI - Conformational transitions of a weak polyampholyte. AB - Using grand canonical Monte Carlo simulations of a flexible polyelectrolyte where the charges are in contact with a reservoir of constant chemical potential given by the solution pH, we study the behavior of weak polyelectrolytes in poor and good solvent conditions for polymer backbone. We address the titration behavior and conformational properties of a flexible diblock polyampholyte chain formed of two oppositely charged weak polyelectrolyte blocks, each containing equal number of identical monomers. The change of solution pH induces charge asymmetry in a diblock polyampholyte. For diblock polyampholyte chains in poor solvents, we demonstrate that a discontinuous transition between extended (tadpole) and collapsed (globular) conformational states is attainable by varying the solution pH. The double-minima structure in the probability distribution of the free energy provides direct evidence for the first-order like nature of this transition. At the isoelectric point electrostatically driven coil-globule transition of diblock polyampholytes in good solvents is found to consist of different regimes identified with increasing electrostatic interaction strength. At pH values above or below the isoelectric point diblock chains are found to have polyelectrolyte-like behavior due to repulsion between uncompensated charges along the chain. PMID- 25296836 TI - Applicability of a particularly simple model to nonlinear elasticity of slide ring gels with movable cross-links as revealed by unequal biaxial deformation. AB - The strain energy density function (F) of the polyrotaxane-based slide-ring (SR) gels with movable cross-links along the network strands is characterized by unequal biaxial stretching which can achieve various types of deformation. The SR gels as prepared without any post-preparation complication exhibit considerably smaller values of the ratio of the stresses (sigmay/sigmax) in the stretched (x) and constrained (y) directions in planar extension than classical chemical gels with heterogeneous and nearly homogeneous network structures do. This feature of the SR gels leads to the peculiar characteristic that the strain energy density function (F) has no explicit cross term of strains in different directions, which is in contrast to F with explicit strain cross terms for most chemical gels and elastomers. The biaxial stress-strain data of the SR gels are successfully described by F of the Gent model with only two parameters (small-strain shear modulus and a parameter representing ultimate elongation), which introduces the finite extensibility effect into the neo-Hookean model with no explicit cross term of strain. The biaxial data of the deswollen SR gels examined in previous study, which underwent a considerable reduction in volume from the preparation state, are also well described by the Gent model, which is in contrast to the case of the classical chemical gels that the stress-strain relations before and after large deswelling are not described by a common type of F due to a significant degree of collapse of the network strands in the deswollen state. These intriguing features of nonlinear elasticity of the SR gels originate from a novel function of the slidable cross-links that can maximize the arrangement entropy of cross-linked and non-cross-linked cyclic molecules in the deformed networks. PMID- 25296837 TI - Orientation and surface activity of Janus particles at fluid-fluid interfaces. AB - We study the influence of shape of Janus particles on their orientation and surface activity at fluid-fluid interfaces via molecular dynamics simulations. The Janus particles are characterized by two regions with different wettability divided along their major axes. Three types of Janus particles are considered: Janus spheres, Janus rods, and Janus disks. We find that Janus spheres and Janus rods prefer one orientation at the interface, regardless of the surface property. In contrast, Janus disks can adopt one of two orientations when adhered to a fluid-fluid interface: one orientation corresponds to the equilibrium state and the other is a kinetically trapped metastable state. The orientation of Janus disks strongly depends on the disk characteristics, such as their size, aspect ratio, and surface property. Furthermore, we find that changes in the shape of Janus particles strongly influence the interfacial tension at the fluid-fluid interface. According to the time evolution of the interfacial tension, the adsorption of Janus particles is characterized by three adsorption stages based on different surface activities and adsorption kinetics depending on the particle shape. PMID- 25296838 TI - Electric fields enhance miscibility of polystyrene/poly(vinyl methyl ether) blends. AB - How the presence of electric fields alters the miscibility of mixtures has been studied since the 1960s with conflicting reports on both the magnitude and direction of the shift in the phase separation temperature Ts. Theoretical understanding of the phenomenon has been hampered by the lack of experimental data with unambiguously large shifts in Ts outside of experimental error. Here, we address these concerns by presenting data showing that uniform electric fields strongly enhance the miscibility of polystyrene (PS)/poly(vinyl methyl ether) (PVME) blends. Reliable shifts in Ts of up to 13.5 +/- 1.4 K were measured for electric fields strengths of E = 1.7 * 10(7) V/m in a 50/50 PS/PVME mixture. By using a sensitive fluorescence method to measure Ts, the PS/PVME blend can be quenched back into the one phase region of the phase diagram when the domains are still small allowing the blend to be remixed such that Ts can be measured repeatedly on the same sample. In this manner, highly reproducible Ts values at non-zero and zero electric field can be ascertained on the same sample. Our results agree with the vast majority of existing experimental data on various mixtures finding that electric fields enhance miscibility, but are opposite to the one previous study on PS/PVME blends by Reich and Gordon [J. Polym. Sci.: Polym. Phys. Ed. 17, 371 (1979)] reporting that electric fields induce phase separation, a study which has been considered anomalous in the field. PMID- 25296839 TI - Multidimensional free energy surface of unfolding of HP-36: microscopic origin of ruggedness. AB - The protein folding funnel paradigm suggests that folding and unfolding proceed as directed diffusion in a multidimensional free energy surface where a multitude of pathways can be traversed during the protein's sojourn from initial to final state. However, finding even a single pathway, with the detail chronicling of intermediates, is an arduous task. In this work we explore the free energy surface of unfolding pathway through umbrella sampling, for a small globular alpha-helical protein chicken-villin headpiece (HP-36) when the melting of secondary structures is induced by adding DMSO in aqueous solution. We find that the unfolding proceeds through the initial separation or melting of aggregated hydrophobic core that comprises of three phenylalanine residues (Phe7, Phe11, and Phe18). This separation is accompanied by simultaneous melting of the second helix. Unfolding is found to be a multistage process involving crossing of three consecutive minima and two barriers at the initial stage. At a molecular level, Phe18 is observed to reorient itself towards other hydrophobic grooves to stabilize the intermediate states. We identify the configuration of the intermediates and correlate the intermediates with those obtained in our previous works. We also give an estimate of the barriers for different transition states and observe the softening of the barriers with increasing DMSO concentration. We show that higher concentration of DMSO tunes the unfolding pathway by destabilizing the third minimum and stabilizing the second one, indicating the development of a solvent modified, less rugged pathway. The prime outcome of this work is the demonstration that mixed solvents can profoundly transform the nature of the energy landscape and induce unfolding via a modified route. A successful application of Kramer's rate equation correlating the free energy simulation results shows faster rate of unfolding with increasing DMSO concentration. This work perhaps presents the first systematic theoretical study of the effect of a chemical denaturant on the microscopic free energy surface and rates of unfolding of HP-36. PMID- 25296840 TI - Mechanical unfolding of a simple model protein goes beyond the reach of one dimensional descriptions. AB - We study the mechanical unfolding of a simple model protein. The Langevin dynamics results are analyzed using Markov-model methods which allow to describe completely the configurational space of the system. Using transition-path theory we also provide a quantitative description of the unfolding pathways followed by the system. Our study shows a complex dynamical scenario. In particular, we see that the usual one-dimensional picture: free-energy vs end-to-end distance representation, gives a misleading description of the process. Unfolding can occur following different pathways and configurations which seem to play a central role in one-dimensional pictures are not the intermediate states of the unfolding dynamics. PMID- 25296841 TI - Early oligomerization stages for the non-amyloid component of alpha-synuclein amyloid. AB - In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Abeta amyloid component (NAC) of the monomer, dimer, and trimer of alpha-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from alpha-helix to beta-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two alpha-helical regions, between residues 2-13 and 19 25. As the dimer and trimer form, beta-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of beta-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation. PMID- 25296843 TI - Simultaneous determination of seven phenolic acids in three Salvia species by capillary zone electrophoresis with beta-cyclodextrin as modifier. AB - A capillary zone electrophoresis method was developed for the simultaneous determination of seven phenolic acids, including protocatechuic aldehyde (1), salvianolic acid C (2), rosmarinic acid (3), salvianolic acid A (4), danshensu (5), salvianolic acid B (6), and protocatechuic acid (7), in Danshen and related medicinal plants. A running buffer composed of 20 mM sodium tetraborate adjusted to pH 9.0, and containing 12 mM beta-cyclodextrin as modifier. Baseline separation was achieved within 17 min running at the voltage of 20 kV, temperature of 25 degrees C and detection wavelength of 280 nm. The relative standard deviations of migration time ranged from 0.2 to 0.7% and the peak area ranged from 1.5 to 3.7% for the seven analytes, indicating the good repeatability of the proposed method. The method was extensively validated by evaluating the linearity (R(2) >= 0.9992), limits of detection (0.14-0.36 MUg/mL), limits of quantification (0.47-1.19 MUg/mL), and recovery (96.0-102.6%). Under the optimum conditions, samples of Danshen and related medicinal plants were analyzed using the developed method with high separation efficiency. PMID- 25296844 TI - Excess entropy scaling for the segmental and global dynamics of polyethylene melts. AB - The range of validity of the Rosenfeld and Dzugutov excess entropy scaling laws is analyzed for unentangled linear polyethylene chains. We consider two segmental dynamical quantities, i.e. the bond and the torsional relaxation times, and two global ones, i.e. the chain diffusion coefficient and the viscosity. The excess entropy is approximated by either a series expansion of the entropy in terms of the pair correlation function or by an equation of state for polymers developed in the context of the self associating fluid theory. For the whole range of temperatures and chain lengths considered, the two estimates of the excess entropy are linearly correlated. The scaled bond and torsional relaxation times fall into a master curve irrespective of the chain length and the employed scaling scheme. Both quantities depend non-linearly on the excess entropy. For a fixed chain length, the reduced diffusion coefficient and viscosity scale linearly with the excess entropy. An empirical reduction to a chain length independent master curve is accessible for both dynamic quantities. The Dzugutov scheme predicts an increased value of the scaled diffusion coefficient with increasing chain length which contrasts physical expectations. The origin of this trend can be traced back to the density dependence of the scaling factors. This finding has not been observed previously for Lennard-Jones chain systems (Macromolecules, 2013, 46, 8710-8723). Thus, it limits the applicability of the Dzugutov approach to polymers. In connection with diffusion coefficients and viscosities, the Rosenfeld scaling law appears to be of higher quality than the Dzugutov approach. An empirical excess entropy scaling is also proposed which leads to a chain length-independent correlation. It is expected to be valid for polymers in the Rouse regime. PMID- 25296845 TI - Struggling with issues about cardiopulmonary resuscitation (CPR) for end-stage heart failure patients. AB - BACKGROUND: Integrating heart failure and palliative care teams combines unique expertise from both cardiology and palliative care. However, professionals from the two arenas of life-saving cardiology and palliative care may well have different experiences with and approaches to patient care. Little is known how to optimally discuss cardiopulmonary resuscitation with patients and their relatives and what challenges are for healthcare providers. OBJECTIVE: The aim of this study was to describe the experiences and thoughts of members of an integrated heart failure and palliative care team concerning talking about CPR with end stage heart failure patients. METHOD: We used a descriptive qualitative design, conducting group interviews during 2011 with professionals from different disciplines working with heart failure patients over a 1-year period. A qualitative content analysis was performed to examine the interview data. RESULTS: Professional caregivers in integrated heart failure and palliative homecare are struggling with the issue of CPR of end-stage heart failure patients. They wrestle with the question of whether CPR should be performed at all in these terminally ill patients. They also feel challenged by the actual conversation about CPR with the patients and their relatives. Despite talking them about CPR with patients and relatives is difficult, the study participants described that doing so is important, as it could be the start of a broader end of-life conversation. CONCLUSION: Talking with patient and relatives about CPR in end-stage heart failure, as suggested in the current heart failure guidelines, is a challenge in daily clinical practice. It is important to discuss the difficulties within the team and to decide whether, whom, how and when to talk about CPR with individual patients and their relatives. PMID- 25296846 TI - Etiological diagnostic tools to elucidate 'isolated' ventriculomegaly. PMID- 25296847 TI - Higher glucose level can enhance the H. pylori adhesion and virulence related with type IV secretion system in AGS cells. AB - BACKGROUND: Hyperglycemia increases the risk of gastric cancer in H. pylori infected patients. High glucose could increase endothelial permeability and cancer-associated signaling. These suggest high glucose may affect H. pylori or its infected status.We used two strains to investigate whether H. pylori growth, viability, adhesion and CagA-phosphorylation level in the infected-AGS cells were influenced by glucose concentration (100, 150, and 200 mg/dL). RESULTS: The growth curves of both strains in 200 mg/dL of glucose were maintained at the highest optimal density after 48 h and the best viability of both strains were retained in the same glucose condition at 72 h. Furthermore, adhesion enhancement of H. pylori was significantly higher in 200 mg/dL of glucose as compared to that in 100 and 150 mg/dL (p < 0.05). CagA protein also increased in higher glucose condition. The cell-associated CagA and phosphorylated-CagA was significantly increased in 150 and 200 mg/dL of glucose concentrations as compared to that of 100 mg/dL (p < 0.05), which were found to be dose-dependent. CONCLUSION: Higher glucose could maintain H. pylori growth and viability after 48 h. H. pylori adhesion and CagA increased to further facilitate the enhancement of cell associated CagA and phosphorylated CagA in higher glucose conditions. PMID- 25296848 TI - Evaluation of heart rate variability in dogs during standard and microburst vagus nerve stimulation: a pilot study. AB - Vagus nerve stimulation (VNS) is an established treatment for epilepsy and depression in human patients, but in both humans and dogs, optimal stimulation parameters remain unknown. Delivering afferent bursts of stimulation may be promising as a means of increasing efficacy, but evaluation of potential effects on the heart due to unavoidable efferent stimulation is required. The present study investigated heart rate variability (HRV) in healthy Beagle dogs treated with 1 h of sham, standard or microburst left-sided VNS in a crossover design. No significant differences were found between the stimulation paradigms for any of the cardiac parameters. Short-term left-sided VNS, including a novel bursting pattern (microburst VNS), had no statistically significant effect on HRV in ambulatory healthy dogs. Studies in a larger number of animals with long-term VNS are recommended. PMID- 25296849 TI - Practical aspects of vaccination of poultry against avian influenza virus. AB - Although little has changed in vaccine technology for avian influenza virus (AIV) in the past 20 years, the approach to vaccination of poultry (chickens, turkeys and ducks) for avian influenza has evolved as highly pathogenic AIV has become endemic in several regions of the world. Vaccination for low pathogenicity AIV is also becoming routine in regions where there is a high level of field challenge. In contrast, some countries will not use vaccination at all and some will only use it on an emergency basis during eradication efforts (i.e. stamping-out). There are pros and cons to each approach and, since every outbreak situation is different, no one method will work equally well in all situations. Numerous practical aspects must be considered when developing an AIV control program with vaccination as a component, such as: (1) the goals of vaccination must be defined; (2) the population to be vaccinated must be clearly identified; (3) there must be a plan to obtain and administer good quality vaccine in a timely manner and to achieve adequate coverage with the available resources; (4) risk factors for vaccine failure should be mitigated as much as possible; and, most importantly, (5) biosecurity must be maintained as much as possible, if not enhanced, during the vaccination period. PMID- 25296850 TI - The use of liquid chromatography tandem mass spectrometry to detect proteins in saliva from horses with and without systemic inflammation. AB - The objective of the study was to assess global expression of proteins in equine saliva using liquid chromatography tandem mass spectrometry (LC-MS/MS). Saliva was obtained from seven horses with and six horses without evidence of systemic inflammatory disease. Tryptic peptides from saliva were analysed by LC-MS/MS. Of 195 unique proteins identified, 57 were detected only in saliva samples from horses with systemic inflammation (in two to six of the seven horses). Among the differentially expressed proteins were several acute phase proteins (APPs) such as serum amyloid A, fibrinogen, haptoglobin, and alpha1-acid glycoprotein. The study is the first to describe detection of inflammatory proteins in horse saliva. The proteins detected were similar to those described in saliva from cattle, small ruminants and pigs. Detection of APPs in horses with systemic inflammation suggests that saliva may be used for non-invasive disease monitoring in horses as in humans, pigs and dogs. PMID- 25296851 TI - Comparison of the head and neck position of elite dressage horses during top level competitions in 1992 versus 2008. AB - Among veterinary surgeons, interest has recently increased in the role of the horse's neck as a causative factor in complex locomotor disturbances. Specifically, controversy surrounds the trend for the head to be carried behind the vertical (BHV) in contravention of Federation Equestre Internationale (FEI) rules. The aim of this study was to determine whether the head angulation of elite dressage horses has changed over the last 25 years, and whether head angulation correlates with the competition score awarded. Head angle was measured from videos recorded during the Grand Prix test at the 1992 Olympic Games and the 2008 World Cup Final, during collected canter (CC), collected trot (CT), passage (Pa), and piaffe (Pi). Head angulations were BHV in CC and CT in both 1992 and 2008. The likelihood of being BHV during Pa or Pi was significantly greater in 2008 than in 1992 (P <0.05). Higher scores correlated significantly with head positions that were further BHV during Pi in 2008 (P <0.05). Head angulations were orientated BHV in all paces in 2008, whereas in 1992 this was only the case for CT and CC. These findings support the hypothesis that, in recent years, FEI dressage judges have not penalised horses for a head position BHV. The findings also support the need for further studies of the effects of head and neck position on the health of horses. PMID- 25296852 TI - Thoroughbred horses in race training have lower levels of subchondral bone remodelling in highly loaded regions of the distal metacarpus compared to horses resting from training. AB - Bone is repaired by remodelling, a process influenced by its loading environment. The aim of this study was to investigate the effect of a change in loading environment on bone remodelling by quantifying bone resorption and formation activity in the metacarpal subchondral bone in Thoroughbred racehorses. Sections of the palmar metacarpal condyles of horses in race training (n = 24) or resting from training (n = 24) were examined with light microscopy and back scattered scanning electron microscopy (BSEM). Bone area fraction, osteoid perimeter and eroded bone surface were measured within two regions of interest: (1) the lateral parasagittal groove (PS); (2) the lateral condylar subchondral bone (LC). BSEM variables were analysed for the effect of group, region and interaction with time since change in work status. The means +/- SE are reported. For both regions of interest in the training compared to the resting group, eroded bone surface was lower (PS: 0.39 +/- 0.06 vs. 0.65 +/- 0.07 per mm, P = 0.010; LC: 0.24 +/- 0.04 vs. 0.85 +/- 0.10 per mm, P < 0.001) and in the parasagittal groove osteoid perimeter was higher (0.23 +/- 0.04% vs. 0.12 +/- 0.02%). Lower porosity was observed in the subchondral bone, reflected by a higher bone area fraction in the LC of the training group (90.8 +/- 0.6%) compared to the resting group (85.3 +/- 1.4%, P = 0.0010). Race training was associated with less bone resorption and more bone formation in the subchondral bone of highly loaded areas of the distal metacarpus limiting the replacement of fatigued bone. Periods of reduced intensity loading are important for facilitating subchondral bone repair in Thoroughbred racehorses. PMID- 25296853 TI - Cementless total hip arthroplasty for haemophilic arthropathy: follow-up result of more than 10 years. AB - The improvement of prophylaxis and adequate replacement of clotting factors, the quality of life and natural history of haemophilia have been significantly improved. However, significant functional impairment is inevitable. This study was performed to evaluate over 10 years clinical and radiographic outcomes of cementless total hip arthroplasty (THA) for treatment of haemophilic hip arthropathy. Between 1995 and 2003, 27 cases of cementless total hip arthroplasties were performed in 23 haemophilic patients. A total of 21 cases from 17 patients were available for follow-up analysis over 10 years. Modified Harris hip score, the range of motion of the hip joint, perioperative coagulation factor requirements and complications associated with bleeding were evaluated as part of the clinical assessment. For the radiographic assessment, fixation of component, osteolysis, loosening and other complications were evaluated. Clinically, the mean Harris hip score improved from 57 points before the operation to 94 points at the last follow-up. The mean flexion contracture was 10 degrees preoperatively and 0.9 degrees at the final follow-up. The further flexion improved from 68.4 degrees to 90.5 degrees after surgery. The mean monthly requirement of factor VIII reduced from 3150 units before surgery to 1800 units at the time of the last follow-up. There were three cases of rebleeding. In one case, a progressive haemophilic pseudotumour was found. Reoperation for any reason including revision was performed in three cases. We believe that cementless THA in patient with haemophilic hip arthropathy can bring reliable pain relief and functional improvement for longer than 10 years. PMID- 25296854 TI - Biomimetic total synthesis of cyanosporaside aglycons from a single enediyne precursor through site-selective p-benzyne hydrochlorination. AB - The cyanosporasides A-F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes Salinispora and Streptomyces sp. All derivatives feature one of two types of cyanocyclopenta[a]indene frameworks, which are regioisomeric in the position of a single chlorine atom. It is proposed that these chloro-substituted benzenoids are formed biosynthetically through the cycloaromatization of a bicyclic nine-membered enediyne precursor. Herein, we report the synthesis of such a bicyclic precursor, its spontaneous transannulation into a p-benzyne, and its differential 1,4 hydrochlorination reactivity under either organochlorine or chloride-salt conditions. Our bioinspired approach culminated in the first regiodivergent total synthesis of the aglycons A/F and B/C, as well as cyanosporasides D and E. In addition, empirical insights into the site selectivity of a natural-like p-benzyne, calculated to be a ground-state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed. PMID- 25296856 TI - Unravelling the Triterpenoid Saponin Biosynthesis of the African Shrub Maesa lanceolata. AB - Maesasaponins produced by the African shrub Maesa lanceolata are oleanane-type saponins with diverse biological activities. Candidate maesasaponin biosynthesis genes were identified through transcript profiling of M. lanceolata shoot cultures treated with methyl jasmonate, a well-known elicitor of plant specialized metabolism. Heterologous expression of the identified genes in Saccharomyces cerevisiae led to the identification of one oxidosqualene cyclase (MlbAS) and two cytochrome P450s, CYP716A75 and CYP87D16, which catalyse three enzymatic steps of maesasaponin biosynthesis. MlbAS is a beta-amyrin synthase that converts 2,3-oxidosqualene to beta-amyrin in yeast, and its role in maesasaponin biosynthesis was confirmed by gain- and loss-of-gene-function experiments in transgenic M. lanceolata plants. When expressed in beta-amyrin producing yeast, CYP716A75 catalyses the C-28 oxidation of beta-amyrin, leading to the accumulation of mainly erythrodiol. Accordingly, expression of CYP716A75 in a Medicago truncatula mutant lacking C-28 oxidase activity partially complemented the mutant phenotype. CYP87D16 catalyses the C-16alpha oxidation of beta-amyrin in yeast, leading to the accumulation of 16alpha-hydroxy beta-amyrin. This activity was hitherto only linked to a CYP716-type P450 from a distinct plant species, thereby suggesting that C-16alpha oxidase activity has evolved independently in different plant lineages. The identified biosynthesis genes will be useful for synthetic biology programs toward the production of bioactive triterpenoids. PMID- 25296855 TI - Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix. AB - BACKGROUND: Tumour microenvironment is a fundamental aspect of tumour behaviour, modulating important events as cancer cell migration and invasion, as well as angiogenesis and metastisation. Among other microenvironment features, hypoxia and acidity play important roles in this modulation. As the metabolic reprogramming of cancer cells induces extracellular acidity, which in turn induces angiogenesis, and hypoxia induces both the metabolic reprogramming and angiogenesis, the present study aims to evaluate the immunohistochemical expression of a variety of metabolic and vascular markers as common targets of the hypoxic microenvironment in a series of cervical squamous cells carcinoma, as well as using an in vitro 3D culture model. METHODS: Immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX was assessed in a series of 28 chronic cervicitis, 34 LSIL, 29 HSIL, 38 cases of squamous cells carcinoma (SCC), as well as in in vitro 3D culture of keratinocytes expressing HPV genes. Furthermore, VEGF family members' expression was assessed in the SCC cases. The expression profiles were associated with patients' clinicopathological parameters. RESULTS: We found an increase of MCT4 expression along progression to malignancy in cervical samples. Also, MCT4 was associated with CD147 and CAIX expression. VEGF-A expression was more frequently found in cases without MCT1 expression. Both MCT4 and CD147 were more frequently expressed in younger patients at diagnosis while no associations were found between VEGF family and clinicopathological parameters. Finally, we show evidence for the upregulation of MCT4, as well as CD147 and CAIX, after HPV transfection. CONCLUSIONS: The results herein presented point at MCT4 as a promising therapeutic target in squamous cells carcinoma of the uterine cervix. Importantly, we show a possible association between lactate transport and angiogenesis, which should be further explored. PMID- 25296858 TI - A Fully Automated Method for Discovering Community Structures in High Dimensional Data. AB - Identifying modules, or natural communities, in large complex networks is fundamental in many fields, including social sciences, biological sciences and engineering. Recently several methods have been developed to automatically identify communities from complex networks by optimizing the modularity function. The advantage of this type of approaches is that the algorithm does not require any parameter to be tuned. However, the modularity-based methods for community discovery assume that the network structure is given explicitly and is correct. In addition, these methods work best if the network is unweighted and/or sparse. In reality, networks are often not directly defined, or may be given as an affinity matrix. In the first case, each node of the network is defined as a point in a high dimensional space and different networks can be obtained with different network construction methods, resulting in different community structures. In the second case, an affinity matrix may define a dense weighted graph, for which modularity-based methods do not perform well. In this work, we propose a very simple algorithm to automatically identify community structures from these two types of data. Our approach utilizes a k-nearest-neighbor network construction method to capture the topology embedded in high dimensional data, and applies a modularity-based algorithm to identify the optimal community structure. A key to our approach is that the network construction is incorporated with the community identification process and is totally parameter-free. Furthermore, our method can suggest appropriate preprocessing/normalization of the data to improve the results of community identification. We tested our methods on several synthetic and real data sets, and evaluated its performance by internal or external accuracy indices. Compared with several existing approaches, our method is not only fully automatic, but also has the best accuracy overall. PMID- 25296859 TI - Functional (psychogenic) painful legs moving toes syndrome. PMID- 25296860 TI - Epigenetic regulation of cardiac myofibril gene expression during heart development. AB - Cardiac gene expression regulation is controlled not only by genetic factors but also by environmental, i.e., epigenetic factors. Several environmental toxic effects such as oxidative stress and ischemia can result in abnormal myofibril gene expression during heart development. Troponin, one of the regulatory myofibril proteins in the heart, is a well-known model in study of cardiac gene regulation during the development. In our previous studies, we have demonstrated that fetal form troponin I (ssTnI) expression in the heart is partially regulated by hormones, such as thyroid hormone. In the present study, we have explored the epigenetic role of histone modification in the regulation of ssTnI expression. Mouse hearts were collected at different time of heart development, i.e., embryonic day 15.5, postnatal day 1, day 7, day 14 and day 21. Levels of histone H3 acetylation (acH3) and histone H3 lysine 9 trimethylation (H3K9me(3)) were detected using chromatin immunoprecipitation assays in slow upstream regulatory element (SURE) domain (TnI slow upstream regulatory element), 300-bp proximal upstream domain and the first intron of ssTnI gene, which are recognized as critical regions for ssTnI regulation. We found that the levels of acH3 on the SURE region were gradually decreased, corresponding to a similar decrease of ssTnI expression in the heart, whereas the levels of H3K9me(3) in the first intron of ssTnI gene were gradually increased. Our results indicate that both histone acetylation and methylation are involved in the epigenetic regulation of ssTnI expression in the heart during the development, which are the targets for environmental factors. PMID- 25296857 TI - Age-triggered and dark-induced leaf senescence require the bHLH transcription factors PIF3, 4, and 5. AB - Leaf senescence can be triggered and promoted by a large number of developmental and environmental factors. Numerous lines of evidence have suggested an involvement of phytochromes in the regulation of leaf senescence, but the related signaling pathways and physiological mechanisms are poorly understood. In this study, we initially identified phytochrome-interacting factors (PIFs) 3, 4, and 5 as putative mediators of leaf senescence. Mutations of the PIF genes resulted in a significantly enhanced leaf longevity in age-triggered and dark-induced senescence, whereas overexpressions of these genes accelerated age-triggered and dark-induced senescence in Arabidopsis. Consistently, loss-of-function of PIF4 attenuated dark-induced transcriptional changes associated with chloroplast deterioration and reactive oxygen species (ROS) generation. ChIP-PCR and Dual Luciferase assays demonstrated that PIF4 can activate chlorophyll degradation regulatory gene NYE1 and repress chloroplast activity maintainer gene GLK2 by binding to their promoter regions. Finally, dark-induced ethylene biosynthesis and ethylene-induced senescence were both dampened in pif4, suggesting the involvement of PIF4 in both ethylene biosynthesis and signaling pathway. Our study provides evidence that PIF3, 4, and 5 are novel positive senescence mediators and gains an insight into the mechanism of light signaling involved in the regulation of leaf senescence. PMID- 25296861 TI - STIM1 triggers a gating rearrangement at the extracellular mouth of the ORAI1 channel. AB - The ER-resident regulatory protein STIM1 triggers store-operated Ca(2+) entry by direct interaction with the plasma membrane Ca(2+) channel ORAI1. The mechanism of channel gating remains undefined. Here we establish that STIM1 gates the purified recombinant ORAI1 channel in vitro, and use Tb(3+) luminescence and, separately, disulfide crosslinking to probe movements of the pore-lining helices. We show that interaction of STIM1 with the cytoplasmic face of the human ORAI1 channel elicits a conformational change near the external entrance to the pore, detectable at the pore Ca(2+)-binding residue E106 and the adjacent pore-lining residue V102. We demonstrate that a short nonpolar segment of the pore including V102 forms a barrier to ion flux in the closed channel, implicating the STIM1 dependent movement in channel gating. Our data explain the close coupling between ORAI1 channel gating and ion selectivity, and open a new avenue to dissect the gating, modulation and inactivation of ORAI-family channels. PMID- 25296863 TI - Mechanochemical stimulation of MCF7 cells with rod-shaped Fe-Au Janus particles induces cell death through paradoxical hyperactivation of ERK. AB - Multifunctional nanoparticles that actively target-specific tissues are studied for cancer diagnosis and treatment. Magnetically and optically active particles are of particular interest because they enable multiple imaging modalities and physically modulated therapies, such as magnetic hyperthermia. Fe-Au nanorods are synthesized that have a long iron segment, coated with polyethylene glycol, and a short gold tip functionalized with heregulin (HRG), a known ligand of ErbB family of receptors. HRG-nanorods preferentially target MCF7 cells relative to MDA-MB 231 cells, as demonstrated in a novel microfluidics device. Targeting rates of these classical breast cancer cells correlate with their differential expression of ErbB2/3 receptors. HRG-nanorod binding stimulates the extracellular signal regulated kinase 1/2 (ERK) phosphorylation in MCF7 cells. The increase in ERK phosphorylation is linked to "active zones," dynamic regions in the cell periphery, which exhibit higher rates of particle binding than the rest of the cell. Periodically stretching cells using magnetic tweezers further activates ERK, which leads to cell death in cells co-treated with B-Raf inhibitors, through ERK hyperactivation. Although to a lesser extent, cell death is also achieved through magnetic hyperthermia. These results demonstrate nanoscale targeting and localized mechanochemical treatment of specific cancer cell lines based on their receptor expression using multifunctional nanoparticles. PMID- 25296864 TI - Growing healthy muscles to optimise metabolic health into adult life. AB - The importance of skeletal muscle for metabolic health and obesity prevention is gradually gaining recognition. As a result, interventions are being developed to increase or maintain muscle mass and metabolic function in adult and elderly populations. These interventions include exercise, hormonal and nutritional therapies. Nonetheless, growing evidence suggests that maternal malnutrition and obesity during pregnancy and lactation impede skeletal muscle development and growth in the offspring, with long-term functional consequences lasting into adult life. Here we review the role of skeletal muscle in health and obesity, providing an insight into how this tissue develops and discuss evidence that maternal obesity affects its development, growth and function into adult life. Such evidence warrants the need to develop early life interventions to optimise skeletal muscle development and growth in the offspring and thereby maximise metabolic health into adult life. PMID- 25296862 TI - Calcium channel blockers and outcomes in older patients with heart failure and preserved ejection fraction. AB - BACKGROUND: Little is known about associations of calcium channel blockers (CCBs) with outcomes in patients with heart failure and preserved ejection fraction (EF). METHODS AND RESULTS: Of the 10 570 hospitalized patients with heart failure and preserved EF, >=65 years, EF >=40%, in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF; 2003-2004), linked to Medicare data (through December 31, 2008), 7514 had no prior history of CCB use. Of these, 815 (11%) patients received new discharge prescriptions for CCBs. Propensity scores for CCB initiation, calculated for each of the 7514 patients, were used to assemble a matched cohort of 1620 (810 pairs) patients (mean age, 80 years; mean EF, 56%; 65% women; 10% black) receiving and not receiving CCBs, balanced on 114 baseline characteristics. The primary composite end point of all-cause mortality or heart failure hospitalization occurred in 82% and 81% of patients receiving and not receiving CCBs (hazard ratio for CCBs, 1.03; 95% confidence interval, 0.92-1.14). Hazard ratios (95% confidence intervals) for all-cause mortality, heart failure hospitalization, and all-cause hospitalization were 1.05 (0.94-1.18), 1.05 (0.91-1.21), and 1.03 (0.93 1.14), respectively. Similar associations were observed when we categorized patients into those receiving amlodipine and nonamlodipine CCBs. Among 7514 prematch patients, multivariable-adjusted and propensity-adjusted hazard ratios (95% confidence interval) for primary composite end point were 1.03 (0.95-1.12) and 1.02 (0.94-1.11), respectively. CONCLUSIONS: In hospitalized older patients with heart failure, new discharge prescriptions for CCBs had no associations with composite or individual end points of mortality or heart failure hospitalization, regardless of the class of CCBs. PMID- 25296865 TI - Censored linear regression models for irregularly observed longitudinal data using the multivariate- t distribution. AB - In acquired immunodeficiency syndrome (AIDS) studies it is quite common to observe viral load measurements collected irregularly over time. Moreover, these measurements can be subjected to some upper and/or lower detection limits depending on the quantification assays. A complication arises when these continuous repeated measures have a heavy-tailed behavior. For such data structures, we propose a robust structure for a censored linear model based on the multivariate Student's t-distribution. To compensate for the autocorrelation existing among irregularly observed measures, a damped exponential correlation structure is employed. An efficient expectation maximization type algorithm is developed for computing the maximum likelihood estimates, obtaining as a by product the standard errors of the fixed effects and the log-likelihood function. The proposed algorithm uses closed-form expressions at the E-step that rely on formulas for the mean and variance of a truncated multivariate Student's t distribution. The methodology is illustrated through an application to an Human Immunodeficiency Virus-AIDS (HIV-AIDS) study and several simulation studies. PMID- 25296866 TI - On the analysis of composite measures of quality in medical research. AB - Composite endpoints are commonplace in biomedical research. The complex nature of many health conditions and medical interventions demand that composite endpoints be employed. Different approaches exist for the analysis of composite endpoints. A Monte Carlo simulation study was employed to assess the statistical properties of various regression methods for analyzing binary composite endpoints. We also applied these methods to data from the BETTER trial which employed a binary composite endpoint. We demonstrated that type 1 error rates are poor for the Negative Binomial regression model and the logistic generalized linear mixed model (GLMM). Bias was minimal and power was highest in the binomial logistic regression model, the linear regression model, the Poisson (corrected for over dispersion) regression model and the common effect logistic generalized estimating equation (GEE) model. Convergence was poor in the distinct effect GEE models, the logistic GLMM and some of the zero-one inflated beta regression models. Considering the BETTER trial data, the distinct effect GEE model struggled with convergence and the collapsed composite method estimated an effect, which was greatly attenuated compared to other models. All remaining models suggested an intervention effect of similar magnitude. In our simulation study, the binomial logistic regression model (corrected for possible over/under dispersion), the linear regression model, the Poisson regression model (corrected for over-dispersion) and the common effect logistic GEE model appeared to be unbiased, with good type 1 error rates, power and convergence properties. PMID- 25296868 TI - Characterization of susceptibility variants of influenza virus grown in the presence of T-705. AB - T-705 (favipiravir) is a potent inhibitor of RNA polymerases of influenza viruses. Susceptibility variants were isolated during passages in the presence of T-705. Nine variants with 0.4 to 2.1 times the 50% inhibitory concentration for plaque formation of the parent A/PR/8/34 (H1N1) strain had amino acid variations in the PB1, PB2, and PA genes of the RNA polymerase complex. However, the variation patterns in the RNA polymerase complex indicated that T-705 does not work as a mutagen, and resistant mutants were not isolated, possibly because a mutation leading to resistance would be lethal to the RNA polymerase function. PMID- 25296867 TI - Clozapine linked to nanocapsules minimizes tissue and oxidative damage to biomolecules lipids, proteins and DNA in brain of rats Wistar. AB - Clozapine, atypical antipsychotic, can change oxidative stress parameters. It is known that reactive species, in excess, can have a crucial role in the etiology of diseases, as well as, can potentiating adverse effects induce by drugs. The nanocapsules have attracted attention as carriers of several drugs, with consequent reduction of adverse effects. This study aimed to evaluate histopathology and oxidative damage of biomolecules lipids, proteins and DNA in the brain of Wistar rats after treatment with nanocapsules containing clozapine. The study consisted of eight groups of male Wistar rats (n = 6): saline (SAL), free clozapine (CZP) (25 mg/Kg i.p.), blank uncoated nanocapsules (BNC), clozapine-loaded uncoated nanocapsules (CNC) (25 mg/Kg i.p.), blank chitosan coated nanocapsules (BCSN), clozapine-loaded chitosan-coated nanocapsules (CCSN) (25 mg/Kg i.p.), blank polyethyleneglycol-coated nanocapsules (BPEGN), clozapine loaded polyethyleneglycol-coated nanocapsules (CPEGN) (25 mg/Kg i.p.). The animals received the formulation once a day for seven consecutive days and euthanized in the eighth day. After euthanasia, the brain was collected and homogenate was processed for further analysis. The histopathology showed less brain tissue damage in nanocapsules-treated groups. The lipid peroxidation and carbonylation of proteins showed a significant increase (p < 0.05) induced by CZP. CNC and CPEGN groups obtained a reduction membrane of lipids damage and nanocapsules-treated groups showed significant improvement protein damage. CZP was able to induce genetic oxidative damage, while the nanocapsules causing less damage to DNA. The findings show that different coatings can act protecting target tissues decreasing oxidative damage, suggesting that the drug when linked to different nanocapsules is able to mitigate the harmful effects of clozapine. PMID- 25296869 TI - [Natalizumab: an antibody targeting alpha4-integrin]. AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), in which inflammation develops upon leukocyte invasion into the CNS via the blood-brain barrier. alpha4-Integrin is an important cell adhesion molecule involved in the penetration process. Natalizumab is an alpha4-integrin-targeting monoclonal antibody that was recently approved for use as a disease-modifying therapy for MS in Japan. In this article, the mechanism of action, efficacy, and side effects of natalizumab will be reviewed. PMID- 25296870 TI - [Use of tocilizumab, an antibody against interleukin-6 receptor, for the treatment of neuromyelitis optica]. AB - Our lab has previously shown that Interleukin (IL)-6- dependent production of autoantibodies against aquaporin 4 in plasmablasts may play a central role in the pathogenesis of neuromyelitis optica (NMO). In this study, we explored the efficacy of tocilizumab, a humanized antibody against IL-6 receptor, in intractable cases of NMO. Eight NMO patients who were unresponsive to current treatments received monthly injections of tocilizumab for at least one year. Tocilizumab significantly reduced the annual relapse rate, neurogenic pain, and fatigue in NMO patients. These results indicate that IL-6 signaling plays a crucial role in the pathogenesis of NMO and highlight the value of IL-6 receptor inhibition for the treatment of NMO. PMID- 25296871 TI - [Rituximab (anti-CD20) in neurological disorders]. AB - Rituximab is a chimeric murine/human monoclonal antibody that specifically targets CD20 molecules on the surface of B-cells, thereby depleting B-cells and regulating humoral immunity. This antibody is mostly used in CD20-positive B-cell lymphoma, but is also widely used in many other connective tissue and neurological disorders. These neurological disorders include multiple sclerosis, neuromyelitis optica, myasthenia gravis, Lambert-Eaton myasthenic syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, paraneoplastic neurological syndromes, primary central nervous system lymphoma, inflammatory myopathy, and some other autoimmune-mediated neurological disorders. Rituximab may be useful even in refractory cases of these disorders. There are some notable side effects in each phase after administration. An infusion reaction can occur just after administration in more than half of cases, though most reactions are negligible. Several months after administration, sustained suppression of humoral immunity with myelosuppression can cause reactivation of Hepatitis B Virus (HBV) progressive multifocal leukoencephalopathy (PML), and severe opportunistic infections, some of which are fatal once they occur. Severe interstitial pneumonia can be treated with steroid pulse therapy, if necessary. To reduce the risk of infusion reactions and improve long-term tolerability, the human-derived components of the antibody have been increased to form humanized or human monoclonal antibodies like ocrelizumab and ofatumumab. PMID- 25296872 TI - [Alemtuzumab, a monoclonal antibody against CD52: hopes and fears]. AB - CD52, an antigen expressed on immune cells including mature T lymphocytes, is thought to be involved in immunomodulatory mechanisms. Alemtuzumab is a humanized monoclonal antibody against CD52, which causes a marked and long-term decrease in immune cells, especially CD4-positive T lymphocytes. A few randomized clinical trials have revealed the efficacy of alemtuzumab to be much greater than that of interferon-beta in patients with relapsing-remitting multiple sclerosis. However, the development of other autoimmune disorders, including autoimmune thyroid disorders and thrombocytic purpura, because of alemtuzumab application has been considered an obstacle in its widespread use. PMID- 25296873 TI - [C5: eculizumab]. AB - Eculizumab is a recombinant humanized monoclonal antibody that specifically binds to a C5 terminal complement and inhibits the cleavage of C5 to C5a and C5b through complement activation. Eculizumab has been used clinically for paroxysmal nocturnal hemoglobinuria. Clinical studies have been initiated for neurological disorders, such as, optic neuromyelitis and myasthenia gravis, mediated by the complement system. In addition, eculizumab is expected to be useful for the treatment of intractable neurological diseases. PMID- 25296874 TI - [Cognitive impairment in multiple sclerosis]. AB - Cognitive impairment may occur in up to 70% of all patients with multiple sclerosis (MS). Although MS can affect various sites within the central nervous system, a specific pattern of cognitive deficits tends to be seen, especially in the early stages of the disease. These deficits include problems with attention, information processing speed, and working memory. This constellation of deficits can occur with any disease course, and a minimal correlation has been found between physical disability assessed by EDSS and cognitive impairment. Many studies have shown that cognitive impairment is correlated with brain lesion volume, as well as brain atrophy. There are promising neuroimaging indicators that may be useful for identifying patients at risk for cognitive impairment, such as diffusion tensor imaging, the magnetization transfer ratio, and N-acetyl aspartate levels. Cognitive dysfunction is associated with adverse effects on quality of life, employment status, and social activities. Today, there are three avenues for treatment: disease modifying therapies, symptomatic treatments, and cognitive rehabilitation. Unfortunately, data linking therapeutic interventions are limited. A better understanding of cognitive function and its correlation with disease mechanisms will assist in providing a new comprehensive treatment strategy that begins immediately with the diagnosis of MS. PMID- 25296875 TI - [Japan Spastic Paraplegia Research Consortium (JASPAC)]. AB - Japan Spastic Paraplegia Research Consortium (JASPAC), a nationwide clinical and genetic survey of patients with hereditary spastic paraplegia (HSP), was started in 2006 as a project of the Research Committee for Ataxic Diseases of the Ministry of Health, Labor, and Welfare, Japan. To date (April 4, 2014), 448 indexed patients with HSP have been registered from 46 prefectures in Japan. We are now performing molecular testing of the HSP patients using Sanger sequencing (SPG4, SPG11, SPG31, and ARSACS), comparative genomic hybridization (CGH) array (SPG1, 2, 3A, 4, 5, 6, 7, 8, 10, 11, 13, 15, 17, 20, 21, 31, 33, 39, 42, ABCD1, alsin, and ARSACS), and resequencing microarray (SPG1, 2, 3A, 4, 5, 6, 7, 8, 10, 11, 13, 17, 20, 21, 31, 33, and ABCD1). In 206 Japanese families with autosomal dominant HSP, SPG4 was the most common form, accounting for 38%, followed by SPG3A (5%), SPG31 (5%), SPG10 (2%), and SPG8 (1%). In 88 patients with autosomal recessive HSP, although SPG11 was the most common form, accounting for 6%, most showed significant genetic heterogeneity. The results of molecular testing will be applicable to patients in terms of improved positive diagnosis, follow-up, and genetic counseling. JASPAC will contribute to elucidating the molecular mechanisms underlying HSP, and will facilitate the development of better treatments for HSP. PMID- 25296876 TI - [Clinical course of recovery from cognitive dysfunction in a patient with anti-N methyl-D-aspartate receptor encephalitis]. AB - Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder, which occurs commonly in young women and is often associated with ovarian teratomas. We report the case of a patient with this disease, who exhibited cognitive deficits, and describe the clinical course of recovery from cognitive dysfunction. A 29-year-old right-handed woman suffered from chills and fever for 7 days prior to admission to hospital, and complained that she could not understand the content of TV programs. Following admission to hospital, she was found to have an ovarian teratoma and underwent oophorectomy. She was diagnosed with anti-NMDA receptor encephalitis based on the presence of antibodies in the serum and cerebrospinal fluid. She subsequently experienced phases with disturbance of consciousness and involuntary movement, and then moved into the gradual recovery phase 3 months after onset. Cerebral SPECT revealed a left dominant decrease of blood flow in the prefrontal regions bilaterally. Neuropsychological examination 3 months after onset revealed frontal lobe syndrome comprising executive dysfunction, decreased spontaneity, and environmental dependency in addition to recent memory deficits. Approximately 6 months after onset, recent memory impairments and environmental dependency were resolved, and a gradual improvement in spontaneity and executive function was seen. One year after onset, the patient had regained independence and ability to self-care, and returned to her workplace. Our observations suggest that patients with anti-NMDA receptor encephalitis may recover from frontal lobe syndrome, including executive dysfunction and decreased spontaneity, slower than patients with other cognitive dysfunctions do. PMID- 25296877 TI - [A case of migraine presenting with thunderclap headache associated with posterior reversible encephalopathy syndrome]. AB - We report a 47-year-old woman who developed a thunderclap headache. Head axial, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) revealed high signal lesions in the left occipital and right parietal lobes. Apparent diffusion coefficient mapping showed a vasogenic edema pattern. Upon admission, the patient's blood pressure was normal and the neurological examination was unremarkable. As thunderclap headaches are associated with a repeated rise in blood pressure, we considered cerebral vasoconstriction and administered a calcium channel blocker. Thereafter, her headache with high blood pressure eased significantly and the high signal lesions on FLAIR MRI disappeared. We diagnosed the condition as posterior reversible encephalopathy syndrome (PRES). In addition, head magnetic resonance angiogram showed vasoconstriction of the right anterior cerebral artery, left middle cerebral artery, and bilateral posterior cerebral artery. Calcium channel blocker use was continued and vasoconstriction improved by day 70. In this case, the presenting symptom was thunderclap headache, which is a characteristic feature of reversible cerebral vasoconstriction syndrome (RCVS). Therefore, PRES may be caused by RCVS. PMID- 25296878 TI - Effect of recombinant human keratinocyte growth factor in inducing Ras-Raf-Erk pathway-mediated cell proliferation in emphysematous mice lung. AB - CONTEXT: Pulmonary emphysema is resulted due to destruction of the structure of the alveoli. Recently, exogenous recombinant human Keratinocyte growth factor (rHuKGF) has been reported to induce the regeneration of gas exchange structures. However, the molecular mechanisms governing this process are so far unknown. OBJECTIVE: The objective of this study was to investigate the effect of rHuKGF in the lungs of emphysema-challenged mice on Ras-Raf-Erk (Erk, extracellular signal regulated kinase) mediated signaling pathway that regulates alveolar epithelial cell proliferation. METHODS: Three experimental groups (i.e. emphysema, therapy and control group) were prepared. Lungs of mice were therapeutically treated at three occasions by oropharyngeal instillation of 10 mg rHuKGF per kg body weight after induction of emphysema by porcine pancreatic elastase (PPE). Subsequently, lung tissues from each mouse were collected for histopathology and molecular biology studies. RESULTS AND DISCUSSION: Histopathology photomicrographs and Destructive Index analysis have shown that elastase induced airspace enlargement and loss of alveoli were recovered in therapy group. Moreover, proliferating cell nuclear antigen (PCNA) at mRNA and protein expression level was markedly increased in therapy group than emphysema group. Upon validation at mRNA level, expressions of FGF-7, FGF-R, Ras, c-Raf, Erk-1, Erk-2, c-Myc and were significantly increased, whereas Elk-1 was notably decreased in therapy group when compared with emphysema group and were well comparable with the control group. CONCLUSION: Therapeutic supplementation of rHuKGF rectifies the deregulated Ras-Raf-Erk pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence, rHuKGF may prove to be a potential drug in the treatment of emphysema. PMID- 25296879 TI - A comparative study of the toxicological aspects of vanadium pentoxide and vanadium oxide nanoparticles. AB - Indiscriminate use of vanadium oxide nanoparticles (NPs) in steel industries and their release during combustion of fossil fuels makes it essential to study their toxic potential. Herein, we assessed the toxicological effects of two types of in house synthesized vanadium oxide NPs in Wistar rats exposed to NPs through inhalation route. V2O5 and VO2 NPs exhibited rod and spherical symmetry, respectively with a mean diameter of 50+/-20 and 30+/-10 nm. Assessment of bronchoalveolar lavage fluid parameters demonstrated that VO2 NP-exposed animals had higher levels of lactate dehydrogenase, gamma-glutamyl transpeptidase and alkaline phosphatase as compared to V2O5 NP-exposed animals. The levels of oxidative stress markers malondialdehyde and reduced glutathione also indicated higher toxic potential of VO2 NPs. Moreover, after 7-day recovery, the levels of the above parameters were closer to normal levels only in V2O5-exposed animals. Interestingly, histopathological and immune-histopathology analysis (TNF-alpha) of lung tissue showed higher damage and inflammatory response in VO2 NP-exposed animals, which persisted even after 7 days of recovery period. Surprisingly, the carcinogenic potential of vanadium oxide NPs came into light which was indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay as well as the decreased levels of p53 and Bax, in lung tissue of NP-exposed animals. Notably, the physiochemical characterization of NPs, especially the shape and the size, play a central role in shaping the toxicity of these NPs and thus should be extensively evaluated for outlining the regulatory guidelines. PMID- 25296880 TI - Molecular weight and molar substitution are more important in HES-induced renal impairment than concentration after hemorrhagic and septic shock. AB - BACKGROUND: Clinical studies have raised concerns about the safety of 6% hydroxyethylstarch (HES) 130/0.42, but the pathomechanisms of this renal impairment remain unknown. To evaluate the effects of different HES concentrations, molar substitutions and molecular weights in HES-induced renal impairment, we used a porcine two-hit model that combined haemorrhagic and septic shock. METHODS: We conducted a prospective, randomised, double-blinded, controlled study in a university animal laboratory. Thirty anaesthetised and ventilated pigs were randomised to receive volume replacement therapy using 6% HES130/0.42, 6% HES200/0.5, 10% HES130/0.42 or 10% HES200/0.5, all dissolved in 0.9% NaCl rather than 0.9% NaCl alone. First, we bled the animals until they reached half of their baseline mean arterial pressure (MAP) for 45 minutes followed by fluid resuscitation. As a second hit, sepsis was induced using an Escherichia coli-laden clot 6 hours after haemorrhagic shock. Volume resuscitation started with a delay of two hours and a central venous pressure goal of 12 mmHg. RESULTS: At the end of the study, the groups showed no difference in cardiac output or MAP, but the volume balance (mL/kg BW) was significantly higher in the 0.9% NaCl group (346+/-90; P<=0.05) than in the other groups (6% HES130, 125+/-26; 6% HES200, 105+/-15; 10% HES130, 114+/-17; 10% HES200, 96+/-23). Creatinine clearance (mL/min) was significantly lower in the 6% HES200 (26+/-33) and 10% HES200 (15+/-18) groups compared to the 0.9% NaCl group (104+/-46; P<=0.05) but not in the HES 130 formulations (6% HES130: 64+/-51; 10% HES130: 58+/-38) at the end of the study. CONCLUSION: In this porcine two-hit shock model, treatment with 0.9% NaCl, HES 130/0.42 or HES 200/0.5 led to a similar maintenance of haemodynamic values. Despite this similar maintenance of the haemodynamic values, volume replacement with 6% and 10% HES 200/0.5 led to an accumulation of HES, higher colloid osmotic pressure and significantly reduced renal function after haemorrhagic and septic shock. These facts support the presumption that not the concentration but the degree of substitution and the molecular weight play a decisive role in HES-induced renal impairment. PMID- 25296883 TI - Novel polymer gel electrolyte with organic solvents for quasi-solid-state dye sensitized solar cells. AB - A cross-linked copolymer was previously synthesized from poly(oxyethylene) diamine (POE-amine) and an aromatic anhydride and cured to generate an amide imide cross-linking structure. The copolymer containing several chemical groups such as POE, amido acids, and imide, enabled to absorb liquid electrolytes in methoxypropionitrile (MPN) for suitable uses in dye-sensitized solar cells. To establish the advantages of polymer gel electrolytes (PGE), the same copolymer was studied by using different electrolyte solvents including propylene carbonate (PC), dimethylformamide, and N-methyl-2-pyrrolidone, and shown their long-term stability. The morphology of the copolymer after absorbing liquid electrolytes in these solvents was proven the same as a 3D interconnected nanochannels, evidenced field emission-scanning electron microscopy. Among these solvents, PC was selected as the optimized PGE, which demostrated a higher power conversion efficiency (8.31%) than that of the liquid electrolyte (7.89%). In particular, the long-term stability of only a 5% decrease in the cell efficiency after 1000 h of testing was achieved. It was proven the developed copolymer as PGE was versatile for different solvents showing high efficiency and long-term durability. PMID- 25296881 TI - The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-alpha expression following short-term morphine withdrawal. AB - BACKGROUND AND PURPOSE: The endocannabinoid (eCB) system is involved in pathways that regulate drug addiction and eCB-mediated synaptic plasticity has been linked with addictive behaviours. Here, we investigated the molecular mechanisms underlying the changes in eCB-dependent synaptic plasticity in the nucleus accumbens core (NAcc) following short-term withdrawal from repeated morphine treatment. EXPERIMENTAL APPROACH: Conditioned place preference (CPP) was used to evaluate the rewarding effects of morphine in rats. Evoked inhibitory postsynaptic currents of medium spiny neurons in NAcc were measured using whole cell patch-clamp recordings. Changes in depolarization-induced suppression of inhibition (DSI) in the NAcc were assessed to determine the effect of short-term morphine withdrawal on the eCB system. To identify the potential modulation mechanism of short-term morphine withdrawal on the eCB system, the expression of diacylglycerol lipase alpha (DGL-alpha) and monoacylglycerol lipase was detected by Western blot analysis. KEY RESULTS: Repeated morphine administration for 7 days induced stable CPP. Compared with the saline group, the level of DSI in the NAcc was significantly increased in rats after short-term morphine withdrawal. Furthermore, this increase in DSI coincided with a significant increase in the expression of DGL-alpha. CONCLUSIONS AND IMPLICATIONS: Short-term morphine withdrawal potentiates eCB modulation of inhibitory synaptic transmission in the NAcc. We also found that DGL-alpha expression was elevated after short-term morphine withdrawal, suggesting that the eCB 2-arachidonyl-glycerol but not anandamide mediates the increase in DSI. These findings provide useful insights into the mechanisms underlying eCB-mediated plasticity in the NAcc during drug addiction. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc. PMID- 25296882 TI - Role of nerve growth factor and its TRKA receptor in normal ovarian and epithelial ovarian cancer angiogenesis. AB - In normal ovarian function a controlled angiogenesis is essential. Several growth factors are involved in this process, such as the vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). The angiogenesis process in the normal ovary is a tightly controlled process that occurs in each ovarian cycle. Also, angiogenesis is critical for ovarian cancer development and it is responsible for tumor spread, metastasis and its peritoneal dissemination. Ovarian cancer is the fifth leading cause of cancer death in women and it is distinguished as the most lethal gynecologic cancer. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Several molecules have been reported to promote angiogenesis, such as platelet-derived growth factor (PDGF) and its receptors, the angiopoietin/Tie ligand/receptor system and fibroblast growth factor (FGF). Primarily, VEGF has been identified to play key roles in driving angiogenesis. The above-mentioned molecules are candidate drug targets. Used in combination with other treatments, anti-angiogenic therapies have managed to reduce disease progression. The present review is focused in NGF and its high affinity receptor tyrosine kinase A (TRKA). The expression of VEGF, proliferation and the angiogenesis process in ovarian cancer is importantly induced by NGF, among other molecules. PMID- 25296884 TI - Rapid down-regulation of hepatic lipid metabolism by phenolic fraction from extra virgin olive oil. AB - PURPOSE: Regular consumption of extra virgin olive oil (EVOO) is associated with a low incidence of atherosclerotic diseases. The phenolic component contributes to the hypolipidemic action of EVOO, although the biochemical mechanisms leading this beneficial outcome are not fully understood. Since liver plays a pivotal role in the whole body lipid homeostasis, we investigated the short-term effects of EVOO extract, with a high phenol content (HPE), on lipid synthesis in primary rat hepatocytes. Refined olive oil extract, with a low phenol content, was used throughout this study as a control. METHODS: Olive oil phenols isolated with methanolic extractions were subsequently analyzed by high performance liquid chromatography, electrospray ionization tandem mass spectrometry, and gas chromatography mass spectrometry. Rat hepatocytes were obtained from collagenase perfusion of liver. A colorimetric assay was performed to exclude cytotoxicity of the extracts. Radioenzymatic methods were used in order to investigate hepatic lipid metabolism. RESULTS: HPE, dose- (0.1-50 MUg/mL) and time-dependently (0.5-4 h) inhibited both lipogenesis and cholesterogenesis (n = 6, P < 0.05), as well as triglycerides synthesis (n = 5, P < 0.05). We showed that these effects are attributable to a short-term modulation by HPE of the key enzymes implicated in the abovementioned pathways (n = 5, P < 0.05). CONCLUSIONS: The decrease in hepatic lipid synthesis may represent a potential mechanism underlying the hypolipidemic effect of EVOO phenols. PMID- 25296885 TI - Dairy products and the risk of stroke and coronary heart disease: the Rotterdam Study. AB - PURPOSE: We examined whether consumption of total dairy and dairy subgroups was related to incident stroke and coronary heart disease (CHD) in a general older Dutch population. METHODS: The study involved 4,235 participants of the Rotterdam Study aged 55 and over who were free of cardiovascular disease (CVD) and diabetes at baseline (1990-1993). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) for the intake of total dairy and dairy subgroups in relation to incident CVD events. RESULTS: Median intake of total dairy was 397 g/day, which mainly comprised low-fat dairy products (median intake of 247 g/day). During a median follow-up time of 17.3 years, 564 strokes (182 fatal) and 567 CHD events (350 fatal) occurred. Total dairy, milk, low-fat dairy, and fermented dairy were not significantly related to incident stroke or fatal stroke (p > 0.2 for upper vs. lower intake categories). High-fat dairy was significantly inversely related to fatal stroke (HR of 0.88 per 100 g/day; 95% CI 0.79, 0.99), but not to incident stroke (HR of 0.96 per 100 g/day; 95% CI 0.90, 1.02). Total dairy or dairy subgroups were not significantly related to incident CHD or fatal CHD (HRs between 0.98 and 1.05 per 100 g/day, all p > 0.35). CONCLUSIONS: In this long-term follow-up study of older Dutch subjects, total dairy consumption or the intake of specific dairy products was not related to the occurrence of CVD events. The observed inverse association between high-fat dairy and fatal stroke warrants confirmation in other studies. PMID- 25296888 TI - Highlights from the United States Food and Drug Administration's public workshop on the development of animal models of pregnancy to address medical countermeasures in an "at-risk" population of pregnant women: Influenza as a case study. AB - The U.S. Food and Drug Administration (FDA) and other federal agencies partner to ensure that medical countermeasures (e.g., drug therapies and vaccines) are available for public health emergencies (FDA, 2014). Despite continuing progress, providing medical countermeasures and treatment guidelines for certain populations (e.g., pregnant women) is challenging due to the lack of clinical and/or animal data. Thus, a workshop was convened to discuss animal models of pregnancy for the evaluation of disease progression and medical countermeasures. PMID- 25296887 TI - 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration. AB - PURPOSE: The vitamin D system plays a role in metabolism regulation. 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) suppressed 3T3-L1 white adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure, whereas mice with adipose-specific VDR over-expression showed decreased energy expenditure. Brown adipose tissue (BAT), now known to be present in adult humans, functions in non-shivering thermogenesis by uncoupling ATP synthesis from respiration and plays an important role in energy expenditure. However, the effects of 1,25(OH)2D3/VDR on brown adipocyte differentiation and mitochondrial respiration have not been reported. METHODS: mRNA expression of VDR and the metabolizing enzymes 1alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) were examined in BAT of mice models of obesity and during brown adipocyte differentiation. The effects of 1,25(OH)2D3 and VDR over-expression on brown adipocyte differentiation and functional outcomes were evaluated. RESULTS: No significant changes in mRNA of VDR and CYP27B1 were noted in both diet-induced obese (DIO) and ob/ob mice, whereas uncoupling protein 1 mRNA was downregulated in BAT of ob/ob, but not DIO mice when compared to the controls. In contrast, mRNA of VDR, CYP24A1, and CYP27B1 were downregulated during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, accompanied by suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak. Consistently, over expression of VDR also suppressed brown adipocyte differentiation. Further, both 1,25(OH)2D3 and VDR over-expression suppressed PPARgamma transactivation in brown preadipocytes. CONCLUSION: Our results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)2D3/VDR system in regulating BAT development and function in obesity warrant further investigation. PMID- 25296889 TI - Why strategies to control Leishmania spp. multiplication based on the use of proteinase inhibitors should consider multiple targets and not only a single enzyme. AB - The use of proteinases as targets to develop novel chemotherapies against Leishmania spp. infections is a very promising strategy. Based on a previous study by Goyal et al. [J Mol Model (2014) 20:2099], we discuss herein the idea that only a combined treatment with distinct proteinase inhibitors would be an effective antileishmanial therapy. PMID- 25296886 TI - Dietary sugars: their detection by the gut-brain axis and their peripheral and central effects in health and diseases. AB - BACKGROUND: Substantial increases in dietary sugar intake together with the increasing prevalence of obesity worldwide, as well as the parallels found between sugar overconsumption and drug abuse, have motivated research on the adverse effects of sugars on health and eating behaviour. Given that the gut brain axis depends on multiple interactions between peripheral and central signals, and because these signals are interdependent, it is crucial to have a holistic view about dietary sugar effects on health. METHODS: Recent data on the effects of dietary sugars (i.e. sucrose, glucose, and fructose) at both peripheral and central levels and their interactions will be critically discussed in order to improve our understanding of the effects of sugars on health and diseases. This will contribute to the development of more efficient strategies for the prevention and treatment for obesity and associated co-morbidities. RESULTS: This review highlights opposing effects of glucose and fructose on metabolism and eating behaviour. Peripheral glucose and fructose sensing may influence eating behaviour by sweet-tasting mechanisms in the mouth and gut, and by glucose-sensing mechanisms in the gut. Glucose may impact brain reward regions and eating behaviour directly by crossing the blood-brain barrier, and indirectly by peripheral neural input and by oral and intestinal sweet taste/sugar-sensing mechanisms, whereas those promoted by fructose orally ingested seem to rely only on these indirect mechanisms. CONCLUSIONS: Given the discrepancies between studies regarding the metabolic effects of sugars, more studies using physiological experimental conditions and in animal models closer to humans are needed. Additional studies directly comparing the effects of sucrose, glucose, and fructose should be performed to elucidate possible differences between these sugars on the reward circuitry. PMID- 25296890 TI - Hydration Gibbs free energies of open and closed shell trivalent lanthanide and actinide cations from polarizable molecular dynamics. AB - The hydration free energies, structures, and dynamics of open- and closed-shell trivalent lanthanide and actinide metal cations are studied using molecular dynamics simulations (MD) based on a polarizable force field. Parameters for the metal cations are derived from an ab initio bottom-up strategy. MD simulations of six cations solvated in bulk water are subsequently performed with the AMOEBA polarizable force field. The calculated first-and second shell hydration numbers, water residence times, and free energies of hydration are consistent with experimental/theoretical values leading to a predictive modeling of f-elements compounds. PMID- 25296891 TI - Mechanistic aspects of superacid mediated condensation of polyphenols with ketones. Implications for polymer synthesis. AB - A detailed computational study of possible reaction paths for methanesulfonic and triflic acid mediated polyhydroxyalkylation reaction between resorcinol and trifluoracetone accompanied by cyclodehydration to give 9H-xanthene containing polymers has been carried out at M06-2X/6-311+G level of theory. A cluster solvation model was used for the calculations. The calculations revealed that the most kinetically favorable reaction path involves the cyclodehydration occurring during the polymer forming step. In this case 9H-xanthene formation is promoted by the activated phenyl ring in Wheland intermediate assisting the aromatic nucleophilic substitution of OH group which leads to the cyclization. It has been demonstrated that the inability of methanesulfonic acid to catalyze the formation of 9H-xanthene containing polymers is due to the very high barrier of the rate limiting step of the polymer forming reaction and not the cyclodehydration process. PMID- 25296892 TI - Relationship management strategies for daughters in conflicted relationships with their ageing mothers. AB - AIMS: To study relationship management strategies of daughters in conflicted relationships with their mothers and how they promoted or prevented elder abuse. BACKGROUND: Daughters have enduring, unique relationships with their mothers that often carry over into caregiving. Pre-caregiving relationship quality is related to many caregiving outcomes, although it is unclear how. DESIGN: Qualitative study. METHODS: Grounded theory design, informed by feminism, with telephone interviews conducted between January 2013-July 2013. The sample (N = 13) was recruited through an online recruitment strategy, with advertisements posted on relevant websites asking 'Are you in an abusive relationship with your ageing mother?' RESULTS/FINDINGS: Daughters used coping strategies and self-protective strategies aimed at decreasing their exposure to aggression and emotional distress when interacting with their ageing mothers. Daughters also used spiteful aggression out of the desire for revenge. CONCLUSION: Although the daughters' strategies served their personal needs, they jeopardized the mothers' needs by creating an environment where neglect could occur. Daughters also readily and intentionally used aggression against their mothers. These were strategies daughters have found useful. These strategies may be potential areas for designing interventions to promote healthy family relationships and decrease the occurrence of elder abuse and neglect. PMID- 25296893 TI - POEMS syndrome (polyneuropathy organomegaly endocrinopathy M-protein skin changes) with xanthoma--a case report. PMID- 25296894 TI - Towards novel efficient and stable nuclear import signals: synthesis and properties of trimethylguanosine cap analogs modified within the 5',5' triphosphate bridge. AB - A trimethylguanosine (TMG) cap is present at the 5' end of several small nuclear and nucleolar RNAs. Recently, it has been reported that the TMG cap is a potential nuclear import signal for nucleus-targeting therapeutic nucleic acids and proteins. The import is mediated by recognition of the TMG cap by the snRNA transporting protein, snurportin1. This work describes the synthesis and properties of a series of dinucleotide TMG cap (m3(2,2,7)GpppG) analogs modified in the 5',5'-triphosphate bridge as tools to study TMG cap-dependent biological processes. The bridge was altered at different positions by introducing either bridging (imidodiphosphate, O to NH and methylenebisphosphonate, O to CH2) or non bridging (phosphorothioate, O to S and boranophosphate, O to BH3) modifications, or by elongation to tetraphosphate. The stability of novel analogs in blood serum was studied to reveal that the alpha,beta-bridging O to NH substitution (m3(2,2,7)GppNHpG) confers the highest resistance. Short RNAs capped with analogs containing alpha,beta-bridging (m3(2,2,7)GppNHpG) or beta-non-bridging (m3(2,2,7)GppSpG D2) modifications were resistant to decapping pyrophosphatase, hNudt16. Preliminary studies on binding by human snurportin1 revealed that both O to NH and O to S substitutions support this binding. Due to favorable properties in all three assays, m3(2,2,7)GppNHpG was selected as a promising candidate for further studies on the efficiency of the TMG cap as a nuclear import signal. PMID- 25296895 TI - Pain sensitization and degenerative changes are associated with aberrant plantar loading in patients with painful knee osteoarthritis. AB - OBJECTIVES: This study focused on the biomechanical implications of knee osteoarthritis (OA) and the association with pain. The plantar loading force distribution of the foot was determined and correlated to degenerative knee changes, function, pain intensity, and pain sensitization. METHOD: Knee OA patients (n = 34) with moderate and mild knee pain were characterized and compared to matched controls (n = 16). The Plantar Foot Posture Index (FPI) and mean maximum plantar forces were determined by pressure-sensitive insoles. Pain intensity and function were assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Brief Pain Inventory (BPI). Local knee pain sensitization was assessed by pressure pain thresholds (PPTs) from eight knee locations. Spreading sensitization was assessed by PPTs from two extra segmental test sites. Temporal summation to repeated pressure stimulation (knee and extra-segmental stimulation) and conditioning pain modulation (CPM) were assessed, representing central pain mechanisms. RESULTS: The maximum force (MF) applied by the medial forefoot correlated to knee PPTs (r = 0.524, p < 0.001), CPM potency (r = 0.532, p < 0.001), and BPI (r = -0.325, p < 0.05) and WOMAC scores (pain r = -0.425, p < 0.01; stiffness r = -0.386, p < 0.01; function r = 0.378, p < 0.05). The MF applied by the medial hindfoot correlated negatively to scores on the FPI (r = -0.394, p < 0.01) and the Kellgren-Lawrence (K-L) grading scale (r = -0.330, p < 0.05). The MF applied by the medial forefoot correlated to extra-segmental PPTs (r = 0.554, p < 0.001) and the potency of CPM (r = 0.561, p < 0.0001). The MF applied by the lateral hindfoot correlated negatively to the PPT assessed extra-segmentally (r = -0.367, p < 0.05) and positively to CPM potency (r = 0.322, p < 0.05). CONCLUSIONS: This study shows that mean maximum plantar foot force distribution in patients with painful knee OA is associated with specific pain mechanisms, function, radiological findings, and pain intensity. PMID- 25296896 TI - Isolated limb perfusion using tumour necrosis factor alpha and melphalan in patients with advanced aggressive fibromatosis. AB - BACKGROUND: Aggressive fibromatoses (desmoid tumours) may be locally aggressive, but do not metastasize. Although a conservative approach is advocated for most patients, pain and functional impairment are indications for active treatment. Tumour necrosis factor (TNF) alpha and melphalan-based isolated limb perfusion (TM-ILP) is a limb-saving treatment modality for soft tissue tumours. This study reports the results of TM-ILP treatment in patients with aggressive fibromatosis. METHODS: Institutional databases of three European centres were searched. All patients who received TM-ILP treatment for aggressive fibromatosis between 1990 and 2012 were included. Before therapy, the patients were discussed at multidisciplinary tumour board meetings. RESULTS: Twenty-five patients received 28 TM-ILP treatments. The median age of patients was 28 (i.q.r. 19-34) years and median hospital stay was 8 (7-12) days. Median follow-up was 84 (34-114) months. A complete response was achieved after two TM-ILP treatments, and a partial response after 17 treatments in 16 patients. Stable disease was reported after eight treatments in seven patients, including a patient with stable disease after the first treatment and progression after the second TM-ILP. Toxicity was modest after most treatments; Wieberdink grade IV (extensive epidermolysis, and threatening or manifest compartment syndrome) was seen after two TM-ILP treatments. Systemic leakage was reported after one treatment, but did not lead to systemic toxicity. Functional outcome was good; 16 patients had no physical limitations, and six patients had some limitations but did not need medical aids. Amputation was prevented in all but three patients. CONCLUSION: TNF-alpha-based ILP is effective in patients with aggressive fibromatosis. PMID- 25296897 TI - Enhanced degradation of eletrooxidized textile effluent by petroleum degrading Pseudomonas aeruginosa (MTCC No.1201) at compressed gas pressure. AB - The textile dyeing industry produces large volumes of wastewater during dyeing processes where the major step includes the color removal and COD removal. In the present study, the combined electrooxidation process and a novel biological degradation at high compressed gas pressure were studied. The removal of color in the real textile dye effluent was achieved by electrooxidation with Titanium Substrate Insoluble anode and titanium as cathode through generation of hypochlorite. The hypochlorite produced during the electrooxidation was removed by exposing the solution to direct sunlight. The impact of compressed atmospheric condition on the degradation of organics by Pseudomonas aeruginosa (MTCC No.1201, GenBank Acc. No KC545414) was studied. The compressed gas pressure condition increases the level of dissolved gas in the liquid phase and exerts the pressure on the growing cells in the liquid phase. Interesting synchronization between the utilization of oxygen by active microbial cells and the dissolution of oxygen in the water from gas phase was observed which enhanced the bacterial degradation process. It should be mentioned here that the P. aeruginosa was grown without addition of nutrients. The compressed atmospheric pressure enhances the bacterial proliferation, EPS production and COD reduction in the electrooxidized effluent. FTIR and HPLC reveal the degradation of organics in the compressed pressure condition. PMID- 25296898 TI - Kloss gibbon (Hylobates klossii) behavior facilitates the avoidance of human predation in the Peleonan forest, Siberut Island, Indonesia. AB - Kloss gibbons (Hylobates klossii) are endemic to the Mentawai Islands in Indonesia and have been subject to human predation for more than 2000 years in the absence of any other significant predators. We investigate the behavior of Kloss gibbons that may be attributed to avoiding human predation. We observed Kloss gibbons in the Peleonan forest in the north of Siberut Island, the northernmost of the Mentawai island chain, over 18 months in 2007 and 2008, and collected data on their singing behavior, the number of individuals present during different conditions and their responses to humans. We examine behaviors that may reduce the risk of predation by humans during singing (the most conspicuous gibbon behavior), daily non-singing activities and encounters with humans. The individual risk of being stalked by hunters is reduced by singing in same-sex choruses and the risk of successful capture by hunters during singing is reduced by singing less often during daylight hours and by leaving the location of male pre-dawn singing before full light (reducing the visual signal to hunters). Groups in the Peleonan also fission during non-singing daily activity and rarely engage in play or grooming, enhancing the crypticity of their monochromatic black pelage in the canopy. We also observed a coordinated response to the presence of humans, wherein one adult individual acted as a "decoy" by approaching and distracting human observers, while other group members fled silently in multiple directions. "Decoy" behavior occurred on 31% of 96 encounters with unhabituated Kloss gibbons that detected our presence. "Decoy" individuals may put themselves at risk to increase the survival of related immatures (and adult females with infants) who have a greater risk of predation. We argue that, in combination, these behaviors are an evolved response to a long history of predation by humans. PMID- 25296899 TI - Three-Tesla MR imaging of the elbow in non-symptomatic professional baseball pitchers. AB - OBJECTIVES: To retrospectively evaluate the qualitative and quantitative 3-T MR imaging features of the elbow in non-symptomatic professional baseball pitchers presenting as major league draft picks or trades. MATERIALS AND METHODS: The Institutional Review Board (IRB) approved the HIPPA-compliant study. Informed consent was waived. Twenty-one professional non-symptomatic baseball pitchers (mean age 23, range 18 to 34 years old) underwent 3-T MR imaging of the pitching elbow. Two experienced readers independently performed qualitative (collateral ligaments, tendons, cartilage, bones, ulnar nerve, olecranon fossa, and joint fluid) and quantitative (collateral ligaments and posteromedial plica) evaluation. Descriptive statistics were calculated. RESULTS: Collateral ligament thickening was seen in a high proportion, nearly half, however, without features of full thickness tearing. Tendinosis without tearing was seen in 19 % (4/21) of common extensors. Cartilage abnormalities were infrequent. Bone abnormalities manifested as edema in 24 % (5/21) and humeroulnar osteophytosis. Ulnar nerve signal and/or morphologic abnormalities were seen in a very high proportion, up to 81 % (17/21). The olceranon fat pad showed scarring features in about one third. The median ligament thicknesses in mm measured: 4.6 UCL anterior bundle, 1.8 UCL posterior bundle, 1.9 RCL, 2.5 LUCL, and 0.7 mm anular. The median plica dimensions were 5.3 by 2.2 by 2.7 mm. CONCLUSION: High-resolution 3-T MR imaging frequently shows abnormalities involving the ligaments, tendons, nerves, olecranon fat pad, and bones in non-symptomatic baseball pitchers. PMID- 25296901 TI - Machines that go "ping" may improve balance but may not improve mobility or reduce risk of falls: a systematic review. AB - OBJECTIVE: To determine the effectiveness of computer-based electronic devices that provide feedback in improving mobility and balance and reducing falls. DATA SOURCES: Randomized controlled trials were searched from the earliest available date to August 2013. DATA EXTRACTION: Standardized mean differences were used to complete meta-analyses, with statistical heterogeneity being described with the I squared statistic. The GRADE approach was used to summarize the level of evidence for each completed meta-analysis. Risk of bias for individual trials was assessed with the (Physiotherapy Evidence Database) PEDro scale. DATA SYNTHESIS: Thirty trials were included. There was high-quality evidence that computerized devices can improve dynamic balance in people with a neurological condition compared with no therapy. There was low-to-moderate-quality evidence that computerized devices have no significant effect on mobility, falls efficacy and falls risk in community-dwelling older adults, and people with a neurological condition compared with physiotherapy. CONCLUSION: There is high-quality evidence that computerized devices that provide feedback may be useful in improving balance in people with neurological conditions compared with no therapy, but there is a lack of evidence supporting more meaningful changes in mobility and falls risk. PMID- 25296900 TI - Magnetic resonance analysis of loaded meniscus deformation: a novel technique comparing participants with and without radiographic knee osteoarthritis. AB - OBJECTIVE: To establish a novel method of quantifying meniscal deformation using loaded MRI. More specifically, the goals were to evaluate the (1) accuracy, (2) inter-rater reliability, (3) intra-rater reliability, and (4) scan-rescan reliability. The secondary purpose of this experiment was to evaluate group differences in meniscal deformation in participants with and without radiographic knee OA. MATERIALS AND METHODS: Weight-bearing 3-T MRIs of the knee in full extension and 30 degrees of flexion were processed to create 3D models of meniscal deformation. Accuracy was assessed using a custom-designed phantom. Twenty-one participants either with or without signs of OA were evaluated, and another six participants (14 knees, one subject was scanned twice) underwent repeated imaging to assess scan-rescan reproducibility. Intraclass correlation coefficient (ICC), root-mean squared error (RMSE), and root-mean-square percent coefficient-of-variation (RMS%CV) analyses were performed. Exploratory comparisons were made between those with and without OA to evaluate potential group differences. RESULTS: All variables were found to be accurate with RMSE ranging from 0.08 to 0.35 mm and 5.99 to 14.63 mm(2). Reproducibility of peak anterior-posterior meniscal deformation was excellent (ICC > 0.821; p < 0.013) with RMS%CV for intra-rater ranging from 0.06 to 1.53 % and 0.17 to 1.97 %, inter rater ranging from 0.10 to 7.20 % and 3.95 to 18.53 %, and scan-rescan reliability ranging from 1.531 to 7.890 % and 4.894 to 9.142 %, for distance and area metric, respectively. Participants with OA were found to have significantly greater anterior horn movement of both the medial (p = 0.039) and lateral meniscus (p = 0.015), and smaller flexed medial meniscus outer area (p = 0.048) when compared to controls. CONCLUSIONS: MRI-based variables of meniscus deformation were found to be valid in participants with and without OA. Significant differences were found between those with and without radiographic OA; further study is warranted. PMID- 25296902 TI - Long-term outcome of chronic myeloid leukaemia patients with p210 and p190 co expression at baseline. PMID- 25296903 TI - Direct measurement of beta-agonists in swine hair extract in multiplexed mode by surface-enhanced Raman spectroscopy and microfluidic paper. AB - Bare gold nanoparticles selectively enhance the Raman signal of beta-agnonists in swine hair extract at 780 nm, which enables analysis of beta-agonists in swine hair extract without chemical labeling, purification, or separation. The analysis is multiplexable and the LOD of beta-agonists is around ng/mL in the assistance of microfluidic paper. PMID- 25296904 TI - [Mental disease as disturbance of essential functions]. AB - BACKGROUND: The article defends an interpretation of mental illness as mental dysfunction. It develops a concept in line with the naturalistic viewpoint in the philosophy of medicine. METHODS: The concept of mental function is scrutinized. Functions are regarded as effects of traits that enable an organism to live independently. The significance of this theoretical perspective for the psychiatric practice is discussed. Finally, the developed conceptualization is compared to the current edition of the diagnostic and statistical manual of mental disorders (DSM). RESULTS AND DISCUSSION: It is emphasized that the theoretical conceptualization of mental disorder determines what may justifiably and in a scientifically valid way be deemed a disease entity. Nevertheless, the practical perspective needs an additional element of individual well-being as not every mental dysfunction involves impairment in this respect. It is claimed that the DSM takes a perspective similar to the one defended in this article. PMID- 25296905 TI - [Disease versus disorder. Medical and socio-environmental aspects of mental suffering]. AB - A disease concept should be broad enough to provide social protection for all subjects suffering from this malady but at the same time it needs to be narrow enough to avoid pathologization of behavior that is merely socially undesirable. From a medical perspective a"disease" is present if functions are impaired that are relevant for individual survival. In the field of psychiatry and psychotherapy, such medically relevant functions include the ability to be alert and fully oriented, to ascribe one's own intentions to oneself and to modulate affects according to the situation. Beyond such medically relevant symptoms of a disease, any clinically relevant dysfunction should also be harmful for the individual if a mental malady is to be diagnosed. One such harmful consequence of a disease can be that the person feels ill and suffers from this state, another negative consequence for the individual can be due to an impairment of activities of daily living and social participation. These harmful consequences of a disease are usually discussed under the heading of the"illness experience" and the"sickness aspect" of any disorder. Beyond mental maladies characterized by disease symptoms that are accompanied either by an illness experience or impaired activities of daily living and social participation (sickness), there are many states of human suffering which can be objectified and classified but do not constitute a disease in the medical sense and should more aptly be named a disorder. PMID- 25296906 TI - Upregulated expression of monocyte chemoattractant protein-1 in human periodontal ligament cells induced by interleukin-1beta. AB - BACKGROUND: Root resorption during orthodontic treatment is a complex and sterile inflammatory process, characterized by the recruitment of mononuclear cells in the local periodontal ligament. This study aimed to investigate whether interleukin (IL)-1beta could induce the migration of monocytes through upregulating monocyte chemoattractant protein (MCP)-1 expression in human periodontal ligament cells. METHODS: Human periodontal ligament cells were cultured in medium containing various IL-1beta concentrations. After 24 hours of incubation, the messenger RNA (mRNA) and MCP-1 protein in periodontal ligament cells were detected by reverse transcriptase-polymerase chain reaction and Western blot analysis, respectively. The effect of supernatants of periodontal ligament cells on THP-1 cells was analysed via migration assay. RESULTS: IL-1beta (10 ng/mL and 25 ng/mL) increased the expression of MCP-1 mRNA and protein in periodontal ligament cells (p < 0.05). In addition, the supernatants from the IL 1beta-treated periodontal ligament cells increased the migratory response of THP 1 cells (p < 0.05), which could be blocked by the anti-MCP-1 antibody. CONCLUSIONS: IL-1beta had the potential to induce the migratory response of monocytes via upregulation of the expression of MCP-1 in human periodontal ligament cells and could contribute to orthodontic root resorption. PMID- 25296908 TI - Sb-triggered beta-to-alpha transition: solvothermal synthesis of metastable alpha Cu2Se. AB - Control over phase stabilities during synthesis processes is of great importance for both fundamental studies and practical applications. We describe herein a facile strategy for the synthesis of Cu2Se with phase selectivity through a simple solvothermal method. In the presence and absence of SbCl3, monoclinic alpha-Cu2Se and cubic beta-Cu2Se can be synthesized, respectively. The formation of alpha-Cu2Se requires optimization of the Cu/Se molar ratio in the starting reagents, the reaction temperature, as well as the timing for the addition of SbCl3. Differential scanning calorimetry of the synthesized alpha-Cu2Se has shown that a part of it undergoes a phase transition to beta-Cu2Se at 135 degrees C, and that this phase transition is irreversible on cooling to ambient temperature. Kinetic studies have revealed that in the presence of Sb species the kinetically favored beta-Cu2Se transforms to the thermodynamically favored alpha-Cu2Se. In this beta-to-alpha phase transition process, the distribution of Cu ions in beta Cu2Se, as determined by the Cu/Se ratio and temperature, is likely to play a crucial role. PMID- 25296910 TI - Impedimetric characterization of adsorption of Listeria monocytogenes on the surface of an aluminum-based immunosensor. AB - The impedimetric characteristics of an immunosensor depend on the electrical properties of an immunosensor substrate. The impedimetric characteristics of an immunosensor compared with adsorption of Listeria monocytogenes were investigated on an aluminum surface insulated with an electrically resistive aluminum oxide layer. Antibody for L. monocytogenes (anti-L. monocytogenes) was immobilized on an aluminum surface that was insulated with a native air-formed aluminum oxide layer. The resistance of impedance (R) value of an aluminum-based immunosensor decreased, especially at 10(4) to 10(6) Hz, where the effect of the reactance of impedance (X) was minimal when L. monocytogenes was adsorbed on the immunosensor surface. The R value of the immunosensor at 81 kHz decreased proportionally to the concentration of L. monocytogenes from 1.3 to 4.3 log CFU mL(-1) . The adsorption of L. monocytogenes produced local protrusions on the immunosensor surface, causing physicochemical changes in the ionic layer formed on the immunosensor surface by a sinusoidal electrical signal input, which might help electrical current to flow and cause the R value to decrease. PMID- 25296907 TI - Oxidative and energy metabolism as potential clues for clinical heterogeneity in nucleotide excision repair disorders. AB - Nucleotide excision repair (NER) is an important DNA repair pathway involved in the removal of a wide array of DNA lesions. The absence or dysfunction of NER results in the following distinct disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, UV-sensitive syndrome (UVSS), trichothiodystrophy (TTD), or combined syndromes including XP/CS, XP/TTD, CS/TTD, and COFS/TTD. In addition to their well-characterized role in the NER signaling pathway, NER factors also seem to be important in biological processes that are not directly associated with DNA damage responses, including mitochondrial function and redox homeostasis. The potential causative role of these factors in the large clinical spectrum seen in NER diseases is discussed in this review. PMID- 25296909 TI - Coronary atheroma composition and its association with segmental endothelial dysfunction in non-ST segment elevation myocardial infarction: novel insights with radiofrequency (iMAP) intravascular ultrasonography. AB - Little is known of the relationship between coronary atheroma composition and corresponding endothelial dysfunction. We tested the hypothesis that segmental epicardial vasoreactivity relates to atheroma composition in patients with non-ST segment elevation myocardial infarction (NSTEMI) in vivo. In 23 NSTEMI patients referred for coronary angiography, a non-culprit vessel underwent intracoronary salbutamol (0.30 MUg/min) provocation during automated IVUS pullback. A 40 MHz rotational IVUS catheter delivered radiofrequency signals at constant 67 MUm intervals via a custom-built IVUS console (iMAP, iLAB, Boston Scientific). Macrovascular response [change in segmental lumen volume (SLV) at baseline and following salbutamol], percent atheroma volume (PAV) and tissue composition was evaluated in 187 contiguous non-overlapping 5 mm coronary segments. Compared with segments that dilated, constrictive segments showed similar SLV, but greater vessel volumes and PAV at baseline. The extent of necrotic and lipidic plaque was significantly greater in constrictive segments, whereas fibrotic plaque content was significantly greater in segments that dilated. Calcific plaque content did not relate to endothelium-dependent vasoreactivity. The change in SLV correlated inversely with the amount of lipidic and necrotic plaque (both r = -0.23, p = 0.002), and directly with fibrotic plaque content (r = 0.23, p = 0.002). In a multivariable model, the extent of both lipidic and necrotic plaque independently associated with segmental vasoconstriction (beta = 1.2, p = 0.023; beta = 0.66, p = 0.027). Following NSTEMI, both lipidic and necrotic plaque content each associate with segmental endothelial dysfunction. The link between plaque composition and vessel reactivity provides a mechanistic basis of the pathogenesis associated with vulnerable plaque in humans in vivo. PMID- 25296913 TI - 'Stratified' approach to individualized anaesthetic care. PMID- 25296912 TI - Rescuing the obese or burned airway: are conventional training manikins adequate? A simulation study. AB - BACKGROUND: Percutaneous tracheal access is required in more than 40% of major airway emergencies, and rates of failure are high among anaesthetists. Supraglottic airway management is more likely to fail in patients with obesity or neck pathology. Commercially available manikins may aid training. In this study, we modified a standard 'front of neck' manikin and evaluated anaesthetists' performance of percutaneous tracheal access. METHODS: Two cricothyroidotomy training manikins were modified using sections of belly pork to simulate a morbidly obese patient and an obese patient with neck burns. An unmodified manikin was used to simulate a slim patient. Twenty consultant anaesthetists were asked to manage a 'can't intubate, can't ventilate' scenario involving each of the three manikins. Outcome measures were success using their chosen technique and time to first effective breath. RESULTS: Success rates using first-choice equipment were: 'slim' manikin 100%, 'morbidly obese' manikin 60%, and 'burned obese' manikin 77%. All attempts on the 'slim' manikin succeeded within 240 s, the majority within 120 s. In attempts on the 'morbidly obese' manikin, 60% succeeded within 240 s and 20% required more than 720 s. All attempts on the 'burned obese' manikin succeeded within 180 s. CONCLUSIONS: Significantly greater technical difficulty was experienced with our 'morbidly obese' manikin compared with the unmodified manikin. Failure rates and times to completion were considerably more consistent with real-life reports. Modifying a standard manikin to simulate an obese patient is likely to better prepare anaesthetists for this challenging situation. Development of a commercial manikin with such properties would be of value. PMID- 25296911 TI - Genomic and transcriptome analyses reveal that MAPK- and phosphatidylinositol signaling pathways mediate tolerance to 5-hydroxymethyl-2-furaldehyde for industrial yeast Saccharomyces cerevisiae. AB - The industrial yeast Saccharomyces cerevisiae is a traditional ethanologenic agent and a promising biocatalyst for advanced biofuels production using lignocellulose materials. Here we present the genomic background of type strain NRRL Y-12632 and its transcriptomic response to 5-hydroxymethyl-2-furaldehyde (HMF), a commonly encountered toxic compound liberated from lignocellulosic biomass pretreatment, in dissecting the genomic mechanisms of yeast tolerance. Compared with the genome of laboratory model strain S288C, we identified more than 32,000 SNPs in Y-12632 with 23,000 missense and nonsense SNPs. Enriched sequence mutations occurred for genes involved in MAPK- and phosphatidylinositol (PI)- signaling pathways in strain Y-12632, with 41 and 13 genes containing non synonymous SNPs, respectively. Many of these mutated genes displayed consistent up-regulated signature expressions in response to challenges of 30 mM HMF. Analogous single-gene deletion mutations of these genes showed significantly sensitive growth response on a synthetic medium containing 20 mM HMF. Our results suggest at least three MAPK-signaling pathways, especially for the cell-wall integrity pathway, and PI-signaling pathways to be involved in mediation of yeast tolerance against HMF in industrial yeast Saccharomyces cerevisiae. Higher levels of sequence variations were also observed for genes involved in purine and pyrimidine metabolism pathways. PMID- 25296914 TI - Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. AB - In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research. PMID- 25296915 TI - Hippocampal synaptic connectivity in phenylketonuria. AB - In humans, lack of phenylalanine hydroxylase (Pah) activity results in phenylketonuria (PKU), which is associated with the development of severe mental retardation after birth. The underlying mechanisms, however, are poorly understood. Mutations of the Pah gene in Pah(enu2)/c57bl6 mice result in elevated levels of phenylalanine in serum similar to those in humans suffering from PKU. In our study, long-term potentiation (LTP) and paired-pulse facilitation, measured at CA3-CA1 Schaffer collateral synapses, were impaired in acute hippocampal slices of Pah(enu2)/c57bl6 mice. In addition, we found reduced expression of presynaptic proteins, such as synaptophysin and the synaptosomal associated protein 25 (SNAP-25), and enhanced expression of postsynaptic marker proteins, such as synaptopodin and spinophilin. Stereological counting of spine synapses at the ultrastructural level revealed higher synaptic density in the hippocampus, commencing at 3 weeks and persisting up to 12 weeks after birth. Consistent effects were seen in response to phenylalanine treatment in cultures of dissociated hippocampal neurones. Most importantly, in the hippocampus of Pah(enu2)/c57bl6 mice, we found a significant reduction in microglia activity. Reorganization of hippocampal circuitry after birth, namely synaptic pruning, relies on elimination of weak synapses by activated microglia in response to neuronal activity. Hence, our data strongly suggest that reduced microglial activity in response to impaired synaptic transmission affects physiological postnatal remodelling of synapses in the hippocampus and may trigger the development of mental retardation in PKU patients after birth. PMID- 25296916 TI - CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. AB - Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonus-dystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation were studied using whole-cell and single channel patch recordings. High-resolution analyses at the single-channel level showed that, when open, R1389H CaV2.2 channels carried less current compared with WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique myoclonus-dystonia-like syndrome associated with cardiac arrhythmias. PMID- 25296919 TI - Acute movement disorders in children: experience from a developing country. AB - We describe acute movement disorders in 92 children, aged 5 days to 15 years, from an Indian tertiary hospital. Eighty-nine children had hyperkinetic movement disorders, with myoclonus in 25, dystonia in 21, choreoathetosis in 19, tremors in 15, and tics in 2. Tetany and tetanus were seen in 5 and 2 children, respectively. Hypokinetic movement disorders included acute parkinsonism in 3 children. Noninflammatory and inflammatory etiology were present in 60 and 32 children, respectively. Benign neonatal sleep myoclonus in 16 and opsoclonus myoclonus syndrome in 7 accounted for the majority of myoclonus cases. Vitamin B12 deficiency in 13 infants was the most common cause of tremors. Rheumatic fever and encephalitis were the most common causes of acute choreoathetosis. Acute dystonia had metabolic etiology in 6 and encephalitis and drugs in 3 each. Psychogenic movement disorders were seen in 4 cases only, although these patients may be underreported. PMID- 25296917 TI - Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. AB - Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome wide significantly associated with both endometriosis and fat distribution (waist to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 * 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 * 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 * 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other. PMID- 25296920 TI - Assessment of cognitive function in children with beta-thalassemia major: a cross sectional study. AB - Multiple risk factors contribute to cognitive impairment in children with beta thalassemia major. For a more refined understanding of this issue, we attempted to evaluate cognitive function in beta-thalassemia major patients and identify the relationship between possible cognitive dysfunction and the following: demography, transfusion and chelation characteristics, iron overload, and disease complications. We studied 100 beta-thalassemia major children and 100 healthy controls who matched well in terms of age, sex, and socioeconomic status. All participants underwent psychometric assessment using Wechsler Intelligence Scale for Children-Third Edition, Arabic version. The mean Full-Scale IQ and Performance IQ of patients were significantly lower than those of controls, whereas no significant difference was found for Verbal IQ. No significant relationship existed between IQ and any of the assessed parameters. We concluded that Performance IQ, not Verbal IQ, was significantly affected in beta thalassemia major patients, but there was no clear association between IQ and any of the parameters. PMID- 25296918 TI - Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T SNCA overexpression. AB - The common age-related neurodegeneration of Parkinson's disease can result from dominant causes like increased dosage of vesicle-associated alpha-synuclein (SNCA) or recessive causes like deficiency of mitophagy factor PINK1. Interactions between these triggers and their convergence onto shared pathways are crucial, but currently conflicting evidence exists. Here, we crossed previously characterized mice with A53T-SNCA overexpression and with Pink1 deletion to generate double mutants (DMs). We studied their lifespan and behavior, histological and molecular anomalies at late and early ages. DM animals showed potentiated phenotypes in comparison with both single mutants (SMs), with reduced survival and strongly reduced spontaneous movements from the age of 3 months onwards. In contrast to SMs, a quarter of DM animals manifested progressive paralysis at ages >1 year and exhibited protein aggregates immunopositive for pSer129-SNCA, p62 and ubiquitin in spinal cord and basal brain. Brain proteome quantifications of ubiquitination sites documented altered degradation of SNCA and the DNA-damage marker H2AX at the age of 18 months. Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at the age of 6 weeks, which were absent from SMs. The observed downregulations for Dapk1, Dcaf17, Rab42 and the novel SNCA-marker Lect1 as well as the upregulations for Dctn5, Mrpl9, Tmem181a, Xaf1 and H2afx reflect changes in ubiquitination, mitochondrial/synaptic/microtubular/cell adhesion dynamics and DNA damage. Thus, our study confirmed that SNCA-triggered neurotoxicity is exacerbated by the absence of PINK1 and identified a novel molecular signature that is detectable early in the course of this double pathology. PMID- 25296921 TI - Amplitude-integrated electroencephalographic activity and middle cerebral artery Doppler flow measurements in preterm small for gestational age infants. AB - Amplitude-integrated encephalography (EEG) is frequently used in neonatal intensive care units to monitor brain functions. Its bedside application and easy interpretation are the most important features. Brain development of small for gestational age infants can be affected by intrauterine chronic hypoxia. The current study aimed to evaluate cerebral functions of small for gestational age infants by means of amplitude-integrated EEG. Thirty- to 34-week-old 22 small for gestational age and 27 appropriate for gestational age preterm infants were included in the study. The mode of delivery, gender, birth weight, and Apgar scores of the patients were recorded. Following middle cerebral artery mean velocity measurement with cranial Doppler at the 24th hour of birth, an amplitude integrated EEG recording was performed on all infants, for a period of 4 to 24 hours. Small for gestational age infants had significantly higher middle cerebral artery mean velocity than appropriate for gestational age infants (21.09 +/- 4.25 vs 17.8 +/- 4.07; P = .029). The amplitude-integrated EEG recordings showed lower "lower border of quiet sleep" and total Burdjalov score in small for gestational age infants when compared with appropriate for gestational age infants (2.5 [1 3.25] uV vs 3 [2.75-4] uV; P = .04, 8 [6-10], 9 [9-11]; P = .04, respectively). Increased middle cerebral artery blood flow observed in small for gestational age infants might be a marker of chronic intrauterine hypoxia to which these infants were exposed. These infants demonstrated a more immature pattern of amplitude integrated EEG. PMID- 25296922 TI - Deletion of 16q24.1 supports a role for the ATP2C2 gene in specific language impairment. AB - A 10-year-old boy presented with a history of significant delay in language acquisition as well as receptive and expressive language impairment that persisted into elementary school. In school, he exhibited difficulty with reading comprehension, telling and understanding narratives, and making inferences. Other aspects of his neurodevelopment were normal, with no history of significant medical concerns. He did not have hearing impairment, oromotor dysfunction, or specific neurologic abnormalities. He did not meet testing criteria for autism. Chromosomal microarray analysis and quantitative polymerase chain reaction determined that he had a de novo 159-kilobase deletion of chromosome 16q24.1 that included the ATP2C2 gene. ATP2C2 is a known candidate gene for specific language impairment and is postulated to have neurobiological significance in memory related circuits. Our patient's language deficits were consistent with a global type of specific language impairment impacting language comprehension, formulation, semantics, syntax, and phonology attributed to his de novo chromosome deletion. PMID- 25296923 TI - Pediatric Concussion, Cognitive Rest and Position Statements, Practice Parameters, and Clinical Practice Guidelines. AB - There are several organizations that have published statements related to concussion management especially as it relates to cognitive rest. A review of these statements reveals that this issue is more complicated than proposed. Further research is needed to establish (1) the type and severity of concussion symptoms that may benefit from cognitive rest, if any, and the (2) type, degree, and duration of cognitive rest. Parents need to be counseled that definitive recommendations about cognitive rest are not currently based on sufficient research to make specific recommendations for every child with a concussion. This issue has important clinical and medicolegal ramifications to practitioners. PMID- 25296924 TI - The prevalence of migraine and tension-type headache among schoolchildren in Kayseri, Turkey: an evaluation of sensitivity and specificity using multivariate analysis. AB - This study aimed to determine the prevalence as well as psychosocial and demographic features of migraine and tension-type headache among school children between the ages of 7 and 17, and using the International Classification of Headache Disorders II. The study was conducted during the questionnaire phase and the interview phase. The prevalence of recurrent headache was 47.5%, whereas that of primary recurrent headache was 21%. The estimated prevalence rates of migraine and tension-type headache were 7.2% and 7.8%, respectively. Unilateral headache, throbbing-type headache, severe headache, and the severity of the headache with physical activity were specific for migraine. Headache was significantly higher in first-degree relatives of the children with migraine compared to the children with tension-type headache (P < .0001). We determined the prevalence rates of migraine and tension-type headache and revealed the characteristics as well as the psychosocial and demographic features of migraine and tension-type headache. Sensitivity, specificity, and multivariate analysis were also evaluated. PMID- 25296925 TI - Pyridox(am)ine-5-Phosphate Oxidase Deficiency Treatable Cause of Neonatal Epileptic Encephalopathy With Burst Suppression: Case Report and Review of the Literature. AB - Pyridox(am)ine-5-phosphate oxidase deficiency is an autosomal recessive disorder of pyridoxine metabolism. Intractable neonatal epileptic encephalopathy is the classical presentation. Pyridoxal-5-phosphate or pyridoxine supplementation improves symptoms. We report a patient with myoclonic and tonic seizures at the age of 1 hour. Pyridoxal-5-phosphate was started on the first day of life and seizures stopped at the age of 3 days, but encephalopathy persisted for 4 weeks. She had normal neurodevelopmental outcome at the age of 12 months on pyridoxal-5 phosphate monotherapy. She had novel homozygous pathogenic frameshift mutation (c.448_451del;p.Pro150Argfs*27) in the PNPO gene. Long-lasting encephalopathy despite well-controlled clinical seizures does neither confirm nor exclude pyridox(am)ine-5-phosphate oxidase deficiency. Normal neurodevelopmental outcome of our patient emphasizes the importance of pyridoxal-5-phosphate treatment. Pyridox(am)ine-5-phosphate oxidase deficiency should be included in the differential diagnosis of Ohtahara syndrome and neonatal myoclonic encephalopathy as a treatable underlying cause. In addition, we reviewed the literature for pyridox(am)ine-5-phosphate oxidase deficiency and summarized herein all confirmed cases. PMID- 25296926 TI - Pediatric Cerebral Palsy in Africa: Where Are We? AB - Cerebral palsy is the most common cause of physical disability in children worldwide. However, little is reported on this condition in the African context. Doctors from 22 countries in Africa, and representatives from a further 5 countries outside Africa, met to discuss the challenges in the evaluation and management of children with cerebral palsy in Africa and to propose service needs and further research. Basic care is limited by the poor availability of diagnostic facilities or medical personnel with experience and expertise in managing cerebral palsy, exacerbated by lack of available interventions such as medications, surgical procedures, or even regular therapy input. Relevant guidelines are lacking. In order to guide services for children with existing disabilities, to effectively target the main etiologies and to develop preventive strategies for the continent, research priorities must include multicenter collaborative studies looking at the prevalence, risk factors, and treatment of cerebral palsy. PMID- 25296927 TI - Comparative Study of Refractive Errors, Strabismus, Microsaccades, and Visual Perception Between Preterm and Full-Term Children With Infantile Cerebral Palsy. AB - The purpose of this study was to examine the refractive status, orthoptic status and visual perception in a group of preterm and another of full-term children with cerebral palsy, in order to investigate whether prematurity has an effect on the development of refractive errors and binocular disorders. A hundred school aged children, 70 preterm and 30 full-term, with congenital cerebral palsy were examined. Differences for hypermetropia, myopia, and emmetropia were not statistically significant between the 2 groups. Astigmatism was significantly increased in the preterm group. The orthoptic status was similar for both groups. Visual perception was markedly reduced in both groups, but the differences were not significant. In conclusion, children with cerebral palsy have impaired visual skills, leading to reading difficulties. The presence of prematurity does not appear to represent an additional risk factor for the development of refractive errors and binocular disorders. PMID- 25296928 TI - Cognitive Improvement of Attention and Inhibition in the Late Afternoon in Children With Attention-Deficit Hyperactivity Disorder (ADHD) Treated With Osmotic-Release Oral System Methylphenidate. AB - Long-acting medications have been developed and approved for use in the treatment of attention-deficit hyperactivity disorder (ADHD). These compounds are intended to optimize and maintain symptoms control throughout the day. We tested prolonged effects of osmotic-release oral system methylphenidate on both attention and inhibition, in the late afternoon. A double-blind, randomized, placebo-controlled study was conducted in 36 boys (7-12 years) with ADHD and 40 typically developing children. The ADHD children received an individualized dose of placebo or osmotic release oral system methylphenidate. They were tested about 8 hours after taking with 2 continuous performance tests (continuous performance test-X [CPT-X] and continuous performance test-AX [CPT-AX]) and a counting Stroop. A positive effect of osmotic-release oral system methylphenidate was present in CPT-AX with faster and less variable reaction times under osmotic-release oral system methylphenidate than under placebo, and no difference with typically developing children. In the counting Stroop, we found a decreased interference with osmotic release oral system methylphenidate but no difference between children with ADHD under placebo and typically developing children. PMID- 25296929 TI - Crossing the line: increasing body size in a trans-Wallacean lizard radiation (Cyrtodactylus, Gekkota). AB - The region between the Asian and Australian continental plates (Wallacea) demarcates the transition between two differentiated regional biotas. Despite this striking pattern, some terrestrial lineages have successfully traversed the marine barriers of Wallacea and subsequently diversified in newly colonized regions. The hypothesis that these dispersals between biogeographic realms are correlated with detectable shifts in evolutionary trajectory has however rarely been tested. Here, we analyse the evolution of body size in a widespread and exceptionally diverse group of gekkotan lizards (Cyrtodactylus), and show that a clade that has dispersed eastwards and radiated in the Australopapuan region appears to have significantly expanded its body size 'envelope' and repeatedly evolved gigantism. This pattern suggests that the biotic composition of the proto Papuan Archipelago provided a permissive environment in which new colonists were released from evolutionary constraints operating to the west of Wallacea. PMID- 25296930 TI - Demonstrating frequency-dependent transmission of sarcoptic mange in red foxes. AB - Understanding the relationship between disease transmission and host density is essential for predicting disease spread and control. Using long-term data on sarcoptic mange in a red fox Vulpes vulpes population, we tested long-held assumptions of density- and frequency-dependent direct disease transmission. We also assessed the role of indirect transmission. Contrary to assumptions typical of epidemiological models, mange dynamics are better explained by frequency dependent disease transmission than by density-dependent transmission in this canid. We found no support for indirect transmission. We present the first estimates of R0 and age-specific transmission coefficients for mange in foxes. These parameters are important for managing this poorly understood but highly contagious and economically damaging disease. PMID- 25296931 TI - Female social preference for males that have evolved via monogamy: evidence of a trade-off between pre- and post-copulatory sexually selected traits? AB - When females mate with multiple males both pre- and post-copulatory sexual selections occur. It has been suggested that females benefit from polyandry when better-quality males are successful in sperm competition and sire high-quality offspring. Indeed, studies of experimental evolution have confirmed that sperm competition selects for both increased ejaculate quality and elevated offspring viability. Fewer investigations have explored whether these fitness benefits are evident beyond early life-history stages. Here, I used house mice (Mus domesticus) from selection lines that had been evolving for 25 generations under either polygamy or monogamy to test whether females preferred males from lines that had evolved with sperm competition. Males from the polygamous lines had previously been shown to achieve a fitness advantage under semi-natural conditions, deeming them to be of high genetic quality and leading to the a priori expectation that females would prefer males that had evolved with sperm competition compared with males that had not. Contrary to expectation, the data showed that sexually receptive females spent more time associating with males from the monogamous lines. This unexpected but interesting result is discussed in relation to sperm competition theory that predicts a trade-off between male investment in pre- and post-copulatory sexually selected traits. PMID- 25296933 TI - Parents' help-seeking behaviours during acute childhood illness at home: A contribution to explanatory theory. AB - Uncertainty and anxiety surround parents' decisions to seek medical help for an acutely ill child. Consultation rates for children are rising, yet little is known about factors that influence parents' help-seeking behaviours. We used focus groups and interviews to examine how 27 parents of children under five years, from a range of socioeconomic groups in the East Midlands of England, use information to make decisions during acute childhood illness at home. This article reports findings elucidating factors that influence help-seeking behaviours. Parents reported that decision-making during acute childhood illness was influenced by a range of personal, social and health service factors. Principal among these was parents' concern to do the right thing for their child. Their ability to assess the severity of the illness was influenced by knowledge and experience of childhood illness. When parents were unable to access their general practitioner (GP), feared criticism from or had lost trust in their GP, some parents reported using services elsewhere such as Accident and Emergency. These findings contribute to explanatory theory concerning parents' help-seeking behaviours. Professional and political solutions have not reduced demand; therefore, collaborative approaches involving the public and professionals are now needed to improve parents' access to information. PMID- 25296932 TI - Sonic hedgehog signalling proteins are frequently expressed in retinoblastoma and are associated with aggressive clinicopathological features. AB - AIMS: This study aimed to examine the expression of Sonic hedgehog (SHH) signalling proteins in retinoblastoma and to evaluate its clinical significance. METHODS: Seventy-nine enucleated retinoblastoma tumours were investigated immunohistochemically using antibodies against SHH pathway proteins, such as SHH, glioma-associated oncogene homologue (GLI) 1, GLI2, GLI3 and ABC binding cassette G2 (ABCG2). Western blotting of SHH signalling proteins was performed in two retinoblastoma cell lines. RESULTS: SHH was expressed in most retinoblastoma cases (78 of 79, 98.7%), with 21 cases (26.6%) showing strong expression. GLI1 and GLI2 were also frequently expressed: 67 of 78 cases (85.9%) and 71 of 77 cases (92.2%), respectively. GLI3, a transcriptional repressor, was expressed at low levels in 23 of the 78 cases (29.5%). High ABCG2 expression was found in 23 of the 78 cases (29.5%). High expression levels of these proteins in retinoblastoma cell lines were confirmed by western blotting. The expression of SHH was associated with advanced stages, local invasion and metastasis (all p<0.05). CONCLUSIONS: SHH signalling molecules were frequently expressed in retinoblastoma tumour cells, and high SHH expression was closely related to an advanced disease status. Our results suggest that the SHH signalling pathway may play a role in the progression of retinoblastoma. PMID- 25296934 TI - A comparison of the quality of care in accident and emergency departments in England and the Netherlands as experienced by patients. AB - BACKGROUND: Measuring patients' experiences to determine health-care performance and quality of care from their perspective can provide valuable evidence for international improvements in the quality of care. We compare patients' experiences in Accident & Emergency departments (A&E) in England and the Netherlands and discuss the usefulness of this comparison. METHODS: A cross sectional survey was conducted among patients attending A&Es aged 18 years and older. In England, 134 A&Es were surveyed. In the Netherlands, nine hospitals participated in the study. Main outcome measures were patients' experiences represented by six domain scores aggregated on the country level or on the A&E level. RESULTS: In England, 43 892 completed questionnaires were received (40%). In the Netherlands, 1865 completed questionnaires were received (42%). Three of six domain scores were significantly higher for patients in the Netherlands: 'waiting time' [mean scores of 73.8 (NL) versus 67.2 (ENG)], 'doctors and nurses' [mean scores of 85.7 (NL) versus 80.6 (ENG)] and 'your care and treatment' [mean scores of 82.6 (NL) and 80.2 (ENG)]. The variance among the English A&Es was large. The best and worst practices on five domains were English. CONCLUSIONS: The mean quality of care in the A&E appeared to be better in the Netherlands on three domains, but the best practices were English A&Es. The within-country differences between A&Es were much larger than differences between countries. Healthcare performance in the A&E can be compared between countries by surveying patients' experiences, and there seems much to learn across A&Es both within and among countries. PMID- 25296935 TI - A new methodology for assessing health policy and systems research and analysis capacity in African universities. AB - BACKGROUND: The importance of health policy and systems research and analysis (HPSR+A) has been increasingly recognised, but it is still unclear how most effectively to strengthen the capacity of the different organisations involved in this field. Universities are particularly crucial but the expansive literature on capacity development has little to offer the unique needs of HPSR+A activity within universities, and often overlooks the pivotal contribution of capacity assessments to capacity strengthening. METHODS: The Consortium for Health Policy and Systems Analysis in Africa 2011-2015 designed and implemented a new framework for capacity assessment for HPSR+A within universities. The methodology is reported in detail. RESULTS: Our reflections on developing and conducting the assessment generated four lessons for colleagues in the field. Notably, there are currently no published capacity assessment methodologies for HPSR+A that focus solely on universities - we report a first for the field to initiate the dialogue and exchange of experiences with others. Second, in HPSR+A, the unit of assessment can be a challenge, because HPSR+A groups within universities tend to overlap between academic departments and are embedded in different networks. Third, capacity assessment experience can itself be capacity strengthening, even when taking into account that doing such assessments require capacity. CONCLUSIONS: From our experience, we propose that future systematic assessments of HPSR+A capacity need to focus on both capacity assets and needs and assess capacity at individual, organisational, and systems levels, whilst taking into account the networked nature of HPSR+A activity. A genuine partnership process between evaluators and those participating in an assessment can improve the quality of assessment and uptake of results in capacity strengthening. PMID- 25296936 TI - Conclusions of the Worldwide Integrated Assessment on the risks of neonicotinoids and fipronil to biodiversity and ecosystem functioning. PMID- 25296937 TI - Mass burden and estimated flux of heavy metals in Pakistan coast: sedimentary pollution and eco-toxicological concerns. AB - Heavy-metal contamination in coastal areas poses a serious threat to aquatic life and public health due to their high toxicity and bio-accumulation potential. In the present study, levels of different heavy metals (Cu, Cd, Cr, Ni, Co, Pb, Zn, and Mn), their spatial distribution, geochemical status, and enrichment indices (Cu, Cd, Cr, Ni, Co, Pb, Zn) were investigated in the sediment samples from 18 coastal sites of Pakistan. The analyses of coastal sediments indicated the presence of heavy metals in order such as Cr > Zn > Cu > Pb > Ni > Mn > Co > Cd. Geo-accumulation index (I geo), enrichment factor (EF), and contamination factor (CF) showed diverse range in heavy-metal enrichment site by site. Pollution load index (PLI) has shown that average pollution load along the entire coastal belt was not significant. Based on the mean effect range medium quotient, coastal sediments of Pakistan had 21% probability of toxicity. The estimated sedimentary load of selected heavy metals was recorded in the range of 0.3-44.7 g/cm(2)/year, while the depositional flux was in the range of 0.07-43.5 t/year. Heavy-metal inventories of 9.8 * 10(2)-3.8 * 10(5) t were estimated in the coastal sediments of Pakistan. The enrichment and contamination factors (EF and CF) suggested significant influence of anthropogenic and industrial activities along the coastal belt of Pakistan. PMID- 25296938 TI - Influence of fermented tannery solid waste on morphological, biochemical, yield and nutritional responses of tomato plants. AB - The non-tanned proteinaceous tannery solid waste animal fleshing (ANFL), containing high nutritive value, was hydrolyzed using bacteria Selenomonas ruminantium HM000123 through submerged (SmF) and solid-state (SSF) fermentation processes. In addition, the effects of ANFL fermentative hydrolysate on growth, yield and biochemical properties of tomato plants were investigated. The treatments included T1 (SmF-ANFL), T2 (SSF-ANFL), T3 (recommended dose of NPK fertilizers) and a control without any amendment. Hydrolysates of both SmF-ANFL and SSF-ANFL treatments increased the biomass and yield as evidenced by plant height, stem girth, number of leaves and fruit yield when compared with both NPK and control plants. In this 90-day study, significant (p <= 0.05) changes were observed in SSF-ANFL treated plants compared to the other treatments. Protein profile analyzed through SDS-PAGE indicates the expression of a high molecular weight protein (205 kDa) and other proteins in the leaves of the SSF-ANFL treated plants. Overall results revealed that SSF-ANFL can be successfully utilized as a fertilizer particularly for cultivating tomato plants. PMID- 25296940 TI - One in three people worldwide is at risk of ill health from household air pollution. PMID- 25296939 TI - Use of different organic wastes as strategy to mitigate the leaching potential of phenylurea herbicides through the soil. AB - In this study, the leaching of 14 substituted phenylurea herbicides (PUHs) through disturbed soil columns packed with three different soils was investigated in order to determine their potential for groundwater pollution. Simultaneously, a series of experiments were conducted to demonstrate the effect of four different organic wastes (composted sheep manure (CSM), composted pine bark (CPB), spent coffee grounds (SCG) and coir (CR)) on their mobility. All herbicides, except difenoxuron, showed medium/high leachability through the unamended soils. In general, addition of agro-industrial and composted organic wastes at a rate of 10% (w/w) increased the adsorption of PUHs and decreased their mobility in the soil, reducing their leaching. In all cases, the groundwater ubiquity score (GUS) index was calculated for each herbicide on the basis of its persistence (as t 1/2) and mobility (as K OC). The results obtained point to the interest in the use of agro-industrial and composted organic wastes in reducing the risk of groundwater pollution by pesticide drainage. PMID- 25296941 TI - Perspectives on Communication and Participation in Research Notification Focus Groups. AB - Researchers are slowly acknowledging an ethical obligation to inform research participants about study findings. Research notification may help participants become aware of and manage potential health risks. Scholars and practitioners have acknowledged the need for better understanding of this process. This study investigates transcripts of focus groups conducted to gauge audience reactions to notification materials that communicate scientific research findings about occupational exposures. Focus groups are a useful way to tailor notification materials to audiences, but we caution that transmission models of communication used in risk research may obscure the full value of focus groups. The emphasis on translating scientific communication into "lay" language may overlook how scientists and lay audiences can work together to bridge differences in language, experiences, goals, and orientations toward health. This study demonstrates limitations in scientific risk communication that minimize participation in communicating science. The conclusion provides instructive insights for strengthening the process of communicating science. PMID- 25296942 TI - Schistosomiasis manifesting as a colon polyp: a case report. AB - INTRODUCTION: Schistosomiasis is a rare disease with a common intestinal involvement. However, colon polyps associated with Schistosoma in the absence of inflammation have rarely been reported, especially in young people; this is the first case with the following presentation. CASE PRESENTATION: We describe the case of a 20-year-old Ethiopian woman living in Lebanon who presented with nonspecific abdominal symptoms. Her biochemical profile was normal in addition to the results of her stool and urine tests. A colonoscopy showed normal colonic mucosa but surprisingly a large pedunculated polyp was found in her ascending colon. Pathology revealed a hamartomatous polyp but it was full of partially calcified parasitic eggs of Schistosoma mansoni compatible with chronic schistosomiasis. CONCLUSIONS: She was treated with two doses of praziquantel and showed immediate marked clinical improvement. This unusual case will give us the opportunity to discuss schistosomiasis, its occurrence in colon polyps, clinical significance and the various means of management. PMID- 25296944 TI - Laparoscopic distal pancreatectomy: Educating surgeons about advanced laparoscopic surgery. AB - INTRODUCTION: Laparoscopic distal pancreatectomy (Lap-DP) has been recognized worldwide as a feasible and highly beneficial procedure. The aim of this study is to investigate whether Lap-DP techniques are being implemented safely by surgeons training to perform this procedure. METHODS: We retrospectively compared the perioperative outcomes of Lap-DP in patients operated on by the surgeon originating this procedure at our hospital (expert surgeon group [E group], n = 47) and patients operated on by surgeons training to perform this procedure (training surgeons group [T group], n = 53). RESULTS: The median operating times for the E group and T group were 321 min (range, 150-653 min) and 314 min (range, 173-629 min), respectively; these times were not significantly different (P = 0.4769). The median blood loss in the T group (100 mL; range, 0-1950 mL) was significantly smaller than in the E group (280 mL; range, 0-1920 mL) (P = 0.0003). There were no significant intergroup differences in other operative results: combined operation ratio, spleen- and splenic vessels-preserving ratio, hand-assisted procedure ratio, and the ratio of transition to open. The frequency of pancreatic fistulas in the E group and T group was 12.8% and 16.9%, respectively; these rates were not significantly different (P = 0.5886). There were no significant differences between the two groups in terms of other complications and reoperation rates. The median hospital stay for the E group was significantly shorter than for the T group (10 vs 13 days; P = 0.0307). CONCLUSION: This retrospective analysis shows that teaching safe Lap-DP techniques to surgeons is reflected in stable perioperative outcomes. PMID- 25296945 TI - Monitoring ASA and P2Y12-specific platelet inhibition--comparison of conventional (single) and multiple electrode aggregometry. AB - OBJECTIVE: Several platelet function test systems exist for the evaluation of the platelet inhibitory effect in patients on P2Y12 inhibitors and/or acetylsalicylic acid (ASA, aspirin) therapy. Studies comparing different available assays found only a poor correlation. The objective of the present study was to evaluate the correlation and agreement between single electrode (SEA) and multiple electrode (MEA) aggregometry. METHODS AND RESULTS: In whole blood arachidonic acid (AA) and adenosine diphosphate (ADP)-induced platelet aggregation was measured simultaneously using SEA (Chrono-Log) and MEA (Multiplate). We analyzed a total of 226 measurements taken from 58 patients on single ASA therapy or dual antiplatelet therapy with ASA and a thienopyridine. A cut-off value for clopidogrel/prasugrel high on-treatment platelet reactivity (HPR) of > 47 units (U) was chosen for MEA testing using hirudin and > 5 Ohm for SEA with citrate anticoagulated blood samples. The respective cut-off values for ASA HPR were > 30 U for the MEA assay and > 1 Ohm for SEA testing. There was a good correlation of the prevalence of thienopyridine-HPR in both whole blood assays (Spearman rank correlation coefficient r = 0.698) and a good inter-rate accordance (Cohen's Kappa statistic kappa = 0.648). For AA-induced aggregation, the correlation of the results obtained was significant (r = 0.536; p < 0.001) and detecting ASA-HPR revealed a moderate (kappa = 0.482) correlation between both impedance aggregometry assays. CONCLUSION: Platelet function testing using SEA and MEA provided both good accordance and correlation and therefore study results obtained by these two assays similarly enabled the detection of HPR of thienopyridine (and ASA) therapy. PMID- 25296946 TI - Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis. AB - The original definition of atypical antipsychotic drugs (APD) was drugs that are effective against positive symptoms in schizophrenia with no or little extrapyramidal symptoms (EPS). However, atypical APD have been reported to be more effective for cognitive dysfunction and negative symptoms in schizophrenia than typical APD, which expands the definition of 'atypicality'. This article provides a critical review of the pharmacology of atypical APD, especially from the viewpoint of receptor binding profiles and neurotransmitter regulations as well as neuroprotection and neurogenesis. A variety of serotonin (5-HT) receptors, such as 5-HT2A / 2C , 5-HT1A , 5-HT6 and 5-HT7 receptors, may contribute to the mechanisms of action of 'atypicality'. The dopaminergic modulations, including a low affinity for dopamine D2 receptors and a partial D2 receptor agonistic action, and glutamatergic regulations may also be involved in the pharmacological backgrounds of 'atypicality'. Atypical APD, but not typical APD, may facilitate cortical neuroprotection and hippocampal neurogenesis, which might be a part of the action mechanisms of atypical APD. The facilitation of cortical neuroprotection and hippocampal neurogenesis induced by atypical APD might be mediated by an increase in the Ser9 phosphorylation of glycogen synthase kinase-3beta (GSK-3beta). The stimulation of 5-HT1A receptors and/or the blockade of 5-HT2 receptors, which is characteristic of atypical APD, might increase Ser9 phosphorylation of GSK-3beta. Moreover, atypical APD increase brain-derived neurotrophic factor (BDNF) levels. BDNF increases Ser9 phosphorylation of GSK 3beta and has neuroprotective and neurogenic effects, as in the case of atypical APD. These findings suggest that GSK-3beta might play a role in the action mechanisms of atypical APD, in both the 5-HT-dependent and BDNF-dependent mechanisms. PMID- 25296948 TI - When hepatoma rupture happens in situs inversus totalis: side matters. AB - The authors reported a 73-year-old alcoholic man with previously-unrecognized situs inversus totalis suffering from left upper quadrant pain. Acute myocardial infarction was diagnosed and coronary angioplasty was performed immediately. However, the massive bleeding from the previously-unfound hepatomas caused hypovolemic shock and fatal outcome. Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs. Although being considered a benign entity, it would disturb diagnosis-making of the visceral diseases owing to the altered anatomy. To our knowledge, the coexistence of the coronary artery disease and ruptured hepatomas in situs inversus totalis, as in our patient, is never described. Recognition of any situs anomalies in time is the key to avoid misdiagnosis, inappropriate managements, and unwanted consequences. PMID- 25296949 TI - Heat-shrink tubing as a solid-phase microextraction coating for the enrichment and determination of phthalic acid esters. AB - Heat-shrink tubing, which shrinks in one plane only (its diameter) when heated, commonly used for sealing protection in electrical engineering, was found to be able to function as a solid-phase microextraction coating. Its utility was demonstrated for the determination of phthalic acid esters in an aqueous solution combined with high-performance liquid chromatography equipped with a UV absorbance detector. The preparation procedure was rather simple and only ~10 min was needed. The fiber cost is extremely low (~10 cent each). The parameters affecting the extraction were optimized. Heat-shrink tubing fiber exhibited a significant enrichment effect for the three examined phthalic acid esters and up to 931-fold enrichment factor was obtained. The limit of detection was <10 MUg/L for all analytes. The operation repeatability and fiber-to-fiber reproducibility were 1.2-8.3 and 5.4-9.1%, respectively. It was successfully applied for the analysis of bottled drinking water with recoveries ranging from 90.1-100.5%. PMID- 25296950 TI - Therapists' in-session experiences with depressive clients: A grounded theory. AB - OBJECTIVE: This study explores the experiential process of psychotherapists during a session with a currently depressive client. METHOD: Individual and focus group interviews were conducted with 30 therapists and the grounded theory method was used as a methodological framework. RESULTS: The therapists' experience was conceptualized as Experiential oscillation between getting closer to a client's depressive experience and moving away from it. Its development over the course of a session is depicted by a six-phase Depression Co-experiencing Trajectory model. CONCLUSIONS: The resultant theory interconnects different therapists' emotional responses to a depressive client within a coherent process model, which allows us to track the changes in therapists' experiences, to name the relations between them, and to connect them with the therapy's in-session microprocesses. PMID- 25296951 TI - Maternal hyperoxygenation improves left heart filling in fetuses with atrial septal aneurysm causing impediment to left ventricular inflow. AB - OBJECTIVES: Aneurysm of the atrial septum (AAS) with excessive excursion of septum primum into the left atrium is an uncommon and relatively benign fetal condition associated with impediment to left ventricular (LV) filling and the appearance of a slender, but apex-forming, LV on fetal echocardiography. Impediment to filling can be severe, creating the image of LV hypoplasia with retrograde aortic flow. We hypothesize that maternal hyperoxygenation alters atrial septal position, improves LV filling, and normalizes aortic flow in fetuses with AAS by increasing fetal pulmonary venous return. METHODS: Fetal echocardiography was performed prior to, and at 10 min of, maternal hyperoxygenation in 12 fetuses with AAS who were referred to our center because of LV hypoplasia. Atrial septal excursion (ASE), LV and right ventricular (RV) sphericity index (SI) and direction of flow in the aortic isthmus, as determined by Doppler, were measured. RESULTS: With maternal hyperoxygenation, mean +/- SD ASE decreased (0.76 +/- 0.17 before maternal hyperoxygenation vs 0.53 +/- 0.23 after maternal hyperoxygenation; P < 0.01), consistent with increased pulmonary venous return, LV-SI increased (0.29 +/- 0.06 vs 0.42 +/- 0.06; P < 0.001), indicating increased LV filling, and the direction of aortic isthmus flow changed from retrograde in all cases prior to maternal hyperoxygenation to antegrade in 10 and to bidirectional in two. RV-SI remained unchanged (0.53 +/- 0.13 vs 0.52 +/- 0.10; P = 0.7). CONCLUSIONS: In cases of AAS, short-term maternal hyperoxygenation increases fetal pulmonary venous return, substantially alters LV geometry and promotes antegrade flow in the aortic isthmus. This demonstrates proof-of-concept that maternal hyperoxygenation can improve filling of the left side of the fetal heart in AAS. PMID- 25296952 TI - Higher body mass index and larger waist circumference may be predictors of thyroid carcinoma in patients with Hurthle-cell lesion/neoplasm fine-needle aspiration diagnosis. AB - OBJECTIVE: High body mass index (BMI) has been found to be associated with raised thyroid cancer risk, particularly in women. We examined the associations for BMI and waist circumference (WC) with thyroid cancer risk among women with Hurthle cell lesion/neoplasm (HLN) on fine-needle aspiration biopsy (FNAB) with the hypothesis that BMI and WC could guide the management of these challenging indeterminate lesions. METHODS: This cross-sectional study included 224 women with HLN who underwent thyroidectomy. In all patients, TSH and thyroid auto antibodies were evaluated, and thyroid nodule features were recorded. Patients were grouped according to BMI (<30 or >=30 kg/m(2)) and WC (<88 or >=88 cm). Relationships of thyroid cancer with BMI and WC were assessed using logistic regression analysis. RESULTS: Mean weight, BMI (31.26 +/- 5.1 vs 26.47 +/- 5.9, P < 0.001), WC (98.23 +/- 7.6 vs 86.18 +/- 11, P = 0.001), and proportion of patients with high BMI (>=30 kg/m(2)) (65.9 vs 33.8%, P < 0.001) or large WC (>=88 cm) (84.1 vs 47.9%, P < 0.001) were significantly higher in malignant group compared to benign group. In regression analysis, BMI and WC significantly associated with existence of malignancy. Malignancy risk was 3.819-fold higher (95% CI: 2.068-7.054) in BMI>=30 kg/m(2) group compared to BMI<30 kg/m(2), which was independent of TSH and age. Large WC was also associated with increased risk (OR = 5.593, 95% CI: 2.736-11.434). Baseline tumour characteristics were similar according to BMI and WC groups. CONCLUSIONS: A great BMI and large WC were associated with higher thyroid cancer risk in patients with FNAB diagnosis of HLN. Further studies are needed to use BMI or WC in the management of patients with HLN. PMID- 25296953 TI - Prospective image planning in radiation therapy for optimization of image quality and reduction of patient dose. AB - INTRODUCTION: CT simulation data in image-guided radiation therapy (IGRT) provides patient-specific subject contrast. This information can be exploited to establish, a priori, a suitable imaging goal and to select patient-specific imaging acquisition parameters that optimize the similarity between reference and daily set-up images and reduce imaging dose. This study aims to describe and clinically validate a computerized algorithm designed to provide such optimization. MATERIAL AND METHODS: An image planning system (IPS) was developed to assist in planar kV imaging technique selection for radiation therapy. The system's patient-specific image quality and dose reduction capabilities were validated herein. Anthropomorphic phantom and clinical data were acquired. Mutual information (MI) was used to compare simulated and measured images in both phantom and clinical tests. Variations in contrast resolution resulting from imaging panel underexposure, saturation and a contrast plateau were investigated. For evaluation of patient-specific imaging dose reduction, the IPS was used to modify acquisition settings for six patients. RESULTS: Phantom data confirmed the IPS's predictive capability regarding image contrast. Measured and simulated images showed similar progressions from under-exposure, image quality peak, and loss of contrast due to detector saturation. Clinical data demonstrated that contrast resolution and imaging dose could be prospectively improved without loss of image contrast. The algorithm reduced imaging dose by an average of 47%, and a maximum of 80%. CONCLUSIONS: Loss of image contrast resulting from under-exposure or over-exposure, as well as a contrast plateau can be predicted by use of a prospective image planning algorithm. Image acquisition parameters can be predicted that reduce patient dose without loss of useful contrast. PMID- 25296954 TI - Are there systemic comorbidities in haemophilia unrelated to bleeding and transfusion-transmitted infections? PMID- 25296955 TI - Validation of computerized wheeze detection in young infants during the first months of life. AB - BACKGROUND: Several respiratory diseases are associated with specific respiratory sounds. In contrast to auscultation, computerized lung sound analysis is objective and can be performed continuously over an extended period. Moreover, audio recordings can be stored. Computerized lung sounds have rarely been assessed in neonates during the first year of life. This study was designed to determine and validate optimal cut-off values for computerized wheeze detection, based on the assessment by trained clinicians of stored records of lung sounds, in infants aged <1 year. METHODS: Lung sounds in 120 sleeping infants, of median (interquartile range) postmenstrual age of 51 (44.5-67.5) weeks, were recorded on 144 test occasions by an automatic wheeze detection device (PulmoTrack(r)). The records were retrospectively evaluated by three trained clinicians blinded to the results. Optimal cut-off values for the automatically determined relative durations of inspiratory and expiratory wheezing were determined by receiver operating curve analysis, and sensitivity and specificity were calculated. RESULTS: The optimal cut-off values for the automatically detected durations of inspiratory and expiratory wheezing were 2% and 3%, respectively. These cutoffs had a sensitivity and specificity of 85.7% and 80.7%, respectively, for inspiratory wheezing and 84.6% and 82.5%, respectively, for expiratory wheezing. Inter-observer reliability among the experts was moderate, with a Fleiss' Kappa (95% confidence interval) of 0.59 (0.57-0.62) for inspiratory and 0.54 (0.52 - 0.57) for expiratory wheezing. CONCLUSION: Computerized wheeze detection is feasible during the first year of life. This method is more objective and can be more readily standardized than subjective auscultation, providing quantitative and noninvasive information about the extent of wheezing. PMID- 25296956 TI - Synthesis and unique photoluminescence properties of nitrogen-rich quantum dots and their applications. AB - Nitrogen-rich quantum dots (N-dots) were serendipitously synthesized in methanol or aqueous solution at a reaction temperature as low as 50 degrees C. These N dots have a small size (less than 10 nm) and contain a high percentage of the element nitrogen, and are thus a new member of quantum-dot family. These N-dots show unique and distinct photoluminescence properties with an increasing percentage of nitrogen compared to the neighboring carbon dots. The photoluminescence behavior was adjusted from blue to green simply through variation of the reaction temperature. Furthermore, the detailed mechanism of N dot formation was also proposed with the trapped intermediate. These N-dots have also shown promising applications as fluorescent ink and biocompatible staining in C. elegans. PMID- 25296958 TI - Anti-inflammatory effects of propofol on lipopolysaccharides-treated rat hepatic Kupffer cells. AB - This study is set to explore the role of commonly used intravenous anesthetic propofol on the inflammatory response of rat liver Kupffer cells (KCs) induced by lipopolysaccharides (LPS). The isolated KCs were cultured at the density of 1 * 10(5)/ml, divided into five groups randomly after 48 h culture: group C, control group; group L, KCs were treated with 1 MUg/ml LPS for 24 h; groups P1, P2, P3, KCs were pretreated with propofol at low (25 MUM), medium (50 MUM), high (100 MUM) concentration for 2 h, respectively, and then were stimulated with 1 MUg/ml LPS for 24 h. The expressions of tumor necrosis factor-alpha (TNF-alpha) mRNA and interleukin-1beta (IL-1beta) mRNA of every group were measured by RT-PCR. Nuclear NF-KappaB p65 was determined by Western blot. The concentrations of IL-1beta and TNF-alpha in supernatant were measured by ELISA. Compared with the group C, TNF alpha mRNA and IL-1beta mRNA in group L were significantly up-regulated and NF KappaB p65 was significantly up-regulated after LPS treatment (P < 0.05). Meanwhile, TNF-alpha and IL-1beta were also significantly increased (P < 0.05). With propofol the mRNA expressions of aforementioned inflammatory mediators were significantly down-regulated and NF-KappaB p65 was significantly inhibited in group P2 and P3 (P < 0.05), compared with group L. However, low propofol concentration did not exhibit any effect (group P1, P > 0.05). Propofol at medium and high concentration can counteract the LPS-induced inflammatory response in KCs by regulating NF-KappaB p65 protein expression. PMID- 25296957 TI - Effects of levodopa on regional cerebral metabolism and blood flow. AB - Levodopa (L-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to the understanding of the effects of L-dopa and other dopaminergic treatment on the activity of abnormal motor and cognitive brain circuits in Parkinson's disease patients. Progress has also been made in understanding the functional pathology of dyskinesias, a common side effect of l dopa treatment, at both regional and network levels. Here, we review these studies, focusing mainly on the new mechanistic insights provided by metabolic brain imaging and network analysis. PMID- 25296959 TI - Computational study on the interaction between CCR5 and HIV-1 entry inhibitor maraviroc: insight from accelerated molecular dynamics simulation and free energy calculation. AB - C-C chemokine receptor type 5 (CCR5) is the co-receptor of human immunodeficiency virus type 1 (HIV-1) and plays an important role in HIV-1 virus infection. Maraviroc has been proved to be effective for anti-HIV-1 by targeting CCR5. Understanding the detailed interaction mechanism between CCR5 and Maraviroc will be of great help to the rational design of a more potential inverse agonist to block HIV-1 infection. Here, we performed molecular dynamics (MD) simulation and accelerated MD simulation (aMD) to study the interaction mechanism between CCR5 and Maraviroc based on a recently reported crystal structure. The results of MD simulation demonstrate that Maraviroc can form stable hydrogen bonds with residues Tyr37(1.39), Tyr251(6.51) and Glu283(7.39). The results of aMD simulation indicate that the carboxamide moiety is more flexible than the tropane group of Maraviroc in the pocket of CCR5. The electrostatic potential analysis proves that Maraviroc can escape from the pocket of CCR5 along the negative electrostatic potential pathway during the dissociation process. The free energy calculation illustrates that there exist three binding pockets during the dissociation process of Maraviroc. Our results will be useful for understanding the interaction mechanism between CCR5 and Maraviroc as well as for the rational design of a more potent inverse agonist. PMID- 25296960 TI - Conformational transitions and stop-and-go nanopore transport of single-stranded DNA on charged graphene. AB - Control over interactions with biomolecules holds the key to applications of graphene in biotechnology. One such application is nanopore sequencing, where a DNA molecule is electrophoretically driven through a graphene nanopore. Here we investigate how interactions of single-stranded DNA and a graphene membrane can be controlled by electrically biasing the membrane. The results of our molecular dynamics simulations suggest that electric charge on graphene can force a DNA homopolymer to adopt a range of strikingly different conformations. The conformational response is sensitive to even very subtle nucleotide modifications, such as DNA methylation. The speed of DNA motion through a graphene nanopore is strongly affected by the graphene charge: a positive charge accelerates the motion, whereas a negative charge arrests it. As a possible application of the effect, we demonstrate stop-and-go transport of DNA controlled by the charge of graphene. Such on-demand transport of DNA is essential for realizing nanopore sequencing. PMID- 25296961 TI - A moldable putty containing silk fibroin yolk shell particles for improved hemostasis and bone repair. AB - During minimally invasive orthopedic surgeries, surgical intervention is required at two stages; to attain hemostasis and subsequently to implant the bone graft or its substitute. There is an apparent need for a material which can simultaneously control bone bleeding and provide support for bone repair. In this work, a moldable putty, which can be applied to bone defects (usually irregular in shape), was developed to address this need. It comprises of a hemostatic factor thrombin, osteoinductive "yolk-shell" particles containing bone growth factor (BMP-2), and an osteoconductive component hydroxyapatite. The yolk shell particles allowed controlled release of BMP-2 and showed significantly enhanced osteogenic differentiation of C2C12 (mouse myoblast) cells as demonstrated by increased alkaline phosphatase (ALP) activity and relative gene expressions of osteogenic differentiation markers. These particles were assembled into a moldable putty by mixing them with hydroxyapatite and silk fibroin solution (binding agent) supplemented with thrombin. The putty showed non-cytotoxicity, hemostatic ability, sustained release of BMP-2 and induced increased mineralization in C2C12 cells. This putty, if applied to bone defects during surgeries, may help attain hemostasis and may enhance bone repair by providing sustained release of bone growth factors. PMID- 25296962 TI - The effect of dietary estimates calculated using food frequency questionnaires on micronuclei formation in European pregnant women: a NewGeneris study. AB - The use of biomarkers of early genetic effects, predictive for cancer, such as micronuclei (MN) in lymphocytes, may help to investigate the association between diet and cancer. We hypothesised that the presence of mutagens in the diet may increase MN formation. A 'pooled' standardised analysis was performed by applying the same experimental protocol for the cytokinesis block micronucleus assay in 625 young healthy women after delivery from five European study populations (Greece, Denmark, UK, Spain and Norway). We assessed MN frequencies in mono- and binucleated T-lymphocytes (MNMONO and MNBN) and the cytokinesis blocked proliferation index using a semi-automated image analysis system. Food frequency questionnaires (FFQs) were used to estimate intake of fatty acids and a broad range of immunotoxic and genotoxic/carcinogenic compounds through the diet. Pooled difference based on delivery type revealed higher MNMONO frequencies in caesarean than in vaginal delivery (P = 0.002). Statistical analysis showed a decrease in MNMONO frequencies with increasing calculated omega-6 PUFA concentrations and a decrease in MNBN frequencies with increasing calculated omega-3 PUFA concentrations. The expected toxic compounds estimated by FFQs were not associated with MN formation in mothers after delivery. In pregnant women, an omega-3 and -6 rich diet estimated by FFQ is associated with lower MN formation during pregnancy and delivery. PMID- 25296963 TI - High-sensitivity C-reactive Protein, Lipoprotein(a) and Homocysteine are Risk Factors for Coronary Artery Disease in Japanese Patients with Peripheral Arterial Disease. AB - AIM: The goal of the study was to investigate the relationships between coronary artery disease (CAD) and risk factors, including the serum levels of high sensitivity C-reactive protein (hs-CRP), lipoprotein(a) (Lp(a)) and homocysteine, in Japanese patients with peripheral arterial disease (PAD). METHODS: Coronary angiography was performed in 451 patients with PAD, among whom the prevalence and clinical characteristics of CAD were analyzed. A multiple logistic analysis was used to evaluate the relationships between CAD and the risk factors. The relationships between the severity of coronary arterial lesions and the risk factors were evaluated using multiple regression analysis. RESULTS: The prevalence of CAD (>=70% luminal diameter narrowing or a history of CAD) and coronary artery stenosis (>=50%) was 55.9% and 74.1%, respectively, and the rate of CAD (>=70%) with single-, double- and triple-vessel disease was 25.9%, 13.5% and 10.6%, respectively. The prevalence of diabetes was higher among the patients with CAD than among those without. The serum levels of hs-CRP, Lp(a), and homocysteine were higher in the patients with CAD, whereas the estimated glomerular filtration rates and HDL-cholesterol levels were lower in these patients. According to the multiple logistic analysis, CAD was related to diabetes (hazard ratio [HR]: 2.253; 95% confidence interval [CI]: 1.137-4.464, p=0.020), hs-CRP (HR: 1.721; 95% CI: 1.030-2.875, p=0.038), Lp(a) (HR: 1.015; 95% CI: 1.001-1.029, p=0.041) and homocysteine (HR: 1.084; 95% CI: 1.012-1.162, p=0.021). Furthermore, diabetes and the D-dimer and LDL-cholesterol levels exhibited significant relationships with the number of stenotic coronary lesions in the stepwise multiple regression analysis (p<0.05). CONCLUSIONS: Diabetes, hs CRP, Lp(a), homocysteine and lipid abnormalities are critical risk factors for CAD in Japanese patients with PAD. PMID- 25296964 TI - Deconstructing violence as a medical syndrome: mapping psychotic, impulsive, and predatory subtypes to malfunctioning brain circuits. AB - Violence is a major management issue for forensic mental health systems. Violence can be approached as a medical syndrome and deconstructed into psychotic, impulsive, and predatory subtypes, which are hypothetically mapped onto corresponding malfunctioning brain circuits. Rational management of violence balances treatment with security, while targeting each subtype of violence with approaches unique to the psychotic, impulsive, and predatory forms of violence. PMID- 25296965 TI - Violence risk assessment and treatment. PMID- 25296966 TI - Assessment of aggression in inpatient settings. AB - The threat of violence is a major concern for all individuals working or receiving treatment in an inpatient psychiatric setting. One major focus in forensic psychology and psychiatry over the past several decades has been the development of risk assessments to aid in the identification of those individuals most at risk of exhibiting violent behavior. So-called second- and third generation risk assessments were developed to improve the accuracy of decision making. While these instruments were developed for use in the community, many have proven to be effective in identifying patients more likely to exhibit institutional aggression. Because the purpose of risk assessment is the reduction of violence, dynamic factors were included in third-generation risk instruments to provide opportunities for intervention and methods for measuring change. Research with these instruments indicates that both static factors (second generation) and dynamic factors (third-generation) are important in identifying those patients most likely to engage in institutional aggression, especially when the aggression is categorized by type (impulsive/reactive, organized/predatory/instrumental, psychotic). Recent research has indicated that developing a typology of aggressive incidents may provide insight both into precipitants to assaults as well as appropriate interventions to reduce such aggression. The extant literature suggests that both static and dynamic risk factors are important, but may be differentially related to the type of aggression exhibited and the characteristics of the individuals exhibiting the aggression. PMID- 25296967 TI - Positive experiences associated with acquired hearing loss, Meniere's disease, and tinnitus: a review. AB - OBJECTIVE: It is common to study and understand how various illness and disorders result in negative consequences. However, positive experiences have been reported in a range of disabling conditions including multiple sclerosis, heart disease, physical and sensory disabilities. This paper presents a literature review of studies that have explored positive experiences associated with acquired hearing loss, Meniere's disease, and tinnitus. DESIGN: A review of the peer reviewed scientific literature. STUDY SAMPLE: A comprehensive search strategy identified 15 articles after applying inclusion criteria. RESULTS: A range of positive experiences have been reported by patients with hearing and balance disorders and by their significant others. Associations between demographic variables (e.g. age, gender), audiological variables (e.g. severity of the condition, duration) and the reported positive experiences are low. In Meniere's disease, self reported positive experiences can predict the impact of the condition. However, this phenomenon has not yet been demonstrated in relation to hearing loss and tinnitus. CONCLUSIONS: Positive experiences associated with audio-vestibular disorders have been demonstrated. Further research is needed on the long-term benefits of the encouragement of such experiences and positive attitudes in persons with hearing loss, tinnitus, and imbalance. PMID- 25296968 TI - Dermatological approach to vemurafenib skin toxicity: a single centre experience. AB - BACKGROUND: Targeted therapies have recently changed the approach to advanced melanoma. RAF inhibitors represent the emerging standard of care for metastatic BRAF mutated melanomas. Cutaneous reactions are the most common side effects during vemurafenib treatment, and affect the quality of life. The aim of this study was to provide some practical advices to manage the drug related cutaneous reactions. METHODS: A cohort of BRAF-mutated metastatic melanoma patients treated at our institution included 20 female and 21 male patients; median age was 56 years (32-87 years). All patients were treated at a dose of 960 mg b.i.d. orally. RESULTS: After a median treatment duration of 7 months (range 0.5-25.2), 29/39 patients (74.4%) developed cutaneous toxicities. We identified 22 cases of maculo papular rash (56%) and 18 of warts (46%); in a total of 10 cases we observed alterations of keratinization (25.6%), while 6 of our patients presented photosensitivity (15 %). Six patients developed keratoacanthomas; no second melanomas were observed. CONCLUSIONS: Skin involvement during vemurafenib treatment is frequent but in the majority of cases cutaneous side effects are self-limiting and easy to manage. Moreover, sun protection is mandatory in vemurafenib treated patients, and should be started together with BRAF inhibitor in order to minimize the impact of photosensitivity on quality of life. PMID- 25296969 TI - Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. AB - Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome. PMID- 25296970 TI - Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences. AB - Mutational profiling of triple-negative breast cancer (TNBC) by whole exome sequencing (WES) yielded a landscape of genomic alterations in this tumor entity. However, the clinical significance of these findings remains enigmatic. Further, integration of WES in routine diagnostics using formalin-fixed paraffin-embedded (FFPE) material is currently not feasible. Therefore, we designed and validated a breast cancer specific gene panel for semiconductor-based sequencing comprising 137 amplicons covering mutational hotspots in 44 genes and applied this panel on a cohort of 104 well-characterized FFPE TNBC with complete clinical follow-up. TP53 mutations were present in more than 80% of cases. PI3K pathway alterations (29.8%) comprising mainly PIK3CA mutations (22.1%) but also mutations and/or amplifications/deletions in other PI3K-associated genes (7.7%) were far more frequently observed, when compared to WES data. Alterations in MAPK signaling genes (8.7%) and cell-cycle regulators (14.4%) were also frequent. Mutational profiles were linked to TNBC subgroups defined by morphology and immunohistochemistry. Alterations in cell-cycle pathway regulators were linked with better overall (p=0.053) but not disease free survival. Taken together, we could demonstrate that breast cancer targeted hotspot sequencing is feasible in a routine setting and yields reliable and clinically meaningful results. Mutational spectra were linked to clinical and immunohistochemically defined parameters. PMID- 25296971 TI - HSP90 inhibition downregulates thymidylate synthase and sensitizes colorectal cancer cell lines to the effect of 5FU-based chemotherapy. AB - Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50 nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition, ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines. Ganetespib sensitized CRC cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib, oxaliplatin and 5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation. Ganetespib sensitizes CRC cell lines to the effects of 5FU-based chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC. PMID- 25296972 TI - Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways. AB - We recently proposed a new bioinformatic algorithm called OncoFinder for quantifying the activation of intracellular signaling pathways. It was proved advantageous for minimizing errors of high-throughput gene expression analyses and showed strong potential for identifying new biomarkers. Here, for the first time, we applied OncoFinder for normal and cancerous tissues of the human bladder to identify biomarkers of bladder cancer. Using Illumina HT12v4 microarrays, we profiled gene expression in 17 cancer and seven non-cancerous bladder tissue samples. These experiments were done in two independent laboratories located in Russia and Canada. We calculated pathway activation strength values for the investigated transcriptomes and identified signaling pathways that were regulated differently in bladder cancer (BC) tissues compared with normal controls. We found, for both experimental datasets, 44 signaling pathways that serve as excellent new biomarkers of BC, supported by high area under the curve (AUC) values. We conclude that the OncoFinder approach is highly efficient in finding new biomarkers for cancer. These markers are mathematical functions involving multiple gene products, which distinguishes them from "traditional" expression biomarkers that only assess concentrations of single genes. PMID- 25296973 TI - CAMK2N1 inhibits prostate cancer progression through androgen receptor-dependent signaling. AB - Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while CAMK2N1 inhibited AR expression and transactivation through CAMKII and AKT pathways. Knockdown of CAMK2N1 in prostate cancer cells alleviated Casodex inhibition of cell growth, while re-expression of CAMK2N1 in castration resistant cells sensitized the cells to Casodex treatment. Taken together, our findings suggest that CAMK2N1 plays a tumor suppressive role and serves as a crucial determinant of the resistance of prostate cancer to endocrine therapies. PMID- 25296974 TI - Pilot study of p62 DNA vaccine in dogs with mammary tumors. AB - Our previous data demonstrated profound anti-tumor and anti-metastatic effects of p62 (sqstm1) DNA vaccine in rodents with various types of transplantable tumors. Testing anti-cancer medicine in dogs as an intermediary step of translational research program provides two major benefits. First, clinical data collected in target animals is required for FDA/USDA approval as a veterinary anti-cancer drug or vaccine. It is noteworthy that the veterinary community is in need of novel medicine for the prevention and treatment of canine and feline cancers. The second more important benefit of testing anti-cancer vaccines in dogs is that spontaneous tumors in dogs may provide invaluable information for human trials. Here, we evaluated the effect(s) of p62 DNA vaccine on mammary tumors of dogs. We found that p62 DNA vaccine administered i.m. decreased or stabilized growth of locally advanced lesions in absence of its overall toxic effects. The observed antitumor activity was associated with lymphocyte infiltration and tumor encapsulation via fibrotic reaction. This data justifies both human clinical trials and veterinary application of p62 DNA vaccine. PMID- 25296975 TI - Regulation of NADPH-dependent Nitric Oxide and reactive oxygen species signalling in endothelial and melanoma cells by a photoactive NADPH analogue. AB - Nitric Oxide (NO) and Reactive oxygen species (ROS) are endogenous regulators of angiogenesis-related events as endothelial cell proliferation and survival, but NO/ROS defect or unbalance contribute to cancers. We recently designed a novel photoactive inhibitor of NO-Synthases (NOS) called NS1, which binds their NADPH site in vitro. Here, we show that NS1 inhibited NO formed in aortic rings. NS1 induced NO decrease led to an inhibition of angiogenesis in a model of VEGF induced endothelial tubes formation. Beside this effect, NS1 reduced ROS levels in endothelial and melanoma A375 cells and in aorta. In metastatic melanoma cells, NS1 first induced a strong decrease of VEGF and blocked melanoma cell cycle at G2/M. NS1 decreased NOX(4) and ROS levels that could lead to a specific proliferation arrest and cell death. In contrast, NS1 did not perturb melanocytes growth. Altogether, NS1 revealed a possible cross-talk between eNOS- and NOX(4) associated pathways in melanoma cells via VEGF, Erk and Akt modulation by NS1 that could be targeted to stop proliferation. NS1 thus constitutes a promising tool that modulates NO and redox stresses by targeting and directly inhibiting eNOS and, at least indirectly, NADPH oxidase(s), with great potential to control angiogenesis. PMID- 25296976 TI - CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis. AB - Poor clinical outcome of lung cancer (LuCa) is primarily due to lack of knowledge about specific molecules involved in its progression and metastasis. In this study, we for the first time show the clinical and biological significance of CC chemokine receptor-9 (CCR9) in non-small cell lung cancer (NSCLC). Expression of CCR9 and CCL25, the only natural ligand of CCR9, was significantly higher (p<0.0001) in NSCLC tissues and serum respectively, compared to their respective controls. Interestingly, expression of both CCR9 and CCL25 was significantly higher in adenocarcinomas (ACs) compared to squamous cell carcinomas (SCCs) (p = 0.04, and p< 0.0001). Similar to tissues, AC and SCC cell lines were positive for CCR9 expression. Despite of marginal difference in CCR9 expression, AC cells showed higher migratory and invasive potential in response to CCL25, compared to SCC cells. This differential biological response of AC cells was primarily due to differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases under the influence of CCL25. Our results suggest CCR9 as a potential target for developing new treatment modality for NSCLC. Additionally, differential serum CCL25 level in ACs and SCCs, two NSCLC subtypes, suggest its potential as a non-invasive diagnostic/prognostic biomarker. PMID- 25296977 TI - The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells. AB - The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1 103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer. PMID- 25296979 TI - Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with adipose tissue stem cells. AB - Evidences indicate that tumor development and progression towards a malignant phenotype depend not only on cancer cells themselves, but are also deeply influenced by tumor stroma reactivity. The present study uses mesenchymal stem cells from normal human uterine cervix (hUCESCs), isolated by the minimally invasive method of routine Pap cervical smear, to study their effect on the three main cell types in a tumor: cancer cells, fibroblasts and macrophages. Administration of hUCESCs-conditioned medium (CM) to a highly invasive breast cancer MDA-MB-231 cell line and to human breast tumors with high cell proliferation rates had the effect of reducing cell proliferation, modifying the cell cycle, inducing apoptosis, and decreasing invasion. In a xenograft mouse tumor model, hUCESCs-CM reduced tumor growth and increased overall survival. In cancer-associated fibroblasts, administration of hUCESCs-CM resulted in reduced cell proliferation, greater apoptosis and decreased invasion. In addition, hUCESCs-CM inhibited and reverted macrophage differentiation. The analysis of hUCESCs-CM (fresh and lyophilized) suggests that a complex paracrine signaling network could be implicated in the anti-tumor potential of hUCESCs. In light of their anti-tumor potential, the easy cell isolation method, and the fact that lyophilization of their CM conserves original properties make hUCESCs good candidates for experimental or clinical applications in anticancer therapy. PMID- 25296978 TI - Preclinical efficacy of sepantronium bromide (YM155) in multiple myeloma is conferred by down regulation of Mcl-1. AB - The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin--YM155--is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma. PMID- 25296980 TI - Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas. AB - The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-kappaB accumulation. RES+CUR administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. Overall, combinations of CUR and RES was more effective in inhibiting in vivo and in vitro cancer growth than the treatment with CUR. Additional studies will be needed to define the therapeutic potential of these compounds in combination. PMID- 25296981 TI - Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation. AB - The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC50 in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G0/G1 phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B pre ALL patients. PMID- 25296982 TI - Presynaptic adenosine A2A receptors dampen cannabinoid CB1 receptor-mediated inhibition of corticostriatal glutamatergic transmission. AB - BACKGROUND AND PURPOSE: Both cannabinoid CB1 and adenosine A2A receptors (CB1 receptors and A2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB1 -A2A receptor interaction has already been elucidated, but the presynaptic A2A receptor-mediated control of presynaptic neuromodulation by CB1 receptors remains to be defined. Because the corticostriatal terminals provide the major input to the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions. EXPERIMENTAL APPROACH: Pharmacological manipulation of CB1 and A2A receptors was carried out in brain nerve terminals isolated from rats and mice, using flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement. Whole-cell patch-clamp recordings were made in horizontal corticostriatal slices. KEY RESULTS: Flow synaptometry showed that A2A receptors were extensively co-localized with CB1 receptor-immunopositive corticostriatal terminals and A2A receptors co-immunoprecipitated CB1 receptors in these purified terminals. A2A receptor activation decreased CB1 receptor radioligand binding and decreased the CB1 receptor-mediated inhibition of high K(+) -evoked glutamate release in corticostriatal terminals. Accordingly, A2A receptor activation prevented CB1 receptor-mediated paired-pulse facilitation and attenuated the CB1 receptor-mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices. CONCLUSIONS AND IMPLICATIONS: Activation of presynaptic A2A receptors dampened CB1 receptor-mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB1 receptor-mediated presynaptic inhibition, allowing frequency-dependent enhancement of synaptic efficacy at corticostriatal synapses. PMID- 25296983 TI - Sertoli-Leydig cell tumor with unique nail findings in a post-menopausal woman: a case report and literature review. AB - BACKGROUND: Sertoli-Leydig cell tumor (SLCT) is a rare sex-cord tumor that usually occurs unilaterally and accounts for < 0.5% of all ovarian tumors. SLCT is uncommon in post-menopausal women, with the average age of diagnosis being 25 years. CASE: We present a case of a 63-year-old post-menopausal woman presenting with progressive hirsutism, and male-pattern baldness. Unusual nail changes were also observed. METHODS: Hormonal profile of the patient revealed increased testosterone and estradiol levels, and a 3.5 cm left ovarian mass. The patient was evaluated and was not found to be anemic or iron-deficient. Intraoperative frozen section assessment during laparoscopic exploration revealed SLCT, which was confirmed subsequently by histopathological and immunohistochemical (IHC) examination. Nail bed tissues were collected from normal females and evaluated by IHC for the presence of androgen receptors (AR). RESULTS: The patient had an excellent postoperative course and all her testosterone-related manifestations were reversed within one year of surgery. Following surgery, the patient's unique nail abnormalities also resolved gradually. The IHC evaluation also confirmed the presence of AR in nail bed tissues of females. CONCLUSION: SLCT, albeit rare, should be considered in post-menopausal women presenting with virilization and elevated androgen levels. Unusual nail signs may develop in response to increased androgen levels in these patients. PMID- 25296985 TI - Real-time, selective detection of Pb(2+) in water using a reduced graphene oxide/gold nanoparticle field-effect transistor device. AB - A field-effect transistor (FET) device-based sensor is developed to specifically detect Pb(2+) ions in an aqueous environment that is notably toxic. Reduced graphene oxide (rGO), as the semiconducting channel material, was utilized in the FET device through a self-assembly method. An l-glutathione reduced was employed as the capture probe for the label-free detection. By monitoring the electrical characteristics of the FET device, the performance of the sensor was measured and investigated. Compared with conventional detection technologies, this sensor enabled real-time detection with a response time of 1-2 s. A lower detection limit for Pb(2+) ions as low as 10 nM was achieved, which is much lower than the maximum contaminant level for Pb(2+) ions in drinking water recommended by the World Health Organization. Furthermore, the rGO FET sensor was able to distinguish Pb(2+) from other metal ions. Without any sample pretreatment, the platform is user-friendly. PMID- 25296984 TI - Abi3bp regulates cardiac progenitor cell proliferation and differentiation. AB - RATIONALE: Cardiac progenitor cells (CPCs) are thought to differentiate into the major cell types of the heart: cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified ABI family, member 3 (NESH) binding protein (Abi3bp) as a protein important for mesenchymal stem cell biology. Because CPCs share several characteristics with mesenchymal stem cells, we hypothesized that Abi3bp would similarly affect CPC differentiation and proliferation. OBJECTIVE: To determine whether Abi3bp regulates CPC proliferation and differentiation. METHODS AND RESULTS: In vivo, genetic ablation of the Abi3bp gene inhibited CPC differentiation, whereas CPC number and proliferative capacity were increased. This correlated with adverse recovery after myocardial infarction. In vitro, CPCs, either isolated from Abi3bp knockout mice or expressing an Abi3bp shRNA construct, displayed a higher proliferative capacity and, under differentiating conditions, reduced expression of both early and late cardiomyocyte markers. Abi3bp controlled CPC differentiation via integrin-beta1, protein kinase C-zeta, and v-akt murine thymoma viral oncogene homolog. CONCLUSIONS: We have identified Abi3bp as a protein important for CPC differentiation and proliferation. PMID- 25296986 TI - Individual genetic and genomic variation: a new opportunity for personalized nursing interventions. AB - AIMS: A discussion of the potential for improving nursing interventions through tailoring in consideration of patients' individual genetic/genomic variation. BACKGROUND: Nurses have not yet maximized use of genetic/genomic information in planning and delivering nursing care outside of the context of monogenetic disease. Approaches from personalized medicine and pharmacogenomics have not yet been applied to development or delivery of nursing interventions. There are potentially many nursing interventions that would be more effective if they were individually tailored to the patient's genetic/genomic profile. DESIGN: Discussion paper. DATA SOURCES: Published literature from 2008-2014 (one legacy paper from 1994 is also cited); Wellcome Trust and Genome.gov websites. IMPLICATIONS FOR NURSING: There is a need for development of genetic/genomic research that directly addresses questions vital to nursing science, including biological plausibility studies. Research is also needed to inform the design and delivery of nursing interventions for common complex diseases tailored to consider genetic/genomic variability. Predicting responses to nursing interventions based on genetic/genomic variability may increase the probability that the first intervention employed will lead to optimal outcomes for each patient. CONCLUSION: Integrating genetic/genomic variability, from biological plausibility research through intervention research into evidence-based practice, has the potential to move nursing forward. PMID- 25296987 TI - Authors' reply to Wang et al. comment on "Parkinson's disease associated with myasthenia gravis and rheumatoid arthritis". PMID- 25296988 TI - Toward on-the-fly quantum mechanical/molecular mechanical (QM/MM) docking: development and benchmark of a scoring function. AB - We address the challenges of treating polarization and covalent interactions in docking by developing a hybrid quantum mechanical/molecular mechanical (QM/MM) scoring function based on the semiempirical self-consistent charge density functional tight-binding (SCC-DFTB) method and the CHARMM force field. To benchmark this scoring function within the EADock DSS docking algorithm, we created a publicly available dataset of high-quality X-ray structures of zinc metalloproteins ( http://www.molecular-modelling.ch/resources.php ). For zinc bound ligands (226 complexes), the QM/MM scoring yielded a substantially improved success rate compared to the classical scoring function (77.0% vs 61.5%), while, for allosteric ligands (55 complexes), the success rate remained constant (49.1%). The QM/MM scoring significantly improved the detection of correct zinc binding geometries and improved the docking success rate by more than 20% for several important drug targets. The performance of both the classical and the QM/MM scoring functions compare favorably to the performance of AutoDock4, AutoDock4Zn, and AutoDock Vina. PMID- 25296989 TI - Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. AB - The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of alpha-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of alpha synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of alpha-synuclein (monomeric, oligomeric and fibrillar), and recombinant alpha-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that alpha-synuclein present in the human PD brain lysate and distinct recombinant alpha-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated alpha-synuclein. In conclusion, we here provide the first experimental evidence that different alpha-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated alpha-synuclein in neurons. PMID- 25296991 TI - The influence of shoulder pain on functional limitation, perceived health, and depressive mood in patients with traumatic paraplegia. AB - OBJECTIVE: To assess whether functional activity, perceived health, and depressive symptoms differ between individuals with traumatic paraplegia with and without shoulder pain. DESIGN: Cross sectional and comparative investigation using the unified questionnaire. SETTING: Neural Regeneration and Repair Division unit of Taipei Veterans General Hospital in Taiwan. PARTICIPANTS: Seventy-six patients with paraplegia (23 with and 53 without shoulder pain) who had experienced spinal cord injury at American Spinal Injury Association Impairment Scale T2 to T12 neurologic level (at least 6 months previously). OUTCOME MEASURES: Spinal Cord Independence Measure (SCIM), a single item from the Medical Outcomes Study 36-Item Short-Form Health Survey, and Patient Health Questionnaire 9 (PHQ-9) depression scale. RESULTS: Shoulder pain was prevalent in 30% patients. Patients with shoulder pain had significantly worse perceived health and greater depressive symptoms than those without. No significant difference was found in functional ability between groups. Greater shoulder pain intensity was related to higher depressive scores (r=0.278, P=0.017) and lower self-perceived health scores (r=-0.433, P<0.001) but not SCIM scores (P=0.342). CONCLUSION: Although shoulder pain was unrelated to functional limitation, it was associated with lower perceived health and higher depressive mood levels. PMID- 25296992 TI - Quantifying transmission by stage of infection in the field: the example of SIV-1 and STLV-1 infecting mandrills. AB - The early stage of viral infection is often followed by an important increase of viral load and is generally considered to be the most at risk for pathogen transmission. Most methods quantifying the relative importance of the different stages of infection were developed for studies aimed at measuring HIV transmission in Humans. However, they cannot be transposed to animal populations in which less information is available. Here we propose a general method to quantify the importance of the early and late stages of the infection on micro organism transmission from field studies. The method is based on a state space dynamical model parameterized using Bayesian inference. It is illustrated by a 28 years dataset in mandrills infected by Simian Immunodeficiency Virus type-1 (SIV 1) and the Simian T-Cell Lymphotropic Virus type-1 (STLV-1). For both viruses we show that transmission is predominant during the early stage of the infection (transmission ratio for SIV-1: 1.16 [0.0009; 18.15] and 9.92 [0.03; 83.8] for STLV-1). However, in terms of basic reproductive number (R0 ), which quantifies the weight of both stages in the spread of the virus, the results suggest that the epidemics of SIV-1 and STLV-1 are mainly driven by late transmissions in this population. PMID- 25296993 TI - What is covered by "cancer rehabilitation" in PubMed? A review of randomized controlled trials 1990-2011. AB - OBJECTIVE: This focused review examines randomized controlled studies included by the term "cancer rehabilitation" in PubMed. The research questions concern the type of interventions performed and their methodological quality. DESIGN: Using the Medical Subject Headings (MeSH) terms: neoplasm AND rehabilitation, all articles with randomized controlled studies that included adult cancer patients, written in English, were extracted from PubMed. Papers covering physical exercise, psychiatric/psychological treatment or social support only were excluded as they had been reviewed recently. Abstracts and papers were assessed by 3 pairs of reviewers, and descriptive information was extracted systematically. Methodological quality was rated on a 10-item index scale, and the cut-off for acceptable quality was set at >= 8. RESULTS: A total of 132 (19%) of the 683 identified papers met the eligibility criteria and were assessed in detail. The papers were grouped into 5 thematic categories: 44 physical; 15 art and expressive; 47 psycho-educative; 21 emotionally supportive; and 5 others. Good quality of design was observed in 32 studies, 18 of them uni-dimensional and 14 multi-dimensional. CONCLUSION: Published randomized controlled studies on cancer rehabilitation are heterogeneous in terms of content and samples, and are mostly characterized by suboptimal design quality. Future studies should be more specific and well-designed with sufficient statistical strength. PMID- 25296994 TI - The bowel wall target sign. PMID- 25296995 TI - Multi-detector CT of blunt mesenteric injuries: usefulness of imaging findings for predicting surgically significant bowel injuries. AB - PURPOSE: The objective of this study is to determine which imaging features of blunt mesenteric injuries best predict the presence of a bowel injury requiring surgical correction. METHODS: The radiology archives at a Level 1 trauma center were searched over a 5-year period to identify patients with mesenteric injuries seen on admission 64 slice MDCT. Two emergency radiologists, blinded to clinical and surgical outcomes, retrospectively recorded mesenteric injury size, the presence/absence of active mesenteric bleeding, bowel wall thickening, adjacent interloop free fluid, extraluminal gas, mesenteric vessel termination, mesenteric vessel "beading", focal bowel wall defect, and bowel wall perfusion abnormality. Based on all of the imaging findings, the radiologists were asked to determine if they thought the patient had a surgical bowel injury. RESULTS: One hundred twenty six patients with mesenteric injuries were identified. Eighteen patients underwent laparotomy confirming the presence of bowel injury in 15. The remaining patients were successfully managed non-operatively. There was no statistically significant difference in size of mesenteric injury for surgical vs. non-surgical bowel injuries. Active bleeding, adjacent interloop free fluid, and bowel wall perfusion defects were strong predictors of the presence of a surgically significant bowel injury (p < 0.001, 0.002, and 0.020, respectively). The overall accuracy, sensitivity, specificity, PPV, and NPV of 64-MDCT were 73.8%, 80%, 73.0%, 28.6%, and 96.4%, respectively. CONCLUSIONS: Mesenteric active bleeding, adjacent interloop free fluid and bowel wall perfusion defects are associated with surgically significant bowel injuries. The diagnosis of surgical bowel injuries remains challenging despite 64-slice MDCT technology. PMID- 25296996 TI - Half-dose non-contrast CT in the investigation of urolithiasis: image quality improvement with third-generation integrated circuit CT detectors. AB - PURPOSE: The objective of this study is to establish the effect of third generation integrated circuit (IC) CT detector on objective image quality in full and half-dose non-contrast CT of the urinary tract. METHODS: 51 consecutive patients with acute renal colic underwent non-contrast CT of the urinary tract using a 128-slice dual-source CT before (n = 24) and after (n = 27) the installation of third-generation IC detectors. Half-dose images were generated using projections from detector A using the dual-source RAW data. Objective image noise in the liver, spleen, right renal cortex, and right psoas muscle was compared between DC and IC cohorts for full-dose and half-dose images reconstructed with FBP and IR algorithms using 1 cm(2) regions of interest. Presence and size of obstructing ureteric calculi were also compared for full dose and half-dose reconstructions using DC and IC detectors. RESULTS: No statistical difference in age and lateral body size was found between patients in the IC and DC cohorts. Radiation dose, as measured by size-specific dose estimates, did not differ significantly either between the two cohorts (10.02 +/- 4.54 mGy IC vs. 12.28 +/- 7.03 mGy DC). At full dose, objective image noise was not significantly lower in the IC cohort as compared to the DC cohort for the liver, spleen, and right psoas muscle. At half dose, objective image noise was lower in the IC cohort as compared to DC cohort at the liver (21.32 IC vs. 24.99 DC, 14.7% decrease, p < 0.001), spleen (19.33 IC vs. 20.83 DC, 7.20% decrease, p = 0.02), and right renal cortex (20.28 IC vs. 22.98 DC, 11.7% decrease, p = 0.005). Mean obstructing ureteric calculi size was not significantly different when comparison was made between full-dose and half-dose images, regardless of detector type (p > 0.05 for all comparisons). CONCLUSIONS: Third-generation IC detectors result in lower objective image noise at full- and half-radiation dose levels as compared with traditional DC detectors. The magnitude of noise reduction was greater at half-radiation dose indicating that the benefits of using novel IC detectors are greater in low and ultra-low-dose CT imaging. PMID- 25296997 TI - Metabolic signatures of malignant and non-malignant mass-forming lesions in the periampulla and pancreas in FDG PET/CT scan: an atlas with pathologic correlation. AB - Positron emission tomography (PET) has been used for the characterization of pancreatic and periampullary lesions. Pancreatitis-associated inflammation affecting only a portion of the pancreas gives the appearance of a mass lesion on imaging. Consequently, the differential diagnosis between cancer and pancreatitis becomes a commonly encountered problem. Traditionally, PET was interpreted as positive (to denote malignancy) if fluorodeoxyglucose (FDG) activity in the pancreas exceeded background activity and as negative (to denote benign) if activity was less than or equal to background activity. However, the specificity was limited with this method of interpretation. A relatively wide overlap has been reported between semiquantitative uptake values obtained in cancers and those in inflammatory lesions. Also, the qualitative (metabolic patterns) and quantitative variables (standardized uptake values) have been complementary and at sometimes controversial to each other in various clinical situations. There is paucity of data in the literature highlighting the role of FDG PET/CT in characterization of such mass lesions. The primary aim of this pictorial review is to list the various pathologic processes of pancreas and periampulla that could be studied with FDG PET/CT and recognize the different FDG uptake patterns and apply this information to characterize the different lesions affecting the pancreas and periampulla. We have also discussed the limitations of conventional imaging and advantages of FDG PET/CT for the evaluation mass-forming lesions of the pancreas and periampulla. PMID- 25296999 TI - Osteopathia striata with cranial sclerosis: when a fetal malformation syndrome reveals maternal pathology. PMID- 25296998 TI - Protective effects of n-6 fatty acids-enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor. AB - BACKGROUND AND PURPOSE: Long-term intake of dietary fatty acids is known to predispose to chronic inflammation, but their effects on acute intestinal ischaemia/reperfusion (I/R) injury is unknown. The aim of this study was to determine the consequences of a diet rich in n-3 or n-6 polyunsaturated fatty acids (PUFA) on intestinal I/R-induced damage. EXPERIMENTAL APPROACH: Mice were fed three different isocaloric diets: a balanced diet used as a control and two different PUFA-enriched diets, providing either high levels of n-3 or of n-6 PUFA. Intestinal injury was evaluated after intestinal I/R. PUFA metabolites were quantitated in intestinal tissues by LC-MS/MS. KEY RESULTS: In control diet-fed mice, intestinal I/R caused inflammation and increased COX and lipoxygenase derived metabolites compared with sham-operated animals. Lipoxin A4 (LxA4 ) was significantly and selectively increased after ischaemia. Animals fed a high n-3 diet did not display a different inflammatory profile following intestinal I/R compared with control diet-fed animals. In contrast, intestinal inflammation was decreased in the I/R group fed with high n-6 diet and level of LxA4 was increased post-ischaemia compared with control diet-fed mice. Blockade of the LxA4 receptor (Fpr2), prevented the anti-inflammatory effects associated with the n-6 rich diet. CONCLUSIONS AND IMPLICATIONS: This study indicates that high levels of dietary n-6, but not n-3, PUFAs provides significant protection against intestinal I/R-induced damage and demonstrates that the endogenous production of LxA4 can be influenced by diet. PMID- 25297000 TI - [Intraosseous hibernoma : a possibly not so rare cause of sclerotic bone lesions]. PMID- 25297001 TI - Severe motor neuropathy or neuronopathy due to nitrous oxide toxicity after correction of vitamin B12 deficiency. AB - INTRODUCTION: Nitrous oxide (N2 O) toxicity can cause a sensory predominant myeloneuropathy identical to subacute combined degeneration caused by vitamin B12 deficiency. We describe a patient with a typical vitamin B12 deficiency syndrome after N2 O abuse who recovered and then developed a severe lower motor neuron syndrome following vitamin B12 correction. This suggests N2 O toxicity independent of functional vitamin B12 deficiency. METHODS: Electrophysiological, serological, and clinical evaluations were undertaken in the evaluation of this patient. RESULTS: A 22-year-old man abused N2 O and presented with a dorsal column syndrome with low vitamin B12 and high homocysteine serum levels. He recovered with treatment but presented later with profound motor axonal degeneration and normal vitamin B12, homocysteine, and methlymalonic acid levels. CONCLUSIONS: This case illustrates that N2 O-associated severe motor neuropathy or neuronopathy can develop separately from typical vitamin B12 deficiency dorsal column myelopathy. This syndrome can present when functional measures of vitamin B12 deficiency have normalized. PMID- 25297002 TI - Selective host-guest interaction between metal ions and metal-organic frameworks using dynamic nuclear polarization enhanced solid-state NMR spectroscopy. AB - The host-guest interaction between metal ions (Pt(2+) and Cu(2+) ) and a zirconium metal-organic framework (UiO-66-NH2 ) was explored using dynamic nuclear polarization-enhanced (15) N{(1) H} CPMAS NMR spectroscopy supported by X ray absorption spectroscopy and density functional calculations. The combined experimental results conclude that each Pt(2+) coordinates with two NH2 groups from the MOF and two Cl(-) from the metal precursor, whereas Cu(2+) do not form chemical bonds with the NH2 groups of the MOF framework. Density functional calculations reveal that Pt(2+) prefers a square-planar structure with the four ligands and resides in the octahedral cage of the MOF in either cis or trans configurations. PMID- 25297003 TI - Nomogram-based evaluation of thyroid function in appropriate-for-gestational-age neonates in intensive care unit. AB - OBJECTIVE: The objective of this study was to help neonatologists to interpret the thyroid hormone results accurately, and also to provide reference ranges and/or nomograms of FT4 (free thyroxine) and thyrotropin against gestational age at postnatal 1 week and 1 month in order to assess thyroid function in AGA (appropriate for gestational age) neonates in intensive care unit. STUDY DESIGN: This is a retrospective study. We included a total number of 515 AGA neonates between 24 and 42 weeks of gestation. Routine results of serum FT4 and TSH that had been analyzed with an immunoassay were collected from existing laboratory data. Least square regression analyses were used to estimate both the mean and the s.d. curves as polynomial functions of gestational age. RESULT: Free T4 levels were correlated with gestational age both at postnatal 1 week (r=0.39, P<0.001) and 1 month (r=0.26, P<0.001). Serum TSH levels at postnatal 1 week and 1 month did not show any correlation with gestational age. Scatterplots of FT4 levels against gestational age at 1 week and 1 month, showing the predicted 2.5th, 50th and 97.5th percentiles and central 95% reference ranges for TSH were provided. CONCLUSION: Gestational age-specific nomograms for FT4 and reference ranges for TSH at postnatal 1 week and 1 month in AGA neonates have been developed. This can help neonatologists to interpret the thyroid hormone results accurately. Further studies providing reference ranges/nomograms for thyroid function in small-for-gestational-age neonates are needed. PMID- 25297004 TI - Moral distress in the neonatal intensive care unit: an Italian study. AB - OBJECTIVE: The objective of this study was to evaluate the frequency, the intensity and the level of moral distress experienced by nurses working in neonatal intensive care units (NICUs). STUDY DESIGN: We conducted a cross sectional questionnaire survey involving 472 nurses working in 15 level III NICUs. Frequency, intensity and level of moral distress was evaluated using a modified version of Moral Distress Scale Neonatal-Pediatric Version. Socio demographic data were also collected. RESULT: Four hundred six nurses completed the study material indicating a low-to-moderate experience of moral distress. The situations receiving the highest scores for frequency, intensity and level of moral distress related to the initiation of extensive life-saving actions and participation to the care of ventilator-dependent child. No difference in the mean scores of moral distress was found according to the socio-demographic characteristics investigated. CONCLUSION: The present study provides further insight into the moral distress experienced by nurses working in Italian NICUs. PMID- 25297005 TI - Wnt signaling in kidney tubulointerstitium during disease. AB - The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide array of biologic processes including embryonic development, branching morphogenesis, proliferation and carcinogenesis. Over the past ten years it has become increasingly clear that Wnt signaling also regulates the response of adult organs to disease processes, including kidney disease. This review will focus on the growing literature implicating important roles for Wnt signaling during disease in two separate kidney compartments: the tubular epithelium and the interstitium. PMID- 25297006 TI - Fluorescent labeling for clonal selection of Marc 145 cells secreting high levels of recombinant protein PBD-1. AB - Despite the powerful impact gene expression markers like the green fluorescent protein (GFP) or enhanced GFP (EGFP) exert on linking the expression of recombinant protein for selection of high producers in recent years, there is still a strong incentive to develop more economical and efficient methods for isolating mammalian cell clones secreting high levels of recombinant proteins. Here we present a new method based on the co-expression of EGFP that allows clonal selection in standard 96-well cell culture plates. The genes encoding the EGFP protein and the related protein are linked by an internal ribosome entry site and thus are transcribed into the same mRNA in an independent translation process. Since both proteins arise from a common mRNA, the EGFP expression level correlates with the expression level of the therapeutic protein in each clone. By expressing recombinant porcine beta-defensin 1 in Marc 145 cells, we demonstrate the robustness and performance of this technique. The method can be served as an alternative to identify high-producer clones with various cell sorting methods. PMID- 25297008 TI - Temporal sodium release related to gel microstructural properties-implications for sodium reduction. AB - The microstructure of food can be engineered to enhance sodium release during mastication, which may be used as a strategy to reduce sodium content in foods. This study aimed to relate sodium release to microstructural properties of solid lipoproteic colloid (SLC) foods. The SLC gels with 1.5% (w/w) NaCl were prepared by homogenization of whey protein isolate and anhydrous milk fat, followed by heat-induced gelation. The gels varied in protein content (8% or 16%), fat content (0%, 11%, 22%, or 33%), and homogenization pressures (14 or 55 MPa). The maximum rate of sodium release during the initial gel compression increased with increasing gel porosity and pore size. This was due to more releasable serum in the gels with larger pore volume and larger pores. The maximum concentration of sodium at the end of sodium release increased with reduced size of the fat particles in the gels. The smaller fat particles were dispersed more uniformly and interrupted the protein network more, and facilitated the gel breakdown. The above findings suggested that, during the breakdown of the SLC gels, the major mechanisms of sodium release are via serum release followed by sodium diffusion, which are governed by the gel porosity and the particle size of fat, respectively. This study demonstrated the dependence of temporal sodium release properties on the microstructural properties of an SLC food system. The findings from this study could lay the foundation for further investigation of the dependence of saltiness perception on SLC microstructure, which can provide insight for sodium reduction in SLC products. PMID- 25297007 TI - Oridonin suppress cell migration via regulation of nonmuscle myosin IIA. AB - Oridonin, which is isolated from Chinese herb Rabdosia rubescens (Hemsl.) Hara, has been implicated in regulation of tumor cell migration and invasion. In this study, treatment with oridonin enhanced the phosphorylation of myosin regulatory light chain (T18/S19) that regulates the ATPase activity of myosin IIA. Meanwhile, stress fibers were significantly more prominent after oridonin incubation, which impaired cell migration in transwell migration assays. All of these effects may be caused by the decreased interaction between myosin IIA and myosin phosphatase complex, but not kinases. Our data provide clear evidence of this novel pharmacological function for oridonin in treating cancer cell migration. PMID- 25297009 TI - A macroecological glance at the structure of late Miocene rodent assemblages from Southwest Europe. AB - Deep-time perspectives in macroecology are essential with regard to understanding the impact of climate forcing on faunal communities. Using late Miocene rodent faunas (12 to 5 Ma) from two different biogeographical provinces from southwestern Europe, we asked whether the waxing and waning of faunas with dissimilar ecological affinities tracked climate in different ways. The latest middle Miocene featured a fauna dominated by dormice with forest and mixed habitat affinities. This group declined towards the Upper Miocene. Rodent taxa with the highest values of richness at the beginning of the Upper Miocene are generalists in the southern province and specialists of forested habitats in the northern province. Finally, we identified a third, increasingly significant group of rodents linked to open landscapes towards the end of the Miocene. These three broad ecological groups showed differential responses to a complex set of interconnected circumstances, including the biogeographic structure of the study area and climatic changes throughout time. PMID- 25297010 TI - Using surface segregation to design stable Ru-Ir oxides for the oxygen evolution reaction in acidic environments. AB - The methods used to improve catalytic activity are well-established, however elucidating the factors that simultaneously control activity and stability is still lacking, especially for oxygen evolution reaction (OER) catalysts. Here, by studying fundamental links between the activity and stability of well characterized monometallic and bimetallic oxides, we found that there is generally an inverse relationship between activity and stability. To overcome this limitation, we developed a new synthesis strategy that is based on tuning the near-surface composition of Ru and Ir elements by surface segregation, thereby resulting in the formation of a nanosegregated domain that balances the stability and activity of surface atoms. We demonstrate that a Ru0.5Ir0.5 alloy synthesized by using this method exhibits four-times higher stability than the best Ru-Ir oxygen evolution reaction materials, while still preserving the same activity. PMID- 25297011 TI - Idalopirdine for Alzheimer's disease: written in the stars. PMID- 25297012 TI - Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi stage, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial. METHODS: This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622. FINDINGS: Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0.51 units per month, 95% CI 0.02 to 1.00; p=0.0416), but in stage 3 functional decline between the treatment groups did not differ (0.09, -0.06 to 0.24; p=0.2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0.90, 95% CI 0.71 to 1.15; p=0.4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0.0004; hepatobiliary, 211 [62%] vs 19 [11%], p<0.0001). Significantly more participants who received ceftriaxone had serious hepatobiliary serious adverse events (41 participants [12%]) than did those who received placebo (0 participants). INTERPRETATION: Despite promising stage 2 data, stage 3 of this trial of ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The adaptive design allowed for seamless transition from one phase to another, and central venous catheter use in the home setting was shown to be feasible. FUNDING: National Institute of Neurological Disorders and Stroke. PMID- 25297013 TI - Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention. METHODS: In this randomised, double-blind, placebo-controlled, exploratory, proof-of-concept phase 2 trial, patients aged 18-55 years with five to 14 migraine days per 28-day period were randomly assigned (1:1) via an interactive web response system to receive an intravenous dose of ALD403 1000 mg or placebo. Site investigators, patients, and the sponsor were masked to treatment allocation during the study. The primary objective was to assess safety at 12 weeks after infusion. The primary efficacy endpoint was the change from baseline to weeks 5-8 in the frequency of migraine days, as recorded in patient electronic diaries. Patients were followed up until 24 weeks for exploratory safety and efficacy analyses. Safety and efficacy analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, NCT01772524. FINDINGS: Between Jan 28, 2013, and Dec 23, 2013, of 174 patients randomly assigned at 26 centres in the USA, 163 received either ALD403 (n=81) or placebo (n=82). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. The most frequent adverse events were upper respiratory tract infection (placebo 6 [7%] patients vs ALD403 7 [9%] patients), urinary tract infection (4 [5%] vs 1 [1%]), fatigue (3 [4%] vs 3 [4%]), back pain (4 [5%] vs 3 [4%]), arthralgia (4 [5%] vs 1 [1%]), and nausea and vomiting (2 [2%] vs 3 [4%]). Six serious adverse events were reported by three patients and were judged to be unrelated to study drug: in the ALD403 group, one patient had four serious adverse events and one had one serious adverse event, and in the placebo group, one patient had one serious adverse event. There were no differences in vital signs or laboratory safety data between the two treatment groups. The mean change in migraine days between baseline and weeks 5-8 was -5.6 (SD 3.0) for the ALD403 group compared with -4.6 (3.6) for the placebo group (difference -1.0, 95% CI -2.0 to 0.1; one-sided p=0.0306). INTERPRETATION: No safety concerns were noted with an intravenous dose of ALD403 1000 mg. This study also provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days. FUNDING: Alder Biopharmaceuticals. PMID- 25297014 TI - Therapy of amyotrophic lateral sclerosis remains a challenge. PMID- 25297015 TI - CGRP as a new target in prevention and treatment of migraine. PMID- 25297017 TI - Ebola virus re-emergence: is it really knocking at our door? PMID- 25297016 TI - Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo controlled phase 2 trial. AB - BACKGROUND: In human beings, 5-HT6 receptors are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex. We assessed the effect on cognitive performance of Lu AE58054 (idalopirdine), a selective 5-HT6 receptor antagonist, in donepezil-treated patients with moderate Alzheimer's disease. METHODS: For this randomised, double blind, placebo-controlled phase 2 trial (LADDER), we recruited patients from 48 outpatient clinical sites in seven countries. Patients were 50 years or older, had moderate Alzheimer's disease (a mini-mental state examination score of 12 19), and had been stably treated with donepezil 10 mg per day for 3 or more months. Using a computer-generated sequence, we randomly assigned patients (1:1, stratified by site) to receive either idalopirdine 90 mg per day (30 mg thrice daily) or placebo. The primary endpoint was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at week 24. We analysed all efficacy endpoints in the full-analysis set (modified intention-to treat analysis). This trial is registered with ClinicalTrials.gov, number NCT01019421. FINDINGS: Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1.38 (SD 0.53) in the placebo group and -0.77 (0.55) in the idalopirdine group (treatment difference of -2.16 points, 95% CI -3.62 to -0.69; p=0.0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased gamma-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment. INTERPRETATION: Idalopirdine improved cognitive function in donepezil-treated patients with moderate Alzheimer's disease. Larger studies in a broader population of patients are ongoing to substantiate the effects reported here. FUNDING: H Lundbeck A/S. PMID- 25297018 TI - The threat of Ebola: an update. PMID- 25297019 TI - Future of diagnostic microbiology. AB - Diagnostic Microbiology is the tool that makes it possible to identify the exact etiology of infectious diseases and the most optimal therapy at the level of individual patients as well as communities. Conventional methods require time to grow the microbes in vitro under specific conditions and not all microbes are easily cultivable. This is followed by biochemical methods for identification which also require hours and sometimes days. Transport of the specimens under less than ideal conditions, prior use of antibiotics and small number of organisms are among the factors that render culture-based methods less reliable. Newer methods depend on amplification of nucleic acids followed by use of probes for identification. This mitigates the need for higher microbial load, presence of metabolically active viable organisms and shortens the time to reporting. These methods can be used to detect antibiotic resistance genes directly from the specimen and help direct targeted therapy. Since these methods will not fulfill all the diagnostic needs, a second approach is being used to shorten the time to identification after the organism has already grown. Mass spectrometry and bioinformatics are the tools making this possible. This review gives a historical perspective on diagnostic microbiology, discusses the pitfalls of current methodology and provides an overview of newer and future methods. PMID- 25297020 TI - Refractory giardiasis: a molecular appraisal from a tertiary care centre in India. AB - PURPOSE: The intestinal flagellate Giardia lamblia includes many genetically distinct assemblages, of which assemblage A and B, predominantly infect humans. Nitroimidazoles derivatives (metronidazole and tinidazole) and nitazoxanide are some of the therapeutic agents for treatment of giardiasis. Nevertheless, some individuals with giardiasis are non-responsive to standard therapy. The present study highlights cases of refractory giardiasis and attempts to elucidate if genetic heterogeneity in the parasite is associated with treatment failure. MATERIALS AND METHODS: Three stool samples were obtained on three consecutive days from 4000 patients with diarrhoea and were microscopically examined for the detection of trophozoites, and/or cysts, using both normal saline and Lugol's iodine. A hemi-nested polymerase chain reaction (PCR) assay using triose phosphate isomerase (tpi) as the target gene was performed to determine the assemblages. Sequencing of the PCR products of the patients showing failure to treatment of giardiasis was also performed. RESULTS: Two per cent (82/4000) of the total patients were microscopically positive for Giardia lamblia in the stool samples. All these patients were treated with metronidazole/tinidazole as per the standard regimens. However, eight patients showed treatment failure to giardiasis as stool examinations were repeatedly positive even after treatment with multiple courses of anti-giardial therapy. Genetic characterisation of all eight Giardia isolates showed that they belonged to Assemblage B and had homogeneous sequences. These patients were either treated with extended regimens or with combination therapy of anti-giardials. CONCLUSION: In our experience, combination of two or more drugs for a longer duration is the treatment modality to treat refractory giardiasis. PMID- 25297021 TI - Research on Toxocara canis antibodies obtained from patients with eosinophilia. AB - BACKGROUND: Eosinophils may suggest the presence of a great variety of anomalies whereupon allergies, malignancies, certain tissue disorders, idiopathic hypereosynophilic syndrome and parasitic infections (with the exception of protozoons) can be cited as a few. Although the clinical manifestations may differ, the eosinophils level is quite an important data in cases related to the helminth infections. Similarly, in parasitic infections related to larva migrans (visceral, cutaneous, ocular), the eosinophils level is again a primary indicator and its evident cause is the roundworm Toxocara spp. AIM: The aim of this study was to evaluate the significance characteristics of Toxocara spp. in patients with eosonophilia. MATERIALS AND METHODS: In our study, serums were collected from 93 patients of various age groups with eosonophilia (10% and above) while visiting Istanbul University Medical Faculty due to various complaints. RESULTS: Serum samples were treated with Toxocara IgG ready ELISA kit and Toxocara western blot IgG ready kit. Based on the ELISA method; out of 93 patients, 30 patients (32.3%) were positive. Western blot technique; 45 (48.4%) were positive with anti toxocara IgG antibodies. CONCLUSION: Results point out to western blot technique being more sensitive and superior on a scale of (P < 0.0001) when compared with the ELISA method. PMID- 25297022 TI - Possibility of scrub typhus in fever of unknown origin (FUO) cases: an experience from Rajasthan. AB - PURPOSE: Fever of unknown origin (FUO) has multiple causes. Scrub typhus is less known cause of FUO in India. The present study reports a recent epidemic of scrub typhus amongst cases of FUO from different areas of Rajasthan, India. There was high mortality in undiagnosed cases of FUO which lead to the diagnosis of scrub typhus. OBJECTIVE: To study the possibility of scrub typhus as a causative factor in FUO cases by qualitative detection of IgM antibodies with ELISA. MATERIALS AND METHODS: From September 2012 to December 2012, 271 serum samples of FUO cases were analysed for IgM antibodies to Orientia tsutsugamushi along with dengue, malaria, typhoid, tuberculosis and brucellosis. RESULTS: Scrub typhus IgM antibodies by ELISA were detected in 133 (49.1%) patients. Scrub typhus positivity was significantly higher among female in comparison to males (P<0.05). Maximum positivity of scrub typhus was found in females of 46-60 years age group. The laboratory parameters were abnormal in most of the patients as evident by thrombocytopenia (63%), deranged liver functions (56%) and renal functions (25%). CONCLUSION: The present study emphasises the importance of scrub typhus among cases of FUO especially after rainy season and during early cooler months. The study also highlights the significance of ELISA method for rapid and early reporting and ruling out scrub typhus in FUO cases. PMID- 25297023 TI - Distribution of different yeasts isolates among trauma patients and comparison of accuracy in identification of yeasts by automated method versus conventional methods for better use in low resource countries. AB - INTRODUCTION: As most trauma patients require long-term hospital stay and long term antibiotic therapy, the risk of fungal infections in such patients is steadily increasing. Early diagnosis and rapid treatment is life saving in such critically ill trauma patients. AIMS: To see the distribution of various species of Candida among trauma patients and compare the accuracy, rapid identification and cost effectiveness between VITEK 2, CHROMagar and conventional methods. SETTINGS AND DESIGN: Retrospective laboratory-based surveillance study performed over a period of 52 months (January 2009 to April 2013) at a level I trauma centre in New Delhi, India. MATERIALS AND METHODS: All microbiological samples positive for Candida were processed for microbial identification using standard methods. Identification of Candida was done using chromogenic medium and by automated VITEK 2 Compact system and later confirmed using the conventional method. Time to identification in both was noted and accuracy compared with conventional method. STATISTICAL ANALYSIS: Performed using the SPSS software for Windows (SPSS Inc. Chicago, IL, version 15.0). P values calculated using chi2 test for categorical variables. A P<0.05 was considered significant. RESULTS: Out of 445 yeasts isolates, Candida tropicalis (217, 49%) was the species that was maximally isolated. VITEK 2 was able to correctly identify 354 (79.5%) isolates but could not identify 48 (10.7%) isolates and wrongly identified or showed low discrimination in 43 (9.6%) isolates but CHROM agar correctly identified 381 (85.6%) isolates with 64 (14.4%) misidentification. Highest rate of misidentification was seen in C. tropicalis and C. glabrata (13, 27.1% each) by VITEK 2 and among C. albicans (9, 14%) by CHROMagar. CONCLUSIONS: Though CHROMagar gives identification at a lower cost compared with VITEK 2 and are more accurate, which is useful in low resource countries, its main drawback is the long duration taken for complete identification. PMID- 25297024 TI - Rapid screening of rpoB and katG mutations in Mycobacterium tuberculosis isolates by high-resolution melting curve analysis. AB - BACKGROUND: Early detection of multidrug-resistant tuberculosis (MDR-TB) is essential to prevent its transmission in the community and initiate effective anti-TB treatment regimen. MATERIALS AND METHODS: High-resolution melting curve (HRM) analysis was evaluated for rapid detection of resistance conferring mutations in rpoB and katG genes. We screened 95 Mycobacterium tuberculosis clinical isolates including 20 rifampin resistant (RIF-R), 21 isoniazid resistant (INH-R) and 54 fully susceptible (S) isolates determined by proportion method of drug susceptibility testing. Nineteen M. tuberculosis isolates with known drug susceptibility genotypes were used as references for the assay validation. The nucleotide sequences of the target regions rpoB and katG genes were determined to investigate the frequency and type of mutations and to confirm HRM results. RESULTS: HRM analysis of a 129-bp fragment of rpoB allowed correct identification of 19 of the 20 phenotypically RIF-R and all RIF-S isolates. All INH-S isolates generated wild-type HRM curves and 18 out of 21 INH-R isolates harboured any mutation in 109-bp fragment of katG exhibited mutant type HRM curves. However, 1 RIF-R and 3 INH-R isolates were falsely identified as susceptible which were confirmed for having no mutation in their target regions by sequencing. The main mutations involved in RIF and INH resistance were found at codons rpoB531 (60% of RIF-R isolates) and katG315 (85.7% of INH-R isolates), respectively. CONCLUSION: HRM was found to be a reliable, rapid and low cost method to characterise drug susceptibility of clinical TB isolates in resource-limited settings. PMID- 25297025 TI - Is universal sample processing methodology better than conventional techniques for detection of tuberculosis? AB - BACKGROUND: The identification of infectious cases is a crucial first step for tuberculosis control programmes worldwide. It relies exclusively on the detection of acid-fast bacilli in sputum by smear microscopy. Therefore, there is an urgent and definite need to improve the sensitivity of smear microscopy. OBJECTIVE: The USP method was compared with the two most commonly used conventional methods of smear microscopy namely; direct smear microscopy and the microscopy by modified Petroff's method. MATERIALS AND METHODS: Two samples from each patient were taken from 197 patients of presumptive tuberculosis. One smear was made for direct Ziehl-Neelsen staining and two smears were made after processing by two concentration methods i.e., modified Petroff's and USP solution. LJ media were inoculated for culture after processing by both concentration methods. RESULTS: Among 197 cases 93 were culture positive by either method. Out of 93 culture positive sample, 78.5% were direct smear positive, 89% were 4%NaOH smear positive and 96% were USP smear-positive samples but difference in diagnostic accuracy of USP (96%) and modified Petroff method (93%) is not statistically significant (P>0.01). CONCLUSION: The present study evaluated the smear microscopy by USP method with two conventional methods, direct microscopy and microscopy by modified Petroff's method. The study concludes that although USP method is more sensitive than conventional methods, it is not feasible to include it in diagnosis of early tuberculosis within RNTCP. PMID- 25297026 TI - Emerging antimicrobial resistance pattern of Helicobacter pylori in central Gujarat. AB - BACKGROUND: Antimicrobial resistance is a growing problem in H. pylori treatment. The study was intended to evaluate the prevalence of resistance amongst 80 H.pylori isolates cultured from biopsy taken during routine endoscopies in 2008 2011. MATERIALS AND METHODS: 855 gastro duodenal biopsies were collected and cultured on H.pylori selective medium (containing Brucella agar and Columbia agar (Hi media), with Skirrow's supplement (antibiotic supplement) and 7% human blood cells). H.pylori was isolated from 80 specimens. The antimicrobial susceptibility of H.pylori isolates was carried out by the Kirby Bauer technique against metronidazole (5 ug), clarithromycin (15 ug), ciprofloxacin (5 ug), amoxicillin (10 ug), tetracycline (30 ug), erythromycin (15 ug), levofloxacin (5 ug), and furazolidone (50 ug) (Sigma- Aldrich, MO). RESULTS: 83.8% isolates were resistant to metronidazole, 58.8% were resistant to Clarithromycin 72.5% were resistant to Amoxicillin, 50% to Ciprofloxacin and 53.8% to tetracycline. furazolidone, erythromycin and Levofloxacin showed only 13.8% resistance to H.pylori. Multi drug resistance with metronidazole+clarithromycin+tetracycline was 85%. For all the drugs Antimicrobial resistance rate was found higher in males compare to females. Metronidazole and amoxicillin resistance was found noteworthy in patients with duodenal ulcer (p=0.018), gastritis (P=0.00), and in reflux esophagitis (P=0.00). clarithromycin and tetracycline resistance was suggestively linked with duodenitis (P=0.018), while furazolidone, erythromycin and levofloxacin showed excellent sensitivity in patients with duodenitis (P value- 0.018), gastritis (P=0.00) and reflux esophagitis (P=0.00). Resistance with metronidazole (P=0.481), clarithromycin (P=0.261), amoxicillin (P=0.276), tetracycline (P=0.356), ciprofloxacin (P=0.164) was not correlated well with Age group and Gender of the patients. CONCLUSION: A very high percentage of patients were infected with metronidazole and clarithromycin resistant strains. The use of antibiotics for other indications seems to be the major risk factor for the development of primary resistance. High incidence should alarm the gastroenterologist while prescribing the eradication regimen. PMID- 25297027 TI - A possible alternative to the error prone modified Hodge test to correctly identify the carbapenemase producing Gram-negative bacteria. AB - CONTEXT: The modified Hodge test (MHT) is widely used as a screening test for the detection of carbapenemases in Gram-negative bacteria. This test has several pitfalls in terms of validity and interpretation. Also the test has a very low sensitivity in detecting the New Delhi metallo-beta-lactamase (NDM). Considering the degree of dissemination of the NDM and the growing pandemic of carbapenem resistance, a more accurate alternative test is needed at the earliest. AIMS: The study intends to compare the performance of the MHT with the commercially available Neo-Sensitabs - Carbapenemases/Metallo-beta-Lactamase (MBL) Confirmative Identification pack to find out whether the latter could be an efficient alternative to the former. SETTINGS AND DESIGN: A total of 105 isolates of Klebsiella pneumoniae resistant to imipenem and meropenem, collected prospectively over a period of 2 years were included in the study. SUBJECTS AND METHODS: The study isolates were tested with the MHT, the Neo-Sensitabs - Carbapenemases/MBL Confirmative Identification pack and polymerase chain reaction (PCR) for detecting the blaNDM-1 gene. RESULTS: Among the 105 isolates, the MHT identified 100 isolates as carbapenemase producers. In the five isolates negative for the MHT, four were found to produce MBLs by the Neo-Sensitabs. The Neo Sensitabs did not have any false negatives when compared against the PCR. CONCLUSIONS: The MHT can give false negative results, which lead to failure in detecting the carbapenemase producers. Also considering the other pitfalls of the MHT, the Neo-Sensitabs--Carbapenemases/MBL Confirmative Identification pack could be a more efficient alternative for detection of carbapenemase production in Gram negative bacteria. PMID- 25297028 TI - Use of MALDI-TOF MS technique for rapid identification of bacteria from positive blood cultures. AB - We evaluated the feasibility of same-day routine aerobic bacterial identification using the following procedures: Picking colonies from 4 and 6 h incubated subculture from positive blood culture bottle and analyzing them by matrix assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). The matched identification rate of this procedure at the species level was 80.6% (141/175) for the 4-h cultures compared with overnight cultures and 90.9% (159/175) for the 6-h cultures. Thus, our technique provides an easy and rapid method for identification of aerobic bacteria in routine clinical microbiology laboratories. PMID- 25297029 TI - MALDI-TOF MS for rapid identification of clinically relevant bacterial and fungal isolates. PMID- 25297030 TI - Prevalence and antibiotic susceptibility of thermophilic Campylobacters from sources implicated in horizontal transmission of flock colonisation. AB - Thermophilic Campylobacter are commonly associated with poultry as commensals of the avian gut and are the causative agent responsible for human Campylobacteriosis. This study aimed to establish the prevalence of Campylobacter spp. from environmental sources that have previously been implicated as sources of horizontal transmission. The highest prevalence of thermophilic Campylobacter was found in water samples (87.5%) and lowest from flies (7.2%). Only C. jejuni was isolated from all sources. A secondary aim was to provide a baseline of resistance profiles of Campylobacter spp. isolates obtained. Alarmingly all the C. jejuni isolates from environmental sources as well as humans were multi-drug resistant. PMID- 25297031 TI - Declining trend of resistance to first-line anti-tubercular drugs in clinical isolates of Mycobacterium tuberculosis in a tertiary care north Indian hospital after implementation of revised national Tuberculosis control programme. AB - Trends showing drug-resistance pattern are needed to understand direction of tuberculosis (TB) control programme. The drug-resistance pattern in state of Uttar Pradesh, India, is not documented. Here we are reporting the prevalence of multi-drug-resistant (MDR) and drug-resistant TB in previously treated cases of pulmonary tuberculosis following launch of revised national TB control programme (RNTCP) in whole of Uttar Pradesh. Isolates of Mycobacterium tuberculosis, from patients of pulmonary tuberculosis, who were treated with antitubercular drugs for more than 4 weeks, were tested for resistance to first-line drugs; streptomycin (S), Ethambutol (E), Rifampicin (R) and isoniazid (H) over a period of 4 years, 2009-2012. Total 2496 isolates of M. tuberculosis were tested, of which 1139 isolates (45.6%) were pan-sensitive and 370 (14.8%) were pan resistant. Total 695 isolates (27.8%) were MDR. Maximum resistance was with Isoniazid (n=1069, 42.8%) followed by streptomycin (n=840, 33.7%), rifampicin (n=742, 29.7%), and ethambutol (n=613, 24.6%). A decline in number of MDR strains and individual drug resistance was seen. Total MDR strains in the year 2009, 2010, 2011 and 2012 were 35.6%, 30.8%, 26.7% and 22.8% respectively. The drug resistance pattern reported from time to time may vary substantially. The decline in drug resistance visible over last four years, after implementation of DOTS, appears promising. PMID- 25297032 TI - Clonal diversity and drug resistance in Mycobacterium tuberculosis isolated from extra-pulmonary samples in central India--a pilot study. AB - In India, extrapulmonary tuberculosis (EPTB) accounts for 10 - 15% of all types of tuberculosis. To identify and compare predominant spoligotypes and drug resistance patterns in strains of Mycobacterium tuberculosis isolated from extrapulmonary and pulmonary specimens in central India, drug susceptibility testing and spoligotyping were carried out. Spoligotyping data was analyzed using SITVIT2 database. ST11/EAI3_Ind with 33% isolates among extrapulmonary specimens and ST26/CAS1_DEL with 28% isolates among pulmonary specimens were the most predominant lineages. Multidrug resistance was found in 5.5% of the strains isolated from extrapulmonary specimens in contrast to 17% isolated from pulmonary specimens. PMID- 25297033 TI - Disseminated Bacillus Calmette-Guerin infections after intravesical therapy. AB - Intravesical instillation of Bacillus Calmette-Guerin (BCG) is the treatment of choice for superficial bladder carcinoma. Disseminated BCG infection presenting as granulomatous hepatitis or pneumonitis is a very rare complication of this treatment. Here we report a case series of seven patients previously treated with BCG presenting with pneumonitis. In two of the cases, identification of Mycobacterium bovis was achieved with molecular methods. PMID- 25297034 TI - Cerebral phaeohyphomycosis--could early diagnosis have saved the patient? AB - Cladophialophora bantiana brain abscess is a rare and frequently fatal infection, often seen in immunocompetent individuals. 34 year old immunocompetent woman who presented with convulsions is reported. She was initially treated with antituberculous drug. During 15 days of treatment, she deteriorated. Hence she underwent craniotomy, which revealed brain abscesses due to C. bantiana. Subsequently she was treated with fluconazole , but eventually succumbed to the infection on the 7th day of treatment. Mortality remains high with this rare mycosis, even in immunocompetent patients. The case illustrates the clinical and radiological similarities between tuberculoma and other etiologies of brain abscesses. This emphasizes the need to perform histological and microbiological studies prior to the initiation of any form of therapy. PMID- 25297035 TI - Diphtheria-like illness in a fully immunised child caused by Corynebacterium pseudodiphtheriticum. AB - Corynebacterium pseudodiphtheriticum is a common commensal flora of the upper respiratory tract in humans. Though the pathogenicity of C. pseudodiphtheriticum is not rare, its role as an opportunistic pathogen is mainly limited to the lower respiratory tract, particularly in patients with underlying systemic conditions or immune-compromisation. We hereby present the first case of C. pseudodiphtheriticum causing diphtheria-like illness affecting the upper respiratory tract of a 6-year-old fully immunised otherwise healthy child. In countries with very low incidence of diphtheria, C. pseudodiphtheriticum should be included in differential diagnosis for a child presenting with diphtheria-like illness. Simple, rapid screening tests should be used to differentiate it from C. diphtheriae and hence, to prevent unnecessary concern in community. PMID- 25297036 TI - Subdural empyma due to Mycobacterium fortuitum in a non-HIV patient. AB - A 14-year-old male child presented with high grade intermittent fever with altered sensorium since 5-6 days and generalised seizures. On examination neck stiffness noticed with normal haemogram and chest X-ray. CSF microscopy was normal and no growth seen in aerobic culture. CT scan showed loculated lesion. Drained pus showed acid fast organism and culture on Lowestein Jensen medium showed pale-coloured growth on 3 rd day. Organism identified as Mycobacterium fortuitum by biochemical test. Interesting aspect of this case was there is no history of trauma or injection and patient was negative for HIV antibody. PMID- 25297037 TI - A rare case of subcutaneous mucormycosis due to Syncephalastrum racemosum: case report and review of literature. AB - Zygomycosis represent a group of uncommon but potentially fatal fungal infections. The incidence of zygomycosis has increased manifold in recent years. Despite aggressive treatment, it can lead to a highly invasive disease state with fatal outcomes, especially among immuno-compromised. Syncephalastrum racemosum is a fungus belonging to Zygomycetes. Very few cases of human disease caused by this particular fungus have been documented. However, it has been clearly implicated in causing highly invasive disease in recent reported cases. Knowledge about the pathogenicity and clinical presentation of this rare fungal infection will alert the clinicians for instituting an early appropriate therapy leading to better outcomes. PMID- 25297038 TI - Sphingomonas paucimobilis bacteraemia and shock in a patient with rheumatic carditis. AB - Acute rheumatic fever (ARF) carditis is treated with steroids, which can cause changes in the cellular immune response, especially decreased CD3 (+) T cells. Nosocomial infections due to steroid use for treatment of ARF carditis or secondary to the changes in the cellular immune response have not been reported in the literature. Sphingomonas paucimobilis is a Gram-negative bacillus causing community- and hospital-acquired infections. It has been reported as causing bacteraemia/sepsis, pneumonia or peritonitis in patients with malignancies, immunosuppression or diabetes. We present a case with S. paucimobilis bacteraemia/sepsis and shock after administration of steroids for treatment of ARF carditis. We suggest early identification of the causative agent and appropriate adjustments of the treatment plan to avoid shock and possible mortality. This is the first reported case of S. paucimobilis bacteraemia/sepsis in the setting of steroid use for ARF carditis. PMID- 25297039 TI - High prevalence of New Delhi metallo-beta-lactamase in Acinetobacter calcoaceticus-A. baumannii complex at two tertiary care centres in north India. PMID- 25297040 TI - Kocuria kristinae, an unusual pathogen causing opportunistic infections in patients with malignancy. PMID- 25297041 TI - Role of cold agglutination test in the diagnosis Mycoplasma pneumoniae infection in HIV infected children. PMID- 25297042 TI - Production of neuraminidase in relation with biofilm formation among clinical and healthy skin isolates of Acinetobacter species. PMID- 25297043 TI - Small colony variants of Staphylococcus aureus: enemies with hidden weapons. PMID- 25297044 TI - Vancomycin resistance due to VanA in an Aerococcus viridans isolate. PMID- 25297045 TI - Azithromycin zone interpretation for Salmonella: time to adopt BSAC's zone diameters? PMID- 25297046 TI - Impact of diet alteration on oral microflora by addition of probiotics. PMID- 25297047 TI - Biofilm formation by Candida species on intrauretheral catheter and its antifungal susceptibility profile. PMID- 25297048 TI - Prevalence of multiple antibiotic resistant Escherichia coli serotypes in raw sewage of North-Western Punjab, India. PMID- 25297049 TI - Imaging assessment and clinical significance of pneumatosis in adult patients. AB - Gas detection in the bowel wall and in portomesenteric venous vessels in adults has long been related to intestinal infarction and poor outcome; many case reports have shown that pneumatosis may be associated with a large variety of pathological situations, ranging from absolutely benign and asymptomatic forms to abdominal catastrophes. Several studies have been conducted on this topic with different conclusions, probably due to differences in population so that the clinical value of these signs is still questioned. Intestinal pneumatosis, especially if presenting with a band-like pattern and if associated with portomesenteric vein gas, when observed in an acute abdominal setting should raise the suspicion of mesenteric infarct and prompt a careful search for other signs of intestinal involvement, so as not to miss cases of life-threatening intestinal infarct or allow them to further evolve into extensive necrosis with worse prognosis. In this review we illustrate the most relevant aspects of these debated but significant radiological signs. PMID- 25297050 TI - Meeting new challenges: The 2014 HUPO-PSI/COSMOS Workshop: 13-15 April 2014, Frankfurt, Germany. AB - The Annual 2014 Spring Workshop of the Proteomics Standards Initiative (PSI) of the Human Proteome Organization (HUPO) was held this year jointly with the metabolomics COordination of Standards in MetabOlomicS (COSMOS) group. The range of existing MS standards (mzML, mzIdentML, mzQuantML, mzTab, TraML) was reviewed and updated in the light of new methodologies and advances in technologies. Adaptations to meet the needs of the metabolomics community were incorporated and a new data format for NMR, nmrML, was presented. The molecular interactions workgroup began work on a new version of the existing XML data interchange format. PSI-MI XML3.0 will enable the capture of more abstract data types such as protein complex topology derived from experimental data, allosteric binding, and dynamic interactions. Further information about the work of the HUPO-PSI can be found at http://www.psidev.info. PMID- 25297051 TI - Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) syndrome associated with azithromycin presenting like septic shock: a case report. AB - INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms syndrome is a potentially life-threatening cutaneous hypersensitivity reaction characterized by extensive mucocutaneous eruption, fever, hematologic abnormalities including eosinophilia and/or atypical lymphocytosis, and extensive organ involvement. The drugs most often responsible for causing drug reaction with eosinophilia and systemic symptoms syndrome are anticonvulsants, antimicrobial agents and antipyretic or anti-inflammatory analgesics. Although azithromycin is widely prescribed in clinical practice, serious cutaneous reactions from this agent have been rarely described. We report the first adult case of drug reaction with eosinophilia and systemic symptoms syndrome associated with azithromycin. CASE PRESENTATION: A 44-year-old previously healthy Caucasian man with history of tobacco use presented to his primary care physician with fever and productive cough. He was prescribed azithromycin, promethazine hydrochloride and dextromethorphan hydrobromide syrup. One week later, he developed a blistering erythematous rash over both hands, which over the next two weeks spread to involve nearly his entire body surface, sparing only his face. He was admitted to an outside hospital with signs of systemic inflammatory response syndrome and severe sepsis, presumably from a skin infection. Despite aggressive therapy he deteriorated, with worsening diffuse erythema, and was transferred to our institution. He developed multiple organ failure requiring ventilatory and hemodynamic support. Pertinent laboratory studies included a leukocytosis with a white blood cell count of 17.6 * 10(9)/L and 47% eosinophils. A skin biopsy showed evidence of spongiotic lichenoid dermatitis with eosinophils and neutrophils, compatible with a systemic drug-induced hypersensitivity reaction. Our patient was started on high-dose steroids and showed dramatic improvement within 48 hours. CONCLUSIONS: We report the first adult case of drug reaction with eosinophilia and systemic symptoms syndrome associated with azithromycin exposure. Clinicians should be aware of this potentially devastating complication from this commonly prescribed medication. PMID- 25297053 TI - Prenatal detection of transposition of the great arteries reduces mortality and morbidity. AB - OBJECTIVES: To evaluate the prenatal detection of transposition of the great arteries (TGA), after the introduction of a Dutch screening program in 2007, as well as the effect of prenatal detection on pre- and postsurgical mortality and morbidity. METHODS: In a geographical cohort study, all infants with TGA who were born between 1 January 2002 and 1 January 2012 were included. The cases were divided into two groups: those with and those without a prenatal diagnosis. Pre- and postsurgical mortality was assessed, with a follow-up of 1 year. Presurgical morbidity was assessed in terms of cardiovascular compromise, metabolic acidosis, renal and/or hepatic dysfunction and closure of the duct before initiation of therapy. RESULTS: Of all cases (n = 144), 26.4% were diagnosed prenatally, with detection rates of 15.7% and 41.0% in the first and last 5 years of the study period, respectively. First-year mortality was significantly lower in cases with a prenatal diagnosis of TGA than in those without (0.0% vs 11.4%, respectively). Presurgical mortality (4.9%) only occurred in undetected simple TGA cases. Closure of the duct before treatment, renal dysfunction and hypoxia occurred significantly more often in the group without a prenatal diagnosis. CONCLUSIONS: The prenatal detection rate of TGA has increased significantly since the introduction of the screening program in 2007. Prenatal diagnosis is an important factor that contributes to survival of the infant in the first postnatal year. Furthermore, some morbidity indicators were significantly higher in the group without a prenatal diagnosis. These results justify efforts to improve prenatal screening programs. PMID- 25297052 TI - A novel nanobiotherapeutic poly-[hemoglobin-superoxide dismutase-catalase carbonic anhydrase] with no cardiac toxicity for the resuscitation of a rat model with 90 minutes of sustained severe hemorrhagic shock with loss of 2/3 blood volume. AB - We crosslink hemoglobin (Hb), superoxide dismutase (SOD), catalase (CAT), and carbonic anhydrase (CA) to form a soluble polyHb-SOD-CAT-CA nanobiotechnological complex. The obtained product is a soluble complex with three enhanced red blood cell (RBC) functions and without blood group antigens. In the present study, 2/3 of blood volume was removed to result in 90-min hemorrhagic shock at mean arterial blood pressure (MAP) of 30 mmHg. This was followed by the reinfusion of different resuscitation fluids, then followed for another 60 min. PolyHb-SOD-CAT CA maintained the MAP at 87.5 +/- 5 mmHg as compared with 3 volumes of lactated Ringer's solution, 43.3 +/- 2.8 mmHg; blood, 91.3 +/- 3.6 mmHg; polyHb-SOD-CAT, 86.0 +/- 4.6 mmHg; poly stroma-free hemolysate (polySFHb), 85.0 +/- 2.5 mmHg; and polyHb, 82.6 +/- 3.5 mmHg. PolyHb-SOD-CAT-CA was superior to the blood and other fluids based on the following criteria. PolyHb-SOD-CAT-CA reduced tissue pCO2 from 98 +/- 4.5 mmHg to 68.6 +/- 3 mmHg. This was significantly (p < 0.05) more effective than lactated Ringer's solution (98 +/- 4.5 mmHg), polyHb (90.1 +/- 4.0 mmHg), polyHb-SOD-CAT (90.9 +/- 1.4 mmHg), blood (79.1 +/- 4.7 mmHg), and polySFHb (77 +/- 5 mmHg). PolyHb-SOD-CAT-CA reduced the elevated ST level to 21.7 +/- 6.7% and is significantly (< 0.05) better than polyHb (57.7 +/- 8.7%), blood (39.1 +/- 1.5%), polySFHb (38.3% +/- 2.1%), polyHb-SOD-CAT (27.8 +/- 5.6%), and lactated Ringer's solution (106 +/- 3.1%). The plasma cardiac troponin T (cTnT) level of polyHb-SOD-CAT-CA group was significantly (P < 0.05) lower than that of all the other groups. PolyHb-SOD-CAT-CA reduced plasma lactate level from 18 +/- 2.3 mM/L to 6.9 +/- 0.3 mM/L. It was significantly more effective (P < 0.05) than lactated Ringer's solution (12.4 +/- 0.6 mM/L), polyHb (9.6 +/- 0.7 mM/L), blood (8.1 +/- 0.2 mM/L), polySFHb (8.4 +/- 0.1 mM/L), and polyHb-SOD-CAT (7.6 +/- 0.3 mM/L). PolyHb-SOD-CAT-CA can be stored for 320 days at room temperature. Lyophilized poly-Hb-SOD-CAT-CA can be heat pasteurized at 68F for 2 h. This can be important if there is a need to inactivate human immunodeficiency virus, Ebola virus, and other infectious organisms. PMID- 25297054 TI - Theories and Messages in South Korean Antismoking Advertising. AB - This study evaluated antismoking advertisements in South Korean television by drawing upon a Health Communication article by Cohen, Shumate, and Gold (2007) and on Gold, Cohen, and Shumate's (2008) typology. This study examined the theories and messages in South Korean antismoking advertisements. First, South Korean antismoking advertisements primarily targeted adults. In addition, the advertisements for adults normally used statistical evidence, whereas those for adolescents often used testimonial evidence. In terms of the type of performance, narration was often used in advertisements for both adults and adolescents. Second, the most prevalent persuasive health message used social norms, whereas the most prevalent affective appeal used fear appeals. Third, antismoking advertisements in South Korea mentioned more benefits of not smoking than barriers to not smoking. This study also identified the message difference in the U.S. and South Korean antismoking advertisements. PMID- 25297055 TI - Individual- and regional-level determinants of human papillomavirus (HPV) vaccine refusal: the Ontario Grade 8 HPV vaccine cohort study. AB - BACKGROUND: Studies on the determinants of human papillomavirus (HPV) vaccine use have generally focused on individual-level characteristics, despite the potentially important influence of regional-level characteristics. Therefore, we undertook a population-based, retrospective cohort study to identify individual- and regional-level determinants of HPV vaccine refusal (non-receipt) in Ontario's (Canada) Grade 8 HPV Immunization Program. METHODS: Ontario's administrative health and immunization databases were used to identify girls eligible for free HPV vaccination in 2007-2011 and to ascertain individual-level characteristics of cohort members (socio-demographics, vaccination history, health care utilization, medical history). The social and material characteristics of the girl's region (health unit) were derived from the 2006 Canadian Census. Generalized estimating equations (binomial distribution, logit link) were used to estimate the population-average effects of individual- and regional-level characteristics on HPV vaccine refusal. RESULTS: Our cohort consisted of 144,047 girls, 49.3% of whom refused HPV vaccination. Factors associated with refusal included a previous diagnosis of Down's syndrome (OR = 1.37, 95% CI 1.16-1.63) or autism (OR = 1.60, 95% CI 1.34-1.90), few physician visits (OR = 1.45, 95% CI 1.35-1.55), and previous refusal of mandatory (OR = 2.23, 95% CI 2.07-2.40) and optional (OR = 3.96, 95% CI 3.87-4.05) vaccines. Refusal was highest among the lowest and highest income levels. Finally, a previous diagnosis of obesity and living in an area of high deprivation were associated with lower refusal (OR = 0.87, 95% CI 0.83-0.92 and OR = 0.82 95%, CI 0.79-0.86, respectively). CONCLUSIONS: Studies on HPV vaccine determinants should consider regional-level factors. Efforts to increase HPV vaccine acceptance should include vulnerable populations (such as girls of low income) and girls with limited contact with the healthcare system. PMID- 25297056 TI - Reliability and validity of the DBT-VLCS: A measure to code validation strategies in dialectical behavior therapy sessions. AB - OBJECTIVE: There are six strategies or validation levels in dialectical behavior therapy (DBT), yet there are no measures designed to code for them. This absence limits our understanding of the relationship between validation strategies and treatment outcome. The DBT-Validation Level Coding Scale (DBT-VLCS) was developed to overcome this limitation. METHOD: This research reports on the interrater reliability and content validity for the DBT-VLCS. RESULTS: Overall, interrater reliability was excellent for all items, with the exception of two items that demonstrated good reliability. Good content validity was demonstrated for six of the seven items. CONCLUSIONS: This preliminary study suggests that the DBT-VLCS is a reliable and valid measure to code the presence of validation in DBT. This measure creates the opportunity for research that has not previously been possible. PMID- 25297057 TI - Adolescent's psychotic-like symptoms associated with Internet addiction. PMID- 25297060 TI - Validity, internal consistency reliability and one-year stability of the Slovene translation of the Measure of Processes of Care (20-item version). AB - BACKGROUND: The Measure of Processes of Care (MPOC) was developed as a self administered questionnaire for parents to report on behaviours of healthcare providers. The original (MPOC-56) and the 20-item version (MPOC-20) have established reliability and validity, but the instrument must be rechecked whenever translated and applied in a different social and cultural setting. The aim of our study was to evaluate validity, internal consistency reliability and 1 year stability of the Slovene translation of MPOC-20. METHODS: Parents of children who were admitted as inpatients or outpatients of several hospitals and health centres were invited to participate. MPOC-20, the Client Satisfaction Questionnaire (CSQ-8) and a separate question on stress and worries were sent by mail. Descriptive item analysis was performed. Cronbach's alpha coefficient and corrected item-total correlations were used to assess internal consistency for each of the five MPOC-20 subscales. To evaluate validity, we correlated the MPOC 20 subscale scores with CSQ-8 scores and a stress alleviation rating. Assessment with MPOC-20 was performed again 1 year later and we used paired-samples tests to compare mean scores of both assessments. RESULTS: Parents of 235 children participated in the study (80% mothers). They reported high general satisfaction as 15 out of the 20 MPOC-20 mean item scores were above 5 (out of 7) and none was below 4. The mean MPOC-20 mean subscale scores were 5.83 (SD 1.10) for Coordinated and Comprehensive Care for Child and Family, 5.62 (SD 1.12) for Respectful and Supportive Care, 5.45 (SD 1.23) for Enabling and Partnership, 5.33 (SD 1.61) for Providing Specific Information about the Child and 4.59 (SD 1.65) for Providing General Information. The ranking order of the mean rating of the MPOC-20 subscales was similar to previous studies. The parents reported that they felt their stress and worries had been notably or slightly reduced through the process of care in the last year in more than two-thirds of the cases. All the MPOC-20 subscales (as well as the CSQ-8 scale) showed high internal consistency: the corrected item-total correlations were far above the lower limit for item's acceptance of 0.3. After 1 year (66 returned questionnaires) none of the mean subscale scores changed statistically significantly (P-values 0.159-0.910). CONCLUSION: The Slovene translation of the MPOC-20 can be considered as a valid and reliable instrument that shows good stability over a period of 1 year, and as such it can be adopted in clinical practice. PMID- 25297061 TI - Hospital trust borrows L114m to end private financing deal 19 years early. PMID- 25297058 TI - A 14-week randomized, placebo-controlled, double-blind clinical trial to evaluate the efficacy and safety of ginseng polysaccharide (Y-75). AB - BACKGROUND: The Y-75 (Ginsan) acidic polysaccharide from Korean Panax ginseng has been shown to function as an immunomodulatory molecule. However, the efficacy of Y-75 has not been evaluated in clinical trial. METHODS: We verified Y-75 (6 g/day) for safety and immune efficacy in 72 healthy volunteers aged 50-75 years using a randomized, placebo-controlled, parallel, double-blind study. The activities of natural killer (NK) cells and peripheral blood phagocytes, as well as serum levels of monocyte-derived mediators, were assessed before and after administration for 8 and 14 weeks. This trial is registered at ClinicalTrials.gov (NCT02161198). RESULTS: Y-75 significantly enhanced NK cell cytotoxic activity by 35.2% and 40.2% from baseline after administration for 8 and 14 weeks, respectively. The phagocytic activity of peripheral blood cells was also significantly increased by 25.2% and 39.4% and serum level of TNF-alpha by 38.2% and 44.5% after treatment for 8 and 14 weeks, respectively. Differences in the efficacy of variables compared to the placebo group were also significant. Administration of Y-75 was well tolerated without treatment-related adverse events or alteration of complete blood cell count or blood chemistry over the entire study period. CONCLUSION: Y-75 was shown to be a safe and potentially effective natural alternative for enhancing immune function. PMID- 25297062 TI - Comparison of periodontal inflammatory conditions among habitual gutka chewers and betel quid chewers. AB - OBJECTIVE: The aim was to compare the periodontal inflammatory conditions among habitual gutka chewers and betel quid (BQ) chewers. MATERIAL AND METHODS: Forty five gutka chewers, 45 BQ chewers and 50 non-chewers (controls) were included. Demographic data regarding age, gender, duration, and frequency of gutka- and BQ chewing habits and gingival bleeding were collected using a questionnaire. Clinical periodontal parameters [plaque index (PI), bleeding on probing (BOP), probing depth (PD) and clinical attachment loss (AL)] were recorded. Marginal bone loss (MBL) was measured on digital panoramic radiographs. Group differences in periodontal inflammatory parameters were tested using univariate and multivariable analyses (alpha < 5%). RESULTS: Periodontal inflammatory parameters [PI, BOP, PD (4-6 and >6 mm), clinical AL and MBL] were significantly high in gutka and BQ chewers than controls. There was no significant difference in periodontal inflammatory parameters among gutka and BQ chewers. The odds for gingival bleeding were six times and 13 times higher in gutka and BQ chewers, respectively, compared to controls. Comparison of gutka and BQ chewers did not significantly increase the odds of gingival bleeding. CONCLUSION: Periodontal inflammatory conditions were comparable among habitual gutka and BQ chewers; which suggests that gutka chewers and BQ chewers are equally susceptible to periodontal disease. PMID- 25297063 TI - Facilitated transport of small molecules and ions for energy-efficient membranes. AB - In nature, the biological membrane can selectively transport essential small molecules/ions through facilitated diffusion via carrier proteins. Intrigued by this phenomenon and principle, membrane researchers have successfully employed synthetic carriers and carrier-mediated reversible reactions to enhance the separation performance of synthetic membranes. However, the existing facilitated transport membranes as well as the relevant facilitated transport theories have scarcely been comprehensively reviewed in the literature. This tutorial review primarily covers the two aspects of facilitated transport theories: carrier mediated transport mechanisms and facilitated transport chemistries, including the design and fabrication of facilitated transport membranes. The applications of facilitated transport membranes in energy-intensive membrane processes (gas separation, pervaporation, and proton exchange membrane fuel cells) have also been discussed. Hopefully, this review will provide guidelines for the future research and development of facilitated transport membranes with high energy efficiency. PMID- 25297065 TI - Control of the transition between Ni-C and Ni-SI(a) states by the redox state of the proximal Fe-S cluster in the catalytic cycle of [NiFe] hydrogenase. AB - [NiFe] hydrogenase catalyzes the reversible cleavage of H2. The electrons produced by the H2 cleavage pass through three Fe-S clusters in [NiFe] hydrogenase to its redox partner. It has been reported that the Ni-SI(a), Ni-C, and Ni-R states of [NiFe] hydrogenase are involved in the catalytic cycle, although the mechanism and regulation of the transition between the Ni-C and Ni SI(a) states remain unrevealed. In this study, the FT-IR spectra under light irradiation at 138-198 K show that the Ni-L state of [NiFe] hydrogenase is an intermediate between the transition of the Ni-C and Ni-SI(a) states. The transition of the Ni-C state to the Ni-SI(a) state occurred when the proximal [Fe4S4]p(2+/+) cluster was oxidized, but not when it was reduced. These results show that the catalytic cycle of [NiFe] hydrogenase is controlled by the redox state of its [Fe4S4]p(2+/+) cluster, which may function as a gate for the electron flow from the NiFe active site to the redox partner. PMID- 25297064 TI - Effect of an alpha-lactalbumin-enriched infant formula supplemented with oligofructose on fecal microbiota, stool characteristics, and hydration status: a randomized, double-blind, controlled trial. AB - AIMS: To evaluate the impact of oligofructose (OF)-supplemented infant formula on fecal microbiota, stool characteristics, and hydration. METHODS: Ninety-five formula-fed infants were randomized to alpha-lactalbumin-enriched control formula (CF) or identical formula with 3.0 g/L OF (EF) for 8 weeks; 50 infants fed human milk (HM) were included. RESULTS: Eighty-four infants completed the study, 70 met per-protocol criteria. Over 8 weeks, bifidobacteria increased more in EF than CF group (0.70 vs. 0.16 log10 bacterial counts/g dry feces, P = .008); EF was not significantly different from HM group (P = .32). EF group stool consistency was intermediate between CF and HM groups; at week 8, EF group had softer stools than CF (5-point scale: 1 = hard, 5 = watery; consistency score 3.46 vs. 2.82, P = .015) without significant differences in stool frequency. Physician-assessed hydration status was normal for all infants. CONCLUSIONS: Infant formula with 3.0 g/L OF promoted bifidobacteria growth and softer stools without adversely affecting stool frequency or hydration. PMID- 25297066 TI - Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement. AB - The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic alpha2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4 dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions. PMID- 25297067 TI - Visual workflows for 13C-metabolic flux analysis. AB - MOTIVATION: The precise quantification of intracellular metabolic flow rates is of fundamental importance in bio(techno)logy and medical research. The gold standard in the field is metabolic flux analysis (MFA) with 13C-labeling experiments. 13C-MFA workflows orchestrate several, mainly human-in-the-loop, software applications, integrating them with plenty of heterogeneous information. In practice, this had posed a major practical barrier for evaluating, interpreting and understanding isotopic data from carbon labeling experiments. RESULTS: Graphical modeling, interactive model exploration and visual data analysis are the key to overcome this limitation. We have developed a first-of its-kind graphical tool suite providing scientists with an integrated software framework for all aspects of 13C-MFA. Almost 30 modules (plug-ins) have been implemented for the Omix visualization software. Several advanced graphical workflows and ergonomic user interfaces support major domain-specific modeling and proofreading tasks. With that, the graphical suite is a productivity enhancing tool and an original educational training instrument supporting the adoption of 13C-MFA applications in all life science fields. AVAILABILITY: The Omix Light Edition is freely available at http://www.omix-visualization.com CONTACT: k.noeh@fz-juelich.de, p.droste@omix-visualization.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25297068 TI - Genome measures used for quality control are dependent on gene function and ancestry. AB - MOTIVATION: The transition/transversion (Ti/Tv) ratio and heterozygous/nonreference-homozygous (het/nonref-hom) ratio have been commonly computed in genetic studies as a quality control (QC) measurement. Additionally, these two ratios are helpful in our understanding of the patterns of DNA sequence evolution. RESULTS: To thoroughly understand these two genomic measures, we performed a study using 1000 Genomes Project (1000G) released genotype data (N=1092). An additional two datasets (N=581 and N=6) were used to validate our findings from the 1000G dataset. We compared the two ratios among continental ancestry, genome regions and gene functionality. We found that the Ti/Tv ratio can be used as a quality indicator for single nucleotide polymorphisms inferred from high-throughput sequencing data. The Ti/Tv ratio varies greatly by genome region and functionality, but not by ancestry. The het/nonref-hom ratio varies greatly by ancestry, but not by genome regions and functionality. Furthermore, extreme guanine + cytosine content (either high or low) is negatively associated with the Ti/Tv ratio magnitude. Thus, when performing QC assessment using these two measures, care must be taken to apply the correct thresholds based on ancestry and genome region. Failure to take these considerations into account at the QC stage will bias any following analysis. CONTACT: yan.guo@vanderbilt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25297069 TI - ExomeAI: detection of recurrent allelic imbalance in tumors using whole-exome sequencing data. AB - SUMMARY: Whole-exome sequencing (WES) has extensively been used in cancer genome studies; however, the use of WES data in the study of loss of heterozygosity or more generally allelic imbalance (AI) has so far been very limited, which highlights the need for user-friendly and flexible software that can handle low quality datasets. We have developed a statistical approach, ExomeAI, for the detection of recurrent AI events using WES datasets, specifically where matched normal samples are not available. AVAILABILITY: ExomeAI is a web-based application, publicly available at: http://genomequebec.mcgill.ca/exomeai. CONTACT: JavadNadaf@gmail.com or somayyeh.fahiminiya@mcgill.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25297070 TI - Quantifying tumor heterogeneity in whole-genome and whole-exome sequencing data. AB - MOTIVATION: Most tumor samples are a heterogeneous mixture of cells, including admixture by normal (non-cancerous) cells and subpopulations of cancerous cells with different complements of somatic aberrations. This intra-tumor heterogeneity complicates the analysis of somatic aberrations in DNA sequencing data from tumor samples. RESULTS: We describe an algorithm called THetA2 that infers the composition of a tumor sample-including not only tumor purity but also the number and content of tumor subpopulations-directly from both whole-genome (WGS) and whole-exome (WXS) high-throughput DNA sequencing data. This algorithm builds on our earlier Tumor Heterogeneity Analysis (THetA) algorithm in several important directions. These include improved ability to analyze highly rearranged genomes using a variety of data types: both WGS sequencing (including low ~7* coverage) and WXS sequencing. We apply our improved THetA2 algorithm to WGS (including low pass) and WXS sequence data from 18 samples from The Cancer Genome Atlas (TCGA). We find that the improved algorithm is substantially faster and identifies numerous tumor samples containing subclonal populations in the TCGA data, including in one highly rearranged sample for which other tumor purity estimation algorithms were unable to estimate tumor purity. PMID- 25297071 TI - Comparison of therapeutic characteristics of islet cell transplantation simultaneous with pancreatic mesenchymal stem cell transplantation in rats with Type 1 diabetes mellitus. AB - Although, pancreas islet call transplantation is a new, promising method for type 1 diabetic patients, it remains as an experimental procedure applied in selected patients. The present study aimed to investigate effect of pancreatic mesenchymal stem cell transplantation simultaneous with islet cell transplantation on islet liveliness and thus on the treatment of diabetes in type 1 diabetic rats. The study used Wistar Albino Rats and was performed in a total of four groups [control (G1), mesenchymal stem cell (G2), islet (G3) and islet + mesencymal stem cell (G4)] each including 8 rats. Blood glucose level of the rats, in which diabetes model has been created using streptozotocin, was measured after 72 h. Blood samples were obtained from the rats 30 days after transplantation and then, their livers and pancreases were kept in 10% formaldehyde and the experiment was ended. Following staining with H&E, they were morphologically evaluated under a light microscope. Change in mean blood glucose level was statistically significant in G3 and G4 versus G1 and G2 (p = 0.001, p < 0.001, p < 0.001, and p < 0.001 respectively). Histological examination revealed that mean number of islet cells in the pancreases of the rats was higher in G4; difference between the groups was statistically significant (p < 0.001). Transplantation of islet cells together with mesenchymal stem cells showed beneficial effects in terms of prolonging survival of islet grafts suggesting that transplantation of mesenchymal stem cells together with islet cells during clinical islet transplantation may be beneficial in increasing the number of noninsulin dependent patients in Type 1 diabetes. PMID- 25297072 TI - Cost-effectiveness of initiating extrafine- or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study. AB - BACKGROUND: Real-life studies are needed to determine the cost-effectiveness of asthma therapies in clinical practice. AIM: To compare the cost-effectiveness of extrafine-particle inhaled corticosteroid (ICS) with standard size-particle ICS in the United Kingdom (UK) and United States (US). METHODS: These retrospective matched cohort analyses used large electronic databases to study asthma-related outcomes for patients in the UK (12-60 years old; n=1730) and US (12-80 years; n=10,312) prescribed extrafine beclomethasone or fluticasone as their first ICS therapy for asthma. Patients were matched on demographic characteristics and asthma severity during 1 baseline year, and asthma control and asthma-related costs were compared during 1 outcome year. RESULTS: In both the UK and US, adjusted odds of risk-domain asthma control were similar, whereas the odds of overall control (no hospitalisation or oral steroids for asthma, no antibiotics for lower respiratory infection, limited reliever use) were greater for extrafine ICS in both countries (UK odds ratio, 1.23; 95% confidence interval (CI), 1.01 1.50). Asthma-related annual costs, adjusted for baseline, were significantly lower for extrafine-particle ICS cohorts in both countries (UK difference, -L66 (95% CI,-93 to -37)). Cost-effectiveness analyses using the two measures of asthma control found 92 and 98% probabilities of extrafine-particle ICS being the preferred treatment strategy (less costly and more effective than standard size particle ICS) in the UK, and 84 and 100% probabilities in the US. CONCLUSIONS: Initiating ICS therapy for asthma as extrafine-particle ICS seems the dominant treatment option (less costly and more effective) compared with standard size particle ICS in both the UK and the US. PMID- 25297074 TI - Schistura megalodon species nova, a new river loach from the Irra-waddy basin in Dehong, Yunnan, China (Teleostei: Cypriniformes: Nemacheilidae). AB - A new species of river loach, Schistura megalodon sp. nov., is described from the Irrawaddy basin in Yingjiang County, Dehong Autonomous Prefecture, Yunnan Province, China. The following combination of diagnostic characters serve to distinguish it from all other congeners in the given zoogeographical region: a large processus dentiformes in the upper jaw, a short pre-anus length of 65.4% 66.3% of SL, long paired fins (pectoral: 20.8%-24.2% of SL; pelvic: 17.9%-20.6% of SL), a wide body of 9.7%-11.3% of SL at anal fin origin, an incomplete lateral line, the absence of an orbital lobe, and a oad and distinct basicaudal bar with forward extensions. PMID- 25297073 TI - Contrast-enhanced multidetector computed tomography to diagnose pulmonary thromboembolism in an awake dog with pyothorax. AB - OBJECTIVES: To (1) describe the use of contrast-enhanced multidetector computed tomography (CE-MDCT) for identifying pulmonary thromboembolism (PTE) in an awake dog with pyothorax, (2) report the first documented case of PTE associated with pyothorax in veterinary medicine, and (3) review diagnostic imaging modalities and therapeutic options for PTE. CASE SUMMARY: A 5-year, 4-month-old female neutered Labrador Retriever was presented for respiratory distress secondary to a pyothorax. The dog underwent thoracic exploratory surgery in which no underlying etiology was identified. Aerobic bacterial culture grew Streptococcus canis. The patient remained hypoxemic despite thoracocentesis and surgery. CE-MDCT was performed without general anesthesia and showed luminal-filling defects in the right cranial and right and left caudal lobar primary pulmonary arteries consistent with PTE. Anticoagulant therapy using unfractionated heparin was initiated. The dog responded well and was discharged 3 days postoperatively. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first reported case of PTE diagnosed in a dog with pyothorax using CE-MDCT. PMID- 25297075 TI - Influence of a large dam on the longitudinal patterns of fish assemblages in Qingyi Stream. AB - Using seasonally collected data (2009-2010) from 15 sampling sites that represent first- to fifth-order streams within the Qingyi watershed, we examined the spatio temporal patterns of fish assemblages along two longitudinal gradients to explore the effects of a large dam on fish assemblages at the watershed scale. No significant variation was observed in either species richness or assemblage structure across seasons. Species richness significantly varied according to stream order and gradient. Dam construction appeared to decrease species richness upstream substantially, while a significant decrease between gradients only occurred within fourth-order streams. Along the gradient without the large dam, fish assemblage structures presented distinct separation between two neighboring stream orders, with the exception of fourth-order versus fifth-order streams. However, the gradient disrupted by a large dam displayed the opposite pattern in the spatial variation of fish assemblages related with stream orders. Significant between-gradient differences in fish assemblage structures were only observed within fourth-order streams. Species distributions were determined by local habitat environmental factors, including elevation, substrate, water depth, current discharge, wetted width, and conductivity. Our results suggested that dam construction might alter the longitudinal pattern in fish species richness and assemblage structure in Qingyi Stream, despite the localized nature of the ecological effect of dams. PMID- 25297076 TI - Population sizes and group characteristics of Siberian Crane (Leuco-geranus leucogeranus) and Hooded Crane (Grus monacha) in Poyang Lake Wetland. AB - Both the Siberian Crane (Leucogeranus leucogeranus) and Hooded Crane (Grus monacha) have limited population sizes and are considered endangered by domestic Chinese and international agencies. To document the current size of their respective populations and characterize their groups, between October 2012 and April 2013 we undertook fieldwork at four nature reserve areas within the Poyang Lake wetlands. We divided Poyanghu National Nature Reserve (PYH) into the Wucheng (PWC) and Hengfeng areas (PHF), because each are each located in different counties. Our fieldwork showed that the Siberian Crane occurred mainly in PYH (364 in the PHF, 158 in the PWC) and the Nanjishan Wetland National Nature Reserve (NJS, with 200 individuals). The Hooded Crane was mainly distributed in PYH (302 in the PHF and 154 in the PWC). Family groups accounted for more than 50% of the total number of groups among both species, with Hooded Cranes forming more family groups than Siberian Cranes. Typically, these groups were formed of two adults with one offspring (Siberian Crane), and two adults with two offspring (Hooded Crane), with the mean family group size of the Siberian Crane and Hooded Crane being respectively 2.65 +/- 0.53 (n=43) and 3.09 +/- 0.86 (n=47) individuals per group. The mean collective group size of the Siberian Crane and Hooded Crane included 28.09 +/- 24.94 (n=23) and 28.94 +/- 27.97 (n=16) individuals per group, respectively, with the proportion of juveniles among Hooded Cranes being more than double that seen among the Siberian Cranes. PMID- 25297077 TI - Gene cloning and induced expression pattern of IRF4 and IRF10 in the Asian swamp eel (Monopterus albus). AB - The Asian swamp eel (Monopterus albus) is one of the most economically important freshwater fish in East Asia, but data on the immune genes of M. albus are scarce compared to other commercially important fish. A better understanding of the eel's immune responses may help in developing strategies for disease management, potentially improving yields and mitigating losses. In mammals, interferon regulatory factors (IRFs) play a vital role in both the innate and adaptive immune system; though among teleosts IRF4 and IRF10 have seldom been studied. In this study, we characterized IRF4 and IRF10 from M. albus (maIRF4 and maIRF10) and found that maIRF4 cDNA consists of 1 716 nucleotides encoding a 451 amino acid (aa) protein, while maIRF10 consists of 1 744 nucleotides including an open reading frame (ORF) of 1 236 nt encoding 411 aa. The maIRF10 gene was constitutively expressed at high levels in a variety of tissues, while maIRF4 showed a very limited expression pattern. Expression of maIRF4 and maIRF10 in head kidney, and spleen tissues was significantly up-regulated from 12 h to 48 h post-stimulation with polyinosinic: polycytidylic acid (poly I:C), lipopolysaccharide (LPS) and a common pathogenic bacteria Aeromonas hydrophila. These results suggest that IRF4 and IRF10 play roles in immune responses to both viral and bacterial infections in M. albus. PMID- 25297078 TI - Molecular cloning, sequence analysis, and cadmium stress-rated expression changes of BTG1 in freshwater pearl mussel (Hyriopsis schlegelii). AB - The B cells translocation gene 1 (BTG1) is a member of the BTG/TOB family of anti proliferative genes, which have recently emerged as important regulators of cell growth and differentiation among verteates. Here, for the first time we cloned the full-length cDNA sequence of Hyriopsis schlegelii (Hs-BTG1), an economically important freshwater shellfish and potential indicator of environmental heavy metal pollution, for the first time. Using rapid amplification of cDNA ends (RACE) together with splicing the EST sequence from a haemocyte cDNA liary, we found that Hs-BTG1 contains a 525 bp open reading frame (ORF) encoding a 174 amino-acid polypeptide, a 306 bp 5' untranslated region (5' UTR), and a 571 bp 3' UTR with a Poly(A) tail as well as a transcription termination signal (AATAAA). Homologue searching against GenBank revealed that Hs-BTG1 was closest to Crassostrea gigas BTG1, sharing 50.57% of protein identities. Hs-BTG1 also shares some typical features of the BTG/TOB family, possessing two well-conserved A and B boxes. Clustering analysis of Hs-BTG1 and other known BTGs showed that Hs-BTG1 was also closely related to BTG1 of C. gigas from the inverteate BTG1 clade. Function prediction via homology modeling showed that both Hs-BTG1 and C. gigas BTG1 share a similar three-dimensional structure with Homo sapiens BTG1. Tissue specific expression analysis of the Hs-BTG1 via real-time PCR showed that the transcripts were constitutively expressed, with the highest levels in the hepatopancreas and gills, and the lowest in both haemocyte and muscle tissue. Expression levels of Hs-BTG1 in hepatopancreas (2.03-fold), mantle (2.07-fold), kidney (2.2-fold) and haemocyte (2.5-fold) were enhanced by cadmium (Cd2+) stress, suggesting that Hs-BTG1 may have played a significant role in H. schlegelii adaptation to adverse environmental conditions. PMID- 25297079 TI - Cloning the sterol carrier protein 2 genes of Japanese toad (Bufo japonicus formosus) and Chinese toad (Bufo gargarizans) and its tissue expression analysis. AB - In this study, to clarify the bioactive polypeptides included in the skins and secretions of Bufo, we screened the Japanese toad (Bufo japonicus formosus) skin cDNA liary by colony polymerase chain reaction (PCR), and obtained a transcript of 1 075 bp consisting of 1 37 bp 5' untranslated region (UTR), 515 bp 3' UTR and a 423 bp open reading frame (ORF) encoding a polypeptide of 140 amino acid residues (GenBank accession number: KF359945). Homolog analysis showed a 70%-96% homology with sterol carrier protein-2 (SCP-2) present in other animals, which is implicated in lipid metabolism of other organisms. The gene SCP-2 of Chinese toad (B. gargarizans) was cloned from a first strand cDNA of Bufo skin (GenBank accession number: KF381341) via PCR, whose encoding polypeptide has only one amino acid difference from that of Japanese toad. Tissue distribution analysis showed that SCP-2 expressed in all organs tested, though in the liver and spleen it manifested lower expression than in other organs. These findings might indicate SCP-2 being one of the active ingredients in toad skin. These findings may in turn have implications for further drug development from traditional Chinese medicine sources. PMID- 25297080 TI - MicroRNA signature in response to nutrient restriction and re-feeding in fast skeletal muscle of grass carp (Ctenopharyngodon idella). AB - The grass carp (Ctenopharyngodon idella) is one of the most important cultivated fish species in China. Mounting evidences suggests that microRNAs (miRNAs) may be key regulators of skeletal muscle among the grass carp, but the knowledge of the identity of myogenic miRNAs and role of miRNAs during skeletal muscle anabolic state remains limited. In the present study, we choose 8 miRNAs previously reported to act as muscle growth-related miRNAs for fasting-refeeding research. We investigated postprandial changes in the expression of 8 miRNAs following a single satiating meal in grass carp juveniles who had been fasting for one week and found that 7 miRNAs were sharply up-regulated within 1 or 3 h after refeeding, suggesting that they may be promising candidate miRNAs involved in a fast-response signaling system that regulates fish skeletal muscle growth. PMID- 25297081 TI - Effects of surround suppression on response adaptation of V1 neurons to visual stimuli. AB - The influence of intracortical inhibition on the response adaptation of visual cortical neurons remains in debate. To clarify this issue, in the present study the influence of surround suppression evoked through the local inhibitory interneurons on the adaptation effects of neurons in the primary visual cortex (V1) were observed. Moreover, the adaptations of V1 neurons to both the high contrast visual stimuli presented in the classical receptive field (CRF) and to the costimulation presented in the CRF and the surrounding nonclassical receptive field (nCRF) were compared. The intensities of surround suppression were modulated with different sized grating stimuli. The results showed that the response adaptation of V1 neurons decreased significantly with the increase of surround suppression and this adaptation decrease was due to the reduction of the initial response of V1 neurons to visual stimuli. However, the plateau response during adaptation showed no significant changes. These findings indicate that the adaptation effects of V1 neurons may not be directly affected by surround suppression, but may be dynamically regulated by a negative feedback network and be finely adjusted by its initial spiking response to stimulus. This adaptive regulation is not only energy efficient for the central nervous system, but also beneficially acts to maintain the homeostasis of neuronal response to long presenting visual signals. PMID- 25297082 TI - Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma. AB - Here, we used reverse transcription-PCR (RT-PCR) and western blot to detect protease-activated receptor (PAR) 1, PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma, and investigated the co relationship between PAR expression and clinic-pathological data for esophageal cancer. The methylation of PAR4 gene promoter involved in esophageal carcinoma was also analyzed. By comparing the mRNA expressions of normal esophageal tissue and human esophageal epithelial cells (HEEpiC), we found that among the 28 cases of esophageal squamous cell carcinoma, PAR1 (60%) and PAR2 (71%) were elevated in 17 and 20 cases, respectively, and PAR4 (68%) expression was lowered in 19 cases. Whereas, in human esophageal squamous cells (TE-1 and TE-10), PAR1 and PAR2 expression was increased but PAR4 was decreased. Combined with clinical data, the expression of PAR1 in poorly differentiated (P=0.016) and middle and lower parts of the esophagus (P=0.016) was higher; expression of PAR4 in poorly differentiated carcinoma was lower (P=0.049). Regarding TE-1 and TE-10 protein expression, we found that in randomized esophageal carcinoma, PAR1 (P=0.027) and PAR2 (P=0.039) expressions were increased, but lowered for PAR4 (P=0.0001). In HEEpiC, TE-1, TE-10, esophageal and normal esophagus tissue samples (case No. 7), the frequency of methylation at the 19 CpG loci of PAR4 was 35.4%, 95.2%, 83.8%, 62.6% and 48.2%, respectively. Our results indicate that the expression of PAR1 and PAR2 in esophageal squamous cell carcinoma is increased but PAR4 is decreased. Hypermethylation of the promoter of the PAR4 gene may contribute to reduced expression of PAR4 in esophageal squamous cell carcinoma. PMID- 25297083 TI - Differences in cocaine-induced place preference persistence, locomotion and social behaviors between C57BL/6J and BALB/cJ mice. AB - C57BL/6J and BALB/cJ mice display significant differences in sociability and response to drugs, but the phenotypic variability of their susceptibility to cocaine is still not well known. In this study, the differences between these two mice strains in the persistence of cocaine-induced conditioned place preference (CPP), as well as the locomotion and social behaviors after the 24-hour withdrawal from a four-day cocaine (20 mg/kg/day) administration were investigated. The results showed that the cocaine-induced CPP persisted over two weeks in C57BL/6J mice, while it diminished within one week among BALB/cJ mice. After 24-hours of cocaine withdrawal, high levels of locomotion as well as low levels of social interaction and aggressive behavior were found in C57BL/6J mice, but no significant changes were found in BALB/cJ mice, indicating that cocaine induced CPP persistence, locomotion and social behavior are not consistent between these two strains, and that overall C57BL/6J mice are more susceptible to cocaine than BALB/cJ mice at the tested doses. PMID- 25297085 TI - The medial prefrontal cortex and the deceptiveness of memory. PMID- 25297084 TI - Progress on low susceptibility mechanisms of transmissible spongiform encephalopathies. AB - Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative diseases detected in a wide range of mammalian species. The "protein-only" hypothesis of TSE suggests that prions are transmissible particles devoid of nucleic acid and the primary pathogenic event is thought to be the conversion of cellular prion protein (PrP(C)) into the disease-associated isoform (PrP(Sc)). According to susceptibility to TSEs, animals can be classified into susceptible species and low susceptibility species. In this review we focus on several species with low susceptibility to TSEs: dogs, rabbits, horses and buffaloes. We summarize recent studies into the characteristics of low susceptibility regarding protein structure, and biochemical and genetic properties. PMID- 25297086 TI - Neuroinflammation mediates synergy between cerebral ischemia and amyloid-beta to cause synaptic depression. PMID- 25297087 TI - Motor cortex is functionally organized as a set of spatially distinct representations for complex movements. AB - There is a long-standing debate regarding the functional organization of motor cortex. Intracortical microstimulation (ICMS) studies have provided two contrasting views depending on the duration of stimulation. In the rat, short duration ICMS reveals two spatially distributed forelimb movement representations, the rostral forelimb area (RFA) and caudal forelimb area (CFA), eliciting identical movements. In contrast, long-duration ICMS reveals spatially distributed, complex, multijoint movement areas, with grasping found exclusively in the rostral area and reach-shaping movements of the arm located in the caudal area. To provide corroboration for which interpretation is correct, we selectively inactivated the RFA/grasp area during the performance of skilled forelimb behaviors using a reversible cortical cooling deactivation technique. A significant impairment of grasping in the single-pellet retrieval task and manipulations of pasta was observed during cooling deactivation of the RFA/grasp area, but not the CFA/arm area. Our results indicate a movement-based, rather than a muscle-based, functional organization of motor cortex, and provide evidence for a conserved homology of independent grasp and reach circuitry shared between primates and rats. PMID- 25297088 TI - Mutant alpha-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. AB - Parkinson disease (PD) is an alpha-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T) in the alpha-synuclein gene (SNCA) are sufficient to cause PD, but the mechanism of their selective action on vulnerable DA SN neurons is unknown. In a mouse model overexpressing mutant alpha-synuclein (A53T-SNCA), we identified a SN-selective increase of in vivo firing frequencies in DA midbrain neurons, which was not observed in DA neurons in the ventral tegmental area. The selective and age-dependent gain-of-function phenotype of A53T-SCNA overexpressing DA SN neurons was in part mediated by an increase of their intrinsic pacemaker frequency caused by a redox-dependent impairment of A-type Kv4.3 potassium channels. This selective enhancement of "stressful pacemaking" of DA SN neurons in vivo defines a functional response to mutant alpha-synuclein that might be useful as a novel biomarker for the "DA system at risk" before the onset of neurodegeneration in PD. PMID- 25297090 TI - Abeta selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer's disease. AB - Degeneration of basal forebrain (BF) cholinergic neurons is one of the early pathological events in Alzheimer's disease (AD) and is thought to be responsible for the cholinergic and cognitive deficits in AD. The functions of this group of neurons are highly influenced by glutamatergic inputs from neocortex. We found that activation of metabotropic glutamate receptor 7 (mGluR7) decreased NMDAR mediated currents and NR1 surface expression in rodent BF neurons via a mechanism involving cofilin-regulated actin dynamics. In BF cholinergic neurons, beta amyloid (Abeta) selectively impaired mGluR7 regulation of NMDARs by increasing p21-activated kinase activity and decreasing cofilin-mediated actin depolymerization through a p75(NTR)-dependent mechanism. Cell viability assays showed that activation of mGluR7 protected BF neurons from NMDA-induced excitotoxicity, which was selectively impaired by Abeta in BF cholinergic neurons. It provides a potential basis for the Abeta-induced disruption of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD. PMID- 25297089 TI - Frontoparietal correlation dynamics reveal interplay between integration and segregation during visual working memory. AB - Working memory requires large-scale cooperation among widespread cortical and subcortical brain regions. Importantly, these processes must achieve an appropriate balance between functional integration and segregation, which are thought to be mediated by task-dependent spatiotemporal patterns of correlated activity. Here, we used cross-correlation analysis to estimate the incidence, magnitude, and relative phase angle of temporally correlated activity from simultaneous local field potential recordings in a network of prefrontal and posterior parietal cortical areas in monkeys performing an oculomotor, delayed match-to-sample task. We found long-range intraparietal and frontoparietal correlations that display a bimodal distribution of relative phase values, centered near 0 degrees and 180 degrees , suggesting a possible basis for functional segregation among distributed networks. Both short- and long-range correlations display striking task-dependent transitions in strength and relative phase, indicating that cognitive events are accompanied by robust changes in the pattern of temporal coordination across the frontoparietal network. PMID- 25297091 TI - Alzheimer's disease-like pathology induced by amyloid-beta oligomers in nonhuman primates. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-beta (Abeta) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble Abeta oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, Abeta oligomers diffused into the brain and accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation, astrocyte and microglial activation, were observed in regions of the macaque brain where Abeta oligomers were abundantly detected. Most importantly, oligomer injections induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with Abeta oligomers, as fibrillar amyloid deposits were not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus, generation of a macaque model of AD that links Abeta oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD. PMID- 25297092 TI - Human muscle spindle sensitivity reflects the balance of activity between antagonistic muscles. AB - Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The "alpha-gamma coactivation" hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its antagonist. By recording spindle afferent responses from alert humans using microneurography, I show that spindle output does reflect antagonistic muscle balance. Specifically, regardless of identical kinematic profiles across active finger movements, stretch of the loaded antagonist muscle (i.e., extensor) was accompanied by increased afferent firing rates from this muscle compared with the baseline case of no constant external load. In contrast, spindle firing rates from the stretching antagonist were lowest when the agonist muscle powering movement (i.e., flexor) acted against an additional resistive load. Stepwise regressions confirmed that instantaneous velocity, extensor, and flexor muscle activity had a significant effect on spindle afferent responses, with flexor activity having a negative effect. Therefore, the results indicate that, as consequence of their efferent control, spindle sensitivity (gain) to muscle stretch reflects the balance of activity between antagonistic muscles rather than only the activity of the spindle-bearing muscle. PMID- 25297093 TI - Phasic activation of individual neurons in the locus ceruleus/subceruleus complex of monkeys reflects rewarded decisions to go but not stop. AB - Neurons in the brainstem nucleus locus ceruleus (LC) often exhibit phasic activation in the context of simple sensory-motor tasks. The functional role of this activation, which leads to the release of norepinephrine throughout the brain, is not yet understood in part because the conditions under which it occurs remain in question. Early studies focused on the relationship of LC phasic activation to salient sensory events, whereas more recent work has emphasized its timing relative to goal-directed behavioral responses, possibly representing the end of a sensory-motor decision process. To better understand the relationship between LC phasic activation and sensory, motor, and decision processing, we recorded spiking activity of neurons in the LC+ (LC and the adjacent, norepinephrine-containing subceruleus nucleus) of monkeys performing a countermanding task. The task required the monkeys to occasionally withhold planned, saccadic eye movements to a visual target. We found that many well isolated LC+ units responded to both the onset of the visual cue instructing the monkey to initiate the saccade and again after saccade onset, even when it was initiated erroneously in the presence of a stop signal. Many of these neurons did not respond to saccades made outside of the task context. In contrast, neither the appearance of the stop signal nor the successful withholding of the saccade elicited an LC+ response. Therefore, LC+ phasic activation encodes sensory and motor events related to decisions to execute, but not withhold, movements, implying a functional role in goal-directed actions, but not necessarily more covert forms of processing. PMID- 25297094 TI - A feedforward inhibitory circuit mediates lateral refinement of sensory representation in upper layer 2/3 of mouse primary auditory cortex. AB - Sensory information undergoes ordered and coordinated processing across cortical layers. Whereas cortical layer (L) 4 faithfully acquires thalamic information, the superficial layers appear well staged for more refined processing of L4 relayed signals to generate corticocortical outputs. However, the specific role of superficial layer processing and how it is specified by local synaptic circuits remains not well understood. Here, in the mouse primary auditory cortex, we showed that upper L2/3 circuits play a crucial role in refining functional selectivity of excitatory neurons by sharpening auditory tonal receptive fields and enhancing contrast of frequency representation. This refinement is mediated by synaptic inhibition being more broadly recruited than excitation, with the inhibition predominantly originating from interneurons in the same cortical layer. By comparing the onsets of synaptic inputs as well as of spiking responses of different types of neuron, we found that the broadly tuned, fast responding inhibition observed in excitatory cells can be primarily attributed to feedforward inhibition originating from parvalbumin (PV)-positive neurons, whereas somatostatin (SOM)-positive interneurons respond much later compared with the onset of inhibitory inputs to excitatory neurons. We propose that the feedforward circuit-mediated inhibition from PV neurons, which has an analogous function to lateral inhibition, enables upper L2/3 excitatory neurons to rapidly refine auditory representation. PMID- 25297095 TI - The fusion of mental imagery and sensation in the temporal association cortex. AB - It is well understood that the brain integrates information that is provided to our different senses to generate a coherent multisensory percept of the world around us (Stein and Stanford, 2008), but how does the brain handle concurrent sensory information from our mind and the external world? Recent behavioral experiments have found that mental imagery--the internal representation of sensory stimuli in one's mind--can also lead to integrated multisensory perception (Berger and Ehrsson, 2013); however, the neural mechanisms of this process have not yet been explored. Here, using functional magnetic resonance imaging and an adapted version of a well known multisensory illusion (i.e., the ventriloquist illusion; Howard and Templeton, 1966), we investigated the neural basis of mental imagery-induced multisensory perception in humans. We found that simultaneous visual mental imagery and auditory stimulation led to an illusory translocation of auditory stimuli and was associated with increased activity in the left superior temporal sulcus (L. STS), a key site for the integration of real audiovisual stimuli (Beauchamp et al., 2004a, 2010; Driver and Noesselt, 2008; Ghazanfar et al., 2008; Dahl et al., 2009). This imagery-induced ventriloquist illusion was also associated with increased effective connectivity between the L. STS and the auditory cortex. These findings suggest an important role of the temporal association cortex in integrating imagined visual stimuli with real auditory stimuli, and further suggest that connectivity between the STS and auditory cortex plays a modulatory role in spatially localizing auditory stimuli in the presence of imagined visual stimuli. PMID- 25297096 TI - Spontaneous microsaccades reflect shifts in covert attention. AB - Microsaccade rate during fixation is modulated by the presentation of a visual stimulus. When the stimulus is an endogenous attention cue, the ensuing microsaccades tend to be directed toward the cue. This finding has been taken as evidence that microsaccades index the locus of spatial attention. But the vast majority of microsaccades that subjects make are not triggered by visual stimuli. Under natural viewing conditions, spontaneous microsaccades occur frequently (2-3 Hz), even in the absence of a stimulus or a task. While spontaneous microsaccades may depend on low-level visual demands, such as retinal fatigue, image fading, or fixation shifts, it is unknown whether their occurrence corresponds to changes in the attentional state. We developed a protocol to measure whether spontaneous microsaccades reflect shifts in spatial attention. Human subjects fixated a cross while microsaccades were detected from streaming eye-position data. Detection of a microsaccade triggered the appearance of a peripheral ring of grating patches, which were followed by an arrow (a postcue) indicating one of them as the target. The target was either congruent or incongruent (opposite) with respect to the direction of the microsaccade (which preceded the stimulus). Subjects reported the tilt of the target (clockwise or counterclockwise relative to vertical). We found that accuracy was higher for congruent than for incongruent trials. We conclude that the direction of spontaneous microsaccades is inherently linked to shifts in spatial attention. PMID- 25297097 TI - Sparse coding and lateral inhibition arising from balanced and unbalanced dendrodendritic excitation and inhibition. AB - The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral-granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID- 25297098 TI - Presynaptic BK channels modulate ethanol-induced enhancement of GABAergic transmission in the rat central amygdala nucleus. AB - Large-conductance calcium-activated potassium BK channels are widely expressed in the brain and are involved in the regulation of neuronal functions such as neurotransmitter release. However, their possible role in mediating ethanol induced GABA release is still unknown. We assessed the role of BK channels in modulating the action of ethanol on inhibitory synaptic transmission mediated via GABAA receptors in the rat central nucleus of the amygdala (CeA). Evoked IPSCs (eIPSCs) mediated by GABAA receptors were isolated from CeA neurons under whole cell voltage clamp, and their response to selective BK channel antagonists, channel activators, or ethanol was analyzed. Blocking BK channels with the specific BK channel antagonist paxilline significantly increased the mean amplitude of eIPSCs, whereas the activation of BK channels with the channel opener NS1619 reversibly attenuated the mean amplitude of eIPSCs. Ethanol (50 mM) alone enhanced the amplitude of eIPSCs but failed to further enhance eIPSCs in the slices pretreated with paxilline. Bath application of either BK channel blockers significantly increased the frequency of miniature IPSCs (mIPSCs). Similarly, 50 mM ethanol alone also enhanced mIPSC frequency. Increases in mIPSC frequency by either selective BK channel antagonists or ethanol were not accompanied with changes in the amplitude of mIPSCs. Furthermore, following bath application of BK channel blockers for 10 min, ethanol failed to further increase mIPSC frequency. Together, these results suggest that blocking BK channels mimics the effects of ethanol on GABA release and that presynaptic BK channels could serve as a target for ethanol effects in CeA. PMID- 25297099 TI - The schizophrenia susceptibility gene dysbindin regulates dendritic spine dynamics. AB - Dysbindin is a schizophrenia susceptibility gene required for the development of dendritic spines. The expression of dysbindin proteins is decreased in the brains of schizophrenia patients, and neurons in mice carrying a deletion in the dysbindin gene have fewer dendritic spines. Hence, dysbindin might contribute to the spine pathology of schizophrenia, which manifests as a decrease in the number of dendritic spines. The development of dendritic spines is a dynamic process involving formation, retraction, and transformation of dendritic protrusions. It has yet to be determined whether dysbindin regulates the dynamics of dendritic protrusions. Here we address this question using time-lapse imaging in hippocampal neurons. Our results show that dysbindin is required to stabilize dendritic protrusions. In dysbindin-null neurons, dendritic protrusions are hyperactive in formation, retraction, and conversion between different types of protrusions. We further show that CaMKIIalpha is required for the stabilization of mushroom/thin spines, and that the hyperactivity of dendritic protrusions in dysbindin-null neurons is attributed in part to decreased CaMKIIalpha activity resulting from increased inhibition of CaMKIIalpha by Abi1. These findings elucidate the function of dysbindin in the dynamic morphogenesis of dendritic protrusions, and reveal the essential roles of dysbindin and CaMKIIalpha in the stabilization of dendritic protrusions during neuronal development. PMID- 25297100 TI - Stress induces pain transition by potentiation of AMPA receptor phosphorylation. AB - Chronic postsurgical pain is a serious issue in clinical practice. After surgery, patients experience ongoing pain or become sensitive to incident, normally nonpainful stimulation. The intensity and duration of postsurgical pain vary. However, it is unclear how the transition from acute to chronic pain occurs. Here we showed that social defeat stress enhanced plantar incision-induced AMPA receptor GluA1 phosphorylation at the Ser831 site in the spinal cord and greatly prolonged plantar incision-induced pain. Interestingly, targeted mutation of the GluA1 phosphorylation site Ser831 significantly inhibited stress-induced prolongation of incisional pain. In addition, stress hormones enhanced GluA1 phosphorylation and AMPA receptor-mediated electrical activity in the spinal cord. Subthreshold stimulation induced spinal long-term potentiation in GluA1 phosphomimetic mutant mice, but not in wild-type mice. Therefore, spinal AMPA receptor phosphorylation contributes to the mechanisms underlying stress-induced pain transition. PMID- 25297101 TI - Working memory contributions to reinforcement learning impairments in schizophrenia. AB - Previous research has shown that patients with schizophrenia are impaired in reinforcement learning tasks. However, behavioral learning curves in such tasks originate from the interaction of multiple neural processes, including the basal ganglia- and dopamine-dependent reinforcement learning (RL) system, but also prefrontal cortex-dependent cognitive strategies involving working memory (WM). Thus, it is unclear which specific system induces impairments in schizophrenia. We recently developed a task and computational model allowing us to separately assess the roles of RL (slow, cumulative learning) mechanisms versus WM (fast but capacity-limited) mechanisms in healthy adult human subjects. Here, we used this task to assess patients' specific sources of impairments in learning. In 15 separate blocks, subjects learned to pick one of three actions for stimuli. The number of stimuli to learn in each block varied from two to six, allowing us to separate influences of capacity-limited WM from the incremental RL system. As expected, both patients (n = 49) and healthy controls (n = 36) showed effects of set size and delay between stimulus repetitions, confirming the presence of working memory effects. Patients performed significantly worse than controls overall, but computational model fits and behavioral analyses indicate that these deficits could be entirely accounted for by changes in WM parameters (capacity and reliability), whereas RL processes were spared. These results suggest that the working memory system contributes strongly to learning impairments in schizophrenia. PMID- 25297103 TI - Mirror reversal and visual rotation are learned and consolidated via separate mechanisms: recalibrating or learning de novo? AB - Motor learning tasks are often classified into adaptation tasks, which involve the recalibration of an existing control policy (the mapping that determines both feedforward and feedback commands), and skill-learning tasks, requiring the acquisition of new control policies. We show here that this distinction also applies to two different visuomotor transformations during reaching in humans: Mirror-reversal (left-right reversal over a mid-sagittal axis) of visual feedback versus rotation of visual feedback around the movement origin. During mirror reversal learning, correct movement initiation (feedforward commands) and online corrections (feedback responses) were only generated at longer latencies. The earliest responses were directed into a nonmirrored direction, even after two training sessions. In contrast, for visual rotation learning, no dependency of directional error on reaction time emerged, and fast feedback responses to visual displacements of the cursor were immediately adapted. These results suggest that the motor system acquires a new control policy for mirror reversal, which initially requires extra processing time, while it recalibrates an existing control policy for visual rotations, exploiting established fast computational processes. Importantly, memory for visual rotation decayed between sessions, whereas memory for mirror reversals showed offline gains, leading to better performance at the beginning of the second session than in the end of the first. With shifts in time-accuracy tradeoff and offline gains, mirror-reversal learning shares common features with other skill-learning tasks. We suggest that different neuronal mechanisms underlie the recalibration of an existing versus acquisition of a new control policy and that offline gains between sessions are a characteristic of latter. PMID- 25297102 TI - The amygdala and basal forebrain as a pathway for motivationally guided attention. AB - Visual stimuli associated with rewards attract spatial attention. Neurophysiological mechanisms that mediate this process must register both the motivational significance and location of visual stimuli. Recent neurophysiological evidence indicates that the amygdala encodes information about both of these parameters. Furthermore, the firing rate of amygdala neurons predicts the allocation of spatial attention. One neural pathway through which the amygdala might influence attention involves the intimate and bidirectional connections between the amygdala and basal forebrain (BF), a brain area long implicated in attention. Neurons in the rhesus monkey amygdala and BF were therefore recorded simultaneously while subjects performed a detection task in which the stimulus-reward associations of visual stimuli modulated spatial attention. Neurons in BF were spatially selective for reward-predictive stimuli, much like the amygdala. The onset of reward-predictive signals in each brain area suggested different routes of processing for reward-predictive stimuli appearing in the ipsilateral and contralateral fields. Moreover, neurons in the amygdala, but not BF, tracked trial-to-trial fluctuations in spatial attention. These results suggest that the amygdala and BF could play distinct yet inter-related roles in influencing attention elicited by reward-predictive stimuli. PMID- 25297104 TI - Early alterations in functional connectivity and white matter structure in a transgenic mouse model of cerebral amyloidosis. AB - Impairment of brain functional connectivity (FC) is thought to be an early event occurring in diseases with cerebral amyloidosis, such as Alzheimer's disease. Regions sustaining altered functional networks have been shown to colocalize with regions marked with amyloid plaques burden suggesting a strong link between FC and amyloidosis. Whether the decline in FC precedes amyloid plaque deposition or is a consequence thereof is currently unknown. The sequence of events during early stages of the disease is difficult to capture in humans due to the difficulties in providing an early diagnosis and also in view of the heterogeneity among patients. Transgenic mouse lines overexpressing amyloid precursor proteins develop cerebral amyloidosis and constitute an attractive model system for studying the relationship between plaque and functional changes. In this study, ArcAbeta transgenic and wild-type mice were imaged using resting state fMRI methods across their life-span in a cross-sectional design to analyze changes in FC in relation to the pathology. Transgenic mice show compromised development of FC during the first months of postnatal life compared with wild type animals, resulting in functional impairments that affect in particular the sensory-motor cortex already in preplaque stage. These functional alterations were accompanied by structural changes as reflected by reduced fractional anisotropy values, as derived from diffusion tensor imaging. Our results suggest cerebral amyloidosis in mice is preceded by impairment of neuronal networks and white matter structures. FC analysis in mice is an attractive tool for studying the implications of impaired neuronal networks in models of cerebral amyloid pathology. PMID- 25297105 TI - Ganglioside GD3 is required for neurogenesis and long-term maintenance of neural stem cells in the postnatal mouse brain. AB - The maintenance of a neural stem cell (NSC) population in mammalian postnatal and adult life is crucial for continuous neurogenesis and neural repair. However, the molecular mechanism of how NSC populations are maintained remains unclear. Gangliosides are important cellular membrane components in the nervous system. We previously showed that ganglioside GD3 plays a crucial role in the maintenance of the self-renewal capacity of NSCs in vitro. Here, we investigated its role in postnatal and adult neurogenesis in GD3-synthase knock-out (GD3S-KO) and wild type mice. GD3S-KO mice with deficiency in GD3 and the downstream b-series gangliosides showed a progressive loss of NSCs both at the SVZ and the DG of the hippocampus. The decrease of NSC populations in the GD3S-KO mice resulted in impaired neurogenesis at the granular cell layer of the olfactory bulb and the DG in the adult. In addition, defects of the self-renewal capacity and radial glia like stem cell outgrowth of postnatal GD3S-KO NSCs could be rescued by restoration of GD3 expression in these cells. Our study demonstrates that the b series gangliosides, especially GD3, play a crucial role in the long-term maintenance NSC populations in postnatal mouse brain. Moreover, the impaired neurogenesis in the adult GD3S-KO mice led to depression-like behaviors. Thus, our results provide convincing evidence linking b-series gangliosides deficiency and neurogenesis defects to behavioral deficits, and support a crucial role of gangliosides in the long-term maintenance of NSCs in adult mice. PMID- 25297106 TI - Adult neurogenesis is necessary to refine and maintain circuit specificity. AB - The circuitry of the olfactory bulb contains a precise anatomical map that links isofunctional regions within each olfactory bulb. This intrabulbar map forms perinatally and undergoes activity-dependent refinement during the first postnatal weeks. Although this map retains its plasticity throughout adulthood, its organization is remarkably stable despite the addition of millions of new neurons to this circuit. Here we show that the continuous supply of new neuroblasts from the subventricular zone is necessary for both the restoration and maintenance of this precise central circuit. Using pharmacogenetic methods to conditionally ablate adult neurogenesis in transgenic mice, we find that the influx of neuroblasts is required for recovery of intrabulbar map precision after disruption due to sensory block. We further demonstrate that eliminating adult born interneurons in naive animals leads to an expansion of tufted cell axons that is identical to the changes caused by sensory block, thus revealing an essential role for new neurons in circuit maintenance under baseline conditions. These findings show, for the first time, that inhibiting adult neurogenesis alters the circuitry of projection neurons in brain regions that receive new interneurons and points to a critical role for adult-born neurons in stabilizing a brain circuit that exhibits high levels of plasticity. PMID- 25297108 TI - Presynaptic modulation of spinal nociceptive transmission by glial cell line derived neurotrophic factor (GDNF). AB - The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRalpha1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRalpha1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRalpha1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities. PMID- 25297107 TI - Cortical activation associated with muscle synergies of the human male pelvic floor. AB - Human pelvic floor muscles have been shown to operate synergistically with a wide variety of muscles, which has been suggested to be an important contributor to continence and pelvic stability during functional tasks. However, the neural mechanism of pelvic floor muscle synergies remains unknown. Here, we test the hypothesis that activation in motor cortical regions associated with pelvic floor activation are part of the neural substrate for such synergies. We first use electromyographic recordings to extend previous findings and demonstrate that pelvic floor muscles activate synergistically during voluntary activation of gluteal muscles, but not during voluntary activation of finger muscles. We then show, using functional magnetic resonance imaging (fMRI), that a region of the medial wall of the precentral gyrus consistently activates during both voluntary pelvic floor muscle activation and voluntary gluteal activation, but not during voluntary finger activation. We finally confirm, using transcranial magnetic stimulation, that the fMRI-identified medial wall region is likely to generate pelvic floor muscle activation. Thus, muscle synergies of the human male pelvic floor appear to involve activation of motor cortical areas associated with pelvic floor control. PMID- 25297109 TI - Ceiling effects prevent further improvement of transcranial stimulation in skilled musicians. AB - The roles of the motor cortex in the acquisition and performance of skilled finger movements have been extensively investigated over decades. Yet it is still not known whether these roles of motor cortex are expertise-dependent. The present study addresses this issue by comparing the effects of noninvasive transcranial direction current stimulation (tDCS) on the fine control of sequential finger movements in highly trained pianists and musically untrained individuals. Thirteen pianists and 13 untrained controls performed timed-sequence finger movements with each of the right and left hands before and after receiving bilateral tDCS over the primary motor cortices. The results demonstrate an improvement of fine motor control in both hands in musically untrained controls, but deterioration in pianists following anodal tDCS over the contralateral cortex and cathodal tDCS over the ipsilateral cortex compared with the sham stimulation. However, this change in motor performance was not evident after stimulating with the opposite montage. These findings support the notion that changes in dexterous finger movements induced by bihemispheric tDCS are expertise-dependent. PMID- 25297112 TI - Author-initiated retraction: Warne et al, Coordinated regulation of hepatic energy stores by leptin and hypothalamic Agouti-related protein. PMID- 25297111 TI - The TRIM-NHL protein Brat promotes axon maintenance by repressing src64B expression. AB - The morphology and the connectivity of neuronal structures formed during early development must be actively maintained as the brain matures. Although impaired axon stability is associated with the progression of various neurological diseases, relatively little is known about the factors controlling this process. We identified Brain tumor (Brat), a conserved member of the TRIM-NHL family of proteins, as a new regulator of axon maintenance in Drosophila CNS. Brat function is dispensable for the initial growth of Mushroom Body axons, but is required for the stabilization of axon bundles. We found that Brat represses the translation of src64B, an upstream regulator of a conserved Rho-dependent pathway previously shown to promote axon retraction. Furthermore, brat phenotypes are phenocopied by src64B overexpression, and partially suppressed by reducing the levels of src64B or components of the Rho pathway, suggesting that brat promotes axon maintenance by downregulating the levels of Src64B. Finally, Brat regulates brain connectivity via its NHL domain, but independently of its previously described partners Nanos, Pumilio, and d4EHP. Thus, our results uncover a novel post transcriptional regulatory mechanism that controls the maintenance of neuronal architecture by tuning the levels of a conserved rho-dependent signaling pathway. PMID- 25297110 TI - Early monocular defocus disrupts the normal development of receptive-field structure in V2 neurons of macaque monkeys. AB - Experiencing different quality images in the two eyes soon after birth can cause amblyopia, a developmental vision disorder. Amblyopic humans show the reduced capacity for judging the relative position of a visual target in reference to nearby stimulus elements (position uncertainty) and often experience visual image distortion. Although abnormal pooling of local stimulus information by neurons beyond striate cortex (V1) is often suggested as a neural basis of these deficits, extrastriate neurons in the amblyopic brain have rarely been studied using microelectrode recording methods. The receptive field (RF) of neurons in visual area V2 in normal monkeys is made up of multiple subfields that are thought to reflect V1 inputs and are capable of encoding the spatial relationship between local stimulus features. We created primate models of anisometropic amblyopia and analyzed the RF subfield maps for multiple nearby V2 neurons of anesthetized monkeys by using dynamic two-dimensional noise stimuli and reverse correlation methods. Unlike in normal monkeys, the subfield maps of V2 neurons in amblyopic monkeys were severely disorganized: subfield maps showed higher heterogeneity within each neuron as well as across nearby neurons. Amblyopic V2 neurons exhibited robust binocular suppression and the strength of the suppression was positively correlated with the degree of hereogeneity and the severity of amblyopia in individual monkeys. Our results suggest that the disorganized subfield maps and robust binocular suppression of amblyopic V2 neurons are likely to adversely affect the higher stages of cortical processing resulting in position uncertainty and image distortion. PMID- 25297113 TI - Reducing the risk of infection in end-stage kidney failure patients treated by dialysis. PMID- 25297114 TI - Restoration materials and secondary caries using an in vitro biofilm model. AB - This in vitro study investigated whether restoration materials and adhesives influence secondary caries formation in gaps using a short-term in vitro biofilm model. Sixty enamel-dentin blocks were restored with 6 different restoration materials with or without adhesives (n = 10 per group) with a gap: 1) Clearfil AP X composite, 2) Clearfil AP-X composite + SE Bond, 3) Clearfil AP-X composite + ProtectBond, 4) Filtek Silorane composite, 5) Filtek Silorane composite + Silorane System adhesive, or 6) Tytin amalgam. Specimens were subjected to an intermittent 1% sucrose biofilm model for 20 days to create artificial caries lesions. Lesion progression in the enamel-dentin next to the different materials was measured in lesion depth (LD) and mineral loss (ML) using transversal wavelength independent microradiography (T-WIM). A regression analysis was used to compare the LD and ML of the different restoration materials at 4 measurement locations: 1 location at the surface of the enamel, 1 location at the wall of the enamel, and 2 locations at the wall of the dentin. A statistically significant effect of AP-X composite with Protect Bond was found for LD and ML at the WallDentin1 location, leading to less advanced wall lesions. An additional finding was that gap size was also statistically significant at the 2 wall locations in dentin, leading to increasing lesion progression with wider gaps. In conclusion, adhesives can influence wall lesion development in gaps. Protect Bond showed significantly less caries progression compared to bare restoration materials or other adhesives in this short-term in vitro biofilm model. PMID- 25297115 TI - Role of interstitial fluid pressurization in TMJ lubrication. AB - In temporomandibular joints (TMJs), the disc and condylar cartilage function as load-bearing, shock-absorbing, and friction-reducing materials. The ultrastructure of the TMJ disc and cartilage is different from that of hyaline cartilage in other diarthrodial joints, and little is known about their lubrication mechanisms. In this study, we performed micro-tribometry testing on the TMJ disc and condylar cartilage to obtain their region- and direction dependent friction properties. Frictional tests with a migrating contact area were performed on 8 adult porcine TMJs at 5 different regions (anterior, posterior, central, medial, and lateral) in 2 orthogonal directions (anterior posterior and medial-lateral). Some significant regional differences were detected, and the lateral-medial direction showed higher friction than the anterior-posterior direction on both tissues. The mean friction coefficient of condylar cartilage against steel was 0.027, but the disc, at 0.074, displayed a significantly higher friction coefficient. The 2 tissues also exhibited different frictional dependencies on sliding speed and normal loading force. Whereas the friction of condylar cartilage decreased with increased sliding speed and was independent of the magnitude of normal force, friction of the disc showed no dependence on sliding speed but decreased as normal force increased. Further analysis of the Peclet number and frictional coefficients suggested that condylar cartilage relies on interstitial fluid pressurization to a greater extent than the corresponding contact area of the TMJ disc. PMID- 25297116 TI - Saliva suppresses osteoclastogenesis in murine bone marrow cultures. AB - Saliva can reach mineralized surfaces in the oral cavity; however, the relationship between saliva and bone resorption is unclear. Herein, we examined whether saliva affects the process of osteoclastogenesis in vitro. We used murine bone marrow cultures to study osteoclast formation. The addition of fresh sterile saliva eliminated the formation of multinucleated cells that stained positive for tartrate-resistant acid phosphatase (TRAP). In line with the histochemical staining, saliva substantially reduced gene expression of cathepsin K, calcitonin receptor, and TRAP. Addition of saliva led to considerably decreased gene expression of receptor activator of nuclear factor kappa-B (RANK) and, to a lesser extent, that of c-fms. The respective master regulators of osteoclastogenesis (c-fos and NFATc1) and the downstream cell fusion genes (DC STAMP and Atp6v0d2) showed decreased expression after the addition of saliva. Among the costimulatory molecules for osteoclastogenesis, only OSCAR showed decreased expression. In contrast, CD40, CD80, and CD86-all costimulatory molecules of phagocytic cells-were increasingly expressed with saliva. The phagocytic capacity of the cells was confirmed by latex bead ingestion. Based on these in vitro results, it can be concluded that saliva suppresses osteoclastogenesis and leads to the development of a phagocytic cell phenotype. PMID- 25297120 TI - [Not Available]. PMID- 25297117 TI - Dual role of autophagy in lipopolysaccharide-induced preodontoblastic cells. AB - Odontoblasts derive from neural crest-derived odontogenic mesenchymal cells, and they are an important barrier of defense for the host. Survival and immunity of odontoblasts play important roles in protecting the dentin-pulp structure. Autophagy can eliminate damaged organelles and recycle cellular components to facilitate cellular homeostasis. Autophagy can be activated with external stressors, such as starvation, hypoxia, and infection. In this study, the role of autophagy in inflamed odontoblasts was explored, and its possible mechanism was investigated. Cell viability was not affected by mild lipopolysaccharide (LPS) stimulation, and autophagy was activated during this process. Immunofluorescence of light chain 3 confirmed that autophagy was induced with LPS treatment. Early stage autophagy inhibition resulted in down-regulated cell viability, contrary to the up-regulated cell viability at late-stage autophagy inhibition. Western blot suggested that p-Akt and survivin were not activated in the early stage, and they gradually increased and peaked in the late stage. Meanwhile, autophagy was down regulated through the Akt/mTOR/survivin pathway in the late stage. Thus, autophagy has a dual role in inflamed odontoblasts, which indicates its importance in maintaining the microenvironment homeostasis of odontoblasts. Autophagy was induced as a survival mechanism in the early stage, and it decreased through the Akt/mTOR/survivin signaling pathway in the late stage. PMID- 25297118 TI - Significant interethnic differencies in functional variants of PON1 and P2RY12 genes in Roma and Hungarian population samples. AB - Antiplatelet therapy with clopidogrel is one of the most common therapies given to patients worldwide. However, the clinical efficacy and toxicity of clopidogrel is not constant in every patient due to interindividual variations. There are several factors that contribute to these interindividual differencies such as SNPs in genes of specific receptors and enzymes. PON1 (paraoxonase 1) plays an important role in the bioactivation of clopidogrel. Single nucleotide polymorphisms of this gene decrease the activity of paraoxonase enzyme and lead to an unefficient clopidogrel effect. P2RY12 (purinergic receptor P2Y, G-protein coupled, 12) gene is coding a receptor, which is situated on the surface of the platelets and plays a role in ADP-induced platelet aggregation. In this study we investigated 2 functional SNPs of PON1 gene (rs662 and rs854560) and 3 variants of the P2RY12 gene (rs2046934, rs6798347, rs6801273) in samples pooled from average Hungarian Roma and Hungarian population samples with PCR-RFLP method. For the PON1 variants we detected that the R allele frequency was significantly lower in the Roma group compared to the Hungarian population. (0.249 vs 0.318 p < 0.001). By contrast, the frequency of the M allele was significantly higher in Roma than in Hungarians (0.332 vs 0.290 p < 0.05). For the 3 P2RY12 variants we could find significant differencies only in rs2046934: the frequency of the CC genotype is 7 times higher in Hungarians than in Romas (1.4 vs 0.2 %, p < 0.05). The data presented here represent a unique genetic profile in Roma people that has not been reported for other populations. PMID- 25297119 TI - Physiotherapy-led arthroplasty review clinic: a preliminary outcomes analysis. AB - OBJECTIVE: With the rising demand for Orthopaedics in the healthcare sector, service delivery innovations need to be explored to accommodate the increasing workload. Senior Musculoskeletal Physiotherapists have the specialised skills in the assessment of musculoskeletal conditions to determine the impact of surgery on patient outcomes. The aim of the present study was to compare outcomes between a physiotherapy-led arthroplasty review clinic (PT clinic) and the traditional model of orthopaedic surgeon review (OS clinic) after hip and knee replacement. METHODS: This study was a retrospective case-controlled audit using a comprehensive database. Twenty-four patients who had a hip arthroplasty and 52 patients who had a knee arthroplasty were reviewed solely by the PT clinic at 3, 6 and 12 months after surgical reviews. These patients were matched 1:2 against patients seen only by the OS clinic. The outcome measures included International Knee Score (IKS), Harris Hip Score (HHS) and the Short Form (SF)-12. RESULTS: There were no significant differences in HHS or SF-12 scores for patients after hip arthroplasty. Significant differences for knee arthroplasty were observed favouring the PT clinic; IKS, PT clinic 147.6 (37.07), OS clinic 135.4 (35.68), P<=0.01, and physical component of the SF-12, PT clinic 41.98 (10.45), OS clinic 37.20 (10.44), P<0.01. CONCLUSION: Implementation of a physiotherapy-led arthroplasty review clinic appears to be a safe and effective service alternative to reviews conducted by orthopaedic surgeons. WHAT IS KNOWN ABOUT THE TOPIC?: Osteoarthritis (OA) is a leading cause of musculoskeletal pain and disability and the burden of the disease is rapidly increasing. Joint arthroplasty surgery is the mainstay of treatment for people with end-stage OA; it is a high-cost, high volume procedure that dominates surgical wait lists around Australia. Long-term follow up is encouraged by the Arthroplasty Society of Australia and endorsed by the Australian Orthopaedics Association, but it is acknowledged that it is impossible to achieve this with solely orthopaedic surgeon reviews, an issue that is only going to worsen with the increased demand for surgery. Physiotherapists have become involved in many advanced scope roles within public health care, and emerging research suggests that patients are highly satisfied with their care in these types of clinics. WHAT DOES THIS PAPER ADD?: Although it has been shown that patients are satisfied in physiotherapy-led advanced clinics, there is a paucity of evidence in the outcomes of patients attending these clinics. Implementation of a physiotherapy-led arthroplasty review clinic demonstrated that outcome measures in this patient cohort were not compromised and, following knee joint arthroplasty, may even be improved. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS?: The findings of this study indicate that joint review clinics involving physiotherapists acting in an advanced scope role are unlikely to compromise patient outcomes. The use of this role substitution on a broader scale can be recommended. PMID- 25297121 TI - [Not Available]. PMID- 25297122 TI - [Not Available]. PMID- 25297123 TI - [Not Available]. PMID- 25297124 TI - [Not Available]. PMID- 25297125 TI - [Not Available]. PMID- 25297126 TI - [Not Available]. PMID- 25297127 TI - [Not Available]. PMID- 25297128 TI - [Not Available]. PMID- 25297129 TI - [Not Available]. PMID- 25297130 TI - [Not Available]. PMID- 25297132 TI - [Not Available]. PMID- 25297131 TI - Symposium 2-1 The autoimmunome: Similarities and differences among genetic susceptibility to common immune-related diseases. AB - Autoimmune disorders arise when physiological tolerance to "self" antigens is lost. Although several mechanisms may be involved in this pathogenic process, dysregulation of T-cell and B-cell activation and of pathways leading to inflammation are logical candidates. Susceptibility to autoimmune diseases has been associated with multiple factors including genetics, epigenetics, and the environment. While the modest concordance rate in monozygotic twins suggests that environmental factors are major players in most autoimmune diseases, increased heritability within families and the decrease in risk with the degree of relatedness all argue in favor of genetic factors. With the advent of high throughput genomics, massive amounts of genetic data are being produced and reported on a monthly basis. Although considerable insight has been gained from each of these individual studies, a detailed comparative analysis will likely identify both unique and common pathways operating in autoimmunity. More than 40 genome-wide association studies (GWAS) have been published to date in several autoimmune diseases (AID) and hundreds of common variants have been identified that confer risk or protection. While statistical adjustments are essential to refine the list of potential associations with each disease, valuable information can be extracted by the systematic collection of moderately significant variants present in more than one trait. While involvement of the MHC region in chromosome 6p21 is not in question for most AID, the complex genetic architecture of this locus poses a significant analytical challenge. On the other hand, by considering the contribution of non-MHC-related genes, similarities and differences among AID can be readily computed thus gaining insights into possible pathogenic mechanisms. For example, statistically significant excess sharing of non-MHC genes was found between type I diabetes (T1D) and all other AID studied, a result also seen for RA. A smaller but significant degree of sharing was observed for multiple sclerosis (MS), Celiac disease (CeD) and Crohn's disease (CD). We have developed a bioinformatics tool called iCTNet (integrated Complex Traits networks), that enables downloading and visualization of large volumes of data and the relationships among the different data types, information that is not typically available for the general user. The most recent version of iCNet (scheduled to be released in Spring 2014) includes data from genome-wide association studies, OMIM, protein interactions, tissue expression, drug targets, drug side effects, and miRNA targets among other data types. During my presentation I will describe practical examples of how this tools may facilitate the biological interpretation of large throughput data in human immune-related diseases and how this can help to generate new hypotheses for drug repositioning strategies. Using this class of approaches the unique genetic landscape for each autoimmune disease can start to be defined. Furthermore, this kind of analysis may set the basis for more targeted and rational therapeutic approaches. PMID- 25297133 TI - [Not Available]. PMID- 25297134 TI - [Not Available]. PMID- 25297136 TI - [Not Available]. PMID- 25297135 TI - [Not Available]. PMID- 25297137 TI - [Not Available]. PMID- 25297139 TI - [Not Available]. PMID- 25297138 TI - [Not Available]. PMID- 25297140 TI - [Not Available]. PMID- 25297141 TI - [Not Available]. PMID- 25297142 TI - [Not Available]. PMID- 25297143 TI - [Not Available]. PMID- 25297144 TI - Rising star symposium 4 the role of autophagy in rheumatoid arthritis, to protect or to kill? PMID- 25297145 TI - [Not Available]. PMID- 25297147 TI - [Not Available]. PMID- 25297146 TI - [Not Available]. PMID- 25297149 TI - [Not Available]. PMID- 25297148 TI - [Not Available]. PMID- 25297151 TI - [Not Available]. PMID- 25297150 TI - [Not Available]. PMID- 25297152 TI - [Not Available]. PMID- 25297153 TI - [Not Available]. PMID- 25297154 TI - [Not Available]. PMID- 25297155 TI - [Not Available]. PMID- 25297156 TI - [Not Available]. PMID- 25297157 TI - [Not Available]. PMID- 25297158 TI - [Not Available]. PMID- 25297159 TI - [Not Available]. PMID- 25297160 TI - [Not Available]. PMID- 25297161 TI - [Not Available]. PMID- 25297162 TI - [Not Available]. PMID- 25297163 TI - [Not Available]. PMID- 25297164 TI - [Not Available]. PMID- 25297165 TI - [Not Available]. PMID- 25297166 TI - [Not Available]. PMID- 25297167 TI - [Not Available]. PMID- 25297168 TI - [Not Available]. PMID- 25297169 TI - [Not Available]. PMID- 25297170 TI - [Not Available]. PMID- 25297171 TI - [Not Available]. PMID- 25297172 TI - [Not Available]. PMID- 25297173 TI - [Not Available]. PMID- 25297174 TI - [Not Available]. PMID- 25297175 TI - [Not Available]. PMID- 25297176 TI - [Not Available]. PMID- 25297177 TI - [Not Available]. PMID- 25297178 TI - [Not Available]. PMID- 25297179 TI - [Not Available]. PMID- 25297180 TI - [Not Available]. PMID- 25297181 TI - [Not Available]. PMID- 25297182 TI - [Not Available]. PMID- 25297183 TI - [Not Available]. PMID- 25297185 TI - [Not Available]. PMID- 25297184 TI - [Not Available]. PMID- 25297187 TI - [Not Available]. PMID- 25297186 TI - [Not Available]. PMID- 25297189 TI - [Not Available]. PMID- 25297188 TI - [Not Available]. PMID- 25297190 TI - [Not Available]. PMID- 25297191 TI - [Not Available]. PMID- 25297192 TI - [Not Available]. PMID- 25297193 TI - [Not Available]. PMID- 25297194 TI - [Not Available]. PMID- 25297195 TI - [Not Available]. PMID- 25297196 TI - [Not Available]. PMID- 25297197 TI - [Not Available]. PMID- 25297198 TI - [Not Available]. PMID- 25297199 TI - [Not Available]. PMID- 25297200 TI - [Not Available]. PMID- 25297201 TI - [Not Available]. PMID- 25297202 TI - [Not Available]. PMID- 25297204 TI - [Not Available]. PMID- 25297203 TI - [Not Available]. PMID- 25297205 TI - [Not Available]. PMID- 25297206 TI - [Not Available]. PMID- 25297207 TI - [Not Available]. PMID- 25297208 TI - [Not Available]. PMID- 25297209 TI - [Not Available]. PMID- 25297210 TI - [Not Available]. PMID- 25297211 TI - [Not Available]. PMID- 25297212 TI - [Not Available]. PMID- 25297213 TI - [Not Available]. PMID- 25297214 TI - [Not Available]. PMID- 25297216 TI - [Not Available]. PMID- 25297215 TI - [Not Available]. PMID- 25297217 TI - [Not Available]. PMID- 25297218 TI - [Not Available]. PMID- 25297219 TI - [Not Available]. PMID- 25297220 TI - [Not Available]. PMID- 25297221 TI - [Not Available]. PMID- 25297222 TI - [Not Available]. PMID- 25297223 TI - [Not Available]. PMID- 25297224 TI - [Not Available]. PMID- 25297225 TI - [Not Available]. PMID- 25297226 TI - [Not Available]. PMID- 25297227 TI - [Not Available]. PMID- 25297229 TI - [Not Available]. PMID- 25297228 TI - P2-006 profiles of receptors for specialized lipid mediators on synoviocyte from osteoarthritis. AB - ?Background? As specialized pro-resolving mediators (SPM) derived from fatty acids are detectable in synovial fluids in osteoarthritis (OA), they appear to take some roles for disease pathogenesis. Receptors for SPMs have been found, such as leukotriene B4 receptor (BLT1), formyl peptide receptor 2 (FPR2), and chemokine like receptor 1 (CMKLR1). ?Purpose? To identify the significance of receptors for SPMs on the cells in synovial tissue from OA joints. ?Methods? Expression of BLT1, FPR2 and CMKLR1 on synoviocytes from OA patients (45.5% women, mean age 69 years, mean BMI 27.9 kg/m(2)) and macrophage were analysed by flow cytometry and quantitative PCR. ?Results? FPR2 and CMKLR1 are found on synoviocyte, in which mean expression by flow cytometry were 8.5% and 6.2%, respectively, but BLT1 was less than 2.0%, although all of them decreased by keeping incubation. LPS treatment increased rather FPR2, but not so much CMKLR1, on synoviocytes and macrophage. ?Conclusion? There are FPR2 or CMKLR1 positive cells in synovial tissues, and especially FPR2 seems to have a certain function under inflammatory conditions. PMID- 25297230 TI - [Not Available]. PMID- 25297231 TI - [Not Available]. PMID- 25297232 TI - [Not Available]. PMID- 25297233 TI - [Not Available]. PMID- 25297234 TI - [Not Available]. PMID- 25297235 TI - [Not Available]. PMID- 25297236 TI - [Not Available]. PMID- 25297237 TI - [Not Available]. PMID- 25297238 TI - [Not Available]. PMID- 25297239 TI - [Not Available]. PMID- 25297240 TI - [Not Available]. PMID- 25297241 TI - [Not Available]. PMID- 25297242 TI - [Not Available]. PMID- 25297243 TI - [Not Available]. PMID- 25297244 TI - [Not Available]. PMID- 25297245 TI - [Not Available]. PMID- 25297246 TI - [Not Available]. PMID- 25297247 TI - [Not Available]. PMID- 25297248 TI - P4-006 Natural peptidome presented by HLA-A24 of cancer and cancer stem cells. AB - Circulating CD8+ T cells (CTL) survey the peptide/MHC class I complexes on cell surface to discriminate self and eliminate foreign/transformed cells. Thus, the MHC class I peptide repertoire directly influences cells fate, and provides information for immunotherapy strategy. Here we target HLA-A24 (A24), the most frequent serotype in Asia, and perform large-scale mass spectrometric profiling of natural peptides. Using the antibody specific to A24, we identified 264 peptides from colon (SW480, Colo320, HCT15/b2m) and 331 peptides from lung (LHK2, Sq-1) cancer cells. Although, known A24 binding anchors (Y/F at P2 and F/L/I at P9) are strongly conserved among the detected ligands, a subset of peptides with an unusual anchor (K/R at the C-terminal P9 or P10) is observed, suggesting diverse usage of anchors in certain types of cancer cells. Moreover, some peptides (and their genes) are exclusively expressed in cancer stem cells (cells able to exclude Hoechst dye). In summary, we identified approx. 500 non overlapping natural peptides presented by A24 from colon and lung cancer cells. A combination of natural peptides specific to tumors could be an ideal way for a CTL-based immunotherapy. PMID- 25297249 TI - [Not Available]. PMID- 25297250 TI - [Not Available]. PMID- 25297251 TI - [Not Available]. PMID- 25297252 TI - [Not Available]. PMID- 25297253 TI - [Not Available]. PMID- 25297254 TI - [Not Available]. PMID- 25297255 TI - [Not Available]. PMID- 25297256 TI - [Not Available]. PMID- 25297257 TI - [Not Available]. PMID- 25297258 TI - [Not Available]. PMID- 25297259 TI - [Not Available]. PMID- 25297260 TI - [Not Available]. PMID- 25297261 TI - [Not Available]. PMID- 25297262 TI - [Not Available]. PMID- 25297263 TI - [Not Available]. PMID- 25297264 TI - [Not Available]. PMID- 25297265 TI - [Not Available]. PMID- 25297266 TI - [Not Available]. PMID- 25297267 TI - P6-005 Plasmacytoid dendritic cells and mast cells associated with sialadenitis in primary Sjoren's syndrome. AB - To study the precise role of Plasmacytoid dendritic cells (PDCs) and mast cells (MC) in Sjogren's Syndrome (SS). Lip specimen (178 SS vs 7 Sicca) were performed on lymphocytes infiltration, acinar atrophy and intralobular fibrosis. MC, PDCs, CD68 and CXCL13 were detected by IHC or toluidine blue. CXCL13 gene was detected by PCR. Significant lymphocytes infiltration, acinar atrophy and intralobular fibrosis were observed in SS. PDCs and MC were increased in SS than Sicca (p=0.03/0.02). Positive correlation between PDCs with lymphocytes infiltration (p=0.02) and MC with intralobular fibrosis (p=0.03) in primary SS (pSS) was observed. Within the pSS, PDCs correlated with CXCL13+cells, especially CXCL13+macrophages. When macrophages were stimulated with IFN-a in vitro, CXCL13 gene was up-regulated.Our data suggests the specific role of PDCs in lymphocyte infiltration and MCs in intralobular fibrosis of pSS. Therefore, it is likely that PDCs in early stage inducing CXCL13 production from macrophages due to IFN-a contributing to lymphocyte infiltration further constructing germinal centers. In addition, MC seems to be involved in intralobular fibrosis which occurs in mid to late stage of SS. PMID- 25297268 TI - [Not Available]. PMID- 25297269 TI - [Not Available]. PMID- 25297270 TI - [Not Available]. PMID- 25297271 TI - [Not Available]. PMID- 25297272 TI - [Not Available]. PMID- 25297273 TI - [Not Available]. PMID- 25297274 TI - [Not Available]. PMID- 25297275 TI - P7-003 Mesenchymal stem cells in combination with nano-fiber scaffold suppressed arthritis in rats. AB - ?Objectives? Mesenchymal stem cells (MSC) possess immunoregulatory ability with osteoblastogenesis which makes them an ideal tool for arthritis treatment. Here we utilized nano-fiber poly-lactic-co-glycolic acid as a scaffold to deliver MSC into arthritic models. ?Methods? MSC were injected intra-articularly (IA) or intra-peritoneally (IP) or seeded on nano-fiber and implanted into ankles (nano MSC) of collagen induced arthritis (CIA) rats. ?Results? Arthritis and bone destruction were significantly suppressed by nano-MSC treatment, while IA or IP demonstrated no effects. Serum anti-type II collagen IgG and the proliferation and cytokine production of CD4+ T cells in nano-MSC rats were significantly decreased compared to control rats. Inoculation of MSC transfected with green fluorescent protein plasmid DNA showed MSC remained within nano-fiber and did not migrate to other organs. MSC cultured on nano-fiber showed increased transforming growth factor (TGF)-beta1 production compared to MSC cultured on plate. ?Conclusion? Administration of MSC with nano-fiber efficiently suppressed arthritis, bone destruction, suggesting a novel MSC delivery system for future arthritis treatment. PMID- 25297276 TI - P7-004 Histamine inhibits differentiation of skin fibroblasts into myofibroblasts. AB - ?Background? Histamine (HA) and TGF-beta, major mediators secreted by mast cells are involved in skin inflammation and systemic sclerosis. However, it remains largely unclear how the respective signaling are integrated to achieve development of skin fibrosis. ?Objectives? Investigate the effect of HA signaling during myofibroblasts differentiation. ?Methods? Skin fibroblasts (SFBs) were stimulated with TGF-beta, HA, or HA receptor antagonists. Expression of alpha smooth muscle actin (alphaSMA), HA receptors, and Smads were analyzed at mRNA and protein. ?Results? Expression of H1-receptor (H1R) and H2-receptor (H2R) were detectable in SFBs at both mRNA and protein level. Interestingly, addition of HA inhibited alphaSMA expression induced by TGF-beta which was antagonized by H1R antagonist but not H2R antagonist. Correspondingly, phosphorylated Smad2 was induced by TGF-beta stimulation whereas inhibited its phosphorylation after HA treatment. ?Conclusions? HA inhibited differentiation of SFBs into myofibroblast induced by TGF-beta in a H1R dependent manner, which emphasized the cirtical functions of H1R in the development of skin fibrosis. Thus, H1R may be a therapeutic target for skin fibrosis. PMID- 25297277 TI - [Not Available]. PMID- 25297278 TI - [Not Available]. PMID- 25297280 TI - [Not Available]. PMID- 25297279 TI - [Not Available]. PMID- 25297281 TI - [Not Available]. PMID- 25297282 TI - [Not Available]. PMID- 25297283 TI - [Not Available]. PMID- 25297284 TI - [Not Available]. PMID- 25297286 TI - [Not Available]. PMID- 25297285 TI - [Not Available]. PMID- 25297287 TI - [Not Available]. PMID- 25297288 TI - [Not Available]. PMID- 25297289 TI - [Not Available]. PMID- 25297290 TI - [Not Available]. PMID- 25297291 TI - [Not Available]. PMID- 25297293 TI - [Not Available]. PMID- 25297292 TI - [Not Available]. PMID- 25297294 TI - [Not Available]. PMID- 25297295 TI - [Not Available]. PMID- 25297296 TI - [Not Available]. PMID- 25297297 TI - [Not Available]. PMID- 25297298 TI - [Not Available]. PMID- 25297299 TI - [Not Available]. PMID- 25297300 TI - [Not Available]. PMID- 25297301 TI - [Not Available]. PMID- 25297302 TI - [Not Available]. PMID- 25297303 TI - [Not Available]. PMID- 25297304 TI - [Not Available]. PMID- 25297305 TI - [Not Available]. PMID- 25297306 TI - [Not Available]. PMID- 25297307 TI - [Not Available]. PMID- 25297308 TI - [Not Available]. PMID- 25297309 TI - [Not Available]. PMID- 25297311 TI - [Not Available]. PMID- 25297310 TI - [Not Available]. PMID- 25297312 TI - [Not Available]. PMID- 25297313 TI - Biomechanics of fibrous proteins of the extracellular matrix studied by Brillouin scattering. AB - Brillouin light scattering (BLS) spectroscopy is a technique that is able to detect thermally excited phonons within a material. The speed of propagation of these phonons can be determined from the magnitude of the Brillouin frequency shift between incident and scattered light, thereby providing a measure of the mechanical properties of the material in the gigahertz range. The mechanical properties of the extracellular matrices of biological tissues and their constituent biopolymers are important for normal tissue function and disturbances in these properties are widely implicated in disease. BLS offers the prospect of measuring mechanical properties on a microscopic scale in living tissues, thereby providing insights into structure-function relationships under normal and pathological conditions. In this study, we investigated BLS in collagen and elastin-the fibrous proteins of the extracellular matrix (ECM). Measurements were made on type I collagen in rat tail tendon, type II collagen in articular cartilage and nuchal ligament elastin. The dependence of the BLS spectrum on fibre orientation was investigated in a backscattering geometry using a reflective substrate. Two peaks, a bulk mode arising from phonon propagation along a quasi-radial direction to the fibre axis and a mode parallel to the surface, depending on sample orientation relative to the fibre axis, could be distinguished. The latter peak was fitted to a model of wave propagation through a hexagonally symmetric elastic solid, and the five components of the elasticity tensor were combined to give axial and transverse Young's, shear and bulk moduli of the fibres. These were 10.2, 8.3, 3.2 and 10.9 GPa, and 6.1, 5.3, 1.9 and 8 GPa for dehydrated type I collagen and elastin, respectively. The former values are close to those previously reported. A microfocused BLS approach was also applied providing selection of single fibres. The moduli of collagen and elastin are much higher than those measured at lower frequency using macroscopic strains, and the difference between them is much less. We therefore believe, like previous investigators, that molecular-scale viscoelastic effects are responsible for the frequency dependence of the fibre biomechanics. Combining BLS with larger-scale mechanical testing methods therefore should, in the future, provide a means of following the evolution of mechanical properties in the formation of the complex structures found in the ECM. PMID- 25297314 TI - Structural changes and biological responsiveness of an injectable and mouldable monetite bone graft generated by a facile synthetic method. AB - Brushite (dicalcium phosphate dihydrate) and monetite (dicalcium phosphate anhydrous) are of considerable interest in bone augmentation owing to their metastable nature in physiological fluids. The anhydrous form of brushite, namely monetite, has a finer microstructure with higher surface area, strength and bioresorbability, which does not transform to the poorly resorbable hydroxyapatite, thus making it a viable alternative for use as a scaffold for engineering of bone tissue. We recently reported the formation of monetite cements by a simple processing route without the need of hydrothermal treatment by using a high concentration of sodium chloride in the reaction mix of beta tricalcium phosphate and monocalcium phosphate monohydrate. In this paper, we report the biological responsiveness of monetite formed by this method. The in vitro behaviour of monetite after interaction and ageing both in an acellular and cellular environment showed that the crystalline phase of monetite was retained over three weeks as evidenced from X-ray diffraction measurements. The crystal size and morphology also remained unaltered after ageing in different media. Human osteoblast cells seeded on monetite showed the ability of the cells to proliferate and express genes associated with osteoblast maturation and mineralization. Furthermore, the results showed that monetite could stimulate osteoblasts to undergo osteogenesis and accelerate osteoblast maturation earlier than cells cultured on hydroxyapatite scaffolds of similar porosity. Osteoblasts cultured on monetite cement also showed higher expression of osteocalcin, which is an indicator of the maturation stages of osteoblastogenesis and is associated with matrix mineralization and bone forming activity of osteoblasts. Thus, this new method of fabricating porous monetite can be safely used for generating three dimensional bone graft constructs. PMID- 25297315 TI - Turbulence-induced resonance vibrations cause pollen release in wind-pollinated Plantago lanceolata L. (Plantaginaceae). AB - In wind pollination, the release of pollen from anthers into airflows determines the quantity and timing of pollen available for pollination. Despite the ecological and evolutionary importance of pollen release, wind-stamen interactions are poorly understood, as are the specific forces that deliver pollen grains into airflows. We present empirical evidence that atmospheric turbulence acts directly on stamens in the cosmopolitan, wind-pollinated weed, Plantago lanceolata, causing resonant vibrations that release episodic bursts of pollen grains. In laboratory experiments, we show that stamens have mechanical properties corresponding to theoretically predicted ranges for turbulence-driven resonant vibrations. The mechanical excitation of stamens at their characteristic resonance frequency caused them to resonate, shedding pollen vigorously. The characteristic natural frequency of the stamens increased over time with each shedding episode due to the reduction in anther mass, which increased the mechanical energy required to trigger subsequent episodes. Field observations of a natural population under turbulent wind conditions were consistent with these laboratory results and demonstrated that pollen is released from resonating stamens excited by small eddies whose turnover periods are similar to the characteristic resonance frequency measured in the laboratory. Turbulence-driven vibration of stamens at resonance may be a primary mechanism for pollen shedding in wind-pollinated angiosperms. The capacity to release pollen in wind can be viewed as a primary factor distinguishing animal- from wind-pollinated plants, and selection on traits such as the damping ratio and flexural rigidity may be of consequence in evolutionary transitions between pollination systems. PMID- 25297317 TI - Finite-element modelling reveals force modulation of jaw adductors in stag beetles. AB - Male stag beetles carry large and heavy mandibles that arose through sexual selection over mating rights. Although the mandibles of Cyclommatus metallifer males are used in pugnacious fights, they are surprisingly slender. Our bite force measurements show a muscle force reduction of 18% for tip biting when compared with bites with the teeth located halfway along the mandibles. This suggests a behavioural adaptation to prevent failure. We confirmed this by constructing finite-element (FE) models that mimic both natural bite situations as well as the hypothetical situation of tip biting without muscle force modulation. These models, based on micro-CT images, investigate the material stresses in the mandibles for different combinations of bite location and muscle force. Young's modulus of the cuticle was experimentally determined to be 5.1 GPa with the double indentation method, and the model was validated by digital image correlation on living beetles. FE analysis proves to be a valuable tool in the investigation of the trade-offs of (animal) weapon morphology and usage. Furthermore, the demonstrated bite force modulation in male stag beetles suggests the presence of mechanosensors inside the armature. PMID- 25297316 TI - Cell morphology and focal adhesion location alters internal cell stress. AB - Extracellular mechanical cues have been shown to have a profound effect on osteogenic cell behaviour. However, it is not known precisely how these cues alter intracellular mechanics to initiate changes in cell behaviour. In this study, a combination of in vitro culture of MC3T3-E1 cells and finite-element modelling was used to investigate the effects of passive differences in substrate stiffness on intracellular mechanics. Cells on collagen-based substrates were classified based on the presence of cell processes and the dimensions of various cellular features were quantified. Focal adhesion (FA) density was quantified from immunohistochemical staining, while cell and substrate stiffnesses were measured using a live-cell atomic force microscope. Computational models of cell morphologies were developed using an applied contraction of the cell body to simulate active cell contraction. The results showed that FA density is directly related to cell morphology, while the effect of substrate stiffness on internal cell tension was modulated by both cell morphology and FA density, as investigated by varying the number of adhesion sites present in each morphological model. We propose that the cells desire to achieve a homeostatic stress state may play a role in osteogenic cell differentiation in response to extracellular mechanical cues. PMID- 25297318 TI - A typology of street patterns. AB - We propose a quantitative method to classify cities according to their street pattern. We use the conditional probability distribution of shape factor of blocks with a given area and define what could constitute the 'fingerprint' of a city. Using a simple hierarchical clustering method, these fingerprints can then serve as a basis for a typology of cities. We apply this method to a set of 131 cities in the world, and at an intermediate level of the dendrogram, we observe four large families of cities characterized by different abundances of blocks of a certain area and shape. At a lower level of the classification, we find that most European cities and American cities in our sample fall in their own sub category, highlighting quantitatively the differences between the typical layouts of cities in both regions. We also show with the example of New York and its different boroughs, that the fingerprint of a city can be seen as the sum of the ones characterizing the different neighbourhoods inside a city. This method provides a quantitative comparison of urban street patterns, which could be helpful for a better understanding of the causes and mechanisms behind their distinct shapes. PMID- 25297319 TI - Analytical model for instantaneous lift and shape deformation of an insect-scale flapping wing in hover. AB - In the analysis of flexible flapping wings of insects, the aerodynamic outcome depends on the combined structural dynamics and unsteady fluid physics. Because the wing shape and hence the resulting effective angle of attack are a priori unknown, predicting aerodynamic performance is challenging. Here, we show that a coupled aerodynamics/structural dynamics model can be established for hovering, based on a linear beam equation with the Morison equation to account for both added mass and aerodynamic damping effects. Lift strongly depends on the instantaneous angle of attack, resulting from passive pitch associated with wing deformation. We show that both instantaneous wing deformation and lift can be predicted in a much simplified framework. Moreover, our analysis suggests that resulting wing kinematics can be explained by the interplay between acceleration related and aerodynamic damping forces. Interestingly, while both forces combine to create a high angle of attack resulting in high lift around the midstroke, they offset each other for phase control at the end of the stroke. PMID- 25297320 TI - Interest communities and flow roles in directed networks: the Twitter network of the UK riots. AB - Directionality is a crucial ingredient in many complex networks in which information, energy or influence are transmitted. In such directed networks, analysing flows (and not only the strength of connections) is crucial to reveal important features of the network that might go undetected if the orientation of connections is ignored. We showcase here a flow-based approach for community detection through the study of the network of the most influential Twitter users during the 2011 riots in England. Firstly, we use directed Markov Stability to extract descriptions of the network at different levels of coarseness in terms of interest communities, i.e. groups of nodes within which flows of information are contained and reinforced. Such interest communities reveal user groupings according to location, profession, employer and topic. The study of flows also allows us to generate an interest distance, which affords a personalized view of the attention in the network as viewed from the vantage point of any given user. Secondly, we analyse the profiles of incoming and outgoing long-range flows with a combined approach of role-based similarity and the novel relaxed minimum spanning tree algorithm to reveal that the users in the network can be classified into five roles. These flow roles go beyond the standard leader/follower dichotomy and differ from classifications based on regular/structural equivalence. We then show that the interest communities fall into distinct informational organigrams characterized by a different mix of user roles reflecting the quality of dialogue within them. Our generic framework can be used to provide insight into how flows are generated, distributed, preserved and consumed in directed networks. PMID- 25297322 TI - Impact of hospitalization on the sleep patterns of newborns, infants and toddlers admitted to a pediatric ward: a cross-sectional study. AB - AIM: Sleep is essential for children's physical and mental recovery and it is indispensable for their growth, for endocrine and for immune function, and for the development of cognitive behavioral skills. The purpose of this study is to describe the impact of hospitalization on the sleep patterns of newborns, infants and toddlers, as well as mothers' perceptions of any changes in their children's sleep patterns. METHODS: This was a single-centre cross-sectional study. The study included children aged up to 2 years who had been hospitalized for more than two days, selected by accidental sampling. Data were collected using an anonymous questionnaire with open and closed questions administered to mothers. RESULTS: Two hundred and one children aged on average 11.2 months (SD 10.3) were enrolled in the study. The percentage of children who at home used to sleep less than 5 hours a night increased by 4.7% in hospital, while the percentage of children sleeping 9 to 11 hours at home decreased by 5.9% in hospital. In hospital mothers put their children to bed later than at home. Indeed, the number of individuals going to bed between 9 and 10 p.m. decreased by 9.8% in hospital, while the number of children going to bed between 10 and 11 p.m. increased by 10.1%. The number of children who had 2 to 4 awakenings per night increased by 13.9% and the number of those who had 4 to 6 nocturnal awakenings increased by 4.8%; 50.5% of mothers reported that their children's sleep was interrupted by nurses to provide care. Mothers generally perceived their children's sleep as adequate, even if they noticed that their children were more restless and irritable. Mothers with only one child reported that they had more difficulty helping their children fall asleep (P=0.02). CONCLUSION: The study highlights the need to review the routine in paediatric wards on the basis of the sleep needs of children. Further studies are needed to estimate the effectiveness of the specific measures suggested by mothers. PMID- 25297323 TI - A novel Pseudomonas aeruginosa strain with an oprD mutation in relation to a nosocomial respiratory infection outbreak in an intensive care unit. AB - Seven imipenem-resistant Pseudomonas aeruginosa isolates were recovered from the sputum samples of pneumonia patients in southwestern China. They had identical antibiotic resistance patterns and indistinguishable pulsed-field gel electrophoresis profiles. Nucleotide sequence analysis revealed a 4-bp (AGTC) insertion in the oprD gene, resulting in a frameshift in the cognate open reading frame. These isolates became imipenem susceptible when the chromosomal oprD lesion was complemented, indicating that the 4-bp insertion in the oprD gene resulted in imipenem resistance. PMID- 25297324 TI - Clinical validation of the Cervista HPV HR test according to the international guidelines for human papillomavirus test requirements for cervical cancer screening. AB - This study demonstrates that both the clinical sensitivity and specificity of the Cervista HPV HR test for high-risk human papillomavirus (HPV) detection are not inferior to those of the Hybrid Capture 2 (HC2) test. The intra- and interlaboratory reproducibilities of Cervista were 92.0% (kappa, 0.83) and 90.4% (kappa, 0.80), respectively. The Cervista HPV HR test fulfills all the international HPV test requirements for cervical primary screening purposes. PMID- 25297325 TI - Evaluation of the Xpert vanA/vanB assay using enriched inoculated broths for direct detection of vanB vancomycin-resistant Enterococci. AB - Rapid and accurate detection of VRE (vancomycin-resistant enterococci) is required for adequate antimicrobial treatment and infection prevention measures. Previous studies using PCR for the detection of VRE, including Cepheid's Xpert vanA/vanB assay, reported accurate detection of vanA VRE; however, many false positive results were found for vanB VRE. This is mainly due to nonenterococcal vanB genes, which can be found in the gut flora. Our goal was to optimize the rapid and accurate detection of vanB VRE and to improve the positive predictive value (PPV) by limiting false-positive results. We evaluated the use of the Xpert vanA/vanB assay on rectal swabs and on enriched inoculated broths for the detection of vanB VRE. By adjusting the cycle threshold (CT) cutoff value to <= 25 for positivity by PCR on enriched broths, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 96.9%, 100%, 100%, and 99.5% for vanB VRE, respectively. As shown in this study, CT values of <= 25 acquired from enriched broths can be considered true positive. For broths with CT values between 25 and 30, we recommend confirming the results by culture. CT values of >30 appeared to be true negative. In conclusion, this study shows that the Cepheid's Xpert vanA/vanB assay performed on enriched inoculated broths with an adjusted cutoff CT value is a useful and rapid tool for the detection of vanB VRE. PMID- 25297326 TI - Name changes in medically important fungi and their implications for clinical practice. AB - Recent changes in the Fungal Code of Nomenclature and developments in molecular phylogeny are about to lead to dramatic changes in the naming of medically important molds and yeasts. In this article, we present a widely supported and simple proposal to prevent unnecessary nomenclatural instability. PMID- 25297327 TI - A highly sensitive europium nanoparticle-based immunoassay for detection of influenza A/B virus antigen in clinical specimens. AB - We report the development of a novel europium nanoparticle-based immunoassay (ENIA) for rapid detection of influenza A and influenza B viruses. The ENIA demonstrated sensitivities of 90.7% (147/162) for influenza A viruses and 81.80% (9/11) for influenza B viruses compared to those for an in-house reverse transcription (RT)-PCR assay in testing of influenza-positive clinical samples. PMID- 25297328 TI - Primary cutaneous mucormycosis produced by the new species Apophysomyces mexicanus. AB - A case of fungal necrotizing fasciitis that appeared in an immunocompetent Mexican woman after a car accident is described. The patient did not respond to antifungal treatment and died 4 days later. The fungus was molecularly identified as a new species of Apophysomyces, namely, Apophysomyces mexicanus. PMID- 25297329 TI - Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry using the Vitek MS system for rapid and accurate identification of dermatophytes on solid cultures. AB - The objective of this research was to extend the Vitek MS fungal knowledge base version 2.0.0 to allow the robust identification of clinically relevant dermatophytes, using a variety of strains, incubation times, and growth conditions. First, we established a quick and reliable method for sample preparation to obtain a reliable and reproducible identification independently of the growth conditions. The Vitek MS V2.0.0 fungal knowledge base was then expanded using 134 well-characterized strains belonging to 17 species in the genera Epidermophyton, Microsporum, and Trichophyton. Cluster analysis based on mass spectrum similarity indicated good species discrimination independently of the culture conditions. We achieved a good separation of the subpopulations of the Trichophyton anamorph of Arthroderma benhamiae and of anthropophilic and zoophilic strains of Trichophyton interdigitale. Overall, the 1,130 mass spectra obtained for dermatophytes gave an estimated identification performance of 98.4%. The expanded fungal knowledge base was then validated using 131 clinical isolates of dermatophytes belonging to 13 taxa. For 8 taxa all strains were correctly identified, and for 3 the rate of successful identification was >90%; 75% (6/8) of the M. gypseum strains were correctly identified, whereas only 47% (18/38) of the African T. rubrum population (also called T. soudanense) were recognized accurately, with a large quantity of strains misidentified as T. violaceum, demonstrating the close relationship of these two taxa. The method of sample preparation was fast and efficient and the expanded Vitek MS fungal knowledge base reliable and robust, allowing reproducible dermatophyte identifications in the routine laboratory. PMID- 25297330 TI - Genetic diversity and dynamic distribution of Mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in Thailand. AB - This study examined the genetic diversity and dynamicity of circulating Mycobacterium tuberculosis strains in Thailand using nearly neutral molecular markers. The single nucleotide polymorphism (SNP)-based genotypes of 1,414 culture-positive M. tuberculosis isolates from 1,282 pulmonary tuberculosis (PTB) and 132 extrapulmonary TB (EPTB) patients collected from 1995 to 2011 were characterized. Among the eight SNP cluster groups (SCG), SCG2 (44.1%), which included the Beijing (BJ) genotype, and SCG1 (39.4%), an East African Indian genotype, were dominant. Comparisons between the genotypes of M. tuberculosis isolates causing PTB and EPTB in HIV-negative cases revealed similar prevalence trends although genetic diversity was higher in the PTB patients. The identification of 10 reported sequence types (STs) and three novel STs was hypothesized to indicate preferential expansion of the SCG2 genotype, especially the modern BJ ST10 (15.6%) and ancestral BJ ST19 (13.1%). An association between SCG2 and SCG1 genotypes and particular patient age groups implies the existence of different genetic advantages among the bacterial populations. The results revealed that increasing numbers of young patients were infected with M. tuberculosis SCGs 2 and 5, which contrasts with the reduction of the SCG1 genotype. Our results indicate the selection and dissemination of potent M. tuberculosis genotypes in this population. The determination of heterogeneity and dynamic population changes of circulating M. tuberculosis strains in countries using the Mycobacterium bovis BCG (bacillus Calmette-Guerin) vaccine are beneficial for vaccine development and control strategies. PMID- 25297331 TI - First case reports of Ignatzschineria (Schineria) indica associated with myiasis. AB - We report three cases of infection due to the Gram-negative rod Ignatzschineria (Schineria) indica involving bacteremia and the urinary tract. Two cases were clearly associated with maggot infestation, and the third could conceivably have had unrecognized maggot infestation of the urinary tract. We believe these cases to be the first I. indica infections reported in association with maggot infestation and myiasis. PMID- 25297332 TI - Laboratory evaluation of three rapid diagnostic tests for dual detection of HIV and Treponema pallidum antibodies. AB - The performance of three research-use-only, dual HIV and syphilis rapid diagnostic tests (RDTs) was evaluated for 150 patient serum samples and compared to reference HIV and Treponema pallidum antibody detection methods. The RDTs performed comparably, with sensitivities of 93 to 99% and specificities of 97 to 100%. The kappa statistic between the RDTs was 0.95. PMID- 25297333 TI - Development of a new molecular subtyping tool for Salmonella enterica serovar Enteritidis based on single nucleotide polymorphism genotyping using PCR. AB - The lack of a sufficiently discriminatory molecular subtyping tool for Salmonella enterica serovar Enteritidis has hindered source attribution efforts and impeded regulatory actions required to disrupt its food-borne transmission. The underlying biological reason for the ineffectiveness of current molecular subtyping tools such as pulsed-field gel electrophoresis (PFGE) and phage typing appears to be related to the high degree of clonality of S. Enteritidis. By interrogating the organism's genome, we previously identified single nucleotide polymorphisms (SNP) distributed throughout the chromosome and have designed a highly discriminatory PCR-based SNP typing test based on 60 polymorphic loci. The application of the SNP-PCR method to DNA samples from S. Enteritidis strains (n = 55) obtained from a variety of sources has led to the differentiation and clustering of the S. Enteritidis isolates into 12 clades made up of 2 to 9 isolates per clade. Significantly, the SNP-PCR assay was able to further differentiate predominant PFGE types (e.g., XAI.0003) and phage types (e.g., phage type 8) into smaller subsets. The SNP-PCR subtyping test proved to be an accurate, precise, and quantitative tool for evaluating the relationships among the S. Enteritidis isolates tested in this study and should prove useful for clustering related S. Enteritidis isolates involved in outbreaks. PMID- 25297334 TI - Toward standardization of BK virus monitoring: evaluation of the BK virus R-gene kit for quantification of BK viral load in urine, whole-blood, and plasma specimens. AB - Screening of BK virus (BKV) replication is recommended to identify patients at increased risk of BKV-associated diseases. However, the heterogeneity of molecular techniques hinders the establishment of universal guidelines for BKV monitoring. Here we aimed to compare the performance of the CE-marked BK virus R gene kit (R-gene) to the performance of our in-house assay for quantification of BKV DNA loads (BKVL). A 12-specimen panel from the Quality Control for Molecular Diagnostics (QCMD) organization, 163 urine samples, and 88 paired specimens of plasma and whole blood (WB) from transplant recipients were tested. Both the R gene and in-house assays showed a good correlation within the QCMD panel (r = 0.995 and r = 0.989, respectively). BKVL were highly correlated between assays, although positive biases were observed with the in-house assay in analysis of urine (0.72 +/- 0.83 log10 copies/ml), plasma (1.17 +/- 0.63 log10 copies/ml), and WB (1.28 +/- 0.37 log10 copies/ml). Recalibration with a common calibrator significantly reduced the bias in comparisons between assays. In contrast, BKVL was underestimated with the in-house PCR in eight samples containing BKV genotype II, presenting point mutations at primer-annealing sites. Using the R-gene assay, plasma and WB specimens were found to be equally suitable for quantification of BKVL, as indicated by the high correlation coefficient (r = 0.965, P < 0.0001). In conclusion, the R-gene assay demonstrated reliable performance and higher accuracy than the in-house assay for quantification of BKVL in urine and blood specimens. Screening of BKV replication by a well-validated commercial kit may enable clinical laboratories to assess viral loads with greater reproducibility and precision. PMID- 25297335 TI - Comparing whole-genome sequencing with Sanger sequencing for spa typing of methicillin-resistant Staphylococcus aureus. AB - spa typing of methicillin-resistant Staphylococcus aureus (MRSA) has traditionally been done by PCR amplification and Sanger sequencing of the spa repeat region. At Hvidovre Hospital, Denmark, whole-genome sequencing (WGS) of all MRSA isolates has been performed routinely since January 2013, and an in house analysis pipeline determines the spa types. Due to national surveillance, all MRSA isolates are sent to Statens Serum Institut, where the spa type is determined by PCR and Sanger sequencing. The purpose of this study was to evaluate the reliability of the spa types obtained by 150-bp paired-end Illumina WGS. MRSA isolates from new MRSA patients in 2013 (n = 699) in the capital region of Denmark were included. We found a 97% agreement between spa types obtained by the two methods. All isolates achieved a spa type by both methods. Nineteen isolates differed in spa types by the two methods, in most cases due to the lack of 24-bp repeats in the whole-genome-sequenced isolates. These related but incorrect spa types should have no consequence in outbreak investigations, since all epidemiologically linked isolates, regardless of spa type, will be included in the single nucleotide polymorphism (SNP) analysis. This will reveal the close relatedness of the spa types. In conclusion, our data show that WGS is a reliable method to determine the spa type of MRSA. PMID- 25297337 TI - Oral verapamil in paroxysmal supraventricular tachycardia recurrence control: a randomized clinical trial. AB - BACKGROUND: Adenosine is the first-line medication in patients with paroxysmal supraventricular tachycardia. Because it is cleared so rapidly from the circulation, recurrence of paroxysmal supraventricular tachycardia after initial successful conversion may occur. OBJECTIVE: This study was conducted to evaluate the role of oral verapamil administration to control early recurrences of paroxysmal supraventricular tachycardia after adenosine infusion. METHODS: Patients with acute paroxysmal supraventricular tachycardia and no contraindications for adenosine or verapamil treatment were included in study. All patients received an adenosine protocol (6 mg rapid bolus intravenous injection followed by two repeated doses of 12 mg if necessary). Patients in the adenosine-only group did not received any other medications but patients in the adenosine/verapamil group received 40 mg verapamil orally immediately after converting the rhythm to sinus rhythm. All patients were followed up for 6 h in the acute care area of the emergency department under continuous cardiac monitoring. RESULTS: A total of 113 patients were assessed for eligibility and 92 patients were randomized into two groups (adenosine only versus adenosine/verapamil). There was no statistically significant difference in paroxysmal supraventricular tachycardia recurrence rate between the two groups in the first 30 min after treatment. Recurrence rate was statistically significantly lower in the adenosine/verapamil group than in the adenosine-only group between 30 and 120 min after treatment and thereafter. Two patients in the adenosine-only group experienced flushing and one patient in the adenosine/verapamil group experienced decreased systolic blood pressure. CONCLUSION: Oral verapamil can decrease paroxysmal supraventricular tachycardia recurrence after successful control with intravenous adenosine. PMID- 25297336 TI - External quality assessments for microbiologic diagnosis of diphtheria in Europe. AB - The European Diphtheria Surveillance Network (EDSN) ensures the reliable epidemiological and microbiologic assessment of disease prevalence in the European Union. Here, we describe a survey of current diagnostic techniques for diphtheria surveillance conducted across the European Union and report the results from three external quality assessment (EQA) schemes performed between 2010 and 2014. PMID- 25297338 TI - Light-emitting-diodes based on ordered InGaN nanocolumns emitting in the blue, green and yellow spectral range. AB - The growth of ordered arrays of InGaN/GaN nanocolumnar light emitting diodes by molecular beam epitaxy, emitting in the blue (441 nm), green (502 nm), and yellow (568 nm) spectral range is reported. The device active region, consisting of a nanocolumnar InGaN section of nominally constant composition and 250 to 500 nm length, is free of extended defects, which is in strong contrast to InGaN (planar) layers of similar composition and thickness. Electroluminescence spectra show a very small blue shift with increasing current (almost negligible in the yellow device) and line widths slightly broader than those of state-of-the-art InGaN quantum wells. PMID- 25297339 TI - Cryopreservation of MHC multimers: Recommendations for quality assurance in detection of antigen specific T cells. AB - Fluorescence-labeled peptide-MHC class I multimers serve as ideal tools for the detection of antigen-specific T cells by flow cytometry, enabling functional and phenotypical characterization of specific T cells at the single cell level. While this technique offers a number of unique advantages, MHC multimer reagents can be difficult to handle in terms of stability and quality assurance. The stability of a given fluorescence-labeled MHC multimer complex depends on both the stability of the peptide-MHC complex itself and the stability of the fluorochrome. Consequently, stability is difficult to predict and long-term storage is generally not recommended. We investigated here the possibility of cryopreserving MHC multimers, both in-house produced and commercially available, using a wide range of peptide-MHC class I multimers comprising virus and cancer-associated epitopes of different affinities presented by various HLA-class I molecules. Cryopreservation of MHC multimers was feasible for at least 6 months, when they were dissolved in buffer containing 5-16% glycerol (v/v) and 0.5% serum albumin (w/v). The addition of cryoprotectants was tolerated across three different T cell staining protocols for all fluorescence labels tested (PE, APC, PE-Cy7 and Quantum dots). We propose cryopreservation as an easily implementable method for stable storage of MHC multimers and recommend the use of cryopreservation in long term immunomonitoring projects, thereby eliminating the variability introduced by different batches and inconsistent stability. PMID- 25297341 TI - Renal arteriovenous fistula. PMID- 25297340 TI - Children's Developing Intuitions About the Truth Conditions and Implications of Novel Generics Versus Quantified Statements. AB - Generic statements express generalizations about categories and present a unique semantic profile that is distinct from quantified statements. This paper reports two studies examining the development of children's intuitions about the semantics of generics and how they differ from statements quantified by all, most, and some. Results reveal that, like adults, preschoolers (a) recognize that generics have flexible truth conditions and are capable of representing a wide range of prevalence levels; and (b) interpret novel generics as having near universal prevalence implications. Results further show that by age 4, children are beginning to differentiate the meaning of generics and quantified statements; however, even 7- to 11-year-olds are not adultlike in their intuitions about the meaning of most-quantified statements. Overall, these studies suggest that by preschool, children interpret generics in much the same way that adults do; however, mastery of the semantics of quantified statements follows a more protracted course. PMID- 25297342 TI - Reliability and validity of the capabilities of upper extremity test (CUE-T) in subjects with chronic spinal cord injury. AB - OBJECTIVE: To determine the reliability and validity of the capabilities of upper extremity test (CUE-T), a measure of functional limitations, in patients with chronic tetraplegia. DESIGN: Repeated measures. SETTING: Outpatient rehabilitation center. PARTICIPANTS: Fifty subjects (36 male/14 female) with spinal cord injury (SCI) of >=1-year duration participated. Subjects were 17-81 years old (mean 48.1 +/- 18.2); neurological levels ranged from C2 through T6, American Spinal Injury Association Impairment Scale grades A-D. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Intraclass correlation coefficients (ICC), weighted kappa and repeatability values for CUE-T; Spearman correlations of CUE-T with upper extremity motor scores (UEMS), and self-care and mobility portions of the Spinal Cord Independence Measure, vIII (SCIM III). RESULTS: Score ranges for UEMS were 8-50, CUE-T 7-135, self-care SCIM 0-20, and mobility SCIM 0-40. The ICC values for total, right, and left side scores were excellent (0.97-0.98; 95% confidence interval 0.96-0.99). Item weighted kappa values were >=0.60 for all but five items, four of which were right and left pronation and supination. Repeatability of total score was 10.8 points, right and left sides 6.3 and 6.1 points. Spearman correlations of the total CUE-T with the UEMS and SCIM self-care and mobility scores were 0.83, 0.70, and 0.55 respectively. CONCLUSIONS: The CUE T displays excellent test-retest reliability, and good-excellent correlation with impairment and capacity measures in persons with chronic SCI. After revising pronation and supination test procedures, the sensitivity to change should be determined. PMID- 25297343 TI - microRNA 490-3P enhances the drug-resistance of human ovarian cancer cells. AB - BACKGROUND: MicroRNAs (miRNAs) are non-coding, single-stranded small RNAs that regulate gene expression negatively, which is involved in fundamental cellular processes. In this study, we investigated the role of miR-490-3P in the development of drug resistance in ovarian cancer cells. METHODS: The human ovarian carcinoma cell line A2780 and A2780/Taxol were exposed to paclitaxel in the presence or absence of microRNA 490-3P transfection, after which cell viability were performed by CCK-8 assay. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to assess the mRNA and protein expression levels of GST-pi, MDR1 or P-gp. RESULTS: Our results showed higher miR 490-3P mRNA expression level in A2780/Taxol cells than in A2780 cells (p < 0.05). Following miR-490-3P transfection, both A2780 and A2780/Taxol cells showed decreased sensitivity to paclitaxel. The mRNA expression levels of MDR1, GST-pi (p < 0.05) and protein expression levels of P-gp, GST-pi were up-regulated [corrected] after miR-490-3P transfection in comparison to mock and negative control cancer cells. CONCLUSION: Our results demonstrate for the first time that microRNA 490-3P may be involved in the development of drug resistance in ovarian cancer. PMID- 25297344 TI - Caffeine delays autonomic recovery following acute exercise. AB - BACKGROUND: Impaired autonomic recovery of heart rate (HR) following exercise is associated with an increased risk of sudden death. Caffeine, a potent stimulator of catecholamine release, has been shown to augment blood pressure (BP) and sympathetic nerve activity; however, whether caffeine alters autonomic function after a bout of exercise bout remains unclear. METHODS: In a randomized, crossover study, 18 healthy individuals (26 +/- 1 years; 23.9 +/- 0.8 kg.m(-2)) ingested caffeine (400 mg) or placebo pills, followed by a maximal treadmill test to exhaustion. Autonomic function and ventricular depolarization/repolarization were determined using heart rate variability (HRV) and corrected QT interval (QTc), respectively, at baseline, 5, 15, and 30 minutes post-exercise. RESULTS: Maximal HR (HRmax) was greater with caffeine (192 +/- 2 vs. 190 +/- 2 beat.min( 1), p < 0.05). During recovery, HR, mean arterial pressure (MAP), and diastolic blood pressure (DBP) remained elevated with caffeine (p < 0.05). Natural log transformation of low-to-high frequency ratio (LnLF/LnHF) of HRV was increased compared with baseline at all time points in both trials (p < 0.05), with less of an increase during 5 and 15 minutes post-exercise in the caffeine trial (p < 0.05). QTc increased from baseline at all time points in both trials, with greater increases in the caffeine trial (p < 0.05). CONCLUSIONS: Caffeine ingestion disrupts post-exercise autonomic recovery because of increased sympathetic nerve activity. The prolonged sympathetic recovery time could subsequently hinder baroreflex function during recovery and disrupt the stability of autonomic function, potentiating a pro-arrhythmogenic state in young adults. PMID- 25297345 TI - Violence against women in India: comprehensive care for survivors. PMID- 25297346 TI - Liver biopsy interpretation & the regression of hepatitis B virus related cirrhosis. PMID- 25297347 TI - Clobazam: the phoenix drug (from the very old to the brand new). PMID- 25297348 TI - Pneumococcal disease in India: the dilemma continues. PMID- 25297349 TI - Relationship of household air pollution from solid fuel combustion with tuberculosis? PMID- 25297350 TI - Establishment of Biosafety Level-3 (BSL-3) laboratory: important criteria to consider while designing, constructing, commissioning & operating the facility in Indian setting. AB - Since the enactment of Environmental Protection Act in 1989 and Department of Biotechnology (DBT) guidelines to deal with genetically modified organisms, India has embarked on establishing various levels of biosafety laboratories to deal with highly infectious and pathogenic organisms. Occurrence of outbreaks due to rapidly spreading respiratory and haemorrhagic fever causing viruses has caused an urgency to create a safe laboratory environment. This has thus become a mandate, not only to protect laboratory workers, but also to protect the environment and community. In India, technology and science are progressing rapidly. Several BSL-3 [=high containment] laboratories are in the planning or execution phase, to tackle biosafety issues involved in handling highly infectious disease agents required for basic research and diagnosis. In most of the developing countries, the awareness about biocontainment has increased but planning, designing, constructing and operating BSL-3 laboratories need regular updates about the design and construction of facilities and clear definition of risk groups and their handling which should be in harmony with the latest international practices. This article describes the major steps involved in the process of construction of a BSL-3 laboratory in Indian settings, from freezing the concept of proposal to operationalization phase. The key to success of this kind of project is strong institutional commitment to biosafety norms, adequate fund availability, careful planning and designing, hiring good construction agency, monitoring by experienced consultancy agency and involvement of scientific and engineering personnel with biocontainment experience in the process. PMID- 25297351 TI - Health behaviours & problems among young people in India: cause for concern & call for action. AB - The young people in the age group of 10-24 yr in India constitutes one of the precious resources of India characterized by growth and development and is a phase of vulnerability often influenced by several intrinsic and extrinsic factors that affect their health and safety. Nearly 10-30 per cent of young people suffer from health impacting behaviours and conditions that need urgent attention of policy makers and public health professionals. Nutritional disorders (both malnutrition and over-nutrition), tobacco use, harmful alcohol use, other substance use, high risk sexual behaviours, stress, common mental disorders, and injuries (road traffic injuries, suicides, violence of different types) specifically affect this population and have long lasting impact. Multiple behaviours and conditions often coexist in the same individual adding a cumulative risk for their poor health. Many of these being precursors and determinants of non communicable diseases (NCDs) including mental and neurological disorders and injuries place a heavy burden on Indian society in terms of mortality, morbidity, disability and socio-economic losses. Many health policies and programmes have focused on prioritized individual health problems and integrated (both vertical and horizontal) coordinated approaches are found lacking. Healthy life-style and health promotion policies and programmes that are central for health of youth, driven by robust population-based studies are required in India which will also address the growing tide of NCDs and injuries. PMID- 25297352 TI - Effect of clobazam as add-on antiepileptic drug in patients with epilepsy. AB - BACKGROUND & OBJECTIVES: The use of clobazam in epilepsy has increased since its introduction in 1975. However, it has not been audited for its overall usefulness in Indian set up. The present study was aimed to evaluate usage pattern, retention rate, effectiveness and tolerability of clobazam during routine practice in an outpatient epilepsy clinic of a tertiary care hospital in New Delhi, India. METHODS: This study was performed on the patients prescribed antiepileptic medication who had clobazam as last added drug in their treatment regimen during October 2010-March 2012. These patients were followed up for two OPD visits. The primary points evaluated were retention rate, percentage of seizure-free patients and reasons for discontinuing clobazam. RESULTS: Of the 417 consecutive patients, 132 (31.7%) were on clobazam treatment for more than four years (median 6 yr, range 4-15 yr). No seizure for previous 12 months was considered as seizure free and was observed in 151 (36.2%) patients. There was no improvement in seizure control in 32 (7.7%) patients. A decrease in seizure severity without any change in seizure frequency was observed in 76 (18.2%) patients. Clobazam was discontinued by 15 (3.6%) patients due to complaints like drowsiness (13), fatigue/tiredness (8), headache (6), poor memory (6), irritable behaviour (5), abdominal pain (3) and dizziness (3). INTERPRETATION & CONCLUSIONS: Our results provide valuable information about the clinical use of clobazam as add-on antiepileptic drug therapy in the management of patients with epilepsy. PMID- 25297353 TI - Nasopharyngeal carriage, antibiogram & serotype distribution of Streptococcus pneumoniae among healthy under five children. AB - BACKGROUND & OBJECTIVES: Information related to nasopharyngeal carriage of Streptococcus pneumoniae among healthy children is scanty in India. This prospective study was undertaken to determine the presence of asymptomatic nasopharyngeal colonization, assess serogroups/types (SGT) and drug resistance of S. pneumoniae in children below five years of age. METHODS: A total of 109 male and 81 female children in the age group of three months to five years belonging to different socio-economic classes were enrolled. They were recruited across all age groups from those attending paediatric OPD of a tertiary care and research centre for immunization program. Fifty three isolates identified as pneumococci were tested for their antimicrobial susceptibility pattern by Kirby-Bauer's disc diffusion and E-Test methods. Serotyping was performed by detection of the quelling reaction with specific antiserum. RESULT: The pneumococcal carriage rate in the study population was 27.9 per cent. The isolation rate was associated with age being higher (49.2%) in smaller children (3-12 months) and among male (62.2%). The most prevalent SGTs were 19 followed by 10, 14 and 7; 21 per cent of isolates belonging to serotype 10 (n=7) were 11 (n=4) were not covered in any of the conjugate vaccines currently available in Indian market. Resistance to co trimoxazole, tetracycline, penicillin and erythromycin was observed in 91 per cent (n=48), 36 per cent (n=19), 17 per cent (n=9) and 9 per cent (n=5) isolates, respectively. All the penicillin resistant isolates were found to be intermediately resistant by E-Test. Multidrug resistance was observed in 19 per cent (n=10) isolates. INTERPRETATION & CONCLUSIONS: High level of antibiotic resistance was present in S. pneumoniae isolated from healthy children below age five. A pneumococcal conjugate vaccine with the prevailing SGTs would help to reduce the pool of antibiotic resistant pneumococci. Continued surveillance of serotypes and tracking susceptibility pattern of S. pneumoniae will help to introduce appropriate vaccination protocols. PMID- 25297354 TI - Novel mutations in PRG4 gene in two Indian families with camptodactyly arthropathy-coxa vara-pericarditis (CACP) syndrome. AB - BACKGROUND & OBJECTIVES: Camptodactyly--arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive disorder caused by mutations in the PRG4 (proteoglycan 4) gene. Hallmarks of the syndrome include congenital or early onset camptodactyly and arthropathy with synovial hyperplasia, progressive coxa vara deformity and non-inflammatory pericardial effusions. Till date only around 25 pathogenic mutations have been reported in this gene and none have been reported from India. We report here the mutations in the PRG4 gene in three patients of CACP from two unrelated families from India. METHODS: Molecular genetic studies were done for the three patients with the CACP syndrome, from two unrelated Indian families, through sequence analysis of all coding exons and the exon-intron boundaries of the PRG4 gene. RESULTS: Two novel frame-shift deletion mutations leading to premature protein termination were found. One patient was identified to be homozygous for a 2 base pair deletion in exon 6 (c.2645_2646delGA) and the two affected siblings from the other family were found to be homozygous for a 4 base pair deletion in exon 6 (c.2883_2886delAAGA). CONCLUSIONS: This is perhaps the first report of PRG4 mutations from India. Further mutation studies in Indian CACP cases will help to determine the mutation spectrum of the PRG4 gene in the Indian population and also help to further elucidate the molecular pathology and the genotype-phenotype correlation of this rare disease. PMID- 25297355 TI - Intra-articular injection of dexketoprofen in rat knee joint: histopathologic assessment of cartilage & synovium. AB - BACKGROUND & OBJECTIVES: Effective pain control following outpatient surgical procedures is an important aspect of patient discharge. This study was carried out with an aim to investigate the histopathological effects of intra-articular dexketoprofen trometamol injection in knee joint on synovium and cartilage in an experimental rat model. METHODS: In each of 40 rats, the right knee was designated as the study group and the left knee as the control group (NS group). Under aseptic conditions, 35 rats received an injection of 0.25 ml (6.25 mg) dexketoprofen trometamol into the right knee joint and an injection of 0.25 ml 0.9 per cent normal saline solution into the left knee joint. On the 1st, 2nd, 7th, 14th, and 21st days after intra-articular injection, rats in specified groups were sacrificed by intraperitoneal injection of 120 mg/kg sodium thiopental. Knee joints were separated and sectioned for histopathological examination. Inflammatory changes in the joints were recorded according to a grade scale. RESULTS: No significant difference in terms of pathological changes both in synovium and cartilage was observed between the NS group and the study group on days 1, 2, 7, 14 and 21 after intra-articular injection of dexketoprofen or saline in the knee joint. INTERPRETATION & CONCLUSIONS: The findings showed no evidence of significant histopathological damage to the cartilage and synovia for a period up to 21 days following intra-articular administration of dexketoprofen trometamol in the knee joints of rats. PMID- 25297356 TI - Alpha thalassaemia in tribal communities of coastal Maharashtra, India. AB - BACKGROUND & OBJECTIVES: In a routine community health survey conducted in adult Adivasis of the costal Maharashtra, microcytosis and hyprochromia were observed in more than 80 per cent of both males and females having normal haemoglobin levels suggesting the possibility of alpha-thalassaemia in these communities. We conducted a study in Adivasi students in the same region to find out the magnitude of alpha-thalessaemia. METHODS: The participants (28 girls and 23 boys) were 14-17 yr old studying in a tribal school. Fasting venous blood samples (5 ml) were subjected to complete blood count (CBC), Hb-HPLC and DNA analysis using gap-PCR for deletion of -alpha3.7 and -alpha4.2, the two most common molecular lesions observed in alpha-thalassaemia in India. RESULTS: Microcytic hypochromic anaemia was observed 50 and 35 per cent girls and boys, respectively. Iron supplementation improved Hb levels but did not correct microcytois and hypochromia. m0 ore than 80 per cent non-anaemic students of both sexes showed microcytois and hypochromia. DNA analysis confirmed that the haematological alterations were due to alpha-thalassaemia trait characterized by deletion of alpha3.7. Majority (>60%) of the affected students had two deletions (-alpha3.7/ alpha3.7 genotype alpha+ thalassaemia. INTERPRETATION & CONCLUSIONS: This is perhaps the first report on the occurrence of alpha-thalassaemia in tribal communities of coastal Maharashtra. Very high (78.4%) haplotype frequency of alpha3.7 suggests that the condition is almost genetically fixed. These preliminary observations should stimulate well planned large scale epidemiological studies on alpha-thalassaemia in the region. PMID- 25297357 TI - Expression of interleukins 7 & 8 in peripheral blood mononuclear cells from patients with metabolic syndrome: a preliminary study. AB - BACKGROUND & OBJECTIVES: Metabolic syndrome (MS) is a common but serious public health problem in developed countries. Chronic inflammation plays a key role in MS. Interleukins (IL)-7 and 8 are considered to have proinflammatory effects and may be involved in the pathogenesis of MS. Therefore, the aim of this study was to determine gene expression level of IL-7 and IL-8 in peripheral blood mononuclear cells (PBMCs) of patients with MS compared to healthy control subjects. METHODS: Using real-time RT-PCR, the relative amounts of IL-7 and IL-8 mRNA were determined in PBMCs from 20 female patients with MS and compared with those of 20 healthy control subjects. Biochemical and anthropometric parameters of MS were also assessed. RESULTS: Total cholesterol, triglyceride, and fasting blood sugar were significantly higher in MS patients compared to healthy subjects. There were no significant differences in HDLc and LDLc between the two groups. IL-8 expression in PBMC was significantly decreased in MS versus control subjects (fold of change was 0.395+/-0.1824), while no difference in the IL-7 expression was detected between them. IL-8 expression had negative correlation with MS components especially with triglyceride and total cholesterol (r=0.5, P<0.001). INTERPRETATION & CONCLUSIONS: In this preliminary study, no detectable differences were found in IL-7 expression and decreased expression of IL-8 in PBMCs of MS patients as compared to those of control subjects. Study on a larger population and investigating the mechanisms involved can reveal more details. PMID- 25297358 TI - Antiviral drug profile of human influenza A & B viruses circulating in India: 2004-2011. AB - BACKGROUND & OBJECTIVES: Recent influenza antiviral resistance studies in South East Asia, Europe and the United States reveal adamantane and neuraminidase inhibitor (NAIs) resistance. This study was undertaken to evaluate antiviral resistance in influenza viruses isolated from various parts of India, during 2004 to 2011. METHODS: Influenza viruses were analyzed genetically for known resistance markers by M2 and NA gene sequencing. Influenza A/H1N1 (n=206), A/H3N2 (n=371) viruses for amantadine resistance and A/H1N1 (n=206), A/H3N2 (n=272) and type B (n=326) for oseltamivir resistance were sequenced. Pandemic (H1N1) (n=493) isolates were tested for H274Y mutation by real time reverse transcription (rRT) PCR. Randomly selected resistant and sensitive influenza A/H1N1 and A/H3N2 viruses were confirmed by phenotypic assay. RESULTS: Serine to asparagine (S3IN) mutation was detected in six isolates of 2007-2008. One dual-resistant A/H1N1 was detected for the first time in India with leucine to phenylalanine (L26F) mutation in M2 gene and H274Y mutation in NA gene. A/H3N2 viruses showed an increase in resistance to amantadine from 22.5 per cent in 2005 to 100 per cent in 2008 onwards with S3IN mutation. Fifty of the 61 (82%) A/H1N1 viruses tested in 2008-2009 were oseltamivir resistant with H274Y mutation, while all A/H3N2, pandemic A/H1N1 and type B isolates remained sensitive. Genetic results were also confirmed by phenotypic analysis of randomly selected 50 resistant A/H1N1 and 40 sensitive A/H3N2 isolates. INTERPRETATION & CONCLUSIONS: Emergence of influenza viruses resistant to amantadine and oseltamivir in spite of negligible usage of antivirals emphasizes the need for continuous monitoring of antiviral resistance. PMID- 25297359 TI - Diagnostic efficacy of a real time-PCR assay for Chlamydia trachomatis infection in infertile women in north India. AB - BACKGROUND & OBJECTIVES: Little is known about the prevalence of Chlamydia trachomatis infection in Indian women with infertility. To improve the diagnosis of C. trachomatis infection in developing countries, there is an urgent need to establish cost-effective molecular test with high sensitivity and specificity. This study was conducted to determine the diagnostic utility of a real time-PCR assay for detention of C. trachomatis infection in infertile women attending an infertility clinic in north India. The in house real time-PCR assay was also compared with a commercial real-time PCR based detection system. METHOD: Endocervical swabs, collected from 200 infertile women were tested for C. trachomatis by three different PCR assays viz. in-house real time-PCR targeting the cryptic plasmid using published primers, along with omp1 gene and cryptic plasmid based conventional PCR assays. Specimens were also subjected to direct fluorescence assay (DFA) and enzyme immunoassay (EIA) Performance of in-house real time-PCR was compared with that of COBAS Taqman C. trachomatis Test, version 2.0 on all in-house real time-PCR positive sample and 30 consecutive negative samples. RESULTS: C. trachomatis infection was found in 13.5 per cent (27/200) infertile women by in-house real time-PCR, 11.5 per cent (23/200) by cryptic plasmid and/or omp1 gene based conventional PCR, 9 per cent (18/200) by DFA and 6.5 per cent (7/200) by EIA. The in-house real time-PCR exhibited a sensitivity and specificity of 100 per cent, considering COBAS Taqman CT Test as the gold standard. The negative and positive predictive values of the in-house real time PCR were 100 per cent. The in-house real time-PCR could detect as low as 10 copies of C. trachomatis DNA per reaction. INTERPRETATION & CONCLUSIONS: In-house real time-PCR targeting the cryptic plasmid of C. trachomatis exhibited an excellent sensitivity and specificity similar to that of COBAS Taqman CT Test, v2.0 for detection of C. trachomatis infection in women attending an infertility clinic. In an effort to prevent Chlamydia infection associated infertility, we recommend screening of women with infertility due to C. trachomatis infection by in-house molecular method as a cost-effective solution in resource limited settings. PMID- 25297360 TI - Multiple drug resistant carbapenemases producing Acinetobacter baumannii isolates harbours multiple R-plasmids. AB - BACKGROUND & OBJECTIVES: The nosocomial human pathogen Acinetobacter baumannii has high propensity to develop resistance to antimicrobials and to become multidrug resistant (MDR), consequently complicating the treatment. This study was carried out to investigate the presence of resistant plasmids (R-plasmids) among the clinical isolates of A. baumannii. In addition, the study was performed to check the presence of common beta-lactamases encoding genes on these plasmids. METHODS: A total of 55 clinical isolates of A. baumannii were included in the study and all were subjected to plasmid DNA isolation, followed by PCR to check the presence of resistance gene determinants such as blaOXA-23, blaOXA-51, blaOXA 58 and blaIMP-1 on these plasmids that encode for oxacillinase (OXA) and metallo beta-lactamase (MBL) type of carbapenemases. Plasmid curing experiments were carried out on selected isolates using ethidium bromide and acridine orange as curing agents and the antibiotic resistance profiles were evaluated before and after curing. RESULTS: All the isolates were identified as A. baumannii by 16SrDNA amplification and sequencing. Plasmid DNA isolated from these isolates showed the occurrence of multiple plasmids with size ranging from 500bp to >=25 kb. The percentage of blaOXA-51 and blaOXA-23 on plasmids were found to be 78 and 42 per cent, respectively and 20 isolates (36%) carried blaIMP-1 gene on plasmids. Significant difference was observed in the antibiograms of plasmid cured isolates when compared to their parental ones. The clinical isolates became susceptible to more than two antibiotic classes after curing of plasmids indicating plasmid borne resistance. INTERPRETATION & CONCLUSIONS: Our study determined the plasmid mediated resistance mechanisms and occurrence of different resistance genes on various plasmids isolated from MDR A. baumannii. The present findings showed the evidence for antibiotic resistance mediated through multiple plasmids in A. baumannii clinical isolates. This indicates towards a need for preventive measures to avert the dissemination of plasmid resistance determinants in clinical environments. PMID- 25297361 TI - Clinical profile of HIV infected patients attending a HIV referral clinic in Pune, India. AB - BACKGROUND & OBJECTIVES: Human immunodeficiency virus (HIV) has infected several million individuals in India. Various interventions have been implemented for early detection and prevention of transmission of HIV infection. This has progressively changed the clinical profile of HIV infected individuals and this study documents the clinical presentation of individuals positive for HIV in 2010, in Pune, Maharashtra, India. METHODS: This cross-sectional study included subjects who had come to the HIV referral clinic for HIV testing from January to December 2010. Children as well as individuals with indeterminate HIV result were excluded from the study, and data for 1546 subjects were finally analysed. RESULTS: The HIV positivity rate among all referred cases for the year 2010 was 35 per cent (male 55% and females 45%). The median age (Q1, Q3) was 31 (25.75, 39) yr. The median CD4 cell count for all HIV infected individuals (whose CD4 count was available n=345) was 241 cells/ul and for asymptomatic HIV infected individuals was 319 cells/ul. There were 673 (43.5%) symptomatic and 873 (56.5%) asymptomatic participants. Fever, breathlessness, cough with expectoration, weight loss, loss of appetite, generalized weakness, pallor and lymphadenopathy (axillary and cervical) were found to be associated (P<0.001) with HIV positivity. On multivariate analysis, history of Herpes zoster [AOR 11.314 (6.111 20.949)] and TB [AOR 11.214 (6.111-20.949)] was associated with HIV positivity. INTERPRETATION & CONCLUSIONS: Signs and symptoms associated with HIV positivity observed in this study can be used by health care providers to detect HIV infection early. Moreover, similar to HIV testing in patients with tuberculosis, strategies can be developed for considering Herpes zoster as a predictor of HIV infection. PMID- 25297362 TI - Spatiotemporal distribution of dengue vectors & identification of high risk zones in district Sonitpur, Assam, India. AB - BACKGROUND & OBJECTIVES: Dengue is an arboviral disease of public health importance in many parts of India and recently many cases have been reported from northeastern India. Aedes mosquitoes, which are the vectors of dengue, are widely prevalent in the region. A study was initiated in Sonitpur district of Assam to understand the spatiotemporal distribution and seasonal prevalence of dengue vectors and to identify the high risk zones. METHODS: Ovitrap surveys were conducted in three randomly selected villages under each of the eight public health centres (PHC) in district Sonitpur of Assam, northeastern India during March 2011-February 2012. Three risk zones (high, medium and low) were identified on the basis of per trap density of Aedes mosquitoes. Meteorological data were collected to study the temporal distribution of dengue vectors. RESULTS: Aedes albopictus (99.3%) was the predominant dengue vector followed by Ae. aegypti (0.7%) recorded in the ovitraps. The highest vector density was observed during the post-monsoon (60.1+/-18 per trap) while the lowest during the winter (7.6+/ 4.9 per trap) and the season-wise differences in the vector density were significant (P=0.005). Maximum temperature (correlation coefficient, r=0.45) and minimum temperature (r=0.408) showed the highest positive correlation with the vector density, whereas the number of rainy days showed high positive correlation (r=0.185) than the total rainfall (r=0.117). The high risk zone (Dekhiajuli, Behali, Bihaguri and Gohpur PHC) as indicated by the high larval densities of dengue vectors, 45.3+/-18, 42.1+/-22.3, 36.9+/-29.1, 35.3+/-22.6 per trap, respectively, was validated by dengue epidemiological data collected during 2012. INTERPRETATION & CONCLUSIONS: Yearlong monitoring of dengue vectors was done for the first time in this region. Monthly maximum temperature and the number of rainy days could be used for the prediction of larval density of Aedes mosquitoes. The identification high dengue risk zones would help in adopting targeted interventions for disease management in future. PMID- 25297363 TI - Laboratory evaluation of molluscicidal & mosquito larvicidal activities of leaves of Solanum nigrum L. AB - BACKGROUND & OBJECTIVES: Indiscriminate use of synthetic pesticides has created serious problem for the aquatic flora and fauna, and also resulted in appearance of pesticide resistance in vector population. This study was designed to evaluate the biocontrol efficacy of aqueous and solvent extracts of mature leaves of Solanum nigrum L., against fresh water snail Lymnaea acuminata f. rufescens (Gray) (an intermediate host of parasites causing fasciolopsiasis) and larvae of Culex vishnui group (Reuben) (vector of Japanese encephalitis). METHODS: Aqueous and solvent extracts of fresh, mature, green/shed dried leaves of S. nigrum were tested against adult L. acuminata and larvae of Cx. vishnui group. The lethal concentration was determined and the appropriate lethal concentration at 24 h of benzene extract was also studied on non target organisms such as Daphnia sp, Diplonychus annulatum and Chironomus circumdatus. A qualitative phytochemical analysis was carried out in search of active ingredient and the chemical nature of the active substance was also evaluated by infrared (IR) analysis. RESULTS: In a 72 h bioassay experiment with the aqueous extract, the highest mortality was recorded in 0.5 and 3 per cent extract against larvae of Cx. vishnui group and L. acuminata, respectivela. In the benzene solvent extract, the maximum mortality was recorded at a concentration of 150 ppm against L. acuminata and at 50 ppm against larvae of Cx. vishnui group with LC 50 values of 55.45 and 11.59 ppm, respectively at 72 h. The log probit analysis (95% confidence level) recorded lowest value at 72 h of exposure. Qualitative phytochemical analysis reported the presence of some biochemical compounds, such as saponin, flavonoids, steroid and tannin. Among these, the toxic compound was detected by IR analysis having Rf=0.87 (showed 66.70% and 76.70% mortality of L. acuminata and larvae of Cx. vishnui group, respectively). IR analysis provided preliminary information about the aliphatic amide nature of the active ingredient. INTERPRETATION & CONCLUSIONS: The study results provide considerable scope in exploiting local indigenous plant resources for molluscicidal and mosquito larvicidal activities. PMID- 25297364 TI - Environmental management through sluice gated bed-dam: a revived strategy for the control of Anopheles fluviatilis breeding in streams. AB - BACKGROUND & OBJECTIVES: Integrated vector management (IVM) emphasizes sustainable eco-friendly methods and minimal use of chemicals. In this context, the present study highlights the environmental control of breeding of Anopheles fluviatilis, the primary malaria vector, through water management in a natural stream in Koraput district, Odisha, India. METHODS: The District Rural Development Agency (DRDA), Koraput, constructed two bed-dams across streams, one in Barigaon and the other in Pipalapodar village. The bed-dam in the former village was fitted with two sluice gates whereas the bed dam constructed in the latter village was without the sluice gate. the sluice gates were opened once in a week on a fixed day to flush out the water from the dam. Anopheles immatures were sampled systematically in the streams using a dipper for density measurement and species composition. RESULTS: There was a reduction of 84.9 per cent in the proportion of positive dips for anopheles larvae/pupae and a reduction of 98.4 per cent in immature density (number/dip) of An. fluviatilis in the experimental downstream compared to the control following opening of the sluice gates. INTERPRETATION & CONCLUSIONS: Our findins showed that opening of sluice gates of the bed-dam regularly once in a week resulted in the control of vector breeding in the downstream due to the flushing effect of the water released with a high flow from the bed-dam that stagnated water in the upstream. The outcome of the study encourages upscaling this measure to other areas, wherever feasible. PMID- 25297365 TI - Presence of diabetes mellitus in the 'Dawoodi Bohra youth community' in Udaipur, Rajasthan. AB - BACKGROUND & OBJECTIVES: Diabetes mellitus is a major public health problem worldwide. With the rising incidence of diabetes in India, it becomes particularly relevant to ascertain its prevalence in various ethnic groups. The objective of this study was to find out the presence of diabetes mellitus in the 'Dawoodi Bohra Youth Community' and also to assess the factors responsible for it. METHODS: A house-to-house study was conducted and 2179 subjects were questioned randomly; children below 18 yr of age were excluded. A questionnaire was given to each member and questions were also asked to test their level of awareness regarding diabetes which was graded on a 5-pointer scale where 1 meant 'very poor' and 5-'excellent'. Diabetes was diagnosed using GOD-POD (oxidase peroxidase) method according to the WHO criteria. RESULTS: Total number of diabetic subjects found was 246 (11.29%) with a mean age of 60.21+/-10.91 years. The condition was more common in males (58.94%). The highest prevalence was recorded in the age group of 65-69 yr (22.01%) and none had diabetes in the age group 11-24 yr. Pedigree analysis showed that 109 (44.30%) subjects had at least one affected relative and 23 (9.34%) had at least two diabetic family members; 52 were found to have parents with diabetes. On the 5-pointer scale, the overall care in diabetic subjects was 3.76+/-0.56 as compared to 2.86+/-0.60 in non diabetic subjects (p<0.001). INTERPRETATION & CONCLUSIONS: Our results indicated that the marital alliances, familial aggregation and lifestyle could be the major factors which enhanced the chances of diabetes in this community. This research work also reflected poor awareness among these people regarding their health and diseases. PMID- 25297366 TI - Microbial contamination of soft contact lenses & accessories in asymptomatic contact lens users. AB - BACKGROUND & OBJECTIVES: With increasing use of soft contact lenses the incidence of contact lens induced infections is also increasing. This study was aimed to assess the knowledge of new and existing contact lens users about the risk of microbial contamination associated with improper use and maintenance of contact lenses, type of microbial flora involved and their potential to cause ophthalmic infections. METHODS: Four samples each from 50 participants (n=200) were collected from the lenses, lens care solutions, lens care solution bottles and lens cases along with a questionnaire regarding their lens use. The samples were inoculated onto sheep blood agar, Mac Conkey's agar and Sabouraud's dextrose agar. Organisms were identified using standard laboratory protocols. RESULTS: Overall rate of microbial contamination among the total samples was 52 per cent. The most and the least contaminated samples were found to be lens cases (62%) and lens care solution (42%), respectively. The most frequently isolated contaminant was Staphylococcus aureus (21%) followed by Pseudomonas species (19.5%). Majority (64%) of the participants showed medium grade of compliance to lens cleaning practices. Rate of contamination was 100 and 93.75 per cent respectively in those participants who showed low and medium compliance to lens care practices as compared to those who had high level of compliance (43.75%) (P<0.05). INTERPRETATION & CONCLUSIONS: Lens care practices amongst the participants were not optimum which resulted into high level contamination. Hence, creating awareness among the users about the lens care practices and regular cleaning and replacements of lens cases are required. PMID- 25297367 TI - Trends of typhoid fever seropositivity over ten years in north India. PMID- 25297368 TI - Durability of protective fabrics against dengue vector Aedes albopictus in northeastern India. PMID- 25297369 TI - Multiple epidermal cysts of scrotum. PMID- 25297370 TI - Childhood cerebral adrenoleukodystrophy. PMID- 25297371 TI - Spontaneous pneumothorax in ataxia telangectasia. PMID- 25297372 TI - Bias in feline plasma biochemistry results between three in-house analysers and a commercial laboratory analyser: results should not be directly compared. AB - In-house analysers are commonplace in small animal practices but cannot be calibrated by the operator; therefore, any bias in the generated plasma analyte values cannot be corrected. Guidelines such as grading of renal disease and published reference intervals (RIs) in veterinary textbooks assume plasma biochemistry values generated by different analysers are equivalent. This study evaluated the degree of bias, as well as if bias was constant or proportional, for feline plasma biochemical analytes assessed by three in-house biochemistry analysers compared with a commercial laboratory analyser. Blood samples were collected on 101 occasions from 94 cats and, after centrifugation, plasma was divided into four aliquots. One aliquot was sent to the commercial laboratory and the remaining three were tested using the in-house biochemistry analysers. Results from each analyser were compared with the commercial laboratory results by difference plots and analyses, and by comparing percentages of results within provided RIs. Substantial bias was evident relative to the results of the commercial analyser for at least half of the analytes tested for each machine. In most cases, bias was proportional, meaning that the difference between the methods varied with the concentration of the analyte. The results demonstrate that values obtained from these analysers should not be directly compared and that RIs are not transferable between these analysers. Potential effects of bias on clinical decision-making may be overcome by use of appropriately generated RIs, or reference change values which, for most biochemistry analytes, are more appropriate than subject-based RIs. PMID- 25297373 TI - Social media attacks on public health advocates. PMID- 25297374 TI - Alleviation effect of arbutin on oxidative stress generated through tyrosinase reaction with L-tyrosine and L-DOPA. AB - BACKGROUND: Hydroxyl radical that has the highest reactivity among reactive oxygen species (ROS) is generated through L-tyrosine-tyrosinase reaction. Thus, the melanogenesis might induce oxidative stress in the skin. Arbutin (p hydroxyphenyl-beta-D-glucopyranoside), a well-known tyrosinase inhibitor has been widely used for the purpose of skin whitening. The aim of the present study was to examine if arbutin could suppress the hydroxyl radical generation via tyrosinase reaction with its substrates, L-tyrosine and L-DOPA. RESULTS: The hydroxyl radical, which was determined by an electron spin resonance-spin trapping technique, was generated by the addition of not only L-tyrosine but L DOPA to tyrosinase in a concentration dependent manner. Arbutin could inhibit the hydroxyl radical generation in the both reactions. CONCLUSION: It is presumed that arbutin could alleviate oxidative stress derived from the melanogenic pathway in the skin in addition to its function as a whitening agent in cosmetics. PMID- 25297376 TI - Identification of a novel cyprinid herpesvirus 3 genotype detected in koi from the East Asian and South-East Asian Regions. AB - Cyprinid herpesvirus 3 (CyHV-3) is a highly contagious virus that causes significant morbidity and mortality in common carp Cyprinus carpio L. and considered to be one of the most important pathogens of koi and common carp worldwide. Cyprinid herpesvirus 3 infected consignments imported from East Asian and South-East Asian regions were identified during quarantine period in Singapore, and virus from a 2005 consignment was successfully isolated in koi fin cells. A combination of sequence analyses and duplex PCR were used to characterize 15 CyHV-3 isolates detected in koi consignments between 2005 and 2011. Sequence analyses of the enlarged 9/5, SphI-5 and TK gene regions identified both the Asian 1 (n = 11) and European 4 (n = 4) genotypes. Duplex PCR analysis of two variable marker regions between ORF29 and ORF30 (marker I) as well as ORF133 and its upstream region (marker II) revealed viruses of genotypes J (I++ II+ ), U/I (I-- II- ), an intermediate genotype (I++ II- ) and a novel genotype, I++ II+Delta , which was identified in viruses from seven different consignments. This novel genotype has a 13-bp deletion in marker II, while maintaining the I++ allele of marker I. The I++ II+Delta genotype may have emerged from East Asian and South-East Asian regions in recent years. PMID- 25297377 TI - QSAR and 3D-QSAR studies applied to compounds with anticonvulsant activity. AB - INTRODUCTION: Quantitative structure-activity relationships (QSAR and 3D-QSAR) have been applied in the last decade to obtain a reliable statistical model for the prediction of the anticonvulsant activities of new chemical entities. However, despite the large amount of information on QSAR, no recent review has published and discussed this data in detail. AREAS COVERED: In this review, the authors provide a detailed discussion of QSAR studies that have been applied to compounds with anticonvulsant activity published between the years 2003 and 2013. They also evaluate the mathematical approaches and the main software used to develop the QSAR and 3D-QSAR model. EXPERT OPINION: QSAR methodologies continue to attract the attention of researchers and provide valuable information for the development of new potentially active compounds including those with anticonvulsant activity. This has been helped in part by improvements in the size and performance of computers; the development of specific software and the development of novel molecular descriptors, which have given rise to new and more predictive QSAR models. The extensive development of descriptors, and the way by which descriptor values are derived, have allowed the evolution of the QSAR methods. This evolution could strengthen the QSAR methods as an important tool in research and development of new and more potent anticonvulsant agents. PMID- 25297375 TI - Urinary bladder inflammation induces changes in urothelial nerve growth factor and TRPV1 channels. AB - BACKGROUND AND PURPOSE: The urinary bladder urothelium expresses various receptors and in response to chemical and mechanical stimuli releases mediators, thereby modulating bladder sensory pathways. Transient receptor potential vanilloid 1 (TRPV1) ion channels and nerve growth factor (NGF) in those cells are implicated in this modulatory effect and play a role in sensitizing pain-related afferent pathways during inflammation. In this study, we investigated the interaction between NGF and TRPV1 channels in urothelial cells. EXPERIMENTAL APPROACH: Urothelial cells from female Sprague-Dawley rat bladders were cultured to quantify membrane expression of TRPV1 channels and capsaicin-induced ATP release in the presence of NGF alone or with TrKA or PI3K inhibitors. Pain scores from rats with cyclophosphamide (CYP)-induced bladder inflammation were assessed after treatment with a TrkA antagonist. Bladders (from control and CYP rats) were collected and analysed for NGF content and TRPV1 channel expression. KEY RESULTS: Cultured cells responded to NGF with increased TRPV1 channel expression in the cell membrane and increased release of ATP. Both responses were blocked by either a TrkA antagonist or a PI3K inhibitor. Treatment in vivo with the TrkA antagonist alleviated pain symptoms and reduced CYP-induced NGF overexpression in the mucosa. Furthermore, in urothelial cells from animals with bladder inflammation, expression of TRPV1 channels in the membrane was significantly increased. CONCLUSIONS AND IMPLICATIONS: During bladder inflammation, increased production of NGF in urothelial cells induced increased expression and activity of TRPV1 channels in the cell membrane. This effect was primarily mediated by the PI3K pathway. PMID- 25297378 TI - Asymmetric hydrogenation of pyridinium salts with an iridium phosphole catalyst. AB - Iridium-catalyzed asymmetric hydrogenation of N-alkyl-2-alkylpyridinium salts provided 2-aryl-substituted piperidines with high levels of enantioselectivity. Simple benzyl and other alkyl groups successfully activated the challenging pyridine substrates toward hydrogenation. The use of the unusual chiral-phosphole based MP(2) -SEGPHOS was the key to the success of this approach which provides a versatile and practical procedure for the synthesis of chiral piperidines. PMID- 25297379 TI - Structural insights into trapping and dissociation of small molecules in K+ channels. AB - K(+) channels play a critical role in numerous physiological and pathophysiological processes rendering them an attractive target for therapeutic intervention. However, the hERG K(+) channel poses a special challenge in drug discovery, since block of this channel by a plethora of diverse chemical entities can lead to long QT syndrome and sudden death. Of particular interest is the so called trapping phenomenon, characterized by capture of a drug behind closed channel gates, which harbors an increased pro-arrhythmic risk. In this study we investigated the influence of trapped blockers on the gating dynamics and probed the state dependence of dissociation in K(+) channels by making use of the quaternary tetrabutylammonium. By applying essential dynamics simulations and two electrode voltage clamp we obtained detailed insights into the dynamics of trapping in KcsA and hERG. Our simulations suggest that the trapped TBA influences the F656 flexibility during gate closure. Based on these findings, we provide a structural hypothesis for drug trapping. Further our simulations reveal the extent of gate opening necessary for drug dissociation. PMID- 25297380 TI - Support and monitoring of families after child abuse detection based on parental characteristics at the Emergency Department. AB - BACKGROUND: The 'Hague Protocol' enables professionals at the adult Emergency Department (ED) to detect child abuse based on three parental characteristics: (i) suicide attempt or self-harm, (ii) domestic violence or (iii) substance abuse, and to refer them to the Reporting Centre for Child Abuse and Neglect (RCCAN). This study investigates what had happened to the families three months after this referral. METHOD: ED referrals based on parental characteristics (N = 100) in which child abuse was confirmed after investigation by the RCCAN were analysed. Information was collected regarding type of child abuse, reason for reporting, duration of problems prior to the ED referral, previous involvement of support services or other agencies, re-occurrence of the problems and outcome of the RCCAN monitoring according to professionals and the families. RESULTS: Of the 100 referred cases, 68 families were already known to the RCCAN, the police or family support services, prior to the ED referral. Of the 99 cases where information was available, existing support was continued or intensified in 31, a Child Protection Services (CPS) report had to be made in 24, new support was organized for 27 cases and in 17 cases support was not necessary, because the domestic problems were already resolved. Even though the RCCAN is mandated to monitor all referred families after three months, 31 cases which were referred internally were not followed up. CONCLUSION: Before referral by the ED two thirds of these families were already known to organizations. Monitoring may help provide a better, more sustained service and prevent and resolve domestic problems. A national database could help to link data and to streamline care for victims and families. We recommend a Randomized Controlled Trial to test the effectiveness of this Protocol in combination with the outcomes of the provided family support. PMID- 25297381 TI - Diketopyrrolopyrrole-bitellurophene containing a conjugated polymer and its high performance thin-film transistor sensor for bromine detection. AB - A new bitellurophene-based pi-conjugated polymer (PDPPBTe) was synthesized and its semiconducting property was utilized for detecting Br2. The PDPPBTe polymer exhibited a highly sensitive response to Br2, which was indicated by a significant variation of the drain current in thin-film transistors. PMID- 25297382 TI - Parkinson's disease, the subthalamic nucleus, inhibition, and impulsivity. AB - Although Parkinson's disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra- or perioperatively in patients with PD having surgery for DBS of the STN (STN-DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN-DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN-DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control. PMID- 25297383 TI - Prevalence and Profile of Phonological and Surface Subgroups in College Students With a History of Reading Disability. AB - The purpose of the present study was to identify and characterize surface and phonological subgroups of readers among college students with a prior diagnosis of developmental reading disability (RD). Using a speeded naming task derived from Castles and Coltheart's subtyping study, we identified subgroups of readers from among college students with RD and then compared them on a number of component reading tasks. Most of our adults with RD showed a discrepancy in lexical versus sublexical reading skills. The majority of classified individuals were in the phonological dyslexia group, and this group's performance was worse than that of other groups on a range of reading-related tasks. Specifically, being relatively less skilled at reading nonwords compared to irregular words was associated with deficits in both sublexical and lexical tasks, and with unique deficits compared to the surface dyslexia group not only in an independent measure of phonological coding but also in spelling, rapid automatized naming, and speeded oral reading. The surface dyslexia group was small, and the pattern of results for these readers was not consistent with the predicted profile of a specific deficit in lexical and automatized reading processes. Our surface group did not show reduced skill in lexical mechanisms specifically, nor any unique deficit compared to the phonological group. These results seem more supportive of models of reading that place phonological processing impairments at the core of RD, with all other impairments being clearly subsidiary. PMID- 25297384 TI - 'I wish they would remember that I forget:' The effects of memory loss on the lives of individuals with mild-to-moderate dementia. AB - PURPOSE OF STUDY: Due to changing cognitive and functional capabilities, individuals with dementia face challenging care-related issues such as feelings of embarrassment, relationship strain, and symptoms of depression and anxiety. Limited research exists examining individuals with dementia's perceptions and concerns about these issues and how their perspectives can impact the quality and process of their illness experience. DESIGN AND METHODS: As part of a larger study, individuals with dementia (n = 114) answered five open-ended questions about their illness experience including: (1) daily routine, (2) concerns about memory loss, (3) relationships with others, (4) fears, and (5) what they wish others understood/knew. For each question, individuals with dementia's responses were analyzed for common themes within and across questions. RESULTS: Individuals with dementia commented on a wide range of issues involving their memory loss, including negative emotional impacts, future concerns and illness progression, forgetting, loss of independence, and the negative and positive influences on interpersonal relationships. Across questions, many individuals also stated that their memory loss did not significantly impact their lives. IMPLICATIONS: Discussion highlights how these findings can be used to expand our understanding of individuals with dementia's illness experience and to develop efficacious interventions for addressing negative aspects of living with memory loss while supporting positive aspects. PMID- 25297385 TI - Researchers "disappointed" that influential study was not retracted. PMID- 25297386 TI - A systems biology analysis of the changes in gene expression via silencing of HPV 18 E1 expression in HeLa cells. AB - Previous studies have reported the detection of a truncated E1 mRNA generated from HPV-18 in HeLa cells. Although it is unclear whether a truncated E1 protein could function as a replicative helicase for viral replication, it would still retain binding sites for potential interactions with different host cell proteins. Furthermore, in this study, we found evidence in support of expression of full-length HPV-18 E1 mRNA in HeLa cells. To determine whether interactions between E1 and cellular proteins play an important role in cellular processes other than viral replication, genome-wide expression profiles of HPV-18 positive HeLa cells were compared before and after the siRNA knockdown of E1 expression. Differential expression and gene set enrichment analysis uncovered four functionally related sets of genes implicated in host defence mechanisms against viral infection. These included the toll-like receptor, interferon and apoptosis pathways, along with the antiviral interferon-stimulated gene set. In addition, we found that the transcriptional coactivator E1A-binding protein p300 (EP300) was downregulated, which is interesting given that EP300 is thought to be required for the transcription of HPV-18 genes in HeLa cells. The observed changes in gene expression produced via the silencing of HPV-18 E1 expression in HeLa cells indicate that in addition to its well-known role in viral replication, the E1 protein may also play an important role in mitigating the host's ability to defend against viral infection. PMID- 25297388 TI - Level of plasma thioredoxin in male patients with manic episode at initial and post-electroconvulsive or antipsychotic treatment. AB - AIM: Oxidative stress is defined as exposure to excessive oxidants and/or decrease in antioxidant capacity. Several studies have shown the effects of free radicals and antioxidant defense systems in bipolar disorder. We aimed to investigate the role of thioredoxin (TRX), which is a novel oxidative stress marker in patients with bipolar disorder. METHODS: Sixty-eight hospitalized bipolar patients who were in manic episode were included in the study. As a control group, 30 healthy people were elected. Two groups were formed. The first group consisted of patients who were undergoing electroconvulsive treatment + antipsychotic treatment (haloperidol+quetiapine) and members of the other group were taking only antipsychotic treatment. Plasma thioredoxin levels were measured before and after treatment. RESULTS: Pretreatment plasma TRX levels of patients were significantly lower than the controls (P < 0.05). Comparing pre- and post treatment plasma TRX levels of all patients, post-treatment plasma TRX levels were significantly lower than the pre-treatment plasma TRX levels (P < 0.05). When we compared TRX levels between the electroconvulsive treatment + antipsychotic treatment group and the antipsychotic treatment group (P > 0.05) and within groups (P > 0.05) we did not find any statistically significant difference. CONCLUSION: Oxidative balance is impaired in bipolar disorder manic episode in favor of the oxidants. Decreased plasma TRX levels in the manic episode probably mean that antioxidant capacity is decreased in the bipolar disorder patients in the manic episode. Further studies in euthymic and depressive states are also needed to gain more insight into the role of TRX in bipolar disorder. PMID- 25297387 TI - From induction to conduction: how intrinsic transcriptional priming of extrinsic neuronal connectivity shapes neuronal identity. AB - Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming. PMID- 25297389 TI - Repeated transcatheter arterial chemoembolization is safe for hepatocellular carcinoma in cirrhotic patients with transjugular intrahepatic portosystemic shunt. AB - PURPOSE: We aimed to investigate the safety and long-term outcomes of repeated transcatheter arterial chemoembolization (TACE) in cirrhotic patients with transjugular intrahepatic portosystemic shunt (TIPS). METHODS: Data of patients with hepatocellular carcinoma, who had previous TIPS implantation and received TACE between January 2010 and December 2012, were reviewed retrospectively. The primary outcome measure was liver function, which was represented by model for end-stage liver disease score, Child-Pugh-Turcotte score, serum total bilirubin, alanine aminotransferase, and aspartate aminotransferase. Changes in liver function before and after the initial TACE procedure and hepatobiliary severe adverse events (SAEs) were compared. Liver function following the initial TACE session was compared with that obtained in later TACE sessions. The secondary outcome measures were tumor response to multiple TACE sessions and survival. RESULTS: Seventeen patients underwent at least two TACE sessions, while nine patients underwent at least three sessions during the follow-up period. There was no statistically significant difference between the liver function tests performed before and one-month after the TACE procedure. Grade 3 or 4 SAEs occurred in six (31.6 %) patients within one month. The one, two-, and three-year survival rates were 88%, 53%, and 32%, respectively. Tumor response of multiple TACE sessions was the only predictive risk factor of mortality (OR=4.40; P = 0.030; 95% CI, 1.15-16.85). CONCLUSION: Our results suggest that repeated TACE is safe in selected patients with TIPS. PMID- 25297390 TI - Nonodontogenic mandibular lesions: differentiation based on CT attenuation. AB - Mandibular lesions are classified as odontogenic and nonodontogenic based on the cell of origin. Odontogenic lesions are frequently encountered at head and neck imaging. However, several nonodontogenic pathologies may also involve mandible and present further diagnostic dilemma. Awareness of the imaging features of nonodontogenic lesions is crucial in order to guide clinicians in proper patient management. Computed tomography (CT) may provide key information to narrow diagnostic considerations. Nonodontogenic mandibular lesions may have lytic, sclerotic, ground-glass, or mixed lytic and sclerotic appearances on CT. In this article, our aim is to present various nonodontogenic lesions of the mandible by categorizing them according to their attenuations on CT. PMID- 25297391 TI - Diffusion-weighted MRI findings of treated and untreated retroperitoneal fibrosis. AB - PURPOSE: We aimed to evaluate diffusion-weighted imaging (DWI) findings in patients with treated and untreated retroperitoneal fibrosis (RPF). METHODS: We analyzed magnetic resonance imaging examinations of 44 RPF patients (36 male, 8 female), of which 15 were untreated and 29 were under therapy. Qualitative DWI and T1 postcontrast signal intensities and the largest perivascular extent of RPF were compared between treated and untreated groups and correlated to erythrocyte sedimentation rate and C-reactive protein values. Quantitative DWI signal intensities and apparent-diffusion-coefficients were calculated in regions-of interest, together with a relative index between signal intensities of RPF and psoas muscle in 15 untreated patients and 14 patients under treatment with remaining perivascular fibrosis of more than 5 mm. RESULTS: The extent of RPF in untreated patients was significantly larger compared with the extent of RPF in treated patients (P <0.0001). DWI signal intensities were significantly higher in untreated patients than in patients under therapy (mean, 27 s/mm2 vs. 20 s/mm2; P = 0.009). The calculated DWI-index was significantly higher in untreated patients than in patients under therapy (P = 0.003). CONCLUSION: Our data show significant differences in the DWI findings (b800 signal intensities and relative DWI-index) of patients with treated and untreated RPF. DWI is a promising technique in the assessment of disease activity and the selection of patients suitable for medical therapy. PMID- 25297392 TI - An association study on the CHRNA5/A3/B4 gene cluster, smoking and psoriasis vulgaris. AB - Genome-wide association and large cohort studies have consistently linked several single nucleotide polymorphisms (SNPs) located in the CHRNA5/A3/B4 gene cluster to smoking behaviors and nicotine dependence. Smoking is one of the well established environmental risk factors for psoriasis and also associated with severity of the disease. Then we conduct the study to examine whether the genetic variations related to smoking behavior located in the CHRNA5/A3/B4 gene cluster also predict the risk of psoriasis vulgaris (PV). The investigations may help explain the mechanisms of the smoking-PV relationship. This is a hospital base case-control study including 634 subjects (329 PV patients and 305 controls), all Chinese Han population. 8 SNPs were selected based on findings from recent studies on smoking and nicotine dependence, all located in the nicotinic acetylcholine receptor subunits CHRNA5/A3/B4 gene cluster. The variants were typed by SNaPshot Multiplex Kit (Applied Biosystems Co., USA). We confirmed that smoking, alcohol consumption and higher body mass index (BMI >=25) were risk factors for PV. However, none of the selected SNPs was associated with PV risk in the overall analysis and stratification analysis. And we found no association between the selected SNPs in CHRNA5/A3/B4 gene cluster and the clinical features of PV in case-only analysis. This exploratory study does not provide a relationship between these smoking-related SNPs in the CHRNA5/A3/B4 gene cluster and PV in Chinese Han population. PMID- 25297393 TI - Dermoscopic features of clinically inflammatory dermatoses and their correlation with histopathologic reaction patterns. AB - Dermoscopy can be used in diagnosis of some chronic inflammatory dermatoses. In this study, the single most recent, fully developed lesion in 74 patients with clinically inflammatory dermatoses was examined dermoscopically and correlated histopathologically with psoriasiform, lichenoid, or spongiotic reaction patterns. Vascular component (morphology and arrangement) was the most prominent feature in the studied patterns mostly in the shape of dots (45 specimens, 60.8%), globules (30 specimens, 40.5%), and lines (45 specimens, 60.8%). Psoriasiform pattern showed vascular dots (20 specimens, 76.92%), and/or red globules (15 specimen, 57.69%), regularly distributed (17 specimens, 65.38%), on intense red background (15 specimens, 57.69%), and diffuse (13 specimens, 50%) white scales (18 specimen, 69.23%), with probability of these features together 100%. Lichenoid pattern showed red lines (23 cases, 65.71%), on dull or light red background (14 cases, 40% for each), with discolored areas (15 cases, 42.86%), brown reticular pigmentation (21 cases, 60%), and white scales (13 cases, 37.14%). Spongiotic pattern was characterized by follicular component and diffuse or peripheral scale distribution, with probability of both features together 100%. The main histopathologic features of inflammatory dermatoses, which influenced their dermoscopic patterns, are depth and size of vessels, presence and shape of epidermal hyperplasia, presence of spongiosis, and degree of dermal inflammation and oedema. These features influenced vascular morphology and distribution, corneal component, and background color. Among the studied reaction patterns, psoriasiform pattern showed the most consistent correlation with dermoscopic features. Dermoscopic picture of lichenoid reaction was the most contradictory. Spongiotic reaction showed absent specific vascular component. PMID- 25297394 TI - Reproducibility of measuring amniotic fluid index and single deepest vertical pool throughout gestation. AB - OBJECTIVE: The aim of this study is to assess the intraobserver and interobserver reproducibility of measurement of amniotic fluid index (AFI) and single deepest vertical pool (SDVP), also known as the maximal vertical pocket. METHODS: A total of 175 fetuses were evaluated. For each fetus, two observers acquired duplicate sets of AFI and SDVP. Measurement differences were expressed as actual and percentage values. For all comparisons, Bland-Altman plots were used to compare differences, and limits of agreement were calculated. RESULTS: Intraobserver and interobserver agreement remained fairly constant with gestation, both for AFI and SDVP. The intraobserver limits of agreement for AFI were -5.2 to 5 cm or -39% to 37%; whereas for SDVP, these were -2.6 to 2.4 cm or -52% to 48%. The interobserver limits of agreement for AFI measurement were -7.3 to 7.1 cm or -54% to 53% and for SDVP measurement were -2.5 to 2.5 cm or -51% to 52%. Intraobserver coefficient of variation for SDVP was 14% and for AFI was 19%; the interobserver coefficient was 19% for both AFI and SDVP. CONCLUSION: Limits of agreement for both methods are wide. The choice of method should be dictated by clinical considerations other than method reproducibility. PMID- 25297396 TI - Out of Africa. PMID- 25297397 TI - A little knowledge. PMID- 25297398 TI - Holy cows. PMID- 25297399 TI - A call to those who care about Europe's science. PMID- 25297410 TI - US plans upgrade for ageing Greenland research station. PMID- 25297411 TI - Australian cuts rile researchers. PMID- 25297412 TI - Rivals join forces to nail down Big G. Metrologists meet to design the ultimate gravitational-constant experiment. PMID- 25297413 TI - Marmosets are stars of Japan's ambitious brain project. PMID- 25297414 TI - Blue LED wins physics Nobel. PMID- 25297415 TI - Prize for place cells. PMID- 25297416 TI - Neuroscience: Brains of Norway. PMID- 25297417 TI - Large Hadron Collider: The big reboot. PMID- 25297418 TI - Does evolutionary theory need a rethink? PMID- 25297421 TI - Renewables: Can harm environment. PMID- 25297422 TI - Renewables: Costly long-distance power. PMID- 25297423 TI - Awards: Maths medal boosts Brazilian morale. PMID- 25297424 TI - Renewables: The sky is the limit. PMID- 25297426 TI - History: Photosynthesis and the Nobel physicist. PMID- 25297427 TI - Satellite data: Beyond sharing Earth observations. PMID- 25297428 TI - Archaeology: Art on the move. PMID- 25297429 TI - Ultraluminous X-ray sources: Small field with a large impact. PMID- 25297430 TI - Particle physics: The mass of a top. PMID- 25297431 TI - Materials analysis: Good vibrations. PMID- 25297432 TI - A mass of less than 15 solar masses for the black hole in an ultraluminous X-ray source. AB - Most ultraluminous X-ray sources have a typical set of properties not seen in Galactic stellar-mass black holes. They have luminosities of more than 3 * 10(39) ergs per second, unusually soft X-ray components (with a typical temperature of less than about 0.3 kiloelectronvolts) and a characteristic downturn in their spectra above about 5 kiloelectronvolts. Such puzzling properties have been interpreted either as evidence of intermediate-mass black holes or as emission from stellar-mass black holes accreting above their Eddington limit, analogous to some Galactic black holes at peak luminosity. Recently, a very soft X-ray spectrum was observed in a rare and transient stellar-mass black hole. Here we report that the X-ray source P13 in the galaxy NGC 7793 is in a binary system with a period of about 64 days and exhibits all three canonical properties of ultraluminous sources. By modelling the strong optical and ultraviolet modulations arising from X-ray heating of the B9Ia donor star, we constrain the black hole mass to be less than 15 solar masses. Our results demonstrate that in P13, soft thermal emission and spectral curvature are indeed signatures of supercritical accretion. By analogy, ultraluminous X-ray sources with similar X ray spectra and luminosities of up to a few times 10(40) ergs per second can be explained by supercritical accretion onto massive stellar-mass black holes. PMID- 25297433 TI - An ultraluminous X-ray source powered by an accreting neutron star. AB - The majority of ultraluminous X-ray sources are point sources that are spatially offset from the nuclei of nearby galaxies and whose X-ray luminosities exceed the theoretical maximum for spherical infall (the Eddington limit) onto stellar-mass black holes. Their X-ray luminosities in the 0.5-10 kiloelectronvolt energy band range from 10(39) to 10(41) ergs per second. Because higher masses imply less extreme ratios of the luminosity to the isotropic Eddington limit, theoretical models have focused on black hole rather than neutron star systems. The most challenging sources to explain are those at the luminous end of the range (more than 10(40) ergs per second), which require black hole masses of 50-100 times the solar value or significant departures from the standard thin disk accretion that powers bright Galactic X-ray binaries, or both. Here we report broadband X-ray observations of the nuclear region of the galaxy M82 that reveal pulsations with an average period of 1.37 seconds and a 2.5-day sinusoidal modulation. The pulsations result from the rotation of a magnetized neutron star, and the modulation arises from its binary orbit. The pulsed flux alone corresponds to an X-ray luminosity in the 3-30 kiloelectronvolt range of 4.9 * 10(39) ergs per second. The pulsating source is spatially coincident with a variable source that can reach an X-ray luminosity in the 0.3-10 kiloelectronvolt range of 1.8 * 10(40) ergs per second. This association implies a luminosity of about 100 times the Eddington limit for a 1.4-solar-mass object, or more than ten times brighter than any known accreting pulsar. This implies that neutron stars may not be rare in the ultraluminous X-ray population, and it challenges physical models for the accretion of matter onto magnetized compact objects. PMID- 25297434 TI - Vibrational spectroscopy in the electron microscope. AB - Vibrational spectroscopies using infrared radiation, Raman scattering, neutrons, low-energy electrons and inelastic electron tunnelling are powerful techniques that can analyse bonding arrangements, identify chemical compounds and probe many other important properties of materials. The spatial resolution of these spectroscopies is typically one micrometre or more, although it can reach a few tens of nanometres or even a few angstroms when enhanced by the presence of a sharp metallic tip. If vibrational spectroscopy could be combined with the spatial resolution and flexibility of the transmission electron microscope, it would open up the study of vibrational modes in many different types of nanostructures. Unfortunately, the energy resolution of electron energy loss spectroscopy performed in the electron microscope has until now been too poor to allow such a combination. Recent developments that have improved the attainable energy resolution of electron energy loss spectroscopy in a scanning transmission electron microscope to around ten millielectronvolts now allow vibrational spectroscopy to be carried out in the electron microscope. Here we describe the innovations responsible for the progress, and present examples of applications in inorganic and organic materials, including the detection of hydrogen. We also demonstrate that the vibrational signal has both high- and low-spatial-resolution components, that the first component can be used to map vibrational features at nanometre-level resolution, and that the second component can be used for analysis carried out with the beam positioned just outside the sample--that is, for 'aloof' spectroscopy that largely avoids radiation damage. PMID- 25297435 TI - Pleistocene cave art from Sulawesi, Indonesia. AB - Archaeologists have long been puzzled by the appearance in Europe ~40-35 thousand years (kyr) ago of a rich corpus of sophisticated artworks, including parietal art (that is, paintings, drawings and engravings on immobile rock surfaces) and portable art (for example, carved figurines), and the absence or scarcity of equivalent, well-dated evidence elsewhere, especially along early human migration routes in South Asia and the Far East, including Wallacea and Australia, where modern humans (Homo sapiens) were established by 50 kyr ago. Here, using uranium series dating of coralloid speleothems directly associated with 12 human hand stencils and two figurative animal depictions from seven cave sites in the Maros karsts of Sulawesi, we show that rock art traditions on this Indonesian island are at least compatible in age with the oldest European art. The earliest dated image from Maros, with a minimum age of 39.9 kyr, is now the oldest known hand stencil in the world. In addition, a painting of a babirusa ('pig-deer') made at least 35.4 kyr ago is among the earliest dated figurative depictions worldwide, if not the earliest one. Among the implications, it can now be demonstrated that humans were producing rock art by ~40 kyr ago at opposite ends of the Pleistocene Eurasian world. PMID- 25297440 TI - POLRMT does not transcribe nuclear genes. PMID- 25297441 TI - Dendrimer-type peptoid-decorated hexaphenylxylenes and tetraphenylmethanes: synthesis and structure in solution and in the gas phase. AB - Branched organic nanostructures are useful scaffolds that find multiple applications in a variety of fields. Here, we present a novel approach to dendrimer-like structures. Our design contains a rigid hydrocarbon-based core (hexaphenylxylylene/tetraethynylphenylmethane) combined with a library of N substituted oligoglycines (so-called peptoids) providing a flexible shell. The use of click chemistry allows rapid assembly of the nanostructures. The possibility of tuning the size and the solubility of this new type of nanostructure will be advantageous for future applications such as heterogeneous catalysis. PMID- 25297443 TI - Hospital volume and patient outcomes in hepato-pancreatico-biliary surgery: is assessing differences in mortality enough? AB - BACKGROUND: The impact of regionalization on morbidity, failure to rescue (FTR), length of stay (LOS), and readmission remains unclear. We sought to examine hospital-volume-related differences in outcomes following complex hepato pancreatico-biliary (HPB) surgery and define potential benefits of regionalization across quality metrics. METHODS: Patients undergoing HPB surgery in the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data from 1986 to 2002 were identified. Hospital volume was stratified into tertiles (low volume [LV] <4 cases/year; intermediate volume [IV] 4-10 cases/year; high volume [HV] >=11 cases/year). The incidence of complications, FTR (mortality following a complication), and LOS was compared across hospital-volume strata. A counterfactual model examined hypothetical outcomes assuming all patients had been treated at HV centers. RESULTS: Ten thousand two hundred eight patients underwent pancreatic (46.1 %), hepatic (36.2 %), or biliary (17.8 %) procedures. Overall mean age ranged from 72.7 years at HV centers to 73.4 at LV centers (P < 0.001), and patients at HV centers (75.4 %) were more likely to have >=3 comorbidities versus IV (70.0 %) or LV (64.7 %) centers (P < 0.001). The incidence of post-operative complications was lower at HV (39.1 %) compared with IV (41.9 %) or LV (44.8 %) centers. Major complications included hemorrhagic anemia (7.3 %), failure to thrive (5.1 %), and respiratory infection/failure (3.5 %); each was less common in HV hospitals (P < 0.05). FTR after major complication tended to be higher at LV (36.7 %) and IV (37.3 %) hospitals compared with HV hospitals (29.7 %) (P = 0.10). Mortality was higher at LV (10.5 %) and IV (8.1 %) hospitals versus HV centers (5.4 %) (P < 0.001). HV hospital patients had shorter median LOS (10 days) compared with IV (12 days) or LV (12 days) hospital patients (P < 0.001). Readmission varied across centers (HV 19.1 % vs. IV 19.2 % vs. 16.7 %; P = 0.02). In a counterfactual model with all patients treated at a HV center, 6.4 % fewer complications and a 26.0 % increase in post-complication rescue would be expected, along with a 32.0 % reduction in index mortality and an 8.1 % reduction in total patient-days. A minor increase in readmissions (7.1 %) would be anticipated with 13.3 % fewer deaths during readmission. CONCLUSION: Although patients treated at HV hospitals had more medical comorbidities, outcomes across a wide spectrum of quality metrics were better than at IV or LV hospital following complex HPB surgery. A 20-30 % reduction in morbidity and mortality and an 8 % reduction in hospital patient-days could be anticipated had all patients been treated at HV hospitals. PMID- 25297442 TI - Generalized estimating equations for genome-wide association studies using longitudinal phenotype data. AB - Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study. PMID- 25297444 TI - Re-examining the BMI threshold for bariatric surgery in the USA. AB - BACKGROUND: The optimal BMI threshold above which gastric bypass surgery should be offered to obese patients is controversial. The objective of this study was to compare the impact of Roux-en-Y gastric bypass (RYGB) vs. diet and exercise (D&E) on life expectancy to find the BMI at which patients experience an improvement in their life expectancy by undergoing surgery. METHODS: A Markov state transition model was designed to implement a decision tree that simulated the lives of obese patients. Life expectancies following RYGB and 2 years of D&E were estimated and compared. Ten thousand patients' lives were simulated in each weight-loss intervention group in the model. In addition to base case analysis (45 kg/m(2) BMI pre-intervention), sensitivity analysis of initial BMI at the start of the study was completed. Markov model parameters were extracted from the literature. RESULTS: The impact of RYGB on survival relative to D&E depended on the patient's initial BMI. Compared to patients who underwent 2 years of "optimal" diet and exercise (7 % total body weight loss/year), RYGB improved long-term survival for patients above a BMI of 31.3 kg/m(2). CONCLUSIONS: Roux-en-Y gastric bypass can improve long-term survival for patients with class I obesity. This study suggests that RYGB should not be reserved solely for patients with class II or III obesity. PMID- 25297445 TI - A new pN staging system based on both the number and anatomic location of metastatic lymph nodes in gastric cancer. AB - BACKGROUND: Our aim was to establish a new pN staging system for gastric cancer based on the number and location of metastatic lymph nodes (MLNs) and to compare it with other systems. METHODS: We retrospectively analyzed the prognostic data of 521 gastric cancer patients who underwent curative resection. Survival analyses were used to establish a pN staging system that considers both the number and location of MLNs and to compare discriminatory ability and monotonicity of gradients (linear trend chi (2) score), homogeneity ability (likelihood ratio test), and prognostic stratification ability (Akaike information criterion) between Japanese Gastric Cancer Association (JGCA) and Union for International Cancer Control (UICC) systems. RESULTS: Cut-point survival analysis divided pN(+) patients into two groups: Nxn1~6 and Nxn>=7. N0, N1, N2, and N3 (the previous classifications) were replaced by N0, N1n1~6, N2n1~6, and N1n>=7 + N2n>=7 + N3n1~6 + N3n>=7, respectively. Compared with two widely used staging systems, the new system had the highest likelihood ratio test [106.06 (new) vs 95.09 (JGCA) vs 94.33 (UICC)] and linear trend chi (2) scores [102.30 (new) vs 89.12 (JGCA) vs 86.97(UICC)] and the lowest Akaike information criterion (AIC) score [2,283.88 (new) vs 2,285.31 (JGCA) vs 2,299.88 (UICC)]. CONCLUSION: A new pN staging system based on the number and location of MLNs is an efficient prognostic indicator of the survival of patients with gastric cancer following radical surgery. PMID- 25297446 TI - Predictive factors analysis for malignant peritoneal mesothelioma. AB - BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an uncommon disease with a dismal prognosis and unclear natural history. The present study aims to assess potential prognostic factors and management of MPM. METHODS: Clinical records of 39 patients with MPM between December 2003 and April 2014 were retrospectively reviewed. Overall survival was identified with Kaplan-Meier curves and Cox regression analysis. RESULTS: Mean age of 39 patients was 55.0 years; asbestos exposure was recorded in two patients. Main presentations were abdominal distension, abdominal pain, and weight loss. Thrombocytosis, low serum albumin level, and anemia were principal laboratory abnormalities. Ascites, peritoneal cavity mass, and peritoneum thickening were the main signs on CT scans. Cytoreductive surgery (CRS) plus adjuvant therapies were performed in 22 patients, single chemotherapy in 13, and best supportive care in 4. Median survival time was 10.0 months after pathological diagnosis, with a 6-, 12-, 18-, and 24-month survival rate of 84.4, 31.6, 18.5, and 15.8 %, respectively. Significant prognostic factors were age, performance status (PS), abdominal pain, serum albumin level, thrombocytosis, and treatment strategy on univariate analysis, while only age, abdominal pain, and treatment strategy hold statistical significance on multivariate analysis. CONCLUSIONS: Age <=65 years, abdominal pain, and CRS plus adjuvant therapy are independent positive prognostic factors of MPM. PMID- 25297448 TI - Midwife-physician collaboration: a conceptual framework for interprofessional collaborative practice. AB - INTRODUCTION: Since the passage of the Affordable Care Act, collaborative practice has been cited as one method of increasing access to care, decreasing costs, and improving efficiency. How and under what conditions might these goals be achieved? Midwives and physicians have built effective collaborative practice models over a period of 30 years. Empirical study of interprofessional collaboration between midwives and physicians could be useful in guiding professional education, regulation, and health policy in women's health and maternity care. METHODS: Construction of a conceptual framework for interprofessional collaboration between midwives and physicians was guided by a review of the literature. A theory derivation strategy was used to define dimensions, concepts, and statements of the framework. RESULTS: Midwife-physician interprofessional collaboration can be defined by 4 dimensions (organizational, procedural, relational, and contextual) and 12 concepts (trust, shared power, synergy, commitment, and respect, among others). The constructed framework provides the foundation for further empirical study of the interprofessional collaborative process. DISCUSSION: The experiences of midwife-physician collaborations provide solid support for a conceptual framework of the collaborative process. A conceptual framework provides a point from which further research can increase knowledge and understanding about how successful outcomes are achieved in collaborative health care practices. Construction of a measurement scale and validation of the model are important next steps. PMID- 25297449 TI - Ethnic differences in attitudes and bias toward older people comparing White and Asian nursing students. AB - PURPOSES: To identify attitudes and bias toward aging between Asian and White students and identify factors affecting attitudes toward aging. METHODS: A cross sectional sample of 308 students in a nursing program completed the measure of Attitudes Toward Older People and Aging Quiz electronically. FINDINGS: There were no differences in positive attitudes and pro-aged bias between Asian and White groups, but Asian students had significantly more negative attitudes and anti aged bias toward older people than White students. Multiple regression analysis showed ethnicity/race was the strongest variable to explain negative attitudes toward older people. Feeling uneasy about talking to older adults was the most significant factor to explain all attitudinal concepts. CONCLUSIONS: Asian students were uneasy about talking with older people and had negative attitudes toward older adults. To become competent in cross-cultural care and communication in nursing, educational strategies to reduce negative attitudes on aging are necessary. PMID- 25297450 TI - Spiritual Healing Practices Among Rural Postpartum Thai Women. AB - PURPOSE: Postpartum Thai women follow family instructions to recover health at home. This study explores first-time mothers' experiences with postpartum family practices. This article presents the experiences with spiritual healing, one of the three essences of Thai traditional medicine. DESIGN: An interpretive phenomenological study was conducted in rural Thailand. Participants were 16 pregnant women purposively recruited. Data were collected using in-depth interviews, participant observations, and a demographic record and were analyzed using thematic and exemplar analysis. RESULTS: The women adhered to practices and rituals related to beliefs about three essences (the body, mind-heart, and energy). Spiritual healing works on mind-heart essences. CONCLUSION: A new mother healed her spirit through traditional postpartum practices. The findings provide an understanding of the practices within the context of rural Thai women's families. This information can guide future implementation of postpartum care, with awareness of and respect for cultural practices in fulfilling spiritual needs. PMID- 25297451 TI - Retraction note to: immunotherapy of metastatic colorectal cancer with vitamin D binding protein-derived macrophage-activating factor, GcMAF. PMID- 25297452 TI - Cytokine production in peripheral blood cells of patients with differentiated thyroid cancer: elevated Th2/Th9 cytokine production before and reduced Th2 cytokine production after radioactive iodine therapy. AB - Cytokines play a key role in the regulation of cells of the immune system and also have been implicated in the pathogenesis of malignant diseases. The aim of this study was to evaluate cytokine profiles in patients with differentiated thyroid cancer (DTC) before and 7 days after radioactive iodine (131-I) therapy. Cytokine levels were determined in supernatants obtained from phytohemagglutinin stimulated whole blood cultures of 13 patients with DTC and 13 control subjects. The concentrations of selected cytokines: Th1-interferon gamma (IFN-gamma), interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha); Th2-interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13) and interleukin 10 (IL 10); Th9-interleukin-9 (IL-9); and Th17-interleukin 17 (IL-17A) were measured using multiplex cytokine detection systems for Human Th1/Th2/Th9/Th17/Th22. We have shown that peripheral blood cells of DTC patients produce significantly higher concentrations of Th2/Th9 cytokines (IL-5, IL-13 and IL-9) than control subjects. The 131-I therapy led to reduced secretion of Th2 cytokines (IL-4, IL-5 and IL-13). Despite this, the calculated cytokine ratios (Th1/Th2) in DTC patients before and 7 days after 131-I therapy were not different from those in healthy subjects. DTC patients have significantly higher concentrations of Th2/Th9 cytokines (IL-5, IL-13 and IL-9) than control subjects. There is no influence of hypothyroidism or stage of disease on cytokine production in DTC patients before 131-I therapy. The radioactive 131-I therapy leads to reduced secretion of Th2 cytokines (IL-4, IL-5 and IL-13). Additional studies are needed to determine the significance of these findings. PMID- 25297454 TI - Cobalt sulfide nanosheet/graphene/carbon nanotube nanocomposites as flexible electrodes for hydrogen evolution. AB - Flexible three-dimensional (3D) nanoarchitectures have received tremendous interest recently because of their potential applications in wearable electronics, roll-up displays, and other devices. The design and fabrication of a flexible and robust electrode based on cobalt sulfide/reduced graphene oxide/carbon nanotube (CoS2 /RGO-CNT) nanocomposites are reported. An efficient hydrothermal process combined with vacuum filtration was used to synthesize such composite architecture, which was then embedded in a porous CNT network. This conductive and robust film is evaluated as electrocatalyst for the hydrogen evolution reaction. The synergistic effect of CoS2 , graphene, and CNTs leads to unique CoS2 /RGO-CNT nanoarchitectures, the HER activity of which is among the highest for non-noble metal electrocatalysts, showing 10 mA cm(-2) current density at about 142 mV overpotentials and a high electrochemical stability. PMID- 25297455 TI - Toward a theory of persuasive hope: effects of cognitive appraisals, hope appeals, and hope in the context of climate change. AB - Hope has the potential to be a powerful motivator for influencing behavior. However, hope and messages that evoke hope (hope appeals) have rarely been the focus of theoretical development or empirical research. As a step toward the effective development and use of hope appeals in persuasive communication, this study conceptualized and operationalized hope appeals in the context of climate change prevention. Then, the study manipulated components of the hope evocation part of a hope appeal. Specifically, the components were designed to address appraisals of the importance, goal congruence, future expectation, and possibility of climate protection, resulting in a 2 (strong/weak importance) * 2 (strong/weak goal congruence) * 2 (strong/weak future expectation) * 2 (strong/weak possibility) between-subjects pretest-posttest factorial design. Two hundred forty-five undergraduate students were randomly assigned to one of the 16 message conditions and completed the study online. The study tested whether the four appraisals predict feelings of hope. It determined whether message components that address importance, goal congruence, future expectation, and possibility affect appraisals, feelings of hope, and persuasion outcomes. Finally, this study tested the effects of feelings of hope on persuasion outcomes. This study takes an important step toward enabling the effective use of hope appeals in persuasive communication. PMID- 25297453 TI - Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside-perpetrated herb-drug interactions on OATP1B3. AB - BACKGROUND AND PURPOSE: Ginsenosides are bioactive saponins derived from Panax notoginseng roots (Sanqi) and ginseng. Here, the molecular mechanisms governing differential pharmacokinetics of 20(S)-protopanaxatriol-type ginsenoside Rg1 , ginsenoside Re and notoginsenoside R1 and 20(S)-protopanaxadiol-type ginsenosides Rb1, Rc and Rd were elucidated. EXPERIMENTAL APPROACH: Interactions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels. A rifampin-based inhibition study in rats evaluated the in vivo role of organic anion-transporting polypeptide (Oatp)1b2. Plasma protein binding was assessed by equilibrium dialysis. Drug-drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside-mediated interactions due to inhibition of human OATP1Bs. KEY RESULTS: All the ginsenosides were bound to human OATP1B3 and rat Oatp1b2 but only the 20(S)-protopanaxatriol-type ginsenosides were transported. Human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein (BCRP)/bile salt export pump (BSEP)/multidrug resistance protein-1 and rat Mrp2/Bcrp/Bsep also mediated the transport of the 20(S)-protopanaxatriol-type ginsenosides. Glomerular-filtration-based renal excretion of the 20(S) protopanaxatriol-type ginsenosides was greater than that of the 20(S) protopanaxadiol-type counterparts due to differences in plasma protein binding. Rifampin-impaired hepatobiliary excretion of the 20(S)-protopanaxatriol-type ginsenosides was effectively compensated by the renal excretion in rats. The 20(S)-protopanaxadiol-type ginsenosides were potent inhibitors of OATP1B3. CONCLUSION AND IMPLICATIONS: Differences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides. Caution should be exercised with the long-circulating 20(S)-protopanaxadiol-type ginsenosides as they could induce hepatobiliary herb-drug interactions, particularly when patients receive long term therapies with high-dose i.v. Sanqi or ginseng extracts. PMID- 25297456 TI - Preclinical assessment of Orteronel((r)), a CYP17A1 enzyme inhibitor in rats. AB - Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t 1/2) of Orteronel with intravenous (i.v.) route was found to be 1.65 +/- 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 +/- 3.09 mL/min/kg and 3.94 +/- 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 +/- 76.4, 1,764 +/- 166, 4,652 +/- 300 and 17,518 +/- 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t 1/2 by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine. PMID- 25297458 TI - Effect of interval training on cognitive functioning and cerebral oxygenation in obese patients: a pilot study. AB - OBJECTIVE: To assess the effect of a 4-month high-intensity interval training programme on cognitive functioning, cerebral oxygenation, central haemodynamic and cardiometabolic parameters and aerobic capacity in obese patients. METHODS: Cognitive functioning, cerebral oxygenation, central haemodynamic, cardiometabolic and exercise para-meters were measured before and after a 4-month high-intensity interval training programme in 6 obese patients (mean age 49 years (standard deviation 8), fat mass percentage 31 +/- 7%). RESULTS: Body composition (body mass, total and trunk fat mass, waist circumference) and fasting insulin were improved after the programme (p < 0.05). V. O2 and power output at ventilatory threshold and peak power output were improved after the programme (p < 0.05). Cognitive functioning, including short-term and verbal memory, attention and processing speed, was significantly improved after training (p < 0.05). Cerebral oxygen extraction was also improved after training (p < 0.05). CONCLUSION: These preliminary results indicate that a 4-month high-intensity interval training programme in obese patients improved both cognitive functioning and cere-bral oxygen extraction, in association with improved exercise capacity and body composition. PMID- 25297457 TI - Differential modulation of host genes in the kidney of brown trout Salmo trutta during sporogenesis of Tetracapsuloides bryosalmonae (Myxozoa). AB - Tetracapsuloides bryosalmonae (Myxozoa) is the causative agent of proliferative kidney disease in various species of salmonids in Europe and North America. In Europe, spores of T. bryosalmonae develop in the kidney of infected brown trout Salmo trutta and are released via urine to infect the freshwater bryozoan Fredericella sultana. The transcriptomes of kidneys of infected and non-infected brown trout were compared by suppressive subtractive hybridization. Differential screening and a subsequent NCBI BLAST analysis of expressed sequence tags revealed 21 transcripts with functions that included cell stress and cell growth, ribonucleoprotein, signal transduction, ion transporter, immune response, hemoglobin and calcium metabolisms. Quantitative real time PCR was used to verify the presence of these selected transcripts in brown trout kidney at sporogonic stages of T. bryosalmonae development. Expression of cold-inducible RNA-binding protein, cyclin-dependent kinase inhibitor 2A, prothymosin alpha, transforming protein RhoA, immunoglobulin light chain and major histocompatibility complex class I were up-regulated significantly in infected brown trout. Expression of both the hemoglobin subunit beta and stanniocalcin precursor were down-regulated significantly in infected brown trout. This study suggests that cell stress and cell growth processes, signal transduction activities, erythropoiesis and calcium homeostasis of the host are modulated during sporogonic stages of parasite development, which may support the sporogenesis of T. bryosalmonae in the kidney of brown trout. PMID- 25297459 TI - Sexual orientation and non-suicidal self-injury: a meta-analytic review. AB - The aim of this study was to conduct the first meta-analysis comparing risk for NSSI between sexual minority and heterosexual persons. Eleven published and 4 unpublished studies were reviewed, describing associations between sexual orientation and NSSI in 7,147 sexual minority and 61,701 heterosexual participants. The overall weighted effect size for the relationship between sexual orientation and NSSI using a random-effects model was OR = 3.00 (95% CI = 2.46-3.66), indicating a medium-to-large effect. Sexual minority adolescents and bisexuals were found to be at particularly high-risk. These findings highlight the need to examine mechanisms linking sexual orientation and NSSI in future research. Building on these findings can add to understanding the associations between sexual orientation, NSSI, and suicidality, as well as prevention/intervention. PMID- 25297460 TI - Three-dimensional attosecond resonant stimulated X-ray Raman spectroscopy of electronic excitations in core-ionized glycine. AB - We investigate computationally the valence electronic excitations of the amino acid glycine prepared by a sudden nitrogen core ionization induced by an attosecond X-ray pump pulse. The created superposition of cationic excited states is probed by two-dimensional transient X-ray absorption and by three dimensional attosecond stimulated X-ray Raman signals. The latter, generated by applying a second broadband X-ray pulse combined with a narrowband pulse tuned to the carbon K-edge, reveal the complex coupling between valence and core-excited manifolds of the cation. PMID- 25297461 TI - Lungeing on hard and soft surfaces: Movement symmetry of trotting horses considered sound by their owners. AB - REASONS FOR PERFORMING STUDY: Lungeing is often part of the clinical lameness examination. The difference in movement symmetry, which is a commonly employed lameness measure, has not been quantified between surfaces. OBJECTIVES: To compare head and pelvic movement symmetry between surfaces and reins during lungeing. STUDY DESIGN: Quantitative gait analysis in 23 horses considered sound by their owners. METHODS: Twenty-three horses were assessed in-hand and on the lunge on both reins on hard and soft surfaces with inertial sensors. Seven movement symmetry parameters were quantified and used to establish 2 groups, namely symmetrical (n = 9) and forelimb-lame horses (n = 14), based on values from straight-line assessment. Movement symmetry values for left rein measurements were side corrected to allow comparison of the amount of movement symmetry between reins. A mixed model (P<0.05) was used to study effects on movement symmetry of surface (hard/soft) and rein (inside/outside with respect to movement symmetry on the straight). RESULTS: In forelimb-lame horses, surface and rein were identified as significantly affecting all head movement symmetry measures (rein, all P<0.0001; surface, all P<0.042). In the symmetrical group, no significant influence of surface or rein was identified for head movement symmetry (rein, all P>0.245; surface, all P>0.073). No significant influence of surface or rein was identified for any of the pelvic movement symmetry measures in either group. CONCLUSIONS: While more symmetrical horses showed a consistent amount of movement symmetry across surfaces/reins, horses objectively quantified as lame on the straight showed decreased movement symmetry during lungeing, in particular with the lame limb on the inside of a hard circle. The variation within group questions straight-line movement symmetry as a sole measure of lameness without quantification of movement symmetry on the lunge, ideally on hard and soft surfaces to evaluate differences between reins and surfaces. In future, thresholds for lungeing need to be determined using simultaneous visual and objective assessment. PMID- 25297463 TI - Women's perceptions of information about alcohol use during pregnancy: a qualitative study. AB - BACKGROUND: A number of alcohol guidelines worldwide suggest that pregnant women should abstain from alcohol. However, high prevalence rates of alcohol consumption during pregnancy still exist. It is unknown whether there are problems with the dissemination of guideline information that is potentially contributing to such consumption. This qualitative study aimed to explore women's perceptions of information they received about alcohol use during pregnancy after the introduction of abstinence guidelines. METHODS: Nineteen women from the Australian Longitudinal Study on Women's Health (ALSWH) 1973-78 cohort that reported a pregnancy in 2009 were recruited for semi-structured telephone interviews. The interviews were conducted until data saturation was reached. Interviews were transcribed, then thematically analysed. ALSWH survey data was used to augment the findings. The main outcome measure was women's perceptions of information received about alcohol use during pregnancy after the introduction of the 2009 Australian guidelines promoting abstinence during pregnancy. RESULTS: Women reported a number of problems with the information about alcohol use during pregnancy and with its dissemination. There were inconsistencies in the information about alcohol use during pregnancy and in the advice provided. Mixed messages and confusion about identifying a safe level of consumption had implications on women's decisions to drink or abstain during pregnancy. Women expressed a need for a clear, consistent message to be provided to women as early as possible. They preferred that the message come from healthcare professionals or another reputable source. CONCLUSIONS: To make an informed decision about alcohol use during pregnancy, women must first be provided with the latest evidence-based information. As this study found a number of limitations with information provision, it is suggested that a systematic approach be adopted by healthcare professionals, in line with best-practice guidelines, to ensure all women are made aware of the alcohol recommendations for pregnancy. PMID- 25297464 TI - Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies. AB - OBJECTIVES: To report clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood in screening for trisomies 21, 18 and 13 in twin pregnancies and examine variables that could influence the failure rate of the test. METHODS: cfDNA testing was performed in 515 twin pregnancies at 10-28 weeks' gestation. The failure rate of the test to provide results was compared with that in 1847 singleton pregnancies, and logistic regression analysis was used to determine which factors among maternal and pregnancy characteristics were significant predictors of test failure. RESULTS: Failure rate of the cfDNA test at first sampling was 1.7% in singletons and 5.6% in twins. Of those with a test result, the median fetal fraction in twins was 8.7% (range, 4.1-30.0%), which was lower than that in singletons (11.7% (range, 4.0-38.9%)). Multivariable regression analysis demonstrated that twin pregnancy, higher maternal weight and conception by in-vitro fertilization provided significant independent prediction of test failure. Follow-up was available in 351 (68.2%) of the twin pregnancies and comprised 334 with euploid fetuses, 12 discordant for trisomy 21 and five discordant for trisomy 18. In all 323 euploid cases with a result, the risk score for each trisomy was < 1:10 000. In 11 of the 12 cases with trisomy 21 and in the five with trisomy 18, the cfDNA test gave a high-risk result, but in one case of trisomy 21, the score was < 1:10 000. CONCLUSION: In twin pregnancies screening by cfDNA testing is feasible, but the failure rate is higher and detection rate may be lower than in singletons. PMID- 25297462 TI - The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism. AB - Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of reperfusion injury have been identified, including alterations in cytosolic Ca(2+) handling, sarcoplasmic reticulum mediated Ca(2+) oscillations and hypercontracture, proteolysis secondary to calpain activation and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca(2+) oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischaemia/reperfusion and preserved by ischaemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischaemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction. PMID- 25297465 TI - The p38alpha mitogen-activated protein kinase limits the CNS proinflammatory cytokine response to systemic lipopolysaccharide, potentially through an IL-10 dependent mechanism. AB - BACKGROUND: The p38alpha mitogen-activated protein kinase (MAPK) is a well characterized intracellular kinase involved in the overproduction of proinflammatory cytokines from glia. As such, p38alpha appears to be a promising therapeutic target for neurodegenerative diseases associated with neuroinflammation. However, the in vivo role of p38alpha in cytokine production in the CNS is poorly defined, and prior work suggests that p38alpha may be affecting a yet to be identified negative feedback mechanism that limits the acute, injury-induced proinflammatory cytokine surge in the CNS. METHODS: To attempt to define this negative feedback mechanism, we used two in vitro and two in vivo models of neuroinflammation in a mouse where p38alpha is deficient in cells of the myeloid lineage. RESULTS: We found that p38alpha in myeloid cells has an important role in limiting amplitude of the acute proinflammatory cytokine response to a systemic inflammatory challenge. Moreover, we identified IL-10 as a potential negative feedback mechanism regulated by p38alpha. CONCLUSIONS: Our data suggest that p38alpha regulates a proper balance between the pro- and anti inflammatory cytokine responses to systemic inflammation, and that if circulating IL-10 levels are not elevated to counter-balance the increased systemic proinflammatory responses, the spread of the inflammatory response from the periphery to the CNS is exaggerated. PMID- 25297466 TI - A mindfulness-based program for improving quality of life among hematopoietic stem cell transplantation survivors: feasibility and preliminary findings. AB - Health-related quality of life (HRQoL) is often substantially reduced among individuals who have undergone hematopoietic stem cell transplantation (HSCT), and incidences of depression, fatigue, and anxiety are elevated. We examined effects of a mindfulness-based intervention (MBI) compared to psycho-oncological telephone consultation upon HRQoL, depression, anxiety, and fatigue among HSCT survivors. Sixty-two medically stable patients participated in the study; they had completed HSCT >=6 months previously. Thirty-two were randomly assigned to intervention arms, and 30 were offered their treatment preference. MBI consisted of a structured 8-week program of mindfulness training. Assessments were made at baseline, post-intervention and 3 months follow-up. Primary outcome was HRQoL. Depression, fatigue, anxiety, and personal goal attainment were secondary measures. Non-completion of interventions was low in both groups (9 %, MBI; 7 % control). Employing intention-to-treat analysis, MBI, compared with comparison procedure, improved HRQoL and reduced depression and anxiety at post-intervention (p's < 0.05); Cohen's d effect sizes, 0.6-0.7; 3-month follow-up benefits were modest. These findings demonstrate broad feasibility and acceptance of, as well as satisfaction and adherence with, a program of mindfulness training for HSCT survivors; findings also suggest improved HRQoL and well-being as a consequence of MBI. Nevertheless, this is a preliminary study; a larger trial with more prolonged intervention phase is warranted. PMID- 25297467 TI - Sleep disturbance in cancer patients and caregivers who contact telephone-based help services. AB - PURPOSE: Insomnia is highly prevalent in people who are affected by cancer. However, options available to receive support for insomnia are limited. Telephone based help services, such as cancer helplines, may be ideally placed to meet unmet needs regarding insomnia after cancer. The present study describes the prevalence and predictors of insomnia in patients and caregivers who call cancer helplines seeking support. METHODS: Participants (N = 500 patients, N = 234 caregivers) were recruited through an Australian state-based telephone-delivered cancer helpline. In addition to routine screening with the Distress Thermometer, participants were administered the Insomnia Severity Index. RESULTS: Most participants were female, older than 50 years of age, and were three (caregivers) to four (patients) months post-diagnosis. Insomnia symptoms were reported by 59.4 % of patients and 62.9 % of caregivers, with moderate to severe levels of insomnia reported by 27 % of patients and 30 % of caregivers. Insomnia was predicted by distress level for both patients (beta = .31, p < .001) and caregivers (beta = .32, p < .001) and age for patients only (beta = -.13, p < .01). CONCLUSIONS: Insomnia symptoms are common in patients and caregivers who call cancer helplines and appear to be related to distress. Telephone-based helplines have the potential to act as the first line of support in a stepped care approach addressing insomnia. PMID- 25297468 TI - Black esophagus: new insights and multicenter international experience in 2014. AB - BACKGROUND: Black esophagus or acute esophageal necrosis (AEN) is a striking medical condition characterized by circumferential black appearing esophageal mucosa affecting various lengths of the organ with nearly universal involvement of the distal esophagus and abrupt transition at the gastroesophageal junction. This syndrome is gaining acceptance as an important cause of upper gastrointestinal hemorrhage in hospitalized patients. AIMS: To better describe clinical features, risk factors, associated conditions, etiology, treatment, complications, and outcome in patients with AEN at various medical centers across the globe. METHODS: We analyze this syndrome as a first international multicenter series of eight patients who presented with AEN. Clinical characteristics were recorded for each case by treating physicians, and data were retrospectively analyzed and compared. RESULTS: AEN is more common in geriatric males and characteristically (88 %) presents with signs of upper gastrointestinal hemorrhage. Risk factors include alcohol abuse, hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, malnourishment, and vascular disease. Hypoalbuminemia was universal, while anemia, renal insufficiency, and hyperglycemia were seen in nearly 90 % of the patients. Endoscopically, distal esophageal involvement with various proximal extension and sharp demarcation at the GE junction was seen in all patients. Duodenal pathology was seen in 50 % of the cases. Causes of AEN were largely multifactorial with all patients affected by a combination of ischemic insult, compromised mucosal defenses, and corrosive reflux injury of gastric contents. Treatment with acid suppression and correction of underlying medical conditions was implemented in all patients. Esophageal stricture formation was seen in 25 % of the patients and was associated with concurrent duodenal pathology. Mortality was 12.5 % and unrelated to AEN. CONCLUSION: Black esophagus or AEN syndrome is an important cause of upper gastrointestinal hemorrhage with striking endoscopic presentation in a clinically compromised individual with multiple co-morbidities. Structured conservative management with correction of underlying etiology and acid suppression is essential to improved prognosis. Associated duodenal pathology on endoscopy is a reflection of the degree of initial insult and a clinical predictor for potential stricture development. Proximal extension of the black esophagus may be related to the degree of hyperglycemia. Increased awareness of AEN syndrome will lead to early recognition and proper treatment. PMID- 25297469 TI - Effect of posterior impaction and setback of the maxilla on retropalatal airway and velopharyngeal dimensions after two-jaw surgery in skeletal Class III patients. AB - OBJECTIVE: To evaluate the changes in retropalatal airway and velopharyngeal dimensions after posterior impaction (PI) only or PI and setback (PI/SB) of the maxilla in patients with skeletal Class III undergoing two-jaw surgery. MATERIALS AND METHODS: Subjects consisted of 60 Class III patients treated with two-jaw surgery. They were divided into two groups: group 1 (n = 30; PI of the maxilla; mean = 2.6 mm) and group 2 (n = 30; PI/SB of the maxilla; mean = 2.8 mm and 1.8 mm, respectively). Using three dimensional computed tomography images taken 1month before surgery (T0) and at least 6 months after surgery (T1), retropalatal airway volume, minimum cross-sectional area, and lateral and anteroposterior (AP) dimensions of minimum cross-sectional area, soft palate angle, soft palate length, and pharyngeal depth were measured. A paired t-test and independent t test were used for statistical analysis. RESULTS: Group 1 showed increase in retropalatal airway volume and minimum cross-sectional area (P < .01 and P < .05, respectively). Group 2 exhibited decrease in retropalatal airway volume, minimum cross-sectional area, and lateral and AP dimensions of minimum cross-sectional area (all P < .01). Although groups 1 and 2 showed an increase in soft palate length (P < .01 and P < .001, respectively), pharyngeal depth significantly increased only in group 1 (P < .01). Groups 1 and 2 were significantly different in retropalatal airway volume, minimum cross-sectional area, and AP dimension (P < .05, P < .001, and P < .05, respectively). CONCLUSION: Because the direction of surgical movement in the maxilla can determine the changes in the retropalatal airway and velopharyngeal dimensions, it is recommended that clinicians investigate whether patients suffer from sleep-related breathing disorders before performing PI/SB of the maxilla. PMID- 25297470 TI - A novel osmolality-shift fermentation strategy for improving acarbose production and concurrently reducing byproduct component C formation by Actinoplanes sp. A56. AB - Component C (Acarviosy-1,4-Glc-1,1-Glc) was a highly structural acarbose analog, which could be largely formed during acarbose fermentation process, resulting in acarbose purification being highly difficult. By choosing osmolality level as the key fermentation parameter of acarbose-producing Actinoplanes sp. A56, this paper successfully established an effective and simplified osmolality-shift strategy to improve acarbose production and concurrently reduce component C formation. Firstly, the effects of various osmolality levels on acarbose fermentation were firstly investigated in a 50-l fermenter. It was found that 400-500 mOsm/kg of osmolality was favorable for acarbose biosynthesis, but would exert a negative influence on the metabolic activity of Actinoplanes sp. A56, resulting in an obviously negative increase of acarbose and a sharp formation of component C during the later stages of fermentation (144-168 h). Based on this fact, an osmolality-shift fermentation strategy (0-48 h: 250-300 mOsm/kg; 49-120 h: 450 500 mOsm/kg; 121-168 h: 250-300 mOsm/kg) was further carried out. Compared with the osmolality-stat (450-500 mOsm/kg) fermentation process, the final accumulation amount of component C was decreased from 498.2 +/- 27.1 to 307.2 +/- 9.5 mg/l, and the maximum acarbose yield was increased from 3,431.9 +/- 107.7 to 4,132.8 +/- 111.4 mg/l. PMID- 25297471 TI - A pharmacoeconomic assessment of recombinant tissue plasminogen activator therapy for acute ischemic stroke in a tertiary hospital in China. AB - OBJECTIVES: To conduct a pharmacoeconomic assessment of thrombolysis by intravenous recombinant tissue plasminogen activator (rt-PA) therapy for acute ischemic stroke (AIS) in 6 hours in a tertiary hospital in China. MATERIALS AND METHODS: A retrospective analysis was conducted using medical records data among patients hospitalized for AIS and receiving treatment with or without rt-PA (6 hours after AIS) from January 2006 to December 2008. The conservative therapy group was matched (1?1) on age, gender, risk factors, Glasgow Coma Scale, and National Institutes of Health Stroke Scale (NIHSS). Two groups were compared on fourteenth-day clinical outcomes. Utilities were estimated from modified Rankin Scale (mRS) scores and costs. All cost data reflected 2006-2008 values. RESULTS: A total of 152 patients were enrolled in the study (76 patients in each group). No differences were found in mortality rate between these two groups at day 14. Among survivors on day 14, NIHSS and mRS were lower in rt-PA than conservative group. Barth Index (BI) was higher in the rt-PA group versus conservative group. The rt-PA group had a higher pharmacy cost (Y13 065+/-4197 versus Y9622+/-5439; P = 0.002) compared to the conservative group, but the total cost was not significantly different. Compared to conservative care, rt-PA therapy was associated with incremental cost of Y4122 with 0.04 utilities gained, yielding an incremental cost-effectiveness ratio of Y103 050 ($14 231) per utility gained. One-way sensitivity analysis showed that the results were most sensitivity to utility. CONCLUSIONS: Intravenous rt-PA was associated with lower patients' disabilities, fewer in-hospital days, and comparable total costs compared to conservative therapy for the management of AIS. PMID- 25297472 TI - Individual Differences in the Context-Dependent Recruitment of Cognitive Control: Evidence From Action Versus State Orientation. AB - The ability to flexibly adapt to deviations from optimal performance is an important aspect of self-control. In the present study, the authors present first evidence that the personality trait action versus state orientation (Kuhl, 2000) modulates the ability of adaptive control adjustments in response to experienced conflicts. Sixty-two German individuals with extreme scores on the action-state dimension performed a response interference task, that is, 31 extreme action oriented individuals (30 females; Mage = 20.35 years) and 31 extreme state oriented individuals (20 females; Mage = 23.23 years), respectively. Action oriented individuals displayed a stronger conflict adaptation effect as evidenced by a stronger reduction of interference on trials following conflict. These results were further corroborated by a correlational analysis including a sample of 105 participants: the higher the score on the action-state dimension, the lower the interference effect following conflict (i.e., stronger conflict adaptation). The results provide evidence that even low-level, bottom-up-driven processes of self-control such as conflict adaptation are systematically moderated by individual differences in control modes and provide insights into the cognitive mechanisms underlying action versus state orientation. PMID- 25297473 TI - Fracture-induced amorphization of polycrystalline SiO2 stishovite: a potential platform for toughening in ceramics. AB - Silicon dioxide has eight stable crystalline phases at conditions of the Earth's rocky parts. Many metastable phases including amorphous phases have been known, which indicates the presence of large kinetic barriers. As a consequence, some crystalline silica phases transform to amorphous phases by bypassing the liquid via two different pathways. Here we show a new pathway, a fracture-induced amorphization of stishovite that is a high-pressure polymorph. The amorphization accompanies a huge volume expansion of ~100% and occurs in a thin layer whose thickness from the fracture surface is several tens of nanometers. Amorphous silica materials that look like strings or worms were observed on the fracture surfaces. The amount of amorphous silica near the fracture surfaces is positively correlated with indentation fracture toughness. This result indicates that the fracture-induced amorphization causes toughening of stishovite polycrystals. The fracture-induced solid-state amorphization may provide a potential platform for toughening in ceramics. PMID- 25297474 TI - Identifying predictors of resilience at inpatient and 3-month post-spinal cord injury. AB - OBJECTIVES: To identify (1) changes in psychosocial factors, (2) relationships between psychosocial factors, and (3) significant predictors of resilience in adults with spinal cord injury (SCI) during inpatient rehabilitation and at 3 month post-discharge. DESIGN: Cross sectional with convenience sample based on inclusion/exclusion criteria. SETTING: Inpatient rehabilitation hospital and community-based follow-up. PARTICIPANTS: Individuals with a SCI. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Demographic, resilience, self-efficacy for managing a chronic health issue, depression, social roles/activity limitations, and pain. RESULTS: The final sample consisted of 44 respondents (16 women and 28 men). Results of repeated measure analyses of variance indicated no significant changes in variables between inpatient and 3-month follow-up. Bivariate correlations revealed associations between resilience and self-efficacy at inpatient (r = 0.54, P < 0.001), and resilience and depression (r = -0.69, P < 0.001) and self-efficacy (r = 0.67, P < 0.001) at 3-month follow-up. Hierarchical regression analyses a significant model predicting resilience at inpatient stay (R = 0.61; adjusted R(2) = 0.24, P = 0.023), and at 3-month follow-up (R = 0.83; adjusted R(2) = 0.49, P = 0.022). Self-efficacy was the strongest predictor at inpatient stay (beta = 0.46, P = 0.006) and depression was strongest at 3-month follow-up (beta = -0.80, P = 0.007). CONCLUSION: Results suggest that although resilience appears to be stable from inpatient to 3-month follow-up, different factors are stronger predictors of resilience across time. Based on current results, an assessment of self-efficacy during inpatient rehabilitation and an identification of depression at 3-month follow-up may be important factors to help identify those at risk of health issues overtime. PMID- 25297475 TI - [Hemicrania continua and paroxysmal hemicrania: clinical and therapeutic characteristics in a series of 23 patients]. AB - INTRODUCTION: Hemicranias are an uncommon type of headache characterised by strictly unilateral pain, either as a continuous, although fluctuating, headache in hemicrania continua (HC) or in the form of recurring attacks in paroxysmal hemicrania (PH). In both types of headache, an absolute response to indomethacin is reported. AIMS. To analyse the fulfilment of current diagnostic criteria for HC and PH and the recent introduction of HC within the group of trigeminal autonomic cephalgias. PATIENTS AND METHODS: The clinical and therapeutic characteristics of patients diagnosed with HC or PH were evaluated retrospectively. Demographic and symptomatological information as well as data regarding the analogical pain scale and response to indomethacin were included. RESULTS: A sample of 12 HC (four males and eight females) was evaluated from a total of 520 cases (2.3%). Mean age at onset: 47.1 +/- 16.4 years. Baseline pain intensity: 3.3 +/- 1,9. Exacerbations: 9.2 +/- 1.1. Eight cases (66.7%) presented autonomic symptoms, four (33.3%) followed a time pattern, and two (16.7%) did not respond to indomethacin. We evaluated a sample of 11 PH (100% females) from 520 cases (2.1%). Mean age at onset: 37.0 +/- 13.9 years. Pain intensity: 8.7 +/- 2.7. Nine cases (81.8%) presented autonomic symptoms, three (27.3%) followed a time pattern and one (9.1%) did not respond to indomethacin. CONCLUSIONS: Hemicranias are not frequently diagnosed in day-to-day clinical practice. Their diagnosis requires the fulfilment of certain criteria that are sometimes not fully satisfied. We believe that the criteria need revising and we also support the recent inclusion of HC within the group of trigeminal-autonomic cephalgias. PMID- 25297476 TI - [Influence of meteorological and chronological factors in epilepsy]. AB - INTRODUCTION: The professionals who deal with medical emergencies observe peaks in the incidence of epileptic seizures. Some epileptic patients attribute their seizures to climatic and seasonal changes. AIMS. To analyse the relationship between meteorological, calendar-related and circadian variables and the appearance of epileptic seizures. PATIENTS AND METHODS: A retrospective study was conducted in a residential home for persons with intellectual disability. RESULTS: The 16 residents who were studied presented 855 epileptic attacks, including 159 in peaks or clusters, over the period 2009-2012. The predominance of seizures observed in autumn and during the fourth quarter of the year is not significant (p > 0.05). There is no statistically significant relation between the presence of epileptic seizures and the phases of the moon or days of the week. Most epileptic seizures (87.2%) occur during the daytime (p < 0.001). Findings showed that 36.3% occur in the morning between 08:00 and 10:59. There is no statistical correlation between the number of epileptic seizures and the atmospheric pressure, rainfall, degree of humidity or mean temperature (p > 0.05). CONCLUSIONS: The appearance of peaks or clustering of epileptic seizures was observed. Their presence shows a marked circadian component. The influence of meteorological factors, the phases of the moon and seasons of the year on epilepsy is not significant. PMID- 25297477 TI - [Peripheral vertigo versus central vertigo. Application of the HINTS protocol]. AB - INTRODUCTION: One of the most important dilemmas concerning vertigo in emergency departments is its differential diagnosis. There are highly sensitive warning signs in the examination that can put us on the path towards finding ourselves before a case of central vertigo. AIM: To determine how effective the application of the HINTS protocol is in the diagnosis of cerebrovascular accidents that mimics peripheral vertigo. PATIENTS AND METHODS: We conducted a descriptive observation-based study on patients admitted to hospital with a diagnosis of acute vestibular syndrome in the emergency department. All the patients were monitored on a day-to-day basis until their symptoms improved, with information about nystagmus, the oculocephalic manoeuvre and the skew test. The results from the magnetic resonance imaging study were compared with the alteration of any of those three signs during the time the patient was hospitalised. RESULTS: Altogether 91 patients were examined, with a mean age of 55.8 years. A cerebrovascular accident was observed in eight cases. Of these (mean age: 71 years), in seven of them there were alterations in some of the HINTS signs, and in one case the study was normal (sensitivity: 0.88; specificity: 0.96). All of them had some vascular risk factor. CONCLUSIONS: Faced with a patient who visits the emergency department with an acute vestibular syndrome, a suitably directed examination is essential to be able to establish the differential diagnosis between peripheral and central pathology, since some cerebrovascular accidents can present with the appearance of acute vertigo. Applying a protocol like HINTS makes it possible to suspect the central pathology with a high degree of sensitivity and specificity. PMID- 25297478 TI - [Diffuse superficial siderosis of the central nervous system: four case reports and review of the literature]. AB - INTRODUCTION: Diffuse superficial siderosis of the central nervous system (CNS) is a rare condition due to hemosiderin deposits in the subpial layers of the brain and spinal cord. The source of chronic or recurrent bleeding into the subarachnoid space is detected in only 50 % of cases. The most characteristic symptoms are cerebellar ataxia and sensorineural hearing impairment. T2-weighted gradient echo magnetic resonance imaging constitutes the diagnostic method of choice. CASE REPORTS: We report four patients of diffuse superficial siderosis of the CNS associated to cerebral amyloid angiopathy, oral anticoagulation, schwannoma VIII, and without known source of bleeding in one case. Two patients developed cerebellar ataxia, three of them present transient focal neurological episodes, one dementia and, the last one, the diffuse superficial siderosis of the CNS is a radiological finding. No clinical progression was observed during follow-up (2-11 years) in three of them. The patient with cerebral amyloid angiopathy progresses to dementia. CONCLUSIONS: Transient focal neurological episodes were the most common symptom in our cases of diffuse superficial siderosis of the CNS. The natural history of this condition is not very known and may be regarded as a radiological finding. PMID- 25297479 TI - [Generation and functions of dreams]. AB - INTRODUCTION: Over the last decade an ever-increasing number of articles have been published on dreams, which reflects the interest that several fields of neuroscience have in the topic. In this work we review the main scientific theories that have contributed to the body of knowledge on how they are produced and what function they serve. DEVELOPMENT: The article discusses the evolution of their scientific study, following a neurophysiological and neurocognitive approach. The first of these two methods seeks to determine the neurobiological mechanisms that generate them and the brain structures involved, while the second considers dreams to be a kind of cognition interacting with that of wake-fulness. Several different hypotheses about the function of dreams are examined, and more particularly those in which they are attributed with a role in the consolidation of memory and the regulation of emotional states. CONCLUSIONS: Although the exact mechanism underlying the generation of dreams has not been determined, neurobiological data highlight the importance of the pontine nuclei of the brainstem, several memory systems, the limbic system and the brain reward system and a number of neocortical areas. Neurocognitive data underline the relation between the cognitive and emotional processing that occurs during wakefulness and during sleep, as well as the influence of the surroundings on the content of dreams. With regard to their function, one point to be stressed is their adaptive value, since they contribute to the reprocessing of the information acquired in wakefulness and the control of the emotions. This suggests that dreams participate in the development of the cognitive capabilities. PMID- 25297480 TI - Review of the novelties presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III). AB - The most relevant data presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in October 2013 in Denmark, were summarised at the sixth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2013, resulting in this review, which is being published in three parts. This third part of the Post-ECTRIMS review discusses the effects of immunomodulatory therapy on the natural history of multiple sclerosis, with special attention to the assessment of long-term effects and the use of historical controls as an alternative to randomised trials compared with placebo. This article contains possible future therapeutic strategies to be tested in experimental models and discusses clinical trials that are underway and future treatments. It also summarises the results of recent studies of disease modifying treatments and developments in symptom management. Briefly, on the horizon are many drugs with different mechanisms of action, although new strategies and treatment algorithms are needed, as are new biomarkers and assessment measures of secondary progression and long-term records to assess safety. As for the symptomatic treatment of the disease, the proposal is a personalised treatment plan and a multidisciplinary approach to improve the quality of life of patients. PMID- 25297481 TI - [Rhombencephalitis in a returning traveller]. PMID- 25297482 TI - [Ocular myasthenia and dysautonomia associated to thymoma]. PMID- 25297483 TI - [Genetic confirmation of myoadenylate deaminase deficiency]. PMID- 25297484 TI - [Hardware complications of deep brain stimulation]. PMID- 25297485 TI - Radio guided radical prostatectomy: evaluation of feasibility, safety and clinical outcomes. AB - BACKGROUND: The standard surgical treatment of PCa consists of radical prostatectomy (RP). Lymphadenectomy with removal of the sentinel lymph node (SLN) is now evolving towards the concept of radio guided surgery as an instrument for the removal of the lymph nodes of primary drainage. METHODS: From October 2012 to September 2013 laparotomic SLN dissection was performed in 43 patients during standard open radical prostatectomy. Twenty hours before surgery, 240 MBq of 99mTc nanocolloid were injected into the prostate gland under transrectal ultrasound guidance. A planar scintigraphy and a SPET/CT scan were performed 1-2 hours after the injection. Intraoperatively, all LNs detected by gamma-probe with an activity significantly higher than background were removed and classified as SLNs. We evaluated operative time, complications, postoperative outcomes and costs of the procedures of patients who underwent radio guided surgery. We measured radioactive exposure rates. RESULTS: The intraoperative detection of SLNs occurred in all 43 patients, while the scintigraphic localization was observed in 42/43 patients. A total of 77 SLNs were found, at histopathological analysis 7/77 SLNs resulted positive for metastases (4/43 patients): 3 were in the obturator fossa while the remaining SLNs were in the internal iliac chain (1), common iliac chain (1), external iliac chain (2). Global radiation exposure was not significant. CONCLUSION: Our preliminary data confirm the feasibility and the safety of SLN biopsy in nodal staging of PCa. The intraoperatively SLN detection rate resulted 100%. In 3 patients (7%) a micrometastases was found outside of obturator fossa in a not routinely sampled site. PMID- 25297486 TI - ProteoAnnotator--open source proteogenomics annotation software supporting PSI standards. AB - The recent massive increase in capability for sequencing genomes is producing enormous advances in our understanding of biological systems. However, there is a bottleneck in genome annotation--determining the structure of all transcribed genes. Experimental data from MS studies can play a major role in confirming and correcting gene structure--proteogenomics. However, there are some technical and practical challenges to overcome, since proteogenomics requires pipelines comprising a complex set of interconnected modules as well as bespoke routines, for example in protein inference and statistics. We are introducing a complete, open source pipeline for proteogenomics, called ProteoAnnotator, which incorporates a graphical user interface and implements the Proteomics Standards Initiative mzIdentML standard for each analysis stage. All steps are included as standalone modules with the mzIdentML library, allowing other groups to re-use the whole pipeline or constituent parts within other tools. We have developed new modules for pre-processing and combining multiple search databases, for performing peptide-level statistics on mzIdentML files, for scoring grouped protein identifications matched to a given genomic locus to validate that updates to the official gene models are statistically sound and for mapping end results back onto the genome. ProteoAnnotator is available from http://www.proteoannotator.org/. All MS data have been deposited in the ProteomeXchange with identifiers PXD001042 and PXD001390 (http://proteomecentral.proteomexchange.org/dataset/PXD001042; http://proteomecentral.proteomexchange.org/dataset/PXD001390). PMID- 25297487 TI - [Interdisciplinary and individualized therapy of prostate cancer : International prostate cancer symposium Bonn 2013 - challenges and targets]. AB - Multimodal treatment of prostate cancer is based on specific staging via imaging, clinical parameters, tumor markers and histopathological grading. Risk-adapted therapy encompasses wait and see, active surveillance, surgical intervention, radiotherapy and hormone therapy. Some patients also need a combination of these treatment options. Even though clinical parameters guide the treatment plan, patient wishes and preferences are incorporated. Against this background leading basic research scientists, urologists, radiotherapists, epidemiologists and members of other associated disciplines discussed state of the art treatment concepts, innovative trial designs and translational research projects at the international meeting "Challenges and Chances in Prostate Cancer Research" organized by the German Cancer Aid (Deutsche Krebshilfe). PMID- 25297488 TI - [Importance of long chain omega-3 fatty acids in prostate cancer]. AB - The benefits of long chain polyunsaturated omega-3 fatty acids (n-3 PUFA) from fish or administered as supplements remain controversial regarding prostate cancer (PCa). Based on the currently available evidence no clear benefit of n-3 PUFA intake to generally reduce PCa incidence has been found. On the other hand n 3 PUFAs have a clear influence on the development of already existing PCa. The intake of n-3-PUFAs considerably reduces the risk of metastasis and PCa-related mortality. PMID- 25297489 TI - [Importance of complementary medicine approaches for patients with prostate cancer]. AB - BACKGROUND: In Germany, many prostate cancer patients use complementary medicine (CM) or have an interest in these treatment approaches; however, the information and consultation situation of cancer patients is insufficient and therefore the Competence Network Complementary Medicine in Oncology (COCON) was launched by the German Cancer Aid Society. One of the projects of the COCON examines the use of CM and the information and counseling needs regarding these topics in various groups of cancer patients. The focus of this article is on the qualitative study reporting selected results for the subgroup of prostate cancer patients. STUDY DESIGN AND STUDY METHODS: A total of 19 semi-structured qualitative interviews with prostate cancer patients were conducted regarding the use of CM as well as their information and consultation needs. RESULTS: It was found that the patients interviewed discussed various issues surrounding nutrition, particularly a healthy diet, the selective use of certain foods and the use of dietary supplements. Additional themes mentioned by interviewees were physical exercise, psychological well-being, mistletoe therapy, homeopathy and traditional Chinese medicine. Patients indicated that they wanted more information and counseling opportunities with regards to CM. They also expressed a desire for more holistic care. CONCLUSION: The results show that prostate cancer patients use a range of CM and have a need for information about CM. Prostate cancer patients are in a special situation because of a regular feedback on the prostate-specific antigen (PSA) value. This should be taken into consideration in consultation with prostate cancer patients regarding CM. PMID- 25297490 TI - [Prostate cancer in routine healthcare: health-related quality of life after inpatient treatment]. AB - BACKGROUND: Prostate cancer (PCA) is the most common form of neoplasm in men and various treatment options are available. Knowledge of health-related quality of life (HRQL) can provide information to support informed decision-making. In addition, information on factors influencing HRQL can provide indications for the further development of medical treatment. The aim of the study was to obtain data on HRQL after inpatient treatment of PCA and the identification of determinants of HRQL after PCA in routine healthcare. MATERIALS AND METHODS: In this study a total of 1165 beneficiaries of a German health insurance with a hospital stay due to prostate cancer (ICD C61) were surveyed on their health-related quality of life using the European Organization for Research and Treatment of Cancer quality of life questionnaire version 3 (EORTC QLQ-C30 V3.0) and disease-specific symptoms using the perceived sensitivity to medicine (PSM) scale 14 months after discharge. Survey data were linked with pseudonymous claims data of the health insurance provider. Determinants of HRQL were examined by logistic regression. RESULTS: Responses from 825 men (mean age 67.6 years and 80% treated with radical prostatectomy) were available for analysis (response 70.8%). Compared to the reference population impairments in HRQL were reported especially in terms of the roles and social functionality. The prostate-specific symptoms varied depending on the treatment strategy. A nerve-sparing surgical technique reduced the likelihood of erectile dysfunction. Other protective factors were no pre-existing comorbidities and younger age. DISCUSSION: The effects of PCA on the HRQOL varied by age, comorbidities and treatment modality which should be considered in healthcare information and counseling of patients. PMID- 25297491 TI - [Study on the therapy of castration-resistant prostate cancer: randomized phase II study of abiraterone acetate plus LHRH therapy vs. abiraterone acetate without LHRH therapy in patients with progressive chemotherapy-naive castration-resistant prostate cancer [SPARE - AP 67/11 of the Association of Urogenital Oncology (AUO)]]. PMID- 25297493 TI - Ultrasound and anatomical correlation of the radial nerve at the arcade of Frohse. AB - INTRODUCTION: In this anatomical study we evaluated the feasibility of ultrasound (US) guided perineural injection of the deep branch of the radial nerve (DBRN) at the arcade of Frohse as potential therapy for nerve entrapment at this site. METHODS: We examined 21 arms from 11 nonembalmed cadavers with US. Under US guidance, we injected ink into the DBRN perineural sheath beneath the arcade of Frohse. In subsequent anatomical dissection we evaluated the distribution of the ink. RESULTS: It was possible to apply ink at the DBRN in 95%. In 80% the ink remained within the supinator and did not reach the DBRN segment proximal to the arcade. CONCLUSIONS: With US guidance, it is possible to apply injection fluid safely around the DBRN inside the supinator tunnel. Due to the limited extent of the fluid, a second injection proximal to the arcade should be considered in the clinical setting. PMID- 25297492 TI - [Laparoscopic partial nephrectomy for renal tumors. Time for a new standard?]. AB - PURPOSE: Our aim was to evaluate the laparoscopic partial nephrectomies (LPN) performed at our hospital and compare the results with those from other current studies on partial nephrectomy. PATIENTS AND METHODS: Between March 2006 and January 2014, 280 patients were treated with LPN in our hospital. We evaluated age, sex, and surgical parameters like operating time, warm ischemia time (WIT), hospital stay, complications, tumor staging, grading, and size RESULTS: The patients were 61.6+/-12.4 years old. The median operating time for LPN was 134+/ 51 min. A total of 30% of the operations were treated using the zero ischemia technique. The WIT was 19.9+/-9.8 min. The WIT of the last 50 LPN performed was 13+/-7 min. Complications were documented in 15% of the LPNs. CONCLUSION: LPN is a curative treatment option for the renal cell carcinoma similar to open partial nephrectomy; however, laparoscopy is associated with lower morbidity. PMID- 25297494 TI - The dendritic effect illustrated with phosphorus dendrimers. AB - The dendritic (or dendrimer) effect is observed when a functional group behaves differently when it is alone or linked to a dendrimer; its properties can even vary depending on the generation of the dendrimers. The dendritic effect can be observed with any type of dendrimer, and for any type of property, even if it has been most generally tracked in catalysis and biology, and to a lesser extent in the field of materials. This review is mainly oriented towards the various types of dendritic effects observed with polyphosphorhydrazone dendrimers, even if many examples obtained with other types of dendrimers are given. PMID- 25297495 TI - Spanish authorities investigate how nurse contracted Ebola. PMID- 25297496 TI - KRAS mutation in adenocarcinoma of the gastrointestinal type arising from a mature cystic teratoma of the ovary. AB - Mature cystic teratomas (MCT) in the ovary rarely undergo malignant transformation. Moreover, adenocarcinoma of the gastrointestinal type is much rarer. We present two cases of perimenopausal female pateints with mature cystic teratoma of single ovary, while local adenocarcinoma arising in the MCT. The malignancies showed immunohistochemical features of intestinal differentiation, such as strong positivity for CDX-2, villin and CK-20, and negativity for CK-7. Furthermore, the mutation analysis of molecular alteration revealed a KRAS gene mutation in the intestinal adenocarcinoma part, extending into benign intestinal type epithelium linings. Yet the mutation was not present in the epidermal component of the teratoma. We present these as two unique cases of mucinous adenocarcinoma of the intestinal type arising from mature cystic teratoma. Moreover, we also submit that this KRAS mutation might contribute to identify malignant transformation of a MCT and suggest possible effect on targeted treatment decisions for anti-epidermal growth factor receptor (EGFR) therapy in metastasized patients. PMID- 25297498 TI - Pediatric choroid plexus tumors: epidemiology, treatments, and outcome analysis on 202 children from the SEER database. AB - Choroid plexus papillomas (CPPs) and carcinomas (CPCs) are rare neoplasms that affect mostly children. Due to their rarity, their epidemiology and outcomes are incompletely understood. The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program is a well-established population based group of registries that collects and publishes cancer incidence and survival data representing approximately 28 % of the US population. SEER-STAT v8.1.2 was used to identify patients with ICD-O-3 codes for choroid plexus tumors in patients aged 0-19. Demographics, initial treatment, and follow-up data were collected. Statistical methods including Kaplan-Meier curves, log rank tests, and Cox proportional hazards regression were used to estimate associations between independent variables and survival. The SEER registries contained 107 CPPs (2004 2010) and 95 CPCs (1978-2010). Median follow-up was 38 and 40 months, respectively. More than 75 % of CPCs were diagnosed before the age of 5 years, versus 48 % for CPPs. Sixty-five percent of CPCs and 57 % of CPPs occurred in males. In both groups at least 90 % of children underwent surgical resection. Gross total resection (GTR) was achieved in 67.0 % of CPCs and 63.6 % of CPPs. Almost 17 % of CPCs were treated with radiation versus only 0.9 % of CPPs. More than 98 % of patients with CPP were alive at the last follow-up, versus 62 % of CPC patients. For CPC, surgery was significantly associated with increased overall survival, but contrary to previous reports, extent of surgical resection was not associated with survival. Age, sex, race, and radiation treatment also had no effect on survival. This report, using the SEER datasets, corroborates many findings of previous smaller studies on CPTs. CPC occurs in younger children, with a male predominance, and a much worse prognosis than CPP. As such, these tumors have been treated aggressively with high rates of GTR and radiation treatment. Despite these treatments, overall survival for CPC remains poor. PMID- 25297499 TI - Pseudomonas aeruginosa: the making of a pathogen. PMID- 25297500 TI - Efficacy of catheter ablation for atrial fibrillation in patients with a permanent pacemaker for atrioventricular block. AB - Catheter ablation has been established to be an effective therapy for drug refractory paroxysmal AF and is recommended as the treatment of choice for many patients, including those with a permanent pacemaker (PM). However, the clinical efficacy of catheter ablation of paroxysmal AF in patients with a permanent PM for atrioventricular block (AVB) is not clear. Twenty-nine patients with a permanent PM for AVB (AVB + PM group), and 145 age- and gender-matched control patients (on a 1:5 basis) without AVB and without a permanent PM (no-AVB + no-PM group), were included in this study. Atrial fibrillation (AF) recurrence was defined as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30 seconds beyond 3 months after catheter ablation in the absence of any antiarrhythmic treatment. During a mean follow-up period of 14.2 +/- 8.6 months (range, 3-30 months), 54 patients (31.0%) developed recurrence of AF. The recurrence rate was higher in the AVB + PM group than in the no-AVB + no-PM group (48.3% versus 27.6%, P = 0.005). Cox regression analysis with adjustment for age, valvular heart disease, AVB and a PM together, left atrial (LA) diameter and PV isolation identified LA diameter (hazard ratio 1.054, 95% confidence interval 1.001-1.110, P = 0.047) and AVB and a PM together (hazard ratio 2.095, 95% confidence interval 1.109-3.960, P = 0.023) as two independent predictors of recurrence of AF. Patients with a permanent PM for AVB were at an increased risk of recurrence of AF after catheter ablation. PMID- 25297501 TI - The successful management of respiratory complications with long-term, low-dose macrolide administration in pediatric heart transplant recipients. AB - We report three pediatric heart transplant (HTx) patients whose respiratory symptoms were successfully controlled with long-term, low-dose macrolide administration (clarithromycin: CAM; approximately 2.5 mg/kg bid). The first case was an 18-year-old boy who underwent HTx at the age of three for dilated cardiomyopathy (DCM). Beginning at age 5, he had repeated fevers and respiratory symptoms. He was diagnosed with chronic sinusitis at age 11 and sinobronchial syndrome with mild bronchiectasis at age 14. Administration of long-term, low dose CAM and otolaryngeal topical therapy led to significant improvement of his symptoms. The second case was a 7-year-old boy who underwent HTx for DCM at age one. Starting at age 4, he had repeated fevers and cough due to atelectasis and pneumonia. As antibiotics and respiratory physical therapy proved ineffective, he received long-term, low-dose CAM, resulting in successful control of his atelectasis and recurrent pneumonia. The third case was a 13-year-old boy who underwent HTx at age 6 for DCM. He had chronic sinusitis starting at age 7, and was diagnosed with obstructive sleep apnea syndrome at age 10. Adenotonsillectomy and continuous positive airway pressure support therapy were indicated. At age 13, long-term, lowdose CAM administration was started following mycoplasma infection. In all three cases, the levels of calcineurin inhibitors (cyclosporine and tacrolimus) and everolimus were kept in the optimal range with careful drug monitoring. Longterm, low-dose macrolide administration effectively prevents and treats respiratory complications in pediatric HTx patients as long as attention is paid to potential drug interactions. PMID- 25297502 TI - On-pump versus off-pump coronary artery bypass surgery in high-risk patients. AB - This study aimed to evaluate on-pump versus off-pump coronary artery bypass grafting (CABG) in patients with a high-risk operative profile.The pre-, intra- and post-operative data of high-risk patients with additive European system for cardiac operative risk evaluation (additive Euro-SCORE) over 6 undergoing isolated CABG from January 2008 to December 2011 in this center were investigated and retrospectively analyzed. Using the propensity score-matching method, those patients with similar pre- and intra-operative characteristics were selected and their early clinical outcomes were compared.From January 2008 to December 2011, 485 consecutive patients (398 males, with a mean age of 70.9 +/- 9.0 years) whose additive Euro-SCORE was over 6 were entered into this study. Off-pump coronary bypass grafting (OPCAB) was performed in 58.1% (n = 282), and the remaining patients underwent conventional coronary artery bypass grafting (CCABG). After propensity score matching, the two groups of patients (90 OPCAB patients versus 90 CCABG patients) were similar with regard to pre- and intra-operative characteristics but not duration of surgical procedure. No significant differences in hospital mortality were found. Compared to CCABG, high-risk patients undergoing OPCAB had significantly lower prevalence of postoperative respiratory failure and postoperative renal failure (6.7% versus 17.8%, P = 0.0386, 5.6% versus 16.7%, P = 0.0307, respectively). Through multivariate logistic regression analysis, type of procedure (CCABG versus OPCAB), as an independent risk factor, had an impact on the postoperative respiratory failure (OR = 2.36, 95%CI 1.44-4.97, P = 0.0312) and postoperative renal failure (OR = 2.86, 95%CI 1.61-5.81, P = 0.0037).Compared with CCABG, OPCAB reduced postoperative respiratory and renal morbidity in high-risk patients. PMID- 25297503 TI - Aortic regurgitation due to fibrous strand rupture in the fenestrated left coronary cusp of the tricuspid aortic valve. AB - Fenestration-related massive aortic regurgitation is rare. The underlying mechanism is reported to be rupture of the fenestrated fibrous strand, and most ruptured cords have been reported in the bicuspid valve or in the right coronary cusp of the tricuspid aortic valve. We encountered a rare case of acute aortic regurgitation due to fibrous strand rupture in the fenestrated left coronary cusp. Preoperative echocardiography detected left coronary cusp prolapse, and operative findings revealed rupture of a fibrous strand in the left coronary cusp. For cases such as this, preoperative echocardiography would be useful for appropriate diagnosis. PMID- 25297504 TI - A case of ascending aortic dissection and rupture caused by giant cell arteritis. AB - Giant cell arteritis (GCA) is an autoimmune disease characterized by granulomatous inflammation in the wall of medium-sized and large-sized arteries, and it usually occurs in patients over 50 years of age.(1)) Symptoms are nonspecific, and include fatigue, fever, and headache.(2)) It is occasionally combined with aortic complications, and ruptures resulting in death. These complications occur as late events, usually several years after diagnosis and often after other symptoms have subsided.(3)) Physicians should therefore be alert for complications of the large arteries in GCA. Here we present a case of GCA combined with ascending aortic dissection and rupture 3 weeks after diagnosis. PMID- 25297505 TI - CABG versus PCI in the treatment of diabetic patients affected by coronary artery disease. AB - Surgical coronary revascularization and percutaneous coronary intervention were demonstrated to be effective treatments for coronary artery disease. However, the optimal revascularization strategy remains unclear in certain patient subsets. The recently published Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial is a randomized study evaluating the use of CABG versus PCI in diabetic patients with multivessel coronary disease. The purpose of this study was to review the available literature based on randomized trials and observational studies in order to allow clinicians to make evidence-based decisions when treating diabetic patients with multivessel coronary disease. The current evidence suggests that CABG should remain the standard of care for this patient population. PMID- 25297506 TI - Laser atherectomy for balloon failure in chronic total occlusion. When the going gets tough. AB - Excimer laser coronary atherectomy (ELCA) is based on ultraviolet energy and is capable of disintegrating atheroma, without burning or grossly fragmenting it. ELCA has proven effective in the percutaneous treatment of a variety of complex lesions, including chronic total occlusions (CTO) and severely calcified lesions, in case of balloon failure-tocross or failure-to-expand. Here we present a case of a successful CTO recanalization with ELCA after balloon failure, review the literature on this topic, and present an algorithm outlining the management of this challenging clinical scenario. PMID- 25297507 TI - Attenuation of experimental autoimmune myocarditis by si-RNA mediated CD40 silencing. AB - CD40 plays an important role in the pathogenesis of myocarditis, and inhibition of CD40 expression could be a promising treatment for myocarditis. In this study, we used an animal model, experimental autoimmune myocarditis (EAM), to investigate whether CD40 siRNA could be exploited for myocarditis therapy.Lewis rats were immunized with purified porcine cardiac myosin to induce EAM or were injected with phosphate buffered saline (PBS) alone (PBS group), scrambled small interfering RNA (siRNA) (negative control group), or CD40siRNA (CD40 siRNA group).CD40 siRNA treatment suppressed the increase in heart weight/body weight ratio, and attenuated the severity of myocardial lesions. Cytokine production, including Th1-type cytokines, was significantly suppressed in rats with myocarditis after CD40 siRNA treatment; however, production of Th2-type cytokines was higher. Specific knockdown of CD40 in EAM rats resulted in increased FOXP3 gene expression and the CD25+ CD4+ subpopulation of T cells but also a decrease in CD80 and CD86 expression. Lymphocyte (T and B cell) proliferation in response to myosin stimulation was significantly inhibited by CD40 silencing.CD40-siRNA is a useful tool for inhibiting in vivo CD40 expression, and it could have therapeutic potential in the prevention and treatment of myocarditis in humans. PMID- 25297508 TI - Single-incision lift laparoscopic appendicectomy: a less expensive technique easy to learn. AB - Appendicectomy is the most common abdominal operation performed on an emergency basis in most parts of the world. The laparoscopic technique has many advantages over conventional open surgery especially in women and obese patients. A further improved version introduced recently is using a single-incision (SILS). Inducing a pneumoperitoneum, as a necessary precondition of laparoscopic procedures, represents a restriction of the surgeon's freedom of movement and can lead to typical though rare complications. Gasless laparoscopic surgery has most of the advantages of laparoscopic surgery without many of the disadvantages. It is also less expensive, and can be combined with regional anaesthesia. Furthermore, fewer disposable materials are necessary. We describe a series of single umbilical incision gasless laparoscopic appendicectomies performed in rural areas of India. PMID- 25297510 TI - Platelet lysate embedded scaffolds for skin regeneration. AB - INTRODUCTION: The work presents the development of acellular scaffolds extemporaneously embedded with platelet lysate (PL), as an innovative approach in the field of tissue regeneration/reparation. PL embedded scaffolds should have a tridimensional architecture to support cell migration and growth, in order to restore skin integrity. For this reason, chondroitin sulfate (CS) was associated with sodium alginate (SA) to prepare highly porous systems. METHODS: The developed scaffolds were characterized for chemical stability to gamma-radiation, morphology, hydration and mechanical properties. Moreover, the capability of fibroblasts and endothelial cells to populate the scaffold was evaluated by means of proliferation test 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and confocal laser scanning microscopy study. The scaffolds, not altered by sterilization, were characterized by limited swelling and high flexibility, by foam-like structure with bubbles that formed a high surface area and irregular texture suitable for cell adhesion. RESULTS: Cell growth and scaffold population were evident on the bubble surface, where the cells appeared anchored to the scaffold structure. CONCLUSION: Scaffold network based on CS and SA demonstrated to be an effective support to enhance and to allow fibroblasts and endothelial cells (human umbilical vein endothelial cells, HUVEC) adhesion and proliferation. In particular, it could be hypothesized that cell adhesion was facilitated by the synergic effect of PL and CS. Although further in vivo evaluation is needed, on the basis of in vitro results, PL embedded scaffolds seem promising systems for skin wound healing. PMID- 25297509 TI - Afadin requirement for cytokine expressions in keratinocytes during chemically induced inflammation in mice. AB - Afadin is a filamentous actin-binding protein and a mediator of nectin signaling. Nectins are Ig-like cell adhesion molecules, and the nectin family is composed of four members, nectin-1 to nectin-4. Nectins show homophilic and heterophilic interactions with other nectins or proteins on adjacent cells. Nectin signaling induces formation of cell-cell junctions and is required for the development of epithelial tissues, including skin. This study investigated the role of afadin in epithelial tissue development and established epithelium-specific afadin deficient (CKO) mice. Although showing no obvious abnormality in the skin development and homeostasis, the mice showed the reduced neutrophil infiltration into the epidermis during chemical-induced inflammation with 12-O tetradecanoylphorbol 13-acetate (TPA). Immunohistochemical and quantitative real time PCR analyses showed that the expression levels of cytokines including Cxcl2, Il-1beta and Tnf-alpha were reduced in CKO keratinocytes compared with control keratinocytes during TPA-induced inflammation. Primary-cultured skin keratinocytes from CKO mice also showed reduced expression of these cytokines and weak activation of Rap1 compared with those from control mice after the TPA treatment. These results suggested a remarkable function of afadin, which was able to enhance cytokine expression through Rap1 activation in keratinocytes during inflammation. PMID- 25297511 TI - Is probabilistic evidence a source of knowledge? AB - We report a series of experiments examining whether people ascribe knowledge for true beliefs based on probabilistic evidence. Participants were less likely to ascribe knowledge for beliefs based on probabilistic evidence than for beliefs based on perceptual evidence (Experiments 1 and 2A) or testimony providing causal information (Experiment 2B). Denial of knowledge for beliefs based on probabilistic evidence did not arise because participants viewed such beliefs as unjustified, nor because such beliefs leave open the possibility of error. These findings rule out traditional philosophical accounts for why probabilistic evidence does not produce knowledge. The experiments instead suggest that people deny knowledge because they distrust drawing conclusions about an individual based on reasoning about the population to which it belongs, a tendency previously identified by "judgment and decision making" researchers. Consistent with this, participants were more willing to ascribe knowledge for beliefs based on probabilistic evidence that is specific to a particular case (Experiments 3A and 3B). PMID- 25297512 TI - Polymorphism in CYP2D6 and CYP2C19, members of the cytochrome P450 mixed-function oxidase system, in the metabolism of psychotropic drugs. AB - Numerous studies in the field of psychopharmacological treatment have investigated the possible contribution of genetic variability between individuals to differences in drug efficacy and safety, motivated by the wide individual variation in treatment response. Genomewide analyses have been conducted in several large-scale studies on antidepressant drug response. However, no consistent findings have emerged from these studies. In a recent meta-analysis of genomewide data from the three studies capturing common variation for association with symptomatic improvement and remission revealed the absence of any strong genetic association and failed to replicate results of individual studies in the pooled data. However, there are good reasons to consider the possible importance of pharmacogenetic variants separately. These variants explain a large portion of the manifold variability in individual drug metabolism. More than 20 psychotropic drugs have now been relabelled by the FDA adding information on polymorphic drug metabolism and therapeutic recommendations. Furthermore, dose recommendations for polymorphisms in drug metabolizing enzymes, first and foremost CYP2D6 and CYP2C19, have been issued with the advice to reduce the dosage in poor metabolizers to 50% or less (in eight cases), or to choose an alternative treatment. Beside the well-described role in hepatic drug metabolism, these enzymes are also expressed in the brain and play a role in biotransformation of endogenous substrates. These polymorphisms may therefore modulate brain metabolism and affect the function of the neural substrates of cognition and emotion. PMID- 25297513 TI - Avoid 'prognostic paralysis'--just get ahead and plan and co-ordinate care. PMID- 25297514 TI - The World Health Organization's report on suicide: a fundamental step in worldwide suicide prevention. PMID- 25297516 TI - The therapeutic factor inventory-8: Using item response theory to create a brief scale for continuous process monitoring for group psychotherapy. AB - OBJECTIVE: We tested a very brief version of the 23-item Therapeutic Factors Inventory-Short Form (TFI-S), and describe the use of Item Response Theory (IRT) for the purpose of developing short and reliable scales for group psychotherapy. METHOD: Group therapy patients (N = 578) completed the TFI-S on one occasion, and their data were used for the IRT analysis. Of those, 304 completed the TFI-S and other measures on more than one occasion to assess sensitivity to change, concurrent, and predictive validity of the brief version. RESULTS: Results suggest that the new TFI-8 is a brief, reliable, and valid measure of a higher order group therapeutic factor. CONCLUSION: The TFI-8 may be used for continuous process measurement and feedback to improve the functioning of therapy groups. PMID- 25297517 TI - Flexible conductive-bridging random-access-memory cell vertically stacked with top Ag electrode, PEO, PVK, and bottom Pt electrode. AB - Flexible conductive-bridging random-access-memory (RAM) cells were fabricated with a cross-bar memory cell stacked with a top Ag electrode, conductive polymer (poly(n-vinylcarbazole): PVK), electrolyte (polyethylene oxide: PEO), bottom Pt electrode, and flexible substrate (polyethersulfone: PES), exhibiting the bipolar switching behavior of resistive random access memory (ReRAM). The cell also exhibited bending-fatigue-free nonvolatile memory characteristics: i.e., a set voltage of 1.0 V, a reset voltage of -1.6 V, retention time of >1 * 10(5) s with a memory margin of 9.2 * 10(5), program/erase endurance cycles of >10(2) with a memory margin of 8.4 * 10(5), and bending-fatigue-free cycles of ~1 * 10(3) with a memory margin (I(on)/I(off)) of 3.3 * 10(5). PMID- 25297518 TI - Aiming to be NEAT: safely improving and sustaining access to emergency care in a tertiary referral hospital. AB - OBJECTIVE: To implement and evaluate strategies for improving access to emergency department (ED) care in a tertiary hospital. METHODS: A retrospective pre-post intervention study using routinely collected data involving all patients presenting acutely to the ED of a major tertiary hospital over a 2-year period. Main outcome measures were changes in: the percentage of patients exiting the ED (all patients, patients discharged directly from the ED, patients admitted to inpatient wards); mean patient transit times in the ED; inpatient mortality rates; rates of ED 'did not wait' and re-presentations within 48 h of ED discharge; and selected safety indicators. Qualitative data on staff perceptions of interventions were also gathered. RESULTS: Working groups focused on ED internal processes, ED-inpatient unit interface, hospital-wide discharge processes and performance monitoring and feedback. Twenty-five different reforms were enacted over a 9-month period from April to December 2012. Comparing the baseline period (January-March 2012) with the post-reform period (January-March 2013), the percentage of patients exiting the ED within 4 h rose for all patients presenting to the ED (from 32% to 62%), for patients discharged directly from the ED (from 41% to 75%) and for admitted patients (from 12% to 32%; P<0.001 for all comparisons). The mean (+/-s.d.) time all patients spent in the ED was reduced from 7.2+/-5.8 to 4.4+/-3.5 h (P<0.001) and, for admitted patients, was associated with reduced in-hospital mortality (from 2.3% to 1.7%; P=0.045). The 'did not wait' rates in ED fell from 6.9% to 1.9% (P<0.001), whereas ED re presentations within 48 h among patients discharged from the ED rose slightly (from 3.1% to 3.8%; P=0.023). Improvements in outcome measures were maintained over the subsequent 12 months. CONCLUSIONS: Multiple reforms targeting processes both within the ED and its interface with inpatient units greatly improved access to ED care over 12 months and were associated with decreased in-hospital mortality. WHAT IS KNOWN ABOUT THIS TOPIC?: Prolonged stays in the ED result in overcrowding, delayed ambulance access to ED care and increased adverse outcomes for admitted patients. The introduction in Australia of National Emergency Access Targets (NEAT), which stipulate at least 70% of patients in the ED must exit the department within 4h, have spurred hospitals into implementing a wide range of reforms with varying levels of success in achieving such targets. WHAT DOES THIS PAPER ADD?: This study demonstrates how multiple reforms implemented in a poor performing tertiary hospital caused the proportion of patients exiting the ED within 4h to double within 9 months to reach levels comparable with best performing peer hospitals. This was associated with a 26% reduction in in hospital mortality for admitted patients and no clinically significant adverse effects. It demonstrates the importance of robust governance structures, executive sponsorship, cross-disciplinary collaboration, regular feedback of NEAT performance data and major redesign of existing clinical processes, work practices and bed management operations. WHAT ARE THE IMPLICATIONS FOR CLINICIANS AND MANAGERS?: Improving access to emergency care should be regarded as a problem located and resolved both within and without the ED. It requires a whole-of hospital solution involving interdisciplinary collaboration and significant change in culture and practice relating to inpatient units and their interface with the ED. PMID- 25297520 TI - Entrapment of elusive guests within metal-seamed nanocapsules. AB - Anions play a crucial role in locking alkali metals on the interior of metal organic capsules that contain structural water gates. This role is further evidenced when stitching-up the capsule seam, resulting in either expulsion or trapping of cesium ions depending on the anion employed. PMID- 25297519 TI - Prognosis significance of HER2 status and TACC1 expression in patients with gastric carcinoma. AB - HER2 amplification and/or expression occurs in gastric carcinoma (GC), but the role of HER2 in the prognosis of GC remains unclear. The dysregulation of transforming acidic coiled coil 1 (TACC1), a downstream gene of HER2, is thought to be involved in the development of GC. The aim of this study was to investigate the role and relationship of HER2 and TACC1 in GC. The expression of HER2 and TACC1 was analyzed using immunohistochemistry on 129 primary resected GC patients, and HER2 amplification was additionally determined by FISH. The data on clinicopathological features and relevant prognostic factors in these patients were analyzed. The expression (3+, 2+ and 1+) and the amplification of HER2 was observed in 57 cases (44.2 %) and 25 cases (19.4 %), respectively, and the correlation between HER2 expression and amplification was strong (p < 0.001). According to the FDA criteria, 24 cases (18.6 %) would have been considered as HER2 positive. A total 62 (48.1 %) GC tissues showed positive cytoplasmic staining of TACC1. There was a significant and positive association between TACC1 and HER2. HER2 positive was significantly associated with TNM stage (p = 0.019), and TACC1 expression was significantly associated with lymph node metastasis (p = 0.004) and TNM stage (p = 0.004). TNM stage, TACC1 expression and co-positive of both HER2 and TACC1 were independent prognostic factors. TACC1 expression is an independent prognostic indicator of GC. The correlation between TACC1 expression and HER2-positive status indicated a possible synergistic regulation of the two molecules and co-positive of both HER2 and TACC1 maybe a more valuable prognostic marker. PMID- 25297521 TI - The relationship between parental fatigue, parenting self-efficacy and behaviour: implications for supporting parents in the early parenting period. AB - BACKGROUND: Emerging evidence indicates that parental fatigue is associated with low warmth and increased hostility in parent-child interactions. One possible pathway by which fatigue may impact on parenting behaviour is via parental self efficacy (PSE), whereby high fatigue may undermine PSE, which is often associated with suboptimal parenting behaviour. The current study sought to explore a model of the relationships between parental fatigue, parenting warmth and hostility, where PSE mediates these relationships and whether the nature of these relationships differ by social or family context. METHODS: The current sample was drawn from a larger Australian community sample survey on parent well-being and parenting. It consisted of 1143 parents (mothers, n = 1003; fathers, n = 140) of children aged 0-4 years. RESULTS: Path analysis revealed that the relationship between fatigue and parenting warmth and hostility was fully mediated by PSE. CONCLUSIONS: These results indicate that fatigue has the potential to negatively influence parenting behaviours that are important for their children's well-being and development, and that fatigue plays a mediating role in this relationship. Implications of the study for psycho-education and interventions targeting the management of parental fatigue are discussed. PMID- 25297522 TI - Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. AB - Ebola viruses and Marburg viruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers, with case fatality rates in the range 25-90%. The diagnosis of filovirus using formalin-fixed tissues from fatal cases poses a significant challenge. The most characteristic histopathological findings are seen in the liver; however, the findings overlap with many other viral and non-viral haemorrhagic diseases. The need to distinguish filovirus infections from other haemorrhagic fevers, particularly in areas with multiple endemic viral haemorrhagic agents, is of paramount importance. In this review we discuss the current state of knowledge of filovirus infections and their pathogenesis, including histopathological findings, epidemiology, modes of transmission and filovirus entry and spread within host organisms. The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system, with release of pro inflammatory cytokines, chemokines and growth factors, endothelial dysfunction, alterations of the innate and adaptive immune systems, direct organ and endothelial damage from unrestricted viral replication late in infection, and coagulopathy. Although our understanding of the pathogenesis of filovirus infections has rapidly increased in the past few years, many questions remain unanswered. PMID- 25297523 TI - Synthesis and in vitro evaluation of the antitubercular and antibacterial activity of novel oxazolidinones bearing octahydrocyclopenta[c]pyrrol-2-yl moieties. AB - A novel series of oxazolidinone-class antimicrobial agents with 5-substituted octahydrocyclopenta[c]pyrrole moieties at the C-ring of linezolid and an acetamide or 1,2,3-triazole ring as the C-5 side chain of the oxazolidinone ring were prepared. The resulting series of compounds were evaluated for in vitro antimicrobial activity against Mycobacterium tuberculosis and a panel of clinically important resistant Gram-positive and -negative bacteria. Among them, endo-alcohol 2a and exo-alcohol 2b showed potent inhibitory activity against M. tuberculosis H37Rv, which was superior to that of linezolid. Several analogues in this series showed potent in vitro antibacterial activity against the clinically important vancomycin-resistant bacteria and showed similar or better potency against linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains. The hydroxyl group in the azabicyclic C-ring interacted with the same hydrophobic pocket as linezolid based on a docking study. Selected compounds with high antimicrobial activity showed good human microsomal stability and low CYP isozyme and monoamine oxidase (MAO) inhibition. PMID- 25297524 TI - Neuropathology of multiple system atrophy: new thoughts about pathogenesis. AB - Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA-P and MSA-C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA-C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded alpha-Synuclein (alpha-Syn). In addition to the ectopic appearance of alpha-Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of alpha-Syn triggered neurodegeneration are not completely understood, neuron-to oligodendrocyte transfer of alpha-Syn by prion-like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system-specific pattern of neurodegeneration. PMID- 25297526 TI - Paroxysmal non-epileptic events in infants and toddlers: A phenomenologic analysis. AB - AIM: The aim of this study was to analyze in detail the clinical phenomenology of paroxysmal non-epileptic events (PNEE) in infants and toddlers. METHODS: We studied all children aged <=2 years who were diagnosed with PNEE based on video electroencephalographic (VEEG) recordings. We analyzed the following four clinical domains of each clinical event: (i) motor manifestations (body/limb jerking, complex motor, and asymmetric limb posturing); (ii) oral/vocal (crying, vocalization, sighing); (iii) behavioral change (arrest of activity, staring); (iv) and autonomic (facial flushing, breath holding). RESULTS: Thirty-one of 81 (38.3%) infants and toddlers had 38 PNEE recorded during the study period (12 girls and 19 boys, mean age 10.5 months). The predominant clinical features were as follows: motor in 26/38 events, oral/verbal in 14/38 events, behavioral in 11/38 events, and autonomic in 8/38 events. Epileptic seizures and PNEE coexisted in four children (12.9%). Seventeen children (54.8%) had one or more risk factors suggestive of epilepsy. Twelve children (38.7%) had a normal neurologic examination, 10 (32.3%) had developmental delay, and eight (25.8%) had a family history of epilepsy or seizures. CONCLUSION: VEEG recorded PNEE in nearly 40% of 81 infants and toddlers referred for unclear paroxysmal events in our cohort. Non epileptic staring spells and benign sleep myoclonus were the most common events recorded, followed by shuddering attacks and infantile masturbation. In addition, greater than one-half of the infants and toddlers had risk factors, raising a concern for epilepsy in the family and prompting the VEEG evaluation, suggesting that paroxysmal non-epileptic seizures may frequently coexist in young children with epilepsy. PMID- 25297525 TI - In-depth profiling and analysis of host and viral microRNAs in Japanese flounder (Paralichthys olivaceus) infected with megalocytivirus reveal involvement of microRNAs in host-virus interaction in teleost fish. AB - BACKGROUND: MicroRNAs (miRNAs) regulate gene expression by binding to mRNA transcripts in various biological processes. In mammals and birds, miRNAs are known to play vital parts in both host immune defense and viral infection. However, in lower vertebrates such as teleost, systematic investigations on host and viral miRNAs are lacking. RESULTS: In this study, we applied high-throughput sequencing technology to identify and analyze both host and viral miRNAs in Japanese flounder (Paralichthys olivaceus), an economically important teleost fish farmed widely in the world, infected with megalocytivirus at a timescale of 14 days divided into five different time points. The results showed that a total of 381 host miRNAs and 9 viral miRNAs were identified, the latter being all novel miRNAs that have no homologues in the currently available databases. Of the host miRNAs, 251 have been reported previously in flounder and other species, and 130 were discovered for the first time. The expression levels of 121 host miRNAs were significantly altered at 2 d to 14 d post-viral infection (pi), and these miRNAs were therefore classified as differentially expressed host miRNAs. The expression levels of all 9 viral miRNAs increased from 0 d pi to 10 d pi and then dropped from 10 d pi to 14 d pi. For the 121 differentially expressed host miRNAs and the 9 viral miRNAs, 243 and 48 putative target genes, respectively, were predicted in flounder. GO and KEGG enrichment analysis revealed that the putative target genes of both host and viral miRNAs were grouped mainly into the categories of immune response, signal transduction, and apoptotic process. CONCLUSIONS: The results of our study provide the first evidences that indicate existence in teleost fish (i) infection-responsive host and viral miRNAs that exhibit dynamic changes in expression profiles during the course of viral infection, and (ii) potential involvement of miRNAs in host-viral interaction. PMID- 25297527 TI - Prenatal diagnosis of Greig cephalopolysyndactyly syndrome: a case report. PMID- 25297529 TI - An experimental means of transmitting pancreas disease in Atlantic salmon Salmo salar L. fry in freshwater. AB - A challenge model for pancreas disease in Atlantic salmon, Salmo salar L. fry, was developed comparing two salmonid alphavirus (SAV) subtypes: SAV1 and SAV5. Viral doses of 3 * 10(5) TCID50 mL(-1) for SAV1 and 3 * 10(4) for SAV5 were tested in triplicate tanks, each containing 450 salmon fry. Cumulative mortalities of 1.2% were recorded. Titres of virus recovered from the mortalities ranged from 10(2) to 10(7) TCID50 mL(-1) . Fry were sampled at 3, 5 and 7.5 weeks post-challenge. Sampling after 3 weeks revealed a high prevalence of infection in the absence of clinical signs, and infectious virus was recovered from 80% and 43% of sampled fry infected with SAV1 and SAV5, respectively. After 5 weeks pancreas, heart and red skeletal muscle lesions were generally observed, whilst degeneration in white skeletal muscle was observed only in fish infected with SAV1. In situ hybridisation confirmed the presence of viral genome in infected pancreas, heart and muscle. After 7.5 weeks, infectious virus (both isolates) was recovered from 13.3% of the fish sampled, with a viral titre of 10(2) TCID50 mL(-1) . Clearly, salmon fry are susceptible to SAV infection and pancreas disease. PMID- 25297528 TI - Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses. AB - Oseltamivir-resistant H1N1 influenza viruses carrying the H275Y neuraminidase mutation predominated worldwide during the 2007-2009 seasons. Although several neuraminidase substitutions were found to be necessary to counteract the adverse effects of H275Y, the order and impact of evolutionary events involved remain elusive. Here we reconstruct H1N1 neuraminidase phylogeny during 1999-2009, estimate the timing and order of crucial amino acid changes and evaluate their impact on the biological outcome of the H275Y mutation. Of the 12 neuraminidase substitutions that occurred during 1999-2009, 5 (chronologically, V234M, R222Q, K329E, D344N, H275Y and D354G) are necessary for maintaining full neuraminidase function in the presence of the H275Y mutation by altering protein accumulation or enzyme affinity/activity. The sequential emergence and cumulative effects of these mutations clearly illustrate a role for epistasis in shaping the emergence and subsequent evolution of a drug-resistant virus population, which can be useful in understanding emergence of novel viral phenotypes of influenza. PMID- 25297531 TI - Diadenosine tetraphosphate induces tight junction disassembly thus increasing corneal epithelial permeability. AB - BACKGROUND AND PURPOSE: Here, we have studied the effects of the dinucleotide P(1), P(4)-Di (adenosine-5') tetraphosphate (Ap4 A) on corneal barrier function conferred by the tight junction (TJ) proteins and its possible involvement in ocular drug delivery and therapeutic efficiency. EXPERIMENTAL APPROACH: Experiments in vitro were performed using human corneal epithelial cells (HCLEs) treated with Ap4 A (100 MUM) for 5 min. Western blot analysis and transepithelial electrical resistance (TEER) were performed to study the TJ protein levels and barrier function respectively. Intracellular pathways involved were determined using an ERK inhibitor and P2Y(2) receptor siRNAs. In in vivo assays with New Zealand rabbits, TJ integrity was examined by zonula occludens-1 (ZO-1) staining. The hypotensive compound 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) was used to assess improved delivery, measuring its levels by HPLC and measuring intraocular pressure using 5-MCA-NAT, P2Y receptor antagonists and P2Y2 siRNAs. KEY RESULTS: Two hours after Ap4 A pretreatment, TJ protein levels in HCLE cells were reduced around 40% compared with control. TEER values were significantly reduced at 2 and 4 h (68 and 52% respectively). TJ reduction and ERK activation were blocked by the ERK inhibitor U012 and P2Y(2) siRNAs. In vivo, topical application of Ap4 A disrupted ZO-1 membrane distribution. 5-MCA-NAT levels in the aqueous humour were higher when Ap4 A was previously instilled and its hypotensive effect was also increased. This action was reversed by P2Y receptor antagonists and P2Y(2) siRNA. CONCLUSIONS AND IMPLICATIONS: Ap4 A increased corneal epithelial barrier permeability. Its application could improve ocular drug delivery and consequently therapeutic efficiency. PMID- 25297530 TI - Is it time to rethink cord management when resuscitation is needed? AB - A newborn who receives a placental transfusion at birth, either from cord milking or delayed cord clamping, obtains about 30% more blood volume than the newborn whose cord is cut immediately. Receiving an adequate blood volume from placental transfusion at birth may be protective for the distressed neonate as it prevents hypovolemia and can support optimal perfusion to all organs. New research shows that ventilating before clamping the umbilical cord can reduce large swings in cardiovascular function and help to stabilize the newborn. Hypovolemia, often associated with nuchal cord or shoulder dystocia, may lead to an inflammatory cascade and subsequent ischemic injury. A sudden unexpected neonatal asystole at birth may occur from severe hypovolemia. The restoration of blood volume is an important action to protect the hearts and brains of these neonates. Current protocols for resuscitation imply immediate cord clamping and the care of the newborn away from the mother's bedside. We suggest that an intrapartum care provider can achieve placental transfusion for the distressed neonate by milking the cord several times or resuscitating the neonate at the perineum with an intact cord. Milking the cord can be done quickly within the current Neonatal Resuscitation Program guidelines. Cord blood gases can be collected with delayed cord clamping. Bringing the resuscitation to the mother's bedside is a novel concept and supports an intact cord. Adopting a policy for resuscitation with an intact cord in a hospital setting will take concentrated effort and team work by obstetrics, pediatrics, midwifery, and nursing. PMID- 25297532 TI - Effects of Valenced Media Frames of Cancer Diagnoses and Therapies: Quantifying the Transformation and Establishing of Evaluative Schemas. AB - Journalists portray health issues within different frames, which may shape news recipients' evaluations, attitudes, and behaviors. As the research on framing continues to face theoretical challenges and methodological concerns, this study examines the transformation and establishing of evaluative schemas, which are steps in the process toward attitudinal change. The study measures recipients' evaluations of actual television clips dealing with cancer diagnoses and cancer therapies. Two valenced (positive vs. negative) media frames were tested in a 3 week online panel (n = 298) using a pretest-posttest design with a German sample. The results offer limited support for the hypothesis that media frames transform participants' schemas, but do not support the hypothesis that new schemas are established in response to media frames. The study also investigates interactions between framing and participants' issue involvement, as well as between framing and topic-specific interest and media use. PMID- 25297533 TI - Compound lesion of a basal cell carcinoma and a malignant melanoma: is there a common genetic origin? PMID- 25297534 TI - Sinus biofilms in patients with cystic fibrosis: is adjusted eradication therapy needed? AB - The paranasal sinuses can be a focus for colonisation of the cystic fibrosis (CF) lungs with pathogens. In the sinuses, bacteria can adapt to the lung environment and enhance their antibiotic resistance, with biofilm formation thought to be the most important adaptive mechanism, causing recalcitrant disease. The presence of biofilms in CF sinuses is sparsely described. In this descriptive cross-sectional study, the sinus mucosa from 16 CF patients were analysed by fluorescence in situ hybridization using specific peptide nucleic acid (PNA-FISH) probes for Pseudomonas aeruginosa and Staphylococcus aureus to demonstrate the presence of biofilms. Small clusters of biofilm were visualised lining the sinus mucosa of CF patients. Biofilms were found in 10 out of 18 cases; 7 with intermittent lung colonisation, 2 chronically infected, and one lung transplanted patient. Finding P. aeruginosa biofilms in intermittently lung-colonised patients encourage us to intensify the attempt to eradicate pathogenic bacteria from the CF sinuses in an early stage using combined antibiotic therapy in the prolonged exposure of the sinus-mucosal surface. PMID- 25297535 TI - Multicolour fluorescent memory based on the interaction of hydroxy terphenyls with fluoride anions. AB - Memory operations based on variation of a molecule's properties are important because they may lead to device miniaturization to the molecular scale or increasingly complex information processing protocols beyond the binary level. Molecular memory also introduces possibilities related to information-storage security where chemical information (or reagents) might be used as an encryption key, in this case, acidic/basic reagents. Chemical memory that possesses both volatile and non-volatile functionality requires reversible conversion between at least two chemically different stable or quasi-stable states. Here we have developed the phenol-phenoxide equilibrium of phenol fluorophores as a data storage element, which can be used to write or modulate data using chemical reagents. The properties of this system allow data to be stored and erased either in non-volatile or volatile modes. We also demonstrate non-binary switching of states made possible by preparation of a composite containing the molecular memory elements. PMID- 25297536 TI - Five year monitoring of considerable changes in tyrosine phosphorylation motifs of Helicobacter pylori cagA gene in Iran. PMID- 25297538 TI - Pulmonary masses in a patient with dyspnea: Apply Occam's razor or Hickam's dictum? PMID- 25297539 TI - Changes in levels of angiotensin II and its receptors in a model of inverted stress-induced cardiomyopathy. AB - BACKGROUND: Stress-induced cardiomyopathy (SIC) has gained increasing attention worldwide and is characterized by extensive ventricular akinesis, Beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are the main treatments for SIC patients. The pharmacological mechanism of action of beta-blockers results in the inhibition of the biological effects of catecholamines. However, the mechanism of action of ACEIs in the treatment of cardiomyopathy is not known. Our aim is to assess changes in levels of angiotensin II, angiotensin-II receptors and ACE responses to SIC. METHODS: A model of inverted SIC was established in rabbits by vagal electrical stimulation. The serum concentration of angiotensin II and angiotensin (1-7) was detected by enzyme-linked immunosorbent assay. Expression of angiotensin-II receptors was measured by Western blotting and real time reverse transcription-polymerase chain reaction (RT-PCR), with localization detected by immunofluorescent staining. ACE-II expression in the myocardium was measured by Western blotting. RESULTS: From one day after vagal stimulation, concentrations of angiotensin II were significantly higher in the experimental group than those in the control group (P <0.05). Stress induced a time-dependent decrease in angiotensin subtype-1 (AT1) expression and a time-dependent increase in AT2 expression only in the apical portion of the myocardium. From three days after vagal stimulation, angiotensin (1-7) levels were significantly lower in the experimental group compared with the control group (P <0.05). Expression of the ACE-II protein was significantly downregulated in the experimental group compared with the control group from three days after vagal stimulation (P <0.05). CONCLUSIONS: Expression of angiotensin II, its receptors, ACE-II and angiotensin (1-7) was altered in response to SIC. The renin-angiotensin system could represent a therapeutic target in the prevention of SIC. PMID- 25297540 TI - phyA-GFP is spectroscopically and photochemically similar to phyA and comprises both its native types, phyA' and phyA''. AB - Low-temperature fluorescence investigations of phyA-GFP used in experiments on its nuclear-cytoplasmic partitioning were carried out. In etiolated hypocotyls of phyA-deficient Arabidopsis thaliana expressing phyA-GFP, it was found that it is similar to phyA in spectroscopic parameters with both its native types, phyA' and phyA'', present and their ratio shifted towards phyA'. In transgenic tobacco hypocotyls, native phyA and rice phyA-GFP were also identical to phyA in the wild type whereas phyA-GFP belonged primarily to the phyA' type. Finally, truncated oat Delta6-12 phyA-GFP expressed in phyA-deficient Arabidopsis was represented by the phyA' type in contrast to full-length oat phyA-GFP with an approximately equal proportion of the two phyA types. This correlates with a previous observation that Delta6-12 phyA-GFP can form only numerous tiny subnuclear speckles while its wild-type counterpart can also localize into bigger and fewer subnuclear protein complexes. Thus, phyA-GFP is spectroscopically and photochemically similar or identical to the native phyA, suggesting that the GFP tag does not affect the chromophore. phyA-GFP comprises phyA'-GFP and phyA''-GFP, suggesting that both of them are potential participants in nuclear-cytoplasmic partitioning, which may contribute to its complexity. PMID- 25297542 TI - Differences between nurse practitioner and physician care providers on rates of secondary cancer screening and discussion of lifestyle changes among breast cancer survivors. AB - PURPOSE: Breast cancer survivorship care is provided by surgical and medical oncologists, primary care physicians (PCPs), and nurse practitioner survivorship specialists (NPs). The study objective was to identify whether frequency of cancer screening and discussion of healthy lifestyles differed across these provider types. We also determined differences by provider in survivor reported follow through with lifestyle recommendations. METHODS: Breast cancer survivors completed surveys regarding the type of health-care provider they most recently saw, cancer screening, discussion, and self-reported lifestyle change since their breast cancer diagnosis. RESULTS: Seven hundred fifty-nine breast cancer survivors (78.7 % of those invited) completed the survey; 51.8 % indicated that their last visit was with a medical oncologist. There was no difference in rates of cancer screening (colon, cervical, and breast) among types of providers. A significantly larger proportion of patients who last saw an NP reported that they had discussed physical activity (78.6 %) as compared to medical oncologist 54.4 %, surgeon 43.1 %, radiation oncologist 64.1 %, and PCP 61.3 % (p < 0.001). Similar observations were observed for discussion of nutrition and weight (NP 70.0 %, medical oncologist 36.5 %, surgeon 25.7 %, radiation oncologist 48.7 %, PCP 35.5 %; p < 0.001). There was no significant difference across provider type in self-reported implementation of change in physical activity or diet. CONCLUSIONS: Our data indicate that a visit to the NP was related to comparable screening rates, but despite that NPs are more often discussing lifestyle modification, self-reported change in nutrition and physical exercise did not differ across provider type. IMPLICATIONS FOR CANCER SURVIVORS: NPs perform favorably with respect to lifestyle recommendations. Given the reported lack of lifestyle change, it is important to triage to providers who specialize in lifestyle modification and, if plausible, learn and provide actual evidence-based approaches to achieve positive outcomes in this area. PMID- 25297543 TI - Central role of 5'-AMP-activated protein kinase in chicken sperm functions. AB - Avian gametes present specific features related to their internal long-term mode of fertilization. Among other central actors of energetic metabolism control, it has been suspected that 5'-AMP-activated protein kinase (AMPK) influences sperm functions and thus plays a key role in fertilization success. In the present work, we studied AMPK localization and function in chicken sperm incubated in vitro. Effects of the pharmacological AMPK activators (AICAR, metformin) and the AMPK inhibitor compound C were assessed by evaluating AMPKalpha (Thr(172)) phosphorylation (by Western blotting), semen quality (by viability, motility, and ability to perform acrosome reaction), and energetic metabolism indicators (lactate, ATP). Localization of AMPK in subcellular sperm compartments was evaluated by immunocytochemistry. Total AMPK was found in all compartments except for the nucleus, but the phosphorylated form phospho-Thr(172)-AMPK was essentially localized in the flagellum and acrosome. AMPK activators significantly improved AMPK phosphorylation, sperm motility (increased by 40% motile, 90% progressive, and 60% rapid sperm), acrosome reaction and lactate production (increased by 40%) and viability. The AMPK inhibitor significantly reduced AMPK phosphorylation and percentages of motility (decrease by 25%), progressive energy (decrease by 35%), and rapid sperm (decreased by 30%), acrosome reaction, lactate production, and ATP release. The two activators differed in their effect on ATP concentration: AICAR stimulated ATP formation, whereas metformin did not. Our results indicate that AMPK plays a key role in the regulation of chicken sperm functions and metabolism. This action differs from that suggested in mammals, mainly by its crucial involvement in the acrosome reaction process. PMID- 25297544 TI - The cumulus cell layer protects the bovine maturing oocyte against fatty acid induced lipotoxicity. AB - Mobilization of fatty acids from adipose tissue during metabolic stress increases the amount of free fatty acids in blood and follicular fluid and is associated with impaired female fertility. In a previous report, we described the effects of the three predominant fatty acids in follicular fluid (saturated palmitate and stearate and unsaturated oleate) on oocyte maturation and quality. In the current study, the effects of elevated fatty acid levels on cumulus cells were investigated. In a dose-dependent manner, the three fatty acids induced lipid storage in cumulus cells accompanied by an enhanced immune labeling of perilipin 2, a marker for lipid droplets. Lipidomic analysis confirmed incorporation of the administered fatty acids into triglyceride, resulting in a 3- to 6-fold increase of triglyceride content. In addition, palmitate selectively induced ceramide formation, which has been implicated in apoptosis. Indeed, of the three fatty acids tested, palmitate induced reactive oxygen species formation, caspase 3 activation, and mitochondria deterioration, leading to degeneration of the cumulus cell layers. This effect could be mimicked by addition of the ceramide-C2 analog and could be inhibited by the ceramide synthase inhibitor fumonisin-B1. Interfering with the intactness of the cumulus cell layers, either by mechanical force or by palmitate treatment, resulted in enhanced uptake of lipids in the oocyte and increased radical formation. Our results show that cumulus cells act as a barrier, protecting oocytes from in vitro induced lipotoxic effects. We suggest that this protective function of the cumulus cell layers is important for the developmental competence of the oocyte. The relevance of our findings for assisted reproduction technologies is discussed. PMID- 25297545 TI - The role of CCCTC-binding factor (CTCF) in genomic imprinting, development, and reproduction. AB - CCCTC-binding factor (CTCF) is the major protein involved in insulator activity in vertebrates, with widespread DNA binding sites in the genome. CTCF participates in many processes related to global chromatin organization and remodeling, contributing to the repression or activation of gene transcription. It is also involved in epigenetic reprogramming and is essential during gametogenesis and embryo development. Abnormal DNA methylation patterns at CTCF motifs may impair CTCF binding to DNA, and are related to fertility disorders in mammals. Therefore, CTCF and its binding sites are important candidate regions to be investigated as molecular markers for gamete and embryo quality. This article reviews the role of CTCF in genomic imprinting, gametogenesis, and early embryo development and, moreover, highlights potential opportunities for environmental influences associated with assisted reproductive techniques (ARTs) to affect CTCF mediated processes. We discuss the potential use of CTCF as a molecular marker for assessing gamete and embryo quality in the context of improving the efficiency and safety of ARTs. PMID- 25297547 TI - Canine placental prostaglandin E2 synthase: expression, localization, and biological functions in providing substrates for prepartum PGF2alpha synthesis. AB - The prepartum output of PGF2alpha in the bitch is associated with increased placental PGE2-synthase (PTGES) mRNA levels. Contrasting with this is a decreased expression of PGF2alpha-synthase (PGFS/AKR1C3) in uteroplacental compartments during prepartum luteolysis, suggesting an involvement of alternative synthetic pathways in PGF2alpha synthesis, for example, conversion of PGE2 to PGF2alpha. However, because the expression and possible functions of the respective PTGES proteins remained unknown, no further conclusion could be drawn. Therefore, a canine-specific PTGES antibody was generated and used to investigate the expression, cellular localization, and biochemical activities of canine uteroplacental PTGES throughout pregnancy and at prepartum luteolysis. Additionally, the biochemical activities of these tissues involved in the conversion of PGE2 to PGF2alpha were investigated. The endometrial PTGES was localized in the uterine surface epithelium at preimplantation and in superficial and deep uterine glands, endothelial cells, and myometrium throughout pregnancy and at parturition. Placental signals were mostly in the trophoblast. The biochemical properties of recombinant PTGES protein were confirmed. Additionally, expression of two PGE2-receptors, PTGER2/EP2 and PTGER4/EP4, revealed their decreasing expression during luteolysis. In contrast, the uteroplacental expression of prostaglandin transporter (PGT) was strongly elevated prior to parturition. These localization patterns resembled that of PTGES. The increased expression of PTGES and PGT at parturition, together with the accompanying decreased levels of PGE2-receptors and the capability of canine uterine and placental homogenates to take part in the conversion of PGE2 to PGF2alpha, as found in this study, suggest that PGE2 could be used locally as a substrate for prepartum PGF2alpha synthesis in the dog. PMID- 25297546 TI - The p160/steroid receptor coactivator family: potent arbiters of uterine physiology and dysfunction. AB - The p160/steroid receptor coactivator (SRC) family comprises three pleiotropic coregulators (SRC-1, SRC-2, and SRC-3; otherwise known as NCOA1, NCOA2, and NCOA3, respectively), which modulate a wide spectrum of physiological responses and clinicopathologies. Such pleiotropy is achieved through their inherent structural complexity, which allows this coregulator class to control both nuclear receptor and non-nuclear receptor signaling. As observed in other physiologic systems, members of the SRC family have recently been shown to play pivotal roles in uterine biology and pathobiology. In the murine uterus, SRC-1 is required to launch a full steroid hormone response, without which endometrial decidualization is markedly attenuated. From "dovetailing" clinical and mouse studies, an isoform of SRC-1 was recently identified which promotes endometriosis by reprogramming endometrial cells to evade apoptosis and to colonize as endometriotic lesions within the peritoneal cavity. The endometrium fails to decidualize without SRC-2, which accounts for the infertility phenotype exhibited by mice devoid of this coregulator. In related studies on human endometrial stromal cells, SRC-2 was shown to act as a molecular "pacemaker" of the glycolytic flux. This finding is significant because acceleration of the glycolytic flux provides the necessary bioenergy and biomolecules for endometrial stromal cells to switch from quiescence to a proliferative phenotype, a critical underpinning in the decidual progression program. Although studies on uterine SRC 3 function are in their early stages, clinical studies provide tantalizing support for the proposal that SRC-3 is causally linked to endometrial hyperplasia as well as with endometrial pathologies in patients diagnosed with polycystic ovary syndrome. This proposal is now driving the development and application of innovative technologies, particularly in the mouse, to further understand the functional role of this elusive uterine coregulator in normal and abnormal physiologic contexts. Because dysregulation of this coregulator triad potentially presents a triple threat for increased risk of subfecundity, infertility, or endometrial disease, a clearer understanding of the individual and combinatorial roles of these coregulators in uterine function is urgently required. This minireview summarizes our current understanding of uterine SRC function, with a particular emphasis on the next critical questions that need to be addressed to ensure significant expansion of our knowledge of this underexplored field of uterine biology. PMID- 25297549 TI - Knockout of the two evolutionarily conserved peroxisomal 3-ketoacyl-CoA thiolases in Arabidopsis recapitulates the abnormal inflorescence meristem 1 phenotype. AB - A specific function for peroxisomal beta-oxidation in inflorescence development in Arabidopsis thaliana is suggested by the mutation of the abnormal inflorescence meristem 1 gene, which encodes one of two peroxisomal multifunctional proteins. Therefore, it should be possible to identify other beta oxidation mutants that recapitulate the aim1 phenotype. Three genes encode peroxisomal 3-ketoacyl-CoA thiolase (KAT) in Arabidopsis. KAT2 and KAT5 are present throughout angiosperms whereas KAT1 is a Brassicaceae-specific duplication of KAT2 expressed at low levels in Arabidopsis. KAT2 plays a dominant role in all known aspects of peroxisomal beta-oxidation, including that of fatty acids, pro-auxins, jasmonate precursor oxophytodienoic acid, and trans-cinnamic acid. The functions of KAT1 and KAT5 are unknown. Since KAT5 is conserved throughout vascular plants and expressed strongly in flowers, kat2 kat5 double mutants were generated. These were slow growing, had abnormally branched inflorescences, and ectopic organ growth. They made viable pollen, but produced no seed indicating that infertility was due to defective gynaecium function. These phenotypes are strikingly similar to those of aim1. KAT5 in the Brassicaceae encodes both cytosolic and peroxisomal proteins and kat2 kat5 defects could be complemented by the re-introduction of peroxisomal (but not cytosolic) KAT5. It is concluded that peroxisomal KAT2 and KAT5 have partially redundant functions and operate downstream of AIM1 to provide beta-oxidation functions essential for inflorescence development and fertility. PMID- 25297548 TI - Melatonin enhances plant growth and abiotic stress tolerance in soybean plants. AB - Melatonin is a well-known agent that plays multiple roles in animals. Its possible function in plants is less clear. In the present study, we tested the effect of melatonin (N-acetyl-5-methoxytryptamine) on soybean growth and development. Coating seeds with melatonin significantly promoted soybean growth as judged from leaf size and plant height. This enhancement was also observed in soybean production and their fatty acid content. Melatonin increased pod number and seed number, but not 100-seed weight. Melatonin also improved soybean tolerance to salt and drought stresses. Transcriptome analysis revealed that salt stress inhibited expressions of genes related to binding, oxidoreductase activity/process, and secondary metabolic processes. Melatonin up-regulated expressions of the genes inhibited by salt stress, and hence alleviated the inhibitory effects of salt stress on gene expressions. Further detailed analysis of the affected pathways documents that melatonin probably achieved its promotional roles in soybean through enhancement of genes involved in cell division, photosynthesis, carbohydrate metabolism, fatty acid biosynthesis, and ascorbate metabolism. Our results demonstrate that melatonin has significant potential for improvement of soybean growth and seed production. Further study should uncover more about the molecular mechanisms of melatonin's function in soybeans and other crops. PMID- 25297550 TI - A highly charged region in the middle domain of plant endoplasmic reticulum (ER) localized heat-shock protein 90 is required for resistance to tunicamycin or high calcium-induced ER stresses. AB - Heat-shock protein 90 (HSP90) is a highly conserved molecular chaperone that is involved in modulating a multitude of cellular processes under both physiological and stress conditions. In Arabidopsis, there are seven HSP90 isoforms (HSP90.1 HSP90.7) that are localized in the cytoplasm/nucleus, mitochondrion, chloroplast, and endoplasmic reticulum (ER) where protein folding actively takes place. In this study, we analysed the sequence of ER-localized Arabidopsis HSP90.7 and the other ER GRP94 proteins from plants and animals, and identified a short, charged region that is specifically present in the middle domain of plant-derived GRP94 proteins. To understand the role of this charged region, we analysed transgenic plants that expressed a mutant protein, HSP90.7(Delta22), which had this charged region deleted. We showed that seedlings expressing HSP90.7(Delta22) had significantly enhanced sensitivity to ER stress induced by tunicamycin or a high concentration of calcium, although its general chaperone activity in preventing the model protein from heat-induced aggregation was not significantly affected. We also analysed the ATP-binding and hydrolysis activity of both wild-type and mutant HSP90.7 proteins, and found that they had slightly different ATP-binding affinities. Finally, using a yeast two-hybrid screen, we identified a small set of HSP90.7 interactors and showed that the charged region is not required for the candidate client interaction, although it may affect their binding affinity, thus providing potential targets for further investigation of HSP90.7 functions. PMID- 25297551 TI - The efficacy of calcineurin inhibitors for the treatment of interstitial lung disease associated with polymyositis/dermatomyositis. AB - Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DM associated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported. PMID- 25297552 TI - Acquired ichthyosis and secondary hyperparathyroidism with systemic lupus erythematosus. PMID- 25297553 TI - Acute longitudinal myelitis following Cryptococcus laurentii pneumonia in a patient with systemic lupus erythematosus. AB - Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is reported in about 50% of patients. Among the neuropsychiatric features of SLE, myelopathy, including acute transverse myelitis (ATM) or acute longitudinal myelitis (ALM), represents an uncommon event. A possible vascular aetiology of SLE myelopathies has been hypothesized and it seems to be much more associated to SLE-associated antiphospholipid syndrome (APS). Furthermore, a possible infectious cause of ATM or ALM in healthy subjects has been described. SLE patients are susceptible to infection due to the disease itself or to the immunosuppressive therapy. Cryptococci non-neoformans have been rarely associated to infections in humans. Here we describe the case of a 47-year-old woman with SLE and Sjogren Syndrome who developed an ALM concurrently with a Cryptococcus laurentii pneumonia. The patient was treated with antimycotics, high doses of glucocorticoids and intravenous immunoglobulins with a significant clinical and radiological improvement. As far as we know, this is the first case of Cryptococcus laurentii infection and ALM in a patient with SLE who later developed a seronegative APS. Even though myelopathy may be considered primarily associated to SLE, a possible role of the infection in ALM development cannot be excluded. PMID- 25297554 TI - A retrospective, multicenter study evaluating the prognostic value of minor salivary gland histology in a large cohort of patients with primary Sjogren's syndrome. AB - OBJECTIVE: The objective of this report is to investigate the prognostic value of minor salivary glands (MSG) assessment, routinely performed with hematoxilin eosin (H&E) staining, for the diagnosis of primary Sjogren's syndrome (pSS). METHODS: We retrospectively evaluated clinical, serological and histological features of 794 pSS patients. H&E-stained sections were assessed using the Chisholm and Mason grading system and/or the focus score (FS). RESULTS: FS allowed the identification of a number of differences in the disease spectrum, and its prognostic role was further confirmed by quantifying the association between FS value and clinical/serological variables with binary logistic regression. Moreover, hypocomplementemia and FS resulted the only variables associated with lymphoma at univariate analysis, and FS appeared to be associated with lymphoma independently on complement fraction concentrations. Conversely, when patients were divided according to the Chisholm and Mason grading system, we failed to observe any significant difference between subgroups. CONCLUSION: In addition to its diagnostic role, our data seem to support that the routine assessment of MSG-FS with H&E staining is useful to predict at the time of diagnosis the adverse outcomes, such as lymphoma and extraglandular manifestations, that complicate the pSS course. On this basis, it should be recommended that an MSG biopsy be performed even in those patients displaying clinical and serological criteria, allowing the diagnosis of pSS independent of histological status. PMID- 25297555 TI - Incidence of palmar process fractures of the distal phalanx and association with front hoof conformation in foals. AB - REASONS FOR PERFORMING STUDY: Recent studies indicate a high prevalence of fractures of the palmar processes (PP) of the distal phalanx in foals. However, information on the prevalence of such fractures in different breeds and the effect of predisposing factors, such as hoof conformation, is limited. OBJECTIVES: To examine the prevalence of distal phalanx PP fractures in foals and report the relationship of distal limb and hoof conformation with the prevalence of fracture. STUDY DESIGN: Longitudinal study. METHODS: Front hooves of 19 Thoroughbred, Quarter Horse and Arabian foals were examined. Digital radiographic and photographic images of the distal aspect of the forelimbs were taken at ~2.5 month intervals. Five radiographic projections of each limb were as follows: lateromedial; horizontal beam dorsopalmar; dorso60 degrees proximal-palmarodistal oblique; dorso60 degrees proximo45 degrees lateral-palmarodistomedial oblique; and dorso60 degrees proximo45 degrees medial-palmarodistolateral oblique. The relationship between measurements and the prevalence of fractures was assessed by 3-way ANOVA. RESULTS: Fractures were found in 74% (n = 14) of the foals during the study period. The prevalences of lateral PP and medial PP fractures were not significantly different. Several hoof measurements were associated with PP fractures. Longer dorsal length of the distal phalanx was associated with medial PP fractures, while smaller lateral angle and shorter lateral palmar length were associated with a higher prevalence of lateral PP fractures. CONCLUSIONS: This study revealed a high prevalence of PP fractures in young foals, particularly in Thoroughbred foals. The hoof conformation may be one of the contributory factors to PP fractures in foals. PMID- 25297557 TI - Animal models of disease: feline hyperthyroidism: an animal model for toxic nodular goiter. AB - Since first discovered just 35 years ago, the incidence of spontaneous feline hyperthyroidism has increased dramatically to the extent that it is now one of the most common disorders seen in middle-aged to senior domestic cats. Hyperthyroid cat goiters contain single or multiple autonomously (i.e. TSH independent) functioning and growing thyroid nodules. Thus, hyperthyroidism in cats is clinically and histologically similar to toxic nodular goiter in humans. The disease in cats is mechanistically different from Graves' disease, because neither the hyperfunction nor growth of these nodules depends on extrathyroidal circulating stimulators. The basic lesion appears to be an excessive intrinsic growth capacity of some thyroid cells, but iodine deficiency, other nutritional goitrogens, or environmental disruptors may play a role in the disease pathogenesis. Clinical features of feline toxic nodular goiter include one or more palpable thyroid nodules, together with signs of hyperthyroidism (e.g. weight loss despite an increased appetite). Diagnosis of feline hyperthyroidism is confirmed by finding the increased serum concentrations of thyroxine and triiodothyronine, undetectable serum TSH concentrations, or increased thyroid uptake of radioiodine. Thyroid scintigraphy demonstrates a heterogeneous pattern of increased radionuclide uptake, most commonly into both thyroid lobes. Treatment options for toxic nodular goiter in cats are similar to that used in humans and include surgical thyroidectomy, radioiodine, and antithyroid drugs. Most authorities agree that ablative therapy with radioiodine is the treatment of choice for most cats with toxic nodular goiter, because the animals are older, and the disease will never go into remission. PMID- 25297556 TI - Resveratrol and curcumin enhance pancreatic beta-cell function by inhibiting phosphodiesterase activity. AB - Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against beta-cell dysfunction, we studied their mechanism(s) of action in beta-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic beta-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic beta-cells. In our current study, we found that both RES (0.1-10 MUmol/l) and CUR (1-100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating beta-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in beta-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic beta-cell function. PMID- 25297558 TI - Combustion smoke-induced inflammation in the olfactory bulb of adult rats. AB - BACKGROUND: The damaging effect of combustion smoke inhalation on the lung is widely reported but information on its effects on the olfactory bulb is lacking. This study sought to determine the effects of smoke inhalation on the olfactory bulb, whose afferent input neurons in the nasal mucosa are directly exposed to external stimuli, such as smoke. METHODS: Adult male Sprague-Dawley rats were subjected to combustion smoke inhalation and sacrificed at different time points. Changes in olfactory bulb proteins including vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), Na+-K+-Cl- cotransporter 1 (NKCC1), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4) were evaluated by Western blot analysis. In addition, ELISA was conducted for cytokine and chemokine levels, and double immunofluorescence labeling was carried out for GFAP/VEGF, GFAP/AQP4, NeuN/nNOS, GFAP/NKCC1, NeuN/NKCC1, GFAP/Rhodamine isothiocyanate (RITC), and transferase dUTP nick end labeling (TUNEL). Aminoguanidine was administered to determine the effects of iNOS inhibition on the targets probed after smoke inhalation. RESULTS: The results showed a significant increase in VEGF, iNOS, eNOS, nNOS, NKCC1, and GFAP expression in the bulb tissues, with corresponding increases in inflammatory cytokines and chemokines after smoke inhalation. Concurrent to this was a drastic increase in AQP4 expression and RITC permeability. Aminoguanidine administration decreased the expression of iNOS and RITC extravasation after smoke inhalation. This was coupled with a significant reduction in incidence of TUNEL + cells that was not altered with administration of L-NG-nitroarginine methyl ester (L-NAME). CONCLUSIONS: These findings suggest that the upregulation of iNOS in response to smoke inhalation plays a major role in the olfactory bulb inflammatory pathophysiology, along with a concomitant increase in pro-inflammatory molecules, vascular permeability, and edema. Overall, these findings indicate that the olfactory bulb is vulnerable to smoke inhalation. PMID- 25297559 TI - A single aromatic core mutation converts a designed "primitive" protein from halophile to mesophile folding. AB - The halophile environment has a number of compelling aspects with regard to the origin of structured polypeptides (i.e., proteogenesis) and, instead of a curious niche that living systems adapted into, the halophile environment is emerging as a candidate "cradle" for proteogenesis. In this viewpoint, a subsequent halophile to-mesophile transition was a key step in early evolution. Several lines of evidence indicate that aromatic amino acids were a late addition to the codon table and not part of the original "prebiotic" set comprising the earliest polypeptides. We test the hypothesis that the availability of aromatic amino acids could facilitate a halophile-to-mesophile transition by hydrophobic core packing enhancement. The effects of aromatic amino acid substitutions were evaluated in the core of a "primitive" designed protein enriched for the 10 prebiotic amino acids (A,D,E,G,I,L,P,S,T,V)-having an exclusively prebiotic core and requiring halophilic conditions for folding. The results indicate that a single aromatic amino acid substitution is capable of eliminating the requirement of halophile conditions for folding of a "primitive" polypeptide. Thus, the availability of aromatic amino acids could have facilitated a critical halophile to-mesophile protein folding adaptation-identifying a selective advantage for the incorporation of aromatic amino acids into the codon table. PMID- 25297562 TI - The use of CA-IX as a diagnostic method for oral leukoplakia. AB - The presence and degree of dysplasia are important diagnostic and prognostic criteria for oral leukoplakia, but evaluation of dysplasia is difficult and subjective. Carbonic anhydrase-IX (CA-IX) is expressed primarily in tumor cells and is considered a specific hypoxia marker. We investigated the role of CA-IX in oral leukoplakia. We investigated 30 specimens of oral leukoplakia and 35 dysplasia specimens adjacent to the tumor margin. We analyzed clinical variables including age, sex, degree of dysplasia, and smoking, clinical appearance of leukoplakia, number of lesions, location, size, clinical monitoring, malignant transformation and recurrence. For the immunohistochemical study, we used a noncommercial monoclonal antibody against human CA-IX MAb M75. We found greater CA-IX positivity in nonsmokers, erythroplakia and mottled leukoplakia, those located on the tongue, patients with multiple lesions, 2-4 cm leukoplakias and in recurrent cases, although differences were not statistically significant. All lesions in all samples without dysplasia were negative for CA-IX; however, for all other categories of dysplasia, the percentages of positivity and negativity varied. Regarding the diagnostic index values, we found a sensitivity of 32%, specificity of 100%, a positive predictive value of 100% and a negative predictive value of 13%. Leukoplakias appear mainly in females and potentially are malignant; more than 90% have some degree of dysplasia, and therefore require close clinical and histopathological monitoring. The CA-IX immunohistochemical marker may be useful for screening samples without dysplasia owing to its high specificity. PMID- 25297561 TI - Differential misclassification of confounders in comparative evaluation of hospital care quality: caesarean sections in Italy. AB - BACKGROUND: Despite extensive studies on exposure and disease misclassification, few studies have investigated misclassification of confounders. This study aimed to identify differentially misclassified confounders in a comparative evaluation of hospital care quality and to quantify their impact on hospital-specific risk adjusted estimates, focusing on the appropriateness of caesarean sections (CS). METHODS: We gathered data from the Hospital Information System in Italy for women admitted in 2005-2010. We estimated adjusted proportions of CS with logistic regression models. Among several confounders, we focused on high fetal head at term (HFH), which is seldom objectively documentable in medical records. RESULTS: A total of 540 maternity units were compared. The median HFH prevalence was 0.9%, ranging from 0 to 70%. In some units, HFH was coded so frequently that it was unlikely to reflect a natural heterogeneity. This "over-coding" was conditional on the outcome because it occurred more frequently for women that underwent CS. This suggested an opportunistic coding to justify the choice of a CS. HFH misclassification was not randomly distributed over Italy; it had an excess in the Campania region where, in some units, the proportion of HFHs gradually increased from 2005 to 2010 (e.g., from 0 to 26%), but the national average remained constant (2.5%). The inclusion of the misclassified diagnosis in the models favored those hospitals that codified in a less-than-fair manner. CONCLUSIONS: Our findings emphasized the importance of rigorously inspecting for differential misclassification of confounders. Their validity may be subject to substantial heterogeneity over hospitals, over time and geographical areas. PMID- 25297563 TI - Low molecular weight polyethylenimine as a transgenic vector for tumor gene therapy. AB - We constructed a polymer composed of a series of small molecule polyethylenimine (PEI) using 4-arm polyethylenimine (PEG) as a core for tumor gene therapy. N,N' carbonyldiimidazole and N-succinimidyl-3-(2-pyridyldithio) propionate were used as chemical connecting reagents to synthesize 4-arm PEG-PEI2000 and 4-arm PEG PEI2000-MC11. Chemical characterization was performed using (1)H-NMR. The retardation effect of polymers on plasmid DNA was observed using electrophoretic mobility shift and MTT assays to test the toxicity of the polymers. The gene delivery capability of 4-arm PEG-PEI2000 and 4-arm PEG-PEI2000-MC11, and the effect of MC11 were determined by an in vitro gene delivery experiment with human hepatoma HepG2 cells. At a N:P ratio of 3, the 4-arm PEG-PEI2000 could retard successfully plasmid DNA with low toxicity. In experiments in vitro, when the N:P ratio was 30, the gene delivery efficiency of 4-arm PEG-PEI2000 in HepG2 cells was five times that of PEI2000; After connecting ligand MC11, however, the gene delivery efficiency was twice as great. Free MC11 effectively inhibited the gene delivery efficiency of the 4-arm PEG-PEI2000-MC11. Four-arm PEG-PEI2000 has low toxicity and high gene delivery efficiency, and is an effective gene delivery vector after linking ligand MC11. PMID- 25297564 TI - Nano-CuO and interaction with nano-ZnO or soil bacterium provide evidence for the interference of nanoparticles in metal nutrition of plants. AB - The expansion of nanotechnology raises concerns about the consequences of nanomaterials in plants. Here, the effects of nanoparticles (NPs; 100-500 mg/kg) on processes related to micronutrient accumulation were evaluated in bean (Phaseolus vulgaris) exposed to CuO NPs, a mixture of CuO and ZnO (CuO:ZnO) NPs, and in CuO NP-exposed plants colonized by a root bacterium, Pseudomonas chlororaphis O6 (PcO6) in a sand matrix for 7 days. Depending on exposure levels, the inhibition of growth by CuO NPs was more apparent in roots (10-66 %) than shoots (9-25 %). In contrast, CuO:ZnO NPs or root colonization with PcO6 partially mitigated growth inhibition. At 500 mg/kg exposure, CuO NPs increased soluble Cu in the growth matrix by 23-fold, relative to the control, while CuO:ZnO NPs increased soluble Cu (26-fold), Zn (127-fold) and Ca (4.5-fold), but reduced levels of Fe (0.8-fold) and Mn (0.75-fold). Shoot accumulations of Cu (3.8-fold) and Na (1-fold) increased, while those of Fe (0.4-fold), Mn (0.2 fold), Zn (0.5-fold) and Ca (0.5-fold) were reduced with CuO NP (500 mg/kg) exposure. CuO:ZnO NPs also increased shoot Cu, Zn and Na levels, while decreasing that of Fe, Mn, Ca and Mg. Root colonization reduced shoot uptake of Cu and Na, 15 and 24 %, respectively. CuO NPs inhibited ferric reductase (up to 49 %) but stimulated cupric (up to 273 %) reductase activity; while CuO:ZnO NPs or root colonization by PcO6 altered levels of ferric, but not copper reductase activity, relative to CuO NPs. Cu ions at the level released from the NPs did not duplicate these effects. Our findings demonstrate that in addition to the apparent phytotoxic effects of NPs, NP exposure may also have subtle impacts on secondary processes such as metal nutrition. PMID- 25297565 TI - A contextual analysis of nervous force in medico-scientific and literary writings in English of the nineteenth and early-twentieth centuries. AB - This study concerns the context of use of the term "nervous force," as it appears in scientific and literary publications in English over the course of the nineteenth century and the first two decades of the twentieth century. The context of use, loss, or waste of nervous force and the context of nervous force as an expression of an attribute are analyzed in 189 scientific and 105 literary writings. Both contexts appeared in literary writings, where nervous force expresses the attributes of strength, forcefulness, vigor, or energy and use, loss or waste of nervous force explains such nonmorbid conditions as why someone is tired or needs rest. Only the context of use-loss-waste appeared in the medico scientific literature, but here it explained both nonmorbid conditions (for example, effects of old age) and morbid conditions (like epilepsy). Changes in the number of these references give insights into the medico-scientific and the literary disciplines. Discussions include why nervous force is associated with explanation of disease, the persistence of its use in this capacity, and its influence on a similar use in literary writings. PMID- 25297566 TI - Multiparametric oxygen-enhanced functional lung imaging in 3D. AB - OBJECTIVE: To develop a self-gated free-breathing 3D sequence allowing for simultaneous T1-weighted imaging and quantitative T2* mapping in different breathing phases in order to assess the feasibility of oxygen-enhanced 3D functional lung imaging. MATERIALS AND METHODS: A 3D sequence with ultrashort echo times and interleaved double readouts was implemented for oxygen-enhanced lung imaging at 1.5 T. Six healthy volunteers were examined while breathing room air as well as 100 % oxygen. Images from expiratory and inspiratory breathing phases were reconstructed and compared for the two breathing gases. RESULTS: The average T2* value measured for room air was 2.10 ms, with a 95 % confidence interval (CI) of 1.95-2.25 ms, and the average for pure oxygen was 1.89 ms, with a 95 % CI of 1.76-2.01 ms, resulting in a difference of 10.1 % (95 % CI 8.9-11.3 %). An 11.2 % increase in signal intensity (95 % CI 10.4-12.1 %) in the T 1 weighted images was detected when subjects were breathing pure oxygen compared to room air. Furthermore, a significant change in signal intensity (26.5 %, 95 % CI 18.8-34.3 %) from expiration to inspiration was observed. CONCLUSIONS: This study demonstrated the feasibility of simultaneous T2* mapping and T1-weighted 3D imaging of the lung. This method has the potential to provide information about ventilation, oxygen transfer, and lung expansion within one experiment. Future studies are needed to investigate the clinical applicability and diagnostic value of this approach in various pulmonary diseases. PMID- 25297567 TI - Management of feline distal tibial fractures using a hybrid external skeletal fixator. AB - OBJECTIVE: To document the results of management of feline distal tibial fractures with circular-linear hybrid external skeletal fixators. METHODS: Retrospective examination of case records and radiographs of cats with distal tibial fractures managed with hybrid external skeletal fixators. Signalment, pre operative fracture conformation, post-operative fracture reduction, implant complications, time to tibial and fibular fracture healing and time to hybrid external skeletal fixators removal were analysed. RESULTS: Case records of eight cats were reviewed and included three closed fractures and five type 1 open fractures. Post-operative fracture reduction was considered appropriate in all cases. Healing of five tibial fractures was complete and hybrid external skeletal fixators were removed within a mean of 13 weeks. Healing of the fibular fracture was complete within a mean of 12 . 1 weeks. Three tibial fractures demonstrated non-union and were revised after a mean duration of 24 weeks. All three non-union fractures were open on presentation. CLINICAL SIGNIFICANCE: Feline distal tibial fractures may be managed with hybrid external skeletal fixators, however, non union still occurs. In this study type I open feline distal tibial fractures appeared more likely to develop non-union. PMID- 25297560 TI - Cardiac NO signalling in the metabolic syndrome. AB - It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high-density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation. ROS/RNS can modulate cardiac NO signalling and trigger various adaptive changes in NOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardial RNS generation and decreased NO bioavailability. The increased oxidative and nitrative stress also impairs the NO-soluble guanylate cyclase (sGC) signalling pathway, limiting the ability of NO to exert its fundamental signalling roles in the heart. Enhanced ROS/RNS generation in the presence of risk factors also facilitates activation of redox-dependent transcriptional factors such as NF-kappaB, promoting myocardial expression of various pro-inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation of NO signalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation of NO signalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such as ACE inhibitors, certain beta-blockers, and sGC activators. Better understanding of the above-mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiac NO signalling. PMID- 25297568 TI - Phosphorescent cyclometalated iridium(III) complexes that contain substituted 2 acetylbenzo[b]thiophen-3-olate ligand for red organic light-emitting devices. AB - We report the synthesis of a new class of thermally stable and strongly luminescent cyclometalated iridium(III) complexes 1-6, which contain the 2 acetylbenzo[b]thiophene-3-olate (bt) ligand, and their application in organic light-emitting diodes (OLEDs). These heteroleptic iridium(III) complexes with bt as the ancillary ligand have a decomposition temperature that is 10-20 % higher and lower emission self-quenching constants than those of their corresponding complexes with acetylacetonate (acac). The luminescent color of these iridium(III) complexes could be fine-tuned from orange (e.g., 2-phenyl-6 (trifluoromethyl)benzo[d]thiazole (cf3 bta) for 4) to pure red (e.g., lpt (Hlpt=4 methyl-2-(thiophen-2-yl)quinolone) for 6) by varying the cyclometalating ligands (C-deprotonated C^N). In particular, highly efficient OLEDs based on 6 as dopant (emitter) and 1,3-bis(carbazol-9-yl)benzene (mCP) as host that exhibit stable red emission over a wide range of brightness with CIE chromaticity coordinates of (0.67, 0.33) well matched to the National Television System Committee (NTSC) standard have been fabricated along with an external quantum efficiency (EQE) and current efficiency of 9 % and 10 cd A(-1) , respectively. A further 50 % increase in EQE (>13 %) by replacing mCP with bis[4-(6H-indolo[2,3-b]quinoxalin-6 yl)phenyl]diphenylsilane (BIQS) as host for 6 in the red OLED is demonstrated. The performance of OLEDs fabricated with 6 (i.e., [(lpt)2Ir(bt)]) was comparable to that of the analogous iridium(III) complex that bore acac (i.e., [(lpt)2 Ir(acac)]; 6a in this work) [Adv. Mater.- 2011, 23, 2981] fabricated under similar conditions. By using ntt (Hnnt=3-hydroxynaphtho[2,3-b]thiophen-2 yl)(thiophen-2-yl)methanone) ligand, a substituted derivative of bt, the [(cf3bta)2Ir(ntt)] was prepared and found to display deep red emission at around 700 nm with a quantum yield of 12 % in mCP thin film. PMID- 25297569 TI - KAISO inhibition: an atomic insight. AB - In today's world, the pursuit of a novel anti-cancer agent remains top priority because of the fact that the global burden of this malady is continuously increasing. Our work is no different from others in searching for new therapeutic solutions. To achieve this, we are looking into Epigenetics, the phenomenon governed by hypermethylation and hypomethylation of tumor suppressor genes and oncogenes, respectively. Our target for this study is an important intermediary methyl-CpG binding protein named kaiso. In our study, we have used the X-ray crystallographic structure of Kaiso for virtual screening and molecular dynamics simulations to study the binding modes of possible inhibitors. The C2H2 domain comprising LYS539 was used for screening the inter bio screen Database having 48,531 natural compounds. Our approach of using computer-aided drug designing methods helped us to remove the execrable compounds and narrowed our focus on a selected few for molecular simulation studies. The top ranked compound (chem. ID 28127) exhibited the highest binding affinity and was also found to be stable throughout the 20 ns timeframe. This compound is therefore a good starting point for developing strong inhibitors. PMID- 25297570 TI - Graphene surface plasmons at the near-infrared optical regime. AB - Graphene has been identified as an emerging horizon for a nanoscale photonic platform because the Fermi level of intrinsic graphene can be engineered to support surface plasmons (SPs). The current solid back electrical gating and chemical doping methods cannot facilitate the demonstration of graphene SPs at the near-infrared (NIR) window because of the limited shift of the Fermi level. Here, we present the evidence for the existence of graphene SPs on a tapered graphene-silicon waveguide tip at a NIR wavelength, employing a surface carrier transfer method with molybdenum trioxides. The coupling between the graphene surface plasmons and the guiding mode in silicon waveguides allows for the observation of the concentrated field of the SPs in the tip by near-field scanning optical microscopy. Thus the hot spot from the concentrated SPs in the graphene layer can be used as a key experimental signature of graphene SPs. The NIR graphene SPs opens a new perspective for optical communications, optical sensing and imaging, and optical data storage with extreme spatial confinement, broad bandwidth and high tunability. PMID- 25297571 TI - The adverse association of diabetes with risk of first acute myocardial infarction is modified by physical activity and body mass index: prospective data from the HUNT Study, Norway. AB - AIMS/HYPOTHESIS: Diabetes increases the risk of acute myocardial infarction (AMI) and effective means for primary prevention are warranted. We prospectively examined the joint association of diabetes and leisure-time physical activity, as well as of diabetes and BMI, with the risk of AMI. METHODS: A total of 55,534 men and women in the Norwegian HUNT Study were followed-up for first AMI by hospital admission registries and the Cause of Death Registry. Cox proportional adjusted HRs with 95% CIs were estimated. RESULTS: Overall, 1,887 incident AMIs occurred during 12.3 years. Compared with inactive people without diabetes, inactive people with diabetes had an HR of 2.37 (95% CI 1.58, 3.57), whereas the HR among highly active persons with diabetes was 1.04 (95% CI 0.62, 1.74). Normal-weight (BMI 18.5-25 kg/m(2)) persons with diabetes had an HR of 1.60 (95% CI 1.05, 2.44) and obese (BMI > 30 kg/m(2)) persons with diabetes had an HR of 2.55 (95% CI 1.97, 3.29) compared with normal-weight persons without diabetes. The data suggest biological interaction between diabetes and physical activity, with a relative excess risk of inactivity and diabetes of 1.43 (95% CI 0.08, 2.78). For obesity and diabetes, the excess risk due to interaction was smaller (0.67; 95% CI -0.24, 1.58). CONCLUSIONS/INTERPRETATION: Body weight and, in particular, physical activity modified the association between diabetes and risk of first AMI. This highlights the potential importance of physical activity and weight maintenance in primary prevention of AMI among people with diabetes. PMID- 25297572 TI - The effect of glibenclamide on insulin secretion at normal glucose concentrations. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate the incremental and proportional effect of a sulfonylurea on insulin secretion rates at low, elevated and high blood glucose, using parallel groups with ascending or descending glucose steps to minimise potential biases of a single stepped clamp order. METHODS: Following 14 days on placebo or glibenclamide (2.5 mg) tablets twice daily, separated by 14 days washout, 19 type 2 diabetic patients had ascending or descending three-step hyperinsulinaemic glucose clamps at 4, 8 and 12 mmol/l. C peptide secretion was estimated by two-compartment C-peptide deconvolution. RESULTS: Patients in the ascending glucose steps group (n = 10) had mean (SD) age of 60.3 (6.5) years, BMI of 29.8 (4.9) kg/m(2) and fasting glucose on diet alone of 10.6 (2.9) mmol/l; while those in the descending glucose steps group (n = 9) had mean age of 58.2 (8.0) years, BMI of 30.5 (5.4) kg/m(2) and fasting glucose on diet alone of 9.8 (2.2) mmol/l. The geometric means (95% CI) of C-peptide secretion rates on placebo for glucose at 4.0, 8.0 and 12.0 mmol/l were 63 (46, 86), 143 (105, 195) and 205 (149, 281) pmol/min, respectively. On glibenclamide, this increased by 140 (99, 181), 126 (85, 167) and 158 (117, 199) pmol/min, respectively (p < 0.001 vs placebo). The absolute increment was significant (p < 0.001) and independent of clamp glucose concentration (p = 0.54). The proportional increase was greater at 4 mmol/l: 2.8-fold (2.4, 3.2), compared with 1.8-fold (1.5, 2.0) and 1.7-fold (1.4, 1.9) at 8 and 12 mmol/l, respectively (p < 0.001). CONCLUSIONS/INTERPRETATION: At low-normal glucose, glibenclamide exerted a disproportionate effect on insulin secretion. This study highlights the risks of hypoglycaemia when aiming for tight glucose control on this agent. PMID- 25297576 TI - Synthesis and crystal chemistry of new ternary pnictides containing lithium- adding structural complexity one step at a time. AB - This study focuses on the exploration of the ternary systems A-Li-Pn with A = Ca Ba, Eu and Yb and Pn = As-Bi resulting in the extensions of the ALiPn series (A = Ca, Sr, Eu and Yb; Pn = As-Bi; orthorhombic Pnma) with the MgSrSi structure type and of the A3Li4Pn4 family (A = Ba, Eu; Pn = As-Bi; orthorhombic Immm) with the Zr3Cu4Si4 structure type, as well as the novel compound Eu4Li7Bi6 (monoclinic, C2/m) with its own structure type. The relevant structural relationships are discussed. The building blocks and the topology of the polyanionic networks among the three different structures are compared side-by-side. Electronic band structure calculations for EuLiSb, Eu3Li4Sb4 and Eu4Li7Bi6 are discussed; the magnetic susceptibility and resistivity of single-crystalline Eu3Li4Sb4 are also presented. PMID- 25297575 TI - Bochum ultrasound score versus clinical and electrophysiological parameters in distinguishing acute-onset chronic from acute inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: The aim of this study was to evaluate whether a nerve ultrasound score (Bochum ultrasound score, BUS), clinical, and electrophysiological parameters could distinguish subacute chronic (CIDP) from acute inflammatory demyelinating polyneuropathy (AIDP). METHODS: Phase 1: The charts of 35 patients with polyradiculoneuropathy were evaluated retrospectively regarding BUS, clinical, and electrophysiological parameters (A-waves, sural nerve sparing pattern, sensory ratio>1). Phase 2: All parameters were evaluated prospectively in 10 patients with subacute polyradiculoneuropathy. RESULTS: Phase 1: A sum score of >=2 points in BUS and the presence of sensory symptoms were significantly more frequent in the subacute CIDP group than in the AIDP group (P<0.001).The electrophysiological parameters showed no significant changes between the 2 groups. Phase 2: BUS (83.3%; 100%;), sensory symptoms (100%; 75%), absence of autonomic nervous system dysfunction (83.3%; 75%), or bulbar palsy (83.3%; 50%) showed the best sensitivity and specificity in distinguishing subacute CIDP from AIDP. CONCLUSIONS: BUS is a useful diagnostic tool for distinguishing subacute CIDP from AIDP. PMID- 25297574 TI - Interferon Gamma potentiates the injury caused by MPP(+) on SH-SY5Y cells, which is attenuated by the nitric oxide synthases inhibition. AB - This study examined whether the cytokine interferon (IFN) gamma plays a role in the injury of SH-SY5Y cells caused by MPP(+) (1-methyl-4-phenylpyridinium). First of all, IFN-gamma sensitized cells to the neurotoxin MPP(+), as determined by MTT (3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide) assay. MPP(+) injured cells showed higher reactive oxygen species (ROS) levels, which was reinforced by IFN-gamma. The injury triggered a marked expression of the neuronal NOS (nNOS) enzyme. L-NAME [N(omega)-nitro-L-arginine methyl ester, a non-specific NOS inhibitor] reestablished the cell viability after IFN-gamma challenging, and recovered cells from MPP(+) injury (95.0 vs. 84.7 %; P < 0.05). Seven-NI (7 nitroindazole, a nNOS inhibitor) protected cells against the injury by MPP(+) co administered with IFN-gamma. Both inhibitors restrained the apoptosis of SH-SY5Y cells caused by MPP(+)/IFN-gamma. Regarding oxidative stress, L-NAME and 7-NI attenuated the increase in ROS levels caused by MPP(+) (45.3 or 48.4 vs. 87.9 %, P < 0.05). Indeed, L-NAME was more effective than 7-NI for reducing oxidative stress caused by MPP(+) under IFN-gamma exposition. The nNOS gene silencing by small-interfering RNAs recovered cells challenged by IFN-gamma (24 h), or MPP(+) (8 h). In conclusion, IFN-gamma sensitizes cells to MPP(+)-induced injury, also causing an increase in ROS levels. Pretreating cells with L-NAME or 7-NI reverts both the oxidative stress and apoptosis triggered by the neurotoxin MPP(+). Taking together, our data reinforce that IFN-gamma and NOS enzymes play a role in oxidative stress and dopaminergic cell death triggered by MPP(+). PMID- 25297573 TI - Thiamine deficiency: an update of pathophysiologic mechanisms and future therapeutic considerations. AB - Thiamine is an essential vitamin that is necessary to maintain the functional integrity of cells in the brain. Its deficiency is the underlying cause of Wernicke's encephalopathy (WE), a disorder primarily associated with, but not limited to, chronic alcoholism. Thiamine deficiency leads to the development of impaired energy metabolism due to mitochondrial dysfunction in focal regions of the brain resulting in cerebral vulnerability. The consequences of this include oxidative stress, excitotoxicity, inflammatory responses, decreased neurogenesis, blood-brain barrier disruption, lactic acidosis and a reduction in astrocyte functional integrity involving a loss of glutamate transporters and other astrocyte-specific proteins which together contribute in a major way to the resulting neurodegeneration. Exactly how these factors acting in concert lead to the demise of neurons is unclear. In this review we reassess their relative importance in the light of more recent findings and discuss therapeutic possibilities that may provide hope for the future for individuals with WE. PMID- 25297577 TI - [Screening of common deafness gene mutations in 17 000 Chinese newborns from Chengdu based on microarray analysis]. AB - OBJECTIVE: To achieve early diagnosis for inheritable hearing loss and determine carrier rate of deafness causing gene mutations in order to provide information for premarital, prenatal and postnatal genetic counseling. METHODS: A total of 17 000 dried heel blood spots of normal newborns in Chengdu were collected with informed consent obtained from their parents. Genomic DNA was extracted from dried blood spots using Qiagen DNA extraction kits. Microarrays with 9 common mutation loci of 4 deafness-associated genes in Chinese population were used. Nine hot mutations including GJB2 (35delG, 176del16, 235delC and 299delAT), GJB3 (538C> T), SLC26A4 (IVS 7-2A> G, 2168A> G), and mitochondrial DNA 12S rRNA (1555A> G, 1494C> T) were detected by PCR amplification and microarray hybridization. Mutations detected by microarray were verified by Sanger DNA sequencing. RESULTS: Of the 17 000 new-borns, 542 neonates had mutations of the 4 genes. Heterozygous mutations of GJB2, at 235delC, 299delAT, and 176del16 were identified in 254, 55, and 15 newborns, respectively. Two newborns had homozygous mutation of GJB2, 235delC. Heterozygous mutations at 538C> T of GJB3, 2168A> G and IVS 7-2A> G of SLC26A4 were found in 23, 17 and 128 newborns, respectively. For mutation analysis of mitochondrial DNA 12S rRNA, 1494C> T and 1555A> G were homogeneous mutations in 4 and 42 neonates, respectively. In addition, 6 complexity mutations were detected, which demonstrated that one newborn had heterozygous mutations at GJB2 235delC and SLC26A4, IVS7-2A> G, one had heterozygous mutation GJB2 235delC and 12S rRNA homogeneous mutation, 1555 A> G, one heterozygous mutations at GJB2, 299delAT, and GJB3, 538C> T, one at GJB2, 299delAT and 12S rRNA, 1555 A> G, two at GJB2, 299delAT, and SLC26A4, IVS7-2A> G. All mutations as above were confirmed by DNA sequencing. CONCLUSION: The total mutation carrier rate of the 4 deafness genes is 3.19% in healthy newborns at Chengdu. Mutations of GJB2 and SLAC26A4 are major ones (86.5% of total). The mutation rate of mitochondrial DNA 12S rRNA is 2.710/00, which may have deafness induced by aminoglycoside antibiotics. Newborn screening for mutation of genes related to hereditary deafness plays an important role in the early detection and proper management for neonatal deafness as well as genetic counseling for premarital, prenatal and postnatal diagnosis. PMID- 25297578 TI - [A pedigree with familial polyposis coli and colon carcinoma]. PMID- 25297579 TI - [Analysis and prenatal diagnosis of deafness-related gene mutations in patients with nonsyndromic hearing loss]. AB - OBJECTIVE: To analyze deaf-related genes in patients with nonsyndromic hearing loss (NSHL) and set up a prenatal diagnosis system for such patients. METHODS: Nine NSHL families were collected. Potential mutations of GJB2 (35delG, 176del16, 235delC, 299delAT), SLC26A4 (2168A> G, IVS7-2A> G), GJB3 (538C> T) and mtDNA (1494C> T, 12S rRNA 1555A> G) were detected by direct sequencing. Maternal blood contamination was excluded prior to the testing. RESULTS: Sixteen patients from 4 families were detected with GJB2 mutations, 8 patients from 2 families were found with SLC26A4 mutations, and 4 patients from 2 families were found with mutations in mtDNA. For 2 patients from one remaining family, no mutations were found with above genes. CONCLUSION: A diagnostic system for NSHL has been established, which may provide a basis for prenatal diagnosis and genetic counseling to NSHL families. PMID- 25297580 TI - [Application of noninvasive fetal trisomy testing based on massively parallel sequencing for the detection of chromosomal deletions and duplications]. AB - OBJECTIVE: To assess the value of noninvasive fetal trisomy testing based on massively parallel sequencing for the detection of chromosomal deletions and duplications. METHODS: Peripheral venous blood was taken from pregnant women with a high risk. Free fetal DNA in maternal plasma was used for library construction and subjected to massively parallel sequencing. Positive results were validated by traditional karyotype analysis or array-CGH. Phenotype of the fetus was observed through patholoical evaluation. RESULTS: Thirteen out of 629 cases were suspected to harbor chromosomal aberrations, which included 9 aneuploid cases and 4 structural abnormalities. The latter included one case with dup (18q) (14.35 Mb), del (18q) (21.34 Mb), one with dup (3q) (35 Mb) and two with dup (7q) (7.0 Mb). Among these, dup (18q ) (14.35 Mb), del (18q) (21.34 Mb) and dup (3q) (35 Mb) were confirmed by karyotype analysis and patholoical evaluation. However, the two cases with dup (7q) were validated by karyotype analysis and array-CGH as false positives. The phenotype with the fetus also presented as normal. CONCLUSION: The introduction of maternal plasma sequencing for prenatal testing could dramatically improve the efficiency for detecting large, partial (> 10 Mb) chromosomal deletions and duplications. PMID- 25297581 TI - [Analysis of beta -thalassemia mutations in Guizhou Province]. AB - OBJECTIVE: To investigate the spectrum of beta -thalassemia mutations in Guizhou Province. METHODS: For 542 individuals suspected to have beta -thalassemia by decreased mean corpuscular volume (MCV) and corpuscle hemoglobin (MCH) by routine blood test and hemoglobin electrophoresis, reverse dot blot hybridization (RDB) was performed to detect 17 known beta -thalassemia mutations, including 8 common and 9 rare mutations. For cases where no mutation was identified, the entire human beta -globin gene was screened to find other rare mutations. The distribution and frequencies of detected beta -thalassemia mutations were then analyzed. RESULTS: A total of 460 individuals were diagnosed as beta -thalassemia by DNA analysis, which included 352 heterozygotes, 67 compound heterozygotes and 41 mutant homozygotes. A total of 12 beta -thalassemia mutations were detected in these individuals. The mutations have ranked from high to low frequency as: CD17 (40.74%), CD41-42 (33.69%), IVS-II-654 (13.76%), -28 (3.70%), beta E (3.35%), CD71-72(1.94%), CD43 (1.06%), IVS-I-1 (0.71%), CD27-28 (0.35%), -29(0.35%), CAP (0.18%), and CD121 (0.18%). The former six mutations have accounted for 97.18% of all. CD121 (GAA> TAA) detected from a heterozygote, as a dominant mutation, has been firstly found in the Chinese population. CONCLUSION: The spectrum of beta thalassemia in Guizhou Province showed certain distinct characteristics, with CD17 being the most common mutation. The newly discovered mutation of CD121 has expanded the spectrum of beta -thalassemia in Chinese population. Our result may provide valuable information for the prevention and control of beta -thalassemia in Guizhou. PMID- 25297582 TI - [Analysis of ornithine transcarbamylase gene mutations in three boys affected with late-onset ornithine transcarbamylase deficiency]. AB - OBJECTIVE: To identify the types of OTC gene mutations in three male patients with late onset ornithine transcarbamylase deficiency (OTCD, MIM #311250). METHODS: Genomic DNA was extracted from peripheral blood leukocytes. The 10 exons and their flanking sequences of the OTC gene were amplified with polymerase chain reaction and subjected to direct DNA sequencing. RESULTS: Based on DNA sequence analysis, all of the three patients have carried OTC gene mutations. Patients 1 and 2 were both hemizygous for mutation c.586G> A(p.D196N). A novel mutation c.800G> C(p.S267T) were confirmed in patient 3. CONCLUSION: p.S267T mutation has affected the conserved amino acid motif of the OTC protein, and is therefore a pathogenic mutation. PMID- 25297583 TI - [Analysis of clinical phenotype and genetic mutations of a pedigree of familial hemophagocytic lymphohistiocytosis]. AB - OBJECTIVE: To analyze mutations in a pedigree of familial hemophagocytic lymphohistiocytosis (FHLH) from Sichuan and provide genetic counseling for the family. METHODS: Clinical data of a case with FHLH diagnosed at West China Second Hospital was retrospectively analyzed. Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Eight candidate genes for primary HLH were amplified with PCR and analyzed by direct sequencing. RESULTS: The proband was diagnosed as HLH based on clinical manifestations of recurrent fever for 2 months, hepatosplenomegaly, lymphadenopathy, pancytopenia, hyperferritinemia, and decreased fibrinogen and hemophagocytosis in bone marrow. Genetic testing for primary HLH was carried out considering the relapse of illness after hormone therapy for 8 weeks and the family history. The results of gene sequencing showed that the proband has carried compound heterozygous mutations in PRF1 gene (c.1349C> T in exon 3 and c.445G> A in exon 2). His father has carried a heterozygous mutation (c.445G> A in exon 2) and nonsense mutation (c.900C> T in exon 3), and his mother carried a heterozygous mutation (c.1349C> T in exon 3). Both c.1349C> T and c.445G> A have been previously reported as pathogenic mutations. CONCLUSION: The family has been diagnosed as familial HLH type 2 based on clinical and laboratory examinations and molecular genetic testing. Gene sequencing has indicated that is was a recessive type familial HLH. PMID- 25297584 TI - [A novel mutation of NTRK1 gene in a family with congenital insensitivity to pain with anhidrosis]. AB - OBJECTIVE: To screen for mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1) gene in a Chinese family affected with congenital insensitivity to pain with anhidrosis (CIPA). METHODS: With informed consent obtained, peripheral blood samples were obtained from the patient and his family members. Seventeen coding exons and intron-exon boundaries of the NTRK1 gene were amplified with PCR and analyzed by direct sequencing. RESULTS: A novel mutation c.2086_2087insC (p.Arg696 fsx) was identified in exon 16 of the NTRK1 gene in the proband. This insertion has caused open reading frame shifting and a premature termination has occurred just one codon downstream. Truncation of 72 amino acids at the C terminus has wiped out part of the tyrosine kinase domain (TKD) of the protein. Both of the proband's parents and two grandmothers have carried the c.2086_2087insC (p.Arg696 fsx) mutation. No mutation was found in the NTRK1 gene of other siblings. CONCLUSION: Mutation analysis of the NTRK1 gene has been carried out in a Chinese family affected with CIPA, and a novel NTRK1 gene mutation was identified. PMID- 25297585 TI - [Identification of a novel NOTCH3 mutation in a family featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy]. AB - OBJECTIVE: To analyze potential mutations of NOTCH3 gene in a Chinese family featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL) in order to facilitate genetic counseling and prenatal diagnosis. METHODS: The proband and related family members and 100 healthy controls were recruited. The NOTCH3 gene was screened for mutations by polymerase chain reaction and direct DNA sequencing. PolyPhen-2 and SIFT software were used to predict the protein function. RESULTS: The proband and two affected individuals from the family were adult-onset, with main clinical manifestations including recurrent transient ischemic attacks and(or) strokes, cognitive impairment, memory decline, and depression. MRI findings suggested multiple cerebral infarcts and severe leukoencephalopathy. A novel heterozygous missense mutation c.3043T> A (p.Cys1015Ser) located in exon 19 of NOTCH3 gene was identified not only in the proband and two patients, but also in an asymptomatic relative from the family. The same mutation was detected in none of the 100 unrelated healthy controls. Function analysis suggested that this mutation can severely affect the functions of this protein. Multiple sequence alignment revealed that the mutation site was extremely conserved in various species. CONCLUSION: A novel heterozygous Cys1015Ser mutations in exon 19 of the NOTCH3 gene probably underlies the CADASIL in this family. PMID- 25297586 TI - [Application of methylation-specific multiplex ligation-dependent probe amplification for the study of DNA methylation in placenta tissues]. AB - OBJECTIVE: To study the feasibility of using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for the detection of DNA methylation in placenta tissue. METHODS: For blood cells from 13 non-pregnant women and 9 euploid placenta, the ratios of DNA methylation were evaluated for 4 genes including CGI149, CGI113, HLCS and ACTB with MS-MLPA and bisulfite sequencing, respectively. RESULTS: The methylation ratio of the ACTB gene was 0 0.1 for the blood cells when the digestion control was completely digested. The cutoff value for the methylation ratio of MS-MLPA has been determined as 0.1. For the 9 placenta samples, results of MS-MLPA and bisulfite sequencing were concordant for all of the four genes. CONCLUSION: MS-MLPA is an effective alternative to bisulfite sequencing for the assessment of methylation ratios in placental tissues. PMID- 25297587 TI - [Genome wide screening and characterization of long non-coding RNAs in esophageal cancer]. AB - OBJECTIVE: To screen for esophageal squamous cell carcinoma (ESCC)-associated long non-coding RNAs (lncRNA) and identify oncogenic lncRNA contributing to ESCC pathogenesis. METHODS: A lncRNA array containing 7419 lncRNA was used to detect the transcriptional profiles of lncRNA of four pairs of ESCC and matched normal esophageal tissue. Bioinformatic analysis was employed to identify differentially expressed ESCC associated lncRNA (ESCCAL). Quantitative real-time PCR was used to verify selected dysregulated lncRNA on independent ESCC samples. RESULTS: Genome wide transcriptome profiling (coding and or noncoding RNA transcripts) was able to distinguish ESCC from normal tissue. Among these, bioinformatic analysis has identified 154 differentially expressed ESCC associated lncRNA (ESCCALs), which included 111 downregulated and 43 upregulated lncRNA in ESCC relative to the normal tissue (P< 0.01). The highest upregulated lncRNA (ESCCAL_1) and known onco lncRNA HOTAIR was further verified in 26 paired ESCC samples. ESCCAL_1 and HOTAIR were found to be highly expressed in 17 ESCC and 18 ESCC compared with normal esophageal tissues. CONCLUSION: This investigation has revealed large scale aberrant expression of lncRNA in ESCC. About 70% of novel lncRNA-ESCCAL_1, together with a known lncRNA-HOTAIR, are highly expressed in ESSC, suggesting that ESCCAL_1 and HOTAIR may participate in the pathological process of ESCC. Furthermore, lncRNA could be potential diagnostic and prognostic biomarkers for ESCC. PMID- 25297588 TI - [Effect of alpha -1,2 fucosyltransferase gene 682A> G and 547_552delAG mutations on the activity of fucosyltransferase]. AB - OBJECTIVE: To explore the effect of alpha -1,2 fucosyltransferase (FUT1) gene 682A> G and 547_552delAG mutations on the expression of FUT1 mRNA and activity of alpha -1,2 fucosyltransferase. METHODS: Recombinant expression vectors of FUT1 682A> G and FUT1 547_552delAG were constructed and transfected into COS-7 cells for stable expression screening. Expression of FUT1 mRNA was determined using real-time quantitative PCR. The activity of FUT1 was measured with high performance liquid chromatography. RESULTS: Stably transfected COS-7 cells with wild type FUT1, FUT1 682A> G and FUT1 547_552delAG were respectively obtained. The FUT1 mRNA level of transfected cells with 682A> G and 547_552delAG recombination vectors have measured 101.69% and 102.79% compared with that of wild type FUT1 transfected cells. A specific protein band with about 46 kD was confirmed in the 682A> G transfected cell lysates by SDS-PAGE electrophoresis and Western blotting with 6* His Tag antibody. Similar protein was not identified in the 547_552delAG cells lysates. Enzymes activity of FUT1 682A> G has measured 61.01% compared with wild type FUT1 protein, whilst the activity of FUT1 547_557delAG was completely abolished. CONCLUSION: FUT1 682A> G and 547_552delAG mutations do not affect the transcript efficiency, although various mutations have different impact on the enzyme's activity. PMID- 25297589 TI - [PRRT2 gene-related paroxysmal disorders]. AB - Proline-rich transmembrane protein 2 (PRRT2), the causative gene of paroxysmal kinesigenic dyskinesias (PKD), benign familial infantile seizures (BFIS) and infantile convulsions with paroxysmal choreoathetosis (ICCA), also causes a variety of neurological paroxysmal disorders. These diseases share the same characteristics which may be due to the same genetic defect. We therefore propose to name them as PRRT2-related paroxysmal disorders (PRPDs) in order to assist clinical diagnosis, treatment and prognosis. This paper has reviewed the clinical phenotype, common features and pathogenesis of the PRPDs. PMID- 25297590 TI - [Research progress of TSPY1 gene family]. AB - TSPY1 (testis-specific protein, Y-linked 1) gene family, located in male-specific region of Y-chromosome (MSY), has the maximum number of copies organized as a long tandem repeat array in protein-coding gene families of human genome. TSPY1 is identified to be the most important candidate gene for gonadoblastoma, and its coding protein can promote the proliferation and differentiation of tumor cells. Recently, TSPY1 gene family is also proposed to play an important role in spermatogenesis. In this review, the structure characteristics of the gene family were illustrated, and the functional studies of TSPY1 in the process of tumorigenesis and spermatogenesis were discussed. PMID- 25297591 TI - [Analysis of SEDL gene mutation in a Chinese pedigree with X-linked spondyloepiphyseal dysplasia tarda]. AB - OBJECTIVE: To explore the molecular mechanism for a family with hereditary X linked spondyloepiphysealdysplasia tarda (SEDT). METHODS: For 3 affected males and 2 obligate carrier females from the family, exons 3 to 6 of SEDL gene were amplified with PCR and sequenced. RESULTS: In the three patients, a deletional mutation (c.267_271delAAGAC) in exon 5 has been identified, which has caused frameshift of the protein product. CONCLUSION: c.267_271delAAGAC frameshift mutation of the exon 5 of the SEDL gene probably underlies the disease in this family. PMID- 25297592 TI - [Clinical investigation and genetic analysis of a Chinese family with glutaric acidemia type I]. AB - OBJECTIVE: To review the clinical features of a families affected with glutaric acidemia type I (GA-1) and screen potential mutations in glutaryl-CoA dehydrogenase (GCDH) gene. METHODS: Clinical data of the patients and their family members was analyzed. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of the GCDH gene were amplified with PCR and subjected to direct DNA sequencing. RESULTS: Two patients have manifested macrocephaly. Imaging analysis revealed arachnoid cyst and subdural effusion. The elder sister had encephalopathy crisis. The younger sister had significantly raised glutaric acid, whilst the elder sister was normal during the non-acute phase. Genetic analysis has revealed a homozygous c.1244-2A> C mutation of the GCDH gene in both patients. CONCLUSION: The clinical features and mutation of the GCDH gene have been delineated in a Chinese family affected with GA-1. The c.1244 2A> C mutation may be particularly common in the Chinese population. PMID- 25297593 TI - [Genetic analysis of a novel mutation resulting in autosomal dominant osteopetrosis II]. AB - OBJECTIVE: To analyze potential mutation of chloride channel 7(CLCN7) gene in a patient with autosomal dominant osteopetrosis II (ADO II). METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and 100 healthy subjects. The DNA was used as template of polymerase chain reaction (PCR) to amplify the exons of CLCN7. Then the PCR products were sequenced to detect the mutation. RESULTS: A novel heterozygous deletional mutation (c.2460delA) was detected in exon 25 of the CLCN7 gene in the patient, which has resulted in substitution of Gly residue for Arg at position 784 of the CLCN7 protein and caused frame shift of the following 28 amino acids (Arg784GlyfsX29). The same mutation was not found in the healthy subjects. CONCLUSION: The ADO II in the patient probably results from a Arg784GlyfsX29 mutation in the CLCN7 gene. PMID- 25297594 TI - [Analysis of phenotype and genotype in a family with late infantile metachromatic leukodystrophy]. AB - OBJECTIVE: To study genotype-phenotype correlation of a family with late infantile metachromatic leukodystrophy(MLD). METHODS: Clinical data were collected and ARSA gene was tested by PCR and sequencing in a pedigree. RESULTS: The male proband onset with walking dysfunction at 19 months, arylsulfatase A activity of leucocyte from his peripheral blood was 20.2 nmol/mg.17h, and his cranial MRI showed wildly symmetrical demyelination. Homozygosis for novel c.622delC (p.His208Metfs46X) in exon 3 of ARSA gene was identified in proband, and heterozygous for the same mutation in parents and grandma of the proband. CONCLUSION: Late infantile metachromatic leukodystrophy is characterized by rapid and progressive regression of neuropsychiatric and motor development. There is a significant correlation between the mutation of c.622delC(p.His208Metfs*46) in the ARSA gene and the phenotype presenting as O/O patients. PMID- 25297596 TI - [Genotype and phenotype study of two patients with 22q11.2 deletion syndrome]. AB - OBJECTIVE: To carry out genetic analysis for two patients affected with congenital heart disease, developmental delay with or without cleft palate. METHODS: Cytogenetic and molecular genetic methods including karyotyping, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and single nucleotide polymorphisms array (SNP-array) were employed to detect potential mutations. For parents of both patients, MLPA was used to analyze whether they were carrier of the deletion. RESULTS: For neither patient, no abnormality was detected upon karyotype analysis. However, FISH analysis has indicated the presence of 22q11.2 deletion. SNP-array analysis has confirmed that both patients have carried a 2.5 Mb deletion in the 22q11.2 region. MLPA analysis suggested none of the parents has carried the same deletion. CONCLUSION: Although the phenotypes of our patients were not identical, they were both diagnosed as 22q11.2 deletion syndrome by multiple methods. The deletions in both cases were de novo in nature. Precise delineation of the genotype can facilitate better understanding of the patients' phenotype. PMID- 25297595 TI - [Mitochondrial DNA mutation associated with hypertension in tRNA(Ile) and tRNA(Gln) genes]. AB - OBJECTIVE: To study the relationship between mitochondrial DNA (mtDNA) mutations and hypertension. METHODS: Clinical data of two pedigrees with maternally transmitted hypertension was collected. Whole mtDNA sequence was analyzed. RESULTS: The family members on the maternal side presented with various levels of hypertension, with the onset age ranging from 44 to 55 years old. Analysis of the mtDNA sequence of the two families members showed all patients have carried a matrilineal 4329C> G mutation of the tRNA(Ile) and tRNA(Gln) genes. The same mutation was not found in 366 healthy controls. The 4329C site of mtDNA is highly conserved across species, and has been associated with the fidelity of amino acid accept arm of the tRNAs, as well as functionality and stability in the formation of tRNAs. CONCLUSION: The 4329C> G point mutation in tRNA(Ile) and tRNA(Gln) probably has contributed to the pathogenesis of hypertension, possibly in association with other modifying factors. PMID- 25297597 TI - [Significance of BCL6, MYC, P53 genes abnormalities for the prognosis of diffuse large B-cell lymphoma]. AB - OBJECTIVE: To explore the influence of BCL6, MYC, P53 genes abnormalities can on the prognosis of diffuse large B-cell lymphoma (DLBCL), and to identify independent prognostic factors for DLBCL in order to facilitate clinical prognosis and selection of stratification treatment for the patients. METHODS: Sixty five newly diagnosed DLBCL pathological specimens were collected from 2009 to 2012. Interphase fluorescence in situ hybridization technique (I-FISH) was used to detect the status of BCL6, MYC and P53 genes. Clinical factors were combined with immunohistochemical results for multiple-factor survival analysis. RESULTS: The rates of BCL6 gene rearrangement, P53 gene deletion and MYC rearrangement were 21.5% (14/65), 35.4% (23/65) and 7.7% (5/65), respectively. BCL6 rearrangement group has obviously poorer overall survival (OS)(P< 0.05). COX proportional hazards model analysis showed that gender, BCL6 protein, BCL6 rearrangement, Ki67 index were prognosis factors independent of international prognostic index (IPI). CONCLUSION: BCL6 can influence the prognosis of patients with DLBCL at gene and protein levels and both are independent prognostic factors for DLBCL. PMID- 25297598 TI - [Results of prenatal screening for fetal chromosome abnormality during the first trimester pregnancy in Guangzhou]. AB - OBJECTIVE: To evaluate the efficiency of first trimester prenatal screening for fetal chromosome abnormality using maternal serum marker test and(or) plus nuchal translucency (NT) in Guangzhou region. METHODS: The results of prenatal screening were retrospectively analyzed among 43 703 women with singleton pregnancies from January 2007 to September 2012. A total of 43 703 pregnancies between 9 and 13(+6) weeks of pregnancy were collected and analyzed for maternal serum pregnancy-associated plasma protein A (PAPPA), free beta -human chorionic gonadotropin (free beta -hCG) with or without crown-rump length (CRL). Nuchal translucency was measured by ultrasonographic scan between 11 and 13(+6) weeks of pregnancy. Gestational age was estimated by ultrasonographic scan. The risk values of Down syndrome (DS) and trisomy 18 were calculated using the software Lifcycle. Comparing the difference between the combined screening (PAPPA, free beta -hCG and NT) and serum marker screening (PAPPA and free beta -hCG). RESULTS: Among the 43 703 pregnant women, screening showed that 1385 (3.17%) were Down syndrome positive and 55 (0.13%) were trisomy 18 positive. The final outcomes of pregnancy showed that 142 cases presented chromosomal abnormalities, of which 54 cases suffered from Down syndrome, 13 had trisomy 18, and 75 had other chromosome abnormalities. The total detection rate of Down syndrome and trisomy 18 were 83.33% and 76.92%, respectively.The positive rate is lower, and the detection rate is higher in combined screening group than serum marker screening group. The median PAPPA MoM was lower and the median free beta -hCG MoM and NT measured value was higher in Down syndrome pregnancies than control group. The median PAPPA and free beta -hCG MoM were lower and the median NT measured value was higher in trisomy 18 pregnancies than control group. CONCLUSION: The first trimester prenatal screening can effectively detect Down syndrome and trisomy 18 pregnancy. The combined screening method is superior to the serum marker screening and is the preferred strategy in the first trimester prenatal screening. PMID- 25297599 TI - [Application of different technologies for distinguishing true and pseudo mosaicisms during prenatal diagnosis]. AB - OBJECTIVE: To use different technologies to distinguish true and pseudo mosaicisms among cultured amniocytes in order to attain more accurate diagnosis. METHODS: With informed consent, 20 mL of amniotic fluid was obtained from pregnant women at between 18 to 24 gestational week. Each amniotic fluid sample was processed as two separate lines for the culturing, observation, harvesting and analysis. All procedures were conducted conforming to the Technology Standards of Cytogenetic Prenatal Diagnosis of Fetal Chromosome Abnormalities issued by the Ministry of Health in 2010. Umbilical cord blood, fluorescence in situ hybridization (FISH), single nucleotide polymorphism array (SNP-array) and flow cytometer were applied when necessary. RESULTS: Among 3910 cases, 128(3.3%) were detected as mosaicisms. Further analysis with the above technologies has verified 6 cases as true mosaicisms and the remaining 120 as pseudomosaicisms. For one case detected by karyotype analysis as 47, XXY/46, XY, the ratio of different cell lines was confirmed by FISH as 1:2. Another case, detected by karyotype analysis as 47, XX,+mar/46, XX (1:1), was verified by SNP-array as 18p duplication. A suspected polyploidy mosaicism was rejected by flow cytometry and cord blood karyotyping. CONCLUSION: Two separate cell cultures are important for distinguishing true and pseudo mosaicisms. Combined FISH, SNP-array and flow cytometry can attain more reliable and accurate diagnosis for mosaicisms. PMID- 25297600 TI - [Molecular epidemiology analysis of glucose-6-phosphate dehydrogenase gene mutations among infertile patients in Shenzhen]. AB - OBJECTIVE: To explore the incidence and genotypes of glucose-6-phosphate dehydrogenase (G6PD) gene mutations among infertile patients in Shenzhen. METHODS: DNA samples from 851 infertile patients were tested for 25 G6PD gene mutation sites using a multiplex SNaPshot assay. RESULTS: The incidence of G6PD gene mutations among infertile patients in Shenzhen was 17.63%. Male and female abnormal rates were 15.13% and 20.09% respectively. Most of the female abnormal cases were heterozygotes. Mutations involved 11 haplotypes in 10 sites. 1311C> T/IVS-11 93T> C was the most common mutation, accounting for 72.00% (108/150) abnormal cases. Forty three cases of missense mutations were detected, including 19 cases of 1376G> T, 9 cases of 1388G> A, 5 cases of 95A> G and 871G> A/1311C> T/IVS-11 93T> C, 1 case of 202G> A, 835A> T, 1360C> T, 1376G> T and 392G> T/1311C> T/IVS-11 93T> C. CONCLUSION: The incidence of G6PD gene mutations among infertile patients in Shenzhen was high and the mutation types were various. Therefore, the G6PD deficiency genetic screening should be performed prior to assisted reproduction. This investigated results provided valuable basic data for genetic counseling, preimplantation genetic diagnosis and prenatal diagnosis. PMID- 25297601 TI - [Association of serotonin transporter linked polymorphic region 44 bp variable number of tandem repeat polymorphism with Tourette syndrome]. AB - OBJECTIVE: To assess the association between the serotonin transporter linked polymorphic region (5-HTTLPR) 44 bp variable number of tandem repeat (VNTR) polymorphism and Tourette syndrome (TS) in ethnic Han Chinese trios. METHODS: A total of 252 TS trios (patients and their parents) were recruited. Genetic contribution of the 5-HTTLPR 44 bp VNTR polymorphism was evaluated by genotyping, haplotype relative risk (HRR) analysis and transmission disequilibrium test (TDT) statistics. To enhance the efficiency of the test, haplotype-based HRR (HHRR) was also performed. RESULTS: The TDT, HRR and HHRR analyses have revealed a significant association of the 5-HTTLPR 44 bp VNTR polymorphism with TS, and provided a strong evidence for an over-transmission of L allele from parents to the affected children (TDT: chi2 = 6.680, df= 1, P= 0.012; HRR: chi2 = 9.345, P= 0.002, OR= 1.739, 95% CI for 1.218-2.483). For 204 male and 48 female TS trios, TDT and HRR were analyzed separately. The results showed a significant association between 5-HTTLPR and male TS (for males. TDT: chi2 = 4.643, df= 1, P= 0.038; for females, TDT: chi2 = 2.189, df= 1, P= 0.188). CONCLUSION: 5-HTTLPR may be the susceptibility gene for male TS patients among the Chinese Han population. However, the results need to be replicated in datasets collected from different populations. PMID- 25297602 TI - [Lack of association of COMT Val158Met polymorphism with attention and executive function in patients with schizophrenia]. AB - OBJECTIVE: To explore the association of a functional polymorphism Val158Met of COMT gene and attention and executive function in first-episode treatment-naive patients with schizophrenia and healthy controls. METHODS: Trail making test (TMT) and clinical performances were evaluated in 103 first-episode treatment naive patients with schizophrenia and 99 healthy controls. Polymorphism of COMT Val158Met was analyzed using polymerase chain reaction-restriction fragment length polymorphism method. A general linear model was used to investigate the effect of genotype subgroups on the attention and executive function. RESULTS: There was a significant difference between control subjects and patients with schizophrenia on the TMT-A and B. However, no significant difference among Val/Val, Val/Met and Met/Met on the TMT-A and B in control subjects and patients with schizophrenia was detected. CONCLUSION: The association among COMT Met variant and trail making testing (attention and executive function) has been replicated. However, no association of COMT Met variant with disruption of dopaminergic influence on neurocognitive function was detected. This may be due to the heterogeneity of population. PMID- 25297603 TI - [Expression pattern of congenital chloride diarrhea pathogenic gene Slc26a3 in the reproductive tract of male rodents]. AB - OBJECTIVE: To determine the expression pattern of Slc26a3 gene in reproductive tract of male rodents to clarify whether the expression pattern is related to the subfertility observed in congenital chloride diarrhea (CLD) disease. METHODS: The expression of Slc26a3 in mouse and rat epididymis has been studied with immunohistochemistry and Western blotting. Its developmental expression pattern in rat testis was detected by Western blotting, while both of immunofluorescence and Western blotting were used to localize the expression of Slc26a3 in mouse sperms. The potential change of Slc26a3 expression in CFTR (cystic fibrosis transmembrane conductance regulator) knockout mice and CFTR mutant mice was also detected with Western blotting. RESULTS: The expression level of Slc26a3 gradually decreased along epididymis from its caput to corpus, then to its cauda part. This gradually decreasing expression pattern was also found in rat testis during development. Slc26a3 was localized mainly on the trunk of mouse sperm tail. In the testis and epididymis of CFTR knockout mice and CFTR mutant mice, no significant change of Slc26a3 expression was found. CONCLUSION: Slc26a3 is expressed in male reproductive tract, and its expression pattern is related to the function. Thus, the subfertility observed in CLD disease may be related to the important role of SLC26A3 in acid-base regulation of epididymis. PMID- 25297604 TI - [Serological characteristic and molecular basis of A2 subgroup in Shanghai population]. AB - OBJECTIVE: To investigate the similarity and difference in blood group serology and molecular biology of A2 and A2B phenotypes between healthy blood donors and patients. METHODS: The A and AB phenotypes were screened with anti-A1. Exons 1 to 7 and intron 6 of the ABO gene were analyzed with polymerase chain reaction sequence-based typing (PCR-SBT) method. The blood type was determined by referring to the Blood Group Antigen Gene Mutation Database (BGMUT). RESULTS: Among 7111 tested individuals, 75 were assigned as A2 or A2B phenotypes. However, only 28 individuals still belonged to the A2-related allele group based on genetic analysis. Among these, A205/B101 was the most common genotype. Among those non-A2-related alleles, A102/B101 was the most common genotype. Based on serologic testing, there was an imbalance between the A2 and A2B subgroups. In both donor group and patient group, the proportion of A2B was significantly higher than that of the A2. There were statistical differences between different groups (chi2 = 64.613, 33.137, 34.963, P< 0.01). At the gene level, the imbalance still existed in both the overall population and the donor group, though there was a statistical difference between the two (chi2 = 17.678, 14.157, P< 0.01). The same imbalance did not exist in the patient group (with continuous correction, chi2 = 2.351, P= 0.125). CONCLUSION: The concordance rate for blood type determined by serology and genetic analysis has been low and deserves attention. For A2 and A2B phenotypes by serological screening, A102/B101 was the most common gene among non-A2-related alleles. Further study is needed to clarify this phenomenon. PMID- 25297605 TI - [Identification of a novel HLA allele HLA-DRB1*09:01:07]. AB - OBJECTIVE: To identify and confirm a novel HLA allele in a Chinese Han individual. METHODS: HLA typing was performed by polymerase chain reaction sequence specific oligonucleotide probes (PCR-SSOP) for HLA-A, -B and -DRB1 in a registered donor of China Marrow Donor Program(CMDP). Sequencing-based typing (SBT) was carried out to further confirm the novel allele of HLA-DRB1. RESULTS: The SSOP result showed HLA-DRB1*09:03,15GEP, but an unusual pattern that could not be defined indicated potential presence of a novel allele. The SBT result showed the novel sequence has 1nt change from its closest allele DRB1*09:01:02 at nt306 where C to T(codon 73 GCC to GCT) resulting in no amino acid change. 73A was not changed. CONCLUSION: A novel HLA allele, HLA-DRB1*09:01:07, has been identified and named officially by WHO Nomenclature Committee for Factors of the HLA System. PMID- 25297606 TI - [A family with early-onset Alzheimer disease]. PMID- 25297607 TI - [Hereditary spastic paraplegias: a family with seven affected members in four generations]. PMID- 25297609 TI - A case report: Blastic plasmacytoid dendritic cell neoplasm is misdiagnosed as breast infiltrating ductal carcinoma. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic tumor that typically occurs in older adults. Patients with BPDCN usually present with solitary or multiple skin lesions. Localized or disseminated lymphadenopathy at presentation is common. A case report illustrating histopathologically proven BPDCN initially misdiagnosed as breast infiltrating ductal carcinoma in a 39-year-old woman is presented. In this case, the patient presented with a breast mass without an obvious skin lesion initially. The morphology of the tumor cells mimicked high grade breast carcinoma cells. Without complete immunohistochemical study, this case was initially misdiagnosed as infiltrating ductal carcinoma. Reviewing the previous literature about BPDCN, no case with a breast mass and an absence of characteristic skin lesions initially has been reported. The purpose for which we are discussing this case is to reduce misdiagnosis when the initial symptom is unusual. PMID- 25297608 TI - Reduced expression of SOX7 in ovarian cancer: a novel tumor suppressor through the Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Products of the SOX gene family play important roles in the life process. One of the members, SOX7, is associated with the development of a variety of cancers as a tumor suppression factor, but its relevance with ovarian cancer was unclear. In this study, we investigated the involvement of SOX7 in the progression and prognosis of epithelial ovarian cancer (EOC) and the involved mechanisms. METHODS: Expression profiles in two independent microarray data sets were analyzed for SOX7 between malignant and normal tissues. The expression levels of SOX7 in EOC, borderline ovarian tumors and normal ovarian tissues were measured by immunohistochemistry. We also measured levels of COX2 and cyclin-D1 to examine their possible involvement in the same signal transduction pathway as SOX7. RESULTS: The expression of SOX7 was significantly reduced in ovarian cancer tissues compared with normal controls, strongly indicating that SOX7 might be a negative regulator in the Wnt/beta-catenin pathway in ovarian cancer. By immunohistochemistry staining, the protein expression of SOX7 showed a consistent trend with that of the gene expression microarray analysis. By contrast, the protein expression level of COX2 and cyclin-D1 increased as the tumor malignancy progressed, suggesting that SOX7 may function through the Wnt/beta-catenin signaling pathway as a tumor suppressor. In comparison between the protein expression levels of SOX7 with pathological features of the cancer, we found that SOX7 was down-regulated mainly in serous cystadenocarcinoma and advanced stages of the cancers. CONCLUSIONS: The expression of SOX7 correlates with tumor progression as a tumor suppressor, possibly through the Wnt/beta-catenin signaling pathway in ovarian cancers, suggesting that SOX7 may be a promising prognostic marker. PMID- 25297610 TI - No enhancing effect of vitamin A administration on iron absorption or body total iron content in preschool children from Chengdu, China. AB - To explore the effect of vitamin A supplements on iron metabolic homeostasis for preschoolers. This was a randomized, placebo-controlled and blinded intervention trial with 3- to 6-y old preschoolers. A total of 445 subjects were randomly divided into four groups: a vitamin A supplementation group (group 1, a single oral dose of vitamin A as retinol 200,000 IU), an iron supplement group (group 2, daily oral supplement with the elemental iron 1-2 mg/kg/d for 5 d a week, lasting for 6 mo) a combined vitamin A and iron (group 3) and administration of no vitamin A or iron as a placebo-control (group 4). A total of 387 (95, 98, 90 and 104 from groups 1, 2, 3 and 4) children completed the intervention. After intervention, serum retinol levels of children in group 1 and group 3 was markedly higher than those of children in groups 2 and 4 (p<0.05). The serum ferritin level of children in group 1 significantly decreased after intervention (p<0.05), but increased in group 2 (p<0.05). The sTfR-SF index (TFR-F) and total body iron content (BTIC) showed the same change after intervention. In group 2 and group 3, the levels of TRF-F index and BTIC had statistically increased to the same degree after intervention (p<0.05). The impact of vitamin A intervention on iron metabolic homeostasis was mainly manifested in storage and mobilization; there was no direct effect on total body iron content or iron absorption in the intestine. PMID- 25297611 TI - A cross-sectional study to find out the relationship of methylenetetrahydrofolate reductase (MTHFR) C677T genotype with plasma levels of folate and total homocysteine by daily folate intake in Japanese. AB - In those with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, enzyme activity is lowered. Therefore, these individuals might require an increased intake of folate to maintain or control blood levels of plasma folate or total homocysteine (tHcy). We examined associations of dietary folate intake with fasting plasma folate and total homocysteine (tHcy) according to genotype among 554 Japanese (207 men and 347 women aged 39-89 y) recruited in 2009. Intake of folate was estimated with a food frequency questionnaire. The MTHFR polymorphism was genotyped by a polymerase chain reaction with confronting two pair primers. The log-transformed concentration of folate or tHcy was regressed on energy-adjusted folate intake in a linear regression analysis. Higher folate intake was associated with higher plasma folate among those with the CC (beta=0.165, p=0.066) or CT (beta=0.248, p<0.001) genotypes, and with lower tHcy levels only among those with the CC (beta=-0.141, p=0.013) genotype. Plasma folate was significantly and inversely associated with tHcy, irrespective of MTHFR genotype. When the analysis was restricted to those with tHcy levels higher than the reference range (>=13.5 nmol/mL, n=20), these significant associations were not found. The interaction between folate intake or plasma folate and genotype was not significant in any analysis. In conclusion, dietary folate intake was positively associated with plasma folate among those with the CC or CT genotypes and inversely associated with tHcy among those with the CC genotype, but the associations were not clear among those with higher levels of tHcy. PMID- 25297612 TI - The association between vitamin E intake and hypertension: results from the re analysis of the National Health and Nutrition Survey. AB - Recently, there has been an increasing concern about noncommunicable diseases (NCDs), in which oxidative damage plays a role. In this paper, we have re analyzed the data from the National Health and Nutrition Survey (NHNS) 2007 to study the relationship between an NCD (e.g. hypertension) and the dietary intake of vitamin E, a potent anti-oxidative vitamin. The inclusion criteria were those aged 40 and over, excluding pregnant or lactating women, and data from 1,405 males and 2,102 females were analyzed. The mean ages were 63.5 and 62.4, respectively. Nutrients intake was evaluated from a semi-weighted, 1-d household dietary record. When the subjects were categorized into tertiles based on their vitamin E intake, higher vitamin E intake was associated with a lower percentage of subjects with hypertension (p for trend=0.01). Subjects with higher vitamin E intake had higher energy intake-adjusted intake of other nutrients which have been considered to be related to hypertension such as potassium, magnesium, and vitamin C. Logistic regression analysis was done with the low tertile of vitamin E intake as the reference. The medium and high tertiles of vitamin E intake were associated with a significantly lower odds ratio for hypertension, 0.73 (95% CI; 0.62-0.87) for the former and 0.81 (95% CI; 0.69-0.96) for the latter. Additional analyses, one adjusted for the indices associated with hypertension and one excluding the subjects with vitamin E supplementation, have yielded the similar results. In summary, re-analysis of data from NHNS has revealed that higher vitamin E intake was significantly associated with lower prevalence of hypertension. PMID- 25297613 TI - Evaluation of the relative available energy of several dietary fiber preparations using breath hydrogen evolution in healthy humans. AB - A standardized simple, indirect method for assessing the relative energy of dietary fiber carbohydrates is not yet established. There is a need for a standardized in vivo assay. The objective of the present study was to evaluate the relative available energy (RAE) for 9 major dietary fiber materials (DFMs) based on fermentability from breath hydrogen excretion (BHE) in subjects. Fructooligosaccharide (FOS) was used as a reference. The study was conducted using a within-subject, repeated measures design and approved by the Ethical Committee of University of Nagasaki. After DFM ingestion, end-expiratory gas (750 mL) was collected at 1-h intervals for 8 h, as well as at 2-h intervals between 8 h and 14 h, and 30 min after waking up and 24 h after DFM ingestion. Breath hydrogen concentration was assessed with a gas chromatograph. The RAE of DFMs tested was evaluated based on the area under the curve (AUC) of BHE of FOS. Based on the ratio of AUC for 8 h, the RAE of polydextrose, partially hydrolysed guar gum, resistant maltodextrin and partially hydrolysed alginate was 1 kcal/g, and that of glucomannan, heat-moisture treatment and high-amylose cornstarch and cellulose was 0 kcal/g, while the RAE of all tested DEMs including cellulose and glucomannan was 1 kcal/g in the calculation based on AUCs for 14 h and 24 h in subjects. We suggest that a breath hydrogen collection period of 14 h or more could be used to measure RAE for a range of fiber preparations in vivo. PMID- 25297614 TI - Time-dependent effects of L-tryptophan administration on urinary excretion of L tryptophan metabolites. AB - We have previously reported that dietary supplementation with up to 5.0 g/d of L tryptophan (L-Trp) for 21 d has no adverse effects, judging from the levels of general blood variables, in healthy women. We performed a randomized, double blind, placebo-controlled, crossover intervention study in 17 apparently healthy Japanese women. The subjects were randomly assigned to receive a placebo (0 g/d) or 1.0, 2.0, 3.0, 4.0, or 5.0 g/d of L-Trp for 21 d each with a 5-wk washout period between trials. We examined the 24-h urine profiles on days -1 (1 d before starting L-Trp), 7, 14, and 21 to determine whether administration of L-Trp at doses of up to 5.0 g/d affects time-dependent urinary excretion of L-Trp or its metabolites in healthy women. The urinary excretion of L-Trp, kynurenic acid, 3 hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid, quinolinic acid, N(1)-methylnicotinamide, N(1)-methyl-2-pyridone-5-carboxamide, and N(1)-methyl-4 pyridone-3-carboxamide increased in an L-Trp dose-dependent manner on day 7. The amount of urinary excretion of these compounds was unchanged on days 14 and 21. The urinary excretion of serotonin, 5-hydroxyindole-3-acetic acid, 2-oxoadipic acid, and nicotinamide was unaffected by L-Trp at any of the doses tested. L-Trp doses had weak effects on the urinary excretion of kynurenine and anthranilic acid. Based on these findings, we conclude that there are no time-dependent effects of L-Trp administration in urinary excretion of L-Trp metabolites. Additionally, L-Trp and its metabolites do not accumulate in the body. PMID- 25297615 TI - The urinary ratio of 3-hydroxykynurenine/3-hydroxyanthranilic acid is an index to predicting the adverse effects of D-tryptophan in rats. AB - The adverse effects of D-tryptophan and the possibility of it being a surrogate index for predicting adverse effects in rats were investigated. Male rats were fed one of several test diets (20% casein diets with 0% (control), 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% D-tryptophan) for 21 d, and 24-h urine samples on the final day of the experiment were collected. Analyses of food intake and body-weight changes revealed adverse effects to be observed in the group fed the 0.3% D tryptophan diet. We propose urinary levels of 3-hydroxykynurenine/3 hydroxyanthranilic acid to be surrogate indicators for predicting the adverse effects of D-tryptophan from the break point of body-weight gains and urinary levels of D-tryptophan metabolites. The reaction 3-hydroxykynurenine->3 hydroxyanthranilic acid is catalyzed by the pyridoxal phosphate-dependent enzyme kynureninase. Increasing urinary 3-hydrokykynurenine indicates kynureninase deficiency. Intake of D-tryptophan in rats fed the 0.3% D-tryptophan diet was 0.21 g/kg body weight and feeding of the 0.3% D-tryptophan diet did not elicit adverse effects. Thus, the safe level of D-tryptophan was less than 0.2% in the diet, 0.15 g/kg body weight, in rats. PMID- 25297616 TI - Maternal vitamin D deficiency in early pregnancy is not associated with gestational diabetes mellitus development or pregnancy outcomes in Korean pregnant women in a prospective study. AB - The association between vitamin D deficiency in the first trimester and GDM development remains controversial in various ethnicities. We prospectively assessed whether pregnant women with vitamin D deficiency during early pregnancy had an increased likelihood of GDM development or poor fetal growth or pregnancy outcomes compared to those with sufficient vitamin D levels. Serum 25-OH-D measurements and fetal ultrasonograms were carried out at 12-14, 20-22, and 32-34 wk in 523 pregnant women. Each woman was screened for GDM at 24-28 wk. There were no differences in serum 25-OH-D levels at 12-14 wk or 22-24 wk of pregnancy between GDM and non-GDM women after adjusting for maternal age, BMI at prepregnancy, BMI at first visit, BMI at GDM screening, gestational age at sampling, previous history of GDM, vitamin D intake, and seasonal variation in sampling. The risk of GDM, insulin resistance, and impaired beta-cell function had no association with serum 25-OH-D levels in crude or adjusted logistic regression analysis. GDM was not associated with maternal serum 25-OH-D deficiency during the first trimester or fetal growth during the first and second trimesters. Pregnancy outcomes such as miscarriage, Apgar 1, Apgar 5 and birth weight were independent of maternal serum 25-OH-D levels during the first, second and third trimester of pregnancy. In conclusion, neither GDM prevalence nor fetal growth during pregnancy is associated with vitamin D deficiency at the first trimester in Korean women. Pregnancy outcomes are also independent of maternal vitamin D status. PMID- 25297617 TI - Resveratrol inhibits hypoxia-inducible factor-1alpha-mediated androgen receptor signaling and represses tumor progression in castration-resistant prostate cancer. AB - Androgen-dependent prostate cancer inevitably progresses to incurable castration resistant prostate cancer (CRPC) after androgen deprivation therapy. Because castration-induced hypoxia-inducible factor (HIF)-1alpha enhances the transcriptional activity of androgen receptor (AR) at low androgen levels mimicking the castration-resistant stage, HIF-1alpha is expected to be a promising target for suppression of growth of CRPC. We investigated the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene) on the growth of human prostate cancer LNCaP xenografts in castrated male BALB/cSlc-nu/nu mice (5 wk old). The mice were administered a control diet or a resveratrol diet (4 g/kg diet) for 40 d. The resveratrol diet significantly suppressed tumor growth compared to the control diet. In LNCaP xenografts, dietary resveratrol decreased the protein level of HIF-1alpha, but not the AR coactivator beta-catenin, and reduced the mRNA levels of androgen-responsive genes. In the control group, beta-catenin was predominantly localized in the nucleus with HIF-1alpha in LNCaP xenografts, whereas dietary resveratrol inhibited the nuclear accumulation of beta-catenin. In hypoxic LNCaP cells at a low androgen level mimicking the castration-resistant stage, hypoxia-induced nuclear accumulation of beta-catenin was inhibited by resveratrol. Furthermore, resveratrol repressed the expression level of HIF 1alpha even in the presence of a proteasome inhibitor and suppressed hypoxia enhanced AR transactivation. These results indicate that dietary resveratrol represses nuclear localization of beta-catenin by decreasing the HIF-1alpha expression, perhaps in a proteasome-independent manner, and inhibits beta-catenin mediated AR signaling; this contributes to suppression of tumor growth of CRPC. PMID- 25297618 TI - Effects of enzyme-treated asparagus extract on heat shock protein 70, stress indices, and sleep in healthy adult men. AB - Enzyme-treated asparagus extract (ETAS) has been developed as a novel anti-stress functional food ingredient that is produced from asparagus. Two human intervention trials with ETAS were conducted in healthy adult male volunteers. Study 1 was a randomized, double-blind, placebo-controlled study to assess the effects of ETAS on expression of heat shock protein 70 (HSP70) mRNA in blood and the autonomic nervous system (ANS). The ETAS group showed a tendency to enhance HSP70 mRNA expression level compared to the placebo group. Several ANS condition parameters were significantly improved in the ETAS group when compared to the placebo group. In Study 2, a randomized, double-blind, placebo-controlled, crossover trial investigated the influence on stress-related hormones and sleep. Serum and salivary cortisol levels were significantly elevated compared to baseline during the placebo period, but remained unchanged during the ETAS period. The salivary chromogranin A level was significantly decreased in the ETAS treated subjects compared to their baseline levels. The actual sleep time was not significantly different between ETAS and placebo. However, when the subjects were divided into two categories based on sleep efficiency or the average of night sleeping time, ETAS intake was effective to modulate the sleep state among those with low sleep efficiency or excess sleep time. PMID- 25297619 TI - S-equol enantioselectively activates cAMP-protein kinase A signaling and reduces alloxan-induced cell death in INS-1 pancreatic beta-cells. AB - S-Equol is enantioselectively produced from the isoflavone daidzein by gut microflora and is absorbed by the body. An increase of pancreatic beta-cell death is directly associated with defects in insulin secretion and an increased risk of type 2 diabetes mellitus. In the present study, we demonstrate that only the S enantiomer has suppressive effects against alloxan-induced oxidative stress in INS-1 pancreatic beta-cells. S-Equol reduced alloxan-induced cell death in a dose dependent manner, whereas R-equol had no effects. In contrast, no significant differences were observed between the enantiomers in estrogenic activity. The cytoprotective effects of S-equol were stronger than those of its precursor daidzein and were blocked by the protein synthesis inhibitor cycloheximide. The cytoprotection was diminished when cells were incubated with a protein kinase A (PKA) inhibitor (H89), but not an estrogen receptor inhibitor. S-Equol increased intracellular cAMP levels in an enantioselective manner. S-Equol, but not R equol, induced phosphorylation of cAMP-response element-binding protein at Ser 133, and induced cAMP-response element-mediated transcription, both of which were diminished in the presence of H89. Taken together, these results show that S equol enantioselectively increases the survival of INS-1 cells presumably through activating PKA signaling. Thus, S-equol might have applications as an anti-type 2 diabetic agent. PMID- 25297620 TI - Dietary D-sorbose decreases serum insulin levels in growing Sprague-Dawley rats. AB - D-Sorbose is naturally occurring rare sugar. In this study, we examined the effects of dietary D-sorbose in rats. Four-week-old male Sprague-Dawley rats were fed either an AIN-93G-based control diet or a 3% D-sorbose diet for 28 d. Body weight and body fat accumulation were not different between the two diet groups. Dietary supplementation of D-sorbose lowered the serum insulin level (*p<0.05) significantly compared to the control, although the glucose was not changed. In addition, the relative weight of the cecum increased significantly in the D sorbose group (**p<0.01). These findings suggest that intake of D-sorbose may improve the glucose metabolism by reducing insulin secretion, and D-sorbose can be used as a food ingredient. PMID- 25297621 TI - In vivo digestibility of rice prolamin/protein body-I particle is decreased by cooking. AB - Rice has storage proteins, e.g., glutelin, globulin and prolamin, in the seeds, which are used as nitrogen sources during germination. Rice prolamin has been reported to be an indigestible protein that decreases the nutritional value of rice. However, the causes for the indigestibility of prolamin are currently not clear. The objective of this study was to determine if prolamin is naturally indigestible or if cooking affects its digestibility. The gastrointestinal (GI) transit of rice 23 kDa glutelin (23G) and 13 kDa prolamin (13P) in Wistar/ST rats fed raw rice (RR) and cooked rice (CR) diets was assessed using Western blot analysis. We also measured the excretion of these proteins in the feces of these rats. Additionally, morphological observation of the structure of type-I protein bodies in the feces was performed using electron microscopy. Assessment of GI transit revealed that 23G rapidly disappeared from the GI contents of both the RR and CR groups, but 13P accumulated in the cecum of the CR group. In the CR group, prolamin, maintaining the structure of PB-I, was fully excreted in the feces. These results indicate that rice prolamin is not indigestible by nature, but is rendered indigestible by cooking. PMID- 25297622 TI - Too soon to discard advice against saturated fats, professors say. PMID- 25297623 TI - Binding to Cep164, but not EB1, is essential for centriolar localization of TTBK2 and its function in ciliogenesis. AB - Primary cilia are formed by extending the microtubule-based axoneme from the mother centriole-derived basal body. Recruitment of Tau tubulin kinase-2 (TTBK2) to the mother centriole and subsequent removal of CP110 and its interactor Cep97 are crucial for the initiation of ciliogenesis. We analyzed the roles of two TTBK2-binding proteins, EB1 and Cep164, in centriolar localization of TTBK2. TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline-rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline-rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Depletion of TTBK2 inhibited CP110 removal and ciliogenesis, whereas expression of wild-type TTBK2, but not non-Cep164 binding mutants, rescued CP110 removal and ciliogenesis in TTBK2-depleted cells. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled-3 (an important regulator of ciliogenesis) in a kinase activity-dependent manner. PMID- 25297624 TI - Controlling an electron-transfer reaction at a metal surface by manipulating reactant motion and orientation. AB - The loss or gain of vibrational energy in collisions of an NO molecule with the surface of a gold single crystal proceeds by electron transfer. With the advent of new optical pumping and orientation methods, we can now control all molecular degrees of freedom important to this electron-transfer-mediated process, providing the most detailed look yet into the inner workings of an electron transfer reaction and showing how to control its outcome. We find the probability of electron transfer increases with increasing translational and vibrational energy as well as with proper orientation of the reactant. However, as the vibrational energy increases, translational excitation becomes unimportant and proper orientation becomes less critical. One can understand the interplay of all three control parameters from simple model potentials. PMID- 25297625 TI - A phasin with extra talents: a polyhydroxyalkanoate granule-associated protein has chaperone activity. AB - Phasins are proteins associated to intracellular polyhydroxyalkanoate granules that affect polymer accumulation and the number and size of the granules. Previous work demonstrated that a phasin from Azotobacter sp FA-8 (PhaPAz ) had an unexpected growth-promoting and stress-protecting effect in Escherichia coli, suggesting it could have chaperone-like activities. In this work, in vitro and in vivo experiments were performed in order to investigate this possibility. PhaPAz was shown to prevent in vitro thermal aggregation of the model protein citrate synthase and to facilitate the refolding process of this enzyme after chemical denaturation. Microscopy techniques were used to analyse the subcellular localization of PhaPAz in E. coli strains and to study the role of PhaPAz in in vivo protein folding and aggregation. PhaPAz was shown to colocalize with inclusion bodies of PD, a protein that aggregates when overexpressed. A reduction in the number of inclusion bodies of PD was observed when it was coexpressed with PhaPAz or with the known chaperone GroELS. These results demonstrate that PhaPAz has chaperone-like functions both in vitro and in vivo in E. coli recombinants, and suggests that phasins could have a general protective role in natural polyhydroxyalkanoate producers. PMID- 25297626 TI - Competency of different cell models to predict human hepatotoxic drugs. AB - INTRODUCTION: The liver is the most important target for drug-induced toxicity. This vulnerability results from functional liver features and its role in the metabolic elimination of most drugs. Drug-induced liver injury is a significant leading cause of acute, chronic liver disease and an important safety issue when developing new drugs. AREAS COVERED: This review describes the advantages and limitations of hepatic cell-based models for early safety risk assessment during drug development. These models include hepatocytes cultured as monolayer, collagen-sandwich; emerging complex 3D configuration; liver-derived cell lines; stem cell-derived hepatocytes. EXPERT OPINION: In vitro toxicity assays performed in hepatocytes or hepatoma cell lines can potentially provide rapid and cost effective early feedback to identify toxic candidates for compound prioritization. However, their capacity to predict hepatotoxicity depends critically on cells' functional performance. In an attempt to improve and prolong functional properties of cultured cells, different strategies to recreate the in vivo hepatocyte environment have been explored. 3D cultures, co-cultures of hepatocytes with other cell types and microfluidic devices seem highly promising for toxicological studies. Moreover, hepatocytes derived from human pluripotent stem cells are emerging cell-based systems that may provide a stable source of hepatocytes to reliably screen metabolism and toxicity of candidate compounds. PMID- 25297627 TI - Determinants of valid measurements of global changes in 5'-methylcytosine and 5' hydroxymethylcytosine by immunolocalisation in the early embryo. AB - A classical model of epigenetic reprogramming of methyl-cytosine-phosphate guanine (CpG) dinucleotides within the genome of the early embryo involves a process of active demethylation of the paternally derived genome immediately following fertilisation, creating marked asymmetry in global cytosine methylation levels in male and female pronuclei, followed by passive demethylation of the maternally derived genome over subsequent cell cycles. This model has dominated thinking in developmental epigenetics over recent decades. Recent re-analyses of the model show that demethylation of the paternally derived genome is more modest than formerly thought and results in overall similar levels of methylation of the paternal and maternal pronuclei in presyngamal zygotes, although there is little evidence for a pervasive process of passive demethylation during the cleavage stage of development. In contrast, the inner cell mass of the blastocyst shows some loss of methylation within specific classes of loci. Improved methods of chemical analysis now allow global base-level analysis of modifications to CpG dinucleotides within the cells of the early embryo, yet the low cost and convenience of the immunolocalisation techniques mean that they still have a valuable place in the analysis of the epigenetics of embryo development. In this review we consider the key strengths and weaknesses of this methodology and some factors required for its valid use and interpretation. PMID- 25297628 TI - HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization. AB - The kinase PRKD2 (protein kinase D) is a crucial regulator of tumor cell endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here, we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of hypoxia-inducible factor 1alpha (HIF1alpha) and activation of NF-kappaB in tumor cells. Notably, ectopic expression of PRKD2 was able to partially restore HIF1alpha and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-kappaB/VEGF-A signaling axis to promote tumor angiogenesis and tumor growth. PMID- 25297629 TI - MHC-restricted phosphopeptides from insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer. AB - Cancer cells display novel phosphopeptides in association with MHC class I and II molecules. In this study, we evaluated two HLA-A2-restricted phosphopeptides derived from the insulin receptor substrate (IRS)-2 and the cell-cycle regulator CDC25b. These proteins are both broadly expressed in multiple malignancies and linked to cancer cell survival. Two phosphopeptides, termed pIRS-21097-1105 and pCDC25b38-46, served as targets of strong and specific CD8 T-cell memory responses in normal human donors. We cloned T-cell receptor (TCR) cDNAs from murine CD8 T-cell lines specific for either pIRS-21097-1105 or pCDC25b38-46. Expression of these TCRs in human CD8 T cells imparted high-avidity phosphopeptide-specific recognition and cytotoxic and cytokine-secreting effector activities. Using these cells, we found that endogenously processed pIRS-21097 1105 was presented on HLA-A2(+) melanomas and breast, ovarian, and colorectal carcinomas. Presentation was correlated with the level of the Ser(1100) phosphorylated IRS-2 protein in metastatic melanoma tissues. The highest expression of this protein was evident on dividing malignant cells. Presentation of endogenously processed pCDC25b38-46 was narrower, but still evident on HLA A2(+) melanoma, breast carcinoma, and lymphoblastoid cells. Notably, pIRS-21097 1105-specific and pCDC25b38-46-specific TCR-expressing human CD8 T cells markedly slowed tumor outgrowth in vivo. Our results define two new antigens that may be developed as immunotherapeutic agents for a broad range of HLA-A2(+) cancers. PMID- 25297630 TI - CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. AB - Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8(+) T cells restored combinatorial efficacy. Furthermore, ablation of CD8(+) T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8(+) CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8(+) T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses. PMID- 25297631 TI - Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNgamma. AB - Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNgamma receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting. PMID- 25297632 TI - ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy. AB - Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2alpha in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2alpha stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2alpha and that targeting ITPR1 significantly increased susceptibility of 786 0 cells to NK-mediated lysis. Mechanistically, HIF2alpha in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK-mediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2alpha, the ITPR1 related pathway, and natural immunity and strongly suggest a role for the HIF2alpha/ITPR1 axis in regulating RCC cell survival. PMID- 25297633 TI - Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers. AB - Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Furthermore, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation, and this effect was suppressed by Hh inhibition. Our results demonstrate that Gli1 that is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy, where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy. PMID- 25297636 TI - Insights into an autonomously formed oxygen-evacuated Cu2O electrode for the selective production of C2H4 from CO2. AB - Electrochemical conversion of carbon dioxide (CO2) to small organic fuels (e.g. formate, methanol, ethylene, ethanol) is touted as one of the most promising approaches for solving the problems of climate change and energy security. In this study, we report the highly efficient electrochemical reduction of CO2 using cuprous oxide (Cu2O) electrodes to produce ethylene (C2H4) primarily. During CO2 electrolysis using electrodeposited Cu2O on a carbon electrode, we observe the transformation of a compact metal oxide layer to a metal oxide structure with oxygen vacant sites at the bulk region. In contrast to previous studies, our results clearly indicate that Cu2O remains at the surface of the catalyst and it efficiently catalyzes the conversion process of CO2 at low overpotential, exhibiting a high selective faradaic efficiency of over 20% towards C2H4 formation even in long-term electrolysis. PMID- 25297634 TI - Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. AB - Metabolic heterogeneity is a key factor in cancer pathogenesis. We found that a subset of BRAF- and NRAS-mutant human melanomas resistant to the MEK inhibitor selumetinib displayed increased oxidative phosphorylation (OxPhos) mediated by the transcriptional coactivator PGC1alpha. Notably, all selumetinib-resistant cells with elevated OxPhos could be resensitized by cotreatment with the mTORC1/2 inhibitor AZD8055, whereas this combination was ineffective in resistant cell lines with low OxPhos. In both BRAF- and NRAS-mutant melanoma cells, MEK inhibition increased MITF expression, which in turn elevated levels of PGC1alpha. In contrast, mTORC1/2 inhibition triggered cytoplasmic localization of MITF, decreasing PGC1alpha expression and inhibiting OxPhos. Analysis of tumor biopsies from patients with BRAF-mutant melanoma progressing on BRAF inhibitor +/- MEK inhibitor revealed that PGC1alpha levels were elevated in approximately half of the resistant tumors. Overall, our findings highlight the significance of OxPhos in melanoma and suggest that combined targeting of the MAPK and mTORC pathways may offer an effective therapeutic strategy to treat melanomas with this metabolic phenotype. PMID- 25297635 TI - Inhibition of adaptive immunity by IL9 can be disrupted to achieve rapid T-cell sensitization and rejection of progressive tumor challenges. AB - The tolerogenic cytokine IL9 promotes T regulatory cell function and allergic airway inflammation, but it has not been extensively studied in cancer. In this report, we used IL9-deficient mice to investigate the effects of IL9 in multiple models of breast and colon cancer development. Eliminating endogenous IL9 enabled sensitization of host T cells to tumors, leading to their early rejection without the requirement of vaccines or immunomodulatory therapies. Notably, IL9-deficient mice acquired immunologic memory, which actively protected from residual disease and tumor rechallenge, an effect linked to activation of CD8(+) T cells. Depletion of either CD8(+) or CD4(+) T cells abolished the benefits of IL9 loss to tumor control. Adoptive transfer experiments showed that T cells from tumor rejecting IL9-deficient mice retained their effector competency in wild-type animals. Moreover, neutralizing IL9 antibody phenocopied the effects of IL9 gene deletion by slowing tumor progression in wild-type animals. Our results show the ability of IL9 to function as an inhibitor of adaptive immunity that prevents the formation of immunologic memory to a growing tumor, highlighting the potential for IL9 neutralization as a unique tool for cancer immunotherapy. PMID- 25297638 TI - Symptomatic carotid near-occlusion with full collapse might cause a very high risk of stroke. AB - BACKGROUND: The risk of early stroke recurrence amongst patients with symptomatic carotid near-occlusion with and without full collapse is unknown. Therefore, the aim of this study was to analyse the 90-day risk of recurrent ipsilateral ischaemic stroke in patients with symptomatic carotid near-occlusion both with and without full collapse. METHODS: This study was a secondary analysis of the Additional Neurological SYmptoms before Surgery of the Carotid Arteries: a Prospective study (ANSYSCAP). We prospectively analysed 230 consecutive patients with symptomatic 50-99% carotid stenosis or near-occlusion. Based on the combination of several imaging modalities, 205 (89%) patients were classified as having 50-99% carotid stenosis, and 10 (4%) and 15 (7%) as having near-occlusion with and without full collapse, respectively. The 90-day risk of recurrent ipsilateral ischaemic stroke was compared between these three groups. Only events that occurred before carotid endarterectomy were analysed. RESULTS: The 90-day risk of recurrent stroke was 18% [95% confidence interval (CI) 12-25%; n = 29] for patients with 50-99% carotid stenosis, 0% for patients with near-occlusion without full collapse and 43% (95% CI 25-89%; n = 4) for patients with near occlusion with full collapse (P = 0.035, log-rank test). The increased risk of recurrent ipsilateral ischaemic stroke for patients with symptomatic near occlusion with full collapse remained significant after multivariable adjustment for age, sex and type of presenting event. CONCLUSIONS: Patients with symptomatic carotid near-occlusion with full collapse might have a very high risk of stroke recurrence. Carotid endarterectomy could be considered for these patients. PMID- 25297639 TI - Nickel nanoparticles effect on the electrochemical energy storage properties of carbon nanocomposite films. AB - The growth of nanostructured nickel : carbon (Ni : C) nanocomposite thin films by the supersonic cluster beam deposition of nickel and carbon clusters co-deposited from two separate beam sources has been demonstrated. Ni : C films retain the typical highly disordered structure with predominant sp(2) hybridization, low density, high surface roughness and granular nanoscale morphology of cluster assembled nanostructured carbon, but display enhanced electric conductivity. The electric double layer (EDL) capacitance of Ni : C films featuring the same thickness (200 nm) and different nickel volumetric concentrations (0-35%) has been investigated by electrochemical impedance spectroscopy employing an aqueous solution of potassium hydroxide (KOH 1 M) as electrolyte solution. Evidence of increased electric conductivity, facilitated EDL formation and negligible porous structure modification was found as consequence of Ni embedding. This results in the ability to synthesize electrodes with tailored specific power and energy density by the accurate control of the amount of deposited Ni and C clusters. Moreover, nickel nanoparticles were shown to catalyze the formation of tubular onion-like carbon structures upon mild thermal treatment in inert atmosphere. Electrochemical characterization of the heated nanocomposite electrodes revealed that the presence of long range ordered sp(2) structures further improves the power density and energy storage properties. PMID- 25297637 TI - A pharmacokinetic and pharmacodynamic comparison of a novel pegylated recombinant consensus interferon-alpha variant with peginterferon-alpha-2a in healthy subjects. AB - AIMS: The aims of the study were to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of a novel, pegylated recombinant human consensus interferon-alpha variant (PEG-IFN-SA) in healthy volunteers. A pharmacokinetic and pharmacodynamic comparison of PEG-IFN-SA and peginterferon alpha-2a in healthy subjects was evaluated. METHODS: A randomized, dose escalating, single administration dose phase I clinical study was conducted. Thirty healthy subjects received PEG-IFN-SA as a single dose of 0.5-2.0 MUg kg( 1) by subcutaneous (s.c.) injection in four parallel groups. Eight subjects received peginterferon-alpha-2a as a single dose of 180 MUg s.c. RESULTS: The incidence rates of adverse events for PEG-IFN-SA and peginterferon-alpha-2a were 29 of 30 and 7 of 8, respectively. The adverse events for PEG-IFN-SA were mild to moderate and similar to those of peginterferon-alpha-2a. Within 168 h after injection, the mean values of maximal concentration and area under the plasma concentration-time curve from time of dosing to 168 h [AUC(0-168h) ] for 2',5' oligoadenylate, neopterin and beta2 -microglobulin for PEG-IFN-SA at 1.5 MUg kg( 1 ) s.c. were similar to or higher than those for peginterferon-alpha-2a at a dose of 180 MUg s.c. After s.c. injection of PEG-IFN-SA at 1.5 MUg kg(-1) , the mean geometric mean values of plasma half-life, time to maximal concentration, maximal concentration and AUC(0-168h) were 55.3 h, 26.9 h, 0.53 MUg l(-1) and 44.0 MUg l(-1) h, respectively. CONCLUSIONS: The tolerance, pharmacokinetic and pharmacodynamic characteristics of PEG-IFN-SA support its administration by s.c. injection as a single dose of 1.5 MUg kg(-1) or at 2.0 MUg kg(-1) per week. PMID- 25297640 TI - Case of neuroleptic malignant syndrome with diffuse neurofibrillary tangles with calcification. PMID- 25297641 TI - Neurocysticercosis. AB - Neurocysticercosis is the commonest parasitic disease of the nervous system in humans, and constitutes a major public health problem for most of the developing world. The clinical manifestations of Neurocysticercosis (NCC) largely depend on number of lesions, site, and host immune response against the parasite. Diagnosis is mainly based upon neuro imaging studies and is supported by antibody/antigen detection in the serum and occasionally the cerebrospinal fluid. Randomized controlled trials evaluating the clinical benefit of treatment with cysticidal agents have shown hastened resolution of lesions in most, and reduced seizure recurrence in some studies. Outcome is favourable in single lesion parenchymal NCC but is guarded in multiple lesion and extra parenchymal NCC. PMID- 25297642 TI - Novel mutation of OCRL1 in Lowe syndrome. AB - Lowe syndrome is a rare, X-linked recessive genetic disease with multi-organ involvement. The pathogenic gene is OCRL1. The authors analyzed the OCRL1 mutation and summarized the clinical features of a Chinese child with Lowe syndrome. The patient is a 3 year 7 mo-old boy. He presented with hypotonia at birth and gradually presented with bilateral congenital cataracts, psychomotor retardation, hypophosphatemic rickets and renal tubular function disorder. Sequence analysis of OCRL1 revealed a novel insertion mutation, c.2367insA (p. Ala813X), in exon 22. This mutation was suspected to cause a premature stop codon of OCRL1 and truncation of the OCRL1 protein. His mother, who carried a heterozygous mutation, had no sign of abnormality. PMID- 25297643 TI - Role of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia. AB - OBJECTIVE: To determine prophylactic role of single dose of vitamin K in prevention of antibiotic induced hypoprothrombinemia. METHODS: This prospective comparative study included critically ill children in age group 2 mo to 12 y, admitted to a tertiary care hospital in India, likely to receive prolonged antibiotic therapy. One hundred twenty children, 60 in each group (A & B) were enrolled in the study. Patient allocation was done on alternate basis. Group A children received prophylactic vitamin K while group B did not. Baseline coagulation studies and other investigations were done in all children. Coagulation studies were repeated on day 10 and day 14 of antibiotic therapy and in between if required clinically. Children who developed deranged INR were given therapeutic vitamin K. If deranged INR returns to normal at 12 h of vitamin K administration then it indirectly confirms vitamin K deficiency. Analysis was done by fisher's t test and chi square test. RESULTS: In children on prolonged antibiotic therapy, vitamin K deficiency was a common problem (15%). It was common in male sex, severe grade of protein energy malnutrition (PEM), N methylthiotetrazole (NMTT) group containing antibiotics use and duration of antibiotic more than 10 d. It was same in children whether they received or did not receive prophylactic vitamin K on day 1 of antibiotic therapy (95% CI; p value 0.79). CONCLUSIONS: Vitamin K deficiency is common problem in patients on prolonged antibiotic therapy. There is no role of single dose of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia. PMID- 25297644 TI - CDC Kerala 16: Early Detection of developmental delay/disability among children below 6 y--a district model. AB - OBJECTIVE: To develop a district model for establishing early detection of childhood disability below 6 y of age and to develop appropriate referral linkages for confirmation of the diagnosis and establish home based early intervention therapy to all needy children. METHODS: Trained Accredited Social Health Activist (ASHA) workers conducted the preliminary survey for identifying developmental delay/disability among children below 6 y of age using Trivandrum Developmental Screening Chart (TDSC) (0-6 y) and a team of experts assessed the screen positives in developmental evaluation camps conducted at primary health centres (PHCs). RESULTS: Community survey was carried out and 1,01,438 children below 6 y of age in Thiruvananthapuram district were screened by ASHA workers and 2,477 (2.45%) positive cases (TDSC two or more item delay) were identified and these children were called for the developmental evaluation camps conducted at 80 PHCs in the district. Among the 1,329 children who reached the evaluation camps 43.1% were normal. 24.98% children had speech and language delay and 22.95% children had multiple disabilities. Developmental delay was observed among 49.89% children and cerebral palsy in 8.43% and intellectual disability 16.85% were confirmed. Visual impairment in 3.31% and neuromuscular disorders in 1.35 were found among children evaluated in the camp. CONCLUSIONS: The results of this district wide early detection of disability survey by trained ASHA workers among children below 6 y of age showed a community prevalence of 3.08% observed, based on two or more item delay in TDSC and among these children, 43.1% were normal, 49.89% had developmental delay, 24.98% had speech and language delay and 22.95% had multiple disabilities. PMID- 25297645 TI - ICD-10 and alternative diagnostic criteria for childhood autism among children with intellectual disability. AB - OBJECTIVES: The diagnosis of Childhood Autism (CA) among children with Intellectual Disability (ID) based on clinical criteria validated for populations with average intelligence compromises it's diagnostic accuracy in this special population. This study documents the diagnostic accuracy of ICD-10 and alternative criteria for CA in ID population. METHODS: Consensus clinical diagnosis of autism made by a multi-disciplinary team as the reference data were extracted from the case notes and psychological tests details by two trainee psychologists, and ICD-10 based clinical diagnosis, demographics, ID, CA related data documented independently of the psychiatrist. The appropriate statistical analyses were completed. RESULTS: Repetitive behaviors formed the most common symptom cluster. The high internal consistency (kappa = 0.75) among the three groups of ICD-10 symptoms indicate their usefulness in the diagnosis of CA among children with ID, but significantly more children with ID failed to meet the ICD 10 criteria for CA. The fourth alternative criteria had the highest concordance with the reference standard (100%) and the first alternative criteria had the highest agreement with the reference standard (kappa = 0.88) in identifying CA among ID. The diagnostic accuracy of all the alternative criteria was significantly better than that of ICD-10 with the first alternative criteria having the best diagnostic accuracy (Sn = 98%; Sp = 100%; PPV = 1; NPV =0.83) closest to the reference standard. CONCLUSIONS: The symptom clusters in ICD-10 for CA should be retained, however reorganising the diagnostic criteria is required for diagnosing CA accurately among children with ID. The first alternative criteria can significantly improve the case identifying ability and diagnostic accuracy altering there by the epidemiological data on Childhood Autism among children with Intellectual Disability. PMID- 25297646 TI - Independent effects of sham laparotomy and anesthesia on hepatic microRNA expression in rats. AB - BACKGROUND: Studies on liver regeneration following partial hepatectomy (PH) have identified several microRNAs (miRNAs) that show a regulated expression pattern. These studies involve major surgery to access the liver, which is known to have intrinsic effects on hepatic gene expression and may also affect miRNA screening results. We performed two-third PH or sham laparotomy (SL) in Wistar rats to investigate the effect of both procedures on miRNA expression in liver tissue and corresponding plasma samples by microarray and qRT-PCR analyses. As control groups, non-treated rats and rats undergoing anesthesia only were used. RESULTS: We found that 49 out of 323 miRNAs (15%) were significantly deregulated after PH in liver tissue 12 to 48 hours postoperatively (>20% change), while 45 miRNAs (14%) were deregulated following SL. Out of these miRNAs, 10 miRNAs were similarly deregulated after PH and SL, while one miRNA showed opposite regulation. In plasma, miRNA upregulation was observed for miR-133a and miR-133b following PH and SL, whereas miR-100 and miR-466c were similarly downregulated following anesthesia and surgery. CONCLUSIONS: We show that miRNAs are indeed regulated by sham laparotomy and anesthesia in rats. These findings illustrate the critical need for finding appropriate control groups in experimental surgery. PMID- 25297647 TI - Chemopreventive effects of (-)-hinokinin against 1,2-dimethylhydrazine-induced genotoxicity and preneoplastic lesions in rat colon. AB - (-)-Hinokinin (1) is a dibenzylbutyrolactone lignan obtained by the partial synthesis of (-)-cubebin. This study reports the antigenotoxic and anticarcinogenic potential of 1 by the comet and aberrant crypt focus assays in the peripheral blood and colon of 4-5-week-old Wistar rats, respectively. The rats were exposed to 1,2-dimethylhydrazine (40 mg/kg) and were treated by gavage with doses of 10, 20, and 40 mg/kg of 1. The results showed that the dose of 40 mg/kg was neither genotoxic nor carcinogenic. In the comet assay, all 1 doses displayed antigenotoxic effects. In addition, this compound (20 and 40 mg/kg) exhibited an anticarcinogenic effect in the aberrant crypt focus assay. PMID- 25297648 TI - Progress and challenges in the development of a cell-based therapy for hemophilia A. AB - Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells. PMID- 25297650 TI - Resection of primary leiomyosarcoma of the inferior vena cava (IVC) with reconstruction: a case series and review of the literature. AB - BACKGROUND: Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor which presents a unique surgical challenge. We present a series of six cases of leiomyosarcoma resection performed with IVC reconstruction. METHODS: Retrospective chart review was performed for patients undergoing initial operative resection of primary leiomyosarcoma with IVC reconstruction, at a tertiary care center. RESULTS: Between 2005-2013, six patients underwent resection with reconstruction. Half were female, and the mean age at presentation was 57 +/- 15.4 years. Three patients required en bloc resection with adjacent organs. Three patients were resected on venovenous bypass, and one on cardiopulmonary bypass. Three underwent IVC patch repair (bovine pericardium, n = 2; saphenous vein, n = 1), and three had IVC reconstruction with graft (Dacron, n = 1; PTFE, n = 1; aortic homograft, n = 1). All achieved grossly negative margins. Median disease-free survival was 34 months (IQR 7-52 months), and median disease-specific survival was 51 months (IQR 20-108). Five year disease-free and disease-specific survival rates were 30% and 66.7%, respectively. CONCLUSIONS: Leiomyosarcomas of the IVC present a technical challenge to the surgeon. Careful preoperative workup and a collaborative team consisting of experienced cardiac and vascular surgeons and surgical oncologists can allow for a safe and successful operation despite extensive tumor involvement. PMID- 25297649 TI - A novel compound VSC2 has anti-inflammatory and antioxidant properties in microglia and in Parkinson's disease animal model. AB - BACKGROUND AND PURPOSE: Neuroinflammation through microglial activation is involved in the pathogenesis of neurodegenerative diseases including Parkinson's disease (PD), a major neurodegenerative disorder characterized by dopaminergic neuronal death in the substantia nigra. We examined our novel synthetic compound VSC2 for its anti-inflammatory properties towards development of a PD therapy. EXPERIMENTAL APPROACH: We tested the effects of VSC2 on production of various NF kappaB-dependent proinflammatory molecules and Nrf2-dependent antioxidant enzymes in BV-2 microglia and in vivo. KEY RESULTS: The vinyl sulfone compound, VSC2, most effectively suppressed the production of NO in LPS-activated microglia. It also down-regulated expression of inducible NOS (iNOS), COX-2, IL-1beta and TNF alpha and inhibited nuclear translocalization and transcriptional activity of NF kappaB. VSC2 increased total and nuclear Nrf2 levels, induced Nrf2 transcriptional activity and was bound to Keap1 with high affinity. Expression of the Nrf2-regulated antioxidant enzyme genes NAD(P)H quinone oxidoreducase-1 (NQO 1), haem oxygenase-1 (HO-1) and glutamylcysteine ligase (GCL) were up-regulated by VSC2. In the MPTP mouse model of PD, oral administration of VSC2 decreased the number of activated microglia in the substantia nigra, lowered the levels of iNOS, COX-2 and IL-1beta, and protected the dopaminergic neurons. VSC2 also elevated the levels of NQO1, HO-1, GCL and Nrf2 in the nigrostriatal area. CONCLUSIONS AND IMPLICATIONS: VSC2 has both anti-inflammatory and antioxidant properties and prevented neuroinflammation in microglia and in an animal model of PD. This suggests VSC2 as a potential candidate for PD therapy. PMID- 25297651 TI - Expanded intrathoracic space in fetal cases of isolated congenital diaphragmatic hernia contributes to disparity between percent predicted lung volume and observed to expected total lung volume. AB - OBJECTIVE: The aim of this study was to determine whether fetal lung volume and visceral herniation are associated with changes in intrathoracic space in congenital diaphragmatic hernia(CDH). METHODS: We retrospectively examined the relationship between magnetic resonance imaging-derived measurements of intrathoracic space [predicted lung volume (PLV)] and residual lung volume or visceral herniation among isolated left-sided CDH fetuses. RESULTS: Data from fetal magnetic resonance imaging studies of 60 isolated left-sided CDH cases were analyzed. The median PLV of the CDH fetuses was found to be much greater than the expected total lung volume (eTLV) of a normal fetus at the same gestational age. Surprisingly, liver herniation and observed TLV(oTLV) were positively correlated with the PLV. Although the PPLV was consistently less than the o/eTLV, both indices were greater in survivors than in non-survivors, whereas no significant difference was seen in the PLV/eTLV ratio in regard to survivorship. CONCLUSION: The intrathoracic domain available for lungs and viscera is expanded in CDH fetuses and positively affected by the lung volume and the presence of liver herniation, leading to the difference in the PPLV and o/eTLV. Future study of intrathoracic space as it relates to the growth of the lung and herniated viscera is needed to better characterize the relationship between these parameters. PMID- 25297653 TI - Successful treatment of angioma serpiginosum using a novel 532 nm potassium titanyl phosphate (KTP) laser. AB - Angioma serpiginosum (AS) is a rare, benign, vascular disorder comprising non blanchable punctate red to purple lesions in a gyrate or serpiginous configuration. We report a case of a 38-year-old woman with a red colored eruption on her chest which was present since puberty. A novel 532 nm potassium titanyl phosphate (KTP) laser (Excel V, Cutera Inc., Brisbane, CA, USA) was applied which resulted in near complete resolution after two sessions of treatment. PMID- 25297652 TI - The solution structure of the forkhead box-O DNA binding domain of Brugia malayi DAF-16a. AB - Brugia malayi is a parasitic nematode that causes lymphatic filariasis in humans. Here the solution structure of the forkhead DNA binding domain of Brugia malayi DAF-16a, a putative ortholog of Caenorhabditis elegans DAF-16, is reported. It is believed to be the first structure of a forkhead or winged helix domain from an invertebrate. C. elegans DAF-16 is involved in the insulin/IGF-I signaling pathway and helps control metabolism, longevity, and development. Conservation of sequence and structure with human FOXO proteins suggests that B. malayi DAF-16a is a member of the FOXO family of forkhead proteins. PMID- 25297654 TI - Correlations among ocular surface temperature difference value, the tear meniscus height, Schirmer's test and fluorescein tear film break up time. AB - PURPOSE: To report the use of a thermographer for measuring ocular surface temperature, and to evaluate the correlation among the obtained temperature difference values (TDVs) and dry eye parameters (tear meniscus height (TMH); Schirmer's test results; fluorescent tear breakup time (FTBUT)). METHODS: Forty three participants (age 40.2+/-14.7 years; range 21-67 years) from Far Eastern Memorial Hospital, Taiwan were recruited for the study. The surface temperature was measured at the centre of the ocular surface for 4 s after blinking. TDV was defined as the change in corneal surface temperature relative to that of the preceding eye opening, where TDV01, TDV02, TDV03, and TDV04 represent the values obtained 1, 2, 3, and 4 s after blinking, respectively. Anterior segment optical coherence tomography (AS-OCT) was employed to measure the lower TMH. Schirmer's test with topical anaesthetic was conducted to measure the basal tear secretion. The FTBUT was recorded using a digital camera. RESULTS: TDV measurement exhibited high reliability (intraclass correlation coefficient=0.91). TDV03 exhibited the highest significance and strongest positive correlation with the TMH (r=0.52, p=0.0003) and Schirmer's test value (r=0.39, p=0.008), whereas the TDV03-FTBUT correlation was non-significant. Age correlated negatively and significantly with the TDV (r= -0.35, p=0.021), TMH (r= -0.33, p=0.031), and Schirmer's test value (r= -0.31, p=0.044). TDV03 remained significantly correlated with the TMH and Schirmer's test value after adjustment for age. CONCLUSIONS: The thermographer was effective in capturing temperature changes in the ocular surface. The temperature difference 3 s after blinking appears to be correlated with lower TMH and Schirmer test values. PMID- 25297655 TI - 2-Alkynylbenzaldoxime: a versatile building block for the generation of N heterocycles. AB - 2-Alkynylbenzaldoxime as a versatile building block has been applied widely for the construction of N-heterocycles in organic synthesis. Since it could be easily transferred to isoquinoline N-oxide via intramolecular 6-endo cyclization in the presence of metal catalysts or electrophiles, the subsequent [3 + 2] cycloaddition/nucleophilic addition and rearrangement could be expected. On the other hand, a Beckmann rearrangement could occur first since an oxime moiety is present in the molecule, which would then undergo an intramolecular cyclization to furnish nitrogen-containing heterocycles. This review reports the recent advancement in the generation of N-heterocycles starting from 2 alkynylbenzaldoximes via tandem reactions based on different reaction types. PMID- 25297656 TI - Quantifying long-term care preferences. AB - BACKGROUND: . Current policies redirecting long-term care (LTC) delivery away from institutional care to home- and community-based services are being made in the absence of crucial evidence on preferences. Studies indicate that the shift to home care is generally not cost-saving; thus, an empirical assessment of effectiveness is needed to evaluate policies incenting home care investment. This study quantifies LTC preferences between different delivery modes. DESIGN: . This study extended the time tradeoff method to elicit utilities and LTC preferences associated with the receipt of different modes of LTC services, conditional on health states defined by varying levels of functional and cognitive impairment. Users' LTC preferences are measured as differential utilities between alternative LTC options for each health state. RESULTS: . For the same health state, respondents (n = 81) significantly preferred home care over institutional care, except for the most impaired health state. The preference for home care over institutional care is quantified as 0.30 quality-of-life (QOL) weight when people need help with only 1 activity of daily living (ADL). The preference for home care depends significantly on levels of disability and was weaker once the need for help became greater. Under the most severe health state of having moderate to severe dementia and needing help with 6 ADLs, the quantified home care preference was only 0.03 QOL weight and was not statistically significant. LIMITATIONS: . Because the sample is mostly composed of African Americans, the results may not be generalizable to other racial and ethnic groups. CONCLUSIONS: . People do not always strongly prefer home care over institutional care, as is often assumed. The costs of expanding home- and community-based care should be weighed against these preferences. PMID- 25297657 TI - Parental decision-making in uptake of the MMR vaccination: a systematic review of qualitative literature. AB - BACKGROUND: Controversy has surrounded MMR vaccination in the aftermath of Wakefield's 1998 paper suggesting links between MMR and the development of pervasive developmental disorder in children. The paper sparked off media debate and contributed to a lack of parental trust in health-care providers and reduction in MMR uptake. This review aims to identify and evaluate research on the subject, with a view to present the reasons behind, and influences on parental decision-making in relation to MMR. METHODS: Systematic search strategy identified 14 relevant papers on which thematic analysis was performed. RESULTS: Themes identified were categorized as follows: perceptions of risk; roles and responsibility; experience and knowledge. There were limited changes in parental decision-making factors over the time period despite an increase in uptake. Many studies fail to differentiate between accepters and rejecters, making it difficult to draw out clear conclusions. CONCLUSION: Policymakers need to adapt information provided to address these concerns. Future research should focus more on distinguishing between accepters and rejecters to determine which factors can alter outcome. PMID- 25297658 TI - Low levels of mitochondrial DNA and symbiont diversity in the worldwide agricultural pest, the greenhouse whitefly Trialeurodes vaporariorum (Hemiptera: Aleyrodidae). AB - Trialeurodes vaporariorum, the greenhouse whitefly, is a cosmopolitan agricultural pest. Little is known about the genetic diversity of T. vaporariorum and the bacterial symbionts associated with this species. Here, we undertook a large phylogeographic study by investigating both the mitochondrial (mt) diversity and the infection status of 38 T. vaporariorum collections from 18 countries around the world. Genetic diversity of T. vaporariorum was studied by analyzing sequence data from the mt cytochrome oxidase I, cytochrome b, and NADH dehydrogenase subunit 5 genes. Maximum-likelihood (ML) phylogeny reconstruction delineated 2 clades characterized by limited sequence divergence: one clade comprised samples only from the Northern hemisphere whereas the other comprised samples from a broader geographical range. The presence of secondary symbionts was determined by PCR using primers specific for Hamiltonella, Rickettsia, Arsenophonus, Cardinium, Wolbachia, and Fritschea. Most individuals examined harbored at least one secondary endosymbiont, and Arsenophonus was detected in almost all male and female individuals. Wolbachia was present at a much lower frequency, and Cardinium was detected in only a few individuals from Greece. Rickettsia, Hamiltonella, and Fritschea were not found. Additionally, we set out to further analyze Arsenophonus diversity by multilocus sequence typing analysis; however, the Arsenophonus sequences did not exhibit any polymorphism. Our results revealed remarkably low diversity in both mtDNA and symbionts in this worldwide agricultural pest, contrasting sharply with that of the ecologically similar Bemisia tabaci. PMID- 25297659 TI - The Mount Sinai clinical pathway for the management of pheochromocytoma. AB - OBJECTIVE: Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team. METHODS: To achieve these ends, The Mount Sinai Adrenal Center hosted an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas. RESULTS: The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature. CONCLUSION: Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management. PMID- 25297660 TI - Patient-led versus physician-led titration of insulin glargine in patients with uncontrolled type 2 diabetes: a randomized multinational ATLAS study. AB - OBJECTIVE: Self-adjustment of insulin dose is commonly practiced in Western patients with type 2 diabetes but is usually not performed in Asian patients. This multinational, 24-week, randomized study compared patient-led with physician led titration of once-daily insulin glargine in Asian patients with uncontrolled type 2 diabetes who were on 2 oral glucose-lowering agents. METHODS: Patient-led (n = 275) or physician-led (n = 277) subjects followed the same dose-titration algorithm guided by self-monitored fasting blood glucose (FBG; target, 110 mg/dL [6.1 mmol/L]). The primary endpoint was change in mean glycated hemoglobin (HbA1c) at week 24 in the patient-led versus physician-led titration groups. RESULTS: Patient-led titration resulted in a significantly higher drop in HbA1c value at 24 weeks when compared with physician-led titration (-1.40% vs. -1.25%; mean difference, -0.15; 95% confidence interval, -0.29 to 0.00; P = .043). Mean decrease in FBG was greatest in the patient-led group (-2.85 mmol/L vs. -2.48 mmol/L; P = .001). The improvements in HbA1c and FBG were consistent across countries, with similar improvements in treatment satisfaction in both groups. Mean daily insulin dose was higher in the patient-led group (28.9 units vs. 22.2 units; P<.001). Target HbA1c of <7.0% without severe hypoglycemia was achieved in 40.0% and 32.9% in the patient-led and physician-led groups, respectively (P = .086). Severe hypoglycemia was not different in the 2 groups (0.7%), with an increase in nocturnal and symptomatic hypoglycemia in the patient-led arm. CONCLUSION: Patient-led insulin glargine titration achieved near-target blood glucose levels in Asian patients with uncontrolled type 2 diabetes who were on 2 oral glucose-lowering drugs, demonstrating that Asian patients can self-uptitrate insulin dose effectively when guided. PMID- 25297661 TI - Diabetes Status and Race are Associated with Cardiovascular Risk Markers in Obese Adolescents. AB - OBJECTIVE: The objective of this study was to evaluate differences in cardiovascular disease (CVD) risk markers in obese adolescents based on diabetes status and race in order to improve risk-reduction intervention strategies. METHODS: This was a retrospective, cross-sectional study of obese adolescents, age 10 to 21 years, who were evaluated at Children's of Alabama between 2000 and 2012. Subjects were classified by glycated hemoglobin (HbA1c) as having normoglycemia, prediabetes, or type 2 diabetes mellitus (T2DM). RESULTS: There were a total of 491 African American (AA) or Caucasian American (CA) subjects. Body mass index was not different between HbA1c and racial groups. Compared to subjects with normoglycemia or prediabetes, subjects with T2DM had higher levels of total cholesterol (TC) (178.6 +/- 43.8 mg/dL vs. 161.5 +/- 32.5 mg/dL vs. 162.4 +/- 30.6 mg/dL; P<.0001) and low-density-lipoprotein cholesterol (107.4 +/- 39.2 mg/dL vs. 97.0 +/- 31.0 mg/dL vs. 97.5 +/- 26.9 mg/dL; P = .0073). Compared with AA subjects, CA subjects had lower high-density-lipoprotein cholesterol (HDL C) levels (40.4 +/- 10.4 mg/dL vs. 44.3 +/- 11.9 mg/dL; P = .0005) and higher non HDL-C levels (129.6 +/- 36.2 mg/dL vs. 122.5 +/- 37.5 mg/dL; P = .0490). Of the characteristics studied, HbA1c had the most significant positive association with dyslipidemia and was strongly correlated with both TC (beta, 4.21; P<.0001) and non-HDL-C (beta, 4.3; P<.0001). CONCLUSION: Obese adolescents with T2DM have more abnormal lipoprotein profiles than those with normoglycemia or prediabetes. Obese CA adolescents have more abnormal lipids than obese AA adolescents. HbA1c was the characteristic most highly associated with abnormal lipoprotein profiles in our subjects. Our results show that CVD risk markers in obese adolescents vary by race and HbA1c concentration. PMID- 25297662 TI - The performance and reproducibility of late-night salivary cortisol estimation by enzyme immunoassay for screening Cushing disease. AB - OBJECTIVE: Our study aimed to establish a local reference range for late-night salivary cortisol (LNSC) using enzyme immunoassay (EIA) and to study the intra individual reproducibility of LNSC. METHODS: Prospective study involving 30 healthy subjects (HS) with body mass index (BMI) <25 kg/m2, 37 obese/overweight subjects (OS) with BMI >25 kg/m2 and 28 patients with Cushing disease (CD). Salivary sampling was performed on 2 consecutive nights and assayed by EIA. The reference range was established using LNSC values of HS, and receiver operating characteristic (ROC) curves were used to determine diagnostic cutoffs. RESULTS: The mean LNSC level of CD was significantly higher than HS and OS (CD: 16.96 +/- 9.11 nmol/L, HS: 1.30 +/- 0.95 nmol/L, and OS 1.21 +/- 0.78 nmol/L). A cutoff of 2.92 nmol/L differentiated CD from HS with 100% sensitivity and 96.7 % specificity, and a cutoff of 5.04 nmol/L yielded a specificity of 100% with a sensitivity of 96.4% to distinguish CD from OS. There was more intra-individual variability in HS (55%) than in CD (49%) and OS (22%). There was no difference in the sensitivity and specificity derived from the ROCs using day 1 values or the higher of the 2 LNSCs. CONCLUSIONS: In our cohort, we found that LNSC assayed by EIA showed good sensitivity and specificity to screen patients suspected to have CD. Although intra-individual variability was significant, it did not hamper the diagnostic performance of the test. PMID- 25297663 TI - Menopausal Hormone Therapy and Chronic Disease Risk in the Women's Health Initiative: Is Timing Everything? AB - OBJECTIVE: This review provides a comprehensive overview of the most recent findings from the Women's Health Initiative (WHI) hormone therapy (HT) trials and highlights the role of age and other clinical risk factors in risk stratification. METHODS: We review the findings on cardiovascular disease, cancer outcomes, all-cause mortality, and other major endpoints in the two WHI HT trials (conjugated equine estrogens [CEEs, 0.625 mg/day] with or without medroxyprogesterone acetate [MPA, 2.5 mg/day]). RESULTS: The hazard ratio (HR) for coronary heart disease (CHD) was 1.18 (95% confidence interval [CI], 0.95 to 1.45) in the CEE+MPA trial and 0.94 (95% CI, 0.78 to 1.14) in the CEE-alone trial. In both HT trials, there was an increased risk of stroke and deep vein thrombosis and a lower risk of hip fractures and diabetes. The HT regimens had divergent effects on breast cancer. CEE+MPA increased breast cancer risk (cumulative HR, 1.28; 95% CI, 1.11 to 1.48), whereas CEE alone had a protective effect (cumulative HR, 0.79; 95% CI, 0.65 to 0.97). The absolute risks of HT were low in younger women (ages 50 to 59 years) and those who were within 10 years of menopause onset. Furthermore, for CHD, the risks were elevated for women with metabolic syndrome or high low-density-lipoprotein cholesterol concentrations but not in women without these risk factors. Factor V Leiden genotype was associated with elevated risk of venous thromboembolism on HT. CONCLUSION: HT has a complex pattern of benefits and risks. Women in early menopause have low absolute risks of chronic disease outcomes on HT. Use of HT for management of menopausal symptoms remains appropriate, and risk stratification will help to identify women in whom benefits would be expected to outweigh risks. PMID- 25297664 TI - Insulin-like growth factors, insulin, and growth hormone signaling in breast cancer: implications for targeted therapy. AB - OBJECTIVE: In recent decades, multiple therapeutics targeting the estrogen and human epidermal growth factor-2 (HER2) receptors have been approved for the treatment of breast cancer. METHODS: This review discusses a number of growth factor pathways that have been implicated in resistance to both anti-estrogen and HER2-targeted therapies. The association between growth factors and breast cancer is well established. Over decades, numerous laboratories have studied the link between insulin-like growth factor (IGF), insulin, and growth hormone (GH) to the development and progression of breast cancer. RESULTS: Although preclinical data demonstrates that blockade of these receptors inhibits breast cancer growth, progression, and drug resistance, therapies targeting the IGF, insulin, and GH receptors (GHRs) have not been successful in producing significant increases in progression-free, disease-free, or overall survival for patients with breast cancer. The failure to demonstrate a benefit of growth factor blockade in clinical trials can be attributed to redundancy in IGF, insulin, and GHR signaling pathways. All 3 receptors are able to activate oncogenic phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. CONCLUSION: Consequently, multitargeted blockade of growth factor receptors and their common downstream kinases will be necessary for the successful treatment of breast cancer. PMID- 25297665 TI - Comparison of the efficacy and safety of ultrasound-guided core needle biopsy versus fine-needle aspiration for evaluating thyroid nodules. AB - OBJECTIVE: Ultrasound-guided core needle biopsy (UG-CNB) is a procedure that is often performed either after repeated inadequate or nondiagnostic ultrasound guided fine-needle aspiration (UG-FNA) or in combination with UG-FNA in the evaluation of thyroid nodules. The purpose of this study was to compare the efficacy and safety of UG-CNB and UG-FNA for evaluating thyroid nodules. METHODS: This was a retrospective study of 350 consecutive patients who had thyroid nodules biopsied by UG-CNB or UG-FNA from January 2007 until November 2011 at our institution. Biopsy results were compared to the surgical specimen pathology reports for the 105 patients who subsequently underwent hemi- or total thyroidectomy in order to determine whether UG-CNB has advantages over UG-FNA for diagnosing thyroid malignancy and neoplasia. RESULTS: Out of 461 thyroid nodules biopsied from 350 patients, 365 (79%) involved UG-CNB and 96 (21%) involved UG FNA. The UG-FNA biopsy group had a significantly higher rate of inadequate sampling than the UG-CNB group (P<.0001; Fisher's exact test). Out of 365 UG-CNB samples, 6 (2%) were deemed inadequate for histologic diagnosis, whereas 26 (27%) of the 96 UG-FNA samples were considered inadequate for cellularity. Comparison of biopsy results with the surgical specimen pathology reports revealed that the diagnostic accuracy of UG-CNB and UG-FNA for detecting malignancy was similar, at 89 and 94%, respectively (not significant by Fisher's exact test). However, the UG-CNB group had a higher detection rate for benign follicular lesions compared to the UG-FNA group (65% versus 48% for UG-FNA; P = .002). Although UG-FNA detected neoplasia with high sensitivity (100%), the specificity was poor (30%). Neither biopsy group had any significant immediate or delayed procedure-related complications. CONCLUSION: Our study demonstrated that UG-CNB is safe and is less likely to result in a nondiagnostic biopsy. The accuracy of the UG-CNB technique is similar to that of UG-FNA for detecting thyroid malignancy. PMID- 25297666 TI - Commentary on silent renal stones in primary hyperparathyroidism: prevalence and clinical features. PMID- 25297667 TI - Teriparatide as a systemic treatment for lower extremity nonunion fractures: a case series. AB - OBJECTIVE: To investigate the effect of teriparatide (parathyroid hormone [1-34]) on the healing of long bone nonunion fractures. METHODS: We performed a retrospective chart review of patients with fracture nonunion, aged 10 to 99 years who were treated with teriparatide at the Children's Hospital of Philadelphia or the Hospital of the University of Pennsylvania between November 2002 and January 2013. The primary endpoints were radiographic evidence of callus formation and fracture union, ability to bear weight without affected limb limp, and normal range of motion and strength. RESULTS: Six patients aged 19 to 64 years with tibial or femoral fractures that had not healed for 3 to 36 months were treated with teriparatide 20 MUg/day. Accelerated healing of fracture nonunion was confirmed in 5 of 6 patients with time to complete union of 3 to 9 months. The shortest time to recovery was observed in younger patients without comorbidities. Treatment was well tolerated. CONCLUSION: Teriparatide is a promising treatment for nonunion fractures, but its response depends on associated comorbidities. The potential benefit of teriparatide as an adjunct to treat nonunion justifies randomized placebo-controlled trials to determine its efficacy and safety in broader populations. PMID- 25297668 TI - Ethnicity, Clothing Style, and Body Mass Index are Significant Predictors of Vitamin D Insufficiency in Germany. AB - OBJECTIVE: To analyze risk factors for vitamin D insufficiency in Germany with respect to ethnicity, sex, and clothing style. METHODS: We analyzed the routine diagnostic work-ups of 1,231 adult (45.9 +/- 17.9 years old) German (n = 1,034) and Turk residents (n = 197) referred with nonspecific symptoms to the Thyroid Centers at St. Elisabeth-Hospital in Dorsten, Germany and Bottrop, Germany to assess for metabolic diseases. All subjects underwent a routine examination that consisted of a questionnaire, lab tests for 25-hydroxyvitamin-D (25OHD), and thyroid profile. Turk females with traditional clothing (headscarf and covered legs and arms) were considered to wear "covered clothing." Logistic-regression was performed to identify factors that could predict vitamin D deficiency (<20 ng/mL) and insufficiency (20-30 ng/mL). RESULTS: Vitamin D insufficiency was seen in 33% of Germans and 74.1% of Turks, and vitamin D deficiency was present in 11.3% and 44.2% of Germans and Turks, respectively (P<.001). The mean 25OHD value in Turk females with covered clothes was lower than that in Turk females with conventional clothing (16.3 +/- 12.3 vs. 27.2 +/- 15.8, P<.001). Vitamin D insufficiency was present in 86.0% of Turk females with covered clothing versus 62.8% with conventional clothing (odds ratio [OR] = 3.6, P = .002). Ethnicity, body mass index (BMI), and clothing style were significant predictors of vitamin D deficiency and insufficiency by logistic regression (P<.001). CONCLUSIONS: (1) Vitamin D insufficiency among Turk residents in Germany is higher compared to Germans. The highest prevalence was present in Turk females with covered clothing. (2) Monitoring vitamin D in Turk residents in Germany is warranted. (3) Vitamin D supplements and access to facilities with sunlight exposure for females with covered clothing and all individuals with poor diets or limited access to sun exposure may prevent future health burden due to vitamin D insufficiency. PMID- 25297670 TI - The dawn phenomenon: variability in occurrence may cause need for change in treatment strategy. PMID- 25297669 TI - Vitamin D Insufficiency is Associated with Reduced Parasympathetic Nerve Fiber Function in Type 2 Diabetes. AB - OBJECTIVE: Vitamin D insufficiency is prevalent in subjects with type 2 diabetes mellitus (T2DM) and is associated with peripheral neuropathy. However, there are little data regarding vitamin D status in patients with cardiovascular autonomic neuropathy. Our objective was to evaluate the association of cardiovascular autonomic function, 25-hydroxyvitamin D (25[OH]D) insufficiency (i.e., levels <30 ng/mL), and multiple metabolic parameters in subjects with T2DM. METHODS: We examined 50 individuals with T2DM. Cardiovascular autonomic function (i.e., parasympathetic function) was assessed by RR-variation during deep breathing (i.e., mean circular resultant [MCR] and expiration/inspiration [E/I] ratio). Metabolic parameters included measures of adiposity, glycemic control, insulin resistance, calcium metabolism, and 25(OH)D. RESULTS: Participants with 25(OH)D insufficiency (n = 26) were younger (66 +/- 9 vs. 60 +/- 10 years, P<.05), more insulin resistant, had a higher body mass index (BMI) and lower adiponectin levels. The MCR (39.5 +/- 26.3 vs. 27.6 +/- 17.2, P<.01) and E/I ratio (1.21 +/- 0.17 vs. 1.15 +/- 0.09, P<.01) were lower for those with 25(OH)D insufficiency after controlling for age. A stepwise selection procedure regressing MCR and E/I ratio on a number of metabolic parameters resulted in a model identifying age and 25(OH)D insufficiency as significant determinants for both measures. The interaction of age x 25(OH)D insufficiency was also included (MCR model, R2 = 0.491, P<.001; E/I ratio, R2 = 0.455, P<.001). Neither glycemic control nor other metabolic parameters were selected. CONCLUSION: Our results suggest that 25(OH)D insufficiency is associated with reduced parasympathetic function, with a stronger association in younger persons with T2DM. Studies are needed to determine if vitamin D supplementation into the sufficient range could prevent or delay the onset of cardiovascular autonomic dysfunction. PMID- 25297671 TI - Advances in diagnosis and treatment of pancreatic neuroendocrine tumors. AB - OBJECTIVE: To review the current state of pancreatic neuroendocrine tumors (PNETS)Methods: The literature published between 2005 and 2014 in PUBMED, Medline, Google Scholar, Cochrane reports, and ClinicalTrials.gov was examined for relevance to the topic. RESULTS: PNETS have an incidence <1 per 100,000 individuals and may functionally secrete biologically active substances or be nonfunctional (NF-PNETs). PNETs occur both sporadically and in patients with various inherited disorders. Pathology and staging range from benign, well differentiated to metastatic and dedifferentiated and are dependent on the mitotic and Ki67 indices of cell proliferation. Bone alkaline phosphatase and N terminal telopeptide (N-telopeptide) are markers of osteoblasts and osteoclast activation, and pancreastatin, neurokinin A (NKA), chromogranin A (CgA) and neuron-specific enolase are used to determine response to therapy and prognosis. Surgical resection of the primary tumor is recommended, even when there are metastases. New techniques are being developed for tumor localization (68Ga-tetra azacyclododecane tetra-acetic acid-octreotate [DOTATATE] positron emission tomography [PET] scans). Somatostatin (SST) that binds to SST receptors (SSTRs) 2 and 5 partially controls symptoms and tumor growth. Two new agents have been approved for treating PNETs: a tyrosine kinase inhibitor and a mammalian target of rapamycin (mTOR) inhibitor that increases progression-free survival (PFS). An exciting addition is the use of peptide receptor radiotherapy (PRRT) using SST as the peptide with a carrier such as 68Gallium (68Ga) for localization or 177Lutetium (177Lu) or 99Yttrium (99Y) for therapy. CONCLUSION: There have been advances in PNET diagnosis, tumor localization, and therapies in the last decade, and increased understanding of their pathophysiology is likely to be rewarded with new and emerging treatments for PNETs in the not too distant future. PMID- 25297672 TI - Visual vignette. PMID- 25297673 TI - A perspective of sensor-augmented insulin pump therapy in the treatment of type 1 diabetes. PMID- 25297674 TI - Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity. AB - Mutations in the X-linked gene encoding the transcriptional modulator methyl-CpG binding protein 2 (MeCP2) impair postnatal development of the brain. Here we use neuronal-type specific gene deletion in mice to show that conditional Mecp2 deletion in GABAergic parvalbumin-expressing (PV) cells (PV-Mecp2(-/y)) does not cause most Rett-syndrome-like behaviours, but completely abolishes experience dependent critical period plasticity of primary visual cortex (V1) that develops normal visual functions. However, selective loss of Mecp2 in GABAergic somatostatin-expressing cells or glutamatergic pyramidal cells does not affect the critical period plasticity. MeCP2-deficient PV cells exhibit high intrinsic excitability, selectively reduced efficacy of recurrent excitatory synapses in V1 layer 4 circuits, and decreased evoked visual responses in vivo. Enhancing cortical gamma-aminobutyric acid (GABA) inhibition with diazepam infusion can restore critical period plasticity in both young and adult PV-Mecp2(-/y) mice. Thus, MeCP2 expression in inhibitory PV cells during the critical period is essential for local circuit functions underlying experience-dependent cortical plasticity. PMID- 25297675 TI - Cross-Cultural Validation of the Rorschach Developmental Index. AB - The Developmental Index (DI) has recently been introduced as a composite Rorschach measure of psychological development and maturation, which can be used both with the Comprehensive System (Exner, 2003), and with the recently developed Rorschach Performance Assessment System (Meyer, Viglione, Mihura, Erard, & Erdberg, 2011). As the DI is new, and its validity has not yet been investigated with independent non-U.S. samples, we tested the correlation between DI and age using 3 relatively large samples, 2 of which were from outside the United States (total N = 902). Other Rorschach variables presumably associated with maturation, such as complexity and productivity, were also investigated. As expected, the DI significantly correlated with age, with small variations across the 3 samples. Importantly, the correlation between DI and age remained statistically significant also after controlling for productivity (i.e., the number of responses) and complexity. PMID- 25297676 TI - John Bradshaw (1918-1989): putting doctors on trial. AB - John S. Bradshaw (1918-1989) qualified as a doctor, but spent most of his professional life as a writer and journalist. His best-known work, Doctors on Trial (1978), a polemical book which attacked modern medicine, concluded that "western doctors today are certainly more productive, directly or indirectly, of ill-health, in every sense, than of health". This book was partly inspired by the writings of Ivan Illich, the Austrian priest and social philosopher. This article examines Bradshaw's life and the influence of Illich's thinking on Doctors on Trial. PMID- 25297677 TI - Association of the interleukin-22 genetic polymorphisms with ulcerative colitis. AB - BACKGROUND: Interleukin-22 (IL-22) is a member of the IL-10 family of anti inflammatory cytokines that mediates epithelial immunity. IL-22 expression was found to be increased in patients with ulcerative colitis (UC). Whether genetic polymorphisms of IL-22 also influence UC risk is still unknown. The purpose of this study was to investigate the association between the IL-22 gene polymorphisms (-429 C/T, +1046 T/A and +1995 A/C) and the risk of UC in Chinese Han patients. METHODS: This hospital-based case-control study comprised 180 patients with UC and 180 age- and gender-matched controls. Genotypes of 3 common polymorphisms of the IL-22 gene were determined by fluorogenic 5' exonuclease assays (TaqMan). RESULTS: Patients with UC had a significantly higher frequency of IL-22 -429 TT genotype [odds ratio (OR) =2.43, 95% confidence interval (CI) =1.35, 4.37; P=0.003] and -429 T allele (OR =1.54, 95% CI=1.14, 2.07; P=0.004) than controls. The findings are still emphatic by the Bonferroni correction. The IL-22+1046 T/A and IL-22+1995 A/C gene polymorphisms were not associated with a risk of UC. When stratifying by clinical type, location and disease severity of UC, no significant differences were found in any groups. CONCLUSION: This is the first study to provide evidence for an association of IL-22 -429 C/T gene polymorphisms with UC risk. Additional well-designed large studies were required for the validation of our results. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_183. PMID- 25297678 TI - Colonization of Bordetella pertussis clinical isolates that differ by pulsed field gel electrophoresis types in the lungs of naive mice or mice immunized with the whole-cell pertussis vaccine used in Poland. AB - The goal of our study was to compare the elimination of Bordetella pertussis clinical isolates that differ according to pulsed field gel electrophoresis (PFGE), serotypes and genes encoding virulence factors from the lungs of naive mice or mice immunized with commercial diphtheria-tetanus-whole-cell pertussis vaccine used in Poland. When a mixture of four isolates, given in equal proportions and harboring different PFGE profiles, serotypes, and alleles encoding virulence factors, was used to infect non-immunized mice, a single isolate, characterized by PFGE type IVgamma, Fim2 phenotype and ptxA1-prn2-tcfA2 fim2-1-ptxP1-ptxC1-fim3-1 alleles, was found to be significantly predominant compared to the others. This PFGE profile is commonly found in B. pertussis isolates circulating in some European countries since the late 1990s, confirming its high fitness. The Polish commercial whole-cell pertussis vaccine induced an immunity effective at eliminating the B. pertussis isolates from the lungs. However, the elimination of the isolate harboring PFGE type C profile, Fim2,3 phenotype and ptxA1-prn1-tcfA2-fim2-1-ptxP1-ptxC1-fim3-1 alleles was delayed as compared to the others, suggesting phenotypic differences with the other isolates and vaccine strains. Nevertheless, the same isolate, when challenged into mice in the defined mixture of strains, lost the competition with the others, as measured by lung colonization efficiency. This PFGE profile represents 15 % of the isolates circulating in Poland between 2001 and 2012. PMID- 25297679 TI - A robust estimation of exon expression to identify alternative spliced genes applied to human tissues and cancer samples. AB - BACKGROUND: Accurate analysis of whole-gene expression and individual-exon expression is essential to characterize different transcript isoforms and identify alternative splicing events in human genes. One of the omic technologies widely used in many studies on human samples are the exon-specific expression microarray platforms. RESULTS: Since there are not many validated comparative analyses to identify specific splicing events using data derived from these types of platforms, we have developed an algorithm (called ESLiM) to detect significant changes in exon use, and applied it to a reference dataset of 270 human genes that show alternative expression in different tissues. We compared the results with three other methodological approaches and provided the R source code to be applied elsewhere. The genes positively detected by these analyses also provide a verified subset of human genes that present tissue-regulated isoforms. Furthermore, we performed a validation analysis on human patient samples comparing two different subtypes of acute myeloid leukemia (AML) and we experimentally validated the splicing in several selected genes that showed exons with highly significant signal change. CONCLUSIONS: The comparative analyses with other methods using a fair set of human genes that show alternative splicing and the validation on clinical samples demonstrate that the proposed novel algorithm is a reliable tool for detecting differential splicing in exon-level expression data. PMID- 25297683 TI - Orientation- and passivation-dependent stability and electronic properties of alpha-Si3N4 nanobelts. AB - The energetic stability and electronic properties of unpassivated, hydrogen (-H) and hydroxyl (-OH) passivated alpha-Si3N4 nanobelts orientating along the [101], [210], [011], [100], [001], and [110] directions are investigated by first principles calculations. Calculations show that the energetic stabilities of alpha-Si3N4 nanobelts depend weakly upon orientations of nanobelts, but sensitively on passivation treatments. The most stable nanobelt is the OH cluster partially passivated alpha-Si3N4, followed by the H atom fully passivated and the unpassivated systems. All the unpassivated nanobelts show metallic characteristics due to the presence of dangling bonds of surficial atoms in nanobelts, while all the passivated nanobelts exhibit semiconducting characteristics. The valence band maximum (VBM) and the conduction band minimum (CBM) mainly originate from the surface N-2p and Si-3p states, respectively. For alpha-Si3N4 nanobelts orientating along [101], [210], [011] and [110] directions, the OH passivated systems exhibit a much smaller band gap than the H passivated systems, while the [100] and [001] orientated nanobelts exhibit the opposite band gap properties. PMID- 25297681 TI - Subsartorial adductor canal vs femoral nerve block for analgesia after total knee replacement. AB - PURPOSE: Providing effective analgesia for total knee arthroplasty (TKA) patients remains challenging. Femoral nerve block (FNB) offers targeted pain control; however, its effect on motor function, related fall risk and impact on rehabilitation has been the source of controversy. Adductor canal block (ACB) potentially spares motor fibres of the femoral nerve, but the comparative effect of the two approaches has not yet been well defined due to considerable variability in pain perception. Our study compares both single-shot FNB and ACB, side to side, in the same patients undergoing bilateral TKA. METHODS: Sixty patients scheduled for bilateral TKA were randomised to receive ultrasound-guided FNB on one leg and ACB on the other, in addition to combined spinal epidural anaesthesia. The primary outcome was comparative postoperative pain in either extremity at six to eight, 24 and 48 hours postoperatively. Secondary comparative outcomes included motor strength (manually and via dynamometer), physical therapy milestones and patient satisfaction. RESULTS: While pain levels were lowest at six to eight hours postoperatively and increased thereafter (P < 0.001), no significant differences were seen between extremities at any time point with regard to pain in the quantitative comparison using visual analogue scale (VAS) scores (P = 0.4154), motor strength (P = 0.7548), physical therapy milestones or patient satisfaction. However, in the qualitative comparison, a significant proportion of patients reported the leg receiving ACB to be more painful than that receiving FNB at 24 h [50.9 % (n = 30) vs 25.42 % (n = 15), P = 0.0168)]. CONCLUSIONS: Although we could not confirm a benefit in motor function between ACB and FNB, given the equivalent analgesic potency combined with its potentially lower overall impact if neuropraxia should occur, ACB may represent an attractive alternative to FNB. PMID- 25297684 TI - Lingual nerve palsy associated with submandibular gland carcinoma. PMID- 25297687 TI - Effect of Motivational Goals on the Causal Realism of Counterfactual Thoughts. AB - Counterfactual thinking refers to mental comparisons of reality with imagined alternatives of it. The "functional view" of counterfactual thinking suggests that upward counterfactuals (which improve on reality) serve a preparative function and downward counterfactuals (which worsen reality) serve an affective function. This view presumes that people generate counterfactuals that focus on cause(s) that have actually produced the negative outcomes. The two experiments reported here demonstrate that people spontaneously manipulate the causal content of their counterfactuals, depending on their motivational goals. Specifically, it was found that when people aim to feel better about a poor decision they generate less realistic (upward) counterfactuals, experience less negative affect and tend to attribute the outcome to less controllable causes than when they aim to learn from their experience. The theoretical and practical implications of these findings are discussed. PMID- 25297688 TI - Masayuki Endo. PMID- 25297690 TI - Docking analysis insights quercetin can be a non-antibiotic adjuvant by inhibiting Mmr drug efflux pump in Mycobacterium sp. and its homologue EmrE in Escherichia coli. AB - Drug efflux pumps (EP) like Mmr in Mycobacterium transported drugs out of cell, a main reason for drug resistance developing in Mycobacterium tuberculosis. In this in silico study, mainly analysed EP inhibitory potential of a plant-derived flavonoid, quercetin, through docking analysis. Mmr present in Mycobacterium smegmatis and M. tuberculosis, and its homologue EmrE of Escherichia coli was used. Initially, homology modelling of EP monomers and dimers constructed from M. smegmatis, M. tuberculosis and E. coli; the stabilities of models were analysed from Ramachandran plots prepared in PROCHECK. Docking analysis of quercetin with EP protein showed that in all three organisms, the residues for function and stability are important and quercetin had best interactions comparing to compounds such as, verapamil, reserpine, chlorpromazine, Carbonyl Cyanide m- Chloro Phenylhydrazone. Molecular dynamics and simulation studies showed that during the entire course of simulation quercetin-Mmr complex were stable. It insights quercetin can act as a non-antibiotic adjuvant for treatment of tuberculosis by bring down the efflux of drug from bacteria. PMID- 25297689 TI - Total pancreatectomy with islet cell autotransplantation as the initial treatment for minimal-change chronic pancreatitis. AB - OBJECTIVES: Patients with minimal-change chronic pancreatitis (MCCP) are traditionally managed medically with poor results. This study was conducted to review outcomes following total pancreatectomy with islet cell autotransplantation (TP/IAT) as the initial surgical procedure in the treatment of MCCP. METHODS: All patients submitted to TP/IAT for MCCP were identified for inclusion in a single-centre observational study. A retrospective chart review was performed to identify pertinent preoperative, perioperative and postoperative data. RESULTS: A total of 84 patients with a mean age of 36.5 years (range: 15-60 years) underwent TP/IAT as the initial treatment for MCCP. The most common aetiology of chronic pancreatitis in this cohort was idiopathic (69.0%, n = 58), followed by aetiologies associated with genetic mutations (16.7%, n = 14), pancreatic divisum (9.5%, n = 8), and alcohol (4.8%, n = 4). The most common genetic mutations pertained to CFTR (n = 9), SPINK1 (n = 3) and PRSS1 (n = 2). Mean +/- standard error of the mean preoperative narcotic requirements were 129.3 +/- 18.7 morphine-equivalent milligrams (MEQ)/day. Overall, 58.3% (n = 49) of patients achieved narcotic independence and the remaining patients required 59.4 +/- 10.6 MEQ/day (P < 0.05). Postoperative insulin independence was achieved by 36.9% (n = 31) of patients. The Short-Form 36-Item Health Survey administered postoperatively demonstrated improvement in all tested quality of life subscales. CONCLUSIONS: The present report represents one of the largest series demonstrating the benefits of TP/IAT in the subset of patients with MCCP. PMID- 25297691 TI - How to prepare neuroanatomical image data. AB - As image data from a single neuroanatomical study can easily exceed tens of gigabytes, managing, analyzing, and presenting it is not trivial. Careful planning along multiple axes is required and includes the following: (1) Organizational methods developed for images should allow for easy and efficient access, selection, and potential reorganization of images. (2) Experimental information and other metadata should be readily available and accompany image data. (3) Even if a study's entire body of image data is made available, highlighting key results and preparing figures requires selecting image regions and resolutions, creating annotations, and adhering to publishing and community guidelines for image adjustments. Further, it may be necessary to assess Internet accessibility and infrastructure issues and to consider image formats appropriate for Web publishing. Finally, a strategy for robust, long-term, and efficient storage of image data should be developed. This unit provides a guide for preparing neuroanatomical image data. PMID- 25297692 TI - Primary porcine brain microvessel endothelial cell isolation and culture. AB - Cell culture models of the blood-brain barrier (BBB) are useful tools to study the functionality of the BBB in health and disease. Several good in vitro BBB models are available from different species. However, most brain endothelial cells lose some of their in vivo BBB phenotype in culture. Porcine brain endothelial cells (PBECs) tend to retain most of their in vivo BBB characteristics and usually give higher transendothelial electrical resistance (TEER, representing functional well-developed tight junctions) compared to brain endothelial cells from other species. The protocol described in this unit gives detailed instructions for isolation and culture of PBECs from fresh porcine brains. This porcine BBB model generates high TEER without the need for co culture with astrocytes. However, astrocyte-derived factors can be introduced to the system through the use of astrocyte-conditioned medium or co-culture with astrocytes, which may be necessary for further enhancing the BBB phenotype for certain complex studies. PMID- 25297693 TI - Examining object location and object recognition memory in mice. AB - This unit is designed to provide sufficient instruction for the setup and execution of tests for object location and object recognition in adult mice. This task is ideally suited for the study of a variety of mouse models that examine disease mechanisms and novel therapeutic targets. By altering several key parameters, the experimenter can investigate short-term or long-term memory and look for either memory impairments or enhancements. Object location and object recognition memory tasks rely on a rodent's innate preference for novelty, and can be conducted sequentially in the same cohort of animals. These two tasks avoid the inherent stress induced with other common measures of rodent memory such as fear conditioning and the Morris water maze. This protocol covers detailed instructions on conducting both tasks, as well as key points concerning data collection, analysis, and interpretation. PMID- 25297694 TI - Emotional information processing in depression and burnout: an eye-tracking study. AB - Whether burnout is a form of depression is unclear. The aim of this study was to examine the relevance of the burnout-depression distinction by comparing attentional processing of emotional information in burnout and depression. Eye tracking technology was employed for assessing overt attentional deployment. The gaze of 54 human services employees was monitored as they freely viewed a series of emotional images, labeled as dysphoric, positive, anxiogenic, and neutral. Similar to depression, burnout was associated with increased attention for dysphoric stimuli and decreased attention for positive stimuli. Hierarchical multiple regression analyses revealed that burnout no longer predicted these attentional alterations when depression was controlled for and vice versa, suggesting interchangeability of the two entities in this matter. To our knowledge, this study is the first to (a) investigate emotional attention in burnout and (b) address the issue of the burnout-depression overlap at both cognitive and behavioral levels using eye movement measurement. Overall, our findings point to structural similarities between burnout and depression, thus deepening concerns regarding the singularity of the burnout phenomenon. PMID- 25297695 TI - Complexin2 modulates working memory-related neural activity in patients with schizophrenia. AB - The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as 'neural inefficiency,' these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults. PMID- 25297696 TI - Prevalence of dyslipidemia and its association with insomnia in a community based population in China. AB - BACKGROUND: Studies of the prevalence of dyslipidemia and its association with insomnia are scarce in China. This study investigated the prevalence of dyslipidemia and its association with insomnia in a community based Chinese population. METHODS: We conducted a cross-sectional survey in Beijing and recruited 10054 participants aged >= 18 years. The association between self reported insomnia and dyslipidemia was determined by multiple logistic regression models. Age, gender, education, obesity, body mass index, physical activity, current smoking, current drinking, diabetes, and hypertension were adjusted as confounders. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were reported as effect measurements. RESULTS: The prevalence of dyslipidemia in those with no insomnia, occasional insomnia, and frequent insomnia were 53.3%, 54.3%, and 54.5% in men and 52.0%, 54.8%, and 61.2% in women. Compared with subjects with no insomnia, the multivariate adjusted ORs and 95% CIs for those with occasional insomnia and frequent insomnia were 1.07(0.86 ~ 1.34) and 1.19(0.89 ~ 1.60) for men, and 1.00(0.86 ~ 1.14) and 1.23(1.03 ~ 1.47) for women. CONCLUSIONS: These observations indicate that frequent insomnia was associated with a higher prevalence of dyslipidemia in women. This association was not significant in men. PMID- 25297697 TI - Chemoselective peptide functionalization of starPEG-GAG hydrogels. AB - Glycosaminoglycan (GAG)-based hydrogels gain increasing interest in regenerative therapies. To support specific applications, the biomolecular functionality of gel matrices needs to be customized via conjugation of peptide sequences that mediate cell adhesion, expansion and differentiation. Herein, we present an orthogonal strategy for the formation and chemoselective functionalization of starPEG-GAG hydrogels, utilizing the uniform and specific conjugation of peptides and GAGs for customizing the resulting materials. The introduced approach was applied for the incorporation of three different types of RGD peptides to analyze the influence of peptide sequence and conformation on adhesion and morphogenesis of endothelial cells (ECs) grown on the peptide-containing starPEG-GAG hydrogels. The strongest cellular response was observed for hydrogels functionalized with cycloRGD followed by linear forms of RGDSP and RGD, showing that morphogenesis and growth rate of ECs is controlled by both type and quantity of the conjugated peptides. PMID- 25297698 TI - Parasitoses with central nervous system involvement. AB - Most of the parasitoses manifest systemically, including the central nervous system (CNS). Among the most prevalent parasitoses in Central Europe (cysticercosis, toxocarosis, echinococcosis, and toxoplasmosis), cerebral involvement is well recognized and part of the clinical presentation, which cannot be neglected. CNS involvement results from invasion of larvae of these parasites via the blood stream or by direct migration into the CNS. Most frequently larvae reside within the cerebral parenchyma, but sometimes also within the ventricles, in the meningeas within cerebral aneurysms, or in the parenchyma of the spinal cord. Depending on the stage of their development, they cause a local defect or more widespread damage, such as encephalitis, ventriculitis, ependymitis, arachnoiditis, meningitis, myelitis, polyradiculitis, mechanical obstruction of the arterial or cerebrospinal fluid (CSF) flow, or vasculitis with appropriate clinical presentations. These include epilepsy, headache, impaired consciousness, orientation, cognition, focal neurological motor, sensory, or vegetative deficits, or visual impairment. CNS involvement is diagnosed on the clinical presentation, the epidemiological background, blood and CSF investigations, imaging studies, and sometimes biopsy. Treatment is based on various antihelminthic agents and, occasionally, surgery. PMID- 25297701 TI - Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma. AB - AIM: Amino acid transporters play an important role in tumor progression and survival of cancer cells. However, the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino acid transporter-2 (ASCT2) and xCT expression in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC. METHODS: We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67 and microvessel density (MVD) determined by CD34. RESULTS: LAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and alpha-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery. CONCLUSION: LAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery. PMID- 25297700 TI - Use of a structural alphabet to find compatible folds for amino acid sequences. AB - The structural annotation of proteins with no detectable homologs of known 3D structure identified using sequence-search methods is a major challenge today. We propose an original method that computes the conditional probabilities for the amino-acid sequence of a protein to fit to known protein 3D structures using a structural alphabet, known as "Protein Blocks" (PBs). PBs constitute a library of 16 local structural prototypes that approximate every part of protein backbone structures. It is used to encode 3D protein structures into 1D PB sequences and to capture sequence to structure relationships. Our method relies on amino acid occurrence matrices, one for each PB, to score global and local threading of query amino acid sequences to protein folds encoded into PB sequences. It does not use any information from residue contacts or sequence-search methods or explicit incorporation of hydrophobic effect. The performance of the method was assessed with independent test datasets derived from SCOP 1.75A. With a Z-score cutoff that achieved 95% specificity (i.e., less than 5% false positives), global and local threading showed sensitivity of 64.1% and 34.2%, respectively. We further tested its performance on 57 difficult CASP10 targets that had no known homologs in PDB: 38 compatible templates were identified by our approach and 66% of these hits yielded correctly predicted structures. This method scales-up well and offers promising perspectives for structural annotations at genomic level. It has been implemented in the form of a web-server that is freely available at http://www.bo-protscience.fr/forsa. PMID- 25297699 TI - Hydrogen sulphide protects against NSAID-enteropathy through modulation of bile and the microbiota. AB - BACKGROUND AND PURPOSE: Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID-induced intestinal damage and bleeding. We evaluated the ability of a hydrogen sulphide donor to protect against NSAID-induced enteropathy. EXPERIMENTAL APPROACH: Intestinal ulceration and bleeding were induced in Wistar rats by oral administration of naproxen. The effects of suppression of endogenous hydrogen sulphide synthesis or administration of a hydrogen sulphide donor (diallyl disulphide) on naproxen-induced enteropathy was examined. Effects of diallyl disulphide on small intestinal inflammation and intestinal microbiota were also assessed. Bile collected after in vivo naproxen and diallyl disulphide administration was evaluated for cytotoxicity in vitro using cultured intestinal epithelial cells. KEY RESULTS: Suppression of endogenous hydrogen sulphide synthesis by beta-cyano-L-alanine exacerbated naproxen-induced enteropathy. Diallyl disulphide co-administration dose dependently reduced the severity of naproxen-induced small intestinal damage, inflammation and bleeding. Diallyl disulphide administration attenuated naproxen induced increases in the cytotoxicity of bile on cultured enterocytes, and prevented or reversed naproxen-induced changes in the intestinal microbiota. CONCLUSIONS AND IMPLICATIONS: Hydrogen sulphide protects against NSAID enteropathy in rats, in part reducing the cytotoxicity of bile and preventing NSAID-induced dysbiosis. PMID- 25297702 TI - Ya gotta have friends: social support and self-efficacy predict success following immersion treatment. AB - OBJECTIVE: This study examined the impact of perceived social support and self efficacy on predicting success in weight management following immersion treatment of adolescent obesity. METHODS: 198 overweight and obese adolescents (M% overweight = 81.4%; M BMI = 36.0) participated in Wellspring's cognitive behavioral therapeutic camps for 3-10 weeks during the summer of 2011. The campers and one of their caretakers completed a series of questionnaires at the halfway point during immersion. One year following camp, campers and their parents provided follow-up heights and weights. RESULTS: Multiple regression intent to treat analyses indicated that campers who perceived their friends as supportive, reported confidence in their ability to succeed, and believed that their families functioned well achieved relatively more substantial reductions in percent overweight 1 year after immersion. Perceptions of support anticipated from parents failed to predict success. Campers who more fully engaged in the process of change at camp also achieved somewhat greater success in the long run. CONCLUSIONS: These results suggest that participants in cognitive-behavioral immersion treatment may improve outcomes by nurturing support from their friends, increasing self-efficacy, and having their families consider family therapy if warranted. PMID- 25297703 TI - Diffusion-weighted magnetic resonance imaging for the diagnosis of patients with lumbar nerve root entrapment syndromes: results from a pilot study. AB - PURPOSE: Lumbar nerve root entrapment syndromes cause radicular signs and symptoms in the affected leg. The applicability of diffusion-weighted imaging (DWI) for the assessment of lower lumbar nerves (L4-S1) has been demonstrated. The purpose of this pilot study was to establish DWI reference data for the all lumbosacral nerve roots (L1-S1) in a healthy, asymptomatic study population and to determine its potential as a diagnostic tool for patients with lumbar radicular syndromes. METHODS: 20 asymptomatic healthy volunteers were included (average age 39 years (24-59 years; n = 10 female, n = 10 male). The lumbosacral spine was scanned twice in a standardized fashion (1.5 T Magnetom Avanto and 3 T Magnetom Skyra, Siemens AG Healthcare, Erlangen, Germany). A spin-echo type echo planar (SE-EPI) sequence was used to determine axial ADC maps and measurements (length, width, and angulation) of the dorsal root ganglion (DRG) and distal spinal nerves (DSN). Disc pathology, lumbar foraminal stenosis and nerve root compromise were classified. RESULTS: Using 3 T images 218 (91%) lumbar nerve roots had no pathologic finding [1.5 T: 226 (94%)]. All DRG and DSN could be visualized and identified on axial apparent diffusion coefficient (ADC). On average we measured ADC values of 1,231 mm(2)/s (SD 308 mm(2)/s) at the DRG for the 1.5 T scanner and 1,756 mm(2)/s (SD 465 mm(2)/s) for the 3 T scanner. There were no statistically significant gender or side differences in the 1.5 and 3 T images (p > 0.05). We noted an increase of the ADC values starting from cranial (L1: 1,444 mm(2)/s) to caudal (S1: 1,918 mm(2)/s). The average ADC value at the DSN was 1,018 mm(2)/s for the 1.5 T scanner compared to 1,589 mm(2)/s for the 3 T scanner (p < 0.001). CONCLUSIONS: For the first time, we have established data for the DRG and DSN in human lumbosacral spinal nerves (L1-S1), using diffusion weighted magnetic resonance imaging techniques. 3 T ADC maps have a higher signal to noise ratio, thus offering better image quality. Results from this study suggest that DWI has added value as new diagnostic tools for patients with symptomatic lumbar nerve root entrapment syndromes as well. PMID- 25297704 TI - Good survivorship of all-polyethylene tibial component UKA at long-term follow up. AB - PURPOSES: To determine the long-term survival rate of an all-polyethylene tibial unicompartmental knee arthroplasty (UKA) in a large series of consecutive patients and to investigate the possible factors that could influence the outcome. METHODS: A retrospective evaluation of 273 patients at 6-13 years of follow-up was performed. Clinical evaluation was based on KSS and WOMAC scores. Subjective evaluation was based on a visual analogue scale for pain self assessment. Radiographic evaluation was performed to assess femoral-tibial angle (FTA), posterior tibial slope (PTS) and tibial plateau angle (TPA). A Kaplan Meier survival analysis was performed assuming revision for any reason as primary endpoint. RESULTS: The 10-year implant survivorship was 87.6%. Twenty-five revisions (9.2%) were performed, and aseptic loosening of the tibial component was the most common failure mode (11 cases, 4%). The comparison of survival rate according to age at surgery did not show significant difference. Age at surgery, FTA, TPA and PTS were not related to higher risk of revision. No correlations were found between BMI, age at surgery and clinical scores. Finally, no statistical differences of radiographic measurements were found between revisions and non-revisions. CONCLUSIONS: The present study has demonstrated on a large series of patients that UKA with an all-polyethylene tibial component, with an accurate technique and a proper patient selection, can provide a satisfactory clinical and functional outcome and a good overall survivorship of the implant at long-term follow-up. These advantages could be achieved at a lower cost. LEVEL OF EVIDENCE: Retrospective Therapeutic Study, Level IV. PMID- 25297705 TI - Two-dimensional planning can result in internal rotation of the femoral component in total knee arthroplasty. AB - PURPOSE: The first purpose of this study was to compare the reproducibility of two-dimensional (2D) and three-dimensional (3D) measurements for preoperative planning of the femoral side in total knee arthroplasty (TKA). The second purpose was to evaluate the factors affecting the differences between the 2D and 3D measurements. METHODS: Two-dimensional and 3D measurements for preoperative planning of the femoral side in TKA were evaluated in 75 varus knees with osteoarthritis. The femoral valgus angle, defined as the angle between the mechanical and anatomical axes of the femur, and the clinical rotation angle and surgical rotation angle, defined by the angles between the posterior condylar line and the clinical or surgical transepicondylar axes, respectively, were analysed using 2D (radiographs and axial CT slices) and 3D (3D bone models reconstructed from CT images) measurements. RESULTS: For all variables, 3D measurements were more reliable and reproducible than 2D measurements. The medians and ranges of the clinical rotation angle and surgical rotation angle were 6.6 degrees (-1.7 degrees to 12.1 degrees ) and 2.3 degrees (-2.5 degrees to 8.6 degrees ) in 2D, and 7.1 degrees (2.7 degrees to 11.4 degrees ) and 3.0 degrees (-2.0 degrees to 7.5 degrees ) in 3D. Varus/valgus alteration of the CT scanning direction relative to the mechanical axis affected the difference in clinical rotation angles between 2D and 3D measurements. CONCLUSION: Significantly, smaller values of the clinical rotation angle and surgical rotation angle were obtained by 2D compared to 3D measurements, which could result in internal rotation of the femoral component even if the surgeon performs the bone cutting precisely. Regarding clinical relevance, first, this study confirmed the reliability of 3D measurements. Second, it underscored the risk of internal rotation of the femoral component when using 2D measurement, even with precise bone cutting technique. These results will help surgeons avoid malpositioning of the femoral component if 2D measurements are used for preoperative planning in TKA. LEVEL OF EVIDENCE: Prospective comparative study, Level SH. PMID- 25297707 TI - Association between toe flexor strength and spatiotemporal gait parameters in community-dwelling older people. AB - BACKGROUND: The toe flexor muscles perform a crucial function to control foot movement and assist with propulsive force when walking. However, the association between toe flexor strength and spatio-temporal gait parameters is largely unknown. Spatiotemporal gait parameters represent gait characteristics, and are good measures of the functional status and degree of safe ambulation among community-dwelling older adults. Herein, we examined the association between the toe flexor strength and spatiotemporal gait parameters in community-dwelling older adults. METHODS: Ninety-three community-dwelling older people (mean age: 73.2 +/- 4.2 years, 53 women) participated in this study. The strength of the toe flexor muscles was assessed using a toe strength measuring instrument and a strain gauge. The measurements were performed once on each foot, and the average of the right and left was used in the analysis. Gait analysis was performed on a 15-m walkway under usual- and fast-pace conditions. The medial 10-m walking time was measured and walking speed was calculated. Acceleration and angular velocity of the right heel were measured using a wireless miniature sensor unit and used to compute cadence, percent of swing time in gait cycle (%swing time), and stride length. RESULTS: In multiple regression analyses adjusted for age, sex, body height, body weight, and hand grip strength, no associations between toe flexor strength and spatiotemporal gait parameters at usual pace were found. Conversely, under the fast-pace condition, decreased toe flexor strength was significantly associated with slower walking speed (beta = 0.22, p = 0.049), lower%swing time (beta = 0.34, p = 0.009), and shorter stride length (beta = 0.22, p = 0.011) after adjustment. CONCLUSION: In community-dwelling older people, decreased strength of toe flexor was correlated with slower walking speed, shorter periods of single-limb support phase, and shorter stride length during fast-pace walking. These data provide further support for an important role of toe flexor muscles in walking. PMID- 25297708 TI - Benzene solubility in ionic liquids: working toward an understanding of liquid clathrate formation. AB - The solubility of benzene in 15 imidazolium, pyrrolidinium, pyridinium, and piperidinium ionic liquids has been determined; the resulting, benzene-saturated ionic liquid solutions, also known as liquid clathrates, were examined with (1) H and (19) F nuclear magnetic resonance spectroscopy to try and understand the molecular interactions that control liquid clathrate formation. The results suggest that benzene interacts primarily with the cation of the ionic liquid, and that liquid clathrate formation (and benzene solubility) is controlled by the strength of the cation-anion interactions, that is, the stronger the cation-anion interaction, the lower the benzene solubility. Other factors that were determined to be important in the final amount of benzene in any given liquid clathrate phase included attractive interactions between the anion and benzene (when significant), and larger steric or free volume demands of the ions, both of which lead to greater benzene solubility. PMID- 25297709 TI - Global lung cancer risk from PAH exposure highly depends on emission sources and individual susceptibility. AB - The health impacts of polycyclic aromatic hydrocarbons (PAHs), the most concerning organic pollutants, depend not only on the locations and strengths of emission sources, but also on individual susceptibility. Moreover, trans-boundary transport makes them a global concern. In this study, a comprehensive analysis of the global health impacts of polycyclic aromatic hydrocarbons (PAHs) in ambient air is presented. Model resolution is critical in exposure modelling. Globally, incremental lifetime lung cancer risk (ILCR) induced by ambient PAH exposure is 3.1 * 10(-5). If the individual susceptibility was not taken into consideration, the overall risk would be underestimated by 55% and the proportion of highly vulnerable population would be underestimated by more than 90%. Emphasizing on individual susceptibility, our study provides an instrumental revision of current risk assessment methodology. In terms of lung cancer risk, the most important sources are combustion of biomass fuels (40%) and fossil fuels (14%) in the residential/commercial sector, coke (13%) and aluminium (12%) production, and motor vehicles (9%). PAHs can travel long distance globally especially within the Eurasian continent. Still, the risk is dominantly contributed by local. PMID- 25297710 TI - Acethylcholinesterase inhibitory potential and antioxidant properties of pyrogallol. AB - Pyrogallol is found naturally in crops and fruits of many plants. It is also an active ingredient of many pharmaceuticals. For this reason, we employed different in vitro antioxidant assays such as cupric ion Cu(2+) reducing power, Fe(3+) reducing power, total antioxidant activity by ferric thiocyanate method, ABTS radical scavenging, DMPD radical scavenging, DPPH * scavenging, Fe(2+) chelating, [Formula: see text] scavenging and H(2)O(2) scavenging activities of pyrogallol. Pyrogallol inhibited 77.95% lipid peroxidation of linoleic acid emulsion at 30 MUg/mL concentration. BHA, BHT, alpha-tocopherol and trolox exhibited inhibitions of 89.88, 89.97, 83.82 and 91.85% against peroxidation of linoleic acid emulsion at the same concentration, respectively. In addition, pyrogallol was an effective of all the scavenging and reducing power results. In this study, pyrogallol was also evaluated as potential inhibitor for acethycholinesterse enzyme. The results showed that pyrogallol exhibited potent acetylcholinesteras inhibitory activity with IC(50) and K(I) values 10.2 and 8.6 MUM, respectively. PMID- 25297711 TI - Groundwater vulnerability assessment using DRASTIC and Pesticide DRASTIC models in intense agriculture area of the Gangetic plains, India. AB - Delineating areas susceptible to contamination from anthropogenic sources form an important component of sustainable management of groundwater resources. The present research aims at estimating vulnerability of groundwater by application of DRASTIC and Pesticide DRASTIC models in the southern part of the Gangetic plains in the state of Bihar. The DRASTIC and Pesticide DRASTIC models have considered seven parameters viz. depth to water level, net recharge, aquifer material, soil material, topography, impact of vadose zone and hydraulic conductivity. A third model, Pesticide DRASTIC LU has been adopted by adding land use as an additional parameter, to assess its impact on vulnerability zonation. The DRASTIC model indicated two vulnerable categories, moderate and high, while the Pesticide DRASTIC model revealed moderate, high and very high vulnerable categories. Out of the parameters used, depth to water level affected the vulnerability most. The parameter caused least impact was topography in DRASTIC, while in case of Pesticide DRASTIC and Pesticide DRASTIC LU models, the parameter was hydraulic conductivity. A linear regression between groundwater NO3 concentrations and the vulnerability zonation revealed better correlation for Pesticide DRASTIC model, emphasising the effectiveness of the model in assessing groundwater vulnerability in the study region. Considering all three models, the most vulnerable areas were found to be concentrated mainly in two zones, (i) in the south-western part along Ekangarsarai-Islampur patch and (ii) around Biharsharif-Nagarnausa area in the central part. Both zones were characterised by intensive vegetable cultivation with urban areas in between. PMID- 25297712 TI - Spatial distribution, temporal variation, and sources of heavy metal pollution in groundwater of a century-old nonferrous metal mining and smelting area in China. AB - This study first presents the spatial distribution, temporal variation, and sources of heavy metal pollution in groundwater of a nonferrous metal mine area in China. Unconfined groundwater was polluted by Pb, Zn, As, and Cu, in order, while confined karst water in the mines showed pollution in the following sequence: Zn, Cd, Cu, Pb, and As. Pollution by Pb was widespread, while Zn, As, Cu, and Cd were found to be high in the north-central industrial region and to decrease gradually with distance from smelters and tailings. Vertically, more Pb, Zn, Cu, and Cd have accumulated in shallow Quaternary groundwater, while more As have migrated into the deeper fracture groundwater in the local discharge area. Zn, Cd, and Cu concentrations in groundwater along the riverside diminished owing to reduced wastewater drainage since 1977, while samples in the confluence area were found to have increasing contents of Pb, Zn, As, Cu, and Cd since industrialization began in the 1990s. Sources of heavy metals in groundwater were of anthropogenic origin except for Cr. Pb originated primarily from airborne volatile particulates, wastewater, and waste residues and deposited continuously, while Zn, Cd, and Cu were derived from the wastewater of smelters and leakage of tailings, which corresponded to the related soil and surface residue researches. Elevated As values around factories might be the result of chemical reactions. Flow patterns in different hydrogeological units and adsorption capability of from Quaternary sediments restricted their cross-border diffusion. PMID- 25297713 TI - Bovine serum albumin adsorbed PGA-co-PDL nanocarriers for vaccine delivery via dry powder inhalation. AB - PURPOSE: Dry powder vaccine delivery via the pulmonary route has gained significant attention as an alternate route to parenteral delivery. In this study, we investigated bovine serum albumin (BSA) adsorbed poly(glycerol adipate co-omega-pentadecalactone), PGA-co-PDL polymeric nanoparticles (NPs) within L leucine (L-leu) microcarriers for dry powder inhalation. METHODS: NPs were prepared by oil-in-water single emulsion-solvent evaporation and particle size optimised using Taguchi's design of experiment. BSA was adsorbed onto NPs at different ratios at room temperature. The NPs were spray-dried in aqueous suspension of L-leu (1:1.5) using a Buchi-290 mini-spray dryer. The resultant nanocomposite microparticles (NCMPs) were characterised for toxicity (MTT assay), aerosolization (Next Generation Impactor), in vitro release study and BSA was characterized using SDS-PAGE and CD respectively. RESULTS: NPs of size 128.50 +/- 6.57 nm, PDI 0.07 +/- 0.03 suitable for targeting lung dendritic cells were produced. BSA adsorption for 1 h resulted in 10.23 +/- 1.87 MUg of protein per mg of NPs. Spray-drying with L-leu resulted in NCMPs with 42.35 +/- 3.17% yield. In vitro release study at 37 degrees C showed an initial burst release of 30.15 +/- 2.33% with 95.15 +/- 1.08% over 48 h. Aerosolization studies indicated fine particle fraction (FPF%) dae < 4.46 MUm as 76.95 +/- 5.61% and mass median aerodynamic diameter (MMAD) of 1.21 +/- 0.67 MUm. The cell viability was 87.01 +/ 14.11% (A549 cell line) and 106.04 +/- 21.14% (16HBE14o- cell line) with L-leu based NCMPs at 1.25 mg/ml concentration after 24 h treatment. The SDS-PAGE and CD confirmed the primary and secondary structure of the released BSA. CONCLUSIONS: The results suggest that PGA-co-PDL/L-leu NCMPs may be a promising carrier for pulmonary vaccine delivery due to excellent BSA adsorption and aerosolization behaviour. PMID- 25297715 TI - Molecular pathogenesis in granulosa cell tumor is not only due to somatic FOXL2 mutation. AB - Granulosa cell tumors are rare ovarian malignancies. Their characteristics include unpredictable late recurrent and malignant behavior. Recent molecular studies have characterized the FOXL2 402C > G mutation in adult-type granulosa cell tumor. In this study, we report an 80-year-old woman with a granulosa cell tumor arising from ovary. She presented with a huge pelvic mass with postmenopausal bleeding. No obvious intraperitoneal tumor implants were observed during operation. Final diagnosis was granulosa-theca cell tumor without capsule invasion. No recurrent disease was noted during 3-year post-operation follow-up period. Molecular studies showed a heterozygous FOXL2 402C > G mutation in the tumor by direct gene sequencing. In addition, DNA replication error, on analysis of the lengths of CAG repeats in androgen receptor gene, revealed defective DNA mismatch repair system in the granulosa cell tumor. We propose that the 402C > G mutation in FOXL2 is critical to the development of adult granulosa cell tumor. However, the malignant behavior of this tumor is driven by DNA mismatch repair deficiency. Unequal DNA copy numbers were noted on array comparative genomic hybridization. This implies that there is malignant potential even in the early stage of the granulosa cell tumor. Late malignant recurrence may be a late event of DNA repair function disability, not directly related to pathognomonic FOXL2 mutation. PMID- 25297714 TI - Pulmonary biodistribution and cellular uptake of intranasally administered monodisperse particles. AB - PURPOSE: For the rational design of nanovaccines against respiratory pathogens, careful selection of optimal particle size and chemistry is paramount. This work investigates the impact of these properties on the deposition, biodistribution, and cellular interactions of nanoparticles within the lungs. METHOD: In this work, biodegradable poly(sebacic anhydride) (poly(SA)) nanoparticles of multiple sizes were synthesized with narrow particle size distributions. The lung deposition and retention as well as the internalization by phagocytic cells of these particles were compared to that of non-degradable monodisperse polystyrene nanoparticles of similar sizes. RESULTS: The initial deposition of intranasally administered particles in the lungs was dependent on primary particle size, with maximal deposition occurring for the 360-470 nm particles, regardless of chemistry. Over time, both particle size and chemistry affected the frequency of particle-positive cells and the specific cell types taking up particles. The biodegradable poly(SA) particles associated more closely with phagocytic cells and the dynamics of this association impacted the clearance of these particles from the lung. CONCLUSIONS: The findings reported herein indicate that both size and chemistry control the fate of intranasally administered particles and that the dynamics of particle association with phagocytic cells in the lungs provide important insights for the rational design of pulmonary vaccine delivery vehicles. PMID- 25297717 TI - Median nerve ultrasound: normal and cut-off values in carpal tunnel syndrome in an Afro-Caribbean population. PMID- 25297716 TI - Respiration and ecological niche influence bacterial membrane lipid compositions. AB - Bacterial membrane compositions vary widely between phyla and within related species. The types of lipids within membranes are as diverse as the selective pressures that influence bacterial lifestyles such as their mode of respiration and habitat. This study has examined the extent that respiration and habitat affect bacterial fatty acid (FA) and polar lipid (PL) compositions. To accomplish this, over 300 FA and PL profiles from 380 previously characterized species were assembled and subjected to multivariate statistical analyses in order to determine lipid to habitat/respiration associations. It was revealed that PL profiles showed a slight advantage over FA profiles for discriminating taxonomic relationships between species. FA profiles showed greater correlation with respiration and habitat than PL. This study identified that respiration did not consistently favour uniform FA or PL changes when lipid profiles were compared between examined phyla. This suggests that although phyla may adopt similar respiration methods, it does not result in consistent lipid attributes within one respiration state. Examination of FA and PL compositions were useful to identify taxonomic relationships between related species and provides insight into lipid variations influenced by the niche of its host. PMID- 25297718 TI - Facile tandem Suzuki coupling/transfer hydrogenation reaction with a bis heteroscorpionate Pd-Ru complex. AB - Design and synthesis of the bis(pyrazol-1-yl)methane based bis-heteroscorpionate Pd-Ru complex results in efficient tandem Suzuki coupling/transfer hydrogenation reaction with a broad range of substrate reactivity. PMID- 25297719 TI - The response of human nasal and bronchial organotypic tissue cultures to repeated whole cigarette smoke exposure. AB - Exposure to cigarette smoke (CS) is linked to the development of respiratory diseases, and there is a need to understand the mechanisms whereby CS causes damage. Although animal models have provided valuable insights into smoking related respiratory tract damage, modern toxicity testing calls for reliable in vitro models as alternatives for animal experimentation. We report on a repeated whole mainstream CS exposure of nasal and bronchial organotypic tissue cultures that mimic the morphological, physiological, and molecular attributes of the human respiratory tract. Despite the similar cellular staining and cytokine secretion in both tissue types, the transcriptomic analyses in the context of biological network models identified similar and diverse biological processes that were impacted by CS-exposed nasal and bronchial cultures. Our results demonstrate that nasal and bronchial tissue cultures are appropriate in vitro models for the assessment of CS-induced adverse effects in the respiratory system and promising alternative to animal experimentation. PMID- 25297721 TI - Treating umbilical granuloma with topical clobetasol propionate cream at home is as effective as treating it with topical silver nitrate in the clinic. AB - AIM: There is a lack of evidence on the best treatment option for umbilical granuloma. The primary aim of this study was to compare three treatments for umbilical granuloma: standard treatment with topical silver nitrate, clobetasol propionate cream (0.05%) and ethanol wipes. The secondary aim was to evaluate whether the treatment could be successfully administered by a parent at home, rather than in the outpatient clinic. METHODS: A total of 109 infants were randomised to one of three groups and 94 infants completed the assigned treatment: 30 infants received standard treatment with silver nitrate (99%) in the outpatient clinic, 30 infants had topical clobetasol propionate cream (0.05%) applied at home, and 34 infants received cleansing with ethanol wipes (82%) at home. RESULTS: Silver nitrate and clobetasol propionate cream (0.05%) were significantly superior to ethanol wipes, with shorter healing times and higher resolution rates (p = 0.0001). Healing time and resolution rates were identical for silver nitrate and clobetasol propionate cream (0.05%). Mild side effects were occasionally reported, all of which were self-limiting. CONCLUSION: Treating umbilical granuloma with topical clobetasol propionate cream (0.05%) at home is as effective as treating it with topical silver nitrate (99%) in the clinic. PMID- 25297720 TI - Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications. AB - AIM: Drug-drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug-drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir. METHOD: Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach. RESULTS: Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required. CONCLUSION: There are substantial drug interactions between artemether lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients. PMID- 25297723 TI - Suffering, silence, and status: the importance and challenges of qualitative research on AIDS orphanhood. AB - Drawing on ethnographic fieldwork with Ugandan children affected by AIDS conducted from 2007 to 2014, this report summarizes findings of a study conducted to better understand the ways children experience orphanhood at the hands of HIV/AIDS. Three crucial, interrelated concepts emerged: suffering, silence, and status. This study explored the social context of AIDS orphanhood as both a cause of social suffering and a context for the suffering of individual children. Though problematic, silence about suffering is often due to continuing HIV/AIDS stigma in Uganda that makes one's status unspeakable, in spite of the adverse effect this has on the social order and efforts to eradicate the disease. Approaching silence as a distinct form of communication rather than an absence of it, the report considers silence's intergenerational functions, its detriments, and its consolations, in the context of HIV/AIDS-affected children's lives. In doing so, it also highlights the need for more child-centered, qualitative research on AIDS' psychosocial effects on children, despite the challenges of doing such research. PMID- 25297724 TI - Gastro-esophageal reflux disease and exacerbations in chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: We tested the hypothesis that gastro-esophageal reflux disease is a risk factor for exacerbations in individuals with chronic obstructive pulmonary disease (COPD). METHODS: Among 9622 participants in the Copenhagen City Heart Study, we identified 1259 individuals with COPD and information on gastro-esophageal reflux disease and the regular use of acid inhibitory treatment. These individuals were followed for 5 years with regard to medically treated COPD exacerbations, which we defined as a short course treatment with oral corticosteroids alone or in combination with antibiotics. We applied a multivariable Cox regression analysis with adjustment for well established risk factors associated with COPD exacerbations or gastro-esophageal reflux disease, including COPD severity, and symptoms. RESULTS: Individuals with COPD and gastro-esophageal reflux disease had more chronic bronchitis (31 vs 21%, P = 0.004), more breathlessness (39 vs 22%, P < 0.001), and more of them had a history of respiratory infections (6.8 vs 1.4%, P < 0.001) than individuals with COPD but without gastro-esophageal reflux disease. Among individuals with COPD and gastro-esophageal reflux disease, those who did not use acid inhibitory treatment regularly had an increased risk of COPD exacerbations during follow-up, hazards ratio (HR): HR = 2.7 (1.3-5.4, P = 0.006). Individuals with gastro esophageal reflux disease, using acid inhibitory treatment regularly did not have an increased risk of exacerbations, HR = 1.2 (0.6-2.7, P = 0.63). CONCLUSIONS: Gastro-esophageal reflux disease was associated with an increased risk of medically treated exacerbations of COPD, but only in those individuals who did not use acid inhibitory treatment regularly. PMID- 25297725 TI - Facile synthesis of Cu-Pd bimetallic multipods for application in cyclohexane oxidation. AB - The synergy between Cu and Pd makes Cu-Pd bimetallic nanocrystals interesting materials for investigation. The scarcity of shapes of Cu-Pd bimetallic nanocrystals motivated us to explore highly branched structures, which may promote a wide range of applications. In this communication, we report a facile synthesis of Cu-Pd bimetallic multipods (19.2 +/- 1.2 nm), on branches of which some high-index facets were exposed. Modification of reaction parameters concerning capping agents and reductant led to the formation of other shapes, including sphere-like nanocrystals (SNCs). When loaded onto TiO2, the as-prepared Cu-Pd bimetallic multipods exhibited excellent catalytic activity for the oxidation of cyclohexane by hydrogen peroxide and higher selectivity towards cyclohexanone than monometallic catalysts and SNCs/TiO2. PMID- 25297722 TI - Spider mites suppress tomato defenses downstream of jasmonate and salicylate independently of hormonal crosstalk. AB - Plants respond to herbivory by mounting a defense. Some plant-eating spider mites (Tetranychus spp.) have adapted to plant defenses to maintain a high reproductive performance. From natural populations we selected three spider mite strains from two species, Tetranychus urticae and Tetranychus evansi, that can suppress plant defenses, using a fourth defense-inducing strain as a benchmark, to assess to which extent these strains suppress defenses differently. We characterized timing and magnitude of phytohormone accumulation and defense-gene expression, and determined if mites that cannot suppress defenses benefit from sharing a leaf with suppressors. The nonsuppressor strain induced a mixture of jasmonate- (JA) and salicylate (SA)-dependent defenses. Induced defense genes separated into three groups: 'early' (expression peak at 1 d postinfestation (dpi)); 'intermediate' (4 dpi); and 'late', whose expression increased until the leaf died. The T. evansi strains suppressed genes from all three groups, but the T. urticae strain only suppressed the late ones. Suppression occurred downstream of JA and SA accumulation, independently of the JA-SA antagonism, and was powerful enough to boost the reproductive performance of nonsuppressors up to 45%. Our results show that suppressing defenses not only brings benefits but, within herbivore communities, can also generate a considerable ecological cost when promoting the population growth of a competitor. PMID- 25297726 TI - High-throughput development of a hybrid-type fluorescent glutamate sensor for analysis of synaptic transmission. AB - Fluorescent sensors are powerful tools for visualizing cellular molecular dynamics. We present a high-throughput screening system, designated hybrid-type fluorescence indicator development (HyFInD), to identify optimal position specific fluorophore labeling in hybrid-type sensors consisting of combinations of ligand-binding protein mutants with small molecular fluorophores. We screened sensors for glutamate among hybrid molecules obtained by the reaction of four cysteine-reactive fluorescence probes with a set of cysteine-scanning mutants of the 274 amino acid S1S2 domain of AMPA-type glutamate receptor GluA2 subunit. HyFInD identified a glutamate-responsive probe (enhanced glutamate optical sensor: eEOS) with a dynamic range >2400 %, good photostability, and high selectivity. When eEOS was specifically tethered to neuronal surfaces, it reliably visualized the spatiotemporal dynamics of glutamate release at single synapses, revealing synapse-to-synapse heterogeneity of short-term plasticity. PMID- 25297729 TI - Non-coding RNA: a match made by crosslinking. PMID- 25297730 TI - Plant genetics: Following the early root of plastome degradation. PMID- 25297727 TI - Evolutionary dynamics of coding and non-coding transcriptomes. AB - Gene expression changes may underlie much of phenotypic evolution. The development of high-throughput RNA sequencing protocols has opened the door to unprecedented large-scale and cross-species transcriptome comparisons by allowing accurate and sensitive assessments of transcript sequences and expression levels. Here, we review the initial wave of the new generation of comparative transcriptomic studies in mammals and vertebrate outgroup species in the context of earlier work. Together with various large-scale genomic and epigenomic data, these studies have unveiled commonalities and differences in the dynamics of gene expression evolution for various types of coding and non-coding genes across mammalian lineages, organs, developmental stages, chromosomes and sexes. They have also provided intriguing new clues to the regulatory basis and phenotypic implications of evolutionary gene expression changes. PMID- 25297731 TI - [Involvement of aberrant DNA methylation in hematological malignancies]. PMID- 25297728 TI - High-resolution digital profiling of the epigenome. AB - The widespread adoption of short-read DNA sequencing as a digital epigenomic readout platform has motivated the development of genome-wide tools that achieve base-pair resolution. New methods for footprinting and affinity purification of nucleosomes, RNA polymerases, chromatin remodellers and transcription factors have increased the resolution of epigenomic profiling by two orders of magnitude, leading to new insights into how the chromatin landscape affects gene regulation. These digital epigenomic tools have also been applied to directly profile both turnover kinetics and transcription in situ. In this Review, we describe how these new genome-wide tools allow interrogation of diverse aspects of the epigenome. PMID- 25297732 TI - [Molecular basis of hematological malignancies]. PMID- 25297733 TI - [Role of p53 in leukemia]. PMID- 25297734 TI - [Tumor-associated macrophages]. PMID- 25297735 TI - [Abnormal hematopoiesis in Down syndrome]. PMID- 25297736 TI - [Pathophysiology approached by abnormal morphology of blood cells]. PMID- 25297737 TI - [New immunological aspect of hemophagocytosis]. PMID- 25297738 TI - [Recent progress in the management of aplastic anemia]. PMID- 25297739 TI - [Treatment of aplastic anemia in children]. PMID- 25297740 TI - [Comparative hematology in vertebrate erythropoiesis]. PMID- 25297741 TI - [Identification of erythropoietin producing cells and erythropoietin gene regulation]. PMID- 25297742 TI - [Blood cell generation from iPS cells]. PMID- 25297743 TI - Management considerations in older patients with AML: a 2014 perspective. PMID- 25297744 TI - [Treatment of adult patients with acute myeloid leukemia (excluding acute promyelocytic leukemia)]. PMID- 25297745 TI - [Treatment for acute promyelocytic leukemia]. PMID- 25297746 TI - [Molecular pathogenesis of acute myeloid leukemia]. PMID- 25297747 TI - [New mutations in myeloproliferative neoplasms; 2014 update]. PMID- 25297748 TI - [Treatment strategy for myeloproliferative neoplasms]. PMID- 25297749 TI - [Treatment of chronic myeloid leukemia in chronic phase]. PMID- 25297750 TI - [Management of advanced stage chronic myeloid leukemia]. PMID- 25297751 TI - [Allogeneic hematopoietic stem cell transplantation for the treatment of high risk myelodysplastic syndrome]. PMID- 25297752 TI - [Treatment of MDS]. PMID- 25297753 TI - [TET2 dysregulation in hematologic malignancies]. PMID- 25297754 TI - [ILROG guideline of radiation therapy for nodal lymphomas: involved site radiation therapy]. PMID- 25297755 TI - [Treatment strategy of gray zone lymphomas]. PMID- 25297756 TI - [Standard of care and new drugs for diffuse large B-cell lymphoma]. PMID- 25297757 TI - [Management of follicular lymphoma]. PMID- 25297758 TI - Advances in management of follicular lymphoma. PMID- 25297759 TI - [Treatment strategy of Hodgkin lymphoma]. PMID- 25297761 TI - [Treatment of adult Ph-negative acute lymphoblastic leukemia]. PMID- 25297760 TI - [Treatment of adult T-cell leukemia-lymphoma]. PMID- 25297762 TI - [Current treatment of philadelphia chromosome-positive acute lymphoblastic leukemia]. PMID- 25297763 TI - [Chronic lymphocytic leukemia: diagnosis and gene mutations]. PMID- 25297764 TI - [Reactive lymphadenopathy and malignant lymphoma: a practical guide to differential diagnosis]. PMID- 25297765 TI - [Supportive care in multiple myeloma for continuing anti-myeloma therapies]. PMID- 25297766 TI - [Current status of clinical trials of novel agents for multiple myeloma]. PMID- 25297767 TI - [Treatment of transplant-eligible symptomatic multiple myeloma]. PMID- 25297768 TI - [Treatment of untreated multiple myeloma patients ineligible for autologous stem cell transplantation]. PMID- 25297769 TI - [Chromosomal abnormalities and clonal evolution in multiple myeloma]. PMID- 25297770 TI - [Ionizing radiation and hematological neoplasms]. PMID- 25297771 TI - [Recent progress in platelet laboratory testing]. PMID- 25297772 TI - [Front line of hemophilia care for hematologist]. PMID- 25297773 TI - [Thrombosis and DIC in hematological malignancies]. PMID- 25297774 TI - [Treatment of thrombotic thrombocytopenic purpura]. PMID- 25297775 TI - [Management of idiopathic thrombocytopenic purpura (primary immune thrombocytopenia, ITP)]. PMID- 25297776 TI - [Role of platelets in lymphangiogenesis]. PMID- 25297777 TI - [Graft source of hematopoietic stem cell transplantation in adult patients with hematologic diseases]. PMID- 25297778 TI - [Diagnosis and management of chronic graft-versus-host disease]. PMID- 25297779 TI - [Systematic approach to organ-specific complications after allogeneic hematopoietic cell transplantation]. PMID- 25297780 TI - [Post-transplant infectious diseases]. PMID- 25297781 TI - [Role of NK cells in transplantation immunology]. PMID- 25297782 TI - [Risk of transfusion-transmitted infection in Japan]. PMID- 25297783 TI - [Adoptive immunotherapy using gene-modified T cells to express target-specific receptors against hematological malignancy]. PMID- 25297784 TI - [Innate immunity]. PMID- 25297785 TI - [Regulatory T cells in cancer immunotherapy]. PMID- 25297786 TI - Control of immune responses by mesenchymal stromal cells. PMID- 25297787 TI - [Application of disease-specific iPS cells for pathogenic analysis of congenital neutropenia]. PMID- 25297788 TI - [Induced pluripotent stem cells from leukemia patients as a platform for dissecting pathogenesis]. PMID- 25297789 TI - [Infections associated with hematologic diseases]. PMID- 25297790 TI - [Lymphoproliferative disorders: Epstein-Barr virus and heritable predisposition]. PMID- 25297791 TI - [Current treatment of pediatric acute lymphoblastic leukemia]. PMID- 25297792 TI - [Genetic, environmental and developmental factors in childhood leukemia]. PMID- 25297793 TI - Genomic evaluations of childhood acute lymphoblastic leukemia susceptibility across race/ethnicities. PMID- 25297794 TI - [Conflicts-of-interests in medical research: its management and current status]. PMID- 25297795 TI - A three-photon probe with dual emission colors for imaging of Zn(II) ions in living cells. AB - A novel three-photon probe for the imaging of exogenous Zn(II) ions in live cells with varying emission colors under three-photon excitation is developed. The tuning of the charge transfer state and the emission color of the probe was also demonstrated in the presence of acid. PMID- 25297796 TI - Uncontrolled hypertension among hypertensive patients on treatment in Lupane District, Zimbabwe, 2012. AB - BACKGROUND: More than half of hypertensive patients reviewed at Lupane District Hospital during the first half of 2011 had uncontrolled hypertension. This prompted an investigation on the prevalence of uncontrolled hypertension and associated factors among hypertensives on treatment. METHODS: Analytical cross sectional study was conducted. Three hundred fifty-four consenting participants were consecutively selected from eligible hypertensive patients on treatment attending the outpatients department at Lupane District Hospital for their reviews. An interviewer administered questionnaire adapted from the World Health Organization was used to collect data on risk factors. Blood pressure and anthropometric measurements were taken as per World Health Organization guidelines. Uncontrolled hypertension was defined as systolic blood pressure of >=140 mmHg and/or diastolic blood pressure of >=90 mmHg in a patient taking anti hypertensive medication. RESULTS: Mean systolic BP was 151.0 mmHg and mean diastolic BP was 92.6 mmHg. Prevalence of uncontrolled hypertension was (238) 67.2%. Independent risk factors for uncontrolled hypertension were obesity (AOR 3.28, 95% CI 1.39-7.75) and adding salt to food at the table (AOR 2.77, 95% CI 1.41-5.43) whilst being compliant with the drug treatment regimen (AOR 0.34, 95% CI 0.16-0.72) and having received health education on hypertension (AOR 0.49, 95% CI 0.25- 0.97) were protective against uncontrolled hypertension. CONCLUSION: There prevalence of uncontrolled hypertension is high despite all the participants being on treatment. The findings suggest that interventions at the patient, the provider and the health delivery system are needed to improve hypertension control in Lupane, Zimbabwe. PMID- 25297799 TI - Who's cheating? Agreements about sexual exclusivity and subsequent concurrent partnering in Australian heterosexual couples. AB - Background Concurrent relationships are a driver of generalised epidemics of sexually transmissible infections (STIs). In Australia, explicit negotiation of agreements about sex outside regular relationships has been recommended in health promotion for gay men but not for heterosexuals. OBJECTIVE: To ascertain the annual incidence of concurrency among people in ongoing male-female relationships according to their reported expectations of exclusivity. METHODS: In a national cohort recruited by household random digit dialling in 2004-05, people aged 16-64 years completed computer-assisted telephone interviews including questions about expectations of sexual exclusivity, discussion and agreements. A year later, those in ongoing sexual relationships (5323 people) were asked about sexual partner numbers in the past year. RESULTS: The huge majority (96%) expected sexual exclusivity of themselves and their partner. However, only 48% of men and 64% of women had discussed the matter and explicitly agreed. Older respondents were less likely to report discussion. Only 1% reported mutually nonexclusive ('open') relationships. A year later, 93% of respondents were still in the same relationship, among whom 4% of men and 2% of women had had sex outside the relationship. Those with agreements that one or both partners could have sex with others were more likely to do so, but the majority of respondents who had sex with someone else were in relationships that were explicitly or implicitly expected to be exclusive. CONCLUSIONS: Sexual health promotion should stress the importance of STI testing and establishing agreements about exclusivity before condoms are abandoned in new relationships. PMID- 25297798 TI - Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat. AB - BACKGROUND AND PURPOSE: The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. EXPERIMENTAL APPROACH: Morphine minipumps (6 mg.day(-1) ) induced tolerance during 5 days in Sprague-Dawley rats, after which s.c. ketamine (10 mg.kg(-1) ) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3 glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. KEY RESULTS: In morphine-naive rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naive rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. CONCLUSIONS AND IMPLICATIONS: The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID- 25297800 TI - Differential contributions of microglial and neuronal IKKbeta to synaptic plasticity and associative learning in alert behaving mice. AB - Microglia are CNS resident immune cells and a rich source of neuroactive mediators, but their contribution to physiological brain processes such as synaptic plasticity, learning, and memory is not fully understood. In this study, we used mice with partial depletion of IkappaB kinase beta, the main activating kinase in the inducible NF-kappaB pathway, selectively in myeloid lineage cells (mIKKbetaKO) or excitatory neurons (nIKKbetaKO) to measure synaptic strength at hippocampal Schaffer collaterals during long-term potentiation (LTP) and instrumental conditioning in alert behaving individuals. Resting microglial cells in mIKKbetaKO mice showed less Iba1-immunoreactivity, and brain IL-1beta mRNA levels were selectively reduced compared with controls. Measurement of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the CA3-CA1 synapse in mIKKbetaKO mice showed higher facilitation in response to paired pulses and enhanced LTP following high frequency stimulation. In contrast, nIKKbetaKO mice showed normal basic synaptic transmission and LTP induction but impairments in late LTP. To understand the consequences of such impairments in synaptic plasticity for learning and memory, we measured CA1 fEPSPs in behaving mice during instrumental conditioning. IKKbeta was not necessary in either microglia or neurons for mice to learn lever-pressing (appetitive behavior) to obtain food (consummatory behavior) but was required in both for modification of their hippocampus-dependent appetitive, not consummatory behavior. Our results show that microglia, through IKKbeta and therefore NF-kappaB activity, regulate hippocampal synaptic plasticity and that both microglia and neurons, through IKKbeta, are necessary for animals to modify hippocampus-driven behavior during associative learning. PMID- 25297801 TI - Molecular markers for colon diagnosis, prognosis and targeted therapy. AB - Colorectal adenocarcinoma (CRC), the second leading cancer-related death in the United States, remains a global public health issue. Sporadic CRC is considered the result of sequential mucosal changes from normal colonic mucosa to adenocarcinoma. Efforts in understanding the molecular pathways leading to CRC tumorigenesis may lead to identifying novel, individually tailored therapeutic targets for patients. In this review, we focus on well-published prognostic and predictive markers in CRC and examine their role in clinical practice. PMID- 25297802 TI - Fetal lung growth represented by longitudinal changes in MRI-derived fetal lung volume parameters predicts survival in isolated left-sided congenital diaphragmatic hernia. AB - OBJECTIVE: The aim of this study was to evaluate fetal lung growth rate for isolated left-sided congenital diaphragmatic hernia (CDH) using serial magnetic resonance imaging (MRI)-based volumetric measures. METHODS: Early and late gestational (22-30 and >30 weeks' gestation) lung volumetry was obtained by fetal MRI in 47 cases of isolated left-sided CDH. At both of these time points, lung volume indices, including total lung volume (TLV), observed to expected TLV (o/e TLV), and percentage of predicted lung volume (PPLV) as well as their change rates (Delta) and relative Delta during gestation were calculated and analyzed in regard to their capacity to predict neonatal survival. RESULTS: TLV, o/e TLV, and PPLV had various changes during gestation. Late TLV, early and late o/e TLV, and late PPLV were predictive of neonatal survival. Non-survivors had lower DeltaTLV and more negative relative DeltaPPLV than survivors (1.18 vs 1.85 mL/week, P = 0.004 and -4.15%/week vs -1.95%/week, P = 0.002, respectively). CONCLUSIONS: The severity of pulmonary hypoplasia is dynamic and can worsen in the third trimester. MRI lung volumetry repeated in late gestation can provide additional information on individual lung growth that may facilitate prenatal counseling and focus perinatal management. PMID- 25297803 TI - A sporadic elder case of erythrokeratodermia variabilis with a single base-pair transversion in GJB3 gene successfully treated with systemic vitamin A derivative. PMID- 25297804 TI - A necessarily complex model to explain the biogeography of the amphibians and reptiles of Madagascar. AB - Pattern and process are inextricably linked in biogeographic analyses, though we can observe pattern, we must infer process. Inferences of process are often based on ad hoc comparisons using a single spatial predictor. Here, we present an alternative approach that uses mixed-spatial models to measure the predictive potential of combinations of hypotheses. Biodiversity patterns are estimated from 8,362 occurrence records from 745 species of Malagasy amphibians and reptiles. By incorporating 18 spatially explicit predictions of 12 major biogeographic hypotheses, we show that mixed models greatly improve our ability to explain the observed biodiversity patterns. We conclude that patterns are influenced by a combination of diversification processes rather than by a single predominant mechanism. A 'one-size-fits-all' model does not exist. By developing a novel method for examining and synthesizing spatial parameters such as species richness, endemism and community similarity, we demonstrate the potential of these analyses for understanding the diversification history of Madagascar's biota. PMID- 25297806 TI - Addressing Issues in the Development and Use of the Composite International Reference Values as Rorschach Norms for Adults. AB - This article describes 3 studies evaluating normative reference data for the Rorschach Comprehensive System (CS; Exner, 2003, 2007), with a particular focus on the viability of the Composite International Reference Values (CIRVs) that were compiled from 21 adult studies by Meyer, Erdberg, and Shaffer (2007). Study 1 documented how the CIRV norms are virtually identical when organized into 3 groups differentiated by the quality of their data collection effort, including an optimal group of 4 samples that relied on multiple experienced examiners and provided ongoing quality control over administration and coding. Analyses also showed that relative to the group of more optimal samples, the group of less optimal samples did not produce more variability in summary scores within or across samples or lower interrater reliability for coding. Study 2 used the existing CS reference norms to generate T scores for the CIRV means and documented how the CS norms make other samples of healthy nonpatients look psychologically impaired in multiple domains. Study 3 documented with examples from 4 different countries how 2 sets of within-country local norms produced notably different results on some variables, which compromises the ability of local norms to be used instead of the CIRVs. Taken together, the 3 studies provide support for the use of CIRVs in clinical practice as norms that are generalizable across samples, settings, languages, and cultures and that account for the natural variability that is present when clinicians and researchers contend with the ambiguity contained in the standard CS reference materials concerning the proper ways to administer and code. We conclude by urging CS users to rely on the CIRVs when making clinical inferences and to adopt alternative methods of ensuring they are following cohesively standardized administration and coding guidelines. PMID- 25297805 TI - Sublingual (SLIT) versus oral immunotherapy (OIT) for food allergy. AB - Food allergy is a common condition for which the only currently approved treatments are avoidance of the allergenic food and the administration of emergency medications upon accidental exposure. Over the past 10 years, significant advances have been made in the field of food immunotherapy, with efforts focusing on allergen exposure via the oral mucosa. Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are the two modalities that have been most extensively studied, and this article will review recent advances in our knowledge of the efficacy and safety of these treatments. PMID- 25297807 TI - Terpene-containing PEGylated liposomes as transdermal carriers of a hydrophilic compound. AB - We investigated the effect of PEGylated liposomes (PLs) containing a terpene on the penetration of a hydrophilic compound through porcine skin. PLs composed of N (carbonyl-methoxypolyethyleneglycol-2000)-1,2-distearoyl-sn-glycero-3 phosphoethanolamine (PEG2000-DSPE), the sodium salt of PEG2000-DSPE, phosphatidylcholine (PC), cholesterol (Chol), Tween 20, and d-limonene were prepared as carriers for fluorescein sodium (NaFI). The physicochemical characteristics of PLs and their effects on in vitro skin penetration were evaluated. Tape stripping was used to evaluate NaFI deposition in skin layers, and confocal laser scanning microscopy (CLSM) was used to investigate the depth of skin penetration and the pathways used by NaFI-loaded vesicles. PLs containing d-limonene were smaller and conferred higher entrapment efficiency and skin penetration on NaFI than did PLs and conventional liposomes (CLs). The deposition of NaFI from PLs with d-limonene was greater in epidermis and dermis (6.10+/-1.74 ug) than stratum corneum (2.06+/-0.47 ug). CLSM images revealed that NaFI penetrated into the deepest skin layer with maximum fluorescence intensity. NaFI penetrated deeper (180 um) in follicular than nonfollicular regions (145 um), suggesting a transfollicular pathway predominates in skin penetration by NaFI loaded PLs. In conclusion, grafting PEG onto ultra-deformable liposomes may enhance transdermal NaFI delivery and may be used as a carrier to prolong liposome circulation time. PMID- 25297809 TI - Safety and Effectiveness of Palivizumab in Children at High Risk of Serious Disease Due to Respiratory Syncytial Virus Infection: A Systematic Review. AB - INTRODUCTION: Lower respiratory tract infection (LRTI) is the leading cause of infant mortality globally in post-neonatal infants (i.e., 28-364 days of age). Respiratory syncytial virus (RSV) is the most commonly identified pathogen for infant LRTI and is the second most important cause of death in post-neonatal infants. Despite 50 years of RSV vaccine research, there is still no approved vaccine. Therefore, passive immunity with the monoclonal antibody palivizumab is the sole regulatory-approved option for the prevention of serious LRTI caused by RSV in pediatric patients at high risk of RSV disease. METHODS: We conducted a comprehensive systematic literature review of randomized controlled trials (RCTs), open-label non-comparative clinical trials, and prospective observational studies/registries, and summarized the evidence related to the safety, efficacy, and effectiveness of palivizumab. RESULTS: The efficacy of palivizumab, as measured by the relative reduction in RSV-related hospitalization rate compared with placebo ranged from 39% to 78% (P < 0.05) in the 2 pivotal RCTs. A meta analysis of the RSV-related hospitalization rate from 5 randomized placebo controlled trials yielded an overall odds ratio of 0.41 (95% CI, 0.31-0.55) in favor of palivizumab prophylaxis over placebo (P < 0.00001). Low rates of RSV related hospitalizations were observed in palivizumab recipients consistently over time in more than 42,000 pediatric subjects across 7 RCTs, 4 open-label non comparative trials, and 8 observational studies/registries conducted in 34 countries. In addition, among palivizumab-prophylaxed subjects with breakthrough RSV LRTI, rates of intensive care unit admission and mechanical ventilation from RSV hospitalization also were low and consistent across studies. With respect to safety, no differences were observed between palivizumab and placebo in the blinded RCTs. CONCLUSION: Rates of RSV hospitalizations and RSV hospitalization related endpoints in pediatric subjects who received prophylaxis with palivizumab were low and constant over time and across RCTs, open-label non-comparative trials, and observational studies/registries. PMID- 25297810 TI - NLRP3 gene is associated with ulcerative colitis (UC), but not Crohn's disease (CD), in Chinese Han population. AB - OBJECTIVE: This study aimed to investigate whether NLRP3 is associated with IBD in Chinese Han population. METHODS: Three SNPs were genotyped using polymerase chain reaction with sequence-specific primers in 288 patients [232 Crohn's disease (CD) patients, 56 ulcerative colitis (UC) patients] and 274 controls. RESULTS: In IBD group, the results showed no significant association. When subdivided to CD and UC, it showed in CD subgroup, there was no significant association. However, in UC subgroup, rs10754558 (P allele=0.015272, P genotype=0.029776, OR [95% CI]=0.604190[0.401200-0.909886]) and rs10925019 (P allele=0.013042, P genotype=0.037045, OR [95% CI]=2.022613[1.149854-3.557812]) have significant associations with UC. The G and T alleles were risk factors of the susceptibility of UC, the GG and TT genotypes may increase risk of this disease. Rs4925648 has no association with UC. The haplotypes analysis results showed as follow: for rs4925648-rs10925019, CC and TT are risk factors for UC (for CC, chi2=3.605, P=0.057613, OR [95% CI]=1.645 [0.980-2.761], for TT, chi2=5.522, P=0.018804, OR [95% CI]=0.426[0.205-0.884]), and for rs10754558 rs10925019, CT and GC haplotypes are risk factors for UC (for CT, chi2=3.545, P=0.059739, OR [95% CI]=0.571[0.317-1.029], for GC, chi2=9.359, P=0.002228, OR [95% CI]=1.904 [1.255-2.887]). CONCLUSIONS: We first demonstrated that rs10754558 and rs10925019 are significantly associated with the susceptibility of UC, but not CD in Chinese Han population, suggesting that NLRP3 may play an important role in the pathogenesis of UC. PMID- 25297814 TI - Anomalous diffusion models and their properties: non-stationarity, non ergodicity, and ageing at the centenary of single particle tracking. AB - Modern microscopic techniques following the stochastic motion of labelled tracer particles have uncovered significant deviations from the laws of Brownian motion in a variety of animate and inanimate systems. Such anomalous diffusion can have different physical origins, which can be identified from careful data analysis. In particular, single particle tracking provides the entire trajectory of the traced particle, which allows one to evaluate different observables to quantify the dynamics of the system under observation. We here provide an extensive overview over different popular anomalous diffusion models and their properties. We pay special attention to their ergodic properties, highlighting the fact that in several of these models the long time averaged mean squared displacement shows a distinct disparity to the regular, ensemble averaged mean squared displacement. In these cases, data obtained from time averages cannot be interpreted by the standard theoretical results for the ensemble averages. Here we therefore provide a comparison of the main properties of the time averaged mean squared displacement and its statistical behaviour in terms of the scatter of the amplitudes between the time averages obtained from different trajectories. We especially demonstrate how anomalous dynamics may be identified for systems, which, on first sight, appear to be Brownian. Moreover, we discuss the ergodicity breaking parameters for the different anomalous stochastic processes and showcase the physical origins for the various behaviours. This Perspective is intended as a guidebook for both experimentalists and theorists working on systems, which exhibit anomalous diffusion. PMID- 25297813 TI - Predicting research use in a public health policy environment: results of a logistic regression analysis. AB - BACKGROUND: Use of research evidence in public health policy decision-making is affected by a range of contextual factors operating at the individual, organisational and external levels. Context-specific research is needed to target and tailor research translation intervention design and implementation to ensure that factors affecting research in a specific context are addressed. Whilst such research is increasing, there remain relatively few studies that have quantitatively assessed the factors that predict research use in specific public health policy environments. METHOD: A quantitative survey was designed and implemented within two public health policy agencies in the Australian state of Victoria. Binary logistic regression analyses were conducted on survey data provided by 372 participants. Univariate logistic regression analyses of 49 factors revealed 26 factors that significantly predicted research use independently. The 26 factors were then tested in a single model and five factors emerged as significant predictors of research over and above all other factors. RESULTS: The five key factors that significantly predicted research use were the following: relevance of research to day-to-day decision-making, skills for research use, internal prompts for use of research, intention to use research within the next 12 months and the agency for which the individual worked. CONCLUSIONS: These findings suggest that individual- and organisational-level factors are the critical factors to target in the design of interventions aiming to increase research use in this context. In particular, relevance of research and skills for research use would be necessary to target. The likelihood for research use increased 11- and 4-fold for those who rated highly on these factors. This study builds on previous research and contributes to the currently limited number of quantitative studies that examine use of research evidence in a large sample of public health policy and program decision-makers within a specific context. The survey used in this study is likely to be relevant for use in other public health policy contexts. PMID- 25297811 TI - Benzo pyrene-induced DNA adducts and gene expression profiles in target and non target organs for carcinogenesis in mice. AB - BACKGROUND: Gene expression changes induced by carcinogens may identify differences in molecular function between target and non-target organs. Target organs for benzo[a]pyrene (BaP) carcinogenicity in mice (lung, spleen and forestomach) and three non-target organs (liver, colon and glandular stomach) were investigated for DNA adducts by 32P-postlabelling, for gene expression changes by cDNA microarray and for miRNA expression changes by miRNA microarray after exposure of animals to BaP. RESULTS: BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific. Gene ontology analysis also revealed that BaP-induced bioactivities were tissue specific; eight genes (Tubb5, Fos, Cdh1, Cyp1a1, Apc, Myc, Ctnnb1 and Cav) showed significant expression difference between three target and three non-target organs. Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs. Changes in miRNA expression were generally tissue specific, involving, in total, 21/54 miRNAs significantly up- or down-regulated. CONCLUSIONS: Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs. However, mechanisms related to early changes in p53, Stat3 and Wnt/beta-catenin pathways may play roles in defining BaP organotropism. PMID- 25297815 TI - Laparoscopic versus open liver resection for hepatocellular carcinoma at a North American Centre: a 2-to-1 matched pair analysis. AB - INTRODUCTION: Oncological implications of laparoscopic resection in primary hepatic malignancy are not well defined. Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) in comparison to an open liver resection (OLR) in peri-operative and long-term oncological outcomes are described from a single North American institution. METHODS: From 2006 to 2013, all forty-three LLR patients for HCC were evaluated. Each patient was matched to two OLR patients for age at operation, maximal tumour size and tumour number. RESULTS: When compared with OLR, LLR had a lower severity of complication (0% versus 27%, P = 0.050) and lower 30-day readmission rate (2.3% versus 18.6%, P = 0.010). The length of stay (LOS) was shorter in LLR patients (5 versus 7 days, P < 0.001) and the estimated blood loss was also lower in LLR (300 versus 700 ml, P = 0.004). Admission to intensive care unit (ICU), emergency room (ER) visits and complication rates were similar. Overall, recurrence-free and intra-hepatic recurrence-free survival were comparable between LLR and OLR. DISCUSSION: LLR confers the widely-accepted benefits of laparoscopic surgery, namely severity of complication, 30-day readmission rate, LOS and blood loss. Further studies are required to examine intra- and extra-hepatic recurrence after LLR. LLR for HCC should be considered for appropriately selected patients in centres with requisite volume and expertise. PMID- 25297816 TI - Respiratory variation predicts optimal endotracheal tube placement for intra operative nerve monitoring in thyroid and parathyroid surgery. AB - BACKGROUND: Intra-operative nerve monitoring (IONM) of the recurrent laryngeal nerve (RLN) during thyroid and parathyroid surgery is thought to aid in identification and dissection of the RLN. While utilization of IONM is increasing, one area of variability in its application is the assessment of adequate endotracheal tube electrode placement for IONM during the case. The main objective of this study is to assess the overall success of utilizing respiratory variation to confirm proper endotracheal tube placement for RLN monitoring. METHODS: A prospective study of RLN monitoring during thyroid and parathyroid surgery at an academic referral center. RESULTS: Fifty-five cases were included. Fifty (91 %) achieved optimal respiratory variation during endotracheal tube position. Five (9 %) required repeat laryngoscopy to confirm correct endotracheal tube placement following patient positioning. For the respiratory variation group, average amplitude achieved during initial vagus, maximum vagus, initial RLN, and maximal RLN was 700 (+/- 474) mA, 921 (+/- 616) mA, 887 (+/- 584) mA, and 1330 (+/- 843) mA during evoked stimulation, respectively. For the repeat laryngoscopy group, average amplitude achieved during initial vagus, maximum vagus, initial RLN, and maximal RLN evoked stimulation was 591 (+/- 364) mA, 959 (+/- 306) mA, 771 (+/- 424) mA, and 1462 (+/- 855) mA during evoked stimulation, respectively. There was no statistical difference between the two groups for average initial vagus amplitude (p = 0.62), average maximum vagus amplitude (p = 0.89), average initial RLN amplitude (p = 0.67), or average maximum RLN amplitude (p = 0.74). CONCLUSION: The findings of this study support the International Neural Monitoring Study Group recommendation that confirmation of endotracheal tube electrode placement be performed either by confirmation of adequate respiratory variation or by repeat direct laryngoscopy. PMID- 25297817 TI - The magic of an appendicitis score. PMID- 25297818 TI - Distinct spatial relationship of the interleukin-9 receptor with interleukin-2 receptor and major histocompatibility complex glycoproteins in human T lymphoma cells. AB - The interleukin-9 receptor (IL-9R) consists of an alpha subunit and a gamma(c) chain that are shared with other cytokine receptors, including interleukin-2 receptor (IL-2R), an important regulator of T cells. We previously showed that IL 2R is expressed in common clusters with major histocompatibility complex (MHC) glycoproteins in lipid rafts of human T lymphoma cells, which raised the question about what the relationship between clusters of IL-2R/MHC and IL-9R is. Confocal microscopy colocalization and fluorescence resonance energy transfer experiments capable of detecting membrane protein organization at different size scales revealed nonrandom association of IL-9R with IL-2R/MHC clusters at the surface of human T lymphoma cells. Accommodation of IL-9Ralpha in membrane areas segregated from the IL-2R/MHC domains was also detected. The bipartite nature of IL-9R distribution was mirrored by signal transducer and activator of transcription (STAT) activation results. Our data indicate that co-compartmentalization with MHC glycoproteins is a general property of gamma(c) receptors. Distribution of receptor chains between different membrane domains may regulate their function. PMID- 25297819 TI - Assessing the Contribution of Songbirds to the Movement of Ticks and Borrelia burgdorferi in the Midwestern United States During Fall Migration. AB - The geographic distributions of Ixodes scapularis (black-legged tick) and the bacterium Borrelia burgdorferi (the causative agent of Lyme disease) are expanding in the USA. To assess the role of migratory songbirds in the spread of this tick and pathogen, we captured passerines in central Illinois during the fall of 2012. We compared forested sites in regions where I. scapularis populations were either previously or not yet established. Ticks were removed from birds and blood samples were taken from select avian species. Ticks were identified by morphology and molecular techniques were used to detect B. burgdorferi and other tick-borne pathogens in ticks and avian blood samples. Ixodes spp. were detected on 10 of 196 migrants (5.1%), with I. scapularis larvae found on 2 individuals. Borrelia burgdorferi sensu stricto was detected in the blood of 9 of 29 birds sampled (31%), yet only 1 infected bird was infested by ticks. The ticks were mostly Haemaphysalis leporispalustris and I. dentatus larvae, and none tested positive for B. burgdorferi. Infestation of birds by Ixodes spp. differed significantly by region, while B. burgdorferi infection did not. These data suggest that migratory birds may play a larger role in the dispersal of B. burgdorferi than previously realized. PMID- 25297821 TI - Protrusio acetabuli: joint loading with severe pincer impingement and its theoretical implications for surgical therapy. AB - Severe pincer impingement (acetabular protrusio) is an established cause of hip pain and osteoarthritis. The proposed underlying pathomechanism is a dynamic pathological contact of the prominent acetabular rim with the femoral head-neck junction. However, this cannot explain the classically described medial osteoarthritis in these hips. We therefore asked: (1) Does an overload exist in the medial aspect of the protrusio joint? and (2) What is the influence of three contemporary joint-preserving procedures on load distribution in protrusio hips? In vivo force and motion data for walking and standing to sitting were applied to six 3D finite element models (normal, dysplasia, protrusio, acetabular rim trimming, acetabular reorientation, and combined reorientation/rim trimming). Compared with dysplasia, the protrusio joint resulted in opposite patterns of von Mises stress and contact pressure during walking. In protrusio hips, we found an overload at the medial margin of the lunate surface (54% higher than normal). Isolated rim trimming further increased the medial overload (up to 28% higher than protrusio), whereas acetabular reorientation with/without rim trimming reduced stresses by up to 25%. Our results can be used as an adjunct for surgical decision making in the treatment of acetabular protrusio. PMID- 25297820 TI - Ecological niche and phylogeography elucidate complex biogeographic patterns in Loxosceles rufescens (Araneae, Sicariidae) in the Mediterranean Basin. AB - BACKGROUND: Understanding the evolutionary history of morphologically cryptic species complexes is difficult, and made even more challenging when geographic distributions have been modified by human-mediated dispersal. This situation is common in the Mediterranean Basin where, aside from the environmental heterogeneity of the region, protracted human presence has obscured the biogeographic processes that shaped current diversity. Loxosceles rufescens (Araneae, Sicariidae) is an ideal example: native to the Mediterranean, the species has dispersed worldwide via cohabitation with humans. A previous study revealed considerable molecular diversity, suggesting cryptic species, but relationships among lineages did not correspond to geographic location. RESULTS: Delimitation analyses on cytochrome c oxidase subunit I identified 11 different evolutionary lineages, presenting two contrasting phylogeographic patterns: (1) lineages with well-structured populations in Morocco and Iberia, and (2) lineages lacking geographic structure across the Mediterranean Basin. Dating analyses placed main diversification events in the Pleistocene, and multiple Pleistocene refugia, identified using ecological niche modeling (ENM), are compatible with allopatric differentiation of lineages. Human-mediated transportation appears to have complicated the current biogeography of this medically important and synanthropic spider. CONCLUSIONS: We integrated ecological niche models with phylogeographic analyses to elucidate the evolutionary history of L. rufescens in the Mediterranean Basin, with emphasis on the origins of mtDNA diversity. We found support for the hypothesis that northern Africa was the center of origin for L. rufescens, and that current genetic diversity originated in allopatry, likely promoted by successive glaciations during the Pleistocene. We corroborated the scenario of multiple refugia within the Mediterranean, principally in northern Africa, combining results from eight atmosphere-ocean general circulation models (AOGCMs) with two different refugium-delimitation methodologies. ENM results were useful for providing general views of putative refugia, with fine-scale details depending on the level of stringency applied for agreement among models. PMID- 25297822 TI - Unconscious emotion regulation: Nonconscious reappraisal decreases emotion related physiological reactivity during frustration. AB - Reappraisal of negative events is known to be useful in decreasing their emotional impact. However, existent evidence for this conclusion mostly relies on conscious, deliberate reappraisal that comes with the cost of cognitive efforts. The aim of the present study was to compare emotion regulation effects of conscious and unconscious reappraisal, which has been shown to be less costly in previous studies. Subjects randomly assigned to an unconscious reappraisal, conscious reappraisal, and control condition performed a frustrating arithmetic task. Subjective emotional experience and heart-rate reactivity were recorded. Participants primed with unconscious reappraisal showed the same decrease in heart-rate reactivity as those explicitly instructed to reappraise. In addition, the unconscious reappraisal group did not show reductions in subjective negative emotion, whereas this was significantly decreased in the conscious reappraisal group. Heart-rate reactivity was positively correlated with negative emotion ratings and negatively correlated with the positive emotion ratings. These results suggest that unconscious reappraisal is only effective in decreasing physiological consequences of frustrating emotion, but not in reducing subjective experience. PMID- 25297823 TI - Accelerometer measurement of upper extremity movement after stroke: a systematic review of clinical studies. AB - The aim of this review was to identify and summarise publications, which have reported clinical applications of upper limb accelerometry for stroke within free living environments and make recommendations for future studies. Data was searched from MEDLINE, Scopus, IEEExplore and Compendex databases. The final search was 31st October 2013. Any study was included which reported clinical assessments in parallel with accelerometry in a free-living hospital or home setting. Study quality is reflected by participant numbers, methodological approach, technical details of the equipment used, blinding of clinical measures, whether safety and compliance data was collected. First author screened articles for inclusion and inclusion of full text articles and data extraction was confirmed by the third author. Out of 1375 initial abstracts, 8 articles were included. All participants were stroke patients. Accelerometers were worn for either 24 hours or 3 days. Data were collected as summed acceleration counts over a specified time or as the duration of active/inactive periods. Activity in both arms was reported by all studies and the ratio of impaired to unimpaired arm activity was calculated in six studies. The correlation between clinical assessments and accelerometry was tested in five studies and significant correlations were found. The efficacy of a rehabilitation intervention was assessed using accelerometry by three studies: in two studies both accelerometry and clinical test scores detected a post-treatment difference but in one study accelerometry data did not change despite clinical test scores showing motor and functional improvements. Further research is needed to understand the additional value of accelerometry as a measure of upper limb use and function in a clinical context. A simple and easily interpretable accelerometry approach is required. PMID- 25297824 TI - Flows of living polymer fluids. AB - We report on the recent progress made on flows of living polymer fluids. Such fluids have been model systems for rheological research for more than twenty years and they continue to be fascinating. Like most if not all soft matter systems, living polymers under flow show a strong feedback between the structure of the fluid and that of the flow, the first influencing the second and vice versa. In our opinion, such interplay between microscopic kinetics and macroscopic kinematics has historically been mostly understood from a "structural perspective", in the tradition of physical chemistry. Nevertheless, in recent years, a more "hydrodynamical perspective" has emerged by making fruitful analogies with elastic and inertio-elastic instabilities known in solutions of regular polymers. We also underline how this new perspective constrains theoretical modelling and calls for the use of new tools of investigation. PMID- 25297826 TI - Electrochemically generated versus photoexcited luminescence from semiconductor nanomaterials: bridging the valley between two worlds. PMID- 25297825 TI - The effects of dexamethasone on the proliferation and apoptosis of human ovarian cancer cells induced by paclitaxel. AB - BACKGROUND: Dexamethasone (DEX) has been routinely used as a pre-treatment in the clinical application of paclitaxel (PTX) to treat ovarian cancer. However, PTX induced apoptosis might be inhibited by DEX. This study was undertaken to investigate the effects of DEX on the apoptosis induced by PTX. METHODS: Both of SKOV-3 and HO-8910 human ovarian cancer cells were divided into four groups: (1) untreated (Con); (2) treated with DEX (0.1 MUM) alone; (3) treated with PTX (50 nM); and (4) pre-treated with DEX (0.1 MUM), and 24 h later, treated with PTX (DEX + PTX). Cell proliferation was determined by the 3-(4,5)-dimethylthiahiazo ( z-y1)-3,5-di- phenytetrazoliumromide (MTT) dye uptake method, while cell apoptosis was analyzed by propidium iodide (PI) staining and flow cytometry. Then, reverse transcription polymerase chain reactions (RT-PCRs) were applied to semi-quantitative analysis, followed by western blot analysis. Statistical analysis was performed, with Fisher's least significant difference test. RESULTS: Our results demonstrated that DEX can differentially inhibit SKOV-3 and HO-8910 cell proliferation induced by PTX and decrease the apoptosis rates in cancer cells. Pre-treatment with DEX could up-regulate the expressions of members of anti-apoptotic Bcl-2 family (Bcl-2 and Bcl-XL) and members of IAP family (survivin). The expression of cleaved caspase-3 was down-regulated by DEX, shown by semi-quantitative RT-PCRs and western blot analysis. CONCLUSIONS: Our data gained invaluable insights of the antagonistic mechanisms of DEX on PTX-induced cancer cell death and may provide new methods of using DEX as antineoplastic drugs or agents in the clinical treatment for ovarian cancer patients. PMID- 25297827 TI - Human placental extract treatment for non-alcoholic steatohepatitis non responsive to lifestyle intervention: A pilot study. AB - AIM: No pharmacological therapies have been established for non-alcoholic steatohepatitis (NASH), which can lead to liver-related mortality. Human placental extract (HPE), which has anti-inflammatory effects, has been expected to be a promising treatment for chronic liver disease. This pilot study was conducted to evaluate the efficacy of HPE for biopsy-diagnosed NASH. METHODS: After a lifestyle intervention for 12 weeks, 10 subjects with abnormal alanine aminotransferase (>=30 IU/L) and biopsy-proven NASH (Non-Alcoholic Fatty Liver Disease Activity Score [NAS], >=4) received i.m. injections of HPE (Laennec) at a dose of 4 mL/day twice per week for 24 weeks, and seven of them underwent a second liver biopsy after the treatment. Liver biopsies were scored for NAS and fibrosis. Histological response was defined as a decrease of 2 points or more in NAS and no increase in fibrosis. RESULTS: Serum transaminase activities were significantly lower at 8 weeks compared with pretreatment levels in nine patients who continued treatment for 24 weeks. One patient refused to continue the treatment soon after starting therapies. In seven patients undergoing post treatment biopsies, NAS (mean [standard deviation]) mildly decreased from 5.29 (0.95) to 4.00 (1.83) without reaching statistical significance (P = 0.078). Histological response was observed in all three obese patients and in only one of four non-obese ones. No significant changes were observed in body mass index, lipid profiles and diabetic control/insulin resistance. CONCLUSION: In NASH patients who received HPE treatment, significant reductions in serum liver enzymes were obtained after 8 weeks. Histological efficacy may be better in obese patients than in non-obese ones. PMID- 25297828 TI - Mistic's membrane association and its assistance in overexpression of a human GPCR are independent processes. AB - The interaction of the Bacillus subtilis protein Mistic with the bacterial membrane and its role in promoting the overexpression of other membrane proteins are still matters of debate. In this study, we aimed to determine whether individual helical fragments of Mistic are sufficient for its interaction with membranes in vivo and in vitro. To this end, fragments encompassing each of Mistic's helical segments and combinations of them were produced as GFP-fusions, and their cellular localization was studied in Escherichia coli. Furthermore, peptides corresponding to the four helical fragments were synthesized by solid phase peptide synthesis, and their ability to acquire secondary structure in a variety of lipids and detergents was studied by circular dichroism spectroscopy. Both types of experiments demonstrate that the third helical fragment of Mistic interacts only with LDAO micelles but does not partition into lipid bilayers. Interestingly, the other three helices interact with membranes in vivo and in vitro. Nevertheless, all of these short sequences can replace full-length Mistic as N-terminal fusions to achieve overexpression of a human G-protein-coupled receptor in E. coli, although with different effects on quantity and quality of the protein produced. A bioinformatic analysis of the Mistic family expanded the number of homologs from 4 to 20, including proteins outside the genus Bacillus. This information allowed us to discover a highly conserved Shine-Dalgarno sequence in the operon mstX-yugO that is important for downstream translation of the potassium ion channel yugO. PMID- 25297829 TI - Does 2-phosphoglycolate serve as an internal signal molecule of inorganic carbon deprivation in the cyanobacterium Synechocystis sp. PCC 6803? AB - Cyanobacteria possess CO2 -concentrating mechanisms (CCM) that functionally compensate for the poor affinity of their ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) to CO2 . It was proposed that 2-phosphoglycolate (2PG), produced by the oxygenase activity of Rubisco and metabolized via photorespiratory routes, serves as a signal molecule for the induction of CCM related genes under limiting CO2 level (LC) conditions. However, in vivo evidence is still missing. Since 2PG does not permeate the cells, we manipulated its internal concentration. Four putative phosphoglycolate phosphatases (PGPases) encoding genes (slr0458, sll1349, slr0586 and slr1762) were identified in the cyanobacterium Synechocystis PCC 6803. Expression of slr0458 in Escherichia coli led to a significant rise in PGPase activity. A Synechocystis mutant overexpressing (OE) slr0458 was constructed. Compared with the wild type (WT), the mutant grew slower under limiting CO2 concentration and the intracellular 2PG level was considerably smaller than in the wild type, the transcript abundance of LC-induced genes including cmpA, sbtA and ndhF3 was reduced, and the OE cells acclimated slower to LC - indicated by the delayed rise in the apparent photosynthetic affinity to inorganic carbon. Data obtained here implicated 2PG in the acclimation of this cyanobacterium to LC but also indicated that other, yet to be identified components, are involved. PMID- 25297830 TI - The contribution of childhood cardiorespiratory fitness and adiposity to inflammation in young adults. AB - OBJECTIVE: Cardiorespiratory fitness and adiposity may influence cardiovascular risk through their effects on inflammation. The long-term effects of these modifiable factors on adult inflammation remain uncertain. The associations of childhood and adulthood cardiorespiratory fitness and adiposity with adult inflammation [C-reactive protein (CRP), fibrinogen] were examined. METHODS: 1,976 children examined in 1985 and re-examined as young adults in 2004-2006 were included. Cardiorespiratory fitness and adiposity were assessed at both waves. CRP and fibrinogen were measured at follow-up. RESULTS: Higher childhood fitness was associated with lower adult inflammation in both sexes. After adjusting for childhood adiposity, the association with CRP attenuated in males, but remained in females (average reduction of CRP 18.1% (95% CI 11.3-24.4%) per 1-SD increase in childhood fitness). Higher adult fitness, adjusting for childhood fitness (an increase in fitness from childhood to adulthood), was associated with lower adult CRP in females and lower fibrinogen in males. Higher childhood and adulthood adiposity (an increase in adiposity from childhood to adulthood) were associated with higher adult inflammation in both sexes. CONCLUSIONS: Prevention programs to increase fitness and reduce adiposity in childhood, and maintain a favorable fitness and weight into adulthood, may lead to reduction in adult systemic inflammation. PMID- 25297831 TI - Clinical and biochemical analysis of acute paint thinner intoxication in adults: a retrospective descriptive study. AB - CONTEXT: Paint thinner contains a mixture of various aromatic hydrocarbons. A few studies have reported biochemical abnormalities and clinical symptoms of paint thinner intoxication among adult patients. OBJECTIVE: We aimed to design a retrospective descriptive study to evaluate clinical and laboratory biochemistry abnormalities due to paint thinner intoxication among adult patients. METHODS: Data were obtained by using questionnaires from paint thinner-intoxicated patients recruited at the Loghman-Hakim General Teaching Hospital Poison Center. RESULTS: Clinical and paraclinical data from a total of 37 patients, 24 males (64.86%) and 13 females (35.14%) with the mean age of 34.35 +/- 14.15 years and mode of 22 years, was obtained and analyzed. Patients' ages ranged between 15 and 70 years. The estimated mean consumed dose was 246.70 +/- 390.72 ml with a mode of 60 ml (range of 1-1500 ml). Nausea, vomiting, asthma, sore throat, stomach ache, drowsiness, dizziness, agitation, cough and diarrhea were the most frequent clinical features, respectively. Reported tissue damage biomarkers were alkaline phosphatase (ALP, 233.84 +/- 122.06) and lactate dehydrogenase enzymes (LDH, 749.33 +/- 471.03 IU/l). They reflected development of liver and pulmonary toxicities. Arterial blood gas (ABG) showed acidosis without hypoxia in adult paint thinner-intoxicated patients. DISCUSSION AND CONCLUSION: Focusing on biochemical abnormalities and clinical toxicity symptoms is essential for screening organs in paint thinner toxicity. In addition, they provide good information for physicians/clinical toxicologists to perform appropriate conservative treatments in adult paint thinner-intoxicated patients. PMID- 25297832 TI - Aptamer-gelatin composite for a trigger release system mediated by oligonucleotide hybridization. AB - Nucleic acid aptamers not only specifically bind to their target proteins with high affinity but also form intermolecular hybridization with their complementary oligonucleotides (CO). The hybridization can interrupt aptamer/protein interaction due to the changes of aptamer secondary structure which rely on hybridization length and base-pairing positions. Herein we aim to use this unique property of the aptamers, when combined with gelatin to develop a novel composite with desirable protein release profiles. Platelet-derived growth factor-BB (PDGF BB) and its aptamer were used as target molecules. Prior to performing the release study, the effects of CO on aptamer-protein interaction were observed by surface plasmon resonance (SPR). The SPR sensorgram indicated that the aptamer dissociated from the bounded proteins when it hybridized with the CO. The aptamer was then immobilized onto streptavidin coated polystyrene particles via biotin/streptavidin interaction. Then, PDGF-BB and aptamer functionalized particles were mixed with gelatin solution and cast as small pieces of composite. The success of the composite preparation was confirmed by flow cytometry and microscopy. PDGF-BB release at several time points was quantified by ELISA. The results showed that the aptamer-gelatin composite could slow the release rate of the proteins from the composite due to strong binding of proteins and aptamers. Once the CO was added to the system, the release rate was significantly enhanced because the aptamer hybridized with the CO and lost its active secondary structure. Therefore, the proteins were triggered to release out from the composite. This work suggests a promising strategy for controlling the release of bioactive molecules in medical treatments. PMID- 25297833 TI - Resistance to antiplatelet drugs: what progress has been made? AB - INTRODUCTION: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the 'wide variability' and the phenomenon of 'antiplatelet resistance'. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a 'therapeutic window' of P2Y12 receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed. AREAS COVERED: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on treatment platelet reactivity to ADP during P2Y12 receptor blocker therapy was collected from a selective literature search. EXPERT OPINION: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y12 receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome. PMID- 25297834 TI - Neuropsychiatric symptoms accompanying thrombocytopenia following pregabalin treatment for neuralgia: a case report. AB - CASE DESCRIPTION: A 28-year-old female patient developed an increased temperature and neuropsychiatric symptoms after receiving 75 mg pregabalin therapy for neuralgia. She presented initially with pyrexia and dizziness, followed by disorganized speech within an acute confusional state. Her body temperature returned to normal after taking 60 mg loxoprofen sodium several hours later. However, the neuropsychiatric symptoms did not improve until the next morning. Routine blood tests showed decreased platelet counts (from 131 * 109/L to 85 * 109/L). The following day, a further dose of 75 mg pregabalin was administered because of its effective amelioration of the patient's neuralgia. One hour later, the same symptoms appeared as had previously including increased body temperature of 39.2 degrees C accompanied by a lower platelet count (73 * 109/L). CONCLUSION: Clinicians should be alert to the serious neuropsychiatric symptoms and thrombocytopenia associated with the use of pregabalin. Routine blood tests may be necessary upon initiation of pregabalin treatment. PMID- 25297836 TI - Confinement-modulated junctionless nanowire transistors for logic circuits. AB - We report the controlled formation of nanoscale constrictions in junctionless nanowire field-effect transistors that efficiently modulate the flow of the current in the nanowire. The constrictions act as potential barriers and the height of the barriers can be selectively tuned by gates, making the device concept compatible with the crossbar geometry in order to create logic circuits. The functionality of the architecture and the reliability of the fabrication process are demonstrated by designing decoder devices. PMID- 25297835 TI - Genitourinary health in a population-based cohort of males with Duchenne and Becker Muscular dystrophies. AB - INTRODUCTION: Genitourinary (GU) health among patients with Duchenne and Becker muscular dystrophies (DBMD) has not been explored using population-based data. METHODS: Medical records of 918 males ascertained by the Muscular Dystrophy Surveillance, Tracking, and Research Network were reviewed for documentation of GU-related hospitalizations and prescribed medications. Percentages of males who received these medical interventions were calculated, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for associations with sociodemographics (study site, race/ethnicity), symptoms (early- vs. late-onset, ambulation status, scoliosis), and treatments (respiratory support, steroids). RESULTS: Among the 918 males, 81 (9%) had a GU condition, with voiding dysfunction (n = 40), GU tract infection (n = 19), and kidney/ureter calculus (n = 9) most frequently seen. The Kaplan-Meier curve produced a cumulative probability of 27%. Cox regression showed GU conditions were more common when males were non-ambulatory (HR 2.7, 95% CI 1.3-5.6). CONCLUSIONS: Our findings highlight the need for increased awareness of GU health and multidisciplinary care of DBMD patients. PMID- 25297837 TI - Inferring demographic structure with moccasin size data from the Promontory Caves, Utah. AB - The moccasin assemblage Julian Steward recovered from the Promontory caves in 1930-31 provides a novel example in which material culture can be used to understand the structure of an AD thirteenth century population. Several studies shed light on the relationship between shoe size, foot size, and stature. We develop an anthropometric model for understanding the composition of the Promontory Cave population by using moccasin size as a proxy for foot size. We then predict the stature of the individual who would have worn a moccasin. Stature is closely related to age for children, subadults and adult males. Although there are predictable sex and age factors biasing moccasin discard practices, moccasin dimensions suggest a relatively large proportion of children and subadults occupied the Promontory caves. This bison and antelope hunting population appears to have thrived during its stay on Promontory Point. PMID- 25297838 TI - Biphasic modulation by mGlu5 receptors of TRPV1-mediated intracellular calcium elevation in sensory neurons contributes to heat sensitivity. AB - BACKGROUND AND PURPOSE: Elevation of glutamate, an excitatory amino acid, during inflammation and injury plays a crucial role in the reception and transmission of sensory information via ionotropic and metabotropic receptors. This study aimed to investigate the mechanisms underlying the biphasic effects of metabotropic glutamate mGlu5 receptor activation on responses to noxious heat. EXPERIMENTAL APPROACH: We assessed the effects of intraplantar quisqualate, a non-selective glutamate receptor agonist, on heat and mechanical pain behaviours in mice. In addition, the effects of quisqualate on the intracellular calcium response and on membrane currents mediated by TRPV1 channels, were examined in cultured dorsal root ganglion neurons from mice. KEY RESULTS: Activation of mGlu5 receptors in hind paw transiently increased, then decreased, the response to noxious heat. In sensory neurons, activation of mGlu5 receptors potentiated TRPV1-mediated intracellular calcium elevation, while terminating activation of mGlu5 receptors depressed it. TRPV1-induced currents were potentiated by activation of mGlu5 receptors under voltage clamp conditions and these disappeared after washout. However, voltage-gated calcium currents were inhibited by the mGlu5 receptor agonist, even after washout. CONCLUSIONS AND IMPLICATIONS: These results suggest that, in sensory neurons, mGlu5 receptors biphasically modulate TRPV1-mediated intracellular calcium response via transient potentiation of TRPV1 channel induced currents and persistent inhibition of voltage-gated calcium currents, contributing to heat hyper- and hypoalgesia. PMID- 25297840 TI - Disparities in obesity among rural and urban residents in a health disparate region. AB - BACKGROUND: The burden of obesity and obesity-related conditions is not borne equally and disparities in prevalence are well documented for low-income, minority and rural adults in the United States. The current literature on rural versus urban disparities is largely derived from national surveillance data which may not reflect regional nuances. There is little practical research that supports the reality of local service providers such as county health departments that may serve both urban and rural residents in a given area. Conducted through a community-academic partnership, the primary aim of this study is to quantify the current levels of obesity (BMI), fruit and vegetable (FV) intake and physical activity (PA) in a predominately rural health disparate region. Secondary aims are to determine if a gradient exists within the region in which rural residents have poorer outcomes on these indicators compared to urban residents. METHODS: Conducted as part of a larger ongoing community-based participatory research (CBPR) initiative, data were gathered through a random digit dial telephone survey using previously validated measures (n = 784). Linear, logistic and quantile regression models are used to determine if residency (i.e. rural, urban) predicts outcomes of FV intake, PA and BMI. RESULTS: The majority (72%) of respondents were overweight (BMI = 29 +/- 6 kg/m2), with 29% being obese. Only 9% of residents met recommendations for FV intake and 38% met recommendations for PA. Statistically significant gradients between urban and rural and race exist at the upper end of the BMI distribution. In other words, the severity of obesity is worse among black compared to white and for urban residents compared to rural residents. CONCLUSIONS: These results will be used by the community-academic partnership to guide the development of culturally relevant and sustainable interventions to increase PA, increase FV intake and reduce obesity within this health disparate region. In particular, local stakeholders may wish to address disparities in BMI by allocating resources to the vulnerable groups identified. PMID- 25297841 TI - Updating the natural history of diabetic nephropathy. AB - Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with both types of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. The classical, five-stage natural history of DN, after an initial phase of hyperfiltration, is characterized by a progressive increase of albuminuria from normoalbuminuria to proteinuria, followed by a decline of glomerular filtration rate (GFR). Accumulating evidence indicates that clinical course of DN has changed profoundly, likely as a consequence of changes in treatment. In fact, remission/regression of microalbuminuria is a common feature of both type 1 and 2 diabetes which far outweighs progression to proteinuria. Moreover, GFR loss has been shown to occur independently of albuminuria or even in the absence of it. Nonalbuminuric renal impairment probably represents a different pathway to loss of renal function, which might recognize different pathogenic mechanisms, prognostic implications, and possibly therapeutic measures, as compared with the albuminuric pathway. The nonalbuminuric phenotype might be related to macroangiopathy instead of microangiopathy and/or be the consequence of repeated and/or unresolved episodes of acute kidney injury, even of mild degree. Reduced GFR and albuminuria are both powerful risk factor for cardiovascular events, whereas albuminuria appears to predict death and progression to ESRD better than GFR loss. Finally, it is unclear whether reduced GFR and albuminuria warrant different interventions and whether GFR decline may also regress in response to treatment, as proteinuria does. Further epidemiological, pathologic, pathophysiological, and intervention studies are needed to clarify the distinctive features of nonalbuminuric renal impairment. PMID- 25297842 TI - A new bulky iminophosphonamide as an N,N'-chelating ligand: synthesis and structural characterization of heteroleptic group 13 element complexes. AB - A sterically demanding iminophosphonamine ligand [(2,6-iPr2C6H3N)P(Ph2)(NtBu)]H (LH) and its lithium derivative [(2,6-iPr2C6H3N)P(Ph2)(NtBu)](Li.2THF) (1) were used to prepare complexes of group 13 elements. The reaction of LH with AlH3.NMe2Et and AlMe3 respectively, affords [LAlH2]2 (2) and LAlMe2 (3). The lithium derivative 1 when treated with the MCl3 compound of group 13 yields [(2,6 iPr2C6H3N)P(Ph2)(NtBu)]MCl2 (M = B (4); Al (5); and Ga (6). Compound 3 on reaction with a Lewis acid B(C6F5)3 generates the cationic complex [{(2,6 iPr2C6H3N)P(Ph2)(NtBu)}AlMe](+) [MeB(C6F5)3](-) (7) that slowly undergoes rearrangement to yield [(2,6-iPr2C6H3N)P(Ph2)(NtBu)]AlMe(C6F5) (8) and MeB(C6F5)2. Compounds 1-8 were characterized using multinuclear NMR, EI-MS and IR techniques and the solid state structure of 1-6 and 8 was elucidated by single crystal X-ray diffraction analyses. PMID- 25297839 TI - Genetic variation in the HLA region is associated with susceptibility to herpes zoster. AB - Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 * 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine. PMID- 25297843 TI - Rare-Earth doped particles as dual-modality contrast agent for minimally-invasive luminescence and dual-wavelength photoacoustic imaging. AB - Multi-modal imaging is an emerging area that integrates multiple imaging modalities to simultaneously capture visual information over many spatial scales. Complementary contrast agents need to be co-developed in order to achieve high resolution and contrast. In this work, we demonstrated that rare-earth doped particles (REDPs) can be employed as dual-modal imaging agents for both luminescence and photoacoustic (PA) imaging to achieve intrinsic high contrast, temporal and spatial resolution, reaching deeper depth. REDPs synthesized with different surfactants (citric acid, polyacrylic acid, ethylenediaminetetraacetic acid and sodium citrate) exhibit tunable emission properties and PA signal amplitudes. Amongst these samples, sodium citrate-modified REDPs showed the strongest PA signals. Furthermore, since REDPs have multiple absorption peaks, they offer a unique opportunity for multi-wavelength PA imaging (e.g. PA signals were measured using 520 and 975 nm excitations). The in vivo PA images around the cortical superior sagittal sinus (SSS) blood vessel captured with enhanced signal arising from REDPs demonstrated that in addition to be excellent luminescent probes, REDPs can also be used as successful PA contrast agents. Anisotropic polyacrylic acid-modified REDPs were found to be the best candidates for dual modal luminescence and PA imaging due to their strong luminescence and PA signal intensities. PMID- 25297844 TI - Genomic overview of the phytopathogen Pectobacterium wasabiae strain RNS 08.42.1A suggests horizontal acquisition of quorum-sensing genes. AB - The blackleg and soft-rot diseases caused by pectinolytic enterobacteria such as Pectobacterium and Dickeya are major causes of losses affecting potato crop in the field and upon storage. In this work, we report the isolation, characterization and genome analysis of the Pectobacterium wasabiae (formerly identified as Pectobacterium carotovorum subsp. carotovorum) strain RNS 08.42.1A, that has been isolated from a Solanum tuberosum host plant in France. Comparative genomics with 3 other P. wasabiae strains isolated from potato plants in different areas in North America and Europe, highlighted both a strong similarity at the whole genome level (ANI > 99 %) and a conserved synteny of the virulence genes. In addition, our analyses evidenced a robust separation between these four P. wasabiae strains and the type strain P. wasabiae CFBP 3304(T), isolated from horseradish in Japan. In P. wasabiae RNS 08.42.1A, the expI and expR nucleotidic sequences are more related to those of some Pectobacterium atrosepticum and P. carotovorum strains (90 % of identity) than to those of the other potato P. wasabiae strains (70 to 74 % of identity). This could suggest a recruitment of these genes in the P. wasabiae strain RNS 08.42.1A by an horizontal transfer between pathogens infecting the same potato host plant. PMID- 25297845 TI - Sensitization, pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts. AB - Late allograft failure (LAF) is a common cause of end stage renal disease. These patients face interrelated challenges regarding immunosuppression management, risk of graft intolerance syndrome (GIS), and sensitization. This retrospective study analyzes sensitization, pathology, imaging, and transfusion requirements in 33 LAFs presenting either with GIS (22) or grafts remaining quiescent (11). All patients underwent immunosuppression weaning to discontinuation at LAF. Profound increases in sensitization were noted for all groups and occurred in the GIS group prior to transplant nephrectomy (TxN). Patients with GIS experienced a major upswing in sensitization at, or before the time of their symptomatic presentation. For both GIS and quiescent grafts, sensitization appeared to be closely linked to immunosuppression withdrawal. Most transfusion naive patients became highly sensitized. Fourteen patients in the GIS group underwent TxN which revealed grade II acute cellular rejection or worse, with grade 3 chronic active T-cell-mediated rejection. Blinded comparisons of computed tomography scan of GIS group revealed swollen allografts with fluid collections compared with the quiescent allografts (QAs), which were shrunken and atrophic. The renal volume on imaging and weight of explants nearly matched. Future studies should focus on interventions to avoid sensitization and GIS. PMID- 25297846 TI - Reversible adaptation to photoinduced shape switching by oligomer-macrocycle interconversion with component selection in a three-state constitutional dynamic system. AB - Light irradiation of the molecular photoswitch 1-E causes isomerization into the 1-Z configuration stabilized by an internal hydrogen bond. 1-E bears aldehyde groups allowing for dynamic covalent reaction with linear diamines. On photoinduced E/Z shape switching of 1 in presence of diamines, the system undergoes interconversion between two states, a non-cyclic oligomeric one and a macrocyclic one, corresponding respectively to the E and Z configurations of 1. With a mixture of linear alpha,omega-diamines, 1-E yields non-selective dynamic oligomers by random incorporation of diamine components. Photoswitching to the 1 Z form leads to constitutional adaptation with preferential formation of the macrocycle incorporating the best suited diamine, H2 N(CH2 )7 NH2 . In presence of metal cations, the E form switches from its unbound W shape to its coordinated U shape and yields the macrocycle resulting from the selective incorporation of the diamine H2 NCH2 CH2 OCH2 CH2 NH2 that contains an additional O coordination site. Taken together, the results obtained describe constitutional adaptation in a triple state system: an oligomeric one and two different macrocyclic ones generated in response to two orthogonal agents, a physical stimulus, light, or a chemical effector, metal cations. These three states present, towards the incorporation of diamine components, respectively no selection, photoselection and metalloselection. PMID- 25297847 TI - Biofunctional hybrid materials: bimolecular organosilane monolayers on FeCr alloys. AB - Hybrid organic-inorganic interfaces are the key to functionalization of stainless steel (SS). We present a solution-based deposition method for fabricating uniform bimolecular organosilane monolayers on SS and show that their properties and functionalities can be further developed through site-specific biotinylation. We correlate molecular properties of the interface with its reactivity via surface sensitive synchrotron radiation mediated high-resolution photoelectron spectroscopy (HR-PES) and chemical derivatization (CD), and we demonstrate specific bonding of streptavidin proteins to the hybrid interface. The method facilitates efficient growth of uniform bimolecular organosilane monolayers on SS under ambient conditions without the need to prime the SS surface with vacuum deposited inorganic buffer layers. The obtained insights into molecular bonding, orientation, and behaviour of surface-confined organofunctional silanes on SS enable a new generic approach to functionalization of SS surfaces with versatile nanomolecular organosilane layers. PMID- 25297848 TI - Spiritual coping predicts CD4-cell preservation and undetectable viral load over four years. AB - In this study of 177 people living with HIV, we examined if spiritual coping leads to slower HIV disease progression (CD4 cells, viral load [VL]), and more positive health behaviors (adherence, safer sex, less substance use). Prior research suggests that physicians' assessment of spiritual coping can be an interventional aid in promoting positive spiritual coping. Longitudinal spiritual coping was rated using qualitative content analysis of six-monthly interviews/essays. Positive spiritual coping (65%) was predominant over negative (7%), whereas 28% did not make significant use of spirituality as a means to cope. Spiritual coping was associated with less substance use disorder but not with less sexual risk behavior. Hierarchical linear modeling demonstrated that spiritual coping predicted sustained undetectable VL and CD4-cell preservation over four years, independent of sociodemographics, baseline disease status, and substance use disorder. Achieving undetectable VL significantly increased over time in participants with positive spiritual coping but decreased among those with negative spiritual coping. For every participant with positive spiritual coping achieving undetectable VL, four with negative spiritual coping reported with detectable/transmittable HIV. Notably, even when controlling for the effect of VL suppression, CD4-cell decline was 2.25 times faster among those engaged in negative versus positive spiritual coping. In conclusion, spiritual coping is associated with positive health behaviors, such as maintaining long-term VL suppression and less onset/relapse of substance use disorder over time. Among those who are sexually active, positive spiritual coping reduces the risk of HIV transmission via VL suppression but may not prevent the transmission of other STDs because spiritual coping is not related to safer sexual behavior. Notably, the association between spiritual coping and immune preservation was direct (i.e., not explained by VL suppression), suggesting potential psychoneuroimmunological pathways. Thus, assessment of spiritual coping may be an important area of intervention to achieve undetectable VL, reduce HIV disease progression, and prevent substance use onset/relapse. PMID- 25297849 TI - Gene expression plasticity resulting from parental leaf damage in Mimulus guttatus. AB - Leaf trichome density in Mimulus guttatus can be altered by the parental environment. In this study, we compared global gene expression patterns in progeny of damaged and control plants. Significant differences in gene expression probably explain the observed trichome response, and identify additional responsive pathways. Using whole transcriptome RNA sequencing, we estimated differential gene expression between isogenic seedlings whose parents had, or had not, been subject to leaf damage. We identified over 900 genes that were differentially expressed in response to parental wounding. These genes clustered into groups involved in cell wall and cell membrane development, stress response pathways, and secondary metabolism. Gene expression is modified as a consequence of the parental environment in a targeted way that probably alters multiple developmental pathways, and may increase progeny fitness if they experience environments similar to that of their parents. PMID- 25297850 TI - Aurora kinase A is superior to Ki67 as a prognostic indicator of survival in neuroblastoma. AB - AIMS: To compare the expression and prognostic value of the cell cycle markers Aurora kinase A (AURKA) and Ki67 in neuroblastoma, because AURKA expression levels have greater prognostic significance than those of Ki67 in some cancers. METHODS AND RESULTS: Eighty-eight neuroblastomas were immunostained with anti AURKA and Ki67 antibodies. Digitally scanned slides were scored using imaging analysis software. Median AURKA and Ki67 proliferation indices (PIs) were 1.5% and 26%, respectively. Higher than median AURKA and Ki67 levels were detected in the neuroblastomas from patients belonging to the high-risk group, those with MYCN amplification, and those with unfavourable pathology, including a high mitosis-karyorrhexis index (MKI). High AURKA and Ki67 levels were significantly associated with shorter overall survival (OS) and event-free survival (EFS) in univariate analyses. In multivariate analyses, high AURKA level was associated with significantly shorter OS and EFS, independently of risk group, and of MYCN amplification and MKI. High Ki67 level was not associated with shorter OS or EFS after adjustment for risk group or MYCN amplification and MKI. CONCLUSIONS: High AURKA and Ki67 levels were associated with adverse prognostic factors and shorter survival, but AURKA provides more valuable prognostic information than Ki67 in neuroblastoma. PMID- 25297852 TI - Phototunable liquid-crystalline phases made of nanoparticles. AB - The properties of liquid-crystalline (LC) hybrid systems made of inorganic nanoparticles grafted with photosensitive azo compounds are presented. For materials with a large density of azo ligands at the surface, the LC structure can be reversibly melted by UV light, and the return to the LC state does not require the absorption of visible light. For systems with a lower density of azo ligands, UV light causes shortening of the distance between metal sublayers in the lamellar phase. Interestingly, the azo derivatives attached to the nanoparticle surface show very different kinetics of cis/trans conformational change as compared to the free molecules. The cis form of free ligands in solution is stable for days, whereas the isomerization of molecules attached to the nanoparticle surface to the trans form takes only a few minutes. Apparently, owing to the crowded environment, azo ligands immobilized at a metal surface behave as they would in the condensed state. PMID- 25297851 TI - BMP-9 regulates the osteoblastic differentiation and calcification of vascular smooth muscle cells through an ALK1 mediated pathway. AB - The process of vascular calcification shares many similarities with that of physiological skeletal mineralization, and involves the deposition of hydroxyapatite crystals in arteries. However, the cellular mechanisms responsible have yet to be fully explained. Bone morphogenetic protein (BMP-9) has been shown to exert direct effects on both bone development and vascular function. In the present study, we have investigated the role of BMP-9 in vascular smooth muscle cell (VSMC) calcification. Vessel calcification in chronic kidney disease (CKD) begins pre-dialysis, with factors specific to the dialysis milieu triggering accelerated calcification. Intriguingly, BMP-9 was markedly elevated in serum from CKD children on dialysis. Furthermore, in vitro studies revealed that BMP-9 treatment causes a significant increase in VSMC calcium content, alkaline phosphatase (ALP) activity and mRNA expression of osteogenic markers. BMP-9 induced calcium deposition was significantly reduced following treatment with the ALP inhibitor 2,5-Dimethoxy-N-(quinolin-3-yl) benzenesulfonamide confirming the mediatory role of ALP in this process. The inhibition of ALK1 signalling using a soluble chimeric protein significantly reduced calcium deposition and ALP activity, confirming that BMP-9 is a physiological ALK1 ligand. Signal transduction studies revealed that BMP-9 induced Smad2, Smad3 and Smad1/5/8 phosphorylation. As these Smad proteins directly bind to Smad4 to activate target genes, siRNA studies were subsequently undertaken to examine the functional role of Smad4 in VSMC calcification. Smad4-siRNA transfection induced a significant reduction in ALP activity and calcium deposition. These novel data demonstrate that BMP-9 induces VSMC osteogenic differentiation and calcification via ALK1, Smad and ALP dependent mechanisms. This may identify new potential therapeutic strategies for clinical intervention. PMID- 25297853 TI - Co-delivery of autoantigen and b7 pathway modulators suppresses experimental autoimmune encephalomyelitis. AB - Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigen-specific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway. PMID- 25297855 TI - Antibacterial effect of triantibiotic mixture versus calcium hydroxide in combination with active agents against Enterococcus faecalis biofilm. AB - The aim of the present study was to compare the antibacterial effect of calcium hydroxide (CH), triantibiotic mixture (TAM), and CH in combination with chlorhexidine (CHX), sodium hypochlorite (NaOCl) or colchicine (COL) against Enterococcus faecalis (E. faecalis) in surface and deep dentinal tubules. Seventy five fresh single-rooted human teeth were infected and divided into five experimental groups (n=15). The experimental groups were treated with CH+distilled water, CH+CHX, CH+NaOCl, CH+COL+distilled water and TAM+distilled water. Dentin chips obtained from surface and deep dentin of these root canals were prepared and analyzed by counting the number of colony forming units. There was significant difference between groups in the surface dentin (p<0.05). TAM showed higher antibacterial activity compared to CH-containing groups. There was no significant difference between TAM and CH-containing groups in the deep dentin (p>0.05). CH-containing medications and TAM can be used as effective disinfectants in treatment of infected root canals. PMID- 25297854 TI - Single-tube, highly parallel mutation enrichment in cancer gene panels by use of temperature-tolerant COLD-PCR. AB - BACKGROUND: Multiplexed detection of low-level mutations presents a technical challenge for many technologies, including cancer gene panels used for targeted resequencing. Analysis of mutations below approximately 2%-5% abundance in tumors with heterogeneity, samples with stromal contamination, or biofluids is problematic owing to increased noise from sequencing errors. Technologies that reduce noise via deep sequencing unavoidably reduce throughput and increase cost. Here we provide proof of principle that coamplification at lower denaturation temperature (COLD)-PCR technology enables multiplex low-level mutation detection in cancer gene panels while retaining throughput. METHODS: We have developed a multiplex temperature-tolerant COLD-PCR (fast-TT-COLD-PCR) approach that uses cancer gene panels developed for massively parallel sequencing. After multiplex preamplification from genomic DNA, we attach tails to all amplicons and perform fast-TT-COLD-PCR. This approach gradually increases denaturation temperatures in a step-wise fashion, such that all possible denaturation temperatures are encompassed. By introducing modified nucleotides, fast-COLD-PCR is adapted to enrich for melting temperature (Tm)-increasing mutations over all amplicons, in a single tube. Therefore, in separate reactions, both Tm-decreasing and Tm increasing mutations are enriched. RESULTS: Using custom-made and commercial gene panels containing 8, 50, 190, or 16 000 amplicons, we demonstrate that fast-TT COLD-PCR enriches mutations on all examined targets simultaneously. Incorporation of deoxyinosine triphosphate (dITP)/2,6-diaminopurine triphosphate (dDTP) in place of deoxyguanosine triphosphate (dGTP)/deoxyadenosine triphosphate (dATP) enables enrichment of Tm-increasing mutations. Serial dilution experiments demonstrate a limit of detection of approximately 0.01%-0.1% mutation abundance by use of Ion-Torrent and 0.1%-0.3% by use of Sanger sequencing. CONCLUSIONS: Fast-TT-COLD-PCR improves the limit of detection of cancer gene panels by enabling mutation enrichment in multiplex, single-tube reactions. This novel adaptation of COLD-PCR converts subclonal mutations to clonal, thereby facilitating detection and subsequent mutation sequencing. PMID- 25297856 TI - Surfacers change their dive tactics depending on the aim of the dive: evidence from simultaneous measurements of breaths and energy expenditure. AB - Air-breathing divers are assumed to have evolved to apportion their time between surface and underwater periods to maximize the benefit gained from diving activities. However, whether they change their time allocation depending on the aim of the dive is still unknown. This may be particularly crucial for 'surfacers' because they dive for various purposes in addition to foraging. In this study, we counted breath events at the surface and estimated oxygen consumption during resting, foraging and other dives in 11 green turtles (Chelonia mydas) in the wild. Breath events were counted by a head-mounted acceleration logger or direct observation based on an animal-borne video logger, and oxygen consumption was estimated by measuring overall dynamic body acceleration. Our results indicate that green turtles maximized their submerged time, following this with five to seven breaths to replenish oxygen for resting dives. However, they changed their dive tactic during foraging and other dives; they surfaced without depleting their estimated stores of oxygen, followed by only a few breaths for effective foraging and locomotion. These dichotomous surfacing tactics would be the result of behavioural modifications by turtles depending on the aim of each dive. PMID- 25297857 TI - Archaeological evidences are still missing: a comment on Farina et al. Arroyo del Vizcaino site, Uruguay. PMID- 25297859 TI - The movement ecology of seagrasses. AB - A movement ecology framework is applied to enhance our understanding of the causes, mechanisms and consequences of movement in seagrasses: marine, clonal, flowering plants. Four life-history stages of seagrasses can move: pollen, sexual propagules, vegetative fragments and the spread of individuals through clonal growth. Movement occurs on the water surface, in the water column, on or in the sediment, via animal vectors and through spreading clones. A capacity for long distance dispersal and demographic connectivity over multiple timeframes is the novel feature of the movement ecology of seagrasses with significant evolutionary and ecological consequences. The space-time movement footprint of different life history stages varies. For example, the distance moved by reproductive propagules and vegetative expansion via clonal growth is similar, but the timescales range exponentially, from hours to months or centuries to millennia, respectively. Consequently, environmental factors and key traits that interact to influence movement also operate on vastly different spatial and temporal scales. Six key future research areas have been identified. PMID- 25297861 TI - Aquatic polymers can drive pathogen transmission in coastal ecosystems. AB - Gelatinous polymers including extracellular polymeric substances (EPSs) are fundamental to biophysical processes in aquatic habitats, including mediating aggregation processes and functioning as the matrix of biofilms. Yet insight into the impact of these sticky molecules on the environmental transmission of pathogens in the ocean is limited. We used the zoonotic parasite Toxoplasma gondii as a model to evaluate polymer-mediated mechanisms that promote transmission of terrestrially derived pathogens to marine fauna and humans. We show that transparent exopolymer particles, a particulate form of EPS, enhance T. gondii association with marine aggregates, material consumed by organisms otherwise unable to access micrometre-sized particles. Adhesion to EPS biofilms on macroalgae also captures T. gondii from the water, enabling uptake of pathogens by invertebrates that feed on kelp surfaces. We demonstrate the acquisition, concentration and retention of T. gondii by kelp-grazing snails, which can transmit T. gondii to threatened California sea otters. Results highlight novel mechanisms whereby aquatic polymers facilitate incorporation of pathogens into food webs via association with particle aggregates and biofilms. Identifying the critical role of invisible polymers in transmission of pathogens in the ocean represents a fundamental advance in understanding and mitigating the health impacts of coastal habitat pollution with contaminated runoff. PMID- 25297860 TI - Developmental stress increases reproductive success in male zebra finches. AB - There is increasing evidence that exposure to stress during development can have sustained effects on animal phenotype and performance across life-history stages. For example, developmental stress has been shown to decrease the quality of sexually selected traits (e.g. bird song), and therefore is thought to decrease reproductive success. However, animals exposed to developmental stress may compensate for poor quality sexually selected traits by pursuing alternative reproductive tactics. Here, we examine the effects of developmental stress on adult male reproductive investment and success in the zebra finch (Taeniopygia guttata). We tested the hypothesis that males exposed to developmental stress sire fewer offspring through extra-pair copulations (EPCs), but invest more in parental care. To test this hypothesis, we fed nestlings corticosterone (CORT; the dominant avian stress hormone) during the nestling period and measured their adult reproductive success using common garden breeding experiments. We found that nestlings reared by CORT-fed fathers received more parental care compared with nestlings reared by control fathers. Consequently, males fed CORT during development reared nestlings in better condition compared with control males. Contrary to the prediction that developmental stress decreases male reproductive success, we found that CORT-fed males also sired more offspring and were less likely to rear non-genetic offspring compared with control males, and thus had greater overall reproductive success. These data are the first to demonstrate that developmental stress can have a positive effect on fitness via changes in reproductive success and provide support for an adaptive role of developmental stress in shaping animal phenotype. PMID- 25297862 TI - The straight and narrow path: the evolution of straight-line dispersal at a cane toad invasion front. AB - At the edge of a biological invasion, evolutionary processes (spatial sorting, natural selection) often drive increases in dispersal. Although numerous traits influence an individual's displacement (e.g. speed, stamina), one of the most important is path straightness. A straight (i.e. highly correlated) path strongly enhances overall dispersal rate relative to time and energetic cost. Thus, we predict that, if path straightness has a genetic basis, organisms in the invasion vanguard will exhibit straighter paths than those following behind. Our studies on invasive cane toads (Rhinella marina) in tropical Australia clearly support this prediction. Radio-tracking of field-collected toads at a single site showed that path straightness steadily decreased over the first 10 years post-invasion. Consistent with an evolved (genetic) basis to that behavioural shift, path straightness of toads reared under common garden conditions varied according to the location of their parents' origin. Offspring produced by toads from the invasion vanguard followed straighter paths than did those produced by parents from long-established populations. At the individual level, offspring exhibited similar path straightness to their parents. The dramatic acceleration of the cane toad invasion through tropical Australia has been driven, in part, by the evolution of a behavioural tendency towards dispersing in a straight line. PMID- 25297863 TI - Onshore-offshore gradient in metacommunity turnover emerges only over macroevolutionary time-scales. AB - Invertebrate lineages tend to originate and become extinct at a higher rate in onshore than in offshore habitats over long temporal durations (more than 10 Myr), but it remains unclear whether this pattern scales down to durations of stages (less than 5 Myr) or even sequences (less than 0.5 Myr). We assess whether onshore-offshore gradients in long-term turnover between the tropical Eocene and the warm-temperate Plio-Pleistocene can be extrapolated from gradients in short term turnover, using abundances of molluscan species from bulk samples in the northeast Atlantic Province. We find that temporal turnover of metacommunities does not significantly decline with depth over short durations (less than 5 Myr), but significantly declines with depth between the Eocene and Plio-Pleistocene (approx. 50 Myr). This decline is determined by a higher onshore extinction of Eocene genera and families, by a higher onshore variability in abundances of genera and families, and by an onshore expansion of genera and families that were frequent offshore in the Eocene. Onshore-offshore decline in turnover thus emerges only over long temporal durations. We suggest that this emergence is triggered by abrupt and spatially extensive climatic or oceanographic perturbations that occurred between the Eocene and Plio-Pleistocene. Plio Pleistocene metacommunities show a high proportion of bathymetric generalists, in contrast to Eocene metacommunities. Accordingly, the net cooling and weaker thermal gradients may have allowed offshore specialists to expand into onshore habitats and maintain their presence in offshore habitats. PMID- 25297865 TI - Among others, cut-marks are archaeological evidence: reply to 'Archaeological evidences are still missing: a comment on Farina et al. Arroyo del Vizcaino Site, Uruguay' by Suarez et al. PMID- 25297864 TI - Ecological opportunities and specializations shaped genetic divergence in a highly mobile marine top predator. AB - Environmental conditions can shape genetic and morphological divergence. Release of new habitats during historical environmental changes was a major driver of evolutionary diversification. Here, forces shaping population structure and ecotype differentiation ('pelagic' and 'coastal') of bottlenose dolphins in the North-east Atlantic were investigated using complementary evolutionary and ecological approaches. Inference of population demographic history using approximate Bayesian computation indicated that coastal populations were likely founded by the Atlantic pelagic population after the Last Glacial Maxima probably as a result of newly available coastal ecological niches. Pelagic dolphins from the Atlantic and the Mediterranean Sea likely diverged during a period of high productivity in the Mediterranean Sea. Genetic differentiation between coastal and pelagic ecotypes may be maintained by niche specializations, as indicated by stable isotope and stomach content analyses, and social behaviour. The two ecotypes were only weakly morphologically segregated in contrast to other parts of the World Ocean. This may be linked to weak contrasts between coastal and pelagic habitats and/or a relatively recent divergence. We suggest that ecological opportunity to specialize is a major driver of genetic and morphological divergence. Combining genetic, ecological and morphological approaches is essential to understanding the population structure of mobile and cryptic species. PMID- 25297866 TI - Evolution of cultural traits occurs at similar relative rates in different world regions. AB - A fundamental issue in understanding human diversity is whether or not there are regular patterns and processes involved in cultural change. Theoretical and mathematical models of cultural evolution have been developed and are increasingly being used and assessed in empirical analyses. Here, we test the hypothesis that the rates of change of features of human socio-cultural organization are governed by general rules. One prediction of this hypothesis is that different cultural traits will tend to evolve at similar relative rates in different world regions, despite the unique historical backgrounds of groups inhabiting these regions. We used phylogenetic comparative methods and systematic cross-cultural data to assess how different socio-cultural traits changed in (i) island southeast Asia and the Pacific, and (ii) sub-Saharan Africa. The relative rates of change in these two regions are significantly correlated. Furthermore, cultural traits that are more directly related to external environmental conditions evolve more slowly than traits related to social structures. This is consistent with the idea that a form of purifying selection is acting with greater strength on these more environmentally linked traits. These results suggest that despite contingent historical events and the role of humans as active agents in the historical process, culture does indeed evolve in ways that can be predicted from general principles. PMID- 25297867 TI - Partitioning the net effect of host diversity on an emerging amphibian pathogen. AB - The 'dilution effect' (DE) hypothesis predicts that diverse host communities will show reduced disease. The underlying causes of pathogen dilution are complex, because they involve non-additive (driven by host interactions and differential habitat use) and additive (controlled by host species composition) mechanisms. Here, we used measures of complementarity and selection traditionally employed in the field of biodiversity-ecosystem function (BEF) to quantify the net effect of host diversity on disease dynamics of the amphibian-killing fungus Batrachochytrium dendrobatidis (Bd). Complementarity occurs when average infection load in diverse host assemblages departs from that of each component species in uniform populations. Selection measures the disproportionate impact of a particular species in diverse assemblages compared with its performance in uniform populations, and therefore has strong additive and non-additive properties. We experimentally infected tropical amphibian species of varying life histories, in single- and multi-host treatments, and measured individual Bd infection loads. Host diversity reduced Bd infection in amphibians through a mechanism analogous to complementarity (sensu BEF), potentially by reducing shared habitat use and transmission among hosts. Additionally, the selection component indicated that one particular terrestrial species showed reduced infection loads in diverse assemblages at the expense of neighbouring aquatic hosts becoming heavily infected. By partitioning components of diversity, our findings underscore the importance of additive and non-additive mechanisms underlying the DE. PMID- 25297868 TI - Macroevolutionary consequences of profound climate change on niche evolution in marine molluscs over the past three million years. AB - In order to predict the fate of biodiversity in a rapidly changing world, we must first understand how species adapt to new environmental conditions. The long-term evolutionary dynamics of species' physiological tolerances to differing climatic regimes remain obscure. Here, we unite palaeontological and neontological data to analyse whether species' environmental tolerances remain stable across 3 Myr of profound climatic changes using 10 phylogenetically, ecologically and developmentally diverse mollusc species from the Atlantic and Gulf Coastal Plains, USA. We additionally investigate whether these species' upper and lower thermal tolerances are constrained across this interval. We find that these species' environmental preferences are stable across the duration of their lifetimes, even when faced with significant environmental perturbations. The results suggest that species will respond to current and future warming either by altering distributions to track suitable habitat or, if the pace of change is too rapid, by going extinct. Our findings also support methods that project species' present-day environmental requirements to future climatic landscapes to assess conservation risks. PMID- 25297869 TI - Cranial biomechanics underpins high sauropod diversity in resource-poor environments. AB - High megaherbivore species richness is documented in both fossil and contemporary ecosystems despite their high individual energy requirements. An extreme example of this is the Late Jurassic Morrison Formation, which was dominated by sauropod dinosaurs, the largest known terrestrial vertebrates. High sauropod diversity within the resource-limited Morrison is paradoxical, but might be explicable through sophisticated resource partitioning. This hypothesis was tested through finite-element analysis of the crania of the Morrison taxa Camarasaurus and Diplodocus. Results demonstrate divergent specialization, with Camarasaurus capable of exerting and accommodating greater bite forces than Diplodocus, permitting consumption of harder food items. Analysis of craniodental biomechanical characters taken from 35 sauropod taxa demonstrates a functional dichotomy in terms of bite force, cranial robustness and occlusal relationships yielding two polyphyletic functional 'grades'. Morrison taxa are widely distributed within and between these two morphotypes, reflecting distinctive foraging specializations that formed a biomechanical basis for niche partitioning between them. This partitioning, coupled with benefits associated with large body size, would have enabled the high sauropod diversities present in the Morrison Formation. Further, this provides insight into the mechanisms responsible for supporting the high diversities of large megaherbivores observed in other Mesozoic and Cenozoic communities, particularly those occurring in resource limited environments. PMID- 25297871 TI - Serotonin transporter polymorphism modifies the association between depressive symptoms and sleep onset latency complaint in elderly people: results from the 'InveCe.Ab' study. AB - Previous studies have documented the involvement of the central nervous system serotonin in promoting wakefulness. There are few and conflicting results over whether there is an actual association between bearing the short allele of serotonin transporter promoter polymorphism (5-HTTLPR) and worse sleep quality. This study examined whether sleep onset latency complaint is associated with the 5-HTTLPR triallelic polymorphism in the SLC6A4 gene promoter and whether this polymorphism influences the relationship between sleep onset latency complaint and depressive symptoms in elderly people. A total of 1321 community-dwelling individuals aged 70-74 years were interviewed for sleep onset latency complaint and for sleep medication consumption. Participants' genomic DNA was typed for 5 HTTLPR and rs25531 polymorphisms. Depressive symptoms were evaluated with the Geriatric Depression Scale Short form and general medical comorbidity was assessed by the Cumulative Illness Rating Scale. The presence of a past history of depression was recorded. The S' allele of the 5-HTTLPR triallelic polymorphism was associated with sleep onset latency complaint. This association was maintained after adjusting for depressive symptoms, sex, age, history of depression and medical comorbidity. After stratification for 5-HTTLPR/rs25531, only in S'S' individuals high depressive symptoms were actually associated with sleep onset latency complaint. These data indicate that the low-expressing 5 HTTLPR triallelic polymorphism is an independent risk factor for sleep onset latency disturbance. Furthermore, the 5-HTTLPR genotype influences the association between depressive symptoms and sleep onset latency complaint. PMID- 25297872 TI - Surgical margins in rectal cancer-quality measures using the National Cancer Data Base. PMID- 25297873 TI - Atypical chemokine receptor ACKR2 mediates chemokine scavenging by primary human trophoblasts and can regulate fetal growth, placental structure, and neonatal mortality in mice. AB - Inflammatory chemokines produced in the placenta can direct the migration of placental leukocytes using chemokine receptors that decorate the surface of these cells. Fetal trophoblasts can also express receptors for inflammatory chemokines, and they are one of the few cell types that express atypical chemokine receptor 2 (ACKR2), previously known as D6. ACKR2 binds many inflammatory CC chemokines but cannot stimulate cell migration or activate signaling pathways used by conventional chemokine receptors. Existing evidence suggests that ACKR2 is a specialized chemokine scavenger, but its function in primary human trophoblasts has not been explored. In mice, ACKR2 is thought to be dispensable for the reproductive success of unchallenged females that have conceived naturally, but it can suppress inflammation-induced abortion and aid the survival of implanted allogeneic embryos. In this article, we demonstrate that cultured primary human trophoblasts express ACKR2 far more strongly than genes encoding conventional receptors for inflammatory CC chemokines. Moreover, these cells are capable of the rapid internalization and efficient scavenging of extracellular chemokine, and this is mediated by ACKR2. We also report that in unchallenged DBA/1j mice, Ackr2 deficiency increases the incidence of stillbirth and neonatal death, leads to structural defects in the placenta, and can decrease fetal weight. Loss of Ackr2 specifically from fetal cells makes a key contribution to the placental defects. Thus, primary human trophoblasts use ACKR2 to scavenge chemokines, and ACKR2 deficiency can cause abnormal placental structure and reduced neonatal survival. PMID- 25297874 TI - The C5a anaphylatoxin receptor (C5aR1) protects against Listeria monocytogenes infection by inhibiting type 1 IFN expression. AB - Listeria monocytogenes is a major cause of mortality resulting from food poisoning in the United States. In mice, C5 has been genetically linked to host resistance to listeriosis. Despite this genetic association, it remains poorly understood how C5 and its activation products, C5a and C5b, confer host protection to this Gram-positive intracellular bacterium. In this article, we show in a systemic infection model that the major receptor for C5a, C5aR1, is required for a normal robust host immune response against L. monocytogenes. In comparison with wild-type mice, C5aR1(-/-) mice had reduced survival and increased bacterial burden in their livers and spleens. Infected C5aR1(-/-) mice exhibited a dramatic reduction in all major subsets of splenocytes, which was associated with elevated caspase-3 activity and increased TUNEL staining. Because type 1 IFN has been reported to impede the host response to L. monocytogenes through the promotion of splenocyte death, we examined the effect of C5aR1 on type 1 IFN expression in vivo. Indeed, serum levels of IFN-alpha and IFN-beta were significantly elevated in L. monocytogenes-infected C5aR1(-/-) mice. Similarly, the expression of TRAIL, a type 1 IFN target gene and a proapoptotic factor, was elevated in NK cells isolated from infected C5aR1(-/-) mice. Treatment of C5aR1(-/-) mice with a type 1 IFNR blocking Ab resulted in near complete rescue of L. monocytogenes-induced mortality. Thus, these findings reveal a critical role for C5aR1 in host defense against L. monocytogenes through the suppression of type 1 IFN expression. PMID- 25297877 TI - Pustular psoriasis occurring after total colectomy for ulcerative colitis and relieved by administration of infliximab. PMID- 25297876 TI - Endosomal localization of TLR8 confers distinctive proteolytic processing on human myeloid cells. AB - Nucleic acid-sensing TLRs are involved in both antimicrobial immune responses and autoimmune inflammation. TLR8 is phylogenetically and structurally related to TLR7 and TLR9, which undergo proteolytic processing in the endolysosomes to generate functional receptors. Recent structural analyses of human TLR8 ectodomain and its liganded form demonstrated that TLR8 is also cleaved, and both the N- and C-terminal halves contribute to ligand binding. However, the structures and ssRNA recognition mode of endogenous TLR8 in human primary cells are largely unknown. In this study, we show that proteolytic processing of TLR8 occurs in human monocytes and macrophages in a different manner compared with TLR7/9 cleavage. The insertion loop between leucine-rich repeats 14 and 15 in TLR8 is indispensable for the cleavage and stepwise processing that occurs in the N-terminal fragment. Both furin-like proprotein convertase and cathepsins contribute to TLR8 cleavage in the early/late endosomes. TLR8 recognizes viral ssRNA and endogenous RNA, such as microRNAs, resulting in the production of proinflammatory cytokines. Hence, localization sites of the receptors are crucial for the nucleic acid-sensing mode and downstream signaling. PMID- 25297875 TI - Epigenetic control of Ccr7 expression in distinct lineages of lung dendritic cells. AB - Adaptive immune responses to inhaled allergens are induced following CCR7 dependent migration of precursor of dendritic cell (pre-DC)-derived conventional DCs (cDCs) from the lung to regional lymph nodes. However, monocyte-derived (moDCs) in the lung express very low levels of Ccr7 and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7 associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung. PMID- 25297878 TI - Exploring Creole women's health using ethnography and Photovoice in Bluefields, Nicaragua. AB - Bluefields, Nicaragua is the largest city in the Southern Atlantic Autonomous Region (RAAS), and home to communities of Nicaragua's six ethnic groups. Photovoice research techniques were used in this ethnographic study to explore the health experiences of Creole women. After participating in focus groups to discuss women's health, 12 Creole women took photographs to describe their health experiences. The researcher then interviewed them about what each picture meant, and participants selected photos for a community-wide exhibition in Bluefields. Photos and narratives were analyzed to construct a description of the cultural context in which Creole women experienced health. One of the greatest women's health concerns reported was that participants believed the younger generation was losing touch with Creole culture, putting them at risk of disease and illness. For participants, photos were a way to document Creole traditions of healing, traditions in the Creole home, and environmental health concerns. PMID- 25297879 TI - I2-catalyzed oxidative C(sp3)-H/S-H coupling: utilizing alkanes and mercaptans as the nucleophiles. AB - By using alkanes and mercaptans as the nucleophiles with di-tert-butyl peroxide (DTBP) as the oxidant, I2-catalyzed oxidative C(sp(3))-H/S-H coupling was achieved. This protocol provides a novel process to construct C(sp(3))-S bonds from commercially available hydrocarbons and mercaptans. PMID- 25297881 TI - Integration of graphene oxide and DNA as a universal platform for multiple arithmetic logic units. AB - By a combination of graphene oxide and DNA, a universal platform was developed for integration of multiple logic gates to implement both half adder and half subtractor functions. A constant undefined threshold range between high and low fluorescence output signals was set for all the developed logic gates. PMID- 25297880 TI - Evidence relating sodium intake to blood pressure and CVD. AB - Sodium is an essential nutrient, mostly ingested as salt (sodium chloride). Average sodium intake ranges from 3 to 6 g per day (7.5-15 g/day of salt) in most countries, with regional variations. Increasing levels of sodium intake have a positive association with higher blood pressure. Randomized controlled trials report a reduction in blood pressure with reducing sodium intake from moderate to low levels, which is the evidence that forms the basis for international guidelines recommending all people consume less than 2.0 g of sodium per day. However, no randomized trials have demonstrated that reducing sodium leads to a reduction in cardiovascular disease (CVD). In their absence, the next option is to examine the association between sodium consumption and CVD in prospective cohort studies. Several recent prospective cohort studies have indicated that while high intake of sodium (>6 g/d) is associated with higher risk of CVD compared to those with moderate intake (3 to 5 g/d), lower intake (<3 g/day) is also associated with a higher risk (despite lower blood pressure levels). However, most of these studies were conducted in populations at increased risk of cardiovascular disease. Current epidemiologic evidence supports that an optimal level of sodium intake is in the range of about 3-5 g/day, as this range is associated with lowest risk of CVD in prospective cohort studies. Randomized controlled trials, comparing the effect of low sodium intake to moderate intake on incidence of cardiovascular events and mortality, are required to truly define optimal intake range. PMID- 25297882 TI - When envy leads to schadenfreude. AB - Previous research has yielded inconsistent findings concerning the relationship between envy and schadenfreude. Three studies examined whether the distinction between benign and malicious envy can resolve this inconsistency. We found that malicious envy is related to schadenfreude, while benign envy is not. This result held both in the Netherlands where benign and malicious envy are indicated by separate words (Study 1: Sample A, N = 139; Sample B, N = 150), and in the USA where a single word is used to denote both types (Study 2, N = 180; Study 3, N = 349). Moreover, the effect of malicious envy on schadenfreude was independent of other antecedents of schadenfreude (such as feelings of inferiority, disliking the target person, anger, and perceived deservedness). These findings improve our understanding of the antecedents of schadenfreude and help reconcile seemingly contradictory findings on the relationship between envy and schadenfreude. PMID- 25297883 TI - A rare cause of Cushing's syndrome: an ACTH-secreting phaeochromocytoma. AB - Excess glucocorticoid levels cause Cushing's syndrome (CS) and may be due to pituitary, adrenal or ectopic tumours. Adrenocorticotropic hormone (ACTH) levels are useful in identifying adrenal tumours. In rare cases, ACTH-producing phaeochromocytomas are the cause of CS. We present two cases of ACTH-secreting phaeochromocytoma as the underlying cause of CS. In both cases, female patients presented with the classical clinical signs of CS and an adrenal mass. High ACTH levels raised the suspicion of an ACTH-secreting phaeochromocytoma. The diagnosis was confirmed by urinary catecholamine levels and positive fluorine-18-L dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) CT (Case 1) and fluorodeoxyglucose PET-CT (Case 2). Both patients were treated with an alpha blocker prior to surgical intervention. The two cases underline the importance of thorough diagnostic workup in patients with CS. An ACTH-secreting phaeochromocytoma should be checked for in patients with an adrenal mass and elevated ACTH levels. PMID- 25297884 TI - Apert syndrome: temporal lobe abnormalities on fetal brain imaging. AB - OBJECTIVES: Apert syndrome is characterized by craniosynostosis and complex hand and foot syndactyly, and an increased risk of brain, palate, heart, and visceral malformations, and intellectual disability. This study aims to describe the structural brain abnormalities detected by dedicated neuroimaging of fetuses with Apert syndrome. METHODS: Retrospective review of ultrasound and magnetic resonance imaging brain imaging obtained in six fetuses with a diagnosis of Apert syndrome. RESULTS: Five fetuses had attenuation of the septal leaflets, and two had corpus callosum dysgenesis. All six had temporal lobe expansion and overconvolution and temporal lobe clefts. The temporal lobe abnormalities preceded the development of cranial deformity in two fetuses. CONCLUSION: Overexpansion and overconvolution of the temporal lobe is evident antenatally and is particularly conspicuous in the fetus when the normal brain is still relatively smooth (approximately 24 to 28 weeks of gestation). PMID- 25297886 TI - KvarQ: targeted and direct variant calling from fastq reads of bacterial genomes. AB - BACKGROUND: High-throughput DNA sequencing produces vast amounts of data, with millions of short reads that usually have to be mapped to a reference genome or newly assembled. Both reference-based mapping and de novo assembly are computationally intensive, generating large intermediary data files, and thus require bioinformatics skills that are often lacking in the laboratories producing the data. Moreover, many research and practical applications in microbiology require only a small fraction of the whole genome data. RESULTS: We developed KvarQ, a new tool that directly scans fastq files of bacterial genome sequences for known variants, such as single nucleotide polymorphisms (SNP), bypassing the need of mapping all sequencing reads to a reference genome and de novo assembly. Instead, KvarQ loads "testsuites" that define specific SNPs or short regions of interest in a reference genome, and directly synthesizes the relevant results based on the occurrence of these markers in the fastq files. KvarQ has a versatile command line interface and a graphical user interface. KvarQ currently ships with two "testsuites" for Mycobacterium tuberculosis, but new "testsuites" for other organisms can easily be created and distributed. In this article, we demonstrate how KvarQ can be used to successfully detect all main drug resistance mutations and phylogenetic markers in 880 bacterial whole genome sequences. The average scanning time per genome sequence was two minutes. The variant calls of a subset of these genomes were validated with a standard bioinformatics pipeline and revealed >99% congruency. CONCLUSION: KvarQ is a user friendly tool that directly extracts relevant information from fastq files. This enables researchers and laboratory technicians with limited bioinformatics expertise to scan and analyze raw sequencing data in a matter of minutes. KvarQ is open-source, and pre-compiled packages with a graphical user interface are available at http://www.swisstph.ch/kvarq. PMID- 25297888 TI - Whole genome mapping as a fast-track tool to assess genomic stability of sequenced Staphylococcus aureus strains. AB - BACKGROUND: Whole genome (optical) mapping (WGM), a state-of-the-art mapping technology based on the generation of high resolution restriction maps, has so far been used for typing clinical outbreak strains and for mapping de novo sequence contigs in genome sequencing projects. We employed WGM to assess the genomic stability of previously sequenced Staphylococcus aureus strains that are commonly used in laboratories as reference standards. RESULTS: S. aureus strains (n = 12) were mapped on the ArgusTM Optical Mapping System (Opgen Inc, Gaithersburg, USA). Assembly of NcoI-restricted DNA molecules, visualization, and editing of whole genome maps was performed employing MapManager and MapSolver softwares (Opgen Inc). In silico whole genome NcoI-restricted maps were also generated from available sequence data, and compared to the laboratory-generated maps. Strains showing differences between the two maps were resequenced using Nextera XT DNA Sample Preparation Kit and Miseq Reagent Kit V2 (MiSeq, Illumina) and de novo assembled into sequence contigs using the Velvet assembly tool. Sequence data were correlated with corresponding whole genome maps to perform contig mapping and genome assembly using MapSolver. Of the twelve strains tested, one (USA300_FPR3757) showed a 19-kbp deletion on WGM compared to its in silico generated map and reference sequence data. Resequencing of the USA300_FPR3757 identified the deleted fragment to be a 13 kbp-long integrative conjugative element ICE6013. CONCLUSIONS: Frequent subculturing and inter-laboratory transfers can induce genomic and therefore, phenotypic changes that could compromise the utility of standard reference strains. WGM can thus be used as a rapid genome screening method to identify genomic rearrangements whose size and type can be confirmed by sequencing. PMID- 25297889 TI - Statin use and risk of gallstone disease: A meta-analysis. AB - AIM: There is emerging evidence from animal and human studies that current statins can decrease the formation of gallbladder cholesterol gallstones and subsequently decrease the risk of gallstone disease, but consistent results have not been reported. We performed a meta-analysis to provide an overview of the relevant studies. METHODS: Relevant studies published between January 1980 and February 2014 were identified by searching Medline, Embase and the Cochrane Library. Studies were selected using a priori defined criteria. The strength of the relationship between statin use and risk of gallstone disease was assessed by adjusted odds ratio (OR). RESULTS: A total of 622 868 participants from six studies (four case-control studies, one cohort study and one cross-sectional study) were identified in this meta-analysis. The studies provided adjusted overall OR estimates for current statin use versus non-use, leading to a pooled OR of 0.86 (95% confidence interval [CI], 0.77-0.97; P < 0.001). The overall OR of population-based case-control studies and cholecystectomy due to gallstone disease were 0.83 (95% CI, 0.73-0.95; P = 0.0131) and 0.78 (95% CI, 0.74-0.82; P = 0.615), respectively. CONCLUSION: There is evidence that current statin use lowers the risk of gallstone disease compared with non-use, especially for cholecystectomy due to gallstone disease. Low statin use (1-4 prescriptions) did not decrease the risk of gallstone disease, but moderate and high statin use significantly decreased the risk. Further multicenter and better controlled studies are needed to confirm these findings. PMID- 25297887 TI - Molecular identification of Cryptosporidium spp. in seagulls, pigeons, dogs, and cats in Thailand. AB - Zoonotic Cryptosporidium spp., particularly C. meleagridis, C. canis, and C. felis, are enteric protozoa responsible for major public health concerns around the world. To determine the spread of this parasite in Thailand, we conducted molecular identification of Cryptosporidium spp. from animal samples around the country, by collecting and investigating the feces of seagulls (Chroicocephalus brunnicephalus and Chroicocephalus ridibundus), domestic pigeons (Columba livia domestica), dogs, and cats. Seagull and pigeon samples were collected at the seaside and on the riverside to evaluate their potential for waterborne transmission. Ten pigeon samples were combined into one set, and a total of seven sets were collected. Seventy seagull samples were combined into one set, and a total of 13 sets were collected. In addition, 111 dog samples were collected from cattle farms, and 95 dog and 80 cat samples were collected from a temple. We identified C. meleagridis in pigeons, Cryptosporidium avian genotype III in seagulls, C. canis in dogs, and C. felis in cats. In the temple, the prevalence was 2.1% (2/95) for dogs and 2.5% (2/80) for cats. No Cryptosporidium was found in dog samples from cattle farms. These are the first findings of C. meleagridis in domestic pigeons, and Cryptosporidium avian genotype III in seagulls. Our study invites further molecular epidemiological investigations of Cryptosporidium in these animals and their environment to evaluate the public health risk in Thailand. PMID- 25297890 TI - Residual effect after oral bisphosphonate treatment and healthy adherer effects- the Swedish Adherence Register Analysis (SARA). AB - Little is known of the effect of alendronate and risedronate on osteoporotic fractures after discontinuation of therapy. We found that time on treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. Our results will inform health economic analysis of osteoporosis interventions. INTRODUCTION: Real-world persistence to treatment of osteoporosis is well-understood, but little is known of the posttreatment residual effect on fractures. The objective of this study was to investigate the residual effect of alendronate and risedronate on fractures and assess whether a healthy adherer effect confounds the association between persistence and residual anti-fracture effect. METHODS: A treatment-naive cohort from the Swedish Prescribed Drug Register was identified through prescriptions for alendronate or risedronate between 2005 and 2009. Persistence was estimated, and patients were stratified by time on treatment (<1 month, 1-6 months, 7-12 months, and >12 months). Survival analysis was used to study hospitalized fractures and mortality up to 18 months after treatment discontinuation. RESULTS: The crude incidence proportion of fractures the first 6 months after treatment discontinuation ranged from 2.26% (<1 month of treatment) to 1.16% (>12 months). The corresponding estimates for month 7 to 12 after discontinuation was 3.18 to 1.96%, and for month 13 to 18 after discontinuation 2.69 to 1.95%. Adjusted regression results showed that patients persisting with therapy for >12 months had 60% lower fracture risk the first six months after treatment discontinuation (RR 0.40, p = 0.001). Patient characteristics, including prevalent fractures and co morbidities, and posttreatment mortality were comparable across persistence durations, and we found no evidence of a healthy adherer effect. CONCLUSIONS: Time on bisphosphonate treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. We found no evidence of a healthy adherer effect confounding the relationship between treatment persistence and fracture risk. PMID- 25297892 TI - Residual angulation of distal tibial diaphyseal fractures in children younger than ten years. AB - BACKGROUND: The purpose of this study was to evaluate the factors that influence residual angulation after treating pediatric distal tibial diaphyseal fractures. METHODS: We retrospectively reviewed the records of 75 children under the age of ten who were treated at two referral centers for distal tibial diaphyseal fractures. The mean patient age was 6.8 +/- 2.3 years, and the mean follow-up duration was 4.1 +/- 1.3 years (range, 3 to 6 years). Early postoperative and late follow-up radiographs were used to measure angulation. RESULTS: Twenty-four patients had valgus angulations >5 degrees at the final follow-up. There was no varus, or anteroposterior residual angulations >5 degrees . There was more residual valgus angulation when the postoperative angulation was >5 degrees (p = 0.006) and when intramedullary nail and external fixators were applied for treatment (p = 0.004). Multivariate logistic regression analysis showed that postoperative angulation (adjusted odds ratio (OR) 4.33, 95% confidence interval (CI) 1.07-17.53) and treatment methods (intramedullary nail: adjusted OR 7.33, 95% CI 1.31-41.07; external fixator: adjusted OR 11.35, 95% CI 1.91-67.40 compared with the cast group) were associated with residual deformity. CONCLUSIONS: Valgus angulation after pediatric distal tibial fractures persisted in this study sample. Accurate reduction should be performed to prevent residual deformity. PMID- 25297891 TI - Dysmobility syndrome and mortality risk in US men and women age 50 years and older. AB - Mortality risk was significantly elevated in older adults from NHANES 1999-2002 with dysmobility syndrome. INTRODUCTION: Dysmobility syndrome was recently proposed as an approach to evaluate the musculoskeletal health of older persons, but data linking this syndrome to adverse outcomes are currently lacking. The present study used data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 to assess the relationship between dysmobility and mortality in adults age 50 years and older by age, sex, and race or ethnicity. METHODS: Dysmobility was defined as three or more of the following: high body fat, osteoporosis, low muscle mass, low muscle strength, slow gait speed, or falling risk. Body composition and bone density were assessed with dual energy X-ray absorptiometry. Gait speed was measured via a timed walk, muscle strength via isokinetic knee extension, and fall risk via self-reported balance problems in the past year. Hazard ratios (HRs) for mortality were calculated with Cox proportional hazard models. RESULTS: Twenty-two percent of adults age 50+ years had dysmobility in 1999-2002. Mortality risk by dysmobility varied significantly by age (pinteraction = 0.001). HRs for those aged 50-69 years were 3.63 (95% confidence interval (CI) 2.69, 4.90) and 2.59 (95% CI 1.82, 3.69), respectively, before and after adjusting for all confounders, compared with 1.46 (95% CI 1.07, 1.99) and 1.23 (95% CI 0.89, 1.69) for those aged 70+ years. The relationship was significant when examined by sex or race/ethnicity within age group for most subgroups. CONCLUSIONS: Dysmobility was associated with increased mortality risk in adults age 50 years and older, with risk being higher in those age 50-69 years than in those age 70+ years. PMID- 25297894 TI - Oxidative nucleophilic strategy for synthesis of thiocyanates and trifluoromethyl sulfides from thiols. AB - Thiocyanates and trifluoromethyl sulfides are important compounds and have classically been synthesized via multistep procedures together with the formation of significant amounts of byproducts. Herein, we demonstrate an oxidative nucleophilic strategy for the synthesis of thiocyanates and trifluoromethyl sulfides from thiol starting materials using nucleophilic reagents such as TMSCN and TMSCF3 (TMS = trimethylsilyl). In the presence of a 2 * 2 manganese oxide based octahedral molecular sieve (OMS-2) and potassium fluoride (KF), various structurally diverse thiocyanates and trifluoromethyl sulfides could be synthesized in almost quantitative yields (typically >90%). The presented cyanation and trifluoromethylation reactions proceed through the OMS-2-catalyzed oxidative homocoupling of thiols to give disulfides followed by nucleophilic bond cleavage to produce the desired compounds and thiolate species (herein S trimethylsilylated thiols). OMS-2 can catalyze oxidative homocoupling of the thiolate species, thus resulting formally in the quantitative production of thiocyanates and trifluoromethyl sulfides from thiols. PMID- 25297893 TI - Long-term psychosocial and behavioral adjustment in individuals receiving genetic test results in Lynch syndrome. AB - A cross-sectional study of 155 participants who underwent genetic testing for Lynch syndrome (LS) examined long-term psychosocial and behavioral outcomes. Participants completed standardized measures of perceived risk, psychosocial functioning, knowledge, and a questionnaire of screening activities. Participants were on average 47.3 years and had undergone testing a mean of 5.5 years prior. Eighty four (54%) tested positive for a LS mutation and 71 (46%) negative. For unaffected carriers, perceived lifetime risk of colorectal cancer was 68%, and surprisingly, 40% among those testing negative. Most individuals demonstrated normative levels of psychosocial functioning. However, 25% of those testing negative had moderate depressive symptoms, as measured by the Center for Epidemiologic Studies for Depression Scale, and 31% elevated state anxiety on the State-Trait Anxiety Inventory. Being female and a stronger escape - avoidant coping style were predictive of depressive symptoms. For state anxiety, similar patterns were observed. Quality of life and social support were significantly associated with lower anxiety. Carriers maintained higher knowledge compared to those testing negative, and were more engaged in screening. In summary, most individuals adapt to genetic test results over the long term and continue to engage in screening. A subgroup, including some non-carriers, may require added psychosocial support. PMID- 25297897 TI - EBI2 regulates intracellular signaling and migration in human astrocyte. AB - The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7alpha, 25-dihydroxycholesterol (7alpha25HC) and plays a role in T cell-dependant antibody response and B cell migration. Aberrant EBI2 signaling is implicated in a range of autoimmune disorders however its role in the CNS remains unknown. Here we characterize the functional role of EBI2 in GLIA cells using primary human astrocytes and EBI2 knockout animals. We find human and mouse astrocytes express EBI2 and the enzymes necessary for synthesis and degradation of 7alpha25HC. In astrocytes, EBI2 activation stimulates ERK phosphorylation, Ca(2+) signaling and induces cellular migration. These results, for the first time, demonstrate a role for EBI2 in astrocyte function and suggest that modulation of this receptor may be beneficial in neuroinflammatory disorders. PMID- 25297896 TI - A stable and efficient nuclear transformation system for the diatom Chaetoceros gracilis. AB - Chaetoceros gracilis belongs to the centric diatoms, and has recently been used in basic research on photosynthesis. In addition, it has been commercially used in fisheries and is also attracting interest as a feedstock for biofuels production and biorefinery. In this study, we developed an efficient genetic transformation system for C. gracilis. The diatom cells were transformed via multi-pulse electroporation using plasmids containing various promoters to drive expression of the nourseothricin acetyltransferase gene (nat) as a selectable marker. The transformation efficiency reached ~400 positive transgenic clones per 10(8) recipient cells, which is the first example of successful transformation with electroporation in a centric diatom species. We further produced two expression vectors: the vector pCgLhcr5p contains the light-dependent promoter of a fucoxanthin chlorophyll a/c binding protein gene and the vector pCgNRp contains the inducible promoter of a nitrate reductase gene to drive the expression of introduced genes. In both vectors, an acetyl-CoA acetyltransferase promoter drives nat gene expression for antibiotic selection. Stable integration and expression of reporter genes, such as the firefly luciferase and green fluorescent protein Azami-Green genes, were observed in transformed C. gracilis cells. This efficient and stable transformation system for C. gracilis will enable both functional analysis of diatom-specific genes and strain improvement for further biotechnological applications. PMID- 25297898 TI - Direct visualization of flow-induced conformational transitions of single actin filaments in entangled solutions. AB - While semi-flexible polymers and fibres are an important class of material due to their rich mechanical properties, it remains unclear how these properties relate to the microscopic conformation of the polymers. Actin filaments constitute an ideal model polymer system due to their micron-sized length and relatively high stiffness that allow imaging at the single filament level. Here we study the effect of entanglements on the conformational dynamics of actin filaments in shear flow. We directly measure the full three-dimensional conformation of single actin filaments, using confocal microscopy in combination with a counter-rotating cone-plate shear cell. We show that initially entangled filaments form disentangled orientationally ordered hairpins, confined in the flow-vorticity plane. In addition, shear flow causes stretching and shear alignment of the hairpin tails, while the filament length distribution remains unchanged. These observations explain the strain-softening and shear-thinning behaviour of entangled F-actin solutions, which aids the understanding of the flow behaviour of complex fluids containing semi-flexible polymers. PMID- 25297899 TI - Surgeon-performed ultrasound-guided fine-needle aspiration cytology of head and neck mass lesions: sampling adequacy and diagnostic accuracy. AB - BACKGROUND: Studies of surgeon-performed ultrasound-guided fine-needle aspiration cytology (US-FNAC) have been limited largely to thyroid nodules. This study evaluated the sampling adequacy and diagnostic accuracy of surgeon-performed US FNAC for a large range of head and neck mass lesions, including lesions of the thyroid, salivary glands, and lymph nodes. METHODS: The study included 617 cases of US-FNAC performed by a single surgeon between 2009 and 2013. Their medical histories and ultrasound (US) findings were retrospectively reviewed. Sample adequacy was analyzed according to the surgeon's experience, anatomic tumor location, and US tumor characteristics. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of FNAC were calculated after correlation with the surgical histopathologic results. RESULTS: The overall adequacy rate for surgeon-performed US-FNAC was 91.9 % (567/617). Inadequate specimens were obtained from 9.7 % (29/282) of the thyroid glands, 6.1 % of the salivary glands (6/98), and 6.3 % (15/237) of the lymph nodes. The effect of the surgeon's experience plateaued (inadequate sampling rate, 6-8 %) after 100 US-FNAC procedures. Inadequate sampling was associated with tumor characteristics such as cystic change and rim calcification. Overall, US-FNAC showed a sensitivity of 88.2 %, a specificity of 98.2 %, a PPV of 98.5 %, an NPV of 85.7 %, and a diagnostic accuracy of 91.6 %. CONCLUSION: With proper training and experience managing at least 100 US-FNAC cases, surgeons can ensure a low inadequate sampling rate and good diagnostic accuracy for a range of head and neck mass lesions. PMID- 25297900 TI - Impact of multifocal or multicentric disease on surgery and locoregional, distant and overall survival of 6,134 breast cancer patients treated with neoadjuvant chemotherapy. AB - BACKGROUND: The impact of tumor focality on type of surgery, local recurrence rate, and survival after neoadjuvant chemotherapy (NACT) for breast cancer is not fully understood. This study aimed to compare local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) according to focality stratified by type of surgery and pathologic complete response (pCR), with a focus on breast conservation. METHODS: Participants (n = 6,134) in the GeparTrio, GeparQuattro, and GeparQuinto trials with operable or locally advanced tumors receiving NACT were classified as having unifocal (1 lesion), multifocal (>= 2 lesions in 1 quadrant), or multicentric (>= 1 lesion in >= 2 quadrants) disease. The study investigated LRFS, DFS, and OS according to focality stratified by type of surgery and pathologic complete response. RESULTS: The patients were classified as having unifocal (n = 4,733, 77.1 %), multifocal (n = 820, 13.4 %), or multicentric (n = 581, 9.5 %) tumors. The respective pCR rates were 19.4, 16.5, and 14.4 %. Breast conservation was performed for 71.6, 58.5, and 30 % of these patients, respectively (P < 0.001). The LRFS rate was 92.9 % for the unifocal, 95.1 % for the multifocal, and 90.4 % for the multicentric tumors (P = 0.002). The patients with multicentric tumors but not the patients with multifocal tumors had worse DFS (P < 0.001) and OS (P = 0.009) than the patients with unifocal tumors. However, LRFS, DFS, and OS were not inferior for the patients with multicentric or multifocal tumors if pCR was achieved or breast conservation was performed after NACT. CONCLUSION: Breast conservation is feasible for clinically multifocal or multicentric breast cancer patients who undergo NACT without worsening LRFS if tumor-free margins can be attained or if patients achieve a pCR. PMID- 25297901 TI - Navigating the management of follicular variant papillary thyroid carcinoma subtypes: a classic PTC comparison. AB - BACKGROUND: There are three subtypes of follicular variant papillary thyroid carcinoma (fvPTC): completely encapsulated, well circumscribed, and infiltrative. While infiltrative tumors are more aggressive than completely encapsulated, controversy exists regarding management of fvPTC subtypes. We compared the clinicopathologic features of fvPTC subtypes to those of classic PTC (cPTC) to help guide fvPTC management, using cPTC as a reference. METHODS: A retrospective review was performed on 316 patients with PTC treated at a single institution from 2004 to 2011. There were 197 cPTC and 119 fvPTC tumors, including completely encapsulated (n = 46), well circumscribed (n = 46), and infiltrative (n = 27). Clinicopathologic data were compared between groups. RESULTS: fvPTC patients had larger tumors than cPTC patients (1.6 cm vs. 1.2 cm, p = 0.001), but age, sex, and family history did not differ. Thirty-one percent of cPTC tumors had extrathyroidal extension compared to 0 % of completely encapsulated, 0 % of well circumscribed, and 52 % of infiltrative fvPTC tumors (p < 0.05). Central lymph node metastasis occurred in 50 % of cPTC compared to 0 % in completely encapsulated, 20 % in well-circumscribed, and 72 % in infiltrative fvPTC tumors (p < 0.05). Notably, lymph node metastasis was significantly lower in completely encapsulated than in well-circumscribed tumors, without a difference in the median number of nodes sampled. There were no differences in lymphovascular invasion or extranodal extension. CONCLUSIONS: Like cPTC tumors, infiltrative fvPTC tumors have aggressive clinicopathologic features and thus should be treated similarly. Conversely, completely encapsulated and well-circumscribed tumors have less aggressive features compared to cPTC and are more self-limiting; however, well-circumscribed tumors still have a notable incidence of lymph node metastasis. Clinicians should consider this variability in their management algorithm for fvPTC. PMID- 25297902 TI - Is Liver Transplantation an Option in Colorectal Cancer Patients with Nonresectable Liver Metastases and Progression on All Lines of Standard Chemotherapy? AB - BACKGROUND: About 50 % of patients with metastatic colorectal cancer (CRC) will develop metastatic disease with liver as primary metastatic site. The majority of CRC patients has nonresectable disease and receives palliative chemotherapy. Overall survival (OS) from time of progression on last line of chemotherapy in metastatic CRC is about 5 months. CLM have been considered a contraindication for liver transplantation. However, we have previously reported 5-year OS of 60 % after liver transplantation for nonresectable CLM. There were six patients who had progressive disease (PD) on last line of standard chemotherapy at the time of liver transplantation; here we report the outcome for these six patients. METHODS: Patients with nonresectable liver-only CLM received liver transplantation in the SECA study, a subgroup of six patients whose disease had progressed on all standard lines of chemotherapy. RESULTS: These patients with nonresectable disease and PD on the last line of standard chemotherapy at time of liver transplantation had 8-35 metastatic lesions in the liver with the largest diameter at 2.8-13.0 cm. All patients had a relapse within 2.1-12.4 months after liver transplantation. Some patients received treatment with curative intent at the time of relapse, and median OS after transplantation was 41 months with a Kaplan-Meier calculated 5-year OS of 44 %. CONCLUSIONS: Liver transplantation in nonresectable CLM patients with extensive tumor load and PD on the last line of chemotherapy had extended OS compared with any other treatment option reported in the literature. PMID- 25297903 TI - Occult invasive cervical cancer found after inadvertent simple hysterectomy: is the ideal management: systematic parametrectomy with or without radiotherapy or radiotherapy only? AB - BACKGROUND: After the diagnosis of occult cervical cancer during simple hysterectomy, is the best treatment option for the patient surgery with or without radiotherapy or radiation therapy only? Our study aims to answer this question. MATERIALS AND METHODS: We retrospectively analyzed 29 patients with occult cervical cancer found after inadvertent simple hysterectomy and who were referred to our cancer center between 2000 and 2010. All of the patients were discussed by the tumor board. Thirteen patients underwent surgery (radical parametrectomy and pelvic lymphadenectomy) using the minimally invasive approach (surgical group), and 16 patients underwent pelvic lymphadenectomy and radiation therapy or concurrent chemoradiation (radiation group). RESULTS: Age, BMI, and the tumor diameter were not statistically different between the surgical and radiation group: 44 and 49 (+/- 11) years (p = .23), 24.6 (+/- 6.2) and 26.7 (+/- 5) (p = 0.33), and 22 (+/- 13) and 31 (+/- 11) mm (p = .09), respectively. The 5 year overall and disease-free survivals for the surgical and radiation groups were: 100 and 77 % (p = .04), and 86 and 37 % (p = .02), respectively. These results were statistically significant. CONCLUSIONS: In the case of occult cervical cancer found after simple hysterectomy, radical parametrectomy with pelvic lymphadenectomy using minimally invasive surgery seems to be more efficient than radiation therapy or concurrent chemoradiation, with acceptable minimal morbidity being observed. PMID- 25297904 TI - Avian paramyoxvirus-8 immunization reduces viral shedding after homologous APMV-8 challenge but fails to protect against Newcastle disease. AB - BACKGROUND: Protection against infection by Newcastle disease virus (NDV), also designated as avian paramyxovirus subtype-1 (APMV-1), is mediated by immune responses to the two surface glycoproteins, hemagglutinin-neuraminidase (HN) and fusion (F) protein. Thus, a chimeric APMV-1 based vaccine that encodes APMV-8 HN- and F-proteins and expresses the hemagglutinin of avian influenza virus (AIV) H5N1, is able to protect against HPAIV H5N1 but fails to protect against NDV [PLoS One8:e72530, 2013]. However, it is unclear whether avirulent APMV-subtypes, like APMV-8 can induce subtype-specific immunity and protect from a homologous challenge. FINDINGS: APMV-8 infections of 3- and 6-weeks-old specific pathogen free (SPF)-chickens did not induce any clinical signs but was associated with virus shedding for up to 6 days. Viral replication was only detected in oropharyngeal- and never in cloacal swabs. Upon reinfection with homologous APMV 8, viral shedding was restricted to day 2 and in contrast to naive SPF-chickens, only RNA but no infectious virus was recovered. No protection was induced against virulent NDV challenge, although morbidity and mortality was delayed in APMV-8 primed chickens. This lack of protection is in line with a lack of reactivity of APMV-8 specific sera to APMV-1 HN-protein: Neither by hemagglutin-inhibition (HI) test nor immunoblot analyses, cross-reactivity was detected, despite reactivity to internal proteins. CONCLUSIONS: Immune responses mounted during asymptomatic APMV-8 infection limit secondary infection against homologues reinfection and facilitates a delay in the onset of disease in a subtype independent manner but is unable to protect against Newcastle disease, a heterologous APMV-subtype. PMID- 25297906 TI - Safety assessment of 6-hydroxyindole as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6 hydroxyindole, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that 6-hydroxyindole is safe for use in oxidative hair dye formulations. PMID- 25297905 TI - kappa-Opioid receptors are not necessary for the antidepressant treatment of neuropathic pain. AB - BACKGROUND AND PURPOSE: Tricyclic antidepressants are used clinically as first line treatments for neuropathic pain. Opioid receptors participate in this pain relieving action, and preclinical studies in receptor-deficient mice have highlighted a critical role for delta-, but not MU-opioid receptors. In this study, we investigated whether kappa-opioid (KOP) receptors have a role in the antiallodynic action of tricyclic antidepressants. EXPERIMENTAL APPROACH: We used a model of neuropathic pain induced by unilateral sciatic nerve cuffing. In this model, the mechanical allodynia was evaluated using von Frey filaments. Experiments were conducted in C57BL/6J mice, and in KOP receptor-deficient mice and their wild-type littermates. The tricyclic antidepressant nortriptyline (5 mg . kg(-1)) was delivered twice a day for over 2 weeks. Agonists and antagonists of opioid receptors were used to test the selectivity of the KOP receptor antagonist norbinaltorphimine (nor-BNI) in mice with neuropathic pain. KEY RESULTS: After 12 days of treatment, nortriptyline relieved neuropathic allodynia in both wild-type and KOP receptor-deficient mice. Surprisingly, acute nor-BNI reversed the effect of nortriptyline in both wild-type and KOP receptor-deficient mice. Further experiments showed that nor-BNI action was selective for KOP receptors at a late time-point after its administration (8 h), but not at an early time-point, when it may also interact with delta-opioid (DOP) receptors. CONCLUSIONS AND IMPLICATIONS: KOP receptors are not necessary for the effect of a tricyclic antidepressant against neuropathic allodynia. These findings together with previous data indicate that the DOP receptor is the only opioid receptor that is necessary for the antiallodynic action of antidepressants. PMID- 25297907 TI - Safety assessment of modified terephthalate polymers as used in cosmetics. AB - The safety of 6 modified terephthalate polymers as cosmetic ingredients was assessed. These ingredients mostly function as exfoliants, bulking agents, hair fixatives, and viscosity-increasing agents-nonaqueous. Polyethylene terephthalate (PET) is used in leave-on products up to 100% and in rinse-off products up to 2%. The Cosmetic Ingredient Review Expert Panel (Panel) considered that the PET used in cosmetics is chemically equivalent to that used in medical devices. The Panel determined that the Food and Drug Administration's determination of safety of PET in several medical devices, which included human and animal safety data, can be used as the basis for the determination of safety of PET and related polymers used in cosmetics. Use studies of cosmetic eye products that contain PET demonstrated no ocular irritation or dermal sensitization. The Panel concluded that modified terephthalate polymers were safe as cosmetic ingredients in the practices of use and concentration described in this safety assessment. PMID- 25297908 TI - Safety assessment of Vitis vinifera (grape)-derived ingredients as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 24 Vitis vinifera (grape)-derived ingredients and found them safe in the present practices of use and concentration in cosmetics. These ingredients function in cosmetics mostly as skin-conditioning agents, but some function as antioxidants, flavoring agents, and/or colorants. The Panel reviewed the available animal and clinical data to determine the safety of these ingredients. Additionally, some constituents of grapes have been assessed previously for safety as cosmetic ingredients by the Panel, and others are compounds that have been discussed in previous Panel safety assessments. PMID- 25297910 TI - Around the mandible. PMID- 25297909 TI - Amended safety assessment of Hypericum perforatum-derived ingredients as used in cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) has issued an amended safety assessment of 7 Hypericum perforatum-derived ingredients as used in cosmetics. A common name for this plant is St John wort. These ingredients function in cosmetics as skin-conditioning agents-miscellaneous and antimicrobial agents. The Panel reviewed relevant animal and human data related to the H perforatum-derived ingredients. Because formulators may use more than 1 botanical ingredient in a formulation, caution was urged to avoid levels of toxicological concern for constituent chemicals and impurities. The Panel concluded that H perforatum derived ingredients were safe as cosmetic ingredients in the practices of use and concentration as described in this safety assessment. PMID- 25297915 TI - Effects of different extents of pulley release on tendon excursion efficiency and tendon moment arms. AB - To compare the excursion efficiency and moment arms of flexor digitorum superficialis (FDS) and profundus (FDP) among different conditions of pulley integrity related to trigger finger treatment, cadaveric fingers were first tested with an intact pulley system, and then the first (A1) and second (A2) annular pulleys were released gradually from the proximal to distal part. Linear position sensors and a motion capture system were used to measure the tendon excursion and joint rotation simultaneously. The tendon excursion efficiency was defined as the range of motion of the involved joints per unit of tendon excursion, and the tendon moment arm was determined by the slope of the linear fitting result of tendon excursion versus metacarpophalangeal (MCP) joint rotation. No significant differences were found between the release of the A1 pulley and the release extending to half the proximal part of the A2 pulley in the FDP excursion efficiency and the moment arms of FDS and FDP with respect to the MCP joint. These results imply that the release could extend to half the proximal A2 pulley, if necessary, without significantly decreasing the FDP excursion efficiency and increasing the moment arms of FDS and FDP with respect to the MCP joint. PMID- 25297911 TI - Linagliptin: an update of its use in patients with type 2 diabetes mellitus. AB - Linagliptin (Trajenta((r)), Tradjenta((r))) is a dipeptidyl peptidase (DPP)-4 inhibitor approved for the treatment of adults with type 2 diabetes mellitus in several countries. A fixed-dose combination of linagliptin/metformin (Jentadueto((r))) is also available. This article reviews the pharmacology, therapeutic efficacy and tolerability of linagliptin in the management of type 2 diabetes, with the aim of updating its place in therapy based on recently published data. In randomized, controlled trials, oral linagliptin 5 mg once daily (or 2.5 mg twice daily when combined with metformin) improved glycaemic control when used alone or in combination with other antidiabetic agents, including metformin, a sulfonylurea, thiazolidinedione or insulin. Improvements in glycaemic control were also shown in patients with renal impairment, including severe impairment, and the elderly (aged >=70 years). Linagliptin is the first DPP-4 inhibitor to be eliminated primarily via a nonrenal route, enabling its use without dosage adjustment in patients with any degree of renal impairment. Linagliptin is generally well tolerated and, as with other DPP-4 inhibitors, it is associated with a low risk of hypoglycaemia and has no effect on bodyweight. Some data indicate that linagliptin may have beneficial effects on cardiovascular and renal safety profiles in patients with type 2 diabetes, but more data are needed. Meanwhile, the low risk of hypoglycaemia and the nonrenal route of elimination may provide important advantages for some patient groups, including elderly or renally impaired patients. PMID- 25297916 TI - Resting heart rate as a marker for identifying the risk of undiagnosed type 2 diabetes mellitus: a cross-sectional survey. AB - BACKGROUND: Fast resting heart rate might increase the risk of developing type 2 diabetes mellitus (T2DM). However, it is unclear whether resting heart rate could be used to predict the risk of undiagnosed T2DM. Therefore, the purposes of this study were to examine the association between resting heart rate and undiagnosed T2DM, and evaluate the feasibility of using resting heart rate as a marker for identifying the risk of undiagnosed T2DM. METHODS: A cross-sectional survey was conducted. Resting heart rate and relevant covariates were collected and measured. Fasting blood samples were obtained to measure blood glucose using the modified hexokinase enzymatic method. Predictive performance was analyzed by Receiver Operating Characteristic (ROC) curve. RESULTS: This study included 16, 636 subjects from rural communities aged 35-78 years. Resting heart rate was significantly associated with undiagnosed T2DM in both genders. For resting heart rate categories of <60, 60-69, 70-79, and >=80 beats/min, adjusted odds ratios for undiagnosed T2DM were 1.04, 2.32, 3.66 and 1.05, 1.57, 2.98 in male and female subjects, respectively. For male subjects, resting heart rate >=70 beats/min could predict undiagnosed T2DM with 76.56% sensitivity and 48.64% specificity. For female subjects, the optimum cut-off point was >=79 beats/min with 49.72% sensitivity and 67.53% specificity. The area under the ROC curve for predicting undiagnosed T2DM was 0.65 (95% CI: 0.64-0.66) and 0.61(95% CI: 0.60 0.62) in male and female subjects, respectively. CONCLUSIONS: Fast resting heart rate is associated with an increased risk of undiagnosed T2DM in male and female subjects. However, resting heart rate as a marker has limited potential for screening those at high risk of undiagnosed T2DM in adults living in rural areas. PMID- 25297917 TI - Interaction of Abeta(25-35) fibrillation products with mitochondria: Effect of small-molecule natural products. AB - The 25-35 fragment of the amyloid beta (Abeta) peptide is a naturally occurring proteolytic by-product that retains the pathophysiology of its larger parent molecule, whose deposition has been shown to involve mitochondrial dysfunction. Hence, disruption of Abeta(25-35) aggregates could afford an effective remedial strategy for Alzheimer's disease (AD). In the present study, the effect of a number of selected small-molecule natural products (polyphenols: resveratrol, quercetin, biochanin A, and indoles: indole-3-acetic acid, indole-3-carbinol (I3C)) on Abeta(25-35) fibrillogenesis was explored under physiological conditions, and interaction of the resulting structures with rat brain mitochondria was investigated. Several techniques, including fluorescence, circular dichroism, and transmission electron microscopy were utilized to characterize the aggregation products, and possible mitochondrial membrane permeabilization was determined following release of marker enzymes. Results demonstrate the capacity of Abeta(25-35) fibrils to damage mitochondria and suggest how small molecules may afford protection. While I3C appeared more effective in inhibiting the fibrillation process, all natural products behaved similarly in destabilizing preformed aggregates. It is concluded that elucidation of such protection may provide important insights into the development of preventive and therapeutic agents for AD. PMID- 25297918 TI - Interplay between genetic and epigenetic factors governs common fragile site instability in cancer. AB - Common fragile sites (CFSs) are regions within the normal chromosomal structure that were characterized as hotspots for genomic instability in cancer almost 30 years ago. In recent years, many efforts have been made to understand the basis of CFS fragility and their involvement in the genomic signature of instability found in malignant tumors. CFSs are among the first regions to undergo genomic instability during cancer development because of their intrinsic sensitivity to replication stress conditions, which result from oncogene expression. The preferred sensitivity of CFSs to replication stress stems from various mechanisms including: replication fork arrest at AT-rich repeats, origin paucity along large genomic regions, failure in activation of dormant origins, late replication timing, collision between replication and transcription along large genes, all leading to incomplete replication of the CFS region and resulting in chromosomal instability. Here we review shared and unique characteristics of CFSs, their underlying causes and implications, particularly for the development of cancer. PMID- 25297920 TI - Chromogranin A: a paradoxical player in angiogenesis and vascular biology. AB - Half a century after the discovery of chromogranin A as a secreted product of the catecholamine storage granules in the bovine adrenal medulla, the physiological role for the circulating pool of this protein has been recently coined, namely as an important player in vascular homeostasis. While the circulating chromogranin A since 1984 has proved to be a significant and useful marker of a wide range of pathophysiological and pathological conditions involving the diffuse neuroendocrine system, this protein has now been assigned a physiological "raison d'etre" as a regulator in vascular homeostasis. Moreover, chromogranin A processing in response to tissue damage and blood coagulation provides the first indication of a difference in time frame of the regulation of angiogenesis evoked by the intact chromogranin A and its two major peptide products, vasostatin-1 and catestatin. The impact of these discoveries on vascular homeostasis, angiogenesis, cancer, tissue repair and cardio-regulation will be discussed. PMID- 25297919 TI - Of von Willebrand factor and platelets. AB - Hemostasis and pathological thrombus formation are dynamic processes that require multiple adhesive receptor-ligand interactions, with blood platelets at the heart of such events. Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and alphaIIbbeta3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury. This review will recapitulate our current knowledge on the subject from the rheological aspect to the spatio temporal development of thrombus formation. We will also discuss the signaling events generated by VWF/GPIb-IX-V interaction, leading to platelet activation. Additionally, we will review the growing body of evidence gathered from the recent development of pathological mouse models suggesting that VWF binding to GPIb-IX-V is a promising target in arterial and venous pathological thrombosis. Finally, the pathological aspects of VWF and its impact on platelets will be addressed. PMID- 25297922 TI - Magnetic resonance histology. PMID- 25297921 TI - MicroRNAs in adrenal tumors: relevance for pathogenesis, diagnosis, and therapy. AB - Several lines of evidence support the relevance of microRNAs in both adrenocortical and adrenomedullary (pheochromocytomas) tumors. Significantly differentially expressed microRNAs have been described among benign and malignant adrenocortical tumors and different forms of pheochromocytomas that might affect different pathogenic pathways. MicroRNAs can be exploited as markers of malignancy or disease recurrence. Besides tissue microRNAs, novel data show that microRNAs are released in body fluids, and blood-borne microRNAs can be envisaged as minimally invasive markers of malignancy or prognosis. MicroRNAs might even serve as treatment targets that could expand the rather-limited therapeutic repertoire in the field of adrenal tumors. In this review, we present a critical synopsis of the recent observations made in the field of adrenal tumor-associated microRNAs regarding their pathogenic, diagnostic, and potential therapeutic relevance. PMID- 25297924 TI - Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review of the literature. AB - Granule cell neuronopathy (GCN) is a rare JC virus (JCV)-related disease in immunocompromised patients, characterized by lytic infection of the cerebellar granule cell layer. To enable early diagnosis and intervention, we identify features of GCN and describe possible aspects of disease heterogeneity. We report on two new cases of GCN in HIV-infected patients of whom we retrospectively assessed clinical and radiologic data. In addition, we carried out a literature search and review of clinical, radiologic and histopathologic findings of all published GCN cases. Including the two new cases reported here, a total of 18 GCN cases were included in this study. HIV infection, present in 12 of the cases, was the most common underlying condition, followed by monoclonal antibody treatment which was present in three cases. Cerebellar atrophy was detected in all except two cases. In 12 patients a heterogeneous distribution pattern of white matter changes in the cerebellum and brainstem was observed. Imaging findings in GCN are remarkably heterogeneous; exhibiting cerebellar atrophy, as well as white matter pathology, particularly in the adjacent infratentorial white matter. This suggests an overlap of GCN with other JCV-related diseases, such as progressive multifocal leukoencephalopathy. PMID- 25297925 TI - miR-185-3p regulates nasopharyngeal carcinoma radioresistance by targeting WNT2B in vitro. AB - Aberrant microRNA (miRNA) expression contributes to a series of malignant cancer behaviors, including radioresistance. Our previous study showed differential expression of miR-185-3p in post-radiation nasopharyngeal carcinoma (NPC) cells. To investigate the role of miR-185-3p in NPC radioresistance, CNE-2 and 5-8F cells were transfected with miR-185-3p mimic and miR-185-3p inhibitor, respectively. CCK-8 assay and colony formation experiment confirmed that the expression of miR-185-3p affected the radioresistance of NPC cells. A negative correlation between miR-185-3p and WNT2B expression was observed in NPC cells and tissues. Luciferase reporter assays confirmed that miR-185-3p directly targeted the coding region of WNT2B. Furthermore, we found radioresistance decreased in WNT2B-silenced NPC cells. Activation of the WNT2B/beta-catenin pathway was accompanied by epithelial-mesenchymal transition biomarker changes in NPC. We concluded that miR-185-3p contributed to the radioresistance of NPC via modulation of WNT2B expression in vitro. PMID- 25297926 TI - Loss of Dfg5 glycosylphosphatidylinositol-anchored membrane protein confers enhanced heat tolerance in Saccharomyces cerevisiae. AB - The protein product of Saccharomyces cerevisiae DFG5 gene is a glycosylphosphatidylinositol (GPI)-anchored plasma membrane protein and a putative glycosidase/glycosyltransferase that links other GPI-anchored proteins to beta-glucans in the cell wall. Upon exposure to heat (41 degrees C), DFG5 deletion mutant dfg5Delta displayed significantly enhanced heat tolerance as well as lowered level of reactive oxygen species and decreased membrane permeability compared with those in the control (BY4741). Comparative transcriptome profiles of BY4741 and dfg5Delta revealed that 38 and 23 genes were up- and down-regulated in dfg5Delta respectively. Of the 23 down-regulated genes, 11 of 13 viable deletion mutants were identified to be tolerant to heat, suggesting that the down regulation of those genes might have contributed to the enhanced heat tolerance in dfg5Delta. Deletion of DFG5 caused slight activation of mitogen-activated protein kinases Hog1 in the high-osmolarity glycerol pathway and Slt2 in the cell wall integrity pathway. Therefore, a model is proposed on the signal transduction pathways associated with deletion of DFG5 upon heat stress. PMID- 25297927 TI - Detection of high levels of anti-alpha-galactosyl antibodies in sera of patients with Old World cutaneous leishmaniasis: a possible tool for diagnosis and biomarker for cure in an elimination setting. AB - In the Kingdom of Saudi Arabia (KSA), Old World cutaneous leishmaniasis (CL) is mainly caused by Leishmania major and Leishmania tropica parasites. Diagnosis of CL is predominately made by clinicians, who at times fail to detect the disease and are unable to identify parasite species. Here, we report the development of a chemiluminescent enzyme-linked immunosorbent assay (CL-ELISA) to measure the levels of anti-alpha-galactosyl antibodies in human sera. Using this assay, we have found that individuals infected with either Leishmania spp. had significantly elevated levels (up to 9-fold higher) of anti-alpha-Gal IgG compared to healthy control individuals. The assay sensitivity was 96% for L. major (95% CI; 94-98%) and 91% for L. tropica (95% CI; 86-98%) infections and therefore equivalent to restriction fragment length polymorphism-polymerase chain reaction analysis of parasite ITS1 gene. In addition, the assay had higher sensitivity than microscopy analysis, which only detected 68 and 45% of the L. major and L. tropica infections, respectively. Interestingly, up to 2 years following confirmed CL cure individuals had 28-fold higher levels of anti-alpha Gal IgG compared to healthy volunteers. Monitoring levels of anti-alpha-Gal antibodies can be exploited as both a diagnostic tool and as a biomarker of cure of Old World CL in disease elimination settings. PMID- 25297928 TI - HIV disclosure and nondisclosure among migrant women from sub-Saharan Africa living in Switzerland. AB - No study to date has focused specifically on the reasons for and against disclosure of HIV-positive status among sub-Saharan migrant women. Thirty HIV positive women from 11 sub-Saharan countries living in French-speaking Switzerland participated in semi-structured individual interviews. The reasons women reported for disclosure or nondisclosure of their HIV serostatus were classified into three categories: social, medical, and ethical. The women identified the stigma associated with HIV as a major social reason for nondisclosure. However, this study identifies new trends related to disclosure for medical and ethical reasons. Being undetectable played an important role in the life of sub-Saharan migrant women, and analysis revealed their medical reasons for both disclosure and nondisclosure. Disclosure to new sexual partners occurred when women had a more positive perception about HIV and when they believed themselves to be in a long-term relationship. Women reported nondisclosure to family members when they did not need help outside the support provided by the medical and social fields. The results on ethical reasons suggested that challenging stigma was a reason for disclosure. Since the women' perceptions on HIV changed when they came to see it as a chronic disease, disclosure occurred in an attempt to normalize life with HIV in their communities in migration and to challenge racism and discrimination. Our findings can help health providers better understand the communication needs of sub-Saharan migrant women with respect to HIV/AIDS and sexuality and offer them adequate disclosure advice that takes into account migration and gender issues. PMID- 25297929 TI - A clinicopathological analysis of primary mucosal malignant melanoma. AB - PURPOSES: Primary mucosal malignant melanoma (PMMM) is a rare and highly lethal neoplasm associated with a poor prognosis. CXC chemokine receptor 4 (CXCR4) is expressed on various tumor cells, including malignant melanoma. Recent data indicate that CXCL12 and CXCR4 play a critical role in the behavior of cancer cells and in the survival of cancer patients. However, there has been no study that has addressed the expression and function of CXCR4/CXCL12 signaling in PMMM. METHODS: Immunohistochemical staining for CXCL12 and Ki67 in biopsy tissues from 10 cases of PMMM was performed. We analyzed the correlations between the clinicopathological features and expression levels of CXCL12 and Ki67. RESULTS: Six cases showed a high level of CXCL12 expression, while four cases had a low level of expression. High expression of CXCL12 correlated with a poor prognosis, although statistical significance was not reached (p = 0.054). Ki67 was highly expressed in five cases, while the expression in the other five cases was low. There was no correlation between the Ki67 expression and prognosis. CONCLUSIONS: The findings of this study suggest that CXCL12 expression may play an important role in the biological behavior of PMMM and may be associated with a poor prognosis of PMMM patients. PMID- 25297930 TI - Initial experiences with MR Image-guided laparoscopic microwave coagulation therapy for hepatic tumors. AB - PURPOSE: Percutaneous thermal ablation is used for treating hepatic tumors. Recent advances in laparoscopy and imaging modalities have led to the development of a novel image-guided minimally invasive loco-regional treatment. The aim of this trial was to apply laparoscopic assistance to magnetic resonance (MR) image guided thermoablation instead of ultrasonography, because of its various advantages. METHODS: Patients with hepatic tumors and liver cirrhosis underwent magnetic resonance (MR) image-guided laparoscopic microwave coagulation therapy using a borescope and endoscopic forceps. Six cases of laparoscopic microwave coagulation treatment using MR image guidance were successfully performed between January 2000 and December 2008. Tumors were detected, punctured, and ablated in an open-configured MR scanner. A total of nine hepatocellular carcinoma nodules were preoperatively identified in S3, S5 and S6 (mean diameter = 20.8 +/- 5.4 mm). RESULTS: MR-guided microwave coagulation was laparoscopically achieved in all patients without any significant complications that required invasive treatment. The mean length of the operation was 275.3 +/- 60.5 min, and the mean postsurgical hospital stay was 10.0 +/- 2.3 days. Postoperative confirmation scanning was performed without moving the patients. CONCLUSION: MR-guided laparoscopic microwave coagulation therapy is an effective treatment for hepatic tumors adjacent to other organs, as it allows for more accurate detection of lesions and for tumors to be treated safely while avoiding adjacent organs. It is less invasive than conventional procedures, because the MR real-time guidance enabled continuous monitoring throughout the procedure. PMID- 25297931 TI - Serum 25-hydroxyvitamin D levels and metabolic health status in extremely obese individuals. AB - OBJECTIVE: Vitamin D deficiency is prevalent in obese individuals. 25 hydroxyvitamin D [25(OH)D] levels in metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) adult individuals were examined and the relationship between 25(OH)D levels and other clinical parameters was evaluated. METHODS: This is a retrospective chart review of outpatient medical records from the Nutrition and Weight Management Center at Boston Medical Center. Subjects were divided into two groups, MHO and MUO, using the homeostasis model assessment of insulin resistance criteria. RESULTS: A total of 191 obese subjects were included in this analysis. The average body mass index (BMI) was 43.0 +/- 9.2 kg/m(2) . Sixty-three subjects (33%) met criteria for MHO. MHO subjects had lower BMI and waist circumferences compared to MUO subjects. 25(OH)D levels were not significantly different between the two groups (P = 0.242). Overall, there were high prevalences of vitamin D deficiency (48.7%) and vitamin D insufficiency (33.0%). 25(OH)D levels were inversely correlated with BMI, body weight, waist circumferences, and HbA1c levels but not with blood pressure, total cholesterol, HDL, triglycerides, or LDL. CONCLUSIONS: In extremely obese individuals, 25(OH)D levels were not related to metabolic health status or insulin resistance but correlated with the degree of adiposity. PMID- 25297932 TI - The potential of psychological interventions to improve quality of life and mood in muscle disorders. AB - Quality of life (QoL) and mood are reduced in many patients with muscle disorders. Psychological variables appear to be contributors to both QoL and mood, suggesting that psychological interventions could improve these outcomes, yet research in this area is sparse. We review the roles of psychological variables, plus context and disease severity, in explaining QoL. A cognitive behavioral model of disease self-management, with acceptance as the central component, is discussed. This model is then used to describe how psychological interventions derived from cognitive behavioral therapy (CBT), in particular Acceptance and Commitment Therapy (ACT), might be applied to address the issues of distress, nonadherence to treatments, pain, and fatigue in people with muscle disorders. PMID- 25297933 TI - Variant adiponutrin confers genetic protection against cholestatic itch. AB - Lysophosphatidic acid (LPA) mediates cholestatic pruritus. Recently the enzyme PNPLA3, expressed in liver and skin, was demonstrated to metabolise LPA. Here we assess the association of the PNPLA3 variant p.Ile148Met, known to be associated with (non-)alcoholic fatty liver disease (NAFLD) in genome-wide association studies, with cholestatic itch in 187 patients with primary biliary cirrhosis (PBC) and 250 PBC-free controls as well as 201 women with intrahepatic cholestasis of pregnancy (ICP) and 198 female controls without a history of ICP. Our hypothesis was that the intensity of cholestatic itch differs in carriers of distinct PNPLA3 p.Ile148Met genotypes. Patients with PBC carrying the allele p.148Met that confers an increased NAFLD risk reported less itching than carriers of the p.148Ile allele (ANOVA P = 0.048). The PNPLA3 p.148Ile allele increased the odds of requiring plasmapheresis for refractory pruritus (OR = 3.94, 95% CI = 0.91-17.00, P = 0.048). In line with these findings, the PNPLA3 p.148Met allele was underrepresented in the ICP cohort (OR = 0.66, 95% CI = 0.47-0.92, P = 0.013). Notwithstanding the need for further replication of these findings, we conclude that the PNPLA3 allele p.148Met might confer protection against cholestatic pruritus, possibly due to increased LPA-acyltransferase activity in liver and/or skin. PMID- 25297935 TI - Formation of hydroxyl-functionalized stilbenoid molecular sieves at the liquid/solid interface on top of a 1-decanol monolayer. AB - Specific molecular tectons can be designed to form molecular sieves through self assembly at the solid-liquid interface. After demonstrating a model tecton bearing apolar alkyl chains, we then focus on a modified structure involving asymmetric functionalization of some alkyl chains with polar hydroxyl groups in order to get chemical selectivity in the sieving. As the formation of supramolecular self-assembled networks strongly depends on molecule-molecule, molecule-substrate and molecule-solvent interactions, we compared the tectons' self-assembly on graphite for two types of solvent. We demonstrate the possibility to create hydroxylated stilbenoid molecular sieves by using 1-decanol as a solvent. Interestingly, with this solvent, the porous network is developed on top of a 1-decanol monolayer. PMID- 25297934 TI - The inhomogeneous distribution of liver function: possible impact on the prediction of post-operative remnant liver function. AB - BACKGROUND: Previous studies have shown that liver function is inhomogeneously distributed in diseased livers, and this uneven distribution cannot be compensated for if a global liver function test is used for the prediction of post-operative remnant liver function. Dynamic Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) can assess segmental liver function, thus offering the possibility to overcome this problem. METHODS: In 10 patients with liver cirrhosis and 10 normal volunteers, the contribution of individual liver segments to total liver function and volume was calculated using dynamic Gd-EOB-DTPA enhanced MRI. Remnant liver function predictions using a segmental method and global assessment were compared for a simulated left hemihepatectomy. For the prediction based on segmental functional MRI assessment, the estimated function of the remnant liver segments was added. RESULTS: Global liver function assessment overestimated the remnant liver function in 9 out of 10 patients by as much as 9.3% [median -3.5% (-9.3-3.5%)]. In the normal volunteers there was a slight underestimation of remnant function in 9 out of 10 cases [median 1.07% ( 0.7-2.5%)]. DISCUSSION: The present study underlines the necessity of a segmental liver function test able to compensate for the non-homogeneous nature of liver function, if the prediction of post-operative remnant liver function is to be improved. PMID- 25297937 TI - The mysterious pathways of cardiac myxomas: a review of histogenesis, pathogenesis and pathology. AB - Cardiac myxoma is the most common benign cardiac tumour, localized generally in the left atrium. The majority of cardiac myxomas occur sporadically, while a relatively small proportion of cases develop as a part of Carney complex syndrome. Currently, the histogenesis of myxoma is poorly understood; however, the mesenchymal and endothelial properties of myxoma cells suggest that a clearer understanding of tumour origins can be achieved through a detailed investigation of heart development and endocardial histogenesis. Growing evidence appears to indicate the reactivated expression in cardiac myxoma of genes encoding heart precursor markers, although the exact mechanisms have not yet been described. In this paper we review the most recent scientific literature concerning cardiac embryology and relate this to recent advances in our understanding of the histogenesis of cardiac myxoma. Moreover, given that much of the literature regarding myxoma is of single case reports, we review progress in our knowledge of the pathology and pathogenesis of this condition. PMID- 25297938 TI - Effect of the physicochemical properties of pure or chitosan-coated poly(L-lactic acid)scaffolds on the chondrogenic differentiation of mesenchymal stem cells from osteoarthritic patients. AB - Due to the attractive properties of poly(L-lactic acid) (PLLA) and chitosan (CHT) for tissue engineering applications, this study is aimed at analyzing the chondrogenic potential of human bone marrow-derived mesenchymal stem cells (BM MSCs) derived from osteoarthritic (OA) patients, in pure or CHT-coated PLLA, using different coating methodologies. Although PLLA scaffolds coated in one-step (PLLA-CHT1) yielded CHT smooth pellicles filling the PLLA macropores, a two-step strategy resulted in a CHT fiber-like thin coating covering PLLA pore walls (PLLA CHT2). Both strategies led to the incorporation of similar content of CHT and a two-fold increase in the scaffold's water uptake capacity, providing elastic moduli values comparable to the ones found for human articular cartilage. After confirming OA-derived BM-MSCs, metabolic activity in the scaffolds, the chondrogenic potential was tested at 30 and 60 days, in a chondrogenic differentiation medium. PLLA scaffolds improved the chondrogenic differentiation of BM-MSCs, regarding cell pellet conventional culture and presented a typical cartilage zonal distribution, although was not able to revert a terminal differentiation. In PLLA-CHT1, on a short term, a rather heterogeneous tissue was formed, with confined areas of either slower cell infiltration or a faster maturation, with enhanced chondrogenic phenotype. In PLLA-CHT2, a similar tissue to PLLA was obtained, albeit on the long term, these scaffolds helped to maintain a hyaline-like phenotype and prevented the advance of the hypertrophic process. These results demonstrate the importance of the scaffolds microenvironment on the cellular events of chondrogenesis. PMID- 25297939 TI - Lipid index changes in the blood serum of patients with hyperplastic and early neoplastic lesions in the ovaries. AB - BACKGROUND: The authors used the lipid index (WL) to monitor lipid changes before and after surgery. The surgical operation performed was the simultaneous enucleation of a cystic tumor of the hilum ovarii in its entirety (with diagnosis of a simple cyst or teratoma adultum) in groups of 20 patients. OBJECTIVES: To compare the lipid index WL in the blood serum of patients undergoing surgery treatment at the following times: before and 7 days after surgery, and 6 and 12 months after surgery. MATERIAL AND METHODS: The research material was the blood serum of women aged about 24 years. The authors divided the patients into 3 groups: two groups of 20 women and a control group. The concentrations of the lipid parameters were measured and the lipid index WL was calculated. RESULTS: Statistically significant differences were found between the lipid index of serum from patients with diagnosed ovarian neoplasms and the index of serum from healthy subjects; differences were demonstrated in the postoperative period, particularly 6 and 12 months after surgery. CONCLUSIONS: The lipid index WL proved useful in diagnosing ovarian neoplasm (simple cysts and teratoma adultum) and in monitoring the postoperative period. PMID- 25297941 TI - Astrochemistry of transition metals? The selected cases of [FeN](+), [FeNH](+) and [(CO)2FeN](+): pathways toward CH3NH2 and HNCO. AB - Transition metals (TMs) are proposed to play a role in astrophysical environments in both gas and solid state astrochemistry by co-determining the homogeneous/heterogeneous chemistry represented by the gas-gas and gas-dust grain interactions. Their chemistry is a function of temperature, radiation field and chemical composition/coordination sphere and as a consequence, dependent on the astrophysical object in which TMs are localized. Here five main categories of TM compounds are proposed and classified as: (a) pure bulk and clusters; (b) TM naked ions; (c) TM oxides/minerals or inorganic compounds; (d) TM-L (L = ligand) with L = (sigma and/or pi)-donor/acceptor species like H/H2, N/N2, CO, and H2O and (e) TM-organoligands such as Cp, PAH, and R1===R2. Each of the classes is correlated to their possible localization within astrophysical objects. Because of this variety coupled with their ability to modulate reactivity and regio/enantioselectivity by ligand sphere composition, TM compounds can introduce a fine organic synthesis in astrochemistry. For the selection of small TM parental compounds to be analyzed as first examples, by constraining the TMs and the second element/molecule on the basis of their cosmic abundance and mutual reactivity, Fe atoms coupled with N and CO are studied by developing the chemistry of [FeN](+), [FeNH](+) and [(CO)2FeN](+). These molecules, due to their ability to perform C-C and C-H bond activation, are able to open the pathway toward nitrogenation/amination and carbonylation of organic substrates. By considering the simplest organic substrate CH4, the parental reaction schemes (gas phase, T = 30 K): (I) [FeN](+) + CH4 + H -> [Fe](+) + H3C-NH2; (II) [FeNH](+) + CH4 -> [Fe](+) + H3C-NH2 and (III) [(CO)2FeN](+) + H -> [FeCO](+) + HNCO are analyzed by theoretical methods (B2PLYP double hybrid functional/TZVPPP basis set). All reactions are thermodynamically favored and first step transition states can follow a minimal energy path by spin crossing, while H extraction in reaction II shows very high activation energies. The need to overcome high activation energy barriers underlines the importance of molecular activation by radiation and particle collision. TM chemistry is expected to contribute to the known synthesis of organic compounds in space leading towards a new direction in the astrochemistry field whose qualitative (type of compounds) and quantitative contributions must be unraveled. PMID- 25297940 TI - Imaging of oxidation-specific epitopes with targeted nanoparticles to detect high risk atherosclerotic lesions: progress and future directions. AB - Oxidation-specific epitopes (OSE) within developing atherosclerotic lesions are key antigens that drive innate and adaptive immune responses in atherosclerosis, leading to chronic inflammation. Oxidized phospholipids and malondialdehyde lysine epitopes are well-characterized OSE present in human atherosclerotic lesions, particularly in pathologically defined vulnerable plaques. Using murine and human OSE-specific antibodies as targeting agents, we have developed radionuclide and magnetic resonance based nanoparticles, containing gadolinium, manganese or lipid-coated ultrasmall superparamagnetic iron oxide, to non invasively image OSE within experimental atherosclerotic lesions. These methods quantitate plaque burden, allow detection of lesion progression and regression, plaque stabilization, and accumulation of OSE within macrophage-rich areas of the artery wall, suggesting they detect the most active lesions. Future studies will focus on using "natural" antibodies, lipopeptides, and mimotopes for imaging applications. These approaches should enhance the clinical translation of this technique to image, monitor, evaluate efficacy of novel therapeutic agents, and guide optimal therapy of high-risk atherosclerotic lesions. PMID- 25297943 TI - Placental growth factor in cancer. AB - INTRODUCTION: Placental growth factor (PLGF) belongs to the VEGF family, which among the three VEGF receptors binds exclusively to VEGFR1, present on various cell types. Isoform PLGF-2 also binds the neuropilin co-receptors. PLGF is dispensable for development and health but has a prominent role in pathology including cancer. This has triggered the question whether PLGF targeting might offer an alternative to current antiangiogenesis therapy, which encounters problems of refractoriness and acquired resistance. AREAS COVERED: This article reviews the available literature on the characteristics of PLGF, its role(s) in cancer and the findings on PLGF inhibition in preclinical models with attention to as yet unresolved questions and summarizes data from initial clinical trials. EXPERT OPINION: Preclinical studies show that inhibition of PLGF, either by genetic inhibition or by pharmacological blockade using distinct independently generated anti-PLGF antibodies, slows down tumor growth and metastasis and even induces regression of pre-existing medulloblastoma, the most frequent brain cancer in children. These promising preclinical findings, together with the acceptable safety profile of anti-PLGF administration in Phase I clinical trials, have attracted attention to PLGF as a potential target for therapy. PMID- 25297942 TI - Long non-coding RNAs in non-small cell lung cancer as biomarkers and therapeutic targets. AB - Lung cancer-associated mortality is the most common cause of cancer death worldwide. Non-coding RNAs (ncRNAs), with no protein-coding ability, have multiple biological roles. Long non-coding RNAs (lncRNAs) are a recently characterized class of ncRNAs that are over 200 nucleotides in length. Many lncRNAs have the ability of facilitating or inhibiting the development and progression of tumours, including non-small cell lung cancer (NSCLC). Because of their fundamental roles in regulating gene expression, along with their involvement in the biological mechanisms underlying tumourigenesis, they are a promising class of tissue- and/or blood-based cancer biomarkers. In this review, we highlight the emerging roles of lncRNAs in NSCLC, and discuss their potential clinical applications as diagnostic and prognostic markers and as therapeutic targets. PMID- 25297944 TI - Foreward to special issue on health analytics. PMID- 25297945 TI - A single-center experience with 200 dual kidney transplantations. AB - This study reports on a large series of 200 dual kidney transplantations (DKTs) from expanded criteria donors (ECDs) and proposes specific ways to optimize outcomes. Data concerning 200 DKTs performed in the last 14 yr were retrospectively analyzed. Kidneys from high-risk ECD were allocated for use in DKTs on an old-for-old basis after histological assessment. Different surgical techniques and immunosuppressant regimens were used over time, and the outcomes are discussed. Donors and recipients were a median 73 (70-77) and a 62 (58-67) yr old, respectively. Delayed graft function occurred in 31.5% of cases, and acute rejection in 13.5%. Patient and graft survival at five yr were 90.4% and 85.8%, respectively. Unilateral kidney placement was preferred for 75% of patients, and was associated with a low rate of surgical complications. Our current standard therapy comprising low-dose calcineurin inhibitors (CNIs) associated with mammalian target of rapamycin inhibitors (mTOR) and steroids appears to offer the best risk/benefit profile for elderly patients undergoing DKT. In our experience, outcomes after DKT can be improved by: (i) kidney clinical-histological assessment; (ii) unilateral kidney placement; (iii) minimal use of CNI associated with mTOR. PMID- 25297946 TI - Pro-thrombotic effect of exercise in a polluted environment: a P-selectin- and CD63-related platelet activation effect. AB - Exposure to diesel exhaust is an important cardiovascular risk factor and may promote atherothrombotic events. Some data suggest that polluted air exposure could affect haemostasis through platelet activation. The aim of the study was to investigate the effects of acute exposure to diesel exhaust on platelet activation and platelet function. We tested the hypothesis in a randomised, crossover study in 25 healthy men exposed to ambient and polluted air; 11 of the subjects also performed exercise during exposure sessions. Platelet activation was evaluated by surface expression of CD62P (P-selectin) and CD63 (dense granule glycoprotein) using flow cytometry of labelled platelets. Platelet function was measured using the PFA-100 platelet function analyser and by Multiplate whole blood impedance platelet aggregometry. Acute diesel exhaust exposure had no effect on platelet activation at rest, but exercise in polluted air increased the collagen-induced expression of CD62P and CD63 (both p< 0.05). The increase in the expression of CD62P and CD63 was related to the total amount of PM2.5 inhaled during the exercise sessions (r=+0.58 and +0.60, respectively, both p< 0.05). Platelet aggregation was not impaired after polluted air exposure at rest or during exercise. In conclusion, in healthy subjects, diesel exhaust exposure induces platelet activation as illustrated by a dose-response increase in the release of CD62P and CD63. This platelet priming effect could be a contributor to the triggering of atherothrombotic events related to air pollution exposure. PMID- 25297948 TI - Host diversity affects the abundance of the extraradical arbuscular mycorrhizal network. AB - Arbuscular mycorrhizal fungi (AMF) can form complex networks in the soil that connect different host plants. Previous studies have focused on the effects of these networks on individual hosts and host communities. However, very little is known about how different host species affect the success of the fungal network itself. Given the potentially strong selection pressure against hosts that invest in a fungal network which benefits their competitors, we predict that the presence of multiple host species negatively affects the growth of the extraradical network. We designed an experiment using an in vitro culture approach to investigate the effect of different hosts (carrot, chichory and medicago) on the formation of a common mycelial network. In vitro root cultures, each inoculated with their own fungal network, were grown in a double split plate design with two host compartments and a common central compartment where fungal networks could form. We found that the size of fungal networks differs depending on the social environment of the host. When host species were propagated in a mixed species environment, the fungal abundance was significantly reduced compared to monoculture predictions. Our work demonstrates how host-to-host conflict can influence the abundance of the fungal partner. PMID- 25297949 TI - Reaction phenotyping: advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes. AB - During the process of drug discovery, the pharmaceutical industry is faced with numerous challenges. One challenge is the successful prediction of the major routes of human clearance of new medications. For compounds cleared by metabolism, accurate predictions help provide an early risk assessment of their potential to exhibit significant interpatient differences in pharmacokinetics via routes of metabolism catalyzed by functionally polymorphic enzymes and/or clinically significant metabolic drug-drug interactions. This review details the most recent and emerging in vitro strategies used by drug metabolism and pharmacokinetic scientists to better determine rates and routes of metabolic clearance and how to translate these parameters to estimate the amount these routes contribute to overall clearance, commonly referred to as fraction metabolized. The enzymes covered in this review include cytochrome P450s together with other enzymatic pathways whose involvement in metabolic clearance has become increasingly important as efforts to mitigate cytochrome P450 clearance are successful. Advances in the prediction of the fraction metabolized include newly developed methods to differentiate CYP3A4 from the polymorphic enzyme CYP3A5, scaling tools for UDP-glucuronosyltranferase, and estimation of fraction metabolized for substrates of aldehyde oxidase. PMID- 25297950 TI - Influence of Groundwater Hydraulic Gradient on Bank Storage Metrics. AB - The hydraulic gradient between aquifers and rivers is one of the most variable properties in a river/aquifer system. Detailed process understanding of bank storage under hydraulic gradients is obtained from a two-dimensional numerical model of a variably saturated aquifer slice perpendicular to a river. Exchange between the river and the aquifer occurs first at the interface with the unsaturated zone. The proportion of total water exchanged through the river bank compared to the river bed is a function of aquifer hydraulic conductivity, partial penetration, and hydraulic gradient. Total exchange may be estimated to within 50% using existing analytical solutions provided that unsaturated zone processes do not strongly influence exchange. Model-calculated bank storage is at a maximum when no hydraulic gradient is present and increases as the hydraulic conductivity increases. However, in the presence of a hydraulic gradient, the largest exchange flux or distance of penetration does not necessarily correspond to the highest hydraulic conductivity, as high hydraulic conductivity increases the components of exchange both into and out of an aquifer. Flood wave characteristics do not influence ambient groundwater discharge, and so in large floods, hydraulic gradients must be high to reduce the volume of bank storage. Practical measurement of bank storage metrics is problematic due to the limitations of available measurement technologies and the nested processes of exchange that occur at the river-aquifer interface. Proxies, such as time series concentration data in rivers and groundwater, require further development to be representative and quantitative. PMID- 25297947 TI - Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility. AB - PURPOSE: Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. METHODS: Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing. RESULTS: In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing. CONCLUSION: A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492. PMID- 25297951 TI - Six-coordinate lanthanide complexes: slow relaxation of magnetization in the dysprosium(III) complex. AB - A series of six-coordinate lanthanide complexes {(H3O)[Ln(NA)2]?H2O}n (H2NA=5 hydroxynicotinic acid; Ln=Gd(III) (1?Gd); Tb(III) (2?Tb); Dy(III) (3?Dy); Ho(III) (4?Ho)) have been synthesized from aqueous solution and fully characterized. Slow relaxation of the magnetization was observed in 3?Dy. To suppress the quantum tunneling of the magnetization, 3?Dy diluted by diamagnetic Y(III) ions was also synthesized and magnetically studied. Interesting butterfly-like hysteresis loops and an enhanced energy barrier for the slow relaxation of magnetization were observed in diluted 3?Dy. The energy barrier (Delta(tau)) and pre-exponential factor (tau0) of the diluted 3?Dy are 75 K and 4.21*10(-5) s, respectively. This work illustrates a successful way to obtain low-coordination-number lanthanide complexes by a framework approach to show single-ion-magnet-like behavior. PMID- 25297952 TI - Effect of residence on mothers' health care seeking behavior for common childhood illness in Northwest Ethiopia: a community based comparative cross--sectional study. AB - BACKGROUND: Children are at higher risk of acquiring infections and developing severe disease. This study assessed the health care seeking behavior and associated factors of urban and rural mothers for common childhood illness in Northwest Ethiopia. METHODS: A comparative community based cross-sectional study was conducted among urban and rural mothers living in the district. A multistage sampling technique was used to select the study participants. A pre-tested and structured questioner via interview was used to collect the data. Binary logistic regression analysis was used to identify associated factors. Odds ratio with 95% CI was computed to assess the strength of the associations. RESULT: A total of 827 (274 urban and 553 rural) mothers were interviewed. Among these, 79.3% (95% CI: (76.5%, 82.06%)) of the mothers were sought health care in the district. Health care seeking behavior was higher among urban mothers (84.6%) than rural mothers (76.7%). Marital status, completion health extension package, and sex of child were significantly associated with health care seeking behavior of urban mothers. Whereas age of child, age and occupation of mothers, educational level of fathers, wealth quintile, and type of reported illness were significantly associated with rural mothers. Perceived severity of illness was significantly associated with both urban and rural mothers for health care seeking behavior. CONCLUSION: The overall health seeking behaviors of mothers for common childhood illness was high. However, urban mothers seek health care more than rural. Socio Economic position and types of reported illness has an effect for health seeking behavior of rural mothers. Whereas child sex preference and graduation status for health extension package has an effect for health care seeking behavior of urban mothers. Work on strengthen accessibility of health care services in the rural mothers and increase awareness of mothers about the disadvantage of sex preferences will improve the health care seek behavior of families regardless of the severity of illness and types of illnesses. PMID- 25297953 TI - Analysing the movement of a hair swatch using video and image analysis: a promising technique for exploring the dynamic properties of hair. AB - OBJECTIVE: The aim of this paper is to present a new instrumental evaluation method of hair movement in order to propose new criteria in the performances of hair products. The in vitro evaluation of hair swatches movement allows us to better understand the phenomena that appear when various hair care and styling technologies are applied upon the mechanisms of hair movements. METHODS: The method consists of a video acquisition system with fast cameras (100 frames/second). The swatch is placed on a motor drive and moved with a back and forth movement. The frequency and amplitude are set by the operator. Facing each camera, a backlight provides high contrast to capture all the fibres of the swatch. A software was specifically developed to analyse the video recordings and provide the physical parameters that characterize the movement. Accordingly, it is possible to follow the surface and shape of the swatch during movement from the 'skeleton' of the swatch and to study the contraction and expansion phases of the swatch(es) during the movement together with 'the envelope' of the swatch. RESULTS: Results show that applying various hair treatments modifies the behaviour of the swatch through the hair shapes contraction or expansion induced by the oscillating movement. Expansion of the swatch suggests that the interactions between hair fibres (adhesions or frictions) play an important role, leading to an 'individualization' of hair swatch (more 'space' between fibres) or to a 'wider' movement related to the increase of the total surface developed by the swatch. As an example, the application of a highly conditioning formula on a hair swatch largely decreases its expansion by a two-fold factor during movements and increases the horizontal amplitude by a two-fold factor, as compared to a commercial bland shampoo. CONCLUSION: In conclusion, this method is complementary to the ones used generally to characterize global visual perceptions (colour, styling, shine). This dynamic component not only opens doors to new qualitative evaluations, linked with sensorial experts and consumers perceptions, but also to new quantitative parameters. PMID- 25297954 TI - Who should stay, who should leave? PMID- 25297955 TI - A little bit of both. PMID- 25297956 TI - Truth (validity) and use despite consequences: the DSM-5 substance use disorder unidimensional syndrome. PMID- 25297957 TI - 'Truth or consequences'--what about truth or dare. PMID- 25297958 TI - Response to commentaries. PMID- 25297959 TI - Commentary on Heinzerling et al. (2014): a growing methamphetamine dependence therapeutics graveyard. PMID- 25297960 TI - Commentary on Unick et al. (2014): policy, price and purity. PMID- 25297961 TI - Commentary on Scharkow et al. (2014): Welcomed and yet to come. Are we looking at what we are looking for? PMID- 25297962 TI - Commentary on Dixon et al. (2014): understanding the abuse liability of modern electronic gaming machines. PMID- 25297964 TI - Simultaneous quantification of olanzapine and its metabolite N desmethylolanzapine in human plasma by liquid chromatography tandem mass spectrometry for therapeutic drug monitoring. AB - A simple, sensitive, and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of olanzapine (OLZ) and its metabolite N-desmethylolanzapine (DMO) in human plasma for therapeutic drug monitoring. Sample preparation was performed by one step protein precipitation with methanol. The analytes were chromatographed on a reversed-phase YMC-ODS-AQ C18 Column (2.0 * 100 mm,3 um) by a gradient program at a flow rate of 0.30 mL/min. Quantification was performed on a triple quadrupole tandem mass spectrometer via electrospray ionization in positive ion mode. The method was validated for selectivity, linearity, accuracy, precision, matrix effect, recovery and stability. The calibration curve was linear over the concentration range 0.2-120 ng/mL for OLZ and 0.5-50 ng/mL for DMO. Intra- and interday precisions for OLZ and DMO were <11.29%, and the accuracy ranged from 95.23 to 113.16%. The developed method was subsequently applied to therapeutic drug monitoring for psychiatric patients receiving therapy of OLZ tablets. The method seems to be suitable for therapeutic drug monitoring of patients undergoing therapy with OLZ and might contribute to prediction of the risk of adverse reactions. PMID- 25297965 TI - A grouping approach to homotop global optimization in alloy nanoparticles. AB - We propose an approach to accelerate the computational exploration and the prediction of the preferred chemical ordering in alloy nanoparticles. This approach, named Grouping Global Optimization (GGO), is based on grouping atoms into equivalence sets constrained to be occupied by the same elemental species, with a consequent significant reduction in the compositional degrees of freedom of the system. The equivalence sets are defined on the basis of point group symmetry or in general of any given order parameter, thus leaving the user a great freedom in the implementation to each specific system. The GGO approach can be used within both systematic and stochastic sampling algorithms as demonstrated by tests conducted on prototypical nanoalloys, namely on Pd-Pt and Ag-Cu binary pairs, as representative of high- or low-miscibility alloys, respectively, and on particles of two different sizes, i.e., truncated octahedra composed of 586 and 4033 atoms. It is found that GGO enables an extremely quick scan of the chemical ordering in nanoalloys containing thousands of atoms and to predict low-energy chemical ordering patterns as a function of size and composition with a modest computational effort even for the larger and symmetry-broken particles. The strategy here proposed should be applicable equally well in other fields than that of nanoalloys. PMID- 25297966 TI - The face of schadenfreude: Differentiation of joy and schadenfreude by electromyography. AB - The present study investigated whether the facial expression of the social emotion schadenfreude, the pleasant emotion which arises in response to another's misfortune, can be differentiated from the facial expression of joy. Schadenfreude was induced by videos displaying unsuccessful penalty shots of Dutch soccer players and joy by successful penalty shots of German soccer players. Thirty-two participants watched videos while the activity of four facial muscles was recorded electromyographically. Furthermore, they judged each stimulus according to valence, arousal, joy, schadenfreude and sadness. Electromyography (EMG) results revealed that schadenfreude expressions did not differ from joy with regard to involved muscles (increase of Musculus zygomaticus major and M. orbicularis oculi activity, decrease of M. corrugator supercilii activity, no activity change of M. frontalis medialis). Furthermore, facial reactions developed fast in both conditions and EMG indicated stronger reactions in the schadenfreude condition, but according to ratings participants felt more pleasure in the joy condition. PMID- 25297967 TI - Synthetic lethal interaction of combined CD26 and Bcl-xL inhibition is a powerful anticancer therapy against hepatocellular carcinoma. AB - AIM: CD26 is a membrane glycoprotein that has multiple functions, including dipeptidyl peptidase IV activity. CD26 expression varies in different tumor types, and its role in tumor growth in hepatocellular carcinoma (HCC) remains unclear. METHODS: CD26 expression levels were examined in resected HCC and surrounding non-cancerous lesions. The effect of CD26 knockdown on the cellular proliferation of HepG2 or Huh7 cells, both of which highly express CD26, was studied in vitro. RESULTS: CD26 mRNA expression levels were significantly increased in HCC compared with their surrounding non-cancerous lesions. We confirmed that various HCC cell lines, especially HepG2 and Huh7 cells, showed high expression levels of CD26. siRNA-mediated knockdown of CD26 suppressed hepatoma cell growth in vitro. CD26 knockdown induced cell cycle arrest through the upregulation of Cip/Kip family proteins, p21 in HepG2 cells and p27 in Huh7 cells. CD26 knockdown did not affect apoptosis, but it increased expressions of the pro-apoptotic proteins Bim and Bak and the anti-apoptotic protein Bcl-xL, suggesting an addiction of CD26 knockdown cells to Bcl-xL for survival. We thus treated CD26 knockdown cells with ABT-737, a Bcl-xL/-2/-w inhibitor, and observed that the synthetic lethal interaction of combined Bcl-xL and CD26 inhibition induced significant apoptosis and impaired cellular viability. CONCLUSION: CD26 mRNA was overexpressed in HCC, and its inhibition suppressed cellular proliferation through cell cycle arrest. The combined use of CD26 knockdown with a Bcl-xL inhibitor further elicited substantial apoptosis and therefore may serve as a powerful anticancer combination therapy against HCC. PMID- 25297968 TI - Components of late-life exercise and cognitive function: an 8-year longitudinal study. AB - The preventive effect of late-life physical exercise on cognitive deterioration has been reported in many cohort studies. However, the effect of exercise, independent of other cognitively demanding and social activities, is equivocal and little is known about the relative contributions of frequency, intensity, and duration of exercise. This study aimed to examine the relationships of exercise and its underlying components with cognitive function and rate of cognitive change over an 8-year period in a nationally representative sample of older Taiwanese. Data from the 1999, 2003, and 2007 phases of the nationwide longitudinal survey were used. Data from a fixed cohort of 1,268 participants aged 70 years or older in 1999 with 8 years of follow-up were analyzed. Cognitive function was assessed using the Short Portable Mental Status Questionnaire. Self reported frequency, intensity, and duration of exercise were collected. A generalized estimating equation with multivariate adjustment for sociodemographic variables, cognitive and social leisure activities, lifestyle behaviors, and health status was calculated. Participants who were physically active during leisure time had better subsequent cognitive function (incident rate ratios [IRR] = 0.63; 95 % CI, 0.54-0.75) and a slower rate of cognitive decline (p = 0.01). Among the components of exercise, only duration emerged as a predictor of cognitive function (p = 0.01). Older adults engaging in exercise for at least 30 min or more per session are likely to reduce the risk of subsequent cognitive decline. This research supports the case for physical exercise programs for older adults in order to help prevent loss of cognitive function. PMID- 25297970 TI - What Happens in Their Bedrooms Stays in Their Bedrooms: Staff and Residents' Reactions Toward Male-Female Sexual Intercourse in Residential Aged Care Facilities. AB - This study aimed to investigate and compare the reactions of staff and residents of residential aged care facilities (RACFs) toward male-female sexual intercourse taking place in a private space within the facility. A total of 53 professionals and 47 residents from five RACFs located in Catalonia, Spain, were asked to reflect upon what they would think and do if they entered the bedroom of a resident and found him or her having sex with another resident of the opposite gender. The results suggest that male-female partnered sexual activity would generally be considered acceptable and would be respected, although some respondents called into question the appropriateness of such behavior and stated that they would react in a restrictive way. Overall, professionals appeared to be more accepting and permissive than were residents. Although our findings are broadly optimistic, they also suggest that male-female sexual intercourse may be considered an unwelcome sexual practice by some residents and professionals even if it occurs in a private space within the RACF. The fact that both staff and residents may also react in a negative way to the event could constitute a barrier to sexual expression among institutionalized older people. PMID- 25297969 TI - Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice. AB - Previous studies have suggested that Klotho provides reno-protection against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis (RTF). Because the existing studies are mainly performed using heterozygous Klotho mutant (HT) mice, we focused on the effect of UUO on homozygous Klotho mutant (kl/kl) mice. UUO kidneys from HT mice showed a significantly higher level of RTF and TGF-beta/Smad3 signaling than wild-type (WT) mice, whereas both were greatly suppressed in kl/kl mice. Primary proximal tubular epithelial culture cells isolated from kl/kl mice showed no suppression in TGF-beta1-induced epithelial mesenchymal transition (EMT) compared to those from HT mice. In the renal epithelial cell line NRK52E, a large amount of inorganic phosphate (Pi), FGF23, or calcitriol was added to the medium to mimic the in vivo homeostasis of kl/kl mice. Neither Pi nor FGF23 antagonized TGF-beta1-induced EMT. In contrast, calcitriol ameliorated TGF-beta1-induced EMT in a dose dependent manner. A vitamin D3-deficient diet normalized the serum 1,25 (OH)2 vitamin D3 level in kl/kl mice and enhanced UUO-induced RTF and TGF-beta/Smad3 signaling. In conclusion, the alleviation of UUO-induced RTF in kl/kl mice was due to the TGF beta1 signaling suppression caused by an elevated serum 1, 25(OH)2 vitamin D3. PMID- 25297971 TI - Revisiting the sparteine surrogate: development of a resolution route to the (-) sparteine surrogate. AB - The improved performance of the sparteine surrogate compared to sparteine in a range of applications has highlighted the need to develop an approach to the (-) sparteine surrogate, previously inaccessible in gram-quantities. A multi-gram scale, chromatography-free synthesis of the racemic sparteine surrogate and its resolution via diastereomeric salt formation with (-)-O,O'-di-p-toluoyl-l tartaric acid is reported. Resolution on a 10.0 mmol scale gave the diastereomeric salts in 33% yield from which (-)-sparteine surrogate of 93 : 7 er was generated. This work solves a key limitation: either enantiomer of the sparteine surrogate can now be readily accessed. PMID- 25297972 TI - Quick method (FT-NIR) for the determination of oil and major fatty acids content in whole achenes of milk thistle (Silybum marianum (L.) Gaertn.). AB - BACKGROUND: Calibration models for the Fourier transform-near infrared (FT-NIR) instrument were developed for quick and non-destructive determination of oil and fatty acids in whole achenes of milk thistle. Samples with a range of oil and fatty acid levels were collected and their transmittance spectra were obtained by the FT-NIR instrument. Based on these spectra and data gained by the means of the reference method - Soxhlet extraction and gas chromatography (GC) - calibration models were created by means of partial least square (PLS) regression analysis. RESULTS: Precision and accuracy of the calibration models was verified via the cross-validation of validation samples whose spectra were not part of the calibration model and also according to the root mean square error of prediction (RMSEP), root mean square error of calibration (RMSEC), root mean square error of cross-validation (RMSECV) and the validation coefficient of determination (R(2) ). R(2) for whole seeds were 0.96, 0.96, 0.83 and 0.67 and the RMSEP values were 0.76, 1.68, 1.24, 0.54 for oil, linoleic (C18:2), oleic (C18:1) and palmitic (C16:0) acids, respectively. CONCLUSION: The calibration models are appropriate for the non-destructive determination of oil and fatty acids levels in whole seeds of milk thistle. PMID- 25297975 TI - Synthesis, structure, and properties of O6 -Corona[3]arene[3]tetrazines. AB - O6 -Corona[3]arene[3]tetraazines, a new class of macrocyclic compounds, were synthesized efficiently in a one-pot reaction from the nucleophilic aromatic substitution reaction between 1,4-dihydroxybenzene derivatives and 3,6 dichlorotetrazine in warm acetonitrile. In the crystalline structure, the resulting macrocycles adopt highly symmetric structures of a regular hexagonal cavity with all bridging oxygen atoms and tetrazine rings located on the same plane with phenylene units orthogonally orientated. The constitutional aromatic rings are able to rotate around the macrocyclic annulus, depending on the steric effect of the substituents and temperature, in solution. The electron-deficient nature revealed by cyclic voltammetry, differential pulse voltammetry, and characteristic absorbances at a visible region show the O6 corona[3]arene[3]tetrazines to be suitable macrocyclic receptors for electron rich guests. PMID- 25297974 TI - An evolutionary analysis of genome expansion and pathogenicity in Escherichia coli. AB - BACKGROUND: There are several studies describing loss of genes through reductive evolution in microbes, but how selective forces are associated with genome expansion due to horizontal gene transfer (HGT) has not received similar attention. The aim of this study was therefore to examine how selective pressures influence genome expansion in 53 fully sequenced and assembled Escherichia coli strains. We also explored potential connections between genome expansion and the attainment of virulence factors. This was performed using estimations of several genomic parameters such as AT content, genomic drift (measured using relative entropy), genome size and estimated HGT size, which were subsequently compared to analogous parameters computed from the core genome consisting of 1729 genes common to the 53 E. coli strains. Moreover, we analyzed how selective pressures (quantified using relative entropy and dN/dS), acting on the E. coli core genome, influenced lineage and phylogroup formation. RESULTS: Hierarchical clustering of dS and dN estimations from the E. coli core genome resulted in phylogenetic trees with topologies in agreement with known E. coli taxonomy and phylogroups. High values of dS, compared to dN, indicate that the E. coli core genome has been subjected to substantial purifying selection over time; significantly more than the non-core part of the genome (p<0.001). This is further supported by a linear association between strain-wise dS and dN values (beta = 26.94 +/- 0.44, R2~0.98, p<0.001). The non-core part of the genome was also significantly more AT-rich (p<0.001) than the core genome and E. coli genome size correlated with estimated HGT size (p<0.001). In addition, genome size (p<0.001), AT content (p<0.001) as well as estimated HGT size (p<0.005) were all associated with the presence of virulence factors, suggesting that pathogenicity traits in E. coli are largely attained through HGT. No associations were found between selective pressures operating on the E. coli core genome, as estimated using relative entropy, and genome size (p~0.98). CONCLUSIONS: On a larger time frame, genome expansion in E. coli, which is significantly associated with the acquisition of virulence factors, appears to be independent of selective forces operating on the core genome. PMID- 25297976 TI - [Effects of age, period, and cohort on the trends in obesity rate and energy intake ratio from fat in Japanese adults]. AB - OBJECTIVES: In the present study, we aimed to clarify the specific effects of age, period, and cohort on trends in obesity rate and energy intake ratio from fat in Japanese adults using a Bayesian age-period-cohort (APC) analysis and to evaluate the relationship between changes in obesity rate and energy intake ratio from fat. METHODS: We obtained data regarding obesity rate and calorie intake of fat, animal fat, carbohydrate, protein, animal protein, and total energy intake of Japanese adults from the National Nutrition Survey. The data were tabulated for five 10-year age groups (from 20-29 years to 60-69 years) and 17 annual demographic profiles (from 1995 to 2011), with regard to the energy intake ratio. These standard cohort tables were analyzed using a Bayesian APC model. RESULTS: With regard to obesity rate, the effect of age was the greatest and increased rapidly in the age group of 30-39 years for both genders. Moreover, the period effect consistently increased in men, but had very little variation in women. The cohort effect indicated a reverse of the decreasing trend in the cohorts born after 1962-1971 in men and indicated a reverse of the increasing trend in the cohorts born after 1965-1974 in women. With regard to the energy intake ratio from fat, the trends for the three effects differed from those for obesity rate for both genders. The age effect generally decreased with increasing age. Furthermore, for both genders, the period effect gradually decreased after 1998 and markedly decreased in 2001, remained constant or slightly increased until 2008, and increased thereafter. However, the cohort effect was the greatest among the three, and although a decreasing trend was observed in the cohorts born after 1976-1985 in women, the energy intake from fat increased in the younger cohorts in both genders. The overall effect on energy intake ratio from animal fat had a slope similar to that of the energy intake ratio from fat. CONCLUSION: Each effect affected obesity and energy intake ratio from fat in a different manner, suggesting that factors other than energy intake ratio from fat, such as energy expenditure, contributed to the changes in obesity rate. However, obesity risk markedly increased in the age group of 30-39 years, and younger generations had a higher energy intake ratio from fat. These results suggest that dietary guidelines, particularly the optimal intake of animal products, is needed for younger generations to prevent the development of obesity in adulthood. PMID- 25297973 TI - Contraceptive methods and risk of HIV acquisition or female-to-male transmission. AB - Effective family planning with modern contraception is an important intervention to prevent unintended pregnancies which also provides personal, familial, and societal benefits. Contraception is also the most cost-effective strategy to reduce the burden of mother-to-child HIV transmission for women living with HIV who wish to prevent pregnancy. There are concerns, however, that certain contraceptive methods, in particular the injectable contraceptive depot medroxyprogesterone acetate (DMPA), may increase a woman's risk of acquiring HIV or transmitting it to uninfected males. These concerns, if confirmed, could potentially have large public health implications. This paper briefly reviews the literature on use of contraception among women living with HIV or at high risk of HIV infection. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommendations place no restrictions on the use of hormonal contraceptive methods by women with or at high risk of HIV infection, although a clarification recommends that, given uncertainty in the current literature, women at high risk of HIV who choose progestogen-only injectable contraceptives should be informed that it may or may not increase their risk of HIV acquisition and should also be informed about and have access to HIV preventive measures, including male or female condoms. PMID- 25297977 TI - [Relationship between the attitudes towards improving eating habits and prevalence of metabolic syndrome. Data from the 2005 National Health and Nutrition Survey and the Comprehensive Survey of Living Conditions]. AB - OBJECTIVES: The aim of the present study was to examine the constructive attitudes towards improving eating habits and their relationship with the prevalence of metabolic syndrome (MetS) using data from the National Health and Nutrition Survey (2005) and the Comprehensive Survey of Living Conditions (2005). METHODS: Individuals aged >30 years (N=3084) were enrolled in this study. Exploratory factor analyses were performed to examine the constructive attitudes towards improving eating habits by using 14 parameters. In addition, confirmatory factor analysis was performed and the Cronbach alpha value was calculated. Furthermore, the relationship between attitudes towards improving eating habits and MetS prevalence was examined according to gender by using multinomial logistic regression analysis, after adjusting for age, number of members in a household, exercise habits, and rest by sleeping. RESULTS: Two factors were extracted: balanced diet (BD) and control of food intake (CFI) (Cronbach alpha, 0.82 and 0.75, respectively). The goodness of fit model, based on the structural equation models, was adequate (goodness of fit, 0.96). No relationship was noted between BD and MetS prevalence. The MetS prevalence differed according to gender: "Strongly suspected MetS (sure MetS)", 16.3% (male, 24.4%; female, 10.7%), "Preliminary MetS (pre MetS)", 15.2% (male, 24.1%; female, 8.9%), "non-suspected MetS (non MetS)", 68.5% (male, 51.5%; female, 80.5%). The odds ratios (95% confidence interval) for pre MetS and sure MetS were 0.57 (0.42-0.78) and 0.52 (0.38-0.71) in males and 0.36 (0.25-0.53) and 0.39 (0.27-0.56) in females, respectively, when non MetS was used as a reference. CONCLUSION: The results of this study indicated that the attitudes towards improving eating habits primarily focused on BD and CFI. Therefore, improving eating habits towards in terms of better CFI would be effective in preventing MetS in both genders. PMID- 25297978 TI - Expression of Gls and Gls2 glutaminase isoforms in astrocytes. AB - The expression of glutaminase in glial cells has been a controversial issue and matter of debate for many years. Actually, glutaminase is essentially considered as a neuronal marker in brain. Astrocytes are endowed with efficient and high capacity transport systems to recapture synaptic glutamate which seems to be consistent with the absence of glutaminase in these glial cells. In this work, a comprehensive study was devised to elucidate expression of glutaminase in neuroglia and, more concretely, in astrocytes. Immunocytochemistry in rat and human brain tissues employing isoform-specific antibodies revealed expression of both Gls and Gls2 glutaminase isozymes in glutamatergic and GABAergic neuronal populations as well as in astrocytes. Nevertheless, there was a different subcellular distribution: Gls isoform was always present in mitochondria while Gls2 appeared in two different locations, mitochondria and nucleus. Confocal microscopy and double immunofluorescence labeling in cultured astrocytes confirmed the same pattern previously seen in brain tissue samples. Astrocytic glutaminase expression was also assessed at the mRNA level, real-time quantitative RT-PCR detected transcripts of four glutaminase isozymes but with marked differences on their absolute copy number: the predominance of Gls isoforms over Gls2 transcripts was remarkable (ratio of 144:1). Finally, we proved that astrocytic glutaminase proteins possess enzymatic activity by in situ activity staining: concrete populations of astrocytes were labeled in the cortex, cerebellum and hippocampus of rat brain demonstrating functional catalytic activity. These results are relevant for the stoichiometry of the Glu/Gln cycle at the tripartite synapse and suggest novel functions for these classical metabolic enzymes. PMID- 25297979 TI - Time lag between peak concentrations of plasma and salivary cortisol following a stressful procedure in dairy cattle. AB - BACKGROUND: Measurement of salivary cortisol has been used extensively as a non invasive alternative to blood sampling to assess adrenal activity in ruminants. However, there is evidence suggesting a considerable delay in the transfer of cortisol from plasma into saliva. Previous studies in cattle have used long sampling intervals making it difficult to characterise the relationship between plasma and salivary cortisol (PLCort and SACort, respectively) concentrations at different time points and determine whether or not such a time lag exist in large ruminants. Therefore, the objective of this study was to characterise the relationship between plasma and salivary cortisol and determine if there is a significant time lag between reaching peak cortisol concentrations in plasma and saliva across a 4.25 h time-period, using short sampling intervals of 10-15 min, following social separation in dairy cattle.Five cows were separated from their calves at 4 days after calving, and six calves were separated from a group of four peers at 8 weeks of age. Following separation, the animals were moved to an unfamiliar surrounding where they could not see their calves or pen mates. The animals were catheterised with indwelling jugular catheters 1 day before sampling. Blood and saliva samples were obtained simultaneously before and after separation. RESULTS: In response to the stressors, PLCort and SACort increased reaching peak concentrations 10 and 20 min after separation, respectively. This suggested a 10 min time lag between peak cortisol concentrations in plasma and saliva, which was further confirmed with a time-series analysis. Considering the 10 min time lag, SACort was strongly correlated with PLCort (P < 0.0001). CONCLUSIONS: Salivary cortisol correlates well with plasma cortisol and is a good indicator of the time-dependent variations in cortisol concentrations in plasma following acute stress. However, there is a time lag to reach peak cortisol concentrations in saliva compared to those in plasma, which should be considered when saliva samples are used as the only measure of hypothalamic-pituitary adrenal axis response to stress in cattle. PMID- 25297981 TI - A case of dermatitis herpetiformis with blister formation between laminin-332 and type 7 collagen. PMID- 25297980 TI - Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction. AB - The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2's ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1-/-) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. PMID- 25297982 TI - Dimerized plasmin fragment D as a potential biomarker to predict successful catheter-directed thrombolysis therapy in acute deep vein thrombosis. AB - OBJECTIVES: The value of dimerized plasmin fragment D in the clinical monitoring during the catheter-directed thrombolysis in patients with acute deep vein thrombosis is not known. METHODS: Dimerized plasmin fragment D levels in 24 patients with acute deep vein thrombosis undergoing catheter-directed thrombolysis were prospectively evaluated. The plasma dimerized plasmin fragment D level was measured serially before and at every 12 h during catheter-directed thrombolysis for 24 h. Technical success was defined as restoration of patency and flow with less than 50% residual thrombus by surveillance rotational venography. RESULTS: Technical success was achieved in 79.2% (19 of 24) of the treated limbs after catheter-directed thrombolysis. In univariate analysis, there was significant elevation of the dimerized plasmin fragment D at 12th h after starting the catheter-directed thrombolysis (P < 0.05) in patients with less than 50% residual thrombus stenosis. The optimal cut-off value of dimerized plasmin fragment D to predict successful catheter-directed thrombolysis was determined as 18.4 ug/ml at the 12th h after starting the catheter-directed thrombolysis with sensitivity 0.8 and specificity 0.8 (P = 0.03). It was further validated in multivariate logistic regression analysis (odds ratio: 14.38; 95% CI: 1.22 169.20; P = 0.03). CONCLUSIONS: Catheter-directed thrombolysis is safe and effective for restoration of blood flow in patients with acute deep vein thrombosis. Dimerized plasmin fragment D value greater than 18.4 ug/ml at the 12th h after starting catheter-directed thrombolysis had a high predictive rate of greater than 50% lysis at the end of catheter-directed thrombolysis. PMID- 25297983 TI - Nitrogen and sulfur co-doped carbon dots with strong blue luminescence. AB - Sulfur-doped carbon dots (S-CDs) with a quantum yield (QY) of 5.5% and nitrogen, sulfur co-doped carbon dots (N,S-CDs) with a QY of 54.4% were synthesized, respectively, via the same hydrothermal route using alpha-lipoic acid as the carbon source. The obtained S-CDs and N,S-CDs had similar sizes but different optical features. The QY of N,S-CDs was gradually enhanced when extending the reaction time to increase the nitrogen content. After careful characterization of these CDs, the doped nitrogen element was believed to be in the form of C=N and C N bonds which enhanced the fluorescence efficiency significantly. Meanwhile, the co-doped sulfur element was found to be synergistic for nitrogen doping in N,S CDs. The optimal N,S-CDs were successfully employed as good multicolor cell imaging probes due to their fine dispersion in water, excitation-dependent emission, excellent fluorescence stability and low toxicity. Besides, such N,S CDs showed a wide detection range and excellent accuracy as fluorescent sensors for Fe(3+) ions. PMID- 25297985 TI - In vivo remodelling of vascularizing engineered tissues. AB - A critical aspect of creating vascularized tissues is the remodelling that occurs in vivo, driven in large part by the host response to the tissue construct. Rather than a simple inflammatory response, a beneficial tissue remodelling response results in the formation of vascularised tissue. The characteristics and dynamics of this response are slowly being elucidated, especially as they are modulated by the complex interaction between the biomaterial and cellular components of the tissue constructs and the host. This process has elements that are similar to both wound healing and tumour development, and its features are illustrated by reference to the bottom-up generation of a tissue using modular constructs. These modular constructs consist of mesenchymal stromal cells (MSC) embedded in endothelial cell (EC)-covered collagen gel rods that are a few hundred microns in size. Particular attention is paid to the role of hypoxia and macrophage recruitment, as well as the paracrine effects of the MSC and EC in this host response. PMID- 25297984 TI - CHD1 and CHD2 are positive regulators of HIV-1 gene expression. AB - BACKGROUND: Retroviruses encode a very limited number of proteins and therefore must exploit a wide variety of host proteins for completion of their lifecycle. METHODS: We performed an insertional mutagenesis screen to identify novel cellular regulators of retroviral replication. RESULTS: This approach identified the ATP-dependent chromatin remodeler, chromodomain helicase DNA-binding protein 2 (CHD2), as well as the highly related CHD1 protein, as positive regulators of both MLV and HIV-1 replication in rodent and human cells. RNAi knockdown of either CHD2 or the related CHD1 protein, in human cells resulted in a block to infection by HIV-1, specifically at the level of transcription. CONCLUSIONS: These results demonstrate that CHD1 and CHD2 can act as positive regulators of HIV-1 gene expression. PMID- 25297986 TI - Left ventricular lateral wall pseudoaneurysm presented with decompensated heart failure. PMID- 25297987 TI - Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration-response curves reflect differential coupling to G proteins. AB - BACKGROUND AND PURPOSE: In a recently conducted phase III clinical trial, RELAX AHF, serelaxin infusion over 48 h improved short- and long-term clinical outcomes in patients with acute heart failure. In this study we used human primary cells from the umbilical vasculature to better understand the signalling mechanisms activated by serelaxin. EXPERIMENTAL APPROACH: We examined the acute effects of serelaxin on signal transduction mechanisms in primary human umbilical vascular cells and its chronic actions on markers of cardiovascular function and disease. KEY RESULTS: The RXFP1 receptor, the cognate serelaxin receptor, was expressed at the cell surface in HUVECs and human umbilical vein smooth muscle cells (HUVSMCs), human umbilical artery smooth muscle cells (HUASMCs) and human cardiac fibroblasts (HCFs), but not human umbilical artery endothelial cells. In HUVECs and HUVSMCs, serelaxin increased cAMP, cGMP accumulation and pERK1/2, and the concentration-response curves (CRCs) were bell-shaped. Similar bell-shaped CRCs for cGMP and pERK1/2 were observed in HCFs, whereas in HUASMCs, serelaxin increased cAMP, cGMP and pERK1/2 with sigmoidal CRCs. Galphai/o and lipid raft disruption, but not Galphas inhibition, altered the serelaxin CRC for cAMP and cGMP accumulation in HUVSMC but not HUASMC. Longer term serelaxin exposure increased the expression of neuronal NOS, VEGF, ETbeta receptors and MMPs (gelatinases) in RXFP1 receptor-expressing cells. CONCLUSIONS AND IMPLICATIONS: Serelaxin caused acute and chronic changes in human umbilical vascular cells that were cell background dependent. Bell-shaped CRCs that were observed only in venous cells and fibroblasts involved Galphai/o located within membrane lipid rafts. PMID- 25297988 TI - The beneficial fungus Piriformospora indica protects Arabidopsis from Verticillium dahliae infection by downregulation plant defense responses. AB - BACKGROUND: Verticillium dahliae (Vd) is a soil-borne vascular pathogen which causes severe wilt symptoms in a wide range of plants. The microsclerotia produced by the pathogen survive in soil for more than 15 years. RESULTS: Here we demonstrate that an exudate preparation induces cytoplasmic calcium elevation in Arabidopsis roots, and the disease development requires the ethylene-activated transcription factor EIN3. Furthermore, the beneficial endophytic fungus Piriformospora indica (Pi) significantly reduced Vd-mediated disease development in Arabidopsis. Pi inhibited the growth of Vd in a dual culture on PDA agar plates and pretreatment of Arabidopsis roots with Pi protected plants from Vd infection. The Pi-pretreated plants grew better after Vd infection and the production of Vd microsclerotia was dramatically reduced, all without activating stress hormones and defense genes in the host. CONCLUSIONS: We conclude that Pi is an efficient biocontrol agent that protects Arabidopsis from Vd infection. Our data demonstrate that Vd growth is restricted in the presence of Pi and the additional signals from Pi must participate in the regulation of the immune response against Vd. PMID- 25297989 TI - Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial. AB - PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents. PMID- 25297990 TI - Risk factors for 6-month continuation of S-1 adjuvant chemotherapy for resected pancreatic cancer. AB - BACKGROUND: The factors which affect the 6-month continuation of adjuvant chemotherapy with S-1 have not been fully evaluated in pancreatic cancer. The objective of this retrospective study was to clarify the risk factors for the discontinuation of S-1 adjuvant chemotherapy after 6 months of treatment. METHODS: The study included patients who underwent curative surgery for pancreatic cancer, were diagnosed with stage II or III disease, had a serum creatinine level <=1.2 mg/dl and received adjuvant S-1 between June 2007 and March 2014. RESULTS: Forty patients were eligible for the present study. A comparison of the 6-month continuation stratified by each clinical factor using the log-rank test revealed a significant difference in the creatinine clearance (CCr) between the patients who continued and discontinued the treatment. A CCr of 60 ml/min was regarded as a critical point. The uni- and multivariate Cox's proportional hazard analyses demonstrated that the CCr was the only significant independent predictive factor. The 6-month continuation rate was 70.8 % in the patients with a CCr >=60 ml/min and was 25.0 % in patients with a CCr <60 ml/min (P = 0.008). The patients with a CCr <60 ml/min developed adverse events more frequently and earlier than those with a CCr >=60 ml/min. CONCLUSIONS: A CCr < 60 ml/min was a significant risk factor for the 6-month discontinuation of S-1 adjuvant chemotherapy in pancreatic cancer patients, even though the renal function was judged to be normal based on the serum creatinine level. Careful attention is therefore required to improve the S-1 continuation in patients with a CCr < 60 ml/min. PMID- 25297992 TI - Tumor necrosis factor alpha and interleukin-6 facilitate corneal lymphangiogenesis in response to herpes simplex virus 1 infection. AB - Herpes simplex virus 1 (HSV-1) is a common human pathogen of clinical significance due to its association with vision impairment and encephalitis. In a mouse model of ocular neovascularization, we have previously shown that HSV-1 elicits the genesis of lymphatic vessels into the cornea proper through epithelial cell expression of vascular endothelial growth factor A (VEGFA) dependent upon expression of VEGFR2 during acute infection. We hypothesized that other factors may be involved in lymphangiogenesis, with proinflammatory cytokines as the leading candidates. In the absence of infection or inflammation, intrastromal administration of tumor necrosis factor alpha (TNF-alpha) coupled with VEGFA elicited lymphatic vessel genesis significantly above either factor alone as well as a vehicle control. Consistent with this observation, anti-TNF alpha antibody (Ab) blocked HSV-1-mediated corneal lymphangiogenesis within the first 5 days postinfection. However, TNF-alpha-deficient (TNF-alpha(-/-)) mice displayed a level of corneal vessel growth similar to that shown by wild-type (WT) controls. To investigate the likely redundant nature of cytokines, PCR array analysis of HSV-1-infected TNF-alpha(-/-) mice was conducted, and it revealed several factors elevated above those found in HSV-1-infected WT mice, including interleukin-1beta (IL-1beta), platelet-derived growth factor, angiopoietin 2, insulin-like growth factor 2, and IL-6. Subconjunctival administration of neutralizing Ab to IL-6 blocked lymphangiogenesis in TNF-alpha(-/-) mice. Whereas the cornea levels of IL-6 were significantly reduced, there was no appreciable change in the level of IL-1beta or other proangiogenic factors analyzed. Collectively, the results suggest in addition to VEGFA, TNF-alpha and IL-6 promote and likely synergize with VEGFA in corneal lymphangiogenesis during acute HSV-1 infection. IMPORTANCE: We have identified at least two proinflammatory cytokines expressed locally that are involved in the genesis of lymphatic vessels in the normally avascular cornea in response to HSV-1 infection. This finding provides the basis to target IL-6 and TNF-alpha as additional proangiogenic factors in the cornea during the development of herpetic stromal keratitis as a means to alleviate further neovascularization and tissue pathology associated with the host immune response to the pathogen. PMID- 25297993 TI - Complex expression of the UL136 gene of human cytomegalovirus results in multiple protein isoforms with unique roles in replication. AB - Human cytomegalovirus (HCMV) is a complex DNA virus with a 230-kb genome encoding 170 and up to 750 proteins. The upper limit of this coding capacity suggests the evolution of complex mechanisms to substantially increase the coding potential from the 230-kb genome. Our work examines the complexity of one gene, UL136, encoded within the ULb' region of the genome that is lost during serial passage of HCMV in cultured fibroblasts. UL136 is expressed as five protein isoforms. We mapped these isoforms and demonstrate that they originate from both a complex transcriptional profile and, possibly, the usage of multiple translation initiation sites. Intriguingly, the pUL136 isoforms exhibited distinct subcellular distributions with varying association with the Golgi apparatus. The subcellular localization of membrane-bound isoforms of UL136 differed between when they were expressed exogenously and when they were expressed in the context of viral infection, suggesting that the trafficking of these isoforms is mediated by infection-specific factors. While UL136, like most ULb' genes, was dispensable for replication in fibroblasts, the soluble 23- and 19-kDa isoforms suppressed virus replication. In CD34(+) hematopoietic progenitor cells (HPCs) infected in vitro, disruption of the 23- and 19-kDa isoforms resulted in increased replication and a loss of the latency phenotype, similar to the effects of the UL138 latency determinant encoded within the same genetic locus. Our work suggests a complex interplay between the UL136 isoforms which balances viral replication in multiple cell types and likely contributes to the cell type dependent phenotypes of the UL133/8 locus and the outcome of HCMV infection. IMPORTANCE: HCMV is a significant cause of morbidity in immunocompromised individuals, including transplant patients. The lifelong persistence of the virus results in a high seroprevalence worldwide and may contribute to age-related pathologies, such as atherosclerosis. The mechanisms of viral persistence are poorly understood; however, understanding the molecular basis of persistence is imperative for the development of new treatments. In this work, we characterize a complex HCMV gene, UL136, which is expressed as five protein isoforms. These isoforms arise predominantly from complex transcriptional mechanisms, which contribute to an increased coding capacity of the virus. Further, the UL136 isoforms oppose the activity of one another to balance HCMV replication in multiple cell types. We identify soluble isoforms of UL136 that function to suppress virus replication in fibroblasts and in CD34(+) HPCs for latency. PMID- 25297994 TI - Unabated adenovirus replication following activation of the cGAS/STING-dependent antiviral response in human cells. AB - The cGAS/STING DNA sensing complex has recently been established as a predominant pathogen recognition receptor (PRR) for DNA-directed type I interferon (IFN) innate immune activation. Using replication-defective adenovirus vectors and replication-competent wild-type adenovirus, we have modeled the influence of the cGAS/STING cascade in permissive human cell lines (A549, HeLa, ARPE19, and THP1). Wild-type adenovirus induced efficient early activation of the cGAS/STING cascade in a cell-specific manner. In all responsive cell lines, cGAS/STING short hairpin RNA (shRNA) knockdown resulted in a loss of TBK1 and interferon response factor 3 (IRF3) activation, a lack of beta interferon transcript induction, loss of interferon-dependent STAT1 activation, and diminished induction of interferon stimulated genes (ISGs). Adenoviruses that infect through the coxsackievirus adenovirus receptor (CAR) (Ad2 and Ad5) and the CD46 (Ad35) and desmoglein-2 (Ad7) viral receptors all induce the cGAS/STING/TBK1/IRF3 cascade. The magnitude of the IRF3/IFN/ISG antiviral response was strongly influenced by serotype, with Ad35>Ad7>Ad2. For each serotype, no enhancement of viral DNA replication or virus production occurred in cGAS or STING shRNA-targeted cell line pools. We found no replication advantage in permissive cell lines that do not trigger the cGAS/STING cascade following infection. The cGAS/STING/TBK1/IRF3 cascade was not a direct target of viral antihost strategies, and we found no evidence that Ad stimulation of the cGAS/STING DNA response had an impact on viral replication efficiency. IMPORTANCE: This study shows for the first time that the cGAS DNA sensor directs a dominant IRF3/IFN/ISG antiviral response to adenovirus in human cell lines. Activation of cGAS occurs with viruses that infect through different high affinity receptors (CAR, CD46, and desmoglein-2), and the magnitude of the cGAS/STING DNA response cascade is influenced by serotype-specific functions. Furthermore, activation of the cGAS cascade occurred in a cell-specific manner. Activation of the cGAS/STING response did not impact viral replication, and viral immune evasion strategies did not target the cGAS/STING/TBK1/IRF3 cascade. These studies provide novel insight into the early innate recognition response to adenovirus. PMID- 25297995 TI - The VP40 protein of Marburg virus exhibits impaired budding and increased sensitivity to human tetherin following mouse adaptation. AB - The Marburg virus VP40 protein is a viral matrix protein that spontaneously buds from cells. It also functions as an interferon (IFN) signaling antagonist by targeting Janus kinase 1 (JAK1). A previous study demonstrated that the VP40 protein of the Ravn strain of Marburg virus (Ravn virus [RAVV]) failed to block IFN signaling in mouse cells, whereas the mouse-adapted RAVV (maRAVV) VP40 acquired the ability to inhibit IFN responses in mouse cells. The increased IFN antagonist function of maRAVV VP40 mapped to residues 57 and 165, which were mutated during the mouse adaptation process. In the present study, we demonstrate that maRAVV VP40 lost the capacity to efficiently bud from human cell lines, despite the fact that both parental and maRAVV VP40s bud efficiently from mouse cell lines. The impaired budding in human cells corresponds with the appearance of protrusions on the surface of maRAVV VP40-expressing Huh7 cells and with an increased sensitivity of maRAVV VP40 to restriction by human tetherin but not mouse tetherin. However, transfer of the human tetherin cytoplasmic tail to mouse tetherin restored restriction of maRAVV VP40. Residues 57 and 165 were demonstrated to contribute to the failure of maRAVV VP40 to bud from human cells, and residue 57 was demonstrated to alter VP40 oligomerization, as assessed by coprecipitation assay, and to determine sensitivity to human tetherin. This suggests that RAVV VP40 acquired, during adaptation to mice, changes in its oligomerization potential that enhanced IFN antagonist function. However, this new capacity impaired RAVV VP40 budding from human cells. IMPORTANCE: Filoviruses, which include Marburg viruses and Ebola viruses, are zoonotic pathogens that cause severe disease in humans and nonhuman primates but do not cause similar disease in wild-type laboratory strains of mice unless first adapted to these animals. Although mouse adaptation has been used as a method to develop small animal models of pathogenesis, the molecular determinants associated with filovirus mouse adaptation are poorly understood. Our study demonstrates how genetic changes that accrued during mouse adaptation of the Ravn strain of Marburg virus have impacted the budding function of the viral VP40 matrix protein. Strikingly, we find impairment of mouse-adapted VP40 budding function in human but not mouse cell lines, and we correlate the impairment with an increased sensitivity of VP40 to restriction by human but not mouse tetherin and with changes in VP40 oligomerization. These data suggest that there are functional costs associated with filovirus adaptation to new hosts and implicate tetherin as a filovirus host restriction factor. PMID- 25297996 TI - Putative domain-domain interactions in the vesicular stomatitis virus L polymerase protein appendage region. AB - The multidomain polymerase protein (L) of nonsegmented negative-strand (NNS) RNA viruses catalyzes transcription and replication of the virus genome. The N terminal half of the protein forms a ring-like polymerase structure, while the C terminal half encoding viral mRNA transcript modifications consists of a flexible appendage with three distinct globular domains. To gain insight into putative transient interactions between L domains during viral RNA synthesis, we exchanged each of the four distinct regions encompassing the appendage region of vesicular stomatitis virus (VSV) Indiana serotype L protein with their counterparts from VSV New Jersey and analyzed effects on virus polymerase activity in a minigenome system. The methyltransferase domain exchange yielded a fully active polymerase protein, which functioned as well as wild-type L in the context of a recombinant virus. Exchange of the downstream C-terminal nonconserved region abolished activity, but coexchanging it with the methyltransferase domain generated a polymerase favoring replicase over transcriptase activity, providing strong evidence of interaction between these two regions. Exchange of the capping enzyme domain or the adjacent nonconserved region thought to function as an "unstructured" linker also abrogated polymerase activity even when either domain was coexchanged with other appendage domains. Further probing of the putative linker segment using in-frame enhanced green fluorescent protein (EGFP) insertions similarly abrogated activity. We discuss the implications of these findings with regard to L protein appendage domain structure and putative domain domain interactions required for polymerase function. IMPORTANCE: NNS viruses include many well-known human pathogens (e.g., rabies, measles, and Ebola viruses), as well as emerging viral threats (e.g., Nipah and Hendra viruses). These viruses all encode a large L polymerase protein similarly organized into multiple domains that work in concert to enable virus genome transcription and replication. But how the unique L protein carries out the multiplicity of individual steps in these two distinct processes is poorly understood. Using two different approaches, i.e., exchanging individual domains in the C-terminal appendage region of the protein between two closely related VSV serotypes and inserting unrelated protein domains, we shed light on requirements for domain domain interactions and domain contiguity in polymerase function. These findings further our understanding of the conformational dynamics of NNS L polymerase proteins, which play an essential role in the pathogenic properties of these viruses and represent attractive targets for the development of antiviral measures. PMID- 25297997 TI - Recombinant modified vaccinia virus Ankara generating excess early double stranded RNA transiently activates protein kinase R and triggers enhanced innate immune responses. AB - Double-stranded RNA (dsRNA) is an important molecular pattern associated with viral infection and is detected by various extra- and intracellular recognition molecules. Poxviruses have evolved to avoid producing dsRNA early in infection but generate significant amounts of dsRNA late in infection due to convergent transcription of late genes. Protein kinase R (PKR) is activated by dsRNA and triggers major cellular defenses against viral infection, including protein synthesis shutdown, apoptosis, and type I interferon (IFN-I) production. The poxviral E3 protein binds and sequesters viral dsRNA and is a major antagonist of the PKR pathway. We found that the highly replication-restricted modified vaccinia virus Ankara (MVA) engineered to produce excess amounts of dsRNA early in infection showed enhanced induction of IFN-beta in murine and human cells in the presence of an intact E3L gene. IFN-beta induction required a minimum overlap length of 300 bp between early complementary transcripts and was strongly PKR dependent. Excess early dsRNA produced by MVA activated PKR early but transiently in murine cells and induced enhanced systemic levels of IFN-alpha, IFN-gamma, and other cytokines and chemokines in mice in a largely PKR-dependent manner. Replication-competent chorioallantois vaccinia virus Ankara (CVA) generating excess early dsRNA also enhanced IFN-I production and was apathogenic in mice even at very high doses but showed no in vitro host range defect. Thus, genetically adjuvanting MVA and CVA to generate excess early dsRNA is an effective method to enhance innate immune stimulation by orthopoxvirus vectors and to attenuate replicating vaccinia virus in vivo. IMPORTANCE: Efficient cellular sensing of pathogen-specific components, including double-stranded RNA (dsRNA), is an important prerequisite of an effective antiviral immune response. The prototype poxvirus vaccinia virus (VACV) and its derivative modified vaccinia virus Ankara (MVA) produce dsRNA as a by-product of viral transcription. We found that inhibition of cellular dsRNA recognition established by the virus-encoded proteins E3 and K3 can be overcome by directing viral overexpression of dsRNA early in infection without compromising replication of MVA in permissive cells. Early dsRNA induced transient activation of the cellular dsRNA sensor protein kinase R (PKR), resulting in enhanced production of interferons and cytokines in cells and mice. Enhancing the capacity of MVA to activate the innate immune system is an important approach to further improve the immunogenicity of this promising vaccine vector. PMID- 25297999 TI - Cardiac rehabilitation-mediated molecular mechanisms of cardiovascular protection. PMID- 25297998 TI - Blocking ESCRT-mediated envelopment inhibits microtubule-dependent trafficking of alphaherpesviruses in vitro. AB - Herpes simplex virus (HSV) and, as reported here, pseudorabies virus (PRV) utilize the ESCRT apparatus to drive cytoplasmic envelopment of their capsids. Here, we demonstrate that blocking ESCRT-mediated envelopment using the dominant negative inhibitor Vps4A-EQ (Vps4A in which glutamate [E] at position 228 in the ATPase active site is replaced by a glutamine [Q]) reduced the ability of HSV and PRV particles to subsequently traffic along microtubules in vitro. HSV and PRV capsid-associated particles with bound green fluorescent protein (GFP)-labeled Vps4A-EQ were readily detected by fluorescence microscopy in cytoplasmic extracts of infected cells. These Vps4A-EQ-associated capsid-containing particles bound to microtubules in vitro but were unable to traffic along them. Using a PRV strain expressing a fluorescent capsid and a fluorescently tagged form of the envelope protein gD, we found that similar numbers of gD-positive and gD-negative capsid associated particles accumulated in cytoplasmic extracts under our conditions. Both classes of PRV particle bound to microtubules in vitro with comparable efficiency, and similar results were obtained for HSV using anti-gD immunostaining. The gD-positive and gD-negative PRV capsids were both capable of trafficking along microtubules in vitro; however, motile gD-positive particles were less numerous and their trafficking was more sensitive to the inhibitory effects of Vps4A-EQ. We discuss our data in the context of microtubule-mediated trafficking of naked and enveloped alphaherpesvirus capsids. IMPORTANCE: The alphaherpesviruses include several important human pathogens. These viruses utilize microtubule-mediated transport to travel through the cell cytoplasm; however, the molecular mechanisms of trafficking are not well understood. In this study, we have used a cell-free system to examine the requirements for microtubule trafficking and have attempted to distinguish between the movement of so-called "naked" and membrane-associated cytoplasmic alphaherpesvirus capsids. PMID- 25298001 TI - Multi-stage decomposition of 5-aminotetrazole derivatives: kinetics and reaction channels for the rate-limiting steps. AB - The thermal behavior, decomposition kinetics and mechanisms of 1-amino-1 (tetrazol-5-yldiazenyl) guanidine (tetrazene) and 2-(tetrazol-5-yldiazenyl) guanidine (MTX-1) have been investigated using DSC, TG techniques, and quantum chemical calculations. It has been found that MTX-1 is much more stable than tetrazene and MTX-1, and both of them decompose in three steps with different kinetic parameters. Tetrazene is melted-dehydrated at 128.4 degrees C with a heat absorption of 50 J g(-1) and then it starts to decompose at around 118.6 degrees C with a peak temperature of 126.3 degrees C covered by a heat release of 1037 J g(-1) at a heating rate of 1.0 degrees C min(-1), while MTX-1 starts at 167.7 degrees C with a main peak of 191.1 degrees C covered by a heat change of 1829 J g(-1) under the same conditions. The activation energy is almost the same for their first decomposition steps (225 kJ mol(-1)), which are controlled by a three dimensional nucleation and growth model (A3). The mechanisms of the rate-limiting steps are supported by quantum chemical calculations. They could undergo a similar rate-limiting chemical process producing 1H-tetrazole and N2 for both cases, while the former also produces aminocyanamide and the latter produces cyanamide. PMID- 25298000 TI - In vivo experimental intervertebral disc degeneration induced by bleomycin in the rhesus monkey. AB - BACKGROUND: Recently, biological therapies for early intervention of degenerative disc disease have been introduced and developed; however, a functional animal model that mimics slowly progressive disc degeneration of humans does not exist. The objective of this study was to establish a slowly progressive and reproducible intervertebral disc (IVD) degeneration model. METHODS: The subchondral bone adjacent to the lumbar IVDs (L3/4 and L5/6) of ten rhesus monkeys was randomly injected with 4 ml bleomycin solution (1.5 mg/ml), or 4 ml phosphate buffer saline (PBS) per segment as control, respectively. The degenerative process was investigated by using radiography and T1rho MR imaging at 1, 3, 6, 9, 12 and 15 months postoperatively. Histological scoring, Sulfated Glycosaminoglycans (GAGs) analysis and real-time PCR were performed at 15 months. The correlation between histological score, GAGs and T1rho values were also analyzed. RESULTS: The results showed that the mean T1rho values of nucleus pulposus (NP) and annulus fibrosus (AF) in the bleomycin group significantly decreased after 3 and 6 months respectively, followed by slowly decrease until at 15 months. At 15 months, the histological scores was significantly higher, and the GAGs of NP was significantly lower in the bleomycin group, compared with the control group (P<0.05). The results of real-time PCR revealed a significant increase in matrix metalloprotease (MMP)-3, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, tumor necrosis factor alpha, interleukin 1beta, interleukin-6 expressions, transforming growth factor (TGF-beta1) and marked reduction in aggrecan, type II collagen, von willebrand factor (vWF) expressions at the mRNA levels in the bleomycin group. Spearman correlation analysis showed a strong positive correlation between GAGs and T1rho values of NP (r =0.740, P<0.01), and a significant inverse correlation between histological score and T1rho values of NP and AF (r=-0.761, r=-0.729, respectively, P<0.01). CONCLUSIONS: Injection of bleomycin into the subchondral bone adjacent to the lumbar IVDs of rhesus monkeys can results in mild, slowly progressive disc degeneration, which mimics the onset of human disc degeneration. T1rho MR imaging is an effective and noninvasive technique for assessment of early stage disc degeneration. PMID- 25298003 TI - [Analysis of heart rate variability. Mathematical description and practical application]. AB - The analysis of heart rate variability (HRV) has recently become established as a non-invasive measurement for estimation of demands on the cardiovascular system. The HRV reflects the interaction of the sympathetic and parasympathetic nervous systems and allows the influence of the autonomic nervous system on the regulation of the cardiovascular system to be mathematically described. This review explicates the analysis method of HRV for time, frequency and non-linear methods as well as the range of parameters and the demand on acquisition time. The necessity and possibilities of artefact correction and advice for the selection of a reasonable acquisition period are discussed and standard values for selected HRV parameters are presented. PMID- 25298002 TI - Interactions of amelogenin with phospholipids. AB - Amelogenin protein has the potential to interact with other enamel matrix proteins, mineral, and cell surfaces. We investigated the interactions of recombinant amelogenin rP172 with small unilamellar vesicles as model membranes, toward the goal of understanding the mechanisms of amelogenin-cell interactions during amelogenesis. Dynamic light scattering (DLS), fluorescence spectroscopy, circular dichroism (CD), and nuclear magnetic resonance (NMR) were used. In the presence of phospholipid vesicles, a blue shift in the Trp fluorescence emission maxima of rP172 was observed (~334 nm) and the Trp residues of rP172 were inaccessible to the aqueous quencher acrylamide. DLS studies indicated complexation of rP172 and phospholipids, although the possibility of fusion of phospholipids following amelogenin addition cannot be ruled out. NMR and CD studies revealed a disorder-order transition of rP172 in a model membrane environment. Strong fluorescence resonance energy transfer from Trp in rP172 to DNS-bound-phospholipid was observed, and fluorescence polarization studies indicated that rP172 interacted with the hydrophobic core region of model membranes. Our data suggest that amelogenin has ability to interact with phospholipids and that such interactions may play key roles in enamel biomineralization as well as reported amelogenin signaling activities. PMID- 25298004 TI - Epigenetic programming by early-life stress: Evidence from human populations. AB - BACKGROUND: A substantial body of experimental and epidemiological evidence has been accumulated suggesting that stressful events in early life including acute perinatal stress, maternal deprivation or separation, and variation in maternal care may lead to neuroendocrine perturbations thereby affecting reproductive performance, cognitive functions, and stress responses as well as the risk for infectious, cardio-metabolic and psychiatric diseases in later life. RESULTS: Findings from recent studies based on both genome-wide and candidate gene approaches highlighted the importance of mechanisms that are involved in epigenetic regulation of gene expression, such as DNA methylation, histone modifications, and non-coding RNAs, in the long-term effects of exposure to stress in early life. CONCLUSIONS: This review is focused on the findings from human studies indicating the role of epigenetic mechanisms in the causal link between early-life stress and later-life health outcomes. PMID- 25298005 TI - Effect of age and other factors on macular pigment optical density measured with resonance Raman spectroscopy. PMID- 25298006 TI - Probiotic Lactobacillus rhamnosus GG (LGG) and prebiotic prevent neonatal inflammation-induced visceral hypersensitivity in adult rats. AB - BACKGROUND: Increasing evidence indicates a positive effect of probiotics on the nervous system. The objective of this study was to determine if probiotic Lactobacillus rhamnosus GG (LGG) and/or prebiotics polydextrose/galactooligosaccharide (PDX/GOS) can alter the colonic sensitivity in a neonatal rat model of chronic visceral hyperalgesia and to determine whether altered sensitivity is associated with changes in neurotransmitter levels in the brain. METHODS: Chronic visceral hyperalgesia was induced in rats by intracolonic administration of zymosan for 3 days during postnatal day 14-16 (P14-P16). After weaning (P21), these pups were divided into groups that received either (1) control diet (CD), (2) PDX/GOS, (3) LGG, or (4) PDX/GOS + LGG. These diets were continued until visceral sensitivity was tested at P60. The viscero-motor response (VMR) to graded colorectal distension (CRD) was determined by measuring the electromyographic (EMG) activity from the abdominal external oblique muscles. The levels of neurotransmitters and biogenic amines were quantified in the frontal cortex, subcortex, brain stem, and cerebellum. KEY RESULTS: At P60, the VMR to CRD in the neonatal zymosan-treated rats was significantly higher than neonatal saline-treated rats. In contrast, neonatal zymosan-treated rats that received PDX/GOS or LGG did not exhibit visceral hyperalgesia. The levels of serotonin, noradrenaline, and dopamine were significantly altered in LGG-treated rats compared to other groups. CONCLUSIONS & INFERENCES: Results document that in rats LGG can attenuate neonatally induced chronic visceral pain measured in adulthood. Prolonged intake of LGG alters some key brain neurotransmitters and biogenic amines that could be involved in pain modulation. PMID- 25298007 TI - The road not taken. PMID- 25298008 TI - Are people at risk of psychosis also at risk of suicide and self-harm? A systematic review and meta-analysis. AB - BACKGROUND: Suicide and self-harm are prevalent in individuals diagnosed with psychotic disorders. However, less is known about the level of self-injurious thinking and behaviour in those individuals deemed to be at ultra-high risk (UHR) of developing psychosis, despite growing clinical interest in this population. This review provides a synthesis of the extant literature concerning the prevalence of self-harm and suicidality in the UHR population, and the predictors and correlates associated with these events. METHOD: A search of electronic databases was undertaken by two independent reviewers. A meta-analysis of prevalence was undertaken for self-harm, suicidal ideation and behaviour. A narrative review was also undertaken of analyses examining predictors and correlates of self-harm and suicidality. RESULTS: Twenty-one eligible studies were identified. The meta-analyses suggested a high prevalence of recent suicidal ideation (66%), lifetime self-harm (49%) and lifetime suicide attempts (18%). Co morbid psychiatric problems, mood variability and a family history of psychiatric problems were among the factors associated with self-harm and suicide risk. CONCLUSIONS: Results suggest that self-harm and suicidality are highly prevalent in the UHR population, with rates similar to those observed in samples with diagnosed psychotic disorders. Appropriate monitoring and managing of suicide risk will be important for services working with the UHR population. Further research in this area is urgently needed considering the high rates identified. PMID- 25298009 TI - Beautiful friendship: Social sharing of emotions improves subjective feelings and activates the neural reward circuitry. AB - Humans have a strong tendency to affiliate with other people, especially in emotional situations. Here, we suggest that a critical mechanism underlying this tendency is that socially sharing emotional experiences is in itself perceived as hedonically positive and thereby contributes to the regulation of individual emotions. We investigated the effect of social sharing of emotions on subjective feelings and neural activity by having pairs of friends view emotional (negative and positive) and neutral pictures either alone or with the friend. While the two friends remained physically separated throughout the experiment-with one undergoing functional magnetic resonance imaging and the other performing the task in an adjacent room-they were made aware on a trial-by-trial basis whether they were seeing pictures simultaneously with their friend (shared) or alone (unshared). Ratings of subjective feelings were improved significantly when participants viewed emotional pictures together than alone, an effect that was accompanied by activity increase in ventral striatum and medial orbitofrontal cortex, two important components of the reward circuitry. Because these effects occurred without any communication or interaction between the friends, they point to an important proximate explanation for the basic human motivation to affiliate with others, particularly in emotional situations. PMID- 25298011 TI - Emergence delirium is related to the invasiveness of strabismus surgery in preschool-age children. AB - OBJECTIVES: To investigate the correlation between preoperative anxiety and emergence delirium (ED), and to identify other factors that contribute to ED (such as invasiveness of surgery), in preschool-age paediatric patients undergoing strabismus surgery. METHODS: This prospective observational study enrolled Korean children (aged 2-5 years), scheduled for strabismus surgery. After completing the modified Yale Preoperative Anxiety Scale, general anaesthesia was induced. Postoperatively, Pediatric Anesthesia Emergence Delirium (PAED) scores (used as an index of the degree of ED) and a four-point delirium scale (ED incidence), were collected and measured every 5 min. Patients were categorized according to the degree of surgical invasiveness: group U-S, single muscle correction in a unilateral eye; group U-M, multiple-muscle correction in a unilateral eye; group B-S, single-muscle correction in bilateral eyes; group B-M, multiple-muscle correction in bilateral eyes. RESULTS: A total of 90 paediatric patients participated in the study. Maximum PAED scores did not correlate with the presence of preoperative anxiety. The maximum PAED score of group B-M was significantly higher than scores observed in other groups. CONCLUSIONS: Preoperative anxiety was not related to ED in preschool-age paediatric patients undergoing strabismus surgery. The incidence and severity of ED was higher in patients who underwent more complicated strabismus surgery, compared with those undergoing simpler procedures. PMID- 25298010 TI - Is moral beauty different from facial beauty? Evidence from an fMRI study. AB - Is moral beauty different from facial beauty? Two functional magnetic resonance imaging experiments were performed to answer this question. Experiment 1 investigated the network of moral aesthetic judgments and facial aesthetic judgments. Participants performed aesthetic judgments and gender judgments on both faces and scenes containing moral acts. The conjunction analysis of the contrasts 'facial aesthetic judgment > facial gender judgment' and 'scene moral aesthetic judgment > scene gender judgment' identified the common involvement of the orbitofrontal cortex (OFC), inferior temporal gyrus and medial superior frontal gyrus, suggesting that both types of aesthetic judgments are based on the orchestration of perceptual, emotional and cognitive components. Experiment 2 examined the network of facial beauty and moral beauty during implicit perception. Participants performed a non-aesthetic judgment task on both faces (beautiful vs common) and scenes (containing morally beautiful vs neutral information). We observed that facial beauty (beautiful faces > common faces) involved both the cortical reward region OFC and the subcortical reward region putamen, whereas moral beauty (moral beauty scenes > moral neutral scenes) only involved the OFC. Moreover, compared with facial beauty, moral beauty spanned a larger-scale cortical network, indicating more advanced and complex cerebral representations characterizing moral beauty. PMID- 25298012 TI - Construction of target-specific virus-like particles for the delivery of algicidal compounds to harmful algae. AB - Harmful algal blooms (HABs) can lead to substantial socio-economic losses and extensive damage to aquatic ecosystems, drinking water sources and human health. Common algicidal techniques, including ozonation, ultrasonic treatment and dispersion of algae-killing chemicals, are unsatisfactory both economically and ecologically. This study therefore presents a novel alternative strategy for the efficient control of deleterious algae via the use of host-specific virus-like particles (VLPs) combined with chemically synthesized algicidal compounds. The capsid protein of HcRNAV34, a single-stranded RNA virus that infects the toxic dinoflagellate, Heterocapsa circularisquama, was expressed in and purified from Escherichia coli and then self-assembled into VLPs in vitro. Next, the algicidal compound, thiazolidinedione 49 (TD49), was encapsidated into HcRNAV34 VLPs for specific delivery to H. circularisquama. Consequently, HcRNAV34 VLPs demonstrated the same host selectivity as naturally occurring HcRNAV34 virions, while TD49 encapsidated VLPs showed a more potent target-specific algicidal effect than TD49 alone. These results indicate that target-specific VLPs for the delivery of cytotoxic compounds to nuisance algae might provide a safe, environmentally friendly approach for the management of HABs in aquatic ecosystems. PMID- 25298013 TI - Delayed relief of hemifacial spasm after microvascular decompression: can it be avoided? AB - BACKGROUND: Although microvascular decompression (MVD) surgery has been widely accepted as an effective treatment for hemifacial spasm (HFS), delayed relief cases have been frequently reported. Therefore, the value of an immediate redo MVD should be discussed. METHODS: This study included 1,435 HFS patients who underwent MVD with intraoperative abnormal muscle response (AMR) monitoring from 2011 through 2013 at XinHua Hospital. These cases were analyzed retrospectively with emphasis on the postoperative outcomes and introaperative findings. RESULTS: After MVD, 1,384 HFS patients obtained relief immediately. The 51 unrelieved patients underwent AMR monitoring again the next day; this was positive in 48 and negative in 3 patients. These three patients with negative AMR obtained relief spontaneously within a week. Among the 48 positive patients, 31 and 11 were underwent redo MVD within a week and 5-22 months, respectively, and all achieved relief after the second operation. Of the six remainig patients, two obtained relief within 2 months and 4 remained unchanged in the up-to-3-year's follow-up period. In redo MVDs, insufficient decompression of the facial nerve accounted for the failure. Finally, in this database, the immediate postoperative cure rate was 96.4 %; with earlier redo MVD, the final cure rate could be increased to 99.9 %. CONCLUSIONS: Despite being a reasonable remedy for HFS in the hands of an experienced neurosurgeon, sometimes small vessels can be missed while managing the main offending arteries during MVDs, which might account for the delayed relief. Therefore, reexamination of the AMR is necessary for unimproved patients; if a positive result is recorded, an immediate redo MVD is suggested. PMID- 25298014 TI - Knowing is not enough: a qualitative report on HIV testing among heterosexual African-American men. AB - Despite having higher rates of HIV testing than all other racial groups, African Americans continue to be disproportionately affected by the HIV epidemic in the United States. Knowing one's status is the key step to maintaining behavioral changes that could stop the spread of the virus, yet little is known about the individual- and socio-structural-level barriers associated with HIV testing and communication among heterosexual African-American men. To address this and inform the development of an HIV prevention behavioral intervention for heterosexual African-American men, we conducted computerized, structured interviews with 61 men, focus group interviews with 25 men in 5 different groups, and in-depth qualitative interviews with 30 men living in high HIV prevalence neighborhoods in New York City. Results revealed that HIV testing was frequent among the participants. Even with high rates of testing, the men in the study had low levels of HIV knowledge; perceived little risk of HIV; and misused HIV testing as a prevention method. Factors affecting HIV testing, included stigma, relationship dynamics and communication, and societal influences, suggesting that fear, low perception of risk, and HIV stigma may be the biggest barriers to HIV testing. These results also suggest that interventions directed toward African-American heterosexual men must address the use of "testing as prevention" as well as correct misunderstandings of the window period and the meaning of HIV test results, and interventions should focus on communicating about HIV. PMID- 25298015 TI - Assessment of health care cost for complex surgical patients: review of cost, re imbursement and revenue involved in pancreatic surgery at a high-volume academic medical centre. AB - BACKGROUND: Pancreatic surgery is complex with the potential for costly hospitalization. METHODS: A retrospective review of patients undergoing a pancreatic resection was performed. RESULTS: The median age of the study population was 64 years. Half of the cohort was female (51%), and the majority were white (62%). Most patients underwent a pancreaticoduodenectomy (PD) (69%). The pre-operative age-adjusted Charlson comorbidity index was zero for 36% (n = 50), 1 for 31% (n = 43) and >=2 for 33% (n = 45). The Clavien-Dindo grading system for post-operative complication was grade I in 17% (n = 24), whereas 45% (n = 62) were higher grades. The medians direct fixed, direct variable, fixed indirect and total costs were $2476, $15,397, $13,207 and $31,631, respectively. There was a positive contribution margin of $7108, whereas the net margin was a loss of $6790. On univariate analyses, age, type of operation and complication grade were associated with total cost (P <= 0.05), whereas operation type and complication grade were associated with a net margin (P = 0.01). These findings remained significant on multivariate analysis (P < 0.05). CONCLUSIONS: Increased cost, reimbursement and revenue were associated with type of operation and post operative complications. PMID- 25298018 TI - Skull bone metastasis with adjacent leptomeningeal involvement from pleomorphic lobular carcinoma of the breast. PMID- 25298017 TI - A high-resolution LC-MS-based secondary metabolite fingerprint database of marine bacteria. AB - Marine bacteria are the most widely distributed organisms in the ocean environment and produce a wide variety of secondary metabolites. However, traditional screening for bioactive natural compounds is greatly hindered by the lack of a systematic way of cataloguing the chemical profiles of bacterial strains found in nature. Here we present a chemical fingerprint database of marine bacteria based on their secondary metabolite profiles, acquired by high resolution LC-MS. Till now, 1,430 bacterial strains spanning 168 known species collected from different marine environments were cultured and profiled. Using this database, we demonstrated that secondary metabolite profile similarity is approximately, but not always, correlated with taxonomical similarity. We also validated the ability of this database to find species-specific metabolites, as well as to discover known bioactive compounds from previously unknown sources. An online interface to this database, as well as the accompanying software, is provided freely for the community to use. PMID- 25298016 TI - A randomized controlled trial comparing scalable weight loss treatments in primary care. AB - OBJECTIVE: Primary-care (PC) settings may be an opportune place to deliver obesity interventions. Scalable interventions utilizing motivational interviewing (MI), supported by Internet resources, may overcome obstacles to effective obesity treatment dissemination. This study was a randomized controlled trial testing two Web-supported interventions, motivational interviewing (MIC) and nutrition psychoeducation (NPC), an attention-control intervention, in comparison with usual care (UC). METHODS: Eighty-nine overweight/obese patients, with and without binge eating disorder (BED), were randomly assigned to MIC, NPC, or UC for 3 months in PC. Patients were assessed independently at post-treatment and at 3-month follow-up. RESULTS: Weight, triglyceride levels, and depression scores decreased significantly in NPC when compared to UC but not MIC; UC and MIC did not differ significantly. Weight loss results maintained at 3-month follow-up: approximately 25% MIC and NPC patients achieved at least 5% weight loss which did not differ by BED status. Fidelity ratings were high and treatment adherence was associated with weight loss. CONCLUSIONS: This is the first randomized controlled trial in PC testing MI for weight loss to include an attention-control intervention (NPC). NPC, but not MIC, showed a consistent pattern of superior benefits relative to UC. BED status was not associated, but treatment adherence was associated, with weight loss outcomes. PMID- 25298019 TI - Amyotrophic lateral sclerosis surveillance in Baltimore and Philadelphia. AB - INTRODUCTION: Limited epidemiological data on amyotrophic lateral sclerosis (ALS) exist in defined geographic areas in the United States. METHODS: Neurologists submitted case reports for patients under their care between January 1, 2009, and December 31, 2011, who met the El Escorial criteria. Diagnosis was confirmed for a sample of cases by the consulting neurologist. Death certificate data were used for supplemental case identification. RESULTS: The 248 reported cases were most likely to be 50-69 years old, men, white, and non-Hispanic. The total crude average annual incidence rate was 1.46 per 100,000 person-years. CONCLUSIONS: The reported demographic characteristics were consistent with previously published findings. The crude annual incidence was slightly lower than the expected rate of 1.6 but was within the range reported previously (0.7-2.5). These findings help quantify the burden of ALS in the United States. PMID- 25298020 TI - Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements. AB - INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor regulatory sequence interaction, resulting in altered expression of target genes. This study explored the association between single-nucleotide polymorphisms (SNPs) within the ERE-associated sequences and breast cancer progression. METHODS: The ERE-associated sequences throughout the whole genome that have been demonstrated to bind ERalpha in vivo were blasted against online information from SNP data sets and 54 SNPs located adjacent to estrogen-responsive genes were selected for genotyping in two independent cohorts of breast cancer patients: 779 patients in the initial screening stage and another 888 in the validation stage. Deaths due to breast cancer or recurrence of breast cancer were defined as the respective events of interest, and the hazard ratios of individual SNPs were estimated based on the Cox proportional hazards model. Furthermore, functional assays were performed, and information from publicly available genomic data and bioinformatics platforms were used to provide additional evidence for the associations identified in the association analyses. RESULTS: The SNPs at 21q22.3 ERE were significantly associated with overall survival and disease-free survival of patients. Furthermore, these 21q22.3 SNPs (rs2839494 and rs1078272) could affect the binding of this ERE-associated sequence to ERalpha or Rad21 (an ERalpha coactivator), respectively, which resulted in a difference in ERalpha activated expression of the reporter gene. CONCLUSION: These findings support the idea that functional variants in the ERalpha-regulating sequence at 21q22.3 are important in determining breast cancer progression. PMID- 25298021 TI - A metabolomics-driven approach to predict cocoa product consumption by designing a multimetabolite biomarker model in free-living subjects from the PREDIMED study. AB - SCOPE: The aim of the current study was to apply an untargeted metabolomics strategy to characterize a model of cocoa intake biomarkers in a free-living population. METHODS AND RESULTS: An untargeted HPLC-q-ToF-MS based metabolomics approach was applied to human urine from 32 consumers of cocoa or derived products (CC) and 32 matched control subjects with no consumption of cocoa products (NC). The multivariate statistical analysis (OSC-PLS-DA) showed clear differences between CC and NC groups. The discriminant biomarkers identified were mainly related to the metabolic pathways of theobromine and polyphenols, as well as to cocoa processing. Consumption of cocoa products was also associated with reduced urinary excretions of methylglutarylcarnitine, which could be related to effects of cocoa exposure on insulin resistance. To improve the prediction of cocoa consumption, a combined urinary metabolite model was constructed. ROC curves were performed to evaluate the model and individual metabolites. The AUC values (95% CI) for the model were 95.7% (89.8-100%) and 92.6% (81.9-100%) in training and validation sets, respectively, whereas the AUCs for individual metabolites were <90%. CONCLUSIONS: The metabolic signature of cocoa consumption in free-living subjects reveals that combining different metabolites as biomarker models improves prediction of dietary exposure to cocoa. PMID- 25298024 TI - Anomalous surface states modify the size-dependent mechanical properties and fracture of silica nanowires. AB - Molecular dynamics simulations of amorphous silica nanowires under tension were analyzed for size and surface stress effects on mechanical properties and for structural modifications via bond angle distributions. Their fracture behavior was also investigated beyond the elastic limit. The Young's moduli of silica nanowires were predicted to be about 75-100 GPa, depending on the nanowire size. The ultimate strength was calculated to be ~10 GPa, depending on the diameter, which is in excellent agreement with the experiments. The dependence of the Young's modulus on nanowire diameter is explained in terms of surface compressive stress effects. The fracture behavior of nanowires was also found to be influenced by surface compressive stresses. Bond angle distribution analysis of various nanowires reveals significant compressive surface states, as evidenced by the appearance of a secondary peak in the Si-O-Si bond angle distribution at ~97 degrees , which is absent in bulk silica. The strain rate was found to have a negligible effect on the Young's modulus of the silica nanowires, but it has a critical role in determining their fracture mode. PMID- 25298023 TI - Assessing metal contamination from construction and demolition (C&D) waste used to infill wetlands: using Deroceras reticulatum (Mollusca: Gastropoda). AB - Large quantities of construction and demolition waste (C&D) are produced globally every year, with little known about potential environmental impacts. In the present study, the slug, Deroceras reticulatum (Mollusca: Gastropoda) was used as the first biomonitor of metals (Ag, As, Ba, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, Sb, Se, Ti, Tl, V and Zn) on wetlands post infilling with construction and demolition (C&D) waste. The bioaccumulation of As, Ba, Cd, Co, Sb, Se and Tl were found to be significantly elevated in slugs collected on C&D waste when compared to unimproved pastures (control sites), while Mo, Se and Sr had significantly higher concentrations in slugs collected on C&D waste when compared to known contaminated sites (mining locations), indicating the potential hazardous nature of C&D waste to biota. Identifying exact sources for these metals within the waste can be problematic, due to its heterogenic nature. Biomonitors are a useful tool for future monitoring and impact studies, facilitating policy makers and regulations in other countries regarding C&D waste infill. In addition, improving separation of C&D waste to allow increased reuse and recycling is likely to be effective in reducing the volume of waste being used as infill, subsequently decreasing potential metal contamination. PMID- 25298025 TI - Shallow-tunnelling correction factor for use with Wigner-Eyring transition-state theory. AB - We obtain a shallow-tunnelling correction factor for use with Wigner-Eyring transition-state theory (TST). Our starting point is quantum transition state theory (QTST), which approximates the accurate quantum rate as the instantaneous flux through a delocalised transition-state ensemble of ring-polymers. Expanding the ring-polymer potential to second order gives the well-known Wigner tunnelling factor which diverges at the cross-over temperature between deep and shallow tunnelling. Here, we show how to remove this divergence by integrating numerically over the two softest ring-polymer normal modes. This results in a modified Wigner correction factor involving a one-dimensional integral evaluated along a straight line on the potential energy surface. Comparisons with accurate quantum calculations indicate that the newly derived correction factor gives realistic estimates of quantum rate coefficients in the shallow-tunnelling regime. PMID- 25298022 TI - Perceived Barriers and Support Strategies for Reducing Sodium Intake in Patients with Chronic Kidney Disease: a Qualitative Study. AB - BACKGROUND: Reducing sodium intake can prevent cardiovascular complications and further decline of kidney function in patients with chronic kidney disease. However, the vast majority of patients fail to reach an adequate sodium intake, and little is known about why they do not succeed. PURPOSE: This study aims to identify perceived barriers and support strategies for reducing sodium intake among both patients with chronic kidney disease and health-care professionals. METHOD: A purposive sample of 25 patients and 23 health-care professionals from 4 Dutch medical centers attended 8 focus groups. Transcripts were analyzed thematically and afterwards organized according to the phases of behavior change of self-regulation theory. RESULTS: Multiple themes emerged across different phases of behavior change, including the patients' lack of practical knowledge and intrinsic motivation, the maladaptive illness perceptions and refusal skills, the lack of social support and feedback regarding disease progression and sodium intake, and the availability of low-sodium foods. CONCLUSIONS: The results indicate the need for the implementation of support strategies that target specific needs of patients across the whole process of changing and maintaining a low-sodium diet. Special attention should be paid to supporting patients to set sodium-related goals, strengthening intrinsic motivation, providing comprehensive and practical information (e.g., about hidden salt in products), increasing social support, stimulating the self-monitoring of sodium intake and disease progression, and building a supportive patient-professional relationship that encompasses shared decision making and coaching. Moreover, global programs should be implemented to reduce sodium levels in processed foods, introduce sodium related product labels, and increase consumer awareness. PMID- 25298026 TI - Coculture of peripheral blood-derived mesenchymal stem cells and endothelial progenitor cells on strontium-doped calcium polyphosphate scaffolds to generate vascularized engineered bone. AB - Vascularization of engineered bone tissue is critical for ensuring its survival after implantation and it is the primary factor limiting its clinical use. A promising approach is to prevascularize bone grafts in vitro using endothelial progenitor cells (EPC) derived from peripheral blood. Typically, EPC are added together with mesenchymal stem cells (MSC) that differentiate into osteoblasts. One problem with this approach is how to promote traditional tissue engineering bone survival with a minimally invasive method. In this study, we examined the effectiveness of administering to stimulate the release of peripheral blood stem cells and their co-culturing system for generating prevascularized engineered bone. Cells were isolated by Ficoll density gradient centrifugation and identified as EPC and MSC based on morphology, surface markers, and functional analysis. EPC and MSC were cocultured in several different ratios, and cell morphology and tube formation were assessed by microscopy. Expression of osteogenesis and vascularization markers was quantified by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction, and histochemical and immunofluorescence staining. Increasing the proportion of EPC in the coculture system led to greater tube formation and greater expression of the endothelial cell marker CD31. An EPC:MSC ratio of 75:25 gave the highest expression of osteogenesis and angiogenesis markers. Cocultures adhered to a three-dimensional scaffold of strontium-doped calcium polyphosphate and proliferated well. Our findings show that coculturing peripheral blood-derived EPC and MSC may prove useful for generating prevascularized bone tissue for clinical use. PMID- 25298027 TI - Delineating the Epidemiology-Host-Microbe Relationship for Methicillin-Resistant Staphylococcus aureus Infection. PMID- 25298029 TI - Coordination-driven macrocyclization for locking of photo- and thermal cis->trans isomerization of azobenzene. AB - Both trans and cis isomers of azobenzene-linked bis-terpyridine ligand L1 were incorporated in rigid macrocycles linked by Fe(II) (tpy)2 (tpy: terpyridine) units. The complex of the longer trans-L1 is dinuclear [(trans-L1)2 ?Fe(II) 2 ], whereas the complex of the shorter cis-L1 is mononuclear [cis-L1?Fe(II) ]. The complex cis-L1?Fe(II) was not only thermally stable but also photochemically inactive. These results indicate a perfectly locked state of cis-azobenzene. The stable macrocyclic structure of cis-L1?Fe(II) causes locking of the isomerization. To the best of our knowledge, this is first example of dual locking of photo- and thermal isomerization of cis-azobenzene. PMID- 25298030 TI - Order of arrival structures arbuscular mycorrhizal colonization of plants. AB - Priority effects - the impact of a species' arrival on subsequent community development - have been shown to influence species composition in many organisms. Whether priority effects among arbuscular mycorrhizal fungi (AMF) structure fungal root communities is not well understood. Here, we investigated whether priority effects influence the success of two closely related AMF species (Rhizophagus irregularis and Glomus aggregatum), hypothesizing that a resident AMF suppresses invader success, this effect is time-dependent and a resident will experience reduced growth when invaded. We performed two glasshouse experiments using modified pots, which permitted direct inoculation of resident and invading AMF on the roots. We quantified intraradical AMF abundances using quantitative PCR and visual colonization percentages. We found that both fungi suppressed the invading species and that this effect was strongly dependent on the time lag between inoculations. In contrast to our expectations, neither resident AMF was negatively affected by invasion. We show that order of arrival can influence the abundance of AMF species colonizing a host. These priority effects can have important implications for AMF ecology and the use of fungal inocula in sustainable agriculture. PMID- 25298028 TI - Cytotoxic Virulence Predicts Mortality in Nosocomial Pneumonia Due to Methicillin Resistant Staphylococcus aureus. AB - The current study identified bacterial factors that may improve management of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Isolates were obtained from 386 patients enrolled in a randomized, controlled study of antibiotic efficacy. Isolates were screened for production of virulence factors and for vancomycin susceptibility. After adjustment for host factors such as severity of illness and treatment modality, cytotoxic activity was strongly and inversely associated with mortality; however, it had no effect on clinical cure. Isolates having low cytotoxicity, which were derived largely from healthcare associated clones, exhibited a greater prevalence of vancomycin heteroresistance, and they were recovered more often from patients who were older and frailer. Additionally, a clone with low cytotoxic activity was associated with death and poor clinical improvement. Clone specificity and attenuated virulence appear to be associated with outcome. To our knowledge, these are the first correlations between MRSA virulence and mortality in nosocomial pneumonia. PMID- 25298031 TI - The predictive value of allergen skin prick tests and IgE tests at pre-school age: the PACT study. AB - BACKGROUND: Sensitization toward allergens, as determined by skin prick test (SPT) or specific IgE (sIgE), is a predictor for the later presence of allergy related disease (atopic eczema, allergic rhinoconjuctivitis and asthma). However, it is not known whether SPT or sIgE should be the preferred test. The aim of this study was to compare the predictive ability of SPT and sIgE when performed in a general population of 2-yr-old children. METHODS: In a prospective, longitudinal population-based study of children aged 2-6 yr, SPT and sIgE for nine common allergens were performed at 2 yr. Allergy-related disease was evaluated by clinical examination and questionnaire at 2 and 6 yr of age (n = 199). RESULTS: Skin prick test or sIgE was positive in 10.6% and 21.1% in the 2-yr-old children, respectively. The prevalence of allergy-related disease was 25.6% at 2 yr and 25.1% at 6 yr. Half of the cases at 2 yr were transient. Both SPT and sIgE were statistically significant predictors for later allergy-related disease, OR = 6.5 (95% CI 2.3-18.6) and OR = 4.1 (95% CI 1.9-9.0), respectively. Receiver operating characteristic analysis showed that SPT and sIgE had comparable predictive ability for atopic eczema, asthma or any allergy-related disease, but sIgE had better ability to predict later allergic rhinoconjunctivitis. CONCLUSION: Sensitization at 2 yr may be useful predictors of allergy-related disease later in childhood. The predictive ability of SPT and sIgE were mainly comparable; however, it may be that sIgE is the preferred choice in young children when the aim is to predict allergic rhinoconjunctivitis. PMID- 25298032 TI - Clues in the differential diagnosis of primary vs secondary cough, exercise, and sexual headaches. AB - Activity-related headaches can be provoked by Valsalva maneuvers ("cough headache"), prolonged exercise ("exertional headache") and sexual excitation ("sexual headache"). These entities are a challenging diagnostic problem as can be primary or secondary and the etiologies for secondary cases differ depending on the headache type. In this paper we review the clinical clues which help us in the differential diagnosis of patients consulting due to activity-related headaches. Cough headache is the most common in terms of consultation. Primary cough headache should be suspected in patients older than 50 years, if pain does not predominate in the occipital area, if pain lasts seconds, when there are no other symptoms/signs and if indomethacin relieves the headache attacks. Almost half of cough headaches are secondary, usually to a Chiari type I malformation. Secondary cough headache should be suspected in young people, when pain is occipital and lasts longer than one minute, and especially if there are other symptoms/signs and if there is no response to indomethacin. Every patient with cough headache needs cranio-cervical MRI. Primary exercise/sexual headaches are more common than secondary, which should be suspected in women especially with one episode, when there are other symptoms/signs, in people older than 40 and if the headache lasts longer than 24 hours. These patients must have quickly a CT and then brain MRI with MRA or an angioCT to exclude space-occupying lesions or subarachnoid hemorrhage. PMID- 25298033 TI - Differential cellular effects of old and new oral anticoagulants: consequences to the genesis and progression of atherosclerosis. AB - The main purpose of anticoagulants is to diminish fibrin formation, thereby decreasing the risk of venous or arterial thrombosis. Vitamin K antagonist have been used for many decades in order to achieve reduced thrombotic risk, despite major drawbacks of this class of drugs such as cumbersome dossing and monitoring of anticoagulant status. To overcome these drawbacks of VKA, new classes of anticoagulants have been developed including oral anticoagulants for direct inhibition of either thrombin or factor Xa, which can be administrated in a fixed dose without monitoring. Coagulation factors can activate cellular protease activated receptors, thereby inducing cellular processes as inflammation, apoptosis, migration, and fibrosis. Therefore, inhibition of coagulation proteases not only attenuates fibrin formation, but may also influence pathophysiological processes like vascular calcification and atherosclerosis. Animal models revealed that VKA therapy induced both intima and media calcification and accelerated plaque vulnerability, whereas specific and direct inhibition of thrombin or factor Xa attenuated atherosclerosis. In this review we provide an overview of old and new oral anticoagulants, as well discuss potential pleiotropic effects with regard to calcification and atherosclerosis. Although translation from animal model to clinical patients seems difficult at first sight, effort should be made to fully understand the clinical implications of long-term oral anticoagulant therapy on vascular side effects. PMID- 25298034 TI - How I treat smoldering multiple myeloma. AB - Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as "early myeloma." It is defined as either serum M-protein >= 3 g/L or >= 10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. PMID- 25298035 TI - Thrombopoietin/MPL signaling confers growth and survival capacity to CD41 positive cells in a mouse model of Evi1 leukemia. AB - Ecotropic viral integration site 1 (Evi1) is a transcription factor that is highly expressed in hematopoietic stem cells and is crucial for their self renewal capacity. Aberrant expression of Evi1 is observed in 5% to 10% of de novo acute myeloid leukemia (AML) patients and predicts poor prognosis, reflecting multiple leukemogenic properties of Evi1. Here, we show that thrombopoietin (THPO) signaling is implicated in growth and survival of Evi1-expressing cells using a mouse model of Evi1 leukemia. We first identified that the expression of megakaryocytic surface molecules such as ITGA2B (CD41) and the THPO receptor, MPL, positively correlates with EVI1 expression in AML patients. In agreement with this finding, a subpopulation of bone marrow and spleen cells derived from Evi1 leukemia mice expressed both CD41 and Mpl. CD41(+) Evi1 leukemia cells induced secondary leukemia more efficiently than CD41(-) cells in a serial bone marrow transplantation assay. Importantly, the CD41(+) cells predominantly expressing Mpl effectively proliferated and survived on OP9 stromal cells in the presence of THPO via upregulating BCL-xL expression, suggesting an essential role of the THPO/MPL/BCL-xL cascade in enhancing the progression of Evi1 leukemia. These observations provide a novel aspect of the diverse functions of Evi1 in leukemogenesis. PMID- 25298036 TI - The formin DIAPH1 (mDia1) regulates megakaryocyte proplatelet formation by remodeling the actin and microtubule cytoskeletons. AB - Megakaryocytes are highly specialized precursor cells that produce platelets via cytoplasmic extensions called proplatelets. Proplatelet formation (PPF) requires profound changes in microtubule and actin organization. In this work, we demonstrated that DIAPH1 (mDia1), a mammalian homolog of Drosophila diaphanous that works as an effector of the small GTPase Rho, negatively regulates PPF by controlling the dynamics of the actin and microtubule cytoskeletons. Moreover, we showed that inhibition of both DIAPH1 and the Rho-associated protein kinase (Rock)/myosin pathway increased PPF via coordination of both cytoskeletons. We provide evidence that 2 major effectors of the Rho GTPase pathway (DIAPH1 and Rock/myosin II) are involved not only in Rho-mediated stress fibers assembly, but also in the regulation of microtubule stability and dynamics during PPF. PMID- 25298038 TI - Biosimilars: the science of extrapolation. AB - Despite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called "biosimilars") and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars. PMID- 25298037 TI - Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I. AB - Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of alpha-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring alpha-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear. PMID- 25298039 TI - Interleukin 27 inhibits cytotoxic T-lymphocyte-mediated platelet destruction in primary immune thrombocytopenia. AB - Cytotoxic T-lymphocyte (CTL)-mediated platelet destruction and aberrant cytokine profiles play important roles in the pathogenesis of primary immune thrombocytopenia (ITP). Interleukin-27 (IL-27) has pleiotropic immunomodulatory effects. However, the effect of IL-27 on CTL activity in ITP has not been reported. In the present study, platelets from ITP patients were cultured with autologous CTLs in the presence of IL-27. We found that IL-27 could inhibit CTL mediated platelet destruction. In these IL-27-treated CTLs, granzyme B and T-bet expression decreased significantly, whereas granzyme A, perforin, and eomesodermin were not affected. To further investigate the role of granzyme B in CTL-mediated platelet destruction, granzyme B inhibitor was added and platelet apoptosis was significantly inhibited. These results suggest that IL-27 negatively regulates CTL cytotoxicity toward platelets in ITP by decreasing granzyme B expression, which is associated with reduced T-bet expression. IL-27 may have a therapeutic role in treating ITP patients. PMID- 25298040 TI - APOBEC3A catabolism of electroporated plasmid DNA in mouse muscle. AB - The mouse is widely used as a model for DNA therapy and vaccination even though the efficiency of DNA delivery in higher mammals and humans is much less. The human APOBEC3 (A3) enzymes impact viral genomes by cytidine deamination, which introduces multiple uridine residues into single-stranded DNA, a process known as genetic editing. This initiates rapid DNA catabolism via a uracil DNA glycosylase dependent pathway. In tissue culture, A3A, A3C and A3B can hyperedit transfected plasmid DNA. We explored plasmid catabolism in vivo initiated by A3A, the most efficient of the human enzymes and one that is functionally conserved across most mammals. As rodents do not encode an A3A enzyme, it was possible to explore DNA degradation in the mouse model. Human A3A genetically edits co-electroporated luciferase plasmid DNA in mouse skeletal muscle that initiates DNA degradation resulting in approximately fourfold decrease in bioluminescence. Part of the degradation occurs in the nucleus as indicated by complex hyperedited DNA molecules. As human A3A is strongly upregulated by interferon alpha and DNA sensing pathways, it is a strong candidate enzyme for restricting plasmid DNA in higher mammals. PMID- 25298041 TI - Molecular characterization of enteroviruses including a new type EV-C99 isolated from Xinjiang students in Shandong, China in 2011. AB - The last case of infection with wild-type poliovirus indigenous to China was reported in 1994. In 2011, a poliomyelitis outbreak caused by imported wide-type poliovirus occurred in Xinjiang Uighur Autonomous Region. Here, we report the results of enterovirus (EV) isolation from Xinjiang students that returned to school in Shandong after summer vacation during this outbreak. Stool specimens from 376 students were collected and 10 EV strains were isolated including 4 polioviruses (All Sabin strains), 1 coxsackievirus (CV) A13, 3 CVA17 and 2 EV C99. VP1 sequence analysis revealed these CVA13, CVA17 and EV-C99 strains had 71.3-81.8%, 76.5-84.6% and 74.2-82.9% nucleotide similarity with strains from other countries within a serotype, respectively. EV-C99 strains had 82.7-92.8% VP1 similarity with two previously reported Xinjiang strains. Complete genome analysis on EV-C99 strains revealed intra-serotypic genetic recombination events. These findings reflect great genetic divergence between Chinese strains and strains from other countries of the three types, and provide valuable information on monitoring EV transmission over long distance. PMID- 25298042 TI - Urine cortisol concentration as a biomarker of stress is unrelated to IVF outcomes in women and men. AB - PURPOSE: Our primary objective was to assess associations between urine cortisol as a biomarker of psychological stress and in vitro fertilization (IVF) outcomes. A secondary objective was to assess associations between toxic metals and cortisol. METHODS: Urine and blood specimens were collected from 52 women and 28 male partners completing a first IVF procedure, on the day of oocyte retrieval. Urine cortisol was measured with an enzyme-linked immunosorbent assay. Mercury (Hg), cadmium (Cd), and lead (Pb) were determined in blood and Cd in urine by inductively coupled plasma-mass spectrometry. RESULTS: No associations were indicated for cortisol with IVF outcomes in multivariable regression models adjusted for covariates. However, we detected positive linear associations for cortisol and urine Cd (beta = 9.96, 95%CI 1.52, 21.44) and blood Hg (beta = 1.44, 95%CI 0.31, 3.18). An exploratory stratified analysis suggested a potential inverse association between urine cortisol and oocyte fertilization among women with low, but not high blood Hg. CONCLUSION: While limited, these preliminary data suggest that psychological stress may not play a major role in IVF outcomes, which therefore could be one less concern for couples and their clinicians. Our data also raise the possibility for toxic metals to modify associations between cortisol and IVF outcomes among women. However, these preliminary results require corroboration in an experimental animal model and confirmation in a larger, more definitive observational study. PMID- 25298043 TI - Lessons in participant retention in the course of a randomized controlled clinical trial. AB - BACKGROUND: Clinical trials are increasingly being conducted as new products seek to enter the market. Deployment of such interventions is based on evidence obtained mainly from the gold standard of randomized controlled clinical trials (RCCT). A crucial factor in the ability of RCCTs to provide credible and generalisable data is sample size and retention of the required number of subjects at completion of the follow-up period. However, recruitment and retention in clinical trials are hindered by prevalent peculiar challenges in Africa that need to be circumvented. This article shares experiences from a phase II trial that recorded a high retention rate at 14 months follow-up at a new clinical trial site. METHODS: Mothers bringing children less than two months of age to the health facility were given information and invited to have their child enrolled if the inclusion criteria were fulfilled. Participants were enrolled over 8 months. Trial procedures, duration and risks/benefits were painstakingly and sequentially explained to the communities, parents and relevant relatives before and during the trial period. The proportions of participants that completed or did not complete the trial were analyzed including the reasons for failure to complete all trial procedures. RESULTS: 1044 individuals received information regarding the trial of which 371 returned for screening. 300 (81%) of them who fulfilled the inclusion criteria and did not meet any exclusion criteria were enrolled and 94% of these completed the trial. Consent withdrawal was the main reason for not completing the trial largely (75%) due to the father not being involved at the point of consenting or parents no longer being comfortable with blood sampling. CONCLUSIONS: Participant retention in clinical trials remains a crucial factor in ensuring generalisability of trial data. Appropriate measures to enhance retention should include continuous community involvement in the process, adequate explanation of trial procedures and risks/benefits; and innovative tracing of participants adapted for the setting. PMID- 25298044 TI - Changing microbial epidemiology in hematopoietic stem cell transplant recipients: increasing resistance over a 9-year period. AB - Infections remain important contributors to mortality in hematopoietic stem cell transplantation (HSCT). METHOD: We studied the evolving epidemiology and trends in susceptibility of bacterial and Candida isolates at an Australian HSCT center. A total of 528 HSCTs in 508 patients were performed from April 2001 to May 2010. A total of 605 isolates were eligible for study inclusion; 318 (53%) were gram positive, 268 (44%) were gram-negative, and 19 (3%) were Candida species. RESULTS: The most common site for isolates was blood (380 isolates, 63%). Staphylococcus aureus was the most common gram-positive organism (n = 107, 34%), but trends to increasing coagulase-negative staphylococci (P = 0.002) and vancomycin-resistant Enterococcus (P < 0.001) were observed. Escherichia coli was the most common gram-negative isolate (n = 74, 28%). Fluoroquinolone resistance increased with widespread use of protocol fluoroquinolone prophylaxis (P = 0.001). Carbapenem resistance was found in 44% of Pseudomonas or Acinetobacter isolates. Bloodstream infection with a multidrug-resistant organism (odds ratio 3.61, 95% confidence interval: 1.40-9.32, P = 0.008) was an independent predictor of mortality at 7 days after a positive blood culture. CONCLUSIONS: Antimicrobial resistance is an increasing problem in this vulnerable patient population, and not only has an impact on choice of empiric therapy for febrile neutropenia but also on mortality. PMID- 25298045 TI - Psychological stress has the potential to cause a decline in the epidermal permeability barrier function of the horny layer. AB - OBJECTIVE: Psychological stress is known to have a negative effect on a large number of skin diseases. However, there is little research on the relationship between psychological stress and the epidermal permeability barrier function (EPBF) of healthy individuals. We hypothesize that psychological stress deteriorates EPBF and aimed to investigate this relationship. METHODS: Psychological stress was assessed using salivary alpha-amylase (sAmy; KIU L(-1) ), and chromogranin A level corrected with total protein (CgAP; pmol mg(-1) protein) as psychological stress biomarkers. Measurements were obtained from 16 healthy female students during two periods of presumed higher stress (final examinations and returning from a long vacation), and a period considered as a control. The EPBF level was evaluated by measuring transepidermal water loss (TEWL; g m(-2) h(-1) ). The TEWL was measured three times: just before (TEWL [Intact]), immediately after (TEWL [Str]) and 4 h after (TEWL [4 h]) barrier disruption by tape stripping. The rate of barrier disruption was evaluated by comparing the difference between the TEWL [Intact] and the TEWL [Str] (delta-BD: g m(-2) h(-1) ). The recovery was assessed by comparing the difference between the TEWL [Intact] and TEWL [4 h] (delta-RE: g m(-2) h(-1) ). RESULTS: The subjects demonstrated a significant increase in the sAmy value after the long vacation compared with the control. There was no change in the CgAP value between the groups. Meanwhile, the EPBF level showed significant deterioration during both higher stress periods. There was a significant increase in delta-BD and delta-RE after the long vacation. CONCLUSIONS: The results indicate the possibility that psychological stress causes a decline in EPBF and deterioration in barrier disruption and recovery. Furthermore, it implies a relationship between psychological stress and the exacerbation or protracted healing of skin disease. PMID- 25298047 TI - Short- and Long-Term Self-Regulation and Sexual Risk-Taking Behaviors in Unmarried Heterosexual Young Adults. AB - The goal of this study was to explore associations between short- and long-term self-regulation and dimensions of oral and coital sexual risk-taking in emerging adulthood. A total of 287 unmarried heterosexual young adults ages 18 to 26 years (62% female; 87% European American; 81% enrolled in college) provided study data via Internet surveys. High levels of long-term self-regulation predicted later initiation of oral sex and coitus, fewer lifetime coital partners, increased likelihood of condom and other contraceptive use at last intercourse, and low composite levels of coital risk. High levels of short-term self-regulation predicted reduced likelihood of condom use and high overall coital risk. The discussion focuses on the interpretation of these effects and potential directions for future research. PMID- 25298046 TI - Drug combinations in the treatment of neuropathic pain. AB - Pharmacotherapy, the main treatment option for neuropathic pain, remains a major clinical challenge. The most commonly studied drug classes in the context of neuropathic pain-antidepressants, anticonvulsants, and opioids-have only limited efficacy and frequent dose-limiting adverse effects. Yet, most guidelines recommend monotherapy as the first line of neuropathic pain treatment. Recent understanding of neuropathic pain pathophysiology suggests that multiple mechanisms, both at the peripheral and the central nervous system levels, underlie neuropathic pain, pointing to the possibility that targeting multiple mechanisms simultaneously can improve treatment outcome. A few clinical trials using various drug combinations for neuropathic pain have already been published but yielded inconsistent results, partially due to methodological problems associated with the conduction of such trials. Nonetheless, combination therapy remains an intriguing treatment option for neuropathic pain, awaiting future high quality validating trials. PMID- 25298048 TI - Effectiveness and implementation of patient safety care. PMID- 25298049 TI - Workplace empowerment and nurses' job satisfaction: a systematic literature review. AB - AIMS: This systematic review aimed to synthesize and analyse the studies that examined the relationship between nurse empowerment and job satisfaction in the nursing work environment. BACKGROUND: Job dissatisfaction in the nursing work environment is the primary cause of nursing turnover. Job satisfaction has been linked to a high level of empowerment in nurses. EVALUATION: We reviewed 596 articles, written in English, that examined the relationship between structural empowerment, psychological empowerment and nurses' job satisfaction. Twelve articles were included in the final analysis. KEY ISSUE: A significant positive relation was found between empowerment and nurses' job satisfaction. Structural empowerment and psychological empowerment affect job satisfaction differently. CONCLUSION: A satisfying work environment for nurses is related to structural and psychological empowerment in the workplace. Structural empowerment is an antecedent of psychological empowerment and this relationship culminates in positive retention outcomes such as job satisfaction. IMPLICATION FOR NURSING MANAGEMENT: This review could be useful for guiding leaders' strategies to develop and maintain an empowering work environment that enhances job satisfaction. This could lead to nurse retention and positive organisational and patient outcomes. PMID- 25298050 TI - Challenges regarding the implementation of the basic antenatal care approach in eThekwini District, Kwazulu-Natal. AB - AIM: The aim of the study was to investigate the challenges experienced by midwives during the implementation of the Basic Antenatal Care programme. BACKGROUND: The National Department of Health recommended that all primary health care facilities in South Africa start to implement the Basic Antenatal Care programme by the end of 2008. In her work as coordinator of the Maternal Child and Women's Health programme for the eThekwini Municipality, the researcher observed the slow progress in implementation of the programme in the eThekwini district. METHOD: A descriptive qualitative design using questionnaires was used to assess the challenges being experienced by midwives during the implementation of the programme. RESULTS: The challenges identified included: shortage of staff, lack of cooperation from referral hospitals, lack of in-service training, problems with transportation of specimens to laboratories, lack of material resources, unavailability of Basic Antenatal Care programme guidelines and lack of management support. CONCLUSION: The challenges were the possible cause of the slow progress in the implementation of the programme. IMPLICATIONS FOR NURSING MANAGEMENT: The successful implementation of the new programme is dependent on support and guidance offered by the nurse manager to the staff at operational level. The manager should monitor and develop strategies to address and overcome challenges that hinder implementation of the Basic Antenatal Care programme. PMID- 25298051 TI - Direct spectroscopic evidence of hyperconjugation unveils the conformational landscape of hydrazides. AB - The stereochemistry of hydrazides makes them especially interesting as building blocks for molecular design. An exhaustive conformational analysis of three model hydrazides was conducted in a conformer-selective approach by using a combination of high-level quantum chemistry calculations and vibrational spectroscopy in the gas phase and in solution. The NH stretch frequency was found to be highly sensitive to hyperconjugation, thus making it an efficient probe of the conformation of the neighboring nitrogen atom. This property greatly assisted the identification of the isomers observed experimentally in the conformer pool. A rationalization of the hydrazide conformational landscape is proposed, therefore paving the way for a better characterization of secondary structures in larger systems. PMID- 25298052 TI - Reliability and validity of a Chinese version of the Oral Health Impact Profile for edentulous subjects. AB - OBJECTIVES: The aim of this study was to evaluate the reliability and validity of the Chinese version of the Oral Health Impact Profile for edentulous subjects (OHIP-EDENT-C). METHODS: After translation and cross-cultural adaptation following international guidelines, 162 complete denture wearers were recruited to complete the questionnaire. The reliability of the OHIP-EDENT-C was evaluated using internal consistency and test-retest methods. The validity of the OHIP EDENT-C was analyzed by construct validity and convergent validity. Construct validity was determined based on factor analysis and convergent validity by analyzing the correlation between OHIP-EDENT-C subscale scores and the global question. RESULTS: Cronbach's alpha value (internal reliability) for the total OHIP-EDENT-C score was 0.972, and the intraclass correlation coefficient value (test-retest reliability) was 0.763 (similar to the original OHIP-EDENT). Construct validity was determined by factor analysis, extracting five factors, accounting for 74.31 % of the variance. All items had factor loadings above 0.40. In terms of convergent validity, the OHIP-EDENT-C subscale was significantly highly correlated to the global question. CONCLUSION: The results suggest that the OHIP-EDENT-C is a reliable and valid measure to evaluate OHRQoL for edentulous subjects in China. PMID- 25298053 TI - Evidence-based medicine and myocardial protection--where is the evidence? AB - OBJECTIVE: Myocardial protection with cardioplegia is an integral component of most cardiac surgical procedures, providing protection of the heart by limiting metabolic activity and increasing the myocardium's capacity to withstand ischemia for prolonged periods of time. Cardioplegia has greatly affected the landscape of cardiothoracic surgery since its introduction in the 1960s, but, to this day, there continues to be a debate over what the ideal cardioplegic solution should be. The goal of this analysis is to describe current practices in cardioplegia and to point out the lack of quality human research and subsequent publications that prevent best practices from being utilized. METHODS: This study is a systematic review of journal publications pertaining to the composition of commonly used cardioplegic solutions. Four main types of cardioplegia were assessed to give a narrower field of examination; specifically, microplegia, del Nido, Custodiol HTK, and 4:1 blood cardioplegia. Other combinations of cardioplegia, including St. Thomas's Solution and the University of Wisconsin (UW) Solution, were considered when applicable according to the context of the publication being reviewed. Factors being assessed consisted of scientific validity, nature of the test subject (isolated organ vs. animal vs. human studies), experimental setup (retrospective trials vs. randomized clinical trials) and patient outcomes. RESULTS: There are very few randomized clinical trials with human subjects comparing commonly used cardioplegic solutions. Numerous retrospective studies exist, but often show similar intraoperative and postoperative outcomes between the solutions. Some solutions, del Nido cardioplegia in particular, were found to have few or no significant human trials to back the rigor required in such a highly specialized field as cardiovascular surgery. A wide variation in the types of surgeries and primary outcomes were included in the publications, so it is difficult to perform an accurate systematic review of the topic. CONCLUSION: Uniform variables among different studies would be preferable for analysis of this topic; thus, it is the researchers' recommendation that the collection of multicenter data be undertaken in order to more fully answer this research question.Comparative effectiveness studies to associate commonly used solutions are needed. Without this research, surgeon preference remains the primary determining factor for deciding which cardioplegic solution to use. Cardioplegia selection should rely more on higher scientific research, using evidenced-based medicine and ranking of clinical studies. PMID- 25298055 TI - Rapid identif ication and comparative analysis of chemical constituents in herbal medicine Fufang decoction by ultra-high-pressure liquid chromatography coupled with a hybrid linear ion trap-high-resolution mass spectrometry. AB - This study was conducted to reveal the relation between herbal medicine Fufang decoction and a single drug in terms of material base. Da-Cheng-Qi decoction (DCQD) was used as a model. Ultrahigh-pressure liquid chromatography coupled with a hybrid linear ion trap-high-resolution mass spectrometry (UHPLC-LTQ-Orbitrap) was applied to detect and identify the main chemical compounds. This technique was also employed to determine the different chemical components. Under optimized liquid chromatography and mass spectrometry conditions, 64 components, including iridoids, flavonoids, anthraquinones and coumarins, were separated and tentatively characterized in Da-Cheng-Qi decoction. After decoction, the contents of 18 compounds were markedly changed, and two components were no longer detected in Fufang decoction compared with single-medicine decoction. The established method provided a good example for the rapid identification of complicated polar constituents in herbal medicine prescriptions. PMID- 25298056 TI - Antibiotic resistance-poised at a pivotal point in time. PMID- 25298057 TI - Cardiovascular disease in COPD: a call for action. PMID- 25298054 TI - Biased beta2-adrenoceptor signalling in heart failure: pathophysiology and drug discovery. AB - The body is constantly faced with a dynamic requirement for blood flow. The heart is able to respond to these changing needs by adjusting cardiac output based on cues emitted by circulating catecholamine levels. Cardiac beta-adrenoceptors transduce the signal produced by catecholamine stimulation via Gs proteins to their downstream effectors to increase heart contractility. During heart failure, cardiac output is insufficient to meet the needs of the body; catecholamine levels are high and beta-adrenoceptors become hyperstimulated. The hyperstimulated beta1-adrenoceptors induce a cardiotoxic effect, which could be counteracted by the cardioprotective effect of beta2-adrenoceptor-mediated Gi signalling. However, beta2-adrenoceptor-Gi signalling negates the stimulatory effect of the Gs signalling on cardiomyocyte contraction and further exacerbates cardiodepression. Here, further to the localization of beta1- and beta2 adrenoceptors and beta2-adrenoceptor-mediated beta-arrestin signalling in cardiomyocytes, we discuss features of the dysregulation of beta-adrenoceptor subtype signalling in the failing heart, and conclude that Gi-biased beta2 adrenoceptor signalling is a pathogenic pathway in heart failure that plays a crucial role in cardiac remodelling. In contrast, beta2-adrenoceptor-Gs signalling increases cardiomyocyte contractility without causing cardiotoxicity. Finally, we discuss a novel therapeutic approach for heart failure using a Gs biased beta2-adrenoceptor agonist and a beta1-adrenoceptor antagonist in combination. This combination treatment normalizes the beta-adrenoceptor subtype signalling in the failing heart and produces therapeutic effects that outperform traditional heart failure therapies in animal models. The present review illustrates how the concept of biased signalling can be applied to increase our understanding of the pathophysiology of diseases and in the development of novel therapies. PMID- 25298058 TI - NO2 in the lungs: a weighty matter. PMID- 25298059 TI - Maternal antibiotic use and risk of asthma in offspring. PMID- 25298060 TI - Non-invasive positive pressure ventilation for severe COPD. PMID- 25298061 TI - Maternal antibiotic use and risk of asthma in offspring--Authors' reply. PMID- 25298062 TI - Non-invasive positive pressure ventilation for severe COPD. PMID- 25298063 TI - Non-invasive positive pressure ventilation for severe COPD--Authors' reply. PMID- 25298064 TI - Electroporation transiently decreases GJB2 (connexin 26) expression in B16/BL6 melanoma cell line. AB - Connexins are proteins that form gap junctions. Perturbations in the cell membrane reportedly promote changes in the expression profile of connexins. Electroporation promotes destabilization by applying electrical pulses, and this procedure is used in electrochemotherapy and gene therapy, among others. This in vitro work aimed to study the interference of electroporation on the expression profile of GJB2 (Cx26 gene) and Connexin 26 in melanoma cell line B16/BL6. The techniques of immunocytochemistry, Western blot, and real-time PCR were used. After electroporation, cells showed a transient decrease in GJB2 mRNA. The immunostaining of Cx26 showed no noticeable change after electroporation at different time points. However, Western blot showed a significant reduction in Cx26 30 min after electroporation. Our results showed that electroporation interferes transiently in the expression of Connexin 26 in melanoma and are consistent with the idea that electroporation is a process of intense stress that promotes cell homeostatic imbalance and results in disruption of cell physiological processes such as transcription and translation. PMID- 25298065 TI - Elemental composition of edible nuts: fast optimization and validation procedure of an ICP-OES method. AB - BACKGROUND: An inductively coupled plasma-optical emission spectrometry method for the speedy simultaneous detection of 19 elements in edible nuts (walnuts: Juglans nigra; almonds: Prunus dulcis; hazelnuts: Corylus avellana; Brazil nuts: Bertholletia excelsa; cashews: Anacardium occidentalle; pistachios: Pistacia vera; and peanuts: Arachis hypogaea) available on the Serbian markets, was optimized and validated through the selection of instrumental parameters and analytical lines free from spectral interference and with the lowest matrix effects. RESULTS: The analysed macro-elements were present in the following descending order: Na > Mg > Ca > K. Of all the trace elements, the tested samples showed the highest content of Fe. The micro-element Se was detected in all the samples of nuts. The toxic elements As, Cd and Pb were either not detected or the contents were below the limit of detection. One-way analysis of variance, Student's t-test, Tukey's HSD post hoc test and hierarchical agglomerative cluster analysis were applied in the statistical analysis of the results. CONCLUSION: Based on the detected content of analysed elements it can be concluded that nuts may be a good additional source of minerals as micronutrients. PMID- 25298067 TI - Local determination of the amount of integration of an atom into a crystal surface. AB - Collective vibrational modes of crystal lattices, called phonons, determine fundamental material properties, such as their thermal and electrical conductivities. Bulk phonon spectra are influenced by point defects. More recently, the importance of phonons on nanostructures has come into the focus of attention. Here we show a spatially resolved phonon spectra of point defects that reveal distinctly different signatures for a cavity alone and an impurity atom fully integrated into the surface as opposed to one placed into a cavity. The spectra are indicative for delocalized phonons and localized vibrations, respectively, as confirmed by theory. PMID- 25298066 TI - Chiral separation of G-type chemical warfare nerve agents via analytical supercritical fluid chromatography. AB - Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(-) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(-) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. PMID- 25298068 TI - Value of serum procalcitonin and interleukin-6 in patients with bullous impetigo and staphylococcal scalded skin syndrome. PMID- 25298069 TI - Movement disorders in neuroleptic-naive patients with schizophrenia spectrum disorders. AB - BACKGROUND: Spontaneous Movements Disorders (SMDs) or dyskinetic movements are often seen in patients with schizophrenia and other psychotic disorders, and are widely considered to be adverse consequences of the use of antipsychotic medications. Nevertheless, SMDs are also observed in the pre-neuroleptic ear and among patients who were never exposed to antipsychotic medications. The aim of this study was to determine the extent of SMDs among antipsychotic-naive patients in a low income setting, and to evaluate contextually relevant risk factors. METHODS: The study was a cross-sectional facility-based survey conducted at a specialist psychiatric hospital in Addis Ababa, Ethiopia. Consecutive consenting treatment-naive patients with a diagnosis of schizophrenia, schizoaffective disorder and schizophreniform disorder contacting services for the first time were assessed using the Simpson-Angus Rating Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS) to evaluate the presence of SMDS. Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) were administered to evaluate negative and positive symptom profiles respectively. Body mass index (BMI) was used as a proxy measure for nutritional status. RESULT: Sixty-four patients, 67.2% male (n = 43), with first contact psychosis who met the DSM-IV-TR criteria for schizophrenia (n = 47), schizophreniform disorder (n= 5), and schizoaffective disorder (n = 12) were assessed over a two month study period. Seven patients (10.9%) had SMDs. BMI (OR = 0.6, 95% CI = 0.40, 0.89; p = 0.011) and increasing age (OR = 1.10; 95% CI = 1.02, 1.20; p = 0.017) were associated with SMD. CONCLUSIONS: This finding supports previous suggestions that abnormal involuntary movements in schizophrenia and other psychotic disorders may be related to the pathophysiology of psychotic disorders and therefore cannot be attributed entirely to the adverse effects of neuroleptic medication. PMID- 25298070 TI - Contrast-enhanced molecular ultrasound differentiates endoglin genotypes in mouse embryos. AB - Targeted ultrasound contrast imaging has the potential to become a reliable molecular imaging tool. A better understanding of the quantitative aspects of molecular ultrasound technology could facilitate the translation of this technique to the clinic for the purposes of assessing vascular pathology and detecting individual response to treatment. The objective of this study was to evaluate whether targeted ultrasound contrast-enhanced imaging can provide a quantitative measure of endogenous biomarkers. Endoglin, an endothelial biomarker involved in the processes of development, vascular homeostasis, and altered in diseases, including hereditary hemorrhagic telangiectasia type 1 and tumor angiogenesis, was the selected target. We used a parallel plate perfusion chamber in which endoglin-targeted (MBE), rat isotype IgG2 control and untargeted microbubbles were perfused across endoglin wild-type (Eng+/+), heterozygous (Eng+/-) and null (Eng-/-) embryonic mouse endothelial cells and their adhesion quantified. Microbubble binding was also assessed in late-gestation, isolated living transgenic Eng+/- and Eng+/+ embryos. Nonlinear contrast-specific ultrasound imaging performed at 21 MHz was used to collect contrast mean power ratios for all bubble types. Statistically significant differences in microbubble binding were found across genotypes for both in vitro (p<0.05) and embryonic studies (p<0.001); MBE binding was approximately twofold higher in Eng+/+ cells and embryos compared with their Eng+/- counterparts. These results suggest that molecular ultrasound is capable of reliably differentiating between molecular genotypes and relating receptor densities to quantifiable molecular ultrasound levels. PMID- 25298071 TI - Relationship between social determinants of health and processes and outcomes in adults with type 2 diabetes: validation of a conceptual framework. AB - BACKGROUND: The aim of this study was to empirically validate a conceptual framework and elucidate the pathways linking social determinants of health to outcomes in individuals with type 2 diabetes. METHODS: 615 adults were recruited from adult primary care clinics in the southeastern United States. The model was estimated using path analysis to determine if socioeconomic (education, employment, income) and psychosocial (fatalism, self-efficacy, depression, diabetes distress, serious psychological distress, social support, and perceived stress) factors would independently predict glycemic control or be associated with mediator/moderators of self-care, access to care, and processes of care. Covariates were gender, age, race and health literacy. RESULTS: The final model (chi2 (15) = 17.68, p = 0.28; RMSEA = 0.02, CFI = 0.99) showed lower glycemic control was directly associated with less hours worked (r = 0.13, p = 0.002), more fatalistic attitudes (r = -0.09, p = 0.03), more self-efficacy (r = -0.30, p < 0.001), and less diabetes distress (r = 0.12, p = 0.03), with the majority of total effects being direct. Significant paths associated self-care with diabetes distress (r = -0.14, p = 0.01) and perceived stress (r = -0.15, p = .001); access to care with income (r = 0.08, p = 0.03), diabetes distress (r = -0.21, p < 0.001) and social support (r = 0.08, p = 0.03); and processes of care with income (r = -0.11, p = 0.03), social support (r = 0.10, p = 0.04), and perceived stress (r = 0.10, p = 0.04). The paths explained 76% of the variance in the model. CONCLUSIONS: Consistent with the conceptual framework, social determinants were associated with glycemic control through a direct association and mediators/moderators of self-care, access to care and processes of care. This study provides the first validation of a conceptual framework for the relationship between socioeconomic and psychological components of social determinants of health and diabetes outcomes. PMID- 25298072 TI - Yersinia protein kinase A phosphorylates vasodilator-stimulated phosphoprotein to modify the host cytoskeleton. AB - Pathogenic Yersinia species evolved a type III secretion system that injects a set of effectors into the host cell cytosol to promote infection. One of these effectors, Yersinia protein kinase A (YpkA), is a multidomain effector that harbours a Ser/Thr kinase domain and a guanine dissociation inhibitor (GDI) domain. The intercellular targets of the kinase and GDI domains of YpkA were identified to be Galphaq and the small GTPases RhoA and Rac1, respectively, which synergistically induce cytotoxic effects on infected cells. In this study, we demonstrate that vasodilator-stimulated phosphoprotein (VASP), which is critical for regulation of actin assembly, cell adhesion and motility, is a direct substrate of YpkA kinase activity. Ectopic co-expression of YpkA and VASP in HEK293T cells leads to the phosphorylation of VASP at S157, and YpkA kinase activity is essential for VASP phosphorylation at this site. Moreover, YpkA directly phosphorylates VASP in in vitro kinase assay. YpkA-mediated VASP phosphorylation significantly inhibits actin polymerization and promotes the disruption of actin cytoskeleton, which inhibits the phagocytosis. Taken together, our study found a novel molecular mechanism used by YpkA to disrupt cytoskeleton dynamics, thereby promoting the anti-phagocytosis ability of pathogenic Yersiniae. PMID- 25298073 TI - Endarteritis obliterans in the pathogenesis of Buerger's disease from the pathological and immunohistochemical points of view. AB - Buerger's disease (thromboangiitis obliterans) is considered to be a nonatherosclerotic, inflammatory, and vaso-occlusive disease, although the details of the mechanisms of pathogenesis remain unknown. The occurrence of the disease is strongly related to tobacco abuse and its progression is closely linked to continued smoking. The purpose of this review article is to demonstrate the pathological characteristics of arteries affected with Buerger's disease from a possible immunoreactive point of view. In addition, we present the mechanisms for preserving the architecture of the arterial wall in affected vasculatures. Thereafter, we discuss the possibility that the pathogenesis of Buerger's disease is a type of endarteritis obliterans, deeply connected to the Notch pathway, distinct from arteriosclerosis obliterans and other vasculitides. PMID- 25298074 TI - Takotsubo cardiomyopathy. PMID- 25298075 TI - Takotsubo cardiomyopathy. PMID- 25298077 TI - A novel hollowed CoO-in-CoSnO3 nanostructure with enhanced lithium storage capabilities. AB - The search for well-defined porous/hollowed metal oxide nanocomposites for high performance energy storage is promising. Herein, atomic layer deposition (ALD) has been utilized for the construction of a novel hollowed wire-in-tube nanostructure of CoO-in-CoSnO3, for which Co2(OH)2CO3 nanowires are first obtained by a hydrothermal method and then deposited with ALD SnO2. After a proper thermal treatment, a CoO wire-void-CoSnO3 tube was formed with the decomposition of Co2(OH)2CO3 and its simultaneous reaction with the outer SnO2 layer. In this unique wire-in-tube structure, both CoO and CoSnO3 are promising materials for lithium ion battery anodes with high theoretical capacities, and the porous + hollow feature is essential for better electrode/electrolyte contact, shorter ion diffusion path and better structure stability. After a further facile carbon coating, the hollowed wire-in-tube structure delivered an improved capacity of 1162.1 mA h g(-1), which is much higher than that of the bare CoO nanowire. Enhanced rate capability and cycling stability have also been demonstrated with the structure, showing its promising application for the anode material of lithium ion battery. The work also demonstrated an effective way of using ALD SnO2 for electrochemical energy storage that ALD SnO2 plays a key role in the structure formation and also serves as both active material and surface coating. PMID- 25298076 TI - Bacterial community composition of three candidate insect vectors of palm phytoplasma (Texas Phoenix Palm Decline and Lethal Yellowing). AB - Texas Phoenix Palm Decline (TPPD) and Lethal Yellowing are two phytoplasma-linked diseases in palms. The phytoplasma causing TPPD is thought to be transmitted by three putative planthopper vectors, Ormenaria rufifascia, Omolicna joi, and Haplaxius crudus. These insects have been morphologically and molecularly described, and have screened positive for Candidatus Phytoplasma palmae. Individuals from each species were subjected to 16S bacterial community sequencing using the Roche 454 platform, providing new information regarding the previously unexplored bacterial communities present in putative vectors. PMID- 25298078 TI - Liminality and low-income aging families by choice: meanings of family and support. AB - Through the lens of individualization, aging families demonstrate changes both in family composition and in meanings of family and support. So, also, do low-income families that - in order to survive - choose flexible, sometimes novel, social support relations, including kin and non-kin: these are aging families by choice. Applying the concept of liminality (transitional states of being) created through individualization, we explored the experiences of close relations in low-income families consisting of aging kin and non-kin members. Qualitative interviews with respondents representing two or three generations of aging families of choice illustrated how these families perceive the meanings of family and social support. We find that reciprocity is less vital to relationships of older with younger members in familial networks than may be expected. Liminality contours meanings and exchanges in low-income aging families of choice such that no matter how tenuous relations may be, they provide a sense of belonging and meaning. PMID- 25298079 TI - Seven-year clinical outcomes of patients with moderate coronary artery stenosis after deferral of revascularization based on gray-zone fractional flow reserve. AB - The range (0.75-0.80) of fractional flow reserve (FFR) is known as the gray zone. Although the FFR of 0.80 was recently adopted as the cutoff value for coronary revascularization, the long-term clinical outcomes of patients with angiographically moderate coronary artery stenosis (FFR: 0.75-0.80) remain unknown. The objective of the present study was to investigate the clinical outcomes of patients with angiographically moderate coronary artery stenosis, whose FFR was 0.75-0.80. One hundred and twenty consecutive patients, for whom coronary revascularization was deferred based on FFR, were categorized to groups I and II, in which 55 and 65 patients had FFRs of 0.75-0.80 and 0.81-0.85, respectively. Adverse cardiac events included all-cause death, cardiac death, myocardial infarction, coronary revascularization for the FFR-measured and unmeasured arteries, congestive heart failure, and admission for chest symptoms. Patients were followed up for 7 years after coronary angiography. Event-free survival rates of all adverse cardiac events were 73 % in group I and 63 % in group II (P = 0.35) and those of adverse cardiac events related to the FFR measured artery were 94 and 85 % (P = 0.08). Throughout the follow-up period, the medication rate of statins was significantly lower in group II than in group I (P = 0.008). Seven-year clinical outcomes of patients with the gray-zone FFR were good. Furthermore, FFR-measured artery-related events in patients with the gray zone FFR tended to occur less frequently than in patients with better FFR of 0.81 0.85. Optimal medical therapy is required for them, regardless of coronary stenosis severity and FFR. PMID- 25298080 TI - Aldehyde dehydrogenase (ALDH) in Alzheimer's and Parkinson's disease. AB - Evidence suggests that aldehyde dehydrogenase (ALDH; E.C. 1.2.1.3) gene, protein expression and activity are substantially decreased in the substantia nigra of patients with Parkinson's disease (PD). This holds especially true for cytosolic ALDH1A1, while mitochondrial ALDH2 is increased in the putamen of PD. Similarly, in Alzheimer's disease (AD) several studies in genetic, transcriptomic, protein and animal models suggest ALDH involvement in the neurodegeneration processes. Such data are in line with findings of increased toxic aldehydes, like for example malondialdehyde, nonenal, 3,4-dihydroxyphenylacetaldehyde and others. Genetic, transcriptomic and protein alterations may contribute to such data. Also in vitro and in vivo experimental work points to an important role of ALDH in the pathology of neurodegenerative disorders. Aims at investigating dysfunctions of aldehyde detoxification are suitable to define genetic/molecular targets for new therapeutic strategies balancing amine metabolism in devastating disorders like PD and probably also AD. PMID- 25298082 TI - Peptide and peptide nucleic acid syntheses using a DNA/RNA synthesizer. AB - The use of an ABI 394 DNA/RNA synthesizer for peptide and peptide nucleic acid (PNA) syntheses is described. No additional physical part or software is needed for the application. A commercially available large DNA synthesis column was used, and only about half of its volume was filled with resin when the resin was fully swollen. With additional space in the top portion of the column, agitation of reaction mixture was achieved by bubbling argon from the bottom without losing solution. Removing solutions from column was achieved by flushing argon from top to bottom. Two peptide and two PNA sequences were synthesized. Good yields were obtained in all the cases. The method is easy to follow by researchers who are familiar with DNA/RNA synthesizer. PMID- 25298081 TI - Disease diagnosis in primary care in Uganda. AB - BACKGROUND: The overall burden of disease (BOD) especially for infectious diseases is higher in Sub-Saharan Africa than other regions of the world. Existing data collected through the Health Management Information System (HMIS) may not be optimal to measure BOD. The Infectious Diseases Capacity Building Evaluation (IDCAP) cooperated with the Ugandan Ministry of Health to improve the quality of HMIS data. We describe diagnoses with associated clinical assessments and laboratory investigations of outpatients attending primary care in Uganda. METHODS: IDCAP supported HMIS data collection at 36 health center IVs in Uganda for five months (November 2009 to March 2010) prior to implementation of the IDCAP interventions. Descriptive analyses were performed on a cross-sectional dataset of 209,734 outpatient visits during this period. RESULTS: Over 500 illnesses were diagnosed. Infectious diseases accounted for 76.3% of these and over 30% of visits resulted in multiple diagnoses. Malaria (48.3%), cough/cold (19.4%), and intestinal worms (6.6%) were the most frequently diagnosed illnesses. Body weight was recorded for 36.8% of patients and less than 10% had other clinical assessments recorded. Malaria smears (64.2%) and HIV tests (12.2%) accounted for the majority of 84,638 laboratory tests ordered. Fewer than 30% of patients for whom a laboratory investigation was available to confirm the clinical impression had the specific test performed. CONCLUSIONS: We observed a broad range of diagnoses, a high percentage of multiple diagnoses including true co-morbidities, and underutilization of laboratory support. This emphasizes the complexity of illnesses to be addressed by primary healthcare workers. An improved HMIS collecting timely, quality data is needed. This would adequately describe the burden of disease and processes of care at primary care level, enable appropriate national guidelines, programs and policies and improve accountability for the quality of care. PMID- 25298084 TI - Affinity capillary electrophoresis to evaluate the complex formation between poliovirus and nanobodies. AB - It was demonstrated that nanobodies with an in vitro neutralizing activity against poliovirus type 1 interact with native virions. Here, the use of capillary electrophoresis was investigated as an alternative technique for the evaluation of the formation of nanobody-poliovirus complexes, and therefore predicting the in vitro neutralizing activity of the nanobodies. The macromolecules are preincubated offline in a specific nanobody-to-virus ratio and analyzed by capillary electrophoresis with UV detection. At low nanobody-to-virus ratios, a clear shift in migration time of the viral peak was observed. A broad peak was obtained, indicating the presence of a heterogeneous population of nanobody-virion complexes, caused by the binding of different numbers of nanobodies to the virus particle. At elevated nanobody-to-virus ratios, a cluster of peaks appeared, showing an additional increase in migration times. It was shown that, at these high molar excesses, aggregates were formed. The developed capillary electrophoresis method can be used as a rapid, qualitative screening for the affinity between poliovirus and nanobodies, based on a clearly visible and measurable shift in migration time. The advantages of this technique include that there is no need for antigen immobilization as in enzyme-linked immunosorbent assays or surface plasmon resonance for the use of radiolabeled virus or for the performance of labor- and time-intensive plaque-forming neutralization assays. PMID- 25298083 TI - Murine and human tissue-engineered esophagus form from sufficient stem/progenitor cells and do not require microdesigned biomaterials. AB - PURPOSE: Tissue-engineered esophagus (TEE) may serve as a therapeutic replacement for absent foregut. Most prior esophagus studies have favored microdesigned biomaterials and yielded epithelial growth alone. None have generated human TEE with mesenchymal components. We hypothesized that sufficient progenitor cells might only require basic support for successful generation of murine and human TEE. MATERIALS AND METHODS: Esophageal organoid units (EOUs) were isolated from murine or human esophagi and implanted on a polyglycolic acid/poly-l-lactic acid collagen-coated scaffold in adult allogeneic or immune-deficient mice. Alternatively, EOU were cultured for 10 days in vitro prior to implantation. RESULTS: TEE recapitulated all key components of native esophagus with an epithelium and subjacent muscularis. Differentiated suprabasal and proliferative basal layers of esophageal epithelium, muscle, and nerve were identified. Lineage tracing demonstrated that multiple EOU could contribute to the epithelium and mesenchyme of a single TEE. Cultured murine EOU grew as an expanding sphere of proliferative basal cells on a neuromuscular network that demonstrated spontaneous peristalsis in culture. Subsequently, cultured EOU generated TEE. CONCLUSIONS: TEE forms after transplantation of mouse and human organ-specific stem/progenitor cells in vivo on a relatively simple biodegradable scaffold. This is a first step toward future human therapies. PMID- 25298085 TI - Interactive histone acetylation and methylation in regulating transdifferentiation-related genes during tunicate budding and regeneration. AB - BACKGROUND: In the budding tunicate Polyandrocarpa misakiensis, retinoic acid (RA)-triggered transdifferentiation occurs during bud development and zooid regeneration. We aimed to reveal how and to what extent epigenetic histone modifications are involved in transdifferentiation-related gene expression. RESULTS: Acetylated histone H3 lysine 9 (H3K9ac) was observed in transdifferentiating bud tissues and regenerating zooid tissues, where a histone acetyltransferase (HAT) gene, PmGCN5, was strongly expressed. Results of chromatin immunoprecipitation (ChIP) indicated that in transdifferentiating bud tissues, retinoic acid receptor (PmRAR), retinoid X receptor (PmRXR), external signal-regulated kinase (PmERK), and beta-catenin (PmbetaCTN) genes conspicuously underwent H3K9 acetylation in their core promoter regions. RA was found to induce PmGCN5, causing histone acetylation of PmRAR, PmRXR, and PmERK. A GCN5 inhibitor, CPTH2, attenuated acetylation and weakened transcription of transdifferentiation related genes, except PmERK, indicating that RA-induced GCN5 facilitates gene expression via histone acetylation. In regenerating zooids, H3K9ac occurred exclusively in PmERK, but PmERK expression did not change, and, surprisingly, the PmProhibitin2 expression decreased substantially. In the core promoter regions of these genes, suppressive histone methylation occurred at H3K9 and H3K27. CONCLUSIONS: These results, along with other evidence, indicate that cooperative and conflicting histone modifications enable the minute regulation of gene expression in P. misakiensis. PMID- 25298087 TI - [Relationships between prevalence of youth risk behaviors and sleep duration among Japanese high school students]. AB - OBJECTIVES: This study aimed to clarify relationships between prevalence of risk behaviors and sleep duration among Japanese high school students. METHODS: Data from a national survey, the Japan Youth Risk Behavior Survey 2011 (the subjects were 9,778 students: 5,027 males, 4,751 females, in the first grade to the third grade of 102 schools randomly selected among high schools throughout Japan) was used for this analysis. We focused on nine items of risk behavior in JYRBS: "lack of vigorous physical activity," "skipping breakfast," "current cigarette use," "current alcohol use," "lifetime thinner use," "ever had sexual intercourse," "rarely or never wore seatbelts," "in a physical fight," and "seriously considered attempting suicide." RESULTS: Students with less than six hours of sleep duration accounted for approximately 40% of males and females. The odds ratios of prevalence of each of the nine risk behaviors were calculated on the basis of the group "six hours or more and less than eight hours" of sleep, whose prevalence of risk behaviors was the lowest. In the group with "four hours or more and less than six hours," the odds ratios of "lack of vigorous physical activity" and "skipping breakfast" for both males and females were significantly high. Furthermore, in the group with shorter sleep duration of "less than four hours," the odds ratios of all nine risk behaviors for males (odds ratios: 1.47 3.28) and eight risk behaviors (except for "rarely or never wore seatbelts") for females (1.54-4.68) were significantly high. On the other hand, in the group with long sleep duration of "10 hours or more," the odds ratios of "current cigarette use" and "lifetime thinner use" for both males and females were significantly high. CONCLUSION: It was shown that short sleep duration of less than six hours and long sleep duration of 10 hours or more related to the prevalence of youth risk behaviors among Japanese high school students. It was suggested that sleep duration should be considered as an important category of youth risk behaviors. PMID- 25298088 TI - [Age differences in decision-making factors on end-of-life care location for Musashino-city residents]. AB - OBJECTIVES: Japan is predicted to continue its fast-aging trend, especially in urban areas. Therefore, promoting end-of-life services in urban areas is an urgent policy issue. In addition, the recognition of end-of-life care greatly varies by age. The aim of this study was thus to clarify the association by age between preferences regarding care location among people in urban communities and their experiences, knowledge, and perceptions related to end-of-life care. METHODS: A total of 1,500 people aged 40 and older in Musashino-city participated in a cross-sectional nationwide survey. We asked about preferences regarding care location, demographic data, experiences, knowledge, and perceptions related to end-of-life care. We used logistic regression analyses. RESULTS: A total of 769 (51.6%) responded. Of those over 65, 40.9% preferred homes and 59.1% preferred places other than homes as end-of-life care locations. For those aged 40-64, 54.1% preferred homes and 45.9% preferred places other than homes (P<0.001). Logistic regression analyses revealed that the following factors affect people's preferences regarding location of care for those over 65: not recognizing that medication use can lead to addiction (odds ratio: 1.90; 95% confidence interval: 1.17-3.08); taking precautions before taking medicine (1.97; 1.21-3.22); volunteering (2.38; 1.34-4.21) ; recognizing that home cost is cheaper than hospital cost (1.82; 1.10-3.03); recognizing that they have health care workers to consult (1.90; 1.06-3.41); and recognizing that end-of-life care at home provides enough treatment (2.30; 1.37-3.87). Factors for the 40-64 year old group were as follows: not wanting informal caregivers to care (2.80; 1.62-4.83); recognizing that they can respond to sudden changes at home (2.97; 1.15-7.66); and want to be free at the end of the life (4.57; 2.43-8.59). CONCLUSION: These results suggest that changing people's thinking about the socialization of care is required to increase preferences of people over 65 for home death. For the 40 64 year old group, developing an awareness of death is required. For all generations, providing appropriate information and educating the people is required. PMID- 25298086 TI - Chemical shift separation with controlled aliasing for hyperpolarized (13) C metabolic imaging. AB - PURPOSE: A chemical shift separation technique for hyperpolarized (13) C metabolic imaging with high spatial and temporal resolution was developed. Specifically, a fast three-dimensional pulse sequence and a reconstruction method were implemented to acquire signals from multiple (13) C species simultaneously with subsequent separation into individual images. THEORY AND METHODS: A stack of flyback echo-planar imaging readouts and a set of multiband excitation radiofrequency pulses were designed to spatially modulate aliasing patterns of the acquired metabolite images, which translated the chemical shift separation problem into parallel imaging reconstruction problem. An eight-channel coil array was used for data acquisition and a parallel imaging method based on nonlinear inversion was developed to separate the aliased images. RESULTS: Simultaneous acquisitions of pyruvate and lactate in a phantom study and in vivo rat experiments were performed. The results demonstrated successful separation of the metabolite distributions into individual images having high spatial resolution. CONCLUSION: This method demonstrated the ability to provide accelerated metabolite imaging in hyperpolarized (13) C MR using multichannel coils, tailored readout, and specialized RF pulses. PMID- 25298089 TI - [Subjective symptoms and miscarriage after drinking well water exposed to diphenylarsinic acid]. AB - OBJECTIVES: An outbreak of neurological health disorder caused by drinking well water occurred in 2003 at one apartment building in Kamisu, Ibaraki, Japan. This was the first case of mass poisoning due to well water contaminated with diphenylarsinic acid (DPAA). Subsequently, other residents in Kamisu were confirmed to have drunk well water containing lower concentrations of DPAA. The present study aimed to investigate neurological and other subjective symptoms and miscarriage occurrences after DPAA exposure. METHODS: Subjects were residents of Kamisu aged 10-65 years in 2004. Twenty residents (high-level exposure group) had lived in the apartment building and drunk well water containing DPAA at arsenic concentrations of 2,262 MUg/L. The moderate/low-level exposure group (67 residents) had drunk other well water containing DPAA at arsenic concentrations of 2-230 MUg/L (mean: 85 MUg/L) and DPAA was detected in their hair or nails. A control group (134 residents), matched to the latter group by sex and age, had only drunk tap water. Public health nurses completed a questionnaire on symptoms, pregnancy, and miscarriage through interviews. RESULTS: Dizziness, unsteadiness, dysesthesia, writing disturbance, diplopia, insomnia, melancholy, headache, itchiness, weight change, diarrhea, cough, and dyspnea were significantly higher in the moderate/low-level exposure group than in the control group. A similar tendency was found in the high-level exposure group. From 1999 through 2003, no miscarriages occurred among 15 pregnancies in the control group, while three miscarriages occurred among five pregnancies in the moderate/low-level group. CONCLUSION: DPAA exposure via well water caused miscarriage, in addition to neurological and other subjective symptoms. PMID- 25298090 TI - [Reliability and validity of the Japanese version of the Relational Coordination Scale]. AB - OBJECTIVES: The Relational Coordination Scale is used to measure teamwork with specific subjects about specific tasks. We translated the scale into Japanese (J RCS) and examined its reliability and validity. METHODS: We translated the scale into Japanese. In July 2013, we conducted an internet survey for 124 home visiting nurses of 11 agencies in Shiga prefecture. The J-RCS items asked about teamwork with physicians, care managers, and colleague nurses. RESULTS: Eighty one home visiting nurses (65.3%) answered the survey, and 70 (56.5% of the responders) answered the re-test survey. Cronbach's alpha coefficients of J-RCS were 0.770 to 0.859, and the intraclass correlation coefficients for test-retest reliability were 0.673 to 0.830 (P<0.001). In the confirmatory factor analysis, only J-RCS [physicians] met the well fit indices and showed factorial validity. Concurrent validity was supported by correlations of J-RCS and the degree of confidence about collaboration (r=0.559 to 0.585, P<0.001) and social support (r=0.549 to 0.789, P<0.001). CONCLUSION: While issues such as factorial validity and the concentration of responses on some scale items will be a topic for further research, the J-RCS has been shown to have an acceptable level of reliability and validity. PMID- 25298092 TI - Experiencing antipsychotic discontinuation: results from a survey of Australian consumers. AB - Despite high reported rates of antipsychotic non-adherence, little is known about consumer experiences during discontinuation. This study was designed to increase understanding of antipsychotic discontinuation from consumer perspectives. In 2011-2012, 98 Australian consumers involved with participating organizations completed an anonymous survey detailing past antipsychotic discontinuation attempts. Of the 88 participants who reported at least one discontinuation attempt, over half (n = 47, 54.7%) reported stopping without clinician knowledge or support. This group was 35% (confidence interval 15.4-54.6%) more likely to stop abruptly than those (n = 41, 45.3%) stopping with clinician support (P = 0.002). Only 10 participants (23.3%) recalled being given information about discontinuation symptoms other than relapse; however, 68 participants (78.2%) reported experiencing a range of discontinuation symptoms including physical, cognitive, emotional, psychotic or sleep-related disturbances. Findings cannot be readily generalized because of sampling constraints. However, the significant number of participants who reported discontinuation symptoms, in addition to psychosis, is consistent with previous research. This study provides new insight into consumer motivations for discontinuation and possible problems in clinical communication that may contribute to frequent non-collaborative discontinuation attempts. Mental health nurses, who play a pivotal role in medication communication events, may benefit from increased awareness of consumer perspectives on this topic. PMID- 25298091 TI - Non-invasive characterization of the adipogenic differentiation of human bone marrow-derived mesenchymal stromal cells by HS-SPME/GC-MS. AB - A non-invasive method to characterize human mesenchymal stromal cells during adipogenic differentiation was developed for the first time. Seven fatty acid methyl esters (FAMEs), including methyl laurate, methyl myristate, methyl palmitate, methyl linoleate, methyl oleate, methyl elaidate and methyl stearate, were used for characterizing adipogenic differentiation using headspace solid phase microextraction (HS-SPME) which is a very simple and non-invasive method for the extraction of volatile compounds. Glassware was used for culturing mesenchymal stromal cells rather than the common plasticware to minimize contamination by volatile impurities. The optimal SPME fiber was selected by comparing diverse fibers containing two pure liquid polymers (PDMS and PA) and two porous solids (PDMS/DVB and CAR/PDMS). Using optimized procedures, we discovered that seven FAMEs were only detected in adipogenic differentiated mesenchymal stromal cells and not in the mesenchymal stromal cells before differentiation. These data could support the quality control of clinical mesenchymal stromal cell culture in the pharmaceutical industry in addition to the development of many clinical applications using mesenchymal stromal cells. PMID- 25298093 TI - OncoCis: annotation of cis-regulatory mutations in cancer. AB - Whole genome sequencing has enabled the identification of thousands of somatic mutations within non-coding genomic regions of individual cancer samples. However, identification of mutations that potentially alter gene regulation remains a major challenge. Here we present OncoCis, a new method that enables identification of potential cis-regulatory mutations using cell type-specific genome and epigenome-wide datasets along with matching gene expression data. We demonstrate that the use of cell type-specific information and gene expression can significantly reduce the number of candidate cis-regulatory mutations compared with existing tools designed for the annotation of cis-regulatory SNPs. The OncoCis webserver is freely accessible at https://powcs.med.unsw.edu.au/OncoCis/. PMID- 25298094 TI - Plant-derived flavones as inhibitors of aurora B kinase and their quantitative structure-activity relationships. AB - Although several plant-derived flavones inhibit aurora B kinase (aurB), quantitative relationships between the structural properties of plant-derived flavones and their inhibitory effects on aurB remain unclear. In this report, these quantitative structure-activity relationships were obtained. For quercetagetin, found in the Eriocaulon species, showing the best IC50 value among the flavone derivatives tested in this report, further biological tests were performed using cell-based assays, including Western blot analysis, flow cytometry, and immunofluorescence microscopy. In vitro cellular experiments demonstrated that quercetagetin inhibits aurB. The molecular-binding mode between quercetagetin and aurB was elucidated using in silico docking. Quercetagetin binds to aurB, aurA, and aurC and prevents the active phosphorylation of all three aurora kinases. In addition, quercetagetin triggers mitotic arrest and caspase-mediated apoptosis. These observations suggest that quercetagetin is an aurora kinase inhibitor. Induction of mitosis-associated tumor cell death by quercetagetin is a promising strategy for developing novel chemotherapeutic anticancer agents. PMID- 25298095 TI - Introduction: the influence and legacy of Barbara Grier. AB - This special issue of the Journal of Lesbian Studies focuses on the life and legacy of the lesbian publisher, editor, and author Barbara Grier. Through Grier's "Lesbiana" column in Daughters of Bilitis's magazine The Ladder, three editions of The Lesbian in Literature (1967, 1975, 1985), to her role as publisher of the Naiad Press from 1973-2003, Grier introduced hundreds of new lesbian books to readers and kept several lesbian classics on the literary horizon. The articles in this issue focus on Grier's biography, history, and impact through archival analysis, interviews, and content analysis. This introduction contextualizes and outlines the articles in this special issue. PMID- 25298096 TI - Barbara Grier and the world she built. AB - Mentored in the art of lesbian literary detection by Jeannette Howard Foster, Barbara Grier became part of a vibrant print-based network of lesbians through her involvement with The Ladder. Building on that foundation, she developed Naiad Press into a successful lesbian business, one that opened doors for lesbian writers and preserved lesbian classics for new generations of readers. Shaped by her class and the times in which she came of age, Grier understood the power of print to change women's lives. Some challenged her commitment to lesbian feminism, but few questioned her dedication to building Naiad into a press that heightened lesbian visibility, fostered self-understanding, and contributed to the creation of community. PMID- 25298097 TI - Lesbis sustineo! Naiad press authors remember Barbara Grier. AB - Drawing from semi-structured interviews with some of Naiad Press's most celebrated women, including Katherine V. Forrest, Barbara's supervising editor at Naiad from 1983-1993; Sheila Ortiz Taylor, author of what is considered by many to be the first lesbian novel with a Chicana heroine; and the incomparable Lee Lynch, this work aims to sustain an ongoing remembrance of Grier's life and work by encouraging memory exploration--a symphonic blending of the printed and spoken word. PMID- 25298098 TI - "The black and white of it": Barbara Grier editing and publishing women of color. AB - In the 1970s and 1980s, lesbian-feminist writing and publishing expressed new theoretical insights about race and envisioned new, intersectional identities. Using texts published and edited by Grier in The Ladder and subsequent Ladder anthologies published by Diana Press, archival documents from Diana Press, and the Grier-Naiad Press papers, this article explores Grier's editorial practices and compares Grier's work to other lesbian-feminist editors and publishers to illuminate different generational understandings of racial-ethnic and class formations within lesbianism and feminism and highlight some of the strategies that White publishers like Grier utilized to realize a vision of multicultural publishing. PMID- 25298099 TI - Tender heroes and twilight lovers: re-reading the romance in mass-market pulp novels, 1950-1965. AB - In mid-century popular presses published paperbacks about lesbians, gay men, and characters with male and female lovers. Barbara Grier was the first to catalog novels featuring lesbian subplots by classifying stories based on the extent and style of lesbian content. I perform a content analysis of 49 novels, motivated by these questions: How did novels with lesbian and gay characters differ from heterosexual romances? What do differences reveal about cultural understandings of love, gender, and sexuality? I find uniformity in the structural logic of novels. However, there are different narrative strategies, and protagonists' gender and sexuality predict a novel's trajectory. PMID- 25298100 TI - Making space for young lesbians in church? Intersectional sites, scripts, and sticking points. AB - This article is a case-study exploration of Christianity and sexuality in the lives of young lesbians in the United Kingdom. Religion matters as a personal and political force, but secularizing trends arguably obscure its influence on the complex convergence and intersection of personal, political, familial, and institutional realms (Brierley, 2006; Heelas and Woodhead, 2005). While the question of homosexuality has been a central focus in much discussion, highlighting around the presumed discontinuity between sexual identity and Christian identity (O'Brien, 2004), there is still a gap in terms of locating first-hand narratives of self-identified young queer Christians. Rather than assuming that these are separate and divergent paths (Wilcox, 2000), this article explores intersectional convergences and divergences, illustrating how religious participation can convey (de)legitimation within family, community and society. Such (de)legitimation is revealed in unpacking scripts of inclusion and exclusion (Taylor and Snowdon, 2014), which are (re)circulated via hetero-homo normative ideals, and perpetuated and contested in the context of intersectional Equalities legislation (Monro and Richardson, 2010). Here, we examine the highly gendered and heteronormative "role models," "mentors," and (familial) mediations experienced by young lesbian Christians, as intersecting public-private domains in the production of queer religious subjectivity and dis-identification. PMID- 25298101 TI - Sappho's shifting fortunes from antiquity to the early Renaissance. AB - Although Sappho was revered as the greatest woman poet of all time by the Greeks, in later antiquity and the Middle Ages, her love of women was considered shameful and overshadowed her excellent reputation. She was also called a prostitute, and fictional accounts of her affairs with men further "tarnished" her reputation. Dual representations of Sappho existed within two centuries of her death. On the one hand, she was a role model for other poets to follow in their quest for fame, on the other she was the quintessential representation of female vice, which, at least by the Roman period, brought her infamy. Late antique and medieval Christian authors inherited this latter view, and vilified Sappho's sexuality, while church authorities, at least according to legend, had her works publicly burned. In the initial stages of the Renaissance, then, the humanist desire to reconnect with the pagan past had to proceed in the context of late medieval Christianity. Sappho's homoeroticism was erased, ultimately, in order that her skill could be lauded to fight misogyny. Hence, the humanists "rehabilitated" Sappho's virtue in a Christian context where same-sex love was considered an "unmentionable" vice. In order to argue that women were smart and capable, the humanists needed Sappho. She was perhaps the most famous, and most skilled, woman who had ever lived, and her example was used in an attempt to improve the lot of women in the early Renaissance. PMID- 25298102 TI - Expanding sisterhood: Jewish lesbians and externalizations of Jewishness. AB - The body is a canvas that can be used to express a kaleidoscope of identities. For Jewish lesbians, who experience marginalization at the hands of both secular and religious society, externalizations of Jewishness can be empowering. For some women, this embodied Jewishness makes a political statement; for others, it gives voice to their Jewish spirituality. In both cases, this ethnographic study probes the ways in which Jewish lesbians experience queerness and Jewishness and how overlaps of these identities manifest in hair styling, yarmulkes, and the wearing of prayer shawls. PMID- 25298104 TI - Soluble factors from colonic epithelial cells contribute to gut homeostasis by modulating macrophage phenotype. AB - Intestinal macrophages originate from inflammatory blood monocytes which migrate to the intestine, where they differentiate into anti-inflammatory macrophages through a number of transitional stages. These macrophages typically remain hypo responsive to commensal bacteria and food Ags in the intestine, yet also retain the ability to react to invading pathogens. In this study we examined the role of epithelial cells in inducing this intestinal macrophage phenotype. Using an in vitro system we showed that, in two-dimensional culture, epithelial cell-derived factors from a murine cell line, CMT-93, are sufficient to induce phenotypic changes in macrophages. Exposure of monocyte-derived macrophages, J774A.1, to soluble factors derived from epithelial cells, induced an altered phenotype similar to that of intestinal macrophages with decreased production of IL-12p40, IL-6 and IL-23 and expression of MHC II and CD80 following TLR ligation. Furthermore, these conditioned macrophages showed enhanced phagocytic activity in parallel with low respiratory burst and NO production, similar to the response seen in intestinal macrophages. Our findings suggest a role for colonic epithelial cells in modulation of macrophage phenotype for maintenance of gut homeostasis. Further understanding of the cell interactions that maintain homeostasis in the gut could reveal novel therapeutic strategies to restore the balance in disease. PMID- 25298105 TI - Effect of human saliva on the consistency of thickened drinks for individuals with dysphagia. AB - BACKGROUND: Thickening of foods and fluids is commonly used in the management of dysphagia to reduce the risk of aspiration. The use of starch-based thickeners is established. However, the use of gums in thickeners is gaining interest as they are resistant to salivary amylase, which may promote safer swallowing. AIMS: To compare the effect of human saliva on the consistency of drinks thickened with a gum-containing (GC) thickener with that of drinks thickened with four starch based (SB) thickeners. METHODS & PROCEDURES: Three drinks (artificial tap water, hot coffee and full-fat milk) were thickened to custard consistency with the different thickeners. Compression force and amount of thin liquid formed were determined after 10 and 50 min of contact with human saliva with standardized amylase activity and compared with a control inoculated with water. OUTCOMES & RESULTS: Drinks thickened with GC thickener were significantly less sensitive to thinning by human saliva compared with drinks thickened with all four SB thickeners (p < 0.05). Moreover, incubation of SB-thickened drinks with human saliva resulted in the formation of at least 10 g of decantable liquid, while for GC-thickened drinks, almost no liquid was formed. CONCLUSIONS & IMPLICATIONS: These results show that GC thickeners contain their consistency better in contact with human saliva than SD thickeners. This may enhance the swallowing safety of people with dysphagia. PMID- 25298107 TI - An assessment of HIV testing in Tanzania to inform future strategies and interventions. AB - This study identified characteristics of Tanzanians who have never tested for HIV in order to inform localized interventions to increase HIV testing coverage and uptake. A total of 3257 randomly selected participants aged 18-49 years were surveyed in 16 Mainland regions. Those surveyed were asked about demographics, HIV risk perception, HIV testing behavior, knowledge of both their own and partner's HIV status, and if they were tested with their partner. Approximately 22% of women and 46% of men reported never testing for HIV, with those who are younger (18-24 years), single/never married, living in rural areas, less educated, and having multiple sexual partners in the past year less likely to have tested. The gender differences in HIV testing behavior identified are supported by existing research. No association was found in either gender between HIV risk perception and testing, however, those least likely to test were those with multiple sex partners. These findings can help better target localized interventions focused on younger, single people, and those with multiple sex partners. PMID- 25298108 TI - Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies. AB - AIMS: The human equilibrative nucleoside transporter 1 (hENT1) expression level in pancreatic ductal adenocarcinoma (PDAC) may predict survival in gemcitabine treated patients after resection. These results have been obtained with a murine anti-hENT1 antibody (10D7G2) that is not commercially available. Another antibody, which is rabbit-derived (SP120), appears to have no predictive value in local, advanced or metastatic PDAC. We aimed to study whether the two antibodies are equivalent. METHODS AND RESULTS: We compared hENT1 expression with both antibodies in resected PDAC. The results were correlated with overall survival (OS) following gemcitabine treatment. Tissues from two sets of patients (n = 147 each) were stained with SP120 by the use of different equipment, with an amplification technique being used for set 2. The rate of 'hENT1 high' cases was lower with SP120 (set 1, 7% versus 48%; set 2, 11% versus 38%). With the amplification technique, the rate of hENT1 high cases was globally similar between both antibodies. However, concordance between the antibodies was found in only 50% of cases. High hENT1 expression was predictive of OS only with 10D7G2 (hazard ratio 0.49; 95% confidence interval 0.24-0.98; P = 0.045). CONCLUSIONS: The two antibodies are not equivalent. Further prospective studies seem to be warranted before hENT1 testing for PDAC is used in daily practise. PMID- 25298109 TI - Impaired haemophilus influenzae type b transplacental antibody transmission and declining antibody avidity through the first year of life represent potential vulnerabilities for HIV-exposed but -uninfected infants. AB - To determine whether immune function is impaired among HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers and to identify potential vulnerabilities to vaccine-preventable infection, we characterized the mother-to infant placental transfer of Haemophilus influenzae type b-specific IgG (Hib-IgG) and its levels and avidity after vaccination in Ugandan HEU infants and in HIV unexposed U.S. infants. Hib-IgG was measured by enzyme-linked immunosorbent assay in 57 Ugandan HIV-infected mothers prenatally and in their vaccinated HEU infants and 14 HIV-unexposed U.S. infants at birth and 12, 24, and 48 weeks of age. Antibody avidity at birth and 48 weeks of age was determined with 1 M ammonium thiocyanate. A median of 43% of maternal Hib-IgG was transferred to HEU infants. Although its level was lower in HEU infants than in U.S. infants at birth (P < 0.001), Hib-IgG was present at protective levels (>1.0 MUg/ml) at birth in 90% of HEU infants and all U.S. infants. HEU infants had robust Hib-IgG responses to a primary vaccination. Although Hib-IgG levels declined from 24 to 48 weeks of age in HEU infants, they were higher than those in U.S. infants (P = 0.002). Antibody avidity, comparable at birth, declined by 48 weeks of age in both populations. Early vaccination of HEU infants may limit an initial vulnerability to Hib disease resulting from impaired transplacental antibody transfer. While initial Hib vaccine responses appeared adequate, the confluence of lower antibody avidity and declining Hib-IgG levels in HEU infants by 12 months support Hib booster vaccination at 1 year. Potential immunologic impairments of HEU infants should be considered in the development of vaccine platforms for populations with high maternal HIV prevalence. PMID- 25298110 TI - Immunologic characterization of a rhesus macaque H1N1 challenge model for candidate influenza virus vaccine assessment. AB - Despite the availability of annually formulated vaccines, influenza virus infection remains a worldwide public health burden. Therefore, it is important to develop preclinical challenge models that enable the evaluation of vaccine candidates while elucidating mechanisms of protection. Here, we report that naive rhesus macaques challenged with 2009 pandemic H1N1 (pH1N1) influenza virus do not develop observable clinical symptoms of disease but develop a subclinical biphasic fever on days 1 and 5 to 6 postchallenge. Whole blood microarray analysis further revealed that interferon activity was associated with fever. We then tested whether type I interferon activity in the blood is a correlate of vaccine efficacy. The animals immunized with candidate vaccines carrying hemagglutinin (HA) or nucleoprotein (NP) exhibited significantly reduced interferon activity on days 5 to 6 postchallenge. Supported by cellular and serological data, we conclude that blood interferon activity is a prominent marker that provides a convenient metric of influenza virus vaccine efficacy in the subclinical rhesus macaque model. PMID- 25298111 TI - Is 'peak N' key to understanding the timing of flowering in annual plants? AB - Flowering time in annual plants has large fitness consequences and has been the focus of theoretical and empirical study. Previous theory has concluded that flowering time has evolved over evolutionary time to maximize fitness over a particular season length. We introduce a new model where flowering is cued by a growth-rate rule (peak nitrogen (N)). Flowering is therefore sensitive to physiological parameters and to current environmental conditions, including N availability and the presence of competitors. The model predicts that, when overall conditions are suitable for flowering, plants should never flower after 'peak N', the point during development when the whole-plant N uptake rate reaches its maximum. Our model further predicts correlations between flowering time and vegetative growth rates, and that the response to increased N depends heavily on how this extra N is made available. We compare our predictions to observations in the literature. We suggest that annual plants may have evolved to use growth-rate rules as part of the cue for flowering, allowing them to smoothly and optimally adjust their flowering time to a wide range of local conditions. If so, there are widespread implications for the study of the molecular biology behind flowering pathways. PMID- 25298112 TI - Comments on: 'Anaphylaxis caused by in-season switchover of sublingual immunotherapy formulation'. PMID- 25298113 TI - Gaussian modeling of the P-wave morphology time course applied to anticipate paroxysmal atrial fibrillation. AB - This paper introduces a new algorithm to quantify the P-wave morphology time course with the aim of anticipating as much as possible the onset of paroxysmal atrial fibrillation (PAF). The method is based on modeling each P-wave with a single Gaussian function and analyzing the extracted parameters variability over time. The selected Gaussian approaches are associated with the amplitude, peak timing, and width of the P-wave. In order to validate the algorithm, electrocardiogram segments 2 h preceding the onset of PAF episodes from 46 different patients were assessed. According to the expected intermittently disturbed atrial conduction before the onset of PAF, all the analyzed Gaussian metrics showed an increasing variability trend as the PAF onset approximated. Moreover, the Gaussian P-wave width reported a diagnostic accuracy around 80% to discern between healthy subjects, patients far from PAF, and patients less than 1 h close to a PAF episode. This discriminant power was similar to those provided by the most classical time-domain approach, i.e., the P-wave duration. However, this newly proposed parameter presents the advantage of being less sensitive to a precise delineation of the P-wave boundaries. Furthermore, the linear combination of both metrics improved the diagnostic accuracy up to 86.69%. In conclusion, morphological P-wave characterization provides additional information to the metrics based on P-wave timing. PMID- 25298115 TI - Prolonging the circulatory retention of SPIONs using dextran sulfate: in vivo tracking achieved by functionalisation with near-infrared dyes. AB - The rapid reticuloendothelial system (RES) mediated clearance of superparamagnetic iron oxide nanoparticles (SPIONs) from circulation is considered a major limitation of their clinical utility. We aimed to address this by using dextran sulfate 500 (DSO4 500), a Kupffer cell blocking agent, to prolong SPIONs circulatory time. Blood concentrations of SPIONs are difficult to quantify due to the presence of haemoglobin. We therefore developed methods to functionalise SPIONs with near-infrared (NIR) dyes in order to trace their biodistribution. Two SPIONs were investigated: Nanomag(r)-D-spio-NH(2) and Ferucarbotran. Nanomag(r)-D-spio-NH(2) was functionalised using NHS (N hydroxysuccinimide) ester NIR dye and Ferucarbotran was labelled using periodate oxidation followed by reductive amination or a combination of EDC (ethyl(dimethylaminopropyl) carbodiimide )/NHS and click chemistries. Stability after conjugation was confirmed by dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and transmission electron microscopy (TEM). In vivo experiments with the functionalised SPIONs showed a significant improvement in SPIONs blood concentrations in mice pre-treated with dextran sulfate sodium salt 500 (DSO4 500). PMID- 25298114 TI - Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. AB - The HIV-1 envelope (Env) mediates viral entry into host cells. To enable the direct imaging of conformational dynamics within Env, we introduced fluorophores into variable regions of the glycoprotein gp120 subunit and measured single molecule fluorescence resonance energy transfer within the context of native trimers on the surface of HIV-1 virions. Our observations revealed unliganded HIV 1 Env to be intrinsically dynamic, transitioning between three distinct prefusion conformations, whose relative occupancies were remodeled by receptor CD4 and antibody binding. The distinct properties of neutralization-sensitive and neutralization-resistant HIV-1 isolates support a dynamics-based mechanism of immune evasion and ligand recognition. PMID- 25298116 TI - Tracing phosphate ions generated during DNA amplification and its simple use for visual detection of isothermal amplified products. AB - A yes/no answer for DNA isothermal amplification can be visually obtained with this phosphate ion-based method described in this communication. An extremely rapid detection for cross-priming isothermal amplification was proved and the feasibility of this strategy was systematically studied. PMID- 25298117 TI - Real-world economic impact of onabotulinumtoxinA in patients with chronic migraine. AB - OBJECTIVE: To determine whether the utilization of healthcare resources is reduced after chronic migraine patients are treated for 6 months with onabotulinumtoxinA. BACKGROUND: OnabotulinumtoxinA is indicated for headache prophylaxis in patients with chronic migraine, but its effect on healthcare resource use is unknown. METHODS: We analyzed data from an open-label study of 230 chronic migraine patients refractory to >=2 oral prophylactics who presented to a headache specialty clinic and who were treated with two cycles of onabotulinumtoxinA. Frequency and cost of migraine-related healthcare resource use, including visits to emergency departments, urgent care, or hospitalization, were compared for the 6 months before and after initial treatment. Costs were based on publicly available sources. RESULTS: Compared with the 6 months predating initial treatment, patients had 55% fewer emergency department visits (174 vs 385), 59% fewer urgent care visits (61 vs 150), and 57% fewer hospitalizations (19 vs 45) during the 6-month treatment period (P < .01 for all). Analysis of treatment-related costs yielded an average reduction of $1219.33/patient, off-setting 49.7% of the total estimated cost for 6 months of treatment with onabotulinumtoxinA. CONCLUSIONS: Although we are unable to distinguish onabotulinumtoxinA's treatment effect from other potential confounding variables, our analysis showed that severely afflicted, treatment refractory patients with chronic migraine experienced a significant cost-offset through reduced migraine-related emergency department visits, urgent care visits, and hospitalizations in the 6 months following treatment initiation of onabotulinumtoxinA. Future analyses will assess the longer-term effect of onabotulinumtoxinA treatment and the potential contribution of regression to the mean. PMID- 25298119 TI - Management of non-cognitive symptoms associated with dementia. AB - Up to 75% of patients with dementia will experience non-cognitive symptoms.1 These often present as psychotic symptoms, behavioural disturbances and changes in mood.1 Such symptoms provide a significant challenge for patients and their carers, and are often difficult to manage. Antipsychotic drugs have been widely used to treat non-cognitive symptoms of dementia. However, in 2004 data emerged linking the use of some antipsychotic drugs with an increased risk of stroke and death in patients with dementia.2 Since then, there has been a national drive to ensure that antipsychotic drugs are used appropriately. In 2007, we reviewed the safety of antipsychotics in people with dementia.3 Here, we provide an update on the evidence for the efficacy and safety of interventions used to manage non cognitive symptoms of dementia. PMID- 25298118 TI - Effect of central metal ions of analogous metal-organic frameworks on adsorption of organoarsenic compounds from water: plausible mechanism of adsorption and water purification. AB - The adsorptive removal of organoarsenic compounds such as p-arsanilic acid (ASA) and roxarsone (ROX) from water using metal-organic frameworks (MOFs) has been investigated for the first time. A MOF, iron benzenetricarboxylate (also called MIL-100-Fe) exhibits a much higher adsorption capacity for ASA and ROX than activated carbon, zeolite (HY), goethite, and other MOFs. The adsorption of ASA and ROX over MIL-100-Fe is also much more rapid than that over activated carbon. Moreover, the used MIL-100-Fe can be recycled by simply washing with acidic ethanol. Therefore, it is determined that a MOF such as MIL-100-Fe can be used to remove organoarsenic compounds from contaminated water because of its high adsorption capacity, rapid adsorption, and ready regeneration. Moreover, only one of three analogous MIL-100 species (MIL-100-Fe, rather than MIL-100-Al or MIL-100 Cr) can effectively remove the organoarsenic compounds. This selective and high adsorption over MIL-100-Fe, different from other analogous MIL-100 species, can be explained (through calculations) by the facile desorption of water from MIL 100-Fe as well as the large (absolute value) replacement energy (difference between the adsorption energies of the organoarsenic compounds and water) exhibited by MIL-100-Fe. A plausible adsorption/desorption mechanism is proposed based on the surface charge of the MOFs, FTIR results, calculations, and the reactivation results with respect to the solvents used in the experiments. PMID- 25298120 TI - Potassium hydroxide 5% for the treatment of molluscum contagiosum. AB - Molluscum contagiosum is a common reason for consultation in primary care. The condition is normally benign and self-limiting1 and the standard advice is to wait for the lesions to resolve spontaneously.2 Recently, potassium hydroxide 5% (MolluDab-Alliance Pharmaceuticals Limited) has been marketed in the UK for the treatment of the condition.3 It is sold as a medical device rather than a licensed medicinal product. Here we consider the evidence for potassium hydroxide 5% in the management of molluscum contagiosum. PMID- 25298121 TI - Genetic analysis should be included in clinical practice when screening for antithrombin deficiency. AB - Antithrombin (AT) deficiency increases the risk of thrombosis. Current evidence shows that some SERPINC1 mutations responsible for antithrombin deficiency often present a slightly decreased or normal activity and therefore could not be detected by functional tests. This study was designed to compare activity assays and direct genetic analyses in identifying hereditary antithrombin deficiency. In total, 400 consecutive patients with venous thrombosis were enrolled. Functional assays showed that 16 of the 400 individuals had decreased antithrombin activity, and 14 of them were confirmed by genetic analysis. Of the remaining 384 patients, 95 individuals without a known risk factor and 95 individuals with predisposing factors were also selected for gene sequencing. Eight additional causative mutations were identified in nine individuals and they should also be considered as antithrombin deficiency. In addition, a recurrent mutation, p.Arg356_Phe361del, was characterised. The mutant appeared to have a partially impaired secretion and a reduction in functional activity by 50 %. This study indicated that including genetic analysis in screening tests for identifying antithrombin deficiency was essential. Specifically, a genetic analysis of SERPINC1 is strongly recommended when individuals experience unprovoked thrombotic diseases, even if the AT activities are normal. PMID- 25298124 TI - A general approach to spirolactonized Si-rhodamines. AB - A general approach has been developed for the synthesis of spirolactonized Si rhodamines (SiRBs). The alternative synthetic route provides a facile opportunity to access various s bearing ring-expanded scaffolds and substituents for conjugation. By click reaction, a near-infrared (NIR) mitochondrial tracker was prepared, displaying specific mitochondrial staining in cells. PMID- 25298123 TI - Seeking potential anticonvulsant agents that target GABAA receptors using experimental and theoretical procedures. AB - The aim of this study was to identify compounds that possess anticonvulsant activity by using a pentylenetetrazol (PTZ)-induced seizure model. Theoretical studies of a set of ligands, explored the binding affinities of the ligands for the GABA(A) receptor (GABA(A)R), including some benzodiazepines. The ligands satisfy the Lipinski rules and contain a pharmacophore core that has been previously reported to be a GABA(A)R activator. To select the ligands with the best physicochemical properties, all of the compounds were analyzed by quantum mechanics and the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital were determined. Docking calculations between the ligands and the GABA(A)R were used to identify the complexes with the highest Gibbs binding energies. The identified compound D1 (dibenzo(b,f)(1,4)diazocine 6,11(5H,12H)-dione) was synthesized, experimentally tested, and the GABA(A)R-D1 complex was submitted to 12-ns-long molecular dynamics (MD) simulations to corroborate the binding conformation obtained by docking techniques. MD simulations were also used to analyze the decomposition of the Gibbs binding energy of the residues involved in the stabilization of the complex. To validate our theoretical results, molecular docking and MD simulations were also performed for three reference compounds that are currently in commercial use: clonazepam (CLZ), zolpidem and eszopiclone. The theoretical results show that the GABA(A)R D1, and GABA(A)R-CLZ complexes bind to the benzodiazepine binding site, share a similar map of binding residues, and have similar Gibbs binding energies and entropic components. Experimental studies using a PTZ-induced seizure model showed that D1 possesses similar activity to CLZ, which corroborates the predicted binding free energy identified by theoretical calculations. PMID- 25298122 TI - Identification and characterization of OSTL (RNF217) encoding a RING-IBR-RING protein adjacent to a translocation breakpoint involving ETV6 in childhood ALL. AB - Genomic aberrations involving ETV6 on band 12p13 are amongst the most common chromosomal abnormalities in human leukemia. The translocation t(6;12)(q23;13) in a childhood B-cell acute lymphoblastic leukemia (ALL) cell line fuses ETV6 with the putative long non-coding RNA gene STL. Linking STL properties to leukemia has so far been difficult. Here, we describe a novel gene, OSTL (annotated as RNF217 in Genbank), which shares the first exon and a CpG island with STL but is transcribed in the opposite direction. Human RNF217 codes for a highly conserved RING finger protein and is mainly expressed in testis and skeletal muscle with different splice variants. RNF217 shows regulated splicing in B cell development, and is expressed in a number of human B cell leukemia cell lines, primary human chronic myeloid leukemia, acute myeloid leukemia with normal karyotype and acute T-ALL samples. Using a yeast two-hybrid screen, we identified the anti-apoptotic protein HAX1 to interact with RNF217. This interaction could be mapped to the C terminal RING finger motif of RNF217. We propose that some of the recurring aberrations involving 6q might deregulate the expression of RNF217 and result in imbalanced apoptosis signalling via HAX1, promoting leukemia development. PMID- 25298125 TI - Post-transplant lymphoproliferative disorders are not associated with IgG4 sclerosing disease. AB - BACKGROUND: Although the majority of post-transplant lymphoproliferative disorder (PTLD) cases are associated with Epstein-Barr virus (EBV), 20-42% of cases are EBV negative (EBV-N). The antigenic stimulus that drives EBV-N PTLD is unknown, but is likely heterogeneous. A common feature of PTLD, regardless of EBV status, is an abnormal polytypic lymphoplasmacytic infiltrate. Immunglobulin-G4 (IgG4) syndrome is also characterized by a polytypic lymphoplasmacytic infiltrate with a predominance of IgG4-positive (IgG4-P) plasma cells. METHODS: We investigated the possibility of an association between EBV-N PTLD and IgG4 syndrome. Of 33 evaluated PTLD cases, 9 (27%) were EBV-N. EBV-N PTLD cases showed longer transplantation-to-diagnosis times than EBV-positive cases. RESULTS: A single patient had a preceding benign duodenal biopsy with focally prominent IgG4-P plasma cells; however, no clinical data supported IgG4 syndrome, precluding an association between IgG4 syndrome and subsequent EBV-N PTLD in this patient. CONCLUSION: As none of 29 evaluable cases of PTLD (including all 9 EBV-N cases) were associated with an increase in IgG4-P plasma cells, IgG4 syndrome does not appear to play a role in the etiology of EBV-N PTLD. The significance of these findings and the current understanding of the etiology of EBV-N PTLD are discussed. PMID- 25298127 TI - Endodontic biofilm, technology and pulpal regenerative therapy: where do we go from here? PMID- 25298128 TI - Postoperative hypocaloric peripheral parenteral nutrition with branched-chain enriched amino acids provides no better clinical advantage than fluid management in nonmalnourished colorectal cancer patients. AB - To assess clinical efficacy of using postoperative branched-chain amino acids (BCAAs)-enriched nutritional support in lower gastrointestinal cancer patients, we conducted a retrospective observational study comparing this regimen with traditional fluid management. Sixty-one eligible colorectal cancer patients consecutively admitted in the Colorectal Surgery Ward to receive postoperative hypocaloric peripheral parenteral nutrition (HPPN) were categorized into dextrose only control group (n = 20), dextrose plus low-dose BCAA fat group (n = 20), and dextrose plus high-dose BCAA fat group (n = 21). Nutritional, clinical, and biochemical outcomes were collected on the day before and 7 days after surgery. Patients were nonmalnourished. Over the 7-day observation period, the control group had a significantly higher reduction in body mass index than the lower dose and the higher dose BCAA groups (P = 0.023 and P = 0.002, respectively). Compared to high-dose BCAA group, the control group also had a lower nitrogen excretion (P < 0.0001) and less reduction in nitrogen balance (P < 0.0001). There were no differences between study groups in biochemical measures, phlebitis, postoperative hospital stay, and in-hospital mortality. We found no better clinical advantage to the postoperative administration of BCAA-enriched HPPN than fluid management in nonmalnourished colorectal cancer patients. PMID- 25298129 TI - Painfully thin but locked inside a fatter body: abnormalities in both anticipation and execution of action in anorexia nervosa. AB - BACKGROUND: People with anorexia nervosa (AN) usually report feeling broader than they really are. The objective of the present study was to better understand the body schema's involvement in this false self-representation in AN. We tested the potential for correction of the body schema impairment via the sensorimotor feedback provided by a real, executed action and relative to an imagined action. We also took account of the impact of the AN patients' weight variations on the task outcomes. METHODS: Fourteen inpatient participants with AN and fourteen control participants were presented with a doorway-like aperture. The participants had to (i) judge whether or not various apertures were wide enough for them to pass through in a motor imagery task and then (ii) actually perform the action by passing through various apertures. RESULTS: We observed a higher passability ratio (i.e. the ratio between the critical aperture size and shoulder width) in participants with AN (relative to controls) for both motor imagery and real action. Moreover, the magnitude of the passability ratio was positively correlated with weight recovery. CONCLUSION: The body schema alteration in AN appears to be strong enough to affect the patient's actions. Furthermore, the alteration resists correction by the sensorimotor feedback generated during action. This bias is linked to weight variations. The central nervous system might be locked to a false representation of the body that cannot be updated. Moreover, these results prompt us to suggest that emotional burden during weight recovery could also alter sensorimotor aspects of body representation. New therapeutic methods should take account of body schema alterations in AN as adjuncts to psychotherapy. PMID- 25298126 TI - Biomarkers in the diagnosis of ADHD--promising directions. AB - The etiology and pathogenesis of attention-deficit/hyperactivity disorder (ADHD) are unclear and a more valid diagnosis would certainly be welcomed. Starting from the literature, we built an hypothetical pyramid representing a putative set of biomarkers where, at the top, variants in DAT1 and DRD4 genes are the best candidates for their associations to neuropsychological tasks, activation in specific brain areas, methylphenidate response and gene expression levels. Interesting data come from the noradrenergic system (norepinephrine transporter, norepinephrine, 3-methoxy-4-hydroxyphenylglycol, monoamine oxidase, neuropeptide Y) for their altered peripheral levels, their association with neuropsychological tasks, symptomatology, drugs effect and brain function. Other minor putative genetic biomarkers could be dopamine beta hydroxylase and catechol-O methyltransferase. In the bottom, we placed endophenotype biomarkers. A more deep integration of "omics" sciences along with more accurate clinical profiles and new high-throughput computational methods will allow us to identify a better list of biomarkers useful for diagnosis and therapies. PMID- 25298130 TI - Dynamic formation of hybrid peptidic capsules by chiral self-sorting and self assembly. AB - Owing to their versatility and biocompatibility, peptide-based self-assembled structures constitute valuable targets for complex functional designs. It is now shown that artificial capsules based on beta-barrel binding motifs can be obtained by means of dynamic covalent chemistry (DCC) and self-assembly. Short peptides (up to tetrapeptides) are reversibly attached to resorcinarene scaffolds. Peptidic capsules are thus selectively formed in either a heterochiral or a homochiral way by simultaneous and spontaneous processes, involving chiral sorting, tautomerization, diastereoselective induction of inherent chirality, and chiral self-assembly. Self-assembly is shown to direct the regioselectivity of reversible chemical reactions. It is also responsible for shifting the tautomeric equilibrium for one of the homochiral capsules. Two different tautomers (keto enamine hemisphere and enol-imine hemisphere) are observed in this capsule, allowing the structure to adapt for self-assembly. PMID- 25298131 TI - Defining the role of oxidative stress in atrial fibrillation and diabetes. PMID- 25298132 TI - Compatibility of reduced-risk insecticides with the non-target predatory mite Iphiseius degenerans (Acari: Phytoseiidae). AB - BACKGROUND: Iphiseius degenerans (Berlese) (Acari: Phytoseiidae) is a common predatory mite in citrus orchards in some areas of the Mediterranean basin and an important biological control agent of the thrips Frankliniella occidentalis (Pergande) in Integrated Pest Management (IPM) programmes in greenhouse crops. In this study, we evaluated the effects of the 'reduced-risk' insecticides acetamiprid, chlorantraniliprole, flubendiamide, metaflumizone, methoxyfenozide, spinetoram and thiamethoxam on I. degenerans, as a means of testing their compatibility in IPM programmes. RESULTS: Although all pesticides decreased immature survival, high mortality was only recorded for young larvae when exposed to acetamiprid, while metaflumizone, thiamethoxam and spinetoram resulted in intermediate lethal effects. The estimated LC50 values of acetamiprid, spinetoram and thiamethoxam for I. degenerans females were 0.52, 0.84 and 0.16-fold lower than the respective maximum recommended doses of the pesticides for field application. Although all pesticides tested significantly decreased fecundity, highest rates corresponded to the three pesticides already mentioned. CONCLUSION: Chlorantraniliprole, flubendiamide and methoxyfenozide may preliminarily be included in IPM programmes, whereas the effects of acetamiprid, metaflumizone, spinetoram and thiamethoxam on I. degenerans should be clarified in further field toxicological tests. This information could be useful for rationally planning and implementing pest management on a sustainable basis. PMID- 25298133 TI - Complicated type B aortic dissection causing ischemia in the celiac and inferior mesenteric artery distribution despite patent superior mesenteric artery bypass. AB - Mortality rates associated with acute type B aortic dissection (ABAD) complicated by malperfusion remains significant. Optimal management of patients with ABAD is still debatable. We present a case report of a 50-year-old man who was admitted due to ABAD. He was treated medically with his pain resolved and he was discharged on oral antihypertensive medications. One month after initial diagnosis, he was readmitted with abdominal pain, nausea, vomiting, and diarrhea. On imaging, an extension of the aortic dissection into the visceral arteries with occlusion of the celiac and superior mesenteric arteries (SMA) was noted. He underwent thoracic endovascular aortic repair (TEVAR) and bypass grafting to the SMA. Despite the intervention, the patient developed large bowel, liver, and gastric ischemia and underwent bowel resection. He died from multi-organ failure. In selected cases of uncomplicated ABAD, TEVAR should be considered and when TEVAR fails and visceral malperfusion develops, an aggressive revascularization of multiple visceral arteries should be attempted. PMID- 25298134 TI - Diagnostic performance of CE-MRA in grading stenosis and therapy planning with TASC II classification. AB - OBJECTIVES: To assess to what extent results of CE-MRA coincide with DSA in grading of stenosis and planning of therapy in patients with PAOD. MATERIALS AND METHODS: Retrospectively, images of 71 PAOD-patients were studied by three observers. For evaluation, the lower limb was subdivided into 31 segments and categorized with TASCII-score. RESULTS: In grading stenosis, both modalities agreed in 93.26%. CE-MRA achieved sensitivity of 92.69% and specificity of 96.87% (kappa = 0.88). The concordance of TASCII-classification was almost perfect. CONCLUSION: CE-MRA is an excellent method for the evaluation of PAOD with some tendency to overrate the grade of stenosis. PMID- 25298135 TI - Geometric changes of the inferior vena cava in trauma patients subjected to volume resuscitation. AB - OBJECTIVE: Dynamic changes in anatomic geometry of the inferior vena cava from changes in intravascular volume may cause passive stresses on inferior vena cava filters. In this study, we aim to quantify variability in inferior vena cava dimensions and anatomic orientation to determine how intravascular volume changes may impact complications of inferior vena cava filter placement, such as migration, tilting, perforation, and thrombosis. METHODS: Retrospective computed tomography measurements of major axis, minor axis, and horizontal diameters of the inferior vena cava at 1 and 5 cm below the lowest renal vein in 58 adult trauma patients in pre-resuscitative (hypovolemic) and post-resuscitative (euvolemic) states were assessed in a blinded fashion by two independent readers. Inferior vena cava perimeter, area, and volume were calculated and correlated with caval orientation. RESULTS: Mean volumes of the inferior vena cava segment on pre- and post-resuscitation scans were 9.0 cm(3) and 11.0 cm(3), respectively, with mean percentage increase of 48.6% (P < 0.001). At 1 cm and 5 cm below the lowest renal vein, the inferior vena cava expanded anisotropically, with the minor axis expanding by an average of 48.7% (P < 0.001) and 30.0% (P = 0.01), respectively, while the major axis changed by only 4.2% (P = 0.11) and 6.6% (P = 0.017), respectively. Cross-sectional area and perimeter at 1 cm below the lowest renal vein expanded by 61.6% (P < 0.001) and 10.7% (P < 0.01), respectively. At 5 cm below the lowest renal vein, the expansion of cross-sectional area and perimeter were 43.9% (P < 0.01) and 10.7% (P = 0.002), respectively. The major axis of the inferior vena cava was oriented in a left-anterior oblique position in all patients, averaging 20 degrees from the horizontal plane. There was significant underestimation of inferior vena cava maximal diameter by horizontal measurement. In pre-resuscitation scans, at 1 cm and 5 cm below the lowest renal vein, the discrepancy between the horizontal and major axis diameter was 2.1 +/- 1.2 mm (P < 0.001) and 1.7 +/- 1.0 mm (P < 0.001), respectively, while post resuscitation studies showed the same underestimation at 1 cm and 5 cm below the lowest renal vein to be 2.2 +/- 1.2 mm (P < 0.01) and 1.9 +/- 1.0 mm (P < 0.01), respectively. CONCLUSIONS: There is significant anisotropic variability of infrarenal inferior vena cava geometry with significantly greater expansive and compressive forces in the minor axis. There can be significant volumetric changes in the inferior vena cava with associated perimeter changes but the major axis left-anterior oblique caval configuration is always maintained. These significant dynamic forces may impact inferior vena cava filter stability after implantation. The consistent major axis left-anterior oblique obliquity may lead to underestimation of the inferior vena cava diameter used in standard anteroposterior venography, which may influence initial filter selection. PMID- 25298136 TI - Endovascular repair of a complex giant infrarenal abdominal aortic aneurysm. AB - Giant aortic aneurysms (transverse diameter greater than 10.0 cm) are rare and open surgery is often the treatment of choice. We report an infrarenal saccular giant aortic aneurysm (measuring 25 cm in transverse diameter), which was treated with endovascular repair, with immediate technical success. No similar report of a giant infrarenal aortic aneurysm treated with an endovascular technique was found in the literature. High-risk patients could possibly benefit from the endovascular technique. Nevertheless, patient survival remains strongly influenced by comorbidities. PMID- 25298137 TI - Comparison of morphological and rheological conditions between conventional and eversion carotid endarterectomy using computational fluid dynamics--a pilot study. AB - PURPOSE: To compare postoperative morphological and rheological conditions after eversion carotid endarterectomy versus conventional carotid endarterectomy using computational fluid dynamics. BASIC METHODS: Hemodynamic metrics (velocity, wall shear stress, time-averaged wall shear stress and temporal gradient wall shear stress) in the carotid arteries were simulated in one patient after conventional carotid endarterectomy and one patient after eversion carotid endarterectomy by computational fluid dynamics analysis based on patient specific data. PRINCIPAL FINDINGS: Systolic peak of the eversion carotid endarterectomy model showed a gradually decreased pressure along the stream path, the conventional carotid endarterectomy model revealed high pressure (about 180 Pa) at the carotid bulb. Regions of low wall shear stress in the conventional carotid endarterectomy model were much larger than that in the eversion carotid endarterectomy model and with lower time-averaged wall shear stress values (conventional carotid endarterectomy: 0.03-5.46 Pa vs. eversion carotid endarterectomy: 0.12-5.22 Pa). CONCLUSIONS: Computational fluid dynamics after conventional carotid endarterectomy and eversion carotid endarterectomy disclosed differences in hemodynamic patterns. Larger studies are necessary to assess whether these differences are consistent and might explain different rates of restenosis in both techniques. PMID- 25298138 TI - Bowel ischemia caused by a giant thrombus in the ascending aorta. A case report. AB - Although an ascending aortic thrombus is a rare condition, it can cause serious complications of thromboembolism. Here we present a rare case of a patient who was hospitalized due to ileal arteries embolization caused by emboli from a giant thrombus in the ascending aorta. After 10 days anti-coagulation therapy, we performed a surgery to replace the ascending aorta containing the strip organized thrombus with a synthetic graft. During two years of postoperative follow-up, no recurrence of aortic thrombosis was found. Although the exact cause of this thrombus remains unclear, we believe that it is important to perform a surgery as soon as the presence of an ascending aortic thrombus is confirmed, which could help preventing the major recurrent embolic events. PMID- 25298139 TI - Distal renal tubular acidosis in AIDS young woman with wasting syndrome. PMID- 25298140 TI - Urinary TGF-1 has a supplementary value in predicting renal function recovery post unilateral ureteral obstruction. AB - PURPOSE: To evaluate whether urine transforming growth factor-beta1 (TGF-beta1) can help identifying kidneys that would recover their function after drainage of unilateral ureteric obstructive. METHODS: Forty-five patients with unilateral ureteral obstruction were included. Glomerular filtration rate (GFR) of the obstructed kidney was <10 ml/min, and all patients were treated with percutaneous nephrostomy. TGF-beta1 level was measured in the urine from the obstructed kidney at the time of drainage. GFR before nephrostomy insertion and 3 months after were calculated. RESULTS: Patients with renal function improvement (significant increase in GFR) after nephrostomy insertion had significantly lower concentration of urine TGF-beta1 (p<0.05) compared with the group that showed no change in GFR (non-functioning kidneys) The sensitivity, specificity and accuracy of urine TGF-beta1 in identifying non-functioning kidney was 82, 82 and 82%, respectively. CONCLUSIONS: Urine TGF-beta1 is a cytokine leading to renal fibrosis and has a supplementary value in differentiating, at early stage, between kidneys that would recover function after releasing unilateral ureteral obstruction from those which will not (non-functioning kidneys). PMID- 25298142 TI - Prompt diagnosis of multiple sclerosis should be routine, says NICE. PMID- 25298141 TI - Study of mizoribine therapy in elderly patients with membranous nephropathy: comparison with patients not receiving mizoribine. AB - BACKGROUND: We have previously reported the results of mizoribine (MZR) treatment for elderly patients with membranous nephropathy (MN). Here, we retrospectively compared these patients with those who had been initially treated with prednisolone (PSL) alone. METHODS: The subjects were patients with MN aged >=65 years who were examined between April 2007 and September 2010 and followed for at least 1 year. RESULTS: The median period until the start of treatment in the MZR group (MZR-G) was 60 days. The urinary protein level at the start of MZR treatment was 3.89+/-2.3 g/gCr. Urinary protein in the group not treated with MZR (N-MZR-G) was 1.0+/-1.1 g/gCr, showing a tendency to improve in patients with nephrotic syndrome relative to the MZR-G (p=0.055). The PSL dose in the MZR-G versus N-MZR-G at 1 year was 5.7+/-3.0 versus 6.25+/-2.5 mg/day, the urinary protein level was 0.19+/-0.2 versus 0.13+/-0.1 g/gCr, and the remission rate was 80 versus 75%. In the MZR-G, the total PSL dose at 1 year after the start of MZR treatment was 5,058+/-1,904 versus 6,649+/-875 mg in the N-MZR-G. Adverse events occurred in 3/5 patients (60%) in the MZR-G and in 3/4 patients (75%) in the N MZR-G. CONCLUSION: Elderly patients with MN who respond poorly to PSL treatment may be treated successfully with MZR. PMID- 25298143 TI - Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling. AB - Recent reports have highlighted the roles of free fatty acid receptor 2 (FFAR2) in the regulation of metabolic and inflammatory processes. However, the potential function of FFAR2 in type 1 diabetes (T1D) remains unexplored. Our results indicated that the mRNA level of FFAR2 was upregulated in peripheral blood mononuclear cells of T1D patients. The human FFAR2 promoter regions were cloned, and luciferase reporter assays revealed that NFkappaB activation induced FFAR2 expression. Furthermore, we showed that FFAR2 activation by overexpression induced cell apoptosis through ERK signaling. Finally, treatment with the FFAR2 agonists acetate or phenylacetamide 1 attenuated the inflammatory response in multiple-low-dose streptozocin-induced diabetic mice, and improved the impaired glucose tolerance. These results indicate that FFAR2 may play a protective role by inducing apoptosis of infiltrated macrophage in the pancreas through its feedback upregulation and activation, thus, in turn, improving glucose homeostasis in diabetic mice. These findings highlight FFAR2 as a potential therapeutic target of T1D, representing a link between immune response and glucose homeostasis. PMID- 25298145 TI - Development and validation of a simple and isocratic reversed-phase HPLC method for the determination of rilpivirine from tablets, nanoparticles and HeLa cell lysates. AB - In the present investigation, a simple and isocratic HPLC-UV method was developed and validated for determination of rilpivirine (RPV) from dosage forms (tablets and nanoparticles) and biological matrices like HeLa cell lysates. The separation and analysis of RPV was carried out under isocratic conditions using (a) a Gemini reversed-phase C18 column (5 um; 4.6 * 150 mm) maintained at 35 degrees C, (b) a mobile phase consisting of a mixture of acetonitrile and 25 m m potassium dihydrogen phosphate (in the ratio 50:50 v/v) at a flow rate of 0.6 mL/min and (c) atazanavir as an internal standard. The total run time was 17 min and the analysis of RPV and internal standard was carried out at 290 nm. The method was found to be linear (r(2) value > 0.998), specific, accurate and precise over the concentration range of 0.025-2 ug/mL. The lower limit of quantification was 0.025 ug/mL, the limit of detection was 0.008 ug/mL and the recovery of RPV was >90%. The stability of the RPV analytical method was confirmed at various conditions such as room temperature (24 h), -20 degrees C (7 days), three freeze-thaw cycles and storage in an autosampler (4 degrees C for 48 h). The method was successfully applied for the determination of RPV from conventional dosage forms like tablets, from polymeric nanoparticles and from biological matrices like HeLa cell lysates. PMID- 25298144 TI - Spinal blockage of P/Q- or N-type voltage-gated calcium channels modulates functional and symptomatic changes related to haemorrhagic cystitis in mice. AB - BACKGROUND AND PURPOSE: Spinal voltage-gated calcium channels (VGCCs) are pivotal regulators of painful and inflammatory alterations, representing attractive therapeutic targets. We examined the effects of epidural administration of the P/Q- and N-type VGCC blockers Tx3-3 and Phalpha1beta, respectively, isolated from the spider Phoneutria nigriventer, on symptomatic, inflammatory and functional changes allied to mouse cyclophosphamide (CPA)-induced haemorrhagic cystitis (HC). The effects of P. nigriventer-derived toxins were compared with those displayed by MVIIC and MVIIA, extracted from the cone snail Conus magus. EXPERIMENTAL APPROACH: HC was induced by a single i.p. injection of CPA (300 mg.kg(-1) ). Dose- and time-related effects of spinally administered P/Q and N type VGCC blockers were assessed on nociceptive behaviour and macroscopic inflammation elicited by CPA. The effects of toxins were also evaluated on cell migration, cytokine production, oxidative stress, functional cystometry alterations and TRPV1, TRPA1 and NK1 receptor mRNA expression. KEY RESULTS: The spinal blockage of P/Q-type VGCC by Tx3-3 and MVIIC or N-type VGCC by Phalpha1beta attenuated nociceptive and inflammatory events associated with HC, including bladder oxidative stress and cytokine production. CPA produced a slight increase in bladder TRPV1 and TRPA1 mRNA expression, which was reversed by all the toxins tested. Noteworthy, Phalpha1beta strongly prevented bladder neutrophil migration, besides HC-related functional alterations, and its effects were potentiated by co-injecting the selective NK1 receptor antagonist CP-96345. CONCLUSIONS AND IMPLICATIONS: Our results shed new light on the role of spinal P/Q and N-type VGCC in bladder dysfunctions, pointing out Phalpha1beta as a promising alternative for treating complications associated with CPA-induced HC. PMID- 25298146 TI - Assessing the impact of an eating disorders treatment team approach with college students. AB - An interdisciplinary treatment team approach is considered the standard of care for individuals with eating disorders; however, there is limited research on the efficacy of such teams. This study used retrospective chart review to compare client characteristics and treatment utilization for college students treated with psychotherapy alone versus an interdisciplinary treatment team approach (i.e., a mental health counselor, a physician, and a dietitian). Clients with prior counseling histories, a bulimia nervosa diagnosis, or a personality disorder diagnosis were more likely to be referred to the eating disorders treatment team. Female counselors were more likely than male counselors to refer clients to the team. Overall, findings suggest that the team approach is associated with students staying in therapy longer and terminating therapy in a planned fashion. PMID- 25298147 TI - Protecting the brain: do we know the way? PMID- 25298148 TI - A dry lung is a happy lung: more supporting evidence. PMID- 25298149 TI - Fontan modification with a Y-graft. PMID- 25298150 TI - Impact of the second internal thoracic artery on short- and long-term outcomes in obese patients: a propensity score matched analysis. AB - OBJECTIVES: A limited number of patients undergoing coronary artery bypass grafting (CABG) currently receive bilateral internal thoracic arteries (BITA) as a consequence of lack of evidence on survival benefit and concerns about sternal wound complications. This study was undertaken to determine the impact of BITA grafting on short- and long-term outcomes in obese patients. METHODS: Propensity score matching for short- and long-term outcomes was conducted for 1522 obese (body mass index >= 30 kg/m(2)) patients undergoing CABG using BITA (n = 229, 15.0%) or a single internal thoracic artery (SITA, n = 1293, 85.0%). RESULTS: Propensity score matching created 229 matching sets. In the matched sample, operative mortality (within 30 days) occurred in 3 (1.3%) and 4 (1.7%) patients in the BITA and SITA groups, respectively (P = 1). Deep sternal wound infection occurred in 6 (2.6%) and 2 (0.9%) patients (P = .2) in the BITA and SITA group, respectively. After a median follow-up of 4.5 +/- 3.3 years, the use of BITA was associated with an improved late survival (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.13-0.97; P = .03) and a reduced need for repeat revascularization (HR, 0.45; 95% CI, 0.23-0.85; P = .01). CONCLUSIONS: BITA grafting can be safely offered to obese patients with significant long-term advantages without substantial additional risk of operative complications including deep sternal wound infection. PMID- 25298151 TI - Influence of stage of lactation and year season on composition of mares' colostrum and milk and method and time of storage on vitamin C content in mares' milk. AB - BACKGROUND: Mares' milk is becoming increasingly popular in Western Europe. This study was thus aimed at investigating the impact of stage of lactation and season on chemical composition, somatic cell count and some physicochemical parameters of mares' colostrum and milk, and at developing a method for the determination of vitamin C (ascorbic acid) in mares' milk and to determine its content in fresh and stored milk. RESULTS: The analysis conducted showed an effect of the stage of lactation on contents of selected chemical components and physicochemical parameters of mares' milk. In successive lactation periods levels of fat, cholesterol, energy value, citric acid and titratable acidity decreased, whereas levels of lactose and vitamin C, as well as the freezing point, increased. Analysis showed that milk produced in autumn (September, October, November) had a higher freezing point and lower concentrations of total solids, protein, fat, cholesterol, citric acid and energy value in comparison to milk produced in summer (June, July, August). Mares' milk was characterised by low somatic cell count throughout lactation. In terms of vitamin C stability the most advantageous method of milk storage was 6-month storage of lyophilised milk. CONCLUSION: In general, the results confirmed that mares' milk is a raw material with a unique chemical composition different from that produced by other farm animals. PMID- 25298152 TI - Mixture toxicity of imidacloprid and cyfluthrin to two non-target species, the fathead minnow Pimephales promelas and the amphipod Hyalella azteca. AB - Two species, the fathead minnow Pimephales promelas and the amphipod Hyalella azteca, were tested to examine acute toxicity to two insecticides, cyfluthrin and imidacloprid individually and as a mixture. Cyfluthrin was acutely toxic to P. promelas and H. azteca with EC50 values and 95 % confidence intervals of 0.31 ug L(-1) (0.26-0.35 ug L(-1)) and 0.0015 ug L(-1) (0.0011-0.0018 ug L(-1)), respectively. Imidacloprid was not acutely toxic to P. promelas at water concentrations ranging from 1 to 5000 ug L(-1), whereas it was toxic to H. azteca with a EC50 value of 33.5 ug L(-1) (23.3-47.4 ug L(-1)). For the P. promelas mixture test, imidacloprid was added at a single concentration to a geometric series of cyfluthrin concentrations bracketing the EC50 value. A synergistic ratio (SR) of 1.9 was found for P. promelas, which was calculated using the cyfluthrin-only exposure and mixture-exposure data. Because cyfluthrin and imidacloprid were toxic to H. azteca, the mixture test was designed based on an equipotent toxic unit method. Results from the mixture test indicated a model deviation ratio (MDR) of 1.7 or 2.7 depending on the model. Mixture test results from the simultaneous exposure to cyfluthrin and imidacloprid with both species indicated a greater than expected toxic response because the SR or MDR values were >1. Because these two insecticides are commonly used together in the same product formulations, nontarget species could be more affected due to their greater-than-additive toxicity observed in the current study. PMID- 25298153 TI - Occurrence and fate of selected endocrine-disrupting chemicals in water and sediment from an urban lake. AB - Occurrence of five endocrine-disrupting chemicals (EDCs)-bisphenol-A (BPA), triclosan (TCS), 17alpha-ethinyl estradiol (EE2), benzophenone-3, and 4 methylbenzylidene camphor-were monitored in East Lake, the largest urban lake in China. Other than EE2, all selected EDCs were detected at least once in the lake water with concentrations <=89.1 ng/L. EDCs were detected with greater occurrence in spring than in other seasons. In lake sediment, TCS was detected at the greatest concentration (30.9 ng g(-1)), whereas BPA and EE2 were not detected. Spatial distribution of the EDCs in the lake water and the lake sediment showed similar patterns, and greater EDC residuals were found from those sites with known wastewater input. The linear adsorption coefficients (K d) varied from 17.9 to 1,017 L kg(-1) and were related to the octanol-water partition coefficient (K ow) values of the compounds. Photodegradation was a major process removing the EDCs from the lake water, and the presence of dissolved organic material and NO3 (-) in the lake water can accelerate the photodegradation process. Degradation of the EDCs in the lake sediment was relatively slow and occurred mainly due to the microbial processes. All compounds were found more persistent under anoxic conditions than under oxic conditions. PMID- 25298154 TI - Engineering charge injection and charge transport for high performance PbSe nanocrystal thin film devices and circuits. AB - We study charge injection and transport in PbSe nanocrystal thin films. By engineering the contact metallurgy and nanocrystal ligand exchange chemistry and surface passivation, we demonstrate partial Fermi-level pinning at the metal nanocrystal interface and an insulator-to-metal transition with increased coupling and doping, allowing us to design high conductivity and mobility PbSe nanocrystal films. We construct complementary nanocrystal circuits from n-type and p-type transistors realized from a single nanocrystal material by selecting the contact metallurgy. PMID- 25298156 TI - Novel reactions in acyl editing of phosphatidylcholine by lysophosphatidylcholine transacylase (LPCT) and acyl-CoA:glycerophosphocholine acyltransferase (GPCAT) activities in microsomal preparations of plant tissues. AB - MAIN CONCLUSION: Plants have lysophosphatidylcholine transacylase (LPCT) and acyl CoA:glycerophosphocholine acyltransferase (GPCAT) activities. The combined action of LPCT and GPCAT provides a novel route of PC re-synthesis after its deacylation. Phosphatidylcholine (PC) is the major lipid in eukaryotic membranes and has a central role in overall plant lipid metabolism. It is also the site of production of polyunsaturated fatty acids in plants. The recently discovered acyl CoA:glycerophosphocholine acyltransferase (GPCAT) activity in yeast provides a novel route of re-synthesising PC via lysophosphatidylcholine (LPC) after its deacylation. This route does not require the degradation of the glycerophosphocholine (GPC) into free choline, the activation of choline to CDP choline, nor the utilization of CDP-choline by the CDP-choline:diacylglycerol cholinephosphotransferase. We show here that GPCAT activities also are present in membrane preparations from developing oil seeds of safflower and other species as well as in membrane preparations of roots and leaves of Arabidopsis, indicating that GPCAT activity plays a ubiquitous role in plant lipid metabolism. The last step in formation of GPC, the substrate for GPCAT, is the deacylation of LPC. Microsomal membranes of developing safflower seeds utilized LPC in LPC:LPC transacylation reactions (LPCT activities) creating PC and GPC. The results demonstrate that safflower membranes have LPCT and GPCAT activities that represent novel reactions for PC acyl editing. The physiological relevance of these reactions probably has to await identification of the enzymes catalysing these reactions. PMID- 25298157 TI - Surgical management of umbilical basal cell carcinoma: Published work review and the optimal depth of surgical excision. AB - Basal cell carcinoma (BCC) is a common malignant skin tumor. However, BCC that arise at the umbilicus is rare. We present three cases of umbilical BCC. Each BCC was excised at a different depth level, and all deep surgical margins were negative. All patients had no evidence of local recurrence or metastasis during the follow-up periods (12, 24, and 52 months). Reviewing the reported cases of umbilical BCC, the BCC cells did not seem to invade into the umbilical scar in most cases, and the deepest invasion levels of tumor cells were up to the middle layer of the subcutaneous tissue. However, the dermatological surgeons have to consider the possibility of surgical excision down to and including the umbilical attachment to the peritoneum, and intraoperative margin assessment should be necessary to avoid the risk of excessive or incomplete excision. PMID- 25298155 TI - Magneto-fluorescent core-shell supernanoparticles. AB - Magneto-fluorescent particles have been recognized as an emerging class of materials that exhibit great potential in advanced applications. However, synthesizing such magneto-fluorescent nanomaterials that simultaneously exhibit uniform and tunable sizes, high magnetic content loading, maximized fluorophore coverage at the surface and a versatile surface functionality has proven challenging. Here we report a simple approach for co-assembling magnetic nanoparticles with fluorescent quantum dots to form colloidal magneto-fluorescent supernanoparticles. Importantly, these supernanoparticles exhibit a superstructure consisting of a close-packed magnetic nanoparticle 'core', which is fully surrounded by a 'shell' of fluorescent quantum dots. A thin layer of silica coating provides high colloidal stability and biocompatibility, and a versatile surface functionality. We demonstrate that after surface pegylation, these silica-coated magneto-fluorescent supernanoparticles can be magnetically manipulated inside living cells while being optically tracked. Moreover, our silica-coated magneto-fluorescent supernanoparticles can also serve as an in vivo multi-photon and magnetic resonance dual-modal imaging probe. PMID- 25298159 TI - Kinetic model for microbial growth and desulphurisation with Enterobacter sp. AB - Biodesulphurisation was investigated by using Enterobacter sp. D4, which can selectively desulphurise and convert dibenzothiophene into 2-hydroxybiphenyl (2 HBP). The experimental values of growth, substrate consumption and product generation were obtained at 95 % confidence level of the fitted values using three models: Hinshelwood equation, Luedeking-Piret and Luedeking-Piret-like equations. The average error values between experimental values and fitted values were less than 10 %. These kinetic models describe all the experimental data with good statistical parameters. The production of 2-HBP in Enterobacter sp. was by "coupled growth". PMID- 25298158 TI - Evaluating an e-mental health program ("deprexis") as adjunctive treatment tool in psychotherapy for depression: design of a pragmatic randomized controlled trial. AB - BACKGROUND: Major depressive disorder (MDD) places a significant disease burden on individuals as well as on societies. Several web-based interventions for MDD have shown to be effective in reducing depressive symptoms. However, it is not known whether web-based interventions, when used as adjunctive treatment tools to regular psychotherapy, have an additional effect compared to regular psychotherapy for depression. METHODS/DESIGN: This study is a currently recruiting pragmatic randomized controlled trial (RCT) that compares regular psychotherapy plus a web-based depression program ("deprexis") with a control condition exclusively receiving regular psychotherapy. Adults with a depressive disorder (N = 800) will be recruited in routine secondary care from therapists over the course of their initial sessions and will then be randomized within therapists to one of the two conditions. The primary outcome is depressive symptoms measured with the Beck Depression Inventory (BDI-II) at three months post randomization. Secondary outcomes include changes on various indicators such as anxiety, somatic symptoms and quality of life. All outcomes are again assessed at the secondary endpoint six months post randomization. In addition, the working alliance and feasibility/acceptability of the treatment condition will be explored. DISCUSSION: This is the first randomized controlled trial to examine the feasibility/acceptability and the effectiveness of a combination of traditional face-to-face psychotherapy and web-based depression program compared to regular psychotherapeutic treatment in depressed outpatients in routine care. TRIAL REGISTRATION: ISRCTN20165665. PMID- 25298160 TI - Selective growth-inhibitory effect of 8-hydroxyquinoline towards Clostridium difficile and Bifidobacterium longum subsp. longum in co-culture analysed by flow cytometry. AB - The major risk factor for Clostridium difficile infection (CDI) is the use of antibiotics owing to the disruption of the equilibrium of the host gut microbiota. To preserve the beneficial resident probiotic bacteria during infection treatment, the use of molecules with selective antibacterial activity enhances the efficacy by selectively removing C. difficile. One of them is the plant alkaloid 8-hydroxyquinoline (8HQ), which has been shown to selectively inhibit clostridia without repressing bifidobacteria. Selective antimicrobial activity is generally tested by culture techniques of individual bacterial strains. However, the main limitation of these techniques is the inability to describe differential growth dynamics of more bacterial strains in co-culture within the same experiment. In the present study, we combined fluorescent in situ hybridization and flow cytometry to describe the changes in active and non-active cells of a mixed culture formed by the opportunistic pathogen C. difficile CECT 531 and the beneficial Bifidobacterium longum subsp. longum CCMDMND BL1 after exposure to 8HQ. It was observed that without 8HQ, the proportion of both strains was almost equal, oscillating between 22.7 and 77.9 % during a time lapse of 12 h, whereas with 8HQ the proportion of active C. difficile decreased after 4 h, and persisted only between 8.8 and 17.5 %. In contrast, bifidobacterial growth was not disturbed by 8HQ. The results of this study showed the selective inhibitory effect of 8HQ on clostridial and bifidobacterial growth dynamics, and the potential of this compound for the development of selective agents to control CDIs. PMID- 25298161 TI - Interactions of uroseptic Escherichia coli with renal (A-498) and gastrointestinal (HT-29) cell lines. AB - We investigated the ability of Escherichia coli isolated from septic patients with urinary tract infection (UTI) to translocate through the gastrointestinal (GI) tract of the same patients using cell-culture models. Forty-seven hospitalized patients with urosepsis were included in this study. E. coli was isolated from their urine and blood (total 94 isolates) and investigated for genetic relatedness and interaction with the cell lines A-498 and HT-29. An initial comparison of the strains isolated from urine and blood showed that 44 out of 47 patients (94 %) had identical strains in their blood and urine. The blood isolates adhered to both cell lines, although their rate of adherence to A 498 cells was significantly higher than that to HT-29 cells (5.8+/-3.8 per cell vs 2.8+/-1.9; P<0.0001). The rate of translocation in A-498 cells was also significantly higher after 120 min (8.7*10(5) vs 2.9*10(5); P = 0.0006). Three non-identical blood isolates were unable to translocate in HT-29 cells, indicating that host immune factors might be more important than bacterial ability to translocate the GI epithelium in these patients. Our data showed that blood isolates from uroseptic patients are able to adhere to and translocate through both cell lines. This suggests that E. coli in patients with UTI may translocate from either the GI tract or the urinary tract, hence questioning the assumption that the urinary tract is the only source of septicaemia in these patients. PMID- 25298162 TI - Type three secretion system in non-toxigenic Vibrio cholerae O1, Mexico. PMID- 25298163 TI - Validity of the Swedish SCID and ADDIS diagnostic interviews for substance use disorders: sensitivity and specificity compared with a LEAD golden standard. AB - OBJECTIVE: The study explores agreement on diagnoses and diagnostic criteria for substance use disorders between two structured assessment interviews, the Structured Clinical Interview for the DSM-IV (SCID) and the Alkohol/Drog Diagnos InStrument (ADDIS). Both interviews are compared with a golden standard (GS), based on a LEAD model (Longitudinal, Expert, All Data). METHOD: Patients were interviewed concerning substance use problems by trained interviewers using SCID and ADDIS separately and blind to each other's results. SCID and ADDIS interviews were compared with each other, and both were compared with a GS. RESULTS: Satisfactory agreement exists between SCID and ADDIS on criteria as well as final diagnostic suggestions, although ADDIS tended to propose dependence diagnoses somewhat more often than SCID. Agreement between SCID and GS is moderate. Sensitivity of SCID is satisfactory, as is specificity for lifetime diagnoses, while specificity for current diagnoses is perfect. ADDIS demonstrates substantial to perfect agreement with GS on dependence diagnoses and moderate agreement on abuse diagnoses (both lifetime and current), as well as showing excellent to perfect overall sensitivity and specificity. Both instruments are in almost perfect agreement with the GS on severity ratings. CONCLUSION: Both ADDIS and SCID can be used to ensure good standards in the diagnostic assessment of substance use disorders (both alcohol and drugs), with and without psychiatric comorbidity. Significant outcomes. Both SCID and ADDIS are in good agreement with the GS based on a LEAD model concerning substance use disorders. PMID- 25298164 TI - Metal-to-metal electron transfer in Co/Fe Prussian Blue molecular analogues: the ultimate miniaturization. AB - Co/Fe Prussian Blue analogues are known to display both thermally and light induced electron transfer attributed to the switching between diamagnetic {Fe(II)LS(MU-CN)Co(III)LS} and paramagnetic {Fe(III)LS(MU-CN)Co(II)HS} pairs (LS = low spin; HS = high spin). In this work, a dinuclear cyanido-bridged Co/Fe complex, the smallest {Fe(MU-CN)Co} moiety at the origin of the remarkable physical properties of these systems, has been designed by a rational building block approach. Combined structural, spectroscopic, magnetic and photomagnetic studies reveal that a metal-to-metal electron transfer that can be triggered in solid state by light, temperature and solvent contents, is observed for the first time in a dinuclear complex. PMID- 25298165 TI - Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial. AB - AIMS: To evaluate glucose-lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted. METHODS: A total of 316 patients, with type 2 diabetes diagnosed for <=12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5-12.0%, were randomized 1:1 to double-blind, free combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245). RESULTS: The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean +/- standard error (s.e.) HbA1c decreased from baseline by -2.8 +/- 0.1% with linagliptin/metformin and -2.0 +/- 0.1% with linagliptin; a treatment difference of -0.8% (95% confidence interval -1.1 to -0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean +/- s.e. changes in HbA1c of -2.7 +/- 0.1% and -1.8 +/- 0.1%, respectively; treatment difference of -0.9% (95% CI -1.3 to -0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (-1.3 kg between-group difference; p =0.0033). CONCLUSIONS: Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy. PMID- 25298166 TI - Enhanced bioactive myocardial transforming growth factor-beta in advanced human heart failure. AB - BACKGROUND: Transforming growth factor (TGF)-beta activation is known to play a central role in progressive ventricular remodeling in advanced heart failure in animal models, but there has been no direct evidence of increased TGF-beta activity in the myocardium of patients with advanced human heart failure. METHODS AND RESULTS: Using a recently developed bioassay that measures TGF-beta bioactivity rather than TGF-beta abundance, we measured bioactive TGF-beta in human myocardium from control non-failing donors (NF), and patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Both free and total soluble TGF-beta were significantly increased in ICM and DCM compared with NF. Free TGF-beta had an excellent correlation with phosphorylated Smad2 (R(2)=0.55, P<0.0001), a downstream marker of TGF-beta signaling. Collagen type I and type III were significantly upregulated in DCM compared with NF, consistent with histological evidence of myocardial fibrosis. Expression of fibulin-2, a positive modulator of TGF-beta, was significantly increased in DCM compared with NF, and the free TGF-beta level was correlated with fibulin-2 mRNA (R(2)=0.24, P<0.006). CONCLUSIONS: Although both free and total soluble TGF-beta are significantly increased in ICM and DCM compared with NF, the superior correlation of free TGF beta with downstream signaling suggests that this is the most functionally relevant form. The present findings suggest that sustained TGF-beta activation in both ICM and DCM contributes to excess myocardial fibrosis. PMID- 25298167 TI - Adding coronary computed tomography angiography to invasive coronary angiography improves prediction of cardiac events. AB - BACKGROUND: The additive value of plaque characteristics determined by computed tomography angiography (CTA) in patients undergoing invasive coronary angiography (ICA) has not been established. METHODS AND RESULTS: We studied 676 patients undergoing ICA and CTA within 3 months. The luminal diameter narrowing based on ICA and the presence of high risk plaque (HRP) based on CTA were assessed in all coronary artery segments except for those after or before scheduled treatment. We followed their cardiac events including cardiac death, acute coronary syndrome (ACS), and revascularization for de novo lesions >=3 months after ICA. The incidence of coronary events was higher in the segments including >25% luminal narrowing than in those without (2.94% vs. 0.31%, P<0.0001), and higher in the segments containing HRP than in those without (12.6 vs. 0.46%, P<0.0001). Greater than 25% residual luminal narrowing and the presence of HRP were identified as independent predictors of cardiac events after risk adjustment for age, gender, and history of ACS (hazard ratio [HR], 3.22; 95% confidence interval [CI]: 1.29 10.76; P=0.0092, HR, 2.64; 95% CI: 1.59-4.35; P=0.0002, respectively). Adding the presence of HRP to a model including age, gender, ACS history, and >25% residual stenosis improved the prediction of cardiac events. CONCLUSIONS: Assessment of coronary plaque characteristics on CTA improves the prediction of cardiac events in patients undergoing ICA. PMID- 25298168 TI - Bare-metal vs. drug-eluting stents in patients with atrial fibrillation undergoing percutaneous coronary intervention. AB - BACKGROUND: We explored 12-month clinical outcomes of 929 patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) with bare metal stents (BMS) vs. drug-eluting stents (DES) from the prospective multicenter AFCAS (Atrial Fibrillation undergoing Coronary Artery Stenting) registry. METHODS AND RESULTS: Endpoints included the first occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), target vessel revascularization, definite/probable stent thrombosis (ST), transient ischemic attack or stroke. Bleeding events were defined according to the Bleeding Academic Research Consortium criteria. Altogether, 673 (72.4%) patients received BMS and 220 (23.7%) at least one DES. Patients treated with DES more often had diabetes and prior ischemic events, and a longer stent length (P<0.05 for all), whereas patients treated with BMS more often had heart failure and were more likely to present with acute ST-elevation MI (P<0.05 for both). At 12-month follow-up, rates and risks of MACCE and total bleeding events were comparable between the groups (22.0% with BMS vs. 19.5% with DES, P=0.51, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.63-1.25 for DES) and (19.5% vs. 15.0%, respectively, P=0.16, HR 0.75, 95% CI 0.51-1.09 for DES). Definite/probable ST was more frequent in the BMS group (1.9% vs. 0%, respectively, P=0.046). CONCLUSIONS: In real-world patients with AF undergoing PCI, DES use was associated with outcomes comparable to those with BMS without excess bleeding complications. More ST was seen in BMS-treated patients. PMID- 25298170 TI - Tumour 18 F-FDG Uptake on preoperative PET/CT may predict axillary lymph node metastasis in ER-positive/HER2-negative and HER2-positive breast cancer subtypes. AB - OBJECTIVES: To evaluate the association between tumour FDG uptake on preoperative PET/CT and axillary lymph node metastasis (ALNM) according to breast cancer subtype. METHODS: The records of 671 patients with invasive breast cancer who underwent (18) F-FDG PET/CT and surgery were reviewed. Using immunohistochemistry, tumours were divided into three subtypes: oestrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive, and triple-negative. Tumour FDG uptake, expressed as maximum standardized uptake value (SUVmax), and clinicopathological variables were analysed. RESULTS: ALNM was present in 187 of 461 ER-positive/HER2-negative, 54 of 97 HER2-positive, and 38 of 113 triple-negative tumours. On multivariate analysis, high tumour SUVmax (>=4.25) (P < 0.001), large tumour size (>2 cm) (P = 0.003) and presence of lymphovascular invasion (P < 0.001) were independent variables associated with ALNM. On subset analyses, tumour SUVmax maintained independent significance for predicting ALNM in ER-positive/HER2-negative (adjusted odds ratio: 3.277, P < 0.001) and HER2-positive tumours (adjusted odds ratio: 14.637, P = 0.004). No association was found for triple-negative tumours (P = 0.161). CONCLUSIONS: Tumour SUVmax may be an independent prognostic factor for ALNM in patients with invasive breast cancer, especially in ER-positive/HER2 negative and HER2-positive subtypes, but not in those with triple-negative subtype. KEY POINTS: * Tumour SUVmax could be an imaging biomarker for predicting ALNM * Tumour SUVmax predicting ALNM is effective in ER-positive/HER2-negative and HER2-positive subtypes * Tumour SUVmax predicting ALNM is inaccurate in triple-negative subtypes * Accurate prognostic prediction based on molecular subtype may facilitate individualized management. PMID- 25298171 TI - Two-dimensional shear wave elastography as promising diagnostic tool for predicting malignant thyroid nodules: a prospective single-centre experience. AB - OBJECTIVES: To evaluate the diagnostic performance of two-dimensional shear wave elastography (2D-SWE) in distinguishing malignant from benign thyroid nodules. METHODS: A total of 331 focal thyroid nodules from 271 patients scheduled for fine-needle aspiration or thyroid surgery were included. After a routine conventional ultrasound evaluation, 2D-SWE examinations were performed to obtain 2D-SWE measurements on a colour-coded mapping, which were then correlated with pathology results. RESULTS: A total of 230 nodules were benign and 101 were malignant on pathology. The areas under the receiver operating characteristic curve (AUC) of mean and minimum values in the largest region of interest (ROI) over the whole nodule, and mean, maximum and minimum values in 2-mm ROI over the stiffest area of the nodule were 0.794, 0.673, 0.808, 0.805 and 0.799, respectively. The most accurate cut-off value, 39.3 kPa, for mean value in a 2-mm ROI achieved 66.3 % sensitivity and 84.4 % specificity to discriminate malignancy. Nodule size correlated with 2D-SWE value for malignant nodules (P < 0.01). In the group of nodules <=10 mm, the AUC was 0.730, while it was 0.883 in nodules sized 11-30 mm and 0.821 in nodules >30 mm. CONCLUSION: 2D-SWE is a promising diagnostic tool for discriminating malignant thyroid nodules, although the performance for nodules <=10 mm is not satisfactory. PMID- 25298173 TI - Right and left amygdalae activation in patients with major depression receiving antidepressant treatment, as revealed by fMRI. AB - BACKGROUND: A differential contribution of the right and left amygdalae to affective information processing has been proposed. However, the direction of this lateralization has not been confirmed. In this study, we used a pre- and post-treatment (escitalopram) design to analyze the relative differences between neural activity in the right and left amygdalae during exposure to emotional stimuli in currently depressed patients. To the best of our knowledge, this study is to compare neural activity between the left and right amygdalae in people with depression. Our findings could lead to the development of parameters or biomarkers for depressive symptoms and treatment response. METHODS: We used a pre post-test design without a control group. Twenty currently depressed participants underwent an emotion processing task during fMRI. These participants were then treated with an antidepressant for 6 weeks. We used amygdala region-of-interest analysis to evaluate the hemodynamic response during exposure to colored emotional pictures. RESULTS: In total, thirteen of the 20 participants were placed into a separate group based on degree of response to antidepressants. The partial response group had an averaged HDRS score of 10.75 +/- 2.25 and an averaged DBOLDLR signal of 189.18 +/- 140.23 (m1 = 8), and the remitted group had an averaged HDRS score of 4.80 +/- 1.64 and an averaged DBOLDLR signal of 421.26 +/- 109.19 (m2 = 5). Each individual had lateralized amygdala activity, and the direction of asymmetry persisted following treatment. Amygdala responses to four types of emotional stimuli did not significantly change (p > 0.05) with treatment in either the right or the left amygdala. However, the difference in neural activity between the right and left amygdalae was greater after treatment, and the variation in neural activity was larger in the left amygdala. CONCLUSIONS: We found that the response between the right and left amygdala did not differ in terms of time series, although activity increased after pharmaceutical treatment for each emotion tested. In the future, changes in BOLD signals as revealed by fMRI might be useful in evaluating the clinical manifestation of major depression. PMID- 25298174 TI - The association between obesity and nighttime blood pressure in obese children by adjustments of insulin resistance and arterial stiffness. PMID- 25298175 TI - Response to the association between obesity and nighttime blood pressure in obese children by adjustments of insulin resistance and arterial stiffness. PMID- 25298176 TI - Biological correlates of blood pressure variability in elderly at high risk of cardiovascular disease. AB - BACKGROUND: Visit-to-visit variability in blood pressure is an independent predictor of cardiovascular disease. This study investigates biological correlates of intra-individual variability in blood pressure in older persons. METHODS: Nested observational study within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) among 3,794 male and female participants (range 70-82 years) with a history of, or risk factors for cardiovascular disease. Individual visit-to-visit variability in systolic and diastolic blood pressure and pulse pressure (expressed as 1 SD in mm Hg) was assessed using nine measurements over 2 years. Correlates of higher visit-to-visit variability were examined at baseline, including markers of inflammation, endothelial function, renal function and glucose homeostasis. RESULTS: Over the first 2 years, the mean intra-individual variability (1 SD) was 14.4mm Hg for systolic blood pressure, 7.7mm Hg for diastolic blood pressure, and 12.6mm Hg for pulse pressure. After multivariate adjustment a higher level of interleukin-6 at baseline was consistently associated with higher intra-individual variability of blood pressure, including systolic, diastolic, and pulse pressure. Markers of endothelial function (Von Willebrand factor, tissue plasminogen activator), renal function (glomerular filtration rate) and glucose homeostasis (blood glucose, homeostatic model assessment index) were not or to a minor extent associated with blood pressure variability. CONCLUSION: In an elderly population at risk of cardiovascular disease, inflammation (as evidenced by higher levels of interleukin-6) is associated with higher intra-individual variability in systolic, diastolic, and pulse pressure. PMID- 25298177 TI - Potential blood-based markers of celiac disease. AB - BACKGROUND: Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers. METHODS: We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-kappaB complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone. CONCLUSIONS: The CD markers identified in this study further emphasize the significance of components related to NF-kappaB regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-kappaB interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD. PMID- 25298179 TI - Residential mobility of elderly Canadians: trends and determinants. AB - An understanding of trends and determinants for the residential mobility of elderly Canadians is essential for public policy and planning. Study of the patterns, changes over time, and determinants of the mobility of older Canadians has become increasingly important as the population ages. Elderly residential mobility has decreased substantially since 1971, and almost one-half of this decrease is due to changes in population composition. Because the multivariate analysis described here does not account for most of the downward trends in residential mobility, however, further work is needed on speculative explanations discussed in this article. PMID- 25298178 TI - Behavioral characterization of mice overexpressing human dysbindin-1. AB - BACKGROUND: The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of function is beneficial or detrimental. RESULTS: To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin 1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice. CONCLUSIONS: The present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo. PMID- 25298181 TI - Characterization of the first columbid herpesvirus 1 isolate from a hybrid meat type pigeon flock in China. AB - Infections of pigeons with herpesviruses have been described in several species of domestic and wild birds. In July 2012, increased mortality was observed in a hybrid meat-type pigeon flock in Beijing, China. Diagnostic tests led to the isolation of a virus designated columbid herpesvirus 1 BJ strain (CoHV-1BJ). Sequence analysis of the viral DNA polymerase catalytic subunit gene revealed a single open reading frame of 3753 nt encoding 1250 amino acids. Phylogenetic analysis revealed that the CoHV-1BJ is closely related to the members of the genus Mardivirus within the subfamily Alphaherpesvirinae. An experimental infection demonstrated that CoHV-1BJ is pathogenic to young pigeons, resulting in systemic infection with scattered focal necrosis in the liver and spleen. The results provide an initial assessment of herpesvirus infection in domestic pigeons in China. PMID- 25298180 TI - Catalase inhibition in diabetic rats potentiates DNA damage and apoptotic cell death setting the stage for cardiomyopathy. AB - Diabetes is a risk factor for cardiovascular disease that has a multifactorial etiology, with oxidative stress as an important component. Our previous observation of a significant diabetes-related increase in rat cardiac catalase (CAT) activity suggested that CAT could play a major role in delaying the development of diabetic cardiomyopathy. Thus, in the present work, we examined the effects of the daily administration of the CAT inhibitor, 3-amino-1,2,4 triazole (1 mg/g), on the hearts of streptozotocin (STZ)-induced diabetic rats. Administration of CAT inhibitor was started from the 15th day after the last STZ treatment (40 mg/kg/5 days), and maintained until the end of the 4th or 6th weeks of diabetes. Compared to untreated diabetic rats, at the end of the observation period, CAT inhibition lowered the induced level of cardiac CAT activity to the basal level and decreased CAT protein expression, mediated through a decline in the nuclear factor erythroid-derived 2-like 2 /nuclear factor-kappa B p65 (Nrf2/NF-kappaB p65) subunit ratio. The perturbed antioxidant defenses resulting from CAT inhibition promoted increased H2O2production (P < 0.05) and lipid peroxidation (P < 0.05). Generated cytotoxic stimuli increased DNA damage (P < 0.05) and activated pro-apoptotic events, observed as a decrease (P < 0.05) in the ratio of the apoptosis regulator proteins Bcl-2/Bax, increased (P < 0.05) presence of the poly(ADP-ribose) polymerase-1 (PARP-1) 85 kDa apoptotic fragment and cytoplasmic levels of cytochrome C. These findings confirm an important function of CAT in the suppression of events leading to diabetes-promoted cardiac dysfunction and cardiomyopathy. PMID- 25298182 TI - Vaccine and oncogenic strains of gallid herpesvirus 2 contain specific subtype variations in the 5' region of the latency-associated transcript that evolve in vitro and in vivo. AB - Gallid herpesvirus 2 (GaHV-2) is the alphaherpesvirus responsible for Marek's disease (MD), a T-cell lymphoma of chickens. The virulence of the GaHV-2 field strain is steadily increasing, but MD is still controlled by the CVI988/Rispens vaccine. We tried to determine distinguishing traits of the CVI988/Rispens vaccine by focusing on the 5' end region of the latency-associated transcript (5'LAT). It includes a variable number of 60-bp tandem repeats depending on the GaHV-2 strain. By analyzing six batches of vaccine, we showed that CVI988/Rispens consisted of a population of 5'LAT molecular subtypes, all with deletions and lacking 60-bp tandem repeat motifs, with two major subtypes that probably constitute CVI988/Rispens markers. Serial passages in cell culture led to a substantial change in the frequency of CVI988/Rispens 5'LAT subtypes, with non deleted subtypes harboring up to four 60-bp repeats emerging during the last few passages. Dynamic changes in the distribution of 5'LAT-deleted subtypes were also detected after infection of chickens. By contrast, the 5'LAT region of the oncogenic clonal RB-1B strain, which was investigated at every step from the isolation of the clonal bacmid RB-1B DNA to the isolation of the ovarian lymphoma cell line, consisted of non-deleted 5'LAT subtypes harboring at least two 60-bp repeats. Thus, vaccine and oncogenic GaHV-2 strains consist of specific populations of viral genomes that are constantly evolving in vivo and in vitro and providing potential markers for epidemiological surveys. PMID- 25298183 TI - Training situational awareness to reduce surgical errors in the operating room. AB - BACKGROUND: Surgical errors result from faulty decision-making, misperceptions and the application of suboptimal problem-solving strategies, just as often as they result from technical failure. To date, surgical training curricula have focused mainly on the acquisition of technical skills. The aim of this review was to assess the validity of methods for improving situational awareness in the surgical theatre. METHODS: A search was conducted in PubMed, Embase, the Cochrane Library and PsycINFO using predefined inclusion criteria, up to June 2014. All study types were considered eligible. The primary endpoint was validity for improving situational awareness in the surgical theatre at individual or team level. RESULTS: Nine articles were considered eligible. These evaluated surgical team crisis training in simulated environments for minimally invasive surgery (4) and open surgery (3), and training courses focused at training non-technical skills (2). Two studies showed that simulation-based surgical team crisis training has construct validity for assessing situational awareness in surgical trainees in minimally invasive surgery. None of the studies showed effectiveness of surgical crisis training on situational awareness in open surgery, whereas one showed face validity of a 2-day non-technical skills training course. CONCLUSION: To improve safety in the operating theatre, more attention to situational awareness is needed in surgical training. Few structured curricula have been developed and validation research remains limited. Strategies to improve situational awareness can be adopted from other industries. PMID- 25298184 TI - Highly selective isolation and purification of heme proteins in biological samples using multifunctional magnetic nanospheres. AB - Magnetic particles with suitable surface modification are capable of binding proteins selectively, and magnetic separations have advantages of rapidity, convenience, and high selectivity. In this paper, new magnetic nanoparticles modified with imidazolium ionic liquid (Fe3O4 @SiO2 @ILs) were successfully fabricated. N-Methylimidazolium was immobilized onto silica-coated magnetic nanoparticles via gamma-chloropropyl modification as a magnetic nanoadsorbent for heme protein separation. The particle size was about 90 nm without significant aggregation during the preparation process. Hemoglobin as one of heme proteins used in this experiment was compared with other nonheme proteins. It has been found that the magnetic nanoparticles can be used for more rapid, efficient, and specific adsorption of hemoglobin with a binding capacity as high as 5.78 mg/mg. In comparison with other adsorption materials of proteins in the previous reports, Fe3 O4 @SiO2 @ILs magnetic nanoparticles exhibit the excellent performance in isolation of heme proteins with higher binding capacity and selectivity. In addition, a short separation time makes the functionalized nanoparticles suitable for purifying unstable proteins, as well as having other potential applications in a variety of biomedical fields. PMID- 25298185 TI - [The role of biomarkers in the diagnostics of acute mesenteric ischemia]. AB - Acute mesenteric ischemia is a severe and challenging disease. Unspecific symptoms in the initial phase make a fast diagnosis difficult although it is of major importance to protect patients from irreversible ischemia, extended bowel resection, sepsis and death in the late phase. In contrast to troponin as an early biomarker for cardiac ischemia, a reliable biomarker for acute intestinal ischemia has not yet been identified in the current literature and clinical practice. This would allow the early identification of these critically ill patients in the initial reversible phase of acute intestinal ischemia.This review highlights the pathophysiology, epidemiology and clinical findings of acute mesenteric ischemia and gives an overview of biomarkers which have been investigated in mesenteric ischemia with a special focus on lactate, which is the only parameter routinely used in the diagnostic setting of acute mesenteric ischemia. PMID- 25298186 TI - [The effect of peridural analgesia on long-term survival after surgery in patients with colorectal cancer : A systematic meta-analysis]. AB - BACKGROUND: The results of recent clinical studies suggest a potential benefit of peridural analgesia (PDA) during general anesthesia on long-term survival in patients after surgery for colorectal cancer. In order to test the hypothesis a meta-analysis was performed. OBJECTIVES: To determine the prognostic impact of perioperative PDA on long-term survival in patients with colorectal cancer who underwent surgical resection. MATERIAL AND METHODS: By searching the relevant literature (up to May 2014) a total of 5 studies were identified from a total of 608 publications and a meta-analysis was carried out. Adjusted hazard ratios (HR) with 95 % confidence intervals (CI) were used to assess the strength of associations. The random effects model was used to analyze the data and a modified forest plot was applied. Additionally, a potential publication bias was visually examined in a funnel plot. RESULTS: A positive association between PDA and improved long-term survival was observed in patients who underwent surgery for colorectal cancer without metastases (HR = 0.81, 95 % CI 0.68-0.96, p = 0.055). CONCLUSION: Despite a publication bias the use of PDA in patients who underwent surgery for colorectal cancer without metastases seemed to be advantageous. Randomized controlled trials are warranted to confirm the positive effects of additional PDA. The exact mechanisms of tumor suppressive effects of PDA have not yet been elucidated. PMID- 25298187 TI - [Liver transection: modern procedure: Technique, results and costs]. AB - Liver resection has developed into the current standard procedure due to modern resection techniques, profound knowledge of the liver anatomy and optimized surgical and anesthesiological strategies to allow extended resections with both low morbidity and mortality. Initially major blood loss was the biggest concern with liver resection and a Pringle's manoeuvre was necessary. Nowadays, biliary leakage is the major problem after liver surgery. Besides the classical conventional clamp crushing technique for parenchymal transection, various devices including ultrasound, microwaves and staplers have been introduced. Minimally invasive techniques have become increasingly important for liver resection but are still applied in selected patients only. The selection of the resection technique and device mainly depends on the extent of the resection and also on the liver parenchyma, the liver disease, costs, personal experiences and preferences. This article presents a selection of techniques used in modern parenchymal transection during liver resection with special focus on transection time, blood loss, bile leakage and costs. PMID- 25298188 TI - Chondroitin 6-O-sulfotransferases are required for morphogenesis of the notochord in the ascidian embryo. AB - BACKGROUND: Chondroitin sulfate (CS) is a sulfated polysaccharide chain that binds to various core proteins to form proteoglycans. The amount and position of sulfate groups in CS are variable among different tissues, and are determined by specific sulfotransferases. Although the ascidians are the closest relatives of vertebrates, the functions of their sulfotransferases have not been studied. RESULTS: The genome of the ascidian Ciona intestinalis contains eight genes encoding proteins similar to chondroitin 6-O-sulfotransferases (C6STs), which appear to have independently diverged in the ascidian lineage during evolution. Among them, Ci-C6ST-like1 and Ci-C6ST-like7 were predominantly expressed in the developing notochord. In addition, they were weakly expressed in the neural tube. The disruption of either one of them affected the convergent extension movement of notochordal cells. Presumptive notochord cells coming from both sides of the embryo did not intercalate. The results suggest that both of them are necessary. In some cases, the anterior neural tube failed to close. Forced expression of Ci C6ST-like1 or Ci-C6ST-like7 in the notochord restored the normal intercalation of notochordal cells, indicating that the effects of morpholino oligos are specific. CONCLUSIONS: Ci-C6ST-like1 and Ci-C6ST-like7 are required for the morphogenesis of the notochord in the ascidian embryo. PMID- 25298189 TI - Metabolic imaging of hyperpolarized [1-(13) C]acetate and [1-(13) C]acetylcarnitine - investigation of the influence of dobutamine induced stress. AB - PURPOSE: The metabolism of acetate in the heart resembles fatty acid metabolism, which is altered in several diseases like ischemia, diabetes mellitus, and heart failure. A signal-to-noise ratio (SNR) optimized imaging framework for in vivo measurements of hyperpolarized [1-(13) C]acetate and its metabolic product [1 (13) C]acetylcarnitine (ALCAR) in rats at 3 Tesla (T) is presented in this work. METHODS: A spectrospatial pulse was combined with IDEAL encoding to acquire well separated metabolic maps. The influence of dobutamine induced stress onto this metabolic system was investigated in spectra and in an imaging study. RESULTS: An increase of the ALCAR to acetate ratio with dobutamine induced stress was shown in slice selective spectra containing the rat hearts and skeletal muscles. Metabolic maps of acetate and ALCAR were acquired with an acceptable SNR. Quantification of the apparent conversion rate showed stable results in the heart in a time-window of 30 s. The effect of dobutamine on the signal intensities was shown to originate mainly from skeletal than cardiac muscles. CONCLUSION: The acetate activation was mapped with hyperpolarized [1-(13) C]acetate in a clinical 3T system. Quantitative measurement of the activity was possible in the heart, indicating that dobutamine induced stress does not improve the ALCAR SNR in the heart. PMID- 25298190 TI - Creatine kinase inhibits ADP-induced platelet aggregation. AB - Bleeding risk with antiplatelet therapy is an increasing clinical challenge. However, the inter-individual variation in this risk is poorly understood. We assessed whether the level of plasma creatine kinase, the enzyme that utilizes ADP and phosphocreatine to rapidly regenerate ATP, may modulate bleeding risk through a dose-dependent inhibition of ADP-induced platelet activation. Exogenous creatine kinase (500 to 4000 IU/L, phosphocreatine 5 mM) added to human plasma induced a dose-dependent reduction to complete inhibition of ADP-induced platelet aggregation. Accordingly, endogenous plasma creatine kinase, studied in 9 healthy men (mean age 27.9 y, SE 3.3; creatine kinase 115 to 859 IU/L, median 358), was associated with reduced ADP-induced platelet aggregation (Spearman's rank correlation coefficient, -0.6; p < 0.05). After exercise, at an endogenous creatine kinase level of 4664, ADP-induced platelet aggregation was undetectable, normalizing after rest, with a concomitant reduction of creatine kinase to normal values. Thus, creatine kinase reduces ADP-induced platelet activation. This may promote bleeding, in particular when patients use platelet P2Y12 ADP receptor inhibitors. PMID- 25298191 TI - The accuracy of a patient or parent-administered bleeding assessment tool administered in a paediatric haematology clinic. AB - Classifying and describing bleeding symptoms is essential in the diagnosis and management of patients with mild bleeding disorders (MBDs). There has been increased interest in the use of bleeding assessment tools (BATs) to more objectively quantify the presence and severity of bleeding symptoms. To date, the administration of BATs has been performed almost exclusively by clinicians; the accuracy of a parent-proxy BAT has not been studied. Our objective was to determine the accuracy of a parent-administered BAT by measuring the level of agreement between parent and clinician responses to the Condensed MCMDM-1VWD Bleeding Questionnaire. Our cross-sectional study included children 0-21 years presenting to a haematology clinic for initial evaluation of a suspected MBD or follow-up evaluation of a previously diagnosed MBD. The parent/caregiver completed a modified version of the BAT; the clinician separately completed the BAT through interview. The mean parent-report bleeding score (BS) was 6.09 (range: -2 to 25); the mean clinician report BS was 4.54 (range: -1 to 17). The mean percentage of agreement across all bleeding symptoms was 78% (mean kappa = 0.40; Gwet's AC1 = 0.74). Eighty percent of the population had an abnormal BS (defined as >=2) when rated by parents and 76% had an abnormal score when rated by clinicians (86% agreement, kappa = 0.59, Gwet's AC1 = 0.79). While parents tended to over-report bleeding as compared to clinicians, overall, BSs were similar between groups. These results lend support for further study of a modified proxy-report BAT as a clinical and research tool. PMID- 25298193 TI - Testing goodness-of-fit for the proportional hazards model based on nested case control data. AB - Nested case-control sampling is a popular design for large epidemiological cohort studies due to its cost effectiveness. A number of methods have been developed for the estimation of the proportional hazards model with nested case-control data; however, the evaluation of modeling assumption is less attended. In this article, we propose a class of goodness-of-fit test statistics for testing the proportional hazards assumption based on nested case-control data. The test statistics are constructed based on asymptotically mean-zero processes derived from Samuelsen's maximum pseudo-likelihood estimation method. In addition, we develop an innovative resampling scheme to approximate the asymptotic distribution of the test statistics while accounting for the dependent sampling scheme of nested case-control design. Numerical studies are conducted to evaluate the performance of our proposed approach, and an application to the Wilms' Tumor Study is given to illustrate the methodology. PMID- 25298192 TI - Targeting receptor tyrosine kinases and their downstream signaling with cell penetrating peptides in human pulmonary artery smooth muscle and endothelial cells. AB - Cell-penetrating peptide (CPP) intracellular delivery of receptor signaling motifs provides an opportunity to regulate specific receptor tyrosine kinase signal transductions. We targeted tyrosine residues Y740 and Y751 of the PDGF receptor beta (PDGFRbeta) and Y1175 of the VEGF receptor 2 (VEGFR2). The Y740 and Y751 motifs activated ERK and Akt, while the Y1175 motif activated ERK. Targeting either Y740 or Y751 of the PDGFRbeta in human pulmonary artery smooth muscle cells (HPASMC) effectively inhibited PDGF activation of ERK or Akt. Interfering with the Y751 region of the PDGFRbeta proved more effective than targeting the Y740 region. The phosphorylation of Y751 of the CPP and the length and exact sequence of the mimicking peptide proved crucial. On the other hand, in human pulmonary artery endothelial cell phosphorylation of the VEGFR2 Y1175 CPP was not a determinant in blockage of ERK activation. Likewise, the length of the peptide mimic was not crucial with a very small sequence containing the Y1175 remaining effective. Physiologic proof of concept for the effectiveness of the CPP was confirmed by blockage of HPASMC migration in response to PDGF following culture injury. Thus targeted blockage of tyrosine kinase receptor signaling can be very effective. PMID- 25298194 TI - Type II diabetes and its therapy in clinical practice - results from the standardised non-interventional registry SIRTA. AB - BACKGROUND AND METHODS: Modern antidiabetic therapies should achieve low HbA1c values and avoid hypoglycaemic complications. The registry SIRTA included 1522 patients with type II diabetes mellitus (T2DM) from 306 German medical practices. Patients had an HbA1c > 6.5% under the maximum tolerated metformin dose. If required, they received combination therapy with other antidiabetics according to the guideline of the German Diabetes Society [Deutsche Diabetes Gesellschaft (DDG)] or usual medical practice. Patients were followed up for 6 months. The target criteria included the achievement of HbA1c target values and the emergence of severe hypoglycaemic episodes. RESULTS: Most patients (64.0%) were planned to achieve an HbA1c target < 6.5%, the standard target recommended by the 2009 DDG guideline valid throughout the registry. Primarily to reduce the individual risk for hypoglycaemia, 32.4% of patients had a less strict HbA1c-target of 6.5-7.0%. These targets were achieved by 31.3% and 44.3% of patients, respectively. Combination therapies increased from 45% to 56% over the 6 months registry. Four patients had severe hypoglycaemias (0.26%). CONCLUSIONS: The registry confirms results from other epidemiologic studies on the therapy of T2DM in everyday practice. The treatment strategies applied effectively reduced blood glucose and avoided severe hypoglycaemias. An early therapy of insufficiently controlled patients with T2DM is important, as lower baseline values facilitated achieving HbA1c targets. PMID- 25298195 TI - Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin. AB - BACKGROUND: The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain. METHODS: The glomerular expressions of the slit diaphragm (SD) molecules nephrin, podocin and NEPH1 in rat puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, were analyzed. The effects of Ang II receptor blockade (ARB) (irbesartan 15 mg/kg body weight/day) on proteinuria and on the expression of the SD molecules were analyzed. RESULTS: mRNA expressions of nephrin, podocin and NEPH1 were decreased to an undetectable level at 1 h. The staining of these SD molecules shifted to a discontinuous pattern, and their intensity was reduced. NEPH1 staining was reduced to an undetectable level on day 10. ARB treatment ameliorated the peak value of proteinuria (237.6 +/- 97.0 vs. 359.0 +/- 63.3 mg/day, p < 0.05), and prevented the decrease in the mRNA expression of the SD molecules (nephrin 66.96 %, podocin 60.40 %, NEPH1 77.87 % of normal level). The immunofluorescence staining of NEPH1 was restored by ARB. ARB treatment enhanced the expression of NEPH1 of normal rats. CONCLUSIONS: Dysfunction of the SD molecules including NEPH1 is a crucial initiation event of PAN nephropathy. ARB treatment ameliorates proteinuria in PAN nephropathy by inhibiting the reduction of NEPH1 and nephrin. Ang II action regulates the expression of NEPH1 and nephrin in not only the pathological but also physiological state. PMID- 25298196 TI - Loneliness in HIV-infected smokers. AB - Loneliness is common in persons living with HIV (PLWH). Lonely people smoke at higher rates than the general population, and loneliness is a likely contributor to the ongoing smoking epidemic among PLWH. We explored factors associated with loneliness in a cohort of 272 PLWH smokers enrolled in two separate tobacco treatment trials. Loneliness was independently associated with lack of a spouse or partner, lower educational attainment, "other or unknown" HIV exposure category, depression, anxiety, recent alcohol consumption, and higher daily cigarette consumption. Referral to group therapy reduced loneliness, whereas referral to an individual web-based tobacco treatment did not. PMID- 25298197 TI - Expression profile of mucins (MUC1, MUC2, MUC5AC, and MUC6) in ovarian mucinous tumours: changes in expression from benign to malignant tumours. AB - AIMS: Mucins (MUCs) constitute a family of glycoproteins expressed by epithelial cells. They show specific tissue-type expression, and are useful for differentiating between different cancers. Studies have shown changes in MUC expression with tumour progression in a variety of cancers. The aim of this study was to characterize the profile of MUC expression in benign, borderline and malignant intestinal-type ovarian mucinous tumours (OMTs). METHODS AND RESULTS: MUC1, MUC2, MUC5AC and MUC6 expression was studied by immunohistochemistry in 53 OMTs (19 malignant, 25 borderline, and nine benign). The positivity frequencies of MUC1 in benign, borderline and malignant OMTs were 22.2%, 12%, and 31.6%, respectively. For MUC2, they were 0%, 40%, and 42.1%, respectively. For MUC5AC, they were 100%, 100%, and 94.8%, respectively. For MUC6, they were 66.7%, 16%, and 26.3%, respectively. Significantly increased MUC2 expression and decreased MUC6 expression were seen in borderline and malignant OMTs, as compared with benign tumours. CONCLUSION: This is the first study to compare the expression of all four MUCs in OMT with statistical analysis. We show that MUC2 expression and MUC6 expression change with the progression of benign to borderline and malignant tumours. We suggest that these changes may contribute to malignant transformation. PMID- 25298198 TI - Increased selenoprotein P in choroid plexus and cerebrospinal fluid in Alzheimer's disease brain. AB - Subjects with Alzheimer's disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium. PMID- 25298199 TI - Memory and emotion processing performance contributes to the diagnosis of non semantic primary progressive aphasia syndromes. AB - BACKGROUND: The two non-semantic variants of primary progressive aphasia (PPA), nonfluent/agrammatic PPA (nfv-PPA) and logopenic variant PPA (lv-PPA), share language features despite their different underlying pathology, and may be difficult to distinguish for non-language experts. OBJECTIVE: To improve diagnostic accuracy of nfv-PPA and lv-PPA using tasks measuring non-language cognition and emotion processing. METHODS: Thirty-eight dementia patients meeting diagnostic criteria for PPA (nfv-PPA 20, lv-PPA 18) and 21 matched healthy Controls underwent a comprehensive assessment of cognition and emotion processing, as well as a high-resolution structural MRI and a PiB-PET scan, a putative biomarker of Alzheimer's disease. Task performances were compared between the groups and those found to differ significantly were entered into a logistic regression analysis. RESULTS: Analyses revealed a double dissociation between nfv-PPA and lv-PPA. nfv-PPA exhibited significant emotion processing disturbance compared to lv-PPA and Controls. In contrast, only the lv-PPA group was significantly impaired on tasks of episodic memory. Logistic regression analyses showed that 87% of patients were correctly classified using emotion processing and episodic memory composite scores, together with a measure of visuospatial ability. CONCLUSIONS: Non-language presenting features can help differentiate between the two non-semantic PPA syndromes, with a double dissociation observed on tasks of episodic memory and emotion processing. Based on performance on these tasks, we propose a decision tree as a complementary method to differentiate between the two non-semantic variants. These findings have important clinical implications, with identification of patients who may potentially benefit existing therapeutic interventions currently available for Alzheimer's disease. PMID- 25298200 TI - Utility of transcranial ultrasound in predicting Alzheimer's disease risk. AB - Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by an increasing incidence. One of the pathologic processes that underlie this disorder is impairment of brain microvasculature. Transcranial ultrasound is a non-invasive examination of cerebral blood flow that can be employed as a simple and useful screening tool for assessing the vascular status of brain circulation in preclinical and clinical stages of AD. The objective of this review is to explore the utility of using a transcranial ultrasound to diagnose AD. With transcranial ultrasound, the most frequently studied parameters are cerebral blood flow velocities and pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. On the basis of current knowledge, we recommend using as a transcranial Doppler sonography screening method of choice the assessment of cerebrovascular reserve capacity with breath holding test. PMID- 25298201 TI - Brain toxicity and inflammation induced in vivo in mice by the amyloid-beta forty two inducer aftin-4, a roscovitine derivative. AB - Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-beta (Abeta)1-42 from amyloid-beta protein precursor through gamma-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Abeta1-42, but not Abeta1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1beta, IL 6, and TNFalpha, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the gamma secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin 4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin 4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain. PMID- 25298202 TI - The fungal perspective of arbuscular mycorrhizal colonization in 'nonmycorrhizal' plants. PMID- 25298203 TI - Skin testing with raw egg does not predict tolerance to baked egg in egg-allergic children. AB - BACKGROUND: Most children with egg allergy tolerate egg in baked foods, such as cake, but tolerance cannot be predicted with conventional allergy testing. We hypothesized that the skin prick test (SPT) wheal to unprocessed raw egg might predict tolerance of baked egg at formal oral food challenge (OFC). METHODS: We conducted a retrospective chart review to assess the utility of SPT wheal to egg extract (EE), raw egg (RE), and the ratio of EE:RE in predicting outcome of baked egg OFC in children presenting to our tertiary referral centers with a physician diagnosis of egg allergy and following complete egg avoidance in their diet, between 2009 and 2013. OFC were performed following a standardized protocol using baked egg in cake, to a total dose equivalent to 3g egg protein. RESULTS: Data were analyzed from 186 completed challenges: OFC was positive in 64 (34%) children and negative in 122 (66%). Six children experienced anaphylaxis at OFC. Children tolerant to baked egg were more likely to have a lower SPT to egg extract/raw egg and EE:RE (median 0.56) than their allergic counterparts (0.70, p < 0.05). However, ROC curve analysis demonstrated poor predictivity of challenge outcome, with AUC for SPT to egg extract, raw egg and EE:ER equal to 0.71, 0.63 and 0.60, respectively. CONCLUSION: EE:RE was not helpful in predicting outcome of baked-egg OFC. Indeed, SPT to egg extract was slightly better at predicting outcome than either SPT to raw egg or EE:RE. Unfortunately, tolerance to baked egg can only be predicted from previous history or through controlled exposure. PMID- 25298204 TI - Bioconjugated gold nanoparticles accelerate the growth of new blood vessels through redox signaling. AB - We have designed and developed novel pro-angiogenic bio-synthesized gold nanoconjugates (b-Au-HP) that make new blood vessels, as observed by several in vitro and in vivo assays, suggesting their future potential applications in alternative treatment strategies for wound healing, cardiovascular diseases (CVD) and ischemic diseases using a nanomedicine approach. PMID- 25298205 TI - Terminal alkenes as versatile chemical reporter groups for metabolic oligosaccharide engineering. AB - The Diels-Alder reaction with inverse electron demand (DAinv reaction) of 1,2,4,5 tetrazines with electron rich or strained alkenes was proven to be a bioorthogonal ligation reaction that proceeds fast and with high yields. An important application of the DAinv reaction is metabolic oligosaccharide engineering (MOE) which allows the visualization of glycoconjugates in living cells. In this approach, a sugar derivative bearing a chemical reporter group is metabolically incorporated into cellular glycoconjugates and subsequently derivatized with a probe by means of a bioorthogonal ligation reaction. Here, we investigated a series of new mannosamine and glucosamine derivatives with carbamate-linked side chains of varying length terminated by alkene groups and their suitability for labeling cell-surface glycans. Kinetic investigations showed that the reactivity of the alkenes in DAinv reactions increases with growing chain length. When applied to MOE, one of the compounds, peracetylated N butenyloxycarbonylmannosamine, was especially well suited for labeling cell surface glycans. Obviously, the length of its side chain represents the optimal balance between incorporation efficiency and speed of the labeling reaction. Sialidase treatment of the cells before the bioorthogonal labeling reaction showed that this sugar derivative is attached to the glycans in form of the corresponding sialic acid derivative and not epimerized to another hexosamine derivative to a considerable extent. PMID- 25298207 TI - Computational Integrative Biology--on the joint analysis of diverse biological data sets. PMID- 25298206 TI - The adipokine apelin-13 induces expression of prothrombotic tissue factor. AB - Adipocytes are cells able to produce and secrete several active substances (adipokines) with direct effects on vascular cells. Apelin, one of the most recently identified adipokines has been studied in cardiovascular system physiology in regard to vessel vasodilation and myocardial contraction, but it has not yet completely characterised for its pathophysiological role in cardiovascular disease and especially in acute coronary syndromes (ACS). Several studies have indicated that tissue factor (TF) plays a pivotal role in the pathophysiology of ACS by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates the effects of apelin 12 and apelin 13 on TF in human umbilical endothelial cells (HUVECs) and monocytes. Cells were stimulated with increasing concentrations of apelin 12 or apelin 13 and then processed to evaluate TF-mRNA levels by real-time PCR as well as TF expression/activity by FACS analysis and pro-coagulant activity. Finally, a potential molecular pathway involved in modulating this phenomenon was investigated. We demonstrate that apelin 13 but not apelin 12 induces transcription of mRNA for TF. In addition, we show that this adipokine promotes surface expression of TF that is functionally active. Apelin 13 effects on TF appear modulated by the activation of the G-protein-transcription factor nuclear factor (NF)-kappaB axis since G-protein inhibitors suppressed NF-kappaB mediated TF expression. Data of the present study, although in vitro, indicate that apelin 13, induces a procoagulant phenotype in HUVECs and monocytes by promoting TF expression. These observations support the hypothesis that this adipokine might play a relevant role as an active partaker in athero-thrombotic disease. PMID- 25298208 TI - Amphiregulin promotes the immunosuppressive activity of intrahepatic CD4+ regulatory T cells to impair CD8+ T-cell immunity against hepatitis B virus infection. AB - Hepatitis B virus (HBV) infection causes liver diseases and hepatocellular carcinoma. Immunotolerance in HBV-infected patients is one of the factors that incur failure of HBV clearance and persistent HBV amplification. However, the mechanisms underlying immunotolerance after HBV infection are yet to be thoroughly understood. Using a novel HBV mouse model, we found for the first time that epidermal growth factor receptor (EGFR) is up-regulated on intrahepatic regulatory T (Treg) cells in HBV-infected mouse livers. The EGFR-positive Treg cells are more immunosuppressive than EGFR-negative Treg cells, demonstrated by higher expression of immunosuppressive cytokines and robust inhibition of CD8+ T cell proliferation in vitro. Furthermore, EGFR-positive Treg cells potently restrain CD8+ T-cell-mediated anti-viral activity, leading to higher HBV burden in hepatocytes. Amphiregulin, a cytokine of the EGF family, is significantly up regulated in HBV-infected livers, but the cellular sources of amphiregulin are still elusive. Amphiregulin promotes the immunosuppressive activity of EGFR positive Treg cells in vitro, so as to profoundly inhibit production of anti viral components in CD8+ T cells. Taken together, our discovery elucidated a novel mechanism contributing to immunotolerance and viral amplification after HBV infection. Our study may provide new clues for developing therapeutic strategies against HBV infection. PMID- 25298209 TI - Increased lodging resistance in long-culm, low-lignin gh2 rice for improved feed and bioenergy production. AB - Lignin modification has been a breeding target for the improvements of forage digestibility and energy yields in forage and bioenergy crops, but decreased lignin levels are often accompanied by reduced lodging resistance. The rice mutant gold hull and internode2 (gh2) has been identified to be lignin deficient. GH2 has been mapped to the short arm of chromosome 2 and encodes cinnamyl-alcohol dehydrogenase (CAD). We developed a long-culm variety, 'Leaf Star', with superior lodging resistance and a gh phenotype similar to one of its parents, 'Chugoku 117'. The gh loci in Leaf Star and Chugoku 117 were localized to the same region of chromosome 2 as the gh2 mutant. Leaf Star had culms with low lignin concentrations due to a natural mutation in OsCAD2 that was not present in Chugoku 117. However, this variety had high culm strength due to its strong, thick culms. Additionally, this variety had a thick layer of cortical fiber tissue with well-developed secondary cell walls. Our results suggest that rice can be improved for forage and bioenergy production by combining superior lodging resistance, which can be obtained by introducing thick and stiff culm traits, with low lignin concentrations, which can be obtained using the gh2 variety. PMID- 25298210 TI - Blood pressure-decreasing effect of etamicastat alone and in combination with antihypertensive drugs in the spontaneously hypertensive rat. AB - Hyperactivation of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. This study evaluated the efficacy of etamicastat, a dopamine-beta-hydroxylase (DbetaH) inhibitor, in controlling high blood pressure in the spontaneously hypertensive rat (SHR), either alone or in combination with other classes of antihypertensives. SHRs were administered with etamicastat by gavage, and its pharmacodynamic and pharmacokinetic properties were evaluated. Etamicastat induced a time-dependent decrease in noradrenaline-to-dopamine ratios in the heart and kidney, and had no effect on catecholamine levels in the frontal cortex of SHRs. Cardiovascular pharmacodynamic effects following administration of etamicastat alone or in combination with other classes of antihypertensive drugs were assessed by telemetry. Etamicastat was evaluated in combination with captopril, losartan, hydrochlorothiazide, metoprolol, prazosin and/or diltiazem. Etamicastat monotherapy induced a dose-dependent reduction in blood pressure without reflex tachycardia. Combination therapy amplified the antihypertensive effects of all tested drugs. In conclusion, inhibition of peripheral DbetaH with etamicastat, as a monotherapy or combination therapy, may constitute a valid alternative treatment for high blood pressure. PMID- 25298211 TI - Reliability of meat, fish, dairy, and egg intake over a 33-year interval in Adventist Health Study 2. AB - We studied Adventist Health Study 2 (AHS-2) cohort members to determine the reliability of long-term recall of adult dietary intake that occurred 33 years ago. Establishing the reliability of these measures supports studies of how dietary exposure across the life course affects risk of cancer and other noncommunicable disease outcomes. Among 1816 AHS-2 cohort members, we conducted a statistical comparison of long-term recall of meat, fish, dairy, and eggs at AHS 2 baseline with their report of current diet 33 years before AHS-2 baseline at an age of 30-60 years. Major findings are as follows: 1) a high correlation for frequency of red meat (R = 0.71), poultry (R = 0.67), and fish (R = 0.60); lower correlations for dairy (R = 0.19) and eggs (R = 0.28); 2) good concordance for dichotomous measures of red meat [sensitivity: 0.70; specificity: 0.92; positive predictive value (PPV): 0.91], poultry (sensitivity: 0.76; specificity: 0.87; PPV: 0.83), fish (sensitivity: 0.61; specificity: 0.93; PPV: 0.89), dairy (sensitivity: 0.95; specificity: 0.57; PPV: 0.99), and eggs (sensitivity: 0.95; specificity: 0.41; PPV: 0.96); negative predictive value for dairy and eggs was poor. Among older AHS-2 cohort members, we found good reliability of recall of red meat, poultry, and fish intake that occurred 33 years earlier. PMID- 25298212 TI - Electroanatomical mapping of the right atrium during atrial tachycardia originating from right superior pulmonary vein: additional insights on differential diagnosis. AB - BACKGROUND: Atrial tachycardia (AT) from the right superior pulmonary vein (RSPV) may mimic right atrial (RA)-AT due to its proximity to the superior vena cava (SVC) and the preferential connections between the left atrium and right atrium. OBJECTIVE: RA electroanatomical mapping was performed and analyzed during RSPV-AT to differentiate it from RA-AT. METHODS: Electroanatomical mapping of the RA was performed in 16 consecutive patients with RSPV-AT and eight consecutive patients with SVC-AT served as control group. RESULTS: RA mapping revealed single breakthrough in six patients and double breakthroughs in 10 patients in the RSPV AT group. The initial 10-ms atrial depolarization area averaged 4.3 +/- 1.5 cm(2). None of the SVC-ATs exhibited double breakthrough sites with an initial 10 ms atrial depolarization area of 2.0 +/- 0.6 cm(2) (P = 0.001). A cutoff value of activation area of initial 10 ms > 3.15 cm(2) was able to predict RSPV-AT with a sensitivity of 87.5% and a specificity of 100%. Preceding far-field RSPV potentials could be documented in the RA in six patients during RSPV-AT. CONCLUSIONS: During RSPV-AT, diffused initial depolarization and one or two separated breakthrough sites consistent with the preferential connections as revealed by RA mapping could help rule out RA-AT and avoid unnecessary ablation at the RA. PMID- 25298213 TI - The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer. AB - BACKGROUND: Despite the increased rate of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Dendritic cell (DC)-based immunotherapy has been developed as a novel strategy for generating antitumor immunity as part of cancer treatments. The present study aimed to assess the feasibility and clinical effects of DC therapy for recurrent ovarian cancer (ROC). METHODS: This retrospective study included 56 ROC patients who initially received standard chemotherapy followed by DC-based immunotherapy targeting synthesized peptides at 2 institutions between March 2007 and August 2013. The adverse events (AEs) and clinical responses were examined. RESULTS: No serious treatment-related AEs were observed. Seventy one percent of the enrolled patients developed an immunologic response. The median survival time (MST) from ROC diagnosis was 30.4 months, and that from the first vaccination was 14.5 months. Albumin levels of >=4.0 g/dL and lactate dehydrogenase levels of <200 IU/L before vaccination were identified as significant independent factors by multivariate Cox proportional hazard analysis. The MST from the first vaccination in patients with albumin levels of >=4.0 and <4.0 g/dL were 19.9 and 11.6 months, respectively. The corresponding disease control rates were 36% and 15%, respectively. CONCLUSIONS: Our results demonstrated the feasibility and potential clinical effectiveness of DC-based immunotherapy for ROC patients. Additionally, a good nutritional status might be an important factor for further clinical effects. PMID- 25298214 TI - A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. AB - Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18 MUM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 mediated side effects. These results support the interest in MAGL as a target for the treatment of MS. PMID- 25298215 TI - Epicardial-only scar in cardiomyopathy:where the LAVA lurks. PMID- 25298217 TI - The cumulative damage index method: a new method for evaluating the effectiveness of control measures for Plutella xylostella (Lepidoptera: Plutellidae). AB - BACKGROUND: All previously and currently used methods for effectiveness evaluation of control measures for the diamondback moth (DBM) do not simultaneously take the actual damage and population size into consideration. Here, we propose a new method, the cumulative damage index method, in which the number of larvae and their amount of food consumption are simultaneously included in the calculation of the theoretical cumulative damage index (T) and actual cumulative damage index (A). Evaluation was based on the reduced degree of damage calculated according to indexes T and A. RESULTS: Based on the new method, the corrected effectiveness of the combined use of biological measures, chemical insecticides, Bacillus thuringiensis (Bt) and P. xylostella granulosis virus (PxGV) on DBM was 35.85, 2.37, 12.50 and 11.77% respectively. Under the action of natural factors, the Population Developmental Index (I) of DBM was 5.1 +/- 1.4; under the integrated actions of natural factors and these four types of measure, index I of DBM was 0.34 +/- 0.1, 6.1 +/- 1.5, 2.1 +/- 0.5 and 1.1 +/- 0.3 respectively. The sole effectiveness of Trichogramma spp. when integrated with other natural factors, integrated biological measures and chemical insecticides was 21.43 +/- 1.69%, 45.27 +/- 4.09% and 20.68 +/- 2.60% respectively. CONCLUSIONS: There was some difference between the effectiveness evaluated by the new method and index I, and the actual damage caused by DBM could be reflected well by index A. The new method is more scientifically appropriate and practical for effectiveness evaluation than existing methods. (c) 2014 Society of Chemical Industry. PMID- 25298218 TI - Recent development of synthetic preparation methods for guanidines via transition metal catalysis. AB - Multisubstituted guanidines have received much attention because of important applications in many fields, such as pharmaceutics, organometallic and coordination chemistry, and organic synthesis. Although classical methods are available for the preparation of guanidines, synthetic preparation approaches to guanidines are still in great demand. In this review, we summarize recent developments on synthetic methods via the C-N bond formation. Three aspects are included: transition-metal-catalyzed guanidine synthesis based on classical methods; catalytic guanylation reaction of amines with carbodiimides; and tandem catalytic guanylation/cyclization reactions. PMID- 25298216 TI - Antimicrobial activity of the imipenem/rifampicin combination against clinical isolates of Acinetobacter baumannii grown in planktonic and biofilm cultures. AB - To investigate the antimicrobial activity of imipenem and rifampicin alone and in combination against clinical isolates of Acinetobacter baumannii grown in planktonic and biofilm cultures. Minimum inhibitory concentrations were determined for each isolate grown in suspension and in biofilm using a microbroth dilution method. Chequerboard assays and the agar disk diffusion assay were used to determine synergistic, indifferent or antagonistic interactions between imipenem and rifampicin. We used the tissue culture plate method for A. baumannii biofilm formation to measure the percentage of biofilm inhibition and the amount of extracellular DNA after the treatment. To understand the synergistic mechanisms, we conducted hydroxyl radical formation assays. The results were verified by confocal laser scanning microscopy. Imipenem and rifampicin showed effective antimicrobial activity against suspensions and biofilm cultures of A. baumannii, respectively. Synergistic antimicrobial effects between imipenem and rifampicin were observed in 13 and 17 of the 20 clinical isolates when in suspension and in biofilms, respectively. Imipenem and rifampicin alone and in combination generated hydroxyl radicals, which are highly reactive oxygen forms and the major components of bactericidal agents. Furthermore, treatment with imipenem and rifampicin individually or in combination has obvious antibiofilm effects. The synergistic activity of imipenem and rifampicin against clinical isolates of A. baumannii (in suspension and in biofilms) was observed in vitro. Therefore, we conclude that imipenem combined with rifampicin has the potential to be used as a combinatorial therapy for the treatment of infectious diseases caused by A. baumannii. PMID- 25298219 TI - Stability-indicating HPLC assay for lysine-proline-valine (KPV) in aqueous solutions and skin homogenates. AB - A simple, sensitive and stability-indicating high-performance liquid chromatographic (HPLC) assay method was developed and validated for a bioactive peptide, lysine-proline-valine (KPV) in aqueous solutions and skin homogenates. Chromatographic separation was achieved on a reversed phase Phenomenex C18 column (4.6 * 250 mm, packed with 5 um silica particles) with a gradient mobile phase consisting of 0.1% trifluoroacetic acid (TFA) in water (A) and 0.1% TFA in acetonitrile (B). The proposed HPLC method was validated with respect to accuracy, precision, linearity, repeatability, limit of detection (LOD) and limit of quantitation (LOQ). The calibration curve was linear with a correlation coefficient (r) of 0.9999. Relative standard deviation values of accuracy and precision experiments were <2. The LOD and LOQ of KPV were 0.01 and 0.25 ug/mL, respectively. Under stress conditions (acid, alkali and hydrogen peroxide) KPV yielded lys-pro-diketopiperazine as major degradation product, which was identified by flow injection MS analysis. The developed HPLC method was found to be efficient in separating the active peptide from its degradation products generated under various stress conditions. Also, the validated method was able to separate KPV from other peaks arising from endogenous components of the skin homogenate. PMID- 25298220 TI - Who seeks residential treatment? A report of patient characteristics, pathology, and functioning in females at a residential treatment facility. AB - There has been a growth in the availability and use of residential treatment for eating disorders. Yet there is a paucity of information on the individuals who seek this treatment. This study provides data on 259 consecutive patients (116 adults and 143 adolescents) entering residential treatment for their eating disorders. Upon admission all patients provided individual characteristics data and the following measures: the Eating Disorder Inventory-3 (EDI-3), the Beck Depression Inventory-II, the Beck Anxiety Inventory, the Eating Disorder Quality of Life (EDQOL), and the SF-36 Health Survey-Version 2. Findings are presented by diagnosis (anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified) and age (adult and adolescent). Results show that 61% of adolescents and 80% of adults were above the clinical cutoff for depression, and 59% of adolescents and 78% of adults were above the clinical cutoff for anxiety. Scores on the EDI-3 are presented by subscale and diagnosis. Very low quality of life is reported for both adults and adolescents on the EDQOL. For both adolescents and adults the SF-36 showed average population scores for the physical scale but very low mental scores. Implications for these findings and future directions for this work are discussed. PMID- 25298221 TI - Acceptability and characterization of extruded pinto, navy and black beans. AB - BACKGROUND: Consumption of dry beans has been relatively flat over the last decade. Creating new bean products may increase the consumption of beans and allow more consumers to obtain the health benefits of beans. In this study, pinto, navy and black beans were milled and the resulting flours extruded into puffs. Unflavored extruded puffs were evaluated by untrained panelists using a hedonic scale for appearance, flavor, texture and overall acceptability. The compositions of raw flours and extrudates were characterized. RESULTS: Sensory results indicated that all beans met or exceeded the minimum requirement for acceptability. Overall acceptability of navy and pinto beans was not significantly different, while acceptability of black bean puffs was significantly lower. Total protein (198-217 g kg(-1)) in extrudates was significantly different among the three beans. Total starch ranged from 398 to 406 g kg(-1) and was not significantly different. Resistant starch, total extractable lipid and raffinose contents were significantly reduced by extrusion. Extrusion did not affect crude fiber and phytic acid contents. CONCLUSION: The minimal effects on protein and fiber contents, the significant reduction in raffinose content and the acceptability of the unflavored extruded puffs support using various bean flours as ingredients in extruded puffed products. PMID- 25298222 TI - Low-dose antithrombotic treatment in coronary thrombosis of Kawasaki disease. AB - To explore effective and convenient rescue therapy options for coronary artery aneurysms (CAA) with thrombosis in Kawasaki disease (KD). A total of 210 patients with KD between the years 2003 and 2013 were retrospectively reviewed in our institute. 144 of these 210 KD developed CAA, and 10 patients with CAA had associated thrombosis. Thrombosis was confirmed by two-dimensional echocardiograms (2-DE). Laboratory values for CAA were analyzed with and without the thrombus group. The characteristics of CAA were monitored by ultrasound. All patients with thrombus received intravenous (IV) antithrombotic therapy, including urokinase, heparin, and oral warfarin. The effectiveness of antithrombotic treatment was evaluated by measuring the ability to dissolve the thrombus. All thrombi in these patients were preceded by a giant CAA and a history of KD. There are no differences in the blood analyses of both CAA with and without thrombus. Moreover, typical KD symptoms and acute myocardial infarction were not found in CAA with thrombosis. The progression of coronary thrombosis in these patients was arrested by antithrombotic and anti-platelet treatment including low-dose urokinase and heparin. Neither clinical features nor laboratory data could reliably predict CAA associated thrombosis. Therapy with IV anti-thrombus and anti-platelet treatment with low-dose warfarin can effectively dissolve thrombi in KD patients. PMID- 25298224 TI - Mental health professionals' perspectives on the implementation of smoke-free policies in psychiatric units across England. AB - BACKGROUND: The original audit on which this 2013 secondary analysis is based, was conducted in 2010. It explored implementation of smoke-free policies from the perspective of unit managers in 147 psychiatric units across England comprising a randomly selected sample of nine different unit types. MATERIAL: Two main themes are presented: positive perspectives of smoke-free policy implementation, and barriers and problems with smoke-free policy implementation. Analysis of unit managers' experiences and perspectives found that 96% of participants thought smoke-free policy had achieved positive outcomes for staff, patients, services and care. DISCUSSION: Consistency of response was the most prominent factor associated with policy success. Quality of the physical environment and care delivery were clear positive outcomes which enabled the environment to be more conducive to supporting staffs' and patients' quit attempts. Lack of consistency and a prevailing culture of acceptance of smoking were identified as some of the most reported perceived continuing problems. Solutions included the need to acknowledge that this type of complex systems change takes time and ongoing staff education and training. CONCLUSION: Our results demonstrate the importance of taking into account the experiences and attitudes of staff responsible for enacting smoke-free policy. PMID- 25298223 TI - Intergenerational and cross-cultural differences in emotional wellbeing, mental health service utilisation, treatment-seeking preferences and acceptability of psychological treatments for Arab Australians. AB - BACKGROUND: Little is known about the intergenerational and cross-cultural differences in emotional wellbeing and acceptability of psychological treatments for Arab Australians. AIM: To contribute to the emerging data about the mental health status and needs of Arab Australians. METHOD: An Internet survey examined psychological distress and functional impairment as measured by the Kessler 10 Item scale (K-10) and the Sheehan Disability Scale (SDS) among Arab Australians. Additional questions enquired about their help-seeking behaviours, barriers to accessing psychological treatments and preferences for delivery of psychological treatments. A total of 252 participants were recruited through public talks, media and online promotions. RESULTS: Forty-three percent of the respondents reported moderate-to-severe functional impairment (M = 9.5; standard deviation (SD) = 1.8), 32% reported high psychological distress (M = 28.5; SD = 5.4) and 30% were born overseas. First-generation Arab Australians experiencing high psychological distress (i.e. K-10 >= 22), reported a greater preference for Internet-delivered treatment when compared to their second-generation counterparts. Only 18% of the sample reported seeking help from a mental health professional in the past year. The significant barriers reported by respondents with high psychological distress were poor mental health literacy, lack of time and stigma. Respondents preferred face-to-face (90%) over Internet-delivered treatment (55%). Finally, Arab Australians experienced higher psychological distress and underutilised mental health services when compared to the Australian population. CONCLUSION: Targeted public health campaigns that make culturally relevant interventions such as modifying existing Internet-delivered treatment for Arab Australians may reduce barriers and increase treatment options for this population. PMID- 25298226 TI - Influence of cyclopentadienyl ring-tilt on electron-transfer reactions: redox induced reactivity of strained [2] and [3]ruthenocenophanes. AB - In contrast to ruthenocene [Ru(eta(5) -C5 H5 )2 ] and dimethylruthenocene [Ru(eta(5) -C5 H4 Me)2 ] (7), chemical oxidation of highly strained, ring-tilted [2]ruthenocenophane [Ru(eta(5) -C5 H4 )2 (CH2 )2 ] (5) and slightly strained [3]ruthenocenophane [Ru(eta(5) -C5 H4 )2 (CH2 )3 ] (6) with cationic oxidants containing the non-coordinating [B(C6 F5 )4 ](-) anion was found to afford stable and isolable metal?metal bonded dicationic dimer salts [Ru(eta(5) -C5 H4 )2 (CH2 )2 ]2 [B(C6 F5 )4 ]2 (8) and [Ru(eta(5) -C5 H4 )2 (CH2 )3 ]2 [B(C6 F5 )4 ]2 (17), respectively. Cyclic voltammetry and DFT studies indicated that the oxidation potential, propensity for dimerization, and strength of the resulting Ru?Ru bond is strongly dependent on the degree of tilt present in 5 and 6 and thereby degree of exposure of the Ru center. Cleavage of the Ru?Ru bond in 8 was achieved through reaction with the radical source [(CH3 )2 NC(S)S?SC(S)N(CH3 )2 ] (thiram), affording unusual dimer [(CH3 )2 NCS2 Ru(eta(5) -C5 H4 )(eta(3) -C5 H4 )C2 H4 ]2 [B(C6 F5 )4 ]2 (9) through a haptotropic eta(5) -eta(3) ring-slippage followed by an apparent [2+2] cyclodimerization of the cyclopentadienyl ligand. Analogs of possible intermediates in the reaction pathway [C6 H5 ERu(eta(5) -C5 H4 )2 C2 H4 ][B(C6 F5 )4 ] [E=S (15) or Se (16)] were synthesized through reaction of 8 with C6 H5 E?EC6 H5 (E=S or Se). PMID- 25298225 TI - Experience of stigma and discrimination reported by people experiencing the first episode of schizophrenia and those with a first episode of depression: The FEDORA project. AB - AIM: To record and measure the nature and severity of stigma and discrimination experienced by people during a first episode of schizophrenia and those with a first episode of major depressive disorder. METHODS: The Discrimination and Stigma Scale (DISC-12) was used in a cross-sectional survey to elicit service user reports of anticipated and experienced discrimination by 150 people with a diagnosis of first-episode schizophrenia and 176 with a diagnosis of first episode major depressive disorder in seven countries (Austria, Croatia, Czech Republic, Poland, Romania, Sweden and Turkey). RESULTS: Participants with a diagnosis of major depressive disorder reported discrimination in a greater number of life areas than those with schizophrenia, as rated by the total DISC-12 score (p = .03). With regard to specific life areas, participants with depression reported more discrimination in regard to neighbours, dating, education, marriage, religious activities, physical health and acting as a parent than participants with schizophrenia. Participants with schizophrenia reported more discrimination with regard to the police compared to participants with depression. CONCLUSION: Stigma and discrimination because of mental illness change in the course of the mental diseases. Future research may take a longitudinal perspective to better understand the beginnings of stigmatisation and its trajectory through the life course and to identify critical periods at which anti-stigma interventions can most effectively be applied. PMID- 25298227 TI - Palladium-catalyzed debenzylative cross-coupling of aryl benzyl sulfides with aryl bromides: synthesis of diaryl sulfides. AB - A novel debenzylative approach to synthesize diaryl sulfides from aryl benzyl sulfides and aryl bromides in good to excellent yields is reported. Mechanistic studies suggest a single catalyst, derived from Pd(dba)2 and NiXantPhos, efficiently catalyzes alpha-arylation of sulfides, C-S bond cleavage, and C-S bond formation in a tricatalytic cycle. PMID- 25298228 TI - In situ transmission electron microscopy observation of dislocation motion in 9Cr steel at elevated temperatures: influence of shear stress on dislocation behavior. AB - To elucidate high-temperature plastic deformation (creep) mechanism in materials, it is essential to observe dislocation motion under tensile loading. There are many reports on in situ transmission electron microscopy (TEM) observations in the literature; however, the relationship between the dislocation motion and shear stress in 9Cr steel is still not clear. In this study, in order to evaluate this relationship quantitatively, in situ TEM observations were carried out in conjunction with finite element method (FEM) analysis. A tensile test sample was strained at an elevated temperature (903 K) inside a transmission electron microscope, and the stress distribution in the strained sample was analyzed by FEM. The dislocation behavior was clearly found to depend on the shear stress. At a shear stress of 66 MPa, both the dislocation velocity and mobile dislocation density were low. However, a high shear stress level of 95 MPa caused a noticeable increase in the dislocation velocity and mobile dislocation density. Furthermore, in this article, we discuss the dependence of the dislocation behavior on stress. The results presented here also indicate that the relationship between the microstructure and the strength of materials can be revealed by the methods used in this work. PMID- 25298230 TI - A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3'UTR enhances chromosomal DNA damage. AB - Human APOBEC3A (A3A) cytidine deaminase is a host enzyme that can introduce mutations into chromosomal DNA. As APOBEC3B (A3B) encodes a C-terminal catalytic domain ~91% identical to A3A, we examined its genotoxic potential as well as that of a highly prevalent chimaeric A3A-A3B deletion allele (DeltaA3B), which is linked to a higher odds ratio of developing breast, ovarian and liver cancer. Interestingly, breast cancer genomes from DeltaA3B(-/-) patients show a higher overall mutation burden. Here it is shown that germline A3B can hypermutate nuclear DNA, albeit less efficiently than A3A. Chimaeric A3A mRNA resulting from DeltaA3B was more stable, resulting in higher intracellular A3A levels and greater DNA damage. The cancer burden implied by the higher A3A levels could be considerable given the high penetration of the DeltaA3B allele in South East Asia. PMID- 25298231 TI - New HIV diagnoses in UK continue to decline. PMID- 25298229 TI - Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases. AB - Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs. PMID- 25298232 TI - Standing posture at work and overweight exacerbate varicose veins: Shimane CoHRE Study. AB - Varicose veins (VV) in legs are commonly observed in the general global population. However, the prevalence of and risk factors for VV in Japan are not clear. This study aimed at clarifying the risk factors for VV in traditional rural areas of Shimane prefecture. Subjects (113 men and 205 women aged >=45 years) were recruited from health examinations in those areas in 2012. VV were defined as a reflux of blood in the great and/or small saphenous vein and incompetent perforating veins detected by ultrasonography. Risk factors for VV were analyzed using logistic regression models that included various parameters. We also investigated the possible interaction between standing at work and overweight and calculated the synergistic index. VV were found in 20.1% of the subjects (12.4% of men and 24.4% of women). The previously known risk factors of prolonged upright standing posture during work, higher body mass index (BMI), female sex, and age were also significant factors for VV. There was a significant combined effect of overweight (BMI >=25) and prolonged upright standing posture at work [adjusted odds ratio = 3.42; 95% confidence interval (CI), 1.07-10.89], although the synergistic effect was not significant [synergistic index = 1.3; 95% CI, 0.2-8.7]. The prevalence of VV in the traditional rural area of Shimane prefecture was comparable to that reported previously in European countries. Our results confirm that exposure to both prolonged standing at work and overweight exacerbate VV development. This finding is useful to develop strategies for VV prevention. PMID- 25298233 TI - Conserved metallomics in two insect families evolving separately for a hundred million years. AB - MUetal cofactors are required for enzymatic catalysis and structural stability of many proteins. Physiological metal requirements underpin the evolution of cellular and systemic regulatory mechanisms for metal uptake, storage and excretion. Considering the role of metal biology in animal evolution, this paper asks whether metal content is conserved between different fruit flies. A similar metal homeostasis was previously observed in Drosophilidae flies cultivated on the same larval medium. Each species accumulated in the order of 200 ug iron and zinc and approximately ten-fold less manganese and copper per gram dry weight of the adult insect. In this paper, data on the metal content in fourteen species of Tephritidae, which are major agricultural pests worldwide, are presented. These fruit flies can be polyphagous (e.g., Ceratitis capitata) or strictly monophagous (e.g., Bactrocera oleae) or oligophagous (e.g., Anastrepha grandis) and were maintained in the laboratory on five distinct diets based on olive oil, carrot, wheat bran, zucchini and molasses, respectively. The data indicate that overall metal content and distribution between the Tephritidae and Drosophilidae species was similar. Reduced metal concentration was observed in B. oleae. Feeding the polyphagous C. capitata with the diet of B. oleae resulted in a significant quantitative reduction of all metals. Thus, dietary components affect metal content in some Tephritidae. Nevertheless, although the evidence suggests some fruit fly species evolved preferences in the use or storage of particular metals, no metal concentration varied in order of magnitude between these two families of Diptera that evolved independently for over 100 million years. PMID- 25298234 TI - Late-onset temperature reduction can retard the aging process in aged fish via a combined action of an anti-oxidant system and the insulin/insulin-like growth factor 1 signaling pathway. AB - Two different mechanisms are considered to be related to aging. Cumulative molecular damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Deregulated nutrient sensing by the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway is the second mechanism (IIS concept). Temperature reduction (TR) is known to modulate aging and prolong life span in a variety of organisms, but the mechanisms remain poorly defined. Here we first demonstrate that late-onset TR from 26 degrees C to 22 degrees C extends mean life span and maximum life span by approximately 5.2 and 3 weeks, respectively, in the annual fish Nothobranchius guentheri. We then show that TR is able to decrease the accumulation of the histological aging markers senescence-associated beta galactosidase (SA-beta-Gal) in the epithelium and lipofuscin (LF) in the liver and to reduce protein oxidation and lipid peroxidation levels in the muscle. We also show that TR can enhance the activities of catalase, glutathione peroxidase, and superoxide dismutase, and stimulate the synthesis of SirT1 and FOXO3A/FOXO1A, both of which are the downstream regulators of the IIS pathway. Taken together, our findings suggest that late-onset TR, a simple non-intrusion intervention, can retard the aging process in aged fish, resulting in their life span extension, via a synergistic action of an anti-oxidant system and the IIS pathway. This also suggests that combined assessment of the ROS and IIS concepts will contribute to providing a more comprehensive view of the anti-aging process. PMID- 25298235 TI - An economic assessment of embryo diagnostics (Dx) - the costs of introducing non invasive embryo diagnostics into IVF standard treatment practices. AB - BACKGROUND: New techniques in assessing oocytes and embryo quality are currently explored to improve pregnancy and delivery rates per embryo transfer. While a better understanding of embryo quality could help optimize the existing "in vitro fertilization" (IVF) therapy schemes, it is essential to address the economic viability of such technologies in the healthcare setting. METHODS: An Embryo-Dx economic model was constructed to assess the cost-effectiveness of 3 different IVF strategies from a payer's perspective; it compares Embryo-Dx with single embryo transfer (SET) to elective single embryo transfer (eSET) and to double embryo transfer (DET) treatment practices. RESULTS: The introduction of a new non invasive embryo technology (Embryo-Dx) associated with a cost up to ?460 is cost effective compared to eSET and DET based on the cost per live birth. The model assumed that Embryo-Dx will improve ongoing pregnancy rate/realize an absolute improvement in live births of 9% in this case. CONCLUSIONS: This study shows that improved embryo diagnosis combined with SET may have the potential to reduce the cost per live birth per couple treated in IVF treatment practices. The results of this study are likely more sensitive to changes in the ongoing pregnancy rate and consequently the live birth rate than the diagnosis costs. The introduction of a validated Embryo-Dx technology will further support a move towards increased eSET procedures in IVF clinical practice and vice versa. PMID- 25298236 TI - Lipozyme RM IM-catalyzed acidolysis of Cinnamomum camphora seed oil with oleic acid to produce human milk fat substitutes enriched in medium-chain fatty acids. AB - In the present study, a human milk fat substitute (HMFS) enriched in medium-chain fatty acids (MCFAs) was synthesized through acidolysis reaction from Cinnamomum camphora seed oil (CCSO) with oleic acid in a solvent-free system. A commercial immobilized lipase, Lipozyme RM IM, from Rhizomucor miehei, was facilitated as a biocatalyst. Effects of different reaction conditions, including substrate molar ratio, enzyme concentration, reaction temperature, and reaction time were investigated using response surface methodology (RSM) to obtain the optimal oleic acid incorporation. After optimization, results showed that the maximal incorporation of oleic acid into HMFS was 59.68%. Compared with CCSO, medium chain fatty acids at the sn-2 position of HMFS accounted for >70%, whereas oleic acid was occupied predominantly at the sn-1,3 position (78.69%). Meanwhile, triacylglycerol (TAG) components of OCO (23.93%), CCO (14.94%), LaCO (13.58%), OLaO (12.66%), and OOO (11.13%) were determined as the major TAG species in HMFS. The final optimal reaction conditions were carried out as follows: substrate molar ratio (oleic acid/CCSO), 5:1; enzyme concentration, 12.5% (w/w total reactants); reaction temperature, 60 degrees C; and reaction time, 28 h. The reusability of Lipozyme RM IM in the acidolysis reaction was also evaluated, and it was found that it could be reused up to 9 times without significant loss of activities. Urea inclusion method was used to separate and purify the synthetic product. As the ratio of HMFS/urea increased to 1:2, the acid value lowered to the minimum. In a scale-up experiment, the contents of TAG and total tocopherols in HMFS (modified CCSO) were 77.28% and 12.27 mg/100 g, respectively. All of the physicochemical indices of purified product were within food standards. Therefore, such a MCFA-enriched HMFS produced by using the acidolysis method might have potential application in the infant formula industry. PMID- 25298238 TI - Biventricular pacing: more is better! PMID- 25298237 TI - Prognostic role of restenosis in 10 004 patients undergoing routine control angiography after coronary stenting. AB - AIM: Routine control angiography is a valuable tool with high-sensitivity in detecting restenosis after coronary stenting. However, the prognostic role of restenosis is still controversial. We investigated the impact of restenosis on 4 year mortality in patients undergoing routine control angiography after coronary stenting. METHODS AND RESULTS: All the patients undergoing successful implantation of coronary stents for de novo lesions from 1998 to 2009 and routine control angiography after 6-8 months at two centres in Munich, Germany were studied. Restenosis was defined as diameter stenosis >=50% in the in-segment area at follow-up angiography. The primary outcome was 4-year mortality. The study included 10 004 patients with 15 004 treated lesions. Restenosis was detected in 2643 (26.4%) patients. Overall, there were 702 deaths during the follow-up. Of these, 218 deaths occurred among patients with restenosis and 484 deaths occurred among patients without restenosis [unadjusted hazard ratio: HR: 1.19; (95% confidence interval CI: 1.02-1.40); P = 0.03]. The Cox proportional hazards model adjusting for other variables identified restenosis as an independent correlate of 4-year mortality [HR: 1.23; (95% CI: 1.03-1.46); P = 0.02]. Other independent correlates of 4-year mortality were age [for each 10-year increase, HR: 2.34; (95% CI: 2.12-2.60); P < 0.001], diabetes mellitus [HR: 1.68; (95% CI: 1.41 1.99); P < 0.001], current smoking habit [HR: 1.39; (95% CI: 1.09-1.76); P = 0.01], and left ventricular ejection fraction [for each 5% decrease, HR: 1.39; (95% CI: 1.31-1.48); P < 0.001]. CONCLUSIONS: In this large cohort of patients, the presence of restenosis at follow-up angiography after coronary stenting was predictive of 4-year mortality. Whether routine control angiography after coronary stenting is beneficial and influences outcomes should be evaluated by properly designed randomized trials. PMID- 25298239 TI - Serological evidence for influenza virus infection in Korean wild boars. AB - Serum samples from 1,011 wild boars hunted in 2012 were collected for serological surveillance for 4 subtypes (pandemic A (H1N1) 2009 and classical H1N1, H1N2 and H3N2) of swine influenza virus (SIV). Samples from 12 of the boars were identified as positive for SIV (pandemic A (H1N1) 2009, n=9; classical H1N1, n=2; and H1N2, n=1) by a hemagglutination inhibition test (HI test) and a nucleoprotein (NP)-based enzyme-linked immunosorbent assay (NP-ELISA). Although the overall seroprevalence of SIV in the Korean wild boar population was somewhat low compared with that in China and the U.S.A., the apparent prevalence of pandemic H1N1 was notable. Therefore, continuous monitoring of the wild boar population is needed as it may be a major reservoir for pandemic H1N1, facilitating its spread to humans and domestic pigs. PMID- 25298240 TI - Efficacy of levamisole alone and in combination with mebendazole against Gongylonema pulchrum infection in rabbits. AB - Gongylonema pulchrum is an important parasite of captive primates. Twelve rabbits were infected with 30 third-stage larvae of G. pulchrum. At 4-7 months post infection, animals were administered levamisole at a single dose of 12 mg/kg, levamisole at 8 mg/kg three times at 2-day intervals, levamisole at a single dose of 8 mg/kg after administration of mebendazole at 70 mg/kg for 3 days or 8 ml of distilled water for 3 days (control). Necropsy at 14 days after treatment revealed that single and multiple dosages of levamisole reduced nematode burdens by 68.4% and 89.5%, respectively. The combined regimen of mebendazole and levamisole exhibited high efficacy for treating G. pulchrum located widely within the upper digestive tract, with a reduction of 98.2%. These results suggest that this combined chemotherapy treatment may be effective against G. pulchrum infection, including buccal and lingual gongylonemiasis in primates. PMID- 25298241 TI - Calcium ions are involved in egress of Babesia bovis merozoites from bovine erythrocytes. AB - Bovine babesiosis is a livestock disease known to cause economic losses in endemic areas. The apicomplexan parasite Babesia bovis is able to invade and destroy the host's erythrocytes leading to the serious pathologies of the disease, such as anemia and hemoglobinuria. Understanding the egress mechanisms of this parasite is therefore a key step to develop new therapeutic strategies. In this study, the possible involvement of Ca(2+) in the egress of B. bovis merozoites from infected erythrocytes was investigated. Egress was artificially induced in vitro using calcium ionophore A23187 and thapsigargin to increase Ca(2+) concentration in the cytosol of the parasite cells. The increased intracellular Ca(2+) concentration following these treatments was confirmed using live cell Ca(2+) imaging with confocal laser scanning microscopy. Based on our findings, we suggest a Ca(2+) signalling pathway in the egress of B. bovis merozoites. PMID- 25298242 TI - Thulium laser versus standard transurethral resection of the prostate for benign prostatic obstruction: a systematic review and meta-analysis. AB - PURPOSE: To assess the efficacy and safety of thulium laser versus standard transurethral resection of the prostate (TURP) for treating patients with benign prostatic obstruction. METHODS: A systematic search of the electronic databases, including Medline, Embase, Web of Science, and The Cochrane Library, was performed up to February 1, 2014. The pooled estimates of demographic and clinical baseline characteristics, perioperative variables, complications, and postoperative efficacy including International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), and postvoid residual (PVR) were calculated. RESULTS: Seven trials assessing thulium laser versus standard TURP were considered suitable for meta-analysis including four randomized controlled trials (RCTs) and three non-RCTs. Compared with TURP, although thulium laser prostatectomy (TmLRP) needed a longer operative time [weighted mean difference (WMD) 8.18 min; 95 % confidence interval (CI) 1.60-14.75; P = 0.01], patients having TmLRP might benefit from significantly less serum sodium decreased (-3.73 mmol/L; 95 % CI -4.41 to -3.05; P < 0.001), shorter time of catheterization (WMD 1.29 days; 95 % CI -1.95 to -0.63; P < 0.001), shorter length of hospital stay (WMD -1.83 days; 95 % CI -3.10 to -0.57; P = 0.005), and less transfusion (odds ratio 0.09; 95 % CI 0.02-0.41; P = 0.002). During the 1, 3, and, 12 months of postoperative follow-up, the procedures did not demonstrate a significant difference in IPSS, QoL, Qmax, and PVR. CONCLUSIONS: TmLRP had a similar efficacy to standard TURP in terms of IPSS, QoL, Qmax, and PVR, and offered several advantages over TURP in terms of blood transfusion, serum sodium decreased, catheterization time, and hospital stay, while TURP was superior in terms of operation duration. Well-designed multicentric/international RCTs with long-term follow-up are still needed. PMID- 25298244 TI - Prolonged Laboratory Interference After Administration of Intravenous Lipid Emulsion Therapy. AB - BACKGROUND: Pancreatitis and laboratory interference are rarely reported complications of intravenous lipid emulsion (ILE) therapy. We report a case of significant laboratory interference after ILE administration. CASE REPORT: A 43 year-old female was admitted to the hospital after an unwitnessed ingestion of propranolol, tramadol, zolpidem, and alprazolam. She was intubated and treated with intravenous normal saline, insulin/glucose, and norepinephrine infusions due to hypotension. Two bolus doses and one maintenance dose of 20 % ILE were administered. Beginning approximately 2 h after ILE administration, laboratory assays were unable to be performed due to the presence of lipemia. The patient developed refractory hypotension and was transferred to a tertiary care center. Upon admission to the ICU, the patient received one additional bolus of 20 % ILE. Laboratory assays were again attempted but were unable to be adequately performed due to a pinkish-white discoloration of the patient's blood. Percutaneous femoral extracorporeal membrane oxygenation (ECMO) was initiated, but laboratory interference noted with the arterial blood gas analyzer prevented the analysis of oxygenation. The patient's hemodynamic condition did not improve; she expired 31 h after initial admission. CASE DISCUSSION: In one previous report, centrifugation was effective in removing more than 90 % of glycerol-banked triglycerides, thus minimizing lipid interference with laboratory assays. We noted persistent laboratory interference for more than 20 h after ILE administration, despite ultracentrifugation of specimens. CONCLUSION: Clinicians should be aware that ILE administration may cause significant and prolonged interference with laboratory assays, which may affect the monitoring of critically ill patients. PMID- 25298243 TI - Effect of percutaneous assisted approach on functional rehabilitation for total hip replacement compared to anterolateral approach: study protocol for a randomized controlled trial. AB - BACKGROUND: The anterolateral approach is a commonly used technique for total hip replacement. It requires the detachment of a large part of the gluteus medius muscle. However, it is known that this muscle has a great impact on hip stability. Using the percutaneous assisted approach the damage to the gluteus medius can be limited. The purpose of this study is to compare the effect of the percutaneous assisted approach with the anterolateral approach on postoperative functional outcome. METHODS/DESIGN: This study uses a prospective, randomized, parallel-group design with blinded assessment and unblinded treatment to compare the percutaneous assisted approach with the anterolateral approach in total hip replacement surgery. The postoperative results of patients operated on using the percutaneous assisted approach will be compared with those of patients operated on using the anterolateral approach. Prior to surgery patients will undergo baseline measurements. These will consist of gluteus medius measurements (surface electromyography, strength measurements of abductors and quadriceps and the Trendelenburg test), questionnaires (Oxford Hip Score and 36-item Short Form Health Survey) and functional measures (the Timed Get-Up-and-Go test, Five times Sit-to-Stand test and Six-Minute Walk test). These measurements will be repeated four and 12 weeks after surgery. After surgery both groups will receive usual care. DISCUSSION: The gluteus medius is the main stabilizer of the hip joint. Therefore, we assume that functional outcome and gluteus medius function of patients after the percutaneous assisted approach will be better than after the anterolateral approach. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on 8 January 2014, registration number: NCT02032017. PMID- 25298245 TI - Serological characterization of surface-exposed proteins of Coxiella burnetii. AB - The obligate intracellular Gram-negative bacterium Coxiella burnetii causes Q fever, a worldwide zoonosis. Here we labelled Cox. burnetii with biotin and used biotin-streptavidin affinity chromatography to isolate surface-exposed proteins (SEPs). Using two-dimensional electrophoresis combined with mass spectrometry, we identified 37 proteins through bioinformatics analysis. Thirty SEPs expressed in Escherichia coli (recombinant SEPs, rSEPs) were used to generate microarrays, which were probed with sera from mice experimentally infected with Cox. burnetii or sera from Q fever patients. Thirteen rSEPs were recognized as seroreactive, and the majority reacted with at least 50 % of the sera from mice infected with Cox. burnetii but not with sera from mice infected with Rickettsia rickettsii, R. heilongjiangensis, or R. typhi. Further, 13 proteins that reacted with sera from patients with Q fever did not react with sera from patients with brucellosis or mycoplasma pneumonia. Our results suggest that these seroreactive SEPs have potential as serodiagnostic antigens or as subunit vaccine antigens against Q fever. PMID- 25298246 TI - Down-regulated aquaporin 5 inhibits proliferation and migration of human epithelial ovarian cancer 3AO cells. AB - BACKGROUND: Recent studies suggested that aquaporins 5 (AQP5) was associated with many kinds of cancers and regulated many processes of various kinds of cancer cells. Our previous studies also demonstrated that AQP5 was highly expressed in epithelial ovarian cancer and contributed to the progress of ovarian cancer. METHODS: Lentivirus for knocking-down the expression of AQP5 was prepared and verified by qPCR and Western blotting. Cell counting kit-8 (CCK8) assay and transwell assay were performed to investigate the role of AQP5 on proliferation and migration of 3AO cells. The effects of down-regulating AQP5 on tumorigenesis were tested by tumor xenografts experiments. RESULTS: An effective lentivirus silencing AQP5 expression was obtained and used in this study. Down-regulating AQP5 inhibited proliferation and migration of cultured human epithelial ovarian cancer 3AO Cell. Furthermore, interfering of AQP5 during tumorigenesis could efficiently decrease the tumor growth in athymic mice. CONCLUSIONS: These findings altogether suggest that AQP5 regulated multi processes in ovarian carcinogenesis and may be an attractive therapeutic target. PMID- 25298247 TI - An explosive outbreak of Streptococcus pneumoniae serotype-8 infection in a highly vaccinated residential care home, England, summer 2012. AB - In August 2012, an explosive outbreak of severe lower respiratory tract infection (LRTI) due to Streptococcus pneumoniae serotype-8 occurred in a highly vaccinated elderly institutionalized population in England. Fifteen of 23 residents developed LRTI over 4 days (attack rate 65%); 11 had confirmed S. pneumoniae serotype-8 disease, and two died. Following amoxicillin chemoprophylaxis and pneumococcal polysaccharide vaccine (PPV) re-vaccination no further cases occurred in the following 2 months. No association was found between being an outbreak-associated case and age (P = 0.36), underlying comorbidities [relative risk (RR) 0.84 95% confidence interval (CI) 0.34-2.09], or prior receipt of PPV (RR 1.4, 95% CI 0.60-3.33). However, the median number of years since PPV was significantly higher for cases (n = 15, 10.2 years, range 7.3-17.9 years) than non-cases (n = 8, 7.2 years, range 6.8-12.8 years) (P = 0.045), provided evidence of waning immunity. Alternative vaccination strategies should be considered to prevent future S. pneumoniae outbreaks in institutionalized elderly populations. PMID- 25298248 TI - Two polydimethylsiloxane rod extraction methods for the sensitive determination of phenolic compounds in water samples. AB - Simple, precise, and low-cost methods for the simultaneous determination of phenolic endocrine disrupting compounds such as bisphenol A, trichlorophenol, pentachlorophenol, 4-nonylphenol, and 4-octylphenol in water samples were developed. The Direct, in situ derivatization methods are based on polydimethylsiloxane rod extraction followed by liquid desorption and chromatographic analysis by liquid chromatography and diode array detection. Several parameters affecting the extraction and desorption of the phenolic compounds and their acetylated derivates were studied, as well as the chromatographic and detection conditions. For the direct method, determination coefficients (r(2) ) > 0.990 and LODs in the 0.6-2 MUg/L range were obtained for all compounds except bisphenol A (9.5 MUg/L). With the derivatization-based method, based on in situ acetylation, lower limits of detection (0.3-0.9 MUg/L) were obtained for all the compounds with r(2) > 0.988 and RSDs in the 2-9% range. The developed methods were applied to the analysis of spiked water samples obtaining recoveries of between 60.2 and 131.7% for the direct method, and of between 76.6 and 108.2% for the derivatization-based method. The results demonstrate the feasibility of using these two methods for determining bisphenol A, trichlorophenol, pentachlorophenol, 4-nonylphenol, and 4-octylphenol in water. PMID- 25298249 TI - Detection of a novel avian influenza A (H7N9) virus in humans by multiplex one step real-time RT-PCR assay. AB - BACKGROUND: A novel avian influenza A (H7N9) virus emerged in eastern China in February 2013. 413 confirmed human cases, including 157 deaths, have been recorded as of July 31, 2014. METHODS: Clinical specimens, including throat swabs, sputum or tracheal aspirates, etc., were obtained from patients exhibiting influenza-like illness (ILIs), especially from those having pneumonia and a history of occupational exposure to poultry and wild birds. RNA was extracted from these samples and a multiplex one-step real-time RT-PCR assay was developed to specifically detect the influenza A virus (FluA). PCR primers targeted the conserved M and Rnase P (RP) genes, as well as the hemagglutinin and neuraminidase genes of the H7N9 virus. RESULTS: The multiplex assay specifically detected the avian H7N9 virus, and no cross-reaction with other common respiratory pathogens was observed. The detection limit of the assay was approximately 0.05 50% tissue culture infective doses (TCID50), or 100 copies per reaction. Positive detection of the H7N9 virus in sputum/tracheal aspirates was higher than in throat swabs during the surveillance of patients with ILIs. Additionally, detection of the matrix (M) and Rnase P genes aided in the determination of the novel avian H7N9 virus and ensured the quality of the clinical samples. CONCLUSIONS: These results demonstrate that the multiplex assay detected the novel avian H7N9 virus with high specificity and sensitivity, which is essential for the early diagnosis and treatment of infected patients. PMID- 25298250 TI - Oncological outcome of malignant colonic obstruction in the Dutch Stent-In 2 trial. AB - BACKGROUND: The Stent-In 2 trial randomized patients with malignant colonic obstruction to emergency surgery or stent placement as a bridge to elective surgery. The aim of this study was to compare the oncological outcomes. METHODS: Disease recurrence, and disease-free, disease-specific and overall survival were evaluated, including a subgroup analysis of patients with a stent- or guidewire related perforation. RESULTS: Of 98 patients included in the original Stent-In 2 trial, patients with benign (16) or incurable (23) disease were excluded from this study, along with a patient who had withdrawn from the trial. Of the remaining 58 patients, 32 were randomized to emergency surgery (31 resection, 1 stoma only) and 26 to stenting. Unsuccessful stenting required emergency surgery in six patients owing to wire or stent perforation. Locoregional or distant disease recurrence developed in nine of 32 patients in the emergency surgery group and 13 of 26 in the stent group. Disease-free survival was worse in the subgroup with stent- or guidewire-related perforation. Five of six patients in this subgroup developed a recurrence, compared with nine of 32 in the emergency surgery group and eight of 20 who had unperforated stenting. CONCLUSION: Stent placement for malignant colonic obstruction was associated with a risk of recurrence in this trial, but the numbers are small. There is not enough evidence to refute the approach strongly. REGISTRATION NUMBER: ISRCTN46462267 ( http://www.controlled-trials.com). PMID- 25298251 TI - Na-Faraday rotation filtering: the optimal point. AB - Narrow-band optical filtering is required in many spectroscopy applications to suppress unwanted background light. One example is quantum communication where the fidelity is often limited by the performance of the optical filters. This limitation can be circumvented by utilizing the GHz-wide features of a Doppler broadened atomic gas. The anomalous dispersion of atomic vapours enables spectral filtering. These, so-called, Faraday anomalous dispersion optical filters (FADOFs) can be by far better than any commercial filter in terms of bandwidth, transition edge and peak transmission. We present a theoretical and experimental study on the transmission properties of a sodium vapour based FADOF with the aim to find the best combination of optical rotation and intrinsic loss. The relevant parameters, such as magnetic field, temperature, the related optical depth, and polarization state are discussed. The non-trivial interplay of these quantities defines the net performance of the filter. We determine analytically the optimal working conditions, such as transmission and the signal to background ratio and validate the results experimentally. We find a single global optimum for one specific optical path length of the filter. This can now be applied to spectroscopy, guide star applications, or sensing. PMID- 25298252 TI - What do we know about gestational diabetes mellitus and risk for postpartum depression among ethnically diverse low-income women in the USA? AB - Many women develop postpartum mental health symptoms, ranging from the maternity blues to clinically diagnosed postpartum depression (PPD). Substantial literature supports an association between depression and type 2 diabetes, but there is limited literature regarding to what extent this relationship pertains to gestational diabetes (GDM) and postpartum depression. Review of the literature regarding GDM and PPD with a particular focus on describing the prevalence of PPD among women who may be at increased risk for GDM, including low-income and ethnic minority groups, was performed. Literature searches were conducted across four databases for studies reporting postpartum mental health outcomes (including postpartum depression, behavioral symptoms, mental disorders, mood, anxiety, quality of life) following a diagnosis of GDM. Studies including subgroups of women with GDM were included if postpartum mental health outcomes were reported. Of the 245 abstracts identified, ten studies were included in the final review. Findings suggest that PPD was high among low-income, ethnic minority women. Additional research is required to understand the complex relationship between GDM and PPD among low-income women, with the ultimate goal of implementing tailored interventions to address their medical and psychiatric needs. PMID- 25298253 TI - An open trial of mindfulness-based cognitive therapy for the prevention of perinatal depressive relapse/recurrence. AB - Pregnant women with histories of depression are at high risk of depressive relapse/recurrence during the perinatal period, and options for relapse/recurrence prevention are limited. Mindfulness-based cognitive therapy (MBCT) has strong evidence among general populations but has not been studied among at-risk pregnant women to prevent depression. We examined the feasibility, acceptability, and clinical outcomes of depression symptom severity and relapse/recurrence associated with MBCT adapted for perinatal women (MBCT-PD). Pregnant women with depression histories were recruited from obstetrics clinics in a large health maintenance organization at two sites and enrolled in MBCT-PD (N = 49). Self-reported depressive symptoms and interview-based assessments of depression relapse/recurrence status were measured at baseline, during MBCT-PD, and through 6-months postpartum. Pregnant women reported interest, engagement, and satisfaction with the program. Retention rates were high, as were rates of completion of daily homework practices. Intent to treat analyses indicated a significant improvement in depression symptom levels and an 18 % rate of relapse/recurrence through 6 months postpartum. MBCT-PD shows promise as an acceptable, feasible, and clinically beneficial brief psychosocial prevention option for pregnant women with histories of depression. Randomized controlled trials are needed to examine the efficacy of MBCT-PD for the prevention of depressive relapse/recurrence during pregnancy and postpartum. PMID- 25298254 TI - [Developmental abnormalities and nevi of the scalp]. AB - Unusual congenital or early-onset skin lesions on the scalp often pose a diagnostic challenge particularly as the clinical evaluation may be hampered by dense hair growth. Thus, this paper provides a concise review on developmental abnormalities and nevi with exclusive or predominant scalp localization. Aplasia cutis congenita occurs as an isolated finding, in association with genetic syndromes, nevi and anomalies or as a consequence of intrauterine trauma and teratogens. A hairless area with a narrow surrounding rim of hypertrichosis (hair collar sign) may point to occult cranial dysraphism, especially if accompanied by further suggestive signs as port-wine stains, large hemangiomas, dimples, congenital dermoid cysts, and sinuses. Many diverse entities may hide behind cutis verticis gyrata with the primary essential form being rare and representing a diagnosis of exclusion. In contrast to former belief, benign adnexal tumors arise in a nevus sebaceus considerably more often than basal cell carcinomas and other malignant epithelial tumors. Provided that tumor development is not suspected, excision of a nevus sebaceus nevus is indicated primarily for aesthetic-psychosocial reasons. However, surgical treatment is considerably easier in small children. Nevus sebaceus may be a cutaneous marker for several complex syndromes whereas nevus psiloliparus presents almost always in connection with encephalocraniocutaneous lipomatosis. Congenital melanocytic nevi of the scalp tend toward clinical regression, so that surgical intervention in large lesions should be carefully considered. In contrast, the threshold for excision of blue nevi and other conspicuous melanocytic nevi on the scalp should be low, especially since they are difficult to monitor. PMID- 25298255 TI - [Current detection rates of multiresistant gram negative bacteria (3MRGN, 4MRGN) in patients with chronic leg ulcers]. AB - BACKGROUND: Due to the increasing problem of antibiotic resistance in gram negative pathogens, the Commission for Hospital Hygiene and Infection Prevention (KRINKO) decided to establish a new clinically oriented definition of multi resistance. Gram-negative pathogens with a multidrug-resistance (MRGN) are divided into those with resistance to three (3MRGN) or four (4MRGN) antibiotic groups. PATIENTS AND METHODS: In this multicenter study which was done in ten dermatological wound clinics, the bacteriological swabs from up to 100 patients with chronic leg ulcers per center were analyzed according to the current classification KRINKO and evaluated. RESULTS: Overall, the results of 970 patients (553 women, 417 men) could be evaluated. We found 681 gram-positive and 1155 gram-negative bacteria. Pseudomonas aeruginosa was with a detection-rate of 31.1% the most frequent gram-negative pathogen, followed by Proteus mirabilis with 13.7% and various enterobacteria with 28.6%. According to the current KRINKO classification,eight patients with 4MRGN and 34 patients with 3MRGN could be identified. CONCLUSIONS: Our results demonstrate the current spectrum of bacteria in patients with chronic leg ulcers with a variety of gram-negative pathogens, some of which are classified as multi-drug resistant. As a clinical consequence some of the patients require individualized preventive measures and therapy. PMID- 25298257 TI - Instrumental variable additive hazards models. AB - Instrumental variable (IV) methods are popular in non-experimental studies to estimate the causal effects of medical interventions. These approaches allow for the consistent estimation of treatment effects even if important confounding factors are unobserved. Despite the increasing use of these methods, there have been few extensions of IV methods to censored data problems. In this article, we discuss challenges in applying IV techniques to the proportional hazards model and demonstrate the utility of the additive hazards formulation for IV analyses with censored data. Assuming linear structural equation models for the hazard function, we develop a closed-form, two-stage estimator for the causal effect in the additive hazard model. The methods permit both continuous and discrete exposures, and enable the estimation of causal relative survival measures. The asymptotic properties of the estimators are derived and the resulting inferences are shown to perform well in simulation studies and in an application to a data set on the effectiveness of a novel chemotherapeutic agent for colon cancer. PMID- 25298259 TI - Fatigue in sarcoidosis and exercise tolerance, dyspnea, and quality of life. AB - Fatigue is one of the major symptoms reported by sarcoidosis patients. The relationship between fatigue and clinical course of sarcoidosis remains unclear. The aim of the study was to evaluate the relationship between fatigue and lung function tests, exercise tolerance, dyspnea, and quality of life among sarcoidosis patients. One hundred eleven sarcoidosis patients completed the following questionnaires: Fatigue and Assessment Scale (FAS), Quality of Life Scale (SF-36), and dyspnea scales: Medical Research Council Questionnaire, Baseline Dyspnea Index, and Oxygen Cost Diagram. Clinical parameters (FVC, FEV1, DLCO, VO2, and VO2/AT, and work load) were derived from the patients' medical files. The exercise tolerance was the only clinical parameter associated with fatigue (Max. Work Load -0.65, VO2 -0.42, VO2/AT -0.51). No correlations were found between FAS and spirometry or diffusing tolerance. Fatigue correlated with all dyspnea domains by means of (r values ranging from 0.47 to 0.77 in multivariate regression analysis) and with quality of life in SF-36 questionnaire (r values ranging from -0.33 to -0.83). We conclude that FAS seems a reliable and valid indicator of dyspnea level, quality of life, and exercise tolerance in sarcoidosis patients. PMID- 25298258 TI - Integrated image reconstruction and gradient nonlinearity correction. AB - PURPOSE: To describe a model-based reconstruction strategy for routine magnetic resonance imaging that accounts for gradient nonlinearity (GNL) during rather than after transformation to the image domain, and demonstrate that this approach reduces the spatial resolution loss that occurs during strictly image-domain GNL correction. METHODS: After reviewing conventional GNL-correction methods, we propose a generic signal model for GNL-affected magnetic resonance imaging acquisitions, discuss how it incorporates into contemporary image reconstruction platforms, and describe efficient nonuniform fast Fourier transform-based computational routines for these. The impact of GNL-correction on spatial resolution by the conventional and proposed approaches is investigated on phantom data acquired at varying offsets from gradient isocenter, as well as on fully sampled and (retrospectively) undersampled in vivo acquisitions. RESULTS: Phantom results demonstrate that resolution loss that occurs during GNL-correction is significantly less for the proposed strategy than for the standard approach at distances >10 cm from isocenter with a 35 cm field-of-view gradient coil. The in vivo results suggest that the proposed strategy better preserves fine anatomical detail than retrospective GNL-correction while offering comparable geometric correction. CONCLUSION: Accounting for GNL during image reconstruction allows geometric distortion to be corrected with less spatial resolution loss than is typically observed with the conventional image domain correction strategy. PMID- 25298260 TI - Posturography in patients with rheumatoid arthritis and osteoarthritis. AB - The purpose of the paper was to investigate the usefulness of posturographic analysis in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). RA is a chronic inflammatory disorder responsible for destruction of active and passive components of joints. It is the most common autoimmune disease, and the second most common form of arthritis after OA. OA is a chronic disorder characterized by irreversible changes in the joint structure developing with advancing age. Both diseases lead to the destruction of many parts of the motor system, cause pain, weakness, and damage of ligaments, muscles, bones, and articular cartilage. The etiology of the diseases remains unknown. In the present study, evaluation of body balance in the standing position was performed by means of Pro-Med force plate system. Three posturographic tests were applied: with eyes open, closed, and with the biofeedback--under conscious visual control of body movements. The following posturographic parameters were measured: the radius of sways, the developed area, and the total length of posturograms, and also two directional components of sways: the length of left-right (in frontal plane) and forward-backward (in sagittal plane) motions. The results demonstrate that the biofeedback test is most useful in the evaluation of instability in rheumatic patients; it is more powerful than the other posturographic tests evaluated. PMID- 25298261 TI - Organic changes in the central nervous system in children on chronic inhaled corticosteroid therapy. AB - Treatment of asthma, the most common chronic respiratory disease in children, includes long-term inhaled corticosteroids (ICS). The purpose of this study was to analyze the impact of chronic inhaled steroids in children with asthma on changes in the central nervous system (CNS). Eleven children (8-17 years) on at least 4 years inhaled corticosteroid therapy were assessed with magnetic resonance imaging (MRI). All participants underwent a pediatric and neurological examination and spirometry. MRI data were obtained using a 1.5 T scanner with parallel imaging capability. Structural images consisted of axial T1, T2 using turbo spin echo, FLAIR and DWI sequences using typical parameters. Images were assessed in three planes (axial, coronal, and sagittal). Pediatric and neurological examination were normal in all children. In six, the MRI studies revealed small subcortical hyperintense foci. Three had more than five lesions, all of which were smaller than 3 mm. Features of mild supratentorial cortical atrophy were apparent in four. The cerebellum was unremarkable in all children imaged. In conclusion, patients receiving chronic inhaled corticosteroids had small subcortical hyperintense foci and features of mild supratentorial cortical atrophy. These findings suggest that ICS exposure may be associated with the development of organic changes in CNS. Further studies are needed to detail the extent of brain ICS-induced changes in children on chronic inhalative corticosteroid therapy as well as delayed impact of these changes on psychomotor functioning in adulthood. PMID- 25298262 TI - Circulating Thrombospondin-2 and FGF-2 in Patients with Advanced Non-small Cell Lung Cancer: Correlation with Survival. AB - Thrombospondin-2 (TSP-2) is an endogenous negative regulator of vascularization in human cancer. TSP-2 regulates angiogenesis through binding and sequestration of the proangiogenic fibroblast growth factor-2 (FGF-2). However, it is unclear whether TSP-2 and FGF-2 are related to prognosis in non-small cell lung cancer (NSCLC). To study this issue, we measured serum (Elisa) levels of TSP-2 and FGF-2 in 40 NSCLC patients (before chemotherapy) and 22 healthy subjects. Both TSP-2 and FGF-2 concentrations were elevated in the NSCLC group compared with control (TSP-2: 26.72+/-8.00 vs. 18.64+/-5.50 ng/ml, p=0.002; FGF-2: 11.90+/-5.80 vs. 7.26+/-3.90 pg/ml, p=0.01). Receiver-operating characteristic (ROC) curves were applied to find the cut-off serum levels of TSP-2 and FGF-2 (NSCLC vs. healthy: TSP-2=15.09 ng/ml, FGF-2=2.23 pg/ml). Patients before treatment with the TSP-2 level<24.15 ng/ml had a median survival of 23.7 months, but those with TSP 2>24.15 ng/ml had only 9 months' median survival (p=0.007). Patients with FGF-2 level>11.21 pg/ml had significantly shorter survival than patients with FGF 2<11.21 pg/ml (7.5 months vs. 16 months, p=0.034). We conclude that NSCLC patients have higher serum concentrations of TSP-2 and FGF-2 than healthy people. High levels of TSP-2 and FGF-2 may predict worse survival. PMID- 25298263 TI - The rs1800471 Polymorphism of TGFB1 Gene, Serum TGF-Beta1 Level and Chronic Kidney Disease Progression. AB - The aim of the study was to investigate whether rs1800471 polymorphism in TGFB1 gene is associated with the development and progression of non-diabetic chronic kidney disease. Moreover, we examined the serum TGF-beta1 concentration and its association with that polymorphism and progression of the disease. We applied two different methodological approaches. Firstly, a family based study was carried out, comprised of 109 patients with non-diabetic chronic kidney disease and their 218 healthy parents, using the transmission/disequilibrium test. The rs1800471 polymorphism and serum TGF-beta1 level were determined in all subjects. Serum TGF beta1 concentration was also measured in 40 healthy controls. Secondly, we performed a case-control orientated study to determine whether rs1800471 polymorphism and other factors influence the progression of renal impairment. We found no relationships between rs1800471 polymorphism allele transfer and the incidence or progression of non-diabetic chronic kidney disease. We found, however, that the serum TGF-beta1 was significantly higher in patients than in controls. In conclusion, rs1800471 polymorphism in TGFB1 gene does not have an impact on the development and progression of non-diabetic chronic kidney disease caused by primary glomerulopathy and chronic interstitial nephritis. The increased serum TGF-beta1 concentration in such patients suggests its role in the pathomechanism of the disease. Circulating TGF-beta1 level is determined in a multifactorial way, not by rs1800471 polymorphism in TGFB1 gene. PMID- 25298264 TI - Efficacy of Canakinumab vs. triamcinolone acetonide according to multiple gouty arthritis-related health outcomes measures. AB - AIM: Canakinumab (CAN), a selective, fully human, anti-IL-1beta monoclonal antibody, has demonstrated long-term benefits in gouty arthritis (GA) patients, who have contraindications for, or are unresponsive or intolerant of, non steroidal anti-inflammatory drugs (NSAIDs) or colchicine (two trials:beta RELIEVED [n = 228]; beta-RELIEVED II [n = 226]). The trials collected different responses, including patient-reported outcomes (PRO). A composite response end point (CRE) was used to interpret each patient's overall response to treatment. METHODS: Data from beta-RELIEVED trials were pooled for this retrospective analysis. The CRE representing overall change in GA-related health outcomes, from baseline to 12 weeks, included clinical markers; PROs from the Gout Impact Scale (GIS); and the SF-36 bodily pain scale. Response to each variable (i.e. markedly important difference) was determined a priori. Variable values [1 (responder) or 0 (non-responder)] were summed to create a CRE score for each patient. RESULTS: For eight of 12 variables measured, the percentage of CAN responders was significantly greater than for TA (p < 0.05). On average, patients receiving CAN met a higher percentage of response criteria (65%) than patients receiving triamcinolone acetonide (TA) (49%), p < 0.001. Mean CRE scores were significantly higher for CAN vs. TA (mean [SD]; 4.7 [2.7] vs. 3.7 [2.4], p < 0.001). Treatment differences remained even after serially removing individual responder variables and domains from the composite end-point, indicating that the differences between CAN and TA were robust. CONCLUSION: CAN was superior to TA across multiple health outcome variables comprising clinical markers and PRO over 12 weeks in patients contraindicated, intolerant or unresponsive to NSAIDs and/or colchicine. PMID- 25298265 TI - Association between patient engagement in HIV care and antiretroviral therapy medication adherence: cross-sectional evidence from a regional HIV care center in Kenya. AB - Consistent individual effort in engagement in HIV medical services has been associated with positive health outcomes in people living with HIV (PLHIV). However, whether these benefits are facilitated by improved medication adherence has not been widely studied. This study aimed to investigate the marginal effect of engagement in HIV care on medication adherence at a public health facility in Kenya. Between February and April 2013, 392 patients on HIV care at Nyeri Provincial General Hospital participated in this study. Data were collected using a self-administered health survey questionnaire assessing health and sociodemographic statuses. A manual stepwise general linear model was specified to measure the effect of engagement in HIV and other associated predictors on medication adherence. Engagement in HIV care was significantly associated with log-transformed medication adherence in the sample (100.beta = 9.2%, 95% CI 3.2 15.1) irrespective of gender and other selected predictors. Longer duration on antiretroviral therapy was also a significant predictor of better medication adherence (100.beta = 3.2%, 95% CI 2.3-4.1). Despite inter-gender differences in adherence and engagement determinants, gender's independent effect on medication adherence and engagement in care were not statistically significant. Poor medication adherence was associated with lower patient engagement in HIV care services, suggesting that interventions which remove obstacles to regular observance of scheduled clinic appointments and eventual retention may have a beneficial impact on medication adherence and, accordingly, health outcomes in PLHIV. PMID- 25298266 TI - Interspecific variation in the repair of UV damaged DNA in the genus Xiphophorus as a factor in the decline of the Rio Grande Platyfish. AB - The fish genus Xiphophorus consists of 26 species distributed along the eastern slopes of mountain ranges extending from northern Mexico to Belize and Nicaragua. We analyzed light-dependent repair of UV-induced DNA damage in at least two species from each of the four monophyletic Xiphophorus groups. We found that the northern platyfish had significantly reduced photoenzymatic repair compared to the other three groups, including the northern swordtails, southern platyfish and southern swordtails. All of the species of the northern platyfish, including the Marbled (meyeri), Northern (gordoni) and Monterrey Platyfish (couchianus) are the northernmost species in the genus and are the only three species in the genus that are currently found on the IUCN Red List of Threatened Species. Satellite data from the past 30 years (1979-2008) correlate greater increases in shorter wavelength UVB with higher latitudes within the Xiphophorus range. We suggest that, combined with other consequences of human population growth, anthropogenic deozonation resulting in a disproportionate increase in UVB in temperate latitudes may be a contributing factor in the decline and extirpation of the northern platyfish. PMID- 25298269 TI - Haemorrhagic and thrombotic diatheses in mouse models with thrombocytosis. AB - We studied haemostasis in two mouse models with thrombocytosis caused by different pathogenic mechanisms. In one strain (Yall;Mpl-/-) thrombocytosis is driven by a misbalance between thrombopoietin and its receptor, whereas in the other strain, thrombocytosis is caused by expressing a human JAK2-V617F transgene (FF1) that depends on activation by Cre-recombinase (VavCre;FF1, MxCre;FF1). Thrombotic responses were increased following some, but not all types of challenges. In a vaso-occlusive thrombotic model following collagen-adrenaline injection we found increased mortality in both strains. Arterial thrombosis, examined after ferric chloride-induced carotid injury, was accelerated but with little impact on maximal thrombus size. In a vena cava stasis model, clots were of similar size as in wild-type controls, but exhibited a different composition with a higher platelet to fibrin ratio. Both thrombocytosis strains displayed increased haemorrhagic tendency in a tail bleeding assay. Yall;Mpl and VavCre;FF1 displayed a lower proportion of the more reactive high-molecular-weight forms of von Willebrand factor in their plasma, mimicking essential thrombocythaemia with very high platelet counts. Bleeding could not be explained by clear defects in platelet activation, which were normal or only weakly decreased. In conclusion, these models of thrombocytosis recapitulate several features of the haemorrhagic and thrombotic diatheses in ET and PV demonstrating potentials but also some limitations to study these major complications. PMID- 25298270 TI - Dual gold catalysis: synthesis of polycyclic compounds via C-H insertion of gold vinylidenes. AB - New and interesting polycyclic compounds have been synthesized from non conjugated diyne systems by dual gold catalysis. A quaternary carbon center in the backbone and the accompanying Thorpe-Ingold effect enabled the unprecedented insertion of sp(3) and sp(2) C?H bonds that for the first time were incorporated within the backbone of the diyne system and allowed the construction of complex polycyclic carbon scaffolds inaccessible by previous approaches in which the C?H bonds for the insertion were situated at the other end of the alkyne. PMID- 25298272 TI - Splash dispersal of Phyllosticta citricarpa conidia from infected citrus fruit. AB - Rain-splash dispersal of Phyllosticta citricarpa (syn. Guignardia citricarpa) conidia (pycnidiospores) from infected oranges was studied in still air and combined with wind. High power microscopy demonstrated the presence of conidia in splash droplets from diseased oranges, which exuded conidia for over one hour during repeated wetting. The largest (5 mm) incident drops produced the highest splashes (up to 41.0 cm). A linear-by-quadratic surface model predicted highest splashes to be 41.91 cm at a horizontal distance of 25.97 cm from the target orange. Large splash droplets contained most conidia (4-5.5 mm splashes averaged 308 conidia), but were splashed <30 cm horizontal distance. Most (80-90%) splashes were <1 mm diameter but carried only 0-4 conidia per droplet. In multiple splash experiments, splashes combined to reach higher maxima (up to 61.7 cm; linear-by-quadratic surface model prediction, 62.1 cm) than in the single splash experiments. In combination with wind, higher wind speeds carried an increasing proportion of splashes downwind travelling horizontally at least 8 m at the highest wind speed tested (7 m/s), due to a small proportion of droplets (<1 mm) being aerosolised. These experiments suggest that P. citricarpa conidia can be dispersed from infected oranges by splashes of water in rainfall events. PMID- 25298273 TI - Motivations, concerns, and experiences of women who donate normal breast tissue. AB - BACKGROUND: The Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center (KTB) was established in 2007 with funding from Susan G. Komen for the Cure to provide scientists with a resource for normal breast tissue. To date, nearly 3,500 women have donated their healthy breast tissue to the bank, but little is known about their perspectives. This study was designed to examine their motivations, concerns, and experiences. METHODS: We conducted brief interviews with donors (n = 221) to investigate their donation-related motivations, concerns, and experiences. Donor responses were coded and quantitatively analyzed (descriptive statistics and chi(2)). RESULTS: The most frequent motivation to donate (48% of donors) was personal connection to a breast cancer patient/survivor. A majority of donors (60%) were unconcerned about donation before the event; reported concerns included pain, fear, and dislike of surgical procedures. The most frequent positive experiences were minimal pain and positive behavior by KTB staff and volunteers. A majority of donors (61%) reported no negative experience, but reported negative experiences included the biopsy machine and anesthetic. Younger donors (ages 18-24) reported more concerns and negative experiences than older donors (25+). CONCLUSIONS: Donors of healthy breast tissue are motivated by survivor connections and the ability to help by donating. Their concerns and experiences are relatively positive and consistent with undergoing a minor surgical procedure. Younger donors have more concerns and negative experiences. IMPACT: Findings from this study can inform recruitment campaigns and donation procedures for banking of healthy tissue. PMID- 25298274 TI - The intestinal microbiota composition and weight development in children: the KOALA Birth Cohort Study. AB - OBJECTIVE: To investigate whether the intestinal microbiota composition in early infancy is associated with subsequent weight development in children. METHODS: Analyses were conducted within the KOALA Birth Cohort Study (n = 2834). This cohort originates from two recruitments groups: pregnant women with a conventional lifestyle (no selection based on lifestyle) and pregnant women recruited through alternative channels (organic shops, anthroposophic clinicians/midwives, Steiner schools and relevant magazines). From 909 one-month old infants, fecal samples were collected and analyzed by quantitative PCR targeting bifidobacteria, Bacteroides fragilis group, Clostridium difficile, Escherichia coli, Lactobacilli and total bacteria counts. Between the ages of 1 and 10 years, parent-reported weight and height was collected at 7 time points. Age- and gender-standardized body mass index (BMI) z-scores were calculated. Data were analyzed using generalized estimating equation. RESULTS: Colonization with B. fragilis group was borderline significantly associated with a higher BMI z score of 0.15 (95% confidence interval (CI): -0.02 to 0.31), in the conventional subcohort. After stratification for fiber intake (P(forinteraction) = 0.003), colonization with B. fragilis group was associated with a 0.34 higher BMI z-score among children with a low-fiber intake in this subcohort (95% CI: 0.17-0.53). Higher counts among colonized children were positively associated with BMI z score only in children within the conventional subcohort and a high-fiber diet (BMI z-score 0.08; 95% CI: 0.01-0.14), but inversely associated in children with a low-fiber diet (BMI z-score -0.05; 95% CI: -0.10 to 0.00), and in children recruited through alternative channels (BMI z-score -0.10; 95% CI: -0.17 to 0.03). The other bacteria were not associated with BMI z-scores, regardless of subcohort. CONCLUSION: Using a targeted approach, we conclude that the intestinal microbiota, particularly the B. fragilis group, is associated with childhood weight development. To identify the potential impact of additional bacterial taxa, further prospective studies applying an unconstrained in-depth characterization of the microbiota are needed. PMID- 25298275 TI - Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea. AB - BACKGROUND: Sleep fragmentation (SF) increases food intake and the risk of obesity, and recruits macrophages to visceral white adipose tissue (VWAT) promoting tissue inflammation and insulin resistance. Administration of resveratrol (Resv) has been associated with significant improvements in high-fat diet-induced obesity, inflammation and insulin resistance. METHODS: Male mice were subjected to SF or sleep control conditions for 8 weeks, and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin and leptin were obtained and VWAT insulin sensitivity tests were performed (phosphorylated AKT/total AKT), along with flow-cytometric assessments for VWAT macrophages (M1 and M2) and T-cell lymphocytes (CD4+, CD8+ and T regulatory cell (Treg)). RESULTS: SF-Veh and SF-Resv mice showed increased food consumption and weight gain. However, although SF-Veh mice exhibited increased fasting insulin and leptin levels, and reduced VWAT p-AKT/AKT responses to insulin, such alterations were abrogated in SF-Resv-treated mice. Increases in M1, reduced M2 counts and increased tumor necrosis factor-alpha release emerged in SF-Veh macrophages compared with all other three groups. Similarly, increased CD8+ and reduced Treg lymphocyte counts were apparent in SF-Veh. CONCLUSIONS: Resveratrol does not reverse the SF-induced increases in food intake and weight gain, but markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy in the context of sleep disorders manifesting metabolic morbidity. PMID- 25298277 TI - Gestational weight gain in normal weight women and offspring cardio-metabolic risk factors at 20 years of age. AB - OBJECTIVE: Limited knowledge exists on the long-term implications of maternal gestational weight gain (GWG) on offspring health. Our objective was to examine whether high GWG in normal weight women is associated with adult offspring cardio metabolic risk factors. METHODS: We used a cohort of 308 Danish women who gave birth in 1988-89 and whose offspring participated in a clinical examination at 20 years of age. Main outcome measures were offspring body mass index (BMI), waist circumference, weight-regulating hormones, blood lipids and glucose metabolism. Associations were assessed using multivariable linear and logistic regression models. RESULTS: A weak positive association was observed between GWG during the first 30 weeks and offspring anthropometry. Each 1-kg increase in maternal GWG was associated with 0.1-kg m(-2) higher (95% confidence interval (CI): 0.01, 0.2) offspring BMI and 10% (95% CI: 0.1%, 20%) higher odds of offspring overweight at the age of 20 years, with similar associations observed in both sexes. However, sex differences were observed for the association between maternal GWG and specific cardio-metabolic risk factors. Hence, a 1-kg increase in GWG was associated with 3.4% (95% CI; 0.8, 6.0%) higher homeostasis model assessment estimated insulin resistance (HOMA-IR), 3.7% (95% CI: 1.4%, 6.2%) higher insulin and 10.7% (95% CI: 5.7%, 15.9%) higher leptin levels in male offspring. These associations were not observed in females, which may partly be explained by more frequent reports of dieting and physical exercise at follow-up among female offspring. CONCLUSIONS: In normal-weight women, high GWG may have modest long term implications on offspring cardio-metabolic risk factors at adult age. PMID- 25298278 TI - Milk, yogurt, and lactose intake and ovarian cancer risk: a meta-analysis. AB - Inconclusive information for the role of dairy food intake in relation to ovarian cancer risk may associate with adverse effects of lactose, which has been hypothesized to increase gonadotropin levels in animal models and ecological studies. Up to now, several studies have indicated the association between dairy food intake and risk of ovarian cancer, but no identified founding was reported. We performed this meta-analysis to derive a more precise estimation of the association between dairy food intake and ovarian cancer risk. Using the data from 19 available publications, we examined dairy food including low-fat/skim milk, whole milk, yogurt and lactose in relation to risk of ovarian cancer by meta-analysis. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to assess the association. We observed a slightly increased risk of ovarian cancer with high intake of whole milk, but has no statistical significance (OR = 1.228, 95% CI = 1.031-1.464, P = 0.022). The results of other milk models did not provide evidence of positive association with ovarian cancer risk. This meta analysis suggests that low-fat/skim milk, whole milk, yogurt and lactose intake has no associated with increased risk of ovarian cancer. Further studies with larger participants worldwide are needed to validate the association between dairy food intake and ovarian cancer. PMID- 25298276 TI - Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. AB - BACKGROUND/OBJECTIVES: Cesarean section (CS) and antibiotic use during pregnancy may alter normal maternal-offspring microbiota exchange, thereby contributing to aberrant microbial colonization of the infant gut and increased susceptibility to obesity later in life. We hypothesized that (i) maternal use of antibiotics in the second or third trimester of pregnancy and (ii) CS are independently associated with higher risk of childhood obesity in the offspring. SUBJECTS/METHODS: Of the 727 mothers enrolled in the Northern Manhattan Mothers and Children Study, we analyzed the 436 mother-child dyads followed until 7 years of age with complete data. We ascertained prenatal antibiotic use by a questionnaire administered late in the third trimester, and delivery mode by medical record. We derived age- and sex-specific body mass index (BMI) z-scores using the CDC SAS Macro, and defined obesity as BMI z?95th percentile. We used binary regression with robust variance and linear regression models adjusted for maternal age, ethnicity, pre-gravid BMI, maternal receipt of public assistance, birth weight, sex, breastfeeding in the first year and gestational antibiotics or delivery mode. RESULTS: Compared with children not exposed to antibiotics during the second or third trimester, those exposed had 84% (33-154%) higher risk of obesity, after multivariable adjustment. Second or third trimester antibiotic exposure was also positively associated with BMI z-scores, waist circumference and % body fat (all P<0.05). Independent of prenatal antibiotic usage, CS was associated with 46% (8-98%) higher offspring risk of childhood obesity. Associations were similar for elective and non-elective CS. CONCLUSIONS: In our cohort, CS and exposure to antibiotics in the second or third trimester were associated with higher offspring risk of childhood obesity. Future studies that address the limitations of our study are warranted to determine if prenatal antibiotic use is associated with offspring obesity. Research is also needed to determine if alterations in neonatal gut microbiota underlie the observed associations. PMID- 25298279 TI - Letter to the Editor: Can Internet information on vertebroplasty be a reliable means of patient self-education? PMID- 25298281 TI - Obituary: a remembrance of William Fisher Enneking MD (1926-2014). PMID- 25298280 TI - CORR curriculum - orthopaedic education: Faculty development begins at home. PMID- 25298282 TI - CORR Insights(r): rotator cuff fatty infiltration and atrophy are associated with functional outcomes in anatomic shoulder arthroplasty. PMID- 25298283 TI - CORR Insights((r)): what effects have resident work-hour changes had on education, quality of life, and safety? A systematic review. PMID- 25298284 TI - Identification of differentially methylated genes in the malignant transformation of ovarian endometriosis. AB - BACKGROUND: Key roles for epigenetic mechanisms in tumorigenesis are well accepted, while the relationship between gene methylation and malignant transformation of ovarian endometriosis (EMS) was seldom reported. In this study, we aimed to screen for aberrantly methylated genes associated with the malignant transformation of ovarian EMS and to preliminarily verify the reliability of screened results by detecting the methylation status and protein expression of the candidate gene in a larger scale of formaldehyde-fixed and paraffin-embedded (FFPE) samples. METHODS: Methylated CpG island amplification coupled with representational difference analysis (MCA-RDA) was performed on 3 couples of endometriosis-associated ovarian carcinoma (EAOC) fresh samples to identify differentially methylated candidate genes related to malignant transformation of ovarian EMS; Methylation-specific PCR (MSP) and immunohistochemistry were performed in 30 EAOC samples to detected the methylation status and protein expression of RASSF2 gene to verify the reliability of MCA-RDA results. RESULTS: Nine differentially methylated genes were obtained by MCA-RDA as candidate genes for malignant transformation of EMS; Methylation frequency of RASSF2 in the neoplastic tissues of EAOC group was higher than that in the ectopic endometria (p < 0.05). While protein expression of RASSF2 in the neoplastic tissues was lower than that in the ectopic endometria of the EAOC group (p < 0.05) Absence of protein expression of RASSF2 was significantly correlated with the promoter methylation of the gene (p < 0.05). CONCLUSIONS: RASSF2, RUNX3, GSTZ1, CYP2A, GBGT1, NDUFS1, SPOCK2, ADAM22, and TRIM36 were candidate genes for malignant transformation of ovarian EMS and epigenetic inactivation of RASSF2 by promoter hypermethylation is an early event in malignant transformation of ovarian EMS. The screen results were reliable and worthy of further study. PMID- 25298286 TI - Rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes. AB - A rhodium-catalyzed chemo-, regio-, and enantioselective addition of 2-pyridones to terminal allenes to give branched N-allyl 2-pyridones is reported. Preliminary mechanistic studies support the hypothesis that the reaction was initiated from the more acidic 2-hydroxypyridine form, and the initial kinetic O-allylation product was finally converted into the thermodynamically more stable N-allyl 2 pyridones. PMID- 25298285 TI - Prediction of matrix-to-cell stress transfer in heart valve tissues. AB - Non-linear and anisotropic heart valve leaflet tissue mechanics manifest principally from the stratification, orientation, and inhomogeneity of their collagenous microstructures. Disturbance of the native collagen fiber network has clear consequences for valve and leaflet tissue mechanics and presumably, by virtue of their intimate embedment, on the valvular interstitial cell stress strain state and concomitant phenotype. In the current study, a set of virtual biaxial stretch experiments were conducted on porcine pulmonary valve leaflet tissue photomicrographs via an image-based finite element approach. Stress distribution evolution during diastolic valve closure was predicted at both the tissue and cellular levels. Orthotropic material properties consistent with distinct stages of diastolic loading were applied. Virtual experiments predicted tissue- and cellular-level stress fields, providing insight into how matrix-to cell stress transfer may be influenced by the inhomogeneous collagen fiber architecture, tissue anisotropic material properties, and the cellular distribution within the leaflet tissue. To the best of the authors' knowledge, this is the first study reporting on the evolution of stress fields at both the tissue and cellular levels in valvular tissue and thus contributes toward refining our collective understanding of valvular tissue micromechanics while providing a computational tool enabling the further study of valvular cell-matrix interactions. PMID- 25298287 TI - Clinical integration of next generation sequencing: a policy analysis. AB - Clinical next generation sequencing (NGS) technologies are challenging existing regulatory paradigms. We advocate a coordinate policy approach, which first requires a comprehensive understanding of the existing regulatory and legal structures. This paper introduces four key policy domains - including quality assurance, insurance coverage, intellectual property management, and data sharing - that must be addressed to ensure high quality clinical NGS. In bringing these policy issues into conversation through this special issue for the Journal of Law, Medicine & Ethics, we hope to lay the foundation for further discussion by a range of stakeholder groups with diverse and strong interests in the governance of NGS. PMID- 25298288 TI - Regulation of next generation sequencing. AB - Next generation sequencing raises new questions within the context of an existing and still evolving regulatory landscape for device manufacturers and clinical laboratories. FDA cleared the first NGS sequencing platform in November 2013, but it is unclear what lies ahead for this technology. NGS will require new types of training and expertise to interpret the vast quantities of genetic data so as to provide meaningful clinical information to physicians and patients. This paper will describe the current regulatory landscape for NGS technologies, identify the regulatory challenges they present, and consider whether new regulatory paradigms are needed to accommodate NGS technologies and services. PMID- 25298289 TI - Clinical integration of next generation sequencing: coverage and reimbursement challenges. AB - Public and private payers face complex decisions regarding whether, when, and how to cover and reimburse for next generation sequencing (NGS)-based tests. Yet a predictable reimbursement pathway is critical both for patient access and incentives to provide the market with better clinical evidence. While preliminary data suggests that payers will use similar evidentiary standards as those used to evaluate established molecular diagnostic tests, the volume and complexity of information generated by NGS raises a host of additional considerations for payers that are specific to this technology. PMID- 25298290 TI - Patents and genome-wide DNA sequence analysis: is it safe to go into the human genome? AB - Some claims in patents on individual genes and methods of detecting variations appear to be infringed by whole-genome and all-exome sequencing and genomic analysis. But what is the real risk of infringement liability? The risk is probably low. This is partly because it will rarely make sense to sue, but also because the patent-holder may well lose if they do sue. Courts have recently narrowed standards of patentable subject matter, invalidating broad method claims and DNA-based claims for sequences that would be found in nature. Moreover, claims broad enough to cover WGS are likely to be invalid on other grounds, and not worth risking a lawsuit to enforce. PMID- 25298291 TI - Economic regulation of next-generation sequencing. AB - Next-generation sequencing broadens the debate about appropriate regulatory oversight of genetic testing and may force scholars to move beyond familiar privacy and health and safety regulatory issues to address new problems with industry structure and economic regulation. The genetic testing industry is passing through a period of profound structural change in response to shifts in technology and in the legal environment. Making genetic testing safe and effective for consumers increasingly requires access to comprehensive genomic data infrastructures that can support accurate, state-of-the-art interpretation of genetic test results. At present, there are significant barriers to access and there is no sector-specific regulator with power to ensure appropriate data access. Without it, genetic testing will not be safe for consumers even when it is performed at CLIA-certified laboratories using tests that have been FDA cleared or approved. This article explores the emerging structure of the genetic testing industry and describes its present economic regulatory vacuum. In view of this gap in regulation, the article explores whether generally applicable law, particularly antitrust law, may offer solutions to the industry's data access problems. It concludes that courts may have a useful role to play, particularly in Europe and other jurisdictions where the essential facilities doctrine enjoys continued vitality. After Verizon Communications v. Law Offices of Curtis V. Trinko, the role of U.S. federal courts is less certain. Congress has demonstrated willingness to address access issues as they emerged in other infrastructure industries in recent decades. This article expresses no preference between legislative and judicial solutions. Its aim is simply to highlight an emerging economic regulatory issue which, if left unresolved, presents real health and safety concerns for consumers who receive genetic tests. PMID- 25298293 TI - In pain thou shalt bring forth children: the peak-and-end rule in recall of labor pain. AB - Childbirth is usually the most painful event of a mother's life, and resonates in individual and collective memory for years. The current study examined the relationship between the experience of labor pain and its recollection 2 days and 2 months after delivery. We found that despite the exceptional physical and emotional experiences of childbirth, the memory of the pain involved in labor was biased toward the average of the peak pain and the end pain, whereas the duration of the delivery had a relatively negligible effect on the recollected intensity of pain. A comparison of mothers whose labor ended with or without epidural analgesia corroborated previous findings that the level of pain toward the end of an experience greatly influences the way the overall experience is remembered. Although both short- and long-term retention of memories of labor exhibited the peak-and-end effect, having given birth before weakened the effect 2 months after delivery. PMID- 25298294 TI - Optimism and death: predicting the course and consequences of depression trajectories in response to heart attack. AB - The course of depression in relation to myocardial infarction (MI), commonly known as heart attack, and the consequences for mortality are not well characterized. Further, optimism may predict both the effects of MI on depression as well as mortality secondary to MI. In the current study, we utilized a large population-based prospective sample of older adults (N=2,147) to identify heterogeneous trajectories of depression from 6 years prior to their first reported MI to 4 years after. Findings indicated that individuals were at significantly increased risk for mortality when depression emerged after their first-reported MI, compared with resilient individuals who had no significant post-MI elevation in depression symptomatology. Individuals with chronic depression and those demonstrating pre-event depression followed by recovery after MI were not at increased risk. Further, optimism, measured before MI, prospectively differentiated all depressed individuals from participants who were resilient. PMID- 25298292 TI - Making working memory work: a meta-analysis of executive-control and working memory training in older adults. AB - This meta-analysis examined the effects of process-based executive-function and working memory training (49 articles, 61 independent samples) in older adults (> 60 years). The interventions resulted in significant effects on performance on the trained task and near-transfer tasks; significant results were obtained for the net pretest-to-posttest gain relative to active and passive control groups and for the net effect at posttest relative to active and passive control groups. Far-transfer effects were smaller than near-transfer effects but were significant for the net pretest-to-posttest gain relative to passive control groups and for the net gain at posttest relative to both active and passive control groups. We detected marginally significant differences in training-induced improvements between working memory and executive-function training, but no differences between the training-induced improvements observed in older adults and younger adults, between the benefits associated with adaptive and nonadaptive training, or between the effects in active and passive control conditions. Gains did not vary with total training time. PMID- 25298295 TI - Anti-dieting advice from teammates: a pilot study of the experience of female collegiate cross country runners. AB - Disordered eating behaviors and restrictive dieting can have negative health consequences for female athletes. Teammates can play an important role in primary and secondary prevention of these unhealthy eating practices through verbal and non-verbal communication about what behaviors are normative and desirable. The present study tested two tested hypotheses related to the way anti-dieting advice from teammates is distributed: (a) that there are significant between-team differences in the level of anti-dieting advice received, and (b) that the frequency of anti-dieting advice from teammates is positively associated with the severity of an individual's eating disorder symptomatology and negatively associated with their body mass index (BMI). Participants were female members (n = 89) of six U.S. National Collegiate Athletic Association Division I women's cross country teams. Findings revealed significant between-team differences in the frequency of anti-dieting advice, controlling for team levels of disordered eating. Eating pathology and BMI were positively associated with anti-dieting advice received. Implications for the design of interventions to encourage effective within-team communication for promoting teammate health are discussed. PMID- 25298296 TI - A validated LC-MS/MS assay for simultaneous quantification of methotrexate and tofacitinib in rat plasma: application to a pharmacokinetic study. AB - A highly sensitive, specific and rapid LC-ESI-MS/MS method has been developed and validated for simultaneous quantification of methotrexate (MTX) and tofacitinib (TFB) in rat plasma (50 MUL) using phenacetin as an internal standard (IS), as per the US Food and Drug Administration guidelines. After a solid-phase extraction procedure, the separation of the analytes and IS was performed on a Chromolith RP18e column using an isocratic mobile phase of 5 m m ammonium acetate (pH 5.0) and acetonitrile at a ratio of 25:75 (v/v) using flow-gradient with a total run time of 3.5 min. The detection was performed in multiple reaction monitoring mode, using the transitions of m/z 455.2 -> 308.3, m/z 313.2 -> 149.2 and m/z 180.3 -> 110.2 for MTX, TFB and IS, respectively. The calibration curves were linear over the range of 0.49-91.0 and 0.40-74.4 ng/mL for MTX and TFB, respectively. The intra- and interday accuracy and precision values for MTX and TFB were <15% at low quality control (QC), medium QC and high QC and <20% at lower limit of quantification. The validated assay was applied to derive the pharmacokinetic parameters for MTX and TFB post-dosing of MTX and TFB orally and intravenously to rats. PMID- 25298297 TI - Layer-by-layer fabrication of AgCl-PANI hybrid nanocomposite films for electronic tongues. AB - The fabrication of nanostructured films with tailored properties is essential for many applications, particularly with materials such as polyaniline (PANI) whose electrical characteristics may be easily tuned. In this study we report the one step synthesis of AgCl-PANI nanocomposites that could form layer-by-layer (LbL) films with poly(sodium 4-styrenesulfonate) (PSS) and be used for electronic tongues (e-tongues). The first AgCl-PANI layer was adsorbed on a quartz substrate according to a nucleation-and-growth mechanism explained using the Johnson-Mehl Avrami (JMA) model, revealing a 3D film growth confirmed by atomic force microscopy (AFM) measurements for the AgCl-PANI/PSS LbL films. In contrast to conventional PANI-containing films, the AgCl-PANI/PSS LbL films deposited on interdigitated electrodes exhibited electrical resistance that was practically unaffected by changes in pH from 4 to 9, and therefore these films can be used in e-tongues for both acidic and basic media. With a sensor array made of AgCl PANI/PSS LbL films with different numbers of bilayers, we demonstrated the suitability of the AgCl-PANI nanocomposite for an e-tongue capable of clearly discriminating the basic tastes from salt, acid and umami solutions. Significantly, the hybrid AgCl-PANI nanocomposite is promising for any application in which PANI de-doping at high pH is to be avoided. PMID- 25298298 TI - Quality attributes and composition of meat from red deer (Cervus elaphus), fallow deer (Dama dama) and Aberdeen Angus and Holstein cattle (Bos taurus). AB - BACKGROUND: The consumption of venison from deer species has increased in recent years owing to presumably positive health effects. Therefore a comparison was made of the physical characteristics, chemical composition and sensory attributes of meat obtained from red deer, fallow deer and Aberdeen Angus and Holstein cattle raised under conditions typical for commercial farming practice and slaughtered at similar ages. RESULTS: Venison had one-quarter the crude fat content, lower total collagen and a higher proportion of heat-soluble collagen. It was darker and less yellow than beef. Deer species provided meat with higher polyunsaturated/saturated fatty acid ratio and lower atherogenic index. In addition, the venison of red deer contained five times as much n-3 polyunsaturated fatty acids as the beef. Steaks prepared from venison were scored higher than beef for flavour and aroma intensity; they were also tenderer and more easily chewable. CONCLUSION: Compared with beef, venison from two widely farmed deer species was superior in nutrient composition, thus offering potential benefits for human consumption, and it received higher scores for most of the sensory attributes examined. PMID- 25298300 TI - Polytype and stacking faults in the Li2CoSiO4 Li-ion battery cathode. AB - Atomic-resolution imaging of the crystal defects of cathode materials is crucial to understand their formation and the correlation between the structure, electrical properties, and electrode performance in rechargeable batteries. The polytype, a stable form of varied crystal structure with uniform chemical composition, holds promise to engineer electronic band structure in nanoscale homojunctions.1-3 Analyzing the exact sites of atoms and the chemistry of the boundary in polytypes would advance our understanding of their formation and properties. Herein, the polytype and stacking faults in the lithium cobalt silicates are observed directly by aberration-corrected scanning transmission electron microscopy. The atomic-scale imaging allows clarification that the polytype is formed by stacking of two different close-packed crystal planes in three-dimensional space. The formation of the polytype was induced by Li-Co cation exchange, the transformation of one phase to the other, and their stacking. This finding provides insight into intrinsic structural defects in an important Li2 CoSiO4 Li-ion battery cathode. PMID- 25298299 TI - Local diagnostic reference level based on size-specific dose estimates: assessment of pediatric abdominal/pelvic computed tomography at a Japanese national children's hospital. AB - BACKGROUND: A child's body size is not accurately reflected by volume CT dose index (CTDIvol) and dose-length product (DLP). Size-specific dose estimation (SSDE) was introduced recently as a new index of radiation dose. However, it has not yet been established as a diagnostic reference level (DRL). OBJECTIVE: To calculate the SSDE of abdominal/pelvic CT and compare the SSDE with CTDIvol. To calculate the DRLs of CTDIvol and SSDE. Our hypotheses are: SSDE values will be greater than CTDIvol, and our DRL will be smaller than the known DRLs of other countries. MATERIALS AND METHODS: The CTDIvol and DLP of 117 children who underwent abdominal/pelvic CT were collected retrospectively. The SSDE was calculated from the sum of the lateral and anteroposterior diameters. The relationships between body weight and effective diameter and between effective diameter and CTDIvol/SSDE were compared. Further, the local DRL was compared with the DRLs of other countries. RESULTS: Body weight and effective diameter and effective diameter and SSDE were positively correlated. In children ages 1, 5 and 10 years, the SSDE is closer to the exposure dose of CTDIvol for the 16-cm phantom, while in children ages 15 years, the SSDE falls between CTDIvol for the 16-cm phantom and that for the 32-cm phantom. The local DRL was lower than those of other countries. CONCLUSION: With SSDE, the radiation dose increased with increasing body weight. Since SSDE takes body size into account, it proved to be a useful indicator for estimating the exposure dose. PMID- 25298301 TI - Development of new P-chiral P,pi-dihydrobenzooxaphosphole hybrid ligands for asymmetric catalysis. AB - A new family of P-chiral P,pi-hybrid ligands was prepared from the dihydrobenzooxaphosphole core. These new ligands were demonstrated to be both sterically and electronically tunable at the substituents on the phosphorus atom and the pi-system of the ligand. Application of these new ligands to the catalytic asymmetric addition of boronic acids to imine electrophiles was shown to proceed with high levels of enantioinduction. PMID- 25298303 TI - Diagnostic accuracy of brainstem auditory evoked potentials during microvascular decompression. AB - OBJECTIVE: The primary aim of the study was to assess the sensitivity and specificity of intraoperative monitoring in predicting postoperative hearing loss during microvascular decompression (MVD). METHODS: The study was designed as an examination of the diagnostic accuracy of brainstem evoked potentials compared with reference standard for nonserviceable hearing loss (Class C/D), which is a change of more than 50 dB on pure tone threshold, and change of speech discrimination score of more than 50. All patients underwent surgery and audiograms at a University of Pittsburgh Medical Center facility in the study period 2005-2012. All participants received a pre- and postaudiogram within 90 days before or after the operation. During the operation, participants received intraoperative monitoring with a supervising physician. A total of 238 patients were selected. Brainstem auditory evoked potentials (BAEPs) were indexed into categories of change based on their maximum change and response at the end of surgery. Differences in hearing outcome by BAEP change were analyzed. RESULTS: Age and sex did not affect outcomes. Patient outcome was affected by condition. The BAEP categories significant changes, transient loss, and persistent loss show a sensitivity/specificity of 0.905/0.701, 0.667/0.903, and 0.429/0.972, respectively. The receiver operating characteristic curve has an area under the curve of 0.870 with a 95% confidence interval of 0.783 to 0.957. CONCLUSIONS: Loss of wave V during MVD is a specific indicator of postoperative hearing loss. The current alarm criteria used to warn the surgeon is a sensitive indicator of impending postoperative hearing loss. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients undergoing MVD, intraoperative BAEPs accurately identifies those who will have postoperative hearing loss. PMID- 25298304 TI - The PRO-ACT database: design, initial analyses, and predictive features. AB - OBJECTIVE: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS. METHODS: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p = 0.003. RESULTS: The ALSFRS-R rate of decline was 1.02 (+/ 2.3) points per month and the VC rate of decline was 2.24% of predicted (+/-6.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p < 0.0001). CONCLUSION: The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival. PMID- 25298305 TI - Healthy diet and lifestyle and risk of stroke in a prospective cohort of women. AB - OBJECTIVE: To investigate the association between a low-risk lifestyle and risk of stroke. METHODS: The study population comprised 31,696 women, in the population-based Swedish Mammography Cohort who at baseline had completed a questionnaire about diet and lifestyle and were free from cardiovascular disease and cancer. We defined a low-risk lifestyle as a healthy diet (top 50% of a Recommended Food Score), moderate alcohol consumption (5-15 g/d), never smoking, physically active (walking/bicycling >=40 min/d and exercise >=1 h/wk), and body mass index below 25 kg/m(2). Stroke cases were identified from the Swedish National Patient Register and the Swedish Cause of Death Register. RESULTS: We ascertained 1,554 incident stroke cases, including 1,155 cerebral infarctions, 246 hemorrhagic strokes, and 153 unspecified strokes during 10.4 years of follow up. The risk of stroke, in particular cerebral infarction, decreased steadily with increasing number of low-risk lifestyle factors. Compared with no low-risk factors, the multivariable relative risks (95% confidence interval) of cerebral infarction across increasing number of low-risk factors (1-5) were 0.72 (0.56 0.93), 0.67 (0.52-0.85), 0.57 (0.44-0.74), 0.54 (0.40-0.73), and 0.38 (0.20 0.73). CONCLUSIONS: These findings indicate that a low-risk lifestyle can substantially reduce the risk of stroke, especially cerebral infarction. PMID- 25298307 TI - The third leg of neurology training: the business of medicine. PMID- 25298306 TI - Imaging prodromal Parkinson disease: the Parkinson Associated Risk Syndrome Study. AB - OBJECTIVES: The purpose of this study is to evaluate the relative risk of abnormal dopamine transporter (DAT) imaging for subjects with and without hyposmia and the feasibility of acquiring a large, community-based, 2-tiered biomarker assessment strategy to detect prodromal Parkinson disease (PD). METHODS: In this observational study, individuals without a diagnosis of PD, recruited through 16 movement disorder clinics, underwent tier 1 assessments (olfactory testing, questionnaires). Tier 2 assessments (neurologic examination, DAT imaging, and other biomarker assessments) were completed by 303 subjects. The main outcome of the study is to compare age-expected [(123)I]beta-CIT striatal binding ratio in hyposmic and normosmic subjects. RESULTS: Tier 1 assessments were mailed to 9,398 eligible subjects and returned by 4,999; 669 were hyposmic. Three hundred three subjects (203 hyposmic, 100 normosmic) completed baseline evaluations. DAT deficit was present in 11% of hyposmic subjects compared with 1% of normosmic subjects. Multiple logistic regression demonstrates hyposmia (odds ratio [OR] 12.4; 95% confidence interval [CI] 1.6, 96.1), male sex (OR 5.5; 95% CI 1.7, 17.2), and constipation (OR 4.3; 95% CI 1.6, 11.6) as factors predictive of DAT deficit. Combining multiple factors (hyposmia, male sex, and constipation) increased the percentage of subjects with a DAT deficit to >40%. CONCLUSION: Subjects with DAT deficit who do not meet criteria for a diagnosis of PD can be identified by olfactory testing. Sequential biomarker assessment may identify those at risk of PD. Selecting hyposmic individuals enriches the population for DAT deficit, and combining hyposmia with other potential risk factors (male sex, constipation) increases the percentage of subjects with a DAT deficit compatible with prodromal PD. PMID- 25298308 TI - Cathepsin D deficiency causes juvenile-onset ataxia and distinctive muscle pathology. PMID- 25298309 TI - Should genetic testing for SCAs be included in the diagnostic workup for MSA? AB - OBJECTIVE: To examine the prevalence of mutations in spinocerebellar ataxia (SCA) genes in patients who were clinically diagnosed with multiple system atrophy (MSA). METHODS: Genetic tests for SCA were performed in 302 of 528 patients who met the diagnostic criteria for MSA based on clinical features. Generally, when a patient had cerebellar symptoms or cerebellar atrophy on neuroimaging, genetic tests for SCA types 1, 2, 3, 6, 7, and 17, and dentatorubropallidoluysian atrophy were done, and when a patient had parkinsonism without cerebellar symptoms, genetic tests for SCA types 2, 3, and 17 were done. RESULTS: Mutations in SCA genes were found in 22 of the 302 patients (7.3%) with SCA17 comprising more than half of the mutation-positive cases. The age at disease onset in these 22 patients was not different compared with the 280 patients without mutations (55.9 +/- 9.3 vs 59.2 +/- 8.9, p = 0.102). All patients had urinary symptoms, and 10 patients also had orthostatic dizziness or orthostatic hypotension. A family history was reported in only 3 patients. Of note, dream enactment behavior suggesting REM sleep behavior disorder was reported in 9 of the 11 patients (81.8%) asked. CONCLUSIONS: The high proportion of patients with SCA mutations in this study indicates that genetic testing for SCA should be included for patients with MSA, especially for patients with cerebellar dysfunctions. PMID- 25298310 TI - HLA-DRB1*15 influences the development of brain tissue damage in early PPMS. AB - OBJECTIVES: To investigate whether (1) there were differences between HLA-DRB1*15 positive and -negative patients at baseline, and (2) HLA-DRB1*15-positive patients showed a greater development of brain and spinal cord damage, as assessed by MRI, and greater progression of disability, during a 5-year follow up, compared with HLA-DRB1*15-negative patients. METHODS: HLA-DRB1*15 typing was performed in 41 patients with primary progressive multiple sclerosis (PPMS) who were recruited within 5 years of symptom onset. All patients and 18 healthy controls were studied clinically and with MRI at baseline, and every 6 months for 3 years, and then at 5 years. Magnetization transfer ratio parameters and volumes for brain gray matter and normal-appearing white matter, brain T2 lesion load, and spinal cord cross-sectional area were obtained. Patient disability was assessed at each visit using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite subscores. RESULTS: There were no significant differences between HLA-DRB1*15-positive and -negative patients at baseline. HLA DRB1*15-positive patients showed a greater decline in brain magnetization transfer ratio for gray matter and normal-appearing white matter (both p = 0.005) than HLA-DRB1*15-negative patients over 5 years, while the same parameters did not change over time in healthy controls. HLA-DRB1*15-positive patients also showed a trend toward a faster increase in brain T2 lesion load than HLA-DRB1*15 negative patients (0.29 [95% confidence interval 0.20-0.38] vs 0.21 [0.13-0.30] mL/mo, p = 0.085) and higher T2 lesion volumes at all time points (average difference [95% confidence interval]: 10.58 mL [7.09-14.07], p < 0.001) during the follow-up, after adjusting for disease duration. CONCLUSIONS: These findings suggest that HLA-DRB1*15 influences the progression of brain pathology in PPMS. PMID- 25298311 TI - Education in medical billing benefits both neurology trainees and academic departments. AB - The objective of residency training is to produce physicians who can function independently within their chosen subspecialty and practice environment. Skills in the business of medicine, such as clinical billing, are widely applicable in academic and private practices but are not commonly addressed during formal medical education. Residency and fellowship training include limited exposure to medical billing, but our academic department's performance of these skills was inadequate: in 56% of trainee-generated outpatient notes, documentation was insufficient to sustain the chosen billing level. We developed a curriculum to improve the accuracy of documentation and coding and introduced practice changes to address our largest sources of error. In parallel, we developed tools that increased the speed and efficiency of documentation. Over 15 months, we progressively eliminated note devaluation, increased the mean level billed by trainees to nearly match that of attending physicians, and increased outpatient revenue by $34,313/trainee/year. Our experience suggests that inclusion of billing education topics into the formal medical curriculum benefits both academic medical centers and trainees. PMID- 25298313 TI - Laser-targeted photofabrication of gold nanoparticles inside cells. AB - Nanoparticle manipulation is of increasing interest, since they can report single molecule-level measurements of the cellular environment. Until now, however, intracellular nanoparticle locations have been essentially uncontrollable. Here we show that by infusing a gold ion solution, focused laser light-induced photoreduction allows in situ fabrication of gold nanoparticles at precise locations. The resulting particles are pure gold nanocrystals, distributed throughout the laser focus at sizes ranging from 2 to 20 nm, and remain in place even after removing the gold solution. We demonstrate the spatial control by scanning a laser beam to write characters in gold inside a cell. Plasmonically enhanced molecular signals could be detected from nanoparticles, allowing their use as nano-chemical probes at targeted locations inside the cell, with intracellular molecular feedback. Such light-based control of the intracellular particle generation reaction also offers avenues for in situ plasmonic device creation in organic targets, and may eventually link optical and electron microscopy. PMID- 25298314 TI - Heterogeneous interesterification of triacylglycerols catalyzed by using potassium-doped alumina as a solid catalyst. AB - Heterogeneous interesterification of vegetable oils offers an environmentally more attractive option for the modification of edible oils to meet the specifications for certain food applications. In this work, potassium-doped alumina (KNO3/Al2O3) was prepared using an impregnation method, followed by calcinations at a temperature of 700 degrees C, and was then employed as heterogeneous catalysts for the interesterification of triacylglycerols. The solid catalyst was characterized by means of Hammett titration method, power X ray diffraction, scanning electron microscopy, and nitrogen adsorption-desorption techniques. It was determined that the catalyst with KNO3 loading of 35% on alumina support and calcined at 700 degrees C exhibited the best catalytic activities toward the interesterification between soybean oil and methyl stearate under solvent-free conditions. Also, the solid base catalyst was successfully applied to the interesterification of soybean oil and lard blends in a heterogeneous manner. The physicochemical properties of the interesterified products were investigated using gas chromatography, high-performance liquid chromatography, and confocal laser scanning microscopy. It was found that the slip melting point and crystal morphology had a significant variation after the interesterification reaction as a result of the modification in the TAG profile. With the solid base catalyst, an environmentally friendly approach for the interesterification of triacylglycerols in a heterogeneous manner was developed. PMID- 25298312 TI - Physical activity attenuates age-related biomarker alterations in preclinical AD. AB - OBJECTIVE: To examine whether engagement in physical activity might favorably alter the age-dependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults. METHODS: Three hundred seventeen enrollees in the Wisconsin Registry for Alzheimer's Prevention underwent T1 MRI; a subset also underwent (11)C-Pittsburgh compound B-PET (n = 186) and (18)F-fluorodeoxyglucose-PET (n = 152) imaging. Participants' responses on a self-report measure of current physical activity were used to classify them as either physically active or physically inactive based on American Heart Association guidelines. They also completed a comprehensive neuropsychological battery. Covariate-adjusted regression analyses were used to test whether the adverse effect of age on imaging and cognitive biomarkers was modified by physical activity. RESULTS: There were significant age * physical activity interactions for beta-amyloid burden (p = 0.014), glucose metabolism (p = 0.015), and hippocampal volume (p = 0.025) such that, with advancing age, physically active individuals exhibited a lesser degree of biomarker alterations compared with the physically inactive. Similar age * physical activity interactions were also observed on cognitive domains of Immediate Memory (p = 0.042) and Visuospatial Ability (p = 0.016). In addition, the physically active group had higher scores on Speed and Flexibility (p = 0.002) compared with the inactive group. CONCLUSIONS: In a middle-aged, at-risk cohort, a physically active lifestyle is associated with an attenuation of the deleterious influence of age on key biomarkers of AD pathophysiology. However, because our observational, cross-sectional design cannot establish causality, randomized controlled trials/longitudinal studies will be necessary for determining whether midlife participation in structured physical exercise forestalls the development of AD and related disorders in later life. PMID- 25298315 TI - Detection of rickettsial DNA in ticks and wild boars in Kyoto City, Japan. AB - The tick is a well-known vector for arthropod-borne pathogens, such as tick-borne encephalitis, Lyme disease, Japanese spotted fever and severe fever with thrombocytopenia syndrome. It is therefore important to know the tick population and distribution in our environment and wild animals in order to prevent tick borne diseases. Here, we report the results of tick surveillance from May to September 2011 at 14 geographical points and in 5 wild boars in Kyoto City, Kyoto prefecture, Japan. We collected 3,198 ticks comprising 5 tick species, Haemaphysalis (H.) longicornis, H. flava, H. kitaokai, Amblyomma testudinarium and Dermacentor taiwanensis. Interestingly, the proportion of tick species varied according to geographical region within the city. The ticks collected in the city were reported as potential vectors of pathogens, such as rickettsiosis. We detected rickettsial DNA by PCR in 71.1% of 201 ticks investigated. The ticks that carried rickettsiae were distributed across the whole the city. The sequences of PCR-amplified DNA fragments were determined and showed similarities to spotted fever group rickettsiae. Although their pathogenicity for animals including humans is still unclear, it is important to stay alert and pay attention to tick-borne diseases in order to ensure the safety of the citizens of the city as well as that of visitors. PMID- 25298316 TI - Organocatalytic enantioselective alpha-amination of 5-substituted rhodanines: an efficient approach to chiral N,S-acetals. AB - We report a highly efficient approach to constructing chiral N,S-acetals using 5 substituted rhodanines as sulfur-bound pronucleophiles catalyzed by natural cinchona alkaloids quinine or quinidine. This alpha-amination reaction has a broad substrate scope, and the products featuring both rhodanine and N,S-acetal structural motifs were obtained in high yields and excellent enantioselectivities. PMID- 25298317 TI - Five years of advancing science, improving health. PMID- 25298318 TI - Type 2 diabetes: genotype-based therapy. AB - Targeting a genetic variant with an antagonist may restore insulin secretion in a subgroup of type 2 diabetes patients (Tang et al., this issue). PMID- 25298319 TI - Bionic limbs: clinical reality and academic promises. AB - Three recent articles in Science Translational Medicine (Tan et al. and Ortiz Catalan et al., this issue; Raspopovic et al., 5 Feb 2014 issue, 222ra19) present neuroprosthetic systems in which sensory information is delivered through direct nerve stimulation while controlling an action of the prosthesis--in all three cases, arm and hand movement. We discuss such sensory-motor integration and other key issues in prosthetic reconstruction, with an emphasis on the gap existing between clinically available systems and more advanced, custom-designed academic systems. In the near future, osseointegration, implanted muscle, and nerve electrodes for decoding and stimulation may be components of prosthetic systems for clinical use, available to a large patient population. PMID- 25298320 TI - A neural interface provides long-term stable natural touch perception. AB - Touch perception on the fingers and hand is essential for fine motor control, contributes to our sense of self, allows for effective communication, and aids in our fundamental perception of the world. Despite increasingly sophisticated mechatronics, prosthetic devices still do not directly convey sensation back to their wearers. We show that implanted peripheral nerve interfaces in two human subjects with upper limb amputation provided stable, natural touch sensation in their hands for more than 1 year. Electrical stimulation using implanted peripheral nerve cuff electrodes that did not penetrate the nerve produced touch perceptions at many locations on the phantom hand with repeatable, stable responses in the two subjects for 16 and 24 months. Patterned stimulation intensity produced a sensation that the subjects described as natural and without "tingling," or paresthesia. Different patterns produced different types of sensory perception at the same location on the phantom hand. The two subjects reported tactile perceptions they described as natural tapping, constant pressure, light moving touch, and vibration. Changing average stimulation intensity controlled the size of the percept area; changing stimulation frequency controlled sensation strength. Artificial touch sensation improved the subjects' ability to control grasping strength of the prosthesis and enabled them to better manipulate delicate objects. Thus, electrical stimulation through peripheral nerve electrodes produced long-term sensory restoration after limb loss. PMID- 25298321 TI - Genotype-based treatment of type 2 diabetes with an alpha2A-adrenergic receptor antagonist. AB - The feasibility of exploiting genomic information for individualized treatment of polygenic diseases remains uncertain. A genetic variant in ADRA2A, which encodes the alpha(2A)-adrenergic receptor (alpha(2A)AR), was recently associated with type 2 diabetes. This variant causes receptor overexpression and impaired insulin secretion; thus, we hypothesized that blocking alpha(2A)AR pharmacologically could improve insulin secretion in patients with the risk genotype. A total of 50 type 2 diabetes patients were recruited on the basis of ADRA2A genotype for a randomized placebo-controlled intervention study with the alpha(2A)AR antagonist yohimbine. The patients received 0, 10, or 20 mg of yohimbine at three separate visits. The primary endpoint was insulin secretion at 30 min (Ins30) during an oral glucose tolerance test (OGTT). Patients with the risk variant had 25% lower Ins30 than those without risk genotype. After administration of 20 mg of yohimbine, Ins30 was enhanced by 29% in the risk group, making secretion similar to patients carrying the low-risk allele. The corrected insulin response and disposition index in individuals with the high-risk (but not low-risk) allele were improved by 59 +/- 18% and 43 +/- 14%, respectively. The beneficial effect of yohimbine was not a consequence of improved insulin sensitivity. In summary, the data show that the insulin secretion defect in patients carrying the ADRA2A risk genotype can be corrected by alpha(2A)AR antagonism. The findings show that knowledge of genetic risk variants can be used to guide therapeutic interventions that directly target the underlying pathophysiology and demonstrate the potential of individualized genotype-specific treatment of type 2 diabetes. PMID- 25298322 TI - An osseointegrated human-machine gateway for long-term sensory feedback and motor control of artificial limbs. AB - A major challenge since the invention of implantable devices has been a reliable and long-term stable transcutaneous communication. In the case of prosthetic limbs, existing neuromuscular interfaces have been unable to address this challenge and provide direct and intuitive neural control. Although prosthetic hardware and decoding algorithms are readily available, there is still a lack of appropriate and stable physiological signals for controlling the devices. We developed a percutaneous osseointegrated (bone-anchored) interface that allows for permanent and unlimited bidirectional communication with the human body. With this interface, an artificial limb can be chronically driven by implanted electrodes in the peripheral nerves and muscles of an amputee, outside of controlled environments and during activities of daily living, thus reducing disability and improving quality of life. We demonstrate in one subject, for more than 1 year, that implanted electrodes provide a more precise and reliable control than surface electrodes, regardless of limb position and environmental conditions, and with less effort. Furthermore, long-term stable myoelectric pattern recognition and appropriate sensory feedback elicited via neurostimulation was demonstrated. The opportunity to chronically record and stimulate the neuromuscular system allows for the implementation of intuitive control and naturally perceived sensory feedback, as well as opportunities for the prediction of complex limb motions and better understanding of sensory perception. The permanent bidirectional interface presented here is a critical step toward more natural limb replacement, by combining stable attachment with permanent and reliable human-machine communication. PMID- 25298323 TI - Noninvasive brain-computer interface enables communication after brainstem stroke. AB - Brain-computer interfaces (BCIs) provide communication that is independent of muscle control, and can be especially important for individuals with severe neuromuscular disease who cannot use standard communication pathways or other assistive technology. It has previously been shown that people with amyotrophic lateral sclerosis (ALS) can successfully use BCI after all other means of independent communication have failed. The BCI literature has asserted that brainstem stroke survivors can also benefit from BCI use. This study used a P300 based event-related potential spelling system. This case study demonstrates that an individual locked-in owing to brainstem stroke was able to use a noninvasive BCI to communicate volitional messages. Over a period of 13 months, the participant was able to successfully operate the system during 40 of 62 recording sessions. He was able to accurately spell words provided by the experimenter and to initiate dialogues with his family. The results broadly suggest that, regardless of the precipitating event, BCI use may be of benefit to those with locked-in syndrome. PMID- 25298324 TI - [Artificial cornea: current treatment options and future perspectives]. PMID- 25298326 TI - Alison Murdoch: Planting trees for posterity. PMID- 25298325 TI - Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia. AB - BACKGROUND: Excessive use of empirical antibiotics is common in critically ill patients. Rapid biomarker-based exclusion of infection may improve antibiotic stewardship in ventilator-acquired pneumonia (VAP). However, successful validation of the usefulness of potential markers in this setting is exceptionally rare. OBJECTIVES: We sought to validate the capacity for specific host inflammatory mediators to exclude pneumonia in patients with suspected VAP. METHODS: A prospective, multicentre, validation study of patients with suspected VAP was conducted in 12 intensive care units. VAP was confirmed following bronchoscopy by culture of a potential pathogen in bronchoalveolar lavage fluid (BALF) at >10(4) colony forming units per millilitre (cfu/mL). Interleukin-1 beta (IL-1beta), IL-8, matrix metalloproteinase-8 (MMP-8), MMP-9 and human neutrophil elastase (HNE) were quantified in BALF. Diagnostic utility was determined for biomarkers individually and in combination. RESULTS: Paired BALF culture and biomarker results were available for 150 patients. 53 patients (35%) had VAP and 97 (65%) patients formed the non-VAP group. All biomarkers were significantly higher in the VAP group (p<0.001). The area under the receiver operator characteristic curve for IL-1beta was 0.81; IL-8, 0.74; MMP-8, 0.76; MMP-9, 0.79 and HNE, 0.78. A combination of IL-1beta and IL-8, at the optimal cut-point, excluded VAP with a sensitivity of 100%, a specificity of 44.3% and a post-test probability of 0% (95% CI 0% to 9.2%). CONCLUSIONS: Low BALF IL-1beta in combination with IL-8 confidently excludes VAP and could form a rapid biomarker based rule-out test, with the potential to improve antibiotic stewardship. PMID- 25298327 TI - Stereotactic radiotherapy in epithelial ovarian cancer brain metastases patients. AB - BACKGROUND: In this report we present the results of the retrospective (survival and classification) analyses of possible prognostic factors prolonging survival in epithelial ovarian cancer brain metastases patients after stereotactic radiotherapy. We focus on a wide range of available predictors to establish survival in patients with a good health status and no more than three lesions. METHODS: Two parallel statistical methods in survival analysis were used: classical and Bayesian methods to verify statistical results. To display the predicted and posterior survivals, classification trees were built. RESULTS: From the initial set of prognostic factors, only four were established as statistically significant in multivariate regression. They were: survival to metastases to brain after epithelial ovarian cancer diagnosis, number of metastases at diagnosis, central nervous system radiotherapy prior to stereotactic radiotherapy, and interval to stereotactic radiotherapy after metastases diagnosis. CONCLUSIONS: When considering evidence-based standards of treatment of patients suffering from epithelial ovarian cancer brain metastases, the established clinical factors are suggested to be prognostic. PMID- 25298328 TI - What is the role of bosentan in healing of femur fractures in a rat model? AB - The purpose of this study was to examine the effects bosentan (which is a strong vasoconstrictor) on bone fracture pathophysiology, and investigate the roles of the nonselective endothelin 1 receptor blocker bosentan on the bone fractures formed in rats through radiographic, histopathologic, and immunohistochemical methods. The rats were divided into three groups (six rats in each group): a femoral fracture control group, a femoral fracture plus bosentan at 50 mg/kg group, and a femoral fracture plus bosentan at 100 mg/kg group. The femoral fracture model was established by transversely cutting the femur at the midsection. After manual reduction, the fractured femur was fixed with intramedullary Kirschner wires. The radiographic healing scores of the bosentan 100 and 50 mg/kg groups were significantly better that those of the fracture control group. The fracture callus percent of new bone in the bosentan 100 mg/kg group was significantly greater than that in the control group. Also, semiquantitative analysis showed higher positive vascular endothelial growth factor and osteocalcin staining and lower positive endothelin receptor type A staining in the treatment groups than in the control group. Bosentan treatment also decreased tissue endothelin 1 expression relative to that in the fracture control group. As a result of our study, the protective effect of bosentan was shown in experimental femoral fracture healing in rats by radiographic, histopathologic, and molecular analyses. PMID- 25298330 TI - [Immune reconstitution inflammatory syndrome related with infliximab interruption in patient with Crohn's disease and active tuberculosis]. AB - Tumor necrosis factor alpha inhibitors are associated with an increased risk of active tuberculosis. However, its interruption in this setting may trigger a paradoxical response to tuberculosis treatment, as an immune reconstitution inflammatory syndrome. We present the case of a 36-year-old patient, with Crohn's disease, treated with infliximab for the last 8 years, who was admitted with miliary tuberculosis. A pan-susceptible Mycobacterium tuberculosis strain was isolated. Infliximab was interrupted and standard antituberculous therapy was started, as well as systemic corticotherapy, without any clinical or radiological improvement. After exclusion of other opportunistic infections and primary or acquired immunodeficiency, we considered the possibility of an immune reconstitution inflammatory syndrome triggered by infliximab interruption. Thus, infliximab was reintroduced after 2 months of antituberculous therapy and clinical and radiological improvement was observed. PMID- 25298329 TI - Skeletal deterioration following ovarian failure: can some features be a direct consequence of estrogen loss while others are more related to physical inactivity? AB - Findings on experimental animals show that ovarian failure is accompanied by a decrease in motor activity. As mechanical loading has a vital role in the maintenance of skeletal health, our aim was to determine to what extent this decrease in motor activity contributes to ovariectomy-induced bone loss. Thirty two female Wistar rats were ovariectomized or sham-operated and housed in standard cages or with access to running wheels for 36 weeks with their running distance monitored. Markers of bone turnover were assayed in the serum, and bone geometry, trabecular and cortical bone microarchitecture, mineralization degree, and biomechanical properties were assessed in the femur. Differences between groups were determined by one-way ANOVA. Although reduced motor activity and sex steroid deficiency both resulted in decreases in trabecular bone volume, trabecular number decreases were mostly associated with sex steroid deficiency, whereas trabecular thickness decreases were mostly associated with sedentary behavior. Cortical bone appeared to be more sensitive to variations in motor activity, whereas bone turnover rate and bone tissue mineralization degree seemed to be primarily affected by sex steroid deficiency, even though they were further aggravated by sedentary behavior. Increases in femur length were mostly a consequence of sex steroid deficiency, whereas femoral neck length was also influenced by sedentary behavior. Differences in mechanical properties resulted mostly from differences in physical activity. Both the direct effect of sex steroid deficiency and the indirect effect of motor activity changes are implicated in bone loss following ovariectomy. PMID- 25298331 TI - [Therapy of recurrent or metastatic head and neck squamous cell carcinoma : highlights of the ASCO Meeting 2014]. AB - The treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) requires exceptional interdisciplinary cooperation within the treatment team, as many factors need to be taken into account to come to an adequate treatment decision. Most of these patients need to be treated in a palliative concept, as comorbidities and prior oncologic treatment limit the treatment options. Inhibitors of epidermal growth factor receptor (EGFR) in combination with platinum and 5-fluorouracil (5-FU) may be considered as standard. However, survival rates are poor and new therapeutic approaches and substances are therefore tested continuously. At the annual meeting of the American Society of Clinical Oncology (ASCO) in 2014, numerous studies on first- and second-line treatment of R/M-HNSCC were presented. A selection is discussed in this paper, including a report about the combined therapy of cetuximab with established chemotherapies, new results from protocols including small molecules and investigations of mTOR inhibitors. PMID- 25298332 TI - Nanoscopy for nanoscience: how super-resolution microscopy extends imaging for nanotechnology. AB - Imaging methods have presented scientists with powerful means of investigation for centuries. The ability to resolve structures using light microscopes is though limited to around 200 nm. Fluorescence-based super-resolution light microscopy techniques of several principles and methods have emerged in recent years and offer great potential to extend the capabilities of microscopy. This resolution improvement is especially promising for nanoscience where the imaging of nanoscale structures is inherently restricted by the resolution limit of standard forms of light microscopy. Resolution can be improved by several distinct approaches including structured illumination microscopy, stimulated emission depletion, and single-molecule positioning methods such as photoactivated localization microscopy and stochastic optical reconstruction microscopy and several derivative variations of each of these. These methods involve substantial differences in the resolutions achievable in the different axes, speed of acquisition, compatibility with different labels, ease of use, hardware complexity, and compatibility with live biological samples. The field of super-resolution imaging and its application to nanotechnology is relatively new and still rapidly developing. An overview of how these methods may be used with nanomaterials is presented with some examples of pioneering uses of these approaches. PMID- 25298333 TI - New evidence for favourable effects on haemodynamics and ventricular performance after Parachute((r)) implantation in humans. AB - AIMS: The Parachute((r)) Ventricular Partitioning Device offers an additional strategy for heart failure patients with exclusion of the infarcted wall to decrease left ventricular volumes, myocardial work, and wall stress. The aim of the present study was to evaluate if Parachute implantation might influence acute haemodynamic and functional performance in patients with left ventricular aneurysm after anteroapical infarction. METHODS AND RESULTS: Sixteen patients underwent a Parachute device implantation. Invasive right and left heart haemodynamic assessments as well as left ventricular analysis for evaluating left ventricle end-diastolic and end-systolic volumes, and regional ventricular function were analysed. After implantation a significant increase in stroke volume (+25.4%, P = 0.0005), stroke volume index (+26.5%, P = 0.0005), cardiac output (+25.8%, P < 0.0001) and cardiac index (+25.9%, P < 0.0001) was found. In addition to an increase in mean aortic (P = 0.0050) and pulmonary pressure (P = 0.0347), there were significant increases in stroke work index (P = 0.0003), left (P = 0.0015) and right (P = 0.0024) ventricular stroke work index as well as left and right cardiac work index (both P = 0.0001), while the remaining haemodynamic parameters remained unchanged. Left ventricular analysis showed an acute reduction of the left ventricular end-diastolic volume (-18.0%, P < 0.0001) and left ventricular end-systolic volume (-26.3%, P < 0.0001) and an increase in ejection fraction from 22.9 to 30.6% (+38.4%, P < 0.0001). Most interestingly, the basal wall segments displayed an increased contribution to the left ventricular ejection fraction with increased wall motion in nearly all segments (except the apex region). CONCLUSION: The data demonstrate the acute haemodynamic efficacy of Parachute device implantation. The implantation of the device displays immediate significant left ventricular volume reduction leading to an acute improved right and left cardiac function, proving the concept of left ventricular partitioning. PMID- 25298334 TI - Mechanical circulatory support improves diabetic control in patients with advanced heart failure. AB - AIMS: Left ventricular assist devices (LVADs) are increasingly being used as life saving therapy for end-stage advanced heart failure. Diabetes is prevalent in advanced heart failure patients. In this study, we sought to investigate the effects of mechanical circulatory support on diabetic parameters with LVAD implantation. METHODS AND RESULTS: In this retrospective study, data on 244 LVAD recipients between 2006 and 2013 were reviewed. Patients without history of diabetes, death within the first 3 months after LVAD implantation, heart transplantation after LVAD, or LVAD explantation were excluded from the study. Baseline demographic, laboratory, and echocardiographic information prior to LVAD placement and 6-month follow-up were obtained. Laboratory values indicative of diabetic control were found to improve significantly at 6 months post-LVAD implantation (glycated haemoglobin, 7.2 vs. 6.1%, P < 0.0001; serum fasting glucose, 141 vs. 122 mg/dL, P = 0.003; mean daily insulin dose, 30 vs. 24 IU/day, P = 0.02). Additionally, the use of oral hypoglycaemic medication was successfully discontinued in six patients at 6 months post-LVAD implantation. CONCLUSIONS: Long-term LVAD therapy is associated with improvement in diabetic control which is probabvly due to improvements in cardiac output and normalization of biochemical derangements resulting from diabetes. PMID- 25298335 TI - Overview and historical perspective. PMID- 25298336 TI - Urea. AB - Urea is generated by the urea cycle enzymes, which are mainly in the liver but are also ubiquitously expressed at low levels in other tissues. The metabolic process is altered in several conditions such as by diets, hormones, and diseases. Urea is then eliminated through fluids, especially urine. Blood urea nitrogen (BUN) has been utilized to evaluate renal function for decades. New roles for urea in the urinary system, circulation system, respiratory system, digestive system, nervous system, etc., were reported lately, which suggests clinical significance of urea. PMID- 25298337 TI - Mathematical modeling of urea transport in the kidney. AB - Mathematical modeling techniques have been useful in providing insights into biological systems, including the kidney. This article considers some of the mathematical models that concern urea transport in the kidney. Modeling simulations have been conducted to investigate, in the context of urea cycling and urine concentration, the effects of hypothetical active urea secretion into pars recta. Simulation results suggest that active urea secretion induces a "urea selective" improvement in urine concentrating ability. Mathematical models have also been built to study the implications of the highly structured organization of tubules and vessels in the renal medulla on urea sequestration and cycling. The goal of this article is to show how physiological problems can be formulated and studied mathematically, and how such models may provide insights into renal functions. PMID- 25298338 TI - Genes and proteins of urea transporters. AB - A urea transporter protein in the kidney was first proposed in 1987. The first urea transporter cDNA was cloned in 1993. The SLC14a urea transporter family contains two major subgroups: SLC14a1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14a2, the UT-A group originally isolated from kidney inner medulla. Slc14a1, the human UT-B gene, arises from a single locus located on chromosome 18q12.1-q21.1, which is located close to Slc14a2. Slc14a1 includes 11 exons, with the coding region extending from exon 4 to exon 11, and is approximately 30 kb in length. The Slc14a2 gene is a very large gene with 24 exons, is approximately 300 kb in length, and encodes 6 different isoforms. Slc14a2 contains two promoter elements: promoter I is located in the typical position, upstream of exon 1, and drives the transcription of UT-A1, UT-A1b, UT A3, UT-A3b, and UT-A4; while promoter II is located within intron 12 and drives the transcription of UT-A2 and UT-A2b. UT-A1 and UT-A3 are located in the inner medullary collecting duct, UT-A2 in the thin descending limb and liver, UT-A5 in testis, UT-A6 in colon, UT-B1 primarily in descending vasa recta and erythrocytes, and UT-B2 in rumen. PMID- 25298340 TI - Expression of urea transporters and their regulation. AB - UT-A and UT-B families of urea transporters consist of multiple isoforms that are subject to regulation of both acutely and by long-term measures. This chapter provides a brief overview of the expression of the urea transporter forms and their locations in the kidney. Rapid regulation of UT-A1 results from the combination of phosphorylation and membrane accumulation. Phosphorylation of UT A1 has been linked to vasopressin and hyperosmolality, although through different kinases. Other acute influences on urea transporter activity are ubiquitination and glycosylation, both of which influence the membrane association of the urea transporter, again through different mechanisms. Long-term regulation of urea transport is most closely associated with the environment that the kidney experiences. Low-protein diets may influence the amount of urea transporter available. Conditions of osmotic diuresis, where urea concentrations are low, will prompt an increase in urea transporter abundance. Although adrenal steroids affect urea transporter abundance, conflicting reports make conclusions tenuous. Urea transporters are upregulated when P2Y2 purinergic receptors are decreased, suggesting a role for these receptors in UT regulation. Hypercalcemia and hypokalemia both cause urine concentration deficiencies. Urea transporter abundances are reduced in aging animals and animals with angiotensin-converting enzyme deficiencies. This chapter will provide information about both rapid and long-term regulation of urea transporters and provide an introduction into the literature. PMID- 25298339 TI - Structure of urea transporters. AB - Members of the urea transporter (UT) family mediate rapid, selective transport of urea down its concentration gradient. To date, crystal structures of two evolutionarily distant UTs have been solved. These structures reveal a common UT fold involving two structurally homologous domains that encircle a continuous membrane-spanning pore and indicate that UTs transport urea via a channel-like mechanism. Examination of the conserved architecture of the pore, combined with crystal structures of ligand-bound proteins, molecular dynamics simulations, and functional data on permeation and inhibition by a broad range of urea analogs and other small molecules, provides insight into the structural basis of urea permeation and selectivity. PMID- 25298341 TI - Biochemical properties of urea transporters. AB - Urea and urea transporters (UT) are critical to the production of concentrated urine and hence in maintaining body fluid balance. The UT-A1 urea transporter is the major and most important UT isoform in the kidney. Native UT-A1, expressed in the terminal inner medullary collecting duct (IMCD) epithelial cells, is a glycosylated protein with two glycoforms of 117 and 97 kDa. Vasopressin is the major hormone in vivo that rapidly increases urea permeability in the IMCD through increases in phosphorylation and apical plasma-membrane accumulation of UT-A1. The cell signaling pathway for vasopressin-mediated UT-A1 phosphorylation and activity involves two cAMP-dependent signaling pathways: protein kinase A (PKA) and exchange protein activated by cAMP (Epac). In this chapter, we will discuss UT-A1 regulation by phosphorylation, ubiquitination, and glycosylation. PMID- 25298342 TI - Transport characteristics of urea transporter-B. AB - UT-B represents the major urea transporter in erythrocytes, in addition to being expressed in kidney descending vasa recta, brain, spleen, ureter, bladder, and testis. Expression of urea transporter UT-B confers high urea permeability to mammalian erythrocytes. Erythrocyte membranes are also permeable to various urea analogues, suggesting common transport pathways for urea and structurally similar solutes. UT-B is highly permeable to urea and the chemical analogues formamide, acetamide, methylurea, methylformamide, ammonium carbamate, and acrylamide, each with a Ps > 5.0 * 10(-6) cm/s at 10 degrees C. The amides formamide, acetamide, acrylamide, and butyramide efficiently diffuse across lipid bilayers. The urea analogues dimethylurea, acryalmide, methylurea, thiourea, and methylformamide inhibit UT-B-mediated urea transport by >60 % by a pore-blocking mechanism. UT-B is also a water channel in erythrocytes and has a single-channel water permeability that is similar to aquaporin-1. Whether UT-B is an NH3 channel still needs further study. Urea permeability (Purea) in erythrocytes differs between different mammals. Carnivores (dog, fox, cat) exhibit high Purea. In contrast, herbivores (cow, donkey, sheep) show much lower Purea. Erythrocyte Purea in human and pig (omnivores) was intermediate. Rodents and lagomorphs (mouse, rat, rabbit) have Purea intermediate between carnivores and omnivores. Birds that do not excrete urea and do not express UT-B in their erythrocytes have very low values. In contrast to Purea, water permeability is relatively similar in all mammals studied. This chapter will provide information about the transporter characteristics of UT-B. PMID- 25298343 TI - Urea transporter knockout mice and their renal phenotypes. AB - Urea transporter gene knockout mice have been created for the study of the urine concentrating mechanism. The major findings in studies of the renal phenotype of these mice are as follows: (1) Urea accumulation in the inner medullary interstitium is dependent on intrarenal urea recycling mediated by urea transporters; (2) urea transporters are essential for preventing urea-induced osmotic diuresis and thus for water conservation; (3) NaCl concentration in the inner medullary interstitium is not significantly affected by the absence of IMCD, descending limb of Henle and descending vasa recta urea transporters. Studies in urea transporter knockout mouse models have highlighted the essential role of urea for producing maximally concentrated urine. PMID- 25298344 TI - Extrarenal phenotypes of the UT-B knockout mouse. AB - The urea transporter UT-B is expressed in multiple tissues including erythrocytes, kidney, brain, heart, liver, colon, bone marrow, spleen, lung, skeletal muscle, bladder, prostate, and testis in mammals. Phenotype analysis of UT-B-null mice has confirmed that UT-B deletion results in a urea-selective urine concentrating defect (see Chap. 9 ). The functional significance of UT-B in extrarenal tissues studied in the UT-B-null mouse is discussed in this chapter. UT-B-null mice present depression-like behavior with urea accumulation and nitric oxide reduction in the hippocampus. UT-B deletion causes a cardiac conduction defect, and TNNT2 and ANP expression changes in the aged UT-B-null heart. UT-B also plays a very important role in protecting bladder urothelium from DNA damage and apoptosis by regulating the urea concentration in urothelial cells. UT-B functional deficiency results in urea accumulation in the testis and early maturation of the male reproductive system. These results show that UT-B is an indispensable transporter involved in maintaining physiological functions in different tissues. PMID- 25298346 TI - Clinical aspects of urea transporters. AB - Jk antigens, which were identified as urea transporter B (UT-B) in the plasma membrane of erythrocytes, and which determine the Kidd blood type in humans, are involved in transfusion medicine, and even in organ transplantation. The Jk(a-b-) blood type is a consequence of a silent Slc14A1 gene caused by various mutations related to lineage. In addition, the specific mutations related to hypertension and metabolic syndrome cannot be ignored. Genome-wide association studies established Slc14A1 as a related gene of bladder cancer and some genotypes are associated with higher morbidity. This chapter aims to introduce the clinical significance of urea transporters. PMID- 25298345 TI - Small-molecule inhibitors of urea transporters. AB - Urea transporter (UT) proteins, which include isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, facilitate urinary concentrating function. Inhibitors of urea transporter function have potential clinical applications as sodium-sparing diuretics, or 'urearetics,' in edema from different etiologies, such as congestive heart failure and cirrhosis, as well as in syndrome of inappropriate antidiuretic hormone (SIADH). High-throughput screening of drug-like small molecules has identified UT-A and UT-B inhibitors with nanomolar potency. Inhibitors have been identified with different UT-A versus UT-B selectivity profiles and putative binding sites on UT proteins. Studies in rodent models support the utility of UT inhibitors in reducing urinary concentration, though testing in clinically relevant animal models of edema has not yet been done. PMID- 25298347 TI - Active urea transport in lower vertebrates and mammals. AB - Some unicellular organisms can take up urea from the surrounding fluids by an uphill pumping mechanism. Several active (energy-dependent) urea transporters (AUTs) have been cloned in these organisms. Functional studies show that active urea transport also occurs in elasmobranchs, amphibians, and mammals. In the two former groups, active urea transport may serve to conserve urea in body fluids in order to balance external high ambient osmolarity or prevent desiccation. In mammals, active urea transport may be associated with the need to either store and/or reuse nitrogen in the case of low nitrogen supply, or to excrete nitrogen efficiently in the case of excess nitrogen intake. There are probably two different families of AUTs, one with a high capacity able to establish only a relatively modest transepithelial concentration difference (renal tubule of some frogs, pars recta of the mammalian kidney, early inner medullary collecting duct in some mammals eating protein-poor diets) and others with a low capacity but able to maintain a high transepithelial concentration difference that has been created by another mechanism or in another organ (elasmobranch gills, ventral skin of some toads, and maybe mammalian urinary bladder). Functional characterization of these transporters shows that some are coupled to sodium (symports or antiports) while others are sodium-independent. In humans, only one genetic anomaly, with a mild phenotype (familial azotemia), is suspected to concern one of these transporters. In spite of abundant functional evidence for such transporters in higher organisms, none have been molecularly identified yet. PMID- 25298348 TI - Urea transport mediated by aquaporin water channel proteins. AB - Aquaporins (AQPs) are a family of membrane water channels that basically function as regulators of intracellular and intercellular water flow. To date, thirteen aquaporins have been characterized. They are distributed wildly in specific cell types in multiple organs and tissues. Each AQP channel consists of six membrane spanning alpha-helices that have a central water-transporting pore. Four AQP monomers assemble to form tetramers, which are the functional units in the membrane. Some of AQPs also transport urea, glycerol, ammonia, hydrogen peroxide, and gas molecules. AQP-mediated osmotic water transport across epithelial plasma membranes facilitates transcellular fluid transport and thus water reabsorption. AQP-mediated urea and glycerol transport is involved in energy metabolism and epidermal hydration. AQP-mediated CO2 and NH3 transport across membrane maintains intracellular acid-base homeostasis. AQPs are also involved in the pathophysiology of a wide range of human diseases (including water disbalance in kidney and brain, neuroinflammatory disease, obesity, and cancer). Further work is required to determine whether aquaporins are viable therapeutic targets or reliable diagnostic and prognostic biomarkers. PMID- 25298349 TI - Quantification of multiple compounds containing heterogeneous elements in the mixture by one-dimensional nuclear magnetic resonance spectroscopy of different nuclei using a single universal concentration reference. AB - One-dimensional (1D) quantitative NMR (qNMR) is a useful tool for concentration determination due to its experimental simplicity and the direct proportionality of the integrated signal area to the number of nuclei spin. For complex mixtures, however, signal overlapping often in one-dimensional quantitative (1) H NMR (1D (1) H qNMR) spectrum limits the accurate quantification of individual compound. Here, we introduced employing joint 1D qNMR methods of different nuclei, such as (1) H and (31) P (or/and (19) F), to quantify multiple compounds in a complex mixture using a single universal concentration reference. When the concentration ratio of several compounds containing different elements in a complex mixture is of interest, the result calculated from measured intensities from 1D qNMR of different nuclei is independent of the gravimetric error from the reference. In this case, the common reference also serves as a 'quantitative bridge' among these 1D qNMR of different nuclei. Quantitative analysis of choline, phosphocholine, and glycerophosphocholine mixture is given as an example using trimethylphosphine oxide ((CH(3))(3) P(O)) as concentration reference. Compounds containing multiple elements, such as tetramethylammonium hexafluorophosphate (N(+) (CH(3))(4 PF6 (-) are proposed as the common concentration reference for (1) H, (13) C, (15) N, (31) P, and (19) F qNMR for the quantitative analysis of complex mixture containing these different elements. We anticipate that the proposed joint 1D qNMR approach using a universal concentration reference will be a valuable alternative for simultaneous quantification of multiple compounds in a complex mixture due to its accuracy and single and simple sample preparation. PMID- 25298350 TI - Oculocutaneous albinism in sub-Saharan Africa: adverse sun-associated health effects and photoprotection. AB - Oculocutaneous albinism (OCA) is a genetically inherited autosomal recessive condition. Individuals with OCA lack melanin and therefore are susceptible to the harmful effects of solar ultraviolet radiation, including extreme sun sensitivity, photophobia and skin cancer. OCA is a grave public health issue in sub-Saharan Africa with a prevalence as high as 1 in 1000 in some tribes. This article considers the characteristics and prevalence of OCA in sub-Saharan African countries. Sun-induced adverse health effects in the skin and eyes of OCA individuals are reviewed. Sun exposure behavior and the use of photoprotection for the skin and eyes are discussed to highlight the major challenges experienced by these at-risk individuals and how these might be best resolved. PMID- 25298351 TI - The optimal management of patients on oral anticoagulation undergoing coronary artery stenting. The 10th Anniversary Overview. AB - Even 10 years after the first appearance in the literature of articles reporting on the management of patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S), this issue is still controversial. Nonetheless, some guidance for the everyday management of this patient subset, accounting for about 5-8 % of all patients referred for PCI-S, has been developed. In general, a period of triple therapy (TT) of OAC, with either vitamin K-antagonists (VKA) or non-vitamin K-antagonist oral anticoagulants (NOAC), aspirin, and clopidogrel is warranted, followed by the combination of OAC, and a single antiplatelet agent for up to 12 months, and then OAC alone. The duration of the initial period of TT is dependent on the individual risk of thromboembolism, and bleeding, as well as the clinical context in which PCI-S is performed (elective vs acute coronary syndrome), and the type of stent implanted (bare-metal vs drug-eluting). In this article, we aim to provide a comprehensive, at-a-glance, overview of the management strategies, which are currently suggested for the peri-procedural, medium-term, and long-term periods following PCI-S in OAC patients. While acknowledging that most of the evidence has been obtained from patients on OAC because of atrial fibrillation, and with warfarin being the most frequently used VKA, we refer in this overview to the whole population of OAC patients undergoing PCI-S. We refer to the whole population of patients on OAC undergoing PCI-S also when OAC is carried out with NOAC rather than VKA, pointing out, when appropriate, the particular management issues. PMID- 25298352 TI - Effect of ginger (Zingiber officinale) on heavy menstrual bleeding: a placebo controlled, randomized clinical trial. AB - OBJECTIVE: A wide range of herbal plants have been reported to treat various gynecological problems of women. This study was set out to investigate the effect of ginger (Zingiber officinale) on heavy menstrual bleeding (HMB) in high school girls. METHODS: Ninety-two young women who experienced HMB and met the inclusion criteria were recruited in this study. Participants were evaluated for six consecutive menstrual cycles. During 3 assessment cycles, their HMB was confirmed by Pictorial Blood Assessment Chart. They were then randomly allocated to two study groups to receive either ginger or placebo capsules. The participants filled in the same chart during three intervention cycles. RESULTS: The level of menstrual blood loss dramatically declined during the three intervention cycles in ginger-receiving group. The decrease of blood loss in ginger-receiving group was significantly more remarkable than that of participants receiving placebo (p<0.001). Minimum number of participants reported adverse effects. CONCLUSION: HMB is highly prevalent among young women. Considering the significance of appropriate and timely treatment and also the importance of prevention of unwanted consequences, ginger may be considered as an effective therapeutic option for HMB. PMID- 25298353 TI - [The CORAL study]. PMID- 25298354 TI - [The Symplicity HTN-3 study]. PMID- 25298355 TI - [Role of G-CSF and GM-CSF therapy in patients with acute myocardial infarction and critical limb ischemia]. AB - In spite of novel pharmacological and reperfusion strategies, many patients with acute myocardial infarction (AMI) and critical limb ischemia (CLI) due to peripheral arterial disease (PAD) have an unfavorable prognosis. Recent studies suggest that bone marrow cell mobilization with granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) may have a beneficial effect in AMI and CLI, likely due to endothelial progenitor cell-mediated angiogenesis and enhanced blood flow to the ischemic tissues. However, controversy still exists because published studies evaluated the effect of bone marrow cell mobilization in different patient populations, timing for drug administration in relationship to the acute event and to the reperfusion procedure differed, clinical endpoints and the techniques used for assessing cardiac function and volumes were not the same. Nevertheless, these small clinical studies provided useful information that helped design large phase III clinical trials and, ultimately, will establish whether bone marrow cell mobilization can have a role in AMI and CLI treatment. PMID- 25298356 TI - [Technical features of Absorb(TM) BVS implantation in the IT-DISAPPEARS registry]. AB - Currently, one of the most relevant innovations in interventional cardiology is the advent of bioresorbable vascular scaffolds (BVS). Among the BVS developed so far, the AbsorbTM BVS 1.1 (Abbott(r)) is one of the two devices that achieved the CE mark for the use in clinical practice. A reasonable amount of clinical evidence on AbsorbTM BVS has been built up from a large series of trials, of which some have been completed and others are in the enrollment and/or follow-up phases. However, at present there is paucity of data on the efficacy and safety of AbsorbTM BVS in patients with more complex coronary artery disease, who represent the majority of those undergoing coronary stenting in everyday clinical practice. To fill this gap, several all-comers registries are ongoing, with the aim to assess the efficacy and safety of the scaffold in subgroups with particularly complex coronary lesions. The AbsorbTM BVS 1.1 registries include IT DISAPPEARS (NCT02004730), an Italian multicenter registry, started in December 2013, and endorsed by the Italian Society of Invasive Cardiology (GISE). This registry will enroll only patients with long lesions and/or multivessel coronary disease, with an expected considerable proportion of included patients having complex disease. Therefore, the implementation of meticulous and appropriate implantation technique is of key importance for the accurate assessment of scaffold performance in a broad spectrum of coronary lesions. With the aim of standardizing the procedure for patients included in the IT-DISAPPEARS registry, the present article reports the technical features of Absorb TM BVS 1.1 implantation. PMID- 25298357 TI - [Genetic determinants of response to vitamin K antagonists]. AB - The narrow therapeutic index, the large interindividual variability, and the severity of adverse drug reactions connected with vitamin K antagonists, together with their ample use in medical therapy, have prompted the search for strategies to better assist doctors in the choice of the safest and most effective dose of these drugs. The molecular mechanism by which oral anticoagulants exert their effect is an interference with the bioactivation of vitamin K. This mechanism is therefore the subject of numerous pharmacogenetic studies, aimed at finding the relationship between genetic variants influencing the metabolism or action of the drug and therapeutic outcomes. However, genes involved in the metabolism or action of vitamin K antagonists are many, and the role of some of them has not yet been fully understood. In this review we present and discuss current knowledge about the relationship between genotypes and the development of adverse drug reactions, focusing on gene variants that appear to influence dosing and clinical endpoints, and aiming at clarifying the usefulness of pharmacogenetic approaches as applied to this treatment. PMID- 25298358 TI - [Current role of echocardiography in patients with atrial fibrillation]. AB - Atrial fibrillation is the most common arrhythmia encountered in clinical practice. Cardiologists are often called upon to manage atrial fibrillation both in the acute urgent setting for the presence of hemodynamic compromise and electively for rhythm and/or heart rate control as well as for anti-remodeling strategies. In all these cases echocardiography is generally used. In particular, different echocardiographic techniques (transthoracic, transesophageal) and modalities (two-dimensional, three-dimensional, speckle tracking) can be indicated depending on the stage of the arrhythmia management and the need for cardioversion or interventional procedures. The purpose of this review is to clarify the current role of echocardiography, including specific techniques and modalities, in the managing process of atrial fibrillation. PMID- 25298359 TI - [GISE/AIAC position paper on percutaneous left atrial appendage occlusion in patients with nonvalvular atrial fibrillation: recommendations for patient selection, facilities, competences, organizing and training requirements]. AB - Thromboembolism from the left atrial appendage is the most feared complication in patients with atrial fibrillation (AF). The cornerstone for the management of chronic nonvalvular AF is stroke reduction with oral anticoagulation (OAC). However, poor compliance, maintaining a narrow therapeutic window, and major side effects such as bleeding have severely limited its use, creating a therapeutic dilemma. About 20% of AF patients do not receive OAC due to contraindications and less than half of AF patients are not on OAC due to reluctance of the prescribing physician and/or patient non-compliance. Fortunately, over the past decade, the introduction of percutaneous approaches for left atrial appendage occlusion has offered a viable alternative to the management of nonvalvular AF in patients with OAC contraindication. Occlusion devices such as the Amplatzer Cardiac Plug and Watch man device have shown their noninferiority to OAC for stroke prophylaxis with less bleeding complications, while more recently some new devices have been introduced. The aim of this position paper is to review the most relevant clinical aspects of left atrial appendage occlusion from patient selection to periprocedural and follow-up management. In addition, the importance of a medical team and an organizational environment adequate to optimize all the steps of this procedure is discussed. PMID- 25298362 TI - Secure privacy-preserving biometric authentication scheme for telecare medicine information systems. AB - Healthcare delivery services via telecare medicine information systems (TMIS) can help patients to obtain their desired telemedicine services conveniently. However, information security and privacy protection are important issues and crucial challenges in healthcare information systems, where only authorized patients and doctors can employ telecare medicine facilities and access electronic medical records. Therefore, a secure authentication scheme is urgently required to achieve the goals of entity authentication, data confidentiality and privacy protection. This paper investigates a new biometric authentication with key agreement scheme, which focuses on patient privacy and medical data confidentiality in TMIS. The new scheme employs hash function, fuzzy extractor, nonce and authenticated Diffie-Hellman key agreement as primitives. It provides patient privacy protection, e.g., hiding identity from being theft and tracked by unauthorized participant, and preserving password and biometric template from being compromised by trustless servers. Moreover, key agreement supports secure transmission by symmetric encryption to protect patient's medical data from being leaked. Finally, the analysis shows that our proposal provides more security and privacy protection for TMIS. PMID- 25298361 TI - Luteal activity of pregnant rats with hypo-and hyperthyroidism. AB - BACKGROUND: Luteal activity is dependent on the interaction of various growth factors, cytokines and hormones, including the thyroid hormones, being that hypo- and hyperthyroidism alter the gestational period and are also a cause of miscarriage and stillbirth. Because of that, we evaluated the proliferation, apoptosis and expression of angiogenic factors and COX-2 in the corpus luteum of hypo- and hyperthyroid pregnant rats. METHODS: Seventy-two adult female rats were equally distributed into three groups: hypothyroid, hyperthyroid and control. Hypo- and hyperthyroidism were induced by the daily administration of propylthiouracil and L-thyroxine, respectively. The administration began five days before becoming pregnant and the animals were sacrificed at days 10, 14, and 19 of gestation. We performed an immunohistochemical analysis to evaluate the expression of CDC-47, VEGF, Flk-1 (VEGF receptor) and COX-2. Apoptosis was evaluated by the TUNEL assay. We assessed the gene expression of VEGF, Flk-1, caspase 3, COX-2 and PGF2alpha receptor using real time RT-PCR. The data were analyzed by SNK test. RESULTS: Hypothyroidism reduced COX-2 expression on day 10 and 19 (P < 0.05), endothelial/pericyte and luteal cell proliferation on day 10 and 14 (p < 0.05), apoptotic cell numbers on day 19 (p < 0.05) and the expression of Flk-1 and VEGF on day 14 and 19, respectively (p < 0.05). Hyperthyroidism increased the expression of COX-2 on day 19 (P < 0.05) and the proliferative activity of endothelial/pericytes cells on day 14 (p <0.05), as well as the expression of VEGF and Flk-1 on day 19 (P < 0.05). CONCLUSIONS: Hypothyroidism reduces the proliferation, apoptosis and expression of angiogenic factors and COX 2in the corpus luteum of pregnant rats, contrary to what is observed in hyperthyroid animals, being this effect dependent of the gestational period. PMID- 25298364 TI - The Ross procedure: total root technique. AB - We describe our technique for the Ross procedure using a total root technique without any foreign material for autograft support. We insist on technical principles, based on the surgical anatomy of the aortic and pulmonary root, aimed at optimizing aortic root dynamics while ensuring long-term stability of the autograft root. PMID- 25298363 TI - Transapical transcatheter aortic valve implantation using the second-generation self-expanding Symetis ACURATE TA valve. AB - Transapical transcatheter aortic valve implantation (TA-TAVI) is the recognized first choice surgical TAVI access. Expansion of this well-established treatment modality with subsequent broader patient inclusion has accelerated development of second-generation TA-TAVI devices. The Swiss ACURATE TA Symetis valve allows for excellent anatomical positioning, resulting in a very low incidence of paravalvular leaks. The self-expanding stent features an hourglass shape to wedge the native aortic valve annulus. A specially designed delivery system facilitates controlled release aided by tactile operator feedback. The ACURATE TA valve made of three native porcine non-coronary leaflets has received CE approval in September 2011. Since then, this valve is the third most frequently implanted TAVI device with over 1200 implants in Europe and South America. Results from the Symetis ACURATE TATM Valve Implantation ('SAVI') Registry showed a procedural success rate of 98.0% and a survival rate of 93.2% at 30 days. This presentation provides technical considerations and detailed procedural aspects of device implantation. PMID- 25298365 TI - Retrograde pulmonary perfusion as an adjunct to standard pulmonary embolectomy for acute pulmonary embolism. AB - Mortality rates for pulmonary embolectomy in patients with acute massive pulmonary embolism have decreased in recent years. However, it still ranges from 30 to 45% when surgery is performed on critically ill patients, and the mortality rates reach 60% in patients who have experienced a cardiac arrest before the procedure. The causes of death in these patients are generally attributed to right heart failure due to persistent pulmonary hypertension, intractable pulmonary oedema, and massive parenchymal and intrabronchial haemorrhage. Clinical and experimental findings indicate that venous air embolism causes severe or even lethal damage to the pulmonary microvasculature and the lung parenchyma consequent to the release of endothelium-derived cytokines. These findings are similar to those observed when severely compromised patients undergo pulmonary embolectomy for air entrapped in the pulmonary artery during embolectomy, which may lead to fatal outcomes. Retrograde pulmonary perfusion (RPP), besides enabling the removal of residual thrombotic material from the peripheral branches of the pulmonary artery, fills the pulmonary artery with blood and prevents pulmonary air embolism. We believe that the use of RPP as an adjunct to conventional pulmonary embolectomy decreases the morbidity and mortality rates associated with pulmonary embolectomy in critically ill patients. PMID- 25298367 TI - Does previous intra-articular steroid injection increase the risk of joint infection following total hip arthroplasty or total knee arthroplasty? A meta analysis. AB - BACKGROUND: Joint infection might be one of the rare but serious complications following a total knee or hip arthroplasty (TKA, THA). A previous intra-articular steroid injection was considered as a risk factor. The purpose of present study was to access the effects of ipsilateral intra-articular steroid injection followed by TKA or THA on the incidence of infections later. MATERIAL AND METHODS: Clinical studies reporting infection in THA or TKA after previous injection of intra-articular steroid were identified from the online database of PubMed, Embase, the Cochrane Library, and additional manual searches until July 2013. The pooled effects were measured by risk difference (RD), together with 95% confidence intervals (CIs). RESULTS: A total of 11 related studies met our inclusion criteria. The final meta-analysis investigated 6 clinical studies designed as retrospectively created cohort studies with control groups, involving 1474 participants reporting 14 deep infections and 72 superficial infections. Compared with the control group, there was no significantly increased rate of infection among the participant with steroid injection prior to THA or TKA, with corresponding RD (95% CIs) of 0.01 (-0.01, 0.02) for deep infection, 0.01 (-0.02, 0.03) for superficial infection, and 0.02 (-0.02, 0.07) for total infection. The data from 3 prospective studies without control groups and 2 case-control studies were consistent with the results of our meta-analysis. CONCLUSIONS: No increased risk of infection among patients who received steroid injections prior to the surgery was identified from the present evidence. A multicenter prospective study with more defined variables is needed further investigate this issue. PMID- 25298369 TI - Multiple sclerosis: summary of NICE guidance. PMID- 25298368 TI - The global epidemiology of waterpipe smoking. AB - OBJECTIVES: In the past decade, waterpipe smoking (a.k.a. hookah, shisha, narghile) has become a global phenomenon. In this review, we provide an updated picture of the main epidemiological trends in waterpipe smoking globally. DATA SOURCES: Peer-reviewed publications indexed in major biomedical databases between 2004 and 2014. Search keywords included a combination of: waterpipe, hookah, shisha along with epidemiology, patterns, prevalence and predictors. We also used different spellings of waterpipe terms commonly used. STUDY SELECTION: The focus was on studies with large representative samples, national data or high-quality reports that illuminated aspects of the epidemiology and trends in waterpipe smoking. DATA EXTRACTION: Multiple researchers extracted the data independently and collectively decided on the most important and pertinent studies to include in the review. DATA SYNTHESIS: Waterpipe smoking has become a global phenomenon among youth. The global waterpipe epidemic is likely driven by (1) the introduction of manufactured flavoured tobacco (Maassel); (2) the intersection between waterpipe's social dimension and thriving cafe culture; (3) the evolution of mass communication media; (4) the lack of regulatory/policy framework specific to the waterpipe. Waterpipe smoking is becoming the most popular tobacco use method among youth in the Middle East, and is quickly gaining popularity elsewhere. Important patterns of waterpipe smoking include the predominance among younger, male, high socioeconomic, and urban groups. Intermittent and social use are also noted patterns. CONCLUSIONS: Waterpipe smoking has become a global public health problem. Developing surveillance, intervention and regulatory/policy frameworks specific to the waterpipe has become a public health priority. PMID- 25298370 TI - Reliable generation of induced pluripotent stem cells from human lymphoblastoid cell lines. AB - Patient-specific induced pluripotent stem cells (iPSCs) hold great promise for many applications, including disease modeling to elucidate mechanisms involved in disease pathogenesis, drug screening, and ultimately regenerative medicine therapies. A frequently used starting source of cells for reprogramming has been dermal fibroblasts isolated from skin biopsies. However, numerous repositories containing lymphoblastoid cell lines (LCLs) generated from a wide array of patients also exist in abundance. To date, this rich bioresource has been severely underused for iPSC generation. We first attempted to create iPSCs from LCLs using two existing methods but were unsuccessful. Here we report a new and more reliable method for LCL reprogramming using episomal plasmids expressing pluripotency factors and p53 shRNA in combination with small molecules. The LCL derived iPSCs (LCL-iPSCs) exhibited identical characteristics to fibroblast derived iPSCs (fib-iPSCs), wherein they retained their genotype, exhibited a normal pluripotency profile, and readily differentiated into all three germ-layer cell types. As expected, they also maintained rearrangement of the heavy chain immunoglobulin locus. Importantly, we also show efficient iPSC generation from LCLs of patients with spinal muscular atrophy and inflammatory bowel disease. These LCL-iPSCs retained the disease mutation and could differentiate into neurons, spinal motor neurons, and intestinal organoids, all of which were virtually indistinguishable from differentiated cells derived from fib-iPSCs. This method for reliably deriving iPSCs from patient LCLs paves the way for using invaluable worldwide LCL repositories to generate new human iPSC lines, thus providing an enormous bioresource for disease modeling, drug discovery, and regenerative medicine applications. PMID- 25298371 TI - Wrongful termination: lessons from the Geron clinical trial. AB - Geron Corporation is a publically traded company that launched a phase I clinical trial of a human embryonic stem cell-based therapy for spinal cord injury. The company enrolled the first patient in October 2010 and stopped the trial 1 year later. The fifth patient had been enrolled but not transplanted when the company announced the trial's end. After discussions with clinical staff and family, an agreement was reached to add her to the cohort and proceed with the transplant. Two and half years later, the research is still waiting to restart. With this background in mind, we discuss the major ethical and social questions raised by the Geron case. We offer recommendations for institutional review boards and clinical sites as they deliberate approvals of early-phase trials in frontier medicine. PMID- 25298372 TI - Concise review: animal substance-free human embryonic stem cells aiming at clinical applications. AB - Human embryonic stem cells have been considered the gold standard as a cell source for regenerative medicine since they were first cultured in 1998. They are pluripotent and can form principally all the cells types in the body. They are obtained from supernumerary human in vitro fertilization embryos that cannot be used for infertility treatment. Following studies on factors regulating pluripotency and differentiation, we now have techniques to establish and effectively expand these cells in animal substance-free conditions, even from single cells biopsied from eight-cell stage embryos in chemically defined feeder free cultures. The genetic stability and absence of tumorigenic mutations can be determined. There are satisfactory animal tests for functionality and safety. The first clinical trials are ongoing for two indications: age-related macular degeneration and spinal cord injury. PMID- 25298374 TI - Seasonal dynamics in photosynthesis of woody plants at the northern limit of Asian tropics: potential role of fog in maintaining tropical rainforests and agriculture in Southwest China. AB - The lowland tropical rainforests in Xishuangbanna, Southwest (SW) China, mark the northern limit of Asian tropics. Fog has been hypothesized to play a role in maintaining rainforests and tropical crop production in this region, but the physiological mechanism has not been studied. The goals of this study were to characterize the seasonal dynamics in photosynthesis and to assess the potential for fog to mitigate chilling-induced photodamage for tropical trees and crops in Xishuangbanna. We measured seasonal dynamics in light-saturated net photosynthetic rate (Aa), stomatal conductance (gs), intercellular CO2 concentration, quantum yield of Photosystem II (Fv/Fm) and maximum P700 changes (Pm; indicates the amount of active PSI complex), as well as chilling resistance and fog (light/shading) effects on low temperature-induced decline in Fv/Fm and Pm for native tree and introduced lower latitude tree or woody shrub species grown in a tropical botanical garden. Despite significant decreases in Aa, gs, Pm and Fv/Fm, most species maintained considerably high Aa during the cool season (2.51-14.6 MUmol m(-2) s(-1)). Shaded leaves exposed to seasonal low temperatures had higher Fv/Fm than sun-exposed leaves in the cool season. All species could tolerate 1.4 degrees C in the dark, whereas a combined treatment of low temperature and high light caused a distinctly faster decline in Pm and Fv/Fm compared with low temperature treatment alone. Because fog persistence avoids or shortens the duration of high light condition in the morning when the temperatures are still low, our results provide support for the hypothesis that fog reduces chilling damage to tropical plants in this region and thus plays a role in maintaining tropical rainforests and agriculture in SW China. PMID- 25298373 TI - Reprogramming human retinal pigmented epithelial cells to neurons using recombinant proteins. AB - Somatic cells can be reprogrammed to an altered lineage by overexpressing specific transcription factors. To avoid introducing exogenous genetic material into the genome of host cells, cell-penetrating peptides can be used to deliver transcription factors into cells for reprogramming. Position-dependent C-end rule (CendR) cell- and tissue-penetrating peptides provide an alternative to the conventional cell-penetrating peptides, such as polyarginine. In this study, we used a prototypic, already active CendR peptide, RPARPAR, to deliver the transcription factor SOX2 to retinal pigmented epithelial (RPE) cells. We demonstrated that RPE cells can be directly reprogrammed to a neuronal fate by introduction of SOX2. Resulting neuronal cells expressed neuronal marker mRNAs and proteins and downregulated expression of RPE markers. Cells produced extensive neurites and developed synaptic machinery capable of dye uptake after depolarization with potassium. The RPARPAR-mediated delivery of SOX2 alone was sufficient to allow cell lineage reprogramming of both fetal and stem cell derived RPE cells to become functional neurons. PMID- 25298376 TI - Effect of long-term exposure to air pollution on type 2 diabetes mellitus risk: a systemic review and meta-analysis of cohort studies. AB - OBJECTIVE: To assess the effect of long-term exposure to air pollution on type 2 diabetes risk, a meta-analysis of prospective cohort studies was performed. METHODS: Literature search was conducted with Pubmed, Embase, and Web of Science for prospective cohort studies investigating the association of type 2 diabetes risk with increments in particulate matter (PM, diameter<2.5 MUm (PM2.5) or <10 MUm (PM10)) or nitrogen dioxide (NO2). We used a random-effects model to calculate the overall relative risk (RR) with 95% CI. RESULTS: Of 808 identified articles, ten cohort studies were finally included, which involved a total of 2 37,1 907 participants and 21,095 incident cases of type 2 diabetes. Elevated risk of type 2 diabetes was significantly associated with long-term exposures to high levels of PM2.5 (RR=1.28, 95% CI 1.06-1.55, P=0.009, I2=83.5%), PM10 (RR=1.15, 95% CI 1.02-1.30, P=0.022, I2=0%), and NO2 (RR=1.12, 95% CI 1.02-1.23, P=0.015, I2=63.5%). When using standardized risk estimates, the RRs of type 2 diabetes were significant for increments in concentrations of PM2.5 (1.39 per 10 MUg/m3 increment, 95% CI 1.14-1.68, P=0.001), PM10 (1.34 per 10 MUg/m3 increment, 95% CI 1.22-1.47, P<0.001), and NO2 (1.11 per 10 MUg/m3 increment, 95% CI 1.07-1.16, P<0.001). No obvious evidence of publication bias was observed. CONCLUSION: Long term exposure to high levels of main air pollutants is significantly associated with elevated risk of type 2 diabetes mellitus. PMID- 25298375 TI - External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals. AB - BACKGROUND AND AIMS: Simple clinical algorithms including the fatty liver index (FLI) and lipid accumulation product (LAP) have been developed as surrogate markers for non-alcoholic fatty liver disease (NAFLD), constructed using (semi quantitative) ultrasonography. This study aimed to validate FLI and LAP as measures of hepatic steatosis, as determined quantitatively by proton magnetic resonance spectroscopy (1H-MRS). METHODS: Data were collected from 168 patients with NAFLD and 168 controls who had undergone clinical, biochemical and anthropometric assessment. Values of FLI and LAP were determined and assessed both as predictors of the presence of hepatic steatosis (liver fat>5.5%) and of actual liver fat content, as measured by 1H-MRS. The discriminative ability of FLI and LAP was estimated using the area under the receiver operator characteristic curve (AUROC). As FLI can also be interpreted as a predictive probability of hepatic steatosis, we assessed how well calibrated it was in our cohort. Linear regression with prediction intervals was used to assess the ability of FLI and LAP to predict liver fat content. Further validation was provided in 54 patients with type 2 diabetes mellitus. RESULTS: FLI, LAP and alanine transferase discriminated between patients with and without steatosis with an AUROC of 0.79 (IQR=0.74, 0.84), 0.78 (IQR=0.72, 0.83) and 0.83 (IQR=0.79, 0.88) respectively although could not quantitatively predict liver fat. Additionally, the algorithms accurately matched the observed percentages of patients with hepatic steatosis in our cohort. CONCLUSIONS: FLI and LAP may be used to identify patients with hepatic steatosis clinically or for research purposes but could not predict liver fat content. PMID- 25298377 TI - Main air pollutants and diabetes-associated mortality: a systematic review and meta-analysis. AB - OBJECTIVE: Exposure to high levels of air pollutants may be linked to diabetes associated mortality, but the associations remain unclear. To assess the associations between main air pollutants and diabetes-associated mortality, a systematic review and meta-analysis was performed. METHODS: PubMed, Embase and Web of Science were searched for studies investigating the associations between increments in gaseous (nitrogen dioxide (NO2), sulphur dioxide, ozone (O3) and carbon monoxide) and particulate matter (PM; diameter<2.5 MUm (PM2.5) or <10 MUm (PM10)) air pollutants and diabetes-associated mortality. Using a random-effects model, relative risks (RRs) and 95% CIs were calculated per interquartile range (IQR) increment or per 10 MUg/m3 increment in pollutant concentrations. RESULTS: Out of 925 identified articles, 36 were reviewed in depth and 12 studies from 13 articles satisfying the inclusion criteria (five time-series, five case crossovers and two cohorts) were finally included. Increased risk of diabetes associated mortality was associated with higher levels of PM2.5 (per 10 MUg/m3: RR=1.123, 95% CI 1.036-1.217, P=0.005, I2=96.1%), PM10 (per 10 MUg/m3: RR=1.008, 95% CI 1.004-1.013, P<0.001, I2=0%), NO2 (per 10 MUg/m3: RR=1.024, 95% CI 1.007 1.041, P=0.006, I2=49.7%) and O3 (per IQR increment: RR=1.065, 95% CI 1.017 1.115, P=0.007, I2=0.0%). No obvious risk of publication bias was observed. CONCLUSIONS: Exposure to high levels of air pollutants is significantly associated with an increased risk of diabetes-associated mortality. PMID- 25298378 TI - Mesonia aquimarina sp. nov., a marine bacterium isolated from coastal seawater. AB - A Gram-staining-negative, aerobic, yellow, non-flagellated, non-gliding, rod shaped bacterium, designated strain IMCC1021(T), was isolated off the coast of the East Sea. Optimal growth of strain IMCC1021(T) was observed at 25 degrees C, pH 7.0-7.5 and in the presence of 3.0-3.5 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain belonged to the genus Mesonia, showing a close relationship with Mesonia mobilis KMM 6059(T) (97.4 % similarity) followed by Mesonia phycicola MDSW-25(T) (96.1 %). DNA-DNA relatedness between strain IMCC1021(T) and M. mobilis KMM 6059(T) was 17.5 % (reciprocal 7.4 %), which indicated that the new isolate represents a novel genomic species of the genus Mesonia. The major fatty acids were iso-C15 : 0 and iso-C17 : 0 3-OH, and the G+C content of the genomic DNA was 41.4 mol%. Strain IMCC1021(T) contained menaquinone-6 (MK-6) as the respiratory quinone, and polar lipids comprising phosphatidylethanolamine, two unknown aminolipids and three unknown polar lipids. On the basis of the phylogenetic distinctions and differential phenotypic characteristics, it is suggested that strain IMCC1021(T) ( = KCTC 32320(T) = NBRC 109485(T)) should be assigned to the genus Mesonia as the type strain of a novel species, for which the name Mesonia aquimarina sp. nov. is proposed. PMID- 25298379 TI - Epilithonimonas ginsengisoli sp. nov., isolated from soil of a ginseng field. AB - A novel Gram-staining-negative, rod-shaped bacterium, designated DCY78(T), was isolated from soil of a ginseng field in Yeon-cheon province (38 degrees 04' 00" N 126 degrees 57' 00" E), Republic of Korea. The phylogenetic analysis based on 16S rRNA gene sequences showed that strain DCY78(T) belonged to the genus Epilithonimonas and was most closely related to Epilithonimonas lactis DSM 19921(T) (98.5 % sequence similarity) and Epilithonimonas tenax DSM 16811(T) (97.8 %). Growth occurred at 10-30 degrees C with an optimum temperature of 28 degrees C. The pH range for growth was pH 5.5-8.0. The major polar lipids were found to be phosphatidylethanolamine three unidentified amino lipids and one unidentified polar lipid. The only predominant quinone was MK-6. The major polyamines were sym-homospermidine and spermidine. The major fatty acids were summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c), iso-C15 : 0 and iso-C17 : 0 3-OH. The DNA G+C content was 37.9 mol%. On the basis of the phenotypic and genotypic analysis, the isolate is classified as representative of a novel species in the genus Epilithonimonas, for which the name Epilithonimonas ginsengisoli is proposed. The type strain is DCY78(T) ( = KCTC 32174(T) = JCM 19896(T)). PMID- 25298380 TI - Parapedobacter indicus sp. nov., isolated from hexachlorocyclohexane-contaminated soil. AB - Strain RK1(T), a Gram-stain-negative, non-spore-forming, rod-shaped, non-motile bacterium was isolated from a hexachlorocyclohexane (HCH) dumpsite, Lucknow, India. 16S rRNA gene sequence analysis revealed that strain RK1(T) belongs to the family Sphingobacteriaceae and showed highest sequence similarity to Parapedobacter koreensis Jip14(T) (95.63%). The major cellular fatty acids of strain RK1(T) were iso-C15:0, summed feature 3 (C16:1omega7c and/or C16:1omega6c), iso-C17:0 3-OH, summed feature 9 (10-methyl C16:0 and/or iso C17:1omega9c), iso-C15:0 3-OH and C16 : 0. The major respiratory pigment and polyamine of RK1(T) were menaquinone (MK-7) and homospermidine, respectively. The main polar lipids were phosphatidylethanolamine and sphingolipid. The G+C content of the DNA was 44.5 mol%. The results of physiological and biochemical tests and 16S rRNA sequence analysis clearly demonstrated that strain RK1(T) represents a novel species of the genus Parapedobacter, for which the name Parapedobacter indicus sp. nov. is proposed. The type strain is RK1(T) ( = DSM 28470(T) =MCC 2546(T)). PMID- 25298381 TI - STI/HIV test result disclosure between female sex workers and their primary, non commercial male partners in two Mexico-US border cities: a prospective study. AB - OBJECTIVES: Disclosure of sexually transmitted infections (STI)/HIV diagnoses to sexual partners is not mandated by public health guidelines in Mexico. To assess the feasibility of couples-based STI/HIV testing with facilitated disclosure as a risk-reduction strategy within female sex workers' (FSW) primary partnerships, we examined STI/HIV test result disclosure patterns between FSWs and their primary, non-commercial male partners in two Mexico-US border cities. METHODS: From 2010 to 2013, 335 participants (181 FSWs and 154 primary male partners) were followed for 24 months. At semiannual visits, participants were tested for STIs/HIV and reported on their disclosure of test results from the previous visit. Multilevel logistic regression was used to identify individual-level and partnership-level predictors of cumulative (1) non-disclosure of >=1 STI test result and (2) non disclosure of >=1 HIV test result within couples during follow-up. RESULTS: Eighty-seven percent of participants reported disclosing all STI/HIV test results to their primary partners. Non-disclosure of >=1 STI test result was more common among participants who reported an STI diagnosis as part of the study (adjusted OR=3.05, 95% CI 1.13 to 8.25), while non-disclosure of >=1 HIV test result was more common among participants in longer-duration partnerships (AOR=1.15 per year, 95% CI 1.03 to 1.28). Drug use before/during sex within partnerships was associated with non-disclosure of both STI (AOR=5.06, 95% CI 1.64 to 15.62) and HIV (AOR=4.51, 95% CI: 1.32 to 15.39) test results. CONCLUSIONS: STI/HIV test result disclosure was highly prevalent within FSWs' primary partnerships, suggesting couples-based STI/HIV testing with facilitated disclosure may be feasible for these and potentially other high-risk, socially marginalised couples. PMID- 25298382 TI - Nicotinic and muscarinic acetylcholine receptors shape ganglion cell response properties. AB - The purpose of this study was to evaluate the expression patterns of nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively) in relation to one another and to understand their effects on rabbit retinal ganglion cell response properties. Double-label immunohistochemistry revealed labeled inner-retinal cell bodies and complex patterns of nAChR and mAChR expression in the inner plexiform layer. Specifically, the expression patterns of m1, m4, and m5 muscarinic receptors overlapped with those of non-alpha7 and alpha7 nicotinic receptors in presumptive amacrine and ganglion cells. There was no apparent overlap in the expression patterns of m2 muscarinic receptors with alpha7 nicotinic receptors or of m3 with non-alpha7 nicotinic receptors. Patch-clamp recordings demonstrated cell type-specific effects of nicotinic and muscarinic receptor blockade. Muscarinic receptor blockade enhanced the center responses of brisk-sustained/G4 On and G4 Off ganglion cells, whereas nicotinic receptor blockade suppressed the center responses of G4 On-cells near the visual streak but enhanced the center responses of nonstreak G4 On-cells. Blockade of muscarinic or nicotinic receptors suppressed the center responses of brisk-sustained Off-cells and the center light responses of subsets of brisk-transient/G11 On- and Off-cells. Only nicotinic blockade affected the center responses of G10 On-cells and G5 Off-cells. These data indicate that physiologically and morphologically identified ganglion cell types have specific patterns of AChR expression. The cholinergic receptor signatures of these cells may have implications for understanding visual defects in disease states that result from decreased ACh availability. PMID- 25298384 TI - Excitability changes in primary motor cortex just prior to voluntary muscle relaxation. AB - We postulated that primary motor cortex (M1) activity does not just decrease immediately prior to voluntary muscle relaxation; rather, it is dynamic and acts as an active cortical process. Thus we investigated the detailed time course of M1 excitability changes during muscle relaxation. Ten healthy participants performed a simple reaction time task. After the go signal, they rapidly terminated isometric abduction of the right index finger from a constant muscle force output of 20% of their maximal voluntary contraction force and performed voluntary muscle relaxation. Transcranial magnetic stimulation pulses were randomly delivered before and after the go signal, and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle. We selected the time course relative to an appropriate reference point, the onset of voluntary relaxation, to detect excitability changes in M1. MEP amplitude from 80 to 60 ms before the estimated electromyographic offset was significantly greater than that in other intervals. Dynamic excitability changes in M1 just prior to quick voluntary muscle relaxation indicate that cortical control of muscle relaxation is established through active processing and not by simple cessation of activity. The cortical mechanisms underlying muscle relaxation need to be reconsidered in light of such dynamics. PMID- 25298383 TI - Three timescales in prism adaptation. AB - It has been proposed that motor adaptation depends on at least two learning systems, one that learns fast but with poor retention and another that learns slowly but with better retention (Smith MA, Ghazizadeh A, Shadmehr R. PLoS Biol 4: e179, 2006). This two-state model has been shown to account for a range of behavior in the force field adaptation task. In the present study, we examined whether such a two-state model could also account for behavior arising from adaptation to a prismatic displacement of the visual field. We first confirmed that an "adaptation rebound," a critical prediction of the two-state model, occurred when visual feedback was deprived after an adaptation-extinction episode. We then examined the speed of decay of the prism aftereffect (without any visual feedback) after repetitions of 30, 150, and 500 trials of prism exposure. The speed of decay decreased with the number of exposure trials, a phenomenon that was best explained by assuming an "ultraslow" system, in addition to the fast and slow systems. Finally, we compared retention of aftereffects 24 h after 150 or 500 trials of exposure: retention was significantly greater after 500 than 150 trials. This difference in retention could not be explained by the two-state model but was well explained by the three-state model as arising from the difference in the amount of adaptation of the "ultraslow process." These results suggest that there are not only fast and slow systems but also an ultraslow learning system in prism adaptation that is activated by prolonged prism exposure of 150-500 trials. PMID- 25298385 TI - Information theoretic analysis of proprioceptive encoding during finger flexion in the monkey sensorimotor system. AB - There is considerable debate over whether the brain codes information using neural firing rate or the fine-grained structure of spike timing. We investigated this issue in spike discharge recorded from single units in the sensorimotor cortex, deep cerebellar nuclei, and dorsal root ganglia in macaque monkeys trained to perform a finger flexion task. The task required flexion to four different displacements against two opposing torques; the eight possible conditions were randomly interleaved. We used information theory to assess coding of task condition in spike rate, discharge irregularity, and spectral power in the 15- to 25-Hz band during the period of steady holding. All three measures coded task information in all areas tested. Information coding was most often independent between irregularity and 15-25 Hz power (60% of units), moderately redundant between spike rate and irregularity (56% of units redundant), and highly redundant between spike rate and power (93%). Most simultaneously recorded unit pairs coded using the same measure independently (86%). Knowledge of two measures often provided extra information about task, compared with knowledge of only one alone. We conclude that sensorimotor systems use both rate and temporal codes to represent information about a finger movement task. As well as offering insights into neural coding, this work suggests that incorporating spike irregularity into algorithms used for brain-machine interfaces could improve decoding accuracy. PMID- 25298388 TI - Perceptual and motor learning underlies human stick-balancing skill. AB - We investigated the acquisition of skill in balancing a stick (52 cm, 34 g) on the fingertip in nine participants using three-dimensional motion analysis. After 3.5 h of practice over 6 wk, the participants could more consistently balance the stick for longer durations with greatly reduced magnitude and speed of stick and finger movements. Irrespective of level of skill, the balanced stick behaved like a normal noninverted pendulum oscillating under greater-than-gravity torque with simple harmonic motion about a virtual pivot located at the radius of gyration above the center of mass. The control input parameter was the magnitude ratio between the torque applied on the stick by the participant and the torque due to gravity. The participants utilized only a narrow range of this parameter, which did not change with practice, to rotate the stick like a linear mass-spring system. With increased skill, the stick therefore maintained the same period of oscillation but showed marked reductions in magnitude of both oscillation and horizontal translation. Better balancing was associated with 1) more accurate visual localization of the stick and proprioceptive localization of the finger and 2) reduced cross-coupling errors between finger and stick movements in orthogonal directions; i.e., finger movements in the anteroposterior plane became less coupled with stick tip movements in the mediolateral plane, and vice versa. Development of this fine motor skill therefore depended on perceptual and motor learning to provide improved estimation of sensorimotor state and precision of motor commands to an unchanging internal model of the rotational dynamics. PMID- 25298386 TI - Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat. AB - We tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek were characterized for their responses to graded mechanical and thermal stimuli and intradermal injections of pruritogens (serotonin, chloroquine, and beta-alanine), partial pruritogens (histamine and capsaicin), and an algogen (mustard oil). All pruriceptive VcPbT neurons were responsive to mechanical stimuli, and more than half were additionally responsive to thermal stimuli. The majority of VcPbT neurons were activated by injections of serotonin, histamine, capsaicin, and/or mustard oil. A subset of neurons were inhibited by injection of chloroquine. The large majority of VcPbT neurons projected to the ipsilateral and/or contralateral external lateral parabrachial and Kolliker-Fuse nuclei, as evidenced by antidromic mapping techniques. Analyses of mean responses and spike-timing dynamics of VcPbT neurons suggested clear differences in firing rates between responses to noxious and pruritic stimuli. Comparisons between the present data and those previously obtained from trigeminothalamic tract (VcTT) neurons demonstrated several differences in responses to some pruritogens. For example, responses of VcPbT neurons to injection of serotonin often endured for nearly an hour and showed a delayed peak in discharge rate. In contrast, responses of VcTT neurons endured for roughly 20 min and no delayed peak of firing was noted. Thus the longer duration responses to 5-HT and the delay in peak firing of VcPbT neurons better matched behavioral responses to stimulation in awake rats than did those of VcTT neurons. The results indicate that VcPbT neurons may have important roles in the signaling of itch as well as pain. PMID- 25298387 TI - Hierarchical effects of task engagement on amplitude modulation encoding in auditory cortex. AB - We recorded from middle lateral belt (ML) and primary (A1) auditory cortical neurons while animals discriminated amplitude-modulated (AM) sounds and also while they sat passively. Engagement in AM discrimination improved ML and A1 neurons' ability to discriminate AM with both firing rate and phase-locking; however, task engagement affected neural AM discrimination differently in the two fields. The results suggest that these two areas utilize different AM coding schemes: a "single mode" in A1 that relies on increased activity for AM relative to unmodulated sounds and a "dual-polar mode" in ML that uses both increases and decreases in neural activity to encode modulation. In the dual-polar ML code, nonsynchronized responses might play a special role. The results are consistent with findings in the primary and secondary somatosensory cortices during discrimination of vibrotactile modulation frequency, implicating a common scheme in the hierarchical processing of temporal information among different modalities. The time course of activity differences between behaving and passive conditions was also distinct in A1 and ML and may have implications for auditory attention. At modulation depths >= 16% (approximately behavioral threshold), A1 neurons' improvement in distinguishing AM from unmodulated noise is relatively constant or improves slightly with increasing modulation depth. In ML, improvement during engagement is most pronounced near threshold and disappears at highly suprathreshold depths. This ML effect is evident later in the stimulus, and mainly in nonsynchronized responses. This suggests that attention-related increases in activity are stronger or longer-lasting for more difficult stimuli in ML. PMID- 25298390 TI - Suppression of putative tinnitus-related activity by extra-cochlear electrical stimulation. AB - Studies on animals have shown that noise-induced hearing loss is followed by an increase of spontaneous firing at several stages of the central auditory system. This central hyperactivity has been suggested to underpin the perception of tinnitus. It was shown that decreasing cochlear activity can abolish the noise induced central hyperactivity. This latter result further suggests that an approach consisting of reducing cochlear activity may provide a therapeutic avenue for tinnitus. In this context, extra-cochlear electric stimulation (ECES) may be a good candidate to modulate cochlear activity and suppress tinnitus. Indeed, it has been shown that a positive current applied at the round window reduces cochlear nerve activity and can suppress tinnitus reliably in tinnitus subjects. The present study investigates whether ECES with a positive current can abolish the noise-induced central hyperactivity, i.e., the putative tinnitus related activity. Spontaneous and stimulus-evoked neural activity before, during and after ECES was assessed from single-unit recordings in the inferior colliculus of anesthetized guinea pigs. We found that ECES with positive current significantly decreases the spontaneous firing rate of neurons with high characteristic frequencies, whereas negative current produces the opposite effect. The effects of the ECES are absent or even reversed for neurons with low characteristic frequencies. Importantly, ECES with positive current had only a marginal effect on thresholds and tone-induced activity of collicular neurons, suggesting that the main action of positive current is to modulate the spontaneous firing. Overall, cochlear electrical stimulation may be a viable approach for suppressing some forms of (peripheral-dependent) tinnitus. PMID- 25298389 TI - Representation of remembered stimuli and task information in the monkey dorsolateral prefrontal and posterior parietal cortex. AB - Both dorsolateral prefrontal and posterior parietal cortex have been implicated in spatial working memory and representation of task information. Prior experiments training animals to recall the first of a sequence of stimuli and examining the effect of subsequent distractors have identified increased ability of the prefrontal cortex to represent remembered stimuli and filter distractors. It is unclear, however, if this prefrontal functional specialization extends to stimuli appearing earlier in a sequence, when subjects are cued to remember subsequent ones. It is also not known how task information interacts with persistent activity representing remembered stimuli and distractors in the two areas. To address these questions, we trained monkeys to remember either the first or second of two stimuli presented in sequence and recorded neuronal activity from the posterior parietal and dorsolateral prefrontal cortex. The prefrontal cortex was better able to represent the actively remembered stimulus, whereas the posterior parietal cortex was more modulated by distractors; however, task effects interfered with this representation. As a result, large proportions of neurons with persistent activity and task effects exhibited a preference for a stimulus when it appeared as a distractor in both areas. Additionally, prefrontal neurons were modulated to a greater extent by task factors during the delay period of the task. The results indicate that the prefrontal cortex is better able than the posterior parietal cortex to differentiate between distractors and actively remembered stimuli and is more modulated by the task; however, this relative preference is highly context dependent and depends on the specific requirements of the task. PMID- 25298391 TI - Effect of acute noxious stimulation to the leg or back on muscle synergies during walking. AB - This study aimed to examine how acute muscle pain affects muscle coordination during gait with consideration of muscle synergies (i.e., group of muscles activated in synchrony), amplitude of muscle activity and kinematics. A secondary aim was to determine whether any adaptation was specific to pain location. Sixteen participants walked on a treadmill during 5 conditions [control, low back pain (LBP), washout LBP, calf pain (CalfP), and washout CalfP]. Five muscle synergies were identified for all of the conditions. Cross-validation analysis showed that muscle synergy vectors extracted for the control condition accounted for >81% of variance accounted for from the other conditions. Muscle synergies were altered very little in some participants (n = 7 for LBP; n = 10 for CalfP), but were more affected in the others (n = 9 for LBP; n = 6 for CalfP). No systematic differences between pain locations were observed. Considering all participants, synergies related to propulsion and weight acceptance were largely unaffected by pain, whereas synergies related to other functions (trunk control and leg deceleration) were more affected. Gastrocnemii activity was less during both CalfP and LBP than control. Soleus activity was further reduced during CalfP, and this was associated with reduced plantar flexion. Some lower leg muscles exhibited adaptations depending on pain location (e.g., greater vastus lateralis and rectus femoris activity during CalfP than LBP). Overall, these changes in muscle coordination involve a participant-specific strategy that is important to further explore, as it may explain why some people are more likely to develop persistence of a painful condition. PMID- 25298392 TI - Cost and disability trends of work-related musculoskeletal disorders in Ohio. AB - BACKGROUND: With expected changes in age demographics many industry sectors may see their workforce significantly increase in age. The impact of claims and costs associated with musculoskeletal disorders in these industries may also change accordingly. AIMS: To determine the age-related trends in musculoskeletal disorders, including claims and costs, in different industrial sectors in the state of Ohio, USA. METHODS: Worker's compensation claims for musculoskeletal disorders in the state of Ohio between 1999 and 2004 were analysed in respect of age, industry sector, body region, and impact on cost and medical care (percentage of claims associated with surgery and number of procedures costing in excess of US$600). RESULTS: More than 570000 claims were analysed. Patterns of cost and disability among the majority of body regions demonstrated an increasing trend until 55 years of age, decreasing in older age groups. However, many industries demonstrated a continued increasing trend in costs with age. Shoulder and lumbar spine disorders showed unique industry-specific trends for older age groups as compared to the bell-shaped relationships for other body regions. CONCLUSIONS: Ageing appeared to have a role in the frequency and costs of musculoskeletal disorder claims in this study. However, industry-specific trends in the data suggest that job-specific risk factors may also play a role. The impact of age alone on the cost of musculoskeletal disorders cannot be determined because age is confounded by numerous lifestyle and work-related factors not identifiable in this study. PMID- 25298394 TI - Keep the white coat. PMID- 25298393 TI - Elevated levels of protein in urine in adulthood after exposure to the Chinese famine of 1959-61 during gestation and the early postnatal period. AB - BACKGROUND: Animal models have suggested that undernutrition during gestation and the early postnatal period may adversely affect kidney development and compromise renal function. As a natural experiment, famines provide an opportunity to test such potential effects in humans. We assessed whether exposure to the Chinese famine of 1959-1961 during gestation and early postnatal life was associated with the levels of proteinuria among female adults three decades after exposure to the famine. METHODS: We measured famine intensity using the cohort size shrinkage index and we constructed a difference-in-difference model to compare the levels of proteinuria, measured with a dipstick test of random urine specimens, among Chinese women (n = 70 543) whose exposure status to the famine varied across birth cohorts (born before, during or after the famine) and counties of residence with different degrees of famine intensity. RESULTS: Famine exposure was associated with a greater risk [odds ratio (OR) = 1.54; 95% confidence interval (CI): 1.04, 2.28; P = 0.029) of having higher level of proteinuria among women born during the famine years (1959-61) compared with the unexposed post famine born cohort (1964-65) in rural samples. No association was observed among urban samples. Results were robust to adjustment for covariates. CONCLUSIONS: Severe undernutrition during gestation and the early postnatal period may have long-term effects on levels of proteinuria in humans, but the effect sizes may be small. PMID- 25298395 TI - Inhibitor-3 ensures bipolar mitotic spindle attachment by limiting association of SDS22 with kinetochore-bound protein phosphatase-1. AB - Faithful chromosome segregation during mitosis is tightly regulated by opposing activities of Aurora B kinase and protein phosphatase-1 (PP1). PP1 function at kinetochores has been linked to SDS22, but the exact localization of SDS22 and how it affects PP1 are controversial. Here, we confirm that SDS22 is required for PP1 activity, but show that SDS22 does not normally localize to kinetochores. Instead, SDS22 is kept in solution by formation of a ternary complex with PP1 and inhibitor-3 (I3). Depletion of I3 does not affect the amount of PP1 at kinetochores but causes quantitative association of SDS22 with PP1 on KNL1 at the kinetochore. Such accumulation of SDS22 at kinetochores interferes with PP1 activity and inhibits Aurora B threonine-232 dephosphorylation, which leads to increased Aurora B activity in metaphase and persistence in anaphase accompanied with segregation defects. We propose a model in which I3 regulates an SDS22 mediated PP1 activation step in solution that precedes SDS22 dissociation and transfer of PP1 to kinetochores, and which is required for PP1 to efficiently antagonize Aurora B. PMID- 25298396 TI - OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. AB - Cristae, the organized invaginations of the mitochondrial inner membrane, respond structurally to the energetic demands of the cell. The mechanism by which these dynamic changes are regulated and the consequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPase responsible for inner membrane fusion and maintenance of cristae structure. Here, we report that OPA1 responds dynamically to changes in energetic conditions to regulate cristae structure. This cristae regulation is independent of OPA1's role in mitochondrial fusion, since an OPA1 mutant that can still oligomerize but has no fusion activity was able to maintain cristae structure. Importantly, OPA1 was required for resistance to starvation-induced cell death, for mitochondrial respiration, for growth in galactose media and for maintenance of ATP synthase assembly, independently of its fusion activity. We identified mitochondrial solute carriers (SLC25A) as OPA1 interactors and show that their pharmacological and genetic blockade inhibited OPA1 oligomerization and function. Thus, we propose a novel way in which OPA1 senses energy substrate availability, which modulates its function in the regulation of mitochondrial architecture in a SLC25A protein-dependent manner. PMID- 25298397 TI - Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells. AB - Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or entero-endocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell type-specific transcriptome analysis combined with Dam-ID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POU-domain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiation-promoting factors, such as Pdm1. PMID- 25298398 TI - HDAC6-ubiquitin interaction controls the duration of HSF1 activation after heat shock. AB - After heat shock, HSF1 controls a major cellular transcriptional response involving the activation of early (HSP70) and late (HSP25) heat shock gene expression. Here we show that a full response to heat shock (activation of both HSP70 and HSP25) depends on the duration of HSF1 activation, which is itself controlled by HDAC6, a unique deacetylase known to bind monoubiquitin and polyubiquitin with high affinity. On the basis of a comparative analysis of the heat shock response in cells knocked out for HDAC6 or expressing HDAC6 mutants, we show that HDAC6 binding to ubiquitinated proteins controls the duration of HSF1 activation after heat shock. In cells expressing HDAC6 mutated in the ubiquitin-binding domain, the AAA ATPase factor p97/VCP mediates rapid inactivation of HSF1, precluding late activation of the HSP25 gene. In these cells, knockdown of p97/VCP rescues HSF1 from this rapid inactivation and restores HSP25 expression. We present here a new regulatory circuit that adjusts the duration of the heat shock response to the extent of protein ubiquitination after heat shock. PMID- 25298400 TI - Spatiotemporal dynamics of triglyceride storage in unilocular adipocytes. AB - The spatiotemporal dynamics of triglyceride (TG) storage in unilocular adipocytes are not well understood. Here we applied ex vivo technology to study trafficking and metabolism of fluorescent fatty acids in adipose tissue explants. Live imaging revealed multiple cytoplasmic nodules surrounding the large central lipid droplet (cLD) of unilocular adipocytes. Each cytoplasmic nodule harbors a series of closely associated cellular organelles, including micro-lipid droplets (mLDs), mitochondria, and the endoplasmic reticulum. Exogenously added free fatty acids are rapidly adsorbed by mLDs and concurrently get esterified to TG. This process is greatly accelerated by insulin. mLDs transfer their content to the cLD, serving as intermediates that mediate packaging of newly synthesized TG in the large interior of a unilocular adipocyte. This study reveals novel cell biological features that may contribute to the mechanism of adipocyte hypertrophy. PMID- 25298399 TI - Olfactomedin 2, a novel regulator for transforming growth factor-beta-induced smooth muscle differentiation of human embryonic stem cell-derived mesenchymal cells. AB - Transforming growth factor-beta (TGF-beta) plays an important role in smooth muscle (SM) differentiation, but the downstream target genes regulating the differentiation process remain largely unknown. In this study, we identified olfactomedin 2 (Olfm2) as a novel regulator mediating SM differentiation. Olfm2 was induced during TGF-beta-induced SM differentiation of human embryonic stem cell-derived mesenchymal cells. Olfm2 knockdown suppressed TGF-beta-induced expression of SM markers, including SM alpha-actin, SM22alpha, and SM myosin heavy chain, whereas Olfm2 overexpression promoted the SM marker expression. TGF beta induced Olfm2 nuclear accumulation, suggesting that Olfm2 may be involved in transcriptional activation of SM markers. Indeed, Olfm2 regulated SM marker expression and promoter activity in a serum response factor (SRF)/CArG box dependent manner. Olfm2 physically interacted with SRF without affecting SRF myocardin interaction. Olfm2-SRF interaction promoted the dissociation of SRF from HERP1, a transcriptional repressor. Olfm2 also inhibited HERP1 expression. Moreover, blockade of Olfm2 expression inhibited TGF-beta-induced SRF binding to SM gene promoters in a chromatin setting, whereas overexpression of Olfm2 dose dependently enhanced SRF binding. These results demonstrate that Olfm2 mediates TGF-beta-induced SM gene transcription by empowering SRF binding to CArG box in SM gene promoters. PMID- 25298401 TI - An astral simulacrum of the central spindle accounts for normal, spindle-less, and anucleate cytokinesis in echinoderm embryos. AB - Cytokinesis in animal cells depends on spindle-derived spatial cues that culminate in Rho activation, and thereby actomyosin assembly, in a narrow equatorial band. Although the nature, origin, and variety of such cues have long been obscure, one component is certainly the Rho activator Ect2. Here we describe the behavior and function of Ect2 in echinoderm embryos, showing that Ect2 migrates from spindle midzone to astral microtubules in anaphase and that Ect2 shapes the pattern of Rho activation in incipient furrows. Our key finding is that Ect2 and its binding partner Cyk4 accumulate not only at normal furrows, but also at furrows that form in the absence of associated spindle, midzone, or chromosomes. In all these cases, the cell assembles essentially the same cytokinetic signaling ensemble-opposed astral microtubules decorated with Ect2 and Cyk4. We conclude that if multiple signals contribute to furrow induction in echinoderm embryos, they likely converge on the same signaling ensemble on an analogous cytoskeletal scaffold. PMID- 25298402 TI - Formation of alpha-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes. AB - Aggregates of alpha-synuclein (alpha-syn) accumulate in neurons in Parkinson's disease and other synucleinopathies. These inclusions predominantly localize to axons even in the early stages of the disease, but their affect on axon function has remained unknown. Previously we established a model in which the addition of preformed alpha-syn fibrils to primary neurons seeds formation of insoluble alpha syn inclusions built from endogenously expressed alpha-syn that closely recapitulate the neuropathological phenotypes of Lewy neurites found in human diseased brains. Here we show, using live-cell imaging, that immobile alpha-syn inclusions accumulate in axons from the recruitment of alpha-syn located on mobile alpha-syn-positive vesicles. Ultrastructural analyses and live imaging demonstrate that alpha-syn accumulations do not cause a generalized defect in axonal transport; the inclusions do not fill the axonal cytoplasm, disrupt the microtubule cytoskeleton, or affect the transport of synaptophysin or mitochondria. However, the alpha-syn aggregates impair the transport of Rab7 and TrkB receptor-containing endosomes, as well as autophagosomes. In addition, the TrkB receptor-associated signaling molecule pERK5 accumulates in alpha-syn aggregate-bearing neurons. Thus alpha-syn pathology impairs axonal transport of signaling and degradative organelles. These early effects of alpha-syn accumulations may predict points of intervention in the neurodegenerative process. PMID- 25298403 TI - Alternative splicing of human NT5E in cirrhosis and hepatocellular carcinoma produces a negative regulator of ecto-5'-nucleotidase (CD73). AB - Ecto-5'-nucleotidase (CD73), encoded by NT5E, is the major enzymatic source of extracellular adenosine. CD73 controls numerous pathophysiological responses and is a potential disease target, but its regulation is poorly understood. We examined NT5E regulation by alternative splicing. Genomic database analysis of human transcripts led us to identify NT5E-2, a novel splice variant that was expressed at low abundance in normal human tissues but was significantly up regulated in cirrhosis and hepatocellular carcinoma (HCC). NT5E-2 encodes a shorter CD73 isoform we named CD73S. The presence of CD73S protein, which lacks 50 amino acids, was detected in HCC using an isoform-specific antibody. A noncanonical mouse mRNA, similar to human CD73S, was observed, but the corresponding protein was undetectable. The two human isoforms exhibited functional differences, such that ectopic expression of canonical CD73 (CD73L) in human HepG2 cells was associated with decreased expression of the proliferation marker Ki67, whereas CD73S expression did not have an effect on Ki67 expression. CD73S was glycosylated, catalytically inactive, unable to dimerize, and complexed intracellularly with the endoplasmic reticulum chaperone calnexin. Furthermore, CD73S complexed with CD73L and promoted proteasome-dependent CD73L degradation. The findings reveal species-specific CD73 regulation, with potential significance to cancer, fibrosis, and other diseases characterized by changes in CD73 expression and function. PMID- 25298404 TI - GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration. AB - ADAMs are cell surface metalloproteases that control multiple biological processes by cleaving signaling and adhesion molecules. ADAM13 controls cranial neural crest (CNC) cell migration both by cleaving cadherin-11 to release a promigratory extracellular fragment and by controlling expression of multiple genes via its cytoplasmic domain. The latter activity is regulated by gamma secretase cleavage and the translocation of the cytoplasmic domain into the nucleus. One of the genes regulated by ADAM13, the protease calpain8, is essential for CNC migration. Although the nuclear function of ADAM13 is evolutionarily conserved, it is unclear whether the transcriptional regulation is also performed by other ADAMs and how this process may be regulated. We show that ADAM13 function to promote CNC migration is regulated by two phosphorylation events involving GSK3 and Polo-like kinase (Plk). We further show that inhibition of either kinase blocks CNC migration and that the respective phosphomimetic forms of ADAM13 can rescue these inhibitions. However, these phosphorylations are not required for ADAM13 proteolysis of its substrates, gamma-secretase cleavage, or nuclear translocation of its cytoplasmic domain. Of significance, migration of the CNC can be restored in the absence of Plk phosphorylation by expression of calpain-8a, pointing to impaired nuclear activity of ADAM13. PMID- 25298405 TI - Rap1-dependent pathways coordinate cytokinesis in Dictyostelium. AB - Cytokinesis is the final step of mitosis when a mother cell is separated into two daughter cells. Major cytoskeletal changes are essential for cytokinesis; it is, however, not well understood how the microtubules and actomyosin cytoskeleton are exactly regulated in time and space. In this paper, we show that during the early stages of cytokinesis, in rounded-up Dictyostelium discoideum cells, the small G protein Rap1 is activated uniformly at the cell cortex. When cells begin to elongate, active Rap1 becomes restricted from the furrow region, where the myosin contractile ring is subsequently formed. In the final stages of cytokinesis, active Rap1 is only present at the cell poles. Mutant cells with decreased Rap1 activation at the poles showed strongly decreased growth rates. Hyperactivation of Rap1 results in severe growth delays and defective spindle formation in adherent cells and cell death in suspension. Furthermore, Rap mutants show aberrant regulation of the actomyosin cytoskeleton, resulting in extended furrow ingression times and asymmetrical cell division. We propose that Rap1 drives cytokinesis progression by coordinating the three major cytoskeletal components: microtubules, actin, and myosin II. Importantly, mutated forms of Rap also affect cytokinesis in other organisms, suggesting a conserved role for Rap in cell division. PMID- 25298406 TI - Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein. AB - Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcgammaRI and FcgammaRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T cell responses could be complemented with a SHe-based antigen to further improve immune protection. PMID- 25298409 TI - PDT with a glucose-conjugated chlorin for GIST--letter. PMID- 25298407 TI - The landscape of somatic chromosomal copy number aberrations in GEM models of prostate carcinoma. AB - Human prostate cancer is known to harbor recurrent genomic aberrations consisting of chromosomal losses, gains, rearrangements, and mutations that involve oncogenes and tumor suppressors. Genetically engineered mouse (GEM) models have been constructed to assess the causal role of these putative oncogenic events and provide molecular insight into disease pathogenesis. While GEM models generally initiate neoplasia by manipulating a single gene, expression profiles of GEM tumors typically comprise hundreds of transcript alterations. It is unclear whether these transcriptional changes represent the pleiotropic effects of single oncogenes, and/or cooperating genomic or epigenomic events. Therefore, it was determined whether structural chromosomal alterations occur in GEM models of prostate cancer and whether the changes are concordant with human carcinomas. Whole genome array-based comparative genomic hybridization (CGH) was used to identify somatic chromosomal copy number aberrations (SCNA) in the widely used TRAMP, Hi-Myc, Pten-null, and LADY GEM models. Interestingly, very few SCNAs were identified and the genomic architecture of Hi-Myc, Pten-null, and LADY tumors were essentially identical to the germline. TRAMP neuroendocrine carcinomas contained SCNAs, which comprised three recurrent aberrations including a single copy loss of chromosome 19 (encoding Pten). In contrast, cell lines derived from the TRAMP, Hi-Myc, and Pten-null tumors were notable for numerous SCNAs that included copy gains of chromosome 15 (encoding Myc) and losses of chromosome 11 (encoding p53). IMPLICATIONS: Chromosomal alterations are not a prerequisite for tumor formation in GEM prostate cancer models and cooperating events do not naturally occur by mechanisms that recapitulate changes in genomic integrity as observed in human prostate cancer. PMID- 25298408 TI - Therapeutic targeting of cellular metabolism in cells with hyperactive mTORC1: a paradigm shift. AB - mTORC1 is an established master regulator of cellular metabolic homeostasis, via multiple mechanisms that include altered glucose and glutamine metabolism, and decreased autophagy. mTORC1 is hyperactive in the human disease tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by germline mutations in the TSC1 or TSC2 gene. In TSC-deficient cells, metabolic wiring is extensively disrupted and rerouted as a consequence of mTORC1 hyperactivation, leading to multiple vulnerabilities, including "addiction" to glutamine, glucose, and autophagy. There is synergy between two rapidly evolving trajectories: elucidating the metabolic vulnerabilities of TSC-associated tumor cells, and the development of therapeutic agents that selectively target cancer-associated metabolic defects. The current review focuses on recent work supporting the targeting of cellular metabolic dysregulation for the treatment of tumors in TSC, with relevance to the many other human neoplasms with mTORC1 hyperactivation. These data expose a fundamental paradox in the therapeutic targeting of tumor cells with hyperactive mTORC1: inhibition of mTORC1 may not represent the optimal therapeutic strategy. Inhibiting mTORC1 "fixes" the metabolic vulnerabilities, results in a cytostatic response, and closes the door to metabolic targeting. In contrast, leaving mTORC1 active allows the metabolic vulnerabilities to be targeted with the potential for a cytocidal cellular response. The insights provided here suggest that therapeutic strategies for TSC and other tumors with activation of mTORC1 are at the verge of a major paradigm shift, in which optimal clinical responses will be accomplished by targeting mTORC1-associated metabolic vulnerabilities without inhibiting mTORC1 itself. PMID- 25298410 TI - PDT with a glucose-conjugated chlorin for GIST--response. PMID- 25298411 TI - Influence of axial length on thickness measurements using spectral-domain optical coherence tomography. AB - PURPOSE: The purpose of this study was to assess the influence of axial length on spectral-domain optical coherence tomography (SD-OCT) thickness measurements in patients with subretinal visual implants. METHODS: Data from eight emmetropic pseudophakic eyes of eight patients with subretinal visual implants were analyzed retrospectively. These patients participated in the monocentric part of a multicenter trial. The axial length was measured in three short (<22.5 mm), three medium (22.51-25.50 mm), and two long (>25.52 mm) eyes. Using Heidelberg Spectralis, the known thickness of a subretinal implant microchip (70 MUm) was measured on 15 images per eye with SD-OCT, using the software calipers. RESULTS: The mean axial length was 20.8 +/- 0.8 mm in short eyes, 23.3 +/- 0.4 mm in medium eyes, and 26.3 +/- 0.5 mm in long eyes. We found in short eyes, in medium eyes, and in long eyes a mean value of microchip thickness measurements from SD OCT of 82.9 +/- 1.4 MUm, 70.5 +/- 1.3 MUm, and 64.2 +/- 1.3 MUm, respectively. The thickness measurements decreased in SD-OCT measurements with longer axial lengths significantly (P < 0.0001). CONCLUSIONS: Axial length influences SD-OCT thickness measurements. Our findings demonstrate accuracy of the scaling in SD OCT thickness measurements in emmetropic medium eyes. Caution is recommended when comparing the measured values of short and long eyes with the normative database of the instrument. There is a need for larger sample-size studies to confirm our results. (ClinicalTrials.gov number, NCT01024803.). PMID- 25298412 TI - Identification of vinculin as a potential plasma marker for age-related macular degeneration. AB - PURPOSE: To identify plasma protein biomarkers for age-related macular degeneration (AMD) using a large-scale quantitative proteomic discovery procedure. METHODS: Plasma proteomes from 20 exudative AMD patients and 20 healthy control patients were comparatively profiled by four-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins existing at statistically different levels were validated by enzyme-linked immunosorbent assay (ELISA) and Western blotting in 233 case-controlled samples. Newly discovered plasma biomarkers were further confirmed using in vivo and in vitro experiments. RESULTS: Out of 320 proteins identified, vinculin, protein S100A9, triosephosphate isomerase, protein S100A8, protein Z-dependent protease inhibitor, C-X-C motif chemokine 7, and tenascin X showed significantly differential expression in AMD patient plasma compared to control plasma. Among these, the area under the curve (AUC) for vinculin was 0.871 for discriminating between exudative AMD and controls (n = 201) and 0.879 for discriminating between AMD and controls (n = 233). A proteogenomic combination model using vinculin and two known risk genotypes in ARMS2 and CFH genes additionally provided excellent discrimination of AMD from controls (AUC = 0.916). The plasma level of vinculin was not associated with any confounding clinical variables, such as age, smoking, and other comorbidities. Additionally, vinculin was strongly expressed in retinal pigment epithelial cells of human eyes, and its expression was elevated when exposed to oxidative stress in vitro. CONCLUSIONS: Vinculin was identified as a potential plasma biomarker for AMD. The early detection of AMD using novel plasma biomarkers with genetic modeling may enable timely treatment and vision preservation in the elderly. PMID- 25298413 TI - Amplitude of accommodation in type 1 diabetes. AB - PURPOSE: People with diabetes have accelerated age-related biometric ocular changes compared with people without diabetes. We determined the effect of type 1 diabetes on amplitude of accommodation. METHODS: There were 43 participants (33 +/- 8 years) with type 1 diabetes and 32 (34 +/- 8 years) age-balanced controls. There was no significant difference in mean equivalent refractive error and visual acuity between the groups. Amplitude of accommodation was measured using two techniques: objective by determining the accommodative response to a stimulus in a COAS-HD wavefront aberrometer and subjective with a Badal hand optometer. Influences of age and diabetes duration on amplitude of accommodation were analyzed using multiple regression analysis. RESULTS: People with diabetes had lower objective (2.7 +/- 1.6 diopters [D]) and subjective (4.0 +/- 1.7 D) amplitudes than controls (objective 4.1 +/- 2.1 D, subjective 5.6 +/- 2.1 D). Across both groups, objective amplitude was less than subjective amplitude by 1.4 +/- 1.2 D. For objective amplitude and the whole group, the duration of diabetes contributed 57% variation to the loss of amplitude relative to that provided by age. For the objective amplitude and only the diabetes group, this was 78%. For subjective amplitude, the corresponding proportions were 68% and 103%. CONCLUSIONS: Lowered amplitude of accommodation exists in individuals with type 1 diabetes when compared with age-matched controls. The loss correlated strongly with duration of diabetes. The results suggest that individuals with diabetes will experience presbyopia earlier in life than people without diabetes, mainly due to changes in the lens. PMID- 25298415 TI - Ultra-widefield fluorescein angiographic findings in patients with recurrent vitreous hemorrhage after diabetic vitrectomy. AB - PURPOSE: To analyze differences in ultra-widefield fluorescein angiography (UWFFA) findings between patients with recurrent postvitrectomy diabetic vitreous hemorrhage (PVDVH) and patients with non-PVDVH (NPVDVH). METHODS: Patients were categorized as PVDVH when vitreous hemorrhage recurred after diabetic vitrectomy. Age-matched control diabetic patients in whom vitreous hemorrhage did not recur after vitrectomy were assigned to the NPVDVH group. Baseline characteristics were compared between groups. Also peripheral angiographic findings such as peripheral neovascularization, nonperfusion, and late peripheral vascular leakage were analyzed by UWFFA. RESULTS: A total of 46 eyes were included this retrospective study: 22 with PVDVH and 24 with NPVDVH. Preoperative, 3-month postoperative, and final-visit best corrected visual acuity (BCVA) were not different between the two groups. The rate of peripheral neovascularization was significantly different (PVDVH 40.9%, NPVDVH 8.3%, P = 0.010). The rate of peripheral nonperfusion was significantly greater in PVDVH eyes than in NPVDVH eyes (81.8% vs. 37.5%, P = 0.002). The rate of late peripheral vascular leakage was also significantly greater in PVDVH eyes (90.9% vs. 29.2%, P < 0.001). These differences in peripheral angiographic findings were not seen within the conventional Early Treatment Diabetic Retinopathy Study (ETDRS) 7 standard fields. Ischemic index was also significantly higher in the PVDVH group than in the NVDVH group. CONCLUSIONS: Compared with diabetic vitrectomized eyes that did not have recurring vitreous hemorrhage, PVDVH eyes had a higher rate of peripheral neovascularization, nonperfusion, and late peripheral vascular leakage. These differences were not found within the conventional ETDRS 7 standard fields. Therefore, it is important to assess peripheral retinal vessels by UWFFA after diabetic vitrectomy. Furthermore, in cases of peripheral neovascularization, peripheral nonperfusion, and late peripheral vascular leakage, additional treatment may be necessary to prevent PVDVH. PMID- 25298414 TI - Interleukin 17 regulates Mer tyrosine kinase-positive cells in Pseudomonas aeruginosa keratitis. AB - PURPOSE: To determine if IL-17 regulates Mer tyrosine kinase-positive (MerTK+) cells in Pseudomonas aeruginosa keratitis. METHODS: Interleukin 17 was tested in normal and infected cornea of susceptible C57BL/6 and resistant BALB/c mice. The latter were treated with recombinant mouse (rm) IL-17; both groups were treated with IL-17 neutralizing antibody. Mice were infected, and clinical score, PCR, ELISA, and myeloperoxidase (MPO) assays tested expression of proinflammatory and anti-inflammatory mediators and polymorphonuclear neutrophilic leukocyte (PMN) infiltrate. Fas and Fas ligand (FasL) protein levels were assessed in both mouse strains, while MerTK+ cells were examined by immunostaining and cell sorting before and after IL-17 neutralization. RESULTS: The IL-17 mRNA and protein were higher in C57BL/6 versus BALB/c cornea after infection. The rmIL-17 treatment of BALB/c mice modified proinflammatory and anti-inflammatory mediators, but clinical score and MPO assay revealed no differences. However, only BALB/c mice treated with IL-17 neutralizing antibody showed increased disease, macrophage inflammatory protein (MIP) 2, and MPO levels. Fas and FasL protein levels, elevated earlier in BALB/c versus C57BL/6 mice, correlated with significantly more MerTK+ cells in BALB/c cornea at 3 days after infection. Neutralization of IL-17 in C57BL/6 mice elevated MerTK+ cells, while similar treatment of BALB/c mice significantly decreased them. CONCLUSIONS: These data provide evidence that IL-17 expression is higher in C57BL/6 versus BALB/c cornea after infection and that the latter group has more MerTK+ cells. Exogenous rmIL-17 failed to shift the disease response in resistant mice, but its neutralization resulted in worsened disease and reduced MerTK+ cells. Neutralization of IL-17 in C57BL/6 mice increased MerTK+ cells but did not dramatically shift the disease response. PMID- 25298416 TI - Sustained neuroprotection from a single intravitreal injection of PGJ2 in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy. AB - PURPOSE: Prostaglandin J2 (PGJ2) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ2 in a nonhuman primate model of NAION (pNAION). METHODS: We assessed PGJ2 toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ2 or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ2 or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves. RESULTS: TOXICITY: PGJ2 caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ2 used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ2; however, the amplitudes returned to normal in all animals within 1 week. EFFICACY: In all eyes, a single IVT dose of PGJ2 administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts). CONCLUSIONS: In nonhuman primates, PGJ2 administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ2 is neuroprotective when administered up to 5 hours after induction of pNAION. PMID- 25298417 TI - Role of Bax in death of uninfected retinal cells during murine cytomegalovirus retinitis. AB - PURPOSE: Extensive death of uninfected bystander neuronal cells is an important component of the pathogenesis of cytomegalovirus retinitis. Our previous results have shown that caspase 3-dependent and -independent pathways are involved in death of uninfected bystander cells during murine cytomegalovirus (MCMV) retinitis and also that Bcl-2, an important inhibitor of apoptosis via the Bax mediated mitochondrial pathway, is downregulated during this process. The purpose of this study was to determine whether Bax-mediated mitochondrial damage has a significant role in the death of uninfected retinal cells. METHODS: BALB/c mice, Bax(-/-) mice, or Bax(+/+) mice were immunosuppressed with methylprednisolone and infected with 5 * 10(3) plaque-forming units (PFU) of the K181 strain of MCMV via the supraciliary route. Injected eyes were analyzed by plaque assay, electron microscopy, hematoxylin and eosin (H&E) staining, TUNEL assay, Western blot (for caspase 3, caspase 12, Bax, receptor interacting protein-1 [RIP1] and receptor interacting protein-3 [RIP3]), as well as immunohistochemical staining for MCMV early antigen and cleaved caspase 3. RESULTS: Significantly more Bax was detected in mitochondrial fractions of MCMV-infected eyes than in mitochondrial fractions of mock-infected control eyes. Furthermore, the level of cleaved caspase 3 was significantly lower in MCMV-infected Bax(-/-) eyes than in MCMV-infected Bax(+/+) eyes. However, more caspase 3-independent cell death of uninfected bystander retinal cells and more cleaved RIP1 were observed in Bax(-/-) than in Bax(+/+) eyes. CONCLUSIONS: During MCMV retinitis, Bax is activated and has an important role in death of uninfected bystander retinal cells by caspase 3-dependent apoptosis. Although the exact mechanism remains to be deciphered, active Bax might also prevent death of some types of uninfected retinal cells by a caspase 3 independent pathway. PMID- 25298418 TI - Induction of trabecular meshwork cells from induced pluripotent stem cells. AB - PURPOSE: Loss or dysfunction of trabecular meshwork (TM) cells has been associated with the development of pathologically elevated IOP, and it is conceivable that replacement of damaged TM cells could restore function to the TM. We propose that the use of TM-like cells derived from induced pluripotent stem cells (iPSCs) created from a patient's own dermal fibroblasts offers the best solution to this challenge. Here we demonstrate that mouse iPSCs can be induced to differentiate into TM-like cells suitable for autologous transplantation. METHODS: Directed induction of stem cell differentiation was achieved through coculture of mouse iPSCs with human TM cells for up to 21 days. The resultant TM-like cells (iPSC-TM) were characterized morphologically, immunohistochemically, and functionally. RESULTS: The iPSC-TM cells closely resembled cultured human TM cells morphologically and began to express many markers of TM cells while ceasing to express pluripotency markers such as Nanog, Oct4, and Sox2. Functionally, these cells developed the ability to phagocytose particles. Finally, exposure to dexamethasone or phorbol 12-myristate acetate caused a distinct increase in the production and secretion of myocilin and matrix metalloproteinase-3, respectively, behavior characteristic of TM cells. CONCLUSIONS: Our data demonstrate that iPSCs can be induced to assume a phenotype that resembles native TM cells in many important aspects. Not only do these cells represent a valuable research tool, but transplantation into glaucomatous eyes with elevated IOP may also restore function to the TM, resulting in re establishment of IOP. PMID- 25298420 TI - Flicker light-induced retinal vasodilation is unaffected by inhibition of epoxyeicosatrienoic acids and prostaglandins in humans. AB - PURPOSE: To investigate the role of epoxyeicosatrienoic acids (EETs) and prostaglandins (PGs) in retinal blood vessel calibers and vasodilation during flicker light stimulation in humans. METHODS: Twelve healthy nonsmokers participated in a balanced crossover study. Oral fluconazole 400 mg and dispersible aspirin 600 mg were used to inhibit production of EETs and PGs, respectively. Retinal imaging was performed 1 hour after drug ingestion with the Dynamic Vessel Analyzer. Resting calibers of selected vessel segments were recorded in measurement units (MU). Maximum percentage dilations during flicker stimulation were calculated from baseline calibers. We then studied six participants each after fluconazole and aspirin ingestions at 30-minute intervals for 2 hours. Within-subject differences were assessed by ANOVA and Dunnett adjusted pairwise comparisons with significance taken at P < 0.05. RESULTS: In crossover study participants, mean (SD) arteriole and venule dilations without drug administration were 4.4% (2.0%) and 4.6% (1.7%), respectively. Neither drug affected vasodilation during flicker stimulation. Mean (SD) resting arteriole and venule calibers on no-drug visits were 119.6 (10.6) MU and 145.7 (17.0) MU, respectively. Fluconazole reduced mean (+/-95% CI) resting venule calibers by 5.1 (4.3) MU. In repeated measures participants, neither drug affected vasodilations, but fluconazole reduced resting venule calibers over 2 hours (P < 0.001). CONCLUSIONS: Epoxyeicosatrienoic acids and prostaglandins are unlikely to be primary mediators of flicker light-induced retinal vasodilation in humans. However, EETs may play a role in the regulation of retinal vascular tone and blood flow under resting physiological conditions. PMID- 25298419 TI - Transethnic replication of association of CTG18.1 repeat expansion of TCF4 gene with Fuchs' corneal dystrophy in Chinese implies common causal variant. AB - PURPOSE: To test the association between the CTG18.1 trinucleotide repeat expansion of TCF4 gene and Fuchs' endothelial corneal dystrophy (FECD) in a Chinese population. METHODS: The trinucleotide repeat polymorphism CTG18.1 was genotyped using short tandem repeat and triplet repeat primed polymerase chain reaction assays in 57 Chinese subjects with FECD and 121 controls. Statistical association of the expanded CTG18.1 allele and 18 single nucleotide polymorphisms (SNPs) across TCF4 with FECD was evaluated. To investigate the linkage disequilibrium structure of the TCF4 region, haplotype analysis was performed on our study subjects and compared with genotyping data of 97 Han Chinese and 85 Caucasians in the 1000 Genomes Project. RESULTS: The expanded CTG18.1 allele was associated with FECD (P = 4.7 * 10(-14)), with the odds ratio of each copy of the expanded allele estimated to be 66.5 (95% confidence interval: 12.6-350.1). Five TCF4 SNPs showed association with FECD at a nominal level (P < 5.0 * 10(-2)); however, conditional on the expanded CTG18.1 polymorphism, none of the SNPs showed association with FECD. The only haplotype associated with the disease was the one with the expansion at the CTG18.1 locus. CONCLUSIONS: Transethnic replication of the association between the CTG18.1 repeat expansion in the TCF4 gene and FECD suggests it is a common, causal variant shared in Eurasian populations conferring significant risk for the development of FECD. Our data suggest that the expanded CTG18.1 allele is the main, if not sole, causal variant at this gene locus in the Chinese population. PMID- 25298421 TI - Epigenetic memory for stress response and adaptation in plants. AB - In contrast to the majority of animal species, plants are sessile organisms and are, therefore, constantly challenged by environmental perturbations. Over the past few decades, our knowledge of how plants perceive environmental stimuli has increased considerably, e.g. the mechanisms for transducing environmental stress stimuli into cellular signaling cascades and gene transcription networks. In addition, it has recently been shown that plants can remember past environmental events and can use these memories to aid responses when these events recur. In this mini review, we focus on recent progress in determination of the epigenetic mechanisms used by plants under various environmental stresses. Epigenetic mechanisms are now known to play a vital role in the control of gene expression through small RNAs, histone modifications and DNA methylation. These are inherited through mitotic cell divisions and, in some cases, can be transmitted to the next generation. They therefore offer a possible mechanism for stress memories in plants. Recent studies have yielded evidence indicating that epigenetic mechanisms are indeed essential for stress memories and adaptation in plants. PMID- 25298422 TI - Na+-independent phosphate transport in Caco2BBE cells. AB - Pi transport in epithelia has both Na(+)-dependent and Na(+)-independent components, but so far only Na(+)-dependent transporters have been characterized in detail and molecularly identified. Consequently, in the present study, we initiated the characterization and analysis of intestinal Na(+)-independent Pi transport using an in vitro model, Caco2BBE cells. Only Na(+)-independent Pi uptake was observed in these cells, and Pi uptake was dramatically increased when cells were incubated in high-Pi DMEM (4 mM) from 1 day to several days. No response to low-Pi medium was observed. The increased Pi transport was mainly caused by Vmax changes, and it was prevented by actinomycin D and cycloheximide. Pi transport in cells grown in 1 mM Pi (basal DMEM) decreased at pH > 7.5, and it was inhibited with proton ionophores. Pi transport in cells incubated with 4 mM Pi increased with alkaline pH, suggesting a preference for divalent phosphate. Pi uptake in cells in 1 mM Pi was completely inhibited only by Pi and partially inhibited by phosphonoformate, oxalate, DIDS, SITS, SO4 (2-), HCO3 (-), and arsenate. This inhibition pattern suggests that more than one Pi transporter is active in cells maintained with 1 mM Pi. Phosphate transport from cells maintained at 4 mM Pi was only partially inhibited by phosphonoformate, oxalate, and arsenate. Attempts to identify the responsible transporters showed that multifunctional anion exchangers of the Slc26 family as well as members of Slc17, Slc20, and Slc37 and the Pi exporter xenotropic and polytropic retrovirus receptor 1 are not involved. PMID- 25298423 TI - Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte. AB - Iodide is captured by thyrocytes through the Na(+)/I(-) symporter (NIS) before being released into the follicular lumen, where it is oxidized and incorporated into thyroglobulin for the production of thyroid hormones. Several reports point to pendrin as a candidate protein for iodide export from thyroid cells into the follicular lumen. Here, we show that a recently discovered Ca(2+)-activated anion channel, TMEM16A or anoctamin-1 (ANO1), also exports iodide from rat thyroid cell lines and from HEK 293T cells expressing human NIS and ANO1. The Ano1 mRNA is expressed in PCCl3 and FRTL-5 rat thyroid cell lines, and this expression is stimulated by thyrotropin (TSH) in rat in vivo, leading to the accumulation of the ANO1 protein at the apical membrane of thyroid follicles. Moreover, ANO1 properties, i.e., activation by intracellular calcium (i.e., by ionomycin or by ATP), low but positive affinity for pertechnetate, and nonrequirement for chloride, better fit with the iodide release characteristics of PCCl3 and FRTL-5 rat thyroid cell lines than the dissimilar properties of pendrin. Most importantly, iodide release by PCCl3 and FRTL-5 cells is efficiently blocked by T16Ainh-A01, an ANO1-specific inhibitor, and upon ANO1 knockdown by RNA interference. Finally, we show that the T16Ainh-A01 inhibitor efficiently blocks ATP-induced iodide efflux from in vitro-cultured human thyrocytes. In conclusion, our data strongly suggest that ANO1 is responsible for most of the iodide efflux across the apical membrane of thyroid cells. PMID- 25298425 TI - Force enhancement after stretch in mammalian muscle fiber: no evidence of cross bridge involvement. AB - Stretching of activated skeletal muscles induces a force increase above the isometric level persisting after stretch, known as residual force enhancement (RFE). RFE has been extensively studied; nevertheless, its mechanism remains debated. Unlike previous RFE studies, here the excess of force after stretch, termed static tension (ST), was investigated with fast stretches (amplitude: 3-4% sarcomere length; duration: 0.6 ms) applied at low tension during the tetanus rise in fiber bundles from flexor digitorum brevis (FDB) mouse muscle at 30 degrees C. ST was measured at sarcomere length between 2.6 and 4.4 MUm in normal and N-benzyl-p-toluene sulphonamide (BTS)-added (10 MUM) Tyrode solution. The results showed that ST has the same characteristics and it is equivalent to RFE. ST increased with sarcomere length, reached a peak at 3.5 MUm, and decreased to zero at ~4.5 MUm. At 4 MUm, where active force was zero, ST was still 50% of maximum. BTS reduced force by ~75% but had almost no effect on ST. Following stimulation, ST developed earlier than force, with a time course similar to internal Ca(2+) concentration: it was present 1 ms after the stimulus, at zero active force, and peaked at ~3-ms delay. At 2.7 MUm, activation increased the passive sarcomere stiffness by a factor of ~7 compared with the relaxed state All our data indicate that ST, or RFE, is independent of the cross-bridge presence and it is due to the Ca(2+)-induced stiffening of a sarcomeric structure identifiable with titin. PMID- 25298424 TI - The role of proteases in excitation-contraction coupling failure in muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is one of the most frequent types of muscular dystrophy. Alterations in intracellular calcium (Ca(2+)) handling are thought to contribute to the disease severity in DMD, possibly due to the activation of Ca(2+)-activated proteases. The purpose of this study was twofold: 1) to determine whether prolonged excitation-contraction (E-C) coupling disruption following repeated contractions is greater in animals lacking both dystrophin and utrophin (mdx/Utr(-/-)) compared with mice lacking only dystrophin (mdx); and 2) to assess whether protease inhibition can prevent E-C coupling failure following repeated tetani in these dystrophic mouse models. Excitation-contraction coupling was assessed using Fura-2 ratio, as an index of intracellular free Ca(2+) concentration, in response to electrical stimulation of single muscle fibers from the flexor digitorum brevis muscle. Resting Fura-2 ratio was higher in dystrophic compared with control (Con) fibers, but peak Fura-2 ratios during stimulation were similar in dystrophic and Con fibers. One hour after a series of repeated tetani, peak Fura-2 ratios were reduced by 30 +/- 5.6%, 23 +/- 2%, and 36 +/- 3.1% in mdx, mdx/Utr(+/-), and mdx/Utr(-/-), respectively, with the greatest reduction in mdx/Utr(-/-) fibers (P < 0.05). Protease inhibition attenuated this decrease in peak Fura-2 ratio. These data indicate that E-C coupling impairment after repeated contractions is greatest in fibers lacking both dystrophin and utrophin and that prevention of protease activation can mitigate the prolonged E C coupling impairment. These data further suggest that acute protease inhibition may be useful in reducing muscle weakness in DMD. PMID- 25298507 TI - Geographic atrophy and cardiovascular disease. PMID- 25298426 TI - Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. AB - Vascular aging has been implicated in the progression of diabetes and age-related cardiovascular disorders. Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of cytoprotective actions in addition to its glucose-lowering effect. The present study was undertaken to examine whether Exendin-4, a specific ligand for the GLP-1 receptor, could prevent angiotensin (ANG) II-induced premature senescence in vascular smooth muscle cells (VSMCs) and to determine the underlying mechanism involved. Senescence-associated beta-galactosidase (SA beta gal) assay showed that ANG II induced premature senescence of VSMCs. Pretreatment with Exendin-4 significantly attenuated ANG II-induced generation of H2O2 and the subsequent VSMC senescence. These effects were, however, reversed in the presence of exendin fragment 9-39, a GLP-1 receptor antagonist, or PKI14-22. Moreover, a marked increase in the levels of p53 and p21 induced by ANG II was blunted by the treatment with Exendin-4. Nevertheless, Exendin-4 failed to decrease ANG II induced expression of NAD(P)H oxidase 1 (Nox1), NAD(P)H oxidase 4 (Nox4), p22(phox), or p47(phox) in VSMCs. Mechanistically, Exendin-4 blocked ANG II induced Rac1 activation through the cAMP/PKA signaling cascade. Specifically, NSC23766, a Rac1 inhibitor, abrogated the suppressive effects of Exendin-4 on ANG II-induced premature senescence and H2O2 generation, respectively. Thus Exendin-4 confers resistance to ANG II-induced superoxide anion generation from NAD(P)H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. These findings demonstrate that GLP-1 as well as its analogs (GLP-1-related reagents) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease. PMID- 25298508 TI - Author response: Geographic atrophy and cardiovascular disease. PMID- 25298509 TI - Does emmetropization need rods? PMID- 25298510 TI - Effectiveness of behavioural weight loss interventions delivered in a primary care setting: a systematic review and meta-analysis. AB - BACKGROUND: Overweight and obesity have negative health effects. Primary care clinicians are best placed to intervene in weight management. Previous reviews of weight loss interventions have included studies from specialist settings. The aim of this review was to estimate the effect of behavioural interventions delivered in primary care on body weight in overweight and obese adults. METHODS: The review included randomized controlled trials (RCTs) of behavioural interventions in obese or overweight adult participants in a primary care setting, with weight loss as the primary outcome, and a minimum of 12 months of follow-up. A systematic search strategy was implemented in Medline, Embase, Web of Science and the Cochrane Central Registry of Controlled Trials. Risk of bias was assessed using the Cochrane Risk of Bias tool and behavioural science components of interventions were evaluated. Data relating to weight loss in kilograms were extracted, and the results combined using meta-analysis. RESULTS: Fifteen RCTs, with 4539 participants randomized, were selected for inclusion. The studies were heterogeneous with respect to inclusion criteria and type of intervention. Few studies reported interventions informed by behavioural science theory. Pooled results from meta-analysis indicated a mean weight loss of -1.36 kg (-2.10 to 0.63, P < 0.0001) at 12 months, and -1.23 kg (-2.28 to -0.18, P = 0.002) at 24 months. CONCLUSION: Behavioural weight loss interventions in primary care yield very small reductions in body weight, which are unlikely to be clinically significant. More effective management strategies are needed for the treatment of overweight and obesity. PMID- 25298511 TI - Hypoxia-sensitive pathways in inflammation-driven fibrosis. AB - Tissue injury can occur for a variety of reasons, including physical damage, infection, and ischemia. The ability of tissues to effectively recover from injury is a cornerstone of human health. The healing response in tissues is conserved across organs and typically involves distinct but overlapping inflammatory, proliferative, and maturation/resolution phases. If the inflammatory phase is not successfully controlled and appropriately resolved, an excessive healing response characterized by scar formation can lead to tissue fibrosis, a major clinical complication in disorders such as Crohn's disease (CD). As a result of enhanced metabolic and inflammatory processes during chronic inflammation, profound changes in tissue oxygen levels occur leading to localized tissue hypoxia. Therefore, inflammation, fibrosis, and hypoxia are coincidental events during inflammation-driven fibrosis. Our current understanding of the mechanism(s) underpinning fibrosis is limited as are the therapeutic options available. In this review, we discuss what is known about the cellular and molecular mechanisms underpinning inflammation-driven fibrosis and how hypoxia may play a role in shaping this process. PMID- 25298512 TI - Gene expression and cellular localization of ROMKs in the gills and kidney of Mozambique tilapia acclimated to fresh water with high potassium concentration. AB - Regulation of plasma K(+) levels in narrow ranges is vital to vertebrate animals. Since seawater (SW) teleosts are loaded with excess K(+), they constantly excrete K(+) from the gills. However, the K(+) regulatory mechanisms in freshwater (FW) acclimated teleosts are still unclear. We aimed to identify the possible K(+) regulatory mechanisms in the gills and kidney, the two major osmoregulatory organs, of FW-acclimated Mozambique tilapia (Oreochromis mossambicus). As a potential molecular candidate for renal K(+) handling, a putative renal outer medullary K(+) channel (ROMK) was cloned from the tilapia kidney and tentatively named "ROMKb"; another ROMK previously cloned from the tilapia gills was thus renamed "ROMKa". The fish were acclimated to control FW or to high-K(+) (H-K) FW for 1 wk, and we assessed physiological responses of tilapia to H-K treatment. As a result, urinary K(+) levels were slightly higher in H-K fish, implying a role of the kidney in K(+) excretion. However, the mRNA expression levels of both ROMKa and ROMKb were very low in the kidney, while that of K(+)/Cl(-) cotransporter 1 (KCC1) was robust. In the gills, ROMKa mRNA was markedly upregulated in H-K fish. Immunofluorescence staining showed that branchial ROMKa was expressed at the apical membrane of type I and type III ionocytes, and the ROMKa immunosignals were more intense in H-K fish than in control fish. The present study suggests that branchial ROMKa takes a central role for K(+) regulation in FW conditions and that K(+) excretion via the gills is activated irrespective of environmental salinity. PMID- 25298513 TI - Reduced uterine perfusion pressure induces hypertension in the pregnant mouse. AB - Despite preeclampsia being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for its pathogenesis have yet to be fully elucidated. Growing evidence indicates that reduced uteroplacental perfusion and the resulting placental ischemia triggers the cascade of events leading to this maternal disorder. While the well established rat model of reduced uterine perfusion pressure (RUPP) is providing invaluable insight into the etiology of preeclampsia, the aim of this study was to develop a mouse model of reduced uterine perfusion to expand mechanistic investigation by incorporation with novel gene-targeted mice. To accomplish this aim, a sham surgical procedure or a restriction of blood flow at the abdominal aorta and the ovarian arteries was initiated at day 13 of gestation in C57BL/6J mice. Mean arterial pressure measured in conscious, chronically instrumented mice was significantly elevated in the RUPP (120 +/- 4 mmHg) compared with the sham (104 +/- 4 mmHg) mice at day 18 of gestation (P < 0.01). Placental ischemia reduced fetal weights (0.95 +/- 0.04 and 0.80 +/- 0.02 g; RUPP vs. Sham, respectively; P < 0.02) and increased circulating levels of antiangiogenic soluble fms-related tyrosine kinases (sFlt)-1 (P < 0.05) in the RUPP at day 18 of gestation. Plasma concentrations of sFlt-1 are increased in preeclamptic patients and in response to reduced uterine perfusion in the rat. Thus, these results suggest that the mouse model of reduced uterine perfusion is applicable to facilitate novel mechanistic investigation into the etiology of hypertension that results from placental ischemia during pregnancy. PMID- 25298514 TI - Leptin receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake. AB - Pontine parabrachial nucleus (PBN) neurons integrate visceral, oral, and other sensory information, playing an integral role in the neural control of feeding. Current experiments probed whether lateral PBN (lPBN) leptin receptor (LepRb) signaling contributes to this function. Intra-lPBN leptin microinjection significantly reduced cumulative chow intake, average meal size, and body weight in rats, independent of effects on locomotor activity or gastric emptying. In contrast to the effects observed following LepRb activation in other nuclei, lPBN LepRb stimulation did not affect progressive ratio responding for sucrose reward or conditioned place preference for a palatable food. Collectively, results suggest that lPBN LepRb activation reduces food intake by modulating the neural processing of meal size/satiation signaling, and highlight the lPBN as a novel site of action for leptin-mediated food intake control. PMID- 25298515 TI - Comment on: Comparison of oral amoxicillin given thrice or twice daily to children between 2 and 59 months old with non-severe pneumonia: a randomized controlled trial. PMID- 25298516 TI - A sensitive and reproducible in vivo imaging mouse model for evaluation of drugs against late-stage human African trypanosomiasis. AB - OBJECTIVES: To optimize the Trypanosoma brucei brucei GVR35 VSL-2 bioluminescent strain as an innovative drug evaluation model for late-stage human African trypanosomiasis. METHODS: An IVIS(r) Lumina II imaging system was used to detect bioluminescent T. b. brucei GVR35 parasites in mice to evaluate parasite localization and disease progression. Drug treatment was assessed using qualitative bioluminescence imaging and real-time quantitative PCR (qPCR). RESULTS: We have shown that drug dose-response can be evaluated using bioluminescence imaging and confirmed quantification of tissue parasite load using qPCR. The model was also able to detect drug relapse earlier than the traditional blood film detection and even in the absence of any detectable peripheral parasites. CONCLUSIONS: We have developed and optimized a new, efficient method to evaluate novel anti-trypanosomal drugs in vivo and reduce the current 180 day drug relapse experiment to a 90 day model. The non-invasive in vivo imaging model reduces the time required to assess preclinical efficacy of new anti-trypanosomal drugs. PMID- 25298517 TI - Efficacy of a reduced dose of darunavir/ritonavir in a cohort of antiretroviral naive and -experienced HIV-infected patients: a medium-term follow-up. PMID- 25298518 TI - Ectopic centromere nucleation by CENP--a in fission yeast. AB - The centromere is a specific chromosomal locus that organizes the assembly of the kinetochore. It plays a fundamental role in accurate chromosome segregation. In most eukaryotic organisms, each chromosome contains a single centromere the position and function of which are epigenetically specified. Occasionally, centromeres form at ectopic loci, which can be detrimental to the cell. However, the mechanisms that protect the cell against ectopic centromeres (neocentromeres) remain poorly understood. Centromere protein-A (CENP-A), a centromere-specific histone 3 (H3) variant, is found in all centromeres and is indispensable for centromere function. Here we report that the overexpression of CENP-A(Cnp1) in fission yeast results in the assembly of CENP-A(Cnp1) at noncentromeric chromatin during mitosis and meiosis. The noncentromeric CENP-A preferentially assembles near heterochromatin and is capable of recruiting kinetochore components. Consistent with this, cells overexpressing CENP-A(Cnp1) exhibit severe chromosome missegregation and spindle microtubule disorganization. In addition, pulse induction of CENP-A(Cnp1) overexpression reveals that ectopic CENP-A chromatin can persist for multiple generations. Intriguingly, ectopic assembly of CENP A(cnp1) is suppressed by overexpression of histone H3 or H4. Finally, we demonstrate that deletion of the N-terminal domain of CENP-A(cnp1) results in an increase in the number of ectopic CENP-A sites and provide evidence that the N terminal domain of CENP-A prevents CENP-A assembly at ectopic loci via the ubiquitin-dependent proteolysis. These studies expand our current understanding of how noncentromeric chromatin is protected from mistakenly assembling CENP-A. PMID- 25298519 TI - Quantitative genetic analysis indicates natural selection on leaf phenotypes across wild tomato species (Solanum sect. Lycopersicon; Solanaceae). AB - Adaptive evolution requires both raw genetic material and an accessible path of high fitness from one fitness peak to another. In this study, we used an introgression line (IL) population to map quantitative trait loci (QTL) for leaf traits thought to be associated with adaptation to precipitation in wild tomatoes (Solanum sect. Lycopersicon; Solanaceae). A QTL sign test showed that several traits likely evolved under directional natural selection. Leaf traits correlated across species do not share a common genetic basis, consistent with a scenario in which selection maintains trait covariation unconstrained by pleiotropy or linkage disequilibrium. Two large effect QTL for stomatal distribution colocalized with key genes in the stomatal development pathway, suggesting promising candidates for the molecular bases of adaptation in these species. Furthermore, macroevolutionary transitions between vastly different stomatal distributions may not be constrained when such large-effect mutations are available. Finally, genetic correlations between stomatal traits measured in this study and data on carbon isotope discrimination from the same ILs support a functional hypothesis that the distribution of stomata affects the resistance to CO2 diffusion inside the leaf, a trait implicated in climatic adaptation in wild tomatoes. Along with evidence from previous comparative and experimental studies, this analysis indicates that leaf traits are an important component of climatic niche adaptation in wild tomatoes and demonstrates that some trait transitions between species could have involved few, large-effect genetic changes, allowing rapid responses to new environmental conditions. PMID- 25298521 TI - Influence of chemical straightening on the stability of drugs of abuse in hair. AB - Chemical straightening, also known as a relaxer, is ubiquitously used among African American women to obtain straighter hair compared with their natural tresses. This study focused on the stability of drugs of abuse in hair after a single application of the relaxer. Commercially available 'Lye' or 'No-Lye' chemical straightening products (Silk ElementsTM) were applied in vitro to drug fortified hair (standard reference materials (SRM) 2379 and 2380) and hairs clipped from established drug users. Target analytes (cocaine (COC), benzoylecgonine (BZE), cocaethylene (CE), phencyclidine and tetrahydrocannabinol) were isolated using solid-phase extraction and then analyzed with isotope dilution gas chromatography-mass spectrometry with selective ion monitoring. After either treatment, drug concentrations were significantly (P < 0.05) decreased in both the SRM sample and the hair from authentic abusers. In the SRM groups, 6-67% of the original concentration remained after a single chemical treatment. Similarly, only 5-30% of the original concentration remained in authentic drug hairs that had formerly tested positive for COC, BZE and CE. PMID- 25298520 TI - Developmental defects in a Caenorhabditis elegans model for type III galactosemia. AB - Type III galactosemia is a metabolic disorder caused by reduced activity of UDP galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been hypothesized for humans, whereas a nonlethal partial loss-of function allele causes a variety of developmental abnormalities, likely resulting from the impairment of the glycosylation process. We also observed that gale-1 mutants are hypersensitive to galactose as well as to infections. Interestingly, we found interactions between gale-1 and the unfolded protein response. PMID- 25298522 TI - Children's Divorce and Parent-Child Contact: A Within-Family Analysis of Older European Parents. AB - OBJECTIVES: Studies have shown that a parental divorce has a negative effect on parent-child relations. This study examines how adult children's divorce affects the amount of contact children have with older parents, making a distinction between the effects of being single on the one hand and the effects of divorce on the other hand. METHOD: Using data on older adults in 11 European countries, I estimate within-family regression models to compare multiple adult children per parent (19,454 children aged 30-49; 10,476 parents aged 50-96). I analyze contact frequency while taking into account coresidence and distance. RESULTS: When comparing single divorced children and married children, no difference in contact is observed, but divorced children are more likely to live with their parents. When comparing among children who are single, divorced children have less frequent contact with parents than never-married children. This negative divorce effect exists for sons and daughters and is found in 9 of the 11 countries. DISCUSSION: The divorce of a child has a double meaning: it leads to being single, which is associated with stronger intergenerational ties, but it is also a non-normative and stressful life event, which is associated with weaker intergenerational ties. PMID- 25298523 TI - Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters. AB - Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 MUM. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na(+), K(+), or Cl(-) levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics. PMID- 25298524 TI - Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension. AB - Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng.kg(-1).min(-1) sc) for 6 wk or shams. RLX was administered (4 MUg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 +/- 5 vs. 135 +/- 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 +/- 6 vs. 41 +/- 4 mg.day(-1).100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects. PMID- 25298526 TI - Local pH domains regulate NHE3-mediated Na+ reabsorption in the renal proximal tubule. AB - The proximal tubule Na(+)/H(+) exchanger 3 (NHE3), located in the apical dense microvilli (brush border), plays a major role in the reabsorption of NaCl and water in the renal proximal tubule. In response to a rise in blood pressure NHE3 redistributes in the plane of the plasma membrane to the base of the brush border, where NHE3 activity is reduced. This NHE3 redistribution is assumed to provoke pressure natriuresis; however, it is unclear how NHE3 redistribution per se reduces NHE3 activity. To investigate if the distribution of NHE3 in the brush border can change the reabsorption rate, we constructed a spatiotemporal mathematical model of NHE3-mediated Na(+) reabsorption across a proximal tubule cell and compared the model results with in vivo experiments in rats. The model predicts that when NHE3 is localized exclusively at the base of the brush border, it creates local pH microdomains that reduce NHE3 activity by >30%. We tested the model's prediction experimentally: the rat kidney cortex was loaded with the pH sensitive fluorescent dye BCECF, and cells of the proximal tubule were imaged in vivo using confocal fluorescence microscopy before and after an increase of blood pressure by ~50 mmHg. The experimental results supported the model by demonstrating that a rise of blood pressure induces the development of pH microdomains near the bottom of the brush border. These local changes in pH reduce NHE3 activity, which may explain the pressure natriuresis response to NHE3 redistribution. PMID- 25298525 TI - Exocyst Sec10 protects renal tubule cells from injury by EGFR/MAPK activation and effects on endocytosis. AB - Acute kidney injury is common and has a high mortality rate, and no effective treatment exists other than supportive care. Using cell culture models, we previously demonstrated that exocyst Sec10 overexpression reduced damage to renal tubule cells and speeded recovery and that the protective effect was mediated by higher basal levels of mitogen-activated protein kinase (MAPK) signaling. The exocyst, a highly-conserved eight-protein complex, is known for regulating protein trafficking. Here we show that the exocyst biochemically interacts with the epidermal growth factor receptor (EGFR), which is upstream of MAPK, and Sec10 overexpressing cells express greater levels of phosphorylated (active) ERK, the final step in the MAPK pathway, in response to EGF stimulation. EGFR endocytosis, which has been linked to activation of the MAPK pathway, increases in Sec10 overexpressing cells, and gefitinib, a specific EGFR inhibitor, and Dynasore, a dynamin inhibitor, both reduce EGFR endocytosis. In turn, inhibition of the MAPK pathway reduces ligand-mediated EGFR endocytosis, suggesting a potential feedback of elevated ERK activity on EGFR endocytosis. Gefitinib also decreases MAPK signaling in Sec10-overexpressing cells to levels seen in control cells and, demonstrating a causal role for EGFR, reverses the protective effect of Sec10 overexpression following cell injury in vitro. Finally, using an in vivo zebrafish model of acute kidney injury, morpholino-induced knockdown of sec10 increases renal tubule cell susceptibility to injury. Taken together, these results suggest that the exocyst, acting through EGFR, endocytosis, and the MAPK pathway is a candidate therapeutic target for acute kidney injury. PMID- 25298527 TI - ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney. AB - Stress-activated kinases p38 MAPK and JNK promote renal fibrosis; however, how the pathways by which these kinases are activated in kidney disease remain poorly defined. Apoptosis signal-regulating kinase 1 (ASK1/MAPKKK5) is a member of the MAPKKK family that can induce activation of p38 and JNK. The present study examined whether ASK1 induces p38/JNK activation and renal fibrosis in unilateral ureteric obstruction (UUO) using wild-type (WT) and Ask1-deficient (Ask1(-/-)) mice. Basal p38 and JNK activation in WT kidneys was increased three- to fivefold in day 7 UUO mice in association with renal fibrosis. In contrast, there was no increase in p38 activation in Ask1(-/-) UUO mice, whereas JNK activation was only partially increased. The progressive increase in kidney collagen (hydroxyproline) content seen on days 7 and 12 of UUO in WT mice was significantly reduced in Ask1(-/-) UUO mice in association with reduced alpha-smooth muscle actin-positive myofibroblast accumulation. However, cultured WT and Ask1(-/-) renal fibroblasts showed equivalent proliferation and matrix production, indicating that ASK1 acts indirectly on fibroblasts. Tubular epithelial cells are the main site of p38 activation in the obstructed kidney. Angiotensin II and H2O2, but not IL-1 or lipopolysaccharide, induced p38 activation and upregulation of transforming growth factor-beta1, platelet-derived growth factor-B, and monocyte chemoattractant protein-1 production was suppressed in Ask1(-/-) tubular epithelial cells. In addition, macrophage accumulation was significantly inhibited in Ask1(-/-) UUO mice. In conclusion, ASK1 is an important upstream activator of p38 and JNK signaling in the obstructed kidney, and ASK1 is a potential therapeutic target in renal fibrosis. PMID- 25298529 TI - Cutting to the chase: taking the pulse of label-retaining cells in kidney. PMID- 25298528 TI - Simultaneous assessment of glomerular filtration and barrier function in live zebrafish. AB - The zebrafish pronephros is a well-established model to study glomerular development, structure, and function. A few methods have been described to evaluate glomerular barrier function in zebrafish larvae so far. However, there is a need to assess glomerular filtration as well. In the present study, we extended the available methods by simultaneously measuring the intravascular clearances of Alexa fluor 647-conjugated 10-kDa dextran and FITC-conjugated 500 kDa dextran as indicators of glomerular filtration and barrier function, respectively. After intravascular injection of the dextrans, mean fluorescence intensities of both dextrans were measured in the cardinal vein of living zebrafish (4 days postfertilization) by confocal microscopy over time. We demonstrated that injected 10-kDa dextran was rapidly cleared from the circulation, became visible in the lumen of the pronephric tubule, quickly accumulated in tubular cells, and was detectably excreted at the cloaca. In contrast, 500-kDa dextran could not be visualized in the tubule at any time point. To check whether alterations in glomerular function can be quantified by our method, we injected morpholino oligonucleotides (MOs) against zebrafish nonmuscle myosin heavy chain IIA (zMyh9) or apolipoprotein L1 (zApol1). While glomerular filtration was reduced in zebrafish nonmuscle myosin heavy chain IIA MO-injected larvae, glomerular barrier function remained intact. In contrast, in zebrafish apolipoprotein L1 MO-injected larvae, glomerular barrier function was compromised as 500-kDa dextran disappeared from the circulation and became visible in tubular cells. In summary, we present a novel method that allows to simultaneously assess glomerular filtration and barrier function in live zebrafish. PMID- 25298530 TI - Interventions to Increase Physical Activity Among Older Adults: A Meta-Analysis. AB - PURPOSE OF THE STUDY: To determine the overall effectiveness of interventions designed to increase physical activity (PA) behavior among community-dwelling older adults. DESIGN AND METHODS: Comprehensive literature searching identified eligible PA intervention studies among community-dwelling adults aged 65 and older, or sample mean age of 70. Diverse study characteristics were extracted and outcome data were duplicate coded. Overall mean effect sizes (ESs) were synthesized using a random-effects model. Heterogeneity of effects was analyzed using Q and I(2) statistics. Moderator analyses were conducted using meta analytic analogues of ANOVA and regression for dichotomous and continuous moderators, respectively. RESULTS: ESs were calculated from 13,829 primary study subjects. The overall mean ES for two-group posttest comparisons was 0.18 (95% CI 0.10-0.26, p < .001). This represents a difference of 620 steps/day or 73 min of PA/week between treatment and control groups. Significant moderators included the use of theory, how interventions were delivered, and cognitive plus behavioral type intervention components. Non-significant moderators include the type of interventionist, delivery setting, and various measures of intervention dose. IMPLICATIONS: PA interventions significantly improved PA behavior among community dwelling older adults. Effective PA interventions may be efficiently delivered using already available resources and personnel. Future PA intervention research should be theoretically based, incorporate more diverse subjects, and compare intervention delivery methods. PMID- 25298531 TI - Multivariate biophysical markers predictive of mesenchymal stromal cell multipotency. AB - The capacity to produce therapeutically relevant quantities of multipotent mesenchymal stromal cells (MSCs) via in vitro culture is a common prerequisite for stem cell-based therapies. Although culture expanded MSCs are widely studied and considered for therapeutic applications, it has remained challenging to identify a unique set of characteristics that enables robust identification and isolation of the multipotent stem cells. New means to describe and separate this rare cell type and its downstream progenitor cells within heterogeneous cell populations will contribute significantly to basic biological understanding and can potentially improve efficacy of stem and progenitor cell-based therapies. Here, we use multivariate biophysical analysis of culture-expanded, bone marrow derived MSCs, correlating these quantitative measures with biomolecular markers and in vitro and in vivo functionality. We find that, although no single biophysical property robustly predicts stem cell multipotency, there exists a unique and minimal set of three biophysical markers that together are predictive of multipotent subpopulations, in vitro and in vivo. Subpopulations of culture expanded stromal cells from both adult and fetal bone marrow that exhibit sufficiently small cell diameter, low cell stiffness, and high nuclear membrane fluctuations are highly clonogenic and also exhibit gene, protein, and functional signatures of multipotency. Further, we show that high-throughput inertial microfluidics enables efficient sorting of committed osteoprogenitor cells, as distinct from these mesenchymal stem cells, in adult bone marrow. Together, these results demonstrate novel methods and markers of stemness that facilitate physical isolation, study, and therapeutic use of culture-expanded, stromal cell subpopulations. PMID- 25298534 TI - Role of pendant proton relays and proton-coupled electron transfer on the hydrogen evolution reaction by nickel hangman porphyrins. AB - The hangman motif provides mechanistic insights into the role of pendant proton relays in governing proton-coupled electron transfer (PCET) involved in the hydrogen evolution reaction (HER). We now show improved HER activity of Ni compared with Co hangman porphyrins. Cyclic voltammogram data and simulations, together with computational studies using density functional theory, implicate a shift in electrokinetic zone between Co and Ni hangman porphyrins due to a change in the PCET mechanism. Unlike the Co hangman porphyrin, the Ni hangman porphyrin does not require reduction to the formally metal(0) species before protonation by weak acids in acetonitrile. We conclude that protonation likely occurs at the Ni(I) state followed by reduction, in a stepwise proton transfer-electron transfer pathway. Spectroelectrochemical and computational studies reveal that upon reduction of the Ni(II) compound, the first electron is transferred to a metal-based orbital, whereas the second electron is transferred to a molecular orbital on the porphyrin ring. PMID- 25298532 TI - Molecular basis of mycobacterial lipid antigen presentation by CD1c and its recognition by alphabeta T cells. AB - CD1c is a member of the group 1 CD1 family of proteins that are specialized for lipid antigen presentation. Despite high cell surface expression of CD1c on key antigen-presenting cells and the discovery of its mycobacterial lipid antigen presentation capability, the molecular basis of CD1c recognition by T cells is unknown. Here we present a comprehensive functional and molecular analysis of alphabeta T-cell receptor (TCR) recognition of CD1c presenting mycobacterial phosphomycoketide antigens. Our structure of CD1c with the mycobacterial phosphomycoketide (PM) shows similarities to that of CD1c-mannosyl-beta1 phosphomycoketide in that the A' pocket accommodates the mycoketide alkyl chain; however, the phosphate head-group of PM is shifted ~6 A in relation to that of mannosyl-beta1-PM. We also demonstrate a bona fide interaction between six human TCRs and CD1c-mycoketide complexes, measuring high to moderate affinities. The crystal structure of the DN6 TCR and mutagenic studies reveal a requirement of five complementarity determining region (CDR) loops for CD1c recognition. Furthermore, mutagenesis of CD1c reveals residues in both the alpha1 and alpha2 helices involved in TCR recognition, yet not entirely overlapping among the examined TCRs. Unlike patterns for MHC I, no archetypical binding footprint is predicted to be shared by CD1c-reactive TCRs, even when recognizing the same or similar antigens. PMID- 25298535 TI - Importance of the DNA "bond" in programmable nanoparticle crystallization. AB - If a solution of DNA-coated nanoparticles is allowed to crystallize, the thermodynamic structure can be predicted by a set of structural design rules analogous to Pauling's rules for ionic crystallization. The details of the crystallization process, however, have proved more difficult to characterize as they depend on a complex interplay of many factors. Here, we report that this crystallization process is dictated by the individual DNA bonds and that the effect of changing structural or environmental conditions can be understood by considering the effect of these parameters on free oligonucleotides. Specifically, we observed the reorganization of nanoparticle superlattices using time-resolved synchrotron small-angle X-ray scattering in systems with different DNA sequences, salt concentrations, and densities of DNA linkers on the surface of the nanoparticles. The agreement between bulk crystallization and the behavior of free oligonucleotides may bear important consequences for constructing novel classes of crystals and incorporating new interparticle bonds in a rational manner. PMID- 25298536 TI - An RNAi-based suppressor screen identifies interactors of the Myt1 ortholog of Caenorhabditis elegans. AB - Oocyte maturation in all species is controlled by a protein complex termed the maturation promoting factor (MPF). MPF comprises a cyclin-dependent kinase (CDK) and its partner cyclin, and it is regulated by dueling regulatory phosphorylation events on the CDK. In Caenorhabditis elegans, the Wee1/Myt1 ortholog WEE-1.3 provides the inhibitory phosphorylations on CDK-1 that keep MPF inactive and halt meiosis. Prior work has shown that depletion of WEE-1.3 in C. elegans results in precocious oocyte maturation in vivo and a highly penetrant infertility phenotype. This study sought to further define the precocious maturation phenotype and to identify novel interactors with WEE-1.3. We found that WEE-1.3 is expressed throughout the germline and in developing embryos in a perinuclear pattern, and demonstrated that oocytes in WEE-1.3-depleted germlines have begun to transcribe embryonic genes and exhibit inappropriate expression of proteins normally restricted to fertilized eggs. In addition, we performed an RNAi suppressor screen of the infertile phenotype to identify novel factors that, when co-depleted with WEE-1.3, restore fertility to these animals. We screened ~1900 essential genes by RNAi feeding and identified 44 (~2% of the tested genes) that are suppressors of the WEE-1.3 depletion phenotype. The suppressors include many previously unidentified players in the meiotic cell cycle and represent a pool of potential WEE-1.3 interacting proteins that function during C. elegans oocyte maturation and zygotic development. PMID- 25298537 TI - Fast and efficient Drosophila melanogaster gene knock-ins using MiMIC transposons. AB - Modern molecular genetics studies necessitate the manipulation of genes in their endogenous locus, but most of the current methodologies require an inefficient donor-dependent homologous recombination step to locally modify the genome. Here we describe a methodology to efficiently generate Drosophila knock-in alleles by capitalizing on the availability of numerous genomic MiMIC transposon insertions carrying recombinogenic attP sites. Our methodology entails the efficient PhiC31 mediated integration of a recombination cassette flanked by unique I-SceI and/or I-CreI restriction enzyme sites into an attP-site. These restriction enzyme sites allow for double-strand break-mediated removal of unwanted flanking transposon sequences, while leaving the desired genomic modifications or recombination cassettes. As a proof-of-principle, we mutated LRRK, tau, and sky by using different MiMIC elements. We replaced 6 kb of genomic DNA encompassing the tau locus and 35 kb encompassing the sky locus with a recombination cassette that permits easy integration of DNA at these loci and we also generated a functional LRRK(HA) knock in allele. Given that ~92% of the Drosophila genes are located within the vicinity (<35 kb) of a MiMIC element, our methodology enables the efficient manipulation of nearly every locus in the fruit fly genome without the need for inefficient donor-dependent homologous recombination events. PMID- 25298538 TI - Characterization of the lipopolysaccharide produced by Pasteurella multocida serovars 6, 7 and 16: identification of lipopolysaccharide genotypes L4 and L8. AB - Pasteurella multocida is an important veterinary pathogen that produces a wide range of lipopolysaccharide (LPS) structures, many of which mimic host glycoproteins. In this study, we complete our analysis of the LPS produced by the P. multocida Heddleston serovars by reporting the LPS structure and the LPS outer core biosynthesis loci of the type strains representing Heddleston serovars 6, 7 and 16. Genetic analysis revealed that the type strains representing serovars 6 and 7 share the same LPS outer core biosynthesis locus which we have designated LPS genotype L4. Comparative bioinformatic analysis revealed that although the serovar 16 type strain contained a different LPS locus, L8, there was a significant degree of nucleotide identity between the L4 and L8 loci. Structural analysis revealed that the LPS glycoforms produced by the L4 and L8 strains all contained the highly conserved inner core produced by all other P. multocida strains examined to date. The residues within the LPS outer core produced by the L4 and L8 strains were either Gal or derivatives of Gal; unlike all other P. multocida Heddleston type strains examined there are no heptosyltransferases encoded in the L4 and L8 outer core biosynthesis loci. The structure of the L4 LPS outer core produced by the serovar 6 type strain consisted of beta-Gal-(1-3) beta-N-acetylgalactosamine (GalNAc)-(1-4)-beta-GalNAc3OAc-(1-4)-alpha-GalNAc3OAc (1-3)-beta-Gal, whereas the serovar 7 type strain produced a highly truncated LPS outer core containing only a single beta-Gal residue. The structure of the L8 LPS outer core produced by the serovar 16 type strain consisted of beta-Gal-(1-3) beta-GalNAc-(1-4)-(alpha-GalNAc-(1-3)-)-alpha-GalNAc. PMID- 25298539 TI - Bone marrow Th17 TNFalpha cells induce osteoclast differentiation, and link bone destruction to IBD. AB - OBJECTIVE: Under both physiological and pathological conditions, bone volume is determined by the rate of bone formation by osteoblasts and bone resorption by osteoclasts. Excessive bone loss is a common complication of human IBD whose mechanisms are not yet completely understood. Despite the role of activated CD4(+) T cells in inflammatory bone loss, the nature of the T cell subsets involved in this process in vivo remains unknown. The aim of the present study was to identify the CD4(+) T cell subsets involved in the process of osteoclastogenesis in vivo, as well as their mechanism of action. DESIGN: CD4(+) T cells were studied in IL10-/- mice and Rag1-/- mice adoptively transferred with naive CD4(+)CD45RB(high) T cells, representing two well-characterised animal models of IBD and in patients with Crohn's disease. They were phenotypically and functionally characterised by flow cytometric and gene expression analysis, as well as in in vitro cocultures with osteoclast precursors. RESULTS: In mice, we identified bone marrow (BM) CD4(+) T cells producing interleukin (IL)-17 and tumour necrosis factor (TNF)-alpha as an osteoclastogenic T cell subset referred to as Th17 TNF-alpha(+) cells. During chronic inflammation, these cells migrate to the BM where they survive in an IL-7-dependent manner and where they promote the recruitment of inflammatory monocytes, the main osteoclast progenitors. A population equivalent to the Th17 TNF-alpha(+) cells was also detected in patients with Crohn's disease. CONCLUSIONS: Our results highlight the osteoclastogenic function of the Th17 TNF-alpha(+) cells that contribute to bone loss in vivo in IBD. PMID- 25298540 TI - Low-income residents in three states view Medicaid as equal to or better than private coverage, support expansion. AB - Expansion of Medicaid under the Affordable Care Act to millions of low-income adults has been controversial, yet little is known about what these Americans themselves think about Medicaid. We conducted a telephone survey in late 2013 of nearly 3,000 low-income adults in three Southern states--Arkansas, Kentucky, and Texas--that have adopted different approaches to the options for expansion. Nearly 80 percent of our sample in all three states favored Medicaid expansion, and approximately two-thirds of uninsured respondents said that they planned to apply for either Medicaid or subsidized private coverage in 2014. Yet awareness of their state's actual expansion plans was low. Most viewed having Medicaid as better than being uninsured and at least as good as private insurance in overall quality and affordability. While the debate over Medicaid expansion continues, support for expansion is strong among low-income adults, and the perceived quality of Medicaid coverage is high. PMID- 25298542 TI - The Prescription of the Morning-After Pill in a Berlin Emergency Department Over a Four-Year Period - User Profiles and Reasons for Use. AB - Questions: There are no current health care studies from Germany regarding the "morning-after pill". This paper will use routine data to analyse details regarding the users' profiles, reasons for using it and the utilisation of hospital outpatient facilities. Patient Collective and Methods: Retrospective analysis of all triage sheets in the emergency department of the Virchow Hospital Campus/Charite University Hospital, Berlin, over a four-year period from 2007 to 2010 that were coded with the ICD diagnosis Z30 (= contraception advice) and statistical processing of the associated administrative data. Results: 860 triage sheets were included in the analysis. The emergency department is used most frequently for the prescription of the "morning-after pill" at the weekend. The average age of the users was 25.1 years. The most common reason cited for needing emergency contraception was unprotected sexual intercourse, with the second-most common being "condom failure". Around half of the women attended the department within 12 hours of having unprotected sex. Less than 2 % (n = 14) of all women decided against a prescription of emergency contraceptive after counselling. Conclusions: The user profile and reasons for using emergency oral contraception correlate largely with the information contained in international literature. Although the "morning-after pill" is probably prescribed mainly in general practices in Germany, and despite the availability of new drugs with a permitted post-exposure interval of up to 120 hours after unprotected sex, there appears to still be a high demand for counselling and prescriptions of the "morning-after pill" in the context of the emergency department. PMID- 25298541 TI - RANK, RANKL and OPG Expression in Breast Cancer - Influence on Osseous Metastasis. AB - In women, malignant breast tumours are among the most common malignant diseases in Europe. In advanced breast cancer, the risk of bone metastasis increases to 65 75 %. The discovery of the physiological bone metabolism parameters RANK (receptor activator of nuclear factor-kappaB), RANKL (receptor activator of nuclear factor-kappaB ligand) and OPG (osteoprotegerin) as well as their pathophysiological involvement in bone-related diseases is the subject of new therapeutic strategies. The formation of osteolytic bone metastasis requires increased osteoclast activity. Activation of osteoclasts by excessive direct RANKL or reduced OPG expression of osseous metastatic tumour cells remains to be elucidated. More than 50 % of primary breast cancer cells express OPG and RANK, while RANKL could be detected only in 14-60 %. Increased OPG concentrations in the serum of patients with bone metastases have been shown in several studies, whereas the RANKL results are described in an opposite manner. The use of OPG as a biomarker for the detection of osteolytic bone metastases is not consistent and needs to be proved in further studies. Increased RANKL activity was found in diseases characterised by excessive bone loss and formed the basis of new therapeutic options. In several studies, a human monoclonal antibody to RANKL (denosumab) was investigated for the treatment of bone diseases. Denosumab is a promising therapeutic option due to its bone-protective effects. PMID- 25298543 TI - Child Abuse and Neglect: Screening for Risks During the Perinatal Period. AB - Purpose: Currently, there is a claim for earlier interventions for families in order to prevent child maltreatment. Here, a screening instrument to assess risk indicators for child abuse and neglect already in the context of maternity clinics is introduced. The present study is the first report on the psychometric properties of this instrument, the "short questionnaire for risk indices around birth" (RIAB). Material and Methods: Data were collected in the context of three different studies conducted at Ulm University Hospital. To examine interrater reliability eight case vignettes were rated by n = 90 study participants (50 students and 40 experts working at a maternity clinic). Criterion validity was examined in two studies applying the German version of the child abuse potential inventory CAPI (n = 96 families at risk and n = 160 additional families). Results: Both laymen and experts were able to understand and use the screening instrument correctly, leading to a high agreement with the sample solutions given. A high concordance was found between parents' and experts' ratings: In case of no reported risk factors applying the screening instrument RIAB, parents themselves reported significantly less stressors and burdens, compared to those parents with an indication for a thorough examination as pointed out in the RIAB. Conclusion: In the context of maternity clinics the RIAB is a useful, broadly applicable instrument, screening for existing risk factors at the earliest and thus allowing for the initiation of specific interventions when needed. PMID- 25298544 TI - Career and Family - Are They Compatible?: Results of a Survey of Male and Female Gynaecologists in Germany. AB - Purpose: Nowadays, most gynaecologists are female and the compatibility of job related career and family life is an upcoming issue. The working group "Gender and Career" of the German Society for Gynaecology and Obstetrics (DGGG) designed a survey to reflect the present situation with a focus on the compatibility of career and family. Material and Methods: A web-based 74-item survey was filled out by members of the DGGG. In total, there were 1037 replies, 75 % female (n = 775) and 25 % male (n = 261) gynaecologists. Results: 62 % of the female and 80 % of the male respondents had already finished their doctoral theses and 2 % female and 13 % male had finished their PhD. Mean number of children was 1.06 (SD 1.08) in female and 1.68 (SD 1.34) in male gynaecologists. The majority of females desired day care for their children, but only 5 to 13 % of employers offer any day care. 88 % of the female and 72 % of the male physicians think that job related career and family are not compatible. Conclusion: The majority of female gynaecologists wished to have professional child care, but most employers or other institutions do not offer this. This might be one of the reasons why career and family appear incompatible. PMID- 25298545 TI - Pilot Study on the Detection of Simulated Lesions Using a 2D and 3D Digital Full Field Mammography System with a Newly Developed High Resolution Detector Based on Two Shifts of a-Se. AB - Purpose: Experimental study of a new system for digital 2D and 3D full-field mammography (FFDM) using a high resolution detector based on two shifts of a-Se. Material and Methods: Images were acquired using the new FFDM system Amulet(r) (FujiFilm, Tokio, Japan), an a-Se detector (receptor 24 * 30 cm2, pixel size 50 um, memory depth 12 bit, spatial resolution 10 lp/mm, DQE > 0.50). Integrated in the detector is a new method for data transfer, based on optical switch technology. The object of investigation was the Wisconsin Mammographic Random Phantom, Model 152A (Radiation Measurement Inc., Middleton, WI, USA) and the same parameters and exposure data (Tungsten, 100 mAs, 30 kV) were consistently used. We acquired 3 different pairs of images in the c-c and ml planes (2D) and in the c-c and c-c planes with an angle of 4 degrees (3D). Five radiologists experienced in mammography (experience ranging from 3 months to more than 5 years) analyzed the images (monitoring) which had been randomly encoded (random generator) with regard to the recognition of details such as specks of aluminum oxide (200-740 um), nylon fibers (0.4-1.6 mm) and round lesions/masses (diameters 5-14 mm), using special linear glasses for 3D visualization, and compared the results. Results: A total of 225 correct positive decisions could be detected: we found 222 (98.7 %) correct positive results for 2D and 3D visualization in each case. Conclusion: The results of this phantom study showed the same detection rates for both 2D and 3D imaging using full field digital mammography. Our results must be confirmed in further clinical trials. PMID- 25298546 TI - Rare Benign Entities of the Breast - Myoid Hamartoma and Capillary Hemangioma. AB - Hamartomas can occur in different areas of the breast, but they are rarely found in the breast. Myoid hamartomas with smooth muscle cells of the type described here are particularly unusual. The pathogenesis of this benign entity with its tendency to growth and recurrence is not clear. Excision is the therapy of choice. Capillary hemangiomas are rare vascular malformations of the breast which, in contrast to cavernous hemangiomas, usually remain clinically occult. It is important to differentiate these benign findings from malignant angiosarcoma. The possible heterogeneities between myoid hamartoma and capillary hemangioma using current breast imaging methods for the differential diagnosis (high resolution ultrasound, duplex sonography, shear wave elastography, digital mammography, minimally invasive intervention) are discussed together with an overview of the literature. PMID- 25298547 TI - GOVERNING HEALTH. PMID- 25298548 TI - Medical subject headings (MeSH) terms. PMID- 25298550 TI - Misconceptions about the three point bony relationship of the elbow. AB - INTRODUCTION: The 3 bony point relationship of the elbow is an important surface evaluation done in all cases of elbow pathology; its importance is highlighted by the fact that significant emphasis is also laid on this during the specialty board examinations. Confusion about the exact inter relationship exists even in the standard orthopaedic books, with various authors labeling it as isosceles, equilateral or a different triangle, without any citation to back this statement. MATERIALS AND METHODS: The knowledge of the three bony points relationship in elbow was verified after a survey of orthopaedic surgeons undertaken by the senior author, produced disparate answers. Most (63%) classified this as an isosceles triangle. To clarify this further, 200 elbows were prospectively evaluated to measure the distances between these points and the angles were calculated. CONCLUSION: Our observations indicate that this triangle is neither isosceles, nor equilateral, but a scalene triangle of unequal sides. There may even be a minimal difference in the 2 sides of the same individual, which has the potential to complicate routine comparison of the two elbows during examination. RESULTS: The analysis of data revealed that all surgeons were aware of the three bony points relationship; however 21 of the 179 (mostly senior surgeons) did not give too much importance to this evaluation in daily clinical practice. Nine surgeons were not sure what type of triangle was formed, 17 thought it was an equilateral triangle, 40 thought it was some other type of triangle while 113 (63%) thought these points formed an isosceles triangle. This is a reflection of the disparity in the perception about this triangle in the orthopaedic community in general. PMID- 25298549 TI - Understanding risks and complications in the management of ankle fractures. AB - Ankle fracture (AF) is a common injury with potentially significant morbidity associated with it. The most common age groups affected are young active patients, sustaining high energy trauma and elderly patients with comorbidities. Both these groups pose unique challenges for appropriate management of these injuries. Young patients are at risk of developing posttraumatic osteoarthritis, with a significant impact on quality of life due to pain and impaired function. Elderly patients, especially with poorly controlled diabetes and osteoporosis are at increased risk of wound complications, infection and failure of fixation. In the most severe cases, this can lead to amputation and mortality. Therefore, individualized approach to the management of AF is vital. This article highlights commonly encountered complications and discusses the measures needed to minimize them when dealing with these injuries. PMID- 25298551 TI - Outcome of surgical management of developmental dysplasia of hip in children between 18 and 24 months. AB - BACKGROUND: Developmental dysplasia of hip (DDH) is a common condition presenting to a pediatric orthopedic surgeon. There is a consensus on the surgical treatment of children with ages ranged from 18 to 24 months where majority agree on open reduction and hip spica. Open reduction was done with an additional pelvic procedure wherever required to get better results and prevent residual acetabular dysplasia (RAD) and early osteoarthritis. MATERIALS AND METHODS: 35 children with unilateral DDH were operated between 2002 and 2007 at our institute. Open reduction was performed in all using the standard anterior approach and peroperative test for hip stability was done. Nine children got an additional pelvic procedure in the form of Dega acetabuloplasty. All were followed up for a minimal period of 2 years (range 2-7 years). RESULTS: No hip got redislocated. At the end of 18 months, there were seven cases of RAD with acetabular index (AI) of 35 degrees and above. These were all from the group where open reduction alone was done. CONCLUSION: We feel that a preoperative AI of >40 degrees and a per operative safe-zone <20 degrees increases the need for supplementary pelvic osteotomy in age group of 18 to 24 months because in such cases, the remodeling capacity of the acetabulum is unable to overcome the dysplasia and to form a relatively normal acetabulum. PMID- 25298552 TI - Tuberculosis of the hip in children: A retrospective analysis of 27 patients. AB - BACKGROUND: We retrospectively evaluated the pretreatment radiological presentation and the clinicoradiological outcome at the completion of 1 year chemotherapy in osteoarticular tuberculosis of hip in children to prognosticate correlation between them. MATERIALS AND METHODS: We retrospectively analyzed the clinical and plain radiographic findings in 27 patients with an age of 12 years or younger in whom hip tuberculosis was diagnosed and treated between 2006 and 2010. The diagnosis was based on histopathology in 14 and clinicoradiological basis in 13 patients. The pre and post treatment plain radiographs were evaluated according to Shanmugasundaram radiological classification and our observations regarding unclassified cases which were not fit in this classification were suggested. The functional outcome at the completion of chemotherapy was assessed using modified Moon's criteria. RESULTS: The male female ratio was 11:16. The left hip was involved more frequently than the right (17:10). The average age was 7.37 years (range, 2-12 years). In the pretreatment radiographs, 9 hips were normal, 6 traveling, 4 dislocating, 1 protrusio acetabuli, 3 atrophic and 4 unclassified types (3 triradiate; 1 pseudarthrosis coxae). There were no Perthes and mortar pestle at the initial presentation. Posttreatment, the types changed to 9 normal, 3 Perthes, 1 protrusio acetabuli, 1 atrophic, 4 mortar pestle and 9 unclassified types (3 triradiate, 3 pseudarthrosis coxae and 3 ankylosed). There were 37% excellent, 18.5% good, 26% fair and 18.5% poor results. The prognosis was best with initial "triradiate" and normal types and worst with posttreatment atrophic and "ankylosed" types. CONCLUSIONS: The Shanmugasundaram radiological types accurately predict prognosis only in normal types and "triradiate" pattern. The functional outcome is independent of radiological morphology of the hip in smaller children. PMID- 25298553 TI - Results of triple muscle (sartorius, tensor fascia latae and part of gluteus medius) pedicle bone grafting in neglected femoral neck fracture in physiologically active patients. AB - BACKGROUND: Femoral neck fractures are notorious for complications like avascular necrosis and nonunion. In developing countries, various factors such as illiteracy, low socioeconomic status, ignorance are responsible for the delay in surgery. Neglected fracture neck femur always poses a formidable challenge. The purpose of this study was to evaluate the results of triple muscle pedicle bone grafting using sartorius, tensor fasciae latae and part of gluteus medius in neglected femoral neck fracture. MATERIALS AND METHODS: This is a retrospective study with medical record of 50 patients, who were operated by open reduction, internal fixation along with muscle pedicle bone grafting by the anterior approach. After open reduction, two to three cancellous screws (6.5 mm) were used for internal fixation in all cases. A bony chunk of the whole anterior superior iliac spine of 1 cm thickness, 1 cm width and 4.5 cm length, taken from the iliac crest comprised of muscle pedicle of sartorius, tensor fascia latae and part of gluteus medius. Then the graft with all three muscles mobilized and put in the trough made over the anterior or anterosuperior aspect of the femoral head. The graft was fixed with one or two 4.5 mm self-tapping cortical screw in anterior to posterior direction. RESULTS: 14 patients were lost to followup. The results were based on 36 patients. We observed that in our series, there was union in 34, out of 36 (94.4%) patients. All patients were within the age group of 15-51 years (average 38 years) with displaced neglected femoral neck fracture of >=30 days. Mean time taken for full clinicoradiological union was 14 weeks (range-10-24 weeks). CONCLUSION: Triple muscle pedicle bone grafting gives satisfactory results for neglected femoral neck fracture in physiologically active patients. PMID- 25298554 TI - Computed tomographic evaluation of the proximal femur: A predictive classification in displaced femoral neck fracture management. AB - BACKGROUND: Femoral neck fracture is truly an enigma due to the high incidence of avascular necrosis and nonunion. Different methods have been described to determine the size of the femoral head fragment, as a small head has been said to be associated with poor outcome and nonunion due to inadequate implant purchase in the proximal fragment. These methods were two dimensional and were affected by radiography techniques, therefore did not determine true head size. Computed tomography (CT) is an important option to measure true head size as images can be obtained in three dimensions. Henceforth, we subjected patients to CT scan of hip in cases with displaced fracture neck of femur. The study aims to define the term small head or inadequate size femoral head" objectively for its prognostic significance. MATERIALS AND METHODS: 70 cases of displaced femoral neck fractures underwent CT scan preoperatively for proximal femoral geometric measurements of both hips. Dual energy X-ray absorptiometry scan was done in all cases. Patients were treated with either intertrochanteric osteotomy or lag screw osteosynthesis based on the size of the head fragment on plain radiographs. RESULTS: The average femoral head fragment volume was 57 cu cm (range 28.3-84.91 cu cm; standard deviation 14 cu cm). Proximal fragment volume of >43 cu cm was termed adequate size (type I) and of <=43 cu cm as small femoral head (type II). Fractures which united (n = 54) had a relatively large average head size (59 cu cm) when compared to fractures that did not (n = 16), which had a small average head size (49 cu cm) and this difference was statistically significant. In type I fractures union rate was comparable in both osteotomy and lag screw groups (P > 0.05). Lag screw fixation failed invariably, while osteotomy showed good results in type II fractures (P < 0.05). CONCLUSION: Computed tomography scan of the proximal femur is advisable for measuring true size of head fragment. An objective classification based on the femoral head size (type I and type II) is proposed. Osteosynthesis should be the preferred method of treatment in type I and osteotomy or prosthetic replacement is the method of choice for type II femoral neck fractures. PMID- 25298555 TI - Acetabular roof arc angles and anatomic biomechanical superior acetabular weight bearing area. AB - BACKGROUND: Acetabular fracture involves whether superior articular weight bearing area and stability of the hip are assessed by acetabular roof arc angles comprising medial, anterior and posterior. Many previous studies, based on clinical, biomechanics and anatomic superior articular surface of acetabulum showed different degrees of the angles. Anatomic biomechanical superior acetabular weight bearing area (ABSAWBA) of the femoral head can be identified as radiographic subchondral bone density at superior acetabular dome. The fracture passes through ABSAWBA creating traumatic hip arthritis. Therefore, acetabular roof arc angles of ABSAWBA were studied in order to find out that the most appropriate degrees of recommended acetabular roof arc angles in the previous studies had no ABSAWBA involvement. MATERIALS AND METHODS: ABSAWBA of femoral head was identified 68 acetabular fractures and 13 isolated pelvic fractures without unstable pelvic ring injury were enrolled. Acetabular roof arc angle was measured on anteroposterior, obturator and iliac oblique view radiographs of normal contralateral acetabulum using programmatic automation controller digital system and measurement tools. RESULTS: Average medial, anterior and posterior acetabular roof arc angles of the ABSAWBA of 94 normal acetabulum were 39.09 (7.41), 42.49 (8.15) and 55.26 (10.08) degrees, respectively. CONCLUSIONS: Less than 39 degrees , 42 degrees and 55 degrees of medial, anterior and posterior acetabular roof arc angles involve ABSAWBA of the femoral head. Application of the study results showed that 45 degrees , 45 degrees and 62 degrees from the previous studies are the most appropriate medial, anterior and posterior acetabular roof arc angles without involvement of the ABSAWBA respectively. PMID- 25298556 TI - Hip spica versus Rush pins for management of femoral diaphyseal fractures in children. AB - BACKGROUND: Femoral fractures are common in children between 2 and 12 years of age and 75% of the lesions affect the femoral shaft. Traction followed by a plaster cast is universally accepted as conservative treatment. We compared primary hip spica with closed reduction and fixation with retrogradely passed crossed Rush pins for diaphyseal femur fracture in children. The hypothesis was that Rush pin might provide better treatment with good clinical results in comparison with primary hip spica. MATERIALS AND METHODS: Fifty children with femoral fractures were evaluated; 25 of them underwent conservative treatment using immediate hip spica (group A) and 25 were treated with crossed retrograde Rush pins (group B). The patients ages ranged from 3 to 13 years (mean of 9 years). RESULTS: Mean duration of fracture union was 15 weeks in group A and 12 weeks in group B. Mean duration of weight bearing 14 weeks in group and 7 weeks in group B. Mean hospital stay was 4 days in group A and 8 days in group B. Mean followup period in group A was 16 months and group B was 17 months. Complications such as angulation, shortening, infection were compared. CONCLUSIONS: Closed reduction and internal fixation with crossed Rush pins was superior in terms of early weight bearing and restoration of normal anatomy. PMID- 25298557 TI - Ensuring precision in lower limb deformity correction through a combination of temporary external fixation followed by internal fixation: Results of a retrospective study. AB - BACKGROUND: It is important to plan preoperatively when contemplating internal fixation following deformity correction. Surgeons often find it difficult to retain the achieved correction till the end of internal fixation. To maintain precise correction we used hybrid technique which uses both external and internal fixation. The objective of the study was to evaluate the effectiveness of this hybrid technique in achieving and retaining desired correction. MATERIALS AND METHODS: In this retrospective study, we evaluated the magnitude of deformity with radiological parameters. We compared correction which was planned and correction which was achieved. The technique was used during surgery for corrective osteotomies. Before carrying out the osteotomy, rail fixator with two swivel clamps was applied. After osteotomy swivel clamps were loosened. Desired correction was achieved. While fixator held the fragments in corrected position, definitive internal fixation was carried out. External fixator was removed after completion of internal fixation. Position of mechanical axis ratio, mechanical lateral distal femoral angle and mechanical medial proximal tibial angle were measured before and 12 weeks after surgery. Student t-test was used to analyze the difference between correction which was planned and correction which was achieved. RESULTS: There was no statistical difference between the desired correction and the correction achieved. CONCLUSIONS: Temporary use of external fixator while correcting angular deformities of lower limb allows to achieve accurate correction. PMID- 25298558 TI - Medial patellofemoral ligament reconstruction in patellar instability. AB - BACKGROUND: Medial patellofemoral ligament (MPFL) is one of the major static medial stabilising structures of the patella. MPFL is most often damaged in patients with patellar instability. Reconstruction of MPFL is becoming a common surgical procedure in treating patellar instability. We hypothesised that MPFL reconstruction was adequate to treat patients with patellar instability if the tibial tubercle and the centre of the trochlear groove (TT-TG) value was less than 20 mm and without a dysplastic trochlea. MATERIALS AND METHODS: 30 patients matching our inclusion criteria and operated between April 2009 and May 2011 were included in the study. MPFL reconstruction was performed using gracilis tendon fixed with endobutton on the patellar side and bio absorbable interference screw or staple on the femoral side. Patients were followed up with subjective criteria, Kujala score and Lysholm score. RESULTS: The mean duration of followup was 25 months (range 14-38 months). The mean preoperative Kujala score was 47.5 and Lysholm score was 44.7. The mean postoperative Kujala score was 87 and Lysholm score was 88.06. None of the patients had redislocation. CONCLUSION: MPFL reconstruction using gracilis tendon gives excellent results in patients with patellar instability with no redislocations. Some patients may have persistence of apprehension. PMID- 25298559 TI - Commentary. PMID- 25298560 TI - Anterior tibial plateau fracture: An often missed injury. AB - BACKGROUND: In most classifications of tibial plateau fractures, including one used most widely-Schatzker classification, fractures are described as a combination of medial and lateral condyle, primarily in the sagittal plane. Coronal component of these fractures, affecting the posterior tibial condyle is now well recognized. What is not described is anterior coronal component of the fracture, what we are calling "anterior tibial condyle fracture". These fractures are often missed on routine antero-posterior and lateral knee X-rays due to an overlap between the fracture and the normal bone. MATERIALS AND METHODS: Eight cases of anterior tibial condyle fractures with posterior subluxation of the tibia, six of which were missed by the initial surgeon and two referred to us early, are described. Two of the six late cases and both the early ones were operated. Reconstruction of the anterior condyle and posterior cruciate ligament reconstruction was done. Primary outcome measures such as union of the fracture, residual flexion deformity, range of motion and stability were studied at the end of 6 months. RESULTS: All operated fractures united. There was no posterior sag in any. In those presenting late and were operated, the flexion deformity got corrected in all (average from 15 degrees to 0 degrees ) and mean flexion achieved was 100 degrees (range: 80-120 degrees ). In those presenting early and were operated, there was no flexion deformity at 6 months and a mean flexion achieved was 115 degrees (range: 100-130 degrees ). None of the operated patients had instability. CONCLUSION: This article attempts to highlight that this injury is often missed. They should be suspected, diagnosed early and treated by reconstruction of anterior condyle, posterior cruciate ligament reconstruction. PMID- 25298561 TI - Evaluation of characteristics and surgical outcomes in cervical spondylotic amyotrophy. AB - BACKGROUND: Cervical spondylotic amyotrophy (CSA) is a rare clinical syndrome resulting from cervical spondylosis. Surgical treatment includes anterior cervical decompression and fusion (ACDF), and laminoplasty with or without foraminotomy. Some studies indicate that ACDF is an effective method for treating CSA because anterior decompression with or without medial foraminotomy can completely eliminate anterior and/or anterolateral lesions. We retrospectively evaluated outcome of surgical outcome by anterior cervical decompression and fusion (ACDF). MATERIALS AND METHODS: 28 CSA patients, among whom 12 had proximal type CSA and 16 had distal type CSA, treated by ACDF, were evaluated clinicoradiologically. The improvement in atrophic muscle power was assessed by manual muscle testing (MMT) and the recovery rate of the patients was determined on the basis of the Japanese Orthopedic Association (JOA) scores. Patient satisfaction was also examined. RESULTS: The percentage of patients, who gained 1 or more grades of muscle power improvement, as determined by MMT, was 91.7% for those with proximal type CSA and 37.5% for those with distal type CSA (P < 0.01). The JOA score-based recovery rates of patients with proximal type and distal type CSA were 60.8% and 41.8%, respectively (P < 0.05). Patient satisfaction was 8.2 for those with proximal type CSA and 6.9 for those with distal type CSA (P < 0.01). A correlation was observed among the levels of improvement in muscle power, JOA score based recovery rate, patient satisfaction and course of disease (P < 0.05). CONCLUSION: ACDF can effectively improve the clinical function of patients with CSA and result in good patient satisfaction despite the surgical outcomes for distal type CSA being inferior to those for proximal type CSA. Course of disease is the fundamental factor that affects the surgical outcomes for CSA. We recommend that patients with CSA undergo surgical intervention as early as possible. PMID- 25298562 TI - Scapholunate interosseus ligament reconstruction on a cadaver: A technique. AB - BACKGROUND: Acute rupture of the scapholunate interosseus ligament is a relatively frequent occurrence which can be repaired primarily by direct suturing. However, patients are often seen a few weeks after injury when most of the ligament fibers have degenerated. This poses a challenge because direct repair can be difficult and long term results have not been satisfying. In the present study, a technique is presented to address this problem and its possible advantages are discussed. MATERIALS AND METHODS: A fresh frozen wrist cadaver specimen, thawed to room temperature, was used to carry out the procedure. The scapholunate joint was exposed through a dorsal approach and stabilized using two percutaneous Kirschner wires. Using a U shaped chisel, a groove along the scapholunate articular margin was created to accommodate a strip from the extensor retinaculum as a ligament plasty. This has been secured using six anchor sutures and several pictures taken during the procedure to expose the key steps. RESULTS: The ligamentoplasty presented in this article preserves most of the articular surface of proximal carpus and at the same time stabilizes the scapholunate joint. However, more in vivo research should be carried out to validate this treatment. CONCLUSION: The technique suggests a possible way to repair a ruptured scapholunate interosseus ligament that cannot be repaired primarily. Because osteointegration of the ligament strips is not possible in the present experiment, biomechanics of the construct cannot be fully tested. PMID- 25298563 TI - Epitheloid hemangioendothelioma of the subcutaneous tissues of a finger. AB - Epithelioid hemangioendotheliomas (EHEs) are known to have a variable malignant potential. EHEs are rarely seen in the hand and there is no consensus about their management. The options include excision, excision followed by adjuvant radiotherapy and amputation. In this paper, we report a case of EHE of a finger that was treated by excision. Although the tumor had ill-defined borders and there was histological evidence of tumor extension to all resection margins, no local recurrence or metastasis were noted during the 3 years of followup. The literature is reviewed and an argument is made that EHEs of the hand may have a more benign behavior compared with EHEs of the lower limbs and viscera. PMID- 25298564 TI - Irreducible, incarcerated vertical dislocation of patella into a Hoffa fracture. AB - Rotational dislocations of patella, which involve rotation of the patella around a horizontal or vertical axis are rare. These rotational dislocations of patella are difficult to reduce by close methods. These dislocations can have associated osteochondral and retinacular injury. We report a case of a 20-year-old male who presented with swelling and pain in the right knee following a motor cycle accident. Radiological evaluation using the computed tomography revealed a patellar dislocation with a concomitant Hoffa fracture. Patella was rotated around the vertical axis and was incarcerated into the Hoffa fracture. This is a very rare injury and first of its kind to be reported. The difficulties in diagnosis, mechanism of injury and management have been discussed. We feel closed reduction of such an injury is likely to fail and open reduction is recommended. PMID- 25298565 TI - Hydatid disease of spine: Multiple meticulous surgeries and a long term followup. AB - We present a long term followup (13 years) of spinal hydatid disease with multiple recurrences and intradural dissemination of the disease at the last followup. Intradural extension of the disease in our case was supposedly through the dural rent which has not been reported in English literature. An early followup of the same case has been reported previously by the authors. A 53 year old female came with progressive left leg pain and difficulty in walking since 2 months. On examination, she had grade four power of ankle and digit dorsiflexors (L4 and L5 myotomes) on the left side (Medical Research Council grade). There was no sensory loss, no myelopathy and sphincters were intact. Plain radiographs showed consolidation at D10-D11 (old operated levels) with stable anterior column and there were no implant related problems. Magnetic resonance imaging showed a cystic lesion at L3-L4, signal intensity same as of cerebrospinal fluid in T2 and T1, displacing the cauda equina roots. The proximal extent of the lesion could not be identified because of artifacts from previous stainless steel instrumentation. Computed tomography myelogram showed complete block at L3-L4 junction with "meniscus sign". This is the longest followup of hydatid disease of the spine that has ever been reported. Hydatid disease should always be included in the differential diagnosis of destructive or infectious lesions of the spine. Aggressive radical resection whenever possible and chemotherapy is the key to good results. Recurrence is known to occur even after that. Disease can have long remission periods. Possibility of intradural dissemination through dural injury is highly likely. Hence, it should always be repaired whenever possible. PMID- 25298566 TI - Klebsiella pneumoniae carrying bla NDM-1 gene in orthopedic practice. AB - Emergence and spread of carbapenemases in Enterobacteriaceae is a cause of concern worldwide, the latest threat being New Delhi metallo-beta-lactamase (NDM 1). This report is of an orthopedic case with fracture femur managed with internal fixation and bone grafting, who subsequently developed secondary infection with Klebsiella pneumoniae harboring bla NDM-1 gene. Minimum inhibitory concentration (MIC) of imipenem was >=8 MUg/ml by E-test, suggestive of carbapenemase production. Phenotypic and further genotypic detection confirmed the presence of bla NDM-1 gene. The isolate remained susceptible only to tigecycline, colistin, and polymyxin B. PMID- 25298567 TI - Primary total elbow arthroplasty. PMID- 25298568 TI - Author's reply. PMID- 25298569 TI - Classification of relapse pattern in clubfoot treated with Ponseti technique. PMID- 25298570 TI - Author's reply. PMID- 25298571 TI - Ecological Observations of Native Geocoris pallens and G. punctipes Populations in the Great Basin Desert of Southwestern Utah. AB - Big-eyed bugs (Geocoris spp. Fallen, Hemiptera: Lygaeidae) are ubiquitous, omnivorous insect predators whose plant feeding behavior raises the question of whether they benefit or harm plants. However, several studies have investigated both the potential of Geocoris spp. to serve as biological control agents in agriculture and their importance as agents of plant indirect defense in nature. These studies have demonstrated that Geocoris spp. effectively reduce herbivore populations and increase plant yield. Previous work has also indicated that Geocoris spp. respond to visual and olfactory cues when foraging and choosing their prey and that associative learning of prey and plant cues informs their foraging strategies. For these reasons, Geocoris spp. have become models for the study of tritrophic plant-herbivore-predator interactions. Here, we present detailed images and ecological observations of G. pallens Stal and G. punctipes (Say) native to the Great Basin Desert of southwestern Utah, including observations of their life histories and color morphs, dynamics of their predatory feeding behavior and prey choice over space and time, and novel aspects of Geocoris spp.'s relationships to their host plants. These observations open up new areas to be explored regarding the behavior of Geocoris spp. and their interactions with plant and herbivore populations. PMID- 25298572 TI - Four and half decades of Indian Journal of Pharmacology. PMID- 25298573 TI - A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model. AB - OBJECTIVE: Experimental pain models in human healthy volunteers are advantageous for early evaluation of analgesics. All efforts to develop nonsteroidal anti inflammatory drugs (NSAIDs) which are devoid of gastrointestinal and cardiovascular system effects are still far from achieving a breakthrough. Hence we evaluated the analgesic activity of an ayurvedic drug, Boswellia serrata by using validated human pain models which has shown its analgesic activity both in vitro and preclinical studies to evaluate the analgesic activity of single oral dose (125 mg, 2 capsules) of Boswellia serrata compared to placebo using mechanical pain model in healthy human subjects. MATERIALS AND METHODS: After taking written informed consent, twelve healthy subjects were randomized (1:1) to receive single oral dose of Boswellia serrata (Shallaki ((r))) 125 mg, 2 capsules or identical placebo in a crossover design. Mechanical pain was assessed using Ugo basile analgesymeter (by Randall Selitto test) at baseline and at 1 hr, 2 hrs and 3 hrs after test drug administration. Pain Threshold force and time and Pain Tolerance force and time were evaluated. Statistical analysis was done by paired t-test. RESULTS: Twelve healthy volunteers have completed the study. Mean percentage change from baseline in Pain Threshold force and time with Boswellia serrata when compared to placebo had significantly increased [Force: 9.7 +/- 11.0 vs 2.9 +/- 3.4 (P = 0.05) and time: 9.7 +/- 10.7 vs 2.8 +/- 3.4 (P = 0.04)] at third hr. Mean Percentage change from baseline in Pain Tolerance force and time with Boswellia serrata when compared to placebo had significantly (P <= 0.01) increased at 1 hr, 2 hrs and 3 hrs. CONCLUSION: In the present study, Boswellia serrata significantly increased the Pain Threshold and Pain Tolerance force and time compared to placebo. Both study medications were well tolerated. Further multiple dose studies may be needed to establish the analgesic efficacy of the drug. PMID- 25298574 TI - Assessment of quality of prescribing in patients of hypertension at primary and secondary health care facilities using the Prescription Quality Index (PQI) tool. AB - OBJECTIVE: To determine the quality of prescribing in hypertension in primary and secondary health care settings using the Prescription Quality Index (PQI) tool and to assess the reliability of this tool. MATERIALS AND METHODS: An observational cross-sectional study was carried out for 6 months in order to assess quality of prescribing of antihypertensive drugs using Prescription Quality Index (PQI) at four primary (PHC) and two secondary (SHC) health care facilities. Patients attending these facilities for at least 3 months were included. Complete medical history and prescriptions received were noted. Total and criteria wise PQI scores were derived for each prescription. Prescriptions were categorized as poor (score of <=31), medium (score 32-33) and high quality (score 34-43) based on PQI total score. Psychometric analysis using factor analysis was carried out to assess reliability and validity. RESULTS: Total 73 hypertensive patients were included. Mean age was 61.2 +/- 11 years with 35 (48%) patients above 65 years of age. Total PQI score was 26 +/- 11. There was a significant difference in PQI score between PHC and SHC (P < 0.05) Out of 73 prescriptions, 43 (59%) were of poor quality with PQI score <31. The value of Cronbach's alpha for the entire 22 criteria of PQI was 0.71 suggesting good reliability of PQI tool in our setting. CONCLUSIONS: Based on PQI scores, quality of prescribing in hypertensive patients was poor, somewhat better in primary as compared to secondary health care facility. PQI is reliable for measuring prescribing quality in hypertension in Indian set up. PMID- 25298575 TI - Cost-effectiveness analysis of nebivolol and metoprolol in essential hypertension: a pharmacoeconomic comparison of antihypertensive efficacy of beta blockers. AB - OBJECTIVE: To estimate and compare the cost-effectiveness and safety of nebivolol with sustained-release metoprolol in reducing blood pressure by 1 mm of Hg per day in hypertensive patients. MATERIALS AND METHODS: This was a prospective, randomized, open label, observational analysis of cost-effectiveness, in a questionnaire-based fashion to compare the cost of nebivolol (2.5 mg, 5 mg, 10 mg) and sustained released metoprolol succinate (25 mg, 50 mg, 100 mg) in hypertensive patients using either of the two drugs. A total of 60 newly detected drug naive hypertensive patients were considered for the comparison, of which 30 patients were prescribed nebivolol and the other 30 were prescribed metoprolol succinate as per the recommended dosage. Based on the data, statistical analysis was carried out using GraphPad Prism 5 and MS Excel Spreadsheet 2007. RESULT: The cost of reducing 1 mm of Hg blood pressure per day with nebivolol was 0.60, 0.70, and 1.06 INR, whereas that of metoprolol succinate was 0.93, 1.18, and 1.25 INR at their respective equivalent doses, hence significantly lower with the nebivolol group as compared to the metoprolol group (P < 0.05). CONCLUSION: This pharmacoeconomic analysis shows that nebivolol is more cost-effective as compared to metoprolol when the cost per reduction in blood pressure per day is considered. This may affect the patients economically during their long-term use of these molecules for the treatment of hypertension. PMID- 25298576 TI - Supervised conventional interferon alpha2a in combination with ribavirin therapy is the preferred alternative for treatment of chronic hepatitis C. AB - OBJECTIVE: To document the significant sustained virological response with supervised conventional interferon alpha and ribavirin therapy in hepatitis C virus (HCV)-infected patients, this study was planned. MATERIALS AND METHODS: Sixty chronic hepatitis C naive patients were included in this study. Complete blood counts, prothrombin time, ALT, AST, and qualitative HCV RNA were done. Conventional interferon (INF) alpha2a, 3MIU, S.C and ribavirin 1000 mg PO was given as supervised therapy for 24 weeks in genotype 3 and 48 weeks in genotype 1 and 4 HCV patients. Qualitative HCV RNA was repeated at 12 weeks, 24 weeks for HCV infections with genotype 1, 2, 3 and 4, at 48 weeks for genotype 1 and 4, and thereafter 6 months after completion of treatment. End virological and sustained virological responses were observed. RESULTS: Out of 60 patients, 55 completed the study. Five patients were lost to follow-up. Overall SVR was seen in 47 patients (85.4%) and 4 patients had relapses. CONCLUSION: Significant sustained virological response rates were seen in patients with supervised conventional INF alpha2a and ribavirin therapy. PMID- 25298577 TI - Comparative cardiovascular safety of risperidone and olanzapine, based on electrocardiographic parameters and blood pressure: a prospective open label observational study. AB - OBJECTIVE: To assess the cardiovascular safety of two commonly prescribed atypical antipsychotics risperidone (RSP) and olanzapine (OZP) in schizophrenic patients, using electrocardiography (ECG) and Blood Pressure (BP). MATERIALS AND METHODS: This was a 10-week prospective open label, observational study, carried out in a newly diagnosed 64 schizophrenic patients receiving either RSP or OZP. RSP (n = 32) was started with dose of 2 mg/day and increased to 4 mg/day after 2 weeks, whereas OZP (n = 32) was started at a dose of 5 mg/day and was increased to 10 mg/day after 2 weeks. Heart rate (HR), ECG parameters (PR, RR, QRS, QT intervals and QTc and QTd) and BP (systolic and diastolic in supine and standing position) were recorded at baseline (before drug therapy)) and during follow-up visits at 2(I), 6(II) and 10(III) weeks. RESULTS: In the RSP group, at II and III follow-ups, a significant increase in the HR (P = 0.018, P = 0.011 respectively) as well as in QTc (P = 0.025, P = 0.015, respectively) was observed when compared to the basal values. In the OZP group, diastolic BP was significantly decreased in standing position at II and III follow-ups (P = 0.045 and P = 0.024, respectively) compared to the basal values. When the two groups were compared with each other, no significant differences were observed in the changes of HR, PR, QRS, QT, RR, QT, QTd and SBP (supine and standing position); and DBP (supine position). However, DBP in standing position showed a significant decrease in the OZP group at II and III follow-up (P = 0.036 and P = 0.016, respectively) compared to the RSP group. CONCLUSIONS: Patients treated with OZP are at higher risk to develop postural hypotension as compared with RSP; hence RSP could be better tolerated by patients taking antihypertensive drugs as compared with OZP whereas OZP would have a safer cardiac profile. PMID- 25298578 TI - Randomized controlled trial of effectiveness of lafutidine versus pantoprazole in uninvestigated dyspepsia. AB - OBJECTIVES: Lafutidine is a new H2-blocker in India claimed to be more potent and effective than existing H2-blockers. Proton pump inhibitors (PPIs), by virtue of their mechanism of action, have greater efficacy than H2-blockers in gastric acid suppression. However, clinical trials comparing H2-blockers directly with PPIs are limited. We carried out a head-to-head comparison of the effectiveness of lafutidine versus the PPI pantoprazole in uninvestigated dyspepsia [CTRI/2013/12/004261]. MATERIALS AND METHODS: A prospective, open label, randomized, controlled trial was conducted in a tertiary care hospital. Ambulatory adult patients with dyspepsia, not yet subjected to endoscopy, were recruited if they had at least moderately severe symptoms, defined as a score of >= 4 on a 7-point Global Overall Symptom (GOS) Scale. Those with alarm features or significant comorbidity were excluded. Subjects received either once daily lafutidine 10 mg or pantoprazole 40 mg, orally, for 8 weeks. Reflux, dysmotility and pain scores were assessed by Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSGERD), and quality of life (QoL) by SF-8 scale. The latter had physical and mental components summarized by physical component summary score (PCS) and a mental component summary score (MCS). RESULTS: Of 122 patients enrolled, data of 57 on lafutidine and 60 on pantoprazole were analyzed. At 4 weeks, proportion of subjects responding (GOS score <= 2) in the two arms (lafutidine 45.61% vs. pantoprazole 48.33%, P = 0.854) or showing symptom resolution (GOS score <= 1) (lafutidine 12.28% vs. pantoprazole 5.00%; P = 0.197) were comparable. Similarly at 8 weeks, both responder (lafutidine 52.63% vs. pantoprazole 56.67%; P = 0.712) and symptom resolution proportions (lafutidine 33.33% vs. pantoprazole 30%; P = 0.843) were comparable. Total score on mFSSGERD scale, as well as all its three component scores, and PCS and MCS scores on QoL SF-8 scale showed improvement but no statistically significant difference between the two arms. Tolerability of both drugs was excellent. CONCLUSIONS: Lafutidine is well-tolerated and there is no clinically worthwhile difference between the two drugs in the empirical treatment of uninvestigated dyspepsia. PMID- 25298579 TI - A study of use of fixed dose combinations in Ahmedabad, India. AB - OBJECTIVE: The aim of this study was to evaluate the pattern of fixed dose combinations (FDCs) in Ahmedabad, a city in western part of India. MATERIALS AND METHODS: Over a period of 24 months, prescriptions were collected from 24 pharmacy stores across 6 zones of Ahmedabad city. The information was recorded in pre-formed Data Record Form after written consent from the patients (or relative (s) of the patients). The pattern of use of FDC, rationality and seasonal variation in their use were analyzed. At the end of study, results were analyzed using Chi-square test. RESULTS: Out of the total 1170 prescriptions, 941 (80.3%) contained 1647 FDC formulations. The average number of FDCs prescribed was 1.41 +/- 1.04 (mean +/- SD). The FDCs were more frequently prescribed in the age group of 31 to 40 years (23.7%) and in males (54.4%). FDCs were most commonly prescribed by oral route (92.7%). As per drug category analysis, a higher number of FDCs containing nutritional supplements (20.2%), and those for CNS (18.1%) complaints were prescribed. A seasonal analysis showed that FDCs were commonly prescribed for respiratory complaints (23.4%), central nervous system (CNS) complaints (20.3%) and as nutritional supplements (22.4%) in winter, monsoon and summer months, respectively. Only 5.8%, 9.8% and 10.9% FDCs prescribed were included in WHO (2010), National (2011) and Gujarat State (2011) Essential Medicines Lists (EML), respectively (P < 0.0001). Irrational FDCs that are banned or FDCs containing irrational active ingredients were 1343 (81.5%) and 203 (12.3%), respectively. CONCLUSION: FDCs are widely prescribed with seasonal influence in their use. FDCs containing banned or controversial ingredients are prescribed widely. PMID- 25298580 TI - Effects of tongxinluo on the neointima formation and expression of inflammatory cytokines in rats after carotid artery balloon injury. AB - OBJECTIVE: Tongxinluo (TXL) is a traditional Chinese medicine (TCM). It is used to treat coronary heart disease and atherosclerosis. We investigated the effects of TXL on the neointima formation and expression of inflammatory cytokines in rats after carotid artery balloon injury. MATERIALS AND METHODS: Male Sprague Dawley rats were randomly divided into four groups: sham operation group (Sham, n = 15), balloon injury group treated with vehicle (Control, n = 15), TXL low-dose group treated with TXL of 0.5 g/kg/d (TXL-L, n = 15), and TXL high-dose group treated with TXL of 1.0 g/kg/d (TXL-H, n = 15). TXL was given by gavage daily. 14 days after injury', the levels of serum nitric oxide (NO), endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated. The morphology of carotid artery tissue was observed with hematoxylin-eosin staining. Expressions of MCP-1 and ICAM-1 in the artery were detected by real-time polymerase chain reaction (RT-PCR) and western blotting. RESULTS: 14 days after injury, a significant increase in concentrations of serum ET-1, MCP-1, and sICAM-1 (P < 0.05), as well as a significant decrease in NO serum level were observed in rats subjected to artery injury compared to the sham rats (P < 0.05). TXL significantly decreased ET-1, MCP-1 and sICAM-1 serum levels (P < 0.05), whereas significantly increased NO serum level compared with the control (P < 0.05). TXL significantly reduced the neointimal thickening at day14 after injury (P < 0.05). In addition, TXL significantly reduced mRNA and protein expressions of ICAM-1 and MCP-1 in injured artery (P < 0.05). CONCLUSIONS: This study demonstrates that TXL is effective in improving endothelial function, attenuating neointimal formation of artery after balloon injury, and reducing expression of inflammatory cytokine MCP-1 and ICAM-1. It may be a useful agent for protecting the artery against injury. PMID- 25298581 TI - Evaluation of antinociceptive effect of methanolic leaf and root extracts of Clitoria ternatea Linn. in rats. AB - AIM: Clitoria ternatea Linn. (C. ternatea) is an Ayurvedic herb traditionally used as medicine to relieve inflammatory, rheumatism, ear diseases, fever, arthritis, eye ailments, sore throat and body ache. This study aims to evaluate and elucidate the possible mechanism underlying the antinociceptive action of methanolic extracts of C. ternatea leaf and root using several antinociception models. MATERIALS AND METHODS: The different antinociception models such as hot plate, tail-flick and formalin tests were used along with naloxone (a non selective opioid antagonist) to establish the antinociceptive activity of both leaf and root extracts. RESULTS: Both C. ternatea leaf and root extracts markedly demonstrated antinociceptive action in experimental animals. Results of formalin test showed that the antinociceptive activity of the extracts may be mediated at both central and peripheral level. Moreover, the results of hot plate and tail flick tests further implies that C. ternatea root extract mediates antinociceptive activity centrally at supraspinal and spinal levels whereas, the C. ternatea leaf extract's antinociceptive activity is mediated centrally at supraspinal level only. It is believed that the opioid receptors are probably involved in antinociceptive activity of both C. ternatea root extract. CONCLUSIONS: Our studies support the traditional use of C. ternatea leaf and root against pain. The extracts can also be utilised as a new source of central analgesics in treatment of pain. PMID- 25298582 TI - Novel 2,5-disubstituted-1,3,4-oxadiazoles as anti-inflammatory drugs. AB - OBJECTIVE: 1,3,4-oxadiazole ring is a versatile moiety with a wide range of pharmacological properties. The present work deals with the synthesis and evaluation of the anti-inflammatory activity of two novel 2,5-disubstituted-1,3,4 oxadiazoles (OSD and OPD). MATERIALS AND METHODS: Carrageenan-induced rat hind paw edema was employed as an acute model of inflammation. For evaluating sub acute anti-inflammatory activity, carrageenan-induced inflammation in rat air pouch was employed. Complete Freund's adjuvant-induced arthritis in rats was used as a model of chronic inflammation. To evaluate in vitro anti-inflammatory activity, lipopolysaccharide (LPS)-stimulated RAW264.7 cells were used. RESULTS: OSD (100 mg/kg) reduced carrageen-induced paw edema by 60%, and OPD (100 mg/kg) produced a modest 32.5% reduction. OSD also reduced leukocyte influx and myeloperoxidase in carrageenan-induced rat air pouch model. In complete Freund's adjuvant-induced arthritis model, both OSD and OPD (200 mg/kg for 14 days) reduced paw edema and NO levels. In LPS-stimulated RAW264.7 cells, OSD and OPD inhibited formation of nitric oxide and reactive oxygen species, with OPD showing a better activity in comparison to OSD. CONCLUSIONS: OSD was the better of the two compounds in in vivo models of inflammation. The o-phenol substitution at position 2 of oxadiazole ring in OSD may be responsible for its better in vivo anti-inflammatory activity. The ability of the compounds to inhibit LPS-induced pro-inflammatory mediator release suggests an anti-inflammatory mechanism targeting LPS-TLR4-NF-kappaB signalling pathway, which needs to be explored in detail. The disparate efficacy in vitro and in vivo also requires in-depth evaluation of the pharmacokinetics of these novel oxadiazoles. PMID- 25298583 TI - Cardioprotective effect of ammonium glycyrrhizinate against doxorubicin-induced cardiomyopathy in experimental animals. AB - OBJECTIVE: The objective of this study was to evaluate the cardioprotective effect of herbal bioactive compound ammonium glycyrrhizinate against doxorubicin induced cardiomyopathy, in experimental animals. MATERIALS AND METHODS: Ammonium glycyrrhizinate (50, 100, 200 mg/kg, p.o.) was administered for four weeks in albino rats. Cardiomyopathy was induced with a dose of 2.5 mg/kg i.p. of doxorubicin on 1(th), 7(th), 14(th), 21(th), 28(th) day in the experimental animals. At the end of the experiment, on 29(th) day, serum and heart tissues were collected and hemodynamic, biochemical and histopathological studies were carried out. RESULTS: Administration of doxorubicin in normal rats showed significant (P < 0.001) changes in body weight, feed intake, urine output, hemodynamic parameters like (blood pressure, heart rate, cardiac output) and in lipid profile (cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, very low density lipoprotein) indicating cardiomyopathy symptoms. Animals treated with ammonium glycyrrhizinate significantly (P < 0.05) decreased triglyceride, cholesterol, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels. Moreover, high density lipoprotein (HDL) levels increased in rats treated with ammonium glycyrrhizinate as compared with the normal group. CONCLUSION: Ammonium glycyrrhizinate is effective in controlling serum lipid profile and cardiac complications in experimentally induced cardiomyopathy in animals. PMID- 25298584 TI - Chemopreventive potential of Apium leptophyllum (Pers.) against DMBA induced skin carcinogenesis model by modulatory influence on biochemical and antioxidant biomarkers in Swiss mice. AB - AIM: The study was designed to investigate the chemopreventive potential of flavonoidal fractions of Apium leptophyllum fruits (FFALF) on Swiss mice. MATERIALS AND METHODS: Skin tumor or papilloma was developed by topical application of DMBA (25 MUg in 0.1 ml acetone) on intrascapular region of mice, twice weekly for 8 weeks. The animals were divided into six groups: Group I (vehicle control); group II (FFALF control, 5 mg/kg); group III (carcinogenic control, DMBA treated initially for 8 weeks); and group IV, V and VI as pre treated group (FFALF 5, 10 and 20 mg/kg respectively for 16 weeks along with DMBA treatment). After the 16(th) week of treatment; the tumor morphology, skin histopathology, and biochemical and antioxidant biomarkers were measured and compared with carcinogenic control as well as vehicle control. RESULTS: The co administration of FFALF with DMBA-treated groups showed significant (P <= 0.001) prevention against skin papilloma and normalized the status of lipid peroxidation with antioxidant biomarkers in a dose-dependent manner as compared to carcinogenic control. CONCLUSIONS: Thus, the present study suggests that the FFALF is non-carcinogenic and has chemopreventive potential on DMBA-induced carcinogenesis in mouse, which may be due to the modulation of cutaneous lipid peroxidation or enhancement of total antioxidant capacity. PMID- 25298585 TI - Effect of various drugs used in conservative therapy of hepatorenal syndrome: a retrospective drug utilization study. AB - OBJECTIVES: To analyze the impact of various drugs used in conservative therapy on renal failure and mortality in hepatorenal syndrome (HRS) at a tertiary care teaching hospital. MATERIALS AND METHODS: Retrospective review of hospital admission records was conducted for case records with HRS as diagnosis. Demographic and clinical data and drug utilization pattern were collected in a pre-designed patient information sheet. Impact of various drugs especially hepatoprotector antioxidant, silymarin, on survival benefits in terms of number of patients alive, change in mean arterial pressure (MAP) and change in serum creatinine at the end of treatment period were estimated by univariate and followed by multivariate analysis. RESULTS: Of the total 89 case records, 31 met the eligibility criteria and were included in the analysis. On multivariate analysis, a significant correlation between use of intravenous fluids (IVFs) and survival benefits was observed (P < 0.05); wherein patients treated with IVFs had an increase in log odds of survival by 2.42 (95% CI = 1.06 to 121.13) as compared to patient not treated with IVF. However, MAP was not affected by any of the treatment modalities. While change in serum creatinine level was not significantly (P = 0.06, regression correlation = -0.3) correlated with duration of treatment with IVFs. CONCLUSION: Use of IVFs may be associated with better short-term survival benefits and favor HRS reversal. Use of silymarin as hepatoprotector antioxidant has no beneficial effects on HRS reversal or survival benefits. PMID- 25298586 TI - A prospective observational study to evaluate safety reporting of antidepressants at a tertiary care hospital in India. AB - OBJECTIVE: This prospective observational study was carried out to identify the prevalence and Severity of ADRs of antidepressant in a tertiary care teaching hospital. MATERIALS AND METHODS: Patients prescribed with at least one antidepressant were randomly selected and monitored for adverse drug reactions (ADRs), irrespective of their age and gender. RESULTS: Of the 401 patients who received antidepressants, 170 patients (42.39%) experienced 204 ADRs. Selective serotonin receptor inhibitors (SSRIs) [110 (53.92)] was the most common therapeutic class of drugs associated with ADRs. Gastrointestinal system [54 (26.47)] was most commonly affected system organ class. Dry mouth (n = 30) and diaphoresis (n = 21) were the most frequently reported ADRs. As assessed by the World Health organization (WHO) probability scale, 61% of the ADRs were 'probable' causality. Among all the ADRs, 22.54% (46) were preventable. Majority of the ADRs [(n = 184) 90.17%] were 'mild' in their severity. CONCLUSION: In this study, incidence of adverse reaction to antidepressants was 42.3% were the most common SSRI inplicated drug group for the ADRs. PMID- 25298587 TI - A rare debilitating neurological adverse effect of ranolazine due to drug interaction with clarithromycin. AB - Medication errors may occur at any point during patient care in the health care system. Drug interaction in known with macrolide antibiotics and ranolazine and is primarily related to effects on the cytochrome P4503A (CYP3A) metabolic pathway. This case highlights medication errors that resulted in rare debilitating neurological adverse effects of ranolazine in an elderly due to drug interaction with clarithromycin. PMID- 25298588 TI - CYP2C9*3 polymorphism presenting as lethal subdural hematoma with low-dose warfarin. AB - Warfarin is the most common and cheap oral anticoagulant currently used in clinical practice. A high inter-individual variation is seen in the response to warfarin. Recently, pharmacogenetics has gained importance in managing patients on warfarin, both in predicting the optimum required dose as well as in decreasing the risk of bleeding. This case report is a description of a 49-year old patient who had a lethal subdural hematoma with low-dose warfarin. He was subsequently found to have CYP2C9 gene polymorphism (*1/*3). This case report stresses the importance of pre-prescription assessment of genetic analysis for those initiated on warfarin. PMID- 25298589 TI - Symmetrical drug-related intertriginous and flexural exanthema due to ranitidine. AB - Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an adverse drug reaction which has been reported to be caused by various drugs. In this report, we describe a case induced by ranitidine, a drug which has not been previously reported to cause SDRIFE. PMID- 25298590 TI - Factor XI deficiency diagnosed following use of adalimumab. AB - Adalimumab is a drug used in the treatment of refractory psoriasis. We present a case of a 55-year-old male patient who developed petechiae and purpura after the ninth dose of adalimumab therapy. The results of laboratory investigations revealed factor XI (F.XI) deficiency. It should be recognized that F XI deficiency may develop in patients using long-term adalimumab, leading to increased risk of bleeding. PMID- 25298591 TI - Gastrointestinal bleed induced by a fixed dose combination of rabeprazole and diclofenac sodium. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause gastrointestinal (GI) bleed. Co-administration of proton pump inhibitors (PPIs) has been widely suggested as one of the strategies to prevent these GI complications among NSAIDs users. Herein, we present a case of severe GI bleeding in a patient taking fixed dose combination (FDC) of rabeprazole (20 mg) and diclofenac sodium (100 SR). PMID- 25298592 TI - Steven's Johnson syndrome with toxic epidermal necrolysis due to thalidomide in a case of multiple myeloma. AB - Thalidomide developed in 1954 for morning sickness had proven to be a teratogen and hence was withdrawn from market. Resurgence of thalidomide began as an immunomodulator when it was shown to be effective in the management of multiple myeloma and many conditions like erythema nodosum leprosum, graft versus host disease, recurrent aphthous ulcers etc. We report a case of Stevens Johnson syndrome-toxic epidermal necrolysis developing in an elderly male who was prescribed thalidomide after being diagnosed with multiple myeloma. PMID- 25298593 TI - Levetiracetam induced acute reversible psychosis in a patient with uncontrolled seizures. AB - Levetiracetam (LEV) is a relatively newer antiepileptic drug with novel mechanism of action. It was introduced to the market in the year 2000. Pre-marketing clinical trials of the drug reported good tolerability with a wide safety margin. On post-marketing updates, there are few reports of psychosis after treatment with the drug. Here, we report a case of 52-year-old epileptic man who developed acute, reversible psychosis within 3 days of initiation of treatment. The drug was prescribed at a dose of 500 mg per day. After 3 days of treatment, the patient developed visual hallucinations, mood swings, withdrawal and suspicious behavior. Delirium was ruled out as there was no fluctuation in his sensorium or focal neurological deficits. His lab investigations for electrolytes, renal function test, thyroid, liver function and other related tests levels were within normal limits. A diagnosis of LEV induced psychosis was reached based on clinical judgment and causality assessment. PMID- 25298594 TI - Aspirin potentiates blood glucose lowering effect of glimepiride-pioglitazone combination in streptozotocin-induced diabetic rats. PMID- 25298595 TI - Social pharmacology and diabetes. PMID- 25298596 TI - Stevens Johnson syndrome and neurotoxic effects of metronidazole. PMID- 25298597 TI - Author's reply: To PMID 24550598. PMID- 25298599 TI - A randomised controlled trial of opioid only versus combined opioid and non steroidal anti inflammatory analgesics for pain relief in the first 48 hours after Caesarean section. AB - BACKGROUND: Post-Caesarean section pain is complex in nature, requiring a combination of pharmacological and non-pharmacological methods. Effective management of postoperative pain will reduce postoperative morbidity, hospital stay and cost. The objective of this study was to compare the clinical effectiveness and adverse effects of a combination of non-selective cyclooxygenase (COX) inhibitor (Diclofenac sodium 50 mg) and opioid (Pentazocine 60 mg) to opiod only (Pentazocine 60 mg) for pain management after Caesarean section (CS) at Aminu Kano Teaching Hospital (AKTH). MATERIALS AND METHODS: This was a randomised double-blind controlled study conducted at AKTH, Kano, Nigeria. A total of 166 patients scheduled to undergo either emergency or elective Caesarean section were studied. Group I received a combination of COX inhibitor and opiod while Group II received opiod only for pain management after CS. RESULTS: The average age of the patients was 28.35 years (SD +/- 6.426) in the group I and 26.9(SD +/- 6.133) in group II. The mean parity was 3.27(SD +/- 2.67) and 2.75(SD +/- 2.14) while the mean gestational age at admission was 37.68(SD +/ 2.69) and 38.18(SD +/- 2.63) weeks in the first and second groups, respectively. Comparison of the level of pain experienced and patients satisfaction during the first 48 hours postoperatively revealed that the level of pain was statistically significantly less and patient's satisfaction significantly better in group I compared to group II (P-value 0.00001). CONCLUSION: The use of combined compared to single agent analgesia is safe, significantly reduced pain and improved patient satisfaction after a caesarian section (CS). PMID- 25298598 TI - The effect of light-activation sources on tooth bleaching. AB - Vital bleaching is one of the most requested cosmetic dental procedures asked by patients who seek a more pleasing smile. This procedure consists of carbamide or hydrogen peroxide gel applications that can be applied in-office or by the patient (at-home/overnight bleaching system). Some in-office treatments utilise whitening light with the objective of speeding up the whitening process. The objective of this article is to review and summarise the current literature with regard to the effect of light-activation sources on in-office tooth bleaching. A literature search was conducted using Medline, accessed via the National Library of Medicine Pub Med from 2003 to 2013 searching for articles relating to effectiveness of light activation sources on in-office tooth bleaching. This study found conflicting evidence on whether light truly improve tooth whitening. Other factors such as, type of stain, initial tooth colour and subject age which can influence tooth bleaching outcome were discussed. CONCLUSIONS: The use of light activator sources with in-office bleaching treatment of vital teeth did not increase the efficacy of bleaching or accelerate the bleaching. PMID- 25298600 TI - Value of the use of absolute lymphocyte as surrogate for CD4 count in resource poor situations. AB - BACKGROUND: The initiation of antiretroviral (ARV) drugs and monitoring of human immunodeficiency virus (HIV) treatment in developing nations such as sub-Sahara Africa is based on the clinical stage and level of CD4 count. Clinical stages can easily be determined using the World Health Organisation (WHO) criteria, this is not so with CD4 count where the right equipment and expertise are not easily available. This lead to various studies being carried out in search of surrogates for CD4 count with use of total lymphocyte count (TLC) being suggested by some studies. OBJECTIVE: In situation where determination of CD4 cell count is not available or feasible, lymphocyte count is believed to be one alternative method for immunological classification of Acquired Immunodeficiency Syndrome (AIDS). Such assumption may not be true of every population. The objective is, therefore, to examine the correlation between the absolute lymphocyte count and the CD4+ lymphocyte count in HIV positive patients. MATERIALS AND METHODS: One hundred and sixty-five consecutive HIV positive patients were recruited for the study before the commencement of ARV drugs over a period of 13 months. The haemotological parameters such as the CD4 count was done by flow cytometry using Partec cyflow counter machine made in Germany, with strict adherence to the manufacturer's standard operating procedure. TLC were also determined using Sysmex haematology blood analyser, following the manufacturer's standard operating procedure. Patients were then grouped into CD4 and Total lymphocyte (TLC) categories. These were then compared to determine if there is any correlation as shown in previous studies. Statistical analysis of data was done using Statistical Package for Social Sciences (SPSS) and statistical significance of data was based on P value of less than 0.05. There was significant positive correlation (P value 0.000) between TLC and CD4 count. RESULTS: Majority of the patients with TLC less than 1000/mm([3]) had CD4 count <200 cells/MUl. Using TLC <1000/mm([3]) threshold, there was high sensitivity of 81.8% but low specificity and positive predictive value of 47.5% and 19.4%, respectively, for CD4 count <200 cells/MUl. Further assessment using TLC of <1,200/mm([3]) for the currently accepted CD4 count cut off of <350 cells/MUl for initiation of antiretroviral drugs, the sensitivity, specificity, positive predictive value were found to be 76.5%, 26.7%, 21.3%, respectively. CONCLUSIONS: Considering the low specificity and positive predictive value, it was concluded that the use of TLC of as a surrogate for CD4 count is unreliable. However, where there is no alternative, it could be used with caution bearing in mind its limitations. PMID- 25298601 TI - The effect of preoperative intravenous paracetamol administration on postoperative fever in pediatrics cardiac surgery. AB - BACKGROUND: Post-operative fever is a common complication of cardiac operations, which is known to be correlated with a greater degree of cognitive dysfunction 6 weeks after cardiac surgery. The aim of the present study was to examine efficacy and safety of single dose intravenous Paracetamol in treatment of post-operative fever in children undergoing cardiac surgery. MATERIALS AND METHODS: In this randomised, double-blind, placebo-controlled clinical trial, 80 children, aged 1 12 years, presenting for open heart surgery were entered in the trial and randomly allocated into two groups: Placebo and Paracetamol. After induction of anaesthesia, 15 mg/kg intravenous Paracetamol solution was infused during 1 h in the Paracetamol group. Patients in placebo group received 15 mg/kg normal saline infusion during the same time. Since the end of operation until next 24 h in intensive care unit, axillary temperature of the two group patients was recorded in 4-h intervals. Any fever that occurred during this period had been treated with Paracetamol suppository (125 mg) and the amount of antipyretic drug consumption for each patient had been recorded. In order to examine the safety of Paracetamol, patients were evaluated for drug complication at the same time. RESULTS: Mean axillary temperature during first 24 h after operation was significantly lower in Paracetamol group compared with placebo group (P = 0.001). Overall fever incidence during 24 h after operation was higher in placebo group compared with Paracetamol group (P = 0.012). Of Paracetamol group patients, 42.5% compared with 15% of placebo group participants had no consumption of antipyretic agent (Paracetamol suppository) during 24 h after operation (P = 0.001). CONCLUSION: This study suggests that single dose administration of intravenous Paracetamol before paediatric cardiac surgeries using cardiopulmonary bypass; reduce mean body temperature in the first 24 h after operation. PMID- 25298602 TI - Hypertensive disorders in pregnancy among pregnant women in a Nigerian Teaching Hospital. AB - BACKGROUND: Hypertensive disorders in pregnancy (HDP) represent a group of conditions associated with high blood pressure during pregnancy. It is an important cause of feto-maternal morbidity and mortality, particularly in developing countries. The aims of the study were to find the prevalence of hypertensive disorders and its associated risk factors among women attending the antenatal clinic of Usmanu Danfodiyo University Teaching Hospital,(UDUTH) Sokoto. MATERIALS AND METHODS: A longitudinal study of 216 consecutively recruited women that were less than 20 weeks pregnant at booking was carried out. Blood pressure was measured for each woman at booking and at subsequent visits. Urinalysis was done at booking and whenever blood pressure was elevated. Patients were followed up to delivery and 6 weeks postpartum. Data entry and analysis was done using Statistical Analysis System (SAS) statistical package. RESULTS: The prevalence of HDP in the study was 17% while preeclampsia was 6%. Previous history of preeclampsia (P < 0.001; Relative risk (RR) 4.2; conficence interval (CI) 2.144 6.812), multiple gestation (P < 0.03; RR 3.8; CI 1.037-6.235), gestational diabetes (P < 0.02; RR 4.8; CI 1.910-6.751) and obesity (P < 0.002; RR 2.7; CI 1.373-5.511) were the significant risk factors in the development of HDP among the study population. CONCLUSION: The prevalence of HDP in the study group is high. Therefore, paying attention to the risk factors will ensure early detection and prevention of the progression of the disease and its sequelae. PMID- 25298603 TI - Contributing death factors in very low-birth-weight infants by path method analysis. AB - BACKGROUND: Neonatal deaths account for 40% of deaths under the age of 5 years worldwide. Therefore, efforts to achieve the UN Millennium Development Goal 4 of reducing childhood mortality by two-thirds by 2015 are focused on reducing neonatal deaths in high-mortality countries. The aim of present study was to determine death factors among very low-birth-weight infants by path method analysis. MATERIALS AND METHODS: In this study, medical records of 2,135 infants admitted between years 2008 and 2010 in neonatal intense care unit of Alzahra Educational-Medical centre (Tabriz, Iran) were analysed by path method using statistical software SPSS 18. RESULTS: Variables such as duration of hospitalisation, birth weight, gestational age have negative effect on infant mortality, and gestational blood pressure has positive direct effect on infant mortality that at whole represented 66.5% of infant mortality variance (F = 1018, P < 0.001). Gestational age termination in the positive form through birth weight, and also gestational blood pressure in negative form through hospitalisation period had indirect effect on infant mortality. CONCLUSION: The results of the study indicated that the duration of low-birth-weight infant's hospitalisation is also associated with infant's mortality (coefficient -0.7; P < 0.001). This study revealed that among the maternal factors only gestational blood pressure was in relationship with infants' mortality. PMID- 25298605 TI - Risk management assessment of Health Maintenance Organisations participating in the National Health Insurance Scheme. AB - BACKGROUND: The National Health Insurance Scheme (NHIS), operated majorly in Nigeria by health maintenance organisations (HMOs), took off formally in June 2005. In view of the inherent risks in the operation of any social health insurance, it is necessary to efficiently manage these risks for sustainability of the scheme. Consequently the risk-management strategies deployed by HMOs need regular assessment. This study assessed the risk management in the Nigeria social health insurance scheme among HMOs. MATERIALS AND METHODS: Cross-sectional survey of 33 HMOs participating in the NHIS. RESULTS: Utilisation of standard risk management strategies by the HMOs was 11 (52.6%). The other risk-management strategies not utilised in the NHIS 10 (47.4%) were risk equalisation and reinsurance. As high as 11 (52.4%) of participating HMOs had a weak enrollee base (less than 30,000 and poor monthly premium and these impacted negatively on the HMOs such that a large percentage 12 (54.1%) were unable to meet up with their financial obligations. Most of the HMOs 15 (71.4%) participated in the Millennium development goal (MDG) maternal and child health insurance programme. CONCLUSIONS: Weak enrollee base and poor monthly premium predisposed the HMOs to financial risk which impacted negatively on the overall performance in service delivery in the NHIS, further worsened by the non-utilisation of risk equalisation and reinsurance as risk-management strategies in the NHIS. There is need to make the scheme compulsory and introduce risk equalisation and reinsurance. PMID- 25298604 TI - Experience with percutaneous closure of ductus arteriosus using the Amplatzer duct occluder in 243 consecutive patients and long-term results-A single centre study. AB - BACKGROUND: Percutaneous closure of patent ductus arteriosus (PDA) with Amplatzer duct occluder (ADO) has become increasingly popular in many cardiovascular centres. This study analysed the long-term results of percutaneous closure of PDA with ADO in a single centre. MATERIALS AND METHODS: Between May 2004 and January 2013, 243 patients with median age of 2.5 years (range = 30 months to 38 years) and median weight of 10 Kg (range 4.5-80.5 Kg) underwent percutaneous closure of PDA using the ADO. The devices were implanted under fluoroscopic guidance. Patients were followed-up for any complications. RESULTS: The mean diameter of narrow part of PDA was 6.4 +/- 2.2 mm. The mean diameter of devices was 7.8 +/- 2.3 mm. The devices were successfully implanted in 239 (98.3%) cases. At immediate, 1 day, 1, 6, 12 months and late follow-up, the complete occlusion rate was 33% (79 case), 97.1% (236 case), 97.5% (237 case), 98.3% (238 case), 98.3% (238 case) and 98.3% (238 case), respectively. Residual shunt remained in one case at late follow-up. The device embolisation occurred in five patients. The devices were successful retrieved in three patient and second larger devices were inserted. Two other devices were surgically retrieved and PDAs were ligated. Moderate left pulmonary artery stenosis (LPA) in one child and mild LPA stenosis in one infant were detected. Mild aortic obstruction occurred in one infant. CONCLUSIONS: Long-term follow-up of patients indicate that percutaneous closure of PDA using ADO is a safe and effective procedure. However, some complications, including device embolisation, left pulmonary stenosis and aortic obstruction may be observed in some cases. PMID- 25298606 TI - Preterm delivery and low maternal serum cholesterol level: Any correlation? AB - BACKGROUND: The study assessed whether low maternal serum cholesterol during early pregnancy is associated with preterm delivery. PATIENTS AND METHODS: It was a prospective observational cohort study involving pregnant women at gestational age of 14-20 weeks over a period of 12 months. Blood samples were obtained to measure total serum cholesterol concentrations and the sera were then analysed enzymatically by the cholesterol oxidase: p-aminophenazone (CHOD PAP) method. RESULTS: The study showed an incidence of 5.0% for preterm delivery in the low risk study patients. Preterm birth was 4.83-times more common with low total maternal cholesterol than with midrange total cholesterol (11.8% versus 2.2%, P = 0.024). CONCLUSION: Low maternal serum cholesterol (hypocholesterolaemia) is associated with preterm delivery. Optimal maternal serum cholesterol during pregnancy may have merit, therefore pregnant women should be encouraged to follow a healthy, balanced diet. PMID- 25298607 TI - Communicating tobacco health risks: How effective are the warning labels on tobacco products? AB - BACKGROUND: Health hazards of tobacco are well known but only small numbers of tobacco users are fully aware of the harmful effects of tobacco. Warning labels on tobacco products are an effective way of communicating the consequences of tobacco use and bring about behavioural changes like quitting and reducing the tobacco consumption. So the present study was conducted to investigate the awareness and effectiveness of warning labels on tobacco products among health and non-healthcare professional of Barwala, Panchkula. MATERIALS AND METHODS: A descriptive cross-sectional survey was carried out among 408 subjects who were randomly selected from different professional colleges of Barwala, Panchkula. Data obtained were anlysed using descriptive statistics and Chi-square test using SPSS 20.0. RESULTS: Most of study participants has noticed the warnings on tobacco products and most of them believe that they could understand warning labels. More that 70% believe that warnings create awareness about health hazards of tobacco and help in reducing or quitting tobacco. Pictorial warning was found to be better as compared to text warning. Health professionals were able to assess pictorial warnings more correctly as compared to non-healthcare professionals. CONCLUSION: Warning labels on tobacco packs effectively inform people about adverse health effects of tobacco but the mandated warnings do not serve the desired purpose since they are not properly understood. PMID- 25298609 TI - Serum lipid profile and uric acid levels in preeclampsia in University of Benin Teaching Hospital. AB - BACKGROUND: Preeclampsia is a pregnancy-specific disease associated with significant maternal and perinatal mortality and morbidity. Lipid abnormality and elevated serum uric acid have been reported as early features of the disease. We aimed to detect the level of serum lipid profile and uric acid abnormalities in severe preeclamptics in Benin City and to measure their clinical significance. MATERIALS AND METHODS: A prospective case-control study was conducted with subjects presenting with severe preeclampsia to the Obstetric Unit of the UBTH, Benin City. Fasting serum lipid profile and uric acid levels of 40 severe preeclamptic subjects and 80 gestation-matched normotensive controls were done at recruitment. The preeclamptic subjects were managed according to our departmental protocol which included stabilisation and delivery. Their sociodemographic and clinical characteristics were used to generate a database for analysis. RESULTS: The mean serum uric acid level was 28% higher in severe preeclamptics than normotensive women (5.96 +/- 2.54 mg/dl versus 4.30 +/- 0.85; P = 0.005). There were statistically significant differences in levels of triglycerides (TG), low density lipoprotein (LDL) and high-density lipoprotein (HDL) between the preeclamptics and their normotensive controls (P = 0.006, P = 0.000, P = 0.000, respectively). Abnormal serum uric acid was associated with advanced maternal age (P = 0.000), early-onset preeclampsia (P = 0.000) and abnormal body mass index (BMI; P = 0.000). Low birth weight was more likely in preeclamptics with elevated serum uric acid levels (P = 0.041). CONCLUSION: Abnormality of serum uric acid in preeclampsia was significantly associated with increased frequency of complications but lipid profile abnormalities were not shown in the subjects studied. We recommend a larger scale study to determine lipid profile in normal and complicated pregnancies in our environment. PMID- 25298610 TI - Defective lipid metabolism in sickle cell anaemia subjects in vaso-occlusive crisis. AB - BACKGROUND: Abnormal lipid homeostasis has been reported in sickle cell anaemia (SCA) as well as in other haematological disorders. However, there is little information on the lipid profile of SCA subjects in vaso-occlusive crisis (VOC). This study determined the lipid profile of adult SCA subjects in VOC and in steady state (SSCA). MATERIALS AND METHODS: Fifty-eight (58) adults with HbSS (30 in steady state and 28 in vaso-occlusive crisis) and 24 age-matched healthy individuals with HbAA genotype were recruited into this study. Standard methods were used for the determination of blood pressure (BP), packed cell volume (PCV), total white blood cell count (WBC) and haemoglobin phenotype. After an overnight fast, 5 ml of venous blood was obtained from each SSCA and the controls while samples were collected upon admission in the VOC group. Plasma lipid profile was determined using enzymatic method. Differences between two groups were determined using independent Student's t-test or Man-Whitney U as appropriate. P-values less than 0.05 were considered significant. RESULTS: Plasma total cholesterol (TC) and high density lipoprotein (HDL) were significantly lower while the ratio of triglyceride (TG) to HDL (TG/HDL) was significantly higher in SSCA compared with the controls. Low density lipoprotein (LDL) and TC were significantly lower in SCA subjects in VOC compared with controls. However, TC, TG, LDL and TG/HDL were significantly lower while HDL was significantly higher in VOC compared with SSCA. CONCLUSION: Sickle cell anaemia subjects have defective fasting lipid metabolism which becomes pronounced with VOC. PMID- 25298608 TI - A cohort study to evaluate cardiovascular risk of selective and nonselective cyclooxygenase inhibitors (COX-Is) in arthritic patients attending orthopedic department of a tertiary care hospital. AB - BACKGROUND: Cyclooxygenase-2 inhibitors (COX-2-Is) have recently been concerned in the occurrence of adverse cardiovascular (CV) events. Rofecoxib and valdecoxib has been withdrawn from the market, but celecoxib, etoricoxib and parecoxib continues to be used. Other nonsteroidal anti-inflammatory drugs (NSAIDs) may also increase the risk of CV events. However, clinical trial databases for COX-2 Is had created lots of controversies regarding cardiovascular safety of selective and nonselective cyclooxygenase inhibitors (COX-Is). This study was, conducted to assess and compare the CV risk of COX-Is in arthritic patients over a period of time. MATERIALS AND METHODS: In this prospective cohort study adult arthritics of either sex those were freshly diagnosed or taking COX-Is for < 3 months; were included. Patients were grouped into nonselective and selective COX-2-I groups with reference to treatment they received. The CV risk factors like blood pressure (BP), blood sugar level (BSL), lipid profile, body mass index (BMI) were assessed and compared; demography of CV risk factors was also studied. Data obtained was analysed using Student's 't'-test of OpenEpi statistical software. RESULTS: Study clearly revealed that all NSAIDs exhibit variable CV risk; however, selective COX-2-Is found to exhibit more CV risk. BMI, BP and lipid profile; the potential CV risk factors, showed significant impairment in selective COX-2-Is group; P < 0.01, P < 0.001 and P < 0.05, respectively, compared to baseline and P < 0.05 vs. nonselective COX-Is for BMI. CONCLUSIONS: This study portrays the potential CV risk of selective COX-2-Is; confirms and re evaluate the results of earlier studies in this regard. PMID- 25298611 TI - Sclerosing stromal tumour of the ovary: A case report and the review of literature. AB - Sclerosing stromal tumours are rare benign ovarian neoplasms of the sex cord stromal that occur predominantly in the second and third decades of life. To date, 208 cases have been recorded in the literature. Most patients have menstrual irregularities and pelvic pain. Infertility and virilisation have also been described. In this article, histopathological features and differential diagnosis of the benign sclerosing stromal tumour were described together with the literature data. It is imperative to consider the differential diagnosis of a sclerozing stromal tumour of the ovary in a young woman with an ovarian tumour. A combination of morphological, immunohistochemical, radiological and clinical findings is needed in differentiating the tumour from thecoma, fibroma/fibrosarcoma, lipoid tumours and Krukenberg tumour. PMID- 25298612 TI - Incidental detection of microfilariae in a lymph node aspirate: A case report. AB - Lymphatic filariasis is a global health problem endemic in Nigeria. Peripheral blood smears are frequently negative for microfilariae in a significant number of infected patients in whom conventional diagnostic methods may also fail to identify the disease. In such cases, fine needle aspiration cytology may play an important role in disease identification. A 49-year-old South-western male Nigerian farmer, presented with a one-year history of a right groin swelling, which became painful 2 weeks before coming to the hospital. A clinical assessment of lymphogranuloma venereum was made to rule out a non-Hodgkin lymphoma. Initial laboratory investigations only showed mild eosinophilia and haematuria. However, fine needle aspiration cytology performed on the swelling showed microfilariae of Wuchereria bancrofti for which appropriate treatment was instituted with excellent outcome. This case demonstrates that lymphatic filariasis should be considered in the differential diagnosis of lymph node swellings in the groin and that aspiration cytology may play an important role in its diagnosis, especially in an endemic resource poor country. PMID- 25298613 TI - Assessment of attitude in KAP study: A comment on: A survey on doctors' knowledge and attitude of treating chronic pain in three tertiary hospitals in Nigeria. PMID- 25298614 TI - Percutaneous closure of atrial septal defect and persistent fossa ovalis: Nuances with implications. PMID- 25298615 TI - Inner Wellbeing: Concept and Validation of a New Approach to Subjective Perceptions of Wellbeing-India. AB - This paper describes the conceptual development of a multi-domain, psychosocial model of 'Inner Wellbeing' (IWB) and assesses the construct validity of the scale designed to measure it. IWB expresses what people think and feel they are able to be and do. Drawing together scholarship in wellbeing and international development it is grounded in field research in marginalised, rural communities in the global South. Results from research in India at two points in time (2011 and 2013) are reported. At Time 1 (n = 287), we were unable to confirm an eight factor, correlated model as distinct yet interrelated domains. However, at Time 2 (n = 335), we were able to confirm a revised, seven-factor correlated model with economic confidence, agency and participation, social connections, close relationships, physical and mental health, competence and self-worth, and values and meaning (five items per domain) as distinct yet interrelated domains. In particular, at Time 2, a seven-factor, correlated model provided a significantly better fit to the data than did a one-factor model. PMID- 25298616 TI - Evaluating capacity to live independently and safely in the community: Performance Assessment of Self-care Skills. AB - To determine clients' capacity for community living, occupational therapists must use measures that capture the person-task-environment transaction and compare clients' task performance to a performance standard. The Performance Assessment of Self-care Skills, a performance-based, criterion-referenced, observational tool, fulfills this purpose. In this practice analysis, using data from this tool from multiple clinical studies (N = 941), the authors describe tasks that clients from various diagnostic populations could and could not perform independently and safely. For clinicians, the Performance Assessment of Self-care Skills can be used to identify which daily tasks are compromised and the point of task breakdown, as well as to provide guidance about potential interventions. PMID- 25298617 TI - The Racial and Ethnic Identity Formation Process of Second-Generation Asian Indian Americans: A Phenomenological Study. AB - This phenomenological study elucidates the identity development processes of 12 second-generation adult Asian Indian Americans. The results identify salient sociocultural factors and multidimensional processes of racial and ethnic identity development. Discrimination, parental, and community factors seemed to play a salient role in influencing participants' racial and ethnic identity development. The emergent Asian Indian American racial and ethnic identity model provides a contextualized overview of key developmental periods and turning points within the process of identity development. PMID- 25298618 TI - The antioxidant profiles, lysosomal and membrane enzymes activity in patients with acute pancreatitis. AB - Oxidative stress and inflammatory mediators, such as IL-6, play an important role in the pathophysiology of acute pancreatitis. The study was aimed to assess the degree of the pro/antioxidative imbalance and estimate which antioxidant plays a role in the maintenance of pro/antioxidative balance during acute pancreatitis. The study was investigated in the blood of 32 patients with acute pancreatitis and 37 healthy subjects. IL-6 concentration as early marker of inflammation was determinated. The intensity of oxidative stress was assessed by TBARS concentration. To investigate antioxidative status, the GPx and Cu/Zn SOD activities and the levels of GSH, MT, SH groups, and TRAP were measured. The concentrations of Cu and Zn as ions participating in the maintenance of antioxidant enzymes stability and playing a role in the course of disease were determinated. The activities of GGT, AAP, NAG, and beta-GD as markers of tissue damage were also measured. An increase in IL-6 concentration, which correlated with Ranson criteria, and an increase in GPx activity, levels of MT, TBARS, or GGT, and NAG activities in patients group compared to healthy subjects were demonstrated. A decrease in GSH level in patients group compared to control group was noted. The studies suggest that GPx/GSH and MT play the role of the first line of defence against oxidative stress and pro/antioxidant imbalance in the course of acute pancreatitis. PMID- 25298620 TI - The dynamic roles played by a biochemist. PMID- 25298619 TI - MicroRNA-146a decreases high glucose/thrombin-induced endothelial inflammation by inhibiting NAPDH oxidase 4 expression. AB - Diabetes is associated with hyperglycemia and increased thrombin production. However, it is unknown whether a combination of high glucose and thrombin can modulate the expression of NAPDH oxidase (Nox) subtypes in human aortic endothelial cells (HAECs). Moreover, we investigated the role of a diabetes associated microRNA (miR-146a) in a diabetic atherothrombosis model. We showed that high glucose (HG) exerted a synergistic effect with thrombin to induce a 10.69-fold increase in Nox4 mRNA level in HAECs. Increased Nox4 mRNA expression was associated with increased Nox4 protein expression and ROS production. Inflammatory cytokine kit identified that the treatment increased IL-8 and IL-6 levels. Moreover, HG/thrombin treatment caused an 11.43-fold increase of THP-1 adhesion to HAECs. In silico analysis identified the homology between miR-146a and the 3'-untranslated region of the Nox4 mRNA, and a luciferase reporter assay confirmed that the miR-146a mimic bound to this Nox4 regulatory region. Additionally, miR-146a expression was decreased to 58% of that in the control, indicating impaired feedback restraint of HG/thrombin-induced endothelial inflammation. In contrast, miR-146a mimic transfection attenuated HG/thrombin induced upregulation of Nox4 expression, ROS generation, and inflammatory phenotypes. In conclusion, miR-146a is involved in the regulation of endothelial inflammation via modulation of Nox4 expression in a diabetic atherothrombosis model. PMID- 25298621 TI - Hydrogen breath tests in gastrointestinal diseases. AB - Hydrogen breath tests are widely used to explore pathophysiology of functional gastrointestinal (GI) disorders. Small intestinal bacterial overgrowth (SIBO) and carbohydrate malabsorption are disorders detected by these tests that have been proposed to be of great importance for symptoms of GI diseases. Glucose hydrogen breath test is more acceptable for diagnosis of SIBO whereas lactose and fructose hydrogen breath tests are used for detection of lactose and fructose maldigestion respectively. Lactulose hydrogen breath test is also used widely to measure the orocecal transit time for GI motility. These methods are noninvasive and inexpensive. Many patients with functional gut disorders are unaware of the relationship between diet and GI symptoms they present. In particular, patients with chronic symptoms may regard their condition as normal and may not be aware that their symptoms can be effectively managed following a proper diagnosis. Patients with symptoms of abdominal pain, bloating, flatulence and altered bowel movements (diarrhea and constipation), or with a medical diagnosis of irritable bowel syndrome or celiac disease, may have undiagnosed carbohydrate malabsorption or SIBO. Hydrogen breath tests are specific and sensitive diagnostic tests that can be used to either confirm or eliminate the possibility of carbohydrate malabsorption or SIBO in such patients. Breath tests, though valuable tools, are underutilized in evaluating dyspepsia and functional bloating and diarrhea as well as suspected malabsorption. However, because of their simplicity, reproducibility and safety of procedure they are now being substituted to more uncomfortable and expensive techniques that were traditionally used in gastroenterology. PMID- 25298622 TI - Immunoisolated transplantation of purified langerhans islet cells in testis cortex of male rats for treatment of streptozotocin induced diabetes mellitus. AB - The objective of this study is to induce experimental diabetes mellitus by streptozotocin in normal adult Wistar rats via comparison of changes in body weight, consumption of food, volume of water, urine and levels of glucose, insulin and C-peptide in serum, between normal and diabetic rats. Intra-venous injection of 60 mg/kg dose of streptozotocin in 250-300 g (75-90 days) adult Wistar rats makes pancreas swell and causes degeneration in Langerhans islet beta cells and induces experimental diabetes mellitus in 2-4 days. For a microscopic study of degeneration of Langerhans islet beta-cells of diabetic rats, biopsy from pancreas tissue of diabetic and normal rats, staining and comparison between them, were done. In this process, after collagenase digestion of pancreas, islets were isolated, dissociated and identified by dithizone method and then with enzymatic procedure by DNase and trypsin, the islet cells changed into single cells and beta-cells were identified by immune fluorescence method and then assayed by flow-cytometer. Donor tissue in each step of work was prepared from 38 adult male Wistar rats weighted 250-300 g (75-90 days). Transplantation was performed in rats after 2-4 weeks of diabetes induction. In this study, the levels of insulin, C-peptide and glucose in diabetic rats reached to normal range as compared to un-diabetic rats in 20 days after transplantation of islet cells. Transplantation was performed under the cortex of testis as immunoisolated place for islet cells transplantation. PMID- 25298623 TI - Alleviation of Dimethylnitrosamine-Induced Liver Injury and Fibrosis by Supplementation of Anabasis articulata Extract in Rats. AB - Anabasis articulata (Forssk) Moq. (Chenopodiaceae) is an herb, grows in Egypt, and used in folk medicine to treat diabetes, fever, and kidney infections. The protective and therapeutic effects of the ethanol extract of A. articulata aerial parts were evaluated against dimethylnitrosamine (DMN)-induced liver fibrosis, compared with the standard drug, silymarin. Hepatic hydroxyproline content, serum transforming growth factor-beta1 (TGF-beta1), interleukin 10 (IL-10) and fructosamine were measured as liver fibrosis markers. Hepatic malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), glutathione reductase (GR) and glutathione content (GSH) were measured as oxidant/antioxidant markers. Parallel histopathological investigations were also performed. Protective and therapeutic administration of A. articulata (100 mg/kg daily for 4 weeks), markedly prevented DMN-induced loss in body and liver weights. The extract significantly inhibited the elevation of hepatic hydroxyproline, NO and MDA (P < 0.05), as well as serum fructosamine, and TGF-beta1 (P < 0.05) induced by DMN while it restored IL-10 to normal level in both protective and therapeutic groups. Furthermore, A. articulata prevented the depletion in CAT, GR, and GSH levels (P <= 0.05). In addition, oral administration of A. articulata extract and silymarin to both protective and therapeutic groups reduced the increase in liver function enzyme activities; alanine and aspartate amintransferases, gamma-glutamyl transferase in addition to alkaline phosphatase, and caused significant increase in serum albumin concentration as compared to DMN group. These data corresponded closely with those obtained for the drug silymarin. Histopathological studies confirmed the biochemical data and revealed remarkable improvement in liver architecture. Thus, it could be concluded that, A. articulata extract exhibited in vivo hepatoprotective and therapeutic effects against DMN-induced liver injury and may act as a useful agent in controlling the progression of hepatic fibrosis through reduction of oxidative stress and improving liver function. PMID- 25298624 TI - Delineation of the Structural Elements of Oriental Liver Fluke PLA2 Isoforms for Potent Drug Designing. AB - Clonorchis sinensis or the Chinese liver fluke is one of the most prevalent parasites affecting a major population in the oriental countries. The parasite lacks lipid generating mechanisms but is exposed to fatty acid rich bile in the liver. A secretory phospholipase A2, an enzyme that breaks down complex lipids, is important for the growth of the parasite. The enzyme is also implicated in the pathogenesis leading up to the hepatic fibrosis and its complications including cancer. The five isoforms of this particular enzyme from the parasite therefore qualify as potential drug targets. In this study, a detailed structural and ligand binding analysis of the isoforms has been done by modeling. The overall three dimensional structures of the isoforms are well conserved with three helices and a beta-wing stabilized by four disulfide bonds. There are characteristic differences at the calcium binding loop, hydrophobic channel and the C-terminal domain that can potentially be exploited for drug binding. But the most significant feature pertains to the catalytic site where the isoforms exhibit three variations of either a histidine-aspartate-tyrosine or histidine glutamate-tyrosine or histidine-aspartate-phenylalanine. Molecular docking studies show that isoform specific residues and their conformations in the substrate binding hydrophobic channel make unique interactions with certain inhibitor molecules resulting in a perfect tight fit. The proposed ligand molecules have a predicted affinity in micro-molar to nano-molar range. Interestingly, few of the ligand binding interaction patterns is in accordance to the phylogenetic studies to thereby establish the usefulness of evolutionary mechanisms in aiding ligand design. The molecular diversity of the parasitic PLA2 described in this study provides a platform for personalized medicine in the therapeutics of clonorchiasis. PMID- 25298625 TI - Administering the Optimum Dose of l-Arginine in Regional Tumor Therapy. AB - The purpose of this study is optimizing the l-arginine (l-Arg) doses on the basis of chemical structure in regional accessible tumor therapy to settle down a new protocol for the treatment of cancer. (3)H-thymidine-based cell proliferation assay was performed in vitro on tumor cell lines of fibrosarcoma (FS), lymphosarcoma-ascitic and on normal cell line of NIH 3T3 after treatment with different concentrations of l-Arg in phosphate buffered saline (PBS). The cultures were harvested after 22 h and the incorporated radioactivity was counted to identify their histologic grades as described in earlier studies. In vivo therapy of murine tumors was conducted where FS cells injected subcutaneously at ventro-lateral position of mice. Various drug delivery schedules were injected into the centre of tumor base, once a day for 4 days. Tumor diameter and survivals were monitored where the day of sacrifice was considered for monitoring the survival period. By identifying the histologic grades of the treated cultures in vitro and in vivo by different concentrations of l-Arg, the corresponding energy of such concentrations were determined. An efficient model with a good fit (R(2) = 0.98) was established to describe the energy yield by l-Arg dose. The equivalence between the tumor histologic grade and energy of the l-Arg dose delivered in saline (PBS) environment is the optimum condition for regional tumor therapy achieves higher survival rate. The selective cytotoxicity to tumor cells with minimal damage to normal cells by l-Arg due to its chemical structure suggests to be considered the most promising drug for regional therapy of the accessible tumors like breast cancers of early stage with no distant metastasis. PMID- 25298626 TI - Additive effect of lipid lowering drug (simvastatin) in combination with antidiabetic drug (glibenclamide) on alloxan induced diabetic rats with long term dyslipidemia. AB - High blood glucose level, elevated level of liver enzyme, necrosis and shrinkage of islets of Langerhans has been implicated in the pathogenesis of type 2 diabetes. High blood glucose cause oxidative stress, production of free radical as well as elevated SGPT and SGOT level. Both glibenclamide and simvastatin in fixed dose used as antihyperglycemic antidyslipidemic and antioxidative agents for type 2 diabetes treatment. This study therefore aimed to evaluate the antihyperglycemic, antidyslipidemic and antioxidative effect of fixed dose combination of glibenclamide (0.6 mg/70 kg body weight) and simvastatin (5 mg/70 kg body weight) on long term alloxan induced diabetic rats with cardiovascular disease using various diagnostic kits as a parameter of phamacotherapeutic and pharmacological effect. The study was carried out using 96 Swiss Albino male rats weighing about 200-220 g. Combination therapy induced a significant decrease in blood glucose level in alloxan induced diabetic rats, from 33.75 +/- 1.65 to 5.80 +/- 0.07 mmol/l 2 h after last dose administration, after 4 weeks treatment. In case of dyslipidemic effect, combination therapy reduced total cholesterol (45 %), triglyceride (36 %) and low density lipoprotein-cholesterol (32 %) levels significantly and increased high density lipoprotein-cholesterol level (57 %) in comparison with their respective diabetic control groups. Results of this study showed that combination therapy effectively decreased SGPT (ALAT) (55 %) and SGOT (ASAT) (51 %) in comparison with diabetic control group. It was also observed that catalase and superoxide dismutase enzyme activity was increased by 58 and 91 % respectively in comparison with diabetic control group after 4 weeks treatment with combination of both drugs. In conclusion, these findings of combination therapy (glibenclamide and simvastatin) on alloxan induced diabetes in rats are significantly better than monotherapy using single drug. The results of the present study suggest that, combination of the fixed dose of glibenclamide and simvastatin might be efficacious in patients with diabetic dyslipidemia and increased oxidative stress. Furthermore, this combination therapy offer dosage convenience to the patients and by virtue of its dual mode of action might be a useful addition to the therapeutic armamentarium for patients with diabetic dyslipidemia and oxidative stress. PMID- 25298627 TI - Maternal leptin, adiponectin, resistin, visfatin and tumor necrosis factor-alpha in normal and gestational diabetes. AB - Gestational diabetes mellitus (GDM) is a common medical complication associated with pregnancy. The present study evaluates the changes in maternal adipocytokines (leptin, adiponectin, resistin, visfatin and tumor necrosis factor alpha; TNF-alpha) in pregnancy complicated with GDM compared to normal pregnancy at 2nd and 3rd trimesters. The study included total number of 142 pregnant women classified into 4 groups: normal pregnancy (n = 33) and pregnancy with GDM (n = 24) both at 2nd trimester and normal pregnancy (n = 38) and GDM (n = 47) at 3rd trimester. Both GDM groups were significantly presented with elevated body mass index, fasting blood sugar and abnormal oral glucose tolerance test compared to their matched control. Results indicated reduction in maternal serum leptin and adiponectin in GDM compared to normal pregnancy at 3rd trimester. Elevated resistin and TNF-alpha were evident among pregnancy complicated with GDM at both tested trimesters. On the other hand, significant elevation in maternal visfatin was noted between GDM and matched control at 2nd trimester only. Significant increase in maternal leptin and visfatin and resistin was noted by advances in gestational period in healthy pregnancy. On the other hand, reduced adiponectin and elevated visfatin mean values were noticed in GDM at 3rd compared to 2nd trimester. It could be concluded that increased insulin resistance accompanies GDM is associated with suppressed leptin and adiponectin and increased resistin and TNF-alpha which might suggest their involvement in the development of GDM. PMID- 25298628 TI - Lactobacillus acidophilus Protected Organs in Experimental Arthritis by Regulating the Pro-inflammatory Cytokines. AB - Arthritis is an inflammatory disease of joints. Exact etiology of the disease is not understood yet; but histopathological examination of vital organs like liver, kidney, ovary and knee joint can anticipate immune mediated damage. In this study, Lactobacillus acidophilus was administered orally by both prophylactic and curative protocol in freund's complete adjuvant induced arthritic rats. Indomethacin was used as standard anti-arthritic drug. Histopathology of liver, kidney, ovary and right hind knee joint were done. Cytokine concentrations were determined by using ELISA. Effects shown by L. acidophilus were comparable with indomethacin. Histopathological analysis of liver, kidney, ovaries and knee joints of L. acidophilus fed groups revealed significantly less damage as compared with other counterparts. Lactobacillus treatment has down-regulated pro inflammatory level and up-regulated anti-inflammatory cytokines level in serum samples. L. acidophilus managed organs damage associated with arthritis. It has significantly down regulated the pro-inflammatory cytokines. PMID- 25298629 TI - When is a South Indian Really Anemic? AB - To determine the normal range of Hemoglobin and cutoff values in healthy adults of Southern India, blood samples were analyzed for parameters of RBC and iron metabolism in 177 male and 203 female medical students. The data were compared with the American white population (NHANES III) and the WHO criteria for detection of anemia. The mean values for hemoglobin and hematocrit in male students differed minimally from American white males. However, values for parameters of iron metabolism were lower except total iron binding capacity (TIBC) which was higher. In female students, hemoglobin, hematocrit and parameters of iron metabolism were lower than American white females, except TIBC which was higher. Lower 5th percentile cutoff point (Mean - 1.645 SD) in males and females were 13.5 and 10 g/dl respectively. In conclusion, South Indian adult males have Hb values similar to American male adults, but South Indian females have considerably lower Hb levels than American females, raising the questions about appropriateness of WHO or US criteria for detection of anemia in Indian females. PMID- 25298630 TI - Salivary alpha amylase activity in human beings of different age groups subjected to psychological stress. AB - Salivary alpha-amylase (sAA) has been proposed as a sensitive non-invasive biomarker for stress-induced changes in the body that reflect the activity of the sympathetic nervous system. Though several experiments have been conducted to determine the validity of this salivary component as a reliable stress marker in human subjects, the effect of stress induced changes on sAA level in different age groups is least studied. This article reports the activity of sAA in human subjects of different age groups subjected to psychological stress induced through stressful video clip. Differences in sAA level based on sex of different age groups under stress have also been studied. A total of 112 subjects consisting of both the male and female subjects, divided into two groups on basis of age were viewed a video clip of corneal transplant surgery as stressor. Activity of sAA from saliva samples of the stressed subjects were measured and compared with the activity of the samples collected from the subjects before viewing the clip. The age ranges of subjects were 18-25 and 40-60 years. The sAA level increased significantly in both the groups after viewing the stressful video. The increase was more pronounced in the younger subjects. The level of sAA was comparatively more in males than females in the respective groups. No significant change in sAA activity was observed after viewing the soothed video clip. Significant increase of sAA level in response to psychological stress suggests that it might act as a reliable sympathetic activity biochemical marker in different stages of human beings. PMID- 25298631 TI - Induction of multiple sclerosis and response to tyrosine kinase inhibitors. AB - The goal of this work is to determine the role of the autoimmune cells in multiple sclerosis (MS) induction and the immunomodulatory mechanism of therapy with tyrosine kinase inhibitors (TKIs) in MS attenuation. Samples (5 * 10(5) cells per well) of C6 and primary rat astrocytes were stimulated with 10 ng/mL of platelet-derived growth factor (PDGFbb) as a positive control forming a mouse model of MS. PDGFbb was added to the astrocytes in the absence or presence of 0.1 and 1 MUM of imatinib. Proliferation of C6 and primary rat astrocytes samples were assessed for samples staging by the addition of 1 MUCi of (3)H-thymidine per well. Samples of RAW 264.7 cells were stimulated for 48 h with 10 ng/mL of PDGFbb in the absence or presence of 0.1 and 1 MUM of sorafenib. Tumour necrotic factor (TNF) levels in culture supernatants from RAW 264.7 cells were measured by ELISA. The histologic grade (HG) and the level of TNF of the mouse model of MS was 1/5 and 5 times respectively of those in the control one to clarify that MS induction is due to a major decrease in HG inversely proportional to the accompanied increase in TNF level perpetuating local inflammation and demyelination in MS lesion. The addition of 0.1 and 1 MUM doses of imatinib increased HG of the mouse model of MS by 6 and 11 times respectively while 0.1 and 1 MUM doses of sorafenib decreased TNF level to be 1/2 and 1/5 of that in the mouse model of MS respectively restoring normal rate of TNF level of normal lesion to show that HGand TNF level would be strongly inversely correlated (r = -0.99) in attenuating MS effectively by TKIs therapy but not in an inverse proportion as in MS induction. PMID- 25298632 TI - Does friedewald formula underestimate the risk of ischemic heart disease? AB - Traditionally Friedewald formula has been used to calculate low density lipoprotein cholesterol (LDL-C) concentration though now direct homogenous methods for its measurement are also available. Clinical guidelines recommend the use of calculated LDL-C to guide therapy because the evidence base for cholesterol management is derived almost exclusively from trials that use calculated LDL, with direct measurement of LDL-C being reserved for those patients who are non fasting or with significant hypertriglyceridemia. In this study our aim was to compare calculated and direct LDL and their variation at different cholesterol and triglyceride levels. Fasting lipid profile estimation was done on 503 outpatients in a tertiary hospital. Both direct and calculated LDL were then compared. Mean fasting direct LDL was found to be higher than calculated LDL in 87.1 % of subjects by 8.64 +/- 8.35 mg/dl. This difference was seen a all levels of cholesterol and triglyceride. Using 130 mg/dl LDL cholesterol as cut off fewer subjects were classified as high risk by calculated LDL than direct LDL. In conclusion, direct LDL is higher than calculated LDL. Compared with direct measurement, the Friedewald calculation underestimates the risk for ischemic heart disease. PMID- 25298633 TI - Effects of nanoliposomal and pegylated nanoliposomal artemisinin in treatment of breast cancer. AB - This study is aimed to investigate the nanoliposomal artemisinin preparation, and its implementation on breast cancer cells. Side effects have been one of the common challenges of drug usage, as well as cancer treatment. In order to reduce such effects, nanotechnology has been a great help. Nanoliposomes are provided through reverse phase evaporation. In this method, certain proportions of phosphatidylcholine, cholesterol and artemisinin were mixed together. Besides, the obtained formulation was pegylated by using polyethylene glycol 2000 in order to increase its stability and solubility. The mean diameter of non-pegylated and pegylated liposomal artemisinin was determined by Zeta sizer system. The percent of drug released from liposome was performed by dialysis. The encapsulation efficiency of both formulations was estimated by spectrophotometry method. As a result, encapsulation and drug release of nanoliposomal formulation were more than the pegylation of the same formulation. In addition, this study indicated that cytotoxicity effect of pegylated nanoliposomal artemisinin was more, in comparison with nanoliposomal artemisinin. PMID- 25298634 TI - Monitoring and root cause analysis of clinical biochemistry turn around time at an academic hospital. AB - Quality can be defined as the ability of a product or service to satisfy the needs and expectations of the customer. Laboratories are more focusing on technical and analytical quality for reliability and accuracy of test results. Patients and clinicians however are interested in rapid, reliable and efficient service from laboratory. Turn around time (TAT), the timeliness with which laboratory personnel deliver test results, is one of the most noticeable signs of laboratory service and is often used as a key performance indicator of laboratory performance. This study is aims to provide clue for laboratory TAT monitoring and root cause analysis. In a 2 year period a total of 75,499 specimens of outdoor patient department were monitor, of this a total of 4,142 specimens exceeded TAT. With consistent efforts to monitor, root cause analysis and corrective measures, we are able to decreased the specimens exceeding TAT from 7-8 to 3.7 %. Though it is difficult task to monitor TAT with the help of laboratory information system, real time documentation and authentic data retrievable, along with identification of causes for delays and its remedial measures, improve laboratory TAT and thus patient satisfaction. PMID- 25298635 TI - An Evaluation of the Point-of-Care Analyzer, i-Smart 30, for Measurement of Electrolytes. AB - Analytical functioning of a point-of-care analyzer, i-Smart 30 (i-sens: Seoul, South Korea), for electrolyte quantification was investigated at Sant Parmanand Hospital, a tertiary-care hospital in Delhi, India. Samples that were received for electrolyte assay were assayed, double-blinded for their Na and K level using the arterial blood gas analyzer, the ABL 555 (Radiometer, Copenhagen) and the i Smart 30 electrolyte analyzer. There was satisfactory correlation between the results obtained with the two analyzers with an encouraging bias, standard deviation and the 95 % limits of agreement between the data generated for Na and K levels. The performance of the i-Smart 30 would be satisfactory during the point-of-care measurements of Na and K levels in emergency rooms and clinical laboratories with inadequate infrastructure only if its day-to-day performance was monitored to ensure reliability of the generated reports. PMID- 25298636 TI - Fatty Acid oxidation disorder with secondary mitochondrial energy production defect: a case report. AB - The presentation of long-chain fatty acid oxidation disorders (FAOD), unlike short and medium-chain disorders can be with secondary defects in mitochondrial function along with typical features of FAOD. We report an infant with Reye-like presentation and acylcarnitine profile suggestive of very-long-chain acyl-CoA dehydrogenase deficiency who had lactic acidosis and urine gas chromatographic pattern of mitochondrial defects. PMID- 25298637 TI - Hb Hope: A Rare Variant of Haemoglobin-Forged a Rise in HbA1c on Immunoturbidimetric Assay. AB - Glycosylated hemoglobin (HbA1c) determination is a powerful means for assessing the evaluation and management of patients with diabetes mellitus. Hemoglobin (Hb) variants and chemically modified derivatives of Hb can affect the accuracy of measurement of HbA1c done by various analytical methods. We report a patient with a rare variant of Hb (Hb Hope) that caused an abnormally high value of HBA1c when assayed using immunoturbidimetric assay ("Tina-quant" 2nd generation assay) and also elucidate the nature of the variant. PMID- 25298638 TI - A Case of Sanfillippo's Disease Correlating Clinical and Biochemical Findings. AB - The mucopolysaccharidoses (MPSs) are a heterogeneous group of rare inherited disorders caused by deficiency of lysosomal enzyme necessary to break down mucopolysaccharides or glycosaminoglycans (GAGs). We had combined clinical findings and ophthalmological features. Biochemical test for urine glycosaminoglycans was done for confirmation of diagnosis in the patient. The case of Sanfillippo's disease was characterized by delayed development, hyperactivity with aggressive behaviour. Coarse facial feature, hirsutism and sleep disorder. Urine GAG tests for MPS was positive in the case. Based on clinical findings and biochemical tests for MPS, this case was diagnosed as a type III mucopolysaccharidoses. Urinary GAG's electrophoresis is an important screening test for MPS suspected cases. PMID- 25298639 TI - The self-adjusting file (SAF) system: An evidence-based update. AB - Current rotary file systems are effective tools. Nevertheless, they have two main shortcomings: They are unable to effectively clean and shape oval canals and depend too much on the irrigant to do the cleaning, which is an unrealistic illusionThey may jeopardize the long-term survival of the tooth via unnecessary, excessive removal of sound dentin and creation of micro-cracks in the remaining root dentin. The new Self-adjusting File (SAF) technology uses a hollow, compressible NiTi file, with no central metal core, through which a continuous flow of irrigant is provided throughout the procedure. The SAF technology allows for effective cleaning of all root canals including oval canals, thus allowing for the effective disinfection and obturation of all canal morphologies. This technology uses a new concept of cleaning and shaping in which a uniform layer of dentin is removed from around the entire perimeter of the root canal, thus avoiding unnecessary excessive removal of sound dentin. Furthermore, the mode of action used by this file system does not apply the machining of all root canals to a circular bore, as do all other rotary file systems, and does not cause micro cracks in the remaining root dentin. The new SAF technology allows for a new concept in cleaning and shaping root canals: Minimally Invasive 3D Endodontics. PMID- 25298641 TI - Effect of oxalic acid pre-treatment in restorations of non-carious cervical lesions: A randomized clinical trial. AB - CONTEXT: Non-carious cervical lesions are usually associated with dentin hypersensitivity. The use of oxalic acid in restorations of these lesions could be beneficial in relieving pain. AIMS: To evaluate the use of oxalic acid in restorations of non-carious cervical lesions. SETTINGS AND DESIGN: A randomized clinical trial. SUBJECTS AND METHODS: One operator placed 90 restorations in 20 volunteers of both sexes, with at least two lesions to be restored with the techniques: Control - Restoration with total-etch technique and Experimental - Restoration with pretreatment with oxalic acid followed by application of adhesive system. The restorative adhesive system used was XP Bond/Durafill. The restorations were directly assessed by two independent examiners using a modified United States Public Health Service (USPHS) method at baseline, 6 and 12 months, taking into account the following criteria: Retention (R), marginal integrity (MI), marginal discoloration (MD), postoperative sensitivity (S), caries (C), and anatomic form (AF). STATISTICAL ANALYSIS USED: The data were statistically analyzed using the Fisher exact and McNemar tests. The level of significance was set at 5%. RESULTS: After 1 year, the results of restorations clinically satisfactory obtained for the control and experimental group respectively were: R (97% / 89%), MI (100% / 100%), MD (100% / 100%), S (100% / 100%), C (100% / 100%), and AF (100% / 100%). CONCLUSIONS: The use of oxalic acid as an agent of dentin pretreatment did not influence the clinical performance of restorations in non-carious cervical lesions after 1 year. PMID- 25298640 TI - Validity of bond strength tests: A critical review-Part II. AB - BACKGROUND: Macro-bond strength tests resulted in cohesive failures and overestimation of bond strengths. To reduce the flaws, micro-bond strength tests were introduced. They are the most commonly used bond-strength tests. OBJECTIVE: Thus the objective of this review is to critically review the reliability of micro-bond strength tests used to evaluate resin-tooth interface. DATA COLLECTION: Relevant articles published between January 1994 and July 2013 were collected from Pubmed database, Google scholar and hand searched journals of Conservative Dentistry, Endodontics and Dental materials. DATA SYNTHESIS: Variables that influence the test outcome are categorized into substrate related factors, factors related to specimen properties, specimen preparation and test methodology. Impact of these variables on the test outcome is critically analyzed. CONCLUSION: Micro-bond tests are more reliable than macro-bond tests. However, no standard format exists for reporting the bond strength tests which could lead to misinterpretation of the data and bonding abilities of adhesives. PMID- 25298642 TI - Intraosseous injection as an adjunct to conventional local anesthetic techniques: A clinical study. AB - BACKGROUND: The achievement of successful local anesthesia is a continual challenge in dentistry. Adjunctive local anesthetic techniques and their armamentaria, such as intraosseous injection (the Stabident system and the X-tip system) have been proposed to be advantageous in cases where the conventional local anesthetic techniques have failed. AIM: A clinical study was undertaken using intraosseous injection system by name X-tip to evaluate its effectiveness in cases where inferior alveolar nerve block has failed to provide pulpal anesthesia. MATERIALS AND METHODS: Sixty adult patients selected were to undergo endodontic treatment for a mandibular molar tooth. Inferior alveolar nerve block was given using 4% articaine with 1:100,000 epinephrine. Twenty-four patients (40%) had pain even after administration of IAN block; intraosseous injection was administered using 4% articaine containing 1:100,000 epinephrine, using the X-tip system. The success of X-tip intraosseous injection was defined as none or mild pain (Heft-Parker visual analog scale ratings <= 54 mm) on endodontic access or initial instrumentation. RESULTS: Intraosseous injection technique was successful in 21 out of 24 patients (87.5%), except three patients who had pain even after supplemental X-tip injection. CONCLUSION: Within the limits of this study, we can conclude that supplemental intraosseous injection using 4% articaine with 1:100,000 epinephrine has a statistically significant influence in achieving pulpal anesthesia in patients with irreversible pulpitis. PMID- 25298643 TI - Influence of citric acid on the surface texture of glass ionomer restorative materials. AB - AIM: This study determined the effectiveness of G-coat plus surface protective agent over petroleum jelly on the surface texture of conventional Glass ionomer restorative materials. MATERIALS AND METHODS: Three chemically cured conventional glass ionomer restorative materials type II, type IX and ketac molar were evaluated in this study. Sixty specimens were made for each restorative material. They were divided into two groups of thirty specimens each. Of the sixty specimens, thirty were coated with G-coat plus (a nano-filler coating) and the rest with petroleum jelly. Thirty samples of both protective coating agents were randomly divided into six groups of five specimens and conditioned in citric acid solutions of differing pH (pH 2, 3, 4, 5, 6 & 7). Each specimen was kept in citric acid for three hours a day, and the rest of time stored in salivary substitute. This procedure was repeated for 8 days. After conditioning, the surface roughness (Ra, MUm) of each specimen was measured using a surface profilometer (Taylor & Habson, UK). Data was analyzed using one-way analysis of variance (ANOVA) and Tukey's HSD test at a significance level of 0.05. RESULTS: The surface textures of all the tested glass ionomer restorative materials protected with G-coat plus were not significantly affected by acids at low pH. The surface textures of all the tested glass ionomer restorative materials protected with petroleum jelly coating were significantly affected by acids at low pH. CONCLUSION: The effects of pH on the surface texture of glass ionomer restoratives are material dependent. Among all the materials tested the surface texture of Type II GIC (Group I) revealed marked deterioration when conditioned in solutions of low pH and was statistically significant. Hence, a protective coating either with G-coat plus or with light polymerized low viscosity unfilled resin adhesives is mandatory for all the glass ionomer restorations to increase the wear resistance of the restorative materials. PMID- 25298644 TI - Comparison of shear bond strength of resin-modified glass ionomer to conditioned and unconditioned mineral trioxide aggregate surface: An in vitro study. AB - INTRODUCTION: The aim of this study was to compare the shear bond strength of resin modified glass ionomer cement to conditioned and unconditioned mineral trioxide aggregate surface. MATERIALS AND METHOD: White Mineral Trioxide Aggregate (WMTA) and Resin Modified Glass Ionomer Cement (RMGIC) were used for the study. 60 WMTA specimens were prepared and stored in an incubator at 37 degrees C and 100% humidity for 72 hrs. The specimens were then divided into two groups- half of the specimens were conditioned and remaining half were left unconditioned, subsequent to which RMGIC was placed over MTA. The specimens were then stored in an incubator for 24 hrs at 37 degrees C and 100% humidity. The shear bond strength value of RMGIC to conditioned and unconditioned WMTA was measured and compared using unpaired 't ' test. RESULTS: The mean shear bond strength of value of RMGIC to conditioned and unconditioned WMTA was 6.59 MPa and 7.587 MPa respectively. Statistical analysis using unpaired t-test revealed that the difference between values of two groups was not statistically significant (P > 0.05). CONCLUSIONS: During clinical procedures like pulp capping and furcal repair, if RMGIC is placed as a base over MTA, then conditioning should be done to increase the bond strength between RMGIC and dentin and any inadvertent contact of conditioner with MTA will not significantly affect the shear bond strength value of RMGIC to MTA. PMID- 25298645 TI - Viability and antibacterial efficacy of four root canal disinfection techniques evaluated using confocal laser scanning microscopy. AB - BACKGROUND: Several disinfection techniques have been recently introduced with the main objective of improving root canal disinfection in the inaccessible areas of the root canal system. This in vitro study was done to evaluate the antimicrobial effect and viability of Enterococcus faecalis biofilms using conventional irrigation, EndoActivator (Dentsply, Tulsa Dental, USA), diode laser irradiation and photon-initiated photoacoustic streaming (PIPS). MATERIALS AND METHODS: Root canals of 130 single rooted mandibular premolars, standardized to a uniform length of 20 mm were instrumented until finishing file, F1 (Universal Protaper Rotary System, Dentsply, Tulsa Dental Specialties, USA). After smear layer removal and sterilization, five teeth were randomly selected to assure sterility before bacterial inoculation. The remaining 125 samples were contaminated with E. faecalis suspension, incubated for 21 days and divided into five groups (n = 25). In Group 1; untreated group (positive control), the root canals were not subjected to any disinfection procedure. Sampling was performed within the canals and the colony-forming unit count was evaluated for 20 samples. Five samples were selected to visualize the pattern of colonization at Level 1 (4 mm from the apex) and Level 2 (1 mm from the apex) by confocal laser scanning microscopy. Samples in Groups 2-5 namely conventional needle irrigation, EndoActivator, diode laser and PIPS were subjected to their respective disinfection procedures. Postdisinfection sample evaluation criteria was followed for all groups as same as that for Group 1. RESULTS: Diode laser displayed the highest antibacterial efficacy and least viable bacteria than the other three disinfection techniques. CONCLUSION: Diode laser group showed better antibacterial efficacy and least viable bacteria when compared to conventional needle irrigation, PIPS and EndoActivator groups in minimally instrumented, experimentally infected root canals. PMID- 25298646 TI - Chemical constituent and antimicrobial effect of essential oil from Myrtus communis leaves on microorganisms involved in persistent endodontic infection compared to two common endodontic irrigants: An in vitro study. AB - INTRODUCTION: Persistent infections of human root canals play a fundamental role in the failure of endodontic treatment. The purpose of this study is to determine the chemical composition of Myrtus communis (M. communis) essential oil and to assess its antimicrobial activity against Enterococcus faecalis, Staphylococcus aureus and Candida albicans compared to that of sodium hypochlorite (NaOCl) and chlorhexidine (CHX). MATERIALS AND METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to determine the chemical composition of essential oil from M. communis leaves. A micro-dilution susceptibility assay and disk diffusion methods were utilized to evaluate the antimicrobial activity [minimum inhibitory concentration (MIC) and minimum lethal dose concentration] of the tested solutions against selected microorganisms. RESULTS: GC-MS analyses revealed that M. communis contained 1, 8-Cineole (28.62%), alpha-Pinene (17.8%), Linalool (17.55%), and Geranylacetate (6.3%) as the major compounds and Geraniol (1.6%), alpha-Humulene (1.5%), eugenol (1.3%), isobutyl-isobutyrate (0.8%), and methyl chavicol (0.5%) as minor components. Chlorhexidine had the lowest MIC value among all medicaments tested. M. communis oil had less MIC values than NaOCl against both bacteria, but it had more MIC value against C. albicans. CONCLUSION: M. communis essential oil with the minimum inhibitory concentration in the range of 0.032-32 MUg/mL was an effective antimicrobial agent against persistent endodontic microorganisms. PMID- 25298647 TI - Retrievabilty of calcium hydroxide intracanal medicament with Chitosan from root canals: An in vitro CBCT volumetric analysis. AB - AIM: This study compared the amount of aqueous-based and oil-based calcium hydroxide [Ca(OH)2 ] remaining in the canal, after removal with two different chelators 17% EDTA and 0.2% Chitosan in combination with ultrasonic agitation. MATERIALS AND METHODS: Cleaning and shaping of root canals of 28 mandibular premolar was done and canals were filled either with Metapex or Ca(OH)2 mixed with distilled water. Volumetric analysis was performed utilizing cone beam computed tomography (CBCT) after 7 days of incubation. Ca(OH)2 was removed using either 17% EDTA or 0.2% Chitosan in combination with ultrasonic agitation. Volumetric analysis was repeated and percentage difference was calculated and statistically analysed using Kruskal-Wallis and Mann-Whitney U test. RESULTS: Both the chelators failed to remove aqueous-based as well as oil-based Ca(OH)2 completely from the root canal. Aqueous-based Ca(OH)2 was easier to be removed than oil-based Ca(OH)2. 0.2% Chitosan was significantly more effective for removal of oil-based Ca(OH)2 (P < 0.01) while both 17% EDTA and 0.2% Chitosan were equally effective in removing aqueous-based Ca(OH)2 . CONCLUSION: Combination of 0.2% Chitosan and ultrasonic agitation results in lower amount of Ca(OH)2 remnants than 17% EDTA irrespective of type of vehicle present in the mix. PMID- 25298648 TI - Effect of desensitizing treatments on bond strength of resin composites to dentin - an in vitro study. AB - OBJECTIVES: Hypersensitivity is a common clinical multietiological problem. Many desensitizing treatments are there to overcome hypersensitivity. The aim of this study was to evaluate the effect of different dentin-desensitizing treatments on the tensile bond strength of composite restoration. MATERIALS AND METHODS: Twenty four sound human molars were used. Enamel was wet abraded to expose flat dentin surfaces, polished with sandpaper. The specimens were then divided into three groups (n = 8) based on the type of dentin-desensitizing treatment given. The first group: G1 was the control group where no desensitizing agent was used. The second group: G2 was treated with desensitizing dentifrice containing a combination of potassium nitrate, triclosan, and sodium monoflorophosphate. The third group: G3 was treated with Er:YAG laser. Afterwards, the desensitized specimens were treated with one step self-etch adhesive according to manufacturer's instructions and composite microcylinders were packed. The specimens were then examined for tensile bond strength using universal tensile machine (KMI(TM) ). RESULTS: Statistical analysis of the data obtained revealed the mean values for the tensile bond strengths were 10.2613 MPa, 5.9400 MPa and 6.3575 MPa for groups 1, 2 and 3, respectively. These values were statistically significantly different between groups pretreated with laser or dentifrice as compared to control group. CONCLUSIONS: Dentifrice and Laser pre-treated dentin has lower tensile bond strength with resin composites as compared to dentin that is untreated. PMID- 25298649 TI - The effect of 5% sodium hypochlorite, 17% EDTA and triphala on two different rotary Ni-Ti instruments: An AFM and EDS analysis. AB - AIM: To use Atomic Force Microscope and Energy Dispersive X-ray Spectroscopy to evaluate the effect of 5% NaOCl, 17% EDTA and triphala on ProTaper and iRaCe rotary Ni-Ti instruments. METHODOLOGY: A total of eight Ni-Ti rotary files, four files each of ProTaper - S2 (Dentsply) and iRaCe - R3 (FKG DENTAIRE) were used. Three out of four files each from ProTaper and iRaCe were immersed in 5% NaOCl, 17% EDTA and Triphala separately for five minutes. The Roughness average (Ra), Root Mean Square (RMS) and Mean Height of Roughness Profile Elements (Rc) of the scanned profiles were then recorded using AFM and the elemental composition was evaluated with EDS. Data were analyzed by Student's t test, One Way ANOVA and Duncan's Multiple Range Test. RESULTS: Topographic irregularities at the nanometric scale were observed for all files. Files immersed in EDTA and NaOCl showed highly significant surface roughness than untreated files. CONCLUSION: Short-term contact with 17% EDTA and 5% NaOCl can cause significant surface deterioration of ProTaper and iRaCe rotary NiTi files. AFM proves to be a suitable method for evaluating the instrument surface. PMID- 25298650 TI - Cytotoxicity evaluation of root repair materials in human-cultured periodontal ligament fibroblasts. AB - AIM: To evaluate the cytotoxicity of three root repair materials, mineral trioxide aggregate (MTA), Endosequence Root Repair Material and Biodentine in human periodontal ligament fibroblasts. MATERIALS AND METHODS: Periodontal ligament fibroblasts were cultured from healthy premolar extracted for orthodontic purpose. Cells in the third passage were used in the study. The cultured fibroblast cells were placed in contact with root repair materials: (a) Biodentine, (b) MTA, (c) Endosequence, (d) control. The effects of these three materials on the viability of Periodontal ligament (PDL) fibroblasts were determined by trypan blue dye assay after 24 hours and 48-hour time period. Cell viability was determined using inverted phase contrast microscope. STATISTICAL ANALYSIS: Cell viability was compared for all the experimental groups with Wilcoxons matched pair test. RESULTS: At the 24-hour examination period, all the materials showed increased cell viability. At 48-hour time period, there is slight decrease in cell viability. Mineral trioxide aggregate showed statistically significant increase in the cell viability when compared to other root repair materials. CONCLUSION: Mineral trioxide aggregate was shown to be less toxic to periodontal ligament fibroblasts than Endosequence Root Repair Material and Biodentine. PMID- 25298651 TI - Evaluation of effect of ultrasonic scaling on surface roughness of four different tooth-colored class V restorations: An in-vitro study. AB - AIMS: This study evaluated the effect of ultrasonic scaling on surface roughness of four different tooth-colored class V restorations. MATERIALS AND METHODS: Out of 100 human extracted teeth, 20 were randomly selected for each group, marked with the outline of class V cavity. Class V cavities were prepared on facial surface of teeth of all groups except control group. These cavities were then restored with GC 2, GC 9, GC 2 LC, and Filtek Z 250 XT. All the specimens were stored in artificial saliva at 37 degrees C for 1 month. Initial surface roughness values (Ra in MUm) of restorations were evaluated with the surface roughness tester. Ultrasonic instrumentation was then carried out for 60 s on the restoration surface and final roughness values were evaluated. Data were analyzed with Paired t-test, One-way ANOVA, Tukey's test. RESULTS: Mean Pre instrumentation surface roughness was highest with GC 2, whereas it was least in case of Filtek Z 250 XT. Mean post-instrumentation surface roughness was highest with GC 2, whereas it is least in case of Filtek Z 250 XT. CONCLUSION: GC 2 LC showed highest and Filtek Z 250 XT showed least susceptibility to ultrasonic scaling. PMID- 25298652 TI - Effects of ultrasonic root-end cavity preparation with different surgical-tips and at different power-settings on glucose-leakage of root-end filling material. AB - AIM: The aim of this in vitro study was to evaluate the effects of different ultrasonic surgical-tips and power-settings on micro-leakage of root-end filling material. MATERIALS AND METHODS: The root canals were instrumented using rotary files and were filled with tapered gutta-percha and root canal sealer using a single-cone technique. The apical 3 mm of each root was resected and the roots were divided into six experimental groups; negative and positive control groups. Root-end cavities were prepared with diamond-coated, zirconum-nitride-coated and stainless-steel ultrasonic retro-tips at half-power and high-power settings. The time required to prepare the root-end cavities for each group was recorded. Root end cavities were filled with Super-EBA. Leakage values of all samples evaluated with glucose penetration method on 7, 14, 21 and 28(th) days. The results were statistically analyzed with Kruskal-Wallis and Hollander-Wolfe tests. RESULTS: The mean time required to prepare retro cavities using diamond-coated surgical tip at high-power setting was significantly less than other groups (P < 0.01). There were no statistically significant differences in the glucose penetration between the groups at first and second weeks (P > 0.01). Diamond-coated surgical tip showed the least leakage at high-power setting at 3(rd) and 4(th) weeks (P < 0.01). CONCLUSIONS: Under the conditions of this study, cavity preparation time was the shortest and the leakage of the root-end filling was the least when diamond-coated retro-tip used at high-power setting. PMID- 25298653 TI - Endodontic management of a maxillary molar with formation supradentalis: A case report. AB - Anatomic variations may be observed in the crown or in the roots of maxillary molars. In rare instances, crown and root morphology, both show variations. Occurrence of paramolar cusp on the occlusal surface as central cusp or on the buccal surface as parastyle has been frequently reported in maxillary molars. However, presence of paramolar cusp on the palatal surface has not been reported. 'Formation supradentalis' is a condition in which supernumerary cusp is associated with a supernumerary root in a molar. The occurrence of such concomitant corono-radicular morphology is multifactorial, that is primary polygenic with secondary environmental influences. This case reports the diagnosis and endodontic management of Formation-supradentalis that had six cusps and four roots in the maxillary first molar. The tooth exhibited a prominent paramolar palatal cusp and cusp of Carabelli along with a supernumerary palatal root. To the best of author's knowledge, this is the first documentation of endodontic management of Formation supradentalis. PMID- 25298654 TI - Non-invasive endodontic management of fused mandibular second molar and a paramolar, using cone beam computed tomography as an adjunctive diagnostic aid: A case report. AB - Tooth fusion is a developmental anomaly characterized by the union between the dentin and/or enamel of at least two separately developing teeth. Fusion is a rare occurrence, with overall prevalence to be approximately 0.5% in deciduous teeth and 0.1% in permanent dentition. The significance of this particular case was that the unilateral fusion occurred in a permanent mandibular second molar with a paramolar and successful endodontic management was done. The rarity with which this entity appears, along with its complex characteristics, often makes it difficult to treat. In this case, a new advanced three-dimensional imaging Cone Beam Computed Tomography (CBCT) was used as an adjunctive diagnostic aid to differentiate between fusion occurred before or after root formation and help to reach the correct diagnosis. PMID- 25298655 TI - Use of photoactivated disinfection and platelet-rich fibrin in regenerative Endodontics. AB - AIM: Photoactivated disinfection has been used as an adjunct to conventional endodontic treatment. Its use in regenerative endodontics is not reported in literature. The aim of this case report was to describe a new proposal for pulp revascularization with disinfection of pulp canal space using a unique combination of a photosensitizer solution and low-power laser light. MATERIALS AND METHODS: A 9-year-old boy came with the chief complaint of discolored upper central incisors (#8, #9). A diagnosis of pulp necrosis was made on the basis of clinical and radiographic findings. The canal was irrigated with 5.25% sodium hypochlorite solution and dried with paper points. Photodynamic therapy was used to disinfect the root canal and platelet-rich fibrin was used to revitalize the pulp. Three millimeters of gray mineral trioxide aggregate was placed directly over the platelet-rich plasma clot. Three days later, the tooth was double-sealed with permanent filling materials. RESULTS: Clinical examination revealed no sensitivity to percussion or palpation tests. Radiograph revealed continued thickening of the dentinal walls, root lengthening, regression of the peri-apical lesion and apical closure. Both the roots showed complete apical closure at the 10-month follow-up. However, the teeth were not responsive to electric pulp test. CONCLUSION: This report of pulp revascularization shows that disinfection with photodynamic therapy combined with platelet-rich fibrin leads to satisfactory root development in necrotic immature teeth. PMID- 25298656 TI - Mandibular premolars with aberrant canal morphology: An endodontic challenge. AB - Complete cleaning and shaping is the key to successful endodontic treatment. A thorough understanding of the internal anatomy and morphology of the root canal system is an important consideration when performing cleaning and shaping procedures. Mandibular premolars are one of the most difficult teeth to treat endodontically because of aberrant root canal anatomy. This article describes case series of mandibular premolars with variations in root canal anatomy treated successfully by conventional endodontic treatment. PMID- 25298657 TI - Smile rejuvenation: A case report. AB - Mesiodens is the commonly occurring supernumerary tooth seen between the maxillary central incisors which causes compromised aesthetics and malocclusion. Till date orthodontic therapy provides an excellent solution for the management of mesiodens. Recently, Restorative Space Management (RSM) has been used successfully to correct tooth shape, proportions and colour with minimal tooth preparations. This case report describes the successful management of an unaesthetic smile due to presence of a mesiodens in the midline primarily using aesthetic treatment only. PMID- 25298658 TI - A rare report of mandibular facial talon cusp and its management. AB - Talon cusp is an uncommon dental anomaly showing morphologically well delineated, accessory cusp-like structure projecting from cingulum to the incisal edge of anterior teeth. This anomaly is rare in the mandibular dentition and rarer on the facial aspect. A case of this infrequent entity of mandibular facial talon cusp and its management is reported here. PMID- 25298659 TI - High performance liquid chromatography profiling of health-promoting phytochemicals and evaluation of antioxidant, anti-lipoxygenase, iron chelating and anti-glucosidase activities of wetland macrophytes. AB - BACKGROUND: The phytochemistry and bioactivity of wetland macrophytes are underexplored. Plants are known as the natural sources of phytochemical beneficial to health. OBJECTIVE: The objective of this study is to analyze the phytochemical profiles and bioactivities of 10 extracts prepared from different plant parts of wetland macrophytes Hanguana malayana, Ludwigia adscendens and Monochoria hastata. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) was used to analyze the phytochemical profile of the extracts. Antioxidant assay such as 2,2-diphenyl-1-picrylhydrazyl, nitric oxide (NO) radical scavenging activity and ferric reducing antioxidant power were performed. Bioactivity assays carried out were anti-lipoxygenase, anti-glucosidase, and iron chelating. RESULTS: Leaf extract of L. adscendens had the highest 2,2-diphenyl-1 picrylhydrazyl (half of maximal effective concentration [EC50] =0.97 mg/mL) and NO (EC50 = 0.31 mg/mL) scavenging activities. The extract also exhibited the highest iron chelating (EC50 = 3.24 mg/mL) and anti-glucosidase (EC50 = 27.5 MUg/mL) activities. The anti-glucosidase activity of L. adscendens leaf extract was comparable or superior to those of acarbose, myricetin and quercetin. Correlation between iron chelating and radical scavenging activities among the extracts implies the presence of dual-function phytoconstituents with concurrent iron chelating and radical scavenging activities. HPLC analysis revealed the presence of p-coumaric acid (p-CA), gallic acid (GA) and myricetin in all or most extracts. M. hastata fruit and leaf extracts had the highest p-hydroxybenzoic acid content. Antioxidant and anti-glucosidase activities of the extracts were correlated with p-CA, GA, and myricetin contents. CONCLUSION: Our study demonstrated that wetland macrophytes H. malayana, L. adscendens and M. hastata are potential sources of health-promoting phytochemicals with potent therapeutically-relevant bioactivities. PMID- 25298660 TI - Chemical constituents and toxicological studies of leaves from Mimosa caesalpiniifolia Benth., a Brazilian honey plant. AB - BACKGROUND: Mimosa caesalpiniifolia Benth. (Leguminosae) is widely found in the Brazilian Northeast region and markedly contributes to production of pollen and honey, being considered an important honey plant in this region. OBJECTIVE: To investigate the chemical composition of the ethanol extract of leaves from M. caesalpiniifolia by GC-MS after derivatization (silylation), as well as to evaluate the in vitro and in vivo toxicological effects and androgenic activity in rats. MATERIALS AND METHODS: The ethanol extract of leaves from Mimosa caesalpiniifolia was submitted to derivatization by silylation and analyzed by gas chromatography-mass spectrometry (GC-MS) to identification of chemical constituents. In vitro toxicological evaluation was performed by MTT assay in murine macrophages and by Artemia salina lethality assay, and the in vivo acute oral toxicity and androgenic evaluation in rats. RESULTS: Totally, 32 components were detected: Phytol-TMS (11.66%), lactic acid-2TMS (9.16%), alpha-tocopherol TMS (7.34%) and beta-sitosterol-TMS (6.80%) were the major constituents. At the concentrations analyzed, the ethanol extract showed low cytotoxicity against brine shrimp (Artemia salina) and murine macrophages. In addition, the extract did not exhibit any toxicological effect or androgenic activity in rats. CONCLUSIONS: The derivatization by silylation allowed a rapid identification of chemical compounds from the M. caesalpiniifolia leaves extract. Besides, this species presents a good safety profile as observed in toxicological studies, and possess a great potential in the production of herbal medicines or as for food consumption. PMID- 25298661 TI - Anti-melanogenic activity of the novel herbal medicine, MA128, through inhibition of tyrosinase activity mediated by the p38 mitogen-activated protein kinases and protein kinase signaling pathway in B16F10 cells. AB - BACKGROUND: Recently, our research group developed MA128, a novel herbal medicine, and demonstrated that MA128 is effective for the treatment of asthma and atopic dermatitis (AD). In particular, postinflammatory hyper-pigmentation in AD mice was improved with MA128 treatment. Thus, in this study, we determined the effect of MA128 on melanogenesis and its underlying mechanism in murine B16F10 melanoma cells. MATERIALS AND METHODS: After treatment with MA128 at 100 and 250 MUg/mL and/or alpha-melanocyte stimulating hormone (alpha-MSH) (1 MUM), cellular melanin content and tyrosinase activity in B16F10 cells were measured. Using western blotting, expression levels of tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, microphthalmia-associated transcription factor (MITF), and activation of c-AMP-dependent protein kinase (PKA), c-AMP-related element binding protein (CREB) and mitogen-activated protein kinases (MAPKs) were examined. RESULTS: MA128 significantly inhibited melanin synthesis and tyrosinase activity in a resting state as well as alpha-MSH-stimulating condition, and significantly decreased the expression of tyrosinase, TRP-1, TRP-2 and MITF. In addition, phosphorylation of PKA and CREB by alpha-MSH stimulation was efficiently blocked by MA128 pretreatment. Moreover, MA128 as an herbal mixture showed synergistic anti-melanogenic effects compared with each single constituent herb. CONCLUSION: MA128 showed anti-melanogenic activity through inhibition of tyrosinase activity mediated by p38 MAPK and PKA signaling pathways in B16F10 cells. These results suggest that MA128 may be useful as an herbal medicine for controlling hyper pigmentation and as a skin-whitening agent. PMID- 25298662 TI - Ultra high performance liquid chromatography-ultraviolet-electrospray ionization micrOTOF-Q II analysis of flavonoid fractions from Jatropha tanjorensis. AB - BACKGROUND: Jatropha tanjorensis (Euphorbiaceae) an exotic traditional plant unique to Thanjavur district of Southern India also commonly called as Catholic vegetable. It has been used traditionally in decoctions for treating various ailments and as a health tonic. OBJECTIVE: The objective of the present work is to study a comprehensive characterization of methanolic extract fractions using ultra high performance liquid chromatography (UHPLC)+-electrospray ionization (ESI)-micrOTOF-Q II and correlate their bioactivities. MATERIALS AND METHODS: Phytoconstituents from J. tanjorensis leaves were extracted with methanol (MeOH) followed by successive chromatography using linear gradient polar solvents system. All fractions obtained were evaluated for their chemical potential using micrOTOF-Q II techniques and identified key molecules were determined for their anticancer and anti-oxidant potential using in vitro methods. RESULTS: Successive column chromatography of the MeOH residue yielded six fractions. Compounds such as such as C-glycosylflavones (mono-C-, di-C-), O, C-diglycosylflavones and aglycones were identified for the first time in this plant using UHPLC ultraviolet-micrOTOF-Q II ESI and a correlation with their anticancer using 3 [4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay on Ehrlich ascites cells (EAC) and antioxidant activities using 2,2-diphenyl-1 picrylhydrazyl and lipid peroxidation were studied; fraction D extract exhibited the strongest activity against cancer cell. CONCLUSIONS: LC-mass spectrometry has been successfully applied for a quick separation and identification of the major phytoconstituents. All fractions have shown potent antioxidative activity as compared to standard antioxidant 3,5-di-tert-butyl-4-hydroxytoluene. EAC cell based cytotoxicity assay also revealed encouraging results. The antioxidant and anticancer activity determined in the present work can be attributed to the presence of flavonoids and flavone glycosides. Present work provides the first scientific report on phytoconstituents of J. tanjorensis and its ethnopharmacological significance. PMID- 25298663 TI - Multiple shoot regeneration and effect of sugars on growth and nitidine accumulation in shoot cultures of Toddalia asiatica. AB - BACKGROUND: Toddalia asiatica (Rutaceae) is an important medicinal plant in traditional medicinal system of India and China. Nitidine production from callus cultures of the plant had been investigated, but in vitro multiplication and secondary metabolite production from shoot cultures is not reported. OBJECTIVE: The aim of the present work is to establish protocol for in vitro multiple shoot regeneration of T. asiatica and to investigate the secondary metabolite, nitidine production from the shoot cultures. MATERIALS AND METHODS: Different explants were used for shoot regeneration on MS supplemented with benzyl adenine (BA) either alone or in combination with naphthalene acetic acid (NAA) in different combinations. Effect of different sugars and different concentrations of sucrose on biomass accumulation in shoot cultures in liquid medium was investigated. For in vitro rooting, shoots culture were inoculated to half strength MS medium supplemented with different concentrations of indole butyric acid. Quantitative analysis of shoot culture extracts was done for estimation of nitidine by HPTLC. RESULTS: Shoot cultures were successfully initiated and established from nodal and shoot tip explants on MS medium supplemented with benzyl adenine and sucrose (3% w/v). Sucrose at a concentration of 3 % w/v was found to be optimum for growth and biomass accumulation. In vitro rooting of shoots was achieved on half strength MS medium supplemented with indole butyric acid 3 mg/l. Investigation of secondary metabolite production ability of the in vitro regenerated shoot cultures revealed their ability to biosynthesize nitidine. CONCLUSION: Shoot cultures were established and nitidine production has been observed. PMID- 25298664 TI - Effects of rhamnocitrin 4-beta-D-galactopyranoside, isolated from Astragalus hamosus on toxicity models in vitro. AB - BACKGROUND: Astragalus hamosus L. (Fabaceae) is used in herbal medicine as emollient, demulcent, phrodisiac, diuretic, laxative, and good for inflammation, ulcers, and leukoderma. It is useful in treating irritation of the mucous membranes, nervous affections, and catarrh. OBJECTIVE: Rhamnocitrin 4-beta-D galactopyranoside (RGP), isolated from A. hamosus, was investigated for its possible protective effect on different models of toxicity in vitro on sub cellular and cellular level. MATERIALS AND METHODS: The effects of RGP were evaluated on isolated rat brain synaptosomes, prepared by Percoll reagent and on rat hepatocytes, isolated by two-stepped collagenase perfusion. RESULTS: In synaptosomes, RGP had statistically significant protective effect, similar to those of silymarin, on 6-hydroxy (OH)-dopamine-induced oxidative stress. These results correlate with literature data about protective effects of kempferol and rhamnocitrin on oxidative damage in rat pheochromocytoma PC12 cells. In rat hepatocytes, we investigate the effect of RGP on two models of liver toxicity: Bendamustine and cyclophosphamide. In these models, the compound had statistically significant cytoprotective and antioxidant activity, similar to those of silymarin. CONCLUSION: According to these results, we can suggest that such cytoprotective effect of RGP might be due to an influence on bendamustine and cyclophosphamide metabolism in rat hepatocytes. In isolated rat hepatocytes, in combination with bendamustine and cyclophosphamide and in 6-OH-dopamine induced oxidative stress in isolated rat synaptosomes, RGP, isolated from A. hamosus, was effective protector and antioxidant. The effects were closed to those of flavonoid silymarin-the classical hepatoprotector and antioxidant. PMID- 25298665 TI - Inhibition of inducible nitric oxide synthase and osteoclastic differentiation by Atractylodis Rhizoma Alba extract. AB - BACKGROUND: Atractylodis Rhizoma Alba (ARA) has been used in Korean folk medicine for constipation, dizziness, and anticancer agent. In the present study, we performed to test whether the methanolic extract of ARA has antioxidant and antiosteoclastogenesis activity in RAW 264.7 macrophage cells. MATERIALS AND METHODS: Antioxidant capacities were tested by measuring free radical scavenging activity, nitric oxide (NO) levels, reducing power, and inducible nitric oxide synthase (iNOS) expression in response to lipopolysaccharides (LPS). Antiosteoclastogenesis activity was evaluated by performing tartrate-resistant acid phosphatase assay in RAW 264.7 macrophage cells. RESULTS: The extract exerted significant 1,1-diphenyl-2-picrylhydrazyl and NO radical scavenging activity, and it exerted dramatic reducing power. Induction of iNOS and NO by LPS in RAW 264.7 cells was significantly inhibited by the extract, suggesting that the ARA extract inhibits NO production by suppressing iNOS expression. Strikingly, the ARA extracts substantially inhibited the receptor activator of NF kappaB ligand-induced osteclastic differentiation of LPS-activated RAW 264.7 cells. The ARA extract contains a significant amount of antioxidant components, including phenolics, flavonoids and anthocyanins. CONCLUSION: These results suggest that the methanolic extract of ARA exerts significant antioxidant activities potentially via inhibiting free radicals and iNOS induction, thereby leading to the inhibition of osteoclastogenesis. PMID- 25298666 TI - New steroidal saponin from Antigonon leptopus Hook. and Arn. AB - BACKGROUND: Antigonon leptopus Hook. and Arn., Polygonaceae (cadena de amor), is a herbal remedy for pain and gout-like symptoms in the Philippines. The methanol extract of A. leptopus have shown strong inhibitory action against xanthine oxidase. OBJECTIVE: To isolate and identify the compound responsible for the xanthine oxidase inhibitory action. MATERIALS AND METHODS: A bioassay-guided isolation scheme using an in vitro assay for the inhibition of xanthine oxidase was employed. The structure was established using spectroscopic analysis and chemical methods. RESULTS: The isolated compound was determined to be a noncompetitive inhibitor of xanthine with an IC50 of 1.79 MUg/mL. CONCLUSION: The isolated compound may represent a new class of xanthine oxidase inhibitors. PMID- 25298667 TI - So-Cheong-Ryong-Tang, a herbal medicine, modulates inflammatory cell infiltration and prevents airway remodeling via regulation of interleukin-17 and GM-CSF in allergic asthma in mice. AB - BACKGROUND: So-Cheong-Ryong-Tang (SCRT), herbal medicine, has been used for the control of respiratory disease in East Asian countries. However, its therapeutic mechanisms, especially an inhibitory effect on inflammatory cell infiltration and airway remodeling in allergic asthma are unclear. OBJECTIVE: The present study investigated the mechanism of antiasthmatic effects of SCRT in allergic asthma in mice. MATERIALS AND METHODS: We investigated the influence of SCRT on levels of interleukin-17 (IL-17), granulocyte/macrophage colony-stimulating factor (GM CSF), IL-4, and interferon gamma (IFN-gamma) in bronchoalveolar lavage fluid (BALF), ovalbumin (OVA)-specific IgE in serum, and histopathological changes in allergen-induced asthma. RESULTS: So-Cheong-Ryong-Tang decreased levels of IL-17 and GM-CSF in BALF. IL-4, a Th2-driven cytokine, was also decreased by SCRT, but IFN-gamma, a Th1-driven cytokine, was not changed. Levels of OVA-specific IgE in serum were also decreased by SCRT. With SCRT treatment, histopathological findings showed reduced tendency of inflammatory cell infiltration, and prevention from airway remodeling such as epithelial hyperplasia. CONCLUSION: In this study, we firstly demonstrated that regulation of IL-17 and GM-CSF production may be one of the mechanism contributed to a reduction of inflammatory cell infiltration and prevention from airway remodeling. PMID- 25298668 TI - Efficacy evaluation of Bauhinia variegata L. stem bark powder as adjunct therapy in chronic Staphylococcus aureus mastitis in goat. AB - OBJECTIVE: The objective was to study the effect of Bauhinia variegata L. stem bark powder as adjunct therapy in chronic Staphylococcus aureus mastitis in goat. MATERIALS AND METHODS: Mastitis was induced by intracisternal inoculation of coagulase positive S. aureus (J638) at the concentration of 2000 colony forming units. Group I animals were treated with repeated dose of ceftriaxone at 20 mg/kg intravenously, and Group II animals were treated with once daily oral administration of B. variegata L. stem bark powder at 6 g/kg for 7 days followed by maintenance dose at 3 g/kg for next 7 days along with repeated dose of the antibiotic at 20 mg/kg intravenously at 4 days interval. RESULTS: No significant improvement in the clinical condition of the udder was noticed in the group treated with repeated dose of ceftriaxone alone. However, in the group treated with B. variegata L. stem bark powder along with repeated dose of ceftriaxone, no S. aureus colony was seen at 96 h and onwards in milk samples with a marked decrease in somatic cell count and milk alkaline phosphatase activity and increased lactoperoxidase activity. Further, plasma and milk concentration of ceftriaxone/ceftizoxime was increased, which indicated antibacterial, bioenhancing and antiinflammatory properties of the bark powder. The Group II animals also exhibited marked reduction in polymorphonuclear cells and fibrous tissue indicating antifibrotic property of B. variegata L. CONCLUSION: B. variegata L. stem bark powder can be considered as an effective adjunct therapy to intravenous ceftriaxone in S. aureus chronic mastitis in goat. PMID- 25298669 TI - Anticancer activity of flavane gallates isolated from Plicosepalus curviflorus. AB - BACKGROUND: Previous investigation of the methanol extract of Plicosepalus curviflorus leaves led to the isolation of two new flavane gallates (1, 2), together with other compounds including quercetin (3). The stems of P. curviflorus are used traditionally for the treatment of cancer in Yemen. OBJECTIVE: The aim of this study was to evaluate the anticancer activity of the plant methanol extract as well as isolated compounds (1-3). MATERIALS AND METHODS: The human cancer cell lines used were; MCF-7, HepG-2, HCT-116, Hep-2, HeLa and normal, Vero cell line using the Crystal Violet Staining method (CVS). RESULTS: Quercetin (3) possessed the highest anticancer effect against all five cell lines (IC50 ranging from 3.6 to 16.2 MUg/ml). It was followed by 2S, 3R-3, 3', 4', 5, 7-pentahydroxyflavane-5-O-gallate (1), with IC50 ranging from 11.6 to 38.8 MUg/ml. The weakest anticancer activity was given by 2S, 3R-3,3',4',5,5',7 hexahydroxyflavane-3',5-di-O-gallate (2) with IC50 ranging from 39.8 to above 50 MUg/ml, compared to vinblastine sulphate as reference drug. Colon, liver and breast cell lines seemed to be more sensitive to the tested compounds than the cervical and laryngeal cell lines. Concerning the cytotoxic effect on Vero cell line, the pentahydroxyflavane-5-O-gallate (1) showed the highest IC50 ( 138.2 MUg/ml), while quercetin exhibited the lowest IC50 to Vero cells (30.5 MUg/ml), compared to vinblastine sulphate as reference drug (IC50: 39.7 MUg/ml). CONCLUSION: The results suggest the possible use of compounds 1 and 3 as anticancer drugs especially against colon and liver cancers. PMID- 25298670 TI - Anticancer potential of Conium maculatum extract against cancer cells in vitro: Drug-DNA interaction and its ability to induce apoptosis through ROS generation. AB - OBJECTIVE: Conium maculatum extract is used as a traditional medicine for cervix carcinoma including homeopathy. However, no systematic work has so far been carried out to test its anti-cancer potential against cervix cancer cells in vitro. Thus, in this study, we investigated whether ethanolic extract of conium is capable of inducing cytotoxicity in different normal and cancer cell lines including an elaborate study in HeLa cells. MATERIALS AND METHODS: Conium's effects on cell cycle, reactive oxygen species (ROS) accumulation, mitochondrial membrane potential (MMP) and apoptosis, if any, were analyzed through flow cytometry. Whether Conium could damage DNA and induce morphological changes were also determined microscopically. Expression of different proteins related to cell death and survival was critically studied by western blotting and ELISA methods. If Conium could interact directly with DNA was also determined by circular dichroism (CD) spectroscopy. RESULTS: Conium treatment reduced cell viability and colony formation at 48 h and inhibited cell proliferation, arresting cell cycle at sub-G stage. Conium treatment lead to increased generation of reactive oxygen species (ROS) at 24 h, increase in MMP depolarization, morphological changes and DNA damage in HeLa cells along with externalization of phosphatidyl serine at 48 hours. While cytochrome c release and caspase-3 activation led HeLa cells toward apoptosis, down-regulation of Akt and NFkB inhibited cellular proliferation, indicating the signaling pathway to be mediated via the mitochondria-mediated caspase-3-dependent pathway. CD-spectroscopy revealed that Conium interacted with DNA molecule. CONCLUSION: Overall results validate anti-cancer potential of Conium and provide support for its use in traditional systems of medicine. PMID- 25298671 TI - Euphorbia hirta accelerates fibroblast proliferation and Smad-mediated collagen production in rat excision wound. AB - BACKGROUND: Euphorbia hirta L. (Euphorbiaceae) is a traditional herbal medicine used for treatment of various diseases. OBJECTIVE: E. hirta was investigated for in vitro/in vivo wound healing activity using human dermal fibroblast cell line and Wistar rats. MATERIALS AND METHODS: Petroleum ether, chloroform, methanol and water successive extracts of E. hirta leaves were evaluated for antioxidant, antimicrobial and fibroblast proliferation activities. Among different extracts, the promising methanol extract was screened for wound healing activity in Wistar rats, using gentamicin sulfate (0.01% w/w) as a reference. Wound contraction, hydroxyproline content and the protein expression of COL3A1, bFGF, Smad-2,-3,-4 and -7 were measured. RESULTS: The E. hirta methanol extract showed a potent antimicrobial (MIC 0.250 mg/ml against Escherichia coli and Klebsiella pneumoniae, both), antioxidant activities (IC50 = 10.57 MUg/ml, 2,2-diphenyl-1 picrylhydrazyl; 850.23 MUg/ml, superoxide-anion radical scavenging activity and 23.63 mg gallic acid equivalent per gram extract) with significant fibroblast proliferating activity (112% at 12.5 MUg/ml) as compared to other extracts. In vivo study also supported the wound healing potential of methanol extract, as evidenced by faster wound contraction, higher hydroxyproline (4.240 mg/100 mg tissue) and improved histopathology of granulation tissue as compared to control groups and gentamicin sulfate-treated ones. Western blot also revealed a significantly altered expression of Smad-mediated proteins resulting in collagen production. CONCLUSION: The study suggested that E. hirta accelerates the wound healing by augmenting the fibroblast proliferation and Smad-mediated collagen production in wound tissue. PMID- 25298672 TI - A new mulinane diterpenoid from the cushion shrub Azorella compacta growing in Peru. AB - BACKGROUND: Azorella compacta is a rare yellow-green compact resinous cushion shrub growing from the high Andes of southern Peru to northwestern Argentina, and which is a producer of biologically active and unique diterpenoids. OBJECTIVE: This study investigated the secondary metabolites present in a Peruvian sample of Azorella compacta and the evaluation of gastroprotective activity of the isolated compounds in a gastric- induced ulcer model in mice. MATERIAL AND METHODS: Six secondary metabolites (diterpenoids 1-6) present in the dichloromethane (DCM) extract of A. compacta growing in Peru were isolated by a combination of Sephadex LH-20 permeation and silica gel chromatography and their chemical structures were elucidated by spectroscopic methods (NMR) and molecular modeling. The gastroprotective activity of the new compound 1 was evaluated on the HCl/EtOH induced gastric lesion model in mice and compared to the activity showed by the known compounds. RESULTS: A new mulinane diterpene along with five known diterpenoids have been isolated from a Peruvian sample of A. compacta and the gastroprotective results show that compound 1 is less active than the other known mulinane diterpenoids isolated. CONCLUSIONS: A. compacta growing in Peru showed the presence of the new mulinane 1, which was poorly active in the HCl/EtOH induced gastric lesion model in mice. Indeed, the activity was lower than other diterpenoids (2-6) showing an oxygenated function at C-16 or/and C-20, which confirm the role of an oxygenated group (OH or carboxylic acid) for the gastroprotective activity of mulinane compounds. PMID- 25298673 TI - Effect of three fatty acids from the leaf extract of Tiliacora triandra on P glycoprotein function in multidrug-resistant A549RT-eto cell line. AB - BACKGROUND: Cancer cells have the ability to develop resistance to chemotherapy drugs, which then leads to a reduced effectiveness and success of the treatment. Multidrug resistance (MDR) involves the resistance in the same cell/tissue to a diverse range of drugs of different structures. One of the characteristics of MDR is an overexpression of P-glycoprotein (P-gp), which causes the efflux of the accumulated drug out of the cell. The MDR human non-small cell lung carcinoma cell line with a high P-gp expression level (A549RT-eto) was used to investigate the bioactive compounds capable of reversing the etoposide resistance in this cell line. MATERIALS AND METHODS: The leaves of Tiliacora triandra were sequentially extracted with hexane, dichloromethane, methanol and water. Only the hexane extract reduced the etoposide resistance of the A549RT-eto cell line, and was further fractionated by column chromatography using the TLC-pattern and the restoration of etoposide sensitivity as the selection criteria. RESULTS: The obtained active fraction (F22) was found by nuclear magnetic resonance and gas chromatography-mass spectroscopy analyses to be comprised of a 49.5:19.6:30.9 (w/w/w) mixture of hexadecanoic: octadecanoic acid: (Z)-6-octadecenoic acids. This stoichiometric mixture was recreated using pure fatty acids (MSFA) and gave a similar sensitization to etoposide and enhanced the relative rate of rhodamine 123 accumulation to a similar extent as F22, supporting the action via reducing P gp activity. In contrast, the fatty acids alone did not show this effect. CONCLUSION: This is the first report of the biological activity from the leaves of T. triandra as a potential source of a novel chemosensitizer. PMID- 25298674 TI - Strophanthus hispidus attenuates the Ischemia-Reperfusion induced myocardial Infarction and reduces mean arterial pressure in renal artery occlusion. AB - BACKGROUND: The myocardium is generally injured in the case of reperfusion injury and arterial damage is caused by hypertension. In reference to these statements, the present study was focused. Cardiac glycosides were said to have protective effects against myocardial infarction and hypertension. Strophanthus hispidus was thus incorporated in the study. OBJECTIVE: The prime objective of the study was to investigate the protective effects of Strophanthus hispidus against ischemia reperfusion myocardial Infarction and renal artery occluded hypertension in rats. MATERIALS AND METHODS: The animal model adopted was surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was assessed by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Hypertension was induced by clamping the renal artery with renal bulldog clamp for 4 h. RESULTS: The study was fruitful by the effect of Strophanthus hispidus on infarction size, which got reduced to 27.2 +/- 0.5and 20.0 +/- 0.2 by 500 mg/Kg and 1000 mg/Kg ethanolic extracts which was remarkably significant when compared with that of the control group 52.8 +/- 4.6. The plant extract did reduce heart rate at various time intervals. There was also a protective effect in the case of mean arterial blood pressure were the 500 mg/Kg and 1000 mg/Kg of the plant extract did reduce the hypertension after 60 minutes was 60.0 +/- 4.80 and 50.50 +/- 6.80. CONCLUSION: The results suggest that 500 mg/Kg and 100 mg/Kg ethanolic extract of Strophanthus hispidus was found to possess significant cardiac protective and anti-hypertensive activity. PMID- 25298675 TI - Hepatoprotective effects of Limonium tetragonum, edible medicinal halophyte growing near seashores. AB - BACKGROUND: During the process of hepatic fibrosis, the activation of hepatic stellate cells (HSCs) is responsible for the increased formation and reduced degradation of extracellular matrix in the liver. By employing the hepatic stellate cell line, HSC-T6, it was found that the methanol extract of Limonium tetragonum, a halophyte living in salt marsh near south and western seashores of Korea significantly inhibited the proliferation of HSC-T6 cells. OBJECTIVE: In the present study, we attempted to investigate the antifibrotic effects of the mathanolic extract of L. tetragonum (MELT) in the activated HSC-T6 cells. MATERIALS AND METHODS: The proliferation of HSC-T6 was stimulated by culturing environment or platelet-derived growth factor (PDGF-BB) insult, and then the inhibitory activities of MELT were measured. RESULTS: It was found that MELT suppressed the proliferation of the activated HSC-T6 in concentration- and time dependent manners. The increased collagen deposition in the activated HSC-T6 cells was also decreased by the treatment of MELT. The maximal dose of MELT, however, had little effect on primary cultured rat hepatocytes. Wlammatory cytokine, tumor necrosis factor alpha (TNF-alpha) produced by lipopolysaccharide stimulated RAW264.7 macrophages was inhibited by MELT. CONCLUSION: Collectively, the above results demonstrated that MELT suppressed HSCs proliferation but not in hepatocytes, implying that L. tetragonum may be useful candidates for developing therapeutic agents for the prevention and treatment of hepatic fibrosis. PMID- 25298676 TI - The effects of extraction method on recovery rutin from Calendula officinalis L. (Asteraceae). AB - BACKGROUND: Calendula officinalis L. (Asteraceae) is a Mediterranean specie, but in Europe and America it is cultivated for ornamental or medicinal purposes. This species is widely used for presenting activities, antiinflammatory antibacterial and antioxidant. However the therapeutic action is linked to the amount of assets of the extracted raw material. The extraction method of bioactive compounds is an important step in the manufacturing of herbal medicines, because secondary metabolites with therapeutic potential are usually found in small quantities in plant materials. OBJECTIVE: Due the medical and commercial importance of C. officinalis, this study aimed to evaluate the impact of the extraction method on the quality of herbal extract and optimize the extraction of rutin from C. officinalis. MATERIALS AND METHODS: The extraction of rutin was performed by ultrasound and shaker and the optimized conditions were determined by response surface methodology. RESULTS: The results of ultrasound extraction assisted (UEA) and maceration dynamic (MD) showed that rutin yield ranged from 0.218 to 2.28% (w/w) when extract by ultrasound and 0.1-1.44% by MD. The optimal extraction condition for rutin (2.48% to UEA or 1.46% to MD) from C. officinalis by UEA or MD were a 19-22 min extraction, ethanol: water ratio of 35-40% and 0.05-0.056 mg/mL to raw material: solvent ratio. CONCLUSION: The UEA is more efficient to extraction rutin. PMID- 25298677 TI - Chemical composition and hepatotoxic effect of Geranium schiedeanum in a thioacetamide-induced liver injury model. AB - One of the major components of some geraniums is geraniin, described by its discoverer as crystallizable tannin, well known as an excellent antioxidant, and also found in fruits such as pomegranate. Recently, natural antioxidants have attracted great attention from consumers over the world due to their lower toxicity than synthetics. But geraniin is not a stable compound, and also is difficult to obtain, that is why in the present study we obtained acetonylgeraniin from Geranium schideanum (Gs), a stable acetone condensate of geraniin. In the present study the effect of Gs acetone-water extract was studied in reference to postnecrotic liver regeneration induced by thioacetamide (TA) in rats. Two months male rats were pretreated with daily dose of Gs extract for 4 days (300 mg/kg) and the last day also were intraperitoneally injected with TA (6.6 mmol/kg). Samples of blood were obtained from rats at 0, 24, 48, 72 and 96 h following TA intoxication. The pre-treatment with the crude extract in the model of thioacetamide-induced hepatotoxicity in rats decreased and delayed liver injury by 66% at 24 h. This result suggests that Gs extract may be used as an alternative for reduction of liver damage. On the other hand, acute toxicity study revealed that the LD50 value of the Gs extract is more than the dose 5000 mg/kg in rats, according to the Lorke method. PMID- 25298678 TI - Efficacy of ellagic acid and sildenafil in diabetes-induced sexual dysfunction. AB - BACKGROUND: Diabetes induced sexual dysfunction is a leading cause of male sexual disorder and an early indicator of cardiovascular complication. Reactive oxygen species generated in body during diabetes is a main causative factor for erectile dysfunction, a sexual dysfunction. Adjuvant antioxidant therapy along with phosphodiesterases type 5 enzyme inhibitor (PDE5i) is more effective than PDE5i alone. OBJECTIVE: The aim of the study was to investigate efficacy of ellagic acid a known antioxidant and sildenafil in diabetes induced erectile dysfunction. MATERIALS AND METHODS: Type 1 diabetes was induced in male rats and rats were treated with ellagic acid (50 mg/kg, p.o.) and a combination of ellagic acid (50 mg/kg, p.o.) and sildenafil (5 mg/kg, p.o.), a PDE5i for 28 days. Sexual function was observed in diabetic rat and compared with those of treatment group and normal rats. Effect of ellagic acid was studied on advanced glycation end products (AGE) and isolated rat corpus cavernosum in vitro. RESULTS: Sexual function of diabetic rats was found to be reduced and ellegic acid treatment could preserve sexual function of diabetic rats to some extent. Ellagic acid + sildenafil treatment was more efficient in management of diabetes induced sexual dysfunction. Ellagic acid inhibited (AGE) in vitro implying its role in reducing oxidative stress in diabetes. The polyphenol could not increase sexual function in normal rats and relax isolated rat corpus cavernosum smooth muscle significantly. CONCLUSION: The study proves usefulness of adjuvant antioxidant therapy in the management of erectile dysfunction in diabetes. PMID- 25298679 TI - Anti-inflammatory effect of Artemisiae annuae herba in lipopolysaccharide stimulated RAW 264.7 Cells. AB - BACKGROUND: Artemisiae annuae herba (AAH) has been traditionally used as a drug for the treatment of malaria, heat stroke, bacterial infection, and fever in East Asia. Although AAH has been used for the treatment of inflammation-related symptoms, the underlying mechanism of antiinflammatory activity of AAH is still unknown. OBJECTIVE: We investigated whether AAH have an inhibitory effect on the production of pro-inflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. MATERIALS AND METHODS: The investigation was forced on the inhibitory effect of AAH on the production of tumor necrosis factor (TNF) alpha, interleukin (IL)-6, nitric oxide (NO), and inducible NO synthase (iNOS) in macrophages. Furthermore, we examined the effect of AAH on the activation of nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) pathways. RESULTS: We found that AAH suppresses NO production and TNF-alpha, IL 6, and iNOS gene expression. Moreover, AAH inhibited the nuclear translocation of p65 and IkappaBalpha degradation in NF-kappaB pathway and decreased the extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase phosphorylation in MAPK signaling pathway. CONCLUSIONS: Consequently, these results indicate that AAH contains antiinflammatory activity and this effect is derived from the repression on the activation of NF-kappaB and MAPKs pathways. We first demonstrated that antiinflammatory effect of AAH and its underlying mechanism in macrophage cells. PMID- 25298680 TI - Bioassay-guided isolation, identification and molecular ligand-target insight of lipoxygenase inhibitors from leaves of Anisomeles malabarica R.Br. AB - BACKGROUND: Anisomeles malabarica R. Br. (Lamiaceae) is extensively used in traditional medicine in major parts of India for several medicinal purposes, including their use in rheumatism. MATERIALS AND METHODS: The air-dried leaves of A. malabarica were extracted with ethanol, defatted with n-hexane and then successively partitioned into chloroform and n-butanol fractions. Bioassay-guided fractionation and purification of chloroform fraction from A. malabarica lead to the isolation of lipoxygenase (LOX) inhibitors. The structures of isolated compounds were elucidated by ultraviolet, infrared, (1)H nuclear magnetic resonance (NMR), (13)C NMR and mass spectrometry spectroscopic techniques and assessed further by in vitro soybean lipoxygenase (sLOX) assay. In addition, the enzyme type inhibition was evaluated through molecular docking technique as a part of computational study. RESULTS: The bioactive compounds 3, 4 dihydroxy benzoic acid (1) and 4', 5, 7-trihydroxyflavone (2) were isolated from chloroform fraction of A. malabarica, whose bioactivity was observed to be dose-dependent compared to n-butanol fraction. Among the compounds, 3, 4 dihydroxy benzoic acid showed significant sLOX inhibitory activity with 74.04% +/-2.6% followed by 4', 5, 7-trihydroxyflavone (34.68% +/-1.9%). The computational analysis of compounds showed their molecular interaction with important amino acid residues and nonheme iron atom in the catalytic site of LOX by enlightening their potential binding mode at molecular level. CONCLUSIONS: The LOX inhibitory constituents were identified from A. malabarica by means of bioassay-guided fractionation process. The results derived from in vitro and computational experiments confirm the potential of the isolated compounds and provide additional evidence for its traditional use in inflammatory disorders. PMID- 25298681 TI - Optimization of the extraction process for the seven bioactive compounds in Yukmijihwang-tang, an herbal formula, using response surface methodology. AB - BACKGROUND: Yukmijihwang-tang (YJT) contains multiple bioactive compounds. Heat reflux extraction was employed and optimized for the extraction of the bioactive compounds in YJT. OBJECTIVE: The determination of optimal conditions with maximum yields of bioactive compounds, gallic acid, 5-hydroxymethylfurfural, morroniside, loganin, paeoniflorin, benzoic acid and paeonol, in YJT. MATERIALS AND METHODS: The extraction ratio (ratio of water to herbal formula), extraction time and extraction number were set as individual values and the yields of the seven compounds were the response values that were optimized with a Box-Behnken design. RESULTS: The optimal conditions obtained from response surface methodology (RSM) were 1:11.99 for the extraction ratio, 94.53 min for the extraction time and 2.21 for the extraction number. Under the optimal conditions, the response value of the experiment closely agreed with the predicted response value. CONCLUSIONS: The result suggests that RSM is successfully applied for optimizing the extraction of the marker compounds in YJT. PMID- 25298682 TI - Effect of whole plant of Rostellularia diffusa Willd. on experimental stress in mice. AB - BACKGROUND: Rostellularia diffusa is an unexplored medicinal plant used as brain tonic in traditional medicine system. OBJECTIVE: This study was designed to investigate the antioxidant and anti-stress potential of R. diffusa by experimental animal models. MATERIALS AND METHODS: The extracts of R. diffusa were subjected to preliminary phytochemical screening and high performance thin layer chromatography (HPTLC) finger printing analysis. The antioxidant potential of the extracts was found by different in vitro models. The anti-stress activity was investigated by using acetic acid induced writhing test, swimming endurance test, and restraint stress in experimental mice. Serum parameters such as glucose, triglyceride and cholesterol, oxidative stress parameter thiobarbituric acid reactive substance, antioxidant parameters such as reduced glutathione, superoxide dismutase and catalase and organ weights were evaluated after restraint stress in mice. Diazepam was used as reference standard to compare the anti-stress activity of plant extract. RESULTS: High performance thin layer chromatography finger printing analysis revealed the presence of flavone compounds in both extracts. The extracts also showed good antioxidant property in different in vitro antioxidant models. Administration of extracts of R. diffusa decreased the number of wriths and immobility time when compared with control group in acetic acid-induced writhing test and swimming endurance test respectively in experimental mice. They also suppressed the restraint stress induced alterations in serum parameters, oxidative stress, and antioxidant parameters in brain and also restored the organ weights in normal level. CONCLUSION: From these results, it has been concluded that the potential anti stress activity of R. diffusa is through its adaptogenic and antioxidant properties. PMID- 25298683 TI - Signal transducer and activators of transcription 3 regulates cryptotanshinone induced apoptosis in human mucoepidermoid carcinoma cells. AB - BACKGROUND: Cryptotanshinone (CT) is a biologically active compound from the root of Salvia miltiorrhiza that has been reported to induce apoptosis in various cancer cell lines; but, it has not yet been fully explored in human mucoepidermoid carcinoma (MEC). OBJECTIVE: Here, we demonstrated the apoptotic effects and its related mechanism in MC-3 and YD-15 human MEC cell lines. MATERIALS AND METHODS: The effects of CT on apoptotic activity were evaluated by cell proliferation assay, Western blotting, 4'-6-diamidino-2-phenylindole staining, reverse transcription-polymerase chain reaction, and luciferase assay. RESULTS: Our data show that CT treatment of MC-3 cells results in anti proliferative and apoptotic activities in MC-3 and it is accompanied by a decrease in phosphorylation and dimerization of signal transducer and activators of transcription 3 (STAT3). CT decreased the expression levels of myeloid cell leukemia-1 (Mcl-1) and surviving, whereas Bcl-xL expression was not changed. CT clearly regulates survivin protein at a transcriptional level and alters Mcl-1 through proteasome-dependent protein degradation. In addition, CT-induced apoptotic cell death in YD-15, another human MEC cell line, was associated with the inhibition of STAT3 phosphorylation. CONCLUSION: These data suggest that CT could be a good apoptotic inducer through modification of STAT3 signaling in human MEC cell lines. PMID- 25298684 TI - The Pavonia xanthogloea (Ekman, Malvaceae): Phenolic compounds quantification, anti-oxidant and cytotoxic effect on human lymphocytes cells. AB - INTRODUCTION: Pavonia xanthogloea is traditionally used as an antimicrobial and anti-tumour medicine in Southern Brazilian region. However, investigations about this species are still incipient. HYPOTHESIS TESTED: The study postulated that P. xanthologea specie present some phenolic compound and present some biological properties as anti-oxidant and cytoprotective effect against oxidative stress. MATERIALS AND METHODS: The content of eight phenolic molecules in the crude ethanolic extract of the aerial part of P. xanthogloea and its five fractions (hexane, dichloromethane, ethyl-acetate, n-butanol, and water) was determined by heterotrophic plate count method. The anti-oxidant capacity of the extract and the fractions was determined by 1,1-diphenyl-2-picryl-hydrazyl assay. The potential anti-oxidant and cytoprotective effect was also analyzed in human lymphocyte culture treated with extract/fractions at different concentrations with and without oxidative stress generated by hydrogen peroxide (H2O2) and sodium nitroprusside (SNP) exposition. RESULTS: Tiliroside was the molecule detected in all extract. Water and ethyl-acetate fractions showed the highest radical-scavenging activity. The crude extract, hexane, water, and n-butanol reversed the higher reactive oxygen specie levels generated by H2O2 and SNP to levels similar to those observed in the control group. In addition, crude extract, hexane, ethyl-acetate and n-butanol did not caused cytotoxicity, whereas water fraction was cytotoxic at higher concentration tested here (300 MUg/mL). The cytotoxicity reversion caused by SNP exposition was concentration-dependent of the extract and fractions. However, dichloromethane fraction increased cell mortality in all concentrations investigated and was not able to decrease cell death in the lymphocytes exposed to SNP. CONCLUSION: The results suggest potential medicine use of this species. PMID- 25298685 TI - Identification of natural inhibitors against angiotensin I converting enzyme for cardiac safety using induced fit docking and MM-GBSA studies. AB - BACKGROUND: Cleistanthins A and B are isolated compounds from the leaves of Cleistanthus collinus Roxb (Euphorbiaceae). This plant is poisonous in nature which causes cardiovascular abnormalities such as hypotension, nonspecific ST-T changes and QTc prolongation. The biological activity predictions spectra of the compounds show the presence of antihypertensive, diuretic and antitumor activities. OBJECTIVE: Objective of the present study was to determine the in silico molecular interaction of cleistanthins A and B with Angiotensin I- Converting Enzyme (ACE-I) using Induced Fit Docking (IFD) protocols. MATERIALS AND METHODS: All the molecular modeling calculations like IFD docking, binding free energy calculation and ADME/Tox were carried out using Glide software (Schrodinger LLC 2009, USA) in CentOS EL-5 workstation. RESULTS: The IFD complexes showed favorable docking score, glide energy, glide emodel, hydrogen bond and hydrophobic interactions between the active site residues of ACE-I and the compounds. Binding free energy was calculated for the IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of ACE-I were observed based on changes of the back bone Calpha atoms and side-chain chi (x) angles. The various physicochemical properties were calculated for these compounds. Both cleistanthins A and B showed better docking score, glide energy and glide emodel when compared to captopril inhibitor. CONCLUSION: These compounds have successively satisfied all the in silico parameters and seem to be potent inhibitors of ACE-I and potential candidates for hypertension. PMID- 25298686 TI - Lactobacilli-fermented Hwangryunhaedoktang has enhanced anti-inflammatory effects mediated by the suppression of MAPK signaling pathway in LPS-stimulated RAW 264.7 cells. AB - BACKGROUND: Hwangryunhaedoktang (HR) has been traditionally used in oriental medicine as a drug for the treatment of melena, hemoptysis, and apoplexy. OBJECTIVE: We investigated whether HR and lactobacilli-fermented HRs have an inhibitory effect on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. MATERIALS AND METHODS: The investigation was focused on whether HR and fermented HRs could inhibit the production of prostaglandin (PG)E2, nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and mitogen-activated protein kinases (MAPKs) in LPS stimulated RAW 264.7 cells. RESULTS: We found that HR weakly inhibited various inflammatory mediators induced by LPS. However, fermentation with lactobacilli significantly increased the inhibitory effect of HR on most of the inflammatory mediator expression. Furthermore, fermented HRs exerted a stronger inhibitory effect on MAPKs phosphorylation than that by non-fermented HR. CONCLUSIONS: These results suggest that lactobacilli-fermented HRs contains elevated potent anti inflammatory activity that is mediated by inhibiting MAPKs pathway in macrophages. PMID- 25298687 TI - Antinociceptive effect of Encholirium spectabile: A Bromeliaceae from the Brazilian caatinga biome. AB - BACKGROUND: Encholirium spectabile is a species found in outcrops rocky throughout the Brazilian Caatinga. OBJECTIVE: This study was carried out to evaluate the antinociceptive effects of ethanolic extract of the leaves from E. spectabile (Es-EtOH) in mice using chemical and thermal models of nociception. MATERIAL AND METHODS: HPLC was used to determine the fingerprint chromatogram. The Es-EtOH was examined for its antinociceptive activity at the doses of 100, 200 and 400 mg/kg intraperitoneal (i.p.). The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing, formalin and hot plate tests in mice. Rota-rod test was used for the evaluation of motor coordination. RESULTS: In the acetic acid-induced writhing test, the Es-EtOH (100, 200 and 400 mg/kg, i.p.) reduced the number of writhings by 68.59, 79.33 and 65.28%, respectively. Additionally, Es-EtOH (100, 200 and 400 mg/kg, i.p.) decreased by 34.14, 52.61 and 60.97% the paw licking time in the first phase, as well as 89.56, 79.90 and 96.71% in the second phase of the formalin test, respectively. Es-EtOH also showed effect in the hot plate test, since increased the latency time at dose of 100 mg/kg after 60 minutes. In addition, Es-EtOH did not impair motor coordination. The presence of phenolic compounds in the extract was confirmed using HPLC. These results indicate that Es-EtOH has antinociceptive activity, probably of peripheral origin. The mechanism involved is not completely understood but, at least in part there is the participation of opioid receptors. PMID- 25298688 TI - Anti-cancer effects of Kochia scoparia fruit in human breast cancer cells. AB - BACKGROUND: The fruit of Kochia scoparia Scharder is widely used as a medicinal ingredient for the treatment of dysuria and skin diseases in China, Japan and Korea. Especially, K. scoparia had been used for breast masses and chest and flank pain. OBJECTIVE: To investigate the anti-cancer effect of K. scoparia on breast cancer. MATERIALS AND METHODS: We investigated the anti-cancer effects of K. scoparia, methanol extract (MEKS) in vitro. We examined the effects of MEKS on the proliferation rate, cell cycle arrest, reactive oxygen species (ROS) generation and activation of apoptosis-associated proteins in MDA-MB-231, human breast cancer cells. RESULTS: MTT assay results demonstrated that MEKS decreased the proliferation rates of MDA-MB-231 cells in a dose-dependent manner with an IC50 value of 36.2 MUg/ml. MEKS at 25 MUg/ml significantly increased the sub-G1 DNA contents of MDA-MB-231 cells to 44.7%, versus untreated cells. In addition, MEKS induced apoptosis by increasing the levels of apoptosis-associated proteins such as cleaved caspase 3, cleaved caspase 8, cleaved caspase 9 and cleaved Poly (ADP-ribose) polymerase (PARP). CONCLUSION: These results suggest that MEKS inhibits cell proliferation and induces apoptosis in breast cancer cells and that MEKS may have potential chemotherapeutic value for the treatment of human breast cancer. PMID- 25298689 TI - Delivering pediatric cardiac care with limited resources. PMID- 25298690 TI - Efficacy of dexmedetomidine for the control of junctional ectopic tachycardia after repair of tetralogy of Fallot. AB - BACKGROUND: Junctional ectopic tachycardia occurs frequently after congenital cardiac surgery and can be a cause of increased morbidity and mortality. Dexmedetomidine (DEX) is an alpha2 adrenoreceptor agonist, has properties of controlling tachyarrhythmia by regulating the sympatho-adrenal system. OBJECTIVE: To evaluate the efficacy of DEX for control of junctional ectopic tachycardia after repair of Tetralogy of Fallot (TOF). MATERIALS AND METHODS: Two hundred and twenty pediatric cardiac patients with TOFs were enrolled in a prospective randomized control study. Patients underwent correction surgery. They were divided into two groups, i.e., Group 1 (DEX) and Group 2 (control). Heart rate, rhythm, mean arterial pressure (MAP) were recorded after the anesthetic induction (T1), after termination of bypass (T2), after 04 hours (T3), and 08 hours after transferring the patient to intensive care unit (ICU; T4). RESULTS: Heart rate was comparable between two groups before starting the drug but statistically significant after bypass until 08 hours after transferring the patient to ICU. Junctional ectopic tachycardia occurred more in Group-2 (20%) as compared to Group-1 (9.09%; P = 0.022). Junctional ectopic tachycardia occurs early in Group 2 (0.14 +/- 0.527 hours) as compared to Group 1 (0.31 +/- 1.29 hours; P = 0.042). The duration of junctional ectopic tachycardia was more prolonged in Group-2 (1.63 +/- 3.64 hours) as compared to Group-1 (0.382 +/- 1.60 hours; P = 0.012). The time to withdraw from mechanical ventilation and ICU stay of Group 1 patient was less than of Group 2 patients (P = <0.001). CONCLUSION: DEX had a therapeutic role in the prevention of junctional ectopic tachycardia in patients undergoing repair for TOF. PMID- 25298691 TI - Preliminary evaluation of a microtransesophageal probe in neonates and young infants undergoing surgery for congenital heart disease. AB - BACKGROUND: The larger size of the currently available transesophageal echocardiography (TEE) probes limits their use to relatively older infants undergoing cardiac surgery. In very young neonates and infants, epicardial echocardiogram is used to assess postoperative residual defects. Recently, a miniaturized microTEE probe compatible in neonates has been introduced for clinical use. We evaluated the use of this probe in small infants undergoing cardiac surgery. MATERIALS AND METHODS: Thirty-three consecutive neonates and infants undergoing cardiac surgery at our institution were included in the study. Intraoperative echocardiography with Philips s8-3t microTEE probe done using IE33 platform was utilized to study the preoperative anatomy and assess postoperative results. RESULTS: Thirty-three patients aged 3 days-2 years (mean 5.1 months) and weighing 2.5-11 kg (mean 4.4 kg) underwent perioperative evaluation using the microTEE probe. Good quality two-dimensional and color Doppler images were obtained in all patients. There were no complications related to the probe insertion or manipulation. The findings on microTEE led to revision of surgery in five patients. Certain echocardiographic parameters that could never be recorded with epicardial echocardiogram could be easily seen in microTEE. CONCLUSION: On preliminary evaluation, the microTEE probe provided good quality images in very small infants who were not amenable for transesophageal echocardiographic evaluation so far. The probe could be used safely in small infants without complications. It appears to be a promising imaging modality in the perioperative assessment of young infants undergoing cardiac surgery, in whom intraoperative epicardial echocardiography is currently the only tool. PMID- 25298692 TI - Normal reference ranges for left ventricular dimensions in preterm infants. AB - OBJECTIVE: To establish normal reference ranges for the left ventricular dimensions in preterm infants and their correlation with gestational age, body weight and chronological age. MATERIALS AND METHODS: In a prospective study, 268 preterm babies, who fulfilled the criteria for inclusion, were examined in Kuwait during the years (2008-2010). Echocardiograms were performed to measure the left ventricular dimensions on 0-6 day(s) of life and at weekly intervals until they reached 36 weeks. The gestational age was grouped into three: 24-27, 28-31 and 32 35 weeks, and body weight into five: ?999, 1,000-1,499, 1,500-1,999, 2,000-2,499 and >=2,500 grams. The overall group differences were compared for each period of life: 0-6 days, 1-2, 3-4 and >=5 weeks. RESULTS: The mean gestational age was 29.8 (+/- 2.38 SD) weeks, ranging between 24 and 35, and the mean body weight 1,479 (+/- 413 SD) grams, ranging between 588 and 3380. At the first scan (0-6 days of life), all the left ventricular measurements correlated well (P < 0.001) with body weight, and the same was observed with gestational age, except for left ventricular posterior wall thickness at end-systole and end-diastole. A significant gradual increase was noticed in all the dimensions with body weight during each period of life. However, with respect to gestational age, an increase was observed in all the dimensions during first four weeks, but the rate of increase became less after 5 weeks of life. Overall, a progressive and significant increase in all left ventricle measurements was observed during the first nine weeks of life. CONCLUSION: The left ventricular dimension measurements were found to have significant correlation with both gestational age and body weight. The study also provides reference data, which can be used as normal reference tool for left ventricular dimensions for preterm infants against the gestational age, body weight and chronological age. PMID- 25298693 TI - Non-cardiac issues in patients with heterotaxy syndrome. AB - Management of complex congenital heart disease in patients with Heterotaxy syndrome (HS) has steadily improved. However, there is an insufficient appreciation of various non-cardiac issues that might impact the overall status of these patients. This article briefly reviews the implications of gastrointestinal, immunologic, genitourinary, respiratory, and central nervous system involvement in HS patients with a view to aid in their comprehensive clinical management. PMID- 25298694 TI - A systematic method for using 3D echocardiography to evaluate tricuspid valve insufficiency in hypoplastic left heart syndrome. AB - With surgical palliation of hypoplastic left heart syndrome (HLHS), the tricuspid valve (TV) becomes the systemic atrioventricular valve and moderate/severe TV insufficiency (TVI), an adverse risk factor for survival to Fontan, has been reported in up to 35% of patients prior to stage I palliation. Precise echocardiographic identification of the mechanism of TVI cannot be determined by two-dimensional echocardiography. Three-dimensional echocardiography (3DE) can provide significant insight into the mechanisms of TVI. It is the intent of this report to propose a systematic method on how to evaluate and display 3DE images of the TV in HLHS which has not been done previously. TV anatomy, function, and the known mechanisms of insufficiency are reviewed. We defined three regions of the TV (anterior, posterior, septal) that can help define valve "leaflets" that incorporates the many variations of TV anatomy. To determine how the surgeon views the TV, a picture of a pathologic specimen of the TV was placed on a computer screen and rotated until it was oriented as it appears during surgery, the "surgeons view." We have proposed a systematic method for evaluating and displaying the TV using 3DE which can provide significant insight into the mechanisms causing TVI in HLHS. This has the potential to improve both the surgical approach to repairing the valve and, ultimately, patient outcomes. PMID- 25298695 TI - Giant aortic arch aneurysm complicating Kawasaki's disease. AB - Kawasaki disease (KD) is a common acute vasculitis in pediatric population that usually involves small- and middle-sized arteries, commonly coronary arteries. Although the incidence and natural course of coronary aneurysms after KD are well documented in studies, related reports on peripheral arterial and aortic aneurysms are scarce. We report the occurrence of a giant aortic aneurysm involving the horizontal part of aortic arch in a 28-month-old boy diagnosed with KD. This complication was managed by steroids therapy in the beginning. Because of mechanical complication and potential risk of rupture, surgery was undertaken. PMID- 25298696 TI - An unusual cardiac mass resolving with antitubercular treatment. AB - We present an interesting case of a 21/2-year-old child with Tetrology of Fallot with a large intracardiac mass in the left ventricle presenting with fever and bilateral stroke, that resolving with antitubercular therapy alone. PMID- 25298697 TI - Hypoplastic left heart syndrome secondary to intrauterine rhabdomyoma necessitating single ventricle palliation. AB - Rhabdomyoma, a benign hamartomatous tumor of the cardiac embryonic myocyte, is the most common intrauterine cardiac tumor and accounts for 0.12% of prenatal fetal studies. Fetal cardiac rhabdomyomas increase in size during second and early third trimester and spontaneously regress postnatally. The clinical presentation is usually benign, however, compromise of the ventricular outflow tract leading to decreased cardiac output and fetal death have been reported. We present a case of large cardiac rhabdomyoma in a fetus that might have caused complete left ventricular outflow tract obstruction and development of hypoplastic left heart syndrome (HLHS) necessitating postnatal single ventricle palliation therapy. The clinical course and outcomes of prenatally diagnosed cardiac rhabdomyoma are reviewed and theories of the development of hypoplastic left heart syndrome are explored. PMID- 25298698 TI - An unusual case of rupture of left sinus of valsalva aneurysm into main pulmonary artery. AB - We report a case of left sinus of Valsalva aneurysm rupture into main pulmonary artery who underwent successful surgical correction. The preoperative diagnosis was facilitated by echocardiography, cardiac catheterization, and computed tomography. The benefits of surgery are sustained at 8 months on clinical and angiographic follow-up. PMID- 25298699 TI - Angiojet thrombectomy for Blalock-Taussig shunt and pulmonary artery thrombus in an infant with tetralogy of fallot. AB - We describe a new technique for treatment of shunt thrombosis in infants with complex anatomical defects. A 2-month-old girl with Tetralogy of Fallot underwent placement of a modified Blalock-Taussig shunt (MBTS) at day of life (DOL) 6 with revision at DOL 20. Following this surgery, the patient became hypotensive and hypoxic with new evidence of lack of flow through the MBTS on echocardiography. Angiography showed an occluded MBTS and right pulmonary artery with patent distal branches with normal pulmonary venous return. Balloon angioplasty was attempted but failed to fully recanalize the right pulmonary artery (RPA) and MBTS. An AngioJet catheter was then passed through the shunt and RPA to perform rheolyticthrombectomy. Subsequent angiogram showed a widely patent RPA and MBTS. An echocardiogram at 1-month post-thrombectomy showed a widely patent MBTS with continuous flow seen entering both branch pulmonary arteries. The AngioJet system for thrombectomy provides a viable option for complex thrombus removal in patients refractory to other methods. PMID- 25298700 TI - Goldenhar syndrome with right circumflex aortic arch, severe coarctation and vascular ring in a twin pregnancy. AB - Goldenhar syndrome (GS) or oculo-auriculo-vertebral dysplasia (OAVD), involves a wide variety of organ systems. Cardiovascular anomalies are among the frequent malformations. The purpose of this report is to introduce a male case of a dizygotic twin pregnancy with GS and right circumflex aortic arch (RCAA), severe coarctation, hypoplastic aortic arch, aberrant right subclavian artery, vascular ring, bilateral renal artery stenosis, and mild Dandy-Walker syndrome. The embryology of RCAA and coarctation is revisited. PMID- 25298701 TI - Coffin-Siris syndrome with the rarest constellation of congenital cardiac defects: A case report with review of literature. AB - We report a case of type-A Coffin-Siris syndrome (CSS) with a unique constellation of congenital heart defects. A 17-year-old Indian boy was referred to our hospital for central cyanosis with features of right heart failure. The cardiac abnormalities included biventricular outflow tract obstruction, small atrial septal defect (ASD), subaortic ventricular septal defect, drainage of left superior venacava to left atrial appendage, and aortic arch anomaly. Patient underwent successful right ventricular infundibular resection, subaortic membrane resection, closure of atrial and ventricular septal defect, rerouting left superior vena cava to left pulmonary artery and aortic valve replacement. PMID- 25298702 TI - Cervical origin of left subclavian artery: A rare anomaly. AB - A 22-year-old lady was referred to our institute for the management of pulmonary atresia with hypoplastic pulmonary arteries. Computed tomographic Angiography (CTA) showed right aortic arch with left brachicephalic artery as the first branch, which trifurcated into internal carotid, external carotid and subclavian artery high up in the neck at the level of third cervical vertebra. The left subclavian artery then travelled back caudally and entered into the arm after giving rise to a large collateral artery. This is the first ever-reported case of cervical origin of left subclavian artery (COLSA) in the literature. This anomaly can be explained by the absence of left fourth aortic arch with left subclavian artery arising from the left third aortic arch. PMID- 25298703 TI - Anomalous origin of left coronary artery from pulmonary artery - Duped by 2D; saved by color Doppler: Echocardiographic lesson from two cases. AB - Echocardiography is an important first-line investigation for detection of anomalous origin of a coronary artery from the pulmonary artery (ALCAPA). We report two cases of ALCAPA that illustrate the importance of systematic performance of the echocardiogram, mindful of technical artifacts that may mislead the echocardiographer color Doppler imaging in diagnosis of this condition. PMID- 25298704 TI - Novel kissing catheter technique for foreign body retrieval. AB - We report a novel technique 'the kissing catheter technique' for retrieval of a broken catheter fragment in a patient undergoing closure of a patent ductus arteriosus. PMID- 25298705 TI - Abnormal location of umbilical venous catheter due to Scimitar syndrome. AB - Scimitar syndrome is a rare congenital anomaly where the right pulmonary veins return to the inferior vena cava (IVC) just below the diaphragm. On chest X-ray (CXR), an IVC catheter will be in a bizarre location outside the heart if it inadvertently passes into the scimitar vein rather than into the right atrium. PMID- 25298706 TI - Selected summaries. PMID- 25298707 TI - Aortic balloon valvuloplasty in corrected transposition of the great arteries with severe valvular aortic stenosis of congenital bicuspid aortic valve. PMID- 25298708 TI - Oral and maxillofacial surgery in south Asian countries - bridging the gap. PMID- 25298709 TI - Role of dental expert in forensic odontology. AB - Forensic dentistry has become an integral part of forensic science over the past 100 years that utilizes dental or oro-facial findings to serve the judicial system. This has been due to the dedication of people like Gustafson's, Keiser Nielson, and Suzuki for this field. They established the essential role which forensic dentistry plays mainly in the identification of human remains. The tooth has been used as weapons and under certain circumstances, may leave information about the identity of the biter. Dental professionals have a major role to play in keeping accurate dental records and providing all necessary information so that legal authorities may recognize mal practice, negligence, fraud or abuse, and identity of unknown individuals. This paper will try to summarize the various roles of dental experts in forensic medicine. PMID- 25298710 TI - Rapid maxillary canine retraction by dental distraction: A clinical study. AB - AIM: The aim of this clinical study was to perform rapid maxillary canine retraction through distraction of the periodontal ligament and investigate the rate and amount of canine retraction, amount of anchor loss, the nature of tooth movement achieved, and radiographic changes in the periodontal ligament region during and after canine distraction. MATERIALS AND METHODS: This study was conducted on 10 distractions ranging in age from 14 years to 25 years who needed canine retraction and first premolar extraction in the maxillary arch. Ten canine distractions were carried out with custom-made, tooth-borne intra-oral distraction device. RESULTS: The results indicate that the periodontal ligament can be distracted just like the mid-palatal suture in rapid palatal expansion and the maxillary canines are retracted rapidly into the first premolar extraction space at the rate of about 2.53 mm/week. CONCLUSION: Though this study indicates that the periodontal ligament can be distracted to elicit rapid tooth movement, the long-term effects of canine distraction are not well known and need close monitoring. PMID- 25298711 TI - Evaluation of intubating conditions using stylet by conventional through-tube technique and through Murphy's eye in patients with high Mallampati scores. AB - BACKGROUND: Difficult intubation is always a nightmare for an Anaesthetist. This study was planned to study the alternative method of stylet use during difficult oro-tracheal intubation. Outcome measures assessed were ease of intubation, hemodynamic stability and reducing complications. MATERIALS AND METHODS: A cohort of 60 patients of Mallampati class III patients was formed and patients were divided into two groups. In group 1 patients, conventional through tube method was used for inserting stylet, whereas, in group 2 patients, Murphy's eye was used for inserting malleable flexi tip stylet. RESULTS: Hemodynamic stability in terms of mean arterial blood pressure and heart rate was observed in group 2. Intubating time, number of attempts of successful intubation and post operative pharyngo-laryngeal complications was also low in group 2 patients. CONCLUSION: The use of Murphy's eye to pass stylet during difficult airway manoeuvre is a safe alternative over conventional rail-road technique. PMID- 25298712 TI - Awareness of basic life support among dental practitioners. AB - BACKGROUND: It is important that every member of our community should be trained in effective BLS technique to save lives. At least doctors including dental practitioners, and medical and paramedical staff should be trained in high quality CPR, as it is a basic medical skill which can save many lives if implemented timely. AIM: Our aim was to study the awareness of Basic Life Support (BLS) among dental students and practitioners in New Delhi. MATERIALS AND METHODS: This cross sectional study was conducted by assessing responses to 20 selected questions pertaining to BLS among dental students, resident doctors/tutors, faculty members and private practitioners in New Delhi. All participants were given a printed questionnaire where they had to mention their qualifications and clinical experience, apart from answering 20 questions. STATISTICAL ANALYSIS: Data was collected and evaluated using commercially available statistical package for social sciences (SPSS version 12). RESULTS: One hundred and four responders were included. Sadly, none of our responders had complete knowledge about BLS. The maximum mean score (9.19 +/- 1.23) was obtained by dentists with clinical experience between 1-5 years. CONCLUSION: To ensure better and safer healthcare, it is essential for all dental practitioners to be well versed with BLS. PMID- 25298713 TI - Role of coronoidectomy in increasing mouth opening. AB - AIM: To evaluate the effectiveness of coronoidectomy in advanced (stage III-IV) oral submucous fibrosis (OSMF) and temporomandibular joint (TMJ) ankylosis. MATERIALS AND METHODS: Five patients clinically diagnosed as grade III/IV OSMF (group 1) and seven patients clinically and radiographically confirmed as TMJ ankylosis (group 2) underwent surgery entailing coronoidectomy in addition to conventional surgical procedures required in both the conditions followed by vigorous mouth opening exercises. The results were evaluated using the interincisal distance at maximum mouth opening as the objective outcome over a follow-up period of 2 months. RESULTS: OSMF patients (group I) showed a mean preoperative interincisal opening of 14.40 mm which increased to 24.60 mm after conventional procedures and showed further increment to 35 and 44.80 mm after unilateral and bilateral coronoidectomy, respectively; which was statistically significant (P = 0.043). Follow-up of 2 months showed a gradual increase in mean mouth opening compared to baseline which was also found to be statistically significant (P = 0.043). In TMJ ankylosis patients (group II), preoperative mean mouth opening of 6.71 mm increased to 24.29 mm after conventional procedures, and further to 37.29 mm after unilateral coronoidectomy which was statistically significant (P = 0.018). On subsequent follow-up of 2 months, a gradual increase in mean mouth opening compared to baseline was observed which was statistically significant (P = 0.018). CONCLUSION: Coronoidectomy is an effective adjunct in increasing intraoperative and stabilizing postoperative mouth opening. PMID- 25298714 TI - Honey a sweet approach to alveolar osteitis: A study. AB - BACKGROUND: Honey is one of the oldest known medicines. Its use has been rediscovered in later times by the medical profession, especially for dressing wounds. It has been reported from various clinical studies on the usages of honey as a dressing for infected wounds that the wound become sterile in 3-6 days, others have al so reported that the honey is effective in cleaning up infected wound. MATERIALS AND METHODS: The 54 patients of dry socket were selected from the from the outpatient department of oral and maxillofacial surgery. A diagnosis of dry socket was made clinically. This study was under taken to evaluate the effect of honey dressing in management of dry socket. RESULTS: In this study there was significant reduction if inflammation, hyperemia, edema and exudation after honey dressing that results in soothing effect and reduction in pain and discomfort. There was al so significant reduction in CRP level post operative days .There was side effect of honey was observed in our study, so it can be used as alternative for the management of dry socket. DISCUSSION: It has al so been reported that the honey dressing halt advancing necrosis. It has al so been found to act as barrier preventing wounds from becoming infected, preventing cross infection, and allowing burn wound to heal rapidly. CONCLUSIONS: There are no side effects of honey. Excess use of euginol, can lead to necrosis of bone. The honey can be used as medicament for the management of dry socket. PMID- 25298715 TI - Herbal remedies for mandibular fracture healing. AB - PURPOSE: When a bone is fractured it is usually necessary to employ a mechanical means to reduce and maintain the fragments in position. However, healing of the fracture is governed by biological principles, with which the mechanical measures must be coordinated to the end, such that a satisfactory bony union and restoration of form and function are obtained. We have studied the effect of Cissus quadrangularis (Harjor) and Ocimum sanctum (Tulsi), in the healing of mandibular fractures. MATERIALS AND METHODS: A total of 29 cases having a fracture in the body of the mandible were included in the study and divided into three groups. Groups A and B were treated with Ocimum sanctum and Cissus quadrangularis, respectively, and fracture healing was assessed with biochemical markers and the bite force. Group C was the control group. RESULTS: The period of immobilization was the lowest in the Group A followed by Group B. A significant increase in alkaline phosphatase and serum calcium was seen in Group B. The tensile strength in terms of the biting force was the maximum in cases of Group B. CONCLUSION: We conclude that Cissus quadrangularis and Ocimum sanctum help in fracture healing, and use of such traditional drugs will be a breakthrough in the management and early mobilization of facial fractures. PMID- 25298716 TI - Schwannoma of the hard palate. AB - Schwannomas are benign encapsulated perineural tumors. The head and neck region is the most common site. Intraoral origin is seen in only 1% of cases, tongue being the most common site; its location in the palate is rare. We report a case of hard-palate schwannoma with bony erosion which was immunohistochemically confirmed. The tumor was excised completely intraorally. After two months of follow-up, the defect was found to be completely covered with palatal mucosa. PMID- 25298718 TI - Ameloblastoma of the anterior mandible. AB - Ameloblastoma or adamantinoma is the rarest of the three forms of tumor of the odontogenic type. They are benign, locally aggressive neoplasms arising from ameloblasts, which typically occur at the angle of the mandible, and are often associated with an un-erupted tooth and must, therefore, be differentiated from a dentigerous cyst which will be centered on the crown. When in the maxilla (less common), they are located in the premolar region, and can extend up in the maxillary sinus. Ameloblastoma is reported to constitute about 1-3% of tumors and cysts of the jaws. The tumor is by far more common in the mandible than in the maxilla and shows predilection for various parts of the mandible in different racial groups. The relative frequency of the mandible to maxilla is reported as varying from 80-20% to 99-1%. Here, we are representing a case of ameloblastoma of anterior mandible which was considered as a rare site of occurrence. PMID- 25298717 TI - Hereditary gingival fibromatosis. AB - Hereditary gingival fibromatosis (HGF) is a rare condition that can occur as an isolated disease, chromosomal abnormality, or as part of a number of syndromes. The gingival enlargement in HGF can be so severe that it can cover the crowns of teeth completely, causing severe functional derangement and facial disfigurement. Through review of literature revealed that HGF is usually an autosomal dominant condition, however the recessive forms are also reported. The hyperplastic gingiva is firm on palpation and has normal color with abundant stippling on the adjacent gingiva. The buccal and lingual gingiva may be involved in both the mandible and maxilla. The degrees of gingival enlargement show both intra- and interindividual variations. Here, an interesting case report of massive HGF has been presented. PMID- 25298719 TI - Concomitant hypo-hyperdontia with an endocrine etiology. AB - The simultaneous occurrence of hypodontia and supernumerary teeth in the same individual is termed as "concomitant hypohyperdontia" and it is an uncommon condition with the etiology still unknown. Presented here is a very rare case of simultaneous presence of multiple supernumerary teeth and multiple missing teeth (bilateral maxillary second premolars and bilateral mandibular second molars) involving both jaws with a history of subclinical hypothyroidism. Systemic diseases could probably play a role in the etiologic occurrence of co-existent partial anodontia and supernumerary teeth. PMID- 25298720 TI - Ortho-surgical management of condylar hyperplasia: Rare case reports. AB - Condylar hyperplasia of the mandible is a clinical condition of over-development and growth because of excessive cellular growth of one condylar part of the mandible leading to facial asymmetry, mandibular deviation and enlargement of condyle. The elongation of the condylar neck in turn leads to malocclusion and articular dysfunction. In the past the interceptive and corrective procedures of growth and deformity in condylar hyperplasia were either condylectomy or high condylotomy. However, the deformity ceases after growth is completed. Therefore, other surgical procedures have to be undertaken to correct the manifested deformity of condylar hyperplasia. Further it has to be stressed that no single procedure can completely correct the deformity. So in addition to condylectomy, other orthognathic surgical procedures both on body and ramus and also on maxilla can be undertaken to correct the canting of occlusion. Two rare cases of unilateral hyperplasia encountered in our hospital are presented which required different lines of treatment. PMID- 25298722 TI - Retrieval of foreign body from a postoperative defect in the mandible during the follow-up period: A bizarre occurrence. AB - Though reported cases of foreign bodies left intraoperatively in the oral cavity are very few, there is no case mentioned in the literature where foreign body was left behind during follow-up visits. Here, we present an operated case of unicystic ameloblastoma of mandibular ramus region, in which a needle hub was left at the operated site (cavity created because of wound dehiscence) during some of the follow-up visits, which was detected accidently by radiograph and later on retrieved. The case reported was because of negligence of trainee surgeons, might be because of overburden or because of minimal interest in these repeated follow ups. But, a trainee should understand that their work also has similar importance as that of surgeon's work. PMID- 25298721 TI - Recurrent case of central giant cell granuloma with multiple soft tissue involvement. AB - Central giant cell granuloma is a fairly common lesion in the jaws aetiology of which is still completely unknown but thought to be of a reactive process to some unknown stimuli. It usually arises either peripherally in periodontal ligament, mucoperiosteum, or centrally in the bone. The histological hallmark for both peripheral and central giant cell granuloma (CGCG) is the presence of distinctive multinucleated giant cells (MGCs) in a prominent fibrous stroma. Central giant cell granuloma is an uncommon benign proliferative lesion that almost exclusively occurs within the jaw. Eventually, it may become aggressive leading to the expansion and perforation of cortex resulting into mobility and displacement of teeth with root resorption. The present case focuses on the dilemma and perplexity in diagnosing aggressive CGCGs, due to its close proximity with respect to pathology, behavior and prognosis from giant cell tumors (GCT). Central giant cell granuloma persuaded extensive destruction to the hard and soft tissues with high rate of recurrence encourage us the need of exploring the possibilities of giant cell tumors having a definitive presence in the jaws. PMID- 25298723 TI - Endodontic implants. AB - Endodontic implants were introduced back in 1960. Endodontic implants enjoyed few successes and many failures. Various reasons for failures include improper case selection, improper use of materials and sealers and poor preparation for implants. Proper case selection had given remarkable long-term success. Two different cases are being presented here, which have been treated successfully with endodontic implants and mineral trioxide aggregate Fillapex (Andreaus, Brazil), an MTA based sealer. We suggest that carefully selected cases can give a higher success rate and this method should be considered as one of the treatment modalities. PMID- 25298724 TI - An eye for a lost eye: A case of self-inflicting gunshot injury. AB - Maxillofacial defects due to gunshot injuries can have detrimental functional and psychological effects on the patient. These occur predominantly in young males, although all are at risk. Military, civil, accidental or self-inflicted injuries employing guns of varying caliber and ballistic properties may produce a defect or deformity which encompasses the entire spectrum of reconstructive surgery. Patients with facial defects have major difficulties to re-establish their mastication, speech, soft-tissue projections and therefore social integration. Successful prosthetic rehabilitation is crucial for better quality of life in case of large facial deformities. We present a case of 24-year-old male with gunshot injury to the left side face leading damage to the eye, which was rehabilitated with oculo-facial prosthesis. PMID- 25298725 TI - Epidermoid cyst of the floor of the mouth. AB - Dermoid cysts are malformations that are rarely seen in the oral cavity. An intraoral dermoid cyst grows slowly, but may enlarge and interfere with deglutition and speech, or can pose a critical risk to the airway and therefore require immediate surgical intervention. Dermoid cysts may develop above or below the mylohyoid muscle, causing a submental or submandibular swelling. Surgical excision is the treatment of choice and recurrence is rare. An intraoral approach for the treatment of large lesions presenting above the mylohyoid muscle provides good cosmetic and functional results. We report a case of a 26-year-old female who developed an epidermoid cyst presenting as a large sublingual swelling causing speech and swallowing difficulties. The lesion was surgically excised using an intraoral approach. Microscopic examination revealed a dermoid cyst of the epidermoid type. This case shows that dermoid cysts may be successfully diagnosed and managed using a series of simple yet effective clinical procedure. PMID- 25298726 TI - A Type I first branchial cleft cyst masquerading as a parotid tumor. AB - Branchial cleft anomalies are caused by incomplete regression of the cervical sinus of "His" during the 6(th) and 7(th) weeks of embryologic development. Although congenital in origin, first branchial cleft cysts (FBCCs) can present later in life. FBCCs are rare causes of parotid swellings, accounting for <1% of all the branchial cleft abnormalities. The diagnosis of FBCCs is a clinical challenge; the condition is often overlooked and mismanaged. We report a case of Type 1 FBCC in a 22-year-old female with an asymptomatic 3.5 cm * 2.5 cm sized cystic mass. It was removed completely under the impression of a cystic tumor of the parotid. On histopathology, the cyst had a squamous epithelium-lined wall with lymphoid aggregation which was characteristic of a branchial cleft cyst. A good understanding of the regional anatomy and embryology can lead to an early diagnosis and thereby effective management of FBCC. PMID- 25298727 TI - Bilateral keratocystic odontogenic tumor: A report of two cases. AB - The designation "keratocyst" was used to describe any jaw cyst in which keratin was formed to a large extent. A rare incidence of bilateral mandibular cysts (odontogenic keratocysts) was related to third molar teeth. Herein, we report two cases of bilateral keratocystic odontogenic tumor in a 22-year-old male and 15 year-old female, which was diagnosed by a series of investigations and treated appropriately. PMID- 25298728 TI - Dumbbell-shaped lymphangioma of neck and thorax. AB - Vascular malformations consist of a spectrum of lesions involving all parts of the body. They have different terminologies like vascular tumors, vascular malformations, vascular anomalies, and so on, which create a lot of confusion in understanding and treating these pathologies. Of late, classification on the basis of cellular kinetics and clinical behavior has been devised. Hemangioma is the most common vascular tumor. Vascular malformations are of either lymphatic or capillary and venous origin. Sometimes they are of a mixed origin. Lymphangiomas are common in the face and neck area. They are also not unusual in the mediastinum. We present a case where a huge lymphangioma occupied the right supraclavicular area of the neck, extending to nearly the entire right thoracic cavity, compressing the whole lung. The patient had occasional symptoms of cough. Ultrasonography (US) and computed tomography (CT) images clearly described the lesion as cystic, occupying both the supraclavicular and thoracic cavity compressing the lung parenchyma. Surgical excision was planned and we approached the lesion via both cervical and thoracotomy incisions. Complete excision was done, and the lung expended fully after the surgery. PMID- 25298729 TI - Management strategy for facial venous malformations. AB - Venous malformations (VMs) are slow-flow vascular malformations, caused by abnormalities in the development of the veins. Venous malformations vary in size and location within the body. When the skin or tissues just under the skin are affected, they appear as slightly blue-colored skin stains or swellings. These can vary in size from time to time because of swelling within the malformation. As these are vascular malformations, they are present at birth and grow proportionately with the child. Venous malformations can be very small to large in size, and sometimes, can involve a significant area within the body, When the venous malformation is well localized, this may cause localized swelling, however, when the venous malformation is more extensive, there may be more widespread swelling of the affected body part. Some patients with venous malformations have abnormal blood clotting within the malformation. Most venous malformations cause no life-threatening problems for patients. Some venous malformations cause repeated pain due to intermittent swelling and congestion of the malformation or due to the formation of blood clots within the malformation. Rarely, venous malformations may be part of a syndrome (an association of several clinically recognizable features) or be linked to an underlying genetic abnormality. We present 12 cases of venous malformations of the head and neck area, which have been managed at our hospital. PMID- 25298730 TI - Effect of beta-lactam antibiotics on plant regeneration in carrot protoplast cultures. AB - Protoplasts of three carrot cultivars were isolated from in vitro-grown plantlets by overnight incubation in an enzyme mixture composed of 1% (w/v) cellulase Onozuka R-10 and 0.1% (w/v) pectolyase Y-23. After cell immobilization in modified thin alginate layers, three types of beta-lactam antibiotics (cefotaxime, carbenicillin, or timentin) at five different concentrations (100, 200, 300, 400, or 500 mg L-1) were added to the culture medium. In 20-d-old cultures, a different number of cell colonies had formed and varied on average from 27 to 56% in carbenicillin- and cefotaxime-containing media, respectively. Supplementation of the culture media with antibiotics at concentrations higher than 100 mg L-1 resulted in a decrease in plating efficiency in comparison with the controls. However, from all antibiotic treatments, except carbenicillin at concentrations of 400-500 mg L-1, efficient plant regeneration occurred. For this reason, we believe that cefotaxime and timentin in the concentrations analyzed here may be used in complex in vitro procedures or valuable carrot cultures as a prophylactic agent for prevention against occasional contaminations. PMID- 25298731 TI - Polarization and Belief Dynamics in the Black and White Communities: An Agent Based Network Model from the Data. AB - Public health care interventions-regarding vaccination, obesity, and HIV, for example-standardly take the form of information dissemination across a community. But information networks can vary importantly between different ethnic communities, as can levels of trust in information from different sources. We use data from the Greater Pittsburgh Random Household Health Survey to construct models of information networks for White and Black communities--models which reflect the degree of information contact between individuals, with degrees of trust in information from various sources correlated with positions in that social network. With simple assumptions regarding belief change and social reinforcement, we use those modeled networks to build dynamic agent-based models of how information can be expected to flow and how beliefs can be expected to change across each community. With contrasting information from governmental and religious sources, the results show importantly different dynamic patterns of belief polarization within the two communities. PMID- 25298732 TI - Sex-specific relationships between adverse childhood experiences and chronic obstructive pulmonary disease in five states. AB - PURPOSE: Adverse childhood experiences (ACEs) before age 18 have been repeatedly associated with several chronic diseases in adulthood such as depression, heart disease, cancer, diabetes, and stroke. We examined sex-specific relationships between individual ACEs and the number of ACEs with chronic obstructive pulmonary disease (COPD) in the general population. MATERIALS AND METHODS: Data from 26,546 women and 19,015 men aged >=18 years in five states of the 2011 Behavioral Risk Factor Surveillance System were analyzed. We used log-linear regression to estimate prevalence ratios (PRs) and their corresponding 95% confidence intervals (CIs) for the relationship of eight ACEs with COPD after adjustment for age group, race/ethnicity, marital status, educational attainment, employment, asthma history, health insurance coverage, and smoking status. RESULTS: Some 63.8% of women and 62.2% of men reported >=1 ACE. COPD was reported by 4.9% of women and 4.0% of men. In women, but not in men, there was a higher likelihood of COPD associated with verbal abuse (PR =1.30, 95% CI: 1.05, 1.61), sexual abuse (PR =1.69, 95% CI: 1.36, 2.10), living with a substance abusing household member (PR =1.49, 95% CI: 1.23, 1.81), witnessing domestic violence (PR =1.40, 95% CI: 1.14, 1.72), and parental separation/divorce (PR =1.47, 95% CI: 1.21, 1.80) during childhood compared to those with no individual ACEs. Reporting >=5 ACEs (PR =2.08, 95% CI: 1.55, 2.80) compared to none was associated with a higher likelihood of COPD among women only. CONCLUSION: ACEs are related to COPD, especially among women. These findings underscore the need for further research that examines sex-specific differences and the possible mechanisms linking ACEs and COPD. This work adds to a growing body of research suggesting that ACEs may contribute to health problems later in life and suggesting a need for program and policy solutions. PMID- 25298733 TI - Relationship between the GOLD combined COPD assessment staging system and bacterial isolation. AB - BACKGROUND: Acute exacerbations, which are a significant cause of mortality and morbidity, adversely affect chronic obstructive pulmonary disease (COPD) prognosis by accelerating loss of lung function. It is important to know the microorganisms that commonly cause exacerbations in the patient groups classified according to clinical and functional characteristics for fast and accurate treatment of acute exacerbations. OBJECTIVES: The last Global Initiative for Chronic Obstructive Lung Disease (GOLD) publication recommended a new staging system containing obstruction degree, frequency of exacerbations, and quality of life questionnaires. This study is designed to analyze the relationship between the bacteria isolated in acute exacerbations and new GOLD stages. METHODS: Potentially pathogenic bacteria (PPB) isolation with culture and polymerase chain reaction methods were obtained from 114 acute exacerbation COPD patients, classified into A, B, C, and D groups by analyzing the forced expiratory volume in 1 second (FEV1) value, COPD Assessment Test (CAT) score, and exacerbation frequency according to the new GOLD staging system. RESULTS: There was a significant correlation between exacerbation frequency and PPB isolation (P=0.002). There was no relationship between GOLD stage, FEV1, and CAT score with PPB isolation. The isolated bacteria diversity and mixed infection frequency were higher in the GOLD stage D group. Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii were isolated only from D group patients. CONCLUSION: Bacterial infection may cause an acute exacerbation equally in each stage for COPD. The difference in bacterial etiology is more related to exacerbation frequency than FEV1 and CAT scores for an acute exacerbation. Determining exacerbation frequency is significant for treatment success in empirical antibiotic selection. PMID- 25298734 TI - TNYL peptide functional chitosan-g-stearate conjugate micelles for tumor specific targeting. AB - Nowadays, a real challenge in cancer therapy is to design drug delivery systems that can achieve high concentrations of drugs at the target site for improved therapeutic effect with reduced side effects. In this research, we designed and synthesized a homing peptide-(TNYLFSPNGPIA, TNYL) modified chitosan-g-stearate (CS) polymer micelle (named T-CS) for targeting delivery. The peptide displayed specific binding affinity to EphB4 which is a member of the Eph family of receptor tyrosine protein kinases. The amphiphilic polymer T-CS can gather into micelles by themselves in an aqueous environment with a low critical micelle concentration value (91.2 MUg/L) and nano-scaled size (82.1 +/- 2.8 nm). The drug encapsulation efficiency reached 86.43% after loading the hydrophobic drug doxorubicin (DOX). The cytotoxicity of T-CS/DOX against SKOV3 cells was enhanced by approximately 2.3-fold when compared with CS/DOX. The quantitative and qualitative analysis for cellular uptake indicated that TNYL modification can markedly increase cellular internalization in the EphB4-overexpressing SKOV3 cell line, especially with a short incubation time. It is interesting that relatively higher uptake of the T-CS/DOX micelles by SKOV3 cells (positive-EphB4) than A549 cells (negative-EphB4) was observed when the two cells were co-incubated. Furthermore, in vivo distribution experiment using a bilateral-tumor model showed that there was more fluorescence accumulation in the SKOV3 tumor than in the A549 tumor over the whole experiment. These results suggest that TNYL-modified CS micelles may be promising drug carriers as targeting therapy for the EphB4 overexpressing tumor. PMID- 25298736 TI - Laparoscopic versus open colorectal resection for cancer and polyps: a cost effectiveness study. AB - BACKGROUND: Available evidence that compares outcomes from laparoscopic and open surgery for colorectal cancer shows no difference in disease free or survival time, or in health-related quality of life outcomes, but does not capture the short term benefits of laparoscopic methods in the early postoperative period. AIM: To explore the cost-effectiveness of laparoscopic colorectal surgery, compared to open methods, using quality of life data gathered in the first 6 weeks after surgery. METHODS: Participants were recruited in 2006-2007 in a district general hospital in the south of England; those with a diagnosis of cancer or polyps were included in the analysis. Quality of life data were collected using EQ-5D, on alternate days after surgery for 4 weeks. Costs per patient, from a National Health Service perspective (in British pounds, 2006) comprised the sum of operative, hospital, and community costs. Missing data were filled using multiple imputation methods. The difference in mean quality adjusted life years and costs between surgery groups were estimated simultaneously using a multivariate regression model applied to 20 imputed datasets. The probability that laparoscopic surgery is cost-effective compared to open surgery for a given societal willingness-to-pay threshold is illustrated using a cost-effectiveness acceptability curve. RESULTS: The sample comprised 68 laparoscopic and 27 open surgery patients. At 28 days, the incremental cost per quality adjusted life year gained from laparoscopic surgery was L12,375. At a societal willingness-to-pay of L30,000, the probability that laparoscopic surgery is cost-effective, exceeds 65% (at L20,000 ~60%). In sensitivity analyses, laparoscopic surgery remained cost effective compared to open surgery, provided it results in a saving >=L699 in hospital bed days and takes no more than 8 minutes longer to perform. CONCLUSION: The study provides formal evidence of the cost-effectiveness of laparoscopic approaches and supports current guidelines that promote use of laparoscopy where suitably trained surgeons are available. PMID- 25298737 TI - Psychometric validation of patient-reported outcome measures assessing chronic constipation. AB - BACKGROUND: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes. AIM: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures. STUDY METHODS: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F tests, and effect sizes were computed. RESULTS: The CC Symptom Severity Measures demonstrated satisfactory test-retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change. CONCLUSION: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies. PMID- 25298735 TI - Attention-deficit/hyperactivity disorder in postsecondary students. AB - A PubMed review was conducted for papers reporting on attention deficit/hyperactivity disorder (ADHD) in postsecondary students. The review was performed in order to determine the prevalence and symptomatology of ADHD in postsecondary students, to examine its effects on academic achievement, and discuss appropriate management. The prevalence of ADHD symptoms among postsecondary students ranges from 2% to 12%. Students with ADHD have lower grade point averages and are more likely to withdraw from courses, to indulge in risky behaviors, and to have other psychiatric comorbidities than their non-ADHD peers. Ensuring that students with ADHD receive appropriate support requires documented evidence of impairment to academic and day-to-day functioning. In adults with ADHD, stimulants improve concentration and attention, although improved academic productivity remains to be demonstrated. ADHD negatively impacts academic performance in students and increases the likelihood of drug and alcohol problems. Affected students may therefore benefit from disability support services, academic accommodations, and pharmacological treatment. PMID- 25298739 TI - Physician practicing preferences for conventional or homeopathic medicines in elderly subjects with musculoskeletal disorders in the EPI3-MSD cohort. AB - BACKGROUND: Musculoskeletal pain is common in elderly persons. Analgesic use is high in the elderly and may involve unacceptable risk in individuals with chronic pain. Our aim was to compare the socio-demographic characteristics of elderly subjects with musculoskeletal disorders (MSD) and to assess medication use and clinical evolution of musculoskeletal pain according to physician prescribing preference: homeopathy (Ho) group, conventional medicine (CM) group, or mixed prescription (MX) group. METHODS: The EPI3 study was a 1 year observational survey carried out among general practitioners in France between March 2007 and July 2008. This sub-analysis was carried out on elderly subjects aged >=70 years from the original EPI3 cohort. Socio-demographic data were collected at inclusion using a self-administered patient questionnaire and medical data were recorded for each patient. Quality of life was measured using the Short Form-12 questionnaire. Patients completed a structured telephone interview on their functional status (evaluated with the QuickDash questionnaire, EIFEL scale or Lequesne index) within 72 hours of inclusion. This telephone interview was repeated at 1, 3, and 12 months. Drug exposure was also assessed during these interviews. RESULTS: 146 patients (mean age +/- standard deviation: 75.8+/-4.8 years) were analyzed (80.1% female, 74.7% MSD of the spine or lower limbs, 64.4% chronic MSD). Patients in the CM and MX groups were 3.7 times or 2.5 times more likely (odds ratio [OR] =3.71, 95% confidence interval [CI]: 1.12-12.30; OR =2.52, 95% CI: 1.05-6.05; respectively) to have used non-steroidal anti inflammatory drugs (NSAIDs) than those in the Ho group. In contrast, analgesic use was comparable in the three groups (OR =1.06 [CM versus Ho], 95% CI: 0.09 12.11; OR =0.34 [MX versus Ho], 95% CI: 0.07-1.57). Overall functional score evolution was similar in the three groups over time (P=0.16). CONCLUSION: NSAID use was significantly higher in elderly MSD patients consulting a conventional practice general practitioner. In contrast, analgesic use and MSD evolution were similar in the three groups. Consulting a homeopathic physician for MSD management does not appear to represent a loss of therapeutic opportunity, and decreases the use of NSAIDs. PMID- 25298738 TI - The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients. AB - Glioblastoma multiforme (GBM) remains one of the most devastating tumors, and patients have a median survival of 15 months despite aggressive local and systemic therapy, including maximal surgical resection, radiation therapy, and concomitant and adjuvant temozolomide. The purpose of antineoplastic treatment is therefore to prolong life, with a maintenance or improvement of quality of life. GBM is a highly vascular tumor and overexpresses the vascular endothelial growth factor A, which promotes angiogenesis. Preclinical data have suggested that anti angiogenic treatment efficiently inhibits tumor growth. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A, and treatment has shown impressive response rates in recurrent GBM. In addition, it has been shown that response is correlated to prolonged survival and improved quality of life. Several investigations in newly diagnosed GBM patients have been performed during recent years to test the hypothesis that newly diagnosed GBM patients should be treated with standard multimodality treatment, in combination with bevacizumab, in order to prolong life and maintain or improve quality of life. The results of these studies along with relevant preclinical data will be described, and pitfalls in clinical and paraclinical endpoints will be discussed. PMID- 25298740 TI - Arbekacin: another novel agent for treating infections due to methicillin resistant Staphylococcus aureus and multidrug-resistant Gram-negative pathogens. AB - Arbekacin sulfate (ABK), an aminoglycoside antibiotic, was discovered in 1972 and was derived from dibekacin to stabilize many common aminoglycoside modifying enzymes. ABK shows broad antimicrobial activities against not only Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) but also Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ABK has been approved as an injectable formulation in Japan since 1990, under the trade name Habekacin, for the treatment of patients with pneumonia and sepsis caused by MRSA. The drug has been used in more than 250,000 patients, and its clinical benefit and safety have been proven over two decades. ABK currently shows promise for the application for the treatment of multidrug-resistant Gram-negative bacterial infections such as multidrug resistant strains of P. aeruginosa and Acinetobacter baumannii because of its synergistic effect in combination with beta-lactams. PMID- 25298741 TI - Metabolic consequences of second-generation antipsychotics in youth: appropriate monitoring and clinical management. AB - OBJECTIVE: To review the metabolic consequences of second-generation antipsychotics in youth and current monitoring and intervention guidelines for optimal treatment. BACKGROUND: Second-generation antipsychotics have largely replaced the use of first-generation antipsychotics in treating psychotic disorders in youth. In addition, there has been a dramatic increase in using these medications to treat a variety of nonpsychotic disorders. These medications have significant metabolic side effects, including weight gain. This raises concern, given the problem of pediatric obesity. MATERIALS AND METHODS: A review of current literature looking at prescribing practices and possible reasons for the increased use of second-generation antipsychotics in children and adolescents was conducted. Review of the mechanisms for why youth may be particularly vulnerable to the metabolic consequences (particularly weight gain) was similarly completed. In addition, data supporting the efficacy, rationale, and unique side effect profile of each individual second-generation drug were evaluated to help inform providers on when and what to prescribe, along with current monitoring practices. The current evidence base for possible interventions regarding the management of antipsychotic-induced weight gain was also evaluated. RESULTS AND CONCLUSION: On the basis of the literature review, there are several speculated reasons for the increase in prescriptions of second-generation antipsychotics. The choice of antipsychotic for youth should be based upon the disorder being treated along with the unique side-effect profile for the most commonly used second-generation antipsychotics. Monitoring strategies are also individualized to each antipsychotic. The current interventions recommended for antipsychotic induced weight gain include lifestyle management, switching medication to a drug with a lower propensity for weight gain, and pharmacologic (particularly metformin) treatment. PMID- 25298742 TI - Utility of a dermatology interest group blog: the impact of medical student interest groups and Web 2.0 tools as educational resources. AB - The open access University of Texas Dermatology Interest Group blog was established in 2004 for the purposes of increasing communication and collaboration between medical students and dermatology faculty, residents, and alumni, as well as to promote educational opportunities and the missions for which the interest group was created. This blog is unique because of its longevity and continuous postings directed toward the educational and professional needs of medical students and residents. A blog user survey was performed to assess viewers' thoughts, purpose of viewing, demographic profile, subscriber status, usage of the blog and other Web 2.0 tools (forums, Facebook, blogs, Twitter, podcasts), and perceived usefulness. Sixty-one anonymous online surveys were completed during a 1-month period. Statistical analyses of the responses demonstrated that the utilization of web-based tools and the blog were valuable resources for students, especially for blog subscribers, those more involved in an interest group, and those reading the blog for a longer period of time. The usefulness and impact of this method of communication and dissemination of information in medical education may encourage other student groups, faculty advisors, and educators to implement similar educational tools at their institutions. PMID- 25298743 TI - An international validation study of two achievement goal measures in a pharmacy education context. AB - BACKGROUND: Achievement goal theory helps us understand what motivates students to participate in educational activities. However, measuring achievement goals in a precise manner is problematic. Elliot and McGregor's Achievement Goal Questionnaire (AGQ) and Elliot and Murayama's revised Achievement Goal Questionnaire (AGQ-R) are widely used to assess students' achievement goals. Both instruments were developed and validated using undergraduate psychology students in the USA. METHODS: In this study, our aims were to first of all, assess the construct validity of both questionnaires using a cohort of Australian pharmacy students and, subsequently, to test the generalizability and replicability of these tools more widely in schools of pharmacy in other English-speaking countries. The AGQ and the AGQ-R were administered during tutorial class time. Confirmatory factor analysis procedures, using AMOS 19 software, were performed to determine model fit. RESULTS: In contrast to the scale developers' findings, confirmatory factor analysis supported a superior model fit for the AGQ compared with the AGQ-R, in all countries under study. CONCLUSION: Validating measures of achievement goal motivation for use in pharmacy education is necessary and has implications for future research. Based on these results, the AGQ will be used to conduct future cross-sectional and longitudinal analyses of the achievement goals of undergraduate pharmacy students from these countries. PMID- 25298744 TI - Imprinting methylation errors in ART. AB - There has been an increase in incidence reports of rare imprinting disorders associated with assisted reproductive technology (ART). ART, including in vitro fertilization and intracytoplasmic sperm injections, is an important treatment for infertile people of reproductive age and increasingly produces children. The identification of epigenetic changes at imprinted loci in ART infants has led to the suggestion that ART techniques themselves may predispose embryos to acquire imprinting errors and diseases. In this review, we note that the particular steps of ART may be prone to induction of imprinting methylation errors during gametogenesis, fertilization and early embryonic development. In addition, we explain imprint-associated diseases and their causes. Moreover, from a Japanese nationwide epidemiological study of imprint-associated diseases, we determine their associations with ART. Epigenetic studies will be required to understand the pathogenesis, ART-related risk factor(s) and what precautions can be taken to prevent the occurrence of input methylation errors. We hope that the constitution of children born after each ART procedure will reveal the safest and most ethical approach to use, which will be invaluable for the future development of standard ART. PMID- 25298746 TI - Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern. AB - BACKGROUND: Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials. CASE PRESENTATION: Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene. CONCLUSION: This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis. PMID- 25298745 TI - Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis. AB - Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms. How germ cells acquire this ability has been of considerable interest. In mammals, primordial germ cells (PGCs), the precursors of sperm and oocytes, are specified around the time of gastrulation. PGCs are induced by signals from the surrounding extra-embryonic tissues to the equipotent epiblast cells that give rise to all cell types. Currently, the mechanism of PGC specification in mammals is best understood from studies in mice. Following implantation, the epiblast cells develop as an egg cylinder while the extra embryonic ectoderm cells which are the source of important signals for PGC specification are located over the egg cylinder. However, in most cases, including humans, the epiblast cells develop as a planar disc, which alters the organization and the source of the signaling for cell fates. This, in turn, might have an effect on the precise mechanism of PGC specification in vivo as well as in vitro using pluripotent embryonic stem cells. Here, we discuss how the key early embryonic differences between rodents and other mammals may affect the establishment of the pluripotency network in vivo and in vitro, and consequently the basis for PGC specification, particularly from pluripotent embryonic stem cells in vitro. PMID- 25298747 TI - Overexpression of Chemokine (C-X-C) ligand 1 (CXCL1) associated with tumor progression and poor prognosis in hepatocellular carcinoma. AB - BACKGROUND: Many studies support that chemokine (C-X-C motif) ligand 1 (CXCL1) regulate tumor epithelial-stromal interactions involving in tumor growth and invasion. However, limited studies have been conducted on the expression and function of the CXCL1 gene in hepatocellular carcinoma (HCC). METHODS: The mRNA and protein level expression of CXCL1 was examined in HCC tissues and cell lines. The expression of CXCL1 was correlated with clinicopathological features and follow-up data. Overexpression approaches were used to evaluate the biological functions of CXCL1 by MTT and matrigel invasion assays. Protein expression levels of CXCL1 and P65 were determined by western blot analysis. RESULTS: In this study, we found that CXCL1 expression was markedly upregulated in HCC tissues. Ectopic expression of CXCL1 significantly promoted HCC cells proliferation and invasion. Furthermore, CXCL1 promote cell invasion through NF-kB-dependent pathway. CXCL1 expression in HCC associated with clinical stage (P = 0.034) and distant metastasis (P = 0.028). Moreover, Patients with high CXCL1 expression level had poorer overall survival (OS;P = 0.027) than those with low CXCL1 expression. CONCLUSIONS: These data indicated that the CXCL1 upregulation may contribute to both the development and progression of HCC and this effect may be associated with increased proliferation and invasiveness mainly via regulating P65 expression. PMID- 25298748 TI - In vitro assessment of antitumor activities of the PI3K/mTOR inhibitor GSK2126458. AB - BACKGROUND: Up-regulation of the PI3K/mTOR (phosphatidylinositol-3' kinase/mammalian target of rapamycin) signaling is common in carcinoma. Consistently, targeting these molecules has been shown to halt the growth of many tumors. The main purpose of this study was to develop surrogate biomarkers of the antitumor activity of PI3K/mTOR inhibitors. METHODS: Fragments from eight tumors were collected immediately after resection in ice-cold RPMI gassed with 95% O2 :5% CO2. Viability was determined by measuring tumor cellular respiration (mitochondrial O2 consumption). The specimens were incubated at 37 degrees C with and without 50 nM GSK2126458 (a highly potent and selective inhibitor of PI3K/mTOR) for 90 min. The tissue was then processed for histology, measurement of intracellular caspase-3 activity (using the caspase-3 substrate N-acetyl-asp glu-val-asp-7-amino-4-methylcoumarin), and immunohistochemical detection of the apoptotic biomarkers caspase-3, cytochrome C, and annexin A2. RESULTS: GSK2126458 induced morphologic changes in four tumors (two invasive ductal carcinomas, one invasive lobular carcinoma, and one ovarian dysgerminoma), intracellular caspase 3 activity in three tumors (two invasive ductal carcinomas and one poorly differentiated signet ring adenocarcinoma of gastric origin), and immunohistochemical evidence of apoptosis in at least four tumors (three invasive ductal carcinomas and one adenocarcinoma of gastric origin). Two tumors (ovarian serous carcinoma and moderately differentiated adenocarcinoma of colorectal origin) demonstrated no treatment effect. CONCLUSION: These preliminary results demonstrate the feasibility of using in vitro biomarkers for detecting antitumor activities of the rapidly emerging PI3K/mTOR inhibitors. PMID- 25298749 TI - Aged garlic extract protects against oxidative stress and renal changes in cisplatin-treated adult male rats. AB - BACKGROUND: Cisplatin (CP) is one of the effective anticancer drugs, but it causes many side effects. Aged garlic extract (AGE) is a natural herbal product used in management of many diseases. OBJECTIVE: This study aimed to investigate effect of AGE on CP-induced nephrotoxicity in rats. MATERIAL AND METHODS: Four equal groups of adult male rats: control, AGE -treated (250 mg/kg, once oral dose/ 21days), CP-treated (7.5 mg/kg once i.p. on day 16th.), combined AGE and CP treated were used. Body and kidneys weights of each rat were calculated. Serum levels of kidney biomarkers were assessed. Malondialdehyde (MDA) and reduce glutathione (GSH) levels, superoxide dismutase (SOD) and catalase (CAT) activities of renal tissues were measured as well. Renal samples from each rat were prepared for light and electron microscopic examinations. RESULTS: Hemorrhage, glomerular atrophy, inflammatory cell infiltration, tubular necrosis and degeneration were observed in CP-treated rats. Also, a significant (P<0.001) reduction in SOD & CAT activities, GSH levels accompanied with a significant increase in serum levels of kidney biomarkers and MDA were determined in CP treated rats compared to control group. However, most of CP-induced histomorphological, ultrastructural and biochemical changes were improved in animals pretreated with AGE. CONCLUSION: Such renoprotective effect of AGE may be attributed to its antioxidant activity. PMID- 25298750 TI - Human umbilical cord mesenchymal stem cells promote carcinoma growth and lymph node metastasis when co-injected with esophageal carcinoma cells in nude mice. AB - BACKGROUND: Human umbilical cord blood derived-mesenchymal stem cells (hUCMSCs) offer an attractive alternative to bone marrow-derived MSCs (BMMSCs) for cell based therapy as it is a less invasive source of biological material. However, limited studies have been conducted with hUCMSCs as compared to BMMSCs. The present study was conducted to evaluate the effects of hUCMSCs in esophageal carcinoma (EC). METHODS: hUCMSCs together with EC cells were transplanted subcutaneously into BALB/c nude mice to observe the effects of hUCMSCs on tumor establishment. hUCMSCs injected through the caudal vein to the mice with pre established EC to observe the effects of hUCMSCs on tumor outgrowth. In order to elucidate the underlying mechanisms, we also performed in vitro experiments including directly co-culture, transwell assay, proliferation assay and western blotting analysis. RESULTS: hUCMSCs promoted EC formation in nude mice. In the in vivo model of pre-established EC, intravenously injected hUCMSCs potently promoted tumor growth. When in vitro co-cultured with hUCMSCs, EC cells proliferation increased. After co-cultured with hUCMSCs through transwell system, EC cells showed increased proliferation. Through transwell assay, we also observed that EC cells recruited MSCs, and MSCs promoted EC cells migration and invasion. Western blotting data showed that the expressions of proliferation related proteins Bcl-2, survivin and metastasis related proteins MMP-2 and MMP-9 were up-regulated in the EC cells transwell co-cultured with hUCMSCs. CONCLUSIONS: Our results indicated that hUCMSCs could favor tumor growth in vivo and in vitro. Thus, the exploitation of hUCMSCs in new therapeutic strategies should be cautious under the malignant conditions. PMID- 25298752 TI - Learning Peptide-Spectrum Alignment Models for Tandem Mass Spectrometry. AB - We present a peptide-spectrum alignment strategy that employs a dynamic Bayesian network (DBN) for the identification of spectra produced by tandem mass spectrometry (MS/MS). Our method is fundamentally generative in that it models peptide fragmentation in MS/MS as a physical process. The model traverses an observed MS/MS spectrum and a peptide-based theoretical spectrum to calculate the best alignment between the two spectra. Unlike all existing state-of-the-art methods for spectrum identification that we are aware of, our method can learn alignment probabilities given a dataset of high-quality peptide-spectrum pairs. The method, moreover, accounts for noise peaks and absent theoretical peaks in the observed spectrum. We demonstrate that our method outperforms, on a majority of datasets, several widely used, state-of-the-art database search tools for spectrum identification. Furthermore, the proposed approach provides an extensible framework for MS/MS analysis and provides useful information that is not produced by other methods, thanks to its generative structure. PMID- 25298751 TI - Potential serum biomarkers for glioblastoma diagnostic assessed by proteomic approaches. AB - BACKGROUND: The rapid progress of proteomics over the past years has allowed the discovery of a large number of potential biomarker candidates to improve early tumor diagnosis and therapeutic response, thus being further integrated into clinical environment. High grade gliomas represent one of the most aggressive and treatment-resistant types of human brain cancer, with approximately 9-12 months median survival rate for patients with grade IV glioma (glioblastoma). Using state-of-the-art proteomics technologies, we have investigated the proteome profile for glioblastoma patients in order to identify a novel protein biomarker panel that could discriminate glioblastoma patients from controls and increase diagnostic accuracy. RESULTS: In this study, SELDI-ToF MS technology was used to screen potential protein patterns in glioblastoma patients serum; furthermore, LC MS/MS technology was applied to identify the candidate biomarkers peaks. Through these proteomic approaches, three proteins S100A8, S100A9 and CXCL4 were selected as putative biomarkers and confirmed by ELISA. Next step was to validate the above mentioned molecules as biomarkers through identification of protein expression by Western blot in tumoral versus peritumoral tissue. CONCLUSIONS: Proteomic technologies have been used to investigate the protein profile of glioblastoma patients and established several potential diagnostic biomarkers. While it is unlikely for a single biomarker to be highly effective for glioblastoma diagnostic, our data proposed an alternative and efficient approach by using a novel combination of multiple biomarkers. PMID- 25298753 TI - Rural Versus Urban Comparison: Physical Activity and Functioning Following Coronary Artery Bypass Surgery. AB - PURPOSE: The purpose of this sub-analysis was to compare the early recovery of elderly patients following coronary artery bypass surgery (CABS) by geographic location (urban/rural) on physical functioning and physical activity. METHODS: The sample was 124 subjects who had been in the usual care group (or control group) of a randomized controlled trial. Subjects were categorized into geographic locales using Rural Urban Commuting Area (RUCA) codes: urban n=35, large rural n=17, small rural n=23 and isolated rural n=33. Measures included the Medical Outcomes Study Short-Form 36 and the RT3(r) accelerometer. Mixed linear models were used to analyze the data. RESULTS: No significant differences were found for physical functioning by RUCA group. However, there was a statistically significant difference for physical activity, for average kcals/kg/ per day (F = 3.01, p < .05) and average daily activity counts (F = 3.95, p <.01), with the subjects in large rural communities having significantly (p < 0.05) more average kcals/kg per day than urban subjects (M = 29.04 and M = 27.25 respectively). Subjects in the large rural also had significantly (p < .005) more average daily activity counts than urban (M = 216635 and M = 161221 respectively). CONCLUSIONS: This is the first study to compare early recovery functioning and activity outcomes of CABS subjects by rural/urban locations. Additional study is warranted to evaluate why these differences exist and the potential need to tailor interventions for CABS based on geographic location. PMID- 25298754 TI - Effect of supplementation with chokeberry juice on the inflammatory status and markers of iron metabolism in rowers. AB - BACKGROUND: The aim of this study was to analyze the effect of supplementation with chokeberry (Aronia melanocarpa) juice on the levels of pro-inflammatory cytokines, hepcidin, and selected markers of iron metabolism in rowers subjected to exhaustive exercise. METHODS: This double-blind study included 19 members of the Polish Rowing Team. The subjects were randomly assigned to the supplemented group (n = 10), receiving 150 mL of chokeberry juice for 8 weeks, or to the placebo group (n = 9). The participants performed a 2000-m test on a rowing ergometer at the beginning and at the end of the preparatory camp. Blood samples were obtained from the antecubital vein prior to each exercise test, one minute after completing the test, and after a 24-hour recovery period. The levels of hepcidin, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), ferritin, iron, uric acid, and myoglobin were determined, as well as the total iron-binding capacity, unbound iron-binding capacity, and total antioxidant capacity (TAC). RESULTS: Post-exercise, there was a significant increase in IL-6 and a significant decrease in the TAC in both groups, prior to and after supplementation with chokeberry juice. At the end of the experiment, the supplemented athletes showed significantly lower post-exercise levels of TNF alpha and significantly higher TACs and iron levels than the controls. CONCLUSION: Supplementation with chokeberry juice results in an increase in the antioxidant activity of plasma and contributes significantly to reducing the TNF alpha level. PMID- 25298755 TI - Religiosity and the Transition to Nonmarital Parity. AB - Nonmarital parity is associated with several negative outcomes, including health problems, educational problems, and poverty. Understanding the risk and protective factors associated with nonmarital parenthood can inform policy and interventions, reducing both the incidences and associated consequences. The current study focuses on how intrinsic and extrinsic religiosity (the degree to which individuals or groups employ religious ideology in forming values and making decisions) are related to the timing of nonmarital parity using discrete time hazard modeling of a nationally representative sample of adolescent females (N=7,367) from the National Longitudinal Study of Adolescent Health. The majority of the sample (86 %) claimed a religious affiliation and almost a third (32 %) had a nonmarital birth during the study. Even though the majority of the sample is White (67 %), Black and Hispanic females were more likely to experience a nonmarital birth. Results indicate that intrinsic and extrinsic religiosity and religious affiliation assert protective effects for some populations while religious affiliation increases risk in the full model. Recommendations for policy, intervention, and future research are offered. PMID- 25298756 TI - Reduced chemically modified graphene oxide for supercapacitor electrode. AB - An efficient active material for supercapacitor electrodes is prepared by reacting potassium hydroxide (KOH) with graphene oxide followed by chemical reduction with hydrazine. The electrochemical performance of KOH treated graphene oxide reduced for 24 h (reduced chemically modified graphene oxide, RCMGO-24) exhibits a specific capacitance of 253 F g(-1) at 0.2 A g(-1) in 2 M H2SO4 compared to a value of 141 F g(-1) for graphene oxide reduced for 24 h (RGO-24), and good cyclic stability up to 3,000 cycles. Interestingly, RCMGO-24 demonstrated a higher specific capacitance and excellent cycle stability due to its residual oxygen functional groups that accelerate the faradaic reactions and aid in faster wetting. This non-annealed strategy offers the potential for simple and cost-effective preparation of an active material for a supercapacitor electrode. PMID- 25298757 TI - Ordered and ultrathin reduced graphene oxide LB films as hole injection layers for organic light-emitting diode. AB - In this paper, we demonstrated the utilization of reduced graphene oxide (RGO) Langmuir-Blodgett (LB) films as high performance hole injection layer in organic light-emitting diode (OLED). By using LB technique, the well-ordered and thickness-controlled RGO sheets are incorporated between the organic active layer and the transparent conducting indium tin oxide (ITO), leading to an increase of recombination between electrons and holes. Due to the dramatic increase of hole carrier injection efficiency in RGO LB layer, the device luminance performance is greatly enhanced comparable to devices fabricated with spin-coating RGO and a commercial conducting polymer PEDOT:PSS as the hole transport layer. Furthermore, our results indicate that RGO LB films could be an excellent alternative to commercial PEDOT:PSS as the effective hole transport and electron blocking layer in light-emitting diode devices. PMID- 25298758 TI - Patterned growth of carbon nanotubes over vertically aligned silicon nanowire bundles for achieving uniform field emission. AB - A fabrication strategy is proposed to enable precise coverage of as-grown carbon nanotube (CNT) mats atop vertically aligned silicon nanowire (VA-SiNW) bundles in order to realize a uniform bundle array of CNT-SiNW heterojunctions over a large sample area. No obvious electrical degradation of as-fabricated SiNWs is observed according to the measured current-voltage characteristic of a two-terminal single nanowire device. Bundle arrangement of CNT-SiNW heterojunctions is optimized to relax the electrostatic screening effect and to maximize the field enhancement factor. As a result, superior field emission performance and relatively stable emission current over 12 h is obtained. A bright and uniform fluorescent radiation is observed from CNT-SiNW-based field emitters regardless of its bundle periodicity, verifying the existence of high-density and efficient field emitters on the proposed CNT-SiNW bundle arrays. PMID- 25298759 TI - Coexistence of memory resistance and memory capacitance in TiO2 solid-state devices. AB - This work exploits the coexistence of both resistance and capacitance memory effects in TiO2-based two-terminal cells. Our Pt/TiO2/TiO x /Pt devices exhibit an interesting combination of hysteresis and non-zero crossing in their current voltage (I-V) characteristic that indicates the presence of capacitive states. Our experimental results demonstrate that both resistance and capacitance states can be simultaneously set via either voltage cycling and/or voltage pulses. We argue that these state modulations occur due to bias-induced reduction of the TiO x active layer via the displacement of ionic species. PMID- 25298760 TI - Antimicrobial applications of transition metal complexes of benzothiazole based terpolymer: synthesis, characterization, and effect on bacterial and fungal strains. AB - Terpolymer of 2-amino-6-nitro-benzothiazole-ethylenediamine-formaldehyde (BEF) has been synthesized and characterized by elemental analysis and various spectral techniques like FTIR, UV-Visible, and (1)H and (13)C-NMR. The terpolymer metal complexes were prepared with Cu(2+), Ni(2+), and Zn(2+) metal ions using BEF terpolymer as a ligand. The complexes have been characterized by elemental analysis and IR, UV-Visible, ESR, (1)H-NMR, and (13)C-NMR spectral studies. Gel permeation chromatography was used to determine the molecular weight of the ligand. The surface features and crystalline behavior of the ligand and its complexes were analyzed by scanning electron microscope and X-ray diffraction methods. Thermogravimetric analysis was used to analyze the thermal stability of the ligand and its metal complexes. Kinetic parameters such as activation energy (E a ) and order of reaction (n) and thermodynamic parameters, namely, DeltaS, DeltaF, S*, and Z, were calculated using Freeman-Carroll (FC), Sharp-Wentworth (SW), and Phadnis-Deshpande (PD) methods. Thermal degradation model of the terpolymer and its metal complexes was also proposed using PD method. Biological activities of the ligand and its complexes were tested against Shigella sonnei, Escherichia coli, Klebsiella species, Staphylococcus aureus, Bacillus subtilis, and Salmonella typhimurium bacteria and Aspergillus flavus, Aspergillus niger, Penicillium species, Candida albicans, Cryptococcus neoformans, Mucor species fungi. PMID- 25298761 TI - Endoscopic Sphincterotomy Using the Rendezvous Technique for Choledocholithiasis during Laparoscopic Cholecystectomy: A Case Report. AB - A 50-year-old male was examined at another hospital for fever, general fatigue and slight abdominal pain. He was treated with antibiotics and observed. However, his symptoms did not lessen, and laboratory tests revealed liver dysfunction, jaundice and an increased inflammatory response. He was then admitted to our hospital and underwent an abdominal computed tomography scan and magnetic resonance cholangiopancreatography (MRCP), which revealed common bile duct (CBD) stones. He was diagnosed with mild acute cholangitis. As the same time, he was admitted to our hospital and an emergency endoscopic retrograde cholangiopancreatography was performed. Vater papilla opening in the third portion of the duodenum and presence of a peripapillary duodenal diverticulum made it difficult to perform cannulation of the CBD. In addition, MRCP revealed that the CBD was extremely narrow (diameter 5 mm). We therefore performed laparoscopic cholecystectomy and endoscopic sphincterotomy using the rendezvous technique for choledocholithiasis simultaneously rather than laparoscopic CBD exploration. After the operation, the patient was discharged with no complications. Although the rendezvous technique has not been very commonly used because several experts in the technique and a large operating room are required, this technique is a very attractive and effective approach for treating choledocholithiasis, for which endoscopic treatment is difficult. PMID- 25298762 TI - Primary Biliary Cirrhosis and Primary Sjogren's Syndrome: Insights for the Stomatologist. AB - Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune disease characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Primary Sjogren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly the lachrymal and salivary glands, in the absence of other definitively diagnosed rheumatologic disease. We report a diagnosed case of primary Sjogren's syndrome associated with PBC. A 59-year-old Caucasian woman went to oral evaluation reporting dry mouth, difficulty in eating associated with burning mouth syndrome, dysgeusia and dysphagia. Intraoral examination revealed extensive cervical caries, gingivitis, gingival retraction, angular cheilitis and atrophic tongue. Hyposalivation was detected by salivary flow and Schirmer's test was positive. Antinuclear and antimitochondrial antibodies were both positive. Anti-Ro/SSA and anti-La/SSB antibodies were negative. A minor salivary gland biopsy of the lower lip was performed. Histopathologic analysis revealed lymphocytic infiltrate with destruction of salivary gland architecture in some areas and replacement of glandular tissues by mononuclear cells. Optimal management of PBC associated with Sjogren's syndrome requires a multidisciplinary approach as the key to optimal patient care. Dental practitioners should be able to recognize the clinical features of this associated condition. Appropriate dental care may prevent tooth decay, periodontal disease and oral infections as well as improve the patient's quality of life. PMID- 25298763 TI - An unusually severe case of dermatosis neglecta: a diagnostic challenge. AB - Dermatosis neglecta is a condition secondary to lack of cleanliness, characterized by the formation of hyperkeratotic plaques located in a particular region of the body, usually due to a disability, and it is considered a diagnostic challenge because it can mimic other entities. We present the case of an 18-year-old woman with a 2-month history of progressive brown verrucous plaque in her face. Our first impression was seborrheic dermatitis and she was treated with facial cleanser soap and topic hydrocortisone 1%. One month later, she arrived with new lesions. Because of this our diagnosis changed to Darier's disease versus seborrheic pemphigus versus foliaceus pemphigus. Histopathology and immunofluorescence studies were compatible with seborrheic dermatitis. The patient complained of depression and social withdrawal and denied facial cleansing. Facial cleansing was performed during consultation presenting resolution of the lesions, which confirmed the diagnosis of dermatosis neglecta. Dermatosis neglecta is a disease that can be frequently misdiagnosed, since it has many differential diagnoses, such as hyperkeratotic syndromes. It should be recognized early and aggressive diagnostic and therapeutic methods should be avoided. PMID- 25298764 TI - Carcinoma of unknown primary site treated with Carboplatin + Paclitaxel + bevacizumab + erlotinib and its maintenance chemotherapy. AB - About 3% of all cancer patients suffer from carcinoma of unknown primary site (CUP). In spite of its rarity, we will encounter them. While CUPs manifest a wide variety of clinical presentations, they have often resulted in poor prognosis. Although platinum/taxane combination chemotherapy, e.g. carboplatin (CBDCA) + paclitaxel (PTX) is widely used for patients suffering from CUP, the response rate is only about 30-40% and the median overall survival (OS) is only 9 months, which means that improvement is needed. Among the new regimens, the combination of CBDCA, PTX, bevacizumab (BEV) and erlotinib is thought to be highly promising. Herein, we report a case with CUP treated with this regimen and his maintenance therapy. Our patient was a 75-year-old man who was admitted with a left neck lump. CT revealed systemic massive lymphadenopathy. In spite of various investigations for primary origin, he was diagnosed with CUP and treated with CBDCA + PTX + BEV + erlotinib (AUC 6 + 175 mg/m(2) + 15 mg/kg + 150 mg). Since the evaluation of the efficacy indicated partial response, maintenance chemotherapy (BEV and erlotinib) was performed. Chemotherapy was continued for 9 months until the patient was in a progressive disease state with meningeal dissemination. He died 12 months after the initiation of chemotherapy, which is a longer period than the previously reported OS. Of note, according to our case, CBDCA + PTX + BEV + erlotinib and its maintenance chemotherapy are feasible and well tolerated for CUP. PMID- 25298765 TI - Heart failure as first sign of development of cardiac metastases in a patient with diagnosis of papillary thyroid carcinoma on treatment with tyrosine-kinase inhibitors: differential diagnoses and clinical management. AB - BACKGROUND: Cardiac metastases from papillary thyroid carcinoma are very uncommon. Their incidence is rising due to improvements in survival and diagnosis; nevertheless, our patient is the fourth case reported up to date. There are no clinical trials available in this scenario. Therefore, treatment choice is made based on clinical experience and case reports; notably, the largest case report series was prior to the approval for using tyrosine-kinase inhibitors in thyroid cancer. PATIENT: A 73-year-old lady had dedifferentiated papillary thyroid cancer with ongoing sorafenib. After 9 months on this treatment, she presented with dyspnea and heart failure. Differential diagnosis included infection, progression of disease and cardiotoxicity. After a comprehensive assessment (echocardiography, computed tomography, PET, magnetic resonance), we found progression of lung disease, and the appearance of heart metastases. RESULTS: After recovering from the basal status, she started on second-line treatment with sunitinib, which was well-tolerated. She achieved stable disease with a decrease in tumor marker levels. CONCLUSIONS: We should include cardiac metastases in the differential diagnosis of heart failure in cancer patients. Magnetic resonance imaging is the gold standard for assessment. Sorafenib is the mainstay of the first-line therapy in metastatic thyroid cancer, achieving long-term disease control with good tolerance. Sunitinib could be a safe second-line treatment option (not cardiotoxicity related) with promising results. Therefore, our report presents a sequence of treatment with tyrosine kinase inhibitors in metastatic thyroid carcinoma with an encouraging outcome, which deserves further investigation. PMID- 25298766 TI - An unusual case of isolated peritoneal metastases from lung adenocarcinoma. AB - INTRODUCTION: Peritoneal metastases from lung cancer are a rare event. In this paper, we report the case of a patient with adenocarcinoma of the lungs who had isolated peritoneal metastases at the time of diagnosis. CASE REPORT: We report a 55-year-old female who presented with shortness of breath, decreased effort tolerance, cough, and weight loss. Her initial chest X-ray and subsequent chest CT showed a 12 * 9 * 8 cm mass in the middle lobe of the right lung. The histopathological examination of her biopsy material was consistent with a thyroid transcription factor-1 positive lung adenocarcinoma. In the abdomen, a 5.3-cm mass was identified. A biopsy and immunohistochemistry revealed a lung adenocarcinoma. The patient was administered chemotherapy based on carboplatin paclitaxel-bevacizumab, but only with a partial response. Six months later, the patient showed brain metastases. Therefore, a second-line treatment based on pemetrexed was administered for 9 courses, and a clinical and radiological response was observed. The chemotherapy was stopped and the patient did not exhibit any symptoms of progression while waiting for a new evaluation. DISCUSSION: The incidence of peritoneal involvement of lung cancer without metastases in other parts of the body is scarcely encountered in clinical practice. Out of the different types of lung cancers, adenocarcinoma and large cell carcinoma are most likely to metastasize in the peritoneum. Immunohistochemical staining patterns were important in the differential diagnosis with the other etiologies for peritoneal metastasis and the mesothelioma. Peritoneal metastases are indicative of a disseminated disease and prognosis is extremely poor. PMID- 25298767 TI - Pulmonary tumor thrombotic microangiopathy induced by ureteral carcinoma: a necropsy case report. AB - BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer related pulmonary complication with rapidly progressing dyspnea and pulmonary hypertension that occasionally induces sudden death. We report the first case of PTTM induced by ureter carcinoma. CASE PRESENTATION: The patient was an 80-year old Japanese female with chief complaints of dry cough and dyspnea. An echocardiogram revealed severe pulmonary hypertension. A chest radiograph showed ground glass opacity of bilateral lower lung field predominance, and an abdominal computed tomography scan revealed a left ureter mass suggestive of ureter carcinoma. The patient died of respiratory failure on the eighth day of hospitalization. Postmortem examination indicated that the primary lesion was a left ureter cancer with tumor microemboli extending to both lungs through the right side of the heart. The final diagnosis of this case was PTTM induced by ureter carcinoma. CONCLUSION: The pathogenesis and pathophysiology of PTTM remains obscure with no effective management available. In cases of rapidly progressing respiratory failure with pulmonary hypertension, it is necessary to consider PTTM in the differential diagnosis. PMID- 25298768 TI - Persistent aura with small occipital cortical infarction: implications for migraine pathophysiology. AB - OBJECTIVE: The pathophysiology of migraine with aura is thought to be related to cortical spreading depression and cortical hypersensitivity, in which inhibitory interneurons may play a role. Persistent migraine aura (PMA) without infarction is defined as auras that last longer than 1 week in the absence of infarction. We describe a case of persistent aura with a small occipital cortical infarction and discuss implications of this case and PMA for pathophysiological concepts of migrainous auras. METHODS: We present a case and discuss the implications for pathophysiological concepts. RESULTS: The case presented cannot be diagnosed as PMA as the patient was found to have an occipital cortical infarction with hypoactivity on fluorodeoxyglucose-positron emission tomography. Nevertheless, the patient suffered from persistent aura (with infarction). We argue that the infarction may have been responsible for an increased imbalance in one of the primary visual cortex networks that was already hyperexcitable due to the migraine aura condition. CONCLUSION: PMA with occipital infarction has not been reported previously. We believe the findings of the present case and PMA cases reported in the past may support the intracortical disinhibition hypothesis in migraine. PMID- 25298769 TI - Eyelid tremor in a patient with anti-caspr2 antibody-related encephalitis. AB - We describe the first case of a patient with eyelid tremor probably associated with anti-contactin-associated protein-like 2 (Caspr2) antibody. Encephalitis associated with anti-voltage-gated potassium channel antibody is now attributed to autoantibodies against leucine-rich glioma inactivated 1 (Lgi1) and less frequently against Caspr2. Eyelid tremor or blepharoclonus is a rare or underdiagnosed involuntary movement that has been found in patients with infarction in the thalamus or drug-induced or idiopathic parkinsonism. Since patients with anti-Caspr2 antibody-related encephalitis occasionally have extrapyramidal signs, we speculate that the eyelid tremor was also caused by anti Caspr2 antibody in our patient. Partial resolution of his symptoms by plasmapheresis also supported the involvement in immunological processes. PMID- 25298770 TI - Bilateral sequential non-arteritic anterior ischaemic optic neuropathy following repeat influenza vaccination. AB - A 68-year-old man developed bilateral sequential non-arteritic anterior ischaemic optic neuropathy, each episode occurring with a close temporal relationship to influenza vaccination. PMID- 25298771 TI - Bilateral retrobulbar optic neuropathy in the setting of interferon alpha-2a therapy. AB - The development of biopharmaceutical agents, including the interferons (IFN), offers new treatment options for a wide range of medical conditions. Such advancements, however, have not come without risk to patients. Optic neuropathy in the setting of IFN therapy has been previously documented and is usually attributed to anterior ischaemic optic neuropathy; however, the pathophysiology remains poorly understood. Retrobulbar optic neuropathy associated with IFN treatment has not been described in the medical literature to date. We report the case of a 38-year-old Caucasian female with refractory acute myeloid leukaemia who developed painless bilateral blurred vision within 2 weeks of commencing a course of IFN alpha-2a. Extensive clinical workup demonstrated bilateral retrobulbar optic neuropathy. We report the clinical evaluation of this first documented case and discuss the possible aetiologies of her presentation. PMID- 25298772 TI - Acute isolated dysarthria is associated with a high risk of stroke. AB - BACKGROUND: Isolated dysarthria is an uncommon presentation of transient ischemic attack (TIA)/minor stroke and has a broad differential diagnosis. There is little information in the literature about how often this presentation is confirmed to be a TIA/stroke, and therefore there is debate about the risk of subsequent vascular events. Given the uncertain prognosis, it is unclear how to best manage patients presenting to the emergency department (ED) with isolated dysarthria. The objective of this study was to prospectively identify and follow a cohort of patients presenting to EDs with isolated dysarthria in order to explore their natural history and risk of recurrent cerebrovascular events. Specifically, we sought to determine early outcomes of individuals with this nonspecific and atypical presentation in order to appropriately expedite their management. METHODS: Patients with isolated dysarthria having presented to 8 Canadian EDs between October 2006 and April 2009 were analyzed as part of a prospective multicenter cohort study of patients with acute neurological symptoms as assessed by emergency physicians. The study inclusion criteria were age >=18 years, a normal level of consciousness, and a symptom onset <1 week prior to presentation without an established nonvascular etiology. The primary outcome was a subsequent stroke within 90 days of the index visit. The secondary outcomes were the rate of TIA, myocardial infarction, and death. Isolated dysarthria was defined as slurring with imprecise articulation but without evidence of language dysfunction. The overall rate of stroke in this cohort was compared with that predicted by the median ABCD2 score for this group. RESULTS: Between 2006 and 2009, 1,528 patients were enrolled and had a 90-day follow-up. Of these, 43 patients presented with isolated acute-onset dysarthria (2.8%). Recurrent stroke occurred in 6/43 (14.0%) within 90 days of enrollment. The predicted maximal 90 day stroke rate was 9.8% (based on a median ABCD2 score of 5 for the isolated dysarthria cohort). After adjusting for covariates, isolated dysarthria independently predicted stroke within 90 days (aOR: 3.96; 95% CI: 1.3-11.9; p = 0.014). CONCLUSIONS: The isolated dysarthria cohort carried a recurrent stroke risk comparable to that predicted by the median ABCD2 scores. Although isolated dysarthria is a nonspecific and uncommon clinical presentation of TIA, these findings support the need to view it first and foremost as a vascular presentation until proven otherwise and to manage such patients as if they were at high risk of stroke in accordance with established high-risk TIA guidelines. PMID- 25298773 TI - The longitudinal evolution of cerebral blood flow regulation after acute ischaemic stroke. AB - BACKGROUND: Acute stroke is known to impair cerebral blood flow (CBF) regulation, but the longitudinal changes of these effects have been poorly reported. The main CBF regulatory mechanisms [cerebral autoregulation (CA) and neurovascular coupling (NVC)] were assessed over 3 months after acute ischaemic stroke. METHODS: Recordings of CBF velocity (CBFv), blood pressure (BP), and end-tidal CO2 were performed during 5 min baseline and 1 min passive movement of the elbow. Stroke patients were assessed <72 h of stroke onset, and at 2 weeks, 1 and 3 months after stroke. RESULTS: Fifteen acute stroke subjects underwent all 4 sessions and were compared to 22 control subjects. Baseline recordings revealed a significantly lower CBFv in the affected hemisphere within 72 h after stroke compared to controls (p = 0.02) and a reduction in CA index most marked at 2 weeks (p = 0.009). CBFv rise in response to passive arm movement was decreased bilaterally after stroke, particularly in the affected hemisphere (p < 0.01). Both alterations in CA and NVC returned to control levels during recovery. CONCLUSION: The major novel finding of this study was that both CA and NVC regulatory mechanisms deteriorated initially following stroke onset, but returned to control levels during the recovery period. These findings are relevant to guide the timing of interventions to manipulate BP and potentially for the impact of intensive rehabilitation strategies that may precipitate acute physiological perturbations but require further exploration in a larger population that better reflects the heterogeneity of stroke. Further, they will also enable the potential influence of stroke subtype to be investigated. PMID- 25298774 TI - Retinal vascular fractals and cognitive impairment. AB - BACKGROUND: Retinal microvascular network changes have been found in patients with age-related brain diseases such as stroke and dementia including Alzheimer's disease. We examine whether retinal microvascular network changes are also present in preclinical stages of dementia. METHODS: This is a cross-sectional study of 300 Chinese participants (age: >=60 years) from the ongoing Epidemiology of Dementia in Singapore study who underwent detailed clinical examinations including retinal photography, brain imaging and neuropsychological testing. Retinal vascular parameters were assessed from optic disc-centered photographs using a semiautomated program. A comprehensive neuropsychological battery was administered, and cognitive function was summarized as composite and domain specific Z-scores. Cognitive impairment no dementia (CIND) and dementia were diagnosed according to standard diagnostic criteria. RESULTS: Among 268 eligible nondemented participants, 78 subjects were categorized as CIND-mild and 69 as CIND-moderate. In multivariable adjusted models, reduced retinal arteriolar and venular fractal dimensions were associated with an increased risk of CIND-mild and CIND-moderate. Reduced fractal dimensions were associated with poorer cognitive performance globally and in the specific domains of verbal memory, visuoconstruction and visuomotor speed. CONCLUSION: A sparser retinal microvascular network, represented by reduced arteriolar and venular fractal dimensions, was associated with cognitive impairment, suggesting that early microvascular damage may be present in preclinical stages of dementia. PMID- 25298775 TI - The Memory Alteration Test Discriminates between Cognitively Healthy Status, Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND/AIMS: Dementia is a worldwide public health problem and there are several diagnostic tools for its assessment. The aim of this study was to evaluate the performance of the Memory Alteration Test (M@T) to discriminate between patients with early Alzheimer's disease (AD), patients with amnestic mild cognitive impairment (a-MCI), and subjects with a cognitively healthy status (CHS). METHODS: The discriminative validity was assessed in a sample of 90 patients with AD, 45 patients with a-MCI, and 180 subjects with CHS. Clinical, functional, and cognitive studies were independently performed in a blinded fashion and the gold standard diagnosis was established by consensus on the basis of these results. The test performance was assessed by means of a receiver operating characteristic curve analysis as area under the curve (AUC). RESULTS: M@T mean scores were 17.7 (SD = 5.7) in AD, 30.8 (SD = 2.3) in a-MCI, and 44.5 (SD = 3.1) in CHS. A cutoff score of 37 points had a sensitivity of 98.3% and a specificity of 97.8% to differentiate a-MCI from CHS (AUC = 0.999). A cutoff score of 27 points had a sensitivity of 100% and a specificity of 98.9% to differentiate mild AD from a-MCI and from CHS (AUC = 1.000). CONCLUSIONS: The M@T had a high performance in the discrimination between early AD, a-MCI and CHS. PMID- 25298776 TI - The Extension of the German CERAD Neuropsychological Assessment Battery with Tests Assessing Subcortical, Executive and Frontal Functions Improves Accuracy in Dementia Diagnosis. AB - BACKGROUND/AIMS: Alzheimer's disease (AD) is the most common form of dementia. Neuropsychological assessment of individuals with AD primarily focuses on tests of cortical functioning. However, in clinical practice, the underlying pathologies of dementia are unknown, and a focus on cortical functioning may neglect other domains of cognition, including subcortical and executive functioning. The current study aimed to improve the diagnostic discrimination ability of the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB) by adding three tests of executive functioning and mental speed (Trail Making Tests A and B, S-Words). METHODS: Logistic regression analyses of 594 normal controls (NC), 326 patients with mild AD and 224 patients with other types of dementia (OD) were carried out, and the area under the curve values were compared to those of CERAD-NAB alone. RESULTS: All comparisons except AD-OD (65.5%) showed excellent classification rates (NC-AD: 92.7%; NC-OD: 89.0%; NC-all patients: 91.0%) and a superior diagnostic accuracy of the extended version. CONCLUSION: Our findings suggest that these three tests provide a sensible addition to the CERAD-NAB and can improve neuropsychological diagnosis of dementia. PMID- 25298777 TI - Agitation in dementia: relation to core cerebrospinal fluid biomarker levels. AB - BACKGROUND: The objective of this study was to examine the associations of agitation with the cerebrospinal fluid dementia biomarkers total-tau (T-tau), phosphorylated-tau (P-tau) and Abeta1-42. METHODS: One hundred patients (mean age +/- SD, 78.6 +/- 7.5 years) with dementia and neuropsychiatric symptoms, of whom 67% were female, were included. Agitation was measured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 +/- 11.8 points). RESULTS: Total CMAI correlated with T-tau [rs (31) = 0.36, p = 0.04] and P-tau [rs (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95). CONCLUSIONS: Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD. PMID- 25298778 TI - Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma. AB - Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation. PMID- 25298779 TI - Investigation of the Protective Effects of Taurine against Alloxan-Induced Diabetic Retinal Changes via Electroretinogram and Retinal Histology with New Zealand White Rabbits. AB - The purpose of this study was to investigate the protective role of orally administered taurine against diabetic retinal changes via electroretinogram (ERG) and retinal histology on rabbits. Rabbits were randomly assigned into groups: Group I (vehicle administration only); Group II (diabetes: induced by 100 mg/kg alloxan injection); Group III (diabetes and fed with 200 mg/kg taurine); and Group IV (diabetes and fed with 400 mg/kg taurine). The body weight and blood glucose levels of the rabbits were monitored weekly. The ERG was measured on weeks 5 and 15. Retinal histology was analyzed in the end of the experiment. Results revealed that a taurine supplement significantly ameliorates the alloxan induced hyperglycemia and protects the retina from electrophysiological changes. Group II showed a significant (P < 0.05) change in the mean scotopic b-wave amplitude when compared to that of Group I, whereas the diabetic rabbits treated with taurine (Group III and IV) were analogous to Group I. Histologically, the amount of Bipolar and Muller cells showed no difference (P > 0.05) between all groups and when compared with those of Group I. Our study provides solid evidences that taurine possesses an antidiabetic activity, reduced loss of body weight, and less electrophysiological changes of the diabetic retina. PMID- 25298780 TI - Environmental and organizational factors associated with elbow/forearm and hand/wrist disorder among sewing machine operators of garment industry in Ethiopia. AB - Occupational health problems related to upper limp musculoskeletal disorders were the major issue among sewing machine operators of garment industries in Ethiopia. The aim of this study was to assess the prevalence and associated risk factors of work related elbow and wrist musculoskeletal disorders among sewing machine operators of garment industries in Galan City, Oromia Regional State. A cross sectional study was conducted from April 1 to 30, 2012. A total of 422 study subjects were included in this study. Standard Nordic Musculoskeletal Questionnaire was used to collect detailed information on musculoskeletal symptom, sociodemographic data, and factors associated with the problems through face to face interview. From a total of 422 sewing machine operators included in the study 370 (87.7%) were females and 306 (72.5%) were in the age group of <30 years. The prevalence of self-reported work related elbow and wrist musculoskeletal disorders was 40% and 37.7%, respectively. In multivariate analysis, those who had >16 years of service were about five times more likely to develop elbow and wrist musculoskeletal disorders than those who had short (1-5 years) year of services [AOR = 4.7, 95% CI: 1.55-13.02], physical activities [AOR = 5.02, 95% CI: 1.57-16.00], and methods of payment [AOR = 2.01, 95% CI: 1.23 3.28], factors significantly associated with this disorders. Work related elbow and wrist musculoskeletal disorders were high among sewing machine operators in selected garment industries. Moreover, personal and environmental factors were identified as the potential risk factors related to elbow and wrist musculoskeletal disorders among the study group. Therefore, government and the owner of the garment industries should give special attention to prevent and control the problems through proper occupational health and safety policy implementation in the country. PMID- 25298781 TI - Development of a scale to measure individuals' ratings of peace. AB - BACKGROUND: The evolving concept of peace-building and the interplay between peace and health is examined in many venues, including at the World Health Assembly. However, without a metric to determine effectiveness of intervention programs all efforts are prone to subjective assessment. This paper develops a psychometric index that lays the foundation for measuring community peace stemming from intervention programs. METHODS: After developing a working definition of 'peace' and delineating a Peace Evaluation Across Cultures and Environments (PEACE) scale with seven constructs comprised of 71 items, a beta version of the index was pilot-tested. Two hundred and fifty subjects in three sites in the U.S. were studied using a five-point Likert scale to evaluate the psychometric functioning of the PEACE scale. Known groups validation was performed using the SOS-10. In addition, test-retest reliability was performed on 20 subjects. RESULTS: The preliminary data demonstrated that the scale has acceptable psychometric properties for measuring an individual's level of peacefulness. The study also provides reliability and validity data for the scale. The data demonstrated internal consistency, correlation between data and psychological well-being, and test-retest reliability. CONCLUSIONS: The PEACE scale may serve as a novel assessment tool in the health sector and be valuable in monitoring and evaluating the peace-building impact of health initiatives in conflict-affected regions. PMID- 25298782 TI - Co-production of ethanol and squalene using a Saccharomyces cerevisiae ERG1 (squalene epoxidase) mutant and agro-industrial feedstock. AB - BACKGROUND: Genetically customised Saccharomyces cerevisiae that can produce ethanol and additional bio-based chemicals from sustainable agro-industrial feedstocks (for example, residual plant biomass) are of major interest to the biofuel industry. We investigated the microbial biorefinery concept of ethanol and squalene co-production using S. cerevisiae (strain YUG37-ERG1) wherein ERG1 (squalene epoxidase) transcription is under the control of a doxycycline repressible tet0 7 -CYC1 promoter. The production of ethanol and squalene by YUG37-ERG1 grown using agriculturally sourced grass juice supplemented with doxycycline was assessed. RESULTS: Use of the tet0 7 -CYC1 promoter permitted regulation of ERG1 expression and squalene accumulation in YUG37-ERG1, allowing us to circumvent the lethal growth phenotype seen when ERG1 is disrupted completely. In experiments using grass juice feedstock supplemented with 0 to 50 MUg doxycycline mL(-1), YUG37-ERG1 fermented ethanol (22.5 [+/-0.5] mg mL(-1)) and accumulated the highest squalene content (7.89 +/- 0.25 mg g(-1) dry biomass) and yield (18.0 +/- 4.18 mg squalene L(-1)) with supplements of 5.0 and 0.025 MUg doxycycline mL(-1), respectively. Grass juice was found to be rich in water soluble carbohydrates (61.1 [+/-3.6] mg sugars mL(-1)) and provided excellent feedstock for growth and fermentation studies using YUG37-ERG1. CONCLUSION: Residual plant biomass components from crop production and rotation systems represent possible substrates for microbial fermentation of biofuels and bio based compounds. This study is the first to utilise S. cerevisiae for the co production of ethanol and squalene from grass juice. Our findings underscore the value of the biorefinery approach and demonstrate the potential to integrate microbial bioprocess engineering with existing agriculture. PMID- 25298783 TI - Insights into acetate toxicity in Zymomonas mobilis 8b using different substrates. AB - BACKGROUND: Lignocellulosic biomass is a promising renewable feedstock for biofuel production. Acetate is one of the major inhibitors liberated from hemicelluloses during hydrolysis. An understanding of the toxic effects of acetate on the fermentation microorganism and the efficient utilization of mixed sugars of glucose and xylose in the presence of hydrolysate inhibitors is crucial for economic biofuel production. RESULTS: A new microarray was designed including both coding sequences and intergenic regions to investigate the acetate stress responses of Zymomonas mobilis 8b when using single carbon sources of glucose or xylose, or mixed sugars of both glucose and xylose. With the supplementation of exogenous acetate, 8b can utilize all the glucose with a similar ethanol yield, although the growth, final biomass, and ethanol production rate were reduced. However, xylose utilization was inhibited in both media containing xylose or a mixed sugar of glucose and xylose, although the performance of 8b was better in mixed sugar than xylose-only media. The presence of acetate caused genes related to biosynthesis, the flagellar system, and glycolysis to be downregulated, and genes related to stress responses and energy metabolism to be upregulated. Unexpectedly, xylose seems to pose more stress on 8b, recruiting more genes for xylose utilization, than does acetate. Several gene candidates based on transcriptome results were selected for genetic manipulation, and a TonB dependent receptor knockout mutant was confirmed to have a slight advantage regarding acetate tolerance. CONCLUSIONS: Our results indicate Z. mobilis utilized a different mechanism for xylose utilization, with an even more severe impact on Z. mobilis than that caused by acetate treatment. Our study also suggests redox imbalance caused by stressful conditions may trigger a metabolic reaction leading to the accumulation of toxic intermediates such as xylitol, but Z. mobilis manages its carbon and energy metabolism through the control of individual reactions to mitigate the stressful conditions. We have thus provided extensive transcriptomic datasets and gained insights into the molecular responses of Z. mobilis to the inhibitor acetate when grown in different sugar sources, which will facilitate future metabolic modeling studies and strain improvement efforts for better xylose utilization and acetate tolerance. PMID- 25298784 TI - The 'Ziran' wrap: reconstruction of critical-sized long bone defects using a fascial autograft and reamer-irrigator-aspirator autograft. AB - Reconstruction of critical-size bony defects remains a challenge to surgeons despite recent technological advances. Current treatments include distraction osteogenesis, cancellous autograft, induced membranes (Masquelet procedure), polymeric membranes, and titanium-mesh cages filled with bone graft. In this article, the authors presents two cases in which critical-sized defects were reconstructed using a meshed fascial autograft encasing reamer-irrigator aspirator (RIA) autograft and cancellous allograft. This article will discuss the clinical outcomes of the technique, comparison to other current techniques, and technical insight into the potential biological mechanism. PMID- 25298785 TI - Prenatal diagnosis of a de novo interstitial deletion of 11q (11q22.3 -> q23.3) associated with abnormal ultrasound findings by array comparative genomic hybridization. AB - BACKGROUND: Conventional G-band karyotyping offers low-resolution detection of chromosome abnormalities and cannot provide information about the involved genomic content. On the other hand, array comparative genomic hybridization can offer a rapid and comprehensive detection of genomewide gains and losses with higher resolution, thus providing the genetic basis for prenatal diagnosis of fetal abnormalities. CASE PRESENTATION: A 35-year-old primigravid underwent cordocentesis at 28 weeks gestation due to the presence of polyhydramnios, intrauterine growth retardation, persistent right umbilical vein and mild stenosis of aortic arch at the ultrasound scan. Conventional G-band chromosome analysis revealed an apparently normal karyotype whereas the array CGH detected a de novo 8.97 Mb deletion at chromosome 11q22.3 -> q23.3 and offered a precise characterization of the genetic defect. CONCLUSIONS: The array CGH detected a de novo interstitial 11q deletion with its precise location and size which could be missed or confused by G-band chromosome analysis. The breakpoint was close to the folate sensitive rare fragile site FRA11B and the aphidicolin inducible common fragile site FRA11G, the co-localization fragile site could have caused instability and constitutional chromosomal breakage. This case study indicates that array CGH is a useful technique for detecting small unbalanced chromosomal abnormalities and should be an integral part of prenatal diagnosis for fetal malformations. PMID- 25298786 TI - 5'RUNX1-3'USP42 chimeric gene in acute myeloid leukemia can occur through an insertion mechanism rather than translocation and may be mediated by genomic segmental duplications. AB - BACKGROUND: The runt-related transcription factor 1 (RUNX1) gene is a transcription factor that acts as a master regulator of hematopoiesis and represents one of the most frequent targets of chromosomal rearrangements in human leukemias. The t(7;21)(p22;q22) rearrangement generating a 5'RUNX1-3'USP42 fusion transcript has been reported in two cases of pediatric acute myeloid leukemia (AML) and further in eight adult cases of myeloid neoplasms. We describe the first case of adult AML with a 5'RUNX1-3'USP42 fusion gene generated by an insertion event instead of chromosomal translocation. METHODS: Conventional and molecular cytogenetic analyses allowed the precise characterization of the chromosomal rearrangement and breakpoints identification. Gene expression analysis was performed by quantitative real-time PCR experiments, whereas bioinformatic studies were carried out for revealing structural genomic characteristics of breakpoint regions. RESULTS: We identified an adult AML case bearing a ins(21;7)(q22;p15p22) generating a 5'RUNX1-3'USP42 fusion gene on der(21) chromosome and causing USP42 gene over-expression. Bioinformatic analysis of the genomic regions involved in ins(21;7)/t(7;21) showed the presence of interchromosomal segmental duplications (SDs) next to the USP42 and RUNX1 genes, that may underlie a non-allelic homologous recombination between chromosome 7 and 21 in AML. CONCLUSIONS: We report the first case of a 5'RUNX1-3'USP42 chimeric gene generated by a chromosomal cryptic insertion in an adult AML patient. Our data revealed that there may be a pivotal role for SDs in this very rare but recurrent chromosomal rearrangement. PMID- 25298789 TI - Semantically Interoperable XML Data. AB - XML is ubiquitously used as an information exchange platform for web-based applications in healthcare, life sciences, and many other domains. Proliferating XML data are now managed through latest native XML database technologies. XML data sources conforming to common XML schemas could be shared and integrated with syntactic interoperability. Semantic interoperability can be achieved through semantic annotations of data models using common data elements linked to concepts from ontologies. In this paper, we present a framework and software system to support the development of semantic interoperable XML based data sources that can be shared through a Grid infrastructure. We also present our work on supporting semantic validated XML data through semantic annotations for XML Schema, semantic validation and semantic authoring of XML data. We demonstrate the use of the system for a biomedical database of medical image annotations and markups. PMID- 25298788 TI - Role of the intracellular nucleoside transporter ENT3 in transmitter and high K+ stimulation of astrocytic ATP release investigated using siRNA against ENT3. AB - This study investigates the role of the intracellular adenosine transporter equilibrative nucleoside transporter 3 (ENT3) in stimulated release of the gliotransmitter adenosine triphosphate (ATP) from astrocytes. Within the past 20 years, our understanding of the importance of astrocytic handling of adenosine, its phosphorylation to ATP, and release of astrocytic ATP as an important transmitter has become greatly expanded. A recent demonstration that the mainly intracellular nucleoside transporter ENT3 shows much higher expression in freshly isolated astrocytes than in a corresponding neuronal preparation leads to the suggestion that it was important for the synthesis of gliotransmitter ATP from adenosine. This would be consistent with a previously noted delay in transmitter release of ATP in astrocytes but not in neurons. The present study has confirmed and quantitated stimulated ATP release in response to glutamate, adenosine, or an elevated K(+) concentration from well-differentiated astrocyte cultures, measured by a luciferin-luciferase reaction. It showed that the stimulated ATP release was abolished by downregulation of ENT3 with small interfering RNA (siRNA), regardless of the stimulus. The concept that transmitter ATP in mature astrocytes is synthesized directly from adenosine prior to release is supported by the postnatal development of the expression of the vesicular transporter SLC17A9 in astrocytes. In neurons, this transporter carries ATP into synaptic vesicles, but in astrocytes, its expression is pronounced only in immature cells and shows a rapid decline during the first 3 postnatal weeks so that it has almost disappeared at the end of the third week in well-differentiated astrocytes, where its role has probably been taken over by ENT3. PMID- 25298790 TI - Expanding the scope of cyclopropene reporters for the detection of metabolically engineered glycoproteins by Diels-Alder reactions. AB - Monitoring glycoconjugates has been tremendously facilitated by the development of metabolic oligosaccharide engineering. Recently, the inverse-electron-demand Diels-Alder reaction between methylcyclopropene tags and tetrazines has become a popular ligation reaction due to the small size and high reactivity of cyclopropene tags. Attaching the cyclopropene tag to mannosamine via a carbamate linkage has made the reaction even more efficient. Here, we expand the application of cyclopropene tags to N-acylgalactosamine and N-acylglucosamine derivatives enabling the visualization of mucin-type O-glycoproteins and O GlcNAcylated proteins through Diels-Alder chemistry. Whereas the previously reported cyclopropene-labeled N-acylmannosamine derivative leads to significantly higher fluorescence staining of cell-surface glycoconjugates, the glucosamine derivative gave higher labeling efficiency with protein preparations containing also intracellular proteins. PMID- 25298791 TI - Molecular ordering at electrified interfaces: Template and potential effects. AB - A combination of cyclic voltammetry and in situ scanning tunneling microscopy was employed to examine the adsorption and phase transition of 1,1'-dibenzyl-4,4' bipyridinium molecules (abbreviated as DBV(2+)) on a chloride-modified Cu(111) electrode surface. The cyclic voltammogram (CV) of the Cu(111) electrode exposed to a mixture of 10 mM HCl and 0.1 mM DBVCl2 shows three distinguishable pairs of current waves P1/P'1, P2/P'2, and P3/P'3 which are assigned to two reversible electron transfer steps, representing the reduction of the dicationic DBV(2+) to the corresponding radical monocationic DBV(+*) (P1/P'1) and then to the uncharged DBV(0) (P3/P'3) species, respectively, as well as the chloride desorption/readsorption processes (P2/P'2). At positive potentials (i.e., above P1) the DBV(2+) molecules spontaneously adsorb and form a highly ordered phase on the c(p * ?3)-precovered Cl/Cu(111) electrode surface. A key element of this DBV(2+) adlayer is an assembly of two individual DBV(2+) species which, lined up, forms a so-called "herring-bone" structure. Upon lowering the electrode potential the first electron transfer step (at P1) causes a phase transition from the DBV(2+)-related herring-bone phase to the so-called "alternating stripe" pattern built up by the DBV(+*) species following a nucleation and growth mechanism. Comparison of both observed structures with those found earlier at different electrode potentials on a c(2 * 2)Cl-precovered Cu(100) electrode surface enables a clear assessment of the relative importance of adsorbate-substrate and adsorbate-adsorbate interactions, i.e., template vs self-assembly effects, in the structure formation process of DBV cations on these modified Cu electrode surfaces. PMID- 25298792 TI - Derivatives of the triaminoguanidinium ion, 3. Multiple N-functionalization of the triaminoguanidinium ion with isocyanates and isothiocyanates. AB - 1,2,3-Triaminoguanidinium chloride was combined with benzaldehyde and hydratropic aldehyde to furnish the corresponding tris(imines), which were converted into 1,2,3-tris(benzylamino)guanidinium salts by catalytic hydrogenation in the former, and by borane reduction in the latter case. The resulting alkyl substituted triaminoguanidinium salts underwent a threefold carbamoylation with aryl isocyanates to furnish 1,2,3-tris(ureido)guanidinium salts, while p toluenesulfonyl isocyanate led only to a mono-ureido guanidinium salt. With aryl isothiocyanates, 3-hydrazino-1H-1,2,4-triazole-5(4H)-thione derivatives were obtained. Compounds 7a and 8 show interesting solid-state structures with intra- and intermolecular hydrogen bonds. PMID- 25298793 TI - End group functionalization of poly(ethylene glycol) with phenolphthalein: towards star-shaped polymers based on supramolecular interactions. AB - The synthesis of a new phenolphthalein azide derivative, which can be easily utilized in polymer analogous reactions, is presented. The subsequent cycloaddition reaction with propargyl-functionalized methoxypoly(ethylene glycol) yielded polymers bearing phenolphthalein as the covalently attached end group. In presence of per-beta-cyclodextrin-dipentaerythritol, the formation of stable inclusion complexes was observed, representing an interesting approach towards the formation of star shaped polymers. The decolorization of a basic polymer solution caused by the complexation was of great advantage since this behavior enabled following the complex formation by UV-vis spectroscopy and even the naked eye. PMID- 25298794 TI - (CF3CO)2O/CF3SO3H-mediated synthesis of 1,3-diketones from carboxylic acids and aromatic ketones. AB - A very simple and convenient reaction for 1,3-diketone preparation from carboxylic acids and aromatic ketones in TFAA/TfOH system is described. When the beta-phenylpropionic acids were used as starting materials, they initially gave 1 indanones and then underwent further acylation with the formation of 2-(beta phenylpropionyl)-1-indanones as the main reaction products. In addition, the application of the proposed protocol allowed for the synthesis of selected polysubstituted pyrazoles in a one-pot procedure directly from acids and ketones. PMID- 25298795 TI - Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support. AB - An effective method for the synthesis of short oligoribonucleotides in solution has been elaborated. Novel 2'-O-(2-cyanoethyl)-5'-O-(1-methoxy-1-methylethyl) protected ribonucleoside 3'-phosphoramidites have been prepared and their usefulness as building blocks in RNA synthesis on a soluble support has been demonstrated. As a proof of concept, a pentameric oligoribonucleotide, 3'-UUGCA 5', has been prepared on a precipitative tetrapodal tetrakis(4 azidomethylphenyl)pentaerythritol support. The 3'-terminal nucleoside was coupled to the support as a 3'-O-(4-pentynoyl) derivative by Cu(I) promoted 1,3-dipolar cycloaddition. Couplings were carried out with 1.5 equiv of the building block. In each coupling cycle, the small molecular reagents and byproducts were removed by two quantitative precipitations from MeOH, one after oxidation and the second after the 5'-deprotection. After completion of the chain assembly, treatment with triethylamine, ammonia and TBAF released the pentamer in high yields. PMID- 25298796 TI - Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines via silver triflate catalyzed or electrophile-mediated one-pot tandem reaction. AB - An efficient one-pot tandem cyclization/[3 + 2] cycloaddition reaction of N'-(2 alkynylbenzylidene)hydrazides with ethyl 4,4,4-trifluorobut-2-ynoate under silver triflate-catalyzed or electrophile-mediated conditions is described. Various trifluoromethylated pyrazolo[5,1-a]isoquinolines were afforded in moderate to excellent yield by this developed method. PMID- 25298798 TI - Specific DNA duplex formation at an artificial lipid bilayer: fluorescence microscopy after Sybr Green I staining. AB - The article describes the immobilization of different probe oligonucleotides (4, 7, 10) carrying each a racemic mixture of 2,3-bis(hexadecyloxy)propan-1-ol (1a) at the 5'-terminus on a stable artificial lipid bilayer composed of 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC). The bilayer separates two compartments (cis/trans channel) of an optical transparent microfluidic sample carrier with perfusion capabilities. Injection of unlabeled target DNA sequences (6, 8, or 9), differing in sequence and length, leads in the case of complementarity to the formation of stable DNA duplexes at the bilayer surface. This could be verified by Sybr Green I double strand staining, followed by incubation periods and thorough perfusions, and was visualized by single molecule fluorescence spectroscopy and microscopy. The different bilayer-immobilized complexes consisting of various DNA duplexes and the fluorescent dye were studied with respect to the kinetics of their formation as well as to their stability against perfusion. PMID- 25298797 TI - Reversibly locked thionucleobase pairs in DNA to study base flipping enzymes. AB - Covalently interstrand cross-linked DNA is an interesting tool to study DNA binding proteins that locally open up the DNA duplex by flipping single bases out of the DNA helix or melting whole stretches of base pairs to perform their function. The ideal DNA cross-link to study protein-DNA interactions should be specific and easy to synthesize, be stable during protein binding experiments, have a short covalent linker to avoid steric hindrance of protein binding, and should be available as a mimic for both A/T and G/C base pairs to cover all possible binding specificities. Several covalent interstrand cross-links have been described in the literature, but most of them fall short of at least one of the above criteria. We developed an efficient method to site-specifically and reversibly cross-link thionucleoside base pairs in synthetic duplex oligodeoxynucleotides by bisalkylation with 1,2-diiodoethane resulting in an ethylene-bridged base pair. Both linked A/T and G/C base pair analogs can conveniently be prepared which allows studying any base pair-opening enzyme regardless of its sequence specificity. The cross-link is stable in the absence of reducing agents but the linker can be quickly and tracelessly removed by the addition of thiol reagents like dithiothreitol. This property makes the cross linking reaction fully reversible and allows for a switching of the linked base pair from locked to unlocked during biochemical experiments. Using the DNA methyltransferase from Thermus aquaticus (M.TaqI) as example, we demonstrate that the presented cross-linked DNA with an ethylene-linked A/T base pair analog at the target position is a useful tool to determine the base-flipping equilibrium constant of a base-flipping enzyme which lies mostly on the extrahelical side for M.TaqI. PMID- 25298799 TI - Effect of cyclodextrin complexation on phenylpropanoids' solubility and antioxidant activity. AB - The complexation abilities of five cyclodextrins (CDs) with seven phenylpropanoids (PPs) were evaluated by UV-visible spectroscopy, phase solubility studies and molecular modeling. Formation constants (K f), complexation efficiency (CE), PP:CD molar ratio, increase in formulation bulk and complexation energy were assessed. All complexes exhibited a 1:1 stoichiometry but their stability was influenced by the nature and the position of the phenyl ring substituents. A relationship between the intrinsic solubility of guests (S 0) and the solubilizing potential of CD was proposed. Molecular modeling was used to investigate the complementarities between host and guest. Finally, the antioxidant activity of encapsulated PPs was evaluated by scavenging of the stable DPPH radical. PMID- 25298800 TI - A modular phosphate tether-mediated divergent strategy to complex polyols. AB - An efficient and divergent synthesis of polyol subunits utilizing a phosphate tether-mediated, one-pot, sequential RCM/CM/reduction process is reported. A modular, 3-component coupling strategy has been developed, in which, simple "order of addition" of a pair of olefinic-alcohol components to a pseudo-C 2 symmetric phosphoryl chloride, coupled with the RCM/CM/reduction protocol, yields five polyol fragments. Each of the product polyols bears a central 1,3-anti-diol subunit with differential olefinic geometries at the periphery. PMID- 25298801 TI - Estimation of severe drug-drug interaction warnings by medical specialist groups for Austrian nationwide eMedication. AB - OBJECTIVE: The objective of this study is to estimate the amount of severe drug drug interaction warnings per medical specialist group triggered by prescribed drugs of a patient before and after the introduction of a nationwide eMedication system in Austria planned for 2015. METHODS: The estimations of interaction warnings are based on patients' prescriptions of a single health care professional per patient, as well as all patients' prescriptions from all visited health care professionals. We used a research database of the Main Association of Austrian Social Security Organizations that contains health claims data of the years 2006 and 2007. RESULTS: The study cohort consists of about 1 million patients, with 26.4 million prescribed drugs from about 3,400 different health care professionals. The estimation of interaction warnings show a heterogeneous pattern of severe drug-drug-interaction warnings across medical specialist groups. CONCLUSION: During an eMedication implementation it must be taken into consideration that different medical specialist groups require customized support. PMID- 25298802 TI - The impact of adherence on costs and effectiveness of telemedical patient management in heart failure: a systematic review. AB - OBJECTIVE: This paper analyzes evidence of the impact of patients' adherence to pharmacological and non-pharmacological recommendations on the treatment costs of heart failure (HF) patients. METHODS: A systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Papers were searched using various combinations of the following keywords: 'telemedicine', 'telemonitoring', 'telehealth', 'eHealth', 'remote monitoring', 'adherence', 'compliance', 'cost-effectiveness', 'cost-benefit', 'heart failure', 'healthcare costs', 'hospitalization', and 'drug costs'. We included only papers written in English or German, published between 1998 and 2014, and having one of our search terms in the title. RESULTS: Initially, 73 papers were selected. After a detailed review, these were narrowed done to 9 that reported an association between adherence and/or compliance and costs. However, none established a quantitative relationship between adherence and total healthcare costs. CONCLUSION: A model-based cost-effectiveness analysis that appropriately considers adherence has not been carried out so far, but is needed to fully understand the potential economic benefits of telehealth. PMID- 25298803 TI - JADE: a tool for medical researchers to explore adverse drug events using health claims data. AB - OBJECTIVE: The objective of our project was to create a tool for physicians to explore health claims data with regard to adverse drug reactions. The Java Adverse Drug Event (JADE) tool should enable the analysis of prescribed drugs in connection with diagnoses from hospital stays. METHODS: We calculated the number of days drugs were taken by using the defined daily doses and estimated possible interactions between dispensed drugs using the Austria Codex, a database including drug-drug interactions. The JADE tool was implemented using Java, R and a PostgreSQL database. RESULTS: Beside an overview of the study cohort which includes selection of gender and age groups, selected statistical methods like association rule learning, logistic regression model and the number needed to harm have been implemented. CONCLUSION: The JADE tool can support physicians during their planning of clinical trials by showing the occurrences of adverse drug events with population based information. PMID- 25298804 TI - Information needs for the OR and PACU electronic medical record. AB - OBJECTIVE: The amount of clinical information that anesthesia providers encounter creates an environment for information overload and medical error. In an effort to create more efficient OR and PACU EMR viewer platforms, we aimed to better understand the intraoperative and post-anesthesia clinical information needs among anesthesia providers. MATERIALS AND METHODS: A web-based survey to evaluate 75 clinical data items was created and distributed to all anesthesia providers at our institution. Participants were asked to rate the importance of each data item in helping them make routine clinical decisions in the OR and PACU settings. RESULTS: There were 107 survey responses with distribution throughout all clinical roles. 84% of the data items fell within the top 2 proportional quarters in the OR setting compared to only 65% in the PACU. Thirty of the 75 items (40%) received an absolutely necessary rating by more than half of the respondents for the OR setting as opposed to only 19 of the 75 items (25%) in the PACU. Only 1 item was rated by more than 20% of respondents as not needed in the OR compared to 20 data items (27%) in the PACU. CONCLUSION: Anesthesia providers demonstrate a larger need for EMR data to help guide clinical decision making in the OR as compared to the PACU. When creating EMR platforms for these settings it is important to understand and include data items providers deem the most clinically useful. Minimizing the less relevant data items helps prevent information overload and reduces the risk for medical error. PMID- 25298805 TI - A case report in health information exchange for inter-organizational patient transfers. AB - OBJECTIVE: To provide a case report of barriers and promoters to implementing a health information exchange (HIE) tool that supports patient transfers between hospitals and skilled nursing facilities. METHODS: A multi-disciplinary team conducted semi-structured telephone and in-person interviews in a purposive sample of HIE organizational informants and providers in New York City who implemented HIE to share patient transfer information. The researchers conducted grounded theory analysis to identify themes of barriers and promoters and took steps to improve the trustworthiness of the results including vetting from a knowledgeable study participant. RESULTS: Between May and October 2011, researchers recruited 18 participants: informaticians, healthcare administrators, software engineers, and providers from a skilled nursing facility. Subjects perceived the HIE tool's development a success in that it brought together stakeholders who had traditionally not partnered for informatics work, and that they could successfully share patient transfer information between a hospital and a skilled nursing facility. Perceived barriers included lack of hospital stakeholder buy-in and misalignment with clinical workflows that inhibited use of HIE-based patient transfer data. Participants described barriers and promoters in themes related to organizational, technical, and user-oriented issues. The investigation revealed that stakeholders could develop and implement health information technology that technically enables clinicians in both hospitals and skilled nursing facilities to exchange real-time information in support of patient transfers. User level barriers, particularly in the emergency department, should give pause to developers and implementers who plan to use HIE in support of patient transfers. CONCLUSIONS: Participants' experiences demonstrate how stakeholders may succeed in developing and piloting an electronic transfer form that relies on HIE to aggregate, communicate, and display relevant patient transfer data across health care organizations. Their experiences also provide insights for others seeking to develop HIE applications to improve patient transfers between emergency departments and skilled nursing facilities. PMID- 25298806 TI - Actionable recommendations in the Bright Futures child health supervision guidelines. AB - BACKGROUND: With the growing use of electronic health record systems, there is a demand for an electronic version of the leading American pediatric preventive care guideline, Bright Futures. As computer implementation requires actionable recommendations, it is important to assess to what degree Bright Futures meets criteria for actionability. OBJECTIVES: We aimed to 1) determine the number of actionable recommendations in the current edition of Bright Futures and 2) to recommend a specific format for representing an important class of guidelines in a way that better facilitates computer implementation. METHODS: We consolidated all action statements in Bright Futures into recommendations. We then used two dimensions (decidability and executability) in the Guideline Implementability Appraisal v 2.0 (GLIA) to determine the actionability of the recommendations. Decidability means the recommendation states precisely under what conditions to perform those actions. Executability means actions are stated specifically, unambiguously and in sufficient detail. The results were presented in a figure titled Service Interval Diagram (SID), describing actionable recommendations, age intervals during which they are applicable, and how frequently they should occur in that interval. RESULTS: We consolidated 2161 action items into 245 recommendations and identified 52 that were actionable (21%). Almost exclusively, these recommendations addressed screening, such as newborn metabolic screening, or child safety, such as car seat use. A limited number (n=13) of recommendations for other areas of anticipatory guidance were also actionable. No recommendations on child discipline, family function or mental health met our criteria for actionability. The SID representing these recommendations is presented in a figure. CONCLUSION: Only a portion of the Bright Futures Guidelines meets criteria for actionability. Substantial work lies ahead to develop most recommendations for anticipatory guidance into a computer implementable format. PMID- 25298807 TI - Ontology content patterns as bridge for the semantic representation of clinical information. AB - OBJECTIVE: Semantic interoperability of the Electronic Health Record (EHR) requires a rigorous and precise modelling of clinical information. Our objective is to facilitate the representation of clinical facts based on formal principles. METHODS: We here explore the potential of ontology content patterns, which are grounded on a formal and semantically rich ontology model and can be specialised and composed. RESULTS: We describe and apply two content patterns for the representation of data on tobacco use, rendered according to two heterogeneous models, represented in openEHR and in HL7 CDA. Finally, we provide some query exemplars that demonstrate a data interoperability use case. CONCLUSION: The use of ontology content patterns facilitate the semantic representation of clinical information and therefore improve their semantic interoperability. There are open issues such as the scalability and performance of the approach if a logic-based language is used. Implementation decisions might determine the final degree of semantic interoperability, influenced by the state of the art of the semantic technologies. PMID- 25298808 TI - Comprehensive electronic medical record implementation levels not associated with 30-day all-cause readmissions within Medicare beneficiaries with heart failure. AB - BACKGROUND: Regulatory standards for 30-day readmissions incentivize hospitals to improve quality of care. Implementing comprehensive electronic health record systems potentially decreases readmission rates by improving medication reconciliation at discharge, demonstrating the additional benefits of inpatient EHRs beyond improved safety and decreased errors. OBJECTIVE: To compare 30-day all-cause readmission incidence rates within Medicare fee-for-service with heart failure discharged from hospitals with full implementation levels of comprehensive EHR systems versus those without. METHODS: This retrospective cohort study uses data from the American Hospital Association Health IT survey and Medicare Part A claims to measure associations between hospital EHR implementation levels and beneficiary readmissions. Multivariable Cox regressions estimate the hazard ratio of 30-day all-cause readmissions within beneficiaries discharged from hospitals implementing comprehensive EHRs versus those without, controlling for beneficiary health status and hospital organizational factors. Propensity scores are used to account for selection bias. RESULTS: The proportion of heart failure patients with 30-day all-cause readmissions was 30%, 29%, and 32% for those discharged from hospitals with full, some, and no comprehensive EHR systems. Heart failure patients discharged from hospitals with fully implemented comprehensive EHRs compared to those with no comprehensive EHR systems had equivalent 30-day readmission incidence rates (HR = 0.97, 95% CI 0.73 - 1.3). CONCLUSIONS: Implementation of comprehensive electronic health record systems does not necessarily improve a hospital's ability to decrease 30-day readmission rates. Improving the efficiency of post-acute care will require more coordination of information systems between inpatient and ambulatory providers. PMID- 25298809 TI - Computerized provider order entry reduces length of stay in a community hospital. AB - OBJECTIVE: Does computerized provider order entry (CPOE) improve clinical, cost, and efficiency outcomes as quantified in shortened hospital length of stay (LOS)? Most prior studies were done in university settings with home-grown electronic records, and are now 20 years old. This study asked whether CPOE exerts a downward force on LOS in the current era of HITECH incentives, using a vendor product in a community hospital. METHODS: The methodology retrospectively evaluated correlation between CPOE and LOS on a perpatient, per-visit basis over 22 consecutive quarters, organized by discipline. All orders from all areas were eligible, except verbals, and medication orders in the emergency department which were not available via CPOE. These results were compared with quarterly case mix indices organized by discipline. Correlational and regression analyses were cross checked to ensure validity of R-square coefficients, and data were smoothed for ease of display. Standard models were used to calculate the inflection point. RESULTS: Gains in CPOE adoption occurred iteratively house-wide, and in each discipline. LOS decreased in a sigmoid shaped curve. The inflection point shows that once CPOE adoption approaches 60%, further lowering of LOS accelerates. Overall there was a 20.2% reduction in LOS correlated with adoption of CPOE. Case mix index increased during the study period showing that reductions in LOS occurred despite increased patient complexity and resource utilization. CONCLUSIONS: There was a 20.2% reduction in LOS correlated with rising adoption of CPOE. CPOE contributes to improved clinical, cost, and efficiency outcomes as quantified in reduced LOS, over and above other processes introduced to lower LOS. CPOE enabled a reduction in LOS despite an increase in the case mix index during the time frame of this study. PMID- 25298810 TI - Evaluation of a user guidance reminder to improve the quality of electronic prescription messages. AB - BACKGROUND: Prescribers' inappropriate use of the free-text Notes field in new electronic prescriptions can create confusion and workflow disruptions at receiving pharmacies that often necessitates contact with prescribers for clarification. The inclusion of inappropriate patient direction (Sig) information in the Notes field is particularly problematic. OBJECTIVE: We evaluated the effect of a targeted watermark, an embedded overlay, reminder statement in the Notes field of an EHR-based e-prescribing application on the incidence of inappropriate patient directions (Sig) in the Notes field. METHODS: E prescriptions issued by the same exact cohort of 97 prescribers were collected over three time periods: baseline, three months after implementation of the reminder, and 15 months post implementation. Three certified and experienced pharmacy technicians independently reviewed all e-prescriptions for inappropriate Sig-related information in the Notes field. A physician reviewer served as the final adjudicator for e-prescriptions where the three reviewers could not reach a consensus. ANOVA and post hoc Tukey HSD tests were performed on group comparisons where statistical significance was evaluated at p<0.05. RESULTS: The incidence of inappropriate Sig-related information in the Notes field decreased from a baseline of 2.8% to 1.8% three months post-implementation and remained stable after 15 months. In addition, prescribers' use of the Notes decreased by 22% after 3 months and had stabilized at 18.7% below baseline after 15 months. CONCLUSION: Insertion of a targeted watermark reminder statement in the Notes field of an e-prescribing application significantly reduced the incidence of inappropriate Sig-related information in Notes and decreased prescribers' use of this field. PMID- 25298811 TI - Effect of EHR user interface changes on internal prescription discrepancies. AB - OBJECTIVE: To determine whether specific design interventions (changes in the user interface (UI)) of an electronic health record (EHR) medication module are associated with an increase or decrease in the incidence of contradictions between the structured and narrative components of electronic prescriptions (internal prescription discrepancies). MATERIALS AND METHODS: We performed a retrospective analysis of 960,000 randomly selected electronic prescriptions generated in a single EHR between 01/2004 and 12/2011. Internal prescription discrepancies were identified using a validated natural language processing tool with recall of 76% and precision of 84%. A multivariable autoregressive integrated moving average (ARIMA) model was used to evaluate the effect of five UI changes in the EHR medication module on incidence of internal prescription discrepancies. RESULTS: Over the study period 175,725 (18.4%) prescriptions were found to have internal discrepancies. The highest rate of prescription discrepancies was observed in March 2006 (22.5%) and the lowest in March 2009 (15.0%). Addition of "as directed" option to the dropdown decreased prescription discrepancies by 195 / month (p = 0.0004). An non-interruptive alert that reminded providers to ensure that structured and narrative components did not contradict each other decreased prescription discrepancies by 145 / month (p = 0.03). Addition of a "Renew / Sign" button to the Medication module (a negative control) did not have an effect in prescription discrepancies. CONCLUSIONS: Several UI changes in the electronic medication module were effective in reducing the incidence of internal prescription discrepancies. Further research is needed to identify interventions that can completely eliminate this type of prescription error and their effects on patient outcomes. PMID- 25298812 TI - Attitudes and perceptions of pediatric residents on transitioning to CPOE. AB - BACKGROUND: Many resident physicians have experienced transitioning from traditional paper documentation and ordering to an electronic process during their training. OBJECTIVE: We sought to investigate the attitudes and perceptions of residents related to implementation of computer provider order entry (CPOE) and clinical decision support (CDS). METHODS: Pediatric residents completed web based surveys prior to CPOE implementation and at 6 months and 12 months after implementation. The survey assessed resident attitudes and perceptions related to CPOE and the use of CDS tools. Additionally, at 6 and 12 months, residents were asked how electronic medical record (EMR) resources might impact future career decisions. RESULTS: Prior to CPOE implementation, 70% of residents were looking forward to CPOE, but 28% did not want to transition from paper ordering. At 12 months post-implementation, 80% of residents favored CPOE over paper ordering and only 3.33% wished to revert to paper ordering. Residents reported an increase in time needed to enter admission orders 6-months after CPOE implementation. By 12 months post-implementation, there was no significant difference in perceived time to complete admission orders when compared to pre-CPOE responses. Most residents (91.67%) identified that overall EMR resources were an important factor when considering future employment opportunities. The most important factors included the degree of EMR implementation, technology resources and the amount of support staff. The least important factors included patient portal access and which EMR product is used. CONCLUSIONS: Overall, residents demonstrated a preference for CPOE compared to traditional paper order entry. Many residents remained unaware of CDS tools embedded within CPOE at the 12 month follow-up, but a majority of residents did find them helpful and felt more knowledgeable about current guidelines. EMR resources, including degree of EMR implementation, technology resources and support staff are likely to be important factors as residents take future employment opportunities into consideration. PMID- 25298813 TI - Evaluating a federated medical search engine: tailoring the methodology and reporting the evaluation outcomes. AB - BACKGROUND: Federated medical search engines are health information systems that provide a single access point to different types of information. Their efficiency as clinical decision support tools has been demonstrated through numerous evaluations. Despite their rigor, very few of these studies report holistic evaluations of medical search engines and even fewer base their evaluations on existing evaluation frameworks. OBJECTIVES: To evaluate a federated medical search engine, MedSocket, for its potential net benefits in an established clinical setting. METHODS: This study applied the Human, Organization, and Technology (HOT-fit) evaluation framework in order to evaluate MedSocket. The hierarchical structure of the HOT-factors allowed for identification of a combination of efficiency metrics. Human fit was evaluated through user satisfaction and patterns of system use; technology fit was evaluated through the measurements of time-on-task and the accuracy of the found answers; and organization fit was evaluated from the perspective of system fit to the existing organizational structure. RESULTS: Evaluations produced mixed results and suggested several opportunities for system improvement. On average, participants were satisfied with MedSocket searches and confident in the accuracy of retrieved answers. However, MedSocket did not meet participants' expectations in terms of download speed, access to information, and relevance of the search results. These mixed results made it necessary to conclude that in the case of MedSocket, technology fit had a significant influence on the human and organization fit. Hence, improving technological capabilities of the system is critical before its net benefits can become noticeable. CONCLUSIONS: The HOT-fit evaluation framework was instrumental in tailoring the methodology for conducting a comprehensive evaluation of the search engine. Such multidimensional evaluation of the search engine resulted in recommendations for system improvement. PMID- 25298814 TI - Reducing risk with clinical decision support: a study of closed malpractice claims. AB - OBJECTIVE: Identify clinical opportunities to intervene to prevent a malpractice event and determine the proportion of malpractice claims potentially preventable by clinical decision support (CDS). MATERIALS AND METHODS: Cross-sectional review of closed malpractice claims over seven years from one malpractice insurance company and seven hospitals in the Boston area. For each event, clinical opportunities to intervene to avert the malpractice event and the presence or absence of CDS that might have a role in preventing the event, were assigned by a panel of expert raters. Compensation paid out to resolve a claim (indemnity), was associated with each CDS type. RESULTS: Of the 477 closed malpractice cases, 359 (75.3%) were categorized as substantiated and 195 (54%) had at least one opportunity to intervene. Common opportunities to intervene related to performance of procedure, diagnosis, and fall prevention. We identified at least one CDS type for 63% of substantiated claims. The 41 CDS types identified included clinically significant test result alerting, diagnostic decision support and electronic tracking of instruments. Cases with at least one associated intervention accounted for $40.3 million (58.9%) of indemnity. DISCUSSION: CDS systems and other forms of health information technology (HIT) are expected to improve quality of care, but their potential to mitigate risk had not previously been quantified. Our results suggest that, in addition to their known benefits for quality and safety, CDS systems within HIT have a potential role in decreasing malpractice payments. CONCLUSION: More than half of malpractice events and over $40 million of indemnity were potentially preventable with CDS. PMID- 25298815 TI - Diabetes and hypertension quality measurement in four safety-net sites: lessons learned after implementation of the same commercial electronic health record. AB - BACKGROUND: In this new era after the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009, the literature on lessons learned with electronic health record (EHR) implementation needs to be revisited. OBJECTIVES: Our objective was to describe what implementation of a commercially available EHR with built-in quality query algorithms showed us about our care for diabetes and hypertension populations in four safety net clinics, specifically feasibility of data retrieval, measurements over time, quality of data, and how our teams used this data. METHODS: A cross-sectional study was conducted from October 2008 to October 2012 in four safety-net clinics located in the Midwest and Western United States. A data warehouse that stores data from across the U.S was utilized for data extraction from patients with diabetes or hypertension diagnoses and at least two office visits per year. Standard quality measures were collected over a period of two to four years. All sites were engaged in a partnership model with the IT staff and a shared learning process to enhance the use of the quality metrics. RESULTS: While use of the algorithms was feasible across sites, challenges occurred when attempting to use the query results for research purposes. There was wide variation of both process and outcome results by individual centers. Composite calculations balanced out the differences seen in the individual measures. Despite using consistent quality definitions, the differences across centers had an impact on numerators and denominators. All sites agreed to a partnership model of EHR implementation, and each center utilized the available resources of the partnership for Center-specific quality initiatives. CONCLUSIONS: Utilizing a shared EHR, a Regional Extension Center like partnership model, and similar quality query algorithms allowed safety-net clinics to benchmark and improve the quality of care across differing patient populations and health care delivery models. PMID- 25298816 TI - Optimization of decision support tool using medication regimens to assess rehospitalization risks. AB - BACKGROUND: Unnecessary hospital readmissions are costly for the U.S. health care system. An automated algorithm was developed to target this problem and proven to predict elderly patients at greater risk of rehospitalization based on their medication regimens. OBJECTIVE: Improve the algorithm for predicting elderly patients' risks for readmission by optimizing the sensitivity of its medication criteria. METHODS: Outcome and Assessment Information Set (OASIS) and medication data were reused from a study that defined and tested an algorithm for assessing rehospitalization risks of 911 patients from 15 Medicare-certified home health care agencies. Odds Ratio analyses, literature reviews and clinical judgments were used to adjust the scoring of patients' High Risk Medication Regimens (HRMRs). Receiver Operating Characteristic (ROC) analysis evaluated whether these adjustments improved the predictive strength of the algorithm's components. RESULTS: HRMR scores are composed of polypharmacy (number of drugs), potentially inappropriate medications (PIM) (drugs risky to the elderly), and Medication Regimen Complexity Index (MRCI) (complex dose forms, dose frequency, instructions or administration). Strongest ROC results for the HRMR components were Areas Under the Curve (AUC) of .68 for polypharmacy when excluding supplements; and .60 for PIM and .69 for MRCI using the original HRMR criteria. The "cut point" identifying MRCI scores as indicative of medication-related readmission risk was increased from 20 to 33. CONCLUSION: The automated algorithm can predict elderly patients at risk of hospital readmissions and its underlying criteria is improved by a modification to its polypharmacy definition and MRCI cut point. PMID- 25298817 TI - Physician beliefs about the impact of meaningful use of the EHR: a cross sectional study. AB - BACKGROUND: As adoption and use of electronic health records (EHRs) grows in the United States, there is a growing need in the field of applied clinical informatics to evaluate physician perceptions and beliefs about the impact of EHRs. The meaningful use of EHR incentive program provides a suitable context to examine physician beliefs about the impact of EHRs. OBJECTIVE: Contribute to the sparse literature on physician beliefs about the impact of EHRs in areas such as quality of care, effectiveness of care, and delivery of care. METHODS: A cross sectional online survey of physicians at two academic medical centers (AMCs) in the northeast who were preparing to qualify for the meaningful use of EHR incentive program. RESULTS: Of the 1,797 physicians at both AMCs who were preparing to qualify for the incentive program, 967 completed the survey for an overall response rate of 54%. Only 23% and 27% of physicians agreed or strongly agreed that meaningful use of the EHR will help them improve the care they personally deliver and improve quality of care respectively. Physician specialty was significantly associated with beliefs; e.g., 35% of primary care physicians agreed or strongly agreed that meaningful use will improve quality of care compared to 26% of medical specialists and 21% of surgical specialists (p=0.009). Satisfaction with outpatient EHR was also significantly related to all belief items. CONCLUSIONS: Only about a quarter of physicians in our study responded positively that meaningful use of the EHR will improve quality of care and the care they personally provide. These findings are similar to and extend findings from qualitative studies about negative perceptions that physicians hold about the impact of EHRs. Factors outside of the regulatory context, such as physician beliefs, need to be considered in the implementation of the meaningful use of the EHR incentive program. PMID- 25298818 TI - Drug interaction alert override rates in the Meaningful Use era: no evidence of progress. AB - BACKGROUND: Interruptive drug interaction alerts may reduce adverse drug events and are required for Stage I Meaningful Use attestation. For the last decade override rates have been very high. Despite their widespread use in commercial EHR systems, previously described interventions to improve alert frequency and acceptance have not been well studied. OBJECTIVES: (1) To measure override rates of inpatient medication alerts within a commercial clinical decision support system, and assess the impact of local customization efforts. (2) To compare override rates between drug-drug interaction and drug-allergy interaction alerts, between attending and resident physicians, and between public and academic hospitals. (3) To measure the correlation between physicians' individual alert quantities and override rates as an indicator of potential alert fatigue. METHODS: We retrospectively analyzed physician responses to drug-drug and drug allergy interaction alerts, as generated by a common decision support product in a large teaching hospital system. RESULTS: (1) Over four days, 461 different physicians entered 18,354 medication orders, resulting in 2,455 visible alerts; 2,280 alerts (93%) were overridden. (2) The drug-drug alert override rate was 95.1%, statistically higher than the rate for drug-allergy alerts (90.9%) (p < 0.001). There was no significant difference in override rates between attendings and residents, or between hospitals. (3) Physicians saw a mean of 1.3 alerts per day, and the number of alerts per physician was not significantly correlated with override rate (R2 = 0.03, p = 0.41). CONCLUSIONS: Despite intensive efforts to improve a commercial drug interaction alert system and to reduce alerting, override rates remain as high as reported over a decade ago. Alert fatigue does not seem to contribute. The results suggest the need to fundamentally question the premises of drug interaction alert systems. PMID- 25298819 TI - The use of smartphones on General Internal Medicine wards: a mixed methods study. AB - OBJECTIVE: To describe the uses of institutional and personal smartphones on General Internal Medicine wards and highlight potential consequences from their use. METHODS: A mixed methods study consisting of both quantitative and qualitative research methods was conducted in General Internal Medicine wards across four academic teaching hospitals in Toronto, Ontario. Participants included medical students, residents, attending physicians and allied health professionals. Data collection consisted of work shadowing observations, semi structured interviews and surveys. RESULTS: Personal smartphones were used for both clinical communication and non-work-related activities. Clinicians used their personal devices to communicate with their medical teams and with other medical specialties and healthcare professionals. Participants understood the risks associated with communicating confidential health information via their personal smartphones, but appear to favor efficiency over privacy issues. From survey responses, 9 of 23 residents (39%) reported using their personal cell phones to email or text patient information that may have contained patient identifiers. Although some residents were observed using their personal smartphones for non-work-related activities, personal use was infrequent and most residents did not engage in this activity. CONCLUSION: Clinicians are using personal smartphones for work-related purposes on the wards. With the increasing popularity of smartphone devices, it is anticipated that an increasing number of clinicians will use their personal smartphones for clinical work. This trend poses risks to the secure transfer of confidential personal health information and may lead to increased distractions for clinicians. PMID- 25298820 TI - Measures of user experience in a streptococcal pharyngitis and pneumonia clinical decision support tools. AB - OBJECTIVE: To understand clinician adoption of CDS tools as this may provide important insights for the implementation and dissemination of future CDS tools. MATERIALS AND METHODS: Clinicians (n=168) at a large academic center were randomized into intervention and control arms to assess the impact of strep and pneumonia CDS tools. Intervention arm data were analyzed to examine provider adoption and clinical workflow. Electronic health record data were collected on trigger location, the use of each component and whether an antibiotic, other medication or test was ordered. Frequencies were tabulated and regression analyses were used to determine the association of tool component use and physician orders. RESULTS: The CDS tool was triggered 586 times over the study period. Diagnosis was the most frequent workflow trigger of the CDS tool (57%) as compared to chief complaint (30%) and diagnosis/antibiotic combinations (13%). Conversely, chief complaint was associated with the highest rate (83%) of triggers leading to an initiation of the CDS tool (opening the risk prediction calculator). Similar patterns were noted for initiation of the CDS bundled ordered set and completion of the entire CDS tool pathway. Completion of risk prediction and bundled order set components were associated with lower rates of antibiotic prescribing (OR 0.5; CI 0.2-1.2 and OR 0.5; CI 0.3-0.9, respectively). DISCUSSION: Different CDS trigger points in the clinician user workflow lead to substantial variation in downstream use of the CDS tool components. These variations were important as they were associated with significant differences in antibiotic ordering. CONCLUSIONS: These results highlight the importance of workflow integration and flexibility for CDS success. PMID- 25298821 TI - Patient no-show predictive model development using multiple data sources for an effective overbooking approach. AB - BACKGROUND: Patient no-shows in outpatient delivery systems remain problematic. The negative impacts include underutilized medical resources, increased healthcare costs, decreased access to care, and reduced clinic efficiency and provider productivity. OBJECTIVE: To develop an evidence-based predictive model for patient no-shows, and thus improve overbooking approaches in outpatient settings to reduce the negative impact of no-shows. METHODS: Ten years of retrospective data were extracted from a scheduling system and an electronic health record system from a single general pediatrics clinic, consisting of 7,988 distinct patients and 104,799 visits along with variables regarding appointment characteristics, patient demographics, and insurance information. Descriptive statistics were used to explore the impact of variables on show or no-show status. Logistic regression was used to develop a no-show predictive model, which was then used to construct an algorithm to determine the no-show threshold that calculates a predicted show/no-show status. This approach aims to overbook an appointment where a scheduled patient is predicted to be a no-show. The approach was compared with two commonly-used overbooking approaches to demonstrate the effectiveness in terms of patient wait time, physician idle time, overtime and total cost. RESULTS: From the training dataset, the optimal error rate is 10.6% with a no-show threshold being 0.74. This threshold successfully predicts the validation dataset with an error rate of 13.9%. The proposed overbooking approach demonstrated a significant reduction of at least 6% on patient waiting, 27% on overtime, and 3% on total costs compared to other common flat-overbooking methods. CONCLUSIONS: This paper demonstrates an alternative way to accommodate overbooking, accounting for the prediction of an individual patient's show/no show status. The predictive no-show model leads to a dynamic overbooking policy that could improve patient waiting, overtime, and total costs in a clinic day while maintaining a full scheduling capacity. PMID- 25298822 TI - Bypass vs. Endovascular Therapy of Infrapopliteal Lesions for Critical Limb Ischemia. AB - OBJECTIVE: This study was conducted to determine whether to perform endovascular intervention or bypass surgery as a treatment option for critical limb ischemia (CLI) with lesions in the popliteal artery or below. SUBJECTS AND METHODS: A total of 150 patients (164 limbs) with CLI underwent endovascular intervention or bypass surgery for lesions in the popliteal artery or below at our department between May 1995 and June 2011. Therapeutic outcomes were examined by surgical technique. An indication for endovascular intervention was established with the combination of (1) poor general condition, and (2) a stenotic or occlusive lesion <=5 cm. RESULTS: The bypass group (group B) comprised 119 patients (99 males, 20 females) with 131 affected limbs at 46 to 89 years of age (mean: 70 years). The endovascular intervention group (group E) comprised 31 patients (25 males, 6 females) with 33 affected limbs at 47 to 89 years of age (mean: 72 years). There was no significant difference in patient demography between the two groups. Regarding preoperative complications, hypertension was observed in 54% and 61% of the subjects in groups B and E, respectively, diabetes in 36% and 55%, renal dysfunction in 29% and 58%, ischemic heart disease in 27% and 32%, and cerebrovascular disorder in 18% and 23%; renal dysfunction accounted for a significantly higher percentage in group E. As for early postoperative complications, subjects in group B experienced wound infections (6 patients), hemorrhage (2), thrombosis (2), pneumonia (1), and another complication (1), and those in group E experienced wound infections (1) and another complication (1). The hospital mortality rate was 0.8% (1 patient) for group B and 0% for group E. The 3-year cumulative primary patency rate was 72% for group B and 54% for group E; the rate was significantly higher for group B. The 3-year secondary patency rate was 82% for group B and 60% for group E. The 3-year limb salvage rate was 86% for group B and 82% for group E; there was no significant difference between the two groups. The 5-year survival rate was 57% for group B and 42% for group E; the survival rate was significantly lower for group E. CONCLUSION: For the study population of CLI patients with lesions in the popliteal artery or below, the patency rate was higher for the bypass group than for the endovascular intervention group, whereas there was no difference in the limb salvage rate. Based on the findings in prognosis for survival, the indication for endovascular intervention at our department is believed to be appropriate. (English translation of Jpn J Vasc Surg 2013; 22: 715-718). PMID- 25298823 TI - Management strategy of isolated spontaneous dissection of the superior mesenteric artery. AB - OBJECTIVE: Isolated spontaneous dissection of the superior mesenteric artery (SMA) is very rare among of the visceral artery dissection and its treatment is not established. In this paper we present our experiences and consider the treatment of isolated SMA dissection. METHODS: A retrospective review of our cases from 2005 was performed. Clinical symptoms, radiologic findings and results were evaluated. There were 14 cases of visceral artery dissection, in which all cases were with SMA dissection. There were 12 males and 2 females with a mean age of 57 years (range 41-78 years). RESULTS: We categorized SMA dissection into the six types according to the Sakamoto's and Zerbib's classification. One patient with type VI underwent emergent endovascular surgery with stent. One patient with type VI received thrombectomy and intimectomy with open surgery. One patient with type II underwent aneurysmectomy due to enlarged dissected SMA 3 months later from onset. The other eleven patients were managed conservatively. At follow-up, the diameter of SMA did not enlarged and the length of the dissection significantly decreased to 20.7 +/- 15.7 mm from 38.0 +/- 15.1 mm at onset (p <0.01). After treatment, imaging indicated the following changes in classification: type I, one patient; type II, 4 patients; type IV, 4 patients; complete remodeling, one patient, all without any event during the follow-up period of 5-82 months. CONCLUSION: Most patients with isolated visceral artery dissection occurred in superior mesenteric artery and can be treated conservatively; however, endovascular or surgical procedures including laparotomy are indicated when there is suspicion of severe mesenteric ischemia. Because the dissection configuration will change, long term follow-up is necessary. (English translation of Jpn J Vasc Surg 2013; 22: 695-701). PMID- 25298824 TI - Comparison of Bare-Tip and Radial Fiber in Endovenous Laser Ablation with 1470 nm Diode Laser. AB - OBJECTIVE: Major side effects after endovenous laser ablation (EVLA) are pain and bruising. The aim of this study was to compare outcome and side effects after EVLA for primary varicose veins with 1470 nm diode laser using bare-tip orradial fiber. METHODS: From October 2007 to December 2010, 385 patients (453 limbs) with primary varicose veins treated with 1470 nm laser were studied. Bare-tip fiber was used in 215 patients (242 limbs) (BF group) and radial fiber (ELVeS(TM)Radial, Biolitec AG, Germany) was used in 177 patients (211 limbs) (RF group). This study is a retrospective study and radial fiber was started for use from November 2008. Laser energy was administered at 6-12 W of power in the BF group and 10 W of power in the RF group with constant pullback of laser fiber under tumescent local anesthesia. The patients were assessed by clinical examination and venous duplex ultrasonography at 24-48 h, one week, one month, 4 months and one year follow-up postoperatively. RESULTS: Mean operating time, length of treated vein and linear endovenous laser energy of all cases were 42.6 min, 36.2 cm and 83.4 J/cm, respectively. Major complications such as deep vein thrombosis and skin burns were not noted. Bruising (1.9% vs. 19.4%) and pain (0.9% vs. 7.4%) were significantly lower in the RF group. Cumulative occlusion rates by Kaplan-Meier method were 100% at 32 months in the RF group and 99.5% at 4 years in the BF group. CONCLUSION: EVLA using 1470 nm laser with the radial fiber minimized adverse effects compared with bare-tip laser fiber. (English translation of Jpn J Vasc Surg 2013; 22: 615-621). PMID- 25298826 TI - The Relationship between Tension and Length of the Aortic Adventitia Resected from the Aortic Wall of Acute Aortic Dissection. AB - OBJECTIVE: To our knowledge, no previous study has described the measurement of the tensile strength of the human aortic adventitia. In the present study, we examined the relationship between the tension and length of the aortic adventitia resected from the aortic wall of patients with acute aortic dissection. METHODS: We obtained rectangular specimens from the aortic adventitia that was resected in patients with acute aortic dissection during surgery. The specimens were placed on a tension meter (Digital Force Gauge FGS-10, SHIMPO, Kyoto, Japan) within 15 min after resection and stretched until they were pulled apart, and the tension and length were recorded. RESULTS: We obtained 18 specimens during surgery from 11 cases of acute aortic dissection. When the specimen was being pulled apart, the mean tension recorded was 10.2 +/- 4.9 N/cm specimen width, whereas the mean elongated length recorded was 4.2 +/- 1.1 mm/cm specimen length. DISCUSSION: We determined that the aortic adventitia is elastic and expandable up to 140% of its original length. This indicates that dilation of the aorta to >4.2 cm in diameter may result in a rupture if the original aortic diameter prior to dissection was 3 cm. (English translation of J Jpn Coll Angiol 2013; 53: 77-81). PMID- 25298825 TI - Relationship between Specific Distributions of Isolated Soleal Vein Thrombosis and Risk Factors. AB - OBJECTIVE: The relationship between specific distributions of isolated soleal vein thrombosis (SVT) and risk factors was investigated. SUBJECTS AND METHODS: The subjects included 93 patients with SVT diagnosed with ultrasonography. RESULTS: In the acute thrombus distribution, the thrombi of central veins were significantly more frequent than the thrombi of medial veins in the unilateral SVT. The thrombi of central veins were not more significantly frequent than the thrombi of medial veins in the bilateral SVT. CONCLUSION: The risk factors of bilateral SVT are considered to be different from that of the unilateral SVT. (English translation of J Jpn Coll Angiol 2013; 53: 159-166). PMID- 25298827 TI - Histological study on the left common iliac vein spur. AB - The spur occasionally seen in a left common iliac vein was investigated by anatomical and histological examination of cadavers so the occurrence mechanism could be discussed. Spurs were found in six cases of the 28 cadavers (21.4%) and they were classified into few different kinds of composition of endosporia, tunica media and adventitia. It is considered that there may be different formation mechanisms and stages even in cases of similar anatomical finding. (English translation of J Jpn Coll Angiol 2013; 53: 43-47). PMID- 25298828 TI - Examination of clinical efficacy of keishibukuryogan on non-specific complaints associated with varicose veins of the lower extremity. AB - The subjective symptoms of varicose veins of the lower extremity often include malaise, numbness, coldness, pain, and pruritus of the lower extremity, and relieving these complaints is important in managing the quality of life of patients. We have examined the clinical efficacy of keishibukuryogan, a Kampo prescription for improving oketsu (impaired microcirculation, congestion), on non specific complaints associated with varicose veins of the lower extremity. Keishibukuryogan was administered to 30 patients with non-specific complaints associated with varicose veins of the lower extremity for 12 weeks, resulting in improvements in the scores of subjective symptoms, severity of varicose veins, and oketsu as well as an increase in skin perfusion pressure. And especially the effect was remarkable in female. In addition, oketsu was shown to be involved in the subjective symptoms associated with varicose veins of the lower extremity, demonstrating efficacy of keishibukuryogan. No adverse drug reaction or abnormal laboratory result was observed in patients receiving keishibukuryogan, and the rate of general improvement and usefulness was 73.3%. It was suggested that keishibukuryogan was useful to improve the symptoms of patients with non-specific complaints associated with varicose veins of the lower extremity especially in female patients. (English translation of Jpn J Phlebol 2013; 24: 303-310). PMID- 25298830 TI - Influencing Factors for Abdominal Aortic Aneurysm Sac Shrinkage and Enlargement after EVAR: Clinical Reviews before Introduction of Preoperative Coil Embolization. AB - BACKGROUND: We previously reported effectiveness of coil embolization (CE) to aortic branched vessels before endovascular aortic repair (EVAR) for abdominal aortic aneurysm (AAA) because of significant shrinkage of aneurysmal sac. In this study, we investigated EVAR cases to clarify influential factors of aneurysmal shrinkage and enlargement. METHODS: 148 consecutive cases before the introduction of CE were retrospectively reviewed based on the presence of PT2EL (persistent type 2 endoleak) and change in sac diameter after EVAR by multivariate analysis. RESULTS: (A) PT2EL risk factors were patent inferior mesenteric artery (IMA) and thinner mural thrombus inside aneurysmal sac. (B) Sac enlargement risk factors were antiplatelet intake, PT2EL, and female gender. (C) Sac shrinkage predictive factors were the absences of thoracic aortic aneurysm, antiplatelet intake, PT2EL, and coronary artery disease. CONCLUSION: CE to IMA was considered to be effective because patent IMA and antiplatelet intake were significant risk factors for sac enlargement. So, more meticulous therapeutic strategy, including treatment priority (AAA first or CAD first) and choice of treatment (EVAR vs. AAA) based on anatomical features of AAA was required to improve late outcomes. PMID- 25298829 TI - CT Findings of Risk Factors for Persistent Type II Endoleak from Inferior Mesenteric Artery to Determine Indicators of Preoperative IMA Embolization. AB - PURPOSE: To identify the computed tomography (CT) findings of persistent type II endoleak from the inferior mesenteric artery (IMA) which indicate the need for preoperative IMA embolization. MATERIALS AND METHODS: Included were 120 patients (96 males, 49-93 years old, mean: 77.7) who underwent endovascular aortic aneurysm repair (EVAR) between June 2007 and October 2010. The relationship between persistent type II endoleak and CT findings of IMA orifice was examined. RESULTS: CT showed no type II endoleak from IMA in 106 patients (89%; Group N), and transient type II endoleak from IMA in 10 patients (8.3%; Group T). CT showed persistent type II endoleak from IMA in 4 patients (3.3%; Group P) and three of them underwent reintervention. Univariate Cox-Mantel test analysis indicated that stenosis (p = 0.0003) and thrombus (p = 0.043) in IMA orifice were significant factors for persistent type II endoleak. The ratios of patients with proximal IMA more than 2.5 mm diameter in Groups N, Y, and P were 26/106 (24%), 5/10 (50%) and 4/4 (100%), respectively. CONCLUSION: Indicators for embolization of IMA prior to EVAR for the prevention of type II endoleak appear to be: (1) more than 2.5 mm in diameter and (2) no stenosis due to calcification or mural thrombus in IMA orifice. PMID- 25298831 TI - Direct and transapical central cannulation for acute type a aortic dissection. AB - OBJECTIVE: The choice of cannulation site for the treatment of acute Stanford type A aortic dissection is much debated. We believe that central cannulation is quick to perform, easy to use, and safe to manage acute type A aortic dissection. MATERIALS AND METHODS: We retrospectively investigated 26 cases of acute aortic dissection performed using two different central cannulation methods between April 2011 and March 2012. Direct ascending aortic cannulation was performed using the Seldinger technique in 20 patients, and transapical ascending aortic cannulation was performed in six patients in whom puncture was difficult. RESULTS: Patients were 21-86 years old (mean age, 67 years). The surgical techniques used to treat aortic dissection were hemiarch repair in 21 patients and total arch replacement in 5 patients. The mean length of surgery was 393 min. One death (3.8%) was attributed to intestinal ischemia. CONCLUSION: During surgery for acute aortic dissection, central cannulation using either transapical or direct puncture can be performed quickly and safely, and satisfactory short term outcomes can be obtained. Because acute aortic dissection can present with various conditions, there is no single perfect surgical or cannulation method; therefore, the choice of surgical procedure should be individualized for each patient. PMID- 25298832 TI - Carotid body tumors: a review of 25 years experience in diagnosis and management of 56 tumors. AB - OBJECTIVE: To report our experience in the management of CBTs and review the literature. MATERIALS AND METHODS: 56 CBTs were operated upon over a period of 25 years. Surgical intervention was planned according to the Shamblin classification. Thirty-nine of the tumors were in males (69.64%), and 17 of the tumors were in females (30.36%). The average age was 42 (ages ranging between 32 and 47). Twenty-two tumors were diagnosed and treated with Shamblin type I, twenty-eight with type II and eight tumors with type III. All patients were unilateral except two had bilateral carotid tumors. Thirty-five lumps were de novo (group A), while 21 lumps were treated after a prior trial of removal (group B). RESULTS: The incidence of carotid reconstruction was lower among group A (1/35) compared to group B (9/21). Complications were less in group A than group B (23% vs. 30%). There were 4 cases with suspected malignancy and no recurrences during the follow-up period. CONCLUSION: There is an increased incidence of major vascular reconstruction in cases not properly investigated or diagnosed and in cases with prior attempts of removal in Primary Hospitals. Proper diagnosis of suspicious lumps is mandatory. Resection of CBTs by surgeons with experience in vascular reconstruction is recommended. Vascular reconstructions have to be performed safely without serious complications. Also today, prior attempts of removal are not so common, with preoperative evaluation using the latest diagnostic tools. Cranial nerves injury (especially the Hypoglossal Nv) continues to be the most common complication. PMID- 25298833 TI - Endovascular Surgery for Traumatic Thoracic Aortic Injury: Our Experience with Five Cases, Two of Whom were Young Patients. AB - OBJECTIVES: We present our experience of endovascular surgery for traumatic aortic injury and the results of our procedures. MATERIALS AND METHODS: From January 2009 to December 2013, we performed endovascular repairs of traumatic thoracic aortic injury on 5 male patients 16-75 years old (mean, 50.8), two of whom were young. Three of the patients had multiple organ injuries. The mean interval time to the operation is 22.0 hours (range, 10-36). All patients underwent endovascular repair with heparinization. The isthmus regions were seen in three cases and all of them were needed left subclavian artery (LSA) coverage. In the two young patients, the deployed stent graft was 22 mm (22.2% oversizing for diameter of aorta) and 26 mm (36.8% oversizing), respectively. RESULTS: The procedures were successful in all patients, with no early mortality, paraplegia or stroke. During 3-63 months (mean, 30.8) follow-up period, no one experienced stent graft-related complications. One patient with LSA coverage experienced arm ischemia but the symptom improved with time. CONCLUSION: Endovascular surgery for traumatic thoracic aortic injury can be performed safely with low mortality or morbidity even in young small aorta. Accumulation of clinical experience and evaluation of long-term outcomes are necessary. PMID- 25298834 TI - Relationship between Arterial Inflow Rate and Venous Filling Index of the Lower Extremities Assessed by Air Plethysmography in Subjects with or without Axial Reflux in the Great Saphenous Vein. AB - OBJECTIVE: To evaluate the relationship between arterial inflow rate (AIR) and venous filling index (VFI) in limbs with or without varicose veins, assessed by air plethysmography (APG). MATERIALS AND METHODS: A total of 142 patients (142 limbs) visiting our clinic with leg complaints, but without arterial and venous disease, were defined as the normal group (NG), and 65 patients (65 limbs) with leg varices were defined as the varicose vein group (VG). Both groups underwent duplex ultrasonography and APG to identify venous reflux and measure hemodynamic parameters, respectively. Examinations were performed at the first visit in the NG and before and one month after treatment in the VG. RESULTS: A strong correlation between resting AIR and VFI was found in the NG (r = 0.72) and postoperative VG (r = 0.71). Twenty-two and three limbs in the NG and postoperative VG, respectively, had a VFI over 2.0 mL/s because of the high AIR. In the VG, AIR tended to decrease after treatment (P >0.01). CONCLUSIONS: High leg AIR lead to high VFI measured by APG. AIR and VFI should be measured at the same session to assess venous hemodynamic changes after varicose vein treatment when residual venous reflux cannot be diagnosed with duplex ultrasonography. PMID- 25298835 TI - Pancreaticoduodenal artery aneurysm formation with superior mesenteric artery stenosis. AB - Celiac stenosis or occlusion is attributed partly to increase blood flow at pancreatic arcade from the superior mesenteric artery (SMA) system and may play a causal role in true aneurysm of pancreaticoduodenal artery (PDAA) formation. However, despite possible increased blood flow in the pancreatic arcades like celiac stenosis, PDAAs with a stenotic SMA are extremely rare, with only three cases have been reported in the literature. We report a case of PDAA with SMA stenosis and review the literature. PMID- 25298836 TI - Lower Extremity Fibro-Adipose Vascular Anomaly (FAVA): A New Case of a Newly Delineated Disorder. AB - The acronym FAVA (Fibro-Adipose Vascular Anomaly) has been recently given to a distinct vascular entity that is characterized by fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. We report a new case of FAVA in a 10-year-old girl with pain in her right lower leg and equinus contracture. As in our case, FAVA typically presents in young females with calf involvement and limited ankle dorsiflexion with local pain. FAVA should be considered as a differential diagnosis when evaluating vascular anomalies in the lower extremities. PMID- 25298837 TI - Obstruction of the superior mesenteric artery due to emboli from the thoracic aorta in a patient with thromboangiitis obliterans. AB - A 48-year-old woman presented at our hospital with acute abdominal pain 3 years after being diagnosed with thromboangiitis obliterans (TAO). Computed tomography revealed occlusion of the superior mesenteric artery (SMA) and multiple kidney infarction with thrombus floating in the thoracic aorta connected with the intercostal artery. Despite emergency embolectomy, further thromboembolism eventually required massive resection of the intestine with jejunostomy and colostomy and permanent intravenous hyper-alimentation therapy. Although TAO rarely involves the large artery, the aorta could be the source of embolization in patients with TAO. PMID- 25298838 TI - Traumatic disruption of saphenous vein graft bypassed to the dorsalis pedis artery. AB - We describe a rare case of traumatic disruption of saphenous vein graft bypassed to the dorsalis pedis artery. The vein graft was disrupted at the level of ankle joint by blunt trauma and symptoms of acute foot ischemia were recognized. The injured vein graft was reconstructed with cephalic vein graft interposition. He has been free from any events of foot ischemia at 10 months follow-up with patent vein graft to the dorsalis pedis artery. PMID- 25298839 TI - Elective treatment of middle colic artery aneurysm. AB - Middle colic artery aneurysms are rare and most have been reported with rupture or symptom. We report the successful elective treatment of a middle colic artery aneurysm without symptom, which is very rare. It failed to perform transcatheter arterial embolization for anatomical reasons, and, thus, the patient, a 77-year old man, underwent surgical resection in spite of a history of laparotomy. Although a common cause of middle colic artery aneurysms is segmental arterial mediolysis, the present pathological findings indicated that fragmented or degenerated elastic fibers may also play an important role like aortic aneurysms. PMID- 25298840 TI - Delayed visceral and spinal cord malperfusion after axillo-bifemoral bypass for complicated acute type B aortic dissection. AB - We describe a successfully treated case of acute type B aortic dissection complicated with lower extremity, visceral, and spinal cord malperfusion. To restore perfusion to both lower extremities, we performed an emergency right axillo-bifemoral bypass. Furthermore, we performed total arch replacement, including primary entry closure, because of delayed visceral organ ischemia. Unexpectedly, delayed paraplegia occurred after hospital discharge; however, the patient recovered without any neurologic sequelae after early introduction of hyperbaric oxygen therapy. Because another episode of organ malperfusion in the long term cannot be anticipated, and even though the previous organ malperfusion episode was treated successfully, close observation is mandatory for detecting clinical manifestations in combination with the availability of imaging modalities. PMID- 25298841 TI - Infected internal jugular vein thrombus in a case of infected arterio-venous fistula for dialysis access. AB - Infected internal jugular vein (IJV) thrombus is rare and is sometimes seen in association with jugular vein catheterization and rarely with suppurative upper aero-digestive tract infection. We describe a very rare association of left Infected Internal jugular vein thrombus with an infected arterio-venous fistula in the left elbow region created for dialysis access in a renal failure patient. The infected arterio-venous fistula was addressed surgically by excision and a reverse saphenous vein graft was placed between proximal and distal brachial artery just above it's bifurcation. The patient was put on i.v Clindamycin and Metronidazole for six weeks. Patient recovered uneventfully. PMID- 25298842 TI - Successful surgical exclusion of rapidly expanding kommerell diverticulum following a total arch replacement for an acute type a aortic dissection. AB - A 50-year-old man presented with an acute type A aortic dissection with an aberrant right subclavian artery. Emergent total arch replacement with an elephant trunk was performed. Intraoperatively, the origin of the aberrant right subclavian artery could not be resected because it was located too far from the distal arch. After two weeks, the patient became aware of dysphagia. Postoperative computed tomography showed the esophagus was compressed anteriorly by the aneurismal origin of this aberrant vessel (Kommerell diverticulum) with a patent false lumen. Additional replacement of the descending aorta via left thoracotomy was performed immediately to exclude a Kommerell diverticulum. PMID- 25298843 TI - Two cases of thoracic aortic aneurysm with right aortic arch: comparison of two operative strategies for hybrid thoracic endovascular repair. AB - Hybrid TEVAR was performed in 2 patients with right aortic arch accompanied by Kommerell's diverticulum and aortic aneurysm. In patient 1, total debranch + TEVAR was performed with 1-stage median sternotomy. In patient 2, total arch replacement and insertion of a peripheral elephant trunk were performed first, followed by TEVAR. No endoleaks or aortic events were observed in either case during the observation period, and both patients had good postoperative clinical courses. We report our experience with two such cases that were treated with two different methods of hybrid TEVAR, and discuss the merits and demerits of each treatment method. PMID- 25298844 TI - Conservative management in a young woman affected by isolated left subclavian artery dissection. AB - Subclavian Artery Dissection (SAD) is a rare condition, generally due to arterial catheterization, blunt trauma or connective tissue disease. Spontaneous or minimally traumatic cases have also been reported. Clinical manifestations are usually chest and/or back pain, pulse loss and paresthesia, whereas nausea, dizziness and vomiting are present in case of involvement of the vertebral artery. We report an unusual case of a young woman presenting isolated left SAD after traffic accident, minimally symptomatic, and treated with medical therapy alone. A conservative management and a closed follow-up appear to be a safe approach in patients affected by uncomplicated SAD without other comorbidities. PMID- 25298845 TI - Open Reintervention for Aneurysmal Sac Enlargement after EVAR. AB - We performed a late open reintervention for aneurysmal sac enlargement due to persistent type 2 endoleak (PT2EL) after EVAR for 8 of 286 patients. Surgical techniques are as follows: (1) The entire aneurysmal body was exposed. (2) All the aortic branched vessels were ligated. (3) The aneurysmal sac was opened followed by the performance of complete hemostasis. (4) An equine pericardium was wrapped and sutured to the aneurysmal sac to for reinforcement. This method is considered to be one of the feasible options for the treatment of aneurysmal sac re-enlargement after EVAR. PMID- 25298846 TI - Ascending to Abdominal Aorta Extraanatomic Bypass for Descending Aortic Coarctation: A Reconstruction Technique without Laparotomy or Left Thoracotomy. AB - The descending aortic coarctation is often difficult to anatomically reconstruct. We report two cases of ascending aorta to abdominal aorta bypass without laparotomy or thoracotomy. This approach enabled us to avoid anastomosis close to the inflammatory lesion and left thoracotomy causing bleeding from the collateral vessels, and to allow concomitant cardiac procedures to be performed. The graft contact with the intestines can be preventable by the retroperitoneal approach. This technique is useful for the selective patients. PMID- 25298847 TI - Understanding the Limitations of Circulating Cell Free Fetal DNA: An Example of Two Unique Cases. AB - Circulating cell free fetal DNA (cffDNA) is an effective screening modality for fetal aneuploidy. We report two cases of false positive results. The first case involves a female, with self-reported Down syndrome. CffDNA returned positive for trisomy 18 leading to a maternal diagnosis of mosaicism chromosome 18 with normal fetal karyotype. The second case involves a patient with an anomalous fetal ultrasound and cffDNA positive for trisomy 13. Amniocentesis demonstrated a chromosome 8p duplication/deletion. False positive cffDNA may arise in clinical scenarios where diagnostic testing is clearly indicated. Practitioners should recognize the limitations of cffDNA. PMID- 25298848 TI - Community-based hepatitis B screening: what works? AB - INTRODUCTION: Chronic hepatitis B (CHB) affects over 350 million people worldwide and can lead to life-threatening complications, including liver failure and hepatocellular cancer (HCC). Modern antiviral therapies could stem the rising tide of hepatitis B-related HCC, provided that individuals and populations at risk can be reliably identified through hepatitis B screening and appropriately linked to care. Opportunistic disease screening cannot deliver population-level outcomes, given the large number of undiagnosed people, but they may be achievable through well-organized and targeted community-based screening interventions. MATERIAL AND METHODS: This review summarizes the experience with community-based CHB screening programs published in the English-language literature over the last 30 years. RESULTS: They include experiences from Taiwan, the USA, The Netherlands, New Zealand, and Australia. Despite great variability in program setting and design, successful programs shared common features, including effective community engagement incorporating the target population's cultural values and the ability to provide low-cost or free access to care, including antiviral treatment. CONCLUSION: While many questions still remain about the best funding mechanisms to ensure program sustainability and what the most effective strategies are to ensure program reach, linkage to care, and access to treatment, the evidence suggests scope for cautious optimism. A number of successful, large-scale initiatives in the USA, Asia-Pacific, and Europe demonstrated the feasibility of community-based interventions in effectively screening large numbers of people with CHB. By providing an effective mechanism for community outreach, scaling up these interventions could deliver population level outcomes in liver cancer prevention relevant for many countries with a large burden of disease. PMID- 25298850 TI - Intravenous thrombolysis in a patient using factor Xa inhibitor. AB - Until recently, only warfarin was approved for the prevention of stroke in patients with AF. Patients on warfarin with ischemic stroke were considered candidates for IV tPA as long as their PT/INR was not prolonged. Now, there are several new agents approved for stroke prevention in patients with non-valvular AF. The newer agents include direct thrombin inhibitors, like dabigatran, and factor Xa inhibitors, like rivaroxaban and apixaban. The coagulation profile of patients on direct thrombin inhibitors is more predictable than that of patients on factor Xa inhibitors, and the usage of IV tPA in patients on dabigatran has been previously reported. To our knowledge, there are no prior reports of IV tPA in a patient on a factor Xa inhibitor. We report a case of a 71-year-old man on rivaroxaban who improved with IV tPA after presenting with acute onset of aphasia and right-sided weakness. ABBREVIATIONS: AFAtrial fibrillationIV tPAIntravenous tissue plasminogen activatorINRInternational normalized ratioPTTPartial thromboplastin timeNIHNational Institute of HealthPTProthrombin timeCTComputed tomographyMCAMiddle cerebral arteryMRIMagnetic resonance imaging. PMID- 25298849 TI - Soluble FGL2, a novel effector molecule of activated hepatic stellate cells, regulates T-cell function in cirrhotic patients with hepatocellular carcinoma. AB - PURPOSE: To investigate the effects of soluble FGL2 (sFGL2) secreted by hepatic stellate cells (HSCs) on immune suppression in cirrhotic patients with hepatocellular carcinoma (HCC). METHODS: Serum sFGL2 levels were examined by ELISA in 40 patients with HCC, liver cirrhosis (LC) or chronic HBV (CHB) infection. A double staining of the immunofluorescence analysis of alpha-SMA and FGL2 was performed in two cirrhotic liver specimens. The expression of FGL2 in the LX2 cell line was analyzed by immunofluorescence, Western blot and flow cytometry. T-cells purified from HCC patients using magnetic beads were cultured with LX2 cells at different ratios with anti-CD3-stimulating or FGL2-blocking antibodies. The proliferation index (PI) of CD8 + T cells was assessed by flow cytometry, and the secretion of IFN-gamma was measured by ELISA. RESULTS: sFGL2 levels are significantly higher in patients with HCC or LC compared with those with CHB (p = 0.0039/p = 0.0020). Among HCC patients, those with cirrhosis exhibited significantly higher levels of sFGL2 compared with non-cirrhotic individuals (p = 0.0108). The expressions of FGL2 and alpha-SMA overlapped in HSCs in liver specimens. FGL2 protein secreted by LX2 cells inhibited T-cell proliferation of HCC patients in a dose-dependent manner in vitro. The PI of CD8 + T cells was significantly enhanced following addition of FGL2 antibody to the culture system (LX2/T-cell ratio of 1:10, p = 0.002). The level of IFN-gamma in mixed cultures was inversely correlated with the number of HSCs and was reversed by incubation with FGL2 blocking antibody. CONCLUSION: sFGL2 protein is a novel effector molecule of activated HSCs, which suppresses CD8 + T cell proliferation and interferon-gamma production, and it subsequently might contribute to immune suppression during fibrosis and tumorigenesis in the liver. PMID- 25298851 TI - Endovascular treatment in acute ischemic stroke patient on factor Xa inhibitor. PMID- 25298852 TI - Possible role of Eptifibatide drip in-patient with aneurysmal subarachnoid hemorrhage in vasospasm prevention. AB - OBJECTIVE: Approximately 18,000 patients suffer from a subarachnoid hemorrhage (SAH) in the United States annually. SAH is a form of stroke and comprises 1%-5% of all strokes. Nearly 50% of all SAH cases end in fatality within 30 days of presentation; one of eight patients die before reaching a hospital. Those who survive often have neurological or cognitive impairment. METHODS: This case report describes the course of two patients who presented to the emergency department with aneurismal subarachnoid hemorrhage and received external ventricular drainage and endovascular treatment of their aneurysm. RESULTS: Both patients required treatment with Eptifibatide drip after endovascular approach and their SAH in the basal cisterns resolved by day 5. Neither patient developed signs of clinical or subclinical vasospasm. COMMENTS: Eptifibatide drip facilitated resolution of the thick clot in the subarachnoid space early enough to eliminate the direct toxicity of oxyhemoglobin on the cerebral arteries and arachnoid granulations, thus preventing vasospasm and eliminating the necessity for a long-term shunt. PMID- 25298853 TI - Incidences of unruptured intracranial aneurysms and subarachnoid hemorrhage: results of a statewide study. AB - BACKGROUND: The incidence of unruptured intracranial aneurysms (UIAs) and the current public health impact may be higher than that reported in previous studies owing to an increase in the elderly population in the United States. OBJECTIVE: To report the current incidences of UIAs and subarachnoid hemorrhages (SAH) by using a population-based methodology. METHODS: Statewide estimates of patients admitted with UIAs and SAH were obtained from the data obtained by the Minnesota Hospital Association. We calculated the annual incidences per 100,000 persons by using the 2010 census data from the U.S. Census Bureau. For the denominator, total persons in each year were categorized into 10-year intervals. RESULTS: The incidences of UIAs and SAH were 15.6 and 7.7 per 100,000 persons, respectively. There were higher incidences of both UIAs and SAH among women (22.5 and 9.6 per 100,000 persons, respectively). The highest incidence of UIAs occurred in those aged between 75 and 84 years (61.6 per 100,000 persons). The highest incidence of SAH occurred in those aged 85 years and older (30.1 per 100,000 persons). CONCLUSION: An increase in both incidences of UIAs and SAH can be expected owing to the continued increase of the elderly population, particularly women. PMID- 25298854 TI - Prevalence of vertebral artery origin stenosis and occlusion in outpatient extracranial ultrasonography. AB - BACKGROUND AND PURPOSE: Most data on the prevalence of vertebral artery origin (VAo) disease is derived from hospital-based studies of patients with posterior circulation strokes and TIA. The prevalence of VAo disease in patients without posterior circulation symptoms or asymptomatic patients is poorly characterized. Our objective was to examine the prevalence of VAo stenosis and occlusion in consecutive patients, presenting for extracranial ultrasonography to an outpatient laboratory. METHODS: We retrospectively identified 2490 consecutive extracranial duplex studies performed in an ambulatory neurovascular ultrasound laboratory. All studies were reviewed for the presence of >50% VAo stenosis, defined as a PSV > 114 cm/s, and VA occlusion. We also reviewed the prevalence of >50% carotid stenosis, defined as a PSV > 120 cm/s, in the same population, to draw comparisons with VAo stenosis prevalence. RESULTS: We identified right VAo stenosis in 52/1955 (2.7%) and occlusion in 74/1955 (3.9%) and left-sided VAo stenosis in 45/1973 (2.5%) and occlusion in 64/1973 (3.6%). The prevalence of having any (either right or left) VAo stenosis or occlusion was 8.2% and 1.4% had bilateral VAo stenosis or occlusion. Right carotid stenosis and occlusion was found in 236/2399 (9.8%) and 53/2399 (2.2%) and left carotid stenosis and occlusion in 236/2397 (9.8%) and 45/2397 (1.9%), respectively. Any carotid disease, either right or left, was present in 18.9% and 4.7% had bilateral carotid disease. CONCLUSION: Although less prevalent than cervical carotid disease, we found that approximately 8% of patients who presented to an ambulatory ultrasound laboratory had >50% VAo disease. PMID- 25298855 TI - Cardioembolic stroke secondary to Lambl's excrescence on the aortic valve: a case report. AB - We report a patient who presented with aphasia and was found to have an embolic cerebral infarction secondary to LE. LE is a rare source of cardioembolic stroke. PMID- 25298856 TI - Walk score and risk of stroke and stroke subtypes among town residents. AB - BACKGROUND: Regular physical activity, including light-to-moderate activity, such as walking, has well-established benefits for reducing the risk of ischemic stroke. It remains unknown, however, whether the characteristics of cities themselves can influence the risk of stroke by promoting such activity. OBJECTIVES: We tested the hypothesis that how walkable a city will be associated with the risk of ischemic stroke in persons residing in that city. METHODS: We calculated the age-adjusted annual incidence rates of ischemic stroke among residents in each of the 63 cities in Minnesota for which Walk Scores were available using 2011 Minnesota Hospital Association (MHA) data. Walk Score(r), an online service, uses an exclusive algorithm to compute a walkability score between 0 and 100 for any location within the United States. The score is calculated based on the distance to amenities in nine categories (grocery, restaurants, shopping, coffee, banks, parks, schools, books, and entertainment) weighed according to their importance. RESULTS: There are 2,910,435 persons residing in the 63 Minnesota cities in our data (average population per town is 46,197). The average Walk Score of the 63 towns in Minnesota was 34, ranging from 14 to 69. The average median age of residents was similar in tertiles of towns based on Walk Score as follows: <=25 (n=9) 36 years; 26-50 (n=46) 37 years; and 51-100 (n=8) 35 years. The age-adjusted incidence of ischemic stroke was similar in tertiles of towns based on Walk Score as follows: <=25 (n=9) 341 per 100,000; 26-50 (n=46) 308 per 100,000; and 51-100 (n=8) 330 per 100,000 residents. The correlation between age-adjusted ischemic stroke incidence and Walk Score was low (R (2)=0.09) within Minnesota. CONCLUSIONS: The ready availability of indices such as Walk Score make them attractive options for ischemic stroke risk correlation. Despite the lack of relationship in our study, further studies are required to measure the magnitude and health benefits of light-to-moderate activities performed within a town. PMID- 25298857 TI - A survey of preprocedural intubation practices for endovascular treatment of acute ischemic stroke. AB - BACKGROUND: In the absence of specific guidelines, there is considerable variance in preprocedural intubation practices for endovascular treatment of acute ischemic stroke. The purpose of this study is to understand and characterize the variance in preprocedural intubation practices and identify the reasons that influence the choice of preprocedural intubation practices among treating physicians. METHODS: We selected 10 random cases from a prospective database of patients undergoing endovascular treatment for acute ischemic stroke and prepared a case summary providing pertinent demographic, clinical, and imaging data. Twenty clinicians independently reviewed the case summaries and responded to whether they would intubate any of the 10 patients and identified the reasons for their choices. Clinicians were also asked to identify their training background (neurology-, neurosurgery-, or radiology-trained endovascular specialist, vascular neurologist or neurointensivist). Reasons for intubation and agreement between clinicians for each case were ascertained. RESULTS: The decision to intubate the patient was made in 63 of 200 total clinical scenarios. The major reasons identified by the physicians for preprocedural intubation were high National Institute of Health stroke scale scores on admission 26.9% (n = 17), labored breathing or desaturation 23.8% (n = 15), less than optimal respiratory status of patients combined with drowsiness or reduced level of consciousness 14.3% (n = 9), inability to follow command due to aphasia 12.7% (n = 8), seizures 1.6% ( n = 1), and no reason 20.6% (n = 13). Overall agreement between clinicians regarding decision of preprocedural intubation among the 10 case scenarios was 30.1% (standard error [SE] 2.3%). The agreement between neurosurgeons was 37.5% (SE = 31.6), interventional neurologist 19.8% (SE = 4.7), and vascular neurologist/neurointensivist 39.3% (SE = 5.9). CONCLUSION: The decision of preprocedural intubation varies widely among clinicians. Because of recent data that suggests that decision of preprocedural intubation may impact on patients' outcomes, better standardization of such practices is required. PMID- 25298858 TI - Enrollment of research subjects through telemedicine networks in a multicenter acute intracerebral hemorrhage clinical trial: design and methods. AB - BACKGROUND: Enrollment of subjects in acute stroke trials is often hindered by narrow timeframes, because a large proportion of patients arrive via transfers from outside facilities rather than primary arrival at the enrolling hospital. RATIONALE: Telemedicine networks have been increasingly used for provision of care for acute stroke patients at facilities outside of major academic centers. Treatment decisions made through telemedicine networks in patients with acute ischemic stroke have been shown to be safe, reliable, and effective. With the expanding use of this technology and the impediments to enrolling subjects into clinical trials, this approach can be applied successfully to the field of clinical research. METHODS AND CONCLUSIONS: The Antihypertensive Treatment of Acute Cerebral Hemorrhage II trial is a phase III randomized multicenter trial that has developed a protocol in collaboration with participating sites to implement the use of telemedicine networks for the enrollment of research subjects. The protocol describes the operating procedures and legal and Institutional Review Board perspectives for its implementation. PMID- 25298859 TI - Flow-independent dynamics in aneurysm (FIDA): pressure measurements following partial and complete flow impairment in experimental aneurysm model. AB - BACKGROUND: There have been growing concerns regarding delayed aneurysm rupture subsequent to the flow-diverting stent deployment. Therefore, more investigations are needed regarding hemodynamic changes secondary to flow-diverting stent deployment. OBJECTIVE: To study intra-aneurysmal and perianeurysmal pressures after partial and complete flow impairment into the aneurysm. METHODS: A silicone model of an 8-mm-sized aneurysm (neck diameter: 5 mm, vessel size: 4 mm) was used. The aneurysm wall was encapsulated and sealed within a 5 ml syringe filled with saline and a pressure sensor guide wire (ComboWire, Volcano Corp.) to detect pressure changes in the perivascular compartment (outer aneurysm wall). A second pressure sensor guide wire was advanced inside the aneurysm sac. Both pressure sensors were continuously measuring pressure inside and outside the aneurysm under pulsatile flow under the following conditions: 1) baseline (reference); 2) a 16 mm by 3.75 mm flow-diverting stent (ev3/Covidien Vascular, Mansfield, MA) deployed in front of the aneurysm; 3) two flow-diverting stents (16 mm by 3.5 mm) were deployed; and 4) a covered stent (4 mm by 16 mm VeriFlex coronary artery stent covered with rubber sheet) was deployed. RESULTS: Mean (+/-SD) baseline pressures inside and outside the aneurysm were 53.9 (+/-2.4) mmHg (range 120-40 mmHg) and 15.4 (+/-0.7) mmHg (range 40-8mmHg), respectively. There was no change in pressure inside and outside the aneurysm after deploying the first and second flow-diverting stents (partial flow impairment) and it remained at 53.9 (+/-2.7) mmHg and 14.9 (+/-1) mmHg for the pressure inside and outside the aneurysm, respectively. The pressure recording from outside the aneurysm dropped from 15.4 (+/-0.7) mmHg to 0.3 (+/-0.7) mmHg after deploying the covered stent (complete flow impairment). There was no change in pressure inside the aneurysm after deploying the covered stent. Mean (+/-SD) pressure within the aneurysm was 55.1 (+/-1.7) mmHg and it remained 54.7 (+/-1.7) mmHg after covered stent deployment. CONCLUSION: Our findings suggest a major discordance between the pressures within the aneurysm and partial or complete flow impairment (flow independent). The outer wall pressure is reduced after covered stent placement. These finding may assist clinicians in better understanding of aneurysm hemodynamics and rupture after flow-diverting stent deployment. PMID- 25285202 TI - The net return from animal activity in agro-ecosystems: trading off benefits from ecosystem services against costs from crop damage. AB - Animals provide benefits to agriculture through the provision of ecosystem services, but also inflict costs such as damaging crops. These benefits and costs are mostly examined independently, rather than comparing the trade-offs of animal activity in the same system and quantifying the net return from beneficial minus detrimental activities. Here, I examine the net return associated with the activity of seed-eating birds in almond orchards by quantifying the economic costs and benefits of bird consumption of almonds. Pre-harvest, the consumption of harvestable almonds by birds cost growers AUD$57.50 ha (-1) when averaged across the entire plantation. Post-harvest, the same bird species provide an ecosystem service by removing mummified nuts from trees that growers otherwise need to remove to reduce threats from fungal infection or insect pest infestations. The value of this ecosystem service ranged from AUD$82.50 ha (-1) $332.50 ha (-1) based on the replacement costs of mechanical or manual removal of mummified nuts, respectively. Hence, bird consumption of almonds yielded a positive net return of AUD$25-$275 ha (-1) averaged across the entire plantation. However, bird activity varied spatially resulting in positive net returns occurring primarily at the edges of crops where activity was higher, compared to negative net returns in crop interiors. Moreover, partial mummy nut removal by birds meant that bird activity may only reduce costs to growers rather than replace these costs completely. Similar cost-benefit trade-offs exist across nature, and quantifying net returns can better inform land management decisions such as when to control pests or promote ecosystem service provision. PMID- 25298860 TI - Dual stimulus-dependent effect of Oenothera paradoxa extract on the respiratory burst in human leukocytes: suppressing for Escherichia coli and phorbol myristate acetate and stimulating for formyl-methionyl-leucyl-phenylalanine. AB - Although a growing body of evidence suggests that plant polyphenols can modulate human immune responses, their simultaneous action on monocyte and neutrophil oxidative burst is currently poorly understood. Based on the hypothesis that various polyphenols contained in plant extracts might affect the oxidative burst of phagocytes, we evaluated the effects of ethanolic O. paradoxa extract polyphenols on monocyte and neutrophil oxidative burst in vitro activated by different stimuli, including opsonized bacteria E. coli, phorbol 12-myristate 13 acetate (PMA), and formyl-methionyl-leucyl-phenylalanine (fMLP). Samples were analyzed by the dihydrorhodamine flow cytometry assay. Our results showed that the extract repressed significantly and dose-dependently reactive oxygen species production in both cell types stimulated with E. coli and PMA (P < 0.05) and its inhibitory efficiency was stimulus- and cell-type-dependent. Interestingly, there was significant stimulatory effect of the extract on bursting phagocytes induced by fMLP (P < 0.05). Additionally, several flavonoids and phenolic compounds as well as penta-galloyl-beta-(D)-glucose (PGG), the representative of hydrolyzable tannins, were identified in the 60% extract by high-performance liquid chromatography (HPLC) coupled to electrospray ionization in negative ion mode. In summary, the ethanolic O. paradoxa extract, rich in flavonoids and phenolic compounds, exhibits dual stimulus-dependent effect on the respiratory burst in human leukocytes; hence, it might affect immune responses in humans. PMID- 25298862 TI - Superselective splenic artery embolization for the management of splenic laceration following colonoscopy. AB - Splenic injury is a rare complication following colonoscopy with fewer than 100 reported cases worldwide to date. We describe a case of splenic laceration presenting 5 days following diagnostic colonoscopy. Although hemodynamically stable, active contrast extravasation on contrast-enhanced multidetector computed tomography predicted likely failure of conservative management. Splenic artery angiography confirmed active extravasation from the lower splenic pole and the patient was successfully treated with super selective coil embolization of a lower pole splenic artery branch. This is the eighth reported case of endovascular treatment of splenic injury following colonoscopy. To our knowledge, however, superselective splenic artery embolization has not been previously reported to treat this rare endoscopic complication. PMID- 25298863 TI - Tumor regression of multiple bone metastases from breast cancer after administration of strontium-89 chloride (Metastron). AB - We report a case of tumor regression of multiple bone metastases from breast carcinoma after administration of strontium-89 chloride. This case suggests that strontium-89 chloride can not only relieve bone metastases pain not responsive to analgesics, but may also have a tumoricidal effect on bone metastases. PMID- 25298864 TI - An unusual case of primary hepatic lymphoma mimicking sarcoidosis in MRI. AB - Sarcoidosis is a granulomatous disease, in which liver affection is common, contrary to a primary hepatic lymphoma that is very rarely seen. On MRI both present with almost the same imaging features: hypointense in T1-weighted and hyperintense in T2-weighted sequences. Our patient with a histologically confirmed sarcoidosis in the lungs showed liver lesions that were similar to sarcoidosis manifestations of the liver. Due to size, progression and overlapping features with secondary malignant liver lesions within an interval of 5 months, a biopsy was conducted and confirmed a primary hepatic lymphoma with diffuse large b-cells. Thus, we would recommend performing a biopsy in ambiguous lesions with indistinguishable characteristics and progression within a short follow-up interval. PMID- 25298865 TI - Vertebral metastases from intracranial meningioma. AB - Meningioma rarely gives rise to metastases outside the brain and meninges. We report here a case of a patient who was treated for anaplastic brain meningioma with surgery and fractionated radiation therapy without any recurrence until 5 years after the operation, when she developed vertebral metastases. PMID- 25298866 TI - A longitudinal VBM study monitoring treatment with erythropoietin in patients with Friedreich ataxia. AB - BACKGROUND: Recombinant human erythropoietin (rhuEPO) has received considerable attention because of its neuroprotective properties. It has recently been reported that rhuEPO increases frataxin levels in combination with clinical improvement in rhuEPO treated patients with Friedreich ataxia (FRDA). PURPOSE: To determine possible therapy dependent intracranial volume changes after treatment with rhuEPO using voxel-based morphometry (VBM). MATERIAL AND METHODS: Nine FRDA patients were scanned on the same 1.5-Tesla MRI scanner before and after treatment with rhuEPO. FRDA patients received 5000 IU rhuEPO thrice weekly subcutaneously for a time period of 8 weeks followed by 2000 IU thrice weekly over 6 months. To test for re-test reliability a control group of 12 healthy volunteers were scanned twice on the same scanner without rhuEPO treatment. Neurological state was defined by the Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA). Statistical parametric mapping software was used for image processing and statistical analysis. RESULTS: When comparing follow-up scans after rhuEPO treatment with baseline scans (P <0.001 uncorrected) an increase of gray matter volume was observed bilaterally in the Pulvinar and the posterior parietal cortex. Moreover, clinical improvement detected using specific Ataxia scores correlated with VBM results in the pulvinar. CONCLUSION: Given the limitation of a small sample size, our study confirms previous findings that MRI may serve as reliable biomarker in neurodegenerative diseases as well as in monitoring of microstructural changes representing disease progression and/or therapy effects. PMID- 25298867 TI - Caval variations in neurologically diseased patients. AB - BACKGROUND: The import of the cavum variation and its prevalence rate in healthy individuals is still not clear, likewise in neurologically diseased patients. PURPOSE: To evaluate the frequency and pattern of caval variations in neurologically diseased patients. MATERIAL AND METHODS: The presence or absence of the cavum septum pellucidum (CSP), cavum vergae (CV), or cavum velum interpositum (CVI) was reviewed from successive cranial computerized tomography (CT) images of patients who were aged 6 months and above. Two hundred and seventeen cranial CT images were reviewed. RESULTS: At least a cavum variation was noted in 130 (59.9%) of the CT scan images reviewed. The CV, CVI, and CSP were noted in 86 (39.6%), 53 (24.4%), and 50 images (23%), respectively. Caval multiplicity was noted in 102 patients (47%). There was no significant difference in the rate of occurrence of cavum variations in patients with congenital brain diseases and acquired brain conditions (P = 0.484), neither was there a significant difference in the frequency of cavum variation in children aged older than 6 months compared to adults (P = 0.101). CONCLUSION: Cava variations are relatively common in neurological brain diseases. Patients with congenital brain diseases did not have a higher frequency of cava variation when compared with those that had acquired lesions. The most common type of cavum variation noted in this study was the vergae variety, while the CSP is the rarest. PMID- 25298868 TI - Economically affordable anatomical kidney phantom with calyxes for puncture and drainage training in interventional urology and radiology. AB - BACKGROUND: Trends in interventional radiology and urology training are orientated towards reducing costs and increasing efficiency. In order to comply with the trends, we propose training on inexpensive patient-specific kidney phantoms. PURPOSE: To develop a new kidney phantom for puncture and drainage training in interventional urology and radiology, and to evaluate their anatomical correctness and suitability for training compared to the traditional way of training on home-made phantoms. MATERIAL AND METHODS: A CASE STUDY FOR VALIDATION OF KIDNEY PHANTOMS WAS CONDUCTED WITH NINE RADIOLOGY STUDENTS DIVIDED INTO TWO GROUPS: one trained on standard home-made training phantom (n = 4) and the other on our kidney phantoms (n = 5). Another test phantom was used to evaluate the effectiveness of the training of the two groups. The tests were video recorded and analyzed. Duration of the procedure was used as the primary indicator of procedure's quality. Comparison tests were also conducted with professional radiologists. Anatomical correctness of the kidney phantom was evaluated by comparing the post mortem kidney scans with reconstructed models from CT scans. Subjective feedback was also collected from the participants. Wider use of kidney phantoms was analyzed. RESULTS: The average volumetric difference between post mortem kidney scans and reconstructed CT kidney models was 4.70 +/- 3.25%. All five students practicing on the kidney phantom improved their performance and the results were almost equal to the results of the professional radiologist while in the other group two students out of four trained on standard home-made training phantoms failed to improve their performance. However, the small number of test subjects prevents us from drawing general conclusions about the efficiency of the new practice. The kidney phantoms were found usable also for nephrostomy catheter placement training under fluoroscopy. CONCLUSION: The feedback from radiologists showed that the anatomically correct features of the phantom is an added value for the training and has a potential to increase the quality of minimally invasive procedures in general. PMID- 25298869 TI - Comparison of Danish dichotomous and BI-RADS classifications of mammographic density. AB - BACKGROUND: In the Copenhagen mammography screening program from 1991 to 2001, mammographic density was classified either as fatty or mixed/dense. This dichotomous mammographic density classification system is unique internationally, and has not been validated before. PURPOSE: To compare the Danish dichotomous mammographic density classification system from 1991 to 2001 with the density BI RADS classifications, in an attempt to validate the Danish classification system. MATERIAL AND METHODS: The study sample consisted of 120 mammograms taken in Copenhagen in 1991-2001, which tested false positive, and which were in 2012 re assessed and classified according to the BI-RADS classification system. We calculated inter-rater agreement between the Danish dichotomous mammographic classification as fatty or mixed/dense and the four-level BI-RADS classification by the linear weighted Kappa statistic. RESULTS: Of the 120 women, 32 (26.7%) were classified as having fatty and 88 (73.3%) as mixed/dense mammographic density, according to Danish dichotomous classification. According to BI-RADS density classification, 12 (10.0%) women were classified as having predominantly fatty (BI-RADS code 1), 46 (38.3%) as having scattered fibroglandular (BI-RADS code 2), 57 (47.5%) as having heterogeneously dense (BI-RADS 3), and five (4.2%) as having extremely dense (BI-RADS code 4) mammographic density. The inter-rater variability assessed by weighted kappa statistic showed a substantial agreement (0.75). CONCLUSION: The dichotomous mammographic density classification system utilized in early years of Copenhagen's mammographic screening program (1991 2001) agreed well with the BI-RADS density classification system. PMID- 25298870 TI - Quantification of cerebral circulation and shunt volume in a tentorial dural arteriovenous fistula using two-dimensional phase-contrast magnetic resonance imaging. AB - Venous hypertension is closely related to poor outcome of a dural arteriovenous fistula (DAVF). However, no direct measurements have been made of the shunt flow and impaired venous drainage that are suggestive of venous hypertension. We present a case of a 35-year-old man who presented with cerebral hemorrhage and underwent coil embolization for tentorial DAVF. Two-dimensional (2D) phase contrast magnetic resonance imaging (MRI) was used to evaluate temporal changes in the flow volumes of the shunt and venous drainage between before and after embolization. The results demonstrated the feasibility of using 2D phase-contrast MRI to measure the shunt volume of a DAVF, which might be useful for assessing the improvement in cerebral circulation after embolization treatment. PMID- 25298871 TI - Tumefactive demyelinating disease with isolated spinal cord involvement. AB - Tumefactive multiple sclerosis (TMS) is an unusual variant of demyelinating disease. TMS has a variable and unknown progression and presents with features similar to a neoplasm making the determination a diagnostic challenge to clinicians. This report presents one of the very few reported cases of isolated spinal cord TMS, and the second case to describe TMS of the lower spinal cord, given that the lesions are typically cervical. This case study presents a diagnostic approach based on clinical, laboratory, and imaging characteristics, as well as sheds some light on the response to therapy and disease evolution. PMID- 25298872 TI - Solitary fibrous tumor of the post-styloid parapharyngeal space. AB - Solitary fibrous tumor (SFT) is a well-known tumor composed of spindle cells found most commonly in the pleura. Recently, accounts of their rare occurrence at other sites, including the head and neck area, have been reported. The parapharyngeal space is a rare location even for head and neck SFTs, and thus, could be confused with a variety of other tumors that can originate in this area. Here, we report a case of SFT originating from the post-styloid parapharyngeal space and discuss the possible differential diagnosis on radiographic findings. PMID- 25298873 TI - Percutaneous transhepatic sclerotherapy with embolization of the drainage vein for a gastric varix. AB - We experienced a case with a gastric varix that did not have a catheterizable main drainage vein and had multiple afferent veins. For this case we successfully performed percutaneous transhepatic sclerotherapy using the following procedure. After the drainage vein was embolized by metallic coils and n-butyl cyanoacrylate from a microcatheter that was advanced through the gastric varix, 5% ethanolamine oleate-iopamidol was infused into the gastric varix from one main afferent vein under balloon occlusion. PMID- 25298874 TI - A case of primary rectal angioleiomyoma: review of radiologic finding with histopathologic correlation. AB - Angioleiomyomas are benign smooth muscle tumors that originate from the tunica media of veins and arteries. They can occur anywhere in the body, but the preferential location of these tumors is the lower extremities. We describe a rare case of rectal angioleiomyoma and present our findings obtained by using computed tomography, magnetic resonance imaging, and histopathological analysis. PMID- 25298875 TI - Small bowel feces sign in association with occlusive mesenteric ischemia. AB - Small bowel feces sign (SBFS) is a computed tomography (CT) finding that appears as fecal like material in dilated small bowel loops. This sign is usually seen in association with gradually progressive small bowel obstruction. We present a case of occlusive mesenteric ischemia in which the SBFS appeared on CT scan early on in the course of the disease. We put forward a suggested alternative mechanism to the appearance of this sign in association with mesenteric ischemia. The SBFS might have the potential to serve as an early sign of mesenteric ischemia on CT scan. PMID- 25298876 TI - Intravenous thrombolysis in acute ischemic stroke patients with negative CT perfusion: a case series. AB - BACKGROUND: Computed tomography perfusion (CTP) is a commonly used modality of neurophysiologic imaging to aid the selection of acute ischemic stroke patients for neuroendovascular intervention by identifying the presence of penumbra versus infarcted brain tissue. However many patients present with evidence of cerebral ischemia with normal CTP, and in that case, should intravenous thrombolytics be given? PURPOSE: To demonstrate if tissue-type plasminogen activator (tPA) eligible stroke patients without perfusion defects demonstrated on CTP would benefit from administration of intravenous thrombolytics. MATERIAL AND METHODS: We retrospectively identified patients presenting with acute ischemic symptoms who received intravenous tPA (IV-tPA) from January to June 2012 without a perfusion defect on CTP. Clinical and radiographic findings including the NIHSS at presentation, 24 h, and at discharge, symptomatic and asymptomatic hemorrhagic transformation, and the modified Rankin score at 30 days were collected. A reduction of NIHSS of greater than 4 points or resolution of symptoms was considered significant. RESULTS: Seventeen patients were identified with a mean NIHSS of 8.2 prior to administration of intravenous thrombolytics, 3.5 after 24 h, and 2.5 at discharge. Among them, 13 patients had significant improvement of NIHSS with a mean reduction of 6.15 points at 24 h. One patient initially improved but had delayed hemorrhagic transformation and died. Two patients had improvement in NIHSS but were not significant and two patients had increased in NIHSS at 24 h, although one eventually improved at discharge. There was no asymptomatic hemorrhagic transformation. Mean mRS at 3 months is 1.76. CONCLUSION: The failure to identify a perfusion deficit by CTP should not be used as a contraindication for intravenous thrombolytics. Criteria for administration of intravenous thrombolytics should still be based on time from symptom onset as previously published by NINDS. PMID- 25298877 TI - Marchiafava-Bignami disease with hyperintensity on late diffusion-weighted imaging. AB - A 69-year-old man with a decades-long history of chronic alcohol consumption was admitted with gait disturbance (short steps and spasticity), deterioration of activity, and stuporous consciousness. Head magnetic resonance imaging (MRI) revealed hyperintensity on fluid-attenuated inversion recovery imaging in the corpus callosum and frontal white matter. The lesion later became more apparent on diffusion-weighted imaging. The clinical diagnosis was Marchiafava-Bignami disease (MBD). As temporary treatment, refraining from alcohol consumption and administration of vitamins were prescribed. The condition of the patient gradually improved. The purposes of this study were to demonstrate the clinical and radiological variety of MBD and to identify practical methods of treatment of this pathology. PMID- 25298878 TI - Inflammatory myofibroblastic tumor of the liver mimicking an infiltrative malignancy in computed tomography and magnetic resonance imaging with Gd-EOB. AB - Inflammatory myofibroblastic tumors (IMT) are a benign tumor entity, which rarely develop in the liver. Surgery is the most common treatment for these lesions as it is difficult to distinguish them from malignant liver tumors and local recurrent growth may occur. IMT is a diagnostic challenge for imaging. Only a limited number of reports of single cases or small number of patients described the imaging features on computed tomography. Reports on IMT appearance on magnetic resonance imaging are scarce. We present a case of IMT of the liver with infiltration of the abdominal wall treated with surgery and describe the imaging features with the use of the hepatobiliary contrast agent, gadoxetic acid (Gd EOB). PMID- 25298879 TI - Rare association of acromegaly with left atrial myxoma in Carney's complex due to novel PRKAR1A mutation. AB - Carney complex (CNC) is a rare autosomal dominant syndrome characterized by pigmented lesions of the skin and mucosae along with cardiac, endocrine, cutaneous, and neural myxomatous tumors. Mutations in the PRKAR1A gene have been identified in ~70% of the CNC cases reported worldwide. A 30-year-old male was referred to the endocrinology clinic with suspected acromegaly. He had a history of recurrent atrial myxoma for the past 8 years for which he underwent repeated surgeries. Presently, he complained of having headache, excessive snoring, sweating, and also noticed increase in his shoe size. Evaluation for acromegaly revealed elevated levels of GH in random as well as in suppressed condition. Magnetic resonance imaging scan revealed enlarged sella with microadenoma in the left anterior pituitary. Screening of PRKAR1A gene was carried out for the patient, his parents and siblings who were available and willing to undergo the test. The patient was diagnosed to have the rare CNC syndrome characterized by recurrent atrial myxoma and acromegaly due to a novel 22 bp insertion mutation in PRKAR1A which was predicted to be deleterious by in silico analysis. Screening the available family members revealed the absence of this mutation in them except the elder brother who also tested positive for this mutation. The present study reports on a novel PRKAR1A insertion mutation in a patient with acromegaly and left atrial myxoma in CNC. LEARNING POINTS: Identification of a novel deleterious PRKAR1A insertion mutation causing CNC.It is important that patients with cardiac myxoma be investigated for presence of endocrine overactivity suggestive of CNC.PRKAR1A mutation analysis should be undertaken in such cases to confirm the diagnosis in the patients as well as first degree relatives.This case highlights an important aspect of diagnosis, clinical course, and management of this rare condition. PMID- 25298880 TI - Intermittent everolimus administration for malignant insulinoma. AB - Insulinoma is a rare form of insulin-secreting pancreatic islet cell neuroendocrine (NE) tumor. The medical treatment of the malignant NE disease of the pancreas deeply changed in the last years, thanks to the introduction of new target molecules, as everolimus. Even if the exact mechanism is not actually known, one of the side effects of everolimus, hyperglycemia, has been demonstrated to be useful to contrast the typical hypoglycemia of the insulinoma. We report the case of a patient with a metastatic malignant insulinoma treated with intermittent everolimus, obtaining an important improvement in the quality of life; this suggests the necessity of preclinical studies to analyze the cellular pathways involved in insulin-independent gluconeogenesis. LEARNING POINTS: Effect of somatostatin analogs is long-lasting in the control of functioning NE tumors.Persistent everolimus control of hypoglycemia despite serum insulin levels and disease progression.OPEN ISSUE: are disease progression and the increase in serum markers the only valid criteria to reject a treatment? PMID- 25298881 TI - Synchronous GH- and prolactin-secreting pituitary adenomas. AB - Pituitary adenomas are usually solitary lesions. Rarely, patients may present with two distinct pituitary tumors. We report a case of synchronous secretory pituitary adenomas in a woman who initially presented with elevated prolactin levels. She was initially treated with cabergoline, but, after many years, she began developing symptoms consistent with acromegaly. Imaging revealed two distinct tumors within the pituitary gland. Endocrinological investigation confirmed acromegaly. At the time of surgery, two separate tumors were identified and resected. Pathological analysis demonstrated one tumor as a prolactinoma, and the other tumor as a GH-secreting adenoma. Postoperatively, her GH and IGF1 levels normalized, while the prolactin level remained slightly above normal. This case highlights that GH and prolactin level elevation is not always from co secretion by the same adenoma. LEARNING POINTS: Synchronous pituitary adenomas represent <0.5% of pituitary tumors requiring surgery.In the setting of elevated GH and prolactin levels, one cannot assume that they are co-secreted by the same adenoma.A careful study of hormonal workup and pre-operative imaging is necessary for synchronous pituitary adenomas to assure resection of both tumors. PMID- 25298882 TI - The use of cinacalcet in pregnancy to treat a complex case of parathyroid carcinoma. AB - We present the case of a patient with metastatic parathyroid carcinoma whose hypercalcaemia was medically managed through two pregnancies. The diagnosis was made when the patient presented with chronic knee pain and radiological findings consistent with a brown tumour, at the age of 30. Her corrected calcium and parathyroid hormone (PTH) levels were significantly elevated. Following localisation studies, a right parathyroidectomy was performed with histology revealing parathyroid carcinoma, adherent to thyroid tissue. Aged 33, following biochemical recurrence of disease, the patient underwent a second operation. A subsequent CT and FDG-PET revealed bibasal pulmonary metastases. Aged 35, the patient was referred to our unit for treatment of persistent hypercalcaemia. The focus of treatment at this time was debulking metastatic disease using radiofrequency ablation. Despite advice to the contrary, the patient conceived twice while taking cinacalcet. Even though there are limited available data regarding the use of cinacalcet in pregnancy, both pregnancies continued to term with the delivery of healthy infants, using intensive medical management for persistent hypercalcaemia. LEARNING POINTS: Parathyroid carcinoma is a rare cause of primary hyperparathyroidism.Hypercalcaemia during pregnancy can result in significant complications for both the mother and the foetus.The use of high-dose cinacalcet in pregnancy has been shown, in this case, to aid in the management of resistant hypercalcaemia without teratogenicity. PMID- 25298883 TI - Histologically confirmed isolated IgG4-related hypophysitis: two case reports in young women. AB - IgG4-related hypophysitis is a recently described entity belonging to the group of IgG4-related diseases. Many other organs can also be affected, and it is more common in older men. To date, 32 cases of IgG4-related hypophysitis have been reported in the literature, 11 of which included confirmatory tissue biopsy and the majority affecting multiple organs. The aim of this report is to present two cases of biopsy-proven IgG4-related hypophysitis occurring in two young female patients with no evidence of involvement of other organs at the time of diagnosis. LEARNING POINTS: IgG4-related hypophysitis belongs to the group of IgG4-related diseases, and is a fibro-inflammatory condition characterized by dense lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells and storiform fibrosis.It is more common in older men, but young women may also present this type of hypophysitis.Although involvement of other organs is frequent, isolated pituitary disease is possible.Frequent clinical manifestations include anterior hypopituitarism and/or diabetes insipidus.THE DIAGNOSIS MAY BE CONFIRMED WITH ANY OF THE FOLLOWING CRITERIA: a pituitary biopsy with lymphoplasmacytic infiltrates, with more than ten IgG4-positive cells; a sellar mass and/or thickened pituitary stalk and a biopsy-proven involvement of another organ; a sellar mass and/or thickened pituitary stalk and IgG4 serum levels >140 mg/dl and sellar mass reduction and symptom improvement after corticosteroid treatment.Glucocorticoids are recommended as first-line therapy. PMID- 25298884 TI - Effect of Astragalus membranaceus extract on diabetic nephropathy. AB - Diabetic nephropathy, a microvascular complication of diabetes, is a progressive kidney disease caused by angiopathy of the capillaries in the kidney glomeruli. Herein, we report a case of a 62-year-old patient with a 30 year history of diabetes, who showed a substantial improvement in diabetic nephropathy on administration of 30 g of Astragalus membranaceus extract per day. After 1 month, estimated glomerular filtration rate increased from 47 to 72 ml/min per 1.73 m(2) and was subsequently maintained at the 1-month follow-up. Urinary protein levels also decreased following treatment. Herein, we present and discuss the evidence and mechanism of A. membranaceus on diabetic nephropathy in this patient. LEARNING POINTS: Diabetic nephropathy is a progressive kidney disease.Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are currently used to prevent and delay the progression of diabetic nephropathy. However, their effects are not sufficient to prevent a decline in kidney function.Furthermore, combination therapy with an ACE inhibitor and an ARB can produce adverse effects without additional benefits.In the early phase of diabetic nephropathy, administration of Astragalus membranaceus can be a therapeutic option. PMID- 25298885 TI - The dilemma of the gender assignment in a Portuguese adolescent with disorder of sex development due to 17beta-hydroxysteroid-dehydrogenase type 3 enzyme deficiency. AB - The development of male internal and external genitalia in an XY fetus requires a complex interplay of many critical genes, enzymes, and cofactors. The enzyme 17beta-hydroxysteroid-dehydrogenase type 3 (17betaHSD3) is present almost exclusively in the testicles and converts Delta 4-androstenodione (Delta4) to testosterone. A deficiency in this enzyme is rare and is a frequently misdiagnosed autosomal recessive cause of 46,XY, disorder of sex development. The case report is of a 15-year-old adolescent, who was raised according to female gender. At puberty, the adolescent had a severe virilization and primary amenorrhea. The physical examination showed a male phenotype with micropenis and blind vagina. The Tanner stage was A3B1P4, nonpalpable gonads. The karyotype revealed 46,XY. The endocrinology study revealed: testosterone=2.38 ng/ml, Delta4>10.00 ng/ml, and low testosterone/Delta4 ratio=0.23. Magnetic resonance imaging of the abdominal-pelvic showed the presence of testicles in inguinal canal, seminal vesicle, prostate, micropenis, and absence of uterus and vagina. The genetic study confirmed the mutation p.Glu215Asp on HSD17B3 gene in homozygosity. The dilemma of sex reassignment was seriously considered when the diagnosis was made. During all procedures the patient was accompanied by a child psychiatrist/psychologist. The teenager desired to continue being a female, so gonadectomy was performed. Estrogen therapy and surgical procedure to change external genitalia was carried out. In this case, there was a severe virilization at puberty. It is speculated to be due to a partial activity of 17betaHSD3 in the testicles and/or extratesticular ability to convert Delta4 to testosterone by 17betaHSD5. Prenatal exposure of the brain to androgens has increasingly been put forward as a critical factor in gender identity development, but in this case the social factor was more important for the gender assignment. LEARNING POINTS: In this case, we highlight the late diagnosis, probably because the patient belongs to a poor family without proper primary medical care.We emphasize the psychological and social aspects in the sex assignment decision. PMID- 25298886 TI - Painful fat necrosis resulting from insulin injections. AB - The case is a 34-year-old woman with long-standing type 1 diabetes mellitus with existing follow-up in the outpatient clinic at the Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, UHCW. She had maintained good glycaemic control and glycaemic stability with basal bolus regimen for many years. She had not developed any diabetes-related complications and had no other co-morbidities. Six months ago, she presented to A&E with sudden-onset, well localised and severe pain in the right iliac fossa, just lateral to the para umbilical area. Her biochemistry was normal. Ultrasound scan, however, revealed a right-sided ovarian cyst, which was thought to have caused pain to her. She was discharged from A&E with simple analgesia. On subsequent gynaecological follow-up 4 weeks later, her pain remained severe and examination revealed an exquisitely tender subcutaneous nodule at the same location measuring 2 cm in diameter. Magnetic resonance imaging (MRI) scan at the time revealed a 1 cm mass in the subcutaneous adipose tissue, which co-localised to her pain. The mass demonstrated a central fat signal surrounded by a peripheral ring: observations consistent with fat necrosis. There were other smaller subcutaneous nodules also observed in the left para-umbilical area. Subsequent surgical resection of the main area of fat necrosis was performed. The patient made an excellent recovery and her pain resolved post-operatively. Histology confirmed the presence of fat necrosis. Fat necrosis is a rare complication of s.c. insulin injection. This case illustrates the importance of considering this diagnosis in patients who inject insulin and develop localised injection-site pain. LEARNING POINTS: Fat necrosis is a rare complication of insulin injections that can manifest with severe, persistent and well-localised pain.Fat necrosis can masquerade as other pathologies causing diagnostic confusion.The imaging modality of choice for accurate diagnosis of fat necrosis is MRI.Histological confirmation of fat necrosis is important.Appropriate management of localised fat necrosis is surgical excision, with avoidance of further insulin injections into the affected area. PMID- 25298887 TI - Engaging the private sector to improve antimicrobial use in the community: experience from accredited drug dispensing outlets in Tanzania. AB - OBJECTIVES: A public-private partnership in Tanzania launched the accredited drug dispensing outlet (ADDO) program to improve access to quality medicines and pharmaceutical services in rural areas. ADDO dispensers play a potentially important role in promoting the rational use of antimicrobials, which helps control antimicrobial resistance (AMR). The study objectives were to 1) improve dispensing practices of antimicrobials, 2) build ADDO dispensers' awareness of the consequences of misusing antimicrobials, and 3) educate consumers on the correct use of antimicrobials through the use of printed materials and counseling. METHODS: Our intervention targeted ADDO dispensers and community members in Kilosa district. We promoted AMR awareness using posters hung in public places, health facilities, and ADDOs; sensitizing 84 health care providers on AMR issues; and providing training and on-site support for 124 ADDO dispensers to increase their AMR knowledge and dispensing skills. Baseline and endline assessments included direct observation of dispensers' practices; interviews with ADDO dispensers (71 at baseline and 68 at endline) regarding dispensing experiences; 230 exit interviews with ADDO customers regarding use of antimicrobials during monitoring visits; and review of ADDO records. Indicators were based on product availability, dispensing practices, customers' knowledge of how to take their medicines, and dispenser and public awareness of the AMR threat. RESULTS: Availability of tracer antimicrobials increased by 26% (p = 0.0088), and the proportion of ADDOs with unauthorized items decreased from 53% to 13% (p = 0.0001). The percentage of ADDO dispensers following good dispensing practices increased from an average of 67% in the first monitoring visit to an average of 91% during the last visit (p = 0.0001). After the intervention, more dispensers could name more factors contributing to AMR and negative consequences of inappropriate antimicrobial use, and over 95% of ADDO customers knew important information about the medicines they were dispensed. CONCLUSIONS: Providing educational materials and equipping ADDO dispensers with knowledge and tools helps significantly improve community medicine use and possibly reduces AMR. The number of community members who learned about AMR from ADDO dispensers indicates that they are an important source of information on medicine use. PMID- 25298888 TI - The clinical characteristics and surgical outcomes of epiblepharon in korean children: a 9-year experience. AB - Purpose. To examine the demographic characteristics, clinical features, surgical outcomes, and long-term prognoses of epiblepharon in Korean children. Methods. Epiblepharon patients who were followed for >= 6 month following surgical correction between January 2005 and December 2013. The patient demographics, clinical features, concomitant disorders, surgical outcomes, and complications were retrospectively reviewed. Results. A total of 768 epiblepharon records were included in the analysis. The mean patient age was 6.55 +/- 2.37 years. At presentation, 712 patients (92.8%) complained of typical epiblepharon symptoms. The mean patient age at surgery was 6.95 +/- 2.52 years, with 629 patients (81.9%) on the lower lid and 72 patients (9.4%) on the upper lid and 82 patients (10.7%) undergoing surgery on both lids. The eyelid was well everted with no recurrence in 740 patients (96.4%). Conclusion. Epiblepharon frequently occurs in Korean children and is correctable with a simple surgery. Recurrence and serious complications do not occur often, and any suspicions of epiblepharon should be investigated. A thorough ocular examination can lead to a correct diagnosis and timely corrective surgery. Most procedures are successful and prevent secondary complications that often occur with uncorrected epiblepharon. PMID- 25298889 TI - Effect of Hemodialysis on Retinal Thickness in Patients with Diabetic Retinopathy, with and without Macular Edema, Using Optical Coherence Tomography. AB - Background. Effects of hemodialysis (HD) treatment on retinal thickness and macular edema are unclear. Objective. To evaluate changes in retinal thickness using optical coherence tomography (OCT) in end stage renal disease (ESRD) patients with diabetic retinopathy (DR), with and without diabetic macular edema (DME), undergoing HD. Methods. Nonrandomized prospective study. Forty eyes of DR patients with ESRD treated with HD were divided into two groups: patients with macular edema and patients without macular edema. Both eyes were analyzed. Patients underwent an ophthalmic examination including OCT measurements of retinal thickness, blood albumin and hemoglobin A1C levels, blood pressure, and body weight, 30 minutes before and after HD. Results. We found no significant effects of HD on retinal thickness among patients both with and without DME. The former showed a trend towards reduction in retinal thickness in foveal area following HD, while the latter showed an increase. There was no correlation between retinal thickness and mean blood pressure, weight, kinetic model value Kt/V, glycemic hemoglobin, or albumin levels before and after HD. Conclusions. HD has no significant effect on retinal thickness among patients with or without DME. Further studies on larger cohorts and repeated OCT examinations are needed to confirm the preliminary findings in this study. PMID- 25298890 TI - Validity of nutritional screening tools for hospitalized children. AB - Background. Malnutrition in hospitalized children can be prevented if children with risk of malnutrition are identified. Every hospital is recommended to have a standard nutritional screening tool. Numerous simple screening tools have been developed, namely Paediatric Yorkhill Malnutrition Score (PYMS), Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP), and Screening Tool for Risk on Nutritional Status and Growth (STRONG-kids). None has been accepted as a universal tool. Our study aims to determine the best screening tools compared to Subjective Global Nutrition Assessment (SGNA), an assessment tool which is more complex as our gold standard. Methods. This diagnostic study involved 116 patients aged 1-15 years. Three screening tools and SGNA were examined to each subject. Statistical analysis was used to determine sensitivity, specificity, and likelihood ratio (LR) by results from screening tools divided into low and moderate-high risk of malnutrition compared to results from SGNA divided into no and moderate-severe malnutrition. Results. PYMS showed superior agreement to SGNA resulting in sensitivity 95.32%, specificity 76.92%, positive LR 4.13, and negative LR 0.061. STAMP resulted in sensitivity, specificity, positive LR, and negative LR, respectively, as 100%, 11.54%, 1.13, and 0 and STRONG-kids resulted in 100%, 7.7%, 1.083, and 0. Conclusion. PYMS was the most reliable screening tool. PMID- 25298891 TI - Timing of tracheotomy in mechanically ventilated critically ill morbidly obese patients. AB - Background. The optimal timing of tracheotomy and its impact on weaning from mechanical ventilation in critically ill morbidly obese patients remain controversial. Methods. We conducted a retrospective chart review of morbidly obese subjects (BMI >= 40 kg/m(2) or BMI >= 35 kg/m(2) and one or more comorbid conditions) who underwent a tracheotomy between July 2008 and June 2013 at a medical intensive care unit (ICU). Clinical characteristics, rates of nosocomial pneumonia (NP), weaning from mechanical ventilation (MV), and mortality rates were analyzed. Results. A total of 102 subjects (42 men and 60 women) were included; their mean age and BMI were 56.3 +/- 15.1 years and 53.3 +/- 13.6 kg/m(2), respectively. There was no difference in the rate of NP between groups stratified by successful weaning from MV (P = 0.43). Mortality was significantly higher in those who failed to wean (P = 0.02). A cutoff value of 9 days for the time to tracheotomy provided the best balanced sensitivity (72%) and specificity (59.8%) for predicting NP onset. Rates of NP and total duration of MV were significantly higher in those who had tracheostomy >= 9 days (P = 0.004 and P = 0.002, resp.). Conclusions. The study suggests that tracheotomy in morbidly obese subjects performed within the first 9 days may reduce MV and decrease NP but may not affect hospital mortality. PMID- 25298892 TI - An evaluation of the knowledge and utilization of the partogragh in primary, secondary, and tertiary care settings in calabar, South-South Nigeria. AB - The challenge to maternal well-being with associated maternal wastages especially in labor has remained unsurmountable across the three tiers of health care delivery in Nigeria. This study aimed to determine and compare the factors that influence utilization of the partograph in primary, secondary, and tertiary health care delivery levels in Calabar, Nigeria. This was a descriptive study, using a self-administered semistructured questionnaire on 290 consenting nonphysician obstetric care workers, purposively recruited. The mean age of the respondents was 40.25 +/- 8.68 with a preponderance of females (92.4%). Knowledge of the partograph and previous partograph training had statistically significant relationship with its utilization among respondents from the tertiary and general hospitals. The level of knowledge was higher among workers in the general hospital than those working in the university teaching hospital. Nurses/midwives in the three levels of care were significantly more knowledgeable in partograph use than other nonphysician obstetric care workers. Lack of detailed knowledge of the partograph, its nonavailability and poor staff strength in the study centers were factors militating against its ease of utilization. The authors recommend periodic in-service training and provision of partograph in labor rooms in all maternity wards in our environment. PMID- 25298893 TI - Physiological-social scores in predicting outcomes of prehospital internal patients. AB - The physiological-social modified early warning score system is a newly developed instrument for the identification of patients at risk. The aim of this study was to investigate the feasibility of using the physiological-social modified early warning score system for the identification of patients that needed prehospital emergency care. This prospective cohort study was conducted with 2157 patients. This instrument was used as a measure to detect critical illness in patients hospitalised in internal wards. Judgment by an emergency medicine specialist was used as a measure of standard. Data were analyzed by using receiver operating characteristics curves and the area under the curve with 95% confidence interval. The mean score of the physiological-social modified early warning score system was 2.71 +/- 3.55. Moreover, 97.6% patients with the score >= 4 needed prehospital emergency services. The area under receiver operating characteristic curve was 0.738 (95% CI = 0.708-0.767). Emergency medical staffs can use PMEWS >= 4 to identify those patients hospitalised in the internal ward as at risk patients. The physiological-social modified early warning score system is suggested to be used for decision-making of emergency staff about internal patients' wards in EMS situations. PMID- 25298895 TI - Understanding the Burden on Caregivers of People with Parkinson's: A Scoping Review of the Literature. AB - Caregivers are healthcare assets because they care for patients at home; however, when clinicians focus solely on patients, caregivers' needs may not be recognized. The purpose of this scoping literature review is to identify the burdens on caregivers of people with Parkinson's disease. CINAHL and PubMed databases were searched to locate thirteen original articles, one systematic review, and one meta-analysis within the last five years that highlighted caregivers' burdens. Results indicate the need to identify practical interventions that decrease caregivers' physical, psychological, and socioeconomic burdens. Correlates of Parkinson's caregiver burdens are not clearly available. Caregivers' contextual demographic information is missing, as is an understanding of how caregivers negotiate day-to-day caregiving activities. Gaps exist about how caregivers reconcile multiple medications and manage rehabilitation needs of the patient at home. A recommendation for practice is a systematic evaluation of the caregivers' capacity at the time of clinic visit. PMID- 25298894 TI - Acute effect of topical menthol on chronic pain in slaughterhouse workers with carpal tunnel syndrome: triple-blind, randomized placebo-controlled trial. AB - Topical menthol gels are classified "topical analgesics" and are claimed to relieve minor aches and pains of the musculoskeletal system. In this study we investigate the acute effect of topical menthol on carpal tunnel syndrome (CTS). We screened 645 slaughterhouse workers and recruited 10 participants with CTS and chronic pain of the arm/hand who were randomly distributed into two groups to receive topical menthol (Biofreeze) or placebo (gel with a menthol scent) during the working day and 48 hours later the other treatment (crossover design). Participants rated arm/hand pain intensity during the last hour of work (scale 0 10) immediately before 1, 2, and 3 hours after application. Furthermore, global rating of change (GROC) in arm/hand pain was assessed 3 hours after application. Compared with placebo, pain intensity and GROC improved more following application of topical menthol (P = 0.026 and P = 0.044, resp.). Pain intensity of the arm/hand decreased by -1.2 (CI 95%: -1.7 to -0.6) following topical menthol compared with placebo, corresponding to a moderate effect size of 0.63. In conclusion, topical menthol acutely reduces pain intensity during the working day in slaughterhouse workers with CTS and should be considered as an effective nonsystemic alternative to regular analgesics in the workplace management of chronic and neuropathic pain. PMID- 25298896 TI - Prevalence of hyponatremia in femur neck fractures: a one-year survey in an urban emergency department. AB - This study was aimed at investigating the prevalence of hyponatremia in patients with intracapsular femoral neck fracture. All records containing clinical and laboratory information of patients admitted with femoral neck fractures to the Academic Hospital of Parma (Italy) during the year 2013 were retrieved from the hospital database. The control population consisted of subjects admitted to the outpatient phlebotomy center during the same period. The final population consisted of 543 patients with femoral neck fractures and 700 outpatients. The category of elderly subjects (i.e., >=65 years) included 491 patients and 380 controls. In both the entire population and elderly subjects, serum sodium was lower in patients than in controls (138 versus 139 mmol/L, P < 0.001). The prevalence of hyponatremia was also higher in cases than in controls, both in the entire population (19.5 versus 10.4%, P < 0.001) and in elderly subjects (20.8 versus 11.8%, P < 0.001). The odds ratio of hyponatremia for femoral neck fracture was 2.08 in the entire study population and 1.95 in those aged 65 years and older. In conclusion, we found that hyponatremia is significantly associated with femoral neck fracture. Serum sodium should hence be regularly assessed and hyponatremia eventually corrected. PMID- 25298897 TI - SDHB-Associated Paraganglioma in a Pediatric Patient and Literature Review on Hereditary Pheochromocytoma-Paraganglioma Syndromes. AB - Pheochromocytoma and paraganglioma are rare in the pediatric population occurring in approximately 1 in 50,000 children. While some cases are sporadic, they have commonly been associated with syndromes such as von Hippel-Lindau, multiple endocrine neoplasia types IIa and IIb, neurofibromatosis type 1, and hereditary pheochromocytoma-paraganglioma syndromes. In children less than 18 years of age approximately 60% of pheochromocytomas and paragangliomas are associated with a germline mutation. We present an 11-year-old child with an abdominal paraganglioma related to a succinate dehydrogenase subunit B gene mutation whose father had a previously resected abdominal paraganglioma and was found to carry the same mutation. In addition, we review the etiology, genetics, diagnostic approach, and challenges of preoperative management of secretory pheochromocytomas and paragangliomas in children. PMID- 25298898 TI - An unusual gross appearance of vulval tuberculosis masquerading as tumor. AB - Tuberculosis of the vulva is very rare. It is found in about 0.2% of the cases of genital tract tuberculosis. It usually presents as small shallow ulcers and multiple sinus tracts or rarely as elephantiasis of vulva. Except for very rare cases of primary tuberculosis in the vulva, it is usually associated with tuberculosis elsewhere in the body leading to secondary tuberculosis. Here, we report a case of secondary vulval tuberculosis which presented as a vulval mass in a 40-year-old female patient. The rarity of this presentation in the female genital tract is emphasized. PMID- 25298899 TI - Pathological complete response and long-term survival in a very elderly patient after neoadjuvant chemotherapy for locally advanced, unresectable gastric cancer. AB - We address the pathological complete response and long-term survival of elderly patients after neoadjuvant chemotherapy in locally advanced, unresectable gastric cancer. An 83-year-old man was hospitalized for upper abdominal pain. Gastrointestinal endoscopy showed a large tumor spanning from the gastric angle to the antrum, and extending to the duodenum. Histological analysis of the biopsy specimen revealed a poorly differentiated adenocarcinoma. Computed tomography images showed thickening of the gastric wall and invasion of the body and head of the pancreas, but did not show distant metastases. The patient was diagnosed with unresectable gastric cancer, and was treated with neoadjuvant chemotherapy using S-1 (80 mg/m(2)) and paclitaxel (60 mg/m(2)). After the third course of chemotherapy, gastrointestinal endoscopy and abdominal computed tomography revealed a remarkable reduction in tumor size. This reduction allowed distal gastrectomy to be conducted. Histological examination of the specimen revealed no cancer cells in the primary lesion or lymph nodes. The patient was treated with adjuvant chemotherapy of oral tegafur-uracil (300 mg/day) for one year after surgery. He lived for five years after surgery without recurrence. Neoadjuvant chemotherapy using S-1 and paclitaxel is a potent strategy for improving survival in very elderly patients with unresectable gastric cancer. PMID- 25298900 TI - 63-year-old male with gastric outlet obstruction. AB - We describe a case of a 63-year-old male with complicated Bouveret's syndrome, both in its presentation and in its management. Bouveret's syndrome is a rare cause of gastric outlet obstruction resulting from mechanical obstruction from gallstones at the pyloroduodenal segment. As Bouveret's syndrome can be a diagnostic and therapeutic challenge for clinicians, we aim to identify clinical and radiologic pearls that can lower the threshold for the diagnosis of Bouveret's syndrome. PMID- 25298901 TI - Basal cell carcinoma of the penis: a case report and review of the literature. AB - Basal cell carcinoma of the penis is an extremely rare entity, accounting for less than 0.03% of all basal cell carcinomas. Fortunately, wide local excision of such lesions is generally curative. Fewer than 25 cases have been reported in the literature describing penile basal cell carcinoma. Here we report a case of penile basal cell carcinoma cured with wide local excision. PMID- 25298903 TI - Prophylaxis of human hydrophobia in South Korea. AB - Domestic human hydrophobia has not been reported since the one case of 2004 in South Korea, but still a few animal rabies occur persistently since the reemerging stage of rabies from 1993. The government has made efforts to control animal rabies in many aspects, but whether prophylactic strategy for human hydrophobia is performed adequately is in question. The rate of proper post exposure prophylaxis for animal bite case in 'high-risk region' of rabies is very low with 20% between 2011 and 2013. The National Animal Bite Patient Surveillance targeting 'high-risk region' is missing out animal bite cases who visit directly to hospitals in 'suspect-risk region' of rabies. Little data seems to exist for pre-exposure prophylaxis of domestic hydrophobia. Danger of reoccurrence of human hydrophobia always remain in South Korea. The medical personnel needs to have greater interest on the matter and the government strengthen the management system. PMID- 25298902 TI - Walking along the Fibroblast Growth Factor 10 Route: A Key Pathway to Understand the Control and Regulation of Epithelial and Mesenchymal Cell-Lineage Formation during Lung Development and Repair after Injury. AB - Basic research on embryonic lung development offers unique opportunities to make important discoveries that will impact human health. Developmental biologists interested in the molecular control of branching morphogenesis have intensively studied the developing lung, with its complex and seemingly stereotyped ramified structure. However, it is also an organ that is linked to a vast array of clinical problems in humans such as bronchopulmonary dysplasia in premature babies and emphysema, chronic obstructive pulmonary disease, fibrosis, and cancer in adults. Epithelial stem/progenitor cells reside in niches where they interact with specific extracellular matrices as well as with mesenchymal cells; the latter are still poorly characterized. Interactions of epithelial stem/progenitor cells with their microenvironments are usually instructive, controlling quiescence versus activation, proliferation, differentiation, and migration. During the past 18 years, Fgf10 has emerged not only as a marker for the distal lung mesenchyme during early lung development, but also as a key player in branching morphogenesis and a critical component of the niche for epithelial stem cells. In this paper, we will present the current knowledge regarding the lineage tree in the lung, with special emphasis on cell-lineage decisions in the lung mesenchyme and the role of Fgf10 in this context. PMID- 25298905 TI - Improved Hand Hygiene Compliance is Associated with the Change of Perception toward Hand Hygiene among Medical Personnel. AB - BACKGROUND: Hand hygiene compliance has improved significantly through hand hygiene promotion programs that have included poster campaign, monitoring and performance feedback, and education with special attentions to perceived subjective norms. We investigated factors associated with improved hand hygiene compliance, focusing on whether the improvement of hand hygiene compliance is associated with changed perception toward hand hygiene among medical personnel. MATERIALS AND METHODS: Hand hygiene compliance and perceptions toward hand hygiene among medical personnel were compared between the second quarter of 2009 (before the start of a hand hygiene promotion program) and the second quarter of 2012. We assessed adherence to hand hygiene among medical personnel quarterly according to the WHO recommended method for direct observation. Also, we used a modified self-report questionnaire to collect perception data. RESULTS: Hand hygiene compliance among physicians and nurses improved significantly from 19.0% in 2009 to 74.5% in 2012 (P < 0001), and from 52.3% to 91.2% (P < 0.001), respectively. These improvements were observed in all professional status or all medical specialties that were compared between two periods, regardless of the level of the risk for cross-transmission. Hand hygiene compliance among the medical personnel continued to improve, with a slight decline in 2013. Perceptions toward hand hygiene improved significantly between 2009 and 2012. Specifically, improvements were evident in intention to adhere to hand hygiene, knowledge about hand hygiene methods, knowledge about hand hygiene indications including care of a dirty and a clean body site on the same patient, perceived behavioral and subjective norms, positive attitude toward hand hygiene promotion campaign, perception of difficulty in adhering to hand hygiene, and motivation to improve adherence to hand hygiene. CONCLUSIONS: The examined hand hygiene promotion program resulted in improved hand hygiene compliance and perception toward hand hygiene among medical personnel. The improved perception increased hand hygiene compliance. Especially, the perception of being a role model for other colleagues is very important to improve hand hygiene compliance among clinicians. PMID- 25298904 TI - Therapy of Infections due to Carbapenem-Resistant Gram-Negative Pathogens. AB - The prevalence of carbapenem-resistant gram-negative bacterial pathogens (CRGNs) has increased dramatically during the last 10 years, but the optimal treatment for CRGN infections is not well established due to the relative scarcity of robust clinical data. The polymyxins remain the most consistently active agents against CRGNs in vitro. Tigecycline, based on its in vitro antibacterial spectrum, could also be considered as a therapeutic option in the treatment of infections caused by certain CRGNs. Other agents, including aminoglycosides, rifampin, trimethoprim-sulfamethoxazole, fosfomycin and fluoroquinolones, could be considered as monotherapy or combination therapy against CRGNs in appropriate contexts, as combination therapy with two or more in vitro active drugs appears to be more effective than monotherapy based on some clinical data. Several promising new agents are in late-stage clinical development, including ceftolozane-tazobactam, ceftazidime-avibactam and plazomicin. Given the shortage of adequate treatment options, containment of CRGNs should be pursued through implementation of adequate infection prevention procedures and antimicrobial stewardship to reduce the disease burden and prevent future outbreaks of CRGNs. PMID- 25298906 TI - Oral Antimicrobial Therapy: Efficacy and Safety for Methicillin-Resistant Staphylococcus aureus Infections and Its Impact on the Length of Hospital Stay. AB - BACKGROUND: Carefully switching from intravenous to oral antibiotic therapy has shown to reduce treatment costs and lengths of hospital stay as well as increase safety and comfort in patients with infections. The aim of this study was to compare the clinical efficacy and safety between the patients treated with glycopeptides (case group), and the patients given oral antibiotics, as the initial or step-down therapy (control group), in the treatment of patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. MATERIALS AND METHODS: A multicenter observational study was retrospectively performed in 7 teaching hospitals in Korea from January to December 2012. The study included adult patients (>= 18 years) with infection caused by MRSA isolates, susceptible to clindamycin, erythromycin, and ciprofloxacin. The primary end point was treatment outcome, including all-cause mortality and switching of antibiotics. Drug-related adverse events and the lengths of hospital stay were also compared between the two treatment groups. RESULTS: During the study period, 107 patients (43 cases and 64 controls) with MRSA infections were enrolled from the participating hospitals. The most common sites of MRSA infection were skin and soft tissue (n = 28) and bone and joint (n = 26). The median Charlson comorbidity index (P = 0. 560), the frequency of severe sepsis (P = 0.682) or thrombocytopenia (P = 1.000), and median level of serum C-reactive protein (P = 0.157) at the onset of MRSA infections were not significantly different between the case and control groups. The oral antibiotics most frequently prescribed in the case group, were fluoroquinolones (n = 29) and clindamycin (n = 8). The median duration of antibiotic treatment (P = 0.090) and the occurrence of drug related adverse events (P = 0.460) did not reach statistically significant difference between the two groups, whereas the total length of hospital stay after the onset of MRSA infection was significantly shorter in the case group than the control group [median (interquartile range), 23 days (8-41) vs. 32 days (15-54), P = 0.017]. In multivariate analyses, the type of antibiotic used was not an independent risk factor for treatment failure. The statistically significant factors associated with treatment failure included underlying hepatic diseases, prior receipt of antibiotics, and foreign body retention. CONCLUSIONS: This study indicates that oral antibiotic therapy with active agents against MRSA isolates can be considered as the initial or step-down therapy for the treatment of MRSA infections and also reduce the length of hospital stay. PMID- 25298907 TI - In vitro Synergism between Chloroquine and Antibiotics against Orientia tsutsugamushi. AB - BACKGROUND: To investigate whether chloroquine enhances the effect of antibiotics against Orientia tsutsugamushi, the causative organism of scrub typhus, we compared the effect of antibiotics in combination with chloroquine with the effect of antibiotics alone in vitro. MATERIALS AND METHODS: The Boryong or AFSC 4 strain was inoculated into ECV304 cells, and incubated in medium containing doxycycline (4 ug/mL), rifampin (4 ug/mL), azithromycin (0.5 ug/mL), chloroquine (1 ug/mL), and each of these antibiotics in combination with chloroquine for 7 d. Immunofluorescence (IF) staining for O. tsutsugamushi was performed 4 hr and 7 d after inoculation of the bacteria, and IF-positive foci were enumerated. RESULTS: Chloroquine inhibited the growth of O. tsutsugamushi by 15.5%. In combination with chloroquine, the antimicrobial effects increased by 4.4% for doxycycline (a 92.9% reduction of bacterial numbers for doxycycline versus a 97.3% reduction for doxycycline plus chloroquine), 4.6% for rifampin (90.0% versus 94.6%), and 8.3% for azithromycin (86.9% versus 95.2%). The antimicrobial effect of the antibiotics alone was significantly different compared to the combined effect of antibiotics and chloroquine (Wilcoxon signed-rank test, P = 0.001). CONCLUSIONS: The combined use of chloroquine with an antibiotic for the treatment of O. tsutsugamushi infections may be useful for increasing the efficacy of the antibiotics. PMID- 25298908 TI - In vitro Antagonism between Cefotaxime and Anti-Rickettsial Antibiotics against Orientia tsutsugamushi. AB - We have investigated the in vitro antimicrobial effects of antibiotic combinations against Orientia tsutsugamushi, the causative agent of scrub typhus. ECV304 cells were infected with the Boryong strain of O. tsutsugamushi and incubated in a medium containing doxycycline (4 ug/mL), azithromycin (0.5 ug/mL), rifampin (4 ug/mL), ciprofloxacin (25 ug/mL), gentamicin (5 ug/mL), cefotaxime (2 ug/mL), or combinations of these agents for 7 days, after which immunofluorescent staining for O. tsutsugamushi was performed. The percentages of infective foci in cultures containing antibiotics compared to those in cultures without antibiotics were 6.2% for doxycycline, 9.6% for azithromycin, 8.8% for rifampin, 96.6% for cefotaxime, 29.7% for doxycycline plus cefotaxime, 23.6% for azithromycin plus cefotaxime, and 41.4% for rifampin plus cefotaxime. These findings show an in vitro antagonism between anti-rickettsial agents and cefotaxime against O. tsutsugamushi. These results suggest that the efficacy of antibiotic combinations involving cefotaxime for the treatment of patients with scrub typhus, particularly those with severe pneumonia, needs to be investigated. PMID- 25298909 TI - Physician Attitudes toward the Herpes Zoster Vaccination in South Korea. AB - This survey investigated Korean physician attitudes toward the herpes zoster (HZ) vaccine. A total of 400 physicians answered a self-reported questionnaire. Most physicians knew that HZ poses a significant socioeconomic burden and had good knowledge about HZ and its vaccine. Physicians who did not recommend HZ vaccine were concerned about costs (90.7%, 78/86) and doubted the effectiveness of the vaccine (58.1%, 50/86). Patient demand had a profound effect on physicians decisions; 84.9% (73/86) of them who said not recommending HZ vaccine reported that they would provide the vaccine upon patient request. In conclusion, educational initiatives should be targeted toward both physicians and patients. PMID- 25298910 TI - A Fatal Spontaneous Gas Gangrene due to Clostridium perfringens during Neutropenia of Allogeneic Stem Cell Transplantation: Case Report and Literature Review. AB - Most cases of gas gangrene caused by Clostridium species begin with trauma related injuries but in rare cases, spontaneous gas gangrene (SGG) can occur when patients have conditions such as advanced malignancy, diabetes, or immunosuppression. Clostridium perfringens, a rare cause of SGG, exists as normal flora of skin and intestines of human. Adequate antibiotics with surgical debridement of infected tissue is the only curative therapeutic management. Mortality rate among adults is reported range of 67-100% and majority of deaths are occurred within 24 hours of onset. We experienced a case of SGG on the trunk, buttock and thigh in a neutropenic patient with acute lymphoblastic leukemia. His clinical course was rapid and fatal during pre-engraftment neutropenic period of allogeneic stem cell transplantation. PMID- 25298912 TI - Aspergillus Tracheobronchitis and Influenza A Co-infection in a Patient with AIDS and Neutropenia. AB - Aspergillus tracheobronchitis (AT), an unusual form of invasive pulmonary aspergillosis (IPA), is characterized by pseudomembrane formation, ulcer or obstruction that is predominantly confined to tracheobronchial tree. Hematologic malignancies, neutropenia, solid organ transplantation, chronic corticosteroid therapy and acquired immunodeficiency syndrome (AIDS) are known to be major predisposing conditions. However, since the introduction of highly active antiretroviral therapy, there is only one reported case of AT in AIDS patient. After pandemic of influenza A/H1N1 2009, there are several reports of IPA in patient with influenza and most of them received corticosteroid or immunosuppressive therapy before the development of IPA. We present a 45 year-old AIDS patient with influenza A infection who developed pseudomembranous AT without corticosteroid use or immunosuppressive therapy. PMID- 25298913 TI - Behavioral Perspectives toward Hand Hygiene Promotion. PMID- 25298914 TI - How do you know what you read or hear is the truth? PMID- 25298911 TI - Spontaneous Pneumomediastinum, Pneumopericardium, and Pneumothorax with Respiratory Failure in a Patient with AIDS and Pneumocystis jirovecii Pneumonia. AB - Spontaneous pneumothorax occurs in up to 35% of patients with Pneumocystis jirovecii pneumonia. However, spontaneous pneumomediastinum and pneumopericardium are uncommon complications in patients infected with human immunodeficiency virus, with no reported incidence rates, even among patients with acquired immunodeficiency syndrome (AIDS) and P. jirovecii pneumonia. We report a case of spontaneous pneumomediastinum, pneumopericardium, and pneumothorax with respiratory failure during treatment of P. jirovecii pneumonia in a patient with AIDS; the P. jirovecii infection was confirmed by performing methenamine silver staining of bronchoalveolar lavage specimens. This case suggests that spontaneous pneumomediastinum and pneumopericardium should be considered in patients with AIDS and P. jirovecii pneumonia. PMID- 25298915 TI - Transsylvian selective amygdalohippocampectomy for treatment of medial temporal lobe epilepsy: Surgical technique and operative nuances to avoid complications. AB - BACKGROUND: A number of different surgical techniques are effective for treatment of drug-resistant medial temporal lobe epilepsy. Of these, transsylvian selective amygdalohippocampectomy (SA), which was originally developed to maximize temporal lobe preservation, is arguably the most technically demanding to perform. Recent studies have suggested that SA may result in better neuropsychological outcomes with similar postoperative seizure control as standard anterior temporal lobectomy, which involves removal of the lateral temporal neocortex. METHODS: In this article, the authors describe technical nuances to improve the safety of SA. RESULTS: Wide sylvian fissure opening and use of neuronavigation allows an adequate exposure of the amygdala and hippocampus through a corticotomy within the inferior insular sulcus. Avoidance of rigid retractors and careful manipulation and mobilization of middle cerebral vessels will minimize ischemic complications. Identification of important landmarks during amygdalohippocampectomy, such as the medial edge of the tentorium and the third nerve within the intact arachnoid membranes covering the brainstem, further avoids operator disorientation. CONCLUSION: SA is a safe technique for resection of medial temporal lobe epileptogenic foci leading to drug-resistant medial temporal lobe epilepsy. PMID- 25298916 TI - Paracoccidioidomycosis simulating brain tumor. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis. Involvement of the central nervous system (CNS) occurs in about 10% of cases. CASE DESCRIPTION: A 57-year-old white man presented with the complaint of headache and an episode of focal seizure 1 month earlier. Magnetic resonance imaging (MRI) revealed a ring-enhancing lesion in the right parietal lobe with peri-lesional vasogenic edema suggestive of a primary neoplasm. The patient underwent craniotomy and the intraoperative finding was a yellowish, hard lesion with thick content and yellow inside. Anatomo pathological findings were pathognomonic of PCM: large, thick-walled, spherical yeast cells with multiple peripheral buds. The patient tested negative for human immunodeficiency virus (HIV). Encephalitis and meningitis were ruled out by cerebrospinal fluid analysis. Culture confirmed the diagnosis of PCM and the patient was treated with amphotericin B. The patient responded well to treatment with resolution of the headache and clinical improvement, despite a bitemporal hemianopia. He was clinically stable and then discharged in good general condition. CONCLUSIONS: Radiographic findings of PCM with CNS involvement may suggest neoplasia, making diagnosis difficult. In endemic areas, the diagnosis of PCM should be promptly considered when a ring-enhancing mass associated with peri lesional edema is observed on MRI. PMID- 25298917 TI - Quantitative cerebral perfusion assessment using microscope-integrated analysis of intraoperative indocyanine green fluorescence angiography versus positron emission tomography in superficial temporal artery to middle cerebral artery anastomosis. AB - BACKGROUND: Intraoperative qualitative indocyanine green (ICG) angiography has been used in cerebrovascular surgery. Hyperperfusion may lead to neurological complications after superficial temporal artery to middle cerebral artery (STA MCA) anastomosis. The purpose of this study is to quantitatively evaluate intraoperative cerebral perfusion using microscope-integrated dynamic ICG fluorescence analysis, and to assess whether this value predicts hyperperfusion syndrome (HPS) after STA-MCA anastomosis. METHODS: Ten patients undergoing STA MCA anastomosis due to unilateral major cerebral artery occlusive disease were included. Ten patients with normal cerebral perfusion served as controls. The ICG transit curve from six regions of interest (ROIs) on the cortex, corresponding to ROIs on positron emission tomography (PET) study, was recorded. Maximum intensity (IMAX), cerebral blood flow index (CBFi), rise time (RT), and time to peak (TTP) were evaluated. RESULTS: RT/TTP, but not IMAX or CBFi, could differentiate between control and study subjects. RT/TTP correlated (|r| = 0.534-0.807; P < 0.01) with mean transit time (MTT)/MTT ratio in the ipsilateral to contralateral hemisphere by PET study. Bland-Altman analysis showed a wide limit of agreement between RT and MTT and between TTP and MTT. The ratio of RT before and after bypass procedures was significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.60 +/- 0.032 and 0.80 +/- 0.056, respectively; P = 0.017). The ratio of TTP was also significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.64 +/- 0.081 and 0.85 +/- 0.095, respectively; P = 0.017). CONCLUSIONS: Time dependent intraoperative parameters from the ICG transit curve provide quantitative information regarding cerebral circulation time with quality and utility comparable to information obtained by PET. These parameters may help predict the occurrence of postoperative HPS. PMID- 25298918 TI - Value of routine early post-operative computed tomography in determining short term functional outcome after drainage of chronic subdural hematoma: An evaluation of residual volume. AB - BACKGROUND: Computed tomography (CT) scans are widely used in managing chronic subdural hematoma (CSDH). Factors that determine early post-operative volume have not been examined. The value of routine early post-operative residual volume have not been evaluated. Our study aims to compare pre-operative and early post operative CT findings to determine the factors affecting residual hematoma and evaluate if early post-operative CT scans are useful in the management of CSDH. METHODS: Forty-three patients who underwent burr hole drainage of unilateral CSDH from August 2006 to January 2013 and had routine post-operative CT scans within 48 hours of surgery were selected. Data regarding age, sex, neurological deficit, Glasgow Coma Scale (GCS), pre-existing medical conditions, use of antiplatelets or anticoagulation, operative time, usage of drains, and number of burr holes were obtained. The pre-operative CSDH volume, CSDH density, and midline shift were measured. Residual volume was calculated from early post-operative CT scans. Clinical outcome was evaluated with Glasgow Outcome Scale (GOS) at the time of discharge. Statistical analysis was performed to look for correlation between the pre-operative factors and residual volume, and the residual volume and GOS. RESULTS: Pre-operative volume was found to correlate significantly with post operative residual volume. There was no significant correlation between all other pre-operative factors and residual volume. There was also no correlation between residual volume and GOS at discharge. CONCLUSION: Routine post-operative CT brain for burr hole drainage of CSDH may be unnecessary in view of the good predictive value of pre-operative volume, and also because it is not predictive of the clinical outcome. PMID- 25298920 TI - Cytochrome P450-Mediated Phytoremediation using Transgenic Plants: A Need for Engineered Cytochrome P450 Enzymes. AB - There is an increasing demand for versatile and ubiquitous Cytochrome P450 (CYP) biocatalysts for biotechnology, medicine, and bioremediation. In the last decade there has been an increase in realization of the power of CYP biocatalysts for detoxification of soil and water contaminants using transgenic plants. However, the major limitations of mammalian CYP enzymes are that they require CYP reductase (CPR) for their activity, and they show relatively low activity, stability, and expression. On the other hand, bacterial CYP enzymes show limited substrate diversity and usually do not metabolize herbicides and industrial contaminants. Therefore, there has been a considerable interest for biotechnological industries and the scientific community to design CYP enzymes to improve their catalytic efficiency, stability, expression, substrate diversity, and the suitability of P450-CPR fusion enzymes. Engineered CYP enzymes have potential for transgenic plants-mediated phytoremediation of herbicides and environmental contaminants. In this review we discuss: 1) the role of CYP enzymes in phytoremediation using transgenic plants, 2) problems associated with wild type CYP enzymes in phytoremediation, and 3) examples of engineered CYP enzymes and their potential role in transgenic plant-mediated phytoremediation. PMID- 25298921 TI - Diagnosis and treatment of latent tuberculosis infection: an update. AB - It is estimated that more than two billion people have latent M. tuberculosis infection, and this population serves as an important reservoir for future tuberculosis cases. Prevalence estimates are limited by difficulties in diagnosing the infection, including the lack of an ideal test, and an incomplete understanding of latency. Current tests include the tuberculin skin test and two interferon-gamma release assays: QuantiFERON Gold In-Tube and T-SPOT.TB. This update focuses on recent publications regarding the ability of these tests to predict tuberculosis disease, their reproducibility over serial tests, and discordance between tests. We also discuss recent advances in the treatment of latent M. tuberculosis infection, including the three-month regimen of once weekly rifapentine plus isoniazid, and prolonged isoniazid therapy for HIV infected persons living in high-tuberculosis-incidence settings. We provide an update on the tolerability of the three-month regimen. PMID- 25298925 TI - Distribution of Intravascular and Extravascular Extracellular Volume Fractions by Total Area under Curve for Neovascularization Assessment by Dynamic Contrast Enhanced Magnetic Resonance Imaging. AB - In this paper, we propose and investigate distribution of intravascular and extravascular extracellular volume fractions (DIEEF) as a noninvasive biomarker for neovascularization assessment by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A generalized two-compartment exchange model (G2CXM) that uniformly includes the Patlak model, Tofts model, extended Tofts model, and recent two-compartment exchange model as special instances is first presented. Based on the total area under curve of the G2CXM a method of DIEEF estimation without knowing the artery input function is proposed. The mean square error of DIEEF estimate in the presence of noise and with incomplete DCE-MRI data is analyzed. Simulation results demonstrate that DIEEF estimate is accurate when signal to noise ratio is only 5 dB in both cases of tracer infusion and bolus injection, and slightly favors the bolus injection. Tested on a model of atherosclerotic rabbits, the DIEEF of aorta plaques is positively correlated with the histological neovessel count with correlation coefficient of 0.940 and P = 0.017, and outperforms six semiquantitative parameters in the literature. DIEEF might be useful as a biomarker for noninvasive neovascularization assessment by DCE-MRI. PMID- 25298927 TI - Specification and Verification of Medical Monitoring System Using Petri-nets. AB - To monitor the patient behavior, data are collected from patient's body by a medical monitoring device so as to calculate the output using embedded software. Incorrect calculations may endanger the patient's life if the software fails to meet the patient's requirements. Accordingly, the veracity of the software behavior is a matter of concern in the medicine; moreover, the data collected from the patient's body are fuzzy. Some methods have already dealt with monitoring the medical monitoring devices; however, model based monitoring fuzzy computations of such devices have been addressed less. The present paper aims to present synthesizing a fuzzy Petri-net (FPN) model to verify behavior of a sample medical monitoring device called continuous infusion insulin (INS) because Petri net (PN) is one of the formal and visual methods to verify the software's behavior. The device is worn by the diabetic patients and then the software calculates the INS dose and makes a decision for injection. The input and output of the infusion INS software are not crisp in the real world; therefore, we present them in fuzzy variables. Afterwards, we use FPN instead of clear PN to model the fuzzy variables. The paper follows three steps to synthesize an FPN to deal with verification of the infusion INS device: (1) Definition of fuzzy variables, (2) definition of fuzzy rules and (3) design of the FPN model to verify the software behavior. PMID- 25298926 TI - An Automatic Algorithm for Segmentation of the Boundaries of Corneal Layers in Optical Coherence Tomography Images using Gaussian Mixture Model. AB - Diagnosis of corneal diseases is possible by measuring and evaluation of corneal thickness in different layers. Thus, the need for precise segmentation of corneal layer boundaries is inevitable. Obviously, manual segmentation is time-consuming and imprecise. In this paper, the Gaussian mixture model (GMM) is used for automatic segmentation of three clinically important corneal boundaries on optical coherence tomography (OCT) images. For this purpose, we apply the GMM method in two consequent steps. In the first step, the GMM is applied on the original image to localize the first and the last boundaries. In the next step, gradient response of a contrast enhanced version of the image is fed into another GMM algorithm to obtain a more clear result around the second boundary. Finally, the first boundary is traced toward down to localize the exact location of the second boundary. We tested the performance of the algorithm on images taken from a Heidelberg OCT imaging system. To evaluate our approach, the automatic boundary results are compared with the boundaries that have been segmented manually by two corneal specialists. The quantitative results show that the proposed method segments the desired boundaries with a great accuracy. Unsigned mean errors between the results of the proposed method and the manual segmentation are 0.332, 0.421, and 0.795 for detection of epithelium, Bowman, and endothelium boundaries, respectively. Unsigned mean errors of the inter-observer between two corneal specialists have also a comparable unsigned value of 0.330, 0.398, and 0.534, respectively. PMID- 25298928 TI - The emotion recognition system based on autoregressive model and sequential forward feature selection of electroencephalogram signals. AB - Electroencephalogram (EEG) is one of the useful biological signals to distinguish different brain diseases and mental states. In recent years, detecting different emotional states from biological signals has been merged more attention by researchers and several feature extraction methods and classifiers are suggested to recognize emotions from EEG signals. In this research, we introduce an emotion recognition system using autoregressive (AR) model, sequential forward feature selection (SFS) and K-nearest neighbor (KNN) classifier using EEG signals during emotional audio-visual inductions. The main purpose of this paper is to investigate the performance of AR features in the classification of emotional states. To achieve this goal, a distinguished AR method (Burg's method) based on Levinson-Durbin's recursive algorithm is used and AR coefficients are extracted as feature vectors. In the next step, two different feature selection methods based on SFS algorithm and Davies-Bouldin index are used in order to decrease the complexity of computing and redundancy of features; then, three different classifiers include KNN, quadratic discriminant analysis and linear discriminant analysis are used to discriminate two and three different classes of valence and arousal levels. The proposed method is evaluated with EEG signals of available database for emotion analysis using physiological signals, which are recorded from 32 participants during 40 1 min audio visual inductions. According to the results, AR features are efficient to recognize emotional states from EEG signals, and KNN performs better than two other classifiers in discriminating of both two and three valence/arousal classes. The results also show that SFS method improves accuracies by almost 10-15% as compared to Davies-Bouldin based feature selection. The best accuracies are %72.33 and %74.20 for two classes of valence and arousal and %61.10 and %65.16 for three classes, respectively. PMID- 25298929 TI - A novel method based on learning automata for automatic lesion detection in breast magnetic resonance imaging. AB - Breast cancer continues to be a significant public health problem in the world. Early detection is the key for improving breast cancer prognosis. In this way, magnetic resonance imaging (MRI) is emerging as a powerful tool for the detection of breast cancer. Breast MRI presently has two major challenges. First, its specificity is relatively poor, and it detects many false positives (FPs). Second, the method involves acquiring several high-resolution image volumes before, during, and after the injection of a contrast agent. The large volume of data makes the task of interpretation by the radiologist both complex and time consuming. These challenges have led to the development of the computer-aided detection systems to improve the efficiency and accuracy of the interpretation process. Detection of suspicious regions of interests (ROIs) is a critical preprocessing step in dynamic contrast-enhanced (DCE)-MRI data evaluation. In this regard, this paper introduces a new automatic method to detect the suspicious ROIs for breast DCE-MRI based on region growing. The results indicate that the proposed method is thoroughly able to identify suspicious regions (accuracy of 75.39 +/- 3.37 on PIDER breast MRI dataset). Furthermore, the FP per image in this method is averagely 7.92, which shows considerable improvement comparing to other methods like ROI hunter. PMID- 25298930 TI - Right ventricle functional parameters estimation in arrhythmogenic right ventricular dysplasia using a robust shape based deformable model. AB - Assessment of cardiac right-ventricle functions plays an essential role in diagnosis of arrhythmogenic right ventricular dysplasia (ARVD). Among clinical tests, cardiac magnetic resonance imaging (MRI) is now becoming the most valid imaging technique to diagnose ARVD. Fatty infiltration of the right ventricular free wall can be visible on cardiac MRI. Finding right-ventricle functional parameters from cardiac MRI images contains segmentation of right-ventricle in each slice of end diastole and end systole phases of cardiac cycle and calculation of end diastolic and end systolic volume and furthermore other functional parameters. The main problem of this task is the segmentation part. We used a robust method based on deformable model that uses shape information for segmentation of right-ventricle in short axis MRI images. After segmentation of right-ventricle from base to apex in end diastole and end systole phases of cardiac cycle, volume of right-ventricle in these phases calculated and then, ejection fraction calculated. We performed a quantitative evaluation of clinical cardiac parameters derived from the automatic segmentation by comparison against a manual delineation of the ventricles. The manually and automatically determined quantitative clinical parameters were statistically compared by means of linear regression. This fits a line to the data such that the root-mean-square error (RMSE) of the residuals is minimized. The results show low RMSE for Right Ventricle Ejection Fraction and Volume (<= 0.06 for RV EF, and <= 10 mL for RV volume). Evaluation of segmentation results is also done by means of four statistical measures including sensitivity, specificity, similarity index and Jaccard index. The average value of similarity index is 86.87%. The Jaccard index mean value is 83.85% which shows a good accuracy of segmentation. The average of sensitivity is 93.9% and mean value of the specificity is 89.45%. These results show the reliability of proposed method in these cases that manual segmentation is inapplicable. Huge shape variety of right-ventricle led us to use a shape prior based method and this work can develop by four-dimensional processing for determining the first ventricular slices. PMID- 25298931 TI - A new seeded region growing technique for retinal blood vessels extraction. AB - Distribution of retinal blood vessels (RBVs) in retinal images has an important role in the prevention, diagnosis, monitoring and treatment of diseases, such as diabetes, high blood pressure, or heart disease. Therefore, detection of the exact location of RBVs is very important for Ophthalmologists. One of the frequently used techniques for extraction of these vessels is region growing based Segmentation. In this paper, we propose a new region growing (RG) technique for RBVs extraction, called cellular automata-based segmentation. RG techniques often require manually seed point selection, that is, human intervention. However, due to the complex structure of vessels in retinal images, manual tracking of them is very difficult. Therefore, to make our proposed technique full automatic, we use an automatic seed point selection method. The proposed RG technique was tested on Digital Retinal Images for Vessel Extraction database for three different initial seed sets and evaluated against the manual segmentation of retinal images available at this database. Three quantitative criteria including accuracy, true positive rate and false positive rate, were considered to evaluate this method. The visual scrutiny of the segmentation results and the quantitative criteria show that, using cellular automata for extracting the blood vessels is promising. However, the important point at here is that the correct initial seeds have an effective role on the final results of segmentation. PMID- 25298932 TI - Study of a new design of p-N semiconductor detector array for nuclear medicine imaging by monte carlo simulation codes. AB - Gamma camera is an important apparatus in nuclear medicine imaging. Its detection part is consists of a scintillation detector with a heavy collimator. Substitution of semiconductor detectors instead of scintillator in these cameras has been effectively studied. In this study, it is aimed to introduce a new design of P-N semiconductor detector array for nuclear medicine imaging. A P-N semiconductor detector composed of N-SnO2 :F, and P-NiO:Li, has been introduced through simulating with MCNPX monte carlo codes. Its sensitivity with different factors such as thickness, dimension, and direction of emission photons were investigated. It is then used to configure a new design of an array in one dimension and study its spatial resolution for nuclear medicine imaging. One dimension array with 39 detectors was simulated to measure a predefined linear distribution of Tc(99_m) activity and its spatial resolution. The activity distribution was calculated from detector responses through mathematical linear optimization using LINPROG code on MATLAB software. Three different configurations of one-dimension detector array, horizontal, vertical one sided, and vertical double-sided were simulated. In all of these configurations, the energy windows of the photopeak were +/- 1%. The results show that the detector response increases with an increase of dimension and thickness of the detector with the highest sensitivity for emission photons 15-30 degrees above the surface. Horizontal configuration array of detectors is not suitable for imaging of line activity sources. The measured activity distribution with vertical configuration array, double-side detectors, has no similarity with emission sources and hence is not suitable for imaging purposes. Measured activity distribution using vertical configuration array, single side detectors has a good similarity with sources. Therefore, it could be introduced as a suitable configuration for nuclear medicine imaging. It has been shown that using semiconductor P-N detectors such as P-NiO:Li, N-SnO2 :F for gamma detection could be possibly applicable for design of a one dimension array configuration with suitable spatial resolution of 2.7 mm for nuclear medicine imaging. PMID- 25298933 TI - Prevention and management of type 2 diabetes: Potential role of genomics. PMID- 25298934 TI - A study of calcaneal enthesophytes (spurs) in Indian population. AB - INTRODUCTION: Calcaneus or os calcis forms a major component of the skeleton of foot providing posterior pillars for bony arches of the foot. It is largest of seven tarsal bones of foot and forms prominence of heel. Many times anterior to calcaneal tuberosity an osteophytic outgrowth has been observed (calcaneal or heel spur) extending along entire width, for about 2-2.5 cm. The apex of spur seen embedded in plantar fascia, directly anterior to its origin. Hence, the study of calcaneal spurs has been undertaken. MATERIALS AND METHODS: The material for the study consisted of 200 dry (100 right and 100 left), adult calcanei of unknown age and sex obtained from Department of Anatomy. The calcaneal enthesophytes/spurs were studied in detail and classified according to types of calcaneum. RESULTS: Maximum incidence of calcaneal spurs were found in Type I calcanei (11%) and no calcaneal spurs were found in Type III calcanei. Total incidence of dorsal calcaneal spurs in all types of calcanei was maximal (15.5%). The incidence of plantar spurs was 6.5% being highest in Type I calcanei (4%). The incidence and type of calcaneal spurs were compared with those of previous studies and etiology of heel pain has been discussed. Correlation between type of calcanei and spurs has been studied for the 1(st) time. CONCLUSION: Calcaneal spurs are related to type of calcanei with the highest frequency in Type I and least in Type III (no spurs seen in Type III and least in Type IV). Other factors, which contribute toward increase in incidence of spurs, are increasing age and weight, concurrent orthopedic diseases, and heel pain. PMID- 25298935 TI - A change in the management of intractable obstetrical hemorrhage over 15 years in a tertiary care center. AB - CONTEXT: Peripartum hysterectomy was the gold standard to save a woman with persistent obstetrical bleeding, but compromised the menstrual and reproductive functions. Bilateral internal iliac artery ligation (BIAL) is a potentially effective, fertility preserving means of controlling pelvic hemorrhage, but with surgical and anesthetic risks and low success. Angiographic embolization has the potential to arrest severe pelvic hemorrhage without removing the uterus and without hazarding general anesthesia in a hemodynamically unstable patient. AIMS: The aim of this study is to discuss change in the management of intractable obstetrical hemorrhage from removing to conserving the uterus over 15 years. SETTINGS AND DESIGN: A retrospective analysis of 122 cases of intractable obstetrical hemorrhage over a period of 15 years (January 1997 to December 2011) was done. We started uterine artery embolization (UAE) in 2007 for obstetrical hemorrhage. The patients were analyzed for maternal characteristics, indications, treatment modality, maternal morbidity, and mortality. STATISTICAL ANALYSIS USED: Descriptive. RESULTS: We analyzed 12,055 deliveries, (6029 cesarean sections; 6026 vaginal deliveries). One hundred and twenty-two cases of intractable obstetrical hemorrhage were managed with obstetrical hysterectomies in 63, UAE in 53 cases and BIAL in six cases. During the period between 1997 and 2006 intractable obstetrical hemorrhage was managed by hysterectomy/internal iliac artery ligation. The last 5 years of the study period had 80 patients with intractable obstetrical hemorrhage, 53 patients underwent arterial embolization and 35 had a hysterectomy and two had internal artery ligation. There was no mortality and significantly less morbidity in embolization group in our study. CONCLUSIONS: Embolization should be tried in patients with intractable obstetrical hemorrhage before proceeding for surgical intervention. PMID- 25298936 TI - Intricacy of missing data in clinical trials: Deterrence and management. AB - Missing data is frequently encountered in clinical studies. Unfortunately, they are often neglected or not properly handled during data analysis and this may significantly bias the results of the study, reduce study power and lead to invalid conclusions. Substantial instances of missing data are a serious problem that undermines the scientific trustworthiness of causal conclusions from clinical trials. The assumption that statistical analysis methods can compensate for such missing data is not justified. Hence aspects of clinical trial design that limit the probability of missing data should be an important objective, while planning a clinical trial. In addition to specific aspects of trial design, many components of clinical trial conduct can also limit the extent of missing data. The topic of missing data is often not a major concern until it is time for data collection and data analysis. This article discusses some basic issues about missing data as well as prospective "watch outs" which could reduce the occurrence of missing data. It provides some possible design considerations that should be considered in order to alleviate patients from dropping out of a clinical trial. In addition to these the concept of the missing data mechanism has also been discussed. Three types of missing data mechanisms missing completely at random, missing at random and not missing at random have been discussed in detail. PMID- 25298937 TI - Evaluation of the anti-proliferative and cytostatic effect of Citrus sinensis (orange) fruit juice. AB - AIM: This work has been designed to evaluate the anti-proliferative and cytostatic effects of Citrus sinensis (orange) fruit juice on rapidly proliferating cells. MATERIALS AND METHODS: The study was carried out on the seeds of Sorghum bicolor for 72 h. The mean radicle length (mm) of the seeds was taken at 48 and 72 h. RESULT: The result showed that when compared with the control, methotrexate, the standard drug showed a significant (P < 0.001) anti proliferative effect throughout the experiment. The inhibition of the radicle growth was more after 72 h (87.42%). At a dose of 5% (v/v), the juice showed a slightly significant (P < 0.05) effect affect after 72 h; however, there was no significant effect at 48 h. The juice at doses of 10% and 20% (v/v) showed a highly significant (P < 0.001) anti-proliferative effect throughout the experiment; however, the percentage inhibitions were higher at 72 h. At 72 h, the percentage inhibition for juice at 10% (v/v) was 72.37% and at 20% (v/v) was 91.96%. The concentrations of 40% and 60% (v/v) showed cytostatic effects as no appreciable growth of the radicles of the seeds was observed throughout the experiment. The percentage inhibition for 40% (v/v) was 100% and 99.72% for 48 and 72 h, respectively, while that for the juice concentration of 60% (v/v) was 100% throughout the study. CONCLUSION: The experiment has shown that C. sinensis fruit juice has a potential for causing both anti-proliferative and cytostatic effects on fast proliferating cells and hence cancerous cells. PMID- 25298938 TI - Infected pseudoaneurysms in intravenous drug abusers: Ligation or reconstruction? AB - BACKGROUND: Infected pseudoaneurysm in intravenous (IV) drug abusers is a serious clinical problem, with difficult and controversial management. With existing controversies regarding their optimal management, we present the results of simple ligation and local debridement for treatment of infected pseudoaneurysms. PATIENTS AND METHODS: Records of 72 consecutive patients with pseudoaneurysms in IV drug abusers over the last 20 years were reviewed retrospectively. RESULTS: Ligation and excision of pseudoaneurysm was done in all patients with delayed revascularization in only two patients. Four patients had amputations because they had gangrenous limbs on presentation. All other patients had healthy limbs at the time of discharge. There were three deaths, two due to sepsis with multiorgan dysfunction and one with hemorrhagic shock. CONCLUSION: Infected pseudoaneurysm should be managed by simple ligation of involved artery with delayed revascularization, if required. PMID- 25298940 TI - Composite alginate hydrogel microparticulate delivery system of zidovudine hydrochloride based on counter ion induced aggregation. AB - AIM: The present study deals with preparation of zidovudine loaded microparticle by counter ion induced aggregation method. During this study effect of polyacrylates and hypromellose polymers on release study were investigated. MATERIALS AND METHODS: The ion induced aggregated alginate based microparticles were characterized for surface morphology, particle size analysis, drug entrapment study, in-vitro study, Fourier-transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC) study. RESULTS AND DISCUSSION: The result showed Eudragit RL-100 (ERL) based formulations had smoother surface as well as their mean particle sizes were found greater compared with Eudragit RS 100 (ERS) microparticles. Furthermore, drug entrapments were found to be more in ERL formulae as compared with ERS. RL3 released 101.05% drug over a period of 8(th) h and followed Higuchi profile and Fickian diffusion. Moreover, data obtained illustrated that, higher amount of quaternary ammonium group, alkali value, and glass transition temperature may be possible reason for improving permeability of ERL based formulations. It was also noticed, hyroxypropyl methylcellulose (HPMC) K4M premium grade polymer sustained drug release more than HPMC K15M. In addition, drug-excipient interaction study was carried out by FTIR and DSC study. PMID- 25298939 TI - Inhibition of biofilm formation and lipase in Candida albicans by culture filtrate of Staphylococcus epidermidis in vitro. AB - BACKGROUND: Candida spp. are fourth most common cause of bloodstream infection in developed countries and emerging agents of fungemia in developing countries, with considerable attributable mortality. Candidemia is associated with the formation of complex, structured microbial communities called biofilms. Biofilm formation makes treatment difficult due to improper drug penetration and factors like high cost and adverse effects of antifungal drugs available. Hence, low-cost alternatives are urgently required to treat device-associated invasive candidiasis. OBJECTIVES: To study the effect of culture filtrate of Staphylococcus epidermidis on biofilm formation and lipase expression of Candida albicans in vitro. MATERIALS AND METHODS: Yeast cells isolated from clinical samples were suspended to a turbidity of 10(6) in (a) Yeast extract-peptone dextrose (YPD) broth and (b) culture filtrate, and 100 MUl of each were dispensed in separate wells of microtiter plate. After repeated washing and reloading with respective liquid media, readings were taken spectrophotometrically. To check for lipase inhibition, yeasts were incubated overnight in YPD and filtrate and subcultured on media containing Tween-80 and CaCl2. Positive lipase activity was denoted by haziness around colonies. RESULTS: Mean reading of C. albicans in YPD broth was 0.579 while the same when yeasts were suspended in S. epidermidis culture filtrate was 0.281 (P < 0.05 by Z-test of significance). Lipase of C. albicans was inhibited by culture filtrate. Filtrate was found to be nontoxic to human cell line. CONCLUSIONS: Culture filtrate of S. epidermidis can hence pave the way for development of new strategies to inhibit biofilm formation in device associated candidemia. PMID- 25298941 TI - Oxidative stress indices in Nigerian pesticide applicators and farmers occupationally exposed to organophosphate pesticides. AB - BACKGROUND: Reports have clearly indicated the role of oxidative stress in the pathogenesis of organophosphate pesticides (Op) toxicity. However, there is dearth of information on which group of the farm workers is more at risk of Op induced oxidative stress. AIM: This study determined serum levels of malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), myeloperoxidase (MPO), nitric oxide (NO), and serum activity of acetylcholinesterase (AChE) in farm workers exposed to Op. SUBJECTS AND METHODS: A total of 60 (30 pesticide applicators and 30 farmers) and 30 apparently healthy non-farmers who were nonexposed to Op (controls) were recruited into this study. Serum activity of AChE was determined using high performance liquid chromatography (HPLC), while serum levels of MDA, GSH, and NO and serum activities of CAT, MPO, GPx, and superoxide dismutase (SOD) were determined colorimetrically. RESULTS: Serum activities of AChE and CAT were significantly lower, whereas MPO activity was significantly higher in pesticide applicators compared with controls. Similarly, farmers had significantly reduced serum AChE activity and significantly raised MPO activity compared with controls. However, serum activities of AChE, CAT, and MPO were significantly lower, whereas mean level of MDA was significantly higher in pesticide applicators compared with farmers. CONCLUSION: This study shows that Op applicators are more exposed to oxidative stress than farmers, thus Op applicators require increased antioxidant supplements than farmers. PMID- 25298942 TI - Correlation of insulin resistance by various methods with fasting insulin in obese. AB - BACKGROUND: Several studies indicate that obesity is closely related to insulin resistance (IR). However, this relationship has not been adequately explored. AIMS: This study aims to evaluate the prevalence of IR among obese using some indirect methods for assessment of IR. MATERIALS AND METHODS: We analyzed the correlation of fasting insulin (FI) with body mass index. We examined 100 obese and overweight. Anthropometric measurements were done for all individuals. Blood lipids parameters, glucose, and insulin were assayed after a 10 h fast. The indices McAuley (McA), homeostasis model assessments (HOMA), quantitative insulin sensitivity check index (QUICKI) were used to assess IR. RESULTS: In this study, the correlations of FI with McA, HOMA and QUICKI were significant (P < 0.05). FI test had significant sensitivity and specificity when compared with McA, HOMA and QUICKI indices. FI gives parallel results to the assessment of IR by other methods. Validity of FI was further analyzed by Cohen's kappa test and had a satisfactory agreement (chi =0.940). CONCLUSION: Altogether, this study suggested that FI was sensitive and also specific as McA in assessment of IR in obese. Thus, FI can be used as an easy test to detect IR also in obese. PMID- 25298944 TI - Extranodal anaplastic large cell lymphoma mimicking sarcoma: A report of an interesting case. AB - Lymphomas are malignancies of the lymphoid tissues involving cells of the immune system. Primary systemic anaplastic large cell lymphoma (ALCL) represents an aggressive lymphoma characterized by neoplastic proliferation of lymphoid cells with an anaplastic appearance. Large pleomorphic cells are "hallmark" cells with horseshoe-shaped or kidney-shaped nuclei and a constant expression of the CD30 molecule on all neoplastic cells. There is a vast morphological spectrum posing a challenge to pathologists in the diagnosis of ALCL. PMID- 25298943 TI - The effectiveness of diclofenac gel and eutectic mixture of local anesthetic cream on vein puncture pain severity with vein catheter in patient undergoing cesarean section: A randomized, double-blind, placebo-controlled trial. AB - AIM: This study was aimed to explore the effect of applying diclofenac gel and a eutectic mixture of local anesthetic (EMLA) cream on vein puncture pain severity with vein catheter in the patients undergoing cesarean section. MATERIALS AND METHODS: The sample comprised 90 women undergoing elective cesarean section that referred to Imam Ali Hospital's maternity section in Amol city (Northern Iran). Data collection tools included visual analog scale for pain severity and a checklist for short term possible side-effects of diclofenac gel, EMLA cream and Vaseline ointment as placebo. RESULTS: The pain of vein puncture with diclofenac gel and EMLA cream was significantly lower than that with the Vaseline ointment (P = 0.001). Similarly, there was a significant difference between using diclofenac gel and EMLA cream in catheter insertion pain severity (P = 0.006). In addition, there was no short term possible side-effect with using diclofenac gel and Vaseline ointment, but a short term side-effect (blanching) was detected in 20% of subjects with EMLA cream. CONCLUSION: Compared to Vaseline cream, EMLA cream and diclofenac gel application significantly reduces the pain severity associated with vein catheter insertion. Use of diclofenac gel is preferred compared with EMLA cream, because of economics, more efficiency purpose, and no side-effects. PMID- 25298945 TI - Desmoplastic ameloblastoma. AB - Desmoplastic ameloblastoma is a relatively rare variety of ameloblastoma and only very few cases have been reported so far. The present case is an elderly man who had reported with a swelling in the anterior mandible which turned up to be desmoplastic ameloblastoma. Proper diagnosis is necessary to report such a case, so that the actual incidence can be noted. PMID- 25298946 TI - Sub mucous cleft palate with fenestration. AB - Congenital fenestration in sub mucous cleft palate is not a common identity. This patient is a 16-year-old female who presented with nasal speech. On examination, she had associated microform cleft lip with nasal deformity. Successful palatoplasty with intra velar veloplasty was done. PMID- 25298947 TI - Eventration of diaphragm with dextrocardia and type 2 respiratory failure: A rare entity. AB - Eventration of the diaphragm is a rare condition where the muscle is permanently elevated, but retains its continuity and attachments to costal margin. In this condition, all or part of the diaphragm is largely composed of fibrous tissue with a few or no interspersed muscle fibers. It can be complete or partial. It is seldom symptomatic and often requires no treatment. We present a 70-year-old male who came with progressive breathlessness and was admitted with type 2 respiratory failure, and on evaluation was found to have complete eventration of the left diaphragm with herniation of colon and stomach in the left chest with dextrocardia. Aim of reporting this rare case is to highlight the importance of history taking, good physical examination, and imaging in the diagnosis of diaphragmatic eventration. PMID- 25298948 TI - Missing data in clinical trials: Pitfalls and remedies. PMID- 25298949 TI - Dentigerous cyst in association with impacted inverted mesiodens: Report of a rare case with a brief review of literature. AB - Dentigerous cyst is a developmental odontogenic cyst, which develops due to fluid accumulation between the reduced enamel epithelium and unerupted tooth crown. The condition is frequently seen with the permanent dentition, usually associated with impacted mandibular third molars and maxillary canines. Rarely, dentigerous cyst occurs in association with a supernumerary tooth. Pain, swelling, and facial asymmetry are occasionally seen; however, they are usually asymptomatic and observed during radiographic examination. Early diagnosis and treatment planning entails thorough history taking, clinical and radiographic examination coupled with histopathology. This article reports an unusual occurrence of dentigerous cyst of anterior maxillary region seen with an inverted impacted mesiodens cyst enucleation along with extraction of the mesiodens was carried out and no complications were observed during the follow-up. PMID- 25298950 TI - Transfusion support in patients with dengue fever. AB - Dengue fever has emerged as a global public health problem in the recent decades. The clinical spectrum of the disease ranges from dengue fever to dengue hemorrhagic fever and dengue shock syndrome. The disease is characterized by increased capillary permeability, thrombocytopenia and coagulopathy. Thrombocytopenia with hemorrhagic manifestations warrants platelet transfusions. There is lack of evidence-based guidelines for transfusion support in patients with dengue fever. This contributes to inappropriate use of blood components and blood centers constantly face the challenge of inventory management during dengue outbreaks. The current review is aimed to highlight the role of platelets and other blood components in the management of dengue. The review was performed after searching relevant published literature in PubMed, Science Direct, Google scholar and various text books and journal articles. PMID- 25298951 TI - Childhood obesity-an insight into preventive strategies. AB - Childhood obesity is now a global problem throughout the world. The major factors affecting weight regulation and the development of obesity in children are the result of a large number of biological, behavioral, social, environmental, and economic factors and the complex interactions between them that promote a positive energy balance. The changes in the dietary habits with the adoption of sedentary life style increases manifold obesity-related diseases and their complications. An obese child later on grows up to become an obese adult. Therefore, the role of primary prevention along with methodical diet control, behavioral changes, and physical activity are the important strategies against the battle of childhood obesity. PMID- 25298952 TI - Epidemiology and clinical findings of colorectal carcinoma in two tertiary care hospitals in Benghazi, Libya. AB - AIM: The aim is to determine the pattern of patients with colorectal cancer (CRC) seen in two tertiary hospitals in Benghazi, Libya. MATERIALS AND METHODS: The cohort includes all patients of CRC who were presented between January 2007 and December 2009 to the Oncology Department, Aljomhoria Hospital and 7(th) October Hospital, Benghazi. Patient's age, gender, clinical presentation, location of cancer involvement, and histopathologic diagnosis were reviewed. Tumor staging was carried out according to Astler Coller modification of Duke's system, dividing it into stage A to C depending upon the extent of local involvement and regional node spread. Stage D was added to account for distant metastasis in accordance with Turnbull modification. RESULTS: A total of 152 patients with CRC were included, 84 males (55%) and 68 females (45%) with a male to female ratio of 1.2:1.0. The mean age was 57.4 +/- 12.92 years (range 21-87 years). 18 (11.8%) patients were below 40 years of age. The most common presenting symptoms were rectal bleeding and abdominal pain and were together present in 71% of the patients. The majority (67.8%) of tumors arise from rectum and sigmoid colon. More than one-third of the patients had poorly differentiated adenocarcinoma. Sixty patients (39.5%) presented in stage D, whereas 30.9% (47/152) and 29.6% (45/152) of patients were in stage B and stage C, respectively. None of the patients had stage A at presentation. The radiological evaluation showed presence of liver metastasis in 14 patients (9.2%) and pulmonary metastasis in two patients (1.3%). Anemia was found in 56 patients (36.8%). It was more common in females (P = 0.01) and in the right sided tumors (66.7%) than left sided tumors (29.5%) (P = 0.001). CONCLUSION: The majority of CRC patients in Benghazi were diagnosed in locally advanced or metastatic stage. In order to achieve early detection of CRC, a comprehensive cancer education program and screening of high risk population for CRC should be considered in this part of Libya. PMID- 25298953 TI - An unusual cause of abdominal pain in a male patient: Endometriosis. AB - A rare case of abdominal pain secondary to endometriosis in a 52-year-old man with cirrhosis is presented. The patient had a repair of recurrent inguinal hernia 7 months prior to presentation. An exploratory laparotomy revealed a 4.5 cm * 2.5 cm cystic mass attached to the urinary bladder and the inguinal area. The mass pathology showed a cystic lumen of diameter of 1.5 cm filled with old blood and surrounded by thick muscular mass. Microscopically, the lesion consisted of thick smooth muscle fibers that concentrically surround a central lumen that is bordered by endometrium such as glands and stroma. Immunostains were positive for estrogen receptors and progesterone receptors in the glandular component and for CD10 in the stroma, which is consistent with endometriosis. PMID- 25298954 TI - Unique mitral valve mass: Think beyond vegetation. AB - Osteosarcoma is a rare cardiac malignant tumor. This case of cardiac osteosarcoma presented with atrial fibrillation. Initial echocardiogram demonstrated mitral valve echodensity and mitral valve regurgitation. Surgery and histopathological examination identified the tumor as an osteosarcoma. Tumor grade appeared to be prognostically important in cardiac sarcoma, with poor prognosis in high-grade tumors. PMID- 25298955 TI - Central line placement may terminate ventricular tachycardia! PMID- 25298956 TI - Portomesenteric thrombosis and hypertension in Klippel-Trenaunay syndrome. PMID- 25298957 TI - Liquid base cytology in evaluation of thyroid nodules. AB - BACKGROUND: Palpable thyroid nodules are present in 4-7% of general population and Fine Needle Aspiration (FNA) is now accepted by endocrinologists and thyroid surgeons as a safe, simple and cost effective procedure for evaluating a thyroid nodule. The obtained sample can be spread directly on slides, processed as cell block preparations or prepared as liquid base smears. Liquid base method has been recently accepted due to its shorter preparation time and better preservation of nuclear details. The aim of this study is to compare the diagnostic results of two commonly used methods: Liquid Base Preparation and Cell Block Preparation in evaluation of thyroid nodules. METHODS: The samples were taken from 100 patients with a solitary nodule or a prominent nodule on a multinodular goiter background (excluding hot nodules). The obtained samples were used to prepare conventional smears (CS), Cell Block Preparations (CBP) and Liquid Base Preparations (LBP). The slides were studied by two pathologists, considering the following parameters: Cellularity, Colloid, Lymphocytes/Plasma cells and Macrophages. RESULTS: 87% of cases revealed informative results in LBP method while in the same group of patients only 69% of samples were informative after processing by CBP method. Sensitivity and specificity of both methods compared with the conventional smears and with each other and it is concluded that LBP is a reliable method for evaluating of a thyroid nodule. Other studies also show the same results. CONCLUSION: The liquid base method should be trusted due to its easier procedure, cleaner slide background, its higher specificity and higher diagnostic yields. It can be used instead of CBP and in association with CS to increase the accuracy of evaluation of thyroid nodules. PMID- 25298958 TI - N-acetyl cysteine as an adjunct to standard anti-Helicobacter pylori eradication regimen in patients with dyspepsia: A prospective randomized, open-label trial. AB - BACKGROUND: Increasing antibiotic resistance of Helicobacter pylori (H. pylori) which is associated with diseases of the upper gastrointestinal tract, has made alternative treatments necessary. This study compares the efficacy of adding N acetyl cysteine (NAC) to standard regimen for H. pylori eradication. MATERIALS AND METHODS: We conducted a randomized, open-label trial, comparing the efficacy of 14 days of quadruple therapy with Amoxicillin, Bismuth citrate, Omeprazole, Clarithromycin (group A) versus 14 days of above regimen plus NAC (group B) in adult patients with dyspepsia. Primary objective was H. pylori eradication. Compliance and side effects were determined by questionnaires. Our analysis was by intention-to-treat (ITT) and per-protocol. This study is registered with www.IRCT.ir, number: IRCT201201078634N1. RESULT: A total of 121 participants aged 21-76 years with a mean age of 44.5 +/- 14.1, and 52.9% female, were randomly allocated a treatment: 60 with 14-day standard therapy and 61 with 14-day standard therapy with NAC. The eradication rate in groups A and B with ITT analyses was 49/60 (81.7%; 95% [confidence intervals] CI = 71.6-91.8%) and 50/61 (82%; 95% CI = 72-91.9%), respectively (P = 0.96). In per-protocol analysis, the rate of H. pylori eradication in groups A and B was 45/54 (83.3%; 95% CI = 73.1 93.6%) and 45/53 (84.9%; 95% CI = 74.9-94.9%), respectively (P = 0.82). Minor well tolerated side effects were reported in 15 (34.9%) and 21 (35.6%) patients of groups A and B, respectively, and only one therapy cessation in group A was created. CONCLUSION: Standard 14-day triple-drug therapy with NAC is not preferable to standard drug regimens for H. pylori infection. PMID- 25298959 TI - Molecular cloning of Reteplase and its expression in E. coli using tac promoter. AB - BACKGROUND AND AIMS: This study aimed to clone and express the reteplase cDNA, a thrombolytic agent used for the treatment of acute myocardial infarction and stroke, in E. coli, utilizing tac promoter for its expression. MATERIALS AND METHODS: Reteplase cDNA was amplified by polymerase chain reaction (PCR) with designed primers. The product was then cloned into pTZ57R plasmid. The cloned cDNA was digested out and ligated into pGEX-5x-1 expression vector. The presence of the insert was confirmed by restriction digestion. By using 0.2, 0.5 and 1 mM isopropyl beta-D thiogalactopyranoside (IPTG), expression of reteplase was induced in E. coli TOP10 cells and analyzed by SDS-PAGE. RESULTS: Electrophoresis of PCR product and also double digested recombinant pTZ57R plasmid, also, pGEX-5x 1 vector, showed a 1068bp band of reteplase. SDS-PAGE analysis showed a 60 KDa band of protein product induced with different concentrations of IPTG. CONCLUSION: In the present study, reteplase cDNA was successfully cloned and expressed using tac promoter. This vector will be used for the optimization of the expression of reteplase in E. coli. PMID- 25298960 TI - The association between fasting serum insulin, apo-lipoproteins level, and severity of coronary artery involvement in non-diabetic patients. AB - BACKGROUND: In the previous studies, fasting insulin and apo-lipoproteins are considered as one of the risk-factor of coronary artery disease (CAD) but did not have the same results. In this study, we attempted to define the association of high fasting insulin and apo-lipoproteins of serum in non-diabetic patients who were afflicted with coronary arteries disease with severity of coronary arteries involvement. MATERIALS AND METHODS: This study was conducted between September 2011 and February 2012 on three groups, each one consisting of 100 members while using angiographic scores of Gensini with three equal groups with low, medium, and high stenosis of coronary arteries. The evaluation of non-diabetic patients afflicted with CADs, included the fasting glucose level less than 126 mg/dl or non-consumption of blood glucose reduction drugs or negativity history of diabetes. RESULTS: In this study, there were 300 non-diabetic patients afflicted with CAD in three groups of low, medium, and high extremity. Due to attained results, the patients afflicted with high CAD had a higher level of insulin (18.3 +/- 0.8) in relation with low and medium groups (P < 0.001). As it was observed, the level of serum apo-lipoproteins of A1 (APO-A1) in low group of CAD (175 +/- 36.4) is meaningfully higher than its quantity in high-CAD group (158 +/- 42.4, P < 0.001). Furthermore, the quantity of serum apo-lipoproteins of B (APO-B) in mild CAD group (139 +/- 30.4) is meaningfully less than severe CAD group (155.21 +/- 29.7, P < 0.001). CONCLUSION: Our findings show that insulin, APO-A1, APO-B, and total cholesterol measurement is a good case for defining the severity of coronary artery involvement, while high-density lipoprotein, low-density lipoprotein, and triglyceride are not important risk-factors. PMID- 25298961 TI - A Lifespan Developmental-Stage Approach to Tobacco and Other Drug Abuse Prevention. AB - At least by informal design, tobacco and other drug abuse prevention programs are tailored to human developmental stage. However, few papers have been written to examine how programming has been formulated as a function of developmental stage throughout the lifespan. In this paper, I briefly define lifespan development, how it pertains to etiology of tobacco and other drug use, and how prevention programming might be constructed by five developmental stages: (a) young child, (b) older child, (c) young teen, (d) older teen, and (e) adult (emerging, young to-middle and older adult substages). A search of the literature on tobacco and other drug abuse prevention by developmental stage was conducted, and multiple examples of programs are provided for each stage. A total of 34 programs are described as examples of each stage (five-young children, 12-older children, eight-young teens, four-older teens, and five-adults). Implications for future program development research are stated. In particular, I suggest that programming continue to be developed for all stages in the lifespan, as opposed to focusing on a single stage and that developmentally appropriate features continues to be pursued to maximize program impact. PMID- 25298962 TI - Negative effects of a nonhost proteinase inhibitor of ~19.8 kDa from Madhuca indica seeds on developmental physiology of Helicoverpa armigera (Hubner). AB - An affinity purified trypsin inhibitor from the seed flour extracts of Madhuca indica (MiTI) on denaturing polyacrylamide gel electrophoresis showed that MiTI consisted of a single polypeptide chain with molecular mass of ~19.8 kDa. MiTI inhibited the total proteolytic and trypsin-like activities of the midgut proteinases of Helicoverpa armigera larvae by 87.51% and 76.12%, respectively, at concentration of 5 ug/mL with an IC50 of 1.75 ug/mL against trypsin like midgut proteinases. The enzyme kinetic studies demonstrated that MiTI is a competitive inhibitor with a K i value of 4.1 * 10(-10) M for Helicoverpa trypsin like midgut proteinases. In vivo experiments with different concentrations of MiTI in artificial diet (0.5, 1.0, and 1.5% w/w) showed an effective downfall in the larval body weight and an increase in larval mortality. The concentration of MiTI in the artificial diet to cause 50% mortality (LD50) of larvae was 1.5% w/w and that to cause reduction in mass of larvae by 50% (ED50) was 1.0% w/w. Nutritional indices observations suggest the toxic and adverse effects of MiTI on the growth and development of H. armigera larvae. The results suggest a strong bioinsecticidal potential of affinity purified MiTI which can be exploited in insect pest management of crop plants. PMID- 25298963 TI - Natural compounds and aging: between autophagy and inflammasome. AB - Aging, a natural physiological process, is characterized by a progressive loss of physiological integrity. Loss of cellular homeostasis in the aging process results from different sources, including changes in genes, cell imbalance, and dysregulation of the host-defense systems. Innate immunity dysfunctions during aging are connected with several human pathologies, including metabolic disorders and cardiovascular diseases. Recent studies have clearly indicated that the decline in autophagic capacity that accompanies aging results in the accumulation of dysfunctional mitochondria, reactive oxygen species (ROS) production, and further process dysfunction of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation in the macrophages, which produce the proinflammatory cytokines. These factors impair cellular housekeeping and expose cells to higher risk in many age-related diseases, such as atherosclerosis and type 2 diabetes. In this review, we investigated the relationship between dysregulation of the inflammasome activation and perturbed autophagy with aging as well as the possible molecular mechanisms. We also summarized the natural compounds from food intake, which have potential to reduce the inflammasome activation and enhance autophagy and can further improve the age-related diseases discussed in this paper. PMID- 25298965 TI - Partial splenic embolization with transarterial chemoembolization in patients with hepatocellular carcinoma accompanied by thrombocytopenia. AB - BACKGROUND: Thrombocytopenia often makes the introduction of systemic treatment difficult in patients with cirrhosis and hepatocellular carcinoma (HCC). We retrospectively evaluated the long-term effects of partial splenic embolization (PSE) with transarterial chemoembolization (TACE) in patients with HCC patients accompanied by thrombocytopenia. PATIENTS AND METHODS: Twenty-one patients with HCC complicated by severe thrombocytopenia (platelet count, <5.0 * 10(4)/mm(3)) were treated with PSE and TACE. Both the safety and platelet-increasing effect was evaluated in these patients. RESULTS: Seventeen of 21 patients (81.0%) showed increased platelet counts to >=5.0 * 10(4)/mm(3). Subsequently, 13 patients (61.9%) successfully received systemic chemotherapy. Platelet counts and serum levels of total bilirubin, as well as neutrophil counts, improved significantly one month after treatment. However, serum levels of albumin and hemoglobin decreased significantly one month after treatment. Severe adverse events, including acute liver failure and portal vein thrombus, were observed in two patients. CONCLUSION: PSE with selective TACE made it possible for patients with HCC and severe thrombocytopenia to receive systemic chemotherapy. Although PSE with TACE was safe and tolerable for most patients, the extent of PSE with TACE in a wide area of the liver may increase the risk for fatal liver failure. PMID- 25298966 TI - Nonwearable gaze tracking system for controlling home appliance. AB - A novel gaze tracking system for controlling home appliances in 3D space is proposed in this study. Our research is novel in the following four ways. First, we propose a nonwearable gaze tracking system containing frontal viewing and eye tracking cameras. Second, our system includes three modes: navigation (for moving the wheelchair depending on the direction of gaze movement), selection (for selecting a specific appliance by gaze estimation), and manipulation (for controlling the selected appliance by gazing at the control panel). The modes can be changed by closing eyes during a specific time period or gazing. Third, in the navigation mode, the signal for moving the wheelchair can be triggered according to the direction of gaze movement. Fourth, after a specific home appliance is selected by gazing at it for more than predetermined time period, a control panel with 3 * 2 menu is displayed on laptop computer below the gaze tracking system for manipulation. The user gazes at one of the menu options for a specific time period, which can be manually adjusted according to the user, and the signal for controlling the home appliance can be triggered. The proposed method is shown to have high detection accuracy through a series of experiments. PMID- 25298967 TI - Dual adaptive filtering by optimal projection applied to filter muscle artifacts on EEG and comparative study. AB - Muscle artifacts constitute one of the major problems in electroencephalogram (EEG) examinations, particularly for the diagnosis of epilepsy, where pathological rhythms occur within the same frequency bands as those of artifacts. This paper proposes to use the method dual adaptive filtering by optimal projection (DAFOP) to automatically remove artifacts while preserving true cerebral signals. DAFOP is a two-step method. The first step consists in applying the common spatial pattern (CSP) method to two frequency windows to identify the slowest components which will be considered as cerebral sources. The two frequency windows are defined by optimizing convolutional filters. The second step consists in using a regression method to reconstruct the signal independently within various frequency windows. This method was evaluated by two neurologists on a selection of 114 pages with muscle artifacts, from 20 clinical recordings of awake and sleeping adults, subject to pathological signals and epileptic seizures. A blind comparison was then conducted with the canonical correlation analysis (CCA) method and conventional low-pass filtering at 30 Hz. The filtering rate was 84.3% for muscle artifacts with a 6.4% reduction of cerebral signals even for the fastest waves. DAFOP was found to be significantly more efficient than CCA and 30 Hz filters. The DAFOP method is fast and automatic and can be easily used in clinical EEG recordings. PMID- 25298968 TI - Soft translations and soft extensions of BCI/BCK-algebras. AB - The concept of soft translations of soft subalgebras and soft ideals over BCI/BCK algebras is introduced and some related properties are studied. Notions of Soft extensions of soft subalgebras and soft ideals over BCI/BCK-algebras are also initiated. Relationships between soft translations and soft extensions are explored. PMID- 25298969 TI - Novel modulation method for multidirectional matrix converter. AB - This study presents a new modulation method for multidirectional matrix converter (MDMC), based on the direct duty ratio pulse width modulation (DDPWM). In this study, a new structure of MDMC has been proposed to control the power flow direction through the stand-alone battery based system and hybrid vehicle. The modulation method acts based on the average voltage over one switching period concept. Therefore, in order to determine the duty ratio for each switch, the instantaneous input voltages are captured and compared with triangular waveform continuously. By selecting the proper switching pattern and changing the slope of the carriers, the sinusoidal input current can be synthesized with high power factor and desired output voltage. The proposed system increases the discharging time of the battery by injecting the power to the system from the generator and battery at the same time. Thus, it makes the battery life longer and saves more energy. This paper also derived necessary equation for proposed modulation method as well as detail of analysis and modulation algorithm. The theoretical and modulation concepts presented have been verified in MATLAB simulation. PMID- 25298964 TI - Combating pathogenic microorganisms using plant-derived antimicrobials: a minireview of the mechanistic basis. AB - The emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-derived antimicrobials (PDAs) as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts have been used as a safe, effective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in the last two decades has identified a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. This review highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse effects exerted by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential effect of PDAs on gut microbiota is discussed. PMID- 25298971 TI - Adaptive cuckoo search algorithm for unconstrained optimization. AB - Modification of the intensification and diversification approaches in the recently developed cuckoo search algorithm (CSA) is performed. The alteration involves the implementation of adaptive step size adjustment strategy, and thus enabling faster convergence to the global optimal solutions. The feasibility of the proposed algorithm is validated against benchmark optimization functions, where the obtained results demonstrate a marked improvement over the standard CSA, in all the cases. PMID- 25298970 TI - Biocompatibility and toxicity of poly(vinyl alcohol)/N,O-carboxymethyl chitosan scaffold. AB - The in vivo biocompatibility and toxicity of PVA/NOCC scaffold were tested by comparing them with those of a biocompatible inert material HAM in a rat model. On Day 5, changes in the blood parameters of the PVA/NOCC-implanted rats were significantly higher than those of the control. The levels of potassium, creatinine, total protein, A/G, hemoglobulin, erythrocytes, WBC, and platelets were not significantly altered in the HAM-implanted rats, when compared with those in the control. On Day 10, an increase in potassium, urea, and GGT levels and a decrease in ALP, platelet, and eosinophil levels were noted in the PVA/NOCC implanted rats, when compared with control. These changes were almost similar to those noted in the HAM-implanted rats, except for the unaltered potassium and increased neutrophil levels. On Day 15, the total protein, A/G, lymphocyte, monocyte, and eosinophil levels remained unaltered in the PVA/NOCC-implanted rats, whereas urea, A/G, WBC, lymphocyte, and monocyte levels remained unchanged in the HAM-implanted rats. Histology and immunohistochemistry analyses revealed inflammatory infiltration in the PVA/NOCC-implanted rats, but not in the HAM implanted rats. Although a low toxic tissue response was observed in the PVA/NOCC implanted rats, further studies are necessary to justify the use of this material in tissue engineering applications. PMID- 25298972 TI - A novel matrix for hydrophobic interaction chromatography and its application in lysozyme adsorption. AB - A novel 1-naphthylamine (NA) coupled poly(2-hydroxyethyl methacrylate-co-N methacryloyl-(L)-histidine methyl ester) [NA-PHEMAH] supermacroporous monolithic hydrophobic cryogel was prepared via covalent coupling of NA to PHEMAH for adsorption of lysozyme from aqueous solution. Firstly, PHEMAH monolithic cryogel was prepared by radical cryocopolymerization of HEMA with MAH as a functional comonomer and N,N'-methylene-bisacrylamide (MBAAm) as a crosslinker directly in a plastic syringe, and then NA molecules were covalently attached to the imidazole rings of MAH groups of the polymeric structure. The prepared, NA-PHEMAH, supermacroporous monolithic hydrophobic cryogel was characterized by scanning electron microscopy (SEM). The effects of initial lysozyme concentration, pH, salt type, temperature and flow rate on the adsorption efficiency of monolithic hydrophobic cryogel were studied in a column system. The maximum amount of lysozyme adsorption from aqueous solution in phosphate buffer was 86.1 mg/g polymer at pH 8.0 with a flow rate of 1 mL/min. It was observed that lysozyme could be repeatedly adsorbed and desorbed with the NA-PHEMAH monolithic hydrophobic cryogel without significant loss of the adsorption capacity. PMID- 25298977 TI - In vivo fluorescence sensing of the salicylate-induced change of zinc ion concentration in the auditory cortex of rat brain. AB - This study demonstrates a fluorescence method for in vivo sensing of the dynamic change of Zn(2+) concentration in auditory cortex microdialysates induced by salicylate with N'-(7-nitro-2,1,3-benzoxadiazole-4-yl)-N,N,N'-tris(pyridine-2 ylmethyl) ethane-1,2-diamine (NBD-TPEA) as a probe. The excellent properties of the NBD-TPEA probe make it possible to achieve a high selectivity for Zn(2+) sensing with the co-existence of amino acids and other metal ions as well as the species commonly existing in the cerebral system. To validate the method for in vivo fluorescence sensing of Zn(2+) in the rat brain, we pre-mix the microdialysates in vivo sampled from the auditory cortex with the NBD-TPEA probe and then perfuse the mixtures into a fluorescent cuvette for continuous-flow fluorescence detection. The method demonstrated here shows a linear relationship between the signal output and Zn(2+) concentration within the concentration range from 0.5 MUM to 4 MUM, with a detection limit of 156 nM (S/N = 3). The basal level of extracellular Zn(2+) in auditory cortex microdialysates is determined to be 0.52 +/- 0.082 MUM (n = 4). This value is increased by the injection of 100 mg mL(-1) of salicylate (1 MUL min(-1), 5 min, i.p.), reaches a peak at the time point of 90 min, and levels off with time. Such an increase is attenuated by the injection of MK-801, a potent and specific NMDA receptor antagonist, after the pre-injection of 100 mg mL(-1) salicylate for 5 min. This study offers a fluorescence method for in vivo sensing of Zn(2+) in the rat brain that could be useful for the investigations of chemical processes involved in brain functions. PMID- 25298978 TI - Metallophore mapping in complex matrices by metal isotope coded profiling of organic ligands. AB - Metal isotope coded profiling (MICP) introduces a universal discovery platform for metal chelating natural products that act as metallophores, ion buffers or sequestering agents. The detection of cation and oxoanion complexing ligands is facilitated by the identification of unique isotopic signatures created by the application of isotopically pure metals. PMID- 25298979 TI - [New bank?]. PMID- 25298980 TI - [Coalition agreement: What plans are black-red in outpatient and inpatient care]. PMID- 25298981 TI - [Medications: dear and expensive?]. PMID- 25298982 TI - Evidence behind quality of care measures for venous thromboembolism and atrial fibrillation. AB - Stroke and venous thromboembolism (VTE) are serious and preventable thrombotic events in patients with atrial fibrillation (AF) and who undergo surgery or hospitalization, respectively. Nevertheless, thromboprophylaxis remains greatly underused. The National Quality Forum, the Agency for Healthcare Research and Quality, and the Joint Commission have developed quality measures aimed at improving the provision of appropriate thromboprophylaxis. Reporting of these measures will increasingly become mandatory and hospitals will face financial penalties for failure to report. The approval of new oral anticoagulants (direct thrombin and factor Xa inhibitors) may simplify provision of thromboprophylaxis and eventually increase adherence to guidelines and quality measures. The primary objective of this review is to present evidence supporting the core quality measures for VTE prevention and stroke prevention in patients with AF. The secondary objective is to familiarize physicians with the new anticoagulants and their approved indications. This review concludes with a brief description of the Society of Hospital Medicine online resources for VTE prevention as well as recommendations for planning and implementation of quality improvement in the management of VTE. PMID- 25298983 TI - Health systems science can learn from medicine's evidence revolution. PMID- 25298984 TI - Mammorgraphy reporting at Tygerberg hospital, Cape Town, South Africa. PMID- 25298985 TI - Mammorgraphy reporting at Tygerberg hospital, Cape Town, South Africa. PMID- 25298986 TI - Recommendations for the handling of fluorescent lamps in public schools in Johannesburg, South Africa. PMID- 25298987 TI - A rose by any other name is an emergency department. PMID- 25298988 TI - Certificate of need: legal nightmare in the making? PMID- 25298989 TI - Exchange rate hurting chronic drug supplies - but ARV pipeline safe, says govt. PMID- 25298990 TI - Women doctors have a rougher time - new association born. PMID- 25298991 TI - Obituaries. PMID- 25298992 TI - When is the right time? complex issues around withdrawing life-sustaining treatment in children. AB - When should one withdraw treatment in children? The challenge is to recognise when a decision needs to be made. Parents may be in denial, and deciding which questions to ask may be difficult. Ethically, the guiding principle should be the child's best interests. May the parents or primary caregiver decide what the child's best interests are? Legislation in South Africa prevents a parent or caregiver from refusing treatment that professionals deem to be in the child's best interests. This article discusses the ethical and legal aspects around the decision to palliate in children. PMID- 25298993 TI - Managing pain in children at the end of life: what the GP should know. PMID- 25298994 TI - Physician self-care. PMID- 25298995 TI - [Automated audiometry - hearing tests with iOS based software suitable for "at home" tests?]. PMID- 25298996 TI - [Mastoidectomy - biphasic ceramics as a filler is advantageous]. PMID- 25298997 TI - Evolutionary ecology of resprouting and seeding in fire-prone ecosystems. AB - There are two broad mechanisms by which plant populations persist under recurrent disturbances: resprouting from surviving tissues, and seedling recruitment. Species can have one of these mechanisms or both. However, a coherent framework explaining the differential evolutionary pressures driving these regeneration mechanisms is lacking. We propose a bottom-up approach in addressing this question that considers the relative survivorship of adults and juveniles in an evolutionary context, based on two assumptions. First, resprouting and seeding can be interpreted by analogy with annual versus perennial life histories; that is, if we consider disturbance cycles to be analogous to annual cycles, then resprouting species are analogous to the perennial life history with iteroparous reproduction, and obligate seeding species that survive disturbances solely through seed banks are analogous to the annual life history with semelparous reproduction. Secondly, changes in the selective regimes differentially modify the survival rates of adults and juveniles and thus the relative costs and benefits of resprouting versus seeding. Our approach provides a framework for understanding temporal and spatial variation in resprouting and seeding under crown-fire regimes. It accounts for patterns of coexistence and environmental changes that contribute to the evolution of seeding from resprouting ancestors. PMID- 25298998 TI - Quality of life in intensively treated youths with early-onset type 1 diabetes: a population-based survey. AB - OBJECTIVE: To evaluate factors associated with self-reported generic, chronic generic, and condition-specific quality of life (QoL) impairments in intensively treated patients with early-onset and long-duration type 1 diabetes. STUDY DESIGN: A total of 840 11- to 21-year-olds with type 1 diabetes onset before 5 years of age and at least 10 years diabetes duration completed questionnaires including the generic Revised Children's Quality of Life Questionnaire (KINDL-R), the DISABKIDS chronic-generic module (DCGM-12), and the DISABKIDS diabetes specific module with impact and treatment scales to assess QoL. Regression analyses were conducted using sociodemographic, health-related, and diabetes related independent variables. RESULTS: The strongest associations were observed between QoL scores and diabetes-specific factors, especially glycemic control and treatment satisfaction. The adjusted mean differences [regression coefficients beta (standard error)] between patient groups with high risk vs. optimal glycemic control were beta = -4.6 (1.1) for the KINDL-R total score, beta = -8.6 (1.5) for the DCGM-12, beta = -14.4 (1.9) for the diabetes impact score, and beta = -21.1 (2.7) for the diabetes treatment score (all p < 0.001). The mean differences between patient groups with poor vs. very good treatment satisfaction were beta = -5.9 (1.3) for the KINDL-R total score, beta = -8.5 (1.7) for the DCGM-12, beta = -9.4 (2.0) for the diabetes impact score, and beta = -15.0 (2.9) for the diabetes treatment score (all p < 0.001). In addition, recent severe hypoglycemia and an insulin regimen without an insulin pump were negatively associated with the QoL scores. CONCLUSION: Good glycemic control and a high level of treatment satisfaction are associated with a positive QoL in youths with early-onset type 1 diabetes. PMID- 25298999 TI - Survivors of childhood cancer report high levels of independence five years after diagnosis. AB - The aim was to compare self-rated independence in childhood cancer survivors 5 years after diagnosis with corresponding ratings during initial cancer treatment and those in a comparison group. A further aim was to determine whether and how certain clinical and demographic variables affected self-rated independence. Self rated independence, a dimension included in the health-related quality of life (HRQoL) measure DISABKIDS Chronic Generic Measure (DCGM-37), was assessed in a Swedish cohort of survivors (n = 63, aged 12-22 years) and compared with ratings during initial cancer treatment and those in an age-matched comparison group (n = 257). Potential predictors of self-rated independence were estimated using multiple regression analysis. Survivors rated their independence significantly higher 5 years after diagnosis than during initial cancer treatment and higher than the comparison group. Neither demographic nor clinical variables (age, sex, diagnosis, initial cancer treatment) predicted self-rated independence 5 years post diagnosis. Five years after diagnosis, survivors of childhood cancer appear to have reached a satisfactory level of independence. However, survivors are likely to experience complications over the longer term, and therefore continued follow-up is warranted to follow possible changes in self-reported independence. PMID- 25299000 TI - Cultural influences in pediatric cancer from diagnosis to cure/end of life. AB - OBJECTIVE: To review the literature on cultural factors influencing clinical care and family management of pediatric cancer. METHODS: A literature review including 72 articles related to cultural issues in pediatric cancer was conducted. Information was organized around several clinically driven themes. RESULTS: Cultural factors influenced many aspects of the cancer experience including illness representations, reaction to diagnosis, illness disclosure patterns, complementary and alternative medicine use, management of medical procedures, coping strategies, and end of life issues. CONCLUSION: Increased awareness of cultural factors is needed to improve clinical care and reduce health disparities. Specific strategies to approach cultural differences are provided to enhance patient and family care from diagnosis to cure/end of life. PMID- 25299001 TI - Efficacy and safety of rituximab in elderly patients with rheumatoid arthritis enrolled in a French Society of Rheumatology registry. AB - OBJECTIVE: The aim of this study was to compare the efficacy and safety of rituximab (RTX) as a function of patient age. METHODS: We included all rheumatoid arthritis patients in the AutoImmunity and Rituximab registry with a 2-year followup. RESULTS: Of the 1,709 patients, 191 were age >=75 years, 417 were ages 65-74 years, 907 were ages 50-64 years, and 194 were age <50 years. At baseline, the elderly and very elderly patients presented with longer disease duration, a higher incidence of erythrocyte sedimentation rate and C-reactive protein level, a lower incidence of previous tumor necrosis factor alpha (TNFalpha) therapy, and a smaller number of previously used TNFalpha agents. Disease activity, rheumatoid factor (RF), or anti-cyclic citrullinated peptide (anti-CCP) antibodies and corticosteroid therapy were not statistically different among the groups. At 24 months, no significant difference was shown among the groups for RTX discontinuation rates (36.1% if age <50 years, 32.6% if ages 50-64 years, 34.5% if ages 65-74 years, and 32.5% if age >75 years). The reasons for discontinuation (inefficacy, adverse events) were the same in all 4 groups. Infections were more common in the elderly. Patients ages 65-75 years were more likely to be good responders than nonresponders at 1 year of followup than patients age >=75 years (odds ratio 3.81, 95% confidence interval 1.14-12.79) after adjustment on disease duration, RF/anti-CCP positivity, corticosteroids, anti-TNF use, and baseline Disease Activity Score in 28 joints (DAS28). After the sixth month, the decrease in DAS28 score was less marked in the population age >75 years than in the group age <50 years. CONCLUSION: The efficacy and safety of RTX is affected by age. PMID- 25299002 TI - Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis (Wegener's). AB - OBJECTIVE: Ear, nose, and throat (ENT) involvement is the most prevalent manifestation of granulomatosis with polyangiitis (Wegener's) (GPA) and correlates with permanent damage and decreased quality of life. Although prior studies have evaluated the efficacy of rituximab (RTX) for granulomatous features of GPA, none have evaluated its efficacy solely for ENT manifestations. We compared the effectiveness of RTX to other therapies for the ENT manifestations of GPA in a large, well-characterized cohort. METHODS: We performed a retrospective analysis of 975 visits from 99 GPA patients seen at a tertiary care ENT practice between 2003 and 2013. At each visit, subjects had a complete ENT examination, with ENT activity assessed by a single expert otolaryngologist. ENT disease activity during the observational period in subjects receiving RTX was compared to subjects receiving all other therapy. RESULTS: In total, 48 subjects had never received RTX and 51 received RTX at least once. There was no active ENT disease during 92.4% of the observational period (days) for subjects receiving RTX, compared with 53.7% of the observational period for subjects not receiving RTX (odds ratio 11.0 [95% confidence interval 5.5-22.0], P < 0.0001). Subjects receiving RTX, compared with those receiving methotrexate, azathioprine, cyclophosphamide, or trimethoprim-sulfamethoxazole, were significantly more likely to have no active ENT disease (P < 0.0001 for each comparison). CONCLUSION: RTX is an effective treatment for ENT manifestations of GPA. Subjects treated with RTX were significantly less likely to have active ENT disease compared with those not receiving RTX. Patients being treated with RTX were 11 times less likely to have active ENT disease than patients being treated with other therapies. PMID- 25299003 TI - Reply to Christensen and Christensen and to Malter: Pitfalls of erroneous analyses of hurricanes names. PMID- 25299004 TI - Vaccines: science, health, longevity, and wealth. PMID- 25299005 TI - John Marion Yarborough, Jr., MD, past President ASDS. PMID- 25299006 TI - High amounts of specific antibodies are produced upon antigen stimulation during adaptive immune responses. Preface. PMID- 25299007 TI - Cholera outbreaks. Preface. PMID- 25299008 TI - The Dementia Friendly Hospital Initiative education program for acute care nurses and staff. AB - Individuals with Alzheimer's disease and other dementias have 3.2 million hospital stays annually, which is significantly more than older individuals without dementia. Hospitalized patients with dementia are at greater risk of delirium, falls, overwhelming functional decline that may extend the hospital stay, and prolonged or complicated rehabilitation. These risks highlight the need for staff education on the special care needs of this vulnerable population. This article describes a one-day education program, the Dementia Friendly Hospital Initiative, designed to teach staff how to provide the specialized care required by patients with dementia. Participants (N = 355) from five different hospitals, including 221 nurses, completed a pretest-posttest evaluation for the program. Changes in participants attitudes and practices, confidence, and knowledge were evaluated. Scores indicated significant improvement on the posttest. The evaluation provides further evidence for recommending dissemination of the Dementia Friendly Hospital Initiative. PMID- 25299033 TI - Diabetic emergencies: new strategies for an old disease. AB - Diabetic emergencies are common presentations to the emergency department. It is estimated that diabetes affects 25.8 million people in the United States, at an annual total cost of over $174 billion. There are 2 general categories of diabetic emergencies: hyperglycemic and hypoglycemic. The hyperglycemic emergencies include diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of these conditions requires a careful hydration strategy to restore volume and improve perfusion, intravenous insulin therapy, and electrolyte monitoring. Management of hypoglycemia includes identification of the underlying etiology, oral food and/or glucose, intravenous dextrose, and consideration of glucagon. This review evaluates the current strategies for management of diabetic emergencies and offers new information regarding effective diagnostic strategies, selection of fluids for rehydration, correction of potassium, the use of subcutaneous insulin for mild hyperglycemia, and management of metformin-induced lactic acidosis. PMID- 25299034 TI - Employers need to heed the exclusion list. PMID- 25299041 TI - Confluent granulomas and ulcers lined by epithelioid histiocytes: new ideal method for differentiation of ITB and CD? A meta analysis. AB - BACKGROUND: There are few widely accepted criteria other than caseation, which has low sensitivity, for differentiating intestinal tuberculosis (ITB) and Crohn's disease (CD). OBJECTIVE: We performed a meta-analysis to evaluate the use of confluent granulomas and ulcers lined by epithelioid histiocytes as histological methods for differentiating ITB and CD, compared with that of caseation. METHODS: We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library and Chinese Biomedicine Database for all relevant studies on the histological differentiation of ITB and CD. Sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated for each study. Study quality and heterogeneity were assessed. Meta-regression analysis and sensitivity analyses were performed. RESULTS: Ten randomized trials involving 316 ITB and 376 CD patients were included. The results showed that analysis of caseation showed an overall weighted area under the curve (AUC) of 0.9966, overall sensitivity and specificity were 0.21 and 1.00, respectively, with a positive likelihood ratio (+LR) of 10.79, negative likelihood ratio(-LR) of 0.82 and DOR of 13.74. Confluent granulomas had a lower overall weighted AUC of 0.9381, sensitivity and specificity were 0.38 and 0.99, respectively, with a +LR of 16.29, -LR of 0.65 and DOR of 26.52. Overall weighted AUC for ulcers lined by epithelioid histiocytes was 0.9017, sensitivity and specificity were 0.41 and 0.94, respectively, with a +LR of 6.46, -LR of 0.54 and DOR of 13.17. Significant heterogeneity was noted for the studies. Meta-regression analysis showed that study source, publication year, size, design and quality did not affect heterogeneity. CONCLUSION: Confluent granulomas and ulcers lined by epithelioid histiocytes are helpful in distinguishing ITB from CD, which may provide a new method, other than caseating granulomas and acid-fast bacilli, to differentiate ITB and CD in mucosal biopsies. PMID- 25299042 TI - A model for sigma factor competition in bacterial cells. AB - Sigma factors control global switches of the genetic expression program in bacteria. Different sigma factors compete for binding to a limited pool of RNA polymerase (RNAP) core enzymes, providing a mechanism for cross-talk between genes or gene classes via the sharing of expression machinery. To analyze the contribution of sigma factor competition to global changes in gene expression, we develop a theoretical model that describes binding between sigma factors and core RNAP, transcription, non-specific binding to DNA and the modulation of the availability of the molecular components. The model is validated by comparison with in vitro competition experiments, with which excellent agreement is found. Transcription is affected via the modulation of the concentrations of the different types of holoenzymes, so saturated promoters are only weakly affected by sigma factor competition. However, in case of overlapping promoters or promoters recognized by two types of sigma factors, we find that even saturated promoters are strongly affected. Active transcription effectively lowers the affinity between the sigma factor driving it and the core RNAP, resulting in complex cross-talk effects. Sigma factor competition is not strongly affected by non-specific binding of core RNAPs, sigma factors and holoenzymes to DNA. Finally, we analyze the role of increased core RNAP availability upon the shut down of ribosomal RNA transcription during the stringent response. We find that passive up-regulation of alternative sigma-dependent transcription is not only possible, but also displays hypersensitivity based on the sigma factor competition. Our theoretical analysis thus provides support for a significant role of passive control during that global switch of the gene expression program. PMID- 25299044 TI - [Causality and prediction: differences and points of contact]. AB - This contribution presents the differences between those variables that might play a causal role in a certain process and those only valuable for predicting the outcome. Some considerations are made about the core intervention of the association and the temporal precedence and biases in both cases, the study of causality and predictive modeling. In that context, several relevant aspects related to the design of the corresponding studies are briefly reviewed and some of the mistakes that are often committed in handling both, causality and prediction, are illustrated. PMID- 25299043 TI - Complement alternative pathway activation in human nonalcoholic steatohepatitis. AB - The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94+/-0.12 vs. 0.57+/-0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05) and C3c/C3 activation ratio (rs = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00+/-0.19 vs. 0.71+/ 0.07, p = 0.26; factor D: 1.00+/-0.21 vs. 0.66+/-0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00+/-0.14 vs. 2.37+/-0.72; p = 0.22; protein: 0.51+/ 0.11 vs. 1.97+/-0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00+/-0.09 vs. 0.71+/-0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12+/-0.16 vs. 0.78+/-0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation. PMID- 25299046 TI - Touchscreen-based cognitive tasks reveal age-related impairment in a primate aging model, the grey mouse lemur (Microcebus murinus). AB - Mouse lemurs are suggested to represent promising novel non-human primate models for aging research. However, standardized and cross-taxa cognitive testing methods are still lacking. Touchscreen-based testing procedures have proven high stimulus control and reliability in humans and rodents. The aim of this study was to adapt these procedures to mouse lemurs, thereby exploring the effect of age. We measured appetitive learning and cognitive flexibility of two age groups by applying pairwise visual discrimination (PD) and reversal learning (PDR) tasks. On average, mouse lemurs needed 24 days of training before starting with the PD task. Individual performances in PD and PDR tasks correlate significantly, suggesting that individual learning performance is unrelated to the respective task. Compared to the young, aged mouse lemurs showed impairments in both PD and PDR tasks. They needed significantly more trials to reach the task criteria. A much higher inter-individual variation in old than in young adults was revealed. Furthermore, in the PDR task, we found a significantly higher perseverance in aged compared to young adults, indicating an age-related deficit in cognitive flexibility. This study presents the first touchscreen-based data on the cognitive skills and age-related dysfunction in mouse lemurs and provides a unique basis to study mechanisms of inter-individual variation. It furthermore opens exciting perspectives for comparative approaches in aging, personality, and evolutionary research. PMID- 25299045 TI - Toxoplasma gondii is dependent on glutamine and alters migratory profile of infected host bone marrow derived immune cells through SNAT2 and CXCR4 pathways. AB - The obligate intracellular parasite, Toxoplasma gondii, disseminates through its host inside infected immune cells. We hypothesize that parasite nutrient requirements lead to manipulation of migratory properties of the immune cell. We demonstrate that 1) T. gondii relies on glutamine for optimal infection, replication and viability, and 2) T. gondii-infected bone marrow-derived dendritic cells (DCs) display both "hypermotility" and "enhanced migration" to an elevated glutamine gradient in vitro. We show that glutamine uptake by the sodium dependent neutral amino acid transporter 2 (SNAT2) is required for this enhanced migration. SNAT2 transport of glutamine is also a significant factor in the induction of migration by the small cytokine stromal cell-derived factor-1 (SDF 1) in uninfected DCs. Blocking both SNAT2 and C-X-C chemokine receptor 4 (CXCR4; the unique receptor for SDF-1) blocks hypermotility and the enhanced migration in T. gondii-infected DCs. Changes in host cell protein expression following T. gondii infection may explain the altered migratory phenotype; we observed an increase of CD80 and unchanged protein level of CXCR4 in both T. gondii-infected and lipopolysaccharide (LPS)-stimulated DCs. However, unlike activated DCs, SNAT2 expression in the cytosol of infected cells was also unchanged. Thus, our results suggest an important role of glutamine transport via SNAT2 in immune cell migration and a possible interaction between SNAT2 and CXCR4, by which T. gondii manipulates host cell motility. PMID- 25299047 TI - Interaction mortality: senescence may have evolved because it increases lifespan. AB - Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. We describe a model of interaction mortality that does not involve specific functions, making only modest assumptions. Our model distinguishes explicitly between the physiological state of an organism and potential extrinsic, age-independent threats. The resulting mortality may change with age, depending on whether the organism's state changes with age. We find that depending on the physiological constraints, any outcome, be it 'no senescence' or 'high rate of senescence', can be found in any environment; that the highest optimal rate of senescence emerges for an intermediate physiological constraint, i.e. intermediate strength of trade-off; and that the optimal rate of senescence as a function of the environment is driven by the way the environment changes the effect of the organism's state on mortality. We conclude that knowledge about the environment, physiology and their interaction is necessary before reasonable predictions about the evolution of senescence can be made. PMID- 25299048 TI - Blood tracer kinetics in the arterial tree. AB - Evaluation of blood supply of different organs relies on labeling blood with a suitable tracer. The tracer kinetics is linear: Tracer concentration at an observation site is a linear response to an input somewhere upstream the arterial flow. The corresponding impulse response functions are currently treated empirically without incorporating the relation to the vascular morphology of an organ. In this work we address this relation for the first time. We demonstrate that the form of the response function in the entire arterial tree is reduced to that of individual vessel segments under approximation of good blood mixing at vessel bifurcations. The resulting expression simplifies significantly when the geometric scaling of the vascular tree is taken into account. This suggests a new way to access the vascular morphology in vivo using experimentally determined response functions. However, it is an ill-posed inverse problem as demonstrated by an example using measured arterial spin labeling in large brain arteries. We further analyze transport in individual vessel segments and demonstrate that experimentally accessible tracer concentration in vessel segments depends on the measurement principle. Explicit expressions for the response functions are obtained for the major middle part of the arterial tree in which the blood flow in individual vessel segments can be treated as laminar. When applied to the analysis of regional cerebral blood flow measurements for which the necessary arterial input is evaluated in the carotid arteries, present theory predicts about 20% underestimation, which is in agreement with recent experimental data. PMID- 25299050 TI - Complete mapping of substrate translocation highlights the role of LeuT N terminal segment in regulating transport cycle. AB - Neurotransmitter: sodium symporters (NSSs) regulate neuronal signal transmission by clearing excess neurotransmitters from the synapse, assisted by the co transport of sodium ions. Extensive structural data have been collected in recent years for several members of the NSS family, which opened the way to structure based studies for a mechanistic understanding of substrate transport. Leucine transporter (LeuT), a bacterial orthologue, has been broadly adopted as a prototype in these studies. This goal has been elusive, however, due to the complex interplay of global and local events as well as missing structural data on LeuT N-terminal segment. We provide here for the first time a comprehensive description of the molecular events leading to substrate/Na+ release to the postsynaptic cell, including the structure and dynamics of the N-terminal segment using a combination of molecular simulations. Substrate and Na+-release follows an influx of water molecules into the substrate/Na+-binding pocket accompanied by concerted rearrangements of transmembrane helices. A redistribution of salt bridges and cation-pi interactions at the N-terminal segment prompts substrate release. Significantly, substrate release is followed by the closure of the intracellular gate and a global reconfiguration back to outward-facing state to resume the transport cycle. Two minimally hydrated intermediates, not structurally resolved to date, are identified: one, substrate-bound, stabilized during the passage from outward- to inward-facing state (holo-occluded), and another, substrate-free, along the reverse transition (apo-occluded). PMID- 25299051 TI - Self-assembly of mesoscale isomers: the role of pathways and degrees of freedom. AB - The spontaneous self-organization of conformational isomers from identical precursors is of fundamental importance in chemistry. Since the precursors are identical, it is the multi-unit interactions, characteristics of the intermediates, and assembly pathways that determine the final conformation. Here, we use geometric path sampling and a mesoscale experimental model to investigate the self-assembly of a model polyhedral system, an octahedron, that forms two isomers. We compute the set of all possible assembly pathways and analyze the degrees of freedom or rigidity of intermediates. Consequently, by manipulating the degrees of freedom of a precursor, we were able to experimentally enrich the formation of one isomer over the other. Our results suggest a new approach to direct pathways in both natural and synthetic self-assembly using simple geometric criteria. We also compare the process of folding and unfolding in this model with a geometric model for cyclohexane, a well-known molecule with chair and boat conformations. PMID- 25299049 TI - Myeloid ZFP36L1 does not regulate inflammation or host defense in mouse models of acute bacterial infection. AB - Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is one of several Zinc Finger Protein 36 (Zfp36) family members, which bind AU rich elements within 3' untranslated regions (UTRs) to negatively regulate the post-transcriptional expression of targeted mRNAs. The prototypical member of the family, Tristetraprolin (TTP or ZFP36), has been well-studied in the context of inflammation and plays an important role in repressing pro-inflammatory transcripts such as TNF-alpha. Much less is known about the other family members, and none have been studied in the context of infection. Using macrophage cell lines and primary alveolar macrophages we demonstrated that, like ZFP36, ZFP36L1 is prominently induced by infection. To test our hypothesis that macrophage production of ZFP36L1 is necessary for regulation of the inflammatory response of the lung during pneumonia, we generated mice with a myeloid-specific deficiency of ZFP36L1. Surprisingly, we found that myeloid deficiency of ZFP36L1 did not result in alteration of lung cytokine production after infection, altered clearance of bacteria, or increased inflammatory lung injury. Although alveolar macrophages are critical components of the innate defense against respiratory pathogens, we concluded that myeloid ZFP36L1 is not essential for appropriate responses to bacteria in the lungs. Based on studies conducted with myeloid deficient ZFP36 mice, our data indicate that, of the Zfp36 family, ZFP36 is the predominant negative regulator of cytokine expression in macrophages. In conclusion, these results imply that myeloid ZFP36 may fully compensate for loss of ZFP36L1 or that Zfp36l1-dependent mRNA expression does not play an integral role in the host defense against bacterial pneumonia. PMID- 25299052 TI - Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. AB - Toll-like receptor (TLR)4-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study investigated the expression and biological role of TLR4 in human breast cancer metastasis. MCF-7 and MDA-MB-231 are human breast cancer cell lines with low and high metastatic potential, respectively. Using lipopolysaccharide (LPS) to stimulate MCF-7 and MDA-MB-231 cells, expression of TLR4 mRNA and protein increased compared with that in control cells. TLR4 activation notably up regulated expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor(VEGF) mRNA and their secretion in the supernatants of both cell lines. LPS enhanced invasion of MDA-MB-231 cells by transwell assay and MCF-7 cells by wound healing assay. LPS triggered increased expression of TLR4 downstream signaling pathway protein myeloid differentiation factor 88(MyD88) and resulted in interleukin (IL)-6 and IL-10 higher production by human breast cancer cells. Stimulation of TLR4 with LPS promoted tumorigenesis and formed metastatic lesions in liver of nude mice. Moreover, expression of TLR4 and MyD88 as well as invasiveness and migration of the cells could be blocked by TLR4 antagonist. Combined with clinicopathological parameters, TLR4 was overexpressed in human breast cancer tissue and correlated with lymph node metastasis. These findings indicated that TLR4 may participate in the progression and metastasis of human breast cancer and provide a new therapeutic target. PMID- 25299053 TI - Comparison of statistical and clinical predictions of functional outcome after ischemic stroke. AB - BACKGROUND: To determine whether the predictions of functional outcome after ischemic stroke made at the bedside using a doctor's clinical experience were more or less accurate than the predictions made by clinical prediction models (CPMs). METHODS AND FINDINGS: A prospective cohort study of nine hundred and thirty one ischemic stroke patients recruited consecutively at the outpatient, inpatient and emergency departments of the Western General Hospital, Edinburgh between 2002 and 2005. Doctors made informal predictions of six month functional outcome on the Oxford Handicap Scale (OHS). Patients were followed up at six months with a validated postal questionnaire. For each patient we calculated the absolute predicted risk of death or dependence (OHS>=3) using five previously described CPMs. The specificity of a doctor's informal predictions of OHS>=3 at six months was good 0.96 (95% CI: 0.94 to 0.97) and similar to CPMs (range 0.94 to 0.96); however the sensitivity of both informal clinical predictions 0.44 (95% CI: 0.39 to 0.49) and clinical prediction models (range 0.38 to 0.45) was poor. The prediction of the level of disability after stroke was similar for informal clinical predictions (ordinal c-statistic 0.74 with 95% CI 0.72 to 0.76) and CPMs (range 0.69 to 0.75). No patient or clinician characteristic affected the accuracy of informal predictions, though predictions were more accurate in outpatients. CONCLUSIONS: CPMs are at least as good as informal clinical predictions in discriminating between good and bad functional outcome after ischemic stroke. The place of these models in clinical practice has yet to be determined. PMID- 25299054 TI - Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study. AB - Long-term and high-dose treatment with metformin is known to be associated with vitamin B12 deficiency in patients with type 2 diabetes. We investigated whether the prevalence of B12 deficiency was different in patients treated with different combination of hypoglycemic agents with metformin during the same time period. A total of 394 patients with type 2 diabetes treated with metformin and sulfonylurea (S+M group, n = 299) or metformin and insulin (I+M group, n = 95) were consecutively recruited. The vitamin B12 and folate levels were quantified using the chemiluminescent enzyme immunoassay. Vitamin B12 deficiency was defined as vitamin B12<=300 pg/mL without folate deficiency (folate>4 ng/mL). The mean age of and duration of diabetes in the subjects were 59.4+/-10.5 years and 12.2+/ 6.7 years, respectively. The mean vitamin B12 level of the total population was 638.0+/-279.6 pg/mL. The mean serum B12 levels were significantly lower in the S+M group compared with the I+M group (600.0+/-266.5 vs. 757.7+/-287.6 pg/mL, P<0.001). The prevalence of vitamin B12 deficiency in the metformin-treated patients was significantly higher in the S+M group compared with the I+M group (17.4% vs. 4.2%, P = 0.001). After adjustment for various factors, such as age, sex, diabetic duration, duration or daily dose of metformin, diabetic complications, and presence of anemia, sulfonylurea use was a significant independent risk factor for B12 deficiency (OR = 4.74, 95% CI 1.41-15.99, P = 0.012). In conclusion, our study demonstrated that patients with type 2 diabetes who were treated with metformin combined with sulfonylurea require clinical attention for vitamin B12 deficiency and regular monitoring of their vitamin B12 levels. PMID- 25299055 TI - Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS. AB - Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-kappaB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-alpha and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-kappaB activation despite treatment with dexamethasone. PMID- 25299056 TI - QM/MM molecular dynamics study of the galactopyranose -> galactofuranose reaction catalysed by Trypanosoma cruzi UDP-galactopyranose mutase. AB - The enzyme UDP-Galactopyranose Mutase (UGM) catalyses the conversion of galactopyranose into galactofuranose. It is known to be critical for the survival and proliferation of several pathogenic agents, both prokaryotic and eukaryotic. Among them is Trypanosoma cruzi, the parasite responsible for Chagas' disease. Since the enzyme is not present in mammals, it appears as a promising target for the design of drugs to treat this illness. A precise knowledge of the mechanism of the catalysed reaction would be crucial to assist in such design. In this article we present a detailed study of all the putative steps of the mechanism. The study is based on QM/MM free energy calculations along properly selected reaction coordinates, and on the analysis of the main structural changes and interactions taking place at every step. The results are discussed in connection with the experimental evidence and previous theoretical studies. PMID- 25299058 TI - Preparation of nanowire specimens for laser-assisted atom probe tomography. AB - The availability of reliable and well-engineered commercial instruments and data analysis software has led to development in recent years of robust and ergonomic atom-probe tomographs. Indeed, atom-probe tomography (APT) is now being applied to a broader range of materials classes that involve highly important scientific and technological problems in materials science and engineering. Dual-beam focused-ion beam microscopy and its application to the fabrication of APT microtip specimens have dramatically improved the ability to probe a variety of systems. However, the sample preparation is still challenging especially for emerging nanomaterials such as epitaxial nanowires which typically grow vertically on a substrate through metal-catalyzed vapor phase epitaxy. The size, morphology, density, and sensitivity to radiation damage are the most influential parameters in the preparation of nanowire specimens for APT. In this paper, we describe a step-by-step process methodology to allow a precisely controlled, damage-free transfer of individual, short silicon nanowires onto atom probe microposts. Starting with a dense array of tiny nanowires and using focused ion beam, we employed a sequence of protective layers and markers to identify the nanowire to be transferred and probed while protecting it against Ga ions during lift-off processing and tip sharpening. Based on this approach, high-quality three-dimensional atom-by-atom maps of single aluminum-catalyzed silicon nanowires are obtained using a highly focused ultraviolet laser-assisted local electrode atom probe tomograph. PMID- 25299057 TI - No apparent reduction in schistosome burden or genetic diversity following four years of school-based mass drug administration in mwea, central kenya, a heavy transmission area. AB - BACKGROUND: Schistosomiasis is a debilitating neglected tropical disease that infects over 200 million people worldwide. To combat this disease, in 2012, the World Health Organization announced a goal of reducing and eliminating transmission of schistosomes. Current control focuses primarily on mass drug administration (MDA). Therefore, we monitored transmission of Schistosoma mansoni via fecal egg counts and genetic markers in a typical school based MDA setting to ascertain the actual impacts of MDA on the targeted schistosome population. METHODS: For 4 years, we followed 67 children enrolled in a MDA program in Kenya. Infection status and egg counts were measured each year prior to treatment. For 15 of these children, for which there was no evidence of acquired resistance, meaning they became re-infected following each treatment, we collected microsatellite genotype data from schistosomes passed in fecal samples as a representation of the force of transmission between drug treatments. We genotyped a total of 4938 parasites from these children, with an average of 329.2 parasites per child for the entire study, and an average of 82.3 parasites per child per annual examination. We compared prevalence, egg counts, and genetic measures including allelic richness, gene diversity (expected heterozygosity), adult worm burdens and effective number of breeders among time points to search for evidence for a change in transmission or schistosome populations during the MDA program. FINDINGS: We found no evidence of reduced transmission or schistosome population decline over the course of the program. Although prevalence declined in the 67 children as it did in the overall program, reinfection rates were high, and for the 15 children studied in detail, schistosome egg counts and estimated adult worm burdens did not decline between years 1 and 4, and genetic diversity increased over the course of drug treatment. INTERPRETATION: School based control programs undoubtedly improve the health of individuals; however, our data show that in an endemic area, such a program has had no obvious effect on reducing transmission or of significantly impacting the schistosome population as sampled by the children we studied in depth. Results like these, in combination with other sources of information, suggest more integrated approaches for interrupting transmission and significantly diminishing schistosome populations will be required to achieve sustainable control. PMID- 25299059 TI - Occupations, social vulnerability and HIV/STI risk: The case of bisexual Latino men in the New York City metropolitan area. AB - This article examines the relationship between the work environment, type of occupation and sexual risk-taking among behaviourally bisexual Latino men, in which data were analysed from a mixed-methods study of 148 behaviourally bisexual Latino men, aged 18-60. The authors draw on both sex market theory and the literature on structural violence and labour to situate sexual risk-taking within broader dimensions of social inequalities and organisation. Manual labour, hospitality and retail/professional fields are examined and compared. Major findings include (1) a high incidence of unprotected anal intercourse among manual labourers (2) a high incidence of unprotected vaginal intercourse with alcohol use and concurrent sex with females among hospitality workers (3) less sexual risk behaviour, sexual risk behaviour with alcohol and fewer concurrent sex partners among those in the retail/professional fields. Findings are discussed in relation to global economic forces, masculinity and social and symbolic capital. PMID- 25299060 TI - Inequitable access to health services for older adults with diabetes: potential solutions on a state level. AB - Diabetes is a serious global public health challenge. The cost for health services for diabetes care has increased 41% over the past 5 years. Despite escalating health expenditure, the United States continues to have higher rates of diabetes than many other developed countries. There is a need for health care reform in the United States not only in reducing health care costs but also in improving the quality of preventative care. This study presents the testing of a multilevel model investigating variables on the individual and state levels to develop a better understanding of the most important contextual pathways that can lead to providing older adults (50+) with type 2 diabetes with the recommended preventative quality care they require. The model was tested using a three-level repeated cross-sectional design with data from various existing data sources, using a national sample of 181,870 individuals aged 50 years and older. Results showed that differences in state health care systems contributed to inequitable access. Specifically, in a state where there was a higher percentage of adults 65 and older coupled with a shortage of health care professionals, the likelihood of receiving the recommended preventative quality care decreased. Also, older adults living in states with a higher percentage of people with diagnosed diabetes but with a lower-than-average annual per capita health care expenditure fared worse in receiving quality preventative care. Last, older adults in wealthy states with higher percentages of uninsured people had the lowest odds of receiving quality preventative care. Health care reform, similar to what is currently promoted by the Patient Protection and Affordable Care Act of 2010, is recommended to improve the performance of all health care systems in all states. PMID- 25299062 TI - Improve the operational stability of the inverted organic solar cells using bilayer metal oxide structure. AB - Operational stability is a big obstacle for the application of inverted organic solar cells (OSCs), however, less talked about in the research reports. Due to photoinduced degradation of the metal oxide interlayer, which can cause shunts generation and degeneration in ZnO interlayer, a significant degradation of open circuit voltage (Voc) and fill factor (FF) has been observed by in situ periodic measurements of the device current density-voltage (J-V) curves with light illumination. By combining TiOx and ZnO to form bilayer structures on ITO, the photovoltaic performance is improved and the photoinduced degradation is reduced. It was found that the device based on ZnO/TiOx bilayer structure achieved better operational stability as compared to that with ZnO or TiOx interlayer. PMID- 25299061 TI - Keeping mtDNA in shape between generations. AB - Since the unexpected discovery that mitochondria contain their own distinct DNA molecules, studies of the mitochondrial DNA (mtDNA) have yielded many surprises. In animals, transmission of the mtDNA genome is explicitly non-Mendelian, with a very high number of genome copies being inherited from the mother after a drastic bottleneck. Recent work has begun to uncover the molecular details of this unusual mode of transmission. Many surprising variations in animal mitochondrial biology are known; however, a series of recent studies have identified a core of evolutionarily conserved mechanisms relating to mtDNA inheritance, e.g., mtDNA bottlenecks during germ cell development, selection against specific mtDNA mutation types during maternal transmission, and targeted destruction of sperm mitochondria. In this review, we outline recent literature on the transmission of mtDNA in animals and highlight the implications for human health and ageing. PMID- 25299063 TI - Impairment of bone health in pediatric patients with hemolytic anemia. AB - INTRODUCTION: Sickle cell anemia and thalassemia result in impaired bone health in both adults and youths. Children with other types of chronic hemolytic anemia may also display impaired bone health. STUDY DESIGN: To assess bone health in pediatric patients with chronic hemolytic anemia, a cross-sectional study was conducted involving 45 patients with different forms of hemolytic anemia (i.e., 17 homozygous sickle cell disease and 14 hereditary spherocytosis patients). Biochemical, radiographic and anamnestic parameters of bone health were assessed. RESULTS: Vitamin D deficiency with 25 OH-vitamin D serum levels below 20 ng/ml was a common finding (80.5%) in this cohort. Bone pain was present in 31% of patients. Analysis of RANKL, osteoprotegerin (OPG) and osteocalcin levels indicated an alteration in bone modeling with significantly elevated RANKL/OPG ratios (control: 0.08+0.07; patients: 0.26+0.2, P = 0.0007). Osteocalcin levels were found to be lower in patients compared with healthy controls (68.5+39.0 ng/ml vs. 118.0+36.6 ng/ml, P = 0.0001). Multiple stepwise regression analysis revealed a significant (P<0.025) influence of LDH (partial r2 = 0.29), diagnosis of hemolytic anemia (partial r2 = 0.05) and age (partial r2 = 0.03) on osteocalcin levels. Patients with homozygous sickle cell anemia were more frequently and more severely affected by impaired bone health than patients with hereditary spherocytosis. CONCLUSION: Bone health is impaired in pediatric patients with hemolytic anemia. In addition to endocrine alterations, an imbalance in the RANKL/OPG system and low levels of osteocalcin may contribute to this impairment. PMID- 25299064 TI - A non-stationary relationship between global climate phenomena and human plague incidence in Madagascar. AB - BACKGROUND: Plague, a zoonosis caused by Yersinia pestis, is found in Asia and the Americas, but predominantly in Africa, with the island of Madagascar reporting almost one third of human cases worldwide. Plague's occurrence is affected by local climate factors which in turn are influenced by large-scale climate phenomena such as the El Nino Southern Oscillation (ENSO). The effects of ENSO on regional climate are often enhanced or reduced by a second large-scale climate phenomenon, the Indian Ocean Dipole (IOD). It is known that ENSO and the IOD interact as drivers of disease. Yet the impacts of these phenomena in driving plague dynamics via their effect on regional climate, and specifically contributing to the foci of transmission on Madagascar, are unknown. Here we present the first analysis of the effects of ENSO and IOD on plague in Madagascar. METHODOLOGY/PRINCIPAL FINDINGS: We use a forty-eight year monthly time-series of reported human plague cases from 1960 to 2008. Using wavelet analysis, we show that over the last fifty years there have been complex non stationary associations between ENSO/IOD and the dynamics of plague in Madagascar. We demonstrate that ENSO and IOD influence temperature in Madagascar and that temperature and plague cycles are associated. The effects on plague appear to be mediated more by temperature, but precipitation also undoubtedly influences plague in Madagascar. Our results confirm a relationship between plague anomalies and an increase in the intensity of ENSO events and precipitation. CONCLUSIONS/SIGNIFICANCE: This work widens the understanding of how climate factors acting over different temporal scales can combine to drive local disease dynamics. Given the association of increasing ENSO strength and plague anomalies in Madagascar it may in future be possible to forecast plague outbreaks in Madagascar. The study gives insight into the complex and changing relationship between climate factors and plague in Madagascar. PMID- 25299065 TI - Invivoscribe BIOMED-2 primer mixes in B-cell immunoglobulin gene rearrangement studies: experience of a molecular diagnostics laboratory in a major tertiary care center. AB - AIMS: To determine the frequency of positive reactions obtained using the Invivoscribe BIOMED-2 kit for B-cell gene rearrangement studies in leukemias and lymphomas. MATERIALS AND METHODS: We reviewed the gel patterns for 192 samples tested, using the above-mentioned kit and matched the positive signal with the corresponding mix available in the assay kit. RESULTS: 92.2% had immunoglobulin heavy-chain clonality, of which 74% were detected by the IgH VH-FR1+JH primer set, 75.5% by IgH VH-FR2+JH primer set, 65.1% by IgH VH-FR3+JH primer set, 26% by IgH DH+JH primer set, and 2.1% by IgH DH7+JH primer set. In addition, 55.7% had clonality in the kappa light chain, where 33.3% were positive by the IgK Vkappa +Jkappa primer set and 39.6% by IgK Vkappa and INTR+Kde primer sets. Clonality in the lambda light chain of immunoglobulins was detected in 17.7% of specimens tested using the IgL Vlambda +Jlambda primer set. CONCLUSION: All primer mixes provided by the assay were positive. Thus, the Invivoscribe BIOMED-2 B-cell gene rearrangement kit is very reliable in adequately covering all targets represented by the master mixes. This assay is an integral part of the differential diagnosis of clonal populations of cells. Our report is the first in the literature that describes the full range of coverage of the BIOMED-2 primer mixes provided in this assay. PMID- 25299068 TI - Experimental observation of boron nitride chains. AB - We report the formation and characterization of boron nitride atomic chains. The chains were made from hexagonal boron nitride sheets using the electron beam inside a transmission electron microscope. We find that the stability and lifetime of the chains are significantly improved when they are supported by another boron nitride layer. With the help of first-principles calculations, we prove the heteroatomic structure of the chains and determine their mechanical and electronic properties. Our study completes the analogy between various boron nitride and carbon polymorphs, in accordance with earlier theoretical predictions. PMID- 25299067 TI - Parental restriction of children's access to cochlear implants: case studies. AB - This article reports on four retrospective case studies in which parental behavioral management of the implanted child included withholding the cochlear implant or activities associated with it as a disciplinary measure or as a means of preventing device loss or damage. The need for parental counseling by health care and educational professionals as to the importance of a child's connection to the hearing world all day long through the implant for optimal speech, language, academic, and psychosocial development is emphasized. PMID- 25299066 TI - Glutamate secretion and metabotropic glutamate receptor 1 expression during Kaposi's sarcoma-associated herpesvirus infection promotes cell proliferation. AB - Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with endothelial Kaposi's sarcoma (KS) and B-cell proliferative primary effusion lymphoma (PEL), common malignancies seen in immunocompromised HIV-1 infected patients. The progression of these cancers occurs by the proliferation of cells latently infected with KSHV, which is highly dependent on autocrine and paracrine factors secreted from the infected cells. Glutamate and glutamate receptors have emerged as key regulators of intracellular signaling pathways and cell proliferation. However, whether they play any role in the pathological changes associated with virus induced oncogenesis is not known. Here, we report the first systematic study of the role of glutamate and its metabotropic glutamate receptor 1 (mGluR1) in KSHV infected cell proliferation. Our studies show increased glutamate secretion and glutaminase expression during de novo KSHV infection of endothelial cells as well as in KSHV latently infected endothelial and B-cells. Increased mGluR1 expression was detected in KSHV infected KS and PEL tissue sections. Increased c-Myc and glutaminase expression in the infected cells was mediated by KSHV latency associated nuclear antigen 1 (LANA-1). In addition, mGluR1 expression regulating host RE-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF) was retained in the cytoplasm of infected cells. KSHV latent protein Kaposin A was also involved in the over expression of mGluR1 by interacting with REST in the cytoplasm of infected cells and by regulating the phosphorylation of REST and interaction with beta-TRCP for ubiquitination. Colocalization of Kaposin A with REST was also observed in KS and PEL tissue samples. KSHV infected cell proliferation was significantly inhibited by glutamate release inhibitor and mGluR1 antagonists. These studies demonstrated that elevated glutamate secretion and mGluR1 expression play a role in KSHV induced cell proliferation and suggest that targeting glutamate and mGluR1 is an attractive therapeutic strategy to effectively control the KSHV associated malignancies. PMID- 25299069 TI - A randomized, double-blind, placebo-controlled trial of RBP-8000 in cocaine abusers: pharmacokinetic profile of rbp-8000 and cocaine and effects of RBP-8000 on cocaine-induced physiological effects. AB - RBP-8000 is a double mutant cocaine esterase that rapidly metabolizes cocaine. This study was conducted to assess the pharmacokinetics of cocaine and cocaine induced physiological effects in the absence (placebo) or presence of RBP-8000. Twenty-nine cocaine abusers were randomized 1:1 (active: placebo) to 4 sequences and 2 treatment periods. In the presence of RBP-8000, cocaine plasma exposures dropped by 90% within 2 min; cocaine-induced physiological effects were significantly reduced with higher extent and faster decrease in systolic blood pressure and pulse rate compared to placebo. This study provides strong evidence in support to use RBP-8000 as a pharmacotherapy for cocaine intoxication. PMID- 25299070 TI - The charge carrier localization in the cubic perovskite BaOsO3 revealed by an optical study. AB - We present the optical conductivity spectra for the newly discovered cubic perovskite structure BaOsO3 at various temperatures. The compound exhibits metallic behaviour above 50 K, but becomes non-metallic below 50 K. However, below 550 cm(-1), neither the typical Drude response nor an energy gap is observed in optical conductivity spectra from 300 K to 10 K. A broad peak centred at about 550 cm(-1) is observed in the real part of optical conductivity sigma1(omega). The structure could be well reproduced by the localization modified Drude model. The life time of the carrier, deduced from sigma1(omega) in terms of the localization modified Drude model, decreases with T varying from 300 K to 100 K, then increases slightly at 10 K. The study indicates that the compound is at the boundary of metal-insulator transition. PMID- 25299071 TI - Dimerization capacities of FGF2 purified with or without heparin-affinity chromatography. AB - Fibroblast growth factor-2 (FGF2) is a pleiotropic growth factor exhibiting a variety of biological activities. In this article, we studied the capacity of FGF2 purified with or without heparin affinity chromatography to self-associate. Analyzing the NMR HSQC spectra for different FGF2 concentrations, heparin affinity purified FGF2 showed perturbations that indicate dimerization and are a higher-order oligomerization state. HSQC perturbation observed with different FGF2 concentrations revealed a heparin-binding site and two dimer interfaces. Thus, with increasing protein concentrations, FGF2 monomers make contacts with each other and form dimers or higher order oligomers. On the contrary, FGF2 purified with ion-exchange chromatography did not show similar perturbation indicating that self-association of FGF2 is eliminated if purification is done without heparin-affinity chromatography. The HSQC spectra of heparin-affinity purified FGF2 can be reproduced to some extent by adding heparin tetra-saccharide to ion exchange chromatography purified FGF2. Heparin-affinity purified FGF2 bound to acceptor and donor beads in a tagged form using His-tagged or GST-tagged proteins, also dimerized in the AlphaScreenTM assay. This assay was further validated using different experimental conditions and competitors. The assay constitutes an interesting tool to study dimerization of other FGF forms as well. PMID- 25299072 TI - Study on the promotion of bacterial biofilm formation by a Salmonella conjugative plasmid and the underlying mechanism. AB - To investigate the effect of the pRST98 plasmid, originally isolated from Salmonella enterica serovar Typhi (S. Typhi), on biofilm (BF) formation, we carried out in vitro experiments using S. Typhi, Salmonella enterica serovar Typhimurium (S. Typhimurium) and Escherichia coli (E. coli). We further explored the effects of pRST98 in vivo by establishing two animal models, a tumor-bearing mouse model and a mouse urethral catheter model. Moreover, we examined the relationship between the quorum-sensing (QS) system and pRST98-mediated BF formation. These studies showed that pRST98 enhanced BF formation in different bacteria in vitro. In both animal models, pRST98 promoted BF formation and caused more severe pathological changes. It was previously reported that Salmonella senses exogenous N-acylhomoserine lactones (AHLs) through the regulatory protein SdiA and regulates the expression of genes including the virulence gene rck, which is located on the virulence plasmid of some serotypes of Salmonella. In this study, we confirmed the locus of the rck gene on pRST98 and found that AHLs increased rck expression in pRST98-carrying strains, thereby enhancing bacterial adherence, serum resistance and bacterial BF formation. In conclusion, the Salmonella conjugative plasmid pRST98 promotes bacterial BF formation both in vitro and in vivo, and the mechanism may relate to the AHL-SdiA-Rck signaling pathway. PMID- 25299073 TI - MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma. AB - MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR 181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3' untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR 181b-5p may serve as a novel therapeutic target for astrocytoma. PMID- 25299074 TI - Obesity associated molecular forms of C-reactive protein in human. AB - OBJECTIVE: To describe novel C-reactive protein (CRP) molecular forms (mf) in human plasma. DESIGN AND METHODS: Five novel CRP-mfs, disctinct from the previously described native (nCRP) and modified (mCRP) C-reactive proteins, were separated from human plasma by polyacrylamide gel electrophoresis and immunodetected by western blot in subjects with or without increased BMI, cardiovascular disease (CVD), and diabetes (n = 1800). RESULTS: Three of the five CRP-mfs were present in all samples. One, CRPmf-4, was present in a subgroup of subjects and its presence was associated with elevated body mass index (BMI). CRP mf-5 was present in about 2% of the subjects and was not associated with any other parameters. The presence or distribution of the 5 CRP-mfs were not Ca2+ dependent. Crossed immuno-localization experiments indicated that none of the CRP mfs were complexed with any of the lipoprotein classes or with signature proteins of the complement-factor. Moreover, the distribution of CRP-mfs were not significantly correlated with plasma CRP levels. CRP-mf-4 was significantly associated with increased BMI, but not with other parameters of the metabolic syndrome (HDL-C and triglyceride levels, and diabetes). CONCLUSIONS: We have identified five new CRP-mfs out of which CRP-mf-4 was significantly associated with obesity. We have shown that oligomerization of CRP was not calcium dependent. We hypothesize that adipose tissue produces a factor which influences the formation of CRP mf-4. CRP-mfs might be used as an obesity-associated inflammatory marker. PMID- 25299075 TI - An efficient preparation of mulberroside a from the branch bark of mulberry and its effect on the inhibition of tyrosinase activity. AB - A bioactive ingredient in an ethanol extract from the branch bark of cultivated mulberry Husang-32 (Morus multicaulis Perr.) was isolated using a macroporous resin column. The primary component, which was purified by semi-preparative high performance liquid chromatography diode array detection (HPLC-DAD), was identified as mulberroside A (MA) by liquid chromatograph-mass spectrometer (LC MS), 1H and 13C nuclear magnetic resonance (NMR) spectra. In total, 4.12 g MA was efficiently extracted from one kilogram of mulberry bark. The enzymatic analysis showed that MA inhibited the generation of dopachrome by affecting the activities of monophenolase and diphenolase of tyrosinase in vitro. This analysis indicated that MA and oxyresveratrol (OR), which is the the aglycone of mulberroside A, exhibited strong inhibition of the monophenolase activity with IC50 values of 1.29 umol/L and 0.12 umol/L, respectively. However, the former showed weaker inhibitory activity than the latter for diphenolase. For the monophenolase activity, the inhibitory activity of MA and OR was reversible and showed mixed type 1 inhibition. Additionally, the inhibition constant KI (the inhibition constant of the effectors on tyrosinase) values were 0.385 umol/L and 0.926 umol/L, respectively, and the KIS (the inhibition constants of the enzyme substrate complex) values were 0.177 umol/L and 0.662 umol/L, respectively. However, MA showed competitive inhibition of diphenolase activity, and KI was 4.36 umol/L. In contrast, OR showed noncompetitive inhibition and KI = KIS = 2.95 umol/L. Taken together, these results provide important information concerning the inhibitory mechanism of MA on melanin synthesis, which is widely used in whitening cosmetics. PMID- 25299076 TI - Isotopic fingerprint of the middle Olt River basin, Romania. AB - One of the most important tributaries of the Danube River in Romania, the Olt River, was characterized in its middle catchment in terms of the isotopic composition using continuous flow-isotope ratio mass spectrometry (CF-IRMS). Throughout a period of 10 months, from November 2010 to August 2011, water samples from the Olt River and its more important tributaries were collected in order to investigate the seasonal and spatial isotope patterns of the basin waters. The results revealed a significant difference between the Olt River and its tributaries, by the fact that the Olt River waters show smaller seasonal variations in the stable isotopic composition and are more depleted in (18)O and (2)H. The waters present an overall enrichment in heavy isotopes during the warm seasons. PMID- 25299077 TI - TcCYS4, a cystatin from cocoa, reduces necrosis triggered by MpNEP2 in tobacco plants. AB - In Brazil, most cocoa bean production occurs in Southern Bahia. Witches' broom disease arrived in this area in 1989 and has since caused heavy losses in production. The disease is caused by the basidiomycete fungus Moniliophthora perniciosa, a hemibiotrophic fungus that produces the necrosis and ethylene inducting protein (MpNEP2) during infection; this protein can activate cysteine proteases and induce programmed cell death. Cysteine proteases can be modulated by cystatin. In this study, we overexpressed TcCYS4, a cocoa cystatin, in tobacco plants and evaluated the effect on MpNEP2 in model plants. Tccys4 cDNA was cloned into the pCAMBIA 1390 vector and inserted into the tobacco plants via Agrobacterium tumefaciens. Transgene expression was analyzed by reverse transcription-quantitative PCR and Western blot analysis. Transcript and protein levels in Tcccys4:tobacco lines were 8.9- and 1.5-fold higher than in wild-type plants (wt). Tcccys4:tobacco lines showed no change in growth compared to wt plants. CO2 net assimilation (A) increased in Tcccys4:tobacco lines compared to wt plants. Only one line showed statistically significant stomatal conductance (gs) and transpiration rate (E) changes. MpNEP2 was infiltered into the foliar mesophyll of Tcccys4:tobacco lines and wt plants, and necrotic lesions were attenuated in lines highly expressing Tccys4. Our results suggest that cocoa cystatin TcCYS4 affects MpNEP2 activity related to the progression of programmed cell death in tobacco plants. This may occur through the action of cystatin to inhibit cysteine proteases activated by MpNEP2 in plant tissues. Further studies are necessary to examine cystatin in the Theobroma cacao-M. perniciosa pathosystem. PMID- 25299078 TI - Identification of grapevine rootstock cultivars using expressed sequence tag simple sequence repeats. AB - Grapevine (Vitis) rootstock varieties or cultivars are used to confer resistance and tolerance to insect and disease pests, unfavorable soil conditions, and other environmental conditions to cultivars that are susceptible to these conditions but otherwise have desired properties. The need to genotype and thoroughly identify grapevine rootstock varieties in the grape industry has become increasingly critical as more and more varieties are bred or selected. Although DNA markers have advantageous applications in plant identification, markers developed from classic DNA fingerprint analysis methods are not practical for plant cultivar identification. The manual cultivar identification diagram (MCID), which was previously developed in our research group, has been shown to select DNA markers that are relatively more exploitable in identifications of genotyped plant individuals. Using this MCID strategy and expressed sequence tag-simple sequence repeat (EST-SSR) markers, we identified 22 grapevine rootstock cultivars of diverse origin. All cultivars were clearly separated by fingerprints of seven pairs of EST-SSR primers and the grapevine rootstock CID (V-R-CID) generated is both practical and referable for the identification of any grapevine rootstock cultivars studied here. Furthermore, fewer primers can be used to distinguish all cultivars using this approach since the fingerprint from each primer pair could be used several times once it is generated. This initial version of V-R-CID can be made more informative with the identification and incorporation of more cultivars, thus providing better service to the grape industry. PMID- 25299079 TI - Protective effects of remifentanil preconditioning on cerebral injury during pump assisted coronary artery bypass graft. AB - The protective effects of remifentanil preconditioning on serum superoxide dismutase (SOD) and malondialdehyde (MDA) during pump-assisted coronary artery bypass graft (CABG) were investigated. Forty pump-assisted CABG patients were randomly divided into a remifentanil preconditioning group (R group) and a control group (C group, N = 10; normal saline). The R group was further divided into 3 sub-groups (R1, R2, and R3; N = 10 per group) according to the remifentanil dose (0.6, 1.2, and 1.8 MUg.kg(-1).min(-1), respectively). A venous blood sample was taken at anesthesia induction (T0), before cardiopulmonary bypass (CPB) (T1), CPB 30 min (T2), and after CPB (T3), and protein concentrations were measured. Patients were tested 24 h before and after the operation with the Mini-Mental State Examination (MMSE), and the difference was calculated. The MMSE score difference in the R3 group was lower than those of the other 3 groups (P < 0.05). At T2 and T3, the R3 group showed a significant decrease in S-100beta protein and MDA and an increase in SOD (P < 0.05) compared with the other groups, and S-100beta was negatively correlated with SOD activity (T2: r = -0.76, -0.80, P < 0.01; T3: r = -0.795, P < 0.01), and was positively correlated with MDA density (T2: r = 0.71, P < 0.01; T3: r = 0.71, P < 0.01). In conclusion, high-dosage remifentanil preconditioning played a protective role on brain damage, possibly through inhibition of the oxidative stress response. PMID- 25299080 TI - Changes in the PD-1 and PD-L1 expressions of splenic dendritic cells in multiple organ dysfunction syndrome mice and their significance. AB - The aim of this study was to evaluate the expression of surface molecules in splenic dendritic cells (DC) in multiple-organ dysfunction syndrome (MODS) mice and their effects on the immunosuppression of sepsis and MODS. One hundred thirty C57BL/6 mice were divided into 7 groups: 6, 12, 24, 48 h, 5-7 days, 10-12 days, and the normal control group. The sepsis-MODS mouse model was established by zymson injection into the peritoneal cavity. Histopathological changes in the spleen were evaluated by hematoxylin and eosin (HE) staining. After enrichment with BDTM IMag, the expressions of PD-1, PD-L1, MHC-II (I-A(b)), and CD86 in splenic DCs were examined by flow cytometry, and their relationship with sepsis development and MODS was analyzed. The histological structures of the spleen were damaged in the 24-, 48-h, and 10-12-day groups. PD-L1 expression increased 6 h after zymosan injection, decreased to normal levels at 24 and 48 h, and increased at 5-7 days, peaking at 10-12 days. The change in PD-1 expression roughly paralleled that of PD-L1. MHC-II and CD86 increased at 6 and 12 h, and dropped to normal levels at 10-12 days. In the early stage of injury, splenic DCs were mainly activated, whereas in the later stage, the expressions of the negative co stimulatory molecules, PD-L1 and PD- 1, were upregulated, similar to tolerogenic DCs. Splenic DCs might suppress the stimulation of T lymphocytes in MODS mice through the PD-L1/PD-1 pathway, which would induce immunosuppression and the pathogenesis of MODS. PMID- 25299081 TI - Microsatellite isolation and characterization for Colletotrichum spp, causal agent of anthracnose in Andean blackberry. AB - The genus Colletotrichum, comprised of pathogenic fungi that affect plants grown worldwide, causes the disease known as anthracnose in several fruit and vegetable species. Several studies conducted on plants have shown that the disease is characterized by the presence of one or several species of the fungus attacking the fruit or other organs of the same host. To develop and implement effective control strategies, it is vital to understand the genetic structure of the fungus in agricultural systems, identify associated Colletotrichum species, and define the subpopulations responsible for the disease. Molecular tools were accordingly developed to characterize genotypic populations of Colletotrichum spp, causal agent of anthracnose in commercial crops of Andean blackberry (Rubus glaucus Benth.). A microsatellite-enriched library for Colletotrichum gloeosporioides was developed to identify and characterize microsatellite loci among isolates collected in R. glaucus plantations. Thirty microsatellites were developed and tested in 36 isolates gathered from eight different blackberry-production areas of Colombia. Ten pairs of microsatellites were polymorphic. PMID- 25299082 TI - Expression profiling of CEACAM6 associated with the tumorigenesis and progression in gastric adenocarcinoma. AB - Carcinoembryonic antigen-related cellular adhesion molecule 6 (CEACAM6) is a member of the immunoglobulin superfamily and has been recently reported to affect the neoplastic, metastatic, and invasive ability of malignant cells by regulating intracellular signaling pathways during tumorigenesis and progression. We investigated the expression and amplification of CEACAM6 in relation to the clinicopathological and biological significance of gastric adenocarcinoma. Expression of CEACAM6 mRNA in 75 primary gastric adenocarcinom and 20 adjacent tissues compared to normal gastric mucosas were explored using real-time quantitative-polymerase chain reaction. Immunohistochemical assays were conducted to evaluate the expression and tissue distribution of CEACAM6 protein. Overexpression of CEACAM6 mRNA in both gastric adenocarcinoma (2.513 +/- 0.869) and adjacent tissues (1.171 +/- 0.428) was significantly higher than the relative expressions in non-neoplastic specimens (0.594 +/- 0.513) (P < 0.01). CEACAM6 protein was present in 52 (69.33%) gastric adenocarcinomas, but not in normal gastric tissues. Adenocarcinomas with elevated CEACAM6 expression were significantly associated with lymph node metastases and advanced stages. There were no relationships between CEACAM6 expression and tumor size, histological differentiation, or different subtypes, respectively. Moreover, higher expression of CEACAM6 was found to be correlated with short postoperative survival time of patients with gastric cancer. Amplification and upregulation of CEACAM6 expression was observed in human gastric adenocarcinomas, which may be correlated with the generation or transformation of malignant cells, tumor aggressive progression, and clinical outcome. CEACAM6 may be a valuable biomarker screening for gastric tumor and novel predictor for patients in advanced stages of gastric cancer. PMID- 25299083 TI - Genetic diversity of Mycosphaerella fijiensis in Brazil analyzed using an ERIC PCR marker. AB - The Enterobacterial repetitive intergenic consensus (ERIC) marker was used to analyze the genetic variability of Mycosphaerella fijiensis, the causative agent of Black Sigatoka disease in banana plants. A total of 123 isolates were used, which were divided into populations based on their original hosts and collection sites in Brazil. A total of 9 loci were amplified, 77.8% of which were found to be polymorphic. The genetic diversity found in the population was 0.20. Analysis of molecular variance (AMOVA) demonstrated that the highest level of genetic variation is within populations. Cluster analysis revealed three main groups in Brazil, with no correlation between geographic and genetic distance. PMID- 25299084 TI - Association between rs1049673 polymorphism in CD36 and premature coronary heart disease. AB - Risk factors for premature coronary heart disease in China can be multiple; we investigated Chinese Han patients with premature coronary heart disease and a possible association with CD36 polymorphism at rs1049673, rs7755, and rs321159 sites. Outpatients were recruited according to chest X-ray coronary arteriography results; they were divided into two groups: early coronary artery lesions (premature coronary heart disease group, test group) and a control group. Coronary arteriography and laboratory blood examinations were conducted to analyze risk factors for coronary heart disease and CD36 polymorphisms. Seventy nine test and 56 control group patients were recruited. Compared with the control, the test groups had a significantly higher proportion of male patients, smoking, diabetes and metabolic syndromes, significantly higher levels of TG, LDL C, ox-LDL, WBC, UA, FBG, and significantly lower levels of HDL-C. For rs1049673, rs7755, and rs321159 sites, patients with premature coronary heart disease have family genetic predisposition at high LDL-C level with GA, AA, and TT genotypes. Unconditional logistic regression analysis showed that gender, diabetes, high TG, LDL-C level and C carriers of rs1049673 significantly affected risk for premature coronary heart disease. PMID- 25299085 TI - IL-6 gene promoter polymorphisms and risk of coronary artery disease in a Chinese population. AB - We investigated the relationships between single nucleotide polymorphisms (SNPs) of the interleukin (IL)-6 gene 174 G>C (rs1800795), 572 G>C (rs1800796), and 597 G/A (rs1800797) and coronary artery disease (CAD) risk in a Chinese population. This case-control study recruited 296 CAD patients and 327 controls between January 2009 and May 2012. Genotyping of IL-6 174 G>C (rs1800795), 572 G>C (rs1800796), and 597 G/A (rs1800797) was performed on a 384-well plate format using the Sequenom MassARRAY platform. CAD patients were more likely to be older and male, with a higher body mass index, diabetes, and hypertension, and presented higher triglycerides, and lower total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. We found that the IL-6 174CC genotype was associated with a significantly increased risk of CAD compared to the wild-type GG genotype in a codominant model [odds ratio (95% confidence interval) = 1.94 (1.13-3.37)], whereas IL-6 174 G>C polymorphisms presented an increased risk of CAD in dominant and recessive models. However, we did not find that the IL-6 572 CC and 597 AA genotypes were correlated with an increased risk of CAD. IL-6 174 G>C rs1800795 was associated with CAD risk in a Chinese population. Further large-scale studies are required to determine whether IL-6 SNPs interact with environmental factors in the development of CAD. PMID- 25299086 TI - Antimicrobial activity of fermented Theobroma cacao pod husk extract. AB - Theobroma cacao L. contains more than 500 different chemical compounds some of which have been traditionally used for their antioxidant, anti-carcinogenic, immunomodulatory, vasodilatory, analgesic, and antimicrobial activities. Spontaneous aerobic fermentation of cacao husks yields a crude husk extract (CHE) with antimicrobial activity. CHE was fractioned by solvent partition with polar solvent extraction or by silica gel chromatography and a total of 12 sub fractions were analyzed for chemical composition and bioactivity. CHE was effective against the yeast Saccharomyces cerevisiae and the basidiomycete Moniliophthora perniciosa. Antibacterial activity was determined using 6 strains: Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis (Gram positive) and Pseudomonas aeruginosa, Klebsiella pneumoniae, and Salmonella choleraesuis (Gram-negative). At doses up to 10 mg/mL, CHE was not effective against the Gram-positive bacteria tested but against medically important P. aeruginosa and S. choleraesuis with a minimum inhibitory concentration (MIC) of 5.0 mg/mL. Sub-fractions varied widely in activity and strongest antibacterial activity was seen with CHE8 against S. choleraesuis (MIC of 1.0 mg/mL) and CHE9 against S. epidermidis (MIC of 2.5 mg/mL). All bioactive CHE fractions contained phenols, steroids, or terpenes, but no saponins. Fraction CHE9 contained flavonoids, phenolics, steroids, and terpenes, amino acids, and alkaloids, while CHE12 had the same compounds but lacked flavonoids. PMID- 25299087 TI - Genetic diversity and relationship of chicory (Cichorium intybus L.) using sequence-related amplified polymorphism markers. AB - Chicory is a crop with economically important roles and is cultivated worldwide. The genetic diversity and relationship of 80 accessions of chicories and endives were evaluated by sequence-related amplified polymorphism (SRAP) markers to provide a theoretical basis for future breeding programs in China. The polymorphic rate was 96.83%, and the average polymorphic information content was 0.323, suggesting the rich genetic diversity of chicory. The genetic diversity degree of chicory was higher (GS = 0.677) than that of endive (GS = 0.701). The accessions with the highest genetic diversity (effective number of alleles, NE = 1.609; Nei's genetic diversity, H = 0.372; Shannon information index, I = 0.556) were from Italy. The richest genetic diversity was revealed in a chicory line (NE = 1.478, H = 0.289, I = 0.443) among the 3 types (line, wild, and cultivar). The chicory genetic structure of 8 geographical groups showed that the genetic differentiation coefficient (GST) was 14.20% and the number of immigrants per generation (Nm) was 3.020. A GST of 6.80% and an Nm of 6.853 were obtained from different types. This observation suggests that these chicory lines, especially those from the Mediterranean region, have potential for providing rich genetic resources for further breeding programs, that the chicory genetic structure among different countries obviously differs with a certain amount of gene flow, and that SRAP markers could be applied to analyze genetic relationships and classifications of Cichorium intybus and C. endivia. PMID- 25299088 TI - Effects of acrylonitrile on lymphocyte lipid rafts and RAS/RAF/MAPK/ERK signaling pathways. AB - Acrylonitrile (ACN) is a widely used chemical in the production of plastics, resins, nitriles, acrylic fibers, and synthetic rubber. Previous epidemiological investigations and animal studies have confirmed that ACN affects the lymphocytes and spleen. However, the immune toxicity mechanism is unknown. Lipid rafts are cell membrane structures that are rich in cholesterol and involved in cell signal transduction. The B cell lymophoma-10 (Bcl10) protein is a joint protein that is important in lymphocyte development and signal pathways. This study was conducted to examine the in vitro effects of ACN. We separated lipid rafts, and analyzed Bcl10 protein and caveolin. Western blotting was used to detect mitogen-activated protein kinase (MAPK) and phosphorylated MAPK levels. The results indicated that with increasing ACN concentration, the total amount of Bcl10 remained stable, but was concentrated mainly in part 4 to part 11 in electrophoretic band district which is high density in gradient centrifugation. Caveolin-1 was evaluated as a lipid raft marker protein; caveolin-1 content and position were relatively unchanged. Western blotting showed that in a certain range, MAPK protein was secreted at a higher level. At some ACN exposure levels, MAPK protein secretion was significantly decreased compared to the control group (P < 0.05). These results indicate that ACN can cause immune toxicity by damaging lipid raft structures, causing Bcl10 protein and lipid raft separation and restraining Ras Raf-MAPK-extracellular signal-regulated kinase signaling pathways. PMID- 25299089 TI - Finishing precocity visual score and genetic associations with growth traits in Angus beef cattle. AB - Finishing precocity visual score selection was adopted to estimate the time from birth to reach slaughter age. This study estimated (co)variance components and genetic correlations for the finishing precocity score at weaning (WP) and yearling (YP) stages by using daily weight gain (BWG = from birth to weaning; WYG = from weaning to yearling) and speed of weight gain (BWR = from birth to weaning; WYR = from weaning to yearling) as support for a genetic evaluation program for Angus beef cattle. Genetic parameters were estimated using Bayesian inference, considering multi-trait analysis and assuming a nonlinear model for WP and YP and linear model for all other traits. Direct heritability estimates were 0.17 (WP), 0.19 (YP), 0.15 (BWG), 0.16 (WYG), 0.15 (BWR), and 0.16 (WYR). The genetic correlation between the finishing precocity score at two ages (weaning and yearling) was 0.61. Positive and moderate genetic correlations were obtained between WP and BWG (0.47) and WP and BWR (0.46). In contrast, negative and low genetic associations were estimated between WP and yearling growth traits (-0.16, WYG; -0.15, WYR). Genetic correlations between YP and other traits were positive 0.29 (BWG), 0.28 (BWR), 0.48 (WYG), and 0.47 (WYR). The selection response for the finishing precocity score at weaning and yearling ages would be low. Selection to increase WP and YP should result in favorable genetic changes in daily weight gains as a correlated response. Therefore, to obtain animals suited for beef cattle production systems, finishing precocity score and growth traits should be considered as selection criteria. PMID- 25299090 TI - Independent and joint effects of the IL-6 and IL-10 gene polymorphisms in pulmonary tuberculosis among the Chinese Han population. AB - We investigated the association between interleukin (IL)-6 and IL-10 gene polymorphisms and the susceptibility to pulmonary tuberculosis (PTB). DNA samples were obtained from 191 Han Chinese patients with PTB and 191 healthy control subjects. IL-6 (-572, -174, -597) and IL-10 (-1082, -819) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism. The IL-6 -572 C/C and IL-10 -819 T/T genotypes were observed less frequently in the case group than in the control group, with crude odds ratios of 0.591 [95% confidence interval (CI) = 0.381-0.917] and 0.401 (95%CI = 0.257 0.627), respectively. A significant association remained after adjusting for environmental factors in multivariate logistic analysis. The homozygote genotypes of IL-6 -572 and IL-10 -819 had an adjusted OR of 0.565 (95%CI = 0.356-0.898) and 0.341 (95%CI = 0.210-0.553), respectively. These results indicate that the mutant heterozygote IL-10 -1082 A/ G+G/G genotype and the homozygote IL-10 -819 T/T genotype have a combined effect on PTB. These results suggest that the IL-6 -572 C/C and IL-10 -819 T/T genotype polymorphisms are protective factors against PTB. PMID- 25299091 TI - Value of diffusion weighted imaging in the differential diagnosis of benign and malignant breast lesions at 3.0T MRI. AB - The aim of this study was to investigate the correlation between apparent diffusion coefficients (ADCs), the relative apparent diffusion coefficient (rADC), and the pathological prognostic factor human epidermal growth factor receptor 2 (HER-2) in patients with breast cancer. A total of 64 women with breast cancer underwent breast diffusion-weighted imaging. HER-2 expression was detected in histological specimens. The ADC value, rADC value, and HER-2 level were determined. The ADC and rADC values of the breast cancer group were 1.1495 +/- 0.1499 x 10(-3) and 0.6602 +/- 0.0853, respectively. The differences in the ADC and rADC values between the two groups were statistically significant. There was no correlation between the ADC value and HER-2 expression in patients with breast cancer (r = -0.508, P = 0.043). However, the rADC value eliminated the individual differences to some extent. Therefore, compared to the ADC value, the rADC value had a better correlation with HER-2 expression. PMID- 25299092 TI - Expression and diagnostic value of proteins in Mycobacterium tuberculosis. AB - We constructed a prokaryotic expression vector expressing the Mycobacterium tuberculosis protein TB16.3, as well as 3 other proteins, including TB15.3, CFP 10, and Rv2626C, which were purified and analyzed for their effectiveness as detection antibodies. The TB16.3 genes of M. tuberculosis H37Rv genomic DNA were amplified by polymerase chain reaction, inserted into the expression vector pET 30a, and expressed in Escherichia coli. An enzyme-linked immunosorbent assay was used to detect the 4 M. tuberculosis antibodies. Engineered E. coli bacteria expressing TB16.3 and the 3 other proteins were constructed and found mainly to be soluble. For recombinant TB16.3 proteins, serum samples of 118 tuberculosis (TB) patients and 96 healthy controls were analyzed. Sensitivity, specificity, and adjusted concordance rate for the TB16.3 antibody were 72.9, 86.5, and 79.6%, respectively. The positive rate of Rv2626C antibody in TB patients (44.1%) was significantly lower than that in normal controls (75.0%, chi(2) = 20.8, P < 0.01). TB15.3 and TB16.3 were used for simultaneous detection and showed sensitivity, specificity, and repeatability rates of 69.4, 96.9, and 83.7%. The antibody positive rate and specificity for patients with lung disease was 9.6 and 90.4%, respectively. TB15.3 and TB16.3 were mixed and detected simultaneously. Combined with the results for TB15.3, the sensitivity, specificity, and concordance rates were 82.2, 95.9, and 88.9%, respectively. The concordance rate was the highest value observed. Target genes were cloned into a host strain and expressed successfully. The TB16.3 recombinant protein may be used as a new serological antigen for tuberculosis diagnosis. PMID- 25299093 TI - Association of vitamin D receptor BsmI gene polymorphism with risk of low bone mineral density in post-menopausal women: a meta-analysis. AB - The vitamin D receptor BsmI gene polymorphism is reportedly associated with low bone mineral density (BMD) in postmenopausal women, but results from previous studies are conflicting. In the present study, we investigated the association between this polymorphism and the risk of low BMD through a meta-analysis of published studies. A literature search of the Pubmed, Embase, and CNKI databases from inception through July 2013 was conducted. The meta-analysis was performed using the STATA 12.0 software. Crude odds ratios with 95% confidence intervals were used to assess the strength of any association. Eleven case-control studies were included for a total of 1468 low BMD cases and 2177 healthy controls. No significant variation in low BMD risk was detected in any of the genetic models. Further stratified analyses were performed to examine the effect of ethnicity. In the subgroup analysis, no significant association was found in Caucasians and in Asians. The meta-analysis results suggest that the BsmI polymorphism is not associated with low BMD risk in postmenopausal women. PMID- 25299094 TI - Overregulation of microRNA-212 in the poor prognosis of esophageal cancer patients. AB - There have been few reports evaluating the expression and function of the microRNA miR-212 in esophageal cancer. The aim of this study was to investigate the relationship between miR-212 expression and clinicopathological factors and prognoses of esophageal cancer. MicroRNA was extracted from 46 esophageal cancer patients using the Taqman MicroRNA assay. All patients were at the same tumor node metastasis stage, but with different prognoses, and had all undergone surgery. The correlation between miR-212 expression and clinicopathological features was analyzed and the significance of miR-212 as a prognostic factor as well as its relationship with survival was determined. miR-212 expression was higher in patients with poor prognoses than in those with good prognoses (P < 0.0001). Kaplan-Meier analysis results showed that the miR-212 expression level was significantly correlated with survival time (P = 0.024). Patients with higher expression of miR-212 showed longer survival times. Cox multi-factor model analysis showed that miR-212 expression was significantly correlated with survival time (P = 0.026). mir-212 is related with prognostic factors and survival time and may be a biomarker for esophageal cancer. PMID- 25299095 TI - Association between adiponectin receptor 2 gene polymorphisms and cerebral infarction. AB - We examined the association between the adiponectin receptor 2 gene and the risk of ischemic stroke. Polymerase chain reaction-restriction fragment length polymorphism was used to detect rs12342 genotypes of the adiponectin receptor 2 gene in 300 ischemic stroke patients and 320 age- and gender-matched healthy controls. In the patient group, the AA, GA, and GG genotype frequencies were 39.3, 42.7, and 18.0%, respectively. The A and G allele frequencies were 0.607 and 0.393, respectively. In the control group, the AA, GA, and GG genotype frequencies were 29.0, 51.7, and 19.3%, respectively. The A and G allele frequencies were 0.548 and 0.452, respectively. The AA genotype and A allele frequencies in the patient group were significantly higher than those in the control group (both P < 0.01). The risk of ischemic stroke in AA genotype carriers was 1.786-fold greater than that in GG genotype carriers (odds ratio = 1.786, 95% confidence interval: 1.432-2.775; P = 0.013). After adjusting for various confounding factors, the difference remained significant (odds ratio = 1.874, 95% confidence interval: 1.221-2.765; P = 0.012). The AA genotype and A allele of rs12342 in the adiponectin receptor 2 gene may increase the risk of ischemic stroke, particularly the risk of atherosclerosis cerebral infarction. PMID- 25299096 TI - Modification of vectors for functional genomic analysis in plants. AB - Simple, efficient, and economical recombinant plant binary expression vectors for deciphering large-scale functional genomic research in plants and promoting crop improvement by genetically engineering and biotechnology is in great demand. In this research, using the pCHF3, pCAMBIA1301, pCAMBIA3300, pCAMBIA3301 vectors, we successfully constructed general plant binary expression vectors carrying CaMV35S and Arabidopsis rd29A promoters mediating multiple cloning sites ( MCS: SacI, KpnI, SmaI, BamHI, XbaI, SalI, and PstI). Meanwhile, a series of applicative binary expression vectors that can be utilized for subcellular localization were constructed by fusion of the MCS and eGFP. Subsequently, the recombinant vectors were successfully transferred into Arabidopsis thaliana and Nicotiana benthamiana for further investigation of functional elements in these plant binary expression vectors. Our results demonstrated that this system was a convenient and versatile vector system for phenotypic, functional, subcellular localization, and promoter activity analysis, and it provided a relatively high-efficiency and reliable platform for researchers in vector construction and may facilitate large-scale functional genomics analysis in plants. PMID- 25299097 TI - Dynamics of chromosomal evolution in the genus Hypsiboas (Anura: Hylidae). AB - Hylidae is one of the most species-rich families of anurans, and 40% of representatives in this group occur in Brazil. In spite of such remarkable diversity, little is known about this family and its taxonomical and systematic features. Most hylids have 2n = 24, even though most of the cytogenetic data are mainly obtained based on the conventional chromosomal staining and are available for only 16% of Hypsiboas species, a genus accounting for about 10% of the hylid diversity. In this study, cytogenetic data of distinct species and populations of Hypsiboas were analyzed, and the evolutionary dynamics of chromosomal macro- and microstructure of these amphibians were discussed. Contrary to the conservativeness of 2n = 24, this genus is characterized by a high variation of chromosomal morphology with as much as 8 karyotype patterns. Differences in the number and location of nucleolus organizer regions and C-bands allowed the identification of geographical variants within nominal species and cytotaxonomical chromosomal markers. Comparative analyses revealed a strong phylogeographic relationship between chromosomal patterns in this group. PMID- 25299098 TI - Genome-wide identification and phylogenetic analysis of the AP2/ERF gene superfamily in sweet orange (Citrus sinensis). AB - Sweet orange (Citrus sinensis) plays an important role in the economy of more than 140 countries, but it is grown in areas with intermittent stressful soil and climatic conditions. The stress tolerance could be addressed by manipulating the ethylene response factor (ERF) transcription factors because they orchestrate plant responses to environmental stress. We performed an in silico study on the ERFs in the expressed sequence tag database of C. sinensis to identify potential genes that regulate plant responses to stress. We identified 108 putative genes encoding protein sequences of the AP2/ERF superfamily distributed within 10 groups of amino acid sequences. Ninety-one genes were assembled from the ERF family containing only one AP2/ERF domain, 13 genes were assembled from the AP2 family containing two AP2/ERF domains, and four other genes were assembled from the RAV family containing one AP2/ERF domain and a B3 domain. Some conserved domains of the ERF family genes were disrupted into a few segments by introns. This irregular distribution of genes in the AP2/ERF superfamily in different plant species could be a result of genomic losses or duplication events in a common ancestor. The in silico gene expression revealed that 67% of AP2/ERF genes are expressed in tissues with usual plant development, and 14% were expressed in stressed tissues. Because the AP2/ERF superfamily is expressed in an orchestrated way, it is possible that the manipulation of only one gene may result in changes in the whole plant function, which could result in more tolerant crops. PMID- 25299099 TI - Genetic diversity among Puccinia melanocephala isolates from Brazil assessed using simple sequence repeat markers. AB - Brown rust (causal agent Puccinia melanocephala) is an important sugarcane disease that is responsible for large losses in yield worldwide. Despite its importance, little is known regarding the genetic diversity of this pathogen in the main Brazilian sugarcane cultivation areas. In this study, we characterized the genetic diversity of 34 P. melanocephala isolates from 4 Brazilian states using loci identified from an enriched simple sequence repeat (SSR) library. The aggressiveness of 3 isolates from major sugarcane cultivation areas was evaluated by inoculating an intermediately resistant and a susceptible cultivar. From the enriched library, 16 SSR-specific primers were developed, which produced scorable alleles. Of these, 4 loci were polymorphic and 12 were monomorphic for all isolates evaluated. The molecular characterization of the 34 isolates of P. melanocephala conducted using 16 SSR loci revealed the existence of low genetic variability among the isolates. The average estimated genetic distance was 0.12. Phenetic analysis based on Nei's genetic distance clustered the isolates into 2 major groups. Groups I and II included 18 and 14 isolates, respectively, and both groups contained isolates from all 4 geographic regions studied. Two isolates did not cluster with these groups. It was not possible to obtain clusters according to location or state of origin. Analysis of disease severity data revealed that the isolates did not show significant differences in aggressiveness between regions. PMID- 25299100 TI - Isolation and characterization of simple sequence repeat markers for the herbaceous species Phyla scaberrima (Verbenaceae). AB - Phyla scaberrima (Verbenaceae) is a herbaceous species distributed from Mexico to Panama. Because of its well-known sweet properties and other medicinal uses, this species is cultivated in South America and the Caribbean. Phyla scaberrima has been arbitrarily extracted from nature, resulting in a severe reduction in its gene pool. In this study, we developed and characterized 11 simple sequence repeat markers for P. scaberrima to determine the genetic variability and patterns of population structure of the species. Fifty-six alleles were detected in a sample of 48 individuals belonging to 3 different populations. The average number of alleles per locus was 5.09, while the polymorphic information content ranged from 0.000-0.587. The observed and expected heterozygosities varied from 0.000-0.543 and from 0.000-0.651, respectively. Two loci exhibited significant deviation of the expected Hardy-Weinberg proportion. The 11 primer pairs were also tested for cross-amplification to 6 species of the related genus Lippia. The transferability rate ranged from 4 loci in Lippia florida and L. rotundifolia to 6 loci in L. corymbosa and L. microcephala. The 11 primer sets were shown to be valuable tools for population genetic studies in P. scaberrima and in species of the genus Lippia in which primer transferability was detected. PMID- 25299101 TI - Screening and analyzing genes associated with Amur tiger placental development. AB - The Amur tiger is a unique endangered species in the world, and thus, protection of its genetic resources is extremely important. In this study, an Amur tiger placenta cDNA library was constructed using the SMART cDNA Library Construction kit. A total of 508 colonies were sequenced, in which 205 (76%) genes were annotated and mapped to 74 KEGG pathways, including 29 metabolism, 29 genetic information processing, 4 environmental information processing, 7 cell motility, and 5 organismal system pathways. Additionally, PLAC8, PEG10 and IGF-II were identified after screening genes from the expressed sequence tags, and they were associated with placental development. These findings could lay the foundation for future functional genomic studies of the Amur tiger. PMID- 25299102 TI - Adaptability and stability of conilon coffee in areas of high altitude. AB - In view of the predicted models of global climate change and differences in prices and production costs, there is increased interest in Coffea canephora cultivation in areas of high altitude. However, this species is sensitive to low temperatures, where genotypes vary regarding adaptation/tolerance mechanisms, demonstrating genotype x environment interaction. The aim of this study was to evaluate the stability and adaptability of C. canephora varieties in high altitude areas. The experiments were carried out in February 2004, in Bom Jesus do Itabapoana, Rio de Janeiro State, Brazil, at an altitude of 725 m. Four clonal varieties (EMCAPA 8111, EMCAPA 8121, EMCAPA 8131, and EMCAPA 8151) and five harvests (2006 to 2010) were used. The experimental design was randomized blocks with four treatments and six plots, with 12 plants in each plot and spaced 2.5 x 1.2 m. Adaptability and stability parameters were determined using methods based on nonparametric analysis and analysis of variance. The results showed that the EMCAPA 8131 had the best performance according to stability and adaptability parameters and may be promising for high-altitude regions. PMID- 25299103 TI - Association of the rs7903146 and rs12255372 polymorphisms in the TCF7L2 gene with type 2 diabetes in a population from northeastern Brazil. AB - Approximately 200 million people suffer from type 2 diabetes (T2D) worldwide, and the rapid increase in the prevalence of this disease is likely a result of multiple environmental factors, such as increased food intake and decreased physical activity in genetically predisposed individuals. Different population studies have demonstrated a strong association of two polymorphic variations in the TCF7L2 gene, the noncoding single nucleotide polymorphisms (SNPs) rs7903146 (C/T) and rs12255372 (G/T), with T2D. Herein, we analyzed the association of these SNPs with T2D in a population from northeastern Brazil. Our results showed that the genotype and allele frequencies in TCF7L2 rs7903146 and rs12255372 were similar in the patient and control groups (P > 0.05). In addition, the allele frequencies were not significantly associated with T2D risk [rs7903146: odds ratio (OR) = 0.95, 95% confidence interval (CI) = 0.52-1.76, P = 1.00, and rs12255372: OR = 1.38, 95%CI = 0.72-2.62, P = 0.41]. These data suggest that the TCF7L2 SNPs rs7903146 and rs12255372 may not significantly contribute to T2D susceptibility in this population. However, our results may reflect the small number of subjects. Alternatively, these results may be attributable to specific ethnic effects, as most of the previously reported associations were demonstrated with predominantly European populations. To reach a definitive conclusion on the role of such gene variants for T2D in mixed populations, additional efforts are necessary to replicate this study with larger populations from areas with more ethnic heterogeneity. PMID- 25299104 TI - Distribution of constitutive heterochromatin in Triatoma melanocephala (Hemiptera, Triatominae). AB - In principle, Triatoma melanocephala was included in the Brasiliensis subcomplex on the basis of morphological parameters and geographical layout, since there were no other relevant data available in the literature. On the basis of karyotype, it has been proposed to exclude T. melanocephala, as well as of T. vitticeps and T. tibiamaculata, from the subcomplex, which shows fragmentation of the X sex chromosomes, thereby approaching the species of North America. Therefore, the present study aimed to determine the pattern of constitutive heterochromatin of T. melanocephala to provide new data on the cytotaxonomy of this vector of Chagas disease and especially to try to relate this species to some group, complex or subcomplex of triatomine species, aiding in their classification. This species showed no constitutive heterochromatin in the autosomes or X sex chromosome, but only the Y sex chromosome. The number of chromosomes and heterochromatin pattern of T. melanocephala proved to be identical to that described for Panstrongylus lutzi. Thus, the present study demonstrated a tentative relationship between T. melanocephala and P. lutzi. However, we emphasize that other comparative studies should be conducted between these species, such as experimental crosses and molecular, enzymatic, morphological, and morphometric analyses to determine whether these species are actually evolutionarily related or if the number of chromosomes and the heterochromatin pattern emerged as homoplasies in T. melanocephala and P. lutzi. PMID- 25299105 TI - Multifocal central nervous system hemangioblastoma: a case report and review of the literature. AB - An effective therapy for multifocal central nervous system hemangioblastoma (CNS HB) is needed. Here, we report a case of multifocal CNS HB. A 43-year-old man was diagnosed with CNS HB by enhanced computed tomography and magnetic resonance imaging. Six solid tumors and one cystic nodule were detected in his cerebellum. The patient underwent three surgeries followed by knife radiosurgery and had regular visits after the operation. In addition, histological observation with hematoxylin and eosin staining and immunohistochemistry for alpha-inhibin, Ki67, and vascular endothelial growth factor further provided evidence of cerebral HB. The symptoms of the patient were prominently improved after each operation, suggesting that multiple surgeries and radiation therapy are needed to prevent the proliferation and relapse of multifocal CNS HB. In addition, long-term, regular hospital visits were useful. Furthermore, genetic diagnosis and gene targeted therapy might be a promising strategy against familial CNS HB in the future. PMID- 25299106 TI - Expression and clinical significance of miR-122 and miR-29 in hepatitis B virus related liver disease. AB - MicroRNA molecules have been increasingly regarded as a diagnostic and prognostic marker of certain diseases. The aim of this study was to investigate the expression and clinical significance of miR-122 and miR-29 in liver disease related to hepatitis B virus infection. The serum levels of miR-122 and miR-29 in 20 patients with hepatocellular carcinoma (HCC), 20 patients with liver cirrhosis (LC), 29 patients with chronic hepatitis B (CHB), 20 cases of hepatitis B virus carriers (ASC), and 20 healthy controls (HC) were determined by a fluorescence real-time quantitative PCR method and then evaluated by clinical correlation analysis. Compared with the serum levels of miR-122 in the HC, LC, and ASC groups, those in patients with HCC and CHB were significantly increased. The serum levels of miR-29 in LC patients were lower than those in the healthy controls (P < 0.01). A positive correlation was observed between the expression of miR-122 and miR-29, and HBV DNA in patients with CHB. A negative correlation was found between miR-29 and alpha-fetoprotein in patients with HCC. The elevation in miR-122 was correlated with liver damage in CHB patients and with the pathogenesis of liver cancer in HCC patients. The decrease in miR-29 expression was related to the incidence of liver fibrosis. The detection of miR 122 and miR-29 may be useful in evaluating the inflammatory liver injury and fibrosis associated with chronic HBV infection. PMID- 25299107 TI - Screening for key genes associated with invasive ductal carcinoma of the breast via microarray data analysis. AB - The aim of this study was to identify key genes related to invasive ductal carcinoma (IDC) of the breast by analyzing gene expression data with bioinformatic tools. Microarray data set GSE31138 was downloaded from Gene Expression Omnibus, including 3 breast cancer tissue samples and 3 normal controls. Differentially expressed genes (DEGs) between breast cancer and normal control were screened out (FDR < 0.05 and |logFC| > 2). Coexpression between genes was examined with String, and a network was then constructed. Relevant pathways and diseases were retrieved with KOBAS. A total of 56 DEGs were obtained in the IDC of the breast compared with normal controls. A gene coexpression network including 27 pairs of genes was constructed and all the genes in the network were upregulated. Further study indicated that most of the genes in the coexpression network were enriched in ECM-receptor interaction (COL4A2, FN1, and HMMR) and nucleotide excision repair (CETN2 and PCNA) pathways, and that the most significantly related disease was autoimmune lymphoproliferative syndromes. A number of DEGs were acquired through comparative analysis of gene expression data. These findings are beneficial in promoting the understanding of the molecular mechanisms in breast cancer. More importantly, some key genes were revealed via gene coexpression network analysis, which could be potential biomarkers for IDC of the breast. PMID- 25299108 TI - Cellulolytic activity and structure of symbiotic bacteria in locust guts. AB - Locusts are able to digest the cellulose of Gramineae plants, resulting in their being considered as major crop pests. To illustrate the mechanism involved in cellulose digestion, the cellulolytic activity and zymography in the gut contents of 16 locust species were determined using carboxymethyl cellulose (CMC) as substrate. The diversity of gut symbiotic bacteria was studied using denaturing gradient gel electrophoresis (DGGE). The results showed that high CMC activity was present in Acrididae gut fluid (mean 356.4 U/g proteins). Of the 5 locust species, Oxya chinensis had the highest diversity of intestinal symbiotic bacteria, characterized by the DGGE profile containing more than 20 bands of 16S rRNA. Klebsiella pneumoniae, in the gut of Locusta migratoria manilensis, was identified as the most abundant symbiotic bacterium by DNA sequencing, with a relative abundance of 19.74%. In comparison, Methylobacterium sp was the most dominant species in the Atractomorpha sinensis gut, with a relative abundance of 29.04%. The results indicated that the cellulolytic enzymes and gut microbial communities probably reflected their phylogenetic relationship with different locust species and associated feeding strategies. PMID- 25299109 TI - Effect and mechanism of different ways of transplanting bone marrow mesenchymal stem cells in cardiopulmonary resuscitation in rats. AB - The effect and mechanism of different ways of transplanting bone marrow mesenchymal stem cells (MSCs) were explored for treating cardiopulmonary resuscitation in a rat model. Rats were divided into the cardiopulmonary resuscitation group (Group Con), the stereotactic lateral ventricle transplantation group (Group LV), the internal carotid artery transplantation group (Group A), and the femoral vein transplantation group (Group V). MSCs were transplanted in Groups LV, A, and V. The MSC transplantation groups had a significantly higher neurological score than Group Con on days 3 and 7 after recovery (P < 0.05), and the Group LV score was the highest in all groups (P < 0.05). On day 3 after recovery, the MSC count of Group LV was significantly higher than those of Groups A and V (P < 0.01). On day 7 after recovery, the MSC count in the hippocampus of Group LV was significantly higher than those of Groups A and V (P < 0.05). On day 3 after recovery, the S100B level of Group LV was significantly lower than those of Groups A and V (P < 0.05). On day 7 after recovery, the S100B level was not significantly different between the MSC transplantation groups (P > 0.05). The expressions of vascular endothelial growth factor and brain-derived neurotrophic factor did increased significantly in the MSC transplantation groups on day 7 after recovery, particularly Group LV. Therefore, MSC therapy could significantly improve nerve function after cardiopulmonary resuscitation, and stereotactic lateral ventricle injection transplantation is an optimal method. PMID- 25299110 TI - Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico. AB - In this study, we examined the distribution of genotype and allele frequencies of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase gene (MTHFR) in two ethnic groups in the State of Guerrero, Mexico, which were compared with those of the Mestizo population of the region. A comparative study was conducted on 455 women from two ethnic groups and a group of Mestizo women of the State of Guerrero, Mexico: 135 Nahuas, 124 Mixtecas, and 196 Mestizas. Genotyping of both polymorphisms were performed by using polymerase chain reaction-restriction fragment length polymorphism methods. We found that the 677TT genotype was more frequent in Nahua and Mixteca women compared to Mestiza women (P = 0.008), and the most prevalent genotype in both ethnic groups was the 1298AA genotype (P < 0.001). We also compared the 677T allele frequency obtained from the groups studied with the frequencies reported in other ethnic groups of Mexico (Huichol, Tarahumara, and Purepecha). There were significant differences between the three ethnic groups compared to Nahuas (Huicholes, P = 0.004; Tarahumaras, P < 0.001; Purepechas, P = 0.042). Our results indicated significant differences in the frequencies of the C677T and A1298C polymorphisms between the two ethnic groups and the Mestizo population of the State of Guerrero. In addition, we found strong differences with other ethnic groups in Mexico. These results could be useful for future studies investigating diseases related to folate metabolism, and could help the government to design specific nutrition programs for different ethnic groups. PMID- 25299111 TI - Critical electrolyte concentration of silk gland chromatin of the sugarcane borer Diatraea saccharalis, induced using agrochemicals. AB - The sugarcane borer Diatraea saccharalis is widely known as the main pest of sugarcane crop, causing increased damage to the entire fields. Measures to control this pest involve the use of chemicals and biological control with Cotesia flavipes wasps. In this study, we evaluated the insecticides fipronil (Frontline; 0.0025%), malathion (Malatol Bio Carb; 0.4%), cipermetrina (Galgotrin; 10%), and neem oil (Natuneem; 100%) and the herbicide nicosulfuron (Sanson 40 SC; 100%) in the posterior region silk glands of 3rd- and 5th-instar D. saccharalis by studying the variation in the critical electrolyte concentration (CEC). Observations of 3rd-instar larvae indicated that malathion, cipermetrina, and neem oil induced increased chromatin condensation that may consequently disable genes. Tests with fipronil showed no alteration in chromatin condensation. With the use of nicosulfuron, there was chromatin and probable gene decompaction. In the 5th-instar larvae, the larval CEC values indicated that malathion and neem oil induced increased chromatin condensation. The CEC values for 5th-instar larvae using cipermetrina, fipronil, and nicosulfuron indicated chromatin unpacking. These observations led us to conclude that the quantity of the pesticide does not affect the mortality of these pests, can change the conformation of complexes of DNA, RNA, and protein from the posterior region of silk gland cells of D. saccharalis, activating or repressing the expression of genes related to the defense mechanism of the insect and contributing to the selection and survival of resistant individuals. PMID- 25299112 TI - No difference of complete or incomplete left-sided malignant colonic obstruction on both short- and long-term outcomes. AB - The impact of complete and incomplete colonic obstruction on the short- and long term outcomes of malignant colorectal cancer has not yet been elucidated. The aim of this study was to investigate whether there was a difference in the impacts of the 2 types of obstruction on the short- and long-term outcomes of colorectal resection. This study included 224 colorectal cancer patients (162 patients with incomplete obstruction and 62 with complete obstruction) with left-sided malignant colonic obstruction who underwent surgical therapy between February 2007 and September 2012. The short- and long-term outcomes of surgical therapy were analyzed. No significant difference was found between the 2 groups with regard to short-term outcomes such as the curative resection rate (80.86 vs 70.97%, P = 0.109), hospital stay time (24.20 +/- 16.01 vs 24.19 +/- 12.06, P = 0.999), and the overall and respective complications (32.72 vs 46.77%, P = 0.051). Furthermore, no significant difference was found between the 2 groups with regard to long-term outcomes including the 1-, 3-, and 5-year survival rates (P = 0.089), recurrence rates (P = 0.711), and recurrence-free survival rates (P = 0.440). The 2 types of obstruction, i.e., complete and incomplete left-sided malignant colonic obstruction, had no impact on the short- and long-term outcomes of colorectal resection. Similar therapeutic methods can be used for treating both types of obstruction. PMID- 25299113 TI - Genetic and morphological diversity of Moenkhausia oligolepis (Characiformes: Characidae) populations in the tributaries of the Araguaia River, Brazil: implications for taxonomy and conservation. AB - Molecular genetic assessments that consider ecological information, in addition to endogamy levels, genetic diversity, and the genetic differentiation among species and populations, are particularly important for the conservation of biological diversity. Prime candidates for conservation genetic review are those subject to human use, including harvests for the ornamental fish trade. Colorful South American tetra, such as Moenkhausia oligolepis and M. forestii, are good examples of fish species that are widely collected and exported worldwide. This study aimed to evaluate the population-specific characteristics of M. oligolepis and M. forestii by comparing morphometric and molecular analyses based on ISSR markers, to provide information that would facilitate the sustainable management of these 2 species. Seventy-two specimens were collected from the Araguaia Tocantins and Paraguay River Basins in Brazil. All specimens were measured and analyzed using ISSR markers. Population-exclusive bands were found among the 86 detected bands, while morphometric clusters reflected the geographical distribution of individuals. Correlated genetic and morphological variation supported the presence of 3 distinct groups from tributaries of the Araguaia and Mortes Rivers. Using the same techniques, all M. oligolepis populations were isolated from M. forestii. This study on Moenkhausia presents an interesting example that could be used to construct a framework of South American ichthyodiversity, and reinforces the necessity of habitat conservation to prevent the loss of biological diversity. PMID- 25299114 TI - Study of human acellular amniotic membrane loading bone marrow mesenchymal stem cells in repair of articular cartilage defect in rabbits. AB - The aim of this study was to investigate the repair effect of human acellular amniotic membrane (HAAM) loading bone marrow mesenchymal stem cells (BMSCs) on articular cartilage defect in rabbits. Rabbit BMSCs were isolated and cultured, and they were then inoculated on HAAM to prepare the complex of HAAM and BMSCs. Twenty-four rabbits were randomly divided into groups A and B, with 12 animals in each group. The left and right sides were used as the experimental and control sides, respectively. The models of bilateral articular cartilage defect were established. The defect areas on the experimental side in groups A and B were implanted with the complex of HAAM and BMSCs and HAAM alone, respectively. The control sides of the two groups were not implanted with any material. In the 8th and 12th week after surgery, gross observation, histological examination and cartilage defect scoring were performed. In the 8th and 12th postoperative week, gross observation and histological observation showed that dense cartilage-like cells appeared in group A but not in group B, indicating preferable cartilage repair. The cartilage defect score on the experimental side in group A was 5.31 +/- 0.68 in the 8th week and 3.23 +/- 0.52 in the 12th week, and that in group A was significantly lower than in group B (P < 0.05). HAAM loading BMSCs has a good repair effect on articular cartilage defect under an in vitro environment. PMID- 25299115 TI - Expression of ezrin and moesin related to invasion, metastasis and prognosis of laryngeal squamous cell carcinoma. AB - We examined the expression of ezrin and moesin in laryngeal squamous cell carcinoma (LSCC) and their correlation with patient clinicopathological characteristics and overall survival. Immunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) for ezrin and moesin were applied to 60 carcinoma tissues, adjacent normal tissues, and 33 metastatic lymph nodes. Survival functions were estimated using the Kaplan-Meier method and compared by the log-rank test. RT-PCR demonstrated that the intensity ratios of ezrin and moesin to beta-actin were higher in LSCC than in adjacent normal mucous membrane (P < 0.05). Furthermore, intensity ratios were higher in cervical metastatic lymph nodes than in LSCC (P < 0.05). Immunohistochemical staining showed that ezrin and moesin were well distributed in the cell membrane and cytoplasm. Expression was significantly different between LSCC and adjacent normal tissues (P < 0.05); moreover, expression in the cervical metastatic lymph nodes was higher than in LSCC (P < 0.05). Expression of ezrin and moesin was significantly related to clinical stage, T stage, and cervical lymph node metastasis (P < 0.05), except that moesin showed no significant relationship with clinical stage (P > 0.05). Patients with negative ezrin and moesin expression had a significantly longer overall survival time compared to patients with moderate and intense ezrin and moesin expression (P < 0.001, P < 0.05). Ezrin and moesin expression is related to LSCC invasion and metastasis, and may be important molecular markers for predicting prognosis and therapeutic targets in LSCC patients. PMID- 25299116 TI - Method for obtaining high-resolution proteomic analysis from pericarps of guarana. AB - Guarana has great agricultural potential and is largely used therapeutically and in the production of non-alcoholic energy drinks. Genomic and proteomic studies are crucial to identify proteins that play central roles in the maintenance and viability of fruits, as well as to identify proteins related to the main metabolic pathways. However, the success of any protein analysis starts with the protein extract preparation, which needs to offer an extract that is free of contaminants. This study aimed to evaluate different extraction methods to obtain high-quantity and high-quality extracts that are compatible with analysis by 2 dimensional electrophoresis and tandem mass spectrometry protein identification. Three different methods were tested: trichloroacetic acid (TCA)/acetone, sodium dodecyl sulfate (SDS)/phenol, and polyvinylpolypyrrolidone (PVPP)/SDS/phenol. The extract obtained from the TCA/acetone precipitation presented low solubility and contamination with lipids and carbohydrates. On the other hand, the quality of the extract gradually improved after using phenol and PVPP/phenol, enabling a yield up to 2 mg/g macerated tissues and the detection of 457 spots by 2 dimensional electrophoresis. The effectiveness of the procedure used was validated by identification of 10 randomly selected proteins by mass spectrometry. The procedure described here can be a starting point for applications using tissues of other organs of guarana or tissues of species that are similar to guarana. PMID- 25299117 TI - Matrix metalloproteinase-9 gene polymorphism in hepatocellular carcinoma patients with hepatitis B and C viruses. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. In Egypt, the incidence of HCC has doubled over the last decade. Matrix metalloproteinase-9 (MMP-9) plays a key role in cancer invasion and metastasis by degrading the extracellular matrix and basement membrane barriers. A cytosine (C)/thymidine (T) single nucleotide polymorphism at position -1562 in the MMP-9 promoter is reported to influence the expression of the MMP-9 gene. The association between MMP-9 gene polymorphisms and HCC patients with hepatitis C and B viruses (HCV and HBV) was examined in 91 patients with HCC and viral hepatitis (55 HCV and 36 HBV). The results were compared with those of 42 HCC patients without viral hepatitis and 60 healthy individuals with no liver infection. Polymorphisms of the MMP-9 gene were investigated by polymerase chain reaction amplification followed by restriction fragment length polymorphism analysis. The serum MMP-9 level was quantitatively determined using a human MMP-9 enzyme-linked immunosorbent assay, which showed that homozygosity of the MMP-9 promoter (TT) was more frequent in patients with HCC and chronic HCV or HBV infection when compared with the control group (49.1, 52.8, and 35.7%, respectively). In addition, we observed significant elevation of serum MMP-9 levels in all HCC groups compared to controls. It was concluded that patients with the MMP-9 TT genotype are at risk of developing HCC and HBV or HCV. People with significantly elevated serum levels of MMP-9 are at risk of developing HCC. PMID- 25299118 TI - Development of an improved rat model of dual graft liver transplantation with long-term survival. AB - Dual graft liver transplantation has been demonstrated to be feasible as well as effective in increasing the donor pool and in preventing the potential for small for-size syndrome. However, little is known about the pathophysiological and immune processes following dual graft liver transplantation due to the lack of appropriate animal models. The aim of this study, therefore, was to establish an improved rat model of dual graft liver transplantation, with long-term survival. Male inbred rats were used as both donors and recipients. One middle lobe together with another right middle lobe from the livers of two different donors were used as the dual grafts. The "basin-shaped anastomosis" technique was used to connect the suprahepatic inferior vena cava; "Y-shaped bridge" and "three cuff" techniques were adopted for the anastomosis of the portal veins; and the "two-stent" technique was used for the anastomosis of the bile ducts. Six of the ten recipients survived for more than 100 days after dual graft liver transplantation. There was no difference in graft survival between dual and whole liver transplantation. The long-term survivors with dual grafts from two different donors had unobstructed portal vein flow, unobstructed biliary tract dilatation, normal graft function, and well-preserved hepatic structure. Therefore, this improved model will be potentially useful for evaluating the pathophysiological processes, immune responses between dual grafts and recipient, and mechanisms underlying the liver regeneration in dual grafts after dual graft liver transplantation. PMID- 25299120 TI - Bonding pathways of gold nanocrystals in solution. AB - Nanocrystal bonding is an important phenomenon in crystal growth and nanoscale welding. Here, we show that for gold nanocrystals bonding in solution can follow two distinct pathways: (1) coherent, defect-free bonding occurs when two nanocrystals attach with their lattices aligned to within a critical angle; and (2) beyond this critical angle, defects form at the interfaces where the nanocrystals merge. The critical misalignment angle for ~10 nm crystals is ~15 degrees in both in situ experiments and full-atom molecular dynamics simulations. Understanding the origin of this critical angle during bonding may help us predict and manage strain profiles in nanoscale assemblies and inspire techniques toward reproducible and extensible architectures using only basic crystalline blocks. PMID- 25299119 TI - Diagnosis of gastrointestinal parasites in reptiles: comparison of two coprological methods. AB - BACKGROUND: Exotic reptiles have become increasingly common domestic pets worldwide and are well known to be carriers of different parasites including some with zoonotic potential. The need of accurate diagnosis of gastrointestinal endoparasite infections in domestic reptiles is therefore essential, not only for the well-being of captive reptiles but also for the owners. Here, two different approaches for the detection of parasite stages in reptile faeces were compared: a combination of native and iodine stained direct smears together with a flotation technique (CNF) versus the standard SAF-method. RESULTS: A total of 59 different reptile faeces (20 lizards, 22 snakes, 17 tortoises) were coprologically analyzed by the two methods for the presence of endoparasites. Analyzed reptile faecal samples contained a broad spectrum of parasites (total occurence 93.2%, n = 55) including different species of nematodes (55.9%, n = 33), trematodes (15.3%, n = 9), pentastomids (3.4%, n = 2) and protozoans (47.5%, n = 28). Associations between the performances of both methods to detect selected single parasite stages or groups of such were evaluated by Fisher's exact test and marginal homogeneity was tested by the McNemar test. In 88.1% of all examined samples (n = 52, 95% confidence interval [CI] = 77.1 - 95.1%) the two diagnostic methods rendered differing results, and the McNemar test for paired observations showed highly significant differences of the detection frequency (P < 0.0001). CONCLUSION: The combination of direct smears/flotation proved superior in the detection of flagellates trophozoites, coccidian oocysts and nematode eggs, especially those of oxyurids. SAF-technique was superior in detecting larval stages and trematode eggs, but this advantage failed to be statistically significant (P = 0.13). Therefore, CNF is the recommended method for routine faecal examination of captive reptiles while the SAF-technique is advisable as additional measure particularly for wild caught animals and individuals which are to be introduced into captive collections. PMID- 25299121 TI - Laparoscopic versus open inguinal hernia repair in pediatric patients: a systematic review. AB - AIM: Inguinal hernia is one of the most common surgical conditions in infants and children. However, considerable debate exists regarding the role of laparoscopic hernia repair (herniorrhaphy) (LH) and its benefits over conventional open hernia repair (herniorrhaphy) (OH). The aim of this review is to analyze the current literature to determine the outcome of LH compared with OH. MATERIALS AND METHODS: A literature search was performed on all studies published during the last 20 years, reporting on outcomes of OH and LH, in terms of operative time, recurrence rate and other complications, finding of rare hernias, and incidence of contralateral patency. The chi-squared or Fisher's exact test was used to analyze the results of the study. RESULTS: Fifty-three studies matched our inclusion criteria. As for operative time, in unilateral inguinal hernia repair, there was no significant difference between LH and OH (P=.33). In contrast, in bilateral disease, LH is faster than OH (P=.01). As for the recurrence rate, no significant difference was observed between the two techniques (P=.66), whereas the rate of other complications was significantly higher for OH compared with LH (P=.001). Laparoscopy has the advantage to identify and treat rare hernias (direct, femoral, "en pantalon") that are never reported in articles focused on inguinal OH. In laparoscopic series, in the case of unilateral hernia, the incidence of contralateral patency varied between 19.9% and 66%. CONCLUSIONS: In this systematic review, it seems that LH is faster than OH for bilateral hernias, whereas there is no significant difference in terms of operative time for unilateral inguinal hernia repair. Recurrence rate is similar for both techniques. As for other complications such as wound infections, it is higher for OH compared with LH, especially in infants. A prospective comparative study is necessary on this topic to strongly support the results of our systematic review. PMID- 25299123 TI - Growth and nitrogen uptake characteristics reveal outbreak mechanism of the opportunistic macroalga Gracilaria tenuistipitata. AB - Macroalgae has bloomed in the brackish lake of Shenzhen Bay, China continuously from 2010 to 2014. Gracilaria tenuistipitata was identified as the causative macroalgal species. The aim of this study was to explore the outbreak mechanism of G. tenuistipitata, by studying the effects of salinity and nitrogen sources on growth, and the different nitrogen sources uptake characteristic. Our experimental design was based on environmental conditions observed in the bloom areas, and these main factors were simulated in the laboratory. Results showed that salinity 12 to 20 0/00 was suitable for G. tenuistipitata growth. When the nitrogen sources' (NH4+, NO3-) concentrations reached 40 uM or above, the growth rate of G. tenuistipitata was significantly higher. Algal biomass was higher (approximately 1.4 times) when cultured with NH4+ than that with NO3- addition. Coincidentally, macroalgal bloom formed during times of moderate salinity (~12 0/00) and high nitrogen conditions. The NH4+ and NO3- uptake characteristic was studied to understand the potential mechanism of G. tenuistipitata bloom. NH4+ uptake was best described by a linear, rate-unsaturated response, with the slope decreasing with time intervals. In contrast, NO3- uptake followed a rate saturating mechanism best described by the Michaelis-Menten model, with kinetic parameters Vmax = 37.2 uM g-1 DM h-1 and Ks = 61.5 uM. Further, based on the isotope 15N tracer method, we found that 15N from NH4+ accumulated faster and reached an atom% twice than that of 15N from NO3-, suggesting when both NH4+ and NO3- were available, NH4+ was assimilated more rapidly. The results of the present study indicate that in the estuarine environment, the combination of moderate salinity with high ammonium may stimulate bloom formation. PMID- 25299122 TI - Peripheral serotonin regulates maternal calcium trafficking in mammary epithelial cells during lactation in mice. AB - Lactation is characterized by massive transcellular flux of calcium, from the basolateral side of the mammary alveolar epithelium (blood) into the ductal lumen (milk). Regulation of calcium transport during lactation is critical for maternal and neonatal health. The monoamine serotonin (5-HT) is synthesized by the mammary gland and functions as a homeostatic regulation of lactation. Genetic ablation of tryptophan hydroxylase 1 (Tph1), which encodes the rate-limiting enzyme in non neuronal serotonin synthesis, causes a deficiency in circulating serotonin. As a consequence maternal calcium concentrations decrease, mammary epithelial cell morphology is altered, and cell proliferation is decreased during lactation. Here we demonstrate that serotonin deficiency decreases the expression and disrupts the normal localization of calcium transporters located in the apical (PMCA2) and basolateral (CaSR, ORAI-1) membranes of the lactating mammary gland. In addition, serotonin deficiency decreases the mRNA expression of calcium transporters located in intracellular compartments (SERCA2, SPCA1 and 2). Mammary expression of serotonin receptor isoform 2b and its downstream pathways (PLCbeta3, PKC and MAP-ERK1/2) are also decreased by serotonin deficiency, which might explain the numerous phenotypic alterations described above. In most cases, addition of exogenous 5-hydroxy-L-tryptophan to the Tph1 deficient mice rescued the phenotype. Our data supports the hypothesis that serotonin is necessary for proper mammary gland structure and function, to regulate blood and mammary epithelial cell transport of calcium during lactation. These findings can be applicable to the treatment of lactation-induced hypocalcemia in dairy cows and can have profound implications in humans, given the wide-spread use of selective serotonin reuptake inhibitors as antidepressants during pregnancy and lactation. PMID- 25299124 TI - [Giant Meckel's diverticulum in an adult]. AB - Meckel's diverticulum results from a partial persistence of the omphalomesenteric duct and is the most common congenital anomaly of the gastrointestinal tract, affecting about 2% of the general population. Its presentation as a giant Meckel's diverticulum (>5 cm) is rare and is associated with major complications. We report a case of a 53 year-old woman with constipation for at least ten years. A colonoscopy from eight years ago suggested megacolon. The patient consults in the last month for abdominal pain associated with anorexia. The computed tomography scan image suggested an ileal megadiverticulum. An exploratory laparotomy revealed a saccular dilatation of the distal ileum of 6 x 15.5 cm, located 20 cm away from the ileocecal valve. We resected the involved segment of distal ileum and performed a manual ileo-ascendo anastomosis. The biopsy showed a saccular dilatation of the wall, lined by small intestinal mucosa with areas of gastric metaplasia, supporting the diagnosis of giant Meckel's diverticulum. PMID- 25299126 TI - Accumulation and distribution of multiwalled carbon nanotubes in zebrafish (Danio rerio). AB - No data on the bioaccumulation and distribution of multiwalled carbon nanotubes (MWCNTs) in aquatic vertebrates is available until now. We quantified uptake and elimination of dispersed radiolabeled MWCNTs ((14)C-MWCNT; 1 mg/L) by zebrafish (Danio rerio) over time. The influences of the feeding regime and presence of dissolved organic carbon (DOC) on accumulation of the nanomaterial were determined. The partitioning of radioactivity to different organs and tissues was measured in all experiments. A bioaccumulation factor of 16 L/kg fish wet weight was derived. MWCNTs quickly associated with the fish, and steady state was reached within 1 day. After transfer to clear medium, MWCNTs were quickly released to the water phase, but on average 5 mg of MWCNTs/kg fish dry weight remained associated with the fish. The nanomaterial mainly accumulated in the gut of all fish. Feeding led to lower internal concentrations due to facilitated elimination via the digestive tract. In the presence of DOC, 10-fold less was taken up by the fish after 48 h of exposure compared to without DOC. Quick adhesion to and detachment from superficial tissues were observed. Remarkably, little fractions of the internalized radioactivity were detected in the blood and muscle tissue of exposed fish. The part accumulated in these fish compartments remained constant during the elimination phase. Hence, biomagnification of MWCNTs in the food chain is possible and should be a subject of further research. PMID- 25299125 TI - Detergent-induced stabilization and improved 3D map of the human heteromeric amino acid transporter 4F2hc-LAT2. AB - Human heteromeric amino acid transporters (HATs) are membrane protein complexes that facilitate the transport of specific amino acids across cell membranes. Loss of function or overexpression of these transporters is implicated in several human diseases such as renal aminoacidurias and cancer. HATs are composed of two subunits, a heavy and a light subunit, that are covalently connected by a disulphide bridge. Light subunits catalyse amino acid transport and consist of twelve transmembrane alpha-helix domains. Heavy subunits are type II membrane N glycoproteins with a large extracellular domain and are involved in the trafficking of the complex to the plasma membrane. Structural information on HATs is scarce because of the difficulty in heterologous overexpression. Recently, we had a major breakthrough with the overexpression of a recombinant HAT, 4F2hc LAT2, in the methylotrophic yeast Pichia pastoris. Microgram amounts of purified protein made possible the reconstruction of the first 3D map of a human HAT by negative-stain transmission electron microscopy. Here we report the important stabilization of purified human 4F2hc-LAT2 using a combination of two detergents, i.e., n-dodecyl-beta-D-maltopyranoside and lauryl maltose neopentyl glycol, and cholesteryl hemisuccinate. The superior quality and stability of purified 4F2hc LAT2 allowed the measurement of substrate binding by scintillation proximity assay. In addition, an improved 3D map of this HAT could be obtained. The detergent-induced stabilization of the purified human 4F2hc-LAT2 complex presented here paves the way towards its crystallization and structure determination at high-resolution, and thus the elucidation of the working mechanism of this important protein complex at the molecular level. PMID- 25299128 TI - Clinically essential requirement for brain CT with iterative reconstruction. PMID- 25299127 TI - Extremely low Helicobacter pylori prevalence in North Sulawesi, Indonesia and identification of a Maori-tribe type strain: a cross sectional study. AB - BACKGROUND: Sulawesi in Indonesia has a unique geographical profile with assumed separation from Sundaland. Studies of Helicobacter pylori in this region are rare due to the region's rural location and lack of endoscopy equipment. Indirect methods are, therefore, the most appropriate for measuring H. pylori infection in these areas; with the disposable gastric brush test, we can obtain gastric juice as well as small gastric tissue samples for H. pylori culture. We investigated the prevalence of H. pylori infection and evaluated human migration patterns in the remote areas of North Sulawesi. METHODS: We recruited a total of 251 consecutive adult volunteers and 131 elementary school children. H. pylori infection was determined by urine antibody test. A gastric brush test was used to culture H. pylori. We used next-generation and polymerase chain reaction based sequencing to determine virulence factors and multi-locus sequence typing (MLST). RESULTS: The overall H. pylori prevalence was only 14.3% for adults and 3.8% for children, and 13.6% and 16.7% in Minahasanese and Mongondownese participants, respectively. We isolated a single H. pylori strain, termed -Manado-1. Manado-1 was East Asian type cagA (ABD type), vacA s1c-m1b, iceA1 positive/iceA2 negative, jhp0562-positive/beta-(1,3) galT-negative, oipA "on", and dupA-negative. Phylogenetic analyses showed the strain to be hspMaori type, a major type observed in native Taiwanese and Maori tribes. CONCLUSIONS: Our data support that very low H. pylori infection prevalence in Indonesia. Identification of hspMaori type H. pylori in North Sulawesi may support the hypothesis that North Sulawesi people migrated from north. PMID- 25299130 TI - Ultrafast UV-induced photoisomerization of intramolecularly H-bonded symmetric beta-diketones. AB - In photoinduced molecular reaction dynamics, the effects of electronic charge redistribution can lead to multiple pathways that are determined by the nature of the initial structures involved and the environment the molecule of interest is studied in. The beta-diketones are a common example of this complexity. They show keto-enol tautomerism that is almost totally shifted toward the enolic form. However, compared to the gas phase, the photochemistry proceeds completely differently by virtue of the solvent environment for these compounds, which are used in commercial sunscreen agents due to a high absorption in the ultraviolet (UV) and fast deactivation processes. We disclose these dynamics by investigating three symmetrical beta-diketones in various solvents. To observe these effects on an ultrafast time scale directly in the UV spectral region where the relevant electronic transitions take place, we have developed and employed femtosecond transient absorption with detection capability in the deep UV. Our studies confirm that electronic excitation of the chelated enol form does not lead to any ultrafast photochemistry other than proton transfer followed by rotamerization. The formation of the nonchelated conformers takes place on a picosecond time scale through a dark state, whereas the recovery to the stable chelated enol form is a comparably slow process. PMID- 25299129 TI - Alcohol consumption and the neoplastic progression in Barrett's esophagus: a systematic review and meta-analysis. AB - PURPOSE: In the developed countries, the incidence of esophageal adenocarcinoma (EAC) is increasing over recent decades. The purpose of this meta-analysis was to arrive at quantitative conclusions about the contribution of alcohol intakes and the progression of Barrett's esophagus. METHODS: A comprehensive, systematic bibliographic search of medical literature published up to Oct 2013 was conducted to identify relevant studies. A meta-analysis was conducted for alcohol consumption on the Barrett's esophagus progression. RESULTS: A total of 882 cases in 6,867 individuals from 14 observational studies were indemnified in this meta analysis. The result of this current meta-analysis, including 10 case-control and 4 cohort studies, indicated that alcohol consumption was not associated with the neoplastic progression in Barrett's esophagus (RR, 1.17; 95% CI, 0.93-1.48). When stratified by the study designs, no significant association was detected in either high vs low group or ever vs never group. CONCLUSIONS: Alcohol drinking is not associated with risk of neoplastic progression in Barrett's esophagus. Further well designed studies are needed in this area. PMID- 25299131 TI - Anisotropy of magnetic properties of Fe(1+y)Te. AB - The magnetic properties of Fe(1+y)Te single crystals (y ? 0.1 / 0.18) were studied at temperatures 4.2 / 300 K. At an ambient pressure, with decreasing temperature a drastic drop in chi(T) was confirmed at T ? 60 / 65 K, which appears to be closely related to the antiferromagnetic (AFM) ordering. It is found that the magnitudes of the anisotropy of magnetic susceptibility Deltachi in the AFM phase are close in the studied samples, whereas the sign of the anisotropy apparently depends on the small variations of the excess iron y in Fe(1+y)Te samples. The performed DFT calculations of the electronic structure and magnetic properties for the stoichiometric FeTe compound indicate the presence of frustrated AFM ground states. There are very close energies and magnetic moments for the double stripe configurations, with the AFM axes oriented either on the basal plane or along the [0 0 1] direction. Presumably, both these configurations can be realized in Fe(1+y)Te single crystals, depending on the variations of the excess iron. This can provide different signs of magnetic anisotropy in the AFM phase, presently observed in the Fe(1+y)Te samples. For these types of AFM configuration, the calculations for the FeTe values of Deltachi are consistent with our experimental data. PMID- 25299132 TI - Improving contact prediction along three dimensions. AB - Correlation patterns in multiple sequence alignments of homologous proteins can be exploited to infer information on the three-dimensional structure of their members. The typical pipeline to address this task, which we in this paper refer to as the three dimensions of contact prediction, is to (i) filter and align the raw sequence data representing the evolutionarily related proteins; (ii) choose a predictive model to describe a sequence alignment; (iii) infer the model parameters and interpret them in terms of structural properties, such as an accurate contact map. We show here that all three dimensions are important for overall prediction success. In particular, we show that it is possible to improve significantly along the second dimension by going beyond the pair-wise Potts models from statistical physics, which have hitherto been the focus of the field. These (simple) extensions are motivated by multiple sequence alignments often containing long stretches of gaps which, as a data feature, would be rather untypical for independent samples drawn from a Potts model. Using a large test set of proteins we show that the combined improvements along the three dimensions are as large as any reported to date. PMID- 25299133 TI - Encapsulation of the 4-mercaptobenzoate ligand by macrocyclic metal complexes: conversion of a metallocavitand to a metalloligand. AB - Complexation of the ambidentate ligand 4-mercaptobenzoate (4-SH-C6H4CO2H, H2mba) by the macrocyclic complex [Ni2L(MU-Cl)]ClO4 (L(2-) represents a 24-membered macrocyclic hexaazadithiophenolate ligand) has been examined. The monodeprotonated Hmba(-) ligand reacts with the Ni2 complex in a selective manner by substitution of the bridging chlorido ligand to produce MU1,3-carboxylato bridged complex [Ni2L(Hmba)](+) (2(+)), which can be isolated as an air-sensitive perchlorate (2ClO4) or tetraphenylborate (2BPh4) salt. The reactivity of the new mercaptobenzoate complex is reminiscent of that of a "free" thiophenolate ligand. In the presence of air, 2ClO4 dimerizes via a disulfide bond to generate tetranuclear complex [{Ni2L}2(O2CC6H4S)2](2+) (3(2+)). The auration of 2ClO4 with [AuCl(PPh3)], on the other hand, leads to monoaurated complex [Ni(II)2L(mba)Au(I)PPh3](+) (4(+)). The bridging thiolate functions of the N6S2 macrocycle are deeply buried and are unaffected/unreactive under these conditions. The complexes were fully characterized by electrospray ionization mass spectrometry, IR and UV/vis spectroscopy, density functional theory, cyclic voltammetry, and X-ray crystallography [for 3(BPh4)2 and 4BPh4]. Temperature dependent magnetization and susceptibility measurements reveal an S = 2 ground state that is attained by ferromagnetic coupling between the spins of the Ni(II) ions in 2ClO4 (J = +22.3 cm(-1)) and 4BPh4 (J = +20.8 cm(-1); H = -2JS1S2). Preliminary contact-angle and X-ray photoelectron spectroscopy measurements indicate that 2ClO4 interacts with gold surfaces. PMID- 25299134 TI - Ciliary inclusion disease: report of a new primary ciliary dyskinesia variant. AB - Biopsies from 6 children with clinical presentations suggestive of primary ciliary dyskinesia (PCD) displayed respiratory epithelial cells with disorganized accumulations of basal bodies within the cytoplasm and large intracytoplasmic vesicles into which projected numerous microvilli and cilia. Microvilli, but few cilia, were present at the cell surface. Ultrastructural study revealed a variety of nonspecific abnormalities but demonstrated the cilia generally to be morphologically normal, suggesting that the cause of cilia malfunction was not any recognized primary cause or secondary effect. Repeat studies from 2 patients produced similar findings. It is proposed that this entity, termed ciliary inclusion disease, represents a variant form of PCD manifesting as a consequence of improper ciliogenesis caused by inhibited cytoskeleton-regulated migration of basal bodies to the luminal surface of the airway respiratory epithelial cells. PMID- 25299135 TI - Relationship between coping with interpersonal stressors and depressive symptoms in the United States, Australia, and China: a focus on reassessing coping. AB - OBJECTIVE: Reassessing coping involves efforts to wait patiently for an appropriate opportunity to act or for a change or improvement in the situation, and can be observed in individuals encountering a stressful relationship event. It was hypothesized that reassessing coping would be negatively associated with depressive symptoms. METHODS: A cross-sectional Web-based survey was conducted in order to test this hypothesis by examining relationships between coping strategies including reassessing coping, distancing coping and constructive coping for stressful relationship events and depressive symptoms. Participants were 1,500 individuals recruited from the general populations of the United States, Australia, and China. RESULTS: Structural equation modeling analysis revealed that scores on coping strategies predicted depressive symptom scores in the samples from all three countries with medium or large effect sizes. Further, the beta values for reassessing coping scores were negative and significant in all samples, indicating that the hypothesis was supported for each of the population samples surveyed. In addition, distancing coping, which reflects strategies that attempt to actively damage, disrupt, and dissolve a stressful relationship, was associated with high levels of depressive symptoms. CONCLUSIONS: Reassessing coping for interpersonal stressors was be negatively associated with depressive symptoms in sample from general populations of the United States, Australia, and China. PMID- 25299136 TI - Phenylalanine binding is linked to dimerization of the regulatory domain of phenylalanine hydroxylase. AB - Analytical ultracentrifugation has been used to analyze the oligomeric structure of the isolated regulatory domain of phenylalanine hydroxylase. The protein exhibits a monomer-dimer equilibrium with a dissociation constant of ~46 MUM; this value is unaffected by the removal of the 24 N-terminal residues or by phosphorylation of Ser16. In contrast, phenylalanine binding (Kd = 8 MUM) stabilizes the dimer. These results suggest that dimerization of the regulatory domain of phenylalanine hydroxylase is linked to allosteric activation of the enzyme. PMID- 25299137 TI - From the guest editor: the search for sleep and energy: addressing the needs of cancer patients who suffer from insomnia and fatigue. PMID- 25299138 TI - Sleeping in the arms of cancer: a review of sleeping disorders among patients with cancer. AB - It is well known that cancer patients experience lack of sleep, which affects their symptoms and decrease their much needed energy, particularly while undergoing treatment. Insomnia, which is defined as a predominant complaint of dissatisfaction with sleep quantity or quality during different phases of the sleep cycle, could easily affect patients' quality of life and even cancer treatment outcomes. In this article, we review the current research on and treatments for insomnia, as well as explore cancer-related fatigue and its connections to sleep disorders. PMID- 25299139 TI - Treatment of fatigue and sleep disorders in cancer patients. AB - Sleep disorders are highly prevalent among cancer patients. These disorders can include disorders of sleep onset or maintenance or disorders of excessive sleepiness. A broad differential diagnosis is required to adequately treat these disorders. This review discusses current diagnoses and treatment associated with sleep difficulties that may be seen in cancer patients. With appropriate diagnosis and treatment, the prognosis is good for sleep improvement and improvements in quality of life. PMID- 25299140 TI - Nonpharmacologic approach to fatigue in patients with cancer. AB - Cancer-related fatigue is a common yet underappreciated problem with a significant impact on functional ability and quality of life. Practice guidelines mandate that all cancer patients and survivors be screened for cancer-related fatigue (CRF) at regular intervals. Comorbidities that could contribute to fatigue should be treated, and patients with moderate to severe fatigue should undergo a comprehensive evaluation. Nonpharmacologic interventions are important tools to combat CRF and should be incorporated into routine practice. Physical activity, educational interventions, and cognitive-behavioral therapy have the most supportive data and can be recommended to patients with confidence. From a practical standpoint, general education on CRF is something that most care providers can readily offer patients as part of routine care. Other interventions that appear promising but are as yet lacking convincing evidence include mindfulness-based stress reduction, yoga, and acupuncture. Reiki, Qigong, hypnosis, and music therapy may be worthy of further investigation. PMID- 25299141 TI - Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids. AB - Cancer-related fatigue (CRF) is the most common and debilitating symptom in patients with cancer. Currently, there are very limited pharmacological interventions to effectively treat CRF. In this article, the authors review various pharmacological interventions for CRF and propose future direction for further research. Methylphenidate is the most studied pharmacological agent for the treatment of CRF. Various pharmacological studies have suggested benefit of corticosteroids, especially in terminally ill patients for a short period. However, recent systematic reviews, meta-analyses, and guidelines recommend caution to using pharmacological agents for CRF as evidence points the use of psychostimulants only in patients with moderate to severe fatigue with advanced cancer or those receiving active cancer therapy, with no evidence in their use in cancer patients who have completed active cancer therapy. Further research is needed. PMID- 25299142 TI - Opportunities for targeting the fatigue-anorexia-cachexia symptom cluster. AB - Cancer patients experience multiple symptoms throughout their illness trajectory. Symptoms consistently occurring together, known as symptom clusters, share common pathophysiologic mechanisms. Understanding and targeting such symptom clusters may allow for more effective and efficient use of treatments for a variety of symptoms. Fatigue-anorexia-cachexia is one of the most prevalent symptom clusters and significantly impairs quality of life. In this review, we explore the fatigue anorexia-cachexia symptom cluster and focus on current and emerging therapies with an emphasis on pharmacologic management. PMID- 25299143 TI - Long-term and short-term effects of insomnia in cancer and effective interventions. AB - Sleep disorders and insomnia are more prevalent in patients with cancer than in the normal population. Sleep disorders consist of delayed sleep latency, waking episodes after sleep onset, unrefreshing sleep, reduced quality of sleep, and reduced sleep efficiency. Sleep disorders cluster with pain, fatigue, depression, anxiety, and vasomotor symptoms, depending on stage of disease, treatment, and comorbidities. Premorbid sleep problems and shift work have been associated with a higher prevalence of cancer; in fact, shift work has been labeled a carcinogen. Treatment for insomnia includes cognitive behavioral therapy with sleep hygiene, bright-light therapy, exercise, yoga, melatonin, and hypnotic medications. Unfortunately, there are few randomized trials in cancer-related sleep disorders such that most recommendations particularly for hypnotics are based on treatment for primary insomnia. In this article, insomnia is reviewed as a predisposing factor to cancer, prior to and during treatment, in cancer survivorship and in advanced cancer. Recommendations for treatment are based on low-quality evidence but are also reviewed. PMID- 25299144 TI - Nonpharmacologic approach to sleep disorders. AB - Sleep disturbances are common in patients with cancer, occurring throughout the disease trajectory and sometimes well after treatment has concluded. Insomnia often does not occur in isolation; it may be associated with pain, fatigue, depression, and medication usage. Screening for sleep disturbances is an essential part of caring for oncologic patients. The criterion standard for nonpharmacologic treatment of insomnia in these patients is cognitive-behavioral therapy, a multimodal approach using sleep hygiene and education, stimulus control, sleep restriction, and relaxation. Exercise and complementary and integrative medicine have been studied with varying results, and no firm recommendation can be made about their efficacy. PMID- 25299145 TI - Sleep disorders and fatigue: special issues in the older adult with cancer. AB - Older adults with cancer reporting fatigue and sleep disorders often have coexisting geriatric syndromes and are at high risk of further functional decline. This review summarizes special considerations in the diagnosis and treatment of sleep disorders and fatigue when older persons with cancer present with multiple comorbidities, polypharmacy, dementia, delirium, and/or falls. Physicians caring for these older adults need to be aware of the unique diagnostic and treatment concerns in this population so that these patients can receive optimal care. PMID- 25299146 TI - Understanding frailty in cancer patients. AB - As population ages, the number of older adults with cancer is increasing rapidly. Chronological age per se is a poor guide for an oncologist to determine tolerance to cancer treatment. Older adults have been underrepresented in cancer clinical trials, leading to paucity of guidelines to meet the treatment challenges in this population. To evaluate an older adult with cancer, oncologists must understand age-related changes and identify the subset of population who is vulnerable and at risk of cancer treatment toxicity. Comprehensive geriatric assessments focusing on functional status, multimorbidity, nutritional status, cognitive impairment, and psychosocial support help recognize heterogeneity among older adults, leading to individualized approaches toward cancer treatment. The treatment decisions need to be made in collaboration with the patient's values and preferences. PMID- 25299148 TI - beta-alanine Supplementation Fails to Increase Peak Aerobic Power or Ventilatory Threshold in Aerobically Trained Males. AB - The purpose of the present study was to determine the effect of 30 days of beta alanine supplementation on peak aerobic power and ventilatory threshold (VT) in aerobically fit males. Fourteen males (28.8 +/- 9.8 yrs) were assigned to either a beta-alanine (SUPP) or placebo (PLAC) group; groups were matched for VT as it was the primary outcome measure. beta-alanine supplementation consisted of 3 g/day for 7 days, and 6 g/day for the remaining 23 days. Before and after the supplementation period, subjects performed a continuous, graded cycle ergometry test to determine VO2 peak and VT. Metabolic data were analyzed using a 2 * 2 ANOVA with repeated measures. Thirty days of beta-alanine supplementation (SUPP) did not increase VO2 peak (4.05 +/- 0.6 vs. 4.14 +/- 0.6 L/min) as compared to the placebo (PLAC) group (3.88 +/- 0.2 vs. 3.97 +/- 0.2 L/min) (p > .05). VT did not significantly improve in either the SUPP (3.21 +/- 0.5 vs. 3.33 +/- 0.5 L/min) or PLAC (3.19 +/- 0.1 vs. 3.20 +/- 0.1 L/min) group (p > .05). In conclusion, 30 days of beta-alanine supplementation had no effect on VO2 peak or VT in aerobically trained athletes. PMID- 25299147 TI - Linear motif-mediated interactions have contributed to the evolution of modularity in complex protein interaction networks. AB - The modular architecture of protein-protein interaction (PPI) networks is evident in diverse species with a wide range of complexity. However, the molecular components that lead to the evolution of modularity in PPI networks have not been clearly identified. Here, we show that weak domain-linear motif interactions (DLIs) are more likely to connect different biological modules than strong domain domain interactions (DDIs). This molecular division of labor is essential for the evolution of modularity in the complex PPI networks of diverse eukaryotic species. In particular, DLIs may compensate for the reduction in module boundaries that originate from increased connections between different modules in complex PPI networks. In addition, we show that the identification of biological modules can be greatly improved by including molecular characteristics of protein interactions. Our findings suggest that transient interactions have played a unique role in shaping the architecture and modularity of biological networks over the course of evolution. PMID- 25299149 TI - Pesticidal and pest repellency activities of rhizomes of Drynaria quercifolia (J. Smith) against Tribolium castaneum (Herbst). AB - BACKGROUND: Tribolium castaneum (Herbst) is a harmful pest of stored grain and flour-based products in tropical and subtropical region. In the present study, rhizome of Drynaria quercifolia (J. Smith) was evaluated for pesticidal and pest repellency activities against T. castaneum, using surface film method and filter paper disc method, respectively. In addition, activity of the isolated compound 3,4-dihydroxybenzoic acid was evaluated against the pest. RESULTS: Chloroform soluble fraction of ethanol extract of rhizome of D. quercifolia showed significant pesticidal activity at doses 0.88 to 1.77 mg/cm(2) and significant pest repellency activity at doses 0.94 to 0.23 mg/cm(2). No pesticidal and pest repellency activity was found for petroleum ether, ethyl acetate and methanol soluble fractions of ethanol extract as well as for 3,4-dihydroxybenzoic acid. CONCLUSION: Considering our findings it can be concluded that chloroform soluble fraction of rhizome of D. quercifolia is useful in controlling T. castaneum of stored grain and flour-based products. PMID- 25299151 TI - Liquid chromatography-selected reaction monitoring (LC-SRM) approach for the separation and quantitation of sialylated N-glycans linkage isomers. AB - The study of N-linked glycans is among the most challenging bioanalytical tasks because of their complexity and variety. The presence of glycoform families that differ only in branching and/or linkage position makes the identification and quantitation of individual glycans exceedingly difficult. Quantitation of these individual glycans is important because changes in the abundance of these isomers are often associated with significant biomedical events. For instance, previous studies have shown that the ratio of alpha2-3 to alpha2-6 linked sialic acid (SA) plays an important role in cancer biology. Consequently, quantitative methods to detect alterations in the ratios of glycans based on their SA linkages could serve as a diagnostic tool in oncology, yet traditional glycomic profiling cannot readily differentiate between these linkage isomers. Here, we present a liquid chromatography-selected reaction monitoring (LC-SRM) approach that we demonstrate is capable of quantitating the individual SA linkage isomers. The LC method is capable of separating sialylated N-glycan isomers differing in alpha2-3 and alpha2-6 linkages using a novel superficially porous particle (Fused-Core) Penta HILIC (hydrophilic interaction liquid chromatography) column. SRM detection provides the relative quantitation of each SA linkage isomer, and minimizes interferences from coeluting glycans that are problematic for UV/Fluorescence based quantitation. With our approach, the relative quantitation of each SA linkage isomer is obtained from a straightforward liquid chromatography-mass spectrometry (LC-MS) experiment. PMID- 25299152 TI - Examining health-care utilization in the first year following spinal cord injury. AB - OBJECTIVE: To identify factors associated with health-care utilization during the first year after inpatient rehabilitation (IR) in individuals with traumatic spinal cord injury (SCI). DESIGN: Prospective cohort. METHODS: One hundred and sixty-eight patients were prospectively enrolled and followed over 1 year after discharge from an SCI Model System IR program. Telephone follow-up occurred at 3, 6, 9, and 12 months. Participants were grouped into four impairment levels (C1-4 American Spinal Injury Association (ASIA) Impairment Scale (AIS) A-C, C5-C8 AIS A C, paraplegia AIS A-C, and all AIS D). Three domains of health-care utilization were examined: hospital care, outpatient provider visits, and home services. RESULTS: Health-care utilization in the first year following IR was high with 45% of subjects reporting re-hospitalization. Twenty percent of patients were initially discharged to a skilled nursing facility (SNF), and an additional 10% required SNF care during this first year. Overall, those with C1-4 AIS A-C used the most services. Participants discharged home used less health care compared to those discharged elsewhere. SCI due to falls (vs. vehicular crashes) was associated with fewer in-home service visits. Age, sex, race, and education were unrelated to higher use. CONCLUSION: Those with greater neurological impairment or not discharged home after IR had higher health-care utilization, while age was not associated with utilization. Targeted efforts to reduce genitourinary and respiratory complications may reduce the need for hospital care in the first year after IR. PMID- 25299150 TI - Genetic polymorphisms and asthma: findings from a case-control study in the Madeira island population. AB - BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size >=10 mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management. PMID- 25299153 TI - Coding region SNP analysis to enhance dog mtDNA discrimination power in forensic casework. AB - The high population frequencies of three control region haplotypes contribute to the low discrimination power of the dog mtDNA control region. It also diminishes the evidential power of a match with one of these haplotypes in forensic casework. A mitochondrial genome study of 214 Belgian dogs suggested 26 polymorphic coding region sites that successfully resolved dogs with the three most frequent control region haplotypes. In this study, three SNP assays were developed to determine the identity of the 26 informative sites. The control region of 132 newly sampled dogs was sequenced and added to the study of 214 dogs. The assays were applied to 58 dogs of the haplotypes of interest, which confirmed their suitability for enhancing dog mtDNA discrimination power. In the Belgian population study of 346 dogs, the set of 26 sites divided the dogs into 25 clusters of mtGenome sequences with substantially lower population frequency estimates than their control region sequences. In case of a match with one of the three control region haplotypes, using these three SNP assays in conjunction with control region sequencing would augment the exclusion probability of dog mtDNA analysis from 92.9% to 97.0%. PMID- 25299154 TI - Dual-view plane illumination microscopy for rapid and spatially isotropic imaging. AB - We describe the construction and use of a compact dual-view inverted selective plane illumination microscope (diSPIM) for time-lapse volumetric (4D) imaging of living samples at subcellular resolution. Our protocol enables a biologist with some prior microscopy experience to assemble a diSPIM from commercially available parts, to align optics and test system performance, to prepare samples, and to control hardware and data processing with our software. Unlike existing light sheet microscopy protocols, our method does not require the sample to be embedded in agarose; instead, samples are prepared conventionally on glass coverslips. Tissue culture cells and Caenorhabditis elegans embryos are used as examples in this protocol; successful implementation of the protocol results in isotropic resolution and acquisition speeds up to several volumes per s on these samples. Assembling and verifying diSPIM performance takes ~6 d, sample preparation and data acquisition take up to 5 d and postprocessing takes 3-8 h, depending on the size of the data. PMID- 25299155 TI - Screening and large-scale expression of membrane proteins in mammalian cells for structural studies. AB - Structural, biochemical and biophysical studies of eukaryotic membrane proteins are often hampered by difficulties in overexpression of the candidate molecule. Baculovirus transduction of mammalian cells (BacMam), although a powerful method to heterologously express membrane proteins, can be cumbersome for screening and expression of multiple constructs. We therefore developed plasmid Eric Gouaux (pEG) BacMam, a vector optimized for use in screening assays, as well as for efficient production of baculovirus and robust expression of the target protein. In this protocol, we show how to use small-scale transient transfection and fluorescence-detection size-exclusion chromatography (FSEC) experiments using a GFP-His8-tagged candidate protein to screen for monodispersity and expression level. Once promising candidates are identified, we describe how to generate baculovirus, transduce HEK293S GnTI(-) (N-acetylglucosaminyltransferase I negative) cells in suspension culture and overexpress the candidate protein. We have used these methods to prepare pure samples of chicken acid-sensing ion channel 1a (cASIC1) and Caenorhabditis elegans glutamate-gated chloride channel (GluCl) for X-ray crystallography, demonstrating how to rapidly and efficiently screen hundreds of constructs and accomplish large-scale expression in 4-6 weeks. PMID- 25299158 TI - Validity of linear response theory for time-dependent fluorescence in Staphylococcus nuclease. AB - We report a theoretical study on the relaxation dynamics of Staphylococcus nuclease following photon excitation. Molecular dynamics simulations were implemented for both ground state and excited state surface of Trp140. Over the course of 40 ns ground state simulation, a structural transition was observed from one isomeric protein configuration to another. No obvious isomerization process was exhibited in the excited state simulations. Using linear response theory and direct nonequilibrium approach, time-dependent Stokes shift, as well as its time-infinity value, was evaluated for both ground state isomers. Comparison between these methods exhibits severe disagreement. The nonequilibrium simulations show the similar relaxation dynamics as the excited state linear response approach, whereas they severely differ from the ground state linear response evaluation. Further examination reveals that the isomerization process breaks the characteristics of the energy gap histogram from Gaussian statistics. We also made the comparison between the experimental and simulation results. The significant inertial decay, in theory, is absent in the experiment. The ground state linear response evaluation provides a better agreement with the experimental results among all three approaches. PMID- 25299156 TI - Detecting ultralow-frequency mutations by Duplex Sequencing. AB - Duplex Sequencing (DS) is a next-generation sequencing methodology capable of detecting a single mutation among >1 * 10(7) wild-type nucleotides, thereby enabling the study of heterogeneous populations and very-low-frequency genetic alterations. DS can be applied to any double-stranded DNA sample, but it is ideal for small genomic regions of <1 Mb in size. The method relies on the ligation of sequencing adapters harboring random yet complementary double-stranded nucleotide sequences to the sample DNA of interest. Individually labeled strands are then PCR-amplified, creating sequence 'families' that share a common tag sequence derived from the two original complementary strands. Mutations are scored only if the variant is present in the PCR families arising from both of the two DNA strands. Here we provide a detailed protocol for efficient DS adapter synthesis, library preparation and target enrichment, as well as an overview of the data analysis workflow. The protocol typically takes 1-3 d. PMID- 25299157 TI - Single-cell in situ imaging of palmitoylation in fatty-acylated proteins. AB - Dissecting the subcellular distribution of a fatty-acylated protein is key to the understanding of the molecular mechanisms regulating protein movement and function in a cell. This protocol describes how to perform single-cell imaging of palmitoylation in a fatty-acylated protein of interest with high sensitivity using click chemistry, proximity ligation and fluorescence microscopy. The initial steps in this protocol involve optimization of conditions for (i) metabolic incorporation of an alkynyl analog of palmitic acid into cellular proteins coupled with click chemistry and (ii) detecting a specific protein of interest with primary antibodies using automated fluorescence microscopy, followed by (iii) imaging palmitoylation of the target fatty-acylated protein of interest, such as Wnt, Sonic Hedgehog or H-Ras. Furthermore, we outline strategies for imaging specific fatty-acylated proteins with subcellular organelles and/or total proteome palmitoylation, and we discuss special considerations that need to be given depending on the experimental design. The use of clickable fatty acids with proximity ligation may have promising applications to the investigation of fatty acylation cell biology. The entire protocol takes ~3 weeks to complete. PMID- 25299161 TI - Black phosphorus photodetector for multispectral, high-resolution imaging. AB - Black phosphorus is a layered semiconductor that is intensely researched in view of applications in optoelectronics. In this letter, we investigate a multilayer black phosphorus photodetector that is capable of acquiring high-contrast (V > 0.9) images both in the visible (lambdaVIS = 532 nm) as well as in the infrared (lambdaIR = 1550 nm) spectral regime. In a first step, by using photocurrent microscopy, we map the active area of the device and we characterize responsivity and gain. In a second step, by deploying the black phosphorus device as a point like detector in a confocal microsope setup, we acquire diffraction-limited optical images with submicron resolution. The results demonstrate the usefulness of black phosphorus as an optoelectronic material for hyperspectral imaging applications. PMID- 25299159 TI - The telomerase reverse transcriptase subunit from the dimorphic fungus Ustilago maydis. AB - In this study, we investigated the reverse transcriptase subunit of telomerase in the dimorphic fungus Ustilago maydis. This protein (Trt1) contains 1371 amino acids and all of the characteristic TERT motifs. Mutants created by disrupting trt1 had senescent traits, such as delayed growth, low replicative potential, and reduced survival, that were reminiscent of the traits observed in est2 budding yeast mutants. Telomerase activity was observed in wild-type fungus sporidia but not those of the disruption mutant. The introduction of a self-replicating plasmid expressing Trt1 into the mutant strain restored growth proficiency and replicative potential. Analyses of trt1 crosses in planta suggested that Trt1 is necessary for teliospore formation in homozygous disrupted diploids and that telomerase is haploinsufficient in heterozygous diploids. Additionally, terminal restriction fragment analysis in the progeny hinted at alternative survival mechanisms similar to those of budding yeast. PMID- 25299160 TI - Revisiting galvanomagnetic effects in conducting ferromagnets. AB - The recently proposed coupling between the angular momentum density and magnetic moments is shown to provide a straightforward alternative explanation for galvanomagnetic effects, i.e. for both anisotropic magnetoresistance (AMR) and planar Hall effect (PHE). Such coupling naturally reproduces the general formula associated with AMR and PHE and allows for the occurrence of so-called 'negative AMR'. This coupling also provides a unifying link between AMR, PHE and the anomalous Hall effect (AHE) since this same coupling was previously found to give rise to AHE (Bellaiche et al 2013 Phys. Rev. B 88 161102). PMID- 25299162 TI - Phase transitions in semiflexible-rod diblock copolymers: a self-consistent field theory. AB - We investigate the phase behavior of semiflexible-rod diblock copolymers in a parameter range where the system displays columnar and lamella structures, using a self-consistent field theory based on the wormlike-chain model. Both Flory Huggins and Maier-Saupe orientational interactions are incorporated in the formalism, which allows us to explore microphase separation and liquid-crystal ordering simultaneously. Order-to-order phase transitions induced by chain rigidity and orientational interaction are both reported and analyzed. Coupled orientational ordering and spatial inhomogeneity of the four microphase-separated states are discussed in this work: hexagonal column, ellipse column, smectic-A, and smectic-C. PMID- 25299163 TI - Total body exposure to low-dose ionizing radiation induces long-term alterations to the liver proteome of neonatally exposed mice. AB - Tens of thousands of people are being exposed daily to environmental low-dose gamma radiation. Epidemiological data indicate that such low radiation doses may negatively affect liver function and result in the development of liver disease. However, the biological mechanisms behind these adverse effects are unknown. The aim of this study was to investigate radiation-induced damage in the liver after low radiation doses. Neonatal male NMRI mice were exposed to total body irradiation on postnatal day 10 using acute single doses ranging from 0.02 to 1.0 Gy. Early (1 day) and late (7 months) changes in the liver proteome were tracked using isotope-coded protein label technology and quantitative mass spectrometry. Our data indicate that low and moderate radiation doses induce an immediate inhibition of the glycolysis pathway and pyruvate dehydrogenase availability in the liver. Furthermore, they lead to significant long-term alterations in lipid metabolism and increased liver inflammation accompanying inactivation of the transcription factor peroxisome proliferator-activated receptor alpha. This study contributes to the understanding of the potential risk of liver damage in populations environmentally exposed to ionizing radiation. PMID- 25299164 TI - Factors predisposing to maxillary anchorage loss: a retrospective study of 1403 cases. AB - Anchorage loss is very disturbing for orthodontists and patients during orthodontic treatment, which usually results in bad treatment effects. Despite the same treatment strategy, different patients show different tendencies toward anchorage loss, which influences the treatment results and should preferably be predicted before the treatment is begun. However, relatively little research has been conducted on which patients are more likely to lose anchorage. The mesial tipping of the first molar marks the onset of anchorage loss, and changes in the angulation of the first molar are closely related to anchorage loss. This cross sectional study aimed to determine how the mesiodistal angulation of the upper first molars changes during general orthodontic treatment and to identify the individual physiologic factors leading to these changes in a large sample of 1403 patients with malocclusion. The data indicate that the upper first molars tend to be tipped mesially during orthodontic treatment, and this constitutes a type of anchorage loss that orthodontists should consider carefully. Compared to treatment-related factors, patients' physiologic characteristics have a greater influence on changes in the angulation of the upper first molars during orthodontic treatment. The more distally tipped the upper first molars are before treatment, the more they will tip mesially during treatment. Mesial tipping of the upper first molars, and therefore, anchorage loss, is more likely to occur in adolescents, males, patients with class II malocclusion and patients who have undergone maxillary premolar extraction. This finding is of clinical significance to orthodontists who wish to prevent iatrogenic anchorage loss by tipping originally distally tipped upper molars forward, and provides a new perspective on anchorage during orthodontic treatment planning. PMID- 25299165 TI - Classical nuclear hormone receptor activity as a mediator of complex concentration response relationships for endocrine active compounds. AB - Nonmonotonic concentration response relationships are frequently observed for endocrine active ligands that act via nuclear receptors. The curve of best fit for nonmonotonic concentration response relationships are often inverted U-shaped with effects at intermediate concentrations that are different from effects at higher or lower concentrations. Cytotoxicity is a major mode of action responsible for inverted U-shaped concentration response relationships. However, evidence suggests that ligand selectivity, activation of multiple molecular targets, concerted regulation of multiple opposing endpoints, and multiple ligand binding sites within nuclear receptors also contribute to nonmonotonic concentration response relationships of endocrine active ligands. This review reports the current understanding of mechanisms involved in classical nuclear receptor mediated nonmonotonic concentration response relationships with a focus on studies published between 2012 and 2014. PMID- 25299166 TI - Does bone morphogenetic protein change the operative nonunion rates in spine fusions? AB - STUDY DESIGN: A retrospective cohort study with medical record review. OBJECTIVE: To determine if there is difference in the operative nonunion rates with and without the use of bone morphogenetic protein (BMP) after spinal fusions by analyzing data from an integrated health care system's spine registry. SUMMARY OF BACKGROUND DATA: BMP was first approved in 2002 for use in single-level anterior lumbar fusions. Follow-up studies have advocated its use in reducing the need for reoperations for nonunions. Recent studies, however, have questioned these conclusions and the usefulness of BMP in spinal fusions has been highly debated. METHODS: We identified 9425 spinal fusion cases between 2009 and 2011 from a spine registry in a large integrated health care organization. Patient characteristics, diagnosis, operative times, length of stay, and reoperations were extracted from the registry. Reoperations for nonunions were adjudicated via medical record review. Cox regression models were used to evaluate the risk of reoperation while adjusting for confounders. RESULTS: In our cohort, there were 5456 BMP cases and 3969 non-BMP cases. The mean age was 60.4 years (standard deviation: 12.9 yr), with the majority being females (53%). The median follow-up time was 1.2 years (interquartile range: 0.6-2.0 yr). Reoperation rates for BMP versus non-BMP nonunions for all fusion cases with follow-up of 1 year or more (1.9% vs. 2.2%) and follow-up of 2 years or more (2.3% vs. 2.6%) were not statistically significantly different. Operative nonunion rates did not reach statistical significance for different spine regions and for different fused columns (anterior only, posterior only, or combined). After controlling for differences in patient characteristics, operative times, levels fused, and spinal regions, the risk of reoperation in the BMP versus non-BMP groups was 0.67 (95% CI: 0.42-1.06). CONCLUSION: In this large cohort of spinal fusions at all spine regions involving all fused columns with and without BMP, we found no statistically significant difference in operative nonunion rates. LEVEL OF EVIDENCE: 3. PMID- 25299167 TI - Effect of posterior multilevel vertebral osteotomies on coronal and sagittal balance in fused scoliosis deformity caused by previous surgery: preliminary results. AB - STUDY DESIGN: Prospective case series study. OBJECTIVE: To study the effect of posterior multilevel vertebral osteotomy (posterior crack osteotomy) on coronal and sagittal balance in patients with the fusion mass over the spine caused by previous surgery. SUMMARY OF BACKGROUND DATA: Few studies have investigated revisional scoliosis surgery with the fusion mass using osteotomy. METHODS: Among patients who had a history of prior surgery for scoliosis correction and posterior fusion, those showing progression of the curve postoperatively due to nonunion, implant failure, or adding-on phenomenon were enrolled. All patients were treated using posterior crack osteotomy. For clinical evaluation, the pre- and postoperative Gross Motor Function Classification System score for walking status and the Berg balanced scale were used. For radiological evaluation, pre- and postoperative Cobb angle, and coronal and sagittal balance factors were used. RESULTS: Ten patients (5 males and 5 females) were enrolled. The preoperative diagnosis was neuromuscular scoliosis (3 cases), syndromic scoliosis (1 case), congenital scoliosis (5 cases), and neurofibromatosis (1 case). Osteotomies were performed at 3.3+/-1.3 levels on average. Pre- and postoperative Cobb angles were 70.8 degrees +/-30.0 degrees and 28.1 degrees +/-20.0 degrees (P=0.002 (0.97)), respectively. In pre- and postoperative evaluation of coronal balance, the coronal balance, clavicle angle, and T1-tilt angle were 36.8+/-27.1 mm and 10.4+/ 8.5 mm, 6.7 degrees +/-8.0 degrees and 3.3 degrees +/-1.5 degrees , and 7.8 degrees +/-19.0 degrees and 4.7 degrees +/-2.1 degrees , respectively (P=0.002, 0.002, 0.002). In pre- and postoperative evaluation of sagittal balance, the spinal vertical axis, thoracic kyphosis, and lumbar alignments were 25.1+/-37.8 mm and 14.1+/-21.8 mm, 33.5 degrees +/-51.1 degrees and 29.7 degrees +/-27.4 degrees , and 45.7 degrees +/-34.8 degrees and 48.9 degrees +/-23.1 degrees (P=0.002, 0.169, 0.169). The walking and functional statuses did not change (P=0.317, 0.932). Although pulmonary and gastrointestinal complications were noted, the patients were discharged without complications. CONCLUSION: Posterior crack osteotomy can be used effectively in revisional scoliosis surgery and the clinical and radiological results seem to be acceptable. LEVEL OF EVIDENCE: 4. PMID- 25299168 TI - Comparison of standard 2-rod constructs to multiple-rod constructs for fixation across 3-column spinal osteotomies. AB - STUDY DESIGN: Retrospective matched-cohort comparative study. OBJECTIVE: Compare radiographical outcomes after the use of a standard 2-rod construct (2-RC) versus a multiple-rod construct (multi-RC) across 3-column osteotomy sites in a matched cohort with severe kyphosis and/or scoliosis with minimum 2-year follow-up. SUMMARY OF BACKGROUND DATA: Three-column osteotomies are used for treating severe spinal deformities, typically with a standard 2-RC across the highly unstable osteotomy site. METHODS: Between 1996 and 2010, patients undergoing a 3-column osteotomy by a single surgeon were matched for age/diagnosis/vertebra(e) resected/levels fused and curve magnitude. Sixty-six control patients with a 2-RC were identified and appropriately matched to 66 consecutive patients with a multi RC across the 3-column osteotomy site. Each group included 50 patients with lumbar pedicle subtraction osteotomy and 16 patients with vertebral column resection. Radiographs were measured using standard adult deformity criteria. RESULTS: Averages were compared for 2-RC versus multi-RC demonstrating no statistical differences in mean age at surgery, vertebrae resected, levels fused, bone morphogenetic protein used (patients), or average preoperative Cobb magnitude. There were significant differences in the occurrence of rod breakage and revision surgery for pseudarthroses at the 3-column osteotomy site (rod breakage: 2-RC: 11 vs. multi-RC: 2, P=0.002; and revision: 2-RC: 6 vs. multi-RC: 0, P=0.011). There was no complete implant failure in the multi-RC group but 2 patients had partial implant failure without symptomatic pseudarthrosis. Eight patients in each group (12%) developed a pseudarthrosis above or below the osteotomy site. CONCLUSION: The use of a multi-RC is a safe, simple, and effective method to provide increased stability across 3-column osteotomy sites to significantly prevent implant failure and symptomatic pseudarthrosis versus a standard 2-RC. We strongly recommend using a multi-RC to stabilize 3-column osteotomies of the thoracic and lumbar spine. LEVEL OF EVIDENCE: 3. PMID- 25299169 TI - Patient and surgical factors associated with postoperative urinary retention after lumbar spine surgery. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: The objectives of this study were to (1) determine the rate of postoperative urinary retention (POUR) in a series of patients undergoing lumbar spine surgery, (2) compare length of hospital stay between patients who developed POUR and patients who did not, and (3) identify the patient and surgical factors associated with the development of POUR. SUMMARY OF BACKGROUND DATA: Although POUR is a common complication in many surgical subspecialties, sparse literature is present regarding development of POUR after posterior lumbar surgical procedures. METHODS: A retrospective review was conducted of all posterior lumbar surgery cases performed at single institute from July 2008 to July 2012. Data collected included demographic variables (age, sex, body mass index), length of stay, comorbid medical conditions, and surgical data. The Wilcoxon rank sum test with continuity correction was used to compare length of hospital stay between patients who developed POUR and patients who did not. A multivariate logistic regression model was created using all patient and surgical factors and systematically pruned of variables not improving overall predictive power. RESULTS: A total of 647 patients (291 decompression, 356 decompression and fusion) were included in the study. Of 647 patients, 36 had urinary retention after lumbar spine surgery (5.6%). Patients who developed POUR had a longer length of stay than patients who did not develop POUR (3.94 d vs. 2.34 d; P=0.005). Male sex, benign prostatic hyperplasia, age, diabetes, and depression were significantly associated with development of POUR (odds ratio=3.05, 9.82, 1.04, 3.32, and 2.51, respectively). Smoking was inversely associated with the development of POUR (odds ratio=0.45). CONCLUSION: The risk of developing POUR after posterior lumbar spine surgery is approximately 5%. Male sex, benign prostatic hyperplasia, age, diabetes, and depression were significantly associated with the POUR group. Patients who developed POUR had a greater length of hospital stay. LEVEL OF EVIDENCE: 4. PMID- 25299170 TI - The effect of serial growing rod lengthening on the sagittal profile and pelvic parameters in early-onset scoliosis. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To report the effect of repeated growing rod (GR) lengthenings on the sagittal and pelvic profile in patients with early-onset scoliosis. SUMMARY OF BACKGROUND DATA: Posterior distraction-based GRs have gained popularity as a technique for the surgical management of early-onset scoliosis. However, there are no published studies on the effect of serial GR lengthenings on sagittal balance, thoracic kyphosis (TK), lumbar lordosis (LL), and pelvic parameters. METHODS: We retrospectively reviewed data from a multicenter early-onset scoliosis database. Forty-three patients who were able to walk with minimum 2-year follow-up who underwent single- or dual-GR surgery were included for review. Mean number of lengthenings was 6.4 (range, 3 16). Mean preoperative age was 5.6 years (standard deviation, 2.4 yr), and mean follow-up was 3.5 years. Maximum TK, LL, and sagittal balance were assessed preoperatively, after index surgery, and at the latest follow-up. RESULTS: There was a significant decrease both in TK and LL after index surgery, which then increased during the lengthening period. There was a significant increase in both proximal junctional kyphosis and distal junctional angle. Pelvic parameters (pelvic tilt, pelvic incidence, sacral slope) were unchanged during the treatment period. Significant improvement was observed in sagittal balance. There was a correlation between the change in TK and change in LL. CONCLUSION: TK decreased after index surgery and increased between the index surgery and the latest follow up, which was accompanied by an increase in LL. All-screw proximal constructs had mean 9 degrees more proximal junctional kyphosis than all-hook proximal constructs. An increase in proximal junctional kyphosis and distal junctional angle was found during the treatment period. Although there was an independent effect of number of lengthenings on TK, there was no significant detrimental effect on other sagittal spinopelvic parameters. GRs had a positive effect on sagittal vertical axis, which returned patients to a more neutral alignment through the course of treatment. LEVEL OF EVIDENCE: 4. PMID- 25299171 TI - Point of view. PMID- 25299173 TI - Urban and rural differences in risk of admission to a care home: a census-based follow-up study. AB - Research on admissions to care homes for older people has paid more attention to individual and social characteristics than to geographical factors. This paper considers rural-urban differences in household composition and admission rates. COHORT: 51,619 people aged 65 years or older at the time of the 2001 Census and not living in a care home, drawn from a data linkage study based on c.28% of the Northern Ireland population. Living alone was less common in rural areas; 25% of older people in rural areas lived with children compared to 18% in urban areas. Care home admission was more common in urban (4.7%) and intermediate (4.3%) areas than in rural areas (3.2%). Even after adjusting for age, sex, health and living arrangements, the rate of care home admission in rural areas was still only 75% of that in urban areas. People in rural areas experience better family support by living as part of two or three generation households. Even after accounting for this difference, older rural dwellers are less likely to enter care homes; suggesting that neighbours and relatives in rural areas provide more informal care; or that there may be differential deployment of formal home care services. PMID- 25299174 TI - Identifying problematic Internet users: development and validation of the Internet Motive Questionnaire for Adolescents (IMQ-A). AB - BACKGROUND: Internationally, up to 15.1% of intensive Internet use among adolescents is dysfunctional. To provide a basis for early intervention and preventive measures, understanding the motives behind intensive Internet use is important. OBJECTIVE: This study aims to develop a questionnaire, the Internet Motive Questionnaire for Adolescents (IMQ-A), as a theory-based measurement for identifying the underlying motives for high-risk Internet use. More precisely, the aim was to confirm the 4-factor structure (ie, social, enhancement, coping, and conformity motives) as well as its construct and concurrent validity. Another aim was to identify the motivational differences between high-risk and low-risk Internet users. METHODS: A sample of 101 German adolescents (female: 52.5%, 53/101; age: mean 15.9, SD 1.3 years) was recruited. High-risk users (n=47) and low-risk users (n=54) were identified based on a screening measure for online addiction behavior in children and adolescents (Online-Suchtverhalten-Skala, OSVK S). Here, "high-risk" Internet use means use that exceeds the level of intensive Internet use (OSVK-S sum score >=7). RESULTS: The confirmatory factor analysis confirmed the IMQ-A's 4-factor structure. A reliability analysis revealed good internal consistencies of the subscales (.71 up to .86). Moreover, regression analyses confirmed that the enhancement and coping motive groups significantly predicted high-risk Internet consumption and the OSVK-S sum score. A mixed-model ANOVA confirmed that adolescents mainly access the Internet for social motives, followed by enhancement and coping motives, and that high-risk users access the Internet more frequently for coping and enhancement motives than low-risk users. Low-risk users were primarily motivated socially. CONCLUSIONS: The IMQ-A enables the assessment of motives related to adolescent Internet use and thus the identification of populations at risk. The questionnaire enables the development of preventive measures or early intervention programs, especially dealing with internal motives of Internet consumption. PMID- 25299175 TI - Metagenomic approach reveals variation of microbes with arsenic and antimony metabolism genes from highly contaminated soil. AB - Microbes have great potential for arsenic (As) and antimony (Sb) bioremediation in heavily contaminated soil because they have the ability to biotransform As and Sb to species that have less toxicity or are more easily removed. In this study, we integrated a metagenomic method with physicochemical characterization to elucidate the composition of microbial community and functional genes (related to As and Sb) in a high As (range from 34.11 to 821.23 mg kg-1) and Sb (range from 226.67 to 3923.07 mg kg-1) contaminated mine field. Metagenomic analysis revealed that microbes from 18 phyla were present in the 5 samples of soil contaminated with high As and Sb. Moreover, redundancy analysis (RDA) of the relationship between the 18 phyla and the concentration of As and Sb demonstrated that 5 phyla of microbes, i.e. Actinobacteria, Firmicutes, Nitrospirae, Tenericutes and Gemmatimonadetes were positively correlated with As and Sb concentration. The distribution, diversity and abundance of functional genes (including arsC, arrA, aioA, arsB and ACR3) were much higher for the samples containing higher As and Sb concentrations. Based on correlation analysis, the results showed a positive relationship between arsC-like (R2 = 0.871) and aioA-like (R2 = 0.675) gene abundance and As concentration, and indicated that intracellular As(V) reduction and As(III) oxidation could be the dominant As detoxification mechanism enabling the microbes to survive in the environment. This study provides a direct and reliable reference on the diversity of microbial community and functional genes in an extremely high concentration As- and Sb-contaminated environment. PMID- 25299176 TI - Ozone-initiated terpene reaction products in five European offices: replacement of a floor cleaning agent. AB - Cleaning agents often emit terpenes that react rapidly with ozone. These ozone initiated reactions, which occur in the gas-phase and on surfaces, produce a host of gaseous and particulate oxygenated compounds with possible adverse health effects in the eyes and airways. Within the European Union (EU) project OFFICAIR, common ozone-initiated reaction products were measured before and after the replacement of the regular floor cleaning agent with a preselected low emitting floor cleaning agent in four offices located in four EU countries. One reference office in a fifth country did not use any floor cleaning agent. Limonene, alpha pinene, 3-carene, dihydromyrcenol, geraniol, linalool, and alpha-terpineol were targeted for measurement together with the common terpene oxidation products formaldehyde, 4-acetyl-1-methylcyclohexene (4-AMCH), 3-isopropenyl-6-oxo-heptanal (IPOH), 6-methyl-5-heptene-2-one, (6-MHO), 4-oxopentanal (4-OPA), and dihydrocarvone (DHC). Two-hour air samples on Tenax TA and DNPH cartridges were taken in the morning, noon, and in the afternoon and analyzed by thermal desorption combined with gas chromatography/mass spectrometry and HPLC/UV analysis, respectively. Ozone was measured in all sites. All the regular cleaning agents emitted terpenes, mainly limonene and linalool. After the replacement of the cleaning agent, substantially lower concentrations of limonene and formaldehyde were observed. Some of the oxidation product concentrations, in particular that of 4-OPA, were also reduced in line with limonene. Maximum 2 h averaged concentrations of formaldehyde, 4-AMCH, 6-MHO, and IPOH would not give rise to acute eye irritation-related symptoms in office workers; similarly, 6 AMCH, DHC and 4-OPA would not result in airflow limitation to the airways. PMID- 25299177 TI - Development and clinical study of submicronic-atropine sulphate respiratory fluid as a novel organophosphorous poisoning antidote. AB - CONTEXT: Increased use of organophosphate insecticides (OPI) and possibility of terror groups using stocks of nerve agents underscore the need to develop effective and safe antidotes. While intramuscular administration of antidotes like atropine sulphate (AS) has certain lacunae, intravenous route may not be always feasible in emergency field conditions. OBJECTIVE: Objective was (a) to develop a novel inhalable submicronic-AS respiratory fluid as potential antidote for OPI poisoning, (b) in-vitro and in-vivo evaluation in terms of respiratory fraction, and (c) clinical study to assess drug bioavailability in blood and atropinization pattern post-inhalation. METHODS: Formulation was optimized on the basis of particle size of aerosolized droplets and in-vitro nebulization rate. Anderson cascade impaction (ACI) studies were carried out to validate the advantage of test formulation in terms of respirable fraction. Six healthy volunteers were inhaled the test formulation and blood bioavailability and atropinization were noted serially. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized AS in-vivo. RESULTS: The formulation was optimized using 30% ethanol-saline with particle size in the range of 350-500 nm. In-vitro ACI data showed high respirable fraction (82.6 +/- 3.1%) for the test formulation. In-vivo scintigraphy suggested whole lung deposition of 80.2 +/ 6.8% of the total inhaled dose. Early blood bioavailability and atropinization pattern confirmed that therapeutic concentration of the drug in blood was reached within 5 min. CONCLUSIONS: 3% submicronic-AS respiratory fluid might be used as potential prophylactic/therapeutic option against OPI poisoning with several advantages over intramuscular injection, including early blood bioavailability and atropinization. PMID- 25299179 TI - Determination of local atomic displacements in CeO(1-x)F(x)BiS2 system. AB - We have used Bi and Ce L3-edges extended x-ray absorption fine structure measurements to study local structure of CeO(1-x)F(x)BiS2 system as a function of F-substitution. The local structure of both BiS2 active layer and CeO1-xFx spacer layer changes systematically. The in-plane Bi-S1 distance decreases (DeltaRmax ~ 0.08 A) and the out-of-plane Bi-S2 distance increases (DeltaRmax ~ 0.12 A) with increasing F-content. On the other hand, the Ce-O/F distance increases (DeltaRmax ~ 0.2 A) with a concomitant decrease of the Ce-S2 distance (DeltaRmax ~ 0.15 A). Interestingly, the Bi-S1 distance is characterized by a large disorder that increases with F-content. The results provide useful information on the local atomic displacements in CeO(1-x)F(x)BiS2, that should be important for the understanding of the coexistence of superconductivity and low temperature ferromagnetism in this system. PMID- 25299178 TI - Prevalent and incident HIV diagnoses among Entamoeba histolytica-infected adult males: a changing epidemiology associated with sexual transmission--Taiwan, 2006 2013. AB - BACKGROUND: Sexually transmitted Entamoeba histolytica infection (EHI) has been increasingly recognized among men who have sex with men (MSM). We used the National Disease Surveillance Systems (NDSS) to identify prevalent and incident HIV diagnoses among adults with EHI and to determine the associated factors. METHODOLOGY: The NDSS collect demographic, clinical, and behavioral characteristics of case patients through physician reports and public health interviews. EHI was confirmed by polymerase-chain-reaction assays, histopathology, or serology with documented liver abscess. We linked NDSS databases to identify prevalent and incident HIV diagnoses among noninstitutionalized Taiwanese adults with confirmed EHI during 2006-2013. Cox proportional-hazards analysis was used to determine associated factors. PRINCIPAL FINDINGS: Of noninstitutionalized adults with EHI, we identified prevalent HIV diagnosis in 210 (40%) of 524 males and one (1.7%) of 59 females, and incident HIV diagnosis in 71 (23%) of 314 males. MSM accounted for 183 (87%) and 64 (90%) of prevalent and incident HIV diagnoses in males, respectively. From 2006-2009 to 2010-2013, the prevalence of HIV diagnosis increased from 32% to 45% (P = 0.001) while the incidence of HIV diagnosis increased from 5.4 to 11.3 per 100 person years (P = 0.001) among males with EHI. Incident HIV diagnosis was independently associated with a younger age, residing in metropolitan areas, hospitalization, previous syphilis, and engagement in oral, anal, or oral-anal sex before illness onset. CONCLUSIONS/SIGNIFICANCE: Prevalent and incident HIV diagnoses were increasingly identified among adult males in Taiwan, preferentially affecting younger urban MSM. Surveillance and risk-reduction interventions are recommended against the interplay of HIV epidemic and sexually transmitted EHI. PMID- 25299180 TI - Therapeutic effects of CTLA4Ig gene-transduced adipose tissue-derived mesenchymal stem cell transplantation on established autoimmune thyroiditis. AB - This study aimed to identify the beneficial effects of adipose tissue-derived mesenchymal stem cells (ASCs) and ASCs that overexpress the CTLA4Ig gene (CTLA4Ig ASCs) on established autoimmune thyroiditis and to examine changes in clinical chemistry parameters and the presence of humoral responses upon repeated long term administration of autologous ASCs. This study also aimed to acquire desirable results in a preclinical study by using large-sized lab animals and applying ASCs that overexpress therapeutic genes. Experimental autoimmune thyroiditis was induced by immunization with thyroglobulin. Experimental dogs were divided into five groups: (i) ASC IT + IV, (ii) ASC IV, (iii) CTLA4Ig-ASC IT + IV, (iv) CTLA4Ig-ASC IV, and (v) control IT + IV (saline only), and they received intrathyroidal (IT; 10 million cells/250 ul saline per thyroid) administration one time or intravenous (IV; 20 million cells/5 ml) administration seven times within a 101-day period. Blood samples were collected every week, and thyroids were harvested on days 104-106. After serial ASC or CTLA4Ig transplantation, the levels of canine thyroglobulin autoantibodies (TgAA) in serum and the infiltration of T-lymphocytes between the follicles of the thyroid glands were decreased. The expression of FoxP3 in submandibular lymph nodes was significantly increased. Repeated long-term administration of autologous ASCs or CTLA4Ig-ASCs did not generate changes in clinical chemistry parameters or humoral responses.The TgAA test can detect autoimmune thyroiditis years before clinical signs of hypothyroidism occur. Thus, ASC and CTLA4Ig-ASC transplantation in that period can be attractive candidates to ameliorate autoimmune thyroiditis and prevent the development of hypothyroidism. PMID- 25299181 TI - Aedes hensilli as a potential vector of Chikungunya and Zika viruses. AB - An epidemic of Zika virus (ZIKV) illness that occurred in July 2007 on Yap Island in the Federated States of Micronesia prompted entomological studies to identify both the primary vector(s) involved in transmission and the ecological parameters contributing to the outbreak. Larval and pupal surveys were performed to identify the major containers serving as oviposition habitat for the likely vector(s). Adult mosquitoes were also collected by backpack aspiration, light trap, and gravid traps at select sites around the capital city. The predominant species found on the island was Aedes (Stegomyia) hensilli. No virus isolates were obtained from the adult field material collected, nor did any of the immature mosquitoes that were allowed to emerge to adulthood contain viable virus or nucleic acid. Therefore, laboratory studies of the probable vector, Ae. hensilli, were undertaken to determine the likelihood of this species serving as a vector for Zika virus and other arboviruses. Infection rates of up to 86%, 62%, and 20% and dissemination rates of 23%, 80%, and 17% for Zika, chikungunya, and dengue-2 viruses respectively, were found supporting the possibility that this species served as a vector during the Zika outbreak and that it could play a role in transmitting other medically important arboviruses. PMID- 25299182 TI - Sensors at centrosomes reveal determinants of local separase activity. AB - Separase is best known for its function in sister chromatid separation at the metaphase-anaphase transition. It also has a role in centriole disengagement in late mitosis/G1. To gain insight into the activity of separase at centrosomes, we developed two separase activity sensors: mCherry-Scc1(142-467)-DeltaNLS-eGFP-PACT and mCherry-kendrin(2059-2398)-eGFP-PACT. Both localize to the centrosomes and enabled us to monitor local separase activity at the centrosome in real time. Both centrosomal sensors were cleaved by separase before anaphase onset, earlier than the corresponding H2B-mCherry-Scc1(142-467)-eGFP sensor at chromosomes. This indicates that substrate cleavage by separase is not synchronous in the cells. Depletion of the proteins astrin or Aki1, which have been described as inhibitors of centrosomal separase, did not led to a significant activation of separase at centrosomes, emphasizing the importance of direct separase activity measurements at the centrosomes. Inhibition of polo-like kinase Plk1, on the other hand, decreased the separase activity towards the Scc1 but not the kendrin reporter. Together these findings indicate that Plk1 regulates separase activity at the level of substrate affinity at centrosomes and may explain in part the role of Plk1 in centriole disengagement. PMID- 25299183 TI - Antisense oligonucleotides capable of promoting specific target mRNA reduction via competing RNase H1-dependent and independent mechanisms. AB - Antisense oligonucleotides (ASOs) are most commonly designed to reduce targeted RNA via RNase H1-dependent degradation. In this paper we demonstrate that cellular proteins can compete for sites targeted by RNase H1-dependent ASOs. We further show that some ASOs designed to mediate RNase H1 cleavage can, in certain instances, promote target reduction both by RNase H1-mediated cleavage and by steric inhibition of binding of splicing factors at a site required for efficient processing of the pre-mRNA. In the latter case, RNase H cleavage was prevented by binding of a second protein, HSPA8, to the ASO/pre-mRNA heteroduplex. In addition, using a precisely controlled minigene system, we directly demonstrated that activity of ASOs targeting sites in introns is strongly influenced by splicing efficiency. PMID- 25299184 TI - A novel alpha kinase EhAK1 phosphorylates actin and regulates phagocytosis in Entamoeba histolytica. AB - Phagocytosis plays a key role in nutrient uptake and virulence of the protist parasite Entamoeba histolytica. Phagosomes have been characterized by proteomics, and their maturation in the cells has been studied. However, there is so far not much understanding about initiation of phagocytosis and formation of phagosomes at the molecular level. Our group has been studying initiation of phagocytosis and formation of phagosomes in E. histolytica, and have described some of the molecules that play key roles in the process. Here we show the involvement of EhAK1, an alpha kinase and a SH3 domain containing protein in the pathway that leads to formation of phagosomes using red blood cell as ligand particle. A number of approaches, such as proteomics, biochemical, confocal imaging using specific antibodies or GFP tagged molecules, expression down regulation by antisense RNA, over expression of wild type and mutant proteins, were used to understand the role of EhAK1 in phagocytosis. EhAK1 was found in the phagocytic cups during the progression of cups, until closure of phagosomes, but not in the phagosomes themselves. It is recruited to the phagosomes through interaction with the calcium binding protein EhCaBP1. A reduction in phagocytosis was observed when EhAK1 was down regulated by antisense RNA, or by over expression of the kinase dead mutant. G-actin was identified as one of the major substrates of EhAK1. Phosphorylated actin preferentially accumulated at the phagocytic cups and over expression of a phosphorylation defective actin led to defects in phagocytosis. In conclusion, we describe an important component of the pathway that is initiated on attachment of red blood cells to E. histolytica cells. The main function of EhAK1 is to couple signalling events initiated after accumulation of EhC2PK to actin dynamics. PMID- 25299185 TI - Red wine polyphenol compounds favor neovascularisation through estrogen receptor alpha-independent mechanism in mice. AB - Red wine polyphenol compounds (RWPC) exert paradoxical effects depending on the dose on post-ischemic neovascularisation. Low dose RWPC (0.2 mg/kg/day) is pro angiogenic, whereas high dose (20 mg/kg/day) is anti-angiogenic. We recently reported that the endothelial effect of RWPC is mediated through the activation of a redox-sensitive pathway, mitochondrial biogenesis and the activation of alpha isoform of the estrogen receptor (ERalpha). Here, we investigated the implication of ERalpha on angiogenic properties of RWPC. Using ovariectomized mice lacking ERalpha treated with high dose of RWPC after hindlimb ischemia, we examined blood flow reperfusion, vascular density, nitric oxide (NO) production, expression and activation of proteins involved in angiogenic process and muscle energy sensing network. As expected, high dose of RWPC treatment reduced both blood flow and vascular density in muscles of mice expressing ERalpha. These effects were associated with reduced NO production resulting from diminished activity of eNOS. In the absence of RWPC, ERalpha deficient mice showed a reduced neo-vascularisation associated with a decreased NO production. Surprisingly in mice lacking ERalpha, high dose of RWPC increased blood flow and capillary density in conjunction with increased NO pathway and production as well as VEGF expression. Of particular interest is the activation of Sirt-1, AMPKalpha and PGC 1alpha/beta axis in ischemic hindlimb from both strains. Altogether, the results highlight a pro-angiogenic property of RWPC via an ERalpha-independent mechanism that is associated with an up-regulation of energy sensing network. This study brings a corner stone of a novel pathway for RWPC to correct cardiovascular diseases associated with failed neovascularisation. PMID- 25299186 TI - Effectiveness of GnRH antagonist in the management of subfertile couples undergoing controlled ovarian stimulation and intrauterine insemination: a meta analysis. AB - BACKGROUND: Recent studies have indicated the use of gonadotropin-releasing hormone antagonists (GnRH-ant) as an adjuvant treatment to prevent premature luteinization (PL) and improve the clinical outcomes in patients undergoing controlled ovarian stimulation (COS) with intrauterine insemination (IUI). However, the results of these studies are conflicting. METHODS: We conducted a systematic review and meta-analysis of randomized trials aiming to compare the clinical efficacy of GnRH-ant in COS/IUI cycles. Twelve studies were identified that met inclusion criteria and comprised 2,577 cycles assigned to COS/IUI combined GnRH-ant or COS/IUI alone. RESULTS: Meta-analysis results suggested that GnRH-ant can significantly increase the clinical pregnancy rate (CPR) (OR = 1.42; 95% CI, 1.13-1.78) and decrease the PL rate (OR = 0.22, 95% CI, 0.16-0.30) in COS/IUI cycles. Subgroup analysis results suggested statistically significant improvement in the CPR in non-PCOS patients (OR = 1.54; 95% CI, 1.03-2.31) but not in the PCOS population (OR = 1.65; 95% CI, 0.93-2.94) and multiple mature follicle cycles (OR = 1.87; 95% CI, 0.27-12.66). There were no difference in the miscarriage and multiple pregnancy rates between the groups. CONCLUSION: This meta-analysis suggested that GnRH-ant can reduce the incidence of PL and increase the CPR when used in COS/IUI cycles, and it was especially useful for non-PCOS patients. However, evidence to support its use in PCOS patients is still insufficient. PMID- 25299188 TI - BAF200 is required for heart morphogenesis and coronary artery development. AB - ATP-dependent SWI/SNF chromatin remodeling complexes utilize ATP hydrolysis to non-covalently change nucleosome-DNA interactions and are essential in stem cell development, organogenesis, and tumorigenesis. Biochemical studies show that SWI/SNF in mammalian cells can be divided into two subcomplexes BAF and PBAF based on the subunit composition. ARID2 or BAF200 has been defined as an intrinsic subunit of PBAF complex. However, the function of BAF200 in vivo is not clear. To dissect the possible role of BAF200 in regulating embryogenesis and organ development, we generated BAF200 mutant mice and found they were embryonic lethal. BAF200 mutant embryos exhibited multiple cardiac defects including thin myocardium, ventricular septum defect, common atrioventricular valve, and double outlet right ventricle around E14.5. Moreover, we also detected reduced intramyocardial coronary arteries in BAF200 mutants, suggesting that BAF200 is required for proper migration and differentiation of subepicardial venous cells into arterial endothelial cells. Our work revealed that PBAF complex plays a critical role in heart morphogenesis and coronary artery angiogenesis. PMID- 25299189 TI - The Rosetteless gene controls development in the choanoflagellate S. rosetta. AB - The origin of animal multicellularity may be reconstructed by comparing animals with one of their closest living relatives, the choanoflagellate Salpingoeca rosetta. Just as animals develop from a single cell-the zygote-multicellular rosettes of S. rosetta develop from a founding cell. To investigate rosette development, we established forward genetics in S. rosetta. We find that the rosette defect of one mutant, named Rosetteless, maps to a predicted C-type lectin, a class of signaling and adhesion genes required for the development and innate immunity in animals. Rosetteless protein is essential for rosette development and forms an extracellular layer that coats and connects the basal poles of each cell in rosettes. This study provides the first link between genotype and phenotype in choanoflagellates and raises the possibility that a protein with C-type lectin-like domains regulated development in the last common ancestor of choanoflagellates and animals. PMID- 25299187 TI - Intragenic recombination has a critical role on the evolution of Legionella pneumophila virulence-related effector sidJ. AB - SidJ is a Dot/Icm effector involved in the trafficking or retention of ER-derived vesicles to Legionella pneumophila vacuoles whose mutation causes an observable growth defect, both in macrophage and amoeba hosts. Given the crucial role of this effector in L. pneumophila virulence we investigated the mechanisms shaping its molecular evolution. The alignment of SidJ sequences revealed several alleles with amino acid variations that may influence the protein properties. The identification of HGT events and the detection of balancing selection operating on sidJ evolution emerge as a clear result. Evidence suggests that intragenic recombination is an important strategy in the evolutionary adaptive process playing an active role on sidJ genetic plasticity. This pattern of evolution is in accordance with the life style of L. pneumophila as a broad host-range pathogen by preventing host-specialization and contributing to the resilience of the species. PMID- 25299190 TI - Colostrum from cows immunized with a vaccine associated with bovine neonatal pancytopenia contains allo-antibodies that cross-react with human MHC-I molecules. AB - In 2006, a new haemorrhagic syndrome affecting newborn calves, Bovine Neonatal Pancytopenia (BNP), was reported in southern Germany. It is characterized by severe bleeding, destruction of the red bone marrow, and a high case fatality rate. The syndrome is caused by alloreactive, maternal antibodies that are ingested by the calf with colostrum and result from a dam vaccination with one particular vaccine against Bovine-Viral-Diarrhoea-Virus. Because bovine colostrum is increasingly gaining interest as a dietary supplement for human consumption, the current study was initiated to elucidate whether BNP alloantibodies from BNP dams (i.e. animals that gave birth to a BNP-affected calf) cross-react with human cells, which could pose a health hazard for human consumers of colostral products. The present study clearly demonstrates that BNP alloantibodies cross react with human lymphocytes in vitro. In agreement with previous reports on BNP, the cross-reactive antibodies are specific for MHC-I molecules, and sensitize opsonised human cells for in vitro complement lysis. Cross-reactive antibodies are present in serum and colostrum of individual BNP dams. They can be traced in commercial colostrum powder manufactured from cows immunized with the vaccine associated with BNP, but are absent from commercial powder manufactured from colostrum excluding such vaccinated cows. In humans alloreactive, MHC-I specific antibodies are generally not believed to cause severe symptoms. However, to minimize any theoretical risk for human consumers, manufacturers of bovine colostrum for human consumption should consider using only colostrum from animals that have not been exposed to the vaccine associated with BNP. PMID- 25299191 TI - Association between the EGF rs4444903 polymorphism and liver cancer susceptibility: a meta-analysis and meta-regression. AB - Emerging evidence suggests that a common functional polymorphism, rs4444903 (A>G), in the EGF gene might impact an individual's susceptibility to liver cancer; however, individually published results are inconclusive. This meta analysis aimed to derive a more precise estimation of the relationship between the EGF rs4444903 polymorphism and liver cancer risk. A literature search was conducted in the PubMed, Embase, Web of Science, and CBM databases from inception through May 1st, 2013. Seven case-control studies were included with a total of 1408 liver cancer cases and 1343 healthy controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Our meta-analysis results indicated that the G variant of the rs4444903 polymorphism might be associated with an increased risk of liver cancer (G allele vs A allele: OR = 1.25, 95%CI = 1.01-1.56, P = 0.040; GG + AG vs AA: OR = 1.65, 95%CI = 1.27-2.15, P < 0.001; GG vs AA: OR = 1.77, 95%CI = 1.34-2.35, P < 0.001). Further subgroup analysis by ethnicity also showed significant associations between the G variant of the rs4444903 polymorphism and an increased risk of liver cancer among Asian, Caucasian, and African populations. No publication bias was detected in this meta analysis. In conclusion, the current meta-analysis suggests that the G variant of the rs4444903 polymorphism may increase the risk of liver cancer. The EGF rs4444903 (A>G) polymorphism can be useful as a biomarker in predicting the development of liver cancer. PMID- 25299192 TI - Monocyte/macrophage beta2-AR as a target of antisympathetic excitation-induced atherosclerotic progression. AB - The aim of this study was to determine whether monocyte/macrophage beta2-AR could act as the therapeutic target of antisympathetic excitation-induced atherosclerotic progression. Cultivated human THP-1 cells were divided into different groups and incubated with isoprenaline, metoprolol, propranolol or beta2-AR blocker for 24 h, together with oxidized low-density lipoprotein (ox LDL). Afterwards, each group was analyzed for C-C chemokine receptor type 2 (CCR2) expression, monocyte chemotactic protein 1 (MCP-1) release into medium and cell migration ability. In the isoprenaline group, CCR2 protein level was increased, as well as the secretion of MCP-1, and cell motility was enhanced, in a concentration-dependent manner. Propranolol and ICI 118,551 significantly reversed the stimulatory effect of isoprenaline on THP-1 cells induced by ox-LDL, but only high concentrations of metoprolol interfered significantly with the action of isoprenaline (P < 0.05). Isoprenaline or a beta-AR blocker could mediate through beta2-AR, affecting MCP-1 secretion, CCR2 protein expression and cell migration capacity of THP-1 cells. Therefore, monocyte-macrophage beta2-AR may act as a target of antisympathetic excitation-induced atherosclerotic progression. PMID- 25299193 TI - Possible anticipation in familial epidermolytic palmoplantar keratoderma with the p.R163W mutation of Keratin 9. AB - Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant disease characterized by diffuse hyperkeratosis of the epidermis of the palm and sole with an erythematous margin. The Keratin 9 (KRT9) and Keratin 1 genes are responsible for EPPK. Several previous studies have focused on the genetic basis of EPPK; however, genetic anticipation has not yet been reported. We described a four-generation family with EPPK and identified a p.R163W mutation of KRT9. We observed a decrease in the age of onset in three consecutive generations in the family of the proband, indicating possible genetic anticipation in this familial EPPK. Further studies are needed to elucidate the mechanisms of anticipation in EPPK. PMID- 25299194 TI - Is there a cryptic species of the golden snapper (Lutjanus johnii)? AB - For centuries, morphology-based fish identification has been applied without molecular evaluation. Many studies showed that specimens with a similar morphology are frequently found to be quite genetically distinct. One of the fish species that still remains taxonomically problematic is a commercial snapper species, Lutjanus johnii. Because of morphological ambiguities among local fish taxonomists in Malaysia, we examined the ability of the cytochrome oxidase I (COI) gene to genetically examine the taxonomic status of L. johnii. A 626-base pair COI region was successfully amplified and aligned with conspecific sequences that were retrieved from GenBank. The phylogenetic tree obtained showed two major clusters; the first cluster consists of L. johnii from Straits of Malacca, Thailand, Australia, and China while the second cluster comprises L. johnii from China and India. The latter group showed sequence divergence greater than 3.5%. After observing this, we suspected that there might be a cryptic species between the South China Sea and Indian Ocean. This is the first molecular report concerning the commercial species of snapper, L. johnii, in Malaysia, which had only gained provisional recognition from morphological examination. PMID- 25299195 TI - Effects of bovine SMO gene polymorphisms on the body measurement and meat quality traits of Qinchuan cattle. AB - Beef cattle breeding programs focus on improving important economic traits, including growth rates, and meat quantity and quality. Molecular marker-assisted selection based on genetic variation represents a potential method for breeding genetically improved livestock with better economic traits. Smoothened (SMO) protein is a signal transducer that contributes to the regulation of both osteogenesis and adipogenesis through the hedgehog pathway. In this study, we detected polymorphisms in the bovine SMO gene of Qinchuan cattle, and we analyzed their associations with body measurement traits (BMTs) and meat quality traits (MQTs). Using DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism, 3 novel single nucleotide polymorphisms were identified in the SMO gene of 562 cattle: 1 G > C mutation on exon 9 (G21234C) and 2 C > T mutations on exon 11 (C22424T and C22481T). Association analysis showed that polymorphisms on both the G21234C and C22424T loci significantly affected certain BMTs and MQTs (P < 0.05 or P < 0.01), whereas those on the C22481T locus did not (P > 0.05). Therefore, the SMO gene could be used as a candidate gene to alter BMTs and MQTs in Qinchuan cattle or for marker-assisted selection to breed cattle with superior BMTs and MQTs. PMID- 25299196 TI - Egg laying and egg quality in meat type quails in diallel crosses. AB - This study aimed to assess egg laying and egg quality in quail lines in diallel crosses. We evaluated 16 genetic groups obtained from crosses of four strains of meat quails (L1, L2, L3, and L4) in a complete diallel. We assessed weekly egg number (WEN), egg yield (EY), egg weight (EW), and Haugh unit (HU) for: 51-80, 81 110, 111-140, and 51-140 days (whole period) old. The general combining capacity (GCC) showed significance for WEN and EY, with the exception of the period of 111 140 days. In general, L3 had the highest positive GCC estimates. The additive genetic variability was significant for EW in all periods, as was HU, with the exception of the first period. The specific combining capacity was significant for HU, except in the second period. The largest estimates for GCC were submitted by L1 for EW, followed by L4, considering the whole period. For HU, L2 had the highest estimates for GCC. The more favorable cross for HU was L2xL3, in the whole period. In the third period, there was a significant reciprocal effect, where there was a positive estimate for the cross L2xL3. PMID- 25299197 TI - Decreased retinol-binding protein 4 in the sera of patients with end-stage renal disease after kidney transplantation. AB - Retinol-binding protein 4 (RBP4) is a novel adipokine that has been associated with insulin resistance and type 2 diabetes. Patients with end-stage renal disease (ESRD) have very high serum RBP4 levels. However, whether successful kidney transplantation alleviates these elevated serum RBP4 levels is unclear. The serum RBP4 levels of 24 ESRD patients were determined before transplantation and at 1 day, 1 week, and 1 month after kidney transplantation. The control group included 22 healthy subjects. Serum RBP4 concentrations were measured using a commercial kit via the immunologic turbidimetric method, and were related to biomarkers for renal and liver function. The serum RBP4 level of ESRD patients before kidney transplantation (160.8 +/- 29.1 mg/L) was approximately 7-fold higher than that of normal controls (22.6 +/- 11.0 mg/L; P = 0.000). The serum RBP4 level before transplantation was significantly higher than that at 1 day (65.3 +/- 28.4 mg/L), 1 week (48.3 +/- 22.9 mg/L), and 1 month after transplantation (53.1 +/- 25.5 mg/L; P = 0.000). However, these values were still higher than those of controls (P = 0.000). Univariate regression analysis showed that the percent changes in serum RBP4 concentration before and after kidney transplantation were positively correlated with serum creatinine, blood urea nitrogen, phosphate, and pre-albumin concentrations and negatively correlated with the estimated glomerular filtration rate. The serum RBP4 concentration of patients with ESRD decreased significantly after kidney transplantation; therefore, we found that serum RBP4 concentration was related to renal function. PMID- 25299198 TI - Relationship between the angle of vertebral screws and spinal lateral angulation after fixation of thoracolumbar fractures via an anterior approach. AB - This study investigated possible contributors to lateral spinal angulation after surgical fixation of thoracolumbar fractures via an anterior approach. We retrospectively examined lateral angulation in 172 cases of thoracolumbar fractures treated in this manner. The coronal Cobb angle and angles of the screws relative to the endplates were determined from radiographs. The patients completed the Short Form 36, Oswestry Disability Index, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, and Visual Analogue Scale at the final follow-up visit. The mean coronal Cobb angle was 0.75 degrees +/- 3.91 degrees (-14.25 degrees to 14.55 degrees ) preoperatively, 3.17 degrees +/- 4.07 degrees (-8.18 degrees to 14.01 degrees ) immediately postoperatively, and 3.46 degrees +/- 4.21 degrees (-1.05 degrees to 17.27 degrees ) at the final follow-up visit. The superior posterior and inferior anterior screws were more parallel to their respective endplates when the approach was made >=2 vs <=1 vertebral levels above the fracture (P < 0.001). Lateral angulation was more likely when the approach was made <=1 vs >=2 levels above the fracture (P < 0.001). The coronal Cobb angle differed significantly (P < 0.01) between patients with lumbar and thoracic fractures. The immediate postoperative coronal Cobb angle correlated tightly with the sum of the screw angles (superior plus inferior posterior and/or inferior plus superior anterior). Lateral angulation may occur after surgical fixation of thoracic and lumbar fractures via an anterior approach. Non-parallelism between the vertebral screws and their corresponding endplates may predict postoperative lateral spinal angulation. Postoperative lateral angulation does not correlate with low back pain, quality of life, or preoperative lateral angulation. PMID- 25299199 TI - Characterization of novel microsatellite markers derived from Korean rose bitterling (Rhodeus uyekii) genomic library. AB - Korean rose bitterling (Rhodeus uyekii) is a freshwater fish endemic to Korea. Natural populations of this species have experienced severe declines as a result of habitat fragmentation and water pollution. To conserve and restore R. uyekii, the genetic diversity of this species needs to be assessed at the population level. Eighteen novel polymorphic microsatellite loci for R. uyekii were developed using an enriched partial genomic library. Polymorphisms at these loci were studied in 150 individuals collected from three populations. The number of alleles at each locus ranged from 3 to 47 (mean = 17.1). Within the populations, the observed heterozygosity ranged from 0.032 to 1.000, expected heterozygosity from 0.082 to 0.967, and polymorphism information content from 0.078 to 0.950. Six loci showed significant deviation from Hardy-Weinberg equilibrium after Bonferroni's correction, and no significant linkage disequilibrium was detected between most locus pairs, except in three cases. These highly informative microsatellite markers should be useful for genetic population structure analyses of R. uyekii. PMID- 25299200 TI - Identifying differential expression genes and single nucleotide variations using RNA-seq in metastatic melanoma. AB - Melanoma is a malignant tumor and one of the most frequent metastatic cancers. This study was conducted to identify differential expression genes (DEGs) and single nucleotide variations (SNVs) in metastatic melanoma. We analyzed microarray data of GSE23056 downloaded from the Gene Expression Omnibus, including two normal samples (skinN1 and skinN2) and 2 metastatic melanoma samples (skinT and lymphT). We not only compared DEGs in metastatic melanoma samples with normal samples (lymphT_skinN and skinT_skinN), but also compared DEGs between two metastatic melanoma types (lymphT_skinT). SNVs were identified by using Burrows-Wheeler Aligner and Cufflinks in metastatic melanoma samples using RNA-seq. Sequence Alignment/Map tools and the ANNOVAR software were used to analyze and annotate SNVs. We identified 18 significantly common DEGs in lymphT_skinN and skinT_skinN and one common gene, YBX1, in lymphT_skinN, skinT_skinN, and lymphT_skinT. We identified 49,534, 48,118, 63,812, and 33,096 SNVs in skinN1, skinN2, skinT, and lymphT, respectively. Twenty-nine SNVs were located in exonic regions of two DEGs, HLA-B and TSPAN10. SNVs that exist only in tumors were located in MARVELD1, SLC16A3, and VAV3. The DEGs screened in our study are potential biomarkers for metastatic melanoma therapy. PMID- 25299201 TI - New polymorphic microsatellite markers for the Korean manila clam (Ruditapes philippinarum) and their application to wild populations. AB - Manila clam (Ruditapes philippinarum) is a valuable and intensively exploited shellfish species in Korea. Despite its importance, information on its genetic background is scarce. For the genetic characterization of R. philippinarum, expressed sequence tag-derived microsatellite markers were developed using next generation sequencing. A total of 5879 tandem repeats containing di- to hexanucleotide repeat motifs were obtained from 236,746 reads (mean = 413 bp). Of the 62 loci screened, 24 (38.7%) were successfully amplified, and 10 were polymorphic in 144 individuals from 2 manila clam populations (Incheon and Geoje, Korea). The number of alleles ranged from 2 to 17 in the Incheon population and from 3 to 13 in the Geoje population (overall AR = 7.21). The mean observed and expected heterozygosities were estimated to be 0.402 and 0.555, respectively. Hence, there is less genetic variability in the Geoje population than in the Incheon population, although no significant reductions of genetic diversity were found between the populations (P > 0.05). However, significant genetic differentiation was detected between the populations (FST = 0.064, P < 0.001). Significant deviations from Hardy-Weinberg equilibrium and high inbreeding coefficients (mean FIS = 0.22-0.26) were detected in both populations. The 10 novel polymorphic microsatellite loci used in this study will be useful for future genetic mapping studies and for characterizing population structures, monitoring genetic diversity for successful aquaculture management, and developing conservation strategies for manila clam populations in Korea. PMID- 25299202 TI - Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to systemic sclerosis: a meta-analysis. AB - The purpose of this study was to examine whether the insertion (I) or deletion (D) polymorphism of the angiotensin-converting enzyme gene (ACE) is associated with susceptibility to systemic sclerosis (SSc). A meta-analysis examining the associations between the ACE I/D polymorphism and SSc was conducted in overall and European populations using 1) allelic contrast (D vs I); 2) recessive (DD vs ID + II); 3) dominant (DD + ID vs II); and 4) additive (DD vs ID vs II) models. A total of 7 studies consisting of 837 cases and 754 controls were available for meta-analysis. The meta-analysis revealed no association between the D allele and SSc in any study subjects [odds ratio (OR) = 0.956, 95% confidence interval (CI) = 0.733-1.246, P = 0.737]. Stratification by ethnicity indicated no association between the D allele of the ACE I/D polymorphism and SSc in Europeans (OR = 1.117, 95%CI = 0.776-1.607, P = 0.551). Meta-analysis using all other genetic models showed the same D allele pattern in the overall and European groups. This meta-analysis showed that the ACE I/D polymorphism was not associated with susceptibility to SSc in the study subjects and in Europeans. PMID- 25299203 TI - Population genetic structure of Aedes albopictus in Penang, Malaysia. AB - The mosquito Aedes albopictus is indigenous to Southeast Asian and is a vector for arbovirus diseases. Studies examining the population genetics structure of A. albopictus have been conducted worldwide; however, there are no documented reports on the population genetic structure of A. albopictus in Malaysia, particularly in Penang. We examined the population genetics of A. albopictus based on a 445-base pair segment of the mitochondrial DNA cytochrome oxidase 1 gene among 77 individuals from 9 localities representing 4 regions (Seberang Perai Utara, Seberang Perai Tengah, Northeast, and Southwest) of Penang. A total of 37 haplotypes were detected, including 28 unique haplotypes. The other 9 haplotypes were shared among various populations. These shared haplotypes reflect the weak population genetic structure of A. albopictus. The phylogenetic tree showed a low bootstrap value with no genetic structure, which was supported by minimum spanning network analysis. Analysis of mismatch distribution showed poor fit of equilibrium distribution. The genetic distance showed low genetic variation, while pairwise FST values showed no significant difference between all regions in Penang except for some localities. High haplotype diversity and low nucleotide diversity was observed for cytochrome oxidase 1 mtDNA. We conclude that there is no population genetic structure of A. albopictus mosquitoes in the Penang area. PMID- 25299204 TI - Effect of pinacidil on rat ventricular myocytes during transient hypoxia and reperfusion. AB - The aim of this study was to evaluate the cardioprotective effect of pinacidil postconditioning on rat hearts with transient hypoxia and reperfusion. An acute myocardial anoxia-reperfusion rat model was created by ligating coronary arteries for 10 min and subsequent reperfusion for 60 min. Twenty-four rats in 4 groups received different treatments: normal hearts as control (N = 6), anoxia reperfusion (A/R) only (N = 6), pinacidil postconditioning (N = 6), and pinacidil plus adenosine triphosphate-sensitive potassium channel inhibitors (glibenclamide) (N = 6). The kinetic parameters and electrophysiological properties, including early apoptosis protein expression changes of Bax, Bcl-2, and FN were examined using the isolated perfusion and patch-clamp technique and immunohistochemistry. The left ventricular systolic pressure and maximum -dp/dt in A/R groups were significantly higher than those in the control group (P < 0.05). The left ventricular developing pressure, maximum +dp/dt, and heart rate in the A/R group were slightly decreased. The pinacidil-postconditioned group has better cardiac function recovery after ischemia/reperfusion than the A/R group (P < 0.01). In addition, using the patch-clamp technique, the mean open time and conductance values are significantly higher in the pinacidil postconditioning group, compared with those in the A/R group. The expression of apoptosis proteins (Bax, FN) increased during A/R, while Bcl-2 protein expression decreased. A significant difference was found in the pinacidil treatment group relative to the A/R group. Pinacidil postconditioning can exert cardioprotective effects on A/R injured rat hearts, which may indicate a potential application of pinacidil postconditioning to protect A/R-injured hearts. PMID- 25299205 TI - Roles of GILZ in protein metabolism of L6 muscle cells exposed to serum from septic rats. AB - Sepsis is a complex inflammatory response to infection, associating with dramatic metabolic disorders. Although the mechanisms of immune response during sepsis have been largely clarified, current studies rarely pay attention to the disordered protein metabolism in sepsis. In this study, L6 rat skeletal muscle cells treated with serum from septic rats were used as an in vitro model for sepsis-like condition in skeletal muscle. We found that the expression of glucocorticoid-induced leucine zipper (GILZ) positively correlates with glucocorticoid receptor and negatively correlates with myosin heavy chain expression in L6 muscle cells upon septic serum induction. Moreover, we propose that GILZ may associate with cytokines such as TNF-alpha, IL-1beta as well as IL 10 to cooperatively modulate the glucocorticoid/glucocorticoid receptor-mediated regulation of protein metabolism during sepsis. So the present study provides a new approach and theoretical basis for further studies on the regulation of protein metabolism of skeletal muscle during sepsis. PMID- 25299206 TI - Isolation and characterization of microsatellite markers for Amomum tsaoko (Zingiberaceae), an economically important plant in China. AB - Twenty-four microsatellite markers were isolated from the genomic DNA of Amomum tsaoko Crevost et Lemaire, an important economic plant in China, using the method fast isolation by AFLP of sequences containing repeats (FIASCO). Polymorphism within each locus was assessed in 60 individuals from three populations in Yunnan Province, China, and nine of them were polymorphic. The number of alleles per polymorphic locus was 2, and the expected and observed heterozygosities ranged from 0.224 to 0.513, and from 0.050 to 0.600, respectively. Among nine microsatellite markers with polymorphism, five showed significant deviation from Hardy-Weinberg equilibrium (P < 0.01), probably due to anthropic selection and short-cloning history in cultivation. No significant linkage disequilibrium was detected between loci in our analysis. These polymorphic microsatellite markers will facilitate further studies of gene flow, population structure, identification of cultivated variety, and evaluation of germplasm resources. PMID- 25299207 TI - Expression of aquaporins 1 and 3 in degenerative tissue of the lumbar intervertebral disc. AB - Lumbar intervertebral disc degeneration is induced by multiple factors, but few studies have examined the effects of aquaporins on this process. We compared the expression levels of aquaporins 1 and 3 in normal and degenerative lumbar intervertebral discs. Fifteen normal and 15 degenerative lumbar intervertebral disc tissues were excised from lumbar burst fracture patients during orthopedic operations at the Dali College subsidiary hospital. Tissues were stained with hematoxylin-eosin and the expression levels of aquaporins 1 and 3 were measured by immunohistochemistry. Hematoxylin-eosin-staining results illustrated that the structures of the intervertebral disc tissues from the control group were clear, with distinct collagen fiber shapes and slight edema but without mucoid degeneration. Structures of the intervertebral disc tissues from the disease group were obscure and disordered with hyperplastic collagen fibers and tissues of severe inflammatory edemas with necrosis mucoid degeneration. Immunohistochemistry results demonstrated that the average absorbances of aquaporins 1 and 3 in the disease group were significantly lower than those in the control group (P < 0.01), suggesting that the reduction of aquaporins 1 and 3 may be a factor resulting in lumbar intervertebral disc degeneration. PMID- 25299208 TI - Mutation analysis and prenatal diagnosis for three families affected by isolated methylmalonic aciduria. AB - Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous disorder caused mainly by deficiency of methylmalonyl-CoA mutase. In the present study, we analyzed MUT gene mutations in 3 Chinese couples with a birth history of isolated MMA. We also provided prenatal diagnoses for the detected mutation. Exons and exon-intron boundaries of the MUT gene were analyzed by polymerase chain reaction and direct sequencing. Prenatal genetic diagnoses were performed by chorionic villus sampling after the genotypes of parents were determined. Six heterozygous mutations in the MUT gene were identified in the 3 families, including c.1880A>G (p.H627R) and IVS9-1G>A for family 1, c.1741C>T (p.R581X) and c.729insTT (p.D244fX39) for family 2, and c.616C>T (p.Q206X) and c.1280G>A (p.G427D) for family 3. Among these, c.616C>T (p.Q206X), c.1280G>A (p.G427D), IVS9-1G>A, and c.1741C>T (p.R581X) were novel mutations. These mutations were not detected in 100 normal controls. The fetus in pedigree 3 was free of the mutations carried by the parents, while the fetuses in pedigrees 1 and 2 were heterozygous mutation carriers. All 3 families decided to continue with their pregnancies and the neonates did not show any symptoms of MMA after birth. Our results indicated that mutations in the MUT gene are the primary cause of isolated MMA, and that most mutations were novel. For families with early-onset isolated MMA, direct sequencing of the MUT gene is crucial for genetic counseling, prenatal diagnosis, and identification of carriers. PMID- 25299209 TI - Clinical use of extra-large self-expanding stents. AB - The aim of this study is to describe our clinical experience with an extra-large self-expandable stent specifically designed to treat aortic lesions (E-XL, Jotec GmbH, Hechingen, Germany), now commercially available in Europe. The E-XL was used at our Institution in 14 patients (mean age, 56+/-12 years; 9 males) with the following indications: improve proximal fixation (4 cases), type I endoleak (2 cases), aortic dissection with static malperfusion (1 case) and dynamic malperfusion (7 cases). Early results have been shown to be safe and effective in different clinical settings, including in emergency cases. This peculiar aortic stent could be useful in the armamentarium of the endovascular surgeon. PMID- 25299210 TI - Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells. AB - Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 uM) decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 uM, CsA induced a dose dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 uM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD) showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 uM CsA), but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels. PMID- 25299214 TI - The means to match our ambitions. PMID- 25299212 TI - PO2 cycling reduces diaphragm fatigue by attenuating ROS formation. AB - Prolonged muscle exposure to low PO2 conditions may cause oxidative stress resulting in severe muscular injuries. We hypothesize that PO2 cycling preconditioning, which involves brief cycles of diaphragmatic muscle exposure to a low oxygen level (40 Torr) followed by a high oxygen level (550 Torr), can reduce intracellular reactive oxygen species (ROS) as well as attenuate muscle fatigue in mouse diaphragm under low PO2. Accordingly, dihydrofluorescein (a fluorescent probe) was used to monitor muscular ROS production in real time with confocal microscopy during a lower PO2 condition. In the control group with no PO2 cycling, intracellular ROS formation did not appear during the first 15 min of the low PO2 period. However, after 20 min of low PO2, ROS levels increased significantly by ~30% compared to baseline, and this increase continued until the end of the 30 min low PO2 condition. Conversely, muscles treated with PO2 cycling showed a complete absence of enhanced fluorescence emission throughout the entire low PO2 period. Furthermore, PO2 cycling-treated diaphragm exhibited increased fatigue resistance during prolonged low PO2 period compared to control. Thus, our data suggest that PO2 cycling mitigates diaphragm fatigue during prolonged low PO2. Although the exact mechanism for this protection remains to be elucidated, it is likely that through limiting excessive ROS levels, PO2 cycling initiates ROS-related antioxidant defenses. PMID- 25299213 TI - C William L Jeanes, 1919-2014. PMID- 25299215 TI - Invitation to submit comments on Canadian Thoracic Society strategic directions. PMID- 25299216 TI - Rapid response teams and end-of-life care. PMID- 25299217 TI - Primary tracheobronchial amyloidosis: commonly uncommon? PMID- 25299218 TI - Waiver of consent for low-risk studies. PMID- 25299219 TI - A rare cause of stridor: isolated tracheal amyloidosis. AB - A 50-year-old man presented to clinic with a two-year history of progressive exertional dyspnea and voice hoarseness. This history suggested upper airways obstruction, which was confirmed on computed tomography imaging that revealed extensive thickening of the proximal tracheal wall causing severe luminal narrowing. Bronchoscopic debulking was then performed and the samples obtained confirmed tracheal amyloidoisis. Extensive investigation confirmed that disease was localized solely to the trachea. Ultimately, after multiple discussions, the chosen treatment modality was radiotherapy, which proceeded relatively uneventfully and achieved excellent radiological and clinical response. Although tracheal amyloidosis is rare, it is most commonly observed as part of a multisystem presentation. The present report describes the even more uncommon diagnosis of isolated tracheal amyloidosis and highlights the role of radiotherapy in its management. PMID- 25299220 TI - History of respiratory medicine in Canada: a new Canadian Respiratory Journal series. PMID- 25299221 TI - Hypersensitivity pneumonitis (extrinsic allergic alveolitis): a Canadian historical perspective. PMID- 25299222 TI - The effect of rapid response teams on end-of-life care: a retrospective chart review. AB - BACKGROUND: A subset of critically ill patients have end-of-life (EOL) goals that are unclear. Rapid response teams (RRTs) may aid in the identification of these patients and the delivery of their EOL care. OBJECTIVES: To characterize the impact of RRT discussion on EOL care, and to examine how a preprinted order (PPO) set for EOL care influenced EOL discussions and outcomes. METHODS: A single centre retrospective chart review of all RRT calls (January 2009 to December 2010) was performed. The effect of RRT EOL discussions and the effect of a hospital-wide PPO set on EOL care was examined. Charts were from the Ontario Ministry of Health and Long-Term Care Critical Care Information Systemic database, and were interrogated by two reviewers. RESULTS: In patients whose EOL status changed following RRT EOL discussion, there were fewer intensive care unit (ICU) transfers (8.4% versus 17%; P<0.001), decreased ICU length of stay (5.8 days versus 20 days; P=0.08), increased palliative care consultations (34% versus 5.3%; P<0.001) and an increased proportion who died within 24 h of consultation (25% versus 8.3%; P<0.001). More patients experienced a change in EOL status following the introduction of an EOL PPO, from 20% (before) to 31% (after) (P<0.05). CONCLUSIONS: A change in EOL status following RRT-led EOL discussion was associated with reduced ICU transfers and enhanced access to palliative care services. Further study is required to identify and deconstruct barriers impairing timely and appropriate EOL discussions. PMID- 25299223 TI - Breaking the limits of structural and mechanical imaging of the heterogeneous structure of coal macerals. AB - The correlation between local mechanical (elasto-plastic) and structural (composition) properties of coal presents significant fundamental and practical interest for coal processing and for the development of rheological models of coal to coke transformations. Here, we explore the relationship between the local structural, chemical composition, and mechanical properties of coal using a combination of confocal micro-Raman imaging and band excitation atomic force acoustic microscopy for a bituminous coal. This allows high resolution imaging (10s of nm) of mechanical properties of the heterogeneous (banded) architecture of coal and correlating them to the optical gap, average crystallite size, the bond-bending disorder of sp(2) aromatic double bonds, and the defect density. This methodology allows the structural and mechanical properties of coal components (lithotypes, microlithotypes, and macerals) to be understood, and related to local chemical structure, potentially allowing for knowledge-based modeling and optimization of coal utilization processes. PMID- 25299224 TI - Effects of SNPs (CYP1B1*2 G355T, CYP1B1*3 C4326G, and CYP2E1*5 G-1293C), smoking, and drinking on susceptibility to laryngeal cancer among Han Chinese. AB - PURPOSE: This study was conducted to explore the effects of genetic polymorphisms (CYP1B1*2 G355T, CYP1B1*3 C4326G, and CYP2E1*5 G-1293C) and environmental factors (smoking and drinking) on susceptibility to laryngeal cancer in a Han Chinese study group. METHODS: This case-control study included 552 Han Chinese patients diagnosed with laryngeal cancer and 666 healthy control subjects of the same ethnicity, similar age, and gender. Genetic polymorphisms were examined using multi-PCR and Matrix Assisted Laser Desorption Ionization - Time of Flight (MALDI TOF MS) methodology. The association of these genetic and environmental factors with susceptibility to laryngeal cancer was evaluated using a statistical approach. RESULTS: The frequencies of all three polymorphisms in the patient cohort were significantly different from those in the control cohort. Compared to the control cohort, carriers of variant alleles of CYP1B1*2 355T and CYP2E1*5 1293C showed a higher risk for developing laryngeal cancer (for CYP1B1*2 355T, adjusted OR = 2.657, P <0.001; for CYP2E1*5 -1293C, adjusted OR = 1.938, P <0.001), while carriers of mutation allele CYP1B1*3 4326G showed a lower risk (adjusted OR = 0.562, P <0.001). Joint effects of these polymorphisms were observed. When compared to haplotype G355C4326G-1293, haplotypes T355C4326G-1293 (adjusted OR = 1.809, P <0.001), G355C4326C-1293 (adjusted OR = 1.644, P = 0.044), and T355C4326C-1293 (adjusted OR = 3.104, P <0.001) were associated with a significantly higher laryngeal cancer risk. The adjusted ORs for non-smokers, non-drinkers, smokers, and drinkers with the GT/TT genotype at CYP1B1*2 G355T were 2.190 (P = 0.006), 2.008 (P = 0.001), 5.875 (P <0.001), and 4.518 (P <0.001), respectively. CONCLUSIONS: CYP1B1*2 355T and CYP2E1*5 -1293C are associated with an increased laryngeal cancer risk, while CYP1B1*3 4326G is associated with a decreased risk. These polymorphisms showed joint effects on laryngeal cancer risk. Smoking and drinking showed collaborative effects with two high risk alleles (CYP1B1*2 355T and CYP1B1*3 4326G) for promoting laryngeal cancer risk. PMID- 25299225 TI - Exploring the miRNA regulatory network using evolutionary correlations. AB - Post-transcriptional regulation by miRNAs is a widespread and highly conserved phenomenon in metazoans, with several hundreds to thousands of conserved binding sites for each miRNA, and up to two thirds of all genes under miRNA regulation. At the same time, the effect of miRNA regulation on mRNA and protein levels is usually quite modest and associated phenotypes are often weak or subtle. This has given rise to the notion that the highly interconnected miRNA regulatory network exerts its function less through any individual link and more via collective effects that lead to a functional interdependence of network links. We present a Bayesian framework to quantify conservation of miRNA target sites using vertebrate whole-genome alignments. The increased statistical power of our phylogenetic model allows detection of evolutionary correlation in the conservation patterns of site pairs. Such correlations could result from collective functions in the regulatory network. For instance, co-conservation of target site pairs supports a selective benefit of combinatorial regulation by multiple miRNAs. We find that some miRNA families are under pronounced co targeting constraints, indicating a high connectivity in the regulatory network, while others appear to function in a more isolated way. By analyzing coordinated targeting of different curated gene sets, we observe distinct evolutionary signatures for protein complexes and signaling pathways that could reflect differences in control strategies. Our method is easily scalable to analyze upcoming larger data sets, and readily adaptable to detect high-level selective constraints between other genomic loci. We thus provide a proof-of-principle method to understand regulatory networks from an evolutionary perspective. PMID- 25299226 TI - External validation of the A2DS2 score to predict stroke-associated pneumonia in a Chinese population: a prospective cohort study. AB - BACKGROUND AND PURPOSE: The A2DS2 score was recently developed from the Berlin Stroke Registry for predicting in-hospital pneumonia after acute ischemic stroke and performed well in an external validation in the North-west Germany Stroke Registry. It could be a useful tool for risk stratification in clinical practice or stroke trials. We aimed to prospectively validate the predictive value of A2DS2 score in a Chinese stroke population. METHODS: The prognostic model was used to predict stroke-associated pneumonia (SAP) from Henan Province Stroke Registry (HNSR) in which data were prospectively collected. The receiver operating characteristic curves were plotted, and the C statistics were calculated to assess the discrimination ability. The Hosmer-Lemeshow goodness-of fit test and the plot of observed versus predicted SAP risk were used to assess model calibration. RESULTS: Among 1142 eligible patients, the overall in-hospital SAP was 18.8%, which ranged from 9.0% in patients with lower A2DS2 scores (0-4) to 65.0% in those with higher scores of 5 to 10 (P for trend <0.001). The C statistic was 0.836 (95% confidence interval, 0.803-0.868) through the A2DS2 score, suggesting excellent discrimination in the HNSR. The A2DS2 score also showed excellent calibration (Cox and Snell R2 = 0.243) in the external validation sample from the HNSR. CONCLUSIONS: The A2DS2 score could reliably predict in-hospital SAP in Chinese stroke patients. It might be helpful for the assessment of increased risk monitoring and prophylactic treatment in identified high-risk patients for SAP in clinical routine. PMID- 25299227 TI - Reconstruction of the gene regulatory network involved in the sonic hedgehog pathway with a potential role in early development of the mouse brain. AB - The Sonic hedgehog (Shh) signaling pathway is crucial for pattern formation in early central nervous system development. By systematically analyzing high throughput in situ hybridization data of E11.5 mouse brain, we found that Shh and its receptor Ptch1 define two adjacent mutually exclusive gene expression domains: Shh+Ptch1- and Shh-Ptch1+. These two domains are associated respectively with Foxa2 and Gata3, two transcription factors that play key roles in specifying them. Gata3 ChIP-seq experiments and RNA-seq assays on Gata3-knockdown cells revealed that Gata3 up-regulates the genes that are enriched in the Shh-Ptch1+ domain. Important Gata3 targets include Slit2 and Slit3, which are involved in the process of axon guidance, as well as Slc18a1, Th and Qdpr, which are associated with neurotransmitter synthesis and release. By contrast, Foxa2 both up-regulates the genes expressed in the Shh+Ptch1- domain and down-regulates the genes characteristic of the Shh-Ptch1+ domain. From these and other data, we were able to reconstruct a gene regulatory network governing both domains. Our work provides the first genome-wide characterization of the gene regulatory network involved in the Shh pathway that underlies pattern formation in the early mouse brain. PMID- 25299228 TI - Rates of auxiliary is and are in African American English speaking children with specific language impairment following language treatment. AB - The purpose of this exploratory study is to examine rates of auxiliary is and are across dialect patterns produced by African American English with specific language impairment (AAE-SLI) children following language treatment. The following research question is asked: Do AAE-SLI children exhibit rates of auxiliary is and are across dialect patterns consistent with previous reports of typically developing children and adult AAE speakers? A pre-/post-test design was used to identify patterns in which auxiliary is and are were produced at significant levels. Individual performance was included to examine variable rates of use across patterns. Group and individual results suggest children used auxiliary is and are in dialect patterns at rates consistent with typically developing child and adult AAE speakers. We conclude that rates of use may contribute to evidence-based guidelines for morphological intervention with AAE SLI children. PMID- 25299229 TI - Sertoli-Leydig cell tumors: hormonal profile after dynamic test with GnRH analogue: triptorelin represents a useful tool to evaluate tumoral hyperandrogenism. AB - We report the case of a 15-year-old woman with signs of hyperandrogenism affected by a Sertoli-Leydig cell tumor (SLCT). In our patient, blood analysis showed a high testosterone (T) level (T: 8.53 nmol/L; nv < 1.87 nmol/L) while the GnRH analogue test demonstrated an exaggerated secretion of 17-hydroxyprogesterone (OHP), T, and androstenedione (A) by the ovary after stimulation. We compared the GnRH-analogue test of our patient with that obtained in a group of normal and healthy women (no. 8 subjects, 16-26 years old), men (no. 4 subjects, 18-28 years old), and in a group of PCOS patients with age and body weight compared. We found in our patient a value of OHP, 17-beta estradiol (E2) and T, from 2 to 18 times higher than healthy women. When we compared our patient with healthy men, we differently observed a comparable response of T. The response of our patient was also comparable with that observed in the PCOS group for E2. During the post surgical follow up, the GnRH-analogue test of our patient showed a response of OHP, T, and E2 comparable with that of the PCOS group. The GnRH-analogue test is a useful tool to characterize steroidogenesis in SLCT. PMID- 25299230 TI - The progesterone and estrogen modify the uterine prolactin and prolactin receptor expression of hyperprolactinemic mice. AB - The aim of this study was to evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin (PRL) and PRL receptor's expression in the uterus of mice. For this purpose, 49 Swiss mice were divided into the following groups: GrSS (non-ovariectomized mice given vehicle); GrMET (non-ovariectomized mice treated with metoclopramide); OvSS (ovariectomized mice given vehicle); OvMET (ovariectomized mice treated with metoclopramide); OvMET+17betaE (ovariectomized mice treated with metoclopramide and 17beta estradiol); OvMET+MP (ovariectomized mice treated with metoclopramide and micronized progesterone); OvMET+17betaE+MP (ovariectomized mice treated with metoclopramide and a solution of 17beta estradiol and micronized progesterone). Immunohistochemical analyzes were evaluated semi-quantitatively. Our results showed that GrMET, OvMET+MP, and OvMET+17betaE+MP presented strong PRL expression. OvMET and OvMET+17betaE presented mild reaction, while GrSS and OvSS presented weak reaction. Concerning PRL receptor, OvMET+MP and OvMET+17betaE+MP showed strong reaction; GrMET, OvSS, and OvMET+17betaE showed mild reaction; and GrSS and OvMET showed weak reaction. These findings suggest that progesterone alone or in combination with estrogen may increase the expression of uterine PRL and PRL receptor. PMID- 25299231 TI - Alpha-actinin 4 is associated with cancer cell motility and is a potential biomarker in non-small cell lung cancer. AB - BACKGROUND: Differential expression and secretion of alpha-actinin 4 (ACTN4) in the lung cancer cell lines CL1-0 and CL1-5 have been reported in previous proteomic studies. The aim of this study is to investigate the functional properties of the ACTN4 protein in non-small-cell lung cancer (NSCLC) cells and evaluate its clinical importance. METHODS: We used RNA interference to knock down and overexpress ACTN4 protein to evaluate the effects of this intervention on cancer cell invasion and migration, as well as on microscopic cellular morphology. Furthermore, we examined by immunohistochemistry the expression of ACTN4 protein in tissue samples at different stages of lung cancer and compared the protein levels of ACTN4 in blood plasma samples from patients with histologically confirmed lung cancer and healthy controls. RESULTS: CL1-5 cell motility was significantly suppressed by the knockdown of ACTN4 protein. The morphology of CL1-5 cells changed from a predominantly mesenchymal-like shape into a globular shape in response to ACTN4 protein knockdown. A quantitative immunohistochemical assessment of lung cancer tissues revealed that ACTN4 protein level was considerably higher in cancerous tissues than in the adjacent normal ones, and the area under the receiver operating characteristic curve was 0.736 (p < 0.001). According to an enzyme-linked immunosorbent assay, the plasma levels of ACTN4 protein were significantly different between cancer patients and healthy controls, and the areas under the receiver operating characteristic curves were 0.828 and 0.909, respectively, for two independent cohorts (p < 0.001). CONCLUSIONS: We demonstrate that the knockdown of ACTN4 protein inhibited cell invasion and migration. These results suggest that ACTN4 is associated with lung cancer cell motility. Thus, the level of ACTN4 in cancerous tissue and plasma is related to the presence of lung cancer. PMID- 25299232 TI - Tolerability of nintedanib (BIBF 1120) in combination with docetaxel: a phase 1 study in Japanese patients with previously treated non-small-cell lung cancer. AB - BACKGROUND: This phase I, open-label study evaluated the safety/tolerability and maximum tolerated dose of second-line nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer. METHODS: Eligible patients received docetaxel 60 or 75 mg/m(2) (day 1) plus nintedanib 100, 150, or 200 mg twice daily (bid; days 2-21) in 21-day cycles. Standard 3 + 3 dose escalations were performed separately in patient cohorts with a body surface area (BSA) of less than 1.5 m(2) (BSA <1.5) and BSA greater than or equal to 1.5, respectively. RESULTS: Forty-two patients (17 BSA <1.5, 25 BSA >= 1.5) were treated. The maximum tolerated dose of nintedanib was 150 and 200 mg bid in patients with BSA less than 1.5 and BSA greater than or equal to 1.5 (BSA >= 1.5), respectively, in combination with 75 mg/m(2) of docetaxel. Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred in 12 patients (six per cohort). Drug-related adverse events included neutropenia (95%), leukopenia (83%), fatigue (76%), alopecia (71%), decreased appetite (67%), and elevations in alanine aminotransferase (64%) and aspartate aminotransferase (64%). All hepatic enzyme elevations were reversible and manageable with dose reduction or discontinuation. Among 38 evaluable patients, 10 (26%) had a partial response and 18 (47%) had stable disease. CONCLUSION: Continuous treatment with second-line nintedanib combined with docetaxel was manageable and showed promising signs of efficacy in Japanese patients with advanced non-small-cell lung cancer. PMID- 25299233 TI - Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis. AB - BACKGROUND: The characterization of the molecular alterations in thymic epithelial tumors may lead to a better understanding of tumorigenesis, new therapeutic targets, and biomarkers in these tumors. METHODS: Paired tissue (tumor and matched normal) from 15 thymic carcinomas (TCA) and six B3 thymomas were evaluated by exon capture of 275 cancer-related genes, followed by deep coverage next-generation sequencing, which identifies somatic sequence variants, small insertions and deletions, and copy number alterations involving all exons of the captured genes. RESULTS: Non-silent somatic mutations were identified in 12 of 15 (80%) TCA with a median of one mutation per tumor (range 0-26). Recurrent mutations were identified in tumor suppressor genes TP53 (n = 4), SMAD4 (n = 2), and CYLD (n = 2); and chromatin remodeling genes KDM6A (n = 3), SETD2 (n = 2), MLL3 (n = 2), and MLL2 (n = 2). Tumors with TP53 mutation appeared to exhibit more aggressive behavior. Therefore, the role of P53 was evaluated by immunohistochemistry in an additional ten cases. P53 overexpression correlated with TP53 mutation. These tumors had a higher rate of recurrence and death of disease compared to carcinoma with normal p53 expression (p = 0.02 for disease free survival and p = 0.05 for overall survival). Among the B3 thymomas, mutations were identified in four of six tumors. Mutations in BCOR (BCL6 co repressor) were seen in three thymomas and MLL3 (involved in histone methylation) in one tumor. CONCLUSIONS: Next-generation sequencing of cancer genes in thymic epithelial tumors revealed a low frequency of mutation, with different patterns between TCA and B3 thymomas. TP53 and BCOR were the most frequently mutated genes in TCA and B3 thymomas, respectively. Alterations in p53 are associated with worse prognosis in TCA. PMID- 25299234 TI - Neutrophil-lymphocyte and platelet-lymphocyte ratios as prognostic factors after stereotactic radiation therapy for early-stage non-small-cell lung cancer. AB - INTRODUCTION: The hematologic indices of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are correlated with clinical outcomes after stereotactic radiation. METHODS: We retrospectively evaluated the pretreatment NLR and PLR in patients treated with stereotactic radiation for early stage non small-cell lung cancer at our institution. A total of 149 patients treated for non-small-cell lung cancer were identified, and 59 had stage I disease with neutrophil, platelet, and lymphocyte levels within a 3-month period before treatment. Receiver operating characteristic (ROC) analysis was performed to examine cutoff values for survival and nonlocal failure followed by Kaplan-Meier analysis for survival. RESULTS: With a median follow-up of 17 months, 28 deaths were observed, and the median overall survival for all patients was 43 months. Based on the ROC analysis, NLR and PLR cutoff values for further survival analysis were determined based on the ROC analysis to be 2.98 and 146. The median overall survival was not reached for patients with low NLR or PLR but the survival was 23 months for patients with high NLR or PLR. There was no correlation between NLR and nonlocal failure, but on multivariate analysis PLR was found to be associated with freedom from nonlocal failure. Nonlocal failure rates were 11% for patients with PLR less than 250 and 58% for PLR greater than 250 (p < 0.001). CONCLUSION: The pretreatment NLR and PLR represented significant prognostic indicators of survival in patients treated for early-stage non-small cell lung carcinoma with stereotactic radiation. The PLR may be used as a prognostic indicator for nonlocal failure after stereotactic radiation for early stage lung cancer. PMID- 25299235 TI - Telomere length and recurrence risk after curative resection in patients with early-stage non-small-cell lung cancer: a prospective cohort study. AB - BACKGROUND: We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small-cell lung cancer (NSCLC). METHODS: This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative therapy at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time polymerase chain reaction. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. RESULTS: Median duration of follow-up was 61 months, and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared with those without recurrence (1.13 versus 1.07, p = 0.046). A subgroup analysis indicates that women had longer RTL compared with men (1.12 versus 1.06, p = 0.025), and the patients with adenocarcinoma demonstrated longer RTL compared with those with other histologic types (1.11 versus 1.05, p = 0.042). To determine whether longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, sex, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in women (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.02-4.96, p = 0.044) and adenocarcinoma subgroups (HR, 2.19; 95% CI, 1.05-4.55, p = 0.036). The increased risk of recurrence due to long RTL was more apparent in women with adenocarcinoma (HR, 2.67; 95% CI, 1.19-6.03, p = 0.018). CONCLUSIONS: This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma seem to be special subgroups in which telomere biology may play an important role. PMID- 25299236 TI - Viral hepatitis among drug users in methadone maintenance: associated factors, vaccination outcomes, and interventions. AB - Drug users are at high risk of viral Hepatitis A, B, and C. The prevalence of Hepatitis A, Hepatitis B, and Hepatitis C, associated factors, and vaccine seroconversion among drug treatment program participants in a randomized controlled trial of hepatitis care coordination were examined. Of 489 participants, 44 and 47% required Hepatitis A/Hepatitis B vaccinations, respectively; 59% were Hepatitis C positive requiring linkage to care. Factors associated with serologic statuses, and vaccine seroconversion are reported; implications for strategies in drug treatment settings are discussed. Results suggest generalizable strategies for drug treatment programs to expand viral hepatitis screening, prevention, vaccination, and linkage to care. PMID- 25299238 TI - The operative treatment of pressure sores in the pelvic region: A 10-year period overview. AB - CONTEXT: Pelvic region pressure sores often develop following spinal cord injury. Surgery is often necessary for long standing, large-sized pressure sores not responding to conservative treatment. Authors analyze their results of a 10-year period, and identify factors contributing to the reduction of the recurrence rate. METHODS: A total of 119 pressure sores were operated on 98 patients in two institutions during a 10-year period (1 January 2003 to 31 December 2012). The encountered perioperative complications are summarized, and the recurrence rate is analyzed with a patient follow-up questionnaire. RESULTS: We experienced 15 perioperative complications (12.6%). All complications were fully resolved by conservative treatment. Fifty-eight returned patient replies were processed. The average follow-up time after surgery was 5.2 years. The recurrence rate was 5.47%. CONCLUSION: The strict adherence to surgical indications, full patient compliance, specialized pre- and post-operative patient care, our routinely used preferred surgical method, all contribute to a low post-operative complication rate, long-term flap survival, and an extended recurrence free period. PMID- 25299237 TI - Infusion of bone marrow mononuclear cells reduces lung fibrosis but not inflammation in the late stages of murine silicosis. AB - We hypothesized that infusion of bone marrow mononuclear cells (BMMCs) in the late stages of silica-induced damage would reduce the remodelling process in a murine model of silicosis. C57BL/6 mice were assigned to 2 groups. In the SIL group, mice were instilled with a silica particle suspension intratracheally. Control (C) mice received saline under the same protocol. On the 40th day, some of the animals from both groups were killed. The others were treated with either saline or BMMCs (1*10(6) cells) intravenously (C+BMMC and SIL+BMMC), and the mice were killed 70 days after the start of the protocol. In the mice in the SIL+BMMC group, collagen deposition, the presence of silica particles inside nodules, the presence of macrophages and cells reactive for inducible nitric oxide synthase were reduced. Lung parameters also improved. Beyond that, the total and differential cellularity of bronchoalveolar lavage fluid, immunoexpression of transforming growth factor-beta, the number of T regulatory cells and apoptosis were increased. However, the presence of male donor cells in lung tissue was not observed using GFP+ cells (40d) or Y chromosome DNA (70d). Therefore, BMMC therapy in the late stages of experimental silicosis improved lung function by diminishing fibrosis but inflammatory cells persisted, which could be related to expansion of T regulatory cells, responsible for the beneficial effects of cell therapy. PMID- 25299239 TI - Drybonioside, a new glucoside from the Drynaria bonii H. Christ rhizomes. AB - Drynaria bonii H. Christ, a Vietnam traditional medicinal plant, is used for the treatment of osteoporosis, bone fractures, tinnitus, etc. (Ho PH. 2002. Vietnamese plants. Hanoi: Publisher of Young; Loi DT. 2004. Medicinal plants and remedy of Vietnam. Hanoi: Publisher of Medicine). Based on column chromatography, a new glucoside named drybonioside (5) and four known compounds alpha-tocopherol (1), 24-methylencycloartan-3beta-ol (2), triphyllol (3) and ethyl beta-D fructopyranoside (4) were isolated and identified from hexane and methanol extracts of D. bonii. The structures of new compound were elucidated on the basis of NMR and MS spectroscopic analysis. PMID- 25299240 TI - Changes in substrate utilisation and protein catabolism during multiday cycling in well-trained cyclists. AB - There is a paucity of studies that have evaluated substrate utilisation and protein catabolism during multiday strenuous exercise in athletes. Eleven well trained male cyclists completed 3 h of race-simulated cycling on 4 consecutive days. Cyclist exercised 2 h postprandially and with carbohydrate supplementation (~50 g . h(-1)) during exercise. Whole body substrate utilisation was measured by indirect calorimetry, protein catabolism from sweat and urine urea excretion, and blood metabolite concentration was evaluated. Protein catabolism during exercise was significantly greater on days 2-4 (29.9 +/- 8.8; 34.0 +/- 11.2; 32.0 +/- 7.3 g for days 2, 3, and 4, respectively) compared to day 1 (23.3 +/- 7.6 g), P < 0.05. Fat oxidation was greater at 21 km (~45 min) on days 2-4 (1.06 +/- 0.23; 1.08 +/- 0.25; 1.12 +/- 0.29 g . min(-1)) compared to day 1 (0.74 +/- 0.23 g . min(-1), P < 0.05), but the rate of carbohydrate and fat oxidation was similar between days at 50 and 80 km. Whole body substrate utilisation is altered on subsequent days of multiday prolonged strenuous cycling that includes a quicker transition to greater fat utilisation from exercise onset and a 28-46% greater reliance on endogenous protein catabolism on all successive days. PMID- 25299241 TI - Structure and spin dynamics of multiferroic BiFeO3. AB - Multiferroic materials have attracted much interest due to the unusual coexistence of ferroelectric and (anti-)ferromagnetic ground states in a single compound. They offer an exciting platform for new physics and potentially novel devices. BiFeO3 is one of the most celebrated multiferroic materials and has highly desirable properties. It is the only known room-temperature multiferroic with TC ~ 1100 K and TN ~ 650 K, and exhibits one of the largest spontaneous electric polarisations, P ~ 80 uC cm(-2). At the same time, it has a magnetic cycloid structure with an extremely long period of 620 A, which arises from competition between the usual symmetric exchange interaction and the antisymmetric Dzyaloshinskii-Moriya (DM) interaction. There is also an intriguing interplay between the DM interaction and single ion anisotropy K. In this review, we have attempted to paint a complete picture of bulk BiFeO3 by summarising the structural and dynamic properties of both the spin and lattice parts and their magneto-electric coupling. PMID- 25299242 TI - Biased Random-Key Genetic Algorithms for the Winner Determination Problem in Combinatorial Auctions. AB - In this paper we address the problem of picking a subset of bids in a general combinatorial auction so as to maximize the overall profit using the first-price model. This winner determination problem assumes that a single bidding round is held to determine both the winners and prices to be paid. We introduce six variants of biased random-key genetic algorithms for this problem. Three of them use a novel initialization technique that makes use of solutions of intermediate linear programming relaxations of an exact mixed integer linear programming model as initial chromosomes of the population. An experimental evaluation compares the effectiveness of the proposed algorithms with the standard mixed linear integer programming formulation, a specialized exact algorithm, and the best-performing heuristics proposed for this problem. The proposed algorithms are competitive and offer strong results, mainly for large-scale auctions. PMID- 25299243 TI - X-ray phase-contrast tomography of renal ischemia-reperfusion damage. AB - PURPOSE: The aim of the study was to investigate microstructural changes occurring in unilateral renal ischemia-reperfusion injury in a murine animal model using synchrotron radiation. MATERIAL AND METHODS: The effects of renal ischemia-reperfusion were investigated in a murine animal model of unilateral ischemia. Kidney samples were harvested on day 18. Grating-Based Phase-Contrast Imaging (GB-PCI) of the paraffin-embedded kidney samples was performed at a Synchrotron Radiation Facility (beam energy of 19 keV). To obtain phase information, a two-grating Talbot interferometer was used applying the phase stepping technique. The imaging system provided an effective pixel size of 7.5 um. The resulting attenuation and differential phase projections were tomographically reconstructed using filtered back-projection. Semi-automated segmentation and volumetry and correlation to histopathology were performed. RESULTS: GB-PCI provided good discrimination of the cortex, outer and inner medulla in non-ischemic control kidneys. Post-ischemic kidneys showed a reduced compartmental differentiation, particularly of the outer stripe of the outer medulla, which could not be differentiated from the inner stripe. Compared to the contralateral kidney, after ischemia a volume loss was detected, while the inner medulla mainly retained its volume (ratio 0.94). Post-ischemic kidneys exhibited severe tissue damage as evidenced by tubular atrophy and dilatation, moderate inflammatory infiltration, loss of brush borders and tubular protein cylinders. CONCLUSION: In conclusion GB-PCI with synchrotron radiation allows for non destructive microstructural assessment of parenchymal kidney disease and vessel architecture. If translation to lab-based approaches generates sufficient density resolution, and with a time-optimized image analysis protocol, GB-PCI may ultimately serve as a non-invasive, non-enhanced alternative for imaging of pathological changes of the kidney. PMID- 25299244 TI - Antimicrobial resistance investigation on Staphylococcus strains in a local hospital in Guangzhou, China, 2001-2010. AB - A retrospective study was conducted on 1,739 Staphylococcus isolates from the First Affiliated Hospital of Jinan University (FAHJU) in Guangzhou during 2001 2010. With the exception of teicoplanin and vancomycin, antimicrobial resistance was commonly observed among the isolates examined, with high resistance rates for beta-lactamases (94.0% and 73.7% for penicillin and oxacillin) and resistance percentages for cefoxitin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin, trimethoprim-sulfamethoxazole, and tetracycline ranging from 83.9% to 19.4%. Two hundred sixty-three of the 1,739 isolates were subjected to SCCmec typing and 42 to MLST, spaA, and coa typing. ST239-MRSA-III was prevalently identified along with one distinct coa type HIJKL and 2 spaA types (WGKAOMQ-t037 and WGKAQQ-t030). Class 1 integrons were commonly detected (31.6%), although none of the integron-positive MRSA strains had been isolated since 2009. The widespread detection of integron-based antimicrobial resistance determinants may further contribute to the emergence of superbugs. PMID- 25299245 TI - Non-deterministic modelling of food-web dynamics. AB - A novel approach to model food-web dynamics, based on a combination of chance (randomness) and necessity (system constraints), was presented by Mullon et al. in 2009. Based on simulations for the Benguela ecosystem, they concluded that observed patterns of ecosystem variability may simply result from basic structural constraints within which the ecosystem functions. To date, and despite the importance of these conclusions, this work has received little attention. The objective of the present paper is to replicate this original model and evaluate the conclusions that were derived from its simulations. For this purpose, we revisit the equations and input parameters that form the structure of the original model and implement a comparable simulation model. We restate the model principles and provide a detailed account of the model structure, equations, and parameters. Our model can reproduce several ecosystem dynamic patterns: pseudo cycles, variation and volatility, diet, stock-recruitment relationships, and correlations between species biomass series. The original conclusions are supported to a large extent by the current replication of the model. Model parameterisation and computational aspects remain difficult and these need to be investigated further. Hopefully, the present contribution will make this approach available to a larger research community and will promote the use of non deterministic-network-dynamics models as 'null models of food-webs' as originally advocated. PMID- 25299246 TI - Complex brain malformations associated with chromosome 6q27 gain that includes THBS2, which encodes thrombospondin 2, an astrocyte-derived protein of the extracellular matrix. AB - This case describes the autopsy findings of a 2-month-old male infant with extensive and severe developmental brain abnormalities, including microcephaly, neocortical neuronal layering abnormalities, leptomeningeal heterotopias, commissural agenesis, and cerebellar and brainstem hypoplasia. Microarray analysis identified a gain in chromosome band 6q27, which includes the entire coding region of THBS2. THSB2 encodes thrombospondin 2 (TSP2), an astrocyte secreted protein of the extracellular matrix that promotes synaptogenesis, neurite outgrowth, and cerebellar granule cell migration. Thrombospondin 2 is not a matrix structural protein; instead it serves as an extracellular modulator of cell function, so it is considered a matricellular protein. The neuropathological findings at autopsy are compatible with perturbations in several known functions of TSP2 and demonstrate that TSP2 dysregulation can have a significant negative impact on human brain development. Furthermore, this case demonstrates the important role of astrocytes in human brain development. PMID- 25299248 TI - Hyperscaling relationship between the interfacial tension of liquids and their correlation length near the critical point. AB - Interfaces involving coexisting phases in condensed matter are essential in many phenomena: wetting, nucleation, morphology, phase separation kinetics, membranes, phase coexistence in nanomaterials, etc. The majority of analytical theories available use concepts derived from mean field artifacts which do not describe adequately these systems. Satisfactory numerical simulation of interfaces at the atomistic to mesoscopic scale is still a challenge. In the present work, the interfacial tension between mixtures of organic solvents and water is obtained from mesoscopic computer simulations. The temperature dependence of the interfacial tension is found to obey a scaling law with an average critical exponent MU = 1.23. Additionally, we calculate the evolution of the correlation length, defined as the thickness of the interface between the immiscible fluids, as a function of temperature and find that it obeys also a scaling law with an average critical exponent being nu = 0.67. Finally, we show that the comparison of MU and nu for these binary mixtures constitutes the first test of Widom's hyperscaling relationship between these exponents in 3d, expressed as MU = nu (d 1). Based on these values and those for the 3d Ising model it is argued that both systems belong to the same universality class, which opens up the way for the calculation of new scaling exponents. PMID- 25299247 TI - Cytotoxic activity of the methanolic extract of Turnera diffusa Willd on breast cancer cells. AB - Turnera diffusa Willd, commonly known as Damiana, is employed in traditional medicine as a stimulant, aphrodisiac, and diuretic. Its leaves and stems are used for flavoring and infusion. Damiana is considered to be safe for medicinal use by the FDA. Pharmacological studies have established the hypoglycemic, antiaromatase, prosexual, estrogenic, antibacterial, and antioxidant activity of T. diffusa. The aim of the present study was to evaluate the possible cytotoxic effect of extracts and organic fractions of this plant on five tumor cell lines (SiHa, C-33, Hep G2, MDA-MB-231, and T-47D) and normal human fibroblasts. The results show that the methanolic extract (TdM) displayed greater activity on MDA MB-231 breast cancer cells (with an IC50 of 30.67 MUg/mL) than on the other cancer cell lines. Four organic fractions of this extract exhibited activity on this cancer cell line. In the most active fraction (F4), two active compounds were isolated, arbutin (1) and apigenin (2). This is the first report of a cytotoxic effect by T. diffusa on cancer cells. The IC50 values suggest that the methanolic extract of T. diffusa has potential as an anticancer therapy. PMID- 25299249 TI - Metal-organic frameworks and beta-cyclodextrin-based composite electrode for simultaneous quantification of guanine and adenine in a lab-on-valve manifold. AB - In this work, a novel chemically modified electrode is constructed based on metal organic frameworks and beta-cyclodextrin (Cu3(BTC)2/beta-CD, BTC = benzene-1,3,5 tricarboxylate) composite material. The electrode was used for simultaneous determination of guanine and adenine in a sequential injection lab-on-valve format and exhibited sensitive responses to guanine and adenine oxidation due to the pi-pi stacking interaction of Cu3(BTC)2 and the inclusion behavior of beta CD. The analytical performance was assessed with respect to the supporting electrolyte and its pH, accumulation time and accumulation potential, and the fluid flow rates. Under optimal conditions, linear calibration ranges for both guanine and adenine were from 1.0 * 10(-7) to 1.0 * 10(-5) mol L(-1), and detection limits (S/N = 3) were found to be 5.2 * 10(-8) and 2.8 * 10(-8) mol L( 1), respectively. The proposed sensor showed advantages of high sensitivity, simple sample preparation protocol, enhanced throughput and good reproducibility. Finally, the practical application of the proposed sensor has been performed for the determination of guanine and adenine in real samples with satisfactory results. PMID- 25299250 TI - The crosskey-davies experiment and onchocerciasis control in West Africa. PMID- 25299251 TI - Physician survey to determine how dengue is diagnosed, treated and reported in puerto rico. AB - Dengue is a major cause of morbidity in Puerto Rico and is well-known to its physicians. Early case identification and timely initiation of treatment for patients with severe dengue can reduce medical complications and mortality. To determine clinical management and reporting practices, and assess knowledge of dengue and its management, a survey was sent to 2,512 physicians with a medical license in Puerto Rico. Of the 2,313 physicians who received the survey, 817 (35%) completed the questionnaire. Of the respondents, 708 were currently practicing medicine; 138 were board certified (Group 1), 282 were board eligible (Group 2), and 288 had not finished residency (Group 3). Although respondents clinically diagnosed, on average, 12 cases of dengue in the preceding three months, 31% did not report any suspected cases to public health officials while about half (56%) reported all cases. Overall, 29% of respondents correctly identified early signs of shock and 48% identified severe abdominal pain and persistent vomiting as warning signs for severe dengue with the proportion of correct respondents highest in Group 1. Reportedly about sixty percent (57%) appropriately never give corticosteroids or prophylactic platelet transfusions to dengue patients. One third (30%) of respondents correctly identified administration of intravenous colloid solution as the best treatment option for dengue patients with refractory shock and elevated hematocrit after an initial trial of intravenous crystalloids, and nearly one half (46%) correctly identified administration of a blood transfusion as the best option for dengue patients with refractory shock and decreased hematocrit after a trial of intravenous crystalloids. Even though dengue has been endemic in Puerto Rico for nearly 4 decades, knowledge of dengue management is still limited, compliance with WHO treatment guidelines is suboptimal, and underreporting is significant. These findings were used to design a post graduate training course to improve the clinical management of dengue. PMID- 25299253 TI - Introduction to focus issue. PMID- 25299252 TI - Role of STN1 and DNA polymerase alpha in telomere stability and genome-wide replication in Arabidopsis. AB - The CST (Cdc13/CTC1-STN1-TEN1) complex was proposed to have evolved kingdom specific roles in telomere capping and replication. To shed light on its evolutionary conserved function, we examined the effect of STN1 dysfunction on telomere structure in plants. STN1 inactivation in Arabidopsis leads to a progressive loss of telomeric DNA and the onset of telomeric defects depends on the initial telomere size. While EXO1 aggravates defects associated with STN1 dysfunction, it does not contribute to the formation of long G-overhangs. Instead, these G-overhangs arise, at least partially, from telomerase-mediated telomere extension indicating a deficiency in C-strand fill-in synthesis. Analysis of hypomorphic DNA polymerase alpha mutants revealed that the impaired function of a general replication factor mimics the telomeric defects associated with CST dysfunction. Furthermore, we show that STN1-deficiency hinders re replication of heterochromatic regions to a similar extent as polymerase alpha mutations. This comparative analysis of stn1 and pol alpha mutants suggests that STN1 plays a genome-wide role in DNA replication and that chromosome-end deprotection in stn1 mutants may represent a manifestation of aberrant replication through telomeres. PMID- 25299254 TI - The National Neurosurgery Quality and Outcomes Database (N2QOD): a collaborative North American outcomes registry to advance value-based spine care. AB - STUDY DESIGN: National Prospective Observational Registry. OBJECTIVE: Describe our preliminary experience with the National Neurosurgery Quality and Outcomes Database (NQOD), a national collaborative registry of quality and outcomes reporting after low back surgery. SUMMARY OF BACKGROUND DATA: All major health care stakeholders are now requiring objective data regarding the value of medical services. Surgical therapies for spinal disorders have faced particular scrutiny in recent value-based discussions, in large part due to the dramatic growth in the cost and application of these procedures. Reliable data are fundamental to understanding the value of delivered health care. Clinical registries are increasingly used to provide such data. METHODS: The NQOD is a prospective observational registry designed to establish risk-adjusted expected morbidity and 1-year outcomes for the most common lumbar surgical procedures performed by spine surgeons; provide practice groups and hospitals immediate infrastructure for analyzing their 30-day morbidity and mortality and 3- and 12-month quality data in real-time; generate surgeon-, practice-, and specialty-specific quality and efficacy data; and generate nationwide quality and effectiveness data on specific surgical treatments. RESULTS: In its first 2 years of operation, the NQOD has proven to be a robust data collection platform that has helped demonstrate the objective quality of surgical interventions for medically refractory disorders of the lumbar spine. Lumbar spine surgery was found to be safe and effective at the group mean level in routine practice. Subgroups of patients did not report improvement using validated outcome measures. Substantial variation in treatment response was observed among individual patients. CONCLUSION: The NQOD is now positioned to determine the combined contribution of patient variables to specific clinical and patient-reported outcomes. These analyses will ultimately facilitate shared decision making and encourage efficient allocation of health care resources, thus significantly advancing the value paradigm in spine care. LEVEL OF EVIDENCE: 3. PMID- 25299255 TI - Role of prospective registries in defining the value and effectiveness of spine care. AB - STUDY DESIGN: Literature review and case example. OBJECTIVE: Describe methodological considerations of spine surgery registries. Review existing spine surgery registries. Describe the Vanderbilt Prospective Spine Registry (VPSR) as a case example and demonstrate its impact on comparative effectiveness research, value analysis, quality improvement, and practice-based learning. SUMMARY OF BACKGROUND DATA: To bend the cost curve and ultimately achieve sustainability in health care, medical providers and surgical treatments of the highest quality and effectiveness must be preferentially used and purchased. As the current US health care environment continues to evolve, it will be essential for all spine clinicians to understand and be facile with the principles of evidence-based health care reform. METHODS: We describe the methodological considerations of spine surgery registries, review the literature to describe existing spine surgery registries, and discuss the VPSR as a case example. RESULTS: We were able to obtain detailed information on 13 existing spine surgery registries through various internet-based resources. Of the 13, 2 registries had start dates before 2000, 3 between 2001 and 2005, 5 starting in 2006, and 3 were indeterminate. Follow-up rates were in the range from 22% to 79%, with longer follow-up times consistently producing lower follow-up rates. CONCLUSION: Prospective, longitudinal, patient-reported outcomes registries are powerful tools that allow measurement of cost, safety, effectiveness, and health care value across clinically meaningful episodes of care. Registries entirely based on claims or billing data, safety measures alone, process measures, or other proxies of outcome offer valuable insights, but do not provide comprehensive data to drive patient-centered value-based reform. As more spine-focused registries emerge and their integration into the US health care delivery evolve, the evidence to power value-based reform will be enabled. PMID- 25299256 TI - Triage of spine surgery referrals through a multidisciplinary care pathway: a value-based comparison with conventional referral processes. AB - STUDY DESIGN: Retrospective medical record review. OBJECTIVE: To (1) determine if outpatient referrals for low back pain (LBP) and leg pain triaged through a multidisciplinary spine care pathway (group A) were more likely to be candidates for surgery than conventional physician referrals (group B); (2) compare relevant clinical differences in the 2 groups (e.g., diagnosis, pain scores, level of disability); and (3) compare wait times for magnetic resonance imaging and surgical assessment. SUMMARY OF BACKGROUND DATA: The Saskatchewan Spine Pathway was introduced on the basis of evidence that a co-ordinated, multidisciplinary, and stratified approach to the assessment and management of LBP may improve quality. During early implementation, some physicians began to refer patients to Saskatchewan Spine Pathway clinics, whereas others continued to refer patients directly to the surgeon through the conventional process. METHODS: We retrospectively analyzed consecutive new outpatient referrals for LBP and leg pain, June 1, 2011 through May 30, 2012 for 2 surgeons. RESULTS: We identified 215 referrals, including 66 (30.7%) in group A and 149 (69.3%) in group B. There was no difference in overall health (mean EuroQol Group 5-Dimension Self-Report Questionnaire visual analogue scale) or lower back-related disability score (Oswestry Disability Index). Group A patients were significantly more likely to be candidates for surgery (59.1% vs. 37.6% for group B; P = 0.0034, chi test), had significantly poorer scores for EuroQol Group 5-Dimension Self-Report Questionnaire mobility, a higher proportion of leg dominant pain, and a lower proportion of back dominant pain. Group A patients also had significantly shorter wait times for magnetic resonance imaging and surgical assessment. CONCLUSION: A co-ordinated multidisciplinary pathway with a stratified approach to LBP assessment and care provided a greater proportion of surgery candidates than the conventional referral process. The implementation of such processes may allow surgeons to restrict their practices to patients who are more likely to benefit from their services, thereby reducing wait times and potentially reducing costs. LEVEL OF EVIDENCE: 3. PMID- 25299257 TI - The role of decision analytic modeling in the health economic assessment of spinal intervention. AB - STUDY DESIGN: Narrative review. OBJECTIVE: To review the common tenets, strengths, and weaknesses of decision modeling for health economic assessment and to review the use of decision modeling in the spine literature to date. SUMMARY OF BACKGROUND DATA: For the majority of spinal interventions, well-designed prospective, randomized, pragmatic cost-effectiveness studies that address the specific decision-in-need are lacking. Decision analytic modeling allows for the estimation of cost-effectiveness based on data available to date. Given the rising demands for proven value in spine care, the use of decision analytic modeling is rapidly increasing by clinicians and policy makers. METHODS: This narrative review discusses the general components of decision analytic models, how decision analytic models are populated and the trade-offs entailed, makes recommendations for how users of spine intervention decision models might go about appraising the models, and presents an overview of published spine economic models. RESULTS: A proper, integrated, clinical, and economic critical appraisal is necessary in the evaluation of the strength of evidence provided by a modeling evaluation. As is the case with clinical research, all options for collecting health economic or value data are not without their limitations and flaws. There is substantial heterogeneity across the 20 spine intervention health economic modeling studies summarized with respect to study design, models used, reporting, and general quality. There is sparse evidence for populating spine intervention models. Results mostly showed that interventions were cost-effective based on $100,000/quality-adjusted life-year threshold. Spine care providers, as partners with their health economic colleagues, have unique clinical expertise and perspectives that are critical to interpret the strengths and weaknesses of health economic models. CONCLUSION: Health economic models must be critically appraised for both clinical validity and economic quality before altering health care policy, payment strategies, or patient care decisions. LEVEL OF EVIDENCE: 4. PMID- 25299259 TI - Background to understanding value-based surgical spine care. PMID- 25299258 TI - Setting the equation: establishing value in spine care. AB - STUDY DESIGN: Topic review. OBJECTIVE: Describe value measurement in spine care and discuss the motivation for, methods for, and limitations of such measurement. SUMMARY OF BACKGROUND DATA: Spinal disorders are common and are an important cause of pain and disability. Numerous complementary and competing treatment strategies are used to treat spinal disorders, and the costs of these treatments is substantial and continue to rise despite clear evidence of improved health status as a result of these expenditures. METHODS: The authors present the economic and legislative imperatives forcing the assessment of value in spine care. The definition of value in health care and methods to measure value specifically in spine care are presented. Limitations to the utility of value judgments and caveats to their use are presented. RESULTS: Examples of value calculations in spine care are presented and critiqued. Methods to improve and broaden the measurement of value across spine care are suggested, and the role of prospective registries in measuring value is discussed. CONCLUSION: Value can be measured in spine care through the use of appropriate economic measures and patient-reported outcomes measures. Value must be interpreted in light of the perspective of the assessor, the duration of the assessment period, the degree of appropriate risk stratification, and the relative value of treatment alternatives. PMID- 25299260 TI - Cervical degenerative disease: systematic review of economic analyses. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To perform an evidence-based synthesis of the literature assessing the cost-effectiveness of surgery for patients with symptomatic cervical degenerative disc disease (DDD). SUMMARY OF BACKGROUND DATA: Cervical DDD is a common cause of clinical syndromes such as neck pain, cervical radiculopathy, and myelopathy. The appropriate surgical intervention(s) for a given problem is controversial, especially with regard to quality-of-life outcomes, complications, and costs. Although there have been many studies comparing outcomes and complications, relatively few have compared costs and, more importantly, cost-effectiveness of the interventions. METHODS: We conducted a systematic search in PubMed/MEDLINE, EMBASE, the Cochrane Collaboration Library, the Cost-Effectiveness Analysis registry database, and the National Health Service Economic Evaluation Database for full economic evaluations published through January 16, 2014. Identification of full economic evaluations that were explicitly designed to evaluate and synthesize the costs and consequences of surgical procedures or surgical intervention with nonsurgical management in patients with cervical DDD were considered for inclusion, based on 4 key questions. RESULTS: Five studies were included, each specific to 1 or more of our focus questions. Two studies suggested that cervical disc replacement may be more cost-effective compared with anterior cervical discectomy and fusion. Two studies comparing anterior with posterior surgical procedures for cervical spondylotic myelopathy suggested that anterior surgery was more cost-effective than posterior surgery. One study suggested that posterior cervical foraminotomy had a greater net economic benefit than anterior cervical discectomy and fusion in a military population with unilateral cervical radiculopathy. No studies assessed the cost-effectiveness of surgical intervention compared with nonoperative treatment of cervical myelopathy or radiculopathy, although it is acknowledged that existing studies demonstrate the cost-effectiveness of surgical intervention for these 2 clinical entities. CONCLUSION: A paucity of high-quality economic literature exists regarding cost-effectiveness of surgical intervention for cervical DDD. Future research is necessary to validate the findings of the few studies that do exist to guide decisions for surgery by the physician and patient with respect to cost-effectiveness. LEVEL OF EVIDENCE: 2. PMID- 25299261 TI - Is minimal access spine surgery more cost-effective than conventional spine surgery? AB - STUDY DESIGN: Systematic review. OBJECTIVE: To summarize and critically review the economic literature evaluating the cost-effectiveness of minimal access surgery (MAS) compared with conventional open procedures for the cervical and lumbar spine. SUMMARY OF BACKGROUND DATA: MAS techniques may improve perioperative parameters (length of hospital stay and extent of blood loss) compared with conventional open approaches. However, some have questioned the clinical efficacy of these differences and the associated cost-effectiveness implications. When considering the long-term outcomes, there seem to be no significant differences between MAS and open surgery. METHODS: PubMed, EMBASE, the Cochrane Collaboration database, University of York, Centre for Reviews and Dissemination (NHS-EED and HTA), and the Tufts CEA Registry were reviewed to identify full economic studies comparing MAS with open techniques prior to December 24, 2013, based on the key questions established a priori. Only economic studies that evaluated and synthesized the costs and consequences of MAS compared with conventional open procedures (i.e., cost-minimization, cost-benefit, cost effectiveness, or cost-utility) were considered for inclusion. Full text of the articles meeting inclusion criteria were reviewed by 2 independent investigators to obtain the final collection of included studies. The Quality of Health Economic Studies instrument was scored by 2 independent reviewers to provide an initial basis for critical appraisal of included economic studies. RESULTS: The search strategy yielded 198 potentially relevant citations, and 6 studies met the inclusion criteria, evaluating the costs and consequences of MAS versus conventional open procedures performed for the lumbar spine; no studies for the cervical spine met the inclusion criteria. Studies compared MAS tubular discectomy with conventional microdiscectomy, minimal access transforaminal lumbar interbody fusion versus open transforaminal lumbar interbody fusion, and multilevel hemilaminectomy via MAS versus open approach. CONCLUSION: Overall, the included cost-effectiveness studies generally supported no significant differences between open surgery and MAS lumbar approaches. However, these conclusions are preliminary because there was a paucity of high-quality evidence. Much of the evidence lacked details on methodology for modeling, related assumptions, justification of economic model chosen, and sources and types of included costs and consequences. The follow-up periods were highly variable, indirect costs were not frequently analyzed or reported, and many of the studies were conducted by a single group, thereby limiting generalizability. Prospective studies are needed to define differences and optimal treatment algorithms. LEVEL OF EVIDENCE: 3. PMID- 25299262 TI - More "why" and less "how": is value-based spine care the next breakthrough? PMID- 25299263 TI - Cost-effectiveness of surgical treatment for degenerative spondylolisthesis and spinal stenosis. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To identify cost-effective treatment strategies for lumbar spine degenerative diseases. SUMMARY OF BACKGROUND DATA: There is a paucity of literature assisting physicians and society regarding the cost-efficiency of management of lumbar spine conditions. Limited articles on selective operative and nonoperative therapies have been published for a variety of lumbar conditions. METHODS: A systematic search of PubMed, EMBASE, the Cochrane Collaboration data base, University of York, Centre for Reviews and Dissemination (National Health Services Economic Evaluation Database and health technology assessment), and the Tufts CEA Registry was conducted through December 16, 2013. Three specific questions were addressed for adult patients: (1) What is the evidence that surgery is cost-effective compared with nonsurgical management for lumbar degenerative spondylolisthesis or stenosis? (2) What is the evidence that fusion is cost-effective compared with no fusion for degenerative spondylolisthesis or stenosis? and (3) What is the evidence that instrumentation is cost-effective compared with none for degenerative spondylolisthesis? The Quality of Health Economic Studies instrument was used to provide an initial basis for critical appraisal of included economic studies. Articles were further refined with individual review based on inclusion/exclusion criteria. RESULTS: Initial search resulted in 122 potentially relevant citations, 115 of which were excluded at title and abstract levels and 3 at full-text reviews, leaving 5 for analysis. No non-English language text met inclusion/exclusion criteria. All studies illustrated a clinical benefit of surgical treatment as measured by quality-adjusted life year (0.11-8.05). Surgical treatments had a greater financial cost than nonoperative care ($5883-$26,035). Incremental cost effectiveness ratio calculations noted operative treatment over nonoperative treatment for spondylolisthesis ($59,487-$115,600) per quality-adjusted life year. However, cost for patients without spondylolisthesis varied greatly from nonoperative treat dominating to $77,600 per quality-adjusted life year favoring surgery. Because the articles had heterogeneous methods and patient population, conclusion differed greatly on cost assessment. CONCLUSION: Limited quality data exist on cost-effective treatment of degenerative lumbar spinal conditions, despite more recent interest related to this topic. It is important that future research efforts focus on constructing higher quality trials in this area to help determine the most cost-effective care. LEVEL OF EVIDENCE: 3. PMID- 25299264 TI - Biological substitutes/extenders for spinal arthrodesis: which agents are cost effective? AB - STUDY DESIGN: Systematic review. OBJECTIVE: To evaluate the cost-effectiveness of lumbar or cervical spinal arthrodesis using biological substitutes and extenders compared with iliac crest autograft for the treatment of degenerative spinal conditions. SUMMARY OF BACKGROUND DATA: The cost-effectiveness of using bone graft substitutes and extenders for spinal fusion compared with using iliac crest autograft is not yet well established. METHODS: A systematic search of PubMed/MEDLINE, the Cochrane Collaboration Library, EMBASE, the CRD (Centre for Reviews and Dissemination) database, and Tuft's CEA registry for literature published through December 2013 was performed to identify full formal economic analyses comparing the use of biological grafts with iliac crest bone graft in spinal fusion for thoracolumbar or cervical degenerative, deformity, and traumatic spinal conditions. Economic outcomes such as cost per improved outcome or cost per quality-adjusted life year were reported in the context of the model type, analytic perspective clinical comparisons, and sensitivity analyses employed. RESULTS: The search strategy yielded 88 citations, and 6 full economic analyses ultimately met our inclusion criteria. For the comparison of recombinant human bone morphogenetic protein-2 to iliac crest bone graft in the lumbar spine, data from 4 cost-effectiveness studies and 1 cost-utility study provided discordant conclusions that varied with type of data used, cost-measurement methods, and study design. In the cervical spine, one study suggested that from a societal perspective, anterior cervical discectomy and fusion (ACDF) with allograft is similarly cost-effective as ACDF with autograft. CONCLUSION: The results suggest that compared with use of iliac crest bone graft in lumbar spinal fusion, use of recombinant human bone morphogenetic protein is not cost-effective from a payer perspective with higher upfront costs, but it may be cost-effective from a societal perspective due to a decrease in lost productivity. The data in this study also suggest that from a societal perspective, ACDF with allograft is similarly cost-effective to ACDF with autograft. LEVEL OF EVIDENCE: 3. PMID- 25299265 TI - Health economic studies: an introduction to cost-benefit, cost-effectiveness, and cost-utility analyses. AB - STUDY DESIGN: Narrative overview. OBJECTIVE: To provide clinicians with a basic understanding of economic studies, including cost-benefit, cost-effectiveness, and cost-utility analyses. SUMMARY OF BACKGROUND DATA: As decisions regarding public health policy, insurance reimbursement, and patient care incorporate factors other than traditional outcomes such as satisfaction or symptom resolution, health economic studies are increasingly prominent in the literature. This trend will likely continue, and it is therefore important for clinicians to have a fundamental understanding of the common types of economic studies and be able to read them critically. In this brief article, the basic concepts of economic studies and the differences between cost-benefit, cost-effectiveness, and cost-utility studies are discussed. METHODS: An overview of the field of health economic analysis is presented. RESULTS: Cost-benefit, cost-effectiveness, and cost-utility studies all integrate cost and outcome data into a decision analysis model. These different types of studies are distinguished mainly by the way in which outcomes are valued. Obtaining accurate cost data is often difficult and can limit the generalizability of a study. CONCLUSION: With a basic understanding of health economic analysis, clinicians can be informed consumers of these important studies. PMID- 25299266 TI - Design of high speed and low offset dynamic latch comparator in 0.18 um CMOS process. AB - The cross-coupled circuit mechanism based dynamic latch comparator is presented in this research. The comparator is designed using differential input stages with regenerative S-R latch to achieve lower offset, lower power, higher speed and higher resolution. In order to decrease circuit complexity, a comparator should maintain power, speed, resolution and offset-voltage properly. Simulations show that this novel dynamic latch comparator designed in 0.18 um CMOS technology achieves 3.44 mV resolution with 8 bit precision at a frequency of 50 MHz while dissipating 158.5 uW from 1.8 V supply and 88.05 uA average current. Moreover, the proposed design propagates as fast as 4.2 nS with energy efficiency of 0.7 fJ/conversion-step. Additionally, the core circuit layout only occupies 0.008 mm2. PMID- 25299267 TI - Leishmania donovani infection causes distinct epigenetic DNA methylation changes in host macrophages. AB - Infection of macrophages by the intracellular protozoan Leishmania leads to down regulation of a number of macrophage innate host defense mechanisms, thereby allowing parasite survival and replication. The underlying molecular mechanisms involved remain largely unknown. In this study, we assessed epigenetic changes in macrophage DNA methylation in response to infection with L. donovani as a possible mechanism for Leishmania driven deactivation of host defense. We quantified and detected genome-wide changes of cytosine methylation status in the macrophage genome resulting from L. donovani infection. A high confidence set of 443 CpG sites was identified with changes in methylation that correlated with live L. donovani infection. These epigenetic changes affected genes that play a critical role in host defense such as the JAK/STAT signaling pathway and the MAPK signaling pathway. These results provide strong support for a new paradigm in host-pathogen responses, where upon infection the pathogen induces epigenetic changes in the host cell genome resulting in downregulation of innate immunity thereby enabling pathogen survival and replication. We therefore propose a model whereby Leishmania induced epigenetic changes result in permanent down regulation of host defense mechanisms to protect intracellular replication and survival of parasitic cells. PMID- 25299268 TI - Maternally transmitted mitochondrial DNA mutations can reduce lifespan. AB - We recently showed that germline transmission of mitochondrial DNA mutations via the oocyte cause aggravation of aging phenotypes in prematurely aging mtDNA mutator (PolgA(mut/mut)) mice. We discovered that 32% of these mice also exhibit stochastic disturbances of brain development, when maternal mtDNA mutations were combined with homozygosity for the PolgA mutation, leading to de novo somatic mtDNA mutations. Surprisingly, we also found that maternally transmitted mtDNA mutations can cause mild premature aging phenotypes also in mice with a wild-type nuclear DNA background. We now report that in addition to the early onset of aging phenotypes, these mice, burdened only by low levels of mtDNA mutations transmitted via the germline, also exhibit reduced longevity. Our data thus demonstrate that low levels of maternally inherited mtDNA mutations when present during development can affect both overall health and lifespan negatively. PMID- 25299269 TI - A combretastatin-mediated decrease in neutrophil concentration in peripheral blood and the impact on the anti-tumor activity of this drug in two different murine tumor models. AB - The vascular disrupting agent combretastatin A-4 disodium phosphate (CA4P) induces fluctuations in peripheral blood neutrophil concentration. Because neutrophils have the potential to induce both vascular damage and angiogenesis we analyzed neutrophil involvement in the anti-tumoral effects of CA4P in C3H mammary carcinomas in CDF1 mice and in SCCVII squamous cell carcinomas in C3H/HeN mice. Flow cytometry analyses of peripheral blood before and up to 144 h after CA4P administration (25 and 250 mg/kg) revealed a decrease 1 h after treatment, followed by an early (3-6 h) and a late (>72 h) increase in the granulocyte concentration. We suggest that the early increase (3-6 h) in granulocyte concentration was caused by the initial decrease at 1 h and found that the late increase was associated with tumor size, and hence independent of CA4P. No alterations in neutrophil infiltration into the C3H tumor after CA4P treatment (25 and 250 mg/kg) were found. Correspondingly, neutrophil depletion in vivo, using an anti-neutrophil antibody, followed by CA4P treatment (25 mg/kg) did not increase the necrotic fraction in C3H tumors significantly. However, by increasing the CA4P dose to 250 mg/kg we found a significant increase of 359% in necrotic fraction when compared to neutrophil-depleted mice; in mice with no neutrophil depletion CA4P induced an 89% change indicating that the presence of neutrophils reduced the effect of CA4P. In contrast, neither CA4P nor 1A8 affected the necrotic fraction in the SCCVII tumors significantly. Hence, we suggest that the initial decrease in granulocyte concentration was caused by non tumor-specific recruitment of neutrophils and that neutrophils may attenuate CA4P mediated anti-tumor effect in some tumor models. PMID- 25299276 TI - Of all the nerve (and anterior horn cell and neuromuscular junction). PMID- 25299270 TI - Ethyl acetate fraction from Angelica sinensis inhibits IL-1beta-induced rheumatoid synovial fibroblast proliferation and COX-2, PGE2, and MMPs production. AB - BACKGROUND: The root of Angelica sinensis (AS), also known as "Dang-gui," was a popular herbal medicine widely used in the treatment of gynecological diseases in China, Korea, and Japan for a long time. This study aimed to determine the effects of ethyl acetate fraction from Angelica sinensis (EAAS) on the interleukin-1beta (IL-1beta)-induced proliferation of rheumatoid arthritis synovial fibroblasts (RASFs), and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX) 2, and prostaglandin E2 (PGE2), involved in articular bone and cartilage destruction, by RASFs. RESULTS: RASF proliferation was evaluated with cholecystokinin octapeptide (CCK-8) reagent in the presence of IL-1beta with/without EAAS. Expression of MMPs, tissue inhibitor of metalloproteinases-1 (TIMP-1), COXs, PGE2, and intracellular mitogen-activated protein kinase (MAPK) signaling molecules, including p-ERK, p-p38, p-JNK, and NF-kappaB, were examined using immunoblotting or semi-quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. EAAS inhibited IL-1beta-induced RASF proliferation; MMP-1, MMP-3, and COX-2 mRNA and protein expressions; and PGE2 production. EAAS also inhibits the phosphorylation of ERK-1/2, p38, and JNK, and activation of NF-kappaB by IL-1beta. CONCLUSION: EAAS might be a new therapeutic modality for rheumatoid arthritis management. PMID- 25299277 TI - ALS and other motor neuron diseases. AB - PURPOSE OF REVIEW: This review describes the most common motor neuron disease, ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its pathophysiology, including new genetic underpinnings of the disease. This article also covers other motor neuron diseases, reviews how to distinguish them from ALS, and discusses their pathophysiology. RECENT FINDINGS: In this article, the spectrum of cognitive involvement in ALS, new concepts about protein synthesis pathology in the etiology of ALS, and new genetic associations will be covered. This concept has changed over the past 3 to 4 years with the discovery of new genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. SUMMARY: The anterior horn cells control all voluntary movement: motor activity, respiratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron disease, demonstrates the impact of this class of disorders. ALS and other motor neuron diseases can represent diagnostic challenges. Neurologists are often called upon to serve as a "medical home" for these patients: coordinating care, arranging for durable medical equipment, and leading discussions about end-of-life care with patients and caregivers. It is important for neurologists to be able to identify motor neuron diseases and to evaluate and treat patients affected by them. PMID- 25299278 TI - Charcot-Marie-Tooth disease and other inherited neuropathies. AB - PURPOSE OF REVIEW: Inherited peripheral neuropathies are among the most common genetic neuromuscular disorders worldwide. However, their diagnosis can be challenging due to genotypic and phenotypic variability. Charcot-Marie-Tooth disease (CMT), the most common form, is associated with mutations or copy-number variations in over 70 genes, representing proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Other genetic peripheral neuropathies are associated with multisystem manifestations, including familial amyloid neuropathy and neuropathies associated with metabolic or other genetic syndromes. This article reviews the most recent discoveries in the field and how they are changing the way neurologists diagnose this specific group of peripheral neuropathies. RECENT FINDINGS: In the past few years, several large cohort studies on the molecular diagnosis of CMT have been published, providing guidelines for genetic testing in clinical practice. In the same period, next generation sequencing technology has accelerated the discovery of new CMT genes, expanding our knowledge on genotype-phenotype correlations. SUMMARY: Recent advances in sequencing technology and genotype-phenotype correlation studies are changing the way neurologists diagnose inherited neuropathies. New therapeutic strategies for familial amyloid neuropathy are paving the way for innovative treatments for genetic neuropathies. PMID- 25299279 TI - Diabetic neuropathies. AB - PURPOSE OF REVIEW: This article provides an overview for understanding the diagnosis, pathogenesis, and management of diabetic neuropathy. RECENT FINDINGS: New information about the pathogenesis of diabetic neuropathy continues to emerge, which will lead to identifying new drug targets. It is clear that the natural history of diabetic neuropathy is changing and the rate of progression is slowing. This is likely because of a combination of earlier diagnosis, improved glycemic management, and improved control of related complications such as hyperlipidemia and hypertension. Early diagnosis is critical, and small fiber neuropathy or subclinical diabetic neuropathy may be reversed or significantly improved with appropriate intervention. The American Academy of Neurology recently published guidelines for the treatment of painful diabetic neuropathy. SUMMARY: Diabetic neuropathy is common and can present with varied clinical presentations discussed in this article. Although treatment currently focuses on pain management, attention should be paid to potential risk factors for neuropathy. For example, glycemic control, hyperlipidemia, and hypertension should be managed with diet, exercise, and medications. Class I or II clinical studies indicate that pregabalin, duloxetine, amitriptyline, gabapentin, and opioids are effective in the management of diabetic neuropathic pain. PMID- 25299280 TI - Acquired immune demyelinating neuropathies. AB - PURPOSE OF REVIEW: Acquired immune demyelinating neuropathies refer to a group of disorders that share overlapping sensory, motor, and autonomic clinical, laboratory, and electrodiagnostic features. It is important to recognize acquired immune demyelinating neuropathies as they are generally responsive to immunosuppressive or immunomodulatory therapies. RECENT FINDINGS: This article reviews recently developed early prognostic tools in Guillain-Barre syndrome and discusses the evolving understanding of chronic demyelinating phenotypes with differing treatment responsiveness. SUMMARY: While weakness and numbness progress over 2 to 4 weeks in Guillain-Barre syndrome, they continue to evolve beyond 8 weeks in chronic inflammatory demyelinating polyradiculoneuropathy and over 4 to 8 weeks in subacute inflammatory demyelinating polyradiculoneuropathy. Acquired immune demyelinating neuropathies present uncommonly as variants with predominance of ocular, bulbar, sensory, autonomic, or motor manifestations in addition to regional variants, such as paraparetic acquired immune demyelinating neuropathies. Establishing the correct diagnosis is important as these immune disorders differ in response to corticosteroids and other immunosuppressive therapies. PMID- 25299281 TI - Acquired immune axonal neuropathies. AB - PURPOSE OF REVIEW: This article discusses the clinical features, pathophysiology, and management of primary and secondary acquired immune axonal neuropathies. RECENT FINDINGS: Although there are many collagen vascular disorders associated with vasculitic neuropathy, a quarter of cases have been described to be due to nonsystemic vasculitis of the peripheral nervous system. Enhanced surveillance and aggressive treatment of conditions such as cryoglobulin-related vasculitic neuropathy with cyclophosphamide, rituximab, and alfa interferons has led to improved morbidity and mortality, however, many cases of immune axonal acquired neuropathy are still associated with poor outcomes. Acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) are well-characterized variants of Guillain-Barre syndrome. SUMMARY: Characterizing the clinical and electrophysiologic phenotype can help diagnose conditions such as nonsystemic vasculitic neuropathy, AMAN, AMSAN, and immune small fiber neuropathy, while careful evaluation of systemic features is key to identifying secondary immune axonal neuropathies such as vasculitic neuropathy related to collagen vascular disease. Additional research is needed to determine the exact immune pathogenesis and optimized treatment regimens for all acquired immune axonal neuropathies. PMID- 25299282 TI - Infectious neuropathies. AB - PURPOSE OF REVIEW: Infections are important, potentially treatable causes of peripheral nervous system disease. This article reviews the clinical presentation and management of several common peripheral nervous system diseases due to viral, bacterial, spirochetal, and parasitic infections. RECENT FINDINGS: The clinical presentation and evaluation of infectious peripheral nervous system diseases are well established. Advances in the treatment and, in some cases, the prevention of these diseases are still evolving. SUMMARY: A diverse range of peripheral nervous system diseases, including peripheral neuropathy, radiculopathy, radiculomyelopathy, cranial neuropathy, and motor neuropathy, are caused by numerous infectious agents. In some patients, peripheral neuropathy may be a side effect of anti-infectious drugs. Infectious neuropathies are important to recognize as they are potentially treatable. This article discusses the clinical presentation, evaluation, and treatment of several common peripheral nervous system diseases caused by viral, bacterial, spirochetal, and parasitic infections, as well as some peripheral nerve disorders caused by adverse effects of the treatments of these infectious diseases. PMID- 25299284 TI - Paraproteinemic neuropathies. AB - PURPOSE OF REVIEW: Monoclonal gammopathies are common in the general population and occur in 10% of patients with peripheral neuropathy. It is important for the clinician to be able to determine whether an association exists between the paraprotein and the neuropathy. The clinical phenotype of the neuropathy, as well as the type of monoclonal protein, provides clues for the diagnosis. Optimal management of paraproteinemic neuropathies requires appropriate evaluation of the monoclonal protein for an underlying hematologic disorder. RECENT FINDINGS: Clinical studies in paraproteinemic neuropathies have provided a better understanding of these disorders, but much is still unknown regarding the pathophysiologic mechanisms. Recent clinical trials in immunoglobulin M (IgM) neuropathy have shown that better outcome measures and treatment approaches are needed. Peripheral blood stem cell transplantation has shown promising improvements in the treatment of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome and immunoglobulin light chain (AL) amyloidosis. SUMMARY: Recognizing the frequent association of neuropathy with monoclonal proteins and evaluating for a hematologic malignancy should enable physicians to find better treatments and ultimately improve neuropathy outcome. PMID- 25299283 TI - Peripheral neuropathy due to vitamin deficiency, toxins, and medications. AB - PURPOSE OF REVIEW: Peripheral neuropathies secondary to vitamin deficiencies, medications, or toxins are frequently considered but can be difficult to definitively diagnose. Accurate diagnosis is important since these conditions are often treatable and preventable. This article reviews the key features of different types of neuropathies caused by these etiologies and provides a comprehensive list of specific agents that must be kept in mind. RECENT FINDINGS: While most agents that cause peripheral neuropathy have been known for years, newly developed medications that cause peripheral neuropathy are discussed. SUMMARY: Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and vitamin deficiencies. It is important to consider these etiologies when approaching patients with a variety of neuropathic presentations; additionally, etiologic clues may be provided by other systemic symptoms. While length-dependent sensorimotor axonal peripheral neuropathy is the most common presentation, several examples present in a subacute severe fashion, mimicking Guillain-Barre syndrome. PMID- 25299285 TI - Brachial plexopathies. AB - PURPOSE OF REVIEW: The main objective of this article is to offer a regional approach to brachial plexus assessment because, although the brachial plexus is the largest and most complex peripheral nervous system structure, most of its disorders involve only a portion of it. Consequently, regional assessment typically localizes and characterizes the lesion. RECENT FINDINGS: The sensory axons traversing each region are known and provide localizing information. SUMMARY: Because localization dictates the differential diagnosis and the resulting initial clinical management, examining physicians must first localize the lesion. Localization of a brachial plexus lesion requires an appreciation of brachial plexus anatomy, lesion classification, and the routes traversed by the various axons composing the brachial plexus, especially the sensory axons. This information is reviewed in this article and followed by discussions of several brachial plexus disorders, especially those with regional predilections. PMID- 25299286 TI - Lumbosacral plexopathy. AB - PURPOSE OF REVIEW: This article provides an up-to-date review of the clinical features and pathogenesis of different types of lumbosacral plexopathy and a clinical approach to their evaluation and management. Often, the pathologic involvement is not limited to the plexus and also involves the root and nerve levels. These conditions are called lumbosacral radiculoplexus neuropathies. RECENT FINDINGS: The pathophysiology of diabetic and nondiabetic lumbosacral radiculoplexus neuropathy has been elucidated; it is ischemic injury due to a perivascular inflammatory process and microvasculitis. The clinical and neurophysiologic features of these two entities have been found to be similar, consisting of acute or subacute onset of pain and paresthesia followed by profound motor weakness asymmetrically involving the lower limbs and associated with weight loss. A lower limb and motor predominant neuropathy without pain also occurs in diabetes mellitus and has been shown to be a form of diabetic lumbosacral radiculoplexus neuropathy and not diabetic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The pathophysiology of some cases of postsurgical lumbosacral plexopathies has recently been shown also to be inflammatory from microvasculitis, and treatment with immunotherapy in a timely fashion may be desirable. SUMMARY: Many pathophysiologic processes, such as neoplastic, traumatic, infectious, radiation, and inflammatory/microvasculitic processes, can affect the lumbosacral plexus causing lumbosacral plexopathy. The clinical symptoms and signs depend on the part of the plexus involved and the temporal course. Management depends on the cause of the lumbosacral plexopathy. Many cases of lumbosacral plexopathy previously thought to be idiopathic have been shown to be caused by ischemic injury from microvasculitis; despite lack of evidence for efficacy in improving neurologic deficits, the authors of this article include immunotherapy in their management of patients with this condition. PMID- 25299287 TI - Paraneoplastic neuropathies. AB - PURPOSE OF REVIEW: This article provides an approach to the recognition and management of paraneoplastic neuropathies. RECENT FINDINGS: Paraneoplastic neuropathies may have unique phenotypic presentations, such as sensory neuronopathy, autonomic enteric neuropathy, demyelinating neuropathy, and, rarely, motor neuropathy. Paraneoplastic sensorimotor neuropathy, on the other hand, may be indistinguishable from other common types of axonal polyneuropathy. Certain patterns of neuropathies are commonly seen with different types of cancers, but this relationship is not exclusive and not all patients whose pattern of neuropathy suggests a paraneoplastic disorder have an underlying cancer. In addition to definitive therapy for malignancy, immunomodulatory therapy, such as corticosteroids, IV immunoglobulin (IVIg), or immunosuppressants, may benefit some patients, but there are very few published treatment data for paraneoplastic neuropathies. SUMMARY: Prompt recognition of paraneoplastic neuropathies may lead to identification and treatment of an occult cancer. Treatment can potentially arrest the progression of neuropathy. PMID- 25299288 TI - Autonomic neuropathies. AB - PURPOSE OF REVIEW: This article focuses on the most prevalent forms of autonomic neuropathies, but also discusses conditions such as focal and dysfunctional syndromes (altered autonomic function in the absence of structural lesions). The goal of this review is to allow the reader to promptly recognize these disorders, identify potentially reversible or treatable causes, and implement the appropriate treatment as well as supportive care. RECENT FINDINGS: Secondary forms of autonomic neuropathies (eg, diabetes mellitus, amyloidosis) are much more common than primary forms, of which autoimmune ganglioneuropathies represent a major component. However, the spectrum of the latter is continuously evolving and has diagnostic and therapeutic implications. Testing modalities such as autonomic testing, serum autoimmune antibody testing, and skin biopsies are becoming more widely available. SUMMARY: Autonomic neuropathies are relatively common conditions, and, because of the prognostic implications as well as impact on patient quality of life, they should be promptly recognized and treated aggressively. Testing is critical as other conditions may mimic autonomic neuropathies. Treatment is symptomatic in many cases, but specific therapies are also available in selected autonomic neuropathies. PMID- 25299289 TI - Small fiber neuropathies. AB - PURPOSE OF REVIEW: This article reviews the clinical, neurophysiologic, and neuropathologic findings in patients presenting with small fiber neuropathies. Emphasis is placed on recent updates to the literature, but also on understanding the differential diagnosis and initial evaluation of patients with small fiber neuropathy. RECENT FINDINGS: There have been several updates in the literature about diseases associated with small fiber neuropathy. First, treatment-induced neuropathy in diabetes mellitus is an iatrogenic small fiber neuropathy linked to overly rapid correction in blood glucose levels in the setting of chronic hyperglycemia. Second, several novel mutations to sodium channels have been identified in patients presenting with idiopathic small fiber neuropathy that may significantly alter our understanding and future treatment of small fiber neuropathy. Third, antibodies against voltage-gated potassium channels appear to be associated with a much higher incidence of pain than would be expected, although the mechanism has not been established. Fourth, the link between glucose dysregulation, metabolic syndrome, and neuropathy continues to grow. Finally, several other disorders, including postural orthostatic tachycardia syndrome, have been postulated to be associated with small fiber neuropathies. SUMMARY: Small fiber neuropathies are a heterogeneous group of disorders that may present with a variety of sensory or autonomic symptoms. Recent reports highlight a number of new causes of small fiber neuropathy that continue to reduce the number of remaining idiopathic cases. PMID- 25299290 TI - Myasthenia gravis and Lambert-Eaton myasthenic syndrome. AB - PURPOSE OF REVIEW: This article reviews the clinical presentations, diagnostic findings, and treatment options for autoimmune myasthenia gravis (MG) and Lambert Eaton myasthenic syndrome. RECENT FINDINGS: Immunologic research is unraveling the immunopathology of MG and identifying targets for novel immune-based therapy of this condition. MG patients with antibodies to muscle-specific tyrosine kinase (MuSK) frequently present with symptoms and clinical findings that suggest nerve or muscle disease. SUMMARY: Early diagnosis and treatment have a marked effect on outcome in these diseases. In most cases, the diagnosis of MG or Lambert-Eaton myasthenic syndrome can be made from the history, supplemented with directed questions, and a physical examination designed to demonstrate variable weakness in affected muscle groups. Appropriate confirmatory tests almost always establish the diagnosis. Although several novel treatment modalities for MG are under investigation, currently available therapies produce substantial improvement in function and quality of life in most patients with this condition. Knowledge about the dosing, adverse effects, and costs of immunomodulatory therapies is essential for the effective management of patients with MG and Lambert-Eaton myasthenic syndrome. PMID- 25299291 TI - Medical marijuana for HIV-associated sensory neuropathy: legal and ethical issues. AB - The number of states legalizing medical marijuana is increasing. Medical marijuana is possibly effective therapy for HIV-associated sensory neuropathy. Despite legalization at the state level, however, the current and contradictory federal drug enforcement policy creates the risk that physicians who recommend medical marijuana to their patients will lose their ability to prescribe medications. The federal-state tension has legal and ethical implications for neurologists who receive a request for medical marijuana from their patients since neurologists must strive to both relieve suffering and obey relevant laws. Recommendation of medical marijuana by neurologists to their patients is ethically permissible but is not ethically mandatory. PMID- 25299292 TI - Do all neuropathy patients need an EMG at least once? AB - EMG, which consists of nerve conduction studies and needle electromyography, is an essential diagnostic tool in the evaluation of patients with suspected peripheral neuropathy. Many neurologists order an EMG for all patients with suspected peripheral neuropathy. Not surprisingly, evidence now exists that shows EMG is a major driver of health care costs associated with neuropathy diagnoses. As neurologic practice evolves from fee for service to value-based compensation, neurologists will need to justify the diagnostic utility of EMG (outcome) relative to its cost. While carefully performed studies of diagnostic utility in many patient populations are lacking, a robust literature provides guidance regarding the potential role and limitations of EMG in neuropathy diagnosis as well as the pitfalls referring providers and electrodiagnostic consultants must consider. Do all neuropathy patients need an EMG at least once? This article attempts to answer this question using an illustrative case to highlight critical factors every neurologist must consider before ordering an EMG for neuropathy diagnosis. PMID- 25299293 TI - Coding in peripheral neuropathy. PMID- 25299297 TI - Patient management problem. PMID- 25299302 TI - Comparison of impurity effect between two Tc domes in LaFeAsO(1-x)H(x). AB - Hydrogen-doped LaFeAsO(1-x)H(x) system has a unique 2-dome structure. The effects of Zn impurities on the first and second superconducting domes in LaFe(1 y)Zn(y)AsO(1-x)H(x) (x = 0.10 for the first superconducting phase (SC1) and 0.35 for the second superconducting phase (SC2)) are examined by electrical resistivity, Hall effect and magnetization measurements. Substitution with Zn strongly suppresses the critical temperature (Tc) and behaves as a nonmagnetic impurity. The suppression rates are: 17(4) K/% (SC1) and 6.9(5) K/% (SC2). It was considered that Zn impurities induced Anderson localization, which triggered the disappearance of the superconductivity, but no decisive conclusions on the dominant pairing symmetry for each dome were obtained. PMID- 25299301 TI - Association of common variants in TCF4 and PTPRG with Fuchs' corneal dystrophy: a systematic review and meta-analysis. AB - TOPIC: A meta-analysis of TCF4 and PTPRG gene variants in Fuchs' corneal dystrophy (FCD). CLINICAL RELEVANCE: To identify novel genetic markers in patients with FCD in different ethnic populations. METHODS: MEDLINE and EMBASE were searched for eligible genetic studies on TCF4 and PTPRG in FCD. Odds ratios (OR) and 95% confidence intervals (CI) of each single-nucleotide polymorphism (SNP) in allelic, dominant and recessive models were estimated using fixed-effect model if I2<50% in the test for heterogeneity, otherwise the random effects model was used. RESULTS: Thirty-three records were obtained, with 8 being suitable for meta-analysis, which included five SNPs in TCF4 and two in PTPRG. There were 1610 FCD patients and 1565 controls tested for TCF4 rs613872. This SNP was strongly associated with FCD in Caucasians (P = 5.0*10-106), with the risk allele G conferring an OR of 3.95 (95% CI: 3.49-4.46). A further 4 TCF4 SNPs (rs17595731, rs2286812, rs618869 and rs9954153) were also significantly associated with FCD in Caucasians (P<10-8). However, we found no SNP associated with FCD in Chinese. In addition, there was no significant association between FCD and PTPRG. CONCLUSION: TCF4 rs613872 is strongly associated with FCD in Caucasians but not in Chinese, which may suggest ethnic diversity in FCD SNP associations. SNPs in PTPRG were not associated with FCD in Caucasians or Chinese populations. Results of this meta-analysis indicate the need for larger-scale and multi-ethnic genetic studies on FCD to further explore the associated gene variants and their roles on the mechanism and genetic basis of FCD. PMID- 25299303 TI - Role of chloride in the morphological evolution of organo-lead halide perovskite thin films. AB - A comprehensive morphological study was used to elucidate chloride's role in CH(3)NH(3)PbI(3-x)Cl(x) film evolution on a conducting polymer, PEDOT:PSS. Complex ion equilibria and aggregation in solution, as well as the role they play in nucleation, are found to ultimately be responsible for the unique morphological diversity observed in perovskite films grown in the presence of the chloride ion. An intermediate phase that is generated upon deposition and initial annealing templates continued self-assembly in the case of CH(3)NH(3)PbI(3 x)Cl(x). In the absence of chloride, the film growth of CH(3)NH(3)PbI(3) is directed by substrate interfacial energy. By employing the through-plane TEM analysis, we gain detailed insight into the unique crystallographic textures, grain structures, and elemental distributions across the breadth of films grown from precursor solutions with different chemistries. The lattice coherence seen in morphologies generated under the influence of chloride provides a physical rational for the enhancement in carrier diffusion length and lifetime. PMID- 25299304 TI - Air-stable molecular semiconducting iodosalts for solar cell applications: Cs2SnI6 as a hole conductor. AB - We introduce a new class of molecular iodosalt compounds for application in next generation solar cells. Unlike tin-based perovskite compounds CsSnI3 and CH3NH3SnI3, which have Sn in the 2+ oxidation state and must be handled in an inert atmosphere when fabricating solar cells, the Sn in the molecular iodosalt compounds is in the 4+ oxidation state, making them stable in air and moisture. As an example, we demonstrate that, using Cs2SnI6 as a hole transporter, we can successfully fabricate in air a solid-state dye-sensitized solar cell (DSSC) with a mesoporous TiO2 film. Doping Cs2SnI6 with additives helps to reduce the internal device resistance, improving cell efficiency. In this way, a Z907 DSSC delivers 4.7% of energy conversion efficiency. By using a more efficient mixture of porphyrin dyes, an efficiency near 8% with photon confinement has been achieved. This represents a significant step toward the realization of low-cost, stable, lead-free, and environmentally benign next-generation solid-state solar cells. PMID- 25299306 TI - Carbonylation of cis-disubstituted epoxides to trans-beta-lactones: catalysts displaying steric and contrasteric regioselectivity. AB - trans-beta-Lactones are a versatile and useful class of compounds, but reliable methods for their direct synthesis are still limited. Addressing this problem, we present herein two catalysts for the regioselective carbonylation of cis disubstituted epoxides. The two catalysts show high activities and opposing regioselectivities so that either one of the two possible beta-lactone regioisomers can be obtained selectively. PMID- 25299305 TI - Are female starlings able to recognize the scent of their offspring? AB - BACKGROUND: Although there is growing evidence that birds may have individual chemical profiles that can function in several social contexts, offspring recognition based on olfactory cues has never been explored. This ability should be more likely evolved in colonial birds and/or species suffering brood parasitism, in which the risk of being engaged in costly misdirected parental care is high. METHODOLOGY/PRINCIPAL FINDINGS: We performed a choice experiment to examine whether females of the spotless starling, Sturnus unicolor, a species that is colonial, and where a fraction of the population is exposed to intraspecific brood parasitism, can discriminate between the scent of their offspring and that of unrelated nestlings. We also explored whether the development of the uropygial gland secretion may play a role in such olfactory discrimination by performing the choice experiments to females rearing nestlings of two different ages, that is, without and with developed uropygial glands. Results showed that female starlings did not preferentially choose the scent of their offspring, independently of whether the gland of nestlings was developed or not. CONCLUSIONS/SIGNIFICANCE: Our results suggest that female starlings do not have or do not show the ability to distinguish their offspring based on olfaction, at least up to 12-14 days of nestling age. Further research is needed to examine whether odour-based discrimination may function when fledgling starlings leave the nest and the risk of costly misidentification is likely to increase. PMID- 25299307 TI - Lattice solvent and crystal phase effects on the vibrational spectra of UO2Cl4(2 ). AB - We present the structural and spectroscopic characterization of six uranyl tetrachloride compounds along with a quantified analysis showing the influence of both the crystallographic phase and the lattice solvent upon the vibrational properties of the uranyl moiety. From the uranyl symmetric and asymmetric stretching frequencies we use a valence bond potential model to calculate the stretching and interaction force constants of the uranyl moiety in each compound. Quantifying these second-sphere influences provides insight into the vibrational properties, and indirectly the electronic structure, of the uranyl ion in its ground state. These data provide a better guide for assessing the validity of future comparisons with respect to bond strength, length, and electronic properties among series of actinyl compounds where non-actinide variables may be at play. PMID- 25299308 TI - Endometrial stromal tumors: the new WHO classification. AB - Endometrial stromal tumors are rare uterine mesenchymal neoplasms that have intrigued pathologists for years, not only because they commonly pose diagnostic dilemmas, but also because the classification and pathogenesis of these tumors has been widely debated. The current World Health Organization recognizes 4 categories of endometrial stromal tumor: endometrial stromal nodule (ESN), low grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). uterine sarcoma. These categories are defined by the presence of distinct translocations as well as tumor morphology and prognosis. Specifically, the JAZF1-SUZ12 (formerly JAZF1 JJAZ1) fusion identifies a large proportion of ESN and LG-ESSs, whereas the YWHAE FAM22 translocation identifies HG-ESSs. The latter tumors appear to have a prognosis intermediate between LG-ESS and UUS, which exhibits no specific translocation pattern. This review (1) presents the clinicopathologic features of endometrial stromal tumors; (2) discusses their immunophenotype; and (3) highlights the recent advances in molecular genetics which explain their pathogenesis and lend support for a new classification system. PMID- 25299309 TI - The expanding family of SMARCB1(INI1)-deficient neoplasia: implications of phenotypic, biological, and molecular heterogeneity. AB - Since the description of atypical teratoid/rhabdoid tumors of the central nervous system and renal/extrarenal malignant rhabdoid tumors in children, the clinicopathologic spectrum of neoplasms having in common a highly variable rhabdoid cell component (0% to 100%) and consistent loss of nuclear SMARCB1 (INI1) expression has been steadily expanding to include cribriform neuroepithelial tumor of the ventricle, renal medullary carcinoma and a subset of collecting duct carcinoma, epithelioid sarcoma, subsets of miscellaneous benign and malignant soft tissue tumors, and rare rhabdoid carcinoma variants of gastroenteropancreatic, sinonasal, and genitourinary tract origin. Although a majority of SMARCB1-deficient neoplasms arise de novo, the origin of SMARCB1 deficient neoplasia in the background of a phenotypically or genetically definable differentiated SMARCB1-intact "parent neoplasm" has been convincingly demonstrated, highlighting the rare occurrence of rhabdoid tumors as "double-hit neoplasia." As a group, SMARCB1-deficient neoplasms occur over a wide age range (0 to 80 y), may be devoid of rhabdoid cells or display uniform rhabdoid morphology, and follow a clinical course that varies from benign to highly aggressive causing death within a few months irrespective of aggressive multimodality therapy. Generally applicable criteria that would permit easy recognition of these uncommon neoplasms do not exist. Diagnosis is based on site specific and entity-specific sets of clinicopathologic, immunophenotypic, and/or molecular criteria. SMARCB1 immunohistochemistry has emerged as a valuable tool in confirming or screening for SMARCB1-deficient neoplasms. This review summarizes the different phenotypic and topographic subgroups of SMARCB1 deficient neoplasms including sporadic and familial, benign and malignant, and rhabdoid and nonrhabdoid variants, highlighting their phenotypic heterogeneity and molecular complexity. PMID- 25299310 TI - Myoepithelial tumor of soft tissue: histology and genetics of an evolving entity. AB - Myoepithelial neoplasms represent a heterogeneous group of tumors of which classification is incomplete and evolving. Those of the soft tissues often form genetically distinct subgroups that differ from those arising within salivary glands. Soft-tissue myoepithelial tumors (including mixed tumors that show true glandular or ductal differentiation) exhibit a spectrum of different morphologic patterns, making them difficult to distinguish from a variety of other neoplasms. They have been increasingly shown to harbor genetic fusions involving EWSR1 and partner genes that are not seen in the well-characterized tumor classes involving EWSR1 translocations. We review the spectrum of soft-tissue myoepithelial tumors, discussing recent immunohistochemical and genetic findings and the differential diagnosis. PMID- 25299311 TI - Complexities and challenges in the pathologic assessment of size (T) of invasive breast carcinoma. AB - Size (the "T" in the TNM System) of invasive breast carcinoma is a proven independent prognostic factor; however, its accurate determination can be challenging. The purpose of this review is to discuss the complexities inherent in determining "T"-including those encountered in the clinical measurement ("cT", ie, physical and radiologic assessment) as well as pathologic determination (pT) of invasive breast carcinomas. Pathologic estimation of tumor size, macroscopic, as well as microscopic, can be problematic due to the complexity of multiple situations, seeming confusion regarding staging guidelines, and interobserver variation in interpretation. Additional problematic scenarios in determination of "T" include those incurred in excisions performed after the performance of needle core biopsies, and in cases wherein there are multiple foci of invasive carcinoma, as well as in carcinomas status post-neoadjuvant chemotherapy. It can also be difficult to determine "T" in certain types of invasive carcinoma, particularly those of the lobular type. In this communication, some of the complexities and challenges in determing "T" are discussed, and modest suggestions are offered to assist in optimizing such assessments. PMID- 25299312 TI - Evolution of sentinel lymph node biopsy in breast cancer, in and out of vogue? AB - Sentinel lymph node biopsy (SLNB) was introduced 2 decades ago and thereafter validated for routine surgical management of breast cancer, including cases treated with neoadjuvant chemotherapy. As the number of lymph nodes for staging has decreased, pathologists have scrutinized SLN with a combination of standard hematoxylin and eosin, levels, immunohistochemistry (IHC), and molecular methods. An epidemic of small-volume metastases thereby arose, leading to modifications in the American Joint Committee on Cancer staging to accommodate findings such as isolated tumor cells (ITC) and micrometastases. With the goal of determining the significance of these findings, retrospective followed by prospective trials were performed, showing mixed results. The ACOSOG Z10 and NSABP B-32 trials both independently showed that ITC and micrometastases were not significant and thus discouraged the use of levels and IHC for detecting them. However, the Surveillance Epidemiology and End Results database showed that patients with micrometastases had an overall decreased survival. In addition, the MIRROR (Micrometastases and ITC: Relevant and Robust or Rubbish?) trial, showed that patients with ITC and micrometastases treated with adjuvant therapy had lower hazard ratios compared with untreated patients. Subsequently, the ACOSOG Z0011 trial randomized patients with up to 2 positive SLN to axillary lymph node dissection (ALND) or not, all treated with radiation and chemotherapy, showing no difference in survival or recurrence rates between the 2 groups and causing a shift from ALND. As the rate of ALND has declined, the necessity of performing levels, IHC, frozen section, and molecular studies on SLN needs to be revisited. PMID- 25299313 TI - Perspectives on signet ring stromal cell tumor and related signet ring cell lesions of the gonads. AB - In this article, we discuss advances in our knowledge of the pathology of signet ring stromal cell tumor and related signet ring cell lesions of the ovary and a single case of signet ring stromal cell tumor of the testis. We divide ovarian signet ring cell lesions into 3 categories that reflect differences in their pathogenesis and histologic appearance. With 1 exception, all authentic cases of signet ring stromal cell tumor have been unilateral. Cases of ovarian signet ring stromal cell tumor from the literature can arise in 2 ways. The majority of cases arise multifocally from fibroma, whereas the remainder likely arise directly from the ovarian stroma. In difficult cases, immunocytochemistry provides improved diagnostic accuracy in distinguishing signet ring stromal cell tumor and its mimics from Krukenberg tumor. The most useful antibodies in this regard are epithelial membrane antigen and vimentin. PMID- 25299314 TI - Discovery and diagnostic value of a novel oncofetal protein: glypican 3. AB - Glypican 3 is a membrane-bound heparan sulfate proteoglycan, which has recently been identified as a marker for liver cancer and germ cell malignancies. Individuals with loss-of-function mutations for the glypican 3 gene exhibit Simpson-Golabi-Behmel syndrome, a rare X-linked overgrowth disorder. Expression of glypican 3 mRNA and protein is normally silenced in most adult organs and may reappear during malignant transformation. In the past few years, immunohistochemical and molecular characteristics of glypican 3 in hepatocellular carcinoma have been elucidated. More recently, glypican 3 has been emerging as a new diagnostic marker for germ cell tumors and especially testicular and ovarian yolk sac tumors. However, in other tumors such as renal cell carcinomas, squamous cell carcinomas, and melanomas, studies disagree on the level of glypican 3 expression. Finally, there is the controversial notion of glypican 3 as a tumor suppressor gene. In this review article, we update current knowledge on glypican 3 expression in normal and neoplastic tissues, evaluate its utility as a tumor marker in clinical practice, and explore its role as a novel oncofetal protein with clinical implications. Our focus is on the diagnostic value of glypican 3 in germ cell tumors and other neoplasms in addition to hepatocellular carcinoma. In conclusion, glypican 3 has been proven to be a useful immunohistochemical marker in distinguishing yolk sac tumors, choriocarcinomas, and Wilms tumors from other malignancies histologically mimicking these primitive tumors. Clinically, we recommend that glypican 3 be used as part of a panel of markers in subtyping testicular germ cell tumors. PMID- 25299315 TI - Selected case from the Arkadi M. Rywlin International Pathology Slide Series: Mitochondrial myopathy presenting with chronic progressive external ophthalmoplegia (CPEO): a case report. AB - A 43-year-old female patient diagnosed with chronic progressive external ophthalmoplegia (CPEO) because of mitochondrial myopathy documented by muscle biopsy is presented. The chief complaints were represented by blepharoptosis and ophthalmoplegia. The muscle biopsy was evaluated by histology, using the appropriate histochemical and histoenzimological stains. Ragged red fibers with Gomori trichrome stain were seen, which showed cytochrome c oxydase deficiency and abnormal succinate dehydrogenase staining in around 20% of muscle fibres. Electron microscopy was also performed which demonstrated abnormal, hyperplastic, pleomorphic, and hypertrophic mitochondria, characterized by paracrystalline inclusions arranged in parallel rows ("parking-lot" inclusions), consisting of rectangular arrays of mitochondrial membranes in a linear or grid-like pattern. In conclusion, mitochondrial myopathy was definitely diagnosed. Although molecular analysis, which was subsequently carried out, failed to reveal mutations in the mitochondrial DNA or in selected nuclear genes, the pathologic diagnosis was not changed. The differential diagnosis of CPEO with other forms of ocular myopathies as well as the possible association of CPEO with systemic syndromes is discussed. Ophtalmologists and medical internists should always suspect CPEO when dealing with patients affected by ocular myopathy, either in its pure form or in association with other myopathic or systemic signs. PMID- 25299316 TI - Inverse association between serum bilirubin levels and arterial stiffness in Korean women with type 2 diabetes. AB - BACKGROUND: Considerable evidence suggests that bilirubin is a potent physiologic antioxidant that may provide important protection against cardiovascular disease (CVD) and inflammation. We investigated the relationship between serum total bilirubin (TB) levels and arterial stiffness, measured by the brachial-ankle pulse wave velocity (baPWV), in patients with type 2 diabetes. METHODS: We conducted a cross-sectional analysis of 1,711 subjects with type 2 diabetes (807 men and 904 women; mean age, 57.1 years). The subjects were stratified based on gender-specific tertiles of TB values, and a high baPWV was defined as greater than 1,745 cm/s ( >75th percentile). RESULTS: The serum TB concentration was negatively correlated with the duration of diabetes, HbA1c, the 10-year Framingham risk score, and baPWV and was positively correlated with high-density lipoprotein cholesterol and the eGFR in both genders. Inverse association between TB categories and unadjusted prevalence of high PWV was only observed in women. After adjusting for confounding factors, the TB levels were inversely associated with a greater risk of a high baPWV, both as a continuous variable [a 1-SD difference; odds ratio (OR), 0.70; 95% confidence interval (CI), 0.54-0.90; P = 0.005] and when categorized in tertiles (the highest vs. the lowest tertile; OR, 0.49; 95% CI, 0.28-0.85; P = 0.011) in women but not in men. The relationship remained significant even after adjusting for retinopathy and nephropathy. CONCLUSIONS: Low TB levels were significantly associated with arterial stiffness in Korean women with type 2 diabetes. Our data suggested that bilirubin may protect against macrovascular disease in diabetic women. PMID- 25299318 TI - Contribution of corneal neovascularization to dendritic cell migration into the central area during human corneal infection. AB - Compared with the peripheral corneal limbus, the human central cornea lacks blood vessels, which is responsible for its immunologically privileged status and high transparency. Dendritic cells (DCs) are present in the central avascular area of inflamed corneas, but the mechanisms of their migration to this location are poorly understood. Here, we investigated the contribution of vessel formation to DC migration into the central cornea, and analyzed the DC chemotactic factors produced by human corneal epithelial (HCE) cells. Using human eyes obtained from surgical procedures, we then assessed vessel formation, DC distribution, and activin A expression immunohistochemically. The results demonstrated increased numbers of vessels and DCs in the central area of inflamed corneas, and a positive correlation between the number of vessels and DCs. Activin A was expressed in the subepithelial space and the endothelium of newly formed blood vessels in the inflamed cornea. In infected corneas, DCs were present in the central area but no vascularization was observed, suggesting the presence of chemotactic factors that induced DC migration from the limbal vessels. To test this hypothesis, we assessed the migration of monocyte-derived DCs toward HCE cell supernatants with or without lipopolysaccharide (LPS) stimulation of HCE cells and inflammatory cytokines (released by HCE cells). DCs migrated toward tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and activin A, as well as LPS-stimulated HCE cell supernatants. The supernatant contained elevated TNF-alpha, IL-6, and activin A levels, suggesting that they were produced by HCE cells after LPS stimulation. Therefore, vessels in the central cornea might constitute a DC migration route, and activin A expressed in the endothelium of newly formed vessels might contribute to corneal vascularization. Activin A also functions as a chemotactic factor, similar to HCE-produced TNF-alpha and IL-6. These findings enhance our understanding of the pathophysiology of corneal inflammation during infection. PMID- 25299320 TI - Ruthenium catalyzed cycloisomerization of silicon-tethered 1,7-enynes to give exocyclic 1,3-dienes. AB - The cycloisomerization of vinyl silicon-tethered 1,7-enynes has been accomplished using catalytic Cp*Ru(COD)Cl. The products possess a new silane moiety and trisubstituted alkenes as part of the diene system. The reaction scope includes aryl, alkyl, vinyl, and cyclopropyl alkyne functionalities. Silicon was found not to be a mandatory component of the tether. The utility of the products was demonstrated through manipulation of the vinyl silane and Diels-Alder chemistry. PMID- 25299319 TI - Polyketide intermediate mimics as probes for revealing cryptic stereochemistry of ketoreductase domains. AB - Among natural product families, polyketides have shown the most promise for combinatorial biosynthesis of natural product-like libraries. Though recent research in the area has provided many mechanistic revelations, a basic-level understanding of kinetic and substrate tolerability is still needed before the full potential of combinatorial biosynthesis can be realized. We have developed a novel set of chemical probes for the study of ketoreductase domains of polyketide synthases. This chemical tool-based approach was validated using the ketoreductase of pikromycin module 2 (PikKR2) as a model system. Triketide substrate mimics 12 and 13 were designed to increase stability (incorporating a nonhydrolyzable thioether linkage) and minimize nonessential functionality (truncating the phosphopantetheinyl arm). PikKR2 reduction product identities as well as steady-state kinetic parameters were determined by a combination of LC MS/MS analysis of synthetic standards and a NADPH consumption assay. The d hydroxyl product is consistent with bioinformatic analysis and results from a complementary biochemical and molecular biological approach. When compared to widely employed substrates in previous studies, diketide 63 and trans-decalone 64, substrates 12 and 13 showed 2-10 fold lower K(M) values (2.4 +/- 0.8 and 7.8 +/- 2.7 mM, respectively), indicating molecular recognition of intermediate-like substrates. Due to an abundance of the nonreducable enol-tautomer, the k(cat) values were attenuated by as much as 15-336 fold relative to known substrates. This study reveals the high stereoselectivity of PikKR2 in the face of gross substrate permutation, highlighting the utility of a chemical probe-based approach in the study of polyketide ketoreductases. PMID- 25299321 TI - Environmental sensing of heavy metals through whole cell microbial biosensors: a synthetic biology approach. AB - Whole cell microbial biosensors are offering an alternative means for rapid, on site heavy metal detection. Based in microorganisms, biosensing constructs are designed and constructed to produce both qualitative and quantitative outputs in response to heavy metal ions. Previous microbial biosensors designs are focused on single-input constructs; however, development of multiplexed systems is resulting in more flexible designs. The movement of microbial biosensors from laboratory based designs toward on-site, functioning heavy metal detectors has been hindered by the toxic nature of heavy metals, along with the lack of specificity of heavy metals promoter elements. Applying a synthetic biology approach with alternative microbial chassis may increase the robustness of microbial biosensors and mitigate these issues. Before full applications are achieved, further consideration has to be made regarding the risk and regulations of whole cell microbial biosensor use in the environment. To this end, a standard framework for future whole cell microbial biosensor design and use is proposed. PMID- 25299322 TI - Multimetallic core/interlayer/shell nanostructures as advanced electrocatalysts. AB - The fine balance between activity and durability is crucial for the development of high performance electrocatalysts. The importance of atomic structure and compositional gradients is a guiding principle in exploiting the knowledge from well-defined materials in the design of novel class of core-shell electrocatalysts comprising Ni core, Au interlayer, and PtNi shell (Ni@Au@PtNi). This multimetallic system is found to have the optimal balance of activity and durability due to the synergy between the stabilizing effect of subsurface Au and modified electronic structure of surface Pt through interaction with subsurface Ni atoms. The electrocatalysts with Ni@Au@PtNi core-interlayer-shell structure exhibit high intrinsic and mass activities as well as superior durability for the oxygen reduction reaction with less than 10% activity loss after 10,000 potential cycles between 0.6 and 1.1 V vs the reversible hydrogen electrode. PMID- 25299323 TI - Portrait of a killer: genome of the 2014 EBOV outbreak strain. AB - A recent study by Gire et al. (2014) identifies differences that make the 2014 West Africa Ebola virus unique and details how the virus spread from Guinea to Sierra Leone. This work highlights the power of new genomic technologies to facilitate rapid public health and scientific responses to the crisis. PMID- 25299324 TI - Instructing the instructor: tissue-resident T cells activate innate immunity. AB - A small number of tissue-resident memory T cells (Trm) provide potent protection against infections. Three recent studies by Ariotti et al. (2014), Schenkel et al. (2014a), and Iijima and Iwasaki (2014) report that Trm rapidly produce cytokines after infection and initiate a tissue-wide anti-viral state by instructing innate immune cells. PMID- 25299325 TI - Lost but not forgotten. AB - During its developmental transformation in the mammalian host, Trypanosma cruzi discards it flagellum into the cytoplasm of the host cell. In the current issue of Cell Host & Microbe, Kurup and Tarleton (2014) exploit the antigens made available by this process to develop a more effective vaccine strategy. PMID- 25299326 TI - A delicate balance: maintaining mutualism to prevent disease. AB - The intestinal microbial ecosystem is complex, and few of the principles that contribute to homeostasis in health are well understood. Pham et al. (2014) show that a network including the epithelial interleukin-22 receptor protects against infection with the opportunistic pathogen Enterococcus faecalis through promotion of host-microbiota mutualism. PMID- 25299327 TI - Strength in diversity. AB - In this issue of Cell Host & Microbe, Hammer et al. (2014) show that distinct, slow-growing bacteria have better in vitro and in vivo growth and virulence when cocultured than in isolation. They provide evidence that the observed inter- and intraspecies "complementation" involves the intercellular exchange of metabolites. PMID- 25299328 TI - Targeting bacterial virulence: the coming out of type VII secretion inhibitors. AB - Type VII (ESX) secretion systems of pathogenic mycobacteria, such as Mycobacterium tuberculosis, are crucial for intracellular survival, host cell lysis, and the subsequent cell-to-cell spread. In this issue of Cell Host & Microbe, Rybniker et al. (2014) have used these characteristics to identify two classes of type VII secretion inhibitors. PMID- 25299329 TI - Rethinking "enterotypes". AB - Classification of the human gut microbiome into distinct types, or "enterotypes," provides an attractive framework for understanding microbial variation in health and disease. However, as discussed here, several different methods of collapsing enterotype variation into a few discrete clusters suggest that enterotype distribution is continuous and can vary widely within an individual. PMID- 25299332 TI - Nucleocapsid phosphorylation and RNA helicase DDX1 recruitment enables coronavirus transition from discontinuous to continuous transcription. AB - Coronaviruses contain a positive-sense single-stranded genomic (g) RNA, which encodes nonstructural proteins. Several subgenomic mRNAs (sgmRNAs) encoding structural proteins are generated by template switching from the body transcription regulatory sequence (TRS) to the leader TRS. The process preferentially generates shorter sgmRNA. Appropriate readthrough of body TRSs is required to produce longer sgmRNAs and full-length gRNA. We find that phosphorylation of the viral nucleocapsid (N) by host glycogen synthase kinase-3 (GSK-3) is required for template switching. GSK-3 inhibition selectively reduces the generation of gRNA and longer sgmRNAs, but not shorter sgmRNAs. N phosphorylation allows recruitment of the RNA helicase DDX1 to the phosphorylated N-containing complex, which facilitates template readthrough and enables longer sgmRNA synthesis. DDX1 knockdown or loss of helicase activity markedly reduces the levels of longer sgmRNAs. Thus, coronaviruses employ a unique strategy for the transition from discontinuous to continuous transcription to ensure balanced sgmRNAs and full-length gRNA synthesis. PMID- 25299330 TI - The Trypanosoma cruzi flagellum is discarded via asymmetric cell division following invasion and provides early targets for protective CD8+ T cells. AB - During invasion of host cells by Trypanosoma cruzi, the parasite that causes Chagas disease, the elongated, flagellated trypomastigotes remodel into oval amastigotes with no external flagellum. The underlying mechanism of this remodeling and the fate of the flagellum are obscure. We discovered that T. cruzi trypomastigotes discard their flagella via an asymmetric cellular division. The flagellar proteins liberated become among the earliest parasite proteins to enter the MHC-I processing pathway in infected cells. Indeed, paraflagellar rod protein PAR4-specific CD8(+) T cells detect infected host cells >20 hr earlier than immunodominant trans-sialidase-specific T cells. Overexpression of PAR4 in T. cruzi enhanced the subdominant PAR4-specific CD8(+) T cell response, resulting in improved control of a challenge infection. These results provide insights into previously unappreciated events in intracellular invasion by T. cruzi and highlight the importance of T cells that recognize infected host cells early in the infectious process, in the control of infections. PMID- 25299331 TI - The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. AB - Viral DNA sensing within the cytosol of infected cells activates type I interferon (IFN) expression. MITA/STING plays an essential role in this pathway by acting as both a sensor for the second messenger cGAMP and as an adaptor for downstream signaling components. In an expression screen for proteins that can activate the IFNB1 promoter, we identified the ER-associated protein ZDHHC1 as a positive regulator of virus-triggered, MITA/STING-dependent immune signaling. Zdhhc1(-/-) cells failed to effectively produce IFNs and other cytokines in response to infection with DNA but not RNA viruses. Zdhhc1(-/-) mice infected with the neurotropic DNA virus HSV-1 exhibited lower cytokine levels and higher virus titers in the brain, resulting in higher lethality. ZDHHC1 constitutively associated with MITA/STING and mediates dimerization/aggregation of MITA/STING and recruitment of the downstream signaling components TBK1 and IRF3. These findings support a role for ZDHHC1 in mediating MITA/STING-dependent innate immune response against DNA viruses. PMID- 25299333 TI - Proline isomerization of the immune receptor-interacting protein RIN4 by a cyclophilin inhibits effector-triggered immunity in Arabidopsis. AB - In the absence of pathogen infection, plant effector-triggered immune (ETI) receptors are maintained in a preactivation state by intermolecular interactions with other host proteins. Pathogen effector-induced alterations activate the receptor. In Arabidopsis, the ETI receptor RPM1 is activated via bacterial effector AvrB-induced phosphorylation of the RPM1-interacting protein RIN4 at Threonine 166. We find that RIN4 also interacts with the prolyl-peptidyl isomerase (PPIase) ROC1, which is reduced upon RIN4 Thr166 phosphorylation. ROC1 suppresses RPM1 immunity in a PPIase-dependent manner. Consistent with this, RIN4 Pro149 undergoes cis/trans isomerization in the presence of ROC1. While the RIN4(P149V) mutation abolishes RPM1 resistance, the deletion of Pro149 leads to RPM1 activation in the absence of RIN4 phosphorylation. These results support a model in which RPM1 directly senses conformational changes in RIN4 surrounding Pro149 that is controlled by ROC1. RIN4 Thr166 phosphorylation indirectly regulates RPM1 resistance by modulating the ROC1-mediated RIN4 isomerization. PMID- 25299334 TI - A plant phosphoswitch platform repeatedly targeted by type III effector proteins regulates the output of both tiers of plant immune receptors. AB - Plants detect microbes via two functionally interconnected tiers of immune receptors. Immune detection is suppressed by equally complex pathogen mechanisms. The small plasma-membrane-tethered protein RIN4 negatively regulates microbe associated molecular pattern (MAMP)-triggered responses, which are derepressed upon bacterial flagellin perception. We demonstrate that recognition of the flagellin peptide MAMP flg22 triggers accumulation of RIN4 phosphorylated at serine 141 (pS141) that mediates derepression of several immune outputs. RIN4 is targeted by four bacterial type III effector proteins, delivered temporally after flagellin perception. Of these, AvrB acts with a host kinase to increase levels of RIN4 phosphorylated at threonine 166 (pT166). RIN4 pT166 is epistatic to RIN4 pS141. Thus, AvrB contributes to virulence by enhancing "rerepression" of immune system outputs. Our results explain the evolution of independent effectors that antagonize accumulation of RIN4 pS141 and of a specific plant intracellular NLR protein, RPM1, which is activated by AvrB-mediated accumulation of RIN4 pT166. PMID- 25299335 TI - Shigella subverts the host recycling compartment to rupture its vacuole. AB - Shigella enters epithlial cells via internalization into a vacuole. Subsequent vacuolar membrane rupture allows bacterial escape into the cytosol for replication and cell-to-cell spread. Bacterial effectors such as IpgD, a PI(4,5)P2 phosphatase that generates PI(5)P and alters host actin, facilitate this internalization. Here, we identify host proteins involved in Shigella uptake and vacuolar membrane rupture by high-content siRNA screening and subsequently focus on Rab11, a constituent of the recycling compartment. Rab11-positive vesicles are recruited to the invasion site before vacuolar rupture, and Rab11 knockdown dramatically decreases vacuolar membrane rupture. Additionally, Rab11 recruitment is absent and vacuolar rupture is delayed in the ipgD mutant that does not dephosphorylate PI(4,5)P2 into PI(5)P. Ultrastructural analyses of Rab11 positive vesicles further reveal that ipgD mutant-containing vacuoles become confined in actin structures that likely contribute to delayed vacular rupture. These findings provide insight into the underlying molecular mechanism of vacuole progression and rupture during Shigella invasion. PMID- 25299336 TI - Inter- and intraspecies metabolite exchange promotes virulence of antibiotic resistant Staphylococcus aureus. AB - Adaptations that enable antimicrobial resistance often pose a fitness cost to the microorganism. Resistant pathogens must therefore overcome such fitness decreases to persist within their hosts. Here we demonstrate that the reduced fitness associated with one resistance-conferring mutation can be offset by community interactions with microorganisms harboring alternative mutations or via interactions with the human microbiota. Mutations that confer antibiotic resistance in the human pathogen Staphylococcus aureus led to decreased fitness, whereas coculture or coinfection of two distinct mutants resulted in collective recovery of fitness comparable to that of wild-type. Such fitness enhancements result from the exchange of metabolites between distinct mutants, leading to enhanced growth, virulence factor production, and pathogenicity. Interspecies fitness enhancements were also identified, as members of the human microbiota can promote growth of antibiotic-resistant S. aureus. Thus, inter- and intraspecies community interactions offset fitness costs and enable S. aureus to develop antibiotic resistance without loss of virulence. PMID- 25299338 TI - In-plane mode dynamics of capillary self-alignment. AB - We present an experimental study of the complete in-plane dynamics of capillary self-alignment. The two translational (shift) and single rotational (twist) in plane modes of square millimetric transparent dies bridged to shape-matching receptor sites through a liquid meniscus were selectively excited by preset initial offsets. The entire self-alignment dynamics was simultaneously monitored over the three in-plane degrees of freedom by high-speed optical tracking of the alignment trajectories. The dynamics of the twist mode is shown to qualitatively follow the sequence of dynamic regimes also observed for the shift modes, consisting of initial transient wetting, acceleration toward, and underdamped harmonic oscillations around the equilibrium position. Systematic analysis of alignment trajectories for individually as well as simultaneously excited modes shows that, in the absence of twist offset, the dynamics of the degenerate shift modes are mutually independent. In the presence of twist offset, the three modes conversely evidence coupled dynamics, which is attributed to a synchronization mechanism affected by the wetting of the bounding surfaces. The experimental results, justified by energetic, wetting, and dynamic arguments, provide substantial benchmarks for understanding the full dynamics of the process. PMID- 25299337 TI - Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion. AB - Mycobacterium tuberculosis (Mtb) requires protein secretion systems like ESX-1 for intracellular survival and virulence. The major virulence determinant and ESX 1 substrate, EsxA, arrests phagosome maturation and lyses cell membranes, resulting in tissue damage and necrosis that promotes pathogen spread. To identify inhibitors of Mtb protein secretion, we developed a fibroblast survival assay exploiting this phenotype and selected molecules that protect host cells from Mtb-induced lysis without being bactericidal in vitro. Hit compounds blocked EsxA secretion and promoted phagosome maturation in macrophages, thus reducing bacterial loads. Target identification studies led to the discovery of BTP15, a benzothiophene inhibitor of the histidine kinase MprB that indirectly regulates ESX-1, and BBH7, a benzyloxybenzylidene-hydrazine compound. BBH7 affects Mtb metal-ion homeostasis and revealed zinc stress as an activating signal for EsxA secretion. This screening approach extends the target spectrum of small molecule libraries and will help tackle the mounting problem of antibiotic-resistant mycobacteria. PMID- 25299339 TI - Determination of supplier-to-supplier and lot-to-lot variability in glycation of recombinant human serum albumin expressed in Oryza sativa. AB - The use of different expression systems to produce the same recombinant human protein can result in expression-dependent chemical modifications (CMs) leading to variability of structure, stability and immunogenicity. Of particular interest are recombinant human proteins expressed in plant-based systems, which have shown particularly high CM variability. In studies presented here, recombinant human serum albumins (rHSA) produced in Oryza sativa (Asian rice) (OsrHSA) from a number of suppliers have been extensively characterized and compared to plasma derived HSA (pHSA) and rHSA expressed in yeast (Pichia pastoris and Saccharomyces cerevisiae). The heterogeneity of each sample was evaluated using size exclusion chromatography (SEC), reversed-phase high-performance liquid chromatography (RP HPLC) and capillary electrophoresis (CE). Modifications of the samples were identified by liquid chromatography-mass spectrometry (LC-MS). The secondary and tertiary structure of the albumin samples were assessed with far U/V circular dichroism spectropolarimetry (far U/V CD) and fluorescence spectroscopy, respectively. Far U/V CD and fluorescence analyses were also used to assess thermal stability and drug binding. High molecular weight aggregates in OsrHSA samples were detected with SEC and supplier-to-supplier variability and, more critically, lot-to-lot variability in one manufactures supplied products were identified. LC-MS analysis identified a greater number of hexose-glycated arginine and lysine residues on OsrHSA compared to pHSA or rHSA expressed in yeast. This analysis also showed supplier-to-supplier and lot-to-lot variability in the degree of glycation at specific lysine and arginine residues for OsrHSA. Both the number of glycated residues and the degree of glycation correlated positively with the quantity of non-monomeric species and the chromatographic profiles of the samples. Tertiary structural changes were observed for most OsrHSA samples which correlated well with the degree of arginine/lysine glycation. The extensive glycation of OsrHSA from multiple suppliers may have further implications for the use of OsrHSA as a therapeutic product. PMID- 25299341 TI - One-step synthesis of free-standing alpha-Ni(OH)2 nanosheets on reduced graphene oxide for high-performance supercapacitors. AB - In this work, a hierarchical hybrid structure of reduced graphene oxide (rGO) supported ultrathin alpha-Ni(OH)2 nanosheets (denoted as alpha-Ni(OH)2@rGO NSs) has been developed successfully via an environmentally friendly one-step solution method. The resulting product of alpha-Ni(OH)2@rGO NSs was further characterized by scanning electron microscope, transmission electron microscope, x-ray diffraction, Raman spectroscopy, x-ray photoelectron spectroscopy, and Brunauer Emmett-Teller. The ultrathin alpha-Ni(OH)2 nanosheets of around 6 nm in thickness are uprightly coated on the double sides of rGO substrate. When evaluated as electrodes for supercapacitors, the hybrid alpha-Ni(OH)2@rGO NSs demonstrate excellent supercapacitor performance and cycling stability, compared with the self-aggregated alpha-Ni(OH)2 powder. Even after 2000 cycles, the hybrid electrodes still can deliver a specific capacitance of 1300 F g(-1) at the current density of 5 A g(-1), corresponding to no capacity loss of the initial cycle. Such excellent electrochemical performance should be attributed to the ultrathin, free-standing, and hierarchical nanosheets of alpha-Ni(OH)2, which not only promote efficient charge transport and facilitate the electrolyte diffusion, but also prevent aggregation of electro-active materials effectively during the charge-discharge process. PMID- 25299340 TI - Stimulatory effects of polysaccharide fraction from Solanum nigrum on RAW 264.7 murine macrophage cells. AB - The polysaccharide fraction from Solanum nigrum Linne has been shown to have antitumor activity by enhancing the CD4+/CD8+ ratio of the T-lymphocyte subpopulation. In this study, we analyzed a polysaccharide extract of S. nigrum to determine its modulating effects on RAW 264.7 murine macrophage cells since macrophages play a key role in inducing both innate and adaptive immune responses. Crude polysaccharide was extracted from the stem of S. nigrum and subjected to ion-exchange chromatography to partially purify the extract. Five polysaccharide fractions were then subjected to a cytotoxicity assay and a nitric oxide production assay. To further analyze the ability of the fractionated polysaccharide extract to activate macrophages, the phagocytosis activity and cytokine production were also measured. The polysaccharide fractions were not cytotoxic, but all of the fractions induced nitric oxide in RAW 264.7 cells. Of the five fractions tested, SN-ppF3 was the least toxic and also induced the greatest amount of nitric oxide, which was comparable to the inducible nitric oxide synthase expression detected in the cell lysate. This fraction also significantly induced phagocytosis activity and stimulated the production of tumor necrosis factor-alpha and interleukin-6. Our study showed that fraction SN ppF3 could classically activate macrophages. Macrophage induction may be the manner in which polysaccharides from S. nigrum are able to prevent tumor growth. PMID- 25299342 TI - No evidence of geographical structure of salicinoid chemotypes within Populus tremula. AB - Salicinoids are well-known defense compounds in salicaceous trees and careful screening at the population level is warranted to fully understand their diversity and function. European aspen, Populus tremula, is a foundation species in Eurasia and highly polymorphic in Sweden. We exhaustively surveyed 102 replicated genotypes from the Swedish Aspen collection (SwAsp) for foliar salicinoids using UHPLC-ESI-TOF/MS and identified nine novel compounds, bringing the total to 19 for this species. Salicinoid structure followed a modular architecture of a salicin skeleton with added side groups, alone or in combination. Two main moieties, 2'-cinnamoyl and 2'-acetyl, grouped the SwAsp population into four distinct chemotypes, and the relative allocation of salicinoids was remarkably constant between different environments, implying a highly channeled biosynthesis of these compounds. Slightly more than half of the SwAsp genotypes belonged to the cinnamoyl chemotype. A fraction synthesized the acetyl moiety alone (~7%) or in combination with cinnamoyl (~2%), and close to forty percent lacked either of the two characteristic moieties, and thus resemble P. tremuloides in their salicinoid profile. The two most abundant chemotypes were evenly distributed throughout Sweden, unlike geographical patterns reported for SwAsp phenology traits, plant defense genes, and herbivore community associations. Here we present the salicinoid characterization of the SwAsp collection as a resource for future studies of aspen chemical ecology, salicinoid biosynthesis, and genetics. PMID- 25299343 TI - Benzalkonium chloride suppresses rabbit corneal endothelium intercellular gap junction communication. AB - PURPOSE: Gap junction intercellular communication (GJIC) plays a critical role in the maintenance of corneal endothelium homeostasis. We determined if benzalkonium chloride (BAK) alters GJIC activity in the rabbit corneal endothelium since it is commonly used as a drug preservative in ocular eyedrop preparations even though it can have cytotoxic effects. METHODS: Thirty-six adult New Zealand albino rabbits were randomly divided into three groups. BAK at 0.01%, 0.05%, and 0.1% was applied twice daily to one eye of each of the rabbits in one of the three groups for seven days. The contralateral untreated eyes were used as controls. Corneal endothelial morphological features were observed by in vivo confocal microscopy (IVCM). Immunofluorescent staining resolved changes in gap junction integrity and localization. Western blot analysis and RT-PCR evaluated changes in levels of connexin43 (Cx43) and tight junction zonula occludens-1 (ZO-1) gene and protein expression, respectively. Cx43 and ZO-1 physical interaction was detected by immunoprecipitation (IP). Primary rabbit corneal endothelial cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing BAK for 24 hours. The scrape-loading dye transfer technique (SLDT) was used to assess GJIC activity. RESULTS: Topical administration of BAK (0.05%, 0.1%) dose dependently disrupted corneal endothelial cell morphology, altered Cx43 and ZO-1 distribution and reduced Cx43 expression. BAK also markedly induced increases in Cx43 phosphorylation status concomitant with decreases in the Cx43-ZO-1 protein protein interaction. These changes were associated with marked declines in GJIC activity. CONCLUSIONS: The dose dependent declines in rabbit corneal endothelial GJIC activity induced by BAK are associated with less Cx43-ZO-1 interaction possibly arising from increases in Cx43 phosphorylation and declines in its protein expression. These novel changes provide additional evidence that BAK containing eyedrop preparations should be used with caution to avoid declines in corneal transparency resulting from losses in GJIC activity and endothelial function. PMID- 25299344 TI - Disruption of SUMO-specific protease 2 induces mitochondria mediated neurodegeneration. AB - Post-translational modification of proteins by small ubiquitin-related modifier (SUMO) is reversible and highly evolutionarily conserved from yeasts to humans. Unlike ubiquitination with a well-established role in protein degradation, sumoylation may alter protein function, activity, stability and subcellular localization. Members of SUMO-specific protease (SENP) family, capable of SUMO removal, are involved in the reversed conjugation process. Although SUMO-specific proteases are known to reverse sumoylation in many well-defined systems, their importance in mammalian development and pathogenesis remains largely elusive. In patients with neurodegenerative diseases, aberrant accumulation of SUMO conjugated proteins has been widely described. Several aggregation-prone proteins modulated by SUMO have been implicated in neurodegeneration, but there is no evidence supporting a direct involvement of SUMO modification enzymes in human diseases. Here we show that mice with neural-specific disruption of SENP2 develop movement difficulties which ultimately results in paralysis. The disruption induces neurodegeneration where mitochondrial dynamics is dysregulated. SENP2 regulates Drp1 sumoylation and stability critical for mitochondrial morphogenesis in an isoform-specific manner. Although dispensable for development of neural cell types, this regulatory mechanism is necessary for their survival. Our findings provide a causal link of SUMO modification enzymes to apoptosis of neural cells, suggesting a new pathogenic mechanism for neurodegeneration. Exploring the protective effect of SENP2 on neuronal cell death may uncover important preventive and therapeutic strategies for neurodegenerative diseases. PMID- 25299345 TI - Fetal exposure to environmental neurotoxins in Taiwan. AB - Mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) are recognized neurotoxins in children that particularly affect neurodevelopment and intellectual performance. Based on the hypothesis that the fetal basis of adult disease is fetal toxic exposure that results in adverse outcomes in adulthood, we explored the concentrations of key neurotoxins (i.e., Hg, Pb, Cd, and As) in meconium to identify the risk factors associated with these concentrations. From January 2007 to December 2009, 545 mother-infant pairs were recruited. The geometric mean concentrations of Pb and As in the meconium of babies of foreign born mothers (22.9 and 38.1 ug/kg dry weight, respectively) were significantly greater than those of babies of Taiwan-born mothers (17.5 and 33.0 ug/kg dry weight, respectively). Maternal age (>=30 y), maternal education, use of traditional Chinese herbs during pregnancy, and fish cutlet consumption (>=3 meals/wk) were risk factors associated with concentrations of key prenatal neurotoxins. The Taiwan government should focus more attention on providing intervention programs for immigrant mothers to help protect the health of unborn babies. Further investigation on how multiple neurotoxins influence prenatal neurodevelopment is warranted. PMID- 25299347 TI - Increased antioxidant efficacy of tocopherols by surfactant solubilization in oil in-water emulsions. AB - The physical location of antioxidants in oil-in-water emulsions can have significant influence on their free radical scavenging activity and ability to inhibit lipid oxidation. We aimed to determine the effect of the surfactant concentration on the partitioning behavior of tocopherols (alpha, gamma, and delta) in oil-in-water emulsions. Tween 20 (0.1, 0.5, and 1%) increased the partitioning of the tocopherols into the aqueous phase via the formation of Tween 20-tocopherol comicelles. Partitioning behavior of antioxidants was dependent upon the number of methyl groups and, thus, polarity of the tocopherols. delta Tocopherol (one methyl group) exhibited the most partitioning into the aqueous phase, while alpha-tocopherol (three methyl groups) had the lowest partitioning. Lipid oxidation studies showed that the antioxidant activity of delta- and alpha tocopherols was enhanced by adding Tween 20 to oil-in-water emulsions. This work suggests that surfactant micelles could increase the antioxidant activity of tocopherols by changing their physical location. PMID- 25299346 TI - The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion. AB - Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the alphaC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors. PMID- 25299348 TI - Removal of hexavalent chromium by using red mud activated with cetyltrimethylammonium bromide. AB - The removal of hexavalent chromium [Cr(VI)] from aqueous solution by using red mud activated with cetyltrimethylammonium bromide (CTAB) was studied. The optimum operation parameters, such as CTAB concentration, pH values, contact time, and initial Cr(VI) concentration, were investigated. The best concentration of CTAB for modifying red mud was found to be 0.50% (mCTAB/VHCl,0.6 mol/L). The lower pH (<2) was found to be much more favourable for the removal of Cr(VI). Red mud activated with CTAB can greatly improve the removal ratio of Cr(VI) as high as four times than that of original red mud. Adsorption equilibrium was reached within 30 min under the initial Cr(VI) concentration of 100 mg L(-1). The isotherm data were analysed using Langmuir and Freundlich models. The adsorption of Cr(VI) on activated red mud fitted well to the Langmuir isotherm model, and the maximum adsorption capacity was estimated as 22.20 mg g(-1) (Cr/red mud). The adsorption process could be well described using the pseudo-second-order model. The result shows that activated red mud is a promising agent for low-cost water treatment. PMID- 25299349 TI - Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study. AB - OBJECTIVES: To assess the effect of active vitamin D3 on quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: This is a post hoc analysis of a previous prospective postmarketing observational study conducted without a comparator group. This study was conducted in 60 Japanese hospitals from September 2007 to February 2009. We compared changes from baseline in QOL and pain in patients receiving raloxifene plus active vitamin D3 with those in patients receiving raloxifene monotherapy at 8 and 24 weeks after treatment. CLINICAL TRIAL REGISTRATION: Japan Pharmaceutical Information Center (JapicCTI-070465). MAIN OUTCOME MEASURES: QOL and pain were assessed using Short Form-8 (SF-8), European Quality of Life Instrument 5 Dimensions (EQ-5D), Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), visual analogue pain scales (VAS pain), and pain frequency scores. RESULTS: A total of 506 patients were included in the post hoc analysis. Both raloxifene monotherapy (RLX, n = 354) and active vitamin D3 cotreatment (COMBI, n = 152) significantly improved QOL and reduced pain from the baseline at Week 8 and Week 24. The COMBI group had significantly greater improvements in JOQOL total score and activity of daily living (total) domain at Week 24 and last observation carried forward (LOCF) than the RLX group. The COMBI group also had significantly greater improvements in SF-8 domains of general health (at Week 8, Week 24, and LOCF), role physical (at Week 24 and LOCF), and mental health (at LOCF) than the RLX group. The COMBI group also had significantly greater reduction in VAS pain at LOCF than the RLX group (mean [SD]: RLX = -0.99 [2.72], COMBI = -1.54 [2.21], P = 0.042). CONCLUSIONS: Active vitamin D3 supplementation to raloxifene treatment for 24 weeks may have additional benefits in improving QOL and relieving pain in Japanese women with postmenopausal osteoporosis. PMID- 25299350 TI - A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement. AB - OBJECTIVE: To evaluate the relative efficacy and safety of extended-release tramadol HCl 75 mg/acetaminophen 650 mg (TA-ER) and immediate-release tramadol HCl 37.5 mg/acetaminophen 325 mg (TA-IR) for the treatment of moderate to severe acute pain following total knee replacement. METHODS: This phase III, double blind, placebo-controlled, parallel-group study randomized 320 patients with moderate to severe pain (>=4 intensity on an 11 point numeric rating scale) following total knee replacement arthroplasty to receive oral TA-ER (every 12 hours) or TA-IR (every 6 hours) over a period of 48 hours. In the primary analysis, TA-ER was evaluated for efficacy non-inferior to that of TA-IR based on the sum of pain intensity difference (SPID) at 48 hours after the first dose of study drug (SPID48). Secondary endpoints included SPID at additional time points, total pain relief at all on-therapy time points (TOTPAR), sum of SPID and TOTPAR at all on-therapy time points (SPID + TOTPAR), use of rescue medication, subjective pain assessment (PGIC, Patient Global Impression of Change), and adverse events (AEs). RESULTS: Analysis of the primary efficacy endpoint (SPID48) could not establish the non-inferiority of TA-ER to TA-IR. However, a post hoc analysis with a re-defined non-inferiority margin did demonstrate the non inferiority of TA-ER to TA-IR. No statistically significant difference in SPID at 6, 12, or 24 hours was observed between the TA-ER and TA-IR groups. Similarly, analysis of TOTPAR showed that there were no significant differences between groups at any on-therapy time point, and SPID + TOTPAR at 6 and 48 hours were similar among groups. There was no difference in the mean frequency or dosage of rescue medication required by both groups, and the majority of patients in both the TA-ER and TA-IR groups rated their pain improvement as 'much' or 'somewhat better'. The overall incidence of >=1 AEs was similar among the TA-ER (88.8%) and TA-IR (89.5%) groups. The most commonly reported AEs by patients treated with TA ER and TA-IR included nausea (49.7% vs 44.4%), vomiting (28.0% vs 24.2%), and decreased hemoglobin (23.6% vs 26.1%). This study is limited by the lack of placebo control, and the invalidity of the initial non-inferiority margin. CONCLUSION: This study demonstrated that the analgesic effect of TA-ER is non inferior to TA-IR, and supports TA-ER as an effective and safe treatment for moderate to severe acute pain post total knee replacement. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01814878. PMID- 25299351 TI - A multiplicity of targets: evaluating composite endpoint studies of the GLP-1 receptor agonists in type 2 diabetes. AB - OBJECTIVE: Current type 2 diabetes (T2D) treatment guidelines include weight maintenance or loss, avoidance of hypoglycemia, and targets for blood pressure and circulating lipids, in addition to glycemic control. Increasingly, clinical trials and meta-analyses employ composite endpoints to capture the net clinical benefit of a given T2D intervention. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represent a new class of injected antihyperglycemic agents that may be well suited to reaching many of these targets among patients failing on metformin monotherapy. RESEARCH DESIGNS AND METHODS: Using MEDLINE, Embase and Google Scholar, studies were sought that employed composite endpoints and that reported outcomes with exenatide and/or liraglutide. Bibliographies of relevant review articles were consulted to search for additional reports. RESULTS: Many trials have used the combination of HbA1c <7%, no weight gain and no hypoglycemic episodes as the composite endpoint in evaluating T2D therapies; however, at least 15 other distinct composite endpoints have been reported. Findings were relatively consistent across studies, regardless of how the composite endpoint was defined. Specifically, the GLP-1 RAs appear to be superior to other agents in their efficacy in providing T2D patients failing on metformin with a net clinical benefit, which can include avoidance of hyperglycemia and maintenance or improvement in body weight. CONCLUSIONS: Use of composite endpoints represents an important advance in T2D. While no single such endpoint has achieved dominance in the field, widely used composite endpoints capture efficacy in glycemic control as well as safety and effects on markers of cardiovascular risk. PMID- 25299352 TI - The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants. AB - BACKGROUND: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity, mortality, and healthcare expenditure. Anticoagulant therapy is recommended for at least 3 months in patients with acute VTE to prevent recurrence. Conventional anticoagulants are associated with inherent limitations including route of administration, required monitoring and dose adjustments, potential for food-drug and drug-drug interactions, unpredictable pharmacokinetics and pharmacodynamics, and possible severe adverse events. SCOPE: This manuscript reviews the pharmacology of the novel oral anticoagulants (NOACs), and analyzes the differences in phase 3 clinical trial designs, outcomes, and specific patient populations investigated for the treatment of acute and prevention of secondary VTE. METHODS: A literature search was performed in PubMed using the key words dabigatran, apixaban, rivaroxaban, edoxaban, and venous thromboembolism in PubMed. The search included all years, English language, and peer-reviewed articles relating to phase 3 clinical trials, subanalyses, and meta-analyses of these NOACs for the treatment of acute VTE and secondary prevention. FINDINGS: NOACs have demonstrated comparable efficacy and comparable or superior safety in large, randomized clinical trials in the treatment and prevention of VTE compared with conventional therapy. New oral anticoagulants, including the direct thrombin (dabigatran etexilate) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), have advantages over conventional agents such as oral administration at fixed doses, predictable pharmacokinetics and pharmacodynamics, minimal potential for food-drug and drug-drug interactions, and lack of required monitoring. CONCLUSIONS: NOACs offer additional oral anticoagulation treatment options for patients with VTE. PMID- 25299353 TI - Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. AB - Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics. PMID- 25299354 TI - Effective management of ARDS. AB - Acute respiratory distress syndrome is a serious complication of critical illness that is associated with high morbidity and mortality. There are no effective treatment options, so prevention, early recognition, and appropriate supportive care are essential to improve outcomes. This article provides an overview of the disorder, including current treatment considerations. PMID- 25299355 TI - Reading outcomes of children and adolescents with attention-deficit/hyperactivity disorder and dyslexia following atomoxetine treatment. AB - Abstract Objective: This study assessed the efficacy of atomoxetine on attention deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents having ADHD with comorbid dyslexia (ADHD+D) and the effects of the treatment on reading measures. METHODS: The analyses in this report used data from a study designed to examine the effects of a nonstimulant pharmacological agent, atomoxetine, on reading in children with ADHD+D. Patients ages 10-16 years with ADHD or ADHD+D received open-label atomoxetine for 16 weeks. The ADHD Rating Scale (ADHD-RS) and reading subtests of the Kaufman Test of Educational Achievement (K-TEA) were assessed. Changes in ADHD symptoms and reading scores were also analyzed by ADHD subtype. Treatment effect sizes and correlations between changes in ADHDRS and K TEA scores were calculated. RESULTS: After atomoxetine treatment, both ADHD and ADHD+D patient groups showed significant reduction in ADHD symptom and improvements in K-TEA reading scores. The range of treatment effect sizes on K TEA scores was 0.35-0.53 for the ADHD group and 0.50-0.62 for the ADHD+D group. Pearson's correlation coefficients revealed only a few weak correlations between changes in ADHD symptoms and reading scores, regardless of diagnostic group. CONCLUSIONS: ADHD symptoms and K-TEA reading scores improved for both the ADHD and ADHD+D groups following atomoxetine treatment. Correlation analyses indicate that improvements in reading outcomes cannot be explained by a reduction of ADHD symptoms alone. These findings support further exploration of the potential effects of atomoxetine on reading in children with ADHD and dyslexia or dyslexia alone. PMID- 25299356 TI - Exploring a non-ATP pocket for potential allosteric modulation of PI3Kalpha. AB - Allosteric modulators offer a novel approach for kinase inhibition because they target less conserved binding sites compared to the active site; thus, higher selectivity may be obtained. PIK-108, a known pan phosphoinositide 3-kinase (PI3K) inhibitor, was recently detected to occupy a non-ATP binding site in the PI3Kalpha C-lobe. This newly identified pocket is located close to residue 1047, which is frequently mutated in human cancers (H1047R). In order to assess the interactions, stability, and any possible allosteric effects of this inhibitor on PI3Kalpha, extensive molecular dynamics (MD) simulations in aqueous solution were performed for the wild type (WT) human, WT murine, and H1047R human mutant PI3Kalpha proteins with PIK-108 placed in both catalytic and non-ATP sites. We verify the existence of the second binding site in the vicinity of the hotspot H1047R PI3Kalpha mutation through binding site identification and MD simulations. PIK-108 remains stable in both sites in all three variants throughout the course of the simulations. We demonstrate that the pose and interactions of PIK-108 in the catalytic site are similar in the murine WT and human mutant forms, while they are significantly different in the case of human WT PI3Kalpha protein. PIK 108 binding in the non-ATP pocket also differs significantly among the three variants. Finally, we examine whether the non-ATP binding site is implicated in PI3Kalpha allostery in terms of its communication with the active site using principal component analysis and perform in vitro experiments to verify our hypotheses. PMID- 25299357 TI - Enhanced production of xylanase from locally isolated fungal strain using agro industrial residues under solid-state fermentation. AB - This study is related to the isolation of fungal strain for xylanase production using agro-industrial residues. Forty fungal strains with xylanolytic potential were isolated by using xylan agar plates and quantitatively screened in solid state fermentation. Of all the tested isolates, the strain showing highest ability to produce xylanase was assigned the code Aspergillus niger LCBT-14. For the enhanced production of the enzyme, five different fermentation media were evaluated. Out of all media, M4 containing wheat bran gave maximum enzyme production. Effect of different variables including incubation time, temperature, pH, carbon and nitrogen sources has been investigated. The optimum enzyme production was obtained after 72 h at 30 degrees C and pH 4. Glucose as a carbon source while ammonium sulphate and yeast extract as nitrogen sources gave maximum xylanase production (946 U/mL/min). This study was successful in producing xylanase by A. niger LCBT-14 economically by utilising cheap indigenous substrate. PMID- 25299358 TI - Resin bonding to root dentin: influence of the alveolar bone level and thickness of the cement layer. AB - AIM: Aim of the present study was to evaluate the influence of the alveolar bone level and thickness of the cement layer on the push-out bond strength of fiber posts luted to root dentin. METHODS: We prepared post spaces in 60 bovine roots (16 mm), embedded in acrylic resin to simulate different scenarios of alveolar bone resorption. They were divided into six groups (N.=10), according to the factors "alveolar bone level" (14, 10, and 7 mm) and "cement thickness" (post no. 3/control and post no. 1/ thicker cement layer): G14P3 - 14-mm root + post n. 3; G10P3 - 10-mm root + post n. 3; G7P3 - 7-mm root + post n. 3; G14P1 - 14-mm root + post n. 1; G10P1 - 10-mm root + post n. 1; and G7P1 - 7-mm root + post n. 1. The fiber posts (White Post DC, FGM) were luted, and composite cores were made. Each specimen was subjected to mechanical cycling, and four slices were obtained from each root specimen and subjected to push-out testing in a universal testing machine. The data (MPa) were analyzed by ANOVA (two way) and Tukey's test (5%). RESULTS: The factor "cement thickness" (P=0.0057) significantly influenced bond strength, but the factor "alveolar bone level" (P=0.0605) did not. The thicker cement layer/post n. 3 presented bond strength values higher than those with cement layer/post n. 1. CONCLUSION: Bond strength was not influenced by different scenarios of alveolar bone resorption, although higher bond strength values were found for thinner cement layers. PMID- 25299359 TI - Antibacterial activity of Garcinia mangostana extracts on oral pathogens. AB - AIM: This study was conducted to evaluate the antibacterial activity of Garcinia mangostana (GM) extracts on oral pathogens. METHODS: The 95% ethanol and 70% acetone extracts of the pericarp of GM was prepared and standardized by determining the amount of alpha-mangostin, total phenolic compounds and tannins. The antibacterial activity of GM extracts against oral pathogens was investigated by using minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), and time kill assay. Bacterial morphology was analyzed using scanning electron microscopy (SEM). RESULTS: The results indicated that the content of alpha-mangostin, total phenolic compounds and tannins of the both extracts were different. The 95% ethanol extract contained higher alpha-mangostin and total phenolic compounds. Whereas, the tannins of 70% acetone extract were significantly higher than 95% ethanol extract. The 95% ethanol extract exhibited a potent antibacterial activity with low MIC and MBC values compared to the acetone extract. The morphology of bacteria was significantly changed after treatment with extracts for 24 h. Furthermore, time kill assay revealed that bacterial cells were decreased within 2 h. CONCLUSION: GM extracts was effective against oral bacteria pathogens. The antibacterial activity was varied by the different extraction solvents and the distinction in the contents of the compounds among extracts. These findings indicated that GM extracts showed promising antibacterial activity against oral pathogens in vitro. PMID- 25299360 TI - In vitro evaluation of three electronic apex locators using conventional methods and cone beam computed tomography. AB - AIM: The aim of this paper was to evaluate the measurement accuracy of three electronic apex locators by digital radiography, stereomicroscope and cone beam computed tomography (CBCT). METHODS: This in vitro experimental analytic descriptive study included 90 extracted permanent teeth with mature apices from the inter-canine region, divided into three groups. In vitro electronic root canal measurement was utilized using three different apex locators: ProPex Dentsply, Apex NRG Blue and Romi Apex 15A. After digital radiographic imaging and measurements Cone Beam Computer Tomography (CBCT) imaging with voxel edge size 0.125 mm was utilized and finally the apical portion of the root is grounded (5 mm) along its axis to prepare it for stereomicroscopic measurements. RESULTS: The performed test of significance shows that there is no difference between the apex locators and the control length as measured by computed digital radiography (CDR), P-values of the t-tests are all >0.05. The t-tests showed that there is no significant differences between the measurements conducted by stereomicroscope and the measurements results obtained using CBCT; measurements performed by the three apex locators (Propex, NRG-Blue, and Rami Apex), were accurate within 0.5 mm 87%, 93%, and 87% of the time, respectively. The statistical analysis showed no significant differences between the three tested apex locators (P>0.05). CONCLUSION: Based on the conditions of the present study, it can be concluded that all three apex locators (ProPex Dentsply, Apex NRG Blu and Romi Apex 15A) have demonstrated accurate and dependable measurements performed in vitro conditions. PMID- 25299361 TI - Comparative evaluation of antimicrobial activity of two root canal sealers: MTA Fillapex and AH 26. AB - AIM: Even after a complete root canal therapy, reinfection may occur as a result of incomplete seal and activation of residual bacteria. Thus, antimicrobial activity is an important characteristic of root canal sealers. MTA Fillapex is a newly developed MTA-based sealer. It has been subjected to various studies evaluating its physical and chemical properties. In this study, we aimed to compare the antimicrobial activity of this sealer to the commonly known widely accepted sealer, AH26. METHODS: MTA Fillapex and AH 26 were exposed the bacterial suspension of Enterococcus faecalis, Escherichia coli, Streptococcus mutans, and Candida albicans after setting. After incubation and complete evaporation, BHI was added to microtubes. 24 hours later, the liquid content was placed in agar diffusion plate and bacterial count was performed. ANOVA followed by Tukey test, and t-Test were performed to analyze the data. RESULTS: With regard to all four bacterial groups, the bacterial count was significantly lower in MTAFillapex group comparing to AH 26 group. CONCLUSION: Newly developed MTA Fillapex sealer, has better antimicrobial properties in comparison to the widely accepted AH26 sealer. PMID- 25299362 TI - Adipose derived stem cells: basic science fundaments and clinical application. An update. AB - Soft tissues regeneration can be used to treat several kinds of diseases including congenital and post traumatic deformities, and to fill out tissue depression due to orbital and periorbital surgery, scars or cancer resections. Generally it is performed by the use of autologous tissue flaps, alloplastic implants and autologous fat grafting. All of these methods have several disadvantages, which include resorption of the autologous material, foreign body reaction and implant migration. Stem cell application has been suggested as a possible novel therapy for regenerative medicine thanks to their unlimited capacity of self-renewal, as well as the property to differentiate into multiple cell types under appropriate stimuli. This short review describe the recent development in stem cells isolation, expansion and characterization and their employment in tissue regeneration and tissue engineering. PMID- 25299363 TI - A complementary palette of NanoCluster Beacons. AB - NanoCluster Beacons (NCBs), which use few-atom DNA-templated silver clusters as reporters, are a type of activatable molecular probes that are low-cost and easy to prepare. While NCBs provide a high fluorescence enhancement ratio upon activation, their activation colors are currently limited. Here we report a simple method to design NCBs with complementary emission colors, creating a set of multicolor probes for homogeneous, separation-free detection. By systematically altering the position and the number of cytosines in the cluster nucleation sequence, we have tuned the activation colors of NCBs to green (C8-8, 460 nm/555 nm); yellow (C5-5, 525 nm/585 nm); red (C3-4, 580 nm/635 nm); and near infrared (C3-3, 645 nm/695 nm). At the same NCB concentration, the activated yellow NCB (C5-5) was found to be 1.3 times brighter than the traditional red NCB (C3-4). Three of the four colors (green, yellow, and red) were relatively spectrally pure. We also found that subtle changes in the linker sequence (down to the single-nucleotide level) could significantly alter the emission spectrum pattern of an NCB. When the length of linker sequences was increased, the emission peaks were found to migrate in a periodic fashion, suggesting short range interactions between silver clusters and nucleobases. Size exclusion chromatography results indicated that the activated NCBs are more compact than their native duplex forms. Our findings demonstrate the unique photophysical properties and environmental sensitivities of few-atom DNA-templated silver clusters, which are not seen before in common organic dyes or luminescent crystals. PMID- 25299365 TI - Impact of excessive daytime sleepiness on the safety and health of farmers in Saskatchewan. AB - BACKGROUND: Sleep disorders may negatively impact the health and well-being of affected individuals. The resulting sleepiness and impaired cognitive functioning may also increase the risks for injury. OBJECTIVE: To examine the relationship between daytime sleepiness, defined as an Epworth Sleepiness Scale score >10, and self-reported sleep apnea, as potential determinants of farming-related injury and self-perceived physical health. METHODS: Phase 2 of the Saskatchewan Farm Injury Cohort Study (2013) involved a baseline survey that included 2849 individuals from 1216 farms. A mail-based questionnaire was administered to obtain self-reports regarding sleep, demographics, farm injuries and general physical health. Multilevel logistic regression was used to quantify relationships between excessive daytime sleepiness and health. RESULTS: The prevalence of excessive daytime sleepiness was 15.1%; the prevalence of diagnosed sleep apnea was 4.0%. Sleepiness was highest in the 60 to 79 (18.7%) and >=80 (23.6%) years of age groups, and was higher in men (19.0%) than in women (9.3%). Injuries were reported by 8.4% of individuals, and fair or poor health was reported by 6.2%. Adjusting for confounding, individuals with excessive daytime sleepiness appeared more likely to experience a farming-related injury (OR 1.34 [95% CI 0.92 to 1.96]) and were more likely to report poorer physical health (OR 2.19 [95% CI 1.45 to 3.30]) than individuals with normal daytime sleepiness. CONCLUSION: Excessive daytime sleepiness, a potentially treatable condition, appeared to be common in farmers and to negatively affect their health. Sleep disorder diagnosis and treatment programs did not appear to be used to their full potential in this population. PMID- 25299364 TI - Adaptive evolution of synthetic cooperating communities improves growth performance. AB - Symbiotic interactions between organisms are important for human health and biotechnological applications. Microbial mutualism is a widespread phenomenon and is important in maintaining natural microbial communities. Although cooperative interactions are prevalent in nature, little is known about the processes that allow their initial establishment, govern population dynamics and affect evolutionary processes. To investigate cooperative interactions between bacteria, we constructed, characterized, and adaptively evolved a synthetic community comprised of leucine and lysine Escherichia coli auxotrophs. The co-culture can grow in glucose minimal medium only if the two auxotrophs exchange essential metabolites - lysine and leucine (or its precursors). Our experiments showed that a viable co-culture using these two auxotrophs could be established and adaptively evolved to increase growth rates (by ~3 fold) and optical densities. While independently evolved co-cultures achieved similar improvements in growth, they took different evolutionary trajectories leading to different community compositions. Experiments with individual isolates from these evolved co-cultures showed that changes in both the leucine and lysine auxotrophs improved growth of the co-culture. Interestingly, while evolved isolates increased growth of co cultures, they exhibited decreased growth in mono-culture (in the presence of leucine or lysine). A genome-scale metabolic model of the co-culture was also constructed and used to investigate the effects of amino acid (leucine or lysine) release and uptake rates on growth and composition of the co-culture. When the metabolic model was constrained by the estimated leucine and lysine release rates, the model predictions agreed well with experimental growth rates and composition measurements. While this study and others have focused on cooperative interactions amongst community members, the adaptive evolution of communities with other types of interactions (e.g., commensalism, ammensalism or parasitism) would also be of interest. PMID- 25299366 TI - Pediatric kidney transplant with laparoscopic donor nephrectomy. AB - OBJECTIVES: To evaluate outcomes and complications with pediatric living-donor kidney transplant, mostly performed with laparoscopic donor nephrectomy. MATERIALS AND METHODS: In the 25 years between February 1987 and December 2012, there were 493 children aged <= 17 years who received a kidney transplant. Demographic characteristics, graft and patient survival, rejection episodes, and complications were recorded. Analysis was performed for 3 sequential periods (1987-1994, 1995-2002, and 2003-2012). RESULTS: The mean patient age was 13 +/- 4 years (age range, 2.5-17 y). There were 290 males (59%). Glomerulonephritis was the most common cause of end-stage renal disease. Preemptive kidney transplant was performed in 412 patients (84%). Donor nephrectomy was performed laparoscopically in 445 patients (90%). The 5-year graft and patient survival were improved from 1987-1994 to 2003-2012. The overall death-censored graft survival was 96% at 1 year, 78% at 5 years, and 66% at 10 years after transplant. The overall patient survival was 96% at 1 year, 83% at 5 years, and 75% at 10 years after transplant. CONCLUSIONS: Kidney transplant is available for most pediatric patients and has acceptable graft and patient survivals. Laparoscopic donor nephrectomy improves donor satisfaction and morbidity, and may provide excellent graft outcomes in children. PMID- 25299367 TI - Clinical outcomes of ABO-incompatible kidney transplant with rituximab and double filtration plasmapheresis. AB - OBJECTIVES: The best treatment for end-stage renal disease is kidney transplant, but the shortage of donor organs has caused long waiting times for an appropriate organ allograft. The use of ABO-incompatible kidney transplant can be a valuable option to expand the donor pool. The purpose of the present study was to evaluate 13 patients who had successful ABO-incompatible kidney transplant with double filtration plasmapheresis and rituximab. MATERIALS AND METHODS: From January 2011 to August 2012, there were 13 patients who had ABO-incompatible kidney transplant. Antibody titers were monitored during preconditioning and after transplant. Preconditioning protocol included rituximab, mycophenolate mofetil, tacrolimus, corticosteroids, double-filtration plasmapheresis, and intravenous immunoglobulin. RESULTS: There were no episodes of acute T-cell or antibody mediated rejection. There were no surgical complications except postoperative bleeding in 1 patient. Mean serum creatinine at 2 weeks after transplant was 71 +/- 18 MUmol/L (0.8 +/- 0.2 mg/dL). At mean follow-up 267 days (range, 1-19 mo), there was no graft loss or patient death. CONCLUSIONS: The ABO-incompatible kidney transplants were successful after the preconditioning protocol that included double-filtration plasmapheresis and rituximab. The use of ABO incompatible kidney transplant may increase the availability of kidney transplant and avoid or shorten dialysis. Future multicenter studies are justified to develop a standardized preconditioning protocol. PMID- 25299368 TI - Expression patterns of B cells in acute kidney transplant rejection. AB - OBJECTIVES: To evaluate B-cell expression patterns and association with function and survival in dysfunctional kidney allografts. MATERIALS AND METHODS: There were 110 kidney transplant recipients included who had for-cause biopsies. Demographic and transplant data were collected. Immunostaining for B cells, plasma cells, and C4d was performed by the immunoperoxidase technique in paraffin embedded samples. Circulating antihuman leukocyte antigen donor-specific antibodies were detected in a single-antigen assay at biopsy. The main outcomes were kidney graft survival and function. The patients were evaluated in 3 groups according to the Banff classification: no rejection (40 patients), T-cell mediated rejection (50 patients), and antibody-mediated rejection (20 patients). RESULTS: The CD138-positive plasma cell-rich infiltrates predominated in antibody mediated rejection and were associated with stronger reactivity against panel antibodies (r = 0.41; P <= .001) and positive donor-specific antibodies (r = 0.32; P <= .006). The CD20-positive lymphocytes were associated with T-cell mediated rejection, increased human leukocyte antigen mismatch, and frequency of retransplant. The CD138-positive cell infiltrates also were significantly greater in patients who had late than early rejection. There was no correlation between cellular CD20 and CD138 expression, and neither CD20 nor CD138 predicted worse graft function or survival. Other markers of antibody-mediated rejection such as C4d and donor-specific antibodies were associated with worse graft function and survival at 4 years after transplant. In multivariate analysis, C4d was the only risk factor associated with graft loss. CONCLUSIONS: After kidney transplant, CD20-positive B-cell infiltrates were associated with T-cell-mediated rejection, and CD138-positive plasma cells were associated with antibody-mediated rejection. Graft loss was associated with the presence of C4d. PMID- 25299369 TI - Designation of T-cell-mediated rejection type Ib and IIa reflects the type of rejection rather than the severity in the Banff classification. AB - OBJECTIVES: Whether T-cell-mediated rejection Banff classification type Ib (severe tubulointerstitial rejection) and type IIa (mild vascular rejection) are associated with responses to antirejection therapy and long-term graft survival are unclear. MATERIALS AND METHODS: One hundred ten patients were enrolled who had at least 1 episode of T-cell-mediated rejection and whose highest T-cell mediated rejection severity was T-cell-mediated rejection type Ib or IIa. RESULTS: T-cell-mediated rejection Ib occurred significantly later than T-cell mediated rejection IIa (P < .001). The proportion of partial/no response to antirejection therapy was comparable between the 2 groups (P = .83). Up to 8-year posttransplant, death-censored graft survival rate of the T-cell-mediated rejection Ib group was similar to that of the T-cell-mediated rejection IIa group (P = .51). Early T-cell-mediated rejection IIa had a statistically higher death censored graft survival rate than did late T-cell-mediated rejection IIa (P < .001), while no significant difference in the death-censored graft survival was found between early and late T-cell-mediated rejection Ib (P = .11) or between early T-cell-mediated rejection Ib and early T-cell-mediated rejection IIa (P = .11) or between late T-cell-mediated rejection Ib and late T-cell-mediated rejection IIa (P = .07). Furthermore, the T-cell-mediated rejection IIa with isolated v1 lesion (v1, i0-1, t0-1) showed a similar death-censored graft survival rate compared to T-cell-mediated rejection IIa with intensive tubulointerstitial inflammation (v1, i2-3, t2-3). The timing of rejection, graft number, the number of indicated biopsies and the presence of ci/ct lesions were associated with long-term graft loss. CONCLUSIONS: The designation of T-cell mediated rejection type Ib and IIa reflects the different type rather than the distinct severity of rejection and has no independent prognostic significance. PMID- 25299370 TI - Using low graft/recipient's body weight ratio graft with portal flow modulation an effective way to prevent small-for-size syndrome in living-donor liver transplant: a retrospective analysis. AB - OBJECTIVES: Small-sized grafts are associated with high rates of graft failure and small-for-size syndrome. Portal flow is a causative factor for small-for-size syndrome. We sought to evaluate early graft dysfunction in smaller-sized grafts and the study factors responsible for it. MATERIALS AND METHODS: A total of 450 patients underwent a living-donor liver transplant from January 2010 to June 2013. Fifty-four grafts with graft/recipient's body weight ratio less than 0.8 were included in the study. We used a splenic artery ligation or splenectomy for portal flow modulation if the portal flow after reperfusion was greater than 250 mL/min/100 g. Small-for-size syndrome was defined according to Clavien and Kyushu university definitions. Portal flow was measured with Doppler ultrasound flowmetry. Factors responsible for early graft dysfunction also were analyzed. RESULTS: Six patients out of 54 developed small-for-size syndrome in smaller size group (graft/recipient's body weight ratio < 0.8). There were 28 left lobe grafts and 26 right lobe grafts. Sixteen out of 132 patients from the control group fulfilled the definitions of small-for-size syndrome. There was no statistical significant difference in graft dysfunction between low graft/recipient's body weight ratio group and high graft/recipient's body weight ratio group. On univariate analysis Hepatitis C, Hepatitis B and HCC as etiologies, Model for End stage Liver diease score, and portal flow achieved statistical significane as factors associated with graft dysfunction (P < .05). On multivariate analysis, only portal flow achieved statistical significance. CONCLUSIONS: Lower graft/recipient's body weight ratio graft with portal flow modulation in case of high portal flow is an effective way to increase donor pool and donor safety with low risk of small-for-size syndrome. Portal flow is mainly responsible for small for-size syndrome or early graft dysfunction. PMID- 25299371 TI - Bilateral versus single lung transplant for idiopathic pulmonary fibrosis. AB - OBJECTIVES: It is unknown if uni- or bilateral lung transplant is best for treatment of usual idiopathic pulmonary fibrosis. We reviewed our single-center experience comparing both treatments. MATERIALS AND METHODS: Between 2002 and 2011, one hundred thirty-eight patients at our institution underwent a lung transplant. Of these, 58 patients presented with idiopathic pulmonary fibrosis (56.9%) and were the focus of this study. RESULTS: Thirty-nine patients received a single lung transplant and 19 patients a bilateral sequential lung transplant. The mean patient age was 54 +/- 10 years, and 69% were male. The intraoperative course was uneventful, save for 7 patients who needed extracorporeal membrane oxygenation support. Three patients had respiratory failure before the lung transplant that required mechanical ventilation and was supported by extracorporeal membrane oxygenation. Elevated pulmonary artery pressure > 40 mm Hg was identified as an independent predictor of early mortality by uni- and multivariate analysis (P = .01; OR 9.7). Using a Cox regression analysis, postoperative extracorporeal membrane oxyge-nation therapy (P = .01; OR 10.2) and the need for > 10 red blood cell concentrate during the first 72 hours after lung transplant (P = .01; OR 5.6) were independent predictors of long-term survival. Actuarial survival at 1 and 5 years was 65.6% and 55.3%, with no significant between-group differences (70.6% and 54.3%). CONCLUSIONS: Lung transplant is a safe and curative treatment for idiopathic pulmonary fibrosis. According to our results, unilateral lung transplant for idiopathic pulmonary fibrosis is an alternative to bilateral lung transplant and may affect the allocation process. PMID- 25299372 TI - Human tracheal allotransplant with greater omentum for revascularization. AB - OBJECTIVES: Human tracheal allotransplant is an option for treating long-segment tracheal defects, but no reliable and satisfactory tracheal transplant procedure has been developed. The purpose of this study is to review the results of 2-stage tracheal reconstruction in human tracheal allotransplant for tracheal defects > 5 cm with the use of greater omentum for revascularization. MATERIALS AND METHODS: There were 3 patients who had tracheal allograft. In stage 1, a segment of donor trachea (6 cm) was excised and wrapped in the recipient greater omentum. In stage 2, at 3 to 5 weeks after stage 1, the tracheal allograft and omental pedicle were orthotopically transplanted to the cervical part of the trachea. All patients received immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Fiberoptic bronchoscopy was performed monthly during the 6 months after stage 2. RESULTS: In all 3 patients, no major postoperative complication was observed. Transverse section of the donor trachea showed a mechanically stable chondral framework. Histologic sections stained with hematoxylin-eosin showed complete cartilage rings covered by intact respiratory epithelium. CONCLUSIONS: A 2-stage procedure for human tracheal transplant with greater omentum is a safe and effective technique for tracheal reconstruction. PMID- 25299373 TI - Knowledge and attitudes regarding eye donation and corneal transplant: medical versus nonmedical university students in a developing country in Africa. AB - OBJECTIVES: We sought to assess the knowledge and attitudes of medical and nonmedical University students regarding eye donation and corneal transplant. MATERIALS AND METHODS: The study was a comparative, questionnaire-based, cross sectional survey of fourth-year medical and environmental science students at the University of Nigeria conducted in October 2012. Participants' demographics, knowledge, and attitudes on eye donation and corneal transplant were analyzed using descriptive and comparative statistics. Values for P less than .05 were considered statistically significant. RESULTS: The participants (107 medical students, 75 environmental science students) were 117 men and 65 women aged 22.3 +/- 2.2 years (range, 18-32 y). There were no significant intergroup differences regarding awareness of eye donation (OR 1.71; 95% CI: 0.92-3.17; P = .0924) and willingness to donate their own (OR 0.76; 95% CI: 0.33-1.76; P = .5260) or their relatives ' eyes (OR 0.76; 95% CI: 0.29-1.98; P = .6274). Significantly more medical students than environmental science students knew that donation consent is given by the donor while alive (OR 2.93; 95% CI: 1.56-5.4; P = .0005) and had good knowledge of donor eye preservation (OR 2.43; 95% CI: 1.27-4.68; P = .007). CONCLUSIONS: Among medical and nonmedical undergraduate students, there are crucial deficits in knowledge and attitudes on eye donation and corneal transplant. Tailored donation awareness campaigns and introduction of undergraduate course work on eye donation may reverse the trend. PMID- 25299374 TI - Prophylactic acyclovir and preemptive ganciclovir to prevent cytomegalovirus disease in children after hematopoietic stem cell transplant. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of acyclovir prophylaxis and preemptive ganciclovir treatment in preventing cytomegalovirus disease in children who underwent hematopoietic stem cell transplant. MATERIALS AND METHODS: We reviewed the clinical records of 66 children (36 boys, 30 girls; mean age, 9 +/- 5 y; age range, 2-20 y) who underwent hematopoietic stem cell transplant at Ankara Children's Hematology and Oncology Hospital, Bone Marrow Transplantation Unit, between April 2010 and March 2012. RESULTS: In these 66 children, 61 children (92.4%) received allogeneic transplant; 50 children (76.9%) received a myeloablative regimen; and 14 children (21.2%) received anti-thymocyte globulin as part of the conditioning regimen. All children received acyclovir prophylaxis from the beginning of conditioning regimen until 100 days after transplant, and children received preemptive treatment with ganciclovir when cytomegalovirus DNAemia >= 400 copies/mL on 2 tests or >= 1000 copies/mL on 1 test. There were 19 children (28.8%) who had cytomegalovirus reactivation during median follow-up 381 days (range, 100-720 d). Cytomegalovirus disease was observed in only 2 patients (10.5%); 1 patient had cytomegalovirus hepatitis and 1 patient had cytomegalovirus gastrointestinal disease. Both patients were cured of cytomegalovirus with treatment for 1 month. There was no death attributable to cytomegalovirus reactivation and/or disease. Febrile neutropenia, acute graft-versus-host disease, and steroid use were more frequent in patients who had cytomegalovirus than did not have cytomegalovirus reactivation. The risk of cytomegalovirus reactivation was increased 5-fold in patients who used steroids. CONCLUSIONS: Acyclovir prophylaxis and preemptive treatment with ganciclovir may be effective in preventing cytomegalovirus disease in most children who have hematopoietic stem cell transplant. PMID- 25299375 TI - Lung transplant for a patient with cystic fibrosis and active Burkholderia Cenocepacia pneumonia. AB - Lung transplant for cystic fibrosis has been considered contraindicated in patients who have Burkholderia Cenocepacia infection. A 24-year-old white woman who had cystic fibrosis presented with respiratory failure caused by B. Cenocepacia pneumonia. She was treated with broad-spectrum antibiotics and a double-lung transplant. The chest cavity and both bronchi were irrigated with 0.5% povidone-iodine solution. For immunosuppression, she received induction therapy with alemtuzumab (15 mg) and methylprednisolone and maintenance therapy with tacrolimus, mycophenolate mofetil, and prednisone (5 mg daily). Postoperative antibiotics included intravenous meropenem for 3 weeks; vancomycin for 10 days; and inhaled ceftazidime, oral trimethoprim-sulfamethoxazole, and doxycycline for several months. Follow-up at 25 months after transplant showed that chest radiographs were clear and lung function was normal. At 6 years after transplant, she was working full time and had no recurrence of infection from B. Cenocepacia. This case suggests that patients who have cystic fibrosis and active B. Cenocepacia pneumonia may be successfully treated with a lung transplant. PMID- 25299376 TI - Allogeneic hematopoietic stem cell transplant for high-risk adult patients with chronic granulomatous disease: first case report from Iran. AB - We describe the successful hematopoietic stem cell transplant of a 22-year-old patient with chronic granulomatous disease at our center. Our case was a relatively old male patient compared with other patients having the diagnosis of chronic granulomatous disease who underwent hematopoietic stem cell transplant. The patient was diagnosed as chronic granulomatous disease at the age of 1 year when he developed repeated bacterial infections since 2 months of age and laboratory test revealed 0% of normal control value on nitroblue tetrazolium test. In December 2011, at 22 years of age, he underwent an allogeneic hematopoietic stem cell transplant from human leukocyte antigen fully matched sibling. Conditioning regimen was busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. He received methotrexate and cyclosporine as prophylaxis for graft-versus host disease. Engraftment was achieved at day 13. At the time of this writing, the patient is alive and well with no serious complication and without any evidence of graft-versus-host disease or rejection 12 months after stem cell transplant. PMID- 25299377 TI - The impact of living-unrelated transplant on establishing deceased-donor liver program in Syria. AB - Liver transplant is the criterion standard for patients with end-stage liver disease. Yet there is no liver transplant in Syria. Traveling abroad for a liver transplant is a luxury few Syrians can afford. There is currently an on-going debate whether to start a liver transplant program using living or deceased donors. In 2003, a new law was enacted, authorizing the use of organs from volunteer strangers and deceased donors. Despite the positive aspects of this law (allowing unrelated donors to increase the number of transplants in the country); the negative aspects also were obvious. The poor used the law to sell their organs to the rich, and this model is in violation of the Istanbul Declaration. To better document transplant communities' perceptions on organ donation, an e mail survey was sent to a nationally representative sample of physicians (n = 115) that showed that 58% of respondents did not support the start of liver transplant from live donors, as they fear a considerable risk for the donor and the recipient. Seventy-one percent of respondents believe that unrelated kidney donation has contributed to tarnishing the reputation of transplant, and 56% believe that a deceased-donor program can run in parallel with unrelated organ donations. The interest in deceased-donor program has been affected negatively by the systematic approach of using poor persons as the source of the organ. This lack of interest has affected starting a liver program that relies on deceased donors; especially the need for kidneys is more than livers. Health authorities in Syria were inclined to initiate a liver transplant program from live donors, despite the risks of serious morbidities and mortality. In conclusion then, paid kidney donation in actual effect is actually a hindrance to establishing a deceased-donor liver program. PMID- 25299378 TI - betaB2-Crystallin Promotes Axonal Regeneration in the Injured Optic Nerve in Adult Rats. AB - The purpose of the study was to further scrutinize the potential of betaB2 crystallin in supporting regeneration of injured retinal ganglion cell axons both in vitro and in vivo. Retinal explants obtained from animals after treatment either with lens injury (LI) alone or with combined LI 5 days or 3 days before or simultaneously with an optic nerve crush (ONC) were cultured for 96 h under regenerative conditions, and the regenerating axons were quantified and compared with untreated controls. These measurements were then repeated with LI replaced by intravitreal injections of gamma-crystallin and beta-crystallin at 5 days before ONC. Finally, betaB2-crystallin-overexpressing transfected neural progenitor cells (betaB2-crystallin-NPCs) in the eye were studied after crushing the optic nerve in vivo. Regeneration was monitored with the aid of immunoblotting of the retina and optic nerve both distal and proximal to the lesion site, and this was compared with controls that received injections of phosphate buffer only. LI performed 5 days or 3 days before ONC significantly promoted axonal outgrowth in vitro (p < 0.001), while LI performed alone before explantation did not. Intravitreal injections of beta-crystallin and gamma crystallin mimicked the effects of LI and significantly increased axonal regeneration in culture at the same time intervals (p < 0.001). Western blot analysis revealed that crystallins were present in the proximal optic nerve stump at the lesion site in ONC, but were neither expressed in the undamaged distal optic nerve nor in uninjured tissue. betaB2-crystallin-NPCs supported the regeneration of cut optic nerve axons within the distal optic nerve stump in vivo. The reported data suggest that betaB2-crystallin-producing "cell factories" could be used to provide novel therapeutic drugs for central nervous system injuries. PMID- 25299379 TI - Quality of life of Taiwanese adults with autism spectrum disorder. AB - BACKGROUND: To date, few recent studies have investigated the quality of life of adults with autism spectrum disorder (ASD). It remains unclear how individuals with ASD view their own quality of life. OBJECTIVE: The primary purpose of this study was to compare the quality of life scores among adults with ASD with those of a non-ASD control group and the Taiwanese health population reference group. METHODS: The study comprised 41 adults with ASD (M age = 26.9, SD = 5.0), and without intellectual disabilities (IQ>70). A comparison sample of 41 adults without ASD was selected by matching the age and sex of the participants with ASD. A validated measure, the Taiwanese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF), was used. Independent t-tests were performed to examine the differences in the quality of life between groups. RESULTS: The highest quality of life was scored in the environment domain, followed by the physical health and psychological health domains. The lowest quality of life score was found in the social relationship domain. Adults with ASD scored significantly lower in all domains than did the non-ASD control group. Additionally, adults with ASD scored significantly lower in the physical health, psychological health, and social relationship domains than did the Taiwanese health population reference group. Comorbid psychiatric disorders, self-rated health status, and perceived happiness were correlated with quality of life among adults with ASD. CONCLUSION: The preliminary findings suggest that adults with ASD need more supportive social contexts and interventions to promote their quality of life. Based on our findings, social relationship must be considered in designing and applying treatment programs for adults with ASD. PMID- 25299380 TI - Enhancing transitions from addiction treatment to primary care. AB - Despite long-standing recommendations that patients with substance use disorders receive primary care, only one-half of patients with substance use disorders receive such care. This article presents a conceptual model to facilitate the transition of patients from addiction treatment to primary care. A narrative review of the healthcare transition literature was conducted with an emphasis on identifying substance use disorder-specific model elements. The resulting model is intended to guide addiction treatment and primary care providers and researchers in understanding factors that impact care coordination between addiction treatment and primary care and to provide an overview of evidence-based methods for supporting this care transition. PMID- 25299381 TI - Quantifying environmental DNA signals for aquatic invasive species across multiple detection platforms. AB - The use of molecular surveillance techniques has become popular among aquatic researchers and managers due to the improved sensitivity and efficiency compared to traditional sampling methods. Rapid expansion in the use of environmental DNA (eDNA), paired with the advancement of molecular technologies, has resulted in new detection platforms and techniques. In this study we present a comparison of three eDNA surveillance platforms: traditional polymerase chain reaction (PCR), quantitative PCR (qPCR), and digital droplet PCR (ddPCR) in which water samples were collected over a 24 h time period from mesocosm experiments containing a population gradient of invasive species densities. All platforms reliably detected the presence of DNA, even at low target organism densities within the first hour. The two quantitative platforms (qPCR and ddPCR) produced similar estimates of DNA concentrations. The analyses completed with ddPCR was faster from sample collection through analyses and cost approximately half the expenditure of qPCR. Although a new platform for eDNA surveillance of aquatic species, ddPCR was consistent with more commonly used qPCR and a cost-effective means of estimating DNA concentrations. Use of ddPCR by researchers and managers should be considered in future eDNA surveillance applications. PMID- 25299382 TI - Report on the Carcinogenesis Bioassay of Chloroform (CAS No. 67-66-3). AB - Chloroform, also known as trichloromethane, is primarily used (93%) in the manufacture of fluorocarbons for refrigerants, propellants, and plastics. The remainder is used for many purposes including extracting and purifying antibiotics, as an industrial solvent, in preparation of dyes, drugs and pesticides, as a component of some toothpastes, cough medicines, liniments, salves, in photographic processing and in industrial drycleaning. A carcinogenesis bioassay of USP grade chloroform was conducted using Osborne Mendel rats and B6C3F1 mice. Chloroform was administered orally (by gavage) in corn oil to 50 animals of each sex and at two dose levels five times per week for 78 weeks. Rats were started on test at 52 days of age and sacrificed after 111 weeks. The dose levels for males were 90 and 180 mg/kg body weight. Female rats were started at 125 and 250 mg/kg, reduced to 90 and 180 mg/kg after 22 weeks, with an average level of 100 and 200 mg/kg for the study. A decrease in survival rate and weight gain was evident for all treated groups. The most significant observation (P=.0016) was kidney epithelial tumors in male rats with incidences of: 0% in controls, 8% in the low dose and 24% in the high dose groups. Although an increase in thyroid tumors was also observed in treated female rats, this finding was not considered biologically significant. Mice were started on test at 35 days and sacrificed after 92-93 weeks. Initial dose levels were 100 and 200 mg/kg for males and 200 and 400 mg/kg or female mice. These levels were increased after 18 weeks to 150/300 and 250/500 mg/kg respectively so that the average levels were 138 and 277 mg/kg for males and 238 and 477 mg/kg for female mice. Survival rates and weight gains were comparable for all groups except high dose females which had a decreased survival. Highly significant increases (P<.001) in hepatocellular carcinoma were observed in both sexes of mice with incidences of: 98% and 95% for males and females at the high dose; 36% and 80% for males and females at the low dose as compared with 6% in both matched and colony control males, 0% in matched control females and 1% in colony control females. Nodular hyperplasia of the liver was observed in many low dose male mice that had not developed hepatocellular carcinoma. SYNONYMS: trichloromethane LEVELS OF EVIDENCE OF CARCINOGENICITY: Male Rats: Positive; Female Rats: Negative; Male Mice: Positive; Female Mice: Positive. PMID- 25299384 TI - Plasma metabolic profiling of dairy cows affected with clinical ketosis using LC/MS technology. AB - BACKGROUND: Ketosis in dairy cattle is an important metabolic disorder. Currently, the plasma metabolic profile of ketosis as determined using liquid chromatography-mass spectrometry (LC/MS) has not been reported. OBJECTIVE: To investigate plasma metabolic profiles from cows with clinical ketosis in comparison to control cows. ANIMALS AND METHODS: Twenty Holstein dairy cows were divided into two groups based on clinical signs and plasma beta-hydroxybutyric acid and glucose concentrations 7-21 days postpartum: clinical ketosis and control cows. Plasma metabolic profiles were analyzed using LC/MS. Data were processed using principal component analysis and orthogonal partial least-squares discriminant analysis. RESULTS: Compared to control cows, the levels of valine, glycine, glycocholic, tetradecenoic acid, and palmitoleic acid increased significantly in clinical ketosis. On the other hand, the levels of arginine, aminobutyric acid, leucine/isoleucine, tryptophan, creatinine, lysine, norcotinine, and undecanoic acid decreased markedly. CONCLUSION: Our results showed that the metabolic changes in cows with clinical ketosis involve complex metabolic networks and signal transduction. These results are important for future studies elucidating the pathogenesis, diagnosis, and prevention of clinical ketosis in dairy cows. PMID- 25299385 TI - Investigating the association between obstructive sleep apnea and periodontitis. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a sleep disorder characterized by disruptions of normal sleep architecture. Chronic periodontitis is a chronic disease of the periodontium that elicits a general inflammatory response to local dental plaque. It has been suggested that periodontal disease may increase in severity with increasingly severe OSA because both disease entities share common inflammatory pathways, acting synergistically to alter the host response. The aim of this study is to analyze the association between severity of OSA and the prevalence/severity of periodontitis. METHODS: One hundred patients from a large veterans administration sleep study center (n = 26 normal, n = 21 mild, n = 19 moderate, n = 34 severe) diagnosed with an overnight polysomnogram underwent a comprehensive periodontal examination. Periodontal parameters measured included the following: 1) mean periodontal probing depth (PD); 2) clinical attachment level (CAL); 3) gingival recession; and 4) percentage of sites with bleeding on probing, plaque, PD >=5 mm, and CAL >=3 mm. RESULTS: Seventy-three percent of the sampled population had moderate/severe periodontal disease. chi(2) analyses revealed no significant differences in the prevalence of periodontal disease between the apnea-hypopnea index (AHI) groups, with a negligible Spearman correlation coefficient of 0.246 between AHI severity and periodontal disease severity categories. Analysis of covariance indicated a significant association between AHI severity categories and percentage of sites with plaque, after adjusting for age. Multivariable logistic regression analysis predicting moderate/severe periodontitis with AHI score, age, and smoking status indicated a significant association with age (P = 0.028) but no significant association with the other two predictors. CONCLUSION: OSA was not significantly associated with the prevalence of moderate/severe periodontitis and the periodontal parameters examined, except percentage plaque. PMID- 25299383 TI - Symptomatic Dengue infection during pregnancy and infant outcomes: a retrospective cohort study. AB - BACKGROUND: Dengue is a mosquito-borne disease that is common in many tropical and subtropical areas. Dengue infections can occur at any age and time in the lifespan, including during pregnancy. Few large scale studies have been conducted to determine the risk of preterm birth (PTB) and low birthweight (LBW) for infants born to women who had symptomatic dengue infection during pregnancy. METHODOLOGY/PRINCIPAL FINDINGS: This study is a retrospective cohort study using medical records from 1992-2010 from pregnant women who attended a public regional referral hospital in western French Guiana. Exposed pregnancies were those with laboratory confirmed cases of dengue fever during pregnancy. Each of the 86 exposed infants was matched to the three unexposed births that immediately followed them to form a stratum. Conditional logistic regression was used to analyze these matched strata. Three groups were examined: all infants regardless of gestational age, only infants> = 17 weeks of gestational age and their strata, and only infants> = 22 weeks of age and their strata. Odds ratios were adjusted (aOR) for maternal age, maternal ethnicity, maternal gravidity, interpregnancy interval and maternal anemia. There was an increased risk of PTB among women with symptomatic dengue; (aOR all infants: 3.34 (1.13, 9.89), aOR 17 weeks: 1.89 (0.61, 5.87), aOR 22 weeks: 1.41 (0.39, 5.20)) but this risk was only statistically significant when all infants were examined (p value = 0.03). Adjusted results for LBW were similar, with an increased risk in the exposed group (aOR All infants: 2.23 (1.01, 4.90), aOR 17 weeks: 1.67 (0.71, 3.93), aOR 22 weeks: 1.43 (0.56, 3.70)) which was only statistically significant when all infants were examined (p value = 0.05). CONCLUSIONS/SIGNIFICANCE: Symptomatic dengue infection during pregnancy may increase the risk of PTB and LBW for infants. More research is needed to confirm these results and to examine the role of dengue fever in miscarriage. PMID- 25299386 TI - Oral neutrophil levels: a screening test for oral inflammatory load in pregnancy in a medical setting. AB - BACKGROUND: A multitude of studies suggest an association between periodontal disease and adverse birth outcomes, but the findings have been equivocal. Although the evidence is controversial, it is biologically plausible, and the key link may be inflammation. Because periodontitis is at times either active or inactive, trying to correlate the presence of pockets, for example, to adverse outcome of pregnancy might be preordained to failure or at least confusion. Alternatively, if inflammatory activity associated with periodontitis could be measured, it might be possible to correlate oral inflammatory load (OIL) to adverse pregnancy outcomes more precisely, but given the low incidence of adverse pregnancy outcomes, large populations must be studied. This underscores the need to use a means for assessment of OIL that is reliable, reproducible, and so simple to perform that it does not require dental expertise and can be used for large numbers of patients attending obstetrics units. The objective of this study was to demonstrate that OIL can be measured in a cohort of pregnant females presenting for obstetric care and secondarily to ensure that there was a realistic correlation to the presence of periodontitis. METHODS: Sixty-three pregnant females were recruited, and 15-second saline rinses were collected to measure OIL as represented by counts of oral neutrophil levels. Periodontal examinations were performed to determine the extent of the correlation between the presence of clinical markers of periodontitis, such as pockets and clinical attachment loss to the OIL. RESULTS: Using this small cohort of patients, a test for oral inflammatory disease could be administered successfully in a non-dental setting. In addition, there was a statistically significant increase (two-fold, P < 0.05) in oral neutrophil counts found in patients with periodontitis compared with those without periodontitis. CONCLUSION: The rinse assay can be used as a screening tool for oral inflammation, which was also related to the presence of periodontitis, in pregnant females attending a medical clinic. PMID- 25299387 TI - F-spondin inhibits differentiation of clastic precursors via lipoprotein receptor related protein 8 (LRP8). AB - BACKGROUND: F-spondin, known to be a secreted neuronal glycoprotein, is highly expressed on the tooth root surface. The authors previously reported that F spondin is one of the specific markers of cementoblasts in periodontal tissue. In chronic periodontitis, significant cemental resorption rarely occurs on the root side, although alveolar bone resorption by osteoclasts is one of the major pathologic changes. Thus, it was hypothesized that secretory F-spondin from cementoblasts might be involved in differentiation of clastic cells on the root surface. The authors studied effects of secretory F-spondin from F-spondin expressing cells and its pathway on receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated differentiation of clastic cells. METHODS: Osteoclast precursors were used in this study. With a chamber assay, the authors examined effects of secretory molecules from F-spondin-expressing cells of transgenic mice on RANKL-induced clastic cell differentiation. RESULTS: Secretory molecules from F-spondin-overexpressing cells significantly inhibited the RANKL-mediated tartrate-resistant acid phosphatase (TRAP)-positive cells from primary progenitor cells with the chamber system. F-spondin suppressed RANKL-mediated nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1); TRAP; cathepsin K; and dendritic cell-specific transmembrane protein (DC-STAMP) expression in the cells. The suppressive effect of F-spondin on RANKL-induced differentiation of clastic cells was partially blocked by knockdown of low-density lipoprotein receptor-related protein 8 (LRP8). CONCLUSIONS: These findings indicate that secretory factors from F-spondin-expressing cells, including F-spondin, downregulate differentiation of clastic precursors. Moreover, F-spondin inhibits RANKL mediated differentiation of clastic cells partially via LRP8. It is suggested that secretory F-spondin may act protectively from cemental resorption partially via LRP8 in periodontal tissue. PMID- 25299388 TI - Impact of cigarette smoking on clinical outcomes of periodontal flap surgical procedures: a systematic review and meta-analysis. AB - BACKGROUND: Periodontal flap surgery is frequently used to remove subgingival deposits, yielding consequential reductions in gingival inflammation and probing depth (PD) with a gain in clinical attachment level (CAL) to treat advanced periodontal disease. However, clinical studies have reported diminished periodontal healing in smokers compared with non-smokers. The aim of the present systematic review and meta-analysis was to assess the impact of cigarette smoking on clinical outcomes following periodontal flap surgical procedures. METHODS: A systematic electronic review of articles relevant to periodontal flap surgical procedures in smokers was conducted from 1977 to March 2014 inclusive, using predefined, optimized search strategies. Meta-analyses were done separately for changes in the two primary outcomes of PD and CAL. RESULTS: The initial search yielded 390 titles and abstracts. After screening, eight controlled clinical studies were finally selected. Three studies were assessed as having a low risk of bias, two as having moderate risk of bias, and three as having a high risk of bias. Qualitative assessment of the articles consistently showed an improved treatment effect among non-smokers versus smokers. The reduction in PD in smokers and non-smokers ranged from 0.76 to 2.05 mm and 1.27 to 2.40 mm, respectively. For CAL, the gain in non-smokers versus smokers ranged from 0.29 to 1.6 mm and 0.09 to 1.2 mm, respectively. Meta-analysis on eight studies reporting on 363 study participants demonstrated an increased reduction in mean (95% confidence interval) PD of 0.39 (0.33 to 0.45) mm. Similar results were found for mean gain in CAL (0.35 [0.30 to 0.40] mm, n = 4 studies). CONCLUSIONS: Considering the relatively homogenous information available, the authors conclude that active smokers could be candidates for periodontal flap surgical procedures. However, the magnitude of the therapeutic effect is compromised in smokers compared with non-smokers. Therefore, cigarette smokers should be: 1) encouraged to abstain from smoking; and 2) thoroughly informed preoperatively of substantial reduction in clinical outcomes compared with non-smokers. PMID- 25299389 TI - Quantitative assessment of the associations between interleukin-8 polymorphisms and periodontitis susceptibility. AB - BACKGROUND: This review assesses the associations of interleukin-8 gene (IL-8) 251A/T (rs4073) and -845T/C (rs2227532) polymorphisms with susceptibility to periodontitis. METHODS: Several electronic databases were searched for eligible articles. Twelve studies involving 2,233 cases and 2,655 controls were retrieved and analyzed. Odds ratios (ORs) along with 95% confidence intervals (CIs) were calculated to assess the strength of relationship between the IL-8 polymorphisms and periodontitis risk. RESULTS: No significant association was found for IL-8 251A/T polymorphism with periodontitis in the overall analysis and stratification by periodontitis type and smoking status. Subgroup analysis by ethnicity revealed that -251A/T T allele and TT genotype were associated with decreased risk of periodontitis in a Brazilian mixed population (T allele versus A allele: OR 0.80, 95% CI 0.68 to 0.94, Pheterogeneity = 0.30; TT versus AA: OR 0.65, 95% CI 0.46 to 0.93, Pheterogeneity = 0.39; TT versus AA/AT: OR 0.58, 95% CI 0.35 to 0.98, Pheterogeneity = 0.01). In addition, -251A/T T allele was associated with increased periodontitis risk in Asians. Pooled estimates showed that the -845T/C polymorphism was associated with periodontitis susceptibility in overall analysis and the chronic periodontitis subgroup. In addition, marginal associations were observed between -845T/C polymorphism and periodontitis in a Brazilian mixed population. Moreover, this association was also confirmed to be significant in Brazilian non-smokers. CONCLUSION: This meta-analysis indicated that both IL-8 251A/T and -845T/C polymorphisms may be involved in the development of periodontitis in a Brazilian mixed population, whereas the -251A/T allele T appeared to be a risk factor for periodontitis in Asians. PMID- 25299390 TI - Alveolar bone loss is associated with circulating anti-citrullinated protein antibody (ACPA) in patients with rheumatoid arthritis. AB - BACKGROUND: This study examines: 1) alveolar bone loss (ABL), a hallmark of periodontitis, in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) patients versus control patients with osteoarthritis (OA); and 2) the association of ABL with RA disease activity and ACPA concentrations, including multiple antigen-specific ACPA. METHODS: This multicenter case-control study includes 617 patients diagnosed with RA (n = 287) or OA (n = 330). Panoramic radiographs were taken; patients were categorized into low, moderate, or high tertiles based on mean percentage ABL. Serum ACPA was measured using second-generation anticyclic citrullinated peptide enzyme-linked immunosorbent assay and a multiplex platform to assess distinct antigen-specific ACPA. A generalized linear mixed model for binary data was used to compare stratified ABL in RA versus OA patients. Associations of moderate and high ABL (versus low) with RA disease activity and severity measures were examined using multivariate regression. Antigen-specific ACPA responses were compared among ABL tertiles using significance analysis of microarrays. RESULTS: ACPA-positive patients with RA had a significantly higher mean percentage of sites with ABL >20% compared with patients with OA (P = 0.03). After multivariate adjustment, greater ABL was significantly associated with higher serum ACPA concentration (P = 0.004), 28 joint Disease Activity Score (P = 0.023), health assessment questionnaire disability (P = 0.05), tender joint count (P = 0.02) and joint space narrowing scores (P = 0.05) among patients with RA. ACPAs targeting citrullinated vimentin and histone were significantly higher in moderate and high ABL groups versus low, regardless of smoking status (q <0.1%). CONCLUSIONS: Greater ABL was associated with higher ACPA, consistent with findings at articular sites. ACPA targeting could provide novel insight into important linkages between RA and periodontitis. PMID- 25299391 TI - Assessment of anthelmintic efficacy of mebendazole in school children in six countries where soil-transmitted helminths are endemic. AB - BACKGROUND: Robust reference values for fecal egg count reduction (FECR) rates of the most widely used anthelmintic drugs in preventive chemotherapy (PC) programs for controlling soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm) are still lacking. However, they are urgently needed to ensure detection of reduced efficacies that are predicted to occur due to growing drug pressure. Here, using a standardized methodology, we assessed the FECR rate of a single oral dose of mebendazole (MEB; 500 mg) against STHs in six trials in school children in different locations around the world. Our results are compared with those previously obtained for similarly conducted trials of a single oral dose of albendazole (ALB; 400 mg). METHODOLOGY: The efficacy of MEB, as assessed by FECR, was determined in six trials involving 5,830 school children in Brazil, Cambodia, Cameroon, Ethiopia, United Republic of Tanzania, and Vietnam. The efficacy of MEB was compared to that of ALB as previously assessed in 8,841 school children in India and all the above-mentioned study sites, using identical methodologies. PRINCIPAL FINDINGS: The estimated FECR rate [95% confidence interval] of MEB was highest for A. lumbricoides (97.6% [95.8; 99.5]), followed by hookworm (79.6% [71.0; 88.3]). For T. trichiura, the estimated FECR rate was 63.1% [51.6; 74.6]. Compared to MEB, ALB was significantly more efficacious against hookworm (96.2% [91.1; 100], p<0.001) and only marginally, although significantly, better against A. lumbricoides infections (99.9% [99.0; 100], p = 0.012), but equally efficacious for T. trichiura infections (64.5% [44.4; 84.7], p = 0.906). CONCLUSIONS/SIGNIFICANCE: A minimum FECR rate of 95% for A. lumbricoides, 70% for hookworm, and 50% for T. trichiura is expected in MEB dependent PC programs. Lower FECR results may indicate the development of potential drug resistance. PMID- 25299394 TI - Contact Lens Care among Teenage Students in Italy: A Cross-Sectional Study. AB - AIM: To assess the attitude and practice of contact lens (CL) wearers among teenage school students and to evaluate how much the teenagers adhere to the CL care procedures according to the proper care of CL guidelines. METHODS: A cross sectional descriptive study of Italian teenagers from high schools in Rome who wear CL. We inquired about the different aspects of CL care through a questionnaire. RESULTS: We investigated 3,106 students from high schools in Rome (2% of all Roman high school students), 293 of whom wore CL (9%); 151 (52%) of participants responded, 42 (27.8%) male and 109 (72.8%) female. The mean age was 16.4 +/- 1.6 years. 79.5% of students were daily users. 45.7% wore CL more than nine hours/day. 87.4% wore soft CL. 33.1% wore disposable CL; 7.9% weekly CL, 55% monthly CL. Thirty-four percent wore disposable lenses twice or more. 14.5% of students did not wash their hands before handling CL and 52.3% wore CL after it had fallen in the sink. 39.7% rubbed and cleaned CL before storing it. 10% used expired lens care solutions. Only 31.1% changed CL cases every three months. 38.4% wore CL in a swimming pool. 61.6% were having problems: redness (13.9%), itching (7.9%), and foreign body sensation (29.1%). CONCLUSION: Many students don't properly care for their CL. Education regarding proper care and management of CL among users is advised in view of frequency of symptoms and complications reported. PMID- 25299393 TI - Normalization of the levels of inflammatory molecules in Mycobacterium smegmatis infected U937 cells by fibrate pretreatment. AB - BACKGROUND: Tuberculosis (TB) is a respiratory tract disease caused by Mycobacterium tuberculosis infection. M. tuberculosis exploits immune privilege to grow and divide in pleural macrophages. Fibrates are associated with the immune response and control lipid metabolism through glycolysis with beta oxidation of fatty acids. RESULTS: In this study, we investigated the effect of fibrate pretreatment on the immune response during M. smegmatis infection in U937 cells, a human leukemic monocyte lymphoma cell line. The protein expression of tumor necrosis factor alpha (TNF-alpha), an inflammatory marker, and myeloid differentiation primary response gene 88 (MyD88), a toll like receptor adaptor molecule, in the infected group increased at 1 and 6 h after M. smegmatis infection of U937 cells. Acetyl coenzyme A acetyl transferase-1 (ACAT-1), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), TNF-alpha, and MyD88 decreased in U937 cells treated with fibrates at 12 and 24 h after treatment. More than a 24 h pretreatment with fibrate resulted in similar expression levels of ACAT-1 and PPAR-alpha between infected vehicle control and infected groups which were pretreated with fibrate for 24 h. However, upon exposure to M. smegmatis, the cellular expression of the TNF-alpha and MyD88 in the infected groups pretreated with fibrate for 24 h decreased significantly compared to that in the infected vehicle group. CONCLUSION: These results suggest that fibrate pretreatment normalized the levels of inflammatory molecules in Mycobacterium smegmatis-infected U937 cells. Further studies are needed to confirm the findings on pathophysiology and immune defense mechanism of U937 by fibrates during M. tuberculosis infection. PMID- 25299395 TI - A deeper understanding of the association between CTLA4 +49A/G and acute rejection in renal transplantation: an updated meta-analysis. AB - To reevaluate the association between the costimulatory molecule cytotoxic T lymphocyte-associated antigen4 (CTLA4) single nucleotide polymorphism (SNP) +49A/G and acute rejection (AR) in renal transplantation, nine studies published before June 2013 were analyzed. Meta-analysis and cumulative meta-analysis (metacum) were performed for each genotype in a random/fixed effect model. The combined odds ratios (OR) with 95% confidence intervals (CI) were calculated to estimate the strength of the association. In the sensitivity analysis, a single study involved in the meta-analysis was deleted each time to investigate the influence of the individual data sets on the pooled ORs. Meta-analysis regression was used for some influence factors, such as year of publication, total number in each group (AR group and control group), ethnicity, the ratio of GG to GA + AA, the ratio of G to A in CTLA4 +49A/G. Overall, a significant correlation was noted between the CTLA4 SNP (+49A/G) and the risk of AR (for GG vs. AG + AA: OR = 1.35, 95% CI = 1.05-1.73, p = 0.02; for G vs. A: OR = 1.21, 95% CI = 1.03-1.42, p = 0.02), especially in the Asian subgroup (for GG vs. AG + AA: OR = 1.79, 95% CI = 1.15-2.78, p = 0.009; for G vs. A: OR = 1.47, 95% CI = 1.04-2.07, p = 0.03). Of the influence factors, the ratio of GG to GA+AA (p = 0.046) and the ratio of G to A (p = 0.017) were significant factors. In conclusion, our results suggest that CTLA4 +49A/G contribute to the risk of AR following renal transplantation. PMID- 25299396 TI - Risk factor model to predict a missed clinic appointment in an urban, academic, and underserved setting. AB - In the chronic care model, a missed appointment decreases continuity, adversely affects practice efficiency, and can harm quality of care. The aim of this study was to identify predictors of a missed appointment and develop a model to predict an individual's likelihood of missing an appointment. The research team performed a retrospective study in an urban, academic, underserved outpatient internal medicine clinic from January 2008 to June 2011. A missed appointment was defined as either a "no-show" or cancellation within 24 hours of the appointment time. Both patient and visit variables were considered. The patient population was randomly divided into derivation and validation sets (70/30). A logistic model from the derivation set was applied in the validation set. During the period of study, 11,546 patients generated 163,554 encounters; 45% of appointments in the derivation sample were missed. In the logistic model, percent previously missed appointments, wait time from booking to appointment, season, day of the week, provider type, and patient age, sex, and language proficiency were all associated with a missed appointment. The strongest predictors were percentage of previously missed appointments and wait time. Older age and non-English proficiency both decreased the likelihood of missing an appointment. In the validation set, the model had a c-statistic of 0.71, and showed no gross lack of fit (P=0.63), indicating acceptable calibration. A simple risk factor model can assist in predicting the likelihood that an individual patient will miss an appointment. PMID- 25299392 TI - Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. AB - As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging. PMID- 25299398 TI - Four years follow-up of epicardial left ventricular pacing by mini-thoracotomy for cardiac resynchronisation therapy in congestive heart failure (four cases). AB - BACKGROUND AND AIM: To establish whether left ventricular (LV) pacing by mini thoracotomy is a safe and feasible procedure after failed transvenous cardiac resynchronisation therapy (CRT), we described four cases of patients who demonstrated congestive heart failure (CHF), had transvenous LV lead implantation failures, and underwent a mini-left-lateral thoracotomy and implantation of an epicardial LV lead. METHODS: After a mean follow-up 45 +/- 3.5 months, the haemodynamic benefits of CRT were apparent in four patients. RESULTS: Mean LV ejection fraction increased from 28.4 +/- 6.5% to 44.5 +/- 13.7% (p = 0.024), in association with a reduction of LV end-systolic diameters from 62.3 +/- 10.3 mm to 53.0 +/- 13.11 mm (p = 0.029). QRS width decreased from 162.5 +/- 23.6 ms to 147.5 +/- 18.9 ms (p = 0.014). New York Heart Association values significantly improved before and after the procedure. CONCLUSIONS: These results suggest that epicardial LV pacing by mini-thoracotomy for CRT in CHF is feasible and can bring satisfactory long-term results. PMID- 25299397 TI - Does shape discrimination by the mouth activate the parietal and occipital lobes? - near-infrared spectroscopy study. AB - A cross-modal association between somatosensory tactile sensation and parietal and occipital activities during Braille reading was initially discovered in tests with blind subjects, with sighted and blindfolded healthy subjects used as controls. However, the neural background of oral stereognosis remains unclear. In the present study, we investigated whether the parietal and occipital cortices are activated during shape discrimination by the mouth using functional near infrared spectroscopy (fNIRS). Following presentation of the test piece shape, a sham discrimination trial without the test pieces induced posterior parietal lobe (BA7), extrastriate cortex (BA18, BA19), and striate cortex (BA17) activation as compared with the rest session, while shape discrimination of the test pieces markedly activated those areas as compared with the rest session. Furthermore, shape discrimination of the test pieces specifically activated the posterior parietal cortex (precuneus/BA7), extrastriate cortex (BA18, 19), and striate cortex (BA17), as compared with sham sessions without a test piece. We concluded that oral tactile sensation is recognized through tactile/visual cross-modal substrates in the parietal and occipital cortices during shape discrimination by the mouth. PMID- 25299399 TI - Aortic elastic properties predict occult coronary artery disease: a multidetector row computed tomography study. AB - BACKGROUND: Multidetector row computed tomography (MDCT) is an attractive noninvasive imaging modality to detect coronary atherosclerotic plaques which may be underestimated by conventional angiography. However, its routine clinical use is limited due to contrast-associated problems, high cost, inapplicability at bedside and exposure to radiation. Thus, exploring safer and more practical measurements to predict occult coronary artery disease (CAD) is required. AIM: To demonstrate the predictive value of aortic elastic properties for occult CAD diagnosed by MDCT. METHODS: Forty subjects with angiographically normal coronary arteries were consecutively included in our study. They underwent MDCT including indications and were divided into a no CAD group (23 subjects, 11 males, 46 +/- 8 years) and an occult CAD group (17 subjects, 12 males, 48 +/- 10 years), with respect to the presence of coronary plaque. As a control group, 19 consecutive patients with angiographically proven CAD (16 males, 52 +/- 6 years) were included. Aortic stiffness index (ASI), aortic distensibility and aortic strain were calculated from the aortic diameters measured by echocardiography and blood pressure obtained by sphygmomanometry. RESULTS: It was found that ASI, aortic distensibility and aortic strain were significantly different in the occult CAD group compared to the no CAD group (p = 0.008, p = 0.01, p = 0.03, respectively) and to the evident CAD group (p = 0.01, p = 0.02, p = 0.02). They also differed significantly between the no CAD and the evident CAD groups. Receiver operating characteristics analysis for ASI, to distinguish between the occult CAD group and the no CAD group, revealed an area under the curve of 0.80 (confidence interval 0.68-0.94, p = 0.004) and that the cut-off value of 3.42 could significantly predict patients with occult CAD (sensitivity: 78%; specificity: 63%). CONCLUSIONS: Measurement of ASI is an easily applicable and safe method with its non-radiographic ability for the assessment of aortic stiffness, and it may be useful to predict subclinical atherosclerosis in clinical practice. A cut-off value of 3.42 for ASI may guide to refer individuals to preventive strategies to reduce atherosclerosis progression. PMID- 25299400 TI - Myocardial dysfunction measured by tissue Doppler echocardiography in children with primary arterial hypertension. AB - BACKGROUND AND AIM: To evaluate myocardial function with the use of tissue Doppler echocardiography in children with primary hypertension. METHODS: A total of 64 subjects (34 with hypertension, 30 control) underwent echocardiographic evaluation of systolic and diastolic function with the use of standard and tissue Doppler echocardiography parameters. RESULTS: The left ventricular myocardial performance index was higher in children with hypertension (0.46 +/- 0.08 vs. 0.35 +/- 0.03; p < 0.01). The value of the A wave was higher in the hypertensive children group (0.59 +/- 0.12 m/s vs. 0.49 +/- 0.09 m/s; p < 0.01), while the E/A ratio was significantly lower in this group (1.58 +/- 0.31 vs. 1.77 +/- 0.28; p < 0.01). The values of isovolumetric relaxation time and deceleration time were significantly higher in patients with blood pressure elevation. The velocity of mitral flow propagation was lower (0.61 +/- 0.08 m/s vs. 0.72 +/- 0.10 m/s; p < 0.01) and E/Vp ratio was higher (1.50 +/- 0.27 vs. 1.21 +/- 0.23; p < 0.01) in hypertensive children. Evaluation of the left ventricle function with the use of tissue Doppler echocardiography showed significantly worse values of S' and E' septal, and S' and E' lateral in hypertensive children. The value of septal E'/A' ratio was lower in children with hypertension (1.52 +/- 0.24 vs. 1.69 +/- 0.25; p < 0.01), while the value of this index for lateral wall was similar. The values of E/E' septal and E/E' lateral were higher in patients with hypertension. CONCLUSIONS: In children with primary arterial hypertension, with the use of tissue Doppler echocardiography there are significantly lower values of diastolic and systolic parameters observed, which may be a sign of myocardial function deterioration. PMID- 25299401 TI - The effects of carvedilol and nebivolol on oxidative stress status in patients with non-ischaemic heart failure. AB - BACKGROUND: Carvedilol and nebivolol have favourable properties such as anti oxidative effects in addition to other beta-blockers. However, which of these drugs is more effective on oxidative stress is unclear. AIM: To compare the effects carvedilol and nebivolol on oxidative stress status in non-ischaemic heart failure (HF) patients. METHODS: We included 56 symptomatic non-ischaemic HF patients with ejection fraction <= 40%. The patients were randomised to carvedilol (n = 29, 18 male) or nebivolol (n = 27, 18 male) groups. They were evaluated clinically and echocardiographically after target dose. We evaluated parameters associated with oxidative stress, such as alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), uric acid, total antioxidant capacity (TAC), total oxidative status (TOS), and oxidative stress index (OSI). RESULTS: TAC, TOS, GGT, and ALP levels and OSI were comparable in both groups. Uric acid levels were lower in the carvedilol group compared with the nebivolol group (5.8 +/- 1.6 vs. 7.0 +/- 1.7 mg/dL, p = 0.01). In correlation analysis, uric acid (p < 0.001, r = 0.50) and TOS level (p < 0.001, r = 0.73) were positively correlated with OSI. CONCLUSIONS: Carvedilol and nebivolol have similar effects on oxidative stress status in patients with non-ischaemic HF. PMID- 25299402 TI - The new generation is coming. Percutaneous implantation of the fully repositionable Lotus(r) aortic valve prosthesis: the first Polish experience. AB - Transcatheter aortic valve implantation (TAVI) is nowadays an accepted method of treatment for patients with symptomatic severe aortic stenosis who are inoperable or at very high risk of classic surgical aortic valve replacement. The Lotus valve system is a new generation TAVI device composed of a self-expanding stent prosthesis with implemented bovine pericardial leaflets, which is designed to facilitate repositioning, resheathing, and retrieval, even in the fully expanded and functioning position before the final release. In addition, the Lotus valve is surrounded by a flexible membrane to seal paravalvular gaps between the prosthesis and native valve. We present the first Polish experiences with the Lotus valve system. Due to its unique features, the Lotus valve may improve the prognosis in patients with inoperable or high risk critical aortic stenosis. PMID- 25299403 TI - Asbestos, asbestosis, and cancer, the Helsinki criteria for diagnosis and attribution 2014: recommendations. PMID- 25299404 TI - mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells. AB - Recent studies have shown that virally encoded mRNA sequences of genome maintenance proteins from herpesviruses contain clusters of unusual structural elements, G-quadruplexes, which modulate viral protein synthesis. Destabilization of these G-quadruplexes can override the inhibitory effect on self-synthesis of these proteins. Here we show that the purine-rich repetitive mRNA sequence of Epstein-Barr virus encoded nuclear antigen 1 (EBNA1) comprising G-quadruplex structures, limits both the presentation of MHC class I-restricted CD8(+) T cell epitopes by CD11c(+) dendritic cells in draining lymph nodes and early priming of antigen-specific CD8(+) T-cells. Destabilization of the G-quadruplex structures through codon-modification significantly enhanced in vivo antigen presentation and activation of virus-specific T cells. Ex vivo imaging of draining lymph nodes by confocal microscopy revealed enhanced antigen-specific T-cell trafficking and APC-CD8(+) T-cell interactions in mice primed with viral vectors encoding a codon modified EBNA1 protein. More importantly, these antigen-specific T cells displayed enhanced expression of the T-box transcription factor and superior polyfunctionality consistent with the qualitative impact of translation efficiency. These results provide an important insight into how viruses exploit mRNA structure to down regulate synthesis of their viral maintenance proteins and delay priming of antigen-specific T cells, thereby establishing a successful latent infection in vivo. Furthermore, targeting EBNA1 mRNA rather than protein by small molecules or antisense oligonucleotides will enhance EBNA1 synthesis and the early priming of effector T cells, to establish a more rapid immune response and prevent persistent infection. PMID- 25299407 TI - Computing power revolution and new algorithms: GP-GPUs, clouds and more: general discussion. PMID- 25299405 TI - Reciprocal regulation of epileptiform neuronal oscillations and electrical synapses in the rat hippocampus. AB - Gap junction (GJ) channels have been recognized as an important mechanism for synchronizing neuronal networks. Herein, we investigated the participation of GJ channels in the pilocarpine-induced status epilepticus (SE) by analyzing electrophysiological activity following the blockade of connexins (Cx)-mediated communication. In addition, we examined the regulation of gene expression, protein levels, phosphorylation profile and distribution of neuronal Cx36, Cx45 and glial Cx43 in the rat hippocampus during the acute and latent periods. Electrophysiological recordings revealed that the GJ blockade anticipates the occurrence of low voltage oscillations and promotes a marked reduction of power in all analyzed frequencies.Cx36 gene expression and protein levels remained stable in acute and latent periods, whereas upregulation of Cx45 gene expression and protein redistribution were detected in the latent period. We also observed upregulation of Cx43 mRNA levels followed by changes in the phosphorylation profile and protein accumulation. Taken together, our results indisputably revealed that GJ communication participates in the epileptiform activity induced by pilocarpine. Moreover, considering that specific Cxs undergo alterations through acute and latent periods, this study indicates that the control of GJ communication may represent a focus in reliable anti-epileptogenic strategies. PMID- 25299408 TI - Effects of filtration modes on membrane fouling behavior and treatment in submerged membrane bioreactor. AB - Relaxation or backwashing is obligatory for effective operation of membrane module and intermittent aeration is helpful for nutrients removal. This study was performed to investigate effects of different filtration modes on membrane fouling behavior and treatment in membrane bioreactor (MBR) operated at three modes i.e., 12, 10 and 8min filtration and 3, 2, and 2min relaxation corresponding to 6, 5 and 4cycles/hour, respectively. Various parameters including trans-membrane pressure, specific cake resistance, specific oxygen uptake rate, nutrients removal and sludge dewaterability were examined to optimize the filtration mode. TMP profiles showed that MBR(8+2) with 8min filtration and 2min relaxation reduced the fouling rate and depicted long filtration time in MBR treating synthetic wastewater. MBR(12+3) was more efficient in organic and nutrients removal while denitrification rate was high in MBR(8+2). PMID- 25299406 TI - Suramin inhibits Hsp104 ATPase and disaggregase activity. AB - Hsp104 is a hexameric AAA+ protein that utilizes energy from ATP hydrolysis to dissolve disordered protein aggregates as well as amyloid fibers. Interestingly, Hsp104 orthologues are found in all kingdoms of life except animals. Thus, Hsp104 could represent an interesting drug target. Specific inhibition of Hsp104 activity might antagonize non-metazoan parasites that depend on a potent heat shock response, while producing little or no side effects to the host. However, no small molecule inhibitors of Hsp104 are known except guanidinium chloride. Here, we screen over 16,000 small molecules and identify 16 novel inhibitors of Hsp104 ATPase activity. Excluding compounds that inhibited Hsp104 activity by non specific colloidal effects, we defined Suramin as an inhibitor of Hsp104 ATPase activity. Suramin is a polysulphonated naphthylurea and is used as an antiprotozoal drug for African Trypanosomiasis. Suramin also interfered with Hsp104 disaggregase, unfoldase, and translocase activities, and the inhibitory effect of Suramin was not rescued by Hsp70 and Hsp40. Suramin does not disrupt Hsp104 hexamers and does not effectively inhibit ClpB, the E. coli homolog of Hsp104, establishing yet another key difference between Hsp104 and ClpB behavior. Intriguingly, a potentiated Hsp104 variant, Hsp104A503V, is more sensitive to Suramin than wild-type Hsp104. By contrast, Hsp104 variants bearing inactivating sensor-1 mutations in nucleotide-binding domain (NBD) 1 or 2 are more resistant to Suramin. Thus, Suramin depends upon ATPase events at both NBDs to exert its maximal effect. Suramin could develop into an important mechanistic probe to study Hsp104 structure and function. PMID- 25299409 TI - Spatial epidemiology of the syphilis epidemic in Toronto, Canada. AB - BACKGROUND: Urban centers across Canada and the United States have battled syphilis epidemics with high rates of human immunodeficiency virus (HIV) coinfection for over a decade. We examined the spatial epidemiology of syphilis over time for Toronto (Canada) with the intention of forming new insights and strategies for restoring low syphilis rates. METHODS: Syphilis incidence rates, HIV-syphilis coinfection, and sexual risk behavior prevalences were estimated and mapped from primary, secondary, early latent syphilis cases reported to Toronto Public Health between January 1, 2006, and December 31, 2010, using ArcGIS 9.0. Geographic clusters of significantly elevated syphilis incidence rates were identified using SaTScan 9.0. The relationship between syphilis incidence rates and sociocultural factors was modeled using the Besag, York, and Mollie model. RESULTS: Between 2006 and 2010, syphilis incidence rates were high in Toronto's downtown core area, intensified, and spread outward initiating 3 independent outbreak areas. HIV coinfection was high (47%); however, no spatial clustering was identified. Syphilis incidence rates, HIV coinfection, and behavioral risk factors promoting sexually transmitted infection transmission were high outside the core area, suggesting that peripheral sexual networks may be influencing high syphilis infection rates both inside and outside the core. CONCLUSIONS: Toronto's syphilis epidemic is mature. Response, resources, and intervention activities should target core and noncore areas. PMID- 25299410 TI - Neighborhoods at risk: estimating risk of higher Neisseria gonorrhoeae incidence among women at the census tract level. AB - BACKGROUND: The association between area-based social factors and sexually transmitted diseases has been demonstrated in numerous studies. Such associations have not previously been explored for their potential to quantify likelihood of higher transmission of gonorrhea in small geographic areas. METHODS: Aggregate census tract-level sociodemographic factors in 4 domains (demographics, educational attainment, household income, and housing characteristics) were merged with female gonorrhea incidence data from 113 counties in 10 US states. Multivariate models were constructed, and a tract-level composite gonorrhea risk index was calculated. This composite risk index was validated against gonorrhea incidence among women from 2 independent states. RESULTS: Seven tract-level factors were found to be most strongly correlated with female gonorrhea incidence: educational attainment, proportion of female headed households, annual household income below US $20,000, proportion of population non-Hispanic black, proportion of housing units currently vacant, proportion of population reporting moving in last year, and proportion of households that are nonfamily units. Composite index was highly correlated with female gonorrhea in the study area and validated with independent data. CONCLUSIONS: Social factors predict gonorrhea incidence at the census tract level and identify small areas at risk for higher morbidity. These data may be used by health departments and health care practices to develop geographically based disease prevention and control efforts. This is especially useful because gonorrhea incidence data are not routinely available below the county level in many states. PMID- 25299411 TI - The estimated impact of human papillomavirus vaccine coverage on the lifetime cervical cancer burden among girls currently aged 12 years and younger in the United States. AB - Using a previously published dynamic model, we illustrate the potential benefits of human papillomavirus vaccination among girls currently 12 years or younger in the United States. Increasing vaccine coverage of young girls to 80% would avert 53,300 lifetime cervical cancer cases versus 30% coverage and 28,800 cases versus 50% coverage. PMID- 25299412 TI - The estimated lifetime probability of acquiring human papillomavirus in the United States. AB - BACKGROUND: Estimates of the lifetime probability of acquiring human papillomavirus (HPV) can help to quantify HPV incidence, illustrate how common HPV infection is, and highlight the importance of HPV vaccination. METHODS: We developed a simple model, based primarily on the distribution of lifetime numbers of sex partners across the population and the per-partnership probability of acquiring HPV, to estimate the lifetime probability of acquiring HPV in the United States in the time frame before HPV vaccine availability. RESULTS: We estimated the average lifetime probability of acquiring HPV among those with at least 1 opposite sex partner to be 84.6% (range, 53.6%-95.0%) for women and 91.3% (range, 69.5%-97.7%) for men. Under base case assumptions, more than 80% of women and men acquire HPV by age 45 years. CONCLUSIONS: Our results are consistent with estimates in the existing literature suggesting a high lifetime probability of HPV acquisition and are supported by cohort studies showing high cumulative HPV incidence over a relatively short period, such as 3 to 5 years. PMID- 25299413 TI - Estimating chlamydia screening coverage: a comparison of self-report and health care effectiveness data and information set measures. AB - BACKGROUND: Population-based surveys (self-report) and health insurance administrative data (Healthcare Effectiveness Data and Information Set [HEDIS]) are used to estimate chlamydia screening coverage in the United States. Estimates from these methods differ, but few studies have compared these 2 indices in the same population. METHODS: In 2010, we surveyed a random sample of women aged 18 to 25 years enrolled in a Washington State-managed care organization. Respondents were asked if they were sexually active in last year and if they tested for chlamydia in that time. We linked survey responses to administrative records of chlamydia testing and reproductive/testing services used, which comprise the HEDIS definition of the screened population and the sexually active population, respectively. We compared self-report and HEDIS using 3 outcomes: (1) sexual activity (gold standard = self-report), (2) any chlamydia screening (no gold standard), and (3) within-plan chlamydia screening (gold standard = HEDIS). RESULTS: Of 954 eligible respondents, 377 (40%) completed the survey and consented to administrative record linkage. Chlamydia screening estimates for HEDIS and self-report were 47% and 53%, respectively. The sensitivity and specificity of HEDIS to define sexually active women were 84.8% (95% confidence interval [CI], 79.6%-89.1%) and 63.5% (95% CI, 52.4%-73.7%), respectively. Forty percent of women had a chlamydia test in their administrative record, but 53% self-reported being tested for chlamydia (kappa = 0.35); 19% reported out-of-plan chlamydia testing. The sensitivity of self-reported within-plan chlamydia testing was 71.3% (95% CI, 61.0%-80.1%); the specificity was 80.6% (95% CI, 72.6%-87.2%). CONCLUSIONS: The Healthcare Effectiveness Data and Information Set does not accurately identify sexually active women and may underestimate chlamydia testing coverage. Self-reported testing may not be an accurate measure of true chlamydial testing coverage. PMID- 25299414 TI - For partner services, do we need "face-time," or FaceTime?: Trends in relative proportion of in-person notifications and HIV testing after introduction of a telephone option for HIV exposure notification by public health. AB - Public health usually notifies partners of STD exposure in-person despite availability of other options. We examined trends in in-person versus telephone notification for HIV 3 years after the introduction of a telephone option. Most notifications were made by telephone. Partners notified doubled; however, the proportion HIV testing declined slightly. PMID- 25299416 TI - Vitros 5600 Syphilis TPA assay: evaluation of an automated chemiluminescence assay for detection of Treponema pallidum antibodies in a high prevalence setting. AB - The performance of the Syphilis TPA assay (Ortho-Clinical Diagnostics) on Vitros 5600 Integrated System was evaluated and demonstrated excellent results. Our data support the use of this assay for test confirmation in the traditional algorithm and for screening for syphilis in a routine automated laboratory setting when using the reverse algorithm. PMID- 25299415 TI - Y chromosome and HIV DNA detection in vaginal swabs as biomarkers of semen and HIV exposure in women. AB - BACKGROUND: The inability to quantify sexual exposure to HIV limits the power of HIV prevention trials of vaccines, microbicides, and preexposure prophylaxis in women. We investigated the detection of HIV-1 and Y chromosomal (Yc) DNA in vaginal swabs from 83 participants in the HPTN 035 microbicide trial as biomarkers of HIV exposure and unprotected sexual activity. METHODS: One hundred forty-three vaginal swabs from 85 women were evaluated for the presence of Yc DNA (Quantifiler Duo DNA quantification kit; Applied Biosystems) and total HIV-1 DNA (single-copy in-house quantitative polymerase chain reaction assay). Y DNA detection was paired with self-reported behavioral data with regard to recent coitus (<=1 week before collection) and condom usage (100% vs. <100% compliance). RESULTS: Yc DNA was detected in 62 (43%) of 143 swabs. For the 126 visits at which both behavioral data and swabs were collected, Yc DNA was significantly more frequent in women reporting less than 100% condom usage (odds ratio, 10.69; 95% confidence interval, 2.27-50.32; P = 0.003). Notably, 27 (33%) of 83 swabs from women reporting 100% condom usage were positive for Yc DNA. HIV DNA was only detected in swabs collected postseroconversion. CONCLUSIONS: The use of Yc DNA in HIV prevention trials could reliably identify subgroups of women who have unprotected sexual activity and could provide valuable exposure-based estimates of efficacy. PMID- 25299417 TI - Understanding sexually transmitted infection screening and management in Indiana community health centers. AB - BACKGROUND: The role of community health centers (CHCs) in preventive health care is central to health reform, yet little is known about how CHCs identify and manage sexually transmitted infections (STIs). METHODS: A survey of Indiana CHCs from April to May 2013 measured reported STI services, clinic expectations for STI testing and management, barriers to screening and management, and partner services. Reported practices were compared with current Centers for Disease Control and Prevention (CDC) guidelines for STI testing in clinical settings. RESULTS: Although most CHCs reported screening for syphilis (75.0%), chlamydia, and gonorrhea (85.7%), screening generally did not reflect CDC guidelines. Chlamydia and gonorrhea testing was provided primarily at patient request or when symptomatic by 67.9% of CHCs. Syphilis testing at 67.9% of CHCs reflected CDC guidelines for adults 65 years or younger and at 53.6% for first-trimester pregnant women. Chlamydia and gonorrhea screening reflected CDC guidelines for 17.9% of CHCs for gay/bisexual men and 60.9% for first-trimester pregnant women. One-third (35%) of CHCs reported not knowing the expectation for screening pregnant women and gay/bisexual men. CONCLUSIONS: It is likely that CHCs are not aware of patient sexual health risks because standard of care screening was observed only for gonorrhea and chlamydia during the first trimester and for syphilis testing when symptoms were present. As CHCs increase their role in preventive care with the implementation of the Affordable Care Act, focus must be upon clinician awareness of patient sexual health and training to identify and manage STIs in their patient populations. PMID- 25299418 TI - Predictors of index patient acceptance of expedited partner therapy for Chlamydia trachomatis infection and reasons for refusal, sexually transmitted disease clinics, New York City, 2011 to 2012. AB - BACKGROUND: Expedited partner therapy (EPT) for Chlamydia trachomatis (Ct) reduces repeat Ct infection and was legalized in New York State in 2009. It is a practice in which a Ct-infected index patient delivers medication or a prescription directly to sex partner(s), without those partners receiving medical evaluation. There have been few evaluations of EPT implementation assessing acceptance and uptake among index patients. We measured EPT acceptance among index patients, identified predictors of accepting EPT, and described reasons for declining EPT. METHODS: We conducted a retrospective analysis using electronic medical records from patients attending New York City Department of Health and Mental Hygiene STD clinics from July 2011 to October 2012. A multivariable model examined the associations between accepting EPT and patient and clinic-level characteristics. RESULTS: Overall, 54.8% (1076/1964) of index patients accepted EPT when offered (55.9% of males and 54.4% of females [P = 0.55]). Predictors of EPT acceptance included having a male provider offer EPT (adjusted odds ratio, 1.43; 95% confidence interval, 1.12-1.83). Index patients who had a partner present at the clinic during the treatment visit were less likely to accept EPT (adjusted odds ratio, 0.28; 95% confidence interval, 0.20-0.40). Among 888 patients who refused EPT, common reasons were as follows: "partner in clinic today for treatment" (26.3% [234/888]), "no longer with partner" (25.0% [222/888]), "partner already treated" (20.3% [180/888]), and "prefer medication be delivered by clinician" (19.6% [174/888]). Expedited partner therapy acceptance did not differ by patient age, sex, or race. Excluding persons whose partners were already treated and persons whose partners were in the clinic for treatment, EPT acceptance rates were 69.4%. CONCLUSIONS: Expedited partner therapy acceptance rates were high among index patients whose partners were not otherwise treated. PMID- 25299419 TI - Expedited partner therapy for sexually transmitted diseases--are we there yet? PMID- 25299420 TI - Ultraselective electrochemiluminescence biosensor based on locked nucleic acid modified toehold-mediated strand displacement reaction and junction-probe. AB - Locked nucleic acid (LNA) is applied in toehold-mediated strand displacement reaction (TMSDR) to develop a junction-probe electrochemiluminescence (ECL) biosensor for single-nucleotide polymorphism (SNP) detection in the BRCA1 gene related to breast cancer. More than 65-fold signal difference can be observed with perfectly matched target sequence to single-base mismatched sequence under the same conditions, indicating good selectivity of the ECL biosensor. PMID- 25299422 TI - A visible-light-promoted aerobic metal-free C-3 thiocyanation of indoles. AB - A simple and efficient visible-light-promoted method for the C-3 thiocyanation of indoles has been developed. The transformation uses Rose Bengal as the photocatalyst and air as the terminal oxidant. The reaction is mild, high yielding, and environmentally benign. PMID- 25299423 TI - Long-term use of autologous serum 50% eye drops for the treatment of dry eye disease. AB - PURPOSE: The aim of this study was to describe the outcomes of 50% autologous serum (AS) eye drops after long-term use in a large cohort of patients with dry eyes. METHODS: A retrospective cohort study was conducted on all patients treated with 50% AS eye drops at our institution between June 2008 and January 2013. Records were reviewed for clinical history, systemic risk factors, dry eye etiology, patients' symptoms, and adverse events. Ocular surface evaluation included Schirmer testing with topical anesthesia, fluorescein staining, and ocular surface disease index. Data were reviewed at initial visit, 1 month, and every 3 to 6 months during treatment with AS. Paired t tests were performed to compare the progression of signs and symptoms of dry eye disease. RESULTS: A total of 123 eyes of 63 patients were evaluated with a mean follow-up of 12 months (range, 3-48 months). Corneal fluorescein staining (mean baseline, 1.77 +/ 1.1) improved at the 3- to <6-month, 6- to <12-month, and final follow-up (mean: 1.2 +/- 1.0, 1.3 +/- 1.0, and 1.1 +/- 1.1; P = 0.003, 0.017, and 0.0003, respectively). Schirmer scores (mean baseline, 6.6 +/- 6.5 mm) improved at the 12 to 24-month follow-up (mean = 10.7 +/- 11.4, P = 0.03), whereas ocular surface disease index scores (mean baseline, 54.1 +/- 22.3) improved at the 3- to <6- and 6- to <12-month follow-up (mean: 49.5 +/- 8.2 and 39.3 +/- 21.4, P = 0.029 and 0.003, respectively). No complications were noted. CONCLUSIONS: Fifty percent AS eye drops seem to be a safe and effective long-term treatment for dry eye disease, especially in patients with severe disease who have exhausted all other conventional forms of treatment. PMID- 25299421 TI - Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin induced inflammation. AB - Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune-brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1beta, IL-6 and other cytokines and brain region-specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches. PMID- 25299424 TI - Extramedullary hematopoiesis of the conjunctiva presenting as active systemic disease in a patient with myelofibrosis. AB - PURPOSE: To report the clinicopathological correlation of extramedullary hematopoiesis (EMH) of the conjunctiva in a patient with a history of myelofibrosis. METHODS: Case report. RESULTS: Elevated pink conjunctival lesions developed bilaterally in a 73-year-old man who had been treated for myelofibrosis for 13 years. EMH was detected in the examination of tissue from the lesion of the inferior fornix of the right eye. CONCLUSIONS: The appearance of conjunctival lesions in a patient with myelofibrosis may indicate underlying pathology of EMH that may necessitate a change in systemic treatment of this condition. PMID- 25299425 TI - Long-term follow-up and complications of stripping descemet membrane without placement of graft in eyes with Fuchs endothelial dystrophy. AB - PURPOSE: The aim of this study was to describe the clinical course in Fuchs dystrophy where the central Descemet membrane was removed and not replaced with donor tissue. METHODS: Three patients with Fuchs endothelial dystrophy had descemetorhexis without endothelial keratoplasty. RESULTS: In each case, endothelial cells repopulated the majority of the descemetorhexis area within about 4 months, but 1 localized area failed to repopulate, which led to persistent focal edema and associated symptoms. In each case, the area that was successfully repopulated with endothelium was smooth, whereas the area that did not repopulate successfully had an irregular surface, which seemed to be caused by localized stromal roughening from the descemetorhexis. In case 2, Descemet membrane endothelial keratoplasty was performed without removing the repopulated endothelial cells, and the graft did not stick despite repeated rebubbling, so it was replaced 3 months later. The regraft adhered after stripping off the repopulated endothelial cells before inserting the new graft. CONCLUSIONS: Despite considerable surgeon experience and care exercised while performing the descemetorhexis, some roughening of the posterior stroma seemed to impede repopulation by host endothelial cells in a localized area and led to chronic corneal inflammation when a graft was not implanted. The prolonged corneal edema and associated symptoms resulted in a less desirable postoperative course compared with the rapid corneal clearing regularly achieved with Descemet membrane endothelial keratoplasty. PMID- 25299426 TI - Are febrile seizures an indication for intermittent benzodiazepine treatment, and if so, in which cases? AB - Febrile seizures occur in ~4% of children. After a first febrile seizure, the risk of recurrence is ~40%, but excellent studies document that febrile seizures do not cause brain damage or deficits in cognition or behaviour. The risk of subsequent epilepsy is 2-4%. Prolonged febrile seizures are of concern because a child may later develop mesial temporal sclerosis and intractable epilepsy in rare cases. Most prolonged febrile seizures represent the first febrile seizure and cannot be anticipated. A first prolonged febrile seizure does not increase the risk of recurrence, but if there is a recurrence, it is more likely to be prolonged. Prevention of recurrent febrile seizures is difficult. Antipyretics are ineffective. Daily AED treatment is not often justified. Intermittent oral diazepam at the time of illness is not very successful and has significant side effects. The most optimistic study found that the number of subjects required to treat in order to prevent one recurrence was 14. Intermittent clobazam has fewer side effects than diazepam and may be somewhat effective. Rescue benzodiazepines given outside health care facilities may be effective in selected patients to prevent prolonged recurrences, although this has not been proven with rectal diazepam which has been more extensively studied than buccal or nasal midazolam. Currently, we suggest that, for children with febrile seizures, candidates for consideration for rescue benzodiazepines are those with a prolonged febrile seizure or poor access to medical care. It is possible that the use of a rescue benzodiazepine may alleviate severe parental anxiety, but this remains to be established. PMID- 25299427 TI - Atomic layer deposition of ruthenium on plasma-treated vertically aligned carbon nanotubes for high-performance ultracapacitors. AB - It is challenging to realize a conformal metal coating by atomic layer deposition (ALD) because of the high surface energy of metals. In this study, ALD of ruthenium (Ru) on vertically aligned carbon nanotubes (CNTs) was carried out. To activate the surface of CNTs that lack surface functional groups essential for ALD, oxygen plasma was applied ex situ before ALD. X-ray photoelectron spectroscopy and Raman spectroscopy confirmed surface activation of CNTs by the plasma pretreatment. Transmission electron microscopy analysis with energy dispersive x-ray spectroscopy composition mapping showed that ALD Ru grew conformally along CNTs walls. ALD Ru/CNTs were electrochemically oxidized to ruthenium oxide (RuOx) that can be a potentially useful candidate for use in the electrodes of ultracapacitors. Electrode performance of RuOx/CNTs was evaluated using cyclic voltammetry and galvanostatic charge-discharge measurements. PMID- 25299428 TI - The anomaly Cu doping effects on LiFeAs superconductors. AB - The Cu substitution effect on the superconductivity of LiFeAs has been studied in comparison with Co/Ni substitution. It is found that the shrinking rate of the lattice parameter c for Cu substitution is much smaller than that of Co/Ni substitution. This is in conjugation with the observation of ARPES that shows almost the same electron and hole Fermi surfaces (FSs) size for undoped and Cu substituted LiFeAs sample, except for a very small hole band sinking below Fermi level with doping. This indicates that there is little doping effect at Fermi surface by Cu substitution, in sharp contrast to the more effective carrier doping effect by Ni or Co. PMID- 25299429 TI - Thermoelectric properties of the quaternary chalcogenides BaCu5.9STe6 and BaCu5.9SeTe6. AB - These quaternary chalcogenides are isostructural, crystallizing in a unique structure type comprising localized Cu clusters and Te(2)(2-) dumbbells. With less than six Cu atoms per formula unit, these materials are p-type narrow-gap semiconductors, according to the balanced formula Ba(2+)(Cu(+))6Q(2-)(Te(2)(2-))3 with Q = S, Se. Encouraged by the outstanding thermoelectric performance of Cu(2 x)Se and the low thermal conductivity of cold-pressed BaCu(5.7)Se(0.6)Te(6.4), we determined the thermoelectric properties of hot-pressed pellets of BaCu(5.9)STe(6) and BaCu(5.9)SeTe(6). Both materials exhibit a high Seebeck coefficient and a low electrical conductivity, combined with very low thermal conductivity below 1 W m(-1) K(-1). Compared to the sulfide-telluride, the selenide-telluride exhibits higher electrical and thermal conductivity and comparable Seebeck coefficient, resulting in superior figure-of-merit values zT, exceeding 0.8 at relatively low temperatures, namely, around 600 K. PMID- 25299430 TI - Preschoolers and the endowment effect. AB - We show that preschoolers exhibit the endowment effect as evidenced by experiments where children generally chose to keep their own toys rather than trading them for similar ones. Furthermore, we relate the emergence of this effect to children's innate psychobiological traits--emotional state, gender, handedness, and digit ratio. The trials were conducted with 141 children across 6 kindergartens. We also found support that children, like adults, exhibit a preference for physical possession as opposed to ownership. As with adults, emotions also seem to matter, as children who were described as quiet and calm were more likely to present the endowment effect. Also of note, right-handed children described as quiet were more likely to exhibit the phenomenon. Furthermore, female children were generally found to be calmer than males, while males tended to be more fearful than females. This result was also previously found in teenagers. PMID- 25299431 TI - Highly sensitive and selective anticancer effect by conjugated HA-cisplatin in non-small cell lung cancer overexpressed with CD44. AB - In spite of severe side effects, chemotherapy is widely used as a major anticancer treatment in non-small cell lung cancer (NSCLC). In order to enhance the therapeutic properties and reduce side effects, enormous efforts have been devoted to direct anticancer agents specifically to tumor tissues by the use of nanoparticles, or cancer cell marker attached drugs. However, cell-specific chemotherapy is still in its infancy and is not applicable to all types of cancers due to the complexity of the cancer occurrence and progress. In this study, we demonstrate that hyaluronan (HA)-conjugated cisplatin has highly selective and sensitive anticancer effects in NSCLC cells that overexpress the trans-membrane receptor, CD44, as HA is a specific ligand for CD44. In proliferation experiments, HA-conjugated cisplatin showed dramatic cell viability decreases (from 100% to 42.31%) in H1299 cells, which overexpress CD44, whereas no such change was observed in A549 and HFL1, which have little to no expression of CD44. More importantly, conjugation with HA decreased the dosage concentration of cisplatin by 50-fold for both cytotoxic and anti-metastatic effects. In addition, HA-cisplatin conjugate treatment selectively decreased migration (from 100% to 7.8%) and invasiveness (from 100% to 21.4%, respectively) of H1299. Based on our experimental results, we strongly believe that HA-cisplatin conjugate is a potential anticancer chemo-agent, which target CD44 overexpression in NSCLC, with minimal side effects and high therapeutic properties. PMID- 25299432 TI - Automated analysis of spine dynamics on live CA1 pyramidal cells. AB - Dendritic spines may be tiny in volume, but are of major importance for neuroscience. They are the main receivers for excitatory synaptic connections, and their constant changes in number and in shape reflect the dynamic connectivity of the brain. Two-photon microscopy allows following the fate of individual spines in brain slice preparations and in live animals. The diffraction-limited and non-isotropic resolution of this technique, however, makes detection of such tiny structures rather challenging, especially along the optical axis (z-direction). Here we present a novel spine detection algorithm based on a statistical dendrite intensity model and a corresponding spine probability model. To quantify the fidelity of spine detection, we generated correlative datasets: Following two-photon imaging of live pyramidal cell dendrites, we used serial block-face scanning electron microscopy (SBEM) to reconstruct dendritic ultrastructure in 3D. Statistical models were trained on synthetic fluorescence images generated from SBEM datasets via point spread function (PSF) convolution. After the training period, we tested automatic spine detection on real two-photon datasets and compared the result to ground truth (correlative SBEM data). The performance of our algorithm allowed tracking changes in spine volume automatically over several hours. Using a second fluorescent protein targeted to the endoplasmic reticulum, we could analyze the motion of this organelle inside individual spines. Furthermore, we show that it is possible to distinguish activated spines from non-stimulated neighbors by detection of fluorescently labeled presynaptic vesicle clusters. These examples illustrate how automatic segmentation in 5D (x, y, z, t, lambda) allows us to investigate brain dynamics at the level of individual synaptic connections. PMID- 25299433 TI - Multi-atlas segmentation with augmented features for cardiac MR images. AB - Multi-atlas segmentation infers the target image segmentation by combining prior anatomical knowledge encoded in multiple atlases. It has been quite successfully applied to medical image segmentation in the recent years, resulting in highly accurate and robust segmentation for many anatomical structures. However, to guide the label fusion process, most existing multi-atlas segmentation methods only utilise the intensity information within a small patch during the label fusion process and may neglect other useful information such as gradient and contextual information (the appearance of surrounding regions). This paper proposes to combine the intensity, gradient and contextual information into an augmented feature vector and incorporate it into multi-atlas segmentation. Also, it explores the alternative to the K nearest neighbour (KNN) classifier in performing multi-atlas label fusion, by using the support vector machine (SVM) for label fusion instead. Experimental results on a short-axis cardiac MR data set of 83 subjects have demonstrated that the accuracy of multi-atlas segmentation can be significantly improved by using the augmented feature vector. The mean Dice metric of the proposed segmentation framework is 0.81 for the left ventricular myocardium on this data set, compared to 0.79 given by the conventional multi-atlas patch-based segmentation (Coupe et al., 2011; Rousseau et al., 2011). A major contribution of this paper is that it demonstrates that the performance of non-local patch-based segmentation can be improved by using augmented features. PMID- 25299435 TI - Immobilization of antibodies and enzymes on 3-aminopropyltriethoxysilane functionalized bioanalytical platforms for biosensors and diagnostics. PMID- 25299434 TI - Exploring a 2-naphthoic acid template for the structure-based design of P2Y14 receptor antagonist molecular probes. AB - The P2Y14 receptor (P2Y14R), one of eight P2Y G protein-coupled receptors (GPCR), is involved in inflammatory, endocrine, and hypoxic processes and is an attractive pharmaceutical target. The goal of this research is to develop high affinity P2Y14R fluorescent probes based on the potent and highly selective antagonist 4-(4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2 naphthoic acid (6, PPTN). A model of hP2Y14R based on recent hP2Y12R X-ray structures together with simulated antagonist docking suggested that the piperidine ring is suitable for fluorophore conjugation while preserving affinity. Chain-elongated alkynyl or amino derivatives of 6 for click or amide coupling were synthesized, and their antagonist activities were measured in hP2Y14R-expressing CHO cells. Moreover, a new Alexa Fluor 488 (AF488) containing derivative 30 (MRS4174, Ki = 80 pM) exhibited exceptionally high affinity, as compared to 13 nM for the alkyne precursor 22. A flow cytometry assay employing 30 as a fluorescent probe was used to quantify specific binding to P2Y14R. Known P2Y receptor ligands inhibited binding of 30 with properties consistent with their previously established receptor selectivities and affinities. These results illustrate that potency in this series of 2-naphthoic acid derivatives can be preserved by chain functionalization, leading to highly potent fluorescent molecular probes for P2Y14R. Such conjugates will be useful tools in expanding the SAR of this receptor, which still lacks chemical diversity in its collective ligands. This approach demonstrates the predictive power of GPCR homology modeling and the relevance of newly determined X-ray structures to GPCR medicinal chemistry. PMID- 25299436 TI - Time to rethink how to measure postoperative seizure outcomes for potentially curative resective. PMID- 25299437 TI - Brief report: Play fighting to curb self-reported aggression in young adolescents. AB - This study investigated the effects of play fighting on aggressive behaviors. It was hypothesized that the teaching of play fighting during physical education lessons could reduce self-reported aggression in a group of adolescents to a greater extent than playing volleyball (a low physical contact activity). Participants were 210 young adolescents (mean age = 13.27, SD = 0.48 years) from 10 classrooms that were randomly assigned to an 8-lesson play fighting session or to traditional volleyball lessons. They filled in the 12-item short version of the Aggression Questionnaire (AQ-12) pre- and post-interventions. The play fighting group showed a significant reduction in all the four subscales of the AQ 12 (Cohen d ranging from 0.61 to 0.67), while participants in the volleyball group did not. Results suggest that play fighting might provide useful contents in a physical education curriculum, with possible reduction in aggressive behavior. PMID- 25299440 TI - Impulsive suicide attempts: a systematic literature review of definitions, characteristics and risk factors. AB - BACKGROUND: Extensive research on impulsive suicide attempts, but lack of agreement on the use of this term indicates the need for a systematic literature review of the area. The aim of this review was to examine definitions and likely correlates of impulsive attempts. METHODS: A search of Medline, Psychinfo, Scopus, Proquest and Web of Knowledge databases was conducted. Additional articles were identified using the cross-referencing function of Google Scholar. RESULTS: 179 relevant papers were identified. Four different groups of research criteria used to assess suicide attempt impulsivity emerged: (a) time-related criteria, (b) absence of proximal planning/preparations, (c) presence of suicide plan in lifetime/previous year, and (d) other. Subsequent analysis used these criteria to compare results from different studies on 20 most researched hypotheses. Conclusions regarding the characteristics of impulsive attempts are more consistent than those on the risk factors specific to such attempts. No risk factors were identified that uniformly related to suicide attempt impulsivity across all criteria groups, but relationships emerged between separate criteria and specific characteristics of suicide attempters. LIMITATIONS: Only published articles were included. Large inconsistencies in methods of the studies included in this review prevented comparison of effect sizes. CONCLUSIONS: The vast disparities in findings on risk factors for impulsive suicide attempts among different criteria groups suggest the need to address the methodological issues in defining suicide attempt impulsivity before further research into correlates of such attempts can effectively progress. Specific recommendations are offered for necessary research. PMID- 25299439 TI - Cognitive function after clinical remission in patients with melancholic and non melancholic depression: a 6 month follow-up study. AB - BACKGROUND: Cognitive symptoms are core symptoms with an impact on functioning in depression. Remission is considered as the main objective of the management and treatment of depression. This study was aimed to compare cognitive performance between melancholic (MelD) and non-melancholic depression (NMelD) and to determine whether these cognitive alterations remain after clinical remission. METHODS: We performed a 6 month follow-up study of 88 melancholic and non melancholic depressive patients. Sociodemographic and clinical characteristics were recorded. Depression was examined using the Hamilton Depression Rating Scale and the CORE Index for Melancholia. Cognitive performance was assessed with the Trail Making Test (TMT), the Digit Span subtest of the WAIS-III, Stroop Colour Word Test (SCWT), the Tower of London (TOL DX), the Controlled Oral Word Association Test (FAS), Semantic Verbal Fluency and Finger Tapping Test (FTT). RESULTS: MelD patients show worse performance than N-MelD at baseline, with significant differences at Digit Span subtest of WAIS Part I and Part II, SCWT Part I and Part II, TOL DX, Total Problem Solving, Total Execution Time and FTT- Preferred hand. Cognitive impairment remains at six months follow-up after clinical remission in MelD. In the comparison between remitted and non-remitted patients, cognitive impairment in Trail Making Test Part B and Verbal and Semantic Fluency (Animals) remains after clinical remission in MelD group but not in non-melancholic patients. LIMITATIONS: The use of psychopharmacological treatment and the small sample of melancholic patients. CONCLUSIONS: Patients with MelD do not improve cognitive performance despite clinical remission compared with remitted NMelD patients. The persistence of some cognitive dysfunctions in MelD remitted patients could represent a trait marker of a different depressive subtype and not be secondary to disease severity. PMID- 25299438 TI - Shame in the obsessive compulsive related disorders: a conceptual review. AB - BACKGROUND: Theoretical and anecdotal support for the role of shame in obsessive compulsive related disorders (OCRDs) is prominent. Developing our understanding of shame's role in OCRDs is important to building knowledge about this new diagnostic category. This review aims to consolidate our understanding of shame in each OCRD, through summarizing existing clinical, conceptual, and empirical work. METHODS: We provide an overview of shame, its measurement considerations, and a full review of 110 articles addressing shame in OCRDs. RESULTS: General shame and shame about having a mental illness are the broadest types of shame relevant to OCRDs; symptom-based shame and body shame may be more specific to OCRDs. In OCD, violent, sexual, or blasphemous obsessions may trigger symptom based shame. In trichotillomania (TTM) and skin picking (SP), symptom-based shame may be related to pulling, picking, and post-pulling/picking behaviors. In hoarding disorder, symptom-based shame may accompany beliefs about being defective due to living with clutter. Body shame appears inherent to body dysmorphic disorder, while in TTM and SP it may arise as a secondary response to damage resulting from body focused repetitive behaviors. LIMITATIONS: Much of the current knowledge on shame in OCRDs comes from anecdotal, case, and conceptual work. Empirical studies do not always assess specific types of shame, instead assessing shame as a general construct. CONCLUSIONS: Shame is closely related to OCRDs. Clinical and research recommendations drawing from the literature are provided. PMID- 25299441 TI - Contrasting patterns of larval mortality in two sympatric riverine fish species: a test of the critical period hypothesis. AB - Understanding the causal mechanisms that determine recruitment success is critical to the effective conservation of wild fish populations. Although recruitment strength is likely determined during early life when mortality is greatest, few studies have documented age-specific mortality rates for fish during this period. We investigated age-specific mortality of individual cohorts of two species of riverine fish from yolksac larvae to juveniles, assaying for the presence of a "critical period": A time when mortality is unusually high. Early life stages of carp gudgeons (Hypseleotris spp.) and unspecked hardyhead (Craterocephalus stercusmuscarum fulvus)-two fishes that differ in fecundity, egg size and overlap between endogenous and exogenous feeding-were collected every second day for four months. We fitted survivorship curves to 22 carp gudgeon and 15 unspecked hardyhead four-day cohorts and tested several mortality functions. Mortality rates declined with age for carp gudgeon, with mean instantaneous mortality rates (-Z) ranging from 1.40-0.03. In contrast, mortality rates for unspecked hardyhead were constant across the larval period, with a mean -Z of 0.15. There was strong evidence of a critical period for carp gudgeon larvae from hatch until 6 days old, and no evidence of a critical period for unspecked hardyhead. Total larval mortality for carp gudgeon and unspecked hardyhead up to 24 days of age was estimated to be 97.8 and 94.3%, respectively. We hypothesise that life history strategy may play an important role in shaping overall mortality and the pattern of mortality during early life in these two fishes. PMID- 25299443 TI - Pulsed Shortwave Diathermy and Joint Mobilizations for Achieving Normal Elbow Range of Motion After Injury or Surgery With Implanted Metal: A Case Series. AB - Context : Regaining full, active range of motion (ROM) after trauma to the elbow is difficult. Objective : To report the cases of 6 patients who lacked full ROM in the elbow because of trauma. The treatment regimen was thermal pulsed shortwave diathermy and joint mobilizations. Design : Case series. Setting : University therapeutic modalities laboratory. Patients of Other Participants : Six patients (5 women [83%], 1 man [17%]) lacked a mean active ROM of 24.5 of extension approximately 4.8 years after trauma or surgery. Intervention(s) : Treatment consisted of 20 minutes of pulsed shortwave diathermy at 800 pulses per second for 400 microseconds (40-48 W average power, 150 W peak power) applied to the cubital fossa, immediately followed by 7 to 8 minutes of joint mobilizations. After posttreatment ROM was recorded, ice was applied to the area for about 30 minutes. Main Outcomes Measure(s) : Changes in extension AROM were assessed before and after each treatment. Once the patient achieved full, active ROM or failed to improve on 2 consecutive visits, he or she was discharged from the study. Results : By the fifth treatment, 4 participants (67%) achieved normal extension active ROM, and 2 of the 4 (50%) exceeded the norm. Five participants (83%) returned to normal activities and full use of their elbows. One month later, the 5 participants had maintained, on average, (mean +/- SD) 92% +/- 6% of their final measurements. Conclusions : A combination of thermal pulsed shortwave diathermy and joint mobilizations was effective in restoring AROM of the elbow extension in 5 of the 6 patients (83%) who lacked full ROM after injury or surgery. PMID- 25299442 TI - Quadriceps muscle function after rehabilitation with cryotherapy in patients with anterior cruciate ligament reconstruction. AB - CONTEXT: Persistent muscle weakness after anterior cruciate ligament (ACL) reconstruction may be due to underlying activation failure and arthrogenic muscle inhibition (AMI). Knee-joint cryotherapy has been shown to improve quadriceps function transiently in those with AMI, thereby providing an opportunity to improve quadriceps muscle activation and strength in patients with a reconstructed ACL. OBJECTIVE: To compare quadriceps muscle function in patients with a reconstructed ACL who completed a 2-week intervention including daily cryotherapy (ice bag), daily exercises, or both. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 30 patients with reconstructed ACLs who were at least 6 months post-index surgery and had measurable quadriceps AMI. INTERVENTION(S): The patients attended 4 supervised visits over a 2-week period. They were randomly assigned to receive 20 minutes of knee-joint cryotherapy, 1 hour of therapeutic rehabilitation exercises, or cryotherapy followed by exercises. MAIN OUTCOME MEASURE(S): We measured quadriceps Hoffmann reflex, normalized maximal voluntary isometric contraction torque, central activation ratio using the superimposed-burst technique, and patient-reported outcomes before and after the intervention period. RESULTS: After the 2-week intervention period, patients who performed rehabilitation exercises immediately after cryotherapy had higher normalized maximal voluntary isometric contraction torques (P = .002, Cohen d effect size = 1.4) compared with those who received cryotherapy alone (P = .16, d = 0.58) or performed exercise alone (P = .16, d = 0.30). CONCLUSIONS: After ACL reconstruction, patients with AMI who performed rehabilitation exercises immediately after cryotherapy experienced greater strength gains than those who performed cryotherapy or exercises alone. PMID- 25299444 TI - Health-related quality of life in individuals with chronic ankle instability. AB - CONTEXT: Individuals with chronic ankle instability (CAI) have reported decreased global and regional function. Despite the identification of functional deficits in those with CAI, more research is required to determine the extent to which CAI influences the multidimensional profile of health-related quality of life. OBJECTIVE: To determine whether global, regional, and psychological health related outcomes differ between individuals with and without CAI. DESIGN: Case control study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-five participants with CAI (age = 21.9 +/- 2.5 years, height = 170.8 +/- 8.6 cm, mass = 69.8.0 +/- 11.7 kg) were sex- and limb-matched to 25 healthy participants (age = 22.0 +/- 2.1 years, height = 167.4 +/- 9.1 cm, mass = 64.8 +/- 11.2 kg). MAIN OUTCOME MEASURE(S): Both groups completed the Disablement in the Physically Active Scale, the Foot and Ankle Ability Measure (FAAM), the FAAM-Sport, the Tampa Scale of Kinesiophobia-11, and the Fear-Avoidance Beliefs Questionnaire. Dependent variables were scores on these instruments, and the independent variable was group. RESULTS: Compared with healthy individuals, those with CAI reported decreased function on the Disablement in the Physically Active Scale, FAAM, and FAAM-Sport (P < .001) and increased fear of reinjury on the Tampa Scale of Kinesiophobia-11 and Fear-Avoidance Beliefs Questionnaire (P < .001). In the CAI group, the FAAM and FAAM-Sport demonstrated a significant relationship (r = 0.774, P < .01). CONCLUSIONS: Individuals with CAI reported decreased function and increased fear of reinjury compared with healthy control participants. Also, within the CAI group, there was a strong relationship between FAAM and FAAM-Sport scores but not between any other instruments. These findings suggest that health related quality of life should be examined during the rehabilitation process of individuals with CAI. PMID- 25299446 TI - How do visual and postural cues combine for self-tilt perception during slow pitch rotations? AB - Self-orientation perception relies on the integration of multiple sensory inputs which convey spatially-related visual and postural cues. In the present study, an experimental set-up was used to tilt the body and/or the visual scene to investigate how these postural and visual cues are integrated for self-tilt perception (the subjective sensation of being tilted). Participants were required to repeatedly rate a confidence level for self-tilt perception during slow (0.05 degrees .s(-1)) body and/or visual scene pitch tilts up to 19 degrees relative to vertical. Concurrently, subjects also had to perform arm reaching movements toward a body-fixed target at certain specific angles of tilt. While performance of a concurrent motor task did not influence the main perceptual task, self-tilt detection did vary according to the visuo-postural stimuli. Slow forward or backward tilts of the visual scene alone did not induce a marked sensation of self-tilt contrary to actual body tilt. However, combined body and visual scene tilt influenced self-tilt perception more strongly, although this effect was dependent on the direction of visual scene tilt: only a forward visual scene tilt combined with a forward body tilt facilitated self-tilt detection. In such a case, visual scene tilt did not seem to induce vection but rather may have produced a deviation of the perceived orientation of the longitudinal body axis in the forward direction, which may have lowered the self-tilt detection threshold during actual forward body tilt. PMID- 25299447 TI - Thickness dependence of ice removal stress for a polydimethylsiloxane nanocomposite: Sylgard 184. AB - Minimizing adhesion of ice has been the subject of extensive studies because of importance to applications such aircraft wings, spacecraft, and power transmission wires. A growing interest concerns coatings for wind turbine blades and refrigeration. Herein, a new laboratory test was employed to obtain the thickness dependence of ice adhesion for Sylgard 184-a filled polydimethylsiloxane elastomer. A correlation between ice adhesion and coating thickness (t) was found that follows a relationship developed by Kendall over 40 years ago for removal of a rigid object from an elastomer. With a 0.05 mm/s probe speed a nearly linear relationship between peak removal stress (Ps) and 1/t(1/2) was obtained with Ps ~ 460 kPa for an 18 MUm coating, decreasing to ~120 kPa for 533 MUm. Preliminary results suggest that below ~10 MUm Ps departs from the 1/t(1/2) correlation while above ~500 MUm a limiting value for Ps may be reached. We previously reported that probe speed has negligible effect on the glassy polymer PMMA. In contrast, probe speed is identified as an important variable for testing ice release on elastomeric Sylgard 184 coatings. While work of adhesion, which is related to surface free energy, is recognized as an important factor that can affect ice release, the results reported herein show that coating thickness can override this single parameter for elastomeric substrates. PMID- 25299445 TI - A systematic review of the biomarker S100B: implications for sport-related concussion management. AB - OBJECTIVE: Elevated levels of the astroglial protein S100B have been shown to predict sport-related concussion. However, S100B levels within an athlete can vary depending on the type of physical activity (PA) engaged in and the methodologic approach used to measure them. Thus, appropriate reference values in the diagnosis of concussed athletes remain undefined. The purpose of our systematic literature review was to provide an overview of the current literature examining S100B measurement in the context of PA. The overall goal is to improve the use of the biomarker S100B in the context of sport-related concussion management. DATA SOURCES: PubMed, SciVerse Scopus, SPORTDiscus, CINAHL, and Cochrane. STUDY SELECTION: We selected articles that contained (1) research studies focusing exclusively on humans in which (2) either PA was used as an intervention or the test participants or athletes were involved in PA and (3) S100B was measured as a dependent variable. DATA EXTRACTION: We identified 24 articles. Study variations included the mode of PA used as an intervention, sample types, sample-processing procedures, and analytic techniques. DATA SYNTHESIS: Given the nonuniformity of the analytical methods used and the data samples collected, as well as differences in the types of PA investigated, we were not able to determine a single consistent reference value of S100B in the context of PA. Thus, a clear distinction between a concussed athlete and a healthy athlete based solely on the existing S100B cutoff value of 0.1 MUg/L remains unclear. However, because of its high sensitivity and excellent negative predictive value, S100B measurement seems to have the potential to be a diagnostic adjunct for concussion in sports settings. We recommend that the interpretation of S100B values be based on congruent study designs to ensure measurement reliability and validity. PMID- 25299449 TI - Reversible ion transportation switch by a ligand-gated synthetic supramolecular ion channel. AB - Inspired by the regulation of cellular activities found in the ion channel proteins, here we developed membrane-embedded synthetic chiral receptors 1 and 2 with different terminal structures, where receptor 1 has hydrophobic triisopropylsilyl (TIPS) groups and receptor 2 has hydrophilic hydroxy groups. The receptors have ligand-binding units that interact with cationic amphiphiles such as 2-phenethylamine (PA). Conductance study revealed that the receptors hardly show ion transportation at the ligand-free state. After ligand binding involving a conformational change, receptor 1 bearing TIPS termini displays a significant current enhancement due to ion transportation. The current substantially diminishes upon addition of beta-cyclodextrin (betaCD) that scavenges the ligand from the receptor. Importantly, the receptor again turns into the conductive state by the second addition of PA, and the activation/deactivation of the ion transportation can be repeated. In contrast, receptor 2 bearing the hydroxy terminal groups hardly exhibits ion transportation, suggesting the importance of terminal TIPS groups of 1 that likely anchor the receptor in the membrane. PMID- 25299453 TI - Orbital Kondo effect in a parallel double quantum dot. AB - We construct a theoretical model to study the orbital Kondo effect in a parallel double quantum dot (DQD). Recently, pseudospin-resolved transport spectroscopy of the orbital Kondo effect in a DQD has been experimentally reported. The experiment revealed that when interdot tunneling is ignored, two and one Kondo peaks exist in the conductance-bias curve for pseudospin-non-resolved and pseudospin-resolved cases, respectively. Our theoretical studies reproduce this experimental result. We also investigate the case of all lead voltages being non equal (the complete pseudospin-resolved case) and found that there are at most four Kondo peaks in the curve of the conductance versus the pseudospin splitting energy. When interdot tunneling is introduced, some new Kondo peaks and dips can emerge. Furthermore, the pseudospin transport and the pseudospin flipping current are also studied in the DQD system. Since the pseudospin transport is much easier to control and measure than the real spin transport, it can be used to study the physical phenomenon related to the spin transport. PMID- 25299450 TI - The role of her4 in inner ear development and its relationship with proneural genes and Notch signalling. AB - The generation of sensory neurons and hair cells of the inner ear is under tight control. Different members of the Hairy and Enhancer of Split genes (HES) are expressed in the inner ear, their full array of functions still not being disclosed. We have previously shown that zebrafish her9 acts as a patterning gene to restrict otic neurogenesis to an anterior domain. Here, we disclose the role of another her gene, her4, a zebrafish ortholog of Hes5 that is expressed in the neurogenic and sensory domains of the inner ear. The expression of her4 is highly dynamic and spatiotemporally regulated. We demonstrate by loss of function experiments that in the neurogenic domain her4 expression is under the regulation of neurogenin1 (neurog1) and the Notch pathway. Moreover, her4 participates in lateral inhibition during otic neurogenesis since her4 knockdown results in overproduction of the number of neurog1 and deltaB-positive otic neurons. In contrast, during sensorigenesis her4 is initially Notch-independent and induced by atoh1b in a broad prosensory domain. At later stages her4 expression becomes Notch-dependent in the future sensory domains but loss of her4 does not result in hair cell overproduction, suggesting that there other her genes can compensate its function. PMID- 25299451 TI - Efficient gene targeting in golden Syrian hamsters by the CRISPR/Cas9 system. AB - The golden Syrian hamster is the model of choice or the only rodent model for studying many human diseases. However, the lack of gene targeting tools in hamsters severely limits their use in biomedical research. Here, we report the first successful application of the CRISPR/Cas9 system to efficiently conduct gene targeting in hamsters. We designed five synthetic single-guide RNAs (sgRNAs) -three for targeting the coding sequences for different functional domains of the hamster STAT2 protein, one for KCNQ1, and one for PPP1R12C--and demonstrated that the CRISPR/Cas9 system is highly efficient in introducing site-specific mutations in hamster somatic cells. We then developed unique pronuclear (PN) and cytoplasmic injection protocols in hamsters and produced STAT2 knockout (KO) hamsters by injecting the sgRNA/Cas9, either in the form of plasmid or mRNA, targeting exon 4 of hamster STAT2. Among the produced hamsters, 14.3% and 88.9% harbored germline-transmitted STAT2 mutations from plasmid and mRNA injection, respectively. Notably, 10.4% of the animals produced from mRNA injection were biallelically targeted. This is the first success in conducting site-specific gene targeting in hamsters and can serve as the foundation for developing other genetically engineered hamster models for human disease. PMID- 25299452 TI - Relationship between lung function and metabolic syndrome. AB - Although the link between impaired lung function and cardiovascular events and type 2 diabetes mellitus has been recognized, the association between impaired lung function and metabolic syndrome has not been comprehensively assessed in the United States (U.S.) population. The aim of our study was to explore the association between impaired lung function and metabolic syndrome in a nationally representative sample of men and women. This cross-sectional population-based study included 8602 participants aged 20-65 years in the Third National Health and Nutrition Examination Survey (NHANES III). We examined the relationship between the different features of metabolic syndrome and lung function, including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). After adjusting for potential confounders such as age, body mass index, inflammatory factors, medical condition, and smoking status, participants with more components of metabolic syndrome had lower predicted values of FVC and FEV1 (p for trend <0.001 for both). Impaired pulmonary function was also associated with individual components of metabolic syndrome, such as abdominal obesity, high blood pressure, high triglycerides, and low high density lipoprotein (HDL) cholesterol (p<0.05 for all parameters). These results from a nationally representative sample of US adults suggest that a greater number of features of metabolic syndrome is strongly associated with poorer FVC and FEV1. In clinical practice, more comprehensive management strategies to address subjects with metabolic syndrome and impaired lung function need to be developed and investigated. PMID- 25299456 TI - A water-soluble calix[4]arene-based ligand for the selective linear coordination and stabilization of copper(I) ion in aerobic conditions. AB - A number of serious diseases are linked to copper homeostasis dysfunction. The design of copper(I)-selective chelators is of particular interest not only for the creation of therapeutic objects but also as useful tools to gain insights into the coordination of copper(I) in a biological medium. A water-soluble Cu(I) selective ligand that associates strong Cu(I) binding at pH = 7.4 (10(14) M(-1)), insensitivity to air, and selectivity toward Cu(II) and other biologically relevant cations is described. PMID- 25299454 TI - Local neutral networks help maintain inaccurately replicating ribozymes. AB - The error threshold of replication limits the selectively maintainable genome size against recurrent deleterious mutations for most fitness landscapes. In the context of RNA replication a distinction between the genotypic and the phenotypic error threshold has been made; where the latter concerns the maintenance of secondary structure rather than sequence. RNA secondary structure is treated as a proxy for function. The phenotypic error threshold allows higher per digit mutation rates than its genotypic counterpart, and is known to increase with the frequency of neutral mutations in sequence space. Here we show that the degree of neutrality, i.e. the frequency of nearest-neighbour (one-step) neutral mutants is a remarkably accurate proxy for the overall frequency of such mutants in an experimentally verifiable formula for the phenotypic error threshold; this we achieve by the full numerical solution for the concentration of all sequences in mutation-selection balance up to length 16. We reinforce our previous result that currently known ribozymes could be selectively maintained by the accuracy known from the best available polymerase ribozymes. Furthermore, we show that in silico stabilizing selection can increase the mutational robustness of ribozymes due to the fact that they were produced by artificial directional selection in the first place. Our finding offers a better understanding of the error threshold and provides further insight into the plausibility of an ancient RNA world. PMID- 25299455 TI - The specification and global reprogramming of histone epigenetic marks during gamete formation and early embryo development in C. elegans. AB - In addition to the DNA contributed by sperm and oocytes, embryos receive parent specific epigenetic information that can include histone variants, histone post translational modifications (PTMs), and DNA methylation. However, a global view of how such marks are erased or retained during gamete formation and reprogrammed after fertilization is lacking. To focus on features conveyed by histones, we conducted a large-scale proteomic identification of histone variants and PTMs in sperm and mixed-stage embryo chromatin from C. elegans, a species that lacks conserved DNA methylation pathways. The fate of these histone marks was then tracked using immunostaining. Proteomic analysis found that sperm harbor ~2.4 fold lower levels of histone PTMs than embryos and revealed differences in classes of PTMs between sperm and embryos. Sperm chromatin repackaging involves the incorporation of the sperm-specific histone H2A variant HTAS-1, a widespread erasure of histone acetylation, and the retention of histone methylation at sites that mark the transcriptional history of chromatin domains during spermatogenesis. After fertilization, we show HTAS-1 and 6 histone PTM marks distinguish sperm and oocyte chromatin in the new embryo and characterize distinct paternal and maternal histone remodeling events during the oocyte-to embryo transition. These include the exchange of histone H2A that is marked by ubiquitination, retention of HTAS-1, removal of the H2A variant HTZ-1, and differential reprogramming of histone PTMs. This work identifies novel and conserved features of paternal chromatin that are specified during spermatogenesis and processed in the embryo. Furthermore, our results show that different species, even those with diverged DNA packaging and imprinting strategies, use conserved histone modification and removal mechanisms to reprogram epigenetic information. PMID- 25299457 TI - Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects. AB - Opioids are used to manage all types of pain including acute, cancer, chronic neuropathic and inflammatory pain. Unfortunately, opioid-related adverse effects such as respiratory depression, tolerance, physical dependence and addiction have led to an underutilization of these compounds for adequate pain relief. One strategy to improve the therapeutic utility of opioids is to co-administer them with other analgesic agents such as agonists acting at alpha2-adrenergic receptors (alpha2ARs). Analgesics acting at alpha2ARs and opioid receptors (ORs) frequently synergize when co-administered in vivo. Multimodal analgesic techniques offer advantages over single drug treatments as synergistic combination therapies produce analgesia at lower doses, thus reducing undesired side effects. This inference presumes, however, that the synergistic interaction is limited to the analgesic effects. In order to test this hypothesis, we examined the effects of alpha2AR/OR combination therapy in acute antinociception and in the often-undesired side effects of sedation and cardiovascular depression in awake unrestrained mice. Morphine, clonidine or their combination was administered by spinal or systemic injection in awake mice. Antinociception was determined using the warm water tail flick assay (52.5 degrees C). Sedation/motor impairment was evaluated using the accelerating rotarod assay and cardiovascular function was monitored by pulse oximetry. Data were converted to percent maximum possible effect and isobolographic analysis was performed to determine if an interaction was subadditive, additive or synergistic. Synergistic interactions between morphine and clonidine were observed in the antinociceptive but not in the sedative/motor or cardiovascular effects. As a result, the therapeutic window was improved ~200-fold and antinociception was achieved at non-sedating doses with little to no cardiovascular depression. In addition, combination therapy resulted in greater maximum analgesic efficacy over either drug alone. These data support the utility of combination adrenergic/opioid therapy in pain management for antinociceptive efficacy with reduced side-effect liability. PMID- 25299459 TI - GIS-based multi-criteria analysis for Arabica coffee expansion in Rwanda. AB - The Government of Rwanda is implementing policies to increase the area of Arabica coffee production. Information on the suitable areas for sustainably growing Arabica coffee is still scarce. This study aimed to analyze suitable areas for Arabica coffee production. We analyzed the spatial distribution of actual and potential production zones for Arabica coffee, their productivity levels and predicted potential yields. We used a geographic information system (GIS) for a weighted overlay analysis to assess the major production zones of Arabica coffee and their qualitative productivity indices. Actual coffee yields were measured in the field and were used to assess potential productivity zones and yields using ordinary kriging with ArcGIS software. The production of coffee covers about 32 000 ha, or 2.3% of all cultivated land in the country. The major zones of production are the Kivu Lake Borders, Central Plateau, Eastern Plateau, and Mayaga agro-ecological zones, where coffee is mainly cultivated on moderate slopes. In the highlands, coffee is grown on steep slopes that can exceed 55%. About 21% percent of the country has a moderate yield potential, ranging between 1.0 and 1.6 t coffee ha-1, and 70% has a low yield potential (<1.0 t coffee ha 1). Only 9% of the country has a high yield potential of 1.6-2.4 t coffee ha-1. Those areas are found near Lake Kivu where the dominant soil Orders are Inceptisols and Ultisols. Moderate yield potential is found in the Birunga (volcano), Congo-Nile watershed Divide, Impala and Imbo zones. Low-yield regions (<1 t ha-1) occur in the eastern semi-dry lowlands, Central Plateau, Eastern Plateau, Buberuka Highlands, and Mayaga zones. The weighted overlay analysis and ordinary kriging indicated a large spatial variability of potential productivity indices. Increasing the area and productivity of coffee in Rwanda thus has considerable potential. PMID- 25299458 TI - Indazole-type alkaloids from Nigella sativa seeds exhibit antihyperglycemic effects via AMPK activation in vitro. AB - Six rare naturally occurring indazole-type alkaloids including two new compounds, 17-O-(beta-d-glucopyranosyl)-4-O-methylnigellidine (1) and nigelanoid (2), and four known compounds (3-6) were isolated from a defatted extract of Nigella sativa (black cumin) seeds. 17-O-(beta-d-Glucopyranosyl)-4-O-methylnigellidine (1) increased glucose consumption by liver hepatocytes (HepG2 cells) through activation of AMP-activated protein kinase (AMPK). Also, this is the first report of compounds 4 and 6 from a natural source. PMID- 25299460 TI - PTSD-related alcohol expectancies and impulsivity interact to predict alcohol use severity in a substance dependent sample with PTSD. AB - INTRODUCTION: Problematic alcohol use is highly comorbid with posttraumatic stress disorder (PTSD), and prior work has demonstrated that individuals with PTSD may self-medicate with alcohol in an effort to reduce their symptoms. The combination of impulsivity and alcohol-related expectancies influences the development of problematic drinking patterns. When examining individuals diagnosed with PTSD, PTSD-related alcohol expectancies may be particularly relevant to the etiology of problematic drinking. To date, no studies have specifically examined PTSD-specific alcohol expectancies as they relate to alcohol use severity in a clinical sample. METHODS: The current study examined the relationship between impulsivity, PTSD-related alcohol expectancies, and severity of alcohol use in a sample of 63 individuals diagnosed with comorbid PTSD and substance use disorders who were receiving treatment in a residential substance use treatment program. RESULTS: Results indicated that PTSD-related alcohol expectancies moderated the relationship between impulsivity and alcohol use severity. Specifically, at low to moderate levels of positive PTSD-related alcohol expectancies, impulsivity significantly predicted alcohol use severity, while impulsivity had no impact on the prediction of alcohol use severity when such expectancies were high. Additionally, the relationship between impulsivity, expectancies, and alcohol use severity was significant for positive, but not negative, PTSD-related alcohol expectancies. CONCLUSIONS: Overall, these results suggest that impulsivity and PTSD-related alcohol expectancies interact to predict alcohol use severity in a comorbid PTSD and substance dependent sample. PMID- 25299462 TI - Statement of retraction: Gao P, Yang JL, Wang H, Wu XD, Jiao SC. "A two dimensional model for studying tumor angiogenesis inhibitors". PMID- 25299463 TI - Cefdinir for recent-onset pediatric neuropsychiatric disorders: a pilot randomized trial. AB - OBJECTIVE: Previous studies suggest that the unexplained sudden and severe onset of obsessive-compulsive disorder (OCD) and/or tics may be infection or immune precipitated. Beta lactam antibiotics may be neuroprotective beyond their antimicrobial efficacy. We examine the preliminary safety and efficacy of cefdinir in reducing obsessive-compulsive and/or tic severity in children with new-onset symptoms. METHOD: Twenty subjects were randomized to receive placebo or cefdinir for 30 days for the treatment of recent-onset OCD and/or tics. The placebo group received a comparable inactive treatment matched for taste, color, and consistency. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and Yale Global Tic Severity Scale (YGTSS) were the primary outcome measures utilized. RESULTS: Subjects receiving cefdinir saw notable improvements in tic symptoms, with 44.4% showing at least a 25% reduction in YGTSS (mean decrease=9.5) scores compared with 9.1% of the placebo group (mean decrease=0.13). Despite improvements, significant group differences were not observed for YGTSS (F [1, 13]=4.03, p=0.066) although there were moderate differences between group treatment effects (d=0.72). For OCD symptoms, subjects receiving cefdinir saw improvements in OCD symptoms, with 33.3% showing at least a 25% reduction in CY-BOCS scores (mean decrease=7.8) compared with 27.3% of the placebo group (mean decrease=4.7), but there were also no significant differences for CY-BOCS (F [1, 13]=0.385, p=0.546; d=0.24). CONCLUSIONS: Subjects assigned to cefdinir exhibited notable, albeit nonstatistically significant, improvements in tic symptoms, compared with the placebo group. There were also some improvements in OCD symptoms, although these were not significant. Overall, cefdinir was well tolerated. Given these preliminary results, a fully powered study is warranted to explore the efficacy of cefdinir as a therapeutic tool for new-onset pediatric neuropsychiatric symptoms, particularly those that appear to be precipitated by infection. PMID- 25299464 TI - Simulation of two-dimensional electronic spectra of phycoerythrin 545 at ambient temperature. AB - By using a hierarchical equations-of-motion approach, we reproduce the two dimensional electronic spectra of phycoerythrin 545 from Rhodomonas CS24 at ambient temperature (294 K). The simulated spectra are in agreement with the experimental results reported in Wong et al. (Nat. Chem. 2012, 4, 396). The evolutions of cross peaks for rephasing spectra and diagonal peaks for nonrephasing spectra have also been plotted. The peaks oscillate with the population times, with frequencies, phases, and amplitudes of the oscillating curves also being qualitatively consistent with the experimental results. PMID- 25299461 TI - Beyond muscles stiffness: importance of state-estimation to account for very fast motor corrections. AB - Feedback delays are a major challenge for any controlled process, and yet we are able to easily control limb movements with speed and grace. A popular hypothesis suggests that the brain largely mitigates the impact of feedback delays (~50 ms) by regulating the limb intrinsic visco-elastic properties (or impedance) with muscle co-contraction, which generates forces proportional to changes in joint angle and velocity with zero delay. Although attractive, this hypothesis is often based on estimates of limb impedance that include neural feedback, and therefore describe the entire motor system. In addition, this approach does not systematically take into account that muscles exhibit high intrinsic impedance only for small perturbations (short-range impedance). As a consequence, it remains unclear how the nervous system handles large perturbations, as well as disturbances encountered during movement when short-range impedance cannot contribute. We address this issue by comparing feedback responses to load pulses applied to the elbow of human subjects with theoretical simulations. After validating the model parameters, we show that the ability of humans to generate fast and accurate corrective movements is compatible with a control strategy based on state estimation. We also highlight the merits of delay-uncompensated robust control, which can mitigate the impact of internal model errors, but at the cost of slowing feedback corrections. We speculate that the puzzling observation of presynaptic inhibition of peripheral afferents in the spinal cord at movement onset helps to counter the destabilizing transition from high muscle impedance during posture to low muscle impedance during movement. PMID- 25299466 TI - Dual-phase 11C-choline PET/computed tomography in the early evaluation of prostate cancer recurrence. AB - PURPOSE: The aim of this study was to assess dual-phase 11C-choline PET/computed tomography (CT) for differentiating benign from malignant lesions in patients with biochemical recurrence of prostate cancer. MATERIALS AND METHODS: We prospectively studied 56 patients with prostate cancer treated by surgery (n=22) or radiotherapy (n=34) who had hypermetabolic foci on 11C-choline PET/CT determined for biochemical recurrence (prostate-specific antigen 1.23-9.9 ng/ml). We used the dual-phase technique, calculating the standardized uptake value (SUV) for early (SUVearly) and late (SUVdelay) acquisitions and the difference between the two (SUVvariation) to determine whether tracer uptake remained stable or increased (accumulative pattern) or decreased (washout pattern). We used t-tests to compare mean and receiver operating characteristic curve analysis (SUVearly/SUVdelay/SUVvariation vs. benign/malignant). RESULTS: We identified 106 hypermetabolic foci (34 local, 10 inguinal, 34 infradiaphragmatic, 14 supradiaphragmatic, and 14 in bone). We identified 34 local foci (eight after prostatectomy and 26 after radiotherapy). The eight postsurgical foci had an accumulative pattern and recurrence was confirmed (three histology, five follow up). Of the 26 postradiotherapy foci, three had a washout pattern and follow-up ruled out recurrence; 23 had an accumulative pattern and recurrence was confirmed (14 histology, nine follow-up). The 10 inguinal foci had a washout pattern and were reactive (three histology, seven follow-up). The 34 infradiaphragmatic foci had an accumulative pattern and were malignant (34 follow-up). Of the 14 supradiaphragmatic foci, the three with a washout pattern were benign (three histology) and the 11 with an accumulative pattern were malignant (11 histology). Of the 14 foci in bone, two had a washout pattern and corresponded with signs of spondyloarthropathy. On the receiver operating characteristic curve analysis, SUVvariation best discriminated benign from malignant lesions [area under the curve (AUC)=0.993], followed by SUVdelay (AUC=0.933) and finally SUVearly (AUC=0.665). CONCLUSION: Dual-phase PET/CT with 11C-choline is technically feasible despite this tracer's short physical half-life and is useful for discriminating benign from malignant lesions. SUVvariation accurately discriminated between benign and malignant lesions. PMID- 25299467 TI - The current place and indications of 131I-metaiodobenzylguanidine therapy in the era of peptide receptor radionuclide therapy: determinants to consider for evolving the best practice and envisioning a personalized approach. PMID- 25299465 TI - Leptin downregulates aggrecan through the p38-ADAMST pathway in human nucleus pulposus cells. AB - The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD. PMID- 25299468 TI - A novel dynamic scintigraphic technique for assessing duodenal contractions during gastric emptying in humans: a feasibility study. AB - Duodenal contractions are thought to play a role in the control of gastric emptying. Although noninvasive techniques, such as ultrasonography and MRI, have been proposed for studying duodenal contractile activity in humans, there are no reports on the use of scintigraphy for this purpose. This work aimed to describe a novel scintigraphic technique for assessing duodenal contractility during gastric emptying in humans, and to present preliminary data on the frequency and amplitude of contractions detected in three different duodenal segments. Fasted young healthy volunteers (N=12) were given either a liquid or a solid test meal of similar calorie content (400 kcal) labeled with 99mTc-phytate. Static images were collected to determine gastric emptying. Dynamic images of the anterior aspect of the abdomen (1 frame/s) were also acquired periodically in a standard position for 256 s at 15-30 min intervals. 'Activity versus time' curves were generated for regions of interest corresponding to the proximal, middle, and distal duodenal segments. Curves were digitally filtered and processed to estimate both dominant frequency (fast Fourier transform) and amplitude (mean ejection fraction) of postprandial duodenal contractions. There were no significant differences regarding dominant frequency among proximal, middle, and distal duodenal regions of interest. In addition, there were no significant differences between the liquid and the solid meal in terms of either frequency or amplitude of duodenal contractions. Characterization of duodenal contractions in humans using scintigraphy is feasible and yields consistent data for both the frequency and the amplitude of postprandial contractions, which seems to be rather independent of meal consistency. PMID- 25299469 TI - Prediction of the success of thyroid remnant ablation using preablative 99mTc pertechnetate scintigraphy and postablative dual 131I scintigraphy. AB - OBJECTIVE: The aim of this study was to predict the success of 131I ablation using preablative 99mTc pertechnetate salivary scintigraphy and a postablative dual 131I scan in differentiated thyroid cancer (DTC). PATIENTS AND METHODS: A total of 168 DTC patients who underwent 131I ablation with preablative salivary scintigraphy and a postablative dual (early and delayed) 131I scan were enrolled. For salivary scintigraphy, the thyroid remnant uptake was visually assessed. For the dual 131I scan, the thyroid remnant to background uptake ratios (TBRs) on early and delayed scans were measured and the percentage change in TBR (TBRDelta) was calculated. RESULTS: Thyroid remnant uptake was seen in 69 (41%) patients on salivary scintigraphy and in 162 (96%) patients on the dual 131I scan. The success rate of ablation was higher in patients with negative remnant uptake on salivary scintigraphy (86%) than in patients with positive remnant uptake (58%, P=0.0001). The success rate of ablation was 100% in patients with no remnant uptake on both salivary scintigraphy and the dual 131I scan. The success rate of ablation was higher in patients with TBRDelta 0 or more than in patients with TBRDelta less than 0, irrespective of remnant uptake on salivary scintigraphy (91 vs. 70%, P=0.03, for patients without remnant uptake on salivary scintigraphy; 74 vs. 48%, P=0.05, for patients with remnant uptake on salivary scintigraphy). CONCLUSION: The success of thyroid remnant ablation in DTC can be predicted by the presence of remnant uptake on preablative 99mTc pertechnetate scintigraphy and change in remnant uptake on the postablative dual 131I scan. PMID- 25299470 TI - Localization of parathyroid disease with 'sequential multiphase and dual-tracer' technique and comparison with neck ultrasound. AB - OBJECTIVE: The aim of the study was to evaluate the accuracy of the sequential multiphase and dual-tracer (SMADT) technique utilizing technetium-99m pertechnetate (99mTcO4) and dynamic technetium-99m-2-methoxyisobutylisonitrile (99mTc-MIBI) with single-photon emission computed tomography/computed tomography (SPECT/CT) for localization of hyperfunctioning parathyroid tissue and compare the results with ultrasound (US). MATERIALS AND METHODS: Sixty-four patients with hyperparathyroidism were scanned over 4 years. For the SMADT technique, 80 MBq 99mTcO4 was injected with dynamic thyroid image acquisition started at 20 min, followed by 900 MBq 99mTc-MIBI injection at 30 min; the dynamic imaging continued for 50 min. SPECT was acquired at 60 min, with SPECT/CT of the neck at 3 h. Subsequent subtraction and statistical difference analyses were performed. Neck US was carried out within 3 months. Findings for each parathyroid gland and thyroid were classified as positive or negative. The patients underwent surgical resection of parathyroid tissue on the basis of imaging results. SMADT and US findings were correlated with histology as the gold standard. RESULTS: Eighty-six histological samples were resected. The sensitivity of SMADT for localization to individual glands was 70.6% [95% confidence interval (CI)=58.1-80.7%] and that for neck US was 60.3% (95% CI=47.7-71.8%, P=0.26). Specificity was 94.4% (95% CI=70.6-99.7%) for SMADT and 72.2% (95% CI=46.4-89.2%) for neck US (P=0.13). Sensitivities in multigland disease were 63.6% (95% CI=31.6-87.6%) for SMADT and 36.4% (95% CI=12.4-68.4%) for US (P=0.37) and in nodular thyroid disease were 83.8% (95% CI=67.3-93.2%) and 66.7% (95% CI=48.9-80.9%), respectively (P=0.07). CONCLUSION: SMADT results in better localization of varying parathyroid pathologies and complements the role of US in patients with multigland disease and nodular thyroid. PMID- 25299471 TI - Correlation of the value of 18F-FDG uptake, described by SUVmax, SUVavg, metabolic tumour volume and total lesion glycolysis, to clinicopathological prognostic factors and biological subtypes in breast cancer. AB - OBJECTIVE: The aim of this study was to observe the relationships between different metabolic parameters and clinicopathological features (CPFs) or immunohistochemically defined biological subtypes (IHC-BS) in breast cancer. MATERIALS AND METHODS: Eighty-two women (83 lesions, tumour size>15 mm) underwent PET/computed tomography imaging after a core biopsy. Maximum and average standardized uptake values (SUVmax, SUVavg), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) in the primary tumour were calculated and compared with CPFs and IHC-BS. Tumours with oestrogen receptor (ER) positivity were separately investigated in relation to their progesterone receptor (PR) status. RESULTS: Significant correlation was found between all metabolic parameters and high nuclear grade or ER status or IHC-BS. All parameters were higher in PR(-) and triple-negative cases than in PR(+) and non-triple-negative tumours, and the correlation was significant for most of the metabolic parameters (except for SUVavg in the case of PR status and MTV in the case of triple negativity). Significant correlation was found only for SUVmax regarding the human epidermal growth factor receptor 2 (HER2) status. There was moderate correlation between the Ki67 expression and the SUVmax or SUVavg. All metabolic parameters were higher in ER(+)/PR(-)/HER2(-) lesions compared with ER(+)/PR(+)/HER2(-) cancers. However, ER(+)/PR(-)/HER2(+) tumours had lower SUVmax and SUVavg compared with ER(+)/PR(+)/HER2(+) lesions. CONCLUSION: Our study confirms that the fluorine-18 fluorodeoxyglucose uptake in primary tumour is associated with distinct CPFs or IHC-BS in breast cancer. SUVmax may reflect tumour metabolism more reliably compared with SUVavg, MTV or total lesion glycolysis. Our preliminary results suggest different biological properties in ER(+) tumours with different PR statuses. PMID- 25299472 TI - In vitro biological activity of aromadendrin-4'-methyl ether isolated from root extract of Ventilago madraspatana Gaertn with relevance to anticandidal activity. AB - In this study, antimicrobial and antioxidant activities of the hexane extract of the root of Ventilago madraspatana were evaluated. Based on the significant bioactivity of crude hexane extract, an active compound was purified from the root extract. The active compound was further purified and identified as aromodendrin-4'-methyl ether by the (1)H NMR spectrum. The isolated compound significantly inhibited Staphylococcus epidermidis with the lowest MIC and MBC at 78 MUg/mL (P < 0.05). The compound also exhibited significant anticandidal activity with MIC and MBC values of 312 and 625 MUg/mL, respectively. The radical scavenging activity of aromodendrin-4'-methyl ether was evident by its lower IC50 values of 60 MUg/mL for DPPH scavenging and 3.2 MUg/mL for ABTS scavenging. The compound also exhibited ferrous ion chelation and H2O2 scavenging activities. The study is an attempt to increase the industrial utility of V. madrasapatana. PMID- 25299474 TI - Training highly qualified health research personnel: the pain in Child Health consortium. AB - BACKGROUND AND OBJECTIVES: Pain in Child Health (PICH) is a transdisciplinary, international research training consortium. PICH has been funded since 2002 as a Strategic Training Initiative in Health Research of the Canadian Institutes of Health Research, with contributions from other funding partners and the founding participation of five Canadian universities. The goal of PICH has been to create a community of scholars in pediatric pain to improve child health outcomes. METHODS: Quantitative analyses enumerated PICH faculty, trainees, training activities and scientific outputs. Interviews with PICH stakeholders were analyzed using qualitative methods capturing perceptions of the program's strengths, limitations, and opportunities for development and sustainability. RESULTS: PICH has supported 218 trainee members from 2002 through 2013, from 14 countries and more than 16 disciplines. The faculty at the end of 2013 comprised nine co-principal investigators, 14 Canadian coinvestigators, and 28 Canadian and international collaborators. Trainee members published 697 peer-reviewed journal articles on pediatric pain through 2013, among other research dissemination activities including conference presentations and webinars. Networks have been established between new and established researchers across Canada and in 13 other countries. Perceptions from stakeholders commended PICH for its positive impact on the development of pediatric pain researchers. Stakeholders emphasized skills and abilities gained through PICH, the perceived impact of PICH training on this research field, and considerations for future training in developing researchers in pediatric pain. CONCLUSIONS: PICH has been successfully developing highly qualified health research personnel within a Canadian and international community of pediatric pain scholarship. PMID- 25299473 TI - Knowledge, attitudes and beliefs about chronic noncancer pain in primary care: a Canadian survey of physicians and pharmacists. AB - BACKGROUND: Primary care providers' knowledge, attitudes and beliefs (KAB) regarding chronic noncancer pain (CNCP) are a barrier to optimal management. OBJECTIVES: To evaluate and identify the determinants of the KAB of primary care physicians and pharmacists, and to document clinician preferences regarding the content and format of a continuing education program (CEP). METHOD: Physicians and pharmacists of 486 CNCP patients participated. Physicians completed the original version of the KnowPain-50 questionnaire. Pharmacists completed a modified version. A multivariate linear regression model was developed to identify the determinants of their KAB. RESULTS: A total of 137 of 387 (35.4%) physicians and 110 of 278 (39.5%) pharmacists completed the survey. Compared with the physicians, the pharmacists surveyed included more women (64% versus 38%) and had less clinical experience (15 years versus 26 years). The mean KnowPain-50 score was 69.3% (95% CI 68.0% to 70.5%) for physicians and 63.8% (95% CI 62.5% to 65.1%) for pharmacists. Low scores were observed on all aspects of pain management: initial assessment (physicians, 68.3%; pharmacists, 65.4%); definition of treatment goals and expectations (76.1%; 61.6%); development of a treatment plan (66.4%; 59.0%); and reassessment and management of longitudinal care (64.3%; 53.1%). Ten hours of reported CEP sessions increased the KAB score by 0.3 points. All clinicians considered a CEP for CNCP to be essential. Physicians preferred an interactive format, while pharmacists had no clear preferences. CONCLUSION: A CEP to improve primary care providers' knowledge and competency in managing CNCP, and to reduce false beliefs and inappropriate attitudes regarding CNCP is relevant and perceived as necessary by clinicians. PMID- 25299475 TI - The role of infant pain behaviour in predicting parent pain ratings. AB - BACKGROUND: Research investigating how observers empathize or form estimations of an individual experiencing pain suggests that both characteristics of the observer ('top down') and characteristics of the individual in pain ('bottom up') are influential. However, experts have opined that infant behaviour should serve as a crucial determinant of infant pain judgment due to their inability to self report. OBJECTIVE: To predict parents' immunization pain ratings using archival data. It was hypothesized that infant behaviour ('bottom up') and parental emotional availability ('top down') would directly predict the most variance in parent pain ratings. METHODS: Healthy infants were naturalistically observed during their two-, four-, six- and/or 12-month immunization appointments. Cross sectional latent growth curve models in a structural equation model context were conducted at each age (n=469 to n=579) to examine direct and indirect predictors of parental ratings of their infant's pain. RESULTS: At each age, each model suggested that moderate amounts of variance in parent pain report were accounted for by models that included infant pain behaviours (R2=0.18 to 0.36). Moreover, notable differences were found for older versus younger infants with regard to parental emotional availability, infant sex, caregiver age and amount of variance explained by infant variables. CONCLUSIONS: The results of the present study suggest that parent pain ratings are not predominantly predicted by infant behaviours, especially before four months of age. Current results suggest that recognizing infant pain behaviours during painful events may be an important area of parent education, especially for parents of very young infants. Further work is needed to determine other factors that predict parent judgments of infant pain. PMID- 25299476 TI - Functional restoration of the spine: effect of initial pain level on the performance of subjects with chronic low back pain. AB - BACKGROUND: Chronic low back pain is a persistent lumbar pain of multifactorial origin. The initial pain level remains poorly used to analyze and compare responses in low back pain patients in a reconditioning program. OBJECTIVE: To assess and evaluate the responses of subjects with very painful chronic low back pain in a dynamic and intensive care program. METHODS: A total of 134 patients with chronic low back pain were included in a spine functional restoration program for five weeks. The subjects were classified into two groups by level of pain: a group experiencing severe pain (n=28) and a group experiencing mild to moderate pain (n=106). All subjects received identical support consisting primarily of physiotherapy, occupational therapy, cardiovascular and muscular reconditioning as well as psychological counselling. The physical parameters (flexibility, muscular strength) and psychological (quality of life) were measured before (T0) and after the program (T5sem). RESULTS: All physical and functional performances of the subjects with severe pain were lower and the impact of back pain on quality of life for these subjects was increased. All significant differences at T0 between the two groups were no longer present at T5sem. DISCUSSION: Muscular atrophy is more important in subjects with severe pain at T0. The intense pain would cause kinesiophobia and central inhibition in chronic low back pain. The analgesic effects of the spine functional restoration program allowed subjects to obtain similar physical, functional and psychological performances at the end of the five weeks of support. CONCLUSIONS: Patients with very painful chronic low back pain respond favourably to the dynamic and intensive program. The intensity of low back pain had no effect on responses to the program. The spine functional restoration program enables patients to better manage their pain, whatever its level. PMID- 25299477 TI - Exploring the associations between sleep problems and chronic musculoskeletal pain in adolescents: a prospective cohort study. AB - BACKGROUND: The prevalence of musculoskeletal chronic pain in adolescents is estimated to be approximately 4% to 40%. The development of musculoskeletal pain during teenage years could have a marked impact on physical, psychological and social well-being. OBJECTIVE: To examine whether sleep problems during adolescence are associated with musculoskeletal pain, particularly chronic regional pain and chronic widespread pain. METHODS: Using data from the Avon Longitudinal Study of Children, the relationship between sleep problems at 15 years of age and the presence of chronic regional and widespread pain at 17 years of age was explored. Pain data were not available at 15 years of age. A total of 2493 participants with complete data were identified. Relationships among sleep problems and musculoskeletal pain were examined using logistic regression. ORs were calculated after adjusting for sex, ethnicity, socioeconomic position and depression (15 years of age). RESULTS: Sleep disturbance (usually wakes up more than two or three times), difficulties with hypersomnolence and poor subjective sleep perception were associated with the presence of both musculoskeletal regional and widespread pain. Finally, using ordered logistic regression, poor subjective sleep perception was also found to be associated with greater pain severity in participants with chronic musculoskeletal regional and widespread pain. DISCUSSION: The results of the present study suggest an association between sleep problems during adolescence and the presence of musculoskeletal pain at a later stage. These findings are consistent with adult literature suggesting a link between sleep problems and musculoskeletal pain. Given these associations, sleep problems in adolescence may be an important risk factor for musculoskeletal pain. PMID- 25299478 TI - Prognostic significance of complications after laparoscopic colectomy for colon cancer. AB - AIMS: This study sought to evaluate the prognostic significance of postoperative complications for colon cancer patients undergoing laparoscopic surgery. METHODS: From May 2006 to May 2009, a total 224 patients who underwent laparoscopic curative resection (R0) for colon cancer were included in our retrospective study. Postoperative complications were evaluated according to a standardized grading system. The main outcome measurements of our study were overall survival (OS) and relapse-free survival (RFS), which were then compared between the no complication and complication groups. Univariate and multivariate analysis were used to assess the correlation between complications and prognosis. RESULTS: Fifty-nine postoperative complications occurred in 43 patients. The overall morbidity rate was 26.3%. The 5-year OS in the complication group was 41.4% compared with 78.5% in the no complication group (P<0.001). The cumulative incidence of relapse was also more aggressive in patients with complications (5 year RFS: complication group 40.9% vs. no complication group 82.1%, P<0.001). Multivariate analysis identified complications as a significant factor increasing the risk for both OS (RR 2.737; 95% CI 1.512-4.952; P = 0.001) and RFS (RR 4.247; 95% CI 2.291-7.876; P<0.001). CONCLUSION: Postoperative complications could pose a significant adverse impact not only on OS but also on RFS in patients with colon cancer even when laparoscopic R0 resection is available. PMID- 25299479 TI - Preventive activity of olive oil phenolic compounds on alkene epoxides induced oxidative DNA damage on human peripheral blood mononuclear cells. AB - The aim of this study was to investigate the ability of epoxides of styrene (styrene-7,8-oxide; SO) and 1,3-butadiene (3,4-epoxy-1-butene; 1,2:3,4: diepoxybutane) to cause oxidative stress and oxidative DNA damage on human peripheral blood mononuclear cells (PBMCs) and whether a complex mixture of olive oil phenols (OOPE) could prevent these effects. The DNA damage was measured by the single-cell gel electrophoresis (SCGE; comet assay). We found that the DNA damage induced by alkene epoxides could be prevented by N-acetyl-cysteine (10 mM) and catalase (100 U/ml). Alkene epoxides caused a significant (P < 0.05) increase of both peroxide concentration in extra- and intracellular environment and formamidopyrimidine DNA glycosylase (FPG)- and Endonuclease III (ENDO III) sensitive sites in PBMCs, demonstrating the presence of oxidized bases. OOPE (1 MUg of total phenols/ml) was able to prevent the alkene epoxide induced DNA damage both after 2 and 24 h of incubation. In addition, OOPE completely inhibited the SO-induced intracellular peroxide accumulation in PBMCs and prevented the oxidative DNA damage induced by SO, as evidenced by the disappearance of both FPG- and ENDO III-sensitive sites. This is the first study demonstrating the ability of OOPE to prevent the DNA damage induced by alkene epoxides providing additional information about the chemopreventive properties of olive oil. PMID- 25299480 TI - Synthesis, characterization, and spectroscopic investigation of new iron(III) and copper(II) complexes of a carboxylate rich ligand and their interaction with carbohydrates in aqueous solution. AB - New tetra-iron(III) (K4[1].25H2O.(CH3)2CO and K3[2].3H2O.(OH)) and di-copper(II) (Na3[3].5H2O) complexes as carbohydrate binding models have been synthesized and fully characterized used several techniques including single crystal X-ray crystallography. Whereas K4[1].25H2O.(CH3)2CO and Na3[3].5H2O are completely water-soluble, K3[2].3H2O.(OH) is less soluble in all common solvents including water. The binding of substrates, such as d-mannose, d-glucose, d-xylose, and xylitol with the water-soluble complexes in different reaction conditions were investigated. In aqueous alkaline media, complexes K4[1].25H2O.(CH3)2CO and Na3[3].5H2O showed coordination ability toward the applied substrates. Even in the presence of stoichiometric excess of the substrates, the complexes form only 1:1 (complex/substrate) molar ratio species in solution. Apparent binding constants, pKapp, values between the complexes and the substrates were determined and specific mode of substrate binding is proposed. The pKapp values showed that d-mannose coordinates strongest to K4[1].25H2O.(CH3)2CO and Na3[3].5H2O. Syntheses, characterizations and detailed substrate binding study using spectroscopic techniques and single crystal X-ray diffraction are reported. PMID- 25299482 TI - Discovery of wall-selective carbon nanotube growth conditions via automated experimentation. AB - Applications of carbon nanotubes continue to advance, with substantial progress in nanotube electronics, conductive wires, and transparent conductors to name a few. However, wider application remains impeded by a lack of control over production of nanotubes with the desired purity, perfection, chirality, and number of walls. This is partly due to the fact that growth experiments are time consuming, taking about 1 day per run, thus making it challenging to adequately explore the many parameters involved in growth. We endeavored to speed up the research process by automating CVD growth experimentation. The adaptive rapid experimentation and in situ spectroscopy CVD system described in this contribution conducts over 100 experiments in a single day, with automated control and in situ Raman characterization. Linear regression modeling was used to map regions of selectivity toward single-wall and multiwall carbon nanotube growth in the complex parameter space of the water-assisted CVD synthesis. This development of the automated rapid serial experimentation is a significant progress toward an autonomous closed-loop learning system: a Robot Scientist. PMID- 25299483 TI - Auditory symptoms as an unrecognized manifestation of opioid toxicity: two case reports. AB - Neuropsychiatric and gastrointestinal side effects of opioids are well documented, but self-reported hearing disturbance from opioids is often unrecognized. Two cases are presented illustrating a possible association between auditory symptoms and opioid toxicity. Possible mechanisms are discussed. PMID- 25299481 TI - Benefit of insecticide-treated nets, curtains and screening on vector borne diseases, excluding malaria: a systematic review and meta-analysis. AB - INTRODUCTION: Insecticide-treated nets (ITNs) are one of the main interventions used for malaria control. However, these nets may also be effective against other vector borne diseases (VBDs). We conducted a systematic review and meta-analysis to estimate the efficacy of ITNs, insecticide-treated curtains (ITCs) and insecticide-treated house screening (ITS) against Chagas disease, cutaneous and visceral leishmaniasis, dengue, human African trypanosomiasis, Japanese encephalitis, lymphatic filariasis and onchocerciasis. METHODS: MEDLINE, EMBASE, LILACS and Tropical Disease Bulletin databases were searched using intervention, vector- and disease-specific search terms. Cluster or individually randomised controlled trials, non-randomised trials with pre- and post-intervention data and rotational design studies were included. Analysis assessed the efficacy of ITNs, ITCs or ITS versus no intervention. Meta-analysis of clinical data was performed and percentage reduction in vector density calculated. RESULTS: Twenty-one studies were identified which met the inclusion criteria. Meta-analysis of clinical data could only be performed for four cutaneous leishmaniasis studies which together showed a protective efficacy of ITNs of 77% (95%CI: 39%-91%). Studies of ITC and ITS against cutaneous leishmaniasis also reported significant reductions in disease incidence. Single studies reported a high protective efficacy of ITS against dengue and ITNs against Japanese encephalitis. No studies of Chagas disease, human African trypanosomiasis or onchocerciasis were identified. CONCLUSION: There are likely to be considerable collateral benefits of ITN roll out on cutaneous leishmaniasis where this disease is co-endemic with malaria. Due to the low number of studies identified, issues with reporting of entomological outcomes, and few studies reporting clinical outcomes, it is difficult to make strong conclusions on the effect of ITNs, ITCs or ITS on other VBDs and therefore further studies be conducted. Nonetheless, it is clear that insecticide-treated materials such as ITNs have the potential to reduce pathogen transmission and morbidity from VBDs where vectors enter houses. PMID- 25299484 TI - The influence of medical student gender and drug use on the detection of addiction in patients. AB - Little is known about medical students' interest in their training on drug addiction, their personal experience of consumption, and whether these aspects influence the detection of addiction in patients. Eighty-eight and one half percent considered that drug dependence issues are important to their professional future. The students report consuming alcohol (69%), cigarettes (19.5%), and illegal drugs (15.8%). Female students consumed fewer illegal drugs than the men (p =.022). Male students consumed more illegal drugs more frequently (p =.005), knew more consumers (p =.023), and those who drink alcohol consumed more illegal drugs than women who drink alcohol (p <.005). Drug and alcohol consumption among medical students may serve to normalize consumption and thus, may prevent the detection of addicts. It is important to educate and raise awareness about drugs and alcohol use, as this may influence detection. The focus should be particularly on the male group. PMID- 25299486 TI - Gasification of agricultural residues in a demonstrative plant: corn cobs. AB - Biomass gasification couples the high power efficiency with the possibility of valuably using the byproducts heat and biochar. The use of agricultural wastes instead of woody feedstock extends the seasonal availability of biomasses. The downdraft type is the most used reactor but has narrow ranges of feedstock specifications (above all on moisture and particle size distribution), so tests on a demonstrative scale are conducted to prove the versatility of the gasifier. Measurements on pressure drops, syngas flow rate and composition are studied to assess the feasibility of such operations with corn cobs. Material and energy balances, and performance indexes are compared for the four tests carried out under different biomass loads (66-85 kg/h). A good operability of the plant and interesting results are obtained (gas specific production of 2 m3/kg, gas heating value 5.6-5.8 MJ/m3, cold gas efficiency in the range 66-68%, potential net power efficiency 21.1-21.6%). PMID- 25299485 TI - Fast evolution from precast bricks: genomics of young freshwater populations of threespine stickleback Gasterosteus aculeatus. AB - Adaptation is driven by natural selection; however, many adaptations are caused by weak selection acting over large timescales, complicating its study. Therefore, it is rarely possible to study selection comprehensively in natural environments. The threespine stickleback (Gasterosteus aculeatus) is a well studied model organism with a short generation time, small genome size, and many genetic and genomic tools available. Within this originally marine species, populations have recurrently adapted to freshwater all over its range. This evolution involved extensive parallelism: pre-existing alleles that adapt sticklebacks to freshwater habitats, but are also present at low frequencies in marine populations, have been recruited repeatedly. While a number of genomic regions responsible for this adaptation have been identified, the details of selection remain poorly understood. Using whole-genome resequencing, we compare pooled genomic samples from marine and freshwater populations of the White Sea basin, and identify 19 short genomic regions that are highly divergent between them, including three known inversions. 17 of these regions overlap protein coding genes, including a number of genes with predicted functions that are relevant for adaptation to the freshwater environment. We then analyze four additional independently derived young freshwater populations of known ages, two natural and two artificially established, and use the observed shifts of allelic frequencies to estimate the strength of positive selection. Adaptation turns out to be quite rapid, indicating strong selection acting simultaneously at multiple regions of the genome, with selection coefficients of up to 0.27. High divergence between marine and freshwater genotypes, lack of reduction in polymorphism in regions responsible for adaptation, and high frequencies of freshwater alleles observed even in young freshwater populations are all consistent with rapid assembly of G. aculeatus freshwater genotypes from pre-existing genomic regions of adaptive variation, with strong selection that favors this assembly acting simultaneously at multiple loci. PMID- 25299488 TI - Comparison of in-situ and ex-situ catalytic pyrolysis in a micro-reactor system. AB - In this study, we compared ex-situ catalytic pyrolysis (CP) and in-situ CP of hybrid poplar in a micro-reactor system. When both pyrolysis and catalysis were performed at 700 degrees C, the carbon yield of olefins was greater for ex-situ CP than for in-situ CP (17.4% vs. 5.4%). On the other hand, in-situ CP produced more aromatic hydrocarbons than ex-situ CP (26.1% vs. 18.9%). The remarkably high yield of olefins from ex-situ CP indicates the potential of exploiting the process to preferentially produce olefins as a primary product from biomass, with aromatics being the secondary products. The carbon yield of carbonaceous residues from ex-situ CP was 18.6% compared to 31.3% for in-situ CP. Substantial carbon was deposited as char during ex-situ CP, which could be easily recovered as by product, simplifying catalyst regeneration. The effects of catalyst loading, pyrolysis temperature and catalysis temperature on product distributions for ex situ CP were also investigated. Our results showed that catalyst temperature strongly affected product distribution. While high catalyst temperature enhanced both olefin and aromatic production, yield of olefin increased to a greater extent than did aromatics. Neither pyrolysis temperature nor catalyst loadings had significant effect on product distribution for ex-situ CP. PMID- 25299487 TI - Pyrite-based autotrophic denitrification for remediation of nitrate contaminated groundwater. AB - In this study, pyrite-based denitrification using untreated pyrite (UP) and acid pretreated pyrite (AP) was evaluated as an alternative to elemental sulfur based denitrification. Pyrite-based denitrification resulted in a favorable nitrate removal rate constant (0.95 d(-1)), sulfate production of 388.00 mg/L, and a stable pH. The pretreatment of pyrite with acid led to a further increase in the nitrate removal rate constant (1.03 d(-1)) and reduction in initial sulfate concentration (224.25+/-7.50 mg/L). By analyzing the microbial community structure using Denaturing Gradient Gel Electrophoresis, it was confirmed that Sulfurimonas denitrificans (S. denitrificans) could utilize pyrite as an electron donor. A stable pH was observed over the entire experimental period, indicating that the use of a pH buffer reagent would not be necessary for pyrite-based denitrification. Therefore, pyrite could effectively replace elemental sulfur as an electron donor in autotrophic denitrification for nitrate-contaminated groundwater remediation. PMID- 25299489 TI - Lipid production by a mixed culture of oleaginous yeast and microalga from distillery and domestic mixed wastewater. AB - Lipid productivity by mixed culture of Rhodosporidium toruloides and Chlorella pyrenoidosa was studied using 1:1 mixed real wastewater from distillery and local municipal wastewater treatment plant with initial soluble chemical oxygen demand (SCOD) around 25,000 mg/L, initial cell density of 2*10(7) cells/mL (yeast) and 5*10(6) cells/mL (microalga), at 30 degrees C and 2.93 W/m2 (2000 lux, 12:12 h light and dark cycles). Lipid content and lipid yield achieved were 63.45+/-2.58% and 4.60+/-0.36 g/L with the associated removal efficiencies for SCOD, total nitrogen (TN), and total phosphorus (TP) at 95.34+/-0.07%, 51.18+/-2.17%, and 89.29+/-4.91%, respectively, after 5 days of cultivation without the pH adjustment. Inoculation of microalgae at 40 h of the initial yeast cultivation and harvesting part of inactive biomass at 72 h by sedimentation could improve both lipid production and wastewater treatment efficiency under non-sterile conditions. PMID- 25299490 TI - A multiscale three-zone reactive mixing model for engineering a scale separation in enzymatic hydrolysis of cellulose. AB - This multiscale three-zone reactive mixing model provides a theoretical framework for engineering a scale separation in batch enzymatic hydrolysis of cellulose to strategize significant leaps in glucose yields. Formulated using the Liapunov Schmidt method of the classical bifurcation theory, our model explores the multiscale spatiotemporal dynamics between the fundamental processes of macromixing (convection) and micromixing (diffusion) of the enzymes (Endoglucanase, Exoglucanase, beta-glucasidase) and reducing sugars, adsorption and desorption of enzymes on the solid cellulosic substrates, and the product inhibited liquid and solid phase enzymatic reactions that depolymerize microcrystalline cellulose (Avicel). The model is validated for a range of substrate loadings (2-5%) using our experimental results for the two asymptotic cases of no mixing and continuous mixing, as well as for the macro/micro scale separated optimal mixing strategy that increases the glucose yield by up to 26% by macromixing completely for an initial period followed by micromixing for the remaining duration of the hydrolysis. PMID- 25299491 TI - Influence of high gravity process conditions on the environmental impact of ethanol production from wheat straw. AB - Biofuel production processes at high gravity are currently under development. Most of these processes however use sugars or first generation feedstocks as substrate. This paper presents the results of a life cycle assessment (LCA) of the production of bio-ethanol at high gravity conditions from a second generation feedstock, namely, wheat straw. The LCA used lab results of a set of 36 process configurations in which dry matter content, enzyme preparation and loading, and process strategy were varied. The LCA results show that higher dry matter content leads to a higher environmental impact of the ethanol production, but this can be compensated by reducing the impact of enzyme production and use, and by polyethylene glycol addition at high dry matter content. The results also show that the renewable and non-renewable energy use resulting from the different process configurations ultimately determine their environmental impact. PMID- 25299492 TI - Trace analysis of methylated and hydroxymethylated cytosines in DNA by isotope dilution LC-MS/MS: first evidence of DNA methylation in Caenorhabditis elegans. AB - From 1986 to the present, the popular research model organism Caenorhabditis elegans has been thought to completely lack DNA methylation and seems to have lost DNA methylation enzymes from its genomes. In the present study, we report the development of a sensitive and selective assay based on LC-MS/MS to simultaneously measure 5-methyl-2'-deoxycytidine (5-mdC) and 5-hydroxymethyl-2' deoxycytidine (5-hmdC) in DNA hydrolysates. With the use of isotope internal standards ([2H3]5-mdC and [2H3]5-hmdC) and online solid-phase extraction, the detection limits of 5-mdC and 5-hmdC were estimated to be 0.01 and 0.02 pg respectively, which correspond to a 0.000006% and 0.00001% methylation and hydroxymethylation level. This method was applied to investigate whether DNA methylation/hydroxymethylation exists in C. elegans. The present study for the first time demonstrates that 5-mdC is present in C. elegans genomic DNA (0.0019 0.0033% of cytosine methylated) using LC-MS/MS, whereas another epigenetic modification, 5-hmdC, is not detectable. Furthermore, we found that C. elegans DNA was hypo- or hyper-methylated in a dose-dependent manner by the DNA methyltransferase (DNMT)-inhibiting drug decitabine (5-aza-2'-deoxycytidine) or cadmium respectively. Our data support the possible existence of an active DNA methylation mechanism in C. elegans, in which unidentified DNMTs could be involved. The present study highlights the importance of re-evaluating the evolutionary conservation of DNA-methylation machinery in nematodes which were traditionally considered to lack functional DNA methylation. PMID- 25299493 TI - Differences in the chemical profiles and biological activities of Paeonia lactiflora and Paeonia obovata. AB - Paeonia lactiflora and P. obovata are perennial herbs, each root of which has been consumed as a major oriental medicine, Paeoniae Radix and a famous folk medicine, Mountain Paeony Root, respectively. Although morphological studies have been performed comparing these two plants, there is insufficient scientific evidence that characterizes the differences in their chemical profiles and biological activities. Hence, the present study was undertaken to compare these two medicinal foods using a high-performance liquid chromatography-diode-array detector (HPLC-DAD) analysis and a gastric ulcer model in mice. HPLC analysis employed to assess the nine components revealed that P. lactiflora exhibited higher contents of phenolic compounds than P. obovata. Although a monoterpene glycoside, 6'-O-acetylpaeoniflorin was identified in P. obovata, it was not detected in P. lactiflora. Multivariate statistical analysis for HPLC data revealed that the orthogonal projections to latent structure-discriminant analysis is more appropriate than principal component analysis for differentiating the two groups. Moreover, the 50% methanol P. lactiflora extract (PL) was more effective against experimental gastric ulcer than P. obovata extract (PO) in the HCl/ethanol-induced ulcer model. In addition, PL displayed higher 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and lower nitric oxide production in a murine macrophage cell line, RAW 264.7, than PO. The DPPH radical scavenging activity of PL was as high as that of the positive control, butylated hydroxytoluene, at a concentration of 25 MUg/mL. PMID- 25299494 TI - Chronic complaints after ankle sprains: a systematic review on effectiveness of treatments. AB - STUDY DESIGN: Systematic review. Objective To determine the effectiveness of treatments for patients with chronic complaints after ankle sprain. BACKGROUND: Though most people recover completely after a lateral inversion ankle injury, a considerable percentage have persistent complaints. Currently, it is still unclear which treatment options are best for these patients. METHODS: Major databases, including PubMed, Embase, CINAHL, and PEDro, were searched for randomized controlled trials and controlled clinical trials conducted from 1966 to October 2012. Due to clinical heterogeneity, the data were analyzed using a best-evidence synthesis. RESULTS: A total of 20 randomized controlled trials and 1 controlled clinical trial were included in the analysis. The included studies compared different treatments (training programs, physiotherapy, chiropractic/manual therapy, surgery, postoperative training, and functional treatment). For pain and function outcomes, limited to moderate evidence was found for effectiveness of a training program compared to conservative treatment. Two studies found a decrease of recurrences after a proprioceptive training program. Four studies showed good results for different surgical methods but did not include a nonsurgical control group for comparison. Limited evidence was found for the effectiveness of an early mobilization program after surgery. CONCLUSION: In chronic ankle complaints after an ankle sprain, a training program gives better results for pain and function, and a decrease of recurrent ankle sprains, than a wait-and-see policy. There was insufficient evidence to determine the most effective surgical treatment, but limited evidence suggests that postoperative, early mobilization was more effective than a plaster cast. LEVEL OF EVIDENCE: Therapy, level 1a-. PMID- 25299497 TI - Sustained ventricular tachycardia in structural heart disease. AB - Ventricular arrhythmias are responsible for the majority of sudden cardiac deaths (SCD), particularly in patients with structural heart disease. Coronary artery disease, essentially previous myocardial infarction, is the most common heart disease upon which sustained ventricular tachycardia (VT) occurs, being reentry the predominant mechanism. Other cardiac conditions, such as idiopathic dilated cardiomyopathy, Chagas disease, sarcoidosis, arrhythmogenic cardiomyopathies, and repaired congenital heart disease may also present with VT in follow-up. Analysis of the 12-lead electrocardiogram (ECG) is essential for diagnosis. There are numerous electrocardiographic criteria that suggest VT with good specificity. The ECG also guides us in locating the site of origin of the arrhythmia and the presence of underlying heart disease. The electrophysiological study provides valuable information to establish the mechanism of the arrhythmia and guide the ablation procedure, as well as to confirm the diagnosis when dubious ECG. Given the poor efficacy of antiarrhythmic drug therapy, adjunctive catheter ablation contributes to reduce the frequency of VT episodes and the number of shocks in patients implanted with a cardioverter-defibrillator (ICD). ICD therapy has proven to be effective in patients with aborted SCD or sustained VT in the presence of structural heart disease. It is the only therapy that improves survival in this patient population and its implantation is unquestioned nowadays. PMID- 25299496 TI - CDX-2, MUC-2 and B-catenin as intestinal markers in pure mucinous carcinoma of the breast. AB - BACKGROUND: Pure mucinous adenocarcinoma of the breast is a rare entity characterized by the production of variable amounts of mucin comprising 1% to 6% of breast carcinomas. Some mucinous adenocarcinomas have shown expression of intestinal differentiation markers such as MUC-2. This study examines the expression of intestinal differentiation markers in this type of breast carcinoma. RESULTS: Twenty-two cases of pure mucinous adenocarcinoma of the breast were assessed. Immunochemistry was performed for beta-catenin, CDX-2 and MUC-2. All cases were positive for B-catenin. MUC-2 positivity was observed in all cases; 63. 6% were 3 plus positive. All cases were negative for CDX-2. CONCLUSIONS: These results suggest that mucinous breast carcinomas express some markers of intestinal differentiation, such as MUC-2 and beta-catenin; however, future studies with a larger series of cases and using molecular techniques that help affirm these results are needed. PMID- 25299498 TI - Lead extraction: The road to successful cardiac resynchronization therapy. AB - BACKGROUND: Still increasing life expectancy in patients with implanted devices and large number of leads more and more often induce the need to cure the treatment complications or to change especially to cardiac resynchronization therapy (CRT). In order to prevent further complications, the possibility of damaged or redundant leads extraction should be taken into consideration. The aim of the paper was to assess the effectiveness and safety of transvenous lead extraction (TLE) with co-implantation of resynchronization systems. METHODS AND RESULTS: Between 2008 and March 2013, the system removal with TLE was conducted in 246 patients. In 38 patients (11 women, 28.9%), aged 43-79 (mean 65 years), it was combined with co-implantation of CRT-pacemaker or defibrillator (CRT-P/D). Indications for TLE covered: lead failure in 21 (55.3%) patients, redundant leads in 6 (15.8%), and the occluded venous system in 7 (18.4%). The up-grade of the pacemaker or defibrillator system to CRT-D was performed in 19 cases, CRT-P/D revision in next 19. Together 32 defibrillation leads and 42 pacing leads (27 left ventricular leads, and 1 epicardial lead) were implanted. The intended clinical target--an effective resynchronization therapy--was obtained in all patients. There was no case of death or severe complications. In 2 cases of venous occlusion, the implantation on the contralateral side was required. CONCLUSIONS: TLE enables effective resynchronization therapy also in the case of the presence of too many leads, occlusion of the venous system or lead failure. Significant technical problems can occur especially in patients with venous system occlusion. PMID- 25299499 TI - Ambulatory postural blood pressure changes and history allow a better selection of patients that should undergo a head-up tilt test. AB - BACKGROUND: Syncope is a common symptom and in most cases it is of a neurally mediated origin. Such patients have to be studied with a careful history and a physical exploration that should include simple maneuvers such as blood pressure (BP) recordings in decubitus and standing position. These tools can suggest diagnosis in a good percentage of patients without the need for expensive or invasive testing. METHODS: We carried out a prospective observational study measuring BP and heart rate (HR) with the patients in decubitus and just as they stood up. The patients were sent for a tilt table test in different specialized centers. The BP changes were compared to the results of the tilt test. RESULTS: We included 215 patients, 36.1 +/- 18.8 years old, 118 (54.9%) feminine, of which 143 (66.5%) had a positive tilt test. Patients with a positive test showed a rise in systolic BP (SBP) (121.7 +/- 19.1 vs. 124.2 +/- 20, p < 0.005) and in diastolic BP (DBP) (75 +/- 11 vs. 78 +/- 11.3, p < 0.005) when compared to people with a negative one. On the other hand, percentage BP changes were significantly different (SBP 2.24% vs. 0.48%, p = 0.02; DBP 4.1% vs. 1.2%, p = 0.009). Patients with a positive test had also a lower HR on standing up (72.1 +/- +/- 11.1 vs. 78.3 +/- 17.2, p = 0.01). CONCLUSIONS: Patients with neurally mediated syncope showed an elevation of SBP and DBP when standing up actively, unlike subjects with a negative tilt test. PMID- 25299501 TI - Adjunctive mild hypothermia therapy to primary percutaneous coronary intervention in patients with ST segment elevation myocardial infarction complicated with cardiogenic shock: A pilot feasibility study. AB - BACKGROUND: Despite successful primary reperfusion therapy, patients may develop large myocardial infarction related in part to reperfusion injury. Induction of mild therapeutic hypothermia (TH) applied in patients has demonstrated beneficial effect in reducing reperfusion injury. The aim of the study was to evaluate the feasibility and safety of adjunctive mild TH to primary percutaneous coronary intervention (PPCI) in patients with acute ST elevation myocardial infarction (STEMI) complicated with cardiogenic shock (CS). METHODS: We conducted a prospective single center, open label, historical control study. Patients presenting with STEMI and CS despite maximal support therapy scheduled for PPCI were included. Death was defined as primary endpoint. Secondary outcomes included: TH adverse effect--such as fever, refractory hypotension and arrhythmias, infarct size measured by area under the curve of biomarkers. RESULTS: Eight consecutive patients were prospectively enrolled (TH group). Thirteen clinically similar patients identified from our database, admitted over 2 years, comprised the historical control group (control group). In the hypothermia group, the mortality was 50% compared with 46% in the control group. There was no difference in the secondary outcomes. CONCLUSIONS: TH as adjunctive therapy in STEMI patients complicated with CS is feasible and safe. Based on these preliminary observations there appears to be no significant clinical advantage to this form of therapy. PMID- 25299500 TI - Secondary prevention of coronary artery disease in contemporary clinical practice. AB - BACKGROUND: The highest priority in preventive cardiology was given to patients with established coronary artery disease (CAD). The aim of the study was to assess the implementation of guidelines for secondary prevention in everyday clinical practice by evaluating control of the main risk factors and the cardioprotective medication prescription rates for patients, following their hospitalization for CAD. METHODS: Five hospitals with cardiology departments serving the city and its surround-ing districts in southern part of Poland participated in the study. Consecutive patients aged <= 80 years, hospitalized from January 1 2010 to April 31 2012 due to an acute coronary syndrome or for a myocardial revascularization procedure were recruited and interviewed 6-18 months after hospitalization. RESULTS: The medical records of 595 patients (mean age: 62.8 +/- 9.0 years, 397 men and 198 women) were reviewed and included in the analyses. Proportions of medical records with available information on risk factors were high with the exception of total cholesterol levels as well as weight and height measurements, which were available in less than 80% of the hospital records. The prescription rate at discharge for antiplatelets was 99%, beta-blockers (BB)--85%, angiotensin converting enzyme inhibitors (ACEI) or sartans--85%, and lipid-lowering drugs--94%. Patients scheduled for coronary artery bypass grafting were significantly less often prescribed BB, ACEI or sartans, and lipid-lowering drugs. The proportion of patients with high blood pressure (>= 140/90 mm Hg) 6-18 months after hospitalization was 47%, with high LDL cholesterol level (>= 1.8 mmol/L) 73%, and with a high HbA1c level (>= 7.0%) 14%, whereas 20% of participants were smokers and 80% were overweight. The proportion of patients taking an antiplatelet agent 6-18 months after hospitalization was 90%, BB--82%, ACEI--or sartan 78%, and lipid-lowering drug- 82%. Overall, 33.9% of the study participants declared that they had been advised to participate in a rehabilitation/secondary prevention program following their hospitalization and 30.5% participated in a rehabilitation/secondary prevention program. However, only 28.2% took part in at least half of the planned sessions. Using a multivariate analysis we showed that, in general, risk factors control and the prescription rates of cardioprotective medications were related to the patients' age, education, and participation in a rehabilitation/secondary prevention program following their hospitalization due to CAD. CONCLUSIONS: Our data provide evidence that there is a considerable potential for further reduction of cardiovascular risk in CAD patients. Our results suggest that increasing patient participation rates in rehabilitation/secondary prevention programs may improve the implementation of the secondary prevention. PMID- 25299502 TI - Left atrial appendage closure with the AmplatzerTM Cardiac Plug: Rationale for a higher degree of device oversizing at implantation. AB - BACKGROUND: In left atrial appendage (LAA) closure, the correct sizing of the implantable devices is crucial. Data on the time-dependent changes in the shape and positioning of LAA occlusion devices are missing. We analyzed the results of 33 consecutive patients after implantation of an AmplatzerTM Cardiac Plug (ACP) LAA closure device to get more information on the optimal device sizing during implantation. METHODS AND RESULTS: Thirty-three consecutive patients were enrolled in this observational study. ACP implantation was guided by fluoroscopy and three dimensional transesophageal echocardiography (3-D TEE). Device sizing was based on the largest measured diameter of the intended landing zone adding 2 4 mm of device oversizing. Fluoroscopies were performed at 1 day after, and after 3 months, control 3-D TEE was performed 3 months after implantation. The stability of device positioning and shape was matched with the results of 3-D TEE. Patients' mean age was 70.2 +/- 8 years; mean CHA2DS2VASc score was 3.8 +/- 1.1. According to the manufacture's classification, the post-implant degree of compression of the device-lobe was classified in three categories 1) undercompression "square-like shape" (1 patient); 2) optimal compression "tire like shape" (20 patients), 3) overcompression "strawberry-like shape" (12 patients). Changes in the degree of device compression by more than one classification class occurred in 18/33 of our patients. A complete loss of device compression ("square-like shape") was observed in 9 patients. Despite the changes in device compression, a complete closure of the LAA was achieved in 32/33 patients. CONCLUSIONS: There is a temporal change in shape and positioning of the ACP within 3 months after implantation. A late decompression of the ACP lobe was observed in 61% of our patients, leading to a complete loss in device compression in 27%. This observation may be the rationale for a higher degree of ACP oversizing during implantation. PMID- 25299504 TI - Managing psychogenic pseudosyncope: Facts and experiences. AB - Psychogenic pseudosyncope (PPS) is a common cause of apparent transient loss of consciousness (TLOC) with a dramatic impact on the quality of life. This review aims to give an overview of the definition, incidence, etiology, diagnosis, treatment, and prognosis of PPS based on a combination of literature data and personal experience. The limited literature on the subject suggests that PPS is relatively common but insufficiently recognized. PPS is probably similar to psychogenic nonepiteptic seizures (PNES), in which a long delay to diagnosis worsens the prognosis. A detailed history is of paramount importance for the diagnosis. The key feature in the history of patients with PPS is the occurrence of frequent, long attacks of apparent TLOC with closed eyes. The diagnosis is certain when a typical event is recorded during a tilt-table test with simultaneous blood pressure (BP), heart rate and video-electroencephalographic recordings. Home video and BP recording during an attack can be very useful. The diagnosis should be communicated to the patient in a way that is clear, understandable and does not cause offense. Although treatment options have not been investigated formally, the literature on PNES suggests that cognitive behavioral therapy is beneficial. PMID- 25299503 TI - Cardiovascular risk management in type 2 diabetes of more than 10-year duration: Results of Polish ARETAEUS2-Grupa Study. AB - BACKGROUND: ARETAEUS 1 study showed that a great majority of patients with type 2 diabetes mellitus (T2DM) of short duration did not meet all of the treatment goals. Since then the treatment goals in T2DM have been changed. The aim of the ARETAEUS 2-Grupa Study was to assess cardiovascular (CV) risk management and meeting treatment goals in the population of T2DM of more than 10-year duration. METHODS: ARETAEUS2-Grupa was a cross-sectional questionnaire-based study conducted in Poland in 2012. Randomly selected physicians recruited 1,740 patients with T2DM diagnosed more than 10 years before the study. RESULTS: Lipid treatment goals were met respectively: for total cholesterol in 34.5% of all patients, triglycerides in 53.8%, low density lipoprotein cholesterol (LDL-C) in 26.5% and high density lipoprotein cholesterol (HDL-C) in 38.2%. Most of patients with and without coronary artery disease were receiving aspirin (90.3% and 60%, respectively) and statins (84.4% and 67.7%, respectively). The current blood pressure (BP) goal (140/90 mm Hg) was met in 43.5% of patients and the previous goal (< 130/80 mm Hg) in 12.4%. The patients were mainly treated with >= 3 antihypertensive drugs. All treatment goals (for HbA1c, BP and LDL-C) were reached only by 8.2% of patients, any two goals by 26.3% of patients, one goal by 39.8% of patients, none by 25.6% of patients. CONCLUSIONS: The new less restrictive treatment goals are reached more frequently but still much is to be done in the field of clinical practice guidelines implementation and CV prevention in T2DM population. PMID- 25299505 TI - Is hospital admission valuable in managing syncope? Results from the STePS study. AB - The proper way to test the usefulness of hospitalization in syncope patients would be to conduct a randomized controlled trial. However, this approach is characterized by major theoretical and ethical limitations which make this procedure unfeasible. Data from observational studies indirectly show that hospitalization might help reduce the short-term risk of death and adverse events by promptly identifying and treating life-threatening events or conditions. Future research should focus on identifying which patients will benefit from hospitalization. In this regard, we should be able both to correctly risk stratify patients and to analyze syncope observation units and protocols, which may provide a safe alternative for the evaluation of intermediate-risk patients. PMID- 25299506 TI - Neuropeptides and peptide hormones in syncope and orthostatic intolerance. AB - Syncope and orthostatic intolerance (OI) are common clinical syndromes often requiring medical attention. The former is defined as transient loss of consciousness and postural tone due to self-limited cerebral hypoperfusion, while the latter consists of inappropriate cardiovascular responses to upright posture such as occur with orthostatic hypotension (OH) or postural orthostatic tachycardia syndrome. The most frequent causes of syncope and OI are conditions that temporarily disrupt essential moment-to-moment interaction between the autonomic nervous system and cardiovascular system. In this regard, many neuropeptides (NPs) or peptide hormones (PH) exert cardioactive effects that might contribute to the pathophysiology of certain forms of syncope or OI. To date, the principal peptides that have been studied in this context are: atrial and B-type-neuropeptides, adrenomedullin, endothelin-1 (ET-1), galanin, and vasopressin. While definitive conclusions cannot yet be drawn, the intrinsic vasoconstrictor ET-1 appears to be elevated in OH, presumably to compensate for vasodilation and hypotension of other etiologies. As such elevated ET-1 may become a marker for OH. Further, elevated NT-proBNP may play a role in causing vasodilation and hypotension in some forms of OH of previously unknown cause, and may be a marker in other patients of a cardiovascular cause of syncope and OI. In the end, the study of the role of NPs and PHs in syncope and OI syndromes is at an early stage, and considerable further future effort is needed. PMID- 25299507 TI - Is syncope a risk predictor in the general population? AB - Syncope in the general population is a frequent event often leading to hospitalization, but it is unclear whether syncope in the general population is an independent risk marker for adverse prognosis. In this review, we investigate the current literature and evaluate the prognosis and impact of syncope on adverse outcomes including death and recurrences across different populations with focus on the general population. In wide terms, a syncopal event is related to a higher risk of subsequent falls and injury and cardiac syncope is particularly associated with increased mortality as compared to non-cardiac syncope. The overall prognosis in the general population is by large determined by the underlying presence and severity of a given cardiac disease, but a given underlying cardiac disease can very well be unknown at the time of first syncope so that syncope is the presenting symptom resulting in an independent risk increase. Moreover, syncope is a significant risk predictor of a recurrence across populations. It is important to recognize several risk factors associated with adverse outcome in order to safely navigate in a population where most patients with syncope are healthy and low-risk but where a small number of patients have life-threatening conditions. Further research in the general population should attempt to categorize which patients with syncope need immediate referral and diagnostic testing, and whether this affects the outcome. PMID- 25299508 TI - How can we improve management of syncope in the Emergency Department? AB - Syncope is a common and challenging presenting complaint to the Emergency Department (ED). Despite substantial research efforts, there is still considerable uncertainty about the optimal ED management of syncope. There is continued interest among clinicians and researchers in improving diagnostic algorithms and optimizing resource utilization. In this paper, we discuss 4 strategies to improve the emergency care of syncope patients: (1) Development of accurate and consistent risk-stratification, (2) Increased use of syncope observation protocols, (3) Evaluation of a discharge with ambulatory monitoring pathway, (4) Use of shared decision-making for disposition decisions. Since current risk-stratification tools have fallen short with regard to subsequent validation and implementation into clinical practice, we outline key factors for future risk-stratification research. We propose that observation units have the potential to safely decrease length-of-stay and hospital costs for hemodynamically stable, intermediate risk patients without adversely affecting clinical outcomes. For appropriate patients with a negative ED evaluation, we recommend consideration of direct discharge, with ambulatory monitoring and expedited follow-up, as a means of decreasing costs and reducing iatrogenic harms. Finally, we advocate for the use of shared decision-making regarding the ultimate disposition of select, intermediate risk patients who have not had a serious condition revealed in the ED. If properly implemented, these four strategies could significantly improve the care of ED syncope patients by helping clinicians identify truly high-risk patients, decreasing unnecessary hospitalizations, and increasing patient satisfaction. PMID- 25299509 TI - Toxicity of brominated flame retardants, BDE-47 and BDE-99 stems from impaired mitochondrial bioenergetics. AB - Polybrominated diphenyl ethers (PBDEs) are used as flame retardants, and they have been detected in human blood, adipose tissue and breast milk, a consequence of their physicochemical and bioaccumulative properties, as well as their high environmental persistence. Many studies report liver toxicity related to exposure to PBDEs. In the present study, we investigated the toxicity of BDE-47 and BDE-99 at concentrations ranging from 0.1 to 50 uM in isolated rat liver mitochondria. We evaluated how incubation of a mitochondrial suspension with the PBDEs affected the mitochondrial inner membrane, membrane potential, oxygen consumption, calcium release, mitochondrial swelling, and ATP levels to find out whether the tested compound interfered with the bioenergetics of this organelle. Both PBDEs were toxic to mitochondria: BDE-47 and BDE-99 concentrations equal to or higher than 25 and 50 uM, respectively, modified all the parameters used to assess mitochondrial bioenergetics, which culminated in ATP depletion. These effects stemmed from the ability of both PBDEs to cause Membrane Permeability Transition (MPT) in mitochondria, which impaired mitochondrial bioenergetics. In particular, BDE-47, which has fewer bromine atoms in the molecule, can easily overcome biological membranes what would be responsible for the major negative effects exerted by this congener when compared with BDE-99. PMID- 25299510 TI - Applications and serious games: from docking to protein folding: general discussion. PMID- 25299511 TI - Twelve years of rabies surveillance in Sri Lanka, 1999-2010. AB - BACKGROUND: Rabies is endemic in Sri Lanka, but little is known about the temporal and spatial trends of rabies in this country. Knowing these trends may provide insight into past control efforts and serve as the basis for future control measures. In this study, we analyzed distribution of rabies in humans and animals over a period of 12 years in Sri Lanka. METHODS: Accumulated data from 1999 through 2010 compiled by the Department of Rabies Diagnosis and Research, Medical Research Institute (MRI), Colombo, were used in this study. RESULTS: The yearly mean percentage of rabies-positive sample was 62.4% (47.6-75.9%). Three fourths of the rabies-positive samples were from the Colombo, Gampaha, and Kalutara districts in Western province, followed by Galle in Southern province. A high percentage of the rabies samples were from dogs (85.2%), followed by cats (7.9%), humans (3.8%), wild animals (2.0%), and livestock (1.1%). Among wild animals, mongooses were the main victims followed by civets. The number of suspect human rabies cases decreased gradually in Sri Lanka, although the number of human samples submitted for laboratory confirmation increased. CONCLUSIONS: The number of rabid dogs has remained relatively unchanged, but the number of suspect human rabies is decreasing gradually in Sri Lanka. These findings indicate successful use of postexposure prophylaxis (PEP) by animal bite victims and increased rabies awareness. PEP is free of charge and is supplied through government hospitals by the Ministry of Health, Sri Lanka. Our survey shows that most positive samples were received from Western and Southern provinces, possibly because of the ease of transporting samples to the laboratory. Submissions of wild animal and livestock samples should be increased by creating more awareness among the public. Better rabies surveillance will require introduction of molecular methods for detection and the establishment of more regional rabies diagnostic laboratories. PMID- 25299512 TI - The association of metabolic syndrome and aging with cognition in Asian men. AB - BACKGROUND: The present cross-sectional study examined the associations of individual metabolic factors and age with the short-term memory and perceptual capacity in 472 healthy Asian men. METHODS: The symbol digit and digit span tests from the Swedish Performance Evaluation System were used to assess the perceptual capacity and memory cognitive domains. Linear regression with the stepwise method, and multivariate analyses of the General Linear Model with the Bonferroni correction for multiple comparisons were carried out with the SPSS 21.0 package. RESULTS: High blood pressure and HDL were not significantly associated with either short-term memory or perceptual capacity. Age and glucose level were negatively associated but regular physical exercise was positively associated with perceptual capacity. On the other hand, high triglyceride level (TG) was positively associated but high waist/height ratio was negatively associated with short-term memory. When men without any component of the metabolic syndrome (MetS) were compared with men with one, two or three or more components of MetS, no significant differences in cognitive performance were noted. CONCLUSION: Not all the metabolic factors were significantly associated with short-term memory or the perceptual capacity domains. Those that were did not show a sufficiently consistent pattern of association to support a role for MetS as a whole in cognitive decline with aging. It may not be meaningful to evaluate the association of MetS as a whole with cognition. PMID- 25299513 TI - Human induced pluripotent stem cell and nanotechnology-based therapeutics. AB - Human induced pluripotent stem cells (hiPSCs) can be genetically reprogrammed to an embryonic stem cell-like state and can provide promising medical applications, such as diagnosis, prognosis, drug screening for therapeutical development, and monitoring disease progression. Despite myriad advances, traditional viral-based reprogramming for generating hiPSCs has safety risks that hinder further practical applications of hiPSCs. In the past decade, nonviral-based reprogramming has been used as an alternative to produce hiPSCs and enhance their differentiation. In addition, the efficiency of nonviral-based reprogramming is generally poor, compared to that of viral-based reprogramming. Recent studies in nanoscale-structured particles have made progress in addressing many applications of hiPSCs for clinical practice. The combination of hiPSCs and nanotechnology will actually act as the therapeutic platform for personalized medicine and can be the remedies against various diseases in the future. In this article, we review recent advances in cellular reprogramming and hiPSC-related research, such as cell source, delivery system, and direct reprogramming, as well as some of its potential clinical applications, including mitochondrial and retinal disease. We also briefly summarize the current incorporation of nanotechnology in patient specific hiPSCs for future treatments. PMID- 25299514 TI - Response of African elephants (Loxodonta africana) to seasonal changes in rainfall. AB - The factors that trigger sudden, seasonal movements of elephants are uncertain. We hypothesized that savannah elephant movements at the end of the dry season may be a response to their detection of distant thunderstorms. Nine elephants carrying Global Positioning System (GPS) receivers were tracked over seven years in the extremely dry and rugged region of northwestern Namibia. The transition date from dry to wet season conditions was determined annually from surface- and satellite-derived rainfall. The distance, location, and timing of rain events relative to the elephants were determined using the Tropical Rainfall Measurement Mission (TRMM) satellite precipitation observations. Behavioral Change Point Analysis (BCPA) was applied to four of these seven years demonstrating a response in movement of these elephants to intra- and inter-seasonal occurrences of rainfall. Statistically significant changes in movement were found prior to or near the time of onset of the wet season and before the occurrence of wet episodes within the dry season, although the characteristics of the movement changes are not consistent between elephants and years. Elephants in overlapping ranges, but following separate tracks, exhibited statistically valid non-random near-simultaneous changes in movements when rainfall was occurring more than 100 km from their location. While the environmental trigger that causes these excursions remains uncertain, rain-system generated infrasound, which can travel such distances and be detected by elephants, is a possible trigger for such changes in movement. PMID- 25299515 TI - Mechanisms of photoconductivity in atomically thin MoS2. AB - Atomically thin transition metal dichalcogenides have emerged as promising candidates for sensitive photodetection. Here, we report a photoconductivity study of biased mono- and bilayer molybdenum disulfide field-effect transistors. We identify photovoltaic and photoconductive effects, which both show strong photogain. The photovoltaic effect is described as a shift in transistor threshold voltage due to charge transfer from the channel to nearby molecules, including SiO2 surface-bound water. The photoconductive effect is attributed to the trapping of carriers in band tail states in the molybdenum disulfide itself. A simple model is presented that reproduces our experimental observations, such as the dependence on incident optical power and gate voltage. Our findings offer design and engineering strategies for atomically thin molybdenum disulfide photodetectors, and we anticipate that the results are generalizable to other transition metal dichalcogenides as well. PMID- 25299516 TI - Preparation of efficient excision repair competent cell-free extracts from C. reinhardtii cells. AB - Chlamydomonas reinhardtii is a prospective model system for understanding molecular mechanisms associated with DNA repair in plants and algae. To explore this possibility, we have developed an in vitro repair system from C. reinhardtii cell-free extracts that can efficiently repair UVC damage (Thymine-dimers) in the DNA. We observed that excision repair (ER) synthesis based nucleotide incorporation, specifically in UVC damaged supercoiled (SC) DNA, was followed by ligation of nicks. Photoreactivation efficiently competed out the ER in the presence of light. In addition, repair efficiency in cell-free extracts from ER deficient strains was several fold lower than that of wild-type cell extract. Interestingly, the inhibitor profile of repair DNA polymerase involved in C. reinhardtii in vitro ER system was akin to animal rather than plant DNA polymerase. The methodology to prepare repair competent cell-free extracts described in the current study can aid further molecular characterization of ER pathway in C. reinhardtii. PMID- 25299519 TI - Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant. AB - The British Transplantation Society "Guideline for Transplantation Management of the Failing Kidney Transplant" was published in May 2014. This is the first national guideline in this field. In line with previous guidelines published by the British Transplantation Society, the guideline has used the GRADE system to rate the strength of evidence and recommendations.This article summarizes the Statements of Recommendation contained in the guideline, which provide a framework for the management of the failing kidney graft in the United Kingdom and may be of wide international interest. It is recommended that the full guideline document is consulted for details of the relevant references and evidence base. This may be accessed at: http://www.bts.org.uk/MBR/Clinical/Guidelines/Current/Member/Clinical/Current_Gui elines.aspx. PMID- 25299517 TI - Systematic analysis of Zn2Cys6 transcription factors required for development and pathogenicity by high-throughput gene knockout in the rice blast fungus. AB - Because of great challenges and workload in deleting genes on a large scale, the functions of most genes in pathogenic fungi are still unclear. In this study, we developed a high-throughput gene knockout system using a novel yeast-Escherichia Agrobacterium shuttle vector, pKO1B, in the rice blast fungus Magnaporthe oryzae. Using this method, we deleted 104 fungal-specific Zn(2)Cys(6) transcription factor (TF) genes in M. oryzae. We then analyzed the phenotypes of these mutants with regard to growth, asexual and infection-related development, pathogenesis, and 9 abiotic stresses. The resulting data provide new insights into how this rice pathogen of global significance regulates important traits in the infection cycle through Zn(2)Cys(6)TF genes. A large variation in biological functions of Zn(2)Cys(6)TF genes was observed under the conditions tested. Sixty-one of 104 Zn(2)Cys(6) TF genes were found to be required for fungal development. In-depth analysis of TF genes revealed that TF genes involved in pathogenicity frequently tend to function in multiple development stages, and disclosed many highly conserved but unidentified functional TF genes of importance in the fungal kingdom. We further found that the virulence-required TF genes GPF1 and CNF2 have similar regulation mechanisms in the gene expression involved in pathogenicity. These experimental validations clearly demonstrated the value of a high throughput gene knockout system in understanding the biological functions of genes on a genome scale in fungi, and provided a solid foundation for elucidating the gene expression network that regulates the development and pathogenicity of M. oryzae. PMID- 25299518 TI - Genetic variants in genes of the inflammatory response in association with infective endocarditis. AB - AIMS: Inflammation in infective endocarditis (IE) is a complex network including interactions of inflammatory cytokines and other components of host response. Certainly, any variation in this network could influence susceptibility or disease progression of IE. In this study, 14 single nucleotide variants (SNVs) in genes coding for interleukin-1beta, interleukin-6, interleukin-10, toll-like receptor-4, tumor necrosis factor-alpha, selectin E and intercellular adhesion molecule-1 were analyzed for an association with susceptibility to IE and correlated with disease-related laboratory parameters. Furthermore, the occurrence of SNVs was examined to elucidate pathogen-dependent associations. METHODS AND RESULTS: The distribution of SNVs was determined in IE-patients and healthy blood donors by RFLP analysis. White blood cells (WBC) were counted using flow cytometry, concentration of C-reactive protein and procalcitonin was measured immunologically. Interleukin-6 c.471+870G>A genotypes differed significantly between IE patients and controls. The frequency of the heterozygote genotype GA was considerably higher in the patient group (68.9% vs. 43.8%, Pc<0.0003). Interleukin-6 c.-237 minor allele frequency was increased in patients, although not statistically significant. Additionally, we detected a potential relation between interleukin-1beta c.315C>T and IE. Pathogen-dependent analysis showed no significantly associated subgroup in relation to IE susceptibility, but gave hints towards alterations regarding Enterococcus-caused IE cases. Patients with genotype selectin-E c.-19 GT tend to have higher preoperative WBC counts than patients with genotype GG. We further showed an association between two interleukin-1beta SNVs and laboratory biomarkers. CONCLUSION: This study shows genetic predispositions for the establishment of IE. Furthermore, correlation of SNVs with disease-related biomarkers suggests a role of genetic variants regarding the inflammatory response in IE. PMID- 25299520 TI - Effect of exercise therapy compared with arthroscopic surgery on knee muscle strength and functional performance in middle-aged patients with degenerative meniscus tears: a 3-mo follow-up of a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to compare the effect of a 12-wk exercise therapy program and arthroscopic partial meniscectomy on knee strength and functional performance in middle-aged patients with degenerative meniscus tears. DESIGN: A total of 82 patients (mean age, 49 yrs; 35% women) with a symptomatic, unilateral, magnetic resonance imaging-verified degenerative meniscus tear and no or mild radiographic osteoarthritis were randomly assigned to a supervised neuromuscular and strength exercise program or arthroscopic partial meniscectomy. Outcomes assessed 3 mos after intervention initiation were isokinetic knee muscle strength, lower extremity performance, and self-reported global rating of change. RESULTS: Mean difference in isokinetic knee extension peak torque between the two groups was 16% (95% confidence interval, 7.1-24.0) (P < 0.0001), favoring the exercise group. Patients in the exercise group improved isokinetic knee extension peak by a mean of 25 Nm (range, 18-33 Nm) from baseline to follow-up. Furthermore, patients assigned to exercise therapy showed statistically significant improvements (P <= 0.002) in all other measured variables, with moderate to large effect sizes (0.5-1.3). Patients reported a similar and positive effect of both interventions. CONCLUSION: A 12-wk supervised exercise therapy program yielded clinically relevant and statistically significant improvement in isokinetic quadriceps strength immediately after completion of the program, as compared with treatment with arthroscopic partial meniscectomy. PMID- 25299522 TI - Differences in the course of daily activity level between persons with and without chronic pain. AB - OBJECTIVE: The aim of this study was to determine differences in (the course of) daily activity level between persons with and persons without chronic pain. DESIGN: A total of 18 participants with chronic pain and 19 age-matched healthy controls wore an accelerometer for 7 days, of which two weekdays were taken for analysis. Average movement intensity, peak movement intensity, and postures were compared between the persons with and persons without chronic pain over the day. The course of daily activities was analyzed by comparing the activity in the morning, afternoon, and evening. RESULTS: The participants with chronic pain spent significantly more time in lying and less time in sitting and standing. Total step count showed a trend (P = 0.07) to be lower in participants with chronic pain. Participants with chronic pain showed lower average movement intensity and peak movement intensity (P < 0.01) over the whole day. No differences were found in the course of daily activity between the two groups in both average movement intensity and peak movement intensity. CONCLUSIONS: Persons with and persons without chronic pain differed in daily activity level with regard to average movement intensity, peak movement intensity, and postures. No differences were found in the course of daily activity between the two groups. PMID- 25299521 TI - Agreement Between Actual Height and Estimated Height Using Segmental Limb Lengths for Individuals with Cerebral Palsy. AB - OBJECTIVE: The purpose of this study was to determine the agreement between actual height or segmental length and estimated height from segmental measures among individuals with cerebral palsy. DESIGN: A convenience sample of 137 children and young adults with cerebral palsy (age 2-25 yrs) were recruited from a tertiary care center. Height, body mass, recumbent length, knee height, tibia length, and ulna length were measured. Estimated height was calculated using several common prediction equations. Agreement between measured and estimated height was determined using the Bland-Altman method. RESULTS: Limits of agreement were wide for all equations, usually in the range of +/-10 cm. Repeatability of the individual measures was high, with a coefficient of variation of 1%-2% for all measures. The equation using knee height demonstrated a nonuniform difference in which height estimation worsened as overall height increased. CONCLUSIONS: Accurate measurement of height is important but very difficult in individuals with cerebral palsy. Segmental measures are highly repeatable and thus may be used on their own to monitor growth. However, when an accurate measure of height is needed to monitor nutritional status (i.e., for body mass index calculation), caution is warranted because there is only fair-to-poor agreement between actual height and estimated height. PMID- 25299523 TI - Systematic literature review of abobotulinumtoxinA in clinical trials for adult upper limb spasticity. AB - OBJECTIVE: The aim of this study was to elucidate clinical trial efficacy, safety, and dosing practices of abobotulinumtoxinA (ABO) treatment in adult patients with upper limb spasticity (ULS). METHODS: A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of ABO in the treatment of adult ULS published in English between January 1991 and January 2013. Medical literature databases (PubMed, Cochrane Library, and EMBASE) were searched, and a total of 295 records were identified. Of these, 12 primary publications that evaluated ABO for the management of ULS were included in the final data report. SYNTHESIS: Total ABO doses ranged between 500 and 1500 U for ULS. Most of the studies in ULS showed statistically significant benefits (reduction in muscle tone based on Ashworth score) of ABO vs. placebo. Statistical significance was reached for most evaluations of spasticity using the Modified Ashworth Scale. Statistically significant effects on active movement and pain were demonstrated, albeit less consistently. ABO was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Adverse events considered associated with ABO treatment included fatigue, tiredness, arm pain, skin rashes, flu-like symptoms, worsening of spasm, and weakness. CONCLUSIONS: On the basis of data extracted from 12 randomized clinical studies, a strong evidence base (9/12 studies) exists for the use of ABO to reduce ULS caused by stroke. PMID- 25299524 TI - Clinical Factors of Enteral Tube Feeding in Acute Ischemic Stroke Patients. AB - OBJECTIVE: The aim of this study was to identify possible clinical factors associated with enteral tube feeding use and duration in acute ischemic stroke patients. DESIGN: The medical records of 410 acute ischemic stroke patients were reviewed. Brain lesions were classified into nine regions of interest according to the cerebral vascular system. Brain lesion volume, lesion side, National Institutes of Health Stroke Scale (NIHSS) score, type of feeding during admission, and demographic characteristics were compared between enteral tube feeding and non-enteral tube feeding groups. RESULTS: Of the 410 patients, 61 used enteral feeding tubes. The mean age, NIHSS score, and brain lesion volume were significantly higher in the tube group than the nontube group (P < 0.001). Of the nine regions of interest, the right and left middle cerebral artery areas were strongly correlated with enteral tube feeding (P < 0.001). The NIHSS scores were significantly related to the duration of tube feeding (P < 0.05). The NIHSS consciousness subscores were significantly higher in the tube feeding group than in the non-tube feeding group (P < 0.05). CONCLUSIONS: Older age, lesions in the middle cerebral artery territory, and larger lesions were identified as significant risk factors of enteral tube feeding. Especially, the NIHSS consciousness subscore needs to be evaluated precisely because it was the factor most closely related to the implementation and duration of enteral tube feeding. PMID- 25299525 TI - Ultrasonographic evaluation of the median and sciatic nerves in hemiplegic patients after stroke. AB - OBJECTIVE: The aim of this study was to evaluate morphologically and electrophysiologically the peripheral nerves of hemiplegic patients. DESIGN: Thirty-three (18 women and 15 men) stroke patients were recruited. The mean (SD) age was 55.6 (11.3) yrs, and the mean (SD) disease duration was 14.2 (16.0) mos. Motor nerve conduction study of the median, ulnar, fibular, and tibial nerves as well as sensory nerve conduction study of the median, ulnar, and sural nerves were performed. Diameters and cross-sectional area (CSA) measurements of the median (wrist/midarm levels) and sciatic nerves (midthigh level) were acquired using a 7- to 12-MHz linear probe. The values of the nonparetic limbs were taken as controls. RESULTS: Prolonged distal latency and slowed motor conduction velocity of the tibial nerve as well as reduced amplitudes of the median and ulnar nerves were observed on the paretic sides when compared with those of the nonparetic sides (all P < 0.05). The median and sciatic nerve cross-sectional area values were found to be smaller on the paretic sides when compared with the nonparetic sides (all P < 0.05). The median and ulnar nerve compound muscle action potential amplitudes (paretic side) were positively correlated with arm/hand Brunnstrom Motor Recovery Stage, disease duration, motor Functional Independence Measure score, and Functional Ambulation Category. CONCLUSIONS: The peripheral nerves of stroke patients seem to be affected--morphologically and electrophysiologically--on the paretic side. PMID- 25299526 TI - The need for updated clinical practice guidelines for preservation of upper extremities in manual wheelchair users: a position paper. AB - The purposes of this article were to examine the existing 2005 Clinical Practice Guidelines for preservation of the upper extremities in spinal cord injury and explore the literature to determine what might need to be included in an update. This is a consensus position article based on a literature review and the expertise of the authors. The findings support the original recommendations of the Clinical Practice Guidelines and provide evidence that suggests that information regarding equipment and skills training as well as impact to caregivers is needed. PMID- 25299527 TI - Protein kinase C activator, bryostatin-1, promotes exercise-dependent functional recovery in rats with cerebral infarction. AB - Recently, it has become widely known that neuronal reorganization in the perilesional cortex contributes to some improvement of hemiparesis after stroke. Here, the authors examined in vivo the effects of administration of bryostatin-1, an activator of protein kinase C, combined with voluntary exercise on functional recovery and on cortical phosphorylation of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor subunit GluR1 after infarction.In behavioral evaluation, the mean latency until falling from a rotating rod in the group with exercise and administered agent at 8 days after infarction was significantly longer than that in the other groups. Although there were no significant changes in GluR1 phosphorylation between bryostatin-1 administration alone and the untreated groups, exercise induced an increase in phosphorylated-Ser845-GluR1. Moreover, combining exercise with administration led to increased phosphorylated Ser831-GluR1.These results suggest that bryostatin-1 facilitated exercise-induced paralysis recovery, which is possibly mediated by synaptic plasticity related to an increase in synaptic transmission efficiency. PMID- 25299528 TI - Efficacy of aerobic exercise for treatment of chronic low back pain: a meta analysis. AB - OBJECTIVE: A meta-analysis of relevant cohort studies was performed to investigate the efficacy of aerobic exercise for the treatment of patients with chronic low back pain (CLBP). METHOD: A range of electronic databases were searched: MEDLINE (1966-2013), the Cochrane Library Database (issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945~2013), and the Chinese Biomedical Database (1982-2013), without language restrictions. The Roland-Morris Disability Questionnaire, the Oswestry Disability Questionnaire, the McGill Pain Questionnaire, visual analog scale, and heart rate, sit-and-reach test, and maximum oxygen consumption were used to evaluate the efficacy of aerobic exercise. Meta-analysis was performed with the use of the STATA statistical software. The standardized mean difference (SMD) with its corresponding 95% confidence interval (CI) was calculated. Eight clinical cohort studies with a total of 310 CLBP patients were included in the meta-analysis. RESULTS: The results of this meta-analysis indicated that CLBP patients exhibited positive decreases in scores on the Roland-Morris Disability Questionnaire (SMD, 0.44; 95% CI, 0.20-0.68; P < 0.001), Oswestry Disability Questionnaire (SMD, 1.03; 95% CI, 0.67-1.39; P < 0.001), Hospital Anxiety and Depression Scale (SMD, 1.35; 95% CI, 0.34-2.37; P = 0.009), and McGill Pain Questionnaire (SMD, 0.32; 95% CI, 0.07-0.56; P = 0.011) after aerobic exercise. It was also observed that aerobic exercise could markedly reduce the visual analog scale score for pain of CLBP patients (SMD, 0.75; 95% CI, 0.48-1.02; P < 0.001). Nevertheless, this study's findings showed that aerobic exercise had no effects on heart rate, sit and-reach test, and maximum oxygen consumption of CLBP patients (all P > 0.05). CONCLUSION: The current meta-analysis provides reliable evidence that aerobic exercise could effectively diminish pain intensity and improve the physical and psychologic functioning of CLBP patients. Thus, aerobic exercise may be a good choice in the treatment for CLBP. PMID- 25299529 TI - Comparison of Intact Knee Cartilage Thickness in Patients with Traumatic Lower Extremity Amputation and Nonimpaired Individuals. AB - OBJECTIVE: The aim of this study was to assess the femoral articular cartilage thickness of the intact knee in patients with traumatic lower extremity amputation compared with nonimpaired individuals. DESIGN: A total of 30 male patients with traumatic lower extremity amputation (mean [SD] age, 31.2 [6.3] yrs) and a random sample of 53 age-matched and body mass index-matched male nonimpaired individuals (mean [SD] age, 29.8 [6.3] yrs) participated in the study. Exclusion criteria were age younger than 18 yrs, history of significant knee injury, previous knee surgery, or rheumatic disease. The femoral articular cartilage thickness was measured using ultrasound at the midpoints of the medial condyle, the intercondylar notch, and the lateral condyle. Ultrasonographic cartilage measurement was performed on the intact side of the patients with amputation and on both sides of the nonimpaired individuals. RESULTS: The femoral articular cartilage thickness of the intact knees of the patients with amputation was significantly decreased at the lateral and medial condyles compared with the nonimpaired individuals (P < 0.05). There was no significant difference in the measurements at the intercondylar notch between the patients with amputation and the nonimpaired individuals (P > 0.05). CONCLUSIONS: There was a premature cartilage loss in the intact limb knee of the patients with traumatic amputation. This result supports the view that patients with traumatic lower extremity amputation are at increased risk for developing knee osteoarthritis in the intact limb. PMID- 25299530 TI - Beyond the Hospital Gates: Elucidating the Interactive Association of Social Support, Depressive Symptoms, and Physical Function with 30-Day Readmissions. AB - OBJECTIVE: The aims of this study were to design patient-oriented risk models that elucidate the interactions among depressive symptoms, physical function, and sociodemographic markers and delineate the association of these indicators with 30-day readmissions. DESIGN: This prospective longitudinal study examined readmissions within 30 days of an index operation among adults (>18 yrs) undergoing outpatient surgery. The primary exposures were measures of physical function, depression, and sociodemographic factors. Multivariable logistic regression and hierarchical generalized linear mixed models with fixed and random effects tested interactions and association of these factors with 30-day readmissions. RESULTS: Adjusting for covariates and interaction terms, depressive symptoms (adjusted odds ratio, 2.50; 95% confidence interval, 1.45-4.29) and low physical function (adjusted odds ratio, 1.68; 95% confidence interval, 1.15-2.13) increased the odds of 30-day readmissions. Stratified by socioeconomic status (SES), those in the lowest SES group with depressive symptoms had a 73% increase in probability of readmissions (adjusted odds ratio, 2.67; 95% confidence interval, 1.10-4.07). Stratified by depressive symptom severity, being married or having a life partner lowered the readmission odds (adjusted odds ratio, 0.52; 95% confidence interval, 0.31-0.88). Final models had good discrimination and fitness (area under the curve, 0.710; corrected Akaike Information Criterion, 541.1). CONCLUSIONS: Within 30 days of index surgery, depressive symptom severity moderated the association of sociodemographic, social support and physical function indicators with 30-day readmissions. PMID- 25299531 TI - Recovery of injured arcuate fasciculus in the dominant hemisphere in a patient with an intracerebral hemorrhage. AB - This study reports on a patient with an intracerebral hemorrhage who showed recovery of an injured arcuate fasciculus (AF) in the dominant hemisphere, using follow-up diffusion tensor tractography. A 43-year-old right-handed man presented with severe aphasia and hemiparesis resulting from a spontaneous intracerebral hemorrhage in the left parietotemporal lobes. The patient showed severe aphasia at 1 month after onset, with an aphasia quotient of 5% on the Korean-Western Aphasia Battery. He underwent comprehensive rehabilitative therapy until 22 months after onset and his aphasia showed improvement, with an aphasia quotient of 58% on the Korean-Western Aphasia Battery. On 1-month diffusion tensor tractography, only the thin ascending part of the left AF from the Wernicke area remained. In contrast, on 16-month diffusion tensor tractography, the injured left AF was thickened and elongated to around the left Broca area; however, discontinuation of the left AF was observed around the left Broca area, and this continuation was elongated to the left Broca area on 22-month diffusion tensor tractography. This study reports on a patient who showed recovery from injury of the left AF along with improvement of aphasia. Recovery of the injured AF in the dominant hemisphere appears to be one of the mechanisms for recovery from aphasia. PMID- 25299532 TI - Prospective Cohort Analysis of the Predictive Validity of a Screening Instrument for Severe Restrictions of Work Ability in Patients with Musculoskeletal Disorders. AB - OBJECTIVE: The aim of this study was to determine whether the Screening Instrument zur Feststellung des Bedarfs an medizinisch-beruflich orientierter Rehabilitation (SIMBO) screening instrument can identify persons with a high work disability risk. DESIGN: Patients with chronic musculoskeletal disorders and participation in a rehabilitation program were included in the analysis. Data were collected by questionnaires at admission and at the 6-mo follow-up. Failed return to work (RTW; i.e., unemployment or active employment with sick leave of >12 wks in the follow-up) was the primary outcome. Additional outcome data were obtained from the physician's discharge form (e.g., assessment of work ability). Receiver operating characteristic analyses and logistic regression models were used to analyze the data. RESULTS: Valid data were available for 1755 participants. Of these, 25% reported failed RTW. The area under the curve of the SIMBO score predicting failed RTW was 0.81 (0.79-0.83). The optimal cutoff to identify failed RTW was 23 points (of 100). The odds of failed RTW, unemployment, and sick leave of more than 12 wks were increased 12, 11, and 10 times for the persons with a SIMBO score of 23 points or greater compared with the persons with lower SIMBO scores. The odds of reduced work time capacity were increased 21 times. CONCLUSIONS: The SIMBO predicts work disability in patients with chronic musculoskeletal disorders. Further research should focus on its predictive validity in patients with other disorders and within other rehabilitation systems. PMID- 25299533 TI - Reliability and validity of a smartphone app to measure joint range. AB - In clinical and research settings, objective range of motion measurement is an essential component of lower limb assessment and treatment evaluation. One reliable tool is the digital inclinometer; however, availability and cost preclude its widespread use. Smartphone apps are now widely available, allowing smartphones to be used as an inclinometer. Reliability and validity studies of new technologies are scarce. Intrarater and interrater reliability of the iHandy Level app installed on a smartphone and an inclinometer were assessed in 20 participants for ankle dorsiflexion using a weight-bearing lunge test. Criterion validity was assessed between a Fastrak and the app, and construct validity was assessed between the inclinometer and the app. Intraclass correlation coefficients2,1 demonstrated excellent intrarater and interrater reliability (intraclass correlation coefficient, 0.97 and 0.76, respectively). Tests of validity demonstrated excellent correlation between all three methods (r > 0.99). The smartphone app is both reliable and valid, provides a low-cost method of measuring range of motion, and can be easily incorporated into clinical practice. PMID- 25299534 TI - Efficacy of Pulsed and Continuous Therapeutic Ultrasound in Myofascial Pain Syndrome: A Randomized Controlled Study. AB - OBJECTIVES: This study aimed to compare continuous and pulsed ultrasound therapy with sham ultrasound in terms of pain, severity of muscle spasm, function, depression, and quality of life in patients with myofascial pain syndrome. DESIGN: Patients were randomly divided into three groups, including the continuous ultrasound group (3 MHz, 1 W/cm, n = 20), the pulsed ultrasound group (3 MHz, 1 W/cm, 1:1 ratio, n = 20), and control group (sham, n = 20). The primary outcome measures were severity of pain at rest and during activity (visual analog scale, 0-10 cm). The secondary outcome measures were function (Neck Pain and Disability Scale), depressive mood (Beck Depression Scale), and quality of life (Nottingham Health Profile). All evaluations were performed at baseline, after treatment, and at the 6th and 12th wks. RESULTS: All three groups had significant improvements in all of the pain scores, the severity of muscle spasms, function assessments, and certain subparameters of the quality of life scale (P < 0.05). The continuous ultrasound group had significantly greater improvements in pain at rest (P < 0.05). However, no statistically significant differences were observed in the other parameters (P > 0.05). CONCLUSIONS: Continuous ultrasound therapy is more efficient in reducing pain at rest for myofascial pain syndrome patients than is sham or pulsed ultrasound therapy. PMID- 25299535 TI - Effect of Obesity on Motor Functional Outcome of Rehabilitating Traumatic Brain Injury Patients. AB - OBJECTIVE: The aim of this study was to determine the association between obesity and functional motor outcome of patients undergoing inpatient rehabilitation after traumatic brain injury. DESIGN: This retrospective study at an urban acute inpatient rehabilitation center screened data from 761 subjects in the Traumatic Brain Injury Model System who were admitted from January 2010 to September 2013. Inclusion criteria consisted of age of 18 years or older and an abnormal Functional Independence Measure motor score. Body mass index was used to determine obesity in the study population. Patients with a body mass index of 30.0 kg/m or greater were considered obese. RESULTS: A total of 372 subjects met the criteria for inclusion in the study. Of these, 54 (13.2%) were obese. Both obese and nonobese patients showed similar improvement in Functional Independence Measure motor score (mean [SD], 30.4 [12.8] for the obese patients, P = 0.115, and 27.3 [13.1] for the nonobese patients). The mean (SD) Functional Independence Measure motor scores at discharge for the obese and nonobese patients were 63.0 (12.6) and 62.3 (10.1) (P = 0.6548), respectively. CONCLUSIONS: Obesity had no adverse impact on motor functional outcomes of the traumatic brain injury patients who underwent inpatient rehabilitation. Therefore, obesity should not be considered an obstacle in inpatient rehabilitation after traumatic brain injury, if patients are able to participate in necessary therapy. PMID- 25299536 TI - Effect of Whole-Body Vibration Training on Standing Balance and Muscle Strength in Children with Down Syndrome. AB - OBJECTIVE: The purpose of this study was to determine whether whole-body vibration training could improve standing balance and muscle strength in children with Down syndrome. DESIGN: This study was a randomized controlled trial studying 30 children (8-10 yrs old) with Down syndrome. They were assigned randomly using sealed envelopes, with 15 children allocated to the control group (9 boys, 6 girls) and another 15 children allocated to the study group (8 boys, 7 girls). The control group received a designed physical therapy program, whereas the study group received the same program given to the control group in addition to whole body vibration training. Both groups received the treatment sessions three times per week for 6 successive months. Measurement of stability indices by using the Biodex Stability System as well as muscle strength of the knee flexors and extensors by using a handheld dynamometer was done before and after the 6 mos of the treatment program. RESULTS: Each group demonstrated significant improvements in stability indices and muscle strength after treatment (P < 0.05), with significantly greater improvements seen in the study group when compared with the control group (P < 0.05). CONCLUSIONS: Whole-body vibration may be a useful intervention modality to improve balance and muscle strength in children with Down syndrome. PMID- 25299537 TI - Ultrasonography of snapping hip syndrome. PMID- 25299538 TI - Nineteen reasons why physiatrists should do musculoskeletal ultrasound: EURO MUSCULUS/USPRM recommendations. AB - This article is an eventual consensus of experts from the European Musculoskeletal Ultrasound Study Group (EURO-MUSCULUS) and the Ultrasound Study Group in Physical and Rehabilitation Medicine (USPRM) pertaining to the use of musculoskeletal ultrasound in physical and rehabilitation medicine. Nineteen important reasons (as regards general advantages, specific conditions in physical and rehabilitation medicine, as well as comparisons with other imaging tools) have been highlighted to consolidate the scenario of how/why the probe of ultrasound needs to become the stethoscope, the extended hand, and the pen of physiatrists. PMID- 25299539 TI - Aggravated Dysphagia caused by cervical osteophyte in a patient with Parkinson disease. PMID- 25299540 TI - Ultrasonographic Assessment of the Femoral Cartilage Thickness in Patients with Pes Planus: A Multicenter Study by TURK-MUSCULUS. AB - OBJECTIVE: The aims of this study were to measure the distal femoral cartilage thicknesses of patients with pes planus by using ultrasound imaging and to explore whether ultrasound measurements are associated with degree of pes planus. DESIGN: One hundred seven patients (61 men, 46 women; aged 18-45 yrs) with pes planus and 107 age- and sex-matched as well as body mass index-matched healthy controls were enrolled in this study. After clinical assessment of the patients, measurements for pes planus were done on the radiographs, and ultrasound imaging of the distal femoral cartilage was performed from the right medial condyle, the right lateral condyle, the right intercondylar area, the left medial condyle, the left lateral condyle, and the left intercondylar area. RESULTS: Femoral cartilage values were thicker than those of the control group at all measurement sites (except for the right lateral condyle) (P's < 0.05). In a subgroup analysis regarding the sex difference, right medial condyle and left medial condyle values in the male subjects as well as right lateral condyle, right intercondylar area, left lateral condyle, and left intercondylar area values in the female subjects were found to be thicker (all P < 0.05). CONCLUSIONS: The distal femoral cartilages of the pes planus patients seem to be thicker, and this finding could possibly stem from excessive mechanical stress on the knee joint caused by impaired lower extremity biomechanics. PMID- 25299541 TI - Musculoskeletal Atrophy in an Experimental Model of Knee Osteoarthritis: The Effects of Exercise Training and Low-Level Laser Therapy. AB - OBJECTIVE: The aim of this study was to evaluate the effects of an exercise training protocol and low-level laser therapy (and the association of both treatments) on musculoskeletal atrophy using an experimental model of knee osteoarthritis (OA). DESIGN: Fifty male Wistar rats were randomly divided into five groups: control group, knee OA control group, OA plus exercise training group, OA plus low-level laser therapy group, and OA plus exercise training associated with low-level laser therapy group. The exercise training and the laser irradiation started 4 wks after the surgery, 3 days per week for 8 wks. The exercise was performed at a speed of 16 m/min, 3 days per week, 50 mins per day, for 8 wks. Laser irradiation was applied at two points of the left knee joint (medial and lateral), for 24 sessions. RESULTS: The results showed that both trained groups (irradiated or not) presented a significant increase in the muscle cross-sectional area and a decrease in muscle fiber density compared with the knee OA control group. Moreover, both trained and laser-irradiated groups demonstrated decreased muscle-specific ring-finger protein 1 and atrogin-1 immunoexpression. CONCLUSIONS: These results suggest that exercise training and low-level laser therapy were effective in preventing musculoskeletal alterations related to atrophy caused by the degenerative process induced by knee OA. PMID- 25299542 TI - Ultrasound imaging for the extensor pollicis brevis tendon: when martial arts caused partial rupture. PMID- 25299543 TI - Tumor necrosis factor-alpha antagonists twenty years later: what do Cochrane reviews tell us? AB - In 1998, the U.S. Food and Drug Administration granted regulatory approval to the first tumor necrosis factor-alpha antagonist, infliximab, for the treatment of moderately to severely active Crohn's disease. As of 2013, there were 3 additional tumor necrosis factor-alpha antagonists commercially available for the treatment of inflammatory bowel disease in the United States: adalimumab, certolizumab pegol, and golimumab. Despite a vast literature describing both clinical trial and clinical practice experience with these agents, there remain important questions regarding the efficacy and safety of tumor necrosis factor alpha antagonists for the treatment of inflammatory bowel disease. These questions and the best available evidence to answer them were discussed during a Cochrane Collaboration session held at the 2013 Digestive Diseases Week annual meeting. This article reviews the data from that session. PMID- 25299544 TI - IL-36gamma sustains a proinflammatory self-amplifying loop with IL-17C in anti TNF-induced psoriasiform skin lesions of patients with Crohn's disease. AB - BACKGROUND: Anti-tumor necrosis factor (TNF) therapy-induced psoriasiform skin lesions are a recently described side effect in patients with inflammatory bowel disease. Interleukin (IL)-12/IL-23 neutralization is an effective therapy for these lesions. As Th17 cytokines, such as IL-17A, and IL-1 family members, such as IL-36, play a significant role in plaque psoriasis, we analyzed the involvement of IL-17C and IL-36gamma in anti-TNF-induced skin lesions of patients with Crohn's disease. METHODS: IL-36gamma and IL-17C levels in biopsies of anti TNF-induced psoriasiform skin lesions of patients with Crohn's disease were assessed by immunohistochemical analysis and correlated to additional immunohistochemical data. IL-36gamma and IL-17C messenger RNA, protein, and induced gene expression in human primary keratinocytes were analyzed using quantitative real-time polymerase chain reaction, immunoblotting, and enzyme linked immunosorbent assay. RESULTS: IL-36gamma and IL-17C are increased in anti TNF-induced psoriasiform skin lesions of patients with Crohn's disease, compared with healthy controls. Epidermal IL-36gamma and IL-17C levels strongly correlate with each other (r = 0.748, P = 0.003). In contrast to IL-12 and IL-23, IL 36gamma increases the expression of proinflammatory signals and effector molecules of innate immunity in keratinocytes. However, IL-17C affects keratinocyte defensin gene expression only in combination with TNF-alpha. IL 36gamma induces TNF-alpha expression in keratinocytes and sustains a self amplifying proinflammatory loop with IL-17C by inducing its own expression and that of IL-17C. CONCLUSIONS: Our study demonstrates a unique role of the previously unknown self-amplifying, proinflammatory IL-36gamma/IL-17C loop in the pathogenesis of anti-TNF-induced psoriasiform skin lesions. These findings suggest a beneficial effect of IL-36gamma/IL-17C inhibition during anti-TNF induced psoriasiform lesions in patients with inflammatory bowel disease. PMID- 25299545 TI - Synthesis by direct arylation of thiazole-derivatives: regioisomer configurations optical properties relationship investigation. AB - The synthesis of thiazole(Tz)-based regioisomer materials using selective direct arylation to avoid any protection steps has been developed. A series of trimers in which the Tz groups sandwich either an electron-rich or an electron-deficient unit, with a regioselective orientation of the respective Tz unit, has therefore been synthesized. This chemical strategy has also been followed to synthesize a second series of pentamers in which the Tz group is used as a pi-conjugated bridge between an electron-rich central unit and electron-deficient end-capping groups and vice versa. On both trimers and pentamers, the effect of Tz orientation on the conjugation properties of the synthesized materials was investigated by a combination of experimental measurements and density functional theory calculations. This study highlights that control of the orientation of the Tz unit leads to the synthesis of the most conjugated regioisomer derivative. The present work gives chemical synthesis tools for the synthesis of selectively oriented Tz-based materials as well as a general guideline for the design of Tz based materials with the highest conjugation length, including the Tz-orientation effect. PMID- 25299546 TI - Starch solutions for volume resuscitation in intensive care units. PMID- 25299547 TI - Sedation in mechanically ventilated children: we are advancing. PMID- 25299548 TI - Guidelines for treatment of severe sepsis/septic shock: tissue perfusion assessment. AB - Sepsis is a very frequent condition and causes high mortality rates and healthcare costs; it is the main cause of death in intensive care units. Clear, improved prognosis was shown for early diagnosed and treated patients. Treatment guidelines are fundamental for appropriate therapy. It is clear that hypoperfusion patients should be hemodynamically optimized; therefore, recognition of hypoperfusion signs is one of the main therapeutic steps. This guideline discusses the current literature and available data regarding the evaluation of hemodynamic parameters. PMID- 25299549 TI - Guidelines for the treatment of severe sepsis and septic shock: hemodynamic resuscitation. AB - Sepsis has a high incidence, mortality and cost and is the main cause of death in intensive care units. Early recognition and treatment have been clearly associated with a better prognosis. Establishing new guidelines is a fundamental step for improving treatment. Patients with clear signs of hypoperfusion should undergo hemodynamic optimization. This guideline addresses the main strategies in the literature that are clinically available. PMID- 25299550 TI - II Forum of the "End of Life Study Group of the Southern Cone of America": palliative care definitions, recommendations and integrated actions for intensive care and pediatric intensive care units. AB - Palliative care is aimed to improve the quality of life of both patients and their family members during the course of life-threatening diseases through the prevention, early identification and treatment of the symptoms of physical, psychological, spiritual and social suffering. Palliative care should be provided to every critically ill patient; this requirement renders the training of intensive care practitioners and education initiatives fundamental. Continuing the Technical Council on End of Life and Palliative Care of the Brazilian Association of Intensive Medicine activities and considering previously established concepts, the II Forum of the End of Life Study Group of the Southern Cone of America was conducted in October 2010. The forum aimed to develop palliative care recommendations for critically ill patients. PMID- 25299551 TI - Effect of red blood cell transfusion on parameters of inflammation and oxidative stress in critically ill patients. AB - INTRODUCTION: Red blood cell transfusions are common in intensive care units. For many years, transfusions of red blood were thought to have obvious clinical benefits. However, in recent years, the risks and benefits of blood transfusions have been examined more carefully, including the risk of increased morbidity and mortality due to transfusion-related immunomodulation effects. OBJECTIVES: To evaluate red blood cell transfusion effects and the relationship of this procedure to the production of inflammatory cytokines and oxidative damage in critically ill patients admitted to an intensive care unit. METHODS: For 6 months in 2008, we evaluated patients admitted to an intensive care unit who underwent packed red blood cell transfusions. Pre- and post-transfusion levels of interleukin-6, carbonylated proteins and thiobarbituric acid reactive substances were assessed. RESULTS: Serum post-transfusion interleukin-6 levels were reduced, and thiobarbituric acid reactive substances and carbonylated proteins were significantly increased. No statistically significant relationship was found between the levels of pre- and post-transfusion interleukin-6 and thiobarbituric acid reactive substances and the mortality rate. However, there was a significant relationship between levels of post-transfusion carbonylated proteins and mortality. CONCLUSION: Red blood cell transfusion is associated with increased oxidative damage markers and reduced interleukin-6 levels in critically ill patients. PMID- 25299552 TI - Molecular panel for detection of sepsis-related microorganisms. AB - INTRODUCTION: Sepsis is a systemic inflammatory response related to high mortality rates in the hospital environment. Delayed etiological diagnosis and inadequate antimicrobial therapy are associated with treatment failures. Molecular tests based on polymerase chain reaction are regarded as faster and more accurate procedures than culture techniques for microbial identification, providing a higher rate of therapeutic success. OBJECTIVE: To develop a panel of primers for DNA fragments of sepsis-related microorganisms. METHODS: Primers for amplification of Enterobacter spp., Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida spp. were designed and tested for sensitivity and specificity on the basis of their respective standard strains. RESULTS: The intended specificity was obtained for P. aeruginosa, S. aureus and Candida spp primers. Sensitivity tests showed a threshold for detection from 5 ng to 500 fg in blood samples contaminated with microbial DNA. CONCLUSIONS: The molecular panel presented offers the advantage of a flexible 'open' system when compared to other multiplex detection methods. PMID- 25299553 TI - Antioxidant supplementation for the treatment of acute lung injury: a meta analysis. AB - OBJECTIVE: This meta-analysis was performed to evaluate the evidence supporting antioxidant supplementation as an adjunct therapy to prevent oxidative damage and improve the clinical outcomes (mortality, length of hospital stay and duration of mechanical ventilation). METHODS: The search strategy for randomized controlled trials (RCTs) involved the participation of two researchers who independently assessed the methodological quality of each full-text article that was available in the PubMed, ISI WEB of Knowledge and ScienceDirect databases. RESULTS: We extracted 110 studies from the past 10 years, but only 30 articles met the methodological criteria (RCT, blinded and statistically significant results), for a total of 241 animals and 256 patients. This study found an odds ratio (OR) of 0.45 [95% confidence interval (CI): 0.26 to 0.79] for death in the experimental group compared with placebo (six trials, n = 256), an OR of 0.46 [95% CI: 0.26 to 0.87] for hospitalization time and an OR of 0.63 [95% CI: 0.35 to 1.12] for mechanical ventilation time between groups. CONCLUSION: Conflicting evidence makes it impossible to recommend the routine use of antioxidant supplementation in critically ill patients. PMID- 25299554 TI - Effectiveness of post-pyloric tube placement using magnetic guidance. AB - OBJECTIVE: Appropriate nutritional support is important to the outcomes of critically ill patients. However, a significant portion of these patients experience intestinal motility problems. Administration of enteral nutrition by means of tubes placed in the post-pyloric position has been suggested to improve the nutrition tolerance. The aim of this study was to compare the rate of successful post-pyloric placement using a real-time electromagnetic positioning device to the success rate using the conventional placement method. METHODS: This was a prospective, randomized and controlled study, conducted in a tertiary hospital over a period of three months. The patients were randomized to one of two groups: electromagnetically guided system group, whose patients underwent real-time monitoring of post-pyloric tube placement; or the control group, whose patients underwent tube placment using to the conventional blinded technique. The rates of successful post-pyloric placement and the procedure times were assessed and compared between the groups. RESULTS: Thirty-seven patients were enrolled, 18 in the electromagnetic group and 19 in the control group. The final tube position was evaluated using radiography. The electromagnetic guided group showed better success rates and shorter procedure times when compared to the control group. Additionally, in the electromagnetic guided group, higher pH values were found in the fluids aspirated from the probe, suggesting successful postpyloric placement. CONCLUSION: The electromagnetically guided method provided better placement accuracy than did the conventional technique. PMID- 25299555 TI - Influence of peripheral muscle strength on the decannulation success rate. AB - INTRODUCTION: Tracheostomy is probably the most common surgical procedure in critically ill patients and is generally performed to facilitate mechanical ventilation weaning. Evidence-based guidelines have confirmed the benefits of tracheostomy weaning protocols and of the physiotherapists engagement in this process; however, no consensus decannulation criteria are currently available. Therefore, this study aimed to evaluate the influence of peripheral muscle strength and other indicators on decannulation success. METHODS: This was an observational retrospective study that analyzed the medical records of patients admitted to the medical and surgical intensive care unit of Hospital Agamenon Magalhaes between March 2007 and August 2009. Respiratory and peripheral muscle strengths were evaluated in decannulated patients. RESULTS: Overall, 1,541 patients were evaluated, 143 of which had been tracheostomized, and only 57 of which had been decannulated. Forty-six patients had a satisfactory decannulation outcome, while 11 had decannulation failure, requiring the return to an artificial airway within 2 weeks. The calculated Medical Research Council peripheral muscle strength score was significantly lower for the failure group than for the successful decannulation group (28.33 +/- 15.31 vs. 41.11 +/- 11.52; P = 0.04). Scores above or equal 26 had 94.4% sensitivity and 50.0% specificity for the decannulation outcome, with an area under the ROC curve of 0.7593. In addition, white blood cell counts were higher in decannulation failure group patients (14,070 +/- 3,073 vs. 10,520 +/- 3,402 cells/MUL; P = 0.00). CONCLUSION: This study has shown that peripheral muscle strength and blood leucocyte counts evaluated on the day of decannulation may influence the tracheostomy decannulation success rate. PMID- 25299556 TI - The influence of noise levels on the perception of stress in heart disease patients. AB - OBJECTIVES: To identify the main causes of stress in patients staying in a coronary unit and to assess the influence of noise levels on their perception of stress. METHODS: This was a prospective, descriptive and quantitative study conducted between June and November 2009 in the Coronary Unit of the Hospital de Clinicas da Universidade Estadual de Campinas. The Intensive Care Unit Environmental Stressor Scale was used on the first, second and third days of hospitalization to identify stressors. The noise level was measured on the first and second nights using an Instrutherm DEC-460 decibel meter. RESULTS: Overall, 32 clinical heart disease patients were included. The median Intensive Care Unit Environmental Stressor Scale scores were 67.5, 60.5 and 59.5 for the first, second and third days, respectively. The differences were not statistically significant. The highest noise level (a median of 58.7 dB) was detected on the second night at 9:00 pm; the lowest level (51.5 dB) was measured on the first night at 12:00 am. In a multiple linear regression model, the first-night noise level had a 33% correlation with the second-day stress scale score, and for the second night, the correlation with the third-day stress scale score was 32.8% (p = 0.001). CONCLUSION: Patients admitted into a coronary unit have an increased perception of stress. Higher noise levels are also responsible for the perception of stress in these patients. PMID- 25299557 TI - New anticoagulants in critical care settings. AB - Thromboembolic events commonly occur in critically ill patients, and although they do not consistently present with specific signs and symptoms, they are associated with high morbity and mortality. Antithrombotic agents are the mainstay of the prevention and treatment of venous thromboembolism, and they are also used for stroke prevention in atrial fibrillation, embolism prevention in heart failure, and anticoagulation of prosthetic valves. These drugs have been combined with antiplatelet therapy for the prevention of secondary acute coronary syndrome. Antithrombotic agents such as Aspirin, clopidogrel, vitamin K antagonists and fondaparinux, an indirect Factor Xa inhibitor, are already incorporated into our clinical practice. New small-molecule, selective Factor Xa and thrombin inhibitors that simultaneously inhibit free plasma and clot associated factor activities have received considerable attention recently. These new oral anticoagulants are in various phases of clinical development. dabigatran, rivaroxaban and apixaban are in more advanced phases of clinical development and are already available in a number of countries. This review article highlights the studies describing the use of these three anticoagulants in an intensive care setting. PMID- 25299558 TI - Dilemmas and difficulties involving end-of-life decisions and palliative care in children. AB - This review discusses the main dilemmas and difficulties related to end-of-life decision's in children with terminal and irreversible diseases and propose a rational sequence for delivering palliative care to this patients' group. The Medline and Lilacs databases were searched using the terms 'end of life', 'palliative care', 'death' and 'terminal disease' for articles published in recent years. The most relevant articles and those enrolling pediatric patients were selected and compared to previous authors' studies in this field. The current Brazilian Medical Ethics Code (2010) was analyzed regarding end-oflife practices and palliative care for terminal patients. Lack of knowledge, insufficient specific training, and legal concerns are the main reasons why end of-life decisions in terminal children are based on medical opinion with scarce family participation. The current Brazilian Medical Ethics Code (2010) fully supports end-of-life decisions made consensually with active family participation. Honest dialogue with the family regarding diagnostic, prognostic, therapeutic and palliative care measures should be established gradually to identify the best strategy to meet the child's end-of-life needs. Treatment focused on the child's welfare combined with the family's participation is the basis for successful palliative care of children with terminal diseases. PMID- 25299559 TI - Albumin in critically ill patients: controversies and recommendations. AB - Human albumin has been used as a therapeutic agent in intensive care units for more than 50 years. However, clinical studies from the late 1990s described possible harmful effects in critically ill patients. These studies' controversial results followed other randomized controlled studies and meta-analyses that showed no harmful effects of this colloid solution. In Brazil, several public and private hospitals comply with the Agencia Nacional de Vigilancia Sanitaria (the Brazilian Health Surveillance Agency) recommendations for appropriate administration of intravenous albumin. This review discusses indications for albumin administration in critically ill patients and analyzes the evidence for metabolic and immunomodulatory effects of this colloid solution. We also describe the most significant studies from 1998 to the present time; these reveal an absence of incremental mortality from intravenous albumin administration as compared to crystalloid solutions. The National Health Surveillance Agency indications are discussed relative to the current body of evidence for albumin use in critically ill patients. PMID- 25299561 TI - Fatal sepsis after intravesical instillation of BCG: case report. AB - Intravesical instillation of bacillus Calmette-Guerin (BCG) is the treatment of choice for carcinoma in situ and non-invasive high-grade superficial tumors of the urinary bladder. This treatment is well tolerated overall, but serious complications can occur. An elderly man with coronary disease and recurrent high grade superficial carcinoma of the bladder underwent intravesical instillation of BCG and developed septic shock. He received wide range antibiotics, tuberculostatic and vasoactive drugs, corticosteroids, mechanical ventilation and renal replacement therapy without improvement. He died nine days after the intravesical instillation of BCG because of multiple organ failure. PMID- 25299560 TI - Influence of acute brain injuries on gut motility. AB - Subarachnoid hemorrhage can increase intracranial pressure, causing significant morbidity. Acute gastric dilation and delayed gastric emptying are commonly seen in patients with intracranial hypertension, and correction of these gastric abnormalities can facilitate the recovery of patients with brain injuries. We conducted a literature review of both national and international health sciences medical journals and electronic libraries spanning the last twenty-eight years and focused on the brain, gut motility and gastric emptying functional axis either in experimental animal models of brain injury or patients with acute cerebral injuries. Decreased parasympathetic tonus is a potential cause of intracranial hypertension-related food intolerance. Changes in gastrointestinal transit after a brain injury follow a biphasic pattern: an initial phase of accelerated gastric emptying and a late stage of intestinal lethargy. Changes in the physiology underlying gut motility may be essential for homeostatic stabilization in hemodynamically unstable patients. Research studies are necessary to understand the difficult management of intensive care patients with intracranial hypertension secondary to subarachnoid hemorrhages resulting from traumatic brain injuries or rupture of a cerebral aneurysm. Increased intracranial pressure induces massive increases in sympathetic activity, which is responsible for many of the peripheral systemic and gastrointestinal symptoms. Brain injuries leading to significant increases in intracranial pressure result in delayed gastrointestinal emptying due to autonomic nervous system changes. PMID- 25299562 TI - Saccharomyces cerevisiae infection: an unusual pathogen in the ICU. AB - A case of a mixed fungal yeast infection involving Saccharomyces cerevisiae - well known for its use in the bread and wine industries - and Candida albicans, is described in an intensive care unit patient. Mortality due to mixed fungal infections in the intensive care unit is high. An elderly smoker patient with chronic pulmonary obstructive disease and untreated bladder neoplasm was admitted to the hospital with diarrhea and progressed to septic shock. The above-mentioned yeasts were identified in blood cultures. This case with fatal outcome provides an opportunity to discuss one of the emergent germs found in the intensive care unit, in a case with an atypical presentation. PMID- 25299563 TI - Intraoperative lactate measurements are not predictive of death in high risk surgical patients. PMID- 25299565 TI - Enterovirus 71 infects brain-derived neural progenitor cells. AB - Neural progenitor cells (NPCs) are stem cells that can differentiate into various neural lineage cells. The damage and loss of NPCs are associated with neurological conditions such as cognitive deficits and memory impairment. In a long-term study of patients with EV71, cognitive disorders were observed. Therefore, we hypothesized that NPCs may be permissive to EV71 infection. We demonstrated that NPCs are prone to EV71 infection and that these stem cells can support the active replication of this virus. Furthermore, EV71 infection triggers apoptosis, resulting in significant cell death in infected NPCs. However, EV71 did not replicate in the differentiated cell types that were tested. Our findings suggest that EV71 can infect NPCs and cause the depletion of these cells. PMID- 25299564 TI - Trigeminal neuralgia. AB - INTRODUCTION: Trigeminal neuralgia is a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Pain occurs in paroxysms, which can last from a few seconds to several minutes. The frequency of the paroxysms ranges from a few to hundreds of attacks a day. Periods of remission can last for months to years, but tend to shorten over time. The condition can impair activities of daily living and lead to depression. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of ongoing treatments in people with trigeminal neuralgia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found seven studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: baclofen; carbamazepine; gabapentin; lamotrigine; oxcarbazepine; microvascular decompression; and destructive neurosurgical techniques (radiofrequency thermocoagulation, glycerol rhizolysis, balloon compression, and stereotactic radiosurgery). PMID- 25299567 TI - Modification of Stranski-Krastanov growth on the surface of nanowires. AB - The heteroepitaxial growth of strained islands on a planar substrate offers an attractive route to the fabrication of quantum dots (QDs). To obtain more functions and superior properties, recent efforts have focused on using nanowires (NWs) as substrates to produce attractive structures that combine QDs with NWs. As the lateral size of an NW is large, it is possible that islands are formed on the side walls of the NW. However, no islands exist, and the lateral surface is rather smooth in thin, core-shell NWs. The existing theoretical models on the growth on planar and patterned substrates are not appropriate for the growth transition on the surface with nanoscale curvature. We thus urgently need to understand the basic physics involved in the strain-induced growth on the surface with nanoscale curvature. Here, we established a theoretical model to study the strain-induced growth on the surface, which showed that the Stranski-Krastanov (SK) mode can change to the Frank-van der Merwe (FM) mode due to the limit of the surface to the island's lateral growth. Using the model to investigate the heterostructured core/shell nanowires (NWs), we found, in addition to the SK mode on thick NWs and the FM mode on thin NWs, that there is a multiplex mode on medium NWs which includes the initial layer growth, the intermediate islands' growth and the final layer growth again. The established theoretical model not only explained some puzzling experimental results but also provided useful information to design and control the epitaxial growth on the surface with nanoscale curvature. PMID- 25299566 TI - [ALK-rearranged non-small cell lung cancer: how to optimize treatment with crizotinib in routine practice?]. AB - Crizotinib (XALKORI(TM), Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib. PMID- 25299568 TI - Surface magnetism of Mg doped AlN: a first principle study. AB - Using first-principles calculations, we have systematically investigated the magnetic properties of Mg-doped AlN (1 0 1 0) and (0 0 0 1) surfaces. Both the polar and non-polar surfaces are found to be magnetic and the magnetic moments are mainly due to spin polarized 2p orbitals of surface N atoms surrounding Mg. The splitting of energy levels in both cases favours charge hopping between the minority spin states of N 2p orbitals, which leads to a stable ferromagnetic ground state. However, the range of magnetic coupling and the stability of the ferromagnetic state differ between the polar and non-polar surfaces and are dependent on the nature of localization of the defect states. The ferromagnetic state in a Mg-doped reconstructed (0 0 0 1) surface is more stable than in a Mg doped AlN (1 0 1 0) surface. PMID- 25299569 TI - Plasma steroid dynamics in late- and near-term naturally and artificially conceived bovine pregnancies as elucidated by multihormone high-resolution LC MS/MS. AB - The plasma levels of corticosteroids and sex steroids during pregnancy are key indicators of mammalian placental function and the onset of parturition. Steroid hormones are believed to be disturbed in pregnancies produced using assisted reproductive technologies (ARTs) due to placental dysfunction and the frequently observed lack of parturition signals. To elucidate the plasma steroid dynamics, a liquid chromatography-tandem mass spectrometry method was developed and used to determine the levels of corticosteroids (corticosterone, 11-deoxycortisol, and cortisol) and their direct precursors (progesterone and 17alpha-OH-progesterone) as well as sex steroids (androstenedione, estrone, estrone sulfate, testosterone, and 17beta-estradiol) in bovine plasma. The levels of these 10 steroids in recipient cows carrying naturally conceived (control), in vitro fertilized (IVF), or cloned (somatic cell nuclear transfer) conceptuses were compared during late term pregnancy (30 days before parturition), during near-term pregnancy (1 day before parturition), and on the day of parturition (day 0). Significant differences were observed among the corticosteroid levels: higher levels of corticosterone, 11-deoxycortisol, and cortisol were detected in cloned pregnancies at day 30; lower levels of corticosterone were observed in ART derived pregnancies at days 1 and 0; and estrone and estradiol levels were higher in IVF pregnancies throughout the final development. These results suggested an upregulation of the P450C11 and P450C21 enzymes 30 days before parturition in somatic cell nuclear transfer pregnancies and an overactivation of the aromatase enzyme in IVF pregnancies. Taken together, the monitoring of multiple steroid hormones revealed that the pregnancies obtained using ART exhibited plasma steroid concentration dynamics compatible with the dysregulation of steroidogenic tissues. PMID- 25299570 TI - Evolved sequence contexts for highly efficient amber suppression with noncanonical amino acids. AB - The expansion of the genetic code with noncanonical amino acids (ncAA) enables the function of proteins to be tailored with high molecular precision. In this approach, the ncAA is charged to an orthogonal nonsense suppressor tRNA by an aminoacyl-tRNA-synthetase (aaRS) and incorporated into the target protein in vivo by suppression of nonsense codons in the mRNA during ribosomal translation. Compared to sense codon translation, this process occurs with reduced efficiency. However, it is still poorly understood, how the local sequence context of the nonsense codon affects suppression efficiency. Here, we report sequence contexts for highly efficient suppression of the widely used amber codon in E. coli for the orthogonal Methanocaldococcus jannaschii tRNA(Tyr)/TyrRS and Methanosarcina mazei tRNA(Pyl)/PylRS pairs. In vivo selections of sequence context libraries consisting of each two random codons directly up- and downstream of an amber codon afforded contexts with strong preferences for particular mRNA nucleotides and/or amino acids that markedly differed from preferences of contexts obtained in control selections with sense codons. The contexts provided high amber suppression efficiencies with little ncAA-dependence that were transferrable between proteins and resulted in protein expression levels of 70-110% compared to levels of control proteins without amber codon. These sequence contexts represent stable tags for robust and highly efficient incorporation of ncAA into proteins in standard E. coli strains and provide general design rules for the engineering of amber codons into target genes. PMID- 25299571 TI - Semi-synthesis of chemokines. AB - Protein ligation allows the introduction of a wide range of modifications into proteins that are not accessible by mutagenesis. This includes non-proteinogenic amino acids and even backbone modification. This review summarizes recent reports on modified chemokine variants by ligation technologies and includes the development of the first protein with a full secondary structure motif exchanged by a helix that exclusively consists of beta-amino acids. Furthermore the first protein activatable by light by rearrangement of a depsi-peptide bond is described. Combining different ligation methods, immobilization and specific release of chemokines were achieved, which is of major importance for the gradient forming activity of chemokines. Examples are shown for CXCL8 (interleukin 8, IL-8) and CXCL12 (stromal derived factor 1, SDF 1) including their chemical and structural characterization as well as the most frequently used assays. PMID- 25299572 TI - Serine/threonine ligation for the chemical synthesis of proteins. AB - Advances in the development of efficient peptide ligation methods have enabled the total synthesis of complex proteins to be successfully undertaken. Recently, a Ser/Thr ligation has emerged as a new tool in synthetic protein chemistry. The chemoselective reaction between an N-terminal serine or threonine of an unprotected peptide segment and a C-terminal salicylaldehyde ester of another unprotected peptide segment gives rise to an N,O-benzylidene acetal linked product, which upon acidolysis produces a native peptide bond at the site of ligation. Ser/Thr ligation has been used for the synthesis of the human erythrocyte acylphosphatase protein and MUC1 glycopeptide segments, semisynthesis of peptoid/PEG-RNase S protein hybrids, and cyclic peptide synthesis including cyclic tetrapeptides, cyclomontanin B, yunnanin C, mahafacyclin B, and daptomycin. PMID- 25299573 TI - New chemistries for chemoselective peptide ligations and the total synthesis of proteins. AB - The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. The requirements of the native chemical ligation - an N-terminal cysteine and C-terminal thioesters - have encouraged a search for alternative amide-forming ligation reactions. Among successful alternatives to native chemical ligation, are the alpha-ketoacid hydroxylamine ligation with 5-oxaproline and, serine/threonine ligation, and potassium acyltrifluoroborate (KAT) ligation. In addition, the KAT ligation, along with the non-amide forming alkyne-azide ligation, is very useful for synthetic conjugations. All of these recent ligation methods were applied to synthesize different proteins, and have allowed chemists to incorporate unnatural amino acids, or to modify the peptide backbone. PMID- 25299574 TI - Sortase-mediated ligations for the site-specific modification of proteins. AB - Sortase-mediated ligation (SML) is one of the most commonly used techniques for the site-specific modification of proteins. Here, a brief overview on advantages and limitations of this technology in comparison with other chemoselective protein modification techniques is provided and successful approaches that extend the application range of SML are discussed. PMID- 25299575 TI - The metallothionein gene from the white shrimp Litopenaeus vannamei: characterization and expression in response to hypoxia. AB - Aquatic animals encounter variation in oxygen tension that leads to the accumulation of reactive oxygen species (ROS) that can harm the organisms. Under these circumstances some organisms have evolved to tolerate hypoxia. In mammals, metallothioneins (MTs) protect against hypoxia-generated ROS. Here we report the MT gene from the shrimp Litopenaeus vannamei (LvMT). LvMT is differentially expressed in hemocytes, intestine, gills, pleopods, heart, hepatopancreas and muscle, with the highest levels in hepatopancreas and heart. LvMT mRNA increases during hypoxia in hepatopancreas and gills after 3 h at 1.5 mg L(-1) dissolved oxygen (DO). This gene structure resembles the homologs from invertebrates and vertebrates possessing three exons, two introns and response elements for metal response transcription factor 1 (MTF-1), hypoxia-inducible factor 1 (HIF-1) and p53 in the promoter region. During hypoxia, HIF-1/MTF-1 might participate inducing MT to contribute towards the tolerance to ROS toxicity. MT importance in aquatic organisms may include also ROS-detoxifying processes. PMID- 25299578 TI - Circumventing redox chemistry: synthesis of transition metal boryl complexes from a boryl nucleophile by decarbonylation. AB - The very strong reducing capabilities of the boryllithium nucleophile (THF)2Li{B(NDippCH)2} (1, Dipp = 2,6-iPr2C6H3) render impractical its use for the direct introduction of the {B(NDippCH)2} ligand via metathesis chemistry into the immediate coordination sphere of transition metals (d(n), with n ? 0 or 10). Instead, 1 typically reacts with metal halide, amide and hydrocarbyl electrophiles either via electron transfer or halide abstraction. Evidence for the formation of M-B bonds is obtained only in the case of the d(5) system [{(HCDippN)2B}Mn(THF)(MU-Br)]2. Lower oxidation state metal carbonyl complexes such as Fe(CO)5 and Cr(CO)6 react with 1 via nucleophilic attack at the carbonyl carbon atom to give boryl-functionalized Fischer carbene complexes Fe(CO)4{C(OLi(THF)3)B(NDippCH)2} and Cr(CO)5{C(OLi(THF)2)B(NDippCH)2}. Although C to-M boryl transfer does not occur for these formally anionic systems, more labile charge neutral bora-acyl derivatives of the type LnM{C(O)B(NDippCH)2} [LnM = Mn(CO)5, Re(CO)5, CpFe(CO)2] can be synthesized, which cleanly lose CO to generate M-B bonds. From a mechanistic standpoint, an archetypal organometallic mode of reactivity, carbonyl extrusion, has thus been shown to be applicable to the boryl ligand class, with (13)C isotopic labeling studies confirming a dissociation/migration pathway. These proof-of-methodology synthetic studies can be extended beyond boryl complexes of the group 7 and 8 metals (for which a number of versatile synthetic routes already exist) to provide access to complexes of cobalt, which have hitherto proven only sporadically accessible. PMID- 25299576 TI - Protein kinase A activation enhances beta-catenin transcriptional activity through nuclear localization to PML bodies. AB - The Protein Kinase A (PKA) and Wnt signaling cascades are fundamental pathways involved in cellular development and maintenance. In the osteoblast lineage, these pathways have been demonstrated functionally to be essential for the production of mineralized bone. Evidence for PKA-Wnt crosstalk has been reported both during tumorigenesis and during organogenesis, and the nature of the interaction is thought to rely on tissue and cell context. In this manuscript, we analyzed bone tumors arising from mice with activated PKA caused by mutation of the PKA regulatory subunit Prkar1a. In primary cells from these tumors, we observed relocalization of beta-catenin to intranuclear punctuate structures, which were identified as PML bodies. Cellular redistribution of beta-catenin could be recapitulated by pharmacologic activation of PKA. Using 3T3-E1 pre osteoblasts as a model system, we found that PKA phosphorylation sites on beta catenin were required for nuclear re-localization. Further, beta-catenin's transport to the nucleus was accompanied by an increase in canonical Wnt dependent transcription, which also required the PKA sites. PKA-Wnt crosstalk in the cells was bi-directional, including enhanced interactions between beta catenin and the cAMP-responsive element binding protein (CREB) and transcriptional crosstalk between the Wnt and PKA signaling pathways. Increases in canonical Wnt/beta-catenin signaling were associated with a decrease in the activity of the non-canonical Wnt/Ror2 pathway, which has been shown to antagonize canonical Wnt signaling. Taken together, this study provides a new understanding of the complex regulation of the subcellular distribution of beta catenin and its differential protein-protein interaction that can be modulated by PKA signaling. PMID- 25299577 TI - Supervision and computerized neurocognitive baseline test performance in high school athletes: an initial investigation. AB - CONTEXT: Computerized neuropsychological testing batteries have provided a time efficient and cost-efficient way to assess and manage the neurocognitive aspects of patients with sport-related concussion. These tests are straightforward and mostly self-guided, reducing the degree of clinician involvement required by traditional clinical neuropsychological paper-and-pencil tests. OBJECTIVE: To determine if self-reported supervision status affected computerized neurocognitive baseline test performance in high school athletes. DESIGN: Retrospective cohort study. SETTINGS: Supervised testing took place in high school computer libraries or sports medicine clinics. Unsupervised testing took place at the participant's home or another location with computer access. PATIENTS OR OTHER PARTICIPANTS: From 2007 to 2012, high school athletes across middle Tennessee (n = 3771) completed computerized neurocognitive baseline testing (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]). They reported taking the test either supervised by a sports medicine professional or unsupervised. These athletes (n = 2140) were subjected to inclusion and exclusion criteria and then matched based on age, sex, and number of prior concussions. MAIN OUTCOME MEASURE(S): We extracted demographic and performance based data from each de-identified baseline testing record. Paired t tests were performed between the self-reported supervised and unsupervised groups, comparing the following ImPACT baseline composite scores: verbal memory, visual memory, visual motor (processing) speed, reaction time, impulse control, and total symptom score. For differences that reached P < .05, the Cohen d was calculated to measure the effect size. Lastly, a chi(2) analysis was conducted to compare the rate of invalid baseline testing between the groups. All statistical tests were performed at the 95% confidence interval level. RESULTS: Self-reported supervised athletes demonstrated better visual motor (processing) speed (P = .004; 95% confidence interval [0.28, 1.52]; d = 0.12) and faster reaction time (P < .001; 95% confidence interval [-0.026, -0.014]; d = 0.21) composite scores than self-reported unsupervised athletes. CONCLUSIONS: Speed-based tasks were most affected by self-reported supervision status, although the effect sizes were relatively small. These data lend credence to the hypothesis that supervision status may be a factor in the evaluation of ImPACT baseline test scores. PMID- 25299579 TI - Tunable magnetic and electronic properties of BN nanosheets with triangular defects: a first-principles study. AB - Experimentally, vacancy defects are commonly observed in BN nanosheets, expecially nitrogen-terminated triangular defects. Based on first-principles calculations, we systematically investigate the magnetic and electronic properties of BN nanosheets with these triangular vacancies (referred to as Vi(i = 1 - 4) defects with i representing the number of N atoms on each side of the triangle). It is found that the Vi defects bring diverse magnetic states into BN sheets, which are ferrimagnetic for V1, nonmagnetic for V2, ferrimagnetic for V3 and antiferromagnetic for V4 defects. When the isotropic strains are applied, the ferrimagnetic state is sustained for V1 defect, whereas the V2 defect undergoes a nonmagnetic to antiferromagnetic transition and the V3, V4 defects experience an abrupt change in the absolute magnetic moments under small strains, which are originated from the N-N bond breaking at these defects. Different from the BN nanoribbons, the antiparallel coupling is more favorable for the N atoms at the edges of triangular defects. Due to the triangular defects, the band gaps of BN sheets are reduced substantially, which could be further modulated by the strains. When the defective BN sheets serve as a substrate for graphene, the V1, V3 and V4 defects in BN would induce p-type doping in the graphene sheet. Interestingly, when the V2 defect is embedded in BN sheets, the doping behavior of graphene can be well-controlled by the strain, which is charge neutral at the strain-free state and p-type doped under strains. Our studies demonstrate that the rich magnetic and electronic properties of BN sheets with triangular defects enable the system's potential applications in nanodevices. PMID- 25299580 TI - Tamil merchant in ancient Mesopotamia. AB - Recent analyses of ancient Mesopotamian mitochondrial genomes have suggested a genetic link between the Indian subcontinent and Mesopotamian civilization. There is no consensus on the origin of the ancient Mesopotamians. They may be descendants of migrants, who founded regional Mesopotamian groups like that of Terqa or they may be merchants who were involved in trans Mesopotamia trade. To identify the Indian source population showing linkage to the ancient Mesopotamians, we screened a total of 15,751 mitochondrial DNAs (11,432 from the literature and 4,319 from this study) representing all major populations of India. Our results although suggest that south India (Tamil Nadu) and northeast India served as the source of the ancient Mesopotamian mtDNA gene pool, mtDNA of these ancient Mesopotamians probably contributed by Tamil merchants who were involved in the Indo-Roman trade. PMID- 25299582 TI - Oculomotor control after hemidecortication: a single hemisphere encodes corollary discharges for bilateral saccades. AB - Patients who have had a cerebral hemisphere surgically removed as adults can generate accurate leftward and rightward saccadic eye movements, a task classically thought to require two hemispheres each controlling contralateral saccades. Here, we asked whether one hemisphere can generate sequences of saccades, the success of which requires the use of corollary discharges. Using a double-step saccade paradigm, we tested two hemidecorticate subjects who, by definition, are contralesionally hemianopic. In experiment 1, two targets, T1 and T2, were flashed in their seeing hemifield and subjects had to look in the dark to T1, then T2. In experiment 2, only one target was flashed; before looking at it, the subject had first to saccade voluntarily elsewhere. Both subjects were able to complete the tasks, independent of first and second saccade direction and whether the saccades were voluntarily or visually triggered. Both subjects displayed a strategy, typical in hemianopia, of making multiple-step saccades and placing, at overall movement-end, the recalled locations of T1 and T2 on off foveal locations in their seeing hemifield, in a retinal area typically spanning a 5-15 degrees window, depending on the subject, trial type and target eccentricity. In summary, a single hemisphere monitored the amplitude and direction of the first multiple-step saccade sequence bilaterally, and combined this information with the recalled initial retinotopic location of T2 (no longer visible) to generate a correct target-directed second saccade sequence in the dark. Unexpectedly, our hemidecorticate subjects performed better on the double step task than subjects with isolated unilateral parietal lesions, reported in the literature to have marked deficiencies in monitoring contralesional saccadic eye movements. Thus, plasticity-dependent mechanisms that lead to recovery of function after hemidecortication are different than those deployed after smaller lesions. This implies a reconsideration of the classical links between behavioural deficits and discrete cortical lesions. PMID- 25299581 TI - Role of non-conventional T lymphocytes in respiratory infections: the case of the pneumococcus. AB - Non-conventional T lymphocytes constitute a special arm of the immune system and act as sentinels against pathogens at mucosal surfaces. These non-conventional T cells (including mucosal-associated invariant T [MAIT] cells, gamma delta [gammadelta] T cells, and natural killer T [NKT] cells) display several innate cell-like features and are rapidly activated by the recognition of conserved, stress-induced, self, and microbial ligands. Here, we review the role of non conventional T cells during respiratory infections, with a particular focus on the encapsulated extracellular pathogen Streptococcus pneumoniae, the leading cause of bacterial pneumonia worldwide. We consider whether MAIT cells, gammadelta T cells, and NKT cells might offer opportunities for preventing and/or treating human pneumococcus infections. PMID- 25299583 TI - High resolution magnetic resonance imaging for characterization of the neuroligin 3 knock-in mouse model associated with autism spectrum disorder. AB - Autism spectrum disorders (ASD) comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3) is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and behavioral (social approach and zero maze) tests at 3 different time points (30, 50 and 70 days-of-age) on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD. PMID- 25299584 TI - The NPM1 mutation type has no impact on survival in cytogenetically normal AML. AB - NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML. PMID- 25299586 TI - Collective total synthesis of tetracyclic diquinane Lycopodium alkaloids (+) paniculatine, (-)-magellanine, (+)-magellaninone and analogues thereof. AB - The collective total synthesis of tetracyclic diquinane Lycopodium alkaloids, (+) paniculatine, (-)-magellanine, (+)-magellaninone, and two analogues (-)-13-epi paniculatine and (+)-3-hydroxyl-13-dehydro-paniculatine, has been accomplished. By logic-guided addition of a strategically useful hydroxyl group at C-3 of paniculatine, the formidable tetracyclic core was rapidly synthesized utilizing a site-specific and stereoselective aldol cyclization, thus making the ABD -> ABCD tetracyclic approach to diquinane Lycopodium alkaloids attainable for the first time. PMID- 25299585 TI - Pou3f4-mediated regulation of ephrin-b2 controls temporal bone development in the mouse. AB - The temporal bone encases conductive and sensorineural elements of the ear. Mutations of POU3F4 are associated with unique temporal bone abnormalities and X linked mixed deafness (DFNX2/DFN3). However, the target genes and developmental processes controlled by POU3F4 transcription factor activity have remained largely uncharacterized. Ephrin-B2 (Efnb2) is a signaling molecule with well documented effects on cell adhesion, proliferation, and migration. Our analyses of targeted mouse mutants revealed that Efnb2 loss-of-function phenocopies temporal bone abnormalities of Pou3f4 hemizygous null neonates: qualitatively identical malformations of the stapes, styloid process, internal auditory canal, and cochlear capsule were present in both mutants. Using failed/insufficient separation of the stapes and styloid process as a quantitative trait, we found that single gene Efnb2 loss-of-function and compound Pou3f4/Efnb2 loss-of function caused a more severe phenotype than single gene Pou3f4 loss-of-function. Pou3f4 and Efnb2 gene expression domains overlapped at the site of impending stapes-styloid process separation and at subcapsular mesenchyme surrounding the cochlea; at both these sites, Efnb2 expression was attenuated in Pou3f4 hemizygous null mutants relative to control. Results of immunoprecipitation experiments using chromatin isolated from nascent middle ear mesenchyme supported the hypothesis of a physical association between Pou3f4 and specific non-coding sequence of Efnb2. We propose that Efnb2 is a target of Pou3f4 transcription factor activity and an effector of mesenchymal patterning during temporal bone development. PMID- 25299588 TI - Expanded usage of prazosin in pre-pubertal children with nightmares resulting from posttraumatic stress disorder. PMID- 25299587 TI - Sensory evaluation of tender beef strip loin steaks of varying marbling levels and quality treatments. AB - The palatability of tender [Warner-Bratzler shear force values <33.34N (3.4kg)] beef strip loins of 10 different treatments [USDA Prime, High Choice (upper 1/3 Choice), Low Choice (lower 1/3 Choice), Select, Standard, Australian Wagyu, American Wagyu, Holstein Select, Holstein Top Choice (upper 2/3 Choice) and Grass finished] was evaluated by consumers and a trained flavor panel. In general, tenderness, juiciness, flavor, and overall liking ratings as well as acceptability percentage for each trait, increased with increased fat levels. Moreover, overall liking was highly correlated (P<0.01) with flavor liking (r=0.96) as well as fat percentage (r=0.79). Beef flavor scores were positively associated (P<0.01) with fat-like (r=0.67) and umami (r=0.59) flavors. Fat level was the primary driver of beef flavor acceptability in all samples when no undesirable off-flavors were present. PMID- 25299589 TI - Local pressure changes in lipid bilayers due to adsorption of melittin and magainin-h2 antimicrobial peptides: results from computer simulations. AB - We performed a series of coarse-grained computer simulations in order to study how the placement of melittin and magainin-h2 antimicrobial peptides on the surface of the bilayer changes the local pressure profiles in the bilayer. The simulations were done using the NPT ensemble when the total stress on the bilayer was zero and also using the NP(z)AT ensemble, with a nonzero total stress. In the NPT ensemble, although the total stress was zero, each leaflet of the bilayer experienced a nonzero stress, and the stresses are equal by magnitude, but opposite in their direction. The observed stresses acting on the monolayers may cause the rupture of the monolayers to release the stress. Our simulations were done at different peptide to lipid ratio (P/L). When the P/L ratio was 1/50 there was no large difference in the local pressure profile for bilayers with melittin versus bilayers with magainin-h2. When simulations were performed in the NP(z)AT ensemble at P/L = 3/100 we observed a large difference in the pressure profiles in the bilayers with melittin peptides compared to the bilayer with magainin-h2. The observed in this case difference in stress may explain the difference in actions of melittin and magainin at high P/L. PMID- 25299590 TI - Evaluation of chemical profile and antioxidant activity of Tripleurospermum insularum, a new species from Turkey. AB - This article presents the very first phytochemical investigation on new species Tripleurospermum insularum Inceer & Hayirlioglu-Ayaz. The volatile profile of odorous parts of the plant was analysed by GC/MS, and compounds were identified in headspace and essential oil obtained from aerial parts, representing 70.81% and 92.44% in total, respectively. The major volatiles were n-alkanes (38.43 59.22%), while essential oil was also rich in globulol (13.45%) and beta sesquiphellandrene (9.29%). The content of phenolic compounds in methanolic extract and oil was 3621.62 and 14.4 mg GAE/100 g of dry plant, respectively. Moreover, potential medicinal effects were found in mean of antioxidant activity of this plant measured by using two different assays: radical-scavenging activity and ferric-reducing activity. Samples revealed values ranging from 0.33 to 146.80 MUmol TE/100 g for DPPH assay, and from 2.29 to 5414.17 MUmol AAE/100 g for FRAP assay. PMID- 25299591 TI - Managing alcoholic liver disease. PMID- 25299592 TI - Observer trait anxiety is associated with response bias to patient facial pain expression independent of pain catastrophizing. AB - BACKGROUND: Top-down characteristics of an observer influence the detection and estimation of a sufferer's pain. A comprehensive understanding of these characteristics is important because they influence observer helping behaviours and the sufferer's experience of pain. OBJECTIVES: To examine the hypothesis that individuals who score high in trait anxiety would perceive more intense pain in others, as indicated by a larger negative response bias, and that this association would persist after adjusting for pain catastrophizing. METHODS: Healthy young adult participants (n=99; 50 male) watched videos containing excerpts of facial expressions taken from patients with shoulder pain and were asked to rate how much pain the patient was experiencing using an 11-point numerical rating scale. Sensitivity and response bias were calculated using signal detection methods. RESULTS: Trait anxiety was a predictor of response bias after statistically adjusting for pain catastrophizing and observer sex. More anxious individuals had a proclivity toward imputing greater pain to a sufferer. CONCLUSIONS: Individuals scoring higher on trait anxiety were more likely to impute pain to a sufferer. Anxious caregivers may be better able to respond with appropriate intervention once pain behaviour is detected, or they may exacerbate symptoms by engaging in excessive palliative care and solicitous behaviour. PMID- 25299593 TI - Bird communities and biomass yields in potential bioenergy grasslands. AB - Demand for bioenergy is increasing, but the ecological consequences of bioenergy crop production on working lands remain unresolved. Corn is currently a dominant bioenergy crop, but perennial grasslands could produce renewable bioenergy resources and enhance biodiversity. Grassland bird populations have declined in recent decades and may particularly benefit from perennial grasslands grown for bioenergy. We asked how breeding bird community assemblages, vegetation characteristics, and biomass yields varied among three types of potential bioenergy grassland fields (grass monocultures, grass-dominated fields, and forb dominated fields), and assessed tradeoffs between grassland biomass production and bird habitat. We also compared the bird communities in grassland fields to nearby cornfields. Cornfields had few birds compared to perennial grassland fields. Ten bird Species of Greatest Conservation Need (SGCN) were observed in perennial grassland fields. Bird species richness and total bird density increased with forb cover and were greater in forb-dominated fields than grass monocultures. SGCN density declined with increasing vertical vegetation density, indicating that tall, dense grassland fields managed for maximum biomass yield would be of lesser value to imperiled grassland bird species. The proportion of grassland habitat within 1 km of study sites was positively associated with bird species richness and the density of total birds and SGCNs, suggesting that grassland bioenergy fields may be more beneficial for grassland birds if they are established near other grassland parcels. Predicted total bird density peaked below maximum biomass yields and predicted SGCN density was negatively related to biomass yields. Our results indicate that perennial grassland fields could produce bioenergy feedstocks while providing bird habitat. Bioenergy grasslands promote agricultural multifunctionality and conservation of biodiversity in working landscapes. PMID- 25299594 TI - Genome-wide mapping of yeast RNA polymerase II termination. AB - Yeast RNA polymerase II (Pol II) terminates transcription of coding transcripts through the polyadenylation (pA) pathway and non-coding transcripts through the non-polyadenylation (non-pA) pathway. We have used PAR-CLIP to map the position of Pol II genome-wide in living yeast cells after depletion of components of either the pA or non-pA termination complexes. We show here that Ysh1, responsible for cleavage at the pA site, is required for efficient removal of Pol II from the template. Depletion of Ysh1 from the nucleus does not, however, lead to readthrough transcription. In contrast, depletion of the termination factor Nrd1 leads to widespread runaway elongation of non-pA transcripts. Depletion of Sen1 also leads to readthrough at non-pA terminators, but in contrast to Nrd1, this readthrough is less processive, or more susceptible to pausing. The data presented here provide delineation of in vivo Pol II termination regions and highlight differences in the sequences that signal termination of different classes of non-pA transcripts. PMID- 25299595 TI - Integration at the round table: marine spatial planning in multi-stakeholder settings. AB - Marine spatial planning (MSP) is often considered as a pragmatic approach to implement an ecosystem based management in order to manage marine space in a sustainable way. This requires the involvement of multiple actors and stakeholders at various governmental and societal levels. Several factors affect how well the integrated management of marine waters will be achieved, such as different governance settings (division of power between central and local governments), economic activities (and related priorities), external drivers, spatial scales, incentives and objectives, varying approaches to legislation and political will. We compared MSP in Belgium, Norway and the US to illustrate how the integration of stakeholders and governmental levels differs among these countries along the factors mentioned above. Horizontal integration (between sectors) is successful in all three countries, achieved through the use of neutral 'round-table' meeting places for all actors. Vertical integration between government levels varies, with Belgium and Norway having achieved full integration while the US lacks integration of the legislature due to sharp disagreements among stakeholders and unsuccessful partisan leadership. Success factors include political will and leadership, process transparency and stakeholder participation, and should be considered in all MSP development processes. PMID- 25299596 TI - Probing the effect of force on HIV-1 receptor CD4. AB - Cell-surface proteins are central for the interaction of cells with their surroundings and are also associated with numerous diseases. These molecules are exposed to mechanical forces, but the exact relation between force and the functions and pathologies associated with cell-surface proteins is unclear. An important cell-surface protein is CD4, the primary receptor of HIV-1. Here we show that mechanical force activates conformational and chemical changes on CD4 that may be important during viral attachment. We have used single-molecule force spectroscopy and analysis on HIV-1 infectivity to demonstrate that the mechanical extension of CD4 occurs in a time-dependent manner and correlates with HIV-1 infectivity. We show that Ibalizumab, a monoclonal antibody that blocks HIV-1, prevents the mechanical extension of CD4 domains 1 and 2. Furthermore, we demonstrate that thiol/disulfide exchange in CD4 requires force for exposure of cryptic disulfide bonds. This mechanical perspective provides unprecedented information that can change our understanding on how viruses interact with their hosts. PMID- 25299599 TI - Influence of tooth length on the accuracy of the Root ZX electronic apical foramen locator: an ex vivo study. AB - OBJECTIVE: Electronic apical foramen locators are now widely used to determine working length. This study was designed to determine whether tooth length influenced the accuracy of the Root ZX device. MATERIALS AND METHODS: Forty extracted maxillary canine teeth with a length range of 27-29 mm were selected. Access cavities were prepared and coronal flaring of canals performed. The teeth were mounted in self-polymerizing acrylic resin to facilitate horizontal sectioning except for the apical 3-4-mm portion of the root and embedded in alginate as the electronic medium. Electronic measurements were taken at the major foramen, 'zero' reading using the Root ZX and compared with the actual root canal length. The teeth were sectioned 3 mm from the coronal reference point to create a second group with shorter length; these reductions in the length continued six times in all to create seven groups of 40 specimens each. The actual and electronic lengths of specimens in each group were measured. Data were analyzed by Pearson's correlation coefficient. RESULTS: Identical measurements between the actual and electronic root canal length from the longest to the shortest groups were 12.5%, 10.0%, 20.0%, 27.5%, 37.5%, 35.0% and 45.0%, respectively. There was a mild negative correlation between the precise measurements of the Root ZX and root canal lengths in the seven groups (r = 0.964, p < 0.001). CONCLUSION: Under the conditions of the study, the Root ZX device was more accurate in shorter teeth compared to longer ones. PMID- 25299598 TI - Hydrophobic compounds reshape membrane domains. AB - Cell membranes have a complex lateral organization featuring domains with distinct composition, also known as rafts, which play an essential role in cellular processes such as signal transduction and protein trafficking. In vivo, perturbations of membrane domains (e.g., by drugs or lipophilic compounds) have major effects on the activity of raft-associated proteins and on signaling pathways, but they are difficult to characterize because of the small size of the domains, typically below optical resolution. Model membranes, instead, can show macroscopic phase separation between liquid-ordered and liquid-disordered domains, and they are often used to investigate the driving forces of membrane lateral organization. Studies in model membranes have shown that some lipophilic compounds perturb membrane domains, but it is not clear which chemical and physical properties determine domain perturbation. The mechanisms of domain stabilization and destabilization are also unknown. Here we describe the effect of six simple hydrophobic compounds on the lateral organization of phase separated model membranes consisting of saturated and unsaturated phospholipids and cholesterol. Using molecular simulations, we identify two groups of molecules with distinct behavior: aliphatic compounds promote lipid mixing by distributing at the interface between liquid-ordered and liquid-disordered domains; aromatic compounds, instead, stabilize phase separation by partitioning into liquid disordered domains and excluding cholesterol from the disordered domains. We predict that relatively small concentrations of hydrophobic species can have a broad impact on domain stability in model systems, which suggests possible mechanisms of action for hydrophobic compounds in vivo. PMID- 25299597 TI - Mass-spectrometric identification of T-kininogen I/thiostatin as an acute-phase inflammatory protein suppressed by curcumin and capsaicin. AB - Curcumin and capsaicin are dietary xenobiotics with well-documented anti inflammatory properties. Previously, the beneficial effect of these spice principles in lowering chronic inflammation was demonstrated using a rat experimental model for arthritis. The extent of lowering of arthritic index by the spice principles was associated with a significant shift in macrophage function favoring the reduction of pro-inflammatory molecules such as reactive oxygen species and production and release of anti-inflammatory metabolites of arachidonic acid. Beyond the cellular effects on macrophage function, oral administration of curcumin and capsaicin caused alterations in serum protein profiles of rats injected with adjuvant to develop arthritis. Specifically, a 72 kDa acidic glycoprotein, GpA72, which was elevated in pre-arthritic rats, was significantly lowered by feeding either curcumin or capsaicin to the rats. Employing the tandem mass spectrometric approach for direct sequencing of peptides, here we report the identification of GpA72 as T-kininogen I also known as Thiostatin. Since T-kininogen I is an early acute-phase protein, we additionally tested the efficiency of curcumin and capsaicin to mediate the inflammatory response in an acute phase model. The results demonstrate that curcumin and capsaicin lower the acute-phase inflammatory response, the molecular mechanism for which is, in part, mediated by pathways associated with the lowering of T-kininogen I. PMID- 25299600 TI - Influence of preparation design on fit and ceramic thickness of CEREC 3 partial ceramic crowns after cementation. AB - OBJECTIVE: This study investigated the influence of preparation design on the marginal and internal gap and ceramic thickness of partial ceramic crowns (PCCs) fabricated with the CEREC 3 system. MATERIALS AND METHODS: Sixteen extracted human mandibular molars were prepared according to two different preparation designs (n = 8): a retentive preparation design with traditional cusp capping (Group I) and a non-retentive preparation design with horizontal reduction of cusps (Group II). PCCs were fabricated from IPS Empress CAD with the CEREC 3 system. The parameters for luting space and minimum occlusal ceramic thickness were set to 30 MUm and 1.5 mm, respectively. The fabricated PCCs were cemented to their corresponding teeth with self-adhesive resin cement and were then scanned by micro-computed tomography. The marginal and internal gaps were measured at pre determined measuring points in five bucco-lingual and three mesio-distal cross sectional images. The ceramic thicknesses of the PCCs were measured at the measuring points for cusp capping areas. RESULTS: Group II (167.4 +/- 76.4 MUm) had a smaller overall mean gap, which included the marginal and internal gap measurements, than that of Group I (184.8 +/- 89.0 MUm). The internal gaps were larger than the marginal gaps, regardless of preparation design. Group I presented a thinner ceramic thickness in the cusp capping areas than the minimum occlusal ceramic thickness parameter of 1.5 mm. CONCLUSION. Preparation design had an influence on fit, particularly the internal gap of the PCCs. Ceramic thickness could be thinner than the minimum ceramic thickness parameter. PMID- 25299601 TI - The influence of whole grain products and red meat on intestinal microbiota composition in normal weight adults: a randomized crossover intervention trial. AB - Intestinal microbiota is related to obesity and serum lipid levels, both risk factors for chronic diseases constituting a challenge for public health. We investigated how a diet rich in whole grain (WG) products and red meat (RM) influences microbiota. During a 10-week crossover intervention study, 20 healthy adults consumed two isocaloric diets, one rich in WG products and one high in RM. Repeatedly data on microbiota were assessed by 16S rRNA based denaturing gradient gel electrophoresis (DGGE). A blood sample and anthropometric data were collected. Mixed models and logistic regression were used to investigate effects. Microbiota showed interindividual variability. However, dietary interventions modified microbiota appearance: 8 bands changed in at least 4 participants during the interventions. One of the bands appearing after WG and one increasing after RM remained significant in regression models and were identified as Collinsella aerofaciens and Clostridium sp. The WG intervention lowered obesity parameters, while the RM diet increased serum levels of uric acid and creatinine. The study showed that diet is a component of major relevance regarding its influence on intestinal microbiota and that WG has an important role for health. The results could guide investigations of diet and microbiota in observational prospective cohort studies. Trial registration: ClinicalTrials.gov NCT01449383. PMID- 25299602 TI - DNA binding properties of the actin-related protein Arp8 and its role in DNA repair. AB - Actin and actin-related proteins (Arps), which are members of the actin family, are essential components of many of these remodeling complexes. Actin, Arp4, Arp5, and Arp8 are found to be evolutionarily conserved components of the INO80 chromatin remodeling complex, which is involved in transcriptional regulation, DNA replication, and DNA repair. A recent report showed that Arp8 forms a module in the INO80 complex and this module can directly capture a nucleosome. In the present study, we showed that recombinant human Arp8 binds to DNAs, and preferentially binds to single-stranded DNA. Analysis of the binding of adenine nucleotides to Arp8 mutants suggested that the ATP-binding pocket, located in the evolutionarily conserved actin fold, plays a regulatory role in the binding of Arp8 to DNA. To determine the cellular function of Arp8, we derived tetracycline inducible Arp8 knockout cells from a cultured human cell line. Analysis of results obtained after treating these cells with aphidicolin and camptothecin revealed that Arp8 is involved in DNA repair. Together with the previous observation that Arp8, but not gamma-H2AX, is indispensable for recruiting INO80 complex to DSB in human, results of our study suggest an individual role for Arp8 in DNA repair. PMID- 25299603 TI - Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010. AB - The abuse of prescription drugs has led to a significant increase in emergency department (ED) visits and drug-related deaths over the past decade. Opioid pain relievers (OPRs) and benzodiazepines are the prescription drugs most commonly involved in these events. Excessive alcohol consumption also accounts for a significant health burden and is common among groups that report high rates of prescription drug abuse. When taken with OPRs or benzodiazepines, alcohol increases central nervous system depression and the risk for overdose. Data describing alcohol involvement in OPR or benzodiazepine abuse are limited. To quantify alcohol involvement in OPR and benzodiazepine abuse and drug-related deaths and to inform prevention efforts, the Food and Drug Administration (FDA) and CDC analyzed 2010 data for drug abuse-related ED visits in the United States and drug-related deaths that involved OPRs and alcohol or benzodiazepines and alcohol in 13 states. The analyses showed alcohol was involved in 18.5% of OPR and 27.2% of benzodiazepine drug abuse-related ED visits and 22.1% of OPR and 21.4% of benzodiazepine drug-related deaths. These findings indicate that alcohol plays a significant role in OPR and benzodiazepine abuse. Interventions to reduce the abuse of alcohol and these drugs alone and in combination are needed. PMID- 25299604 TI - Hispanics or Latinos living with diagnosed HIV: progress along the continuum of HIV care - United States, 2010. AB - The goals of the National HIV/AIDS Strategy are to reduce new human immunodeficiency virus (HIV) infections, increase access to care and improve health outcomes for persons living with HIV, and reduce HIV-related health disparities. In July 2013, by presidential executive order, the HIV Care Continuum Initiative was established, focusing on accelerating federal efforts to increase HIV testing, care, and treatment. Hispanics or Latinos are disproportionately affected by HIV infection; the annual rate of HIV diagnosis among Hispanics or Latinos is approximately three times that of non-Hispanic whites. To achieve the goals of the National HIV/AIDS Strategy, and to be consistent with the HIV Care Continuum Initiative, Hispanics or Latinos living with HIV infection need improved levels of care and viral suppression. Achieving these goals calls for 85% of Hispanics or Latinos with diagnosed HIV to be linked to care, 80% to be retained in care, and the proportion with an undetectable viral load (VL) to increase 20% by 2015. Analysis of data from the National HIV Surveillance System (NHSS) and the Medical Monitoring Project (MMP) regarding progress along the HIV care continuum during 2010 for Hispanics or Latinos with diagnosed HIV infection indicated that 80.3% of HIV-diagnosed Hispanics or Latinos were linked to care, 54.4% were retained in care, 44.4% were prescribed antiretroviral therapy (ART), and 36.9% had achieved viral suppression (VL result of <=200 copies/mL). Among Hispanic or Latino males and females, the percentages that were linked to care, were prescribed ART, and had achieved viral suppression were similar; however, the percentage retained in care was lower among males compared with females. The levels of linkage to care and viral suppression were lower among Hispanics or Latinos with HIV infection attributed to injection drug use than among those with HIV infection attributed to heterosexual or male-to male sexual contact. These data demonstrate the need for implementation of interventions and public health strategies that increase linkage to care, retention in care, and consistent ART among Hispanics or Latinos, particularly Hispanics or Latinos who inject drugs. PMID- 25299605 TI - Assessment of ebola virus disease, health care infrastructure, and preparedness - four counties,Southeastern Liberia, august 2014. AB - Ebola virus disease (Ebola) is a multisystem disease caused by a virus of the genus Ebolavirus. In late March 2014, Ebola cases were described in Liberia, with epicenters in Lofa County and later in Montserrado County. While information about case burden and health care infrastructure was available for the two epicenters, little information was available about remote counties in southeastern Liberia. Over 9 days, August 6-14, 2014, Ebola case burden, health care infrastructure, and emergency preparedness were assessed in collaboration with the Liberian Ministry of Health and Social Welfare in four counties in southeastern Liberia: Grand Gedeh, Grand Kru, River Gee, and Maryland. Data were collected by health care facility visits to three of the four county referral hospitals and by unstructured interviews with county and district health officials, hospital administrators, physicians, nurses, physician assistants, and health educators in all four counties. Local burial practices were discussed with county officials, but no direct observation of burial practices was conducted. Basic information about Ebola surveillance and epidemiology, case investigation, contact tracing, case management, and infection control was provided to local officials. PMID- 25299606 TI - Vital signs: health burden and medical costs of nonfatal injuries to motor vehicle occupants - United States, 2012. AB - BACKGROUND: Motor vehicle crashes are a leading cause of death and injury in the United States. The purpose of this study was to describe the current health burden and medical and work loss costs of nonfatal crash injuries among vehicle occupants in the United States. METHODS: CDC analyzed data on emergency department (ED) visits resulting from nonfatal crash injuries among vehicle occupants in 2012 using the National Electronic Injury Surveillance System - All Injury Program (NEISS-AIP) and the Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS). The number and rate of all ED visits for the treatment of crash injuries that resulted in the patient being released and the number and rate of hospitalizations for the treatment of crash injuries were estimated, as were the associated number of hospital days and lifetime medical and work loss costs. RESULTS: In 2012, an estimated 2,519,471 ED visits resulted from nonfatal crash injuries, with an estimated lifetime medical cost of $18.4 billion (2012 U.S. dollars). Approximately 7.5% of these visits resulted in hospitalizations that required an estimated 1,057,465 hospital days in 2012. CONCLUSIONS: Nonfatal crash injuries occur frequently and result in substantial costs to individuals, employers, and society. For each motor vehicle crash death in 2012, eight persons were hospitalized, and 100 were treated and released from the ED. IMPLICATIONS FOR PUBLIC HEALTH: Public health practices and laws, such as primary seat belt laws, child passenger restraint laws, ignition interlocks to prevent alcohol impaired driving, sobriety checkpoints, and graduated driver licensing systems have demonstrated effectiveness for reducing motor vehicle crashes and injuries. They might also substantially reduce associated ED visits, hospitalizations, and medical costs. PMID- 25299607 TI - Acute neurologic illness of unknown etiology in children - Colorado, August September 2014. AB - On September 12, 2014, CDC was notified by the Colorado Department of Public Health and Environment of a cluster of nine children evaluated at Children's Hospital Colorado with acute neurologic illness characterized by extremity weakness, cranial nerve dysfunction (e.g., diplopia, facial droop, dysphagia, or dysarthria), or both. Neurologic illness onsets occurred during August 8 September 15, 2014. The median age of the children was 8 years (range = 1-18 years). Other than neck, back, or extremity pain in some patients, all had normal sensation. All had a preceding febrile illness, most with upper respiratory symptoms, occurring 3-16 days (median = 7 days) before onset of neurologic illness. Seven of eight patients with magnetic resonance imaging of the spinal cord had nonenhancing lesions of the gray matter of the spinal cord spanning multiple levels, and seven of nine with magnetic resonance imaging of the brain had nonenhancing brainstem lesions (most commonly the dorsal pons). Two of five with magnetic resonance imaging of the lumbosacral region had gadolinium enhancement of the ventral nerve roots of the cauda equina. Eight children were up to date on polio vaccination. Eight have not yet fully recovered neurologically. PMID- 25299608 TI - Acute flaccid paralysis with anterior myelitis - California, June 2012-June 2014. AB - In August 2012, the California Department of Public Health (CDPH) was contacted by a San Francisco Bay area clinician who requested poliovirus testing for an unvaccinated man aged 29 years with acute flaccid paralysis (AFP) associated with anterior myelitis (i.e., evidence of inflammation of the spinal cord involving the grey matter including anterior horn cell bodies) and no history of international travel during the month before symptom onset. Within 2 weeks, CDPH had received reports of two additional cases of AFP with anterior myelitis of unknown etiology. Testing at CDPH's Viral and Rickettsial Disease Laboratory for stool, nasopharyngeal swab, and cerebrospinal fluid (CSF) did not detect the presence of an enterovirus (EV), the genus of the family Picornaviridae that includes poliovirus. Additional laboratory testing for infectious diseases conducted at the CDPH Viral and Rickettsial Disease Laboratory did not identify a causative agent to explain the observed clinical syndrome reported among the patients. To identify other cases of AFP with anterior myelitis and elucidate possible common etiologies, CDPH posted alerts in official communications for California local health departments during December 2012, July 2013, and February 2014. Reports of cases of neurologic illness received by CDPH were investigated throughout this period, and clinicians were encouraged to submit clinical samples for testing. A total of 23 cases of AFP with anterior myelitis of unknown etiology were identified. Epidemiologic and laboratory investigation did not identify poliovirus infection as a possible cause for the observed cases. No common etiology was identified to explain the reported cases, although EV-D68 was identified in upper respiratory tract specimens of two patients. EV infection, including poliovirus infection, should be considered in the differential diagnosis in cases of AFP with anterior myelitis and testing performed per CDC guidelines. PMID- 25299609 TI - Notes from the field: use of genotyping to disprove a presumed outbreak of Mycobacterium tuberculosis - Los Angeles County, 2013-2014. AB - In early 2013, the Los Angeles County Department of Public Health learned of two patients diagnosed with tuberculosis (TB) who had received care at the same outpatient health care facility (facility A). Facility A is a center for infusions of chemotherapeutic and biologic agents and serves a large number of immunocompromised persons who were potentially exposed to infectious TB. If infected, immunocompromised persons are at elevated risk for progression to TB disease. The two patients (patient A and patient B) both had pulmonary TB, with acid-fast bacilli found on sputum-smear microscopy, and had visited facility A multiple times during their infectious periods. Despite initial concerns that these two cases could be the result of person-to-person transmission at facility A, genotyping of the Mycobacterium tuberculosis isolates from these two patients showed that they were infected with unrelated strains. PMID- 25299610 TI - Last generation triazoles for imported eumycetoma in eleven consecutive adults. AB - BACKGROUND: Optimal management of eumycetoma, a severely debilitating chronic progressive fungal infection of skin, disseminating to bone and viscera, remains challenging. Especially, optimal antifungal treatment and duration are ill defined. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a monocentric retrospective study of 11 imported cases of eumycetoma treated by voriconazole or posaconazole for at least 6 months. Response to treatment was assessed through evolution of clinical and magnetic resonance imaging (MRI). (1->3) beta-D-glucan (BG) and positron emission tomography using [18F] fluorodeoxyglucose (PET/CT) results were also assessed. Identified species were Fusarium solani complex (n = 3); Madurella mycetomatis, (n = 3), and Exophiala jeanselmei, (n = 1). Moreover, two coelomycetes and one phaeohyphomycetes strains without species identification were retrieved. Serum BG and PET/CT were abnormal in 7/8 and 6/6 patients tested, respectively. Patients received last generation azoles for a mean duration of 25.9+/-18 months. Complete response (major clinical and MRI improvement) was observed in 5/11 patients, partial response (minor MRI improvement or stable MRI findings) in 5 and failure (MRI evidence of disease progression) in one, with a 73+/-39 [6-132] months mean follow-up. Relapse occurred in 2 patients after treatment discontinuation. Optimal outcome was associated with fungal species, initiation of last generation triazole therapy (<65 months since first symptoms), negative serum BG and PET/CT normalization. CONCLUSIONS/SIGNIFICANCE: MRI, PET/CT and serum BG appear as promising tools to assess optimal time of antifungal treatment for eumycetoma. PMID- 25299612 TI - The role of the F-box gene TaFBA1 from wheat (Triticum aestivum L.) in drought tolerance. AB - Drought is one of the most important factors limiting plant growth and development. We identified a gene in wheat (Triticum aestivum L.) under drought stress named TaFBA1. TaFBA1 encodes a putative 325-amino-acid F-box protein with a conserved N-terminal F-box domain and a C-terminal AMN1 domain. Real-time RT PCR analysis revealed that TaFBA1 transcript accumulation was upregulated by high salinity, water stress, and abscisic acid (ABA) treatment. To evaluate the functions of TaFBA1 in the regulation of drought stress responses, we produced transgenic tobacco lines overexpressing TaFBA1. Under water stress conditions, the transgenic tobacco plants had a higher germination rate, higher relative water content, net photosynthesis rate (Pn), less chlorophyll loss, and less growth inhibition than WT. These results demonstrate the high tolerance of the transgenic plants to drought stress compared to the WT. The enhanced oxidative stress tolerance of these plants, which may be involved in their drought tolerance, was indicated by their lower levels of reactive oxygen species (ROS) accumulation, MDA content, and cell membrane damage under drought stress compared to WT. The antioxidant enzyme activities were higher in the transgenic plants than in WT, which may be related to the upregulated expression of some antioxidant genes via overexpression of TaFBA1. PMID- 25299613 TI - Drug use during early pregnancy: cross-sectional analysis from the Childbirth and Health Study in Primary Care in Iceland. AB - OBJECTIVE: To analyse drug use in early pregnancy with special focus on socio demographic factors associated with psychotropic and analgesic drug use. DESIGN: Cross-sectional study. SETTING AND SUBJECTS: A total of 1765 women were invited via their local health care centres, and 1111 participated at 11-16 weeks of pregnancy by filling out a postal questionnaire concerning socio-demographic and obstetric background, stressful life events, and drug use. MAIN OUTCOME MEASURES: Drug use prior to and early on in pregnancy, socio-demographic factors, smoking, and adverse life events were investigated. Drug categories screened for were psychotropics (collective term for antidepressants, relaxants, and sleep medication), analgesics, hormones, nicotine, vitamins/minerals, and homeopathic medicine. RESULTS: Drug use from the aforementioned drug categories, excluding vitamins/minerals and homeopathic medicine, was reduced by 18% during early pregnancy, compared with six months prior to conception (49% vs. 60%). Psychotropic drug use during early pregnancy was associated with elementary maternal education (p < 0.5), being unemployed (p < 0.001), being single/divorced/separated (p < 0.01), smoking prior to or during pregnancy (p < 0.01), forced to change job/move house (p < 0.001), and psychotropic drug use six months prior to pregnancy (p < 0.001). No items on the stressful life events scale were associated with increased analgesic use, which increased only with multiparity. CONCLUSIONS: Use of analgesics and psychotropic drugs seems common in pregnancy. Our results indicate that lack of a support network, stressful life events, and lower status in society may predispose women to more drug use. GPs and midwives responsible for maternity care could take this into account when evaluating risk and gain for women and foetuses in the primary care setting. PMID- 25299611 TI - Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive degeneration of motor neurons, ultimately leading to paralysis and death. Approximately 10% of ALS cases are familial, with the remaining 90% of cases being sporadic. Genetic studies in familial cases of ALS have been extremely informative in determining the causative mutations behind ALS, especially as the same mutations identified in familial ALS can also cause sporadic disease. However, the cause of ALS in approximately 30% of familial cases and in the majority of sporadic cases remains unknown. Sporadic ALS cases represent an underutilized resource for genetic information about ALS; therefore, we undertook a targeted sequencing approach of 169 known and candidate ALS disease genes in 242 sporadic ALS cases and 129 matched controls to try to identify novel variants linked to ALS. We found a significant enrichment in novel and rare variants in cases versus controls, indicating that we are likely identifying disease associated mutations. This study highlights the utility of next generation sequencing techniques combined with functional studies and rare variant analysis tools to provide insight into the genetic etiology of a heterogeneous sporadic disease. PMID- 25299615 TI - Developing and Testing of an Oral Health Screening Tool for Midwives to Assess Pregnant Woman. AB - Maternal oral health is important, and midwives are encouraged to screen women for dental problems. We aimed to develop and test a midwifery oral health screening tool. A three-item tool was tested as part of a trial involving 300 women in Southwestern Sydney. A two-item combination showed better sensitivity (98%) and had a positive predictive value of 88%. Specificity was 40%, and negative predictive value was 80%. A two-item screening tool has been identified that is sensitive to identifying dental problems and facilitating referrals. Further validation using a larger sample is required to reassess the tool's specificity. PMID- 25299614 TI - A randomised, double-blind, controlled efficacy trial of the LiESP/QA-21 vaccine in naive dogs exposed to two leishmania infantum transmission seasons. AB - Canine leishmaniasis is an important zoonosis caused by uncontrolled infection with Leishmania infantum, where an inappropriate immune response is not only responsible for permitting this intracellular parasite to multiply, but is also responsible for several of the pathological processes seen in this disease. Effective canine vaccines are therefore a highly desirable prevention tool. In this randomised, double-blinded, controlled trial, the efficacy of the LiESP/QA 21 vaccine (CaniLeish, Virbac, France) was assessed by exposing 90 naive dogs to natural L. infantum infection during 2 consecutive transmission seasons, in two highly endemic areas of the Mediterranean basin. Regular PCR, culture, serological and clinical examinations were performed, and the infection/disease status of the dogs was classified at each examination. The vaccine was well tolerated, and provided a significant reduction in the risk of progressing to uncontrolled active infection (p = 0.025) or symptomatic disease (p = 0.046), with an efficacy of 68.4% and a protection rate of 92.7%. The probability of becoming PCR positive was similar between groups, but the probability of returning to a PCR negative condition was higher in the vaccinated group (p = 0.04). In conclusion, we confirmed the interest of using this vaccine as part of a comprehensive control program for canine leishmaniasis, and validated the use of a protocol based on regular in-depth assessments over time to assess the efficacy of a canine leishmaniasis vaccine. PMID- 25299616 TI - Vaginal challenge with an SIV-based dual reporter system reveals that infection can occur throughout the upper and lower female reproductive tract. AB - The majority of new HIV infections occur in women as a result of heterosexual intercourse, overcoming multiple innate barriers to infection within the mucosa. However, the avenues through which infection is established, and the nature of bottlenecks to transmission, have been the source of considerable investigation and contention. Using a high dose of a single round non-replicating SIV-based vector containing a novel dual reporter system, we determined the sites of infection by the inoculum using the rhesus macaque vaginal transmission model. Here we show that the entire female reproductive tract (FRT), including the vagina, ecto- and endocervix, along with ovaries and local draining lymph nodes can contain transduced cells only 48 hours after inoculation. The distribution of infection shows that virions quickly disseminate after exposure and can access target cells throughout the FRT, with an apparent preference for infection in squamous vaginal and ectocervical mucosa. JRFL enveloped virions infect diverse CD4 expressing cell types, with T cells resident throughout the FRT representing the primary target. These findings establish a new perspective that the entire FRT is susceptible and virus can reach as far as the ovary and local draining lymph nodes. Based on these findings, it is essential that protective mechanisms for prevention of HIV acquisition must be present at protective levels throughout the entire FRT to provide complete protection. PMID- 25299617 TI - Trauma exposure and cigarette smoking: the impact of negative affect and affect regulatory smoking motives. AB - Cognitive-affective mechanisms related to the maintenance of smoking among trauma exposed individuals are largely unknown. Cross-sectional data from trauma-exposed treatment-seeking smokers (n = 283) were utilized to test a series of multiple mediator models of trauma exposure and smoking, as mediated by the sequential effects of negative affect and affect-modulation smoking motives. The sequential effects of both mediators indirectly predicted the effect of greater trauma exposure types on nicotine dependence, a biochemical index of smoking, perceived barriers to smoking cessation, and greater withdrawal-related problems during past quit attempts. Negative affect and affect-modulation motives for smoking may contribute to the trauma-smoking association. PMID- 25299618 TI - Chemical defense balanced by sequestration and de novo biosynthesis in a lepidopteran specialist. AB - The evolution of sequestration (uptake and accumulation) relative to de novo biosynthesis of chemical defense compounds is poorly understood, as is the interplay between these two strategies. The Burnet moth Zygaena filipendulae (Lepidoptera) and its food-plant Lotus corniculatus (Fabaceae) poses an exemplary case study of these questions, as Z. filipendulae belongs to the only insect family known to both de novo biosynthesize and sequester the same defense compounds directly from its food-plant. Z. filipendulae and L. corniculatus both contain the two cyanogenic glucosides linamarin and lotaustralin, which are defense compounds that can be hydrolyzed to liberate toxic hydrogen cyanide. The overall amounts and ratios of linamarin and lotaustralin in Z. filipendulae are tightly regulated, and only to a low extent reflect the ratio in the ingested food-plant. We demonstrate that Z. filipendulae adjusts the de novo biosynthesis of CNglcs by regulation at both the transcriptional and protein level depending on food plant composition. Ultimately this ensures that the larva saves energy and nitrogen while maintaining an effective defense system to fend off predators. By using in situ PCR and immunolocalization, the biosynthetic pathway was resolved to the larval fat body and integument, which infers rapid replenishment of defense compounds following an encounter with a predator. Our study supports the hypothesis that de novo biosynthesis of CNglcs in Z. filipendulae preceded the ability to sequester, and facilitated a food-plant switch to cyanogenic plants, after which sequestration could evolve. Preservation of de novo biosynthesis allows fine-tuning of the amount and composition of CNglcs in Z. filipendulae. PMID- 25299620 TI - Effects of side chains on DNA binding, cell permeability, nuclear localization and cytotoxicity of 4-aminonaphthalimides. AB - Nucleic acid binding molecules have been extensively explored for nucleic acid assay, nuclear imaging, and antitumor and antivirus therapies. Most of these molecules usually bear positive charges to enhance their binding affinity. However, their in vivo applications are limited by poor membrane permeability and the lack of selectivity to nucleic acids. Here we describe the effects of positive charged side chains (including aminoethyl, dimethylaminopropyl and guanidinoethyl) on the DNA binding ability, cell permeability, cellular localization and cytotoxicity of 4-aminonaphthalimides, a class of DNA intercalating agents and fluorophores. The synthesized 4-aminonaphthalimides have a strong binding ability to duplex DNA, and can be used as pre-staining dyes for gel electrophoresis of DNA and RNA. When entering into cells, they rapidly concentrate in cell nuclei, especially in nucleoli. The guanidinoethyl side chains increase the binding ability to nucleic acids, but do not favour the cell permeability and cytotoxicity; dimethylaminopropyl groups enhance the cell permeability and cytotoxicity of 4-aminonaphthalimides. These results suggest the potential applications of 4-aminonaphthalimides in nucleic acid assay and nuclear imaging, and provide useful information for the molecular design of DNA-binding drugs and fluorescent probes. PMID- 25299619 TI - General immune status and oral microbiology in patients with different forms of periodontitis and healthy control subjects. AB - OBJECTIVE: Immunological processes in the etiopathogenesis of periodontitis, especially the aggressive form, are not well understood. This study examined clinical as well as systemic immunological and local microbiological features in healthy controls and patients with different forms of periodontitis. MATERIALS AND METHODS: 14 healthy subjects, 15 patients diagnosed with aggressive periodontitis, and 11 patients with chronic periodontitis were recruited. Periodontal examination was performed and peripheral blood was collected from each patient. Lymphocyte populations as well as the release of cytokines by T helper cells were determined by flow cytometry and enzyme linked immunosorbent spot assay. Subgingival plaque samples were taken from each individual and immediately cultivated for microbiological examination. RESULTS: When stimulating peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide, a higher IL 1beta release was found in patients with moderate chronic periodontitis compared to the other groups (p<0.01). Numbers of B-cells, naive and transitional B-cells, memory B-cells, and switched memory B-cells were within the reference range for all groups, but patients with chronic periodontitis showed the highest percentage of memory B-cells without class switch (p = 0.01). The subgingival plaque differed quantitatively as well as qualitatively with a higher number of Gram negative anaerobic species in periodontitis patients. Prevotella denticola was found more often in patients with aggressive periodontitis (p<0.001) but did not show an association to any of the systemic immunological findings. Porphyromonas gingivalis, which was only found in patients with moderate chronic periodontitis, seems to be associated with an activation of the systemic immune response. CONCLUSION: Differences between aggressive periodontitis and moderate chronic periodontitis are evident, which raises the question of an inadequate balance between systemic immune response and bacterial infection in aggressive periodontitis. PMID- 25299621 TI - Guidelines for carcinogen bioassay in small rodents. AB - Note to the Reader: These guidelines were published to establish standard procedures for toxicology testing in rodents. PMID- 25299622 TI - Effect of exogenous nitric oxide on sperm motility in vitro. AB - BACKGROUND: Nitric oxide (NO) has been shown to be important in sperm function, and the concentration of NO appears to determine these effects. Studies have demonstrated both positive and negative effects of NO on sperm function, but have not been able to provide a clear link between NO concentration and the extent of exposure to NO. To study the relationship between nitric oxide and sperm capacitation in vitro, and to provide a theoretical basis for the use of NO related preparations in improving sperm motility for in vitro fertilization, we investigated the effects of NO concentration and time duration at these concentrations on in vitro sperm capacitation in both normal and abnormal sperm groups. We manipulated NO concentrations and the time duration of these concentrations using sodium nitroprusside (an NO donor) and NG-monomethyl-L argenine (an NO synthase inhibitor). RESULTS: Compared to the normal sperm group, the abnormal sperm group had a longer basal time to reach the appropriate concentration of NO (p < 0.001), and the duration of time at this concentration was longer for the abnormal sperm group (p < 0.001). Both the basal time and the duration of time were significantly correlated with sperm viability and percentage of progressive sperm (p < 0.001). The experimental group had a significantly higher percentage of progressive sperm than the control group (p < 0.001). CONCLUSIONS: We hypothesize that there is a certain regularity to both NO concentration and its duration of time in regards to sperm capacitation, and that an adequate duration of time at the appropriate NO concentration is beneficial to sperm motility. PMID- 25299624 TI - Fabrication and characterization of chitosan-collagen crosslinked membranes for corneal tissue engineering. AB - This article describes a chitosan-collagen composite membrane as corneal tissue engineering biomaterials. The membrane was prepared by dissolving the chitosan into collagen with the weight ratio of 0, 15, 30, 45, 60, and 100%, followed by crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Mechanical properties, contact angles, and optical transmittance were determined and compared between chitosan membrane and crosslinking composite membrane. As a result, the optical transparency and mechanical strength of the chitosan-collagen membranes were significantly better than that of the sample of chitosan. In addition, in vitro cell culture studies revealed that the collagen has no negative effect on the cell morphology, viability, and proliferation and possess good biocompatibility. Overall, the dendrimer crosslinked chitosan-collagen composite membranes showed promising properties that suggest that these might be suitable biomaterials for corneal tissue-engineering applications. PMID- 25299623 TI - High-dose cytarabine in acute myeloid leukemia treatment: a systematic review and meta-analysis. AB - The optimal dose, scheme, and clinical setting for Ara-C in acute myeloid leukemia (AML) treatment remain uncertain. In this study, we performed a meta analysis to systematically assess the impact of high-dose cytarabine (HDAC) on AML therapy during the induction and consolidation stages. Twenty-two trials with a total of 5,945 de novo AML patients were included in the meta-analysis. Only patients less than 60 year-old were included in the study. Using HDAC in induction therapy was beneficial for RFS (HR = 0.57; 95% CI, 0.35-0.93; P = 0.02) but not so for CR rate (HR = 1.01; 95% CI, 0.93-1.09; P = 0.88) and OS (HR = 0.83; 95% CI, 0.66-1.03; P = 0.1). In consolidation therapy, HDAC showed significant RFS benefits (HR = 0.67; 95% CI, 0.49-0.9; P = 0.008) especially for the favorable-risk group (HR = 0.38; 95% CI, 0.21-0.69; P = 0.001) compared with SDAC (standard dose cytarabine), although no OS advantage was observed (HR = 0.84; 95% CI, 0.55-1.27; P = 0.41). HDAC treatment seemed less effective than auto-BMT/allo-BMT treatment (HR = 1.66, 95% CI, 1.3-2.14; P<0.0001) with similar OS. HDAC treatment led to lower relapse rate in induction and consolidation therapy than SDAC treatment, especially for the favorable-risk group. Auto BMT/allo-BMT was more beneficial in prolonging RFS than HDAC. PMID- 25299625 TI - [Pushing back frontiers in neurology]. PMID- 25299626 TI - [The significance of depot medication in the long-term-treatment of schizophrenia]. AB - Relapse prevention in schizophrenia is a key aim in therapy. However, it is estimated that approximately 75% of patients with schizophrenia relapse within five years. Each relapse might worsen the disease and increase the risk of psychosocial and work-related disadvantages. A continuous long-term therapy is able to reduce this risk, but medical non-adherence, which is influenced by numerous factors, is a limitation. Naturalistic studies show that depot antipsychotics compared with oral antipsychotics lead consistently to a better outcome, for example by reducing relapse rates or hospitalisation. Numerous meta analyses of randomised controlled trials comparing oral versus depot antipsychotics also show this advantages. However these results are not consistent in all meta-analyses. Results of controlled studies do not appropriately reflect the reality of daily practice. The advantages of depot antipsychotics are shown more distinctly in naturalistic studies. The following review reflects the current therapy of schizophrenia and discusses adequately a broad application of depot-antipsychotics based on existing data. In addition, concerns and prejudices of physicians and patients against antipsychotic long term therapy and depot-formulation are discussed and a recommendation is provided. PMID- 25299627 TI - [Optical Coherence Tomography (OCT)--a new diagnostic tool in psychiatry?]. AB - Optical coherence tomography (OCT) is a non-invasive, contact-less imaging method which provides an "in vivo" representation of the retina. It allows the quantitative measurement of retinal nerve fibre layer thickness (RNFLT) and macula thickness (MT) and, in addition, is suitable to measure volumes (e.g., macula volume/MV). In the research of neurodegenerative diseases, OCT has been increasingly used and has shown its potential as a possible diagnostic tool over the course of the last few years. In recent years, the hypothesis that mental disorders like schizophrenia or unipolar depressive disorder have a degenerative component was established through a variety of volumetric MRI studies. This review article aims to present the method of OCT, to display its recent use in medicine and psychiatry, as well as to examine possible additional applications in the field of psychiatry. PMID- 25299628 TI - [Stress-related risk factors for depression in young girls]. AB - The prevalence of major depression in adolescents is remarkable. Stress has been hypothesised to contribute to the maintenance of depression in young patients. This study aims to elucidate stress-related predictive variables for the maintenance of depression in young girls. A longitudinal design with a time interval of six months was used to assess stress load and depression in 135 15 year-old girls. Stress was measured by the "Fragebogen zur Erhebung von Stress und Stressbewaltigung im Kindes- und Jugendalter" and the cortisol awakening response as a biological indicator for hyperactivity of the HPA axis. Depression was quantified by the "Depressionsinventar fur Kinder und Jugendliche". The data were analysed by multiple linear regression. When adjusting for initial depression, psychological stress load, physical stress symptoms, and stress vulnerability proved to be predictive for depression, whereas chronic stress neither at the psychological level nor as indicated by the cortisol awakening response had statistically significant effects. The results show the stability of depression in adolescent girls, but also prove an additional influence of acute stress variables. PMID- 25299629 TI - [Gender-specific differences relating to depressiveness in 1st and 2nd generation migrants: results of a cross-sectional study amongst employees of a university hospital]. AB - AIMS: This study analysed the risk of depression in men and women with a background of immigration by means of a cross-sectional study amongst employees of a German university hospital. In addition we identified gender-specific differences related to risk factors for depressiveness in the subgroups. METHODS: 7062 employees with or without a 1st (1G) or 2nd (2G) generation background of migration were questioned with regard to their socio-economic status, to single markers of acculturation, and to existing symptoms of depression assessed on the general depression scale (CES-D). Odds ratios (OR) were calculated using logistic regression. RESULTS: The response rate was 41.7% (n=2932). In comparison to non migrants a higher risk of clinically relevant depressiveness was found for 1G male migrants (OR 2.35, 95% Cl 1.11-4.96), 1G female migrants (OR 1.94, 95% Cl 1.26-2.97) and for 2G female migrants (OR 1.82, 95% Cl 1.03-3.19). There was no significant increase in risk for 2G male migrants (OR 1.06, 95% Cl 0.31-3.62). 2G female migrants who considered themselves to retain a "close relationship to their native culture" had a significantly higher risk of depression than 2G male immigrants (OR 7.31; p = 0.032). Male 1G migrants without a "close relationship to their native culture" had a significantly higher risk of depression than those with a "close relationship to their native culture" (OR 5.79; p = 0.010). CONCLUSIONS: The results of this study point to gender-specific risk constellations for depression amongst 1st and 2nd generation migrants. It would appear that a strong orientation to the native culture increases the risk of depression for 2G female migrants, whereas for 1G male migrants this factor is associated with a lower risk of depression. PMID- 25299630 TI - [Anti-stigma competence for mental health professionals: results of a pilot study of a further education programme for people working in psychiatric and psychosocial settings]. AB - BACKGROUND: Mental health professionals are an important target group for anti stigma interventions, both as subjects to stigmatisation as well as stigmatising actors. Within the framework of the German Research Network on Schizophrenia, a further education training programme on "anti-stigma competence" was developed and evaluated for this target group in a pilot study. MATERIAL AND METHODS: The control-group pilot study included a total of 11 trainings with 123 participants. "Social distance" and "addressing stigma" were assessed before, directly after and three months after the training sessions. "Addressing stigma" included the ability to recognise stigmatising situations and to act against them. RESULTS: Social distance was significantly lower after the "anti-stigma competence" training than before and remained significantly lower after three months. Moreover, the ability to recognise and counteract stigma was significantly improved after three months. CONCLUSION: The training on "anti-stigma competence" has been shown to be effective. The degree to which the training will have an impact on stigmatisation in real life of patients in mental health care institutions should be a target of future research. PMID- 25299631 TI - [Diagnostics and therapy of "freezing of gait" in patients with Parkinson's disease]. PMID- 25299632 TI - Fibular malalignment in individuals with chronic ankle instability. AB - STUDY DESIGN: Case series. OBJECTIVES: To determine whether abnormal fibular alignment is present in individuals with chronic ankle instability (CAI) using 3 D analysis of computed tomography (CT)-based bone models. BACKGROUND: A positional difference of the distal fibula in individuals with unilateral CAI, when compared to the contralateral side, has been suggested. However, previous studies report no consistent pattern of fibular malalignment in the anteroposterior direction and, to our knowledge, no study has investigated mediolateral malalignment. METHODS: Seventeen males with unilateral CAI (mean +/- SD age, 21.0 +/- 2.4 years) and no history of injury in the contralateral side were enrolled. Geometric bone models of the tibia and fibula were created from non-weight-bearing CT images, and anatomical coordinate systems were embedded in the tibia model. Bilateral tibiae were superimposed using a best-fit algorithm that moved the tibia to the position of best congruity, and the amount of side-to side difference in position of the fibulae was measured. The anteroposterior and mediolateral positional difference of the fibula of the ankle with CAI relative to the contralateral ankle, for the distal 10 cm of the fibula length, was determined using a color-coded map. RESULTS: The fibula of the ankle with CAI was significantly more lateral (0.57-0.68 mm) than that of the contralateral healthy ankle at all reference points from distal 10 cm to the lateral malleolus. There was no significant difference in anteroposterior position between the healthy ankles and those with CAI. CONCLUSION: This study detected malalignment of the distal fibula in ankles with CAI in a non-weight-bearing position. The fibula of the ankles with CAI had a significantly more lateral position than that of the healthy ankles, which may contribute to recurrent lateral ankle sprain or giving way episodes. PMID- 25299633 TI - The architecture of an Okazaki fragment-processing holoenzyme from the archaeon Sulfolobus solfataricus. AB - DNA replication on the lagging strand occurs via the synthesis and maturation of Okazaki fragments. In archaea and eukaryotes, the enzymatic activities required for this process are supplied by a replicative DNA polymerase, Flap endonuclease 1 (Fen1) and DNA ligase 1 (Lig1). These factors interact with the sliding clamp PCNA (proliferating cell nuclear antigen) providing a potential means of co ordinating their sequential actions within a higher order assembly. In hyperthermophilic archaea of the Sulfolobus genus, PCNA is a defined heterotrimeric assembly and each subunit interacts preferentially with specific client proteins. We have exploited this inherent asymmetry to assemble a PCNA polymerase-Fen1-ligase complex on DNA and have visualized it by electron microscopy. Our studies reveal the structural basis of co-occupancy of a single PCNA ring by the three distinct client proteins. PMID- 25299634 TI - Stretchable and transparent electrodes using hybrid structures of graphene-metal nanotrough networks with high performances and ultimate uniformity. AB - Transparent electrodes that can maintain their electrical and optical properties stably against large mechanical deformations are essential in numerous applications of flexible and wearable electronics. In this paper, we report a comprehensive analysis of the electrical, optical, and mechanical properties of hybrid nanostructures based on graphene and metal nanotrough networks as stretchable and transparent electrodes. Compared to the single material of graphene or the nanotrough, the formation of this hybrid can improve the uniformity of sheet resistance significantly, that is, a very low sheet resistance (1 Omega/sq) with a standard deviation of less than +/-0.1 Omega/sq, high transparency (91% in the visible light regime), and superb stretchability (80% in tensile strain). The successful demonstration of skin-attachable, flexible, and transparent arrays of oxide semiconductor transistors fabricated using hybrid electrodes suggests substantial promise for the next generation of electronic devices. PMID- 25299636 TI - Tacrolimus Versus Cyclosporine as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation. AB - Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period. PMID- 25299637 TI - Sugammadex: A Scientific Review Including Safety and Efficacy, Update on Regulatory Issues, and Clinical Use in Europe. AB - Muscle relaxants are used in the perioperative period to aid in endotracheal intubation, facilitate surgical exposure, and in the critical care setting for prolonged relaxation. Until now, the only mechanism to reverse their effect is acetylcholinesterase inhibitors that result in excess parasympathetic activity and require the second drug to prevent this side effect. Additionally, the onset and degree of neuromuscular antagonism are often unpredictable and unreliable. Sugammadex is the first of the cyclodextrins to be used as a therapeutic agent. It quickly, effectively, and safely reverses steroidal neuromuscular blockers by encapsulating the muscle relaxant and rendering it inactive. Sugammadex may be considered the ideal reversal agent and the first drug in its class, which will likely change the practice of anesthesia and clinical neuromuscular pharmacology. PMID- 25299635 TI - Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice. AB - Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT. PMID- 25299638 TI - Sugammadex: A Comprehensive Review of the Published Human Science, Including Renal Studies. AB - Although neuromuscular block (NMB) allows immobility for airway management and surgical exposure, termination of its effect is limited by and associated with side effects of acetylcholinesterase inhibitors. Sugammadex is a selective relaxant binding agent that has been shown to reverse deep NMB, even when administered 3 minutes following a 1.2 mg/kg dose of rocuronium. This novel drug is a modified gamma cyclodextrin, that through encapsulation process terminates the effects of rocuronium and vecuronium (aminosteroid muscle relaxants), and enables the anesthesiologists rapidly to reverse profound NMB induced by rocuronium or vecuronium, in a "can't ventilate, can't intubate" crisis. In this review, data from published phase 1, 2, and 3 clinical trials are reviewed and presented. In addition, clinical trials on special patient populations (patients with pulmonary disease and renal insufficiency) are evaluated. Each article reviewed will conclude with a discussion of relevance, focus on adverse event profile, and clinical usefulness. PMID- 25299641 TI - Plant aquaporins on the move: reversible phosphorylation, lateral motion and cycling. AB - Aquaporins are channel proteins present in the plasma membrane and most of intracellular compartments of plant cells. This review focuses on recent insights into the cellular function of plant aquaporins, with an emphasis on the subfamily of Plasma membrane Intrinsic Proteins (PIPs). Whereas PIPs mostly serve as water channels, novel functions associated with their ability to transport carbon dioxide and hydrogen peroxide are emerging. Phosphorylation of PIPs was found to play a central role in the mechanisms that determine their gating and subcellular dynamics. Dynamic tracking of single aquaporin molecules in native plant membranes and the search for cell signaling intermediates acting upstream of aquaporins are now used to dissect their cellular regulation by hormonal and environmental stimuli. PMID- 25299639 TI - Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody. AB - Human cytomegalovirus (HCMV) infections are life-threating to people with a compromised or immature immune system. Upon adhesion, fusion of the virus envelope with the host cell is initiated. In this step, the viral glycoprotein gB is considered to represent the major fusogen. Here, we present for the first time structural data on the binding of an anti-herpes virus antibody and describe the atomic interactions between the antigenic domain Dom-II of HCMV gB and the Fab fragment of the human antibody SM5-1. The crystal structure shows that SM5-1 binds Dom-II almost exclusively via only two CDRs, namely light chain CDR L1 and a 22-residue-long heavy chain CDR H3. Two contiguous segments of Dom-II are targeted by SM5-1, and the combining site includes a hydrophobic pocket on the Dom-II surface that is only partially filled by CDR H3 residues. SM5-1 belongs to a series of sequence-homologous anti-HCMV gB monoclonal antibodies that were isolated from the same donor at a single time point and that represent different maturation states. Analysis of amino acid substitutions in these antibodies in combination with molecular dynamics simulations show that key contributors to the picomolar affinity of SM5-1 do not directly interact with the antigen but significantly reduce the flexibility of CDR H3 in the bound and unbound state of SM5-1 through intramolecular side chain interactions. Thus, these residues most likely alleviate unfavorable binding entropies associated with extra-long CDR H3s, and this might represent a common strategy during antibody maturation. Models of entire HCMV gB in different conformational states hint that SM5-1 neutralizes HCMV either by blocking the pre- to postfusion transition of gB or by precluding the interaction with additional effectors such as the gH/gL complex. PMID- 25299640 TI - The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV related hepatocellular carcinoma and promotes tumorigenesis and tumor progression. AB - Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Previous studies have shown several long noncoding RNAs (lncRNAs) play various roles in HCC progression, but no research has focused on the expression pattern of microRNA clusters encoded in lncRNAs. The Ftx gene encodes a lncRNA which harbors 2 clusters of microRNAs in its introns, the miR 374b/421 cluster and the miR-545/374a cluster. To date, no research has focused on the role of the miR-545/374a and miR-374b/421 clusters in HBV-related HCC. In this study, 66 pairs of HBV-related HCC tissue and matched non-cancerous liver tissue specimens were analyzed for the expression of the Ftx microRNA clusters. Our results showed that the miR-545/374a cluster was upregulated in HBV-HCC tissue and significantly correlated with prognosis-related clinical features, including histological grade, metastasis and tumor capsule. Transfection studies with microRNA mimics and inhibitors revealed that miR-545/374a expression promoted in vitro cell proliferation, cell migration and invasion. The wild-type HBV-genome-containing plasmid or full-length HBx protein encoding plasmid was transfected into the Bel-7402 cell line and observed for their influence on miR 545/374a expression. We found that transfection of the HBV genome or HBx alone resulted in an increase in miR-545/374a expression. Next, by monitoring the expression of sera miR-545/374a before and after surgical tumor excision, we found serum miR-545/374a was tumor-derived and exhibited a sharp decrease 25 days after tumor excision. We also examined the gender-based difference in miR 545/374a expression among HCC patients and utilized microRNA target prediction software to find the targets of miR-545/374a. One of these targets, namely estrogen-related receptor gamma (ESRRG) was inversely correlated with miR-545 expression. In conclusion, the overexpression of miR-545/374a cluster located in the Ftx lncRNA is partially responsible for a poor prognosis, and monitoring sera levels of miR-545/374a may be a useful diagnostic marker for HCC. PMID- 25299642 TI - Stoichiometry of root and leaf nitrogen and phosphorus in a dry alpine steppe on the Northern Tibetan Plateau. AB - Leaf nitrogen (N) and phosphorus (P) have been used widely in the ecological stoichiometry to understand nutrient limitation in plant. However,few studies have focused on the relationship between root nutrients and environmental factors. The main objective of this study was to clarify the pattern of root and leaf N and P concentrations and the relationships between plant nitrogen (N) and phosphorus (P) concentrations with climatic factors under low temperature conditions in the northern Tibetan Plateau of China. We conducted a systematic census of N and P concentrations, and the N?P ratio in leaf and root for 139 plant samples, from 14 species and 7 families in a dry Stipa purpurea alpine steppe on the northern Tibetan Plateau of China. The results showed that the mean root N and P concentrations and the N?P ratios across all species were 13.05 mg g 1, 0.60 mg g-1 and 23.40, respectively. The mean leaf N and P concentrations and the N?P ratio were 23.20 mg g-1, 1.38 mg g-1, and 17.87, respectively. Compared to global plant nutrients concentrations, plants distributing in high altitude area have higher N concentrations and N?P, but lower P concentrations, which could be used to explain normally-observed low growth rate of plant in the cold region. Plant N concentrations were unrelated to the mean annual temperature (MAT). The root and leaf P concentrations were negatively correlated with the MAT, but the N?P ratios were positively correlated with the MAT. It is highly possible this region is not N limited, it is P limited, thus the temperature biogeochemical hypothesis (TBH) can not be used to explain the relationship between plant N concentrations and MAT in alpine steppe. The results were valuable to understand the bio-geographic patterns of root and leaf nutrients traits and modeling ecosystem nutrient cycling in cold and dry environments. PMID- 25299643 TI - Elevated C-reactive protein levels and enhanced high frequency vasomotion in patients with ischemic heart disease during brachial flow-mediated dilation. AB - PURPOSE: The physiological role of vasomotion, rhythmic oscillations in vascular tone or diameter, and its underlying mechanisms are unknown. We investigated the characteristics of brachial artery vasomotion in patients with ischemic heart disease (IHD). METHODS: We performed a retrospective study of 37 patients with IHD. Endothelial function was assessed using flow-mediated dilation (FMD), and power spectral analysis of brachial artery diameter oscillations during FMD was performed. Frequency-domain components were calculated by integrating the power spectrums in three frequency bands (in ms2) using the MemCalc (GMS, Tokyo, Japan): very-low frequency (VLF), 0.003-0.04 Hz; low frequency (LF), 0.04-0.15 Hz; and high frequency (HF), 0.15-0.4 Hz. Total spectral power (TP) was calculated as the sum of all frequency bands, and each spectral component was normalized against TP. RESULTS: Data revealed that HF/TP closely correlated with FMD (r = -0.33, p = 0.04), whereas VLF/TP and LF/TP did not. We also explored the relationship between elevated C-reactive protein (CRP) levels and vasomotion. HF/TP was significantly increased in subjects with high CRP levels (CRP;>0.08 mg/dL) compared with subjects with low CRP levels (0.052+/-0.026 versus 0.035+/ 0.022, p<0.05). The HF/TP value closely correlated with CRP (r = 0.24, p = 0.04), whereas the value of FMD did not (r = 0.023, p = 0.84). In addition, elevated CRP levels significantly increased the value of HF/TP after adjustment for FMD and blood pressure (beta = 0.33, p<0.05). CONCLUSION: The HF component of brachial artery diameter oscillation during FMD measurement correlated well with FMD and increased in the presence of elevated CRP levels in subjects with IHD. PMID- 25299644 TI - Developmentally-regulated excision of the SPbeta prophage reconstitutes a gene required for spore envelope maturation in Bacillus subtilis. AB - Temperate phages infect bacteria by injecting their DNA into bacterial cells, where it becomes incorporated into the host genome as a prophage. In the genome of Bacillus subtilis 168, an active prophage, SPbeta, is inserted into a polysaccharide synthesis gene, spsM. Here, we show that a rearrangement occurs during sporulation to reconstitute a functional composite spsM gene by precise excision of SPbeta from the chromosome. SPbeta excision requires a putative site specific recombinase, SprA, and an accessory protein, SprB. A minimized SPbeta, where all the SPbeta genes were deleted, except sprA and sprB, retained the SPbeta excision activity during sporulation, demonstrating that sprA and sprB are necessary and sufficient for the excision. While expression of sprA was observed during vegetative growth, sprB was induced during sporulation and upon mitomycin C treatment, which triggers the phage lytic cycle. We also demonstrated that overexpression of sprB (but not of sprA) resulted in SPbeta prophage excision without triggering the lytic cycle. These results suggest that sprB is the factor that controls the timing of phage excision. Furthermore, we provide evidence that spsM is essential for the addition of polysaccharides to the spore envelope. The presence of polysaccharides on the spore surface renders the spore hydrophilic in water. This property may be beneficial in allowing spores to disperse in natural environments via water flow. A similar rearrangement occurs in Bacillus amyloliquefaciens FZB42, where a SPbeta-like element is excised during sporulation to reconstitute a polysaccharide synthesis gene, suggesting that this type of gene rearrangement is common in spore-forming bacteria because it can be spread by phage infection. PMID- 25299645 TI - NK cell phenotypic modulation in lung cancer environment. AB - BACKGROUND: Nature killer (NK) cells play an important role in anti-tumor immunotherapy. But it indicated that tumor cells impacted possibly on NK cell normal functions through some molecules mechanisms in tumor microenvironment. MATERIALS AND METHODS: Our study analyzed the change about NK cells surface markers (NK cells receptors) through immunofluorescence, flow cytometry and real time PCR, the killed function from mouse spleen NK cell and human high/low lung cancer cell line by co-culture. Furthermore we certificated the above result on the lung cancer model of SCID mouse. RESULTS: We showed that the infiltration of NK cells in tumor periphery was related with lung cancer patients' prognosis. And the number of NK cell infiltrating in lung cancer tissue is closely related to the pathological types, size of the primary cancer, smoking history and prognosis of the patients with lung cancer. The expression of NK cells inhibitor receptors increased remarkably in tumor micro-environment, in opposite, the expression of NK cells activated receptors decrease magnificently. CONCLUSIONS: The survival time of lung cancer patient was positively related to NK cell infiltration degree in lung cancer. Thus, the down-regulation of NKG2D, Ly49I and the up-regulation of NKG2A may indicate immune tolerance mechanism and facilitate metastasis in tumor environment. Our research will offer more theory for clinical strategy about tumor immunotherapy. PMID- 25299647 TI - Invitation choice structure has no impact on attendance in a female business training program in Kenya. AB - Business training programs are a common form of support to small businesses, but organizations providing this training often struggle to get business owners to attend. We evaluate the role of invitation choice structure in determining agreement to participate and actual attendance. A field experiment randomly assigned female small business owners in Kenya (N = 1172) to one of three invitation types: a standard opt-in invitation; an active choice invitation where business owners had to explicitly say yes or no to the invitation; and an enhanced active choice invitation which highlighted the costs of saying no. We find no statistically significant effect of these alternative choice structures on willingness to participate in training, attending at least one day, and completing the course. The 95 percent confidence interval for the active treatment effect on attendance is [-1.9%, +9.5%], while for the enhanced active choice treatment it is [-4.1%, +7.7%]. The effect sizes consistent with our data are smaller than impacts measured in health and retirement savings studies in the United States. We examine several potential explanations for the lack of effect in a developing country setting. We find evidence consistent with two potential reasons being limited decision-making power amongst some women, and lower levels of cognition making the enhanced active choice wording less effective. PMID- 25299646 TI - Determinants of acceptance and subsequent uptake of the HPV vaccine in a cohort in Eldoret, Kenya. AB - The development of Human Papillomavirus (HPV) vaccines provides new opportunities in the fight against cervical cancer. Many acceptability studies have revealed high interest in these vaccines, but acceptance is only a precursor of behavior, and many factors, at personal, community and provider level, may inhibit the translation of willingness to vaccinate into actual uptake. Through a longitudinal study in Eldoret, Kenya, HPV vaccine acceptability was measured before a vaccination program (n = 287) and vaccine uptake, as reported by mothers, once the program was finished (n = 256). In between baseline and follow up, a pilot HPV vaccination program was implemented via the GARDASIL Access Program, in which parents could have their daughter vaccinated for free at the referral hospital. The program was promoted at schools: Health staff informed teachers who were then asked to inform students and parents. Even though baseline acceptance was very high (88.1%), only 31.1% of the women reported at follow-up that their daughter had been vaccinated. The vaccine was declined by 17.7%, while another 51.2% had wanted the vaccination but were obstructed by practical barriers. Being well-informed about the program and baseline awareness of cervical cancer were independently associated with vaccine uptake, while baseline acceptance was correlated in bivariate analysis. Side effects were of great concern, even among those whose daughter was vaccinated. Possible partner disapproval lowered acceptance at baseline, and women indeed reported at follow up that they had encountered his opposition. In Kenya, women prove to be very willing to have their daughter vaccinated against cervical cancer. However, in this study, uptake was more determined by program awareness than by HPV vaccine acceptance. School-based vaccination might improve coverage since it reduces operational problems for parents. In addition, future HPV vaccination campaigns should address concerns about side effects, targeting men and women, given both their involvement in HPV vaccination decision-making. PMID- 25299650 TI - Physician assistants in New Zealand. PMID- 25299651 TI - Desperate measures: probing the incentive for scandal in the VHA. PMID- 25299648 TI - Inferring tree causal models of cancer progression with probability raising. AB - Existing techniques to reconstruct tree models of progression for accumulative processes, such as cancer, seek to estimate causation by combining correlation and a frequentist notion of temporal priority. In this paper, we define a novel theoretical framework called CAPRESE (CAncer PRogression Extraction with Single Edges) to reconstruct such models based on the notion of probabilistic causation defined by Suppes. We consider a general reconstruction setting complicated by the presence of noise in the data due to biological variation, as well as experimental or measurement errors. To improve tolerance to noise we define and use a shrinkage-like estimator. We prove the correctness of our algorithm by showing asymptotic convergence to the correct tree under mild constraints on the level of noise. Moreover, on synthetic data, we show that our approach outperforms the state-of-the-art, that it is efficient even with a relatively small number of samples and that its performance quickly converges to its asymptote as the number of samples increases. For real cancer datasets obtained with different technologies, we highlight biologically significant differences in the progressions inferred with respect to other competing techniques and we also show how to validate conjectured biological relations with progression models. PMID- 25299652 TI - Transplant in the 21st century. AB - Organ transplantation has enriched and prolonged the lives of many patients who otherwise would have died of organ failure. Many of these advances, which occurred in the later part of the 20th century, are due to improved techniques and pharmacological management. Today, almost every organ can be transplanted. However, donor and recipient criteria can vary widely according to the organ(s) in question. This article reviews the historical changes that have occurred in transplant along with current criteria for donors and recipients, and describes the newest outreach to increase the donor pool. PMID- 25299649 TI - Predicting the functions and specificity of triterpenoid synthases: a mechanism based multi-intermediate docking approach. AB - Terpenoid synthases construct the carbon skeletons of tens of thousands of natural products. To predict functions and specificity of triterpenoid synthases, a mechanism-based, multi-intermediate docking approach is proposed. In addition to enzyme function prediction, other potential applications of the current approach, such as enzyme mechanistic studies and enzyme redesign by mutagenesis, are discussed. PMID- 25299654 TI - Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances. AB - BACKGROUND: During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances. METHODOLOGY/PRINCIPAL FINDINGS: Levels of ferritin, standard laboratory markers, sIL-2R, IL-18 and coagulation and fibrinolytic markers were determined in samples from patients with uncomplicated dengue in Aruba. Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The results were validated in a cohort of dengue virus infected patients in Brazil. In this cohort levels of ferritin and cytokine profiles were determined. Increased levels of ferritin in dengue virus infected patients in Brazil were associated with disease severity and a pro-inflammatory cytokine profile. CONCLUSIONS/SIGNIFICANCE: Altogether, we provide evidence that ferritin can be used as a clinical marker to discriminate between dengue and other febrile illnesses. The occurrence of hyperferritinaemia in dengue virus infected patients is indicative for highly active disease resulting in immune activation and coagulation disturbances. Therefore, we recommend that patients with hyperferritinaemia are monitored carefully. PMID- 25299653 TI - Key source habitats and potential dispersal of triatoma infestans populations in Northwestern Argentina: implications for vector control. AB - BACKGROUND: Triatoma infestans -the principal vector of the infection that causes Chagas disease- defies elimination efforts in the Gran Chaco region. This study identifies the types of human-made or -used structures that are key sources of these bugs in the initial stages of house reinfestation after an insecticide spraying campaign. METHODOLOGY AND PRINCIPAL FINDINGS: We measured demographic and blood-feeding parameters at two geographic scales in 11 rural communities in Figueroa, northwest Argentina. Of 1,297 sites searched in spring, 279 (21.5%) were infested. Bug abundance per site and female fecundity differed significantly among habitat types (ecotopes) and were highly aggregated. Domiciles (human sleeping quarters) had maximum infestation prevalence (38.7%), human-feeding bugs and total egg production, with submaximal values for other demographic and blood feeding attributes. Taken collectively peridomestic sites were three times more often infested than domiciles. Chicken coops had greater bug abundance, blood feeding rates, engorgement status, and female fecundity than pig and goat corrals. The host-feeding patterns were spatially structured yet there was strong evidence of active dispersal of late-stage bugs between ecotopes. Two flight indices predicted that female fliers were more likely to originate from kitchens and domiciles, rejecting our initial hypothesis that goat and pig corrals would dominate. CONCLUSIONS AND SIGNIFICANCE: Chicken coops and domiciles were key source habitats fueling rapid house reinfestation. Focusing control efforts on ecotopes with human-fed bugs (domiciles, storerooms, goat corrals) would neither eliminate the substantial contributions to bug population growth from kitchens, chicken coops, and pig corrals nor stop dispersal of adult female bugs from kitchens. Rather, comprehensive control of the linked network of ecotopes is required to prevent feeding on humans, bug population growth, and bug dispersal simultaneously. Our study illustrates a demographic approach that may be applied to other regions and triatomine species for the design of innovative, improved vector control strategies. PMID- 25299655 TI - Agrobacterium uses a unique ligand-binding mode for trapping opines and acquiring a competitive advantage in the niche construction on plant host. AB - By modifying the nuclear genome of its host, the plant pathogen Agrobacterium tumefaciens induces the development of plant tumours in which it proliferates. The transformed plant tissues accumulate uncommon low molecular weight compounds called opines that are growth substrates for A. tumefaciens. In the pathogen induced niche (the plant tumour), a selective advantage conferred by opine assimilation has been hypothesized, but not experimentally demonstrated. Here, using genetics and structural biology, we deciphered how the pathogen is able to bind opines and use them to efficiently compete in the plant tumour. We report high resolution X-ray structures of the periplasmic binding protein (PBP) NocT unliganded and liganded with the opine nopaline (a condensation product of arginine and alpha-ketoglurate) and its lactam derivative pyronopaline. NocT exhibited an affinity for pyronopaline (K(D) of 0.6 uM) greater than that for nopaline (KD of 3.7 uM). Although the binding-mode of the arginine part of nopaline/pyronopaline in NocT resembled that of arginine in other PBPs, affinity measurement by two different techniques showed that NocT did not bind arginine. In contrast, NocT presented specific residues such as M117 to stabilize the bound opines. NocT relatives that exhibit the nopaline/pyronopaline-binding mode were only found in genomes of the genus Agrobacterium. Transcriptomics and reverse genetics revealed that A. tumefaciens uses the same pathway for assimilating nopaline and pyronopaline. Fitness measurements showed that NocT is required for a competitive colonization of the plant tumour by A. tumefaciens. Moreover, even though the Ti-plasmid conjugal transfer was not regulated by nopaline, the competitive advantage gained by the nopaline-assimilating Ti-plasmid donors led to a preferential horizontal propagation of this Ti-plasmid amongst the agrobacteria colonizing the plant-tumour niche. This work provided structural and genetic evidences to support the niche construction paradigm in bacterial pathogens. PMID- 25299657 TI - Cumulative risks of foster care placement for Danish children. AB - Although recent research suggests that the cumulative risk of foster care placement is far higher for American children than originally suspected, little is known about the cumulative risk of foster care placement in other countries, which makes it difficult to gauge the degree to which factor foster care placement is salient in other contexts. In this article, we provide companion estimates to those provided in recent work on the US by using Danish registry data and synthetic cohort life tables to show how high and unequally distributed the cumulative risk of foster care placement is for Danish children. Results suggest that at the beginning of the study period (in 1998) the cumulative risk of foster care placement for Danish children was roughly in line with the risk for American children. Yet, by the end of the study period (2010), the risk had declined to half the risk for American children. Our results also show some variations by parental ethnicity and sex, but these differences are small. Indeed, they appear quite muted relative to racial/ethnic differences in these risks in the United States. Last, though cumulative risks are similar between Danish and American children (especially at the beginning of the study period), the age-specific risk profiles are markedly different, with higher risks for older Danish children than for older American children. PMID- 25299656 TI - A simple isothermal DNA amplification method to screen black flies for Onchocerca volvulus infection. AB - Onchocerciasis is a debilitating neglected tropical disease caused by infection with the filarial parasite Onchocerca volvulus. Adult worms live in subcutaneous tissues and produce large numbers of microfilariae that migrate to the skin and eyes. The disease is spread by black flies of the genus Simulium following ingestion of microfilariae that develop into infective stage larvae in the insect. Currently, transmission is monitored by capture and dissection of black flies and microscopic examination of parasites, or using the polymerase chain reaction to determine the presence of parasite DNA in pools of black flies. In this study we identified a new DNA biomarker, encoding O. volvulus glutathione S transferase 1a (OvGST1a), to detect O. volvulus infection in vector black flies. We developed an OvGST1a-based loop-mediated isothermal amplification (LAMP) assay where amplification of specific target DNA is detectable using turbidity or by a hydroxy naphthol blue color change. The results indicated that the assay is sensitive and rapid, capable of detecting DNA equivalent to less than one microfilaria within 60 minutes. The test is highly specific for the human parasite, as no cross-reaction was detected using DNA from the closely related and sympatric cattle parasite Onchocerca ochengi. The test has the potential to be developed further as a field tool for use in the surveillance of transmission before and after implementation of mass drug administration programs for onchocerciasis. PMID- 25299665 TI - Improving community malnutrition. PMID- 25299667 TI - Buccal spectral markers for lung cancer risk stratification. AB - Lung cancer remains the leading cause of cancer deaths in the US with >150,000 deaths per year. In order to more effectively reduce lung cancer mortality, more sophisticated screening paradigms are needed. Previously, our group demonstrated the use of low-coherence enhanced backscattering (LEBS) spectroscopy to detect and quantify the micro/nano-architectural correlates of colorectal and pancreatic field carcinogenesis. In the lung, the buccal (cheek) mucosa has been suggested as an excellent surrogate site in the "field of injury". We, therefore, wanted to assess whether LEBS could similarly sense the presence of lung. To this end, we applied a fiber-optic LEBS probe to a dataset of 27 smokers without diagnosed lung cancer (controls) and 46 with lung cancer (cases), which was divided into a training and a blinded validation set (32 and 41 subjects, respectively). LEBS readings of the buccal mucosa were taken from the oral cavity applying gentle contact. The diagnostic LEBS marker was notably altered in patients harboring lung cancer compared to smoking controls. The prediction rule developed on training set data provided excellent diagnostics with 94% sensitivity, 80% specificity, and 95% accuracy. Applying the same threshold to the blinded validation set yielded 79% sensitivity and 83% specificity. These results were not confounded by patient demographics or impacted by cancer type or location. Moreover, the prediction rule was robust across all stages of cancer including stage I. We envision the use of LEBS as the first part of a two-step paradigm shift in lung cancer screening in which patients with high LEBS risk markers are funnelled into more invasive screening for confirmation. PMID- 25299658 TI - Early staphylococcal biofilm formation on solid orthopaedic implant materials: in vitro study. AB - Biofilms forming on the surface of biomaterials can cause intractable implant related infections. Bacterial adherence and early biofilm formation are influenced by the type of biomaterial used and the physical characteristics of implant surface. In this in vitro research, we evaluated the ability of Staphylococcus epidermidis, the main pathogen in implant-related infections, to form biofilms on the surface of the solid orthopaedic biomaterials, oxidized zirconium-niobium alloy, cobalt-chromium-molybdenum alloy (Co-Cr-Mo), titanium alloy (Ti-6Al-4V), commercially pure titanium (cp-Ti) and stainless steel. A bacterial suspension of Staphylococcus epidermidis strain RP62A (ATCC35984) was added to the surface of specimens and incubated. The stained biofilms were imaged with a digital optical microscope and the biofilm coverage rate (BCR) was calculated. The total amount of biofilm was determined with the crystal violet assay and the number of viable cells in the biofilm was counted using the plate count method. The BCR of all the biomaterials rose in proportion to culture duration. After culturing for 2-4 hours, the BCR was similar for all materials. However, after culturing for 6 hours, the BCR for Co-Cr-Mo alloy was significantly lower than for Ti-6Al-4V, cp-Ti and stainless steel (P<0.05). The absorbance value determined in the crystal violet assay and the number of viable cells on Co-Cr-Mo were not significantly lower than for the other materials (P>0.05). These results suggest that surface properties, such as hydrophobicity or the low surface free energy of Co-Cr-Mo, may have some influence in inhibiting or delaying the two-dimensional expansion of biofilm on surfaces with a similar degree of smoothness. PMID- 25299668 TI - Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and beta-cell function in multi-ethnic vitamin D-deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial. AB - OBJECTIVES: To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, beta-cell function, inflammation and metabolic markers. DESIGN: 6-month randomized, placebo-controlled trial. PARTICIPANTS: Ninety-five adults with serum 25-hydroxyvitamin D [25(OH)D] <=55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score >=15) were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45). INTERVENTION: Daily calcium carbonate (1,200 mg) and cholecalciferol [2,000-6,000 IU to target 25(OH)D >75 nmol/L] or matching placebos for 6 months. MEASUREMENTS: Insulin sensitivity (HOMA2%S, Matsuda index), insulin secretion (insulinogenic index, area under the curve (AUC) for C-peptide) and beta-cell function (Matsuda index x AUC for C peptide) derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-alpha; IL-6; adiponectin; total and undercarboxylated osteocalcin. RESULTS: Participants were middle-aged adults (mean age 54 years; 69% Europid) at risk of type 2 diabetes (48% with prediabetes). Compliance was >80% for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L), but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and beta-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda) was observed. CONCLUSIONS: Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and beta-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes. However, in participants with prediabetes, supplementation with vitamin D and calcium may improve insulin sensitivity. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000043235. PMID- 25299670 TI - FEMALE EDUCATION AND ITS ASSOCIATION WITH CHANGES IN SOCIO-DEMOGRAPHIC BEHAVIOUR: EVIDENCE FROM INDIA. AB - Education is a crucial factor in influencing the pattern and timing of marriage for women, and the changes in levels of female literacy will also change the dynamics of family formation. India has experienced consistent improvement in levels of female literacy; therefore, this study examined the association of women's education with the changes in their demographic behaviour in the Indian context. The central idea of the paper is to examine the differences in age at marriage and first birth, choice of marriage partner and the number of children ever born based on educational attainment of women. In addition, the study examined incongruence in years of schooling and discontinuation from school, for children based on education of the mother. The study utilized data from the third round of District Level Household and Facility Survey. The sample constituted 344,164 ever-married women aged 35 years and above with surviving children aged 5 20 years. The results imply that women with higher education are more likely to marry late and have fewer children compared with less educated women. Accordingly, increase in education of women also increases the probability of marrying men with better education than themselves. The study further observed that education of wife has a greater association with the number of children ever born than the education of husband. At the same time, incongruence in years of schooling and drop-out from school are both high for children of uneducated women. The study also found that the children from urban areas are more likely to drop out than their rural counterparts. In addition to education of the mother, number and composition of children in the family and economic condition of the household are some other factors that influence the educational attainment of children. PMID- 25299669 TI - The formation of endoderm-derived taste sensory organs requires a Pax9-dependent expansion of embryonic taste bud progenitor cells. AB - In mammals, taste buds develop in different regions of the oral cavity. Small epithelial protrusions form fungiform papillae on the ectoderm-derived dorsum of the tongue and contain one or few taste buds, while taste buds in the soft palate develop without distinct papilla structures. In contrast, the endoderm-derived circumvallate and foliate papillae located at the back of the tongue contain a large number of taste buds. These taste buds cluster in deep epithelial trenches, which are generated by intercalating a period of epithelial growth between initial placode formation and conversion of epithelial cells into sensory cells. How epithelial trench formation is genetically regulated during development is largely unknown. Here we show that Pax9 acts upstream of Pax1 and Sox9 in the expanding taste progenitor field of the mouse circumvallate papilla. While a reduced number of taste buds develop in a growth-retarded circumvallate papilla of Pax1 mutant mice, its development arrests completely in Pax9-deficient mice. In addition, the Pax9 mutant circumvallate papilla trenches lack expression of K8 and Prox1 in the taste bud progenitor cells, and gradually differentiate into an epidermal-like epithelium. We also demonstrate that taste placodes of the soft palate develop through a Pax9-dependent induction. Unexpectedly, Pax9 is dispensable for patterning, morphogenesis and maintenance of taste buds that develop in ectoderm-derived fungiform papillae. Collectively, our data reveal an endoderm-specific developmental program for the formation of taste buds and their associated papilla structures. In this pathway, Pax9 is essential to generate a pool of taste bud progenitors and to maintain their competence towards prosensory cell fate induction. PMID- 25299672 TI - Timing and sequence of emergence of deciduous teeth in Jordanian children. AB - OBJECTIVE: The aim of this study was to provide the timing and sequence of deciduous tooth emergence in a sample of Jordanian children. DESIGN: A total of 1988 (885 female and 1103 male) children aged from 1 to 45 months recruited from nursery schools and child and maternity health centres in the northern, middle and southern regions of Jordan underwent a dental examination for the detection of deciduous tooth emergence. Children were categorized into 15 3-month-apart age groups. Using Probit regression (SPSS version 16), the median age of emergence per tooth was calculated for the total sample and for both genders. RESULTS: The period for acquiring deciduous dentition in the total sample ranged from 8.2 to 27.5 months. In either of the maxillary and mandibular arches, deciduous dentition emerged in the following order: central incisor, lateral incisor, first molar, canine and second molar. In addition, there were insignificant differences across side and there was a significant mandibular precedence of the central incisor although the maxillary precedence in the rest of the teeth was insignificant. Moreover, teeth emerged earlier in females although none of the inter-gender differences were significant. CONCLUSIONS: The first standards of the timing and sequence of deciduous tooth emergence specific to the Jordanian population were provided. These standards will be used along with the previously published standards of permanent tooth emergence to aid managing patients in paediatric dentistry and orthodontics and will find applications in forensic and police sciences and in anthropological research. PMID- 25299671 TI - GLUT4 defects in adipose tissue are early signs of metabolic alterations in Alms1GT/GT, a mouse model for obesity and insulin resistance. AB - Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alstrom Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of Alms1 disruption in AT expansion and insulin responsiveness in a murine model for Alstrom Syndrome. A gene trap insertion in Alms1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alstrom mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alstrom mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state. PMID- 25299673 TI - Neutrophil crawling in capillaries; a novel immune response to Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA), particularly the USA300 strain, is a highly virulent pathogen responsible for an increasing number of skin and soft tissue infections globally. Furthermore, MRSA-induced soft tissue infections can rapidly progress into life-threatening conditions, such as sepsis and necrotizing fasciitis. The importance of neutrophils in these devastating soft tissue infections remains ambiguous, partly because of our incomplete understanding of their behaviour. Spinning disk confocal microscopy was used to visualize the behaviour of GR1-labelled neutrophils in subcutaneous tissue in response to GFP-expressing MRSA attached to a foreign particle (agarose bead). We observed significant directional neutrophil recruitment towards the S. aureus agarose bead but not a control agarose bead. A significant increase in neutrophil crawling within the capillaries surrounding the infectious nidus was noted, with impaired capillary perfusion in these vessels and increased parenchymal cell death. No neutrophils were able to emigrate from capillaries. The crawling within these capillaries was mediated by the beta(2) and alpha(4) integrins and blocking these integrins 2 hours post infection eliminated neutrophil crawling, improved capillary perfusion, reduced cell death and reduced lesion size. Blocking prior to infection increased pathology. Neutrophil crawling within capillaries during MRSA soft tissue infections, while potentially contributing to walling off or preventing early dissemination of the pathogen, resulted in impaired perfusion and increased tissue injury with time. PMID- 25299674 TI - Molecular evidence for cryptic speciation in the Cyclophorus fulguratus (Pfeiffer, 1854) species complex (Caenogastropoda: Cyclophoridae) with description of new species. AB - A high degree of intraspecific variation, both genetic and in shell morphology, of the operculate land snail Cyclophorus fulguratus (Pfeiffer, 1854) suggests that its classification as a single species warrants reconsideration. We sequenced two nuclear (18S and 28S) and two mitochondrial (16S and COI) genes of 46 C. fulguratus specimens and used them to estimate the phylogeny and to determine the validity of species boundaries. Molecular phylogenetic analyses revealed the presence of three lineages corresponding to three geographically disjunctive populations of C. fulguratus in Thailand. Likelihood tests of topologies significantly supported the non-monophyly of the C. fulguratus-complex and Bayesian species delimitation analysis significantly supported the potential representation as distinct species of these three lineages. Discriminant function analysis based on geometric-morphometrics of shell shape allowed for significant distinction of these three candidate species, although they revealed a considerable degree of overlap of shell shape reflecting their crypsis morphologically. The diagnostic characters are provided by color pattern, pattern of protoconch and pattern of jaw. In conclusion, the results support that the C. fulguratus s.l., as currently recognized, consists of three distinct species in Thailand: C. fulguratus s.s., C. rangunensis and C. abditus sp.nov., which are described herein. PMID- 25299675 TI - Transgender transitioning and change of self-reported sexual orientation. AB - OBJECTIVE: Sexual orientation is usually considered to be determined in early life and stable in the course of adulthood. In contrast, some transgender individuals report a change in sexual orientation. A common reason for this phenomenon is not known. METHODS: We included 115 transsexual persons (70 male-to female "MtF" and 45 female-to-male "FtM") patients from our endocrine outpatient clinic, who completed a questionnaire, retrospectively evaluating the history of their gender transition phase. The questionnaire focused on sexual orientation and recalled time points of changes in sexual orientation in the context of transition. Participants were further asked to provide a personal concept for a potential change in sexual orientation. RESULTS: In total, 32.9% (n = 23) MtF reported a change in sexual orientation in contrast to 22.2% (n = 10) FtM transsexual persons (p = 0.132). Out of these patients, 39.1% (MtF) and 60% (FtM) reported a change in sexual orientation before having undergone any sex reassignment surgery. FtM that had initially been sexually oriented towards males ( = androphilic), were significantly more likely to report on a change in sexual orientation than gynephilic, analloerotic or bisexual FtM (p = 0.012). Similarly, gynephilic MtF reported a change in sexual orientation more frequently than androphilic, analloerotic or bisexual MtF transsexual persons (p =0.05). CONCLUSION: In line with earlier reports, we reveal that a change in self reported sexual orientation is frequent and does not solely occur in the context of particular transition events. Transsexual persons that are attracted by individuals of the opposite biological sex are more likely to change sexual orientation. Qualitative reports suggest that the individual's biography, autogynephilic and autoandrophilic sexual arousal, confusion before and after transitioning, social and self-acceptance, as well as concept of sexual orientation itself may explain this phenomenon. PMID- 25299677 TI - Invitation to Atlanta. PMID- 25299678 TI - The Focused Scientific Sessions (FSS) of the combined 65th Annual Meeting of the American College of Veterinary Pathologists (ACVP) and 49th Annual Meeting of the American Society for Veterinary Clinical Pathology. PMID- 25299676 TI - Scorpion venom heat-resistant peptide (SVHRP) enhances neurogenesis and neurite outgrowth of immature neurons in adult mice by up-regulating brain-derived neurotrophic factor (BDNF). AB - Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2'-dexoxyuridine (BrdU)-positive cells, BrdU-positive/neuron-specific nuclear protein (NeuN) positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM) positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP. PMID- 25299679 TI - Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity. AB - Reported is an enantiodivergent approach for the synthesis of both enantiomers of sulforaphane (SFN) homologues with different chain lengths between the sulfinyl sulfur and the isothiocyanate groups and different substituents on the sulfinyl sulfur. The homologues were designed in order to unravel the effect of all the diversity elements included in sulforaphane's structure. The key step of the approach is the diastereoselective synthesis of both sulfinate ester epimers at sulfur, using as single chiral auxiliary the sugar derived diacetone-d-glucose. The approach allows the first synthesis of both enantiomers of 5 methylsulfinylpentyl isothiocyanate, and the biologically important 6 methylsulfinylhexyl isothiocyanate (6-HITC) found in Japanese horseradish, wasabi (Wasabia japonica). The ability of the synthesized compounds as inductors of phase II detoxifying enzymes has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2. The cytotoxic activity of all the synthesized compounds against human lung adenocarcinoma (A549) and foetal lung fibroblasts (MRC-5) is also reported. PMID- 25299680 TI - PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives. AB - New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4 triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1 acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 +/- 1.09 MUM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P >= 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes. PMID- 25299681 TI - Identification of novel PTP1B inhibitors by pharmacophore based virtual screening, scaffold hopping and docking. AB - Design and synthesis of protein tyrosine phosphatases-1B (PTP1B) inhibitors are important for the drugs targeted to treat diabetes and obesity. The pharmacophore modeling, docking and scaffold hopping techniques have been applied to discover the novel PTP1B inhibitors. The ten prioritized compounds (115-119, 120-121, 127, 130-131) from the library of 86 compounds were synthesized and found positive in the micro molar range for PTP1B in-vitro inhibitory assays as compared to Suramin (IC50 9.5 MUM). Among these five active compounds (115-119) were tested in STZ-s induced diabetic rat model and the most active compound 115 in this test, was further tested in C57BL/KsJ-db/db mice where it significantly improved OGTT along with the fasting and random blood glucose level. The treatment by the compound 115 significantly improved the insulin resistance and insulin signaling by restoring the insulin level and normalizing the serum lipid profile. Compound 115 also augmented the insulin action by modulating the expression of genes involved in insulin signaling like IRS 1-2, PI3K, PTPN1, Akt2, AMPK and PPAR-alpha. Western blot analysis of both skeletal muscle and liver demonstrated that proteins and intermediate enzymes of insulin signaling were also increased as compared to control group. The compound 115 was also investigated for anti adipogenic effect on 3T3L-1 cells. The compound 115 inhibited MDI induced lipid accumulation in a dose-dependent manner. The oral bioavailability of compound 115 was ~10.29% after 30 mg/kg oral dosing assessed in rat. PMID- 25299682 TI - Synthesis and lipid-lowering evaluation of 3-methyl-1H-purine-2,6-dione derivatives as potent and orally available anti-obesity agents. AB - Obesity accompanied with metabolic disorder is often complicated with a strong link of dyslipidemia and insulin resistance, whose indicator is the excess accumulation of triglycerides (TG) in cells. Consideration the idea of lipid lowering and improving insulin resistance, 34 novel compounds by combination the xanthine scaffold with the chain of Rosiglitazone have been synthesized. Among them, several compounds showed efficiency on reducing TG in 3T3-L1 adipoctyes, and 11c exhibited the most optimal capacity in lipid-lowering and improving obese clinical symptoms in DIO mice. Furthermore, the hydrochloride of 11c (11c.HCl) showed excellent bioavailability, 58.94%, over 2 folds than that (28.03%) of 11c, and the anti-obesity effect of 11c.HCl at 50 mg/kg dose was better than that of Metformin at 150 mg/kg dose in DIO mice, almost reversed HFD to a normal level. Thus, 11c.HCl might be a potent and orally available anti-obesity agent via alleviating the obese clinical symptoms, body fat, improving serum parameters and insulin resistance and TG clearance in liver. PMID- 25299683 TI - Scaffold hopping approach on the route to selective tankyrase inhibitors. AB - A virtual screening procedure was applied to identify new tankyrase inhibitors. Through pharmacophore screening of a compounds collection from the SPECS database, the methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold was identified as nicotinamide mimetic able to inhibit tankyrase activity at low micromolar concentration. In order to improve potency and selectivity, tandem structure-based and scaffold hopping approaches were carried out over the new scaffold leading to the discovery of the 2-(phenyl)-3H-benzo[4,5]thieno[3,2 d]pyrimidin-4-one as powerful chemotype suitable for tankyrase inhibition. The best compound 2-(4-tert-butyl-phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one (23) displayed nanomolar potencies (IC50s TNKS-1 = 21 nM and TNKS-2 = 29 nM) and high selectivity when profiled against several other PARPs. Furthermore, a striking Wnt signaling, as well as cell growth inhibition, was observed assaying 23 in DLD-1 cancer cells. PMID- 25299684 TI - Synthesis, characterization, cytotoxicity of mixed ligand complexes of palladium(II) with dipyrido[3,2-d:2',3'-f]quinoxaline/dipyrido[3,2-a:2',3' c](6,7,8,9-tetrahydro)phenazine and 4-toluensulfonyl-L-amino acid dianion. AB - Ten novel palladium(II) complexes with dipyrido[3,2-d:2',3'-f]quinoxaline (Dpq)/dipyrido[3,2-a:2',3'-c](6,7,8,9-tetrahydro)phenazine (Dpqc) and 4 toluensulfonyl-L-amino acid dianion, [Pd(Dpq)(TsvalNO)].H2O (1a), [Pd(Dpq)(TsileNO)].H2O (1b), [Pd(Dpq)(TsserNO)] (1c), [Pd(Dpq)(TsthrNO)].1.5H2O (1d), [Pd(Dpq)(TsleuNO)].0.5H2O (1e), [Pd(Dpq)(TspheNO)] (1f), [Pd(Dpqc)(TsvalNO)] (2a), [Pd(Dpqc)(TsileNO)] (2b), [Pd(Dpqc)(TsserNO)].H2O (2c) and [Pd(Dpqc)(TsthrNO)].0.5H2O (2d) have been synthesized and characterized by elemental analysis, IR, UV, (1)H NMR and mass spectrometry techniques. Crystal structure of the complex 1f has been determined by X-ray diffraction. The cytotoxicity was tested by MTT assay. The results indicated that the complexes 1a and 2a showed better cytotoxicity than cisplatin against MCF-7. The complex 1e had higher cytotoxicity than cisplatin against K562. Both the N donating ligands and the amino acid have important effects on the cytotoxicity. PMID- 25299685 TI - Density and stability of soil organic carbon beneath impervious surfaces in urban areas. AB - Installation of impervious surfaces in urban areas has attracted increasing attention due to its potential hazard to urban ecosystems. Urban soils are suggested to have robust carbon (C) sequestration capacity; however, the C stocks and dynamics in the soils covered by impervious surfaces that dominate urban areas are still not well characterized. We compared soil organic C (SOC) densities and their stabilities under impervious surface, determined by a 28-d incubation experiment, with those in open areas in Yixing City, China. The SOC density (0-20 cm) under impervious surfaces was, on average, 68% lower than that in open areas. Furthermore, there was a significantly (P<0.05) positive correlation between the densities of SOC and total nitrogen (N) in the open soils, whereas the correlation was not apparent for the impervious-covered soils, suggesting that the artificial soil sealing in urban areas decoupled the cycle of C and N. Cumulative CO2-C evolved during the 28-d incubation was lower from the impervious-covered soils than from the open soils, and agreed well with a first order decay model (Ct = C1+C0(1-e-kt)). The model results indicated that the SOC underlying capped surfaces had weaker decomposability and lower turnover rate. Our results confirm the unique character of urban SOC, especially that beneath impervious surface, and suggest that scientific and management views on regional SOC assessment may need to consider the role of urban carbon stocks. PMID- 25299686 TI - Targeted in vivo inhibition of specific protein-protein interactions using recombinant antibodies. AB - With the growing availability of genomic sequence information, there is an increasing need for gene function analysis. Antibody-mediated "silencing" represents an intriguing alternative for the precise inhibition of a particular function of biomolecules. Here, we describe a method for selecting recombinant antibodies with a specific purpose in mind, which is to inhibit intrinsic protein protein interactions in the cytosol of plant cells. Experimental procedures were designed for conveniently evaluating desired properties of recombinant antibodies in consecutive steps. Our selection method was successfully used to develop a recombinant antibody inhibiting the interaction of ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 3 with such of its upstream interaction partners as the receiver domain of CYTOKININ INDEPENDENT HISTIDINE KINASE 1. The specific down regulation of the cytokinin signaling pathway in vivo demonstrates the validity of our approach. This selection method can serve as a prototype for developing unique recombinant antibodies able to interfere with virtually any biomolecule in the living cell. PMID- 25299687 TI - Full genome characterization of the culicoides-borne marsupial orbiviruses: Wallal virus, Mudjinbarry virus and Warrego viruses. AB - Viruses belonging to the species Wallal virus and Warrego virus of the genus Orbivirus were identified as causative agents of blindness in marsupials in Australia during 1994/5. Recent comparisons of nucleotide (nt) and amino acid (aa) sequences have provided a basis for the grouping and classification of orbivirus isolates. However, full-genome sequence data are not available for representatives of all Orbivirus species. We report full-genome sequence data for three additional orbiviruses: Wallal virus (WALV); Mudjinabarry virus (MUDV) and Warrego virus (WARV). Comparisons of conserved polymerase (Pol), sub-core-shell 'T2' and core-surface 'T13' proteins show that these viruses group with other Culicoides borne orbiviruses, clustering with Eubenangee virus (EUBV), another orbivirus infecting marsupials. WARV shares <70% aa identity in all three conserved proteins (Pol, T2 and T13) with other orbiviruses, consistent with its classification within a distinct Orbivirus species. Although WALV and MUDV share <72.86%/67.93% aa/nt identity with other orbiviruses in Pol, T2 and T13, they share >99%/90% aa/nt identities with each other (consistent with membership of the same virus species - Wallal virus). However, WALV and MUDV share <68% aa identity in their larger outer capsid protein VP2(OC1), consistent with membership of different serotypes within the species - WALV-1 and WALV-2 respectively. PMID- 25299689 TI - Sleep characteristics and psychological symptoms in patients with locally advanced nasopharyngeal carcinoma before and after intensity-modulated radiotherapy and concurrent chemotherapy. AB - Sleep disturbances and psychological distress are the most common adverse effects associated with cancer diagnosis and treatment. The aim of this study was to examine sleep and psychological characteristics in patients with local-advanced nasopharyngeal carcinoma (NPC) following completion of intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy, and to describe the predictors of post-test psychological symptoms after treatment. Sleep quality and psychological symptoms were measured using Pittsburgh sleep-quality index (PSQI) and symptom checklist-90 in 60 local-advanced NPC patients treated with IMRT and concurrent chemotherapy, respectively. After treatment, the subscores of subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction increased significantly compared with their pre-test scores. Similar results were observed for the mean PSQI global score. However, for psychological symptoms, only subscores of somatization and depression were higher than their baseline level. Multivariate analysis revealed that concurrent chemotherapy cycle was the only predictor of depression after treatment among all of the psychological symptoms assessed. These findings indicate that sleep disturbance and psychological distress are significant problems in NPC patients treated with IMRT and concurrent chemotherapy. Patients who receive many cycles of concurrent chemotherapy may be at an increased risk of depression after completion of IMRT. PMID- 25299688 TI - Depletion of the chromatin looping proteins CTCF and cohesin causes chromatin compaction: insight into chromatin folding by polymer modelling. AB - Folding of the chromosomal fibre in interphase nuclei is an important element in the regulation of gene expression. For instance, physical contacts between promoters and enhancers are a key element in cell-type-specific transcription. We know remarkably little about the principles that control chromosome folding. Here we explore the view that intrachromosomal interactions, forming a complex pattern of loops, are a key element in chromosome folding. CTCF and cohesin are two abundant looping proteins of interphase chromosomes of higher eukaryotes. To investigate the role of looping in large-scale (supra Mb) folding of human chromosomes, we knocked down the gene that codes for CTCF and the one coding for Rad21, an essential subunit of cohesin. We measured the effect on chromosome folding using systematic 3D fluorescent in situ hybridization (FISH). Results show that chromatin becomes more compact after reducing the concentration of these two looping proteins. The molecular basis for this counter-intuitive behaviour is explored by polymer modelling usingy the Dynamic Loop model (Bohn M, Heermann DW (2010) Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS ONE 5: e12218.). We show that compaction can be explained by selectively decreasing the number of short-range loops, leaving long range looping unchanged. In support of this model prediction it has recently been shown by others that CTCF and cohesin indeed are responsible primarily for short range looping. Our results suggest that the local and the overall changes in of chromosome structure are controlled by a delicate balance between short-range and long-range loops, allowing easy switching between, for instance, open and more compact chromatin states. PMID- 25299690 TI - Characterization of ring-like F-actin structure as a mechanical partner for spindle positioning in mitosis. AB - Proper spindle positioning and orientation are essential for accurate mitosis which requires dynamic interactions between microtubule and actin filament (F actin). Although mounting evidence demonstrates the role of F-actin in cortical cytoskeleton dynamics, it remains elusive as to the structure and function of F actin-based networks in spindle geometry. Here we showed a ring-like F-actin structure surrounding the mitotic spindle which forms since metaphase and maintains in MG132-arrested metaphase HeLa cells. This cytoplasmic F-actin structure is relatively isotropic and less dynamic. Our computational modeling of spindle position process suggests a possible mechanism by which the ring-like F actin structure can regulate astral microtubule dynamics and thus mitotic spindle orientation. We further demonstrated that inhibiting Plk1, Mps1 or Myosin, and disruption of microtubules or F-actin polymerization perturbs the formation of the ring-like F-actin structure and alters spindle position and symmetric division. These findings reveal a previously unrecognized but important link between mitotic spindle and ring-like F-actin network in accurate mitosis and enables the development of a method to theoretically illustrate the relationship between mitotic spindle and cytoplasmic F-actin. PMID- 25299691 TI - DNA vaccines: MHC II-targeted vaccine protein produced by transfected muscle fibres induces a local inflammatory cell infiltrate in mice. AB - Vaccination with naked DNA holds great promise but immunogenicity needs to be improved. DNA constructs encoding bivalent proteins that bind antigen-presenting cells (APC) for delivery of antigen have been shown to enhance T and B cell responses and protection in tumour challenge experiments. However, the mechanism for the increased potency remains to be determined. Here we have constructed DNA vaccines that express the fluorescent protein mCherry, a strategy which allowed tracking of vaccine proteins. Transfected muscle fibres in mice were visualized, and their relationship to infiltrating mononuclear cells could be determined. Interestingly, muscle fibers that produced MHC class II-specific dimeric vaccine proteins with mCherry were for weeks surrounded by a localized intense cellular infiltrate composed of CD45+, MHC class II+ and CD11b+ cells. Increasing numbers of eosinophils were observed among the infiltrating cells from day 7 after immunization. The local infiltrate surrounding mCherry+ muscle fibers was dependent on the MHC II-specificity of the vaccine proteins since the control, a non-targeted vaccine protein, failed to induce similar infiltrates. Chemokines measured on day 3 in immunized muscle indicate both a DNA effect and an electroporation effect. No influence of targeting was observed. These results contribute to our understanding for why targeted DNA vaccines have an improved immunogenicity. PMID- 25299692 TI - Peripheral and central effects of melatonin on blood pressure regulation. AB - The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology. PMID- 25299694 TI - FT-IR microspectrometry reveals the variation of membrane polarizability due to epigenomic effect on epithelial ovarian cancer. AB - Ovarian cancer, as well as other cancers, is primarily caused by methylation at cytosines in CpG islands, but the current marker for ovarian cancer is low in sensitivity and failed in early-stage detection. Fourier transform infrared (FT IR) spectroscopy is powerful in analysis of functional groups within molecules, and infrared microscopy illustrates the location of specific groups within single cells. In this study, we applied HPLC and FT-IR microspectrometry to study normal epithelial ovarian cell line immortalized ovarian surface epithelium (IOSE), two epithelial ovarian cell lines (A2780 and CP70) with distinct properties, and the effect of a cancer drug 5-aza-2'-deoxycytidine (5-aza) without labeling. Our results reveal that inhibition of methylation on cytosine with 5-aza initiates the protein expression. Furthermore, paraffin-adsorption kinetic study allows us to distinguish hypermethylated and hypomethyated cells, and this assay can be a potential diagnosis method for cancer screening. PMID- 25299693 TI - Development of 3D in vitro technology for medical applications. AB - In the past few years, biomaterials technologies together with significant efforts on developing biology have revolutionized the process of engineered materials. Three dimensional (3D) in vitro technology aims to develop set of tools that are simple, inexpensive, portable and robust that could be commercialized and used in various fields of biomedical sciences such as drug discovery, diagnostic tools, and therapeutic approaches in regenerative medicine. The proliferation of cells in the 3D scaffold needs an oxygen and nutrition supply. 3D scaffold materials should provide such an environment for cells living in close proximity. 3D scaffolds that are able to regenerate or restore tissue and/or organs have begun to revolutionize medicine and biomedical science. Scaffolds have been used to support and promote the regeneration of tissues. Different processing techniques have been developed to design and fabricate three dimensional scaffolds for tissue engineering implants. Throughout the chapters we discuss in this review, we inform the reader about the potential applications of different 3D in vitro systems that can be applied for fabricating a wider range of novel biomaterials for use in tissue engineering. PMID- 25299697 TI - Solvent-induced crystallization behaviors of PLLA ultrathin films investigated by RAIR spectroscopy and AFM measurements. AB - The crystallization of poly(L-lactide acid) (PLLA) ultrathin films induced by different solvents was investigated using reflection-absorption infrared (RAIR) spectroscopy and atomic force microscopy (AFM). Irregular PLLA dendrite lamellae grew in the flat-on orientation with dichloromethane solvent before being redissolved after longer induction times owing to the strong interaction between the PLLA segments and solvent molecules. Faster formation of PLLA spherulites was induced with acetone than with dichloromethane, and these remained unchanged with increasing induction time because of the polarity difference between the PLLA segments and acetone molecules. PLLA ultrathin films could not be induced to crystallize using chloroform because of the very strong interactions between the chloroform (CHCl3) molecules and PLLA amorphous chains, which caused the CHCl3 solvent molecules to rapidly permeate the PLLA random coils and dissolve the amorphous chains. These phenomena are attributed to solvent-specific competition between solvent-induced crystallization and dissolution effects in PLLA ultrathin films, which ultimately leads to the higher degree of crystallinity obtained with acetone than with dichloromethane. PMID- 25299696 TI - FOXO1 content is reduced in cystic fibrosis and increases with IGF-I treatment. AB - Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF). The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, p85 PI3K, and AKT contents were substantially normal in CF cells (CFBE41o-), whereas winged helix forkhead (FOX)O1 contents were reduced both in baseline conditions and after insulin stimulation. In addition, CF cells showed increased ERK1/2, and reduced beta2 arrestin contents. No significant change in SOCS2 was observed. By using a CFTR inhibitor and siRNA, changes in FOXO1 were related to CFTR loss of function. In a CF-affected mouse model, FOXO1 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild-type. Insulin-like growth factor 1 (IGF-I) increased FOXO1 content in vitro and in vivo in muscle and adipose tissue. In conclusion; we present the first description of reduced FOXO1 content in CF, which is compatible with reduced gluconeogenesis and increased adipogenesis, both features of insulin insensitivity. IGF-I treatment was effective in increasing FOXO1, thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis-related diabetes. PMID- 25299698 TI - Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer. AB - BACKGROUND: In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer. RESULTS: We found that carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, carnosol was found to induce beclin1 independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Moreover, we show that carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that carnosol induced a dose-dependent generation of reactive oxygen species (ROS) and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by carnosol. CONCLUSION: In conclusion our findings provide strong evidence that carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration. PMID- 25299695 TI - Curcumin-induced heme oxygenase-1 expression prevents H2O2-induced cell death in wild type and heme oxygenase-2 knockout adipose-derived mesenchymal stem cells. AB - Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2 mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy. PMID- 25299700 TI - Dominant sequences of human major histocompatibility complex conserved extended haplotypes from HLA-DQA2 to DAXX. AB - We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight "common" European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population's haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots. PMID- 25299701 TI - Chagas disease and the london declaration on neglected tropical diseases. PMID- 25299699 TI - Brazilian multicentre study on preterm birth (EMIP): prevalence and factors associated with spontaneous preterm birth. AB - BACKGROUND: Preterm birth rate is increasing and is currently a worldwide concern. The purpose of this study was to estimate the prevalence of preterm birth in a sample of health facilities in Brazil and to identify the main risk factors associated with spontaneous preterm births. METHODS AND FINDINGS: This was a multicentre cross sectional study on preterm births in 20 referral obstetric hospitals with a case-control component to identify factors associated with spontaneous preterm birth. Surveillance was implemented at all centres to identify preterm births. For eligible consenting women, data were collected through a post-delivery questionnaire completed with information from all mother newborn medical records until death or discharge or at a maximum of 60 days post delivery, whichever came first. The risk of spontaneous preterm birth was estimated with OR and 95%CI for several predictors. A non-conditional logistic regression analysis was then performed to identify independently associated factors. The overall prevalence of preterm birth was 12.3%. Among them, 64.6% were spontaneous and 35.4% therapeutic. In the case-control component, 2,682 spontaneous preterm births were compared to a sample of 1,146 term births. Multivariate analyses identified the following as risk factors for spontaneous preterm birth among women with at least one previous birth: a previous preterm birth (ORadj = 3.19, 2.30-4.43), multiple pregnancy (ORadj = 29.06, 8.43-100.2), cervical insufficiency (ORadj = 2.93, 1.07-8.05), foetal malformation (ORadj = 2.63, 1.43-4.85), polyhydramnios (ORadj = 2.30, 1.17-4.54), vaginal bleeding (ORadj = 2.16, 1.50-3.11), and previous abortion (ORadj = 1.39, 1.08-1.78). High BMI (ORadj = 0.94, 0.91-0.97) and weight gain during gestation (ORadj = 0.92, 0.89-0.95) were found to be protective factors. CONCLUSIONS: The preterm birth rate in these health facilities in Brazil is high and spontaneous preterm births account for two thirds of them. A better understanding of the factors associated with spontaneous preterm birth is of utmost importance for planning effective measures to reduce the burden of its increasing rates. PMID- 25299703 TI - Four-year randomized clinical trial to evaluate the clinical performance of a glass ionomer restorative system. AB - OBJECTIVE: The aim of this study was to evaluate the clinical performance of a glass ionomer restorative system compared with a microfilled hybrid posterior composite in a four-year randomized clinical trial. METHODS: A total of 140 (80 Class 1 and 60 Class 2) lesions in 59 patients were either restored with a glass ionomer restorative system (Equia, GC, Tokyo, Japan), which was a combination of a packable glass ionomer (Equia Fil, GC) and a self-adhesive nanofilled coating (Equia Coat, GC), or with a microfilled hybrid composite (Gradia Direct Posterior, GC) in combination with a self-etch adhesive (G-Bond, GC) by two experienced operators according to the manufacturer's instructions. Two independent examiners evaluated the restorations at baseline and at one, two, three, and four years postrestoration according to the modified US Public Health Service criteria. Polyvinyl siloxane impression negative replicas at each recall were observed under scanning electron microscopy (SEM) to evaluate surface characteristics. The statistical analyses were carried out with McNemar, Pearson Chi-square, and Cochran Q-tests (p<0.05). RESULTS: After four years, 126 (76 Class 1 and 50 Class 2) restorations were evaluated in 52 patients, with a recall rate of 88.1%. None of the restorations showed trends to downgrade in anatomical form, secondary caries, surface texture, postoperative sensitivity, and color match (p>0.05). Significant differences in marginal adaptation and discoloration were found at four years compared to baseline for both restorative materials for Class 1 and Class 2 restorations (p<0.05). Only one Class 2 Equia restoration was missing at three years (3.9%), and another one was missing at four years (7.7%) (p>0.05). SEM evaluations were in accordance with the clinical findings. CONCLUSIONS: The use of both materials for the restoration of posterior teeth exhibited a similar and clinically successful performance after four years. PMID- 25299702 TI - Detection of Rickettsia felis, Rickettsia typhi, Bartonella Species and Yersinia pestis in Fleas (Siphonaptera) from Africa. AB - Little is known about the presence/absence and prevalence of Rickettsia spp, Bartonella spp. and Yersinia pestis in domestic and urban flea populations in tropical and subtropical African countries. METHODOLOGY/PRINCIPAL FINDINGS: Fleas collected in Benin, the United Republic of Tanzania and the Democratic Republic of the Congo were investigated for the presence and identity of Rickettsia spp., Bartonella spp. and Yersinia pestis using two qPCR systems or qPCR and standard PCR. In Xenopsylla cheopis fleas collected from Cotonou (Benin), Rickettsia typhi was detected in 1% (2/199), and an uncultured Bartonella sp. was detected in 34.7% (69/199). In the Lushoto district (United Republic of Tanzania), R. typhi DNA was detected in 10% (2/20) of Xenopsylla brasiliensis, and Rickettsia felis was detected in 65% (13/20) of Ctenocephalides felis strongylus, 71.4% (5/7) of Ctenocephalides canis and 25% (5/20) of Ctenophthalmus calceatus calceatus. In the Democratic Republic of the Congo, R. felis was detected in 56.5% (13/23) of Ct. f. felis from Kinshasa, in 26.3% (10/38) of Ct. f. felis and 9% (1/11) of Leptopsylla aethiopica aethiopica from Ituri district and in 19.2% (5/26) of Ct. f. strongylus and 4.7% (1/21) of Echidnophaga gallinacea. Bartonella sp. was also detected in 36.3% (4/11) of L. a. aethiopica. Finally, in Ituri, Y. pestis DNA was detected in 3.8% (1/26) of Ct. f. strongylus and 10% (3/30) of Pulex irritans from the villages of Wanyale and Zaa. CONCLUSION: Most flea-borne infections are neglected diseases which should be monitored systematically in domestic rural and urban human populations to assess their epidemiological and clinical relevance. Finally, the presence of Y. pestis DNA in fleas captured in households was unexpected and raises a series of questions regarding the role of free fleas in the transmission of plague in rural Africa, especially in remote areas where the flea density in houses is high. PMID- 25299704 TI - Ultramorphological assessment of dentin-resin interface after use of simplified adhesives. AB - This study assessed dentin-resin interface integration in Class I cavities restored with simplified adhesives by using a focused ion-beam milling (FIB) and transmission electron microscope (TEM). Class I cavities (1.5-mm depth with dentin thickness of ~0.5 mm, 4-mm length, and 2-mm width) were prepared on freshly extracted, sound human molars. Two all-in-one adhesive systems (Scotchbond/Single Bond Universal [SUD] and Xeno-V(+) [X5D]) were used and compared with a two-step etch-and-rinse system (Prime&Bond NT [NTD]). The adhesives were applied according to the manufacturers' guidelines. A universal resin composite (Filtek Z350 XT Universal) was used to restore the cavities in one bulk filling and was irradiated at 550 mW/cm(2) for 40 seconds by a quartz tungsten-halogen light (Optilux 501). After exposure to liquid nitrogen coolant, the specimens were milled to nanoscale thickness by FIB to view and then assess the area of dentin-resin interface by TEM. Unlike the unfilled X5D, a noticeably smooth transition zone at the dentin-resin interface was shown for the SUD and NTD adhesives. The SUD demonstrated an uneven hybrid layer with clearly demineralized collagen bundles. Ultramorphologically, dispersed needlelike apatite crystals were detected within the partially demineralized dentin or the hybrid layer of both compositionally different all-in-one simplified adhesives. Conversely, these crystals were entirely absent from the hybrid layer of the etch and-rinse NTD adhesive. In the X5D group, a bright band was noted beneath the hybrid layer. The methacryloxydecyl dihydrogen phosphate monomer containing ultramild self-etch adhesive (SUD) was still validated in terms of its capability in dentin adhesion. PMID- 25299705 TI - Antimicrobials, stress and mutagenesis. AB - Cationic antimicrobial peptides are ancient and ubiquitous immune effectors that multicellular organisms use to kill and police microbes whereas antibiotics are mostly employed by microorganisms. As antimicrobial peptides (AMPs) mostly target the cell wall, a microbial 'Achilles heel', it has been proposed that bacterial resistance evolution is very unlikely and hence AMPs are ancient 'weapons' of multicellular organisms. Here we provide a new hypothesis to explain the widespread distribution of AMPs amongst multicellular organism. Studying five antimicrobial peptides from vertebrates and insects, we show, using a classic Luria-Delbruck fluctuation assay, that cationic antimicrobial peptides (AMPs) do not increase bacterial mutation rates. Moreover, using rtPCR and disc diffusion assays we find that AMPs do not elicit SOS or rpoS bacterial stress pathways. This is in contrast to the main classes of antibiotics that elevate mutagenesis via eliciting the SOS and rpoS pathways. The notion of the 'Achilles heel' has been challenged by experimental selection for AMP-resistance, but our findings offer a new perspective on the evolutionary success of AMPs. Employing AMPs seems advantageous for multicellular organisms, as it does not fuel the adaptation of bacteria to their immune defenses. This has important consequences for our understanding of host-microbe interactions, the evolution of innate immune defenses, and also sheds new light on antimicrobial resistance evolution and the use of AMPs as drugs. PMID- 25299708 TI - The role of mechanical boundary conditions in the soft mode dynamics of PbTiO3. AB - The role of different mechanical boundary conditions in the soft mode dynamics of ferroelectric PbTiO3 is systematically investigated using first-principles-based simulations and analytical model. The change in the soft mode dynamics due to hydrostatic pressure, uniaxial and biaxial stresses and biaxial strains is studied in a wide temperature range. Our computations predict: (i) the existence of Curie-Weiss laws that relate the soft mode frequency to the stress or strain; (ii) a non-trivial temperature evolution of the associated Curie-Weiss constants; (iii) a qualitative difference between the soft mode response to stresses/strains and hydrostatic pressure. The latter finding implies that the Curie-Weiss pressure law commonly used for residual stress estimation may not apply for the cases of uniaxial and biaxial stresses and strains. On the other hand, our systematic study offers a way to eliminate this difficulty through the establishment of Curie-Weiss stress and strain laws. Implications of our predictions for some available experimental data are discussed. PMID- 25299706 TI - Permeability changes of integrin-containing multivesicular structures triggered by picornavirus entry. AB - Cellular uptake of clustered alpha2beta1-integrin induces the formation of membrane compartments that subsequently mature into a multivesicular body (MVB). Enhanced internalization mediated by clustered integrins was observed upon infection by the picornavirus echovirus 1 (EVI). We elucidated the structural features of virus-induced MVBs (vMVBs) in comparison to antibody-induced control MVBs (mock infection) by means of high-pressure cryo fixation of cells followed by immuno electron tomography during early entry of the virus. Three-dimensional tomograms revealed a marked increase in the size and complexity of these vMVBs and the intraluminal vesicles (ILVs) at 2 and 3.5 hours post infection (p.i.), in contrast to the control MVBs without virus. Breakages in the membranes of vMVBs were detected from tomograms after 2 and especially after 3.5 h suggesting that these breakages could facilitate the genome release to the cytoplasm. The in situ neutral-red labeling of viral genome showed that virus uncoating starts as early as 30 min p.i., while an increase of permeability was detected in the vMVBs between 1 and 3 hours p.i., based on a confocal microscopy assay. Altogether, the data show marked morphological changes in size and permeability of the endosomes in the infectious entry pathway of this non-enveloped enterovirus and suggest that the formed breakages facilitate the transfer of the genome to the cytoplasm for replication. PMID- 25299707 TI - Cell penetrating peptide (CPP)-conjugated desferrioxamine for enhanced neuroprotection: synthesis and in vitro evaluation. AB - Iron overload causes progressive and sometimes irreversible damage due to accelerated production of reactive oxygen species. Desferrioxamine (DFO), a siderophore, has been used clinically to remove excess iron. However, the applications of DFO are limited because of its inability to access intracellular labile iron. Cell penetrating peptides (CPPs) have become an efficient delivery vector for the enhanced internalization of drugs into the cytosol. We describe, herein, an efficient method for covalently conjugating DFO to the CPPs TAT(47-57) and Penetratin. Both conjugates suppressed the redox activity of labile plasma iron in buffered solutions and in iron-overloaded sera. Enhanced access to intracellular labile iron compared to the parent siderophore was achieved in HeLa and RBE4 (a model of blood-brain-barrier) cell lines. Iron complexes of both conjugates also had better permeability in both cell models. DFO antioxidant and iron binding properties were preserved and its bioavailability was increased upon CPP conjugation, which opens new therapeutic possibilities for neurodegenerative processes associated with brain iron overload. PMID- 25299709 TI - Sepsis: a problem for everyone. PMID- 25299710 TI - Intra-abdominal hypertension associated with acute lung injury: effects on intracranial pressure. PMID- 25299711 TI - Infection with multi-resistant agents in the ICU: how to escape? PMID- 25299712 TI - Guidelines for the management of patients with severe forms of dengue. AB - Dengue is the most common vector-borne viral infection worldwide. In Brazil, the incidence has increased with successive epidemics, and an increasing proportion of patients present with severe forms of the disease. The prognosis for these patients is directly influenced by the quality of medical care. These guidelines present the management of the severe forms of dengue, including the recognition of warning signs, the treatment for prompt re-establishment of euvolemia and the evaluation and appropriate care of potential complications, thus reducing morbidity and mortality of infected children and adults. PMID- 25299713 TI - Guidelines for the treatment of severe sepsis and septic shock - management of the infectious agent - diagnosis. AB - Sepsis is a common and lethal condition that carries a substantial financial burden and is the primary cause of death in intensive care units. Early diagnosis and treatment of patients has been clearly shown to improve prognosis. Therefore, early diagnosis of infections and control of the primary infection site are fundamental to improving patients' prognosis. This guideline reviews the available evidence concerning the primary strategies for the diagnosis of infection. PMID- 25299714 TI - Guidelines for the treatment of severe sepsis and septic shock - management of the infectious agent - source control and antimicrobial treatment. AB - Sepsis is a common and lethal condition that carries a substantial financial burden. In addition, it is the main cause of death in intensive care units. Early diagnosis and treatment of patients has been clearly shown to improve prognosis. Therefore, early diagnosis of the infecting agent, control of the primary infection site and the use of appropriate antibiotic therapy are fundamental to improving outcomes. This guideline reviews the available evidence in the literature concerning infection control and therapy strategies. PMID- 25299715 TI - Inhibition of brain citrate synthase activity in an animal model of sepsis. AB - OBJECTIVE: An extensive body of evidence from experimental studies indicates that sepsis is associated with increased reactive oxygen species production, depletion of antioxidants, and accumulation of markers of oxidative stress. Moreover, mitochondrial dysfunction has been implicated in the pathogenesis of multiple organ dysfunction syndrome (MODS). Citrate synthase is an enzyme localized in the mitochondrial matrix and an important component of the Krebs cycle; consequently, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase activity in the brains of rats submitted to a cecal ligation puncture model of sepsis. METHODS: At several times points (3, 6, 12, 24 and 48 hours) after the cecal ligation puncture operation, six rats were killed by decapitation. Their brains were removed, and the hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex were dissected and used to determine citrate synthase activity. RESULTS: We found that citrate synthase activity in the prefrontal cortex was inhibited 12, 24 and 48 hours after cecal ligation puncture. In the cerebral cortex, citrate synthase activity was inhibited 3, 12, 24 and 48 hours after cecal ligation puncture. Citrate synthase was not affected in the hippocampus, striatum or cerebellum up to 48 hours after cecal ligation puncture. CONCLUSION: Considering that energy impairment due to mitochondrial dysfunction in sepsis has been well described and that oxidative stress plays a crucial role in sepsis development, we believe that energy impairment may also be involved in these processes. If citrate synthase inhibition also occurs in a sepsis model, it is tempting to speculate that a reduction in brain metabolism may be related to the pathophysiology of this disease. PMID- 25299716 TI - Factors associated with variation in intracranial pressure in a model of intra abdominal hypertension with acute lung injury. AB - OBJECTIVE: To evaluate the effects of hemodynamic, respiratory and metabolic changes on intracranial pressure in a model of acute lung injury and abdominal compartment syndrome. METHODS: Eight Agroceres pigs were submitted to five different clinical scenarios after instrumentation: 1) a baseline condition with low intra-abdominal pressure and healthy lungs; 2) pneumoperitoneum with 20 mmHg intra-abdominal pressure; 3) acute lung injury induced by pulmonary lavage with surfactant deactivation; 4) pneumoperitoneum with 20 mmHg intra-abdominal pressure with lung pulmonary injury and low positive end-expiratory pressure; and 5) 27 cmH2O positive end-expiratory pressure with pneumoperitoneum and acute lung injury. Respiratory and hemodynamic variables were collected. A multivariate analysis was conducted to search for variables associated with increased intracranial pressure in the five scenarios. RESULTS: Only plateau airway pressure showed a positive correlation with intracranial pressure in the multivariate analysis. In the models with acute lung injury, plateau airway pressure, CO2 arterial pressure, end tidal CO2 and central venous pressure were positively correlated with increased intracranial pressure. CONCLUSION: In a model of multiple organ dysfunction with associated clinical conditions causing increased intra-thoracic and abdominal pressure, increased intracranial pressure triggered by elevated intra-abdominal pressure is apparently caused by worsened respiratory system compliance and a reduced brain venous drainage gradient due to increased central venous pressure. PMID- 25299717 TI - Fluids in the postoperative period: effects of lack of adjustment to body weight. AB - OBJECTIVE: To compare the differences in fluid and electrolyte balance in patients with low and high weight in the first postoperative day. METHODS: Over a period of 18 months, we prospectively evaluated 150 patients in the first 24 hours after surgery, in a university-affiliated hospital intensive care unit. Patients with low weight (< 60 kg) and high body weight (> 90 Kg) were compared in terms of fluid intake and output. RESULTS: No significant differences were observed in the volume (4334 +/- 1097 vs. 4644 +/- 1957 ml/24 h) and composition of the fluids administered (481 +/- 187 vs. 586 +/- 288 mEq [Na+]administered/24 h). The 24 h urine output was similar (2474 +/- 1597 vs.2208 +/- 678 ml/24 h) but low weight group showed higher electrolyte elimination (296 +/- 195 vs.192 +/- 117 mEq [Na+]urine /24 h, p = 0.0246). When the administered fluids were adjusted for body weight, the volume and amount of electrolytes of fluids administered were higher in the low weight group (79 +/- 21 vs. 47 +/- 22 ml/kg/24 h, p < 0.0001 and 8.8 +/- 3.4 vs. 5.8 +/- 3.3 mEq [Na+]administered/kg/24 h, p = 0.017, respectively). This group also showed higher urine output and electrolyte elimination (45 +/- 28 vs. 22 +/- 7 ml/kg/24 h, p = 0.0002 and 5.3 +/- 3.5 vs. 1.8 +/- 1.2 mEq [Na+]urine/kg/24 h, p < 0.0001, respectively). CONCLUSIONS: The lack of adjustment of the fluid therapy to body weight determined that low weight patients received more fluid than high weight patients according to their body weight. This fluid overload could be compensated by increased urine output and electrolyte elimination. PMID- 25299718 TI - Physicochemical characterization of metabolic acidosis induced by normal saline resuscitation of patients with severe sepsis and septic shock. AB - OBJECTIVE: The aim of this study was to characterize and quantify metabolic acidosis that was caused by initial volume expansion during the reanimation of patients with severe sepsis and septic shock. METHODS: A blood sample was drawn for physicochemical characterization of the patient's acid-base equilibrium both before and after volume expansion using 30 mL/kg 0.9% saline solution. The diagnosis and quantification of metabolic acidosis were based on the standard base excess (SBE). RESULTS: Eight patients with a mean age of 58 +/- 13 years and mean APACHE II scores of 20 +/- 4 were expanded using 2,000 +/- 370 mL of 0.9% saline solution. Blood pH dropped from 7.404 +/- 0.080 to 7.367 +/- 0.086 (p=0.018), and PC O2 increased from 30 +/- 5 to 32 +/- 2 mmHg (p=0.215); SBE dropped from -4.4 +/- 5.6 to -6.0 +/- 5.7 mEq/L (p=0.039). The drop in SBE was associated with the acidifying power of two factors, namely, a significant increase in the strong ion gap (SIG) from 6.1 +/- 3.4 to 7.7 +/- 4.0 mEq/L (p = 0.134) and a non-significant drop in the apparent inorganic strong ion differences (SIDai) from 40 +/- 5 to 38 +/- 4 mEq/L (p = 0.318). Conversely, the serum albumin levels decreased from 3.1 +/- 1.0 to 2.6 +/- 0.8 mEq/L (p = 0.003) with an alkalinizing effect on SBE. Increased serum chloride levels from 103 +/- 10 to 106 +/- 7 mEq/L (p < 0.001) led to a drop in SIDai. CONCLUSION: Initial resuscitation using 30 mL/kg of 0.9% saline solution for patients with severe sepsis and septic shock is associated with worsened metabolic acidosis, as measured by SBE. This worsened SBE can be ascribed to a serum increase in the levels of unmeasurable anions and chloride. PMID- 25299719 TI - Impact of the adequacy of energy intake on intensive care unit mortality in patients receiving enteral nutrition. AB - OBJECTIVE: To investigate the relationship between adequacy of energy intake and intensive care unit mortality in patients receiving exclusive enteral nutrition therapy. METHODS: Observational and prospective study conducted during 2008 and 2009. Patients above 18 years with exclusive enteral nutrition therapy for at least 72 hours were included. The adequacy of energy intake was estimated by the administered/prescribed ratio. Non-conditional logistic regression was used to assess the relationship between predictive variables (adequacy of energy intake, APACHE II, gender, age, and intensive care unit length of stay) and intensive care unit mortality. RESULTS: Sixty-three patients (mean 58 years, 27% mortality) were included, 47.6% of whom received more than 90% of the energy prescribed (mean adequacy 88.2%). Mean energy balance was -190 kcal/day. Significant associations between death in the intensive care unit and the variables age and intensive care unit length of stay were observed, after removing the variables adequacy of energy intake, APACHE II, gender and age during the modeling process. CONCLUSION: In our study, adequacy of energy intake did not affect intensive care unit mortality. Carefully followed enteral nutrition protocols, resulting in an administered/prescribed ratio above 70%, are apparently not sufficient to impact the mortality rates in the intensive care unit. Therefore, it may not be necessary to achieve 100% of the targeted energy, considering the high frequency of enteral feeding interruptions due to gastrointestinal intolerance and fasting for tests and procedures. Additional research is needed to identify the optimal energy intake for improved outcomes and reduced costs. PMID- 25299720 TI - Bronchial hygiene technique with manual hyperinflation and thoracic compression: effectiveness and safety. AB - OBJECTIVES: To evaluate the effects of the manual hyperinflation with thoracic compression (MHTC) maneuver on the clearance of secretions, pulmonary mechanics, hemodynamics and oxygenation in mechanically ventilated patients. METHODS: This was a controlled, crossover study that included twenty patients who were under invasive ventilation for more than 48 hours. Four hours after the last airway suctioning procedure, the patients underwent the study interventions, Suction alone or MHTC plus Suction, in sequence at four hour intervals. The sequence order for the procedures was established by randomization. Data were collected before, during and 5, 15, 30 and 60 minutes after each intervention. The suctioned secretions were collected and weighed. RESULTS: No significant differences between the procedures were found regarding tidal volume, plateau pressure and pulmonary compliance (p>0.05). The hemodynamic variables showed increased pressures and heart rate during the procedures and returned to baseline values five minutes after the end of the procedure (p<=0.001). No significant hemodynamic differences were seen between the interventions (p>0.05). For the duration of the study, oxygen saturation was 99% with only two exceptions during the MHTC + Suction procedure, where saturation was 98% (p<0.05). No significant differences were observed between the techniques regarding the weight of the suctioned secretion. CONCLUSION: The results suggest that MHTC, as performed in this study, adds no benefit with respect to oxygenation optimization, pulmonary mechanics and clearance of secretions. However, the MHTC maneuver did not result in hemodynamic changes when compared to the suctioning procedure alone. PMID- 25299721 TI - Lack of accuracy of ventilatory indexes in predicting extubation success in children submitted to mechanical ventilation. AB - OBJECTIVES: Between 10% and 20% of children submitted to mechanical ventilation in the pediatric intensive care unit present extubation failure. Several ventilatory indexes have been proposed to predict extubation failure. The aim of this study was to analyze the accuracy of these indices in predicting successful extubation in children and to evaluate these variables according to the age of the patient and the specific disease. METHODS: A prospective observational study including all children submitted to mechanical ventilation in a Brazilian referral pediatric intensive care unit was conducted between August 2007 and August 2008. The tidal volume, maximal negative inspiratory pressure, rapid shallow breathing index and other ventilatory indexes were measured before extubation. These variables were analyzed according to the extubation outcome (success or failure) as well as age and specific disease (post cardiac surgery and acute viral bronchiolitis). RESULTS: A total of 100 patients were included (median age of 2.1 years old). Extubation failure was observed in 13% and was associated with lower weight (10.3+8.1 Kg vs. 5.5+2.4 Kg; p=0.01). We also evaluated the relationship between extubation failure and the main cause indicating mechanical ventilation: children who had received cardiac surgery (n=17) presented an extubation failure rate of 29.4% with a relative risk of 4.6 (1.2-17.2) when compared to children with acute viral bronchiolitis (n=47, extubation failure rate of 6.4%). The maximal inspiratory pressure was the only physiologic variable independently associated with the outcome. However, this variable showed a wide dispersion and lack of accuracy for predicting extubation success (sensitivity of 82% and specificity of 55% for a cut point of -37.5 cmH2O predicting successful extubation). The same wide dispersion was observed with other ventilatory indexes. CONCLUSION: The indexes for predicting extubation success in children submitted to mechanical ventilation are not accurate; they vary widely depending on age, main disease and other clinical aspects. New formulas including clinical variables should be developed for better prediction of extubation success in children submitted to mechanical ventilation. PMID- 25299722 TI - Sepsis: an update. AB - This paper aims to provide an update on the main aspects of sepsis, a very relevant health care issue. A number of hypotheses have been proposed to explain its origin, involving interactions between microorganisms and the innate immune system, inflammation/immune mediation and the coagulation system. The clinical features of sepsis are variable and depend on the primary site of infection. The identification of early signs and symptoms is crucial for starting therapeutic measures fundamentally based on volume resuscitation, antibiotic therapy, use of steroids, anticoagulant therapy, biologic viability maintenance interventions and nutritional support. PMID- 25299723 TI - Ultrasound-guided central venous catheterization: what is the evidence? AB - In recent years, international health quality assurance organizations have been recommending ultrasound guidance for central venous punctures. This article reviews the evidence behind these recommendations. The MEDLINE, PubMed and SCIELO databases were searched for the following MeSH terms: central venous access, ultrasonography, and adults. The search was conducted on September 24, 2010, and selected meta-analyses, randomized clinical trials and reviews, retrieving 291 papers. The 21 most important papers were analyzed in this review. The internal jugular vein is the most studied ultrasound-guided puncture site, with meta analysis showing lower relative risks of failure and complications. In addition, the largest available randomized clinical trial demonstrated a reduced central venous catheter-associated blood stream infection rate. There are few studies involving subclavian vein puncture; however, ultrasound was shown to be beneficial in two meta-analyses (however, with small numbers of patients). Regarding the femoral venous site, only one randomized clinical trial (20 patients) was identified, showing positive findings. In a British cost effectiveness study, ultrasound use lead to resource savings for different sites of venous puncture. There is strong evidence for ultrasound benefit for internal jugular vein puncture. Although the method appears attractive for the other sites, the data are not sufficient to support any recommendation. PMID- 25299724 TI - Mechanisms of dysfunction of the blood-brain barrier in critically ill patients: emphasis on the role of matrix metalloproteinases. AB - This paper aims to describe the physiological basis of the blood-brain barrier components and its properties. Additionally, the particular effects of metalloproteinases and their control over the extracellular matrix and its relationship with blood-brain barrier dysfunction are discussed. Finally, the role of metalloproteinases on changes in the central nervous system in critically ill patients is discussed. PMID- 25299725 TI - Benefits and limitations of the use of glucose for the treatment of pain in neonates: a literature review. AB - This article aims to review the main studies evaluating glucose as a therapeutic alternative during mildly to moderately painful procedures in neonatology, highlighting its benefits and limitations. During their stay in neonatal intensive care units, neonates are constantly subjected to a number of painful procedures without proper therapeutic management, although the medical literature emphatically recommends this type of management, highlighting the deleterious neurological consequences of pain. Most of these interventions are frequently necessary in neonatal intensive care units to maintain clinical stability in these children; the use of systemic analgesia, however, is not considered to be a good option. The administration of oral glucose solution is apparently effective and safe for pain control during procedures causing mild-to-moderate pain in neonate intensive care units, with rare adverse effects; however, its mode of action has not yet been described clearly in the literature. The administration of oral glucose solution is well described for use in venous punctures; it is apparently effective also for heel punctures, especially when associated with nonnutritive sucking, with most studies showing favorable results. PMID- 25299726 TI - ABDOPRE: an external device for the reduction of intra-abdominal pressure. AB - This article describes a device for the reduction of intra-abdominal pressure. The device (ABDOPRE) includes a unique external servo-control mechanism, based on urinary bladder pressure measurement. The results of ABDOPRE use in the first four intra-abdominal hypertension patients are reported; the device resulted in a reduction of intra-abdominal pressure between 16% and 35% in 3 cases and in a paradoxical increase of the intra-abdominal pressure in an obese woman, likely due to inappropriate chamber size for the patient's anatomy. These results are promising and ABDOPRE may be useful in clinical practice. PMID- 25299727 TI - Levothyroxine absorption and difficult management of hypothyroid patients in the intensive care unit: two case reports and a literature review. AB - Levothyroxine absorption in hypothyroid patients can be influenced by several factors, particularly medications and concomitant food administration. This is especially evident in intensive care unit patients, where a continual enteral diet and the administration of multiple medications changes its absorption. Changes or adaptations in the hypothalamic-pituitary-thyroid axis, in conjunction with clinical abnormalities possibly related to under-treatment of hypothyroidism, render levothyroxine replacement therapy very challenging. Here, we report two intensive care hypothyroidism patients and their respective levothyroxine replacement management issues, focusing on a number of controversial issues, such as the optimal replacement dose, how fast the levothyroxine doses should be increased, triiodothyronine requirements, the interference of an enteral diet with absorption, and finally, the possible consequences of undertreated hypothyroidism and levothyroxine replacement monitoring useful clinical/laboratory parameters. PMID- 25299728 TI - Odd-electron-bonded sulfur radical cations: X-ray structural evidence of a sulfur sulfur three-electron sigma-bond. AB - The one-electron oxidations of 1,8-chalcogen naphthalenes Nap(SPh)2 (1) and Nap(SPh)(SePh) (2) lead to the formation of persistent radical cations 1(*+) and 2(*+) in solution. EPR spectra, UV-vis absorptions, and DFT calculations show a three-electron sigma-bond in both cations. The former cation remains stable in the solid state, while the latter dimerizes upon crystallization and returns to being radical cations upon dissolution. This work provides conclusive structural evidence of a sulfur-sulfur three-electron sigma-bond (in 1(*+)) and a rare example of a persistent heteroatomic three-electron sigma-bond (in 2(*+)). PMID- 25299729 TI - NZVI modified magnetic filter paper with high redox and catalytic activities for advanced water treatment technologies. AB - The in situ synthesis of air-stable zero-valent iron nanoparticles (NZVI) embedded in cellulose fibers leads to the assembly of highly reactive magnetic filter papers. These engineered materials display a wide range of applications in the treatment of wastewater and drinking water, including chromium removal, phenol degradation, environmental bioremediation, and catalysis. PMID- 25299730 TI - Dynamic kinetic asymmetric cross-benzoin additions of beta-stereogenic alpha-keto esters. AB - The dynamic kinetic resolution of beta-halo alpha-keto esters via an asymmetric cross-benzoin reaction is described. A chiral N-heterocyclic carbene catalyzes the umpolung addition of aldehydes to racemic alpha-keto esters. The resulting fully substituted beta-halo glycolic ester products are obtained with high levels of enantio- and diastereocontrol. The high chemoselectivity observed is a result of greater electrophilicity of the alpha-keto ester toward the Breslow intermediate. The reaction products are shown to undergo highly diastereoselective substrate-controlled reduction to give highly functionalized stereotriads. PMID- 25299731 TI - Unbinding pathways of VEGFR2 inhibitors revealed by steered molecular dynamics. AB - A detailed atomistic description of the unbinding process of sorafenib and sunitinib, two known VEGFR2 inhibitors clinically used to treat renal cell carcinoma, was unraveled by using steered molecular dynamics (SMD) simulations. While sunitinib is a fast-dissociating binder, sorafenib exhibits quite a long residence time at this enzyme, which might impact its duration of action in vivo. In order to gain insights into the kinetically different behaviors of the two inhibitors, an SMD study was carried out, which involved a careful optimization of the force and velocity parameters. We were able to identify two different binding pathways for the two inhibitors, as sunitinib exited the ATP binding site from the cavity entrance without a rupture point while sorafenib moved opposite to the ATP binding site entrance. Furthermore, the calculated DeltaGoff values clearly reflect on a qualitative level the distinct off-rates of the two inhibitors, thus suggesting that this protocol could be tried on other VEGFR2 ligands to assess its robustness and then used to rank structural analogues of these derivatives. PMID- 25299734 TI - Inhibition effect of phenyl compounds from the Oryza sativa roots on melanin production in murine B16-F10 melanoma cells. AB - Five phenyl compounds, vanillin (1), methyl trans-ferulate (2), trans-p-coumaric acid methyl ester (3), N-benzoyltryptamine (4), and N-(trans-cinnamoyl)tryptamine (5), were isolated from the roots of Oryza sativa L. and identified on the basis of spectroscopic data. Compounds 3 and 5 showed strong inhibition effect on melanin production in murine B16-F10 melanoma cells and tyrosinase activity. Also, the quantitative analysis of the compounds was carried out using LC/MS/MS experiment. Compounds 3 and 5 could be used as skin-whitening agents. PMID- 25299735 TI - Diversity-oriented synthesis of medicinally important 1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and higher analogs. AB - 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic) is a constrained analog of phenylalanine (Phe). The Tic unit has been identified as a core structural element present in several peptide-based drugs and forms an integral part of various biologically active compounds. This report covers the biological significance of the Tic core and provides a detailed account of various synthetic approaches available for the construction of Tic derivatives. Along with the traditional methods such as the Pictet-Spengler and Bischler-Nepieralski reactions, we cover various recent approaches such as enyne metathesis, [2 + 2 + 2] cycloaddition and the Diels-Alder reaction to generate Tic derivatives. In addition, syntheses of higher analogs of Tic are also discussed. PMID- 25299733 TI - DNA nanostructure-based universal microarray platform for high-efficiency multiplex bioanalysis in biofluids. AB - Microarrays of biomolecules have greatly promoted the development of the fields of genomics, proteomics, and clinical assays because of their remarkably parallel and high-throughput assay capability. Immobilization strategies for biomolecules on a solid support surface play a crucial role in the fabrication of high performance biological microarrays. In this study, rationally designed DNA tetrahedra carrying three amino groups and one single-stranded DNA extension were synthesized by the self-assembly of four oligonucleotides, followed by high performance liquid chromatography purification. We fabricated DNA tetrahedron based microarrays by covalently coupling the DNA tetrahedron onto glass substrates. After their biorecognition capability was evaluated, DNA tetrahedron microarrays were utilized for the analysis of different types of bioactive molecules. The gap hybridization strategy, the sandwich configuration, and the engineering aptamer strategy were employed for the assay of miRNA biomarkers, protein cancer biomarkers, and small molecules, respectively. The arrays showed good capability to anchor capture biomolecules for improving biorecognition. Addressable and high-throughput analysis with improved sensitivity and specificity had been achieved. The limit of detection for let-7a miRNA, prostate specific antigen, and cocaine were 10 fM, 40 pg/mL, and 100 nM, respectively. More importantly, we demonstrated that the microarray platform worked well with clinical serum samples and showed good relativity with conventional chemical luminescent immunoassay. We have developed a novel approach for the fabrication of DNA tetrahedron-based microarrays and a universal DNA tetrahedron-based microarray platform for the detection of different types of bioactive molecules. The microarray platform shows great potential for clinical diagnosis. PMID- 25299732 TI - Casein kinase 1delta/epsilon inhibitor PF-5006739 attenuates opioid drug-seeking behavior. AB - Casein kinase 1 delta (CK1delta) and casein kinase 1 epsilon (CK1epsilon) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1delta/epsilon inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4 yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1delta/epsilon (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid drug-seeking behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collectively, our data supports further development of 6 as a promising candidate to test the hypothesis of CK1delta/epsilon inhibition in treating multiple indications in the clinic. PMID- 25299736 TI - Albumin decrease is associated with spontaneous preterm delivery within 48 h in women with threatened preterm labor. AB - Threatened preterm labor (TPTL) accounts for ~30% of pregnancy-related hospital admissions. Maternal peripheral leukocytes can be used to monitor a variety of physiological processes occurring in the body. Two high-throughput mass spectrometry methodologies, SWATH and iTRAQ, were used to study differentially expressed peripheral blood leukocyte lysate proteins in symptomatic women admitted for TPTL who had a preterm birth within 48 h (n = 16) and those who did not (n = 24). The SWATH spectral library consisted of 783 proteins. SWATH methodology quantified 258 proteins (using >=2 peptides) and 5 proteins (ALBU, ANXA6, HNRPK, HSP90A, and PDIA1) were differentially expressed (p < 0.05, Mann Whitney U). iTRAQ workflow identified 765 proteins; 354 proteins were quantified and 14 proteins (MIF, UBIQ, HXK3, ALBU, HNRPD, ST1A2, RS15A, RAP1B, CAN1, IQGA2, ST1A1, COX5A, ADDA, and UBQL1) were significantly different between the two groups of women (p < 0.05, Mann-Whitney U). Albumin was the only common differentially expressed protein in both SWATH (28% decrease) and iTRAQ studies (45% decrease). This decrease in albumin was validated using ELISA (11% decrease, p < 0.05, Mann-Whitney U) in another 23 TPTL women. This work suggests that albumin is a broad indicator of leukocyte activation with impending preterm birth and provides new future work directions to understand the pathophysiology of TPTL. PMID- 25299737 TI - Determination of radiostrontium in milk samples by ultra-low-level liquid scintillation counting: a validated approach. AB - Strontium-90 is a hazardous radionuclide derived from nuclear fission processes, and it decays emitting high-energy beta-particles forming yttrium-90. It may be easily absorbed in humans through several food supply chains, since it is chemically similar to some important biological elements such as potassium and calcium. In this work an analytical method for the determination of radiostrontium in milk by liquid scintillation counting was developed in order to obtain a precise quantification at low activity concentration levels. Moreover, a full validative approach was applied to confirm method reliability. Good analytical performance was obtained by developing an in-house validation model according to Regulation 882/2004/EC and Decision 657/2002/EC with a good selectivity, a decision threshold and detection limit corresponding to 0.003 and 0.006 Bq l-1 (alpha = beta = 0.05) respectively, a repeatability value, expressed as CV%, equal to 13%, a mean recovery value equal to 102.5% and a measurement uncertainty equal to 11.5%. Strontium and yttrium chemical yields were determined by a reliable analytical method by inductively coupled mass spectrometry, assuring a suitable correction of final result. The results of the method validation, combined with a quality control assurance, performed on a reference material, demonstrated that the procedure represents a substantial improvement in the determination of 90Sr relating to accurate confirmation analyses. PMID- 25299738 TI - Fixation of Extraocular Muscles to Porous Orbital Implants Using 2-Ocetyl Cyanoacrylate Glue. AB - PURPOSE: To assess the efficacy of recti muscle fixation with 2-ocetyl cyanoacrylate tissue glue to porous orbital implants in human subjects undergoing enucleation. METHODS: This was a prospective interventional study with a historical control group. Over a 1-year period, patients who received orbital implant fixation using 2-ocetyl-cyanoacrylate tissue glue were enrolled in the study. Functional assessment was carried out by measurement of implant motility at the 6-month postoperative period, which was compared with a historical control group of patients with sutured implants. Structural assessment was carried out with a random sample of orbital MRIs. RESULTS: Twelve patients received the glue fixation technique. There were no intraoperative or immediate postoperative complications. There was no statistically significant difference between the glued and sutured groups' horizontal implant movement (7.0 mm +/- 1.5 mm vs. 6.8 mm +/- 1.8 mm, respectively; p = 0.85) or vertical implant movement (5.6 mm +/- 1.7 mm vs. 5.0 mm +/- 1.4 mm, respectively; p = 0.39). Sample orbital MRI demonstrated good muscle approximation to the implants as well as contrast enhancement suggestive of successful fibrovascular proliferation. CONCLUSIONS: Recti muscle fixation using 2-ocetyl-cyanoacrylate tissue glue to porous orbital implants appeared safe and produced good functional and structural results in this proof-of-concept study. This novel technique of implant fixation may offer benefits in terms of reduced operating room time and cost savings. PMID- 25299739 TI - Microvascular Free Flap for Total Eyelid Reconstruction With a Visually Useful Eye. AB - Total eyelid loss, full thickness loss of the upper and lower eyelids, is uncommon and surgically challenging. Eyelid reconstruction after such injuries can be further complicated by loss of adjacent tissue. When tissue for local flaps is unavailable, free flaps must be considered. Few cases of total eyelid reconstruction via microvascular free flap have been reported, especially with an intact globe and good visual acuity. In this report, we describe the use of a microvascular free flap based on the radial artery for total eyelid reconstruction in a patient with an intact globe and useful visual acuity. PMID- 25299740 TI - Evolving Minimally Invasive Techniques for Tear Trough Enhancement. AB - PURPOSE: The aim of this study is to investigate whether volumetric enhancement of the infraorbital rim area or, alternatively, of the deep medial cheek, results in greater improvement of tear trough deformity. METHODS: This prospective, single-blind study recruited 12 patients seeking correction of tear trough deformity. Pretreatment standardized photographs were obtained after which patients were randomized to receive hyaluronic acid gel filler augmentation of the tear trough on one side and hyaluronic acid gel augmentation of the cheek on the contralateral side. The patients were then re-examined at 3 weeks postinjection when standardized photographs were taken again. Following the photographs, filler was added to the side and location where they were not used at the original treatment, resulting in added volume in both the cheek and the tear trough. The patients returned 3 weeks later when final photographs were taken. The pre- and post-treatment images were randomized and evaluated by 3 masked observers asked to evaluate the depth of tear trough. RESULTS: There was a significant improvement in the depth of the tear trough rating after initial treatment on the side treated in the tear trough (p = 0.0001). There was not a significant change in depth of tear trough rating, however, on the side receiving cheek only treatment (p = 0.0963). There was a statistically significant change in tear trough rating after both tear trough and cheek had been treated on each side (p = 0.001). There was no statistically significant difference between sides after lid and cheek treatment had been completed on each side (p = 0.5986). Intraclass correlation between reviewers for all subjects was excellent at 0.94. Tear trough injections were more technique sensitive than cheek volume augmentation to achieve satisfactory results. There were no complications from cheek volume enhancement. Varying degrees of ecchymosis were encountered with tear trough injections. CONCLUSIONS: When the patient's primary concern is the appearance of the tear trough, and the physician is limited to treating either the tear trough or the cheek alone, it appears that treatment in the tear trough offers greater improvement in the appearance of the tear trough deformity when compared with treatment in the cheek alone. PMID- 25299741 TI - Mueller's Muscle Conjunctival Resection With Skin-Only Blepharoplasty: Effects on Eyelid and Eyebrow Position. AB - PURPOSE: To determine the effect of concurrent blepharoplasty and Mueller's muscle conjunctival resection (MMCR) surgery on eyelid position and eyebrow height. METHODS: Clinical data from 274 eyes that met inclusion criteria for this study were reviewed. Mueller's muscle conjunctival resection surgery was performed alone in 198 eyes and was performed with concurrent blepharoplasty in 76 cases. In this study blepharoplasty consisted of only skin removal, leaving the muscle, fat, and tarsus intact. Preoperative and postoperative pupil to eyebrow, and eyelid margin to eyebrow distances were calculated and compared. RESULTS: Preoperative margin reflex distance 1 (MRD1) was similar for both groups of patients (p > 0.05) as was the postoperative MRD1 (p > 0.05). The change in MRD1 was similar between patients undergoing MMCR alone versus those undergoing MMCR with blepharoplasty (1.5 mm vs. 1.3 mm, respectively, p = 0.36). For similar amounts of tissue resection, the postoperative change in MRD1 was similar for patients undergoing MMCR-only surgery and MMCR with blepharoplasty (p > 0.05). Eyebrow height significantly decreased following both MMCR with blepharoplasty (0.73 mm, p < 0.05) and MMCR-only surgery (0.87 mm, p < 0.05), and this change in eyebrow height was not significantly different between the 2 groups. CONCLUSION: Combining MMCR surgery with skin-only blepharoplasty does not significantly alter eyelid height when compared with MMCR surgery alone for the correction of upper eyelid ptosis. This may assist in preoperative planning for combined MMCR with skin-only blepharoplasty. PMID- 25299742 TI - Application of process improvement principles to increase the frequency of complete airway management documentation. AB - BACKGROUND: Process improvement in healthcare delivery settings can be difficult, even when there is consensus among clinicians about a clinical practice or desired outcome. Airway management is a medical intervention fundamental to the delivery of anesthesia care. Like other medical interventions, a detailed description of the management methods should be documented. Despite this expectation, airway documentation is often insufficient. The authors hypothesized that formal adoption of process improvement methods could be used to increase the rate of "complete" airway management documentation. METHODS: The authors defined a set of criteria as a local practice standard of "complete" airway management documentation. The authors then employed selected process improvement methodologies over 13 months in three iterative and escalating phases to increase the percentage of records with complete documentation. The criteria were applied retrospectively to determine the baseline frequency of complete records, and prospectively to measure the impact of process improvements efforts over the three phases of implementation. RESULTS: Immediately before the initial intervention, a retrospective review of 23,011 general anesthesia cases over 6 months showed that 13.2% of patient records included complete documentation. At the conclusion of the 13-month improvement effort, documentation improved to a completion rate of 91.6% (P<0.0001). During the subsequent 21 months, the completion rate was sustained at an average of 90.7% (SD, 0.9%) across 82,571 general anesthetic records. CONCLUSION: Systematic application of process improvement methodologies can improve airway documentation and may be similarly effective in improving other areas of anesthesia clinical practice. PMID- 25299743 TI - Perioperative management of elderly patients with hip fracture. PMID- 25299744 TI - Research at the Harvard Anesthesia Departments. PMID- 25299746 TI - Strain heterogeneity and magnetoelastic behaviour of nanocrystalline half-doped La, Ca manganite, La0.5Ca0.5MnO3. AB - Elastic and anelastic properties of La0.5Ca0.5MnO3 determined by resonant ultrasound spectroscopy in the frequency range ~100-1200 kHz have been used to evaluate the role of grain size in determining the competition between ferromagnetism and Jahn-Teller/charge order of manganites which show colossal magneto resistance. At crystallite sizes of ~75 and ~135 nm the dominant feature is softening of the shear modulus as the charge order transition point, Tco (~225 K), is approached from above and below, matching the form of softening seen previously in samples with 'bulk' properties. This is consistent with a bilinear dominant strain/order parameter coupling, which occurs between the tetragonal shear strain and the Jahn-Teller (Gamma3(+)) order parameter. At crystallite sizes of ~34 and ~42 nm the charge ordered phase is suppressed but there is still softening of the shear modulus, with a minimum near Tco. This indicates that some degree of pseudoproper ferroelastic behaviour is retained. The primary cause of the suppresion of the charge ordered structure in nanocrystalline samples is therefore considered to be due to suppression of macroscopic strain, even though MnO6 octahedra must develop some Jahn-Teller distortions on a local length scale. This mechanism for stabilizing ferromagnetism differs from imposition of either an external magnetic field or a homogeneous external strain field (from a substrate), and is likely to lead both to local strain heterogeneity within the nanocrystallites and to different tilting of octahedra within the orthorhombic structure. An additional first order transition occurs near 40 K in all samples and appears to involve some very small strain contrast between two ferromagnetic structures. PMID- 25299745 TI - The Escherichia coli major exoribonuclease RNase II is a component of the RNA degradosome. AB - Multiprotein complexes that carry out RNA degradation and processing functions are found in cells from all domains of life. In Escherichia coli, the RNA degradosome, a four-protein complex, is required for normal RNA degradation and processing. In addition to the degradosome complex, the cell contains other ribonucleases that also play important roles in RNA processing and/or degradation. Whether the other ribonucleases are associated with the degradosome or function independently is not known. In the present work, IP (immunoprecipitation) studies from cell extracts showed that the major hydrolytic exoribonuclease RNase II is associated with the known degradosome components RNaseE (endoribonuclease E), RhlB (RNA helicase B), PNPase (polynucleotide phosphorylase) and Eno (enolase). Further evidence for the RNase II-degradosome association came from the binding of RNase II to purified RNaseE in far western affinity blot experiments. Formation of the RNase II-degradosome complex required the degradosomal proteins RhlB and PNPase as well as a C-terminal domain of RNaseE that contains binding sites for the other degradosomal proteins. This shows that the RNase II is a component of the RNA degradosome complex, a previously unrecognized association that is likely to play a role in coupling and coordinating the multiple elements of the RNA degradation pathways. PMID- 25299747 TI - PATTERN OF CONSANGUINITY AND INBREEDING COEFFICIENT IN SARGODHA DISTRICT, PUNJAB, PAKISTAN. AB - Consanguinity is widespread in Pakistan. The majority of studies on consanguinity in Pakistan have been carried out in urban metropolitan areas, and data on rural populations are scarce. The present cross-sectional study was conducted in Sargodha district, upper Punjab, Pakistan where the majority of the population reside in rural areas. A random sample of 1800 married females belonging to six tehsils of Sargodha district was obtained and differentials in consanguinity rates and inbreeding coefficient (F) were investigated. The consanguinity rate was calculated to be 56.72% and the inbreeding coefficient was 0.0348. First cousin unions had the highest representation (49.11% of all marriages), and marriages up to distantly related/Biradari constituted 67.94% of all marriages. Among the six tehsils, consanguinity rates ranged from 50.38% in Bhalwal to 62.88% in Sillanwali. A high rate of consanguinity was observed in subjects speaking the Punjabi language, those with self-arranged/arranged-love marriages and those engaged in professional jobs. With respect to the occupation of husbands the highest consanguinity rate was found among landowners (77.59%; F=0.0539) and businessmen (62.62%; F=0.0377). However, consanguinity did not appear to be associated with rural/urban origin or literacy level. The data showed a wide variation in consanguinity rate and inbreeding coefficient across socio-demographic strata in the Sargodha district population. A comparison of Sargodha with other populations of Punjab also showed regional heterogeneity in the pattern of consanguinity, warranting further studies. PMID- 25299748 TI - In vivo antipyretic, antiemetic, in vitro membrane stabilization, antimicrobial, and cytotoxic activities of different extracts from Spilanthes paniculata leaves. AB - BACKGROUND: The study was conducted to evaluate the in vitro antimicrobial activity, cytotoxic, and membrane stabilization activities, and in vivo antiemetic and antipyretic potentials of ethanolic extract, n-hexane and ethyl acetate soluble fractions of Spilanthes paniculata leaves for the first time widely used in the traditional treatments in Bangladesh. RESULTS: In antipyretic activity assay, a significant reduction (P < 0.05) was observed in the temperature in the mice tested. At dose 400 mg/kg-body weight, the n-hexane soluble fraction showed the effect (36.7 +/- 0.63 degrees C ) as like as the standard (dose 150 mg/kg-body weight) after 5 h of administration. Extracts showed significant (P < 0.001) potential when tested for the antiemetic activity compared to the standard, metoclopramide. At dose 50 mg/kg-body weight, the standard showed 67.23% inhibition, whereas n-hexane and ethyl acetate soluble fractions showed 37.53% and 24.93% inhibition of emesis respectively at dose 400 mg/kg-body weight. In antimicrobial activity assay, the n-hexane soluble fraction (400 MUg/disc) showed salient activity against the tested organisms. It exerts highest activity against Salmonella typhi (16.9 mm zone of inhibition); besides, crude, and ethyl acetate extracts showed resistance to Bacillus cereus and Bacillus subtilis, and Vibrio cholera respectively. All the extracts were tested for lysis of the erythrocytes. At the concentration of 1mg/ml, ethanol extract, and n-hexane and ethyl acetate soluble fractions significantly inhibited hypotonic solution induced lysis of the human red blood cell (HRBC) (27.406 +/- 3.57, 46.034 +/- 3.251, and 30.72 +/- 5.679% respectively); where standard drug acetylsalicylic acid (concentration 0.1 mg/ml) showed 77.276 +/- 0.321% inhibition. In case of heat induced HRBC hemolysis, the plant extracts also showed significant activity (34.21 +/- 4.72, 21.81 +/- 3.08, and 27.62 +/- 8.79% inhibition respectively). In the brine shrimp lethality bioassay, the n-hexane fraction showed potent (LC50 value 48.978 MUg/ml) activity, whereas ethyl acetate fraction showed mild (LC50 value 216.77 MUg/ml) cytotoxic activity. CONCLUSIONS: Our results showed that the n-hexane extract has better effects than the other in all trials. In the context, it can be said that the leaves of S. paniculata possess remarkable pharmacological effects, and justify its folkloric use as antimicrobial, antipyretic, anti-inflammatory, and antiemetic agent. Therefore, further research may be suggested to find possible mode of action of the plant part. PMID- 25299749 TI - Age cohort differences in illicit drug use and hepatitis C among African American substance users. AB - Identifying prognostic indicators for undiagnosed Hepatitis C is crucial to attenuate the negative impact of this disease. This study explored the influence of recent and more distal injection drug use on biologically confirmed Hepatitis C infection among a sample (N = 260) of older and younger African Americans. Data from the baseline assessment of the NEURO-HIV epidemiologic study was analyzed using confounder adjusted regression techniques. Older adults were more likely to test positive for Hepatitis C (OR = 2.80, 95% CI = 1.53-5.11) due to lifetime injection drug use (AOR = 5.37, 95% CI = 3.10-9.28). Clinical implications are discussed. PMID- 25299751 TI - The role of mitochondria in fungal aging. AB - Time-dependent impairments of mitochondrial function play a key role in biological aging. Work on fungal aging models has been instrumental in unraveling basic mechanisms leading to mitochondrial dysfunction and the identification of different pathways active in keeping mitochondria 'healthy' over time. Pathways including those involved in reactive oxygen scavenging, repair of damage, proteostasis, mitochondrial dynamics, and biogenesis, are interconnected and part of a complex quality control system. The individual components of this network are limited in capacity. However, if the capacity of one pathway is overwhelmed, another one may be activated. The mechanisms controlling the underlying cross talk are poorly understood and subject of intensive investigation. PMID- 25299750 TI - Persons with chronic hip joint pain exhibit reduced hip muscle strength. AB - STUDY DESIGN: Controlled laboratory cross-sectional study. Objectives To assess strength differences of the hip rotator and abductor muscle groups in young adults with chronic hip joint pain (CHJP) and asymptomatic controls. A secondary objective was to determine if strength in the uninvolved hip of those with unilateral CHJP differs from that in asymptomatic controls. BACKGROUND: Little is known about the relationship between hip muscle strength and CHJP in young adults. METHODS: Thirty-five participants with CHJP and 35 matched controls (18 to 40 years of age) participated. Using handheld dynamometry, strength of the hip external rotators and internal rotators was assessed with the hip flexed to 90 degrees and 0 degrees . To assess external rotator and internal rotator strength, the hip was placed at the end range of external rotation and internal rotation, respectively. Strength of the hip abductors was assessed in sidelying, with the hip in 15 degrees of abduction. Break tests were performed to determine maximum muscle force, and the average torque was calculated using the corresponding moment arm. Independent-sample t tests were used to compare strength values between (1) the involved limb in participants with CHJP and the corresponding limb in the matched controls, and (2) the uninvolved limb in participants with unilateral CHJP and the corresponding limb in the matched controls. RESULTS: Compared to controls, participants with CHJP demonstrated weakness of 16% to 28% (P<.01) in all muscle groups tested in the involved hip. The uninvolved hip of 22 subjects with unilateral CHJP demonstrated weakness of 18% and 16% (P<.05) in the external rotators (0 degrees ) and abductors, respectively, when compared to the corresponding limb of the matched controls. CONCLUSION: The results of the present study demonstrate that persons with CHJP have weakness in the hip rotator and hip abductor muscles. Weakness also was found in the uninvolved hip of persons with CHJP. PMID- 25299752 TI - Improvement of the emission properties from InGaN/GaN dot-in-a-wire nanostructures after treatment in the flowing afterglow of a microwave N2 plasma. AB - Nominally pure GaN nanowires (NWs) and InGaN/GaN dot-in-a-wire heterostructures were exposed to the flowing afterglow of a N2 microwave plasma and characterized by photoluminescence (PL) spectroscopy. While the band-edge emission from GaN NWs and the GaN matrix of the InGaN/GaN NWs strongly decreased due to the creation of non-radiative recombination centers in the near-surface region, the emission from the InGaN dots strongly increased. PL excitation measurements indicate that such an increase cannot be explained by a plasma-induced shift of the GaN absorption edge. It is rather ascribed to the passivation of grown-in defects and dynamic annealing due to the presence of plasma-generated N atoms and N2 metastables without excessive introduction of ion-induced damage. PMID- 25299753 TI - Exogenous adult postmortem neural precursors attenuate secondary degeneration and promote myelin sparing and functional recovery following experimental spinal cord injury. AB - Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and beta-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies. PMID- 25299754 TI - Insulin involved Akt/ERK and Bcl-2/Bax pathways against oxidative damages in C6 glial cells. AB - Insulin, a hypoglycemic hormone, has multiple functions in the brain. The aim of this study to identify the mechanisms of insulin in hydrogen peroxide (H(2)O(2) induced toxicity in the C6 glial cells. Cytotoxicity, lactate dehydrogenase, nitric oxide, reactive oxygen species and calcium ion, lipid peroxidation, protein oxidation and glutathione levels were determined. Signaling pathway molecules were assessed by western blotting and RT-PCR. The results showed that treatment with insulin reduced the cell death and cell membrane damages against H(2)O(2)-induced toxicity. Furthermore, insulin interfered H(2)O(2)-induced intracellular generation of reactive oxygen species and calcium-ion transport, apoptosis, including lipid and protein oxidation products. Cells treated with insulin reverted H(2)O(2)-induced suppression of reduced glutathione levels by blocking oxidized glutathione. Moreover, insulin treatment activates Akt, restores ERK1/2 and Bcl-2 by preventing Bax and Bax/Bcl-2 ratio. Our results suggest that treatment of insulin exerts potential role against 24 h of H(2)O(2) induced toxicity in C6 cells. PMID- 25299759 TI - What's in a kiss? The effect of romantic kissing on mating desirability. AB - Past research suggests that various courtship rituals, such as romantic kissing, may convey useful mate quality information. Two studies were carried out to examine how purported romantic kissing abilities, as a potential cue to some form of mate information, affect appraisals of potential mating partners. In Experiment 1, 724 participants were presented with vignette descriptions of potential mating partners and were asked to rate partner desirability for various mating-related situations. The primary result of this experiment was that purported kissing ability increased mate desirability in "casual sex" mating situations for women to a greater extent than for men. Experiment 2 repeated the same procedure with another 178 participants, this time including visual information alongside vignette descriptions containing kissing-related information to examine the relative effects of these two modalities. It was found that the presence of a picture alongside a descriptive vignette negated the effect of kissing-related information only when rating potential partners on attractiveness or desirability for further courtship, though not when evaluating partners for casual sex or long-term relationship scenarios. Visual information containing "attractive" photos of potential partners was also found to have a greater effect on men's ratings of partner desirability than on women's ratings of partner desirability. The results are discussed in light of romantic kissing's potential function of conveying important mate quality and desirability information, and its relative role in the presence of additional visual mate cues. PMID- 25299760 TI - Psychometrics and life history strategy: the structure and validity of the High K Strategy Scale. AB - In this paper, we critically review the conceptualization and implementation of psychological measures of life history strategy associated with Differential K theory. The High K Strategy Scale (HKSS: Giosan, 2006) was distributed to a large British sample (n = 809) with the aim of assessing its factor structure and construct validity in relation to theoretically relevant life history variables: age of puberty, age of first sexual encounter, and number of sexual partners. Exploratory and confirmatory factor analyses indicated that the HKSS in its current form did not show an adequate statistical fit to the data. Modifications to improve fit indicated four correlated factors (personal capital, environmental stability, environmental security, and social capital). Later puberty in women was positively associated with measures of the environment and personal capital. Among men, contrary to Differential K predictions but in line with female mate preferences, earlier sexual debut and more sexual partners were positively associated with more favorable environments and higher personal and social capital. We raise concerns about the use of psychometric indicators of lifestyle and personality as proxies for life history strategy when they have not been validated against objective measures derived from contemporary life history theory and when their status as causes, mediators, or correlates has not been investigated. PMID- 25299761 TI - Ethological approach to autism spectrum disorders. AB - The purpose of the study was to develop a new ethogram for the assessment of children and adolescents with autism spectrum disorders (ASD) and intellectual developmental disorder (IDD) and to test whether this instrument accurately distinguishes ASD participants (n = 61) from IDD participants (n = 61). An ethogram with 88 behavior elements was generated, including body postures, verbalizations, facial expressions, motor stereotypies, head postures, gaze behavior, gestures, and interpersonal distance. Significant differences were detected between both groups in classic ASD behaviors; in behaviors that are deficient in ASD according to established theoretical models, such as symbolic play, gaze direction, gaze following, and use of mental state language; in atypical behaviors that have also been described previously in ethological studies with ASD; and in the nonspecific behaviors of ASD, such as walk, look own body, explore, and cry. The predictive success of a diagnosis of ASD in the logistic regression model with the ethogram's factors was 98.4%. The results suggest that this ethogram is a powerful and useful tool for both the detailed study of the social behaviors of autistic children and adolescents, and for discriminating ASD and IDD. PMID- 25299762 TI - Evolutionary medicine: semen sampling and seminal plasma hypersensitivity. AB - Evidence suggests that each male may have a unique semen signature, and there are reasons to consider the possibility that semen sampling (i.e., being inseminated by different prospective mates during courtship) may be part of an evolved female mate assessment strategy. Here we theorize that seminal plasma hypersensitivity represents the extreme negative end of this continuum and functions as a deterrent to mating with genetically incompatible suitors. PMID- 25299763 TI - Impressions of dominance are made relative to others in the visual environment. AB - Face judgments of dominance play an important role in human social interaction. Perceived facial dominance is thought to indicate physical formidability, as well as resource acquisition and holding potential. Dominance cues in the face affect perceptions of attractiveness, emotional state, and physical strength. Most experimental paradigms test perceptions of facial dominance in individual faces, or they use manipulated versions of the same face in a forced-choice task but in the absence of other faces. Here, we extend this work by assessing whether dominance ratings are absolute or are judged relative to other faces. We presented participants with faces to be rated for dominance (target faces), while also presenting a second face (non-target faces) that was not to be rated. We found that both the masculinity and sex of the non-target face affected dominance ratings of the target face. Masculinized non-target faces decreased the perceived dominance of a target face relative to a feminized non-target face, and displaying a male non-target face decreased perceived dominance of a target face more so than a female non-target face. Perceived dominance of male target faces was affected more by masculinization of male non-target faces than female non target faces. These results indicate that dominance perceptions can be altered by surrounding faces, demonstrating that facial dominance is judged at least partly relative to other faces. PMID- 25299764 TI - Tembusu-like flavivirus (Perak virus) as the cause of neurological disease outbreaks in young Pekin ducks. AB - A neurological disease of young Pekin ducks characterized by ataxia, lameness, and paralysis was observed at several duck farms in Malaysia in 2012. Gross pathological lesions were absent or inconsistent in most of the cases, but severe and consistent microscopic lesions were found in the brain and spinal cord, characterized by non-purulent panencephalomyelitis. Several virus isolates were obtained in embryonated duck eggs and in cell cultures (Vero and DF-1) inoculated with the brain homogenates of affected ducks. After exclusion of other viruses, the isolates were identified as a flavivirus by flavivirus-specific reverse transcription-polymerase chain reaction (RT-PCR) assays. Inoculation of 2-week old Pekin ducks with a flavivirus isolate by the subcutaneous or intramuscular route resulted in typical clinical signs and histological lesions in the brain and spinal cord. The inoculated virus was detected by RT-PCR from organ samples of ducks with clinical signs and histological lesions. With a few days delay, the disease was also observed among co-mingled contact control birds. Phylogenetic analysis of NS5 and E gene sequences proved that the isolates were representatives of a novel phylogenetic group within clade XI (Ntaya virus group) of the Flavivirus genus. This Malaysian Duck Tembusu Virus (DTMUV), named Perak virus, has moderate genomic RNA sequence similarity to a related DTMUV identified in China. In our experiment the Malaysian strain of DTMUV could be transmitted in the absence of mosquito vectors. These findings may have implications for the control and prevention of this emerging group of flaviviruses. PMID- 25299765 TI - New synchronization criteria for memristor-based networks: adaptive control and feedback control schemes. AB - In this paper, we investigate synchronization for memristor-based neural networks with time-varying delay via an adaptive and feedback controller. Under the framework of Filippov's solution and differential inclusion theory, and by using the adaptive control technique and structuring a novel Lyapunov functional, an adaptive updated law was designed, and two synchronization criteria were derived for memristor-based neural networks with time-varying delay. By removing some of the basic literature assumptions, the derived synchronization criteria were found to be more general than those in existing literature. Finally, two simulation examples are provided to illustrate the effectiveness of the theoretical results. PMID- 25299766 TI - A robust approach to correct for pronounced errors in temperature measurements by controlling radiation damping feedback fields in solution NMR. AB - Accurate temperature measurement is a requisite for obtaining reliable thermodynamic and kinetic information in all NMR experiments. A widely used method to calibrate sample temperature depends on a secondary standard with temperature-dependent chemical shifts to report the true sample temperature, such as the hydroxyl proton in neat methanol or neat ethylene glycol. The temperature dependent chemical shift of the hydroxyl protons arises from the sensitivity of the hydrogen-bond network to small changes in temperature. The frequency separation between the alkyl and the hydroxyl protons are then converted to sample temperature. Temperature measurements by this method, however, have been reported to be inconsistent and incorrect in modern NMR, particularly for spectrometers equipped with cryogenically-cooled probes. Such errors make it difficult or even impossible to study chemical exchange and molecular dynamics or to compare data acquired on different instruments, as is frequently done in biomolecular NMR. In this work, we identify the physical origins for such errors to be unequal amount of dynamical frequency shifts on the alkyl and the hydroxyl protons induced by strong radiation damping (RD) feedback fields. Common methods used to circumvent RD may not suppress such errors. A simple, easy-to-implement solution was demonstrated that neutralizes the RD effect on the frequency separation by a "selective crushing recovery" pulse sequence to equalize the transverse magnetization of both spin species. Experiments using cryoprobes at 500 MHz and 800 MHz demonstrated that this approach can effectively reduce the errors in temperature measurements from about +/-4.0 K to within +/-0.4 K in general. PMID- 25299767 TI - LIGHT-SABRE enables efficient in-magnet catalytic hyperpolarization. AB - Nuclear spin hyperpolarization overcomes the sensitivity limitations of traditional NMR and MRI, but the most general method demonstrated to date (dynamic nuclear polarization) has significant limitations in scalability, cost, and complex apparatus design. As an alternative, signal amplification by reversible exchange (SABRE) of parahydrogen on transition metal catalysts can hyperpolarize a variety of substrates, but to date this scheme has required transfer of the sample to low magnetic field or very strong RF irradiation. Here we demonstrate "Low-Irradiation Generation of High Tesla-SABRE" (LIGHT-SABRE) which works with simple pulse sequences and low power deposition; it should be usable at any magnetic field and for hyperpolarization of many different nuclei. This approach could drastically reduce the cost and complexity of producing hyperpolarized molecules. PMID- 25299768 TI - Women's perspectives on marriage and rights in Morocco: risk factors for forced and early marriage in the Marrakech region. AB - Despite the introduction of the new Family Law, or Moudawana, in Morocco, effectively raising the minimum age for marriage, the number of girls being forced into wedlock is rising. This increase has been a source of concern from a women's rights perspective. The present study explored women's experiences and perspectives in relation to factors that contribute to the occurrence of child and forced marriage in Morocco. Using a participatory approach, focus-group discussions and in-depth interviews were held with women in both urban and rural settings in the greater Marrakech region. Overall, 125 women, between 18 and 69 years of age, participated in the study. Our findings highlight the need for more open dialogue between (grand)parents and children. Overall, the Moudawana is perceived as a considerable step forward for women's rights, yet study findings show that current policy provisions are not effective in abolishing forced marriages. Findings point to the need for a redefinition of the role of organisations, women's associations and other groups, with the recommendation that they focus their future efforts on awareness-raising among older generations and refrain from directly intervening in cases of forced marriage. Sensitisation efforts, including the use of popular media, are crucial to reach members of this older population group, where illiteracy remains widespread. PMID- 25299769 TI - TRAF2 inhibits TRAIL- and CD95L-induced apoptosis and necroptosis. AB - The relevance of the adaptor protein TNF receptor-associated factor 2 (TRAF2) for signal transduction of the death receptor tumour necrosis factor receptor1 (TNFR1) is well-established. The role of TRAF2 for signalling by CD95 and the TNF related apoptosis inducing ligand (TRAIL) DRs, however, is only poorly understood. Here, we observed that knockdown (KD) of TRAF2 sensitised keratinocytes for TRAIL- and CD95L-induced apoptosis. Interestingly, while cell death was fully blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala Asp(OMe)-fluoromethylketone (zVAD-fmk) in control cells, TRAF2-depleted keratinocytes were only partly rescued from TRAIL- and CD95L-induced cell death. In line with the idea the only partially protective effect of zVAD-fmk on TRAIL- and CD95L-treated TRAF2-depleted keratinocytes is due to the induction of necroptosis, combined treatment with zVAD-fmk and the receptor interacting protein 1 (RIP1) inhibitor necrostatin-1 [corrected] fully rescued these cells. To better understand the impact of TRAF2 levels on RIP1- and RIP3-dependent necroptosis and RIP3-independent apoptosis, we performed experiments in HeLa cells that lack endogenous RIP3 and HeLa cells stably transfected with RIP3. HeLa cells, in which necroptosis has no role, were markedly sensitised to TRAIL induced caspase-dependent apoptosis by TRAF2 KD. In RIP3-expressing HeLa transfectants, however, KD of TRAF2 also strongly sensitised for TRAIL-induced necroptosis. Noteworthy, priming of keratinocytes with soluble TWEAK, which depletes the cytosolic pool of TRAF2-containing protein complexes, resulted in strong sensitisation for TRAIL-induced necroptosis but had only a very limited effect on TRAIL-induced apoptosis. The necroptotic TRAIL response was not dependent on endogenously produced TNF and TNFR signalling, since blocking TNF by TNFR2-Fc or anti-TNFalpha had no effect on necroptosis induction. Taken together, we identified TRAF2 not only as a negative regulator of DR-induced apoptosis but in particular also as an antagonist of TRAIL- and CD95L-induced necroptosis. PMID- 25299771 TI - Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice. AB - The pro-apoptotic BH3-only BCL-2 family member BIM is a critical determinant of hematopoietic cell development and homeostasis. It has been argued that the striking hematopoietic abnormalities of BIM-deficient mice (accumulation of lymphocytes and granulocytes) may be the result of the loss of the protein throughout the whole animal rather than a consequence intrinsic to the loss of BIM in hematopoietic cells. To address this issue and allow the deletion of BIM in specific cell types in future studies, we have developed a mouse strain with a conditional Bim allele as well as a new Cre transgenic strain, Vav-CreER, in which the tamoxifen-inducible CreER recombinase (fusion protein) is predominantly expressed in the hematopoietic system. We show that acute loss of BIM in the adult mouse rapidly results in the hematopoietic phenotypes previously observed in mice lacking BIM in all tissues. This includes changes in thymocyte subpopulations, increased white blood cell counts and resistance of lymphocytes to BIM-dependent apoptotic stimuli, such as cytokine deprivation. We have validated this novel conditional Bim knockout mouse model using established and newly developed CreER strains (Rosa26-CreER and Vav-CreER) and will make these exciting new tools for studies on cell death and cancer available. PMID- 25299770 TI - miR-491-5p-induced apoptosis in ovarian carcinoma depends on the direct inhibition of both BCL-XL and EGFR leading to BIM activation. AB - We sought to identify miRNAs that can efficiently induce apoptosis in ovarian cancer cells by overcoming BCL-X(L) and MCL1 anti-apoptotic activity, using combined computational and experimental approaches. We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-X(L) expression and by inducing BIM accumulation in its dephosphorylated form. This latter effect is due to direct targeting of epidermal growth factor receptor (EGFR) by miR-491-5p and consequent inhibition of downstream AKT and MAPK signalling pathways. Induction of apoptosis by miR-491-5p in this cell line is mimicked by a combination of EGFR inhibition together with a BH3-mimetic molecule. In contrast, SKOV3 cells treated with miR-491-5p maintain AKT and MAPK activity, do not induce BIM and do not undergo cell death despite BCL-XL and EGFR downregulation. In this cell line, sensitivity to miR-491-5p is restored by inhibition of both AKT and MAPK signalling pathways. Altogether, this work highlights the potential of miRNA functional studies to decipher cell signalling pathways or major regulatory hubs involved in cell survival to finally propose the rationale design of new strategies on the basis of pharmacological combinations. PMID- 25299772 TI - SMAR1 coordinates HDAC6-induced deacetylation of Ku70 and dictates cell fate upon irradiation. AB - Acetylation status of DNA end joining protein Ku70 dictates its function in DNA repair and Bax-mediated apoptosis. Despite the knowledge of HDACs and HATs that are reported to modulate the acetylation dynamics of Ku70, very little is known about proteins that critically coordinate these key modifications. Here, we demonstrate that nuclear matrix-associated protein scaffold/matrix-associated region-binding protein 1 (SMAR1) is a novel interacting partner of Ku70 and coordinates with HDAC6 to maintain Ku70 in a deacetylated state. Our studies revealed that knockdown of SMAR1 results in enhanced acetylation of Ku70, which leads to impaired recruitment of Ku70 in the chromatin fractions. Interestingly, ionizing radiation (IR) induces the expression of SMAR1 and its redistribution as distinct nuclear foci upon ATM-mediated phosphorylation at serine 370. Furthermore, SMAR1 regulates IR-induced G2/M cell cycle arrest by facilitating Chk2 phosphorylation. Alternatively, SMAR1 provides radioresistance by modulating the association of deacetylated Ku70 with Bax, abrogating the mitochondrial translocation of Bax. Thus, we provide mechanistic insights of SMAR1-mediated regulation of repair and apoptosis via a complex crosstalk involving Ku70, HDAC6 and Bax. PMID- 25299773 TI - Notch signaling regulates myogenic regenerative capacity of murine and human mesoangioblasts. AB - Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells. PMID- 25299774 TI - Neuroglobin, a pro-survival player in estrogen receptor alpha-positive cancer cells. AB - Recently, we reported that human neuroglobin (NGB) is a new player in the signal transduction pathways that lead to 17beta-estradiol (E2)-induced neuron survival. Indeed, E2 induces in neuron mitochondria the enhancement of NGB level, which in turn impairs the activation of a pro-apoptotic cascade. Nowadays, the existence of a similar pathway activated by E2 in non-neuronal cells is completely unknown. Here, the role of E2-induced NGB upregulation in tumor cells is reported. E2 induced the upregulation of NGB in a dose- and time-dependent manner in MCF-7, HepG2, SK-N-BE, and HeLa cells transfected with estrogen receptor alpha (ERalpha), whereas E2 was unable to modulate the NGB expression in the ERalpha devoid HeLa cells. Both transcriptional and extranuclear ERalpha signals were required for the E2-dependent upregulation of NGB in MCF-7 and HepG2 cell lines. E2 stimulation modified NGB intracellular localization, inducing a significant reduction of NGB in the nucleus with a parallel increase of NGB in the mitochondria in both HepG2 and MCF-7 cells. Remarkably, E2 pretreatment did not counteract the H2O2-induced caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, as well as Bcl-2 overexpression in MCF-7 and HepG2 cells in which NGB was stably silenced by using shRNA lentiviral particles, highlighting the pivotal role of NGB in E2-induced antiapoptotic pathways in cancer cells. Present results indicate that the E2-induced NGB upregulation in cancer cells could represent a defense mechanism of E2-related cancers rendering them insensitive to oxidative stress. As a whole, these data open new avenues to develop therapeutic strategies against E2-related cancers. PMID- 25299775 TI - The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors. AB - Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well. PMID- 25299776 TI - Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser727. AB - Chronic lymphoid leukemia (CLL) is characterized by the accumulation of functionally defective CD5-positive B lymphocytes. The clinical course of CLL is highly variable, ranging from a long-lasting indolent disease to an unpredictable and rapidly progressing leukemia requiring treatment. It is thus important to identify novel factors that reflect disease progression or contribute to its assessment. Here, we report on a novel STAT3-mediated pathway that characterizes CLL B cells-extended viability and oxidative stress control. We observed that leukemic but not normal B cells from CLL patients exhibit constitutive activation of an atypical form of the STAT3 signaling factor, phosphorylated on serine 727 (Ser(727)) in the absence of detectable canonical tyrosine 705 (Tyr705)-dependent activation in vivo. The Ser(727)-phosphorylated STAT3 molecule (pSTAT3Ser(727)) is localized to the mitochondria and associates with complex I of the respiratory chain. This pSer(727) modification is further controlled by glutathione-dependent antioxidant pathway(s) that mediate stromal protection of the leukemic B cells and regulate their viability. Importantly, pSTAT3Ser(727), but neither Tyr705 phosphorylated STAT3 nor total STAT3, levels correlate with prolonged in vivo CLL B cells survival. Furthermore, STAT3 activity contributes to the resistance to apoptosis of CLL, but not normal B cells, in vitro. These data reveal that mitochondrial (Mt) pSTAT3Ser(727) overactivity is part of the antioxidant defense pathway of CLL B cells that regulates their viability. Mt pSTAT3Ser(727) appears to be a newly identified cell-protective signal involved in CLL cells survival. Targeting pSTAT3Ser(727) could be a promising new therapeutic approach. PMID- 25299777 TI - The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model. AB - The endoplasmic reticulum (ER) has a major role in protein folding. The accumulation of unfolded proteins in the ER induces a stress, which can be resolved by the unfolded protein response (UPR). Chronicity of ER stress leads to UPR-induced apoptosis and in turn to an unbalance of tissue homeostasis. Although ER stress-dependent apoptosis is observed in a great number of devastating human diseases, how cells activate apoptosis and promote tissue homeostasis after chronic ER stress remains poorly understood. Here, using the Drosophila wing imaginal disc as a model system, we validated that Presenilin overexpression induces chronic ER stress in vivo. We observed, in this novel model of chronic ER stress, a PERK/ATF4-dependent apoptosis requiring downregulation of the antiapoptotic diap1 gene. PERK/ATF4 also activated the JNK pathway through Rac1 and Slpr activation in apoptotic cells, leading to the expression of Dilp8. This insulin-like peptide caused a developmental delay, which partially allowed the replacement of apoptotic cells. Thanks to a novel chronic ER stress model, these results establish a new pathway that both participates in tissue homeostasis and triggers apoptosis through an original regulation. PMID- 25299778 TI - Transformations of the macromolecular landscape at mitochondria during DNA-damage induced apoptotic cell death. AB - Apoptosis is a dynamic process regulated by mitochondrion critical for cellular respiration and survival. Execution of apoptosis is mediated by multiple protein signaling events at mitochondria. Initiation and progression of apoptosis require numerous apoptogenic factors that are either released from or sequestered in mitochondria, which may transform the biomolecular makeup of the organelle. In this communication, using Raman microspectroscopy, we demonstrate that transformation in biomolecular composition of mitochondrion may be used as apoptosis marker in an individual cell. For the first time, we show that significant changes occur in the concentrations of RNA, DNA, protein, and lipid constituents of mitochondria during apoptosis. The structural analysis of proteins on mitochondria demonstrated a decrease in alpha-helix secondary structure content, and an increase in the levels of random coils and beta-sheets on mitochondria. This may represent an additional hallmark of apoptosis. Strikingly, we observed nearly identical changes in macromolecular content of mitochondria both in the presence and absence of a key proapoptotic protein, Bax (Bcl-2-associated X protein). Increased DNA level in mitochondria corresponded with higher mitochondrial DNA (mtDNA), cellular reactive oxygen species (ROS), and mitochondrial ROS production. Upregulation of polymerase-gamma (POLG), mitochondrial helicase Twinkle, and mitochondrial transcription factor A (Tfam) in response to DNA damage correlated with increased mtDNA and RNA synthesis. Elevated activity of oxidative phosphorylation complexes supports functional mitochondrial respiration during apoptosis. Thus, we define previously unknown dynamic correlation of macromolecular structure of mitochondria and apoptosis progression in the presence and absence of Bax protein. These findings open up a new approach for monitoring physiological status of cells by non invasive single cell method. PMID- 25299779 TI - Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity. AB - The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations. PMID- 25299780 TI - c-Rel is a critical mediator of NF-kappaB-dependent TRAIL resistance of pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-kappaB signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-kappaB activity, whereas TRAIL sensitive cells displayed only a small increase in NF-kappaB-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-kappaB complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies. PMID- 25299781 TI - Analysis of BH3-only proteins upregulated in response to oxygen/glucose deprivation in cortical neurons identifies Bmf but not Noxa as potential mediator of neuronal injury. AB - Stress signaling in response to oxygen/glucose deprivation (OGD) and ischemic injury activates a group of pro-apoptotic genes, the Bcl-2 homology domain 3 (BH3)-only proteins, which are capable of activating the mitochondrial apoptosis pathway. Targeted studies previously identified the BH3-only proteins Puma, Bim and Bid to have a role in ischemic/hypoxic neuronal injury. We here investigated the transcriptional activation of pro-apoptotic BH3-only proteins after OGD induced injury in murine neocortical neurons. We observed a potent and early upregulation of noxa at mRNA and protein level, and a significant increase in Bmf protein levels during OGD in neocortical neurons and in the ipsilateral cortex of mice subjected to transient middle cerebral artery occlusion (tMCAO). Surprisingly, gene deficiency in noxa reduced neither OGD- nor glutamate-induced neuronal injury in cortical neurons and failed to influence infarct size or neurological deficits after tMCAO. In contrast, bmf deficiency induced significant protection against OGD- or glutamate-induced injury in cultured neurons, and bmf-deficient mice showed reduced neurological deficits after tMCAO in vivo. Collectively, our data not only point to a role of Bmf as a BH3-only protein contributing to excitotoxic and ischemic neuronal injury but also demonstrate that the early and potent induction of noxa does not influence ischemic neuronal injury. PMID- 25299782 TI - Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice. AB - FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over- and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown. Using our newly generated Rosa26-STOP(flox)-FoxN1 mice, in which over- and ectopic-expression of FoxN1 can be induced by various promoter-driven Cre-mediated deletions of the roadblock STOP(flox) in early life, we found that K14Cre-mediated inborn FoxN1 overexpression induced neonatal lethality, exhibited abnormal permeability in the skin and abnormal nursing. Ubiquitous deletion of the STOP(flox) mediated by progressive uCreER(T) leakage in juvenile mice affected thymus and bone marrow normality, resulting in an increased ratio of medullary/cortical TECs, along with declined T and B lymphopoiesis. Although the K5CreER(T)-mediated FoxN1 overexpression mice had a normal lifespan, induction of K5CreER(T) activation in juveniles adversely influenced total thymoycte development and produced ichthyosis-like skin. Therefore, FoxN1 has temporal and tissue-specific activity. Over- and ectopic-expression of FoxN1 in early life adversely influence immature TEC, T and B cell, and skin epithelial development. PMID- 25299783 TI - Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing. AB - Chronic, non-healing wounds are a major complication of diabetes and are characterized by chronic inflammation and excessive protease activity. Although once thought to function primarily as a pro-apoptotic serine protease, granzyme B (GzmB) can also accumulate in the extracellular matrix (ECM) during chronic inflammation and cleave ECM proteins that are essential for proper wound healing, including fibronectin. We hypothesized that GzmB contributes to the pathogenesis of impaired diabetic wound healing through excessive ECM degradation. In the present study, the murine serine protease inhibitor, serpina3n (SA3N), was administered to excisional wounds created on the dorsum of genetically induced type-II diabetic mice. Wound closure was monitored and skin wound samples were collected for analyses. Wound closure, including both re-epithelialization and contraction, were significantly increased in SA3N-treated wounds. Histological and immunohistochemical analyses of SA3N-treated wounds revealed a more mature, proliferative granulation tissue phenotype as indicated by increased cell proliferation, vascularization, fibroblast maturation and differentiation, and collagen deposition. Skin homogenates from SA3N-treated wounds also exhibited greater levels of full-length intact fibronectin compared with that of vehicle wounds. In addition, GzmB-induced detachment of mouse embryonic fibroblasts correlated with a rounded and clustered phenotype that was prevented by SA3N. In summary, topical administration of SA3N accelerated wound healing. Our findings suggest that GzmB contributes to the pathogenesis of diabetic wound healing through the proteolytic cleavage of fibronectin that is essential for normal wound closure, and that SA3N promotes granulation tissue maturation and collagen deposition. PMID- 25299785 TI - New OPTN/UNOS classification system for nodules in cirrhotic livers detected with MR imaging: effect on hepatocellular carcinoma detection and transplantation allocation. AB - PURPOSE: To assess the effect of the new Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) policy on hepatocellular carcinoma (HCC) detection and liver transplant allocation in patients with cirrhosis undergoing dynamic contrast material-enhanced liver magnetic resonance (MR) imaging. MATERIALS AND METHODS: In this HIPAA-compliant institutional review board-approved retrospective study with waiver of informed consent, 247 patients (196 men, 51 women; mean age, 60 years +/- 11 [standard deviation]) with liver cirrhosis who underwent evaluation for HCC with MR imaging were identified via database search. Three radiologists independently reviewed images and identified number and size of HCC based on criteria within either the prior or revised policy. Based on these interpretations, priority for liver transplantation for each patient was determined with prior and revised transplantation allocation criteria. HCC detection was compared between sessions by using McNemar tests, and interreader agreement for detection of at least one HCC was assessed by using kappa coefficients. RESULTS: All three readers detected significantly more 1-2-cm HCCs with the revised policy (readers detected 22, eight, and 20 1-2-cm HCCs) versus the prior policy (no reader detected 1-2-cm HCCs) (P <= .031). All readers detected significantly fewer 2-5-cm HCCs with the revised policy (readers detected eight, 13, and 14 2-5-cm HCCs) versus the prior policy (readers detected 24, 21, and 24 2-5-cm HCCs) (P <= .027). For all readers, fewer patients met criteria for increased transplantation priority with the revised versus the prior policy (number of patients who received increased priority for the three readers were 4.9% [12 of 247] vs 9.3% [23 of 247]; 5.7% [14 of 247] vs 8.1% [20 of 247]; and 6.9% [17 of 247] vs 8.9% [22 of 247]). Interreader agreement was substantial for the prior policy (kappa = 0.607) and almost perfect for the revised policy (kappa = 0.813). CONCLUSION: Among cirrhotic patients who underwent evaluation for HCC with MR imaging, the revised OPTN/UNOS policy led to increased detection of 1-2-cm HCCs, decreased detection of 2-5-cm HCCs, and fewer patients who met criteria for increased transplant priority. PMID- 25299784 TI - Inhibition of phosphotidylinositol-3 kinase pathway by a novel naphthol derivative of betulinic acid induces cell cycle arrest and apoptosis in cancer cells of different origin. AB - Betulinic acid (BA) is a pentacyclic triterpenoid natural product reported to inhibit cell growth in a variety of cancers. However, the further clinical development of BA got hampered because of poor solubility and pharmacological properties. Interestingly, this molecule offer several hotspots for structural modifications in order to address its associated issues. In our endeavor, we selected C-3 position for the desirable chemical modification in order to improve its cytotoxic and pharmacological potential and prepared a library of different triazoline derivatives of BA. Among them, we previously reported the identification of a potential molecule, that is, 3{1N(5-hydroxy-naphth-1yl)-1H 1,2,3-triazol-4yl}methyloxy betulinic acid (HBA) with significant inhibition of cancer cell growth and their properties. In the present study, we have shown for the first time that HBA decreased the expression of phosphotidylinositol-3 kinase (PI3K) p110alpha and p85alpha and caused significant downregulation of pAKT and of NFkappaB using human leukemia and breast cancer cells as in vitro models. Further it was revealed that PI3K inhibition by HBA induced cell cycle arrest via effects on different cell cycle regulatory proteins that include CDKis cyclins and pGSK3beta. Also, this target-specific inhibition was associated with mitochondrial apoptosis as was reflected by the increased expression of mitochondrial bax, downregulated bcl2 and decreased mitochondrial levels of cytochrome c, together with reactive oxygen species generation and decline in mitochondrial membrane potential. The apoptotic effectors such as caspase 8, caspase 9 and caspase 3 were found to be upregulated besides DNA repair associated enzyme, that is, PARP cleavage caused cancer cell death. Pharmacodynamic evaluation revealed that both HBA and BA were safe upto the dose of 2000 mg/kg body weight and with acceptable pharmacodynamic parameters. The in vitro data corroborated with in vivo anticancer activity wherein Ehrlich solid tumor showed that HBA as a more potent agent than BA without any body weight loss and mortality. PMID- 25299786 TI - High-resolution peripheral quantitative CT imaging: Cortical porosity, poor trabecular bone microarchitecture, and low bone strength in lung transplant recipients. AB - PURPOSE: To characterize bone microarchitecture and quantify bone strength in lung transplant (LT) recipients by using high-resolution (HR) peripheral quantitative computed tomographic (CT) imaging of the ultradistal radius. MATERIALS AND METHODS: After study approval by the local ethics committee, all participants provided written informed consent. Included were 118 participants (58 LT recipients [mean age, 46.8 years +/- 1.9; 30 women, 28 men] and 60 control participants [mean age, 39.9 years +/- 1.9; 41 women, 19 men]) between April 2010 and May 2012. HR peripheral quantitative CT of the ultradistal radius was performed and evaluated for bone mineral density and trabecular and cortical bone microarchitecture. Mechanical competence was quantified by microfinite element analysis. Differences between LT recipients and control participants were determined by using two-way factorial analysis of covariance with age adjustment. RESULTS: Total and trabecular bone mineral density were significantly lower ( 13.4% and -16.4%, respectively; P = .001) in LT recipients than in healthy control participants. LT recipients had lower trabecular number (-9.7%; P = .004) and lower trabecular thickness (-8.1%; P = .025). Trabecular separation and trabecular network heterogeneity were higher (+24.3% and +63.9%, respectively; P = .007 and P = .012, respectively) in LT recipients. Moreover, there was pronounced cortical porosity (+31.3%; P = .035) and lower cortical thickness ( 10.2%, P = .005) after LT. In addition, mechanical competence was impaired, which was reflected by low stiffness (-15.0%; P < .001), low failure force (-14.8%; P < .001), and low bone strength (-14.6%; P < .001). CONCLUSION: Men and women with recent LT showed severe deficits in cortical and trabecular bone microarchitecture. Poor bone microarchitecture and low bone strength are likely to contribute to high fracture susceptibility observed in LT recipients. PMID- 25299787 TI - Parametrial invasion in cervical cancer: fused T2-weighted imaging and high-b value diffusion-weighted imaging with background body signal suppression at 3 T. AB - PURPOSE: To retrospectively investigate the value of fused T2-weighted and high-b value diffusion-weighted imaging with background body signal suppression (DWIBS) at 3 T to evaluate parametrial invasion in cervical cancer. MATERIALS AND METHODS: In this institutional review board-approved study, 152 consecutive patients with biopsy-proven cervical cancer who underwent radical hysterectomies also underwent pretreatment magnetic resonance imaging (T2-weighted imaging and DWIBS) at 3 T. Two radiologists independently evaluated the presence of parametrial invasion at T2-weighted imaging, fused T2-weighted imaging and high-b value DWIBS (ie, fused T2-weighted DWIBS), and combined T2-weighted imaging and fused T2-weighted DWIBS, and the results were compared with histopathologic findings. RESULTS: Parametrial invasion was identified by pathologic analysis in 37 of 152 patients (24.3%). For association with parametrial invasion, the specificity and accuracy of fused T2-weighted DWIBS (97.4% and 90.1%, respectively, for reader 1; 95.7% and 89.5%, respectively, for reader 2) and combined T2-weighted imaging and fused T2-weighted DWIBS (99.1% and 93.4%, respectively, for reader 1; 96.5% and 92.8%, respectively, for reader 2) were significantly better than those of T2-weighted imaging alone (88.7% and 85.5%, respectively, for reader 1; 85.2% and 83.6%, respectively, for reader 2) (all P < .05). The respective sensitivity of T2-weighted imaging, fused T2-weighted DWIBS, and combined T2-weighted imaging and fused T2-weighted DWIBS was 75.7%, 67.6%, and 75.7% for reader 1 and 78.4%, 70.3%, and 81.1% for reader 2, and did not show significant differences (P value, <=.375 to >.999). The respective area under the curve for association with parametrial invasion of T2-weighted imaging, fused T2 weighted DWIBS, and combined T2-weighted imaging and fused T2-weighted DWIBS was 0.912, 0.951, and 0.976 for reader 1 and 0.890, 0.932, and 0.968 for reader 2 (P < .05). Interreader agreements were excellent (kappa = 0.89, 0.9, and 0.86 for T2 weighted imaging, fused T2-weighted DWIBS, and combined T2-weighted imaging and fused T2-weighted DWIBS, respectively). CONCLUSION: Fusion of high-b-value DWIBS with T2-weighted imaging can improve the diagnostic performance in association with parametrial invasion in cervical cancer compared with T2-weighted imaging alone. PMID- 25299789 TI - Feasibility of the combination of 3D CTA and 2D CT imaging guidance for clipping microsurgery of anterior communicating artery aneurysm. AB - OBJECTIVE: We report the technique of three-dimensional computed tomography angiography (3D CTA)+two-dimensional computed tomographic (2D CT) imaging as an adjunct in early surgery for a ruptured anterior communicating artery (ACoA) aneurysm by adopting an anterior interhemispheric approach. These combined imaging modalities provide accurate intraoperative anatomical information. METHODS: To produce images for an anterior interhemispheric approach, 3D CTA+2D coronal CT images, which are perpendicular to the direction of the surgical approach at three levels (brain surface, genu of the corpus callosum and aneurysm neck), were constructed. We also produced two 3D CTA+2D CT images of the lamina terminalis, with a horizontal 10-degree difference, to clarify the vascular architecture around the aneurysm stereotactically, as well as the dissection point and direction to open the lamina terminalis. Furthermore, we produced a 3D CTA+2D sagittal CT image at the midline, which allowed us to understand the anatomical architecture of the aneurysm, planum sphenoidale and tuberculum sellae. In addition, four different 3D CTA aneurysm images were produced for deciding the clip size preoperatively. RESULTS: The imaging findings in 28 patients with 28 ACoA aneurysms facilitated early clipping. Based on these 3D CTA+2D CT images, we conducted aneurysm surgery, and successfully performed neck clipping via an anterior interhemispheric approach. CONCLUSION: The combination of 3D CTA and 2D CT images is a feasible and useful method of image guidance for ACoA aneurysm microsurgery. PMID- 25299790 TI - Predictors for delayed ventriculoperitoneal shunt placement after external ventricular drain removal in patients with subarachnoid hemorrhage. AB - OBJECTIVE: Hydrocephalus after subarachnoid hemorrhage (SAH) requires temporary cerebrospinal fluid (CSF) drainage using an external ventricular drain (EVD). This drain is removed if patients pass a clamp trial, or a ventriculoperitoneal shunt (VPS) is placed. Little is known about the risk factors for delayed VPS placement in patients who pass a clamp trial and have their EVD removed. In order to explore the risk factors associated with delayed VPS placement, we studied a retrospective cohort of SAH patients at our institution. METHODS: We performed a retrospective analysis of SAH patients who had an EVD placed between January 2008 and June 2012 at our institution. We extracted demographic, imaging, and CSF data from the medical record and analyzed risk factors associated with delayed VPS placement. RESULTS: Of 91 patients who passed a clamp trial and had their EVD removed, 12 (13%) required delayed VPS placement at a median of 54 (interquartile range: 15-75) days after EVD removal. After multivariate analysis, risk factors for delayed VPS placement included increased CSF protein concentration within the first 7 days of EVD placement (OR: 1.02, CI: 1-1.04, p=0.023) and increased third ventricular diameter prior to EVD removal (OR: 1.59, CI: 1.11-2.6, p=0.026). CONCLUSION: Patients with increased CSF protein concentration at time of EVD placement and those with increased third ventricular diameter at time of EVD removal should be carefully monitored for development of delayed hydrocephalus. PMID- 25299791 TI - Determining the electronic performance limitations in top-down-fabricated Si nanowires with mean widths down to 4 nm. AB - Silicon nanowires have been patterned with mean widths down to 4 nm using top down lithography and dry etching. Performance-limiting scattering processes have been measured directly which provide new insight into the electronic conduction mechanisms within the nanowires. Results demonstrate a transition from 3 dimensional (3D) to 2D and then 1D as the nanowire mean widths are reduced from 12 to 4 nm. The importance of high quality surface passivation is demonstrated by a lack of significant donor deactivation, resulting in neutral impurity scattering ultimately limiting the electronic performance. The results indicate the important parameters requiring optimization when fabricating nanowires with atomic dimensions. PMID- 25299792 TI - Tactile intervention as a novel technique in improving body stability in healthy elderly and elderly with diabetes. AB - BACKGROUND: Body sway increases in the elderly because of normal aging and high incidence of disease such as diabetes. Prevalence of sway is greater in the elderly with diabetes because of damage to the central and peripheral nervous systems. Increase in body sway is associated with an elevated risk of falling. Falling is one of the major causes of morbidity and mortality in the elderly. The purpose of this study was to develop a new technique to improve body stability and decrease body sway in the elderly people with or without diabetes. SUBJECTS AND METHODS: Twenty-two subjects--12 elderly (mean age, 75.5+/-7.3 years) and 10 age-matched elderly with diabetes (mean age, 72.5+/-5.3 years)--were recruited for this study. Subjects received tactile feedback as a tingling sensation resulting from electrical stimulation triggered by body sway. RESULTS: The results showed a significant reduction in body sway in the elderly while standing on foam with eyes open (1.0+/-0.31 vs. 1.9+/-0.8; P=0.006) and eyes closed (1.8+/ 0.7 vs. 3.3+/-1.5; P=0.001). In the group with diabetes, there was a significant reduction in body sway while standing on foam with eyes closed (1.4+/-0.5 vs. 2.3+/-0.8; P=0.045) but not with eyes open. CONCLUSIONS: In this small study, this technique offers a new tool for training people with diabetes and elderly people to improve body stability and balance. PMID- 25299793 TI - Tenax as sorption sink for in vitro bioaccessibility measurement of polycyclic aromatic hydrocarbons in soils. AB - Physiologically based in vitro methods have been developed to measure bioaccessibility of organic contaminants in soils. However, bioaccessibility of hydrophobic organic contaminants (HOCs) can be underestimated by in vitro tests if gastrointestinal (GI) solution fails to provide sufficient sorption sink for HOCs. To circumvent this drawback, Tenax was included in GI solution as sorption sink to trap mobilized HOCs and maintain the desorption gradient between soil and GI solution. Polycyclic aromatic hydrocarbons (PAHs) were selected as target HOCs, and physiologically based extraction test (PBET) was selected as the in vitro method. Inclusion of Tenax in GI solution increased bioaccessibility of PAHs in five spiked soils from 8.25-20.8% to 55.7-65.9% and the bioaccessibility of PAHs in a field contaminated soil from 3.70-6.92% to 16.3-31.0%. Our results demonstrated the effectiveness of Tenax as sorption sink to enhance PAH mobilization in bioaccessibility measurement in soils. PMID- 25299794 TI - Lipid-content-normalized polycyclic aromatic hydrocarbons (PAHs) in the xylem of conifers can indicate historical changes in regional airborne PAHs. AB - The temporal variation of polycyclic aromatic hydrocarbons (PAHs) concentrations as well as the lipid content in the xylem of Masson pine trees sampled from the same site were determined and compared with the days of haze occurrence and with the historical PAHs reported in sedimentary cores. The patterns of the lipid content as well as the PAH concentrations based on the xylem dry weight (PAHs-DW) decreased from the heartwood to the sapwood. The trajectories of PAHs normalized by xylem lipid content (PAHs-LC) coincided well with the number of haze-occurred days and were partly similar with the historical changes in airborne PAHs recorded in the sedimentary cores. The results indicated that PAHs-LC in the xylem of conifers might reliably reflect the historical changes in airborne PAHs at a regional scale. The species-specificity should be addressed in the utility and application of dendrochemical monitoring on historical and comparative studies of airborne PAHs. PMID- 25299796 TI - Clinical impact of 3-dimensional balanced turbo-field-echo magnetic resonance cholangiopancreatography at 3 T: prospective intraindividual comparison with 3 dimensional turbo-spin-echo magnetic resonance cholangiopancreatography. AB - OBJECTIVE: The objective of this study was to evaluate the clinical utility of 3 dimensional (3D) balanced turbo-field-echo (BTFE) magnetic resonance cholangiopancreatography (MRCP) with gate and track acquisition at 3 T. METHODS: Using a 3-T unit, we subjected 52 consecutive patients to 3D BTFE MRCP with the navigator-gated technique and 3D turbo-spin-echo volume isotropic T2-weighted acquisition (VISTA) MRCP with the navigator-triggered technique. Two radiologists independently rated the image quality and visibility of the right and left hepatic duct, cystic duct, common bile duct, gallbladder, and main pancreatic duct using a 4-point scale. The signal-to-noise ratio, contrast-to-noise ratio, and the acquisition time were evaluated by quantitative analysis. RESULTS: The visual scores of the cystic duct, common bile duct, gallbladder, and overall image quality were significantly higher for BTFE than VISTA MRCP (P < 0.01). The score for the main pancreatic duct was significantly higher with VISTA MRCP (P < 0.01). The image acquisition time was significantly shorter with BTFE than VISTA MRCP (139.8 +/- 45.4 vs 416.9 +/- 108.3 seconds, P < 0.01). There was no significant difference in signal-to-noise ratio and contrast-to-noise ratio. CONCLUSIONS: Three-dimensional BTFE MRCP yields significantly better image quality and visibility of large biliary structures than VISTA MRCP at a significantly shorter acquisition time. Volume isotropic T2-weighted acquisition MRCP provides detailed information on the main pancreatic duct that tends to be obscure on the 3D BTFE sequence. PMID- 25299797 TI - Relationship between the position of the mental foramen and the anterior loop of the inferior alveolar nerve as determined by cone beam computed tomography combined with mimics. AB - OBJECTIVE: The position of the mental foramen and the anterior loop length of the inferior alveolar nerve serve as important anatomical landmarks for surgical procedures in the anterior mandibular region. The purpose of this study was to determine the relationship between the anterior loop of the inferior alveolar nerve and the mental foramen by combining cone beam computed tomography and Mimics, a software used to construct 3-dimensional (3D) interactive models of anatomical structures. METHODS: Cone beam computed tomography images from a total of 60 patients were obtained and studied using GALAXY viewer or were imported into Mimics. The anterior loop of the inferior alveolar nerve was reconstructed 3 dimensionally, and then relevant parameters were measured. RESULTS: The parameters were measured, and their values include mean (SD) anterior loop length, 1.16 (1.78) mm; anterior loop angle, 19.13 (26.89) degrees; inferior alveolar canal diameter, 3.01 (0.67) mm; height of the inferior alveolar canal, 10.32 (1.56) mm; 2-dimensional mental foramen diameter, 2.97 (0.61) mm; 3D mental foramen diameter, 2.95 (0.59) mm; 2-dimensional vertical height of the mental foramen, 14.67 (1.67) mm; and 3D vertical height of the mental foramen, 14.61 (1.69) mm. The mental foramen was located apically between the first and second premolars in 51.67% and below the second premolar in 40.83% of the cases. CONCLUSIONS: A relationship was observed between the location of the mental foramen and the presence of the anterior loop of the inferior alveolar nerve. We highlight the effectiveness of cone beam computed tomography and 3D reconstruction in the identification of important anatomical structures relevant for preoperative assessment for surgical procedures in the anterior region of the mandible. PMID- 25299795 TI - A solid-phase extraction method for rapidly determining the adsorption coefficient of pharmaceuticals in sewage sludge. AB - The partitioning of pharmaceuticals in the environment can be assessed by measuring their adsorption coefficients (Kd) between aqueous and solid phases. Measuring this coefficient in sewage sludge gives an indication of their partitioning behaviour in a wastewater treatment plant and hence contributes to an understanding of their subsequent fate. The regulatory approved method for measuring Kd in sewage sludge is the US Environmental Protection Agency's Office of Prevention, Pesticides and Toxic Substances (OPPTS) guideline 835.1110, which is labour intensive and time consuming. We describe an alternative method for measuring the Kd of pharmaceuticals in sewage sludge using a modified solid-phase extraction (SPE) technique. SPE cartridges were packed at different sludge/PTFE ratios (0.4, 6.0, 24.0 and 40.0% w/w sludge) and eluted with phosphate buffer at pH 7.4. The approach was tested initially using three pharmaceuticals (clofibric acid, diclofenac and oxytetracycline) that covered a range of Kd values. Subsequently, the sorption behaviour of ten further pharmaceuticals with varying physico-chemical properties was evaluated. Results from the SPE method were comparable to those of the OPPTS test, with a correlation coefficient of 0.93 between the two approaches. SPE cartridges packed with sludge and PTFE were stable for up to one year; use within one month reduced variability in measurements (to a maximum of 0.6 log units). The SPE method is low-cost, easy to use and enables the rapid measurement of Kd values for a large number of chemicals. It can be used as an alternative to the more laborious full OPPTS test in environmental fate studies and risk assessments. PMID- 25299798 TI - Breast ultrasound elastography and magnetic resonance imaging of fibrotic changes of breast disease: correlations between elastography findings and pathologic and short Tau inversion recovery imaging results, including the enhancement ratio and apparent diffusion coefficient. AB - PURPOSE: Ultrasound (US) elastography provides information regarding tissue hardness and is expected to become a novel diagnostic tool for breast disease. In contrast, magnetic resonance (MR) images reflect the tissue characteristics. Fibrosis of the stroma of breast diseases may affect their hardness. We investigated the correlation among elasticity score (ES) and signal intensity of short Tau inversion recovery MR images, enhancement ratio, apparent diffusion coefficient (ADC), and the fibrosis in the breast lesions. MATERIALS AND METHODS: We reviewed the findings of US elastography and MR imaging from 41 consecutive patients with breast lesions (25 invasive ductal carcinoma, 3 fibroadenoma, 1 phyllodes tumor, 2 ductal hyperplasia, 2 primary malignant lymphoma, 3 mastopathy, 1 metastasis, 1 tubular adenoma, 1 ductal carcinoma in situ, 1 diabetic mastopathy, and 1 intraductal papilloma). In each patient, elastography images were classified based on Tsukuba ES. We calculated the ratio of signal intensity of the lesion to the muscle on short Tau inversion recovery images (L/M ratio), enhancement ratio of early to precontrast and early to delayed images, and ADC for each lesion. The ES and MR findings were correlated with the degree of fibrosis (based on Masson trichrome stain). RESULTS: The ES significantly correlated with the L/M ratio (P = 0.0306) and the ADC (P = 0.0256). The stromal fibrosis also correlated with ES (P = 0.0023), the L/M ratio (P = 0.0344), and enhancement ratio of the early-to-delayed images (P = 0.049). CONCLUSIONS: The ES and L/M ratio are correlated significantly with each other, and they are correlated with the fibrosis. These results suggest that they will provide the information on the fibrosis and may help the diagnosis of breast lesions. PMID- 25299800 TI - In vitro carcinogenisis: guide to the literature, recent advances and laboratory procedures. AB - PREFACE: In the Fall 1974, plans for a "Workshop on In Vitro Chemical Carcinogenesis" were initiated at the suggestion of Drs. Umberto Saffiotti and I. Bernard Weinstein and developed together with Dr. Donald W. King as part of the conferences held at the Given Instituteof Pathobiology, University of Colorado, Aspen. It was felt that this was an important research area on which to hold an initial small workshop that would bring together most of the leading investigatorsin the field, at a time when several laboratories were attempting to establish criteria for in vitro neoplastic cell transformation following chemical treatment. PMID- 25299799 TI - Coronary computed tomographic angiography in coronary artery bypass grafts: comparison between low-concentration Iodixanol 270 and Iohexol 350. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility of low concentration iso-osmolar Iodixanol 270 compared with Iohexol 350 in patients with coronary artery bypass grafts (CABGs) undergoing coronary computed tomographic angiography (CCTA). METHODS: A total of 80 consecutive patients undergoing CABG follow-up with the use of CCTA were prospectively enrolled, with 40 patients assigned to Iodixanol 270 and 40 patients assigned to Iohexol 350. In both groups, the contrast medium was injected at an injection rate of 4.5 mL/s in the patients with a body mass index of greater than 24 kg/m2 and 3.5 mL/s in the patients with a body mass index of 24 kg/m2 or lower. The contrast volume was determined by the flow rate and scan time. Image quality score and visualization of bypass grafts were evaluated. Subjective assessment of image quality for each coronary artery segment was determined using a 4-point grading scale by 2 reviewers, whereas objective evaluation of image quality was conducted by measuring the mean CT attenuation values (hounsfield unit [HU]) in terms of SD, contrast-noise ratio, and signal-noise ratio in the ascending aorta. RESULTS: The mean (SD) contrast volume for the Iodixanol 270 and Iohexol 350 groups was 66.28 (12.00) and 64.98 (8.12) mL, respectively, with no significant difference (P = 0.57). The mean (SD) CT attenuation value in the Iodixanol 270 group was 414.72 (101.47), which was lower than in the Iohexol 350 group, which was 478.85 (108.73) (P = 0.01). The subjective image quality for the Iodixanol 270 group was superior to that for the Iohexol 350 group in the arterial graft vessels (P = 0.027), whereas there was no significant difference between the 2 groups in the venous graft vessels (P = 0.377). There was no significant difference in terms of SD of the ascending aorta, signal-noise ratio, and contrast-noise ratio between the 2 groups. CONCLUSIONS: Low-concentration iso-osmolar Iodixanol 270 provides image quality comparable with that of Iohexol 350, allowing diagnostic CCTA follow-up of patients with CABGs. PMID- 25299802 TI - An experimental and computational investigation into the gas-phase acidities of tyrosine and phenylalanine: three structures for deprotonated tyrosine. AB - Using mass spectrometry and correlated molecular orbital theory, three deprotonated structures were revealed for the amino acid tyrosine. The structures were distinguished experimentally by ion/molecule reactions involving proton transfer and trimethylsilyl azide. Gas-phase acidities from proton transfer reactions and from G3(MP2) calculations generally agree well. The lowest energy structure, which was only observed experimentally using electrospray ionization from aprotic solvents, is deprotonated at the carboxylic acid group and is predicted to be highly folded. A second unfolded carboxylate structure is several kcal/mol higher in energy and primarily forms from protic solvents. Protic solvents also yield a structure deprotonated at the phenolic side chain, which experiments find to be intermediate in energy to the two carboxylate forms. G3(MP2) calculations indicate that the three structures differ in energy by only 2.5 kcal/mol, yet they are readily distinguished experimentally. Structural abundance ratios are dependent upon experimental conditions, including the solvent and accumulation time of ions in a hexapole. Under some conditions, carboxylate ions may convert to phenolate ions. For phenylalanine, which lacks a phenolic group, only one deprotonated structure was observed experimentally when electrosprayed from protic solvent. This agrees with G3(MP2) calculations that find the folded and unfolded carboxylate forms to differ by 0.3 kcal/mol. PMID- 25299801 TI - BlmB and TlmB provide resistance to the bleomycin family of antitumor antibiotics by N-acetylating metal-free bleomycin, tallysomycin, phleomycin, and zorbamycin. AB - The bleomycin (BLM) family of glycopeptide-derived antitumor antibiotics consists of BLMs, tallysomycins (TLMs), phleomycins (PLMs), and zorbamycin (ZBM). The self resistant elements BlmB and TlmB, discovered from the BLM- and TLM-producing organisms Streptomyces verticillus ATCC15003 and Streptoalloteichus hindustanus E465-94 ATCC31158, respectively, are N-acetyltransferases that provide resistance to the producers by disrupting the metal-binding domain of the antibiotics required for activity. Although each member of the BLM family of antibiotics possesses a conserved metal-binding domain, the structural differences between each member, namely, the bithiazole moiety and C-terminal amine of BLMs, have been suggested to instill substrate specificity within BlmB. Here we report that BlmB and TlmB readily accept and acetylate BLMs, TLMs, PLMs, and ZBM in vitro but only in the metal-free forms. Kinetic analysis of BlmB and TlmB reveals there is no strong preference or rate enhancement for specific substrates, indicating that the structural differences between each member of the BLM family play a negligible role in substrate recognition, binding, or catalysis. Intriguingly, the zbm gene cluster from Streptomyces flavoviridis ATCC21892 does not contain an N-acetyltransferase, yet ZBM is readily acetylated by BlmB and TlmB. We subsequently established that S. flavoviridis lacks the homologue of BlmB and TlmB, and ZbmA, the ZBM-binding protein, alone is sufficient to provide ZBM resistance. We further confirmed that BlmB can indeed confer resistance to ZBM in vivo in S. flavoviridis, introduction of which into wild-type S. flavoviridis further increases the level of resistance. PMID- 25299803 TI - Phytoremediation of phenanthrene by transgenic plants transformed with a naphthalene dioxygenase system from Pseudomonas. AB - Genes from microbes for degrading polycyclic aromatic hydrocarbons (PAHs) are seldom used to improve the ability of plants to remediate the pollution because the initiation of the microbial degradation of PAHs is catalyzed by a multienzyme system. In this study, for the first time, we have successfully transferred the complex naphthalene dioxygenase system of Pseudomonas into Arabidopsis and rice, the model dicot and monocot plant. As in bacteria, all four genes of the naphthalene dioxygenase system can be simultaneously expressed and assembled to an active enzyme in transgenic plants. The naphthalene dioxygenase system can develop the capacity of plants to tolerate a high concentration of phenanthrene and metabolize phenanthrene in vivo. As a result, transgenic plants showed improved uptake of phenanthrene from the environment over wild-type plants. In addition, phenanthrene concentrations in shoots and roots of transgenic plants were generally lower than that of wild type plants. Transgenic plants with a naphthalene dioxygenase system bring the promise of an efficient and environmental-friendly technology for cleaning up PAHs contaminated soil and water. PMID- 25299805 TI - The IMEA project: an intervention based on microfinance, entrepreneurship, and adherence to treatment for women with HIV/AIDS living in poverty. AB - A number of issues affect adherence to treatment and quality of life among women living with HIV/AIDS. In particular, women living in poverty have a higher risk of mortality due to their vulnerable conditions and socioeconomic exclusion. The objective of this study was to evaluate the effectiveness of an intervention that combines microfinance, entrepreneurship and adherence to treatment (IMEA) for women with HIV/AIDS and living in poverty in Cali, Colombia. A pre-post research design without a control was utilized, and 48 women were included in the study. The evaluation showed effectiveness of the program in the majority of the results (knowledge of HIV and treatment, adherence to treatment, self-efficacy, and the formation of a microenterprise) (p < 0.001); the global indicator increased from 28.3% to 85.5% (p < 0.001). The findings of this study demonstrate that the intervention was partially effective; the health outcomes showed beneficial effects. However, at the end of the study and throughout the follow-up phase, only one third of the participants were able to develop and maintain a legal operating business. It is concluded that the IMEA project should be tested in other contexts and that its consequent results should be analyzed; so it could be converted into a large scale public health program. PMID- 25299804 TI - Barbershop Talk With Brothers: using community-based participatory research to develop and pilot test a program to reduce HIV risk among Black heterosexual men. AB - There is a need for feasible, evidence-based interventions that support HIV risk reduction among heterosexual Black men. In this article, we describe the process for development of the Barbershop Talk With Brothers (BTWB) program and evaluation. The BTWB program is a theoretically grounded and community-based HIV prevention program that seeks to improve individual skills and motivation to decrease sexual risk, and that builds men's interest in and capacity for improving their community's health. Formative data collection included barbershop observations and barber focus groups, brief behavioral risk assessments of men in barbershops, and focus groups and individual interviews. Based on this information and in consultation with our steering committee, we developed the BTWB program and accompanying program evaluation. From April through November 2011, 80 men were recruited and completed a baseline assessment of a pilot test of the program; 78 men completed the program and 71 completed a 3-month assessment. The pilot evaluation procedures were feasible to implement, and assessments of pre- and post-test measures indicate that key behavioral outcomes and proposed mediators of those outcomes changed in hypothesized directions. Specifically, attitudes and self-efficacy toward consistent condom use improved, and respondents reported lower levels of sexual risk behavior from baseline to follow-up (all p < 0.05). Perceptions of community empowerment also increased (p = 0.06). While HIV stigma decreased, this difference did not reach statistical significance. Our approach to community-engaged program development resulted in an acceptable, feasible approach to reaching and educating heterosexual Black men about HIV prevention in community settings. PMID- 25299807 TI - The development and implementation of the national evaluation strategy of Access to Care, a multi-site linkage to care initiative in the United States. AB - The Access to Care (A2C) is a multi-site initiative that seeks to increase the access to and retention in effective HIV healthcare and support services by people living with HIV across the United States. As the initiative implemented evidence-based programs in new settings with diverse populations, it was important to document these innovative efforts to contribute to the evidence base for best practices. In a partnership between Johns Hopkins University, AIDS United, and the A2C sites, a national evaluation strategy was developed and implemented to build knowledge about how linkage to care interventions could be most effectively implemented within the context of local, real-world settings. This article provides an overview of the efforts to develop and implement a national monitoring and evaluation strategy for a multi-site initiative. The findings may be of utility for other HIV interventions that are seeking to incorporate a monitoring and evaluation component into their efforts. PMID- 25299806 TI - The effect of a local change team intervention on staff attitudes towards HIV service delivery in correctional settings: a randomized trial. AB - The National Criminal Justice Drug Abuse Treatment Studies research program conducted cluster randomized trials to test an organizational process improvement strategy for implementing evidence-based improvements in HIV services for preventing, detecting, and/or treating HIV for individuals under correctional supervision. Nine research centers conducted cluster randomized trials in which one correctional facility used a modified Network for Improvement of Addiction Treatment (NIATx) change team approach to implementing improved HIV services and the other facility used their own approach to implement the improved HIV services. This paper examines whether the intervention increased the perceived value of HIV services among staff of correctional and community HIV organizations. Baseline and follow-up measures of the perceived acceptability, feasibility, and organizational support for implementing HIV service improvements were collected from correctional, medical, and community HIV treatment staff. Results indicated that the perceived acceptability and feasibility of implementing HIV services improved among staff in the facilities using the modified NIATx change team approach as compared to staff in the comparison facilities. PMID- 25299808 TI - Avatars travel for free: virtual access to evidence-based intervention training and capacity building. AB - Virtual facilitator trainings have the potential to accelerate the dissemination of evidence-based interventions by increasing accessibility and affordability. We explore the feasibility and acceptability of translating facilitator trainings of !Cuidate!, an evidence-based sexual risk intervention for Latino youth, to a multi-user virtual environment (Second Life). We describe the adaptation process and compare participant ratings of face-to-face (n = 35) and Second Life trainings (n = 26). Second Life participants reported that training resources, activities, and demonstrations were good/very good (97%, 88.5%, 94%). While face to-face participants rated training process outcomes significantly higher than those in Second Life (p < 0.05), these differences may not be practically significant given high ratings overall. Results suggest that virtual trainings are an acceptable and feasible option for training community facilitators on evidence-based interventions. This study contributes to the development of trainings necessary to disseminate and implement evidence-based interventions and is an important effort in providing end-users with access to trainings in order to provide needed community services. PMID- 25299809 TI - Reductions in HIV prevalence rates among substance-using men who have sex with men in Los Angeles County, 2008-2011. AB - An outreach program performed street encounters with 5,599 unique substance-using MSM from January 2008 through December 2011. HIV prevalence reduced from 20.2% in the first half of 2008 to 8.1% in the second half of 2011. Older, gay-identified, non-Hispanic/Latino participants were each more likely to report a HIV-positive serostatus. When controlling for these cofactors, robust log-Poisson analysis revealed that each additional day of methamphetamine (RRR = 1.03; 95% CI [1.02, 1.03]) and/or marijuana (RRR = 1.01; 95% CI [1.01, 1.02]) use in the previous 30 days, injection drug use at any point in their lifetime (RRR = 2.01; 95% CI [1.70, 2.37]), and/or unprotected anal intercourse with another male in the previous 30 days (RRR = 1.48; 95% CI [1.29, 1.71]) were associated with HIV positive status. When controlling for all these cofactors, the probability of reporting a HIV-positive status reduced an estimated 9% (95% CI [6%, 12%]) every six months throughout the reporting period. Self-reported HIV prevalence decreased among this sample of substance-using MSM in LAC from 2008 to 2011. PMID- 25299811 TI - Magnetic anisotropy and chirality of frustrated Cr nanostructures on Au(1 1 1). AB - By using a fully relativistic embedded cluster Green's function technique we investigated the magnetic anisotropy properties of four different compact Cr trimers (equilateral triangles) and Cr mono-layers deposited on the Au(1 1 1) surface in both fcc and hcp stackings. For all trimers the magnetic ground state was found to be a frustrated 120 degrees Neel configuration. Applying global spin rotations to the magnetic ground state, predictions of an appropriate second order spin Hamiltonian were reproduced with high accuracy by first principles calculations. For the Cr trimers with adjacent Au atoms in similar geometry, we obtained similar values for the in-plane and out-of-plane anisotropy parameters, however, the Dzyaloshinskii-Moriya (DM) interactions appeared to differ remarkably. For two kinds of trimers we found an unconventional magnetic ground state showing 90 degrees in-the-plane rotation with respect to the high symmetry directions. Due to higher symmetry, the in-plane anisotropy term was missing for the mono-layers and distinctly different DM interactions were obtained for the different stackings. The chiral degeneracy of the Neel configurations was lifted by an energy less than 2 meV for the trimers, while this value increased up to about 15 meV per 3 Cr atoms for the hcp packed mono-layer. PMID- 25299810 TI - Stigma, social support, and treatment adherence among HIV-positive patients in Chiang Mai, Thailand. AB - Our study assessed the influence of HIV-related stigma on treatment adherence among people living with HIV in Chiang Mai, Thailand, and whether social support had a moderating effect on this relationship. We recruited 128 patients living with HIV from Sansai Hospital, a community hospital in Chiang Mai, Thailand, and collected data through structured interviews. All forms of HIV-related stigma considered in this study (personalized experience, disclosure, negative self image, and public attitudes) were negatively correlated with adherence to anti retroviral regimens. Multiple linear regression indicated that total HIV-related stigma was more predictive of treatment adherence than any individual stigma type, after adjusting for socio-demographic and health characteristics. Tests of interaction showed that social support did not appear to moderate the association between HIV stigma and treatment adherence. Our findings suggest that community and government efforts to improve public perceptions about people living with HIV might promote treatment adherence behaviors among HIV-positive patients. PMID- 25299812 TI - From commonsense to science, and back: the use of cognitive concepts in neuroscience. AB - Commonsense cognitive concepts (CCCs) are the concepts used in daily life to explain, predict and interpret behaviour. CCCs are also used to convey neuroscientific results, not only to wider audiences but also to the scientific inner circle. We show that translations from CCCs to brain activity, and from brain data to CCCs are made in implicit, loose and unsystematic ways. This results in hard to connect data as well as possibly unwarranted extrapolations. We argue that the cause of these problems is a covert adherence to a position known in philosophy of mind as 'mental realism'. The most fruitful way forward to a clearer and more systematic employment of CCCs in cognitive neuroscience, we argue, is to explicitly adopt interpretivism as an alternative for mental realism. An interpretative stance will help to avoid conceptual confusion in cognitive science and implies caution when it comes to big conclusions about CCCs. PMID- 25299813 TI - It takes a village to improve care. PMID- 25299814 TI - A descriptive survey study to evaluate the relationship between socio-demographic factors and quality of life in patients with a permanent colostomy. AB - The impact of having a stoma on quality of life is increasingly recognized and studied. A descriptive survey study was conducted between January 2006 and December 2011 among 44 patients (18 women, 26 men) with a permanent stoma receiving care at the Kartal Training and Research Hospital, Istanbul, Turkey, to evaluate socio-demographic factors that may affect the quality of life in Turkish Muslim patients with an enteral stoma. A socio-demographic questionnaire, a 10- item Religious Orientation Scale (Modified Allport-Ross ROS), and the Medical Outcomes Study Short Form 36 Quality of Life survey were administered by a stoma therapy nurse at least 6 months after completion of all surgical and oncological treatments. The mean follow-up period was 15.3 +/- 9.7 (range 6-44) months since completion of all treatments. Data were collected using paper/pencil instruments and entered for data analysis using Student's t-tests or one-way ANOVA univariate and multivariate analyses. No significant differences were observed for income, education level, surgical history, or religion score. Gender, geographic region, and household status were found independently related to quality of life in stoma patients. Female patients had significantly lower scores than males in general health perception (P = 0.049), role emotion (P = 0.02), mental health perception (P = 0.026), and mental component (P = 0.007). Patients living in a village (four) had significantly lower scores than patients living in a big city (33) in all scales (P <0.05 for all comparisons). Village-dwelling patents also had significantly lower scores than patients living in a town (seven) in physical function (P = 0.001), vitality (P = 0.012), social function (P = 0.003), and mental component scores (P = 0.021). Patients living alone (seven) had significantly lower scores than patients living with a partner (11) in three of eight scales (physical functioning [P <0.001], role-physical [P = 0.047], and bodily pain [P = 0.015]) and physical component scores (P <0.001); they also had significantly lower scores than patients living with their families (26) in four of eight scales (physical functioning [P <0.001], role-physical [P = 0.032], bodily pain [P = 0.02], and general health perception [P=0.036]) and physical component scores (P <0.001). Although these findings provide evidence for the relationship between some socio-demographic factors on quality of life of patients with a stoma, the results of the study should be interpreted with caution; multicenter, prospective, controlled studies are needed to substantiate and clarify the relationships among these variables. PMID- 25299815 TI - A systematic review and meta-analysis of randomized controlled trials comparing interventions for peristomal skin care. AB - Standard skin care procedures for percutaneous endoscopic gastrostomy (PEG) tubes and peristomal skin care for colostomy and ileostomy patients are not always sufficient to prevent peristomal skin problems. A systematic review and meta analysis of randomized controlled trials (RCTs) was conducted to compare the effectiveness of standard peristomal skin care to adjunctive techniques or barriers (including glycogel dressings, gelatin- and pectin-based skin barriers, glycerin hydrogel wound dressing, Acacia senegal fiber pockets, hydrocolloid powder crusting, and German chamomile) to manage or treat patients with a stoma. Using systematic literature search techniques, all healthcare databases were searched up through September 2014. No language restrictions were applied. Studies were included if they met criteria for published RCTs or quasi-RCTs that evaluated the outcome of standardized peristomal skin care and other adjunctive techniques or barriers used among patients with a stoma or PEG tube. A meta analysis was performed to calculate a pooled effect size by using random-effect models for the primary (skin irritation/reaction) and secondary (length of pouch wear time) outcomes. Six RCTs comprising 418 total patients were identified. Four evaluated the outcome of colostomy or ileostomy peristomal skin care, and no significant differences were detected in the incidence of skin problems (RR 0.67; 95% CI: 0.31-1.41). In the two studies that included length of pouch wear time, no significant differences were observed (RR 0.48; 95% CI: 0.03-7.97). No significant differences were seen in the rate of skin irritations of gastrostomy patients (RR 0.56; 95% CI: 0.20-1.59), but the difference in treatment outcomes of peristomal damage in patients with a colostomy was significant (P = 0.01). The limited number of studies, study quality, heterogeneity of variability in peristomal care strategies and techniques, clinical factors, and nonuniform reporting of clinical parameters contributed to the heterogeneity among the trials. Well-designed RCTs are needed to investigate the efficacy of various barriers and techniques for peristomal skin care and to help develop evidence based standards of caring for the skin of patients with a colostomy, ileostomy, or gastrostomy. PMID- 25299816 TI - The adjustments experienced by persons with an ostomy: an integrative review of the literature. AB - The person with an ostomy may focus on the negative aspects of the stoma rather than its function to the detriment of self-image, acceptance of a new lifestyle, and ability to self-care. The purpose of this integrative literature review was to explore factors involved in the adaption process of persons with a gastrointestinal stoma with a focus on the role of nonspecialist professional nurses in the process. The authors searched the databases of the Virtual Health Library, the Latin American and Caribbean of Health Sciences Information System, the Scientific Electronic Library Online, the Spanish Bibliographic Index of Health Sciences, International Literature on Health Sciences (MEDLINE), and the Cochrane Library using the keywords ostomy, adaption, and nursing for full text articles in all languages published between 2008 and 2013. Of the 612 articles identified, 21 were not duplicates and met the inclusion criteria of availability of full text, published in the past 5 years, indexed, and covering the topic of stoma adaption; this literature was analyzed using Bardin's thematic analysis. Three categories emerged: experiences and adaption strategies employed by the person with a stoma, the role of the care provider, and education as a tool in healthcare. Persons with a stoma need time and support from caregivers, family, and friends to adjust to the changes and adapt to having a stoma. This includes the ability to overcome the stigma of appearance and activities involving social interaction. Caregivers and health professionals need to serve as information resources while encouraging care autonomy. The more informed the patient, the smoother the adaption process. The literature also suggests nursing education may affect caregiving. Further research to elucidate the adaption experienced by each person with an ostomy is needed to help the multidisciplinary team plan care appropriately. PMID- 25299817 TI - Synthetic advances in macrosphelides: natural anticancer agents. AB - Total synthesis of macrosphelides is summarized. Synthetic approaches contain the preparation of key fragments and the final ring-closure reaction for unique 16- or 15-membered macrolactone skeletons. PMID- 25299818 TI - Efficient biotransformation of polysialogangliosides for preparation of GM1 by Cellulosimicrobium sp. 21. AB - A new ganglioside transformed strain isolated from soil was identified as Cellulosimicrobium sp. 21. It produced a sialidase which transformed polysialo gangliosides GD1 and GT1 into a monosialoterahexosylganglioside, i.e., ganglioside GM1. The sialidase had both NeuAc-alpha-2,3- and NeuAc-alpha-2,8 sialidase activity without producing asiolo-GM1. The optimum conditions were evaluated and it was found that the transformation was optimally performed at 30 degrees C and pH 7.0. The substrate should be added at the beginning of the reaction and the concentration of substrate was 3% (w/v). Under these optimum conditions, Cellulosimicrobium sp. 21 converted GD1 and GT1 into GM1 in inorganic medium in a 5 L bioreactor with the recovery rate of 69.3%. The product contained 50.3% GM1 and was purified on silica to give the product with 95% of GM1 with a recovery rate of 30.5%. Therefore, Cellulosimicrobium sp. 21 has potential to be applied in the production of GM1 in the pharmaceutical industry. PMID- 25299819 TI - Ethanolic extract of Taheebo attenuates increase in body weight and fatty liver in mice fed a high-fat diet. AB - We evaluated whether intake of an ethanolic extract of Taheebo (TBE) from Tabebuia avellanedae protects against body weight increase and fat accumulation in mice with high-fat diet (HFD)-induced obesity. Four-week old male C57BL/6 mice were fed a HFD (25% fat, w/w) for 11 weeks. The diet of control (HFD) mice was supplemented with vehicle (0.5% sodium carboxymethyl cellulose by gavage); the diet of experimental (TBE) mice was supplemented with TBE (150 mg/kg body weight/day by gavage). Mice administered TBE had significantly reduced body weight gain, fat accumulation in the liver, and fat pad weight, compared to HFD mice. Reduced hypertrophy of fat cells was also observed in TBE mice. Mice administered TBE also showed significantly lower serum levels of triglycerides, insulin, and leptin. Lipid profiles and levels of mRNAs and proteins related to lipid metabolism were determined in liver and white adipose tissue of the mice. Expression of mRNA and proteins related to lipogenesis were decreased in TBE administered mice compared to mice fed HFD alone. These results suggest that TBE inhibits obesity and fat accumulation by regulation of gene expression related to lipid metabolism in HFD-induced obesity in mice. PMID- 25299820 TI - Epoxidized vegetable oils plasticized poly(lactic acid) biocomposites: mechanical, thermal and morphology properties. AB - Plasticized poly(lactic acid) PLA with epoxidized vegetable oils (EVO) were prepared using a melt blending method to improve the ductility of PLA. The plasticization of the PLA with EVO lowers the Tg as well as cold-crystallization temperature. The tensile properties demonstrated that the addition of EVO to PLA led to an increase of elongation at break, but a decrease of tensile modulus. Plasticized PLA showed improvement in the elongation at break by 2058% and 4060% with the addition of 5 wt % epoxidized palm oil (EPO) and mixture of epoxidized palm oil and soybean oil (EPSO), respectively. An increase in the tensile strength was also observed in the plasticized PLA with 1 wt % EPO and EPSO. The use of EVO increases the mobility of the polymeric chains, thereby improving the flexibility and plastic deformation of PLA. The SEM micrograph of the plasticized PLA showed good compatible morphologies without voids resulting from good interfacial adhesion between PLA and EVO. Based on the results of this study, EVO may be used as an environmentally friendly plasticizer that can improve the overall properties of PLA. PMID- 25299821 TI - Characterization and quantification of the compounds of the ethanolic extract from Caesalpinia ferrea stem bark and evaluation of their mutagenic activity. AB - Caesalpinia ferrea Martius has traditionally been used in Brazil for many medicinal purposes, such as the treatment of bronchitis, diabetes and wounds. Despite its use as a medicinal plant, there is still no data regarding the genotoxic effect of the stem bark. This present work aims to assess the qualitative and quantitative profiles of the ethanolic extract from the stem bark of C. ferrea and to evaluate its mutagenic activity, using a Salmonella/microsome assay for this species. As a result, a total of twenty compounds were identified by Flow Injection Analysis Electrospray Ionization Ion Trap Mass Spectrometry (FIA-ESI-IT-MS/MSn) in the ethanolic extract from the stem bark of C. ferrea. Hydrolyzable tannins predominated, principally gallic acid derivatives. The HPLC DAD method was developed for rapid quantification of six gallic acid compounds and ellagic acid derivatives. C. ferrea is widely used in Brazil, and the absence of any mutagenic effect in the Salmonella/microsome assay is important for pharmacological purposes and the safe use of this plant. PMID- 25299822 TI - Two new xanthones from the pericarp of Garcinia mangostana. AB - Two new xanthones, designated garcimangosxanthone F (1) and garcimangosxanthone G (2), were isolated from the EtOAc-soluble fraction of ethanolic extract from the pericarp of Garcinia mangostana. Their structures were established as 1,6,7 trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6',6' dimethylpyrano[2',3':3,2]xanthone and 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8 (3-hydroxy-3-methylbutyl)-6',6'-dimethyl-4',5'-dihydropyrano[2',3':3,2]xanthone, respectively, on the basis of their 1D, 2D NMR and MS data interpretation. PMID- 25299823 TI - Wirelike charge transport dynamics for DNA-lipid complexes in chloroform. AB - The dynamics of charge separation and charge recombination have been determined for lipid complexes of DNA capped hairpins possessing stilbene electron-acceptor and -donor chromophores separated by base-pair domains that vary in length and base sequence in chloroform solution by means of femtosecond time-resolved transient absorption spectroscopy. The results obtained for the DNA-lipid complexes are compared with those previously obtained in our laboratories for the same hairpins in aqueous buffer. The charge separation and charge recombination times for the lipid complexes are consistently much shorter than those determined in aqueous solution and are only weakly dependent on the number of base pairs separating the acceptor and donor. The enhanced rate constants for forward and return charge transport in DNA-lipid complexes support proposals that solvent gating is responsible, to a significant extent, for the relatively low rates of charge transport for DNA in water. Moreover, they suggest that DNA-lipid complexes may prove useful in the development of DNA-based molecular electronic devices. PMID- 25299824 TI - Symmetry-preserving mean field theory for electrostatics at interfaces. AB - We derive an instantaneous symmetry-preserving mean field equation relating the long-ranged component of the intermolecular interaction to an effective single particle potential. We verify the efficiency and accuracy of the symmetry preserving mean field approach to treat complex nonuniform electrostatics and foresee its application to study self-assembly and disassembly processes at interfaces in many computer simulations. PMID- 25299825 TI - The development of education indicators for measuring quality in the English speaking Caribbean: how far have we come? AB - Education evaluation has become increasingly important in the English-speaking Caribbean. This has been in response to assessing the progress of four regional initiatives aimed at improving the equity, efficiency, and quality of education. Both special interest groups and local evaluators have been responsible for assessing the progress of education and providing an overall synthesis and summary of what is taking place in the English-speaking Caribbean. This study employed content analysis to examine the indicators used in these education evaluation studies since the declaration of the Caribbean Plan of Action 2000 2015 to determine these indicators' appropriateness to the Caribbean context in measuring education progress. Findings demonstrate that the English-speaking Caribbean has made strides in operationalizing quality input, process, and output indicators; however quality outcome indicators beyond test scores are yet to be realized in a systematic manner. This study also compared the types of collaborative partnerships in conducting evaluation studies used by special interest groups and local evaluators and pinpointed the one that appears most suitable for special interest groups in this region. PMID- 25299826 TI - Care utilization and patient characteristics of veterans who misuse alcohol. AB - Substance abuse treatment utilization and patient characteristics of veterans (N = 167) drinking alcohol at risky levels at a Department of Veterans Affairs hospital were examined. Rates of brief intervention and specialty care were higher than those found in national samples in 2010, but fall short of recommended guidelines. Veterans receiving more care were older, lower-income, and less likely to be in a relationship. Care-receiving veterans had higher rates of mental health comorbidities and mental health treatment in the prior year for an issue other than substance use. Understanding patients' recent care history may help primary care providers to deliver care effectively. PMID- 25299827 TI - Method to estimate the complete and two-turn cochlear duct length. AB - HYPOTHESIS: Using a linear measurement of the cochlea on a single radiographic image can reliably estimate the complete and two-turn cochlear duct length (CDL) in a normal human temporal bone. BACKGROUND: CDL is measured from the middle of the round window to the helicotrema. Histologic studies have shown the length of the organ of Corti (OC) to range from 25 to 35 mm. CDL measurements, performed either radiographically or histologically, are quite tedious and time-consuming. We propose equations that can reliably estimate both two-turn and complete CDL using a single computed tomography (CT) image. METHODS: Prior studies of CDL, measured either histologically or radiographically, were reviewed, which yielded distributions of CDL measured at the OC and the lateral wall of the cochlea. Using Escude's third equation as a basis, we were able to extrapolate complete and two-turn CDL based on a CT scan measurement of the diameter of the basal turn (A). RESULTS: Using measurement A, the relationship of two-turn CDL measured at the OC is 2TL(oc) = 3.65(A-1) and for 2TL(i) = 3.65(A-0.7). The equation for estimation of complete CDL is CDL(oc) = 4.16A - 4 and for CDL(i) = 4.16A - 2.7. CONCLUSION: Using a single linear measurement from a CT scan image can reliably estimate the two-turn and complete CDLs in human temporal bones. The two-turn length represents the best compromise of cochlear coverage while minimizing intracochlear trauma for electrode insertions. PMID- 25299828 TI - Review of otorrhea microbiology: is there a pathogenic role of corynebacter? AB - OBJECTIVE: Identification of a causative pathogen in otologic infections assists in maximizing therapy efficacy particularly in refractory and chronic cases. Current standards for treatment of otologic infections focus on targeted species (spp.) that are assumed to be the most common pathogens. Corynebacterium spp. may play a pathogenic role but are not routinely speciated or included in antibiotic susceptibility analysis. Our objective is to investigate the prevalence and pathogenicity of nondiphtheroid Corynebacterium spp. in commonly encountered purulent and mucopurulent otologic infections. STUDY DESIGN: Retrospective case review. SETTING: Academic tertiary referral center. PATIENTS: Review of 140 microbiology cultures from adults and children presenting with purulent and mucopurulent otologic infections from 2010 to 2012. INTERVENTION(S): Clinical history, demographics, and microbiology cultures with speciation and antibiotic susceptibility analyses. MAIN OUTCOME MEASURE(S): Microbiologic speciation and census, species association with clinical characteristics, antibiotic susceptibility to oral and systemic agents, therapy frequency and agent selection. RESULTS: Corynebacterium spp. was the second most common bacteria isolated from patients with clinically significant otologic infections. Corynebacterium spp. were found in 24 (33.3%) unique patients with otologic infections and were the only pathogen isolated in six (8.33%) patients. Corynebacterium-positive infections were significantly associated with the use of hearing aids, a diagnosis of chronic granular myringitis, and less otalgia. Corynebacterium isolates were highly resistant to first-line fluoroquinolone therapy. The majority of patients with Corynebacterium-positive infections harbored at least one resistant strain, and patients with strains resistant to first-line topical therapy had a nonsignificant trend to an alteration in antibiotic therapy after antibiotic susceptibility data became available. CONCLUSION: Corynebacterium spp. may be underestimated in their potential to cause clinically significant otologic infections. Our results indicate a potential need for expanding surveillance for Corynebacterium spp. PMID- 25299830 TI - Pediatric cholesteatoma surgery using a single-staged canal wall down approach: results of a 5-year longitudinal study. AB - OBJECTIVE: To present the results of a 5-year longitudinal study in a pediatric population undergoing surgery for extensive cholesteatoma using a canal wall down (CWD) approach with obliteration. STUDY DESIGN: Prospective longitudinal study. PATIENTS: Children (<16 years) undergoing surgery for cholesteatoma (58 ears) between 1999 and 2013. INTERVENTIONS: Therapeutic. SETTING: District general hospital. MAIN OUTCOME MEASURES: (1) Residual, recurrence, and recidivist cholesteatoma rates at 5 years post-surgery; (2) postoperative hearing; (3) postoperative waterproofing of the ear; (4) number of subsequent ear surgery required. RESULTS: Fifty-five children (58 ears) contributed to the study. At 5 years, 16 of 58 (27.6%) had been lost to follow-up. Using Kaplan-Meier survival analysis, the residual rate after 5 years was 9.9% (95% CI: 3.8-24.4%), representing four residual cholesteatomas, and there were no recurrences detected. Using a cross-sectional analysis at 12 months of follow-up, the otorrhea risk was 0% and the risk of definitive waterproofing was 94.8%. There was a re-operation risk of 17.2% within 5 years which included second-stage ossiculoplasty. Regarding hearing, of the data available (n = 16), 10 children (62.5%) maintained their hearing (change between -10 and =10 dB), 2 (12.5%) had hearing gain (>10 dB), and 4 children (25%) had hearing reduction at 12 months postoperation. Four of 16 children (25%) had a postoperative hearing level of 30 dB or lower. CONCLUSION: The use of a CWD approach with obliteration of the mastoid cavity to surgically treat extensive cholesteatoma in children results in a low recurrence rate and high rate of a trouble-free ear in the long term. PMID- 25299829 TI - Altered autonomic regulation as a cardiovascular risk marker for patients with sudden sensorineural hearing loss. AB - OBJECTIVES: To measure autonomic nervous system function after idiopathic sudden sensorineural hearing loss (ISSHL). STUDY DESIGN: Diagnostic prospective cohort single-center study. SETTING: Tertiary referral university hospital. PATIENTS: Twenty-three adult patients with ISSHL and 10 normal-hearing control patients without ISSHL (CON) matched with respect to age, sex, hypertension, and medication. MAIN OUTCOME MEASURES: Bivariate analysis of autonomic regulation (ISSHL versus CON) using 30-minute heart rate (HR) and systolic and diastolic blood pressure (BP) time series at baseline, based on cardiovascular coupling, HR and BP regulatory patterns, high-resolution coupling analysis based on joint symbolic dynamics (High-Resolution Joint Symbolic Dynamics). INTERVENTION: No intervention. RESULTS: Multivariate discrimination between ISSHL and CON achieved values of area under the receiver operator characteristic curve = 95.5, sensitivity = 90.9%, and specificity = 88.9%. Independent from medication and hypertension increased the complexity of nonlinear HR regulation and reduced cardiovascular coupling of ISSHL patients and independent from hypertension altered nonlinear systolic and diastolic BP regulation. Coupling patterns are characterized by a less pronounced strong and fast decrease of systolic BP when HR increases and rapidly changes in ISSHL patients. Disturbed BP modulation and complexity by impaired baroreflex activities resulting in short-term BP fluctuations, altered peripheral resistance, and reduced cochlear blood flow. Increased values for the pulse wave velocity in the aorta and carotid-femoral were early indicators that the elasticity of the arteries might be restricted in ISSHL patients. CONCLUSION: ISSHL patients show an altered autonomic regulation. At least a subgroup of ISSHL patients seems to exist where a vascular impairment might play an important role in the pathogenesis of this disease. PMID- 25299831 TI - Metal casts showing the three-dimensional structure of the human inner ear were converted into jewelry. AB - This article describes a straightforward method for making metal casts of the human inner ear developed in 1937 by M. Wharton Young of Howard University College of Medicine. These casts were used to study anatomy, but there do not appear to be any published photographs of the casts. Inner ear casts converted into jewelry provide the only known images of this work. Later, Young studied the inner ear in living rhesus monkeys by injecting mercury into their membranous labyrinths. Young's investigations indicated a blind-ending perilymphatic sac that was not in continuity with the subarachnoid space. PMID- 25299832 TI - Hearing loss is associated with decreased nonverbal intelligence in rural Nepal. AB - OBJECTIVE: To evaluate the association between adolescent and young-adult hearing loss and nonverbal intelligence in rural Nepal. STUDY DESIGN: Cross-sectional assessment of hearing loss among a population cohort of adolescents and young adults. SETTING: Sarlahi District, southern Nepal. PATIENTS: Seven hundred sixty four individuals aged 14 to 23 years. INTERVENTION: Evaluation of hearing loss, defined by World Health Organization criteria of pure-tone average greater than 25 decibels (0.5, 1, 2, 4 kHz), unilaterally and bilaterally. MAIN OUTCOME MEASURE: Nonverbal intelligence, as measured by the Test of Nonverbal Intelligence, 3rd Edition standardized score (mean, 100; standard deviation, 15). RESULTS: Nonverbal intelligence scores differed between participants with normal hearing and those with bilateral (p = 0.04) but not unilateral (p = 0.74) hearing loss. Demographic and socioeconomic factors including male sex; higher caste; literacy; education level; occupation reported as student; and ownership of a bicycle, watch, and latrine were strongly associated with higher nonverbal intelligence scores (all p < 0.001). Subjects with bilateral hearing loss scored an average of 3.16 points lower (95% confidence interval, -5.56 to -0.75; p = 0.01) than subjects with normal hearing after controlling for socioeconomic factors. There was no difference in nonverbal intelligence score based on unilateral hearing loss (0.97; 95% confidence interval, -1.67 to 3.61; p = 0.47). CONCLUSION: Nonverbal intelligence is adversely affected by bilateral hearing loss even at mild hearing loss levels. Socio economic well-being appears compromised in individuals with lower nonverbal intelligence test scores. PMID- 25299833 TI - Hearing preservation and improved speech perception with a flexible 28-mm electrode. AB - OBJECTIVE: The present study aimed to determine the extent of hearing preservation retrospectively after atraumatic cochlear implant (CI) surgery using a specialized surgical technique and specially designed flexible electrode to minimize cochlear trauma. STUDY DESIGN: Retrospective study. SETTING: Academic tertiary care center. PATIENTS: A consecutive series of 34 patients who had some preoperative residual hearing were included in this study. INTERVENTION: Patients underwent CI surgery with a flexible 28-mm electrode using a round window insertion technique. MAIN OUTCOME MEASURES: All patients had at least 6 months of postoperative follow-up including audiometric testing and speech perception determined using the Freiburg monosyllable word test and the Oldenburger Sentence Test in noise. Audiometric testing served as a proxy for the evaluation of cochlear trauma and hearing preservation. RESULTS: Hearing was preserved to within 20 dB of preoperative low-frequency pure-tone audiometry (PTA) in 40.7% of patients. Hearing was preserved to within 20 dB of preoperative high-frequency PTA in 35.7% of patients. Overall, a deterioration in hearing thresholds was observed between preoperative assessment and first fitting. Speech perception improved significantly over time after surgery. CONCLUSION: Using appropriate surgical techniques, and electrodes specially designed to minimize cochlear trauma, hearing preservation can be achieved. PMID- 25299834 TI - A nonrandomized comparison of the thulium laser and the CO2 laser in primary stapedotomy for otosclerosis. AB - OBJECTIVE: Comparing hearing results in patients with otosclerosis treated with laser-assisted stapedotomy using the 2-MUm thulium laser or the CO2 laser. STUDY DESIGN: Prospective nonrandomized clinical study. SETTING: In a tertiary referral center in France (Jean Causse Ear Clinic, Beziers), 208 primary stapedotomies were performed in 204 patients between March 2008 and November 2009. Sufficient follow-up data were available for 194 procedures. METHODS: The fenestration in the footplate was made with the thulium laser in 98 procedures and with a flexible CO2 laser in 96 procedures. Preoperative and postoperative audiometric results were compared. Side effects, such as vertigo and tinnitus, were scored. RESULTS: Patients treated with the CO2 laser had better hearing outcome compared with those treated with the thulium laser at both 3 and 12 months of follow-up. At 3 months, the success of the surgery, defined as closure of the air-bone gap to within 10 dB, was 90.0% in the thulium group compared with 96.8% in the CO2 group. Bone conduction shift showed an overall deterioration of 1.6 dB (standard deviation, 6.9 dB) in the thulium group compared with an improvement of 1.3 dB (standard deviation, 4 dB) in the CO2 group. In the thulium group, there were four patients with sensorineural hearing loss (4.4%) and three with tinnitus (3.1%) compared with none in the CO2 group. CONCLUSION: Stapedotomy surgery performed with a fiber-delivered thulium laser resulted in a higher chance of inner ear damage measured by bone conduction shift compared with the use of a fiber-delivered CO2 laser. We advise not to use the thulium laser for stapedotomy. PMID- 25299835 TI - Comment on "Efficacy of Tympanoplasty Without Mastoidectomy on MRSA-infected Chronic Otitis Media". PMID- 25299836 TI - Response to Comment on "Efficacy of Tympanoplasty Without Mastoidectomy on MRSA infected Chronic Otitis Media". PMID- 25299838 TI - 1H NMR-based urinary metabolic profiling reveals changes in nicotinamide pathway intermediates due to postnatal stress model in rat. AB - The maternal separation protocol in rodents is a widely recognized model of early life stress allowing acute and chronic physiological consequences to be studied. An (1)H NMR-based metabolomic approach was applied to urines to evaluate the systemic metabolic consequences of maternal separation stress in female rats after the beginning of weaning and 4 weeks later when the rats were reaching adulthood. Furthermore, because maternal separation is considered as a model mimicking the inflammatory bowel syndrome, the lactulose/mannitol test was used to evaluate the influence of postnatal maternal separation on gut permeability and mucosal barrier function by (1)H NMR spectroscopy analysis of urine. The results showed no statistical differences in gut permeability due to maternal separation. The application of ANOVA simultaneous component analysis allowed the contributions of physiological adaptations to the animal's development to be separated from the metabolic consequences due to postnatal stress. Systemic metabolic differences in the maternally separated pups were mainly due to the tryptophan/NAD pathway intermediate levels and to the methyladenosine level. Urinary NMR-based metabolic profiling allowed us to disentangle the metabolic adaptive response of the rats to postnatal stress during the animal's growth, highlighting the metabolic changes induced by weaning, gut closure, and maturity. PMID- 25299837 TI - Apoptosis in HEp-2 cells infected with Ureaplasma diversum. AB - BACKGROUND: Bacterial pathogens have many strategies for infecting and persisting in host cells. Adhesion, invasion and intracellular life are important features in the biology of mollicutes. The intracellular location of Ureaplasma diversum may trigger disturbances in the host cell. This includes activation or inhibition of pro and anti-apoptotic factors, which facilitate the development of host damage. The aim of the present study was to associate U. diversum infection in HEp-2 cells and apoptosis induction. Cells were infected for 72hs with four U. diversum clinical isolates and an ATCC strain. The U. diversum invasion was analyzed by Confocal Laser Scanning Microscopy and gentamicin invasion assay. The apoptosis was evaluated using pro-apoptotic and anti-apoptotic gene expression, and FITC Annexin V/Dead Cell Apoptosis Kit. RESULTS: The number of internalized ureaplasma in HEp-2 cells increased significantly throughout the infection. The flow cytometry analysis with fluorochromes to detect membrane depolarization and gene expression for caspase 2, 3 and 9 increased in infected cells after 24 hours. However, after 72 hours a considerable decrease of apoptotic cells was observed. CONCLUSIONS: The data suggests that apoptosis may be initially induced by some isolates in association with HEp-2 cells, but over time, there was no evidence of apoptosis in the presence of ureaplasma and HEp-2 cells. The initial increase and then decrease in apoptosis could be related to bacterial pathogen associated molecular pattern (PAMPS). Moreover, the isolates of U. diversum presented differences in the studied parameters for apoptosis. It was also observed that the amount of microorganisms was not proportional to the induction of apoptosis in HEp-2 cells. PMID- 25299840 TI - Species fractionation in atomic chains from mechanically stretched alloys. AB - Bettini et al (2006 Nat. Nanotechnol. 1 182-5) reported the first experimental realization of linear atomic chains (LACs) composed of different atoms (Au and Ag). The different contents of Au and Ag were observed in the chains from what was found in the bulk alloys, which raises the question of what the wire composition is, if it is in equilibrium with a bulk alloy. In this work we address the thermodynamic driving force for species fractionation in LACs under tension, and we present the density-functional theory results for Ag-Au chain alloys. A pronounced stabilization of the wires with an alternating Ag-Au sequence is observed, which could be behind the experimentally observed Au enrichment in LACs from alloys with high Ag content. PMID- 25299839 TI - Protective effect of bixin on carbon tetrachloride-induced hepatotoxicity in rats. AB - BACKGROUND: The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl4) in rats. RESULTS: The animals were divided into four groups with six rats in each group. CCl4 (0.125 mL kg(-1) body wt.) was injected intraperitoneally, and bixin (5.0 mg kg(-1) body wt.) was given by gavage 7 days before the CCl4 injection. Bixin prevented the liver damage caused by CCl4, as noted by the significant decrease in serum aminotransferases release. Bixin protected the liver against the oxidizing effects of CCl4 by preventing a decrease in glutathione reductase activity and the levels of reduced glutathione and NADPH. The peroxidation of membrane lipids and histopathological damage of the liver was significantly prevented by bixin treatment. CONCLUSION: Therefore, we can conclude that the protective effect of bixin against hepatotoxicity induced by CCl4 is related to the antioxidant activity of the compound. PMID- 25299841 TI - Lewis acid promoted construction of chromen-4-one and isoflavone scaffolds via regio- and chemoselective domino Friedel-Crafts acylation/Allan-Robinson reaction. AB - A facile and efficient synthesis of chromen-4-one and isoflavone frameworks is achieved by the domino C-acylation/O-acylation/aldolization sequence. This operationally simple one-pot elegant strategy provides structurally unique chromen-4-ones and isoflavones directly from phenols via concomitant formation of multiple C-C and C-O bonds in a single operation. The outcomes of the buttressing effect, substituent dependence, and catalyst and solvent specificity during the course of the Friedel-Crafts acylation reactions are demonstrated and supported by fitting experiments. PMID- 25299842 TI - A novel application of teleneurology: robotic telepresence in supervision of neurology trainees. AB - BACKGROUND: Telemedicine is used for specialist consultation, patient evaluation, and remote monitoring. We propose that telemedicine has a valuable role in medical education through facilitating faculty supervision of trainees. MATERIALS AND METHODS: We surveyed resident physician trainees and faculty at a single institution who provided service for acute neurologic consultations over 29 months. The survey compared experiences using the supervisory methods of telephone, robotic telepresence (RTP), and in-person interaction. Participants answered 10 questions addressing their experience relevant to faculty-trainee interaction quality and clinical supervision, achieved with the three supervisory methods under study. RESULTS: Surveys were received from 20 of 36 trainees (56%) and 8 of 10 faculty members (80%). More than 90% of trainees and faculty strongly agreed that in-person communication was satisfactory for patient data review, problem synthesis, and refinement of the trainees' impressions, with RTP ranking a close second. Moreover, 38% of faculty and 70% of trainees reported the telephone method as unsatisfactory for reacquisition of patient history, data synthesis, and direct observation of trainees' clinical skills. RTP provided more than 90% of trainees with sufficient staff support and facilitated trainee autonomy. CONCLUSIONS: Overall, 85% of both trainees and faculty preferred in person supervision most, with RTP ranked second and telephone being least favored. Although in-person faculty supervision of trainees' management of neurologic emergencies is always preferred, it is not always practical. This survey highlights the valuable role of RTP in graduate medical education and RTP as preferred over telephone as an adjunctive supervision tool in residency. PMID- 25299843 TI - The effects of temperature and seasons on subcutaneous white adipose tissue in humans: evidence for thermogenic gene induction. AB - CONTEXT: Although brown adipose tissue (BAT) activity is increased by a cold environment, little is known of the response of human white adipose tissue (WAT) to the cold. DESIGN: We examined both abdominal and thigh subcutaneous (SC) WAT from 71 subjects who were biopsied in the summer or winter, and adipose expression was assessed after an acute cold stimulus applied to the thigh of physically active young subjects. RESULTS: In winter, UCP1 and PGC1alpha mRNA were increased 4 to 10-fold (p < 0.05) and 1.5 to 2-fold, respectively, along with beige adipose markers, and UCP1 protein was 3-fold higher in the winter. The seasonal increase in abdominal SC WAT UCP1 mRNA was considerably diminished in subjects with a BMI > 30 kg/m(2), suggesting that dysfunctional WAT in obesity inhibits adipose thermogenesis. After applying an acute cold stimulus to the thigh of subjects for 30 min, PGC1alpha and UCP1 mRNA was stimulated 2.7-fold (p < 0.05) and 1.9-fold (p = 0.07), respectively. Acute cold also induced a 2 to 3 fold increase in PGC1alpha and UCP1 mRNA in human adipocytes in vitro, which was inhibited by macrophage-conditioned medium and by the addition of TNFalpha. CONCLUSION: Human SC WAT increases thermogenic genes seasonally and acutely in response to a cold stimulus and this response is inhibited by obesity and inflammation. PMID- 25299845 TI - Pediatric palliative care consultation services in California hospitals. AB - BACKGROUND: The American Academy of Pediatrics recommends that palliative care be available to seriously ill hospitalized children, yet little is known about how these services are structured. OBJECTIVE: The study's aim is to report the prevalence of pediatric palliative care services (PCS) and compare the structure of pediatric PCS to adult PCS within California hospitals. METHODS: We surveyed 377 hospitals to assess the prevalence, structure, and characteristics of pediatric and adult PCS. Hospitals were categorized as children's hospitals with a pediatric-only PCS, mixed hospitals with pediatric and adult PCS, and hospitals with adult-only PCS. RESULTS: All 8 children's hospitals in the state reported having a pediatric PCS, and 36 pediatric PCSs were in mixed hospitals. Mixed hospitals saw fewer (p=0.0001) children per year (mean=5.6, standard deviation [SD]=3.6) than pediatric-only PCSs (mean=168, SD=73). Pediatric-only PCSs treated more patients for noncancer-related illness (82.5%) than pediatric PCSs in mixed hospitals (34.5%, p=0.03) or adult-only PCSs (52.4%, p=0.001). All PCSs were universally available (100%) during weekday business hours and half were available during weekend business hours. Pediatric-only PCSs had a mean total full-time equivalent (FTE) of 1.9, which was not significantly different (p=0.3) from the total FTE for pediatric PCSs in mixed hospitals (mean=1.1, SD=1.4) or for adult-only PCSs (mean=2.7, SD=2.0). However, in mixed hospitals the adult PCS had a significantly higher (p=0.005) total FTE (mean=2.4, SD=1.3) than the pediatric PCS (mean=1.1, SD=1.4). CONCLUSION: All children's hospital and a few mixed hospitals offer pediatric PCS. Better understanding of the palliative care needs of seriously ill children in mixed hospitals and assessment of the quality of care provided will help ensure that children seen in these hospitals receive necessary care. PMID- 25299844 TI - Endocrine disruption in human placenta: expression of the dioxin-inducible enzyme, CYP1A1, is correlated with that of thyroid hormone-regulated genes. AB - CONTEXT: Thyroid hormone (TH) is essential for normal development; therefore, disruption of TH action by a number of industrial chemicals is critical to identify. Several chemicals including polychlorinated biphenyls are metabolized by the dioxin-inducible enzyme CYP1A1; some of their metabolites can interact with the TH receptor. In animals, this mechanism is reflected by a strong correlation between the expression of CYP1A1 mRNA and TH-regulated mRNAs. If this mechanism occurs in humans, we expect that CYP1A1 expression will be positively correlated with the expression of genes regulated by TH. OBJECTIVE: The objective of the study was to test the hypothesis that CYP1A1 mRNA expression is correlated with TH-regulated mRNAs in human placenta. METHODS: One hundred sixty-four placental samples from pregnancies with no thyroid disease were obtained from the GESTE study (Sherbrooke, Quebec, Canada). Maternal and cord blood TH levels were measured at birth. The mRNA levels of CYP1A1 and placental TH receptor targets [placental lactogen (PL) and GH-V] were quantitated by quantitative PCR. RESULTS: CYP1A1 mRNA abundance varied 5-fold across 132 placental samples that had detectable CYP1A1 mRNA. CYP1A1 mRNA was positively correlated with PL (r = 0.64; P < .0001) and GH-V (P < .0001, r = 0.62) mRNA. PL and GH-V mRNA were correlated with each other (r = 0.95; P < .0001), suggesting a common activator. The mRNAs not regulated by TH were not correlated with CYP1A1 expression. CONCLUSIONS: CYP1A1 mRNA expression is strongly associated with the expression of TH-regulated target gene mRNAs in human placenta, consistent with the endocrine-disrupting action of metabolites produced by CYP1A1. PMID- 25299846 TI - Involvement of heme oxygenase-1 in neuroprotection by sanguinarine against glutamate-triggered apoptosis in HT22 neuronal cells. AB - Sanguinarine is a natural compound isolated from the roots of Macleaya cordata and M. microcarpa, has been reported to possess several biological activities such as anti-inflammatory and anti-oxidant effects. In the present study, we demonstrated that sanguinarine markedly induces the expression of HO-1 which leads to a neuroprotective response in mouse hippocampus-derived neuronal HT22 cells from apoptotic cell death induced by glutamate. Sanguinarine significantly attenuated the loss of mitochondrial function and membrane integrity associated with glutamate-induced neurotoxicity. Sanguinarine protected against glutamate induced neurotoxicity through inhibition of HT22 cell apoptosis. JC-1 staining, which is a well-established measure of mitochondrial damage, was decreased after treatment with sanguinarine in glutamate-challenged HT22cells. In addition, sanguinarine diminished the intracellular accumulation of ROS and Ca(2+). Sanguinarine also induced HO-1, NQO-1 expression via activation of Nrf2. Additionally, we found that si RNA mediated knock-down of Nrf2 or HO-1 significantly inhibited sanguinarine-induced neuroprotective response. These findings revealed the therapeutic potential of sanguinarine in preventing the neurodegenerative diseases. PMID- 25299847 TI - Evaluation of ameliorative potential of selenium on carbendazim induced oxidative stress in male goats. AB - In the present investigation, ameliorative effect of selenium on carbendazim induced oral sub chronic toxicity in bucks was assessed by studying various indices of antioxidant defense system. Bucks were randomly divided into four groups of four animals each. Group I served as control, Group II was orally drenched carbendazim at the dose rate of 50mg/kg body weight for 90 consecutive days. Group III was orally administered selenium in the form of sodium selenite at the dose rate of 0.05mg/kg body weight for 90 consecutive days. Group IV was orally administered carbendazim along with selenium at the same dosages as Group II and III. Prolonged administration of carbendazim produced oxidative stress in goat bucks as evidenced by increase in lipid peroxidation and decline in total antioxidant capacity. The increase in the activity of antioxidant enzymes was not sufficient to prevent pesticide induced oxidative stress. Selenium supplementation provides some amelioration against this effect. Further study is needed to prove ameliorative potential of this antioxidant against carbendazim induced toxicity in goat bucks. PMID- 25299848 TI - Histopathological lesions, P-glycoprotein and PCNA expression in zebrafish (Danio rerio) liver after a single exposure to diethylnitrosamine. AB - The presence of carcinogenic compounds in the aquatic environment is a recognized problem. ABC transporters are well known players in the multidrug-resistance (MDR) phenomenon in mammals associated with resistance to chemotherapy, however little is known in fish species. Thus, the aim of this study was to induce hepatic tumours and evaluate long-term effects on P-glycoprotein (P-gp) and proliferating cell nuclear antigen (PCNA) proteins in Danio rerio liver, after exposure to diethylnitrosamine (DEN). Several hepatic histopathological alterations were observed in zebrafish after exposure to DEN including pre neoplastic lesions 6 and 9 months post-exposure. After 3, 6 and 9 months of exposure to DEN, P-gp and PCNA proteins expression were up-regulated. In conclusion, this study has shown that zebrafish ABC transporters can play a similar role as in human disease, hence zebrafish can be used also as a biological model to investigate in more deep mechanisms involved in disease processes. PMID- 25299850 TI - Synthesis, optical properties and alignment of poly(9,9-dioctylfuorene) nanofibers. AB - Poly(9,9-dioctlylfluorene) (PFO) nanofibers were fabricated by solution template wetting of anodic alumina membranes. Nanofibers with controlled thickness of 23 nm and length between 0.8 and 10 MUm, were obtained, regulated by the dimensions of the used template. Nanofibers displayed spectroscopic characteristics associated with the formation of significant percentages of planar and elongated beta phase within the amorphous PFO glassy-phase. Optical polarized microscopy displayed high birefringence resulting from the high degree of internal order induced by beta phase generation within the fibers. The structural intra-chain reorganization associated with formation of beta phase was promoted by the strong geometrical confinement imposed on the material by the porous template during polymer wetting and solvent evaporation. Flow and shear force alignment techniques were used to control the orientation of fabricated PFO nanofibers, yielding to formation of large oriented nanofiber arrays on transparent substrates. PMID- 25299849 TI - eNOS-JNK1-AR signaling pathway mediates deltamethrin-induced germ cells apoptosis in testes of adult rats. AB - The purpose of this study is to examine germ cells apoptosis and reduction of spermatogenesis which might be induced by deltamethrin (DM). Furthermore, the study is performed to determine if the apoptosis is mediated by the signaling proteins: eNOS, JNK1 and androgen receptor (AR). Fifty-four male SD rats were divided into nine groups (six rats each): blank control group; corn oil treated group; DM treated group; saline treated group; DM+saline treated group; DM+histamine (eNOS specific agonist) treated group; 50% ethanol treated group; DM+50% ethanol group and DM+quercetagetin (JNK1 specific inhibitor) treated group. The experiment was conducted for 15 days. Apoptosis was evaluated by TUNEL; S-nitrosylation of JNK1 was examined by the biotin switch assay; eNOS expression and Ser650 phosphorylation of AR were assessed by immunoblotting and immunohistochemical analysis, respectively. DM treated group showed notable apoptotic cells and reduced production of sperm, while DM plus histamine group and DM plus quercetagetin group showed remarkably decreased apoptosis and improved production of sperm. Administration of DM inhibited spermatogenesis, the activity of eNOS and S-nitrosylation of JNK1. Meanwhile, phosphorylation of AR was shown to be elevated. Histamine and quercetagetin were also examined to have a further confirmation. It is suggested DM-induced germ cells apoptosis and reduction of sperm production were mediated by eNOS-JNK1-AR signaling pathway. PMID- 25299851 TI - Can bundled payment improve quality and efficiency of care for patients with hip fractures? AB - The current Medicare reimbursement for hip fractures lacks accountability and promotes cost cutting. A bundled payment system-analogous to the Medicare Acute Care Episodes Demonstration for Orthopedic and Cardiovascular Surgery-may help curtail costs, foster communication among health care providers, and improve their accountability for patient outcomes. In hip fracture care, bundled payment may spur development of multidisciplinary best practice guidelines, quality assessment, and reporting, and result in benchmarking and best practices sharing. However, its implementation may face challenges: the need for quality assessment criteria and risk adjustment methods and possible risks of pushing costs outside of Medicare boundaries. PMID- 25299852 TI - Synthesis and dynamic behavior of an anthyridine-ligated ruthenium complex. AB - A ruthenium complex containing a 1,9,10-anthyridine derivative, [Ru(L)(bpy)2](PF6)2 ([1](PF6)2; L = 1,13,14-triazadibenz[a,j]anthracene, bpy = 2,2'-bipyridyl), was synthesized. X-ray crystal structural analysis of [1](PF6)2 showed that L is coordinated to the Ru center as a bidentate ligand. When [1](PF6)2 was dissolved in acetonitrile, a new complex incorporating one acetonitrile molecule, [Ru(L)(CH3CN)(bpy)2](PF6)2 ([2](PF6)2), was formed. X-ray crystallographic data revealed that, in [2](PF6)2, L is coordinated to the Ru center in a monodentate fashion. The coordinated L in [2](PF6)2 shows a unique haptotropic rearrangement in an acetonitrile solution. PMID- 25299853 TI - An examination of distress intolerance in undergraduate students high in symptoms of generalized anxiety disorder. AB - People with generalized anxiety disorder (GAD) engage in maladaptive coping strategies to reduce or avoid distress. Evidence suggests that uncertainty and negative emotions are triggers for distress in people with GAD; however, there may also be other triggers. Recent conceptualizations have highlighted six types of experiences that people report having difficulty withstanding: uncertainty, negative emotions, ambiguity, frustration, physical discomfort, and the perceived consequences of anxious arousal. The present study examined the extent to which individuals high in symptoms of GAD are intolerant of these distress triggers, compared to individuals high in depressive symptoms, and individuals who are low in GAD and depressive symptoms. Undergraduate students (N = 217) completed self report measures of GAD symptoms, depressive symptoms, and distress intolerance. Individuals high in GAD symptoms reported greater intolerance of all of the distress triggers compared to people low in symptoms of GAD and depression. Individuals high in GAD symptoms reported greater intolerance of physical discomfort compared to those high in depressive symptoms. Furthermore, intolerance of physical discomfort was the best unique correlate of GAD status, suggesting that it may be specific to GAD (versus depression). These findings support continued investigation of the transdiagnosticity and specificity of distress intolerance. PMID- 25299854 TI - Chronic respiratory disease: the forgotten NCD? PMID- 25299855 TI - Preventive chemotherapy for contacts of MDR-TB: is the proof in the pudding? PMID- 25299856 TI - The role of biomarkers in the management of airways disease. AB - Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease, are responsible for a large global disease burden. The recognition of airway disease phenotypes is important for the application of new therapies targeted at specific underlying biological mechanisms. Biomarkers are indicators of biological or pathogenic processes that are objectively measured. In airway disease, biomarkers will ideally provide predictive information regarding diagnosis, disease mechanisms, phenotypes, treatment responses and prognosis or future risk. Non-invasive biomarkers that aid phenotyping are crucial to the development of targeted and more efficacious treatment, leading to personalised approaches to airway disease management. Sputum and peripheral blood eosinophils and fractional exhaled nitric oxide (FeNO) are current examples of potential biomarkers. However, recent advances in technology have demonstrated the role for airway transcriptomics in biomarker discovery. This perspective piece discusses the need for biomarkers in airway disease, the use of eosinophil counts and FeNO as biomarkers, the use of transcriptomics for biomarker discovery, and the application of biomarkers in clinical and research settings. A combined approach incorporating clinical information with biological markers such as eosinophils, FeNO and inflammatory gene markers is likely to have the most success in predicting patient outcomes. PMID- 25299857 TI - Global burden of asthma among children. AB - About 334 million people worldwide suffer from asthma, and this figure may be an underestimation. It is the most common chronic disease in children. Asthma is among the top 20 chronic conditions for global ranking of disability-adjusted life years in children; in the mid-childhood ages 5-14 years it is among the top 10 causes. Death rates from asthma in children globally range from 0.0 to 0.7 per 100 000. There are striking global variations in the prevalence of asthma symptoms (wheeze in the past 12 months) in children, with up to 13-fold differences between countries. Although asthma symptoms are more common in many high-income countries (HICs), some low- and middle-income countries (LMICs) also have high levels of asthma symptom prevalence. The highest prevalence of symptoms of severe asthma among children with wheeze in the past 12 months is found in LMICs and not HICs. From the 1990s to the 2000s, asthma symptoms became more common in some high-prevalence centres in HICs; in many cases, the prevalence stayed the same or even decreased. At the same time, many LMICs with large populations showed increases in prevalence, suggesting that the overall world burden is increasing, and that therefore global disparities in asthma prevalence are decreasing. The costs of asthma, where they have been estimated, are relatively high. The global burden of asthma in children, including costs, needs ongoing monitoring using standardised methods. PMID- 25299858 TI - Respiratory effects in children from passive smoking of cigarettes and narghile: ISAAC Phase Three in Syria. AB - BACKGROUND: The association between environmental tobacco smoke (ETS) and asthma symptoms is well documented, but a causal relationship is inconclusive. International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three was the first to report a dose-response relationship between current wheezing and exposure to parental cigarette smoke. As exposure of children to water pipe (narghile) smoke is of concern in Syria, in the ISAAC Phase Three Tartous Centre we also examined the role of parental smoking of the narghile. METHODS: Parents of children aged 6-7 years completed core written questionnaires about the prevalence of symptoms, and an environmental questionnaire for other risk factors, including parental cigarette smoking. We added questions about narghile to the questionnaire. RESULTS: Among 2 734 pupils (49% females) surveyed, we found an association between exposure to ETS of the mother smoking cigarette or narghile and ever wheezing, nocturnal cough and severe wheeze; however, the strongest association was found when the mother smoked narghile. Mother smoking narghile was also associated with exercise wheeze. Father smoking narghile, but not cigarettes, was associated with nocturnal cough, severe wheeze and exercise wheeze. The association with current wheeze became significant when mother smoked both cigarettes and narghile; however, the effect was addititive and not synergic. CONCLUSION: We recommend that international studies investigating ETS include questions on narghile smoking. PMID- 25299859 TI - Cigarette smoking among tuberculosis patients increases risk of transmission to child contacts. AB - SETTING: Observational cohort study in Lima, Peru. OBJECTIVE: To determine the association between exposure to a smoking tuberculosis (TB) case and latent tuberculous infection (LTBI). METHOD: Between September 2009 and August 2012, we identified 2132 patients with drug-susceptible TB and their 2054 child household contacts. Data were collected on active and secondhand smoking status and other risk factors for infection specific to the index case, the household and the exposed contacts. Contacts underwent a tuberculin skin test (TST) to determine their tuberculous infection status at baseline, 6-month and 12-month follow-up. We estimated the association between exposure to a smoking index case and LTBI using a modified Poisson regression model. RESULTS: The 21 children (age ?15 years) exposed to smoking index TB patients were more likely to be TST-positive at baseline (RR 2.64, 95%CI 1.78-3.91), by 6 months (RR 1.91, 95%CI 1.40-2.60) and by 12 months (RR 1.48, 95%CI 1.07-2.06), than those who were not exposed. TST positivity among children at these time points did not vary with secondhand smoke exposure. CONCLUSIONS: TB patients who smoke may be more likely to transmit infection to their contacts. Interventions designed to reduce smoking among TB patients may minimise further spread of the disease. PMID- 25299860 TI - Children exposed to multidrug-resistant tuberculosis at a home-based day care centre: a contact investigation. AB - SETTING: In high tuberculosis (TB) burden settings, day care centres may be an underestimated source of exposure of children to infectious drug-susceptible (DS) and drug-resistant (DR) TB cases. OBJECTIVE: To describe the results of a contact investigation of children exposed to an adult with DR-TB at a South African home based day care centre. DESIGN: Retrospective descriptive community-based cohort study. RESULTS: Mycobacterium tuberculosis resistant to isoniazid (INH), rifampicin and amikacin was cultured from the sputum of an adult index case residing in a home-based day care centre. Of 38 children aged <15 years identified during routine contact investigation, consent was obtained for 34; the median age was 3.9 years (IQR 2.9-5.2); 23/34 were aged <5 years, none were human immunodeficiency virus infected. The median contact score was 4/10, 8 had a reactive tuberculin skin test (?10 mm) and none had TB. Of the 34 study children, 24 received 6 months of DR-TB preventive therapy comprising ofloxacin, ethambutol and high-dose INH; 21 completed 12 months' follow-up and none developed TB. CONCLUSIONS: TB at day care centres may result in many exposed young children with high TB contact scores, similar to household contact investigations. Active identification and initiation of preventive treatment may be able to avert DR-TB cases. PMID- 25299861 TI - Identifying multidrug resistance in previously treated tuberculosis patients: a mixed-methods study in Cambodia. AB - SETTING: Previously treated tuberculosis (TB) patients are a priority for drug susceptibility testing (DST) to identify cases with multidrug-resistant TB (MDR TB). A Cambodia study found that one third of smear-positive previously treated patients had DST results. OBJECTIVE: To quantify the gaps in the detection of MDR TB in previously treated TB patients in Cambodia, and describe health workers' perspectives on barriers, facilitators and potential interventions. DESIGN: Analysis of Cambodia's 2004-2012 case notifications and semi-structured interviews with stakeholders. RESULTS: The proportion of previously treated notifications varied significantly across provinces in 2010-2012. If there had been no attrition along the path to detecting MDR-TB among smear-positive notified cases in 2012, an estimated 75 additional MDR-TB cases could have been identified, which would double the number actually detected. Most were lost due to misclassification of previously treated patients as 'new'. Barriers include patients' reluctance to disclose and staff difficulty in eliciting treatment history, partly attributed to the availability of streptomycin (SM) only in hospitals. Facilitators include collection of sputum for DST even if previously treated patients are not receiving SM, streamlining sputum transportation and prompt reporting of results. CONCLUSION: Improved monitoring, supportive staff supervision and training, patient education, and correct classification of previously treated cases are essential for improving the detection of MDR-TB. PMID- 25299863 TI - Initial experience of bedaquiline use in a series of drug-resistant tuberculosis patients from India. AB - Drug-resistant tuberculosis (DR-TB) is a major problem both in India and worldwide. Newer drugs such as TMC-207 (bedaquiline) may have an important role to play in making up an effective drug regimen in such cases. There have been a few reports of bedaquiline use in a non-trial setting from Europe. Our series of five patients is the first series of DR-TB patients from India to receive bedaquiline. All five patients showed striking improvement, with microbiological conversion and an absence of notable adverse effects (e.g., prolonged QTcF), indicating the potential impact of this drug in such a population. PMID- 25299862 TI - Geographic predictors of primary multidrug-resistant tuberculosis cases in an endemic area of Lima, Peru. AB - SETTING: Peru reports among the highest multidrug-resistant tuberculosis (MDR-TB) rates in the Americas, with a growing proportion in previously untreated tuberculosis (TB) cases. The identification of clusters of primary MDR-TB compared with drug-susceptible TB (DS-TB) could help prioritize interventions. OBJECTIVE: To examine the clustering of primary MDR-TB case residences and their proximity to high-risk locations in San Juan de Lurigancho District, Lima, Peru. DESIGN: Enrolled primary MDR-TB and primary DS-TB cases were interviewed and their primary residence was recorded using handheld Global Positioning System devices. Kuldorff's spatial scan statistic was used for cluster detection (SaTScan(TM), v. 9.1.1). Identified clusters were visualized in Quantum Geographic Information Systems software (v1.8.0). The following cluster centers were tested: a health centre with the highest TB and MDR-TB rates (Clinic X), a hospital and two prisons. Using regression analyses, we examined predictors of primary MDR-TB cases. RESULTS: A statistically significant cluster of primary MDR TB cases was identified within a 2.29 km radius around Clinic X. Proximity to Clinic X remained a significant predictor of primary MDR-TB in adjusted regression analyses. CONCLUSION: We identified a hotspot of primary MDR-TB cases around Clinic X in a TB-endemic area. Causes of this clustering require investigation; targeted interventions for this high-risk area should be considered. PMID- 25299864 TI - The disconnect between a national tuberculosis drug resistance survey and treatment outcomes: a lost opportunity. AB - We linked results from the Fourth Botswana National Drug Resistance Survey (DRS), 2007-2008, to patient records from the national Electronic Tuberculosis Registry to determine treatment outcomes. Of 915 new patients, 651 (71%) had treatment data available. Completion or cure was achieved for 10/15 (67%, 95%CI 42-85) with isoniazid monoresistance, (6/16, 38%, 95%CI 18-61) with multidrug resistance, while 73% (391/537, 95%CI 69-76) were susceptible to first-line drugs. The analysis was limited because of unavailable treatment records and undocumented outcomes. Prospective analyses following DRSs should be considered to ensure adequate outcome data. PMID- 25299865 TI - What is the role for Xpert(r) MTB/RIF in high-resource settings? Experience from a central London hospital. AB - The role of Xpert((r)) MTB/RIF for tuberculosis (TB) diagnosis remains to be clearly delineated in high-resource settings. At a London hospital, we evaluated a policy of selective assay use, with testing restricted to defined sub-groups of patients. Management was directly influenced in 30% of patients studied, including 'ruling-in' a TB diagnosis (leading to initiation of treatment for TB or for potential multidrug-resistant TB); negative assay results also helped support decisions for cessation of empirical anti-tuberculosis treatment or the safe initiation of other treatments such as immunosuppressant drugs. The benefits and pitfalls of this assay's use within high-resource settings are discussed. PMID- 25299867 TI - Elevated hepcidin at HIV diagnosis is associated with incident tuberculosis in a retrospective cohort study. AB - Hepcidin inhibits ferroportin-mediated iron efflux, leading to intracellular macrophage iron retention, possibly favoring Mycobacterium tuberculosis iron acquisition and tuberculosis (TB) pathogenesis. Plasma hepcidin was measured at human immunodeficiency virus (HIV) diagnosis in a retrospective HIV-prevalent, antiretroviral-naive African cohort to investigate the association with incident pulmonary and/or extra-pulmonary TB. One hundred ninety-six participants were followed between 5 August 1992 and 1 June 2002, with 32 incident TB cases identified. Greater hepcidin was associated with significantly increased likelihood of TB after a median time to TB of 6 months. Elucidation of iron related causal mechanisms and time-sensitive biomarkers that identify individual changes in TB risk are needed. PMID- 25299868 TI - Impact of three empirical anti-tuberculosis treatment strategies for people initiating antiretroviral therapy. AB - BACKGROUND: Early mortality in people initiating antiretroviral treatment (ART) remains high. Empirical anti-tuberculosis treatment strategies aim to reduce early mortality by initiating anti-tuberculosis treatment in individuals at high risk of death from undiagnosed TB. METHODS: Using data from 16 913 individuals starting ART under program conditions, we simulated the impact of three empirical treatment strategies (two clinical trials and a pragmatic approach), assuming that 50% of early deaths and 100% of incident TB are averted in those eligible. RESULTS: Compared to starting anti-tuberculosis treatment on clinical or mycobacteriological grounds, 4.4-31.4% more individuals were eligible for anti tuberculosis treatment, 5.5-25.4% of deaths were averted and 10.9-57.3% of incident TB cases were prevented under empirical anti-tuberculosis treatment strategies. The proportion receiving any anti-tuberculosis treatment during the first 6 months of ART increased from the observed 24.0% to an estimated 27.5%, 40.4% and 51.3%, under the PrOMPT, REMEMBER and pragmatic approach, respectively. CONCLUSION: The impact of empirical anti-tuberculosis treatment strategies depends greatly on the eligibility criteria chosen. The additional strain placed on anti-tuberculosis treatment facilities and the relatively limited impact of some empirical TB strategies raise the question as to whether the benefits will outweigh the risks at population level. PMID- 25299870 TI - Extending tuberculosis notification to the private sector in India: programmatic challenges? AB - In May 2012, the Government of India declared tuberculosis a notifiable disease, requiring all public and private health sectors throughout the country to report all cases. Until then, TB disease was notifiable only by public authorities. In India, the private sector dominates anti-tuberculosis treatment, and poorly managed cases lead to severe forms of TB. Several challenges need to be addressed for effective implementation, including the creation of an electronic case-based web-based mechanism for TB notification. Stricter enforcement backed by regulation and punitive measures for non-compliance, along with vigilant mechanisms in place to monitor private health facilities, is required. Massive campaigns and advocacy programmes for a notification drive may be the way forward. PMID- 25299869 TI - Longevity loss among cured tuberculosis patients and the potential value of prevention. AB - BACKGROUND: Evidence of substantial, quantifiable and preventable burdens of mortality hazard even after anti-tuberculosis treatment and cure would be a compelling, concrete, and useful measure of the value of prevention. METHODS: We compared years of potential life lost between a cohort of 3 933 cured tuberculosis (TB) patients and 9 166 persons with latent tuberculous infection. We constructed a regression model to predict the expected years of potential life lost in each cohort and for demographic subgroups. RESULTS: Among decedents, a history of fully treated TB is associated with a predicted average 3.6 more years of potential life loss than a comparable population without active TB. Greater longevity losses were predicted among those identified as White and Hispanic than among Black and Asian counterparts. CONCLUSION: We found significant differences in predicted longevity of treated TB survivors relative to a similar group without active TB. These excess losses are substantial: a total of 14 158 life years or the equivalent of more than 188 75-year lifespans. These findings illustrate an important opportunity cost associated with each preventable TB case - an average of 3.6 potential years of life. We conclude that substantial preventable mortality burdens remain despite adequate anti-tuberculosis treatment, a compelling rationale for more widespread and systematic use of prevention. PMID- 25299871 TI - Estimated incidence of tuberculosis by capture-recapture in the Balearic Islands, 2010-2012. AB - SETTING: The Balearic Islands, Spain, 2010-2012. OBJECTIVE: To assess the completeness of TB surveillance, and to examine observed and estimated incidence rates (IR) compared with the period 2005-2007. DESIGN: The completeness of TB surveillance was assessed using the capture-recapture method. Confidence intervals were calculated using log-linear models. Data sources were records of mandatory notifiable diseases, active hospital surveillance and computerised primary health care history. RESULTS: Surveillance completeness for respiratory TB (R-TB) was 99.5%; it was 100% for non-respiratory TB (NR-TB). The overall observed IR was 16.32 cases/100 000 for all types of TB, 3.4 for NR-TB and 12.9 for R-TB. The estimated IR of TB all forms was 16.35/100 000 (95%CI 16.26-16.53), for NR-TB it was 3.4/100 000 (95%CI not calculated) and for R-TB it was 13.0/100 000 (95%CI 12.85-13.12). Surveillance completeness for R-TB during the period 2005-2007 was 65.2%; the observed IR was 22.6/100 000 and the estimated IR 31.3/10 000 (95%CI 25.0-37.7). CONCLUSION: The similarity of observed and estimated IR during the period 2010-2012 indicates the validity of the surveillance and the use of improved systems such as electronic medical records in recent years. PMID- 25299872 TI - Role of adenosine deaminase and the influence of age on the diagnosis of pleural tuberculosis. AB - OBJECTIVE: 1) To determine factors affecting adenosine deaminase (ADA) levels in pleural fluid (PF), and 2) to establish the optimal ADA cut-off level for a Brazilian population. DESIGN: ADA levels in PF of 309 patients were analysed to investigate pleural effusion. All patients were evaluated for age, sex and presence of tuberculosis (TB) based on a positive pleural biopsy. Differences in ADA levels between groups were analysed using Kruskal-Wallis one-way analysis of variance. Logistic regression analysis was also carried out to predict the occurrence of TB. ADA cut-off levels were selected using the receiver operating characteristic (ROC) curve. RESULTS: The mean PF ADA level was significantly higher in the tuberculous pleural group than in non-tuberculous pleural patients (63.3 +/- 29 IU/l vs. 19 +/- 31 IU/l, P < 0.001). There was a significant correlation between PF ADA levels and age: for patients aged ?45 years, the ROC curve for ADA had an area under the curve of 0.91. An ADA level of 29 IU/l resulted in a sensitivity of 88.6% and specificity of 91.5%. CONCLUSIONS: There is a significant negative correlation between PF ADA level and age. The use of a lower ADA cut-off reduces the number of false-negative results. PMID- 25299873 TI - The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review. AB - SETTING: Tuberculosis (TB) rates are decreasing in many areas, while non tuberculous mycobacteria (NTM) infection rates are increasing. The relationship between the epidemiology of TB and NTM infections is not well understood. OBJECTIVE: To understand the epidemiologic relationship between TB and NTM disease worldwide. DESIGN: A systematic review of Medline (1946-2014) was conducted to identify studies that reported temporal trends in NTM disease incidence. TB rates for each geographic area included were then retrieved. Linear regression models were fitted to calculate slopes describing changes over time. RESULTS: There were 22 studies reporting trends in rates of NTM disease, representing 16 geographic areas over four continents: 75% of areas had climbing incidence rates, while 12.5% had stable rates and 12.5% had declining rates. Most studies (81%) showed declining TB incidence rates. The proportion of incident mycobacterial disease caused by NTM was shown to be rising in almost every geographic area (94%). CONCLUSION: We found an increase in the proportion of mycobacterial disease caused by NTM in many parts of the world due to a simultaneous reduction in TB and increase in NTM disease. Research into the interaction between mycobacterial infections may help explain this inverse relationship. PMID- 25299874 TI - Association of surfactant protein B gene with chronic obstructive pulmonary disease susceptibility. AB - SETTING: Genetic predisposition, in addition to smoking, is known to play a key role in susceptibility to chronic obstructive pulmonary disease (COPD). Several candidate genes have been proposed for COPD, including surfactant protein B (SFTPB). However, large studies in populations with different ethnic backgrounds and environments are required to clarify the role of SFTPB in COPD. OBJECTIVE: We investigated the association of SFTPB polymorphisms with COPD susceptibility and lung function in a Chinese Han population. DESIGN: Four single nucleotide polymorphisms (SNPs) in the SFTPB gene were genotyped in 680 COPD patients and 687 controls. Allele frequencies and genotype distributions were compared between cases and controls and the potential relationships between these SNPs and lung function were investigated. Associations between haplotypes and COPD susceptibility were also assessed. RESULTS: The SFTPB exon polymorphism rs1130866 significantly protected subjects from COPD (adjusted P = 0.004) and was associated with an increase in forced expiratory volume in 1 s (FEV(1)) (adjusted P = 0.014). CONCLUSIONS: SFTPB variants are associated with COPD susceptibility and lung function in the Chinese Han population. PMID- 25299875 TI - Changes in QT intervals after azithromycin-containing antibiotic therapy in patients with NTM lung disease. PMID- 25299876 TI - Cost-effectiveness of 12-dose LTBI regimen improved following advocacy to lower the price of rifapentine. PMID- 25299877 TI - Effect of Melissa officinalis supplementation on growth performance and meat quality characteristics in organically produced broilers. AB - 1. A trial was conducted to study the effect of Melissa officinalis supplementation on organic broiler performance and meat chemical, microbiological, sensory and nutritional quality. 2. Male and female day-old Ross 308 chicks were fed on a standard commercial diet containing 0, 2.5, 5 or 10 g/kg feed ground M. officinalis for 84 d before slaughter. 3. Weight gain and feed conversion ratio were significantly improved in the broilers receiving either 5 or 10 mg M. officinalis/kg feed. 4. Inclusion of M. officinalis did not affect muscle chemical and fatty acid composition. 5. On the basis of microbiological and sensory experimental data and subsequent extension of meat shelf life, M. officinalis did not reduce the microbial populations of the meat, but was effective in limiting lipid oxidation. PMID- 25299878 TI - High performance organic photovoltaics with plasmonic-coupled metal nanoparticle clusters. AB - Performance enhancement of organic photovoltaics using plasmonic nanoparticles has been limited without interparticle plasmon coupling. We demonstrate high performance organic photovoltaics employing gold nanoparticle clusters with controlled morphology as a plasmonic component. Near-field coupling at the interparticle gaps of nanoparticle clusters gives rise to strong enhancement in localized electromagnetic field, which led to the significant improvement of exciton generation and dissociation in the active layer of organic solar cells. A power conversion efficiency of 9.48% is attained by employing gold nanoparticle clusters at the bottom of the organic active layer. This is one of the highest efficiency values reported thus far for the single active layer organic photovoltaics. PMID- 25299879 TI - An introduction to evolutionary developmental psychology. AB - Evolutionary developmental psychology represents a synthesis of modern evolutionary theory and developmental psychology. Here we introduce the special issue on evolutionary developmental psychology by briefly discussing the history of this field and then summarizing the variety of topics that are covered. In this special issue, leading researchers provide a collection of theoretical and empirical articles that highlight recent findings and propose promising areas for future research. PMID- 25299866 TI - Detection and management of drug-resistant tuberculosis in HIV-infected patients in lower-income countries. AB - SETTING: Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE: To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN: We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n = 14), East Africa (n = 8), West Africa (n = 7), Central Africa (n = 5), Latin America (n = 7) and the Asia-Pacific (n = 6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs. RESULTS: Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11 (23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS: Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance. PMID- 25299880 TI - A life history theory of father absence and menarche: a meta-analysis. AB - Is the absence of biological fathers related to their daughters' earlier age at menarche? Drawing on evolutionary psychology and life history theory, prior research has suggested such a relationship (Belsky, Steinberg, and Draper, 1991; Draper and Harpending, 1982; Ellis, 2004). Although qualitative reviews have shown narrative support for this relationship (Allison and Hyde, 2013; Ellis, 2004; Kim, Smith, and Palermiti, 1997; Susman and Dorn, 2009), no quantitative review exists to provide empirical support for this relationship or to explain mixed results. Thus, we conducted a random-effects meta-analysis of correlations (Card, 2012) on father absence and daughter menarcheal age (k=33; N=70,403). The weighted mean correlation was .14, 95% CI [.09, .19], suggesting that father absence was significantly related to earlier menarche; effect sizes were heterogeneous. Egger's regression (Egger, Smith, Schneider, and Minder, 1997) showed no evidence of publication bias (file-drawer effect; r=.34, p=.052). Outcome measure differences (menarcheal age vs. menarcheal age embedded in a multi-item pubertal timing scale) did not moderate effect sizes. Study year effects (Schooler, 2011) were also non-significant. Our findings support one aspect of the life history model and provide groundwork for subsequent examination of other pathways in the model. PMID- 25299881 TI - Childhood context explains cultural variance in implicit parenting motivation: results from two studies with six samples from Cameroon, Costa Rica, Germany, and PR China. AB - We investigated the effect of the childhood context variables number of siblings (study 1 and 2) and parental SES (study 2) on implicit parenting motivation across six cultural samples, including Africa (2xCameroon), Asia (PR China), Europe (2xGermany), and Latin America (Costa Rica). Implicit parenting motivation was assessed using an instrument measuring implicit motives (OMT, Operant Multimotive Test; Kuhl and Scheffer, 2001). Replicating and extending results from previous studies, regression analyses and structural equation models show that the number of siblings and parental SES explain a large amount of cultural variance, ranging from 64% to 82% of the cultural variance observed in implicit parenting motivation. Results are discussed within the framework of evolutionary developmental psychology. PMID- 25299882 TI - Ontogeny and social dominance: a developmental view of human power patterns. AB - Developmental science has long evolutionary roots and has historically focused on individual differences. Accordingly, developmental models can inform conversations about phylogeny and personality. The present paper evokes life history theory to describe a theoretical model of competitive behavior that applies to both children and adults (resource control theory: RCT). The model suggests that prosocial and coercive behavior, though different in manifest form, serve similar evolutionary functions. Accordingly, RCT presents a view on social dominance that gives primacy to function over form that contrasts sharply from traditional views. This reformulation gives rise to novel questions (both developmental and non-developmental) and challenges long accepted views on prosociality (e.g., that it is altruistic) and aggression (e.g., that it is maladaptive). Similarly, RCT gives rise to a minority perspective that aligns aggression with social competence. PMID- 25299883 TI - From hitting to tattling to gossip: an evolutionary rationale for the development of indirect aggression. AB - Adult humans are characterized by low rates of intra-group physical aggression. Since children tend to be more physically aggressive, an evolutionary developmental account shows promise for explaining how physical aggression is suppressed in adults. I argue that this is achieved partly through extended dominance hierarchies, based on indirect reciprocity and linguistic transmission of reputational information, mediated by indirectly aggressive competition. Reviewing the literature on indirect and related forms of aggression provides three pieces of evidence for the claim that evolutionarily old impulses towards physical aggression are socialized into indirect aggression in humans: (i) physical aggression falls in early childhood over the same age range at which indirect aggression increases; (ii) the same individuals engage in both direct and indirect aggression; and (iii) socially dominant individuals practice indirect aggression more frequently. Consideration of the developmental course of indirect aggression is complemented by analysis of similar developments in verbal behaviors that are not always thought of as aggressive, namely tattling and gossip. An important puzzle concerns why indirect aggression becomes more covert, and tattling more derogated, in preadolescence and adolescence. This may be due to the development of new strategies aimed at renegotiating social identity and friendship alliances in the peer group. PMID- 25299884 TI - Social defense: an evolutionary-developmental model of children's strategies for coping with threat in the peer group. AB - Navigating the ubiquitous conflict, competition, and complex group dynamics of the peer group is a pivotal developmental task of childhood. Difficulty negotiating these challenges represents a substantial source of risk for psychopathology. Evolutionary developmental psychology offers a unique perspective with the potential to reorganize the way we think about the role of peer relationships in shaping how children cope with the everyday challenges of establishing a social niche. To address this gap, we utilize the ethological reformulation of the emotional security theory as a guide to developing an evolutionary framework for advancing an understanding of the defense strategies children use to manage antagonistic peer relationships and protect themselves from interpersonal threat (Davies and Sturge-Apple, 2007). In this way, we hope to illustrate the value of an evolutionary developmental lens in generating unique theoretical insight and novel research directions into the role of peer relationships in the development of psychopathology. PMID- 25299885 TI - An evolutionary model of the environmental conditions that shape the development of prosociality. AB - The current review presents a model for how prosocial development is driven by sociocognitive mechanisms that have been shaped by natural selection to translate critical environmental factors into locally adaptive levels of prosociality. This is done through a synthesis of two existing literatures. Evolutionary developmental psychologists have demonstrated a biological basis for the emergence of prosocial behavior early in youth, and work based on social learning theory has explored how social experiences can influence prosociality across development. The model forwarded organizes this latter literature in a way that is specific to how the biological mechanisms underpinning prosociality have evolved. This consists of two main psychological mechanisms. 1) A domain-specific program that is responsive to environmental factors that determine the relative success of different levels of prosociality. It uses the local prevalence of prosocial others (i.e., support) and expectations for prosocial behavior (i.e., structure) to guide prosocial development. 2) The domain-general process of cultural learning, by which youth adopt local social norms based on the examples of others. Implications and hypotheses are articulated for both the sociocognitive structure of the individual and the role of social contexts. PMID- 25299886 TI - Revisiting the survival mnemonic effect in children. AB - The survival processing paradigm is designed to explore the adaptive nature of memory functioning. The mnemonic advantage of processing information in fitness relevant contexts, as has been demonstrated using this paradigm, is now well established, particularly in young adults; this phenomenon is often referred to as the "survival processing effect." In the current experiment, we revisited the investigation of this effect in children and tested it in a new cultural group, using a procedure that differs from the existing studies with children. A group of 40 Portuguese children rated the relevance of unrelated words to a survival and a new moving scenario. This encoding task was followed by a surprise free recall task. Akin to what is typically found, survival processing produced better memory performance than the control condition (moving). These data put on firmer ground the idea that a mnemonic tuning to fitness-relevant encodings is present early in development. The theoretical importance of this result to the adaptive memory literature is discussed, as well as potential practical implications of this kind of approach to the study of memory in children. PMID- 25299888 TI - Does playing pay? The fitness-effect of free play during childhood. AB - Evolutionary developmental psychology claims that the sequences and processes of human development, in fact the mere fact of ontogeny itself, have to be viewed as evolutionary products. However, although the functional benefits of childish behavior (child playing) for cognitive and emotional development have been shown repeatedly, claiming evolutionary adaptiveness of playing in childhood suggests that childish play supports evolutionary success in mature stages of development. This hypothesis is tested in a study with N=134 adults (93 females; age range 20 66 years). Participants were asked to recollect their play experiences during childhood in detail, and to report their current developmental status with respect to several aspects of social success. Results show that the opportunity for and the promotion of free play in childhood significantly predict some indicators of social success. Additional analyses strive to explore mediating processes for this relationship. In particular, the mediating role of individual adaptivity (flexibility of goal adjustment) is investigated. Results suggest that freely playing in childhood promotes developmental resources, in particular individual adaptivity in adulthood, which, in turn, promote developmental success. PMID- 25299887 TI - Evolution, development, and the emergence of disgust. AB - Evolutionary developmental psychology typically utilizes an evolutionary lens to explain various phenomena that occur throughout development. In this paper, I argue that the converse is also important: Developmental evidence can inform evolutionary theory. In particular, knowledge about the developmental origins of a psychological trait can be used to evaluate theoretical claims about its evolved function. I use the emotion of disgust as a case study to illustrate this approach. Disgust is commonly thought to be a behavioral adaptation for avoiding the ingestion of pathogens. Given this claim, disgust should be expected to develop at a time when humans are especially vulnerable to the dangers of ingesting pathogens, during the immediate post-weaning period from about 3 to 5 years of age. Despite a strong selective pressure at this point in development, research has suggested that the emotion of disgust and the recognition of the "disgust face" do not reliably emerge until later in ontogeny, at 5 years of age or after. Given the late developmental appearance of disgust, I re-evaluate claims about its adaptive role. PMID- 25299889 TI - Comparative developmental psychology: how is human cognitive development unique? AB - The fields of developmental and comparative psychology both seek to illuminate the roots of adult cognitive systems. Developmental studies target the emergence of adult cognitive systems over ontogenetic time, whereas comparative studies investigate the origins of human cognition in our evolutionary history. Despite the long tradition of research in both of these areas, little work has examined the intersection of the two: the study of cognitive development in a comparative perspective. In the current article, we review recent work using this comparative developmental approach to study non-human primate cognition. We argue that comparative data on the pace and pattern of cognitive development across species can address major theoretical questions in both psychology and biology. In particular, such integrative research will allow stronger biological inferences about the function of developmental change, and will be critical in addressing how humans come to acquire species-unique cognitive abilities. PMID- 25299890 TI - Factors associated with diagnostic accuracy when performing a preablation renal biopsy. AB - BACKGROUND AND PURPOSE: Long-term treatment of patients undergoing definitive management of a small renal mass depends largely on the final pathology determination. Preablation renal biopsy (PABx) is often the only source of determining pathology in patients undergoing thermal ablation of a small renal mass. We sought to evaluate patient and tumor characteristics that may play a role in determining the accuracy of a PABx obtained during radiofrequency ablation (RFA). METHODS: This retrospective study included a review of our prospectively collected database of all laparoscopic and CT-guided RFA (LRFA; CTRFA) performed in our center from November 2001 to July 2013. Three 18-gauge core biopsies were obtained per tumor. Pathology samples were stratified into diagnostic (group 1) and nondiagnostic (ND) (group 2). We used univariate and multivariate analysis to identify potential biopsy result-modifying factors including patient characteristics (age, body mass index [BMI]), biopsy approach (CTRFA vs LRFA), tumor size, orientation, depth, and polarity. RESULTS: A total of 463 treatments in 411 patients were evaluated. Of these, 66% were CTRFA while 34% were LRFA. Mean patient age was 67.4 years (31-88), mean BMI was 28.3 kg/m(2) (16.6-47.2), and mean tumor size was 2.6 cm (0.3-5.5). There was a total of 73 (15.8%) ND biopsies. On multivariate analysis, CTRFA and medial tumors managed with either CTRFA or LRFA were found to be associated with an increased likelihood of a ND biopsy. CONCLUSION: PABx obtained in patients undergoing CTRFA and from medial tumors managed with either CTRFA or LRFA were more likely to be ND. Future RFA patients should be counseled appropriately. Additional biopsy cores may be needed in these subgroups. Further prospective studies are warranted to confirm these findings. PMID- 25299891 TI - Preschoolers' narrative representations and childhood adaptation in an ethnoracially diverse sample. AB - This investigation evaluated relations between preschoolers' representational content and coherence in the MacArthur Story Stem Battery (MSSB) at age four as related to child adjustment at age six. A community sample of 250 preschoolers (50% female; M(age) = 49.05 months, SD = 2.9; 46% Hispanic, 18% Black, 11.2% White, 0.4% Asian, and 24.4% multiracial) completed assessments of relational representations using the MSSB at age four and of child adjustment at age six, including a measure of child-reported depressive symptomatology and observer ratings of child aggression during a Bobo doll task and inhibitory control during a delay of gratification task. Regression analyses demonstrated prospective relations between negative mother representation and less inhibitory control, negative child representation and higher aggression, and narrative coherence and more inhibitory control. Interactive analyses revealed relations between negative mother representation and difficulties in inhibitory control among White children and weaker relations among Black children. Prospective relations between narrative coherence and increased inhibitory control were less pronounced for Hispanic children. Findings indicate that preschoolers' narratives can reveal the thematic content and structural coherence of their internalized beliefs and expectations of self and (m)other. Associations between representations and children's adaptation have clear implications for representational processes and interventions in development. PMID- 25299892 TI - Time to deliver. PMID- 25299893 TI - First PI3k inhibitor launches into crowded hematology markets. PMID- 25299895 TI - Apple moves on health, drug developers shift into smart gear. PMID- 25299901 TI - Pharma partners with efforts to pool patient genotype and phenotype data. PMID- 25299902 TI - Insomniacs get new mechanism sleep drug Belsomra. PMID- 25299905 TI - NRC revisits GE crop risks. PMID- 25299908 TI - Gaucher's disease oral therapy gets nod from FDA. PMID- 25299909 TI - Second MRSA antibiotic reaches the market. PMID- 25299910 TI - The price of priority review: $67.5 million. PMID- 25299913 TI - First rounders podcast: Mary Tanner. PMID- 25299912 TI - Corporate venture capital and Cambridge. PMID- 25299914 TI - Nature's contribution to today's pharmacopeia. PMID- 25299915 TI - Development of the clinical next-generation sequencing industry in a shifting policy climate. PMID- 25299916 TI - Restoring the pharmaceutical industry's reputation. PMID- 25299917 TI - Biopharmaceutical benchmarks 2014. PMID- 25299918 TI - The scope of patent protection for gene technology in China. PMID- 25299920 TI - How deep is enough in single-cell RNA-seq? PMID- 25299921 TI - A blueprint of cell identity. PMID- 25299922 TI - Miniaturizing wireless implants. PMID- 25299924 TI - Bridging the gap between invention and commercialization in medical devices. PMID- 25299926 TI - Thrombotic risk in the antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or pregnancy morbidity in patients with persistent presence of antiphospholipid antibodies (aPL). Patients who are diagnosed with APS are identified to have a high risk of recurrent thrombosis, which can occur despite anticoagulant therapy. The optimal type, intensity, and duration of anticoagulant therapy for the treatment of APS remain controversial issues, particularly for arterial thrombosis and recurrent thrombosis. Patients with persistently positive testing for lupus anticoagulant and elevated levels of anticardiolipin antibodies and anti-beta2 glycoprotein I antibodies-known as triple positivity-appear to be at increased risk for thrombosis compared with patients who test positive for a single aPL. Recognizing that patients with APS may potentially have different thrombotic risk profiles may assist clinicians in assessing the risks, benefits, and optimal duration of anticoagulation. Future studies that delineate thrombotic risk in APS and evaluate current and novel anticoagulants as well as nonanticoagulant therapies are required. PMID- 25299927 TI - Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges. AB - Acquired hemophilia A (AHA) should be suspected in patients with a new onset of bleeding and an isolated prolongation of activated partial thromboplastin time. About 10% of patients do not bleed at the time of diagnosis, but are at risk of future bleeding, particularly during interventions or surgery. Diagnosis of AHA is confirmed by demonstrating markedly reduced factor VIII activity (FVIII:C) and neutralizing anti-FVIII antibodies, so-called inhibitors. Several limitations and pitfalls exist with the assays used to diagnose AHA. Interference can result from anticoagulants or lupus anticoagulant. The Bethesda assay used to measure inhibitor potency assumes a log-linear relationship between inhibitor concentration and effect on residual FVIII:C activity to allow exact quantification. However, this relationship is not present for the type 2 inhibitors typically seen in AHA. Therefore, this assay only provides a rough estimate of inhibitor potency. These limitations can explain, in part, why laboratory data, such as inhibitor potency, failed to predict bleeding or response to treatment in AHA. This article reviews the diagnostic approach to AHA, discusses assay-specific limitations and addresses some of the challenges for future research. PMID- 25299928 TI - Density and energy distribution of interface states in the grain boundaries of polysilicon nanowire. AB - Wafer-scale fabrication of semiconductor nanowire devices is readily facilitated by lithography-based top-down fabrication of polysilicon nanowire (P-SiNW) arrays. However, free carrier trapping at the grain boundaries of polycrystalline materials drastically changes their properties. We present here transport measurements of P-SiNW array devices coupled with Kelvin probe force microscopy at different applied biases. By fitting the measured P-SiNW surface potential using electrostatic simulations, we extract the longitudinal dopant distribution along the nanowires as well as the density of grain boundaries interface states and their energy distribution within the band gap. PMID- 25299929 TI - Clinically essential requirement for brain CT with iterative reconstruction: author reply. PMID- 25299930 TI - Stable H and O isotope variations reveal sources of recharge in Dhofar, Sultanate of Oman. AB - Due to the ability of stable water isotopes to characterize the origin of water and connected processes of groundwater recharge, we used the isotope variations of hydrogen and oxygen in different water sources for assessing the recharge process in the Dhofar region. delta(18)O and delta(2)H of precipitation, spring water, and groundwater cover a range from -10 to +2 and from -70 to +7 0/00 (vs Vienna Standard Mean Ocean Water), respectively, and correlate in a linear relationship close to the Global Meteoric Water Line. No obvious evaporation processes are detected. A clear signal of the recent precipitation is given by the annual monsoon. The monsoon signal is confirmed by several springs existing in the south at the foot of the Dhofar mountains and sources at Gogub above 450 m and Tawi Atir at 650 m above sea level. They occur here first in the form of water intercepted by trees as stemflow and throughflow. The isotope signature of groundwater in the Dhofar mountains reflects the climatic conditions at the time of recharge and the lithological features of the limestone matrix. To the north, the isotope patterns of the groundwater are continuously depleted from the monsoon signal along the outcropping aquifer D (Lower Umm Er Radhuma). Here, a more negative signature towards the wells in the Najd desert region was observed. Cyclone water that flooded wadis in the Dhofar region occasionally, as observed in November 2011, falls isotopically into the same range as we observed in the fossil groundwater. Taking into account the different sources of precipitation and groundwater and thus a clear distinction of the isotopic composition of the water sources, we conclude a recharge process divided into a southward and a northward component in the Dhofar region. PMID- 25299932 TI - The need to develop a strategy for managing incidental findings on maxillofacial imaging studies: a call for action. PMID- 25299931 TI - Dynamic contrast-enhanced MRI for differentiation of major salivary glands neoplasms, a 3-T MRI study. AB - OBJECTIVES: Pre-operative differentiation of salivary gland neoplasms is of great importance. This study was designed to evaluate the use of dynamic contrast enhanced MRI (DCE-MRI) for differentiation between malignant, Warthin and benign non-Warthin (BNW) neoplasms of major salivary glands. METHODS: 46 major salivary gland tumours (SGTs) underwent pre-operative DCE-MRI. Post-surgical histopathological evaluation showed 30 BNW, 6 Warthin and 10 malignant tumours. Time-signal intensity curves (TICs) were categorized as (a) Tpeak >43 s and washout ratio at 180 s (WR180) <4.6%; (b) Tpeak <43 s and WR >22%; (c) Tpeak >43 s and WR180 = 4.6-22.0% RESULTS: Accuracy of Tpeak was 98.9% for differentiation between BNW and Warthin tumours, 83.7% between BNW and malignant and 80% between malignant and Warthin tumours. All Warthin tumours showed Tpeak <=43 s, while one BNW had Tpeak <43 s. A Tpeak <63.5 s differentiated 8/10 (80%) malignant tumours from BNW tumours, whereas 4/30 of BNW tumours had a Tpeak <63.5 s. Two malignant tumours had Tpeak <43 s. WR180 had an accuracy of 100% for differentiation between Warthin and BNW tumours, 87.3% between BNW and malignant, and 93.3% between Warthin and malignant tumours. 29 (96.7%) BNW tumours had a washout <4.60%, while 8 (80%) malignant tumours had a washout >4.60%. All Warthin tumours had a WR180 >22%, while two malignant tumours had a WR180 >22%. 29/30 of BNW tumours demonstrated TIC curve Type A and 1 tumour demonstrated Type C. 6/10 of malignant tumours had TIC Type C, 2 had TIC Type A and 2 Type B. All Warthin tumours were categorized as Type B. CONCLUSIONS: This study showed that DCE-MRI could be helpful in pre-operative differentiation of SGTs; especially for discrimination between Warthin and BNW tumours. PMID- 25299933 TI - Effect of wrinkles on the surface area of graphene: toward the design of nanoelectronics. AB - Graphene has attracted intense attention to the use in extreme applications. However, its small thickness facilitates wrinkle formation, and it is not clear how such structural change affects its area-specific capacitance. Herein, we combine molecular dynamics and continuum mechanics-based simulations to study the changes in surface area induced by wrinkles. We find that the high specific surface area of graphene can only be affected up to 2% regardless of loading conditions, geometry, and defects. PMID- 25299934 TI - The epidemiology of herpes simplex virus eye disease in Northern California. AB - PURPOSE: To calculate the incidence and prevalence of herpes simplex virus (HSV) eye disease in a large, well-defined population in Northern California, USA, and to determine the recurrence rate following an initial episode of disease in this cohort. METHODS: A retrospective, observational, cohort study using population based data and medical record review. The patient database of a large, regional health maintenance organization (Northern California Kaiser Permanente) was searched, and the study population consisted of 1,042,351 people over a 1-year study period from 1 July 1998 through 30 June 1999. Only ocular HSV cases with definitive clinical or laboratory confirmed diagnoses were included. Active and inactive cases were included, however only active cases were used in incidence and prevalence calculations. Bilateral disease was counted as one case. Newly diagnosed cases were followed for recurrence from initial presentation through 31 December 2002. RESULTS: After chart review of 322 possible cases, 71 new cases and 59 previously diagnosed active cases of ocular HSV were confirmed. This resulted in an incidence rate of 6.8 new cases/100,000 person-years (95% confidence interval, CI, 5.3-8.6). Incidence increased with age, and rates were highest in people over 75 years of age (p < 0.001). The recurrence rate in new cases was 18% for the 3-year follow-up time, and was equal to 5% per year (95% CI 3-9%). CONCLUSION: The incidence and prevalence of ocular herpes simplex in this study was lower than previously reported. Incidence increased with age, and there were significantly higher rates in the older population. PMID- 25299935 TI - Alumina polymorphs affect the metal immobilization effect when beneficially using copper-bearing industrial sludge for ceramics. AB - The feasibility of recycling copper-bearing industrial sludge as a part of ceramic raw materials was evaluated through thermal interaction of sludge with aluminum-rich precursors. To observe copper incorporation mechanism, mixtures of copper-bearing sludge with alumina polymorphs (gamma-Al2O3 and alpha-Al2O3) were fired between 750 and 1250 degrees C. Different copper-hosting phases were identified by X-ray diffraction, and CuAl2O4 was found to be the predominant phase throughout the reactions. The experimental results indicate different CuAl2O4 initiating temperatures for two alumina materials, and the optimal temperature for CuAl2O4 formation is around 1100 degrees C. To monitor the stabilization effect, prolonged leaching tests were carried out to leach sintered products for up to 20d. The results clearly demonstrate a substantial decrease in copper leachability for products with higher CuAl2O4 content formed from both alumina precursors despite their different sintering behavior. Meanwhile, the leachability of aluminum was much lower than that of copper, and it decreased by more than fourfold through the formation of CuAl2O4 spinel in gamma-Al2O3 system. This study clearly indicates spinel formation as the most crucial metal stabilization mechanism when sintering multiphase copper-bearing industrial sludge with aluminum-rich ceramic raw materials, and suggests a promising and reliable technique for reusing industrial sludge. PMID- 25299936 TI - Probing the origins of catalytic discrimination between phosphate and sulfate monoester hydrolysis: comparative analysis of alkaline phosphatase and protein tyrosine phosphatases. AB - Catalytic promiscuity, the ability of enzymes to catalyze multiple reactions, provides an opportunity to gain a deeper understanding of the origins of catalysis and substrate specificity. Alkaline phosphatase (AP) catalyzes both phosphate and sulfate monoester hydrolysis reactions with a ~10(10)-fold preference for phosphate monoester hydrolysis, despite the similarity between these reactions. The preponderance of formal positive charge in the AP active site, particularly from three divalent metal ions, was proposed to be responsible for this preference by providing stronger electrostatic interactions with the more negatively charged phosphoryl group versus the sulfuryl group. To test whether positively charged metal ions are required to achieve a high preference for the phosphate monoester hydrolysis reaction, the catalytic preference of three protein tyrosine phosphatases (PTPs), which do not contain metal ions, were measured. Their preferences ranged from 5 * 10(6) to 7 * 10(7), lower than that for AP but still substantial, indicating that metal ions and a high preponderance of formal positive charge within the active site are not required to achieve a strong catalytic preference for phosphate monoester over sulfate monoester hydrolysis. The observed ionic strength dependences of kcat/KM values for phosphate and sulfate monoester hydrolysis are steeper for the more highly charged phosphate ester with both AP and the PTP Stp1, following the dependence expected based on the charge difference of these two substrates. However, the dependences for AP were not greater than those of Stp1 and were rather shallow for both enzymes. These results suggest that overall electrostatics from formal positive charge within the active site is not the major driving force in distinguishing between these reactions and that substantial discrimination can be attained without metal ions. Thus, local properties of the active site, presumably including multiple positioned dipolar hydrogen bond donors within the active site, dominate in defining this reaction specificity. PMID- 25299938 TI - Synthesis of the tetrasaccharide repeating unit of the O-glycan from the polar flagellum flagellin of Azospirillum brasilense Sp7. AB - Chemical synthesis of the tetrasaccharide repeating unit of the O-glycan from the polar flagellum flagellin of Azospirillum brasilense Sp7 in the form of its p methoxyphenyl glycoside is reported. The required glycosidic linkages have been accomplished by activation of thioglycosides with N-iodosuccinimide in the presence of H2SO4-silica. H2SO4-silica was found to be an effective alternative to the classical acid promoters like TfOH or TMSOTf and it can lead to the formation of both 1,2-cis and 1,2-trans glycosidic linkages depending on the protecting group manipulation and control of the reaction condition. PMID- 25299937 TI - Database and data analysis application for structural characterization of gangliosides and sulfated glycosphingolipids by negative ion mass spectrometry. AB - Gangliosides and sulfated glycosphingolipids, as building and functional components of animal cell membranes, participate in cell-to-cell interactions and signaling, but also in changes of cell architecture due to different pathophysiological events. In order to enable higher throughput and to facilitate structural characterization of gangliosides/sulfo-glycosphingolipids (GSL) and their neutral GSL counterparts by negative ion mass spectrometry (MS) and tandem MS techniques, a database and data analysis application have been developed. In silico developed glycosphingolipid database considers a high diversity of ceramide compositions, several sialic acid types (N-acetylneuraminic acid, N glycolylneuraminic acid and 2-keto-3-deoxynononic acid) as well as possible additional substitutions/modifications of glycosphingolipids, such as O acetylation, de-N-acetylation, fucosylation, glucuronosylation, sulfation, attachment of repeating terminal hexose-N-acetylhexosamine- (Hex-HexNAc-)1-6 extension, and possible lactone forms. Data analysis application, named GSL finder, enables correlation of negative ion MS and/or low-energy tandem MS spectra with the database structures. The GSL-database construction and the GSL finder application searching rules are explained. Validation conducted on GD1a fraction as well as on complex mixtures of native gangliosides isolated from different mammalian brain tissues (human fetal and adult brain, and calf brain tissue) demonstrated agreement with previous studies. Plain, fast, and automated routine for structural characterization of gangliosides/sulfated glycosphingolipids and their neutral GSL counterparts described here could facilitate and improve mass spectrometric analysis of complex glycosphingolipid mixtures originating from variety of normal and pathological biomaterial, where it is known that distinctive changes in glycosphingolipid composition occur. PMID- 25299940 TI - Effects of Electronic-State-Dependent Solute Polarizability: Application to Solute-Pump/Solvent-Probe Spectra. AB - Experimental studies of solvation dynamics in liquids invariably ask how changing a solute from its electronic ground state to an electronically excited state affects a solution's dynamics. With traditional time-dependent-fluorescence experiments, that means looking for the dynamical consequences of the concomitant change in solute-solvent potential energy. But if one follows the shift in the dynamics through its effects on the macroscopic polarizability, as recent solute pump/solvent-probe spectra do, there is another effect of the electronic excitation that should be considered: the jump in the solute's own polarizability. We examine the spectroscopic consequences of this solute polarizability change in the classic example of the solvation dye coumarin 153 dissolved in acetonitrile. After demonstrating that standard quantum chemical methods can be used to construct accurate multisite models for the polarizabilities of ground- and excited-state solvation dyes, we show via simulation that this polarizability change acts as a contrast agent, significantly enhancing the observable differences in optical-Kerr spectra between ground- and excited-state solutions. A comparison of our results with experimental solute-pump/solvent-probe spectra supports our interpretation and modeling of this spectroscopy. We predict, in particular, that solute pump/solvent-probe spectra should be sensitive to changes in both the solvent dynamics near the solute and the electronic-state-dependence of the solute's own rotational dynamics. PMID- 25299939 TI - Transcriptional regulation of the human, porcine and bovine OCTN2 gene by PPARalpha via a conserved PPRE located in intron 1. AB - BACKGROUND: The novel organic cation transporter 2 (OCTN2) is the physiologically most important carnitine transporter in tissues and is responsible for carnitine absorption in the intestine, carnitine reabsorption in the kidney and distribution of carnitine between tissues. Genetic studies clearly demonstrated that the mouse OCTN2 gene is directly regulated by peroxisome proliferator activated receptor alpha (PPARalpha). Despite its well conserved role as an important regulator of lipid catabolism in general, the specific genes under control of PPARalpha within each lipid metabolic pathway were shown to differ between species and it is currently unknown whether the OCTN2 gene is also a PPARalpha target gene in pig, cattle, and human. In the present study we examined the hypothesis that the porcine, bovine, and human OCTN2 gene are also PPARalpha target genes. RESULTS: Using positional cloning and reporter gene assays we identified a functional PPRE, each in the intron 1 of the porcine, bovine, and human OCTN2 gene. Gel shift assay confirmed binding of PPARalpha to this PPRE in the porcine, bovine, and the human OCTN2 gene. CONCLUSIONS: The results of the present study show that the porcine, bovine, and human OCTN2 gene, like the mouse OCTN2 gene, is directly regulated by PPARalpha. This suggests that regulation of genes involved in carnitine uptake by PPARalpha is highly conserved across species. PMID- 25299942 TI - Electrodriven selective transport of Cs+ using chlorinated cobalt dicarbollide in polymer inclusion membrane: a novel approach for cesium removal from simulated nuclear waste solution. AB - The work describes a novel and cleaner approach of electrodriven selective transport of Cs from simulated nuclear waste solutions through cellulose tri acetate (CTA)/poly vinyl chloride (PVC) based polymer inclusion membrane. The electrodriven cation transport together with the use of highly Cs+ selective hexachlorinated derivative of cobalt bis dicarbollide, allows to achieve selective separation of Cs+ from high concentration of Na+ and other fission products in nuclear waste solutions. The transport selectivity has been studied using radiotracer technique as well as atomic emission spectroscopic technique. Transport studies using CTA based membrane have been carried out from neutral solution as well as 0.4 M HNO3, while that with PVC based membrane has been carried out from 3 M HNO3. High decontamination factor for Cs+ over Na+ has been obtained in all the cases. Experiment with simulated high level waste solution shows selective transport of Cs+ from most of other fission products also. Significantly fast Cs+ transport rate along with high selectivity is an interesting feature observed in this membrane. The current efficiency for Cs+ transport has been found to be ~100%. The promising results show the possibility of using this kind of electrodriven membrane transport methods for nuclear waste treatment. PMID- 25299943 TI - A novel p.E121G heterozygous missense mutation of SOD1 in an apparently sporadic ALS case with a 14-year course. AB - The frequency of SOD1 mutations differs among populations: in Italy they account for 13.6% of familial ALS and 0.7% of sporadic cases. We describe an apparently sporadic Italian ALS patient, carrying a novel p.E121G heterozygous missense mutation of SOD1, with a 14-year disease course and a prevalent lower motor neuron phenotype, which are not uncommon among SOD1 mutations carriers. To our knowledge, no other mutation of codon 121 of SOD1 has ever been reported. Three in silico models suggest a deleterious effect of the p.E121G mutation. Nevertheless, further studies are necessary to confirm its pathogenic role and to evaluate eventual genotype-phenotype correlations. PMID- 25299941 TI - In vivo volume and hemoglobin dynamics of human red blood cells. AB - Human red blood cells (RBCs) lose ~30% of their volume and ~20% of their hemoglobin (Hb) content during their ~100-day lifespan in the bloodstream. These observations are well-documented, but the mechanisms for these volume and hemoglobin loss events are not clear. RBCs shed hemoglobin-containing vesicles during their life in the circulation, and this process is thought to dominate the changes in the RBC physical characteristics occurring during maturation. We combine theory with single-cell measurements to investigate the impact of vesiculation on the reduction in volume, Hb mass, and membrane. We show that vesicle shedding alone is sufficient to explain membrane losses but not volume or Hb losses. We use dry mass measurements of human RBCs to validate the models and to propose that additional unknown mechanisms control volume and Hb reduction and are responsible for ~90% of the observed reduction. RBC population characteristics are used in the clinic to monitor and diagnose a wide range of conditions including malnutrition, inflammation, and cancer. Quantitative characterization of cellular maturation processes may help in the early detection of clinical conditions where maturation patterns are altered. PMID- 25299944 TI - Ways of sampling voluntary and involuntary autobiographical memories in daily life. AB - Cognitive psychologists have often equaled retrieval of personal events with voluntary recall from autobiographical memory, but more recent research shows that autobiographical memories often come to mind involuntarily-that is, with no retrieval effort. Voluntary memories have been studied in numerous laboratory experiments in response to word-prompts, whereas involuntary memories primarily have been examined in an everyday living context, using a structured diary procedure. However, it remains unclear how voluntary memories sampled in the laboratory map onto self-prompted voluntary memories in daily life. Here, we used a structured diary procedure to compare different types of voluntary autobiographical memories to their involuntary counterparts. The results replicated previous findings with regard to differences between word-prompted voluntary and involuntary memories, whereas there were fewer differences between self-prompted voluntary and involuntary memories. The findings raise the question as to what is the best way of sampling voluntary memories and the best comparison for involuntary memories. PMID- 25299945 TI - Individual differences in cognitive control on self-referenced and other referenced memory. AB - Self-referenced information is better recalled than other-referenced information a mnemonic advantage known as the "self-reference effect" (SRE). By using a modified version of the "think/no-think" (TNT) paradigm (Anderson & Green, 2001), this study examined the effects of cognitive control on the SRE after the encoding stage. The results indicate that individual differences in personality traits and affective states strongly modulated the SRE after the TNT phase. For individuals high in negative cognitive style, an ironic enhancement of negative self-referenced memory produced a "maladaptive" SRE: better memory for negative self-referenced information than for negative other-referenced information, when trying to suppress that information. Before the TNT phase, instead, the SRE was characterized by the opposite bias. These results indicate that (1) the SRE is strongly affected by cognitive control after encoding, and (2) also in the non clinical population, dysfunctional cognitive control can transform the SRE into a "maladaptive" memory bias. PMID- 25299946 TI - Do cortical midline variability and low frequency fluctuations mediate William James' "Stream of Consciousness"? "Neurophenomenal Balance Hypothesis" of "Inner Time Consciousness". AB - William James famously characterized consciousness by 'stream of consciousness' which describes the temporal continuity and flow of the contents of consciousness in our 'inner time consciousness'. More specifically he distinguished between "substantive parts", the contents of consciousness, and "transitive parts", the linkages between different contents. While much research has recently focused on the substantive parts, the neural mechanisms underlying the transitive parts and their characterization by the balance between 'sensible continuity' and 'continuous change' remain unclear. The aim of this paper is to develop so-called neuro-phenomenal hypothesis about specifically the transitive parts and their two phenomenal hallmark features, sensible continuity and continuous change in 'inner time consciousness'. Based on recent findings, I hypothesize that the cortical midline structures and their high degree of variability and strong low frequency fluctuations play an essential role in mediating the phenomenal balance between sensible continuity and continuous change. PMID- 25299947 TI - Ionization energies of three resonance-stabilized radicals: cyclohexadienyl (dn, n = 0, 1, 6, 7), 1-phenylpropargyl, and methylcyclohexadienyl. AB - The ionization energies for three resonance-stabilized radicals are determined: cyclohexadienyl, 1-phenylpropargyl, and methylcyclohexadienyl. The recommended ionization energies are, respectively, 6.820(1), 6.585(1), and 7.232(1) eV. That of cyclohexadienyl is found to be just 0.02 eV above a high level ab initio calculation [Bargholz, A.; Oswald, R.; Botschwina, P. J. Chem. Phys. 2013, 138, 014307], and that of 1-phenylpropargyl is found within the stated error of a recent experimental determination [Holzmeier, F.; Lang, M.; Hemberger, P.; Fischer, I. ChemPhysChem 2014, DOI: 10.1002/cphc.201402446]. The ionization energy of the methylcyclohexadienyl radical is consistent with the ortho isomer. Ionization energies of a range of isotopologues of cyclohexadienyl radical are given, along with their D1 <- D0 origin band positions, which indicate a blue shift of 18 cm(-1) per deuterium atom substituted. The ionization energy of cyclohexadienyl, along with the calculated bond dissociation energy of Bargholz et al., affords a new estimate of the 0 K proton affinity of benzene: 739.7 +/- 2.0 kJ/mol. The ionization energies are discussed in terms of the interplay between radical and cation stabilization energies. PMID- 25299948 TI - Chemoselective reduction of alpha,beta-unsaturated aldehydes using an unsupported nanoporous gold catalyst. AB - The remarkable effect of an unsupported nanoporous gold catalyst (AuNPore) on chemoselective hydrogenation of alpha,beta-unsaturated aldehydes using silane has been described. Enals can be reduced with excellent selectivity, giving the corresponding allylic alcohols in good to high chemical yields. PMID- 25299949 TI - Active sensing and its application to sensor node reconfiguration. AB - This paper presents a perturbation/correlation-based active sensing method and its application to sensor node configuration for environment monitoring. Sensor networks are widely used as data measurement tools, especially in dangerous environments. For large scale environment monitoring, a large number of nodes is required. For optimal measurements, the placement of nodes is very important. Nonlinear spring force-based configuration is introduced. Perturbation/correlation-based estimation of the gradient is developed and it is much more robust because it does not require any differentiation. An algorithm for tuning the stiffness using the estimated gradient for node reconfiguration is presented. The performance of the proposed algorithm is discussed with simulation results. PMID- 25299950 TI - A brightness-referenced star identification algorithm for APS star trackers. AB - Star trackers are currently the most accurate spacecraft attitude sensors. As a result, they are widely used in remote sensing satellites. Since traditional charge-coupled device (CCD)-based star trackers have a limited sensitivity range and dynamic range, the matching process for a star tracker is typically not very sensitive to star brightness. For active pixel sensor (APS) star trackers, the intensity of an imaged star is valuable information that can be used in star identification process. In this paper an improved brightness referenced star identification algorithm is presented. This algorithm utilizes the k-vector search theory and adds imaged stars' intensities to narrow the search scope and therefore increase the efficiency of the matching process. Based on different imaging conditions (slew, bright bodies, etc.) the developed matching algorithm operates in one of two identification modes: a three-star mode, and a four-star mode. If the reference bright stars (the stars brighter than three magnitude) show up, the algorithm runs the three-star mode and efficiency is further improved. The proposed method was compared with other two distinctive methods the pyramid and geometric voting methods. All three methods were tested with simulation data and actual in orbit data from the APS star tracker of ZY-3. Using a catalog composed of 1500 stars, the results show that without false stars the efficiency of this new method is 4~5 times that of the pyramid method and 35~37 times that of the geometric method. PMID- 25299951 TI - Temperature sensing in seawater based on microfiber knot resonator. AB - Ocean internal-wave phenomena occur with the variation in seawater vertical temperature, and most internal-wave detections are dependent on the measurement of seawater vertical temperature. A seawater temperature sensor based on a microfiber knot resonator (MKR) is designed theoretically and demonstrated experimentally in this paper. Especially, the dependences of sensing sensitivity on fiber diameter and probing wavelength are studied. Calculated results show that sensing sensitivity increases with the increasing microfiber diameter with the range of 2.30-3.91 MUm and increases with the increasing probing wavelength, which reach good agreement with results obtained by experiments. By choosing the appropriate parameters, the maximum sensitivity measured can reach to be 22.81 pm/ degrees C. The seawater temperature sensor demonstrated here shows advantages of small size, high sensitivity, easy fabrication, and easy integration with fiber systems, which may offer a new optical method to detect temperature of seawater or ocean internal-wave phenomenon and offer valuable reference for assembling micro sensors used for other parameters related to seawater, such as salinity, refractive index, concentration of NO3- and so on. PMID- 25299952 TI - Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice. AB - Numerous obesity studies have coupled murine models with non-invasive methods to quantify body composition in longitudinal experiments, including X-ray computed tomography (CT) or quantitative nuclear magnetic resonance (QMR). Both microCT and QMR have been separately validated with invasive techniques of adipose tissue quantification, like post-mortem fat extraction and measurement. Here we report a head-to-head study of both protocols using oil phantoms and mouse populations to determine the parameters that best align CT data with that from QMR. First, an in vitro analysis of oil/water mixtures was used to calibrate and assess the overall accuracy of microCT vs. QMR data. Next, experiments were conducted with two cohorts of living mice (either homogenous or heterogeneous by sex, age and genetic backgrounds) to assess the microCT imaging technique for adipose tissue segmentation and quantification relative to QMR. Adipose mass values were obtained from microCT data with three different resolutions, after which the data were analyzed with different filter and segmentation settings. Strong linearity was noted between the adipose mass values obtained with microCT and QMR, with optimal parameters and scan conditions reported herein. Lean tissue (muscle, internal organs) was also segmented and quantified using the microCT method relative to the analogous QMR values. Overall, the rigorous calibration and validation of the microCT method for murine body composition, relative to QMR, ensures its validity for segmentation, quantification and visualization of both adipose and lean tissues. PMID- 25299953 TI - Comparison and characterization of Android-based fall detection systems. AB - Falls are a foremost source of injuries and hospitalization for seniors. The adoption of automatic fall detection mechanisms can noticeably reduce the response time of the medical staff or caregivers when a fall takes place. Smartphones are being increasingly proposed as wearable, cost-effective and not intrusive systems for fall detection. The exploitation of smartphones' potential (and in particular, the Android Operating System) can benefit from the wide implantation, the growing computational capabilities and the diversity of communication interfaces and embedded sensors of these personal devices. After revising the state-of-the-art on this matter, this study develops an experimental testbed to assess the performance of different fall detection algorithms that ground their decisions on the analysis of the inertial data registered by the accelerometer of the smartphone. Results obtained in a real testbed with diverse individuals indicate that the accuracy of the accelerometry-based techniques to identify the falls depends strongly on the fall pattern. The performed tests also show the difficulty to set detection acceleration thresholds that allow achieving a good trade-off between false negatives (falls that remain unnoticed) and false positives (conventional movements that are erroneously classified as falls). In any case, the study of the evolution of the battery drain reveals that the extra power consumption introduced by the Android monitoring applications cannot be neglected when evaluating the autonomy and even the viability of fall detection systems. PMID- 25299954 TI - Sensitivity-improved strain sensor over a large range of temperatures using an etched and regenerated fiber Bragg grating. AB - A sensitivity-improved fiber-optic strain sensor using an etched and regenerated fiber Bragg grating (ER-FBG) suitable for a large range of temperature measurements has been proposed and experimentally demonstrated. The process of chemical etching (from 125 um to 60 um) provides regenerated gratings (at a temperature of 680 degrees C) with a stronger reflective intensity (from 43.7% to 69.8%), together with an improved and linear strain sensitivity (from 0.9 pm/MUepsilon to 4.5 pm/MUepsilon) over a large temperature range (from room temperature to 800 degrees C), making it a useful strain sensor for high temperature environments. PMID- 25299955 TI - Adolescent substance use treatment: the moderating effects of psychopathology on treatment outcomes. AB - The present study tested the influence of co-occurring mental health diagnoses on the relationship between length of stay and treatment outcome among adolescents residing in an inpatient substance abuse treatment facility. Data were collected via record review. Follow-up information was obtained at 7 days and 3 months post discharge. Treatment outcome was defined as abstinence and engagement in recovery activities. Hierarchical linear regression demonstrated that comorbidities differentially moderated the relationship between length of stay and treatment outcome. Results suggest that these adolescents attempt to engage in recovery activities independent of abstinence and may need supplemental aftercare assistance to maintain their efforts. PMID- 25299956 TI - Possible spin frustration in Nd2Ti2O7 probed by muon spin relaxation. AB - Muon spin relaxation on Nd2Ti2O7 (NTO) and NdLaTi2O7 (NLTO) compounds are presented. The time spectra for both compounds are as expected for the paramagnetic state at high temperatures, but deviate from the exponential function below around 100 K. Firstly, the muon spin relaxation rate increases with decreasing temperature and then levels off below around 10 K, which is reminiscent of the frustrated systems. An enhancement of the relaxation rate by a longitudinal field in the paramagnetic state is observed for NTO and eliminated by a magnetic dilution for the NLTO sample. This suggests that the spectral density is modified by a magnetic dilution and thus indicates that the spins behave cooperatively rather than individually. The zero-field measurement at 0.3 K indicates that the magnetic ground state for NTO is ferromagnetic. PMID- 25299957 TI - Studying regioisomer formation in the Pd-catalyzed fluorination of aryl triflates by deuterium labeling. AB - Isotopic labeling has been used to determine that a portion of the desired product in the Pd-catalyzed fluorination of electron-rich, non-ortho-substituted aryl triflates results from direct C-F cross-coupling. In some cases, formation of a Pd-aryne intermediate is responsible for producing undesired regioisomers. The generation of the Pd-aryne intermediate occurs primarily via ortho deprotonation of a L.Pd(Ar)OTf (L = biaryl monophosphine) species by CsF and thus competes directly with the transmetalation step of the catalytic cycle. Deuterium labeling studies were conducted with a variety of aryl triflates. PMID- 25299958 TI - Selective interaction of Hpn-like protein with nickel, zinc and bismuth in vitro and in cells by FRET. AB - Hpn-like (Hpnl) is a unique histidine- and glutamine-rich protein found only in Helicobacter pylori and plays a role on nickel homeostasis. We constructed the fluorescent sensor proteins CYHpnl and CYHpnl_1-48 (C-terminal glutamine-rich region truncated) using enhanced cyan and yellow fluorescent proteins (eCFP and eYFP) as the donor-acceptor pair to monitor the interactions of Hpnl with metal ions and to elucidate the role of conserved Glu-rich sequence in Hpnl by fluorescence resonance energy transfer (FRET). CYHpnl and CYHpnl_1-48 exhibited largest responses towards Ni(II) and Zn(II) over other metals studied and the binding of Bi(III) to CYHpnl was observed in the presence of an excess amount of Bi(III) ions (Kd=115+/-4.8 MUM). Moreover, both CYHpnl and CYHpnl_1-48 showed positive FRET responses towards the binding to Ni(II) and Zn(II) in Escherichia coli cells overexpressing CYHpnl and CYHpnl_1-48, whereas a decrease in FRET upon Bi(III)-binding in E. coli cells overexpressing the latter. Our study provides clear evidence on Hpnl binding to nickel in cells, and intracellular interaction of Hpnl with Bi(III) could disrupt the protein function, thus probably contributing to the efficacy of Bi(III) drugs against H. pylori. PMID- 25299959 TI - Photoswitchable hydride transfer from iridium to 1-methylnicotinamide rationalized by thermochemical cycles. AB - Visible light-triggered hydride transfer from [Cp*Ir(bpy)(H)](+) (1) to organic acids and 1-methylnicotinamide (MNA(+)) is reported (Cp* = pentamethylcyclopentadienyl; bpy = 2,2'-bipyridine). A new thermochemical cycle for determining excited-state hydride donor ability (hydricity) predicted that 1 would be an incredibly potent photohydride in acetonitrile. Phototriggered H2 release was indeed observed from 1 in the presence of various organic acids, providing experimental evidence for an increase in hydricity of at least 18 kcal/mol in the excited state. The rate and product selectivity of hydride transfer to MNA(+) are photoswitchable: 1,4-dihydro-1-methylnicotinamide forms slowly in the dark but rapidly under illumination, and photolysis can also produce doubly reduced 1,4,5,6-tetrahydro-1-methylnicotinamide. PMID- 25299960 TI - Comparative proteomics analysis of Bacillus amyloliquefaciens SQR9 revealed the key proteins involved in in situ root colonization. AB - Bacillus Amyloliquefaciens SQR9 is a well-investigated plant growth-promoting rhizobacteria with strong root colonization capability. To identify the key proteins involved in in situ root colonization and biofilm formation, the proteomic profiles of planktonic and root colonized SQR9 cells were compared. A total of 755 proteins were identified, of which 78 and 95 proteins were significantly increased and deceased, respectively, when SQR9 was colonized on the root. The proteins that were closely affiliated with the root colonization belonged to the functional categories of biocontrol, detoxification, biofilm formation, cell motility and chemotaxis, transport, and degradation of plant polysaccharides. A two-component system protein ResE was increased 100-fold when compared to the planktonic status; impairment of the resE gene postponed the formation of cell biofilm and decreased the root colonization capability, which may be regulated through the spo0A-sinI-yqxM pathway. The SQR9 proteomic data provide valuable clues for screening key proteins in the plant-rhizobacteria interaction. PMID- 25299961 TI - Arctiin blocks hydrogen peroxide-induced senescence and cell death though microRNA expression changes in human dermal papilla cells. AB - BACKGROUND: Accumulating evidence indicates that reactive oxygen species (ROS) are an important etiological factor for the induction of dermal papilla cell senescence and hair loss, which is also known alopecia. Arctiin is an active lignin isolated from Arctium lappa and has anti-inflammation, anti-microbial, and anti-carcinogenic effects. In the present study, we found that arctiin exerts anti-oxidative effects on human hair dermal papilla cells (HHDPCs). RESULTS: To better understand the mechanism, we analyzed the level of hydrogen peroxide (H2O2)-induced cytotoxicity, cell death, ROS production and senescence after arctiin pretreatment of HHDPCs. The results showed that arctiin pretreatment significantly inhibited the H2O2-induced reduction in cell viability. Moreover, H2O2-induced sub-G1 phase accumulation and G2 cell cycle arrest were also downregulated by arctiin pretreatment. Interestingly, the increase in intracellular ROS mediated by H2O2 was drastically decreased in HHDPCs cultured in the presence of arctiin. This effect was confirmed by senescence associated beta galactosidase (SA-beta-gal) assay results; we found that arctiin pretreatment impaired H2O2-induced senescence in HHDPCs. Using microRNA (miRNA) microarray and bioinformatic analysis, we showed that this anti-oxidative effect of arctiin in HHDPCs was related with mitogen-activated protein kinase (MAPK) and Wnt signaling pathways. CONCLUSIONS: Taken together, our data suggest that arctiin has a protective effect on ROS-induced cell dysfunction in HHDPCs and may therefore be useful for alopecia prevention and treatment strategies. PMID- 25299962 TI - Ultrastructural changes of erythrocytes in whole blood after exposure to prospective in silico-designed anticancer agents: a qualitative case study. AB - BACKGROUND: Novel, in silico-designed anticancer compounds were synthesized in our laboratory namely, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16). These compounds were designed to have improved bioavailability when compared to their source compound, 2-methoxyestradiol. This theoretically would be due to their increased binding affinity to carbonic anhydrase II, present in erythrocytes. Since the novel compounds under investigation are proposed to be transported within erythrocytes bound to carbonic anhydrase II, the morphological effect which they may exert on whole blood and erythrocytes is of great significance. A secondary outcome included revision of previously reported procedures for the handling of the whole blood sample. The purpose of this study was twofold. Firstly, the ultrastructural morphology of a healthy female's erythrocytes was examined via scanning electron microscopy (SEM) after exposure to the newly in silico-designed compounds. Morphology of erythrocytes following exposure to ESE 15-ol and ESE-16 for 3 minutes and 24 hours at 22 degrees C were described with the use of SEM. The haemolytic activity of the compounds after 24 hours exposure were also determined with the ex vivo haemolysis assay. Secondly, storage conditions of the whole blood sample were investigated by determining morphological changes after a 24 hour storage period at 22 degrees C and 37 degrees C. RESULTS: No significant morphological changes were observed in the erythrocyte morphology after exposure to the novel anticancer compounds. Storage of the whole blood samples at 37 degrees C for 24 hours resulted in visible morphological stress in the erythrocytes. Erythrocytes incubated at 22 degrees C for 24 hours showed no structural deformity or distress. CONCLUSIONS: From this research the optimal temperature for ex vivo exposure of whole blood samples to ESE-15-ol and ESE-16 for 24 hours was determined to be 22 degrees C. Data from this study revealed the potential of these compounds to be applied to ex vivo study techniques, since no damage occurred to erythrocytes ultrastructure under these conditions. As no structural changes were observed in erythrocytes exposed to ESE-15-ol and ESE-16, further ex vivo experiments will be conducted into the potential effects of these compounds on whole blood. Optimal incubation conditions up to 24 hours for whole blood were established as a secondary outcome. PMID- 25299964 TI - Association between chronic kidney disease and thoracic aortic atherosclerosis detected using transesophageal echocardiography. AB - OBJECTIVE: Accelerated atherosclerosis occurs with a high frequency in patients with chronic kidney disease (CKD). We evaluated the association between CKD and thoracic aortic plaques using transesophageal echocardiography (TEE). METHODS: This study population consisted of 297 patients who underwent TEE. Aortic plaques were evaluated in the proximal thoracic aorta (PTA) (from the ascending aorta to the aortic arch) and the distal thoracic aorta (DTA) (the descending aorta) using TEE. Aortic plaques were defined as complex plaques of >=4 mm thickness and with ulceration or mobile components. CKD was defined as the estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). The association between CKD and aortic plaques was evaluated using multivariate analysis after adjusting for traditional atherosclerotic risk factors. RESULTS: Patients with CKD (n = 144) had a higher incidence of any plaques and complex plaques compared with those without CKD (n = 153) (85% vs. 47% and 42% vs. 17%, respectively, both P < 0.001). Univariate analysis indicated that the presence of CKD was significantly associated with complex plaques both in the DTA and the PTA (both, P < 0.001); however, multivariate analysis indicated that the presence of CKD was associated with only complex plaques in the DTA (P < 0.05), but not with those in the PTA. CONCLUSION: The presence of CKD was associated with complex aortic plaques, with this association being stronger for complex plaques in the DTA than those in the PTA. PMID- 25299965 TI - b-Gamma-glutamyltransferase activity in human vulnerable carotid plaques. AB - OBJECTIVE: The atherosclerotic plaque that is vulnerable to rupture and to superimposed thrombosis is mainly represented by a thin-cap fibroatheroma with or without ulceration/thrombosis and inflammatory infiltrates. Total serum gamma glutamyltransferase (GGT) activity is an independent predictor for cardiovascular events. Four GGT fractions have been identified in plasma and only one of them (b GGT) in atherosclerotic plaques, but the possible role of GGT in plaque pathophysiology has not been assessed yet. We investigated the relationships between plaque b-GGT activity and the histological features of plaque vulnerability. METHODS AND RESULTS: Plaque GGT activity was investigated in 65 patients undergoing carotid endarterectomy; plaques were histologically characterized and immunostained for GGT. Intra-plaque total and fractional GGT activity was determined by a cost-effective test of molecular size exclusion chromatography, and compared with histological markers of plaque vulnerability. Plaque cholesterol content was also measured by chromatography. b-GGT was the only fraction detected within the atherosclerotic plaques and intra-plaque b-GGT activity correlated to plaque cholesterol content (r = 0.667, P < 0.0001), plasma b-GGT and f-GGT fractions (r = 0.249; r = 0.298, both P < 0.05). Higher b-GGT activity was found in thin-cap fibroatheromas and it was associated to histological markers of vulnerable plaques, i.e., larger necrotic areas, greater macrophage infiltration and higher cholesterol content (P < 0.05). CONCLUSIONS: intra-plaque b-GGT activity correlates with the histological markers of vulnerable plaque and with plasma b-GGT in human carotid atherosclerosis; these data support the possible role of b-GGT in clinically significant atherosclerotic disease. PMID- 25299963 TI - The emergence of proton nuclear magnetic resonance metabolomics in the cardiovascular arena as viewed from a clinical perspective. AB - The ability to phenotype metabolic profiles in serum has increased substantially in recent years with the advent of metabolomics. Metabolomics is the study of the metabolome, defined as those molecules with an atomic mass less than 1.5 kDa. There are two main metabolomics methods: mass spectrometry (MS) and proton nuclear magnetic resonance ((1)H NMR) spectroscopy, each with its respective benefits and limitations. MS has greater sensitivity and so can detect many more metabolites. However, its cost (especially when heavy labelled internal standards are required for absolute quantitation) and quality control is sub-optimal for large cohorts. (1)H NMR is less sensitive but sample preparation is generally faster and analysis times shorter, resulting in markedly lower analysis costs. (1)H NMR is robust, reproducible and can provide absolute quantitation of many metabolites. Of particular relevance to cardio-metabolic disease is the ability of (1)H NMR to provide detailed quantitative data on amino acids, fatty acids and other metabolites as well as lipoprotein subparticle concentrations and size. Early epidemiological studies suggest promise, however, this is an emerging field and more data is required before we can determine the clinical utility of these measures to improve disease prediction and treatment. This review describes the theoretical basis of (1)H NMR; compares MS and (1)H NMR and provides a tabular overview of recent (1)H NMR-based research findings in the atherosclerosis field, describing the design and scope of studies conducted to date. (1)H NMR metabolomics-CVD related research is emerging, however further large, robustly conducted prospective, genetic and intervention studies are needed to advance research on CVD risk prediction and to identify causal pathways amenable to intervention. PMID- 25299967 TI - Combination therapy in dyslipidemia: where are we now? AB - Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease: each 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C reduces the incidence of major coronary events, coronary revascularizations, and ischemic stroke by approximately 20%. Statins are a well-established treatment option for dyslipidemia, with LDL-C reduction in the range of 27-55%. Several lipid goal driven guidelines recommend reducing LDL-C to <2.59 mmol/L (100 mg/dL) or <1.81 mmol/L (70 mg/dL) in very high-risk patients. Many patients treated with statins do not reach these goals, and remain at risk of future cardiovascular events. The 2013 American College of Cardiology/American Heart Association guidelines move away from advocating LDL-C treatment targets with focus placed on identifying patients most likely to benefit from high-intensity or moderate-intensity statin therapy. While increasing the statin dose can prove efficacious in some patients, this approach typically offers limited additional LDL-C lowering, and is associated with increased incidence of adverse side effects. Indeed, this has led to the investigation of statins in combination with other lipid-modifying agents for the treatment of dyslipidemia. This review of the evidence for statin use in combination with fibrates, niacin, bile acid sequestrants, and the cholesterol absorption inhibitor, ezetimibe, in dyslipidemic patients at increased risk of cardiovascular disease, explores the impact of such combination therapies on lipids, attainment of lipid targets, inflammatory markers, and on cardiovascular outcomes and pathology. Additionally, new and emerging dyslipidemia treatments are summarized. PMID- 25299968 TI - Unilateral peripapillary intrachoroidal cavitation and optic disk rotation. AB - PURPOSE: To examine the morphology of the optic nerve head in patients with unilateral peripapillary intrachoroidal cavitations (PICCs). METHODS: The hospital-based observational study included patients with unilateral PICCs. Tomographic images of the parapapillary fundus were taken by enhanced depth imaging mode of optical coherent tomography. The ocular biometric parameters were compared between the affected eyes and the contralateral unaffected eyes. RESULTS: The study population consisted of 30 patients with a mean age of 42.7 +/ 13.8 years (range: 22-72 years), mean axial length of 26.7 +/- 2.4 mm (range: 22.00-32.30 mm), and mean refractive error of -8.71 +/- 5.21 diopters (range: 20.50 to +0.50 diopters). In the eyes affected by PICC as compared with the contralateral eyes, the vertical (P = 0.001) and the minimal optic disk diameters (P = 0.01) were significantly shorter, the ratio of minimal to maximal disk diameter was significantly lower (P = 0.03), and the angle of disk rotation was significantly higher (P < 0.001). CONCLUSION: In patients with unilateral PICCS, the eyes with PICCs had optic disks that were more spindlelike configured because of a disk rotation around the vertical axis and around the sagittal axis as compared with the contralateral eyes. PMID- 25299966 TI - The 2013 ACC/AHA cardiovascular prevention guidelines improve alignment of statin therapy with coronary atherosclerosis as detected by coronary computed tomography angiography. AB - The recently released 2013 ACC/AHA guidelines for management of blood cholesterol have substantially increased the number of adults who are eligible for preventive statin therapy. We sought to determine whether eligibility for statin therapy as determined by the 2013 ACC/AHA guideline recommendation is better aligned with the actual presence of coronary artery disease (CAD) as detected by coronary CT angiography (CCTA) when compared to prior guidelines including the 2004 NCEP ATP III and 2011 ESC/EAS guidelines. In this secondary analysis of the prospective observational ROMICAT I (Rule Out Myocardial Infarction with Computer Assisted Tomography) cohort study, we included all men and women aged 40-79 years presenting with acute chest pain but not diagnosed with acute coronary syndrome nor on admission statin. Based on risk factor assessment and lipid data, we determined guideline-based eligibility for statin therapy by the 2013 ACC/AHA, the 2004 NCEP ATP III, and the 2011 ESC/EAS guidelines. We determined the presence and severity of CAD as detected by CCTA. The 2013 ACC/AHA algorithm identified nearly twice as many individuals as eligible for statins (n = 77/189; 41%) as compared to the 2004 ATP III criteria: (n = 41/189; 22%), (p < .0001) In addition, the 2013 ACC/AHA guidelines were more sensitive for treatment of CCTA detected CAD than the 2004 ATP III guidelines [53.4% (42.5-64.1) vs 27.3% (18.3 37.8), p < .001] and the 2011 ESC/EAE guidelines [53.4% (42.5-64.1) vs 34.1% (24.3-45.0), p < .001]. However, the specificity of these guidelines was modestly reduced compared to the 2004 ATP III guidelines [70.3 (60.4-79.0) vs 83.2 (74.4 89.9), p < .001] and the 2011 ESC/EAE guidelines [70.3 (60.4-79.0) vs 86.1 (77.8 92.2), p < .001], suggesting increased treatment of subjects without CCTA detected CAD. Overall, the 2013 ACC/AHA guidelines are more sensitive to identify patients who have CAD detected by CCTA eligible for statin therapy as compared with prior guidelines, with an acceptable trade-off in specificity for recommending statin therapy in those without CAD. PMID- 25299969 TI - Time patterns of recurrences and factors predisposing for a higher risk of recurrence of ocular toxoplasmosis. AB - PURPOSE: To ascertain time patterns of recurrences and factors predisposing for a higher risk of recurrence of ocular toxoplasmosis. METHODS: Retrospective observational case series with follow-up examination. Database of 4,381 patients with uveitis was used. Data of 84 patients with ocular toxoplasmosis (sample group) could be included. RESULTS: Two hundred and eighty active lesions in the first affected eye were detected. The mean number of recurrences per year was 0.29 (standard deviation, 0.24). Median recurrence-free survival time was 2.52 years (95% confidence interval, 2.03-3.02 years). Risk of recurrence was highest in the first year after the most recent episode (26%) implying a decrease with increasing recurrence-free interval. The risk of recurrence decreased with the duration of disease (P < 0.001). Treatment of the first active lesion influenced the risk of recurrence (P = 0.048). Furthermore, the risk of recurrence was influenced by patient age at the time of the first active lesion (P = 0.021) and the most recent episode (P = 0.002). CONCLUSION: A secondary antibiotic prophylaxis could be discussed 1) during the first year after an active lesion has occurred, especially in case of the first active lesion of ocular toxoplasmosis, and 2) in older patients, especially if primarily infected with Toxoplasma gondii at an older age. PMID- 25299971 TI - Columnar organization of stack-assembled trimesic acid on graphene. AB - The stack-assembly of trimesic acid molecules into a highly organized columnar structure and their adsorption on graphene has been investigated by a DFT-based ab initio calculation method. Trimesic acid (TMA, benzene-1,3,5-tricarboxylic acid) constitutes an interesting building block for intermolecular hydrogen bonding architecture by creating a strong net dipole moment which favors a symmetric pi-stacking of molecular wire. Both the single orientation (syn) and alternating orientation (anti) of two- and three-unit TMA configurations are optimized, and determine that anti or AB pattern TMA wire is energetically more favorable than the syn case. Meanwhile, a decreasing band gap during the formation of the molecular wire proves the presence of delocalized pi-electrons over the entire stack-assembly. The adsorption energy for a columnar TMA stack on graphene was found to be roughly less than of a single TMA adsorbed on graphene. The relative contribution of hydrogen bonding to column packing energy showed to be comparative and reasonable, with the energy of a conventional hydrogen bond. The magnitude of the band gap opening appears strongly correlated with the breaking of the symmetry of pi-states of graphene by the TMA columnar patterning on the surface. Our results suggest that a stack-assembled molecular could be used to tune and control the electronic properties of graphene. PMID- 25299970 TI - Thrombophilic risk factors are uncommon in young patients with retinal vein occlusion. AB - PURPOSE: To study the thrombotic factors, namely deficiencies of plasma proteins C, S, and antithrombin, factor V Leiden mutation, and positivity for antiphospholipid antibodies in young patients with retinal vein occlusion. METHODS: The thrombophilia parameters listed above were analyzed from the laboratory records of 50 patients with the clinical diagnosis of retinal vein occlusion, aged less than 50 years. RESULTS: A single prothrombotic factor was seen in 2 (4%) cases. The highest positivity was for the antiphospholipid antibodies (lupus anticoagulant in 6%, anticardiolipin antibodies in 2%, and anti beta 2 glycoprotein 1 in 10% cases). Other than one case where antiphospholipid syndrome was confirmed, these were transient. One patient had antithrombin deficiency. Protein C and protein S deficiency and factor V Leiden mutation were not seen in this group. CONCLUSION: Our data suggest that these thrombophilia risk factors are not commonly associated with retinal vein occlusion, and there is a need for studies on other factors that contribute to the development of this condition. PMID- 25299972 TI - Ultraeffective ZnS nanocrystals sorbent for mercury(II) removal based on size dependent cation exchange. AB - We report a novel nanocrystals (NCs) sorbent, which shows an extraordinary adsorption capacity to aqueous Hg(2+) based on cation exchange and allows for the utmost removal of mercury from water. The NCs sorbent was synthesized by direct coating ZnS NCs on the surface of the alpha-Al2O3 nanoparticles. The as-prepared ZnS NCs sorbent can efficiently remove over 99.9% Hg(2+) in 1 min, and lower the Hg(2+) concentration from 297.5 mg/L (ppm) to below 1.0 MUg/L (ppb) within 5 min. The saturated adsorption capacity of ZnS NCs for Hg(2+) is about 2000 mg/g, which is close to the theoretic saturated adsorption capacity. The mechanism of Hg(2+) removal by ZnS NCs sorbent, the influences of pH value and other cations on Hg(2+) removal were investigated, respectively. Meanwhile, it is found the size dependent cation exchange plays a critical role in the removal of Hg(2+) by ZnS NCs. Small size ZnS NCs shows better performance than the big size ZnS NCs in the adsorption capacity and adsorption rate for Hg(2+). Furthermore, the mercury adsorbed by the ZnS NCs sorbent is readily recycled by extraction with aqueous sodium sulfide. PMID- 25299973 TI - Investigating and biomimicking the surface wetting behaviors of ginkgo leaf. AB - For the first time, the surface composite Cassie-Baxter wetting state is carefully investigated using ginkgo biloba as natural model. Investigations follow two directions: (a) low local solid contact areal fraction leading to high apparent contact angles; and (b) thick air plastron trapped at the contacting interface leading to stable dewetting state. PMID- 25299974 TI - Content Variation of Catechin Markers, Total Phenolics and Caffeine in Green Tea Dietary Supplements. AB - Green tea (Camellia sinensis) preparations are among the top selling products in the United States dietary supplements market. Numerous manufacturers claim different levels of specific catechin markers in their products while many others use total phenolic concentration instead, or not at all. Limited quality control results have been published for green tea dietary supplements over the past seven years. Thus, the goal of this work was to correlate determined levels of phenolics, catechins, and caffeine with manufacturer label claims for selected dietary supplement products (26 total) purchased in the United States. The Folin Ciocalteu (FC) method was used to determine the total phenolic content while reversed-phase (RP) HPLC was used to quantify the major catechins: epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), epigallocatechin gallate (EGCG). The developed HPLC method was validated for accuracy and precision. It utilized a C8 column with gradient elution of acetonitrile in 0.1% aqueous formic acid over 11 min total run time. Peak detection was performed at 280 nm. Caffeine was also included in the HPLC method as another non-phenolic alkaloid marker commonly found in green tea. Both methods showed a good correlation between the content of catechins and polyphenolic compounds in the selected products. The ranges of total catechins and polyphenol concentrations were 3.8-70.2% and 3.6 95.8%, respectively, while that of caffeine was 0.8-11.2%. The selected products displayed a wide range of marker levels. A lack of conformity in disclosing the actual levels of marker compounds was also noticed in the labeling of many products. PMID- 25299976 TI - Medicaid home and community-based services: how consumer access is restricted by state policies. AB - State Medicaid programs have expanded home and community-based services (HCBS). This article compares trends and variations in state policies for Medicaid HCBS programs in 2005 and 2010. State limitations on financial eligibility criteria and service benefits have remained stable. Although the use of consumer direction, independent providers, and family care providers has increased, some states do not have these options. The increased adoption of state cost control policies have led to large increases in persons on waiver wait lists. Access could be improved by standardizing and liberalizing state HCBS policies, but state fiscal concerns are barriers to rebalancing between HCBS and institutional services. PMID- 25299977 TI - Fluorescence spectroscopy of graphene quantum dots: temperature effect at different excitation wavelengths. AB - This paper reports a comprehensive study of temperature dependence of fluorescence spectroscopy of graphene quantum dots at different excitation wavelengths. Very significant (more than 50%) and similar decrease of normalized spectrum intensity is observed within temperature range less than 80 degrees C for excitation wavelengths of 310 nm, 340 nm and 365 nm. Besides, the temperature dependence of the red-shift of spectrum peak shows different wavelength dependence characteristic with coefficient as high as 0.062 nm K(-1) for the same temperature range, which gives us a hint about selecting the right excitation wavelength by compromising the excitation efficiency for fluorescence intensity and the temperature coefficient for peak shift in thermal applications. Temperature dependence of peak width is in a weakly linear relationship with a coefficient of 0.026 nm K(-1). Regarding the excellent stability and reversibility during thermal measurement, graphene quantum dot is a good candidate for the implementation in the nanoscale thermometry, especially in the bio-thermal field considering its superior biocompatibility and low cytotoxicity. PMID- 25299978 TI - Community-based interventions to improve outcomes for cardiovascular disease [letter]. PMID- 25299975 TI - Transcriptional profiling reveals crosstalk between mesenchymal stem cells and endothelial cells promoting prevascularization by reciprocal mechanisms. AB - Mesenchymal stem cells (MSCs) show great promise in blood vessel restoration and vascularization enhancement in many therapeutic situations. Typically, the co implantation of MSCs with vascular endothelial cells (ECs) is effective for the induction of functional vascularization in vivo, indicating its potential applications in regenerative medicine. The effects of MSCs-ECs-induced vascularization can be modeled in vitro, providing simplified models for understanding their underlying communication. In this article, a contact coculture model in vitro and an RNA-seq approach were employed to reveal the active crosstalk between MSCs and ECs within a short time period at both morphological and transcriptional levels. The RNA-seq results suggested that angiogenic genes were significantly induced upon coculture, and this prevascularization commitment might require the NF-kappaB signaling. NF-kappaB blocking and interleukin (IL) neutralization experiments demonstrated that MSCs potentially secreted IL factors including IL1beta and IL6 to modulate NF-kappaB signaling and downstream chemokines during coculture. Conversely, RNA-seq results indicated that the MSCs were regulated by the coculture environment to a smooth muscle commitment within this short period, which largely induced myocardin, the myogenic co-transcriptional factor. These findings demonstrate the mutual molecular mechanism of MSCs-ECs-induced prevascularization commitment in a quick response. PMID- 25299979 TI - Association between living alone and physical inactivity among people with and without disability, Florida Behavioral Risk Factor Surveillance System, 2009. AB - People with disability may be at risk of developing diseases due to physical inactivity; social support from family and friends is positively related to engaging in regular physical activity. We compared the association between living alone and engagement in physical activity among people with and without disability in Florida. We used multivariate logistical regression to analyze 2009 Florida Behavioral Risk Factor Surveillance System data (n = 10,902) to assess differences in physical activity in disability levels for respondents who lived alone versus those who did not. Respondents with a disability were less likely to engage in physical activity than were people without a disability, regardless of disability type, and the lowest rates of engaging in physical activity were found for people with disability who lived alone. Public health efforts should consider the role of household composition when targeting physical activity interventions among people with disability. PMID- 25299981 TI - Joint influence of individual choices, parenting practices, and physician advice on adolescent obesity, Nebraska, 2008. AB - INTRODUCTION: Reducing childhood obesity remains a public health priority given its high prevalence and its association with increased risk of adult obesity and chronic diseases. The objective of this study was to examine the joint influence of multiple risk factors on adolescent overweight status. METHODS: We conducted a random-digit-dialed telephone survey of adolescents aged 12 to 19 years in fall 2008 in a Midwestern city in Nebraska. On the basis of survey data for 791 youths aged 12 to 18 years, we conducted latent class analysis to group youths by the joint occurrence of dietary behavior, physical activity, parenting practices, and physician advice. We then examined the association between the groups and overweight status by using logistic regression, controlling for age, sex, race/ethnicity, and parent and family information. RESULTS: Youths were clustered into 3 groups. Group I (52%) were youths with healthy dietary behavior and physical activity, less permissive parenting practices, and physician advice; Group II (30%) were youths with moderately healthy dietary behavior and physical activity, less permissive parenting practices, and no physician advice; and Group III (18%) were youths with unhealthy dietary behavior and physical activity, permissive parenting practices, and physician advice. Youths in Groups I and II were less likely to be overweight than youths in Group III. CONCLUSIONS: Youths with healthier behavior and less permissive parenting practices were less likely to be overweight. Study findings highlight the need to address obesity risk factors among youths with unhealthy dietary behavior, inadequate exercise, permissive parenting practices, and some physician advice. Tailored interventions should be used to target youths with different obesity risk factors. PMID- 25299980 TI - Obesity and associated factors--Kingdom of Saudi Arabia, 2013. AB - INTRODUCTION: Data on obesity from the Kingdom of Saudi Arabia (KSA) are nonexistent, making it impossible to determine whether the efforts of the Saudi Ministry of Health are having an effect on obesity trends. To determine obesity prevalence and associated factors in the KSA, we conducted a national survey on chronic diseases and their risk factors. METHODS: We interviewed 10,735 Saudis aged 15 years or older (51.1% women) through a multistage survey. Data on sociodemographic characteristics, health-related habits and behaviors, diet, physical activity, chronic diseases, access to and use of health care, and anthropometric measurements were collected through computer-assisted personal interviews. We first compared sociodemographic factors and body mass index between men and women. Next, we conducted a sex-specific analysis for obesity and its associated factors using backward elimination multivariate logistic regression models. We used SAS 9.3 for the statistical analyses and to account for the complex sampling design. RESULTS: Of the 10,735 participants evaluated, 28.7% were obese (body mass index >= 30 kg/m(2)). Prevalence of obesity was higher among women (33.5% vs 24.1%). Among men, obesity was associated with marital status, diet, physical activity, diagnoses of diabetes and hypercholesterolemia, and hypertension. Among women, obesity was associated with marital status, education, history of chronic conditions, and hypertension. CONCLUSION: Obesity remains strongly associated with diabetes, hypercholesterolemia, and hypertension in the KSA, although the epidemic's characteristics differ between men and women. PMID- 25299982 TI - Acculturation and the prevalence of diabetes in US Latino Adults, National Health and Nutrition Examination Survey 2007-2010. AB - INTRODUCTION: US Latinos are growing at the fastest rate of any racial/ethnic group in the United States and have the highest lifetime risk of diabetes. Acculturation may increase the risk of diabetes among all Latinos, but this hypothesis has not been studied in a nationally representative sample. The objective of this study was to test the hypothesis that acculturation was associated with an increased risk of diabetes in such a sample. METHODS: We conducted a cross-sectional analysis including 3,165 Latino participants in the 2007-2010 National Health and Nutrition Examination Survey. Participants with doctor-diagnosed diabetes and participants without diagnosed diabetes who had glycated hemoglobin (HbA1C) values of 6.5% or higher were classified as having diabetes. An acculturation score, ranging from 0 (lowest) to 3 (highest), was calculated by giving 1 point for each of 3 characteristics: being born in the United States, speaking predominantly English, and living in the United States for 20 years or more. Logistic regression was used to determine the association between acculturation and diabetes. RESULTS: The prevalence of diabetes among Latinos in our sample was 12.4%. After adjusting for sociodemographic factors, the likelihood of diabetes (95% confidence interval [CI]) increased with level of acculturation- 1.71 (95% CI, 1.31-2.23), 1.63 (95% CI, 1.11-2.39), and 2.05 (95% CI, 1.27-3.29) for scores of 1, 2, and 3, respectively. This association persisted after further adjustment for body mass index (BMI), total dietary calories, and physical inactivity. CONCLUSION: Acculturation was associated with a higher risk of diabetes among US Latinos, and this risk was only partly explained by BMI and weight-related behaviors. Future research should examine the bio-behavioral mechanisms that underlie the relationship between acculturation and diabetes in Latinos. PMID- 25299983 TI - A qualitative analysis of patient and family perspectives of palliative care. AB - BACKGROUND: To provide truly patient-centered palliative care services, there is a need to better understand the perspectives and experiences of patients and families. Increased understanding will provide insight into the development of health care team competencies and organizational changes necessary to improve patient care. OBJECTIVE: Our aim was to explore patient and family perceptions of palliative care services at the end of life or during serious illness and to identify facilitators and barriers to receipt of palliative care services. METHODS: In-depth, semi-structured patient and family interviews were conducted, transcribed, and independently reviewed using grounded theory methodology and preliminary interpretations. A combined deductive and inductive iterative qualitative approach was used to identify recurring themes. The study was conducted in a physician-led, not-for-profit, multispecialty integrated health system serving three large, western, rural states. A purposive sample of 14 individuals who received palliative care services were interviewed alone or with their families for a total of 12 interviews. RESULTS: Presence, Reassurance, and Honoring Choices emerged as central themes linked to satisfaction with palliative care services. Themes were defined as including health care professional attributes of respect, approachability, genuineness, empathy, connectedness, compassion, sensitivity, an ability to listen, good communication, provision of information, empowerment, and timeliness. Honoring Choices included those pertaining to treatment, spirituality, and family needs. CONCLUSIONS: At end of life or during times of serious illness, patients and families identified behaviors of Presence, Reassurance, and Honoring Choices as important. According to patients/families, health care providers must be compassionate and empathetic and possess skills in listening, connecting, and interacting with patients and families. PMID- 25299984 TI - Aqueous hafnium sulfate chemistry: structures of crystalline precipitates. AB - Crystalline precipitates resulting from the hydrolysis and subsequent condensation of Hf(IV) aqueous acidic solutions at 60-95 degrees C are examined and compared. By varying the concentrations of the acid and sulfate source, a variety of complex hafnium-oxo-hydroxo-sulfate clusters are isolated and structures accessed. Four novel compounds were discovered, while the structures of two known compounds, an 18-mer and a planar hexamer, were updated. In total, the compounds described herein each contain one of four cluster architectures: 18 mer, 11-mer, nonamer, and planar hexamer. In addition, one compound contains small amounts of 19-mers together with 18-mers. As well as examining the individual structure of each complex cluster, we relate them to one another, as well as to the dense phases of HfO2, to gain an understanding of their formation and stability. Finally, the solution conditions under which each cluster forms are identified by plotting the crystallization regions of each cluster against acidity and sulfate concentration. Most clusters form under slightly acidic conditions, in decreasing size as the sulfate concentration is raised. The flat hexamer is the single exception; it appears to require more acidic solutions. The degree of hydroxo- versus oxo-bridges with changing solution conditions is assessed within the broader context of the condensates. Of specific interest is the identification of these products as they relate to the use of hydrolysis reactions in designing new materials. PMID- 25299985 TI - Capillary electrophoresis-chemiluminescence detection for carcino-embryonic antigen based on aptamer/graphene oxide structure. AB - A new strategy is proposed for determination of carcino-embryonic antigen (CEA) based on aptamer/graphene oxide (Apt/GO) by capillary electrophoresis chemiluminescence (CE-CL) detection system. CEA aptamer conjugated with horseradish peroxidase (HRP) firstly mixes with GO, and the CL will be quenched because the stack of HRP-Apt on GO leads to chemiluminescence resonance energy transfer (CRET). When CEA exists, the specific combination of HRP-Apt and CEA can form HRP-Apt-CEA complex, which dissociates from GO. Then, the CL catalyzed by HRP-Apt-CEA complex can be detected without any CRET, and the content of CEA can be estimated by the CL intensity. It has been proved that the interference issue resulted from free HRP-Apt is solved well by mixing GO firstly with HRP-Apt, which blocks the free HRP-Apt's CL signal due to CL quenching effect of GO; and the interference resulted from GO to CL is also solved by CE, then the sensitivity and accuracy can be greatly improved. Results also showed that the CL intensity had a linear relationship with the concentration of CEA in the range from 0.0654 to 6.54 ng/mL, and the limit of detection was approximately 4.8 pg/mL (S/N = 3). This proposed method with high specificity offers a new way for separation and determination of biomolecule, and has good potential in application of biochemistry and bioanalysis. PMID- 25299986 TI - Enhanced photoelectrochemical property of ZnO nanorods array synthesized on reduced graphene oxide for self-powered biosensing application. AB - We have realized the direct synthesis of ZnO nanorods (ZnO NRs) array on reduced graphene layer (rGO), and demonstrated the enhanced photoelectrochemical (PEC) property of the rGO/ZnO based photoanode under UV irradiation compared with the pristine ZnO NRs array. The introduction of the rGO layer resulted in a favorable energy band structure for electron migration, which finally led to the efficient photoinduced charge separation. Such nanostructure was subsequently employed for self-powered PEC biosensing of glutathione in the condition of 0 V bias, with a linear range from 10 to 200 uM, a detection limit of 2.17 uM, as well as excellent selectivity, reproducibility and stability. The results indicated the rGO/ZnO nanostructure is a competitive candidate in the PEC biosensing field. PMID- 25299987 TI - A dumbell probe-mediated rolling circle amplification strategy for highly sensitive transcription factor detection. AB - Highly sensitive detection of transcription factors (TF) is essential to proteome and genomics research as well as clinical diagnosis. We describe herein a novel fluorescent-amplified strategy for ultrasensitive, quantitative, and inexpensive detection of TF. The strategy consists of a hairpin DNA probe containing a TF binding sequence for target TF, a dumbbell-shaped probe, a primer DNA probe designed partly complementary to hairpin DNA probe, and a dumbbell probe. In the presence of target TF, the binding of the TF with hairpin DNA probe will prohibit the hybridization of the primer DNA probe with the "stem" and "loop" region of the hairpin DNA probe, then the unhybridized region of the primer DNA will hybridize with dumbbell probe, subsequently promote the ligation reaction and the rolling circle amplification (RCA), finally, the RCA products are quantified via the fluorescent intensity of SYBR Green I (SG). Using TATA-binding protein (TBP) as a model transcription factor, the proposed assay system can specifically detect TBP with a detection limit as low as 40.7 fM, and with a linear range from 100 fM to 1 nM. Moreover, this assay related DNA probe does not involve any modification and the whole assay proceeds in one tube, which makes the assay simple and low cost. It is expected to become a powerful tool for bioanalysis and clinic diagnostic application. PMID- 25299988 TI - Misrepresentations of evolutionary psychology in sex and gender textbooks. AB - Evolutionary psychology has provoked controversy, especially when applied to human sex differences. We hypothesize that this is partly due to misunderstandings of evolutionary psychology that are perpetuated by undergraduate sex and gender textbooks. As an initial test of this hypothesis, we develop a catalog of eight types of errors and document their occurrence in 15 widely used sex and gender textbooks. Consistent with our hypothesis, of the 12 textbooks that discussed evolutionary psychology, all contained at least one error, and the median number of errors was five. The most common types of errors were "Straw Man," "Biological Determinism," and "Species Selection." We conclude by suggesting improvements to undergraduate sex and gender textbooks. PMID- 25299990 TI - Art as an indicator of male fitness: does prenatal testosterone influence artistic ability? AB - In his groundbreaking research, Geoffrey Miller (1999) suggests that artistic and creative displays are male-predominant behaviors and can be considered to be the result of an evolutionary advantage. The outcomes of several surveys conducted on jazz and rock musicians, contemporary painters, English writers (Miller, 1999), and scientists (Kanazawa, 2000) seem to be consistent with the Millerian hypothesis, showing a predominance of men carrying out these activities, with an output peak corresponding to the most fertile male period and a progressive decline in late maturity. One way to evaluate the sex-related hypothesis of artistic and cultural displays, considered as sexual indicators of male fitness, is to focus on sexually dimorphic traits. One of them, within our species, is the 2nd to 4th digit length (2D:4D), which is a marker for prenatal testosterone levels. This study combines the Millerian theories on sexual dimorphism in cultural displays with the digit ratio, using it as an indicator of androgen exposure in utero. If androgenic levels are positively correlated with artistic exhibition, both female and male artists should show low 2D:4D ratios. In this experiment we tested the association between 2D:4D and artistic ability by comparing the digit ratios of 50 artists (25 men and 25 women) to the digit ratios of 50 non-artists (25 men and 25 women). Both male and female artists had significantly lower 2D:4D ratios (indicating high testosterone) than male and female controls. These results support the hypothesis that art may represent a sexually selected, typically masculine behavior that advertises the carrier's good genes within a courtship context. PMID- 25299991 TI - Dangerous animals capture and maintain attention in humans. AB - Predation is a major source of natural selection on primates and may have shaped attentional processes that allow primates to rapidly detect dangerous animals. Because ancestral humans were subjected to predation, a process that continues at very low frequencies, we examined the visual processes by which men and women detect dangerous animals (snakes and lions). We recorded the eye movements of participants as they detected images of a dangerous animal (target) among arrays of nondangerous animals (distractors) as well as detected images of a nondangerous animal (target) among arrays of dangerous animals (distractors). We found that participants were quicker to locate targets when the targets were dangerous animals compared with nondangerous animals, even when spatial frequency and luminance were controlled. The participants were slower to locate nondangerous targets because they spent more time looking at dangerous distractors, a process known as delayed disengagement, and looked at a larger number of dangerous distractors. These results indicate that dangerous animals capture and maintain attention in humans, suggesting that historical predation has shaped some facets of visual orienting and its underlying neural architecture in modern humans. PMID- 25299992 TI - Covert sexual signaling: human flirtation and implications for other social species. AB - According to signaling theory and a large body of supporting evidence, males across many taxa produce courtship signals that honestly advertise their quality. The cost of producing or performing these signals maintains signal honesty, such that females are typically able to choose the best males by selecting those that produce the loudest, brightest, longest, or otherwise highest-intensity signals, using signal strength as a measure of quality. Set against this background, human flirting behavior, characterized by its frequent subtlety or covertness, is mysterious. Here we propose that the explanation for subtle and ambiguous signals in human courtship lies in socially imposed costs that (a) vary with social context and (b) are amplified by the unusual ways in which language makes all interactions potentially public. Flirting is a class of courtship signaling that conveys the signaler's intentions and desirability to the intended receiver while minimizing the costs that would accompany an overt courtship attempt. This proposal explains humans' taxonomically unusual courtship displays and generates a number of novel predictions for both humans and non-human social animals. Individuals who are courting should vary the intensity of their signals to suit the level of risk attached to the particular social configuration, and receivers may assess this flexible matching of signal to context as an indicator of the signaler's broader behavioral flexibility and social intelligence. PMID- 25299993 TI - The rival wears Prada: luxury consumption as a female competition strategy. AB - Previous studies on luxury consumption demonstrated that men spend large sums of money on luxury brands to signal their mate value to women and, thus, increase their reproductive success. Although women also spend copious amounts of money on luxuries, research focusing on women's motives for luxury consumption is rather scarce. Relying on costly signaling and intrasexual competition theory, the goal of the current study was to test whether female intrasexual competition in a mate attraction context triggers women's spending on luxuries. The results of the first experiment reveal that an intrasexual competition context enhances women's preferences for attractiveness enhancing, but not for non-attractiveness related luxuries such as a smartphone. This finding indicates that women may use luxury consumption as a self-promotion strategy during within-sex competitions, as these luxuries improve their advantages against same-sex rivals for mates. A follow-up study shows that compared to women who do not consume luxuries, women who do so are perceived as more attractive, flirty, young, ambitious, sexy, and less loyal, mature and smart by other women. These results suggest that luxury consumption may provide information about a women's willingness to engage in sex, as well as her views about other women, and consequently, her success in intrasexual competitions. PMID- 25299994 TI - Parental mate choice manipulation tactics: exploring prevalence, sex and personality effects. AB - Parents and children are genetically related but not genetically identical, which means that their genetic interests overlap but also diverge. In the area of mating, this translates into children making mate choices that are not in the best interest of their parents. Parents may then resort to manipulation in order to influence their children's mating decisions in a way that best promotes the former's interests. This paper attempts to identify the structure of manipulation tactics that parents employ on their daughters and sons, as well as on their daughters' and sons' mates, and also to estimate their prevalence. On the basis of the structure of the derived tactics, four hypotheses are tested: Mothers are more willing than fathers to use manipulation tactics; parents are willing to use more manipulation on their daughters than on their sons; the personality of parents predicts the use of tactics on their children and on their children's mates; and the personality of children and of children's mates predicts the use of tactics on them. Evidence from two independent studies provides support for the first three hypotheses, but mixed support for the fourth hypothesis. The implications of these findings are further discussed. PMID- 25299995 TI - The self-regulation effect of fertility status on inbreeding aversion: when fertile, disgust increases more in response to descriptions of one's own than of others' inbreeding. AB - The ovulatory shift modulates emotions related to female sexuality. Because fertility status only affects the individual's own opportunity cost, the adaptive value of this shift is expected to stem from self-regulation. To test this assumption we asked women to contemplate various inbreeding descriptions: 1) they themselves having sex with male relatives; 2) their sister having sex with their common male relatives; and 3) an unrelated woman having sex with her male relatives (in 1, but not 2 and 3, negative fitness consequences are affected by the participant's fertility). We dichotomized the dependent variable disgust (ceiling vs. non-ceiling) and analyzed the interaction between fertility status and description type. The ovulatory shift was stronger in descriptions where they themselves were described as engaging in inbreeding. A smaller increase was also found in reactions to others engaging in inbreeding. We explain the latter effect as due to self-reflection. PMID- 25299997 TI - Deceiving yourself to better deceive high-status compared to equal-status others. AB - The arms race between deception and detection is likely to have played out between individuals in different status hierarchies, with low-status individuals more likely to be deceivers and high-status individuals more likely to be detectors than the other way around. Memory and its distortion may be temporarily employed first to keep truthful information away from both self and others and later to retrieve accurate information to benefit the self. Using a dual retrieval paradigm, we tested the hypothesis that people are likely to deceive themselves to better deceive high- rather than equal-status others. College student participants were explicitly instructed (Study 1 and 2) or induced (Study 3) to deceive either a high-status teacher or an equal-status fellow student. When interacting with the high- but not equal-status target, participants in three studies genuinely remembered fewer previously studied items than they did on a second memory test alone without the deceiving target. The results support the view that self-deception responds to status hierarchy that registers probabilities of deception detection such that people are more likely to self deceive high- rather than equal-status others. PMID- 25299998 TI - Husband's esteem predicts his mate retention tactics. AB - Men sometimes enact mate retention tactics to thwart a partner's infidelity or prevent their defection from the relationship. These tactics include low-risk acts that render the current relationship more attractive by bestowing benefits on the woman, as well as cost-inflicting acts that render defection from the relationship risky or dangerous for her. Previous research has linked men's mate retention behavior with men's mate value (value as a current or potential partner) using women's reports. The current research addresses limitations of that research using self-reports and cross-spousal reports from 107 married couples concerning their self-esteem and their esteem for their partner. The results indicate that the level of esteem that wives have for their husbands is positively associated with their perception of their husband's use of positive inducements and negatively associated with their husband's self-reported use of cost-inflicting mate retention behaviors (i.e., Direct Guarding, Intersexual Negative Inducements, and Intrasexual Negative Inducements). The level of self esteem reported by men was negatively associated with their self-reported direct guarding behavior. Discussion explores the possibility that esteem-both self esteem and esteem from one's partner-functions as an internal gauge of relative mate value. PMID- 25300000 TI - An economic framework for transitioning to capacity building. AB - Global Health Organizations (GHOs) often focus on resource provisioning strategies to assist communities in need, especially when disaster strikes. While such strategies are commendable, how should GHOs approach the challenge of developing sustainable strategic objectives after critical needs have been addressed? Leveraging the context of GHOs partnering with communities in need of support after disaster strikes, we propose an economic framework for use in strategic assessment and transition planning. We focus on a strategic process by which GHOs can systematically assess and manage the temporal shift from resource provisioning to capacity building strategies. The proposed framework is applied to pragmatic field experiences undertaken by the American Red Cross in the aftermath of the 2007 Peru earthquake. We specifically develop and propose: (1) An economic strategy assessment framework for GHOs seeking to provide support to communities characterised by high risk variances, incentive complexities and contingencies, and, (2) A practical strategic transition model for GHOs that emphasises proactively moving towards capacity building programme objectives through an emphasis on co-creation of value with community partners. PMID- 25300002 TI - Central and Eastern European special issue. PMID- 25300001 TI - Light-scattering detection below the level of single fluorescent molecules for high-resolution characterization of functional nanoparticles. AB - Ultrasensitive detection and characterization of single nanoparticles (<100 nm) is important in nanotechnology and life sciences. Direct measurement of the elastically scattered light from individual nanoparticles represents the simplest and the most direct method for particle detection. However, the sixth-power dependence of scattering intensity on particle size renders very small particles indistinguishable from the background. Adopting strategies for single-molecule fluorescence detection in a sheathed flow, here we report the development of high sensitivity flow cytometry (HSFCM) that achieves real-time light-scattering detection of single silica and gold nanoparticles as small as 24 and 7 nm in diameter, respectively. This unprecedented sensitivity enables high-resolution sizing of single nanoparticles directly based on their scattered intensity. With a resolution comparable to that of TEM and the ease and speed of flow cytometric analysis, HSFCM is particularly suitable for nanoparticle size distribution analysis of polydisperse/heterogeneous/mixed samples. Through concurrent fluorescence detection, simultaneous insights into the size and payload variations of engineered nanoparticles are demonstrated with two forms of clinical nanomedicine. By offering quantitative multiparameter analysis of single nanoparticles in liquid suspensions at a throughput of up to 10 000 particles per minute, HSFCM represents a major advance both in light-scattering detection technology and in nanoparticle characterization. PMID- 25300003 TI - Genetic covariance between central corneal thickness and anterior chamber volume: a Hungarian twin study. AB - BACKGROUND: Few, and inconsistent, studies have showed high heritability of some parameters of the anterior segment of the eye; however, no heritability of anterior chamber volume (ACV) has been reported, and no study has been performed to investigate the correlation between the ACV and central corneal thickness (CCT). METHODS: Anterior segment measurements (Pentacam, Oculus) were obtained from 220 eyes of 110 adult Hungarian twins (41 monozygotic and 14 same-sex dizygotic pairs; 80% women; age 48.6 +/- 15.5 years) obtained from the Hungarian Twin Registry. RESULTS: Age- and sex-adjusted heritability of ACV was 85% (bootstrapped 95% confidence interval; CI: 69% to 93%), and 88% for CCT (CI: 79% to 95%). Common environmental effects had no influence, and unshared environmental factors were responsible for 12% and 15% of the variance, respectively. The correlation between ACV and CCT was negative and significant (r ph = -0.35, p < .05), and genetic factors accounted for the covariance significantly (0.934; CI: 0.418, 1.061) based on the bivariate Cholesky decomposition model. CONCLUSION: These findings support the high heritability of ACV and central corneal thickness, and a strong genetic covariance between them, which underscores the importance of identification of the specific genetic factors and the family risk-based screening of disorders related to these variables, such as open-angle and also angle closure glaucoma and corneal endothelial alterations. PMID- 25300005 TI - An academic tribute to Louis Gerald Keith, MD, PhD, ScD (Hon), FACOG, FRCOG, FACS, FICS, FRSM, FRSH, 1935-2014: a multidisciplinary mentor to many. PMID- 25300008 TI - Prolonged Epidural Infusion Improves Functional Outcomes Following Knee Arthroscopy in Patients with Arthrofibrosis after Total Knee Arthroplasty: A Retrospective Evaluation. AB - A total of 20 consecutive patients with knee stiffness post total knee arthroplasty (TKA) underwent arthroscopic lysis of adhesions and manipulation plus indwelling epidural were evaluated retrospectively. Epidural catheters were placed preoperatively for an intended 6 weeks of postoperative analgesia to facilitate intensive physical therapy. The mean loss of knee extension immediately before incision was 13.5 +/- 9.1 degrees (range, 0-35 degrees) and flexion was 77.65 +/- 19.2 degrees (range, 45-125 degrees). At the 6-week and final (mean, 0.47 years) follow-up, the loss of extension was 1.5 +/- 5.1 degrees (range, -10 to +7 degrees) and 5.4 +/- 4.7 degrees (range, 0-15 degrees), respectively, and flexion was 99.7 +/- 12.3 degrees (range, 75-120 degrees) and 98.5 +/- 16.1 degrees (range, 75-130 degrees), respectively. Of the 20 patients, 2 missed their 6-week clinic visit. Improvements in motion immediately preoperative to 6-week and final follow-up were each significant (p < 0.01). At examination 6 weeks postoperatively, 94.4% of patients met the definition for clinical motion success and 70% maintained success at final follow-up. Visual analog scale improved significantly from 5.4 to 2.0 (p < 0.01) at 6 weeks postoperative in the 12 patients with this data recorded. On the basis of this data, use of tunneled epidurals with arthroscopic lysis of adhesions for arthrofibrosis after TKA is correlated with a high likelihood of functional success postoperatively as measured by range of motion improvement. PMID- 25300009 TI - Atomic-scale imaging of cation ordering in inverse spinel Zn2SnO4 nanowires. AB - By using high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) coupled with density functional theory (DFT) calculations, we demonstrate the atomic-level imaging of cation ordering in inverse spinel Zn2SnO4 nanowires. This cation ordering was identified as 1:1 ordering of Zn(2+) and Sn(4+) at the octahedral sites of the inverse spinel crystal with microscopic symmetry transition from original cubic Fd3m to orthorhombic Imma group. This ordering generated a 67.8% increase in the elastic modulus and 1-2 order of magnitude lower in the electric conductivity and electron mobility compared to their bulk counterpart. PMID- 25300010 TI - Precision structural engineering of self-rolled-up 3D nanomembranes guided by transient quasi-static FEM modeling. AB - Micro- and nanoscale tubular structures can be formed by strain-induced self rolled-up nanomembranes. Precision engineering of the shape and dimension determines the performance of devices based on this platform for electronic, optical, and biological applications. A transient quasi-static finite element method (FEM) with moving boundary conditions is proposed as a general approach to design diverse types of three-dimensional (3D) rolled-up geometries. This method captures the dynamic release process of membranes through etching driven by mismatch strain and accurately predicts the final dimensions of rolled-up structures. Guided by the FEM modeling, experimental demonstration using silicon nitride membranes was achieved with unprecedented precision including controlling fractional turns of a rolled-up membrane, anisotropic rolling to form helical structures, and local stress control for 3D hierarchical architectures. PMID- 25300011 TI - Prevalence of and risk factors for pterygia in a rural Northern Chinese population. AB - PURPOSE: To determine the prevalence of and associated risk factors for pterygia development in a high-latitude-dwelling Northern Chinese population. METHODS: A prospective population-based survey was conducted between November 2008 and July 2009. A stratified, clustered, randomized sampling procedure was used to select 8445 subjects, aged >=18 years, all with diagnosed, graded pterygia. Risk factors associated with the occurrence of pterygia were evaluated according to logistic regression models. RESULTS: A total of 8445 residents (aged 18-94 years) from the Heilongjiang Province, China, participated in the study. Of these, 208 (2.5%) had at least one diagnosed pterygium. The prevalence of bilateral pterygia was 1.2% (95% confidence interval, CI, 1.0-1.4%). According to multivariable analysis, pterygia were significantly more likely to occur in persons aged 70-94 years than in those aged 18-39 years (odds ratio, OR, 29.0, 95% CI 13.6-61.6, p < 0.01). Pterygia were significantly associated with male sex (OR 1.9, 95% CI 1.4-2.6, p < 0.01) and outdoor work (OR 1.8, 95% CI 1.2-2.6, p < 0.01). Multivariable analysis indicated that pterygia were not associated with smoking status (OR 1.0, 95% CI 0.8-1.4) or alcohol intake (OR 1.0, 95% CI 0.7-1.4, p > 0.05). CONCLUSIONS: This study details the occurrence of and risk factors for pterygia in a Chinese population residing in a rural, high-latitude, cold-climate area of Northern China. The primary risk factors for pterygia were age, male sex, and outdoor work. PMID- 25300012 TI - Successful treatment of clozapine-associated restless leg syndrome with pramipexole. PMID- 25300013 TI - Mechanisms and energetics of potassium channel block by local anesthetics and antifungal agents. AB - Many drug molecules inhibit the conduction of several families of cation channels by binding to a small cavity just below the selectivity filter of the channel protein. The exact mechanisms governing drug-channel binding and the subsequent inhibition of conduction are not well understood. Here the inhibition of two K(+) channel isoforms, Kv1.2 and KCa3.1, by two drug molecules, lidocaine and TRAM-34, is examined in atomic detail using molecular dynamics simulations. A conserved valine-alanine-valine motif in the inner cavity is found to be crucial for drug binding in both channels, consistent with previous studies of similar systems. Potential of mean force calculations show that lidocaine in its charged form creates an energy barrier of ~6 kT for a permeating K(+) ion when the ion is crossing over the drug, while the neutral form of lidocaine has no significant effect on the energetics of ion permeation. On the other hand, TRAM-34 in the neutral form is able to create a large energy barrier of ~10 kT by causing the permeating ion to dehydrate. Our results suggest that TRAM-34 analogues that remain neutral and permeable to membranes under acidic conditions common to inflammation may act as possible drug scaffolds for combating local anesthetic failure in inflammation. PMID- 25300014 TI - Long term effects of prenatal and postnatal airborne PAH exposures on ventilatory lung function of non-asthmatic preadolescent children. Prospective birth cohort study in Krakow. AB - The main goal of the study was to test the hypothesis that prenatal and postnatal exposures to polycyclic aromatic hydrocarbons (PAH) are associated with depressed lung function in non-asthmatic children. The study sample comprises 195 non asthmatic children of non-smoking mothers, among whom the prenatal PAH exposure was assessed by personal air monitoring in pregnancy. At the age of 3, residential air monitoring was carried out to evaluate the residential PAH exposure indoors and outdoors. At the age of 5 to 8, children were given allergic skin tests for indoor allergens; and between 5 and 9 years lung function testing (FVC, FEV05, FEV1 and FEF25-75) was performed. The effects of prenatal PAH exposure on lung function tests repeated over the follow-up were adjusted in the General Estimated Equation (GEE) model for the relevant covariates. No association between FVC with prenatal PAH exposure was found; however for the FEV1 deficit associated with higher prenatal PAH exposure (above 37 ng/m(3)) amounted to 53 mL (p=0.050) and the deficit of FEF25-75 reached 164 mL (p=0.013). The corresponding deficits related to postnatal residential indoor PAH level (above 42 ng/m(3)) were 59 mL of FEV1 (p=0.028) and 140 mL of FEF25-75 (p=0.031). At the higher residential outdoor PAH level (above 90 ng/m(3)) slightly greater deficit of FEV1 (71 mL, p=0.009) was observed. The results of the study suggest that transplacental exposure to PAH compromises the normal developmental process of respiratory airways and that this effect is compounded by postnatal PAH exposure. PMID- 25300015 TI - Accumulation and potential health effects of organohalogenated compounds in the arctic fox (Vulpes lagopus)--a review. AB - This review addresses biological effects of anthropogenic organohalogenated compounds in the arctic fox (Vulpes lagopus). When considering the current levels, spatial and tissue distributions of selected organic pollutants in arctic fox subpopulations, especially the Svalbard based populations accumulate high levels. The dominating contaminant groups are the polychlorinated biphenyls (PCBs) and chlordanes (CHLs), which reach high levels in adipose tissues, adrenals and liver. Recent controlled exposure studies on domesticated arctic fox and Greenland sledge dogs, show adverse health effects associated with OC concentrations lower than those measured in free-ranging populations. This indicates that especially populations at Svalbard may be at risk of experiencing OC related effects. The arctic fox as such may be an overlooked species in the Arctic Monitoring and Assessment Programs and it would add further information about pollution in the Arctic to include this species in the monitoring program. PMID- 25300016 TI - Novel approach for quantitatively estimating element retention and material balances in soil profiles of recharge basins used for wastewater reclamation. AB - We investigated changes in element content and distribution in soil profiles in a study designed to monitor the geochemical changes accruing in soil due to long term secondary effluent recharge, and its impact on the sustainability of the Soil Aquifer Treatment (SAT) system. Since the initial elemental contents of the soils at the studied site were not available, we reconstructed them using scandium (Sc) as a conservative tracer. By using this approach, we were able to produce a mass-balance for 18 elements and evaluate the geochemical changes resulting from 19 years of effluent recharge. This approach also provides a better understanding of the role of soils as an adsorption filter for the heavy metals contained in the effluent. The soil mass balance suggests 19 years of effluent recharge cause for a significant enrichment in Cu, Cr, Ni, Zn, Mg, K, Na, S and P contents in the upper 4m of the soil profile. Combining the elements lode record during the 19 years suggest that Cr, Ni, and P inputs may not reach the groundwater (20 m deep), whereas the other elements may. Conversely, we found that 58, 60, and 30% of the initial content of Mn, Ca and Co respectively leached from the upper 2-m of the soil profile. These high percentages of Mn and Ca depletion from the basin soils may reduce the soil's ability to buffer decreases in redox potential pe and pH, respectively, which could initiate a reduction in the soil's holding capacity for heavy metals. PMID- 25300017 TI - Arsenic removal from drinking water by a household sand filter in Vietnam--effect of filter usage practices on arsenic removal efficiency and microbiological water quality. AB - Household sand filters are applied to treat arsenic- and iron-containing anoxic groundwater that is used as drinking water in rural areas of North Vietnam. These filters immobilize poisonous arsenic (As) via co-oxidation with Fe(II) and sorption to or co-precipitation with the formed Fe(III) (oxyhydr)oxides. However, information is lacking regarding the effect of the frequency and duration of filter use as well as of filter sand replacement on the residual As concentrations in the filtered water and on the presence of potentially pathogenic bacteria in the filtered and stored water. We therefore scrutinized a household sand filter with respect to As removal efficiency and the presence of fecal indicator bacteria in treated water as a function of filter operation before and after sand replacement. Quantification of As in the filtered water showed that periods of intense daily use followed by periods of non-use and even sand replacement did not significantly (p<0.05) affect As removal efficiency. The As concentration was reduced during filtration from 115.1 +/- 3.4 MUg L(-1) in the groundwater to 5.3 +/- 0.7 MUg L(-1) in the filtered water (95% removal). The first flush of water from the filter contained As concentrations below the drinking water limit and suggests that this water can be used without risk for human health. Colony forming units (CFUs) of coliform bacteria increased during filtration and storage from 5 +/- 4 per 100mL in the groundwater to 5.1 +/- 1.5 * 10(3) and 15 +/- 1.4 * 10(3) per 100mL in the filtered water and in the water from the storage tank, respectively. After filter sand replacement, CFUs of Escherichia coli of <100 per 100mL were quantified. None of the samples contained CFUs of Enterococcus spp. No critical enrichment of fecal indicator bacteria belonging to E. coli or Enterococcus spp. was observed in the treated drinking water by qPCR targeting the 23S rRNA gene. The results demonstrate the efficient and reliable performance of household sand filters regarding As removal, but indicate a potential risk for human health arising from the enrichment of coliform bacteria during filtration and from E. coli cells that are introduced by sand replacement. PMID- 25300018 TI - On the feasibility of measuring urban air pollution by wireless distributed sensor networks. AB - Accurate evaluation of air pollution on human-wellbeing requires high-resolution measurements. Standard air quality monitoring stations provide accurate pollution levels but due to their sparse distribution they cannot capture the highly resolved spatial variations within cities. Similarly, dedicated field campaigns can use tens of measurement devices and obtain highly dense spatial coverage but normally deployment has been limited to short periods of no more than few weeks. Nowadays, advances in communication and sensory technologies enable the deployment of dense grids of wireless distributed air monitoring nodes, yet their sensor ability to capture the spatiotemporal pollutant variability at the sub neighborhood scale has never been thoroughly tested. This study reports ambient measurements of gaseous air pollutants by a network of six wireless multi-sensor miniature nodes that have been deployed in three urban sites, about 150 m apart. We demonstrate the network's capability to capture spatiotemporal concentration variations at an exceptional fine resolution but highlight the need for a frequent in-situ calibration to maintain the consistency of some sensors. Accordingly, a procedure for a field calibration is proposed and shown to improve the system's performance. Overall, our results support the compatibility of wireless distributed sensor networks for measuring urban air pollution at a sub neighborhood spatial resolution, which suits the requirement for highly spatiotemporal resolved measurements at the breathing-height when assessing exposure to urban air pollution. PMID- 25300019 TI - Toxic and essential elements changed in black-legged kittiwakes (Rissa tridactyla) during their stay in an Arctic breeding area. AB - Seasonal fluctuations in mercury (Hg), cadmium (Cd), zinc (Zn), copper (Cu) and selenium (Se) concentrations were studied in black-legged kittiwakes (Rissa tridactyla) from Kongsfjorden, Svalbard (79 degrees 57'N, 12 degrees 12'E). Element concentrations were determined in muscle and liver tissue in kittiwakes collected in May, July and October 2007. Stable isotopes of carbon (delta(13)C) and nitrogen (delta(15)N) were analysed in muscle tissue to calculate trophic position (TP) and examine the possible influence of carbon source on element accumulation. Metallothionein (MT) concentrations in liver, as well as Hg and Cd concentration in size-fractionated liver supernatant were determined to evaluate the association between elements and MT. Mercury concentrations declined from May through July to October in both tissues, while concentrations of Cd were similar in May and July and lower in October. A decline in TP between May and July, indicating a shift from fish-based diet towards an invertebrate-based diet explains the declining Hg concentration. The low Hg and Cd concentrations in October may be a result of an increased elimination, probably related to moulting. Selenium decreased in the same manner as Hg in liver and muscle, possibly related to the formation of Se-Hg complexes. Zinc and Cu did not fluctuate in muscle tissue, whereas hepatic Zn concentrations where highest in May. Hepatic Zn concentrations were higher in females compared to males in May, possibly related to egg production. Hepatic MT concentrations were lower in October compared to July, following the same trend as Hg and Cd. Cadmium was predominantly bound to the MT fraction of proteins in liver tissue, whereas Hg was associated with the larger proteins, indicating that MT was not sequestering Hg in the kittiwakes. PMID- 25300020 TI - An integrated evaluation study of the ventilation rate, the exposure and the indoor air quality in naturally ventilated classrooms in the Mediterranean region during spring. AB - Ventilation rates and indoor air pollutants have been extensively monitored in nine naturally ventilated primary schools of Athens, Greece during spring. The ventilation rates and pollutant levels were studied during the teaching and non teaching periods and ventilation profiles were created for each of the schools. The median ventilation rates per school ranged between 0.7 and 8 ACH while the average ventilation rate in all schools (11.7l/s/p) was greater than the minimum recommended rates by ASHRAE for school classrooms. The average carbon dioxide (CO2) concentrations per school varied between 893 and 2082ppm, while the majority of the cases were slightly above the recommended limit values. CO2 concentrations were also positively correlated to the number of students and negatively correlated to the ventilation rates. Particles of several size ranges (PM10, PM5, PM2.5, PM1, PM0.5 and UFP) were also measured and analyzed. PM10 concentrations exceeded the recommended limit values by more than 10 times for the majority of the cases. There were also many cases that the PM2.5 concentrations exceeded their limit values. PM concentrations were significantly affected by the ventilation rates and the presence of students. All of the measured particle sizes were greater during teaching than the non-teaching hours. For most of the cases the indoor to outdoor (I/O) concentrations ratios of PM10 and PM2.5 were much greater than one, indicating that the indoor environment was being mostly affected by indoor sources instead of the outdoor air. Furthermore it was found that chalk and marker boards' usage significantly affect indoor pollutant concentrations. Overall, the measured levels of exposure were for most of the cases greater than the recommended guideline values due to the intense presence of indoor pollution sources, even though the ventilation rates were in general satisfactory. PMID- 25300021 TI - Photocatalytic degradation of rosuvastatin: analytical studies and toxicity evaluations. AB - Photocatalytic degradation of rosuvastatin, which is a drug that has been used to reduce blood cholesterol levels, was studied in this work employing ZnO as catalyst. The experiments were carried out in a temperature-controlled batch reactor that was irradiated with UV light. Preliminary the effects of the photocatalyst loading, the initial pH and the initial rosuvastatin concentration were evaluated. The experimental results showed that rosuvastatin degradation is primarily a photocatalytic process, with pseudo-first order kinetics. The byproducts that were generated during the oxidative process were identified using nano-ultra performance liquid chromatography tandem mass spectrometry (nano-UPLC MS/MS) and acute toxicity tests using Daphnia magna were done to evaluate the toxicity of the untreated rosuvastatin solution and the reactor effluent. PMID- 25300022 TI - Effects of meteorology and secondary particle formation on visibility during heavy haze events in Beijing, China. AB - The causes of haze formation in Beijing, China were analyzed based on a comprehensive measurement, including PBL (planetary boundary layer), aerosol composition and concentrations, and several important meteorological parameters such as visibility, RH (relative humidity), and wind speed/direction. The measurement was conducted in an urban location from Nov. 16, 2012 to Jan. 15, 2013. During the period, the visibility varied from >20 km to less than a kilometer, with a minimum visibility of 667 m, causing 16 haze occurrences. During the haze occurrences, the wind speeds were less than 1m/s, and the concentrations of PM2.5 (particle matter with radius less than 2.5 MUm) were often exceeded 200 MUg/m(3). The correlation between PM2.5 concentration and visibility under different RH values shows that visibility was exponentially decreased with the increase of PM2.5 concentrations when RH was less than 80%. However, when RH was higher than 80%, the relationship was no longer to follow the exponentially decreasing trend, and the visibility maintained in very low values, even with low PM2.5 concentrations. Under this condition, the hygroscopic growth of particles played important roles, and a large amount of water vapor acted as particle matter (PM) for the reduction of visibility. The variations of meteorological parameters (RH, PBL heights, and WS (wind speed)), chemical species in gas-phase (CO, O3, SO2, and NOx), and gas-phase to particle-phase conversions under different visibility ranges were analyzed. The results show that from high visibility (>20 km) to low visibility (<2 km), the averaged PBL decreased from 1.24 km to 0.53 km; wind speeds reduced from 1m/s to 0.5m/s; and CO increased from 0.5 ppmv to 4.0 ppmv, suggesting that weaker transport/diffusion caused the haze occurrences. This study also found that the formation of SPM (secondary particle matter) was accelerated in the haze events. The conversions between SO2 and SO4 as well as NOx to NO3(-) increased, especially under high humidity conditions. When the averaged RH was 70%, the conversions between SO2 and SO4 accounted for about 20% concentration of PM2.5, indicating that formation of secondary particle matter had important contribution for the haze occurrences in Beijing. PMID- 25300023 TI - The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer. AB - BACKGROUND: Delirium is a common and serious problem among acutely unwell persons. Although linked to higher rates of mortality, institutionalisation and dementia, it remains underdiagnosed. Careful consideration of its phenomenology is warranted to improve detection and therefore mitigate some of its clinical impact. The publication of the fifth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-5) provides an opportunity to examine the constructs underlying delirium as a clinical entity. DISCUSSION: Altered consciousness has been regarded as a core feature of delirium; the fact that consciousness itself should be physiologically disrupted due to acute illness attests to its clinical urgency. DSM-5 now operationalises 'consciousness' as 'changes in attention'. It should be recognised that attention relates to content of consciousness, but arousal corresponds to level of consciousness. Reduced arousal is also associated with adverse outcomes. Attention and arousal are hierarchically related; level of arousal must be sufficient before attention can be reasonably tested. SUMMARY: Our conceptualisation of delirium must extend beyond what can be assessed through cognitive testing (attention) and accept that altered arousal is fundamental. Understanding the DSM-5 criteria explicitly in this way offers the most inclusive and clinically safe interpretation. PMID- 25300024 TI - Variability in PCB and OH-PCB serum levels in children and their mothers in urban and rural U.S. communities. AB - Environmental exposures that affect accumulation of polychlorinated biphenyls (PCBs) in humans are complex and not fully understood. One challenge in linking environmental exposure to accumulation is determining variability of PCB concentrations in samples collected from the same person at different times. We hypothesized that PCBs in human blood serum are consistent from year to year in people who live in the same environment between sampling. We analyzed blood serum from children and their mothers from urban and rural U.S. communities (n = 200) for all 209 PCBs (median ?PCBs = 45 ng/g lw) and 12 hydroxylated PCBs (median ?OH PCBs = 0.09 ng/g fw). A subset of these participants (n = 155) also had blood PCB and OH-PCB concentrations analyzed during the previous calendar year. Although many participants had similar levels of PCBs and OH-PCBs in their blood from one year to the next, some participants had surprisingly different levels. Year-to year variability in ?PCBs ranged from -87% to 567% and in ?OH-PCBs ranged from 51 to 358% (5th-95th percentile). This is the first study to report variability of all PCBs and major metabolites in two generations of people and suggests short term exposures to PCBs may be a significant component of what is measured in human serum. PMID- 25300025 TI - Specific recognition mechanism between RNA and the KH3 domain of Nova-2 protein. AB - The KH3 domain of Nova-2 protein can precisely recognize the sequence-specific target RNA of human glycine receptor alpha2. However, the recognition mechanism between the protein and its target RNA is still hotly debated. In this study, molecular dynamic simulations in explicit solvent were utilized to understand the recognition mechanism. The structural analysis and the Kolmogorov-Smirnov P-test statistics reveal that the KH3 domain might obey a conformational selection mechanism upon RNA binding. However, the induced fit mechanism could not be completely ruled out. Unfolding kinetics indicates that the folding of RNA and KH3 happens first and then the binding between RNA and KH3 follows. Principle component analysis shows that the invariant Gly-Lys-Gly-Gly loop moves toward to the RNA molecule but the C-terminal domain moves away from the RNA molecule upon binding. These specific dominant motions were hypothesized to stabilize the complex structure. The hydrophobic and hydrogen bonding interactions were found to be the driving forces for the specific recognition, in contrast to the dominant electrostatic interactions for nonspecific recognition. PMID- 25300026 TI - Re-evaluating the surface tension analysis of polyelectrolyte-surfactant mixtures using phase-sensitive sum frequency generation spectroscopy. AB - Surface tension (ST) has been the most important measure of a molecule's surface activity. However, in many cases the complex behaviors of ST are challenging to interpret. For example, aqueous solutions of sodium docecyl sulfate (SDS) and poly(diallyldimethylammonium chloride) (PDADMAC) show dramatic changes in ST when the concentration of SDS varies. Although surfactants are generally described as "substances that reduce surface tension", new evidence shows that ST may have little changes when a significant amount of SDS is present at the water surface. The decrease of surface entropy resulting from a better ordering of interfacial molecules, such as water, counteracts the decrease of surface enthalpy and is able to keep the ST nearly unchanged. The dramatic ST decrease and recovery of the SDS-PDADMAC mixtures was discovered to be a result of a surface charge reversal. Similar surface charge reversal was also observed in cationic surfactant and anionic polyelectrolyte mixtures. PMID- 25300027 TI - Annular pancreas: a cause of gastric outlet obstruction in a 20-year-old patient. AB - BACKGROUND: Annular pancreas is a congenital anomaly that consists of a ring of pancreatic tissue partially or completely encircling the descending portion of the duodenum. It is formed due to the failure of the ventral bud to rotate, thus it elongates and encircles the upper part of the duodenum. It can present in a wide range of clinical severities, and can affect neonates to the elderly, making it difficult to diagnosis. Although diagnosis of annular pancreas can be made pre operatively by upper GI series, upper GI endoscopy, or CT scan, 40% of diagnoses require surgery for confirmation. CASE REPORT: We report the case of a 20-year old woman presenting with history of vomiting and weight loss since childhood. We present the clinical characteristics, surgical management in the form of bypass procedure done through a duodenojujenostomy, and follow-up of the patient. CONCLUSIONS: Annular pancreas occasionally presents in adults. Variable presentations have been described in the literature, including pancreatic neoplasm, pancreatitis, obstructive jaundice, duodenal obstruction, and peptic ulcer diseases. Most studies of these lesions are single case reports or small series, which do not allow a surgeon to accumulate extensive experience; therefore, reliance on the combined experience of others in recognition and appropriate management has been the norm. PMID- 25300028 TI - Nuclear motion in the sigma-bound regime of metal-H2 complexes: [Mg(H2)(n=1 6)]2+. AB - The dynamic, quantum structure of [Mg(H2)(n=1-6)](2+)complexes is investigated via ab initio path integral molecular dynamics simulations. These complexes represent the strong, sigma-complex regime of metal-H2 interactions and are representative of bonding motifs found in metal-organic frameworks. Significant nuclear motion within the coordination sphere is observed, even though the ligands remain largely intact. Quantum effects are found to be important in the H H and metal-H2 stretch coordinates, but the remaining motion in the molecule is well represented by classical simulations. Nearly free rotation of the dihydrogen moiety is observed in all complexes. Statistical averages and distributions of structural parameters are found to deviate nontrivially from the same parameters in static, equilibrium structures. PMID- 25300029 TI - Identification of novel glycans with disialylated structures in alpha3 integrin from mouse kidney cells with the phenotype of polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder caused by mutations in the Pkd1 or Pkd2 genes, in which large cysts replace normal kidney tissue, leading to end-stage kidney disease. In this study we have utilized a powerful nano-HPLC-mass spectrometric approach to characterize patterns of normal and abnormal N-linked glycosylation of alpha3 integrin subunit in Pkd1(-/-) cells derived from mouse kidneys. Higher molecular weight glycan structures with a different monosaccharide composition were observed at two sites, namely, Asn-925 and Asn-928 sites in alpha3 integrin isolated from Pkd1(+/+) cells compared with Pkd1(-/-) cells. In addition, an unusual and unique disialic acid glycan structure was observed solely in Pkd1(-/-) cells. Thus, these studies suggest that abnormal protein glycosylation may have a role on the pathogenesis of cyst formation in ADPKD. PMID- 25300030 TI - Hypertension and vulnerability to hemorrhagic shock in a rat model. AB - Trauma mortality may be increased in the presence of preexisting diseases such as chronic hypertension. We hypothesized that systemic and microvascular alterations accompanying chronic hypertension would increase the vulnerability to hemorrhage relative to normotensive controls in a rat model of hemorrhagic shock. We present a novel comparative hemorrhage model of shock vulnerability, quantified by "vulnerability curves" expressing physiological response to hemorrhage as a function of three matched shock metrics: cumulative blood volume, mean arterial pressure (MAP), and oxygen delivery (Do2). Responses were central hemodynamics and respiratory and muscle oxygenation obtained for one hypertensive (spontaneously hypertensive [SHR]) and two normotensive (Sprague-Dawley, Wistar Kyoto) rat strains. Hemorrhagic shock was induced by incremental (0.5 mL) hemorrhage to cardiovascular collapse in anesthetized and mechanically ventilated animals. Shock vulnerability of SHR rats was primarily pressure-driven; in general, SHR exhibited the expected patterns of more rapid deterioration in MAP and Vo2 over smaller ranges of blood loss and Do2. Sternotomy-related depression of CO and thus Do2 in SHR meant that we could not test hypotheses related to the role of Do2 and contribution to perfusion differences between normotensive and hypertensive subjects. Insensitivity of lactate to strain effects suggests that lactate may be a reliable biomarker of shock status. Unexpected similarities between Wistar-Kyoto and SHR suggest strain-related effects other than those related to hypertension per se contribute to hemorrhage response; body size effects and genetic relationships could not be ruled out. Future studies should incorporate phylogenetically based methods to examine the role of hypertension and physiological response to hemorrhage across multiple strains. PMID- 25300031 TI - Plasma metabolite profiles following trauma-hemorrhage: effect of posttreatment with resveratrol. AB - Resveratrol (RSV) has been shown to inhibit the inflammatory reaction and ameliorate the organ damage resulting from trauma-hemorrhage (TH). However, the effects of RSV on the metabolomic profiles under these conditions remain unclear. The aim of this study was to determine the metabolomic profiles of plasma in TH rats and to evaluate the therapeutic effects of RSV using high-performance liquid chromatography-mass spectrometry. Thirty male Sprague-Dawley rats were divided into sham operation (n = 10), sham-operation plus RSV treatment (n = 10), TH (n = 10), and TH plus RSV treatment (n = 10) groups. Plasma samples were obtained at 24 h after surgery. Electrospray ionization-tandem mass spectrometry was used to characterize the plasma metabolomes. The systemic analyses of plasma metabolomes and their targets were determined using a number of computational approaches, including principal component analysis, partial least squares discriminant analysis, and heat map analysis. Using these methods, the effects of RSV on the metabolomic profiles in animals that underwent trauma-hemorrhagic injury were determined. These approaches allowed a clear discrimination of the pathophysiological characteristics among the groups. The results demonstrate RSV treatment significantly reduced the metabolic derangements caused by TH. Compared with the sham-operated rats, the plasma levels of carnitine in the TH rats were relatively lower, but the levels of acetylcarnitine and butyrylcarnitine were higher, suggesting that RSV ameliorated the deranged carnitine metabolism in TH rats. There was a statistically significant increase in carnitine. In addition, RSV treatment reduced ketoacidosis and protein degradation, as evidenced by the attenuation of the elevated plasma branched-chain amino acid levels in the TH rats. Our study showed that the alterations of the metabolomic profiles in the rats subjected to trauma-hemorrhagic shock were attenuated by RSV treatment. In view of the metabolomic evidence, we conclude that RSV exerts beneficial effects in trauma-hemorrhagic shock injury and that these effects are partially mediated by improving energy metabolism and reducing protein degradation. PMID- 25300032 TI - First-principles study of thermodynamic stability and the electronic properties of intrinsic vacancy defects in barium hafnate. AB - The formation of intrinsic vacancy defects in barium hafnate, BaHfO3 and their corresponding electronic structures have been investigated using first-principles calculations. The thermodynamics of pristine and vacancy defects containing barium hafnate have been analyzed. Formation energies for neutral and fully charged Ba, Hf and O vacancies have been evaluated for determining their stability with respect to different chemical environments. From the calculated electronic structure and density of states, it is found that cation deficient barium hafnate is hole-doped, while the incorporation of oxygen vacancy retains the insulating nature of this material. The defect reaction energies for partial and full Schottky reactions are also computed, which controls the properties of non-stoichiometric barium hafnate. PMID- 25300033 TI - Profiling of stable isotope enrichment in specialized metabolites using liquid chromatography and multiplexed nonselective collision-induced dissociation. AB - Engineering of specialized metabolites in plants, microbes, and other organisms is hindered by significant knowledge gaps about metabolic pathways responsible for metabolite accumulation and degradation. While isotopic tracers have provided important information about metabolic fluxes in central metabolism, limitations of mass spectrometric strategies for quantifying stable isotope incorporation into both intact metabolites and specific substructures have slowed extension of these techniques to large specialized metabolites. This report describes the application of electrospray ionization with data-independent multiplexed nonselective collision induced dissociation (CID) on a time-of-flight mass spectrometer. This strategy yields quasi-simultaneous collection, on the chromatographic time scale, of mass spectra with different degrees of fragment ion formation without biases introduced by precursor mass selection or selective ion activation and provides measurements of stable isotope enrichments in intact metabolites and individual substructures. The utility and precision of these analyses is demonstrated by labeling acylsugar metabolites in glandular trichomes of tomato (Solanum lycopersicum) using (13)CO2 and analyzing (13)C enrichments in acylsugar specialized metabolites. The high precision and avoidance of mass bias provide a promising tool for extending metabolic flux analyses to complex specialized metabolites in a wide range of organisms. PMID- 25300034 TI - Do disabled elderly Medicare beneficiaries with major depression make less use of a consumer-directed home care voucher benefit? AB - Older adults with major depression may underutilize consumer-directed long-term care. Systematic underutilization would create disparities in outcomes, undermining program effectiveness. The Medicare Primary and Consumer-Directed Care Demonstration included a consumer-directed indemnity benefit that paid for goods and services not financed by traditional Medicare. Overall and for most categories of goods and services there was little difference in use and expenditures between those with and without major depression. However, among those using the benefit to hire in-home workers, arguably the most important consumer-directed purchase, average spending for workers was about 30% lower for depressed persons. While our findings are generally reassuring for public policy, future research is needed to verify that major depression is associated with less spending on in-home workers. PMID- 25300035 TI - Near-infrared electrochromism in electropolymerized metallopolymeric films of a phen-1,4-diyl-bridged diruthenium complex. AB - A phen-1,4-diyl-bridged tris-bidentate diruthenium complex 3(PF6)2, [Ru2(dpb)(vbpy)4](PF6)2, has been designed and prepared, where dpb is 1,4 di(pyrid-2-yl)benzene and vbpy is 5-vinyl-2,2'-bipyridine. Upon reductive electropolymerization, metallopolymeric thin films of this complex have been deposited on platinum and ITO glass electrode surfaces. These films display two well-separated redox couples at +0.16 and +0.60 V versus Ag/AgCl. In the mixed valent state, these films display intense intervalence charge transfer absorptions around 1300 nm. The electrochromic behavior at this wavelength has been examined by spectroelectrochemical measurements and double-potential-step chronoamperometry. A highest optical contrast ratio of 41% at 1300 nm with a coloration efficiency of 200 cm(2)/C has been achieved. The electrochromic behavior is highly dependent on the surface coverage. The highest contrast ratio was obtained with a film of 6.0 * 10(-9) mol/cm(2). In addition, a monoruthenium complex 2(PF6), [Ru(dpb)(vbpy)2](PF6), has been prepared and electropolymerized for a comparison study. PMID- 25300036 TI - Novel strategies to prevent or exploit phages in fermentations, insights from phage-host interactions. AB - Phages infecting lactic acid bacteria (LAB) provide some of the most advanced model systems for (tailed) phage-host interactions. In particular the identification of receptor molecules of representative lactococcal phages combined with the elucidation of the structure of the receptor-binding protein has permitted crucial insights into the early stages of infection. Dairy and biotechnological fermentations are persistently marred by the destructive activities of phages. Here, we discuss how recent advances in our knowledge on LAB phage-host interactions have provided a basis for the next generation anti phage strategies. Furthermore, the significant increase in genomic data has furthered our understanding of the genetics of these phages, thereby permitting the exploitation of phage-derived components for food safety and biotechnological applications. PMID- 25300037 TI - START (STrAtegies for RelaTives) study: a pragmatic randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of a manual-based coping strategy programme in promoting the mental health of carers of people with dementia. AB - BACKGROUND: Two-thirds of people with dementia live at home, receiving most care from family carers, about 40% of whom have clinically significant depression or anxiety. This impacts on the person with dementia, families and society, predicting care breakdown. There are currently no clinically effective and cost effective NHS family carer interventions. OBJECTIVES: To assess the STrAtegies for RelaTives (START) intervention in the short (4 and 8 months) and long term (1 and 2 years) compared with treatment as usual (TAU). DESIGN: Randomised, parallel group, superiority trial with blinded assessment recruiting participants 2:1 (intervention to TAU) to allow for therapist clustering. SETTING: Three UK mental health services and one neurological service. PARTICIPANTS: Family carers of people with dementia. INTERVENTION: Eight-session manual-based coping intervention delivered by supervised psychology graduates to individuals. MAIN OUTCOME MEASURES: Affective symptoms [Hospital Anxiety and Depression Scale-total (HADS-T)] and cost-effectiveness. Secondary measures: anxiety and depression symptoms and caseness, quality of life (QoL), abusive behaviour and long-term care home admission. RESULTS: Two hundred and sixty participants were randomised (173 intervention, 87 TAU). We used intention-to-treat analysis in the short term (152 intervention, 77 TAU) and in the long term (140 intervention, 69 TAU). In the short term, the intervention group had lower HADS-T [mean difference -1.80, 95% confidence interval (CI) -3.29 to -0.31; p=0.02] and higher quality-adjusted life-years (QALYs) (mean difference 0.03, 95% CI -0.01 to 0.08). Costs were no different between groups [mean L 252 (95% CI -L 28 to L 565) for intervention group]. The cost-effectiveness acceptability curve showed a greater than 99% chance of being cost-effectiveness at a L 30,000/QALY willingness-to-pay threshold and a high probability of cost-effectiveness based on the HADS-T score. Carers in the intervention group had less case-level depression [odds ratio (OR) 0.24, 95% CI 0.07 to 0.76], a trend towards reduced case-level anxiety (OR 0.30, 95% CI 0.08 to 1.05), lower Hospital Anxiety and Depression Scale-anxiety (HADS A) (-0.91, 95% CI -1.76 to -0.07; p = 0.03) and Hospital Anxiety and Depression Scale-depression (HADS-D) (-0.91, 95% CI -1.71 to -0.10; p = 0.03) and higher Health Status Questionnaire (HSQ) QoL (mean difference 4.09, 95% CI 0.34 to 7.83). Group differences in abusive behaviour (OR 0.48, 95% CI 0.18 to 1.27) and the person with dementia's quality of life-Alzheimer's disease (QoL-AD) (mean increase 0.59, 95% CI -0.72 to 1.89) were not significant. In the long term, the intervention group had lower HADS-T (mean difference -2.58, 95% CI -4.26 to 0.90; p = 0.03) and higher QALYs (mean difference 0.03, 95% CI -0.01 to 0.06). Carers in the intervention group had less case-level depression (OR 0.14, 95% CI 0.04 to 0.53), a trend towards reduced case-level anxiety (OR 0.57, 95% CI 0.26 to 1.24), lower HADS-A (-1.16, 95% CI -2.15 to -0.18) and HADS-D (1.45, 95% CI 2.32 to -0.57), and higher HSQ (mean difference 7.47, 95% CI 2.87 to 12.08). Thirty-two (18.7%) people with dementia in the intervention group and 17 (20.2%) in TAU were admitted to a care home (hazard ratio 0.83, 95% CI 0.44 to 1.56; p = 0.56). There were no significant differences between groups in abusive behaviour (OR 0.83, 95% CI 0.36 to 1.94), the person with dementia's QoL-AD (0.17, 95% CI 1.37 to 1.70) or costs (L 336, 95% CI -L 223 to L 895) for intervention group. The probability that the intervention would be seen as cost-effective at L 30,000/QALY threshold and cost-effectiveness on the HADS-T remained high. CONCLUSIONS: The START intervention was clinically effective and cost-effective in the short and longer term. The results are robust to the sensitivity analyses performed. Future work is needed to consider mechanism of action; the effects on people with dementia in clinical terms (cognition, neuropsychiatric symptoms, longer-term care home admission); and on health and social care costs. In addition, we will explore the effects of carer abusive behaviour on the care recipient's care home admission and if this then reduces abusive behaviour. We would also like to implement START and evaluate this implementation in clinical practice. TRIAL REGISTRATION: Current Controlled Trials ISCTRN70017938. PMID- 25300038 TI - Investigation of interaction studies of cefpirome with ACE-inhibitors in various buffers. AB - This work describes a RP-HPLC method for the determination and interaction studies of cefpirome with ACE-inhibitors (captopril, enalapril and lisinopril) in various buffers. The separation and interaction of cefpirome with ACE-inhibitors was achieved on a Purospher Star, C18 (5 MUm, 250*4.6 mm) column. Mobile phase consisted of methanol: water (80:20, v/v, pH 3.3); however, for the separation of lisinopril, it was modified to methanol-water (40:60, v/v, pH 3.3) and pumped at a flow rate of 1 mL min(-1). In all cases, UV detection was performed at 225 nm. Interactions were carried out in physiological pH i.e., pH 1 (simulated gastric juice), 4 (simulated full stomach), 7.4 (blood pH) and 9 (simulated GI), drug contents were analyzed by reverse phase high performance liquid chromatography. Method was found linear in the concentration range of 1.0-50.0 MUg mL(-1) with correlation coefficient (r(2)) of 0.999. Precision (RSD%) was less than 2.0%, indicating good precision of the method and accuracy was 98.0-100.0%. Furthermore, cefpirome-ACE-inhibitors' complexes were also synthesized and results were elucidated on the basis of FT-IR, and (1)H NMR. The interaction results show that these interactions are pH dependent and for the co administration of cefpirome and ACE-inhibitors, a proper interval should be given. PMID- 25300039 TI - A combined experimental and theoretical analysis on molecular structure and vibrational spectra of 2,4-dihydroxybenzoic acid. AB - The FT-IR and FT-Raman spectra of 2,4-dihydroxybenzoic acid (2,4-DHBA) in the solid phase have been recorded in the regions 4000-400 cm(-1) and 3700-100 cm( 1), respectively. The total energies of sixteen stable conformers for 2,4-DHBA have been calculated by density functional theory (DFT) using the B3LYP method with 6-311++G (d, p) basis set, and the C1 conformer with the lowest energy was obtained, the geometrical parameters between X-ray experiment diffraction and DFT calculation show good consistency. Furthermore, the vibrational frequencies of 2,4-DHBA were computed, and the detailed analysis of vibrational spectra was made on the basis of the potential energy distribution (PED) by combining experimental with theoretical data. In addition, frontier molecular orbitals, atomic charge distribution and molecular electrostatic potential (MEP) were also given. PMID- 25300040 TI - Centrin: another target of monastrol, an inhibitor of mitotic spindle. AB - Monastrol, a cell-permeable inhibitor, considered to specifically inhibit kinesin Eg5, can cause mitotic arrest and monopolar spindle formation, thus exhibiting antitumor properties. Centrin, a ubiquitous protein associated with centrosome, plays a critical role in centrosome duplication. Moreover, a correlation between centrosome amplification and cancer has been reported. In this study, it is proposed for the first time that centrin may be another target of the anticancer drug monastrol since monastrol can effectively inhibit not only the growth of the transformed Escherichia coli cells in vivo, but also the Lu(3+)-dependent self assembly of EoCen in vitro. The two closely related compounds (Compounds 1 and 2) could not take the same effect. Fluorescence titration experiments suggest that four monastrols per protein is the optimum binding pattern, and the binding constants at different temperatures were obtained. Detailed thermodynamic analysis indicates that hydrophobic force is the main acting force between monastrol and centrin, and the extent of monastrol inhibition of centrin self assembly is highly dependent upon the hydrophobic region of the protein, which is largely exposed by the binding of metal ions. PMID- 25300041 TI - Multivariate qualitative analysis of banned additives in food safety using surface enhanced Raman scattering spectroscopy. AB - A novel strategy which combines iteratively cubic spline fitting baseline correction method with discriminant partial least squares qualitative analysis is employed to analyze the surface enhanced Raman scattering (SERS) spectroscopy of banned food additives, such as Sudan I dye and Rhodamine B in food, Malachite green residues in aquaculture fish. Multivariate qualitative analysis methods, using the combination of spectra preprocessing iteratively cubic spline fitting (ICSF) baseline correction with principal component analysis (PCA) and discriminant partial least squares (DPLS) classification respectively, are applied to investigate the effectiveness of SERS spectroscopy for predicting the class assignments of unknown banned food additives. PCA cannot be used to predict the class assignments of unknown samples. However, the DPLS classification can discriminate the class assignment of unknown banned additives using the information of differences in relative intensities. The results demonstrate that SERS spectroscopy combined with ICSF baseline correction method and exploratory analysis methodology DPLS classification can be potentially used for distinguishing the banned food additives in field of food safety. PMID- 25300042 TI - Microwave assisted synthesis, spectroscopic studies and non linear optical properties of bis-chromophores. AB - Bis chromophores were synthesized by the terephthalaldehyde with (4-nitrophenyl) acetonitrile/(4-flurophenyl) acetonitrile under microwave irradiation. Bis chromophores were obtained in good to excellent yields. The structures of bis chromophores were established by FT-IR, (1)H NMR, (13)C NMR, EI-MS and elemental analyses. Physical chemical properties such as singlet absorption, extinction coefficient, stokes shift, oscillator strength and dipole moment, were investigated by UV-Vis and fluorescence spectroscopy measurements. Further we also measured the nonlinear refractive index and nonlinear absorption coefficients of these compounds using the single beam z-scan technique with a cw argon ion laser at 514.5 nm at different concentrations in DMSO solvent. The third order nonlinear susceptibility was estimated from these measurements and it shows high nonlinearity. The high negative refractive index makes these compounds suitable for optical limiting application. PMID- 25300043 TI - Spectroscopic and molecular modeling study on the separate and simultaneous bindings of alprazolam and fluoxetine hydrochloride to human serum albumin (HSA): with the aim of the drug interactions probing. AB - The objective of the present research is to study the interaction of separate and simultaneous of alprazolam (ALP) and fluoxetine hydrochloride (FLX) with human serum albumin (HSA) in phosphate buffer (pH 7.4) using different kinds of spectroscopic, cyclic voltammetry and molecular modeling techniques. The absorbance spectra of protein, drugs and protein-drug showed complex formation between the drugs and HSA. Fluorescence analysis demonstrated that ALP and FLX could quench the fluorescence spectrum of HSA and demonstrated the conformational change of HSA in the presence of both drugs. Also, fluorescence quenching mechanism of HSA-drug complexes both separately and simultaneously was suggested as static quenching. The analysis of UV absorption data and the fluorescence quenching of HSA in the binary and ternary systems showed that FLX decreased the binding affinity between ALP and HSA. On the contrary, ALP increased the binding affinity of FLX and HSA. The results of synchronous fluorescence and three dimensional fluorescence spectra indicated that the binding of drugs to HSA would modify the microenvironment around the Trp and Tyr residues and the conformation of HSA. The distances between Trp residue and the binding sites of the drugs were estimated according to the Forster theory, and it was demonstrated that non radiative energy transfer from HSA to the drugs occurred with a high probability. Moreover, according to CV measurements, the decrease of peak current in the cyclic voltammogram of the both drugs in the presence of HSA revealed that they interacted with albumin and binding constants were calculated for binary systems which were in agreement with the binding constants obtained from UV absorption and fluorescence spectroscopy. The prediction of the best binding sites of ALP and FLX in binary and ternary systems in molecular modeling approach was done using of Gibbs free energy. PMID- 25300045 TI - Bio-inspired vapor-responsive colloidal photonic crystal patterns by inkjet printing. AB - Facile, fast, and cost-effective technology for patterning of responsive colloidal photonic crystals (CPCs) is of great importance for their practical applications. In this report, we develop a kind of responsive CPC patterns with multicolor shifting properties by inkjet printing mesoporous colloidal nanoparticle ink on both rigid and soft substrates. By adjusting the size and mesopores' proportion of nanoparticles, we can precisely control the original color and vapor-responsive color shift extent of mesoporous CPC. As a consequence, multicolor mesoporous CPCs patterns with complex vapor responsive color shifts or vapor-revealed implicit images are subsequently achieved. The complicated and reversible multicolor shifts of mesoporous CPC patterns are favorable for immediate recognition by naked eyes but hard to copy. This approach is favorable for integration of responsive CPCs with controllable responsive optical properties. Therefore, it is of great promise for developing advanced responsive CPC devices such as anticounterfeiting devices, multifunctional microchips, sensor arrays, or dynamic displays. PMID- 25300046 TI - Correlation of macular choroidal thickness with concentrations of aqueous vascular endothelial growth factor in high myopia. AB - PURPOSE: To investigate the association of both aqueous and serum vascular endothelial growth factor (VEGF) levels and macular choroidal thickness in high myopia. MATERIALS AND METHODS: VEGF concentrations were measured in aqueous and serum samples via enzyme-linked immunosorbent assay (ELISA) and compared between high myopia (n = 36 eyes, 36 patients) and normal control (n = 42 eyes, 42 patients) eyes. Macular choroidal thickness, the distance from the retinal pigment epithelium (RPE) to the scleral interface, was determined via enhanced depth-imaging optical coherence tomography (EDI-OCT). Axial length was measured using the intraocular (IOL) lens Master. RESULTS: Aqueous levels of VEGF from high myopia patients were significantly lower compared with those from control persons (61.4 +/- 27.6 versus 122.6 +/- 52.4 pg/ml; p < 0.001), respectively. Macular choroidal thickness of high myopia patients was significantly lower compared with that of control persons (111.1 +/- 45.0 versus 230.6 +/- 81.8 MUm; p < 0.001), respectively. Aqueous levels of VEGF were significantly associated with both macular choroidal thickness (R(2)= 0.641; p < 0.001) and axial length (R(2)= 0.679; p < 0.001) in high myopia patients. In addition, there was a significantly negative correlation between macular choroidal thickness and axial length (R(2)= 0.69; p < 0.001). However, no correlation between serum VEGF and either macular choroidal thickness or axial length was detected in high myopia patients (R(2)= 0.009; p = 0.59; R(2)= 0.00002; p = 0.981). CONCLUSIONS: Macular choroidal thickness was significantly correlated with aqueous, but not serum, levels of VEGF in highly myopic eyes. Macular choroidal thickness may be of predictive value for identifying aqueous VEGF levels in high myopia patients and may, thus, be a useful prognostic modality. PMID- 25300047 TI - Gratitude for help among adult friends and siblings. AB - Although gratitude is a key prosocial emotion reinforcing reciprocal altruism, it has been largely ignored in the empirical literature. We examined feelings of gratitude and the importance of reciprocity in same-sex peer relations. Participants were 772 individuals (189 men; mean age = 28.80) who completed an online survey using a vignette design. We investigated (i) differences in reported gratitude and the importance of reciprocity among same-sex siblings and same-sex friends, and (ii) how relationship closeness moderates these associations. Based on the theory of kin altruism, we expect that people would feel more grateful towards friends than towards their siblings, and that lack of gratitude or failure to pay back a loan would bother more with friends than with siblings, irrespective of emotional closeness. Results showed that levels of gratitude and expectations of reciprocity were higher towards friends compared to siblings. This was the case also after controlling for emotional closeness. Being close generally made participants feel more grateful and expect lower displays of gratitude in the other. Closeness was also strongly associated with emotional gratitude among siblings compared to friends. We conclude that feelings and displays of gratitude have a special role in friendships. Although a close sibling may elicit as much gratitude as a friend does, even a very close friend is not exempt from the logic of reciprocity in the same way that a sibling is. PMID- 25300048 TI - Infidelity and kin selection: does cheating seem as bad when it's "all in the family"? AB - The current study explored people's perceptions of how they would feel if their partners cheated on them by having sex with their relatives, such as if a man's wife had sex with his brother. Kin selection theory suggests that in such situations, victims of infidelity might feel slightly better if their partners had sex with biological relatives (compared to sex with nonrelatives) because some of the victims' genes could still get passed on through their relatives. In two experiments, participants reported how they would feel in various scenarios involving their partners having sex with participants' relatives and nonrelatives. As expected, participants generally reported being very disapproving of a partner's hypothetical infidelity with both their relatives and nonrelatives. However, contrary to predictions generated by kin selection theory, participants tended to report that they would feel worse if their partners had sex with their relatives. We propose several explanations for the current findings and discuss their implications for kin selection theory. PMID- 25300049 TI - Sick in the head? Pathogen concerns bias implicit perceptions of mental illness. AB - Biases against the mentally ill are historically and cross-culturally pervasive, suggesting they may have an evolutionary basis. The prevailing view is that people seek to distance themselves from the mentally ill because they are perceived as dangerous, violent, and incompetent. However, because of similarities between sickness behaviors and symptoms of some mental disorders, it was hypothesized that mental illness stigma could be partially explained as a function of behavioral immune system biases designed to avoid potential sources of contagion. In two experiments, it was found that mental illness was implicitly associated more with disease than danger. In Experiment 1, this implicit association was exacerbated among people who have had their biological immune system activated by a recent illness. In Experiment 2, experimentally priming disease salience increased implicit association between mental illness and disease. Implications for the evolutionary origins of prejudice and the prevention of mental illness stigma are discussed. PMID- 25300051 TI - Verbal compliments as a differential source of mate poaching threat for men and women. AB - Two studies tested whether people feel threatened by another individual verbally complimenting their romantic partner. Such compliments may indicate that the other person is a potential rival who will try to "poach" their mate. Across two studies, women were more threatened than men when imagining another person complimenting their partner's physical appearance. There were no sex differences in response to imagining another person complimenting their partner's sense of humor. When another person compliments one's partner's physical appearance, this indicates that they may be sexually attracted to the partner. Mediation analyses revealed that the sex difference occurs because women believe men are more open to casual sex, and therefore more vulnerable to mate poaching when another person expresses sexual interest in them. PMID- 25300050 TI - Red is romantic, but only for feminine females: sexual dimorphism moderates red effect on sexual attraction. AB - Previous researchers have documented that the color red enhances one's sexual attraction to the opposite sex. The current study further examined the moderating role of sexual dimorphism in red effects. The results indicated that red enhanced men's sexual attraction to women with more feminine facial characteristics but had no effect on ratings of perceived general attractiveness. Red clothing also had a marginally significant effect on men's sexual attractiveness. In addition, regardless of sexual dimorphism cues, male participants rated women with red as warmer and more competent. The underlying mechanisms of the red effect, the limitations of the current study, and suggestions for future directions are discussed. PMID- 25300052 TI - Digit ratio (2D:4D) and gender inequalities across nations. AB - Gender inequality varies across nations, where such inequality is defined as the disproportionate representation of one sex over the other in desirable social, economic, and biological roles (typically male over female). Thus in Norway, 40% of parliamentarians are women, in the USA 17%, and in Saudi Arabia 0%. Some of this variation is associated with economic prosperity but there is evidence that this cause and effect can go in either direction. Here we show that within a population the average ratio of index (2D) to ring (4D) finger lengths (2D:4D)-a proxy measure of the relative degree to which offspring is exposed in utero to testosterone versus estrogen-is correlated with measures of gender inequality between nations. We compared male and female 2D:4D ratios to female parliamentary representation, labor force participation, female education level, maternal mortality rates, and juvenile pregnancy rates per nation in a sample of 29 countries. We found those nations who showed higher than expected female fetal exposure to testosterone (low 2D:4D) and lower than expected male exposure to fetal testosterone (high 2D:4D) had higher rates of female parliamentary representation, and higher female labor force participation. In short, the more similar the two sexes were in 2D:4D, the more equal were the two sexes in parliamentary and labor force participation. The other variables were not as strongly correlated. We suggest that higher than expected fetal testosterone in females and lower fetal testosterone in males may lead to high female representation in the national labor force and in parliament. PMID- 25300053 TI - Recreational drug use and fluctuating asymmetry: testing the handicap principle. AB - Zahavi's handicap principle suggests that only organisms with good genetic quality can afford to engage in costly behaviors. Recreational drug use can be harmful to one's health and therefore might be viewed as a costly signal of one's genetic quality. One of the measurements of genetic quality is bodily symmetry assessed by fluctuating asymmetry. If unhealthy drug use is a behavioral example of Zahavi's handicap principle, then men who use different stimulants or recreational drugs should be more symmetrical than men who do not use them at all or use them only in low quantity. The aim of this study was to examine the relationships between drug use and fluctuating asymmetry. The subjects were 190 young women and 202 young men. Six bilaterally symmetrical traits were measured: length of II-V digits, wrist breadth, and ear height. Questionnaires included questions about smoking, alcohol drinking, drug use, and designer drug use. There was no relationship between bodily symmetry and smoking frequency, alcohol drinking frequency, drug or designer drug use, total substance use, age of smoking initiation, or reason of this initiation. The results indicate that drug use does not reflect genetic quality and does not necessarily relate to the handicap hypothesis. PMID- 25300054 TI - Evolutionary awareness. AB - In this article, we advance the concept of "evolutionary awareness," a metacognitive framework that examines human thought and emotion from a naturalistic, evolutionary perspective. We begin by discussing the evolution and current functioning of the moral foundations on which our framework rests. Next, we discuss the possible applications of such an evolutionarily-informed ethical framework to several domains of human behavior, namely: sexual maturation, mate attraction, intrasexual competition, culture, and the separation between various academic disciplines. Finally, we discuss ways in which an evolutionary awareness can inform our cross-generational activities-which we refer to as "intergenerational extended phenotypes"-by helping us to construct a better future for ourselves, for other sentient beings, and for our environment. PMID- 25300055 TI - Sex differences and similarities in urban home ranges and in the accuracy of cognitive maps. AB - Former research has examined potential human sex differences in spatial abilities or home range size. Both are assumed to have an adaptive function. In this study we combined the investigation of home range size in an urban environment and spatial abilities by accuracy analysis of cognitive maps. Participants (n = 87) drew a sketch of their home range in Vienna depicting all places regularly visited in every-day life. We used the sketches' geographical locations to calculate the size of the home range. With the Geometric Morphometric Methodology, we quantified the accuracy of cognitive maps by measuring Euclidean distances between corresponding landmarks in the sketches and the geographical maps of home ranges. Our results showed a non-significant trend for men to have a larger home range. Overall, participants' cognitive maps were fairly accurate. However, men sketched their home range more precisely than women. Female map accuracy increased as a function of residency duration. In addition, accuracy of cognitive maps was influenced by home range size and number of frequently visited places. In summary, findings indicate that sex differences in home range size and spatial abilities may still persist in humans living in urbanized Western societies, but are also influenced by environmental experience. PMID- 25300057 TI - Conceptualizing time preference: a life-history analysis. AB - Life-history theory (LHT) has drawn upon the concept of "time preference" as a psychological mechanism for the development of fast and slow strategies. However, the conceptual and empirical nature of this mechanism is ill-defined. This study compared four traits commonly used as measures of "time preference" (impulsivity, sensation seeking, future orientation and delay discounting) and evaluated their relationship to variables associated with life-history strategies (aggressive behavior and mating attitudes, biological sex, pubertal timing, victimization, and exposure to aggression in the environment). Results indicated that only sensation seeking consistently showed all the predicted associations, although impulsivity, future orientation, and delay discounting showed some significant associations. A unidimensional higher-order factor of "time preference" did not adequately fit the data and lacked structural invariance across age and sex, suggesting that personality traits associated with LHT do not represent a global trait. We discuss the use of personality traits as measures in LHT and suggest that greater caution and clarity is required when conceptualizing this construct in future work. PMID- 25300058 TI - Effects of repeated propranolol administration in a rat model of surgically induced endometriosis. AB - OBJECTIVES: To determine whether propranolol has an inhibitory effect on the angiogenesis of endometriosis in an experimental rat model or not. STUDY DESIGN: This was an experimental animal model study. Twenty-four female Wistar albino rats (200-250 g) were used to create a model for surgical induction of endometriosis. Two rats died during the surgeries. The rats were randomly divided into treatment (n=11) and control groups (n=10), which were treated with daily intraperitoneal propranolol (10 mg/kg) and saline (2 mL), respectively. Study duration was 8 weeks. The volumes and histopathological findings of the implants, and immunochemistry for vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-2, and MMP-9 were evaluated. RESULTS: Viable endometriotic implants were created in all animals. In the propranolol-treated group, the mean implant volume significantly decreased after treatment (142.5 vs. 32.1 mm(3), respectively; p=0.008), while the mean implant volume significantly increased in the control group (141.0 vs. 174.2 mm(3), respectively; p=0.009). There were also significant reductions in VEGF immunoreactivity scores and both stroma and epithelium MMP-2 and MMP-9 immunoreactivity scores in the propranolol treated group compared with the control group (p<0.005 for all scores). CONCLUSIONS: Propranolol may suppress endometrial tissue by its antiangiogenic activity through inhibitory actions on VEGF, MMP-2, and MMP-9. Therefore, propranolol is a promising candidate drug for effective treatment of patients with endometriosis, which needs to be confirmed with further studies. PMID- 25300059 TI - Outcome, complications and future fertility in women treated with uterine artery embolization and methotrexate for non-tubal ectopic pregnancy. AB - OBJECTIVE: To determine the effectiveness and safety of uterine artery methotrexate (MTX) infusion and embolization combined with systemic MTX for treatment of non-tubal ectopic pregnancy. STUDY DESIGN: We retrospectively reviewed the electronic files of all women admitted to a single tertiary, university-affiliated medical center with a diagnosis of non-tubal (cervical, interstitial or cesarean section scar) ectopic pregnancy, who were treated by a combination of uterine artery MTX infusion and embolization and systemic MTX between January 2001 and March 2014. The treatment protocol included a total of 4 MTX injections in doses of 1 mg/kg/day every other day (days 1, 3, 5, 7 of the protocol) alternating with folinic acid 0.1 mg/kg (days 2, 4, 6, 8). The first or second MTX dose was administered by transcatheter intra-arterial injection during the embolization procedure just before injecting Gelfoam for bilateral uterine artery occlusion, and the remaining doses were given intramuscularly. RESULTS: During the study period, 25 women underwent uterine artery infusion and embolization combined with systemic MTX treatment for non-tubal ectopic pregnancy. Ten of the pregnancies were cervical, 9 were interstitial, and 6 were cesarean scar pregnancies. Mean gestational age and beta-human chorionic gonadotropin (beta-HCG) level at admission were 68.6+/-12.9 days and 14,179 (range 436-61596) IU/L, respectively. Treatment was successful in 24 patients (96%) with mean beta-HCG resolution time of 52.6 (6-147) days. Mild immediate side effects were reported including 8 cases (32%) of abdominal discomfort, 3 cases (12%) of groin or leg pain and 3 cases (12%) of puncture-site local skin infection. No serious immediate side effects such as internal vascular bleeding, sepsis or early liver or renal failure were observed. Among 12 women who stated that they tried to conceive and were more than a year from the treatment, 10 (83.3%) had subsequent pregnancy. CONCLUSION: A combination of uterine artery MTX infusion and embolization with systemic MTX seems to be an effective and safe treatment for non-tubal ectopic pregnancies in women who try to conceive. PMID- 25300060 TI - Fascial surgical repair for vaginal prolapse: effect on quality of life and related symptoms. AB - OBJECTIVE: The aim of this study was to evaluate the impact of surgical treatment for pelvic organ prolapse (POP) on quality of life and on bladder, vaginal and bowel symptoms using validated questionnaires such as the prolapse quality of life questionnaire (P-QoL). STUDY DESIGN: Sixty-five women underwent surgical POP repair. All were evaluated by physical examination and by the use of ICIQ-VS and P-QoL questionnaires before surgery as well as three and six months after surgery. RESULTS: The preoperative scores of all domains on the ICIQ-VS and P-QoL questionnaires and the scores obtained from quantification of the urinary, sexual and bowel symptoms were higher than those at three and six months after surgery (p<0.0001). There was no significant difference in the domain scores for the ICIQ VS and P-QoL questionnaires at three and at six months after surgery (p>0.05). The preoperative staging was higher than that at three and six months after surgery (p<0.001), and there was no difference in staging between the two postoperative time points (p>0.05). CONCLUSIONS: Surgery with fascial repair for the treatment of pelvic organ prolapse improved health-related quality of life, as assessed by the P-QoL and ICIQ-VS, as well as urinary, vaginal and intestinal symptoms. PMID- 25300061 TI - Nickel adsorption on chalk and calcite. AB - Nickel uptake from solution by two types of chalk and calcite was investigated in batch sorption studies. The goal was to understand the difference in sorption behavior between synthetic and biogenic calcite. Experiments at atmospheric partial pressure of CO2, in solutions equilibrated with calcite and chalk and pH ranging from 7.7 to 8.8, explored the influence of initial concentration and the amount and type of sorbent on Ni uptake. Adsorption increases with increased surface area and pH. A surface complexation model describes the data well. Stability constants for the Ni surface complex are log KNi=-1.12 on calcite and log KNi=-0.43 and -0.50 on the two chalk samples. The study confirms that synthetic calcite and chalk both take up nickel, but Ni binds more strongly on the biogenic calcite than on inorganically precipitated, synthetic powder, because of the presence of trace amounts of polysaccharides and clay nanoparticles on the chalk surface. PMID- 25300062 TI - Finite element modeling of multilayered structures of fish scales. AB - The interlinked fish scales of Atractosteus spatula (alligator gar) and Polypterus senegalus (gray and albino bichir) are effective multilayered armor systems for protecting fish from threats such as aggressive conspecific interactions or predation. Both types of fish scales have multi-layered structures with a harder and stiffer outer layer, and softer and more compliant inner layers. However, there are differences in relative layer thickness, property mismatch between layers, the property gradations and nanostructures in each layer. The fracture paths and patterns of both scales under microindentation loads were different. In this work, finite element models of fish scales of A. spatula and P. senegalus were built to investigate the mechanics of their multi layered structures under penetration loads. The models simulate a rigid microindenter penetrating the fish scales quasi-statically to understand the observed experimental results. Study results indicate that the different fracture patterns and crack paths observed in the experiments were related to the different stress fields caused by the differences in layer thickness, and spatial distribution of the elastic and plastic properties in the layers, and the differences in interface properties. The parametric studies and experimental results suggest that smaller fish such as P. senegalus may have adopted a thinner outer layer for light-weighting and improved mobility, and meanwhile adopted higher strength and higher modulus at the outer layer, and stronger interface properties to prevent ring cracking and interface cracking, and larger fish such as A. spatula and Arapaima gigas have lower strength and lower modulus at the outer layers and weaker interface properties, but have adopted thicker outer layers to provide adequate protection against ring cracking and interface cracking, possibly because weight is less of a concern relative to the smaller fish such as P. senegalus. PMID- 25300063 TI - The effects of repeated heat-pressing on the mechanical properties and microstructure of IPS e.max Press. AB - OBJECTIVES: We evaluated the effects of repeated heat-pressing on the mechanical properties and microstructure of IPS e.max Press. METHODS: A total of 20 specimens were fabricated including 10 heat-pressed once and another 10 heat pressed twice. The density, porosity, and surface roughness (Ra) were evaluated. Three-point flexural strength following the ISO 6872 and Vickers hardness were measured, and fracture toughness (KIC) was calculated. Specimens were characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM). RESULTS: Compared to a single heat-press treatment, the density decreased and porosity increased after two heat-pressing events. A significant difference in density was observed. The flexural strength, Vickers hardness and fracture toughness significantly decreased after two heat-pressing events. The XRD patterns show that the intensity of the crystalline phase better corresponds to lithium disilicate (Li2Si2O5) after two heat-presses than only one. The SEM images detailed the interlocking microstructure of rod-shaped Li2Si2O5 crystals after one heat-press. These became oriented after two heat-presses, and the crystal size became larger. CONCLUSION: This study showed that repeated heat pressing was detrimental to the density, porosity, strength, hardness, and toughness of IPS e.max Press. PMID- 25300064 TI - Characterization of the microstructure of GaP films grown on {111} Si by liquid phase epitaxy. AB - The development of a cost-effective Si based platform on which III-V's can be grown is of great interest. This work investigates the morphology of gallium phosphide (GaP) films grown on {111} silicon (Si) substrates by means of liquid phase epitaxy in a tin (Sn) - based solvent bath. Two types of single-crystal {111} Si substrates were used; the first type was oriented exactly along the ?111? surface (no-miscut) and the second was miscut by 4 degrees . The growth rate of the GaP films was found to be markedly different for the two types of substrates; the GaP films on the miscut Si substrate grew ~4 times faster than those on the no-miscut substrate. The GaP films grew epitaxially on both types of substrates, but contained Si and Sn as inclusions. In the case of the no-miscut substrate, a number of large Sn particles were incorporated at the GaP/Si interface. As a result, these interfacial Sn particles affected the strain state of the GaP films dramatically, which, in turn, manifested itself in the form of a duplex microstructure that consists of strained and strain-free regions. PMID- 25300065 TI - Structure and function of the UV-B photoreceptor UVR8. AB - UVR8 is a UV-B photoreceptor that employs specific tryptophans in its primary sequence as chromophores in photoreception. UV-B absorption causes dissociation of the dimeric photoreceptor by neutralizing interactions between monomers. The monomeric form initiates signalling through interaction with the COP1 protein, leading to transcriptional responses. This article discusses the structural basis of UVR8 function, highlighting recent research on the mechanism of photoreception and on interactions with other proteins involved in signalling and regulation. PMID- 25300066 TI - Giant magnetoconductance oscillations in hybrid superconductor-semiconductor core/shell nanowire devices. AB - The magnetotransport of GaAs/InAs core/shell nanowires contacted by two superconducting Nb electrodes is investigated, where the InAs shell forms a tube like conductive channel around the highly resistive GaAs core. By applying a magnetic field along the nanowire axis, regular magnetoconductance oscillations with an amplitude in the order of e(2)/h are observed. The oscillation amplitude is found to be larger by 2 orders of magnitude compared to the measurements of a reference sample with normal metal contacts. For the Nb-contacted core/shell nanowire the oscillation period corresponds to half a flux quantum Phi0/2 = h/2e in contrast to the period of Phi0 of the reference sample. The strongly enhanced magnetoconductance oscillations are explained by phase-coherent resonant Andreev reflections at the Nb-core/shell nanowire interface. PMID- 25300067 TI - U.S. masters track participation reveals a stable sex difference in competitiveness. AB - It is well established that men are more likely than women to engage in direct competition, but it is unclear if this reflects social structural conditions or evolved predispositions. These hypotheses can be addressed by quantifying competitiveness in sports and testing if the sex difference is decreasing over time in the U.S., a society where social roles have converged. Study 1 assessed participation and the occurrence of relatively fast performances by masters runners (40-74 years old) at recent road races and track meets. Fast performances occurred over 20 times more often at track meets than at road races. Women comprised 55% of finishers at roads races but only 15-28% of finishers at track meets. Thus, the sex difference in masters track participation can serve as a measure of the sex difference in competitiveness. Study 2 used data from national championship meets and yearly rankings lists to test whether the sex difference in masters track participation decreased from 1988-2012. The sex difference decreased overall, but there was no evidence of change since the late 1990s. Therefore, the sex difference in the willingness to engage in direct sports competition appears to reflect both social structural conditions and evolved predispositions. PMID- 25300068 TI - The association between obesity and lethal blood alcohol concentrations: a nationwide register-based study of medicolegal autopsy cases in Sweden. AB - Obesity is a global problem and in aspects of lethal ethanol intoxications virtually unexplored. The cause of death in ethanol intoxication is generally considered to be suppression of the respiratory function. Previous research indicates that respiratory function is more vulnerable in obese subjects than in those of normal weight. We hypothesized that lethal blood alcohol concentration (BAC) is lower in obese subjects compared to those of normal weight. We used the Swedish medicolegal autopsy register and identified all medicolegal autopsy cases in Sweden during the period from 1999 to 2013 (N=79,060), and identified 1545 cases with ethanol intoxication identified as the primary cause of death. We studied the association between body mass index and lethal BAC using logistic regression models that we adjusted using several potential confounders such as age, sex, drugs, and extent of decomposition. We observed an association between obesity and lower lethal BACs. The estimated adjusted odds ratio of the association between obesity and a lethal BAC >30/00, using subjects of normal weight as reference, was 0.54, 95% confidence interval: 0.39-0.74. The result indicates that in obese subjects the lethal BAC is lower than in those of normal weight. PMID- 25300070 TI - Aspirin: still a wonder drug? Sorting out aspirin's role in heart attack and stroke prevention. PMID- 25300069 TI - Coding ill-defined and unknown cause of death is 13 times more frequent in Denmark than in Finland. AB - Exact cause and manner of death determination improves legislative safety for the individual and for society and guides aspects of national public health. In the International Classification of Diseases, codes R00-R99 are used for "symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified" designated as "ill-defined" or "with unknown etiology". The World Health Organisation recommends avoiding the use of ill-defined and unknown causes of death in the death certificate as this terminology does not give any information concerning the possible conditions that led to the death. Thus, the aim of the study was, firstly, to analyse the frequencies of R00-R99-coded deaths in mortality statistics in Finland and in Denmark and, secondly, to compare these and the methods used to investigate the cause of death. To do so, we extracted a random 90% sample of the Finnish death certificates and 100% of the Danish certificates from the national mortality registries for 2000, 2005 and 2010. Subsequently, we analysed the frequencies of forensic and medical autopsies and external clinical examinations of the bodies in R00-R99-coded deaths. The use of R00-R99 codes was significantly higher in Denmark than in Finland; OR 18.6 (95% CI 15.3-22.4; p<0.001) for 2000, OR 9.5 (95% CI 8.0-11.3; p<0.001) for 2005 and OR 13.2 (95% CI 11.1-15.7; p<0.001) for 2010. More than 80% of Danish deaths with R00-R99 codes were over 70 years of age at the time of death. Forensic autopsy was performed in 88.3% of Finnish R00-R99-coded deaths, whereas only 3.5% of Danish R00-R99-coded deaths were investigated with forensic or medical autopsy. The codes that were most used in both countries were R96-R99, meaning "unknown cause of death". In Finland, all of these deaths were investigated with a forensic autopsy. Our study suggests that if all deaths in all age groups with unclear cause of death were systematically investigated with a forensic autopsy, only 2-3/1000 deaths per year would be coded as an ill-defined and unknown cause of death in national mortality statistics. At the same time the risk to overlook unnatural deaths is decreased to a minimum. To achieve this in Denmark requires that the existing legislation on cause of death investigation would need to be changed to ensure that all deaths with unknown cause of death are investigated with a forensic autopsy. PMID- 25300071 TI - Inside gastroparesis. Understanding and coping with a serious stomach disorder. PMID- 25300072 TI - Dip into easy-on-the-joints fitness. PMID- 25300073 TI - Blood transfusion precautions to take. PMID- 25300074 TI - New worries about epidural steroid shots. PMID- 25300075 TI - Despite brushing and flossing, I still have bad breath. How can I get rid of it? PMID- 25300076 TI - I take vitamin B12supplements daily, but blood tests show that I have a deficiency. How is this possible? PMID- 25300078 TI - Add years to your life: eat lots of fresh produce. PMID- 25300077 TI - Light eyes, drugs and the sun: a bad mix. PMID- 25300079 TI - Avoid a stroke: keep calm and carry on. PMID- 25300080 TI - Medication highlight: dexmedetomidine hydrochloride use in the NICU. PMID- 25300081 TI - Maintain a healthy weight to help prevent COPD. Excess belly fat could lead to chronic obstructive pulmonary disease; underweight also is a risk factor. PMID- 25300083 TI - New technique restores failing prosthetic valves. While not yet widely available, valve-in-valve TAVR is a promising option to surgical valve replacement for many. PMID- 25300082 TI - Four key nutrients decrease the risk of bone and muscle degeneration. The interaction of calcium, vitamin D, phosphorus, and protein affect musculoskeletal health in aging adults. PMID- 25300084 TI - Exercise as medicine for older women. Exercise extends mortality and wards off cognitive decline; health care professionals should prescribe exercise programs. PMID- 25300085 TI - Goal! A new health kick. PMID- 25300086 TI - A pill of a different color. PMID- 25300087 TI - Personality change tied to hearing loss. PMID- 25300088 TI - Got milk? It might help your arthritis. PMID- 25300089 TI - An exercise program can keep you moving. PMID- 25300090 TI - Could protein lower stroke risk? PMID- 25300091 TI - Physician assistants in cardiovascular surgery. PMID- 25300092 TI - Nurse practitioners in cardiovascular surgery. PMID- 25300093 TI - Wound debridement. PMID- 25300094 TI - Physician assistants in urology. PMID- 25300095 TI - Endovascular grafts. PMID- 25300096 TI - Nurse practitioners in bariatrics. PMID- 25300097 TI - Ever improving. PMID- 25300098 TI - Fluid filtration and reabsorption across microvascular walls: control by oncotic or osmotic pressure? (secondary publication). AB - AIM: Relationships between hydrostatic and oncotic (colloid osmotic) pressures in both capillaries and interstitium are used to explain fluid filtration and reabsorption across microvascular walls. These pressures are incorporated in the Starling oncotic hypothesis of capillaries which fails, however, to explain fluid homeostasis when hydrostatic capillary pressure is high (in feet during orthostasis) and low (in lungs), or when oncotic plasma pressure is significantly decreased in experiments and some clinical states such as genetic analbuminaemia. METHODS: To explain fluid homeostasis we propose osmotic counterpressure hypothesis of capillaries which claims: 1) during water filtration across microvascular wall in arterial capillary, the plasma osmolytes are sieved (retained) so that plasma osmotic counterpressure is generated, 2) this osmotic counterpressure rises along the length of capillary and when it reaches capillary hydrostatic pressure the water filtration is halted, and 3) in venous capillaries and postcapillary venules where hydrostatic pressure is low, the osmotic counterpressure is instrumental in water reabsorption from interstitium what leads to dissipation of osmotic counterpressure. According to modified van't Hoff's equation the generation of osmotic counterpressure depends on plasma concentration of osmolytes and their restricted passage (reflection coefficient) across microvascular wall in comparison to water. RESULTS: Plasma NaCl makes 83% of plasma osmolarity and shows restricted passage across the walls of cerebral and peripheral continuous capillaries, so that Na and Cl are the most important osmolytes for generation of osmotic counterpressure. Our calculation indicates that at various rates of water filtration the osmotic counterpressure of NaCl acts as negative feedback control: higher hydrostatic pressure and water filtration rate create higher osmotic counterpressure which opposes filtration and leads to higher water reabsorption rate. Furthermore, our analysis indicates that fluid volume changes in arterial capillaries are proportionally 100 times larger than in interstial fluid. CONCLUSION: The osmotic counterpressure hypothesis explains fluid homeostasis at high, mean and low capillary hydrostatic pressures. Plasma proteins and inorganic electrolytes contribute 0.4% and 94% to plasma osmolarity, respectively, so that plasma proteins have low osmotic (oncotic) pressure and despite high restriction of their passage across microvascular wall they contribute little to build up of osmotic counterpressure in comparison to electrolytes. However, absence or very low concentration of plasma proteins increases microvascular wall permeability to water and osmolytes compromising build up of osmotic counterpressure leading to development of interstial oedema. PMID- 25300099 TI - 3M ESPE: easing the transition to CAD/CAM dentistry. PMID- 25300100 TI - D4D: CAD/CAM that's focused on faster, easier, better- without compromise. PMID- 25300101 TI - Ivoclar Vivadent's "all-ceramic, all-options" philosophy gives clinicians flexibility. PMID- 25300102 TI - Sirona's CEREC technology: win-win for patients and practitioners. PMID- 25300103 TI - [Effects of vitamins deficiency on the cytochrome P450 inducibility in rats]. AB - The purpose of the study was to determine multi-vitamin deficiency effects on the inducibility of main isoforms of cytochrome P450 in the rat liver. The study was carried out on 4 groups of Wistar rats. Rats of the 1st and 3rd group received semi-synthetic diets containing adequate (100% of recommended vitamin level) level of vitamins, the 2nd and 4th--the semi-synthetic diet containing vitamins in the amount of 20% from adequate level. The duration of the experiment was 4 weeks. During the last week indole-3-carbinol (I-3-C) in dose of 20 mg/kg body weight was added to the diet of the 3rd and 4th group of rats. Vitamin E content in liver and blood serum declined by 59 and 34%, respectively in rats which were fed vitamin-deficient diet (2nd group); vitamin A level decreased by 5 times in the liver, but was not changed in blood serum. Multi-vitamin deficiency in the diet led to the increase in the liver ethoxyresorufin O-dealkylase (EROD) activity of CYP1A1, methoxyresorufin O-dealkylase (MROD) activity of CYP1A2 and testosteron 6beta-hydroxylase (6beta-TG) activity of CYP3A by 11, 80 and 53%, respectively, and gene expression of CYP1A1, CYP1A2, CYP3A and AhR by 8,5; 1,6; 2,4 and 3,6 fold. In rats fed diet with adequate levels of vitamins (3rd group) I 3-C increased activity of EROD and MROD by 4,4 and 5,5 fold, and the expression of CYP1A1, CYP1A2 and AhR genes by 148; 3 and 3,5 fold compared to the parameters of the 1st group (without I-3-C). Multi-vitamin deficiency increased I-3-C related induction of EROD activity and expression of CYP1A1 and CYP1A2 genes, but decreased I-3-C-related induction of the MROD activity. Thus, 5-fold reducing of vitamin content in rat diet lead to significant changes in activity and inducibility of cytochrome P450 of CYP1A and 3A family, which play a key role in the detoxification and metabolism of drugs. PMID- 25300104 TI - [State of the energy-supply system of the liver mitochondria under the conditions of alimentary deficiency of protein]. AB - The NADH-dehydrogenase and succinate dehydrogenase activity of the rats' liver mitochondria under the conditions of alimentary deprivation of protein has been studied. Research was carried out on 65 white non-linear rats divided according to the diet protein content into three groups: 1--rats fed a hypoprotein diet (7% of protein, 10% of fat u 83% of carbohydrates; n = 26); 2--rats fed a protein free diet (n = 26); 3--rats fed a complete semi-synthetic ration (14% of protein, 10% of fat u 76% of carbohydrates; n = 13). The NADH-dehydrogenase activity was estimated by spectrophotometric method, succinate dehydrogenase activity--by the intensity of reduction of the potassium ferricyanide. It has been estimated that the decrease of NADH-dehydrogenase activity of mitochondria occurred on the 14th day of feeding rats with protein-free diet, and four-week feeding of rats under these conditions lead to the decrease of enzyme activity by 5,5 fold compared with the control group (0.506 +/- 0.040 nmol NADH/min/mg of protein) and by 3,0 fold compared with the previous stage of the experiment. At the same time a hypoprotein diet caused 2-fold decrease of NADH-dehydrogenase activity of liver mitochondria only on the 28th day. It has been shown that the succinate dehydrogenase activity didn't change significantly after two-week maintenance of rats on a protein-free diet as compared with control, while the four-week maintenance on both hypoprotein and protein-free diet lead to the decrease of the succinate dehydrogenase activity. Specifically, under the conditions of the hypoprotein diet succinate dehydrogenase activity of liver mitochondria decreased twofold and under the conditions of the protein free diet-- threefold. Probably, the disorders at the level of Complex I of respiratory chain underlie the realization of the changes in the system of energy biotransformation in mitochondria under the conditions of alimentary protein deficiency. PMID- 25300105 TI - [Effects of nighttime snacking in students on their physiological parameters]. AB - The purpose of the research was a comparative assessment of the level of diet nutrients, characteristics of higher nervous activity, specificity of chronobiological changes of the sleep-wake cycle, the daily dynamics of cortisol level and total antioxidant activity in saliva in students with the presence of night eating compared with students who do not eat at night. The participants were 72 university students aged 17-22 years (59 females and 13 males), a self administered diet diary for a week was used to acquire dietary pattern and nutrient content. All participants were divided into two groups: group 1- students with food consumption from 06.00 am to 10.00 pm without night meals (n = 34), and group 2--students, whose food consumption include all day period and night snaking from 10.00 pm to 06.00 am (n = 38). High nervous activity parameters were detected according to the Eysenck questionnaire, Spielberg and Taylor anxiety tests, the test "Stress", the three-factor eating questionnaire; chronobiological state was evaluated according to sleep quality, sleep hygiene, daily sleepiness, chronotype. Levels of cortisol and total antioxidant activity were estimated in saliva twice a day: in the morning and in the evening. In both groups, the majority of students (97%) have reduced consumption of vitamins and minerals such as biotin, vitamin D, choline, iodine, cobalt, manganese, sulfur, fluorine and zinc. Deficit of carbohydrates was found in 93% of respondents. The number of students with calcium deficiency was increased in the group 2 compared to the group 1 and reached 27.8% vs 3% (p < 0.05), niacin insufficiency was revealed in 41.7% vs 18.2% (p < 0.05) and proteins insufficiency frequency reached 30.6% vs 0% (p < 0.05). The students from the group 2 had a significantly lower (p < 0.05) intake of vitamins A, B6 and C. In the group 2 it was detected the time shift of food consumption acrophase (15.1 h vs. 13.8 h; p < 0.05), decrease of persons with morning chronotype (5.55% vs 24.24%; p < 0.05), increase of anxiety and daily sleepiness (26 vs 20; p < 0.01, and 10 vs 6; p < 0.03 respectively); decrease of sleep quality (13 vs 15; p < 0.01), increase of evening saliva cortisol level [9.41 (6.96; 13.11) vs 6.51 (5.61; 9.88) ng/ml; p < 0.005) and decrease of saliva total antioxidant activity in the morning [13.00 (9.82; 14.98) vs 16.41 (15.21; 17.51) mg/l; p < 0.001] and in the evening [11.11 (7.85; 12.89)vs 14.32 (13.27; 15.29) mg/l; p < 0.001]. PMID- 25300106 TI - [Antioxidative and membranotropic activities of rosmarinic acid]. AB - The metabolic damages and inflammatory diseases are closely connected with high increase of the contents of the reactive oxygen species (ROS) and lipid peroxidation products in organism. In connection with this natural antioxidants are actively used for efficient fight with oxidative stress. In current work we have estimated an antioxidative potential of rosmarinic acid (RA), which is broadly wide-spread amongst plants and possesses the useful spectrum of biological activities. It has been shown that RA noticeably exceeded known antioxidants in test on antioxidant activities in Hb-H2O2-luminol and 2,2'-azo bis (2-methylpropionamidine) dihydrochloride-luminol systems, as well as on inhibition of linoleic acid peroxidation. On antioxidant activities the investigated substances can be arranged in the following order: RA > dihydroquercetin > trolox > ascorbic acid. RA molecules are localized mainly in the lipid bilayer of polar groups, but have no significant effect on its structural and functional properties: RA does not cause significant changes in permeability of planar bilayer membranes in a dose range of 0.5 to 10 microg/ml. Spontaneous incorporating of 1 mol% of RA into the lipid bilayer is sufficient for the complete prevention of lipid peroxidation. Thus, the antioxidant activity of RA is based on its ability to inhibit the initiation stage of free radical reactions of lipid peroxidation, largely caused by the formation of ROS. In this regard RA, as a powerful and effective inhibitor of ROS and lipid peroxidation, has great potential for wide use not only in medicine but also in the food industry to preserve the quality of perishable food products. PMID- 25300107 TI - [Regulation of food supplements in the European Union and its member states. Part I]. AB - The article discusses aspects of the regional (the European Union) and national (European countries) regulation of food supplements. The definition of the supplement category is given. The contemporary issues of nutrition in developed countries are discussed, and the essential role of food supplements in the diet is emphasized. In particular, the use of vitamins, minerals, botanicals and their chemical constituents in food supplements as well as the issue of setting maximum daily limits are discussed. The positive lists of vitamins, minerals and their chemical modifications are presented. The paper also outlines aspects of supplement safety, requirements for their labelling and pre-market notification procedure. PMID- 25300108 TI - [Gradation in the level of vitamin consumption: possible risk of excessive consumption]. AB - The ratio between the levels of consumption of certain vitamins and minerals [recommended daily allowance for labelling purposes < maximum supplement levels < tolerable upper intake level (UL) < safe level (limit) of consumption < or = therapeutic dose has been characterized. Vitamin A and beta-carotene maximum supplement levels coincides with UL, and recommended daily allowance for these micronutrients coincides with the maximal level of consumption through dietary supplements and/or multivitamins. Except for vitamin A and beta-carotene recommended daily allowance for other vitamins adopted in Russia are considerably lower than the upper safe level of consumption. For vitamin A and beta-carotene there is a potential risk for excess consumption. According to the literature data (meta-analysis) prolonged intake of high doses of antioxidant vitamins (above the RDA) both alone and in combination with two other vitamins or vitamin C [> 800 microg (R.E.) of vitamin A, > 9.6 mg of beta-carotene, > 15 mg (T.E.) of vitamin E] do not possess preventive effects and may be harmful with unwanted consequences to health, especially in well-nourished populations, persons having risk of lung cancer (smokers, workers exposed to asbestos), in certain conditions (in the atmosphere with high oxygen content, hyperoxia, oxygen therapy). Proposed mechanisms of such action may be due to the manifestation of prooxidant action when taken in high doses, shifting balance with other important natural antioxidants, their displacement (substitution), interference with the natural defense mechanisms. Athletes are the population group that requires attention as used antioxidant vitamins A, C, E, both individually and in combination in extremely high doses. In summary, it should be noted that intake of physiological doses which are equivalent to the needs of the human organism, as well as diet inclusion of fortified foods not only pose no threat to health, but will bring undoubted benefits, filling the existing lack of vitamins in the ration. PMID- 25300109 TI - [Toxicological assessment of nanostructured silica. I. Integral indices, adducts of DNA, tissue thiols and apoptosis in liver]. AB - Nanostructured amorphous silica (SiO2) is widely used in food additives, pharmaceuticals and cosmetics. Available data on the oral toxicity of this nanomaterial (NM) in vivo, obtained in acute and subacute experiments are contradictory. The purpose of this study is evaluation of some parameters of toxicity of nanostructured SiO2 when orally administered to rats for 3 months. We used commercial SiO2 preparation, obtained by gas-phase hydrolysis of tetrachlorosilane with a size of the primary nanoparticles close to 5-30 nm, which was characterized as NM by several independent methods. SiO2 in the form of sonicated aqueous dispersion was administered to male rats with initial weight of 80 +/- 4 g for the first 30 days by intragastric gavage and then for 62 days with consumed diets in daily dose of 0,1; 1,0; 10 and 100 mg/kg body weight. The control animals received vehicle--deionized water. Weight gain, relative mass of internal organs, intestinal permeability to protein macromolecules (determination of ovalbumin level in blood serum by solid-phase bivalent immunoassay), urinary excretion of oxidative degradation product of DNA 8-oxo-2-deoxyguanosine (8-oxo G) (by reversed phase HPLC), the level of thiol compounds in liver (spectrophotometrically), liver cell apoptosis (flow cytometer), fixing efficiency of passive avoidance (CRPA) have been measured. It has been shown that three-month administration of nanostructured SiO2 in all doses resulted in animal body weight decrease by 10-15%; a significant increase in adrenal weight was noticed under doses of 1 and 10 mg/kg and urinary 8-oxo-G excretion was significantly reduced at the dose 10 mg/kg. At the maximum dose of NM, 100 mg/kg, after 2 months of administration the number of animals decreased that entered the dark compartment of the experimental setup at initial testing of CRPA. The rest of the studied indices did not experience any significant changes depending on the dose of NM. It is concluded that no toxic effect were expressed in indices studied under the influence of nanostructured SiO2 in rats at daily doses up to 100 mg per kg body weight for 3 months. PMID- 25300110 TI - [Hygienic aspects of iodic deficiency in the children's population of the Saratov region]. AB - The analysis of clusters of iodine-scarce states formation among the children's population of the Saratov Region is submitted. The hygienic assessment of iodine content in raw food materials and foodstuffs grown up and made on the territory of the Saratov Region is given. It has been revealed that various food groups were characterized by a low iodine content, which was (mcg/100 g) in the bread- 4.5 +/- 1.0; 3,6 +/- 0.8 in wheat grain; 2.7 +/- 0.6 in buckwheat; 2.5 +/- 1.1 in beans; 1.95 +/- 0.9 in peas. The actual iodine content in local vegetables and fruits was 1.3-1.6 fold below than the standard chemical composition according to the national tables, in river fish--twice. The quality analysis of the iodated salt sold in the trading network has been carried out. It has been found out that the use of the iodated salt with low iodine content has decreased the additional direct population risk from 12.34% in 2000 to 0.48% in 2010. For the last few years the use of the iodated salt tends to increase in the Saratov Region. In 2011 the iodated salt was used by 37.2% of urban population and 29.0% of villagers. In 2011 88.6% of school students were provided with the iodated salt in educational institutions of the area. It has been shown that the formation of mass iodine-scarce states among the population in the Saratov Region has lasted for a long time. The screening researches of urine excretion in the organized groups of surveyed children revealed an average level of iodine deficiency. In 2011 the iodine deficiency of moderate degree was registered in 18 areas of the Saratov Region, in 6--of easy degree, whereas the moderately severe deficiency areas were not registered. PMID- 25300111 TI - [Effectiveness of the use of iodized milk protein to improve girls' sufficiency with iodine]. AB - The work presents the results of the research capabilities of the use of iodized milk protein as a component of food supplement and enriched food product for the correction of iodine sufficiency in girls. Milk iodinated protein was produced by the enzyme-effective iodization of amino acid residues of cow's milk whey proteins. The study involved 30 girls, whose average age was 19.9 +/- 1.4 years. Participants of observation were divided into three groups, for 10 people each. The first group received daily serving of meat cutlets (50g), enriched with dairy iodinated protein. Iodine content in the finished minced was 100 mcg. The second group received iodinated milk protein in the form of food supplement with iodine content of 100 mcg. The third group was a control one. The duration of observations was 30 days. To assess the effectiveness of measures the concentration of iodine in urine, blood levels of thyroid-stimulating hormone and free thyroxine have been determined, changes in cognitive processes (memory and attention) with the use of psychological tests have been evaluated. Studies have shown the effectiveness of using of iodized milk protein for the correction of iodine deficiency in girls. The use of iodized protein, as part of the enriched product and in the form of food supplement increased urinary iodine level and had a positive influence on the state of the hypophysial-thyroid system. In addition, the use of iodized milk protein helped to improve the cognitive functions of the students, which can be considered as an additional positive effect of correction of iodine deficiency. PMID- 25300112 TI - [Assessment of efficiency of dietotherapy with addition of a vitamin-mineral complex in patients with diabetes mellitus type 2]. AB - The influence of diet inclusion of vitamin and mineral complex (VMC), potassium and magnesium in the form of asparaginate on micronutrient status, body composition and biochemical parameters in patients with diabetes mellitus type 2 (DM2) has been investigated. 120 female patients with DM2 and obesity of I-III degree (mean age - 58 +/- 6 years) have been included in the study. The patients were divided into two groups: main group (n = 60) and control group (n = 60). For 3 weeks patients of both groups received a low-calorie diet (1600 kcal/day). Patients of the main group received VMC, providing an additional intake of vitamins C and E (100-120% RDA), beta-carotene (40% RDA), nicotinamide (38% RDA), pantothenic acid and biotin (60% RDA), vitamins B12, B2 and folic acid (75-83% RDA), vitamins B1 and B6 (160-300% RDA), zinc (100% RDA) and chromium (400% RDA), and also received magnesium (17.7% RDA) and potassium (9.4% RDA) in the form of asparaginate. Body composition, biochemical parameters and micronutrient status (blood serum level of vitamins C, D, B6, B12, folate, potassium, calcium, magnesium, zinc, phosphorus) were evaluated in all patients before and after the 3-week course of diet therapy. After the low-calorie diet therapy average body weight reduction was 4.2 +/- 0.2 kg in the main group, and 4.4 +/- 0.1 kg in the control group, without statistically significant differences between groups. Statistically significant decrease of total cholesterol, triglycerides, and glucose concentration in blood serum was registered in both groups. It should be noted that in the control group glycemia decreased on 1.2 +/- 0.1 mmol/l, while the main group showed a decrease on 1.8 +/- 0.1 (p < 0.05) to normal values (5.4 +/- 0.1 mmol/l). Initial assessment of vitamin and mineral status revealed that most patients were optimal supplied with vitamins and minerals. After the dietotherapy significant increase of vitamin C, 25-hydroxyvitamin D, vitamin B6, folate, vitamin B12, potassium, magnesium, calcium, zinc and phosphorus concentration in blood serum was observed in patients receiving VMC. While in the control group statistically significant decrease of vitamin C, magnesium, zinc and phosphorus concentration in blood serum after the treatment was revealed. The obtained data shows the necessity of addition of the vitamin-mineral complex to the diet of patients with DM2 and obesity. PMID- 25300113 TI - [Determination of oligomycins hydrophobicity parameters]. AB - The parameters of hydrophobicity of five oligomycins, i. e. A, B, C, F and SC-II were determined by HPLC. The location of the ascending hydrophobicity parameter was set: oligomycin B < oligomycin SC-II < oligomycin A < oligomycin F < oligomycin C. PMID- 25300114 TI - [Kinetics of decamethoxine, an antimicrobial agent]. AB - The kinetics of decamethoxine liberation from medical antimicrobial textiles was studied. The elution of decamethoxine was shown to be a complicated diffusive kinetic process dependent on the exposure and concentration of decamethoxine. PMID- 25300115 TI - [Spectrophotometric method for aminoglycoside concentration measurement in blood plasma]. AB - The aim of the research was to develop a simple, available and rapid spectrophotometric method for measuring aminoglycoside concentration in blood plasma and to evaluate the antibiotic efficacy and susceptibility. The method is based on the ability of aminoglycosides, in particular amikacin, to change the color of Fast Blue B Salt Dye (SIGMA-ALDRICH). An antibiotic at various concentrations and the dye were added to blood plasma. The resulting mixture was filtered to separate the insoluble residue. After that the optical density of the filtrate were measured spectrophotometrically against the control specimen with no antibiotic at the wavelength of 450 nm. It was demonstrated that an increase in the plasma antibiotic concentration led to a directly proportional increase of the antibiotic solution extinction. This is a simple, precise and rapid method. PMID- 25300116 TI - [Antitumor enzyme L-lyzine-alpha-oxidase from Trichoderma harzianum Rifai F-180 and investigation of its action on L-lysine oxidation by capillar electrophoresis]. AB - Trichoderma harzianum Rifai F-180, an organism producing the antitumor enzyme L lysine-alpha-oxidase was cultivated and the enzyme was isolated and purified under the manufacturing conditions. The effect of L-lysine-alpha-oxidase on oxidation of L-lysine was investigated for the first time by capillary electrophoresis and the procedure conditions were developed. The reaction of L lysine oxidative deamination is described and location of the reaction components picks on the elecrophoregrams was identified. The average rate of the catalytic reaction of L-lysine oxidation equal to 0.46 RU/min (7.7 x 10(-3) RU/sec) was determined. The use of the antitumor enzyme L-lysine-alpha-oxidase is recommended as a drug for the treatment of superficial tumors and tissue relative oxygen excess. PMID- 25300117 TI - [Substances from pyrolised tissues of reptile carcases differently modulate immunity of mammals of both sexes]. AB - Substances with gender action on immunity were detected in water soluble hydrolised matter from reptile carcases. The gender action was shown on isolated blood neutrophils, whole blood and in vivo by the antiviral activity on experimental animals, contaminated with three types of viruses: Herpes simplex type 1, the virus of encephalomyocarditis and the virus of hepatitis of mice. The possible mechanism of the inhibitory action on the male immunity was associated with the protein kinase cascade, including protein kinase C, activated by phorbolmyristate in the cells of the immune system. PMID- 25300118 TI - [Cycloferon and management of herpes virus infection]. AB - The treatment of patients with various forms of herpes requires a complex approach with using chemo- and immunotropic drugs. The use of Cycloferon, an interferon inductor (12.5% injection solution, 150 mg tablets or 5% liniment) was shown efficient. It had antiviral and immunotropic action in the mono- and combination therapy of herpes simplex of the skin and mucosa, genital herpes, ophthalmoherpes, herpes zoster, infectious mononucleosis. Cycloferon lowered the level and period of the disease clinical signs, prolonged the remission, corrected the immunity shifts, prevented the complications. The results of the study presented a conclusive proof for recommending such a use of Cycloferon in wide medical practice. PMID- 25300119 TI - [Hepatoprotective effects of extracts and polysaccharides from seaweed]. AB - Antioxidants of natural origin are considered as possible agents for prevention and treatment of liver diseases. Marine algae and in particular their extracts and obtained from them sulfated polysaccharides are significant sources of natural antioxidants. The recent data on the effect of the extracts and sulfated polysaccharides of seaweed on the functional activity of the liver with injuries induced by CCl4, some drugs (paracetamol, diclofenac), N-nitrosocompounds, aflatoxin are presented in the review. Particular attention is paid to the effect of sulfated polysaccharides and in particular fucoidans on the functional activity of the liver in patients with chronic viral hepatitis C. Fucoidan is highly safe and active not only as an antioxidant but also as an inhibitor of HCV replication, has antiinflammatory and immunomodulating effects. The data of the review allow to conclude that seaweed extracts and sulfated polysaccharides may be a basis for development of new generation drugs in the future for the treatment and prevention of liver diseases. PMID- 25300120 TI - [Microbial secondary metabolites as potential reserve of pharmaceuticals]. AB - The major characteristics of new bioactive microbial secondary metabolites are summarized in the review. A wide range of new molecular targets are implicated in discovery of new nonantibiotic compounds with some other pharmacological activities (noninfectious diseases). Microorganisms represent fascinating resources due to their production of novel products with broad spectra of bioactivities. PMID- 25300121 TI - [Pathology of the vitreomacular interface]. AB - Vitreous role in the pathophysiology of retinal diseases has increased importantly over the recent years. This was possible using Optical Coherence Tomography which reviewed the way the vitreoretinal interface should be looked at and defined and classified new pathologies such as Vitreoretinal Traction Syndrome. Vitreous is not an empty space but an important anatomical structure with role in ocular physiology. With age biochemical changes occur so that vitreous starts to liquefy. Once the vitreous is liquefied (sinchisis) it collapses and passes in the retrohialoid space (sineresis). In complete PVD besides sinchisis there is a weakness of the adherence between the posterior cortex and ILM with total detachment of posterior cortex. Abnormal adhesions are associated with incomplete PVD. The definition and understanting of vitreoretinal pathology is an active and continuous process, PVD being the trigger of a lot of retinal pathologies: epiretinal membrane, macular hole, tractional macular oedema, VMTS, myopic traction maculopathy, exacerbations of exudative ARMD. PMID- 25300122 TI - [Practical aspects of automated perimetry]. AB - Visual field testing is a subjective method, but yet a very important part for diagnosis and in follow-up of ocular or neurological diseases. In order to do a correct exam of the visual field, one must know well the equipment and all the factors that could induce errors. Basic skills for working with Optopol or Humphrey perimeter are discussed in this paper. PMID- 25300123 TI - [Considerations in a case of refractive surgery]. AB - We present a case report of a 38 year old patient, with medium myopia LASIK - operated, with rhegmatogenous retinal detachment. We present the seriated surgical interventions (posterior vitrectomy with silicone oil, followed by the extrusion of the silicone oil and the extraction of complicated cataract with IOL CP implantation). PMID- 25300124 TI - [The significance of imaging in a case of intraorbital cystic tumor]. AB - Conjunctival inclusion cyst represents a congenital or, in most cases, an acquired disorder. The most frequent cause of an acquired conjunctival cyst is the implantation of conjunctival epithelium after surgical interventions or ocular trauma. Usually, these cysts are located supero-medially, with a stationary evolution, without a progression in dimension, but in some cases can evolve into enormous translucent cysts. Histologically, they are lined by stratified, nonkeratinized, squamous epithelium and contain desquamated cellular debris, chronic inflammatory cells and mucus, when goblet cells are present. Most cysts can be treated adequately by complete excision with marsupialization of the entire epithelial lining to prevent fluid reaccumulation. PMID- 25300125 TI - [Immunoglobulin-G4-related disease: a challenging diagnosis]. AB - INTRODUCTION: Immunglobulin G4 (IgG4)-related disease was recently described and represents a systemic lymphoproliferative disorder. The orbital form of the disease manifests as chronic lid swelling and proptosis. Visual disturbances may occur due to apical orbital lesions. CASE REPORT: A 65-year old pacient presents with the impossibility of maintaining his right eye open due to a progressive swelling of the upper lid. The general clinical examination shows adenopathy at 3 lymph node stations of the head. On ophthalmologic examination, a large tumor of the upper lid is observed in the right eye and proptosis and central retinal vein occlusion are noted in the left eye. The serum levels of the IgG are very high. A lymph node biopsy was performed. DISCUSSION: The differential diagnosis between the IgG4-related orbital disease and non-Hodgkin lymphoma is discussed. CONCLUSION The diagnosis criteria for IgG4-related disease are both the high serum levels of IgG4 and the specific immunohistochemistry stains. PMID- 25300126 TI - Combined cataract surgery on a Marfan-syndrome patient (case report). AB - Combined cataract surgery of an ectopic lens was performed on a 10 years old girl with Marfan-syndrome. A Cionni capsular tension ring was implanted into the capsular bag, and the bag was pulled to its place and fixed with a scleral suture. Because of the young age of the patient a primary posterior capsulorhexis was performed, through which anterior vitrectomy was carried out and the artificial lens was implanted into the capsular bag. In the literature several surgical solutions are advised for the treatment of the ectopic lens in patients with Marfan-syndrome. We have performed a successful surgery combined with posterior capsulorhexis in our case. Because of its rarity and special surgical solution, we think this case report is interesting and can be helpful in such cases to be published. PMID- 25300127 TI - [Wave front aberrations -- practical conclusions in eye with Restor 3+ difractive multifocal lens]. AB - Implantation of multifocal intraocular lenses has become a rutine nowadays, but achieving good visual results requires a perfect intraoperative technique and also an adequate preoperative selection of the patients. We analysed the wave front aberrations (spherical aberations, coma and astigmatism) in the eyes implanted with ReStor + 3 IOL, and we realized some clinical correlations of these aberations with the pupil diameter in scotopic and fotopic conditions, kappa angle, IOL centration, residual refraction errors postoperatively. Taking into account the causes of postoperative high order aberration will allow the surgeon to make a good selection of the patiens and to a higher degree of satisfaction of both sides. PMID- 25300128 TI - [Malyugin ring--an alternative in the treatment of a miotic pupil]. AB - Small pupil and Intraoperative Floppy Iris Syndrome (lFIS) has always been a challenge in cataract surgery. Iris dilation and mechanical stabilization can be achieved by using intraoperative iris retractors, preferably before capsulorhexis. Malyugin ring is a mechanical iris expansion device, which presents many advantages (gently relaxes the iris tissue, implants easier and less traumatic). The disadvantages of using Malyugin ring consists primarily in the high cost and in an increased duration of surgical procedure. PMID- 25300129 TI - Introduction. Cell adhesion molecules: implications in neurological diseases. PMID- 25300130 TI - Thy-1 modulates neurological cell-cell and cell-matrix interactions through multiple molecular interactions. AB - Thy-1, or CD90, is a glycosylphosphatidylinositol-linked cell surface glycoprotein expressed on multiple cell types, including neurons, thymocytes, fibroblasts, endothelial cells, mesangial cells, and some hematopoietic and stromal stem cells. Thy-1 is developmentally regulated and evolutionarily conserved. Its cellular effects vary between and in some cases within cell types, tissues, and species, indicating that its biological role is context dependent. However, it most often seems to affect cell-cell or cell-matrix interactions and cellular adhesion and migration. In the nervous system, Thy-1 mediates bidirectional cell-cell communication, which modulates cell-matrix adhesion. Neurons express high levels of Thy-1, which interacts with alpha(v)beta3 integrin present in astrocytes and stimulates increased astrocyte adhesion to the underlying surface (trans signaling) and in neurites, the same ligand-receptor association triggers neurite retraction and inhibition of axonal growth (cis signaling). Although Thy-1 lacks a cytoplasmic domain, it affects multiple intracellular signaling cascades through interaction with a number of molecules within lipid raft microdomains. Improved understanding of how this enigmatic adhesion molecule modulates signaling and cell phenotype may yield novel insights into neurodevelopment and nerve recovery after injury. PMID- 25300131 TI - The IgCAMs CAR, BT-IgSF, and CLMP: structure, function, and diseases. AB - The coxsackie-adenovirus receptor (CAR) is the prototype of a small subfamily of IgCAMs composed of CAR itself, CLMP, BT-IgSF, ESAM, CTX, and A33. These six proteins are composed of one V-set and one C2-set Ig domains and a single transmembrane helix followed by a cytoplasmic stretch. They are localized in several tissues and organs and--except for ESAM, CTX, and A33--are expressed in the developing brain. CAR becomes downregulated at early postnatal stages and is absent from the adult brain. CAR, CLMP, and BT-IgSF mediate homotypic aggregation. Interestingly, cell adhesion experiments, binding studies, and crystallographic investigations on the extracellular domain reveal a flexible ectodomain for CAR that mediates homophilic and heterophilic binding. CAR has been extensively investigated in the context of gene therapy and diseases, while research on BT-IgSF and CLMP is at an early stage. Several mouse models as well as studies on patient tissues revealed an essential role for CAR in (1) the development of cardiac, renal, lymphatic, and intestinal tissue; (2) muscle pathology, remodeling, and regeneration; (3) tumor genesis/suppression and metastatic progression; and (4) in virus-mediated infections and gene therapy. Although the in vivo function of CAR in the brain has not been solved its developmentally regulated expression pattern in the brain as well as its function as CAM suggests that CAR might be implicated in neuronal network formation. PMID- 25300132 TI - GlialCAM, a glial cell adhesion molecule implicated in neurological disease. AB - GlialCAM (also named HepaCAM) is a cell adhesion molecule expressed mainly in glial cells from the central nervous system and the liver. GlialCAM plays different roles according to its cellular context. In epithelial cell lines, overexpression of GlialCAM increases cell adhesion and motility but also inhibits cell growth in tumor cell lines, leading to senescence. In glial cells, however, its function is quite different. GlialCAM acts a regulator of subcellular traffic of MLC1, a protein with unknown function involved in the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare neurological condition. Moreover, GlialCAM itself has been found to be responsible for some of the cases of this disease. Additionally, GlialCAM also works as an auxiliary subunit of the chloride channel ClC-2, regulating its targeting to cell-cell junctions and modifying its functional properties. In summary, GlialCAM has different functions not only related to its adhesive nature, and defects in these functions lead to neurological disease. PMID- 25300133 TI - The neuroplastins: multifunctional neuronal adhesion molecules--involvement in behaviour and disease. AB - The neuroplastins np65 and np55 are neuronal and synapse-enriched immunoglobulin (Ig) superfamily cell adhesion molecules that contain 3 and 2 Ig domains, respectively. Np65 is neuron specific whereas np55 is expressed in many tissues. They are multifunctional proteins whose physiological roles are defined by the partner proteins they bind to and the signalling pathways they activate. The neuroplastins are implicated in activity-dependent long-term synaptic plasticity. Thus neuroplastin-specific antibodies and a recombinant peptide inhibit long-term potentiation in hippocampal neurones. This is mediated by activation of the p38MAP kinase signalling pathway, resulting in the downregulation of the surface expression of GluR1 receptors. Np65, but not np55, exhibits trans-homophilic binding. Both np65 and np55 induce neurite outgrowth and both activate the FGF receptor and associated downstream signalling pathways. Np65 binds to and colocalises with GABA(A) receptor subtypes and may play a role in anchoring them to specific synaptic and extrasynaptic sites. Most recently the neuroplastins have been shown to chaperone and support the monocarboxylate transporter MCT2 in transporting lactate across the neuronal plasma membrane. Thus the neuroplastins are multifunctional adhesion molecules which support neurite outgrowth, modulate long-term activity-dependent synaptic plasticity, regulate surface expression of GluR1 receptors, modulate GABA(A) receptor localisation, and play a key role in delivery of monocarboxylate energy substrates both to the synapse and to extrasynaptic sites. The diverse functions and range of signalling pathways activated by the neuroplastins suggest that they are important in modulating behaviour and in relation to human disease. PMID- 25300134 TI - Roles of nectins and nectin-like molecules in the nervous system. AB - Nectins are immunoglobulin-like cell adhesion molecules (CAMs) constituting a family with four members. They exclusively localize at adherens junctions (AJs) between two neighboring cells. Nectins bind to afadin through their C-termini and are linked to the actin cytoskeleton. In addition to nectins, there are nectin like molecules (Necls), which resemble nectins in their structures and constitute a family with five members. Nectins and Necls are involved in the formation of various kinds of cell-cell adhesion and diverse cellular functions including cell polarization, movement, proliferation, survival, and differentiation. In neuronal tissues, nectins and Necls functionally play crucial roles as CAMs at neuron neuron and neuron-glia interactions. For example, the members of the nectin and Necl families are involved in synapse formation and remodeling in the hippocampus, a key brain region for learning and memory. Nectins also play important roles in the auditory system. Moreover, nectins and Necls are associated with human neurological diseases when mutated or upregulated. Thus, nectins and Necls are crucial for physiology and pathology in the nervous system. PMID- 25300135 TI - ICAM-5: a neuronal dendritic adhesion molecule involved in immune and neuronal functions. AB - The neuron-specific intercellular adhesion molecule-5 (ICAM-5, telencephalin) is a member of the ICAM family of adhesion proteins. It has a complex structure with nine external immunoglobulin domains followed by a transmembrane and a cytoplasmic domain. The external part binds to beta1- and beta2-integrins and the matrix protein vitronectin, whereas its transmembrane domain binds to presenilins and the cytoplasmic domain to alpha-actinin and the ERM family of cytoplasmic proteins. In neurons it is confined to the soma and dendrites and it is enriched in dendritic filopodia with less expression in more mature dendritic spines. ICAM 5 strongly stimulates neurite outgrowth. ICAM-5 is cleaved by matrix metalloproteases upon activation of glutamate receptors or degraded through endocytosis resulting in increased spine maturation. Ablation of ICAM-5 expression increases functional synapse formation. The cleaved soluble fragment of ICAM-5 is immunosuppressive, which may be important in neuronal inflammatory diseases. PMID- 25300136 TI - Roundabout receptors. AB - Roundabout receptors (Robo) and their Slit ligands were discovered in the 1990s and found to be key players in axon guidance. Slit was initially described s an extracellular matrix protein that was expressed by midline glia in Drosophila. A few years later, it was shown that, in vertebrates and invertebrates, Slits acted as chemorepellents for axons crossing the midline. Robo proteins were originally discovered in Drosophila in a mutant screen for genes involved in the regulation of midline crossing. This ligand-receptor pair has since been implicated in a variety of other neuronal and non-neuronal processes ranging from cell migration to angiogenesis, tumourigenesis and even organogenesis of tissues such as kidneys, lungs and breasts. PMID- 25300137 TI - New insights into the roles of the contactin cell adhesion molecules in neural development. AB - In vertebrates, the contactin (CNTN) family of neural cell recognition molecules includes six related cell adhesion molecules that play non-overlapping roles in the formation and maintenance of the nervous system. CNTN1 and CNTN2 are the prototypical members of the family and have been involved, through cis- and trans interactions with distinct cell adhesion molecules, in neural cell migration, axon guidance, and the organization of myelin subdomains. In contrast, the roles of CNTN3-6 are less well characterized although the generation of null mice and the recent identification of a common extracellular binding partner have considerably advanced our grasp of their physiological roles in particular as they relate to the wiring of sensory tissues. In this review, we aim to present a summary of our current understanding of CNTN functions and give an overview of the challenges that lie ahead in understanding the roles these proteins play in nervous system development and maintenance. PMID- 25300138 TI - The L1 family of cell adhesion molecules: a sickening number of mutations and protein functions. AB - L1-type proteins are transmembrane cell adhesion molecules with an evolutionary well-conserved protein domain structure of usually six immunoglobulin and five fibronectin type III domains. By engaging in many different protein-protein interactions they are involved in a multitude of molecular functions and are important players during the formation and maintenance of metazoan nervous systems. As a result, mutations in L1-type genes cause a great variety of phenotypes, most of which are neurological in nature. In humans, mutations in the L1CAM gene are responsible for L1 syndrome and other L1-type genes have been implicated in conditions as varied as mental retardation, autism, schizophrenia, multiple sclerosis, and other disorders. Equally, the overexpression of L1-type proteins appears to have deleterious effects in various types of human tumor cells, where they generally contribute to an increase in cell mobility and metastatic potential. PMID- 25300139 TI - Organisation and control of neuronal connectivity and myelination by cell adhesion molecule neurofascin. AB - The neuronal cell adhesion molecule neurofascin is expressed in highly complex temporally and spatially regulated patterns. Accordingly, many different functions have been described including control of neurite outgrowth, clustering of protein complexes at the axon initial segments as well as at the nodes of Ranvier and axoglial contact formation at paranodal segments. At the molecular level, neurofascin provides a link between extracellular interactions of many different interaction partners and cytoskeletal components or signal transduction. Such interactions are subject to intimate regulation by alternative splicing and posttranslational modification. The versatile functional aspects of neurofascin interactions pose it at a central position for the shaping and maintenance of neural circuitry and synaptic contacts which are implicated in nervous system disorders. PMID- 25300140 TI - Roles for DSCAM and DSCAML1 in central nervous system development and disease. AB - DSCAMs (Down syndrome cell adhesion molecules) are a group of immunoglobulin-like transmembrane proteins that contain fibronectin III domains. The founding member of the family was isolated in a positional cloning study that sought to identify genes located on chromosome 21 at the locus 21q22.2-q22.3 that is implicated in the neurological and cardiac phenotypes associated with Down's syndrome. In Drosophila, Dscam proteins are involved in neuronal wiring, while in vertebrates, the role of these cell adhesion molecules in neurogenesis, dendritogenesis, axonal outgrowth, synaptogenesis, and synaptic plasticity is only just beginning to be understood. In this chapter, we will review the functions ascribed to the two paralogous proteins found in humans, DSCAM and DSCAML1 (DSCAM-like 1), based on findings in knockout mice. The signaling pathways downstream of DSCAM activation and the role of DSCAM miss-expression in disease will be also discussed, particularly with regard to the intellectual disability in Down's syndrome. PMID- 25300141 TI - The adhesion molecule anosmin-1 in neurology: Kallmann syndrome and beyond. AB - Anosmin-1 is the glycoprotein encoded by the KAL1 gene and part of the extracellular matrix, which was first identified as defective in human Kallmann syndrome (KS, characterised by hypogonadotropic hypogonadism and anosmia); biochemically it is a cell adhesion protein. The meticulous biochemical dissection of the anosmin-1 domains has identified which domains are necessary for the protein to bind its different partners to display its biological effects. Research in the last decade has unravelled different roles of anosmin-1 during CNS development (axon pathfinding, axonal collateralisation, cell motility and migration), some of them intimately related with the cited KS but not only with this. More recently, anosmin-1 has been identified in other pathological scenarios both within (multiple sclerosis) and outside (cancer, atopic dermatitis) the CNS. PMID- 25300142 TI - Protocadherins in neurological diseases. AB - Cadherins were originally isolated as calcium-dependent cell adhesion molecules and are characterized by their cadherin motifs in the extracellular domain. In vertebrates, including humans, there are more than 100 different cadherin-related genes, which constitute the cadherin superfamily. The protocadherin (Pcdh) family comprises a large subgroup within the cadherin superfamily. The Pcdhs are divided into clustered and non-clustered Pcdhs, based on their genomic structure. Almost all the Pcdh genes are expressed widely in the brain and play important roles in brain development and in the regulation of brain function. This chapter presents an overview of Pcdh family members with regard to their functions, knockout mouse phenotypes, and association with neurological diseases and tumors. PMID- 25300143 TI - Neural cell adhesion molecules belonging to the family of leucine-rich repeat proteins. AB - Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system. PMID- 25300144 TI - Celebrating 50 years of water fluoridation in Birmingham--a time for decision makers to tackle high tooth decay rates elsewhere. PMID- 25300145 TI - Training dental nurses with additional skills in oral health education and application of fluoride varnish: activity impact and challenges. PMID- 25300146 TI - Frequency of daily tooth brushing: predictors of change in 9- to 11-year old US children. AB - OBJECTIVE: To investigate whether an increase in daily tooth brushing frequency in children was predicted by either a) having a strong intention to brush twice a day or b) their parents receiving information about their new caries experience. BASIC RESEARCH DESIGN: Secondary data analyses were conducted on two waves of data from the Aban Aya Youth Project and the Iowa Fluoride Study. PARTICIPANTS: The Aban Aya study included 576 10- and 11-year olds from Chicago, Illinois. The Iowa Fluoride Study included a convenience sample of 709 babies born in Iowa. The present study includes those children at age 9. MAIN OUTCOME MEASURES: In both studies, reported daily tooth brushing frequency was assessed twice six months apart. RESULTS: In the Aban Aya data, compared with children with a weak intention at wave 1 to brush twice a day, children with a strong intention to brush twice a day were more likely to increase their brushing frequency by wave 2, OR 7.0, 95%CI 1.5,32.9. In the Iowa Fluoride Study, compared with children who did not have new caries at wave 1, children who had new caries experience were less likely to increase their brushing frequency by wave 2, OR 0.4, 95%CI 0.2,0.9. CONCLUSIONS: Strengthening intention to brush twice a day might increase children's brushing frequency. However, simply providing parents with information about new caries probably will not. Future studies should assess tooth brushing frequency, habit strength, intention, and situational cues at closely-spaced waves. PMID- 25300147 TI - Caries experience and treatment needs among Albanian 12-year-olds. AB - OBJECTIVE: To determine the dental caries experience and treatment needs among 12 year-olds in Albania. RESEARCH DESIGN: This 2011 cross sectional survey used cluster sampling with DMFT and SiC indexes used to assess dental caries experience; DT/DMFT to assess untreated caries; FT/DMFT the care index and MT/DMFT as missing index. PARTICIPANTS: 1928 12-year-olds selected from state schools across 16 local districts with a mix of urban and rural areas and contrasting socio-economic groups. METHOD: WHO protocols were used. RESULTS: The caries prevalence (DMFT > 0) was 87% (95%CI 85.6,88.4) and 29.6% were without cavitated carious lesions (DT = 0). The mean caries experience (DMFT) was 3.73 (sd 2.71) for boys, 3.71 (sd 2.61, p = 0.88) for girls and 3.72 (sd 2.66) overall. The caries treatment needs DT/DMFT was 56% (sd 0.36), the mean FT/DMFT (Care Index) was 31% (sd 0.34) and the mean SiC index was 6.72 (sd 1.92). CONCLUSIONS: Dental caries experience and untreated dental caries were high compared with 12-year-olds in most European Union Member States. This suggests an urgent need for a national preventive program and improved access to oral care for this age group. PMID- 25300148 TI - Experience of racism and tooth brushing among pregnant Aboriginal Australians: exploring psychosocial mediators. AB - OBJECTIVES: Despite burgeoning evidence regarding the pathways by which experiences of racism influence health outcomes, little attention has been paid to the relationship between racism and oral health-related behaviours in particular. We hypothesised that self-reported racism was associated with tooth brushing, and that this association was mediated by perceived stress and sense of control and moderated by social support. METHODS: Data from 365 pregnant Aboriginal Australian women were used to evaluate tooth brushing behaviour, sociodemographic factors, psychosocial factors, general health, risk behaviours and racism exposure. Bivariate associations were explored and hierarchical logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for tooth brushing. Perceived stress and sense of control were examined as mediators of the association between self-reported racism and tooth brushing using binary mediation with bootstrapping. RESULTS: High levels of self reported racism persisted as a risk indicator for tooth brushing (OR 0.51, 95%CI 0.27,0.98) after controlling for significant covariates. Perceived stress mediated the relationship between self-reported racism and tooth brushing: the direct effect of racism on tooth brushing was attenuated, and the indirect effect on tooth brushing was significant (beta coefficient -0.09; bias-corrected 95%CI 0.166,-0.028; 48.1% of effect mediated). Sense of control was insignificant as a mediator of the relationship between racism and tooth brushing. CONCLUSIONS: High levels of self-reported racism were associated with non-optimal tooth brushing behaviours, and perceived stress mediated this association among this sample of pregnant Aboriginal women.. Limitations and implications are discussed. PMID- 25300149 TI - Dietary intake of calcium, vitamins A and E and bleeding on probing in Sri Lankan preschoolers. AB - OBJECTIVE: To determine the prevalence of gingival bleeding on probing and the associations between dietary intake of calcium, vitamins A and E and gingival bleeding on probing in Sri Lankan preschool children. BASIC RESEARCH DESIGN: A cross-sectional study. PARTICIPANTS: 784 children aged 48-72 months attending preschools in the Kegalle district and their mothers/carers. RESULTS: The prevalence of gingival bleeding on probing was 52.9%. A Poisson logistic regression model revealed that children with a high daily dietary intake of calcium were less likely to have gingival bleeding on probing than those with low intake (PR=0.80; 95%CI 0.64,0.98). Also prevalence of gingival bleeding was higher in children: with plaque on their teeth; whose mothers were not employed; or, were from families with three or more children. CONCLUSIONS: The prevalence of gingivitis was high in the children and the findings suggest that high levels of dietary calcium intake are associated with reduced gingival bleeding in preschool children. PMID- 25300150 TI - Type II diabetes and oral health: perceptions among adults with diabetes and oral/health care providers in Ghana. AB - OBJECTIVE: This study sought to examine oral health beliefs and attitudes, and utilisation of oral health care services among individuals with diabetes and health professionals who serve them in Ghana. BASIC RESEARCH DESIGN: A qualitative study using grounded theory was conducted. CLINICAL SETTING: University of Ghana Dental School at Korle Bu, University of Ghana School of Public Health, National Diabetes Research and Management Centre at Korle Bu, and New York University College of Dentistry. PARTICIPANTS: A convenience sample of 59 patients comprised 7 focus groups conducted in either Twi or English. Seven key informant interviews with healthcare professionals and one spiritual leader were completed. RESULTS: Data from the focus groups and interviews reveal: 1, half of the participants with diabetes have oral manifestations (e.g., bleeding gums) and participants are generally unaware of interrelationship between diabetes and oral health; 2, dental treatment utilisation is minimal and associated almost exclusively with reparative and emergency care; and 3, medical health providers do not acknowledge the interrelationship between oral health and diabetes nor do they incorporate oral health issues into diabetes screening/treatment. CONCLUSION: Oral health knowledge and practices are limited among patients with diabetes in Accra, Ghana. Collaborative efforts for in service education and training for oral health and medical professionals may be beneficial in serving the oral and general health care needs as well as improving the oral health-related quality of life of Ghanaians with diabetes. PMID- 25300151 TI - Dental caries among children in Georgia by age, gender, residence location and ethnic group. AB - OBJECTIVE: To provide prevalence data for dental caries in Georgia. METHODS: This World Health Organization pathfinder survey was conducted among 1,351 (6, 12 and 15 year-old) Georgian children, representing the main ethnic groups in urban and rural locations. Caries was analysed at univariate and multivariate levels, according to age, gender, urban/rural locality and ethnic group. RESULTS: Caries experience levels among 6-year-olds were dmft = 4.57, sd 3.42 (14.8% caries free); DMFT = 2.04 (sd 2.02) among 12-year-olds (31.1% caries-free); and DMFT = 3.51 (sd 3.14) for the 15-year-olds (17.7% caries-free). Urban children at ages 6 and 12 years were more likely to be caries-free and have both lower levels of caries-experience and higher levels of filled or restored teeth. In multivariate regression analyses, most age groups showed a significant contribution from residence location. No differences were found by age and no consistent differences were detected by ethnic group. CONCLUSION: These data should provide the baseline for formulating and conducting public oral health efforts in Georgia, with emphases on rural residence locations. PMID- 25300152 TI - Access, literacy and behavioural correlates of poor self-rated oral health amongst an indigenous south Australian population. AB - OBJECTIVE: To better understand the determinants of self-rated oral health within an Indigenous population by: 1, examining potential individual-level correlates of socio-demographic, health behaviours, dental care access and oral health literacy-related outcomes with self-rated oral health; and, 2, examining the relative contribution of these domains to self-rated oral health in multivariable modelling. METHODS: We conducted nested logistic regression analyses on self reported status of 'fair or poor' versus 'better' oral health using data from a convenience sample of rural dwelling Indigenous Australians (n = 468). Data were collected on background characteristics, health behaviours, access to dental care, oral health literacy-related outcome variables and REALD 30, an oral health literacy scale. RESULTS: Overall 37.0 % of the Indigenous adult population reported fair or poor oral health. In multivariable modelling, risk indicators for fair or poor self-rated oral health that persisted after adjusting for other covariates included being aged 38+ years (OR 2.9, 95%CI 1.9,4.6), holding a Government Health Concession card (OR 2.3, 95%CI 1.1,4.5), avoiding the dentist due to financial constraints (OR 2.3, 95%CI 1.4,3.6), not knowing how to make an emergency dental visit (OR 1.7, 95%CI 1.1,2.7) and poor understanding of the prevention of dental disease (OR 1.7, 95%CI 1.1,2.7). CONCLUSIONS: In this vulnerable population, risk indicators contributing to poor self-rated oral health included socio-demographic, dental care access and oral health literacy related factors. Health behaviours were not significant. PMID- 25300153 TI - Effect of second mailing for consent on child dental survey results. AB - INTRODUCTION: Written parental consent of young children has been required for dental surveys in Wales since 2006. The 2007/08 survey produced much lower caries scores than previous surveys, believed to be associated with low participation of children with caries experience. OBJECTIVE: To test the null hypothesis that decay variables from a second mailing of parental consent are no different from those generated from a first mailing. METHODS: Cross-sectional caries (d3mft) survey of children aged 5-6 during 2011/12. Survey criteria complied with British Association for the Study of Community Dentistry guidance. Comparison of dental epidemiological variables generated from data collected via first and second mailing for consent. RESULTS: The aggregate d3mft for all 7,734 children examined was 1.6. The mean d3mft for the first mailing was 1.5 (6,678 children) compared with a d3mft of 2.2 (1,056 children) for the second mailing. Equivalent data for d3mft(d3mft > 0) and %d3ft > 0 were: d3mft(d3mft > 0) 3.8 first mailing compared with d3mft (d3mft3 > 0) 4.1 second mailing; and %d3mft>0 39.5% first mailing compared with %d3mft > 054.1% second mailing. Mean d3mft and %d3mft > 0 showed statistically significant differences. CONCLUSIONS: Null hypothesis is rejected for d3mft and %d,mft>0O. The findings suggest non-responders to the first mailing do have higher prevalence of decay than responders. To facilitate comparisons of reported decay levels, future surveys using mailed forms for consent purposes should include at least two mailings and report the number of mailings used to facilitate comparisons of reported decay levels. PMID- 25300154 TI - Evaluation of a capacity building clinical educational model for oral health clinicians treating very young children. AB - OBJECTIVE: There are significant levels of dental caries in Australian school aged children, with children aged five years having a mean dmft of 1.3. It has also been identified that, in general, oral health clinicians lack confidence to treat very young children and this study aimed to increase capacity of public sector oral health clinicians to treat preschool children. BASIC RESEARCH DESIGN: An educational program was developed, implemented and evaluated for its capability to increase the confidence and knowledge of oral health clinicians and dental assistants in providing oral care for children aged 12 months to 5 years. RESULTS: In 2011 and 2012, the course was delivered to 36 clinicians (22 dentists, 12 dental therapists, and two oral health therapists) and showed increases in their confidence and knowledge for participants when providing dental procedures to preschool children. CONCLUSIONS: The educational program that was developed and implemented has met its objective of increasing the knowledge and confidence of practicing oral health clinicians and dental assistants in the management of preschool children. Strategies to further enhance the outcomes of this educational program have been proposed. PMID- 25300155 TI - The significance of motivation in periodontal treatment: the influence of adult patients' motivation on the clinical periodontal status. AB - Motivation plays an important role in the treatment process of chronic diseases, as treatment requires behavioural change and lifelong adherence to medical recommendations. Periodontitis is a good example of such health condition as to maintain good periodontal health patients have to adhere to a strict oral hygiene regimen. OBJECTIVE: To examine whether the motivation of patients suffering from chronic periodontitis influences their clinical periodontal condition. BASIC RESEARCH DESIGN: Cross sectional study. CLINICAL SETTING: Department of Periodontology and Oral Medicine, Dental University Clinic, Jagiellonian University, Krakow, Poland. PARTICIPANTS: 199 adult periodontal patients, aged 20 78 years. INTERVENTIONS: Questionnaire concerning patients' medical and dental history, modified Zychlinscy motivation assessment questionnaire, clinical periodontal examination. MAIN OUTCOME MEASURES: The extent of motivation. Periodontal status evaluated with the use of periodontal indices (API, BOP, CPITN). RESULTS: The mean motivation score was 57.4. The mean API and BOP values were 55.7% and 46.4%, respectively. For most of the patients the recorded CPITN value was 3. Correlations were observed between motivation and both API and BOP, and between API and BOP. CONCLUSION: Periodontal patients with greater motivation having better oral health (lower API and BOP) suggests an influence on the quality of their self-management of the disease (i.e. adherence to their oral hygiene regimen). PMID- 25300156 TI - Evaluation of internet search trends of some common oral problems, 2004 to 2014. AB - OBJECTIVE: Internet search trend volumes can provide free, fast and pertinent information about peoples' online interests. No study has yet been conducted on internet search trends in dentistry. This study aims to investigate ten years' data on internet search volumes regarding some oral problems: "toothache", "tooth decay", "gum disease", "wisdom teeth" and "oral cancer". The study also aims to investigate the most common geographic search locations and to examine related searches. RESEARCH DESIGN: Worldwide intermet search trend data over a period of 532 weeks (4 January 2004 and 15 March 2014) retrieved from the Google Trends web site was interrogated for each search term to identify search trends, regional interests, and related searches. RESULTS: The search volumes for the terms "toothache "and "wisdom teeth" increased over the decade while "tooth decay", "gum disease", and "oral cancer" showed slight changes. Each term was most commonly searched in different counties: "toothache", Philippines; "tooth decay", Singapore; "Gum Disease", Ireland; "Wisdom Teeth", United States; and "Oral cancer", India. Related searches were mainly focused on symptoms and remedies of these problems. CONCLUSIONS: Regional and time-related variations in search volumes may provide dental professionals with readily- and freely-available pertinent information on populations' internet searches regarding dental complaints. PMID- 25300157 TI - A wide visible-light-responsive tunneled MgTa2O(6-x)N(x) photocatalyst for water oxidation and reduction. AB - We demonstrate for the first time that a nitrogen-doped tunneled oxide MgTa2O(6 x)N(x) with an absorption edge of ca. 570 nm can drive both water oxidation and reduction half reactions in the presence of scavengers under visible light irradiation, showing great potential in solar water splitting. PMID- 25300159 TI - Re: Evaluation of transobturator tension-free vaginal tapes in the surgical management of mixed urinary incontinence: 3-year outcomes of a randomized controlled trial: M. Abdel-Fattah, L. R. Hopper and A. Mostafa J Urol 2014; 191: 114-119. PMID- 25300160 TI - Re: Effect of aging on storage and voiding function in women with stress predominant urinary incontinence: P. Zimmern, H. J. Litman, C. W. Nager, G. E. Lemack, H. E. Richter, L. Sirls, S. R. Kraus, G. Sutkin And E. R. Mueller J Urol 2014; 192: 464-468. PMID- 25300161 TI - Re: Defining the potential of neoadjuvant chemotherapy use as a quality indicator for bladder cancer care: G. Vemana, K. G. Nepple, J. Vetter, G. Sandhu and S. A. Strope J Urol 2014; 192: 43-49. PMID- 25300162 TI - Re: Monopolar versus bipolar transurethral resection of bladder tumors: a single center, parallel arm, randomized, controlled trial: V. Venkatramani, A. Panda, R. Manojkumar and N. S. Kekre J Urol 2014; 191: 1703-1707. PMID- 25300164 TI - Safinamide for the treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disease caused by a complex interaction of loss of dopaminergic and non-dopaminergic neurotransmitter systems. Drugs acting on the dopaminergic pathways are the mainstay of treatment for motor symptoms today. Safinamide (NW-1015) is a novel drug with multiple actions. It is a monoamine oxidase B inhibitor and improves dopaminergic transmission. In addition, it has antiglutamatergic effects and can thus reduce dyskinesias, which is a side effect limiting most dopaminergic therapy. In Phase III trials, safinamide has been found to be a useful adjunctive to dopamine agonists in early PD and has been shown to increase time without increasing troublesome dyskinesias when used as an adjunct to levodopa in patients with advanced PD. A possible neuroprotective role in inhibiting PD disease progression is envisaged and warrants future studies. PMID- 25300165 TI - Inhaled corticosteroids for cystic fibrosis. AB - BACKGROUND: Reduction of lung inflammation is one of the goals of cystic fibrosis therapy. Inhaled corticosteroids are often used to treat children and adults with cystic fibrosis. The rationale for this is their potential to reduce lung damage arising from inflammation, as well as their effect on symptomatic wheezing. It is important to establish the current level of evidence for the risks and benefits of inhaled corticosteroids, especially in the light of their known adverse effects on growth. OBJECTIVES: To assess the effectiveness of taking regular inhaled corticosteroids, compared to not taking them, in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We requested information from pharmaceutical companies manufacturing inhaled corticosteroids and authors of identified trials.Date of most recent search of the Group's Trials Register: 17 July 2014. SELECTION CRITERIA: Randomised or quasi-randomised trials, published and unpublished, comparing inhaled corticosteroids to placebo or standard treatment in individuals with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two independent authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro formas. MAIN RESULTS: The searches identified 34 citations, of which 26 (representing 13 trials) were eligible for inclusion. These 13 trials reported the use of inhaled corticosteroids in 506 people with cystic fibrosis aged between six and 55 years. One was a withdrawal trial in individuals who were already taking inhaled corticosteroids. Methodological quality and risk of bias were difficult to assess from published information. Many of the risk of bias judgements were unclear due to a lack of available information. Only two trials specified how participants were randomised and less than half of the included trials gave details on how allocation was concealed. Trials were generally judged to have a low risk of bias from blinding, except for two which were open label or did not use a placebo. There were some concerns that a number of trials had not been published in peer reviewed journals, but the risk of bias from this was unclear. Inclusion criteria varied between trials, as did type and duration of treatment and timing of outcome assessments. Objective measures of airway function were reported in most trials but were often incomplete. Significant benefit has not been conclusively demonstrated. Four trials systematically documented adverse effects and growth was significantly affected in one study using high doses. AUTHORS' CONCLUSIONS: Evidence from these trials is insufficient to establish whether inhaled corticosteroids are beneficial in cystic fibrosis, but withdrawal in those already taking them has been shown to be safe. There is some evidence they may cause harm in terms of growth. It has not been established whether long-term use is beneficial in reducing lung inflammation, which should improve survival, but it is unlikely this will be proven conclusively in a randomised controlled trial. PMID- 25300166 TI - Antibiotics for community-acquired pneumonia in adult outpatients. AB - BACKGROUND: Lower respiratory tract infection (LRTI) is the third leading cause of death worldwide and the first leading cause of death in low-income countries. Community-acquired pneumonia (CAP) is a common condition that causes a significant disease burden for the community, particularly in children younger than five years, the elderly and immunocompromised people. Antibiotics are the standard treatment for CAP. However, increasing antibiotic use is associated with the development of bacterial resistance and side effects for the patient. Several studies have been published regarding optimal antibiotic treatment for CAP but many of these data address treatments in hospitalised patients. This is an update of our 2009 Cochrane Review and addresses antibiotic therapies for CAP in outpatient settings. OBJECTIVES: To compare the efficacy and safety of different antibiotic treatments for CAP in participants older than 12 years treated in outpatient settings with respect to clinical, radiological and bacteriological outcomes. SEARCH METHODS: We searched CENTRAL (2014, Issue 1), MEDLINE (January 1966 to March week 3, 2014), EMBASE (January 1974 to March 2014), CINAHL (2009 to March 2014), Web of Science (2009 to March 2014) and LILACS (2009 to March 2014). SELECTION CRITERIA: We looked for randomised controlled trials (RCTs), fully published in peer-reviewed journals, of antibiotics versus placebo as well as antibiotics versus another antibiotic for the treatment of CAP in outpatient settings in participants older than 12 years of age. However, we did not find any studies of antibiotics versus placebo. Therefore, this review includes RCTs of one or more antibiotics, which report the diagnostic criteria and describe the clinical outcomes considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors (LMB, TJMV) independently assessed study reports in the first publication. In the 2009 update, LMB performed study selection, which was checked by TJMV and MMK. In this 2014 update, two review authors (SP, SM) independently performed and checked study selection. We contacted trial authors to resolve any ambiguities in the study reports. We compiled and analysed the data. We resolved differences between review authors by discussion and consensus. MAIN RESULTS: We included 11 RCTs in this review update (3352 participants older than 12 years with a diagnosis of CAP); 10 RCTs assessed nine antibiotic pairs (3321 participants) and one RCT assessed four antibiotics (31 participants) in people with CAP. The study quality was generally good, with some differences in the extent of the reporting. A variety of clinical, bacteriological and adverse events were reported. Overall, there was no significant difference in the efficacy of the various antibiotics. Studies evaluating clarithromycin and amoxicillin provided only descriptive data regarding the primary outcome. Though the majority of adverse events were similar between all antibiotics, nemonoxacin demonstrated higher gastrointestinal and nervous system adverse events when compared to levofloxacin, while cethromycin demonstrated significantly more nervous system side effects, especially dysgeusia, when compared to clarithromycin. Similarly, high-dose amoxicillin (1 g three times a day) was associated with higher incidence of gastritis and diarrhoea compared to clarithromycin, azithromycin and levofloxacin. AUTHORS' CONCLUSIONS: Available evidence from recent RCTs is insufficient to make new evidence-based recommendations for the choice of antibiotic to be used for the treatment of CAP in outpatient settings. Pooling of study data was limited by the very low number of studies assessing the same antibiotic pairs. Individual study results do not reveal significant differences in efficacy between various antibiotics and antibiotic groups. However, two studies did find significantly more adverse events with use of cethromycin as compared to clarithromycin and nemonoxacin when compared to levofloxacin. Multi-drug comparisons using similar administration schedules are needed to provide the evidence necessary for practice recommendations. Further studies focusing on diagnosis, management, cost effectiveness and misuse of antibiotics in CAP and LRTI are warranted in high-, middle- and low-income countries. PMID- 25300167 TI - Antibiotics for bronchiolitis in children under two years of age. AB - BACKGROUND: Bronchiolitis is a serious, potentially life-threatening respiratory illness commonly affecting babies. It is often caused by respiratory syncytial virus (RSV). Antibiotics are not recommended for bronchiolitis unless there is concern about complications such as secondary bacterial pneumonia or respiratory failure. Nevertheless, they are often used. OBJECTIVES: To evaluate the effectiveness of antibiotics for bronchiolitis in children under two years of age compared to placebo or other interventions. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 6), which includes the Cochrane Acute Respiratory Infection Group's Specialised Register, and the Database of Abstracts of Reviews of Effects, MEDLINE (1966 to June 2014), EMBASE (1990 to June 2014) and Current Contents (2001 to June 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing antibiotics to placebo in children under two years diagnosed with bronchiolitis, using clinical criteria (including respiratory distress preceded by coryzal symptoms with or without fever). Primary clinical outcomes included time to resolution of signs or symptoms (pulmonary markers included respiratory distress, wheeze, crepitations, oxygen saturation and fever). Secondary outcomes included hospital admissions, length of hospital stay, readmissions, complications or adverse events and radiological findings. DATA COLLECTION AND ANALYSIS: Two review authors independently analysed the search results. MAIN RESULTS: We included seven studies with a total of 824 participants. The results of these seven included studies were often heterogeneous, which generally precluded meta-analysis, except for deaths, length of supplemental oxygen use and length of hospital admission.In this update, we included two new studies (281 participants), both comparing azithromycin with placebo. They found no significant difference for length of hospital stay, duration of oxygen requirement and readmission. These results were similar to an older study (52 participants) that demonstrated no significant difference comparing ampicillin and placebo for length of illness.One small study (21 participants) with higher risk of bias randomised children with proven RSV infection to clarithromycin or placebo and found a trend towards a reduction in hospital readmission with clarithromycin.The three studies providing adequate data for days of supplementary oxygen showed no difference between antibiotics and placebo (pooled mean difference (MD) (days) -0.20; 95% confidence interval (CI) -0.72 to 0.33). The three studies providing adequate data for length of hospital stay, similarly showed no difference between antibiotics (azithromycin) and placebo (pooled MD (days) -0.58; 95% CI -1.18 to 0.02).Two studies randomised children to intravenous ampicillin, oral erythromycin and control and found no difference for most symptom measures.There were no deaths reported in any of the arms of the seven included studies. No other adverse effects were reported. AUTHORS' CONCLUSIONS: This review did not find sufficient evidence to support the use of antibiotics for bronchiolitis, although research may be justified to identify a subgroup of patients who may benefit from antibiotics. Further research may be better focused on determining the reasons that clinicians use antibiotics so readily for bronchiolitis, how to reduce their use and how to reduce clinician anxiety about not using antibiotics. PMID- 25300168 TI - Androgens for the anaemia of chronic kidney disease in adults. AB - BACKGROUND: Anaemia occurs when blood contains fewer red blood cells and lower haemoglobin levels than normal, and is a common complication among adults with chronic kidney disease (CKD). Although a number of approaches are applied to correct anaemia in adults with CKD, the use of androgen therapy is controversial. OBJECTIVES: The aim of this review was to determine the benefits and harms of androgens for the treatment of anaemia in adult patients with CKD. SEARCH METHODS: We searched CENTRAL, the Cochrane Renal Group's Specialised Register, the Chinese Biomedicine Database (CBM), CNKI, VIP and reference lists of articles without language restriction. The most recent search was conducted in August 2014. SELECTION CRITERIA: All randomised controlled trials (RCTs) that assessed the use of androgens for treating anaemia of CKD in adults were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias in the included studies. Meta-analyses were performed using relative risk (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI). MAIN RESULTS: We included eight studies that reported data from 181 participants. Study quality was assessed as moderate in six studies, one was low quality, and one was high quality. The small number of included studies, and low participant numbers adversely influenced evidence quality overall.We found limited evidence (1 study, 24 participants) to indicate that oxymetholone can increase haemoglobin (Hb) (MD 1.90 g/dL, 95% CI 1.66 to 2.14), haematocrit (HCT) (MD 27.10%, 95% CI 26.49 to 27.71), change in albumin (MD 4.91 g/L, 95% CI 3.69 to 6.13), alanine aminotransferase (ALT) (MD 54.50 U/L, 95% CI 43.94 to 65.06), and aspartate aminotransferase (AST) (MD 47.33 U/L, 95% CI 37.69 to 56.97); and decrease high density lipoprotein (HDL) (MD -15.66 mg/dL, 95% CI -24.84 to -6.48). We also found that compared with erythropoietin alone, nandrolone decanoate plus erythropoietin may increase HCT (3 studies, 73 participants: MD 2.54%, 95% Cl 0.96 to 4.12). Compared with erythropoietin (1 study, 27 participants), limited evidence was found to suggest that nandrolone decanoate can increase plasma total protein (MD 0.40 g/L, 95% CI 0.13 to 0.67), albumin (MD 0.20 g/L, 95% CI 0.01 to 0.39), and transferrin (MD 45.00 mg/dL, 95% CI 12.61 to 77.39) levels. Compared with no therapy (remnant kidney), evidence was found to suggest that nandrolone decanoate can increase Hb (2 studies, 33 participants: MD 1.04 g/dL, 95% Cl 0.66 to 1.41) and HCT (1 study, 24 participants: MD 3.70%, 95% Cl 0.68 to 6.72). Compared with no therapy (anephric), evidence was found (1 study, 5 participants) to suggest that nandrolone decanoate can increase Hb (MD 1.30 g/dL, 95% Cl 0.57 to 2.03), but nandrolone decanoate did not increase HCT (MD 2.00%, 95% Cl -0.85 to 4.85).However, oxymetholone was not found to reduce blood urea nitrogen (BUN), serum creatinine (SCr), cholesterol, or triglycerides; or increase plasma total protein, prealbumin, or transferrin. No evidence was found to indicate that nandrolone decanoate increased prealbumin or decreased BUN, SCr, AST, ALT, cholesterol, triglycerides, HDL or low-density lipoprotein (LDL). Adverse events associated with androgen therapy were reported infrequently. AUTHORS' CONCLUSIONS: We found insufficient evidence to confirm that use of androgens for adults with CKD-related anaemia is beneficial. PMID- 25300169 TI - Early versus late initiation of epidural analgesia for labour. AB - BACKGROUND: Pain during childbirth is arguably the most severe pain some women may experience in their lifetime. Epidural analgesia is an effective form of pain relief during labour. Many women have concerns regarding its safety. Furthermore, epidural services and anaesthetic support may not be available consistently across all centres. Observational data suggest that early initiation of epidural may be associated with an increased risk of caesarean section, but the same findings were not seen in recent randomised controlled trials. More recent guidelines suggest that in the absence of a medical contraindication, maternal request is a sufficient medical indication for pain relief during labour. The choice of analgesic technique, agent, and dosage is based on many factors, including patient preference, medical status, and contraindications. There is no systematically reviewed evidence on the maternal and foetal outcomes and safety of this practice. OBJECTIVES: This systematic review aimed to summarise the effectiveness and safety of early initiation versus late initiation of epidural analgesia in women. We considered the obstetric and fetal outcomes relevant to women and side effects of the treatments, including risk of caesarean section, instrumental birth and time to birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 February 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (January 1966 to February 2014), Embase (January 1980 to February 2014) and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials involving women undergoing epidural labour analgesia that compared early initiation versus late initiation of epidural labour analgesia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted the data and assessed the trial quality. Data were checked for accuracy. MAIN RESULTS: We included nine studies with a total of 15,752 women.The overall risk of bias of the studies was low, with the exception of performance bias (blinding of participants and personnel).The nine studies showed no clinically meaningful difference in risk of caesarean section with early initiation versus late initiation of epidural analgesia for labour (risk ratio (RR) 1.02; 95% confidence interval (CI) 0.96 to 1.08, nine studies, 15,499 women, high quality evidence). There was no clinically meaningful difference in risk of instrumental birth with early initiation versus late initiation of epidural analgesia for labour (RR 0.93; 95% CI 0.86 to 1.01, eight studies, 15,379 women, high quality evidence). The duration of second stage of labour showed no clinically meaningful difference between early initiation and late initiation of epidural analgesia (mean difference (MD) -3.22 minutes; 95% CI -6.71 to 0.27, eight studies, 14,982 women, high quality evidence). There was significant heterogeneity in the duration of first stage of labour and the data were not pooled.There was no clinically meaningful difference in Apgar scores less than seven at one minute (RR 0.96; 95% CI 0.84 to 1.10, seven studies, 14,924 women, high quality evidence). There was no clinically meaningful difference in Apgar scores less than seven at five minutes (RR 0.96; 95% CI 0.69 to 1.33, seven studies, 14,924 women, high quality evidence). There was no clinically meaningful difference in umbilical arterial pH between early initiation and late initiation (MD 0.01; 95% CI -0.01 to 0.03, four studies, 14,004 women, high quality evidence). There was no clinically meaningful difference in umbilical venous pH favouring early initiation (MD 0.01; 95% CI 0.00 to 0.02, four studies, 14,004 women, moderate quality evidence). AUTHORS' CONCLUSIONS: There is predominantly high-quality evidence that early or late initiation of epidural analgesia for labour have similar effects on all measured outcomes. However, various forms of alternative pain relief were given to women who were allocated to delayed epidurals to cover that period of delay, so that is it hard to assess the outcomes clearly. We conclude that for first time mothers in labour who request epidurals for pain relief, it would appear that the time to initiate epidural analgesia is dependent upon women's requests. PMID- 25300170 TI - High dose rate versus low dose rate intracavity brachytherapy for locally advanced uterine cervix cancer. AB - BACKGROUND: This is an updated version of the original Cochrane review published in 2010 (Issue 7).Carcinoma of the uterine cervix is the second most common cancer and the third leading cause of cancer death among women. Radiotherapy has been used successfully to treat cervical cancer for nearly a century. The combination of external beam radiotherapy (EBRT) and intracavity brachytherapy (ICBT) has become a standard treatment for cervical cancer. Whether high dose rate (HDR) or low dose rate (LDR) brachytherapy improves outcomes in terms of local control rates, survival and complications for women with cervical cancer remains controversial. OBJECTIVES: To assess the efficacy and safety of HDR versus LDR ICBT in combination with EBRT for women with uterine cervical cancer. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (1966 to March 2014), EMBASE (1974 to March 2014), and the Chinese Biomedical Literature Database (CBM) (1978 to March 2014) for relevant original, published trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that compared HDR with LDR ICBT, combined with EBRT, for women with locally advanced uterine cervical cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data using standardised forms. Primary outcome measures included overall survival (OS), relapse-free survival (RFS) and pelvic control rate, while secondary outcomes included rates of recurrence and complications. MAIN RESULTS: Four studies involving 1265 women met the inclusion criteria. In our meta-analysis to compare HDR and LDR ICBT, the pooled risk ratios (RRs) were 0.95 (95% confidence interval (CI) 0.79 to 1.15), 0.93 (95% CI 0.84 to 1.04) and 0.79 (95% CI 0.52 to 1.20) for 3-, 5- and 10-year overall survival rates respectively; and 0.95 (95% CI 0.84 to 1.07) and 1.02 (0.88 to 1.19) for 5- and 10-year disease-specific survival (DSS) rates respectively. The RR for RFS was 1.04 (95% CI 0.71 to 1.52) and 0.96 (95% CI 0.81 to 1.14) at 3- and 5- years. For local control rates the RR was 0.95 (95% CI 0.86 to 1.05) and 0.95 (95% CI 0.87 to 1.05) at 3- and 5- years; with a RR of 1.09 (95% CI 0.83 to 1.43) for locoregional recurrence, 0.79 (95% CI 0.40 to 1.53) for local and distant recurrence, 2.23 (95% CI 0.78 to 6.34) for para aortic lymph node metastasis, and 0.99 (95% CI 0.72 to 1.35) for distance metastasis. For bladder, rectosigmoid and small bowel complications, the RR was 1.33 (95% CI 0.53 to 3.34), 1.00 (95% CI 0.52 to 1.91) and 3.37 (95% CI 1.06 to 10.72) respectively. These results indicated that there were no significant differences except for increased small bowel complications with HDRs (P = 0.04). AUTHORS' CONCLUSIONS: Since the last version of this review, no new studies were identified for inclusion in this review to provide additional information. This review showed no significant differences between HDR and LDR ICBT when considering OS, DSS, RFS, local control rate, recurrence, metastasis and treatment related complications for women with cervical carcinoma. Due to some potential advantages of HDR ICBT (rigid immobilization, outpatient treatment, patient convenience, accuracy of source and applicator positioning, individualized treatment) we recommend the use of HDR ICBT for all clinical stages of cervix cancer. The overall risk of bias was high for the included studies as many of the items were either of high or unclear risk. The GRADE assessment of the quality of the evidence was low to moderate. PMID- 25300171 TI - Gene therapy for sickle cell disease. AB - BACKGROUND: Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. OBJECTIVES: The objectives of this review are:- to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;- to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 21 July 2014. SELECTION CRITERIA: All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. DATA COLLECTION AND ANALYSIS: No trials of gene therapy for sickle cell disease were found. MAIN RESULTS: No trials of gene therapy for sickle cell disease were reported. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease. PMID- 25300172 TI - Heparin versus 0.9% sodium chloride intermittent flushing for prevention of occlusion in central venous catheters in adults. AB - BACKGROUND: Heparin intermittent flushing is a standard practice in the maintenance of patency in central venous catheters. However, we could find no systematic review examining its effectiveness and safety. OBJECTIVES: To assess the effectiveness of intermittent flushing with heparin versus 0.9% sodium chloride (normal saline) solution in adults with central venous catheters in terms of prevention of occlusion and overall benefits versus harms. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co ordinator searched the Specialised Register (last searched December 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11). Searches were also carried out in MEDLINE, EMBASE, CINAHL and clinical trials databases (December 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) in adults 18 years of age and older with a central venous catheter (CVC) in which intermittent flushing with heparin (any dose with or without other drugs) was compared with 0.9% normal saline were included. No restriction on language was applied. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted data. Trial authors were contacted to retrieve additional information, when necessary. MAIN RESULTS: Six eligible studies with a total of 1433 participants were included. The heparin concentrations used in these studies were very different (10-5000 IU/mL), and follow-up varied from 20 days to 180 days. The overall risk of bias in the studies was low. The quality of the evidence ranged from very low to moderate for the main outcomes (occlusion of CVC, duration of catheter patency, CVC-related sepsis, mortality and haemorrhage at any site).Combined findings from three trials in which the unit of analysis was the catheter suggest that heparin was associated with reduced CVC occlusion rates (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.29 to 0.94). However, no clear evidence of a similar effect was found when the results of two studies in which the unit of analysis was the participant were combined (RR 0.21, 95% CI 0.03 to 1.70), nor when findings were derived from one study, which considered total line accesses (RR 1.08, 95% CI 0.84 to 1.40). Furthermore, results for other estimated effects were found to be imprecise and compatible with benefit and harm: catheter duration in days (mean difference (MD) 0.41, 95% CI -1.29 to 2.12), CVC-related thrombosis (RR 1.22, 95% CI 0.74 to 1.99), CVC-related sepsis (RR 1.02, 95% CI 0.34 to 3.03), mortality (RR 0.77, 95% CI 0.45 to 1.32) and haemorrhage at any site (RR 1.37, 95% CI 0.49 to 3.85). AUTHORS' CONCLUSIONS: We found no conclusive evidence of important differences when heparin intermittent flushing was compared with 0.9% normal saline flushing for central venous catheter maintenance in terms of efficacy or safety. As heparin is more expensive than normal saline, our findings challenge its continued use in CVC flushing outside the context of clinical trials. PMID- 25300173 TI - High-dose versus low-dose oxytocin infusion regimens for induction of labour at term. AB - BACKGROUND: When women require induction of labour, oxytocin is the most common agent used, delivered by an intravenous infusion titrated to uterine contraction strength and frequency. There is debate over the optimum dose regimen and how it impacts on maternal and fetal outcomes, particularly induction to birth interval, mode of birth, and rates of hyperstimulation. Current induction of labour regimens include both high- and low-dose regimens and are delivered by either continuous or pulsed infusions, with both linear and non-linear incremental increases in oxytocin dose. Whilst low-dose protocols bring on contractions safely, their potentially slow induction to birth interval may increase the chance of fetal infection and chorioamnionitis. Conversely, high-dose protocols may cause undue uterine hyperstimulation and fetal distress. OBJECTIVES: To determine the effectiveness and safety of high- versus low-dose oxytocin for induction of labour at term SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2014) and the reference lists of relevant papers. SELECTION CRITERIA: Randomised controlled trials and quasi randomised controlled trials that compared oxytocin protocol for induction of labour for women at term, where high-dose oxytocin is at least 100 mU oxytocin in the first 40 minutes, with increments delivering at least 600 mU in the first two hours, compared with low-dose oxytocin, defined as less than 100 mU oxytocin in the first 40 minutes, and increments delivering less than 600 mU total in the first two hours. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. MAIN RESULTS: We have included nine trials, involving 2391 women and their babies in this review. Trials were at a moderate to high risk of bias overall.Results of primary outcomes revealed no significant differences in rates of vaginal delivery not achieved within 24 hours (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.78 to 1.14, two trials, 1339 women) or caesarean section (RR 0.96, 95% CI 0.81 to 1.14, eight trials, 2023 women). There was no difference in serious maternal morbidity or death (RR 1.24, 95% CI 0.55 to 2.82, one trial, 523 women), and no difference in serious neonatal morbidity or perinatal death (RR 0.84, 95% CI 0.23 to 3.12, one trial, 781 infants). Finally, no trials reported on the number of women who had uterine hyperstimulation with fetal heart rate changes.Results of secondary outcomes revealed no difference between time from induction to delivery (mean difference (MD) -0.90 hours, 95% CI -2.28 to +0.49 hours; five studies), uterine rupture (RR 3.10, 95% CI 0.50 to 19.33; three trials), epidural analgesia (RR 1.03, 95% CI 0.89 to 1.18; two trials), instrumental birth (RR 1.22, 95% CI 0.88 to 1.66; three trials), Apgar less than seven at five minutes (RR 1.25, 95% CI 0.77 to 2.01, five trials), perinatal death (RR 0.84, 95% CI 0.23 to 3.12; two trials), postpartum haemorrhage (RR 1.08, 95% CI 0.87 to 1.34; five trials), or endometritis (RR 1.35, 95% CI 0.53 to 3.43; three trials). Removal of high bias studies reveals a significant reduction of induction to delivery interval (MD 1.94 hours, 95% CI -0.99 to -2.89 hours, 489 women). A significant increase in hyperstimulation without specifying fetal heart rate changes was found in the high-dose group (RR 1.86, 95% CI 1.55 to 2.25).No other secondary outcomes were reported: unchanged/unfavourable cervix after 12 to 24 hours, meconium-stained liquor, neonatal intensive care unit admission, neonatal encephalopathy, disability in childhood, other maternal side-effects (nausea, vomiting, diarrhoea), maternal antibiotic use, maternal satisfaction, neonatal infection and neonatal antibiotic use. AUTHORS' CONCLUSIONS: The findings of our review do not provide evidence that high-dose oxytocin increases either vaginal delivery within 24 hours or the caesarean section rate. There is no significant decrease in induction to delivery time at meta-analysis but these results may be confounded by poor quality trials. High-dose oxytocin was shown to increase the rate of uterine hyperstimulation but the effects of this are not clear. The conclusions here are specific to the definitions used in this review. Further trials evaluating the effects of high-dose regimens of oxytocin for induction of labour should consider all important maternal and infant outcomes. PMID- 25300174 TI - Virtual reality for treatment compliance for people with serious mental illness. AB - BACKGROUND: Virtual reality (VR) is computerised real-time technology, which can be used an alternative assessment and treatment tool in the mental health field. Virtual reality may take different forms to simulate real-life activities and support treatment. OBJECTIVES: To investigate the effects of virtual reality to support treatment compliance in people with serious mental illness. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (most recent, 17th September 2013) and relevant reference lists. SELECTION CRITERIA: All relevant randomised studies comparing virtual reality with standard care for those with serious mental illnesses. We defined virtual reality as a computerised real-time technology using graphics, sound and other sensory input, which creates the interactive computer-mediated world as a therapeutic tool. DATA COLLECTION AND ANALYSIS: All review authors independently selected studies and extracted data. For homogeneous dichotomous data the risk difference (RD) and the 95% confidence intervals (CI) were calculated on an intention-to-treat basis. For continuous data, we calculated mean differences (MD). We assessed risk of bias and created a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We identified three short-term trials (total of 156 participants, duration five to 12 weeks). Outcomes were prone to at least a moderate risk of overestimating positive effects. We found that virtual reality had little effects regarding compliance (3 RCTs, n = 156, RD loss to follow-up 0.02 CI -0.08 to 0.12, low quality evidence), cognitive functioning (1 RCT, n = 27, MD average score on Cognistat 4.67 CI -1.76 to 11.10, low quality evidence), social skills (1 RCT, n = 64, MD average score on social problem solving SPSI-R (Social Problem Solving Inventory - Revised) -2.30 CI -8.13 to 3.53, low quality evidence), or acceptability of intervention (2 RCTs, n = 92, RD 0.05 CI -0.09 to 0.19, low quality evidence). There were no data reported on mental state, insight, behaviour, quality of life, costs, service utilisation, or adverse effects. Satisfaction with treatment - measured using an un-referenced scale - and reported as "interest in training" was better for the virtual reality group (1 RCT, n = 64, MD 6.00 CI 1.39 to 10.61,low quality evidence). AUTHORS' CONCLUSIONS: There is no clear good quality evidence for or against using virtual reality for treatment compliance among people with serious mental illness. If virtual reality is used, the experimental nature of the intervention should be clearly explained. High-quality studies should be undertaken in this area to explore any effects of this novel intervention and variations of approach. PMID- 25300175 TI - Antiepileptic drugs for the primary and secondary prevention of seizures in viral encephalitis. AB - BACKGROUND: Viral encephalitis is characterised by diverse clinical and epidemiological features. Seizures are an important clinical manifestation and associated with increased mortality and morbidity. Patients may have seizures during the acute illness or they may develop after recovery. There are no recommendations regarding the use of antiepileptic drugs for the primary or secondary prevention of seizures in patients with viral encephalitis. OBJECTIVES: To assess the efficacy and safety of antiepileptic drugs for the primary and secondary prophylaxis of seizures in viral encephalitis. We intended to answer the following questions.1. Do antiepileptic drugs used as primary prophylaxis routinely for all patients with suspected or proven viral encephalitis reduce the risk of seizures during the acute illness and reduce neurological morbidity and mortality?2. Do antiepileptic drugs used as secondary prophylaxis routinely for all patients who have had at least one seizure due to suspected or proven viral encephalitis reduce the risk of further seizures during the acute illness and reduce neurological morbidity and mortality? SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (13 May 2014), the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4) (April 2014), MEDLINE (Ovid, 1946 to 13 May 2014), the WHO ICTRP search portal (13 May 2014) and ClinicalTrials.gov (13 May 2014). We did not impose any language restrictions. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials in which patients were assigned to a treatment or control group (placebo or no drug). DATA COLLECTION AND ANALYSIS: One author (SP) searched the publications by title, abstract and keywords and decided on their suitability for inclusion in the review. For any studies where it was unclear whether they would be suitable for inclusion, the co-authors (CR, BM) were consulted. The co-authors (CR, BM) evaluated the selected studies independently. Since there were no included studies, we carried out no data analysis. MAIN RESULTS: We did not find any randomised or quasi-randomised controlled trials that compared the effects of antiepileptic drugs with placebo (or no drug) for the primary or secondary prevention of seizures in viral encephalitis. We identified two studies from the literature search where different antiepileptic drugs were used in patients with viral encephalitis, however both failed to meet the inclusion criteria. The first study included children with viral encephalitis where antiepileptic drugs were given. However, it is not clear how the diagnosis was established or the aetiologies. In addition, the randomisation and blinding method is not disclosed; the patients received a diverse and ill-defined range of antiepileptic drugs and adjunctive therapies, and none of the primary or secondary outcome measures was assessed. In the second study, adults with status epilepticus (of whom a proportion had viral encephalitis), who had failed to respond to two initial boluses of diazepam, were randomised to either valproate or diazepam. The study was open-label and the randomisation methodology was not disclosed; none of the primary or secondary outcomes were reported. Data on treatment response between the two arms for those patients with viral encephalitis are not presented for subgroup analysis; the Cochrane Epilepsy Group have contacted the authors for these data but have yet to receive a response. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the routine use of antiepileptic drugs for the primary or secondary prevention of seizures in viral encephalitis. There is a need for adequately powered randomised controlled trials in viral encephalitis patients to assess the efficacy and safety of antiepileptic drugs for the primary and secondary prophylaxis of seizures, which is an important clinical problem. PMID- 25300176 TI - High-density genetic map construction and QTLs analysis of grain yield-related traits in sesame (Sesamum indicum L.) based on RAD-Seq techonology. AB - BACKGROUND: Sesame (Sesamum indicum L., 2n = 26) is an important oilseed crop with an estimated genome size of 369 Mb. The genetic basis, including the number and locations of quantitative trait loci (QTLs) of sesame grain yield and quality remain poorly understood, due in part to the lack of reliable markers and genetic maps. Here we report on the construction of a hitherto most high-density genetic map of sesame using the restriction-site associated DNA sequencing (RAD-seq) combined with 89 PCR markers, and the identification of grain yield-related QTLs using a recombinant inbred line (RIL) population. RESULT: In total, 3,769 single nucleotide polymorphism (SNP) markers were identified from RAD-seq, and 89 polymorphic PCR markers were identified including 44 expressed sequence tag simple sequence repeats (EST-SSRs), 10 genomic-SSRs and 35 Insertion-Deletion markers (InDels). The final map included 1,230 markers distributed on 14 linkage groups (LGs) and was 844.46 cM in length with an average of 0.69 cM between adjacent markers. Using this map and RIL population, we detected 13 QTLs on 7 LGs and 17 QTLs on 10 LGs for seven grain yield-related traits by the multiple interval mapping (MIM) and the mixed linear composite interval mapping (MCIM), respectively. Three major QTLs had been identified using MIM with R2 > 10.0% or MCIM with ha 2 > 5.0%. Two co-localized QTL groups were identified that partially explained the correlations among five yield-related traits. CONCLUSION: Three thousand eight hundred and four pairs of new DNA markers including SNPs and InDels were developed by RAD-seq, and a so far most high-density genetic map was constructed based on these markers in combination with SSR markers. Several grain yield-related QTLs had been identified using this population and genetic map. We report here the first QTL mapping of yield-related traits with a high-density genetic map using a RIL population in sesame. Results of this study solidified the basis for studying important agricultural traits and implementing marker assisted selection (MAS) toward genetic improvement in sesame. PMID- 25300178 TI - Levels of the antimicrobial proteins lactoferrin and chromogranin in the saliva of individuals with oral dryness. AB - STATEMENT OF PROBLEM: Many individuals in an aging society experience oral dryness. Maintaining the flow of saliva and the presence of antimicrobial substances is important to maintain oral health. The inhibition of the secretion of antimicrobial substances could lead to oral dryness. PURPOSE: The purpose of this study was to evaluate the antimicrobial substances lactoferrin and chromogranin A in the saliva of elderly individuals with oral dryness. MATERIAL AND METHODS: The study included 25 controls and 28 participants with subjective oral dryness. The levels of lactoferrin and chromogranin A were determined in unstimulated whole saliva with an enzyme-linked immunosorbent assay method. The differences in secretion of lactoferrin and chromogranin A between the controls and the participants with oral dryness were analyzed with the Mann-Whitney U test (alpha=.05). RESULTS: The flow rate of lactoferrin and chromogranin A was lower in the group of participants with oral dryness (lactoferrin, 7.43 +/-7.08 ng/min; chromogranin A, 0.24 +/-0.24 ng/min) than in the control group (lactoferrin, 21.52 +/-7.67 ng/min; chromogranin A, 0.97 +/-0.69 ng/min) (P<.01). The ratio of both antimicrobial proteins to total protein was also lower in participants with oral dryness than in the controls. CONCLUSIONS: The results of this study indicated that the levels of lactoferrin and chromogranin A were lower in those with oral dryness. A reduction in the secretion of these antimicrobial substances may be associated with oral dryness. PMID- 25300177 TI - Human milk glycomics and gut microbial genomics in infant feces show a correlation between human milk oligosaccharides and gut microbiota: a proof-of concept study. AB - Human milk oligosaccharides (HMOs) play a key role in shaping and maintaining a healthy infant gut microbiota. This article demonstrates the potential of combining recent advances in glycomics and genomics to correlate abundances of fecal microbes and fecal HMOs. Serial fecal specimens from two healthy breast-fed infants were analyzed by bacterial DNA sequencing to characterize the microbiota and by mass spectrometry to determine abundances of specific HMOs that passed through the intestinal tract without being consumed by the luminal bacteria. In both infants, the fecal bacterial population shifted from non-HMO-consuming microbes to HMO-consuming bacteria during the first few weeks of life. An initial rise in fecal HMOs corresponded with bacterial populations composed primarily of non-HMO-consuming Enterobacteriaceae and Staphylococcaeae. This was followed by decreases in fecal HMOs as the proportion of HMO-consuming Bacteroidaceae and Bifidobacteriaceae increased. Analysis of HMO structures with isomer differentiation revealed that HMO consumption is highly structure-specific, with unique isomers being consumed and others passing through the gut unaltered. These results represent a proof-of-concept and are consistent with the highly selective, prebiotic effect of HMOs in shaping the gut microbiota in the first weeks of life. The analysis of selective fecal bacterial substrates as a measure of alterations in the gut microbiota may be a potential marker of dysbiosis. PMID- 25300179 TI - An ecosystem services approach to pesticide risk assessment and risk management of non-target terrestrial plants: recommendations from a SETAC Europe workshop. AB - The registration of plant protection products (PPPs) in the EU is under Regulation 1107/2009, which recommends a tiered approach to assessing the risk to non-target terrestrial plants (NTTPs). However, little information is provided on how to perform and implement higher tier studies or how to use them to refine the risk assessments. Therefore, a stakeholder workshop was organized to consolidate current knowledge and expertise to aid the further development of testing and assessment procedures for NTTPs. This brief communication highlights the agreed recommendations of the workshop, which relate to the three main themes, i.e. specific protection goals, risk assessment and mitigation. The participants of the workshop adopted the European Food Safety Authority (EFSA) approach of using an ecosystem services framework for identifying specific protection goals. First, delivery and protection of ecosystem services were discussed for in-crop, in field and off-crop, and off-field areas. Second, lower and higher tier risk assessment methods, including modelling approaches, were evaluated. Third, options for risk mitigation of spray drift and run-off were discussed and evaluated. Several important knowledge gaps were identified, and specific data collation and literature-based tasks were actioned to begin to address them. A full workshop report is planned for the fall of 2014. PMID- 25300180 TI - Lab-scale experimental strategy for determining micropollutant partition coefficient and biodegradation constants in activated sludge. AB - The nitrifying/denitrifying activated sludge process removes several micropollutants from wastewater by sorption onto sludge and/or biodegradation. The objective of this paper is to propose and evaluate a lab-scale experimental strategy for the determination of partition coefficient and biodegradation constant for micropollutant with an objective of modelling their removal. Four pharmaceutical compounds (ibuprofen, atenolol, diclofenac and fluoxetine) covering a wide hydrophobicity range (log Kow from 0.16 to 4.51) were chosen. Dissolved and particulate concentrations were monitored for 4 days, inside two reactors working under aerobic and anoxic conditions, and under different substrate feed conditions (biodegradable carbon and nitrogen). We determined the mechanisms responsible for the removal of the target compounds: (i) ibuprofen was biodegraded, mainly under aerobic conditions by cometabolism with biodegradable carbon, whereas anoxic conditions suppressed biodegradation; (ii) atenolol was biodegraded under both aerobic and anoxic conditions (with a higher biodegradation rate under aerobic conditions), and cometabolism with biodegradable carbon was the main mechanism; (iii) diclofenac and fluoxetine were removed by sorption only. Finally, the abilities of our strategy were evaluated by testing the suitability of the parameters for simulating effluent concentrations and removal efficiency at a full-scale plant. PMID- 25300181 TI - Impact of influent wastewater quality on nitrogen removal rates in multistage treatment wetlands. AB - Nitrogen removal in treatment wetlands is influenced by many factors, and the presence of electron donors (biodegradable organic matter) and electron acceptors (nitrate ions) is the main limiting one; for obtaining these conditions, multistage treatment wetlands (MTWs) are required, where an extensive nitrification can be obtained in the first stages under aerobic conditions leaving then to the following anoxic/anaerobic stages the duty of the denitrification. Most of the biodegradable organic matter is however oxidised in the first stages, and therefore, the inlet to the denitrification beds is usually poor of easily degradable carbon sources. This study is comparing the long-term performances obtained at several MTWs operating in Europe (North and South) and North Africa in order to understand if there is a significant avail in making use of the influent chemical oxygen demand (COD)/N ratio during the design phase for ensuring proper performances in terms of N overall removal. The statistic analysis performed in this study have shown that MTWs are capable to ensure sufficient removal of both organic and nutrients even in unfavourable proportions of macronutrients (C and N). The usual assumptions for conventional biological treatment systems concerning adequate C/N ratios seem to be dubious in case of wastewater treatment in MTWs. PMID- 25300182 TI - Stereoselective degradation of flutriafol and tebuconazole in grape. AB - The stereoselective dissipation of flutriafol and tebuconazole in grape had been studied. A simple and sensitive method for determination of flutriafol and tebuconazole enantiomers in grape was developed by high-performance liquid chromatography on a cellulose tris(3-chloro-4-methylphenylcarbamate) column. The limits of quantification for flutriafol and tebuconazole in grape were 0.033 and 0.043 mg kg(-1), respectively. The dissipations of flutriafol and tebuconazole stereoisomers in grape followed first-order kinetics (R (2) > 0.93). The stereoisomers of flutriafol and tebuconazole were enantioselectively degraded in grape, and tebuconazole was more enantioselective than flutriafol. The half-life of (-)-tebuconazole was 5.2 days and shorter than (+)-tebuconazole with half-life of 6.4 days. The (-)-flutriafol was also preferentially degraded in grape, the half-lives of which were 6.59 and 6.98 days for (-) and (+)-flutriafol, respectively. The enantiomeric ratio value of the two fungicides was nearly 1.0 at the 1st day and increased to 1.143 for flutriafol and 2.015 for tebuconazole at the 28th day. The stereoselective dissipations could provide a reference to fully evaluate the risks of two important chiral triazole fungicides. PMID- 25300183 TI - Concentration and size distribution of viable bioaerosols during non-haze and haze days in Beijing. AB - Accumulation of airborne particulate matter (PM) has profoundly affected the atmospheric environment of Beijing, China. Although studies on health risks have increased, characterization of specific factors that contribute to increased health risks remains an area of needed exploration. Chemical composition studies on PM can readily be found in the literature but researches on biological composition are still limited. In this study, the concentration and size distribution of viable airborne bacteria and fungi were determined in the atmosphere from May to July 2013 in Beijing, China. Samples were collected during non-haze days and haze days based on the value of air quality index (AQI) PM2.5. Multiple linear regression results indicated that concentrations of viable bioaerosol exhibited a negative correlation with PM2.5 (AQI) ranging from 14 to 452. There was a little difference in size distribution of bioaerosol between non haze and haze days that all airborne bacteria showed skewed trends toward larger sizes and airborne fungi followed a Gaussian distribution. Spearman's correlation analysis showed that a fraction of bioaerosol with fine and coarse particles had negative and positive relations with PM2.5 (AQI), respectively. Moreover, the temporal variation of d g (aerodynamic diameter) of bioaerosol with PM2.5 (AQI) fluctuated from 9:00 to 21:00, which suggested that their deposition pattern would vary during a day. The primary research in this study implied that aerodynamic size variation should be considered in assessing the bioaerosol exposure during haze weather. PMID- 25300184 TI - Cluster analysis applied to CO2 concentrations at a rural site. AB - In rural environments, atmospheric CO2 is mainly controlled by natural processes such as respiration-photosynthesis or low atmosphere evolution. This paper considers atmospheric CO2 measurements obtained at a rural site during 2011 using the wavelength-scanned cavity ringdown spectroscopy technique and presents two clustering methods, the silhouette being calculated to evaluate procedure validity. In the first method, clusters were formed depending on the similarity of wind roses, with satisfactory silhouette values. An anticyclonic rotation of the wind direction was observed during the daily cycle and clusters were formed by consecutive directions following the mixing layer evolution. However, monthly roses revealed four quite different wind directions, mainly oriented in the E-W axis. Although CO2 was not used in this procedure, a successful link between clusters and CO2 was obtained. In the second procedure, clusters were formed by the similarity of CO2 histograms calculated in intervals of one or two ancillary variables, wind direction, time of day, or month. The influence of a nearby city, the daily evolution of the low atmosphere, and the growing season were highlighted. Finally, the usefulness of the method lies in its easy extension to other gases or variables. PMID- 25300185 TI - Isolation and cultivation of xylanolytic and cellulolytic Sarocladium kiliense and Trichoderma virens from the gut of the termite Reticulitermes santonensis. AB - The purpose of this work was the isolation and cultivation of cellulolytic and xylanolytic microorganisms extracted from the gut of the lower termite Reticulitermes santonensis. Microcrystalline cellulose (with and without lignin) and beech wood xylan were used as diets instead of poplar wood in order to select cellulose and hemicellulose-degrading fungi. The strain Sarocladium kiliense (Acremonium kiliense) CTGxxyl was isolated from the termites fed on xylan, while the strain Trichoderma virens CTGxAviL was isolated from the termites fed on cellulose (with and without lignin). Both molds were cultivated in liquid media containing different substrates: agro-residues or purified polymers. S. kiliense produced maximal beta-glucosidase, endo-1,4-beta-D-glucanase, exo-1,4-beta-D glucanase and endo-1,4-beta-D-xylanase activities of 0.103, 3.99, 0.53, and 40.8 IU/ml, respectively. T. virens produced maximal beta-xylosidase, endo-1,4-beta-D glucanase, exo-1,4-beta-D-glucanase, and endo-1,4-beta-D-xylanase activities of 0.38, 1.48, 0.69, and 426 IU/ml. The cellulase and the xylanase of S. kiliense, less common than T. virens, were further investigated. The optimal activity of the xylanase was observed at pH 9-10 at 60 degrees C. The cellulase showed its maximal activity at pH 10, 70 degrees C. Zymography identified different xylanases produced by both molds, and some fragment sizes were highlighted: 35, 100, and 170 kDa for S. kiliense and 20, 40, 80, and 170 kDa for T. virens. In both cases, endo-1,4-beta-D-xylanase activities were confirmed through mass spectrometry. PMID- 25300186 TI - Detecting genomic damages in the frog Dendropsophus minutus: preserved versus perturbed areas. AB - The aim of the study was to use the comet assay (single-cell gel electrophoresis) and micronucleus test to assess the extent of genomic damage in the whole blood of Dendropsophus minutus from agroecosystems with great use of agrochemicals and to compare the results to those obtained from animals living in unpolluted areas. Our results indicated that specimens of D. minutus collected in perturbed areas exhibited higher amounts of DNA damage in blood cells in comparison to animals from areas free of agricultural activities. The average and standard deviation of all comet assay parameters (tail length, percentage of DNA in the tail, and olive tail moment) and micronuclei frequency were significantly higher in specimens collected in perturbed areas than in the animals from preserved areas. Our study showed that animals from perturbed areas, such as agroecosystems, tend to have higher amounts of DNA damage than animals from reference areas. Moreover, we can conclude that D. minutus tadpoles could be included as a model organism in biomonitoring studies. PMID- 25300187 TI - Impact of soil primary size fractions on sorption and desorption of atrazine on organo-mineral fractions. AB - In the current study, a mechanical dispersion method was employed to separate clay (<2 MUm), silt (2-20 MUm), and sand (20-50 MUm) fraction in six bulk soils. Batch equilibrium method was used to conduct atrazine sorption and desorption experiments on soil organo-mineral fractions with bulk soils and their contrasting size fractions separately. The potential contribution of total organic carbon (TOC) for atrazine retention in different fractions was further investigated. It was found that clay fraction had the highest adsorption but the least desorption capacities for atrazine, while sand fraction had the lowest adsorption but the highest desorption capacities for atrazine. The adsorption percentage of atrazine, as compared with adsorption by the corresponding bulk soils, ranged from 53.6 to 80.5%, 35.7 to 56.4%, and 0.2 to 4.5% on the clay, silt, and sand fractions, respectively. TOC was one of the key factors affecting atrazine retention in soils, with the exact contribution dependent on varying degree of coating with mineral component in different soil size fractions. The current study may be useful to predict the bioavailability of atrazine in different soil size fractions. PMID- 25300188 TI - Acute intralesional recording in hypothalamic hamartoma: description of 4 cases. AB - Hypothalamic hamartomas (HHs) are intrinsically epileptogenic lesions associated to medically intractable focal epilepsy mainly characterized by gelastic and focal seizures. Intralesional recording with deep electrodes has documented the presence of ictal discharge arising from inside the lesion. Nevertheless interictal and ictal scalp EEG is poorly informative and non-localizing in a great deal of cases. HH disconnection leads to seizure remission in most cases. To describe the intralesional EEG recordings and to compare them with concomitant scalp EEG and with previous cases reported in literature. We reviewed the medical records of 17 children affected by drug-resistant focal epilepsy associated to HH. We recorded intralesional electrical activity during stereo-endoscopic disconnection in three cases and during deep brain stimulation implantation in one. We also correlated it with the simultaneous scalp-EEG recording. Acute intralesional recordings in our cases confirmed the presence of epileptiform abnormalities intermingled with low-voltage activity, mostly on the same side of the HH attachment. Paroxysmal activity recorded inside the HH was always evident. Mapping of HH epileptogenic activity could be useful to confirm the usefulness of disconnection procedure. This should consider on-site recording from the HH and if abnormalities are detected safely proceed to disconnection of the HH. PMID- 25300189 TI - Putative endoglucanase PcGH5 from Phanerochaete chrysosporium is a beta xylosidase that cleaves xylans in synergistic action with endo-xylanase. AB - A predicted endoglucanase gene (PcGH5) was cloned from Phanerochaete chysosporium, and expressed in Pichia pastoris. Although PcGH5 showed similarity with the conserved domains of a cellulase superfamily GH5, a beta-glucosidase/6 phospho-beta-glucosidase/beta-galactosidase superfamily, and an endoglucanase, recombinant PcGH5 exhibited a beta-xylosidase activity, rather than endoglucanase activity. Therefore, the predicted gene was named as PcXyl5. Further characterization of recombinant PcXyl5 showed not only catalysis of the hydrolysis of xylo-oligomers to xylose, but also displayed transglycosylation activity using alcohol as a receptor. Optimum pH of rPcXyl5 was found to be 5.5, whereas optimum temperature was 50 degrees C. rPcXyl5 increased reducing sugar release of birchwood xylan, beechwood xylan, and arabinoxylan by 6.4%, 13%, 15.8%, respectively, in synergistic action with endo-xylanase. Interestingly, the late addition of rPcXyl5 into reaction with endo-xylanase resulted in a larger increase of reducing sugar release from pretreated barley straw that addition at the start or by treatment with endo-xylanases alone. The increases observed were 6.3% and 13.8%, respectively, showing a great potential application for hemicellulose saccharification. PMID- 25300190 TI - Lactobacillus plantarum mediated fermentation of Psidium guajava L. fruit extract. AB - Sixteen hour fermentation of the white flesh raw guava Lucknow 49 cultivar using Lactobacillus plantarum NCIM 2912 was taken up for enhancing the antioxidant potential. The fermented guava product with high antioxidant potential, total phenolic content and short and medium chain fatty acids can be used as functional food. PMID- 25300191 TI - Cystatin C: a useful marker of glomerulopathy in sickle cell disease? AB - As renal dysfunction is a leading cause of morbidity in sickle cell disease it is important that clinicians have accurate means of assessing its risk and severity. Cystatin C (Cys-C) is being recognized as a useful marker of renal function in other populations and this study aims to determine its utility in adults with sickle cell anemia (SCA). 98 persons with the homozygous SS disease (55 females: 43 males; mean age 34+/-2.3 years) had hematological and biochemical, including Cys-C, measurements; and glomerular filtration rate (GFR) measured using a (99m)Tc-DTPA nuclear renal scan. The measured GFR was 94.9+/-27.4mL/min/1.73m(2), and mean Cys-C level was 0.80+/-0.78mg/L. Cys-C was significantly correlated with measured GFR (r=-0.61), hemoglobin (r=-0.32), serum creatinine (r=0.91), urine ACR (r=0.79), and systolic blood pressure (r=0.38). The Cys-C based CKD-EPI showed the greatest agreement than the other commonly used Cys-C based as well as the serum creatinine based MDRD and CKD-EPI equations. Cys-C also showed a strong association with GFR in a significant regression model. In conclusion, Cys-C has shown strong associations with GFR and albuminuria among patients with SCA and so may be a useful screening tool in this patient population. PMID- 25300192 TI - Physical Child Abuse and Teacher Harassment and Their Effects on Mental Health Problems Amongst Adolescent Bully-Victims in Taiwan. AB - This study compared physical child abuse and teacher harassment of bully-victims with other groups and examined their associations with mental health problems in bully-victims. For 6,160 adolescents, experiences of physical child abuse, teacher harassment, peer bullying, and six mental health problem indicators were assessed. Adolescents that had experienced physical child abuse and teacher harassment were more likely to be bully-victims but not neutral or pure victims. Adolescents who reported physical child abuse were more likely to be bully victims but not pure bullies. Bully-victims that had experienced teacher harassment exhibited more severe depression and insomnia than did those without teacher harassment. Gender had moderating effects on the difference in physical child abuse between bully-victims and neutrals and on the association between physical child abuse and suicidality in bully-victims. Physical child abuse and teacher harassment should be considered when preventive and intervention programs are developed for adolescents. PMID- 25300193 TI - Social Anxiety and Mental Health Service Use Among Asian American High School Students. AB - Asian American adults endorse more symptoms of social anxiety (SA) on self-report measures than European Americans, but demonstrate lower prevalence rates of SA disorder in epidemiological studies. These divergent results create ambiguity concerning the mental health needs of Asian Americans. The present study is the first to investigate this issue in adolescents through assessment of self reported SA in Asian American high school students. Parent and self-ratings of impairment related to SA and self-reported mental health service use for SA were also measured. Asian American students endorsed a greater number of SA symptoms and scored in the clinical range more frequently than other ethnic groups. Also, Asian American and Latino students endorsed more school impairment related to SA than other ethnic groups. No differences in parent-reported impairment or service utilization were identified. Implications for future research and treatment for SA among Asian American adolescents are discussed. PMID- 25300194 TI - Mother-Child Interaction and Early Language Skills in Children Born to Mothers with Substance Abuse and Psychiatric Problems. AB - This prospective, longitudinal study with data collected at four time points investigated how maternal psychiatric symptoms, substance abuse and maternal intrusiveness in interaction were related to early child language skills. Three groups of mothers were recruited during pregnancy: One from residential treatment institutions for substance abuse (n = 18), one from psychiatric outpatient treatment (n = 22) and one from well-baby clinics (n = 30). Maternal substance abuse and anti-social and borderline personality traits were assessed during pregnancy, postpartum depression at 3 months, maternal intrusiveness in interaction at 12 months, and child language skills at 2 years. Results showed that the mothers in the substance abuse group had the lowest level of education, they were younger and they were more likely to be single mothers than the mothers in the two other groups. There was a significant difference in expressive language between children born to mothers with substance abuse problems and those born to comparison mothers, however not when controlling for maternal age, education and single parenthood. No group differences in receptive language skills were detected. Results further showed that maternal intrusiveness observed in mother-child interaction at 12 months was significantly related to child expressive language at 2 years, also when controlling for socio-demographic risk factors. This suggests that in addition to addressing substance abuse and psychiatric problems, there is a need for applying treatment models promoting sensitive caregiving, in order to enhance child expressive language skills. PMID- 25300195 TI - Factors perceived to influence risky sexual behaviours among university students in the United Kingdom: a qualitative telephone interview study. AB - BACKGROUND: In the United Kingdom people under the age of 25 years are at increased risk of contracting sexually transmitted infections. Most university students belong to this age group but little is known about their sexual behaviours. The aim of the study was to explore university students' perspectives of factors and mechanisms that influence risky sexual behaviours among university students in the United Kingdom. METHODS: All students at a university in a northern city of England were invited via email to participate in qualitative telephone interviews. Interviews were audio recorded and transcribed verbatim. Framework analytical approach was used. RESULTS: Twenty interviews were conducted with a diverse sample of students. The social context of university lifestyle was perceived to affect risky sex through high levels of alcohol consumption, increased sexual opportunities, liberation from moral surveillance and expectations of the stereotypical highly sexually active student. Individual and cultural differences were also perceived to account for some patterns of risky sex with older students, overseas students and religious students perceived to be less likely to engage in risky sex due to academic priorities and a tendency to be more likely to adhere to moral values. Risk denial was also a key factor that led students to engage in risky sex. Poor access to sexual health services including inconvenient opening times, lack of confidentiality and stigma were perceived to contribute to the limited use of sexually transmitted infections testing and contraceptive services. CONCLUSIONS: Lifestyle, individual and structural factors seem to play an important role in influencing the risky sexual behaviours of university students. Therefore preventive interventions that focus on these factors could be very useful in this sub-population of young people. This study provides useful baseline information that helps us understand how and why some United Kingdom university students engage in risky sexual behaviours that puts them at risk of contracting sexually transmitted infections. PMID- 25300197 TI - A polyoxometalate-based complex with visible-light photochromism as the electrocatalyst for generating hydrogen from water. AB - Two polyoxometalate (POM)-based complexes formulated as (HL1)2(Mo8O26).2HL1.11H2O (L1 = 3-(5-(1H-pyrazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridine) (1) and Co2(L2)4[P2Mo(VI)5O23Mo(II)(H2O)2].3H2O (L2 = 4-(5-(2H-1,2,4-triazol-3-yl)-2H 1,2,4-triazol-3-yl)pyridine) (2) have been synthesized and structurally characterized by single-crystal X-ray diffraction. Complex 1 shows a bi-capped POM with the two Mo centers from the [Mo8O26](4-) moiety coordinated by two HL1 ligands via two Mo-N bonds. Complex 2 consists of a mononuclear unsaturated coordinated Co(ii) unit and a [P2Mo(VI)5O23Mo(II)(H2O)2](4-) moiety, in which [P2Mo(VI)5O23Mo(II)(H2O)2](4-) shows a chain-like structure constructed from edge sharing or vertex-sharing {MoO6} and {PO4} polyhedra. The two complexes are both soluble in neutral aqueous solution and they can electrocatalyze the H2 evolution reaction (HER) from water with lowered overpotentials and enhanced currents, and complex 1 shows better electrocatalytic activity for the HER than complex 2. Complex 1 shows visible-light photochromism. In the presence of complex 1, the HER current is enhanced with visible-light irradiation in comparison with the current without light irradiation. PMID- 25300196 TI - Breast cancer in young women: special considerations in multidisciplinary care. AB - Breast cancer is one of the most prevalent cancers in females, and 5%-7% of breast cancer cases occur in women under 40 years of age. Breast cancer in the young has gained increased attention with an attempt to improve diagnosis and prognosis. Young patients tend to have different epidemiology, presenting with later stages and more aggressive phenotypes. Diagnostic imaging is also more difficult in this age group. Multidisciplinary care generally encompasses surgeons, medical oncologists, radiation oncologists, radiologists, and social workers. Other special considerations include reconstruction options, fertility, genetics, and psychosocial issues. These concerns enlarge the already diverse multidisciplinary team to incorporate new expertise, such as reproductive specialists and genetic counselors. This review encompasses an overview of the current multimodal treatment regimens and the unique challenges in treating this special population. Integration of diagnosis, treatment, and quality of life issues should be addressed and understood by each member in the interdisciplinary team in order to optimize outcomes. PMID- 25300198 TI - Comparison of the analgesic effects of cryoanalgesia vs. parecoxib for lung cancer patients after lobectomy. AB - This study was designed to compare the analgesic effects of cryoanalgesia and parecoxib in lung cancer patients after lobectomy. A total of 178 lung cancer patients awaiting large-sized lobectomy were enrolled in the study. The patients were randomly divided into Group A (intercostal nerve cryoanalgesia) and Group B (parecoxib). The analgesic and adverse effects were compared between the two groups. The pain score of Group A was significantly lower than that of Group B (P < 0.05). The patients in Group A used significantly less morphine than those in Group B (P < 0.05). There were also significantly fewer complications in Group A than in Group B (P < 0.05). Cryoanalgesia of the intercostal nerves can be considered an economical, safe and simple technique for the long-term management of post-lobectomy pain. PMID- 25300199 TI - Solving the mystery of excessive warfarin-induced bleeding: a personal historical perspective. PMID- 25300200 TI - Brain anatomical substrates of mirror movements in Kallmann syndrome. AB - Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements. PMID- 25300202 TI - Better together? The cognitive advantages of synaesthesia for time, numbers, and space. AB - Synaesthesia for time, numbers, and space (TNS synaesthesia) is thought to have costs and benefits for recalling and manipulating time and number. There are two competing theories about how TNS synaesthesia affects cognition. The "magnitude" account predicts that TNS synaesthesia may affect cardinal magnitude judgements, whereas the "sequence" account suggests that it may affect ordinal sequence judgements and could rely on visuospatial working memory. We aimed to comprehensively assess the cognitive consequences of TNS synaesthesia and distinguish between these two accounts. TNS synaesthetes, grapheme-colour synaesthetes, and nonsynaesthetes completed a behavioural task battery. Three tasks involved cardinal and ordinal comparisons of temporal, numerical, and spatial stimuli; we also examined visuospatial working memory. TNS synaesthetes were significantly more accurate than nonsynaesthetes in making ordinal judgements about space. This difference was explained by significantly higher visuospatial working memory accuracy. Our findings demonstrate an advantage of TNS synaesthesia that is more in line with the sequence account. PMID- 25300201 TI - Regional quantification of cerebral venous oxygenation from MRI susceptibility during hypercapnia. AB - There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions. Ten healthy subjects were scanned at 3T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41+/-3mmHg) and hypercapnia (50+/ 4mmHg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region. Hypercapnia induced a relative decrease in OEF of -42.3% in the straight sinus, -39.9% in the internal cerebral veins, and approximately -50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P<0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation. PMID- 25300204 TI - Choosing an appropriate glucose concentration according to different cell types and experimental purposes is very important. PMID- 25300203 TI - Celastrol, an oral heat shock activator, ameliorates multiple animal disease models of cell death. AB - Protein homeostatic regulators have been shown to ameliorate single, loss-of function protein diseases but not to treat broader animal disease models that may involve cell death. Diseases often trigger protein homeostatic instability that disrupts the delicate balance of normal cellular viability. Furthermore, protein homeostatic regulators have been delivered invasively and not with simple oral administration. Here, we report the potent homeostatic abilities of celastrol to promote cell survival, decrease inflammation, and maintain cellular homeostasis in three different disease models of apoptosis and inflammation involving hepatocytes and cardiomyocytes. We show that celastrol significantly recovers the left ventricular function and myocardial remodeling following models of acute myocardial infarction and doxorubicin-induced cardiomyopathy by diminishing infarct size, apoptosis, and inflammation. Celastrol prevents acute liver dysfunction and promotes hepatocyte survival after toxic doses of thioacetamide. Finally, we show that heat shock response (HSR) is necessary and sufficient for the recovery abilities of celastrol. Our observations may have dramatic clinical implications to ameliorate entire disease processes even after cellular injury initiation by using an orally delivered HSR activator. PMID- 25300206 TI - Perforation of the cecum by a toothpick: report of a case and review of the literature. AB - BACKGROUND: Ingesting a foreign body (FB) is not an uncommon occurrence. Most pass through the gastrointestinal (GI) tract uneventfully and rarely cause complications. However, long, sharp, slender, and hard objects such as fish bones, chicken bones, and toothpicks may lead to perforation of the GI tract, which is a potentially life-threatening complication. CASE REPORT: We report the case of a 50-year-old woman who presented to the Emergency Department of our hospital complaining of right lower quadrant abdominal pain of 2 days' duration. Ultrasound imaging and computed tomography scan demonstrated the presence of a foreign body protruding from the lateral cecal wall and surrounded by an area of inflammation. The patient was taken to the operating room, where a toothpick was found to have perforated the cecum. The FB was removed and the defect of the intestinal wall was closed using a TA linear stapler (Covidien, Mansfield, MA). The patient was discharged on the 8(th) postoperative day. We also conducted a literature search for reports on injuries caused by ingested FBs. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Perforation of the GI tract by an ingested FB in the adult population is most commonly secondary to accidental ingestion. Patients rarely recall the episode of the ingestion, or may remember the incident only after a diagnosis is made. We present this case to increase awareness of the diagnosis. PMID- 25300207 TI - Young woman with a headache. PMID- 25300205 TI - Association between acquired resistance to PLX4032 (vemurafenib) and ATP-binding cassette transporter expression. AB - BACKGROUND: Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032. FINDINGS: PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines. CONCLUSION: PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies. PMID- 25300208 TI - Full recovery after prolonged cardiac arrest and resuscitation with mechanical chest compression device during helicopter transportation and percutaneous coronary intervention. AB - BACKGROUND: Despite early cardiopulmonary resuscitation (CPR) by bystanders and early advanced cardiac life support (ACLS) maneuvers, some patients present to the emergency department with persistent cardiac arrest caused by a coronary artery occlusion. Although emergency percutaneous intervention (PCI) has been shown to be effective in improving survival, transporting patients in cardiac arrest to the hospital is not considered to be effective, due to the poor quality of CPR in the ambulance. In the case reported here, a mechanical chest compression device was used while transporting the patient by helicopter emergency medical services (HEMS). CASE REPORT: A mechanical chest compression device was used to deliver chest compressions to a 53-year-old man in cardiac arrest. This device permitted the transfer of the patient by HEMS helicopter to the catheterization laboratory facility for a PCI. Return of spontaneous circulation was achieved 115 min after cardiac arrest and the patient survived without any neurological deficit. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The mechanical chest compression device has permitted safe and effective CPR during helicopter transportation. Although this is only a single case, it may present a new perspective for the treatment of prehospital cardiac arrest that is refractory to ACLS therapies. PMID- 25300209 TI - Skin color change with circulatory assist devices: superior vena cava syndrome. PMID- 25300210 TI - Direct application of gold nanoparticles to one-pot electrochemical biosensors. AB - Gold nanoparticles (AuNPs) have been widely employed for the fabrication of electrochemical biosensors. In most cases, AuNPs are immobilized on the surface of an electrode, so they are difficult to be regenerated, making the use of the biosensor unfriendly. In this work, by adopting AuNPs directly as the electrolytes, we have developed a novel AuNPs-based electrochemical detection system. In brief, AuNPs-catalyzed oxidation of glucose is combined with a HRP catalyzed reaction as well as an electrocatalytic reaction to compose cascade reactions in the electrolyte. Thus, the intensity of the electrocatalytic signals has quantitative relation with the concentration of glucose, and favors the sensitive detection of glucose. Furthermore, because the catalysis of AuNPs may be blocked under the interaction with single-stranded DNA and unblocked in the presence of a complementary sequence, detection of DNA and even single-nucleotide polymorphism can thereby been achieved. This one-pot detection system can be operated and regenerated very easily, since all the components are integrated in the electrolytes of AuNPs, and the unmodified electrode can be reused after being rinsed. This concept by integrating the advantages of sensitive electrochemical detection with the easy-to-operate nanocolloidal system may also promote the development of other kinds of electrochemical biosensors. PMID- 25300211 TI - A novel approach for electromembrane extraction based on the use of silver nanometallic-decorated hollow fibers. AB - A novel approach based on the use of nanometallic-decorated hollow fibers to assist electromembrane extraction is proposed. Microporous polypropylene hollow fibers, on which nanometallic silver was deposited, have been used for the first time as liquid membrane support in electromembrane extraction (EME). Different methods for the generation/deposition of silver nanoparticles (AgNPs) were studied. The best results were obtained with chemical reduction of silver nitrate using NaBH4 in aqueous solution followed by direct deposition on the hollow fibers. The extraction performance of the new supports was compared with a previously developed EME procedure used for the extraction of selected non steroidal anti-inflammatory drugs (NSAIDs), resulting in an increase in the extraction ratio by a factor of 1.2-2 with a 30% reduction in the extraction time. The new nanometallic-decorated supports open new possibilities for EME due to the singular properties of nanometallic particles, including chemical fiber functionalization. PMID- 25300212 TI - Monitoring of an esterification reaction by on-line direct liquid sampling mass spectrometry and in-line mid infrared spectrometry with an attenuated total reflectance probe. AB - A specially designed thermal vaporiser was used with a process mass spectrometer designed for gas analysis to monitor the esterification of butan-1-ol and acetic anhydride. The reaction was conducted at two scales: in a 150 mL flask and a 1L jacketed batch reactor, with liquid delivery flow rates to the vaporiser of 0.1 and 1.0 mLmin(-1), respectively. Mass spectrometry measurements were made at selected ion masses, and classical least squares multivariate linear regression was used to produce concentration profiles for the reactants, products and catalyst. The extent of reaction was obtained from the butyl acetate profile and found to be 83% and 76% at 40 degrees C and 20 degrees C, respectively, at the 1L scale. Reactions in the 1L reactor were also monitored by in-line mid-infrared (MIR) spectrometry; off-line gas chromatography (GC) was used as a reference technique when building partial least squares (PLS) multivariate calibration models for prediction of butyl acetate concentrations from the MIR spectra. In validation experiments, good agreement was achieved between the concentration of butyl acetate obtained from in-line MIR spectra and off-line GC. In the initial few minutes of the reaction the profiles for butyl acetate derived from on-line direct liquid sampling mass spectrometry (DLSMS) differed from those of in-line MIR spectrometry owing to the 2 min transfer time between the reactor and mass spectrometer. As the reaction proceeded, however, the difference between the concentration profiles became less noticeable. DLSMS had advantages over in-line MIR spectrometry as it was easier to generate concentration profiles for all the components in the reaction. Also, it was possible to detect the presence of a simulated impurity of ethanol (at levels of 2.6 and 9.1% mol/mol) in butan-1-ol, and the resulting production of ethyl acetate, by DLSMS, but not by in-line MIR spectrometry. PMID- 25300213 TI - N-alkylpyridinium quaternization combined with liquid chromatography-electrospray ionization-tandem mass spectrometry: A highly sensitive method to quantify fatty alcohols in thyroid tissues. AB - A highly sensitive method was developed for the identification and quantification of fatty alcohols in biological tissues. In the presence of pyridine-d0 and triflic anhydride (Tf2O), fatty alcohols were converted into permanently charged N-alkylpyridinium ions. Stable isotope-labeled derivatives were generated by pyridine-d5 and added as internal standard (IS). The mixture was analyzed by liquid chromatography coupled to positive electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). This method was optimized and validated in terms of reaction time, derivatization efficiency, stability, desalting, and ion suppression effect. Besides, fatty alcohols exhibited good linear relationship (r(2)>0.993) over the concentration range of 10 ngmL(-1)-1 MUgmL(-1). The limits of detection (LODs) were lowered from previously reported 0.1 ngmL(-1) to 0.25 pgmL(-1). Precision (RSD%<15.6%), accuracy (93.0-107.2%), matrix effect, and recovery (in thyroid tissues) were validated as well. Finally, this method was applied for the analysis of ten even carbon-numbered fatty alcohols (C8-C24) in human thyroid carcinoma and para-carcinoma tissues, revealing a significant decrease of fatty alcohols (free and esterified) in thyroid carcinoma tissues (p<0.05). PMID- 25300214 TI - Use of a porous silicon-gold plasmonic nanostructure to enhance serum peptide signals in MALDI-TOF analysis. AB - Small peptides in serum are potential biomarkers for the diagnosis of cancer and other diseases. The identification of peptide biomarkers in human plasma/serum has become an area of high interest in medical research. However, the direct analysis of peptides in serum samples using mass spectrometry is challenging due to the low concentration of peptides and the high abundance of high-molecular weight proteins in serum, the latter of which causes severe signal suppression. Herein, we reported that porous semiconductor-noble metal hybrid nanostructures can both eliminate the interference from large proteins in serum samples and significantly enhance the matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) yields of peptides captured on the nanostructure. Serum peptide fingerprints with high fidelity can be acquired rapidly, and successful discrimination of colorectal cancer patients based on peptide fingerprints is demonstrated. PMID- 25300215 TI - A novel "Turn-On" fluorescent probe for F(-) detection in aqueous solution and its application in live-cell imaging. AB - A novel probe incorporating quaternized 4-pyridinium group into a BODIPY molecule was synthesized and studied for the selective detection of fluoride ions (F(-)) in aqueous solution. The design was based on a fluoride-specific desilylation reaction and the "Turn-On" fluorescent response of probe 1 to F(-) was ascribed to the inhibition of photoinduced electron transfer (PET) process. The probe displayed many desired properties such as high specificity, appreciable solubility, desirable response time and low toxicity to mammalian cells. There was a good linearity between the fluorescence intensity and the concentrations of F(-) in the range of 0.1-1mM with a detection limit of 0.02 mM. The sensing mechanism was confirmed by the NMR, electrospray ionization mass spectrum, optical spectroscopy and the mechanism of "Turn-On" fluorescent response was also determinated by a density functional theory (DFT) calculation using Gaussian 03 program. Moreover, the probe was successfully applied for the fluorescence imaging of F(-) in human epithelial lung cancer (A549) cells and alveolar type II (ATII) cells under physiological conditions. PMID- 25300216 TI - Optofluidics-based DNA structure-competitive aptasensor for rapid on-site detection of lead(II) in an aquatic environment. AB - Lead ions (Pb(2+)), ubiquitous and one of the most toxic metallic pollutants, have attracted increasing attentions because of their various neurotoxic effects. Pb(2+) has been proven to induce a conformational change in G-quadruplex (G4) aptamers to form a stabilizing G4/Pb(2+) complex. Based on this principle, an innovative optofluidics-based DNA structure-competitive aptasensor was developed for Pb(2+) detection in an actual aquatic environment. The proposed sensing system has good characteristics, such as high sensitivity and selectivity, reusability, easy operation, rapidity, robustness, portability, use of a small sample volume, and cost effectiveness. A fluorescence-labeled G4 aptamer was utilized as a molecular probe. A DNA probe, a complementary strand of G4 aptamer, was immobilized onto the sensor surface. When the mixture of Pb(2+) solution and G4 aptamer was introduced into the optofluidic cell, Pb(2+) and the DNA probe bound competitively with the G4 aptamer. A high Pb(2+) concentration reduced the binding of the aptamer and the DNA probe; thus, a low-fluorescence signal was detected. A sensitive sensing response to Pb(2+) in the range of 1.0-300.0 nM with a low detection limit of 0.22 nM was exhibited under optimal conditions. The potential interference of the environmental sample matrix was assessed with spiked samples, and the recovery of Pb(2+) ranged from 80 to 105% with a relative standard deviation value of <8.5%. These observations clearly illustrate that with the use of different DNA or aptamer probes, the sensing strategy presented can be easily extended to the rapid on-site monitoring of other trace analytes. PMID- 25300217 TI - Microplate based optical biosensor for L-Dopa using tyrosinase from Amorphophallus campanulatus. AB - Developing a biosensor which is capable of simultaneously monitoring l-Dopa levels in multiple samples besides requiring small reaction volume is of great value. The present study describes the detection of l-Dopa using tyrosinase enzyme extracted from Amorphophallus campanulatus and immobilized on the surface of the microplate wells. Among the different approaches used for immobilizing tyrosinase onto the microplate wells, glutaraldehyde treatment was found to be most effective. Besides enzyme activity, ESEM-EDS (environmental scanning electron microscope-energy dispersive system) and Atomic Force Microscopy (AFM) were also carried out to confirm the immobilization of tyrosinase enzyme onto the microplate well surface. This immobilized biocomponent was then integrated with an optical transducer for l-Dopa detection and it showed good reproducibility. The sensing property of the system was studied by measuring the initial rate of dopachrome formation at 475 nm. The calibration plot gave a linear range of detection from 10-1000 MUM and the detection limit was calculated to be 3 MUM. The immobilized biocomponent was stable for 41 days and was reused up to nine times. Spiked samples (blood plasma) were also analyzed using this biocomponent. This microplate based biosensor thus provides a convenient system for detection of multiple samples in a single run. PMID- 25300218 TI - Live-cell imaging of biothiols via thiol/disulfide exchange to trigger the photoinduced electron transfer of gold-nanodot sensor. AB - Biothiols have been reported to involve in intracellular redox-homeostasis against oxidative stress. In this study, a highly selective and sensitive fluorescent probe for sensing biothiols is explored by using an ultrasmall gold nanodot (AuND), the dendrimer-entrapped Au8-cluster. This strategy relies upon a thiol/disulfide exchange to trigger the fluorescence change through a photoinduced electron transfer (PET) process between the Au8-cluster (as an electron donor) and 2-pyridinethiol (2-PyT) (as an electron acceptor) for sensing biothiols. When 2-PyT is released via the cleavage of disulfide bonds by biothiols, the PET process from the Au8-cluster to 2-PyT is initiated, resulting in fluorescence quenching. The fluorescence intensity was found to decrease linearly with glutathione (GSH) concentration (0-1500MUM) at physiological relevant levels and the limit of detection for GSH was 15.4MUM. Compared to most nanoparticle-based fluorescent probes that are limited to detect low molecular weight thiols (LMWTs; i.e., GSH and cysteine), the ultrasmall Au8-cluster-based probe exhibited less steric hindrance and can be directly applied in selectively and sensitively detecting both LMWTs and high molecular weight thiols (HMWTs; i.e., protein thiols). Based on such sensing platform, the surface-functionalized Au8-cluster has significant promise for use as an efficient nanoprobe for intracellular fluorescence imaging of biothiols including protein thiols in living cells whereas other nanoparticle-based fluorescent probes cannot. PMID- 25300219 TI - A fluorescence turn-on probe for cysteine and homocysteine based on thiol triggered benzothiazolidine ring formation. AB - We synthesized a new coumarin-based probe TP, containing a disulfide moiety, to detect biothiols in cells. A fluorescence turn-on response is induced by the thiol-disulfide exchange of the probe, with subsequent intramolecular benzothiazolidine ring formation giving rise to a fluorescent product. The probe exhibits an excellent selectivity for cysteine (Cys) and homocysteine (Hcy) over glutathione (GSH) and other amino acids. The fluorescent probe also exhibits a highly sensitive fluorescence turn-on response to Cys and Hcy with detection limits of 0.8 MUM for Cys and 0.5 MUM for Hcy. In addition, confocal fluorescence microscopy imaging using RAW264.7 macrophages demonstrates that the probe TP could be an efficient fluorescent detector for thiols in living cells. PMID- 25300220 TI - Simultaneous determination of the repertoire of classical neurotransmitters released from embryonal carcinoma stem cells using online microdialysis coupled with hydrophilic interaction chromatography-tandem mass spectrometry. AB - Dynamic, continuous, and simultaneous multi-analysis of transmitters is important for the delineation of the complex interactions between the neuronal and intercellular communications. But the analysis of the whole repertoire of classical transmitters of diverse structure is challenging due to their different physico-chemical properties and to their high polarity feature which leads to poor retention in traditional reversed-phase columns during LC-MS analysis. Here, an online microdialysis coupled with hydrophilic interaction chromatography tandem mass spectrometry (online MD-HILIC-MS/MS) detection method was developed for the simultaneous measurement of the repertoire of classical transmitters (acetylcholine, serotonin, dopamine, norepinephrine, glutamate, GABA, and glycine). Stable isotope labeled internal standards and authentic matrix have been applied to guarantee reliable results. The method was successfully employed to reveal the characteristics of transmitter release from embryonal carcinoma stem cells. The method features simple procedure (no sample preparation), high recovery (>= 73%), high accuracy (89.36%<=RE<=116.89%), good reproducibility (2.18%<= RSD <=14.56%), and sensitive limits of detection (2 pg for acetylcholine, serotonin, and glutamate, 10 pg for dopamine, norepinephrine, GABA, and glycine). It can be flexibly applied to determine the contents of the classical transmitters in other biological matrix samples with minor changes. PMID- 25300221 TI - A randomised controlled trial of an intervention to increase the implementation of a healthy canteen policy in Australian primary schools: study protocol. AB - BACKGROUND: The implementation of healthy school canteen policies has been recommended as a strategy to help prevent unhealthy eating and excessive weight gain. Internationally, research suggests that schools often fail to implement practices consistent with healthy school canteen policies. Without a population wide implementation, the potential benefits of these policies will not be realised. The aim of this trial is to assess the effectiveness of an implementation intervention in increasing school canteen practices consistent with a healthy canteen policy of the New South Wales (NSW), Australia, government known as the 'Fresh Tastes @ School NSW Healthy School Canteen Strategy'. METHODS/DESIGN: The parallel randomised trial will be conducted in 70 primary schools located in the Hunter region of New South Wales, Australia. Schools will be eligible to participate if they are not currently meeting key components of the healthy canteen policy. Schools will be randomly allocated after baseline data collection in a 1:1 ratio to either an intervention or control group using a computerised random number function in Microsoft Excel. Thirty-five schools will be selected to receive a multi-component intervention including implementation support from research staff, staff training, resources, recognition and incentives, consensus and leadership strategies, follow-up support and implementation feedback. The 35 schools allocated to the control group will not receive any intervention support as part of the research trial. The primary outcome measures will be i) the proportion of schools with a canteen menu that does not contain foods or beverages restricted from regular sale ('red' and 'banned' items) and ii) the proportion of schools where healthy canteen items ('green' items) represent the majority (>50%) of products listed on the menu. Outcome data will be collected via a comprehensive menu audit, conducted by dietitians blind to group allocation. Intervention effectiveness will be assessed using logistic regression models adjusting for baseline values. DISCUSSION: The proposed trial will represent a novel contribution to the literature, being the first randomised trial internationally to examine the effectiveness of an intervention to facilitate implementation of a healthy canteen policy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000311752. PMID- 25300223 TI - Bathysa cuspidata extract modulates the morphological reorganization of the scar tissue and accelerates skin wound healing in rats: a time-dependent study. AB - The technological development of pharmaceutical products based on plant extracts is currently responsible for a large number of recent innovations in healthcare. The objective of this study was to develop and investigate the effect and potential applicability of an ointment-based Bathysa cuspidata extract (BCE) for the management of skin wounds in rats. Three skin wounds of 12 mm in diameter were made on the backs of the animals, which were randomized into 4 groups according to the application received, i.e. the SAL group: 0.9% saline solution, the LAN group: lanolin, the BCE 2.5% group: 2.5% BCE emulsified in lanolin and the BCE 5% group: 5% BCE emulsified in lanolin. The applications were made daily over 21 days, and every 7 days tissue from different wounds was removed. On days 7, 14 and 21, the BCE 2.5% and BCE 5% groups showed the best results in relation to wound closure, and a higher proportion (in length, density and volume) of blood vessels and fibroblasts compared to the other groups. On days 7 and 14, there was a significant increase in the number of mast cells in these 2 groups when compared to the SAL and LAN groups. On day 21, they also had a higher proportion of collagen I than collagen III. B. cuspidata in an ointment base was effective in stimulating tissue cellularity, mast cell recruitment, neoangiogenesis, synthesis and maturation of collagen, epidermal thickness and surface area in scar tissue. These events were potentially related to the best quality and speed for skin regeneration in the rats treated with the BCE ointment. PMID- 25300222 TI - The effects of treatment on lipoprotein subfractions evaluated by polyacrylamide gel electrophoresis in patients with autoimmune hypothyroidism and hyperthyroidism. AB - BACKGROUND: Atherogenic dyslipoproteinemia is one of the most important risk factor for atherosclerotic changes development. Hypothyroidism is one of the most common causes of secondary dyslipidemias which results from reduced LDL clearance and therefore raised levels of LDL and apoB. Association between small dense LDL (sdLDL) presentation and thyroid status has been examinated using polyacrylamide gel electrophoresis for lipoprotein subfractions evaluation. METHODS: 40 patients with diagnosed autoimmune hypothyroidism and 30 patients with autoimmune hyperthyroidism were treated with thyroxine replacement or thyreo-suppressive treatment. In both groups lipid profiles, LDL subractions, apolipoproteins (apoA1, apoB), apoA1/apoB ratio and atherogenic index of plazma (AIP) were examined before treatment and in state of euthyreosis. RESULTS: Thyroxine replacement therapy significantly reduced levels of total cholesterol (TC), LDL, triglycerides (TG) and also decreased levels of sdLDL (8,55+/-11,671 vs 0,83+/ 1,693mg/dl; p<0,001), apoB and AIP. For estimation of atherogenic lipoprotein profile existence an AIP evaluation seems to be better than apoB measurement because of the more evident relationship with sdLDL (r=0,538; p<0,01). Thyreo suppressive therapy significantly increased levels of TC, LDL, TG and apoB. The sdLDL was not found in hyperthyroid patients. CONCLUSIONS: Atherogenic lipoprotein profile was present in 52.5% of hypothyroid subjects, which is higher prevalence than in normal, age-related population. Substitution treatment leads to an improvement of the lipid levels, TG, apoB, AIP and LDL subclasses. It significantly changed the presentation of sdLDL - we noticed shift to large, less atherogenic LDL particles. Significantly positive correlation between sdLDL and TAG; sdLDL and VLDL alerts to hypertriglyceridemia as a major cardiovascular risk factor. PMID- 25300224 TI - The RD parent empowerment program creates measurable change in the behaviors of low-income families and children: an intervention description and evaluation. AB - Dietary and physical activity habits are developed early in life and are influenced by family environments. We describe and evaluate an intervention for low-income families to encourage healthy habits. The RD Parent Empowerment Program (http://www.eatright.org/programs/kidseatright/activities/content.aspx?id=6442477 91) consists of four workshops centered on the 8 Habits of Healthy Children and Families (Academy of Nutrition and Dietetics Foundation). Registered dietitian nutritionists conduct the workshops in school and community settings using a structured leader guide and tailor the communication and interactive activities to the audience. Participants are parents of young children. Our goals were to use a phenomenologic approach to elicit participant feedback, determine whether participants in the RD Parent Empowerment Program made healthier choices for their families after attending the workshops, and identify which elements of the program participants believed contributed most to its success. The evaluation design used a pragmatic, mixed-methods approach utilizing postintervention focus groups and pre-post intervention scores on the Family Nutrition and Physical Activity (FNPA) survey. All workshop attendees aged 18 years or older were eligible to participate in the evaluation. One hundred twenty-three parents participated in the intervention across seven sites. Focus group results were analyzed using thematic analysis methods to match themes to the main intervention goals. t Tests were used to compare pre- and postintervention FNPA scores and demographic characteristics pooled across sites. FNPA scores significantly improved from pre- to postintervention by a mean of 4.3 FNPA points (6.5%; P<0.01). Focus group participants reported behavior changes as a result of the program and identified the site leaders as integral to the program's success, triangulating the results. The RD Parent Empowerment Program generates meaningful self-reported behavior change in parents. Long-term sustainability of the changes must be investigated. PMID- 25300226 TI - Sandwiches are major contributors of sodium in the diets of American adults: results from What We Eat in America, National Health and Nutrition Examination Survey 2009-2010. AB - Efforts to sharpen the focus of sodium reduction strategies include identification of major food group contributors of sodium intake. Although sandwiches are a staple of the American diet, previous examinations of their contribution to sodium intake captured only a small subset of sandwiches. One day of dietary intake data from 5,762 adults aged 20 years and older in What We Eat in America, National Health and Nutrition Examination Survey 2009-2010 was analyzed. Sandwiches were defined in a manner that more accurately reflected their frequency of consumption. Two-sided t tests were used to compare percentages of men and women reporting sandwiches; contributions of sandwiches to energy and sodium intakes (amounts in kilocalories and milligrams, respectively, and percent of daily totals) by sex; and total energy, total sodium, and sodium density (mg/1,000 kcal) by sandwich reporting status (reporter/nonreporter). On any given day, 49% of American adults ate sandwiches. A significantly higher percentage of men than women reported sandwiches (54% vs 44%, respectively; P<0.001), and sandwiches accounted for higher percentages of men's total energy and sodium intakes. Compared with individuals who did not report a sandwich on the intake day, sandwich reporters had significantly higher energy and sodium intakes; however, sodium density of the diet did not vary by sandwich reporting status. Although much national attention is appropriately focused on reducing sodium in the food supply, consumer choices still play a vital role. Due to sandwiches' frequent consumption and considerable contributions to sodium intake, substituting lower-sodium for higher-sodium ingredients in sandwiches could significantly influence sodium intakes. PMID- 25300225 TI - Dietary energy density is positively associated with breast density among young women. AB - BACKGROUND: Breast density is an established predictor of breast cancer risk, and there is considerable interest in associations of modifiable lifestyle factors, such as diet, with breast density. OBJECTIVE: To determine whether dietary energy density (ED) is associated with percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) in young women. DESIGN: A cross-sectional analysis was conducted with women who participated in the Dietary Intervention Study in Children Follow-Up Study. %DBV and ADBV were measured by magnetic resonance imaging. Diet was assessed by three 24-hour recalls. Dietary ED (kilocalories/gram) was calculated using three methods: food only, food and caloric beverages, and food and all beverages. PARTICIPANTS/SETTING: One hundred seventy-two women (aged 25 to 29 years) who were enrolled in the Dietary Intervention Study in Children Follow-Up Study. Participants who reported breast augmentation or reduction surgery or were pregnant or lactating within 3 months before breast density assessment were excluded. MAIN OUTCOME MEASURES: ADBV and %DBV. STATISTICAL ANALYSES PERFORMED: Multivariable linear mixed effects models were used. Final models were adjusted for race, smoking status, education, parity, duration of sex hormone use, whole body percent fat, childhood body mass index z score, and energy from beverages. RESULTS: After adjustment, each 1 kcal/g unit increase in food-only ED was associated with a 25.9% (95% CI 6.2% to 56.8%) increase in %DBV (P=0.01). Childhood body mass index z score modified the association between food-only ED and %DBV such that a significant positive association was observed only in women who were heavier as children. Food-only ED was not associated with ADBV in all women, but a borderline significant positive association was observed in women who had higher childhood body mass index z scores. CONCLUSIONS: This is the first report to suggest a potential role for dietary ED in breast density; the effects of long-term exposure to high-ED diets on breast cancer risk remain unknown. PMID- 25300227 TI - Polyphenolic extracts from cowpea (Vigna unguiculata) protect colonic myofibroblasts (CCD18Co cells) from lipopolysaccharide (LPS)-induced inflammation -modulation of microRNA 126. AB - Cowpea (Vigna unguiculata) is a drought tolerant crop with several agronomic advantages over other legumes. This study evaluated varieties from four major cowpea phenotypes (black, red, light brown and white) containing different phenolic profiles for their anti-inflammatory property on non-malignant colonic myofibroblasts (CCD18Co) cells challenged with an endotoxin (lipopolysaccharide, LPS). Intracellular reactive oxygen species (ROS) assay on the LPS-stimulated cells revealed antioxidative potential of black and red cowpea varieties. Real time qRT-PCR analysis in LPS-stimulated cells revealed down-regulation of proinflammatory cytokines (IL-8, TNF-alpha, VCAM-1), transcription factor NF kappaB and modulation of microRNA-126 (specific post-transcriptional regulator of VCAM-1) by cowpea polyphenolics. The ability of cowpea polyphenols to modulate miR-126 signaling and its target gene VCAM-1 were studied in LPS-stimulated endothelial cells transfected with a specific inhibitor of miR-126, and treated with 10 mg GAE/L black cowpea extract where the extract in part reversed the effect of the miR-126 inhibitor. This suggests that cowpea may exert their anti inflammatory activities at least in part through induction of miR-126 that then down-regulate VCAM-1 mRNA and protein expressions. Overall, Cowpea therefore is promising as an anti-inflammatory dietary component. PMID- 25300228 TI - Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens. AB - BACKGROUND: Although organoboronic acids are efficient high-throughput sugar sensors, they have not been pursued for gut permeability studies. A modification of the lactulose/mannitol assay is described by which small intestinal permeability is assessed at the time of urine collection using a lactulose/riboflavin ratio. METHODS: Volunteers ingested 50mg riboflavin and either 5 g mannitol or 10 g lactulose. Urine was collected for 6 hrs. Riboflavin was assayed by autofluorescence. Riboflavin was removed by C18 solid phase extraction. Lactulose and mannitol were then assayed using 1,1'-bis(2 boronobenzyl)-4,4'-bipyridinium (4,4'oBBV) coupled to the fluorophore HPTS. RESULTS: The temporal profile over 6 hrs for riboflavin paralleled mannitol. Riboflavin recovery in urine was 11.1 +/- 1.9 % (mean +/- SEM, n=7), similar to mannitol. There was selective binding of 4,4'oBBV to lactulose, likely involving cooperativity between the fructose and galactose moieties. Lower limits of detection and quantification were 90 and 364 MUM. The lactulose assay was insensitive to other permeability probes (e.g., sucrose, sucralose) while tolerating glucose or lactose. This assay can be adapted to automated systems. Stability of 4,4'oBBV exceeds 4 years. CONCLUSIONS: Riboflavin measured by autofluorescence combined with lactulose measured with 4,4'oBBV represents a useful new chemistry for rapid measurement of intestinal permeability with excellent stability, cost and throughput benefits. PMID- 25300229 TI - Reproducibility of histological subtyping of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) has a very poor prognosis. Although clinical stage is currently the only reliable prognostic factor, histologic subtyping reportedly also affects prognosis. Some studies propose reclassification of pleomorphic epithelioid as biphasic or sarcomatoid MPM. This study assessed prognostic significance and interobserver agreement in MPM subtyping of small biopsy specimens. We analyzed biopsy specimens, and clinical and survival data from records of 108 patients who were diagnosed between 2000 and 2010 at the Institute of Pathology University of Zagreb School of Medicine, of whom 98 had epithelioid MPM, six biphasic MPM, and four sarcomatoid MPM. Among epithelioid subtypes, 44 (44.9 %) were solid, 19 (19.4 %) tubulopapillary, 18 (18.4 %) acinar, six (6.1 %) adenomatoid, five (5.1 %) pleomorphic, four (4.1 %) trabecular, and two (2.0 %) micropapillary subtype. Interobserver reliability for histological diagnosis was found to be kappa = 0.72 (P < 0.001). Median overall survival for epithelioid MPM was 10.5 months with an interquartile range (IQR) of 5.8-28.0 months but significantly shorter for the pleomorphic subtype (3 [IQR 3.0 8.0] months; P = 0.034), but not significantly different from biphasic (6.5 [IQR 3.5-15.3] months) and sarcomatoid mesothelioma (4.0 [IQR 1.3-6.8] months; P = 0.270). We found strong reproducibility of MPM subtyping with good interobserver agreement. Furthermore, our results indicate that pleomorphic subtype to be a predictor of poor prognosis and support classifying it with sarcomatoid or biphasic MPM, as patients with the pleomorphic, biphasic, or sarcomatoid subtype show similarly poor overall survival. PMID- 25300230 TI - Successful nucleofection of rat adipose-derived stroma cells with Ambystoma mexicanum epidermal lipoxygenase (AmbLOXe). AB - INTRODUCTION: Adipose-derived stroma cells (ASCs) are attractive cells for cell based gene therapy but are generally difficult to transfect. Nucleofection has proven to be an efficient method for transfection of primary cells. Therefore, we used this technique to transfect ASCs with a vector encoding for Ambystoma mexicanum epidermal lipoxygenase (AmbLOXe) which is a promising bioactive enzyme in regenerative processes. Thereby, we thought to even further increase the large regenerative potential of the ASCs. METHODS: ASCs were isolated from the inguinal fat pad of Lewis rats and were subsequently transfected in passage 1 using Nucleofector(r) 2b and the hMSC Nucleofector kit. Transfection efficiency was determined measuring co-transfected green fluorescent protein (GFP) in a flow cytometer and gene expression in transfected cells was detected by reverse transcription polymerase chain reaction (RT-PCR). Moreover, cell migration was assessed using a scratch assay and results were tested for statistical significance with ANOVA followed by Bonferroni's post hoc test. RESULTS: High initial transfection rates were achieved with an average of 79.8 +/- 2.82% of GFP positive cells although longer cultivation periods reduced the number of positive cells to below 5% after four passages. Although successful production of AmbLOXe transcript could be proven the gene product had no measureable effect on cell migration. CONCLUSIONS: Our study demonstrates the feasibility of ASCs to serve as a vehicle of AmbLOXe transport for gene therapeutic purposes in regenerative medicine. One potential field of applications could be peripheral nerve injuries. PMID- 25300232 TI - [Abdominal paraganglioma. Endoscopic ultrasound as a new diagnostic tool]. PMID- 25300231 TI - Targeting the Small- and Intermediate-Conductance Ca-Activated Potassium Channels: The Drug-Binding Pocket at the Channel/Calmodulin Interface. AB - The small- and intermediate-conductance Ca(2+)-activated potassium (SK/IK) channels play important roles in the regulation of excitable cells in both the central nervous and cardiovascular systems. Evidence from animal models has implicated SK/IK channels in neurological conditions such as ataxia and alcohol use disorders. Further, genome-wide association studies have suggested that cardiovascular abnormalities such as arrhythmias and hypertension are associated with single nucleotide polymorphisms that occur within the genes encoding the SK/IK channels. The Ca(2+) sensitivity of the SK/IK channels stems from a constitutively bound Ca(2+)-binding protein: calmodulin. Small-molecule positive modulators of SK/IK channels have been developed over the past decade, and recent structural studies have revealed that the binding pocket of these positive modulators is located at the interface between the channel and calmodulin. SK/IK channel positive modulators can potentiate channel activity by enhancing the coupling between Ca(2+) sensing via calmodulin and mechanical opening of the channel. Here, we review binding pocket studies that have provided structural insight into the mechanism of action for SK/IK channel positive modulators. These studies lay the foundation for structure-based drug discovery efforts that can identify novel SK/IK channel positive modulators. PMID- 25300233 TI - Collective structural changes in vermiculite clay suspensions induced by cesium ions. AB - Following the Fukushima Daiichi nuclear disaster in 2011, Cs radioisotopes have been dispersed over a wide area. Most of the Cs has remained on the surface of the soil because Cs(+) is strongly adsorbed in the interlayer spaces of soil clays, particularly vermiculite. We have investigated the microscopic structure of an aqueous suspension of vermiculite clay over a wide length scale (1-1000 A) by small-angle X-ray scattering. We determined the effect of the adsorption behavior of Cs(+) on the structural changes in the clay. It was found that the abruption of the clay sheets was induced by the localization of Cs(+) at the interlayer. This work provides important information for predicting the environmental fate of radioactive Cs in polluted areas, and for developing methods to extract Cs from the soil and reduce radioactivity. PMID- 25300234 TI - Interface energy effect on the dispersion relation of nano-sized cylindrical piezoelectric/piezomagnetic composites. AB - Interface between the constituents plays an important role in the non-destructive detection of smart piezoelectric/piezomagnetic devices. The propagation of SH waves in nano-sized cylindrically multiferroic composites consisting of a piezoelectric layer and a piezomagnetic central cylinder is investigated, and the size-dependent dispersion relation with interface effect is derived. The general solutions of decoupled governing equation in different regions are expressed by using Bessel functions, and the unknown coefficients are determined by satisfying the boundary conditions at the inner interface with negligible thickness and the outer surface of the structure. Through the numerical examples of dispersion relation, it is found that the interface around the nano-cylinder may remarkably reduce the phase velocity, depending on the combination of the value of thickness ratio and the surface condition. The interface shows different effect on the first and second modes of dispersion relation. PMID- 25300235 TI - Re-evaluating the PCP challenge as a pre-clinical model of impaired cognitive flexibility in schizophrenia. AB - NMDA-R antagonists are a popular translational pharmacological challenge to induce cognitive deficits associated with schizophrenia. Amongst their many cognitive and non-cognitive effects is an ability to impair cognitive flexibility in general, and reversal learning in particular. Here, we test the hypothesis that the NMDA-R antagonist phencyclidine when given acutely selectively effects reversal learning by simultaneously measuring reversal learning and baseline responding, or acquisition and baseline responding, under identical conditions. Animals were trained to simultaneously perform two different visual discriminations in a touch-screen equipped operant box. Accordingly the reward contingencies associated with one pair could be altered, while the second pair acted as an experimental control. As such, the effect of a manipulation on reversal learning, stimuli acquisition, or baseline responding can be more accurately evaluated through the use of a double visual discrimination. A similar approach was also used to investigate the influence of sub-chronic phencyclidine administration on cognitive flexibility. Phencyclidine (1mg/kg) given before testing caused a slowing in acquisition and reversal learning, while having a minimal effect on secondary measures. Sub-chronic phencyclidine administration had no significant effect on any of the measures used within this study. While acute phencyclidine impairs reversal learning, it is clear from these results that other aspects of cognition (learning/relearning) are also impaired, potentially questioning the specificity of acute phencyclidine in conjunction with reversal learning paradigms as a model of impaired cognitive flexibility. PMID- 25300238 TI - An enantioselective approach to the preparation of chiral sulfones by Ir catalyzed asymmetric hydrogenation. AB - Several chiral sulfonyl compounds were prepared using the iridium catalyzed asymmetric hydrogenation reaction. Vinylic, allylic and homoallylic sulfone substitutions were investigated, and high enantioselectivity is maintained regardless of the location of the olefin with respect to the sulfone. Impressive stereoselectivity was obtained for dialkyl substitutions, which typically are challenging substrates in the hydrogenation. As expected, the more bulky Z substrates were hydrogenated slower than the corresponding E isomers, and in slightly lower enantioselectivity. PMID- 25300237 TI - Opioid prescribing by physicians with and without electronic health records. AB - BACKGROUND: Physicians in the U.S. are adopting electronic health records (EHRs) at an unprecedented rate. However, little is known about how EHR use relates to physicians' care decisions. Using nationally representative data, we estimated how using practice-based EHRs relates to opioid prescribing in primary care. METHODS: This study analyzed 33,090 visits to primary care physicians (PCPs) in the 2007-2010 National Ambulatory Medical Care Survey. We used logistic regression to compare opioid prescribing by PCPs with and without EHRs. RESULTS: Thirteen percent of all visits and 33 % of visits for chronic noncancer pain resulted in an opioid prescription. Compared to visits without EHRs, visits to physicians with EHRs had 1.38 times the odds of an opioid prescription (95 % CI, 1.22-1.56). Among visits for chronic noncancer pain, physicians with EHRs had significantly higher odds of an opioid prescription (adj. OR = 1.39; 95 % CI, 1.03-1.88). Chronic pain visits involving electronic clinical notes were also more likely to result in an opioid prescription compared to chronic pain visits without (adj. OR = 1.51; 95 % CI, 1.10-2.05). Chronic pain visits involving electronic test ordering were also more likely to result in an opioid prescription compared to chronic pain visits without (adj. OR = 1.31; 95 % CI, 1.01-1.71). CONCLUSIONS: We found higher levels of opioid prescribing among physicians with EHRs compared to those without. These results highlight the need to better understand how using EHR systems may influence physician prescribing behavior so that EHRs can be designed to reliably guide physicians toward high quality care. PMID- 25300239 TI - Interaction of age and foam types used in Clinical Test for Sensory Interaction and Balance (CTSIB). AB - Clinical Test for Sensory Interaction and Balance (CTSIB) is a simplified method for investigating the organization of multiple sensory inputs in postural control. The accuracy of the test is based partly on the foam types. Several types of foam are available, but the validity of these foams on CTSIB and the interaction of age and foam types have not been addressed. In this study, postural sway of young (21.6 +/- 3.3 years) and older (53.2 +/- 4.9 years) participants were assessed while standing on four types of foam: NeuroCom((r)), sponge, Ethylene Vinyl Acetate (EVA), and memory foams. Postural sway during stance on solid floor and foams with eyes open and eyes closed were quantified by root-mean-square (RMS) of center of body mass acceleration in the mediolateral (ML) and anteroposterior (AP) directions using the acceleration-based OPAL system. Physical properties of foams including density, Young's modulus, and indentation force deflection (IFD) were determined. Results demonstrated that RMS ML in older subjects was larger than younger subjects (p <= 0.001), especially when standing on the NeuroCom((r)) foam with eyes closed (p = 0.001). There was an interaction of age and foam types as larger differences in RMS-ML were observed between young and older subjects on the NeuroCom((r)) and EVA foams, but not the other foams. The sway characteristics were largest when standing on the NeuroCom((r)) foam which demonstrated high density and high compliance. Our findings suggested the importance of foam selection in CTSIB on accurate postural sway analysis and balance assessment. PMID- 25300236 TI - Cassava genome from a wild ancestor to cultivated varieties. AB - Cassava is a major tropical food crop in the Euphorbiaceae family that has high carbohydrate production potential and adaptability to diverse environments. Here we present the draft genome sequences of a wild ancestor and a domesticated variety of cassava and comparative analyses with a partial inbred line. We identify 1,584 and 1,678 gene models specific to the wild and domesticated varieties, respectively, and discover high heterozygosity and millions of single nucleotide variations. Our analyses reveal that genes involved in photosynthesis, starch accumulation and abiotic stresses have been positively selected, whereas those involved in cell wall biosynthesis and secondary metabolism, including cyanogenic glucoside formation, have been negatively selected in the cultivated varieties, reflecting the result of natural selection and domestication. Differences in microRNA genes and retrotransposon regulation could partly explain an increased carbon flux towards starch accumulation and reduced cyanogenic glucoside accumulation in domesticated cassava. These results may contribute to genetic improvement of cassava through better understanding of its biology. PMID- 25300240 TI - Physiologically corrected coupled motion during gait analysis using a model-based approach. AB - Gait analysis is used in daily clinics for patients' evaluation and follow-up. Stereophotogrammetric devices are the most used tool to perform these analyses. Although these devices are accurate results must be analyzed carefully due to relatively poor reproducibility. One of the major issues is related to skin displacement artifacts. Motion representation is recognized reliable for the main plane of motion displacement, but secondary motions, or combined, are less reliable because of the above artifacts. Model-based approach (MBA) combining accurate joint kinematics and motion data was previously developed based on a double-step registration method. This study presents an extensive validation of this MBA method by comparing results with a conventional motion representation model. Thirty five healthy subjects participated to this study. Gait motion data were obtained from a stereophotogrammetric system. Plug-in Gait model (PiG) and MBA were applied to raw data, results were then compared. Range-of-motion, were computed for pelvis, hip, knee and ankle joints. Differences between PiG and MBA were then computed. Paired-sample t-tests were used to compare both methods. Normalized root-mean square errors were also computed. Shapes of the curves were compared using coefficient of multiple correlations. The MBA and PiG approaches shows similar results for the main plane of motion displacement but statistically significative discrepancies appear for the combined motions. MBA appear to be usable in applications (such as musculoskeletal modeling) requesting better approximations of the joints-of-interest thanks to the integration of validated joint mechanisms. PMID- 25300241 TI - Walking with wider steps increases stance phase gluteus medius activity. AB - Increases in step width have been reported for several clinical populations, including older adults and stroke survivors. These populations often also exhibit decreased hip abductor strength, suggesting that walking with wider steps may be an adaptive response in order to reduce the mechanical demands on the hip abductors. The purpose of this study was to quantify the relationship between step width and gluteus medius (GM) activity during walking. Fourteen young, uninjured adults walked on a treadmill at 1.25 m/s for four step width conditions (Normal, Narrow, Medium, and Wide) while step width and stance phase GM electromyographic (EMG) activity were quantified. We also measured hip abduction torque and GM activity during maximum voluntary isometric contractions (MVICs) at three hip angles (neutral, abducted 10 degrees , and abducted 20 degrees ). During walking trials, GM activity was significantly (p < 0.0001) influenced by step width; compared to Normal walking, GM activity was 47% higher with Wide steps and 24% lower with Narrow steps. We also observed a weak positive correlation (r = 0.18 +/- 0.14) between step width and GM activity during Normal walking, as GM activity was higher with wider steps. These results cannot be attributed to changes in GM conformation under the recording electrode, as GM activity was not influenced by hip angle during MVICs. The increased GM activity with wider steps does not support the proposal that increasing step width would be a beneficial adaptation to weakened hip abductors. A likely alternative explanation is that increased step width is a response to decreased gait balance. PMID- 25300242 TI - Successful autologous fecal transplantation for chronic diversion colitis. PMID- 25300243 TI - Sudden unexpected death in epilepsy: addressing the challenges. AB - Epilepsy is associated with a higher rate of premature death than the general population, and the commonest cause of epilepsy mortality is sudden unexpected death in epilepsy (SUDEP). It is difficult to quantify because of the variable reporting of this cause of death. Death occurs due to autonomic deregulation of cardio-respiratory pathways as a result of seizures. Measures to reduce cardio respiratory dysfunction are discussed together with the importance of seizure control in preventing SUDEP. The role of seizure detection devices, antiepileptic drugs and the importance of providing information about SUDEP to people with epilepsy are highlighted. There is increasing interest in SUDEP and some current initiatives are discussed. PMID- 25300244 TI - Warfarin plus aspirin or aspirin alone for patients with giant coronary artery aneurysms secondary to Kawasaki disease? PMID- 25300245 TI - Brief psychoeducation for bipolar disorder: impact on quality of life in young adults in a 6-month follow-up of a randomized controlled trial. AB - There are scarce follow-up studies evaluating the role of psychoeducation in the treatment of bipolar disorder, especially in a young sample, with a recent diagnosis and that probably received a few previous interventions. This was a randomized clinical trial with young adults aged 18-29 years, who had been diagnosed with bipolar disorder through the Structured Clinical Interview for DSM (SCID). The evaluation of quality of life was carried out using the Medical Outcomes Survey 36-Item Short-Form Health Survey (MOS SF-36). All participants were randomized into two groups: combined intervention (psychoeducation plus medication) and treatment-as-usual (medication). The sample consisted of 61 patients divided in two groups (29 usual treatment; 32 combined intervention). The quality of life domains did not reveal statistically significant differences when comparing baseline, post-intervention and 6-month follow-up evaluations, which indicates that there is no difference between combined intervention and usual intervention regarding quality of life improvement. Both groups presented improvements in quality of life domains, except General Health and Bodily Pain, at post-intervention. Moreover, this improvement persisted at 6-month follow-up, except for the Role Physical Health domain, which remained reduced. Combined Psychoeducation plus pharmacological intervention is so effective in improving quality of life perception as it is pharmacological only intervention. PMID- 25300246 TI - The influence of stromal cells on the pigmentation of tissue-engineered dermo epidermal skin grafts. AB - It has been shown in vitro that melanocyte proliferation and function in palmoplantar skin is regulated by mesenchymal factors derived from fibroblasts. In this study, we investigated in vivo the influence of mesenchymal-epithelial interactions in human tissue-engineered skin substitutes reconstructed from palmar- and nonpalmoplantar-derived fibroblasts. Tissue-engineered dermo epidermal analogs based on collagen type I hydrogels were populated with either human palmar or nonpalmoplantar fibroblasts and seeded with human nonpalmoplantar derived melanocytes and keratinocytes. These skin substitutes were transplanted onto full-thickness skin wounds of immunoincompetent rats. Four weeks after transplantation the development of skin color was measured and grafts were excised and analyzed with regard to epidermal characteristics, in particular melanocyte number and function. Skin substitutes containing palmar-derived fibroblasts in comparison to nonpalmoplantar-derived fibroblasts showed (a) a significantly lighter pigmentation; (b) a reduced amount of epidermal melanin granules; and (c) a distinct melanosome expression. However, the number of melanocytes in the basal layer remained similar in both transplantation groups. These findings demonstrate that human palmar fibroblasts regulate the function of melanocytes in human pigmented dermo-epidermal skin substitutes after transplantation, whereas the number of melanocytes remains constant. This underscores the influence of site-specific stromal cells and their importance when constructing skin substitutes for clinical application. PMID- 25300247 TI - CSF and plasma amyloid-beta temporal profiles and relationships with neurological status and mortality after severe traumatic brain injury. AB - The role of amyloid-beta (Abeta) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-beta1-42 (Abeta42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF Abeta42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. Conversely, plasma Abeta42 levels were significantly increased in TBI with lower levels in patients who survived. A trend analysis showed that both CSF and plasma Abeta42 levels strongly correlated with mortality. A positive correlation between changes in CSF Abeta42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of Abeta42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury. PMID- 25300248 TI - Imprinting analysis of the mouse chromosome 7C region in DNMT1-null embryos. AB - The mouse chromosome 7C, orthologous to the human 15q11-q13 has an imprinted domain, where most of the genes are expressed only from the paternal allele. The imprinted domain contains paternally expressed genes, Snurf/Snrpn, Ndn, Magel2, Mkrn3, and Frat3, C/D-box small nucleolar RNAs (snoRNAs), and the maternally expressed gene, Ube3a. Imprinted expression in this large (approximately 3-4 Mb) domain is coordinated by a bipartite cis-acting imprinting center (IC), located upstream of the Snurf/Snrpn gene. The molecular mechanism how IC regulates gene expression of the whole domain remains partially understood. Here we analyzed the relationship between imprinted gene expression and DNA methylation in the mouse chromosome 7C using DNA methyltransferase 1 (DNMT1)-null mutant embryos carrying Dnmt1(ps) alleles, which show global loss of DNA methylation and embryonic lethality. In the DNMT1-null embryos at embryonic day 9.5, the paternally expressed genes were biallelically expressed. Bisulfite DNA methylation analysis revealed loss of methylation on the maternal allele in the promoter regions of the genes. These results demonstrate that DNMT1 is necessary for monoallelic expression of the imprinted genes in the chromosome 7C domain, suggesting that DNA methylation in the secondary differentially methylated regions (DMRs), which are acquired during development serves primarily to control the imprinted expression from the maternal allele in the mouse chromosome 7C. PMID- 25300249 TI - SAHA inhibits the transcription initiation of HPV18 E6/E7 genes in HeLa cervical cancer cells. AB - High risk human papillomavirus (HPV) is a well recognized causative agent of cervical cancer. Suberoylanilide hydroxamic acid (SAHA) is a potential anti cervical cancer drug; however, its effect on the expression of HPV E6 and E7 genes remains unclear. Here, we show that, in SAHA treated HeLa cells, HPV18 E6 and E7 mRNA and protein levels were reduced, HPV18 promoter activity was decreased, and the association of RNP II with HPV18 promoter was diminished, suggesting that SAHA inhibited the transcription initiation of HPV18 E6 and E7 genes. In SAHA-treated HeLa, although the level of lysine 9-acetylated histone H3 in the whole cell extracts increased obviously, its enrichment on HPV18 promoter was significantly reduced which is correlated with the down-regulation of HPV E6 and E7. PMID- 25300250 TI - Distinct evolutionary rate in the eye field transcription factors found by estimation of ancestral protein structure. AB - Eye-field transcription factors (EFTFs) are a set of genes that compose a regulatory network for eye development in animals, which are highly conserved among various animal phyla. To investigate the processes of conservation and diversification of the transcription factors for eye development, we examined the structural changes in the EFTF proteins by estimating the ancestral sequences with the available genome information. Among the different types of EFTFs, we selected otx2, tbx3, rx1, pax6, six3/6, lhx2 and nr2e1 because they are highly conserved in bilaterian animals. We searched the genome sequences of representative animal phyla for EFTF protein sequences. With deduced ancestral sequences and three-dimensional structures of EFTFs, we traced the evolutionary changes in amino acid residues and found that the DNA-binding domains were always more conserved than other regions, and that the other regions showed distinct evolutionary rates. The EFTF rx1, which resides at the pivotal part of the EFTF network, had a faster evolutionary rate than the others. These results indicated that the evolutionary rates of each protein in the EFTF network, which were expected to be consistent with each other to maintain the interactions in the network, were not constant among or within the factors, but rather, varied to a significant extent. PMID- 25300251 TI - Co-expression analysis reveals a group of genes potentially involved in regulation of plant response to iron-deficiency. AB - Iron (Fe) is an essential element for plant growth and development. Iron deficiency results in abnormal metabolisms from respiration to photosynthesis. Exploration of Fe-deficient responsive genes and their networks is critically important to understand molecular mechanisms leading to the plant adaptation to soil Fe-limitation. Co-expression genes are a cluster of genes that have a similar expression pattern to execute relatively biological functions at a stage of development or under a certain environmental condition. They may share a common regulatory mechanism. In this study, we investigated Fe-starved-related co expression genes from Arabidopsis. From the biological process GO annotation of TAIR (The Arabidopsis Information Resource), 180 iron-deficient responsive genes were detected. Using ATTED-II database, we generated six gene co-expression networks. Among these, two modules of PYE and IRT1 were successfully constructed. There are 30 co-expression genes that are incorporated in the two modules (12 in PYE-module and 18 in IRT1-module). Sixteen of the co-expression genes were well characterized. The remaining genes (14) are poorly or not functionally identified with iron stress. Validation of the 14 genes using real-time PCR showed differential expression under iron-deficiency. Most of the co-expression genes (23/30) could be validated in pye and fit mutant plants with iron-deficiency. We further identified iron-responsive cis-elements upstream of the co-expression genes and found that 22 out of 30 genes contain the iron-responsive motif IDE1. Furthermore, some auxin and ethylene-responsive elements were detected in the promoters of the co-expression genes. These results suggest that some of the genes can be also involved in iron stress response through the phytohormone responsive pathways. PMID- 25300252 TI - Identification of genes related to the phenotypic variations of a synthesized Paulownia (Paulownia tomentosa*Paulownia fortunei) autotetraploid. AB - Paulownia is a fast-growing deciduous tree native to China. It has great economic importance for the pulp and paper industries, as well as ecological prominence in forest ecosystems. Paulownia is of much interest to plant breeder keen to explore new plant varieties by selecting on the basis of phenotype. A newly synthesized autotetraploid Paulownia exhibited advanced characteristics, such as greater yield, and higher resistance than the diploid tree. However, tissue-specific transcriptome and genomic data in public databases are not sufficient to understand the molecular mechanisms associated with genome duplication. To evaluate the effects of genome duplication on the phenotypic variations in Paulownia tomentosa*Paulownia fortunei, the transcriptomes of the autotetraploid and diploid Paulownia were compared. Using Illumina sequencing technology, a total of 82,934 All-unigenes with a mean length of 1109 bp were assembled. The data revealed numerous differences in gene expression between the two transcriptomes, including 718 up-regulated and 667 down-regulated differentially expressed genes between the two Paulownia trees. An analysis of the pathway and gene annotations revealed that genes involved in nucleotide sugar metabolism in plant cell walls were down-regulated, and genes involved in the light signal pathway and the biosynthesis of structural polymers were up-regulated in autotetraploid Paulownia. The differentially expressed genes may contribute to the observed phenotypic variations between diploid and autotetraploid Paulownia. These results provide a significant resource for understanding the variations in Paulownia polyploidization and will benefit future breeding work. PMID- 25300253 TI - Ischemia postconditioning preventing lung ischemia-reperfusion injury. AB - OBJECTIVE: This study evaluates the inhibitory effect of IPO against ischemia reperfusion (I/R) induced lung injury in rats. METHODS: Anesthetized and mechanically ventilated adult Sprague-Dawley rats were randomly assigned to one of the following groups (n=12 each): the sham operated control group, the ischemia-reperfusion (IR) group (30min of left-lung ischemia and 24h of reperfusion), the IPO group (three successive cycles of 30-s reperfusion per 30-s occlusion before restoring full perfusion), and the dexamethasone plus IPO group (rats were injected with dexamethasone (3mg/kg.day(-1)) 10min prior to the experiment and the rest of the procedures were the same as the IPO group). Lung injury was assessed by wet-to-dry lung weight ratio and tissue apoptosis and biochemical changes. RESULTS: Lung ischemia-reperfusion increased lung MDA production, serum proinflammatory cytokine count, and MPO activity and reduced antioxidant enzyme activities (all p<0.05 I/R versus sham), accompanied with a compensatory increase in caspase-3, bax, Fas, FasL proteins and a decrease in Bcl 2 protein. Plasma levels of TNF-alpha, IL-6, and IL-1beta were increased in the I/R group (all p<0.05 versus sham). IPO attenuated or prevented all the above changes. Treatment with dexamethasone enhanced all the protective effects of postconditioning. CONCLUSION: Postconditioning obviously inhibits I/R induced lung injury by its antioxidant, anti-inflammatory and anti-apoptosis activities. PMID- 25300254 TI - Molecular characterization and transcriptional analysis of non-mammalian type Toll like receptor (TLR21) from rock bream (Oplegnathus fasciatus). AB - Toll-like receptors (TLRs) are a large family of pattern recognition receptors, which are involved in triggering host immune responses against various pathogens by detecting their evolutionarily conserved pathogen associated molecular patterns (PAMPs). TLR21 is a non-mammalian type TLR, which recognizes unmethylated CpG DNA, and is considered as a functional homolog of mammalian TLR9. In this study, we attempted to identify and characterize a novel TLR21 counterpart from rock bream (Oplegnathus fasciatus) designated as RbTLR21, at molecular level. The complete coding sequence of RbTLR21 was 2919bp in length, which encodes a polypeptide of 973 amino acids with a predicted molecular mass of 112kDa and a theoretical isoelectric point of 8.6. The structure of the deduced RbTLR21 protein is similar to that of the members of typical TLR family, and includes the ectodomain, which consists of 16 leucine rich repeats (LRRs), a transmembrane domain, and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. According to the pairwise sequence analysis data, RbTLR21 was homologous to that of the orange-spotted grouper (Epinephelus coioides) with 76.9% amino acid identity. Furthermore, our phylogenetic analysis revealed that RbTLR21 is closely related to E. coioides TLR21. The RbTLR21 was ubiquitously expressed in all the tissues tested, but the highest expression was found in spleen. Additionally, upon stimulation with Streptococcus iniae, rock bream iridovirus (RBIV), and Edwardsiella tarda, RbTLR21 mRNA was significantly up-regulated in spleen tissues. Collectively, our findings suggest that RbTLR21 is indeed an ortholog of the TLR21 family and may be important in mounting host immune responses against pathogenic infections. PMID- 25300255 TI - Towards an understanding of semaphorin signalling in the spinal cord. AB - Semaphorins are a large family of proteins that are classically associated with axon guidance. These proteins and their interacting partners, the neuropilins and plexins are now known to be key mediators in a variety of processes throughout the nervous system ranging from synaptic refinement to the correct positioning of neuronal and glial cell bodies. Recently, much attention has been given to the roles semaphorins play in other body tissues including the immune and vascular systems. This review wishes to draw attention back to the nervous system, specifically focusing on the role of semaphorins in the development of the spinal cord and their proposed roles in the adult. In addition, their functions in spinal cord injury at the glial scar are also discussed. PMID- 25300256 TI - CCR5 small interfering RNA ameliorated joint inflammation in rats with adjuvant induced arthritis. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease. C-C chemokine receptor type 5 (CCR5) is found in inflamed synovium of RA patients and is necessary for formation of RA. We aimed to check whether delivery of CCR5 specific small interfering RNA (siRNA) via electroporation suppresses local inflammation in arthritis rats. Vectors encoding siRNA that target CCR5 or negative control siRNA were constructed for gene silencing and the silencing effects of suppressing CCR5 expression in synovium examined by western blot. The vector with strongest effect was delivered into the knee joint of adjuvant induced arthritis (AIA) rats by the in vivo electroporation method 7, 10, 13, and 16 days after immunization with Complete Freund's adjuvant. During an observation of 28 days, behavior, paw swelling, arthritis and histopathologic scoring were estimated. The expression level of CCR5 in synovium was evaluated by western blot and real-time PCR. Anti-CCR5 D1 siRNA was effectively inhibited CCR5 expression in vitro. Moreover, delivery of the siRNA into inflammatory joint also suppressed the expression of CCR5 in vivo and markedly suppressed paw swelling and inflammation. Local electroporation of anti-CCR5 siRNA into the left inflamed joints could achieve the silencing of CCR5 gene and alleviate local inflammation just in the knee joint injected with siRNA other than the opposite joint. Inhibition of CCR5 expression may provide a potential for treatment of RA. PMID- 25300258 TI - Preeclampsia and maternal cardiovascular disease: consequence or predisposition? AB - Formerly preeclamptic women stand a higher chance of developing cardiovascular disease (CVD) later in life and may experience a shortened life span. This review updates the pathophysiology and definition of this complex disease and highlights the protective role of pregnancy by considering the relationship between pregnancy interval and likelihood of disease recurrence. The evidence for persistent maternal cardiovascular impairment following preeclampsia (PE) is considered, e.g. postpartum changes in CVD occurrence, blood pressure elevation and changes in the renin-angiotensin-aldosterone system). Since maternal endothelial dysfunction is a hallmark of PE, we summarize the evidence for reduced flow-mediated dilation in women with previous PE, and consider the utility and shortcomings of this clinical measure. In addition to viewing postpartum changes as a consequence of this disease, we consider the alternative view that PE might be the manifestation of a maternal phenotype that already has some predisposition to or is in the earlier stages of CVD; in this case, some of the postpartum residual deficits (or their antecedents) may have already been present prior to pregnancy. Finally, we consider the use of novel biomarkers for predicting or detecting PE prior to the appearance of clinical symptoms. PMID- 25300259 TI - The Power of Programming and the EarlyNutrition project: opportunities for health promotion by nutrition during the first thousand days of life and beyond. AB - At The Power of Programming 2014 Conference, researchers from multiple disciplines presented and discussed the effects of early nutrition and other environmental cues during the first thousand days of life and beyond on the lifelong risk of noncommunicable diseases. This paper aims to summarize the concepts and some of the first achievements of the EarlyNutrition research project that initiated the conference. The EarlyNutrition consortium is a multinational, multidisciplinary research collaboration of researchers from Europe, the USA, and Australia. A focus is placed on exploration of the developmental origins of obesity, adiposity, and related health outcomes. Here we report on the first findings of experimental approaches, cohort studies, randomized clinical trials, and systematic reviews of current information, as well as position papers, which have all been developed with the involvement of project partners. We conclude that the EarlyNutrition project has successfully established itself during the first 2 project years as a very strong platform for collaborative research on early programming effects. The first results, available already at this early stage of the project, point to great opportunities for health prevention strategies via the implementation of dietary and lifestyle modifications, with large effect sizes. Further results are expected which should support improved recommendations and related policies for optimized nutrition and lifestyle choices before and during pregnancy, in infancy, and in early childhood. PMID- 25300260 TI - Dietary and lifestyle advice for pregnant women who are overweight or obese: the LIMIT randomized trial. AB - Overweight and obesity during pregnancy are common and are associated with an increased risk of adverse health outcomes for both the mother and the infant. However, robust evidence about the effect of antenatal dietary and lifestyle interventions on health outcomes is lacking. We conducted a multicenter, randomized trial, recruiting 2,212 women (from 3 public maternity hospitals across South Australia) with a singleton pregnancy between 10+0 and 20+0 weeks' gestation and a BMI >=25. The women were randomized to lifestyle advice (n = 1,108) or standard care (n = 1,104). Women randomized to lifestyle advice participated in a comprehensive dietary and lifestyle intervention over the course of their pregnancy (delivered by research staff), while women randomized to standard care received pregnancy care according to local guidelines, which did not include such information. Provision of the lifestyle intervention was associated with a significant 18% relative risk reduction in the chance of infants being born with a birth weight above 4 kg. No other significant differences were identified in maternal pregnancy and birth outcomes between the two treatment groups. Observational studies highlight the association between a high infant birth weight and the subsequent risk of childhood and adulthood obesity. Antenatal interventions that are effective in reducing high infant birth weights therefore represent a significant strategy to tackle obesity from a population health perspective, while ongoing interrogation of the biospecimens and measurements, including ongoing childhood follow-up, will provide a unique opportunity to evaluate the mechanistic pathways of maternal-to-infant/childhood obesity. PMID- 25300261 TI - Epigenetic change as the major mediator of fetal programming in humans: Are we there yet? AB - The developmental origins of health and disease (DOHaD) hypothesis predicts that environmental exposures experienced early in life have the potential to modify the risk associated with later-onset disease. The DOHaD hypothesis is supported by a large number of direct animal studies and a smaller number of compelling observational studies in humans, but the mechanism(s) underlying the 'programming' effects of DOHaD remain largely unclear. Given the inherent property of environmental sensitivity, the demonstrated role in gene regulation, and the capacity for stable maintenance over time once established, epigenetic variation has rapidly emerged as a candidate mediator of such effects. However, little direct evidence exists in humans, primarily due to the inherent problems associated with unraveling the relative contributions of genetic and environmental influences to phenotypic outcomes. Robust evidence is required in several domains to establish epigenetic variation in the causal pathway to DoHAD associated disease. Firstly, interindividual epigenetic variability in response to specific early-life environmental exposures needs to be demonstrated. Further, compelling data linking specific epigenetic variants to specific disease(s) is needed. Epigenetic variation should be apparent in a tissue relevant to the disease of interest prior to phenotypic onset in order to avoid confounding and the potential for reverse causation. Finally, the functional relevance of specific epigenetic change must be demonstrated. Compelling evidence is mounting in each of these domains but remains somewhat fragmented, providing small pieces of the overall complex puzzle. It is likely that only large longitudinal life course studies commencing prior to birth, with extensive environmental exposure data and biospecimens, can provide direct evidence in support of a role of epigenetic processes as drivers of the DOHaD in humans. PMID- 25300262 TI - Ethnic disparities in general and abdominal adiposity at school age: a multiethnic population-based cohort study in the Netherlands. AB - BACKGROUND/AIMS: Ethnic differences in obesity prevalence have been reported. We examined ethnic differences in general and abdominal fat distribution in school age children and the influence of parental prepregnancy, pregnancy, and childhood factors on these differences. METHODS: We performed a multiethnic population based prospective cohort study among 5,244 children with information about prepregnancy factors, pregnancy, and childhood factors. At the age of 6 years, the BMI, total fat mass, android/gynoid fat mass ratio, and preperitoneal fat mass were assessed via dual-energy X-ray absorptiometry and abdominal ultrasound. RESULTS: The overweight and obesity prevalences among Dutch children were 10.0 and 2.1%, respectively. Higher prevalences were observed among Cape Verdean (21.0 and 10.3%), Dutch Antillean (18.4 and 13.8%), Moroccan (20.6 and 7.7%), Surinamese-Creole (13.4 and 7.7%), Surinamese-Hindustani (12.3 and 6.2%), and Turkish (23.8 and 12.0%) children. In the models adjusted for age and sex only, Moroccan, Surinamese-Hindustani, and Turkish children had a higher total fat mass than Dutch children, whereas Surinamese-Creole children had a lower total fat mass. Compared to Dutch children, the android/gynoid fat mass ratio was higher in Moroccan, Surinamese-Hindustani, and Turkish children, whereas the preperitoneal fat mass was higher among Dutch Antillean, Moroccan, Surinamese-Hindustani, and Turkish children (all p < 0.05). Prepregnancy factors explained up to 73% of these differences. In addition to prepregnancy factors, pregnancy factors explained up to 34% of the differences. Childhood factors did not significantly explain these associations. CONCLUSIONS: All ethnic minority groups had higher risks of overweight and obesity than Dutch children. Moroccan, Surinamese Hindustani, and Turkish children also had an adverse body fat profile. Prepregnancy and pregnancy might be critical periods for preventive strategies focused on the reduction of ethnic disparities in childhood adiposity. PMID- 25300264 TI - Assessing the public health impact of developmental origins of health and disease (DOHaD) nutrition interventions. AB - Investing in the maternal and early-infancy periods (the first 1,000 days, i.e. from -1 to +2 years) is presently acknowledged as a key priority to ensure good nutrition and prevent all forms of malnutrition. The concept is to invest during this period to maximize the human development potential, and the early-life agenda includes prevention of stunting and promotion of optimal brain development as well as ensuring the quality of life of those who survive. Thus, public health assessments of specific interventions need to go beyond the traditional indices of prevention of death and disease. We need to consider including a full range of outcomes such as disability-adjusted life years (DALY) and quality-adjusted life years (QALY) and not only the number of deaths. The long-term outcomes of maternal and infant interventions to prevent obesity and related noncommunicable diseases remain uncertain in terms of their biological impact even under ideal conditions (efficacy); we need interventions with proven effectiveness under real world conditions (effectiveness). Conversely, interventions to prevent undernutrition have already been proven effective and are considered cost effective based on rigorous economic analyses. Continuous evaluation of interventions implemented using the developmental origins of health and disease (DOHaD) model needs to be undertaken, as this will allow progressive improvement and thus maximize the potential impact on the health and well-being of populations. We need to consider the population-attributable risk of obesity and chronic disease and conduct an economic evaluation of the lifelong impact of chronic diseases not only in terms of lives lost but also in relation to lost DALY and QALY. This should help to prioritize preventive actions in line with patterns of disease and disability considering the existing resources and demands. PMID- 25300263 TI - Insights from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort study. AB - BACKGROUND: The dramatic emergence of noncommunicable diseases (NCD) in Asia, albeit with ethnic variation, has coincided with the rapid socioeconomic and nutritional transition taking place in the region, with the prevalence of diabetes rising 5-fold in Singapore in less than 4 decades. The Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study recruited 1,247 expectant mothers of Chinese, Malay, or Indian ethnicity in their first trimester, with detailed longitudinal tracking--through the antenatal period, birth, and the child's first 4 years of life--to examine the potential roles of fetal, developmental, and epigenetic factors in early pathways to metabolic and neurodevelopmental outcomes. KEY MESSAGES: A number of findings with a translational and clinical focus have already emerged. In the mothers, we found that changes and differences in food consumption varied across ethnic groups, with persistence of traditional beliefs, during pregnancy and the postpartum period. During pregnancy, higher maternal glucose levels, even in the absence of gestational diabetes mellitus, had graded relations with infant adiposity. Relations between maternal emotional health and birth outcomes and neurodevelopment have been identified. Genotype (25%) and in particular gene * environment interactions (75%) shape interindividual variations in the DNA methylome at birth. The complex effects of fixed genetic variations and different in utero environments can influence the epigenetic status at birth and the later life phenotype. CONCLUSIONS: The richness of the clinical data in 3 ethnicities, the extent of the biospecimen collection, and the extensive infancy and preschool follow-up have allowed us to study the biological pathways that link fetal development to health outcomes. In the coming years, more sophisticated analyses of epigenotype-phenotype relationships will become possible as the children grow and develop. Our studies will lead to the development of clinical and population based interventions to reduce the burden of NCD. PMID- 25300265 TI - Paternal obesity, interventions, and mechanistic pathways to impaired health in offspring. AB - BACKGROUND: The global rates of male overweight/obesity are rising, approaching 70% of the total adult population in Western nations. Overweight/obesity increases the risk of chronic diseases; however, there is increasing awareness that male obesity negatively impacts fertility, subsequent pregnancy, and the offspring health burden. Developmental programming is well defined in mothers; however, it is becoming increasingly evident that developmental programming can be paternally initiated and mediated through paternal obesity. KEY MESSAGES: Both human and rodent models have established that paternal obesity impairs sex hormones, basic sperm function, and molecular composition. This results in perturbed embryo development and health and an increased subsequent offspring disease burden in both sexes. The reversibility of obesity-induced parental programming has only recently received attention. Promising results in animal models utilizing diet and exercise interventions have shown improvements in sperm function and molecular composition, resulting in restorations of both embryo and fetal health and subsequent male offspring fertility. The direct mode for paternal inheritance is likely mediated via spermatozoa. We propose two main theories for the origin of male obesity-induced paternal programming: (1) accumulation of sperm DNA damage resulting in de novo mutations in the embryo and (2) changes in sperm epigenetic marks (microRNA, methylation, or acetylation) altering the access, transcription, and translation of paternally derived genes during early embryogenesis. CONCLUSIONS: Paternal overweight/obesity induces paternal programming of offspring phenotypes likely mediated through genetic and epigenetic changes in spermatozoa. These programmed changes to offspring health appear to be partially restored via diet/exercise interventions in obese fathers preconception, which have been shown to improve aspects of sperm DNA integrity. However, the majority of data surrounding paternal obesity and offspring phenotypes have come from rodent models; therefore, we contend that it will be increasingly important to study population-based data to determine the likely mode of inheritance in humans. PMID- 25300266 TI - Association between physical activity in obese pregnant women and pregnancy outcomes: the UPBEAT pilot study. AB - BACKGROUND: Obesity in pregnancy is associated with fetal macrosomia, a raised neonatal fat mass and an increased risk of obesity and poor metabolic health in childhood which persists into adulthood. The offspring of obese women are more likely to be obese than the offspring of lean women when they become pregnant themselves, perpetuating a cycle of obesity and its associated negative metabolic consequences. Increasing physical activity during pregnancy could improve insulin sensitivity and reduce the risk of maternal and offspring adverse outcomes. The UK Pregnancy Better Eating and Activity Trial (UPBEAT) is a trial of a complex intervention designed to improve pregnancy outcomes through dietary changes and physical activity. Data from the pilot trial of 183 women were available for analysis. The relationship between the time spent at different physical activity levels and maternal and infant pregnancy outcomes was examined. KEY MESSAGES: Strong evidence exists that physical activity improves insulin sensitivity in non pregnant populations, and lifestyle interventions of proven effectiveness in non pregnant populations have been developed. Women who are active in pregnancy demonstrate better glucose control and favourable pregnancy outcomes. There is a lack of effective interventions to support obese pregnant women to be physically active. CONCLUSIONS: No difference was detected in objectively measured physical activity between women randomised to the intervention and control arms of the UPBEAT pilot trial. Light-intensity physical activity was lower in early pregnancy in women who delivered macrosomic infants. Maternal sedentary time at 35-36 weeks' gestation was positively associated and moderate-intensity physical activity was inversely associated with neonatal abdominal circumference. Maternal physical activity is associated with infant birth weight and abdominal circumference and is an appropriate target for intervention to improve infant outcomes. The challenge remains to develop an effective intervention to support obese pregnant women to be physically active. PMID- 25300267 TI - Placental fatty acid transfer: a key factor in fetal growth. AB - The functionality of the placenta may affect neonatal adiposity and fetal levels of key nutrients such as long-chain polyunsaturated fatty acids. Fetal macrosomia and its complications may occur even in adequately controlled gestational diabetic (GDM) mothers, suggesting that maternal glycemia is not the only determinant of fetal glycemic status and wellbeing. We studied in vivo the placental transfer of fatty acids (FA) labeled with stable isotopes administered to 11 control and 9 GDM pregnant women (6 treated with insulin). Subjects received orally 13C-palmitic, 13C-oleic, and 13C-linoleic acids and 13C docosahexaenoic acid (13C-DHA) 12 h before an elective caesarean section. FA were quantified by gas chromatography and 13C enrichments by gas chromatography isotope ratio mass spectrometry. The 13C-FA concentration was higher in total lipids of maternal plasma in GDM patients versus controls, except for 13C-DHA. Moreover, 13C-DHA showed a lower placenta/maternal plasma ratio in GDM patients versus controls and a significantly lower cord/maternal plasma ratio. Other FA ratios studied were not different between GDM and controls. A disturbed 13C-DHA placental uptake occurred in GDM patients treated with diet or insulin, while the latter also had lower 13C-DHA levels in the venous cord. The tracer study pointed towards an impaired placental DHA uptake as a critical step, while the transfer of other 13C-FA was less affected. Patients with GDM treated with insulin could also have a greater fetal fat storage, which may have contributed to the reduced 13C-DHA in the venous cord observed. The DHA transfer to the fetus was reduced in GDM pregnancies compared to controls. This might have an influence on fetal neurodevelopment and long-term consequences for the child. PMID- 25300268 TI - Vitamin D measured in maternal serum and offspring neurodevelopmental outcomes: a prospective study with long-term follow-up. AB - BACKGROUND: Vitamin D is obtained from dietary sources and synthesized in the skin during exposure to ultraviolet B radiation in sunlight. During pregnancy, vitamin D is transported from mother to fetus through the placenta in the form of 25-hydroxyvitamin D [25(OH)D]. There is evidence that vitamin D influences neuronal differentiation, endocrine functions, and fetal brain growth. Animal studies indicate alterations in the offspring brain as a consequence of vitamin D deficiency during pregnancy. In humans, maternal vitamin D insufficiency has been linked to impaired child language development. Using data from a prebirth cohort with up to 22 years of follow-up, we examined the association of vitamin D status with proxies of offspring neurodevelopmental outcomes. During 1988-1989, pregnant women were recruited for the DaFO88 cohort (n = 965) in Aarhus, Denmark. Maternal concentrations of 25(OH)D were quantified in serum from week 30 of gestation via the LC-MS/MS method (n = 850). Offspring were followed up through national registries until the age of 22 years. We evaluated the association of the maternal concentration of 25(OH)D with offspring neurodevelopmental outcomes defined as first admission diagnosis or prescription of medication for (1) ADHD, (2) depression, and (3) scholastic achievement based on the mean grade on standardized written examinations in the 9th grade (final exams after 10 years of compulsory school in Denmark). KEY MESSAGES: Maternal concentrations of 25(OH)D were higher compared to current levels (median 76 nmol/l; 5th to 95th percentiles 23-152). There was a direct association between maternal vitamin D status and offspring depression (p(trend) = 0.01); for ADHD there was no association. Scholastic achievement was slightly higher for offspring of mothers with a vitamin D status in the range of >50-125 nmol/l, but this nonlinear association was not statistically significant. CONCLUSIONS: Our analyses based on biomarker measurement of 25(OH)D from a cohort of 850 pregnant women combined with long term follow-up showed no support for a beneficial fetal programming effect of vitamin D status with regard to behavioral and affective disorders and scholastic achievement. PMID- 25300269 TI - Early infant feeding and adiposity risk: from infancy to adulthood. AB - INTRODUCTION: Systematic reviews suggest that a longer duration of breast-feeding is associated with a reduction in the risk of later overweight and obesity. Most studies examining breast-feeding in relation to adiposity have not used longitudinal analysis. In our study, we aimed to examine early infant feeding and adiposity risk in a longitudinal cohort from birth to young adulthood using new as well as published data. METHODS: Data from the Western Australian Pregnancy Cohort (Raine) Study in Perth, W.A., Australia, were used to examine associations between breast-feeding and measures of adiposity at 1, 2, 3, 6, 8, 10, 14, 17, and 20 years. RESULTS: Breast-feeding was measured in a number of ways. Longer breast-feeding (in months) was associated with reductions in weight z-scores between birth and 1 year (beta = -0.027; p < 0.001) in the adjusted analysis. At 3 years, breast-feeding for <4 months increased the odds of infants experiencing early rapid growth (OR 2.05; 95% CI 1.43-2.94; p < 0.001). From 1 to 8 years, children breast-fed for <=4 months compared to >=12 months had a significantly greater probability of exceeding the 95th percentile of weight. The age at which breast-feeding was stopped and a milk other than breast milk was introduced (introduction of formula milk) played a significant role in the trajectory of the BMI from birth to 14 years; the 4-month cutoff point was consistently associated with a higher BMI trajectory. Introduction of a milk other than breast milk before 6 months compared to at 6 months or later was a risk factor for being overweight or obese at 20 years of age (OR 1.47; 95% CI 1.12-1.93; p = 0.005). DISCUSSION: Breast-feeding until 6 months of age and beyond should be encouraged and is recommended for protection against increased adiposity in childhood, adolescence, and young adulthood. Adverse long-term effects of early growth acceleration are fundamental in later overweight and obesity. Formula feeding stimulates a higher postnatal growth velocity, whereas breast-feeding promotes slower growth and a reduced likelihood of overweight and obesity. Biological mechanisms underlying the protective effect of breast-feeding against obesity are based on the unique composition and metabolic and physiological responses to human milk. PMID- 25300270 TI - Excessive weight gain during full breast-feeding. AB - BACKGROUND: Breast-feeding is considered to offer optimal nutrition for healthy infant growth and development. Observational studies have linked breast-feeding to reduced obesity. CASE OBSERVATION: We observed an infant who was born macrosomic (4.56 kg) and showed excessive weight gain markedly exceeding the 97th percentile of weight during full breast-feeding. At the age of 4 months, the weight was greater than 11 kg. Clinical evaluation did not reveal any underlying pathology. After the introduction of complementary feeding and hence reduction of the breast milk intake, the excessive weight gain was attenuated and the slope of the percentile curve paralleled upper percentiles. Since this pattern suggested full breast-feeding as the driver of excessive weight gain, we analyzed the human milk composition at the infant age of 1 year and compared the results with published data on composition at this stage of lactation. RESULTS: The milk contents of lactose, fat, fatty acids, polar lipids, carnitine species, and insulin were similar to the reference data. The adiponectin content was increased. The most remarkable alteration was a high milk protein content (mean 1.25 g/dl, reference 0.8 g/dl). CONCLUSIONS: A very high protein supply in infancy has been previously shown to increase plasma concentrations of the growth factors insulin and IGF-1, weight gain, and later obesity. We speculate that interindividual variations in human milk adiponectin and protein contents may contribute to modulation of the growth of fully breast-fed infants and in this case may have contributed to excessive weight gain during full breast-feeding. This hypothesis merits being tested in future cohort studies. PMID- 25300271 TI - Energetic efficiency of infant formulae: a review. AB - Breast-fed and formula-fed infants differ in terms of nutrient intake, growth, and metabolic and endocrine responses. The energetic efficiency, i.e. the weight or length gain per 100 kcal of energy intake, of breast-fed infants is about 11% higher than the energetic efficiency of formula-fed infants. Only limited data is available on the influence of formula composition on the energetic efficiency of infant formulae. We conducted a review of controlled trials to identify the impact of the macronutrient composition of infant formulae on energetic efficiency. An electronic literature search was conducted in February 2014. Intervention trials that investigated the effect of an infant formula with a modified macronutrient composition and reported the weight, length, and nutritional intake of apparently healthy, term, fully formula-fed infants with a normal weight were included. Thirteen trials met the inclusion criteria. The results showed no effect of the total content of energy, carbohydrate, protein, or fat on energetic efficiency. In contrast, small increasing effects of higher glycemic carbohydrates on energetic efficiency were identified. Improved fat absorption via the use of palmitic acid at the sn-2 ester position of triacylglycerol increased the energetic efficiency by 11%. The quality of formula protein, specifically an increased whey-to-casein ratio, an increased alpha lactalbumin content, or a higher tryptophan content increased the energetic efficiency by about 13%. We conclude that fat absorption and protein quality have the potential to modulate energetic efficiency and may contribute to the observed differences in growth and metabolism between breast-fed and formula-fed infants. PMID- 25300272 TI - Nutritional challenges and opportunities during the weaning period and in young childhood. AB - The early years of life are a period of very rapid growth and development. In this critical phase, food preferences are formed which carry over into childhood and beyond and foundations are laid for a healthy adult life. Excess energy, imbalances in macronutrient quality, and nutritional deficiencies may form inappropriate nutritional signals, leading to metabolic disturbances and affecting the obesity risk. For instance, the intake of protein and sugar sweetened beverages in young children has been associated with an increased risk of overweight and obesity. In reality, scientific reports have shown that the dietary intakes of vegetables, alpha-linolenic acid, docosahexaenoic acid, iron, vitamin D, and iodine are low and the intakes of protein, saturated fatty acids, and added sugar are high in young children living in Europe. A focus on improving feeding habits and approaches to support more balanced nutritional intakes early in life may have significant public health benefits. PMID- 25300273 TI - Rapid growth and childhood obesity are strongly associated with lysoPC(14:0). AB - BACKGROUND: Despite the growing interest in the early-origins-of-later-disease hypothesis, little is known about the metabolic underpinnings linking infant weight gain and childhood obesity. OBJECTIVE: To discover biomarkers reflective of weight change in the first 6 months and overweight/obesity at age 6 years via a targeted metabolomics approach. DESIGN: This analysis comprised 726 infants from a European multicenter randomized trial (Childhood Obesity Programme, CHOP) for whom plasma blood samples at age 6 months and anthropometric data up to the age of 6 years were available. 'Rapid growth' was defined as a positive difference in weight within the first 6 months of life standardized to WHO growth standards. Weight change was regressed on each of 168 metabolites (acylcarnitines, lysophosphatidylcholines, sphingomyelins, and amino acids). Metabolites significant after Bonferroni's correction were tested as predictors of later overweight/obesity. RESULTS: Among the overall 19 significant metabolites, 4 were associated with rapid growth and 15 were associated with a less-than-ideal weight change. After adjusting for feeding group, only the lysophosphatidylcholine LPCaC14:0 remained significantly associated with rapid weight gain (beta = 0.18). Only LPCaC14:0 at age 6 months was predictive of overweight/obesity at age 6 years (OR 1.33; 95% CI 1.04-1.69). CONCLUSION: LPCa14:0 is strongly related to rapid growth in infancy and childhood overweight/obesity. This suggests that LPCaC14:0 levels may represent a metabolically programmed effect of infant weight gain on the later obesity risk. However, these results require confirmation by independent cohorts. PMID- 25300275 TI - Metabolomic biomarkers for obesity in humans: a short review. AB - BACKGROUND: The prevalence and incidence of obesity have become a major public health problem during the last decades, but the underlying biochemical and metabolic processes are not fully understood. Metabolomics, the science of small molecules of the metabolism, is helping to unravel these mechanisms via the identification of markers related to obesity. These biomarkers are used to prevent diseases in later life or for the early diagnosis of diseases. This review focuses on articles dealing with biomarkers for obesity. KEY MESSAGES: Branched-chain amino acids (BCAA), nonesterified fatty acids, organic acids, acylcarnitines, and phospholipids were identified as potential biomarkers for obesity. This indicates a relation between elevated BCAA, and other amino acids, and the obese state. Furthermore, deregulation of beta-oxidation is associated with the development of obesity. The results have several limitations, including the differing ages of the subjects in the studies, the fact that all of the studies had a case-control design and therefore no causal explanatory power, and that most looked for similar metabolites and reported almost equal results. CONCLUSION: The strength of this review is that it gives a comprehensive overview of the current status of the knowledge on metabolomics biomarkers for obesity, but further research is needed because the methods used in the studies to date are very homogenous, e.g. most used a targeted approach and therefore analyzed almost the same group of metabolites. Moreover, prospective studies are lacking since all of the studies are either case-control or cross-sectional studies. PMID- 25300274 TI - Reduced bone mass in 7-year-old children with asymptomatic idiopathic hypercalciuria. AB - BACKGROUND: Idiopathic hypercalciuria (IHC), i.e. an elevated urinary calcium excretion without concomitant hypercalcemia, is a common disorder in children and can have a range of urinary clinical presentations and decreased bone mineral density (BMD). AIM: To assess the effect of IHC on bone mineral content in children without urological symptoms. METHODS: Calcium excretion, BMD (by dual energy X-ray absorptiometry), and anthropometry were assessed in 175 seven-year old children who were classified as IHC or controls. Calcium intake and physical activity were measured as confounding factors. RESULTS: The prevalence of IHC was 17.7%. Both groups (controls and IHC) showed similar baseline characteristics in terms of their anthropometry, gender distribution, and protein and calcium dietary intakes as well as physical activity scores. Urinary calciuria was independent of the calcium dietary intake and anthropometry. BMD correlated with anthropometry and physical activity but not with calcium dietary intake. IHC children had lower whole-body BMD z-scores compared to controls. The role of IHC in reducing the whole-body BMD z-score was still significant even when anthropometry, physical activity, and calcium intake were included as confounders in multivariate analyses. CONCLUSIONS: The prevalence of IHC in this population of 7-year-old children was about 17%. IHC diagnosis was associated with lower BMD z-scores and osteopenia in 22% of them. PMID- 25300276 TI - Clinical practice guidelines: based on eminence or evidence? AB - BACKGROUND: Too often, clinical practice guidelines, or similar documents, are of poor quality or are eminence based. Consequently, health care decisions might be based on biased or erroneous information. Here, issues related to standards for clinical practice guidelines that ensure the inclusion of objective, transparent, and scientifically valid information will be discussed. KEY MESSAGES: To ensure the quality of guidelines, standards for the development of evidence-based clinical practice guidelines have been in development. While differences among them exist, overall, these documents emphasize the need for the establishment of transparency, management of conflicts of interest, use of a multidisciplinary development group, utilization of a systematic literature review, use of grading systems to rate the strength of evidence recommendations, articulation of recommendations, performance of an external review, and regular updating. CONCLUSIONS: No clinical practice guidelines are perfect. They vary significantly in quality and, therefore, in the trustworthiness of the yielded recommendations. Hence, it is important that one can distinguish evidence-based clinical practice guidelines from guidelines that are not based on evidence. Standards for the development of evidence-based guidelines have been developed. If strictly adhered to, this should lead to more valid and trustworthy guidelines. PMID- 25300277 TI - Influences on adherence to diet and physical activity recommendations in women and children: insights from six European studies. AB - BACKGROUND: Across Europe, poor health behaviours are associated with increased risks of non-communicable diseases. There is particular concern about young women, children and families, not least as health behaviours operating before and during pregnancy and in early postnatal life may have profound long-term consequences for children's health. Using findings drawn from 7 European countries, we aimed to identify barriers to the implementation and uptake of dietary and physical activity recommendations, and to consider how best to achieve changes in mothers' behaviours and thereby improve the adoption of health recommendations. Six studies across the 7 countries were used for this narrative synthesis of findings. KEY MESSAGES: A woman's education has a strong influence on her own and her children's health behaviours. Women's diets vary across ethnic groups and according to number of children, but psychological factors, such as self-efficacy and sense of control, which may be amenable to modification, are powerful, too, particularly in women with lower educational attainment. Maternal influences on children's behaviours are strong. Differences exist in infant feeding across countries, and there are apparent urban/rural differences in children's diets and physical activity. CONCLUSIONS: Interventions are needed before, as well as during, pregnancy to improve the diets of families with young children. Interventions to address psychological barriers to eating well and being more active are indicated. PMID- 25300279 TI - One pot, rapid and efficient synthesis of water dispersible gold nanoparticles using alpha-amino acids. AB - A detailed study on the synthesis of spherical and monodispersed gold nanoparticles (AuNPs) using all of the 20 naturally occurring alpha-amino acids has been reported. The synthesized nanoparticles have been further characterized using various techniques such as absorbance spectroscopy, transmission electron microscopy, dynamic light scattering and nuclear magnetic resonance. Size control of the nanoparticles has been achieved by varying the ratio of the gold ion to the amino acid. These monodispersed water soluble AuNPs synthesized using non toxic, naturally occurring alpha-amino acids as reducing and capping/stabilizing agents serve as a remarkable example of green chemistry. PMID- 25300278 TI - Neuronal and physiological correlation to hemodynamic resting-state fluctuations in health and disease. AB - Low-frequency, spatially coherent fluctuations present in functional magnetic resonance imaging time series have had a tremendous impact on brain connectomics. This work aims to explore the degree with which hemodynamic connectivity is associated with neuronal, metabolic, and vascular connectivity measures. For this purpose, GCaMP and nontransgenic mice were used to image neuronal activity and oxidative metabolism activity, respectively, along with blood-oxygenation- and cerebral blood volume (CBV)-sensitive hemodynamic changes from the same animals. Although network clusters calculated using either GCaMP (neuronal activity) or optical imaging of intrinsic signal (OIS)-BOLD (blood oxygenation) data did not exhibit strong spatial similarity, the strengths of node-to-node connectivity measured with these modalities were strongly correlated with one another. This finding suggests that hemodynamic connectivity as measured by blood oxygenation measurements, such as functional connectivity magnetic resonance imaging, is a valuable surrogate for the underlying neuronal connectivity. In nontransgenic animals, greater connectivity correlation was observed between tissue oxidative metabolism (flavoprotein autofluorescence imaging [FAI]) and blood oxygenation measurements, suggesting that metabolic contributions to hemodynamic signals are likely responsible for its significant correlation with neuronal connectivity. Lastly, a mouse model of Alzheimer's disease was used to explore the source of decreases in connectivity reported in these mice, a finding that is thought to be associated with amyloid load-driven metabolic decline. The intercluster connectivity measured by metabolic-sensitive measurements (FAI and OIS-BOLD) was maintained while vascular-only signals (OIS-CBV) provided negligible correlation. Therefore, metabolism-sensitive measurements as used in this work are better positioned to capture changes in neuronal connectivity, such that decreases in hemodynamic connectivity likely reflect decreases in oxidative metabolic function. PMID- 25300280 TI - Design and implementation of a VoIP broadcasting service over embedded systems in a heterogeneous network environment. AB - As the digitization is integrated into daily life, media including video and audio are heavily transferred over the Internet nowadays. Voice-over-Internet Protocol (VoIP), the most popular and mature technology, becomes the focus attracting many researches and investments. However, most of the existing studies focused on a one-to-one communication model in a homogeneous network, instead of one-to-many broadcasting model among diverse embedded devices in a heterogeneous network. In this paper, we present the implementation of a VoIP broadcasting service on the open source-Linphone-in a heterogeneous network environment, including WiFi, 3G, and LAN networks. The proposed system featuring VoIP broadcasting over heterogeneous networks can be integrated with heterogeneous agile devices, such as embedded devices or mobile phones. VoIP broadcasting over heterogeneous networks can be integrated into modern smartphones or other embedded devices; thus when users run in a traditional AM/FM signal unreachable area, they still can receive the broadcast voice through the IP network. Also, comprehensive evaluations are conducted to verify the effectiveness of the proposed implementation. PMID- 25300282 TI - [Orthopedic update - endoprosthesis]. PMID- 25300281 TI - [Osteotomy techniques close to the knee. Effect on wedge volume and bony contact surface]. AB - BACKGROUND: Bone geometry following osteotomy around the knee suggests that biplanar rather than uniplanar open wedge techniques simultaneously create smaller wedge volumes and larger bone surface areas. However, precise data on the bone surface area and wedge volume resulting from both open and closed wedge high tibial osteotomy (HTO) and distal femoral osteotomy (DFO) techniques remain unknown. OBJECTIVES: It was hypothesized that biplanar rather than uniplanar osteotomy techniques better reflect the ideal geometrical requirements for bone healing, representing a large cancellous bone surface combined with a small wedge volume. METHODS: Tibial and femoral artificial bones were assigned to four different groups of valgisation and varisation osteotomy consisting of open wedge and closed wedge techniques in a uniplanar and biplanar fashion. Bone surface areas of all osteotomy planes were quantified. Wedge volumes were determined using a prism-based algorithm and applying standardized wedge heights of 5 mm, 10 mm and 15 mm. RESULTS: Both femoral and tibial biplanar osteotomy techniques created larger contact areas and smaller wedge volumes compared to the uniplanar open wedge techniques. CONCLUSION: Although this idealized geometrical view of bony geometry excludes all biological factors that might influence bone healing, the current data suggest a general rule for the standard osteotomy techniques applied and all surgical modifications: reducing the amount of slow gap healing and simultaneously increasing the area of faster contact healing may be beneficial for osteotomy healing. Thus, biplanar rather than uniplanar osteotomy should be performed for osteotomy around the knee. PMID- 25300283 TI - Antidepressants increase, rather than decrease, risk of suicidal behaviours in younger patients. PMID- 25300284 TI - Author's reply to Bolsin and Colson, Nelson and colleagues, and Vallance-Owen. PMID- 25300285 TI - Effects of 12 weeks of treatment with fermented milk on blood pressure, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind placebo-controlled study. AB - OBJECTIVE: Studies have indicated a blood pressure (BP)-lowering effect of milk derived peptides in non-diabetic individuals, but the cardiometabolic effects of such peptides in patients with type 2 diabetes (T2D) are not known. We investigated the effect of milk fermented with Lactobacillus helveticus on BP, glycaemic control and cardiovascular risk factors in T2D. DESIGN: A randomised, double-blinded, prospective, placebo-controlled study. METHODS: In one arm of a factorial study design, 41 patients with T2D were randomised to receive 300 ml milk fermented with L. helveticus (Cardi04 yogurt) (n=23) or 300 ml artificially acidified milk (placebo yogurt) (n=18) for 12 weeks. BPs were measured over 24-h, and blood samples were collected in the fasting state and during a meal test before and after the intervention. RESULTS: Cardi04 yogurt did not reduce 24-h, daytime or nighttime systolic or diastolic BPs compared with placebo (P>0.05). Daytime and 24-h heart rate (HR) were significantly reduced in the group treated by Cardi04 yogurt compared with the placebo group (P<0.05 for both). There were no differences in HbA1c, plasma lipids, C-reactive protein, plasminogen activator inhibitor-1, tumour necrosis factor alpha, tissue-type plasminogen activator: Ag, and von Willebrand factor: Ag between the groups. The change in fasting blood glucose concentration differed significantly between the two groups with a larger increase in the placebo group (P<0.05). CONCLUSIONS: Ingestion of milk fermented with L. helveticus compared with placebo for 12 weeks did not significantly reduce BP in patients with T2D. Our finding of lower HRs and fasting plasma glucose levels in T2D patients during ingestion of fermented milk needs further validation. PMID- 25300287 TI - Massive transient pulmonary air embolism during transvenous pacemaker implantation: potentially lethal but avoidable complication. PMID- 25300286 TI - Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double blind, randomized, three-arm unicenter study. AB - BACKGROUND: Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups. METHODS: 55 patients with type 2 diabetes (61.6+/-5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months. RESULTS: HbA1c at baseline was, 7.3+/-0.7% in the oral group, 7.3+/ 0.9% and 7.5+/-0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/-0.8%, 6.6+/-0.7% and 6.7+/-0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/-6.4 and 29.4+/- 6.7 units respectively) compared to the group on oral medication (23.2+/-6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/-0.14) at baseline to 0.76mm (+/-0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74). CONCLUSION: The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus. TRIAL REGISTRATION: (Clinical Trials Identifier: NCT00523393). PMID- 25300288 TI - Comparison of the carbon footprint of different patient diets in a Spanish hospital. AB - OBJECTIVES: Mitigating climate change requires management strategies to reduce greenhouse gas emissions in any sector, including the health system. Carbon footprint calculations should play a key role in quantifying and communicating these emissions. Food is among the categories with low accuracy because the carbon footprint for food is still under development. We aimed to quantify the carbon footprint of different diets. METHODS: Average carbon footprint for a normal diet was based on detailed composition data in Juan Ramon Jimenez Hospital (Huelva, Spain). In addition, the carbon footprints of 17 other therapeutic diets were estimated using a streamlined variation of each diet published by Benidorm Clinical Hospital (Spain). RESULTS: The carbon footprint was calculated for 18 hospital diets for a variety of patients. The reference menu corresponds to the normal diet provided to patients who do not have special dietary requirements. This menu has a low carbon footprint of 5.083 CO2 eq/day. CONCLUSIONS: Hospital diets contribute to the carbon footprint of a hospital. The type of diet has a significant impact on the greenhouse gas emissions. A Mediterranean diet is associated with lower environmental impact than diets with more meat, in particular red meat. PMID- 25300289 TI - Has dialysis payment reform led to initial racial disparities in anemia and mineral metabolism management? AB - Implementation of the Medicare ESRD prospective payment system (PPS) and changes to dosing guidelines for erythropoiesis-stimulating agents (ESAs) in 2011 appear to have influenced use of injectable medications among dialysis patients. Given historically higher ESA and vitamin D use among black patients, we assessed the effect of these policy changes on racial disparities in the management of anemia and mineral metabolism. Analyses used cross-sectional monthly cohorts for a period-prevalent sample of 7384 maintenance hemodialysis patients at 132 facilities from the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor. Linear splines with knots at each policy change were used in survey-weighted regressions to estimate time trends in hemoglobin (Hgb), erythropoietin (EPO) dose, intravenous (IV) iron dose, ferritin, transferrin saturation (TSAT) concentration, parathyroid hormone (PTH), IV vitamin D dose, cinacalcet use, and phosphate binder use. From August 2010 to December 2011, mean Hgb declined from 11.5 to 11.0 g/dl (P<0.001), mean EPO dose declined from 20,506 to 14,777 U/wk (P<0.001), and mean serum PTH increased from 340 to 435 pg/ml (P<0.001). No meaningful differences by race were observed regarding the rates of change of management practices or laboratory measures (all P>0.21). Mean EPO and vitamin D dose and serum PTH levels remained higher in blacks. Despite evidence that anemia and mineral metabolism management practices have changed significantly over time, there was no immediate indication of racial disparities resulting from implementation of the PPS or ESA label change. Further studies are needed to examine effects among patient and facility subgroups. PMID- 25300291 TI - Survival in the elderly after acute myocardial infarction: room for more improvement. PMID- 25300290 TI - Activation of protein kinase C-alpha and Src kinase increases urea transporter A1 alpha-2, 6 sialylation. AB - The urea transporter A1 (UT-A1) is a glycosylated protein with two glycoforms: 117 and 97 kD. In diabetes, the increased abundance of the heavily glycosylated 117-kD UT-A1 corresponds to an increase of kidney tubule urea permeability. We previously reported that diabetes not only causes an increase of UT-A1 protein abundance but also, results in UT-A1 glycan changes, including an increase of sialic acid content. Because activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is elevated in diabetes and PKC-alpha regulates UT-A1 urea transport activity, we explored the role of PKC in UT-A1 glycan sialylation. We found that activation of PKC specifically promotes UT-A1 glycan sialylation in both UT-A1-MDCK cells and rat kidney inner medullary collecting duct suspensions, and inhibition of PKC activity blocks high glucose-induced UT-A1 sialylation. Overexpression of PKC-alpha promoted UT-A1 sialylation and membrane surface expression. Conversely, PKC-alpha-deficient mice had significantly less sialylated UT-A1 compared with wild-type mice. Furthermore, the effect of PKC alpha-induced UT-A1 sialylation was mainly mediated by Src kinase but not Raf-1 kinase. Functionally, increased UT-A1 sialylation corresponded with enhanced urea transport activity. Thus, our results reveal a novel mechanism by which PKC regulates UT-A1 function by increasing glycan sialylation through Src kinase pathways, which may have an important role in preventing the osmotic diuresis caused by glucosuria under diabetic conditions. PMID- 25300292 TI - Inappropriate drug use among older persons: is it time for action? PMID- 25300293 TI - Increased serum alkaline phosphatase and serum phosphate as predictors of mortality after stroke. AB - CONTEXT: Serum Alkaline phosphatase (ALP) & phosphate are considered to be indicators of vascular calcification. Link between bone metabolism, vascular calcification, cardiovascular events have been well studied in chronic kidney disease and ischemic heart disease. AIMS: To determine that increased serum phosphate and alkaline phosphatase are predictors of mortality rates and recurrent vascular events in stroke. MATERIALS AND METHODS: Sixty patients admitted with acute stroke (ischemic & haemorrhagic) were included in the study. Their baseline clinical characteristics and biochemical parameters including serum ALP and phosphate were noted. All patients were followed up for a period of one year. The all- cause mortality, the mortality due to cardiovascular events and recurrent vascular events without death were noted during the follow up. Statistical analyses were done to look for any correlation between mortality and baseline levels of serum ALP and phosphate. RESULTS: Of the 60 patients, 8 (13.3%) patients were lost for follow up. Fourteen (26.9%) patients died; of which 12 deaths were due to vascular causes and 2 deaths were due to non vascular causes. Increasing levels of serum ALP and phosphate correlated with all cause mortality and recurrent vascular events without death Conclusion: Serum ALP and phosphate prove to be cost effective prognostic indicator of mortality and recurrent vascular events in stroke. This finding has to be confirmed with studies including larger population. Further research on ALP inhibitors, Vitamin D analogues and phosphate binders to improve mortality in stroke population can be encouraged. PMID- 25300294 TI - Thrombosis: a major contributor to global disease burden. AB - Thrombosis is a common pathology underlying ischaemic heart disease, ischaemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischaemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low, middle and high income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalisation was the leading cause of disability-adjusted-life-years (DALYs) lost in low and middle income countries, and second in high income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low, middle, and high income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilisation of preventive measures will reduce the burden. PMID- 25300295 TI - Serum adiponectin is associated with worsened overall survival in a prospective cohort of hepatocellular carcinoma patients. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The rise in metabolic syndrome has contributed to this trend. Adipokines, such as adiponectin, are associated with prognosis in several cancers, but have not been well studied in HCC. METHODS: We prospectively enrolled 140 patients with newly diagnosed or recurrent HCC with Child-Pugh (CP) class A or B cirrhosis. We examined associations between serum adipokines, clinicopathological features of HCC, and time to death. We also examined a subset of tumors with available pathology for tissue adiponectin receptor (AR) expression by immunohistochemistry. RESULTS: The median age of subjects was 62 years; 79% were men, 59% had underlying hepatitis C, and 36% were diabetic. Adiponectin remained a significant predictor of time to death (hazard ratio 1.90; 95% confidence interval 1.05-3.45; p = 0.03) in a multivariable adjusted model that included age, alcohol history, CP class, stage, and serum alpha-fetoprotein level. Cytoplasmic AR expression (AR1 and AR2) in tumors trended higher in those with higher serum adiponectin levels and in those with diabetes mellitus, but the association was not statistically significant. CONCLUSIONS: In this hypothesis generating study, we found the serum adiponectin level to be an independent predictor of overall survival in a diverse cohort of HCC patients. IMPACT: Understanding how adipokines affect the HCC outcome may help develop novel treatment and prevention strategies. PMID- 25300296 TI - Overexpression of matrix metalloproteinases in lung tissue of patients with primary spontaneous pneumothorax. AB - BACKGROUND: Although blebs and bullae are frequently found in the apexes of lungs of patients with primary spontaneous pneumothorax (PSP), its pathogens remain unclear. OBJECTIVES: To examine the role of proteases [matrix metalloproteinase (MMP)-2, MMP-7 and MMP-9] and antiproteases [tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4] in the pathogenesis of PSP. METHOD: Fifty consecutive PSP patients who received standard surgical care were enrolled in the study. Lung tissues from 20 patients with stage I non-small cell lung cancer were used as a control. Immunohistochemistry (IHC), reverse transcription-polymerase chain reaction (RT-PCR) and gelatin zymography were used to evaluate the expression of MMP and TIMP in the lung tissue of patients with PSP. RESULTS: Overexpression of MMP-2, MMP-7 and MMP-9 was found in the afflicted lung by IHC, zymography and RT-PCR. By IHC, higher expression of MMP-2 and MMP-9 in PSP patients was identified in alveolar macrophages and type II pneumocytes (88 and 92% of patients in macrophages, and 72 and 70% of patients in type II pneumocytes, respectively). MMP-2, MMP-7 and MMP-9 expression in patients was higher in mesothelial cells (66, 76 and 76%). Overexpression of TIMP-2 was detected in the extracellular matrix around bullae and blebs. Expression levels of TIMP-1, TIMP-3 and TIMP-4 were negligible (<10% of cells) in both PSP patients and controls. CONCLUSIONS: MMP-2, MMP-9, MMP-7 and TIMP-2 were upregulated in PSP lesions. These results suggest that an imbalance between the expression of proteases and antiproteases may be involved in the pathogeneses of PSP. PMID- 25300297 TI - Applying policy and health effects of air pollution in South Korea: focus on ambient air quality standards. AB - OBJECTIVES: South Korea's air quality standards are insufficient in terms of establishing a procedure for their management. The current system lacks a proper decision-making process and prior evidence is not considered. The purpose of this study is to propose a measure for establishing atmospheric environmental standards in South Korea that will take into consideration the health of its residents. METHODS: In this paper, the National Ambient Air Quality Standards (NAAQS) of the US was examined in order to suggest ways, which consider health effects, to establish air quality standards in South Korea. Up-to-date research on the health effects of air pollution was then reviewed, and tools were proposed to utilize the key results. This was done in an effort to ensure the reliability of the standards with regard to public health. RESULTS: This study showed that scientific research on the health effects of air pollution and the methodology used in the research have contributed significantly to establishing air quality standards. However, as the standards are legally binding, the procedure should take into account the effects on other sectors. Realistically speaking, it is impossible to establish standards that protect an entire population from air pollution. Instead, it is necessary to find a balance between what should be done and what can be done. CONCLUSIONS: Therefore, establishing air quality standards should be done as part of an evidence-based policy that identifies the health effects of air pollution and takes into consideration political, economic, and social contexts. PMID- 25300298 TI - The Role of Stem Cells in Wound Angiogenesis. AB - Significance: Revascularization plays a critical role in wound healing and is regulated by a complex milieu of growth factors and cytokines. Deficiencies in revascularization contribute to the development of chronic nonhealing wounds. Recent Advances: Stem-cell-based therapy provides a novel strategy to enhance angiogenesis and improve wound healing. With bioethical concerns associated with embryonic stem cells, focus has shifted to different populations of vascular precursors, isolated from adult somatic tissue. Three main populations have been identified: endothelial progenitor cells, mesenchymal stem cells, and induced pluripotent stem cells. These populations demonstrate great promise to positively influence neovascularization and wound repair. Critical Issues: Further studies to more definitively define each population are necessary to efficiently translate stem-cell-based therapeutic angiogenesis to the bedside. Better understanding of the physiologic pathways of how stem cells contribute to angiogenesis in normal tissue repair will help identify targets for successful therapeutic angiogenesis. Future Directions: Active studies in both animal models and clinical trials are being conducted to develop effective delivery routes, including dosing, route, and timing. Stem-cell-based therapy holds significant potential as a strategy for therapeutic angiogenesis in the care of patients with chronic nonhealing wounds. PMID- 25300299 TI - Sphingoid bases inhibit acid-induced demineralization of hydroxyapatite. AB - Calcium hydroxyapatite (HAp), the main constituent of dental enamel, is inherently susceptible to the etching and dissolving action of acids, resulting in tooth decay such as dental caries and dental erosion. Since the prevalence of erosive wear is gradually increasing, there is urgent need for agents that protect the enamel against erosive attacks. In the present study we studied in vitro the anti-erosive effects of a number of sphingolipids and sphingoid bases, which form the backbone of sphingolipids. Pretreatment of HAp discs with sphingosine, phytosphingosine (PHS), PHS phosphate and sphinganine significantly protected these against acid-induced demineralization by 80 +/- 17%, 78 +/- 17%, 78 +/- 7% and 81 +/- 8%, respectively (p < 0.001). On the other hand, sphingomyelin, acetyl PHS, octanoyl PHS and stearoyl PHS had no anti-erosive effects. Atomic force measurement revealed that HAp discs treated with PHS were almost completely and homogeneously covered by patches of PHS. This suggests that PHS and other sphingoid bases form layers on the surface of HAp, which act as diffusion barriers against H(+) ions. In principle, these anti-erosive properties make PHS and related sphingosines promising and attractive candidates as ingredients in oral care products. PMID- 25300300 TI - A specific probe for Hg2+ to delineate even H+ in pure aqueous buffer/Hct116 colon cancer cells: Hg(II)-eta2-arene pi-interaction and a TBET-based fluorescence response. AB - A new molecular probe that demonstrates a distinct TBET process, induced by the Hg(II)-eta(2)-arene pi-interaction, in pure aqueous medium with a large pseudo Stokes shift of 200 nm. PMID- 25300301 TI - Time-resolved and photoluminescence spectroscopy of theta-Al2O3 nanowires for promising fast optical sensor applications. AB - Herein, we have demonstrated the high yield facile growth of Al2O3 nanowires of uniform morphology with different polymorph phases (e.g. gamma, delta and theta) via a hydrothermal method with varying calcination temperatures. The synthesized theta-Al2O3 nanowires were well characterized by XRD, FTIR, SEM/EDAX, AFM and HRTEM techniques. Microstructural analysis confirmed that the dimensions of the individual theta-Al2O3 nanowires are approximately in the ranges 5-20 nm in width and 40-150 nm in length, and the aspect ratio is up to 20. AFM results evidenced the uniform distribution of the nanowires with controlled morphology. Furthermore, UV-vis spectroscopic data reveal that the estimated optical band gap of the theta-Al2O3 nanowires was ~5.16 eV. The photoluminescence spectrum exhibits blue emission upon excitation at a wavelength of 252 nm. Time-resolved spectroscopy demonstrates that these nanowires illustrate a decay time of ~2.23 nanoseconds. The obtained photoluminescence results with a decay time of nanoseconds suggest that the theta-Al2O3 phase could be an exceptional choice for next generation fast optical sensors. PMID- 25300302 TI - A device architecture for three-dimensional, patterned paper immunoassays. AB - Diagnostic assays can provide valuable information about the health status of a patient, which include detection of biomarkers that indicate the presence of an infection, the progression or regression of a disease, and the efficacy of a course of treatment. Critical healthcare decisions must often be made at the point-of-care, far from the infrastructure and diagnostic capabilities of centralized laboratories. There exists an obvious need for diagnostic tools that are designed to address the unique challenges encountered by healthcare workers in limited-resource settings. Paper, a readily-available and inexpensive commodity, is an attractive medium with which to develop diagnostic assays for use in limited-resource settings. In this article, we describe a device architecture to perform immunoassays in patterned paper. These paper-based devices use a combination of lateral and vertical flow to control the wicking of fluid in three-dimensions. We provide guidelines to aid in the design of these devices and we illustrate how patterning can be used to tune the duration and performance of the assay. We demonstrate the use of these paper-based devices by developing a sandwich immunoassay for human chorionic gonadotropin (hCG) in urine, a biomarker of pregnancy. We then directly compare the qualitative and quantitative results of these paper-based immunoassays to commercially available lateral flow tests (i.e., the home pregnancy test). Our results suggest paper based devices may find broad utility in the development of immunoassays for use at the point-of-care. PMID- 25300304 TI - Transcriptome analysis elucidates key developmental components of bryozoan lophophore development. AB - The most recent phylogenomic study suggested that Bryozoa (Ectoprocta), Brachiopoda, and Phoronida are monophyletic, implying that the lophophore of bryozoans, phoronids and brachiopods is a synapomorphy. Understanding the molecular mechanisms of the lophophore development of the Lophophorata clade can therefore provide us a new insight into the formation of the diverse morphological traits in metazoans. In the present study, we profiled the transcriptome of the Bryozoan (Ectoproct) Bugula neritina during the swimming larval stage (SW) and the early (4 h) and late (24 h) metamorphic stages using the Illumina HiSeq2000 platform. Various genes that function in development, the immune response and neurogenesis showed differential expression levels during metamorphosis. In situ hybridization of 23 genes that participate in the Wnt, BMP, Notch, and Hedgehog signaling pathways revealed their regulatory roles in the development of the lophophore and the ancestrula digestive tract. Our findings support the hypothesis that developmental precursors of the lophophore and the ancestrula digestive tract are pre-patterned by the differential expression of key developmental genes according to their fate. This study provides a foundation to better understand the developmental divergence and/or convergence among developmental precursors of the lophophore of bryozoans, branchiopods and phoronids. PMID- 25300305 TI - Chiral spin liquid and emergent anyons in a Kagome lattice Mott insulator. AB - Topological phases in frustrated quantum spin systems have fascinated researchers for decades. One of the earliest proposals for such a phase was the chiral spin liquid, a bosonic analogue of the fractional quantum Hall effect, put forward by Kalmeyer and Laughlin in 1987. Elusive for many years, recent times have finally seen this phase realized in various models, which, however, remain somewhat artificial. Here we take an important step towards the goal of finding a chiral spin liquid in nature by examining a physically motivated model for a Mott insulator on the Kagome lattice with broken time-reversal symmetry. We discuss the emergent phase from a network model perspective and present an unambiguous numerical identification and characterization of its universal topological properties, including ground-state degeneracy, edge physics and anyonic bulk excitations, by using a variety of powerful numerical probes, including the entanglement spectrum and modular transformations. PMID- 25300303 TI - A Halloween gene noppera-bo encodes a glutathione S-transferase essential for ecdysteroid biosynthesis via regulating the behaviour of cholesterol in Drosophila. AB - In insects, the precise timing of moulting and metamorphosis is strictly guided by ecdysteroids that are synthesised from dietary cholesterol in the prothoracic gland (PG). In the past decade, several ecdysteroidogenic enzymes, some of which are encoded by the Halloween genes, have been identified and characterised. Here, we report a novel Halloween gene, noppera-bo (nobo), that encodes a member of the glutathione S-transferase family. nobo was identified as a gene that is predominantly expressed in the PG of the fruit fly Drosophila melanogaster. We generated a nobo knock-out mutant, which displayed embryonic lethality and a naked cuticle structure. These phenotypes are typical for Halloween mutants showing embryonic ecdysteroid deficiency. In addition, the PG-specific nobo knock down larvae displayed an arrested phenotype and reduced 20-hydroxyecdysone (20E) titres. Importantly, both embryonic and larval phenotypes were rescued by the administration of 20E or cholesterol. We also confirm that PG cells in nobo loss of-function larvae abnormally accumulate cholesterol. Considering that cholesterol is the most upstream material for ecdysteroid biosynthesis in the PG, our results raise the possibility that nobo plays a crucial role in regulating the behaviour of cholesterol in steroid biosynthesis in insects. PMID- 25300306 TI - Molecular evidence for natural hybridization between wild loquat (Eriobotrya japonica) and its relative E. prinoides. AB - BACKGROUND: Interspecific hybridization has long been recognized as a pivotal process in plant evolution and speciation. It occurs fairly common in the genera of the subtribe Pyrinae. In Eriobotrya, a small tree genus of Pyrinae, E. prinoides var. daduheensis has been recognized as either a variety of E. prinoides, a natural hybrid between E. prinoides and E. japonica, or a variety of E. japonica. However, to date, there has been no convincing evidence on its status. RESULTS: Four nuclear genes and two chloroplast regions were sequenced in 89 individuals of these three Eriobotrya taxa from two locations where they coexist. A few fixed nucleotide substitutions or gaps were found in each of the investigated nuclear and chloroplast loci between E. japonica and E. prinoides. Of the 35 individuals of E. prinoides var. daduheensis, 33 showed nucleotide additivity of E. japonica and E. prinoides in at least one nuclear gene, and 10 of them harboured nucleotide additivity at all the four nuclear genes. Most haplotypes of E. prinoides var. daduheensis were also shared with those of E. japonica and E. prinoides. In the two chloroplast regions, 28 and 7 individuals were identical with E. japonica and E. prinoides, respectively. CONCLUSIONS: Our study provides compelling evidence for a hybrid status for E. prinoides var. daduheensis. Most hybrid individuals are later-generation hybrids. Both E. japonica and E. prinoides can serve as female parent. Differential adaptation might maintain the species boundary of E. prinoides and E. japonica in the face of hybridization and potential introgression. PMID- 25300307 TI - Atherogenic risk factors and hearing thresholds. AB - The objective of this study was to evaluate the influence of atherogenic risk factors on hearing thresholds. In a cross-sectional study we analyzed data from a Danish survey in 2009-2010 on physical and psychological working conditions. The study included 576 white- and blue-collar workers from children's day care units, financial services and 10 manufacturing trades. Associations between atherogenic risk factors (blood lipids, glycosylated hemoglobin, smoking habits, body mass index (BMI), and ambulatory blood pressure) and hearing thresholds were analyzed using multiple linear regression models. Adjusted results suggested associations between smoking, high BMI and triglyceride level and low high-density lipoprotein level and increased low-frequency hearing thresholds (average of pure-tone hearing thresholds at 0.25, 0.5 and 1 kHz). Furthermore, an increasing load of atherogenic risk factors seemed associated with increased low-frequency hearing thresholds, but only at a borderline level of statistical significance. Associations were generally strongest with hearing levels of the worst hearing ear. We found no statistically significant associations between atherogenic risk factors and high-frequency hearing thresholds (average of pure-tone hearing thresholds at 4, 6 and 8 kHz). PMID- 25300308 TI - Does human saliva decrease the antimicrobial activity of chlorhexidine against oral bacteria? AB - BACKGROUND: Several studies have shown the antibacterial effectiveness of 0.2% chlorhexidine (CHX) in both in vitro and in vivo studies. In this way, CHX comes directly in contact with saliva. This in vitro study aimed at investigating the possible neutralizing effect of saliva on CHX. METHODS: Saliva samples (12 ml) were collected from twenty healthy volunteers. The aerobic and anaerobic bacterial counts in saliva were determined on Colombia blood agar (CBA) and yeast cysteine agar (HCB), respectively. Saliva from each subject was divided among 4 experimental groups (3 ml/group). Samples were centrifuged at 4000 g for 10 min. The centrifuged salivary bacteria were incubated with the following solutions: 0.2% CHX in saliva, CHX in saliva with 7% ethanol, CHX in 0.9% NaCl, CHX in 0.9% NaCl with 7% ethanol. After exposure for 1 min or 3 min to these CHX solutions, the CHX was neutralized and the bacteria were cultivated, after which the number of colony forming units (aerobic and anaerobic) was determined. RESULTS: CHX reduced the CFU in all groups significantly (p = 0.0001). Therefore, CHX had a similar effect on both aerobic and anaerobic microorganisms. Significantly more bacteria survived the effect of CHX when kept in salivary solution. This effect from saliva could be compensated by the addition of ethanol. In the absence of saliva there was no significant difference observed in the effectiveness of CHX with respect to ethanol. Prolonging the exposure time to 3 min enhanced the effectiveness of CHX. CONCLUSIONS: The effect of saliva on the antimicrobial activity of CHX was weak albeit statistically significant. However, addition of 7% ethanol compensates this effect. The impact of saliva on the reduction of the antimicrobial efficacy of mouthrinses such as CHX needs to be taken into consideration with regard to improving their antibacterial properties. PMID- 25300310 TI - French sclerotherapy and compression: Practice patterns. AB - Based on the recommendations of experts, and supported by a low level of proof, compression after sclerotherapy is applied all over the world. OBJECTIVE: Investigating the practice of French vascular physicians for sclerotherapy and the use of post-sclerotherapy compression. METHODS: A questionnaire concerning their practices was sent to French vascular physicians through their regional vascular medicine professional development associations. RESULTS: A total of 366 vascular physicians replied to the questionnaire, of whom 63% (229/366) were in private practice, 6% (21/366) in hospitals and 31% (115/366) had a mixed private hospital practice. Sclerotherapy was practised by 88% (323/366) of them. Two thirds of the vascular physicians used sclerosing foam and practised sclerotherapy using ultrasound guidance. Less than one-third of the vascular physicians regularly applied compression after sclerotherapy. When compression was applied, it was usually after treatment of saphenous or accessory saphenous veins and, in most cases, medical compression stockings of 15-20 mm Hg were used. With respect to the period recommended for wearing compression, this ranged from 48 h to 1 week for 65% (193/299) of the vascular physicians questioned. CONCLUSION: The great majority of vascular physicians who answered the questionnaire employ ultrasound guidance to perform sclerotherapy and use sclerosing foam. Compression after sclerotherapy is diversely applied in France and does not comply with the recommendations of the French Health Authorities who recommend wearing a stocking of 15-20 or 20-36 mm Hg for a period of 4-6 weeks. Thus, less than one-third of the vascular physicians regularly used elastic compression and when they did, it was usually a medical compression stocking of 15-20 mm Hg, for 1 week or less. PMID- 25300309 TI - beta Integrins mediate FAK Y397 autophosphorylation of resistance arteries during eutrophic inward remodeling in hypertension. AB - Human essential hypertension is characterized by eutrophic inward remodeling of the resistance arteries with little evidence of hypertrophy. Upregulation of alphaVbeta3 integrin is crucial during this process. In order to investigate the role of focal adhesion kinase (FAK) activation in this process, the level of FAK Y397 autophosphorylation was studied in small blood vessels from young TGR(mRen2)27 animals as blood pressure rose and eutrophic inward remodeling took place. Between weeks 4 and 5, this process was completed and accompanied by a significant increase in FAK phosphorylation compared with normotensive control animals. Phosphorylated (p)FAK Y397 was coimmunoprecipitated with both beta1- and beta3-integrin-specific antibodies. In contrast, only a fraction (<10-fold) was coprecipitated with the beta3 integrin subunit in control vessels. Inhibition of eutrophic remodeling by cRGDfV treatment of TGR(mRen2)27 rats resulted in the development of smooth-muscle-cell hypertrophy and a significant further enhancement of FAK Y397 phosphorylation, but this time with exclusive coassociation of pFAK Y397 with integrin beta1. We established that phosphorylation of FAK Y397 with association with beta1 and beta3 integrins occurs with pressure-induced eutrophic remodeling. Inhibiting this process leads to an adaptive hypertrophic vascular response induced by a distinct beta1 mediated FAK phosphorylation pattern. PMID- 25300311 TI - Lower pain and faster treatment with mechanico-chemical endovenous ablation using ClariVein(r). AB - OBJECTIVES: To assess the efficacy of the ClariVein((r)) system of mechanico chemical ablation of superficial vein incompetence. METHOD: ClariVein((r)) treatment uses a micropuncture technique and a 4-Fr sheath to allow a catheter to be placed 1.5 cm from the saphenofemoral junction. Unlike laser (endovenous laser treatment (EVLT)) or radiofrequency ablation (RFA), no tumescence is required. The technique depends on a wire rotating at 3500 r/min causing endothelial damage whilst liquid sclerosant (1.5% sodium tetradecyl sulphate) is infused. The wire is pulled back whilst continuously infusing sclerosant along the target vessel's length. Initially, 8 mL of dilute sclerosant was used, but this was subsequently increased to 12 mL. No routine post-op analgesia was prescribed and specifically no non-steroidal anti-inflammatory drugs. Procedure times and pain scores (visual analogue scale) were recorded and compared to EVLT and RFA. All patients were invited for duplex post-procedure. RESULTS: Fifty-one great saphenous veins and six short saphenous veins were treated and followed up with duplex in the 10 months from July 2011. No major complications or deep vein thrombosis were reported. Duplex showed patency of three treated veins with two more veins having only a short length of occlusion, giving a technical success rate of 91%. Comparison with 50 RFA and 40 EVLT showed procedure times were significantly less for ClariVein((r)) (23.0 +/- 8.3 min) than for either RFA (37.9 +/- 8.3 min) or EVLT (44.1 +/- 11.4 min). Median pain scores were significantly lower for ClariVein((r)) than RFA and EVLT (1 vs. 5 vs. 6, p < 0.01). CONCLUSION: Mechanochemical ablation with the ClariVein((r)) system is safe and effective. After some initial failures, the use of 12 mL of dilute sclerosant results in a very high technical success rate >90% which accords with the limited published literature. Procedure times and pain scores are significantly better than for RFA and EVLT. We await the long-term clinical outcomes. PMID- 25300312 TI - Neoplastic zebras of venous thrombosis: Diagnostic challenges in vascular medicine. AB - Venous thrombosis is a common medical problem. Imaging differentiation of neoplasms and venous clots may prove challenging. We report three cases of "mistaken identities" of venous thrombi and neoplasms on the basis of clinical findings and different imaging modalities: ultrasound, computed tomography, and magnetic resonance imaging. Imaging studies are not always reliable and consideration of clinical features, including pretest probability, is necessary for correct diagnosis. A combination of imaging modalities and biopsies is needed for correct diagnosis in some cases. PMID- 25300313 TI - Anatomical and clinical factors favoring the performance of saphenous ablation and microphlebectomy or sclerotherapy as a single-stage procedure. AB - OBJECTIVE: To identify the anatomical and clinical parameters that predict lack of regression of superficial varicosities after ablation of the great saphenous vein. METHODS: Symptomatic patients treated with endovenous ablation from August 2006 to July 2013, by a single surgeon, were included. Recorded parameters included age, sex, size, and extent of varicosities (class I-IV) (patient standing), and diameter and length (patient supine) of treated great saphenous vein. Varicose vein classification was defined as: class I <=6 mm and localized to thigh or leg, class II <=6 mm and present in the thigh and leg (extensive), class III >6 mm and localized to the thigh or leg, and class IV >6 mm and extensive. "Excellent" results were defined as complete resolution of varicosities, "good" results as incomplete resolution, and "poor" results as no improvement. RESULTS: A total of 267 patients and 302 consecutive limbs were included in the study. There were 175 females (65.5%), and the mean age was 54 years old (22-92). The CEAP classification was as follows: C2 (81.5%), C3 (6.3%), C4 (7.9%), C5 (2.0%), and C6 (2.3%). Great saphenous vein diameters was significantly larger in patients with C3-C6 (proximal 0.84 +/- 0.25 versus 0.65 +/- 0.21, p = < 0.0001, distal 0.58 +/- 0.18 versus 0.44 +/- 0.13, p < 0.0001) or class III-IV varicose veins (proximal 0.85 +/- 0.25 versus 0.75 +/- 0.27, p = 0.012, distal 0.62 +/- 0.62 versus 0.50 +/- 0.17, p < 0.0001). Class III-IV limbs had a "good/poor" result 69.8% of the time, as compared to 51.9% of the limbs class I-II varicose veins (p = 0.002). CONCLUSIONS: Advanced chronic venous disease (C3-C6) patients have larger diameter great saphenous veins, reflecting the progressive nature of the disease. Patients with more severe varicosities regardless of CEAP class were more likely to require a secondary procedure. The severity of the varicosities may not correlate with the degree of venous disease, but it is an indication of which patients should undergo secondary procedures, possibly with a one-stage approach. PMID- 25300314 TI - Ultrasound-assisted lysis using recombinant tissue plasminogen activator and the EKOS EkoSonic endovascular system for treating right atrial thrombus and massive pulmonary embolism: A case study. AB - OBJECTIVE: Right atrial thrombus in the setting of a large pulmonary embolus is rare and is associated with serious adverse events. This case report presents the role played by EKOS EkoSonic ultrasound system in successfully treating right atrial thrombus and massive pulmonary embolism. CASE REPORT: A 69-year-old female presented with a massive pulmonary embolus and a large mobile right atrial thrombus. She was treated with catheter-directed lysis using the EKOS EkoSonic ultrasound system and tissue plasminogen activator, with complete resolution of her right atrial thrombus and a marked improvement in her pulmonary embolus and hemodynamics. CONCLUSION: This case report provides a new and an effective option to treat right atrial thrombus associated with a large pulmonary embolus leading to a good outcome. PMID- 25300315 TI - Maggots as a wound debridement agent for chronic venous leg ulcers under graduated compression bandages: A randomised controlled trial. AB - OBJECTIVES: Slough in chronic venous leg ulcers may be associated with delayed healing. The purpose of this study was to assess larval debridement in chronic venous leg ulcers and to assess subsequent effect on healing. METHODS: All patients with chronic leg ulcers presenting to the leg ulcer service were evaluated for the study. Exclusion criteria were: ankle brachial pressure indices <0.85 or >1.25, no venous reflux on duplex and <20% of ulcer surface covered with slough. Participants were randomly allocated to either 4-layer compression bandaging alone or 4-layer compression bandaging + larvae. Surface areas of ulcer and slough were assessed on day 4; 4-layer compression bandaging was then continued and ulcer size was measured every 2 weeks for up to 12 weeks. RESULTS: A total of 601 patients with chronic leg ulcers were screened between November 2008 and July 2012. Of these, 20 were randomised to 4-layer compression bandaging and 20 to 4-layer compression bandaging + larvae. Median (range) ulcer size was 10.8 (3-21.3) cm(2) and 8.1 (4.3-13.5) cm(2) in the 4-layer compression bandaging and 4-layer compression bandaging + larvae groups, respectively (Mann-Whitney U test, P = 0.184). On day 4, median reduction in slough area was 3.7 cm(2) in the 4-layer compression bandaging group (P < 0.05) and 4.2 cm(2) (P < 0.001) in the 4 layer compression bandaging + larvae group. Median percentage area reduction of slough was 50% in the 4-layer compression bandaging group and 84% in the 4-layer compression bandaging + larvae group (Mann-Whitney U test, P < 0.05). The 12-week healing rate was 73% and 68% in the 4-layer compression bandaging and 4-layer compression bandaging + larvae groups, respectively (Kaplan-Meier analysis, P = 0.664). CONCLUSIONS: Larval debridement therapy improves wound debridement in chronic venous leg ulcers treated with multilayer compression bandages. However, no subsequent improvement in ulcer healing was demonstrated. PMID- 25300316 TI - PA32540 for the secondary prevention of cardiovascular disease in patients at risk for aspirin-associated gastric ulcers. AB - Prescribed in patients with a history of myocardial infarction, stroke, transient ischemic attack, coronary intervention or bypass surgery, aspirin is one of the medications most commonly used in the secondary prevention of cardiovascular diseases. It has become a mainstay of therapy after years of solid evidence supporting its efficacy in clinical trials. However, a number of risks and side effects accompany its benefits, including the notable risk of bleeding and gastrointestinal side effects. Numerous mechanisms have been proposed to attenuate these effects to promote adherence and to expand the population for which aspirin is a reasonable treatment option. A polypill or combination formulation that includes a proton pump inhibitor, a drug commonly prescribed alongside aspirin, is one potential avenue of therapy. One such combination pill, PA32540, has undergone Phase I and Phase III trials and shows promising safety and efficacy results in these preliminary trials. PMID- 25300317 TI - Impact of pharmacy worker training and deployment on access to essential medicines and health outcomes in Malawi: protocol for a cluster quasi experimental evaluation. AB - BACKGROUND: Access to essential medicines is core to saving lives and improving health outcomes of people worldwide, particularly in the low- and middle-income countries. Having a trained pharmacy workforce to manage the supply chain and safely dispense medicines is critical to ensuring timely access to quality pharmaceuticals and improving child health outcomes. METHODS/DESIGN: This study measures the impact of an innovative pharmacy assistant training program in the low-income country of Malawi on access to medicines and health outcomes. We employ a cluster quasi-experimental design with pre-and post-samples and decision analytic modeling to examine access to and the use of medicines for malaria, pneumonia, and diarrhea for children less than 5 years of age. Two intervention districts, with newly trained and deployed pharmacy assistants, and two usual care comparison districts, matched on socio-economic, geographic, and health-care utilization indicators, were selected for the study. A baseline household survey was conducted in March 2014, prior to the deployment of pharmacy assistants to the intervention district health centers. Follow-up surveys are planned at 12- and 24-months post-deployment. In addition, interviews are planned with caregivers, and time-motion studies will be conducted with health-care providers at the health centers to estimate costs and resources use. DISCUSSION: This impact evaluation is designed to provide data on the effects of a novel pharmacy assistant program on pharmaceutical systems performance, and morbidity and mortality for the most common causes of death for children under five. The results of this study should contribute to policy decisions about whether and how to scale up the health systems strengthening workforce development program to have the greatest impact on the supply chain and health outcomes in Malawi. PMID- 25300318 TI - Optimal cut-off values of BMI, waist circumference and waist:height ratio for defining obesity in Chinese adults. AB - It has not been established which specific measures of obesity might be most appropriate for predicting CVD risk in Asians. The objectives of the present study were to determine the associations of BMI, waist circumference (WC) and waist:height ratio (WHtR) with CVD risk factors and to evaluate the optimal cut off values to define overweight or obesity in Chinese adults. Data collected from seven nationwide health examination centres during 2008 and 2009 were analysed. The BMI, WC and WHtR of 244 266 Chinese adults aged >= 20 years included in the study were measured. Logistic regression models were fit to evaluate the OR of each CVD risk factor according to various anthropometric indices. Receiver operating characteristic (ROC) analyses were conducted to assess the optimal cut off values to predict the risk of diabetes, hypertension, dyslipidaemia and the metabolic syndrome. WHtR had the largest areas under the ROC curve for all CVD risk factors in both sexes, followed by WC and BMI. The optimal cut-off values were approximately 24.0 and 23.0 kg/m2 for BMI, 85.0 and 75.0 cm for WC, and 0.50 and 0.48 for WHtR for men and women, respectively. According to well-established cut-off values, BMI was found to be a more sensitive indicator of hypertension in both men and women, while WC and WHtR were found to be better indicators of diabetes and dyslipidaemia. A combination of BMI and central obesity measures was found to be associated with greater OR of CVD risk factors than either of them alone in both sexes. The present study demonstrated that WHtR and WC may be better indicators of CVD risk factors for Chinese people than BMI. PMID- 25300319 TI - An HIV intervention tailored for black young men who have sex with men in the House Ball Community. AB - Black young men who have sex with men (BYMSM) are the group most disproportionately impacted by HIV in the USA and most in need of efficacious interventions to address community-level factors that increase their vulnerability to HIV. The House Ball Community (HBC) is a distinct social network within the larger BYMSM community that may be particularly vulnerable to social norms and stigma around HIV. This study tailored an evidence-based, community level popular opinion leader (OL) intervention for use within the HBC. The intervention, called Promoting Ovahness through Safer Sex Education (POSSE), was then piloted to evaluate feasibility, acceptability, and preliminary efficacy. Recruiting OLs from the community and training them to deliver risk reduction messages were found to be feasible and highly acceptable. Community-level surveys (n = 406) were completed over five waves of data collection. Overall exposure to the intervention increased across waves. Statistically significant (p < .05) declines were observed for multiple sexual partners, condomless anal intercourse with any male partners, and with male partners of unknown HIV status. HIV stigma declined as well, but the trend was not statistically significant. PMID- 25300321 TI - Clinical usefulness of lipid ratios to identify men and women with metabolic syndrome: a cross-sectional study. AB - BACKGROUND: Waist circumference, a metabolic syndrome (MetSy) criterion, is not routinely measured in clinical practice making early identification of individuals with MetSy challenging. It has been argued that ratios of commonly measured parameters such as lipids and lipoproteins may be an acceptable alternative for identifying individuals with MetSy. The objective of our study was to explore clinical utility of lipid ratios to identify men and women with MetSy; and to explore the association between lipid ratios and the number of MetSy components. METHODS: Men and women (N = 797) of Aboriginal, Chinese, European, and South Asian origin (35-60 years), recruited across ranges of body mass index (BMI), with no diagnosed cardiovascular disease (CVD) or on medications to treat CVD risk factors were assessed for anthropometrics, family history of CVD, MetSy components (waist circumference, blood pressure, glucose, triglycerides (TG), high-density-lipoprotein-cholesterol (HDL-C)), low-density lipoprotein-cholesterol (LDL-C), nonHDL-C, and health-related behaviours. RESULTS: Mean levels of lipid ratios significantly increased with increasing number of MetSy components in men and women (p < 0.05). After adjustment for age, ethnicity, smoking, alcohol consumption, physical activity, family history of CVD and BMI, (and menopausal status in women), all lipid ratios were associated with the number of MetSy components in men and women (Poisson regression, p < 0.001). Compared to the rest of the lipid ratios (ROC curve analysis), TG/HDL-C was best able to discriminate between individuals with and without MetSy (AUC = 0.869 (95% CI: 0.830, 0.908) men; AUC = 0.872 (95% CI: 0.832, 0.912) women). The discriminatory power of TC/HDL-C and nonHDL-C/HDL-C to identify individuals with MetSY was the same (for both ratios, AUC = 0.793 (95% CI: 0.744, 0.842) men; 0.818 (95% CI: 0.772, 0.864) women). Additionally, LDL-C/HDL-C was a good marker for women (AUC = 0.759 (95% CI: 0.706, 0.812)), but not for men (AUC = 0.689 (95% CI: 0.631, 0.748)). Based on a multiethnic sample, we identified TG/HDL-C cut-off values of 1.62 in men and 1.18 in women that were best able to discriminate between men and women with and without MetSY. CONCLUSIONS: Our results indicate that TG/HDL-C is a superior marker to identify men and women with MetSy compared to TC/HDL-C, LDL-C/HDL-C, and nonHDL-C/HDL-C. PMID- 25300323 TI - Hemispheric asymmetry of emotion words in a non-native mind: a divided visual field study. AB - This study investigates hemispheric specialization for emotional words among proficient non-native speakers of English by means of the divided visual field paradigm. The motivation behind the study is to extend the monolingual hemifield research to the non-native context and see how emotion words are processed in a non-native mind. Sixty eight females participated in the study, all highly proficient in English. The stimuli comprised 12 positive nouns, 12 negative nouns, 12 non-emotional nouns and 36 pseudo-words. To examine the lateralization of emotion, stimuli were presented unilaterally in a random fashion for 180 ms in a go/no-go lexical decision task. The perceptual data showed a right hemispheric advantage for processing speed of negative words and a complementary role of the two hemispheres in the recognition accuracy of experimental stimuli. The data indicate that processing of emotion words in non-native language may require greater interhemispheric communication, but at the same time demonstrates a specific role of the right hemisphere in the processing of negative relative to positive valence. The results of the study are discussed in light of the methodological inconsistencies in the hemifield research as well as the non native context in which the study was conducted. PMID- 25300322 TI - Inorganic phosphate is a trigger factor for Microbispora sp. ATCC-PTA-5024 growth and NAI-107 production. AB - BACKGROUND: NAI-107, produced by the actinomycete Microbispora sp. ATCC-PTA-5024, is a promising lantibiotic active against Gram-positive bacteria and currently in late preclinical-phase. Lantibiotics (lanthionine-containing antibiotics) are ribosomally synthesized and post-translationally modified peptides (RiPPs), encoded by structural genes as precursor peptides. The biosynthesis of biologically active compounds is developmentally controlled and it depends upon a variety of environmental stimuli and conditions. Inorganic phosphate (Pi) usually negatively regulates biologically-active molecule production in Actinomycetes, while it has been reported to have a positive control on lantibiotic production in Firmicutes strains. So far, no information is available concerning the Pi effect on lantibiotic biosynthesis in Actinomycetes. RESULTS: After having developed a suitable defined medium, Pi-limiting conditions were established and confirmed by quantitative analysis of polyphosphate accumulation and of expression of selected Pho regulon genes, involved in the Pi-limitation stress response. Then, the effect of Pi on Microbispora growth and NAI-107 biosynthesis was investigated in a defined medium containing increasing Pi amounts. Altogether, our analyses revealed that phosphate is necessary for growth and positively influences both growth and NAI-107 production up to a concentration of 5 mM. Higher Pi concentrations were not found to further stimulate Microbispora growth and NAI-107 production. CONCLUSION: These results, on one hand, enlarge the knowledge on Microbispora physiology, and, on the other one, could be helpful to develop a robust and economically feasible production process of NAI-107 as a drug for human use. PMID- 25300324 TI - Classification of metabolic syndrome according to lipid alterations: analysis from the Mexican National Health and Nutrition Survey 2006. AB - BACKGROUND: There are 16 possible Metabolic Syndrome (MS) combinations out of 5 conditions (glucose intolerance, low levels of high-density lipoprotein Cholesterol (HDL-C), high triglycerides, high blood pressure and abdominal obesity), when selecting those with at least three. Studies suggest that some combinations have different cardiovascular risk. However evaluation of all 16 combinations is complex and difficult to interpret. The purpose of this study is to describe and explore a classification of MS groups according to their lipid alterations. METHODS: This is a cross-sectional study with data from the Mexican National Health and Nutrition Survey 2006. Subjects (n = 5,306) were evaluated for the presence of MS; four mutually-exclusive MS groups were considered: mixed dyslipidemia (altered triglycerides and HDL-C), hypoalphalipoproteinemia: (normal triglycerides but low HDL-C), hypertriglyceridemia (elevated triglycerides and normal HDL-C) and without dyslipidemia (normal triglycerides and HDL-C). A multinomial logistic regression model was fitted in order to identify characteristics that were associated with the groups. RESULTS: The most frequent MS group was hypoalphalipoproteinemia in females (51.3%) and mixed dyslipidemia in males (43.5%). The most prevalent combination of MS for both genders was low HDL-C + hypertension + abdominal obesity (20.4% females, 19.4% males). The hypoalphalipoproteinemia group was characteristic of women and less developed areas of the country. The group without dyslipidemia was more frequent in the highest socioeconomic level and less prevalent in the south of the country. The mixed dyslipidemia group was characteristic of men, and the Mexico City region. CONCLUSIONS: A simple system to classify MS based on lipid alterations was useful to evaluate prevalences by diverse biologic and sociodemographic characteristics. This system may allow prevention and early detection strategies with emphasis on population-specific components and may serve as a guide for future studies on MS and cardiovascular risk. PMID- 25300325 TI - Paul H. Patterson (October 22, 1943 - June 25, 2014). PMID- 25300326 TI - Gabriele Schilling (September 5, 1968-July 4, 2014). PMID- 25300327 TI - Perhaps the subject of the questionnaire was too sensitive: Do we expect too much too soon? Wishes for the end of life in Huntington's Disease - the perspective of European physicians. PMID- 25300329 TI - TR-FRET Assays for Endogenous Huntingtin Protein Level in Mouse Cells. AB - High-throughput measurement of huntingtin (Htt) levels is useful for Huntington's disease research. For example, identification of genetic or chemical modifiers that reduce Htt levels by high-throughput screening provides promising strategy for HD drug discovery. In the human cells, high-throughput measurement of Htt levels has been established based on the Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) technology, using the 2B7/MW1 antibody pair. Unfortunately, application of this assay in the mouse cells has been problematic due to discrepancies between TR-FRET signals and Western-blots, possibly caused by non-specific antibody binding. Here we report TR-FRET assays that are able to detect endogenous Htt levels of the mouse striatal cell line (STHdh). PMID- 25300330 TI - Huntingtin Supplies a csaA-Independent Function Essential for EDTA-Resistant Homotypic Cell Adhesion in Dictyostelium discoideum. AB - BACKGROUND: The CAG triplet repeat expansion mutation in the HTT locus, which results in neurodegeneration in Huntington's disease, elongates a polyglutamine tract in huntingtin, a HEAT/HEAT-like protein that has been highly structurally conserved through evolution. In several organisms, huntingtin is necessary for proper cell-cell adhesion and normal development. OBJECTIVE: Dictyostelium discoideum huntingtin null (htt-) cells display a variety of developmental abnormalities and completely fail to acquire EDTA-resistant homotypic cell adhesion during starvation in suspension culture. METHODS: Here, we have assessed the hypothesis that htt may be a genetic interactor of csaA, a major regulator of EDTA-resistant homotypic cell adhesion in D. discoideum. Immunoblot analysis demonstrated that csaA protein expression is dysregulated in htt- cells. RESULTS: Unexpectedly, csaA overexpression, previously shown to rescue csaA- cell adhesion, failed to rescue the htt- adhesion defect. Thus, while htt was required for proper expression of the csaA protein, csaA overexpression was not sufficient to confer EDTA-resistant adhesion in the context of the htt- genetic background in contrast to parental cells. This implies a novel role for htt in conferring csaA-dependent, EDTA-resistant cell adhesion that warrants further investigation. Calcium supplementation restored both endogenous csaA protein levels and EDTA resistant adhesion in htt- cells. CONCLUSIONS: Our data suggests the existence of an additional mechanism that overcomes the EDTA-resistant adhesion defect of htt- cells in the early development of D. discoideum. PMID- 25300331 TI - Improved Executive Function and Callosal White Matter Microstructure after Rhythm Exercise in Huntington's Disease. AB - BACKGROUND: Huntington's disease (HD) is an autosominal dominant neurodegenerative condition that leads to progressive loss of motor and cognitive functions. Early symptoms in HD include subtle executive dysfunction related to white and grey matter loss in cortico-striatal-thalamic loops. There is no cure for HD and hence a significant need for early intervention with the potential to delay the clinical onset of the disease. OBJECTIVE: The objective of the present pilot study was to devise a novel behavioural intervention involving drumming and rhythm exercises that targets early dysexecutive problems, such as difficulties in sequence and reversal learning, response speed, timing, and dual tasking. METHOD: One preclinical person and nine people with early to advanced stages of HD were recruited of whom five completed the two months intervention. The effects of rhythm exercise on executive function, basal ganglia volume, and white matter microstructure in the anterior corpus callosum, the anterior thalamic radiation, and the cortico-spinal tract were assessed post- relative to pre-training. RESULTS: After two months training, improvements in executive function and changes in white matter microstructure, notably in the genu of the corpus callosum that connects prefrontal cortices of both hemispheres, were observed. No changes in basal ganglia volume were present. CONCLUSION: This pilot study provides novel preliminary evidence that carefully targeted behavioural stimulation in HD can result in cognitive enhancement and improvements in callosal white matter microstructure. PMID- 25300332 TI - Co-administration of the Dopaminergic Stabilizer Pridopidine and Tetrabenazine in Rats. AB - BACKGROUND: The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission. OBJECTIVE: To investigate pharmacological interactions between pridopidine and tetrabenazine. METHODS: Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4 dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison. RESULTS: Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine. CONCLUSIONS: Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy. PMID- 25300328 TI - Understanding the Outcomes Measures used in Huntington Disease Pharmacological Trials: A Systematic Review. AB - BACKGROUND: The identification of the gene mutation causing Huntington disease has raised hopes for new treatments to ease symptoms and slow functional decline. As such, there has been a push towards designing efficient pharmacological trials (i.e., drug trials), especially with regard to selecting outcomes measures that are both brief and sensitive to changes across the course of the disease, from subtle prodromal changes, to more severe end-stage changes. OBJECTIVES: Recently, to aid in efficient development of new HD research studies, the National Institute of Neurological Disorders and Stroke (NINDS) published recommendations for measurement selection in HD. While these recommendations are helpful, many of the recommended measures have little published data in HD. As such, we conducted a systematic review of the literature to identify the most common outcomes measures used in HD clinical trials. METHODS: Major medical databases, including PubMed, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were used to identify peer-reviewed journal articles in English from 2001 through April 2013; 151 pharmacological trials were identified. RESULTS: The majority of HD clinical trials employed clinician-reported outcomes measures (93%); patient reported outcome measures (11%) and observer reported outcome measures (3%) were used with much less frequency. CONCLUSIONS: We provide a review of the most commonly used measures across these trials, compare these measures to the clinical recommendations made by the NINDS working groups, and provide recommendations for selecting measures for future clinical trials that meet the Food and Drug Administration standards. PMID- 25300333 TI - 'Super-Enrichment' Reveals Dose-Dependent Therapeutic Effects of Environmental Stimulation in a Transgenic Mouse Model of Huntington's Disease. AB - BACKGROUND: Huntington's disease (HD) is caused by a tandem repeat expansion and involves progressive cognitive decline, psychiatric abnormalities and motor deficits. Disease onset and progression in HD mice can be substantially delayed by a housing environment with enhanced sensorimotor and cognitive stimulation. However, the proposed benefits of environmental enrichment (EE) are always taken in the context of 'deprived' standard housing and investigation is warranted into the graded effects of enrichment. OBJECTIVE: To assess if a higher level of environmental stimulation ('super-enrichment') has additional benefits compared to home-cage EE in HD mice. METHODS: One group of R6/1 transgenic HD mice and wild-type (WT) littermates were home-cage enriched (EE group). A second group also had enriched home cages, but from 6 weeks of age were exposed to a large 'super-enrichment' arena (SuperE group) three times per week. A range of motor tests (open field, rotarod, clasping) were conducted from 8 weeks of age and, at the end of the experiment, grip strength was assessed and post-mortem measures were taken (brain weight, striatal volume, dopamine receptor activation and aggregate density). RESULTS: SuperE improved the reduction of exploration in the open field, ameliorated impaired grip strength in home-cage enriched HD mice and delayed, but did not abolish, the onset of rear-paw clasping compared to EE. SuperE increased brain weight compared to EE in HD mice and reduced striatal dopamine D1 receptor agonist-induced c-fos expression, regardless of genotype. Body weight, rotarod performance, aggregate formation and striatal volume in SuperE groups were no different compared to EE groups. CONCLUSIONS: The beneficial effects of sensorimotor and cognitive stimulation are graded and extend beyond merely compensating for the deprivation of standard home cages in specific motor-related phenotypes in HD. Our findings highlight the importance of environmental enrichment quality and quantity and the translational value of stimulating living conditions as experience-dependent modulators of pathogenesis in HD and other brain disorders. PMID- 25300336 TI - Authors' reply. PMID- 25300334 TI - Disease Modifying Potential of Glatiramer Acetate in Huntington's Disease. AB - BACKGROUND: Deficiencies in brain-derived-neurotrophic-factor have been implicated in the pathogenesis of Huntington's disease (HD). OBJECTIVE: Glatiramer acetate, an FDA- approved drug used for the treatment of multiple sclerosis, has been shown to increase brain-derived-neurotrophic-factor levels in immune cells; hence, we investigated whether it could have similar effects in striatal cells. METHODS: Wild-type and HD striatal cells were treated with glatiramer acetate for 48 hrs. HD transgenic and wild-type mice were injected with glatiramer acetate (1.5 to 1.7 mg/mouse) for five days. These treatments were followed by protein measurements for brain-derived-neurotrophic-factor. RESULTS: Glatiramer acetate elicited concentration-dependent increases in brain derived-neurotrophic-factor protein levels in wild-type and HD striatal cells and in striatal tissue from N171-82Q transgenic mice. Glatiramer acetate also improved metabolic activity of HD striatal cells, and significantly reduced the early hyperactivity phenotype exhibited by N171-82Q transgenic mice. CONCLUSIONS: These findings suggest that glatiramer acetate may represent a useful therapeutic approach for HD. The excellent safety and tolerability record of this compound makes it an ideal candidate for drug repurposing efforts. PMID- 25300335 TI - Role of Appropriate Therapy in Combating Mortality among the Ventilated Patients. AB - CONTEXT: Ventilator associated pneumonia (VAP) is a nosocomial infection prevalent among the intensive care unit (ICU) patients despite proper infection control practices. The diagnosis of VAP still remains controversial and hence the mortality rate is higher among this group of patients. AIM: The aim of our study was to identify the antibiotic pattern and the appropriateness of treatment followed in the ICU in relation with the clinical pulmonary infection score (CPIS) as a tool to diagnose VAP. This was compared with patients who had an inappropriate treatment in comparison to the CPIS and the clinical outcome. RESULTS: Out of the 18 VAP patients, 12 (66.7%) received appropriate therapy based on the antibiotic susceptibility pattern of the causative organism, while 1 (5.5%) received partially inappropriate therapy and 5 (27.8%) received totally inappropriate therapy. Nine of the 18 (50%) VAP patients died, while only 5 of the 58 (8.6%) patients without VAP died. 72.2% patients with VAP received appropriate treatment based on the sensitivity of the isolates. The mortality rate in VAP patients receiving inappropriate therapy was 80%, while in those receiving appropriate therapy the mortality rate was 38.5%. The mortality rate among VAP patients with blood culture positivity was 100%, while it was 43.75% among those with negative blood culture. CONCLUSION: The mortality rate among the patients receiving inappropriate therapy is high compared to other group of patients. Hence, a proper evaluation and administration of appropriate antibiotics can curb mortality among the ventilated patients. PMID- 25300337 TI - Managing the load on a reader's mind. PMID- 25300338 TI - Who needs beds? PMID- 25300339 TI - Primary pseudomyogenic haemangioendothelioma of bone: report of two cases. AB - Pseudomyogenic haemangioendothelioma (epithelioid sarcoma-like haemangioendothelioma) is a recently described, rarely metastasising neoplasm of the soft tissues that often presents as multiple discontinuous nodules in different tissue planes of a limb. This tumour type is extremely difficult to diagnose because no morphological evidence suggestive of endothelial differentiation is present to confirm a radiological suspicion of vascular neoplasm. All but one case published in the literature underline that bone involvement is secondary to deep and superficial soft tissue nodules. Here, we report two cases of primary bone pseudomyogenic haemangioendothelioma occurring in the radius and cuboid bone with a multifocal presentation. PMID- 25300340 TI - Suitability of small bronchoscopic tumour specimens for lung cancer genotyping. AB - BACKGROUND: Biomarker-driven clinical trials in advanced non-small cell lung cancer (NSCLC) usually accept biopsy specimens only, as cytology specimens are supposed to be more challenging due to low neoplastic cell content and suboptimal DNA quantity. OBJECTIVES: We aimed to evaluate 2 aspects of bronchoscopic biopsy and cytology specimens: (1) the proportion of neoplastic cells and quantity of DNA extracted, and (2) the detection limit of the Scorpion amplification refractory mutation system on endoscopic samples obtained in daily clinical practice. METHODS: We screened 679 patients with advanced-stage NSCLC for the presence of an activating EGFR mutation according to the guidelines of the European Society of Medical Oncology. Their diagnostic tumour tissue samples were characterized. A dilution experiment was performed to determine the minimal proportion of neoplastic cells for a reliable test result. RESULTS: Surgical biopsies, bronchoscopic forceps biopsy samples and needle aspiration cytology specimens exhibited a median tumour cell proportion of 70 versus 30 versus 20% and a DNA quantity of 2,500 versus 1,610 versus 1,440 ng, respectively. The overall EGFR mutation rate was 11%, with no differences between different sample types. Dilution experiments showed that the detection limit depends on the type of mutation. A neoplastic cell content of at least 10 and 25% for exon 19 deletions and exon 21 L858R point mutation, respectively, was required for a true negative result. CONCLUSIONS: Bronchoscopic forceps biopsy and needle aspiration cytology specimens are suitable for accurate EGFR mutation analysis using single gene quantitative real-time polymerase chain reaction. Technologies with a better analytical sensitivity are evolving and should consider these endoscopic tumour specimens. PMID- 25300341 TI - The coordination of boundary tones and its interaction with prominence. AB - This study investigates the coordination of boundary tones as a function of stress and pitch accent. Boundary tone coordination has not been experimentally investigated previously, and the effect of prominence on this coordination, and whether it is lexical (stress-driven) or phrasal (pitch accent-driven) in nature is unclear. We assess these issues using a variety of syntactic constructions to elicit different boundary tones in an Electromagnetic Articulography (EMA) study of Greek. The results indicate that the onset of boundary tones co-occurs with the articulatory target of the final vowel. This timing is further modified by stress, but not by pitch accent: boundary tones are initiated earlier in words with non-final stress than in words with final stress regardless of accentual status. Visual data inspection reveals that phrase-final words are followed by acoustic pauses during which specific articulatory postures occur. Additional analyses show that these postures reach their achievement point at a stable temporal distance from boundary tone onsets regardless of stress position. Based on these results and parallel findings on boundary lengthening reported elsewhere, a novel approach to prosody is proposed within the context of Articulatory Phonology: rather than seeing prosodic (lexical and phrasal) events as independent entities, a set of coordination relations between them is suggested. The implications of this account for prosodic architecture are discussed. PMID- 25300342 TI - Analysis of BmNPV orf101 disruption: orf101 is essential for mediating budded virus production. AB - In our previous study, Orf101 (Bm101) of Bombyx mori nucleopolyhedrovirus (BmNPV) was identified as a component of the budded virions important for viral late gene expression. In this study we demonstrate that Bm101 is actually a previously unrecognized core gene and that it is essential for mediating budded virus production. To determine the role of Bm101 in the baculovirus life cycle, a Bm101 knockout bacmid containing the BmNPV genome was generated through homologous recombination in Escherichia coli. Furthermore, a Bm101 repair bacmid was constructed by transposing the Bm101 open reading frame with its native promoter region into the polyhedrin locus of the Bm101 knockout bacmid. Bacmid DNA transfection assay revealed that the Bm101 knockout bacmid was unable to produce the infectious budded virus, while the Bm101 repair bacmid rescued this defect, allowing budded-virus titers to reach wild-type levels. Real time PCR analysis indicated that the viral DNA genome in the absence of Bm101 was unaffected in the first 24 h p.t. Thus, studies of a Bm101-null BACmid indicate that Bm101 is required for viral DNA replication during the infection cycle. PMID- 25300343 TI - Chemical structures of constituents from the flowers of Osmanthus fragrans var. aurantiacus. AB - Three new megastigmane glycosides named floraosmanosides I-III and a new gamma decalactone named floraosmanolactone I together with 16 known constituents were isolated from the flowers of Osmanthus fragrans var. aurantiacus cultivated in Guangxi Zhuang Autonomous Region, China. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. Among them, ligustroside and (+)-pinoresinol significantly inhibited nitric oxide production in lipopolysaccharide-activated RAW264.7 macrophages. PMID- 25300344 TI - Structure of diarylheptanoids with antiallergic activity from the rhizomes of Curcuma comosa. AB - The methanolic extract from the dried rhizomes of Curcuma comosa cultivated in Thailand was found to inhibit the release of beta-hexosaminidase as a maker of degranulation from rat basophil leukemia (RBL-2H3) cells. Two new diarylheptanoids, diarylcomosols IV and V, were isolated from the methanolic extract. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The isolated diarylheptanoids showed inhibitory activity, and the structural requirements of the active constituents for the inhibition were clarified. PMID- 25300345 TI - Chemical constituents with NO production inhibitory and cytotoxic activities from Litsea cubeba. AB - A bioassay-guided fractionation of the roots and stems of Litsea cubeba led to the isolation of 14 constituents, including three new compounds, cubebanone (1), N-cis-3,4-methylenedioxycinnamoyl-3-methoxytyramine (2), and 9,9'-O-di-(E) feruloyl-(+)-secoisolariciresinol (3), together with 11 known ones (4-14). Compounds 1, 4, and 8-11 showed obvious in vitro anti-inflammatory activities against NO production in LPS-induced murine microglial (BV-2) cell line and RAW 264.7 macrophages. A cytotoxic evaluation showed that 2, 3, and 5-8 exhibited considerable inhibition against the growth of hepatocyte carcinoma (HepG2) cell line. These findings are evidence, to some extent, for the traditional medicinal application of L. cubeba, especially as folk medicine in the treatment of inflammation-related diseases. PMID- 25300346 TI - PTEN deficiency as a predictive biomarker of resistance to HER2-targeted therapy in advanced gastric cancer. AB - BACKGROUND: To investigate the role of the phosphoinositide 3-kinase (PI3K) pathway activation in human epidermal growth factor receptor 2 (HER2)-targeted therapy. METHODS: We evaluated the predictive roles of PI3K, catalytic alpha (PIK3CA), and phosphatase and tensin homolog (PTEN) in HER2-based therapy (either trastuzumab or lapatinib). PTEN expression and PIK3CA mutation were analyzed using immunohistochemistry and pyrosequencing. RESULTS: Forty-eight patients received trastuzumab (n = 39) or lapatinib (n = 9) combination chemotherapy. PTEN loss was found in 47.9% (n = 23), but no PIK3CA mutations were identified. Twenty six (54.1%) patients responded to HER2-based therapy, without a significant difference between patients with PTEN loss and those without (52.2 vs. 56.0%). Among the patients with responsive disease, time to best response did not differ by PTEN status, but the duration of response was significantly shorter for patients with PTEN loss (median 4.2 vs. 6.1 months, p = 0.04). In addition, patients with PTEN loss had a significantly shorter progression-free survival time (median 4.9 vs. 7.3 months, p = 0.047). CONCLUSIONS: PTEN deficiency is an important predictive marker for early resistance to HER2 inhibitor treatment in gastric cancer patients. This finding may be useful for the development of drug combinations and identification of patients who need a modified treatment strategy. PMID- 25300347 TI - Preoperative interleukin-22 values add valuable information for outcome prediction following orthotopic liver transplantation: a preliminary study. AB - BACKGROUND: Recent findings support the idea that interleukin (IL)-22 serum levels are related to disease severity in end-stage liver disease. Existing scoring systems--Model for End-Stage Liver Disease (MELD), Survival Outcomes Following Liver Transplantation (SOFT) and Pre-allocation-SOFT (P-SOFT)--are well established in appraising survival rates with or without liver transplantation. We tested the hypothesis that IL-22 serum levels at transplantation date correlate with survival and potentially have value as a predictive factor for survival. MATERIAL AND METHODS: MELD, SOFT, and P-SOFT scores were calculated to estimate post-transplantation survival. Serum levels of IL-22, IL-6, IL-10, C reactive protein (CRP), and procalcitonin (PCT) were collected prior to transplantation in 41 patients. Outcomes were assessed at 3 months, 1 year, and 3 years after transplantation. RESULTS: IL-22 significantly correlated with MELD, P SOFT, and SOFT scores (Rs 0.35, 0.63, 0.56 respectively, p<0.05) and with the discrimination in post-transplantation survival. IL-6 showed a heterogeneous pattern (Rs 0.40, 0.63, 0.57, respectively, p<0.05); CRP and PCT did not correlate. We therefore added IL-22 serum values to existing scoring systems in a generalized linear model (GLM), resulting in a significantly improved outcome prediction in 58% of the cases for both the P-SOFT (p<0.01) and SOFT scores (p<0.001). CONCLUSIONS: Further studies are needed to address the concept that IL 22 serum values at the time of transplantation provide valuable information about survival rates following orthotopic liver transplantation. PMID- 25300349 TI - Copper-catalyzed cascade cyclization of 1,7-enynes with aromatic sulfonyl chlorides toward selective assembly of benzo[j]phenanthridin-6(5H)-ones. AB - A step-economical method for the cascade cyclization of 1,7-enynes with aromatic sulfonyl chlorides by using a low-cost and more abundant Cu catalyst is presented. This method allows access to benzo[j]phenanthridin-6(5H)-ones and represents a new Cu-catalyzed cascade cyclization of 1,n-enynes. PMID- 25300348 TI - Plaque pH in caries-free and caries-active young individuals before and after frequent rinses with sucrose and urea solution. AB - OBJECTIVE: To examine pH in the approximal dental biofilm after acid and alkali formation from sucrose and urea, after an adaptation period to these substances, in caries-free (CF) and caries-active (CA) individuals. Saliva flow and buffer capacity, and aciduric bacteria in saliva and plaque were also examined. MATERIAL AND METHODS: Twenty adolescents and young adults (15-21 years) with no caries (n = 10, D(m + i)MFS = 0) or >=1 new manifest lesions/year (n = 10, DmMFS = 3.4 +/- 1.8) participated. After plaque sampling, interproximal plaque pH was measured using the strip method before (baseline) and up to 30 min (final pH) after random distribution of a 1-min rinse with 10 ml of 10% sucrose or 0.25% urea. This procedure was repeated after a 1-week adaptation period of rinsing 5 times/day with 10 ml of the selected solution. After a 2-week washout period the second solution was similarly tested. Mutans streptococci, lactobacilli and pH 5.2 tolerant bacteria were analyzed by culturing. RESULTS: In the CF group, acid adaptation resulted in lowering of baseline and final plaque pH values after a sugar challenge, and in increased numbers of bacteria growing at pH 5.2, which was increased also after alkali adaptation. In the CA group, the final pH was decreased after acid adaptation. No clear effects of alkali adaptation were seen in this group. CONCLUSION: One-week daily rinses with sucrose and urea had the most pronounced effect on the CF group, resulting in increased plaque acidogenicity from the sugar rinses and increased number of acid-tolerant plaque bacteria from both rinses. PMID- 25300350 TI - Antecedent Frequency Effects on Anaphoric Pronoun Resolution: Evidence from Spanish. AB - High-frequency words are usually understood and produced faster than low frequency words. Although the effect of word frequency is a reliable phenomenon in many domains of language processing, it remains unclear whether and how frequency affects pronominal anaphoric resolution. We evaluated this issue by means of two self-paced reading experiments. Native speakers of Spanish read sentences containing the anaphoric noun or pronoun at the subject syntactic position (Experiment 1) or at the object syntactic position (Experiment 2) while the antecedent of the anaphor was either a high-frequency or a low-frequency word. Results showed that nominal anaphors were read faster when referring to high-frequency than to low-frequency antecedents, and faster when referring to subjects than to objects. Critically, pronoun reading times were unaffected by the frequency and by the syntactic position of the antecedent. These results are congruent with theories assuming that syntactic information of the words is not frequency sensitive. PMID- 25300351 TI - Anosmin-1 over-expression increases adult neurogenesis in the subventricular zone and neuroblast migration to the olfactory bulb. AB - New subventricular zone (SVZ)-derived neuroblasts that migrate via the rostral migratory stream are continuously added to the olfactory bulb (OB) of the adult rodent brain. Anosmin-1 (A1) is an extracellular matrix protein that binds to FGF receptor 1 (FGFR1) to exert its biological effects. When mutated as in Kallmann syndrome patients, A1 is associated with severe OB morphogenesis defects leading to anosmia and hypogonadotropic hypogonadism. Here, we show that A1 over expression in adult mice strongly increases proliferation in the SVZ, mainly with symmetrical divisions, and produces substantial morphological changes in the normal SVZ architecture, where we also report the presence of FGFR1 in almost all SVZ cells. Interestingly, for the first time we show FGFR1 expression in the basal body of primary cilia in neural progenitor cells. Additionally, we have found that A1 over-expression also enhances neuroblast motility, mainly through FGFR1 activity. Together, these changes lead to a selective increase in several GABAergic interneuron populations in different OB layers. These specific alterations in the OB would be sufficient to disrupt the normal processing of sensory information and consequently alter olfactory memory. In summary, this work shows that FGFR1-mediated A1 activity plays a crucial role in the continuous remodelling of the adult OB. PMID- 25300352 TI - Preparation of hexagonal GeO2 particles with particle size and crystallinity controlled by peptides, silk and silk-peptide chimeras. AB - We demonstrate the use of silk based proteins to control the particle/crystallite size during GeO2 formation, using a bio-mimetic approach at circumneutral pH and ambient temperature. Multicrystalline GeO2 was prepared from germanium tetraethoxide (TEOG) in the presence of different silk-based proteins: Bombyx mori silk (native silk) and two chimeric proteins prepared by linking a germania binding peptide (Ge28: HATGTHGLSLSH) with Bombyx mori silk via chemical coupling at different peptide loadings (silk-Ge28 10% and silk-Ge28 50%). The mineralisation activity of the silk-based proteins was compared with that of peptide Ge28 as a control system. GeO2 mineralisation was investigated in water and in citric acid/bis-tris propane buffer at pH 6. Morphology, particle size, crystallinity, water and organic content of the materials obtained were analysed to study the effect of added biomolecules and mineralisation environment on material properties. In the presence of silk additives well-defined cube-shape hybrid materials composed of hexagonal germania and up to ca. 5 wt% organic content were obtained. The cubic particles ranged from 0.4 to 1.4 MUm in size and were composed of crystalline domains in the range 35-106 nm depending on the additive used and synthesis conditions. The organic material incorporated in the mineral did not appear to affect the unit cell dimensions. The silk and chimeric proteins in water promote material formation and crystal growth, possibly via an effective ion-channelling mechanism, however further studies are needed to assert to what extent the presence of the silk impacts on nucleation and growth stages. The germania binding peptide alone did not have any significant effect on reaction rate, yield or the material's properties compared to the blank. Interestingly, the peptide content in the silk chimeras tested did not affect mineralisation. The presence of buffer inhibited mineral condensation rate and yield. The use of silk-based biomolecules allows control of crystallite/particle size of hybrid materials opening up opportunities for bio-inspired approaches to be applied for the synthesis of functional germania based devices and materials. PMID- 25300353 TI - Evaluation of biochemical and molecular methods for Lactobacillus reuteri strains differentiation. AB - Several biochemical and molecular methods were used for discrimination of four Lactobacillus reuteri strains isolated from goatling and lamb stomach mucosa. Internal transcribed spacer (ITS)-PCR method and protein analysis by SDS-PAGE and MALDI-TOF showed to be suitable for strain discrimination whereas ITS-PCR/RFLP and enterobacterial repetitive intergenic consensus (ERIC)-PCR were not strain specific. The used methods differentiated tested strains into distinct groups; however, the location of strains in groups varied. Consistency in results was observed in the case of L. reuteri E and L. reuteri KO4m that were clustered into the same groups using all techniques, except of MALDI-TOF MS. The last one grouped goatling strains and lamb isolate into separate clusters. All investigated methods, except of ITS-PCR/RFLP and ERIC-PCR, were assessed as appropriate for distinguishing of L. reuteri strains. PMID- 25300354 TI - Phylogenetic relationships of the wall-synthesizing enzymes of Basidiomycota confirm the phylogeny of their subphyla. AB - Basidiomycota is one of the phyla of kingdom Fungi. This phylum contains besides non-pathogenic species and mushrooms, the important plant pathogens, smuts and rusts, and has been recently divided into three subphyla: Ustilaginomycotina, Pucciniomycotina, and Agaricomycotina (James et al. Nature 443:818-822, 2006; Hibbert et al. Mycological Research 111:509-547, 2007). Although the monophyletic origin of Basidiomycota appears practically undisputed, the phylogenetic relationships of the three subphyla have been considered somewhat uncertain (James et al. Nature 443:818-822, 2006). Previously, we described a hypothetical evolutionary scheme of the fungal cell wall (Ruiz-Herrera and Ortiz-Castellanos FEMS Yeast Research 10:225-243, 2010) that coincided with the accepted evolution tree of kingdom fungi (Cavalier-Smith Proceedings of the Royal Society of London B 271:1251-1262, 2004; James et al. Nature 443:818-822, 2006; Hibbert et al. Mycological Research 111:509-547, 2007). Based on the results of that study, we have now made an analysis of the phylogenetic relationships of the enzymes involved in the synthesis of the cell wall polysaccharides in Basidiomycota. According to our data, there is a close relationship of the wall-synthesizing enzymes with the accepted taxonomy of the group, with a few exceptions, noticeably the absence of chitin synthase IIb subclass in Pucciniomycotina, the duplication of chitin synthase class III in the same group, and the duplication of the gene encoding beta-1,3-glucan synthase (Gls) in Agaricomycotina. These results give some clues on the evolution of the cell wall in Basidiomycota. PMID- 25300355 TI - First report of Wohlfahrtiimonas chitiniclastica from soft tissue and bone infection at an unusually high northern latitude. AB - Wohlfahrtiimonas chitiniclastica is a rare human pathogen mostly associated with parasitic flies. This is the report on W. chitiniclastica infection in the soft tissue and bone at a 58 degrees N latitude in the northern temperate climate zone. The importance of correct identification of clinically relevant bacteria is highlighted. PMID- 25300356 TI - Virulence factors genes in enterococci isolated from beavers (Castor fiber). AB - Only limited information exists concerning the microbiota in beaver (Castor fiber). This study has been focused on the virulence factors genes detection in enterococci from beavers. In general, animals are not affected by enterococcal infections, but they can be a reservoir of, e.g. pathogenic strains. Moreover, detection of virulence factors genes in enterococci from beavers was never tested before. Free-living beavers (12), male and female (age 4-5 years) were caught in the north-east part of Poland. Sampling of lower gut and faeces was provided according to all ethical rules for animal handling. Samples were treated using a standard microbiological method. Pure bacterial colonies were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) identification system. Virulence factors genes-gelE (gelatinase), agg (aggregation), cylA (cytolysin A), efaAfs (adhesin Enterococcus faecalis), efaAfm (adhesin Enterococcus faecium) and esp (surface protein) were tested by PCR. Moreover, gelatinase and antibiotic phenotypes were tested. Species detected were Enterococcus thailandicus, E. faecium, E. faecalis and Enterococcus durans. In literature, enterococcal species distribution was never reported yet up to now. Strains were mostly sensitive to antibiotics. Vancomycin-resistant E. faecalis EE9Tr1 possess cylA, efaAfs, esp and gelE genes. Strains were aggregation substance genes absent. Adhesin E. faecium (efaAfm) gene was detected in two of three E. faecium strains, but it was present also in E. thailandicus. Esp gene was present in EE9Tr1 and E. durans EDTr92. The most detected were gelE, efaAfm genes; in EF 4Hc1 also gelatinase phenotype was found. Strains with virulence factors genes will be tested for their sensitivity to antimicrobial enterocins. PMID- 25300357 TI - Two-dimensional acoustic particle focusing enables sheathless chip Coulter counter with planar electrode configuration. AB - The field of cytometry has grown in scope and importance ever since the early 20th century with leaps in technology introducing the Coulter counter and the flow cytometer. Cytometry methods have brought about a revolution for the medical and biotechnology industry by providing fast and accurate analysis of cell and particle suspensions. Recent developments in the field aim at improving current cytometers and to provide miniaturized low-cost cytometry systems for point-of care clinical diagnostics or research. In an attempt to address the need for particle positioning which is important for both impedance and optically based cytometers we present a microfluidic system which precisely positions cells and particles, using acoustic forces and subsequently performs measurements using an integrated and simple planar electrode Coulter-type impedance cytometer without the need for sheath flows. Data is presented to show how the acoustic method improves the accuracy of the impedance cytometer when prefocusing is employed to particles and cells (diluted whole blood). Confocal imaging and simulations support the findings and provide the basis for further improvements. The acoustophoretic prefocusing technique opens a path towards small, low cost cytometers while also providing an easy way to improve current systems. PMID- 25300358 TI - De novo deletion 17p13.1 as a predictor for disease progression in chronic lymphocytic leukemia. AB - To determine the prognostic impact of de novo deletion 17p13.1 (17p-) in previously untreated chronic lymphocytic leukemia (CLL) patients, we prospectively studied the outcome of 71 treatment-naive CLL patients. About 18.3 % of them had 17p- detected by interphase fluorescent in situ hybridization (FISH) at diagnosis. There was statistically significant difference between 17p- negative and positive patients as regards 2-year overall survival [OS] (89.7 vs. 53.8 %, respectively; P = 0.001). On the other hand, 2-year progression-free survival [PFS] was also significantly higher in 17p- negative group than in 17p- positive one (82.8 vs. 23.1 %, respectively; P < 0.001). On univariate analysis for OS, 17p- positivity was significantly associated with shorter OS (P = 0.003). However, when we performed multivariate analysis, 17p- lost its significant impact. On the other hand, 17p- positivity was a significant risk factor for PFS in both univariate and multivariate analyses [independent risk factor] (P < 0.001 and P = 0.02, respectively). So, 17p- is a predictor for disease progression, but not for survival in CLL patients. PMID- 25300359 TI - Renal denervation therapy for resistant hypertension. AB - OPINION STATEMENT: Hypertension is common and leads to significant cardiovascular morbidity and mortality. Some patients are unable to achieve target blood pressures despite multiple antihypertensive medications; these patients are labeled as having resistant hypertension. To palliate the lack of pharmacologic options, recent technological advances led to the development of an interventional procedure to treat hypertension, namely renal sympathetic denervation. This percutaneous procedure involves the ablation of the afferent and efferent nerves surrounding the renal arteries. Many studies that were primarily observational in nature had very promising results. Systolic blood pressure reductions in the order of 25-30 mm Hg were observed in a series of unblinded studies, leading to the approval and widespread use of this technology across Europe, Australia, and Canada. However, a recent rigorous single blinded sham-controlled clinical trial failed to meet its efficacy endpoints. There are several postulated reasons for the conflicting results, which are discussed in this manuscript. These recent findings make us reflect on the need for rigorous clinical trials prior to the early approval and clinical adoption of novel technologies. At the moment, renal denervation remains an investigational procedure. Several trials are underway using different technologies, which, upon completion, will clarify the proper role of renal denervation for the treatment of patients with resistant hypertension. PMID- 25300360 TI - Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies. AB - Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4. PMID- 25300361 TI - Patients achieved greater range of movement when using high-flexion implants. AB - PURPOSE: NexGen Legacy Posterior Stabilized high-flexion prostheses (LPS-Flex) have been popularized as an alternative to NexGen standard prostheses (LPS) in total knee arthroplasty (TKA). Advocates of this new generation prosthesis suggest improved postoperative knee flexion. The purpose of this study was to summarize the best evidence for comparing the range of motion (ROM) and functional outcomes of LPS-Flex prostheses and LPS in TKA. METHODS: Electronic databases were systematically searched to identify relevant randomized controlled trials (RCTs). The last date for our research was July 2014. Our search strategy was followed the requirements of the Cochrane Library Handbook. The methodological quality was assessed, and the data were extracted independently by two authors. RESULTS: Nine studies that included 978 knees met our inclusion criteria for review. The results showed that there was larger postoperative ROM (1.62, 95% CI 0.52-2.72) in the LPS-Flex group than in the LPS group. There was not a statistically significant difference in the clinical functional scores and complications between the LPS-Flex group and the LPS group in TKA. The pooled mean differences were as follows: total KSS, -0.64 (95% CI -1.41 to 0.13); functional KSS, -0.53 (95% CI -1.51 to 0.45); HSS, 0.23 (95% CI -0.87 to 1.33); complications, 0.49 (95% CI 0.20-1.24); and radiolucent lines, 1.56 (95% CI 0.68 3.55). CONCLUSIONS: The preliminary results indicate that the NexGen LPS-Flex prosthesis provides an alternative to the NexGen LPS prosthesis, with greater range of motion and without severe complications or radiographic outcomes. The clinical advantages were not shown in the KSS or the HSS. Thus, the selection of a high-flexion prosthesis should depend on the characteristics of the patient, particularly high motivation and poor preoperative ROM. The potential benefits in the medium- and long-term outcomes require confirmation by larger, multicenter and well-conducted RCTs. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 25300362 TI - Double metal tibial blocks augmentation in total knee arthroplasty. AB - PURPOSE: Severe uncontained tibial bone defects occurring during total knee arthroplasty are challenging, and which treatment method is the best remains unknown. In this study, clinical and radiographic outcomes of double metal blocks augmentation were examined. METHODS: Between 2004 and 2012, double metal blocks augmentation was carried out in 17 patients with severe asymmetric uncontained tibial bone defects. The first block was attached to the tibial tray with screws, and then the second block was cemented to the first block. Out of 17 patients, 13 (8 primary, 5 revision) were available for final follow-up at a median of 69 months (range 24-99). For clinical assessment, range of motion and Knee Society score were evaluated preoperatively and annually thereafter. At the final follow up, Western Ontario and McMaster Universities Osteoarthritis Index, Oxford knee, Short Form-36, Lower extremity functional scale, and Lower extremity activity scale scores were evaluated. Radiographic assessment for radiolucent lines at the block-cement-bone interfaces and signs of failure was performed annually using fluoroscopy and standard radiographs. RESULTS: Range of motion and Knee Society score were significantly improved post-operatively. Other clinical outcomes were favourable. Radiolucent lines were seen on fluoroscopy in three knees, but no sign of failure, such as loosening, collapse, or instability, was observed at the final follow-up. CONCLUSIONS: Double metal blocks augmentation is a favourable and useful method, which does not cause mechanical failure or protrusion of the prosthetic because of its modularity, to manage severe asymmetric uncontained proximal tibial bone defects >15 mm in total knee arthroplasty. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 25300363 TI - Anatomical reconstruction of posterolateral corner and combined injuries of the knee. AB - PURPOSE: The goal of this study was to present a 2- to 5-year prospective follow up of an anatomical posterolateral corner reconstruction in a series of 16 patients with symptomatic instability and pain complaints of the knee. METHODS: All 16 patients underwent a posterolateral corner reconstruction as described by LaPrade et al. If cruciate ligament ruptures were present and had not been addressed earlier, these were reconstructed as well. Preoperatively and 2-5 years after surgery, multiple subjective knee outcome scores (VAS satisfaction score, Tegner, Lysholm, Noyes score and IKDC subjective knee form) were obtained, and the laxity of the joint was evaluated objectively by using bilateral varus stress radiographs to compare the injured with the uninjured knee. RESULTS: Eleven patients had concomitant ACL or PCL surgery or already had undergone surgery on this cruciate ligament. Mean varus laxity of the injured knee on varus stress radiographs improved significantly from 9.6 degrees (6.6-17.1) to 6.3 degrees (0.3-13.4), p = 0.0011. Post-operative varus laxity did not return to the level of the uninjured knee: 4.4 degrees (1.5-7.7), p = 0.036. VAS satisfaction score, the Tegner, Lysholm, Noyes scores and the IKDC subjective knee form all improved significantly. CONCLUSION: The anatomical reconstruction of the posterolateral corner does provide restoration of the external rotation stability in the majority of patients. However, the varus laxity could not be restored in all patients. Functional knee scores improved significantly, and most reconstructed knees had a laxity of <3 degrees compared with the uninjured knee, but the reconstructed knee did not become as stable as the uninjured knee. The results of this study can assist surgeons and patients to have realistic expectations of this operation. LEVEL OF EVIDENCE: Case series with no comparative group, Level IV. PMID- 25300364 TI - Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome. AB - Several biochemical, neuropathological, and experimental data suggest a possible role of nitric oxide (NO) in the pathophysiology of restless legs syndrome (RLS). Two single nucleotide polymorphisms (SNPs) neuronal nitric oxide synthase (nNOS or NOS1) gene (rs7977109 and rs693534) have been found to be associated with the risk for RLS in Germans, although only one of them (rs7977109) remained as significant after multiple comparison tests. The aim of our study was to replicate the possible association between these SNPs and risk for RLS in the Spanish population. We studied the allelic and genotype frequencies of the SNPs rs7977109 and rs693534 in 205 patients with RLS and 328 healthy controls using TaqMan genotyping. The rs7977109 and rs693534 genotypes and allelic frequencies did not significantly differ between patients with RLS and controls and were unrelated with the age at onset of RLS, gender, ferritin levels, and response to dopaminergic or gabaergic agents. The rs7999109GA genotype was overrepresented in RLS patients with positive family history of RLS, and in patients with symptomatic response to clonazepam. The results of our study suggest that these two NOS1 SNPs are not related to the overall risk for RLS in the Spanish population. PMID- 25300365 TI - Ultrathin polyaniline-based buffer layer for highly efficient polymer solar cells with wide applicability. AB - Interfacial buffer layers often attribute the improved device performance in organic optoelectronic device. Herein, a water-soluble hydrochloric acid doped polyanilines (HAPAN) were utilized as p-type electrode buffer layer in highly efficient polymer solar cells (PSC) based on PBDTTT-EFT and several representative polymers. The PBDTTT-EFT-based conventional PSC featuring ultrathin HAPAN (1.3 nm) delivered high PCE approximately 9%, which is one of the highest values among conventional PSC devices. Moreover, ultrathin HAPAN also exhibited wide applicability in a variety of efficient photovoltaic polymers including PBDTTT-C-T, PTB7, PBDTBDD, PBTTDPP-T, PDPP3T and P3HT. The excellent performances were originated from the high transparency, small film roughness and suitable work function. PMID- 25300366 TI - Visualized effect of oxidation on magnetic recording fidelity in pseudo-single domain magnetite particles. AB - Magnetite (Fe3O4) is an important magnetic mineral to Earth scientists, as it carries the dominant magnetic signature in rocks, and the understanding of its magnetic recording fidelity provides a critical tool in the field of palaeomagnetism. However, reliable interpretation of the recording fidelity of Fe3O4 particles is greatly diminished over time by progressive oxidation to less magnetic iron oxides, such as maghemite (gamma-Fe2O3), with consequent alteration of remanent magnetization potentially having important geological significance. Here we use the complementary techniques of environmental transmission electron microscopy and off-axis electron holography to induce and visualize the effects of oxidation on the magnetization of individual nanoscale Fe3O4 particles as they transform towards gamma-Fe2O3. Magnetic induction maps demonstrate a change in both strength and direction of remanent magnetization within Fe3O4 particles in the size range dominant in rocks, confirming that oxidation can modify the original stored magnetic information. PMID- 25300369 TI - Fluorous microgel star polymers: selective recognition and separation of polyfluorinated surfactants and compounds in water. AB - Immiscible with either hydrophobic or hydrophilic solvents, polyfluorinated compounds (PFCs) are generally "fluorous", some of which have widely been employed as surfactants and water/oil repellents. Given the prevailing concern about the environmental pollution and the biocontamination by PFCs, their efficient removal and recycle from industrial wastewater and products are critically required. This paper demonstrates that fluorous-core star polymers consisting of a polyfluorinated microgel core and hydrophilic PEG-functionalized arms efficiently and selectively capture PFCs in water into the cores by fluorous interaction. For example, with over 10 000 fluorine atoms in the core and approximately 100 hydrophilic arms, the fluorous stars remove perfluorooctanoic acid (PFOA) and related PFCs in water from 10 ppm to as low as a parts per billion (ppb) level, or an over 98% removal. Dually functionalized microgel-core star polymers with perfluorinated alkanes and additional amino (or ammonium) groups cooperatively recognize PFOA or its ammonium salt and, in addition, release the guests upon external stimuli. The "smart" performance shows that the fluorous-core star polymers are promising PFC separation, recovery, and recycle materials for water purification toward sustainable society. PMID- 25300368 TI - Glycemic pattern in diabetic patients on hemodialysis: continuous glucose monitoring (CGM) analysis. AB - BACKGROUND/AIMS: Recent evidences suggest that hemodialysis (HD) induces glycemic variations in diabetic patients. Continuous glucose monitoring (CGM) devices measure interstitial glucose in a 'Holter-like' manner thereby improving the glycemic control assessment method. METHODS: A CGM device (Medtronic iPRO) was used on 12 diabetic patients with chronic HD for 6 days to assess intra- and extra-dialytic interstitial glucose. RESULTS: In all enrolled patients, HD was associated with a decrease of interstitial glucose values. Intradialytic glucose nadir was 79 mg/dl and it was reached at the third hour after the beginning of the session. At the end of HD, interstitial glucose increased in all patients and a glycemic peak (187 mg/dl) occurred after an average time of 2.5 h. No episodes of nocturnal hypoglycemia occurred. CONCLUSION: HD is associated with significant intradialytic reduction of glycemia and postdialytic hyperglycemia. CGM devices result in better monitoring of glycemic trends in diabetic patients on chronic HD and could improve insulin management. PMID- 25300367 TI - Spotlite: web application and augmented algorithms for predicting co-complexed proteins from affinity purification--mass spectrometry data. AB - Protein-protein interactions defined by affinity purification and mass spectrometry (APMS) suffer from high false discovery rates. Consequently, lists of potential interactions must be pruned of contaminants before network construction and interpretation, historically an expensive, time-intensive, and error-prone task. In recent years, numerous computational methods were developed to identify genuine interactions from the hundreds of candidates. Here, comparative analysis of three popular algorithms, HGSCore, CompPASS, and SAINT, revealed complementarity in their classification accuracies, which is supported by their divergent scoring strategies. We improved each algorithm by an average area under a receiver operating characteristics curve increase of 16% by integrating a variety of indirect data known to correlate with established protein-protein interactions, including mRNA coexpression, gene ontologies, domain-domain binding affinities, and homologous protein interactions. Each APMS scoring approach was incorporated into a separate logistic regression model along with the indirect features; the resulting three classifiers demonstrate improved performance on five diverse APMS data sets. To facilitate APMS data scoring within the scientific community, we created Spotlite, a user-friendly and fast web application. Within Spotlite, data can be scored with the augmented classifiers, annotated, and visualized ( http://cancer.unc.edu/majorlab/software.php ). The utility of the Spotlite platform to reveal physical, functional, and disease-relevant characteristics within APMS data is established through a focused analysis of the KEAP1 E3 ubiquitin ligase. PMID- 25300370 TI - Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations. AB - BACKGROUND: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations. METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis. RESULTS: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm. CONCLUSIONS: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life. PMID- 25300371 TI - Significant association between bone-specific alkaline phosphatase and vascular calcification of the hand arteries in male hemodialysis patients. AB - BACKGROUND/AIMS: Bone-specific alkaline phosphatase (BAP) hydrolyzes pyrophosphate, which inhibits vascular calcification. We examined association between serum BAP and vascular calcification of male hemodialysis patients. METHODS: Hand roentgenography of 167 male maintenance hemodialysis patients was conducted, and visible vascular calcification of the hand arteries was evaluated. Serum levels of 3 bone formation markers (BAP, osteocalcin, and N-terminal propeptide of type I collagen) and 2 bone resorption markers (C-terminal telopeptide of type I collagen, and cross-linked N-telopeptide of type I collagen) were measured, along with serum intact parathyroid hormone (PTH). RESULTS: Of 167 patients, visible vascular calcification was seen in 37 patients. Among the bone formation and resorption markers, serum BAP was significantly higher in patients with vascular calcification than in those without (p<0.05); although the other 5 serum bone markers were not significantly different between them. Multivariate logistic regression analyses revealed that log [BAP] was significantly associated with vascular calcification after adjustment for age, hemodialysis duration, presence of diabetes, log [intact PTH] and each of the other 5 bone markers (p<0.0001). CONCLUSIONS: Higher serum BAP, but not other bone markers, is significantly associated with the presence of vascular calcification in male hemodialysis patients. PMID- 25300372 TI - The relationship between obstructive sleep apnea and atrial fibrillation in special patient populations. AB - Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder associated with both cardiovascular morbidity and mortality. Studies have shown a strong relationship between OSA and the most common cardiac arrhythmia - atrial fibrillation (AF). In this review, the authors intend to analyze AF in the context of OSA in populations of special medical interest; specifically investigating OSA in post-cardioversion, post-pulmonary isolation and post coronary artery bypass graft patients as well as those afflicted by congestive heart failure, hypertrophic cardiomyopathy, coronary artery disease, erectile dysfunction and stroke. Moreover, the authors will highlight the importance of OSA severity, our current understanding of its mechanistic link to AF pathophysiology and treatment options. PMID- 25300373 TI - Reamed intramedullary exchange nailing: treatment of choice of aseptic femoral shaft nonunion. AB - BACKGROUND: The aim of this study was to evaluate a standardized method of treatment of femoral nonunion of the isthmal femur excluding non-united metaphyseal fractures. METHODS: Between 2003 and 2010, 72 consecutive patients with nonunion of the femoral shaft were operated using a standardized protocol in our trauma department and followed up for successful union and functional result. RESULTS: Osseous healing was observed in 71 patients (98%). Only one patient was lacking bone healing following a time period of 24 months after the first exchange nailing and 5 months after the second exchange nailing. In 59 patients (82%), uneventful and timely bone healing after exchange nailing was detected. In 18% of patients (n = 13), delayed bone healing was observed and required additional therapy. In the majority of patients (61%), bone healing occurred within the first 2 to 5 months, only 18% of patients' duration of bone healing exceeded 8 months. In 62 patients (86%), no relevant or clinically apparent leg length discrepancy prior to and after exchange nailing was detected as well as no significant axis deviation or malrotation. Functional studies including simple clinical gait and standing analysis, return to activities of daily life, return to sports activities, and return to work were all reached on a satisfying level. DISCUSSION: Reamed intramedullary exchange nailing as described in this study is the treatment of choice for aseptic femoral shaft nonunion with a high rate of bone healing and a low rate of complications including length discrepancy or malrotation and a good functional outcome. PMID- 25300374 TI - Byssus attachment strength of two mytilids in mono-specific and mixed-species mussel beds. AB - The mussel Xenostrobus securis is endemic to the brackish waters of New Zealand and Australia, but has successfully invaded the inner Galician Rias of NW Spain, where it coexists with the indigenous mussel Mytilus galloprovincialis. In this laboratory study, the plasticity of the byssus attachment strength of two mytilids was compared by manipulating substratum, salinity, and bed assembly. M. galloprovincialis showed stronger byssus detachment strength than X. securis, despite lower byssus coverage. Both species responded similarly to the substratum, with substantially lower byssus strength on methacrylate, which offered the lowest surface free energy. Byssus detachment values for M. galloprovincialis were lower at lower salinity. In mixed beds, a number of mussels moved upwards, eventually colonising the upper layers of the assemblage. This behaviour increased byssus strength but only for X. securis. X. securis is adapted to a wide spectrum of abiotic conditions, a trait that may promote its dissemination within estuarine environments. PMID- 25300375 TI - Hepatitis B vaccination for reducing morbidity and mortality in persons with HIV infection. AB - BACKGROUND: Hepatitis B vaccine has been recommended for use in people living with HIV (PLHIV) mostly because of the similarities in routes of infection and their prevalence in the same geographic areas. PLHIV may not develop sero protection after receiving standard hepatitis B vaccine due to their compromised immune status. OBJECTIVES: To evaluate the efficacy of hepatitis B virus vaccine in PLHIV compared to placebo or no vaccine. SEARCH METHODS: We searched 6 English language databases in July 2012, and updated the search in June 2013 and August 2014. We searched the grey literature, conference proceedings, specialised web sites, and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials of hepatitis B vaccine compared to placebo or no vaccine, evaluating relevant outcomes of efficacy and safety. DATA COLLECTION AND ANALYSIS: Two review authors independently sought and extracted data on study design, participants, hepatitis B infection, hepatitis B related morbidity and mortality, anti-HBs immunogenicity and adverse effects related to vaccines from published articles or through correspondence with authors. Data were analysed qualitatively. MAIN RESULTS: One double-blind randomised controlled trial with 26 participants who were on antiretroviral therapy (ART), comparing hepatitis B vaccine to placebo conducted in Spain met our eligibility criteria and was included in this review. The study ran for three years and participants were followed up on a monthly basis. The study reported adequate humoral response to vaccine at 12 months and no local or systematic side effects in both intervention and control groups. This humoral response was lost when the participants stopped taking ART. The sample size of the study was small and the study was conducted in a high income setting unlike the areas of highest burden of hepatitis B and HIV co-infections. AUTHORS' CONCLUSIONS: The evidence from this study is insufficient to support any recommendations regarding the use of hepatitis B vaccine in PLHIV. Neither does this evidence demonstrate that hepatitis B vaccine is unsafe in PLHIV. Further randomised controlled trials in high prevalence areas are required to generate evidence on the long term efficacy and safety of hepatitis B vaccine in PLHIV with and without ART. Different regimens and routes of administration should also be explored. PMID- 25300376 TI - Sex-dependent association between coronary vessel dominance and cardiac syndrome X: a case-control study. AB - BACKGROUND: Previous studies have demonstrated the relevance of left coronary artery dominance in the outcome and prognosis of obstructive coronary artery disease (CAD). However, no studies have investigated the influence of coronary vessel dominance on non obstructive CAD. The aim of this study was to establish the association of left and mixed dominance of the major epicardial arteries with the development of non obstructive CAD and evaluate potential sex-dependent differences in the coronary artery supply. METHODS: A total of 484 patients underwent the same diagnostic procedures. The patients were divided into two groups based on their coronary angiogram results: the control group (242 patients with obstructive CAD; coronary artery stenosis of >=50%) and the experimental group (242 patients with non obstructive CAD; coronary artery stenosis of <50%). RESULTS: Significantly more women than men were affected by non obstructive CAD (P = 0.005). Left dominance was more frequent in the non obstructive CAD group than in the control group (P = 0.018) and was more pronounced in women than in men (P = 0.013). Among men with non obstructive CAD, a left supply was more frequent than a mixed supply (P = 0.012). Women with non obstructive CAD had a higher frequency of a left supply, whereas a mixed supply was less frequent in men than in patients with obstructive CAD (P = 0.013 and 0.018, respectively). CONCLUSION: These results suggest that left dominance (particularly in women) and the absence of a mixed supply in men could cause regional ischemia, thus affecting the development of non obstructive CAD. Furthermore, sex may determine the incidence of specific coronary artery supply types, therefore influencing disease development and prognosis. PMID- 25300377 TI - Can physician laboratory-test requests be influenced by interventions? AB - BACKGROUND: Laboratory tests affect healthcare costs and unnecessary test requests can thus be a concern. We studied whether it was possible to influence physician laboratory-test requests using four structured interventions: introduction of clinical guidelines, education, feedback, and reminder letters. The interventions occurred at different times at Landspitali University Hospital, Reykjavik, Iceland. Akureyri Hospital, northern Iceland, was used as a control, since no formal interventions were introduced there. MATERIALS AND METHODS: Six types of laboratory tests were analyzed. The relative risk of a laboratory test being conducted at Landspitali University Hospital compared to Akureyri Hospital was calculated for various points in time, as well as the associated 95% confidence intervals. The primary estimates compare the pre- and post intervention periods (2007-2009 vs. 2010-2013), but also on a monthly basis in order to observe the trends in greater detail. RESULTS: Interventions at Landspitali University Hospital led to a significant reduction in the average number of laboratory tests (12-52%, p < 0.001) compared with Akureyri Hospital. Relative risk coefficients of laboratory tests at Landspitali University Hospital (LUH) compared to Akureyri Hospital (AH) were calculated pre- and post guidelines, the relative risk for ASAT, CRP and GGT fell markedly, while ALAT and ALP tests did not show a significant decrease. Relative risk for a blood culture test in the period after the guidelines was statistically significantly increased. CONCLUSION: It is possible to influence physician laboratory-test requests using multifaceted interventions that include continuous monitoring and follow-up. PMID- 25300379 TI - Surgical versus nonoperative treatment: how do we choose the right approach to lumbar disk herniation? PMID- 25300380 TI - Minimize opioids by optimizing pain psychology. PMID- 25300381 TI - Twin study highlights possible genetic link in chronic pain. PMID- 25300383 TI - Can neural blocks prevent phantom limb pain? AB - Phantom limb syndrome (PLS) is a syndrome including stump pain, phantom limb pain and not-painful phantom sensations, which involves a large part of amputee patients and often has devastating effects on their quality of life. The efficacy of standard therapies is very poor. Nerve blocks have been investigated for the treatment and prevention of PLS. Epidural and peripheral blocks limited to the first three postamputation days can only reduce acute pain but cannot prevent the later development of PLS. Recent studies have shown that ambulatory prolonged peripheral nerve block (up to 30 days postamputation) may represent a new possible option to treat phantom pain and prevent the development of PLS and chronic pain. PMID- 25300384 TI - A description of clinical characteristics and treatment patterns observed within prescribed opioid users in Germany and the UK. AB - AIMS: To describe a cohort of new opioid users (adult noncancer patients) in terms of clinical characteristics and treatment patterns in the UK and Germany. MATERIAL & METHODS: Data used were extracted from electronic medical records databases (UK: Clinical Practice Research Database-Hospital Episode Statistics; Germany: IMS Disease Analyzer) covering the 2008-2012 period. RESULTS: Most eligible patients were treated with opioids for less than 6 months (UK: 78.7% and Germany: 93.7%) and indexed on weak opioids (UK: 89.5% and Germany: 88.6%). Most prescribed opioids were codeine (UK) and tramadol (Germany). Most prevalent comorbidities were dorsalgia/depression. Constipation was observed in 16.8%/17.4% (UK/Germany) of chronic users (>6 months). CONCLUSION: While both populations were highly morbid populations largely initiated on weak opioids, chronic use was less common in Germany. PMID- 25300385 TI - PASTOR/PROMIS (r) pain outcomes system: what does it mean to pain specialists? AB - The Army Pain Management Task Force was charged with recommending pain management strategies for Army Medical Command that would optimize quality of life for patients living with acute and chronic pain. Among their recommendations was the development of the Pain Assessment Screening Tool and Outcomes Registry (PASTOR). In order to develop this tool, the Pain Management Task Force leveraged the NIH's investment in building the Patient-Reported Outcomes Measurement Information System (PROMIS((r))). The two foci of PASTOR are to enhance the clinical encounter and provide data for comprehensive evaluations of treatment effectiveness. The potential of such information for the future of clinical management is described. PMID- 25300386 TI - Secondary prevention of chronic pain: can internet help? AB - Chronic pain is common and strongly impacts the individual and society as a whole. Although there are effective multidisciplinary treatments available, they are often not easily accessible and designed for people with severe long-lasting problems. The main aim of this paper is to propose and stimulate debate about how the internet can help to increase accessibility and promote a shift toward secondary prevention. Specifically, internet can help by providing access to educational websites containing information for professionals and the general population. Internet can also be useful for creating accessible interventions designed to reduce risk factors for the development of long-term disability. The involvement of society in general and the professionals working in the field is fundamental for advancing in this direction. PMID- 25300387 TI - Diagnosing the bladder as the source of pelvic pain: successful treatment for adults and children. AB - The key to successful therapy of interstitial cystitis (IC) is to correctly diagnose it. The significant majority of patients with IC have a dysfunctional bladder epithelium that allows urinary solutes (primarily potassium) to leak into the bladder wall, causing symptoms and tissue damage. Drugs that correct this dysfunction and suppress symptoms are important to achieve successful outcomes in patients. Today over 95% of females with IC are misdiagnosed as having gynecologic chronic pelvic pain, vulvodynia, vaginitis, endometriosis, overactive bladder or urinary tract infection. Men are misdiagnosed as having prostatitis. Often children are not diagnosed at all. Multimodal drug therapy may be required and can achieve successful resolution of IC in over 90% of patients. IC in children can be treated successfully with pentosan polysulfate. PMID- 25300389 TI - Neuropathic pain in cancer survivors. AB - The occurrence of pain in cancer survivors may be debilitating. These pain syndromes may be of different types, including neuropathic pain. The research related to cancer management has been done extensively in certain areas, but such research in cancer survivors is still lacking. The chronic pain in cancer survivors is not only under-reported but also under-treated. The assessment of pain in cancer survivors is multifaceted because of many domains like physical, social and psychological. Usually, the pain management may be considered similar to that for chronic noncancer pain, but with a caveat that such pain may at times be indicative of cancer recurrence. The multidisciplinary and multimodal management is essential for such neuralgic pain in cancer survivors. This may require a balanced combination of pharmacological and nonpharmacological techniques, including psychological support. The overall goal that remains in such patients for pain management is to improve the quality of life. Here we review certain pertinent aspects of neuropathic pain in cancer survivors. PMID- 25300388 TI - Chronic post-traumatic headache in pediatrics. AB - Both primary headaches and minor head injuries are common in children. If headache presents for the first time or becomes exacerbated soon after head injury it is described as post-traumatic headache (PTH). Acute PTH resolves within 3 months from injury, but chronic PTH continues beyond 3 months. The pathogenesis of PTH is not well understood. Several mechanisms were proposed such as axonal injuries and disturbances of cerebral metabolic processes. The clinical features of PTH are those of primary headache disorders such as migraine and tension-type headache and usually follow a favorable prognosis. Investigations and management should therefore be relevant to the type of headache and focused on clinical needs of the child. PMID- 25300390 TI - Opioid-induced respiratory depression in the acute care setting: a compendium of case reports. AB - Opioid-induced respiratory depression (OIRD) is a potentially fatal complication of treatment with opioids. Little is known about patient- and case-related factors associated with OIRD. One-hundred-and-five available case reports on OIRD in 134 patients (12 years and older) in the perioperative, obstetric or emergency care setting, published since 1980, were retrieved from the literature. The most frequently reported case-related factors were: morphine use, perioperative setting and obstetrics, neuraxial or intravenous administration. The most frequently reported patient-related factors involved were: female gender, sleep disordered breathing, obesity, renal impairment, pulmonary disease and CYP450 enzyme polymorphisms. While the analysis has limitations, it confirms that OIRD in the acute setting involves complex and interrelated factors and is a significant cause of preventable morbidity and mortality. PMID- 25300391 TI - Evidence of ERalpha and ERbeta selectivity and partial estrogen agonism in traditional Chinese medicine. AB - The use of complementary and alternative medicine and herbal products, especially traditional Chinese medicines, is progressively rising for both adults and children. This increased use is based on the popular belief that these medicines are safe and harmless. In this report, we describe the results of a bedside-to bench study that involved a short-statured 4-year-old boy with deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone due to an ectopic posterior pituitary gland and invisible pituitary stalk. Although the boy was given replacement therapy with hydrocortisone and L-thyroxin, the parents refused to treat him with growth hormone and consulted a naturopath who prescribed a traditional Chinese medicine (TCM) to stimulate the boy's growth. From the age of 20 months, the child's growth was regularly monitored while he was being treated with hydrocortisone, thyroxin, and the TCM. Over a 36-month period, the child's growth velocity accelerated (3 cm/year to 8 cm/year), his height increment substantially increased (-2 SD to -0.8 SD), and his bones matured. In the laboratory investigation, estrogen receptor (ER)alpha and ERbeta reporter cell lines were used to characterize the estrogenic activity of the TCM medicine and its 18 components, and the results established that the medicine and some of its components have estrogen receptor ERalpha and ERbeta selectivity and partial estrogen agonism. Partial estrogenic activity of the TCM was confirmed using whole-cell competitive binding, cell proliferation, and endogenous gene expression assays in the ERalpha-positive breast cancer cell lines. Although the presence of evidence is not always evidence of causality, we have concluded that this traditional Chinese medicine contains ingredients with estrogenic activity that can sustain bone growth and maturation without affecting other estrogen dependent tissues. PMID- 25300392 TI - Effect of including fitness testing in preventive health checks on cardiorespiratory fitness and motivation: study protocol of a randomized controlled trial. AB - BACKGROUND: Preventive health checks may identify individuals with an unhealthy lifestyle and motivate them to change behaviour. However, knowledge about the impact of the different components included in preventive health checks is deficient. The aim of this trial is to evaluate whether including cardiorespiratory fitness testing in preventive health checks 1) increases cardiorespiratory fitness level and motivation to change physical activity behaviour and 2) reduces physical inactivity prevalence and improves self-rated health compared with preventive health checks without fitness testing. METHODS/DESIGN: An open-label, household-cluster, randomized controlled trial with a two-group parallel design is used. The trial is embedded in a population based health promotion program, "Check your Health Preventive Program", in which all 30-49 year-old citizens in a Danish municipality are offered a preventive health check. In each arm of the trial, 750 citizens will be recruited (1,500 in total). The primary outcome is cardiorespiratory fitness level assessed by submaximal cycle ergometer testing after one year. An intermediate outcome is the percentage of participants increasing motivation for physical activity behaviour change between baseline and two-weeks follow-up assessed using the Transtheoretical Model's stages of change. Secondary outcomes include changes from baseline to one-year follow-up in physical inactivity prevalence measured by a modified version of the questions developed by Saltin and Grimby, and in self rated health measures using the Short-Form 12, Health Survey, version 2. DISCUSSION: This trial will contribute to a critical appraisal of the value of fitness testing as part of preventive health checks. The conduction in real-life community and general practice structures makes the trial findings applicable and transferable to other municipalities providing support to decision-makers in the development of approaches to increase levels of physical activity and improve health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02224248. Registered 8 August 2014. PMID- 25300393 TI - Early effects of dexamethasone implant on macular morphology and visual function in patients with macular edema secondary to retinal vein occlusion. AB - PURPOSE: To evaluate the early effects of the intravitreal erodible dexamethasone implant Ozurdex in patients with macular edema due to retinal vein occlusion (RVO). METHODS: Eyes with macular edema due to RVO were prospectively included in the study and received a 700-MUg dexamethasone implant. Best-corrected visual acuity (BCVA) measurement, complete ophthalmic evaluation and spectral-domain optical coherence tomography were performed at baseline and 1, 2, 3, 7, 14, 21, 28, 60, and 90 days after treatment. RESULTS: Nineteen eyes of 18 patients were included in the study. Mean central retinal thickness (CRT) decreased rapidly after treatment (p < 0.0001) from 503 MUm at baseline to 288 MUm after 1 day and 199 MUm at the end of the follow-up. BCVA gained on average +6 ETDRS letters after 1 day and +11 letters at day 90 (p = 0.0001). CONCLUSION: The intravitreal dexamethasone implant showed a fast effect in reducing CRT and improving BCVA in RVO patients. PMID- 25300394 TI - Arthroscopic partial meniscectomy is superior to physical rehabilitation in the management of symptomatic unstable meniscal tears. AB - PURPOSE: Meniscus injuries are the most commonly reported in athletes. Meniscectomy is the most common treatment. Stable peripheral tears may heal, while degenerative tears do well with physical therapy. However, the exact role of physical therapy in treating symptomatic unstable meniscal tears is not known. We aimed to identify the role of physical therapy in treating such patients and clarify the role of arthroscopic partial meniscectomy in treating unstable meniscal tears. METHODS: Seventy patients with unstable meniscal tear met the inclusion criteria according to Vande Berg and co-workers. Clinical examination, McMurray test and magnetic resonance imaging were done. Age ranged from 18-67 years (average 39.87). Mild osteoarthritis was seen in 20 cases. Physical therapy thrice a week for eight weeks was offered (faradic quadriceps stimulation and neuromuscular strengthening exercises). After physical therapy, patients still complaining or unsatisfied were offered arthroscopic partial menisectomy (APM). Outcomes were evaluated using the VAS pain score and the Lysholm knee score. RESULTS: Mean VAS before interventions was 7.4, significantly improved to 5.16 after rehabilitation and to 1.9 after APM (p = 0.001). Mean Lysholm score before rehabilitation was 65.1 and improved to 69.6 after rehabilitation, the difference was non-significant. However, Lysholm score difference before and after APM showed a highly significant difference (p = 0.001). CONCLUSIONS: Pain and swelling improved after physical therapy. However, patients were not satisfied as limited range of knee motion persisted. APM was superior to physical therapy in treating symptomatic unstable meniscal tears, with high patient satisfaction and restored knee function. PMID- 25300395 TI - Clinical and radiographic outcomes of an accelerometer-based system for the tibial resection in total knee arthroplasty. AB - PURPOSE: The accelerometer-based system is a portable surgical navigation system for TKA that does not require the use of a large computer console for registration and alignment feedback as required in computer-assisted surgery (CAS). The purpose of this prospective study was to determine the accuracy of the accelerometer-based system in the tibial component positioning and also to evaluate clinical outcomes. METHODS: Between December 2011 and July 2012, a total of 53 consecutive patients with primary gonarthrosis were prospectively enrolled for unilateral TKA using a handheld surgical navigation system to perform the tibial resection. Pre-operatively and postoperatively, patients were asked to fill out a visual analogue scale for pain (VAS) and a knee injury and osteoarthritis outcome score (KOOS). Standing antero-posterior (AP) hip-knee ankle (HKA) and lateral knee-to-ankle radiographs were performed to determine the varus/valgus alignment and the posterior slope of the tibial components relative to the mechanical axis. RESULTS: The mean duration of follow-up was 23 months. Average preoperative VAS was 8.3 +/- 0.67, which significantly improved to a mean 1.2 +/- 0.57 at final follow up (P < 0.001). All scores significantly increased compared with pre-operative scores, except for the KOOS sport component (P = 0.075) and quality of life (P = 0.19). Intra-operatively, the average reading provided by the system with regard to varus/valgus alignment before performing the tibial resection was 0.55 degrees +/- 0.43. The average postoperative radiographic alignment of the tibial component in the coronal plane was 0.65 degrees +/- 0.59 of deviation by the ideal alignment (P > 0.05). CONCLUSION: This study demonstrates that the OrthAlign navigation system combines the accuracy of the computer-assisted surgery systems with the ease of use and familiarity of the traditional instruments while avoiding the drawbacks of the CAS technique and disadvantages of conventional IM femoral alignment systems. The system could demonstrate an improvement in the incidence of outliers in final coronal alignment, as compared with a patient-specific cutting guide. PMID- 25300396 TI - Clinical outcome and return to work following single-stage combined autologous chondrocyte implantation and high tibial osteotomy. AB - PURPOSE: Concomitant unloading procedures, such as high tibial osteotomy (HTO), are increasingly recognized as an important part of cartilage repair. This study presents survival rate, functional outcome, complication rate, and return to work following combined single-stage autologous chondrocyte implantation (ACI) and HTO. METHODS: Forty patients with a mean follow-up of 60 months with isolated full thickness cartilage defects of the medial femoral condyle (MFC) and concomitant varus deformity were included in this retrospective case series. All patients were treated with a single-stage combined ACI and HTO between January 2004 and December 2010. Functional outcome was evaluated prior to surgery and at follow-up using standard scores (Lysholm, VAS, KOOS). Treatment failure was defined as the need for re-operation. Return to work was evaluated using the REFA score. RESULTS: With all patients (mean age 36.8 SD +/- 8.1 years; varus deformity 4.9 +/- 1.8 degrees ; mean defect size 4.6 +/- 2.1 cm2) a clinical investigation was performed a mean of 60.5 months (SD +/- 2.5) postoperatively. Four patients required reintervention (failure rate 10 %). VAS decreased significantly from 6.7 +/- 1.9 points preoperatively to 2.2 +/- 1.3 points postoperatively. The mean Lysholm score at follow-up was 76.2 +/- 19.8 points. The mean KOOS subscales were 81.4 +/- 18.0 for pain, 81.3 +/- 14.0 for symptoms, 87.6 +/- 16.2 for activity in daily living, 66.7 +/- 22.8 for function in sport and recreation, and 55.5 +/- 22.0 for knee-related quality of living. Mean duration of incapacity from work was 94.5 +/- 77 days. Absenteeism from work depended on work load (return to work REFA 0: 68.9 +/- 61.4 days vs. REFA 4: 155.0 +/- 111.0 days). CONCLUSION: Single-stage autologous chondrocyte implantation and concomitant high tibial osteotomy is a reliable and safe treatment with satisfying clinical outcome and improved functional outcome. However, we found a remarkable stay at work rate, which depended on the work load. PMID- 25300397 TI - Evaluation of the accuracy of patient-specific cutting blocks for total knee arthroplasty: a meta-analysis. AB - PURPOSE: Because published studies on the accuracy achieved with patient-specific guides during total knee arthroplasty (TKA) contradict each other, this systematic review and meta-analysis sought to compare radiological TKA outcomes when patient-specific cutting blocks (PSCB) were used to the outcomes when standard manual instrumentation was used. METHODS: The meta-analysis was implemented according to PRISMA Statement Criteria. The primary endpoint was the hip-knee-ankle (HKA) angle, which represents the leg's mechanical axis. The accuracy of component placement in the coronal and sagittal planes, and the accuracy of femoral component rotation were also compiled. After testing for publication bias and heterogeneity across studies, data were aggregated random effects modeling when necessary. RESULTS: Fifteen articles were included: 916 total knee arthroplasty cases in the PSCB group and 998 in the MI group. The mechanical axis did not differ between the two groups (weighted mean difference 0.07 degrees ; 95 % CI, -0.5 degrees to 0.65 degrees ; p = 0.8). Risk ratio analysis revealed no protective effect of using PSCB relative to the appearance of HKA angle outliers (RR = 0.88; 95 % CI, 0.68-1.13; p = 0.3). There was a trend towards a protective effect with PSCB for the risk of femoral component outliers, but the opposite was observed for the tibial component. The implantation procedure was stopped in 30 cases because the surgeon-authors found excessive discrepancies between the intra-operative observations and the pre-operative plan. CONCLUSIONS: This meta-analysis found no evidence that using patient specific cutting blocks provides superior accuracy to using manual instrumentation during TKA. PMID- 25300399 TI - Letter to the editor: where is the lateral femoral wall? PMID- 25300398 TI - Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice. AB - PURPOSE: Iron overload accelerates bone loss in mice lacking the bone morphogenetic protein 6 (Bmp6) gene, which is the key endogenous regulator of hepcidin, iron homeostasis gene. We investigated involvement of other BMPs in preventing haemochromatosis and subsequent osteopenia in Bmp6-/- mice. METHODS: Iron-treated wild-type (WT) and Bmp6-/- mice were analysed for hepcidin messenger RNA (mRNA) and tissue and blood BMP levels by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry, Western blot, enzyme linked immunosorbent assay (ELISA) and proximity extension assay. BMPs labeled with technetium-99m were used in pharmacokinetic studies. RESULTS: In WT mice, 4 h following iron challenge, liver Bmp6 and hepcidin expression were increased, while expression of other Bmps was not affected. In parallel, we provided the first evidence that BMP6 circulates in WT mice and that iron increased the BMP6 serum level and the specific liver uptake of (99m)Tc-BMP6. In Bmp6-/- mice, iron challenge led to blunted activation of liver Smad signaling and hepcidin expression with a delay of 24 h, associated with increased Bmp5 and Bmp7 expression and increased Bmp2, 4, 5 and 9 expression in the duodenum. Liver Bmp7 expression and increased circulating BMP9 eventually contributed to the late hepcidin response. This was further supported by exogenous BMP7 therapy resulting in an effective hepcidin expression followed by a rapid normalisation of plasma iron values and restored osteopenia in Bmp6-/- mice. CONCLUSION: In Bmp6-/- mice, iron activated endogenous compensatory mechanisms of other BMPs that were not sufficient for preventing hemochromatosis and bone loss. Administration of exogenous BMP7 was effective in correcting the plasma iron level and bone loss, indicating that BMP6 is an essential but not exclusive in vivo regulator of iron homeostasis. PMID- 25300400 TI - Combination of multiple databases is necessary for a valid systematic review. PMID- 25300401 TI - Letter regarding Chang et al.: The safety and efficacy of minimally invasive discectomy: a meta-analysis of prospective randomised controlled trials. PMID- 25300402 TI - Online apnea-bradycardia detection based on hidden semi-Markov models. AB - In this paper, we propose a new online apnea-bradycardia detection scheme that takes into account not only the instantaneous values of time series, but also their temporal evolution. The detector is based on a set of hidden semi-Markov models, representing the temporal evolution of beat-to-beat interval (RR interval) time series. A preprocessing step, including quantization and delayed version of the observation vector, is also proposed to maximize detection performance. This approach is quantitatively evaluated through simulated and real signals, the latter being acquired in neonatal intensive care units (NICU). Compared to two conventional detectors used in NICU, our best detector shows an improvement on average of around 15 % in sensitivity and 7 % in specificity. Furthermore, a reduced detection delay of approximately 2 s is also observed with respect to conventional detectors. PMID- 25300403 TI - A new layered sensor for simultaneous measurement of EMG, MMG and oxygen consumption at the same position. AB - A new layered sensor for simultaneous measurement of electromyography (EMG), mechanomyography (MMG) and oxygen consumption based on near-infrared spectroscopy (NIRS) at the same position of the muscle is presented. The proposed sensor is a layered structure of a thin stainless-steel electrode, a PVDF film with transparent electrodes and optical sensors. EMG, MMG and oxygen consumption based on NIRS are measured by the stainless-steel electrodes, PVDF film and optical sensors, respectively. Using the three types of data, muscular activity can be analyzed in more detail. Additionally, the proposed sensor system reduces the constraint of the sensors arranged on the skin in measurements at multiple points because three types of information, previously obtained with three types of general sensors, are detected by a pair of proposed sensors. In an experiment, simultaneous measurement of EMG, MMG and oxygen consumption via NIRS at the forearm was demonstrated using the proposed sensor under fluorescent light. The performance of the layered sensor was evaluated. PMID- 25300405 TI - MAINTAINING FUNCTION WITH AGING WHAT WE HAVE LEARNED FROM THE FELS LONGITUDINAL STUDY. PMID- 25300404 TI - Longitudinal declines in instrumental activities of daily living in stable and progressive mild cognitive impairment. AB - BACKGROUND: Previous cross-sectional studies suggest that assessments of instrumental activities of daily living (IADLs) may be useful for operationalizing the differences in functional deficits seen in mild cognitive impairment (MCI) and dementia. However, their utility for longitudinal changes in IADLs in the transition between MCI and dementia remains unclear. METHODS: We analyzed longitudinal IADL data with the Functional Activities Questionnaire (FAQ) in stable (MCI-S; n = 1,318) or progressive (MCI-P; n = 1,108) MCI patients. RESULTS: Larger increases in FAQ scores were seen in the MCI-P group across a 14.5-month interval, but overlapping distributions in the two groups yielded poorer discriminatory power than prior cross-sectional reports. CONCLUSION: Our findings emphasize the difficulties in operationalizing the criterion of 'essentially intact' IADLs in MCI, which may complicate the interpretation of disease progression in MCI treatment trials. PMID- 25300406 TI - Increased predictive ability of BMI but not other risk factors with time in men: 39-year follow-up of total mortality in the Oslo Study. AB - OBJECTIVE: Risk factor associations to mortality may change, in part due to removal of high-risk persons. We compared strengths of association and ability of risk factors to predict total mortality across short (<15 years), medium (15-29 years) and long (30-39 years) follow-up. METHODS: Cardiovascular risk factors were measured in 1972-1973 in the Oslo Study among 14,846 men born in 1923-1932. Relationships of risk factors to mortality (to 2011) were analyzed using Cox regression models, and receiver operating characteristics (ROC) were estimated. RESULTS: BMI was the only factor that increased strength of association with elapsed time (hazard ratio for >=35 kg/m(2) vs. 22.5-24.9 kg/m(2): 1.25 (95% CI 0.73-2.17), 1.51 (95% CI 1.06-2.16) and 3.73 (95% CI 2.33-5.98) for <15, 15-29 and 30-39 years, respectively). Other factors lost predictive ability with time. Cigarette smoking was the strongest predictor in all periods. Serum lipids and systolic blood pressure increased risk in most periods, and moderate physical activity was protective to 29 years, but these factors and BMI contributed minimally to ROC. DISCUSSION: Risk factors differed in association strengths and ability to predict mortality over four decades. BMI strengthened its association with time, while cigarette smoking was strongest in all periods. PMID- 25300407 TI - Ten-year follow-up of two unrelated patients with Muller cell sheen dystrophy and first report of successful vitrectomy. AB - PURPOSE: To describe clinical characteristics of Muller cell sheen dystrophy (MCSD) in two unrelated patients followed for 10 years. METHODS: Best-corrected visual acuity (BCVA), kinetic perimetry, biomicroscopy, ophthalmoscopy, fundus photography, fluorescein angiography, fundus autofluorescence, near-infrared reflectance, optical coherence tomography (OCT), and electroretinography (ERG). RESULTS: Case 1: A 61-year-old woman showed internal limiting membrane (ILM) folds at the posterior pole (OU), and cystoid macular edema (CME) in OD. During follow-up, BCVA decreased from 0.2 to 0.06 (OD) and from 0.7 to hand movements (OS). Fundus presented fluctuant CME and subretinal fluid, and an increase in ILM folds and intraretinal schisis cavities. ERG was negative in OD and initially normal in OS. Case 2: A 60-year-old man was first diagnosed with epiretinal membrane before MCSD with ILM folds was detected. OCT showed schisis cavities in all retinal layers. After vitrectomy with ILM peeling in OD because of visual loss and massive CME, BCVA recovered from 0.05 to 0.4. BCVA in OS remained at 0.6. OD developed negative ERG. CONCLUSIONS: MCSD presents with late onset, ILM folds, intraretinal schisis cavities, and negative ERG. Visual loss is accompanied by CME and subretinal fluid. Vitrectomy with ILM peeling led to BCVA increase and anatomic improvement. PMID- 25300408 TI - Water Management: Sacrificing Normative Practice Subverting the Traditions of Water Apportionment-'Whose Justice? Which Rationality?'. AB - Since current water governance patterns mandate cooperation and partnership within and between the actors in the hydrosystems, supplementary models are necessary to distinguish the roles and the rules of indoor actions which is why we extend a theory in the frameworks of philosophy of technology. This analysis is empirically grounded on the problematic hydrosystems of a river in central Iran, Zayandehrud. Following a modernist-holistic-based analysis, it illustrates how values in the water apportionment mechanisms are being reshaped. The article by using the theory of normative practice has scrutinised the tasks and the rules of the old and new water-management systems, Mirab. Subsequently according to such philosophical theory, it has argued that the conflicts over the cases are due to interference of structural and directional norms within them. PMID- 25300409 TI - Post- thyroidectomy haematoma causing severe supraglottic oedema and pulmonary oedema - a case report. AB - Large, long standing goiters present multiple challenges to anaesthesiologist. Post thyroidectomy haematoma is a rare but life threatening complication of thyroid surgery leading to airway obstruction. We report a case of huge goiter that underwent near total thyroidectomy and developed post thyroidectomy haematoma. Within no time it resulted in near fatal airway obstruction, pulmonary oedema and cardiac arrest. The haematoma was evacuated immediately and patient was resuscitated successfully. Pulmonary oedema was further worsened by subsequent aggressive fluid resuscitation. She was electively ventilated with PEEP and was extubated after five days. Except for right vocal cord palsy her postoperative stay was uneventful. This is unique case where a post thyoidectomy haematoma has resulted in fatal supraglottic oedema and pulmonary oedema. Early recognition, immediate intubation and evacuation of haematoma are the key to manage this complication. We highlight on the pathophysiology of haematoma and discuss the strategies to prevent similar events in future. PMID- 25300410 TI - New oral anticoagulants for the treatment of venous thromboembolism: understanding differences and similarities. AB - Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. In the United States, approximately 0.1 % of the population experiences an initial VTE event each year. Anticoagulation therapy is the cornerstone of acute VTE treatment and for prevention of recurrent VTE events. Conventional anticoagulants, including heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are widely used but have limitations. Newer oral anticoagulant agents, including direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban) have been developed to attempt to overcome some of the limitations of conventional anticoagulant therapy. These new oral agents have been evaluated for safety and efficacy in large, randomized clinical trials in the treatment and secondary prevention of VTE with results that are comparable to conventional therapy. Dabigatran, rivaroxaban, apixaban, and edoxaban are important new treatment options for patients with VTE. In this review, we compare these new agents and their associated clinical trials in VTE treatment. PMID- 25300411 TI - Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? AB - Phosphodiesterase-4 (PDE4) inhibitors have broad anti-inflammatory activity, inhibiting the airway inflammation associated with chronic obstructive pulmonary disease (COPD), especially by reducing airway neutrophils that are key cells in COPD. A careful evaluation of the results of several meta-analyses allows us to consider the use of PDE4 inhibitors as very important in those patients with COPD who are particularly susceptible to exacerbations, the so-called 'frequent exacerbators'. Consequently, PDE4 inhibitors should be used earlier and more frequently than is the case today, but they are prescribed sporadically because of side effects. Several strategies are conceivable to avoid side effects, but, unfortunately, many of these approaches are yet to be successfully translated into clinical effectiveness after several decades of research. A novel alternative approach is to administer multiple drugs simultaneously or drugs capable of two distinct primary pharmacological actions based on distinct pharmacophores (bifunctional drugs) in order to produce additive or synergistic effects and, consequently, to dispense these drugs at lower doses, inducing fewer side effects. The fact that we have realized that there is a need to target simultaneously more PDEs unquestionably represents an advance in the possible use of PDE inhibitors. Actually, the possibility that multivalent (multifunctional) ligands, which feature two or more pharmacophores, may deliver superior efficacy is an approach that is being explored. Recognizing the role of specific targeted therapy aimed at subcellular domains has changed our understanding of the use of PDE inhibitors, and offers an opportunity to improve both the therapeutic tolerability and efficacy of these drugs. PMID- 25300413 TI - Wellness and Religious Coping Among Thai Individuals Living with Chronic Kidney Disease in Southern California. AB - This qualitative research is based on eight Thai participants living with chronic kidney disease living in Southern California. Four emerging themes are (a) wellness, (b) self-care, (c) impact of illness on life, and (d) religious coping. Family relations, social support, and religious coping affected self-care and how they managed their everyday activities. Knowledge about the disease and its mechanism were crucial to the decision-making process in relation to self-care. Good self-care and appropriate self-management led to wellness and improved quality of life. Religion provided a belief system focusing on the place of acceptance that was essential for coping with emotional stressors. PMID- 25300412 TI - Tiotropium Respimat((r)) Soft MistTM inhaler: a review of its use in chronic obstructive pulmonary disease. AB - The long-acting anticholinergic agent tiotropium bromide (Spiriva((r))) is available as a solution for inhalation via Respimat((r)) Soft MistTM Inhaler in the EU and various other countries for the treatment of chronic obstructive pulmonary disease (COPD). With the Respimat((r)) Soft MistTM Inhaler there is improved lung deposition of drug (allowing a reduced dosage compared with tiotropium HandiHaler((r))), the delivered drug dose is independent of inspiratory effort and the prolonged duration of the aerosol cloud should make the co-ordination of actuation and inhalation easier. In patients with COPD, tiotropium Respimat((r)) improved lung function, COPD exacerbations, health related quality of life and dyspnoea and was at least as effective as tiotropium HandiHaler((r)). Tiotropium Respimat((r)) was generally well tolerated in patients with COPD, with anticholinergic adverse events among the most commonly reported adverse events. In the TIOSPIR trial, tiotropium Respimat((r)) was noninferior to tiotropium HandiHaler((r)) in terms of all-cause mortality, and the risk of cardiovascular mortality or major adverse cardiovascular events did not significantly differ between the two treatment groups. In conclusion, tiotropium Respimat((r)) Soft MistTM Inhaler is a useful option for the treatment of patients with COPD. PMID- 25300414 TI - Complete genome sequence of motherwort yellow mottle virus, a novel putative member of the genus Torradovirus. AB - The complete genome sequence of a new virus isolated from a motherwort plant exhibiting yellow mottle, mild mosaic, and stunting symptoms in Andong, Korea, was determined. The genome of this virus is composed of two single-stranded RNAs (7068 and 4963 nucleotides in length, respectively) carrying poly(A) tails. RNA1 contains one large open reading frame (RNA1-ORF1), while two potential ORFs (RNA2 ORF1 and RNA2-ORF2) were found in RNA2. BLAST searches of protein databases showed that RNA1-ORF1 and RNA2-ORF2 have maximum amino acid sequence identities of 53 % and 57 % to the RNA1-ORF1 and RNA2-ORF2, respectively, of lettuce necrotic leaf curl virus (LNLCV, a recently identified torradovirus). Phylogenetic analysis provided further evidence that the virus identified in this study is probably a member of a new species in the genus Torradovirus. The name "motherwort yellow mottle virus" (MYMoV) is proposed for this new virus. PMID- 25300415 TI - Rapid discrimination of DNA strands using an opto-calorimetric microcantilever sensor. AB - A rapid technique for quantitative detection and discrimination of DNA strands without using immobilized probe molecules is demonstrated using an opto calorimetric, self-powered sensor based on a Pb(Zr(0.52)Ti(0.48))O3 (PZT) microcantilever. Microcalorimetric infrared (IR) spectroscopy provides excellent chemical selectivity based on the unique molecular vibrational characteristics of each nucleotide in the mid IR region. The piezoelectric and pyroelectric properties of the PZT microcantilever were exploited in the quantitative detection and discrimination of adsorbed DNA strands with their spectral characteristics. We report the unique spectral characteristics of different DNA nucleotides that are monitored by wavelength-dependent temperature variations for different relative molar ratio of each nucleotide. This approach offers a fast, label-free technique which is highly sensitive and selective for the detection of single nucleotide differences in DNA strands and has the potential to be used as a rapid prescreening biosensor for various biomolecules. PMID- 25300416 TI - Expression profiles of glyceraldehyde-3-phosphate dehydrogenase from Clonorchis sinensis: a glycolytic enzyme with plasminogen binding capacity. AB - Globally, 15-20 million people are infected with Clonorchis sinensis (C. sinensis) which results in clonorchiasis. In China, clonorchiasis is considered to be one of the fastest-growing food-borne parasitic diseases. That more key molecules of C. sinensis are characterized will be helpful to understand biology and pathogenesis of the carcinogenic liver fluke. Glyceraldehyde-3-phosphate dehydrogenases (GAPDHs) from many species have functions other than their catalytic role in glycolysis. In the present study, we analyzed the sequence and structure of GAPDH from C. sinensis (CsGAPDH) by using bioinformatics tools and obtained its recombinant protein by prokaryotic expression system, to learn its expression profiles and molecular property. CsGAPDH could bind to human intrahepatic biliary epithelial cell in vivo and in vitro by the method of immunofluorescence assays. CsGAPDH also disturbed in lumen of biliary tract near to the parasite in the liver of infected rat. Western blotting analysis together with immunofluorescence assay indicated that CsGAPDH was a component of excretory/secretory proteins (CsESPs) and a surface-localized protein of C. sinensis. Quantitative real-time PCR (Q-PCR) and Western blotting demonstrated that CsGAPDHs are expressed at the life stages of adult worm, metacercaria, and egg, but the expression levels were different from each other. Recombinant CsGAPDH (rCsGAPDH) was confirmed to have the capacity to catalyze the conversion of glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate which was inhibited by AMP in a dose-dependent manner. In addition, rCsGAPDH was able to interact with human plasminogen in a dose-dependent manner by ELISA. The interaction could be inhibited by lysine. The plasminogen binding capacity of rCsGAPDH along with the distribution of CsGAPDH in vivo and in the liver of C. sinensis-infected rat hinted that surface-localized CsGAPDH might play an important role in host invasion of the worm besides its glycolytic activity. Our work will be a cornerstone for getting more messages about CsGAPDH and its role in biology and parasitism of C. sinensis. PMID- 25300417 TI - Histopathological study of ovaries of Rhipicephalus sanguineus (Acari: Ixodidae) exposed to different thymol concentrations. AB - Thymol is a monoterpene with proven acaricide action for several tick species. In addition to killing these ectoparasites, thymol can also reduce oviposition and egg hatch rate. However, the effects of thymol on the morphophysiology of tick ovaries are still unknown. Thus, the aim of this study was to evaluate the morphophysiological changes caused by this active principle in ovaries of Rhipicephalus sanguineus after a 6-day feeding period, through the application of morphohistochemical techniques. After the feeding period, a total of 50 females were divided into five groups and immersed in the following solutions: (I) distilled water (control), (II) 30% ethanol (control), (III) 1.25 mg/mL thymol, (IV) 2.5 mg/mL thymol, and (V) 5.0 mg/mL thymol. The experimental groups were kept in a climatic chamber (27 +/- 1 degrees C; RH 80 +/- 10%) for 5 days. After this period, morphological (hematoxylin/eosin) and histochemical (von Kossa) techniques were applied after remotion of the ovaries. The morphological results revealed large vacuoles in germ cells at different developmental stages and invaginations that represent deformations in the chorionic membrane. From the results obtained in this study, it was concluded that thymol interfered with the development of oocytes, which showed degeneration signs. The treatment containing 5.0 mg/mL thymol affected more accentuately the morphological development. Moreover, thymol also altered the calcium content of yolk granules, which generally showed an intense staining for this element. PMID- 25300418 TI - Muscle attachment sites of Phormia regina (Meigen). AB - An error was found in a previous publication on muscle attachment sites in forensically important blowfly larvae from 2012. The patterns we assigned to Lucilia illustris factually belong to Phormia regina. PMID- 25300419 TI - Evaluation of plant-mediated synthesized silver nanoparticles against vector mosquitoes. AB - Diseases transmitted by blood-feeding mosquitoes, such as dengue fever, dengue hemorrhagic fever, Japanese encephalitis, malaria, and filariasis, are increasing in prevalence, particularly in tropical and subtropical zones. To control mosquitoes and mosquito-borne diseases, which have worldwide health and economic impacts, synthetic insecticide-based interventions are still necessary, particularly in situations of epidemic outbreak and sudden increases of adult mosquitoes. Green nanoparticle synthesis has been achieved using environmentally acceptable plant extract and eco-friendly reducing and capping agents. In view of the recently increased interest in developing plant origin insecticides as an alternative to chemical insecticide, in the present study, the adulticidal activity of silver nanoparticles (AgNPs) synthesized using Heliotropium indicum plant leaf extract against adults of Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus was determined. Adult mosquitoes were exposed to varying concentrations of aqueous extract of H. indicum and synthesized AgNPs for 24 h. AgNPs were rapidly synthesized using the leaf extract of H. indicum, and the formation of nanoparticles was observed within 6 h. The results recorded from UV vis spectrum, Fourier transform infrared, X-ray diffraction, scanning electron microscopy, and transmission electron microscopy support the biosynthesis and characterization of AgNPs. The maximum efficacy was observed in synthesized AgNPs against the adult of A. stephensi (lethal dose (LD)50 = 26.712 MUg/mL; LD90 = 49.061 MUg/mL), A. aegypti (LD50 = 29.626 MUg/mL; LD90 = 54.269 MUg/mL), and C. quinquefasciatus (LD50 = 32.077 MUg/mL; LD90 = 58.426 MUg/mL), respectively. No mortality was observed in the control. These results suggest that the leaf aqueous extracts of H.indicum and green synthesis of AgNPs have the potential to be used as an ideal eco-friendly approach for the control of the A. stephensi, A. aegypti, and C. quinquefasciatus. This is the first report on the adulticidal activity of the plant extracts and AgNPs. PMID- 25300420 TI - Acaricidal activity of five essential oils of Ocimum species on Rhipicephalus (Boophilus) microplus larvae. AB - The aim of this study was to evaluate the acaricidal activity on the cattle tick Rhipicephalus (Boophilus) microplus of essential oils from three Ocimum species. Acaricidal activity of five essential oils extracted from Ocimum gratissimum L. (three samples), O. urticaefolium Roth, and O. canum Sims was evaluated on 14- to 21-day-old Rhipicephalus microplus tick larvae using larval packet test bioassay. These essential oils were analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS) showing great variations of their chemical compositions according to the botanical species and even within the O. gratissimum species; the acaricidal activity of their main compounds was also evaluated. The essential oils of O. urticaefolium and O. gratissimum collected in Cameroon were the most efficient with respective LC50 values of 0.90 and 0.98%. The two essential oils obtained from O. gratissimum collected in New Caledonia were partially active at a dilution of 5% while the essential oil of O. canum collected in Cameroon showed no acaricidal activity. The chemical analysis shows five different profiles. Whereas the essential oils of O. urticaefolium from Cameroon and O. gratissimum from New Caledonia contain high amounts of eugenol (33.0 and 22.3-61.0%, respectively), 1,8-cineole was the main component of the oil of an O. canum sample from Cameroon (70.2%); the samples of O. gratissimum oils from New Caledonia are also characterized by their high content of (Z)-beta ocimene (17.1-49.8%) while the essential oil of O. gratissimum collected in Cameroon is mainly constituted by two p-menthane derivatives: thymol (30.5%) and gamma-terpinene (33.0%). Moreover, the essential oil of O. urticaefolium showed the presence of elemicin (18.1%) as original compound. The tests achieved with the main compounds confirmed the acaricidal activity of eugenol and thymol with residual activity until 0.50 and 1%, respectively, and revealed the acaricidal property of elemicin, which was the most efficient compound with 100 % of acaricidal activity at a dilution of 0.25% and could be a valuable acaricide for the control of the cattle tick R. microplus. PMID- 25300421 TI - In vitro and in vivo efficacy of extracts of leaves of Eucalyptus globulus on ovine gastrointestinal nematodes. AB - The rapid development of anthelminthic resistance has limited the success of traditional control programmes in several countries, thereby forcing the researchers to search for alternatives. In vitro anthelmintic activities of crude aqueous and hydro-alcoholic extracts of the leaves of Eucalyptus globulus were investigated against the egg and larvae of naturally infected sheep. In the phytochemical analyses, tannins and flavonoids were the main metabolites identified in the extract. The aqueous extract of E. globulus was also investigated for in vivo anthelmintic activity in naturally infected sheep. The various blood parameters, coupled with effects on marker enzymes and antioxidant status, were evaluated during the trial period. Methanolic extract showed better ED50 (3.756 mg/ml) and ED99 (33.809 mg/ml) values in comparison with aqueous extract (ED50 = 1.502 and ED99 = 7.10 mg/ml) in the egg hatch assay. Inverse was true in larval development and larval paralysis tests. The aqueous extract's ED50 = 19.994 and ED99 = 108.931 mg/ml values in the larval development test and ED50 = 19.994 and ED99 = 108.931 mg/ml in the larval paralysis test were more potent than those of its methanolic counterpart with ED50 = 15.595 and ED99 = 94.493 mg/ml and ED50 = 15.595 and ED99 = 94.493 mg/ml, respectively. A significant amount of 66% faecal egg count reduction was observed in in vivo trail using the aqueous extract on day 21 post treatment, although in initial stages it showed 58.0 and 80% effectiveness on days 7 and 14 post treatment. Though the FCER reduction was somewhat lower in terms of comparison with albendazole, nevertheless, significant and prolong reduction was noticed. No deleterious ill effect was found in any of the haematological and biochemical parameters suggesting that the plant could be safer for use in sheep. Though significant changes were observed in SGPT, RBCs, Hb and RDWc levels, other parameters showed nonsignificant variations within the normal range in the stipulated time of of herbal trial period. Based on the results of the present study, it could be very well concluded that leaves of E. globulus possess good level of anthelminthic efficacy; further research is thereby warranted before recommending it for use in nematode control programme in ovines. PMID- 25300422 TI - Prediction of persistent storage symptoms after transurethral resection of the prostate in patients with benign prostatic enlargement. AB - OBJECTIVE: To identify the prognostic factors causing persistent storage symptoms following transurethral resection of the prostate in patients with benign prostatic enlargement (BPE). METHODS: A total of 116 men with symptomatic BPE requiring surgery were enrolled in the study between January 2011 and December 2012. The patients underwent basic clinical evaluations including transrectal ultrasound, International Prostate Symptom Score and urodynamic study. After 6 months, International Prostate Symptom Score and uroflowmetry were rechecked. The definition of persistent storage symptoms was patients with storage scores >7 points. Logistic regression analysis and receiver operating characteristic analysis were conducted. RESULTS: The 116 patients were divided into a persistent storage symptom-positive group (n = 33) and a storage symptom-negative group (n = 83). Multivariate analysis showed that the degrees of worse initial storage symptoms (odds ratio [OR] = 8.32), small bladder capacity (OR = 4.31), impaired detrusor contractility (OR = 2.96) and age (OR = 1.05) were consistently associated with persistent storage symptoms. CONCLUSIONS: This short-term study confirms the positive and consistent correlations between the baseline degree of worse initial storage symptoms, bladder capacity, detrusor contractility and age and the improvement in storage symptoms. PMID- 25300423 TI - Direct regioselective phosphonation of heteroaryl N-oxides with H-phosphonates under metal and external oxidant free conditions. AB - A direct C-H/P-H functionalization of heteroaryl N-oxides with H-phosphonates is described. A wide variety of heteroaryl phosphonates were obtained in up to 92% yield in a chemo- and regioselective manner, under oxidant and metal free conditions. This procedure features practicality, high efficiency, environmental friendliness and atom economy. PMID- 25300424 TI - Consumption of whole grains in French children, adolescents and adults. AB - The consumption of whole grain foods is associated with many nutritional, health and weight control benefits. The present study assessed whole grain intake in France on the basis of a 7 d dietary survey in a representative sample of children, adolescents and adults (Comportements et Consommations Alimentaires en France 2010 survey). Special care was taken to identify and assess the intake of all whole grains. All foods consumed were considered, with no lower limit on whole grain content. For the majority of foods, details regarding the whole grain contents were obtained from brand information and quantitative nutrient declarations on food labels. Over half of the respondents reported never consuming any whole grain. In participants who did, consumption levels were very low (about 9.1 g/d in children and 14.4 g/d in adults). The main food sources of whole grains were breakfast cereals in children and adolescents and bread in adults. Consumers of whole grains had higher daily intakes of fibre and several vitamins and minerals than non-consumers. In adults but not in children, the OR for overweight/obesity decreased significantly as the level of whole grain consumption increased. Although a majority of French consumers comply with the national recommendation to consume a starchy food with each meal, they do so with minimal consumption of whole grain foods. PMID- 25300425 TI - BACE1 and cholinesterase inhibitory activities of Nelumbo nucifera embryos. AB - The aim of the present study was to evaluate the comparative anti-Alzheimer's disease (AD) activities of different parts of Nelumbo nucifera (leaves, de-embryo seeds, embryos, rhizomes, and stamens) in order to determine the selectivity and efficient use of its individual components. Anti-AD activities of different parts of N. nucifera were evaluated via inhibitory activities on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) along with scavenging activity on peroxynitrite (ONOO( )). Among the evaluated parts of N. nucifera, the embryo extract exhibited significant inhibitory potential against BACE1 and BChE as well as scavenging activity against ONOO(-). Thus, the embryo extract was selected for detailed investigation on anti-AD activity using BACE1- and ChEs-inhibitory assays. Among the different solvent-soluble fractions, the dichloromethane (CH2Cl2), ethyl acetate (EtOAc), and n-butanol (n-BuOH) fractions showed promising ChEs and BACE1 inhibitory activities. Repeated column chromatography of the CH2Cl2, EtOAc and n BuOH fractions yielded compounds 1-5, which were neferine (1), liensinine (2), vitexin (3), quercetin 3-O-glucoside (4) and northalifoline (5). Compound 2 exhibited potent inhibitory activities on BACE1, AChE, and BChE with respective IC50 values of 6.37 +/- 0.13, 0.34 +/- 0.02, and 9.96 +/- 0.47 uM. Likewise, compound 1 showed potent inhibitory activities on BACE1, AChE, and BChE with IC50 values of 28.51 +/- 4.04, 14.19 +/- 1.46, and 37.18 +/- 0.59 uM, respectively; the IC50 values of 3 were 19.25 +/- 3.03, 16.62 +/- 1.43, and 11.53 +/- 2.21 uM, respectively. In conclusion, we identified potent ChEs- and BACE1-inhibitory activities of N. nucifera as well as its isolated constituents, which may be further explored to develop therapeutic and preventive agents for AD and oxidative stress related diseases. PMID- 25300426 TI - Facile synthesis of CuInGaS2 quantum dot nanoparticles for bilayer-sensitized solar cells. AB - CuIn(0.7)Ga(0.3)S2 quantum dots (QDs) with particle size of 2-5 nm were directly synthesised by a vacuum one-pot-nanocasting process and homogeneously anchored on TiO2 nanocrystals (<50 nm) for the first time. We further present CuIn(0.7)Ga(0.3)S2 quantum dots and dye bilayer-sensitized solar cells with a power conversion efficiency 36.3% higher than mono-dye sensitized solar cells. PMID- 25300427 TI - Optimization of Evans blue quantitation in limited rat tissue samples. AB - Evans blue dye (EBD) is an inert tracer that measures plasma volume in human subjects and vascular permeability in animal models. Quantitation of EBD can be difficult when dye concentration in the sample is limited, such as when extravasated dye is measured in the blood-brain barrier (BBB) intact brain. The procedure described here used a very small volume (30 ul) per sample replicate, which enabled high-throughput measurements of the EBD concentration based on a standard 96-well plate reader. First, ethanol ensured a consistent optic path length in each well and substantially enhanced the sensitivity of EBD fluorescence spectroscopy. Second, trichloroacetic acid (TCA) removed false positive EBD measurements as a result of biological solutes and partially extracted EBD into the supernatant. Moreover, a 1:2 volume ratio of 50% TCA ([TCA final] = 33.3%) optimally extracted EBD from the rat plasma protein-EBD complex in vitro and in vivo, and 1:2 and 1:3 weight-volume ratios of 50% TCA optimally extracted extravasated EBD from the rat brain and liver, respectively, in vivo. This procedure is particularly useful in the detection of EBD extravasation into the BBB-intact brain, but it can also be applied to detect dye extravasation into tissues where vascular permeability is less limiting. PMID- 25300428 TI - mtDNA germ line variation mediated ROS generates retrograde signaling and induces pro-cancerous metabolic features. AB - mtDNA non-synonymous germ line variation (G10398A; p.A114T) has remained equivocal with least mechanistic understanding in showing an association with cancer. This has necessitated showing in-vitro how an over-expression within mitochondria of either of the variants produces higher intracellular ROS, resulting in differential anchorage dependent and independent growth. Both these features were observed to be relatively higher in ND3:114T variant. An elevated amount of intracellular carbonylated proteins and a reduced activity of a key glycolytic enzyme, Pyruvate kinase M2, along with high glucose uptake and lactate production were other pro-cancerous features observed. The retrograde signaling through surplus ROS was generated by post-ND3 over-expression regulated nuclear gene expression epigenetically, involving selectively the apoptotic-DDR-pathways. The feature of ND3 over-expression, inducing ROS mediated pro-cancerous features in the cells in in vitro, was replicated in a pilot study in a limited number of sporadic breast tumors, suggesting the importance of mitochondrial germ-line variant(s) in enabling the cells to acquire pro-cancerous features. PMID- 25300430 TI - Cation-specific conformational behavior of polyelectrolyte brushes: from aqueous to nonaqueous solvent. AB - We have investigated changes in the cation-specific conformational behavior of poly(sodium styrenesulfonate) (PSS) brushes as the solvent changes from water to methanol using a quartz crystal microbalance with dissipation (QCM-D). A solvation to desolvation transition of the grafted chains accompanied by swelling to the collapse transition of the brushes is observed for Na(+). In the case of Cs(+), the brushes undergo solvation to desolvation to resolvation accompanied by swelling to collapse to reswelling transitions. The resolvation and reswelling transitions for Cs(+) are induced by the charge inversion of the brushes via van der Waals interactions between Cs(+) and the brushes. All of the transitions for monovalent cations become less obvious as the methanol content increases. For divalent Ca(2+) and trivalent La(3+), a solvation to desolvation to resolvation transition of the grafted chains accompanied by a swelling to collapse to reswelling transition of the brushes can be observed. The resolvation and reswelling of the brushes for the multivalent cations are induced by the charge inversion of the brushes via charge-image charge interactions. The extent of the transitions for the PSS brushes in the presence of multivalent cations is only slightly influenced by the methanol content. PMID- 25300429 TI - SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans. AB - Slo2 channels are prominent K(+) channels in mammalian neurons but their physiological functions are not well understood. Here we investigate physiological functions and regulation of the Caenorhabditis elegans homologue SLO-2 in motor neurons through electrophysiological analyses of wild-type and mutant worms. We find that SLO-2 is the primary K(+) channel conducting delayed outward current in cholinergic motor neurons, and one of two K(+) channels with this function in GABAergic motor neurons. Loss-of-function mutation of slo-2 increases the duration and charge transfer rate of spontaneous postsynaptic current bursts at the neuromuscular junction, which are physiological signals used by motor neurons to control muscle cells, without altering postsynaptic receptor sensitivity. SLO-2 activity in motor neurons depends on Ca(2+) entry through EGL-19, an L-type voltage-gated Ca(2+) channel (CaV1), but not on other proteins implicated in either Ca(2+) entry or intracellular Ca(2+) release. Thus, SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release. PMID- 25300431 TI - The effects of exercise with TENS on spasticity, balance, and gait in patients with chronic stroke: a randomized controlled trial. AB - BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a useful modality for pain control. TENS has recently been applied to decrease spasticity. The purpose of this study is to determine whether the addition of TENS to an exercise program reduces spasticity and improves balance and gait in chronic stroke patients. MATERIAL AND METHODS: This was a single-blinded, multicenter, randomized controlled trial. Thirty-four ambulatory individuals with chronic stroke participated and were randomly allocated to the TENS or Placebo group. The TENS group performed therapeutic exercise with TENS while the placebo (non stimulation) TENS group performed therapeutic exercise with placebo TENS. Participants in both groups followed the same 30-min exercise regimen 5 times per week for a period of 6 weeks. Spasticity (modified Ashworth scale), static (balance system), and dynamic balance (timed up and go test), and gait ability (gait analyzer) were measured at 1 week before and 1 week after the intervention. RESULTS: Significant differences were observed between the 2 groups. Spasticity improved by 0.80 points in the TENS group. Anterior-posterior and medial-lateral sway velocity among static balance parameters and dynamic balance showed significant differences between the TENS and Placebo TENS groups (p=.000). Gait speed and cadence were enhanced significantly in the TENS group (p=.000). Step and stride length on the paretic side showed a significant difference in the TENS group (p=.000), while only velocity showed a significant difference in the Placebo TENS group (p=.004). CONCLUSIONS: A combination of therapeutic exercise and TENS may reduce spasticity and improve balance, gait, and functional activity in chronic stroke patients. PMID- 25300432 TI - The role of national guidelines while staying abroad with an acute stroke. PMID- 25300433 TI - Protocol for a randomized controlled clinical trial investigating the effectiveness of Fast muscle Activation and Stepping Training (FAST) for improving balance and mobility in sub-acute stroke. AB - BACKGROUND: Following stroke, many people have difficulty activating their paretic muscles quickly and with sufficient power to regain their balance by taking quick and effective steps. Reduced dynamic balance and mobility following stroke, or 'walking balance', is associated with reduced self-efficacy and restrictions in daily living activities, community integration, and quality of life. Targeted training of movement speeds required to effectively regain balance has been largely overlooked in post-stroke rehabilitation. The Fast muscle Activation and Stepping Training (FAST) program incorporates fast functional movements known to produce bursts of muscle activation essential for stepping and regaining standing balance effectively. The purpose of this study is to: 1) compare the effectiveness of an outpatient FAST program to an active control outpatient physiotherapy intervention in improving walking balance following stroke, and 2) explore potential mechanisms associated with improvements in walking balance. METHODS/DESIGN: This will be an assessor-blinded, parallel group randomized controlled trial design. Sixty participants (30 per group) who have sustained a stroke within the previous six months will be randomly assigned with stratification for lower limb motor recovery to receive twelve 45-minute 1:1 physiotherapy intervention sessions over 6 - 10 weeks in an outpatient setting of either: 1) FAST intervention - systematic and progressive practice of fast squatting and stepping exercises, or 2) active control - conventional physiotherapy directed at improving balance and mobility that includes no targeted fast movement training. The same blinded research physiotherapist will assess outcomes at three time points: 1) baseline (prior to intervention), 2) follow up (within one week post-intervention); and 3) retention (one month post intervention). The primary outcome is dynamic balance assessed using the Community Balance and Mobility Scale. We will also assess fast and self-selected walking speed, balance self-efficacy, and the ability to respond to internal and external perturbations to balance and associated changes in postural muscle activation. DISCUSSION: The targeted training of fast functional movements in the FAST program is expected to improve walking balance following stroke compared to the active control intervention. Unique to this study is the investigation of potential mechanisms associated with improvements in walking balance. TRIAL REGISTRATION: NCT01573585. PMID- 25300434 TI - Study of study of changes in antidepressant use after FDA warnings is not reliable. PMID- 25300435 TI - Relative roles of CD90 and c-kit to the regenerative efficacy of cardiosphere derived cells in humans and in a mouse model of myocardial infarction. AB - BACKGROUND: The regenerative potential of cardiosphere-derived cells (CDCs) for ischemic heart disease has been demonstrated in mice, rats, pigs, and a recently completed clinical trial (CADUCEUS). CDCs are CD105(+) stromal cells of intrinsic cardiac origin, but the antigenic characteristics of the active fraction remain to be defined. CDCs contain a small minority of c-kit(+) cells, which have been argued to be cardiac progenitors, and a variable fraction of CD90(+) cells whose bioactivity is unclear. METHODS: We performed a retrospective analysis of data from the CADUCEUS trial and a prospective mouse study to elucidate the roles of c kit(+) and CD90(+) cells in human CDCs. Here, we show, surprisingly, that c-kit expression has no relationship to CDCs' therapeutic efficacy in humans, and depletion of c-kit(+) cells does not undermine the structural and functional benefits of CDCs in a mouse model of myocardial infarction (MI). In contrast, CD90 expression negatively correlates with the therapeutic benefit of CDCs in humans (ie, higher CD90 expression associated with lower efficacy). Depletion of CD90(+) cells augments the functional potency of CDCs in murine MI. CD90(-) CDCs secrete lower levels of inflammatory cytokines and can differentiate into cardiomyocytes in vitro and in vivo. CONCLUSION: The majority population of CDCs (CD105(+)/CD90(-)/c-kit(-)) constitutes the active fraction, both in terms of therapeutic efficacy and in the ability to undergo cardiomyogenic differentiation. The c-kit(+) fraction is neither necessary for, nor contributory to, the regenerative efficacy of CDCs. PMID- 25300436 TI - ECMO support for right main bronchial disruption in multiple trauma patient with brain injury--a case report and literature review. AB - Extracorporeal membrane oxygenation (ECMO) may offer life-saving treatment in severe pulmonary contusion or acute respiratory distress syndrome when conventional treatments have failed. However, because of the bleeding risk of systemic anticoagulation, ECMO should be performed only as a last resort in multiple trauma victims. Here, we report ECMO as a bridge for right main bronchus reconstruction and recovery of traumatic wet lung in a 31-year-old male multi trauma patient with right main bronchial disruption, bilateral pulmonary contusion, cerebral contusion and long bone fracture. The patient was discharged without any obvious complication. ECMO support in a traumatic brain injured patient with severe hypoxemia caused by lung contusion and/or tracheal bronchus disruption is not an absolute contraindication. PMID- 25300437 TI - Nonalcoholic fatty liver disease (NAFLD) and cardiovascular risk in renal transplant recipients. AB - BACKGROUND/AIMS: Renal transplant recipients (RTRs) are at high risk for cardiovascular (CVD) mortality. Recently, nonalcoholic fatty liver disease (NAFLD) has been recognized as a new risk factor for adverse CVD events in the general population. We examined whether transient elastography (TE) defined NAFLD was associated with atherosclerosis in RTRs, as measured by ultrasound in the carotid arteries. METHODS: Carotid atherosclerosis was assesses in 71 RTRs with a TE proven NAFLD. With the help of TE liver stiffness was used to assess liver fibrosis and Controlled Attenuation Parameter (CAP) was used to detect and quantify liver steatosis. NAFLD was defined by the presence of steatosis with CAP values >=238 dB.m(-1). RESULTS: RTRs with NAFLD showed more carotid atherosclerosis than RTRs without NAFLD. RTRs-NAFLD patients had the mean intima media measurements (ITM) of 1.1+/-0.1 mm and that was statistically significant higher than the mean ITM founded in RTRs without NAFLD (1.1+/-0.1 vs. 0.9+/-0.1 mm; p<0.0001). Furthermore, RTRs-NAFLD patients had statistically significant higher prevalence of plaques in comparison with RTRs without NAFLD (p=0.021). CONCLUSION: We showed for the first time that carotid atherosclerosis is advanced in RTRs with NAFLD. Detection of NAFLD by TE should alert to the existence of an increased cardiovascular risk in RTRs. PMID- 25300438 TI - Hemostatic resuscitation for massive hemorrhage with warm fresh whole blood in a patient with severe blunt trauma. AB - A 24-year-old male Navy soldier was struck on the left thigh by a ruptured cable and was subsequently thrown into the sea. Initial evaluation showed an Injury Severity Score of 34. Core body temperature was 34.1 degrees C. Laboratory data included a hemoglobin level of 4.5 g/dL and a hematocrit of 13.3%. Prothrombin time was prolonged (>100 seconds), international normalized ratio was elevated (9.99), and partial thromboplastin time was elevated (>180 seconds). The patient was treated for hypothermia, coagulopathy, and metabolic acidosis during resuscitation. The patient was transfused with 16,320 mL of blood during the first 24 hours following the accident, including 4500 mL (18 units) of warm fresh whole blood (WFWB) donated by the patient's military colleagues. The patient was successfully resuscitated, and the injured leg was salvaged. Component therapy can afford replacement of specific deficiencies or requirements, decrease the risk of transfusion-transmitted infectious diseases, and improve resource utilization. However, a protocol of early transfusion with WFWB should be considered during resuscitation following massive hemorrhage in specific conditions such as battle fields or urgent situations. PMID- 25300439 TI - Great saphenous vein aneurysm presenting as an inguinal hernia. AB - A primary aneurysm in the saphenous vein is very rare. This case study is based on a 55-year-old male patient who applied for general surgery with a complaint of swelling in his left inguinal area, after examinations led to a provisional diagnosis of inguinal hernia. It was decided that surgery was the best option due to the risk of thromboembolism, and pain caused by the condition itself. Confusion with inguinal hernia can affect prognosis. It increases the risk of thromboembolism as well as preventing the chance of early response. PMID- 25300440 TI - Self-harm behavior among individuals with intermittent explosive disorder and personality disorders. AB - Self-harm behaviors are a major public health concern across the lifespan, particularly among individuals with psychiatric disorders. Little research, however, has examined these behaviors among individuals with a diagnosis characterized by recurrent acts of impulsive aggression, Intermittent Explosive Disorder (IED). Furthermore, extant research has not examined variables that might mediate the relationship between IED and self-harm. The current study examined the rates of non-suicidal self-injury (NSSI) and suicide attempts among individuals with IED as compared to healthy controls, individuals with personality disorders (PDs; which are highly comorbid with IED), and individuals with comorbid IED and PD. The study also examined the indirect effects of aggression, impulsivity, and affective lability in the relationship between diagnosis and self-harm. Participants were 1079 community individuals and prevalence rates among the total sample were 18% for NSSI and 13.2% for suicide attempts. Scores on measures aggression, impulsivity, and affect lability showed significant indirect effects on the relationships between IED + PD and NSSI; scores on aggression showed a significant indirect effect on the relationship between PD and NSSI; scores on impulsivity showed a significant indirect effect on the relationship between IED + PD and suicide attempt. These results suggest that individuals with PDs, and particularly those with comorbid IED and PD, are at increased risk for engagement in self-harm behaviors. Furthermore, traits of aggression, impulsivity, and affect lability significantly accounted for the relationship between diagnostic status and self-harm, particularly in regards to NSSI. PMID- 25300442 TI - Psychometric properties of the 16-item Quick Inventory of Depressive Symptomatology: a systematic review and meta-analysis. AB - Effective management of depression is predicated upon reliable assessment. The Quick Inventory of Depressive Symptomatology (QIDS) is a depression severity scale with both self-rated (QIDS-SR16) and clinician-rated (QIDS-C16) versions. Although widely used in research, the psychometric properties of the QIDS16 have not been systematically reviewed. We performed a systematic review of studies of the psychometric properties (factor structure, internal consistency, convergent validity, discriminant validity, test-retest reliability and responsiveness to change) of the QIDS-SR16 or QIDS-C16. Six databases were searched: MEDLINE, EMBASE, PsycINFO, CinAHL, Web of Science and the Cochrane Central Register of Controlled Trials. Findings were summarised, bias assessed and correlations with reference standards were pooled. 37 studies (17,118 participants) were included in the review. Both versions of the QIDS16 were unidimensional. Cronbach's alpha ranged from 0.69 to 0.89 for the QIDS-SR16 and 0.65 to 0.87 for the QIDS-C16. The QIDS-SR16 correlated moderately to highly with several depression severity scales. Seven studies were pooled where QIDS-SR16 was correlated with the HRSD-17 (r = 0.76, CI 0.69, 0.81) in patients diagnosed with depression. Four studies examined convergent validity with the QIDS-C16. Four studies examined discriminant validity, for the QIDS-SR16 alone. Eighteen studies had at least one author who was a co-author of the original QIDS16 study. Most studies were conducted in the USA (n = 26). The QIDS-SR16 and the QIDS-C16 are unidimensional rating scales with acceptable internal consistency. To justify the use of the QIDS16 scale in clinical practice, more research is needed on convergent and discriminant validity, and in populations outside the USA. PMID- 25300443 TI - Acrylate-tethering drug carrier: covalently linking carrier to biological surface and application in the treatment of Helicobacter pylori infection. AB - The development of carriers to sustain drugs at stomach surface is an attractive strategy to increase drug bioavailability locally and systematically. So far, the only reported carrier that can form a covalent bond with mucus, the thiolated carrier, relies on a reversible disulfide exchange reaction between thiols on the carrier and disulfide bridges on the mucus. Here we show the design and fabrication of a cellulose carrier with tethering acrylate groups (denoted here as clickable carrier) that, under a nontoxic condition, can efficiently react with thiols on biomaterials in situ through the thermodynamically driven and kinetically probable Michael thiol-ene click reaction. Here we show the attachments of the clickable carriers to a mucin protein, a surface of human laryngeal carcinoma cells, and a surface of a fresh porcine stomach. We also show that the required thiol moieties can be generated in situ by reducing existing cystine disulfide bridges with either the edible vitamin C or the relatively nontoxic tris(2-carboxyethyl) phosphine. Comparing to a control carrier, the clickable carrier can increase some drug concentrations in an ex vivo stomach tissue, and improve the Helicobacter pylori treatment in infected C57BL/6 mice. PMID- 25300441 TI - Impact of acamprosate on plasma amyloid-beta precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker. AB - BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-beta precursor protein (APP), secreted APPalpha (sAPPalpha), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPalpha holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPalpha function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS) associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPalpha levels but no change occurred in Abeta40 or Abeta42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPalpha processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPalpha may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission. PMID- 25300444 TI - Acute versus chronic exercise-induced left-ventricular remodeling. AB - Exercise-induced cardiac remodeling (EICR) is the process by which the heart adapts to the physiologic stress of exercise. Non-invasive cardiovascular imaging has led to advances in the understanding of EICR, with sport-specific changes in left-ventricular (LV) structure and function being described; however, the majority of data stem from cross-sectional and short-duration longitudinal studies. Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages. Examination of prolonged exposures to exercise training will also be necessary to determine normative values across the age and training spectrums of athletic patients. This information will help to distinguish the boundary between physiology and pathology in athletic patients. PMID- 25300445 TI - Bipolar sealer not superior to standard electrocautery in primary total hip arthroplasty: a meta-analysis. AB - INTRODUCTION: To assess whether bipolar sealer has advantages over standard electrocautery in primary total hip arthroplasty (THA). METHODS: All studies published through November 2013 were systematically searched in PubMed, Embase, ScienceDirect, The Cochrane Library, and other databases. Relevant journals or conference proceedings were searched manually. Only randomized controlled trials were included. Two independent reviewers identified and assessed the literature. Mean difference in blood loss and risk ratios of transfusion rates and of complication rates in the bipolar sealer group versus the standard electrocautery group were calculated. The meta-analysis was conducted using RevMan 5.1 software. RESULTS: Five studies were included, with a total sample size of 559 patients. The use of bipolar sealer did not significantly reduce intraoperative blood loss, hemoglobin drop, hospital stay, and operative time. There were no significant differences in need for transfusion and the incidence of infection between the study groups. CONCLUSION: The available evidence suggests that the use of bipolar sealer was not superior to standard electrocautery in patients undergoing primary THA. The use of bipolar sealer is not recommended in primary THA. PMID- 25300448 TI - Abstracts presented at the Association of British Neurologists: what becomes of them and what is their impact? PMID- 25300446 TI - Psychosocial needs of low-income people with cancer in Korea. AB - PURPOSE: The purpose of the study was to investigate significant psychosocial needs of low-income people with cancer in Korea and the extent to which these needs are unmet and which factors influence them. METHODS: A descriptive study with a cross-sectional design was used. The data were collected by questionnaires from a convenience sample of 238 low-income people with cancer during 2009. A psychosocial needs inventory consisting of 7 categories with 48 items was used to identify significant psychosocial needs and unmet needs. Unmet psychosocial needs were defined to the needs that the participants reported as both important and unsatisfied. Influencing factors defined with multivariate regression analysis. RESULTS: "Health professionals" was the most important needs category, followed by "information. Among the 48 items, 37 were identified to be important or very important by more than 50% of the participants. All 37 important psychosocial needs were also identified to be unmet needs. "Emotional and spiritual" was the most unmet psychosocial needs category, followed by "practical matters" and "identity" categories. The most unmet need item was 'help with financial matters' (50.0%). The strongest influencing factor was 'no one to talk with'. CONCLUSION: Low-income people with cancer experience high levels of unmet needs across a wide range of psychosocial needs. They need to be supported not only for practical matters but also for emotional and spiritual areas. The results provide a first step towards a development of interventions tailored to meet psychosocial needs and expectations of low-income people with cancer. PMID- 25300449 TI - Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. AB - BACKGROUND: Two novel antibodies (abs) directed to gamma-aminobutyric acid B receptor (GABA(B)R) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. METHODS: Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. RESULTS: In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. DISCUSSION: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome. PMID- 25300450 TI - Visual loss in Takayasu Arteritis - Look Beyond the Eye. AB - Patients with Takayasu arteritis often present with reduced vision related either to the disease per se or due to complications of therapy. We report a patient with Takayasu arteritis who developed acute onset bilateral visual loss 6wks following percutaneous revascularization of occluded aortic arch branches. No ocular cause for the visual loss was evident. The reason for visual loss in this patient was an extraocular cause. Ocular and extraocular causes of visual loss in Takayasu arteritis are discussed. PMID- 25300451 TI - Combining Video, Audio and Lexical Indicators of Affect in Spontaneous Conversation via Particle Filtering. AB - We present experiments on fusing facial video, audio and lexical indicators for affect estimation during dyadic conversations. We use temporal statistics of texture descriptors extracted from facial video, a combination of various acoustic features, and lexical features to create regression based affect estimators for each modality. The single modality regressors are then combined using particle filtering, by treating these independent regression outputs as measurements of the affect states in a Bayesian filtering framework, where previous observations provide prediction about the current state by means of learned affect dynamics. Tested on the Audio-visual Emotion Recognition Challenge dataset, our single modality estimators achieve substantially higher scores than the official baseline method for every dimension of affect. Our filtering-based multi-modality fusion achieves correlation performance of 0.344 (baseline: 0.136) and 0.280 (baseline: 0.096) for the fully continuous and word level sub challenges, respectively. PMID- 25300452 TI - Support for a 'Center of Origin' in the Coral Triangle: cryptic diversity, recent speciation, and local endemism in a diverse lineage of reef fishes (Gobiidae: Eviota). AB - The Coral Triangle is widely regarded as the richest marine biodiversity hot-spot in the world. One factor that has been proposed to explain elevated species richness within the Coral Triangle is a high rate of in situ speciation within the region itself. Dwarfgobies (Gobiidae: Eviota) are a diverse genus of diminutive cryptobenthic reef fishes with limited dispersal ability, and life histories and ecologies that increase potential for speciation. We use molecular phylogenetic and biogeographic data from two clades of Eviota species to examine patterns, processes and timing associated with species origination within the Coral Triangle. Sequence data from mitochondrial and nuclear DNA were used to generate molecular phylogenies and median-joining haplotype networks for the genus Eviota, with emphasis on the E. nigriventris and E. bifasciata complexes - two species groups with distributions centered in the Coral Triangle. The E. nigriventris and E. bifasciata complexes both contain multiple genetically distinct, geographically restricted color morphs indicative of recently-diverged species originating within the Coral Triangle. Relaxed molecular-clock dating estimates indicate that most speciation events occurred within the Pleistocene, and the geographic pattern of genetic breaks between species corresponds well with similar breaks in other marine fishes and sessile invertebrates. Regional isolation due to sea-level fluctuations may explain some speciation events in these species groups, yet other species formed with no evidence of physical isolation. The timing of diversification events and present day distributions of Eviota species within the Coral Triangle suggest that both allopatric speciation (driven by ephemeral and/or 'soft' physical barriers to gene flow) and sympatric speciation (driven by niche partitioning and assortative mating) may be driving diversification at local scales within the Coral Triangle. The presence of multiple young, highly-endemic cryptic species of Eviota within the Coral Triangle suggests that (i) the Coral Triangle is indeed a "cradle" of reef fish biodiversity and that (ii) our current approximations of reef fish diversity in the region may be significantly underestimated. PMID- 25300453 TI - The origins and radiation of Australian Coptotermes termites: from rainforest to desert dwellers. AB - The termite genus Coptotermes (Rhinotermitidae) is found in Asia, Africa, Central/South America and Australia, with greatest diversity in Asia. Some Coptotermes species are amongst the world's most damaging invasive termites, but the genus is also significant for containing the most sophisticated mound building termites outside the family Termitidae. These mound-building Coptotermes occur only in Australia. Despite its economic and evolutionary significance, the biogeographic history of the genus has not been well investigated, nor has the evolution of the Australian mound-building species. We present here the first phylogeny of the Australian Coptotermes to include representatives from all described species. We combined our new data with previously generated data to estimate the first phylogeny to include representatives from all continents where the genus is found. We also present the first estimation of divergence dates during the evolution of the genus. We found the Australian Coptotermes to be monophyletic and most closely related to the Asian Coptotermes, with considerable genetic diversity in some Australian taxa possibly representing undescribed species. The Australian mound-building species did not form a monophyletic clade. Our ancestral state reconstruction analysis indicated that the ancestral Australian Coptotermes was likely to have been a tree nester, and that mound building behaviour has arisen multiple times. The Australian Coptotermes were found to have diversified ~13million years ago, which plausibly matches with the narrowing of the Arafura Sea allowing Asian taxa to cross into Australia. The first diverging Coptotermes group was found to be African, casting doubt on the previously raised hypothesis that the genus has an Asian origin. PMID- 25300454 TI - Through thick and thin: cryptic sympatric speciation in the submersed genus Najas (Hydrocharitaceae). AB - Cryptic sympatric species arise when reproductive isolation is established in sympatry, leading to genetically divergent lineages that are highly similar morphologically or virtually indistinguishable. Although cryptic sympatric species have been reported in various animals, fungi, and protists, there are few compelling examples for plants. This investigation presents a case for cryptic sympatric speciation in Najas flexilis, a widespread aquatic plant, which extends throughout northern North America and Eurasia. The taxon is noted for its variable seed morphology, which earlier research associated with cytotypes; i.e., diploids were characterized by thicker seeds and tetraploids by thinner seeds. However, cytotypes are not patterned geographically with diploid and tetraploid plants often found in close proximity within the same lake. Using digital image and DNA sequence analyses, we found that diploids and tetraploids are well isolated and remain genetically distinct throughout their sympatric range, where sterile hybrids occur frequently. Incorporation of sequence data from the single copy nuclear phytoene desaturase locus revealed further that the tetraploids are allopolyploid derivatives of N. flexilis and N. guadalupensis, the latter a closely related species with an overlapping distribution. We conclude that the taxon widely known as N. flexilis actually comprises two cryptic, sibling species, which diverged in sympatry by interspecific hybridization and subsequent chromosomal isolation. By comparing seed morphology of type specimens, we associated the names N. flexilis and N. canadensis to the diploids and tetraploids respectively. Additionally, the narrowly restricted taxon known formerly as N. muenscheri is shown via morphological and genetic evidence to be synonymous with N. canadensis. PMID- 25300455 TI - Diversification of the silverspot butterflies (Nymphalidae) in the Neotropics inferred from multi-locus DNA sequences. AB - The tribe Heliconiini (Lepidoptera: Nymphalidae) is a diverse group of butterflies distributed throughout the Neotropics, which has been studied extensively, in particular the genus Heliconius. However, most of the other lineages, such as Dione, which are less diverse and considered basal within the group, have received little attention. Basic information, such as species limits and geographical distributions remain uncertain for this genus. Here we used multilocus DNA sequence data and the geographical distribution analysis across the entire range of Dione in the Neotropical region in order to make inferences on the evolutionary history of this poorly explored lineage. Bayesian time-tree reconstruction allows inferring two major diversification events in this tribe around 25mya. Lineages thought to be ancient, such as Dione and Agraulis, are as recent as Heliconius. Dione formed a monophyletic clade, sister to the genus Agraulis. Dione juno, D. glycera and D. moneta were reciprocally monophyletic and formed genetic clusters, with the first two more close related than each other in relation to the third. Divergence time estimates support the hypothesis that speciation in Dione coincided with both the rise of Passifloraceae (the host plants) and the uplift of the Andes. Since the sister species D. glycera and D. moneta are specialized feeders on passion-vine lineages that are endemic to areas located either within or adjacent to the Andes, we inferred that they co speciated with their host plants during this vicariant event. PMID- 25300456 TI - Nasal potential difference: Best or average result for CFTR function as diagnostic criteria for cystic fibrosis? AB - BACKGROUND: The current practice of averaging the nasal potential difference (NPD) results of right and left nostril measurements reduce inter-individual variability but may underestimate individual CFTR function. METHODS: Best NPD response to Cl(-)-free and isoproterenol perfusion (=largest DeltaPD(0Cl/Iso)) from the right and left nostril was compared to the average result in 13 cystic fibrosis (CF), 78 query-CF patients and 22 healthy controls from 2 cohorts. RESULTS: Despite moderate to good correlation (p<0.001) between right and left measured DeltaPD(0Cl/Iso), we observed large differences in some individuals. A comparison of average versus best DeltaPD(0Cl/Iso) showed only moderate agreement (Giessen kappa=0.538; Toronto kappa=0.607). Averaging DeltaPD(0Cl/Iso) showed a lower composite chloride response compared to best DeltaPD(0Cl/Iso) and altered diagnostic NPD interpretation in 30 of 113 (27%) subjects. CONCLUSIONS: The current practice of averaging the NPD results of right and left nostril measurements leads to an underestimation of the individual CFTR function and should be reconsidered. PMID- 25300457 TI - A multicenter, prospective, quasi-experimental evaluation study of a patient education program to foster multiple sclerosis self-management competencies. AB - OBJECTIVE: To determine the impact of the self-management training program "S.MS" for new multiple sclerosis (MS) patients. METHOD: Multicenter, prospective, quasi experimental study with 31 MS patients in the intervention group (training program) and 33 participants in the control group (CG) (brochures). Data were collected before, after and 6 months after the interventions. Analysis of change was done by ANCOVA with repeated measurements. RESULTS: At baseline, participants in CG were younger at the time of diagnosis, suffered more frequently from relapsing-remitting MS and took more MS-medication on a permanent basis. The intervention had a stable significant effect on each dimension of self-management ability, on total self-management ability (ES=0.194, p<0.001), on anxiety (ES=0.193, p=0.001), and on disease-specific quality of life (ES=0.120, p=0.007). Regarding depression, a significant interaction effect of time and intervention could be observed (ES=0.106, p=0.011). No effect was found on disease-specific knowledge. High participant acceptance was reported. CONCLUSION: "S.MS" participation was associated with a significant and sustained improvement of self management abilities, anxiety and disease-specific quality of life in a quasi experimental study design. Using RCT or CRT-designs would be desirable to further improve the evidence of treatment effectiveness. PRACTICE IMPLICATIONS: This study provides substantial evidence that "S.MS" fosters patients' self-management ability. PMID- 25300458 TI - Humans at their most ungodly. PMID- 25300459 TI - Assessing the suitability of 8-OHdG and micronuclei as genotoxic biomarkers in chromate-exposed workers: a cross-sectional study. AB - OBJECTIVES: We aimed to investigate suitable conditions of 8-hydroxy-2' deoxyguanosine (8-OHdG) and micronucleus (MN) as genotoxic biomarkers at different levels of occupational chromate exposure. DESIGN: A cross-sectional study was used. PARTICIPANTS: 84 workers who were exposed to chromate for at least 1 year were chosen as the chromate exposed group, while 30 non-exposed individuals were used as controls. MAIN OUTCOME MEASURES: Environmental and biological exposure to chromate was respectively assessed by measuring the concentration of chromate in the air (CrA) and blood (CrB) by inductively coupled plasma mass spectrometer (ICP-MS) in all participants. MN indicators, including micronucleus cell count (MNCC), micro-nucleus count (MNC), nuclear bridge (NPB) and nuclear bud (NBUD) were calculated by the cytokinesis-block micronucleus test (CBMN), while the urinary 8-OHdG was measured by the ELISA method and normalised by the concentration of Cre. RESULTS: Compared with the control group, the levels of CrA, CrB, MNCC, MNC and 8-OHdG in the chromate-exposed group were all significantly higher (p<0.05). There were positive correlations between log(8 OHdG) and LnMNCC or LnMNC (r=0.377 and 0.362). The levels of LnMNCC, LnMNC and log (8-OHdG) all have parabola correlations with the concentration of CrB. However, there was a significantly positive correlation between log (8-OHdG) and CrB when the CrB level was below 10.50 ug/L (r=0.355), while a positive correlation was also found between LnMNCC or LnMNC and CrB when the CrB level was lower than 9.10 ug/L (r=0.365 and 0.269, respectively). CONCLUSIONS: MN and 8 OHdG can be used as genotoxic biomarkers in the chromate-exposed group, but it is only when CrB levels are lower than 9.10 and 10.50 ug/L, respectively, that they can accurately reflect the degree of genetic damage. PMID- 25300460 TI - NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease. AB - INTRODUCTION: This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. METHODS AND ANALYSIS: Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. ETHICS AND DISSEMINATION: The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: EUDRACT Reference Number: 2012-002764-27. PMID- 25300461 TI - Plasmatic oxidative stress biomarkers in multiple sclerosis: relation with clinical and demographic characteristics. AB - OBJECTIVES: In multiple sclerosis (MS) oxidative injury likely plays a major role in disease progression and in damaging tissue in the central nervous system (CNS), although with different mechanisms in the initial and the progressive disease stages. We compared the biomarker levels of plasmatic oxidative stress in patients with relapsing remitting (RR) and secondary progressive (SP) MS in order to correlate biomarker levels with demographic and clinical variables. DESIGN AND METHODS: We included 60 consecutive MS patients (30 with RR-MS and 30 with SP-MS) and a control group of 81 healthy subjects. All patients underwent clinical assessment, including disability, fatigue and sleepiness evaluations and blood sample collection for advanced oxidation protein products (AOPPs), plasmatic ferric reducing ability (FRA) and thiol group dosage. RESULTS: Plasmatic AOPPs were significantly higher while FRA and thiol levels were lower in MS patients compared to healthy controls. No difference was found in oxidative stress biomarker values in RR and SP-MS patients. However, in patients with "active" disease, FRA levels and thiol groups (expression of antioxidant power) were significantly lower. No significant correlation was found with demographic and clinical characteristics of patients, including age, disease duration, disability, fatigue, and daytime sleepiness. CONCLUSIONS: Plasmatic AOPPs, FRA and thiol groups show oxidative damage and reduced antioxidant capability in MS. Although their power to characterize different courses of the disease is limited, they seem to be related to disease activity. PMID- 25300462 TI - [ARAPOC Study: Prevalence of respiratory symptoms and chronic obstructive pulmonary disease in the general population]. AB - OBJECTIVE: The aim of this study was to determine the prevalence of respiratory symptoms and COPD, as well as the characteristics of this population in Aragon (Spain). DESIGN AND LOCATION: It is a cross-sectional epidemiological study in a population between 40 and 75 years of age. Subjects were randomly selected and stratified by age and sex using the data from the health card of the Aragonese Health Service. PARTICIPANTS: A total of 1185 subjects agreed to participate. MAIN MEASUREMENTS: A sociodemographic questionnaire and spirometry before and after bronchodilator test. The diagnosis of COPD was made according to the criteria of the GOLD guide (FEV1/FVC<0.7). RESULTS: COPD prevalence was 10.4%, 16.9% in men and 5.7% in women. Respiratory symptoms appeared in 58% of the general population. There was a higher prevalence of COPD in women than in other studies. Factors associated with developing COPD were, being male, increasing age, smoking more, and a lower education. More than three-quarters (78.9%) of COPD were not diagnosed. Diagnosis was associated with, being older, more smoking more, more severe COPD or poorer quality of life. CONCLUSIONS: The high prevalence of COPD and the significant level of underdiagnoses lead to believe that early diagnosis of this disease is still a pending issue. New strategies need to be developed to resolve this problem. PMID- 25300463 TI - [Health status of the elderly in primary health care practices using an integral geriatric assessment]. AB - OBJECTIVE: To determine the health status of patients 60 years of age or over in Primary Health Care practices using an integral geriatric assessment. DESIGN: Descriptive cross-sectional study. LOCATION: Five primary care units, Instituto Mexicano del Seguro Social; Mexico. PARTICIPANTS: Elderly patient aged 60 years of age or over, who were seen in primary health care practices. Previously signed informed consent was given, with exclusion criteria being non-completion of the integral geriatric assessment. A technical sample of conglomerates and quota was used. MAIN MEASUREMENTS: Medical dimension variables: visual, hearing (Hearing Handicap Inventory for the Elderly), urinary incontinence (Consultation in Incontinence Questionnaire), nutritional condition (Mini Nutritional Assessment), personal clinical history, polypharmacy; mental impairment (Mini Mental State Examination), depression (Yesavaje); functional: basic (Katz) and instrumental (Lawton and Brody) activities of daily living, mobility (Up and go) and social (Social sources scale). The analysis included percentages and confidence intervals. RESULTS: In the medical dimensions; 42.3% with visual impairment, 27.7% hearing, 68.3% urinary incontinence, 37.0% malnutrition, and 54.7% polypharmacy. In the mental dimension: 4.0% severe mental impairment, and 11% depression: functional dimension: 2.0% total dependence of activities of daily living; 14.3% instrumental activities impairment; 29.0% mobility impairment, and 48.0% had moderately deteriorated social resources. CONCLUSION: The health status of the elderly seen in primary health care practices is characterized by independent patients with different levels of alterations in the medical dimensions, low levels in mental alteration, and moderately deteriorated social resources. PMID- 25300464 TI - The plexiform spindle cell nevus nevi and atypical variants: report of 128 cases. AB - The plexiform spindle cell nevus (PLXSCN) is a distinct melanocytic lesion that often provokes concern for melanoma. We describe the features of 119 typical PLXSCNs and 9 atypical/high-grade lesions. Histologically, all cases had a fascicular plexiform architecture and were composed of predominately spindled cells. The 6 atypical plexiform spindle cell tumors (PLXSCTs) exhibited features such as greater mitotic activity, increased cellularity/nodular confluence, and more concerning cytological atypia. Three high-grade tumors (perhaps evolving plexiform spindle cell melanomas) had additional alarming clinical or histologic characteristics, such as patient age greater than 40 years, greater degree of cellularity, higher degree of cytological atypia, mitotic rate greater than 3/mm(2), regional lymph node metastases, and greater than 1 positive sentinel lymph node. Follow-up data were available for 18 typical PLXSCNs: all patients were without tumor recurrence or death in a mean follow-up period of 3.9 years (range, 1 month to 10 years). One atypical PLXSCT and 3 high-grade lesions had follow-up information: the atypical PLXSCT had sentinel lymph node involvement, and the patient was alive without recurrent disease at 1-year follow-up; 2 of the 3 high-grade lesions were positive for lymph node involvement, and all 3 patients were alive with 2-, 4-, and 0.8-year follow-up periods. All PLXSCTs should be completely excised with clear margins, and high-grade or potentially malignant lesions may require management as melanoma. PMID- 25300465 TI - Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: relevance to autism spectrum disorders. AB - Potential environmental risk factors for autism spectrum disorders (ASD) include viral/bacterial infection and an altered microbiome composition. The present study investigated whether administration of immune and gastrointestinal factors during gestation and early life altered startle response and prepulse inhibition in adolescent offspring using lipopolysaccharide (LPS), a bacterial mimetic, and propionic acid (PPA), a short chain fatty acid and metabolic product of antibiotic resistant enteric bacteria. Pregnant Long-Evans rats were injected once a day with PPA (500 mg/kg SC) on G12-16, LPS (50 MUg/kg SC) on G15 and G16, or vehicle control on G12-16 or G15-16. Male and female offspring were injected with PPA (500 mg/kg SC) or vehicle twice a day, every second day from postnatal days 10-18. Acoustic startle and prepulse inhibition was measured on postnatal days 45, 47, 49, and 51. Prenatal and postnatal treatments altered startle behavior in a sex-specific manner. Prenatal LPS treatment produced hyper sensitivity to acoustic startle in males, but not females and did not alter prepulse inhibition. Subtle alterations in startle responses that disappeared with repeated trials occurred with prenatal PPA and postnatal PPA treatment in both male and female offspring. Prenatal PPA treatment decreased prepulse inhibition in females, but not males. Lastly, females receiving a double hit of PPA, prenatal and postnatal, showed sensitization to acoustic startle, providing evidence for the double hit hypothesis. The current study supports the hypotheses that immune activation and metabolic products of enteric bacteria may alter development and behavior in ways that resemble sensory abnormalities observed in ASD. PMID- 25300466 TI - Juvenile stress alters LTP in ventral hippocampal slices: involvement of noradrenergic mechanisms. AB - Childhood adversity is a prominent risk factor for developing stress-related disorders in adulthood. It can be modeled in rodents, where altered stress responses in adulthood have been observed. The ventral hippocampus is thought to be involved in emotional responses and displays a unique modulation of synaptic plasticity following exposure to stress. Here, we investigated the long-term effect of juvenile stress (at postnatal age of 27-29 days) on synaptic plasticity in the ventral and dorsal hippocampus of adult, 3 month old rats. The rats that had experienced juvenile stress expressed impaired LTP in the dorsal hippocampus (DH), while ventral hippocampus (VH) LTP was facilitated. Furthermore, juvenile stress caused reduced sensitivity to the beta-adrenergic agonist isoproterenol (Iso; 1 MUM) in the adult DH, while it enhanced its action in VH slices. Further, juvenile stress resulted in an increase in the expression of beta1-adrenergic receptors in the VH but not in the DH, as revealed by western blot. Taken together, the ventral hippocampus expresses a lasting sensitivity to adrenergic modulation, thus likely to affect the emotional response to challenging situations in adulthood. PMID- 25300468 TI - High maternal choline consumption during pregnancy and nursing alleviates deficits in social interaction and improves anxiety-like behaviors in the BTBR T+Itpr3tf/J mouse model of autism. AB - Autism is a neurodevelopmental disorder with multiple genetic and environmental risk factors. Choline is a fundamental nutrient for brain development and high choline intake during prenatal and/or early postnatal periods is neuroprotective. We examined the effects of perinatal choline supplementation on social behavior, anxiety, and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of autism. The BTBR or the more "sociable" C57BL/6J (B6) strain females were fed a control or choline-supplemented diet from mating, throughout pregnancy and lactation. After weaning to a control diet, all offspring were evaluated at one or two ages [postnatal days 33-36 and 89-91] using open field (OF), elevated plus maze (EPM), marble burying (MB), and three-chamber social interaction tests. As expected, control-diet BTBR mice displayed higher OF locomotor activity, impaired social preference, and increased digging behavior during the MB test compared to control-diet B6 mice. Choline supplementation significantly decreased digging behavior, elevated the percentage of open arm entries and time spent in open arms in the EPM by BTBR mice, but had no effect on locomotion. Choline supplementation did not alter social interaction in B6 mice but remarkably improved impairments in social interaction in BTBR mice at both ages, indicating that the benefits of supplementation persist long after dietary choline returns to control levels. In conclusion, our results suggest that high choline intake during early development can prevent or dramatically reduce deficits in social behavior and anxiety in an autistic mouse model, revealing a novel strategy for the treatment/prevention of autism spectrum disorders. PMID- 25300467 TI - Early postpartum pup preference is altered by gestational cocaine treatment: associations with infant cues and oxytocin expression in the MPOA. AB - Cross-fostering studies suggest cocaine-induced deficits in maternal behavior could be associated with altered behavior of offspring following prenatal cocaine exposure. Neonatal vocalizations are an important offspring cue facilitating early interactions between dam and rodent pup offspring and have been shown to be altered following prenatal cocaine-exposure. It is unclear how variations in acoustic parameters of USVs impact maternal behavior and the mechanism(s) underlying these processes. The present study examined differences in cocaine exposed and control rodent dam maternal preference of cocaine-exposed or untreated pups in a dual choice apparatus. Relationship of preference-like behavior with pup USVs and dam oxytocin expression was explored. Gestational cocaine-exposure interfered with preference-like behavior of dams on postpartum day 1 with cocaine-exposure associated with decreased time spent on the cocaine exposed pup side compared to the control pup side, and decreases in preference like behavior associated in part with decreased number of USVs being emitted by cocaine-exposed pups. On postpartum day 5, decreased oxytocin expression in the medial preoptic area was associated with altered preference-like behavior in cocaine-exposed dams, including frequency and latency to touch/sniff pups. Results indicate cocaine's effects on the mother-infant relationship is likely synergistic, in that cocaine influences mother and offspring both independently and concertedly and that variations within pup vocalizations and the oxytocin system may be potential mechanism(s) underlying this synergistic relationship during the postpartum period. PMID- 25300469 TI - Obama cares about visuo-spatial attention: perception of political figures moves attention and determines gaze direction. AB - Processing an abstract concept such as political ideology by itself is difficult but becomes easier when a background situation contextualizes it. Political ideology within American politics, for example, is commonly processed using space metaphorically, i.e., the political "left" and "right" (referring to Democrat and Republican views, respectively), presumably to provide a common metric to which abstract features of ideology can be grounded and understood. Commonplace use of space as metaphor raises the question of whether an inherently non-spatial stimulus (e.g., picture of the political "left" leader, Barack Obama) can trigger a spatially-specific response (e.g., attentional bias toward "left" regions of the visual field). Accordingly, pictures of well-known Democrats and Republicans were presented as central cues in peripheral target detection (Experiment 1) and saccadic free-choice (Experiment 2) tasks to determine whether perception of stimuli lacking a direct association with physical space nonetheless induce attentional and oculomotor biases in the direction compatible with the ideological category of the cue (i.e., Democrat/left and Republican/right). In Experiment 1, target detection following presentation of a Democrat (Republican) was facilitated for targets appearing to the left (right). In Experiment 2, participants were more likely to look left (right) following presentation of a Democrat (Republican). Thus, activating an internal representation of political ideology induced a shift of attention and biased choice of gaze direction in a spatially-specific manner. These findings demonstrate that the link between conceptual processing and spatial attention can be totally arbitrary, with no reference to physical or symbolic spatial information. PMID- 25300470 TI - Top-down modulation of visual and auditory cortical processing in aging. AB - Age-related cognitive decline has been accounted for by an age-related deficit in top-down attentional modulation of sensory cortical processing. In light of recent behavioral findings showing that age-related differences in selective attention are modality dependent, our goal was to investigate the role of sensory modality in age-related differences in top-down modulation of sensory cortical processing. This question was addressed by testing younger and older individuals in several memory tasks while undergoing fMRI. Throughout these tasks, perceptual features were kept constant while attentional instructions were varied, allowing us to devise all combinations of relevant and irrelevant, visual and auditory information. We found no top-down modulation of auditory sensory cortical processing in either age group. In contrast, we found top-down modulation of visual cortical processing in both age groups, and this effect did not differ between age groups. That is, older adults enhanced cortical processing of relevant visual information and suppressed cortical processing of visual distractors during auditory attention to the same extent as younger adults. The present results indicate that older adults are capable of suppressing irrelevant visual information in the context of cross-modal auditory attention, and thereby challenge the view that age-related attentional and cognitive decline is due to a general deficits in the ability to suppress irrelevant information. PMID- 25300471 TI - Effects of a glycine transporter-1 inhibitor and D-serine on MK-801-induced immobility in the forced swimming test in rats. AB - Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed. In the present study, the effects of the positive modulation of the glycine site on the NMDA receptor were investigated in an animal model of negative symptoms of schizophrenia. The subchronic administration of MK-801 increased immobility in the forced swimming test in rats without affecting spontaneous locomotor activity. The increased immobility induced by MK-801 was attenuated by the atypical antipsychotic clozapine but not by either the typical antipsychotic haloperidol or the antidepressant imipramine, indicating that the increased immobility induced by subchronic treatment with MK-801 in the forced swimming test may represent a negative symptom of schizophrenia. Likewise, positive modulation of the glycine sites on the NMDA receptor using an agonist for the glycine site, D-serine, and a glycine transporter-1 inhibitor, N-[(3R)-3 ([1,1'-biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine hydrochloride (NFPS), significantly reversed the increase in immobility in MK-801-treated rats without reducing the immobility time in vehicle-treated rats. The present results show that the stimulation of the NMDA receptor through the glycine site on the receptor either directly with D-serine or by blocking glycine transporter-1 attenuates the immobility elicited by the subchronic administration of MK-801 and may be potentially useful for the treatment of negative symptoms of schizophrenia. PMID- 25300472 TI - Chronic administration of amitriptyline differentially alters neuropathic pain related behaviour in the presence and absence of a depressive-like phenotype. AB - Chronic pain and depression share a complex, reciprocal relationship. Furthermore, in addition to treating depression, antidepressants such as amitriptyline are a first-line treatment for chronic pain conditions, indicating possible common neural substrates underlying both depression and pain. However, there is a paucity of studies examining the effect of antidepressant treatment on nociceptive and neuropathic pain responding in the presence of a depressive phenotype. The current study aimed to examine the effect of chronic amitriptyline administration on neuropathic pain-related behaviour and associated neuroinflammatory processes in the olfactory bulbectomised (OB) rat model of depression. Nociceptive responding to mechanical, innocuous cold or noxious heat stimuli in sham or OB rats was not altered by chronic amitriptyline administration. The induction of neuropathic pain following L5-L6 spinal nerve ligation (SNL) resulted in robust mechanical and cold allodynia and heat hyperalgesia in both sham and OB vehicle-treated animals. Chronic amitriptyline administration attenuated SNL-induced mechanical allodynia in both sham and OB rats at day 7 post-SNL, an effect which was enhanced and prolonged in OB rats. In comparison, chronic amitriptyline administration attenuated SNL-induced cold allodynia and heat hyperalgesia in sham, but not OB, rats. Evaluating the affective/motivational aspect of pain using the place escape avoidance paradigm revealed that OB-SNL rats exhibit reduced noxious avoidance behaviour when compared with sham counterparts, an effect not altered by chronic amitriptyline administration. Chronic amitriptyline administration prevented the increased expression of GFAP, IL-10 and CCL5, and enhanced the expression of TNFalpha, in the prefrontal cortex of OB-SNL rats. In conclusion, these data demonstrate that chronic amitriptyline differentially alters somatic nociceptive responding following peripheral nerve-injury, depending on stimulus modality and the presence or absence of a depressive-like phenotype, an effect which may involve modulation of neuroinflammatory processes. PMID- 25300473 TI - beta-Cyclodextrin-grafted on multiwalled carbon nanotubes as versatile nanoplatform for entrapment of guanine-based drugs. AB - The design of beta-cyclodextrin/multiwalled carbon nanotubes hybrid (beta-CD MWCNT) as nanoplatform for the entrapment and delivery of guanine based drugs is described here. The functionalized carbon nanomaterials have been characterized by XPS spectroscopy, electron microscopy (FEG-SEM and TEM), AFM, TGA, and FT-IR to achieve insights on structure, morphology and chemical composition. The drug binding abilities of nanocarrier towards the guanine (G) and Acyclovir (Acy) were proved by UV-vis and DSC experiments. Host-guest equilibrium association constants and drug loading have been evaluated for G/beta-CD-MWCNT and Acy/beta CD-MWCNT complexes. The release studies showed a sustained delivery of Acy without initial burst effect confirming a strong interaction of drug with the nanoplatform sites. The preliminary antiviral data indicated that the Acyclovir loaded into the beta-CD-MWCNT platform interferes with HSV-1 replication and the antireplicative effect was higher than the free drug. PMID- 25300474 TI - Opportunities and challenges for the use of large-scale surveys in public health research: a comparison of the assessment of cancer screening behaviors. AB - Large-scale surveys that assess cancer prevention and control behaviors are a readily available, rich resource for public health researchers. Although these data are used by a subset of researchers who are familiar with them, their potential is not fully realized by the research community for reasons including lack of awareness of the data and limited understanding of their content, methodology, and utility. Until now, no comprehensive resource existed to describe and facilitate use of these data. To address this gap and maximize use of these data, we catalogued the characteristics and content of four surveys that assessed cancer screening behaviors in 2005, the most recent year with concurrent periods of data collection: the National Health Interview Survey, Health Information National Trends Survey, Behavioral Risk Factor Surveillance System, and California Health Interview Survey. We documented each survey's characteristics, measures of cancer screening, and relevant correlates; examined how published studies (n = 78) have used the surveys' cancer screening data; and reviewed new cancer screening constructs measured in recent years. This information can guide researchers in deciding how to capitalize on the opportunities presented by these data resources. PMID- 25300476 TI - The age distribution of type-specific high-risk human papillomavirus incidence in two population-based screening trials. AB - BACKGROUND: Age- and type-specific high-risk human papillomavirus (hrHPV) incidence estimates in screen-eligible women are relevant from a public health perspective because they provide an indication of the effect of vaccination on the occurrence of screen-positives in HPV-based screening. However, limited data from women over 25 years of age are available. METHODS: In 24,105 hrHPV-negative women participating in Dutch (Population-Based Screening Study Amsterdam: POBASCAM) and Italian (New Technologies for Cervical Cancer: NTCC) population based randomized controlled screening trials the age- and type-specific distribution of incident hrHPV infections detected at the next screening round was assessed. HPV types were grouped into vaccine (bivalent: HPV16/18; polyvalent HPV16/18/31/33/45/52/58) and nonvaccine types. RESULTS: The incidence of screen detected hrHPV among women ages 29 to 56 years was 2.54% (95% confidence interval, 2.30-2.78) in POBASCAM and 2.77% (2.36-3.19) in NTCC. In both studies, the incidence of bivalent, polyvalent, and nonpolyvalent infections decreased with age (P < 0.0001). Among women with incident infection(s), vaccine-type positivity changed quadratically with age, in particular for the polyvalent vaccine (P values: POBASCAM: bivalent 0.264, polyvalent 0.038; NTCC bivalent 0.039, polyvalent 0.005). However, more than 20% and 50% of women with incident hrHPV were positive for bivalent and polyvalent vaccine types, respectively, in all ages in both studies. CONCLUSIONS: We observed decreasing age trends of hrHPV vaccine and nonvaccine type incidences and age-related differences in the vaccine type positivity among women with incident infections. Most importantly, hrHPV infections continued to be detected in all ages and the contribution of vaccine types remained substantial. IMPACT: Our results indicate a considerable reduction of new hrHPV infections in vaccinated cohorts, ensuing revision of screening guidelines. PMID- 25300477 TI - What role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia? AB - Staphylococcus aureus is a major cause of bacteremia, which frequently results in serious secondary infections such as infective endocarditis, osteomyelitis, and septic arthritis. The ability of S. aureus to cause such a wide range of infections has been ascribed to its huge armoury of different virulence factors, many of which are under the control of the quorum-sensing accessory gene regulator (Agr) system. However, a significant fraction of S. aureus bacteremia cases are caused by agr-defective isolates, calling into question the role of Agr in invasive staphylococcal infections. This review draws on recent work to define the role of Agr during bacteremia and explain why the loss of this major virulence regulator is sometimes a price worth paying for S. aureus. PMID- 25300475 TI - Dietary intake of acrylamide and epithelial ovarian cancer risk in the european prospective investigation into cancer and nutrition (EPIC) cohort. AB - Acrylamide, classified in 1994 by the International Agency for Research on Cancer (IARC) as "probably carcinogenic" to humans, was discovered in 2002 in some heat treated, carbohydrate-rich foods. The association between dietary acrylamide intake and epithelial ovarian cancer risk (EOC) has been previously studied in one case-control and three prospective cohort studies which obtained inconsistent results and could not further examine histologic subtypes other than serous EOC. The present study was carried out in the European Prospective Investigation into Cancer and Nutrition (EPIC) subcohort of women (n = 325,006). Multivariate Cox proportional hazards models were used to assess the association between questionnaire-based acrylamide intake and EOC risk. Acrylamide was energy adjusted using the residual method and was evaluated both as a continuous variable (per 10 MUg/d) and in quintiles; when subgroups by histologic EOC subtypes were analyzed, acrylamide intake was evaluated in quartiles. During a mean follow-up of 11 years, 1,191 incident EOC cases were diagnosed. At baseline, the median acrylamide intake in EPIC was 21.3 MUg/d. No associations and no evidence for a dose-response were observed between energy-adjusted acrylamide intake and EOC risk (HR10MUg/d,1.02; 95% CI, 0.96-1.09; HRQ5vsQ1, 0.97; 95% CI, 0.76-1.23). No differences were seen when invasive EOC subtypes (582 serous, 118 endometrioid, and 79 mucinous tumors) were analyzed separately. This study did not provide evidence that acrylamide intake, based on food intake questionnaires, was associated with risk for EOC in EPIC. Additional studies with more reliable estimates of exposure based on biomarkers may be needed. PMID- 25300479 TI - Assessment of early auditory development of very young Finnish children with LittlEARS((r)) Auditory Questionnaire and McArthur Communicative Developmental Inventories. AB - OBJECTIVES: We analysed the Finnish version of the LittlEARS((r)) Auditory Questionnaire as a method for assessing very young children's early auditory, pre verbal and emerging verbal development. We also examined whether any background factors exist that influence the results and thus the usability of this method. To determine its potential in assessment, the Finnish version of the LittlEARS((r)) Auditory Questionnaire was analysed in relation to the Finnish McArthur Communicative Developmental Inventories. The latter is currently the method most commonly used together with parental interviews. However, this method is neither designed for infants younger than 8 months nor is its main emphasis on auditory development. Thus, we investigated whether the Finnish version of LittlEARS((r)) Auditory Questionnaire could supplement the Finnish McArthur Communicative Developmental Inventories and thereby help in detecting children with hearing impairments. METHODS: Normative data were collected for Finnish children with normal hearing (N=318) using the LittlEARS((r)) Auditory Questionnaire and an abridged version of the Finnish McArthur Communicative Developmental Inventories. In addition, background information was collected with a questionnaire designed for this study. The results of these questionnaires were analysed in relation to each other. RESULTS: Statistical analysis showed that the results gained with the Finnish version of LittlEARS((r)) Auditory Questionnaire and the abridged version of the Finnish McArthur Communicative Developmental Inventories are closely related. However, the LittlEARS((r)) Auditory Questionnaire manages to capture the earlier and subtler changes that occur in infancy, therefore making a good continuum with McArthur Communicative Developmental Inventories. Also, most background factors, such as parents' educational level, did not affect the results significantly, rendering the LittlEARS((r)) Auditory Questionnaire a valuable method for assessment of early auditory development in very young children. CONCLUSIONS: The Finnish version of the LittlEARS((r)) Auditory Questionnaire is a reliable assessment tool with no confounding background factors. It enables evaluation of the early auditory development in even the youngest of children. PMID- 25300478 TI - PPARdelta signaling mediates the cytotoxicity of DHA in H9c2 cells. AB - Docosahexaenoic acid (22:6n3, DHA) is an n-3 polyunsaturated fatty acid (PUFA) known to affect numerous biological functions. While DHA possesses many properties that impact cell survival such as suppressing cell growth and inducing apoptosis, the exact molecular and cellular mechanism(s) remain unknown. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate many cell pathways including cell death. As DHA acts as a ligand to PPARs the aim of this study was to examine the involvement of PPARdelta in DHA-mediated cytotoxicity toward H9c2 cells. Treatment with DHA (100MUM) resulted in a significant decline in cell viability, cellular metabolic activity and total antioxidant capacity coinciding with increased total proteasome activities and activity of released lactate dehydrogenase (LDH). No changes in reactive oxygen species (ROS) production or accumulation of lipid peroxidation products were observed but DHA promoted apoptotic cell death as detected by flow cytometry, increased caspase-3 activity and decreased phosphorylation of Akt. Importantly, DHA enhanced PPARdelta DNA binding activity in H9c2 cells strongly signifying that the cytotoxic effect of DHA might be mediated via PPARdelta signaling. Co-treatment with the selective PPARdelta antagonist GSK 3787 (1MUM) abolished the cytotoxic effects of DHA in H9c2 cells. Cytotoxic effects of DHA were attenuated by co-treatment with myriocin, a selective inhibitor of serine palmitoyl transferase (SPT), preventing de novo ceramide biosynthesis. LC/MS analysis revealed that treatment with DHA resulted in the accumulation of ceramide, which was blocked by GSK 3787. Interestingly, inhibition of cytochrome P450 (CYP) oxidase with MS-PPOH (50MUM) abolished DHA-mediated cytotoxicity suggesting downstream metabolites as the active mediators. We further demonstrate that CYP oxidase metabolites of DHA, methyl epoxy docosapentaenoate (EDP methyl esters, 1MUM) (mix 1:1:1:1:1:1; 4,5-, 7,8-, 10,11-, 13,14-, 16,17- and 19,20-EDP methyl esters) and 19,20-EDP cause cytotoxicity via activation of PPARdelta signaling leading to increased levels of intracellular ceramide. These results illustrate novel pathways for DHA-induced cytotoxicity that suggest an important role for CYP-derived metabolites, EDPs. PMID- 25300480 TI - The incidence and prevalence of juvenile-onset recurrent respiratory papillomatosis in the Free State province of South Africa and Lesotho. AB - BACKGROUND AND OBJECTIVE: Although the estimated incidence and prevalence of juvenile-onset recurrent respiratory papillomatosis (JORRP) has been determined in countries in North America and Europe and in Australia, no studies have attempted to determine the incidence or prevalence of JORRP in African countries. The aim of this study is to determine the incidence and prevalence of JORRP in the Free State province of South Africa and Lesotho. METHODS: This was a retrospective study in which the records of all patients with JORRP from the Free State province of South Africa or Lesotho treated at Universitas Academic Hospital or by otorhinolaryngologists in private practice between 1 January 2011 and 31 December 2013 were reviewed. RESULTS: The estimated incidence and prevalence of JORRP in the Free State were 1.34 and 3.88 per 100,000 population respectively while the estimated incidence and prevalence in Lesotho were 0.49 and 1.04 per 100,000 population respectively. However, these figures are probably an underestimation. CONCLUSION: The incidence and prevalence calculated for the Free State were generally higher than those found in other studies, while those calculated for Lesotho was similar to those obtained in other studies. PMID- 25300481 TI - SMART: recent updates, new developments and status in 2015. AB - SMART (Simple Modular Architecture Research Tool) is a web resource (http://smart.embl.de/) providing simple identification and extensive annotation of protein domains and the exploration of protein domain architectures. In the current version, SMART contains manually curated models for more than 1200 protein domains, with ~ 200 new models since our last update article. The underlying protein databases were synchronized with UniProt, Ensembl and STRING, bringing the total number of annotated domains and other protein features above 100 million. SMART's 'Genomic' mode, which annotates proteins from completely sequenced genomes was greatly expanded and now includes 2031 species, compared to 1133 in the previous release. SMART analysis results pages have been completely redesigned and include links to several new information sources. A new, vector based display engine has been developed for protein schematics in SMART, which can also be exported as high-resolution bitmap images for easy inclusion into other documents. Taxonomic tree displays in SMART have been significantly improved, and can be easily navigated using the integrated search engine. PMID- 25300482 TI - The immune epitope database (IEDB) 3.0. AB - The IEDB, www.iedb.org, contains information on immune epitopes--the molecular targets of adaptive immune responses--curated from the published literature and submitted by National Institutes of Health funded epitope discovery efforts. From 2004 to 2012 the IEDB curation of journal articles published since 1960 has caught up to the present day, with >95% of relevant published literature manually curated amounting to more than 15,000 journal articles and more than 704,000 experiments to date. The revised curation target since 2012 has been to make recent research findings quickly available in the IEDB and thereby ensure that it continues to be an up-to-date resource. Having gathered a comprehensive dataset in the IEDB, a complete redesign of the query and reporting interface has been performed in the IEDB 3.0 release to improve how end users can access this information in an intuitive and biologically accurate manner. We here present this most recent release of the IEDB and describe the user testing procedures as well as the use of external ontologies that have enabled it. PMID- 25300483 TI - sc-PDB: a 3D-database of ligandable binding sites--10 years on. AB - The sc-PDB database (available at http://bioinfo-pharma.u-strasbg.fr/scPDB/) is a comprehensive and up-to-date selection of ligandable binding sites of the Protein Data Bank. Sites are defined from complexes between a protein and a pharmacological ligand. The database provides the all-atom description of the protein, its ligand, their binding site and their binding mode. Currently, the sc PDB archive registers 9283 binding sites from 3678 unique proteins and 5608 unique ligands. The sc-PDB database was publicly launched in 2004 with the aim of providing structure files suitable for computational approaches to drug design, such as docking. During the last 10 years we have improved and standardized the processes for (i) identifying binding sites, (ii) correcting structures, (iii) annotating protein function and ligand properties and (iv) characterizing their binding mode. This paper presents the latest enhancements in the database, specifically pertaining to the representation of molecular interaction and to the similarity between ligand/protein binding patterns. The new website puts emphasis in pictorial analysis of data. PMID- 25300484 TI - Easy quantitative assessment of genome editing by sequence trace decomposition. AB - The efficacy and the mutation spectrum of genome editing methods can vary substantially depending on the targeted sequence. A simple, quick assay to accurately characterize and quantify the induced mutations is therefore needed. Here we present TIDE, a method for this purpose that requires only a pair of PCR reactions and two standard capillary sequencing runs. The sequence traces are then analyzed by a specially developed decomposition algorithm that identifies the major induced mutations in the projected editing site and accurately determines their frequency in a cell population. This method is cost-effective and quick, and it provides much more detailed information than current enzyme based assays. An interactive web tool for automated decomposition of the sequence traces is available. TIDE greatly facilitates the testing and rational design of genome editing strategies. PMID- 25300485 TI - Dye label interference with RNA modification reveals 5-fluorouridine as non covalent inhibitor. AB - The interest in RNA modification enzymes surges due to their involvement in epigenetic phenomena. Here we present a particularly informative approach to investigate the interaction of dye-labeled RNA with modification enzymes. We investigated pseudouridine (Psi) synthase TruB interacting with an alleged suicide substrate RNA containing 5-fluorouridine (5FU). A longstanding dogma, stipulating formation of a stable covalent complex was challenged by discrepancies between the time scale of complex formation and enzymatic turnover. Instead of classic mutagenesis, we used differentially positioned fluorescent labels to modulate substrate properties in a range of enzymatic conversion between 6% and 99%. Despite this variegation, formation of SDS-stable complexes occurred instantaneously for all 5FU-substrates. Protein binding was investigated by advanced fluorescence spectroscopy allowing unprecedented simultaneous detection of change in fluorescence lifetime, anisotropy decay, as well as emission and excitation maxima. Determination of Kd values showed that introduction of 5FU into the RNA substrate increased protein affinity by 14* at most. Finally, competition experiments demonstrated reversibility of complex formation for 5FU-RNA. Our results lead us to conclude that the hitherto postulated long-term covalent interaction of TruB with 5FU tRNA is based on the interpretation of artifacts. This is likely true for the entire class of pseudouridine synthases. PMID- 25300486 TI - Rad9 interacts with Aft1 to facilitate genome surveillance in fragile genomic sites under non-DNA damage-inducing conditions in S. cerevisiae. AB - DNA damage response and repair proteins are centrally involved in genome maintenance pathways. Yet, little is known about their functional role under non DNA damage-inducing conditions. Here we show that Rad9 checkpoint protein, known to mediate the damage signal from upstream to downstream essential kinases, interacts with Aft1 transcription factor in the budding yeast. Aft1 regulates iron homeostasis and is also involved in genome integrity having additional iron independent functions. Using genome-wide expression and chromatin immunoprecipitation approaches, we found Rad9 to be recruited to 16% of the yeast genes, often related to cellular growth and metabolism, while affecting the transcription of ~2% of the coding genome in the absence of exogenously induced DNA damage. Importantly, Rad9 is recruited to fragile genomic regions (transcriptionally active, GC rich, centromeres, meiotic recombination hotspots and retrotransposons) non-randomly and in an Aft1-dependent manner. Further analyses revealed substantial genome-wide parallels between Rad9 binding patterns to the genome and major activating histone marks, such as H3K36me, H3K79me and H3K4me. Thus, our findings suggest that Rad9 functions together with Aft1 on DNA damage-prone chromatin to facilitate genome surveillance, thereby ensuring rapid and effective response to possible DNA damage events. PMID- 25300487 TI - Super Natural II--a database of natural products. AB - Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ~ 50,000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ~ 326,000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ~ 170,000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins. PMID- 25300488 TI - Requirement of CRTC1 coactivator for hepatitis B virus transcription. AB - Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication. PMID- 25300489 TI - Defective histone supply causes condensin-dependent chromatin alterations, SAC activation and chromosome decatenation impairment. AB - The structural organization of chromosomes is essential for their correct function and dynamics during the cell cycle. The assembly of DNA into chromatin provides the substrate for topoisomerases and condensins, which introduce the different levels of superhelical torsion required for DNA metabolism. In particular, Top2 and condensin are directly involved in both the resolution of precatenanes that form during replication and the formation of the intramolecular loop that detects tension at the centromeric chromatin during chromosome biorientation. Here we show that histone depletion activates the spindle assembly checkpoint (SAC) and impairs sister chromatid decatenation, leading to chromosome mis-segregation and lethality in the absence of the SAC. We demonstrate that histone depletion impairs chromosome biorientation and activates the Aurora dependent pathway, which detects tension problems at the kinetochore. Interestingly, SAC activation is suppressed by the absence of Top2 and Smc2, an essential component of condensin. Indeed, smc2-8 suppresses catenanes accumulation, mitotic arrest and growth defects induced by histone depletion at semi-permissive temperature. Remarkably, SAC activation by histone depletion is associated with condensin-mediated alterations of the centromeric chromatin. Therefore, our results reveal the importance of a precise interplay between histone supply and condensin/Top2 for pericentric chromatin structure, precatenanes resolution and centromere biorientation. PMID- 25300490 TI - Profiling the transcription factor regulatory networks of human cell types. AB - Neph et al. (2012) (Circuitry and dynamics of human transcription factor regulatory networks. Cell, 150: 1274-1286) reported the transcription factor (TF) regulatory networks of 41 human cell types using the DNaseI footprinting technique. This provides a valuable resource for uncovering regulation principles in different human cells. In this paper, the architectures of the 41 regulatory networks and the distributions of housekeeping and specific regulatory interactions are investigated. The TF regulatory networks of different human cell types demonstrate similar global three-layer (top, core and bottom) hierarchical architectures, which are greatly different from the yeast TF regulatory network. However, they have distinguishable local organizations, as suggested by the fact that wiring patterns of only a few TFs are enough to distinguish cell identities. The TF regulatory network of human embryonic stem cells (hESCs) is dense and enriched with interactions that are unseen in the networks of other cell types. The examination of specific regulatory interactions suggests that specific interactions play important roles in hESCs. PMID- 25300491 TI - TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei. AB - The metabolic network of a cell represents the catabolic and anabolic reactions that interconvert small molecules (metabolites) through the activity of enzymes, transporters and non-catalyzed chemical reactions. Our understanding of individual metabolic networks is increasing as we learn more about the enzymes that are active in particular cells under particular conditions and as technologies advance to allow detailed measurements of the cellular metabolome. Metabolic network databases are of increasing importance in allowing us to contextualise data sets emerging from transcriptomic, proteomic and metabolomic experiments. Here we present a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describes the generic and condition specific metabolic network of Trypanosoma brucei, a parasitic protozoan responsible for human and animal African trypanosomiasis. In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have also implemented a network-based representation of the information through MetExplore, yielding a novel environment in which to visualise the metabolism of this important parasite. PMID- 25300493 TI - Comparison of two instruments for measurement of quality of life in clinical practice--a qualitative study. AB - BACKGROUND: The study aimed to investigate the meaning patients assign to two measures of quality of life: the Schedule for Evaluation of Individual Quality of Life Direct Weighting (SEIQoL-DW) and the SEIQoL-DW Disease Related (DR) version, in a clinical oncology setting. Even though the use of quality of life assessments has increased during the past decades, uncertainty regarding how to choose the most suitable measure remains. SEIQoL-DW versions assesses the individual's perception of his or her present quality of life by allowing the individual to nominate the domains to be evaluated followed by a weighting procedure resulting in qualitative (domains) as well as quantitative outcomes (index score). METHODS: The study applied a cross-sectional design with a qualitative approach and collected data from a purposeful sample of 40 patients with gastrointestinal cancer. Patients were asked to complete two measures, SEIQoL-DW and the SEIQoL-DR, to assess quality of life. This included nomination of the areas in life considered most important and rating of these areas; after completion patients participated in cognitive interviews around their selections of areas. Interviews were audiotaped and transcribed verbatim which was followed by analysis using a phenomenographic approach. RESULTS: The analyses of nominated areas of the two measures resulted in 11 domains reflecting what patients perceived had greatest impact on their quality of life. Analysis of the cognitive interviews resulted in 16 thematic categories explaining the nominated domains. How patients reflected around their quality of life appeared to differ by version (DW vs. DR). The DW version more often related to positive aspects in life while the DR version more often related to negative changes in life due to having cancer. CONCLUSIONS: The two SEIQoL versions tap into different concepts; health related quality of life, addressing losses and problems related to having cancer and, quality of life, more associated with aspects perceived as positive in life. The SEIQoL-DR and the SEIQoL-DW are recommended in clinical practice to take both negative and positive aspects into account and acting on the problems of greatest importance to the patient. PMID- 25300492 TI - Locus-specific control of DNA resection and suppression of subtelomeric VSG recombination by HAT3 in the African trypanosome. AB - The African trypanosome, Trypanosoma brucei, is a parasitic protozoan that achieves antigenic variation through DNA-repair processes involving Variant Surface Glycoprotein (VSG) gene rearrangements at subtelomeres. Subtelomeric suppression of DNA repair operates in eukaryotes but little is known about these controls in trypanosomes. Here, we identify a trypanosome histone acetyltransferase (HAT3) and a deacetylase (SIR2rp1) required for efficient RAD51 dependent homologous recombination. HAT3 and SIR2rp1 were required for RAD51 focus assembly and disassembly, respectively, at a chromosome-internal locus and a synthetic defect indicated distinct contributions to DNA repair. Although HAT3 promoted chromosome-internal recombination, it suppressed subtelomeric VSG recombination, and these locus-specific effects were mediated through differential production of ssDNA by DNA resection; HAT3 promoted chromosome internal resection but suppressed subtelomeric resection. Consistent with the resection defect, HAT3 was specifically required for the G2-checkpoint response at a chromosome-internal locus. HAT3 also promoted resection at a second chromosome-internal locus comprising tandem-duplicated genes. We conclude that HAT3 and SIR2rp1 can facilitate temporally distinct steps in DNA repair. HAT3 promotes ssDNA formation and recombination at chromosome-internal sites but has the opposite effect at a subtelomeric VSG. These locus-specific controls reveal compartmentalization of the T. brucei genome in terms of the DNA-damage response and suppression of antigenic variation by HAT3. PMID- 25300494 TI - A honeycomb-like porous carbon derived from pomelo peel for use in high performance supercapacitors. AB - A cost-effective approach to obtain electrode materials with excellent electrochemical performance is critical to the development of supercapacitors (SCs). Here we report the preparation of a three-dimensional (3D) honeycomb-like porous carbon (HLPC) by the simple carbonization of pomelo peel followed by KOH activation. Structural characterization indicates that the as-prepared HLPC with a high specific surface area (SSA) up to 2725 m(2) g(-1) is made up of interconnected microporous carbon walls. Chemical analysis shows that the HLPC is doped with nitrogen and also has oxygen-containing groups. Electrochemical measurements show that the HLPC not only exhibits a high specific capacitance of 342 F g(-1) and 171 F cm(-3) at 0.2 A g(-1) but also shows considerable rate capability with a retention of 62% at 20 A g(-1) as well as good cycling performance with 98% retention over 1000 cycles at 10 A g(-1) in 6 M KOH. Furthermore, an as-fabricated HLPC-based symmetric SC device delivers a maximum energy density of ~9.4 Wh kg(-1) in the KOH electrolyte. Moreover, the outstanding cycling stability (only 2% capacitance decay over 1000 cycles at 5 A g(-1)) of the SC device makes it promising for use in a high-performance electrochemical energy system. PMID- 25300496 TI - Artificial photosynthesis on tree trunk derived alkaline tantalates with hierarchical anatomy: towards CO2 photo-fixation into CO and CH4. AB - Artificial photosynthesis, the photochemical fixation and recycling of CO2 back to hydrocarbon fuels using sunlight and water, is both a significant challenge and an opportunity that, if realized, could have a revolutionary impact on our energy system. Herein, we demonstrate one of the first examples using biomass derived hierarchical porous photocatalysts for CO2 photo-fixation into sustainable hydrocarbon fuels. A generic method is proposed to build a series of alkaline tantalates MTaO3 (M = Li, Na, K) with hierarchical anatomy from macro- to nanoscales using activated carbonized tree trunks as templates. Artificial photosynthesis is carried out on MTaO3 series using only artificial sunlight, water, and carbon dioxide as inputs to produce carbon monoxide and methane as the main outputs. The CO2 photo-fixation performance can be enhanced by introducing a macropore network, which mainly enhances light transfer and accelerates gas diffusion. The research provides prototype models that integrate individual nanoscale components into higher level macroscopic artificial photosynthetic systems for better solar-to-fuel conversion efficiencies. This work would have potential significance for the ultimate construction of "artificial trees" and provide envisions creating "forests" of these CO2-capturing artificial trees to remove carbon dioxide from the atmosphere and convert it into sustainable fuels. PMID- 25300497 TI - The role of encoding strategies in contextual memory deficits in patients with bipolar disorder. AB - Contextual memory is important for the encoding and retrieval of episodic memory, which is often impaired in euthymic patients with bipolar disorder (BD). The objective was to investigate the effect of low and high cognitive support on encoding in an incidental contextual memory task in euthymic patients with BD. Twenty-three patients with a BD type I diagnosis (aged 23-63 years, 17 women and 6 men) and 29 healthy controls completed a recognition memory task for context (location of a recognised object). Participants were assigned to one of two incidental encoding conditions: (1) with a binding cue to encourage the association of the object to its location (judging the degree of appropriateness of an object in relation to its location) or (2) without a binding cue (judging daily use of objects). Patients showed a deficit in incidental contextual memory in the absence of a binding cue at encoding. Under incidental encoding with the binding cue, no differences were observed between the groups for contextual memory. Contextual memory deficits in BD patients were reduced by providing cognitive support at encoding. The role of this strategy should be investigated in larger samples to evaluate its use for cognitive remediation in BD patients. PMID- 25300498 TI - Increased cancer incidence risk in type 2 diabetes mellitus: results from a cohort study in Tyrol/Austria. AB - BACKGROUND: Recent meta-analyses revealed an association between type 2 diabetes mellitus (T2DM) and cancer. The strongest relationship was demonstrated for liver and pancreatic cancer, followed by endometrial cancer. We aimed at assessing the association between T2DM and cancer specifically for Tyrolean patients. METHODS: We investigated cancer incidence in Tyrolean subjects with T2DM by linking the data from the Diabetes and the Cancer Registries. 5709 T2DM patients were included and the sex- and age-adjusted standardized incidence ratio (SIR) was calculated, cancer incidence in the Tyrolean population serving as the standard. Endpoints were the time at which cancer was diagnosed, death or end of the observation period (31 December 2010). RESULTS: Site-specific analyses revealed statistically significantly elevated SIRs for cancer of the pancreas (1.78, 95% CI 1.02, 2.89) and corpus (1.79, 95% CI 1.15, 2.66) for women, and cancer of the liver (2.71, 95% CI 1.65, 4.18) and pancreas (1.87, 95% 1.11, 2.96) for men. Sub analyses performed according to the time of diabetes diagnosis revealed that SIR was highest in the first year after diabetes diagnosis, but SIR was demonstrated to be elevated in women for cancer of the liver (SIR 3.37, 95% CI 1.24, 7.34) and corpus (SIR 1.94, 95% CI 1.09, 3.20) and in men for liver (SIR 2.71, 95% CI 1.40, 4.74) in the period more than five years after diabetes diagnosis. In addition, increased risk at borderline statistical significance was observed in females for liver cancer (SIR 2.40, 95% CI 0.96, 4.94) and cervical cancer (SIR 1.81, 95% CI 0.87, 3.32) and in males for kidney cancer (SIR 1.65, 95% CI 0.99, 2.57). CONCLUSION: This study revealed a higher risk for cancer at certain sites in Tyrolean patients with T2DM. However, it is important to interpret the results with great caution due to inherent methodological problems. Optimized care programs for patients with T2DM should be integrated into the recommended procedures for cancer screening. PMID- 25300499 TI - Does knowledge of danger signs of pregnancy predict birth preparedness? A critique of the evidence from women admitted with pregnancy complications. AB - BACKGROUND: Improved knowledge of obstetric danger signs, birth preparedness practices, and readiness for emergency complications are among the strategies aimed at both enhancing utilization of maternal health services and increasing access to skilled care during childbirth, particularly for women with obstetric complications. It is unclear whether knowledge of danger signs translates into improved birth preparedness and complication readiness. The objective was to assess the association between knowledge of danger signs and birth preparedness among women admitted with pregnancy complications. METHODS: The study included 810 women admitted in the antepartum period to Mulago hospital, Uganda. Data was collected on socio-demographic characteristics, reproductive history, pregnancy complications, knowledge of danger signs, and birth preparedness/complication readiness (BPCR). Logistic regression analyses were conducted to explore the relationship between knowledge of danger signs and birth preparedness. RESULTS: Only about 1 in 3 women were able to mention at least three of the five basic components of BPCR, and could be regarded as 'knowledgeable on BPCR'. One in every 4 women could not mention any of the five components. Women with history of obstetric problems during the previous pregnancy were more likely to be knowledgeable on danger signs when compared to those who had no complications in prior pregnancy. Women who were knowledgeable on danger signs were four times more likely to be knowledgeable on BPCR as compared to those who were not knowledgeable. CONCLUSIONS: Though awareness about danger signs was low, knowledge of danger signs was associated with knowledge of birth preparedness. More emphasis should be given to emergency/complication readiness during antenatal care sessions. There is a need to strengthen existing policy interventions to address birth preparedness and complication readiness for obstetric emergencies. PMID- 25300500 TI - Ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) plus L-asparaginase as a first-line therapy improves outcomes in stage III/IV NK/T cell-lymphoma, nasal type (NTCL). AB - The prognosis of patients with stage III/IV NK/T-cell lymphoma (NTCL) is extremely poor. Although L-asparaginase (L-asp) is effective for NTCL, its significance has not been clearly demonstrated. In addition, there are few studies comparing treatment outcomes in stage III/IV NTCL. This study evaluated the efficacy of L-asp-based chemotherapy and prognostic factors in stage III/IV NTCL. Seventy patients with newly diagnosed stage III/IV NTCL were enrolled between January 2000 and February 2013. Patients received ifosfamide, etoposide, methotrexate, and prednisolone (IMEP) plus L-asp (N = 22) or combination chemotherapy without L-asp (N = 48) as a first-line treatment. Clinical prognostic factors, treatment outcomes, and prognostic scores were compared between the groups. After a median follow-up period of 12.8 months (range, 1.1 186.6 months), median overall survival (OS) and progression-free survival (PFS) were 11.3 and 5.6 months, respectively. Treatment outcomes were superior in patients treated with IMEP plus L-asp compared to those treated with chemotherapy without L-asp (overall response rate, 90.0 vs. 34.8 %, P < 0.001; complete remission rate, 65.0 vs. 21.7 %, P = 0.001). The OS and PFS were significantly higher for the IMEP plus L-asp group compared with the chemotherapy without L-asp group. In a multivariate analysis, the use of chemotherapy without L-asp was an independent predictor of reduced OS (hazards ratio (HR) = 2.18, 95 % confidence interval (CI) 1.08-4.40; P = 0.030) and PFS (HR = 2.29, 95 % CI 1.22-4.29; P = 0.010). IMEP plus L-asp is active against stage III/IV NTCL, and it is an independent predictor of improved survival. PMID- 25300502 TI - Physical activity and better medication compliance improve mini-mental state examination scores in the elderly. AB - In addition to hypertension, dyslipidemia, atherosclerosis, and diabetes, a sedentary lifestyle plays a pivotal role in cerebro- and cardiovascular disease and progressive cognitive decline, including vascular dementia and Alzheimer's disease. The present study investigated whether controlling the key risks and participating in physical activity have a beneficial impact on these disorders. Elderly volunteers were enrolled in a 3-month program that consisted of structured exercise three times per week. The daily routine, medical treatment, and vital parameters were evaluated and correlated with the subjects' neuropsychiatric status. High blood pressure was found in 40% of the participants, with no significant differences between the sexes. A higher proportion of females (55%) than males (18%) forgot to take their medication during the observation period. Significant negative correlations were found between Mini-Mental State Examination (MMSE) scores and age, lack of a caregiver, and increased pulse rate before or after exercise. These results suggest that the presence of home assistance and subsequent improvement in medication compliance, vital parameter optimization, and regular physical activity may yield better MMSE results and a lower risk for cerebro- and cardiovascular disease. PMID- 25300501 TI - Copy number variants in short children born small for gestational age. AB - BACKGROUND/AIMS: In addition to genome-wide association studies (GWAS), height associated genes may be uncovered by studying individuals with extreme short or tall stature. METHODS: Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information. RESULTS: CNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature. CONCLUSION: SNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes. PMID- 25300504 TI - Mutational screening of EFNA5 in Chinese age-related cataract patients. AB - BACKGROUND/AIM: In the past few years, Ephrin-A5 (EFNA5) had been identified to be associated with lens development, but so far no sequence variation in EFNA5 has been reported in humans. Therefore, we conduct this study to investigate the EFNA5 genetic variations in Chinese age-related cataract (ARC) patients. METHODS: Sequencing of EFNA5 was performed in 140 sporadic ARC patients and 142 random unrelated healthy subjects. Genomic DNA was extracted from peripheral blood leukocytes. All exons of EFNA5 were sequenced after being amplified by polymerase chain reaction. The functional consequences of the variations were analyzed using PolyPhen2. RESULTS: Three single nucleotide polymorphisms in EFNA5, c.668C>T (rs201008479), c.102C>T (rs199980747) and c.-27C>G (rs200187971), were found in the patients, and none of them presented in the normal controls. Using PolyPhen2, c.668C>T in EFNA5 is predicted to be possibly damaging. CONCLUSIONS: The genetic variations c.668C>T (rs201008479), c.102C>T (rs199980747) and c.-27C>G (rs200187971) may present an additional genetic risk factor for ARC in the Chinese population. This study shows the first cases of these genetic variations in EFNA5 in human beings. PMID- 25300503 TI - Examining the spatial distribution of law enforcement encounters among people who inject drugs after implementation of Mexico's drug policy reform. AB - In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) recruited through targeted sampling, we identified hotspots of extra-judicial encounters (e.g., physical/sexual abuse, syringe confiscation, and money extortion by law enforcement) and routine authorized encounters (e.g., being arrested or stopped but not arrested) using point density maps and the Getis-Ord Gi* statistic calculated at the neighborhood-level. Approximately half of the participants encountered law enforcement more than once in a calendar year and nearly one third of these encounters did not result in arrest but involved harassment or abuse by law enforcement. Statistically significant hotspots of law enforcement encounters were identified in a limited number of neighborhoods located in areas with known drug markets. At the local-level, law enforcement activities continue to target drug users despite a national drug policy that emphasizes drug treatment diversion rather than punitive enforcement. There is a need for law enforcement training and improved monitoring of policing tactics to better align policing with public health goals. PMID- 25300505 TI - Effect of crude extracts of Dolichospermum planctonicum on the demography of Plationus patulus (Rotifera) and Ceriodaphnia cornuta (Cladocera). AB - In this study we evaluated the toxicological effects of crude extracts of Dolichospermum planctonicum on Plationus patulus (Rotifera) and Ceriodaphnia cornuta (Cladocera). The active compound from the laboratory-cultured cyanobacteria was extracted by lyophilizing it at -70 degrees C for 48 h, after which the sample was thawed. The cycle was repeated five times, and between each cycle the cells were sonicated to lyse them. Using the extract of Anabaena, experiments of population growth and life table demography of the two zooplankton species were compared in media with and without (controls) the cyanotoxins. In both experiments two toxic concentrations diluted in US EPA medium were used, one in a 5:15 proportion, and the other in a 2.5:17.5. We found that the rotifers were more resistant to the toxicants than the cladocerans. Their population growth rates ranged from 0.11 d(-1) in controls to 0.08 d(-1) in the presence of the crude extracts for P. patulus and from 0.18 in controls to -0.27 in the presence of the crude extracts for C. cornuta. The crude extract also had a significant negative impact on the demographic parameters, adversely affecting reproduction more than survival. The data have been discussed with emphasis on the importance of further research using cyanobacterial crude extracts. PMID- 25300506 TI - Lethal and sublethal effects of azadirachtin on the bumblebee Bombus terrestris (Hymenoptera: Apidae). AB - Azadirachtin is a biorational insecticide commonly reported as selective to a range of beneficial insects. Nonetheless, only few studies have been carried out with pollinators, usually emphasizing the honeybee Apis mellifera and neglecting other important pollinator species such as the bumblebee Bombus terrestris. Here, lethal and sublethal effects of azadirachtin were studied on B. terrestris via oral exposure in the laboratory to bring out the potential risks of the compound to this important pollinator. The compound was tested at different concentrations above and below the maximum concentration that is used in the field (32 mg L( 1)). As most important results, azadirachtin repelled bumblebee workers in a concentration-dependent manner. The median repellence concentration (RC50) was estimated as 504 mg L(-1). Microcolonies chronically exposed to azadirachtin via treated sugar water during 11 weeks in the laboratory exhibited a high mortality ranging from 32 to 100 % with a range of concentrations between 3.2 and 320 mg L( 1). Moreover, no reproduction was scored when concentrations were higher than 3.2 mg L(-1). At 3.2 mg L(-1), azadirachtin significantly inhibited the egg-laying and, consequently, the production of drones during 6 weeks. Ovarian length decreased with the increase of the azadirachtin concentration. When azadirachtin was tested under an experimental setup in the laboratory where bumblebees need to forage for food, the sublethal effects were stronger as the numbers of drones were reduced already with a concentration of 0.64 mg L(-1). Besides, a negative correlation was found between the body mass of male offspring and azadirachtin concentration. In conclusion, our results as performed in the laboratory demonstrated that azadirachtin can affect B. terrestris with a range of sublethal effects. Taking into account that sublethal effects are as important as lethal effects for the development and survival of the colonies of B. terrestris, this study confirms the need to test compounds on their safety, especially when they have to perform complex tasks such as foraging. The latter agrees with the recent European Food Safety Authority guidelines to assess 'potentially deleterious' compounds for sublethal effects on behavior. PMID- 25300507 TI - Ranibizumab, verteporfin photodynamic therapy or observation for the treatment of myopic choroidal neovascularization: cost effectiveness in the UK. AB - PURPOSE: The aim of this study was to evaluate the cost effectiveness of ranibizumab compared with verteporfin photodynamic therapy (vPDT) or no treatment (observation) in patients with visual impairment due to myopic choroidal neovascularization (CNV). METHODS: A Markov model with health states defined by best-corrected visual acuity and a 3-month cycle length was developed. It had a healthcare provider (UK National Health Service and personal social services) perspective, a lifetime time horizon, and was based on 2011 prices; future costs and health outcomes were discounted at 3.5 % per annum. Baseline characteristics were based on the phase III RADIANCE (Ranibizumab and vPDT Evaluation in Myopic CNV) study, and year 1 health-state transitions were based on this and the VIP (Verteporfin in Photodynamic Therapy) study. Extensive sensitivity analyses tested the robustness of the model. RESULTS: The lifetime cost of treating myopic CNV with ranibizumab was L12,866, whereas vPDT and observation were associated with total costs of L14,421 and L8,163, respectively. Ranibizumab treatment produced higher cumulative quality-adjusted life-years (QALYs; 12.99) than vPDT (12.60) or observation (12.45). Ranibizumab treatment was therefore dominant, with greater health gains and lower overall costs than vPDT. Ranibizumab was cost effective compared with observation, with an incremental cost-effectiveness ratio of L8,778/QALY. In the probabilistic sensitivity analysis, ranibizumab had a 100 % and 88 % probability of being cost effective compared with vPDT and observation, respectively, at a willingness-to-pay threshold of L20,000/QALY. CONCLUSION: This study indicates that ranibizumab therapy is dominant over vPDT for the treatment of visual impairment due to CNV secondary to pathologic myopia in the UK healthcare setting and cost effective compared with observation. PMID- 25300508 TI - Associations of racial discrimination and parental discrimination coping messages with African American adolescent racial identity. AB - Research links racial identity to important developmental outcomes among African American adolescents, but less is known about the contextual experiences that shape youths' racial identity. In a sample of 491 African American adolescents (48% female), associations of youth-reported experiences of racial discrimination and parental messages about preparation for racial bias with adolescents' later racial identity were examined. Cluster analysis resulted in four profiles of adolescents varying in reported frequency of racial discrimination from teachers and peers at school and frequency of parental racial discrimination coping messages during adolescents' 8th grade year. Boys were disproportionately over represented in the cluster of youth experiencing more frequent discrimination but receiving fewer parental discrimination coping messages, relative to the overall sample. Also examined were clusters of adolescents' 11th grade racial identity attitudes about the importance of race (centrality), personal group affect (private regard), and perceptions of societal beliefs about African Americans (public regard). Girls and boys did not differ in their representation in racial identity clusters, but 8th grade discrimination/parent messages clusters were associated with 11th grade racial identity cluster membership, and these associations varied across gender groups. Boys experiencing more frequent discrimination but fewer parental coping messages were over-represented in the racial identity cluster characterized by low centrality, low private regard, and average public regard. The findings suggest that adolescents who experience racial discrimination but receive fewer parental supports for negotiating and coping with discrimination may be at heightened risk for internalizing stigmatizing experiences. Also, the findings suggest the need to consider the context of gender in adolescents' racial discrimination and parental racial socialization. PMID- 25300509 TI - Elder self-neglect is associated with an increased rate of 30-day hospital readmission: findings from the Chicago Health and Aging Project. AB - BACKGROUND/AIM: Elder self-neglect is associated with increased morbidity and mortality. The objective of this study is to examine the prospective relationship between reported elder self-neglect and the rate of 30-day hospital readmission in a community population. METHODS: We conducted a prospective population-based study of community-dwelling older adults who participated in the Chicago Health and Aging Project. Of the 7,219 participants in the Chicago Health and Aging Project, a subset of 1,228 participants was reported to the social services agency for suspected elder self-neglect. The primary predictor was elder self neglect reported to the social services agency. The outcome of interest was the annual rate of 30-day hospital readmission calculated from the Center for Medicare and Medicaid System hospitalization data from 1993 to 2009. Poisson regression models were used to assess these relationships. RESULTS: The average annual rate of 30-day hospital readmission for those without elder self-neglect was 0.2 (SD 0.7) and for those with reported elder self-neglect 0.9 (SD 2.8). After adjusting for sociodemographic and socioeconomic characteristics, medical comorbidities, cognitive function, physical function, and psychosocial well being, elders who self-neglect had a significantly higher rate of 30-day hospital readmission (rate ratio 2.50, 95% confidence interval 2.02-3.10). Greater self neglect severity [mild: parameter estimate (PE) 1.09, standard error (SE) 0.19, p < 0.001; moderate: PE 0.84, SE 0.13, p < 0.001; severe: PE 1.24, SE 0.40, p = 0.002] was associated with increased annual rates of 30-day hospital readmission after considering the same confounders. Interaction term analyses suggest that the significant relationship between self-neglect and 30-day hospital readmission was not moderated by medical conditions, cognitive impairment, physical disability, or psychosocial well-being. CONCLUSION: Reported elder self-neglect was associated with increased rates of 30-day hospital readmission in this community population. Greater self-neglect severity was associated with a greater increase in the rate of 30-day hospital readmission. PMID- 25300512 TI - Gendered innovations in orthopaedic science: From access to zygote: a gender and orthopaedics lexicon. PMID- 25300511 TI - Very large common fragile site genes and their potential role in cancer development. AB - Common fragile sites (CFSs) are large chromosomal regions that are hot-spots for alterations especially within cancer cells. The three most frequently expressed CFS regions (FRA3B, FRA16D and FRA6E) contain genes that span extremely large genomic regions (FHIT, WWOX and PARK2, respectively), and these genes were found to function as important tumor suppressors. Many other CFS regions contain extremely large genes that are also targets of alterations in multiple cancers, but none have yet been demonstrated to function as tumor suppressors. The loss of expression of just FHIT or WWOX has been found to be associated with a worse overall clinical outcome. Studies in different cancers have revealed that some cancers have decreased expression of multiple large CFS genes. This loss of expression could have a profound phenotypic effect on these cells. In this review, we will summarize the known large common fragile site genes and discuss their potential relationship to cancer development. PMID- 25300510 TI - Tools of the trade: podosomes as multipurpose organelles of monocytic cells. AB - Podosomes are adhesion and invasion structures that are particularly prominent in cells of the monocytic lineage such as macrophages, dendritic cells, and osteoclasts. They are multifunctional organelles that combine several key abilities required for cell migration and invasion. The podosome repertoire includes well-established functions such as cell-substrate adhesion, and extracellular matrix degradation, recently discovered abilities such as rigidity and topology sensing as well as antigen sampling, and also more speculative functions such as cell protrusion stabilization and transmigration. Collectively, podosomes not only enable dynamic interactions of cells with their surroundings, they also gather information about the pericellular environment, and are actively involved in its reshaping. This review presents an overview of the current knowledge on podosome composition, architecture, and regulation. We focus in particular on the growing list of podosome functions and discuss the specific properties of podosomes in macrophages, dendritic cells, and osteoclasts. Moreover, this article highlights podosome-related intracellular transport processes, the formation of podosomes in 3D environments as well as potentially podosome-associated diseases involving monocytic cells. PMID- 25300513 TI - CORR Insights(r): Local gentamicin delivery from resorbable viscous hydrogels is therapeutically effective. PMID- 25300514 TI - CORR Insights(r): Diabetes confers little to no increased risk of postoperative complications after hip fracture surgery in geriatric patients. PMID- 25300515 TI - Medical parasitology. Editorial. PMID- 25300517 TI - Catalytic SNAr of unactivated aryl chlorides. AB - We present nucleophilic aromatic substitution of unsubstituted aryl chlorides via a mechanism that is catalytic in [CpRu(p-cymene)]PF6 and involves a Ru(eta(6) arylchloride) intermediate. From the spectroscopic evidence we infer that arene exchange is the rate limiting step in this process and develop several new Ru(ii) complexes that lower the activation barrier to arene exchange. PMID- 25300516 TI - Association analyses of FGFR2 gene polymorphisms with femoral neck bone mineral density in Chinese Han population. AB - Femoral neck (FN) bone mineral density (BMD) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. Identification of genetic variations associated with FN BMD may provide potential targets for therapeutic studies. Given the important biological role of FGFR2 gene involved in bone, we tested the associations between FGFR2 polymorphisms and FN BMD in 1,300 Chinese Han subjects. Of the 28 total SNPs, 2 SNPs, namely rs11200014 and rs1078806, were significantly associated with FN BMD under dominant model (P = 0.0014 and 0.0012, respectively) after conservative Bonferroni correction. The two SNPs were in complete linkage disequilibrium. In addition, haplotype-based association tests identified two haplotypes significantly associated with FN BMD, including one haplotype in block 4 where the two SNPs located. However, different from previous studies in white older men, we did not detect any significant association in sex-stratified analyses. In summary, our findings suggest that the FGFR2 gene may play an important role in variation in FN BMD in Chinese Han population, independent of gender effects. Further studies performed in multiple and large samples are needed to elucidate the underlying molecular mechanism and pathophysiology of osteoporosis. PMID- 25300518 TI - Growth mechanism of metal-oxide nanowires synthesized by electron beam evaporation: a self-catalytic vapor-liquid-solid process. AB - We report the growth mechanism of metal oxide nanostructures synthesized by electron beam evaporation. The condensed electron beam can easily decompose metal oxide sources that have a high melting point, thereby creating a self-catalytic metal nanodot for the vapor-liquid-solid process. The metal oxide nanostructures can be grown at a temperature just above the melting point of the self-catalyst by dissolving oxygen. The morphology of nanostructures, such as density and uniformity, strongly depends on the surface energy and surface migration energy of the substrate. The density of the self-catalytic metal nanodots increased with decreasing surface energies of the substrate due to the perfect wetting phenomenon of the catalytic materials on the high surface energy substrate. However, the surfaces with extremely low surface energy had difficulty producing the high density of self-catalyst nanodot, due to positive line tension, which increases the contact angle to >180 degrees . Moreover, substrates with low surface migration energy, such as single layer graphene, make nanodots agglomerate to produce a less-uniform distribution compared to those produced on multi-layer graphene with high surface migration energy. PMID- 25300519 TI - Four new trinuclear {Cu3(MU3-OH)(oximate)3}2+ clusters: crystal structure and magnetic behaviour. AB - Four new triangular copper(II) complexes with the fragment {Cu3(MU3 OH)(oximate)3}(2+) and formulae [Cu3(MU3-OH)(MU-Cl)(Py2CNO)3((t)BuPO3H)].4H2O (1), [Cu3(MU3-OH)(MU-Br)(Py2CNO)3((t)BuPO3H)].3.5H2O (2), [Cu3(MU3-OH)(MU Br)(PhPyCNO)3((t)BuPO3H)(MeOH)].1.5 MeOH (3), [Cu3(MU3-OH)Cl2(PhPyCNO)3].0.5H2O (4), (Py2CNO = di(2-pyridyl)ketoximate, PhPyCNO = phenyl(2-pyridyl)ketoximate, (t)BuPO3H2 = tert-butylphosphonic acid) are reported. The magnetic properties of compounds 1-4 were studied. The compounds were found to exhibit strong antiferromagnetic coupling and antisymmetric exchange interaction. PMID- 25300520 TI - Nanosecond light induced, thermally tunable transient dual absorption bands in a Ge5As30Se65 thin film. AB - In this article, we report the first observation of nanosecond laser induced transient dual absorption bands, one in the bandgap (TA1) and another in the sub bandgap (TA2) regions of a-Ge5As30Se65 thin films. Strikingly, these bands are thermally tunable and exhibit a unique contrasting characteristic: the magnitude of TA1 decreases while that of TA2 increases with increasing temperature. Further, the decay kinetics of these bands is strongly influenced by the temperature, which signifies a strong temperature dependent exciton recombination mechanism. The induced absorption shows quadratic and the decay time constant shows linear dependence on the laser beam fluence. PMID- 25300521 TI - Engineering polar discontinuities in honeycomb lattices. AB - Unprecedented and fascinating phenomena have been recently observed at oxide interfaces between centrosymmetric cubic materials, where polar discontinuities can give rise to polarization charges and electric fields that drive a metal insulator transition and the appearance of a two-dimensional electron gas. Lower dimensional analogues are possible, and honeycomb lattices offer a fertile playground, thanks to their versatility and the extensive ongoing experimental efforts in graphene and related materials. Here we suggest different realistic pathways to engineer polar discontinuities in honeycomb lattices and support these suggestions with extensive first-principles calculations. Several approaches are discussed, based on (i) nanoribbons, where a polar discontinuity against the vacuum emerges, and (ii) functionalizations, where covalent ligands are used to engineer polar discontinuities by selective or total functionalization of the parent systems. All the cases considered have the potential to deliver innovative applications in ultra-thin and flexible solar energy devices and in micro- and nano-electronics. PMID- 25300522 TI - Transvaginal laparoscopic appendectomy simultaneously with vaginal hysterectomy: initial experience of 10 cases. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) involves the introduction of instruments through a natural orifice into the peritoneal cavity to perform surgical interventions. The vagina is the most widely used approach to NOTES. We report the utilization of the vaginal opening at the time of vaginal hysterectomy as a natural orifice for laparoscopic appendectomy. MATERIAL AND METHODS: We reviewed cases of 10 patients with chronic appendicitis who underwent transvaginal laparoscopic appendectomy simultaneously with vaginal hysterectomy. A laparoscopic approach was established after removal of the uterus, and the appendix was removed transvaginally. Among the 10 cases, 5 were conducted under gasless laparoscopy by using a simple abdominal wall-lifting instrument. RESULTS: All procedures were performed successfully without intraoperative or major postoperative complications. The appendectomy portion of the procedure took approximately 21 minutes to 34 minutes. All patients were discharged less than 4 days after surgery, without external scars. CONCLUSIONS: Transvaginal appendectomy with rigid laparoscopic instruments following vaginal hysterectomy appears to be a feasible and safe modification of established techniques, with acceptable outcomes. PMID- 25300523 TI - Quantitative assessment of systolic right ventricular function using myocardial deformation in patients with a systemic right ventricle. AB - AIMS: Late systolic dysfunction of the systemic right ventricle (RV) in patients with transposition of the great arteries (TGA) is of major concern. Right ventricular global longitudinal strain (GLS) might be able to identify early dysfunction. METHODS AND RESULTS: Adults with TGA after Mustard operation (TGA Mustard) or congenitally corrected-TGA (ccTGA) underwent echocardiography, electrocardiography, and NT-proBNP measurement. Using speckle-tracking echocardiography, we analysed longitudinal strain and strain rate, and compared findings in both patients groups, to healthy controls and with clinical parameters. We included 42 patients (mean age 37 +/- 7 years, 69% male) with a systemic RV [32 TGA-Mustard (34 +/- 4 years after corrective surgery) and 10 ccTGA], and 32 healthy controls (mean age 36 +/- 11 years). Global longitudinal strain of the systemic RV was lower in patients than GLS of the systemic LV in controls (-14.2 +/- 3.5 vs. -20.0 +/- 3.0%, P < 0.001). Average LS of the RV lateral wall was lower in patients with TGA-Mustard (-15.5 +/- 3.4%) than ccTGA ( 18.3 +/- 3.6%, P = 0.047). Right ventricular GLS tended to be lower in patients in NYHA class II than I, and correlated with NT-proBNP (r = 0.49, P = 0.001), RV fractional area change (r = -0.39, P = 0.019), RV apex-base-diameter (r = 0.37, P = 0.021), and QRS duration (r = 0.41, P = 0.014). CONCLUSION: Global longitudinal strain of the systemic RV in patients is lower than GLS of the systemic LV in healthy controls, especially in the apical segment, and tended to be lower in TGA Mustard than ccTGA patients. Since RV GLS correlates with RV function, myocardial deformation is useful as a more quantitative tool to measure systemic RV function. Decreased GLS was associated with elevated NT-proBNP and tended to correlate with worsening NYHA class, which strengthens the potential prognostic value of GLS in patients with a systemic RV. PMID- 25300524 TI - Cardiac involvement in hypereosinophilic syndrome: role of multimodality imaging. PMID- 25300525 TI - Transoesophageal echocardiography of aortic atherosclerosis: the additive value of three-dimensional over two-dimensional imaging. AB - AIMS: Complex aortic atherosclerotic plaques (AAPs) carry a significant risk of embolism. Currently, two-dimensional (2D) transoesophageal echocardiography (TOE) is the principal diagnostic tool of AAPs. However, we hypothesized that the data obtained from three-dimensional (3D) imaging may improve AAPs' spatial assessment. METHODS AND RESULTS: The study included 67 patients (aged 70 +/- 15 years, 35 men), who had routine TEE studies. The thoracic aorta was studied from arch to distal descending aorta, using the x-plane mode (simultaneous short- and long-axis views). If focal intimal thickening (suggestive of AAP) was detected, the 3D zoom algorithm was exercised on the specific site with further post processing on a Q-lab workstation to measure its thickness in the X, Y, and Z dimensions. The AAP contour was defined qualitatively as regular or irregular in each mode. A total of 100 AAPs were investigated. The AAP thickness estimation was significantly greater in the 3D mode than in the 2D mode (0.51 +/- 0.33 vs. 0.28 +/- 0.20 cm, P < 0.001). The rate of complex AAPs (defined by AAP thickness of >=4 mm) was two-fold higher with 3D imaging than with 2D imaging (27% with 2D imaging alone vs. 53% with the addition of 3D imaging). The rate of irregular AAPs increased from 29 to 65% when assessed with 3D imaging compared with 2D imaging. CONCLUSION: This study has shown a significant difference in the estimation of AAPs between 2D and 3D TEE. The significant shift to a more complex AAPs profile may suggest that 3D imaging is preferable for the assessment of aortic atherosclerosis burden. PMID- 25300526 TI - Obstructive mechanical valve thrombosis: utility of 3D trans-oesophageal echocardiography. PMID- 25300527 TI - Synovial sarcoma invades the left atrium: visualization with three-dimensional trans-oesophageal echocardiography. PMID- 25300528 TI - Warfarin use and fracture risk: an evidence-based mechanistic insight. PMID- 25300529 TI - Increased risk of stroke among hip fracture patients: a nationwide cohort study. AB - SUMMARY: Our study indicates that hip fracture is independently associated with increased risk of developing stroke. In addition, the risk of stroke following the incidence of hip fracture is more prominent in younger patients, men, those with cardiovascular comorbidities, and in patients using specific medication, such as diuretics and ABRs. INTRODUCTION: Hip fractures are associated with increased risk of major morbidity. However, few data are available on the risk of stroke after hip fracture. Therefore, we investigated whether hip fracture increases the risk of stroke in a large nationwide cohort study. METHODS: Using universal insurance claims data, we identified a study cohort comprising of 6013 newly diagnosed with hip fracture patients from 2000 to 2010 and a non-hip fracture cohort of 23,802 participants. Incidence and risk of stroke were estimated for both cohorts until the end of 2011. RESULTS: Stroke incidence was 1.69-fold (95% confidence interval [CI]=1.56-1.83) higher in the hip fracture cohort than in the comparison cohort with an adjusted hazard ratio (HR) of 1.54 (95% CI=1.42-1.67) for the hip fracture cohort. The hip fracture patients were at higher risk of developing ischemic stroke (HR=1.55, 95% CI=1.42-1.69) and hemorrhagic stroke (HR=1.55, 95% CI=1.16-1.89), respectively. At an incidence of 64.6 per 1000 person-years, the adjusted HR of stroke increases to 3.10 (95% CI=2.47-3.90) for patients with coexisting diabetes, hypertension, and heart failure compared with those without these three conditions. At an incidence of 60.4 per 1000 person-years, the adjusted HR of stroke increases to 2.92 (95% CI=2.43-3.51) for hip fracture patients prescribed with diuretics and angiotensin II receptor blockers (ARBs) compared with those without hip fracture or prescriptions for diuretics or ARBs. CONCLUSIONS: Hip fracture is independently associated with a subsequent risk of stroke. PMID- 25300530 TI - Relationship between American Society of Anesthesiologists (ASA) grade and 1-year mortality in nonagenarians undergoing hip fracture surgery. AB - This study retrospectively reviewed 327 nonagenarians who underwent hip fracture surgery at six hospitals. Functional status, postoperative complications, and 1 year mortality were evaluated, and relationships between these factors and American Society of Anesthesiologists (ASA) grade were analyzed. ASA grade was significantly associated with postoperative complications and 1-year mortality. INTRODUCTION: Few previous studies have reported outcomes after hip fracture in nonagenarians, and these studies did not report significant associations between ASA grade and mortality. However, most of these studies included only a small number of patients from a single hospital. This study aimed to evaluate the relationships between ASA grade and functional status, postoperative complications, and mortality rate in nonagenarians undergoing hip fracture surgery. METHODS: This study included 327 nonagenarians who underwent hip fracture surgery between January 2000 and December 2012. Patients with open fractures, subtrochanteric fractures, polytrauma, and pathological fractures were excluded. The medical records and X-rays were retrospectively reviewed. The relationships between ASA grade and functional status, postoperative complications, and 1-year mortality were analyzed. RESULTS: There were significant associations between the ASA grade and the rates of postoperative complications and 1-year mortality (both p < 0.05). All pairwise comparisons showed significant differences in postoperative complication rates between ASA grades (all p < 0.05). All pairwise comparisons, except for grades I vs. II and grades II vs. III, also showed significant differences in mortality rates between ASA grades (all p < 0.05). There were significant associations between the preoperative ability to manage activities of daily living and the rates of postoperative complications and 1-year mortality (both p < 0.05). CONCLUSIONS: ASA grade was significantly associated with the rates of postoperative complications and 1-year mortality in nonagenarians undergoing hip fracture surgery. The preoperative functional status was also significantly associated with these outcomes. PMID- 25300531 TI - Genome-wide microRNA changes in human intracranial aneurysms. AB - BACKGROUND: Intracranial aneurysms are pathological dilatations of the cerebral artery, while rupture of intracranial aneurysms causes life-threatening subarachnoid hemorrhage. The molecular mechanisms of pathogenesis of intracranial aneurysms are poorly understood. MicroRNAs have fundamental roles in modulating vascular biology and disease. In the present study, we carried out a genome-wide characterization on expressions of microRNAs, and performed integrative analyses in conjunction with changes of the transcriptome in human intracranial aneurysms. METHODS: Genome-wide microRNA screening was performed in 6 intracranial aneurysmal samples and 6 normal superficial temporal arteries. Each case and control pair was individually matched with gender, age (+/-5 years), and high blood pressure history. Microarray analysis was performed using Agilent Human miRNA arrays. RESULTS: As compared to normal arteries, we identified 157 microRNAs that were differentially expressed in the aneurysmal tissue (P < 0.05 and fold change >= 2), including 72 upregulated and 85 downregulated. The changed microRNAs included endothelium-enriched microRNAs such as members of the let-7 family, miR-17, miR-23b, miR-126, hsa-miR-24-1 and miR-222, and vascular smooth muscle-enriched miRNAs such as miR-143 and miR-145. Moreover, miR-1, miR-10a, miR 125b, and miR-26a, which were implicated in modulating vascular smooth muscle cell functions such as proliferation, apoptosis and shift of phenotype, were also changed. In contrast, microRNAs involved in monocyte and macrophage functions, such as miR-155, miR-146a, miR-223, and miR-124a, were not significantly changed. Bioinformatic analysis revealed that the changed microRNAs were associated with several biological processes related to aneurysm formation, including inflammation, dysregulation of extracellular matrix, smooth muscle cell proliferation, programmed cell death, and response to oxidative stress. Interestingly, we found that a subset of the potential microRNA target genes belonged to the protein translation machinery, including various eukaryotic translation initiation factors and ribosomal proteins, and this finding was highly correlated with our previous transcriptome data showing that multiple genes of the ribosomal proteins and translation initiation and elongation factors were significantly downregulated in human intracranial aneurysms. CONCLUSIONS: Our results support that dysregulated microRNAs may have a pathogenic role in intracranial aneurysms. Disruption of the protein translation process may have a pathogenic role in the development of intracranial aneurysms. PMID- 25300532 TI - 6-O-sulfated chitosan promoting the neural differentiation of mouse embryonic stem cells. AB - Embryonic stem cells (ESCs) can be induced to differentiate into nerve cells, endowing them with potential applications in the treatment of neurological diseases and neural repair. In this work, we report for the first time that sulfated chitosan can promote the neural differentiation of ESCs. As a type of sulfated glycosaminoglycan analog, sulfated chitosan with well-defined sulfation sites and a controlled degree of sulfation (DS) were prepared through simple procedures and the influence of sulfated glycosaminoglycan on neural differentiation of ESCs was investigated. Compared with other sulfation sites, 6 O-sulfated chitosan showed the most optimal effects. By monitoring the expression level of neural differentiation markers using immunofluorescence staining and PCR, it was found that neural differentiation was better enhanced by increasing the DS of 6-O-sulfated chitosan. However, increasing the DS by introducing another sulfation site in addition to the 6-O site to chitosan did not promote neural differentiation as much as 6-O-sulfated chitosan, indicating that compared with DS, the sulfation site is more important. Additionally, the optimal concentration and incubation time of 6-O-sulfated chitosan were investigated. Together, our results indicate that the sulfate site and the molecular structure in a sulfated polysaccharide are very important for inducing the differentiation of ESCs. Our findings may help to highlight the role of sulfated polysaccharide in inducing the neural differentiation of ESCs. PMID- 25300533 TI - Maternal vitamin D deficiency and fetal programming--lessons learned from humans and mice. AB - BACKGROUND/AIMS: Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. METHODS: We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. RESULTS: The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow up. CONCLUSIONS: Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy. PMID- 25300534 TI - Asymptomatic carotid artery stenosis treated with medical therapy alone: temporal trends and implications for risk assessment and the design of future studies. AB - BACKGROUND: The rate of adverse clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone can be used to guide clinical decision-making and to inform future research. We aimed to investigate temporal changes in the incidence rate of clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone and to explore the implications of these changes for the design of future comparative studies. SUMMARY: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, US Food and Drug Administration documents, and reference lists of included studies (last search: December 31, 2012). We selected prospective cohort studies of medical therapy for asymptomatic carotid artery stenosis and we extracted information on study characteristics, risk of bias, and outcomes. We performed meta-analyses to estimate summary incidence rates, meta-regressions to assess trends over time, and simulations to explore sample size requirements for the design of future studies comparing new treatments against medical therapy. The main outcomes of interest were ipsilateral stroke, any stroke, cardiovascular death, death, and myocardial infarction. We identified 41 studies of medical therapy for patients with asymptomatic carotid stenosis (last recruitment year: 1978-2009). The summary incidence rate of ipsilateral carotid territory stroke (25 studies) was 1.7 per 100 person-years. This incidence rate was significantly lower in recent studies (last recruitment year from 2000 onwards) as compared to studies that ended recruitment earlier (1.0 vs. 2.3 events per 100 person-years; p < 0.001). The incidence rates of any territory stroke (17 studies), cardiovascular death (6 studies), death (13 studies), and myocardial infarction (5 studies) were 2.7, 4.1, 4.6, and 1.8 per 100 person-years, respectively. Simulations showed that future studies would need to enroll large numbers of patients with a relatively high incidence rate under medical therapy, and evaluate interventions with large effect sizes, to have adequate power to reliably detect treatment effects. KEY MESSAGES: Improved prognosis under medical therapy alone has narrowed the potential range of risk reduction attainable with new treatments for asymptomatic carotid stenosis. Future comparative studies will need to enroll large numbers of patients to assess treatment effectiveness. PMID- 25300535 TI - Dietary egg white protein inhibits lymphatic lipid transport in thoracic lymph duct-cannulated rats. AB - Dietary egg white protein (EWP) decreases serum cholesterol levels. We previously showed that EWP decreased cholesterol absorption in the intestine. Rats subjected to permanent lymph duct cannulation were used to investigate the effects of dietary EWP on lipid transport. They were fed diets with 20% EWP and casein, and their lymph was collected to quantify lymphatic lipid levels. Dietary EWP decreased lymphatic cholesterol transport compared with casein. It was previously shown that EWP excluded cholesterol from bile acid micelles. Therefore, pepsin hydrolyzed EWP and casein were prepared. EWP was not completely digested. Ovalbumin, which is the most abundant protein in EWP, showed resistance to digestion by pepsin. This study investigated the effects of EWP pepsin hydrolysate (EWP-ph) on cholesterol micellar solubility, cholesterol transfer from the micellar to the oil phase, water-holding capacity (WHC), settling volume in water (SV), and relative viscosity and compared them with the effects of casein pepsin hydrolysate (C-ph). EWP-ph significantly decreased the micellar solubility and transfer rate and increased the WHC, SV, and relative viscosity compared with C-ph. Moreover, the pepsin hydrolysate of ovalbumin, a major protein in EWP, played a role in decreasing cholesterol micellar solubility, leading to the inhibition of cholesterol absorption. In conclusion, dietary EWP decreased cholesterol intestinal absorption by exerting combined effects of these physicochemical properties in the gut. PMID- 25300536 TI - Emission of odorous volatile organic compounds from a municipal manure treatment plant and their removal using a biotrickling filter. AB - Odorous volatile organic compounds (VOCs) from municipal manure treatment facilities are considered as a major nuisance issue for operators and nearby residents. In this study, up to 71 odorous VOCs were detected by gas chromatography-mass spectrometry at the manure treatment plant. These compounds can be classified into five different categories, including alkanes, olefins, aromatics, volatile organosulphur compounds and terpenes. Toluene, dimethyl disulphide, dimethyl sulphide, xylene and ethylbenzene were the five most abundant pollutants. A pilot-scale biotrickling filter (BTF) was employed to treat the complex odorous gases. Correlation analysis showed that the removal efficiency (RE) of the BTF was related with the molecular weight and chemical structure of contaminants. Higher than 85% of REs could be reached for aromatic, terpenes and most alkanes compounds after 180 days of operation. Comparatively, most olefins and partial alkanes compounds with a molecular weight lower than 70 were not removed easily. The REs of these compounds ranged from 0% to 94%, and the average removal efficiency (RE) was only about 33.3%. PMID- 25300537 TI - Potentially coercive self-citation by peer reviewers: a cross-sectional study. AB - OBJECTIVE: Peer reviewers sometimes request that authors cite their work, either appropriately or via coercive self-citation to highlight the reviewers' work. The objective of this study was to determine in peer reviews submitted to one biomedical journal (1) the extent of peer reviewer self-citation; (2) the proportion of reviews recommending revision or acceptance versus rejection that included reviewer self-citations; and (3) the proportion of reviewer self citations versus citations to others that included a rationale. METHODS: Peer reviews for manuscripts submitted in 2012 to the Journal of Psychosomatic Research were evaluated. Data extraction was performed independently by two investigators. RESULTS: There were 616 peer reviews (526 reviewers; 276 manuscripts), of which 444 recommended revision or acceptance and 172 rejection. Of 428 total citations, there were 122 peer reviewer self-citations (29%) and 306 citations to others' work (71%). Self-citations were more common in reviews recommending revision or acceptance (105 of 316 citations; 33%) versus rejection (17/112; 15%; p<0.001). The percentage of self-citations with no rationale (26 of 122; 21%) was higher than for citations to others' work (15 of 306; 5%; p<0.001). CONCLUSIONS: Self-citation in peer reviews is common and may reflect a combination of appropriate citation to research that should be cited in published articles and inappropriate citation intended to highlight the work of the peer reviewer. Providing instructions to peer reviewers about self-citation and asking them to indicate when and why they have self-cited may help to limit self citation to appropriate, constructive recommendations. PMID- 25300538 TI - Assessing psychological factors, social aspects and psychiatric co-morbidity associated with Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) in men -- a systematic review. AB - OBJECTIVE: Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a chronic pain disease with high prevalence rates and substantial health care costs. An interdisciplinary classification system is commonly used (UPOINT) which includes psychosocial factors. Nevertheless, psychosocial influences on CP/CPPS only recently became a research focus. Therefore, we aimed to synthesize the existing data and to identify further research topics. Then, based on our results, diagnosis and treatment can be improved. METHODS: In a systematic review conducted according to the PRISMA reporting guidelines we searched different databases (MEDLINE, EMBASE, PsychINFO) using the broad search terms "chronic pelvic pain syndrome AND men". Two raters independently screened the literature and assessed the risk of bias. RESULTS: We included 69 original research articles which considered psychosocial variables. We found studies investigating different psychosocial factors (pain catastrophizing, stress, personality factors, social aspects), co-morbid psychiatric disorders (depression, anxiety and trauma-related disorders, somatization disorder, substance abuse) and Quality of Life (QoL). In addition, there is a high risk of bias in most studies e.g. concerning the study design or the measures. CONCLUSIONS: There is evidence suggesting that psychological factors are important in understanding CP/CPPS. However, research concentrated on a few aspects while the others were not covered adequately. We found evidence of a higher number of psychosocial factors and psychiatric co morbidities than is currently included in the UPOINT system. More high quality research is needed to understand the interplay of psychosocial factors in CP/CPPS. Furthermore, these factors should be incorporated into treatment approaches. PMID- 25300539 TI - Marine-derived polysaccharides for regulation of allergic responses. AB - Polysaccharides are macromolecules made up of many monosaccharides joined together by glycosidic bonds. Polysaccharides from marine sources are widely distributed as the principle component in cell wall structures of seaweeds or exoskeletons of crustaceans. So far, marine polysaccharides have been used in many fields of biomaterials, food, cosmetic, and pharmacology. Especially, numerous pharmaceutical properties of marine polysaccharides have been revealed such as antioxidant, anti-inflammatory, antiallergic, antitumor, antiobesity, antidiabetes, anticoagulant, antiviral, immunomodulatory, cardioprotective, antihepatopathy, antiuropathy, and antirenalpathy activities. Recently, several marine polysaccharides such alginate, porphyran, fucoidan, and chitin and its derivatives have been found as modulators of allergic responses due to enhancing innate immune system, altering Th1/Th2 balance, inhibiting IgE production, and suppressing mast cell degranulation. This contribution, therefore, focuses specially on the immunomodulatory effect of marine polysaccharides and emphasizes their potential application as candidates of pharmaceuticals as well as nutraceuticals to prevent allergic disorders. PMID- 25300540 TI - Antioxidant effects of chitin, chitosan, and their derivatives. AB - Chitin, chitosan, and their derivatives are considered to promote diverse activities, including antioxidant, antihypertensive, anti-inflammatory, anticoagulant, antitumor and anticancer, antimicrobial, hypocholesterolemic, and antidiabetic effects, one of the most crucial of which is the antioxidant effect. By modulating and improving physiological functions, chitin, chitosan, and their derivatives may provide novel therapeutic applications for the prevention or treatment of chronic diseases. Antioxidant activity of chitin, chitosan, and their derivatives can be attributed to in vitro and in vivo free radical scavenging activities. Antioxidant effect of chitin, chitosan, and their derivatives may be used as functional ingredients in food formulations to promote consumer health and to improve the shelf life of food products. This chapter presents an overview of the antioxidant activity of chitin, chitosan, and their derivatives with the potential utilization in the food and pharmaceutical industries. PMID- 25300541 TI - Antidiabetic activities of chitosan and its derivatives: a mini review. AB - Obesity and diabetes are two important closely related matters to world health with increasing morbidity and mortality rate. Many recent studies promoted chitosan-based substances as lead molecules for treatment and prevention of obesity, diabetes, and related complications due to their easy and potential utilization in the food, pharmaceutical, agricultural, and environmental fields. Although detailed action mechanism and how chitosan-based molecules act as antidiabetics and antiobesity specifically are remain to be enlightened, studies exhibited enough evidence to direct our intention to produce natural therapeutic agents using chitosan and its derivatives as lead substances. In this chapter, some reported antidiabetics and antiobesity applications of chitosan and its derivatives have been briefly summarized in regard to acting pathways and structure-based activity in order to obtain some valuable insights into novel chitosan-based derivatives and their utilization for antidiabetic and antiobesity purposes. PMID- 25300542 TI - Role of alginate in bone tissue engineering. AB - Bone, a typical inorganic-organic biocomposite, is made of approximately 70 wt% inorganic components, mainly hydroxyapatite (HAp,Ca(10)(PO(4))(6)(OH)(2)), and 30 wt% of organic matrix, mainly collagen I. Human organ failure caused by defects, injuries, or other types of damage is one of the most devastating and costly problems in human health care. Recently, tissue engineering has emerged as a promising approach for bone repair and reconstruction. The ultimate goal of bone tissue engineering is the fabrication of a construct that matches the physical and biological properties of the natural bone tissue. Biopolymers have some distinct advantages such as their biodegradation rates and mechanical properties can be tailored to a certain extent for specific applications. Alginate, a natural polysaccharide, is readily processable for applicable three-dimensional scaffolding materials such as hydrogels, microspheres, microcapsules, sponges, foams, and fibers. Alginate can be easily modified via chemical and physical reactions to obtain derivatives having various structures, properties, functions, and applications. The purpose of this chapter is to review recent research on alginate in bone tissue engineering. PMID- 25300543 TI - Chitin and chitosan composites for bone tissue regeneration. AB - In the present world, where there is increased obesity and poor physical activity, the occurrence of bone disorders has also been increased steeply. Therefore, a significant progress has been made in organ transplantation, surgical reconstruction, and the use of artificial prostheses to treat the loss or failure of an organ or bone tissue in the recent years. Bone contains considerable amounts of minerals and proteins. The major component of bone is hydroxyapatite [Ca(10)(PO(4))(6)(OH)(2)] (60-65%) and is one of the most stable forms of calcium phosphate and it occurs along with other materials including collagen, chondroitin sulfate, keratin sulfate, and lipids. To remedy bone defects, new natural and synthetic materials are needed, which will have very similar properties as that of natural bone. Bone tissue engineering is a relatively new and emerging field, which paves the way for bone repair or regeneration. Polymers can serve as a matrix to support cell growth by having various properties such as biocompatibility, biodegradability, porosity, charge, mechanical strength, and hydrophobicity. Considerable attention has been given to chitin and chitosan composite materials and their applications in the field of bone tissue engineering in the recent years, which are natural biopolymers. This chapter reviews the various composites of chitin and chitosan, which are proved to be potential materials for bone tissue regeneration. PMID- 25300544 TI - Chemical modification of chitosan for efficient gene therapy. AB - Gene therapy involves the introduction of foreign genetic material into cells in order to exert a therapeutic effect. Successful gene therapy relies on effective vector system. Viral vectors are highly efficient in transfecting cells, but the undesirable complications limit their therapeutic applications. As a natural biopolymer, chitosan has been considered to be a good gene carrier candidate due to its ideal character which combines biocompatibility, low toxicity with high cationic density together. However, the low cell specificity and low transfection efficiency of chitosan as a gene carrier need to be overcome before undertaking clinical trials. This chapter is principally on those endeavors such as chemical modifications using cell-specific ligands and stimuli-response groups as well as penetrating modifications that have been done to increase the performances of chitosan in gene therapy. PMID- 25300545 TI - Marine carbohydrates of wastewater treatment. AB - Our natural heritage (rivers, seas, and oceans) has been exploited, mistreated, and contaminated because of industrialization, globalization, population growth, urbanization with increased wealth, and more extravagant lifestyles. The scenario gets worse when the effluents or contaminants are discharged directly. So wastewater treatment is a very important and necessary in nowadays to purify wastewater before it enters a body of natural water, or it is applied to the land, or it is reused. Various methods are available for treating wastewater but with many disadvantages. Recently, numerous approaches have been studied for the development of cheaper and more effective technologies, both to decrease the amount of wastewater produced and to improve the quality of the treated effluent. Biosorption is an emerging technology, which uses natural materials as adsorbents for wastewater treatment. Low-cost adsorbents of polysaccharide-based materials obtained from marine, such as chitin, chitosan, alginate, agar, and carrageenan, are acting as rescue for wastewater treatment. This chapter reviews the treatment of wastewater up to the present time using marine polysaccharides and its derivatives. Special attention is paid to the advantages of the natural adsorbents, which are a wonderful gift for human survival. PMID- 25300546 TI - Industrial applications of marine carbohydrates. AB - Biomaterials have been used increasingly in various fields, such as drug delivery, imaging, and tissue engineering. The main reason justifying the widespread use of biomaterials relies on its valuable and low-cost source of new drugs. Current research goals are focused on identifying more potent and specific compounds with antitumor, immunomodulatory, antihyperlipidemic, anticoagulant, and antiviral activities. The increasing knowledge of structural analysis and chemical modifications enables the use of these marine carbohydrates in a newer way for the human welfare. This chapter focuses on the recent developments related to industrial and biomedical applications using chitin, chitosan, alginate, agar, and carrageenan derivatives and reports the main advances published over the last 10-15 years. PMID- 25300547 TI - Nutraceutical and pharmacological implications of marine carbohydrates. AB - Current day's research has been focusing much on the potential pharmacological or nutraceutical agents of selective health benefits with less toxicity. As a consequence of increased demand of nutritional supplements of great medicinal values, development of therapeutic agents from natural sources, in particular, marine environment are being considered much important. A diverse array of marine natural products containing medicinally useful nutritional substances, i.e., marine nutraceuticals have been focused to the benefit of mankind. Carbohydrates, by being constituted in considerable amount of many marine organisms display several nutraceutical and pharmaceutical behavior to defend from various diseases. Moreover, the carbohydrates from algae as well as from shellfish wastes, like chitosan and its derivatives, showed tremendous applications in biology and biomedicine. In the current chapter, several of marine carbohydrates from various marine flora and fauna have been covered with their applications and prospects in the development of nutraceuticals and pharmaceuticals. PMID- 25300548 TI - Pharmaceutical, cosmeceutical, and traditional applications of marine carbohydrates. AB - Marine carbohydrates are most important organic molecules made by photosynthetic organisms. It is very essential for humankind: the role in being an energy source for the organism and they are considered as an important dissolve organic compound (DOC) in marine environment's sediments. Carbohydrates found in different marine environments in different concentrations. Polysaccharides of carbohydrates play an important role in various fields such as pharmaceutical, food production, cosmeceutical, and so on. Marine organisms are good resources of nutrients, and they are rich carbohydrate in sulfated polysaccharide. Seaweeds (marine microalgae) are used in different pharmaceutical industries, especially in pharmaceutical compound production. Seaweeds have a significant amount of sulfated polysaccharides, which are used in cosmeceutical industry, besides based on the biological applications. Since then, traditional people, cosmetics products, and pharmaceutical applications consider many types of seaweed as an important organism used in food process. Sulfated polysaccharides containing seaweed have potential uses in the blood coagulation system, antiviral activity, antioxidant activity, anticancer activity, immunomodulating activity, antilipidepic activity, etc. Some species of marine organisms are rich in polysaccharides such as sulfated galactans. Various polysaccharides such as agar and alginates, which are extracted from marine organisms, have several applications in food production and cosmeceutical industries. Due to their high health benefits, compound-derived extracts of marine polysaccharides have various applications and traditional people were using them since long time ago. In the future, much attention is supposed to be paid to unraveling the structural, compositional, and sequential properties of marine carbohydrate as well. PMID- 25300549 TI - Algal and microbial exopolysaccharides: new insights as biosurfactants and bioemulsifiers. AB - Currently, efforts are being made to utilize more natural biological systems as alternatives as a way to replace fossil forms of carbon. There is a growing concern at global level to have nontoxic, nonhazardous surface-active agents; contrary to synthetic surfactants, their biological counterparts or biosurfactants play a primary function, facilitating microbial presence in environments dominated by hydrophilic-hydrophobic interfaces. Algal and microbial biosurfactants/bioemulsifiers from marine and deep-sea environments are attracting major interest due to their structural and functional diversity as molecules actives of surface and an alternative biomass to replace fossil forms of carbon. Algal and microbial surfactants are lipid in nature and classified as glycolipids, phospholipids, lipopeptides, natural lipids, fatty acids, and lipopolysaccharides. These metabolic bioactive products are applicable in a number of industries and processes, viz., food processing, pharmacology, and bioremediation of oil-polluted environments. This chapter presents an update of the progress and potentialities of the principal producers of exopolysaccharide (EPS)-type biosurfactants and bioemulsifiers, viz., macro- and microalgae (cyanobacteria and diatoms) and bacteria from marine and extreme environments. Particular interest is centered into new sources and applications, viz., marine and deep-sea environments and promissory uses of these EPSs as biosurfactants/emulsifiers and other polymeric roles. The enormous benefits of these molecules encourage their discovery, exploitation, and development of new microbial EPSs that could possess novel industrial importance and corresponding innovations. PMID- 25300550 TI - Complex carbohydrates as a possible source of high energy to formulate functional feeds. AB - Carbohydrates (CHOs) are the most abundant organic compounds found in living organisms and are a great source of metabolic energy, both for plants and animals. Besides of CHOs great potential to solve animal's energy requirements and diminishing high feed cost, we first must to understand its digestibility and assimilation to avoid several inconvenients. Today, CHOs feed animal inclusions are of great concern about cost-benefits, animal's health status, and environmental pollution. In this chapter, we make a brief description about sugars (DP1-2), oligosaccharides (DP3-9), polysaccharides (DP >=10), and their essential characteristics to understand the role of marine and terrestrial CHOs in animal nutrition. Subsequently, we talk about basic concepts, CHOs functional benefits, suggestions about their application and successful cases. This information will contribute to produce a new generation of high-quality and energetic functional feed formulations for livestock and aquaculture farms; which must be of low cost, healthy, and environmentally friendly, with the inclusion of prebiotics and probiotics. PMID- 25300551 TI - Carbohydrates are large molecules and divided into four main categories. Introduction. PMID- 25300554 TI - Tuning the iridescence of chiral nematic cellulose nanocrystal films with a vacuum-assisted self-assembly technique. AB - Iridescent films composed of the chiral nematic liquid crystal phase of cellulose nanocrystals (CNC) have attracted significant interest due to their fascinating optical properties. However, the current fabrication method, i.e., solution casting with a subsequent evaporation process, has significant limitations and therefore hinders the application of CNC iridescent films. In the present study, we demonstrate, for the first time, that vacuum-assisted self-assembly (VASA) can be used to fabricate highly oriented, large area, smooth, and structurally homogeneous CNC iridescent films. It was found that a long ultrasonic pretreatment is necessary for obtaining CNC iridescent films via VASA. Furthermore, it was also found that the iridescent color of the CNC films can be tuned by the sonication time, suspension volume, and degree of vacuum. By combining CD spectroscopy, SEM, and WAXD techniques, the internal structure of CNC iridescent films prepared by VASA has been investigated in detail. Moreover, the origin of the ultrasonic pretreatment effect on the self-assembly behavior of CNCs is also discussed. PMID- 25300552 TI - Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs. AB - The aim of the present work is to synthesize, characterize, and test self assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone. PMID- 25300555 TI - Re: Junior Radiologists' Forum (JRF): national trainee survey. PMID- 25300556 TI - Body packers on your examination table: How helpful are plain x-ray images? A definitive low-dose CT protocol as a diagnosis tool for body packers. AB - AIM: To analyze the clinical value and radiation dose of plain x-rays and CT in examining patients suspected of ingesting drug-filled packets. MATERIALS AND METHODS: Thirty-eight patients with suspected internal concealment of drug-filled packets who were examined with plain x-rays or CT or both were included in the study. CT studies were performed using low-dose and standard-dose techniques. All radiographic images were analysed by two radiologists regarding identification of the packets and estimating the effective radiation dose from standard- and low dose CT versus conventional x-ray examinations. Descriptive calculations were made regarding the number and density of packs and radiation dosage. The diagnostic performance of both radiologists with standard- and low-dose CT was calculated by analysing differences in the mean number of packs found. RESULTS: Thirty-one patients were positively identified as body packers with an average of 13 packs (min: n = 1, max: n = 58, total: n = 390); seven patients were not concealing drug packets. X-ray images were taken of 24 patients prior to CT, thus allowing a direct comparison between the two methods. The correct diagnosis was made in 42%, in 33% the radiologists were uncertain, and in 25% of drug packets were either not or wrongly identified. X-ray imaging had a positive predictive value of 20% with a negative predictive value of 81%. A total of 55 CT examinations were performed on all patients with a mean effective dose of 2 mSv (low dose) versus 9.3 mSv (standard dose). The visibility of packets on low-dose CT images compared to high-dose CT was not reduced: the radiologists identified 385 and 381 of the packets, respectively, with no difference regarding the examination technique (p = 0.24 and p = 0.253, respectively). The radiodensity of all drug-filled packets at CT ranged from 26-292 HU (mean 181.2 HU). CONCLUSION: X-ray imaging of supposed body packers leads to a significant risk of diagnostic errors and additional need for CT. Instead, a single abdominal low-dose CT examination will deliver the correct diagnoses in most cases, leading to safe clinical management of the suspects. PMID- 25300557 TI - Diagnostic value of magnetic resonance elastography for detecting and staging of hepatic fibrosis: a meta-analysis. AB - AIM: A meta-analysis was performed to evaluate the diagnostic value of magnetic resonance elastography (MRE) in detecting and staging hepatic fibrosis. MATERIALS AND METHODS: A systematic search of PubMed, EMBASE, Web of Science, and Cochrane Library Database up to October 2013 was undertaken to find studies on the evaluation of MRE in patients suspected of hepatic fibrosis. Data from the articles were analysed using Meta-disc 1.4 and Stata 12.0 software. The sensitivity, specificity, and area under the summary receiver operating characteristic (ROC) curve (AUROC) were pooled for all stages of hepatic fibrosis (F >= 1, F >= 2, F >= 3, and F = 4). Publication bias was assessed through the Deeks' funnel plot asymmetry tests. RESULTS: Thirteen studies comprising 989 patients met the inclusion criteria. The pooled sensitivity and specificity for F >= 1, F >= 2, F >= 3, and F = 4 were 0.87 (95% CI = 0.84-0.89) and 0.92 (95% CI = 0.87-0.96), 0.87 (95% CI = 0.84-0.90) and 0.92 (95% CI = 0.89-0.95), 0.88 (95% CI = 0.85-0.91) and 0.91 (95% CI = 0.88-0.93), 0.91 (95% CI = 0.87-0.94) and 0.92 (95% CI = 0.89-0.94), respectively. The pooled AUROC for F >= 1, F >= 2, F >= 3, and F = 4 were 0.9502, 0.9663, 0.9644, and 0.9768, respectively. The non significant slope of Deeks' funnel plot asymmetry tests indicated that no significant bias was found. CONCLUSIONS: MRE has a high diagnostic accuracy for the quantitative detection and staging of hepatic fibrosis. PMID- 25300558 TI - Metastatic patterns of breast cancer subtypes: what radiologists should know in the era of personalized cancer medicine. AB - There is accumulating evidence that molecular phenotyping of breast cancer determines the timing, pattern, and outcome of metastatic disease. The most clinically relevant subtypes are hormonal-positive [oestrogen and progesterone receptor (ER/PR) positive], HER2 expressing, and triple-negative breast cancers (TNBCs). ER/PR-positive breast cancers demonstrate the best prognosis; however, metastases, in particular osseous disease, may develop much later. HER2 expressing breast cancers, although aggressive, have improved outcomes due to the advent of HER2-targeted therapies, with increased risk of central nervous system (CNS) relapses later. Finally, TNBCs present in younger women, BRCA1 mutations carriers, and carry the worst overall prognosis, with high incidence of CNS metastases, especially during the first 5 years of diagnosis. It is important for radiologists to understand the nuances of these breast cancer subtypes to predict metastatic behaviours and guide possible imaging surveillance. PMID- 25300559 TI - Re: Junior Radiologists' Forum (JRF): national trainee survey. A reply. PMID- 25300560 TI - Tests for evaluating non-immediate allergic drug reactions. AB - Non-immediate drug reactions (NIR) are induced by specific immunological mechanisms and involve the recognition of hapten molecules by the immune system, with the participation of dendritic cells and other antigen-presenting cells. This process is followed by an effector response that can induce several clinical entities, ranging from mild to severe. The type of immunological recognition can be used as the basis for the diagnostic approach. Both in vivo and in vitro tests are available for the diagnosis of NIR. In vivo tests consist of the reproduction of a diminished immune response with the culprit drug and in vitro tests are based on the stimulation of memory cells in culture. If both tests give negative results, a drug provocation test can be used. PMID- 25300561 TI - The optimal mixture of Toxoplasma gondii recombinant antigens (GRA1, P22, ROP1) for diagnosis of ovine toxoplasmosis. AB - Toxoplasmosis, caused by Toxoplasma gondii, is the major parasitic disease affecting sheep. Infection not only results in significant reproductive losses in these animals, but has public health implications since consumption of infected meat can facilitate zoonotic transmission. Although several serological tests are currently used for diagnosis of ovine toxoplasmosis, production of reliable reagents is a constraint and therefore there is a need to develop new diagnostic tools. In this paper, we assess for the first time, the preliminary diagnostic utility of 19 T. gondii recombinant antigens (GRA1, GRA2ex2, GRA4, GRA5, GRA6, GRA9, SAG1, SAG4, BSR4, P22, ROP1, P36, MIC1ex2, MIC1ex34, MIC3, MAG1, BAG1, LDH1, and LDH2) in immunoglobulin G (IgG) enzyme-linked immunosorbent assays (IgG ELISAs). Following an initial evaluation, eight recombinant antigens (GRA1, GRA9, SAG1, SAG4, P22, MIC1ex2, MIC3, ROP1) were chosen for subsequent testing and comparison against the native Toxoplasma lysate antigen (TLA) in IgG ELISAs using 88 sera from naturally infected sheep and 20 sera from healthy animals. The reactivity of these antigens was variable with the best results for GRA1, P22, ROP1 and TLA. High sensitivity and specificity (100%) was noted for GRA1, ROP1 and TLA; P22 showed a slightly lower sensitivity (98.9%) but the same high specificity (100%). Four different combinations of these antigens (M1: GRA1+ROP1; M2: GRA1+P22; M3: P22+ROP1; M4: GRA1+P22+ROP1) were tested against the same pool of ovine sera; all IgG-positive serum samples were detected by all of the mixtures. However, the most effective for diagnosis of toxoplasmosis in sheep, based on the highest absorbance values, was the mixture M4 containing three proteins. High sensitivity and specificity (100%) was observed from tests containing either M4 or TLA antigens with a new pool of sera (93 seropositive and 35 seronegative). Thus, the present study shows that a cocktail of GRA1+P22+ROP1 recombinant proteins can be used to diagnose T. gondii infection in sheep, and consequently will assist in epidemiological studies. PMID- 25300562 TI - Prevalence and characteristics of cam-type femoroacetabular deformity in 100 hips with symptomatic acetabular dysplasia: a case control study. AB - BACKGROUND: Cam-type femoroacetabular deformity in acetabular dysplasia (AD) has not been well clarified. The primary purpose of this study was to determine the prevalence and characteristics of femoroacetabular deformity in symptomatic AD patients. METHODS: We retrospectively reviewed the cases of 86 women (92 hips) and eight men (eight hips) with symptomatic AD. The mean patient age was 37.9 (range, 14-60) years. All participants underwent lateral cross-table and lateral whole-spine radiographic examinations to measure the alpha angle and pelvic tilt. Pelvic computed tomography scans were used to measure femoral anteversion. The patients were classified into two groups: AD only group, containing hips with an alpha angle less than 55 degrees ; and AD with cam-type femoroacetabular deformity (AD + cam-type deformity) group, containing hips with an alpha angle greater than or equal to 55 degrees . RESULTS: Of the patients with AD, 40 hips displayed additional radiographic evidence of cam-type morphology, while 60 hips had exclusive AD morphology. The patients in the AD + cam-type deformity group had significantly increased forward pelvic tilt in the standing position (p = 0.023) and decreased femoral anteversion (p =0.047) compared with the AD only group. CONCLUSIONS: Our data revealed that 40% of patients with AD also had radiographic evidence of cam-type femoroacetabular deformity. Greater forward pelvic tilt in the standing position and decreased femoral anteversion seemed to be associated with the cam-type deformity in these patients. These results indicate the morphological features that are most likely to induce secondary symptoms to developmental hip dysplasia. It is suggested that the symptoms in the AD + cam-type deformity group could arise through femoroacetabular impingement (FAI) after periacetabular osteotomy, because a predisposition was present preoperatively. PMID- 25300563 TI - Characterization, treatment, and outcome of uveal melanoma in the first two years of life. AB - BACKGROUND AND OBJECTIVES: Features and characteristics of uveal melanoma are well described in adults, but little is known about the presentation of uveal melanoma in infancy. DESIGN: Systematic literature review. METHODS: A review of published, peer-reviewed literature reporting on uveal melanoma presenting during the first two years of life. Outcome measures included demographics, clinical features, histopathological findings, extent of the disease, therapeutic interventions, management outcomes, association with skin lesions or systemic diseases, and survival data. RESULTS: This review revealed 13 reported cases (seven boys and six girls) of uveal melanoma diagnosed within the first two years of life. The median age at diagnosis was seven months. Orbital mass and proptosis were the most common presentations (38%); only one tumor (8%) was melanotic, and pathologically 10 tumors (77%) had epithelioid component. Associated pigmented skin lesions (cutaneous disease) were seen in six cases (46%). All affected eyes were surgically removed; three patients received chemotherapy, and one received radiotherapy. At a median follow-up of 25months, two patients (15%) had metastasis, and one of them (8%) was dead at six months' follow-up with liver and multi-organ metastasis. CONCLUSIONS: Uveal melanoma can present within the first two years of life. In very rare cases, it can present as an intraocular tumor that simulates retinoblastoma, but it can also present as an orbital tumor. It has a tendency to affect patients with cutaneous diseases like familial atypical mole, melanoma syndrome, and dysplastic nevus syndrome. Despite this, uveal melanoma in this group has a more favorable prognosis than adult melanoma. PMID- 25300564 TI - Inferior vena cava filters in patients with advanced-stage cancer. AB - BACKGROUND: Cancer and its treatment are recognized risk factors for venous thromboembolism (VTE). Inferior vena cava (IVC) filters are utilized to provide mechanical thromboprophylaxis to prevent pulmonary embolism (PE) or to avoid bleeding from systemic anticoagulation. PATIENTS AND METHODS: A retrospective analysis of 107 cancer patients who had IVC filters inserted and followed up at our institution was performed. All patients had active cancer; a majority (> 90%) had advanced-stage disease, whereas only five patients (5.8%) had stages I or II disease. RESULTS: Eighty six patients (80.3%) had their IVC filter placed through a jugular approach. Filter insertion was not without complications; recurrent deep vein thrombosis (DVT) was reported in 10 (9.3%), PE in three (2.8%) and filter thrombosis in one patient. The value of IVC filter in patients with advanced stage disease was very limited: among 59 patients with stage IV disease for whom survival data was available, the median survival was only 1.31 months (0.92-2.20) with 23 patients (39.0%) surviving less than a month, and 40 (67.8%) surviving less than three months. CONCLUSIONS: Systemic anticoagulation can be safely offered for the majority of cancer patients. When the risk of bleeding or PE is high, IVC filters can be utilized. However, the placement of such filters should take into consideration the stage of disease and life expectancy of such patients. Patients with advanced-stage disease may gain little benefit from IVC filter insertion. PMID- 25300565 TI - Association between mammographic features and response to neoadjuvant chemotherapy in locally advanced breast carcinoma. AB - PURPOSE: Mammography is the cornerstone of breast cancer (BC) evaluation. This report investigates whether breast density (BD) and mammographic features of the tumor can provide information on both BC susceptibility to chemotherapy and other clinicopathologic features of locally advanced BC (LA BC). MATERIALS AND METHODS: We evaluated mammography films and clinicopathological information of patients with LA BC who received neoadjuvant chemotherapy (NAC) followed by tumor resection at the Instituto Nacional de Enfermedades Neoplasicas (INEN) from 2000 to 2011. RESULTS: We selected 494 LA BC cases. Most cases were at clinical tumor stage 4 (48.5%), node stage 1 (58.8%) and had high histologic grade (53.3%). BI RADS 1, 2, 3, and 4 BD were found in 16.9%, 22%, 35.7% and 25.1% of patients, respectively. High BD has been associated with younger age (p<0.001), obesity (p=0.017) and no skin infiltration (T3 vs T4) (p=0.018). An association between dusty microcalcifications and HER2 group, as well as between casting microcalcifications and TN BC group (p=0.05) was found. NAC included anthracyclines and taxanes in 422 (85.5%) cases. Miller-Payne pathologic responses 4 and 5 (pCR) in the primary lesion and absence of axillary lymph nodes involvement were found in 15.3% of cases and were associated with younger age (p<0.001) and HG-3 lesions (p<0.001), but not with mammographic images. CONCLUSION: Mammographic features are associated with specific clinicopathological features of pre-NAC BC lesions but do not predict pCR. The implications and biological reasons for these findings require further study. PMID- 25300566 TI - Secondary pulmonary alveolar proteinosis in hematologic malignancies. AB - Pulmonary alveolar proteinosis (PAP), characterized by deposition of intra alveolar PAS positive protein and lipid rich material, is a rare cause of progressive respiratory failure first described by Rosen et al. in 1958. The intra-alveolar lipoproteinaceous material was subsequently proven to have been derived from pulmonary surfactant in 1980 by Singh et al. Levinson et al. also reported in 1958 the case of 19-year-old female with panmyelosis afflicted with a diffuse pulmonary disease characterized by filling of the alveoli with amorphous material described as "intra-alveolar coagulum". This is probably the first reported case of PAP in relation to hematologic malignancy. Much progress has been made on PAP first described by Rosen which is currently classified as idiopathic or primary or autoimmune PAP. Idiopathic PAP occurs as a result of auto-antibodies directed against granulocyte-macrophage colony stimulating factor (GM-CSF) impeding the surfactant clearing function of alveolar macrophages leading to progressive respiratory failure. Whole lung lavage and GM-CSF therapy has improved outcomes in patients with idiopathic PAP. Despite major advancement in the management of hematologic malignancy and its complications, little is known about the type of PAP first described by Levinson and now known as secondary PAP; a term also used when PAP occurs due to other causes such as occupational dusts. In this article we review and analyze the limited literature available in secondary PAP due to hematologic malignancies and present a case of PAP associated with chronic lymphocytic leukemia successfully treated with bendamustine and rituximab. PMID- 25300567 TI - Rare but authentic Philadelphia-positive acute myeloblastic leukemia: two case reports and a literature review of characteristics, treatment and outcome. AB - The Philadelphia chromosome (Ph+), corresponding to translocation t(9;22), is found in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia. Several cases of Ph+ acute myeloid leukemia (AML) have been reported in the literature. A retrospective study of Ph+ AML between 2001 and 2012 was conducted through a review of the literature. Among 400 AML patients, two cases of Ph+ AML (0.5%) were identified and treated with conventional chemotherapy with or without tyrosine kinase inhibitors (TKIs), followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). One patient had a complex karyotype including 7 monosomy (-7) and p190 BCR-ABL fusion transcript. Both patients remain in complete molecular remission. To date, 21 Ph+ AML cases treated with TKIs have been described in the literature with a median overall survival of 18months. One third of the patients had additional karyotypic abnormalities, and 14% had -7. Molecular analysis showed 59% p210 and 41% p190 fusion protein. Relapse rate was observed in 38% of patients with p190 compared to 10% in patients with p210. Allo HSCT was performed in eight patients; two relapsed (25%). Cytogenetic (-7) and molecular features help to distinguish Ph+ AML from CML. Survival improved with TKIs, particularly in association with conventional chemotherapy and allo-HSCT. Further studies of Ph+ AML patients are needed to better define this entity, its prognostic value, and therapeutic strategy. PMID- 25300568 TI - Carotid-femoral pulse wave velocity is not increased in obesity. AB - BACKGROUND: There are conflicting results in the literature concerning the relationship between obesity and arterial stiffness, assessed by carotid-femoral pulse wave velocity (PWV). The discrepancies could be due to differences in carotid-femoral distance measurement and/or to the presence of pathologies frequently associated with obesity and which increase arterial stiffness. In this study, we examine the relationship between PWV and weight, without and with associated cardiovascular risk factors (diabetes and/or dyslipidemia). METHODS: PWV was assessed with a Complior SP device (Alam Medical, France) in 2,034 patients referred for ambulatory blood pressure monitoring. The carotid-femoral distance used to calculate PWV was measured with a flexible tape and from the estimated straight carotid-femoral distance obtained with a published equation. RESULTS: In the whole cohort, PWV did not differ significantly according to weight (9.6+/-2.1, 9.8+/-2.2 and 9.7+/-1.9 m/s in normal weight, overweight and obese subjects, respectively, with the distance measured with a tape). PWV was significantly higher in the four groups of patients with cardiovascular risk factors (e.g., 11.1+/-2.4, 11.0+/-2.7 and 10.4+/-2.0 m/s in normal weight, overweight, and obese subjects, respectively, in the group treated for diabetes and dyslipidemia) than in the group of patients without cardiovascular risk factors (8.5+/-1.6, 8.8+/-1.7 and 8.5+/-1.2 in normal weight, overweight, and obese subjects, respectively). There was no relationship between PWV value and weight status, whether or not there were cardiovascular risk factors, and whatever the distance used to calculate PWV. CONCLUSIONS: In our cohort, obesity per se was not associated with increased arterial stiffness. PMID- 25300569 TI - Are persistent throat symptoms atypical features of gastric reflux and should they be treated with proton pump inhibitors? PMID- 25300570 TI - Social-economical decision making in current and remitted major depression. AB - BACKGROUND: Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown. METHOD: In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms. RESULTS: We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05). CONCLUSIONS: Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision making abnormalities in depression. PMID- 25300571 TI - Experimental and theoretical performance analysis for a CMOS-based high resolution image detector. AB - Increasing complexity of endovascular interventional procedures requires superior x-ray imaging quality. Present state-of-the-art x-ray imaging detectors may not be adequate due to their inherent noise and resolution limitations. With recent developments, CMOS based detectors are presenting an option to fulfill the need for better image quality. For this work, a new CMOS detector has been analyzed experimentally and theoretically in terms of sensitivity, MTF and DQE. The detector (Dexela Model 1207, Perkin-Elmer Co., London, UK) features 14-bit image acquisition, a CsI phosphor, 75 um pixels and an active area of 12 cm * 7 cm with over 30 fps frame rate. This detector has two modes of operations with two different full-well capacities: high and low sensitivity. The sensitivity and instrumentation noise equivalent exposure (INEE) were calculated for both modes. The detector modulation-transfer function (MTF), noise-power spectra (NPS) and detective quantum efficiency (DQE) were measured using an RQA5 spectrum. For the theoretical performance evaluation, a linear cascade model with an added aliasing stage was used. The detector showed excellent linearity in both modes. The sensitivity and the INEE of the detector were found to be 31.55 DN/uR and 0.55 uR in high sensitivity mode, while they were 9.87 DN/uR and 2.77 uR in low sensitivity mode. The theoretical and experimental values for the MTF and DQE showed close agreement with good DQE even at fluoroscopic exposure levels. In summary, the Dexela detector's imaging performance in terms of sensitivity, linear system metrics, and INEE demonstrates that it can overcome the noise and resolution limitations of present state-of-the-art x-ray detectors. PMID- 25300572 TI - Twisting lipoma presenting as appendicitis-a rare presentation. AB - Right iliac fossa (RIF) pain is the most common presenting complaint in the general surgical ward. Though there are several causes for the RIF pain, acute appendicitis is the first and common diagnosis. Here we present one of the rare differential diagnoses of RIF pain in a young female patient with one month history of intermittent right lower abdominal pain. Patient's symptoms and clinical findings indicated acute appendicitis, though ultrasonography didn't show any significant abnormality. Through diagnostic laparoscopy we found that there was torsion of anterior abdominal wall parietal peritoneal pedunculated lipoma located in RIF region. The clinical presentation, examination, investigation, laparoscopic findings and further management is presented in this case report. PMID- 25300573 TI - Enhanced expression of retinoic acid receptor alpha (RARA) induces epithelial-to mesenchymal transition and disruption of mammary acinar structures. AB - The early steps of mammary tumorigenesis include loss of epithelial cell polarity, escape from anoikis, and acquisition of proliferative capacity. The genes responsible for these processes are predicted to be early diagnostic markers or new therapeutic targets. Here we tested 51 genes coamplified with ERBB2 in the 17q12-21 amplicon for these tumorigenic activities using an MCF10A 3D culture-based screening system. We found that overexpression of retinoic acid receptor alpha (RARA) disrupted normal acinar structure and induced epithelial-to mesenchymal transition (EMT). The mRNA levels of known EMT-inducing factors, including SLUG, FOXC2, ZEB1, and ZEB2, were significantly increased upon RARA overexpression. Knockdown of ZEB1 suppressed the RARA-mediated EMT phenotype. These results suggest that overexpression of RARA enhances malignant transformation during mammary tumorigenesis. PMID- 25300574 TI - Efficacy and safety of ginger in osteoarthritis patients: a meta-analysis of randomized placebo-controlled trials. AB - The aim of this study was to assess the clinical efficacy and safety of oral ginger for symptomatic treatment of osteoarthritis (OA) by carrying out a systematic literature search followed by meta-analyses on selected studies. Inclusion criteria were randomized controlled trials (RCTs) comparing oral ginger treatment with placebo in OA patients aged >18 years. Outcomes were reduction in pain and reduction in disability. Harm was assessed as withdrawals due to adverse events. The efficacy effect size was estimated using Hedges' standardized mean difference (SMD), and safety by risk ratio (RR). Standard random-effects meta analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). Out of 122 retrieved references, 117 were discarded, leaving five trials (593 patients) for meta-analyses. The majority reported relevant randomization procedures and blinding, but an inadequate intention-to-treat (ITT) analysis. Following ginger intake, a statistically significant pain reduction SMD = -0.30 ([95% CI: [(-0.50, -0.09)], P = 0.005]) with a low degree of inconsistency among trials (I(2) = 27%), and a statistically significant reduction in disability SMD = -0.22 ([95% CI: ([-0.39, -0.04)]; P = 0.01; I(2) = 0%]) were seen, both in favor of ginger. Patients given ginger were more than twice as likely to discontinue treatment compared to placebo ([RR = 2.33; 95% CI: (1.04, 5.22)]; P = 0.04; I(2) = 0%]). Ginger was modestly efficacious and reasonably safe for treatment of OA. We judged the evidence to be of moderate quality, based on the small number of participants and inadequate ITT populations. Prospero: CRD42011001777. PMID- 25300575 TI - Letter to the Editor re: "Cam impingement: defining the presence of a cam deformity by the alpha angle data from the CHECK cohort and Chingford cohort". PMID- 25300576 TI - Response to letter to the editor: "Cam impingement: defining the presence of a cam deformity by the alpha angle data from the CHECK cohort an Chingford cohort". PMID- 25300578 TI - beta-catenin links hepatic metabolic zonation with lipid metabolism and diet induced obesity in mice. AB - beta-catenin regulates the establishment of hepatic metabolic zonation. To elucidate the functional significance of liver metabolic zonation in the chronically overfed state in vivo, we fed a high-fat diet (HFD) to hepatocyte specific beta-catenin transgenic (TG) and knockout (KO) mice. Chow-fed TG and KO mice had normal liver histologic findings and body weight. However, HFD-fed TG mice developed prominent perivenous steatosis with periportal sparing. In contrast, HFD-fed KO mice had increased lobular inflammation and hepatocyte apoptosis. HFD-fed TG mice rapidly developed diet-induced obesity and systemic insulin resistance, but KO mice were resistant to diet-induced obesity. However, beta-catenin did not directly affect hepatic insulin signaling, suggesting that the metabolic effects of beta-catenin occurred via a parallel pathway. Hepatic expression of key glycolytic and lipogenic genes was higher in HFD-fed TG and lower in KO mice compared with wild-type mice. KO mice also exhibited defective hepatic fatty acid oxidation and fasting ketogenesis. Hepatic levels of hypoxia inducible factor-1alpha, an oxygen-sensitive transcriptional regulator of glycolysis and a known beta-catenin binding partner, were higher in HFD-fed TG and lower in KO mice. KO mice had attenuated perivenous hypoxia, suggesting disruption of the normal sinusoidal oxygen gradient, a major determinant of liver carbohydrate and liver metabolism. Canonical Wnt signaling in hepatocytes is essential for the development of diet-induced fatty liver and obesity. PMID- 25300577 TI - Brief alcohol interventions for adolescents and young adults: a systematic review and meta-analysis. AB - This study reports findings from a meta-analysis summarizing the effectiveness of brief alcohol interventions for adolescents (age 11-18) and young adults (age 19 30). We identified 185 eligible study samples using a comprehensive literature search and synthesized findings using random-effects meta-analyses with robust standard errors. Overall, brief alcohol interventions led to significant reductions in alcohol consumption and alcohol-related problems among adolescents (g = 0.27 and g = 0.19) and young adults (g = 0.17 and g = 0.11). These effects persisted for up to 1 year after intervention and did not vary across participant demographics, intervention length, or intervention format. However, certain intervention modalities (e.g., motivational interviewing) and components (e.g., decisional balance, goal-setting exercises) were associated with larger effects. We conclude that brief alcohol interventions yield beneficial effects on alcohol related outcomes for adolescents and young adults that are modest but potentially worthwhile given their brevity and low cost. PMID- 25300581 TI - Establishment of Gal4 transgenic zebrafish lines for analysis of development of cerebellar neural circuitry. AB - The cerebellum is involved in some forms of motor coordination and motor learning. Here we isolated transgenic (Tg) zebrafish lines that express a modified version of Gal4-VP16 (GFF) in the cerebellar neural circuits: granule, Purkinje, or eurydendroid cells, Bergmann glia, or the neurons in the inferior olive nuclei (IO) which send climbing fibers to Purkinje cells, with the transposon Tol2 system. By combining GFF lines with Tg lines carrying a reporter gene located downstream of Gal4 binding sequences (upstream activating sequence: UAS), we investigated the anatomy and developmental processes of the cerebellar neural circuitry. Combining an IO-specific Gal4 line with a UAS reporter line expressing the photoconvertible fluorescent protein Kaede demonstrated the contralateral projections of climbing fibers. Combining a granule cell-specific Gal4 line with a UAS reporter line expressing wheat germ agglutinin (WGA) confirmed direct and/or indirect connections of granule cells with Purkinje cells, eurydendroid cells, and IO neurons in zebrafish. Time-lapse analysis of a granule cell-specific Gal4 line revealed initial random movements and ventral migration of granule cell nuclei. Transgenesis of a reporter gene with another transposon Tol1 system visualized neuronal structure at a single cell resolution. Our findings indicate the usefulness of these zebrafish Gal4 Tg lines for studying the development and function of cerebellar neural circuits. PMID- 25300580 TI - Hedgehog activity controls opening of the primary mouth. AB - To feed or breathe, the oral opening must connect with the gut. The foregut and oral tissues converge at the primary mouth, forming the buccopharyngeal membrane (BPM), a bilayer epithelium. Failure to form the opening between gut and mouth has significant ramifications, and many craniofacial disorders have been associated with defects in this process. Oral perforation is characterized by dissolution of the BPM, but little is known about this process. In humans, failure to form a continuous mouth opening is associated with mutations in Hedgehog (Hh) pathway members; however, the role of Hh in primary mouth development is untested. Here, we show, using Xenopus, that Hh signaling is necessary and sufficient to initiate mouth formation, and that Hh activation is required in a dose-dependent fashion to determine the size of the mouth. This activity lies upstream of the previously demonstrated role for Wnt signal inhibition in oral perforation. We then turn to mouse mutants to establish that SHH and Gli3 are indeed necessary for mammalian mouth development. Our data suggest that Hh-mediated BPM persistence may underlie oral defects in human craniofacial syndromes. PMID- 25300582 TI - [La Revue de medecine interne and the social media]. PMID- 25300579 TI - Alk3 mediated Bmp signaling controls the contribution of epicardially derived cells to the tissues of the atrioventricular junction. AB - Recent studies using mouse models for cell fate tracing of epicardial derived cells (EPDCs) have demonstrated that at the atrioventricular (AV) junction EPDCs contribute to the mesenchyme of the AV sulcus, the annulus fibrosus, and the parietal leaflets of the AV valves. There is little insight, however, into the mechanisms that govern the contribution of EPDCs to these tissues. While it has been demonstrated that bone morphogenetic protein (Bmp) signaling is required for AV cushion formation, its role in regulating EPDC contribution to the AV junction remains unexplored. To determine the role of Bmp signaling in the contribution of EPDCs to the AV junction, the Bmp receptor activin-like kinase 3 (Alk3; or Bmpr1a) was conditionally deleted in the epicardium and EPDCs using the mWt1/IRES/GFP-Cre (Wt1(Cre)) mouse. Embryonic Wt1(Cre);Alk3(fl/fl) specimens showed a significantly smaller AV sulcus and a severely underdeveloped annulus fibrosus. Electrophysiological analysis of adult Wt1(Cre);Alk3(fl/fl) mice showed, unexpectedly, no ventricular pre-excitation. Cell fate tracing revealed a significant decrease in the number of EPDCs within the parietal leaflets of the AV valves. Postnatal Wt1(Cre);Alk3(fl/fl) specimens showed myxomatous changes in the leaflets of the mitral valve. Together these observations indicate that Alk3 mediated Bmp signaling is important in the cascade of events that regulate the contribution of EPDCs to the AV sulcus, annulus fibrosus, and the parietal leaflets of the AV valves. Furthermore, this study shows that EPDCs do not only play a critical role in early developmental events at the AV junction, but that they also are important in the normal maturation of the AV valves. PMID- 25300583 TI - Bias by the inappropriate use of the pseudo-first order approach to estimate second-order reaction rate constants: reply to the commentary by Tratnyek (this issue). PMID- 25300584 TI - Mechanisms of localized activation of the T cell antigen receptor inside clusters. AB - The T cell antigen receptor (TCR) has been shown to cluster both before and upon engagement with cognate antigens. However, the effect of TCR clustering on its activation remains poorly understood. Here, we used two-color photo-activated localization microscopy (PALM) to visualize individual molecules of TCR and ZAP 70, as a marker of TCR activation and phosphorylation, at the plasma membrane of uniformly activated T cells. Imaging and second-order statistics revealed that ZAP-70 recruitment and TCR activation localized inside TCR clusters. Live cell PALM imaging showed that the extent of localized TCR activation decreased, yet remained significant, with cell spreading. Using dynamic modeling and Monte-Carlo simulations we evaluated possible mechanisms of localized TCR activation. Our simulations indicate that localized TCR activation is the result of long-range cooperative interactions between activated TCRs, or localized activation by Lck and Fyn. Our results demonstrate the role of molecular clustering in cell signaling and activation, and are relevant to studying a wide range of multi molecular complexes. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. PMID- 25300585 TI - Detecting protein association at the T cell plasma membrane. AB - At the moment, many models on T cell signaling rely on results obtained via rather indirect methodologies, which makes direct comparison and conclusions to the in vivo situation difficult. Recently, a variety of new imaging methods were developed, which have the potential to directly shed light onto the mysteries of protein association at the T cell membrane. While the new modalities are extremely promising, for a broad readership it may be difficult to judge the results, since technological shortcomings are not always obvious. In this review article, we put key questions on the mechanism of protein interactions in the T cell plasma membrane into relation with techniques that allow to address such questions. We discuss applicability of the techniques, their strengths and weaknesses. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. PMID- 25300586 TI - Emerging treatments for chronic hepatitis C. AB - Advances in understanding the hepatitis C virus (HCV) life cycle and the urgent need to find complementary direct-acting antiviral (DAA) therapies has led to substantial advancements in treating chronic hepatitis C. The introduction of telaprevir and boceprevir in 2011 increased the sustained virological response (SVR) rate from approximately 50% to > 70%, but this therapy further restricted patient eligibility and is only approved for treating HCV genotype 1 infection. Interferon has long remained the backbone of HCV therapy and helps prevent viral breakthrough. However, interferon has limited effectiveness and is associated with severe adverse effects and toxicity, especially among cirrhotic patients. Moving to interferon-free therapies should greatly improve SVR rates and offer new treatments for other HCV genotypes and for ineligible patients or patients failing to respond to prior therapies. However, without the relative safety of interferon to suppress viral escape, vigilance will be required to select appropriate therapies and monitor resistance. Several DAAs are currently undergoing clinical trials and will soon undergo the approval process. Goals of future HCV clinical research will be to identify combinations of DAAs with high genetic barriers, investigate optimal treatment doses and durations, and determine the role of ribavirin in DAA therapies. PMID- 25300587 TI - 2014 UK national guideline on the management of vulval conditions. PMID- 25300588 TI - The association of human papillomavirus vaccination with sexual behaviours and human papillomavirus knowledge: a systematic review. AB - Since the 2008 introduction of the human papillomavirus (HPV) vaccination programme for adolescent girls in the UK, parents and other groups have expressed fears that immunisation condones sexual activity, promotes promiscuity and encourages risky sexual behaviour. This study aimed to explore whether HPV vaccination programmes have increased knowledge surrounding HPV and associated disease and whether uptake has influenced sexual behaviour. MEDLINE, Embase, Cochrane Library and PsycINFO electronic databases were interrogated. Studies of behaviour, attitudes and knowledge associated with HPV vaccination (or vaccination intent) in subjects of any age and gender in programmes reflective of UK practice were included in the review (n = 58). The evidence regarding the association of HPV vaccination with high-risk sexual behaviour was varied, primarily due to the heterogeneous nature of the included studies. Young females typically exhibited better knowledge than males, and vaccinated respondents (or those with vaccination intent) had higher levels of knowledge than the unvaccinated. However, knowledge surrounding HPV and genital warts was generally poor. This review highlights the need to provide effective education regarding the HPV vaccine and HPV-associated disease to adolescents of vaccination age, nurses, teachers, parents and guardians to ultimately allow informed decisions to be made regarding receipt of the HPV vaccine. PMID- 25300589 TI - Miller Fisher syndrome with presynaptic neuromuscular transmission disorder. AB - Miller Fisher syndrome is defined by a triad of symptoms, namely areflexia, ataxia, and ophthalmoparesis. The ophthalmoparesis is mostly severe, undulating weakness of eye movements with ptosis and increased fatigability resembling a neuromuscular transmission disorder. We present a 52-year-old man with severe Miller Fisher syndrome with a high level of anti-GQ1b antibodies and a presynaptic type of neuromuscular transmission disorder. The diagnosis was confirmed by stimulated single-fiber electromyography with the use of a concentric needle electrode and various stimulation rates. PMID- 25300590 TI - Comparative analysis of heterochromatin distribution in wild and cultivated Abelmoschus species based on fluorescent staining methods. AB - A comparative analysis of fluorochrome-binding pattern in nine taxa of Abelmoschus had shown that the type, amount and distribution pattern of heterochromatin were characteristic for each taxa. The fluorescent chromosome binding sites obtained by chromomycin A3 (CMA) and 4',6-diamidino-2-phenylindole (DAPI) staining in all the nine species showed constitutive heterochromatin CMA(+), DAPI(+) and CMA(+)/DAPI(+). Large amount of heterozygosity was observed with regard to heterochromatin distribution pattern in all the taxa studied. The CMA(+)-binding sites are comparatively less than DAPI(+)-binding sites which is clearly evident as AT-rich regions are more than GC-rich regions in all the nine taxa analysed in Abelmoschus. These CMA(+) and DAPI(+)-binding sites apparently rise with the increased in chromosome numbers of the different species. This pattern of heterochromatin heterogeneity seems to be a general characteristic feature. Therefore, the differential pattern of distribution of GC- and AT-rich sequences might have played an important role in diversification of the genus Abelmoschus. Polyploidy is an important factor in the evolution of Abelmoschus and the sole reason for range in chromosome numbers in this genus. It may be noted that, though often, but not always, the increase of DNA is caused by an increase in the amount of heterochromatin, i.e. increase of non-coding sections indicating restructuring of the heterochromatin. Thus, cumulative small and direct numerical changes might have played a role in the speciation of Abelmoschus. PMID- 25300591 TI - Construction of a two-in-one liposomal system (TWOLips) for tumor-targeted combination therapy. AB - In oncology, there is a growing need for simpler, more selective methods to deliver drug therapies directly to the tumor site. For combination therapies, simultaneous targeted delivery of multiple drugs would represent a significant improvement. In contrast to previous work that took a de novo approach, we constructed a novel two-in-one liposomal system (TWOLips) from two single drug loaded liposomes. Our results demonstrated that TWOLips could be prepared by a simple process, through silica coating of one liposome and incubation with the second liposome. TWOLips had a mean diameter of 100 nm, relatively high drug loading rates (96.8%+/-0.9% for doxorubicin and 78.4%+/-1.2% for combretastatin), and high storage stability. TWOLips modification by adding a targeting moiety, an all D-amino acid peptide derived from a natural vascular endothelial growth factor, resulted in strong, selective binding to vascular endothelial growth factor receptor 2, a tumorigenesis marker, in vitro and in vivo. TWOLips significantly inhibited tumor growth and angiogenesis and enhanced survival in mice with A375 melanoma xenografts. The TWOLips system had a low potential risk of toxicity. Since the stepwise assembly could be carried further (additional drug-loaded liposomes), TWOLips shows potential as a treatment for many cancers, especially those that require multiple drugs. PMID- 25300592 TI - Chromatographic analysis of olopatadine in hydrophilic interaction liquid chromatography. AB - In this paper, chromatographic analysis of active substance olopatadine hydrochloride, which is used in eye drops as antihistaminic agent, and its impurity E isomer by hydrophilic interaction liquid chromatography (HILIC) and application of design of experiments (DoE) methodology are presented. In addition, benzalkonium chloride is very often used as a preservative in eye drops. Therefore, the evaluation of its chromatographic behavior in HILIC was carried out as well. In order to estimate chromatographic behavior and set optimal chromatographic conditions, DoE methodology was applied. After the selection of important chromatographic factors, Box-Behnken design was utilized, and on the basis of the obtained models factor effects were examined. Then, multi objective robust optimization is performed aiming to obtain chromatographic conditions that comply with several quality criteria simultaneously: adequate and robust separation of critical peak pair and maximum retention of the first eluting peak. The optimal conditions are identified by using grid point search methodology. The experimental verification confirmed the adequacy of the defined optimal conditions. Finally, under optimal chromatographic conditions, the method was validated and applicability of the proposed method was confirmed. PMID- 25300593 TI - Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe. AB - The global burden of pneumococcal diseases is high, with young children and adults>=50 years of age at highest risk of infection. Two types of vaccine are available for the prevention of pneumococcal diseases caused by specific Streptococcus pneumoniae serotypes: the pneumococcal polysaccharide vaccine (PPV23) and the pneumococcal conjugate vaccine (PCV7, PCV10, and PCV13). Despite pneumococcal immunization programs in adults and children, the burden in adults has remained high. Most European countries have national or local/regional vaccination recommendations. The objective of this review was to provide an overview of the government recommendations for pneumococcal vaccination outside routine childhood vaccination programs for 16 Western European countries as of August 2014. We found that recommendations for pneumococcal immunization across Europe are complex and vary greatly among countries in terms of age groups and risk groups recommended for vaccination, as well as which vaccine should be administered. Clarifying or simplifying these recommendations and improving their dissemination could help to increase pneumococcal vaccine uptake and decrease the high burden of pneumococcal diseases in adults, both through a direct effect of the vaccine and via a herd effect in unvaccinated individuals. PMID- 25300594 TI - Intranasal fentanyl for the management of acute pain in children. AB - BACKGROUND: Pain is the most common symptom in the emergency setting; however, timely management of acute pain in children continues to be suboptimal. Intranasal drug delivery has emerged as an alternative method of achieving quicker drug delivery without adding to the distress of a child by inserting an intravenous cannula. OBJECTIVES: We identified and evaluated all randomized controlled trials (RCTs) and quasi-randomized trials to assess the effects of intranasal fentanyl (INF) versus alternative analgesic interventions in children with acute pain, with respect to reduction in pain score, occurrence of adverse events, patient tolerability, use of "rescue analgesia," patient/parental satisfaction and patient mortality. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 1); MEDLINE (Ovid SP, from 1995 to January 2014); EMBASE (Ovid SP, from 1995 to January 2014); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO Host, from 1995 to January 2014); the Latin American and Caribbean Health Science Information Database (LILACS) (BIREME, from 1995 to January 2014); Commonwealth Agricultural Bureaux (CAB) Abstracts (from 1995 to January 2014); the Institute for Scientific Information (ISI) Web of Science (from 1995 to January 2014); BIOSIS Previews (from 1995 to January 2014); the China National Knowledge Infrastructure (CNKI) (from 1995 to January 2014); International Standard Randomized Controlled Trial Number (ISRCTN) (from 1995 to January 2014); ClinicalTrials.gov (from 1995 to January 2014); and the International Clinical Trials Registry Platform (ICTRP) (to January 2014). SELECTION CRITERIA: We included RCTs comparing INF versus any other pharmacological/non-pharmacological intervention for the treatment of children in acute pain (aged < 18 years). DATA COLLECTION AND ANALYSIS: Two independent review authors assessed each title and abstract for relevance. Full copies of all studies that met the inclusion criteria were retrieved for further assessment. Mean difference (MD), odds ratio (OR) and 95% confidence interval (CI) were used to measure effect sizes. Two review authors independently assessed and rated the methodological quality of each trial using the tool of The Cochrane Collaboration to assess risk of bias, as per Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Three studies (313 participants) met the inclusion criteria. One study compared INF versus intramuscular morphine (IMM); another study compared INF versus intravenous morphine (IVM); and another study compared standard concentration INF (SINF) versus high concentration INF (HINF). All three studies reported a reduction in pain score following INF administration. INF produced a greater reduction in pain score at 10 minutes post administration when compared with IMM (INF group pain score: 1/5 vs IMM group pain score: 2/5; P value 0.014). No other statistically significant differences in pain scores were reported at any other time point. When INF was compared with IVM and HINF, no statistically significant differences in pain scores were noted between treatment arms, before analgesia or at 5, 10, 20 and 30 minutes post analgesia. Specifically, when INF was compared with IVM, both agents were seen to produce a statistically significant reduction in pain score up to 20 minutes post analgesia. No further reduction in pain score was noted after this time. When SINF was compared with HINF, a statistically and clinically significant reduction in pain scores over study time was observed (median decrease for both groups 40 mm, P value 0.000). No adverse events (e.g. opiate toxicity, death) were reported in any study following INF administration. One study described better patient tolerance to INF compared with IMM, which achieved statistical significance. The other studies described reports of a "bad taste" and vomiting with INF. Overall the risk of bias in all studies was considered low. AUTHORS' CONCLUSIONS: INF may be an effective analgesic for the treatment of patients with acute moderate to severe pain, and its administration appears to cause minimal distress to children. However, this review of published studies does not allow any definitive conclusions regarding whether INF is superior, non-inferior or equivalent to intramuscular or intravenous morphine. Limitations of this review include the following: few eligible studies for inclusion (three); no study examined the use of INF in children younger than three years of age; no study included children with pain from a "medical" cause (e.g. abdominal pain seen in appendicitis); and all eligible studies were conducted in Australia. Consequently, the findings may not be generalizable to other healthcare settings, to children younger than three years of age and to those with pain from a "medical" cause. PMID- 25300595 TI - Serum fibroblast growth factor 21 levels are inversely associated with growth rates in infancy. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is a metabolic and growth regulator. AIM: To investigate the role of FGF21 during growth in infancy. METHODS: Blood samples for FGF21, leptin, insulin and glucose were collected from cord blood obtained from 95 preterm and term newborns (cross-sectional group), and at 6 and 12 months of life in 80 preterm and term infants (longitudinal group). Length and weight were measured at birth, 6 months, and 12 months. RESULTS: From birth through 12 months of age, preterm infants' linear growth and weight gain were larger than those of term infants, irrespective of birth weight SDS. At birth and at 12 months, there was no difference in FGF21 levels between preterm and term infants; in contrast, at 6 months, serum FGF21 in term infants was significantly higher than that of preterm ones. In the 0-6-month period, in the whole longitudinal group, serum FGF21 was inversely correlated to the length change SDS, and such a significant inverse correlation persisted in the preterm AGA group in the 6-12-month period. In addition, term infants who experienced length catch-up in the first 6 months of life exhibited lower serum FGF21 levels at 6 months, and those with length catch-up growth between 6 and 12 months had a greater decrease of serum FGF21 level in the same time period. CONCLUSIONS: Our results indicate that FGF21 in infancy is inversely correlated with linear growth rate, thus suggesting that FGF21 is a negative regulator of human growth. PMID- 25300597 TI - PET imaging of adenosine A1 receptor occupancy. PMID- 25300599 TI - Radionuclide imaging in ischemic stroke. AB - Ischemic stroke is caused by interruption or significant impairment of blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphologic damage. The changes in regional cerebral blood flow and regional metabolism can be assessed by radionuclide imaging, especially SPECT and PET. SPECT and PET have broadened our understanding of flow and metabolic thresholds critical for maintenance of brain function and morphology: PET was essential in the transfer of the concept of the penumbra to clinical stroke and thereby had a great impact on developing treatment strategies. Receptor ligands can be applied as early markers of irreversible neuronal damage and can predict the size of the final infarcts, which is important for decisions on invasive therapy in large ("malignant") infarction. With SPECT and PET, the reserve capacity of the blood supply can be tested in obstructive arteriosclerosis, which is essential for planning interventions. The effect of a stroke on surrounding and contralateral primarily unaffected tissue can be investigated, helping to understand symptoms caused by disturbance in functional networks. Activation studies are useful to demonstrate alternative pathways to compensate for lesions and to test the effect of rehabilitative therapy. Radioisotope studies help to detect neuroinflammation and its effect on extension of tissue damage. Despite the limitations of broad clinical application of radionuclide imaging, this technology has a great impact on research in cerebrovascular diseases and still has various applications in the management of stroke. PMID- 25300598 TI - Cerenkov luminescence endoscopy: improved molecular sensitivity with beta- emitting radiotracers. AB - Cerenkov luminescence endoscopy (CLE) is an optical technique that captures the Cerenkov photons emitted from highly energetic moving charged particles (beta(+) or beta(-)) and can be used to monitor the distribution of many clinically available radioactive probes. A main limitation of CLE is its limited sensitivity to small concentrations of radiotracer, especially when used with a light guide. We investigated the improvement in the sensitivity of CLE brought about by using a beta(-) radiotracer that improved Cerenkov signal due to both higher beta particle energy and lower gamma noise in the imaging optics because of the lack of positron annihilation. METHODS: The signal-to-noise ratio (SNR) of (90)Y was compared with that of (18)F in both phantoms and small-animal tumor models. Sensitivity and noise characteristics were demonstrated using vials of activity both at the surface and beneath 1 cm of tissue. Rodent U87MG glioma xenograft models were imaged with radiotracers bound to arginine-glycine-aspartate (RGD) peptides to determine the SNR. RESULTS: gamma noise from (18)F was demonstrated by both an observed blurring across the field of view and a more pronounced fall off with distance. A decreased gamma background and increased energy of the beta particles resulted in a 207-fold improvement in the sensitivity of (90)Y compared with (18)F in phantoms. (90)Y-bound RGD peptide produced a higher tumor-to background SNR than (18)F in a mouse model. CONCLUSION: The use of (90)Y for Cerenkov endoscopic imaging enabled superior results compared with an (18)F radiotracer. PMID- 25300601 TI - State- and trait-greed, its impact on risky decision-making and underlying neural mechanisms. AB - We investigated whether greed would predict risky decision-making and recorded neural responses during a monetary gambling task using the electroencephalogram. We found that individuals high in trait-greed took higher risks to maximize monetary outcome. Furthermore, this relation was moderated by state-greed; specifically, trait-greed had a stronger impact on risky decision-making when activated by situational characteristics. On the neural level, greedy individuals showed a specific response to favorable and unfavorable outcomes. Specifically, they had a reduced feedback-related negativity-difference score to these events, indicating that they might have difficulty in learning from experience, especially from mistakes and negative feedback. It is concluded that greed may explain risky and reckless behavior in diverse settings, such as investment banking, and may account for phenomena such as stock market bubbles. PMID- 25300600 TI - Type and severity of intimate partner violence and its relationship with PTSD in HIV-infected women. AB - HIV has an impact on the presence and severity of both intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) in infected women. However, the relationship of type and severity of IPV with PTSD in this population has not been adequately explored. We focus on the association between the type and severity of IPV and HIV status and PTSD in a sample of South African women. One hundred and sixty-nine women (114 HIV-positive and 55 HIV-negative controls), matched for geographical area, education, and socio-economic status, were recruited from HIV clinics. Clinical and demographic data were collected, including data on childhood trauma, other traumatic life events, IPV, posttraumatic stress symptoms, problematic alcohol use, and depressive symptoms. HIV-positive women had significantly more depressive symptoms, alcohol abuse, and childhood trauma exposure as well as significantly higher rates of PTSD (25.4%) when compared with uninfected women (10.9%). No significant group differences in the rate, pattern, and severity of physical, sexual, psychological, injury, and negotiation IPV were found. In logistic regression analysis, the rate and severity category of IPV did not significantly predict PTSD in HIV-positive women when childhood trauma and life events were controlled for. Our results indicate the need for screening for alcohol abuse, PTSD and depressive symptoms at HIV wellness, and ARV clinics. The high rates of PTSD in HIV-positive women indicate the need for specialized programs to manage PTSD and minimize negative sequelae in this population. These results also highlight the need for improved screening and prevention of childhood trauma and IPV both in infected and uninfected women. PMID- 25300602 TI - Biochemical properties of xylose reductase prepared from adapted strain of Candida tropicalis. AB - Xylose reductase (XR) is an intracellular enzyme, which catalyzes xylose to xylitol conversion in the microbes. It has potential biotechnological applications in the manufacture of various commercially important specialty bioproducts including xylitol. This study aimed to prepare XR from adapted strain of Candida tropicalis and to characterize it. The XR was isolated from adapted C. tropicalis, cultivated on Meranti wood sawdust hemicellulosic hydrolysate (MWSHH) based medium, via ultrasonication, and was characterized based on enzyme activity, stability, and kinetic parameters. It was specific to NADPH with an activity of 11.16 U/mL. The enzyme was stable at pH 5-7 and temperature of 25-40 degrees C for 24 h and retained above 95 % of its original activity after 4 months of storage at -80 degrees C. The K m of XR for xylose and NADPH were 81.78 mM and 7.29 MUM while the V max for them were 178.57 and 12.5 MUM/min, respectively. The high V max and low K m values of XR for xylose reflect a highly productive reaction among XR and xylose. MWSHH can be a promising xylose source for XR preparation from yeast. PMID- 25300603 TI - Agarose gel purification of PCR products for denaturing gradient gel electrophoresis results in GC-clamp deletion. AB - The 16S ribosomal RNA (rRNA) gene of marine archaeal samples was amplified using a nested PCR approach, and the V3 region of 16S rRNA gene of crab gut microbiota (CGM) was amplified using the V3 universal primer pair with a guanine and cytosine (GC)-clamp. Unpurified PCR products (UPPs), products purified from reaction solution (PPFSs), and products purified from gel (PPFGs) of above two DNA samples were used for denaturing gradient gel electrophoresis (DGGE) analysis, respectively. In contrast to almost identical band patterns shared by both the UPP and PPFS, the PPFGs were barely observed on the DGGE gel for both the marine archaea and CGM samples. Both PPFS and PPFG of CGM V3 regions were subjected to cloning. A small amount of positive clones was obtained for PPFS, but no positive clones were observed for PPFG. The melt curve and direct sequencing analysis of PPFS and PPFG of E. coli V3 region indicated that the Tm value of PPFG (82.35 +/- 0.19 degrees C) was less than that of PPFS (83.81 +/- 0.11 degrees C), and the number of shorter GC-clamps was significant higher in PPFG than in PPFS. The ultraviolet exposure experiment indicated that the ultraviolet was not responsible for the deletion of the GC-clamps. We conclude that the gel purification method is not suitable for DGGE PCR products or even other GC-rich DNA samples. PMID- 25300604 TI - Structural model of ubiquitin transfer onto an artificial RING finger as an E3 ligase. AB - The artificial WSTF PHD_EL5 RING finger was designed via "alpha-helical region substitution", and its structural model for the attachment of activated ubiquitin has been demonstrated. Chemical modifications of Cys residues, the circular dichroism spectra, and substrate-independent ubiquitination assays illustrated that the WSTF PHD_EL5 RING finger has E3 activity, and it is ubiquitinated via Lys14. Homology modeling calculations revealed that the WSTF PHD_EL5 RING finger possesses a classical RING fold for specific E2-E3 binding. The docking poses of the WSTF PHD_EL5 RING finger with the UbcH5b-ubiquitin conjugate provided insight into its functional E2 interaction and development of ubiquitination at the atomic level. The structural model of the artificial WSTF PHD_EL5 RING finger proposed by the present work is useful and may help to extend the strategy of alpha-helical region substitution. PMID- 25300605 TI - Unusually high fluorescence quantum yield of a homopolyfluorenylazomethine- towards a universal fluorophore. AB - The absolute fluorescence quantum yield (Phifl) of a polyfluorenyl azomethine homopolymer was measured as a function of solvent polarity. The solvent induced and temperature dependent fluorescence of the homopolymer were also investigated and they were compared to the corresponding monomer and copolymer. The Phifl of the homopolymer was consistent (45-70%), regardless of solvent polarity with Stokes shifts up to 7460 cm(-1) in ethanol. In contrast, the Phifl of its corresponding monomer decreased from 60% in ethanol to 1% in toluene, whereas a Phifl < 5% for its analogous copolymer was measured. Moderate fluorescence yields (Phifl ~ 25%) were also possible in thin film when co-depositing the homopolymer with PMMA. Cryofluorescence was used to probe the excited state deactivation modes. Deactivation by internal conversion was found to compete with fluorescence. The fluorescence deactivation pathways of the homopolymer and its corresponding monomer could be suppressed at 77 K, resulting in fluorescence turn on. Both fluorophores were found to detect nitroaromatics. PMID- 25300606 TI - Applicability of the ACOSOG Z0011 criteria in women with high-risk node-positive breast cancer undergoing breast conserving surgery. AB - BACKGROUND: The relevance of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial in patients with high-risk breast cancer has been questioned. We hypothesize that Z0011 applies to women with HER2-positive disease (HER2+), triple-negative breast cancer (TNBC), and/or age <50 years at diagnosis (YA). METHODS: Women with node-positive HER2+, TNBC, or YA were identified from a prospectively maintained database. Patients were grouped based on Z0011 trial eligibility criteria into those meeting criteria (eligible) and those who did not (ineligible). Patient and tumor characteristics were compared; survival of those meeting Z0011 criteria was determined. RESULTS: We identified 186 node-positive women undergoing lumpectomy/radiation for high-risk breast cancer: 57 of 186 (31 %) HER2+, 55 of 186 (30 %) TNBC, 74 of 186 (40 %) YA. Overall, 125 of 186 (67 %) met Z0011 criteria. HER2-positivity was associated with the lowest rate of ineligibility compared with TNBC and YA (16 vs. 53 and 31 %, respectively, p < 0.01). Larger tumor size, high grade, extranodal extension, and high Ki67 were associated with Z0011 ineligibility. Among those who were eligible, 105 of 125 (84 %) had ALND and 48 of 125 (38 %) had involvement of nonsentinel nodes (NSLN); median number of NSLNs involved was one (range 1-3). With median follow-up of 5.5 years, there was no difference in survival between those who had ALND and those who did not. After patients with clinically palpable nodes were excluded, 125 of 149 (84 %) met criteria. CONCLUSIONS: The Z0011 trial eligibility requirements apply to a significant proportion of patients with HER2+, TNBC, and YA. ALND can be avoided in 67 % node-positive cases and in 84 % of those with clinically negative nodes. PMID- 25300607 TI - Breast reconstruction and revision surgery for implant-associated breast deformities using porcine acellular dermal matrix: a multicenter study of 156 cases. AB - BACKGROUND: Acellular dermal matrix is increasingly used as caudolateral coverage for breast implants in immediate breast reconstruction after skin-sparing mastectomy or in the correction of implant-associated breast deformities. Matrices of human, bovine, and porcine origin are available. The purpose of this retrospective multicenter study was to report experiences with porcine acellular dermal matrices, as only limited data can be found in the literature. METHODS: In the hospital databases of five institutions, 127 patients were identified who underwent breast reconstructions in 156 breasts using an acellular porcine dermal matrix. Medical records were reviewed. Patients were divided into three groups: immediate expander-implant or direct to implant reconstructions (n = 98), delayed expander-implant reconstructions (n = 14), and revision surgery for implant associated breast deformities (n = 44). RESULTS: With a mean follow-up of 19.6 months, total major complication rate was 7.1 %: implant loss (3.2 %), skin flap necrosis (2.6 %), delayed skin healing (2.6 %), hematoma (1.9 %), seroma (1.3 %), infection (0.6 %), and capsular contracture (0.6 %). Total minor complication rate was 22.9 %, with seroma being the most frequent complication (19.2 %). In the group of immediate breast reconstructions, 20.4 % of the breasts had received radiotherapy in the past. These patients exhibited a significantly higher rate of seroma than patients without prior radiotherapy (35.0 vs. 14.9 %, p = 0.031). CONCLUSIONS: Complication rates using porcine acellular dermal matrix in breast reconstruction are comparable to complication rates reported in studies using human acellular dermal matrices. Thus, porcine acellular dermal matrices can safely be applied in breast reconstructive surgery. PMID- 25300608 TI - Abdominal desmoplastic small round cell tumor: multimodal treatment combining chemotherapy, surgery, and radiotherapy is the best option. AB - BACKGROUND: With nearly 450 cases reported since 1991, desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor typically arising in adolescent and young adult white men. With no large series described, the best therapeutic strategy remains unclear. METHODS: All consecutive patients treated in our tertiary care center between January 1991 and December 2013 for a DSRCT were retrospectively studied. RESULTS: Thirty-eight patients with a median age of 27 years (range 13-57 years) were identified; 71 % were men. At the time of diagnosis, 47.4 % patients had extraperitoneal metastases (EPM): 78 % were located in the liver and 11 % were located in the lungs. Fourteen patients (37 %) were treated exclusively with systemic chemotherapy, with a median survival of 21.1 months. Twenty-three patients underwent surgery, 12 (52 %) experienced complete removal of all macroscopic disease, 5 (21.7 %) received additional intraperitoneal chemotherapy, and 7 (30 %) received postoperative whole abdominopelvic radiotherapy (WAP RT). With a median follow-up of 59.9 months, the median survival was 37.7 months, and the median disease-free survival was 15.5 months. The factors predictive of 3-year overall survival were the absence of EPM, complete surgical resection, postoperative WAP RT, and postoperative chemotherapy. The intraperitoneal chemotherapy had no impact on overall survival. CONCLUSIONS: DSRCT is a rare and aggressive disease. In patients without EPM, a multimodal treatment combining systemic chemotherapy, complete macroscopic resection, and postoperative WAP RT could enable prolonged survival. No benefit of surgery was demonstrated for patients with EPM. The value of associated hyperthermic intraperitoneal chemotherapy remains unproven. PMID- 25300609 TI - Personalizing the approach to retroperitoneal soft tissue sarcoma: histology specific patterns of failure and postrelapse outcome after primary extended resection. AB - PURPOSE: To explore patterns of failure and postrelapse outcome of patients with retroperitoneal sarcoma primarily treated by extended resection. METHODS: All consecutive patients with primary retroperitoneal sarcoma, treated between January 2002 and December 2011 at two European sarcoma centers were included. Five-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastases (DM) were calculated. Multivariate analyses for OS and CCI of LR and DM were performed. Postrelapse OS was investigated. RESULTS: A total of 377 patients were identified. Median follow-up from the time of primary surgery was 44 months [interquartile range (IQR) 27-82]. Five-year OS was 64 % [95 % confidence interval (CI) 0.588, 0710]. CCI of LR and DM were 23.6 % (95 % CI 18.9, 29.4) and 21.9 % (95 % CI 17.6, 27.3), respectively. OS, CCI of LR and DM were 87, 18 % and 0 for well-differentiated liposarcoma; 54, 44 and 9 % for grade II dedifferentiated liposarcoma; 41,33, and 44 % for grade III dedifferentiated liposarcoma; 58, 5, and 55 % for leiomyosarcoma; and 85, 4, and 17 % for solitary fibrous tumor, respectively. Seventy-six patients developed LR. Median postrelapse follow-up was 27 months (IQR 10-58). Twenty-one patients (27 %) underwent a second surgical resection (complete in 18), while 55 (73 %) did not (22 multifocal, 17 inoperable, 16 other causes). Median postrelapse OS was 17 months (IQR 7-31). Well-differentiated liposarcoma histology and disease-free interval predicted postrelapse OS, while surgical resection did not. CONCLUSIONS: When primary extended surgery limits LR, histologic subtype and grade determine the outcome. At recurrence, a second surgery is of limited benefit. PMID- 25300610 TI - The prevalence of diabetes-related complications and multimorbidity in the population with type 2 diabetes mellitus in the Basque Country. AB - BACKGROUND: Type 2 diabetes mellitus is associated with a diverse range of pathologies. The aim of the study was to determine the incidence of diabetes related complications, the prevalence of coexistent chronic conditions and to report multimorbidity in people with type 2 diabetes living in the Basque Country. METHODS: Administrative databases, in four cross sections (annually from 2007 to 2011) were consulted to analyse 149,015 individual records from patients aged >= 35 years with type 2 diabetes mellitus. The data observed were: age, sex, diabetes-related complications (annual rates of acute myocardial infarction, major amputations and avoidable hospitalisations), diabetes-related pathologies (prevalence of ischaemic heart disease, renal failure, stroke, heart failure, peripheral neuropathy, foot ulcers and diabetic retinopathy) and other unrelated pathologies (44 diseases). RESULTS: The annual incidence for each condition progressively decreased during the four-year period: acute myocardial infarction (0.47 to 0.40%), major amputations (0.10 to 0.08%), and avoidable hospitalisations (5.85 to 5.5%). The prevalence for diabetes-related chronic pathologies was: ischaemic heart disease (11.5%), renal failure (8.4%), stroke (7.0%), heart failure (4.3%), peripheral neuropathy (1.3%), foot ulcers (2.0%) and diabetic retinopathy (7.2%). The prevalence of multimorbidity was 90.4%. The highest prevalence for other chronic conditions was 73.7% for hypertension, 13.8% for dyspepsia and 12.7% for anxiety. CONCLUSIONS: In the type 2 diabetes mellitus population living in the Basque Country, incidence rates of diabetes complications are not as high as in other places. However, they present a high prevalence of diabetes related and unrelated diseases. Multimorbidity is very common in this group, and is a factor to be taken into account to ensure correct clinical management. PMID- 25300611 TI - Minimally invasive surgery treatment for the patients with spontaneous supratentorial intracerebral hemorrhage (MISTICH): protocol of a multi-center randomized controlled trial. AB - BACKGROUND: The choice of surgical or conservative treatment for patients with spontaneous intracerebral hemorrhage is controversial. Some minimally invasive treatments have been applied to hematoma evacuation and could improve prognosis to some extent. Up to now, studies on minimally invasive surgery for patients with spontaneous intracerebral hemorrhage are still insufficient. DESIGN: The MISTICH is a multi-center, prospective, randomized, assessor-blinded, parallel group, controlled clinical trial. 2448 eligible patients will be assigned to neuroendoscopy group, stereotactic aspiration group and craniotomy group randomly. Patients will receive the corresponding surgery based on the result of randomization. Surgeries will be performed by well-trained surgeons and standard medical treatment will be given to all patients. Patients will be followed up at 7 days, 30 days, and 6 months. The primary outcome of this study is unfavorable outcome at 6 months. Secondary outcomes include: mortality at 30 days and 6 months after surgery; neurological functional status of 6 months after surgery; complications including rebleeding, ischemic stroke and intracranial infection; days of hospitalization. DISCUSSION: The MISTICH trial is a randomized controlled trial designed to determine whether minimally invasive surgeries could improve the prognosis for patients with spontaneous intracerebral hemorrhage compared with craniotomy. (ChiCTR-TRC-12002026. Registered 23 March 2012). PMID- 25300612 TI - Walking in the shoes of patients, not just in their genes: a patient-centered approach to genomic medicine. AB - Genomic technologies are increasing the precision with which clinicians can assess an individual patient's risk for developing diseases and identify which patients are likely to benefit from specific treatments. Also advocating for a shift away from a one-size-fits-all approach is the growing emphasis on "patient centered" care. Using examples from breast cancer, we make a case for why, in order to optimize patient health outcomes, genomic medicine will need to be practiced within a patient-centered framework. We present a six-function conceptual framework for patient-centered care and discuss findings from a national survey evaluating the patient-centeredness of care delivered in the USA. PMID- 25300613 TI - Capturing Patient-Reported Outcome (PRO) Data Electronically: The Past, Present, and Promise of ePRO Measurement in Clinical Trials. AB - Patient-reported outcomes (PROs) are an important means of evaluating the treatment benefit of new medical products. It is recognized that PRO measures should be used when assessing concepts best known by the patient or best measured from the patient's perspective. As a result, there is growing emphasis on well defined and reliable PRO measures. In addition, advances in technology have significantly increased electronic PRO (ePRO) data collection capabilities and options in clinical trials. The movement from paper-based to ePRO data capture has enhanced the integrity and accuracy of clinical trial data and is encouraged by regulators. A primary distinction in the types of ePRO platforms is between telephone-based interactive voice response systems and screen-based systems. Handheld touchscreen-based devices have become the mainstay for remote (i.e., off site, unsupervised) PRO data collection in clinical trials. The conventional approach is to provide study subjects with a handheld device with a device-based proprietary software program. However, an emerging alternative for clinical trials is called bring your own device (BYOD). Leveraging study subjects' own Internet-enabled mobile devices for remote PRO data collection (via a downloadable app or a Web-based data collection portal) has become possible due to the widespread use of personal smartphones and tablets. However, there are a number of scientific and operational issues that must be addressed before BYOD can be routinely considered as a practical alternative to conventional ePRO data collection methods. Nevertheless, the future for ePRO data collection is bright and the promise of BYOD opens a new chapter in its evolution. PMID- 25300614 TI - VEGF mRNA assessment in human pterygium: a new 'scope' for a future hope. AB - PURPOSE: The lack of powerful evidence to support the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in human pterygium can be attributed to incomplete VEGF expression assessment by restrictive use of immunohistochemistry only and failure to use the molecular methods able to confirm immunohistochemical findings. By adding at least one more sensitive method to assess human pterygium VEGF expression, a more accurate selection of patients for bevacizumab therapy could be done and this would improve the efficacy of anti-VEGF therapy in human pterygium. METHODS: We assessed VEGF mRNA amplification on paraffin-embedded specimens by applying the RNAscope method for the first time in human pterygium, an in situ hybridization-based technique able to detect VEGF mRNA as a single gene copy on paraffin-embedded samples. RESULTS: Heterogeneous VEGF mRNA distribution and amplification inside the epithelial compartment of human pterygium were observed. Despite previous reports concerning the immunohistochemical expression of VEGF in the human pterygium fibrovascular compartment, no stromal components were characterized by VEGF mRNA amplification assessed by in situ hybridization in our study. A higher amplification score was observed in epithelium from recurrent pterygium, especially located in the basal and suprabasal epithelial cells. CONCLUSIONS: Based on our findings we consider that in situ hybridization assessment of VEGF for human pterygium specimens can be a useful tool for reconsidering the selection of pterygium patients to be enrolled in anti-VEGF therapy. PMID- 25300615 TI - The wage of fame: how non-epistemic motives have enabled the phenomenal success of modern science. AB - This paper ventures an economic view of modern science. It points out how science works as a closed economy of attention where researchers invest their own attention in order to get the attention of fellow researchers. Attention thus enters economy in two properties: (1) as a scarce resource energising scientific production and (2) as a means of gratification rewarding the effort of the working scientist. Economising on attention as a scarce resource is another expression of thought economy. The income of expert attention is what gives rise to reputation, renown, prominence and eventually fame. By its being conceived as a closed economy of attention, science shows to be capable of self-organising a tendency towards overall efficiency and thus towards collective rationality. PMID- 25300616 TI - Inflammation-driven carcinogenesis is mediated through STING. AB - Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by mechanisms that are not well understood. Here we demonstrate that mutagenic 7,12 dimethylbenz(a)anthracene (DMBA), cisplatin and etoposide induce nuclear DNA leakage into the cytosol that intrinsically activates stimulator of interferon genes (STING)-dependent cytokine production. Inflammatory cytokine levels are subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING(-/-) mice, or wild-type mice adoptively transferred with STING(-/-) bone marrow, are almost completely resistant to DMBA-induced skin carcinogenesis compared with their wild-type counterparts. Our data establish a role for STING in the control of cancer, shed significant insight into the causes of inflammation-driven carcinogenesis and may provide a basis for therapeutic strategies to help prevent malignant disease. PMID- 25300617 TI - Disrupted hyaluronan binding protein 1 (HABP1) expression: one of the key mediator for ovarian dysfunction in polycystic ovary rat. AB - Proper follicular development is crucial for cumulus-oocyte complex (COC) maturation, ovulation and luteinisation. All these ovarian processes are regulated by finely tuned rapid tissue remodeling that involves hyaluronan and interconnecting hyaladherins-rich extracellular matrix synthesis and its breakdown by various proteinase systems like matrix metalloproteinase (MMP). Disrupted tissue remodeling machinery can result into pathophysiologies like atretic follicular cysts formation in polycystic ovary syndrome (PCOS). In present study, we employ superovulated (SO) and polycystic ovary (PCO) rat models and demonstrate that on contrary to SO, PCO rat ovary illustrates abnormal follicular morphology with differential levels of various ovarian factors [like HA (hyaluronan), TSG-6 (TNF-alpha-stimulated gene/protein 6), PTX-3 (pentraxin 3), HABP1 (hyaluronan binding protein 1), MMP2 (matrix metalloproteinase), MT1 MMP (membrane type 1-matrix metalloproteinase) and COX2 (Cyclooxygenase-2)] along with hyperactivities of gelatinases (like MMP9 and -2). Besides cultured COC expansion is blocked by anti-HABP1 antibody treatment showing reduced HABP1 expression. Overall, as MT1-MMP has inverse relation with HABP1 level and direct effect on MMP2 activity, the observations from current in vivo and in vitro studies indicate that disrupted ovarian HABP1 along with concurrent altered expression and hyperactivation of related MMPs can lead to abnormal follicular maturation resulting into ovarian dysfunction in PCO rat. PMID- 25300618 TI - Melanin nanoparticles (MNPs) provide protection against whole-body gamma irradiation in mice via restoration of hematopoietic tissues. AB - During radiotherapy, ionizing irradiation interacts with biological systems to produce free radicals, which attack various cellular components. The hematopoietic system is easily recognized to be radiosensitive and its damage may be severe. Melanin nanoparticles (MNPs) act as free radical scavengers prepared by polymerization of dopamine. In this study, a total of 110 male BALB/C mice were divided into five equal groups. Each group contained 22 mice. Mice of group A did not receive MNPs or irradiation (control group), group B was injected intraperitoneally (i.p.) with 50 mg/kg MNPs. Mice of group C and D were exposed to a dose of 7 Gy gamma-irradiation and injected with the same dose of MNPs as in group B either 30 min pre- or post-irradiation, and group E was exposed to a dose of 7 Gy gamma-irradiation only. The impact of MNPs on peripheral blood, spleen, and DNA damage induced by irradiation was evaluated by blood count, histopathology of the spleen, and comet assay for the DNA in the bone marrow at 1, 4, 8, and 12 days post-irradiation. Results of group E compared with control group (A) showed a significant depression in complete blood count. Additionally, histopathological observation showed the absence of megakaryocytes with delayed time post-irradiation, deposition of eosinophilic protein of their spleen appeared, as well as a remarkable decrease in spleen size was observed. Moreover, gamma-irradiation-induced DNA damage as can be inferred from a significant increase by about 5-10 folds in all comet parameters (% of DNA, tail length, tail moment, and olive moment) in the DNA of the bone marrow. In contrast, pre-post treatment with MNPs protected hematopoietic tissues against radiation damage, and therefore, enhanced the survival of mice with 40 % in groups (C&D) compared with 10 % to group (E) till 30 days post-irradiation. In conclusion, these results demonstrated that synthetic MNPs provide significant radioprotection to the hematopoietic tissues. PMID- 25300619 TI - TGF-beta-induced hCG-beta regulates redox homeostasis in glioma cells. AB - Transforming growth factor (TGF-beta) is associated with the progression of glioblastoma multiforme (GBM)-the most malignant of brain tumors. Since there is a structural homology between TGF-beta and human chorionic gonadotropin (hCG) and as both TGF-beta and hCG-beta are known regulators of oxidative stress and survival responses in a variety of tumors, the role of TGF-beta in the regulation of hCG-beta and its consequences on redox modulation of glioblastoma cells was investigated. A heightened hCG-beta level was observed in GBM tumors. TGF-beta treatment increased hCG-beta expression in glioma cell lines, and this heightened hCG-beta was found to regulate redox homeostasis in TGF-beta-treated glioma cells, as siRNA-mediated knockdown of hCG-beta (i) elevated reactive oxygen species (ROS) generation, (ii) decreased thioredoxin Trx1 expression and thioredoxin reductase (TrxR) activity, and (iii) abrogated expression of TP53 induced glycolysis and apoptosis regulator (TIGAR). Silencing of hCG-beta abrogated Smad2/3 levels, suggesting the existence of TGF-beta-hCG-beta cross talk in glioma cells. siRNA-mediated inhibition of elevated TIGAR levels in TGF beta-treated glioma cells was accompanied by an increase in ROS levels. As a farnesyltransferase inhibitor, Manumycin is known to induce glioma cell apoptosis in a ROS-dependent manner, and we investigated whether Manumycin could induce apoptosis in TGF-beta-treated cells with elevated hCG-beta exhibiting ROS scavenging property. Manumycin-induced apoptosis in TGF-beta-treated cells was accompanied by elevated ROS levels and decreased expression of hCG-beta, Trx1, Smad2/3, and TIGAR. These findings indicate the existence of a previously unknown TGF-beta-hCG-beta link that regulates redox homeostasis in glioma cells. PMID- 25300620 TI - Regulation and biological function of a flagellar glucose transporter in Leishmania mexicana: a potential glucose sensor. AB - In Leishmania mexicana parasites, a unique glucose transporter, LmxGT1, is selectively targeted to the flagellar membrane, suggesting a possible sensory role that is often associated with ciliary membrane proteins. Expression of LmxGT1 is down-regulated ~20-fold by increasing cell density but is up-regulated ~50-fold by depleting glucose from the medium, and the permease is strongly down regulated when flagellated insect-stage promastigotes invade mammalian macrophages and transform into intracellular amastigotes. Regulation of LmxGT1 expression by glucose and during the lifecycle operates at the level of protein stability. Significantly, a ?lmxgt1 null mutant, grown in abundant glucose, undergoes catastrophic loss of viability when parasites deplete glucose from the medium, a property not exhibited by wild-type or add-back lines. These results suggest that LmxGT1 may function as a glucose sensor that allows parasites to enter the stationary phase when they deplete glucose and that in the absence of this sensor, parasites do not maintain viability when they run out of glucose. However, alternate roles for LmxGT1 in monitoring glucose availability are considered. The absence of known sensory receptors with defined ligands and biologic functions in Leishmania and related kinetoplastid parasites underscores the potential significance of these observations. PMID- 25300621 TI - Adipose-derived protein omentin prevents neointimal formation after arterial injury. AB - Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild-type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad-OMT) or control beta-gal and subjected to arterial wire injury. Ad-OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin-mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat-specific human omentin transgenic (OMT-TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT-TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT-TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK-dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders. PMID- 25300622 TI - Is there enough evidence to use bisphosphonates in HIV-infected patients? A systematic review and meta-analysis. AB - An increased prevalence of osteopenia and osteoporosis has been observed in HIV infected cohorts. We investigated the effect of bisphosphonates on bone mineral density in adults with HIV infection. Outcomes of interest were bone mineral density changes measured by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, and total hip, and adverse events. Data were pooled using the fixed effects model. We identified eight randomized controlled trials meeting our inclusion criteria, involving 328 participants. Five trials compared alendronate with placebo or no intervention; in three trials the intervention arm received zoledronate. A significant increase in bone mineral density at the lumbar spine was observed in the bisphosphonate group at 48 weeks (MD: 2.84%; 95% CI: 2.11 3.57) and 96 weeks (MD: 6.76%; 95% CI: 4.98-8.54); analogously, bisphosphonates were associated with an increase in total hip bone mineral density at 48 weeks (MD: 2.12%; 95% CI: 1.43-2.81) and 96 weeks (MD: 3.2%; 95% CI: 1.52-4.88). Bisphosphonates were generally well tolerated; no drug-related withdrawals were reported in the five randomized controlled trials assessing alendronate, whereas two patients out of 104 receiving zoledronate experienced acute-phase reactions. In conclusion, administration of oral and intravenous bisphosphonates was associated with increased bone mineral density at the lumbar spine and total hip over two years in HIV-positive patients. However, none of the included trials were long enough to detect the impact of bisphosphonates on a clinically important outcome such as fracture risk. Larger studies with extended follow-up are warranted. PMID- 25300623 TI - Minority HIV-1 drug-resistant mutations and prevention of mother-to-child transmission: perspectives for resource-limited countries. AB - The detection and clinical significance of HIV-1 minority drug-resistant variants is a major topic of current HIV research. Whereas much attention has been placed on the clinical impact of minority drug-resistant variants in patients initiating antiretroviral therapy, their possible influence on the effectiveness of antiretroviral therapy following prevention of mother-to-child transmission strategies in resource-limited settings remains largely unexplored. This review outlines the clinical significance and detection of minority drug-resistant variants, focusing primarily on studies of minority variants in the context of prevention of mother-to-child transmission and their possible influence on current regimens, especially those available in resource-limited countries. The clinical impact of minority nevirapine-resistant variants that arise in the context of prevention of mother-to-child transmission, for example, is an important factor to consider when these women initiate antiretroviral therapy that may include nevirapine or efavirenz. Minority nonnucleoside reverse transcriptase inhibitor-resistant variants have been associated with treatment failure in women exposed to single-dose nevirapine. In countries like South Africa, with its longstanding use of single-dose nevirapine, this question is relevant as it is for other resource-limited countries where single-dose nevirapine is used. In the same context, various other minority drug-resistant variants (e.g. Y181C, K65R and thymidine analogue mutations etc.) are discussed. The field of next generation sequencing is very dynamic, with rapid improvements on present technologies and the introduction of novel technologies as discussed in this review. As the impact of minority drug-resistant variants in the setting of prevention of mother-to-child transmission becomes more evident, guidelines for this, especially in resource-limited countries, will need revision in order to optimize the clinical benefit from future antiretroviral therapy. PMID- 25300624 TI - [On the retirement of Prof. Dr. Michael Molls -- director of the Department of Radiation Oncology, University of Munich]. PMID- 25300625 TI - Radiotherapy for SMAD4-negative musculoskeletal lesions from pancreatic cancer: case report and review. AB - BACKGROUND: Pancreatic cancer (PC) predominantly metastasizes to liver, lung, and peritoneum. Metastatic disease correlates with SMAD4 status. Musculoskeletal metastases (MSM) are rare in pancreatic cancer. The role of radiation therapy (RT) in patients with musculoskeletal metastases is not clear. METHODS: We present a case of a woman with musculoskeletal metastases of PC evolving 4 years after Whipple's procedure and adjuvant therapy. She was treated with RT for 7 MSM. Radiation dose was 15-45 Gy, delivered in doses of 2.5-5 Gy per fraction. SMAD4 status was examined by immunohistochemistry. Furthermore we undertook a review of the literature to examine the value of RT in musculoskeletal metastasis of PC. RESULTS: In the presented patient we treated 7 MSM of SMAD4-mutant PC with RT. RT achieved local control in 4 of the 7 MSM. At the resection margin of one MSM recurrent tumor was observed after RT. The status of one MSM was unknown and one MSM showed local progression. Follow-up revealed progression of pain in 1 of the 7 MSM. Except of hyperpigmentation no side effects occurred. There was no dose-correlation effect on tumor control observed. A review of the literature showed that a musculoskeletotrophic phenotype of metastases is rare in PC. MSM of PC are rapidly increasing soft tissue masses causing pain and loss of anatomical function. RT as a treatment option for musculoskeletal metastasis is described in the current literature in only 2 cases. Radiotherapy aims to achieve local control, pain relief, and to maintain anatomical function. CONCLUSION: Radiotherapy is an effective and well-tolerated approach for multiple musculoskeletal metastases of PC. PMID- 25300626 TI - OPRM1 receptor as new biomarker to help the prediction of post mastectomy pain and recurrence in breast cancer. AB - Breast cancer is the most common type of cancer among women worldwide. Short-term postsurgical recovery is complicated by many factors, including imbalanced inflammatory and immune response, acute pain associated with functional impairment, and chronic postmastectomy pain (CPMP), developed by about 25-60% of patients. Opioids, most common drugs used for treatment of cancer pain, are immunosuppressive, and therefore, they might directly and/or indirectly influence long-term cancer recurrence. Moreover, they also produce endocrinopathy, which consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic pituitary-adrenal axis dysfunction. The interindividual variability in both CPMP and opioid response is believed to be largely underlined by genetic variability in the gene locus for MU-opioid receptor (OPRM1) that modulates opioid pharmacodynamics. For this reason, OPRM1 genotype may play a key role both in short-term postmastectomy outcome and in long-term follow-up, becoming a new biomarker for breast cancer recurrence in patients suffering from chronic postmastectomy pain managed by opioid therapy. Hence OPRM1 might be used in near future to customize the opioid therapy, avoiding not only opioid side effects but also the disease progression. In this review we evaluate the literature state of the art on this topic and possible steps towards obtaining the safest individualized postmastectomy analgesic therapy. Therefore, a personalized pain treatment strategy might be useful to both manage pain and control cancer disease progression. PMID- 25300627 TI - Setting mechanical ventilation in ARDS patients during VV-ECMO: where are we? AB - Currently, many centers use venovenous extracorporeal membrane oxygenation (VV ECMO) as an adjunctive means of gas exchange to mechanical ventilation (MV) in patients with severe ARDS and refractory hypoxemia. One of the most interesting and controversial issues in the management of these patients is how to set the ventilatory strategy. The support provided by VV-ECMO makes the balance between risks and benefits of MV remarkably different from the conventional setting, since the need for MV to facilitate oxygenation and carbon dioxide clearance is greatly reduced or abolished during VV-ECMO. Therefore, the risks of causing ventilator-induced lung injury are of foremost importance; however, the issue of the optimum ventilatory strategy during VV-ECMO has not received sufficient consideration. This paper will describe the diverse MV strategies applied during VV-ECMO in clinical practice and will highlight specific pathophysiological considerations that are crucial in the process of defining optimal ventilation settings in patients with ARDS supported with VV-ECMO. PMID- 25300628 TI - Tracheostomy, swallowing disorders and rehabilitation: it is never too late. PMID- 25300629 TI - The transcranial Color-Coded Duplex Sonography Operator Competences. PMID- 25300630 TI - Temporal changes in the external validity of clinical trials: asymptomatic carotid artery stenosis. PMID- 25300631 TI - Deep eutectic solvents (DESs) and their applications. PMID- 25300633 TI - Development of fluorescence-based liposome immunoassay for detection of Cronobacter muytjensii in pure culture. AB - Cronobacter spp. are important foodborne pathogens that carry a very high risk of infection to neonates as well as immunocompromised individuals. In the present study, fluorescence-based liposome immunoassay was developed as a new sensitive and rapid diagnostic system for detection of Cronobacter muytjensii (C. muytjensii). Liposomes (size, 206 nm) used in this study were made from cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1 glycerol)], and sulforhodamine B (SRB). The outer surface of liposome was conjugated with rabbit anti-C. muytjensii IgG in order to develop immunoliposome. The immunoliposome was incubated with C. muytjensii, which was coated on a 96 well plate. Immunoliposomes bound to C. muytjensii were lysed with 30 mM octyl beta-D-glucopyranoside, after which the SRB fluorescence signal was measured at an excitation wavelength of 550 nm and emission wavelength of 585 nm. The signal was directly proportional to the amount of bacterial cells in the test sample. The developed fluorescence-based liposome immunoassay was confirmed to be highly specific to C. muytjensii with a detection limit of 6.3 * 10(4) CFU ml(-1) in pure culture as well as sensitive, efficient, and rapid when compared to culture based methods. Based on its rapid efficiency and low cost, this fluorescence based liposome immunoassay may be used to develop diagnostic kits for C. muytjensii detection. PMID- 25300634 TI - New perspectives for the diagnosis, control, treatment, and prevention of strangles in horses. AB - Strangles, characterized by abscessation of the lymph nodes of the head and neck, is the most frequently diagnosed infectious disease of horses worldwide. The persistence of the causative agent, Streptococcus equi, in a proportion of convalescent horses plays a critical role in the recurrence and spread of disease. Recent research has led to the development of effective diagnostic tests that assist the eradication of S equi from local horse populations. This article describes how these advances have been made and provides advice to assist the resolution and prevention of outbreaks. New perspectives on preventative vaccines and therapeutic interventions are discussed. PMID- 25300635 TI - Equine herpesvirus 1 myeloencephalopathy. AB - Equine myeloencephalopathy (EHM), an uncommon manifestation of equine herpesvirus 1 (EHV-1) infection, can cause devastating losses on individual farms, boarding stables, veterinary hospitals, and show and racing venues. An improved understanding of EHM has emerged from experimental studies and from data collected during field outbreaks at riding schools, racetracks, horse shows, and veterinary hospitals throughout North America and Europe. These outbreaks have highlighted the contagious nature of EHV-1 and have prompted a reevaluation of diagnostic procedures, treatment modalities, preventative measures, and biosecurity protocols for this disease. This article focuses on recent data related to the cause, epidemiology, pathogenesis, immunity, diagnosis, treatment, and prevention of EHV-1 infection with emphasis on EHM. PMID- 25300636 TI - Lawsonia intracellularis and equine proliferative enteropathy. AB - Lawsonia intracellularis is the etiologic agent for equine proliferative enteropathy (EPE), which typically affects weanling and yearling horses. In North America, EPE cases often occur between August and January, although cases outside of this time frame have been reported. Clinical signs of EPE are usually nonspecific and include lethargy, pyrexia, anorexia, peripheral edema, weight loss, colic, and diarrhea. Diagnosis is based on the presence of hypoproteinemia and hypoalbuminemia along with clinical signs and positive commercial serologic and/or molecular testing. Treatment requires the use of antimicrobials with good intracellular penetration and supportive care to prevent or decrease secondary complications. PMID- 25300637 TI - Equine piroplasmosis. AB - Equine piroplasmosis, caused by the parasites Theileria equi and Babesia caballi, is a globally important disease, affecting a large percentage of the world's horses. This article serves as a review of these divergent parasites. Discussed are the clinical presentation of disease, diagnosis, and treatment. Special attention is given to the current disease status specifically in North America. PMID- 25300639 TI - Recent development in bioinformatics for utilizing omics data. PMID- 25300640 TI - Laryngitis. PMID- 25300638 TI - National trends in hospitalization and mortality rates for patients with HIV, HCV, or HIV/HCV coinfection from 1996-2010 in the United States: a cross sectional study. AB - BACKGROUND: The comparative impact of chronic viral monoinfection versus coinfection on inpatient outcomes and health care utilization is relatively unknown. This study examined trends, inpatient utilization, and hospital outcomes for patients with HIV, HCV, or HIV/HCV coinfection. METHODS: Data were from the 1996-2010 National Hospital Discharge Surveys. Hospitalizations with primary ICD 9-CM codes for HIV or HCV were included for HIV and HCV monoinfection, respectfully. Coinfection included both HIV and HCV codes. Demographic characteristics, select comorbidities, procedural interventions, average hospital length of stay (LOS), and discharge status were compared by infection status (HIV, HCV, HIV/HCV). Annual disease estimates and survey weights were used to generate hospitalization rates. RESULTS: ~6.6 million hospitalizations occurred in patients with HIV (39%), HCV (56%), or HIV/HCV (5%). The hospitalization rate (hospitalizations per 100 persons with infection) decreased in the HIV group (29.8 in 1996; 5.3 in 2010), decreased in the HIV/HCV group (2.0 in 1996; 1.5 in 2010), yet increased in the HCV group (0.2 in 1996; 0.9 in 2010). Median LOS from 1996 to 2010 (days, interquartile range) decreased in all groups: HIV, 6 (3-10) to 4 (3-8); HCV, 5 (3-9) to 4 (2-6); HIV/HCV, 6 (4-11) to 4 (2-7). Age-adjusted mortality rates decreased for all three groups. The rate of decline was least pronounced for those with HCV monoinfection. CONCLUSION: Hospitalizations have declined more rapidly for patients with HIV infection (including HIV/HCV coinfection) than for patients with HCV infection. This growing disparity between HIV and HCV underscores the need to allocate more resources to HCV care in hopes that similar large-scale improvements can also be accomplished for patients with HCV. PMID- 25300641 TI - Relationship of High Sensitivity C-Reactive Protein Levels to Anthropometric and other Metabolic Parameters in Indian Children with Simple Overweight and Obesity. AB - CONTEXT: High senstivity C-reactive protein (hsCRP) levels correlate well other parameters of obesity related metabolic syndrome (MS) and can be used as predictors of future cardiovascular disease risk. There is limited data on hsCRP levels in Indian children with simple obesity. AIM: To study the relationship of hsCRP levels with various anthropometric as well as metabolic parameters in children with simple overweight and obesity. MATERIALS AND METHODS: This case control study was conducted in Paediatric Endocrinology clinic of a tertiary care hospital in Northern India. Levels of hsCRP were estimated in 100 overweight and obese children (BMI between 85(th) and 95(th) percentiles according to age & gender specific CDC 2000 growth charts) aged between 6 and 16 years and in 100 nearly age and sex matched healthy controls. These levels were then correlated to various anthropometric (body mass index, BMI; waist circumference, WC; hip circumference, HC; waist hip ratio, WHR; blood pressure) and biochemical (fasting blood glucose, FBG; total cholesterol, TC; high-density lipoprotein-cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; very low-density lipoprotein cholesterol, VLDL-C; triglycerides, TG) parameters. RESULTS: Mean levels of hsCRP were significantly higher in the study group (3.92+/-2.20 versus 2.15+/-1.05 mg/L) as compared to controls. Significantly more (58% versus 10%) subjects in the study group had hsCRP (>3 mg/L). Of all the parameters studied, only BMI showed a positive correlation with hsCRP levels in the study group. Multiple logistic regression analysis for predicting outcome of high hsCRP showed positive correlation with BMI; with every 1 kg/m(2) increase in BMI, odds of high hsCRP level were increased by 37% (OR=1.37; 95% CI 1.23-1.53, p-value <0.0001). Mean values of all the biochemical parameters except HDL-C were significantly higher in the study group. CONCLUSION: Levels of hsCRP were significantly elevated in overweight and obese children as compared to non-obese children. In addition, these patients also showed abnormalities of lipid and glucose metabolism. PMID- 25300642 TI - Apolipoprotein e mutation and double filtration plasmapheresis therapy on a new Chinese patient with lipoprotein glomerulopathy. AB - BACKGROUND/AIMS: Lipoprotein glomerulopathy (LPG) is a rare hereditary disease. In this study, we investigated the apoE mutation and the role of double filtration plasmapheresis therapy (DFPP) on a new Chinese patient with LPG. METHODS: Renal biopsy was performed on this patient to allow a definitive diagnosis. The mutations in the coding sequence of apoE and the hereditary pedigree of this patient were investigated by DNA sequencing. The patient was treated with DFPP, and clinical parameters before and after DFPP were compared. RESULTS: Two missense mutations were found in this patient: Cys112Arg and Arg25Cys. Arg25Cys was previously designated as APOE Kyoto. Family genotyping showed that Cys112Arg and Arg25Cys mutation were transmitted through his father and his mother, respectively. The patient's parents are healthy so far to date. Possibly there was a dose effect on apoE mutation induced LPG. Furthermore, DFPP treatment was first used on this patient and led to dramatic changes: Proteinuria and apo E values declined, and hemoglobin level increased significantly. CONCLUSION: APOE Kyoto mutation was found in a new Chinese patient with LPG, accompanied by Cys112Arg. More cases and further functional experiments are needed to investigate the role of these two mutations together in LPG. DFPP is an effective therapeutic modality for improving NS in patients with LPG. PMID- 25300644 TI - Can women determine the success of early medical termination of pregnancy themselves? AB - OBJECTIVE: To determine the outcome of early medical termination of pregnancy (TOP) among women who choose a "self assessment" follow up comprising a self performed low sensitivity urine pregnancy test with instructions on signs/symptoms that mandate contacting the TOP service. STUDY DESIGN: A retrospective review of computer databases of 1726 women choosing self-assessment after early medical TOP (<9 weeks) in the UK. The main outcome measures were (a) number of women choosing self-assessment, (b) contact rates with TOP service and (c) time to presentation with an ongoing pregnancy (failed TOP). RESULTS: Ninety six percent of women having an early medical TOP and going home to expel the pregnancy chose self-assessment. Two percent of women made unscheduled visits to the TOP service. One hundred and eighty-eight women (11%) telephoned the service about concerns related to complications or the success of treatment. There were eight ongoing pregnancies (0.5%; 95% confidence interval 0.2-0.9%). Four were detected within 4 weeks of treatment; the remainder were not detected until one or more missed menses after the procedure. CONCLUSIONS: Most women having an early medical TOP, who go home to expel the pregnancy, choose self-assessment. Relatively few women make unscheduled visits or telephone the TOP service. Most ongoing pregnancies are recognized at an early stage, although late presentation (as with all methods of follow up) does still occur. IMPLICATIONS STATEMENT: If women are given clear instructions on how and when to conduct a urine pregnancy test and on signs/symptoms that mandate contacting the TOP service, then they can confirm the success of early medical TOP themselves. Late presentation due to failure to recognize an ongoing pregnancy is rare. PMID- 25300643 TI - Discriminating imaging findings of acute osteoporotic vertebral fracture: a prospective multicenter cohort study. AB - BACKGROUND: Appropriate treatment of osteoporotic vertebral fractures (OVF) requires knowledge of the age of the fracture. Although diagnostic imaging has made remarkable progress in recent years, it remains difficult to differentiate acute fractures from old. Our purpose was to investigate chronological changes in radiological findings after OVF and to identify discriminators of acute versus older injuries. METHODS: We evaluated 139 vertebrae in 136 patients. All patients underwent X-ray and magnetic resonance imaging (MRI) examination within 2 weeks of injury and again after 6 months. The anterior vertebral height ratio (AVHR) was calculated on lateral X-ray, and the intensity change of the posterior wall of the fractured vertebra was evaluated on T1-weighted MRI. The cutoff AVHR value to diagnose acute fracture was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: Average AVHR fell from 84.6% at initial visit to 63.7% at 6 months. When acute fracture was defined as AVHR >75%, sensitivity was 85.6%, specificity was 67.6%, and positive predictive value was 72.6%. On MRI, 83.5% of fractured vertebrae showed intensity change in the posterior wall in the acute stage, which fell to 41.7% of vertebrae after 6 months. When intensity change in the posterior wall and AVHR >75% were both present, the specificity and positive predictive value for diagnosing acute fracture improved to 87.1% and 84.7%, respectively. CONCLUSIONS: This study suggests that vertebral fracture rarely shows significant collapse on X-ray in the first 2 weeks after injury. The combination of intensity change in the posterior wall on MRI and AVHR >75% on X ray indicates a high probability of acute fracture. PMID- 25300646 TI - Auditory neuroplasticity, hearing loss and cochlear implants. AB - Data from our laboratory show that the auditory brain is highly malleable by experience. We establish a base of knowledge that describes the normal structure and workings at the initial stages of the central auditory system. This research is expanded to include the associated pathology in the auditory brain stem created by hearing loss. Utilizing the congenitally deaf white cat, we demonstrate the way that cells, synapses, and circuits are pathologically affected by sound deprivation. We further show that the restoration of auditory nerve activity via electrical stimulation through cochlear implants serves to correct key features of brain pathology caused by hearing loss. The data suggest that rigorous training with cochlear implants and/or hearing aids offers the promise of heretofore unattained benefits. PMID- 25300645 TI - Cholinergic epithelial cell with chemosensory traits in murine thymic medulla. AB - Specialized epithelial cells with a tuft of apical microvilli ("brush cells") sense luminal content and initiate protective reflexes in response to potentially harmful substances. They utilize the canonical taste transduction cascade to detect "bitter" substances such as bacterial quorum-sensing molecules. In the respiratory tract, most of these cells are cholinergic and are approached by cholinoceptive sensory nerve fibers. Utilizing two different reporter mouse strains for the expression of choline acetyltransferase (ChAT), we observed intense labeling of a subset of thymic medullary cells. ChAT expression was confirmed by in situ hybridization. These cells showed expression of villin, a brush cell marker protein, and ultrastructurally exhibited lateral microvilli. They did not express neuroendocrine (chromogranin A, PGP9.5) or thymocyte (CD3) markers but rather thymic epithelial (CK8, CK18) markers and were immunoreactive for components of the taste transduction cascade such as Galpha-gustducin, transient receptor potential melastatin-like subtype 5 channel (TRPM5), and phospholipase Cbeta2. Reverse transcription and polymerase chain reaction confirmed the expression of Galpha-gustducin, TRPM5, and phospholipase Cbeta2. Thymic "cholinergic chemosensory cells" were often in direct contact with medullary epithelial cells expressing the nicotinic acetylcholine receptor subunit alpha3. These cells have recently been identified as terminally differentiated epithelial cells (Hassall's corpuscle-like structures in mice). Contacts with nerve fibers (identified by PGP9.5 and CGRP antibodies), however, were not observed. Our data identify, in the thymus, a previously unrecognized presumptive chemosensitive cell that probably utilizes acetylcholine for paracrine signaling. This cell might participate in intrathymic infection-sensing mechanisms. PMID- 25300647 TI - Transplantation of devitalized muscle scaffolds is insufficient for appreciable de novo muscle fiber regeneration after volumetric muscle loss injury. AB - Volumetric muscle loss (VML) is a traumatic and functionally debilitating muscle injury with limited treatment options. Developmental regenerative therapies for the repair of VML typically comprise an ECM scaffold. In this study, we tested if the complete reliance on host cell migration to a devitalized muscle scaffold without myogenic cells is sufficient for de novo muscle fiber regeneration. Devitalized (muscle ECM with no living cells) and, as a positive control, vital minced muscle grafts were transplanted to a VML defect in the tibialis anterior muscle of Lewis rats. Eight weeks post-injury, devitalized grafts did not appreciably promote de novo muscle fiber regeneration within the defect area, and instead remodeled into a fibrotic tissue mass. In contrast, transplantation of vital minced muscle grafts promoted de novo muscle fiber regeneration. Notably, pax7+ cells were absent in remote regions of the defect site repaired with devitalized scaffolds. At 2 weeks post-injury, the devitalized grafts were unable to promote an anti-inflammatory phenotype, while vital grafts appeared to progress to a pro-regenerative inflammatory response. The putative macrophage phenotypes observed in vivo were supported in vitro, in which soluble factors released from vital grafts promoted an M2-like macrophage polarization, whereas devitalized grafts failed to do so. These observations indicate that although the remaining muscle mass serves as a source of myogenic cells in close proximity to the defect site, a devitalized scaffold without myogenic cells is inadequate to appreciably promote de novo muscle fiber regeneration throughout the VML defect. PMID- 25300648 TI - Dissociative disorders and possession experiences in Israel: a comparison of opiate use disorder patients, Arab women subjected to domestic violence, and a nonclinical group. AB - This study examined the association between exposure to domestic violence and dissociative symptoms. A sample of 68 Israeli opiate use disorder patients in recovery, 80 battered Arab Israeli women, and 103 respondents from a community sample participated in structured interviews that included the Dissociative Disorders Interview Schedule (DDIS), the Dissociative Trance Disorder Interview Schedule (DTDIS), and the Dissociative Experiences Scale (DES). As predicted, community participants reported significantly less exposure to traumatizing events and lower levels of dissociative psychopathology than individuals sampled from specialized treatment centers. In all, 91% of battered female participants were taxon-positive for dissociative disorder with 1 of every 2 respondents reporting symptoms corresponding to dissociative amnesia and depersonalization disorder, suggesting that this group may be particularly vulnerable to dissociative psychopathology. Extrasensory and paranormal experiences (ESP) and dissociative trance disorder experiences were strongly related to dissociative experiences and features of dissociative identity disorder (DID). These statistical associations suggest that dissociative disorders and ESP/trance experiences may share an underlying construct. Further research is needed on trauma and dissociation among female victims of domestic abuse in patriarchal, collectivist societies, particularly in the Arab world. PMID- 25300650 TI - Changes in taste preference after colorectal surgery: A longitudinal study. AB - BACKGROUND & AIMS: Nutrition is a key component of surgical enhanced recovery programmes. However, alterations in food preferences are often reported as reasons for patients not eating in the early postoperative period. We hypothesised that taste preferences are altered in the early postoperative period and this dysgeusia affects patients' food choices during this critical time. METHODS: This is a longitudinal study looking at taste preferences of patients recovering from surgery. Patients undergoing colonic resections were recruited. Using visual analogue scales participants completed a questionnaire, taste tests and preference scoring of food images for the 6 groups of taste (bitter, salty, savoury, sour, spicy and sweet) preoperatively and on postoperative days 1-3. Patients were also offered snacks postoperatively, which represented foods from the six groups and consumption was measured. Differences from baseline were assessed using the Friedman's and Wilcoxon tests. RESULTS: 31 patients were studied. In the immediate postoperative period participants reported deterioration in their sense of taste (p <= 0.001), increased nausea (p < 0.001) and hunger (p = 0.03). Sweet, savoury and spicy tastes were the most popular during the perioperative period. However, only palatability for salty taste increased (p = 0.001) following surgery. The highest rated images were for savoury food with only the ratings for salty food increasing after surgery (p < 0.05). These findings concurred with the sweet, savoury and salty snacks being the most consumed foods in the postoperative period. Bitter, sour and spicy foods were the least frequently consumed. DISCUSSION: This is the first study to investigate postsurgical patients' food preferences. A consistent change in all the individual tastes with the exception of salty in the postoperative period was observed. The most desirable tastes were for savoury and sweet, reflecting patients' preoperative preferences. An improved understanding of taste may improve the resumption of eating after colonic surgery. PMID- 25300649 TI - Calcium plus vitamin D supplementation affects glucose metabolism and lipid concentrations in overweight and obese vitamin D deficient women with polycystic ovary syndrome. AB - BACKGROUND & AIMS: Few studies have examined the effects of calcium plus vitamin D supplementation on glucose metabolism and lipid concentrations in overweight and obese vitamin D deficient women with polycystic ovary syndrome (PCOS). This study was conducted to determine the effects of calcium plus vitamin D supplementation on glucose metabolism and lipid concentrations among overweight and obese vitamin D deficient women with PCOS. METHODS: This randomized double blind placebo-controlled clinical trial was conducted among 104 overweight and obese vitamin D deficient women diagnosed with PCOS. Participants were randomly assigned into four groups to receive: 1) 1000 mg/d calcium + vitamin D placebo (n = 26); 2) 50,000 IU/wk vitamin D + calcium placebo (n = 26); 3) 1000 mg calcium/d + 50,000 IU/wk vitamin D (n = 26) and 4) calcium placebo + vitamin D placebo (n = 26) for 8 weeks. Fasting blood samples were taken at baseline and after 8 weeks' intervention to measure glucose metabolism and lipid concentrations. RESULTS: Calcium-vitamin D co-supplementation resulted in higher levels of serum calcium (P = 0.002) and vitamin D (P < 0.001) compared with other groups. Co supplementation, compared with other groups, led to decreased serum insulin levels (P = 0.03), homeostasis model of assessment-insulin resistance (HOMA-IR) score (P = 0.04) and a significant rise in quantitative insulin sensitivity check index (QUICKI) (P = 0.001). Furthermore, a significant decrease in serum triglycerides (P = 0.02) and VLDL-cholesterol levels (P = 0.02) was seen following the administration of calcium plus vitamin D supplements compared with the other groups. Co-supplementation with calcium and vitamin D had no significant effects on FPG, total-, LDL-, HDL-, and non-HDL-cholesterol levels. CONCLUSIONS: In conclusion, calcium plus vitamin D supplementation for eight weeks among vitamin D deficient women with PCOS had beneficial effects on serum insulin levels, HOMA-IR, QUICKI, serum triglycerides and VLDL-cholesterol levels, but it did not affect FPG and other lipid profiles. Clinical registration numberwww.irct.ir: IRCT201309275623N10. PMID- 25300651 TI - Attitudes towards alcohol dependence and affected individuals: persistence of negative stereotypes and illness beliefs between 1990 and 2011. AB - BACKGROUND: Alcohol dependence is among the most severely stigmatized mental disorders. We examine whether negative stereotypes and illness beliefs related to alcohol dependence have changed between 1990 and 2011. METHODS: We used data from two population surveys with identical methodology that were conducted among German citizens aged >=18 years, living in the 'old' German states. They were conducted in 1990 and 2011, respectively. In random subsamples (1990: n = 1,022, and 2011: n = 1,167), identical questions elicited agreement with statements regarding alcohol dependence, particularly with regard to the illness definition of alcohol dependence and blame. RESULTS: Overall, agreement with negative stereotypes did not change in the course of 2 decades. About 55% of the respondents agreed that alcohol dependence is an illness like any other, >40% stated that it was a weakness of character and 30% endorsed that those affected are themselves to blame for their problems. CONCLUSIONS: It is apparent that promoting an illness concept of alcohol dependence has not been an easy solution to the problem of stigma. We discuss how the normative functions of alcohol dependence stigma might have prevented a reduction of negative stereotypes. PMID- 25300652 TI - Continuous engineering of nano-cocrystals for medical and energetic applications. AB - Cocrystals, solid mixtures of different molecules on molecular scale, are supposed to be tailor made materials with improved employability compared to their pristine individual components in domains such as medicine and explosives. In medicine, cocrystals are obtained by crystallization of active pharmaceutical ingredients with precisely chosen coformers to design medicaments that demonstrate enhanced stability, high solubility, and therefore high bioavailability and optimized drug up-take. Nanoscaling may further advance these characteristica compared to their micronsized counterparts - because of a larger surface to volume ratio of nanoparticles. In the field of energetic materials, cocrystals offer the opportunity to design smart explosives, combining high reactivity with significantly reduced sensitivity, nowadays essential for a safe manipulation and handling. Furthermore, cocrystals are used in ferroelectrics, non-linear material response and electronic organics. However, state of the art batch processes produce low volume of cocrystals of variable quality and only have produced micronsized cocrystals so far, no nano-cocrystals. Here we demonstrate the continuous preparation of pharmaceutical and energetic micro- and nano-cocrystals using the Spray Flash Evaporation process. Our laboratory scale pilot plant continuously prepared up to 8 grams per hour of Caffeine/Oxalic acid 2:1, Caffeine/Glutaric acid 1:1, TNT/CL-20 1:1 and HMX/Cl-20 1:2 nano- and submicronsized cocrystals. PMID- 25300653 TI - Postoperative lung complications: have multicentre studies been of any help? PMID- 25300654 TI - Experimental behaviour testing: pain. PMID- 25300655 TI - Exercise: the new premed. PMID- 25300656 TI - Refined balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension--a multi-modality approach to the treated lesion. PMID- 25300657 TI - Coconut atrium, an exotic source of cardiac emboli. PMID- 25300658 TI - A new strategy for pericardiocentesis with a visual puncture system: the feasibility and efficiency study in a pericardial effusion model. PMID- 25300659 TI - Left circumflex coronary-pulmonary artery fistula and transmediastinal participation of bronchial arteries best shown by CT. PMID- 25300660 TI - An atypical clinical presentation of renovascular hypertension. PMID- 25300661 TI - [Rational fluid and volume replacement therapy: wishful dream or realistic future option]. PMID- 25300663 TI - Down- and up-converting dual-mode YPO4:Yb(3+),Tb(3+) nanocrystals: synthesis and spectroscopic properties. AB - Tetragonal YPO4 nanocrystals doped with Yb(3+) and Tb(3+) ions were synthesized by 900 degrees C annealing of precursors obtained with a co-precipitation method in the presence of glycerine. These materials exhibited intense green luminescence under ultraviolet excitation and up-conversion emission from the (5)D3 and (5)D4 Tb(3+) excited states after irradiation with near infrared light (lambda = 980 nm). The structure and morphology of the products were analysed by recording X-ray diffraction patterns and transmission electron microscopy images. The obtained nanomaterials were single-phased with spherical shaped nanocrystals that had an average size of 18 +/- 3 nm. The spectroscopic properties of YPO4:Yb(3+),Tb(3+) nanocrystals were investigated based on their excitation and emission spectra. The time-resolved luminescence traces were measured, and the luminescence lifetimes of Tb(3+) and Yb(3+) ions were calculated. The most effective dopant concentrations were determined to be 5% Yb(3+) and 15% Tb(3+), which exhibited the most intense ultraviolet excited emission and up-conversion. Because the integral intensity was observed to be dependent on the power of the pumping laser, a cooperative energy transfer (CET) mechanism underlying the observed up-conversion was proposed. PMID- 25300662 TI - [Which learning methods are expected for ultrasound training? Blended learning on trial]. AB - BACKGROUND: Current teaching methods in graduate and postgraduate training often include frontal presentations. Especially in ultrasound education not only knowledge but also sensomotory and visual skills need to be taught. This requires new learning methods. AIM: This study examined which types of teaching methods are preferred by participants in ultrasound training courses before, during and after the course by analyzing a blended learning concept. It also investigated how much time trainees are willing to spend on such activities. MATERIAL AND METHODS: A survey was conducted at the end of a certified ultrasound training course. Participants were asked to complete a questionnaire based on a visual analogue scale (VAS) in which three categories were defined: category (1) vote for acceptance with a two thirds majority (VAS 67-100%), category (2) simple acceptance (50-67%) and category (3) rejection (< 50%). RESULTS: A total of 176 trainees participated in this survey. Participants preferred an e-learning program with interactive elements, short presentations (less than 20 min), incorporating interaction with the audience, hands-on sessions in small groups, an alternation between presentations and hands-on-sessions, live demonstrations and quizzes. For post-course learning, interactive and media-assisted approaches were preferred, such as e-learning, films of the presentations and the possibility to stay in contact with instructors in order to discuss the results. Participants also voted for maintaining a logbook for documentation of results. CONCLUSION: The results of this study indicate the need for interactive learning concepts and blended learning activities. Directors of ultrasound courses may consider these aspects and are encouraged to develop sustainable learning pathways. PMID- 25300664 TI - Highly efficient transformation of Stenotrophomonas maltophilia S21, an environmental isolate from soil, by electroporation. AB - Stenotrophomonas maltophilia is an emerging opportunistic pathogen, which also exhibits potential of wide applications in industry, environment and agriculture. An efficient transformation method for S. maltophilia would be convenient to its genetic studies. In this report, we focused on developing an efficient transformation protocol for S. maltophilia. Gene transfer by three different methods (chemical transformation, conjugation and electroporation) indicated that electroporation was the most efficient method to transform S. maltophilia S21. Then, the entire electroporation process from competent-cell preparation to post pulse incubation was optimized to get higher efficiencies. Utilizing competent cells prepared at optical density (600 nm) of 1.0, the maximal transformation efficiency of S. maltophilia S21 reached 1.53 * 10(8) transformants/MUg of pBBR1MCS DNA at a field strength of 18 kV/cm, a time constant of 4.8 ms (200 Omega), a DNA amount of 100 ng and a cell concentration of 2.4 * 10(8) CFU/ml after 3 h incubation. Moreover, we successfully transformed the other four isolates of S. maltophilia using this protocol. To date, this is the first report about electroporation of S. maltophilia and it will facilitate the further study of this species. PMID- 25300665 TI - Flow cytometric evaluation of the intracellular bacterium, Wolbachia pipientis, in mosquito cells. AB - Conditions for flow cytometric evaluation of the intracellular bacterium, Wolbachia pipientis, in infected mosquito cells are described. This approach will streamline investigation of Wolbachia's interactions with host cells and facilitate identification of culture conditions that select for Wolbachia infected cells. PMID- 25300666 TI - The Gift Relationship Revisited. AB - If unremunerated blood donors are willing to participate, and if the use of them is economical from the perspective of those collecting blood, I can see no objection to their use. But there seems to me no good reason, moral or practical, why they should be used. The system of paid plasmapheresis as it currently operates in the United States and in Canada would seem perfectly adequate, and while there may always be ways in which the safety and efficiency of supply could be increased, there seems no reason whatever to think that there would be an improvement if the current system changed so as to rely entirely on unpaid donors. Further, given the adequacy of paid plasmapheresis, I could see no problem if the collection of whole blood were to take place on a similar, fully commercial, basis. Such a view is controversial. To argue for it, this paper offers just one strand in a complex argument: a critique of Richard Titmuss's Gift Relationship, which holds an iconic position in the critical literature on the paid provision of blood. As I conclude: all told, there seems no good basis for rejecting supply of whole blood for money--let alone the supply of blood plasma. PMID- 25300667 TI - Dynamics of the stratification process in drying colloidal dispersions studied by terahertz time-domain spectroscopy. AB - We present an optical study that reveals the bulk dynamics of the stratification process in drying colloidal dispersions. Terahertz time-domain spectroscopy has been used to measure in situ solventborne and waterborne paint layers as a function of drying time. The dynamic behavior of the dry top layer and wet bottom layer thickness, as well as the bulk thickness, reflect the principal processes of the established drying mechanism. In addition, the results demonstrate stratification only when the drying process is in the evaporation controlled regime, whereas the coating is shown to remain a single layer for diffusion controlled drying. PMID- 25300668 TI - Clinical and cost impact of a pediatric cataract follow-up program in Western Nepal and adjacent northern Indian states. PMID- 25300669 TI - Botulinum toxin: a novel treatment for pediatric cyclic esotropia. AB - Cyclic esotropia is a rare entity in which an esotropia presents in a regular 48 96 hour cycle, typically described as a 24-hour period of orthotropia followed by a 24-hour period of esotropia. The underlying mechanism of this phenomenon is unknown. Treatment usually involves surgical correction of the manifest strabismus. We report the case of a 3-year-old girl whose cyclic esotropia was broken following injection of botulinum toxin to both medial rectus muscles. She has remained constantly esophoric for 1 year. PMID- 25300670 TI - Nitrites and nitrates in the human diet: Carcinogens or beneficial hypotensive agents? AB - ETHNOPHARMACOLOGICAL RELEVANCE: The presence of nitrite in the human diet was thought to constitute a hazard as secondary nitrosamines are known to cause gastric cancers. MATERIALS AND METHODS: Recent publications on the physiology of serum nitrite have been consulted. PROBLEMS: Nitrite is added to some foodstuffs as an antibotulinum agent. RESULTS AND DISCUSSION: The epidemiological evidence that nitrite causes gastric ulcers is weak. On the other hand, evidence that the presence of nitrite in serum lowers blood pressure is strong. This allows us to explain why a Tang dynasty treatment for angina, given in a Dunhuang medical manuscript, can be successful. CONCLUSION: The presence of nitrite in food is free of danger and a diet high in nitrate is beneficial to the health. PMID- 25300671 TI - Where are patients who have co-occurring mental and physical diseases located? AB - BACKGROUND: Patients with a psychiatric illness have a higher prevalence of physical diseases and thus a higher morbidity and mortality. AIM: The main aim was to investigate where patients with co-occurring physical diseases and mental disorders (psychotic spectrum or mood) in the health and social service system are identified most frequently before admission into psychiatry. The second aim was to compare the differences in the treatment routes taken by the patients before entry into psychiatric services in all the participating countries (Denmark, Germany, Japan, Nigeria and Switzerland). METHODOLOGY: On admission to a psychiatric service, patients diagnosed with schizophrenia, schizotypal or delusional disorders (International Classification of Diseases-10 (ICD-10) group F2) or mood (affective) disorders (ICD-10 group F3) and a co-morbid physical condition (cardiovascular disease, diabetes mellitus and overweight) were asked with which institutions or persons they had been in contact with in the previous 6 months. RESULTS: Patients from Denmark, Germany and Switzerland with mental disorders had almost the same contact pattern. Their primary contact was to public or private psychiatry, with a contact percentage of 46%-91%; in addition, general practice was a common contact, with a margin of 41%-93%. Similar tendencies are seen in Japan despite the small sample size. With regard to general practice, this is also the case with Nigerian patients. However, religious guidance or healing was rarely sought by patients in Europe and Japan, while in Nigeria about 80% of patients with mental disorders had contacted this type of service. CONCLUSION: Promoting prophylactic work between psychiatry and the general practice sector may be beneficial in diminishing physical conditions such as cardiovascular disease, diabetes mellitus and overweight in patients with mental disorders in European countries and Japan. In Nigeria (a low-to-middle income country), religious guides or healers, along with general practitioners, are the most frequently contacted, and they therefore seem to be the most obvious partner to collaborate with. PMID- 25300672 TI - Differential role of insular cortex muscarinic and NMDA receptors in one-trial appetitive taste learning. AB - Our current understanding of the neurobiology of taste learning and memory has been greatly facilitated by the use of a reliable behavioural model, conditioned taste aversion (CTA). This model has revealed that the insular cortex (IC), specifically muscarinic and N-methyl-d-aspartate (NMDA) receptor activation in the IC, is critical for the formation of aversive taste memories. In contrast, current models of appetitive taste learning are less adequate, relying on the use of neophobic tastes (attenuation of neophobia) or on the integration of appetitive and aversive taste memories (latent inhibition of CTA). While these models have implicated IC muscarinic receptors, the involvement of NMDA receptors in the IC remains unclear. Here, we examined the role of both muscarinic and NMDA receptors in appetitive taste learning using a simple paradigm that is independent of neophobic and aversive components. First, we demonstrated that a single exposure to a novel taste, saccharin 0.1%, is sufficient to promote an appetitive taste memory as revealed by an increase in saccharin consumption during the second presentation. This increase was blocked by bilateral infusion in the IC of the muscarinic receptor antagonist, scopolamine. In contrast, infusion of the NMDA receptor antagonist, AP5, did not block appetitive taste learning but did abolish CTA. Therefore, common and distinct molecular substrates within the IC mediate appetitive versus aversive learning about the same taste. PMID- 25300673 TI - Update on the current recommendations and outcomes in pregnant women with antiphospholipid syndrome. AB - Pregnancy morbidity is part of the clinical spectrum of the antiphospholipid syndrome (APS), a chronic autoimmune condition serologically characterized by the persistent positivity of antiphospholipid antibodies (aPL). Antiplatelet and anticoagulant agents are the mainstay of the treatment of obstetric APS. However, there is an ongoing debate about the optimal management of women with most severe aPL-mediated obstetric complications, women not fulfilling APS criteria and those with refractory disease. Unfortunately, the literature cannot provide definite answers to these controversial issues, being flawed by many limitations. The evidence supporting the recommended therapeutic management of different aPL related obstetrical clinical manifestations is presented, with a critical appraisal of each approach. PMID- 25300674 TI - Toxicity and Biodistribution of Activated and Non-activated Intravenous Iron Oxide Nanoparticles. AB - The use of nanoparticles in medical treatment has prompted the question of their safety. In this study, the pathophysiology and biodistribution of three different concentrations of intravenously-delivered dextran-coated Fe3O4 iron oxide nanoparticles (IONP) were evaluated in mice. Some groups of mice were exposed to an AC magnetic field (AMF) at levels comparable with those proposed for cancer treatments. Iron biodistribution analysis for both AMF and non-AMF treated mice was performed for all three concentrations used (.6 mg Fe/mouse, 1.8 mg Fe/mouse, and 5.6 mg Fe/mouse). Blood urea nitrogen, alanine transaminase, alkaline phosphatase, total serum protein, and creatinine were also assessed at 4 hours, 7 days, and 14 days post-injection. Histological analysis of lung, spleen, heart, liver, and kidney tissue was conducted at 7 and 14 days post-injection. Prussian blue and H&E stains were used to histomorphometrically assess iron content in the tissues studied. Preliminary results demonstrate small temporary elevation in liver enzymes and hepatocyte vacuolization at all iron concentrations studied. Liver and spleen were the primary sites of IONP deposition. None of the animals demonstrated systemic or local toxicity or illness, with or without AMF activation. PMID- 25300675 TI - Assessing the knowledge of perinatal mental illness among student midwives. AB - The experience of perinatal mental illness (mental illness occurring around the time of pregnancy) currently affect 1 in 10 women and can have adverse effects on the mother and her child (Massie and Szajnberg, 2002; O'Connor et al., 2002). The care and effective management of women experiencing perinatal mental illness is therefore an important issue for health care staff, managers, psychiatrists, commissioners and campaigners. Midwives play a significant part in caring for women throughout their pregnancies, during labour and up to the first month after birth. Midwives are in a unique position to assess a woman's well-being and to offer appropriate support. However, previous research has revealed that midwives often have poor understanding and knowledge of perinatal mental health issues and require improved training (Ross-Davie et al, 2006; McCann and Clark, 2010). This research project aims to systematically assess student midwives awareness of perinatal mental illness. The findings of this study will inform curriculum development for graduate and post-graduate midwifery students therefore improving the care and support women with mental illness receive from antenatal services. The findings from this study will also be used for the formation of an educational web-based programme for student and qualified midwives. PMID- 25300677 TI - Screen all adults 45 or over for abnormal glucose, says US panel. PMID- 25300676 TI - First validation of a Spanish-translated version of the Edinburgh postnatal depression scale (EPDS) for use in pregnant women. A Chilean study. AB - The objective of the study was to evaluate the psychometric properties of the Edinburg Postnatal Depression Scale (EPDS) to detect depression during pregnancy in Chile. The EPDS was applied to a sample of 111 pregnant women, who were attending an antenatal appointment in primary care centers. The Beck Depression Inventory (BDI-I) was used to assess the convergent validity, and the Depressive Episode module of the MINI was used to identify cases. The factor analysis showed that there was a good fit, with a factor model that explains 57.6 % of the total variance. There was a high degree of internal consistency (Cronbach's alpha = 0.914) and good convergent validity with the BDI-I (rho = 0.850, p < 0.001). The EPDS was capable of differentiating cases of depression from non-cases. The best cutoff point was between 12 and 13, corresponding to an overall accuracy of 87.4 %. The questionnaire has good psychometric properties and can be useful for detecting cases of depression during pregnancy. PMID- 25300678 TI - Observation may be an inadequate approach for injured extremities with single tibial vessel run-off. AB - INTRODUCTION: Trauma patients with sudden loss of distal perfusion due to tibial injuries are frequently not offered vascular interventions if a single vessel retains patency. We hypothesized that sudden loss of either all or some tibial vasculature would result in increased non-operative failure and higher amputation rates. METHODS: In this retrospective observational study, all traumatically injured patients from 2009 to 2012 with CT-angiogram-confirmed anterior tibial, posterior tibial, or peroneal artery injuries were included. RESULTS: From 2009 to 2012, 437 patients were admitted with arterial extremity injury of which 234 (53%) were lower extremity. From this group, 84 (36%) patients were identified with CT-angiogram-confirmed limited or no flow in the tibial arteries. A total of 44% (4/9) with 0 or 1 tibial vessel failed observation while only 8% (2/27) failed if they had 2 or 3 patent vessels (p < 0.05). Amputation rate was inversely related the number of open tibial vessels. There were 2.7 open tibial vessels in the limb salvage group compared to 1.1 in the amputation group (p < 0.05). CONCLUSION: Patients who failed an initial trial of observation were significantly more likely to have 0 or 1 tibial vessels patent. The number of open tibial vessels is significantly associated with limb salvage. PMID- 25300679 TI - Modulation of cGMP accumulation by adenosine A1 receptors at the hippocampus: influence of cGMP levels and gender. AB - Adenosine A1 receptor is highly expressed in hippocampus where it inhibits neurotransmitter release and has neuroprotective activity. Similar actions are obtained by increasing cGMP concentration, but a clear link between adenosine A1 receptor and cGMP levels remains to be established. The present work aims to investigate if cGMP formation is modulated by adenosine A1 receptors at the hippocampus and if this effect is gender dependent. cGMP accumulation, induced by phosphodiesterases inhibitors Zaprinast (100 MUM) and Bay 60-7550 (10 MUM), and cAMP accumulation, induced by Forskolin (20 MUM) and Rolipram (50 MUM), were quantified in rat hippocampal slices using specific enzymatic immunoassays. N6 cyclopentyladenosine (CPA, 100 nM) alone failed to modify basal cGMP accumulation. However, the presence of adenosine deaminase (ADA, 2 U/ml) unmasked a CPA (0.03-300 nM) stimulatory effect on basal cGMP accumulation (EC50: 4.2+/ 1.4 nM; Emax: 17+/-0.9%). ADA influence on CPA activity was specific for cGMP, since inhibition of cAMP accumulation by CPA was not affected by the presence of ADA, though ADA inhibited cAMP accumulation in the absence of CPA. Increasing cGMP accumulation, by about four-fold, with sodium nitroprusside (SNP, 100 MUM) abolished the CPA (100 nM) effect on cGMP accumulation in males but did not modify the effect of CPA in female rats. This effect was reversed by 8 Cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM), indicating an adenosine A1 receptor mediated effect on cGMP accumulation. In conclusion, adenosine A1 receptors increase intracellular cGMP formation at hippocampus both in males and females under basal conditions, but only in females when cGMP levels are increased by SNP. PMID- 25300680 TI - Celastrol suppresses obesity process via increasing antioxidant capacity and improving lipid metabolism. AB - High fat diet, as an important risk factor, plays a pivotal role in atherosclerotic process. Celastrol is one of the active triterpenoid compounds with antioxidative and anti-inflammatory characters. The aims of this study were to evaluate the effect of celastrol on weight, blood lipid and oxidative injury induced by high fat emulsion, and investigate its potential pharmacological mechanisms. Male Sprague-Dawley rats were fed with high fat emulsion for 6 wk to mimic high fat mediated oxidative injury. The effects of celastrol on weight and blood lipid were evaluated, and its mechanisms were disclosed by applying western blot, ELISA and assay kits. Long-term consumption of high fat emulsion could significantly increase weight by enhancing total cholesterol (TC), triacylglycerol (TG), apolipoprotein B (Apo B), low-density lipoprotein cholesterol (LDL-c) levels, attenuating ATP-binding cassette transporter A1 (ABCA1) expression, and decreasing the levels of high-density lipoprotein cholesterol (HDL-c) and apolipoprotein A-I (Apo A-I), and inhibit antioxidant enzymes activities, improve nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Comparing with model group, celastrol was able to effectively suppress weight and attenuate high fat mediated oxidative injury by improving ABCA1 expression, reducing the levels of TC, TG, LDL-c and Apo B in plasma, and increasing antioxidant enzymes activities and inhibiting NADPH oxidase activity, and decreasing the serum levels of Malondialdehyde (MDA) and reactive oxygen species in dose-dependent way. These data demonstrated that celastrol was able to effectively suppress weight and alleviate high-fat mediated cardiovascular injury via mitigating oxidative stress and improving lipid metabolism. PMID- 25300681 TI - Alterations in vagal-immune pathway in long-lasting mental stress. AB - We studied a potential impact of chronic psychosocial load on the allostatic biomarkers--cardiac vagal activity, inflammation, and oxidative stress in healthy undergraduate students. Continuous resting ECG signals were monitored in a group of 16 female healthy students (age: 23.2+/-0.2 years, BMI: 20.9+/-0.5 kg/m2) at two time periods: right after holiday (rest period) and a day before final exams (stress period). Vagal activity was quantified by spectral analysis of heart rate variability at high frequency band (HF-HRV). The immune response was assessed from the level of tumor necrosis factor-alpha (TNF-alpha) in plasma. In addition, mean RR intervals were evaluated. We found that HF-HRV was significantly reduced and the TNF-alpha was increased in the stress period compared with the rest period. No significant changes were found in the RR interval. In conclusion, allostatic load induced by stress and the accompanying greater immune response decreased cardiovagal regulation in healthy young subjects. These findings may help understand the pathway by which stress can influence health and disease. PMID- 25300682 TI - Cardiovascular effects of N-acetylcysteine in meconium-induced acute lung injury. AB - Anti-inflammatory drugs are increasingly used for treatment of neonatal meconium aspiration syndrome (MAS), but their adverse effects are poorly known. Therefore, the aim of this study was to evaluate the effects of the antioxidant N acetylcysteine on cardiovascular parameters in an animal model of MAS. Oxygen ventilated rabbits were intratracheally instilled 4 mL/kg of meconium suspension (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were given N-acetylcysteine (10 mg/kg, i.v.) or the same volume of saline. Changes in cardiovascular parameters (blood pressure, heart rate, and heart rate variability) were recorded over a 5-min course of solution administration, over 5 min after its end, and then hourly for 5 h. Oxidation markers (thiobarbituric acid-reactive substances (TBARS) and total antioxidant status) and aldosterone, as a non-specific marker of cardiovascular injury, were determined in plasma. Meconium instillation did not evoke any significant cardiovascular changes, but induced oxidative stress and elevated plasma aldosterone. N-acetylcysteine significantly reduced the mentioned markers of injury. However, its administration was associated with short-term increases in blood pressure and in several parameters of heart rate variability. Considering these effects of N acetylcysteine, its intravenous administration in newborns with MAS should be carefully monitored. PMID- 25300683 TI - Alterations in the coagulation system of active smokers from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. AB - Smoking is an important and preventable risk factor of cardiovascular diseases with effects on blood coagulation. Our aim was to analyze the influence of smoking on coagulation parameters. Concentrations or activities of blood coagulation factors were compared in 777 active smokers and 1,178 lifetime non smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The association with mortality was examined using Cox regression. The findings show that AS had a tendency toward thrombosis. They displayed significantly higher values for fibrinogen, soluble fibrinogen, factor XIII, and tissue factor pathway inhibitor; whereas FVII, FVIII, FXII, von Willebrand factor (vWF), and thrombomodulin were decreased. The Cox regression analysis showed fibrinogen, FVIII, vWF, thrombomodulin, and tissue factor pathway inhibitor to be independent risk factors for mortality in active smokers with hazard ratios of 1.16 (95% CI: 1.02-1.31), 1.40 (1.22-1.59), 1.37 (1.22-1.56), 1.19 (1.07-1.31), and 1.22 (1.06 1.40) per increase of one standard deviation. We conclude that active smokers have an increased thrombogenic potential associated with significant changes in the coagulation system. Individual parameters of the coagulation system are independent predictors of mortality. Therefore, parameters of the coagulation system, apart from other risk factors for cardiovascular disease (e.g., lipids or life-style) should be determined for risk prediction in active smokers. PMID- 25300684 TI - C-reactive protein and lipoprotein-associated phospholipase A2 in smokers and nonsmokers of the Ludwigshafen Risk and Cardiovascular Health study. AB - Measurement of high sensitivity CRP (hsCRP) and lipoprotein-associated phospholipase A2 (LpPLA2) provides information on systemic inflammation and stability of atherosclerotic plaques. Data analyzing the effect of smoking on these parameters are sparse. The aim of our study was the analysis of these parameters in active smokers and never-smokers. The study included 777 smokers and 1,178 never-smokers, of whom 221 and 302 died during a follow-up, respectively. The values of LpPLA2 and hsCRP were significantly higher in smokers than in never-smokers. Mortality was highest in smokers and never-smokers with elevation of both biomarkers. Multivariate adjusted hazard ratios for patients in the highest tertile of both hsCRP and LpPLA2 compared with patients in the lowest tertile of both markers were 1.85 (1.04-3.28) in never-smokers and 1.94 (1.10 3.45) in smokers. Our data confirmed the predictive value of hsCRP and LpPLA2. However, there were a relevant number of patients with an increase of only one of these parameters. Therefore, beside other risk factors for cardiovascular disease, both parameters should be determined at least in high risk patients. PMID- 25300685 TI - N-acetylcysteine alleviates the meconium-induced acute lung injury. AB - Meconium aspiration in newborns causes lung inflammation and injury, which may lead to meconium aspiration syndrome (MAS). In this study, the effect of the antioxidant N-acetylcysteine on respiratory and inflammatory parameters were studied in a model of MAS. Oxygen-ventilated rabbits were intratracheally given 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were administered N-acetylcysteine (10 mg/kg; i.v.), or were left without treatment. The animals were oxygen-ventilated for additional 5 h. Ventilatory pressures, oxygenation, right-to-left pulmonary shunts, and leukocyte count were measured. At the end of experiment, trachea and lung were excised. The left lung was saline-lavaged and a total and differential count of cells in bronchoalveolar lavage fluid (BAL) was determined. Right lung tissue strips were used for detection of lung edema (expressed as wet/dry weight ratio) and peroxidation (expressed by thiobarbituric acid-reactive substances, TBARS). In lung and tracheal strips, airway reactivity to acetylcholine was measured. In addition, TBARS and total antioxidant status were determined in the plasma. Meconium instillation induced polymorphonuclear-derived inflammation and oxidative stress. N-acetylcysteine improved oxygenation, reduced lung edema, decreased polymorphonuclears in BAL fluid, and diminished peroxidation and meconium-induced airway hyperreactivity compared with untreated animals. In conclusion, N acetylcysteine effectively improved lung functions in an animal model of MAS. PMID- 25300686 TI - Green tea drinking improves erythrocytes and saliva oxidative status in the elderly. AB - We have previously shown that green tea (GT) drinking combined with vitamin E supplementation reduced plasma protein carbonyls and increased erythrocytes catalase activity in exercising healthy elderly. In the present study we set out to investigate the antioxidative effects of GT drinking in an aging population. We performed an interventional, crossover, controlled prospective trial with 35 healthy elderly subjects (mean age 67.3+/-4.8 years), supplemented with four daily placebo maltodextrin "tea-bags" for 12 weeks, followed by four 1.5 g daily GT bags for another 12 weeks. Data were obtained at baseline, at the end of the placebo period, and at the end of the GT intervention period. We found that GT did not alter erythrocyte catalase activity. However, it provided protection against 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced oxidative hemolysis which declined by 10.2% (p<0.001). No changes were observed in saliva oral peroxidase enzymes. Nonetheless, saliva total antioxidant capacity increased by 42.0% (p<0.01). Plasma oxidative products, such as protein carbonyls, lipid peroxides and thiobarbituric acid reactive substances (TBARS) were stable throughout the intervention period. We conclude that four daily cups of GT are well tolerated in elderly free living subjects. Our results demonstrate that both erythrocyte resistances to oxidation and saliva antioxidant capacity are improved by GT drinking. The clinical implications of these oxidation modifications require further research. PMID- 25300687 TI - Polymorphisms of DNA repair genes and lung cancer in chromium exposure. AB - Chromium is a well known carcinogen involved in the lung cancer development. Polymorphism of some of the DNA repair genes may be associated with elevated risk of cancerous transformation. In the present study, we investigated the polymorphisms of the following selected members of the base and nucleotide excision repair genes: XPC (Lys939Gln), XPD (Lys751Gln), XRCC1(Arg399Gln), and hOGG1(Ser326Ser), and the risk they present toward the development of lung cancer, with emphasis on the effect of chromium exposure. We analyzed 119 individuals; 50 patients exposed to chromium with diagnosed lung cancer and 69 healthy controls. Genotypes were determined by a PCR-RFLP method. We found a significantly increased risk of lung cancer development in XPD genotype Lys/Gln (OR=1.94; 95% CI=1.10-3.43; p=0.015) and in the gene combinations: XPD Lys/Gln+XPC Lys/Gln (OR=6.5; 95% CI=1.53-27.49; p=0.009) and XPD Lys/Gln+XPC Gln/Gln(OR=5.2; 95% CI=1.07-25.32; p=0.04). In conclusion, gene polymorphisms in the DNA repair genes may underscore the risk of lung cancer development in the chromium-exposed individuals. PMID- 25300688 TI - Association between single nucleotide polymorphisms of delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) and Delta-like 1 Ligand (DLL 1) with the risk of type 2 diabetes mellitus in a Chinese Han population. AB - The aim of the study was to investigate the association between single nucleotide polymorphisms (SNPs), rs1861612 of delta/notch-like Epidermal Growth Factor (EGF) related receptor (DNER) and rs1884190 in the Delta-like 1 ligand (DLL1) gene and type 2 diabetes mellitus (T2DM) susceptibility in a Chinese Han population. DNER rs1861612 and DLL1 rs1884190 polymorphisms were genotyped in patients with T2DM and age- and sex-matched T2DM-free controls from a Chinese Han population. A total of 298 patients with T2DM and 500 controls were enrolled in this study. We found that TC and TT genotypes of rs1861612 and variant T were associated with a significantly increased risk of T2DM. In contrast, the AG and AA genotypes of rs1884190 were not significantly associated with the risk of T2DM, even after further stratification analysis based on age or sex. Our results showed that DNER rs1861612 C to T change and variant T genotype may contribute to T2DM in a Chinese Han population. PMID- 25300689 TI - A meta-analysis of the protective effect of recombinant human erythropoietin (rhEPO) for neurodevelopment in preterm infants. AB - The purpose of this study is to assess the efficacy and safety of recombinant human erythropoietin (rhEPO) for improving neurodevelopment outcomes in preterm infants. According to the requirements of Cochrane systematic review, a literature search was performed among PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Wan Fang Data, and VIP INFORMATION from the establishment of the database from January 1999 to December 2011. Quality assessments of clinical trials were carried out. Randomized controlled trials (RCTs) or quasi-RCTs with rhEPO in preterm infants were enrolled, and RevMan5.0 software was used for meta-analysis. Data extraction, quality assessment, and meta-analysis for the results of homogeneous studies were done by two reviewers. The trials were analyzed using weighted mean difference (WMD) for continuous data and odds ratio (OR) for dichotomous data, both kinds of data were expressed by 95 % CI. For homogenous data (P >= 0.10), fixed effect model was calculated. Two RCTs and 3 quasi-RCTs including 233 preterm infants (119 of treatment group and 114 of control group) were included in the analysis. The results of quality assessment were that 1 study was A, 1 was B, and 3 were C. There was evidence of a significant effect of therapeutic rhEPO on the outcomes of MDI scores [WMD = 7.77, 95 % CI (3.49-12.06), P = 0.0004], PDI scores [WMD = 3.85, 95 % CI (0.62 7.09), P = 0.02] at 18-22 months and NBNA scores [WMD = 1.96, 95 % CI (1.56 2.37), P < 0.00001] at 40 weeks of corrected gestational age. However, rhEPO had no effect on MDI <70 (OR = 0.70, 95 % CI 0.31-1.61), PDI <70 (OR = 2. 46, 95 % CI 0.94-6.45), cerebral palsy (OR = 1.08, 95 % CI 0.39-2.99), blindness (OR = 0.34, 95 % CI 0.01-8.56), and hearing loss (OR = 1.04, 95 % CI 0.06-17.15). There were no differences between groups with respect to the percentage of preterm infants with severe retinopathy of prematurity of stage III or above (OR = 1.30, 95 % CI 0.50-3.43), severe intraventricular hemorrhage of stage III or above (OR = 2. 91, 95 % CI 0.64-13.23), necrotizing enterocolitis (OR = 0.57, 95 % CI 0.13-2.54), and borderline personality disorder (OR = 1. 06, 95 % CI 0.50-2.26). The rhEPO treatment has beneficial effect on the neurodevelopment outcomes without severe adverse side effect in preterm infants. PMID- 25300690 TI - Suitable depth of epidural puncture in nulliparous pregnant woman. AB - We study the suitable depth for epidural puncture in primiparas so as to decrease epidural complications and provide anesthesiologists with an appropriate insertion guide. A prospective study of 87 primipara patients receiving labor analgesia who had epidural punctures in the course of vaginal delivery were randomly divided into 3 groups: the L 3,4 group (N = 27), the L 2,3 group (N = 29), and the L 1,2 group (N = 26). Predictive statistical models were used for the formulation of the ideal epidural puncture needle depth. Eighty two patients who had non-traumatic epidural punctures were studied. There were no significant changes in age, weight, height, weight/height ratio, gestational weeks, fetus weight, pregnancy weight, weight difference, and fetus weight (P > 0.05). Compared with L 3,4 intervertebral space, the puncture depth in L 1,2 and L 2,3 was significantly shorter (P < 0.05) and (P < 0.001), respectively; Regression equation: PD (cm) = 0.351 [LHZ] + 0.147 [BMI] + 0.017. The correlation coefficient for LHZ was 0.351 (95 % CI 0.278-0.424; P < 0.001), the correlation coefficient for BMI was 0.147 (95 % CI 0.123-0.171; P < 0.001). This formula is accurate and practical with less complex calculations. However, further validation through a prospective study will be required. It is an accurate way to localize the puncture site in parturients and improve the efficiency of puncture in parturients for analgesia labor.Epidural puncture depth prediction in L 1,2, L 2,3, and L 3,4 can supply with a related reference. PMID- 25300691 TI - Effects of gamma irradiation on collagen damage and remodeling. AB - PURPOSE: To evaluate the dose-time dependences of structural changes occurring in collagen within 24 hours to three months after gamma-irradiation at doses from 2 40 Gy in vivo. MATERIALS AND METHODS: Rat's tail tendon was chosen as in vivo model, with its highly ordered collagen structure allowing the changes to be interpreted unambiguously. Macromolecular level (I) was investigated by differential scanning calorimetry (DSC); fibers and bundles level (II) by laser scanning microscopy (LSM), and bulk tissue microstructural level (III) by cross polarization optical coherence tomography (CP-OCT). RESULTS: For (I), the formation of molecular cross-links and breaks appeared to be a principal mechanism of collagen remodeling, with the cross-links number dependent on radiation dose. Changes on level (II) involved primary, secondary and tertiary bundles splitting in a day and a week after irradiation. Bulk collagen microstructure (III) demonstrated early widening of the interference fringes on CP-OCT images observed to occur in the tendon as result of this splitting. At all three levels, the observed collagen changes demonstrated complete remodeling within ~ a month following irradiation. CONCLUSION: The time course and dose dependencies of the observed collagen changes at different levels of its hierarchy further contribute to elucidating the role of connective tissue in the radiotherapy process. PMID- 25300692 TI - Exponential rise of dynamical complexity in quantum computing through projections. AB - The ability of quantum systems to host exponentially complex dynamics has the potential to revolutionize science and technology. Therefore, much effort has been devoted to developing of protocols for computation, communication and metrology, which exploit this scaling, despite formidable technical difficulties. Here we show that the mere frequent observation of a small part of a quantum system can turn its dynamics from a very simple one into an exponentially complex one, capable of universal quantum computation. After discussing examples, we go on to show that this effect is generally to be expected: almost any quantum dynamics becomes universal once 'observed' as outlined above. Conversely, we show that any complex quantum dynamics can be 'purified' into a simpler one in larger dimensions. We conclude by demonstrating that even local noise can lead to an exponentially complex dynamics. PMID- 25300693 TI - Localization of cervical lymphadenopathy due to colorectal adenocarcinoma metastasis to the thyroid with intraoperative ultrasound. PMID- 25300694 TI - Sepsis varies arterial two-pore-domain potassium channel messenger RNA in mice. AB - BACKGROUND: Hemodynamic changes are mainly responsible for organ failure and subsequently for the poor outcome of sepsis. Occurring macro- and micro circulatory dysfunctions are not homogeneously distributed in the vessel beds. Especially mesenteric arterioles are subject to hypoperfusion during sepsis, and in consequence, a dysfunction of the downstream organs develops. Furthermore, impaired perfusion of the splanchnic area may cause intestinal barrier breakdown supporting the translocation of bacteria or toxins into the circulation aggravating a systemic infection and organ failure. The two-pore potassium channels (K2P channels) are responsible for setting the resting membrane potential of smooth muscle cells. Because of their sensitivity by various metabolic or humoral mediators, which are also varying during inflammatory processes, they can determine vascular resistance during sepsis. Dopamine receptors type 1 (D1R) and 2 (D2R) are assumed to be involved in the regulation of arterial tone under hypoxic conditions and are investigated too. MATERIALS AND METHODS: Sepsis was induced in mice by the cecal ligation and puncture model. This study investigates the expression of K2P channels and the dopamine receptors at RNA level by real-time polymerase chain reaction analysis and two K2P channels at the protein level by Western blotting. RESULTS: The RNA levels of K2P channels respond differently to sepsis. Although the weakly inward rectifying K+ channel 2 (TWIK 2) is not affected, TWIK-related acid-sensitive K+ channel 1 and 2 (TASK 1 and TASK 2) and TWIK-related K+ channel 1 (TREK 1) are partially downregulated during the course of the experiment. A downregulation of D1R and an upregulation of the D2R could be observed during the septic phase. CONCLUSIONS: The changes shown could be important factors for the reduced mesenteric perfusion during sepsis. PMID- 25300695 TI - Neuroendocrine tumor biomarkers: current status and perspectives. AB - The identification of accurate harbingers of disease status and therapeutic efficacy are critical requirements in precise diagnosis and effective management. Initially, tissue analysis was regarded as ideal but invasive strategies represent risk compared with peripheral blood sampling. Thus far, most biomarkers, whether in tissue or blood/urine, have been single analytes with varying degrees of sensitivity and specificity. Some analytes have not exhibited robust metrics or have lacked methodological rigor. Neuroendocrine disease represents an area of dire biomarker paucity since the individual biomarkers (gastrin, insulin, etc.) are not widely applicable to the diverse types of neuroendocrine neoplasia. Broad-spectrum markers such as chromogranin A have limitations in sensitivity, specificity and reproducibility. Monoanalytes cannot define the multiple variables (proliferation, metabolic activity, invasive potential, metastatic propensity) that constitute tumor growth. The restricted status of the neuroendocrine neoplasia field has resulted in a lack of comprehensive knowledge of the molecular and cellular biology of the disease, with tardy application of innovative technology. This overview examines limitations in current practice and describes contemporary viable strategies under evaluation, including the identification of novel analytes (gene transcripts, microRNA), circulating tumor cells and metabolic imaging agents that identify disease. Novel requirements are necessary to develop biomathematical algorithms for synchronous calibration of multiple molecular markers and predictive nomograms that interface biological variables to delineate disease progress or treatment efficacy. Optimally, the application of novel techniques and amalgamations of multianalyte assessment will provide a personalized molecular disease signature extrapolative of neuroendocrine neoplasia status and likelihood of progression and predictive of therapeutic opportunity. PMID- 25300696 TI - Minimally invasive esophagectomy and its current role in esophageal cancer. AB - The incidence of esophageal cancer has increased over the previous 4 decades. In 2014 alone, it is estimated that there will be 18,000 patients diagnosed with esophageal cancer, and 15,000 deaths from the disease.Esophagectomy, most commonly with adjuvant chemotherapy and radiation to treat locoregional spread, is the primary vehicle to offer patients cure. Open approaches (transthoracic Ivor Lewis, transhiatal, left thoracoabdominal, and 'three phase' McKeown esophagectomy) have been the most common, and are associated with significant morbidity and mortality.With this morbidity in mind, minimally invasive esophagectomy (MIE) has gained enthusiasm from the surgical community as an approach to minimize post-operative morbidity without sacrificing long-term outcomes. In this article, we review the basic steps of the three major approaches to MIE. We also review the recent data which supports the surgical field's growing enthusiasm for this approach to esophageal cancer. Based on our review of current data, we conclude that patients undergoing MIE have improved short-term outcomes with regard to morbidity and quality of life, with no adverse effects of the quality of oncologic resection. PMID- 25300697 TI - Abdominal organ bioengineering: current status and future perspectives. AB - Organ transplantation represents one of the major milestones of modern medicine and surgical practice in terms of life-years prolonged and quality of life offered for chronic patients. Each year over 100,000 donor organ transplants are performed worldwide. In spite of the rapid advancement and expansion of this niche, it has become a victim of its own success as the donor supply is far oustripped by the demand for replacement organs. Furthermore, current methods only allow for successful transplantation in the setting of life-long, aggressive immunosuppression protocols which enhances the incidence of secondary neoplasm and other associated sequelae. Against this background, recent advances in the fields of regenerative medicine, tissue engineering, and cellular biology have coalesced into a promising new avenue of investigation involving the fabrication of de novo, transplantable organs using autologous cells. Donor organs are stripped of their native cellular material leaving only acellular, extracellular matrix constructs behind. These constructs can then be recellularized with a patient's own cells in order to form transplantable organs that do not require immunosuppression. Furthermore, in theory, these methods could provide a potentially inexhaustible source of organs to meet the growing need for viable transplants. In this review, we describe these methods as well as contemporary successes for various organ systems. PMID- 25300698 TI - Size matching in lung transplantation: new alternatives to an old problem. AB - Current allocation of lungs is based on prioritizing candidates based on a risk benefit ratio. Since the current algorithm does not account for recipient size, waitlist candidates with short stature may wait longer for optimal organs resulting in waitlist mortality. Understanding the pitfalls of lung volume measurements, complications of size mismatch and alternate options for optimizing size may help us better utilize the donor pool. With the advent of ex vivo lung perfusion systems the donor supply is expected to slowly increase. Despite this, concerns with size matching will remain. Finding alternate options such as lobar lung transplant may be a reasonable option for these patients. While lobar lung transplant may not be equivalent to size matched grafts it will continue to be a viable option for those waiting with continued functional decline. PMID- 25300699 TI - Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources. AB - OBJECTIVES: To evaluate the magnitude of serious adverse events (SAEs) observed in postmarketing reports of tocilizumab (TCZ) for rheumatoid arthritis (RA) in relation to SAEs observed in TCZ clinical trials and external epidemiology data. METHODS: A total of 64,000 patient-years (PY) of TCZ exposure was needed to determine, with 90% power, whether rates of SAEs of interest (eg, death, hepatic, gastrointestinal, and cardiovascular) were >=50% higher (agreed with the Food and Drug Administration) than expected. Reporting rates were calculated for spontaneously reported SAEs, open-label or unblinded postmarketing clinical trials (phase 3b/4), and a Japanese postmarketing surveillance program in the global postmarketing safety database. Event rates were calculated for the registrational placebo-controlled trials and long-term extension data. External comparators for anti-tumor necrosis factor (aTNF)-treated RA patients were derived from a US-based health care insurance claims database or published literature. RESULTS: The global postmarketing safety database provided 65,099 PY of TCZ exposure; the aTNF external comparator population provided 53,360 PY. Spontaneous reporting rates per 100 PY (95% confidence interval) were 8.3 (8.1, 8.5) SAEs, 0.39 (0.34, 0.44) deaths, 0.06 (0.04, 0.08) serious hepatic events, 0.15 (0.12, 0.18) serious gastrointestinal events, 0.09 (0.07, 0.12) serious myocardial infarctions, 0.15 (0.12, 0.18) serious strokes, and 0.07 (0.05, 0.09) cardiac deaths in the global postmarketing safety database. These were of similar magnitude to corresponding rates from registrational clinical trials, the aTNF external comparator population, and published literature. CONCLUSIONS: SAE rates observed among postmarketing TCZ users were similar to those of various comparison populations. Predetermined design of studies to compare postmarketing AEs using multiple data sources is a useful strategy that can be applied to other medications. PMID- 25300700 TI - Identification of the best cutoff points and clinical signs specific for early recognition of macrophage activation syndrome in active systemic juvenile idiopathic arthritis. AB - OBJECTIVES: The purpose of our study was to detect early clinical and laboratory signs that help to discriminate macrophage activation syndrome (MAS) from active systemic juvenile idiopathic arthritis (SJIA) without MAS. METHODS: Our retrospective study was based on reviewing the medical charts of the children admitted to the rheumatology department with active SJIA and definite MAS (n = 18) and without MAS (n = 40). We evaluated the data related to SJIA and MAS at the moment of the patient's admission. If the patient had signs of MAS since admission or developed definite MAS later during this flare, he was referred to the main group. The children who did not have MAS during the flare episode and did not have MAS in the past medical history were in the control group. We calculated the cutoff points for MAS parameters, performed the analysis of sensitivity and specificity, identified the predictors, and provided the preliminary diagnostic rule through "the-number-of-criteria-present" approach. RESULTS: The clinical signs were relevant to MAS in SJIA: oligoarticular disease course (OR = 5.6), splenomegaly (OR = 67.6), hemorrhages (OR = 33.0), and respiratory failure (OR = 11.3). The involvement of wrist (OR = 0.2), MCP (OR = 0.1), and PIP joints (OR = 0.1) was protective against MAS development. The best cutoffs for laboratory parameters were PLT <= 211 * 10(9)/l, WBC <= 9.9 * 10(9)/l, AST > 59.7U/l, LDH > 882U/l, albumin <= 2.9g/dl, ferritin > 400MUg/l, fibrinogen <= 1.8g/l, and proteinuria. The laboratory variables were more precise in the discrimination of early MAS than clinical: any 3 or more laboratory criteria provided the highest specificity (1.0) and sensitivity (1.0) and OR = 2997. CONCLUSIONS: We detected clinical and laboratory markers and created preliminary diagnostic (laboratory) guidelines for early discrimination of MAS in active SJIA. PMID- 25300701 TI - Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. AB - OBJECTIVES: To assess the long-term efficacy and safety of single and multiple courses of rituximab therapy in systemic sclerosis (SSc) patients with and without lung disease. METHODS: A total of 20 SSc patients with a diffuse disease were treated with rituximab. At baseline and during follow-up the lung involvement was evaluated with pulmonary function tests (FVC and DLCO) and with lung high-resolution computed tomography (HRCT). RESULTS: The skin score, activity, and severity indices improved significantly after 12 months and at final follow-up compared to baseline. After 12 months, there was a significant increase of FVC and TLC compared to baseline (p = 0.024 and p = 0.005, respectively), while the mean DLCO value remained stable. Considering the last available follow-up in six patients with restrictive lung disease at baseline, two patients (33.3%) experienced an increase of more than 10% of FVC, one patient had a decrease of FVC >10%, while in three patients FVC remained stable (50%). After the mean follow-up of 48.5 +/- 20.4 months, among the patients with normal lung parameters at baseline, FVC remained stable in 12 (85.7%) and in one patient (14.3%) it increased by more than 10%. At the final follow-up, the alveolar and interstitial HRCT scores remained stable in more than 80% of patients, both in patients with and without restrictive lung disease at baseline. CONCLUSIONS: Anti CD20 B cell depletion therapy is effective on skin involvement but seems also to preserve the pulmonary function, as supported by a stable or improved FVC and stable interstitial score, suggesting a possible role of rituximab as a modifying therapy overall in early diffuse SSc. PMID- 25300702 TI - Letter to the editor. PMID- 25300703 TI - Drugs for preventing malaria in pregnant women in endemic areas: any drug regimen versus placebo or no treatment. AB - BACKGROUND: Pregnancy increases the risk of malaria and this is associated with poor health outcomes for both the mother and the infant, especially during the first or second pregnancy. To reduce these effects, the World Health Organization recommends that pregnant women living in malaria endemic areas sleep under insecticide-treated bednets, are treated for malaria illness and anaemia, and receive chemoprevention with an effective antimalarial drug during the second and third trimesters. OBJECTIVES: To assess the effects of malaria chemoprevention given to pregnant women living in malaria endemic areas on substantive maternal and infant health outcomes. We also summarised the effects of intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) alone, and preventive regimens for Plasmodium vivax. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and reference lists up to 1 June 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs of any antimalarial drug regimen for preventing malaria in pregnant women living in malaria-endemic areas compared to placebo or no intervention. In the mother, we sought outcomes that included mortality, severe anaemia, and severe malaria; anaemia, haemoglobin values, and malaria episodes; indicators of malaria infection, and adverse events. In the baby, we sought foetal loss, perinatal, neonatal and infant mortality; preterm birth and birthweight measures; and indicators of malaria infection. We included regimens that were known to be effective against the malaria parasite at the time but may no longer be used because of parasite drug resistance. DATA COLLECTION AND ANALYSIS: Two review authors applied inclusion criteria, assessed risk of bias and extracted data. Dichotomous outcomes were compared using risk ratios (RR), and continuous outcomes using mean differences (MD); both are presented with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Seventeen trials enrolling 14,481 pregnant women met our inclusion criteria. These trials were conducted between 1957 and 2008, in Nigeria (three trials), The Gambia (three trials), Kenya (three trials), Mozambique (two trials), Uganda (two trials), Cameroon (one trial), Burkina Faso (one trial), and Thailand (two trials). Six different antimalarials were evaluated against placebo or no intervention; chloroquine (given weekly), pyrimethamine (weekly or monthly), proguanil (daily), pyrimethamine-dapsone (weekly or fortnightly), and mefloquine (weekly), or intermittent preventive therapy with SP (given twice, three times or monthly). Trials recruited women in their first or second pregnancy (eight trials); only multigravid women (one trial); or all women (eight trials). Only six trials had adequate allocation concealment.For women in their first or second pregnancy, malaria chemoprevention reduces the risk of moderate to severe anaemia by around 40% (RR 0.60, 95% CI 0.47 to 0.75; three trials, 2503 participants, high quality evidence), and the risk of any anaemia by around 17% (RR 0.83, 95% CI 0.74 to 0.93; five trials,, 3662 participants, high quality evidence). Malaria chemoprevention reduces the risk of antenatal parasitaemia by around 61% (RR 0.39, 95% CI 0.26 to 0.58; seven trials, 3663 participants, high quality evidence), and two trials reported a reduction in febrile illness (low quality evidence). There were only 16 maternal deaths and these trials were underpowered to detect an effect on maternal mortality (very low quality evidence).For infants of women in their first and second pregnancies, malaria chemoprevention probably increases mean birthweight by around 93 g (MD 92.72 g, 95% CI 62.05 to 123.39; nine trials, 3936 participants, moderate quality evidence), reduces low birthweight by around 27% (RR 0.73, 95% CI 0.61 to 0.87; eight trials, 3619 participants, moderate quality evidence), and reduces placental parasitaemia by around 46% (RR 0.54, 95% CI 0.43 to 0.69; seven trials, 2830 participants, high quality evidence). Fewer trials evaluated spontaneous abortions, still births, perinatal deaths, or neonatal deaths, and these analyses were underpowered to detect clinically important differences.In multigravid women, chemoprevention has similar effects on antenatal parasitaemia (RR 0.38, 95% CI 0.28 to 0.50; three trials, 977 participants, high quality evidence)but there are too few trials to evaluate effects on other outcomes.In trials giving chemoprevention to all pregnant women irrespective of parity, the average effects of chemoprevention measured in all women indicated it may prevent severe anaemia (defined by authors, but at least < 8 g/L: RR 0.19, 95% CI 0.05 to 0.75; two trials, 1327 participants, low quality evidence), but consistent benefits have not been shown for other outcomes.In an analysis confined only to intermittent preventive therapy with SP, the estimates of effect and the quality of the evidence were similar.A summary of a single trial in Thailand of prophylaxis against P. vivax showed chloroquine prevented vivax infection (RR 0.01, 95% CI 0.00 to 0.20; one trial, 942 participants). AUTHORS' CONCLUSIONS: Routine chemoprevention to prevent malaria and its consequences has been extensively tested in RCTs, with clinically important benefits on anaemia and parasitaemia in the mother, and on birthweight in infants. PMID- 25300704 TI - Chronic obstructive pulmonary disease as a risk factor for lung cancer. AB - The association between chronic obstructive pulmonary disease (COPD) and lung cancer has long been a subject of intense debate. The high prevalence of COPD in elderly smokers inevitably strengthens their coincidence. In addition to this contingent coincidence, recent studies have revealed a close association between the two diseases that is independent of the smoking history; that is, the existence of COPD is an independent risk factor for the development of lung cancer. Molecular-based evidence has been accumulating as a result of the efforts to explain the underlying mechanisms of this association. These mechanisms may include the following: the retention of airborne carcinogens followed by the activation of oncogenes and the suppression of tumor suppressor genes; the complex molecular mechanism associated with chronic inflammation in the distal airways of patients with COPD; the possible involvement of putative distal airway stem cells; and genetic factors that are common to both COPD and lung cancer. The existence of COPD in patients with lung cancer may potentially affect the process of diagnosis, surgical resection, radiotherapy, chemotherapy, and end-of-life care. The comprehensive management of COPD is extremely important for the appropriate treatment of lung cancer. Surgical resections with the aid of early interventions for COPD are often possible, even for patients with mild-to moderate COPD. New challenges, such as lung cancer CT screening for individuals at high risk, are now in the process of being implemented. Evaluating the risk of lung cancer in patients with COPD may be warranted in community-based lung cancer screening. PMID- 25300705 TI - Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo. AB - Simvastatin is effective and well tolerated, with adverse reactions mainly affecting skeletal muscle. Important mechanisms for skeletal muscle toxicity include mitochondrial impairment and increased expression of atrogin-1. The aim was to study the mechanisms of toxicity of simvastatin on H9c2 cells (a rodent cardiomyocyte cell line) and on the heart of male C57BL/6 mice. After, exposure to 10 MUmol/L simvastatin for 24 h, H9c2 cells showed impaired oxygen consumption, a reduction in the mitochondrial membrane potential and a decreased activity of several enzyme complexes of the mitochondrial electron transport chain (ETC). The cellular ATP level was also decreased, which was associated with phosphorylation of AMPK, dephosphorylation and nuclear translocation of FoxO3a as well as increased mRNA expression of atrogin-1. Markers of apoptosis were increased in simvastatin-treated H9c2 cells. Treatment of mice with 5 mg/kg/day simvastatin for 21 days was associated with a 5 % drop in heart weight as well as impaired activity of several enzyme complexes of the ETC and increased mRNA expression of atrogin-1 and of markers of apoptosis in cardiac tissue. Cardiomyocytes exposed to simvastatin in vitro or in vivo sustain mitochondrial damage, which causes AMPK activation, dephosphorylation and nuclear transformation of FoxO3a as well as increased expression of atrogin-1. Mitochondrial damage and increased atrogin-1 expression are associated with apoptosis and increased protein breakdown, which may cause myocardial atrophy. PMID- 25300707 TI - Solid-ionic liquid interfaces: pore filling revisited. AB - The properties of ionic liquids on ordered and non-ordered mesoporous silicas (silica gel, MCM-41, SBA-15) were studied by nitrogen sorption, mercury intrusion and thermogravimetric analyses, as well as (129)Xe-NMR spectroscopy. The ionic liquids investigated are based on the 1-hexyl-3-methylimidazolium cation, which was combined with anions of low (bis(trifluoromethanesulfonyl)imide; [NTf2](-)), medium (trifluoromethylsulfonate; [CF3SO3](-)) to high (acetate; [OAc](-)) basicity. The surface coverage depends on both the type of ionic liquid and support used. This results not only in layer or droplet formation, but also in different physico-chemical properties of the ionic liquid when compared to the bulk, depending mainly on the strength of interaction at the interface. Furthermore, the mercury intrusion analysis of mesopores is shown not to be suitable for supported ionic liquids. PMID- 25300708 TI - Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss. AB - BACKGROUND: Aminoglycosides are a critical component of multidrug-resistant tuberculosis (MDR-TB) treatment but data on their efficacy and adverse effects in Botswana is scarce. We determined the effect of amikacin on treatment outcomes and development of hearing loss in MDR-TB patients. METHODS: Patients started on MDR-TB treatment between 2006 and 2012 were included. Multivariate analysis was used to determine the effect of amikacin on treatment outcomes and development of hearing loss. RESULTS: 437 MDR-TB patients were included, 288 (66%) of whom were HIV co-infected. 270 (62%) developed hearing loss, of whom 147 (54%) had audiometry. Of the 313 (72%) patients who completed treatment, 228 (73%) had a good outcome (cure or treatment completion). Good outcome was associated with longer amikacin treatment (adjusted OR [aOR] 1.13, 95% CI 1.06 - 1.21) and higher dosage (aOR 1.90, 95% CI 1.12 - 2.99). Longer amikacin duration (aOR 1.98, 95% CI 1.86 - 2.12) and higher dosage per weight per month (aOR 1.15, 95% CI 1.04 - 1.28) were associated with development of hearing loss. Amikacin treatment duration modified the effect of the dosage on the risk of hearing loss, increasing this risk as the duration increased. CONCLUSIONS: Amikacin was effective for MDR-TB treatment, but was associated with a high incidence of hearing loss especially in our study population. Total treatment duration and average monthly amikacin dose were associated with improved outcomes; however these were also associated with development of hearing loss. PMID- 25300709 TI - Does species richness affect fine root biomass and production in young forest plantations? AB - Tree species diversity has been reported to increase forest ecosystem above ground biomass and productivity, but little is known about below-ground biomass and production in diverse mixed forests compared to single-species forests. For testing whether species richness increases below-ground biomass and production and thus complementarity between forest tree species in young stands, we determined fine root biomass and production of trees and ground vegetation in two experimental plantations representing gradients in tree species richness. Additionally, we measured tree fine root length and determined species composition from fine root biomass samples with the near-infrared reflectance spectroscopy method. We did not observe higher biomass or production in mixed stands compared to monocultures. Neither did we observe any differences in tree root length or fine root turnover. One reason for this could be that these stands were still young, and canopy closure had not always taken place, i.e. a situation where above- or below-ground competition did not yet exist. Another reason could be that the rooting traits of the tree species did not differ sufficiently to support niche differentiation. Our results suggested that functional group identity (i.e. conifers vs. broadleaved species) can be more important for below ground biomass and production than the species richness itself, as conifers seemed to be more competitive in colonising the soil volume, compared to broadleaved species. PMID- 25300710 TI - Comparison of fecal culture and F57 real-time polymerase chain reaction for the detection of Mycobacterium avium subspecies paratuberculosis in Swiss cattle herds with a history of paratuberculosis. AB - BACKGROUND: Bovine paratuberculosis is an incurable chronic granulomatous enteritis caused by Mycobacterium avium subspecies paratuberculosis (MAP). The prevalence of MAP in the Swiss cattle population is hard to estimate, since only a few cases of clinical paratuberculosis are reported to the Swiss Federal Food Safety and Veterinary Office each year.Fecal samples from 1,339 cattle (855 animals from 12 dairy herds, 484 animals from 11 suckling cow herds, all herds with a history of sporadic paratuberculosis) were investigated by culture and real-time polymerase chain reaction (PCR) for shedding of MAP. RESULTS: By culture, MAP was detected in 62 of 445 fecal pools (13.9%), whereas PCR detected MAP in 9 of 445 pools (2.0%). All 186 samples of the 62 culture-positive pools were reanalyzed individually. By culture, MAP was grown from 59 individual samples (31.7%), whereas PCR detected MAP in 12 individual samples (6.5%), all of which came from animals showing symptoms of paratuberculosis during the study. Overall, MAP was detected in 10 out of 12 dairy herds (83.3%) and in 8 out of 11 suckling cow herds (72.7%). CONCLUSIONS: There is a serious clinically inapparent MAP reservoir in the Swiss cattle population. PCR cannot replace culture to identify individual MAP shedders but is suitable to identify MAP-infected herds, given that the amount of MAP shed in feces is increasing in diseased animals or in animals in the phase of transition to clinical disease. PMID- 25300711 TI - Coming back to oneself: a case of anoxic brain damage from a phenomenological perspective. AB - Struck by a cardiac arrest that lasted 3/4 of an hour, a 53-year-old man suddenly collapsed one day at work. The result was a serious anoxic brain damage that developed into dementia. This essay presents the process of 'coming back to himself' while it questions what this concept might imply. The descriptions and analyses rest upon an ethnographic study of his life, at hospitals and then at home, assisted by his wife, who is also the author of this article. Theoretically, the analysis depends on Merleau-Ponty's phenomenology of perception and is also based on the therapeutic use of music in treating people with dementia championed by Oliver Sachs. It is argued that the field of medicine has much to learn from the anthropological method of long-term observation, as well as theories of embodiment that see the body as simultaneously being an object and a subject. PMID- 25300712 TI - Are single mothers' higher smoking rates mediated by dysfunctional coping styles? AB - BACKGROUND: Smoking prevalence has been shown to be considerably higher among single mothers as compared to their married or cohabiting counterparts. This study examines whether this could be attributed to single mothers' different capability in dealing with stress. METHODS: Based on cross-sectional data of 3129 German mothers, the study explores the associations between single motherhood, coping styles and moderate and heavy smoking pattern using a regression-based 'parallel multiple mediator model'. RESULTS: Single mothers showed higher rates of negative coping styles than partnered mothers, holding for 'self blame/rumination' (p < 0.001), 'blaming others' (p = 0.048) and in particular for 'substance consumption' (p < 0.001). With respect to positive coping styles the findings were heterogeneous: while partnered mothers scored higher on 'active influence' (p < 0.001), single mothers showed higher values of 'positive self verbalisation' (p < 0.001). Evidence for a mediating effect of coping styles on the relationship between single motherhood and moderate as well as heavy smoking was only found for 'substance consumption'. Moreover, single motherhood may moderate the effect of 'self-blame/rumination' on heavy smoking (p = 0.025). Against expectations, higher levels of 'active influence' were not associated with lower but with significant higher odds of moderate smoking (OR = 1.19). CONCLUSION: Single mothers compared to partnered mothers showed a different ability to cope with stress. However, only the coping strategy 'substance consumption' mediates the relationship between single motherhood and smoking. Exclusively in single mothers, 'self-blame/rumination' was associated with heavy smoking, indicating that they might utilize smoking as a way to come to terms with negative ruminative thoughts. PMID- 25300713 TI - Non-contact fiber-optical trapping of motile bacteria: dynamics observation and energy estimation. AB - The dynamics and energy conversion of bacteria are strongly associated with bacterial activities, such as survival, spreading of bacterial diseases and their pathogenesis. Although different discoveries have been reported on trapped bacteria (i.e. immobilized bacteria), the investigation on the dynamics and energy conversion of motile bacteria in the process of trapping is highly desirable. Here, we report a non-contact optical trapping of motile bacteria using a modified tapered optical fiber. Using Escherichia coli as an example, both single and multiple motile bacteria have been trapped and manipulated in a non-contact manner. Bacterial dynamics has been observed and bacterial energy has been estimated in the trapping process. This non-contact optical trapping provides a new opportunity for better understanding the bacterial dynamics and energy conversion at the single cell level. PMID- 25300714 TI - Scientific rigor through videogames. AB - Hypothesis-driven experimentation - the scientific method - can be subverted by fraud, irreproducibility, and lack of rigorous predictive tests. A robust solution to these problems may be the 'massive open laboratory' model, recently embodied in the internet-scale videogame EteRNA. Deploying similar platforms throughout biology could enforce the scientific method more broadly. PMID- 25300715 TI - Body packing: a review of general background, clinical and imaging aspects. AB - To avoid detection at border crossings or airport customs, drug trafficking is increasingly performed by intra-corporeal concealment. Body packers may ingest packets of varying size and containing varying drugs (mostly cocaine, heroin and cannabis) mixed with other compounds, while body pushers will insert packets in the rectum or vaginal cavity. Body packing may lead to potential life-threatening complications with acute overdose syndromes after packet rupture and intestinal obstruction with possible ensuing bowel rupture being the most significant complications. Physicians including radiologists should be aware of the capabilities of imaging techniques to screen for presence of drug packets as well as the potential complications. Although conventional radiography has long been and still is the most important imaging modality for screening for presence of intestinal packets, the better test characteristics in conjunction with the decreasing radiation exposure, will likely render computed tomography (CT) more important in the future. For imaging of symptomatic patients, CT already is the modality of choice. Besides these modalities, ultrasound and magnetic resonance imaging will be discussed in this paper, together with more general background and clinical information. PMID- 25300716 TI - Self-citation rate and impact factor in ophthalmology. AB - PURPOSE: To analyze the self-citation rate (SCR) of ophthalmology journals, determine its possible effect on a journal's impact factor (IF) and compare the SCR of subspecialty journals versus general ophthalmology journals. METHOD: A retrospective consecutive study of ophthalmology journals listed in the Journal Citations Report (JCR) 2013. We retrieved these parameters from each journal's report: IF, total citations, self-citations, SCR and IF without self-citations (corrected IF). RESULTS: A significant correlation was detected between the number of self-citations and publications (R(2) = 86.3, p = 0.000). Subspecialty journals had a significantly higher SCR than general journals (p = 0.017). No significant difference was found in terms of IF and corrected IF between general and subspecialty journals (p = 0.260 and p = 0.108, respectively). No significant correlation between IF and SCR was detected (p = 0.099). The corrected IF was inversely correlated with SCR (R(2) = -32.6, p = 0.013). An inverse correlation was detected between SCR and IF in the 29 ophthalmology journals with the lowest IF (R(2) = -57.3, p = 0.001). CONCLUSION: Unlike other fields of medicine, the IF of an ophthalmology journal does not correlate with its SCR. Self-citation is found more often in journals with a low corrected IF and is inversely correlated with IF in the bottom half. PMID- 25300717 TI - [Attention-deficit/hyperactivity disorder in childhood/adolescence and impairments associated with daily life: French data from the European Lifetime Impairment Survey]. AB - Attention-deficit/hyperactivity disorder (ADHD) has a 3-5 % prevalence in Europe and North America. It is associated with functional impairment and can have a negative impact on social and family relationships and daily living. The experiences of children/adolescents with ADHD in Europe, as reported by parents/caregivers who completed the online Lifetime Impairment Survey (LIS), were evaluated. The LIS was conducted in France, Germany, Italy, Spain, the Netherlands, and the UK to assess the extent to which the daily lives of children/adolescents (aged<20 years) with ADHD are affected by their disorder as reported by parents/caregivers. Participants to the survey were recruited by email from the GfK Global Online Panel, which consisted of a database of 487,533 members (including 85,512 members in France). The control group comprised parents/caregivers of children/adolescents without ADHD. Treatment for ADHD, as perceived by parents/caregivers of children/adolescents with ADHD, was also reviewed. Data from France are described here. In France, 157 (79 with ADHD, 78 without ADHD) parents/caregivers completed the LIS. Median age at diagnosis was 6.0 years (mean [SD], 6.4 [3.18] years) as reported by parents/caregivers; pharmacological treatment was prescribed for 46.8 % (37/79) of children/adolescents with ADHD. Compared with the control group, ADHD was associated with significantly greater impairment across all domains studied (P<0.001), except problems in home life. General impairment scale data demonstrated that more parents/caregivers of children/adolescents in the ADHD group than the control group thought that experiences during childhood/adolescence and unhappy memories would have a negative impact on their child in adult life (29-32 % vs 9-12 %, respectively). Issues that affected school/education were associated with perceived greater impairment in the ADHD group than the control group. Several limitations should be taken into account when reviewing these data, including the lack of questionnaire validation (although developed by expert consensus). In addition, the survey was conducted online and, as such, was more likely to recruit individuals who were well educated, computer-literate, and willing to participate in the survey. Survey participants may also have had greater awareness of ADHD and the associated symptoms and impairment, and greater motivation to seek diagnosis or treatment, than the general population. Furthermore, diagnosis of ADHD and history of diagnosis were parent-/caregiver-reported and the results may have been influenced by recall bias or subjective reporting given that the survey did not directly assess the opinions of the children/adolescents with the disorder. These data provide insights into the negative impact that ADHD imposes on all aspects of life for children/adolescents in France with the disorder. Moreover, ADHD is believed to have a negative impact later in the patient's life. Further progress is needed in France and across Europe to provide a more effective and consistent approach to the treatment of patients with ADHD and to meet the expectations regarding management and treatment for the families concerned. PMID- 25300706 TI - Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial. AB - BACKGROUND AND PURPOSE: WARCEF randomized 2,305 patients in sinus rhythm with ejection fraction (EF) <= 35% to warfarin (INR 2.0-3.5) or aspirin 325 mg. Warfarin reduced the incident ischemic stroke (IIS) hazard rate by 48% over aspirin in a secondary analysis. The IIS rate in heart failure (HF) is too low to warrant routine anticoagulation but epidemiologic studies show that prior stroke increases the stroke risk in HF. In this study, we explore IIS rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified. METHODS: We compared potential stroke risk factors between patients with baseline stroke and those without using the exact conditional score test for Poisson variables. We looked for risk factors for IIS, by comparing IIS rates between different risk factors. For EF we tried cut-off points of 10, 15 and 20%. The cut-off point 15% was used as it was the highest EF that was associated with a significant increase in IIS rate. IIS and EF strata were balanced as to warfarin/aspirin assignment by the stratified randomized design. A multiple Poisson regression examined the simultaneous effects of all risk factors on IIS rate. IIS rates per hundred patient years (/100 PY) were calculated in patient groups with significant risk factors. Missing values were assigned the modal value. RESULTS: Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2,048 (3.1%) without had IIS. IIS rate in patients with baseline stroke (2.37/100 PY) was greater than patients without (0.89/100 PY) (rate ratio 2.68, p < 0.001). Fourteen of 219 (6.4%) patients with ejection fraction (EF) <15% and 70 of 2,079 (3.4%) with EF >= 15% had IIS. In the multiple regression analysis stroke at baseline (p < 0.001) and EF <15% vs. >= 15% (p = 0.005) remained significant predictors of IIS. IIS rate was 2.04/100 PY in patients with EF <15% and 0.95/100 PY in patients with EF >= 15% (p = 0.009). IIS rate in patients with baseline stroke and reduced EF was 5.88/100 PY with EF <15% decreasing to 2.62/100 PY with EF <30%. CONCLUSIONS: In a WARCEF exploratory analysis, prior stroke and EF <15% were risk factors for IIS. Further research is needed to determine if a clinically relevant stroke risk reduction is obtainable with warfarin in HF patients with prior stroke and reduced EF. PMID- 25300719 TI - Contrast-enhanced spectral mammography: an emerging new tool in the clinician's arsenal. PMID- 25300718 TI - Radiotherapy staffing in the European countries: final results from the ESTRO HERO survey. AB - BACKGROUND: The ESTRO Health Economics in Radiation Oncology (HERO) project has the overall aim to develop a knowledge base of the provision of radiotherapy in Europe and build a model for health economic evaluation of radiation treatments at the European level. The first milestone was to assess the availability of radiotherapy resources within Europe. This paper presents the personnel data collected in the ESTRO HERO database. MATERIALS AND METHODS: An 84-item questionnaire was sent out to European countries, through their national scientific and professional radiotherapy societies. The current report includes a detailed analysis of radiotherapy staffing (questionnaire items 47-60), analysed in relation to the annual number of treatment courses and the socio-economic status of the countries. The analysis was conducted between February and July 2014, and is based on validated responses from 24 of the 40 European countries defined by the European Cancer Observatory (ECO). RESULTS: A large variation between countries was found for most parameters studied. Averages and ranges for personnel numbers per million inhabitants are 12.8 (2.5-30.9) for radiation oncologists, 7.6 (0-19.7) for medical physicists, 3.5 (0-12.6) for dosimetrists, 26.6 (1.9-78) for RTTs and 14.8 (0.4-61.0) for radiotherapy nurses. The combined average for physicists and dosimetrists is 9.8 per million inhabitants and 36.9 for RTT and nurses. Radiation oncologists on average treat 208.9 courses per year (range: 99.9-348.8), physicists and dosimetrists conjointly treat 303.3 courses (range: 85-757.7) and RTT and nurses 76.8 (range: 25.7-156.8). In countries with higher GNI per capita, all personnel categories treat fewer courses per annum than in less affluent countries. This relationship is most evident for RTTs and nurses. Different clusters of countries can be distinguished on the basis of available personnel resources and socio-economic status. CONCLUSIONS: The average personnel figures in Europe are now consistent with, or even more favourable than the QUARTS recommendations, probably reflecting a combination of better availability as such, in parallel with the current use of more complex treatments than a decade ago. A considerable variation in available personnel and delivered courses per year however persists among the highest and lowest staffing levels. This not only reflects the variation in cancer incidence and socio-economic determinants, but also the stage in technology adoption along with treatment complexity and the different professional roles and responsibilities within each country. Our data underpin the need for accurate prediction models and long-term education and training programmes. PMID- 25300720 TI - Pulmonary functional magnetic resonance imaging: asthma temporal-spatial maps. AB - RATIONALE AND OBJECTIVES: Hyperpolarized (3)He magnetic resonance imaging (MRI) previously revealed the temporal and spatial heterogeneity of ventilation defects in asthmatics, but these findings have not been used in treatment studies or to guide personalized therapy. Our objective was to exploit the temporal and spatial information inherent to (3)He MRI and develop image processing methods to generate pulmonary ventilation temporal-spatial maps that could be used to measure, optimize, and guide asthma therapy. MATERIALS AND METHODS: In this proof of-concept study, seven asthmatics provided written informed consent to an approved protocol and underwent spirometry and (3)He MRI on three occasions, each 5 +/- 2 days apart. A registration and segmentation pipeline was developed to generate three-dimensional, temporal-spatial, pulmonary function maps. Briefly, (3)He ventilation images were segmented to generate ventilation masks that were coregistered and voxels classified according to their temporal behavior. This enabled the regional mapping of temporally persistent and intermittent ventilation defects that were normalized to the (1)H MRI thoracic cavity volume to generate persistent ventilation defect percent (VDPP) and intermittent ventilation defect percent (VDPI). RESULTS: (3)He temporal-spatial pulmonary function maps identified temporally persistent and intermittent ventilation defects. VDP(I) was significantly greater in the posterior (P = .04) and inferior (P = .04) lung as compared to the anterior and superior lung. Persistent and intermittent ventilation defect percent were strongly correlated with forced expiratory volume in one second/forced vital capacity (VDP(P): r = -0.87, P = .01; VDP(I): r = -0.96, P = .0008). CONCLUSIONS: Temporal-spatial pulmonary maps generated from (3)He MRI can be used to quantify temporally persistent and intermittent ventilation defects as asthma intermediate end points and targets for therapy. PMID- 25300721 TI - Quantitative assessment of effects of motion compensation for liver and lung tumors in CT perfusion. AB - RATIONALE AND OBJECTIVES: To study the effects of four different rigid alignment approaches on both time-concentration curves (TCCs) and perfusion maps in computed tomography perfusion (CTp) studies of liver and lung tumors. MATERIALS AND METHODS: Eleven data sets in patients who were subjected to axial CTp after contrast agent administration were assessed. Each data set consists of four different sequences, according to the different rigid alignment configurations considered to compute blood flow perfusion maps: no alignment, translational, craniocaudal, and three dimensional (3D). The color maps were built on TCCs according to the maximum slope method. The effects of motion correction procedures on the reliability of TCCs and perfusion maps were assessed both quantitatively and visually. RESULTS: TCCs built after 3D alignments show the best indices as well as producing the most reliable maps. We show examinations in which the translational alignment only yields more accurate TCCs, but less reliable perfusion maps, than those achieved with no alignment. Furthermore, we show color maps with two different perfusion patterns, both considered reliable by radiologists, achieved with different motion correction approaches. CONCLUSIONS: The quantitative index we conceived allows relating quality of 3D alignment and reliability of perfusion maps. A better alignment does not necessarily yield more reliable perfusion values: color maps resulting from either alignment procedure must be critically assessed by radiologists. This achievement will hopefully represent a step forward for the clinical use of CTp studies for staging, prognosis, and monitoring values of therapeutic regimens. PMID- 25300722 TI - Quantitative determination of liver triglyceride levels with 3T 1H-MR spectroscopy in mice with moderately elevated liver fat content. AB - RATIONALE AND OBJECTIVES: To diagnose hepatic steatosis with noninvasive magnetic resonance (MR)-based measurements, threshold values of liver fat percentages are used. However, these differ between studies. Consequently, the choice of threshold values influences diagnostic accuracy, especially in subjects with borderline hepatic steatosis. In this study, we compared (1)H-MR spectroscopy (MRS) and biochemically determined liver fat content in mice with moderately elevated fat content and studied the diagnostic accuracy of (1)H-MRS using two literature-based threshold values. MATERIALS AND METHODS: Fifty mice were divided into three groups: 21 C57Bl/6OlaHSD (B6) mice on a high-fat diet, 20 B6 mice on a control diet, and 9 LDLr-/- mice on a high-fat high-cholesterol diet. (1)H-MRS was performed using multi-echo STEAM at 3T to derive a fat mass fraction ((1)H MRS fat content). Biochemical fat content was determined from liver homogenates. Correlation and agreement were assessed with the Pearson correlation coefficient and the Bland-Altman analysis and diagnostic accuracy by calculating sensitivity, specificity, and positive and negative predictive values. RESULTS: All mice were pooled to form a single cohort. Mean (+/-standard deviation) biochemical fat content was 32.2 (+/-13.9) mg/g. Mean (1)H-MRS fat content did not differ at 30.2 (+/-12.0) mg/g (P = .13). Correlation r was 0.74 (P < .0001). Bland-Altman analysis indicated that (1)H-MRS fat content underestimated biochemical fat content by 2.1 mg/g. The diagnostic accuracy of (1)H-MRS depended to a great extent on the chosen reference threshold value. CONCLUSIONS: (1)H-MRS measurement of moderately elevated liver fat content in mice correlated substantially with biochemical fat content measurement. Contrary to earlier studies, diagnostic accuracy of (1)H-MRS fat content in borderline liver fat content appears limited. PMID- 25300723 TI - Small hepatocellular carcinoma: MRI findings for predicting tumor growth rates. AB - RATIONALE AND OBJECTIVES: Current clinical practice favors imaging rather than biopsy to diagnose hepatocellular carcinoma (HCC). There is a need to better understand tumor biology and aggressiveness of HCC. Our goal is to investigate magnetic resonance imaging (MRI) features of HCC that are associated with faster growth rates (GRs). MATERIALS AND METHODS: After approval from institutional review board, a retrospective evaluation was performed of pre-liver transplant patients. Fifty-two patients who developed a >2 cm HCC on serial imaging were included in the study group, with a total of 60 HCCs seen. Precursor foci were identified on serial MRIs before the specific diagnostic features of >2 cm HCC could be made, and GRs and MRI features, including signal on T1- and T2-weighted images (WI), the presence of intralesional steatosis on chemical shift imaging, and enhancement pattern were analyzed. GRs were correlated with imaging features. RESULTS: The average GR of precursor lesions to >2 cm HCC was determined to be 0.23 cm/mo (standard deviation [SD], 0.32), with a doubling time of 5.26 months (SD, 5.44). The presence of increased signal intensity (SI) on T2-WI was associated with significantly higher growth (P = .0002), whereas increased intensity on T1-WI at the initial study was associated with a significantly lower GR (P = .0162). Furthermore, lesions with hypervascular enhancement with washout pattern had significantly higher GR (P = .0164). There is no evidence of differences in GRs seen in lesions with steatosis. CONCLUSIONS: Small precursor lesions with increased SI on T2-WI and a washout pattern of enhancement are associated with faster GRs, which may suggest more aggressive tumor biology. These features may be helpful in patient management and surveillance for HCC. PMID- 25300724 TI - Linear and volumetric evaluation of the adrenal gland--MDCT-based measurements of the adrenals. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to provide normal values of volumetry and linear dimensions of adrenal glands. MATERIALS AND METHODS: Contrast-enhanced multidetector computed tomography scans of 105 patients were evaluated in this retrospective study. Imaging software was used both to measure the adrenal gland volume and to determine linear dimensions and density. For interobserver reliability, determination was repeated by a second reader in 10 patients selected at random. RESULTS: The mean adrenal volume was 4.84 (+/-1.67) cm3 on the left side and 3.62 (+/-1.23) cm3 on the right side. The total adrenal volume was mainly influenced by body weight (P < .001) and gender with women having smaller glands on average. The total width of the adrenal gland was 15.80 (+/-3.05) mm on the right side and 18.96 (+/-3.37) mm on the left side. There was a significant correlation between volume and linear measurements (P < .001). The mean density of both adrenal glands was 32.66 (+/-19.64) HU. Overall, interobserver reliability was high for volumetry (left adrenal, r = 0.98; right adrenal, r = 0.90) and low for linear dimensions. CONCLUSIONS: Normal data for volumetry and linear dimensions are provided. There is a concordance between volumetric and linear assessment. However, volumetry is more reproducible. PMID- 25300725 TI - Testing for interchangeability of imaging tests. AB - RATIONALE AND OBJECTIVES: New tests are typically assessed by estimating their technical and diagnostic performance through comparisons with a reference standard. A valid reference standard, however, is not always available and is not required for assessing the interchangeability of a new test with an existing one. MATERIALS AND METHODS: To show interchangeability of a new test with an existing test, one compares the differences in diagnoses between the new and existing tests to differences between diagnoses made with the existing test on several occasions. We illustrate the test for interchangeability with two studies. In a transcatheter aortic valve replacement study, we test whether semiautomated analysis can be used interchangeably with manual reconstructions from three dimensional computed tomography (CT) images. In patients with femoroacetabular impingement, we test whether magnetic resonance imaging (MRI) can replace CT to measure acetabular version. RESULTS: Although the semiautomated method agreed often with the manual measurement of aortic valve size (87.6%), interchanging the semiautomated method with manual measurements by an expert would lead to a 1.7% 12.2% increase in the frequency of disagreement. Interchanging MRI for CT to measure acetabular version would lead to differences in angle measurements of 2.0 degrees to 3.1 degrees in excess of the differences we would expect to see with CT alone. CONCLUSIONS: Testing for agreement or correlation between a new and an existing test is not sufficient evidence of the performance of a new test. A formal evaluation of interchangeability can be conducted in the absence of a reference standard. PMID- 25300726 TI - Interprofessional education: radiologists and technologists. PMID- 25300727 TI - How is our self altered in psychiatric disorders? A neurophenomenal approach to psychopathological symptoms. AB - The self is central in our experience and has often been assumed to be necessary for any kind of consciousness in philosophy. Recent investigations in neuroscience demonstrate a particular set of regions such as the cortical midline regions to be associated with the processing of stimuli specifically related to the self as distinguished from those remaining unrelated to the self. Furthermore, findings show a close overlap between self-related activity and high levels of resting state activity in especially anterior midline regions. Interestingly, recent findings in psychiatric disorders such as depression and schizophrenia show resting state abnormalities in exactly these regions, that is in the cortical midline structures. Based on phenomenal and neural observations, I here suggest a neurophenomenal approach that directly links neuronal and phenomenal features (without sandwiching cognitive or sensorimotor functions) to psychopathological symptoms of self in depression and schizophrenia. PMID- 25300728 TI - Physical activity in spondyloarthritis: a systematic review. AB - Physical activity (PA) is associated with numerous health-related benefits among adults with chronic diseases and the general population. As the benefits are dose dependent, this review aims to establish the PA levels of adults with spondyloarthritis and to compare these to the general population. Electronic databases (Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE/PubMed, PEDro, AMED, CINAHL) were systematically searched from inception to May 2014 using medical subject headings and keywords. This was supplemented by searching conference abstracts and hand-searching reference lists of included studies. Eligible studies were randomized controlled trials and observational studies of adults with SpA in which free-living PA or energy expenditure levels were measured. Subjects less than 18 years or with juvenile-onset SpA were excluded. Outcomes included objective and self-report measurements. Two reviewers independently screened studies for inclusion and assessed methodological quality using the Cochrane risk of bias tool and the RTI item bank. From the 2,431 records reviewed, nine studies involving 2,972 participants were included. This review focused on qualitative synthesis. Meta-analyses were not undertaken due to differences in study design, measurement tools, and participant characteristics. This heterogeneity, coupled with the risk of bias inherent in the included observational studies, limits the generalizability of findings. Objective measurements suggest PA levels may be lower among adults with spondyloarthritis than in healthy population controls. Self-reported PA and self-reported rates of adherence to PA recommendations varied largely across studies; higher disease activity was associated with lower self-reported PA levels. Physical activity levels may be lower in adults with axial spondyloarthritis, with higher disease activity associated with lower PA levels. PMID- 25300729 TI - Prevalence, incidence, and associated factors of avascular necrosis in Korean patients with systemic lupus erythematosus: a nationwide epidemiologic study. AB - Avascular necrosis (AVN) is one of the most frequent types of organ damage in systemic lupus erythematosus (SLE). However, little is currently known about the epidemiology of AVN in SLE patients. The aim of this study was to estimate the prevalence and incidence of AVN in Korean patients with SLE based on National Health Insurance (NHI) claims data and to determine the risk factors for AVN among SLE patients. This study was conducted using the 2006-2010 data of 25,358 SLE patients from the NHI program. AVN cases were defined as those with at least one diagnosis of AVN. The prevalence was calculated by dividing the number of AVN cases by the number of SLE cases in the same year. The annual incidence was calculated by dividing the number of incident AVN cases by the number of SLE prevalent cases not previously diagnosed with AVN. Patients who developed AVN in 2008-2010 were compared with SLE patients who did not develop AVN to identify any risk factors. The prevalence of AVN among SLE patients (2006-2010) was 31.5-34.2 per 1,000 persons and was similar in all the years studied. The incidence per 1,000 persons of AVN among SLE patients was 8.6 [95 % confidence interval (95 % CI) 6.9-10.3] in 2008, 9.8 (95 % CI 8.0-11.6) in 2009, and 8.4 (95 % CI 6.8-10.0) in 2010. Regression analysis indicated that taking an oral corticosteroid [odds ratio (OR) 2.12, 95 % CI 1.39-3.23] or an intravenous corticosteroid (OR 1.5, 95 % CI 1.2-1.89) was significantly associated with AVN. In addition, AVN was associated with use of immunosuppressive agents (OR 2.12, 95 % CI 1.66-2.72), hydroxychloroquine (OR 1.4, 95 % CI 1.09-1.81), and lipid-lowering agents (OR 1.78, 95 % CI 1.24-2.57) among the prescribed medications, and with hypertension (OR 1.39, 95 % CI 1.08-1.79) among the comorbidities. The prevalence and incidence of AVN among SLE patients, which were 31.5-34.2 and 8.4-9.8 per 1,000 persons, respectively, may be representative of the entire population of symptomatic AVN patients with SLE in Korea. AVN is associated with the use of corticosteroids, immunosuppressants, hydroxychloroquine, lipid-lowering agents, and with hypertension. Studies of large, prospective cohorts are needed to confirm these results. PMID- 25300730 TI - Effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with knee osteoarthritis. AB - Establishing prevention and therapeutic strategies for osteoarthritis (OA) is necessary to minimize functional disability and the impact of the disease on society. The aim of this study was to determine the effects of an exercise therapy protocol on inflammatory markers, perception of pain, and physical performance in individuals with OA of the knee. The protocol consisted of flexibility training and muscle strengthening over 12 weeks with three 80-min sessions per week. Peripheral blood was collected to determine serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and soluble forms of the TNF-alpha receptor (sTNFR1 and sTNFR2). A clinical assessment of the musculoskeletal system and Western Ontario and McMaster Universities (WOMAC) questionnaire were applied to evaluate the specific symptoms of knee OA. Pain intensity was evaluated using a visual analog scale (VAS). All measurements were taken before and after the intervention. Twenty-two individuals (mean age 58.8 +/ 6.4 years) completed the protocol. A decrease in the perception of pain was evident on VAS (p < 0.001) and pain subscale of the WOMAC (p < 0.001). In addition, there was a reduction in serum levels of IL-6 (p < 0.001). However, changes in the levels of the TNF-alpha and its soluble receptors were not statistically significant. Physical function subscale score and the WOMAC global score improved significantly (p < 0.001). The training also promoted an increase in the progression load for all muscles groups analyzed (p < 0.001). Our data suggest that the exercise therapy protocol could be a strategy for reducing IL-6 levels, managing pain, and improving function in individuals with OA of the knee. However, more studies are necessary to investigate the issue. PMID- 25300731 TI - The clinical burden of generalized osteoarthritis represented by self-reported health-related quality of life and activity limitations: a cross-sectional study. AB - The involvement of multiple joints is common in osteoarthritis (OA), often referred to as generalized osteoarthritis (GOA). However, since research and practice mainly focus on a specific OA localization, the health status of patients with GOA is largely unknown. Therefore, we aimed to describe the clinical burden of GOA in terms of self-reported health-related quality of life (HRQoL) and activity limitations. In this cross-sectional study, individuals clinically diagnosed with GOA and referred to multidisciplinary treatment, completed questionnaires on socio-demographics, joint involvement, HRQoL (SF-36) and activity limitations (HAQ-DI). SF-36 physical (PCS) and mental component summary scores (MCS) were calculated using norm-based data. The patient's specific most important activity limitations were linked to the International Classification of Functioning, Disability and Health. A total of 147 patients participated [85 % female; mean (SD) age 60 (8) years]. The majority (93 %) had symptomatic OA in both the upper and lower extremities. Predominant joints with symptomatic OA were the hands (85 %) and knees (82 %). Mean (SD) SF-36 PCS and MCS scores were 37 (7) and 48 (10), respectively, showing a broad impact of GOA on the physical component of health. The mean (SD) HAQ-DI score was 1.27 (0.50) indicating moderate to severe functional limitations. Activities concerning mobility and domestic life were considered most important activity limitations, especially walking. The results show a high clinical burden of GOA in terms of HRQoL and activity limitations. This study points to the need of developing non pharmacological interventions for patients with GOA that should target on improving the physical component of health and mobility limitations. PMID- 25300733 TI - Adult vaccination disparities among foreign-born populations in the U.S., 2012. AB - BACKGROUND: Foreign-born persons are considered at higher risk of undervaccination and exposure to many vaccine-preventable diseases. Information on vaccination coverage among foreign-born populations is limited. PURPOSE: To assess adult vaccination coverage disparities among foreign-born populations in the U.S. METHODS: Data from the 2012 National Health Interview Survey were analyzed in 2013. For non-influenza vaccines, the weighted proportion vaccinated was calculated. For influenza vaccination, Kaplan-Meier survival analysis was used to assess coverage among individuals interviewed during September 2011-June 2012 and vaccinated in August 2011-May 2012. RESULTS: Overall, unadjusted vaccination coverage among U.S.-born respondents was significantly higher than that of foreign-born respondents: influenza, age >=18 years (40.4% vs 33.8%); pneumococcal polysaccharide vaccine (PPV), 18-64 years with high-risk conditions (20.8% vs 13.7%); PPV, >=65 years (62.6% vs 40.5%); tetanus vaccination, >=18 years (65.0% vs 50.6%); tetanus, diphtheria, and acellular pertussis (Tdap), >=18 years (15.5% vs 9.3%); hepatitis B, 18-49 years (37.2% vs 28.4%); shingles, >=60 years (21.3% vs 12.0%); and human papilloma virus (HPV), women 18-26 years (38.7% vs 14.7%). Among the foreign born, vaccination coverage was generally lower for non-U.S. citizens, recent immigrants, and those interviewed in a language other than English. Foreign-born individuals were less likely than U.S.-born people to be vaccinated for pneumococcal (>=65 years), tetanus, Tdap, and HPV (women) after adjusting for confounders. CONCLUSIONS: Vaccination coverage is lower among foreign-born adults than those born in the U.S. It is important to consider foreign birth and immigration status when assessing vaccination disparities and planning interventions. PMID- 25300732 TI - Growth hormone, insulin-like growth factor-1 and the aging brain. AB - Growth hormone (GH) and insulin-like growth factor (IGF)-1 regulate the development and function of cells throughout the body. Several clinical diseases that result in a decline in physical and mental functions are marked by mutations that disrupt GH or IGF-1 signaling. During the lifespan there is a robust decrease in both GH and IGF-1. Because GH and IGF-1 are master regulators of cellular function, impaired GH and IGF-1 signaling in aging/disease states leads to significant alterations in tissue structure and function, especially within the brain. This review is intended to highlight the effects of the GH and IGF-1 on neuronal structure, function, and plasticity. Furthermore, we address several potential mechanisms through which the age-related reductions in GH and IGF-1 affect cognition. Together, the studies reviewed here highlight the importance of maintaining GH and IGF-1 signaling in order to sustain proper brain function throughout the lifespan. PMID- 25300734 TI - Access to healthy food stores modifies effect of a dietary intervention. AB - BACKGROUND: Recent evidence suggests that opening a grocery store in a food desert does not translate to better diet quality among community residents. PURPOSE: This study evaluated the influence of proximity to a healthy food store on the effect of a dietary behavioral intervention on diet among obese adults randomized to either a high fiber or American Heart Association diet intervention. METHODS: Participants were recruited from Worcester County, Massachusetts, between June 2009 and January 2012. Dietary data were collected via 24-hour recalls at baseline and 3, 6, and 12 months post-intervention. Based on in-store inspection data, a store was considered as having adequate availability of healthy foods if it had at least one item available in each of 20 healthy food categories. Linear models evaluated maximum change in dietary outcomes in relation to road distance from residence to the nearest June healthy food store. The analysis was conducted in January to June 2014. RESULTS: On average, participants (N=204) were aged 52 years, BMI=34.9, and included 72% women and 89% non-Hispanic whites. Shorter distance to a healthy food store was associated with greater improvements in consumption of fiber (b=-1.07 g/day per mile, p<0.01) and fruits and vegetables (b=-0.19 servings/day per mile, p=0.03) with and without covariate adjustment. CONCLUSIONS: The effectiveness of dietary interventions is significantly influenced by the presence of a supportive community nutrition environment. Considering the nationwide efforts on promotion of healthy eating, the value of improving community access to healthy foods should not be underestimated. CLINICAL TRIAL REGISTRATION NUMBER: NCT00911885. PMID- 25300735 TI - Childhood adversity and adult chronic disease: an update from ten states and the District of Columbia, 2010. AB - BACKGROUND: Adverse childhood experiences (ACEs), including child abuse and family dysfunction, are linked to leading causes of adult morbidity and mortality. Most prior ACE studies were based on a nonrepresentative patient sample from one Southern California HMO. PURPOSE: To determine if ACE exposure increases the risk of chronic disease and disability using a larger, more representative sample of adults than prior studies. METHODS: Ten states and the District of Columbia included an optional ACE module in the 2010 Behavioral Risk Factor Surveillance Survey, a national cross-sectional, random-digit-dial telephone survey of adults. Analysis was conducted in November 2012. Respondents were asked about nine ACEs, including physical, sexual, and emotional abuse and household member mental illness, alcoholism, drug abuse, imprisonment, divorce, and intimate partner violence. An ACE score was calculated for each subject by summing the endorsed ACE items. After controlling for sociodemographic variables, weighted AORs were calculated for self-reported health conditions given exposure to zero, one to three, four to six, or seven to nine ACEs. RESULTS: Compared to those who reported no ACE exposure, the adjusted odds of reporting myocardial infarction, asthma, fair/poor health, frequent mental distress, and disability were higher for those reporting one to three, four to six, or seven to nine ACEs. Odds of reporting coronary heart disease and stroke were higher for those who reported four to six and seven to nine ACEs; odds of diabetes were higher for those reporting one to three and four to six ACEs. CONCLUSIONS: These findings underscore the importance of child maltreatment prevention as a means to mitigate adult morbidity and mortality. PMID- 25300736 TI - Finding words and word structure in artificial speech: the development of infants' sensitivity to morphosyntactic regularities. AB - To achieve language proficiency, infants must find the building blocks of speech and master the rules governing their legal combinations. However, these problems are linked: words are also built according to rules. Here, we explored early morphosyntactic sensitivity by testing when and how infants could find either words or within-word structure in artificial speech snippets embodying properties of morphological constructions. We show that 12-month-olds use statistical relationships between syllables to extract words from continuous streams, but find word-internal regularities only if the streams are segmented. Seven-month olds fail both tasks. Thus, 12-month-olds infants possess the resources to analyze the internal composition of words if the speech contains segmentation information. However, 7-month-old infants may not possess them, although they can track several statistical relations. This developmental difference suggests that morphosyntactic sensitivity may require computational resources extending beyond the detection of simple statistics. PMID- 25300737 TI - Short-term outcomes following the use of self-expanding metallic stents in acute malignant colonic obstruction--a single centre experience. AB - BACKGROUND: Colonic self-expanding metallic stents (SEMS) may provide prompt relief of acute malignant colorectal obstruction (AMCO) and are increasingly used either palliatively or as a bridge to surgery (BTS) in patients in whom a definitive surgical approach is unsuitable. We evaluated short-term outcomes of malignant colorectal obstructive patients who underwent SEMS insertion in our institution over a 3-year period. METHODS: A prospectively maintained database was reviewed to identify all patients who presented to our institution with AMCO between August 2010 and 2013 and who were treated with a SEMS either temporarily or permanently. Additional data was retrieved from chart reviews and operation notes. RESULTS: Sixteen patients (12 males, 4 females) each had a single stent inserted during the study period, either palliatively (n = 11) or as a BTS (n = 5). The technical and clinical success rates were both 87.5% (14/16). The two unsuccessful stenting cases both had disseminated disease and required emergency surgery while five patients with curable disease proceeded to elective resections. There was no procedure-related mortality or stent-related perforations. The mean (standard deviation) length of stay post acute surgery was longer than elective surgery [45 +/- 21.2 vs. 15.8 +/- 4.0, days]. All patients in the BTS group were stoma-free post-operatively, while both patients who had emergency surgery ended up with permanent stomas. Finally, the stent complication rate was 6.2% (1/16), secondary to migration. CONCLUSIONS: Although limited by a small sample size, the study shows that SEMS have favourable short-term outcomes. Further adequately powered trials are needed to confirm those findings. PMID- 25300738 TI - The real-world application of single incision laparoscopic cholecystectomy. AB - OBJECTIVES: Most previous studies that have investigated single incision laparoscopic cholecystectomy (SILC) are case series with limited sample sizes. We have reviewed the outcome of 500 consecutive cases of SILC performed by a single surgeon at our center. MATERIALS AND METHODS: From April 2009 to October 2012, a single surgeon performed 1250 laparoscopic cholecystectomies for various gallbladder (GB) diseases. SILC was chosen as the surgical modality unless there was evidence of acute cholecystitis or GB empyema, the patient had a prior history of upper abdominal surgery, endoscopic sphincterotomy, or had comorbidities with an ASA score of III or higher. The clinicopathologic features and perioperative data of patients were retrospectively reviewed. RESULTS: The mean age and BMI of included patients were 42.7 years and 23.6 kg/m(2), respectively. The mean operating time was 52 min. Patients stayed in the hospital for an average of 1.3 days postoperatively. In 55 patients, an additional 2 mm trocar was inserted for retraction of the GB. One patient was converted to an open cholecystectomy because of Mirizzi syndrome. There were no observed complications including incisional hernias in this patient population. CONCLUSIONS: SILC is a safe, effective procedure for cholecystectomy that may be considered the main surgical strategy in select patients. PMID- 25300739 TI - Lithiated sulfoxides: alpha-sulfinyl functionalized carbanions. AB - Reactions of alkyl aryl sulfoxides H-CRR'S(O)Ar with n-BuLi-TMEDA (TMEDA = N,N,N',N'-tetramethylethylenediamine) afforded alpha-sulfinyl functionalized alkyl aryl lithium compounds of the type [Li2{CRR'S(O)Ar}2(TMEDA)2] (1, R/R' = H/H, Ar = Ph; 2, R/R' = H/H, Ar = p-Tol; 3, R/R' = Me/Me, Ar = Ph; 4, R/R' = H/Ph, Ar = Ph; 5, R/R' = Me/Ph, Ar = Ph). The compounds were characterized by (1)H, (13)C and (7)Li NMR spectroscopy and, except for 5, by single-crystal X-ray diffraction analyses. In crystals of 1, 2, 3 and 4 .Et2O dinuclear molecules with four-membered Li2O2 rings were found. There are no LiCalpha contacts, thus, "free" carbanions are the main structural feature. Reactions of 1-6 (6, R/R' = H/Me, Ar = Ph) with benzaldehyde and benzophenone afforded the corresponding sulfoxides of the type ArS(O)CRR'CHPhOH (1a-6a) and ArS(O)CRR'CPh2OH (1b-6b), respectively. The reactions yielding / and / proceeded with high diastereoselectivities. By X-ray diffractometry it has been shown that in the case of and the diastereomers consisting of the two enantiomers SSRC and RSSC were formed. PMID- 25300740 TI - Close, but not close enough. PMID- 25300741 TI - Hirayama disease: imaging profile of three cases emphasizing the role of flexion MRI. AB - We report three cases of Hirayama disease, cervical flexion myelopathy presenting as unilateral or bilateral asymmetric muscular atrophy of forearm and hand involving C7 - T1 myotomes in young males. MRI revealed asymmetric cord atrophy, altered signal intensity of cord, posterior dural detachment and enlarged posterior epidural space with multiple flow voids. This article emphasizes the role of Flexion MRI in diagnosing Hirayama disease. PMID- 25300742 TI - Point-of-care diagnostics, a major opportunity for change in traditional diagnostic approaches: potential and limitations. AB - 'Point-of-care' (POC) diagnostics are a powerful emerging healthcare approach. They can rapidly provide statistically significant results, are simple to use, do not require specialized equipment and are cost-effective. For these reasons, they have the potential to play a major role in revolutionizing the diagnosis, initiation and monitoring of treatment of major global diseases. This review focuses on antibody-based POC devices that target four major global diseases: cardiovascular diseases, prostate cancer, HIV infection and tuberculosis. The key statistics and pathology of each disease is described in detail, followed by an in-depth discussion on emerging POC devices that target each disease, highlighting their potential and limitations. PMID- 25300743 TI - GMC lays out charges against headache doctor in research misconduct case. PMID- 25300744 TI - Complete genome sequence of the mushroom-like aerial structure-forming Pseudomonas alkylphenolia, a platform bacterium for mass production of poly-beta d-mannuronates. AB - Pseudomonas alkylphenolia (KCTC 22206, JCM 16553) metabolizes phenols with an alkyl chain (C1-C5) at the para position. This strain forms mushroom-like aerial structures under p-cresol vapor, and its mutants are exploited to augment the production of poly-beta-d-mannuronate and its derivatives. In this study, we report the 5.7Mbp complete genome sequence of P. alkylphenolia, which will provide a basis for biotechnological applications of this strain. PMID- 25300745 TI - Comparison of expert and nonexpert physicians in the assessment of vertebral fractures using the semiquantitative method in Japan. AB - Assessment of vertebral fracture is critically important for the diagnosis and treatment of osteoporosis. This study aimed to clarify the effectiveness of the semiquantitative (SQ) method in the assessment of vertebral fractures in Japanese clinical practice. Forty-four physicians (seven experts and 37 nonexperts) assessed the spinal radiographs of 40 patients participating in the Adequate Treatment of Osteoporosis (A-TOP) Japanese Osteoporosis Intervention Trial (JOINT)-02 at the baseline, 12 months, and 24 months using the SQ method. The proportion of diagnosed fracture cases per spine was higher in the nonexpert group than in the expert group at each time point, and was especially high in the upper thoracic spine (T4-T6). The least mean squares spinal fracture index was significantly higher in the nonexpert group than in the expert group for all time points. The kappa statistics were also higher in the expert group than in the nonexpert group for all vertebral levels at all time points. Assessment of vertebral fractures using the SQ method tended to be overestimated by nonexpert physicians compared with the experts, with poor nonexpert interobserver reliability and well-matched expert interobserver reliability. Conscious efforts to avoid overestimation and to obtain higher reliability with the SQ method should be made to achieve more precise diagnoses and treatment of osteoporosis in Japanese clinical practice. PMID- 25300747 TI - Death of an alcohol-dependent patient following intentional drug intoxication: implication of baclofen? AB - Used in the treatment of spasticity at low doses, baclofen is also prescribed off label at high doses for the treatment of alcohol dependence. Several cases of baclofen intoxication have been reported, but only 1 case deals with the treatment of alcohol dependence. Thus, we report the first death in the context of baclofen off-label use of an alcohol-dependent patient with a high blood baclofen concentration after intentional drug intoxication. The safety profile of baclofen in the treatment of alcohol dependence is reviewed and discussed, underlining the obligatory caution that may support any prescription of high doses of baclofen in this off-label indication and especially in patients with concomitant psychiatric disorders. PMID- 25300746 TI - Sex hormone levels as determinants of bone mineral density and osteoporosis in Vietnamese women and men. AB - This study sought to investigate the prevalence of osteoporosis and the role of sex hormone levels in the determination of bone mineral density (BMD) and osteoporosis in a Vietnamese population of women and men. The cross-sectional study involved 269 women and 222 men aged 13-83 years, who were randomly selected from urban and rural areas in northern Vietnam. Serum concentrations of estradiol and testosterone were analyzed, and BMD was measured by dual X-ray absorptiometry. We found that the prevalence of osteoporosis in postmenopausal women was 18, 17, and 37 % for the femoral neck, total hip, and lumbar spine, respectively. For men aged 50 years or older, the corresponding values were 8, 7, and 12 %. In men, the most important predictors of BMD for the femoral neck and total hip were age, body mass index, and serum levels of estradiol. For the BMD of the lumbar spine, testosterone also had a significant influence. Determinants of osteoporosis in men for the total hip and lumbar spine were age, weight, and serum concentrations of estradiol and testosterone. In postmenopausal women, age, weight, and residence (urban vs rural) were the most important predictors of BMD and osteoporosis. For all women (including those of reproductive age), serum levels of estradiol were also significant. These data suggest that the prevalence of osteoporosis in the Vietnamese population is high also in men, and that estradiol levels are essential for bone mass in both men and women. The results should have clinical implications and increase awareness of an important health issue within Vietnamese society. PMID- 25300748 TI - Solid-phase extraction in segmented flow. AB - Two-phase flow systems are increasingly popular for miniaturized, high-throughput performance of analytical or chemical reactions. In this contribution, we extend a previously described method that allows to increase the range of applications of heterogeneous reactions in two-phase flow, i.e., reactions that rely on isolation and purification of the compound of interest for downstream analysis. Our concept is based on liquid plugs, which serve as miniaturized compartments for the analytical reactions. Purification of the target compound is achieved by extracting the analyte from the aqueous compartments using magnetic beads as solid carriers. In the present paper, we elucidate the influence of parameters such as the polarity of the liquid/liquid and solid/liquid interfaces, the magnetic forces and the fluidic conditions onto the extraction performance. The conditions for reliable extraction and purification of the target compounds are determined. Furthermore, we investigate how to facilitate breaking of the plugs through reduction of the surface tension of the solid/liquid interface. When a lower surface tension is employed, a smaller number of beads is required for the extraction process, which implies a higher sensitivity of the device. In addition, we generate channels with different surface chemistries, which are able to manipulate the flow of the two immiscible liquids. We describe a very simple way to generate such devices and show that we can achieve a transition from segmented flow of plugs to a side-by side flow of the two immiscible liquids, a key requirement for the purification of the compounds. PMID- 25300749 TI - The asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via two sequential tandem ring-closure/N-debenzylation processes. AB - Concise asymmetric syntheses of (-)-lupinine, (+)-isoretronecanol, (+)-5-epi tashiromine and (R,R)-1-(hydroxymethyl)octahydroindolizine (the azabicyclic core within stellettamides A-C) have been achieved in 8 steps or fewer from commercially available starting materials. The key steps in these syntheses involved the preparation of enantiopure beta-amino esters, upon conjugate addition of lithium (R)-N-(p-methoxybenzyl)-N-(alpha-methyl-p-methoxybenzyl)amide to either zeta-chloro or zeta-hydroxy substituted tert-butyl (E)-hept-2-enoate, or epsilon-chloro or epsilon-hydroxy substituted tert-butyl (E)-hex-2-enoate. Activation of the omega-substituent as a leaving group led to SN2-type ring closure, which occurred with concomitant N-debenzylation via an E1-type deprotection step, to give the corresponding pyrrolidine or piperidine in good yield. Subsequent alkylation of these enantiopure azacycles, followed by a second ring-closure/concomitant N-debenzylation step formed the pyrrolizidine, indolizidine or quinolizidine motif, and reduction with LiAlH4 gave the target compounds in diastereoisomerically and enantiomerically pure form. PMID- 25300750 TI - A case of imported Clostridium difficile PCR-ribotype 027 infection within the Czech Republic which has a high prevalence of C. difficile ribotype 176. AB - The first case of Clostridium difficile RT027 infection in the Czech Republic (CZ) was identified. The patient had been hospitalised in Germany prior to moving to CZ. Multiple-Locus Variable number tandem repeat Analysis revealed a genetic relatedness between the patient's isolate and RT027 isolate collected in the German hospital. PMID- 25300751 TI - Formal recycling of e-waste leads to increased exposure to toxic metals: an occupational exposure study from Sweden. AB - Electrical and electronic waste (e-waste) contains multiple toxic metals. However, there is currently a lack of exposure data for metals on workers in formal recycling plants. The objective of this study was to evaluate workers' exposure to metals, using biomarkers of exposure in combination with monitoring of personal air exposure. We assessed exposure to 20 potentially toxic metals among 55 recycling workers and 10 office workers at three formal e-waste recycling plants in Sweden. Workers at two of the plants were followed-up after 6 months. We collected the inhalable fraction and OFC (37-mm) fraction of particles, using personal samplers, as well as spot samples of blood and urine. We measured metal concentrations in whole blood, plasma, urine, and air filters using inductively coupled plasma-mass spectrometry following acid digestion. The air sampling indicated greater airborne exposure, 10 to 30 times higher, to most metals among the recycling workers handling e-waste than among the office workers. The exposure biomarkers showed significantly higher concentrations of chromium, cobalt, indium, lead, and mercury in blood, urine, and/or plasma of the recycling workers, compared with the office workers. Concentrations of antimony, indium, lead, mercury, and vanadium showed close to linear associations between the inhalable particle fraction and blood, plasma, or urine. In conclusion, our study of formal e-waste recycling shows that workers performing recycling tasks are exposed to multiple toxic metals. PMID- 25300752 TI - Frequent migration of introduced cucurbit-infecting begomoviruses among Middle Eastern countries. AB - BACKGROUND: In the early 2000s, two cucurbit-infecting begomoviruses were introduced into the eastern Mediterranean basin: the Old World Squash leaf curl virus (SLCV) and the New World Watermelon chlorotic stunt virus (WmCSV). These viruses have been emerging in parallel over the last decade in Egypt, Israel, Jordan, Lebanon and Palestine. METHODS: We explored this unique situation by assessing the diversity and biogeography of the DNA-A component of SLCV and WmCSV in these five countries. RESULTS: There was fairly low sequence variation in both begomovirus species (SLCV pi = 0.0077; WmCSV pi = 0.0066). Both viruses may have been introduced only once into the eastern Mediterranean basin, but once established, these viruses readily moved across country boundaries. SLCV has been introduced at least twice into each of all five countries based on the absence of monophyletic clades. Similarly, WmCSV has been introduced multiple times into Jordan, Israel and Palestine. CONCLUSIONS: We predict that uncontrolled movement of whiteflies among countries in this region will continue to cause SLCV and WmCSV migration, preventing strong genetic differentiation of these viruses among these countries. PMID- 25300753 TI - Trends of Infertility and Childlessness in India: Findings from NFHS Data. AB - Etiology of infertility varies from region to region and from one population to another and even from one locality to another within the same population. Childlessness has serious demographic, social and health implications. Hence an attempt has been made to get some approximation about levels and patterns of infertility and childlessness in India by using National Family Health Survey-2 (1998-1999) and National Family Health Survey-3 (2005-2006) data. The study population consists of women aged 20-49 years married for >= 5 years. Age of women, age at first marriage, place of residence, standard of living, working status of women, and region are some of the variables related with the rate of infertility and childlessness. Infertility rate is high among women in urban areas. This may be due to lifestyle or a later age at first marriage. Considering religion, Muslims show the lowest infertility rate. Scheduled tribes have high infertility rate. With increasing levels of educational attainment among women, infertility rate increases. This can be related to the fact that with aspirations for attaining higher educational level, marriage is delayed as a result of which in confirmation with aforementioned causation factors (higher age at marriage, urban living style etc.), infertility rate is high among this sub group of population. PMID- 25300754 TI - Intentional injuries and patient survival of burns: a 10-year retrospective cohort in southern Brazil. AB - BACKGROUND: Patients burned intentionally experience extensive injuries with high rates of morbidity and mortality. Nonetheless, there is no consensus if these patients have worse outcomes than unintentional burns considering injury severity and other preexistent comorbidities. METHODS: We conducted a ten-year retrospective review on all patients treated at the Burn Unit of Hospital de Pronto Socorro, Porto Alegre, Brazil, between 2003 and 2012. The aim was to compare survival of self-inflicted burns and burns from assaults with unintentional injuries using a Multivariable Cox Regression Analysis. RESULTS: 1734 patients were included in the study, 87.7% non-intentional, 6.6% self inflicted and 5.8% from aggression. Intentional injuries resulted in more severe injuries and were associated with psychiatric disorders and drug abuse. After controlling for injury severity, previous clinical comorbidities and previous psychiatric disorders, only self-inflicted burns correlated significantly with a higher risk of death (HR=1.59, CI 95% 1.05-2.41, p=0.03). CONCLUSIONS: Self inflicted injuries were independently associated with a higher risk of death. Burns from aggression were not associated with higher mortality in this model. Prevention of these injuries must be priority and treating the main associated factors such as drug abuse and psychiatric disorders may lower its occurrence. PMID- 25300755 TI - Efficacy of a burn-specific cognitive-behavioral group training. AB - OBJECTIVE: The aim of the present study was to evaluate the efficacy of a newly developed cognitive-behavioral group training, specifically designed for burn patients. METHOD: In a multicenter-study data pre- and post treatment and at 6 month follow-up were obtained from participants of the group program (Intervention group, IG; n=86) and a control group who received treatment as usual (TAU; n=128). Outcome variables of psychological distress, resources and health-related quality of life of both groups were compared using linear mixed models. RESULTS: Up to 6 months after group treatment, the IG reported a substantial decline of general symptom severity as well as posttraumatic stress, whereas the TAU group showed no significant change over time. Optimism increased in the IG after group treatment, but not in the TAU group. Regarding overall quality of life both groups showed a gradual improvement over the three assessment points. CONCLUSION: The newly developed burn-specific cognitive behavioral group intervention had positive effects on psychological well-being and resources of burn participants. As a consequence, the group intervention has been implemented as inherent part of the regular burn treatment in two rehabilitation centers in Germany. PMID- 25300756 TI - A systematic review of patient reported outcome measures (PROMs) used in child and adolescent burn research. AB - INTRODUCTION: Patient reported outcome measures (PROMs) can identify important information about patient needs and therapeutic progress. The aim of this review was to identify the PROMs that are being used in child and adolescent burn care and to determine the quality of such scales. METHODS: Computerised and manual bibliographic searches of Medline, Social Sciences Index, Cinahl, Psychinfo, Psycharticles, AMED, and HAPI, were used to identify English-language articles using English-language PROMs from January 2001 to March 2013. The psychometric quality of the PROMs was assessed. RESULTS: 23 studies met the entry criteria and identified 32 different PROMs (31 generic, 1 burns-specific). Overall, the psychometric quality of the PROMs was low; only two generic scales (the Perceived Stigmatisation Questionnaire and the Social Comfort Scale) and only one burns specific scale (the Children Burn Outcomes Questionnaire for children aged 5-18) had psychometric evidence relevant to this population. CONCLUSIONS: The majority of PROMs did not have psychometric evidence for their use with child or adolescent burn patients. To appropriately identify the needs and treatment progress of child and adolescent burn patients, new burns-specific PROMs need to be developed and validated to reflect issues that are of importance to this population. PMID- 25300757 TI - The use of "murder-immolation" or "homicidal-immolation" instead of "forced self immolation". PMID- 25300758 TI - Context-dependent pathways of the transmission of risk from communities to individuals. AB - Research has consistently documented the role of environmental risk factors in the onset of delinquent behavior among youth. Less is known about the processes through which these contextual risks are translated to individual youth behavior. The aim of the current study is to examine the role of family risk factors in the transmission of community risk. Data was obtained from a nationally representative sample of over 30,000 middle school youth and community key informants (CKI). A multilevel, moderated mediation model was estimated with family risk as the moderator of the effect of CKI ratings of community risk on youth perceptions of risk. Results showed that when youth came from low risk families (measured by parental use of positive family management strategies), youth perceptions of risk mediated the effects of community risk on youth delinquency; however, there was no evidence of a significant mediated effect under conditions of high risk (measured by poor family management). This appears to be because youth from high-risk families perceived their neighborhoods as high risk, regardless of actual levels of risk (as reported by CKI). This study finds that the relationship between communities and adolescent behavior is complex and interacts with the family environment. PMID- 25300760 TI - Cloning, expression and characterization of protein disulfide isomerase of Schistosoma japonicum. AB - The excretory/secretory (ES) proteins of schistosomes play important roles in modulating host immune systems and are regarded as potential vaccine candidates and drug targets. Protein disulfide isomerase (PDI) is an essential enzyme that is involved in disulfide bond formation and rearrangement. In the present study, SjPDI, a 52.8 kDa protein previously identified in a proteomics analysis as one of the ES proteins of Schistosoma japonicum, was cloned and characterized. Western blot analysis showed that recombinant SjPDI (rSjPDI) was recognized by serum from rabbits vaccinated with schistosome worm antigen. Worm protein extracts and ES protein extracts from S. japonicum could react with anti-rSjPDI mouse serum. Real-time PCR analysis indicated that SjPDI was expressed at all developmental stages tested, and a high expression level was detected in 42-day old male worms. Immunofluorescence analysis revealed that SjPDI was mainly distributed on the tegument and parenchyma of S. japonicum worms. An enzyme linked immunosorbent assay (ELISA) demonstrated that rSjPDI could induce a high level of rSjPDI-specific IgG antibodies. The biological activity of purified rSjPDI was confirmed by isomerization and antioxidative activity assays. The 35.32%, 26.19% reduction in the worm burden and 33.17%, 31.7% lower liver egg count were obtained in mice vaccinated with rSjPDI compared with the blank control group in two independent trials. Our preliminary results suggest that rSjPDI plays an important role in the development of the schistosome and is a potential vaccine candidate for schistosomiasis. PMID- 25300759 TI - Cardiac and renal effects of atrasentan in combination with enalapril and paricalcitol in uremic rats. AB - BACKGROUND/AIMS: The search for new therapies providing cardiorenal protection in chronic kidney disease (CKD) has led to treatments that combine conventional renin-angiotensin-aldosterone-system inhibitors with other drugs that exhibit potential in disease management. METHODS: In rats made uremic by renal ablation, we examined the effects of addition of the endothelin-A receptor antagonist atrasentan to a previously examined combination of enalapril (angiotensin converting enzyme inhibitor) and paricalcitol (vitamin D receptor activator) on cardiac and renal parameters. The effects of the individual and combined drugs were examined after a 3-month treatment. RESULTS: A decrease in systolic blood pressure, serum creatinine and proteinuria, and improvement of renal histology in uremic rats were attributed to enalapril and/or paricalcitol treatment; atrasentan alone had no effect. In heart tissue, individual treatment with the drugs blunted the increase in cardiomyocyte size, and combined treatment additively decreased cardiomyocyte size to normal levels. Perivascular fibrosis was blunted in uremic control rats with atrasentan or enalapril treatment. CONCLUSIONS: We found distinct cardiac and renal effects of atrasentan. Combination treatment with atrasentan, enalapril and paricalcitol provided positive effects on cardiac remodeling in uremic rats, whereas combination treatment did not offer further protective effects on blood pressure, proteinuria or renal histology. PMID- 25300761 TI - Allergenicity of two Anisakis simplex allergens evaluated in vivo using an experimental mouse model. AB - Anisakis (Anisakidae) is one of the most important causes of helminth-induced allergic reactions and elicits clinical responses that include urticaria, rhinitis, bronco-constriction, cough, and/or gastrointestinal symptoms. More than 13 reactive allergens have been identified in the serum of Anisakis allergy patients, but the allergenicity of only a few of these have been evaluated in vivo using a mouse model. To evaluate the allergenicity of two important allergens, Ani s 1 and Ani s 9, we induced experimental allergic airway inflammation in a mouse model by repeated intranasal administration of the allergens. Both recombinant proteins (rAni s 1 and rAni s 9) elicited increased airway hyperresponsivity, airway infiltration by inflammatory cells (especially eosinophils), bronchial epithelial cell hyperplasia, all of which are characteristic of allergic airway inflammation. These allergens significantly increased the levels of Th2-related cytokines (IL-4, IL-5, IL-13, and IL-25) and Th17 related cytokines (IL-6 and IL-17) in both splenocytes and airway (except IL 17 in airway by rAni s 9). OVA-specific IgE and total IgE were increased in rAni s 1 and rAni s 9 treated mice as compared with controls treated with OVA alone. In addition, these two allergens induced gene expression of thymic stromal lymphopoietin (TSLP) and IL-25 (initiators of the Th2 response), as well as CXCL1 (initiator of the Th17 response) in mouse lung epithelial cells. In conclusion, repeated intranasal treatments with rAni s 1 and rAni s 9 induced airway inflammation in mice by elevating of Th2 and Th17 responses in the lung. PMID- 25300762 TI - A description of parasites from Iranian snakes. AB - Little is known of the parasitic fauna of terrestrial snakes in Iran. This study aimed to evaluate the parasitic infection rates of snakes in Iran. A total of 87 snakes belonging to eight different species, that were collected between May 2012 and September 2012 and died after the hold in captivity, under which they were kept for taking poisons, were examined for the presence of gastrointestinal and blood parasites. According to our study 12 different genera of endoparasites in 64 (73.56%) of 87 examined snakes were determined. Forty one snakes (47.12%) had gastrointestinal parasites. In prepared blood smears, it was found that in 23 (26.43%) of 87 examined snakes there are at least one hemoparasite. To our knowledge, these are the first data on the internal parasitic fauna of Iranian terrestrial snakes and our findings show a higher prevalence of these organisms among them. PMID- 25300763 TI - Therapeutic enhancement of newly derived bacteriocins against Giardia lamblia. AB - Trials for identifying efficient anti-giardial agents are still ongoing. Nowadays, bacteriocins have attracted the attention as potential antimicrobial compounds. For the first time, the current study evaluated the therapeutic efficacy of bacteriocins derived from newly isolated Egyptian strains of probiotics Lactobacilli; L. acidophilus (P106) and L. plantarum (P164) against Giardia lamblia. Bacteriocins' efficacy was evaluated both in vitro; by growth inhibition and adherence assays, and in vivo; through estimation of parasite density, intestinal histopathological examination and ultrastructural analysis of Giardia trophozoites. In vivo bacteriocins' clinical safety was assessed. In vitro results proved that 50 ug of L. acidophilus bacteriocin induced reduction of the mean Giardia lamblia trophozoites by 58.3 +/- 4.04%, while at lower concentrations of 10 and 20 ug of both L. acidophilus and L. plantarum, non significant reduction of the mean parasite density was achieved. In vitro trophozoites adherence was susceptible to the tested bacteriocins at all studied concentrations with variable degrees, while the highest adherence reduction was demonstrated using 50 ug of L acidophilus bacteriocin. In vivo, oral inoculation of 50 ug/mouse L. acidophilus bacteriocin for 5 successive days resulted in a noteworthy decline of the intestinal parasite density, along with amelioration of intestinal pathology of infected mice. Ultrastructural examination proved thatfive doses of L. acidophilus bacteriocin showed marked changes in cellular architecture of the trophozoites with evident disorganization of the cell membrane, adhesive disc and cytoplasmic components. This is the first reported study of the safe anti-giardial efficacy of L. acidophilus (P106) derived bacteriocin, hence highlighting its great promise as a potential therapeutic safe alternative to existing commercial drugs. PMID- 25300764 TI - Identification of Fasciola species based on mitochondrial and nuclear DNA reveals the co-existence of intermediate Fasciola and Fasciola gigantica in Thailand. AB - Molecular techniques were used to identify Fasciola species collected from Chiang Mai Thailand. Morphometrically, 65 stained and 45 fresh worms collected from cattle suggested the possible occurrence of both F. gigantica and F. hepatica. Twenty-two worms comprising 15 from cattle and 7 from human patients, were identified subsequently based on three genetic markers: mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit 1 (nad1), mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS2). All of them presented the F. gigantica type in maternally inherited mitochondrial sequences (nad1 and cox1), with six types in each sequence (FgNDI-CM1 to FgNDI-CM6 and FgCOI-CM1 to FgCOI-CM6, respectively). Remarkably, the predominant nad1 type, FgNDI-CM6, was identical to that of aspermic Fasciola sp. formerly reported from Thailand, Japan, Korea, China, Vietnam, and Myanmar. ITS2 sequences were analyzed successfully in 20 worms. Fifteen worms showed the F. gigantica type and five (including one worm from a patient) had mixed ITS2 sequences of both F. gigantica and F. hepatica in the same worms, with additional heterogeneity within both ITS2 types. This study revealed the intermediate form of Fasciola coexisting with F. gigantica for the first time in Thailand. PMID- 25300766 TI - Fertility before and after surgery for deep infiltrating endometriosis with and without bowel involvement: a literature review. AB - OJECTIVE: Endometriosis affects from 10 to 15% of women of childbearing age and 20% of these women have deep infiltrating endometriosis (DIE). The goal of this review was to assess the impact of various locations of DIE on spontaneous fertility and the benefit of surgery and Medically Assisted Reproduction (MAR) (in vitro fertilization and intrauterine insemination) on fertility outcomes. METHODS: MEDLINE search for articles on fertility in women with DIE published between 1990 and April 2013 using the following terms: "deep infiltrative endometriosis", "colorectal", "bowel", "rectovaginal", "uterosacral", "vaginal", "bladder" and "fertility" or "infertility". Twenty--nine articles reporting fertility outcomes in 2730 women with DIE were analysed. RESULTS: Among the women with DIE and no bowel involvement (n=1295), no preoperative data on spontaneous pregnancy rate (PR) were available. The postoperative spontaneous PR rate in these women was 50.5% (95% Confidence Interval (CI) = 46.8--54.1) and overall PR (spontaneous pregnancies and after MAR) was 68.3% (95% CI = 64.9--71.7). No evaluation of fertility outcome according to locations of DIE was feasible. For women with DIE with bowel involvement without surgical management (n=115), PR after MAR was 29%;; 95% CI = 20.7--37.4). For those with bowel involvement who were surgically managed (n=1320), postoperative spontaneous PR was 28.6% (95% CI = 25--32,3) and overall postoperative PR was 46.9 % (95% CI = 42,9--50,9). CONCLUSION: For women with DIE without bowel involvement, surgery alone offers a high spontaneous PR. For those with bowel involvement, the low spontaneous and relatively high overall PR suggests the potential benefit of combining surgery and MAR. PMID- 25300765 TI - Effects of iron supplementation on blood adenine deaminase activity and oxidative stress in Trypanosoma evansi infection of rats. AB - The aim of this study was to assess the effects of iron supplementation on oxidative stress and on the activity of the adenosine deaminase (ADA) in rats experimentally infected by Trypanosoma evansi. For this purpose, 20 rats were divided into four experimental groups with five animals each as follows: groups A and B were composed by healthy animals, while animals from groups C and D were infected by T. evansi. Additionally, groups B and D received two subcutaneous doses of iron (60 mg kg(-1)) within an interval of 5 days. Blood samples were drawn on day 8 post infection in order to assess hematological and biochemical variables. Among the main results are: (1) animals from group C showed reduced erythrogram (with tendency to anemia); however the same results were not observed for group D; this might be a direct effect of free iron on trypanosomes which helped to reduce the parasitemia and the damage to erythrocytes caused by the infection; (2) iron supplementation was able to reduce NOx levels by inhibiting iNOS, and thus, providing an antioxidant action and, indirectly, reducing the ALT levels in groups Band D; (3) increase FRAP levels in group D; (4) reduce ADA activity in serum and erythrocytes in group C; however, this supplementation (5) increased the protein oxidation in groups B and D, as well as group C (positive control). Therefore, iron showed antioxidant and oxidant effects on animals that received supplementation; and it maintained the activity of E-ADA stable in infected/supplemented animals. PMID- 25300767 TI - Acute spinal cord compression in the third trimester of pregnancy. PMID- 25300768 TI - Prematurity: present and future. AB - The study of preterm labor and prematurity has undergone a major transformation in its approach from an inevitable part of obstetrics with few answers to one in which science has led to knowledge and clinical intervention. Despite these advancements, understanding of preterm labor and prevention of prematurity is still limited. In the current review, we begin the discussion with fetal viability, first from a historical perspective and then from the understanding of this issue from a prospective of various professional organizations. We then present the scope of the problem of preterm birth from various countries including the discrepancy between the US and Europe. We continue with updates on extreme prematurity and outcomes with two longitudinal studies from the past 2 years. We further review available interventions for prematurity and discuss the use of antenatal corticosteroids. First, we examine their use in the context of professional recommendations and then examine the trajectory of their continued use in the late preterm period. We focus on a European-based trial with preliminary results and an ongoing American counterpart. The current knowledge of molecular mechanisms behind preterm labor is presented with a focus on the multiple etiologies of preterm labor, both known and presumed, with updates in the basic science realm. Furthermore, we present up-to-date studies on prediction of preterm birth and prematurity-related morbidity. PMID- 25300770 TI - Prospective induction of peripheral neuropathy by the use of Tartarian Buckwheat. AB - Tartarian Buckwheat is an effective hypoglycemic medicinal herb. Its main active ingredients are flavonoids. We report here 5 cases of new onset polyneuropathy with dyskinesia prospectively induced by tartarian buckwheat products. Clinical and electrophysiological evidence along with laboratory tests were reviewed and analyzed. All patients were male, with an average age of 52.2 +/- 10.9 years old (range: 40-66 years) and had a recent history of using tartarian buckwheat for diabetes therapy. The average time of use was 2.5 +/- 1.0 months (range: 1.5-4 months). The average duration of the clinical course was 0.9 +/- 0.2 months (range: 0.5-1 months). Symptoms included numbness and weakness of the limbs (5/5, 100%), hoarseness (4/5, 80%), dysphagia (1/5, 20%), bilateral facial paralysis (1/5, 20%), urinary disorders (3/5, 60%) and gonadal abnormality (4/4, 100%). Nerve conduction studies suggested more severe damages in motor nerves than sensory nerves. All the patients showed abnormality on Von Frey filaments determination. Hence, tartarian buckwheat products may cause toxic peripheral nerve lesion and the use of herbal medication needs to be better regulated and closely monitored. PMID- 25300769 TI - Alcohol drinking and mammary cancer: Pathogenesis and potential dietary preventive alternatives. AB - Alcohol consumption is associated with an increased risk of breast cancer, increasing linearly even with a moderate consumption and irrespectively of the type of alcoholic beverage. It shows no dependency from other risk factors like menopausal status, oral contraceptives, hormone replacement therapy, or genetic history of breast cancer. The precise mechanism for the effect of drinking alcohol in mammary cancer promotion is still far from being established. Studies by our laboratory suggest that acetaldehyde produced in situ and accumulated in mammary tissue because of poor detoxicating mechanisms might play a role in mutational and promotional events. Additional studies indicated the production of reactive oxygen species accompanied of decreases in vitamin E and GSH contents and of glutathione transferase activity. The resulting oxidative stress might also play a relevant role in several stages of the carcinogenic process. There are reported in literature studies showing that plasmatic levels of estrogens significantly increased after alcohol drinking and that the breast cancer risk is higher in receptor ER-positive individuals. Estrogens are known that they may produce breast cancer by actions on ER and also as chemical carcinogens, as a consequence of their oxidation leading to reactive metabolites. In this review we introduce our working hypothesis integrating the acetaldehyde and the oxidative stress effects with those involving increased estrogen levels. We also analyze potential preventive actions that might be accessible. There remains the fact that alcohol drinking is just one of the avoidable causes of breast cancer and that, at present, the suggested acceptable dose for prevention of this risk is of one drink per day. PMID- 25300771 TI - Effects of ischemic preconditioning on VEGF and pFlk-1 immunoreactivities in the gerbil ischemic hippocampus after transient cerebral ischemia. AB - Ischemia preconditioning (IPC) displays an important adaptation of the CNS to sub lethal ischemia. In the present study, we examined the effect of IPC on immunoreactivities of VEGF-, and phospho-Flk-1 (pFlk-1) following transient cerebral ischemia in gerbils. The animals were randomly assigned to four groups (sham-operated-group, ischemia-operated-group, IPC plus (+) sham-operated-group, and IPC+ischemia-operated-group). IPC was induced by subjecting gerbils to 2 min of ischemia followed by 1 day of recovery. In the ischemia-operated-group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) alone 5 days after ischemia-reperfusion, however, in all the IPC+ischemia-operated-groups, pyramidal neurons in the SP were well protected. In immunohistochemical study, VEGF immunoreactivity in the ischemia operated-group was increased in the SP at 1 day post-ischemia and decreased with time. Five days after ischemia-reperfusion, strong VEGF immunoreactivity was found in non-pyramidal cells, which were identified as pericytes, in the stratum oriens (SO) and radiatum (SR). In the IPC+sham-operated- and IPC+ischemia operated-groups, VEGF immunoreactivity was significantly increased in the SP. pFlk-1 immunoreactivity in the sham-operated- and ischemia-operated-groups was hardly found in the SP, and, from 2 days post-ischemia, pFlk-1 immunoreactivity was strongly increased in non-pyramidal cells, which were identified as pericytes. In the IPC+sham-operated-group, pFlk-1 immunoreactivity was significantly increased in both pyramidal and non-pyramidal cells; in the IPC+ischemia-operated-groups, the similar pattern of VEGF immunoreactivity was found in the ischemic CA1, although the VEGF immunoreactivity was strong in non pyramidal cells at 5 days post-ischemia. In brief, our findings show that IPC dramatically augmented the induction of VEGF and pFlk-1 immunoreactivity in the pyramidal cells of the CA1 after ischemia-reperfusion, and these findings suggest that the increases of VEGF and Flk-1 expressions may be necessary for neurons to survive from transient ischemic damage. PMID- 25300774 TI - Chiral magnetism and spontaneous spin Hall effect of interacting Bose superfluids. AB - Recent experiments on ultracold atoms in optical lattices have synthesized a variety of tunable bands with degenerate double-well structures in momentum space. Such degeneracies in the single-particle spectrum strongly enhance quantum fluctuations, and often lead to exotic many-body ground states. Here we consider weakly interacting spinor Bose gases in such bands, and discover a universal quantum 'order by disorder' phenomenon which selects a novel superfluid with chiral spin order displaying remarkable properties such as spontaneous spin Hall effect and momentum space antiferromagnetism. For bosons in the excited Dirac band of a hexagonal lattice, such a state supports staggered spin loop currents in real space. We show that Bloch oscillations provide a powerful dynamical route to quantum state preparation of such a chiral spin superfluid. Our predictions can be readily tested in spin-resolved time-of-flight experiments. PMID- 25300772 TI - Lateralization of temporal lobe epilepsy by multimodal multinomial hippocampal response-driven models. AB - PURPOSE: Multiple modalities are used in determining laterality in mesial temporal lobe epilepsy (mTLE). It is unclear how much different imaging modalities should be weighted in decision-making. The purpose of this study is to develop response-driven multimodal multinomial models for lateralization of epileptogenicity in mTLE patients based upon imaging features in order to maximize the accuracy of noninvasive studies. METHODS AND MATERIALS: The volumes, means and standard deviations of FLAIR intensity and means of normalized ictal interictal SPECT intensity of the left and right hippocampi were extracted from preoperative images of a retrospective cohort of 45 mTLE patients with Engel class I surgical outcomes, as well as images of a cohort of 20 control, nonepileptic subjects. Using multinomial logistic function regression, the parameters of various univariate and multivariate models were estimated. Based on the Bayesian model averaging (BMA) theorem, response models were developed as compositions of independent univariate models. RESULTS: A BMA model composed of posterior probabilities of univariate response models of hippocampal volumes, means and standard deviations of FLAIR intensity, and means of SPECT intensity with the estimated weighting coefficients of 0.28, 0.32, 0.09, and 0.31, respectively, as well as a multivariate response model incorporating all mentioned attributes, demonstrated complete reliability by achieving a probability of detection of one with no false alarms to establish proper laterality in all mTLE patients. CONCLUSION: The proposed multinomial multivariate response-driven model provides a reliable lateralization of mesial temporal epileptogenicity including those patients who require phase II assessment. PMID- 25300775 TI - Potential nanotechnologies and molecular targets in the quest for efficient chemotherapy in ovarian cancer. AB - INTRODUCTION: Ovarian cancer, considered one of the most fatal gynecological cancers, goes largely undiagnosed until metastasis presents itself, usually once the patient is in the final stages and thus, too late for worthwhile therapy. Targeting this elusive disease in its early stages would improve the outcome for most patients, while the information generated thereof would increase the possibility of preventative mechanisms of therapy. AREAS COVERED: This review discusses various molecular targets as possible moieties to be incorporated in a holistic drug delivery system or the more aptly termed 'theranostic' system. These molecular targets can be used for targeting, visualizing, diagnosing, and ultimately, treating ovarian cancer in its entirety. Currently implemented nanoframeworks, such as nanomicelles and nanoliposomes, are described and the effectiveness of nanostructures in tumor targeting, treatment functions, and overcoming the drug resistance challenge is discussed. EXPERT OPINION: Novel nanotechnology strategies such as the development of nanoframeworks decorated with targeted ligands of a molecular nature may provide an efficient chemotherapy, especially when instituted in combination with imaging, diagnostic, and ultimately, therapeutic moieties. An imperative aspect of utilizing nanotechnology in the treatment of ovarian cancer is the flexibility of the drug delivery system and its ability to overcome standard obstacles such as: i) successfully treating the desired cells through direct targeting; ii) reducing toxicity levels of treatment by achieving direct targeting; and iii) delivery of targeted therapy using an efficient vehicle that is exceptionally degradable in response to a particular stimulus. The targeting of ovarian cancer in its early stages using imaging and diagnostic nanotechnology is an area that can be improved upon by combining therapeutic moieties with molecular biomarkers. The nanotechnology and molecular markers mentioned in this review have generally been used for either imaging or diagnostics, and have not yet been successfully implemented into bi-functional tools, which it is hoped, should eventually include a therapeutic aspect. PMID- 25300776 TI - Multitasking in Gonadotropin-Releasing Hormone Neuron Dendrites. AB - Gonadotropin-releasing hormone (GnRH) neurons integrate synaptic information in their dendrites in order to precisely control GnRH secretion and hence fertility. Recent discoveries concerning the structure and function of GnRH neuron dendrites have shed new light on the control of GnRH neuron excitability and GnRH secretion. This work suggests that GnRH neurons have a unique projection to the median eminence that possesses both dendritic and axonal properties. We propose that this 'dendron' projection allows GnRH neurons to multitask and integrate information in ways that would not be possible in a classically envisioned axon projection. PMID- 25300777 TI - Extracting climate memory using Fractional Integrated Statistical Model: a new perspective on climate prediction. AB - Long term memory (LTM) in climate variability is studied by means of fractional integral techniques. By using a recently developed model, Fractional Integral Statistical Model (FISM), we in this report proposed a new method, with which one can estimate the long-lasting influences of historical climate states on the present time quantitatively, and further extract the influence as climate memory signals. To show the usability of this method, two examples, the Northern Hemisphere monthly Temperature Anomalies (NHTA) and the Pacific Decadal Oscillation index (PDO), are analyzed in this study. We find the climate memory signals indeed can be extracted and the whole variations can be further decomposed into two parts: the cumulative climate memory (CCM) and the weather scale excitation (WSE). The stronger LTM is, the larger proportion the climate memory signals will account for in the whole variations. With the climate memory signals extracted, one can at least determine on what basis the considered time series will continue to change. Therefore, this report provides a new perspective on climate prediction. PMID- 25300778 TI - Performance improvement and failure mechanism of LiNi(0.5)Mn(1.5)O4/graphite cells with biphenyl additive. AB - The cycling performance of the LiNi0.5Mn1.5O4/graphite cells cycled to 4.8 V versus Li/Li(+) at room temperature has been investigated. The control electrolyte is 1.0 M LiPF6 ethylene carbonate (EC)/ethylmethyl carbonate (EMC)/fluoroethylene carbonate (FEC) (10/70/20, v/v) with 2 wt% lithium bis(oxalate)borate (LiBOB). Biphenyl (BP) (0.5 wt% and 1 wt%) is employed as the in situ electrochemical coating additive for LiNi0.5Mn1.5O4 cathode. The results indicate the potential window of electrolyte without BP is up to 5.5 V versus Li/Li(+) on Pt electrode, but still decomposed seriously on both cathode and anode surfaces during prolonged cycles. The improved cycling performance with added 0.5 wt% BP in the control electrolyte can be attributed to the in situ electrochemical coating film on LiNi0.5Mn1.5O4 surface derived from BP electro polymerization, which decreases the Mn dissolution and the lattice changes of LiNi0.5Mn1.5O4 cathode, and further inhibits Mn deposition and additional SEI formation on graphite surface. However, the thicker and compact BP electro polymerization film using 1BP electrolyte on the cathode surface might inhibit the lithium intercalation/deintercalation and increase the polarization, then accelerates the capacity fading. PMID- 25300779 TI - Systemic Delivery of Free Chitosan Accelerates Femur Fracture Healing in Rats. AB - BACKGROUND: Chitosan-containing compounds have been shown to be suitable for bone replacement, but few studies demonstrate the impact of the chitosan as a free drug on the fracture.In this study, we aimed to evaluate possible effects of free chitosan on fracture healing. MATERIALS AND METHODS: Thirty adult male Sprague Dawley rats with a mean body weight of 205 g (range from 200g to 210g) were randomly and equally divided into two groups. Standardized femur fractures were created in all rats. Treatments were administered intraperitoneally twice weekly at 1 mg chitosan per injection and the controls were administered physiological saline. The site of the fracture was compared with the control group at 1, 2 and 4 weeks after surgery (n=5 in each group). The weight, activity and reaction of the rats were observed at all the timepoints. Anterior-posterior radiographs and micro-CT scans of all fractures were taken after surgery, and the parameters included: the volume of callus that was calculated using the Perkins volume formula, BV/TV, BV, BMD of cortical bone, cortical thickness, and cortical number at the fracture sites. After sacrifice, fractured femurs from rats were dissected and carefully cleaned of muscle around the fracture callus to preserve callus integrity. Sections were stained with haematoxylin and eosin for histological evaluation of healing. RESULT: Radiological (X-ray and micro-CT) evaluation showed that fracture healing of the experimental group was better than control group at the second week and fourth week. Histological evaluation revealed fracture healing of the experimental group was better than control group at the same time. There was no statistically significant difference in fracture healing between the two groups at the first week. CONCLUSION: Systemic delivery of free chitosan can accelerate the bone healing process in rat femur fracture at the early-middle stage. PMID- 25300780 TI - Cervical cancer: are there potential new targets? An update on preclinical and clinical results. AB - According to international guidelines, treatment of cervical cancer (CC) consists of surgery in early stages and of chemoradiation in locally advanced disease. Metastatic disease is usually treated with palliative chemotherapeutic regimens, but cytostatic drugs present significant side effects and show limited activity. Thus, the discovery of new anticancer agents, interfering with molecular targets expressed by the tumor's microenvironment or by the tumor cell itself, represents a possible chance for the struggle against this tumor. The aim of this review is to report all targets that have been investigated in preclinical and clinical studies. We discuss these potential targets according to "targeted therapies" NCI classification. The most investigated molecular targets have been epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), both involved in CC etiopathogenesis. Studies with anti-angiogenetic agents showed encouraging clinical efficacy and acceptable toxicity. Other interesting results have been obtained by immunotherapeutic strategies. Since biological characteristics of CC, especially in recurrent disease, are still partially unknown, future studies are necessary to understand mechanisms involved in CC carcinogenesis, in order to give to patients the most tailored and efficient treatments. PMID- 25300781 TI - [Duration of resuscitation in neonates with Apgar scores at 10 minutes of less than 3 in the hypothermia era]. PMID- 25300782 TI - [Efficacy and safety profile of cranberry in infants and children with recurrent urinary tract infection]. AB - OBJECTIVE: Cranberry prophylaxis of recurrent urinary tract infection in infants has proven effective in the experimental model of the adult. There are few data on its efficacy, safety and recommended dose in the pediatric population. METHODS: A controlled, double-blind Phase III clinical trial was conducted on children older than 1 month of age to evaluate the efficacy and safety of cranberry in recurrent urinary tract infection. The assumption was of the non inferiority of cranberry versus trimethoprim. Statistical analysis was performed using Kaplan Meier analysis. RESULTS: A total of 85 patients under 1 year of age and 107 over 1 year were recruited. Trimethoprim was prescribed to 75 patients and 117 received cranberry. The cumulative rate of urinary infection associated with cranberry prophylaxis in children under 1 year was 46% (95% CI; 23-70) in children and 17% (95% CI; 0-38) in girls, effectively at doses inferior to trimethoprim. In children over 1 year-old cranberry was not inferior to trimethoprim, with a cumulative rate of urine infection of 26% (95% CI; 12-41). The cranberry was well tolerated and with no new adverse effects. CONCLUSIONS: Our study confirms that cranberry is safe and effective in the prophylaxis of recurrent urinary tract infection in infants and children. With the doses used, their efficiency is not less than that observed for trimethoprim among those over 1 year-old. (Clinical Trials Registry ISRCTN16968287). PMID- 25300783 TI - Sex-related differences in the effects of high-fat diets on DHEA-treated rats. AB - Several studies have investigated the beneficial effects of dehydroepiandrosterone (DHEA) on lipid and glucose metabolism. However, many of these studies are inconclusive about the effects of DHEA administration on metabolic disorders, and there appear to be sex-related differences in the effects of DHEA treatment. Few animal studies have addressed the effects of DHEA on diet-induced metabolic disorders. The present study sought to ascertain whether sex differences exist in the effects of a high-fat diet (HFD) on weight gain, adiposity, and biochemical and hormonal parameters in DHEA-treated rats. Rats were fed a HFD for 4 weeks and simultaneously received treatment with DHEA (10 mg/kg by subcutaneous injection) once weekly. Body weight, retroperitoneal fat depot weight, serum glucose, insulin, and leptin levels, and hepatic lipids were measured. HFD exposure increased the adiposity index in both sexes, the hepatic triglyceride content in both sexes, and the hepatic total cholesterol level in males. Moreover, the HFD induced an increase in blood glucose levels in both sexes, and hyperinsulinemia in males. In this experimental model, DHEA treatment reduced hepatic triglyceride levels only in females, regardless of HFD exposure. Exposure to a HFD, even if it does not cause obesity, may enhance risk factors for metabolic disorders, and males are more sensitive to this effect. DHEA treatment can help prevent metabolic derangements, but its effect varies with sex. PMID- 25300784 TI - Aromatase enzyme expression in acromegaly and its possible relationship with disease prognosis. AB - The purpose of this study was to evaluate aromatase enzyme expression in growth hormone (GH) secreting adenomas and comparison with prolactinomas, nonfunctional adenomas, and normal pituitary tissues. Also the impact of its expression on clinical and prognostic features was evaluated. 38 acromegaly, 26 prolactinoma, and 31 nonfunctional pituitary adenoma and 11 normal pituitary gland samples from autopsies were included. Aromatase and estrogen receptor-alpha (ERalpha) were evaluated by Immunohistochemical method; demographic, pre- and postoperative features of the patients were noted. Aromatase was expressed in varying degrees in all cases in study including controls. Aromatase expression in patients with acromegaly was significantly higher than patients with prolactinoma, nonfunctional adenoma, and controls (p = 0.04, p = 0.01 and p < 0.001, respectively). Taken together two functional adenoma groups, prolactinoma and acromegaly, aromatase expression was negatively correlated with ER-alpha (p = 0.02, r = -0.34). Also, Ki-67 immunohistochemical results were negatively correlated with aromatase expression (p = 0.03, r = -0.27) while positively correlated with ER expression (p < 0.01). Consistent with the growing evidence about testosterone effect on pituitary functions, aromatase expression was found to be higher in GH-secreting pituitary adenoma. Aromatase was expressed in all pituitary tissues including autopsy samples; however, it was highest in patients with acromegaly. In patients with acromegaly and prolactinoma, aromatase expression was negatively correlated with Ki-67 score, and also it was higher in patients with complete postoperative remission than without remission. Therefore, aromatase expression may be a good prognostic marker predominantly in acromegaly. PMID- 25300785 TI - Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke. AB - BACKGROUND: Elevated maximal clot strength, measured by thrombelastography (TEG) maximum amplitude (MA) has been associated with a higher risk for ischemic events in patients with coronary artery diseases. However, it has not been investigated in patients with cerebrovascular diseases. In the current study, we aimed to evaluate the predictive ability of TEG-MA in assessing the risk for ischemic event recurrence and the functional outcome after index ischemic stroke. METHODS: This was a prospective observational study. Consecutive eligible patients with acute ischemic stroke were included and followed up for one year. Patients were stratified into tertile groups based on MA levels. TEG-hypercoagulability was defined as an MA of >= 69 mm. Ischemic events were defined as a composite of ischemic stroke, myocardial infarction, or vascular death (excluding hemorrhagic death). The functional outcome was evaluated by modified Rankin Scale (mRS). Unfavorable functional outcome was defined as mRS >= 2. RESULTS: Two hundred and eleven patients were enrolled with 27 lost to follow-up at one year contact. At baseline, 38 (18.0%) patients were TEG-hypercoagulopathy after the treatment of antiplatelets. Patients with higher tertile of MA were more likely to be females, and had lower hemoglobin levels, higher platelet counts, higher fibrinogen levels, higher white blood cell counts, as well as higher ESR and hsCRP levels. Patients in the third tertile group were more likely to have intracranial artery stenosis and large-vessel subtype stroke than those in the other two groups. Higher tertile of MA was also related to stroke severity in acute phase (higher NIHSS scores on admission and longer in-hospital stay). At one year of follow-up, a higher percentage of unfavorable functional outcome and a non-significant trend of higher ischemic event rate were observed in higher MA tertile groups. Multivariate logistic analysis revealed that higher MA level (OR = 1.192, p = 0.022) was an independent predictor for unfavorable one-year functional outcome. Other independent predictors included old age (OR = 1.119, p = 0.001), diabetes mellitus (DM) (OR = 4.280, p = 0.014), previous ischemic stroke/TIA history (OR = 4.953, p = 0.008), and higher NIHSS scores on admission (OR = 1.437, p = 0.001). CONCLUSIONS: We found that higher TEG-MA levels could predict an unfavorable functional outcome after index ischemic stroke. Further, large-scale studies are required to investigate the relationship between MA levels and risk of recurrent ischemic events in ischemic stroke patients. PMID- 25300786 TI - Hesitance towards voluntary medical male circumcision in Lesotho: reconfiguring global health governance. AB - Drawing on work examining HIV prevention initiatives in Lesotho, this paper considers the hesitation of national state actors towards the new strategy for HIV prevention - voluntary medical male circumcision (VMMC). Lesotho offers a representative case study on global health governance, given the country's high HIV burden and heavy dependence on foreign donor nations to implement local HIV prevention initiatives. In this paper, I use the case of VMMC opposition in Lesotho to examine how the new era of 'partnerships' has shifted the architecture of contemporary global health, specifically considering how global agreements are translated or negotiated into local practice. I argue that Lesotho's domestic policy-makers, in employing national statistics to assess if VMMC is an effective approach to addressing the local epidemic, are asserting a claim of expertise. In doing so, they challenge the traditional structures of global health politics, which have largely been managed by experts and funders from and in the global North. I explore the development of global VMMC policy, what drives Lesotho's resistance to comply, and consider the impact renegotiation efforts may have on future global health architecture. PMID- 25300788 TI - US increases Ebola screening at five airports. PMID- 25300787 TI - A search for functional histamine H4 receptors in the human, guinea pig and mouse brain. AB - Histamine H4 receptors are expressed in immune cells, but their potential role in the brain is less clear. Although H4 transcripts have been identified in human and rat brain, the presence of H4 receptors on the protein level has so far not been proven since appropriate antibodies fulfilling the strict criteria for G protein-coupled receptors are missing. Here, we searched for functional H4 receptors in human, guinea pig and mouse cortex. We studied whether H4 receptor activation is associated with increased GTPgammaS binding and reduced noradrenaline release. The latter two effects have been previously shown for H3 receptors, which, like the H4 receptors, are coupled to G i/o protein. G protein activation was studied using (35)S-GTPgammaS binding in cortical membranes. The electrically induced (3)H-noradrenaline release was determined in superfused cortical slices. The H4 agonist 4-methylhistamine failed to affect (35)S GTPgammaS binding and/or noradrenaline release in human, guinea pig and mouse cortex although an H 3 receptor-mediated increase in (35)S-GTPgammaS binding and inhibition of noradrenaline release occurred in parallel experiments. In conclusion, functional H4 receptors increasing (35)S-GTPgammaS binding and/or decreasing noradrenaline release are not found in human, guinea pig and mouse cortex. PMID- 25300789 TI - Current evidence on basic emergency obstetric and newborn care services in Addis Ababa, Ethiopia; a cross sectional study. AB - BACKGROUND: Emergency obstetric and neonatal care (EmONC) is a high impact priority intervention highly recommended for improving maternal and neonatal health outcomes. In 2008, Ethiopia conducted a national EmONC survey that revealed implementation gaps, mainly due to resource constraints and poor competence among providers. As part of an ongoing project, this paper examined progress in the implementation of the basic EmONC (BEmONC) in Addis Ababa and compared with the 2008 survey. METHODS: A facility based intervention project was conducted in 10 randomly selected public health centers (HCs) in Addis Ababa and baseline data collected on BEmONC status from January to March 2013. Retrospective routine record reviews and facility observations were done in 29 HCs in 2008 and in10 HCs in 2013. Twenty-five providers in 2008 and 24 in 2013 participated in BEmONC knowledge and skills assessment. All the data were collected using standard tools. Descriptive statistics and t-tests were used. RESULTS: In 2013, all the surveyed HCs had continuous water supply, reliable access to telephone, logbooks & phartograph. Fifty precent of the HCs in 2013 and 34% in 2008 had access to 24 hours ambulance services. The ratio of midwives to 100 expected births were 0.26 in 2008 and 10.3 in 2013. In 2008, 67% of the HCs had a formal fee waiver system while all the surveyed HCs had it in 2013. HCs reporting a consistent supply of uterotonic drugs were 85% in 2008 and 100% in 2013. The majority of the providers who participated in both surveys reported to have insufficient knowledge in diagnosing postpartum haemorrhage (PPH) and birth asphyxia as well as poor skills in neonatal resuscitation. Comparing with the 2008 survey, no significant improvements were observed in providers' knowledge and competence in 2013 on PPH management and essential newborn care (p > 0.05). CONCLUSION: There are advances in infrastructure, medical supplies and personnel for EmONC provision, yet poor providers' competences have persisted contributing to the quality gaps on BEmONC in Addis Ababa. Considering short-term in-service trainings using novel approaches for ensuring desired competences for large number of providers in short time period is imperative. PMID- 25300790 TI - Cell viability assessment using the Alamar blue assay: a comparison of 2D and 3D cell culture models. AB - Comparisons of 2D and 3D cell culture models in literature have indicated differences in cellular morphology and metabolism, commonly attributed the better representation of in vivo conditions of the latter cell culture environment. Thus, interest in the use of 3D collagen gels for in vitro analysis has been growing. Although comparative studies to date have indicated an enhanced resistance of cells on collagen matrices against different toxicants, in the present study it is demonstrated that non-adapted protocols can lead to misinterpretation of results obtained from classical colorimetric dye-based cytotoxic assays. Using the well established Alamar blue assay, the study demonstrates how the transfer from 2D substrates to 3D collagen matrices can affect the uptake of the resazurin itself, affecting the outcome of the assay. Using flow cytometry, it is demonstrated that the cell viability is unaffected when cells are grown on collagen matrices, thus the difference seen in the fluorescence is a result of a dilution of the resazurin dye in the collagen matrix, and an increased uptake rate due to the larger cell surface exposed to the surrounding environment, facilitating more effective diffusion through the cellular membrane. The results are supported by a rate equation based simulation, verifying that differing uptake kinetics can result in apparently different cell viability. Finally, this work highlights the feasibility to apply classical dye based assays on collagen based 3D cell culture models. However, the diffusion and bioavailability of test substances in 3D matrices used in in vitro toxicological assays must be considered and adaption of the protocols is necessary for direct comparison with the traditional 2D models. Moreover, the observations made based on the resazurin dye can be applied to drugs or nanoparticles which freely diffuse through the collagen matrices, thus affecting the effective concentration exposed to the cells. PMID- 25300791 TI - Electroplated and cast double crown-retained removable dental prostheses: 6-year results from a randomized clinical trial. AB - OBJECTIVES: The purpose of this study was to evaluate the clinical performance of removable dental prostheses (RDP) supported by either electroplated (EP-RDP) or cast (C-RDP) double crowns. MATERIAL AND METHODS: Fifty-four participants received a total of 60 RDP. Two hundred and seventeen abutment teeth were provided with double crowns. The participants were randomly assigned to two groups (EP-RDP or C-RDP). Re-evaluations took place after 6 months and then once a year up to 6 years. Primary endpoint was survival time for RDP and abutment teeth; secondary endpoints were failure of facing, decementation of primary crown, and post-prosthetic endodontic treatment. T, U, and chi-squared tests were used to assess the homogeneity of the EP-RDP and C-RDP groups. Survival differences were analyzed with log-rank tests and Cox regression models; secondary endpoints were assessed by the use of logistic regression. RESULTS: Six year survival was 77 % for EP-RDP and 97 % for C-RDP. Cumulative survival of abutment teeth was 85 % for EP-RDP and 91 % for C-RDP; differences between survivals in the two groups did not reach statistical significance. Survival of abutment teeth depended on tooth vitality. Failures of facings, decementations, or post-prosthetic endodontic treatments were not different between groups. CONCLUSIONS: To identify possible differences between different double crown systems, longer follow-up periods and/or larger numbers of patients are needed. CLINICAL RELEVANCE: Survival of teeth supporting double crown-retained RDP is affected by their vitality. Clinical performance was acceptable for both RDP supported by electroplated or cast double crowns. PMID- 25300793 TI - MAP1S controls microtubule stability throughout the cell cycle in human cells. AB - Summary Understanding the molecular basis for proper cell division requires a detailed functional analysis of microtubule (MT)-associated proteins. MT associated protein 1S (MAP1S), the most ubiquitously expressed MAP1 family member, is required for accurate cell division. Here, using quantitative analysis of MT plus-end tracking, we show that MAP1S knockdown alters MT dynamics throughout the cell cycle. Surprisingly, MAP1S downregulation results in faster growing, yet short-lived, MTs in all cell cycle stages and in a global loss of MT acetylation. These aberrations correlate with severe defects in the final stages of cell division. In monopolar cytokinesis assays, we demonstrate that MAP1S guides MT-dependent initiation of cytokinesis. Our data underline the key role of MAP1S as a global regulator of MT stability and demonstrate a new primary function of MAP1S to regulate MT dynamics at the onset of cytokinesis. PMID- 25300792 TI - Muscle stem cells at a glance. AB - Muscle stem cells facilitate the long-term regenerative capacity of skeletal muscle. This self-renewing population of satellite cells has only recently been defined through genetic and transplantation experiments. Although muscle stem cells remain in a dormant quiescent state in uninjured muscle, they are poised to activate and produce committed progeny. Unlike committed myogenic progenitor cells, the self-renewal capacity gives muscle stem cells the ability to engraft as satellite cells and capitulate long-term regeneration. Similar to other adult stem cells, understanding the molecular regulation of muscle stem cells has significant implications towards the development of pharmacological or cell-based therapies for muscle disorders. This Cell Science at a Glance article and accompanying poster will review satellite cell characteristics and therapeutic potential, and provide an overview of the muscle stem cell hallmarks: quiescence, self-renewal and commitment. PMID- 25300794 TI - The position of mitochondria and ER in relation to that of the secretory sites in chromaffin cells. AB - Knowledge of the distribution of mitochondria and endoplasmic reticulum (ER) in relation to the position of exocytotic sites is relevant to understanding the influence of these organelles in tuning Ca(2+) signals and secretion. Confocal images of probes tagged to mitochondria and the F-actin cytoskeleton revealed the existence of two populations of mitochondria, one that was cortical and one that was perinuclear. This mitochondrial distribution was also confirmed by using electron microscopy. In contrast, ER was sparse in the cortex and more abundant in deep cytoplasmic regions. The mitochondrial distribution might be due to organellar transport, which experiences increasing restrictions in the cell cortex. Further study of organelle distribution in relation to the position of SNARE microdomains and the granule fusion sites revealed that a third of the cortical mitochondria colocalized with exocytotic sites and another third located at a distance closer than two vesicle diameters. ER structures were also present in the vicinity of secretory sites but at a lower density. Therefore, mitochondria and ER have a spatial distribution that suggests a specialized role in modulation of exocytosis that fits with the role of cytosolic Ca(2+) microdomains described previously. PMID- 25300795 TI - CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi. AB - The acquisition of proper dendrite morphology is a crucial aspect of neuronal development towards the formation of a functional network. The role of the extracellular matrix and its cellular receptors in this process has remained enigmatic. We report that the CD44 adhesion molecule, the main hyaluronan receptor, is localized in dendrites and plays a crucial inhibitory role in dendritic tree arborization in vitro and in vivo. This novel function is exerted by the activation of Src tyrosine kinase, leading to the alteration of Golgi morphology. The mechanism operates during normal brain development, but its inhibition might have a protective influence on dendritic trees under toxic conditions, during which the silencing of CD44 expression prevents dendritic shortening induced by glutamate exposure. Overall, our results indicate a novel role for CD44 as an essential regulator of dendritic arbor complexity in both health and disease. PMID- 25300796 TI - Signaling in chemotactic amoebae remains spatially confined to stimulated membrane regions. AB - Recent work has demonstrated that the receptor-mediated signaling system in chemotactic amoeboid cells shows typical properties of an excitable system. Here, we delivered spatially confined stimuli of the chemoattractant cAMP to the membrane of differentiated Dictyostelium discoideum cells to investigate whether localized receptor stimuli can induce the spreading of excitable waves in the G protein-dependent signal transduction system. By imaging the spatiotemporal dynamics of fluorescent markers for phosphatidylinositol (3,4,5)-trisphosphate (PIP3), PTEN and filamentous actin, we observed that the activity of the signaling pathway remained spatially confined to the stimulated membrane region. Neighboring parts of the membrane were not excited and no receptor-initiated spatial spreading of excitation waves was observed. To generate localized cAMP stimuli, either particles that carried covalently bound cAMP molecules on their surface were brought into contact with the cell or a patch of the cell membrane was aspirated into a glass micropipette to shield this patch against freely diffusing cAMP molecules in the surrounding medium. Additionally, the binding site of the cAMP receptor was probed with different surface-immobilized cAMP molecules, confirming results from earlier ligand-binding studies. PMID- 25300797 TI - Recurrent LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes promote tumor cell motility in human osteosarcoma. AB - BACKGROUND: The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas. No recurrent fusion has been reported in human osteosarcoma. METHODS: Transcriptome sequencing was used to characterize the gene fusions and mutations in 11 human osteosarcomas. RESULTS: Nine of 11 samples were found to harbor genetic inactivating alterations in the TP53 pathway. Two recurrent fusion genes associated with the 12q locus, LRP1 SNRNP25 and KCNMB4-CCND3, were identified and validated by RT-PCR, Sanger sequencing and fluorescence in situ hybridization, and were found to be osteosarcoma specific in a validation cohort of 240 other sarcomas. Expression of LRP1-SNRNP25 fusion gene promoted SAOS-2 osteosarcoma cell migration and invasion. Expression of KCNMB4-CCND3 fusion gene promoted SAOS-2 cell migration. CONCLUSIONS: Our study represents the first whole transcriptome analysis of untreated human osteosarcoma. Our discovery of two osteosarcoma specific fusion genes associated with osteosarcoma cellular motility highlights the heterogeneity of osteosarcoma and provides opportunities for new treatment modalities. PMID- 25300798 TI - Management of lymph nodes during resection of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a systematic review. AB - The role of lymph node dissection (LND) in the treatment of patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) remains controversial. We sought to systematically review all available evidence to determine the role of LND in patients with HCC and ICC. Studies that reported on LND, lymph node metastasis (LNM), and short- and long-term outcomes for patients with HCC or ICC survival were identified from PubMed, Cochrane, Embase, Scopus, and Web of Science databases. Data were extracted, synthesized, and analyzed using standard techniques. A total of 603 and 434 references were identified for HCC and ICC, respectively. Among HCC patients, the overall prevalence of LND was 51.6 % (95 % confidence interval (CI) 19.7-83.5) with an associated LNM incidence of 44.5 % (95 % CI 27.4-61.7). LNM was associated with a 3- and 5-year survival of 27.5 and 20.8 %, respectively. Among ICC patients, most patients 78.5 % (95 % CI 76.2-80.7) underwent LND; 45.2 % (95 % CI 39.2-51.2) had LNM. Three and 5-year survival among ICC patients with LNM was 0.2 % (95 % CI 0-0.7) and 0 %, respectively. While there are insufficient data to recommend a routine LND in all patients with HCC or ICC, the potential prognostic value of LND suggests that LND should at least be considered at the time of surgery. PMID- 25300799 TI - Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management. AB - INTRODUCTION: Patients with metastatic colorectal cancer can develop jaundice from intrahepatic or extrahepatic causes. Currently, there is little data on the underlying causes and overall survival after onset of jaundice. The purpose of this study was to characterize the causes of jaundice and determine outcomes. METHODS: Six hundred twenty-nine patients treated for metastatic colorectal cancer between 2004 and 2010 were retrospectively reviewed. Those developing jaundice were grouped as having intrahepatic or extrahepatic obstruction. Demographics, clinicopathologic, and outcome data were analyzed. RESULTS: Sixty two patients with metastatic colorectal cancer developed jaundice. Intrahepatic biliary obstruction was most common, occurring in younger patients. Time from metastatic diagnosis to presentation of jaundice was similar between groups, as was the mean number of prior lines of chemotherapy. Biliary decompression was successful 41.7 % of the time and was attempted more commonly for extrahepatic causes. Median overall survival after onset of jaundice was 1.5 months and it was similar between groups, but improved to 9.6 months in patients who were able to receive further chemotherapy. CONCLUSIONS: Jaundice due to metastatic colorectal cancer is an ominous finding, representing aggressive tumor biology or exhaustion of therapies. Biliary decompression is often difficult and should only be pursued when additional treatment options are available. PMID- 25300800 TI - Effect of PKCalpha expression on Bcl-2 phosphorylation and cell death by hypericin. AB - In order to explain the contribution of the protein kinase Calpha (PKCalpha) in apoptosis induced by photo-activation of hypericin (Hyp), a small interfering RNA was used for post-transcriptional silencing of pkcalpha gene expression. We have evaluated the influence of Hyp photo-activation on cell death in non-transfected and transfected (PKCalpha(-)) human glioma cells (U-87 MG). No significant differences were detected in cell survival between non-transfected and transfected PKCalpha(-) cells. However, the type of cell death was notably affected by silencing the pkcalpha gene. Photo-activation of Hyp strongly induced apoptosis in non-transfected cells, but the level of necrotic cells in transfected PKCalpha(-) cells increased significantly. The differences in cell death after Hyp photo-activation are demonstrated by changes in: (i) reactive oxygen species production, (ii) Bcl-2 phosphorylation on Ser70 (pBcl-2(Ser70)), (iii) cellular distributions of pBcl-2(Ser70) and (iv) cellular distribution of endogenous anti-oxidant glutathione and its co-localization with mitochondria. In summary, we suggest that post-transcriptional silencing of the pkcalpha gene and the related decrease of PKCalpha level considerably affects the anti-apoptotic function and the anti-oxidant function of Bcl-2. This implies that PKCalpha, as Bcl-2 kinase, indirectly protects U-87 MG cells against oxidative stress and subsequent cell death. PMID- 25300801 TI - Interferon regulatory factor 7 is involved in the growth of Epstein-Barr virus transformed human B lymphocytes. AB - The cellular interferon (IFN) regulatory factor-7 (IRF7) is closely associated with the Epstein-Barr virus (EBV)-mediated transformation of B lymphocytes in vitro and in vivo. However, the exact role of IRF7 in viral transformation is not clear. We have found that knockdown of IRF7 leads to growth inhibition of EBV transformed cells, and restoration of IRF7 by exogenous plasmid correlates with growth recovery of the viral transformed cells. In addition, IRF7-knockdown cells have a lower proliferation but a higher apoptotic rate than control cells. Moreover, reduction of IRF7 leads to reduction of major viral oncoprotein, latent membrane protein 1 (LMP1). Our data suggest that IRF7 may be a factor in EBV transformation and a useful target in the therapy of EBV-mediated neoplasia. PMID- 25300803 TI - Characterization of the cytopathic BVDV strains isolated from 13 mucosal disease cases arising in a cattle herd. AB - Bovine viral diarrhea virus (BVDV) is a positive single stranded RNA virus belonging to the Pestivirus genus of the Flaviviridae family. BVDV has a wide host range that includes most ruminants. Noncytopathic (ncp) BVDV may establish lifelong persistent infections in calves following infection of the fetus between 40 and 120 days of gestation. Cytopathic (cp) BVDV strains arise from ncp strains via mutations. The most common cp mutations are insertions of RNA derived from either host or a duplication of viral sequences into the region of the genome coding for the NS2/3 protein. Superinfection of a persistently infected animal with a cp virus can give rise to mucosal disease, a condition that is invariably fatal. A herd of 136 bred 3-year old cows was studied. These cows gave birth to 41 PI animals of which 23 succumbed to mucosal disease. In this study, we characterized the ncp and cp viruses isolated from 13 of these animals. All viruses belonged to the BVDV type 2a genotype and were highly similar. All the cp viruses contained an insertion in the NS2/3 coding region consisting of the sequences derived from the transcript encoding a DnaJ protein named Jiv90. Comparison of the inserted DnaJ regions along with the flanking viral sequences in the insertion 3' end of the 13 cp isolates revealed sequence identities ranging from 96% to 99% with common borders. This suggested that one animal likely developed a cp virus that then progressively spread to the other 12 animals. Interestingly, when the inserted mammalian gene replicated within viral genome, it showed conservation of the same conserved motifs between the different species, which may indicate a role for these motifs in the insertion function within the virus genome. This is the first characterization of multiple cp bovine viral diarrhea virus isolates that spread in a herd under natural conditions. PMID- 25300802 TI - Porcine epidemic diarrhea virus infection: inhibition by polysaccharide from Ginkgo biloba exocarp and mode of its action. AB - Porcine epidemic diarrhea virus (PEDV) is the predominant cause of severe entero pathogenic diarrhea in swine. Until now there is no recorded clinically effective antiviral chemotherapeutic agent for treatment of diseases caused by PEDV. This study aimed to investigate in vitro anti-PEDV effect of polysaccharide from Ginkgo biloba exocarp and mode of its action. The polysaccharide exhibited potent antiviral activity against PEDV reducing the formation of a visible CPE [a 50% inhibitory concentration (IC50)=1.7+/-1.3MUg/mL], compared to positive control, ribavirin and it did not show cytotoxicity at 100MUg/mL [a 50% cytotoxicity concentration (CC50)=100MUg/mL]. Polysaccharide also showed effective inhibitory effects when added at the viral attachment and entry steps. Moreover, polysaccharide effectively inactivated PEDV infection in time-, dose- and temperature-dependent manners. Overall, this research revealed that polysaccharide could inhibit PEDV infection, and that polysaccharide may be involved in PEDV-Vero cell interactions, as the virus attachment and entry to the Vero cells was hindered by the polysaccharide. Therefore, polysaccharide possessing effective inhibitory effect on viral attachment and entry steps of PEDV life cycle is a good candidate for development of antivirals. PMID- 25300804 TI - Generation of porcine reproductive and respiratory syndrome virus by in vitro assembly of viral genomic cDNA fragments. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent for a swine disease affecting the pig industry worldwide. Infection with PRRSV leads to reproductive complications, respiratory illness, and weak immunity to secondary infections. To better control PRRSV infection, novel approaches for generating control measures are critically needed. Here, in vitro Gibson assembly (GA) of viral genomic cDNA fragments was tested for its use as a quick and simple method to recover infectious PRRSV in cell culture. GA involves the activities of T5-exonuclease, Phusion polymerase, and Taq ligase to join overlapping cDNA fragments in an isothermal condition. Four overlapping cDNA fragments covering the entire PRRSV genome and one vector fragment were used to create a plasmid capable of expressing the PRRSV genome. The assembled product was used to transfect a co-culture of 293T and MARC-145 cells. Supernatants from the transfected cells were then passaged onto MARC-145 cells to rescue infectious virus particles. Verification and characterization of the recovered virus confirmed that the GA protocol generated infectious PRRSV that had similar characteristics to the parental virus. This approach was then tested for the generation of a chimeric virus. By replacing one of the four genomic fragments with that of another virus strain, a chimeric virus was successfully recovered via GA. In conclusion, this study describes for the first time the use of GA as a simple, yet powerful tool for generating infectious PRRSV needed for studying PRRSV biology and developing novel vaccines. PMID- 25300805 TI - Elevated antinuclear antibodies and altered anti-Epstein-Barr virus immune responses. AB - It has been shown that Epstein-Barr virus (EBV) is able to alter the immune response towards self-antigens and may enhance risk of autoimmune diseases such as systemic lupus erythematosus (SLE) in genetically predisposed individuals. In this study, we evaluated the specific antibody immune response against EBV in patients with anti-nuclear autoantibodies (ANA) in comparison with ANA-negative healthy controls. For this purpose, 92 patients with an high anti-ANA reactivity with or without concomitant extractable nuclear antigen (ENA) or double stranded DNA (dsDNA) positivity were selected and compared with 146 healthy donors. We found that anti-EBV-VCA and EA IgG concentrations were significantly higher in ANA-positive patients in comparison to the controls (VCA P<0.0001 and EA P<0,03) as well as in those ANA-positive patients that showed a concomitant ENA positivity (P=0.0002). Interestingly, elevated anti-EBNA-1 IgG was found in a group of patients who had anti SSA/Ro antibodies. Anti-VCA IgM Abs were more frequently found in those patients with a very high titer of ANA (P=0.06); moreover detection of anti-VCA IgM/IgG in absence of anti-EBNA-1 IgG was more frequent in the patient than in the control group. Both these conditions correlate with a recent EBV infection or reactivation. The data suggest that EBV, particularly during acute infection or in its reactivation phase, could be involved in the ANA and ENA autoantibody formation. PMID- 25300806 TI - Student reflections following exposure to a case-based interprofessional learning experience: Preliminary findings. AB - This study analyzed students' written reflections following their initial exposure to interprofessional teamwork in case-based problem-solving. A three hour seminar featuring three sequenced scenarios was developed and offered 12 times over two semesters. A total of 305 students from a variety of healthcare programs worked together with standardized patients in an on-campus laboratory simulating hospital ward and rehabilitation settings. A thematic analysis of students' reflections showed that they valued the shared learning and realistic case study. However, they felt the experience would be strengthened by working in smaller, more representative teams that included students from medicine, psychology, and social work to enable more effective communication and comprehensive case discussion. While useful for future planning, the identified themes did not enable a comparative statistical analysis of what students found helpful and difficult and a re-coding of students' responses now is underway. Implications for measuring the effectiveness of future interprofessional case based learning center on addressing the identified weaknesses, and establishing a research design that enables a comparison of pre- and post-seminar data, and the effectiveness of the IPE experience compared to profession-specific experiences. PMID- 25300807 TI - "A golden opportunity": Exploring interprofessional learning and practice in rural clinical settings. AB - Little is known about interprofessional practice (IPP) and interprofessional learning (IPL) in rural health services, despite national funding and continuing emphasis on increasing students' clinical placements in rural areas. This short paper outlines a study in Tasmania, Australia, which investigated how and under what contexts and conditions IPP and IPL occur in rural clinical settings, and the enabling factors and strategies that promote this learning and practice. This study employed a mixed method design comprising focus group discussions and a survey involving health professionals from two rural health services. The findings demonstrate that formal and informal arrangements, the collaborative nature of small, close-knit healthcare teams and patient-centred models of care employed in rural practice settings, provide ideal contexts for IPP and IPL. The study has implications for promoting organisational readiness for IPP and IPL and harnessing the potential of rural services to promote and develop students' interprofessional capability. PMID- 25300808 TI - Minding the gap: Prioritization of care issues among nurse practitioners, family physicians and geriatricians when caring for the elderly. AB - Accumulating health problems of the elderly requires recognition of geriatric syndromes, while shifting away from a conventional disease-specific approach. We surveyed 179 practitioners representing Family Physicians (FPs), Nurse Practitioners (NPs) and geriatricians in Ontario, in order to quantify how they prioritize syndromes, diseases and conditions in the elderly. Identifying differences may inform opportunities for interprofessional sharing of expertise among professionals pursuing a common goal, which is expected to improve interprofessional collaboration. Our survey (response rate 36%) identifies that NP, FP and geriatrician respondents all recognize co-occurrence of "multiple morbidities" as one of the most frequently encountered issues when serving the elderly, however FPs and NPs place higher priority on managing individual chronic diseases than explicitly prioritizing geriatric syndromes. Our findings identify a need for a more clearly defined role for the geriatrician as syndrome-educator and implies further need for collaborative approaches to caring for seniors that values different professional's expertise. PMID- 25300809 TI - Combined 23-gauge vitrectomy and femtosecond laser-assisted cataract surgery. AB - BACKGROUND: The aim of this study was to assess the safety and surgical results of femtosecond laser-assisted phacovitrectomy. METHODS: A retrospective analysis of the medical records of patients over 50 years of age with vitreoretinal pathology, who had undergone pars plana vitrectomy using 23-gauge instruments and femtosecond laser-assisted cataract surgery and implantation of an intraocular lens, was performed at the Instituto de Microcirugia Ocular between June 2012 and September 2013. The diameter of the anterior capsulorhexis was set at 4.8 mm in cases where a gas tamponade was used and at 5 mm in all other cases. During the pars plana vitrectomy, posterior capsulotomy was performed on all eyes. An assessment was carried out of preoperative characteristics, surgical indications, postoperative results and complications. Only patients with a minimum of 3 months of follow-up were included. RESULTS: A total of 21 eyes in 21 patients (71.4% women) were treated. Mean age (+/- SD) was 65.8 +/- 6.4 years (range 53-76). The most common indication for surgery was epiretinal membrane (61.9%), followed by vitreous haemorrhage (23.8%) and macular hole (14.3%). The mean preoperative best corrected visual acuity (BCVA) was 0.81 +/- 1.01 logMAR and the mean postoperative BCVA was 0.12 +/- 0.19 logMAR (p = 0.003). 85.7% of patients improved their visual acuity. The remaining patients maintained their visual acuity. The only intraoperative complication related to femtosecond laser was 1 case of suction loss (4.8%). A patient with rhegmatogenous retinal detachment discovered during surgery required an additional circular scleral procedure and developed synechiaes in the early postoperative period (<1 month). There were no cases of subluxation of the intraocular lens. Mean follow-up was 6 months (range 3-14). CONCLUSIONS: The application of femtosecond laser in phacovitrectomy is a safe and effective technique that presents advantages compared to conventional techniques in cases of macular pathology and/or vitreous haemorrhage. PMID- 25300810 TI - A two-step approach (Enzyme-linked immunosorbent assay and confirmation assay) to detect antibodies against von Willebrand factor in patients with Acquired von Willebrand Syndrome. AB - BACKGROUND: Acquired von Willebrand Syndrome is a rare bleeding disorder, which arises in individuals with no personal or family history of bleeding, associated with lymphoproliferative and myeloproliferative disorders or other diseases. AIM: To develop a two-step approach assay to detect autoantibodies against VWF and to verify their prevalence in AVWS. METHODS: AVWS definition: negative personal or family history of bleeding diathesis, VWF below normal range and recent history of bleeding manifestations. Twenty-three consecutive patients affected by AVWS were enrolled. An ELISA assay (first step) using recombinant VWF protein immobilized on plates and sheep/goat polyclonal anti-human IgG or IgM labelled with peroxidase was developed. A group of 40 healthy subjects was tested to calculate the floating cut point value. A confirmation assay (with addition of purified VWF vs buffer) was performed (second step). RESULTS: Twenty-one patients (93%) had an associated disease, two patients had idiopathic AVWS. Anti-VWF autoantibodies were detected in 9 patients (39%). Of these, eight (89%) had VWF:RCo levels <10%, but none of them resulted positive using Bethesda assay (neutralizing antibodies). The confirmation test confirmed the positive results obtained with ELISA and resulted negative in those patients with negative results and in the controls. CONCLUSION: With the present two-step approach assay nine out of 23 (39%) patients affected with AVWS resulted positive for anti-VWF autoantibodies. This ELISA assay might be used as an additional confirmation tool in the diagnostic procedure in patients affected by AVWS or in the follow-up of congenital and acquired patients exposed to replacement therapy. PMID- 25300811 TI - Towards improved diagnosis of von Willebrand disease: comparative evaluations of several automated von Willebrand factor antigen and activity assays. AB - INTRODUCTION: von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing has important management implications and requires a wide range of tests, including VWF activity and antigen, and involves differential identification of qualitative vs quantitative defects. METHODS: We have assessed several VWF antigen and activity assays (collagen binding [VWF:CB], ristocetin cofactor [VWF:RCo] and the new Siemens INNOVANCE assay [VWF:Ac], employing latex particles and gain of function recombinant glycoprotein Ib to facilitate VWF binding and agglutination without need for ristocetin) using different instrumentation, including the new Sysmex CS-5100, with a large sample test set (n=600). We included retrospective plus prospective study designs, and also evaluated desmopressin responsiveness plus differential sensitivity to high molecular weight VWF. RESULTS: VWF:Ag and VWF:RCo results from different methods were respectively largely comparable, although some notable differences were evident, including one high false normal VWF:Ag value (105 U/dL) on a type 3 VWD sample, possibly due to heterophile antibody interference in the latex-based CS 5100 methodology. VWF:Ac was largely comparable to VWF:RCo, but VWF:CB showed discrepant findings to both VWF:RCo and VWF:Ac with some patients, most notably patients with type 2M VWD. CONCLUSIONS: (a) VWF:Ag on different platforms are largely interchangeable, as are VWF:RCo on different platforms, except for occasional (some potentially important) differences, and manufacturer recommended methods may otherwise require some assay optimization; (b) VWF:RCo and VWF:Ac are largely interchangeable, except for occasional differences that may also relate to assay design (differing optimizations); (c) VWF:CB provides an additional activity to supplement VWF:RCo or VWF:Ac activity assays, and is not interchangeable with either. PMID- 25300812 TI - Association between ABCG2 and ABCB1 genes and warfarin stability: a case-control study. PMID- 25300813 TI - A Comparison of Mindfulness-Based Group Training and Skills Group Training in Adults With ADHD. AB - OBJECTIVE: To compare a novel "third wave" mindfulness-based training program with an established skills training derived from dialectical behavior therapy, to reduce ADHD symptoms and improve mindfulness and self-efficacy. METHOD: Ninety one adults with ADHD (combined and inattentive type, mainly medicated) were non randomly assigned to and treated within a mindfulness-based training group (MBTG, n = 39) or a skills training group (STG, n = 52), each performed in 13 weekly 2 hr sessions. RESULTS: General linear models with repeated measures revealed that both programs resulted in a similar reduction of ADHD symptoms, and improvement of mindfulness and self-efficacy. However, the effect sizes were in the small-to medium range. A decrease in ADHD symptoms >=30% was observed in 30.8% of the MBTG participants and 11.5% of the STG participants. CONCLUSION: The comparatively weak results may be due to limitations such as the absence of randomization, the lack of a control group without intervention, and the lack of matching groups for borderline, depression, and anxiety status. Moreover, audio instructions for home exercises and more stringent monitoring of participants' progress and eventual absence from sessions might have improved the outcome. PMID- 25300814 TI - Culturally Appropriate Assessment of Functional Impairment in Diverse Children: Validation of the ADHD-FX Scale With an At-Risk Community Sample. AB - OBJECTIVE: In an effort to reduce disparities in ADHD diagnoses and treatment across cultures, the current study sought to establish initial psychometric and cultural properties of the ADHD-FX: a culturally sensitive assessment measure of functional impairment related to ADHD for diverse families. METHOD: Fifty-four Latino parents (44 mothers and 10 fathers) of school-aged children completed the ADHD-FX, as well as several other measures assessing child behavior and parent acculturation. RESULTS: The ADHD-FX demonstrated adequate reliability (as demonstrated by internal consistency and test-retest reliability), psychometric construct validity (as demonstrated by associations with theoretically related measures), and cultural validity (as demonstrated by or lack of associations with acculturation measures). CONCLUSION: Initial psychometric and cultural properties suggest that the ADHD-FX is a reliable, valid, and culturally appropriate measure to assess functional impairment related to ADHD (i.e., difficulties with academic achievement, social competence, and familial relationships) in an at-risk, school aged population. PMID- 25300815 TI - Sleep impairment: the possible link between childhood ADHD, sensation seeking, and cocaine dependence. PMID- 25300816 TI - Psychostimulant prescription for ADHD in new South Wales: a longitudinal perspective. AB - OBJECTIVE: There is a need for Australian studies of ADHD that utilize the individual child as the unit of analysis because they provide a more accurate picture of national patterns (in new prescriptions, start age, and duration). The aim of this study was to build toward a national picture of patterns in psychostimulant use for ADHD by undertaking a retrospective analysis of archival data on prescriptions within New South Wales (NSW), Australia's most populated state. METHOD: A person-based data set was used to assess (a) rate of new prescriptions by age group, (b) demographic characteristics (age of start, male:female ratio), (c) duration of use, and (d) comparisons across the two decades. RESULTS: Five findings were observed: (a) The prevalence of psychostimulant use was 1.24% in 2010, (b) there was significant variability in the rate of new prescriptions by age group after 2003, (c) start age declined over the 1990 to 2000 period, but began to increase from 2000 to 2010, (d) the male:female ratio declined, and (e) the duration of psychostimulant use declined consistently. CONCLUSION: Results suggest disconnect between persistence across the life span and actual treatment patterns. A decline in medication treatment for more than 1 year and the growing proportion of discontinuous treatment suggests a need for strategies to assist families with the transition onto and off medications. PMID- 25300817 TI - NS5ATP9 suppresses activation of human hepatic stellate cells, possibly via inhibition of Smad3/phosphorylated-Smad3 expression. AB - Activation of hepatic stellate cell (HSC) is the central event in liver fibrosis. NS5ATP9 is related to many malignant tumors, but little is known about its function in HSC activation. The aim of this study is to investigate the role of NS5ATP9 in HSC activation in vitro. Genes related to liver fibrosis were detected after NS5ATP9 overexpression or silencing with or without transforming growth factor (TGF)-beta1 stimulation in the human HSCs by real-time polymerase chain reaction and western blotting. Cell proliferation, migration, and apoptosis were tested, and the mechanisms underlying the effect of NS5ATP9 on HSC activation were studied. We showed that NS5ATP9 suppressed HSC activation and collagen production, with or without TGF-beta1 induction. Also, NS5ATP9 inhibited cell proliferation and migration and promoted apoptosis. Furthermore, NS5ATP9 reduced basal and TGF-beta1-mediated Smad3/phosphorylated-Smad3 expression. The existence of a physical complex between NS5ATP9 and Smad3 was illustrated. NS5ATP9 suppresses HSC activation, extracellular matrix production, and promotes apoptosis, in part through reducing Smad3/phosphorylated-Smad3 expression. PMID- 25300818 TI - The effect of Lactobacillus rhamnosus hsryfm 1301 on the intestinal microbiota of a hyperlipidemic rat model. AB - BACKGROUND: Growing evidence indicates that intestinal microbiota regulate our metabolism. Probiotics confer health benefits that may depend on their ability to affect the gut microbiota. The objective of this study was to examine the effect of supplementation with the probiotic strain, Lactobacillus rhamnosus hsryfm 1301, on the gut microbiota in a hyperlipidemic rat model, and to explore the associations between the gut microbiota and the serum lipids. METHODS: The hyperlipidemic rat model was established by feeding rats a high-fat diet for 28 d. The rats' gut microbiota were analyzed using high-throughput sequencing before and after L. rhamnosus hsryfm 1301 supplementation or its fermented milk for 28 d. The serum lipids level was also tested. RESULTS: The rats' primary gut microbiota were composed of Bacteroidetes, Firmicutes, Proteobacteria, Spirochaetes and Verrucomicrobia. The abundance and diversity of the gut microbiota generally decreased after feeding with a high-fat diet, with a significant decrease in the relative abundance of Bacteroidetes, but with an increase in that of Firmicutes (P < 0.05). Administration of L. rhamnosus hsryfm 1301 or its fermented milk for 28 d, could recover the Bacteroidetes and Verrucomicrobia abundance and could decrease the Firmicutes abundance, which was associated with a significant reduction in the serum lipids' level in the hyperlipidemic rats with high-fat diet induced. The abundance of 22 genera of gut bacteria was changed significantly after probiotic intervention for 28 d (P < 0.05). A positive correlation was observed between Ruminococcus spp. and serum triglycerides, Dorea spp. and serum cholesterol (TC) and low-density lipoprotein (LDL-C), and Enterococcus spp. and high-density lipoprotein. The Butyrivibrio spp. negatively correlated with TC and LDL-C. CONCLUSIONS: Our results suggest that the lipid metabolism of hyperlipidemic rats was improved by regulating the gut microbiota with supplementation of L.rhamnosus hsryfm 1301 or its fermented milk for 28 d. PMID- 25300819 TI - Synthesis and evaluation of novel triazoles and mannich bases functionalized 1,4 dihydropyridine as angiotensin converting enzyme (ACE) inhibitors. AB - A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 MUM, 0.409 MUM and 0.653 MUM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 MUM. PMID- 25300821 TI - On human health. AB - If it is true that health is a priority objective of medicine, then medical practice can only be successful if the meaning of the term "health" is known. Various attempts have been made over the years to define health. This paper proposes a new definition. In addition to current health concepts, it also takes into account the distinction between specifically human (great) health and health as the absence of disease and illness-i.e. small health. The feeling of leading a life that makes sense plays a key role in determining specifically human great health. PMID- 25300820 TI - Chemical synthesis, cytotoxicity, selectivity and bioavailability of 5alpha androstane-3alpha,17beta-diol derivatives. AB - Aminosteroid derivatives represent a new family of compounds with promising antiproliferative activity over different cancer cell lines. Among all the aminosteroid derivatives synthesised in our laboratory, we have identified E-37P as one of the more potent when tested in vitro. Unfortunately, the pharmacokinetic properties of E-37P decrease its effectiveness when tested in vivo. To improve the bioavailability and increase the efficiency of aminosteroid E-37P, two series of analog compounds were synthesised by classic chemical synthesis, they were then characterized, and the concentration that inhibits 50% of cell proliferation (IC50) was determined on different cell lines. RM-133, a 5alpha-androstane-3alpha,17beta-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2beta and an ethinyl at position 17alpha, showed very good antiproliferative activity among the five cancer cell lines studied (IC50=0.1, 0.1, 0.1, 2.0 and 1.1 MUM for HL-60, MCF-7, T-47D, LNCaP and WEHI-3, respectively). Moreover, the plasmatic concentration of RM-133 at 3h, when injected subcutaneously in rats, was 2.3-fold higher than that of E-37P (151 vs 64.8 ng/mL). Furthermore, RM-133 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a very low risk of drug-drug interactions. The cytotoxicity of RM-133 against normal cells was tested on peripheral blood lymphocytes (PBL) obtained from different donors and previously activated with phytohemagglutinin-L. PBL responded differently to treatment with RM-133, we observed a stimulation of cell proliferation and/or cytotoxicity in a dose-dependent manner. Based on these results, additional studies are currently underway to evaluate the selectivity of our lead compound against normal cell lines in a more detailed fashion. PMID- 25300822 TI - Dopaminergic neuron-like cells derived from bone marrow mesenchymal stem cells by Lmx1alpha and neurturin overexpression for autologous cytotherapy in hemiparkinsonian rhesus monkeys. AB - Bone marrow-derived mesenchymal stem cells hold great potential for cytotherapeutics of neurodegenerative disorders, including Parkinson's disease. The neurotrophic factor neurturin can rescue dopaminergic neurons damaged during the disease process. Lmx1alpha can promote mesencephalic dopaminergic differentiation during embryogenesis. In this study, we tested a cytotherapeutic strategy combining NTN/Lmx1alpha gene therapy and cell transplantation to ameliorate disease progression in hemiparkinsonian rhesus. Rhesus BMSCs were prepared for autologous grafting by transfection with recombinant adenoviral vectors expressing secreted NTN and Lmx1alpha,and cultured in the presence of induce factors, particularly the Lmx1alpha regulatory factor sonic hedgehog, to guide dopaminergic differentiation. These induced rh-BMSCs exhibited gene/protein expression phenotypes resembling nigral dopaminergic neurons. They survived and retained dopaminergic function following stereotaxic injection into the MPTP lesioned right-side substantia nigra as indicated by SPECT measurement of DAT activity. Injected cells preserved and supplemented the remaining endogenous population of dopamine neurons (TH-positive cell ipsilateral/contralateral ratio was 56.81% +/- 7.28% vs. 3.86%+/-1.22% in vehicle-injected controls; p<0.05). Cell injection also partially restored motor function and reduce apomorphine evoked rotation (p<0.05). Moreover, function recovery occurred earlier than in previous studies on injected BMSCs. Our findings demonstrate a promising strategy for restoration of PD-associated motor dysfunction by transplantation of autologous BMSCs overexpressing NTN/Lmx1alpha. PMID- 25300824 TI - "Quick fixes" are not answer to financial failure in NHS, says think tank. PMID- 25300823 TI - Update on the current evidence for Tm:YAG vapoenucleation of the prostate 2014. AB - INTRODUCTION: To evaluate the current role of thulium vapoenucleation of the prostate (ThuVEP) for the treatment of benign prostatic obstruction (BPO). METHODS: A Medline search for randomized trials, case series, and comparative studies being published since the initial description of the ThuVEP procedure (2009-2014) was performed to assess the safety, the perioperative morbidity, the efficacy, and the durability of the technique. RESULTS: A total of 14 peer reviewed original articles, seven case series [level of evidence (LOE) 4] and seven comparative studies (LOE 3b), have been identified. ThuVEP has been shown to be a size-independent, safe, efficacious, and durable procedure for the treatment of BPO in large, prospective, and retrospective series (LOE 4/3b). The feasibility and safety of the ThuVEP procedure has also been confirmed in patients at high cardiopulmonary risk on oral anticoagulants (LOE 4). It has also been demonstrated that the erectile function is not impaired by the ThuVEP procedure (LOE 4). However, published ThuVEP series are from very few centers of excellence not exceeding a LOE of 3b. Randomized controlled trials comparing ThuVEP with standard procedures for the treatment of BPO, namely transurethral resection of the prostate, open prostatectomy, or holmium laser enucleation of the prostate, have not been published so far. CONCLUSIONS: ThuVEP appears to be a size-independent, safe, efficacious, and durable procedure for the treatment of BPO (LOE 4/3b). Multicentric PRT are however needed to define the current role of ThuVEP in the armamentarium of minimally invasive transurethral surgery of the prostate. PMID- 25300825 TI - Cooperative interplay of van der Waals forces and quantum nuclear effects on adsorption: H at graphene and at coronene. AB - The energetic barriers that atoms and molecules often experience when binding to surfaces are incredibly important to a myriad of chemical and physical processes. However, these barriers are difficult to describe accurately with current computer simulation approaches. Two prominent contemporary challenges faced by simulation are the role of van der Waals forces and nuclear quantum effects. Here we examine the widely studied model systems of hydrogen on graphene and coronene using a van der Waals inclusive density functional theory approach together with path integral molecular dynamics at 50 K. We find that both van der Waals and quantum nuclear effects work together in a cooperative manner to dramatically reduce the barriers for hydrogen atoms to adsorb. This suggests that the low temperature hydrogenation of graphene is easier than previously thought and in more general terms that the combined roles of van der Waals and quantum tunnelling can lead to qualitative changes in adsorption. PMID- 25300827 TI - Gateway(r)-compatible plant transformation vectors. AB - Studies in functional genomics and crop improvement programs often rely on the introduction and expression of transgenes in plants. There are two essential components required for in planta transgene expression, a plasmid vector on which the transgene sequence is carried and a delivery system capable of transferring the vector to the target cells. Agrobacterium-mediated plant transformation and the binary plasmid vector system is the preferred method of transgene delivery. The cloning technologies used for DNA manipulation underpin many of these studies. Increased demand for efficient high-throughput transformation systems is driving forward improvements in gene cloning techniques. This chapter gives an overview of Gateway((r))-compatible binary vectors for use in Agrobacterium mediated transformation systems. It describes a fast, efficient, and robust cloning protocol for the production of an over-expression binary vector using Gateway((r)) recombinational cloning. PMID- 25300826 TI - Evaluation of a questionnaire to assess selected infectious diseases and their risk factors : findings of a multicenter study. AB - BACKGROUND/OBJECTIVES: The risk to die from an infectious disease in Germany has been continuously decreasing over the last century. Since infections are, however, not only causes of death but risk factors for diseases like cardiovascular diseases, it is essential to monitor and analyze their prevalence and frequency, especially in consideration of the increased life expectancy. To gain more knowledge about infectious diseases as risk factors and their implications on the condition and change of the immune status, the German National Cohort (GNC), a population-based prospective cohort study, will recruit 200,000 subjects between 2014 and 2017. In Pretest 1, a feasibility study for the GNC, we evaluated a self-administered and self-report questionnaire on infectious diseases and on the use of health care facilities (hereinafter called "ID Screen") for feasibility and validity. METHODS: From August-November 2011, 435 participants between the ages of 20-69 completed the ID Screen. All subjects had been recruited via a random sample from the local residents' registration offices by 4 of the 18 participating study centers. The questionnaire encompasses 77 variables in six sections assessing items such as 12-month prevalence of infections, cumulative prevalence of infectious diseases, visit of health care facilities and vaccination. The feasibility was amongst others evaluated by assessing the completeness and comprehensiveness of the questionnaire. To assess the questionnaires ability to measure "immune status" and "susceptibility to infections", multivariate analysis was used. RESULTS: The overall practicability was good and most items were well understood, demonstrated by < 2/33 missing questions per questionnaire and only three variables: vaccination for influenza and pneumococci and infection with chickenpox had a frequency > 5 % of missing values. However, direct comparison of the items 12-month prevalence and lifetime prevalence of nephritis/pyelitis showed poor agreement and thereby poor understanding by 80 % of the participants, illustrating the necessity for a clear, lay person appropriate description of rare diseases to increase comprehensibility. The questionnaire will be used to support the assessment of immune dysfunction and frequency of infection. An analysis of these constructs in an exploratory factor analysis revealed limited applicability due to low interitem correlation (Cronbach's alpha < 0.5). This is corroborated by the extraction of more than one factor with a Kaiser-Meyer-Olkin measure of 0.6 instead of a unidimensional latent construct for "immune status". CONCLUSION: All in all, the ID Screen is a good and reliable tool to measure infectious diseases as risk factors and outcome in general, but requires a better translation of infection specific terms into lay person terms. For the assessment of the overall immune status, the tool has strong limitations. Vaccinations status should also rather be assessed based on vaccination certificates than on participants' recall. PMID- 25300828 TI - Brachypodium distachyon. AB - The small grass Brachypodium distachyon has attributes that make it an excellent model for the development and improvement of cereal crops and bioenergy feedstocks. To realize the potential of this system, many tools have been developed (e.g., the complete genome sequence, a large collection of natural accessions, a high density genetic map, BAC libraries, EST sequences, microarrays, etc.). In this chapter, we describe a high-efficiency transformation system, an essential tool for a modern model system. Our method utilizes the natural ability of Agrobacterium tumefaciens to transfer a well-defined region of DNA from its tumor-inducing (Ti) plasmid DNA into the genome of a host plant cell. Immature embryos dissected out of developing B. distachyon seeds generate an embryogenic callus that serves as the source material for transformation and regeneration of transgenic plants. Embryogenic callus is cocultivated with A. tumefaciens carrying a recombinant plasmid containing the desired transformation sequence. Following cocultivation, callus is transferred to selective media to identify and amplify the transgenic tissue. After 2-5 weeks on selection media, transgenic callus is moved onto regeneration media for 2-4 weeks until plantlets emerge. Plantlets are grown in tissue culture until they develop roots and are transplanted into soil. Transgenic plants can be transferred to soil 6-10 weeks after cocultivation. Using this method with hygromycin selection, transformation efficiencies average 42 %, and it is routinely observed that 50-75 % of cocultivated calluses produce transgenic plants. The time from dissecting out embryos to having the first transgenic plants in soil is 14-18 weeks, and the time to harvesting transgenic seeds is 20-31 weeks. PMID- 25300829 TI - Medicago truncatula transformation using cotyledonary explants. AB - Medicago truncatula has been developed into a model species for legumes. The M. truncatula genotype Jemalong A17 has been used for EST and genome sequencing. However, this genotype is difficult to regenerate from callus cultures. By using cotyledons as explants for Agrobacterium infection and direct shoot formation, this protocol allows for rapid production of transgenic plants from Jemalong A17 and other genotypes. Transgenic plants can be regenerated and established in the greenhouse in only 3-4 months after Agrobacterium-mediated transformation. Transformation frequency was in the range of 5-12 %. PMID- 25300830 TI - Medicago truncatula transformation using leaf explants. AB - Legumes have been for a long time recalcitrant to efficient Agrobacterium transformation. The choice and use of model legume plants (Medicago truncatula and Lotus japonicus) for molecular studies has triggered extensive studies devoted to the development of efficient Agrobacterium-mediated transformation protocols for these two plants. In M. truncatula, transformation protocols rely on the use of highly regenerable lines obtained by recurrent in vitro culture selection. These protocols are based on Agrobacterium-mediated transformation of M. truncatula followed by somatic embryogenesis-mediated plant regeneration. We describe here the protocol developed for M. truncatula R108-1 (c3). PMID- 25300831 TI - Setaria viridis. AB - Interest in plant model systems for genetic, biological, and functional genomics studies stems from advantages they provide in terms of fast generation time, small stature, and simple growth requirements. A model species would be especially advantageous for the studies of C4 photosynthetic grasses, which currently present practical challenges. These include long seed-to-seed generation times, and because of their large size at maturity they require large growing areas. One potential model of interest for C4 photosynthetic grasses is Setaria viridis. It has all the desirable aforementioned attributes for a model; however, for it to be adopted as a model for functional genomics studies, gene transfer methodology is also needed. In this chapter, we describe methods for Agrobacterium tumefaciens-mediated transformation of seed-derived callus. Vectors used for gene constructs contained the hygromycin phosphotransferase gene as a selectable marker. The transition of transgenic lines to soil was straightforward; plants started to flower in 1-3 weeks, with seeds ready to harvest approximately 5 weeks later. PMID- 25300832 TI - Barley (Hordeum vulgare L.) transformation using immature embryos. AB - Barley is a major crop species, and also has become a genetic model for the small grain temperate cereals. A draft barley genome sequence has recently been completed, opening many opportunities for candidate gene isolation and functionality testing. Thanks to the development of customizable endonucleases, also site-directed genome modification recently became feasible for higher plants, which marks the beginning of a new era of genetic engineering. The development of improved binary vectors and hypervirulent Agrobacterium tumefaciens strains has raised the efficiency of genetic transformation in barley to a level where the technique has become relatively routine. The transformation method described here involves immature barley embryos cocultivated with Agrobacterium after removal of their embryo axis. Critical adjustments to the protocol have included the supplementation of the cocultivation medium with the polyphenolic signaling compound acetosyringone at comparatively high concentration and the use of cysteine to reduce the extent of cellular oxidation upon agroinfection. In addition, the use of liquid, rather than solid, cocultivation medium promotes the throughput of the method. The protocol has delivered well over 10,000 transgenic barley plants over the past 10 years. Routine transformation efficiency, calculated on the basis of the recovery of independent transgenics per 100 explants, has reached about 25 % in cultivar (cv.) "Golden Promise". The protocol has proven effective for more than 20 barley cultivars, although some adjustments to the culture conditions have had to be made in some cases. The transformation efficiency of cv. "Golden Promise" remains higher than that of any other cultivar tested. PMID- 25300833 TI - Barley (Hordeum vulgare L.) transformation using embryogenic pollen cultures. AB - The temperate cereal barley is grown as a source of food, feed, and malt. The development of a broad range of genetic resources and associated technologies in this species has helped to establish barley as the prime model for the other Triticeae cereals. The specific advantage of the transformation method presented here is that transgene homozygosity is attained in the same generation as the transgenic event occurred through the coupling of haploid technology with Agrobacterium-mediated transformation. Pollen is haploid and, following transformation, can be induced to regenerate into haploid plantlets, which can subsequently subjected to colchicine treatment to obtain diploid, genetically fixed plants. The routine application of the method based on the winter-type barley cultivar 'Igri' over a period of over 10 years has achieved an average yield of about two transgenic plants per donor spike. The whole procedure from pollen isolation to non-segregating transgenic, mature grain takes less than 12 months. PMID- 25300834 TI - Maize (Zea mays L.). AB - Agrobacterium tumefaciens-mediated transformation is an effective method for introducing genes into maize. In this chapter, we describe a detailed protocol for genetic transformation of the maize genotype Hi II. Our starting plant material is immature embryos cocultivated with an Agrobacterium strain carrying a standard binary vector. In addition to step-by-step laboratory transformation procedures, we include extensive details in growing donor plants and caring for transgenic plants in the greenhouse. PMID- 25300835 TI - Maize, tropical (Zea mays L.). AB - Maize (Zea mays L.) is the third most important food crop globally after wheat and rice. In sub-Saharan Africa, tropical maize has traditionally been the main staple of the diet; 95 % of the maize grown is consumed directly as human food and as an important source of income for the resource-poor rural population. The biotechnological approach to engineer biotic and abiotic traits implies the availability of an efficient plant transformation method. The production of genetically transformed plants depends both on the ability to integrate foreign genes into target cells and the efficiency with which plants are regenerated. Maize transformation and regeneration through immature embryo culture is the most efficient system to regenerate normal transgenic plants. However, this system is highly genotype dependent. Genotypes adapted to tropic areas are difficult to regenerate. Therefore, transformation methods used with model genotypes adapted to temperate areas are not necessarily efficient with tropical lines. Agrobacterium-mediated transformation is the method of choice since it has been first achieved in 1996. In this report, we describe a transformation method used successfully with several tropical maize lines. All the steps of transformation and regeneration are described in details. This protocol can be used with a wide variety of tropical lines. However, some modifications may be needed with recalcitrant lines. PMID- 25300836 TI - Finger millet [Eleusine coracana (L.) Gaertn]. AB - Millets are the primary food source for millions of people in tropical regions of the world supplying mineral nutrition and protein. In this chapter, we describe an optimized protocol for the Agrobacterium-mediated transformation of finger millet variety GPU 45. Agrobacterium strain LBA4404 harboring plasmid pCAMBIA1301 which contains hygromycin phosphotransferase (hph) as selectable marker gene and beta-glucuronidase (GUS) as reporter gene has been used. This protocol utilizes the shoot apex explants for the somatic embryogenesis and regeneration of finger millet after the transformation by Agrobacterium. Desiccation of explants during cocultivation helps for the better recovery of transgenic plants. This protocol is very useful for the efficient production of transgenic plants in finger millet through Agrobacterium-mediated transformation. PMID- 25300837 TI - Oat (Avena sativa L.). AB - Agrobacterium-mediated transformation is a suitable method to transform different cultivars using different systems of A. tumefaciens strains and binary vectors as well as selection cassettes. We describe here a detailed protocol for two cultivars, one naked and one husked, using the AGL1 strain and the pGreen vector containing the nptII selection cassette ( http://www.pgreen.ac.uk/ ), suitable for oat as well as other cereals. The pGreen vector system was recently developed for pBract ( http://www.bract.org/ ) and its transformation ability for cereals was proved. Assuming our experience and the latest knowledge on Agrobacterium mediated transformation of cereals, we suggest using in the protocol one of the newly developed pBract or pCAMBIA ( http://www.cambia.org/daisy/cambia/ ) vector systems which carry different selection cassettes. The commonly used selection genes nptII, bar, and hpt were proved to be applicable for oat transformation and might be used as needed. PMID- 25300838 TI - Rice, indica (Oryza sativa L.). AB - Indica varieties, which are generally recalcitrant to tissue culture and transformation, occupy 80 % of rice cultivation area in the world. Therefore, transformation method for indica rice must be improved greatly so that global rice production would take full advantage of cutting-edge biotechnology. An efficient protocol for indica transformation mediated by Agrobacterium tumefaciens is hereby described. Immature embryos collected from plants in a greenhouse are cocultivated with A. tumefaciens after pretreatment with heat and centrifuging. The protocol was successfully tested in many elite indica cultivars such as IR8, IR24, IR58025B, IR64, IR72, Suweon 258, and Nanjing 11, yielding between 5 and 15 of independent transgenic plants per immature embryo. The use of immature embryos is recommended because gene transfer to them could be much more efficient and much less genotype dependent than gene transfer to callus. PMID- 25300839 TI - Rice, Japonica (Oryza sativa L.). AB - The importance of rice, as a food crop, is reflected in the extensive global research being conducted in an effort to improve and better understand this particular agronomic plant. In regard to biotechnology, this has led to the development of numerous genetic transformation protocols. Over the years, many of these methods have become increasingly straightforward, rapid, and efficient, thereby making rice valuable as a model crop for scientific research and functional genomics. The focus of this chapter is on one such protocol that uses Agrobacterium-mediated transformation of Oryza sativa L. ssp. Japonica cv. Nipponbare with an emphasis on tissue desiccation. The explants consist of callus derived from mature seeds which are cocultivated on filter paper postinfection. Hygromycin selection is used for the recovery of subsequent genetically engineered events. PMID- 25300840 TI - Sorghum (Sorghum bicolor). AB - Agrobacterium-mediated transformation of sorghum (Sorghum bicolor L. Moench) targeting immature embryo explants is a route to introduce transgenic alleles into the crop. The protocol requires maintenance of quality stock plants under greenhouse conditions for a constant supply of immature embryo explants. This is typically carried out by a regular sowing of seeds, minimal use of pesticides, and monitoring of plants to document pollen dispersal and bagging of heads. The time frame from explant inoculation to establishment of a primary transgenic event in the greenhouse typically ranges from 4 to 6 months. Seed set in the primary transformants is comparable to greenhouse-grown stock plants, with the majority of the transgenic alleles being inherited as a single functional locus. PMID- 25300841 TI - Wheat (Triticum aestivum L.) transformation using immature embryos. AB - Wheat may now be transformed very efficiently by Agrobacterium tumefaciens. Under the protocol hereby described, immature embryos of healthy plants of wheat cultivar Fielder grown in a well-conditioned greenhouse were pretreated with centrifuging and cocultivated with A. tumefaciens. Transgenic wheat plants were obtained routinely from between 40 and 90 % of the immature embryos, thus infected in our tests. All regenerants were normal in morphology and fully fertile. About half of the transformed plants carried single copy of the transgene, which are inherited by the progeny in a Mendelian fashion. PMID- 25300842 TI - Wheat (Triticum aestivum L.) transformation using mature embryos. AB - In most protocols for the Agrobacterium-mediated transformation of wheat, the preferred target tissues are immature embryos. However, transformation methods relying on immature embryos require the growth of plants under controlled conditions to provide a continuous supply of good-quality target tissue. The use of mature embryos as a target tissue has the advantage of only requiring good quality seed as the starting material. Here we describe a transformation method based on the Agrobacterium-mediated transformation of callus cultures derived from mature wheat embryos of the genotype Bobwhite S56. PMID- 25300843 TI - Alfalfa (Medicago sativa L.). AB - Alfalfa (Medicago sativa L.) is a high-quality forage crop widely grown throughout the world. This chapter describes an efficient protocol that allows for the generation of large number of transgenic alfalfa plants by sonication assisted Agrobacterium-mediated transformation. Binary vectors carrying different selectable marker genes that confer resistance to phosphinothricin (bar), kanamycin (npt II), or hygromycin (hph) were used to generate transgenic alfalfa plants. Intact trifoliates collected from clonally propagated plants in the greenhouse were sterilized with bleach and then inoculated with Agrobacterium strain EHA105. More than 80 % of infected leaf pieces could produce rooted transgenic plants in 4-5 months after Agrobacterium-mediated transformation. PMID- 25300844 TI - Clovers (Trifolium spp.). AB - Clovers (Trifolium spp.) constitute one of the major forage legumes widely grown for its rich protein content and its major role in maintaining environmental sustainability by improving the soil fertility. Gene technology can assist plant improvement efforts in clovers (Trifolium spp.), aiming to improve forage quality, yield, and adaptation to biotic and abiotic stresses. An efficient and reproducible protocol for Agrobacterium-mediated transformation of a range of Trifolium species, using cotyledonary explants and different selectable marker genes, is described. The protocol is robust and allows for genotype and Agrobacterium strain-independent transformation of clovers. Stable meiotic transmission of transgenes has been demonstrated for selected transgenic clovers carrying single T-DNA inserts recovered from Agrobacterium-mediated transformation. This methodology can also be successfully used for "isogenic transformation" in clovers: the generation of otherwise identical plants with and without the transgene from the two cotyledons of a single seed. Stable transgenes may be used in further functional genomics, develop new traits and profile gene expression using reporters, and facilitate purification of tissue or single cells. PMID- 25300845 TI - Clover, red (Trifolium pratense). AB - Genetic modification of plants by the insertion of transgenes can be a powerful experimental approach to answer basic questions about gene product function. This technology can also be used to make improved crop varieties for use in the field. To apply this powerful tool to red clover, an important forage legume, a population of red clover with high potential for regeneration in tissue culture has been developed. Here we provide a detailed procedure for Agrobacterium mediated transformation of genotypes derived from this regenerable population. We have successfully used this methodology to express beta-glucuronidase (GUS) reporter genes as well as for hairpin RNA-mediated silencing of endogenous genes for polyphenol oxidase and a transferase crucial in phaselic acid accumulation. PMID- 25300846 TI - Cowpea [Vigna unguiculata (L.) Walp]. AB - Agrobacterium tumefaciens-mediated transformation is an efficient method for incorporating genes and recovering stable transgenic plants in cowpea because this method offers several advantages such as the defined integration of transgenes, potentially low copy number, and preferential integration into transcriptional active regions of the chromosome. Cotyledonary node explants of cowpea present an attractive target for T-DNA delivery followed by regeneration of shoots via axillary proliferation without involvement of a de novo regeneration pathway. In this chapter, we describe a detailed protocol for Agrobacterium-mediated transformation of the cowpea variety Pusa Komal. The seedling cotyledonary node explants are used for cocultivation with an Agrobacterium strain EHA105 harboring standard binary vector, pCAMBIA2301 or pNOV2819, and putative transformed plants are selected using aminoglycoside antibiotic or mannose as sole carbon source, respectively. The entire process includes explant infection to transgenic seed generation in greenhouse. PMID- 25300847 TI - Lentil (Lens culinaris Medik). AB - This chapter describes an efficient Agrobacterium-mediated genetic transformation of lentil by use of cotyledonary node explants, an optimized wounding method, and vacuum infiltration. Transformation protocol was followed by direct regeneration of transgenic shoots and micrografting of the shoots on root stocks to obtain whole-plant regeneration. The most efficient transgene expression on the axil region was obtained when the Agrobacterium KYRT1 strain was used. Gradually increasing selection pressure and repeated removal of regenerated shoots between selection steps increased the number of transgene-expressing shoots greatly. This protocol allowed 2.3 % transformation efficiency and stable transgene expression and transmission which were tracked through three generations. PMID- 25300848 TI - Soybean [Glycine max (L.) Merr]. AB - In this chapter we describe an Agrobacterium tumefaciens transformation method of soybean that utilizes mature half seeds and regeneration from the cotyledonary node region. This method results in fertile transformed soybean plants and transgenic seed in approximately 9 months. Using mature half seeds as starting material has proven to be a reliable method that does not require additional wounding for infection to occur. We have continued to make improvements in the protocol, resulting in an efficient plant regeneration system. PMID- 25300849 TI - Brassica oleracea and B. napus. AB - With the accelerating advances in genetics and genomics research in Arabidopsis and Brassica, transformation technologies are now routinely being exploited to elucidate gene function as well as contributing to the development of novel enhanced crops. When a researcher's desired goal is simply to modify or introduce candidate genes into a Brassica, the availability of easy-to-follow protocols and knowledge of readily transformable genotypes becomes a valuable resource. In this chapter we outline a basic A. tumefaciens-mediated transformation method, using 4 day-old cotyledonary explants, that has been successfully applied to a range of different B. oleracea and B. napus genotypes. For demonstration purposes, we focus primarily on the diploid species B. oleracea using a model doubled haploid genotype, AG DH1012. After only 3-4 weeks on kanamycin selection the first transgenic shoots can be isolated. Transformation efficiencies are typically in the region of 15-25 % (based on 15-25 PCR-positive independent shoots from 100 inoculated explants). Most explants will produce multiple shoots (1-3+ per explant) and so the total number of transgenic shoots produced will exceed 15-25 per 100 explant experiment. The protocol is also applicable to B. napus and modifications specific to this species are highlighted accordingly. For researchers wishing to use their own plant genotype, tissue culture phenotypes that are conducive to efficient transformation are also highlighted within this chapter. PMID- 25300850 TI - Cucumber (Cucumis sativus L.) and kabocha squash (Cucurbita moschata Duch). AB - We established improved methods for Agrobacterium-mediated transformation of cucumber (Cucumis sativus L.) and kabocha squash (Cucurbita moschata Duch). Vacuum infiltration of cotyledonary explants with Agrobacterium suspension enhanced the Agrobacterium infection efficiency in the proximal regions of explants. Wounding treatment was also essential for kabocha squash. Cocultivation on filter paper wicks suppressed necrosis of explants, keeping regeneration efficacy. Putative transgenic plants were screened by kanamycin resistance and green fluorescent protein (GFP) fluorescence. These putative transgenic plants grew normally and T1 seeds were obtained, and stable integration and transmission of the transgene in T1 generations were confirmed by Southern hybridization and PCR. The average transgenic efficiency for cucumber and kabocha squash was 11.9 +/- 3.5 and 9.2 +/- 2.9 %, respectively. PMID- 25300851 TI - Pepper, chili (Capsicum annuum). AB - Pepper is a recalcitrant plant for Agrobacterium-mediated genetic transformation. Several obstacles to genetic transformation remain such as extremely low transformation rates; the choice of correct genotype is critical; and there is a high frequency of false positives due to direct shoot formation. Here, we report a useful protocol with a suitable selection method. The most important aspect of the pepper transformation protocol is selecting shoots growing from the callus, which is referred to as callus-mediated shoot formation. This protocol is a reproducible and reliable system for pepper transformation. PMID- 25300852 TI - Pepper, sweet (Capsicum annuum). AB - Capsicum (pepper) species are economically important crops that are recalcitrant to genetic transformation by Agrobacterium (Agrobacterium tumefaciens). A number of protocols for pepper transformation have been described but are not routinely applicable. The main bottleneck in pepper transformation is the low frequency of cells that are both susceptible for Agrobacterium infection and have the ability to regenerate. Here, we describe a protocol for the efficient regeneration of transgenic sweet pepper (C. annuum) through inducible activation of the BABY BOOM (BBM) AP2/ERF transcription factor. Using this approach, we can routinely achieve a transformation efficiency of at least 0.6 %. The main improvements in this protocol are the reproducibility in transforming different genotypes and the ability to produce fertile shoots. An added advantage of this protocol is that BBM activity can be induced subsequently in stable transgenic lines, providing a novel regeneration system for clonal propagation through somatic embryogenesis. PMID- 25300853 TI - Sugar beet (Beta vulgaris L.). AB - Creating transgenic plants is invaluable for the genetic analysis of sugar beet and will be increasingly important as sugar beet genomic technologies progress. A protocol for Agrobacterium-mediated transformation of sugar beet is described in this chapter. Our protocol is optimized for a sugar beet genotype that performs exceptionally well in tissue culture, including the steps of dedifferentiation, callus proliferation, and regeneration. Because of the infrequent occurrence of such a genotype in sugar beet populations, our protocol includes an in vitro propagation method for germplasm preservation. The starting materials for transgenic experiments are aseptic shoots grown from surface-sterilized seed balls. Callus is induced from leaf explants and subsequently infected with Agrobacterium. Plantlets are regenerated from transgenic callus and vernalized for flowering, if necessary. The efficiency of transformation was quite high; in our laboratory, the culture of only ten leaf explants, on average, generated one transgenic plant. PMID- 25300854 TI - Tomato (Solanum lycopersicum). AB - Agrobacterium-mediated transformation is the most common method for the incorporation of foreign genes into the genome of tomato as well as many other species in the Solanaceae family. This chapter describes a protocol for the genetic transformation of tomato cultivar Micro-Tom using cotyledons as explants. Detailed procedures are also included for determining gene-copy number using a duplex qPCR TaqMan assay, and the histochemical analysis of GUS expression. PMID- 25300855 TI - Production and immobilization of enzymes by solid-state fermentation of agroindustrial waste. AB - The recovery of by-products from agri-food industry is currently one of the major challenges of biotechnology. Castilla-La Mancha produces around three million tons of waste coming from olive oil and wine industries, both of which have a pivotal role in the economy of this region. For this reason, this study reports on the exploitation of grape skins and olive pomaces for the production of lignocellulosic enzymes, which are able to deconstruct the agroindustrial waste and, therefore, reuse them in future industrial processes. To this end, solid state fermentation was carried out using two local fungal strains (Aspergillus niger-113 N and Aspergillus fumigatus-3). In some trials, a wheat supplementation with a 1:1 ratio was used to improve the growth conditions, and the particle size of the substrates was altered through milling. Separate fermentations were run and collected after 2, 4, 6, 8, 10 and 15 days to monitor enzymatic activity (xylanase, cellulase, beta-glucosidase, pectinase). The highest values were recorded after 10 and 15 days of fermentation. The use of A. niger on unmilled grape skin yielded the best outcomes (47.05 U xylanase/g by-product). The multi enzymatic extracts obtained were purified, freeze dried, and immobilized on chitosan by adsorption to assess the possible advantages provided by the different techniques. PMID- 25300856 TI - National registry on cardiac electrophysiology (2012). AB - Based on a survey sent to Portuguese centers that perform diagnostic and interventional electrophysiology and/or implantable cardioverter-defibrillator (ICD) implantations, the authors analyze the number and type of procedures performed during 2012 and compare these data with previous years. In 2012, a total of 2561 diagnostic electrophysiologic studies were performed, which were followed by ablation in 2017 cases, representing a steady situation compared with the previous year. There was a 12% increase in the number of ablation procedures for atrial fibrillation, making it for the first time the most frequent indication for ablation, overtaking atrioventricular nodal reentrant tachycardia. The total number of first ICD implantations was 1048 (around 100 per million population), of which 375 were cardiac resynchronization devices (BiV ICDs). This represents a slight decrease (3.3%) in the total number of new implants, with an increase of 10% in the number of BiV ICDs compared to the previous year. However, there was a considerable increase in the number of ICD generator replacements, resulting in an overall increase of 3.5% in implantations performed in 2012. Some comments are made regarding developments in this activity and its current status, and on some factors that may influence the dynamics of this area of interventional cardiology. PMID- 25300857 TI - Ventricular septal defect in children and adolescents in Angola: experience of a tertiary center. AB - INTRODUCTION AND OBJECTIVE: This is the first study in Angola with the aim of characterizing ventricular septal defect (VSD) among children and adolescents. METHODS: A cross-sectional study based on echocardiographic records of the largest pediatric cardiology center in Angola included all children and adolescents (0 to 18 years old) with VSD between April 2010 and March 2011. The diagnosis was made by transthoracic and Doppler echocardiography with a Medison SA 8000 system. The sample was divided into two groups: Group 1, isolated VSD; and Group 2, VSD associated with other congenital heart defects (CHDs). Age, gender, type of VSD, associated CHDs and genetic syndromes were assessed. RESULTS: A total of 490 CHDs were diagnosed, of which 283 were VSDs. In Group 1 (140, 49%) the mean age was 29+/-36 months. The most frequent age (mode) at diagnosis was 24 months. There was no predominance of gender (ratio 1:1). The majority (127, 91%) had perimembranous VSD. In Group 2 (143, 51%) 113 patients (79%) had one, 27 patients (19%) had two and three patients (2%) had three other CHDs. Trisomy 21 was the most common genetic syndrome (23, 96%). CONCLUSIONS: The study shows that VSD is the most common CHD in childhood, the diagnosis is made late and almost half of VSDs are associated with other CHDs. PMID- 25300858 TI - The value of isovolumic acceleration for the assessment of right ventricular function in acute pulmonary embolism. AB - AIM: The aim of this study was to assess the value of tricuspid annulus myocardial isovolumic acceleration (IVA) in the assessment of right ventricular function in patients with acute pulmonary embolism (PE). METHODS: Fifteen patients (mean age 60.6+/-11.3 years) with acute PE were enrolled and a control group was formed of 15 patients with a similar mean age (60.3+/-11.5). Patients who were diagnosed with acute PE by thoracic computed tomography angiography underwent transthoracic echocardiography at the time of diagnosis and at one month after diagnosis. RESULTS: In the control group IVA was 2.8+/-0.2 m/s(2), while in the acute PE group, it was 2.0+/-0.1 m/s(2) at the time of diagnosis and 2.9+/-0.1 m/s(2) at the end of the first month. When IVA values of acute PE patients at the end of the first month were compared with their initial values and those of the control group, they had normalized (control and acute PE p<0.0001; control and PE at one-month follow-up p=0.983). CONCLUSION: In our study, IVA was shown to be a reliable marker of right ventricular systolic function in patients with acute PE. PMID- 25300859 TI - STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. AB - Although type I IFNs play critical roles in antiviral and antitumor activity, it remains to be elucidated how type I IFNs are produced in sterile conditions of the tumor microenvironment and directly affect tumor-infiltrating immune cells. Mouse de novo gliomas show increased expression of type I IFN messages, and in mice, CD11b(+) brain-infiltrating leukocytes (BIL) are the main source of type I IFNs that are induced partially in a STING (stimulator of IFN genes)-dependent manner. Consequently, glioma-bearing Sting(Gt) (/Gt) mice showed shorter survival and lower expression levels of Ifns compared with wild-type mice. Furthermore, BILs of Sting(Gt) (/Gt) mice showed increased CD11b(+) Gr-1(+) immature myeloid suppressor and CD25(+) Foxp3(+) regulatory T cells (Treg) and decreased IFNgamma producing CD8(+) T cells. CD4(+) and CD8(+) T cells that received direct type I IFN signals showed lesser degrees of regulatory activity and increased levels of antitumor activity, respectively. Finally, intratumoral administration of a STING agonist (cyclic diguanylate monophosphate; c-di-GMP) improved the survival of glioma-bearing mice associated with enhanced type I IFN signaling, Cxcl10 and Ccl5, and T-cell migration into the brain. In combination with subcutaneous OVA peptide vaccination, c-di-GMP increased OVA-specific cytotoxicity of BILs and prolonged their survival. These data demonstrate significant contributions of STING to antitumor immunity via enhancement of type I IFN signaling in the tumor microenvironment and suggest a potential use of STING agonists for the development of effective immunotherapy, such as the combination with antigen specific vaccinations. PMID- 25300861 TI - When is good good enough for HIV-1 prophylaxis? PMID- 25300860 TI - c-Abl modulates tumor cell sensitivity to antibody-dependent cellular cytotoxicity. AB - Monoclonal antibodies (mAb) can modulate cancer cell signal transduction and recruit antitumor immune effector mechanisms-including antibody-dependent cellular cytotoxicity (ADCC). Although several clinically effective antibodies can promote ADCC, therapeutic resistance is common. We hypothesized that oncogenic signaling networks within tumor cells affect their sensitivity to ADCC. We developed a screening platform and targeted 60 genes derived from an EGFR gene network using RNAi in an in vitro ADCC model system. Knockdown of GRB7, PRKCE, and ABL1 enhanced ADCC by primary and secondary screens. ABL1 knockdown also reduced cell proliferation, independent of its ADCC enhancement effects. c-Abl overexpression decreased ADCC sensitivity and rescued the effects of ABL1 knockdown. Imatinib inhibition of c-Abl kinase activity also enhanced ADCC phenocopying ABL1 knockdown-against several EGFR-expressing head-and-neck squamous cell carcinoma cell lines by ex vivo primary natural killer cells. Our findings suggest that combining c-Abl inhibition with ADCC-promoting antibodies, such as cetuximab, could translate into increased therapeutic efficacy of mAbs. PMID- 25300862 TI - Atypical manifestations of visceral leishmaniasis in patients with HIV in north Ethiopia: a gap in guidelines for the management of opportunistic infections in resource poor settings. AB - In regions where it is endemic, visceral leishmaniasis is an important opportunistic infectious disease in people living with HIV. Typically, clinical presentation of visceral leishmaniasis includes chronic fever, hepatosplenomegaly, and weight loss. In Leishmania infantum endemic regions in Europe, atypical visceral leishmaniasis presentations have been well documented, with almost every possible organ involved. However, such reports are rare in Leishmania donovani endemic regions such as east Africa. In this Personal View, we describe the various atypical disease presentations in patients screened as part of an HIV and visceral leishmaniasis clinical trial in north Ethiopia, where up to 40% of patients with visceral leishmaniasis are co-infected with HIV. Atypical presentations such as these are not covered in clinical guidelines used in these settings. Apart from the lack of diagnostic facilities, this gap contributes to the underdiagnosis of atypical visceral leishmaniasis, with associated morbidity and mortality. Involvement of clinicians experienced with the management of HIV and visceral leishmaniasis co-infection in the development of HIV clinical guidelines in affected regions is warranted. PMID- 25300864 TI - Effect of acupuncture-like stimulation on cortical cerebral blood flow in aged rats. AB - This study aimed to examine the effect of acupuncture-like stimulation on cortical cerebral blood flow (CBF) in aged rats and the contribution of the intracranial cholinergic vasodilatory system on its response. In urethane anesthetized rats of 30-37 months of age, manual acupuncture-like stimulation of a forepaw produced an increase in the CBF, independent of systemic arterial pressure. The increase in the CBF induced by forepaw stimulation was abolished by intravenous administration of cholinergic receptor antagonists. Manual acupuncture-like stimulation of a forepaw increased extracellular acetylcholine release in the cerebral cortex. These results suggest that natural somatic afferent stimulation, such as acupuncture-like stimulation, activates the intracranial - most likely, basal forebrain - cholinergic vasodilatory system in the cerebral cortex, even in extremely aged rats. PMID- 25300865 TI - The role of autophagic degradation in the heart. AB - Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. Macroautophagy is the most prevalent form and thus referred to as autophagy. Autophagy is initially considered to be a non-selective process as an adaptive response to nutrient starvation. However, damaged mitochondria are selectively removed by autophagy, called mitophagy. Autophagy plays essential roles in starvation, cardiac remodeling, reverse remodeling, aging and inflammation to maintain cellular homeostasis in the heart. This review discusses some recent advances in understanding the basic molecular mechanisms underlying autophagosome and autolysosome formation and mitophagy and the roles of autophagy in cardiomyopathy. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". PMID- 25300863 TI - Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. AB - BACKGROUND: Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. METHODS: We did a randomised, double-blind, placebo-controlled three group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245. FINDINGS: 4410 (99.6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0.71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0.48 cases per 100 person years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0.67, 95% CI 0.39-1.17; p=0.16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0.15, 95% CI 0.06-0.37; p<0.0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0.07, 0.02-0.23; p<0.0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. INTERPRETATION: These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. FUNDING: Bill & Melinda Gates Foundation and US National Institutes of Health. PMID- 25300866 TI - Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation. AB - Refractory acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation. This study evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. Forty-seven patients with refractory aGVHD were enrolled: 28 patients receiving MSC and 19 patients without MSC treatment. MSCs were given at a median dose of 1 * 10(6) cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range, 2 to 8) per patient, overall response rate was 75% in the MSC group compared with 42.1% in the non-MSC group (P = .023). The incidence of cytomegalovirus, Epstein-Barr virus infections, and tumor relapse was not different between the 2 groups during aGVHD treatment and follow-up. The incidence and severity of chronic GVHD in the MSC group were lower than those in the non-MSC group (P = .045 and P = .005). The ratio of CD3(+)CD4(+)/CD3(+)CD8(+) T cells, the frequencies of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), and the levels of signal joint T cell-receptor excision DNA circles (sjTRECs) after MSCs treatment were higher than those pretreatment. MSC-treated patients exhibited higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks after treatment. MSCs derived from bone marrow of a third-party donor are effective to refractory aGVHD. It might reduce the incidence and severity of chronic GVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse. PMID- 25300868 TI - Abnormal echocardiography 7 days after stem cell transplantation may be an early indicator of thrombotic microangiopathy. AB - Cardiac complications after hematopoietic stem cell transplantation (HSCT) can lead to significant morbidity and mortality. Cardiac evaluation during the first 100 days after HSCT is usually performed only if clinically indicated, and no studies have examined whether routine screening is beneficial in this patient population at high risk for tissue injury. We conducted a single-center prospective clinical study to screen for cardiac complications in pediatric and young adult patients. One hundred consecutive HSCT patients underwent scheduled echocardiographic screening on day +7 after transplantation, independent of their clinical condition. At least 1 abnormality was identified in 30% of cases. Seventeen children had a pericardial effusion, 13 elevated right ventricular pressure, and 3 reduced left ventricular function. Survival was reduced in children with any echocardiographic abnormality at day 7 (67% versus 80% in those with and without, respectively, abnormality, P = .073). Moreover, raised right ventricular pressure at day +7 was significantly associated with transplant associated thrombotic microangiopathy (TA-TMA; P = .004) and may indicate early vascular injury in the lungs. These data suggest that echocardiography 7 days after HSCT can detect early cardiac complications of HSCT and may identify early vascular injury associated with TA-TMA. PMID- 25300869 TI - Veno-occlusive disease of the liver in the absence of elevation in bilirubin in pediatric patients after hematopoietic stem cell transplantation. AB - Veno-occlusive disease (VOD) of the liver is a well-described and significant complication of hematopoietic stem cell transplantation (HSCT), with limited successful therapeutic options in severe cases. Prompt diagnosis and initiation of treatment is crucial to restrict the extent of disease. However, a subset of patients may not meet all current diagnostic criteria at presentation, and waiting for these to be met may delay therapy. We retrospectively reviewed 794 HSCT patients treated at our institution between 2003 and 2013, identifying 17 (2.1%) who developed VOD. Of these, 5 (29%) were noted to have an absence of elevated bilirubin at the time of VOD diagnosis and reversal of portal venous flow on ultrasound. Median total and conjugated bilirubin at VOD diagnosis were 1.0 and 0.2 mg/dL, respectively. All 5 patients were subsequently diagnosed with multiorgan failure associated with VOD, including 1 with encephalopathy. Four were treated with intravenous high-dose methylprednisolone (500 mg/m(2) per dose every 12 hours for 6 doses). One patient received defibrotide therapy in addition to steroids and another supportive care alone. VOD resolved in 4 of 5 patients, with median time to resolution of VOD, defined as recovery of all organ function and normalization of bilirubin and portal venous flow, of 8 days. Two patients died later from progressive primary disease and chronic graft-versus-host disease, respectively. We conclude that a high index of suspicion for VOD should be maintained in patients despite lack of bilirubin elevation in the presence of other diagnostic criteria such as hepatomegaly, abdominal pain, ascites, or weight gain. Early ultrasound evaluation in these patients may lead to more timely diagnosis and therapeutic interventions. PMID- 25300867 TI - An exploratory analysis of mitochondrial haplotypes and allogeneic hematopoietic cell transplantation outcomes. AB - Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic hematopoietic cell transplantation (HCT) outcomes. Recipient (n = 437) and donor (n = 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and K2). HCT outcomes for mthap matched siblings (n = 198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR = 3.0; 95% confidence interval [CI], 1.2 to 7.9; and RR = 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR = 2.1; 95% CI, 1.1 to 2.4) with no events for those with K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7-fold (1.2 to 6.2) increased risk of death in 5 years, whereas few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes. PMID- 25300871 TI - A well-tolerated regimen of 800 cGy TBI-fludarabine-busulfan-ATG for reliable engraftment after unmanipulated haploidentical peripheral blood stem cell transplantation in adult patients with acute myeloid leukemia. AB - Eighty adult patients with acute myeloid leukemia (AML) received peripheral blood T cell-replete HLA haploidentical hematopoietic stem cell transplantation (haplo HSCT). Disease status at transplantation was either first or second complete remission (CR, n = 69) or relapse/refractory (n = 11). Identical transplant related procedures with conditioning regimen consisting of fractionated 800 cGy total body irradiation (TBI), fludarabine (30 mg/m(2)/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), and antithymocyte globulin (1.25 mg/kg/day on days -4 to -1) and graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate were used in all patients. Recovery of neutrophil (median, 11 days) and platelet (median, 10 days) counts was achieved in all patients with full donor chimerism (>= 99%), and no delayed engraftment failure was observed. The cumulative incidence of grades III to IV acute GVHD and moderate to severe chronic GVHD was 11.2% and 26.3%, respectively. A donor CD8(+) and CD4(+) T cell dose above the median value was significantly associated with the incidences of grades II to IV acute GHVD and moderate to severe chronic GVHD, respectively. After a median follow-up of 28 months for survivors, the 2-year cumulative incidences of relapse (n = 20) and nonrelapse mortality (n = 10) were 26.6% and 12.2%, respectively. Although all but 1 patient in relapse/refractory status died, the 2-year overall and progression-free survival of patients in first CR was 82.5% and 75.1%, respectively. We suggest the strategy of fractionated 800 cGy TBI-based conditioning with unmanipulated peripheral blood stem cell grafts seems feasible with favorable outcomes for adult patients with AML undergoing haplo-HSCT in CR. PMID- 25300870 TI - Patients with Philadelphia-positive leukemia with BCR-ABL kinase mutations before allogeneic transplantation predominantly relapse with the same mutation. AB - Despite the successes of tyrosine kinase inhibitors (TKIs) in improving outcomes in patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), allogeneic hematopoietic stem cell transplantation (HSCT) continues to be an important and potentially curative option for selected patients with either disease. After HSCT, TKIs are increasingly being used to treat or prevent disease relapse, and practice patterns suggest that these TKIs are often chosen empirically without regard to pre-HSCT mutation status. We investigated whether ABL kinase domain mutations persist after transplantation and, thus, whether pre-HSCT mutation status should inform the selection of post-HSCT TKIs in these patients. We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph + ALL at our institution between 2000 and 2010, and we identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings. In total, 95 CML and 20 Ph + ALL patients with positive PCR transcripts were identified, of which 10 (10.5%) and 4 (20.0%), respectively, were found to have pre-HSCT ABL kinase mutations known to confer TKI resistance. In 9 (64.2%) of these 14 patients, the same kinase mutation was also detectable at an average time of 191 days after HSCT. Seven (50.0%) of the 14 harboring mutations had relapsed/refractory disease by last follow-up, of which, in retrospect, 6 had received a predictably ineffective TKI within the first 100 days after transplantation based on our mutation analysis. These data support the idea that pre-existing mutations in the ABL kinase domain, frequently associated with resistance to TKIs and prevalent in a transplantation population, are persistently detectable in the majority of patients after transplantation. We propose that such resistance patterns should be considered when selecting TKIs in the post-HSCT setting, including clinical trials of post-HSCT TKI prophylaxis. PMID- 25300872 TI - Effects of the estrous cycle and ovarian hormones on central expression of interleukin-1 evoked by stress in female rats. AB - Exposure to stressors such as foot shock (FS) leads to increased expression of multiple inflammatory factors, including the proinflammatory cytokine interleukin 1 (IL-1) in the brain. Studies have indicated that there are sex differences in stress reactivity, suggesting that the fluctuations in gonadal steroid levels across the estrous cycle may play a regulatory role in the stress-induced cytokine expression. The present studies were designed to investigate the role of 17-beta-estradiol (E2) and progesterone (Pg) in regulating the cytokine response within the paraventricular nucleus (PVN) of the hypothalamus through analysis of gene expression with real-time RT-PCR. Regularly cycling female rats showed a stress-induced increase in PVN IL-1 levels during the diestrous, proestrous, and estrous stages. During the metestrous stage, no change in IL-1 levels was seen following FS; however, estrogen receptor (ER)-beta levels did increase. Ovariectomy resulted in an increase in PVN IL-1 levels, which was attenuated by treatment with estradiol benzoate (10 or 50 ug), indicating an E2-mediated anti inflammatory effect. Ovariectomized rats treated with Pg (500 or 1,250 ug) showed no alteration in IL-1 levels, but Pg did up-regulate ER-beta gene expression. The results from the current study implicate a potential mechanism through which high availability of endogenous Pg during the metestrous stage increases ER-beta sensitivity, which in turn attenuates the PVN IL-1 response to stress. Thus, the interaction between gonadal steroid hormones and their central receptors may exert a powerful inhibitory effect on neuroimmune consequences of stress throughout the estrous cycle. PMID- 25300873 TI - Assays, surrogates, and alternative technologies for a TB lead identification program targeting DNA gyrase ATPase. AB - Mycobacterium tuberculosis (Mtb) DNA gyrase ATPase was the target of a tuberculosis drug discovery program. The low specific activity of the Mtb ATPase prompted the use of Mycobacterium smegmatis (Msm) enzyme as a surrogate for lead generation, since it had 20-fold higher activity. Addition of GyrA or DNA did not significantly increase the activity of the Msm GyrB ATPase, and an assay was developed using GyrB alone. Inhibition of the Msm ATPase correlated well with inhibition of Mtb DNA gyrase supercoiling across three chemical scaffolds, justifying its use. As the IC50 of compounds approached the enzyme concentration, surrogate assays were used to estimate potencies (e.g., the shift in thermal melt of Mtb GyrB, which correlated well with IC(50)s >10 nM). Analysis using the Morrison equation enabled determination of K(i)(app)s in the sub-nanomolar range. Surface plasmon resonance was used to confirm these IC(50)s and measure the K ds of binding, but a fragment of Mtb GyrB had to be used. Across three scaffolds, the dissociation half life, t1/2, of the inhibitor-target complex was <= 8 min. This toolkit of assays was developed to track the potency of enzyme inhibition and guide the chemistry for progression of compounds in a lead identification program. PMID- 25300876 TI - A flexible zwitterion ligand based lanthanide metal-organic framework for luminescence sensing of metal ions and small molecules. AB - A new lanthanide metal-organic framework was constructed using a tripodal flexible zwitterion ligand (H3LBr3) which takes a chair-shaped configuration. The luminescence of the compound displays highly selective sensing of the Fe(3+) ion and nitrobenzene. PMID- 25300875 TI - Swedish ambulance managers' descriptions of crisis support for ambulance staff after potentially traumatic events. AB - INTRODUCTION: Ambulance staff face complex and sometimes stressful or potentially traumatic situations, not only in disasters but also in their routine daily work. The aim of this study was to survey ambulance managers' descriptions of crisis support interventions for ambulance staff after potential traumatic events (PTEs). METHODS: Semistructured interviews with a qualitative descriptive design were conducted with six ambulance managers in a health care region in central Sweden. The data was analyzed using content analysis. RESULT: Five categories were found in the result: (1) description of a PTE; (2) description and performance of crisis support interventions; (3) impact of working in potentially traumatic situations; (4) the ambulance managers' role in crisis support interventions; and (5) the ambulance managers' suggestions for improvement. Ambulance managers described crisis support interventions after a PTE as a single, mandatory group meeting with a structure reminiscent of debriefing. The ambulance managers also expressed doubts about the present structures for crisis support and mentioned an alternative approach which is more in line with present evidence-based recommendations. CONCLUSION: The results indicated a need for increased understanding of the importance of the managers' attitudes for ambulance staff; a need for further implementation of evidence-based recommendations for crisis support interventions was also highlighted. PMID- 25300874 TI - Sleep to lower elevated blood pressure: study protocol for a randomized controlled trial. AB - BACKGROUND: Sleep is an essential component of good physical and mental health. Previous studies have reported that poor quality sleep is associated with an increased risk of hypertension and cardiovascular disease. Hypertension is the most common and important risk factor for cardiovascular disease, and even modest reductions in blood pressure can result in significant reductions in the risk of stroke and myocardial infarction. In this trial, we will determine the efficacy of an online sleep intervention in improving blood pressure, in participants with hypertension and poor sleep quality. METHODS: TRIAL DESIGN: Randomized controlled, two-group, parallel, blinded, single-center, Phase II trial of 134 participants. Population and recruitment: Primary prevention population of participants with hypertension (systolic blood pressure, 130 to 160 mm Hg; diastolic blood pressure, <110 mm Hg) and poor sleep quality in a community setting. INTERVENTION: Multicomponent online sleep intervention consisting of sleep information, sleep hygiene education, and cognitive behavioral therapy. Comparator: Standardized cardiovascular risk factor and lifestyle-education session (usual care). PRIMARY OUTCOME: Change in mean 24-hour ambulatory systolic blood pressure between baseline and 8-week follow-up. Hypertension has been selected as the primary outcome measure because of its robust association with both poor sleep quality and cardiovascular disease. STATISTICAL ANALYSES: Intention-to-treat analysis by using a linear mixed model. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01809821, registered March 8, 2013. PMID- 25300877 TI - Motility versus fluctuations in mixtures of self-motile and passive agents. AB - Many biological systems consist of self-motile and passive agents both of which contribute to overall functionality. However, little is known about the properties of such mixtures. Here we formulate a model for mixtures of self motile and passive agents and show that the model gives rise to three different dynamical phases: a disordered mesoturbulent phase, a polar flocking phase, and a vortical phase characterized by large-scale counter rotating vortices. We use numerical simulations to construct a phase diagram and compare the statistical properties of the different phases with observed features of self-motile bacterial suspensions. Our findings afford specific insights regarding the interaction of microorganisms and passive particles and provide novel strategic guidance for efficient technological realizations of artificial active matter. PMID- 25300879 TI - [Efficiency indicators to contribute to sustainability of health services in Spain]. AB - OBJECTIVE: Identifying a minimum set of efficiency indicators calculated from current information sources. Interventions adopted from the analysis of these indicators could contribute to health services sustainability. METHOD: We applied the discussion group technique. A total of 23 quality coordinators from around the country and the representatives of the regional quality societies in SECA (Spanish Society for Quality in Healthcare) participated. RESULTS: Ten efficiency indicators useful for integrated management areas were identified and accepted, 5 in the area of primary care and 5 for hospital management. CONCLUSION: The efficiency indicators agreed upon could contribute to the sustainability of the health system without this affecting the quality of care. PMID- 25300878 TI - Effect on survival of local ablative treatment of metastases from sarcomas: a study of the French sarcoma group. AB - AIMS: Recent data suggest that patients with pulmonary metastases from sarcomas might benefit from ablation of their metastases. Some data are available regarding osteosarcomas/angiosarcomas and lung metastases. The purpose of this study was to assess the efficacy of local ablative treatment on the survival of patients with oligometastases (one to five lesions, any metastatic site, any grade/histology) from sarcomas. MATERIALS AND METHODS: A multicentric retrospective study of the French Sarcoma Group was conducted in sarcoma patients with oligometastases who were treated between 2000 and 2012. Survival was analysed using multivariate sensitivity analyses with propensity scores to limit bias. RESULTS: Of the 281 patients evaluated, 164 patients received local treatment for oligometastases between 2000 and 2012. The groups' characteristics were similar in terms of tumour size and remission of the primary tumours. The median follow-up was 25.7 months; 129 (45.9%) patients had died at this point. The median overall survivals were 45.3 (95% confidence interval = 34-73) months for the local treatment group and 12.6 for the other group (95% confidence interval = 9.33-22.9). Survival was better among patients who received local treatment (hazard ratio = 0.47; 95% confidence interval = 0.29-0.78; P < 0.001). Subgroup analyses revealed similar findings in the patients with single oligometastases (hazard ratio = 0.48; 95% confidence interval = 0.28-0.82; P = 0.007); a significant benefit was observed for grade 3, and a trend was observed for grade 2. CONCLUSION: Local ablative treatment seemed to improve the overall survival of the patients who presented with oligometastatic sarcomas, including soft tissue and bone sarcomas. The survival benefit remained after repeated local treatments for several oligometastatic events. Surgery yielded the most relevant results, but alternative approaches (i.e. radiofrequency ablation and radiotherapy) seemed to be promising. The relevance of these results is strengthened by our analysis, which avoided biases by restricting the population to patients with oligometastatic disease and used propensity scores. PMID- 25300880 TI - [Do patients understand what we explain to them in Informed Consent forms?]. PMID- 25300882 TI - Government underestimated dengue fever in India by factor of 282, finds study. PMID- 25300881 TI - [Impact of a software application to improve medication reconciliation at hospital discharge]. AB - BACKGROUND AND OBJECTIVE: To assess the impact of a software application to improve the quality of information concerning current patient medications and changes on the discharge report after hospitalization. To analyze the incidence of errors and to classify them. MATERIAL AND METHOD DESIGN: Quasi-experimental pre / post study with non-equivalent control group study. STUDY POPULATION: Medical patients at hospital discharge. INTERVENTION: implementation of a software application. VARIABLES: Percentage of reconciled patient medication on discharge, and percentage of patients with more than one unjustified discrepancy. RESULTS: A total of 349 patients were assessed; 199 (pre-intervention phase) and 150 (post-intervention phase). Before the implementation of the application in 157 patients (78.8%) medication reconciliation had been completed; finding reconciliation errors in 99 (63.0%). The most frequent type of error, 339 (78.5%), was a missing dose or administration frequency information. After implementation, all the patient prescriptions were reconciled when the software was used. The percentage of patients with unjustified discrepancies decreased from 63.0% to 11.8% with the use of the application (p<.001). The main type of discrepancy found on using the application was confusing prescription, due to the fact that the professionals were not used to using the new tool. CONCLUSIONS: The use of a software application has been shown to improve the quality of the information on patient treatment on the hospital discharge report, but it is still necessary to continue development as a strategy for improving medication reconciliation. PMID- 25300883 TI - Variation in transfusion rates within a single institution: exploring the effect of differing practice patterns on the likelihood of blood product transfusion in patients undergoing cardiac surgery. AB - OBJECTIVES: Rates of perioperative transfusion vary widely among patients undergoing cardiac surgery. Few studies have examined factors beyond the clinical characteristics of the patients that may be responsible for such variation. The purpose of this study was to determine whether differing practice patterns had an impact on variation in perioperative transfusion at a single center. METHODS: Patients who underwent cardiac surgery at a single center between 2004 and 2011 were considered. Comparisons were made between patients who had received a perioperative transfusion and those who had not from the clinical factors at baseline, intraoperative variables, and differing practice patterns, as defined by the surgeon, anesthesiologist, perfusionist, and the year in which the procedure was performed. The risk-adjusted effect of these factors on perioperative transfusion rates was determined using multivariable regression modeling techniques. RESULTS: The study population comprised 4823 patients, of whom 1929 (40.0%) received a perioperative transfusion. Significant variation in perioperative transfusion rates was noted between surgeons (from 32.4% to 51.5%, P < .0001), anesthesiologists (from 34.4% to 51.9%, P < .0001) and across year (from 28.2% in 2004 to 48.8% in 2008, P < .0001). After adjustment for baseline and intraoperative variables, surgeon, anesthesiologist, and year of procedure were each found to be independent predictors of perioperative transfusion. CONCLUSIONS: Differing practice patterns contribute to significant variation in rates of perioperative transfusion within a single center. Strategies aimed at reducing overall transfusion rates must take into account such variability in practice patterns and account for nonclinical factors as well as known clinical predictors of blood transfusions. PMID- 25300884 TI - Aortic valve repair: easy and reproducible? PMID- 25300885 TI - Targeting individuals with problematic alcohol use via Web-based cognitive behavioral self-help modules, personalized screening feedback or assessment only: a randomized controlled trial. AB - BACKGROUND/AIMS: Most problematic alcohol users never seek professional help to reduce their use, and Web-based interventions might fulfill users' unmet needs for professional support. METHODS: This randomized controlled trial compared two open Web-based interventions, one extended self-help program and one brief screening and feedback intervention, with an assessment-only control group. Participants were 633 Internet help seekers with at least hazardous alcohol use (Alcohol Use Disorders Identification Test, AUDIT >=6 for women and >=8 for men). RESULTS: All groups reduced their alcohol use at 3-month follow-up (p < 0.001), remaining stable at the 6- and 12-month follow-ups (n.s.) according to AUDIT-C and AUDIT scores (intention-to-treat, ITT, analysis). Per protocol (PP) analysis, including only participants who accessed the interventions and also reported accessing additional outside interventions during the trial, showed that about 75% of extended self-help participants moved from probable dependence, harmful or hazardous use to lower alcohol use levels at 3- and 6- and 12-month follow-ups, compared to about 40-60% of brief intervention users and controls who accessed extra help (p < 0.05). CONCLUSION: ITT analysis suggested parity over time for all interventions, including assessment only, in reducing problematic alcohol use. In contrast, PP analysis suggested that cognitive-behavioral extended self help in combination with other interventions was more effective in changing alcohol use than brief intervention or assessment only. PMID- 25300886 TI - Challenges and limitations of patient-specific vascular phantom fabrication using 3D Polyjet printing. AB - Additive manufacturing (3D printing) technology offers a great opportunity towards development of patient-specific vascular anatomic models, for medical device testing and physiological condition evaluation. However, the development process is not yet well established and there are various limitations depending on the printing materials, the technology and the printer resolution. Patient specific neuro-vascular anatomy was acquired from computed tomography angiography and rotational digital subtraction angiography (DSA). The volumes were imported into a Vitrea 3D workstation (Vital Images Inc.) and the vascular lumen of various vessels and pathologies were segmented using a "marching cubes" algorithm. The results were exported as Stereo Lithographic (STL) files and were further processed by smoothing, trimming, and wall extrusion (to add a custom wall to the model). The models were printed using a Polyjet printer, Eden 260V (Objet-Stratasys). To verify the phantom geometry accuracy, the phantom was reimaged using rotational DSA, and the new data was compared with the initial patient data. The most challenging part of the phantom manufacturing was removal of support material. This aspect could be a serious hurdle in building very tortuous phantoms or small vessels. The accuracy of the printed models was very good: distance analysis showed average differences of 120 MUm between the patient and the phantom reconstructed volume dimensions. Most errors were due to residual support material left in the lumen of the phantom. Despite the post-printing challenges experienced during the support cleaning, this technology could be a tremendous benefit to medical research such as in device development and testing. PMID- 25300888 TI - Lingual necrosis caused by mucormycosis in a patient with aplastic anaemia: case report. AB - Mucormycosis is a rare but aggressive fungal infection that predominantly affects immunocompromised patients. We report a case that highlights the importance of knowledge to enable prompt diagnosis and management of an otherwise fatal phenomenon. PMID- 25300887 TI - Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma. AB - BACKGROUND: Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE. METHODS: The effects of HCI2509 on viability, proliferation, anchorage independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509. RESULTS: Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p=0.034). CONCLUSIONS: Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma. PMID- 25300889 TI - Juvenile xanthogranuloma: unusual intraoral finding. AB - Juvenile xanthogranuloma is a rare non-Langerhans cell histiocytosis that usually presents as a self-limiting dermatological condition in young children. Rarely, extracutaneous sites may also be involved. We report a case in a 3-year-old girl that presented intraorally as a solitary, well-defined, soft, purple palatal swelling. Patients with these rare intraoral lesions may present to dentists and subsequently to oral and maxillofacial surgeons. Diagnosis requires histopathological analysis and immunohistochemical staining. Further investigation from other specialties is required to rule out involvement of other organ systems. PMID- 25300890 TI - Point-based superimposition of a digital dental model on to a three-dimensional computed tomographic skull: an accuracy study in vitro. AB - We investigated the accuracy of point-based superimposition of a digital dental model on to a 3-dimensional computed tomographic (CT) skull with intact dentition. The physical model was scanned by CT to give a virtual skull model, and a plaster dental model was taken and laser-scanned to give a digital dental model. Three different background investigators were recruited and calibrated to make the point-based superimposition, and afterwards were asked to repeat 5 superimpositions each. Five bone-to-tooth measurements for the maxilla and 6 for the mandible were selected to indicate the relation of teeth to skull. Repeated measures were made on the physical model to act as a control group, and on the virtual model to act as the test group. The absolute agreement intra-class correlation coefficient (ICC) was used to assess the intra/inter-investigator reliability; Bland-Altman analysis was used to calculate the general differences, limits of agreement, and precision ranges of the estimated limits. Inter/intra investigator reliability was excellent with ICC varying from 0.986 to 1; Bland Altman analysis indicated that general difference was 0.01 (0.25)mm, the upper limit of agreement was 0.50mm and the lower limit -0.47 mm, and the precision range for the upper limit was 0.43 mm to 0.57 mm and for the lower limit -0.54 mm to -0.40 mm. Clinically acceptable accuracy can be achieved using a direct point based method to superimpose a digital dental model on to a 3-dimensional CT skull. PMID- 25300891 TI - Is a polymorphism in 10q25 associated with non-syndromic cleft lip with or without cleft palate? A meta-analysis based on limited evidence. AB - Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common defects in the human facial structure. A polymorphism, rs7078160 in 10q25, has been reported to be involved in susceptibility to the condition but results remain conflicting. To address this we did a meta-analysis of 7 eligible studies. Two authors independently collected information from the papers, and fixed effects or random effects models were used to calculate the combined estimates of risk. The pooled results showed that rs7078160 on 10q25, the minor allele A, had a higher risk of NSCLP than the major allele G (OR: 1.32, 95% CI: 1.18 to 1.47). Overall, the results showed that the 10q25 rs7078160 polymorphism was associated with a risk of NSCL/P. PMID- 25300892 TI - Aesthetic essentiality regained using implant- a case report. AB - The goal of implant therapy is to provide patients with a predictable, aesthetically and functionally satisfying treatment outcome with a low risk of aesthetic complications. Dental implants have been utilized by mankind for thousands of years, but only recently they have achieved widespread acceptance from the profession. Anterior sites are more likely related to aesthetic expectations and often represent a considerable challenge for involved clinicians and dental technicians, since various local risk factors have the potential to compromise the predictability of the result. In recent years, substantial efforts have been made to increase the appeal of implant therapy by shortening the overall treatment time and minimizing the number of surgical intervention. According to traditional protocol, a 12 month healing after extraction was suggested, but over the past few years alternative approaches have been proposed, such as immediate implant placement at the time of extraction or early implant placement following weeks of soft tissue healing. Common to all of these approaches is the requirement of adequate remaining bone volume. If there is no adequate bone volume, techniques like guided bone regeneration (GBR) are used for ridge augmentation before implant placement. The present case has utilized an endosteal root form implant and the advantage of guided bone regeneration technique in regaining aesthetic demands of the patient. PMID- 25300893 TI - Temperature-dependent elastic anisotropy and mesoscale deformation in a nanostructured ferritic alloy. AB - Nanostructured ferritic alloys are a new class of ultrafine-grained oxide dispersion-strengthened steels that have promising properties for service in extreme environments in future nuclear reactors. This is due to the remarkable stability of their complex microstructures containing numerous Y-Ti-O nanoclusters within grains and along grain boundaries. Although nanoclusters account primarily for the exceptional resistance to irradiation damage and high temperature creep, little is known about the mechanical roles of the polycrystalline grains that constitute the ferritic matrix. Here we report an in situ mesoscale characterization of anisotropic responses of ultrafine ferrite grains to stresses using state-of-the-art neutron diffraction. We show the experimental determination of single-crystal elastic constants for a 14YWT alloy, and reveal a strong temperature-dependent elastic anisotropy that leads to elastic softening and instability of the ferrite. We also demonstrate, from anisotropy-induced intergranular strains, that a deformation crossover exists from low-temperature lattice hardening to high-temperature lattice softening in response to extensive plastic deformation. PMID- 25300894 TI - Past, present, future: a review on visual prostheses. AB - This review presents the historic background, the present status and the future prospects of several visual implant types such as retinal implants, as well as optic nerve and thalamus stimulation, and stimulation of the visual cortex. Already achieved milestones, such as improved object recognition and letter reading, give hope that a breakthrough can be achieved in the coming years. Furthermore, clinical results from recent studies are presented in order to describe the obstacles that have to be overcome in the future. Currently, inner eye implants placed within the retina are the preferred option for electrical stimulation of the optic pathway. However, the limited number of stimulating electrodes and the non-focal activation of target neurons are still hindering the generation of percepts of higher quality. In the future, optogenetic approaches may be used to activate retinal neurons with a high temporal and spatial accuracy. The main challenge for all types of visual implants will be to utilize as many parts of the remaining optic pathway as possible and to focally activate functionally different pathways. PMID- 25300895 TI - Clinical and laboratory markers of autosomal dominant polycystic kidney disease (ADPKD) progression: an overview. AB - Autosomal dominant polycystic kidney (ADPKD) is the most common inherited renal cystic disease and it occurs in all races, the reported prevalence is between 1:400 and 1:1000. It is characterized by development of cysts in both kidneys and progressive renal function loss. Among most Autosomal Dominant Polycystic Kidney patients, renal function remains intact until the fourth decade of life. It is very important to identify early markers of disease progression to recognize patients with a worse prognosis. The aim of this study is to review the clinical and laboratory markers of ADPKD progression. The early clinical parameters evaluated seem to be directly correlated with the volume of the cysts that determine the kidney volume. From a clinical point of view, total kidney volume (TKV) appears to be the best marker of early ADPKD progression. This review evaluated several ADPKD progression markers comparing the early consolidated clinical and the new promising laboratory indicators. From a laboratory point of view, copeptin has a potential role between the serum biomarkers of ADPKD progression. However, further studies are necessary to validate the potential predictive value of its serum level and to adopt it for routine use. The combination of biomarkers could probably predict ADPKD progression with more accuracy than the use of a single biomarker. PMID- 25300896 TI - Influence of atrial fibrillation in trans-catheter aortic valve replacement. AB - In high-risk patients with severe aortic stenosis transcatheter aortic valve replacement (TAVR) procedures have been found to be beneficial. Up to now TAVR has been preferably performed on elderly patients, who cannot undergo conventional aortic valve replacement (AVR). Usually, due to their advanced age, these patients suffer from atrial fibrillation (AF) and are also more predisposed to present left ventricular dysfunction. Both conditions influence short and long term prognosis in conventional AVR surgery. We do not really know how this translates in new procedures such as TAVR. The purpose of the present paper was to review how AF could affect TAVR procedures. PMID- 25300897 TI - Role of nanotechnology in development of artificial organs. AB - Improvements in our understanding of the interactions between implants and cells have directed attention towards nanoscale technologies. To date, nanotechnology has played a helping hand in the development of synthetic artificial organs and regenerative medicine. This includes the production of smart nanocomposite materials; fluorescent nanoparticles like Quantum Dots (QD) and magnetic nano particles (MNP) for stem cell tracking; and carbon nanotubes (CNT) and graphene for enhancement of material properties. The scope of this paper includes the role of nanoparticles in the development of nanomaterials; the chemical surface modifications possible to improve implant function and an overview of the performance of nano-engineered organs thus far. This includes implants developed for aesthetic purposes like nasal and auricular scaffolds, plastic and reconstructive surgical constructs (i.e. dermal grafts), hollow organs for cardiothoracic applications; and last but not least, orthopedic implants. The five-year outlook for nano-enhanced artificial organs is also discussed, highlighting the key research and development areas, available funds and the hurdles we face in accomplishing progression from prototypes on the laboratory bench to off-the-shelf products for the consumer market. Ultimately, this review aims to delineate the advantages of incorporating nanotechnology, as an individual entity or as a part of a construct for the development of tissue engineering scaffolds and/or artificial organs, and unravel the mechanisms of tissue cell-biomaterial interactions at the nanoscale, allowing for better progress in the development and optimization of unique nanoscale surface features for a wide range of applications. PMID- 25300898 TI - Biomedical photoacoustics in China. AB - During the last decade, along with its explosive growth globally, biomedical photoacoustics has become a rapidly growing research field in China as well. In particular, photoacoustic tomography (PAT), capable of imaging intact biological tissue in vivo at great depths, has generated intense interest among Chinese researchers. This review briefly summarizes the current status and recent progress of the research in PAT in China. The focus is on the technology development and biomedical applications of three representative embodiments of PAT: photoacoustic microscopy, photoacoustic computed tomography, and photoacoustic endoscopy. In addition, recent development and studies in other related areas are also reviewed shortly. PMID- 25300899 TI - Exogenous Cushing syndrome: a lesson of diaper rash cream. AB - A prolonged use of topical corticosteroids can result in Cushing syndrome, though this is less common than with oral or parenteral steroids. Most pediatric cases were due to application of topical steroids for diaper dermatitis. Adverse cardiovascular effects can occur in Cushing syndrome with significant long-term morbidity and mortality, though so far there have been no reports of cardiovascular complications due to excessive usage of topical steroids. We report a 2.5-month-old boy who rapidly developed severe Cushing syndrome induced by the misuse of topical clobetasol, a very potent steroid, without a doctor's prescription as a diaper rash cream, and developed moderate left ventricular hypertrophy and pericardial effusion. PMID- 25300900 TI - The habit tic: onychotillomania. PMID- 25300901 TI - Intra-arterial signal on arterial spin labeling perfusion MRI to identify the presence of acute middle cerebral artery occlusion. AB - BACKGROUND: The susceptibility vessel sign on gradient echo-type-T2*-weighted imaging is a well-known marker of arterial occlusion. Stagnant flow in front of the middle cerebral artery (MCA) occlusion sites may contribute to the intra arterial, high-intensity signal on arterial spin labeling magnetic resonance imaging (MRI), making it another potential marker of MCA occlusion. We compared the intra-arterial, high-intensity signal and susceptibility vessel sign in patients with symptomatic MCA occlusion and patients without major vessel occlusion. METHODS: We identified transient ischemic attack or ischemic stroke patients with (1) 3-T MRI performed within 24 h after clinical onset including arterial spin labeling, T2*-weighted imaging, and magnetic resonance angiography (MRA) and (2) either having MCA occlusion (n = 34 patients) or without major vessel occlusion (n = 24 patients). The intra-arterial, high-intensity signal was defined as an enlarged circular or linear bright hyperintensity within the artery. The susceptibility vessel sign was defined as an enlarged spot of hypointensity within the MCA, in which the diameter of the hypointense signal within the vessel exceeded the contralateral vessel diameter. The presence or absence of the intra-arterial, high-intensity signal and susceptibility vessel sign were assessed, along with their inter-rater agreement and consistency with the presence of MCA occlusion on MRA. RESULTS: The intra-arterial, high-intensity signal was detectable in 30 patients (52%), and susceptibility vessel sign was observed in 17 patients (29%). The sensitivity of the intra-arterial high intensity signal was significantly higher than that of the susceptibility vessel sign (88% vs. 50%; p < 0.05). The accuracy of the intra-arterial high-intensity signal was also higher than that of the susceptibility vessel sign (93% vs. 71%; p < 0.05). The intra-arterial high-intensity signal was situated in the proximal regions of the susceptibility vessel sign on T2*WI within the MCA. Neither the intra-arterial high-intensity signal nor the susceptibility vessel sign was observed in patients without major vessel occlusion. Inter-rater agreement was good for intra-arterial high-intensity signal detection (kappa = 0.73) and moderate for susceptibility vessel sign detection (kappa = 0.47). The presence or absence of the intra-arterial high-intensity signal was highly consistent with that of MCA occlusion on MRA (kappa = 0.74). CONCLUSIONS: The intra-arterial high intensity signal on arterial spin labeling appears to be useful to identify the presence of acute MCA occlusion and may be associated with stagnant flow in front of occlusion sites. The intra-arterial high-intensity signal may also be used to identify the occlusion site. PMID- 25300902 TI - Dopaminergic modulation of distracter-resistance and prefrontal delay period signal. AB - Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex. PMID- 25300904 TI - Sociodemographic Characteristics of Trans Persons in Belgium: A Secondary Data Analysis of Medical, State, and Social Data. AB - By performing secondary data analyses of existing medical, social, and state data, this study examined the sociodemographic profile of trans persons in Belgium and gains knowledge on those who are functionally invisible in traditional epidemiological studies or clinical samples. Based on medical interventions, post-operative transsexual persons were selected from a social survey data set, to compare their sociodemographic profile with available data on legal sex changes from the Belgian National Register and with published data on clinical samples of post-operative transsexual persons. Furthermore, based on self-chosen gender identity categories in the social survey data, transsexual participants were compared with the transgender participants (those people feeling neither female nor male, or both female and male, or otherwise). The sociodemographic data on the post-operative transsexual persons from the three datasets appeared to be very similar. Based on identity categories, the data on transsexual and transgender persons from the social survey showed differences in marital status and employment. Transsexual persons were significantly more often divorced than transgender persons. Both groups differed significantly in employment status. Information about transgender people (or the "in-between" group) is too often lacking from studies but can be obtained when identity instead of medical criteria are used in research. PMID- 25300905 TI - Health, equity and the post-2015 agenda: raising the voices of marginalized communities. AB - In September 2012 the United Nations (UN) initiated a process that would extend and enhance the unfinished agenda of the Millennium Development Goals (MDGs), integrating a new vision for sustainable development beyond the year 2015. The initial consultation phase has been completed, with the UN and partner organizations undertaking eleven thematic consultations, including one on health. It is in this context that the European Commission (EC) has tasked the research consortium Goals and Governance for Global Health (Go4Health) with providing recommendations for the post-2015 health-related development goals and including voices that are routinely excluded from health-related decision-making processes. This has not been an easy task. It has led us to question how to define marginalization, how to access marginalized communities, as well as how community members could provide informed consent. The context of the communities we worked with was far removed from the reality of the post-2015 debates, where the MDGs and the new goals are remote and abstract, and where the promise of immediate benefit from participation could not be assured. Given the social, historical, cultural, ethnic and geographical diversity of our chosen community partners, and the diversity of their lived experiences, could their unique situations be generalized in ways that could influence the global debate? In this special issue, we have tried to explore the uniqueness and the commonalities of the issues and barriers that marginalized communities face all over the globe, and present them in individual papers that, together, provide a nuanced and complex picture of the challenges that face the post-2015 health-related agenda setting process. PMID- 25300903 TI - Mechanisms and environmental factors that underlying the intensification of 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats. AB - RATIONALE: Illicit use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors. OBJECTIVES: Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome. METHODS: Rats were administered MDMA at doses of 0.3, 1, or 3 mg/kg and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome. RESULTS: Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine. CONCLUSIONS: Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5 hydroxytryptamine (5HT)-dependent mechanism) and therefore is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms). PMID- 25300906 TI - Cardiovascular risk associated with sodium-containing medicines. AB - INTRODUCTION: It is widely recognized that excess sodium intake increases the risk of hypertension, and this subsequently increases the risk of cardiovascular disease. Although efforts are being made to reduce sodium intake in the population in general, there are concerns that a considerable sodium load can be ingested via certain effervescent, dispersible, and soluble formulations of medicines. AREAS COVERED: Reducing dietary sodium intake in the general population has resulted in a significant reduction in cardiovascular disease outcomes. However, no previous studies have highlighted the potential risk of cardiovascular disease by taking sodium-containing medicines such as soluble forms of aspirin, paracetamol, ibuprofen, and other common drugs. We recently conducted a nested case-control study in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodium containing medicines and cardiovascular outcomes. The results showed that compared with standard formulations, patients who took sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 - 1.21). The risks for stroke and hypertension were even higher, (1.22 [1.16 - 1.29] and 7.18 [6.74 - 7.65]), respectively. EXPERT OPINION: Sodium containing formulations should be prescribed with caution only if the perceived benefits outweigh the risks. PMID- 25300907 TI - Co-overexpression of Hsp90-beta and annexin A1 with a significantly positive correlation contributes to the diagnosis of lung cancer. AB - AIM: Hsp90-beta and annexin A1 have been demonstrated to be associated with tumorigenesis. However, the effect of Hsp90-beta and annexin A1 in lung cancer remains poorly understood. In this research, the correlation of Hsp90-beta and annexin A1 in lung cancer patients were analyzed. METHODS: The expression levels of Hsp90-beta and annexin A1 were examined by immunohistochemistry and ELISA. RESULTS: Lung cancer tissues and serum exhibited higher co-expression of Hsp90 beta and annexin A1 than control groups (p < 0.05). Hsp90-beta and annexin A1 could discriminate lung cancer from the control groups (sensitivity of Hsp90-beta was 80.2% in tissues and 96% in serum; specificity of Hsp90-beta was 80% in tissues and 83.33% in serum; sensitivity of annexin A1 was 68.76% in tissues and 95.23% in serum; specificity of annexin A1 was 75% in tissues and 85.7% in serum) and multi-index combined detection had a better diagnostic value. CONCLUSION: The expression levels of Hsp90-beta and annexin A1 positively correlated and such co overexpression of Hsp90-beta and annexin A1 contributed to lung cancer diagnosis. PMID- 25300908 TI - Mouse models of primary central nervous system lymphomas: tools for basing funding and therapeutic strategies. AB - Primary central nervous system lymphomas (PCNSL) include ocular and cerebral lymphomas and are rare aggressive malignancies with poor prognoses. Compared with other lymphomas, they are a challenge for clinicians and scientists, for diagnosis and therapeutic progress and their prognosis remains unsatisfactory, because of the lack of molecular and biological knowledge. Indeed, several limitations of human sample present a major obstacle to the identification of the particular microenvironment of the sanctuary sites where these tumor cells grow. In addition, the generally poor overall condition and performance status of patients with PCNSL limit their participation in prospective trials. Therefore, animal models of PCNSL are essential for tumor microenvironment characterization and for antitumor response studying. In this review, we have compiled the B-and T cell PCNSL mouse models that are used to improve our understanding of the lymphoma microenvironment, tropism and migration and to investigate novel therapeutic strategies. PMID- 25300909 TI - The effects of transdermal insulin treatment of streptozotocin-induced diabetic rats on kidney function and renal expression of glucose transporters. AB - The tight glycemic control required to attenuate chronic complications in type 1 diabetes mellitus requires multiple daily injections of bolus insulin which cause hyperinsulinemic edema and hypertension due to Na(+) retention. Reports indicate that pectin insulin (PI)-containing dermal patches sustain controlled insulin release into the bloodstream of streptozotocin (STZ)-induced diabetic rats. This study investigated whether PI dermal patches can improve the impaired renal function in diabetes. PI patches were prepared by dissolving pectin/insulin in deionized water and solidified with CaCl(2). Short-term (five weeks) effects of thrice daily treatments with PI patches on renal function and urinary glucose outputs were assessed in diabetic animals. Blood and kidney samples were collected after five weeks for measurements of selected biochemical parameters. Blood was also collected for insulin measurement 6 h following treatments. The low plasma insulin concentrations exhibited by STZ-induced diabetic rats were elevated by the application of insulin-containing dermal patches to levels comparable with control non-diabetic rats. Untreated STZ-induced diabetic rats exhibited elevated urinary glucose, K(+) outputs and depressed urinary Na(+) outputs throughout the 5-week period. Treatment with PI dermal patches increased urinary Na(+) output and reduced urine flow, urinary glucose and K(+) excretion rates in weeks 4 and 5. PI dermal patches increased GFR of diabetic rats with concomitant reduction of plasma creatinine concentrations. Transdermal insulin treatment also decreased the renal expressions of GLUT1 and SGLT1 of STZ-induced diabetic rats. We conclude that PI dermal patches deliver physiologically relevant amounts of insulin that can improve kidney function in diabetes. PMID- 25300910 TI - Skin eruptive vascular tumors in a 45 years old man. PMID- 25300911 TI - Cardiopulmonary hydatidosis. PMID- 25300912 TI - Definitions of Internal Medicine activities outside of the im department. AB - The inpatient profile is changing towards patients with multiple diseases, the elderly and those with high comorbidity. The growing complexity of their care, the progressive medical superspecialization and the organizational problems that often hinder daily patient follow-up by the same physician have contributed to a progressive increase in the participation of medical departments, especially Internal Medicine, in the care of patients hospitalized in other medical and surgical specialties. The hospital activities that the departments of internal medicine perform outside of their own department do not have well-established definitions and criteria at the organizational level; their assessment and accountability are different in each hospital. In this document, we establish the definitions for shared care, advisory medicine, perioperative medicine and interconsultation, as well as their types in terms of priority, formality, care setting, timeliness, relationship with surgery and other circumstances. PMID- 25300913 TI - Polycystic kidney and liver disease: A diagnostic challenge. PMID- 25300914 TI - Langerhans cell Histiocytosis of the vulva. PMID- 25300915 TI - A novel anti-proliferative role of HMGA2 in induction of apoptosis through caspase 2 in primary human fibroblast cells. AB - The HMGA2 (high-mobility group AT-hook) protein has previously been shown as an oncoprotein, whereas ectopic expression of HMGA2 is found to induce growth arrest in primary cells. The precise mechanisms underlying this phenomenon remain to be unravelled. In the present study, we determined that HMGA2 was able to induce apoptosis in WI38 primary human cells. We show that WI38 cells expressing high level of HMGA2 were arrested at G2/M phase and exhibited apoptotic nuclear phenotypes. Meanwhile, the cleaved caspase 3 (cysteine aspartic acid-specific protease 3) was detected 8 days after HMGA2 overexpression. Flow cytometric analysis confirmed that the ratio of cells undergoing apoptosis increased dramatically. Concurrently, other major apoptotic markers were also detected, including the up-regulation of p53, Bax and cleaved caspase 9, down-regulation of Bcl-2; as well as release of cytochrome c from the mitochondria. We further demonstrate that the shRNA (small-hairpin RNA)-mediated Apaf1 (apoptotic protease activating factor 1) silencing partially rescued the HMGA2-induced apoptosis, which was accompanied by the decrease of cleaved caspase-3 level and a decline of cell death ratio. Our results also reveal that gammaH2A was accumulated in nuclei during the HMGA2-induced apoptosis along with the up-regulation of cleaved caspase 2, suggesting that the HMGA2-induced apoptosis was dependent on the pathway of DNA damage. Overall, the present study unravelled a novel function of HMGA2 in induction of apoptosis in human primary cell lines, and provided clues for clarification of the mechanistic action of HMGA2 in addition to its function as an oncoprotein. PMID- 25300917 TI - Long live the stem cell: the use of stem cells isolated from post mortem tissues for translational strategies. AB - The "stem cell" has become arguably one of the most important biological tools in the arsenal of translational research directed at regeneration and repair. It remains to be seen whether every tissue has its own stem cell niche, although relatively recently a large amount of research has focused on isolating and characterizing tissue-specific stem cell populations, as well as those that are able to be directed to transdifferentiate into a variety of different lineages. Traditionally, stem cells are isolated from the viable tissue of embryonic, fetal, or adult living hosts; from "fresh" donated tissues that have been surgically or otherwise removed (biopsies), or obtained directly from tissues within minutes to several hours post mortem (PM). These human progenitor/stem cell sources remain potentially highly controversial, since they are accompanied by various still-unresolved ethical, social, moral and legal challenges. Due to the limited number of "live" donors, the small amount of material obtained from biopsies and difficulties during purification processes, harvesting from cadaveric material presents itself as an alternative strategy that could provide a hitherto untapped source of stem cells. However, PM stem cells are not without their own unique set of limitations including difficulty of obtaining samples, limited supply of material, variations in delay between death and sample collection, possible lack of medication history and suboptimal retrospective assignment of diagnostic and demographic data. This article is part of a Directed Issue entitled: Regenerative Medicine: The challenge of translation. PMID- 25300916 TI - Drivers of overweight mothers' food choice behaviors depend on child gender. AB - BACKGROUND: National data suggest a higher prevalence of obesity among boys. One possible cause could be the food choices made by parents on behalf of their children. OBJECTIVES: This study sought to determine whether and how mothers' food choices for their children differ by child gender and to understand the drivers of these differences. DESIGN: Data were analyzed from a randomized controlled trial conducted using a virtual reality-based buffet restaurant. Overweight mothers filled out questionnaires and received an information module. They were then immersed in a virtual buffet restaurant to select a lunch for their 4- to 5-year-old child. RESULTS: Of the 221 overweight mothers recruited, 55% identified their daughters as the child for whom they would be choosing the food. The caloric content of boys' meals was 43 calories higher than girls' (p = .015). This difference was due to extra calories from the less healthy food category (p = .04). Multivariate analyses identified more predictors of calorie choices for daughters' than sons' meals. Predictors of calories chosen for girls included: having both biological parents overweight (beta = 0.26; p = .003), mother's weight (beta = 0.17; p = .05), mother's education (beta = -0.28; p = .001), her restriction of her child's food intake (beta = -0.20; p = .02), and her beliefs about the importance of genetics in causing obesity (beta = 0.19; p = .03). Mother's weight was the sole predictor of boys' meal calories (beta = 0.20; p = .04). CONCLUSIONS: Differences in dietary choices made for young girls and boys may contribute to lifelong gender differences in eating patterns. A better understanding of differences in feeding choices made for girls versus boys could improve the design of childhood obesity prevention interventions. PMID- 25300918 TI - Building a community. PMID- 25300919 TI - Emotional and behavioural resilience to multiple risk exposure in early life: the role of parenting. AB - Ecological and transactional theories link child outcomes to neighbourhood disadvantage, family poverty and adverse life events. Traditionally, these three types of risk factors have been examined independently of one another or combined into one cumulative risk index. The first approach results in poor prediction of child outcomes, and the second is not well rooted in ecological theory as it does not consider that distal risk factors (such as poverty) may indirectly impact children through proximal risk factors (such as adverse life events). In this study, we modelled simultaneously the longitudinal effects of these three risk factors on children's internalising and externalising problems, exploring the role of parenting in moderating these effects. Our sample followed 16,916 children (at ages 3, 5 and 7 years; N = 16,916; 49% girls) from the UK Millennium Cohort Study. Parenting was characterised by quality of parent-child relationship, parental involvement in learning and parental discipline. Neighbourhood disadvantage, family poverty and adverse events were all simultaneously related to the trajectories of both outcomes. As expected, parenting moderated risk effects. Positive parent-child relationship, rather than greater involvement or authoritative discipline, most consistently 'buffered' risk effects. These findings suggest that a good parent-child relationship may promote young children's emotional and behavioural resilience to different types of environmental risk. PMID- 25300920 TI - Selective in vivo imaging of syngeneic, spontaneous, and xenograft tumors using a novel tumor cell-specific hsp70 peptide-based probe. AB - Although in vivo targeting of tumors using fluorescently labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Because of the rapid turnover rate of membrane Hsp70, fluorescently labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast with the commercially available nonpeptide small molecule alphavbeta3-integrin antagonist IntegriSense, TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor specific signal intensity in all tested tumor models. Moreover, in contrast with IntegriSense, TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts, which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70-based targeted therapies. PMID- 25300921 TI - Advancing the understanding of behaviors associated with Bacille Calmette Guerin infection using multivariate analysis. AB - Behavioral indicators in the murine Bacille Calmette Guerin (BCG) model of inflammation have been studied individually; however, the variability of the behaviors across BCG levels and the mouse-to-mouse variation within BCG-treatment group are only partially understood. The objectives of this study were: (1) to gain a comprehensive understanding of sickness and depression-like behaviors in a BCG model of inflammation using multivariate approaches, and (2) to explore behavioral differences between BCG-treatment groups and among mice within group. Adult mice were challenged with either 0mg (saline), 5mg or 10mg of BCG (BCG treatment groups: BCG0, BCG5, or BCG10, respectively) at Day 0 of the experiment. Sickness indicators included body weight changes between Day 0 and Day 2 and between Day 2 and Day 5, and horizontal locomotor activity and vertical activity (rearing) measured at Day 6. Depression-like indicators included duration of immobility in the forced swim test and in the tail suspension test at Day 6 and sucrose consumption in the sucrose preference test at Day 7. The simultaneous consideration of complementary sickness and depression-like indicators enabled a more precise characterization of behavioral changes associated with BCG-treatment and of mouse-to-mouse variation, relative to the analysis of indicators individually. Univariate and multivariate analyses confirmed differences between BCG-treatment groups in weight change early on the trial. Significant differences between BCG-treatment groups in depression-like behaviors were still measurable after Day 5. The potential for multivariate models to account for the correlation between behavioral indicators and to augment the analytical precision relative to univariate models was demonstrated both for sickness and for depression-like indicators. Unsupervised learning approaches revealed the complementary information provided by the sickness and depression-like indicators considered. Supervised learning approaches using cross-validation confirmed subtle differences between BCG-treatment groups and among mice within group identified by the consideration of sickness and depression-like indicators. These findings support the recommendation for multivariate and multidimensional analyses of sickness and depression-like indicators to augment the systemic understanding of the behavioral changes associated with infection. PMID- 25300922 TI - Blood gene expression profiles suggest altered immune function associated with symptoms of generalized anxiety disorder. AB - Prospective epidemiological studies found that generalized anxiety disorder (GAD) can impair immune function and increase risk for cardiovascular disease or events. Mechanisms underlying the physiological reverberations of anxiety, however, are still elusive. Hence, we aimed to investigate molecular processes mediating effects of anxiety on physical health using blood gene expression profiles of 336 community participants (157 anxious and 179 control). We examined genome-wide differential gene expression in anxiety, as well as associations between nine major modules of co-regulated transcripts in blood gene expression and anxiety. No significant differential expression was observed in women, but 631 genes were differentially expressed between anxious and control men at the false discovery rate of 0.1 after controlling for age, body mass index, race, and batch effect. Gene set enrichment analysis (GSEA) revealed that genes with altered expression levels in anxious men were involved in response of various immune cells to vaccination and to acute viral and bacterial infection, and in a metabolic network affecting traits of metabolic syndrome. Further, we found one set of 260 co-regulated genes to be significantly associated with anxiety in men after controlling for the relevant covariates, and demonstrate its equivalence to a component of the stress-related conserved transcriptional response to adversity profile. Taken together, our results suggest potential molecular pathways that can explain negative effects of GAD observed in epidemiological studies. Remarkably, even mild anxiety, which most of our participants had, was associated with observable changes in immune-related gene expression levels. Our findings generate hypotheses and provide incremental insights into molecular mechanisms mediating negative physiological effects of GAD. PMID- 25300923 TI - Astrocytic TNFalpha regulates the behavioral response to antidepressants. AB - Recent studies have suggested that cytokines, and in particular tumor necrosis factor alpha (TNFalpha), have a role in modulating antidepressant efficacy. To directly test this idea, we compared the response of TNFalpha(-/-) mice and astrocyte-specific TNFalpha(-/-) mice to the antidepressants fluoxetine and desipramine. Using standard behavior models for measuring antidepressant efficacy, the forced swim test (FST) and tail suspension test (TST), we determined that TNFalpha(-/-) mice were essentially normal in basal behavior in the FST and TST. However, TNFalpha(-/-) mice showed no behavioral response to a standard dose of chronic antidepressant treatment, in sharp contrast to wildtype mice. Similar results were seen with acute antidepressant treatment, but TNFalpha(-/-) mice did respond to a very high-dose acute antidepressant treatment. We also assessed in vitro and in vivo effects of fluoxetine on TNFalpha expression. Glia responded to serotonin in vitro and fluoxetine in vivo by upregulating TNFalpha mRNA. Consistent with this source of TNFalpha, mice with an astrocyte-specific deletion of TNFalpha also did not respond to standard chronic antidepressant treatment. These data suggest that astrocytic TNFalpha is important to the sensitivity of the behavioral response to administration of antidepressants. PMID- 25300924 TI - Bone Mineralization of Broiler Chicks Challenged with Salmonella enteritidis Fed Diet Containing Probiotic (Bacillus subtilis). AB - The present study was carried out to determine the effect of probiotic, Bacillus subtilis, on ash and calcium contents of tibia bone in unchallenged and challenged broiler chicks with Salmonella enteritidis. In a completely randomized design, 160 chicks were divided into four groups. Each group had four replicates with 10 birds each. Treatments were control group, probiotic-treated group, challenged group and challenged probiotic-treated group. Ash and calcium contents of tibia at 21 and 42 days of age were determined. At 21 days of age, the highest contents of ash and calcium were related to probiotic-treated group and the lowest means to challenged chicks (P < 0.05). At this period, inclusion of probiotic to diet of challenged chick increased (P < 0.05) ash and calcium contents of tibia. With increases in age, the negative effects of challenging and beneficial effects of probiotic on bone mineralization diminished; since at 42 days of age, challenging or probiotic treatment had no effect on ash and calcium contents of tibia. PMID- 25300925 TI - Probing cavitand-organosilane hybrid bilayers via sum-frequency vibrational spectroscopy. AB - Quinoxaline cavitands (QxCav) are transferred by Langmuir-Schaefer method on self assembled monolayers (SAMs) of octadecyltrichlorosilane (OTS) and N,N-dimethyl-N octadecyl-3-aminopropyltrimethoxysilyl chloride (DMOAP) on fused silica substrates. The molecular architectures of both the hydrophobic SAMs templates and the hybrid cavitand-organosilanes bilayers at the solid-air interface are investigated and correlated by sum-frequency vibrational spectroscopy. The results show that QxCav are always in the closed vase configuration and orient with their principal axis normal to the substrates. The role of the alkyl chains density in the SAM templates on the QxCav transfer ratio is pointed out. PMID- 25300926 TI - Genetic polymorphisms in Glutathione S-transferase Omega (GSTO) and cancer risk: a meta-analysis of 20 studies. AB - Glutathione S-transferase Omega (GSTO) plays an important role in the development of cancer. Recently, a number of studies have investigated the association between single nucleotide polymorphisms on GSTO and susceptibility to cancer; however, the results remain inconclusive. We performed a meta-analysis of 20 studies, involving 4770 cases and 5701 controls to identify the strength of association by pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Overall, the pooled results revealed a significantly increased risk of susceptibility for GSTO2 polymorphism (GG vs. AA: OR = 1.20, 95%CI: 1.02 1.41, Pheterogeneity = 0.116), but no significant association was found for GSTO1 polymorphism. Subgroup analysis showed that GSTO2 polymorphism significantly increased cancer risk in Caucasian population (GG vs. AA: OR = 1.32, 95%CI 1.06 1.64, Pheterogeneity = 0.616) and GSTO2 polymorphism was significantly associated with elevated risk of breast cancer (GG vs. AA OR = 1.37, 95%CI: 1.06-1.77; Pheterogeneity = 0.281). This meta-analysis demonstrates that GSTO2 polymorphism may significantly increase cancer risk in Caucasian population and is associated with elevated risk of breast cancer; while GSTO1 polymorphism is not associated with cancer risk. PMID- 25300927 TI - The Neuropathology of Huntington's Disease. AB - The basal ganglia are a highly interconnected set of subcortical nuclei and major atrophy in one or more regions may have major effects on other regions of the brain. Therefore, the striatum which is preferentially degenerated and receives projections from the entire cortex also affects the regions to which it targets, especially the globus pallidus and substantia nigra pars reticulata. Additionally, the cerebral cortex is itself severely affected as are many other regions of the brain, especially in more advanced cases. The cell loss in the basal ganglia and the cerebral cortex is extensive. The most important new findings in Huntington's disease pathology is the highly variable nature of the degeneration in the brain. Most interestingly, this variable pattern of pathology appears to reflect the highly variable symptomatology of cases with Huntington's disease even among cases possessing the same number of CAG repeats. PMID- 25300928 TI - The association between left ventricular twisting motion and mechanical dyssynchrony: a three-dimensional speckle tracking study. AB - Left ventricular (LV) dyssynchrony is a causal factor in LV dysfunction and thought to be associated with LV twisting motion. We tested whether three dimensional speckle tracking (3DT) can be used to evaluate the relationship between LV twisting motion and dyssynchrony. We examined 25 patients with sick sinus syndrome who had received dual chamber pacemakers. The acute effects of ventricular pacing on LV wall motion after the switch from atrial to ventricular pacing were assessed. LV twisting motion and dyssynchrony during each pacing mode were measured using 3DT. LV dyssynchrony was calculated from the time to the minimum peak systolic area strain of 16 LV imaging segments. Ventricular pacing increased LV dyssynchrony and decreased twist and torsion. A significant correlation was observed between changes in LV dyssynchrony and changes in torsion (r = -0.65, p < 0.01). Evaluation of LV twisting motion can potentially be used for diagnosing LV dyssynchrony. PMID- 25300929 TI - Merkel cell carcinoma and chronic lymphocytic leukemia presenting as collision tumor: a possible pitfall in cutaneous lesions. PMID- 25300930 TI - A simplified technique of pancreas transplantation in a porcine model. AB - BACKGROUND: The incidence of diabetes has been steadily increasing. The only curative option for diabetes is pancreas transplantation (PTx). Porcine models are valuable because of their anatomical and physiological similarities to human beings. Our aim is to introduce a simplified technique of PTx in a porcine model. METHODS: In Landrace pigs (n = 32), after median laparotomy, the pancreas was mobilized, and the portal and splenic veins were divided. The proper hepatic and splenic arteries and the bile duct were also prepared, and the duodenal bulb was prepared and stapled. The third portion of the duodenum was freed up to the ligament of Treitz and stapled, and the renal arteries were ligated. After systemic heparinization, the pancreas was perfused through the abdominal aorta with histidine-tryptophan-ketoglutarate solution. The portal and splenic veins were cut for evaluating the sufficiency of perfusion. Whole pancreaticoduodenal graft was procured along with an aortic jump graft containing mesenteric and celiac trunks. In recipients, after total pancreatectomy, the suprarenal inferior vena cava and infrarenal aorta were prepared for vascular anastomosis in an end to-side manner. After pancreas reperfusion, duodenoduodenostomy was performed in an end-to-side manner. RESULTS: Median cold and warm ischemia times were 10 h (range, 9-14 h) and 50 min (range, 35-80 min), respectively. The hemodynamic status was stable throughout the operation. The median follow-up period was 7 days (range, 4-10). There were no major intra- and postoperative complications. CONCLUSION: By using an aortic jump graft, there was no need to perform additional arterial reconstruction resulting in a short warm ischemic and operation time. End-to-side portocaval and duodenoduodenal anastomoses make this model of PTx a very feasible method for experimental evaluations. PMID- 25300931 TI - How does low-molecular-weight polystyrene dissolve: osmotic swelling vs. surface dissolution. AB - By means of multiscale hierarchical modeling we study the real time evolution of low-molecular-weight polystyrene, below the glass transition temperature, in contact with its solvent, toluene. We observe two concurrent phenomena taking place: (1) the solvent diffuses into the polymer by a Case II mechanism, leading to osmotic driven swelling and progressive chain dilution (inside-out mechanism); (2) polymer chains are solvated, detach from the interface and move into the solvent before the film is completely swollen (outside-in mechanism). From our simulations we conclude that, below the entanglement length, a thin swollen layer, also observed in previous experiments, forms almost instantaneously, which allows for the outside-in mechanism to start a few tens of nanoseconds after the polymer-solvent initial contact. After this initial transient time the two mechanisms are concurrent. We furthermore observe that the presence of the solvent significantly enhances the mobility of the polymer chains of the surface layer, but only in the direction parallel to the interface. PMID- 25300932 TI - Daucus carota pentane-based fractions arrest the cell cycle and increase apoptosis in MDA-MB-231 breast cancer cells. AB - BACKGROUND: Daucus carota L.ssp.carota (wild carrot), an herb used in folk medicine worldwide, was recently demonstrated to exhibit anticancer activity. In this study we examined the anticancer effect of Daucus carota oil extract (DCOE) fractions on the human breast adenocarcinoma cell lines MDA-MB-231 and MCF-7 and clarified the mechanism of action. METHODS AND RESULTS: Using the WST assay, the pentane fraction (F1) and 1:1 pentane:diethyl ether fraction (F2) were shown to possess the highest cytotoxicity against both cell lines. Flow cytometric analysis revealed that both fractions induced the accumulation of cells in the sub-G1 phase, increase in apoptotic cell death and chromatin condensation. The increase in apoptosis in response to treatment was also apparent in the increase in BAX and the decrease in Bcl-2 levels as well as the proteolytic cleavage of both caspase-3 and PARP as revealed by Western blot. Furthermore, treatment of MDA-MB-231 cells with either fraction significantly reduced the level of phosphorylated Erk but did not show any effect on phosphorylated Akt. The combined treatment with a potent PI3K inhibitor (wortmannin) and F1 or F2 fraction had a synergistic inhibitory effect on cell survival which shows that these two drugs work on different pathways. CONCLUSIONS: These results suggest that the pentane-based fractions of DCOE possess potential anti-cancer activity that is mainly mediated through the Erk pathway. PMID- 25300934 TI - Speciation analysis of arsenic by selective hydride generation-cryotrapping atomic fluorescence spectrometry with flame-in-gas-shield atomizer: achieving extremely low detection limits with inexpensive instrumentation. AB - This work describes the method of a selective hydride generation-cryotrapping (HG CT) coupled to an extremely sensitive but simple in-house assembled and designed atomic fluorescence spectrometry (AFS) instrument for determination of toxicologically important As species. Here, an advanced flame-in-gas-shield atomizer (FIGS) was interfaced to HG-CT and its performance was compared to a standard miniature diffusion flame (MDF) atomizer. A significant improvement both in sensitivity and baseline noise was found that was reflected in improved (4 times) limits of detection (LODs). The yielded LODs with the FIGS atomizer were 0.44, 0.74, 0.15, 0.17 and 0.67 ng L(-1) for arsenite, total inorganic, mono-, dimethylated As and trimethylarsine oxide, respectively. Moreover, the sensitivities with FIGS and MDF were equal for all As species, allowing for the possibility of single species standardization with arsenate standard for accurate quantification of all other As species. The accuracy of HG-CT-AFS with FIGS was verified by speciation analysis in two samples of bottled drinking water and certified reference materials, NRC CASS-5 (nearshore seawater) and SLRS-5 (river water) that contain traces of methylated As species. As speciation was in agreement with results previously reported and sums of all quantified species corresponded with the certified total As. The feasibility of HG-CT-AFS with FIGS was also demonstrated by the speciation analysis in microsamples of exfoliated bladder epithelial cells isolated from human urine. The results for the sums of trivalent and pentavalent As species corresponded well with the reference results obtained by HG-CT-ICPMS (inductively coupled plasma mass spectrometry). PMID- 25300933 TI - EGFR and K-Ras mutations in women with lung adenocarcinoma: implications for treatment strategy definition. AB - BACKGROUND: We aimed at investigating the outcomes of female patients with stage IIIB-IV adenocarcinoma of the lung according to EGFR and K-Ras mutational status. METHODS: One hundred and three consecutive female patients genotyped at a single Italian Institution were analyzed. Patients were planned to receive first-line platinum-based chemotherapy (CT) and a salvage treatment with anti-EGFR tyrosine kinase inhibitors (TKIs) was proposed irrespective of tumor mutational status. EGFR (exons 18-21) and K-Ras (exon 2, codons 12-13) mutations were evaluated by real-time PCR and pyrosequencing. The association of mutational status with clinical variables and treatment benefit was investigated by chi-square test and log-rank test. RESULTS: EGFR and K-Ras mutations were found in 31 (30%) and 13 (15%) cases, respectively. Sixty-six patients received platinum CT: no correlation was observed between EGFR or K-Ras mutational status and response rate (RR) (p > 0.05). However, patients treated with first-line CT harboring EGFR activating mutations experienced a significantly reduced progression-free survival (PFS) in comparison with wild-type ones (4.4 vs. 6.4 months, respectively; HR 0.597, 95% CI 0.287-0.975; p = 0.048). Thirty-nine patients received salvage treatment with erlotinib: EGFR activating mutations were significantly correlated with RR (60% vs. 12.5%; p = 0.004) and PFS (11.4 vs. 4.5 months; HR 0.491, 95% CI 0.216-0.936; p = 0.044). Responses to erlotinib were not reported among women with K-Ras mutant tumors, while 50% of those with wild-type K-Ras achieved an objective remission (p = 0.296). Median PFS (3.5 vs. 8.8 months; HR 0.284, 95% CI 0.015-0.510; p = 0.010) and OS (3.9 vs. 19.8 months; HR 0.158, 95% CI 0.001-0.075; p < 0.001) were significantly shorter among K-Ras mutant patients treated with TKI. CONCLUSIONS: In our population of Caucasian women with advanced lung adenocarcinoma we observed that the presence of EGFR activating mutations correlates with a significant reduction in the benefit from first-line platinum-based CT, emphasizing the importance of an upfront use of anti-EGFR TKIs in this patient subset. K-Ras mutations seem to correlate with a detrimental effect from anti-EGFR TKI, but this finding deserves further investigation. PMID- 25300935 TI - Amyotrophic lateral sclerosis: new ideas from cancer. PMID- 25300937 TI - Mild P-P bond cleavage in the methyldiphosphenyl complex [Mo2Cp2(MU-PCy2)(MU kappa(2):kappa(2)-P2Me)(CO)2] to give novel phosphide-bridged trinuclear derivatives. AB - Reactions of the title diphosphenyl complex with [Fe2(CO)9] and [W(CO)4(THF)2] gave the trinuclear species [Mo2FeCp2(MU3-P)(MU-PCy2)(MU3-PMe)(CO)5] and [Mo2WCp2(MU3-P)(MU-PCy2)(MU3-PMe)(CO)6] following from formal insertion of the 14 electron fragments Fe(CO)3 and W(CO)4, respectively, in the P-P bond of the diphosphenyl ligand and formation of a new heterometallic bond [Mo-Fe = 2.9294(6) A and Mo-W = 3.146(1) A]. Reactions of the diphosphenyl complex with the tetrahydrofuran adducts [MLn(THF)] (MLn = MnCp'(CO)2, W(CO)5) led instead to trinuclear diphosphenyl complexes [Mo2MCp2(MU-PCy2)(MU3 kappa(2):kappa(2):kappa(1)-P2Me)(CO)2Ln] following from coordination in each case of the corresponding 16-electron fragment MLn to the lone-pair-bearing P atom of the P2Me ligand. However, these diphosphenyl complexes were unstable and decomposed at room temperature or under mild heating by the release of methylphosphinidene (PMe), to give the corresponding derivatives [Mo2MCp2(MU3 P)(MU-PCy2)(CO)2Ln] displaying trigonal-planar phosphide ligands, giving rise to strongly deshielded (31)P NMR resonances (deltaP ca. 1100 ppm), while being involved in strong pi bonding with the unsaturated Mo2 center of these molecules [Mo-Mo = 2.749(1) A and Mo-P = ca. 2.30 A when M = W]. An isolobal analogy could be established between the P->MLn fragments in these products and a carbyne ligand (CR), supported by density functional theory calculations on the tungsten compound, which also enabled an easy interpretation and prediction of their chemical behavior. Thus, the manganese complex could be reversibly carbonylated (pCO = ca. 3 atm, 293 K) to give the corresponding electron-precise pentacarbonyl [MnMo2Cp2Cp'(MU3-P)(MU-PCy2)(CO)5] [Mo-Mo = 3.1318(7) A], a process also involving a trans-to-cis rearrangement of the Mo2Cp2 subunit. On the other hand, decarbonylation of the tungsten complex was accomplished in a refluxing toluene solution to give the hexacarbonyl [Mo2WCp2(MU3-P)(MU-PCy2)(MU-CO)(CO)5], a derivative containing an unsaturated 30-electron dimolybdenum center with an intermetallic triple bond. PMID- 25300938 TI - Controlled synthesis and characterization of the elusive thiolated Ag55 cluster. AB - A stable, Ag55 cluster protected with 4-(tert-butyl)benzyl mercaptan (BBSH) was synthesized which exhibits two prominent absorption bands with maxima at 2.25 and 2.81 eV. A molecular ion peak at m/z 11 500 +/- 20 in matrix assisted laser desorption ionization mass spectrum (MALDI MS), assigned to Ag55(BBS)31 was observed. Electrospray ionization (ESI MS) shows a prominent trication along with higher charged species. An analogous Ag55(PET)31 (PET = 2-phenylethanethiol, in the thiolate form) was also synthesized under optimized conditions which proves the amenability of this cluster and the synthetic methodology to other ligands. PMID- 25300936 TI - Analysis of amyotrophic lateral sclerosis as a multistep process: a population based modelling study. AB - BACKGROUND: Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. METHODS: We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. FINDINGS: We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0.95, Ireland r(2)=0.99, Italy r(2)=0.95, the Netherlands r(2)=0.99, and Scotland r(2)=0.97; overall r(2)=0.99. All five registers gave similar estimates of the linear slope ranging from 4.5 to 5.1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4.8 (95% CI 4.5-5.0), with similar estimates for men (4.6, 4.3-4.9) and women (5.0, 4.5-5.5). INTERPRETATION: A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. FUNDING: UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme). PMID- 25300939 TI - Efficiency of pivot splints as jaw exercise apparatus in combination with stabilization splints in anterior disc displacement without reduction: a retrospective study. AB - OBJECTIVE: To evaluate efficiency of pivot splints in jaw exercises, in combination with stabilization splints, in cases of anterior disc displacement without reduction of temporomandibular joint. SUBJECTS AND METHODS: Twenty-three patients who referred to the prosthodontics clinic in 1995-1997 were included in the study, where anterior disc displacement without reduction of temporomandibular joint was diagnosed using magnetic resonance imaging and clinical examination. Pivot splints were used for jaw exercises for five minutes long; five times/day and stabilization splints were used at all other times. The patients were followed for 24 weeks. Lateral and protrusive excursions along with maximum mouth opening and were evaluated at each control. Bilateral palpation of temporal, masseter, sternocleidomastoid muscles and TMJ was assessed for pain perception before and after treatment. Data were statistically analyzed using Paired sample t-test and Independent Samples t-test (p < .05). RESULTS: Mean mandibular range of motion measurements increased from 28.74 mm prior to 49.17 mm on maximum opening; right/left lateral excursion from 7.61 mm to 12.04 mm and 4.09 mm to 7.3 mm on protrusion after treatment. All changes observed before and after treatment were found to be statistically significant. (p < .001) Pain symptoms were eliminated at the end of 24 weeks of treatment in all patients. CONCLUSION: Using pivot splints as an exercise regimen along with a stabilization splint may be a viable treatment option for patients with anterior disc displacement without reduction; as normal mandibular range of motion was established and pain was eliminated. PMID- 25300940 TI - Elevated brain glucose and glycogen concentrations in an animal model of depression. AB - INTRODUCTION: Recent data indicate that there is a link between depression and diabetes and that excess glucocorticoids may play an underlying role in the pathogenesis of both of these diseases. The aim of the present study was to determine whether there are any alterations in glucose, glycogen, glucose transporters, insulin, insulin receptors or corticosterone concentrations in the hippocampus and frontal cortex in a prenatal stress rat model of depression. METHODS: Male rats whose mothers had been subjected to stress and control animals were subjected to the Porsolt test to verify the experimental model. Next, some of the rats were subjected to acute stress and/or were administered glucose. Glucose, glycogen, corticosterone, insulin, insulin receptor, phospho-insulin receptor and glucose transporter (GLUT1, GLUT3 and GLUT4) concentrations were assayed. RESULTS: Prenatally stressed rats exhibited glucose and glycogen concentrations in both investigated brain structures that exceeded those of the control animals. Prenatal stress also increased the levels of glucose transporters - GLUT1 in both tissues and GLUT4 in the frontal cortex. The changes in the prenatally stressed rats were more prominent in the animals that were subjected to stress or glucose loading in adulthood. CONCLUSION: The increase in carbohydrate brain concentrations evoked by prenatal stress may result from changes in the amounts of glucose transporters, especially GLUT1. Moreover, the obtained results support the hypothesis that stress during the perinatal period permanently increases the sensitivity of brain tissue to factors that act in adulthood. (c) 2014 S. Karger AG, Basel. PMID- 25300941 TI - Thermodynamic analysis of framework deformation in Na,Cs-RHO zeolite upon CO2 adsorption. AB - Fully dehydrated and partially sodium-cesium containing RHO zeolite (Na,Cs-RHO) shows a genuine inflection in the CO2 isotherms in the temperature range 293-333 K that can be attributed to a sorbate-induced framework deformation from an acentric (A) to a centric (C) phase due to a partial cation rearrangement. This peculiar sorption pattern can be captured by the formulation of thermodynamic isotherms, providing a direct enthalpic and entropic signature of the CO2 adsorption-desorption process during deformation. Using this formulation, the energy barrier between the acentric and centric phases for CO2 adsorption desorption was estimated in the range 4.7-9.6 J g(-1) of solid (15-32 kJ mol( 1)), reflecting a higher CO2 affinity for the acentric phase, whereas the elastic energy involved during framework distortion was estimated in the range 6-12 J g( 1) of solid (19-39 kJ mol(-1)) with a relative maximum at 303 K and showing a dominant entropic contribution. PMID- 25300942 TI - Determining equilibrium osmolarity in poly(ethylene glycol)/chondrotin sulfate gels mimicking articular cartilage. AB - We present an experimentally guided, multi-phase, multi-species polyelectrolyte gel model to make qualitative predictions on the equilibrium electro-chemical properties of articular cartilage. The mixture theory consists of two different types of polymers: poly(ethylene gylcol) (PEG), chondrotin sulfate (ChS), water (acting as solvent) and several different ions: H(+), Na(+), Cl(-). The polymer chains have covalent cross-links whose effect on the swelling kinetics is modeled via Doi rubber elasticity theory. Numerical studies on equilibrium polymer volume fraction and net osmolarity (difference in the solute concentration across the gel) show a complex interplay between ionic bath concentrations, pH, cross-link fraction and the average charge per monomer. Generally speaking, swelling is aided due to a higher average charge per monomer (or a higher particle fraction of ChS, the charged component of the polymer), low solute concentration in the bath, a high pH or a low cross-link fraction. A peculiar case arises at higher values of cross-link fraction, where it is observed that increasing the average charge per monomer leads to gel deswelling. PMID- 25300943 TI - Erythema multiforme-like reaction with mucosal involvement following administration of idelalisib for relapse of chronic lymphocytic leukemia. PMID- 25300944 TI - Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma. AB - The maximum tolerated dose of SAR245409 (voxtalisib), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, was determined in a phase 1 dose-escalation study in advanced solid tumors. We report safety, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409 capsules 50 mg twice daily in an expansion cohort of 16 patients with relapsed/refractory lymphoma. The most common treatment-related adverse events (AEs) were nausea (31.3%) and diarrhea (25.0%). The most common grade 3/4 treatment-related AE was increased alanine aminotransferase (12.5%). PK results were consistent with solid tumors, confirming a relatively short steady state half-life (mean 4.61 h). Among 12 evaluable patients, one complete response and two partial responses were achieved in patients with and without PI3K/mTOR pathway alterations. In a patient with mantle cell lymphoma achieving PR, SAR245409 was associated with significant inhibition of PI3K/mTOR and extracellular signal-related kinase (ERK) pathways. Preliminary efficacy warrants further evaluation of SAR245409 in lymphoma. PMID- 25300946 TI - The effects of vital dyes on retinal pigment epithelium cells in oxidative stress. AB - PURPOSE: To determine the effect of the most commonly used vital dyes in vitrectomy [trypan blue at 0.15% concentration and indocyanine green (ICG) at 0.5% concentration] on the viability of human retinal pigment epithelium (RPE) cell lines (ARPE-19) exposed to oxidative stress. METHODS: ARPE-19 cells unexposed or exposed to oxidative stress (hypoxic chamber) were treated for 1 min with one of the dyes. RPE proliferation was measured by (3)H-thymidine incorporation, adhesion by ability to adhere to fibronectin, and safety by annexin V staining. RESULTS: Proliferation: The dyes affected the proliferation of RPE cells differently under non-hypoxic and hypoxic conditions (p = 0.001). In non-hypoxic conditions, there was no statistically significant difference between the proliferation of the treated (both dyes) and untreated RPE cells (p = 0.279). Under hypoxia, both dyes significantly suppressed proliferation, more so with ICG (p = 0.001). Adhesion: The dyes affected adhesion differently under non-hypoxic and hypoxic conditions (p = 0.04). In non-hypoxic conditions, both increased the adhesive properties of RPE cells to fibronectin, ICG more than trypan blue (p = 0.001). Under hypoxia, both dyes suppressed adhesion, with no statistically significant difference between treated and non-treated RPE cells. Apoptosis: Both dyes increased early apoptosis of RPE cells compared with no treatment (p = 0.001), ICG more than trypan blue. Hypoxia increased the apoptosis of both dyes compared to non-hypoxic conditions (p = 0.02). CONCLUSIONS: In hypoxic conditions, both dyes showed an inhibition of RPE adhesion to fibronectin and proliferation capacity and an increase in early apoptosis compared with non hypoxic conditions. Apoptosis was greater in ICG-treated RPE cells than in trypan blue-treated cells. PMID- 25300948 TI - Tore Curstedt - the basic science creator of porcine surfactant. PMID- 25300947 TI - Immunohistochemical molecular phenotypes of gastric cancer based on SOX2 and CDX2 predict patient outcome. AB - BACKGROUND: Gastric cancer remains a serious health concern worldwide. Patients would greatly benefit from the discovery of new biomarkers that predict outcome more accurately and allow better treatment and follow-up decisions. Here, we used a retrospective, observational study to assess the expression and prognostic value of the transcription factors SOX2 and CDX2 in gastric cancer. METHODS: SOX2, CDX2, MUC5AC and MUC2 expression were assessed in 201 gastric tumors by immunohistochemistry. SOX2 and CDX2 expression were crossed with clinicopathological and follow-up data to determine their impact on tumor behavior and outcome. Moreover, SOX2 locus copy number status was assessed by FISH (N = 21) and Copy Number Variation Assay (N = 62). RESULTS: SOX2 was expressed in 52% of the gastric tumors and was significantly associated with male gender, T stage and N stage. Moreover, SOX2 expression predicted poorer patient survival, and the combination with CDX2 defined two molecular phenotypes, SOX2+CDX2- versus SOX2-CDX2+, that predict the worst and the best long-term patients' outcome. These profiles combined with clinicopathological parameters stratify the prognosis of patients with intestinal and expanding tumors and in those without signs of venous invasion. Finally, SOX2 locus copy number gains were found in 93% of the samples reaching the amplification threshold in 14% and significantly associating with protein expression. CONCLUSIONS: We showed, for the first time, that SOX2 combined with CDX2 expression profile in gastric cancer segregate patients into different prognostic groups, complementing the clinicopathological information. We further demonstrate a molecular mechanism for SOX2 expression in a subset of gastric cancer cases. PMID- 25300949 TI - Evidence-based advances in transfusion practice in neonatal intensive care units. AB - BACKGROUND: Transfusions to neonates convey both benefits and risks, and evidence is needed to guide wise use. Such evidence is accumulating, but more information is needed to generate sound evidence-based practices. OBJECTIVE: We sought to analyze published information on nine aspects of transfusion practice in neonatal intensive care units. METHODS: We assigned 'categories of evidence' and 'recommendations' using the format of the United States Preventive Services Task Force of the Agency for Healthcare Research and Quality. RESULTS: The nine practices studied were: (1) delayed clamping or milking of the umbilical cord at preterm delivery - recommended, high/substantial A; (2) drawing the initial blood tests from cord/placental blood from very low birth weight (VLBW, <1,500 g) infants at delivery - recommended, moderate/moderate B; (3) limiting phlebotomy losses of VLBW infants - recommended, moderate/substantial B; (4) selected use of erythropoiesis-stimulating agents to prevent transfusions - recommended, moderate/moderate-moderate/small B, C; (5) using platelet mass, rather than platelet count, in platelet transfusion decisions - recommended, moderate/small C; (6) permitting the platelet count to fall to <20,000/ul in 'stable' neonates before transfusing platelets - recommended, low/small I; (8) permitting the platelet count to fall to <50,000/ul in 'unstable' neonates before transfusing platelets - recommended, moderate/small C, and (9) not performing routine coagulation test screening on every VLBW infant - recommended, moderate/small C. CONCLUSIONS: We view these recommendations as dynamic, to be revised as additional evidence becomes available. We predict this list will expand as new studies provide more information to guide best transfusion practices. PMID- 25300952 TI - Global and domestic legal preparedness and response: 2014 Ebola outbreak. AB - The global rise of Ebola viral diseases in 2014 necessitates legal responses that promote effective public health responses and respect for the health and human rights of populations. Compulsory public health interventions, approval and administration of experimental drugs or vaccines, and allocation of finite resources require difficult choices in law and policy. Crafting legal decisions in real-time emergencies is neither easy nor predictable, but it is essential to controlling epidemics and saving lives. PMID- 25300950 TI - Insulin-like growth factor-1 and anti-vascular endothelial growth factor in retinopathy of prematurity: has the time come? AB - Treatment of retinopathy of prematurity (ROP) is currently evolving. Novel therapeutic options are emerging that have the potential to complement existing therapies and improve treatment outcomes. However, any new therapeutic option must be thoroughly evaluated before existing (and successful) treatment paradigms can be amended. This is particularly so when switching from locally effective therapies like photoablative laser therapy to systemic pharmacological treatments, which may have hitherto unknown widespread side effects. This review compiles the current knowledge of where and when the two most advanced pharmacological treatment options for ROP, insulin-like growth factor-1 supplementation and anti-vascular endothelial growth factor treatment, may have their place in future therapy regimens for ROP. The requirement for clinical studies is emphasized: these are needed to address safety considerations before any of these interventions can achieve the status of standard clinical care in the very vulnerable population of ROP infants. PMID- 25300953 TI - Effect of compounds affecting ABCA1 expression and CETP activity on the HDL pathway involved in intestinal absorption of lutein and zeaxanthin. AB - The antioxidant xanthophylls lutein and zeaxanthin are absorbed from the diet in a process involving lipoprotein formation. Selective mechanisms exist for their intestinal uptake and tissue-selective distribution, but these are poorly understood. We investigated the role of high-density lipoprotein (HDL), apolipoprotein (apo) A1 and ATP-binding cassette transporter (ABC) A1 in intestinal uptake of lutein in a human polarized intestinal cell culture and a hamster model. Animals received dietary lutein and zeaxanthin and either a liver X receptor (LXR) agonist or statin, which up- or down-regulate intestinal ABCA1 expression, respectively. The role of HDL was studied following treatment with the cholesteryl ester transfer protein (CETP) modulator dalcetrapib or the CETP inhibitor anacetrapib. In vitro, intestinal ABCA1 at the basolateral surface of enterocytes transferred lutein and zeaxanthin to apoA1, not to mature HDL. In hamsters, plasma lutein and zeaxanthin levels were markedly increased with the LXR agonist and decreased with simvastatin. Dalcetrapib, but not anacetrapib, increased plasma and liver lutein and zeaxanthin levels. ABCA1 expression and apoA1 acceptor activity are important initial steps in intestinal uptake and maintenance of lutein and zeaxanthin levels by an HDL-dependent pathway. Their absorption may be improved by physiological and pharmacological interventions affecting HDL metabolism. PMID- 25300954 TI - Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth. AB - Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life. PMID- 25300957 TI - "Crossed" somatoparaphrenia: an unusual new case and a review of the literature. AB - Somatoparaphrenia is a delusional misidentification and confabulation of body parts, usually arm or hand, opposite to a cerebral lesion, generally of the "minor" right hemisphere. There is some controversy concerning lesion site (fronto-parietal; parieto-temporal; posterior insula, additional subcortical nuclei) or necessary associated symptoms (hemiparesis/plegia, anosognosia, neglect, position sense deficit). We here present a patient who is unusual in many respects, that is: (1) he is a right-hander with somatoparaphrenia after a "dominant" left-hemisphere lesion associated with aphasia and ideo-motor apraxia, but also with right hemineglect. He thus has "crossed" somatoparaphrenia; (2) his delusional misidentification concerned the right leg and not the arm or hand; (3) he has no anosognosia; (4) his proprioception is disturbed for the leg only; and (5) the lesion site is very posterior, a left occipito-parietal haemorrhage without involvement of the frontal lobe or the posterior insula. We present this case together with the seven other cases of "crossed somatoparaphrenia" with and without aphasia we found since 1935 in the literature and discuss their relevance in relation to the above controversies. PMID- 25300956 TI - Transmission dynamics and control of Ebola virus disease (EVD): a review. AB - The complex and unprecedented Ebola epidemic ongoing in West Africa has highlighted the need to review the epidemiological characteristics of Ebola Virus Disease (EVD) as well as our current understanding of the transmission dynamics and the effect of control interventions against Ebola transmission. Here we review key epidemiological data from past Ebola outbreaks and carry out a comparative review of mathematical models of the spread and control of Ebola in the context of past outbreaks and the ongoing epidemic in West Africa. We show that mathematical modeling offers useful insights into the risk of a major epidemic of EVD and the assessment of the impact of basic public health measures on disease spread. We also discuss the critical need to collect detailed epidemiological data in real-time during the course of an ongoing epidemic, carry out further studies to estimate the effectiveness of interventions during past outbreaks and the ongoing epidemic, and develop large-scale modeling studies to study the spread and control of viral hemorrhagic fevers in the context of the highly heterogeneous economic reality of African countries. PMID- 25300958 TI - Axially evoked postural reflexes: influence of task. AB - Postural reflexes were recorded in healthy subjects (n = 17) using brief axial accelerations and tap stimuli applied at the vertebra prominens (C7) and manubrium sterni. Short latency (SL) responses were recorded from the soleus, hamstrings and tibialis anterior muscles and expressed as a percentage of the background EMG prior to stimulus onset. In the majority of postural conditions tested, subjects were recorded standing erect and leaning forward with their feet together. The SL response was larger for soleus than for the hamstrings during standing (soleus vs hamstrings; 70.4 vs 28.1%), whereas the opposite occurred during kneeling (25.3 vs 127.3%). Concordant head and trunk accelerations produced larger SL responses than discordant accelerations for soleus and hamstrings, but the evoked excitatory response was independent of head direction and as expected for the direction of truncal acceleration. Postural reflexes for soleus and tibialis anterior were strongly affected by conditions that posed a significant threat to postural stability; stimulation at C7 was associated with significant SL enhancement for soleus during anterior lean while sternal stimulation showed SL enhancement for tibialis anterior during posterior lean. Cutaneous anaesthesia applied over the C7 stimulation site had no significant effect on EMG responses, nor did vision or surface type (rigid or compliant). This study provides further evidence that postural reflexes produced by brief axial accelerations are independent of cutaneous receptors, vestibular afferents and ankle proprioceptors, and demonstrates that postural tasks and truncal orientation significantly affect the evoked response, consistent with a role in stabilising posture. PMID- 25300955 TI - Mouse Models of Oxidative Stress Indicate a Role for Modulating Healthy Aging. AB - Aging is a complex process that affects every major system at the molecular, cellular and organ levels. Although the exact cause of aging is unknown, there is significant evidence that oxidative stress plays a major role in the aging process. The basis of the oxidative stress hypothesis is that aging occurs as a result of an imbalance between oxidants and antioxidants, which leads to the accrual of damaged proteins, lipids and DNA macromolecules with age. Age dependent increases in protein oxidation and aggregates, lipofuscin, and DNA mutations contribute to age-related pathologies. Many transgenic/knockout mouse models over expressing or deficient in key antioxidant enzymes have been generated to examine the effect of oxidative stress on aging and age-related diseases. Based on currently reported lifespan studies using mice with altered antioxidant defense, there is little evidence that oxidative stress plays a role in determining lifespan. However, mice deficient in antioxidant enzymes are often more susceptible to age-related disease while mice overexpressing antioxidant enzymes often have an increase in the amount of time spent without disease, i.e., healthspan. Thus, by understanding the mechanisms that affect healthy aging, we may discover potential therapeutic targets to extend human healthspan. PMID- 25300959 TI - Interaction of brain areas of visual and vestibular simultaneous activity with fMRI. AB - Static body equilibrium is an essential requisite for human daily life. It is known that visual and vestibular systems must work together to support equilibrium. However, the relationship between these two systems is not fully understood. In this work, we present the results of a study which identify the interaction of brain areas that are involved with concurrent visual and vestibular inputs. The visual and the vestibular systems were individually and simultaneously stimulated, using flickering checkerboard (without movement stimulus) and galvanic current, during experiments of functional magnetic resonance imaging. Twenty-four right-handed and non-symptomatic subjects participated in this study. Single visual stimulation shows positive blood-oxygen level-dependent (BOLD) responses (PBR) in the primary and associative visual cortices. Single vestibular stimulation shows PBR in the parieto-insular vestibular cortex, inferior parietal lobe, superior temporal gyrus, precentral gyrus and lobules V and VI of the cerebellar hemisphere. Simultaneous stimulation shows PBR in the middle and inferior frontal gyri and in the precentral gyrus. Vestibular- and somatosensory-related areas show negative BOLD responses (NBR) during simultaneous stimulation. NBR areas were also observed in the calcarine gyrus, lingual gyrus, cuneus and precuneus during simultaneous and single visual stimulations. For static visual and galvanic vestibular simultaneous stimulation, the reciprocal inhibitory visual-vestibular interaction pattern is observed in our results. The experimental results revealed interactions in frontal areas during concurrent visual-vestibular stimuli, which are affected by intermodal association areas in occipital, parietal, and temporal lobes. PMID- 25300960 TI - Neuroplasticity of imagined wrist actions after spinal cord injury: a pilot study. AB - Motor imagery (MI - i.e., the mental representation of an action without physically executing it) stimulates brain motor networks and promotes motor learning after spinal cord injury (SCI). An interesting issue is whether the brain networks controlling MI are being reorganized with reference to spared motor functions. In this pilot study, we tested using magnetoencephalography (MEG) whether changes in cortical recruitment during MI were related to the motor changes elicited by rehabilitation. Over a 1-year period of inclusion, C6 SCI participants (n = 4) met stringent criteria for inclusion in a rehabilitation program focused on the tenodesis prehension (i.e., a compensatory prehension enabling seizing of objects in spite of hand and forearm muscles paralysis). After an extended baseline period of 5 weeks including repeated MEG and chronometric assessments of motor performance, MI training was embedded to the classical course of physiotherapy for five additional weeks. Posttest MEG and motor performance data were collected. A group of matched healthy control participants underwent a similar procedure. The MI intervention resulted in changes in the variability of the wrist extensions, i.e., a key movement of the tenodesis grasp (p < .05). Interestingly, the extent of cortical recruitment, quantified by the number of MEG activation sources recorded within Brodmann areas 1-8 during MI of the wrist extension, significantly predicted actual movement variability changes across sessions (p < .001). However, no such relationship was present for movement times. Repeated measurements afforded a reliable statistical power (range .70-.97). This pilot study does not provide straightforward evidence of MI efficacy, which would require a randomized controlled trial. Nonetheless, the data showed that the relationship between action and imagery of spared actions may be preserved after SCI. PMID- 25300961 TI - Effects of dopaminergic treatment on functional cortico-cortical connectivity in Parkinson's disease. AB - Interactions between dorsal premotor cortex (PMd) and primary motor cortex (M1) and interhemispheric inhibition (IHI) between M1 are impaired in Parkinson's disease (PD). We used dual-site transcranial magnetic stimulation to compare effects of first-time levodopa application with chronic dopaminergic therapy on these interactions in PD. Twelve untreated PD patients were studied before and after their first-ever intake of levodopa. The effects of chronic dopaminergic medication were evaluated in 11 patients who had received regular dopaminergic medication for approximately 3 years. Nine of these patients were also measured after overnight withdrawal of medication. For IHI, conditioning stimuli (CS) were applied to left M1 followed by test stimuli (TS) over right M1 and vice versa in separate blocks at interstimulus intervals (ISI) of 6-10 ms. Next, CS were applied to left PMd at subthreshold intensity followed by TS over left M1 at ISIs of 4 and 6 ms. Results were compared to 17 age- and gender-matched controls. In de novo PD patients, levodopa reduced left-to-right IHI, but did not alter PMd-M1 connectivity. In contrast, inhibitory PMd-M1 connectivity was present in early disease patients under chronic dopaminergic stimulation, but not in de novo PD patients at low stimulus intensities at an ISI of 4 ms. First-time exposure to levodopa exerts different effects on cortico-cortical pathways than chronic dopaminergic stimulation in PD, suggesting a change in the responsiveness of cortico-cortical circuits during the course of PD. PMID- 25300962 TI - Efficiency of visual feedback integration differs between dominant and non dominant arms during a reaching task. AB - Recent studies have shown that patterns of endpoint variability following double step reach sequences reflect the influence of both planning and execution-related processes, but are strongly dominated by noise associated with the online updating of movement plans based on visual feedback. However, it is currently unclear whether these results reflect the dominant arm/hemisphere's postulated specialization for visual feedback processing, or whether these effects reflect a more general "arm/hemisphere independent" preference for visual feedback in the control of reaching. To explore this, twelve subjects performed double-step reach sequences with their dominant and non-dominant arms to targets in 3D space with and without visual feedback of the arm. Variability was quantified using the volumes, aspect ratios, and orientations of 95% confidence ellipsoids fit to the distributions of reach endpoints. In consonance with previous findings, the availability of visual feedback resulted in ellipsoids that were significantly smaller, had greater aspect ratios, and were more aligned with the depth axis than those performed without visual feedback. Moreover, the effects of vision on aspect ratio and orientation were similar in magnitude for the dominant and non dominant arms, suggesting that noise associated with planning and execution related processes is managed in a similar way by the sensorimotor systems of each arm. However, the degree to which vision decreased ellipsoid volume was found to be significantly greater for the dominant arm. This suggests that the feedback control system of the dominant arm uses visual information more efficiently to control reaches to visual targets. PMID- 25300963 TI - Visual detail about the body modulates tactile localisation biases. AB - The localisation of tactile stimuli requires the integration of visual and somatosensory inputs within an internal representation of the body surface and is prone to consistent bias. Joints may play a role in segmenting such internal body representations, and may therefore influence tactile localisation biases, although the nature of this influence remains unclear. Here, we investigate the relationship between conceptual knowledge of joint locations and tactile localisation biases on the hand. In one task, participants localised tactile stimuli applied to the dorsum of their hand. A distal localisation bias was observed in all participants, consistent with previous results. We also manipulated the availability of visual information during this task, to determine whether the absence of this information could account for the distal bias observed here and by Mancini et al. (Neuropsychologia 49:1194-1201, 2011). The observed distal bias increased in magnitude when visual information was restricted, without a corresponding decrease in precision. In a separate task, the same participants indicated, from memory, knuckle locations on a silhouette image of their hand. Analogous distal biases were also seen in the knuckle localisation task. The accuracy of conceptual joint knowledge was not correlated with tactile localisation bias magnitude, although a similarity in observed bias direction suggests that both tasks may rely on a common, higher-order body representation. These results also suggest that distortions of conceptual body representation may be more common in healthy individuals than previously thought. PMID- 25300964 TI - Pathophysiology, diagnosis, and management of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a common complication of cirrhosis of the liver. It is also extremely debilitating, with an untreated 3-year survival of only 23 %. While the exact pathophysiology of HE has yet to be elucidated, a number of contributing factors have been described. Abnormal levels and altered metabolism of ammonia play a central role. Recently, inflammation has also been identified as a contributor to HE. Improved understanding of the pathophysiology of HE is crucial, as current therapy centers on reduction of the body's ammonia load. Lactulose is the first-line therapy for HE, with some antibiotics recently showing promise for improved outcomes in patients with HE. The role of anti inflammatory therapies has yet to be evaluated. PMID- 25300965 TI - Anti-inflammatory potential of beta-amyrin, a triterpenoid isolated from Costus igneus. AB - Costus igneus, common name Fiery Costus or Spiral Flag, is a species of herbaceous plant in the Costaceae family. It is cultivated in India for its use in traditional medicine especially for diabetes. The present study was carried out to determine the mechanism of anti-inflammatory action of beta-amyrin isolated from the leaves of Costus igneus (C. igneus) using carrageenan-induced rat model and LPS-induced human peripheral blood mononuclear cells (hPBMCs) in vitro model. The differential fractionation of leaves of Costus igneus showed maximum percentage inhibition of paw edema at a dose of 100 mg/kg body weight in methanolic extract (MEC). MEC elicited significant anti-inflammatory effect by inhibiting cyclooxygenase (COX), lipoxygenase (LOX), myeloperoxidase (MPO) and nitric oxide synthase (NOS) activities in monocytes when compared to carrageenan control. The effect of MEC was more pronounced than standard drug Diclofenac (20 mg/kg body weight). After fractionation of MEC using various solvents such as chloroform, hexane, ethyl acetate and butanol, the mechanism of anti-inflammatory effect of chloroform extract (CEC) of MEC was evaluated since it showed maximum beneficial effect at a dose of 50 mg/kg BW Treatment of carrageenan-induced rats with CEC exerted significantly decreased COX-2, MPO, and NOS activities when compared to carrageenan-induced rats. By the partial purification of CEC by liquid-liquid partition chromatography, TLC, mass, IR and NMR spectroscopy, the active component beta-amyrin was isolated. Significant decrease in edema was observed by the administration of beta-amyrin in a dose-dependent manner and 100 ug of beta-amyrin showed 97 % in carrageenan-induced paw edema in rats. Treatment with beta-amyrin significantly inhibited PGE2, IL-6 secretion, and NF-kappaB activation in a concentration-dependent manner on LPS-induced hPBMCs. Thus, beta amyrin, an active component isolated from C. igneus, serves as a promising and expanding platform for treatment of various inflammatory disorders. PMID- 25300966 TI - Megacities and climate change - A brief overview. AB - Cities have developed into the hotspots of human economic activity. From the appearance of the first cities in the Neolithic to 21st century metropolis their impact on the environment has always been apparent. With more people living in cities than in rural environments now it becomes crucial to understand these environmental impacts. With the immergence of megacities in the 20th century and their continued growth in both, population and economic power, the environmental impact has reached the global scale. In this paper we examine megacity impacts on atmospheric composition and climate. We present basic concepts, discuss various definitions of footprints, summarize research on megacity impacts and assess the impact of megacity emissions on air quality and on the climate at the regional to global scale. The intention and ambition of this paper is to give a comprehensive but brief overview of the science with regard to megacities and the environment. PMID- 25300967 TI - Direct evidence for self-propagation of different amyloid-beta fibril conformations. AB - BACKGROUND: Amyloid fibrils formed by amyloid-beta (Abeta) peptides are associated with Alzheimer's disease and can occur in a range of distinct morphologies that are not uniquely determined by the Abeta sequence. Whether distinct conformations of Abeta fibrils can be stably propagated over multiple cycles of seeding and fibril growth has not been established experimentally. OBJECTIVE: The ability of the 40-residue peptide Abeta1-40 to assemble into fibrils with the conformation of the mutant Abeta1-40 peptide containing the 'Osaka' mutation E22Delta was investigated. METHODS: Fibril formation of highly pure, recombinant Abeta1-40 in the presence of distinct, preformed seeds in vitro was recorded with thioflavin T fluorescence, and distinct fibrillar structures were identified and distinguished by fluorescence spectroscopy and electron microscopy. RESULTS: We propagated the specific quaternary structure of Abeta1-40 E22Delta fibrils with wild-type Abeta1-40 over up to seven cycles of seeding and fibril elongation. As a result of a 10(7)-fold dilution of the initially present Abeta1-40 E22Delta seeds, the vast majority of fibrils formed after the seventh propagation cycle with Abeta1-40 did not contain a single molecule of Abeta1-40 E22Delta, but still retained the conformation of the initial Abeta1-40 E22Delta seeds. Increased critical concentrations of Abeta1-40 fibrils formed in the presence of Abeta1-40 E22Delta nuclei suggest that these fibrils are less stable than homologously seeded Abeta1-40 fibrils, consistent with a kinetically controlled mechanism of fibril formation. CONCLUSION: The propagation of a distinct Abeta fibril conformation over multiple cycles of seeded fibril growth demonstrates the basic ability of the Abeta peptide to form amyloid strains that in turn may cause phenotypes in Alzheimer's disease. PMID- 25300968 TI - Liberian man being treated for Ebola in Texas dies. PMID- 25300969 TI - Pharmacogenetics of etanercept: role of TNF-alpha gene polymorphisms in improving its efficacy. AB - INTRODUCTION: During the last decade, many new biological immune modulators have entered the market as new therapeutic principles. Biologics, including TNF-alpha inhibitors, are the new frontier in the treatment of immune-mediated or inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ankylosing spondylitis, systemic sclerosis, disseminated granuloma annulare, psoriasis and/or psoriatic arthritis. TNF-alpha inhibitors have demonstrated efficacy and are well tolerated in large, randomized, controlled clinical trials. However, a substantial proportion of patients do not respond to these agents and potential adverse drug reactions may be associated with its use. AREAS COVERED: Pharmacogenetics has the potential of increasing drug efficiency by identifying genetic factors responsible for lack of response or toxicities to TNF-alpha inhibitors. In this review, we analyze the influence of several polymorphisms upon the efficacy and safety of TNF-alpha inhibitors. EXPERT OPINION: Several polymorphisms have been proven to influence the response to etanercept. Among them, single nucleotide polymorphisms (SNPs) 308 G/G, -857 C/T, +489 GG and GA, HLA-DRB1-encoding SE (allele *0404 and allele *0101) favor the response to etanercept, whereas SNP -308 A/A and TNFR1A AA decrease the response. Large clinical studies are needed to confirm the relevance of these associations in order to tailor treatment and to decrease unnecessary toxicity. PMID- 25300970 TI - Incidence and risk factors for diffusion-weighted imaging (+) lesions after intracranial stenting and its relationship with symptomatic ischemic complications. AB - BACKGROUND AND PURPOSE: Little is known about high-signal lesions in magnetic resonance diffusion-weighted imaging (DWI [+]) after stenting for intracranial atherosclerotic stenosis. This study aimed to evaluate the incidence, distribution, risk factors, and clinical implications of DWI (+) after intracranial stenting. METHODS: A total of 123 patients (male:female=88:35, mean age, 64.1 years) with symptomatic intracranial atherosclerotic stenosis (mean stenosis, 76.1+/-7.7%) underwent both stenting and poststenting DWI. The incidence, distribution (embolic-alone versus stenosis-associated perforator/mixed), and risk factors of DWI (+) and its relationship with symptomatic ischemic complications (SIC, including stroke or transient ischemic attack) were retrospectively evaluated. RESULTS: Forty-three patients (35.0%) had DWI (+). Middle cerebral artery, smaller distal parent artery, and treatment related dissection were independent risk factors for DWI (+) (P<0.05). SIC occurred in 4 patients (3.3%), all of whom had DWI (+). Of the patients with DWI (+), neither the number nor the volume of DWI (+) differed significantly between SIC and asymptomatic patients: median number/patient, 3.5 (range, 2-11) versus 2.0 (range, 1-11) and median volume/patient, 329.8 mm(3) (range, 76-883.5 mm(3)) versus 119.5 mm(3) (range, 32.5-873.0 mm(3)). However, SIC occurred more frequently in the stenosis-associated perforator/mixed type (3/11, 27.3%) than in the embolic-alone type (1/32, 3.1%; P<0.05). CONCLUSIONS: The incidence of DWI (+) after intracranial stenting for intracranial atherosclerotic stenosis was 35.0%. Middle cerebral artery, smaller distal parent artery, and treatment related dissection were independent risk factors for DWI (+). SIC occurred more frequently in the stenosis-associated perforator/mixed type than in the embolic alone type. PMID- 25300971 TI - Ambient air pollution and stroke. PMID- 25300972 TI - Disparities in accessibility of certified primary stroke centers. AB - BACKGROUND AND PURPOSE: We examine whether the proportion of the US population with <=60 minute access to Primary Stroke Centers (PSCs) varies based on geographic and demographic factors. METHODS: Population level access to PSCs within 60 minutes was estimated using validated models of prehospital time accounting for critical prehospital time intervals and existing road networks. We examined the association between geographic factors, demographic factors, and access to care. Multivariable models quantified the association between demographics and PSC access for the entire United States and then stratified by urbanicity. RESULTS: Of the 309 million people in the United States, 65.8% had <=60 minute PSC access by ground ambulance (87% major cities, 59% minor cities, 9% suburbs, and 1% rural). PSC access was lower in stroke belt states (44% versus 69%). Non-whites were more likely to have access than whites (77% versus 62%), and Hispanics were more likely to have access than non-Hispanics (78% versus 64%). Demographics were not meaningfully associated with access in major cities or suburbs. In smaller cities, there was less access in areas with lower income, less education, more uninsured, more Medicare and Medicaid eligibles, lower healthcare utilization, and healthcare resources. CONCLUSIONS: There are significant geographic disparities in access to PSCs. Access is limited in nonurban areas. Despite the higher burden of cerebrovascular disease in stroke belt states, access to care is lower in these areas. Selecting demographic and healthcare factors is strongly associated with access to care in smaller cities, but not in other areas, including major cities. PMID- 25300973 TI - Comparative effectiveness of carotid revascularization therapies: evidence from a National Hospital Discharge Database. AB - BACKGROUND AND PURPOSE: Clinical equipoise of carotid revascularization therapies remains controversial. We sought to determine whether adverse outcomes after carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAS) were similar using propensity score-matched analysis of retrospective data from a large hospital discharge database. METHODS: All CEA and CAS cases were identified from the 2006 to 2011 Premier Perspective Database and subjected to 1:1 propensity score matching using 33 clinical covariates associated with carotid revascularization. A primary composite end point of peri- or postoperative mortality, stroke, or acute myocardial infarction and a modified composite end point excluding acute myocardial infarction were used to compare our findings with recent prospective controlled trials. Multivariate regression and Cox proportional hazard ratio survival analysis were performed to compare revascularization therapy outcomes. RESULTS: After 1:1 propensity score matching, 24 004 (12 002 CEA and CAS) asymptomatic and 3506 (1753 CEA and CAS) symptomatic procedures were included. The risk of the primary composite end point was significantly higher after CAS than CEA in both asymptomatic (odds ratio, 1.40 [1.19-1.65]; P<0.0001) and symptomatic (odds ratio=2.31 [1.78-3.00]; P<0.0001) presentations, irrespective of age (P=0.28) or sex (P=0.35). Similar findings were observed using the modified composite end point for both asymptomatic (odds ratio, 1.49 [1.25-1.78]; P<0.0001) and symptomatic (odds ratio, 3.02 [2.25-4.07]; P<0.0001) presentations. Acute myocardial infarction risk was not significantly different between revascularization therapies, regardless of clinical presentation (P=0.71 and 0.24). CONCLUSIONS: Among individuals undergoing carotid artery revascularization from a large sample of US hospitals, CAS was associated with higher risk of perioperative mortality, stroke, and unfavorable discharges compared with CEA for all ages and clinical presentations. PMID- 25300974 TI - Spot sign on 90-second delayed computed tomography angiography improves sensitivity for hematoma expansion and mortality: prospective study. AB - BACKGROUND AND PURPOSE: The computed tomography angiography (CTA) spot sign is a validated biomarker for poor outcome and hematoma expansion in intracerebral hemorrhage. The spot sign has proven to be a dynamic entity, with multimodal imaging proving to be of additional value. We investigated whether the addition of a 90-second delayed CTA acquisition would capture additional intracerebral hemorrhage patients with the spot sign and increase the sensitivity of the spot sign. METHODS: We prospectively enrolled consecutive intracerebral hemorrhage patients undergoing first pass and 90-second delayed CTA for 18 months at a single academic center. Univariate and multivariate logistic regression were performed to assess clinical and neuroimaging covariates for relationship with hematoma expansion and mortality. RESULTS: Sensitivity of the spot sign for hematoma expansion on first pass CTA was 55%, which increased to 64% if the spot sign was present on either CTA acquisition. In multivariate analysis the spot sign presence was associated with significant hematoma expansion: odds ratio, 17.7 (95% confidence interval, 3.7-84.2; P=0.0004), 8.3 (95% confidence interval, 2.0-33.4; P=0.004), and 12.0 (95% confidence interval, 2.9-50.5; P=0.0008) if present on first pass, delayed, or either CTA acquisition, respectively. Spot sign presence on either acquisitions was also significant for mortality. CONCLUSIONS: We demonstrate improved sensitivity for predicting hematoma expansion and poor outcome by adding a 90-second delayed CTA, which may enhance selection of patients who may benefit from hemostatic therapy. PMID- 25300975 TI - Guideline-directed low-density lipoprotein management in high-risk patients with ischemic stroke: findings from Get with the Guidelines-Stroke 2003 to 2012. AB - BACKGROUND AND PURPOSE: Limited information is available on stroke prevention in high-risk patients with preexisting cardiovascular disease. Our aim was to use admission low-density lipoprotein (LDL) values to evaluate differences in the attainment of National Cholesterol Education Program-Adult Treatment Panel III guidelines goals at the time of the index event in high-risk patients with stroke and preexisting cardio- or cerebrovascular disease. METHODS: Observational study, using data from the Get-With-The-Guidelines-Stroke Registry including 913 436 patients with an acute ischemic stroke or transient ischemic attack from April 2003 to September 2012. Participants were classified as high risk if they had history of transient ischemic attack (TIA), stroke (cardiovascular disease), and coronary artery disease (CAD). RESULTS: Of the 913 436 patients admitted with an acute stroke or TIA, 194 557 (21.3%) had previous stroke/TIA, 148 833 (16.3%) had previous CAD, and 88 605 (9.7%) had concomitant CAD and cardiovascular disease. Overall, only 68% of patients with stroke were at their preadmission National Cholesterol Education Program III guideline-recommended LDL target; 51.3% had LDL <100 mg/dL; and only 19.8% had LDL<70 mg/dL. Among those presenting with a recurrent stroke, >45% had LDL>100 mg/dL. When compared with patients with CAD, patients with previous TIA/stroke were less likely to have LDL<100 or <70 mg/dL. In multivariable analysis, older age, men, white race, lack of major vascular risk factors, previous use of cholesterol-lowering therapy, and care provided in larger hospitals were associated with meeting LDL targets on admission testing. CONCLUSIONS: Management of dyslipidemia in high-risk patients with preexistent CAD or stroke continues to be suboptimal. Only 1 in 5 patients with prior TIA/stroke had LDL levels <70 mg/dL. PMID- 25300976 TI - Lipids in high-risk patients presenting with ischemic stroke or transient ischemic attack: are we missing the target? PMID- 25300977 TI - Cilostazol decreases cerebral arterial pulsatility in patients with mild white matter hyperintensities: subgroup analysis from the Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study. AB - BACKGROUND: The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of the Transcranial Doppler (ECLIPse) study showed a significant decrease in the transcranial Doppler (TCD) pulsatility index (PI) with cilostazol treatment at 90 days after acute lacunar infarction. The aim of the present study was to perform a subgroup analysis of the ECLIPse study in order to explore the effect of cilostazol in acute lacunar infarction based on cerebral white matter hyperintensities (WMH) volume. METHODS: The ECLIPse study was a multicenter, randomized, double-blind, placebo-controlled trial that evaluated the difference between the efficacy of cilostazol and a placebo to reduce the PI in patients with acute lacunar infarction using serial TCD examinations. The primary outcome was changes in the PIs of the middle cerebral artery (MCA) and basilar artery at 14 and 90 days from the baseline TCD study. For this subgroup analysis, using semi-automated computerized software, the WMH volume was measured for those subjects for whom fluid-attenuated inversion recovery (FLAIR) images were available. RESULTS: Of the 203 patients in eight hospitals in the ECLIPse study, 130 participants from six hospitals were included in this subgroup analysis. Cilostazol was given to 63 patients (48.5%) and placebo to 67 patients (51.5%). All baseline characteristics were well balanced across the two groups, and there were no significant differences in these characteristics except in the changes of PI from the baseline to the 90-day point. There was a significant decrease of TCD PIs at 90-day study from baseline in the cilostazol group (p = 0.02). The mean WMH volume was 11.57 cm(3) (0.13 68.45, median 4.86) and the mean MCA PI was 0.95 (0.62-1.50). The changes in PIs from the baseline to 14 days and to 90 days were 0.09 (-0.21 to 0.33) and 0.10 ( 0.22 to 0.36). While there were no significant correlations between WMH volume and the changes in PIs, a trend of inverse correlation was observed between the WMH volume and the changes in PIs from the baseline to the 90-day point. For the subgroup analysis, the WMH volume was dichotomized based on its median value (4.90 cm(3)). Cilostazol decreased the TCD PIs significantly at the 90-day point in patients with WMH volumes <= 4.9 cm(3) (p = 0.002). Significant treatment effects were observed in the cilostazol group. CONCLUSIONS: This study showed that cilostazol decreased cerebral arterial pulsatility in patients with WMH. Our findings indicate the unique effect of cilostazol in small vessel disease (SVD), especially in patients with mild WMH changes. Further clinical trials focusing on WMH volume and clinical outcomes are required to assess the unique efficacy of cilostazol in SVD. PMID- 25300978 TI - Inborn errors of cytoplasmic triglyceride metabolism. AB - Triglyceride (TG) synthesis, storage, and degradation together constitute cytoplasmic TG metabolism (CTGM). CTGM is mostly studied in adipocytes, where starting from glycerol-3-phosphate and fatty acyl (FA)-coenzyme A (CoA), TGs are synthesized then stored in cytoplasmic lipid droplets. TG hydrolysis proceeds sequentially, producing FAs and glycerol. Several reactions of CTGM can be catalyzed by more than one enzyme, creating great potential for complex tissue specific physiology. In adipose tissue, CTGM provides FA as a systemic energy source during fasting and is related to obesity. Inborn errors and mouse models have demonstrated the importance of CTGM for non-adipose tissues, including skeletal muscle, myocardium and liver, because steatosis and dysfunction can occur. We discuss known inborn errors of CTGM, including deficiencies of: AGPAT2 (a form of generalized lipodystrophy), LPIN1 (childhood rhabdomyolysis), LPIN2 (an inflammatory condition, Majeed syndrome, described elsewhere in this issue), DGAT1 (protein loosing enteropathy), perilipin 1 (partial lipodystrophy), CGI-58 (gene ABHD5, neutral lipid storage disease (NLSD) with ichthyosis and "Jordan's anomaly" of vacuolated polymorphonuclear leukocytes), adipose triglyceride lipase (ATGL, gene PNPLA2, NLSD with myopathy, cardiomyopathy and Jordan's anomaly), hormone-sensitive lipase (HSL, gene LIPE, hypertriglyceridemia, and insulin resistance). Two inborn errors of glycerol metabolism are known: glycerol kinase (GK, causing pseudohypertriglyceridemia) and glycerol-3-phosphate dehydrogenase (GPD1, childhood hepatic steatosis). Mouse models often resemble human phenotypes but may diverge markedly. Inborn errors have been described for less than one third of CTGM enzymes, and new phenotypes may yet be identified. PMID- 25300979 TI - Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron. AB - Neurodegeneration with brain iron accumulation (NBIA) is a group of devastating and life threatening rare diseases. Adult and early-onset NBIA syndromes are inherited as X-chromosomal, autosomal dominant or recessive traits and several genes have been identified as responsible for these disorders. Among the identified disease genes, only two code for proteins directly involved in iron metabolism while the remaining NBIA genes encode proteins with a wide variety of functions ranging from fatty acid metabolism and autophagy to still unknown activities. It is becoming increasingly evident that many neurodegenerative diseases are associated with metabolic dysfunction that often involves altered lipid metabolism. This is not surprising since neurons have a peculiar and heterogeneous lipid composition critical for the development and correct functioning of the nervous system. This review will focus on specific NBIA forms, namely PKAN, CoPAN, PLAN, FAHN and MPAN, which display an interesting link between neurodegeneration and alteration of phospholipids and sphingolipids metabolism, mitochondrial morphology and membrane remodelling. PMID- 25300980 TI - Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: data from the Italian AIFA Anti-diabetics Monitoring Registry. AB - BACKGROUND AND AIMS: In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry. METHODS AND RESULTS: From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (>=75 years, n = 6125 cases), body mass index (BMI) (>=35 kg/m(2), n = 22,015), and metabolic control (HbA(1c) >= 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow up. HbA1c decreased on average by 0.9-1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors. CONCLUSIONS: In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials. PMID- 25300981 TI - A randomized trial comparing balloon kyphoplasty and vertebroplasty for vertebral compression fractures due to osteoporosis. AB - BACKGROUND AND PURPOSE: Several trials have compared vertebral augmentation with nonsurgical treatment for vertebral compression fractures. This trial compares the efficacy and safety of balloon kyphoplasty and vertebroplasty. MATERIALS AND METHODS: Patients with osteoporosis with 1-3 acute fractures (T5-L5) were randomized and treated with kyphoplasty (n = 191) or vertebroplasty (n = 190) and were not blinded to the treatment assignment. Twelve- and 24-month subsequent radiographic fracture incidence was the primary end point. Due to low enrollment and early withdrawals, the study was terminated with 404/1234 (32.7%) patients enrolled. RESULTS: The average age of patients was 75.6 years (77.4% female). Mean procedure duration was longer for kyphoplasty (40.0 versus 31.8 minutes, P < .001). At 12 months, 7.8% fewer patients with kyphoplasty (50/140 versus 57/131) had subsequent radiographic fracture, and there were 8.6% fewer at 24 months (54/110 versus 64/111). The results were not statistically significant (P > .21). When we used time to event for new clinical fractures, kyphoplasty approached statistical significance in longer fracture-free survival (Wilcoxon, P = .0596). Similar pain and function improvements were observed. CT demonstrated lower cement extravasation for kyphoplasty (157/214 versus 164/201 levels treated, P = .047). For kyphoplasty versus vertebroplasty, common adverse events within 30 postoperative days were procedural pain (12/191, 9/190), back pain (14/191, 28/190), and new vertebral fractures (9/191, 17/190); similar 2-year occurrence of device-related cement embolism (1/191, 1/190), procedural pain (3/191, 3/190), back pain (2/191, 3/190), and new vertebral fracture (2/191, 2/190) was observed. CONCLUSIONS: Kyphoplasty and vertebroplasty had similar long-term improvement in pain and disability with similar safety profiles and few device-related complications. Procedure duration was shorter with vertebroplasty. Kyphoplasty had fewer cement leakages and a trend toward longer fracture-free survival. PMID- 25300982 TI - Impact of model-based iterative reconstruction on image quality of contrast enhanced neck CT. AB - BACKGROUND AND PURPOSE: Improved image quality is clinically desired for contrast enhanced CT of the neck. We compared 30% adaptive statistical iterative reconstruction and model-based iterative reconstruction algorithms for the assessment of image quality of contrast-enhanced CT of the neck. MATERIALS AND METHODS: Neck contrast-enhanced CT data from 64 consecutive patients were reconstructed retrospectively by using 30% adaptive statistical iterative reconstruction and model-based iterative reconstruction. Objective image quality was assessed by comparing SNR, contrast-to-noise ratio, and background noise at levels 1 (mandible) and 2 (superior mediastinum). Two independent blinded readers subjectively graded the image quality on a scale of 1-5, (grade 5 = excellent image quality without artifacts and grade 1 = nondiagnostic image quality with significant artifacts). The percentage of agreement and disagreement between the 2 readers was assessed. RESULTS: Compared with 30% adaptive statistical iterative reconstruction, model-based iterative reconstruction significantly improved the SNR and contrast-to-noise ratio at levels 1 and 2. Model-based iterative reconstruction also decreased background noise at level 1 (P = .016), though there was no difference at level 2 (P = .61). Model-based iterative reconstruction was scored higher than 30% adaptive statistical iterative reconstruction by both reviewers at the nasopharynx (P < .001) and oropharynx (P < .001) and for overall image quality (P < .001) and was scored lower at the vocal cords (P < .001) and sternoclavicular junction (P < .001), due to artifacts related to thyroid shielding that were specific for model-based iterative reconstruction. CONCLUSIONS: Model-based iterative reconstruction offers improved subjective and objective image quality as evidenced by a higher SNR and contrast to-noise ratio and lower background noise within the same dataset for contrast enhanced neck CT. Model-based iterative reconstruction has the potential to reduce the radiation dose while maintaining the image quality, with a minor downside being prominent artifacts related to thyroid shield use on model-based iterative reconstruction. PMID- 25300983 TI - Point-TAR: a useful index to follow-up coiled intracranial aneurysms? PMID- 25300984 TI - Are there differences between macrocyclic gadolinium contrast agents for brain tumor imaging? Results of a multicenter intraindividual crossover comparison of gadobutrol with gadoteridol (the TRUTH study). AB - BACKGROUND AND PURPOSE: Gadobutrol (Gadavist) and gadoteridol (ProHance) have similar macrocyclic molecular structures, but gadobutrol is formulated at a 2 fold higher (1 mol/L versus 0.5 mol/L) concentration. We sought to determine whether this difference impacts morphologic contrast-enhanced MR imaging. MATERIALS AND METHODS: Two hundred twenty-nine adult patients with suspected or known brain tumors underwent two 1.5T MR imaging examinations with gadoteridol or gadobutrol administered in randomized order at a dose of 0.1 mmol/kg of body weight. Imaging sequences and T1 postinjection timing were identical for both examinations. Three blinded readers evaluated images qualitatively and quantitatively for lesion detection and for accuracy in characterization of histologically confirmed brain tumors. Data were analyzed by using the Wilcoxon signed rank test, the McNemar test, and a mixed model. RESULTS: Two hundred nine patients successfully completed both examinations. No reader noted a significant qualitative or quantitative difference in lesion enhancement, extent, delineation, or internal morphology (P values = .69-1.00). One hundred thirty nine patients had at least 1 histologically confirmed brain lesion. Two readers found no difference in the detection of patients with lesions (133/139 versus 135/139, P = .317; 137/139 versus 136/139, P = .564), while 1 reader found minimal differences in favor of gadoteridol (136/139 versus 132/139, P = .046). Similar findings were noted for the number of lesions detected and characterization of tumors (malignant/benign). Three-reader agreement for characterization was similar for gadobutrol (66.4% [kappa = 0.43]) versus gadoteridol (70.3% [kappa = 0.45]). There were no significant differences in the incidence of adverse events (P = .199). CONCLUSIONS: Gadoteridol and gadobutrol at 0.1 mmol/kg of body weight provide similar information for visualization and diagnosis of brain lesions. The 2-fold higher gadolinium concentration of gadobutrol provides no benefit for routine morphologic imaging. PMID- 25300985 TI - Diffusivity measurements differentiate benign from malignant lesions in patients with peripheral neuropathy or plexopathy. AB - BACKGROUND AND PURPOSE: Peripheral nerve disorders caused by benign and malignant primary nerve sheath tumors, infiltration or compression of nerves by metastatic disease, and postradiation neuritis demonstrate overlapping features on conventional MR imaging but require vastly different therapeutic approaches. We characterize and compare diffusivities of peripheral nerve lesions in patients undergoing MR neurography for peripheral neuropathy or brachial or lumbosacral plexopathy. MATERIALS AND METHODS: Twenty-three patients, referred for MR neurography at our institution between 2003 and 2009 for a peripheral mononeuropathy or brachial or lumbosacral plexopathy and whose examinations included DWI, received a definitive diagnosis, based on biopsy results or clinical and imaging follow-up, for a masslike or infiltrative peripheral nerve or plexus lesion suspicious for tumor. Mean ADC values were determined within each lesion and compared across 3 groups (benign lesions, malignant lesions, and postradiation changes). RESULTS: Both ANOVA and Kruskal-Wallis tests demonstrated a statistically significant difference in ADC values across the 3 groups (P = .000023, P = .00056, respectively). Post hoc pair-wise comparisons showed that the ADC within malignant tumors differed significantly from that within benign tumors and postradiation changes. ADC within benign tumors and postradiation changes did not differ significantly from each other. CONCLUSIONS: DWI may be highly effective for the differentiation of benign from malignant peripheral nerve masslike or infiltrative lesions. PMID- 25300986 TI - Usefulness of subtraction of 3D T2WI-DRIVE from contrast-enhanced 3D T1WI: preoperative evaluations of the neurovascular anatomy of patients with neurovascular compression syndrome. AB - BACKGROUND AND PURPOSE: High-resolution 3D MR cisternography techniques such as 3D T2WI-driven equilibrium radiofrequency reset pulse (DRIVE) are used preoperatively to assess neurovascular anatomy in patients with neurovascular compression syndrome, but contrast between vessels and cranial nerves at the point of neurovascular contact is limited. The postprocessing technique subtraction of 3D T2WI-driven equilibrium radiofrequency reset pulse from contrast-enhanced 3D T1WI (sDRICE) provides both high spatial resolution and excellent contrast in depicting the neurovascular contact. We evaluated the usefulness of sDRICE compared with 3D T2WI-DRIVE. MATERIALS AND METHODS: Twelve patients who underwent microvascular decompression for hemifacial spasm or trigeminal neuralgia were examined preoperatively with 3D T2WI-DRIVE and sDRICE. Two neuroradiologists retrospectively analyzed and scored lesion conspicuity, defined as the ease of discrimination between offending vessels and compressed nerves or the brain stem at the neurovascular contact. They also quantitatively analyzed the contrast and contrast-to-noise ratio at the neurovascular contact. RESULTS: The lesion conspicuity scores of sDRICE images were significantly higher than those of 3D T2WI-DRIVE for all 12 patients (P = .006) and the 6 cases of hemifacial spasm (P = .023) but were not significantly higher in the 6 trigeminal neuralgia cases alone (P = .102). For all 12 patients, the contrast-to-noise ratio between the offending vessels and the brain stem and between the vessels and nerves on sDRICE images was significantly higher than that on 3D T2WI-DRIVE (P = .003 and P = .007, respectively). Among these structures, the contrast values were also significantly higher on the sDRICE than on the 3D T2WI-DRIVE (P < .001) images. CONCLUSIONS: The postprocessing technique sDRICE is useful to evaluate neurovascular anatomy and to improve contrast and the contrast-to-noise ratio in patients with neurovascular compression syndrome. PMID- 25300987 TI - Congenital segmental spinal muscular atrophy: a case report. AB - Spinal muscular atrophies are genetic disorders in which anterior horn cells in the spinal cord and motor nuclei of the brainstem are progressively lost. We present a patient with arthrogryposis due to congenital spinal muscular atrophy predominantly affecting the upper limbs. Spinal muscular atrophies with onset at birth may be a cause of arthrogryposis. Localized forms of neurogenic arthrogryposis have been divided into cervical and caudal forms. Our case is similar to the cases described by Hageman et al (J Neurol Neurosurg Psychiatry 1993;56:365-368): severe symmetric lower motor neuron deficit in the upper extremities at the time of birth, no history of injury to the cervical spinal cord or the brachial plexus during delivery, and severe muscle wasting suggesting chronic denervation in utero. Because there was improvement of our patient's situation, her disease was also possibly nonprogressive and sporadic. To our knowledge, this is the first reported case of a Turkish patient with congenital cervical spinal muscular atrophy. Congenital cervical spinal muscular atrophy affecting predominantly the upper limbs is a relatively rare form of motor neuron disease and should be considered in the differential diagnosis of infants with congenital contractures and severe muscle weakness by wasting mainly confined to the upper limbs. PMID- 25300988 TI - Sudden infant death syndrome, sleep, and seizures. AB - WORKING HYPOTHESIS: benign febrile seizures seen in 7% of infants before 6 months play a role in the terminal pathway in a subset of sudden infant death syndrome victims. Supporting evidence: (1) lack of 5-hydroxitryptamine, one consistent finding in sudden infant death syndrome that Kinney et al coined a developmental serotonopathy, is consistent with risk for seizures. (2) Non-rapid eye movement sleep increasing during the age of highest risk for sudden infant death syndrome facilitates some seizures (seizure gate). (3) Sudden unexpected death in epilepsy is associated with severe hypoxemia and hypercapnia during postictal generalized electroencephalographic (EEG) suppression. In toddlers, sudden unexplained deaths are associated with hippocampal abnormalities and some seizures. (4) The sudden nature of both deaths warrants an exploration of similarities in the terminal pathway. Moreover, sudden infant death syndrome, febrile seizures, sudden unexplained death in childhood, and sudden unexpected death in epilepsy share some of the following risk factors: prone sleeping, infections, hyperthermia, preterm birth, male gender, maternal smoking, and mutations in genes that regulate sodium channels. State-of-the-art molecular studies can be exploited to test this hypothesis. PMID- 25300989 TI - Inter- and intrarater reliability of ulna variance versus lunate subsidence measurements in Madelung deformity. AB - PURPOSE: To assess inter- and intrarater reliability of both ulna variance and lunate subsidence measurement methods in a large consecutive series of children with Madelung deformity. METHODS: Ulnar variance and lunate subsidence were measured on 41 standard anteroposterior wrist radiographs from 31 patients with Madelung deformity. The patients had a mean age of 13 years (range, 5-25) at the time of presentation. Two pediatric orthopedic hand/upper limb surgeons evaluated all radiographs twice in a 4-week interval using standard digital imaging software. Intraclass correlation coefficients (ICCs) were calculated for inter- and intrarater reliability, and results were reported using the Landis and Koch criteria. RESULTS: The interrater ICC for the ulna variance measurements was substantial, and for the lunate subsidence almost perfect. The intrarater ICC for ulna variance was substantial for both raters. In contrast, the intrarater ICC for lunate subsidence was almost perfect for both raters. CONCLUSIONS: Measurement of lunate subsidence showed both superior interrater and intrarater reliability compared with the ulnar variance method. Whenever relative ulna length is assessed in children and adolescents with Madelung deformity, the lunate subsidence should be the preferred method to characterize deformity. PMID- 25300990 TI - Comparison of transposition techniques to reduce gap associated with high ulnar nerve lesions. AB - PURPOSE: To determine in a cadaveric model which of 3 anterior transposition techniques allows for maximum gap reduction for high ulnar nerve lesions. METHODS: Six fresh-frozen human adult upper extremity cadaveric transhumeral specimens were used. We anchored the ulnar nerve to bone 10 cm proximal and distal to the medial epicondyle along its exact course while keeping the elbow in 30 degrees flexion as the baseline measurement. We then used a thick suture to mimic and measure the exact course of the nerve between the pins in varying elbow positions. The nerve was then transposed first subcutaneously, then intramuscularly, and then submuscularly while taking exact measurements of the distance the nerve had to travel in varying degrees of elbow flexion for each transposition method. We performed comparative analysis to analyze gap reduction with respect to transposition method and elbow position. RESULTS: Transposing the ulnar nerve reduced the repair gap required to cross the elbow regardless of transposition technique. When comparing individual techniques, however, the greatest gap reduction was achieved by intramuscular, followed by submuscular and finally subcutaneous transposition. A maximum gap reduction of 25 mm (average, 23 mm) was achieved using intramuscular transposition with the elbow in 90 degrees flexion. Subcutaneous transposition actually increased the repair gap when the elbow was in an extended position. CONCLUSIONS: An intramuscular transposition with the elbow in 90 degrees flexion provided the best gap reduction. However, post-neurorrhaphy mobilization may compromise repair site integrity and vascularity if elbow flexion is required to achieve a primary repair, and these factors should be considered carefully when planning treatment. CLINICAL RELEVANCE: This study provides guidance on techniques to reduce nerve gap for primary repair of the ulnar nerve at the elbow using transposition and elbow flexion. PMID- 25300991 TI - Camitz tendon transfer using flexor retinaculum as a pulley in advanced carpal tunnel syndrome. AB - PURPOSE: To report the outcomes of modified Camitz abductor plasty using the released flexor retinaculum as a pulley in patients with advanced carpal tunnel syndrome. METHODS: A retrospective review of 46 hands in 43 patients who underwent modified Camitz abductor plasty was performed. Active palmar abduction of thumb and pulp pinch strength were assessed. Patient-reported outcome measures were assessed using the Disabilities of the Arm, Shoulder, and Hand and Carpal Tunnel Syndrome instrument. As an electrophysiological assessment, compound muscle action potential (CMAP) from abductor pollicis brevis (APB) was investigated. RESULTS: At 3 months, active palmar abduction of thumb and pulp pinch strength significantly improved. Although pulp pinch strength further improved, active abduction of thumb did not improve at the final follow-up. Both the patient-reported outcome measures improved at 3 months and further improved at final follow-up. Approximately 75% of improved scores were obtained at the first 3 months after surgery and the balance of improved scores (25%) was obtained by the time of final follow-up. Useful recovery of postoperative APB CMAP (amplitude > 1.8 mV) was obtained in 3 hands (7%) at 3 months after surgery and in 23 hands (50%) at final follow-up. There was no statistical significance of the postoperative results including active palmar abduction of thumb and improvement of patient-reported outcome measures at final follow-up between the hands with useful recovery of postoperative APB-CMAP and the hands without it. CONCLUSIONS: Modified Camitz abductor plasty benefitted the early improvement of activity of daily living in patients with advanced carpal tunnel syndrome. It acted not only as an internal orthosis in patients who eventually recovered thenar muscle function but also as the sole palmar abductor of the thumb in patients who failed to recover useful thenar muscle function. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25300992 TI - Dry wrist arthroscopy. PMID- 25300993 TI - Gamekeeper's thumb--a treatment-oriented magnetic resonance imaging classification. AB - PURPOSE: To investigate by magnetic resonance imaging the degree of ulnar collateral ligament (UCL) displacement in order to create a simple classification to aid in determining which UCL injuries require surgery. METHODS: We evaluated 43 cases of UCL injury with a dedicated extremity magnetic resonance imaging and measured the degree of ligament displacement. This was correlated to clinical outcome with planned surgical intervention reserved for patients with a Stener lesion. By collating results we could generate 4 types of injury based on the appearances of the UCL. RESULTS: Partial and minimally displaced UCL tears (type 1) and tears displaced less than 3 mm (type 2) typically healed by immobilization alone, whereas 90% of tears displaced more than 3 mm (type 3) failed immobilization and required surgery as did all of those with a Stener lesion (type 4). CONCLUSIONS: Our 4-stage, treatment-oriented classification of thumb UCL injury is based on the degree of UCL displacement in, with correlation with the likelihood of success with either immobilization or operative intervention. Tears of the UCL with more than 3 mm of displacement are likely to require operative repair even in the absence of a true Stener lesion. PMID- 25300994 TI - On the electron affinity of cytosine in bulk water and at hydrophobic aqueous interfaces. AB - In the past one possible mechanism of DNA damage in bulk water has been attributed to the presence of hydrated electrons in water. Recently, one important property of hydrated electrons, namely their binding energy, was reported to be smaller at hydrophobic interfaces than in bulk aqueous solution. This possibly opens up new reaction possibilities with different solutes such as the DNA at hydrophobic, aqueous interfaces. Here, we use QM/MM molecular dynamics simulation to study how the molecular environment at the vacuum-water interface and in the bulk alters the electron affinity of cytosine being a characteristic part of the DNA. The electron affinity at the interface is closer to the corresponding binding energy of the partially hydrated electron. The increased energy resonance makes the electron capture process more probable and suggests that hydrated electrons at hydrophobic interfaces may be more reactive than the fully hydrated ones. Additionally, we found that the relaxation of the anionic form after electron attachment also induces a proton transfer from the surrounding solvent that was confirmed by comparison with the experimental reduction potential. PMID- 25300995 TI - Multiscale molecular dynamics simulations of sodium dodecyl sulfate micelles: from coarse-grained to all-atom resolution. AB - Sodium dodecyl sulfate (SDS) is a well-known anionic detergent widely used in both experimental and theoretical investigations. Many molecular dynamics (MD) simulation have been performed on the SDS molecule at coarse-grained (CG), united atom (UA), and all-atom (AA) resolutions. However, these simulations are usually based on general parameters determined from large sets of molecules, and as a result, peculiar molecular specificities are often poorly represented. In addition, the parameters (ideal bond lengths, angles, dihedrals and charge distribution) differ according to the resolution, highlighting a lack of coherence. We therefore propose a new set of parameters for CG, UA, and AA resolutions based on a high quantum mechanics (QM) level optimization of the detergent structure and the charge distribution. For the first time, QM-optimized parameters were directly applied to build the AA, UA, and CG model of the SDS molecule, leading to a more coherent description. As a test case, MD simulations were then performed on SDS preformed micelles as previous experimental and theoretical investigations allow direct comparison with our new sets of parameters. While all three models yield similar macromolecular properties (size, shape, and accessible surface) perfectly matching previous results, the attribution of more coherent parameters to SDS enables the description of the specific interactions inside and outside the micelle. These more consistent parameters can now be used to accurately describe new multi-scale systems involving the SDS molecule. PMID- 25300996 TI - The activity of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in the sera of patients with brain cancer. AB - Human brain tissue contains various alcohol dehydrogenase (ADH) isoenzymes and possess also aldehyde dehydrogenase (ALDH) activity. In our last experiments we have shown that ADH and ALDH are present also in the brain tumour cells. Moreover the activities of total ADH and class I isoenzymes were significantly higher in cancer tissue than healthy cells. It can suggests that these changes may be reflected by enzyme activity in the serum of patients with brain cancer. Serum samples were taken for routine biochemical investigation from 62 patients suffering from brain cancer (36 glioblastoma, 26 meningioma). For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, the fluorometric methods were used. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. A statistically significant increase of class I alcohol dehydrogenase isoenzymes was found in the sera of patients with brain cancer. The median activity of this class isoenzyme in the patients group increased about 24 % in the comparison to the control level. The total alcohol dehydrogenase activity was also significantly higher (26 %) among patients with brain tumour than healthy ones. The activities of other tested ADH isoenzymes and total ALDH were unchanged. The increase of the activity of total ADH and class I alcohol dehydrogenase isoenzyme in the sera of patients with brain cancer seems to be caused by the release of this isoenzyme from tumour's cells. PMID- 25300997 TI - Upregulated expression of human alpha-defensins 1, 2 and 3 in hypercholesteremia and its relationship with serum lipid levels. AB - Human alpha-defensins are natural antimicrobial peptides of neutrophils evolved in host defense reactions and circulating nonstressed alpha-defensins may be associated with serum lipid levels. The aim of this work was to examine whether the expression of alpha-defensins 1, 2 and 3 genes are changed and whether this changes are reversed following treatment in patients with hypercholesteremia. A total of 40 individuals of hypercholesteremia group were studied, compared with 40 individuals of normal control group. Protein levels and gene expression levels of alpha-defensins 1, 2 and 3 were significantly higher in patients with hypercholesteremia compared with subjects in normal control group. In patients with hypercholesteremia, protein levels of alpha-defensins 1, 2 and 3 correlated positively with the levels of total cholesterol and low-density lipoprotein cholesterol. Protein levels and gene expression levels of alpha-defensins 1, 2 and 3 were decreased significantly after a treatment with atorvastatin calcium 20mg daily compared with the patients before the treatment. Our results suggest that the expression of alpha-defensins 1, 2 and 3 genes is involved in dyslipidemia in patients with hypercholesteremia. PMID- 25300998 TI - Intestine-derived Clostridium leptum induces murine tolerogenic dendritic cells and regulatory T cells in vitro. AB - Patients with autoimmune and allergic diseases frequently present with reduced numbers and functionally impaired regulatory T cells (Tregs) and/or tolerogenic dendritic cells (tDCs). tDC-mediated regulation of Treg proliferation (numbers) and activation is crucial to establishing and maintaining an appropriate level of immune tolerance. Colonic colonization of Clostridium spp. is associated with accumulation of Tregs, which inhibits development of inflammatory lesions. To investigate whether infection with the Clostridium leptum sp. can specifically induce Tregs and/or tDCs bone marrow-derived dendritic cells were cultured in the presence or absence of C. leptum then co-cultured with CD4(+)CD25(-) T cells or not. Changes in tDC numbers, Treg numbers, percentages of T cell subsets, and expression of cytokines related to Tregs (IL-10 and transforming growth factor beta (TGF-beta1)), DCs (IL-12p40 and IL-6) and effector T cells (IFN-gamma, IL-4, IL-5, IL-13, and IL-17A) were measured. In the co-culture system, C. leptum stimulated tDCs were able to increase the percentage and total number of Tregs attenuate activation of T helper cells (Th1, Th2, and Th17), and decrease the amount of secreted IL-4, IL-5, IL-13, IFN-gamma and IL-17A. Thus, C. leptum exposure can induce the tDC-mediated stimulation of Tregs while disrupting the immune inflammatory response mediated by Th1, Th2 and Th17 cells. PMID- 25300999 TI - Impact of alloimmune T cell responses on hepatitis C virus replication in liver transplant recipients. AB - We investigated the influence of alloimmune T cell responses on hepatitis C virus (HCV) replication in HCV-infected patients after liver transplantation (LT). To monitor the immune-status in 27 HCV-infected LT recipients, we routinely performed mixed lymphocyte reaction (MLR) assays within 4 weeks after LT. HCV RNA titers in most patients fluctuated in inverse proportion to the stimulation index (SI) of anti-donor reactive T cells early after LT. Two weeks after LT, recipients with high HCV RNA titers (>1000 KIU/mL) displayed a significantly lower SI for anti-donor reactive T cells than recipients with low HCV RNA titers did (<1000 KIU/mL). An in vitro transwell assay mimicking the anatomical features of the interaction between HCV-infected hepatocytes and alloreactive T cells in allograft livers demonstrated that interferon (IFN)-gamma was necessary to suppress HCV replication. This study proves the significant impact of alloimmune T cell responses on HCV replication in HCV-infected LT recipients. PMID- 25301000 TI - 10th World IHEA and ECHE Joint Congress: health economics in the age of longevity. AB - The 10th consecutive World Health Economics conference was organized jointly by International Health Economics Association and European Conference on Health Economics Association and took place at The Trinity College, Dublin, Ireland in July 2014. It has attracted broad participation from the global professional community devoted to health economics teaching,research and policy applications. It has provided a forum for lively discussion on hot contemporary issues such as health expenditure projections, reimbursement regulations,health technology assessment, universal insurance coverage, demand and supply of hospital services, prosperity diseases, population aging and many others. The high-profile debate fostered by this meeting is likely to inspire further methodological advances worldwide and spreading of evidence-based policy practice from OECD towards emerging markets. PMID- 25301001 TI - Optical spectrum of bottom-up graphene nanoribbons: towards efficient atom-thick excitonic solar cells. AB - Recently, atomically well-defined cove-shaped graphene nanoribbons have been obtained using bottom-up synthesis. These nanoribbons have an optical gap in the visible range of the spectrum which make them candidates for donor materials in photovoltaic devices. From the atomistic point of view, their electronic and optical properties are not clearly understood. Therefore, in this work we carry out ab-initio density functional theory calculations combine with many-body perturbation formalism to study their electronic and optical properties. Through the comparison with experimental measurements, we show that an accurate description of the nanoribbon's optical properties requires the inclusion of electron-hole correlation effects. The energy, binding energy and the corresponding excitonic transitions involved are analyzed. We found that in contrast to zigzag graphene nanoribbons, the excitonic peaks in the absorption spectrum are a consequence of a group of transitions involving the first and second conduction and valence bands. Finally, we estimate some relevant optical properties that strengthen the potential of these nanoribbons for acting as a donor materials in photovoltaic. PMID- 25301002 TI - Serum chemokine ligand 5 (CCL5/RANTES) level might be utilized as a predictive marker of tumor behavior and disease prognosis in patients with gastric adenocarcinoma. AB - PURPOSE: Gastric cancer is the second leading cause of cancer-related deaths worldwide and the most common gastrointestinal cancer in Iran. Chemokine ligand 5 (CCL5/RANTES) is one of the most potent angiogenic factors that plays an important role in tumor growth, invasion, and metastasis. We aimed to assess the serum level of CCL5 in patients with gastric adenocarcinoma and its relation with histological grade and tumor stage, as well as the disease prognosis. METHODS: Seventy-four patients with gastric adenocarcinoma that had undergone gastrectomy and 96 non-tumoral cases in which gastric cancer was ruled out by gastroscopy and biopsy were enrolled. Demographic and epidemiological characteristics and patient survival data were reviewed. Histological type, grade, and tumor stage (TNM) were determined by a single expert pathologist. Helicobacter pylori infection status and CCL5 serum level were measured by ELISA. Data were analyzed using SPSS software version 16. RESULTS: Patients with gastric adenocarcinoma had significantly higher serum CCL5 level compared with control group (P < .001). Higher serum CCL5 levels were associated with lower histological differentiation (P < .001), higher depth of tumor invasion (P = .022), more frequent lymph nodes involvement (P = .028), and advanced tumor stage (P = .002). The overall survival of patients with CCL5 levels higher than 70,671 pg/ml was significantly lower than those with lower than this cutoff (P = .043). CONCLUSIONS: Serum CCL5 levels might be utilized as a predictive marker of tumor behavior and disease prognosis in patients with gastric adenocarcinoma. Further studies to assess tissue expression of CCL5 and its gene polymorphisms are suggested. PMID- 25301003 TI - Intra-abdominal hypertension--an experimental study of early effects on intra abdominal metabolism. AB - BACKGROUND: The main aim of this experimental study was to investigate the early effects of intra-abdominal hypertension (IAH) on intra-abdominal metabolism and intestinal mucosal blood flow to evaluate whether metabolites can serve as markers for organ dysfunction during IAH. METHODS: A swine model was used, and the animals were anesthetized and ventilated. Fifteen animals were subjected to IAH of 30 mm Hg for 4 hr by carbon dioxide insufflation. Seven animals served as controls. Hemodynamic data, arterial blood samples, and urine output were analyzed. Intraluminal laser Doppler flowmetry measured intestinal mucosal blood flow. Glucose, glycerol, lactate, and pyruvate concentrations and lactate-to pyruvate (l/p) ratio were measured intraperitoneally and intramurally in the small intestine and rectum using microdialysis. RESULTS: IAH lowered the abdominal perfusion pressure by 12-18 mm Hg, reduced the intestinal mucosal blood flow by 45-63%, and decreased urine output by 50-80%. In the intervention group, glycerol concentrations increased at all locations, pyruvate concentrations decreased, and the l/p ratio increased intraperitoneally and intramurally in the small intestine. Control animals remained metabolically stable. Glucose and lactate concentrations were only slightly affected or unchanged in both the groups. CONCLUSIONS: IAH reduces intestinal blood flow and urinary output and causes early metabolic changes, indicating a discrete shift toward anaerobic metabolism. Intraperitoneal microdialysis may be useful in the early detection of impaired organ dysfunction with metabolic consequences in IAH and abdominal compartment syndrome. PMID- 25301004 TI - Outcomes of femoropopliteal interventions for critical ischemia in the hemodialysis-dependent patient. AB - BACKGROUND: The number of patients maintained on hemodialysis is rising. There are limited data on the outcomes of femoropopliteal interventions, both open and endovascular, in this population. This report examines the anatomic and clinical outcomes in this population. METHODS: A database of patients undergoing open (OPEN) and endoluminal (ENDO) intervention for femoropopliteal disease (2000 to 2010) was retrospectively queried. Patients on hemodialysis with critical ischemia at the time of surgery or intervention were selected. Patients who underwent tibial bypass or had concomitant tibial interventions were excluded. Kaplan-Meier analyses were performed to assess time-dependent outcomes. Factor analyses were performed for time-dependent variables. RESULTS: One hundred sixty one hemodialysis-dependent patients underwent either OPEN or ENDO procedures for critical ischemia. Of these, 70 patients were treated with OPEN procedures and 91 with ENDO procedures. ENDO patients were more likely to present with a higher cardiac risk index (P = 0.0001), metabolic syndrome (P = 0.02), cerebrovascular disease (P = 0.01), and a dependent living status preoperatively (P = 0.04). ENDO patients presented with more rest pain and tissue loss (P = 0.03). OPEN patients presented with more advanced lesions (P = 0.04). Combined morbidity was higher in the OPEN group (P = 0.05). Cumulative patency (P = 0.04) and clinical efficacy (P = 0.05) were higher in the OPEN group compared to those in the ENDO group. CONCLUSIONS: Hemodialysis patients undergoing femoral-popliteal endovascular interventions for symptomatic disease have a low cumulative patency and clinical efficacy. Although open surgical revascularization has higher perioperative morbidity and a trend toward higher perioperative mortality, it provides a superior 5-year cumulative patency and clinical efficacy and should be considered in this population subgroup. PMID- 25301005 TI - Vascular smooth muscle cell proliferation depends on caveolin-1-regulated polyamine uptake. AB - Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis. PMID- 25301006 TI - Association between triglyceride and high-density lipoprotein cholesterol change following fibrate therapy. AB - BACKGROUND: Debate surrounding the role of fibrates has followed mixed outcomes from several randomised controlled trials. Subgroup analysis of even the negative trials reveals significant reduction in cardiovascular risk amongst patients with low HDL-C and high TG. We previously described factors associated with HDL-C change following fibrates. As fibrates influence both HDL-C and TG levels via their action on PPAR-alpha, we now wished to study TG change following fibrate therapy and any associations with baseline and change in HDL-C and TC levels. METHODS: Data was collected from case notes of patients started on fibrates (n=248) between 2002 and 2008 in the lipid clinics at Heart of England NHS Foundation Trust. Regression analyses were carried out to determine factors associated with changes in TG. RESULTS: Multiple regression analysis revealed that TG change was associated with pre-treatment TG (p<0.001) and TC levels (p=0.029). The association between TG change and pre-treatment TG remained significant when all factors including gender, concurrent statin treatment, diabetes and baseline HDL-C were entered into the regression model. Our previous study demonstrated significant post-fibrate HDL-C change in the group with baseline HDL-C values <1.0mmol/l. In our present study significant TG reduction was observed regardless of the baseline patient characteristics including HDL-C levels. CONCLUSIONS: The actions of fibrates are considered to be mediated via PPAR-alpha, but our data suggest that the effects on TG and HDL-C are different. Thus, the mechanisms mediating the changes of these lipids following fibrate treatment may vary. PMID- 25301007 TI - Impact of pharmaceutical care interventions on glycemic control and other health related clinical outcomes in patients with type 2 diabetes: Randomized controlled trial. AB - AIMS: The primary aim of this study was to evaluate the impact of pharmaceutical care interventions on glycemic control and other health-related clinical outcomes in patients with type 2 diabetes patients in Jordan. METHODS: A randomized controlled clinical trial was conducted on 106 patients with uncontrolled type 2 diabetes seeking care in the diabetes clinics at Jordan University Hospital. Patients were randomly allocated into control and intervention group. The intervention group patients received pharmaceutical care interventions developed by the clinical pharmacist in collaboration with the physician while the control group patients received usual care without clinical pharmacist's input. Fasting blood glucose and HbA1c were measured at the baseline, at three months, and six months intervals for both intervention and control groups. RESULTS: After the six months follow-up, mean of HbA1c and FBS of the patients in the intervention group decreased significantly compared to the control group patients (P<0.05). Also, the results indicated that mean scores of patients' knowledge about medications, knowledge about diabetes and adherence to medications and diabetes self-care activities of the patients in the intervention group increased significantly compared to the control group (P<0.05). CONCLUSIONS: This study demonstrated an improvement in HbA1c, FBS, and lipid profile, in addition to self-reported medication adherence, diabetes knowledge, and diabetes self-care activities in patients with type 2 diabetes who received pharmaceutical care interventions. The results suggest the benefits of integrating clinical pharmacist services in multidisciplinary healthcare team and diabetes management in Jordan. PMID- 25301009 TI - Metallo/clusto hybridized supramolecular polymers. AB - The introduction of metal centers to a supramolecular polymer system is an important approach to fabricate hybrid supramolecular polymers with synergistic properties between their inorganic and organic components, which is mainly realized through two strategies: one is the embedment of metal ions through metal ligand coordination to form metallo-supramolecular polymers (MSPs); the other is using metal-containing clusters as hybrid building blocks to prepare clusto supramolecular polymers (CSPs). The available paradigms of MSPs and CSPs not only exhibit the unique functions of metal centers but also hold the good processing ability and the stimuli-responsibility of dynamically bonded polymeric structures, thus representing a new class of hybrid soft materials. In this review, the development and recent progress of MSPs and CSPs are discussed in detail, including their structure design, synthetic procedures and related properties. Finally, challenges and potential areas in metal-containing supramolecular polymers are outlooked. PMID- 25301008 TI - Association of obesity with leukocyte count in obese individuals without metabolic syndrome. AB - AIMS: Inflammation in obesity is associated to insulin resistance (IR), hyperglycemia, hypertension and hyperlipidemia. Leukocytes play an important role in obesity associated inflammation. The initial factors that generate the inflammatory events in the obesity remain unclear. Therefore, the aim of this study was to determine the association of circulating leukocytes with clinical and biochemical parameters in obese individuals with clinical and biochemical parameters in normal range and with or without IR. METHODS: Nineteen obese non diabetic and 9 lean subjects were studied for serum levels of insulin, lipids, glycated hemoglobin, glycemia, for clinical parameters as HOMA-IR, arterial pressure and anthropometric parameters, and for leukocyte counts. Neutrophil/lymphocyte ratio (N/L) was calculated using the loge of leukocyte counts. Association between leukocytes and studied parameters was determined by Pearson's correlation. RESULTS: Two groups of obese individuals were observed: with high levels of insulin (with IR) and with normal levels (without IR). Positive correlations were observed between leukocyte and lymphocyte counts with body mass index and HOMA-IR and negative correlation with decreased HDL levels. Lymphocytes correlated with increased levels of insulin. Leukocytes and neutrophils correlated positively with increased visceral fat and liver steatosis. These associations were absent in the obese group without IR. N/L ratio did not show correlations with studied parameters. The leukocyte associations were mainly observed in obese individuals with IR. CONCLUSIONS: These data may represent initial leukocyte associations with morbidity features and define two different obese individuals that may evolve to the chronic inflammation observed in the obesity. PMID- 25301010 TI - Ommaya reservoir infection rate: a 6-year retrospective cohort study of Ommaya reservoir in pediatrics. AB - OBJECTIVES: In this study, we investigated Ommaya reservoir among pediatric patients, its infection rate, and the predisposing factors. We also investigated its role in the reduction of CSF protein. Finally, we explored other factors that would influence the decision to insert an Ommaya in comparison to external ventricular drainage. METHODS: This is a 6-year retrospective cohort study from a tertiary hospital in Saudi Arabia. RESULTS: In our study, females were 48.9% (n = 22) while males were 51.1% (n = 23). The mean age at insertion was 2.9 days, SD of 1.67 day. The mean weight at insertion was 0.98 kg, SD of 0.57 kg. The total duration of Ommaya days was 2523 days. The median duration of the reservoir was 21 days. The Ommaya reservoir infection rate was 6.6%. We found an association between organisms cultured from urinary tract and the organisms cultured from the CSF. We also found that CSF protein level is lower in non-infected reservoirs in comparison to those with infection. The number of Ommaya days and the number of days of infection could not explain the mean CSF protein. CONCLUSIONS: Ommaya reservoir has a low infection rate. Although CSF protein increased by infection, we failed to prove that Ommaya tapping provides a reduction in the CSF protein and, hence, reduction of shunt malfunctions thereafter. We conclude with expert opinions that take into account the psychological factors in addition to the clinical sense in choosing between Ommaya reservoir and external ventricular drainage (EVD). PMID- 25301011 TI - Effects of two football stud configurations on biomechanical characteristics of single-leg landing and cutting movements on infilled synthetic turf. AB - Multiple playing surfaces and footwear used in American football warrant a better understanding of relationship between different combinations of turf and footwear. The purpose of this study was to examine effects of shoe and stud types on ground reaction force (GRF) and ankle and knee kinematics of a 180 degrees cut and a single-leg 90 degrees land-cut on synthetic turf. Fourteen recreational football players performed five trials of the 180 degrees cut and 90 degrees land-cut in three shoe conditions: non-studded running shoe, and football shoe with natural and synthetic turf studs. Variables were analyzed with a 3 * 2 (shoe * movement) repeated measures analysis of variance (p < 0.05). Peak vertical GRF (p < 0.001) and loading rate (p < 0.001) were greater during 90 degrees land-cut than 180 degrees cut. For 180 degrees cut, natural turf studs produced smaller peak medial GRFs compared to synthetic turf studs and non studded shoe (p = 0.012). For land-cut, peak eversion velocity was reduced in running shoes compared to natural (p = 0.016) and synthetic (p = 0.002) turf studs. The 90 degrees land-cut movement resulted in greater peak vertical GRF and loading rate compared to the 180 degrees cut. Overall, increased GRFs in the 90 degrees land-cut movement may increase the chance of injury. PMID- 25301012 TI - Sealing of a dual feeding coronary artery perforation with homemade spring guidewire. AB - Coronary artery perforation (CAP) after percutaneous coronary intervention is a rare, but potentially life-threatening complication. The source of the bleeding is usually from one of the coronary arteries. In the era of chronic total occlusion technique, retrograde approach strategy sometimes is performed using collateral channels. When CAP occurs distal from the collateral channel, the source of bleeding can be from dual arteries, i.e., main and contra-lateral artery. Therefore, management of this bleeding should be intended to close the channel from both the arteries. We have successfully performed an emergent microcoil embolization in a patient with uncontrolled Ellis grade III perforation resulting cardiac tamponade which need pericardiocentesis. The perforation was sealed with the use of cutting the distal part of spring guidewire deployed at the septal collateral channel and fibered microcoil embolization deployed at the distal part of the other vessel. During 1 month follow-up, the patient was found to be well. In conclusion, CAP may result from two source of bleeding and should be kept into consideration. We successfully stopped the bleeding using the combination of fibered microcoil and tip of the spring guidewire. PMID- 25301013 TI - The mechanism of tautomerisation and geometric isomerisation in thioformic acid and its water complexes: exploring chemical pathways for water migration. AB - A systematic and automated search for chemical pathways of isomerisation between geometric and tautomeric forms of gas-phase thioformic acid (TFA) and its water complexes is performed using a global reaction route mapping (GRRM) method, and an uncovered pathway for cis-trans isomerisation in the thiol form of TFA has been explored through computations performed at CCSD(T)/6-311++G(2d,2p)//B3LYP/6 311++G(2d,2p) level of the coupled cluster and density functional theories. To explore the routes for water migration, a detailed analysis of complexes of TFA with a single-water molecule is presented. Notably, during the isomerisation process in TFA, a positive catalytic effect of water was observed that can arise either by the stabilization of the reactant and/or of the transition state through extensive hydrogen bonding. Interesting behavior of isomeric forms of TFA along the pathways analysed is revealed through the Gibbs free-energy change and its temperature-dependence. The cis form of TFA(thiol) in the complexes of TFA with a single-water molecule is found to be thermodynamically equally feasible as the trans form which though is known to be the most dominating among the isomeric forms of TFA. Besides these, various complexes of TFA with two-water molecules have also been explored to study the hydrogen-bonding interaction through natural bond-orbital (NBO) analysis. The complexes of TFA with two-water molecules have also been characterized using spectral features including vibrational frequency analysis, and the effect of complexation has been observed by noting frequency shift. PMID- 25301014 TI - Time to wave good-bye to phase scrambling: creating controlled scrambled images using diffeomorphic transformations. AB - To isolate the neural mechanisms associated with recognizing objects from those processing basic visual properties, control stimuli are required that contain the same perceptual properties as the objects but are unrecognizable. We demonstrate that conventional methods for generating control stimuli (phase scrambling, box scrambling, texture scrambling) yield poor controls because they dramatically distort the basic visual properties (e.g., spatial frequency, perceptual organization) to which even the earliest stages of visual processing are sensitive. We developed a new scrambling method, using a diffeomorphic transformation that preserves the basic perceptual properties of the image while removing meaning. We acquired perceptual ratings to determine the least amount of scrambling necessary to remove recognition. We hypothesized that our "diffeomorphic" images would produce neural activity at the earliest stages of the visual system that more closely matched activity in response to intact images relative to the other scrambling methods. To test this hypothesis, we used the HMAX computational model of object recognition and compared the simulated neural activity at the earliest stages of the visual system (layers S1, C1, and S2) between a set of 149 images scrambled using each distortion method to their intact version. We found that scrambled "diffeomorphed" images were indistinguishable to intact images in each layer of the model, but all of the other distortion methods yielded quite different patterns. Our results indicate that "diffeomorphed" images serve as more appropriate control stimuli in neuroimaging studies that aim to disentangle the representations of perceptual and semantic object properties. PMID- 25301015 TI - The sensory strength of voluntary visual imagery predicts visual working memory capacity. AB - How much we can actively hold in mind is severely limited and differs greatly from one person to the next. Why some individuals have greater capacities than others is largely unknown. Here, we investigated why such large variations in visual working memory (VWM) capacity might occur, by examining the relationship between visual working memory and visual mental imagery. To assess visual working memory capacity participants were required to remember the orientation of a number of Gabor patches and make subsequent judgments about relative changes in orientation. The sensory strength of voluntary imagery was measured using a previously documented binocular rivalry paradigm. Participants with greater imagery strength also had greater visual working memory capacity. However, they were no better on a verbal number working memory task. Introducing a uniform luminous background during the retention interval of the visual working memory task reduced memory capacity, but only for those with strong imagery. Likewise, for the good imagers increasing background luminance during imagery generation reduced its effect on subsequent binocular rivalry. Luminance increases did not affect any of the subgroups on the verbal number working memory task. Together, these results suggest that luminance was disrupting sensory mechanisms common to both visual working memory and imagery, and not a general working memory system. The disruptive selectivity of background luminance suggests that good imagers, unlike moderate or poor imagers, may use imagery as a mnemonic strategy to perform the visual working memory task. PMID- 25301016 TI - Dealing with delays does not transfer across sensorimotor tasks. AB - It is known that people can learn to deal with delays between their actions and the consequences of such actions. We wondered whether they do so by adjusting their anticipations about the sensory consequences of their actions or whether they simply learn to move in certain ways when performing specific tasks. To find out, we examined details of how people learn to intercept a moving target with a cursor that follows the hand with a delay and examined the transfer of learning between this task and various other tasks that require temporal precision. Subjects readily learned to intercept the moving target with the delayed cursor. The compensation for the delay generalized across modifications of the task, so subjects did not simply learn to move in a certain way in specific circumstances. The compensation did not generalize to completely different timing tasks, so subjects did not generally expect the consequences of their motor commands to be delayed. We conclude that people specifically learn to control the delayed visual consequences of their actions to perform certain tasks. PMID- 25301017 TI - Orientation-sensitivity to facial features explains the Thatcher illusion. AB - The Thatcher illusion provides a compelling example of the perceptual cost of face inversion. The Thatcher illusion is often thought to result from a disruption to the processing of spatial relations between face features. Here, we show the limitations of this account and instead demonstrate that the effect of inversion in the Thatcher illusion is better explained by a disruption to the processing of purely local facial features. Using a matching task, we found that participants were able to discriminate normal and Thatcherized versions of the same face when they were presented in an upright orientation, but not when the images were inverted. Next, we showed that the effect of inversion was also apparent when only the eye region or only the mouth region was visible. These results demonstrate that a key component of the Thatcher illusion is to be found in orientation-specific encoding of the expressive features (eyes and mouth) of the face. PMID- 25301018 TI - Impact of socioeconomic factors on informed decision making and treatment choice in patients with hip and knee OA. AB - It is unclear how socioeconomic (SES) status influences the effectiveness of shared decision making (SDM) tools. The purpose of this study was to assess the impact of SES on the utility of SDM tools among patients with hip and knee osteoarthritis (OA). We performed a secondary analysis of data from a randomized controlled trial of 123 patients with hip or knee OA. Higher education and higher income were independently associated with higher knowledge survey scores. Patients with private insurance were 2.7 times more likely than patients with Medicare to arrive at a decision after the initial office visit. Higher education was associated with lower odds of choosing surgery, even after adjusting for knowledge. Patient knowledge of their medical condition and treatment options varies with SES. PMID- 25301019 TI - Mouse neutrophils express functional umami taste receptor T1R1/T1R3. AB - Neutrophils play an important role in the initiation of innate immunity against infection and injury. Although many different types of G-protein coupled receptors are functionally expressed in neutrophils, no reports have demonstrated functional expression of umami taste receptor in these cells. We observed that mouse neutrophils express the umami taste receptor T1R1/T1R3 through RNA sequencing and quantitative RT-PCR analysis. Stimulation of mouse neutrophils with L-alanine or L-serine, which are ligands for the umami taste receptor, elicited not only ERK or p38 MAPK phosphorylation but also chemotactic migration. Moreover, addition of L-alanine or L-serine markedly reduced the production of several cytokines including TNF-alpha induced by lipopolysaccharide (LPS) through inhibition of NF-kappaB activity or STAT3 phosphorylation in neutrophils. Our findings demonstrate that neutrophils express the umami taste receptor, through which tastants stimulate neutrophils, resulting in chemotactic migration, and attenuation of LPS-induced inflammatory response. PMID- 25301021 TI - Providing care to people on social assistance: how dentists in Montreal, Canada, respond to organisational, biomedical, and financial challenges. AB - BACKGROUND: Dentists report facing difficulties and experiencing frustrations with people on social assistance, one of the social groups with the most dental needs. Scientists ignore how they deal with these difficulties and whether they are able to overcome them. Our objective was to understand how dentists deal with critical issues encountered with people on social assistance. METHODS: We conducted in-depth, semi-structured interviews with 33 dentists practicing in Montreal, Canada. The interview guides included questions on dentists' experiences with people on social assistance and potential strategies developed for this group of people. Analyses consisted of interview debriefing, transcript coding, and data interpretation. RESULTS: Dentists described strategies to resolve three critical issues: missed appointments (organisational issue); difficulty in performing non-covered treatments (biomedical issue); and low government fees (financial issue). With respect to missed appointments, dentists developed strategies to maximise attendance, such as motivating their patients, and to minimise the impact of non-attendance, like booking two people at the same time. With respect to biomedical and financial issues, dentists did not find any satisfactory solutions and considered that it was the government's duty to resolve them. Overall, dentists seem reluctant to exclude people on social assistance but develop solutions that may discriminate against them. CONCLUSIONS: The efforts and failures experienced by dentists with people on social assistance should encourage us to rethink how dental services are provided and financed. PMID- 25301020 TI - Role of Wnt signaling in fracture healing. AB - The Wnt signaling pathway is well known to play major roles in skeletal development and homeostasis. In certain aspects, fracture repair mimics the process of bone embryonic development. Thus, the importance of Wnt signaling in fracture healing has become more apparent in recent years. Here, we summarize recent research progress in the area, which may be conducive to the development of Wnt-based therapeutic strategies for bone repair. PMID- 25301022 TI - Postoperative quality of life in patients with progressive neuromuscular scoliosis and their parents. AB - BACKGROUND CONTEXT: The functional level of children with progressive neuromuscular disease is a major factor that affects the quality of life (QOL) of parents. However, only a few publications have reported changes in the QOL of parents after correctional spinal surgery. PURPOSE: The purpose was to compare changes in QOL for both patients and parents after spinal correctional surgery for better sitting balance and to analyze correlation among radiographic parameters, functional outcome, and QOL questionnaires. Finally, the QOL of patients and parents was compared with the population norm. STUDY DESIGN: This study is a retrospective analysis of prospectively gathered data. PATIENT SAMPLE: From 2008 to 2011, 58 patients who underwent correctional surgery for progressive neuromuscular scoliosis and their parents were enrolled. OUTCOME MEASURES: A Muscular Dystrophy Spine Questionnaire (MDSQ) and short-form questionnaire 36 (SF 36) were used. METHODS: The gathered functional outcome and QOL data using MDSQ and SF-36 for both enrolled patients and parents were compared preoperatively, postoperatively at 3 months, and at 1-year follow-up. RESULTS: Mean age was 15.0+/-4.1 years. Forty male and 18 female patients were enrolled. Mean follow-up was 38.4+/-13.7 months. Cobb angle was 61.5 degrees +/-23.5 degrees preoperatively, 39.0 degrees +/-20.1 degrees immediately postoperative, and 40.0 degrees +/-20.2 degrees at the final follow-up. Cobb angle, pelvic obliquity, and lumbar lordosis were significantly improved after surgery (p<.001). Among sitting-related questions, answers to questions 15 (sitting comfortably), 16 (change weight in wheelchair), 22 (sit all day), 24 (sit at table for meal), 26 (keep balance while sitting in wheelchair), and 27 (look good while sitting in wheelchair) were significantly improved after correctional surgery (p<.001). Regarding the SF-36 scales for patients, bodily pain and social functioning significantly improved postoperatively (p<.001). CONCLUSIONS: Muscular Dystrophy Spine Questionnaire results indicated that patients had significantly improved sitting balance-related outcomes, whereas the SF-36 indicated improvements only in bodily pain and social functioning scales. For parents, no SF-36 scales improved significantly postoperatively. Accordingly, improved sitting balance and QOL for neuromuscular scoliosis patients after surgery do not necessarily increase parent QOL. PMID- 25301023 TI - Epidural chronic inflammatory mass of the lumbar spine in a human immunodeficiency virus positive patient with a history of repeated epidural injections. PMID- 25301025 TI - [Percutaneous mechanical circulatory support: options and importance]. AB - In cases of low cardiac output and chronic cardiac failure despite conventional therapy, mechanical circulatory support may be the only option to ensure adequate organ perfusion and to save the life of the patient. In recent years, several conceptionally different methods of circulatory support have been developed for percutaneous application in interventional cardiology and intensive care. Indications range from elective use in complex cardiac interventions to long-term support as a bridge to recovery. As intra-aortic balloon pump support can no longer be considered for routine use in ischemic cardiogenic shock, micro-axial pumps for extracorporeal membrane oxygenation and extracorporeal life support systems (ECMO/ECLS) gain attractiveness due to a more convincing impact on the hemodynamics. However, an increasing level of support is paralleled by greater invasiveness and complexity of the systems. Due to a lack of larger comparative trials, the benefits and risks of adverse events must be balanced against those of conventional therapy with inotropes and largely on an individual basis. This review summarizes the options for percutaneous circulatory support with special consideration to applications in the catheter laboratory and intensive care units in internal medicine. PMID- 25301024 TI - Effects of acute exercise on markers of inflammation in pediatric chronic kidney disease: a pilot study. AB - BACKGROUND: Children and adolescents with chronic kidney disease (CKD) are chronically exposed to high levels of inflammation, placing them at an increased risk of secondary health complications. Regular exercise may represent an effective therapy to reduce inflammation. The aims of this pilot study were to determine the effects of acute exercise on inflammation and immune cell counts in CKD. METHODS: Nine children and adolescents (4 males) with CKD stages III-V performed a graded exercise test to determine peak oxygen uptake (VO2peak). Following a 10-min break, participants cycled for 20 min at 50 % of VO2peak. Blood samples were collected before and after the exercise period for the determination of complete blood counts, natural killer cells (NK(bright), NK(dim)) and circulating progenitor cell (CPC) counts, as well as interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) concentrations. RESULTS: Complete blood counts and NK(dim) cell and CPC counts were unchanged with exercise. Following exercise, NK(bright) cell counts increased (7.4 +/- 4.3 vs. 12.2 +/- 8.3 * 10(6) cells/L; p = 0.02), while trends were observed for an increase in IL-6 (2.1 +/- 2.2 vs. 2.7 +/- 2.6 pg/mL; p = 0.08), decrease in TNF alpha (4.5 +/- 1.2 vs. 4.2 +/- 1.0 pg/mL; p = 0.08) and an increase in the IL 6:TNF-alpha ratio (0.6 +/- 0.7 vs. 0.8 +/- 0.8; p = 0.07). CONCLUSIONS: Our findings suggest that acute exercise may create an anti-inflammatory environment in children and adolescents with CKD stages III-V. PMID- 25301026 TI - [Fever of unknown origin in 74-year-old multimorbid man]. AB - A 74-year-old multimorbid man was admitted with fever of unknown origin. Over time the fever ceased spontaneously. The patient developed signs of a right heart failure without evidence of a primarily cardiac pathogenesis and died of acute right heart failure. Miliary tuberculosis that had lead to pulmonary artery hypertension was diagnosed at autopsy. PMID- 25301027 TI - [Herbal medicines: when to use or not to use?]. AB - Herbal medicines are popular. It is frequently assumed that they are effective and safe. Sound knowledge of existing, or lacking, data on the efficacy and safety is required for advice and for the decision whether or not to use a particular herbal drug. Cochrane reviews are available for some herbal remedies. Most of them indicate either insufficient knowledge or weak or lacking efficacy. Numerous studies on interactions, some of which are clinically significant, for St. John's wort with conventional drugs are available. Overall, although knowledge about herbal drugs has grown in recent years, it is generally still unsatisfactory. The active recommendation to use an herbal drug is usually not advisable. However, a patient's request for a licensed herbal drug may be acceptable if there is no conventional concomitant comedication that is known or expected to interact, no contra-indication, and no other (conventional) treatment with better, or better known, benefit-risk ratio. PMID- 25301028 TI - Exploring the perceived met and unmet need of life-limited children, young people and families. AB - This article presents an original study commissioned by the UK charity, Together for Short Lives which explored children and young people up to 25 years of age with life-threatening/limiting conditions and their families. Using Appreciative Inquiry and framework analysis, qualitative work sought to explore perceived met and unmet needs of services and care. Fifty-one families were interviewed from one UK area, 18 of which were children/young people up to 25 years old. Findings indicated that children and their families felt medical/nursing needs were well met but provision was needed for broader financial, social and emotional support alongside more responsive specialist therapies. PMID- 25301029 TI - Sudden unexpected death in infancy: biological mechanisms. AB - Sudden unexpected death in infancy (SUDI) covers both explained and unexplained deaths. Unexplained cases or SIDS are likely to have multiple neural mechanisms contributing to the final event. The evidence ranges from subtle physiological signs related to autonomic control, to findings at autopsy of altered neurotransmitter systems, including the serotonergic system, a network that has an extensive homeostatic role in cardio-respiratory and thermoregulatory control. Processes may be altered by the vulnerability of the infant due to age, poor motor ability, or a genetic predisposition. The fatal event may occur in response to an environmental stress. A single final physiological route to death seems unlikely. An understanding of the reasons for explained SUDI also reminds us that a thorough investigation is required after each death occurs. PMID- 25301030 TI - Cardiac abnormalities and sudden infant death syndrome. AB - Many factors have been implicated in SIDS cases including environmental influences such as sleeping arrangements and smoking. Most recently, cardiac abnormalities have been hypothesised to play a role in some cases, particularly the primary genetic arrhythmogenic disorders such as familial long QT syndrome (LQTS). Both post-mortem and clinical studies of SIDS cases have provided supporting evidence for the involvement of cardiac genetic disorders in SIDS. This review provides a summary of this evidence focussing particularly on the primary hypothesis related to underlying familial LQTS. In addition, the current literature relating to other cardiac genetic conditions such as Brugada syndrome (BrS) and structural heart diseases such as hypertrophic cardiomyopathy (HCM) is briefly presented. Finally, the implications of a possible cardiac genetic cause of SIDS is discussed with reference to the need for genetic testing in SIDS cases and subsequent clinical and genetic testing in family members. PMID- 25301031 TI - Dispersal, group formation and kinship in the black-faced lion tamarin (Leontopithecus caissara). AB - We report on (i) new group formation, (ii) sex differences in dispersal and (iii) dispersal distance over 6 years for 3 social groups of the black-faced lion tamarin (Leontopithecus caissara) in the vicinity of Ariri, Sao Paulo state, Brazil. The groups were: Bina (monitored for 74 months), BM5 (52 months) and Teca (13 months). Each group was censused once a week and monitored for 3 days each month. Mating opportunities were found to be the incentive for young adult black faced lion tamarins to either disperse or remain in their kin group. Young adults show delayed dispersal that is related to the cooperative breeding system characteristic of the Callitrichidae and to a low population density which hinders the formation of new breeding pairs. Our findings suggest that in L. caissara (i) both sexes disperse, (ii) successful immigration is related to breeding opportunities in an existing group, (iii) female immigration motivates male emigration and the formation of new groups, and (iv) emigrants tend to form new groups close to their natal groups. These patterns of dispersal and formation of new groups are efficient because the species has been able to avoid loss of genetic diversity despite their small population size. PMID- 25301032 TI - Insecticide resistance and its underlying mechanisms in field populations of Aedes aegypti adults (Diptera: Culicidae) in Singapore. AB - BACKGROUND: In Singapore, dose-response bioassays of Aedes aegypti (L.) adults have been conducted, but the mechanisms underlying resistance to insecticides remain unclear. In this study, we evaluated insecticide resistance and its underlying mechanism in field populations of Ae. aegypti adults. METHODS: Seven populations of Ae. aegypti were collected from public residential areas and assays were conducted according to WHO guidelines to determine their susceptibility to several commonly used insecticides. RESULTS: Various levels of pyrethroid resistance (RR50 = 3.76 to 142.06-fold) and low levels of pirimiphos methyl resistance (RR50 = 1.01 to 1.51-fold) were detected. The insecticide susceptibility profile of Ae. aegypti adults was homogenous among the different study sites. Addition of the synergists piperonyl butoxide, S,S,S,-tributyl phosphorotrithioate, and triphenyl phosphate generally failed to enhance the toxicity of the insecticides investigated, suggesting an insignificant role of metabolic-based insecticide resistance and possible involvement of target site resistance. Further biochemical investigation of specific metabolic enzyme activities provided further evidence that detoxifying enzymes such as mono oxygenases, esterases, glutathione S-transferases and altered acethylcholinesterases generally did not contribute to the resistance observed. CONCLUSIONS: This study confirmed the presence of pyrethroid resistance among Ae. aegypti adults in Singapore and documented the early onset of organophosphate resistance. PMID- 25301033 TI - Microbial contamination of toothbrushes during treatment with multibracket appliances. AB - INTRODUCTION: It was aimed to assess the retention of caries-associated microorganisms on two different manual toothbrushes (conventional and tapered) and to evaluate the influence of multibracket appliances (MB) on the microbial contamination of the brush head. METHODS: 50 MB-patients and 50 subjects without MB received a toothbrush (elmex(r) interX medium short head or meridol(r)) plus toothpaste (elmex(r)) for exclusive use and an information sheet with standardised brushing instructions. After 14 days of regular tooth brushing, the brushes were collected and sluiced in Sputasol solution. The suspension was incubated on selective agar plates and the amount of Streptococcus mutans, lactobacilli and Candida albicans for each brush head was assessed. RESULTS: Regarding the retention of microorganisms, no differences could be detected between the two bristle designs. However, the amount of S. mutans was significantly higher on brushes used by MB-patients (p < 0.005) than on the brushes of subjects without MB. The number of Lactobacilli and C. albicans was minimal in all cases and below statistical evaluation. CONCLUSIONS: During treatment with MB appliances, toothbrushes were contaminated more intensely with S. mutans independent of bristle design. A more frequent replacement of toothbrushes may thus be recommended for patients undergoing MB-treatment. PMID- 25301034 TI - Encapsulation of large dye molecules in hierarchically superstructured metal organic frameworks. AB - Microporous metal-organic frameworks (MOFs) represent a new family of microporous materials, offering potential applications in gas separation and storage, catalysis, and membranes. The engineering of hierarchical superstructured MOFs, i.e., fabricating mesopores in microporous frameworks during the crystallization stage is expected to serve a myriad of applications for molecular adsorption, drug delivery, and catalysis. However, MOFs with mesopores are rarely studied because of the lack of a simple, effective way to construct mesoscale cavities in the structures. Here, we report the use of a perturbation-assisted nanofusion technique to construct hierarchically superstructured MOFs. In particular, the mesopores in the MOF structure enabled the confinement of large dye species, resulting in fluorescent MOF materials, which can serve as a new type of ratiometric luminescent sensors for typical volatile organic compounds. PMID- 25301035 TI - Cigarette smoking and albuminuria are associated with impaired arterial smooth muscle function in patients with type 2 diabetes mellitus: a FIELD substudy. AB - AIM: Impaired arterial function has been implicated in diabetes-related atherosclerosis, but its determinants in high-risk adults have not been well characterised. We investigated factors associated with impaired arterial function in adults with type 2 diabetes. METHODS: Flow-mediated dilatation (a marker of endothelial function) and dilator response to glyceryl trinitrate (to assess smooth muscle function) of the brachial artery were assessed at baseline in 193 patients with type 2 diabetes from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Traditional risk factors were assessed and a multivariable model was constructed to identify factors independently associated with impaired arterial function. RESULTS: Median age was 64 years (interquartile range, 58-69; 61% male) and duration of diabetes was 4 years (interquartile range, 2-9). Flow-mediated dilatation (3.06 +/- 0.25%, mean +/- SEM) was severely impaired but not significantly associated with other risk factors. Dilator responses to glyceryl trinitrate (10.56 +/- 0.52%) were significantly and independently impaired in past and present cigarette smokers (P = 0.005) and in subjects with increased urinary albumin/creatinine ratio (P = 0.01). CONCLUSIONS: In adults with type 2 diabetes and known or suspected atherosclerosis, arterial smooth muscle-dependent dilatation was shown to be significantly impaired in cigarette smokers and those with elevated urinary albumin levels. PMID- 25301037 TI - Re-evaluating cost effectiveness of universal meningitis vaccination (Bexsero) in England: modelling study. AB - OBJECTIVE: To use mathematical and economic models to predict the epidemiological and economic impact of vaccination with Bexsero, designed to protect against group B meningococcal disease, to help inform vaccine policy in the United Kingdom. DESIGN: Modelling study. SETTING: England. POPULATION: People aged 0-99. INTERVENTIONS: Incremental impact of introductory vaccine strategies simulated with a transmission dynamic model of meningococcal infection and vaccination including potential herd effects. Model parameters included recent evidence on the vaccine characteristics, disease burden, costs of care, litigation costs, and loss of quality of life from disease, including impacts on family and network members. The health impact of vaccination was assessed through cases averted and quality adjusted life years (QALYs) gained. MAIN OUTCOME MEASURES: Cases averted and cost per QALY gained through vaccination; programmes were deemed cost effective against a willingness to pay of L20,000 (?25,420, $32,677) per QALY gained from an NHS and personal and social services perspective. RESULTS: In the short term, case reduction is greatest with routine infant immunisation (26.3% of cases averted in the first five years). This strategy could be cost effective at L3 (?3.8, $4.9) a vaccine dose, given several favourable assumptions and the use of a quality of life adjustment factor. If the vaccine can disrupt meningococcal transmission more cases are prevented in the long term with an infant and adolescent combined programme (51.8% after 30 years), which could be cost effective at L4 a vaccine dose. Assuming the vaccine reduces acquisition by 30%, adolescent vaccination alone is the most favourable strategy economically, but takes more than 20 years to substantially reduce the number of cases. CONCLUSIONS: Routine infant vaccination is the most effective short term strategy and could be cost effective with a low vaccine price. Critically, if the vaccine reduces carriage acquisition in teenagers, the combination of infant and adolescent vaccination could result in substantial long term reductions in cases and be cost effective with competitive vaccine pricing. PMID- 25301038 TI - Permanent draft genome sequence of Bacillus flexus strain T6186-2, a multidrug resistant bacterium isolated from a deep-subsurface oil reservoir. AB - Previous studies suggest that antibiotic resistance genes have an ancient origin, which is not always linked to the use of antibiotics but can be enhanced by human activities. Bacillus flexus strain T6186-2 was isolated from the formation water sample of a deep-subsurface oil reservoir. Interestingly, antimicrobial susceptibility testing showed that this strain is susceptible to kanamycin, however, resistant to ampicillin, erythromycin, gentamicin, vancomycin, fosfomycin, fosmidomycin, tetracycline and teicoplanin. To explore our knowledge about the origins of antibiotic resistance genes (ARGs) in the relatively pristine environment, we sequenced the genome of B. flexus strain T6186-2 as a permanent draft. It represents the evidence for the existence of a reservoir of ARGs in nature among microbial populations from deep-subsurface oil reservoirs. PMID- 25301036 TI - Genetic ancestry influences asthma susceptibility and lung function among Latinos. AB - BACKGROUND: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. OBJECTIVE: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. METHODS: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. RESULTS: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 * 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 +/- 19 mL; P = 5.8 * 10(-5) and -83 +/- 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 +/- 21 mL; P = 2.7 * 10(-6) and -107 +/- 22 mL; P = 1.0 x 10(-6), respectively). CONCLUSION: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos. PMID- 25301039 TI - Defining the structure of undergraduate medical leadership and management teaching and assessment in the UK. AB - Medical leadership and management (MLM) skills are essential in preventing failings of healthcare; it is unknown how these attitudes can be developed during undergraduate medical education. This paper aims to quantify interest in MLM and recommends preferred methods of teaching and assessment at UK medical schools. Two questionnaires were developed, one sent to all UK medical school faculties, to assess executed and planned curriculum changes, and the other sent to medical students nationally to assess their preferences for teaching and assessment. Forty-eight percent of UK medical schools and 260 individual student responses were recorded. Student responses represented 60% of UK medical schools. 65% of schools valued or highly valued the importance of teaching MLM topics, compared with 93.2% of students. Students' favoured teaching methods were seminars or lectures (89.4%) and audit and quality improvement (QI) projects (77.8%). Medical schools preferred portfolio entries (55%) and presentations (35%) as assessment methods, whilst simulation exercises (76%) and audit reports (61%) were preferred by students. Preferred methods encompass experiential learning or simulation and a greater emphasis should be placed on encouraging student audit and QI projects. The curriculum changes necessary could be achieved via further integration into future editions of Tomorrow's Doctors. PMID- 25301040 TI - SCCT guidelines for the interpretation and reporting of coronary CT angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee. PMID- 25301041 TI - Coronary CT angiography for acute chest pain in the emergency department. AB - Acute chest pain in the emergency department (ED) is a common and costly public health challenge. The traditional strategy of evaluating acute chest pain by hospital or ED observation over a period of several hours, serial electrocardiography and cardiac biomarkers, and subsequent diagnostic testing such as physiologic stress testing is safe and effective. Yet this approach has been criticized for being time intensive and costly. This review evaluates the current medical evidence which has demonstrated the potential for coronary CT angiography (CTA) assessment of acute chest pain to safely reduce ED cost, time to discharge, and rate of hospital admission. These benefits must be weighed against the risk of ionizing radiation exposure and the influence of ED testing on rates of downstream coronary angiography and revascularization. Efforts at radiation minimization have quickly evolved, implementing technology such as prospective electrocardiographic gating and high pitch acquisition to significantly reduce radiation exposure over just a few years. CTA in the ED has demonstrated accuracy, safety, and the ability to reduce ED cost and crowding although its big-picture effect on total hospital and health care system cost extends far beyond the ED. The net effect of CTA is dependent also on the prevalence of coronary artery disease (CAD) in the population where CTA is used, which significantly influences rates of post-CTA invasive procedures such as angiography and coronary revascularization. These potential costs and benefits will warrant careful consideration and prospective monitoring as additional hospitals continue to implement this important technology into their diagnostic regimen. PMID- 25301042 TI - Comparison of quantitative atherosclerotic plaque burden from coronary CT angiography in patients with first acute coronary syndrome and stable coronary artery disease. AB - BACKGROUND: Coronary CTA allows characterization of non-calcified and calcified plaque and identification of high-risk plaque features. OBJECTIVE: We aimed to quantitatively characterize and compare coronary plaque burden from CTA in patients with a first acute coronary syndrome (ACS) and controls with stable coronary artery disease. MATERIALS AND METHODS: We retrospectively analyzed consecutive patients with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina with a first ACS, who underwent CTA as part of their initial workup before invasive coronary angiography and age- and gender-matched controls with stable chest pain; controls also underwent CTA with subsequent invasive angiography (total n = 28). Culprit arteries were identified in ACS patients. Coronary arteries were analyzed by automated software to quantify calcified plaque (CP), noncalcified plaque (NCP), and low-density NCP (LD-NCP, attenuation <30 Hounsfield units) volumes, and corresponding burden (plaque volume * 100%/vessel volume), stenosis, remodeling index, contrast density difference (maximum percent difference in attenuation/cross-sectional area from proximal cross-section), and plaque length. RESULTS: ACS patients had fewer lesions (median, 1), with higher total NCP and LD-NCP burdens (NCP: 57.4% vs 41.5%; LD NCP: 12.5% vs 8%; P <= .04), higher maximal stenoses (85.6% vs 53.0%; P = .003) and contrast density differences (46.1 vs 16.3%; P < .006). Per-patient CP burden was not different between ACS and controls. NCP and LD-NCP plaque burden was higher in culprit vs nonculprit arteries (NCP: 57.8% vs 9.5%; LD-NCP: 8.4% vs 0.6%; P <= .0003); CP was not significantly different. Culprit arteries had increased plaque lengths, remodeling indices, stenoses, and contrast density differences (46.1% vs 10.9%; P <= .001). CONCLUSION: Noninvasive quantitative coronary artery analysis identified several differences for ACS, both on per patient and per-vessel basis, including increased NCP, LD-NCP burden, and contrast density difference. PMID- 25301043 TI - Safe and rapid disposition of low-to-intermediate risk patients presenting to the emergency department with chest pain: a 1-year high-volume single-center experience. AB - BACKGROUND: Coronary CT angiography (CTA) is a powerful tool for the evaluation of chest pain in the emergency department (ED). Some debate persists regarding its cost-effectiveness in a low-to-intermediate risk population. OBJECTIVE: This study sought to evaluate the safety and cost-effectiveness of coronary CTA for low-to-intermediate risk patients presenting to the ED with chest pain in a closed-loop referral system. METHODS: Chest pain patients were evaluated in the ED via a local rapid coronary CTA protocol and tracked prospectively for ED throughput, disposition, chest pain recidivism, and cost utilization as compared with an age-matched cohort evaluated for chest pain treated with usual care. RESULTS: One hundred eighty-three patients underwent the rapid coronary CTA protocol compared with an age-matched cohort of 184 patients treated with usual care. The median follow-up period for major adverse cardiovascular events in the coronary CTA group was 9.0 months (range, 1.8-14.5 months) and 11.1 months (range, 0-14.0 months) for the age-matched cohort. The median ED length of stay (LOS) was 5.8 hours (range, 2.6-12.3 hours) for the rapid coronary CTA cohort and 12.2 hours (range, 1.7-40.3 hours) for the age-matched cohort (P < .001). The median time to performance of coronary CTA was 2.5 hours (range, 0.4-8.7 hours) with a median time from coronary CTA performance to disposition of 2.9 hours (range, 0.8-8.6 hours). Total median hospital LOS was 5.9 hours (range, 2.7-124 hours) in the rapid coronary CTA cohort compared with 25.0 hours (range, 1.2-208 hours) in the age-matched cohort (P < .001). Hospital admission was more common in the age-matched cohort (98.9% vs 9.3%; P < .001). There was a significant reduction in total payer cost in coronary CTA group when compared to usual care ($182,064.55 vs $685,190.77; P < .001). CONCLUSIONS: Coronary CTA for ED risk stratification and disposition within a closed referral system resulted in the shortest ED LOS published to date while being safe and cost-effective. PMID- 25301044 TI - Radiographic and electrocardiography-gated noncontrast cardiac CT assessment of lead perforation: modality comparison and interobserver agreement. AB - BACKGROUND: Pacemaker or implantable cardioverter-defibrillator lead extraction may be required because of infection, malfunction, or breakage. The preprocedural identification of lead tip position may help ensure safe performance of the procedure. OBJECTIVE: To analyze the ability of chest radiography and CT imaging to characterize lead tip position and identify perforation in a population of patients who underwent lead extraction. METHODS: Among patients who underwent lead extraction between November 2008 and April 2011, a nonrandom subset of 50 patients with 116 leads was selected for retrospective analysis. All patients had undergone chest radiography and thin-section electrocardiography-gated noncontrast cardiac CT. Two radiologists independently evaluated the imaging studies, using oblique multiplanar image reconstruction techniques for the CT examinations. Beam hardening artifacts were graded (0-3). Likelihood of perforation on each imaging study was graded on a 5-point scale. RESULTS: Among 116 leads, 17 were identified as perforated on CT, 12 leads were equivocal, and 87 were not perforated. Interobserver agreement for CT perforation vs nonperforation was good (kappa = 0.71); weighted kappa for the entire 5-point scale was moderate (kappa = 0.54). Beam hardening artifacts were common, with a mean value of 2.1. The 2 observers identified perforation on chest radiography with an average sensitivity of 15% compared with CT. The 2 observers did not agree on any cases of chest radiographic perforation (kappa = -0.1). CONCLUSION: Electrocardiography-gated noncontrast cardiac CT imaging with oblique multiplanar analysis can identify potential lead perforation with a moderate-to-good level of interobserver agreement. Chest radiography demonstrates poor sensitivity and interobserver agreement compared with CT. PMID- 25301046 TI - President's page: patient-centered care, patient consumerism, and cardiac CT. PMID- 25301045 TI - Feasibility of coronary artery calcium scoring on virtual unenhanced images derived from single-source fast kVp-switching dual-energy coronary CT angiography. AB - BACKGROUND: Dual-energy CT technology enables acquisition of virtual unenhanced (VUE) images from contrast-enhanced scans. OBJECTIVE: To assess the feasibility of coronary artery calcium (CAC) scoring on VUE images derived from fast kVp switching dual-energy coronary CT angiography. METHODS: Twenty-seven patients underwent true noncontrast CAC-scoring CT followed by routine single-energy (120 kVp) and fast kVp-switching dual-energy coronary CT angiography, in a random acquisition order on the same day. We calculated the CAC scores on true noncontrast and VUE images. The image noises and the signal-to-noise and contrast to-noise ratios of the aorta and coronary arteries were measured on both the single-energy coronary CT angiography images and dual-energy coronary CT angiography images (70 keV virtual monochromatic spectral images). The Pearson correlation coefficient test and paired t test were used for statistical analysis. RESULTS: Excellent correlation was observed between the CAC scores on the true noncontrast and those on the VUE images (r = 0.88; P < .001). Compared with single-energy coronary CT angiography, dual-energy coronary CT angiography showed significantly reduced image noise and increased signal-to-noise and contrast-to-noise ratios in all regions (all P < .001). The effective dose of dual-energy coronary CT angiography (4.3 +/- 0.3 mSv) was significantly lower than that of true noncontrast CAC-scoring CT plus single-energy coronary CT angiography (5.4 +/- 0.7 mSv; P < .0001). CONCLUSIONS: Excellent correlation was observed between the CAC scores on the VUE images and true noncontrast images. Thus, fast kVp-switching dual-energy coronary CT angiography could allow prediction of the true CAC scores, potentially reducing the total radiation exposure and image acquisition time by obviating the need for true noncontrast CAC-scoring CT. PMID- 25301047 TI - Mandibular Actinomyces Infection Mimicking a Malignancy: Case Report. AB - Actinomycosis is a rare, chronic, suppurative and granulomatous disease caused by Actinomyces israelii, which is a filamentous, anaerobic, gram-positive, saprophytic organism in the oral cavity. Diagnosis of actinomycosis depends on positive culture or identification of Actinomyces colonies and sulfur granules in histological specimens. In our case, a mass had been growing in the mandible for eight months. The mass appeared to be malignant, both clinically and radiologically. A histopathological examination of the mandible revealed actinomycosis. It should be noted that actinomycosis can mimic a malignancy, and for differential diagnosis, bone biopsy or fine-needle aspiration should be performed pre-operatively. PMID- 25301048 TI - Metastasis-associated protein 1 expression in oral squamous cell carcinomas: correlation with metastasis and angiogenesis. AB - OBJECTIVE: Metastasis-associated protein 1 (MTA1) has been associated with poor prognosis in several carcinomas. Recent investigation has found that in different tumors, MTA1 protein significantly correlates with tumor angiogenesis, suggesting that MTA1 may be a possible angiogenesis-promoting molecule in malignant tumors. Thus, the current study was performed to determine the role of MTA1 protein in the biological behavior of oral squamous cell carcinoma and its relation with tumor angiogenesis. MATERIAL AND METHOD: In this study, 44 oral squamous cell carcinomas and 15 normal epitheliums were reviewed by IHC staining for MTA1 and CD105. RESULTS: Frequency of MTA1 expression in SCCs was recorded as 97.7%, which was significantly higher than that of the control group (33.3%). Mean percentage of MTA1 expression in oral squamous cell carcinomas was 76.88 +/- 25.33% which was significantly higher than that of the control group (22.81 +/- 10.83). Our data showed a correlation between MTA1 expression with lymph node metastasis, tumor size and, stage. Evaluation of the correlation between MTA1 protein expression and micro vessel density showed that high micro vessel density was detected more frequently in tumors with MTA1 protein overexpression than in those without overexpression. CONCLUSION: In the present study, high expression of the MTA1 protein was seen in oral squamous cell carcinoma, and was closely associated with tumor progression and increased tumor angiogenesis. The findings may indicate that MTA1 protein has clinical potentials as a useful indicator of progressive phenotype, a promising prognostic predictor to identify patients with poor prognosis and may be a potential novel therapeutic target of anti angiogenesis for patients with oral squamous cell carcinoma. PMID- 25301049 TI - The impact of growth patterns of retinoblastoma (endophytic, exophytic, and mixed patterns). AB - OBJECTIVE: To study the impact of the retinoblastoma growth pattern (endophytic vs. exophytic) on the clinical and pathological features after primary enucleation. MATERIAL AND METHOD: A retrospective case series of 42 eyes of 41 patients who had pathologically confirmed retinoblastoma. The main outcome measures included demographics, laterality, international intraocular retinoblastoma (IIRC) group, vitreous seeding, neovascular glaucoma, choroid invasion, optic nerve invasion, metastasis, and survival. RESULTS: The median age at diagnosis was 30 months. Nineteen (46%) patients were males, and 17(41%) patients had bilateral retinoblastomas. Eight (19%) eyes were IIRC group C, 20 (48%) eyes were IIRC group D, and 14 (33%) eyes were IIRC group E. Nineteen (45%) tumors were endophytic, 14 (33%) were exophytic, and 9 (21%) were mixed. Choroid invasion was seen in 4 (21%) of the endophytic tumors, 5 (36%) of the exophytic tumors, and 8 (89%) of the mixed tumors (p=0.025). A mixed growth pattern was associated with massive choroid invasion in 5 (56%) of eyes. Neovascular glaucoma was seen in 5 (56%) of the mixed tumors (p=0.0376). Vitreous seeds were seen in 6 (67%) of the mixed tumors (p=0.0448). Optic nerve invasion as well as patients' age at diagnosis, gender, and tumor laterality had no correlation with tumor growth pattern. At a median follow up of 36 months, no single case had metastasis or was dead. CONCLUSION: Exophytic tumors have higher risk of choroid invasion, while endophytic tumors have higher risk of vitreous seeding. The mixed tumor growth pattern is associated with more advanced IIRC group, more risk of neovascular glaucoma, and more risk of massive choroid invasion. PMID- 25301050 TI - CXCR-4 and COX-2 expression in basal cell carcinomas and well-differentiated squamous cell carcinomas of the skin; their relationship with tumor invasiveness and histological subtype. AB - OBJECTIVE: Both CXCR-4 and COX-2 are biological markers that play a significant role in several neoplastic processes. We explored the differences in expression of these markers in certain subtypes of basal cell carcinoma, and squamous cell carcinomas in general. MATERIAL AND METHOD: In this study, we investigated the differences between 38 patients with basal cell carcinoma (nodular, infiltrative and micro-nodular subtypes) and 24 patients with well-differentiated squamous cell carcinomas with respect to their depth of invasion, tumor location, age, and CXCR-4 and COX-2 expression. RESULTS: Statistically, we found no significant difference between squamous cell carcinomas and basal cell carcinoma in terms of CXCR-4 and COX-2 expression; however, the degree of marker expression became stronger with increasing depth of invasion in both tumors. The expression of both markers was also higher in infiltrative type basal cell carcinoma compared to all the other subtypes. The results were statistically significant (p<0.05). Additionally, a significantly positive correlation also existed between COX2 and CXCR4 expression (p < 0.05). CONCLUSION: The degree of expression of CXCR-4 and COX-2 is related to invasiveness in both malignancies; thus, infiltrative type of basal cell carcinoma displays the highest degree of CXCR-4 and COX-2 expression among all the subtypes. Furthermore, our results indicate that these two biological markers may both be involved in the process of carcinogenesis and require investigation with further molecular and genetic studies in larger series. PMID- 25301051 TI - Rare structural chromosomal abnormalities in prenatal diagnosis; clinical and cytogenetic findings on 10125 prenatal cases. AB - Objective: The aim of this study was presentation of the ultrasonographic findings and perinatal autopsy of cases with rare chromosomal abnormalities. MATERIAL AND METHOD: A total of 10125 prenatal cases over 17 years including 8731 amniocentesis, 973 chorionic villus sampling, and 421 fetal blood sampling cases were evaluated for prenatal cytogenetic diagnosis. Conventional cytogenetic studies, fluorescence in situ hybridization studies, and Array-CGH analysis techniques were used for genetic analysis. RESULTS: A structural chromosomal abnormality was observed in 95 cases. The most frequently observed structural abnormalities were balanced translocations with a frequency of 53.7% (51 cases) followed by unbalanced translocations (16.8%), inversions (11.6%), supernumerary marker chromosomes (8.4%), duplications (4.2%), deletions and ring chromosomes (2.1%) and complex translocation (1.1%). Rare structural chromosomal abnormalities including de novo balanced translocations, unbalanced translocations, inversions, duplications, deletions, ring chromosomes, and supernumerary marker chromosomes were detected in 24 cases. CONCLUSION: The rate of rare chromosomal abnormalities varies from 2.4% (South East Ireland) to 12.9% (Northern England) in Europe with a total rate of 7.4/10 000 births. In our study, the overall rate of chromosomal abnormality in prenatal cytogenetic diagnosis was 3.7%, similar to South East Ireland. Ultrasonographic and perinatal autopsy findings of the cases with rare structural chromosomal abnormalities are important for proper genetic counseling for further similar cases. PMID- 25301052 TI - Lin28/let-7 axis regulates aerobic glycolysis and cancer progression via PDK1. AB - Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we discover that Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1, in a hypoxia- or hypoxia-inducible factor-1 (HIF-1)-independent manner, illustrating a novel pathway to mediate aerobic glycolysis of cancer cells even in ambient oxygen levels. Importantly, we further demonstrate that PDK1 is critical for Lin28A- and Lin28B-mediated cancer proliferation both in vitro and in vivo, establishing a previously unappreciated mechanism by which Lin28/let-7 axis facilitates Warburg effect to promote cancer progression. Our findings suggest a potential rationale to target PDK1 for cancer therapy in malignancies with aberrant expression of Lin28 and let-7. PMID- 25301053 TI - Kisspeptin-gpr54 signaling at the GnRH neuron is necessary for negative feedback regulation of luteinizing hormone secretion in female mice. AB - Kisspeptin-Gpr54 signaling is critical for regulating the activity of gonadotropin-releasing hormone (GnRH) neurons in mammals. Previous studies have shown that the negative feedback mechanism is disrupted in global Gpr54-null mutants. The present investigation aimed to determine (1) if a lack of cyclical estrogen exposure of the GnRH neuronal network in the life-long hypogonadotropic Gpr54-null mice contributed to their failed negative feedback mechanism and (2) the cellular location of disrupted kisspeptin-Gpr54 signaling. Plasma luteinizing hormone (LH) concentrations were determined in individual adult female mice when intact, following ovariectomy (OVX) and in response to an acute injection of 17beta-estradiol (E2). Control mice exhibited a characteristic rise in LH after OVX that was suppressed by acute E2. Global Gpr54-null mice failed to exhibit any post-OVX increase in LH or response to E2. Adult female global Gpr54-null mice given a cyclical regimen of estradiol for three cycles prior to OVX also failed to exhibit any post-OVX increase in LH or response to E2. To address whether Gpr54 signaling at the GnRH neuron itself was necessary for the failed response to OVX in global Gpr54-null animals, adult female mice with a GnRH neuron selective deletion of Gpr54 were examined. These mice also failed to exhibit any post-OVX increase in LH or response to E2. These experiments demonstrate defective negative feedback in global Gpr54-null mice that cannot be attributed to a lack of prior exposure of the GnRH neuronal network to cyclical estradiol. The absence of negative feedback in GnRH neuron-selective Gpr54-null mice demonstrates the necessity of direct kisspeptin signaling at the GnRH neuron for this mechanism to occur. PMID- 25301054 TI - Cardiac strangulation from epicardial pacemaker leads: diagnosis, treatment, and prevention. AB - Cardiac strangulation from epicardial leads is a rare but potentially lethal complication associated with epicardial pacemaker implantation in growing children. Early diagnosis and quick lead removal are required to rescue patients suffering from cardiac strangulation. In April 2013, the Japanese Association for Thoracic Surgery, Japan Society of Arrhythmia and Japan Cardiovascular Surgery Society published information about cardiac strangulation from epicardial leads in children on the home page of each organization's website to increase awareness of this condition Here, we review ten previously reported cases and discuss cardiac strangulation from the point of view of the pediatric cardiologist. PMID- 25301055 TI - New onset of myasthenia gravis 10 years after proton beam therapy for thymoma. AB - A 36-year-old woman underwent proton beam therapy for encapsulated type B1 thymoma for curative intent at 66 GyE. Radiographically partial response was achieved. Although the tumor size had been stable since that time, she developed systemic myasthenia gravis 10 years after the proton therapy. Extended thymectomy was performed. There were no adhesions between the tumor and the pericardium, and there were no adhesions also between the tumor and the sternum, probably due to the favor of Bragg peak effect. Extensive hyalinization with small foci of viable tumor cells showing degenerated type A-like morphology was observed in the resected tumor. Whether the viable cells represented recurrence with degenerative changes or de novo tumor formation was unable to be determined, and whether the viable cells were responsible for the onset of myasthenia gravis remained unclear. PMID- 25301056 TI - Metals and metalloids in whole blood and tissues of Olive Ridley turtles (Lepidochelys olivacea) from La Escobilla Beach (Oaxaca, Mexico). AB - Concentrations of eight metals and metalloids (Pb, Cd, Cu, Zn, Mn, Se, Ni and As) were evaluated from 41 nesting females (blood) and 13 dead (tissues) Olive Ridley turtles (Lepidochelys olivacea), a species classified as vulnerable and also listed in Appendix I of the Convention of International Trade in Endangered Species (CITES). The mean blood, liver and kidney lead concentration were 0.02 +/ 0.01, 0.11 +/- 0.08 and 0.06 +/- 0.03 MU gg(-1) ww respectively, values lower than other turtle species and locations, which it could be due to the gradual disuse of leaded gasoline in Mexico and Central America since the 1990s. Mean concentration of cadmium was 0.17 +/- 0.08 (blood), 82.88 +/- 36.65 (liver) and 150.88 +/- 110.9 9MUg g(-1) (kidney). To our knowledge, the mean renal cadmium levels found is the highest ever reported worldwide for any sea turtle species, while other six elements showed a concentration similar to other studies in sea turtles. PMID- 25301057 TI - 3D CFD simulations of trailing suction hopper dredger plume mixing: comparison with field measurements. AB - A 3D computational fluid dynamics (CFD) model is used to simulate mixing of an overflow plume within 400 m from a trailing suction hopper dredger (TSHD). The simulations are compared with new field measurements. It is the first time simulations of overflow dredging plumes are compared in such detail to field measurements this close to a TSHD. Seven cases with a large variety in overflow flux and plume characteristics are used. Measured maximum suspended sediment concentrations (SSC) vary between 30 and 500 mg/l and fluxes vary between 0.7% and 20% of the total overflow flux; the CFD model has, subject to the limitations of the field data, been shown to reproduce this in a satisfactory way. The model gives better understanding of important near field processes, which helps to assess the frequency, duration and intensity of stresses like turbidity and sedimentation needed to find the environmental impact of dredging projects. PMID- 25301059 TI - Anion resonances of para-benzoquinone probed by frequency-resolved photoelectron imaging. AB - The resonant attachment of a free electron to a closed shell neutral molecule and the interplay between the following electron detachment and electronic relaxation channels represents a fundamental but common process throughout chemical and biochemical systems. The new methodology of anion frequency-resolved photoelectron imaging is detailed and used to map out molecular excited state dynamics of gas-phase para-benzoquinone, which is the electron accepting moiety in many biological electron-transfer chains. Three-dimensional spectra of excitation energy, electron kinetic energy, and electron ejection anisotropy reveal clear fingerprints of excited and intermediate state dynamics. The results show that many of the excited states are strongly coupled, providing a route to forming the ground state radical anion, despite the fact that the electron is formally unbound in the excited states. The relation of our method to electron impact attachment studies and the key advantages, including the extension to time resolved dynamics and to larger molecular systems, are discussed. PMID- 25301058 TI - Dried fluid spots for peste des petits ruminants virus load evaluation allowing for non-invasive diagnosis and genotyping. AB - BACKGROUND: Active surveillance of peste des petits ruminants (PPR) should ease prevention and control of this disease widely present across Africa, Middle East, central and southern Asia. PPR is now present in Turkey at the gateway to the European Union. In Bangladesh, the diagnosis and genotyping of PPR virus (PPRV) may be hampered by inadequate infrastructures and by lack of proper clinical material, which is often not preserved under cold chain up to laboratories. It has been shown previously that Whatman(r) 3MM filter paper (GE Healthcare, France) preserves the nucleic acid of PPRV for at least 3 months at 32 degrees C. RESULTS: In this study, we demonstrate the performances of filter papers for archiving RNA from local PPRV field isolates for further molecular detection and genotyping of PPRV, at -70 degrees C combined with ambient temperature, for periods up to 16 months. PPR-suspected live animals were sampled and their blood and nasal swabs were applied on filter papers then air dried. Immediately after field sampling, RT-PCR amplifying a 448-bp fragment of the F gene appeared positive for both blood and nasal swabs when animals were in febrile stage and only nasal swabs were detected positive in non-febrile stage. Those tested positive were monitored by RT-PCR up to 10 months by storage at -70 degrees C. At 16 months, using real time RT-PCR adapted to amplify the N gene from filter paper, high viral loads could still be detected (~2 x 10(7) copy numbers), essentially from nasal samples. The material was successfully sequenced and a Bayesian phylogenetic reconstruction achieved adequate resolution to establish temporal relationships within or between the geographical clusters of the PPRV strains. CONCLUSIONS: This clearly reveals the excellent capacity of filter papers to store genetic material that can be sampled using a non-invasive approach. PMID- 25301060 TI - Role of transient receptor potential and pannexin channels in cigarette smoke triggered ATP release in the lung. AB - BACKGROUND: COPD is an inflammatory disease usually associated with cigarette smoking (CS) with an increasing global prevalence and no effective medication. Extracellular ATP is increased in the COPD affected lung and may play a key role in driving CS-induced airway inflammation, but the mechanism involved in ATP release has eluded researchers. Recently, the transient receptor potential (TRP) and pannexin-1 channels have been suggested to play a role in other experimental paradigms. Thus, the aim of this work is to investigate if these channels are involved in CS-induced ATP release in the lung. METHODS: Primary human cells were exposed to CS and extracellular ATP levels measured. Mice were exposed to mainstream CS and airway inflammation assessed. TRPV1/4 mRNA expression was assessed in human lung parenchyma. RESULTS: CS exposure caused a dose-related increase in ATP from primary airway bronchial epithelial cells. This was attenuated by blockers of TRPV1, TRPV4 and pannexin-1 channels. Parallel data was obtained using murine acute CS-driven model systems. Finally, TRPV1/4 mRNA expression was increased in lung tissue samples from patients with COPD. CONCLUSIONS: Extracellular ATP is increased in the COPD affected lung and may play a key role in driving disease pathophysiology. These experiments uncover a novel mechanism which may be responsible for CS-induced ATP release. These findings highlight novel targets that could lead to the development of medicine to treat this devastating disease. PMID- 25301061 TI - Synthesis of two triarylboron-functionalized metal-organic frameworks: in situ decarboxylic reaction, structure, photoluminescence, and gas adsorption properties. AB - Two 3D noninterpenetrating porous metal-organic frameworks (PMOFs) [Cd3(L(1))2(DMA)2].DMA [1, H3L(1) = tris(p-carboxylic acid)tridurylborane] and [Zn3(L(2))3(H2O)2].5H2O.2EtOH [2, H2L(2) = 4,4'-((2,3,5,6 tetramethylphenyl)boranediyl)bis(2,3,5,6-tetramethylbenzoic acid)] were synthesized by employment of a C3-symmetric ligand (H3L(1)) to assembly with Cd(NO3)2 or Zn(NO3)2. Complex 1 exhibits a (3, 6)-connected topological network based on a Cd3 cluster and Y-shaped trinodal organic linker. Complex 2 shows a 6 connected topology, since in situ decarboxylic reaction of the initial H3L(1) occurred to generate a new ligand, H2L(2), which can be considered as a linear linker. Both 1 and 2 exhibit blue fluorescence. Significantly, complex 1 with larger channels is unstable upon the removal of guest molecules. In contrast, activated 2 exhibits higher stability and permanent porosity. PMID- 25301062 TI - Pioneer steps in correcting secondary cleft lip and palate deformities: my philosophy and procedures. PMID- 25301063 TI - Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington's disease. AB - In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyte-neuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. PMID- 25301064 TI - Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition. AB - Over the past decade, a number of ribosomal proteins (RPs) have been found to have a role in activating the tumor suppressor p53 by directly binding to MDM2 and impeding its activity toward p53. Herein, we report that RPL5 and RPL11 can also enhance the transcriptional activity of a p53 homolog TAp73, but through a distinct mechanism. Interestingly, even though RPL5 and RPL11 were not shown to bind to p53, they were able to directly associate with the transactivation domain of TAp73 independently of MDM2 in response to RS. This association led to perturbation of the MDM2-TAp73 interaction, consequently preventing MDM2 from its association with TAp73 target gene promoters. Furthermore, ectopic expression of RPL5 or RPL11 markedly induced TAp73 transcriptional activity by antagonizing MDM2 suppression. Conversely, ablation of either of the RPs compromised TAp73 transcriptional activity, as evident by the reduction of p21 and Puma expression, in response to 5-fluorouracil (5-FU). Consistently, overexpression of RPL5 or RPL11 enhanced, but knockdown of either of them hampered, TAp73-mediated apoptosis. Intriguingly, simultaneous knockdown of TAp73 and either of the RPs was required for rescuing the 5-FU-triggered S-phase arrest of p53-null tumor cells. These results demonstrate a novel mechanism underlying the inhibition of tumor cell proliferation and growth by these two RPs via TAp73 activation. PMID- 25301065 TI - Proteasome inhibition and oxidative reactions disrupt cellular homeostasis during heme stress. AB - Dual control of cellular heme levels by extracellular scavenger proteins and degradation by heme oxygenases is essential in diseases associated with increased heme release. During severe hemolysis or rhabdomyolysis, uncontrolled heme exposure can cause acute kidney injury and endothelial cell damage. The toxicity of heme was primarily attributed to its pro-oxidant effects; however additional mechanisms of heme toxicity have not been studied systematically. In addition to redox reactivity, heme may adversely alter cellular functions by binding to essential proteins and impairing their function. We studied inducible heme oxygenase (Hmox1)-deficient mouse embryo fibroblast cell lines as a model to systematically explore adaptive and disruptive responses that were triggered by intracellular heme levels exceeding the homeostatic range. We extensively characterized the proteome phenotype of the cellular heme stress responses by quantitative mass spectrometry of stable isotope-labeled cells that covered more than 2000 individual proteins. The most significant signals specific to heme toxicity were consistent with oxidative stress and impaired protein degradation by the proteasome. This ultimately led to an activation of the response to unfolded proteins. These observations were explained mechanistically by demonstrating binding of heme to the proteasome that was linked to impaired proteasome function. Oxidative heme reactions and proteasome inhibition could be differentiated as synergistic activities of the porphyrin. Based on the present data a novel model of cellular heme toxicity is proposed, whereby proteasome inhibition by heme sustains a cycle of oxidative stress, protein modification, accumulation of damaged proteins and cell death. PMID- 25301066 TI - E2F1-regulated miR-30b suppresses Cyclophilin D and protects heart from ischemia/reperfusion injury and necrotic cell death. AB - Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Cell death is a hallmark characteristic of various cardiac diseases, including myocardial infarction and heart failure. Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. However, the molecular components regulating programmed necrosis in heart remain largely unidentified. Here we report that miR-30b, Cyclophilin D (CypD) and E2F1 constitute an axis that regulates necrosis. The results show that knockdown of CypD attenuated necrosis in the cellular model and also myocardial infarction in the animal model. miR-30b suppresses the translation of CypD and thus inhibits CypD-mediated necrotic cell death in cardiomyocytes. Cardiac-specific miR-30b transgenic mice exhibit reduced necrosis and myocardial infarct size upon ischemia/reperfusion (I/R) injury. Further, we identify that E2F1 transcriptionally represses miR-30b expression. Knockdown of E2F1 in cardiomyocytes inhibits necrotic cell death, and E2F1 knockout mice show reduced necrosis and myocardial infarct size upon I/R. Our present study identifies a novel signaling pathway composed of E2F1, miR-30b and CypD that regulates myocardial necrosis. This discovery will not only provide de novo regulators in the necrotic process but will also shed new light on the effective therapy of myocardial infarction and heart failure. PMID- 25301067 TI - Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo. AB - Caspase-2 is an atypical caspase that regulates apoptosis, cell cycle arrest and genome maintenance, although the mechanisms are not well understood. Caspase-2 has also been implicated in chemotherapy response in lung cancer, but this function has not been addressed in vivo. Here we show that Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Loss of Caspase-2 leads to enhanced tumor proliferation and progression. Despite being more histologically advanced, Caspase-2-deficient tumors are sensitive to chemotherapy and exhibit a significant reduction in tumor volume following repeated treatment. However, Caspase-2-deficient tumors rapidly rebound from chemotherapy with enhanced proliferation, ultimately hindering long-term therapeutic benefit. In response to DNA damage, Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53. Caspase-2 expression levels are significantly reduced in human lung tumors with wild-type p53, in agreement with the model whereby Caspase-2 functions through Mdm2/p53 regulation. Consistently, p53 target genes including p21, cyclin G1 and Msh2 are reduced in Caspase-2 deficient tumors. Finally, we show that phosphorylation of p53-induced protein with a death domain 1 leads to Caspase-2-mediated cleavage of Mdm2, directly impacting p53 levels, activity and chemotherapy response. Together, these studies elucidate a Caspase-2-p53 signaling network that impacts lung tumorigenesis and chemotherapy response in vivo. PMID- 25301068 TI - Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability. AB - The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis. PMID- 25301069 TI - Neuroprotection requires the functions of the RNA-binding protein HuR. AB - Alterations in the functions of neuronal RNA-binding proteins (RBPs) can contribute to neurodegenerative diseases. However, neurons also express a set of widely distributed RBPs that may have developed specialized functions. Here, we show that the ubiquitous member of the otherwise neuronal Elavl/Hu family of RNA binding proteins, Elavl1/HuR, has a neuroprotective role. Mice engineered to lack exclusively HuR in the hippocampal neurons of the central nervous system (CNS), maintain physiologic levels of neuronal Elavls and develop a partially diminished seizure response following strong glutamatergic excitation; however, they display an exacerbated neurodegenerative response subsequent to the initial excitotoxic event. This response was phenocopied in hippocampal cells devoid of ionotropic glutamate receptors in which the loss of HuR results in enhanced mitochondrial dysfunction, oxidative damage and programmed necrosis solely after glutamate challenge. The molecular dissection of HuR and nElavl mRNA targets revealed the existence of a HuR-restricted posttranscriptional regulon that failed in HuR deficient neurons and is involved in cellular energetics and oxidation defense. Thus, HuR acts as a specialized controller of oxidative metabolism in neurons to confer protection from neurodegeneration. PMID- 25301070 TI - Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFbeta expression. AB - Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfbeta1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFbeta signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. PMID- 25301071 TI - CD44 functions in Wnt signaling by regulating LRP6 localization and activation. AB - Wnt reception at the membrane is complex and not fully understood. CD44 is a major Wnt target gene in the intestine and is essential for Wnt-induced tumor progression in colorectal cancer. Here we show that CD44 acts as a positive regulator of the Wnt receptor complex. Downregulation of CD44 expression decreases, whereas CD44 overexpression increases Wnt activity in a concentration dependent manner. Epistasis experiments place CD44 function at the level of the Wnt receptor LRP6. Mechanistically, CD44 physically associates with LRP6 upon Wnt treatment and modulates LRP6 membrane localization. Moreover, CD44 regulates Wnt signaling in the developing brain of Xenopus laevis embryos as shown by a decreased expression of Wnt targets tcf-4 and en-2 in CD44 morphants. PMID- 25301072 TI - Extracellular ATP, a danger signal, is recognized by DORN1 in Arabidopsis. AB - ATP, the universal energy currency of all organisms, is released into the extracellular matrix and serves as a signal among cells, where it is referred to as an extracellular ATP. Although a signalling role for extracellular ATP has been well studied in mammals over the last 40 years, investigations of such a role in plants are at an early stage. Recently, the first plant receptor for extracellular ATP, DOes not Respond to Nucleotides (DORN1), was identified in Arabidopsis thaliana by mutant screening. DORN1 encodes a legume-type lectin receptor kinase that is structurally distinct from the mammalian extracellular ATP receptors. In the present review, we highlight the genetic and biochemical evidence for the role of DORN1 in extracellular ATP signalling, placing this within the wider context of extracellular ATP signalling during plant stress responses. PMID- 25301073 TI - Metformin and respiratory chain complex I: the last piece of the puzzle? AB - Metformin is the most widely prescribed drug used to treat patients affected by Type 2 diabetes. Metformin has also been shown to prevent some forms of cell death; however, evidence suggests that it may have anti-neoplastic properties. All of these effects have been attributed to complex I inhibition, but the mechanism by which metformin leads to complex I inhibition is not fully understood. Although it has been reported that the incubation of functionally isolated complex I in the presence of high concentrations of metformin led to its inhibition, much lower concentrations of metformin have been shown to inhibit complex I in intact cells. In a recent issue of the Biochemical Journal, Bridges, Jones, Pollak and Hirst [(2014) Biochem. J. 462, 475-487] studied for the first time the effect of metformin on purified complex I. They report that millimolar concentrations of metformin directly inhibit complex I activity in a non competitive manner. They also specify that the binding of metformin to complex I depends on its conformation. To explain the difference in concentration required to inhibit complex I in intact cells and on isolated enzyme, Bridges et al. (2014) propose that metformin concentrates within mitochondria in intact cells. Albeit theoretically plausible, this attractive hypothesis is not directly tested by Bridges et al. (2014) Moreover, although sparse, the current literature does not support this hypothesis. PMID- 25301074 TI - NTBI unveiled by chelatable fluorescent beads. AB - Non-transferrin-bound iron (NTBI) emerges in plasma of patients with systemic iron overload, but has also been documented in further pathological conditions. Quantification of NTBI can be useful for diagnosis and management of these disorders. However, currently available detection methods are tedious and often inaccurate, hampering wide applicability. In this issue of the Biochemical Journal, Ma et al. report the development of a novel assay for NTBI measurement, based on an iron-sensitive fluorescent probe that is linked to magnetic beads. The approach offers several advantages over existing technology and may bring NTBI assessment closer to the clinic. PMID- 25301075 TI - Management of NSCLC: focus on crizotinib. AB - INTRODUCTION: Presence of Anaplastic lymphoma kinase (ALK) translocations identifies a distinct subgroup of NSCLC with different prognosis and therapeutic opportunities. In cancer cells, ALK gene fusion acts as oncogenic driver, representing an attractive therapeutic target in NSCLC. AREAS COVERED: For the purpose of this review article, data from preclinical and clinical trials with crizotinib were collected and analyzed. EXPERT OPINION: Available data demonstrated that crizotinib is the best option we can offer today to ALK positive NSCLC not previously exposed to ALK inhibitors, irrespective of line of therapy. In two large Phase III trials, crizotinib demonstrated to improve response rate and progression-free survival when compared to standard chemotherapy, both in first- and second-line treatment. Furthermore, results from pivotal Phase I and II studies indicated that crizotinib was active even in heavily pretreated populations. In addition, crizotinib displayed a favorable toxicity profile with a broad spectrum of adverse events, most of which is easily to manage and rarely require dose reduction or interruption. Unfortunately, almost all patients became refractory to crizotinib due to emergence of acquired resistance. The optimal management of these patients has not yet been defined. Novel ALK inhibitors are under investigation. PMID- 25301076 TI - Discontinuation of somatostatin analogs while acromegaly is in long-term remission. AB - PURPOSE: We aimed to evaluate the disease activity of medically controlled patients with acromegaly after withdrawal of somatostatin receptor ligands (SRL). METHODS: Sixteen patients who were on a stable dose of SRL for more than 2 years and had at least 1 year of remission were included in the study. Five patients were on 10 mg, four were on 20 mg and three were on 30 mg of octreotide; whereas for lanreotide, one was on 60 mg, two were on 90 mg, and one was on 120 mg. All patients had received SRL with 28-day intervals. Basal GH, IGF1, glucose suppressed GH levels were measured with 3-month intervals for a total of 12 months after withdrawal. Sella MRI evaluation was obtained at 6-month intervals. If the nadir GH level after glucose suppression was >1 ng/ml or IGF1 was above the normal limits during the follow-up period, SRL was restarted. RESULTS: Three months after stopping SRL, 10 (63%) had biochemical disease recurrence. After 12 months of follow-up, in total 13 (81%) of the patients recurred. The final basal GH levels before withdrawal, basal GH at month-3, and glucose suppressed GH levels were significantly lower in patients with sustained remission (p = 0.003, p < 0.001, and p = 0.001). Basal GH and glucose suppressed GH levels at month-3 were correlated with the basal GH levels at month-0 (r = 0.6, p = 0.008 and r = 0.5, p = 0.03). CONCLUSION: The final GH levels prior to discontinuation of SRL should be taken into consideration in patients with acromegaly in long-term remission. Moreover, the first visit 3 months after withdrawal is critically important for determining the future status of remission. PMID- 25301077 TI - Plasma CX3CL1 levels and long term outcomes of patients with atrial fibrillation: the West Birmingham Atrial Fibrillation Project. AB - BACKGROUND: There is growing evidence that chemokines are potentially important mediators of the pathogenesis of atherosclerotic disease. Major atherothrombotic complications, such as stroke and myocardial infarction, are common among atrial fibrillation (AF) patients. This increase in risk of adverse events may be predicted by a score based on the presence of certain clinical features of chronic heart failure, hypertension, age 75 years or greater, diabetes and stroke (the CHADS2 score). Our objective was to assess the prognostic value of plasma chemokines CCL2, CXCL4 and CX3CL1, and their relationship with the CHADS2 score, in AF patients. METHODS: Plasma CCL2, CXCL4 and CX3CL1 were measured in 441 patients (59% male, mean age 75 years, 12% paroxysmal, 99% on warfarin) with AF. Baseline clinical and demographic factors were used to define each subject's CHADS2 score. Patients were followed up for a mean 2.1 years, and major adverse cardiovascular and cerebrovascular events (MACCE) were sought, being the combination of cardiovascular death, acute coronary events, stroke and systemic embolism. RESULTS: Fifty-five of the AF patients suffered a MACCE (6% per year). Those in the lowest CX3CL1 quartile (<= 0.24 ng/ml) had fewest MACCE (p = 0.02). In the Cox regression analysis, CX3CL1 levels >0.24 ng/ml (Hazard ratio 2.8, 95% CI 1.02-8.2, p = 0.045) and age (p = 0.042) were independently linked with adverse outcomes. The CX3CL1 levels rose directly with the CHADS2 risk score (p = 0.009). The addition of CX3CL1 did not significantly increased the discriminatory ability of the CHADS2 clinical factor-based risk stratification (c-index 0.60 for CHADS2 alone versus 0.67 for CHADS2 plus CX3CL1 >0.24 ng/ml, p = 0.1). Aspirin use was associated with lower levels of CX3CL1 (p = 0.0002) and diabetes with higher levels (p = 0.031). There was no association between CXCL4 and CCL2 plasma levels and outcomes. CONCLUSION: There is an independent association between low plasma CX3CL1 levels and low risk of major cardiovascular events in AF patients, as well as a linear association between CX3CL1 plasma levels and CHADS2-defined cardiovascular risk. The potential for CX3CL1 in refining risk stratification in AF patients merits consideration. PMID- 25301079 TI - Clinical profile of uveitis-related ocular hypertension. AB - The purpose of this article is to study the clinical and demographic profile of uveitis-related ocular hypertension (OHT) and evaluate risk factors predisposing to development of OHT in uveitis. Two hundred patients (200 eyes) with uveitis were evaluated for type of uveitis and the presence of OHT [IOP > 21 mmHg]. All patients underwent a complete ophthalmic examination and appropriate systemic evaluation. Patients with OHT were started on appropriate antiglaucoma medication and were followed up for minimum of 6 months. Forty-two eyes (21 %) were found to have OHT. Anterior uveitis alone was seen in 22 (52.4 %), granulomatous uveitis was seen in 8 (19.1 %) eyes, while 13 eyes (30.9 %) had active uveitis. On multiple logistic regression, age greater than 60 years (p = 0.025), peripheral anterior synechiae (PAS) > 180 degrees (p = 0.029), and steroid use (p < 0.001) were found to have significant association with OHT. Mean IOP at baseline was 24.6 +/- 10.1 mmHg which decreased to 17.3 +/- 4.5 mmHg at 6 months (p < 0.001). At 6 months, 30 eyes were medically controlled (71.4 %), 5 eyes underwent trabeculectomy with MMC (11.9 %), and in 7 eyes, antiglaucoma medication could be discontinued. One-fifth of eyes with uveitis had OHT. Risk factors for IOP elevation included increased age, PAS > 180 degrees , and corticosteroid use. PMID- 25301081 TI - Gridded field observations of polycyclic aromatic hydrocarbons in soils from a typical county in Shanxi Province, China. AB - Polycyclic aromatic hydrocarbons (PAHs) were measured in 128 soil samples collected from Xiangfen County, Shanxi Province, China. Sixteen PAH congeners were identified at high concentrations (89-100 %), with the exceptions of Ace and Acy, and were used for statistical analysis. PAH concentrations ranged from 51.91 to 10,523.58 ng/g with a mean of 722.35 ng/g indicating severe pollution at the sample sites. Four-ring PAHs were predominant followed by 3- and 5-ring PAHs. Coal combustion was found to be the greatest contributor of PAHs to the local environment. An analysis of the spatial distribution of PAHs indicated the presence of relatively high concentrations in the northwest region of the county. A source identification analysis showed that Wulidun in Fencheng Town, Shangbeirong Village in Gucheng Town, and Yandian Village in Xincheng Town were the major sources of PAHs in Xiangfen County. Modeling results indicated that the distance among the sampling sites and these point sources had a large influence on the transfer of PAHs to the soils. PMID- 25301082 TI - Neonatal thrombocytopenia and platelet transfusion - a UK perspective. AB - Five percent of newborn infants admitted to UK neonatal units during a recent study developed a platelet count <60 * 10(9)/l, and 60% of these were transfused platelets. This review summarises the common causes and mechanisms of thrombocytopenia in the newborn. Relevant evidence relating the platelet count to the risk of haemorrhage is reviewed, and current UK guidance on transfusion thresholds outlined. The UK policy for the provision of platelets for transfusion to neonates is described, including the particular requirements for neonatal allo immune thrombocytopenia. Finally, we look towards the future and prospects for reducing the need to expose newborns to donor-derived platelets. PMID- 25301080 TI - The neurobiological bases of memory formation: from physiological conditions to psychopathology. AB - The formation of long-term memories is a function necessary for an adaptive survival. In the last two decades, great progress has been made in the understanding of the biological bases of memory formation. The identification of mechanisms necessary for memory consolidation and reconsolidation, the processes by which the posttraining and postretrieval fragile memory traces become stronger and insensitive to disruption, has indicated new approaches for investigating and treating psychopathologies. In this review, we will discuss some key biological mechanisms found to be critical for memory consolidation and strengthening, the role/s and mechanisms of memory reconsolidation, and how the interference with consolidation and/or reconsolidation can modulate the retention and/or storage of memories that are linked to psychopathologies. PMID- 25301083 TI - CUB domain containing protein 1 (CDCP1) modulates adhesion and motility in colon cancer cells. AB - BACKGROUND: Deregulated expression of the transmembrane glycoprotein CDCP1 (CUB domain-containing protein-1) has been detected in several cancers including colon, lung, gastric, breast, and pancreatic carcinomas. CDCP1 has been proposed to either positively or negatively regulate tumour metastasis. In this study we assessed the role of CDCP1 in properties of cells that are directly relevant to metastasis, namely adhesion and motility. In addition, association between CDCP1 and the tetraspanin protein CD9 was investigated. METHODS: CDCP1 and CD9 protein expression was measured in a series of colon cancer cell lines by flow cytometry and Western blotting. Adhesion of Colo320 and SW480 cells was determined using a Matrigel adhesion assay. The chemotactic motility of SW480 cells in which CDCP1 expression had been reduced by RNA interference was analysed using the xCELLigence system Real-Time Cell Analyzer Dual Plates combined with 8 MUm pore filters. Detergent-resistant membrane fractions were generated following density gradient centrifugation and the CDCP1 and CD9 protein composition of these fractions was determined by Western blotting. The potential association of the CDCP1 and CD9 proteins was assessed by co-immunoprecipitation. RESULTS: Engineered CDCP1 expression in Colo320 cells resulted in a reduction in cell adhesion to Matrigel. Treatment of SW480 cells with CDCP1 siRNA reduced serum induced chemotaxis. CDCP1 and CD9 cell-surface protein and mRNA levels showed a positive correlation in colon cancer cell lines and the proteins formed a low level, but detectable complex as judged by co-sedimentation of detergent lysates of HT-29 cells in sucrose gradients as well as by co-immunoprecipitation in SW480 cell lysates. CONCLUSIONS: A number of recent studies have assigned a potentially important role for the cell-surface protein CDCP1 in invasion and metastasis of a several types of human cancer cells. In this study, CDCP1 was shown to modulate cell-substratum adhesion and motility in colon cancer cell lines, with some variation depending on the colon cancer cell type. CDCP1 and CD9 were co expressed at the mRNA and protein level and we obtained evidence for the presence of a molecular complex of these proteins in SW480 colon cancer cells. PMID- 25301084 TI - Reduced neuronal signaling in the ageing apolipoprotein-E4 targeted replacement female mice. AB - The effect of ApoE on NMDAR-dependent ERK/CREB signaling is isoform-dependent, and ApoE4 accelerates memory decline in ageing. However, this isoform-dependent function on neuronal signaling during ageing is unclear. In this study, we have examined NMDAR-associated ERK/CREB signal transduction in young and aged huApoE3 and huApoE4 targeted replacement (TR) mice. At 12 weeks huApoE4 mouse brain, increased NR1-S896 phosphorylation was linked to higher protein kinase C (PKC) activation. This up-regulation was accompanied by higher phosphorylation of AMPA GluR1-S831, CaMKII, ERK1/2 and CREB. But at 32 weeks, there was no significant difference between huApoE3 and huApoE4 TR mice on NMDAR-associated ERK/CREB signaling. Interestingly, in 72-week-old huApoE4 TR mice, protein phosphorylation that were increased in younger mice were significantly reduced. Lower NR1-S896 phosphorylation was linked to reduced PKC, GluR1-S831, CaMKII, ERK1/2 and CREB phosphorylation in huApoE4 TR mice as compared to huApoE3 TR mice. Furthermore, we have consistently detected lower ApoE levels in young and aged huApoE4 TR mouse brain, and this was associated with reduced expression of the ApoE receptor, LRP1 and NR2A-Y1246 phosphorylation. These results suggest age specific, isoform-dependent effects of ApoE on neuronal signaling. PMID- 25301085 TI - Outcome of super-responders to cardiac resynchronization therapy defined by endpoint-derived parameters of left ventricular remodeling: a two-center retrospective study. AB - AIMS: Various studies have attempted to identify super-responders to cardiac resynchronization therapy (CRT) by echocardiographic parameters of reverse remodeling. However, scientific evidence regarding those parameters is scarce. This study aimed at validating the definition of super-response to CRT based on the following frequently employed echocardiographic parameters: left ventricular ejection fraction (LVEF), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI). METHODS AND RESULTS: We retrospectively investigated echocardiographic data and outcomes of 542 patients after CRT implantation. The primary endpoint comprised all-cause mortality, heart transplantation, ventricular assist device implantation (VAD), and hospitalization for heart failure. Secondary endpoints were hospitalization for heart failure, and the combination of all-cause mortality, heart transplantation and VAD. Two approaches were employed defining super-response based on improvement of echocardiographic parameters: one derived from the negative predictive value (NPV) for clinical endpoints, and second from best quartiles of improvement. Using the NPV method, an absolute 25 % increase in LVEF, a relative 38 % reduction in EDVI, and 46 % in ESVI were calculated as optimal cut-offs identifying 4.9, 18.5, and 21.3 % as super-responders. The best quartiles method resulted in lower cut-off values, i.e. 14 % increase in LVEF, 26 % reduction in EDVI, and 36 % in ESVI. All cut offs except LVEF >= 25% were significantly associated with improved outcomes after 5 years (median follow-up 35.7 months). CONCLUSIONS: NPV- and best quartile based cut-offs validate previously applied empirical echocardiographic cut-offs to define super-response to CRT. These data provide evidence for using these empirical cut-offs in daily practice and facilitate inter-study comparability. PMID- 25301087 TI - Racial and ethnic disparities in the diagnosis of breast cancer: changes in presenting stage in minority populations in Florida during 1981-2009. AB - We assessed whether presenting breast cancer stage has changed over time in Florida, and whether there is variation in this change with respect to race, ethnicity, and socioeconomic status (SES). Data were obtained from the Florida Cancer Data System. We included females with invasive breast cancer and complete information on race, ethnicity, and SES during 1981-2009 (n = 226,651). Associations between categorical variables were examined using Chi-square tests. Predictors of SEER stage at diagnosis (local, regional, and distant) were modeled with multinomial ordinal logistic regression models. There was a significant increase in local disease and a decrease in regional and distant disease at presentation (p < 0.0001) over the time period assessed. Compared to whites, black patients continue to have lower odds of local presentation (OR 0.73, 95% CI 0.63, 0.85), as do Hispanic patients (OR 0.80, 95% CI 0.76, 0.84) compared to non Hispanics. The increase in local stage at diagnosis was greater for black than white patients, as was the decrease in regional and distant disease (p < 0.001). Hispanic women also had significant increase in localized disease and decrease in regional and distant disease (p < 0.001), but there was little difference in the change compared to non-Hispanic women. Localized breast cancer stage at diagnosis has become more common over time in all groups. Significant disparity persists, with black and Hispanic patients being less likely to present with localized disease than white patients overall. There was a greater change for black versus white patients, resulting in a narrowing in the racial gap in stage at diagnosis. PMID- 25301086 TI - Metabolic syndrome and outcomes following early-stage breast cancer. AB - The prevalence of risk factors contributing to metabolic syndrome (MetS) is increasing, and numerous components of MetS are associated with increased primary breast cancer (BC) risk. However, less is known about the relationship of MetS to BC outcomes. The aim of this study was to evaluate whether MetS, characterized by increased weight, hypertension, low HDL-cholesterol, high triglycerides, and diabetes or impaired glucose tolerance, is associated with risk of second breast cancer events (SBCE) and BC-specific mortality. Retrospective cohort study of women diagnosed with incident early-stage (I-II) BC between 1990 and 2008, enrolled in an integrated health plan. Outcomes of interest were SBCE, defined as recurrence or second primary BC, and BC-specific mortality. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for time-varying exposure to MetS components while accounting for potential confounders and competing risks. Among 4,216 women in the cohort, 26% had >=3 MetS components and 13% developed SBCE during median follow-up of 6.3 years. Compared to women with no MetS components, presence of MetS (>=3 components) was associated with increased risk of SBCE (HR = 1.50, 95% CI 1.08-2.07) and BC-specific mortality (HR = 1.65, 95% CI 1.02-2.69). Of the individual components, only increased weight was associated with increased risk of SBCE (HR = 1.26, 95% CI 1.06-1.49). MetS is associated with modestly increased risk of SBCE and BC-specific mortality. Given the growing population of BC survivors, further research in larger and more diverse populations is warranted. PMID- 25301088 TI - Contralateral prophylactic mastectomy and its association with reduced mortality: evidence for selection bias. AB - Contralateral prophylactic mastectomy (CPM) refers to removal of the opposite uninvolved breast in women with unilateral breast cancer, and rates are increasing worldwide. In observational studies, CPM is often associated with reductions in breast cancer-specific and all-cause mortality when compared to unilateral surgical treatment alone, but this may reflect selection of a healthier cohort for CPM (selection bias). To further explore this possibility, we examined the association between CPM and non-cancer mortality, an indicator of selection bias. We identified 449,178 adult women diagnosed with unilateral, primary American Joint Committee on Cancer (AJCC) stage I-III ductal or lobular breast cancer, utilizing the 1998-2010 Surveillance, Epidemiology, and End Results dataset. Of these, 5.8% (n = 25,961) underwent CPM as their first course of treatment. We examined associations between CPM and breast cancer-specific, all-cause, and non-cancer mortality utilizing multivariate logistic regression, adjusting for age, race, AJCC stage, estrogen receptor status, progesterone receptor status, and histologic grade of the tumor. Among all patients receiving CPM as first course of treatment, CPM was associated with lower breast cancer specific [HR 0.84 (95% CI 0.79-0.89)], all-cause [HR 0.83 (95% CI 0.80-0.88)], and non-cancer [HR 0.71 (95% CI 0.64-0.80)] 5-year hazard of death. Although our results are consistent with other observational studies showing associations between CPM and reductions in breast cancer-specific and all-cause mortality, we demonstrate an even stronger association between CPM and reduced non-cancer mortality. Thus, the reported associations between CPM and reductions in mortality might at least partly be attributable to selection bias. PMID- 25301089 TI - Small molecule 1'-acetoxychavicol acetate suppresses breast tumor metastasis by regulating the SHP-1/STAT3/MMPs signaling pathway. AB - Signal transducer and activator of transcription 3 (STAT3) is implicated breast cancer metastasis and represents a potential target for developing new anti-tumor metastasis drugs. The purpose of this study is to investigate whether the natural agent 1'-acetoxychavicol acetate (ACA), derived from the rhizomes and seeds of Languas galanga, could suppress breast cancer metastasis by targeting STAT3 signaling pathway. ACA was examined for its effects on breast cancer migration/invasion and metastasis using Transwell assays in vitro and breast cancer skeletal metastasis mouse model in vivo (n = 10 mice per group). The inhibitory effect of ACA on cellular STAT3 signaling pathway was investigated by series of biochemistry analysis. The chavicol preferentially suppressed cancer cell migration and invasion, and this activity was superior to its cytotoxic effects. ACA suppressed both constitutive and interleukin-6-inducible STAT3 activation and diminished the accumulation of STAT3 in the nucleus and its DNA binding activity. More importantly, ACA treatment led to significant up regulation of Src homology region 2 domain-containing phosphatase 1 (SHP-1), and the ACA-induced depression of cancer cell migration and STAT3 signaling could be apparently reversed by blockade of SHP-1. Matrix metalloproteinase (MMP)-2 and 9, gene products of STAT3 that regulate cell invasion, were specifically suppressed by ACA. In tumor metastasis model, ACA potently inhibited the human breast cancer cell-induced osteolysis, and had little apparent in vivo toxicity at the test concentrations. ACA is a novel drug candidate for the inhibition of tumor metastasis through interference with the SHP-1/STAT3/MMPs signaling pathway. PMID- 25301090 TI - The effect of injection speed on remifentanil-induced cough in children. AB - BACKGROUND: Remifentanil sometimes elicits cough during induction of anesthesia, as with the use of other fentanyl congeners. We designed this study to investigate the incidence of remifentanil-induced cough (RIC) in children and to evaluate the effect of injection speed on RIC. METHODS: One hundred twenty ASA physical status I-II patients, aged 3-12 yr, undergoing general anesthesia were enrolled in the study. Patients were randomly assigned to one of the three groups. Patients in Group R30 received remifentanil 1.5 ug/kg at a constant rate over 30 s. Patients in Group R45 received remifentanil 1.5 ug/kg over 45 s, and patients in Group R60 received remifentanil 1.5 ug/kg over 60 s, respectively. Episodes of cough were recorded and graded as mild (1-2), moderate (3-4), or severe (5 or more). Mean arterial pressure (MAP), heart rate (HR), and SpO2 were recorded on arrival in the operating room (baseline) and 1 min after remifentanil infusion. RESULTS: The incidence of RIC was 33.3% in Group R30 (13 of 39 patients), 17.9% in Group R45 (7 of 39 patients), and 5.0% in Group R60 (2 of 40 patients). Patients in Group R60 had a significantly lower incidence of RIC than those in Group R30 (P = 0.001). The MAP, HR, and SpO2 values were not significantly different between groups. CONCLUSIONS: When intravenous remifentanil 1.5 ug/kg was administered in pediatric patients, the incidence of RIC decreased from 33 to 5% by increasing the injection time from 30 to 60 s. Remifentanil should be administered slowly over 60 s in children to suppress cough during anesthesia induction. PMID- 25301091 TI - Temperature-sensitive transient receptor potential channels in corneal tissue layers and cells. AB - We here provide a brief summary of the characteristics of transient receptor potential channels (TRPs) identified in corneal tissue layers and cells. In general, TRPs are nonselective cation channels which are Ca(2+) permeable. Most TRPs serve as thermosensitive molecular sensors (thermo-TRPs). Based on their functional importance, the possibilities are described for drug-targeting TRP activity in a clinical setting. TRPs are expressed in various tissues of the eye including both human corneal epithelial and endothelial layers as well as stromal fibroblasts and stromal nerve fibers. TRP vanilloid type 1 (TRPV1) heat receptor, also known as capsaicin receptor, along with TRP melastatin type 8 (TRPM8) cold receptor, which is also known as menthol receptor, are prototypes of the thermo TRP family. The TRPV1 functional channel is the most investigated TRP channel in these tissues, owing to its contribution to maintaining tissue homeostasis as well as eliciting wound healing responses to injury. Other thermo-TRP family members identified in these tissues are TRPV2, 3 and 4. Finally, there is the TRP ankyrin type 1 (TRPA1) cold receptor. All of these thermo-TRPs can be activated within specific temperature ranges and transduce such inputs into chemical and electrical signals. Although several recent studies have begun to unravel complex roles for thermo-TRPs such as TRPV1 in corneal layers and resident cells, additional studies are needed to further elucidate their roles in health and disease. PMID- 25301092 TI - A Perfusion-based Human Cadaveric Model for Management of Carotid Artery Injury during Endoscopic Endonasal Skull Base Surgery. AB - Objective To create and develop a reproducible and realistic training environment to prepare residents and trainees for arterial catastrophes during endoscopic endonasal surgery. Design An artificial blood substitute was perfused at systolic blood pressures in eight fresh human cadavers to mimic intraoperative scenarios. Setting The USC Keck School of Medicine Fresh Tissue Dissection Laboratory was used as the training site. Participants Trainees were USC neurosurgery residents and junior faculty. Main Outcome A 5-point questionnaire was used to assess pre- and posttraining confidence scores. Results High-pressure extravasation at normal arterial blood pressure mimicked real intraoperative internal carotid artery (ICA) injury. Residents developed psychomotor skills required to achieve hemostasis using suction, cottonoids, and muscle grafts. Questionnaire responses from all trainees reported a realistic experience enhanced by the addition of the perfusion model. Conclusions The addition of an arterial perfusion system to fresh tissue cadavers is among the most realistic training models available. This enables the simulation of rare intraoperative scenarios such as ICA injury. Strategies for rapid hemostasis and implementation of techniques including endoscope manipulation, suction, and packing can all be rehearsed via this novel paradigm. PMID- 25301093 TI - Structural study of gubernaculum testis in fetuses with prune belly syndrome. AB - PURPOSE: We compared and contrasted the structure of the gubernaculum testis in fetuses with prune belly syndrome and normal controls. MATERIALS AND METHODS: We studied a total of 6 gubernacula from 3 male fetuses with prune belly syndrome and a total of 14 from 7 male fetuses without an anomaly. Gubernacular specimens were cut into 5 MUm sections and stained with Masson trichrome to quantify connective tissue and smooth muscle cells, with Weigert stain to observe elastic fibers and with picrosirius red with polarization to observe collagen. Immunohistochemical analysis was done with tubulin to observe the nerves. Images were captured with a BX51 microscope and DP70 camera (Olympus(r)). Stereological analysis was done with Image-Pro and ImageJ (MediaCybernetics(r)) using a grid to determine volumetric density. Means were statistically compared with the Mann Whitney test. All tests were 2-sided with p <0.05 considered statistically significant. RESULTS: Prune belly syndrome fetuses were at 17 to 31 weeks of gestation and control fetuses were at 12 to 35 weeks of gestation. Quantitative analysis showed no difference in the volumetric density of smooth muscle cells in prune belly syndrome vs control gubernacula (mean 15.70% vs 19%, p = 0.2321). Collagen fiber analysis revealed a predominance of green areas in prune belly syndrome gubernacula, suggesting collagen type III, and a predominance of red areas in control gubernacula, suggesting collagen type I. Elastic fibers were significantly smaller in prune belly syndrome gubernacula than in control gubernacula (mean 14.06% vs 24.6%, p = 0.0190). Quantitative analysis demonstrated no difference in the volumetric density of nerves in prune belly syndrome or control gubernacula (mean 5.200% vs 3.158%, p = 0.2302). CONCLUSIONS: The gubernaculum in fetuses with prune belly syndrome had altered concentrations of collagen and elastic fibers. These structural alterations could be one of the factors involved in cryptorchidism in prune belly syndrome. PMID- 25301094 TI - Multi-institutional review of outcomes of robot-assisted laparoscopic extravesical ureteral reimplantation. AB - PURPOSE: We performed a multi-institutional assessment of the outcomes and complications of robot-assisted laparoscopic extravesical ureteral reimplantation for vesicoureteral reflux in children. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent robot-assisted laparoscopic extravesical ureteral reimplantation as done by 1 of 5 surgeons at Children's Medical Center, Dallas, Texas, or Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, from 2010 to 2013. Procedure failure was defined as persistent vesicoureteral reflux on postoperative voiding cystourethrogram or radionuclide cystogram and/or the need for reoperation. Multivariate logistic regression was done to identify possible risk factors for failure using STATA(r), version 11. RESULTS: A total of 61 patients (93 ureters) with a mean age of 6.7 years (range 0.6 to 18.0) underwent a procedure, of which 32 (52%) were bilateral. Ten patients (16%) underwent previous subureteral injection for vesicoureteral reflux. At a mean followup of 11.7 months the procedure was successful in 44 of 61 patients (72%). There were 14 cases of persistent vesicoureteral reflux (23%), 6 complications (10%) and 9 reoperations (11%). Multivariate logistic regression identified no factor that increased the risk of failure (p = 0.737). CONCLUSIONS: Compared to the literature we found a notably lower success rate for robot assisted laparoscopic extravesical ureteral reimplantation in the hands of 5 fellowship trained, robotically experienced pediatric urologists. More than 10% of patients required at least 1 reoperation for persistent vesicoureteral reflux or a surgical complication. Our experience suggests a higher complication rate and a lower success rate for robot-assisted laparoscopic ureteral reimplantation compared to the gold standard of open reimplantation. PMID- 25301095 TI - Anatomical study of pelvic nerves in relation to seminal vesicles, prostate and urethral sphincter: immunohistochemical staining, computerized planimetry and 3 dimensional reconstruction. AB - PURPOSE: Studies of male pelvic neuroanatomy are mandatory to improve functional outcome after radical prostatectomy. We performed a topographical investigation of nerves on the course from the seminal vesicles along the prostate toward the striated urethral sphincter. MATERIALS AND METHODS: Serial whole mount sections (1 mm intervals) of pelvic blocks of human adult male autopsy cadavers were investigated after immunohistochemical nerve staining. Computerized nerve quantification and planimetry of the total nerve surface area were performed within defined regions (ventral, ventrolateral, dorsolateral and dorsal) at the levels of the seminal vesicles and prostate, and at the striated urethral sphincter. The distance between the seminal vesicles and the nerves was measured. For improved topographical understanding 3-dimensional reconstructions were created. Differences between 3 independent variables were tested with the nonparametric Kruskal-Wallis test. RESULTS: We studied a total of 969 whole mount sections of 5 cadavers. Nerves were arranged in a vertical plate lateral to the seminal vesicles. Mean +/- SD distance to the seminal vesicles was 1.68 +/- 0.84, 1.50 +/- 0.12 and 1.76 +/- 0.37 mm at the tip, middle and base, respectively. Periprostatic nerves were mainly found dorsolaterally. At the striated urethral sphincter 38.9% of nerves had shifted to the dorsal region. The total nerve surface area decreased significantly from the seminal vesicle tip (50.2 mm(2)) to the striated urethral sphincter level (13.3 mm(2)) (p = 0.0004). CONCLUSIONS: Our findings underline that during nerve sparing prostatectomy nerve damage might occur during mobilization of the entire seminal vesicles, apical dissection and posterior reconstruction of the rhabdosphincter. Nerve planimetry revealed that 75% of the nerves from the seminal vesicles do not reach the striated urethral sphincter level and seem to innervate structures other than the corpora cavernosa. PMID- 25301098 TI - New molecular-scale information on polystyrene dynamics in PS and PS-BaTiO3 composites from FTIR spectroscopy. AB - A new idea to understand the macromolecular motion occurring along the thermal relaxations of polystyrene (PS) and PS-barium titanate composites is proposed. Detailed analysis of PS infrared bands provides a better knowledge of the factors affecting polymer dynamics. Average spectral positions and integrated absorbance of bands in the region of C-H out-of-plane vibrations showed a continuous decrease with temperature, whereas those in the region of aliphatic and aromatic C-H stretching vibrations showed the sharpest changes with temperature. Relaxation temperatures were determined from the changes observed in the band wavenumber or area with temperature. These results were attributed to changes in the distribution of the phenyl pi-electron cloud, causing important dipole moment variations in the different vibration modes when the thermal transitions are taking place. Finally, although the presence of BaTiO3 particles does not seem to exert any specific effect on the PS dynamics in the glassy state, the Curie transition of these particles might induce a kind of confinement effect observable by FTIR. PMID- 25301096 TI - Transcriptional dysregulation in the ureteric bud causes multicystic dysplastic kidney by branching morphogenesis defect. AB - PURPOSE: The calcineurin-NFAT signaling pathway regulates the transcription of genes important for development. It is impacted by various genetic and environmental factors. We investigated the potential role of NFAT induced transcriptional dysregulation in the pathogenesis of congenital abnormalities of the kidneys and urinary tract. MATERIALS AND METHODS: A murine model of conditional NFATc1 activation in the ureteric bud was generated and examined for histopathological changes. Metanephroi were also cultured in vitro to analyze branching morphogenesis in real time. RESULTS: NFATc1 activation led to defects resembling multicystic dysplastic kidney. These mutants showed severe disorganization of branching morphogenesis characterized by decreased ureteric bud branching and the disconnection of ureteric bud derivatives from the main collecting system. The orphan ureteric bud derivatives may have continued to induce nephrogenesis and likely contributed to the subsequent formation of blunt ended filtration units and cysts. The ureter also showed irregularities consistent with impaired epithelial-mesenchymal interaction. CONCLUSIONS: This study reveals the profound effects of NFAT signaling dysregulation on the ureteric bud and provides insight into the pathogenesis of multicystic dysplastic kidney. Our results suggest that the obstruction hypothesis and the bud theory may not be mutually exclusive to explain the pathogenesis of multicystic dysplastic kidney. Ureteric bud dysfunction such as that induced by NFAT activation can disrupt ureteric bud-metanephric mesenchyma interaction, causing primary defects in branching morphogenesis, subsequent dysplasia and cyst formation. Obstruction of the main collecting system can further enhance these defects, producing the pathological changes associated with multicystic dysplastic kidney. PMID- 25301097 TI - Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. AB - Inflammation is associated with oxidative stress and characterized by elevated levels of damage-associated molecular pattern (DAMP) molecules released from injured or even living cells into the surrounding microenvironment. One of these endogenous danger signals is the extracellular mitochondrial DNA (mtDNA) containing evolutionary conserved unmethylated CpG repeats. Increased levels of reactive oxygen species (ROS) generated by recruited inflammatory cells modify mtDNA oxidatively, resulting primarily in accumulation of 8-oxo-7,8 dihydroguanine (8-oxoG) lesions. In this study, we examined the impact of native and oxidatively modified mtDNAs on the phenotypic and functional properties of plasmacytoid dendritic cells (pDCs), which possess a fundamental role in the regulation of inflammation and T cell immunity. Treatment of human primary pDCs with native mtDNA up-regulated the expression of a costimulatory molecule (CD86), a specific maturation marker (CD83), and a main antigen-presenting molecule (HLA DQ) on the cell surface, as well as increased TNF-alpha and IL-8 production from the cells. These effects were more apparent when pDCs were exposed to oxidatively modified mtDNA. Neither native nor oxidized mtDNA molecules were able to induce interferon (IFN)-alpha secretion from pDCs unless they formed a complex with human cathelicidin LL-37, an antimicrobial peptide. Interestingly, simultaneous administration of a Toll-like receptor (TLR)9 antagonist abrogated the effects of both native and oxidized mtDNAs on human pDCs. In a murine model, oxidized mtDNA also proved a more potent activator of pDCs compared to the native form, except for induction of IFN-alpha production. Collectively, we demonstrate here for the first time that elevated levels of 8-oxoG bases in the extracellular mtDNA induced by oxidative stress increase the immunostimulatory capacity of mtDNA on pDCs. PMID- 25301099 TI - No evidence for desmocollin 3 to serve as a prognostic marker in primary radiotherapy of head and neck cancer. AB - PURPOSE: To investigate the role of desmocollin 3 expression in radiation sensitivity and survival in squamous cell carcinoma of the head and neck. METHODS: Tissue samples of 40 patients undergoing primary radiotherapy were stained for desmocollin 3, a transmembrane desmosomal protein. The protein expression was determined by immunohistochemistry. A retrospective chart review was performed to assess overall survival, radiation sensitivity, and disease-free interval. RESULTS: 18 of 40 patients showed desmocollin 3 immunoreactivity. 78 % (14/18) showed radiation sensitivity in the desmocollin 3 positive group, whereas 59 % (13/22) underwent remission in the desmocollin 3 negative group (p = 0.2). The median overall and disease-free survival time was 21 and 26 months, respectively. Univariate and multivariable Cox regression models revealed no statistically significant hazard ratios. CONCLUSION: In this cohort of squamous cell carcinoma of the head and neck, we found no evidence for a predictive potential of desmocollin 3. PMID- 25301100 TI - Therapy of a clear cell adenocarcinoma of unknown primary arising in the abdominal wall after cesarean section and after hysterectomy. AB - Clear cell carcinoma arising in a cesarean section scar is extremely rare. Due to the rarity of the tumor, treatment strategies still need to be further elucidated. We report a case of a woman with a clear cell carcinoma of 10 cm outside the abdominal cavity in her cesarean section scar. Staging surgery revealed two lymph nodes with metastatic dissemination of a clear cell adenocarcinoma. After staging surgery, six cycles of adjuvant chemotherapy with carboplatin/paclitaxel were performed. The patient was disease-free 10 months after completion of chemotherapy. Comprehensive treatment consisting of radical surgery combined with adjuvant chemotherapy can be considered for this uncommon tumor entity. PMID- 25301101 TI - Imbalance of HCN1 and HCN2 expression in hippocampal CA1 area impairs spatial learning and memory in rats with chronic morphine exposure. AB - The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation (HCN) channels play a vital role in the neurological basis underlying nervous system diseases. However, the role of HCN channels in drug addiction is not fully understood. In the present study, we investigated the expression of HCN1 and HCN2 subunits in hippocampal CA1 and the potential molecular mechanisms underlying the modulation of HCN channels in rats with chronic morphine exposure with approaches of electrophysiology, water maze, and Western blotting. We found that chronic morphine exposure (5 mg/kg, sc, for 7 days) caused an inhibition of long-term potentiation (LTP) and impairment of spatial learning and memory, which is associated with a decrease in HCN1, and an increase in HCN2 on cell membrane of hippocampal CA1 area. Additional experiments showed that the imbalance of cell membrane HCN1 and HCN2 expression under chronic morphine exposure was related to an increase in expression of TPR containing Rab8b interacting protein (TRIP8b) (1a-4) and TRIP8b (1b-2), and phosphorylation of protein kinase A (PKA) and adaptor protein 2 MU2 (AP2 MU2). Our results demonstrate the novel information that drug addiction-induced impairment of learning and memory is involved in the imbalance of HCN1 and HCN2 subunits, which is mediated by activation of TRIP8b (1a-4), TRIP8b (1b-2), PKA and AP2 MU2. PMID- 25301102 TI - siRNA liposome-gold nanorod vectors for multispectral optoacoustic tomography theranostics. AB - Therapeutic applications of gene silencing using siRNA have seen increasing interest over the past decade. The optimization of the delivery and biodistribution of siRNA using liposome-gold nanorod (AuNRs) nanoscale carriers can greatly benefit from adept imaging methods that can visualize the time resolved delivery performance of such vectors. In this work, we describe the effect of AuNR length incorporated with liposomes and show their complexation with siRNA as a novel gene delivery vehicle. We demonstrate the application of multispectral optoacoustic tomography (MSOT) to longitudinally visualize the localisation of siRNA carrying liposome-AuNR hybrids within tumors. Combination of in vivo MSOT with ex vivo fluorescence cryo-slice imaging offers further insight into the siRNA transport and activity obtained. PMID- 25301103 TI - Intravascular foscarnet crystal precipitation causing multiorgan failure. AB - We report a case of multiorgan failure resulting from treatment with the antiviral foscarnet in a kidney transplant recipient. Precipitation of foscarnet crystals was confirmed histologically from a biopsy of the transplant using optical and infrared microscopy. In addition to kidney damage resulting from foscarnet crystal precipitation in the tubular lumen and glomerular capillaries, the patient presented with pancreatitis, pancolitis, and myocarditis with shock. Interruption of the treatment led to rapid improvement in her general condition, but did not prevent permanent loss of the kidney transplant. When faced with unexplained multiorgan failure in a patient treated with foscarnet, one should assume this substance to be toxic. A kidney biopsy can confirm this diagnosis. PMID- 25301104 TI - A genetic marker of uric acid level, carotid atherosclerosis, and arterial stiffness: a family-based study. AB - BACKGROUND: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. FACTOR: Serum uric acid level, rs734553 allele, and age. OUTCOME: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). RESULTS: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8*10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (beta=0.33; P=0.01), whereas no such relationship was found for internal diameter (beta=-0.15; P=0.3) or PWV (beta=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (beta=0.40 [P<0.001] and beta=0.48 [P=0.003], respectively) analyses. LIMITATIONS: This is a hypothesis-generating study. CONCLUSIONS: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis. PMID- 25301105 TI - Strengthening Nepal's Female Community Health Volunteer network: a qualitative study of experiences at two years. AB - BACKGROUND: Nepal's Female Community Health Volunteer (FCHV) program has been described as an exemplary public-sector community health worker program. However, despite its merits, the program still struggles to provide high-quality, accessible services nation-wide. Both in Nepal and globally, best practices for community health worker program implementation are not yet known: there is a dearth of empiric research, and the research that has been done has shown inconsistent results. METHODS: Here we evaluate a pilot program designed to strengthen the Nepali government's FCHV network. The program was structured with five core components: 1) improve local FCHV leadership; 2) facilitate structured weekly FCHV meetings and 3) weekly FCHV trainings at the village level; 4) implement a monitoring and evaluation system for FCHV patient encounters; and 5) provide financial compensation for FCHV work. Following twenty-four months of program implementation, a retrospective programmatic evaluation was conducted, including qualitative analysis of focus group discussions and semi-structured interviews. RESULTS: Qualitative data analysis demonstrated that the program was well-received by program participants and community members, and suggests that the five core components of this program were valuable additions to the pre existing FCHV network. Analysis also revealed key challenges to program implementation including geographic limitations, literacy limitations, and limitations of professional respect from healthcare workers to FCHVs. Descriptive statistics are presented for programmatic process metrics and costs throughout the first twenty four months of implementation. CONCLUSIONS: The five components of this pilot program were well-received as a mechanism for strengthening Nepal's FCHV program. To our knowledge, this is the first study to present such data, specifically informing programmatic design and management of the FCHV program. Despite limitations in its scope, this study offers tangible steps forward for further research and community health worker program improvement, both within Nepal and globally. PMID- 25301107 TI - Polymer translocation: the first two decades and the recent diversification. AB - Probably no other field of statistical physics at the borderline of soft matter and biological physics has caused such a flurry of papers as polymer translocation since the 1994 landmark paper by Bezrukov, Vodyanoy, and Parsegian and the study of Kasianowicz in 1996. Experiments, simulations, and theoretical approaches are still contributing novel insights to date, while no universal consensus on the statistical understanding of polymer translocation has been reached. We here collect the published results, in particular, the famous infamous debate on the scaling exponents governing the translocation process. We put these results into perspective and discuss where the field is going. In particular, we argue that the phenomenon of polymer translocation is non universal and highly sensitive to the exact specifications of the models and experiments used towards its analysis. PMID- 25301108 TI - Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes. AB - Increased abnormal oocytes due to meiotic chromosome misalignment and spindle defects lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Here, we investigated the effect of biotin deficiency on oocyte quality. Three-week-old female ICR mice were fed a biotin-deficient or control diet (0, 0.004 g biotin/kg diet) for 21 days. On day 22, these mouse oocytes were analyzed by immunofluorescence. Due to biotin, undernutrition increased the frequency of abnormal oocytes (the biotin deficient vs. control: 40 vs. 16%). Next, the remaining mice in the biotin-deficient group were fed a control or biotin-deficient diet from day 22 to 42. Although biotin nutritional status in the recovery group was restored, the frequency of abnormal oocytes in the recovery group was still higher than that in the control group (48 vs. 18%). Our results indicate that steady, sufficient biotin intake is required for the production of high-quality oocytes in mice. PMID- 25301106 TI - Application of adenosine triphosphate affinity probe and scheduled multiple reaction monitoring analysis for profiling global kinome in human cells in response to arsenite treatment. AB - Phosphorylation of cellular components catalyzed by kinases plays important roles in cell signaling and proliferation. Quantitative assessment of perturbation in global kinome may provide crucial knowledge for elucidating the mechanisms underlying the cytotoxic effects of environmental toxicants. Here, we utilized an adenosine triphosphate (ATP) affinity probe coupled with stable isotope labeling by amino acids in cell culture (SILAC) to assess quantitatively the arsenite induced alteration of global kinome in human cells. We constructed a SILAC compatible kinome library for scheduled multiple-reaction monitoring (MRM) analysis and adopted on-the-fly recalibration of retention time shift, which provided better throughput of the analytical method and enabled the simultaneous quantification of the expression of ~300 kinases in two LC-MRM runs. With this improved analytical method, we conducted an in-depth quantitative analysis of the perturbation of kinome of GM00637 human skin fibroblast cells induced by arsenite exposure. Several kinases involved in cell cycle progression, including cyclin dependent kinases (CDK1 and CDK4) and Aurora kinases A, B, and C, were found to be hyperactivated, and the altered expression of CDK1 was further validated by Western analysis. In addition, treatment with a CDK inhibitor, flavopiridol, partially restored the arsenite-induced growth inhibition of human skin fibroblast cells. Thus, sodium arsenite may confer its cytotoxic effect partly through the aberrant activation of CDKs and the resultant perturbation of cell cycle progression. Together, we developed a high-throughput, SILAC-compatible, and MRM-based kinome profiling method and demonstrated that the method is powerful in deciphering the molecular modes of action of a widespread environmental toxicant. The method should be generally applicable for uncovering the cellular pathways triggered by other extracellular stimuli. PMID- 25301109 TI - [Depression post stroke in Africa: myth or reality?]. AB - Depression is a complication occurring frequently after a stroke. It negatively affects the physical, cognitive and social recovery. Authors report the results of a casecontrol study section was performed in neurology of the friendship hospital and psychiatry of the general hospital in Bangui, from January to August 2012 to ascertain the existence of a link between stroke and depression in hospitalized patients and to identify factors limiting taken into efficient load. On one hundred five subjects included, thirty five were stroke victims matched with seventy witnesses. The prevalence of post stroke depression was 88.6% (31/35) versus (20/70) 28.5% in controls (p <0.001). This post stroke depression occurred in 58% of men with a sex ratio of 1.4. The mean age of subjects with post stroke depression was 49.1 years, with extremes ranging from 33 to 76 years of age. Most (64.5%) subjects with post stroke depression was no occupation; 71.5% of them had a stroke dating back more than six weeks, and 92% had a motor deficit with a Barthel Index <100. Subjects with stroke suffered mostly moderate depression (48.1%) whereas the controls usually had mild depression (80.4%). This depression was not correlated with motor deficit, or the laterality of the lesion, or cognitive disorder. But, some Central African specificities could explain this phenomenon. These results demonstrate the reality of post stroke depression in Africa, hence the need to think in support of any subject with stroke topic. Moreover, questions about the tools used to evaluate the post stroke depression and the time interval between stroke onset and the onset of depressive symptoms remain and require further consideration. PMID- 25301110 TI - [Severe poisoning by plants used for traditional medicine in Mayotte]. AB - The authors describe three cases of severe accidental poisoning by plants used as part of a traditional treatment in Mayotte. The established, or suspected, toxicity of Thevetia peruviana (Yellow oleander), Cinchona pubescens (Red quinine tree), Melia azaderach (Persian lilac, also called china berry) and Azadirachta indica (Neem), is discussed. The clinical presentation is cardiac (atrioventricular block) and well known for Thevetia and Cinchona intoxications. Neurological signs and multi-organ failure are found for Azadirachta and Melia. The identification of the plants is never easy, nor is the evidence of their accountability. In the three cases reported, no other cause than the traditional treatment has been found to explain the clinical presentation. The outcome was favorable in all cases. The authors emphasize the difficulties to investigate these accidents, the poor medical knowledge of these practices in tropical areas, and in Mayotte particularly. The need for cooperation with local botanists, familiar with traditional medicine, is also underlined. PMID- 25301111 TI - Uracil-DNA glycosylase (UNG) rs246079 G/A polymorphism is associated with decreased risk of esophageal cancer in a Chinese population. AB - Esophageal cancer is the sixth leading cause of cancer-associated death worldwide. In addition to environmental risk factors, genetic factors might play an important role in esophageal cancer carcinogenesis. We conducted a hospital based case-control study to evaluate the association between functional single nucleotide polymorphisms (SNPs) in uracil-DNA glycosylase (UNG) and the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The UNG rs3219218 A/G and UNG rs246079 G/A genotypes were determined using matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). When the UNG rs246079 GG homozygote genotype was used as the reference group, the GA genotype was associated with a significantly decreased risk for ESCC (GA vs. GG: adjusted OR 0.67, 95 % CI 0.49-0.91, P = 0.011); the AA genotype was not associated with the risk of ESCC. In stratification analyses, a significantly decreased risk of ESCC associated with the UNG rs246079 G/A polymorphism was evident among women, younger patients and never-smokers and never-drinkers. The UNG rs3219218 A/G polymorphism was not associated with the risk for ESCC. These findings indicated that UNG rs246079 G/A might contribute to a decreased risk of ESCC in specific populations. Because of the limited sample size, further studies including a larger and more diverse population, as well as tissue-specific biological characterization, are required to confirm the current findings. PMID- 25301112 TI - ABCB1 haplotypes but not individual SNPs predict for optimal response/failure in Egyptian patients with chronic-phase chronic myeloid leukemia receiving imatinib mesylate. AB - Imatinib mesylate (IM) has so far been the standard of care for treating chronic myeloid leukemia (CML), but the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance, which may in part be caused by pharmacogenetic variability. The ATP-binding cassette, subfamily B, member 1 (ABCB1) gene codes for P-glycoprotein (P-gp), a membrane-bound efflux transporter known to affect the pharmacokinetics of many drugs. IM is a substrate of the P-gp-mediated efflux. ABCB1 single nucleotide polymorphisms (SNPs) have been reported as modulators of ABCB1-mediated transport, affecting IM's bioavailability and consequently the treatment outcome of IM therapy. We aimed to examine the association between ABCB1 SNPs and the likelihood of achieving optimal response in IM-treated CML patients. Three ABCB1 SNPs (C1236T, G2677T, and C3435T) were genotyped in 100 Egyptian patients with CML undergoing IM therapy using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The optimal response rate did not differ significantly between C1236T, G2677T, or C3435T genotypes (P > 0.05). Optimal response rate was significantly different among patients with the CGC, TTT, TGC, CGT, TGT, CTC, CTT, and TTC haplotypes (P = 0.023). The 1236T-2677G-3435T haplotype was significantly associated with lower probability of achieving optimal response (P = 0.001). ABCB1 SNPs haplotype analysis should be taken into account in an attempt to get clearer insights into who is likely to respond optimally to IM for identifying CML patients who may not respond optimally to standard-dose IM therapy and potentially need an individualized therapeutic approach. PMID- 25301113 TI - The miRNA23b-regulated signaling network as a key to cancer development- implications for translational research and therapeutics. AB - A growing body of evidence indicates that microRNA23b (miR23b) is pleiotropic-it plays important roles in regulating physiological functions of cells, in regulating differentiation of cells and in regulating cellular immune responses. Our review of the literature showed that dysregulation of miR23b expression is implicated in the disruption of these cellular mechanisms and development of diseases such as cancer. MiR23b dysregulation appears to do this by modulating the expression level of candidate gene products involved in a network of signaling pathways including TGF-beta and Notch pathways that govern malignant properties of cancer cells such as motility and invasiveness. More recently, miR23b regulation of gene expression has also been associated with cancer stem cells and chemoresistance. Our review covers miR23b's role in immunity, endothelial function, differentiation, and cancer as well as its potential for translation into future cancer diagnostics and therapeutics. PMID- 25301115 TI - [The disability associated with osteoarthritis]. AB - Osteoarthritis is a chronic joint disease and a potentially disabling illness, whose prevalence has increased in recent years alongside the aging population. The disability associated with this condition generates a brutal impact on individuals who are limited in their basic daily living activities. The increase in life expectancy is not correlated with an increase in quality of life, since the years of life increase, but characterized for living with disabilities. PMID- 25301116 TI - [Comments on the article "Hemophilia"]. PMID- 25301114 TI - Comparative genomic analysis of genogroup 1 (Wa-like) rotaviruses circulating in the USA, 2006-2009. AB - Group A rotaviruses (RVA) are double stranded RNA viruses that are a significant cause of acute pediatric gastroenteritis. Beginning in 2006 and 2008, respectively, two vaccines, RotarixTM and RotaTeq(r), have been approved for use in the USA for prevention of RVA disease. The effects of possible vaccine pressure on currently circulating strains in the USA and their genome constellations are still under investigation. In this study we report 33 complete RVA genomes (ORF regions) collected in multiple cities across USA during 2006 2009, including 8 collected from children with verified receipt of 3 doses of rotavirus vaccine. The strains included 16 G1P[8], 10 G3P[8], and 7 G9P[8]. All 33 strains had a Wa like backbone with the consensus genotype constellation of G(1/3/9)-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. From maximum likelihood based phylogenetic analyses, we identified 3-7 allelic constellations grouped mostly by respective G types, suggesting a possible allelic segregation based on the VP7 gene of RVA, primarily for the G3 and G9 strains. The vaccine failure strains showed similar grouping for all genes in G9 strains and most genes of G3 strains suggesting that these constellations were necessary to evade vaccine-derived immune protection. Substitutions in the antigenic region of VP7 and VP4 genes were also observed for the vaccine failure strains which could possibly explain how these strains escape vaccine induced immune response. This study helps elucidate how RVA strains are currently evolving in the population post vaccine introduction and supports the need for continued RVA surveillance. PMID- 25301118 TI - [Comments regarding the article "Renal function ..."]. PMID- 25301117 TI - [Answer to comments on the article "Hemophilia"]. PMID- 25301119 TI - [Answer to comments regarding the article "Renal function ..."]. PMID- 25301120 TI - [Comment on "Economical costs and consequences of childhood obesity"]. PMID- 25301121 TI - [Answer to comment on the article "Economical costs ..."]. PMID- 25301122 TI - [Comment on the article "Comments with regards to scientific research in IMSS"]. PMID- 25301123 TI - [Beta-1 adrenoceptor blockade decreases the firing rate to painful stimuli in spinal wide-dynamic range neurons in rats]. AB - BACKGROUND: It is known that epinephrine/norepinephrine inhibit acute pain transmission. However, the role of beta-adrenoceptors is not clear. Thus, we analyzed if beta-1 and/or beta-2 adrenoceptors can modulate acute pain transmission by performing in vivo single unit recordings during painful and non painful peripheral stimulation in rats. METHODS: Longitudinal study in which we analyzed seven groups of male rats Wistar: control group (n = 11): saline (0.9 %); EPI group (n = 8): epinephrine 100 mcg; beta-1 agonist group (n = 8): dobutamine 125 mcg; beta-1-antagonist group (n = 9): metoprolol 100 mcg; beta-2 agonist group (n = 7): clenbuterol 100 mcg; beta-2-antagonist group (n = 8): butoxamine 100 mcg; beta-1-antagonist + EPI group (n = 10): metoprolol 100 mcg + epinephrine 100 mcg. For the statistical analysis we used ANOVA. RESULTS: Epinephrine significantly reduced the basal firing rate (BFR) in 34.1 % (p < 0.05) and also the evoked response by painful stimulation in 56 % (p < 0.05). No change was observed in the evoked response by non-painful stimulation. ANTbeta1 was the only beta-adrenoceptor acting drug that significantly reduced the evoked response by painful stimulation in 41 % (p < 0.05). None of the other drugs alone affected either the BFR or the evoked response to non-painful or painful stimulation. CONCLUSIONS: It is the first time that a beta-1-adrenoceptor antagonist (metoprolol) probes to be effective in reducing the response to painful stimulation in WDR neurons. PMID- 25301124 TI - [The use of therapeutic writing in an institutional context]. AB - BACKGROUND: This article aims to explain the effect of the use of writing, in an institutional therapeutic space, as a means to achieve the therapeutic change in the patient and a greater efficiency in time and in institutional spaces. METHODS: Different forms of using the written document are shown and supported theoretically in the context of narrative and collaborative therapy, as well as examples with the presentation of excerpts of writings of the participants. The sample was composed of patients attending the Hospital de Psiquiatria, Unidad Morelos, to receive treatment in any of the forms (commital and/or outpatient consultation). RESULTS: Written and oral language exchange meaning continuously, showing that the therapeutic process takes place beyond institutional and therapeutic spaces (and times). This encourages the advantages offered by the use of written language in oral psychotherapeutic processes. CONCLUSIONS: Writing is an intellectual resource which facilitates thinking, since when we write our own experiences the events that constitutes them are organized in time. This produces a perception of change, a representation of meanings, and stimulates self efficiency, since it produces several stories of the events and experiences. PMID- 25301125 TI - [Association of Doppler flowmetry with perinatal outcome in patients with oligohydramnios]. AB - BACKGROUND: Oligohydramnios is sometimes associated with poor perinatal outcome. Our aim was to determine the association of Doppler flowmetry with perinatal outcome in patients with oligohydramnios. METHODS: We carried out a prospective cross-sectional study that included 130 patients with pregnancy between 30 to 41 weeks of gestation; we compared the measurement of the resistance index in the umbilical artery by Doppler flowmetry and the measurement of amniotic fluid in patients with oligohydramnios. A follow-up of patients after birth was made, recording the Apgar score and whether they required special attention. The data were analyzed using descriptive statistics and we calculated the sensitivity, specificity, accuracy, and predictive values of the tests. RESULTS: Sensitivity, specificity and accuracy were obtained for oligohydramnios associated to perinatal death and for five-minute Apgar, with results of 100, 0, 50 % and 0, 0, 0 % respectively. The resistance index of umbilical artery related to perinatal death had sensitivity, specificity and accuracy of 100, 96 and 98 %, while in the Apgar were 0, 95 and 47.5 %, respectively. CONCLUSIONS: Doppler flowmetry of the umbilical artery showed a higher sensitivity, specificity and accuracy to diagnose perinatal death than the measurement of oligohydramnios and the Apgar score. PMID- 25301126 TI - [Relationship between dyslipidemia and severity in preeclampsia]. AB - BACKGROUND: It has been found that the cholesterol and triglyceride values are higher in preeclampsia than in normal pregnancy, even though it is unclear whether these levels are related to the severity. The aim of this study was to determine the correlation between dyslipidemia and severity in preeclampsia. METHODS: Comparative cross-sectional study in 200 patients, 100 with normal pregnancy and 100 with preeclampsia. The age, gynecological and obstetric history, total cholesterol and triglycerides were identified. Descriptive statistics were used: Student's t test for comparing the group of patients with preeclampsia and normal pregnancies, and ANOVA and odds ratio for the subanalysis of mild and severe preeclampsia. RESULTS: No statistically significant differences in age or cholesterol were found. Triglycerides showed a statistically significant difference: they were higher in relation to the severity of preeclampsia (normal pregnancy: 245 mg; mild preeclampsia: 308 mg; severe preeclampsia: 349 mg). CONCLUSIONS: Elevated levels of cholesterol and triglycerides in patients with preeclampsia showed no consistent relationship with the severity of preeclampsia. PMID- 25301127 TI - [Predictors of no-reflow phenomenon after primary percutaneous coronary intervention]. AB - BACKGROUND: No-reflow phenomenon is a common event in patients with acute myocardial infarction with ST elevation (STEMI) who underwent primary percutaneous coronary intervention. The objective is to determine the cumulative incidence of no-reflow phenomenon and some predictors related to its occurrence. METHODS: We retrospectively analyzed the reports of 71 patients with STEMI. Subjects were categorized in two groups, those with no-reflow phenomenon and those without it; their clinical findings were compared. Predictive factors were identified by logistic regression analysis. RESULTS: We identified 20 patients with no-reflow phenomenon (with a cumulative incidence of 28.1 %) and 51 with adequate reperfusion. In the univariate analysis the following predictors were related to the no-reflow phenomenon: CK-MB = 160 UI/L, Killip class = II, TIMI flow 0, having more than two Q waves in ECG, the form of reperfusion therapy and the presence of intracoronary thrombus. The multivariate logistic regression analysis identified Killip class = II (OR = 9.3, p = 0.008), = two Q waves in ECG (OR = 1.8, p = 0.05), angioplasty as unique reperfusion therapy (OR = 19.9, p = 0.017) and the presence of intracoronary thrombus (OR = 11.9, p = 0.008) as predictors of no-reflow phenomenon. CONCLUSIONS: The early detection of predictors of no-reflow phenomenon will establish measures aimed to reduce its presentation. PMID- 25301128 TI - [Prognostic factors in elderly patient meningioma]. AB - BACKGROUND: Frequently, therapeutic decisions must be made in order to manage meningioma in geriatric patients. This study analyzes the prognostic factors, as well as the Clinical Radiological Grading Score (CRGS) as a complement to make therapeutic decisions. METHODS: A retrospective study was conducted between 2009 and 2010. The study population consisted of 28 patients over 65 years of age. We analyzed clinical, imaging and histopathological factors. We used the chi-squared test and the Fisher exact test for quantitative variables, as well as the Mann Whitney U for qualitative variables. RESULTS: Overall mortality at 3, 6 and 12 months of follow-up was 7.14, 10.71 and 14.28 %, respectively. The analysis revealed that performance status with Karnofsky scale (p = 0.02), the location of the lesion (p = 0.002), histopathological malignancy grade (p = 0.038), and a score lower than 10 on the CRGS (p = 0.003) were associated with poor prognosis. CONCLUSIONS: The neurosurgical management of geriatric patients is a therapeutic option with a favorable prognosis in patients with a score equal to or greater than 10 and those with adequate functional status. PMID- 25301129 TI - [Dyslalias associated to maloclussion in schoolchildren]. AB - BACKGROUND: The test for evaluating phonological simplification processes (TEPROSIF, according to its initials in Spanish) is a tool which is used to identify dyslalias. Our objective was to establish, by using TEPROSIF, the association between dyslalias and malocclusion in children from 4 to 6 years of age. METHODS: After we standardized the tool with a kappa of 0.9, we applied it to 116 children from 4 to 6 years of age. Patients were conducted to a central occlusion through deglutition. We observed type of bite, overbite, occlusion and terminal plane in order to relate them to the dyslalia presented. For statistical analysis, we used chi-squared test (p < 0.05). RESULTS: They were 55 (47.4 %) boys and 61 (52.6 %) girls, with a median age of 5 years +/- 0.71. Phoneme substitution was the most common alteration. We found significant correlation between omission of the phonemes and terminal plane (p = 0.01), Baume type I arch (p = 0.00) and absence of teeth (p = 0.00), as well as between phoneme substitution and terminal plane (p = 0.03), bite type (p = 0.01) and absence of teeth (p = 0.00). CONCLUSIONS: Phoneme substitution is the most common alteration, followed by omission and distortion of phonemes in children between 4 and 6 years of age. PMID- 25301130 TI - [Premature twins: clinic comparison, reproductive assisted techniques versus spontaneous conception]. AB - BACKGROUND: Twin pregnancies occur one out of every 800. Due to the increase in maternal age and infertility, the use of assisted reproductive technology (ART) has risen. Thirty five percent of pregnancies solved using ART are twin pregnancies. A RT consists of infertility treatments in which oocytes and sperm are manipulated. The objective of this study was to compare the clinical behavior of premature twins born through ART versus those born after spontaneous conception (SC). METHODS: Retrolective cohort study. The data was obtained from the records of preterm twins born between August 2010 and August 2013. Preterm twins were categorized in two groups: the ones conceived using ART versus those conceived through SC. Demographic characteristics and neonatal outcomes were compared. RESULTS: The total was of 398 patients: 208 conceived in consequence of ART and 190 through SC. The primary outcome and neonatal morbidities showed no significant difference, only the incidence of necrotizing enterocolitis and the use of parenteral nutrition showed significant difference. The length of hospital stay between groups was similar. CONCLUSIONS: In our population of preterm twins, the mode of conception had no detectable effect on mortality or short term morbidities. PMID- 25301131 TI - [Clinical research XXIII. From clinical judgment to meta-analyses]. AB - Systematic reviews (SR) are studies made in order to ask clinical questions based on original articles. Meta-analysis (MTA) is the mathematical analysis of SR. These analyses are divided in two groups, those which evaluate the measured results of quantitative variables (for example, the body mass index -BMI-) and those which evaluate qualitative variables (for example, if a patient is alive or dead, or if he is healing or not). Quantitative variables generally use the mean difference analysis and qualitative variables can be performed using several calculations: odds ratio (OR), relative risk (RR), absolute risk reduction (ARR) and hazard ratio (HR). These analyses are represented through forest plots which allow the evaluation of each individual study, as well as the heterogeneity between studies and the overall effect of the intervention. These analyses are mainly based on Student's t test and chi-squared. To take appropriate decisions based on the MTA, it is important to understand the characteristics of statistical methods in order to avoid misinterpretations. PMID- 25301132 TI - [Enviromental factors related to depressive disorders]. AB - BACKGROUND: As a result of their high prevalence, mayor depressive disorder single episode (MDDSE); major depressive disorder recurrent episodes (MDDREC); and dysthymia are considered an important public health problem. The objective of this paper was to identify and correlate environmental factors in patients with MDDSE, MDDREC and dysthymia. METHODS: 121 patients from the Instituto Mexicano del Seguro Social's Subzone General Hospital of San Andres Tuxtla, at Veracruz, were questioned by history with the risk variables. RESULTS: 16 of them were diagnosed with MDDREC, 72 with MDD and 33 with dysthymia; in all of those cases, females prevailed. Depressive disorders were observed more frequently in people over 40 years, married, with medium or low educational level, with dysfunctional family environment, victims of family violence and who were the middle siblings. The main comorbidities that arose were gastrointestinal disorders, obesity and hypertension. RESULTS: 16 of them were diagnosed with MDDREC, 72 with MDD and 33 with dysthymia; in all of those cases, females prevailed. Depressive disorders were observed more frequently in people over 40 years, married, with medium or low educational level, with dysfunctional family environment, victims of family violence and who were the middle siblings. The main comorbidities that arose were gastrointestinal disorders, obesity and hypertension. CONCLUSIONS: The main risk factors identified for developing depressive disorders were: being female, over 40 years old and being married. The differences obtained in this study, if it is compared with others, are probably due to sample size, selection criteria and ethnic origin. PMID- 25301133 TI - [Metabolic syndrome in workers of a second level hospital]. AB - BACKGROUND: People with metabolic syndrome (20-25 % of the world population) are three times more likely to suffer a heart attack or stroke and twice as likely to die from this cause. The objective of this study was to assess the prevalence of metabolic syndrome in workers of a second level hospital. METHODS: This was a cross-sectional study with 160 healthcare workers in Monterrey, Mexico. Sociodemographic, anthropometric and biochemical data were obtained to assess the prevalence of metabolic syndrome. Bivariate and multiple logistic regression analysis were carried out in order to assess the relationship between metabolic syndrome and sociodemographic and occupational variables. RESULTS: The prevalence of metabolic syndrome among workers was 38.1 %. Nurses were more affected with 32.8 %. Overweight and obesity were prevalent in 78 %. In the logistic regression there was a significant association between metabolic syndrome and not having partner (OR 3.98, 95 % CI [1.54-10.25]) and obesity (OR 4.69, 95 % CI [1.73 12.73]). CONCLUSIONS: The prevalence of metabolic syndrome and obesity is alarming. Appropriate and prompt actions must be taken in order to reduce the risk of cardiovascular disease in this population. PMID- 25301134 TI - [Obesity and components of metabolic syndrome in Mexican women survivors of cancer]. AB - BACKGROUND: Some studies suggest that obesity and metabolic syndrome are frequent in cancer survivors. In our country, there is a lack of documentation with regards to this problem in women. Therefore, our aim is to establish the prevalence of obesity and metabolic syndrome components in surviving Mexican women. METHODS: We elected women who received treatment for cancer with a surviving = 24 months. The data evaluated were demography, clinical anthropometry, blood pressure measurement, kind of cancer, surviving time, and comorbidities, as well as glucose, cholesterol, and triglyceride levels. RESULTS: We studied 107 women. Their average age was 60 +/- 10 years, with a surviving time of 77 +/- 43 months, and a body mass index of 31 +/- 6 kg/m2. Their mean glucose level was 120 +/- 58 mg/dL, cholesterol 228 +/- 43 mg/dL, and triglycerides 207 +/- 120 mg/dL. There were 55 (51 %) with glucose > 99 mg/dL, 85 (79 %) with cholesterol > 199 mg/dL, and 67 (63 %) with triglycerides > 149 mg/dL. Obesity (body mass index = 30 kg/m2) occurred in 49 (46 %) and metabolic syndrome in 27 (26 %). CONCLUSIONS: Due to a high prevalence of obesity, metabolic syndrome components were frequent. PMID- 25301135 TI - [Proctocolectomy with ileoanal anastomoses and desmoid tumor treated with resection. One case of familial adenomatous polyposis]. AB - BACKGROUND: Familial adenomatous polyposis (FAP) is a rare disease caused by a mutation in the adenomatous polyposis coli gene (APC). CASE REPORT: We report the case of a 32-year-old woman, with abdominal pain and increased abdominal perimeter, as well as melena and weight loss. She had a tumor of 12 cm in diameter in the right iliac fossa. After the administration of contrast media we found the abdominal tumor compatible with sarcoma versus desmoid tumor. We performed a colonoscopy and we found colorectal polyps. The biopsy reported tubulovillous adenomas. A panendoscopy showed polyps in fundus and body of stomach; the state of the duodenum was normal. Tumor resection was performed with abdominal wall reconstruction with mesh and restorative proctocolectomy with ileoanal reservoir and a temporary ileostomy. The histopathology report demonstrated an abdominal wall desmoid tumor and identified 152 tubulovillous polyps which affected all the portions of colon and rectum. CONCLUSIONS: FAP is an autosomal dominant disease caused by a mutation in the APC gene which results in the development of multiple colorectal polyps. Described in 1991 the APC gene is located at chromosome region 5q21. Without prophylactic surgery, virtually all patients develop colorectal cancer in the third decade of life. Desmoid tumors and duodenal polyps are now the leading cause of death in patients with FAP. PMID- 25301136 TI - [Idiopathic scrotal elephantiasis. A case report]. AB - BACKGROUND: Penoscrotal lymphedema (scrotal elephantiasis) is a condition that has been described in areas in which filariasis is endemic. CASE REPORT: This paper presents a case of a 45-year-old man with idiopathic lymphedema isolated to the scrotum. After acquired causes of lymphedema were ruled out, the patient was treated with scrotectomy and penoscrotal reconstruction. Currently, the patient is receiving follow-up care without evidence of recurrence. CONCLUSIONS: Penoscrotal lymphedema may cause symptoms of weakness, immobility and emotional disturbance. Surgery procedure provides a satisfactory cosmetical and functional outcome. PMID- 25301137 TI - [Thyroglossal cyst and papillary carcinoma. Management proposals]. AB - The thyroid descends through the foramen cecum leaving the thyroglossal duct, which disappears between the fifth and the tenth week of pregnancy. The lack of involution of any part of this duct results in thyroglossal cyst formation. Its diagnostic approach is made by cervical ultrasound, computed tomography and magnetic resonance imaging. Approximately 1 % of the thyroglossal cyst formation contains malignant elements, and the most reported primary tumor has been papillary carcinoma. The recommended treatment for these carcinomas is controversial and it has evolved as time goes by. From Sistrunk procedure to neck dissection with total thyroidectomy and complementary therapies, such as iodine ablation and thyroid supplements, yet there is still no consensus as to the type of surgery and postoperative management it should be used to treat this carcinoma. Therapy should be applied according to each specific case, and it should be based on histological diagnosis, the invasive character of the tumor, and the lymph node affectation. In this paper we review the literature published so far with regards to the treatment of this carcinoma. PMID- 25301138 TI - [Genomics in medicine]. AB - The development of new fields of study in genetics, as the -omic sciences (transcriptomics, proteomics, metabolomics), has allowed the study of the regulation and expression of genomes. Therefore, nowadays it is possible to study global alterations--in the whole genome--and their effect at the protein and metabolic levels. Importantly, this new way of studying genetics has opened new areas of knowledge, and new cellular mechanisms that regulate the functioning of biological systems have been elucidated. In the clinical field, in the last years new molecular tools have been implemented. These tools are favorable to a better classification, diagnosis and prognosis of several human diseases. Additionally, in some cases best treatments, which improve the quality of life of patients, have been established. Due to the previous assertion, it is important to review and divulge changes in the study of genetics as a result of the development of the -omic sciences, which is the aim of this review. PMID- 25301139 TI - Hypomelanosis of Ito with a trisomy 2 mosaicism: a case report. AB - INTRODUCTION: Hypomelanosis of Ito is a rare neurocutaneous disorder, characterized by streaks and swirls of hypopigmentation following the lines of Blaschko that may be associated to systemic abnormalities involving the central nervous system and musculoskeletal system. Despite the preponderance of reported sporadic hypomelanosis of Ito, few reports of familial hypomelanosis of Ito have been described. CASE PRESENTATION: A 6-month-old Caucasian girl presented with unilateral areas of hypomelanosis distributed on the left half of her body and her father presented with similar mosaic hypopigmented lesions on his upper chest. Whereas both blood karyotypes obtained from peripheral lymphocyte cultures were normal, a 16% trisomy 2 mosaicism was found in cultured skinfibroblasts derived from a hypopigmented skin area of her father. CONCLUSIONS: Familial cases of hypomelanosis of Ito are very rare and can occur in patients without systemic involvement. Hypomelanosis of Ito constitutes a non-specific diagnostic definition including different clinical entities with a wide phenotypic variability, either sporadic or familial. Unfortunately, a large number of cases remain misdiagnosed due to both diagnostic challenges and controversial issues on cutaneous biopsies in the pediatric population. PMID- 25301140 TI - Low body weight and tenofovir use are risk factors for renal dysfunction in Vietnamese HIV-infected patients. A prospective 18-month observation study. AB - BACKGROUND: The use of tenofovir has been rapidly increasing in Vietnam. Several studies identified low body weight as a risk factor for tenofovir-induced nephrotoxicity. However, little is known about the impact of tenofovir on renal function in HIV-infected Vietnamese with generally low weight. METHODS: An observational single-center cohort of adult HIV-infected patients on antiretroviral therapy at National Hospital of Tropical Diseases, Hanoi. Patients on tenofovir or with creatinine clearance <=60 ml/min at baseline were excluded. The incidence of renal dysfunction was compared between patients who switched to tenofovir and those who did not. Renal dysfunction was defined as 25% decline of creatinine clearance from baseline. Time to renal dysfunction was analyzed by the Kaplan-Meier method between the two groups. The Cox hazard model was used to determine risk factors for renal dysfunction in uni- and multivariate analyses. RESULTS: Of 556 patients enrolled in this study, 403 were non-tenofovir group while 153 were the tenofovir-switched group. Renal dysfunction occurred at a higher rate in the tenofovir-switched group (92.5 per 1000 person-years) than the non-tenofovir group (47.8 per 1000 person-years)(p = 0.023, Log-rank test). Multivariate analysis confirmed that tenofovir use, low body weight and glucosuria were significant risk factors for renal dysfunction (hazard ratio = 1.980; 95% confidential interval, 1.094-3.582, HR = 1.057; 95%CI, 1.016-1.098, HR = 5.202; 95%CI, 1.245-21.738, respectively). CONCLUSIONS: Tenofovir use, low body weight and glucosuria were significant risk factors for renal dysfunction. We suggest close monitoring of renal function in patients with these risk factors even in resource-limited setting. PMID- 25301141 TI - Analyzing and identifying novel B cell epitopes within Toxoplasma gondii GRA4. AB - BACKGROUND: The identification of specific epitopes targeted by the host antibody response is important for understanding the natural response to infection and for the development of epitope-based marker vaccines and diagnostic tools for toxoplasmosis. In this study, Toxoplasma gondii GRA4 epitopes were identified using software-based prediction and a synthetic peptide technique. METHODS: The complete GRA4 gene sequence was obtained from T. gondii of the Gansu Jingtai strain of tachyzoites. The potential B cell epitopes of GRA4 was predicted using the PROTEAN subroutine in the DNASTAR software package. The peptides with good hydrophilicity, high accessibility, high flexibility and strong antigenicity were chemically synthesized and assessed by ELISA using pig sera from different time points after infection. RESULTS: The potential B cell epitopes of GRA4 predicted by bioinformatics tools focused on six regions of GRA4, 52-77 aa, 93-112 aa, 127 157 aa, 178-201 aa, 223-252 aa and 314-333 aa. Eleven shorter peptides from the six regions were synthesized and assessed by ELISA using pig sera from different time points after infection. Three of the eleven peptides (amino acids 62-77, 233 252 and 314-333) tested were recognized by all sera. CONCLUSIONS: We precisely located the T. gondii GRA4 epitopes using pig sera collected at different time points after infection. The identified epitopes may be useful for additional studies of epitope-based vaccines and diagnostic reagents. PMID- 25301143 TI - Lattice water molecules tuned spin-crossover for an iron(II) complex with thermal hysteresis. AB - A new iron(II) complex based on the 4,4'-dimethyl-2,2'-bipyridine ligand [Fe(4,4' dmbpy)3(ClO4)(SCN).3H2O (1.3H2O)] has been prepared and characterized. Structural studies and Hirshfeld surface analysis for complex 1.3H2O at three different temperatures (300, 240 and 130 K) are described. The UV-vis absorption spectrum of a water-free sample (1) in methanol solution and magnetic susceptibility measurements for solid-state samples 1.3H2O and 1 revealed that the removal of lattice water molecules from complex 1.3H2O changed the magnetic properties from the low-spin state (1.3H2O) to the complete spin-crossover (1) between 350-220 K with a thermal hysteresis of 7 K, and was accompanied by a colour change from brown to red. PMID- 25301144 TI - How we developed a trainee-led book group as a supplementary education tool for psychiatric training in the 21st century. AB - BACKGROUND: Postgraduate medical education has, in recent years, become a dynamic field with the increasing availability of innovative and interactive teaching techniques. Anecdotal evidence suggests that the current focus of psychiatric training on the acquisition of scientific and clinical knowledge is inadequate to address the multidimensional nature of psychiatry. Supplementary teaching tools may be usefully applied to address this need. METHODS: A group of trainees at the Maudsley Hospital and Institute of Psychiatry (UK) pioneered the use of a book group as an innovative teaching tool to enhance the psychiatric training experience by, amongst other aspects, facilitating dialogue between peers on fundamental epistemological issues raised by critical engagement with seminal psychiatric texts. RESULTS: Feedback from members suggested that participation in the book group broadened the overall learning potential and experience of psychiatry. The key ingredients were identified as: (i) collaborative peer-to peer learning; (ii) the use of 'flipped classroom' model; and (iii) joint ownership. CONCLUSION: The book group has demonstrated real potential to facilitate direct trainee engagement with the multi-faceted nature of psychiatry as a complex humanistic discipline within an informal learning space. PMID- 25301142 TI - Distinct subcellular trafficking resulting from monomeric vs multimeric targeting to endothelial ICAM-1: implications for drug delivery. AB - Ligand-targeted, receptor-mediated endocytosis is commonly exploited for intracellular drug delivery. However, cells-surface receptors may follow distinct endocytic fates when bound by monomeric vs multimeric ligands. Our purpose was to study this paradigm using ICAM-1, an endothelial receptor involved in inflammation, to better understand its regulation and potential for drug delivery. Our procedure involved fluorescence microscopy of human endothelial cells to determine the endocytic behavior of unbound ICAM-1 vs ICAM-1 bound by model ligands: monomeric (anti-ICAM) vs multimeric (anti-ICAM biotin-streptavidin conjugates or anti-ICAM coated onto 100 nm nanocarriers). Our findings suggest that both monomeric and multimeric ligands undergo a similar endocytic pathway sensitive to amiloride (~50% inhibition), but not inhibitors of clathrin-pits or caveoli. After 30 min, ~60-70% of both ligands colocalized with Rab11a compartments. By 3-5 h, ~65-80% of multimeric anti-ICAM colocalized with perinuclear lysosomes with ~60-80% degradation, while 70% of monomeric anti-ICAM remained associated with Rab11a at the cell periphery and recycled to and from the cell-surface with minimal (<10%) lysosomal colocalization and minimal (<=15%) degradation. In the absence of ligands, ICAM-1 also underwent amiloride-sensitive endocytosis with peripheral distribution, suggesting that monomeric (not multimeric) anti-ICAM follows the route of this receptor. In conclusion, ICAM-1 can mediate different intracellular itineraries, revealing new insight into this biological pathway and alternative avenues for drug delivery. PMID- 25301145 TI - How we enhanced medical academics skills and reduced social inequities using an academic teaching program. AB - The training of future physicians should be concurrent with the development of different skills and attitudes. This warrants the need to regularly provide students with opportunities for self-development throughout their academic career. This approach was exemplified in a medical school in the Brazilian Amazon, where students were allowed to play the role of high school teachers. As part of this exercise, they conducted reinforcement classes for high school students to increase the number of university admissions. The medical students were solely responsible for organizing and implementing this project, giving them the opportunity to develop teaching and leadership skills, enhance their understanding of communication and administration and contribute toward the society. PMID- 25301146 TI - Exploring the lack of interest in geriatric medicine. PMID- 25301147 TI - Availability of slides before lectures does not decrease attendance at lectures. PMID- 25301148 TI - Sink or swim: Near-peer teaching eases the transition into hospital-based medical education. PMID- 25301149 TI - A new challenge: The training of eHealth professionals, innovative actors of eHealth. PMID- 25301150 TI - Robust DREEM factor analysis. PMID- 25301152 TI - Chronic counterpulsation devices for heart failure. PMID- 25301151 TI - Ambulatory extra-aortic counterpulsation in patients with moderate to severe chronic heart failure. AB - OBJECTIVES: The study sought to assess feasibility, safety, and potential efficacy of a novel implantable extra-aortic counterpulsation system (C-Pulse) in functional class III and ambulatory functional class IV heart failure (HF) patients. BACKGROUND: 30% to 40% of HF patients suffer from poor functional status and quality of life (QoL) but are not in need of end-stage treatments. We undertook a multicenter single-arm study to assess the C-Pulse System in such patients. METHODS: New York Heart Association (NYHA) functional class III or ambulatory functional class IV HF patients were eligible. Safety was assessed continuously through 12 months. Efficacy measurements included changes from baseline to 6 and 12 months in NYHA functional class, Minnesota Living with Heart Failure (MLWHF) and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6-min walk distance (6MWD), and exercise peak oxygen consumption (pVO2; 6 months only). RESULTS: Twelve men and 8 women (56.7 +/- 7 years, 34 to 71 years of age) with ischemic (n = 7) or nonischemic (n = 13) cardiomyopathy were implanted. There was no 30-day mortality and no neurological events or myocardial infarctions through 12 months. At 6 months, there were 3 deaths (1 device-related). One-year survival was 85%. At 6 months, C-Pulse produced improvements in NYHA functional class (3.1 +/- 0.3 to 1.9 +/- 0.7, p = 0.0005), MLWHF (63.6 +/- 19.9 to 40.2 +/- 23.2, p = 0.0005), and KCCQ scores (43.6 +/- 21.1 to 65.6 +/- 21.5, p = 0.0002), but not 6MWD (275.5 +/- 64.0 to 296.4 +/- 104.9, p = NS) or pVO2 (14.5 +/- 3.6 to 13.1 +/ 4.4, p = NS). Improvements continued at 12 months, with 6MWD change becoming statistically significant (336.5 +/- 91.8, p = 0.0425). CONCLUSIONS: Use of C Pulse in this population is feasible, appears safe, and improves functional status and QoL. A prospective, multicenter, randomized controlled trial is underway. (C-Pulse IDE Feasability Study-A Heart Assist System; NCT00815880). PMID- 25301153 TI - Are models better than cardiologists?: An analysis of risk prediction in heart failure. PMID- 25301154 TI - Colchicine in stable chronic heart failure. PMID- 25301155 TI - Reply: Colchicine in stable chronic heart failure. PMID- 25301156 TI - Pseudobendopnea? PMID- 25301157 TI - Reply: Bendopnea and pseudobendopnea. PMID- 25301158 TI - Characterization of a novel symptom of advanced heart failure: bendopnea. PMID- 25301159 TI - What is normal in HFNEF?: The case for HFpEF. PMID- 25301160 TI - Reply: What is normal in HFNEF? The case for HFpEF. PMID- 25301161 TI - "Triple therapy" of heart failure with angiotensin-converting enzyme inhibitor, beta-blocker, and aldosterone antagonist may triple survival time: shouldn't we tell patients? AB - Prescription and adherence to medical therapy for heart failure are disappointing despite convincing randomized controlled trial (RCT) evidence for angiotensin converting enzyme inhibition, beta-blockade, and aldosterone antagonism. In this study, we report an imbalanced approach amongst clinicians, who describe focusing during patient consultations on perceived risks of therapy rather than survival benefits. Only one-half of clinicians mention increased lifespan, and very few suggest to the patient how large this gain might be. We calculate from the available RCT data that, for patients whose lifespan is limited by heart failure, triple therapy triples lifespan. PMID- 25301162 TI - The role of combined Ga-DOTANOC and (18)FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors. AB - PURPOSE: The aim of this study was to evaluate the effect of combined (68)Ga and (18)F-FDG PET/CT on treatment management for patients with pancreatic neuroendocrine tumor (PNET). METHODS: Between January 2012 and April 2014, 49 consecutive patients with a cytologically and/or histologically proven diagnosis of PNET underwent combined (68)Ga and (18)FDG PET/CT on the same day. RESULTS: The study group consisted of 21 males and 28 females with a median age of 59 years. Disease detection was achieved in 48 out of the 49 cases with (68)Ga imaging, and in 36 of the 49 cases with (18)FDG PET/CT. These results corresponded to sensitivities of 98% for (68)Ga versus 73% for (18)FDG PET/CT. Patients with NET-G1/NET-G2 had a positive (68)Ga and negative (18)FDG PET/CT in 13 cases, whereas both (68)Ga and (18)FDG PET/CT were positive in 27 cases. Patients with NEC-G3 were positive by both (68)Ga and (18)FDG PET/CT in 7 cases and positive only by (18)FDG in 1 case. Another NEC-G3 patient was only positive by (68)Ga PET/CT. The median Ki67 was 7% for (68)Ga PET/CT-positive tumors and 10% for tumors with both (68)Ga and (18)FDG PET/CT positivity (p = 0.130). Half of the patients with a prevalent uptake of (18)FDG (n = 7) had an NEC-G3 compared with 12% of patients with a prevalent uptake of (68)Ga (p = 0.012). There were no significant differences between patients with positive (68)Ga and those with positive (18)FDG with regards to treatment choice. CONCLUSIONS: The association of (18)FDG slightly increases sensitivity of (68)Ga PET/CT alone in the diagnosis of PNET. A combined dual tracer PET/CT does not influence the choice of treatment strategy. PMID- 25301163 TI - The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity. AB - T-cell activation is critical for successful immune responses and is controlled at multiple levels. Although many changes of T-cell receptor-associated signalling molecules affect T-cell activation, the transcriptional mechanisms that control this process remain largely unknown. Here we find that T cell specific deletion of the mediator subunit Med23 leads to hyperactivation of T cells and aged Med23-deficient mice exhibit an autoimmune syndrome. Med23 specifically and consistently promotes the transcription of multiple negative regulators of T-cell activation. In the absence of Med23, the T-cell activation threshold is lower, which results in enhanced antitumour T-cell function. Cumulatively, our data suggest that Med23 contributes to controlling T-cell activation at the transcriptional level and prevents the development of autoimmunity. PMID- 25301164 TI - Nick Clegg promises to end "discrimination against mental health for good". PMID- 25301165 TI - Use of brachial plexus blockade and medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (Acinonyx jubatus). AB - BACKGROUND: Regional anaesthetic techniques have been used in combination with systemic analgesics during small animal surgery to provide multimodal analgesia. Brachial plexus nerves block using local anaesthetics provides analgesia of the thoracic limb through desensitization of the nerves that provide sensory and motor innervation. This has been shown to reduce intra-operative anesthetic requirements and provide postoperative pain relief. Decreasing the doses of general anaesthetics allows more stable cardiopulmonary function during anaesthesia and the development of less side effects. The present case reports a successful use of brachial plexus blockade to supplement medetomidine-ketamine isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (acinonyx jubatus). CASE PRESENTATION: An adult male Cheetah weighing about 65 kg was presented with a history of leg carrying lameness of the left forelimb sustained following a car accident a week earlier. Clinical examination under general anaesthesia revealed slight dehydration and a swelling with a wound on the caudo-medial aspect of the left radio-ulna region. Crepitation was present on manipulation and radiography confirmed a complete transverse radio-ulna fracture of the left forelimb, which required open reduction and internal fixation. Brachial plexus blockade using lignocaine hydrochloride was used to supplement medetomidine-ketamine-isoflurane anaesthesia for the surgical procedure. Isoflurane anaesthesia was maintained at 0.5 - 2.0% throughout the surgical procedure, which was uneventful. Temperature and cardio-pulmonary parameters remained stable intra-operatively. Limb paralysis extended for 5 hours post operatively, suggesting prolonged anaesthesia. CONCLUSION: To the researchers' knowledge, this is the first reported case of the use of brachial plexus blockade to supplement general anaesthesia to facilitate forelimb surgery in an adult cheetah. The use of brachial plexus block with a light plane of general anaesthesia proved to be successful. Brachial plexus block had a sparing effect on isoflurane anaesthesia as evidenced by the concentration used for maintenance of anaesthesia and the stability of the cardiopulmonary function. Moreover, absence of autonomic cardiopulmonary reactions to the surgical manipulation may be attributed to the efficacy of brachial plexus block. This anaesthesia protocol is therefore recommended for surgeries of the forelimb in wild cats. PMID- 25301166 TI - Myopericytoma of the liver hilus: a case report. AB - Pericytic tumours is a new category recently introduced in soft tissue pathology describing those entities sharing evidence of myoid differentiation and a tendency of spindle or more rounded cells to grow in a perivascular fashion. The great majority of pericytic tumours are benign but recurrence has been described as well as very rare malignant cases with an aggressive behaviour. Although pericytic tumours arise most commonly in the subcutaneous tissue of distal extremities in middle age patients, additional cases have been recently described in many other organs. Here we describe a case of a 57-year-old man with an 8.5 cm mass of the liver hilus diagnosed as myopericytoma, with particular reference to its biological potential and differential diagnosis. It is important for the pathologists to take this diagnosis into consideration as well for a better management of patient care. PMID- 25301167 TI - Use of external fixation for perilunate dislocations and fracture dislocations. AB - The purpose of this study was to review clinical and radiographic outcomes of perilunate dislocations and fracture dislocations treated with external fixation and K-wire fixation. Twenty patients (18 males and two females) with a mean age of 38 years (range 18-59) who had an acute dorsal perilunate dislocation or fracture dislocation were treated with the use of wrist external fixator and K wires. The injuries included 12 perilunate dislocations, seven trans-scaphoid perilunate fracture dislocations, and one trans-styloid perilunate fracture dislocation. The median time from trauma to operation was 8 h (2-12 h). Indirect reduction via ligamentotaxis was achieved in all perilunate dislocation, and provisional K-wire fixation was added. In five of seven trans-scaphoid perilunate fracture dislocations, indirect reduction was achieved; whereas in the other two as well as in the case of trans-styloid perilunate fracture dislocation, open reduction was required. External fixator was supplemented with K-wires for stabilization of the fractures and the intercarpal intervals. The interosseous and capsular ligaments were not repaired, even after open reduction of fracture dislocations. The mean follow-up was 39 months (range 18-68 months). Range of motion and grip strength were measured. Cooney's scoring system was used for the assessment of clinical function. Radiographic evaluation included time to scaphoid union, measurement of radiographic parameters (scapholunate gap, scapholunate angle, lunotriquetral gap, and carpal height ratio) and any development of arthritis. The flexion-extension motion arc and grip strength of the injured wrist averaged 80 and 88%, respectively, of the corresponding values for the contralateral wrists. According to Cooney's clinical scoring system, overall functional outcomes were rated as excellent in four patients, good in eight, fair in six, and poor in two. Eighteen patients returned to their former occupations. Two patients with a trans-scaphoid perilunate injury developed nonunion of the scaphoid; one of them required scaphoid excision and midcarpal fusion. Two patients had radiographic evidence of arthritis. The use of external fixation and provisional K-wire fixation for the treatment of acute perilunate dislocations is associated with satisfactory midterm functional and radiographic outcomes. This minimally invasive treatment option is simple, reliable, and minimally invasive method that provides proper restoration and stable fixation of carpal alignment. PMID- 25301168 TI - Heterometallic multiple bonding: delocalized three-center sigma and pi bonding in chains of 4d and 5d transition metals. AB - Heterotrimetallic compounds Mo2Ru(dpa)4Cl2 (1) and W2Ru(dpa)4Cl2 (2) are prepared by reactions of M2(dpa)4 (M = Mo or W; dpa = 2,2'-dipyridylamide) with [Ru(CO)3Cl2]2. Crystallographic studies reveal short Mo-Ru and W-Ru distances, 2.38 A (1) and 2.39 A (2), suggestive of delocalized Mo-Mo-Ru and W-W-Ru bonding. In contrast to the sigma bonding found in the corresponding iron compounds, density functional theory calculations reveal both a three-center/two-electron sigma bond and two three-center/four-electron pi bonds in the M-M-Ru compounds. PMID- 25301169 TI - A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice. AB - We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 uM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. PMID- 25301170 TI - Mechanistic understanding for the greater sensitivity of monkeys to antisense oligonucleotide-mediated complement activation compared with humans. AB - Differences in sensitivity of monkeys and humans to antisense oligonucleotide (ASO)-induced complement alternative pathway (AP) activation were evaluated in monkeys, humans, and in serum using biochemical assays. Transient AP activation was evident in monkeys at higher doses of two 2'-O-methoxyethyl (2'-MOE) ASOs (ISIS 426115 and ISIS 183750). No evidence of AP activation was observed in humans for either ASO, even with plasma ASO concentrations that reached the threshold for activation in monkeys. The absence of complement activation in humans is consistent with a query of the Isis Clinical Safety Database containing 767 subjects. The in vivo difference in sensitivity was confirmed in vitro, as monkey and human serum exposed to increasing concentrations of ASO indicated that monkeys were more sensitive to AP activation with this class of compounds. The mechanistic basis for the greater sensitivity of monkeys to AP activation by 2' MOE ASO was evaluated using purified human or monkey factor H protein. The binding affinities between a representative 2'-MOE ASO and either purified protein are similar. However, the IC50 of fluid-phase complement inhibition for monkey factor H is about 3-fold greater than that for human protein using either monkey serum or factor H-depleted human serum. Interestingly, there is a sequence variant in the monkey complement factor H gene similar to a single nucleotide polymorphism in humans that is correlated with decreased factor H protein function. These findings show that monkeys are more sensitive to 2'-MOE ASO mediated complement activation than humans likely because of differences in factor H inhibitory capacity. PMID- 25301171 TI - The safety of concentrated trastuzumab in 100 ml of saline solution for administration to patients with HER2-positive breast cancer: a phase 1 study. AB - BACKGROUND: It is recommended that administration of trastuzumab should be carried out in a volume of 250 ml of saline solution over 90 min. Since 2011, recommendations have allowed a shortening of the administration time to 30 min at the second administration. However, the volume to be administered is still 250 ml. The purpose of this study was to evaluate the safety of trastuzumab administered in 100 ml of saline solution over 30 min. METHODS: This study enrolled patients with HER2-positive breast cancer. Three dose levels of trastuzumab, each in 100 ml of saline solution, were used (2, 6 and 8 mg/kg). The primary end point was the determination of safety. RESULTS: Nine patients were enrolled. Since no adverse events were observed, the 8 mg/kg/100 ml saline solution dose level was the recommended dose. CONCLUSIONS: A 30-min administration of trastuzumab in 100 ml of saline solution is safe in patients with HER2-positive breast cancer. PMID- 25301172 TI - Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. AB - A tumor-selective non-lytic retroviral replicating vector (RRV), Toca 511, and an extended-release formulation of 5-fluorocytosine (5-FC), Toca FC, are currently being evaluated in clinical trials in patients with recurrent high-grade glioma (NCT01156584, NCT01470794 and NCT01985256). Tumor-selective propagation of this RRV enables highly efficient transduction of glioma cells with cytosine deaminase (CD), which serves as a prodrug activator for conversion of the anti-fungal prodrug 5-FC to the anti-cancer drug 5-fluorouracil (5-FU) directly within the infected cells. We investigated whether, in addition to its direct cytotoxic effects, 5-FU generated intracellularly by RRV-mediated CD/5-FC prodrug activator gene therapy could also act as a radiosensitizing agent. Efficient transduction by RRV and expression of CD were confirmed in the highly aggressive, radioresistant human glioblastoma cell line U87EGFRvIII and its parental cell line U87MG (U87). RRV-transduced cells showed significant radiosensitization even after transient exposure to 5-FC. This was confirmed both in vitro by a clonogenic colony survival assay and in vivo by bioluminescence imaging analysis. These results provide a convincing rationale for development of tumor-targeted radiosensitization strategies utilizing the tumor-selective replicative capability of RRV, and incorporation of radiation therapy into future clinical trials evaluating Toca 511 and Toca FC in brain tumor patients. PMID- 25301173 TI - Divergence of RNA localization between rat and mouse neurons reveals the potential for rapid brain evolution. AB - BACKGROUND: Neurons display a highly polarized architecture. Their ability to modify their features under intracellular and extracellular stimuli, known as synaptic plasticity, is a key component of the neurochemical basis of learning and memory. A key feature of synaptic plasticity involves the delivery of mRNAs to distinct sub-cellular domains where they are locally translated. Regulatory coordination of these spatio-temporal events is critical for synaptogenesis and synaptic plasticity as defects in these processes can lead to neurological diseases. In this work, using microdissected dendrites from primary cultures of hippocampal neurons of two mouse strains (C57BL/6 and Balb/c) and one rat strain (Sprague-Dawley), we investigate via microarrays, subcellular localization of mRNAs in dendrites of neurons to assay the evolutionary differences in subcellular dendritic transcripts localization. RESULTS: Our microarray analysis highlighted significantly greater evolutionary diversification of RNA localization in the dendritic transcriptomes (81% gene identity difference among the top 5% highly expressed genes) compared to the transcriptomes of 11 different central nervous system (CNS) and non-CNS tissues (average of 44% gene identity difference among the top 5% highly expressed genes). Differentially localized genes include many genes involved in CNS function. CONCLUSIONS: Species differences in sub-cellular localization may reflect non-functional neutral drift. However, the functional categories of mRNA showing differential localization suggest that at least part of the divergence may reflect activity dependent functional differences of neurons, mediated by species-specific RNA subcellular localization mechanisms. PMID- 25301174 TI - A Rosa canina WUSCHEL-related homeobox gene, RcWOX1, is involved in auxin-induced rhizoid formation. AB - Homeobox (HB) proteins are important transcription factors that regulate the developmental decisions of eukaryotes. WUSCHEL-related homeobox (WOX) transcription factors, known as a plant-specific HB family, play a key role in plant developmental processes. Our previous work has indicated that rhizoids are induced by auxin in rose (Rosa spp.), which acts as critical part of an efficient plant regeneration system. However, the function of WOX genes in auxin-induced rhizoid formation remains unclear. Here, we isolated and characterized a WUSCHEL related homeobox gene from Rosa canina, RcWOX1, containing a typical homeodomain with 65 amino acid residues. Real-time reverse transcription PCR (qRT-PCR) analysis revealed that RcWOX1 was expressed in the whole process of callus formation and in the early stage of rhizoid formation. Moreover, its expression was induced by auxin treatment. In Arabidopsis transgenic lines expressing the RcWOX1pro::GUS and 35S::GFP-RcWOX1, RcWOX1 was specifically expressed in roots and localized to the nucleus. Overexpression of RcWOX1 in Arabidopsis increased lateral root density and induced upregulation of PIN1 and PIN7 genes. Therefore, we postulated that RcWOX1 is a functional transcription factor that plays an essential role in auxin-induced rhizoid formation. PMID- 25301175 TI - Seasonal variation in cell proliferation and cell migration in the brain of adult red-sided garter snakes (Thamnophis sirtalis parietalis). AB - Plasticity in the adult central nervous system has been described in all vertebrate classes as well as in some invertebrate groups. However, the limited taxonomic diversity represented in the current neurogenesis literature limits our ability to assess the functional significance of adult neurogenesis for natural behaviors as well as the evolution of its regulatory mechanisms. In the present study, we used free-ranging red-sided garter snakes (Thamnophis sirtalis parietalis) to test the hypothesis that seasonal shifts in physiology and behavior are associated with seasonal variation in postembryonic neurogenesis. Specifically, we used the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) to determine if the rates of cell proliferation in the adult brain vary between male snakes collected during spring and fall at 1, 5, and 10 days post-BrdU treatment. To assess rates of cell migration within the brain, we further categorized BrdU labeled cells according to their location within the ventricular zone or parenchymal region. BrdU-labeled cells were localized mainly within the lateral, dorsal, and medial cortex, septal nucleus, nucleus sphericus, preoptic area, and hypothalamus. In all regions, the number of BrdU-labeled cells in the ventricular zone was higher in the fall compared to spring. In the parenchymal region, a significantly higher number of labeled cells was also observed during the fall, but only within the nucleus sphericus and the combined preoptic area/hypothalamus. The immunoreactive cell number did not vary significantly with days post-BrdU treatment in either season or in any brain region. While it is possible that the higher rates of cell proliferation in the fall simply reflect increased growth of all body tissues, including the brain, our data show that seasonal changes in cell migration into the parenchyma are region specific. In red-sided garter snakes and other reptiles, the dorsal and medial cortex is important for spatial navigation and memory, whereas the nucleus sphericus, septal nucleus, and preoptic area/hypothalamus are central to reproductive regulation. Thus, our results provide support for the hypothesis that adult neurogenesis plays a role in mediating seasonal rhythms in migratory and reproductive behaviors. PMID- 25301176 TI - Paediatric Obsessive-Compulsive Disorder and Depressive Symptoms: Clinical Correlates and CBT Treatment Outcomes. AB - Depression frequently co-occurs with paediatric obsessive-compulsive disorder (OCD), yet the clinical correlates and impact of depression on CBT outcomes remain unclear. The prevalence and clinical correlates of depression were examined in a paediatric specialist OCD-clinic sample (N = 295; Mean = 15 [7 - 18] years, 42 % female), using both dimensional (Beck Depression Inventory-youth; n = 261) and diagnostic (Development and Wellbeing Assessment; n = 127) measures of depression. The impact of depressive symptoms and suspected disorders on post treatment OCD severity was examined in a sub-sample who received CBT, with or without SSRI medication (N = 100). Fifty-one per-cent of patients reported moderately or extremely elevated depressive symptoms and 26 % (95 % CI: 18 - 34) met criteria for a suspected depressive disorder. Depressive symptoms and depressive disorders were associated with worse OCD symptom severity and global functioning prior to CBT. Individuals with depression were more likely to be female, have had a psychiatric inpatient admission and less likely to be attending school (ps < 0.01). OCD and depressive symptom severity significantly decreased after CBT. Depressive symptoms and depressive disorders predicted worse post-treatment OCD severity (betas = 0.19 and 0.26, ps < 0.05) but became non significant when controlling for pre-treatment OCD severity (betas = 0.05 and 0.13, ns). Depression is common in paediatric OCD and is associated with more severe OCD and poorer functioning. However, depression severity decreases over the course of CBT for OCD and is not independently associated with worse outcomes, supporting the recommendation for treatment as usual in the presence of depressive symptoms. PMID- 25301177 TI - Identifying Moderators of the Link Between Parent and Child Anxiety Sensitivity: The Roles of Gender, Positive Parenting, and Corporal Punishment. AB - A substantial body of literature suggests that anxiety sensitivity is a risk factor for the development of anxiety problems and research has now begun to examine the links between parenting, parent anxiety sensitivity and their child's anxiety sensitivity. However, the extant literature has provided mixed findings as to whether parent anxiety sensitivity is associated with child anxiety sensitivity, with some evidence suggesting that other factors may influence the association. Theoretically, specific parenting behaviors may be important to the development of child anxiety sensitivity and also in understanding the association between parent and child anxiety sensitivity. In this study, 191 families (n = 255 children and adolescents aged 6-17 and their parents) completed measures of child anxiety sensitivity (CASI) and parenting (APQ-C), and parents completed measures of their own anxiety sensitivity (ASI) and their parenting (APQ-P). Corporal punishment was associated with child anxiety sensitivity and the child's report of their parent's positive parenting behaviors moderated the association between parent and child anxiety sensitivity. The child's gender was also found to moderate the association between parent and child anxiety sensitivity, such that there was a positive association between girls' and their parents anxiety sensitivity and a negative association in boys. The findings advance the understanding of child anxiety sensitivity by establishing a link with corporal punishment and by showing that the association between parent and child anxiety sensitivity may depend upon the parenting context and child's gender. PMID- 25301178 TI - Women are designed to deliver vaginally and not by cesarean section: an obstetrician's view. AB - Worldwide, there is a rapid increase in deliveries by cesarean section. The large differences among countries, from about 16% to more than 60%, suggest that the cesarean delivery (CD) rate has little to do with evidence-based medicine. In this review, the background for the increasing CD rate is discussed as well as the limited positive effects on neonatal outcome in both term and preterm neonates. Negative effects of CD, including direct maternal morbidity, complications of subsequent pregnancies and iatrogenic early delivery resulting in increased neonatal morbidity, are discussed in addition to long-term implications for the offspring involving altered development of the immune system. The 'battle' to lower the CD rate will be difficult, but we should not forget that women are designed to deliver vaginally and not by cesarean section. PMID- 25301179 TI - Omacetaxine mepesuccinate in chronic myeloid leukemia. AB - INTRODUCTION: Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy. AREAS COVERED: In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed. EXPERT OPINION: Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs. PMID- 25301180 TI - Empagliflozin for the treatment of type 2 diabetes. AB - INTRODUCTION: Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion. AREAS COVERED: This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin , the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin. EXPERT OPINION: Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM. PMID- 25301183 TI - Cyclin-dependent kinase-specific activity predicts the prognosis of stage I and stage II non-small cell lung cancer. AB - BACKGROUND: Lung cancer is one of the leading causes of cancer death worldwide. Even with complete resection, the prognosis of early-stage non-small cell lung cancer is poor due to local and distant recurrence, and it remains unclear which biomarkers are clinically useful for predicting recurrence or for determining the efficacy of chemotherapy. Recently, several lines of evidence have indicated that the enzymatic activity of cyclin-dependent kinases could be a clinically relevant prognostic marker for some cancers. We investigated whether the specific activity of cyclin-dependent kinases 1 and 2 could predict recurrence or death in early non-small cell lung cancer patients. METHODS: Patients with newly diagnosed, pathologically confirmed non-small cell lung cancer were entered into this blinded cohort study. The activity of cyclin-dependent kinases was determined in 171 samples by the C2P(r) assay, and the results were subjected to statistical analysis with recurrence or death as a clinical outcome. RESULTS: The Cox proportional hazards model revealed that the activity of cyclin-dependent kinase 1, but not 2, was a predictor of recurrence, independent of sex, age, and stage. By contrast, cyclin-dependent kinase 2 activity was a predictor of death, independent of sex and stage. CONCLUSION: This study suggested the possible clinical use of cyclin-dependent kinase 1 as a predictor of recurrence and cyclin dependent kinase 2 as a predictor of overall survival in early-stage non-small cell lung cancer. Thus, a combination of activity of cyclin-dependent kinases 1 and 2 is useful in decision-making regarding treatment strategies for non-small cell lung cancer after surgery. PMID- 25301184 TI - PDGF-BB and bFGF ameliorate radiation-induced intestinal progenitor/stem cell apoptosis via Akt/p53 signaling in mice. AB - Radiation-induced gastrointestinal (GI) syndrome currently has no effective prophylactic or therapeutic treatment. Previous studies and our data have demonstrated the important role of p53 in acute radiation-induced GI syndrome in mice. Many cytokines, such as tumor necrosis factor-alpha and fibroblast growth factor (bFGF), have been found to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. Here, we report blockage of p53 through a protein kinase B (Akt) pathway in intestinal progenitor/stem cells or crypt cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. Treatment with platelet-derived growth factor (PDGF-BB) or bFGF activated Akt phosphorylation in the intestinal crypt, lessened intestinal crypt p53 expression, decreased radiation-induced apoptosis in mouse intestinal progenitor/stem cell marker leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5)-positive cells by an average of 50%, and increased the survival rate of mice with abdominal radiation by 3 days in average. Conversely, the Akt inhibitor perifosine obstructed growth factor simulated Akt phosphorylation while promoting radiation-induced p53 expression in intestinal crypts. Importantly, reduced Akt phosphorylation and elevated p53 expression due to the Akt inhibitor perifosine impaired intestinal progenitor/stem cells radioprotection provided by PDGF-BB and bFGF. Consistently, PDGF-BB and bFGF both upregulated Akt activation, suppressed radiation-induced p53 expression, and abrogated radiation-induced apoptosis in IEC-6 cells, although p53 overexpression in IEC-6 cells partially counteracted the radioprotection of PDGF-BB and bFGF. Our data suggest that intestinal crypt radioprotection by PDGF-BB and bFGF is dependent on regulation of Akt/p53 signaling. PMID- 25301186 TI - Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis. AB - Damage to the enteric nervous system (ENS) associated with intestinal inflammation may underlie persistent alterations to gut functions, suggesting that enteric neurons are viable targets for novel therapies. Mesenchymal stem cells (MSCs) offer therapeutic benefits for attenuation of neurodegenerative diseases by homing to areas of inflammation and exhibiting neuroprotective, anti inflammatory, and immunomodulatory properties. In culture, MSCs release soluble bioactive factors promoting neuronal survival and suppressing inflammation suggesting that MSC-conditioned medium (CM) provides essential factors to repair damaged tissues. We investigated whether MSC and CM treatments administered by enema attenuate 2,4,6-trinitrobenzene-sulfonic acid (TNBS)-induced enteric neuropathy and motility dysfunction in the guinea pig colon. Guinea pigs were randomly assigned to experimental groups and received a single application of TNBS (30 mg/kg) followed by 1 * 10(6) human bone marrow-derived MSCs, 300 MUl CM, or 300 MUl unconditioned medium 3 h later. After 7 days, the effect of these treatments on enteric neurons was assessed by histological, immunohistochemical, and motility analyses. MSC and CM treatments prevented inflammation-associated weight loss and gross morphological damage in the colon; decreased the quantity of immune infiltrate in the colonic wall (P < 0.01) and at the level of the myenteric ganglia (P < 0.001); prevented loss of myenteric neurons (P < 0.05) and damage to nerve processes, changes in ChAT, and nNOS immunoreactivity (P < 0.05); and alleviated inflammation-induced colonic dysmotility (contraction speed; P < 0.001, contractions/min; P < 0.05). These results provide strong evidence that both MSC and CM treatments can effectively prevent damage to the ENS and alleviate gut dysfunction caused by TNBS-induced colitis. PMID- 25301185 TI - P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy. AB - Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2-/ ) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24-72 h) in response to 70% PH were impaired in P2Y2-/- mice. Interestingly, early induction of cytokines (TNF-alpha, IL-6) and cytokine-mediated signaling (NF-kappaB, STAT-3) were intact in P2Y2-/- remnant livers, uncovering the importance of cytokine independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2-/- mice were treated with ATP or ATPgammaS for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH. PMID- 25301188 TI - [Forward: anti-tumor immunity and tumor immunology]. PMID- 25301189 TI - [The immune system - how does anti-tumor immunity arise ?]. PMID- 25301190 TI - [Immuno-Oncology "Coming of Age" - the next generation of immune checkpoint inhibitors ]. PMID- 25301187 TI - Nitrergic neuromuscular transmission in the mouse internal anal sphincter is accomplished by multiple pathways and postjunctional effector cells. AB - The effector cells and second messengers participating in nitrergic neuromuscular transmission (NMT) were investigated in the mouse internal anal sphincter (IAS). Protein expression of guanylate cyclase (GCalpha, GCbeta) and cyclic GMP dependent protein kinase I (cGKI) were examined in cryostat sections with dual labeling immunohistochemical techniques in PDGFRalpha(+) cells, interstitial cells of Cajal (ICC), and smooth muscle cells (SMC). Gene expression levels were determined with quantitative PCR of dispersed cells from Pdgfralpha(egfp/+), Kit(copGFP/+), and smMHC(Cre-egfp) mice sorted with FACS. The relative gene and protein expression levels of GCalpha and GCbeta were PDGFRalpha(+) cells > ICC ? SMC. In contrast, cGKI gene expression sequence was SMC = ICC > PDGFRalpha(+) cells whereas cGKI protein expression sequence was neurons > SMC ? ICC = PDGFRalpha(+) cells. The functional role of cGKI was investigated in cGKI(-/-) mice. Relaxation with 8-bromo (8-Br)-cGMP was greatly reduced in cGKI(-/-) mice whereas responses to sodium nitroprusside (SNP) were partially reduced and forskolin responses were unchanged. A nitrergic relaxation occurred with nerve stimulation (NS, 5 Hz, 60 s) in cGKI(+/+) and cGKI(-/-) mice although there was a small reduction in the cGKI(-/-) mouse. N(omega)-nitro-l-arginine (l-NNA) abolished responses during the first 20-30 s of NS in both animals. The GC inhibitor ODQ greatly reduced or abolished SNP and nitrergic NS responses in both animals. These data confirm an essential role for GC in NO-induced relaxation in the IAS. However, the expression of GC and cGKI by all three cell types suggests that each may participate in coordinating muscular responses to NO. The persistence of nitrergic NMT in the cGKI(-/-) mouse suggests the presence of a significant GC-dependent, cGKI-independent pathway. PMID- 25301191 TI - [Immuno-Oncology therapeutic principles in lung and renal cell carcinoma]. PMID- 25301192 TI - [Cellular immunotherapy as combination partners for the immune checkpoint blockade]. PMID- 25301193 TI - The effect of education on decreasing the prevalence and severity of neck and shoulder pain: a longitudinal study in Korean male adolescents. AB - BACKGROUND: Neck and shoulder pain is fairly common among adolescents in Korea and results in significant health problem. The aims of this prospective study was to identify the effects of education, in terms of recognition of this issue and posture correction, on prevalence and severity of neck and shoulder pain in Korean adolescents. METHODS: A prospective, observational cohort design was used. The 912 students from two academic high schools in the city of Seoul were eligible for the current study and 887 completed this study. After a baseline cross-sectional survey, students listened to a lecture about cervical health, focusing on good posture, habits, and stretching exercises to protect the spine, and were encouraged by their teachers to keep the appropriate position. And follow-ups were conducted 3 months later, to evaluate the effect of education. RESULTS: The prevalence of neck and shoulder pain was decreased 19.5% (from 82.5 to 66.4%). The baseline mean usual and worst numeric rating scale were 19.9/100 (95% CI, 18.1-21.7) and 31.2/100 (95% CI, 28.7-33.2), respectively. On the follow up survey, the mean usual and worst numeric rating scale were decreased significantly by 24.1 and 21.7%, respectively, compared with baseline (P < 0.01). Of the 570 students reporting neck and shoulder pain, 16.4% responded that they had experienced improvement during the 3 months. CONCLUSIONS: Education; recognition of this issue and posture correction, for cervical health appeared to be effective in decreasing the prevalence and severity of neck and shoulder pain at a 3 month follow-up. PMID- 25301194 TI - Smoking, alcohol, diabetes, obesity, socioeconomic status, and the risk of colorectal cancer in a population-based case-control study. AB - PURPOSE: Although previous research has identified factors that may determine willingness to participate in research, relatively few studies have attempted to quantify the impact non-participation may have on exposure-disease associations. The aims of this study were to (a) investigate the associations between smoking, alcohol, diabetes, obesity, and socioeconomic status and the risk of colorectal cancer in a case-control study (59.7 and 47.2 % response fractions among cases and controls, respectively); and (b) perform sensitivity analyses to examine the possible influence of non-participation. METHODS: Logistic regression was used to estimate the exposure-disease associations. We then investigated the associations between various demographic and health factors and the likelihood that an individual would participate in the case-control study and then performed two sensitivity analyses (sampling weights and multiple imputation) to examine whether non-participation bias may have influenced the exposure-disease associations. RESULTS: The exposures alcohol, smoking, and diabetes were associated with an increased risk of colorectal cancer. We found some differences between cases and controls when examining the factors associated with the participation in the study, and in the sensitivity analyses, the exposure-disease associations were slightly attenuated when compared with those from the original analysis. CONCLUSION: Non-participation may have biased the risk estimates away from the null, but generally not enough to change the conclusions of the study. PMID- 25301195 TI - Unique Genotypic Differences Discovered among Indigenous Bangladeshi Rice Landraces. AB - Bangladesh is a reservoir of diverse rice germplasm and is home to many landraces with unique, important traits. Molecular characterization of these landraces is of value for their identification, preservation, and potential use in breeding programs. Thirty-eight rice landraces from different regions of Bangladesh including some high yielding BRRI varieties were analyzed by 34 polymorphic microsatellite markers yielding a total of 258 reproducible alleles. The analysis could locate 34 unique identifiers for 21 genotypes, making the latter potentially amenable to identity verification. An identity map for these genotypes was constructed with all the 12 chromosomes of the rice genome. Polymorphism information content (PIC) scores of the 34 SSR markers were 0.098 to 0.89 where on average 7.5 alleles were observed. A dendogram constructed using UPGMA clustered the varieties into two major groups and five subgroups. In some cases, the clustering matched with properties like aromaticity, stickiness, salt tolerance, and photoperiod insensitivity. The results will help breeders to work towards the proper utilization of these landraces for parental selection and linkage map construction for discovery of useful alleles. PMID- 25301196 TI - Effects of pseudo-phosphorylated rat cardiac troponin T are differently modulated by alpha- and beta-myosin heavy chain isoforms. AB - Interplay between the protein kinase C (PKC)-mediated phosphorylation of troponin T (TnT)- and myosin heavy chain (MHC)-mediated effects on thin filaments takes on a new significance because: (1) there is significant interaction between the TnT- and MHC-mediated effects on cardiac thin filaments; (2) although the phosphorylation of TnT by PKC isoforms is common to both human and rodent hearts, human hearts predominantly express beta-MHC while rodent hearts predominantly express alpha-MHC. Therefore, we tested how alpha- and beta-MHC isoforms differently affected the functional effects of phosphorylated TnT. Contractile measurements were made on cardiac muscle fibers from normal rats (alpha-MHC) and propylthiouracil-treated rats (beta-MHC), reconstituted with the recombinant phosphomimetic-TnT (T204E; threonine 204 replaced by glutamate). Ca2+ -activated maximal tension decreased differently in alpha-MHC + T204E (~68%) and beta-MHC + T204E (~35%). However, myofilament Ca2+ sensitivity decreased similarly in alpha MHC + T204E and beta-MHC + T204E, demonstrating that a decrease in Ca2+ sensitivity alone cannot explain the greater attenuation of tension in alpha-MHC + T204E. Interestingly, dynamic contractile parameters (rates of tension redevelopment, crossbridge (XB) recruitment dynamics, XB distortion dynamics, and XB detachment kinetics) decreased only in alpha-MHC + T204E. Thus, the transition of thin filaments from the blocked- to closed-state was attenuated in alpha-MHC + T204E and beta-MHC + T204E, but the closed- to open-state transition was attenuated only in alpha-MHC + T204E. Our study demonstrates that the effects of phosphorylated TnT and MHC isoforms interact to bring about different functional states of cardiac thin filaments. PMID- 25301197 TI - Boundary objects in clinical simulation and design of eHealth. AB - Development and implementation of eHealth is challenging due to the complexity of clinical work practices and organizations. Standardizing work processes and documentation procedures is one way of coping with these challenges, and acceptance of these initiatives and acceptance of the clinical information system are vital for success. Clinical simulation may be used as "boundary objects" and help transferring of knowledge between groups of stakeholders and help to better understand needs and requirements in other parts of the organization. This article presents a case study about design of electronic documentation templates for nurses' initial patient assessment, where clinical simulation was used as a boundary object and thereby achieved mutual clinical agreement on the content. Results showed that meetings prior to and in between workshops allowed all communities of practice an opportunity to voice their point of view and affect the final result. Implications of considering clinical simulations as boundary objects are discussed. PMID- 25301198 TI - Protecting privacy in a clinical data warehouse. AB - Peking University has several prestigious teaching hospitals in China. To make secondary use of massive medical data for research purposes, construction of a clinical data warehouse is imperative in Peking University. However, a big concern for clinical data warehouse construction is how to protect patient privacy. In this project, we propose to use a combination of symmetric block ciphers, asymmetric ciphers, and cryptographic hashing algorithms to protect patient privacy information. The novelty of our privacy protection approach lies in message-level data encryption, the key caching system, and the cryptographic key management system. The proposed privacy protection approach is scalable to clinical data warehouse construction with any size of medical data. With the composite privacy protection approach, the clinical data warehouse can be secure enough to keep the confidential data from leaking to the outside world. PMID- 25301199 TI - Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. AB - AIMS: Trimethylamine-N-oxide (TMAO) is produced in host liver from trimethylamine (TMA). TMAO and TMA share common dietary quaternary amine precursors, carnitine and choline, which are metabolized by the intestinal microbiota. TMAO recently has been linked to the pathogenesis of atherosclerosis and severity of cardiovascular diseases. We examined the effects of anti-atherosclerotic compound meldonium, an aza-analogue of carnitine bioprecursor gamma-butyrobetaine (GBB), on the availability of TMA and TMAO. MAIN METHODS: Wistar rats received L carnitine, GBB or choline alone or in combination with meldonium. Plasma, urine and rat small intestine perfusate samples were assayed for L-carnitine, GBB, choline and TMAO using UPLC-MS/MS. Meldonium effects on TMA production by intestinal bacteria from L-carnitine and choline were tested. KEY FINDINGS: Treatment with meldonium significantly decreased intestinal microbiota-dependent production of TMA/TMAO from L-carnitine, but not from choline. 24hours after the administration of meldonium, the urinary excretion of TMAO was 3.6 times lower in the combination group than in the L-carnitine-alone group. In addition, the administration of meldonium together with L-carnitine significantly increased GBB concentration in blood plasma and in isolated rat small intestine perfusate. Meldonium did not influence bacterial growth and bacterial uptake of L-carnitine, but TMA production by the intestinal microbiota bacteria K. pneumoniae was significantly decreased. SIGNIFICANCE: We have shown for the first time that TMA/TMAO production from quaternary amines could be decreased by targeting bacterial TMA-production. In addition, the production of pro-atherogenic TMAO can be suppressed by shifting the microbial degradation pattern of supplemental/dietary quaternary amines. PMID- 25301200 TI - Comprehensive quantification of triacylglycerols in soybean seeds by electrospray ionization mass spectrometry with multiple neutral loss scans. AB - Soybean seeds are an important source of vegetable oil and biomaterials. The content of individual triacylglycerol species (TAG) in soybean seeds is difficult to quantify in an accurate and rapid way. The present study establishes an approach to quantify TAG species in soybean seeds utilizing an electrospray ionization tandem mass spectrometry with multiple neutral loss scans. Ten neutral loss scans were performed to detect the fatty acyl chains of TAG, including palmitic (P, 16:0), linolenic (Ln, 18:3), linoleic (L, 18:2), oleic (O, 18:1), stearic (S, 18:0), eicosadienoic (20:2), gadoleic (20:1), arachidic (20:0), erucic (22:1), and behenic (22:0). The abundance of ten fatty acyl chains at 46 TAG masses (mass-to-charge ratio, m/z) were determined after isotopic deconvolution and correction by adjustment factors at each TAG mass. The direct sample infusion and multiple internal standards correction allowed a rapid and accurate quantification of TAG species. Ninety-three TAG species were resolved and their levels were determined. The most abundant TAG species were LLL, OLL, LLLn, PLL, OLLn, OOL, POL, and SLL. Many new species were detected and quantified. This shotgun lipidomics approach should facilitate the study of TAG metabolism and genetic breeding of soybean seeds for desirable TAG content and composition. PMID- 25301201 TI - T helper 17 cells and related cytokines after allergen inhalation challenge in allergic asthmatics. AB - BACKGROUND: T helper (Th)17 cells may play a role in allergic asthma. This study assessed the effect of allergen inhalation challenge on circulating Th17 cells and related cytokines in allergic asthmatics. METHODS: Peripheral blood mononuclear cells were collected from 16 atopic asthmatics before and 24 h after allergen challenge, as well as from 10 atopic nonasthmatics and 10 normal controls. Cells were stained for Th17 cytokines and their receptors (IL-17A, IL 17F, IL-21, IL-22, IL-17R, and IL-23R) using flow cytometry. Cytokine concentrations from cell culture supernatants were quantified using a multiplex assay for IL-17A, IL-17F, IL-21, IL-22, and IL-23. RESULTS: At baseline, asthmatics had a higher percentage of circulating Th17 cells (1.2 +/- 0.5%) compared to normal controls (0.9 +/- 0.66%, p < 0.001) but not compared to atopic nonasthmatics (1.13 +/- 0.5%). There was a significant increase in Th17 cells in asthmatics after allergen challenge to 1.55 +/- 0.4% (p < 0.05) and a trend toward significance in IL-17R expression from 3.4 +/- 4.3 to 6.86 +/- 6.84% after allergen challenge (p = 0.06). There was also a significant reduction in IL-21 positive cells following allergen challenge from 3.46 +/- 1.85 to 2.33 +/- 1.37% (p < 0.001). There were no significant differences in IL-17F, IL-22 and IL-23R expression. The concentration of IL-17A in culture supernatant was significantly higher in asthmatics compared to normal controls and IL-17A significantly increased 24 h after allergen challenge. CONCLUSIONS: The increase of Th17 cells and IL-17A in atopic asthma after allergen inhalation challenge suggests a possible role for Th17 in allergen-induced airway responses. PMID- 25301202 TI - Nanofiber diameter as a critical parameter affecting skin cell response. AB - Electrospun polymer nanofibers have opened new opportunities in the rapidly evolving field of tissue engineering, particularly due to their topography and variability of available biomaterials. In order to better understand nanofiber influence on cell growth, the impact of their diameter was systematically examined. In this study homogenous, randomly oriented poly(vinyl alcohol) nanofibers with five different average diameters, ranging from 70nm to 1120nm, were produced, characterized and their impact on morphology, proliferation and mobility of keratinocytes and skin fibroblasts was evaluated. The results have shown that nanofiber diameter affects cell response and that this response is cell line specific. Nanofiber thickness affected size, morphology and actine organization of keratinocytes much more than fibroblasts. Specifically, the keratinocyte grown on nanofibers were more spherical and smaller compared to the control cells, while the fibroblasts were much less affect. They stayed almost unchanged and spread across growth surface. The cell proliferation determined based on their metabolic activity was the highest, when keratinocytes were grown on 305nm thick nanofibers, whereas proliferation of fibroblasts grown similar nanofibers was decreased. Finally, fibroblasts exerted higher mobility than keratinocytes. Both tested cell lines on nanofiber diameters of 300nm resulted in decreased cell mobility. These findings suggest that the control over nanofiber diameter offers promising possibility to better design the tissue scaffolds, since cells distinguish between differently sized nanofibers and respond accordingly. PMID- 25301203 TI - Extracellular vesicles from MDA-MB-231 breast cancer cells stimulated with linoleic acid promote an EMT-like process in MCF10A cells. AB - Extracellular vesicles (EVs) are membrane-limited vesicles secreted by normal and malignant cells and their function is dependent on the cargo they carry and the cell type from which they originate. Moreover, EVs mediate many stages of tumor progression including angiogenesis, escape from immune surveillance and extracellular matrix degradation. Linoleic acid (LA) is an essential polyunsaturated fatty acid that induces expression of plasminogen activator inhibitor-1, proliferation, migration and invasion in breast cancer cells. However the role of secreted EVs from MDA-MB-231 cells stimulated with LA like mediator of the epithelial-mesenchymal-transition (EMT) process in mammary non tumorigenic epithelial cells MCF10A remains to be studied. In the present study, we demonstrate that treatment of MDA-MB-231 cells for 48 h with 90 uM LA does not induce an increase in the number of secreted EVs. In addition, EVs isolated from supernatants of MDA-MB-231 stimulated for 48 h with 90 uM LA induce a transient down-regulation of E-cadherin expression, and an increase of Snail1 and 2, Twist1 and 2, Sip1, vimentin and N-cadherin expression in MCF10A cells. EVs also promote an increase of MMP-2 and -9 secretions, an increase of NFkappaB-DNA binding activity, migration and invasion in MCF10A cells. In summary, our findings demonstrate, for the first time, that EVs isolated from supernatants of MDA-MB 231 stimulated for 48 h with 90 uM LA induce an EMT-like process in MCF10A cells. PMID- 25301204 TI - Apolipoprotein E isoforms disrupt long-chain fatty acid distribution in the plasma, the liver and the adipose tissue of mice. AB - Evidences suggest that omega-3 fatty acid (n-3 PUFA) metabolism is imbalanced in apolipoprotein E epsilon 4 isoform carriers (APOE4). This study aimed to investigate APOE genotype-dependant modulation of FA profiles, protein and enzyme important to fatty acid (FA) metabolism in the adipose tissue, the liver and the plasma using human APOE-targeted replacement mouse-model (N=37). FA transport (FATP) and binding (FABP) protein levels in tissues and concentrations of liver carnitine palmitoyltransferase 1 (CPT1) were performed. N-3 PUFA concentration was >45% lower in the adipose tissue and liver of APOE4 mice compared to APOE3 mice. In APOE4 mice, there were higher levels of FATP and FABP in the liver and higher FATP in the adipose tissue compared to APOE2 mice. There was a trend towards higher CPT1 concentrations in APOE4 mice compared to APOE3 mice. Therefore, since APOE-isoform differences were not always in line with the unbalanced n-3 PUFA profiles in organs, other proteins may be involved in maintaining n-3 PUFA homeostasis in mice with different APOE-isoforms. PMID- 25301205 TI - The KCaSrTa5O15 photocatalyst with tungsten bronze structure for water splitting and CO2 reduction. AB - KCaSrTa5O15 with tungsten bronze structure and a band gap of 4.1 eV showed activity for water splitting without cocatalysts. The activity was improved by loading the NiO cocatalyst. The apparent quantum yield of optimized NiO-loaded KCaSrTa5O15 was 2.3% at 254 nm for water splitting. When CO2 gas was bubbled into the reactant aqueous solution, Ag cocatalyst-loaded KCaSrTa5O15 produced CO and H2 as reduction products of CO2 and H2O, respectively, and O2 as an oxidation product of H2O. The carbon source of CO was confirmed to be CO2 molecules by using (13)CO2. The ratio of the number of electrons to that of holes calculated from the amounts of products (CO, H2 and O2) was almost unity. Additionally, the ratio of the turnover number of electrons consumed for CO production to the total number of an Ag atom of the cocatalyst that was the active site for CO2 reduction was 8.6 at 20 h. These results indicate that water was consumed as an electron donor for this photocatalytic CO2 reduction in an aqueous medium. Thus, KCaSrTa5O15 with tungsten bronze structure has arisen as a new photocatalyst that is active for water splitting and CO2 reduction utilizing water as an electron donor. PMID- 25301206 TI - Do human extraintestinal Escherichia coli infections resistant to expanded spectrum cephalosporins originate from food-producing animals? A systematic review. AB - To find out whether food-producing animals (FPAs) are a source of extraintestinal expanded-spectrum cephalosporin-resistant Escherichia coli (ESCR-EC) infections in humans, Medline, Embase, and the Cochrane Database of Systematic Reviews were systematically reviewed. Thirty-four original, peer-reviewed publications were identified for inclusion. Six molecular epidemiology studies supported the transfer of resistance via whole bacterium transmission (WBT), which was best characterized among poultry in the Netherlands. Thirteen molecular epidemiology studies supported transmission of resistance via mobile genetic elements, which demonstrated greater diversity of geography and host FPA. Seventeen molecular epidemiology studies did not support WBT and two did not support mobile genetic element-mediated transmission. Four observational epidemiology studies were consistent with zoonotic transmission. Overall, there is evidence that a proportion of human extraintestinal ESCR-EC infections originate from FPAs. Poultry, in particular, is probably a source, but the quantitative and geographical extent of the problem is unclear and requires further investigation. PMID- 25301207 TI - Higher risk of neutropenia associated with piperacillin-tazobactam compared with ticarcillin-clavulanate in children. AB - BACKGROUND: A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C. METHODS: Medical records of subjects aged <18 years who received at least 1 dose of P/T or T/C between 1 January 2008 and 30 June 2011 were reviewed. RESULTS: Two hundred ninety-nine episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell count analysis and were included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all patients were aged <13 years. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group (unadjusted odds ratio, 4.59; 95% confidence interval, 1.48-14.17). Although a statistically significant correlation was observed between age, treatment duration, and total dose and the development of neutropenia (r = -0.121, P = .037; r = 0.267, P < .001; r = 0.260, P < .001, respectively), this was not the case for sex, indications, neutrophil count at initiation, and concomitant drug treatments. CONCLUSIONS: Although our results need to be confirmed, they suggest that children receiving long courses of therapy (>2 weeks) with P/T may be at increased risk of neutropenia, compared with T/C. PMID- 25301209 TI - Pertactin-negative Bordetella pertussis strains: evidence for a possible selective advantage. AB - BACKGROUND: A recent increase in Bordetella pertussis without the pertactin protein, an acellular vaccine immunogen, has been reported in the United States. Determining whether pertactin-deficient (PRN(-)) B. pertussis is evading vaccine induced immunity or altering the severity of illness is needed. METHODS: We retrospectively assessed for associations between pertactin production and both clinical presentation and vaccine history. Cases with isolates collected between May 2011 and February 2013 from 8 states were included. We calculated unadjusted and adjusted odds ratios (ORs) using multivariable logistic regression analysis. RESULTS: Among 753 isolates, 640 (85%) were PRN(-). The age distribution differed between cases caused by PRN(-) B. pertussis and cases caused by B. pertussis producing pertactin (PRN(+)) (P = .01). The proportion reporting individual pertussis symptoms was similar between the 2 groups, except a higher proportion of PRN(+) case-patients reported apnea (P = .005). Twenty-two case-patients were hospitalized; 6% in the PRN(+) group compared to 3% in the PRN(-) group (P = .11). Case-patients having received at least 1 pertussis vaccine dose had a higher odds of having PRN(-) B. pertussis compared with unvaccinated case patients (adjusted OR = 2.2; 95% confidence interval [CI], 1.3-4.0). When restricted to case-patients at least 1 year of age and those age-appropriately vaccinated, the adjusted OR increased to 2.7 (95% CI, 1.2-6.1). CONCLUSIONS: The significant association between vaccination and isolate pertactin production suggests that the likelihood of having reported disease caused by PRN(-) compared with PRN(+) strains is greater in vaccinated persons. Additional studies are needed to assess whether vaccine effectiveness is diminished against PRN(-) strains. PMID- 25301208 TI - Improvements in HIV care engagement and viral load suppression following enrollment in a comprehensive HIV care coordination program. AB - BACKGROUND: Substantial evidence gaps remain regarding human immunodeficiency virus (HIV) intervention strategies that improve engagement in care (EiC) and viral load suppression (VLS). We assessed EiC and VLS before and after enrollment in a comprehensive intervention for persons at risk of poor HIV care outcomes. METHODS: New York City's Ryan White Part A HIV Care Coordination Program (CCP), launched at 28 agencies in 2009, applies multiple strategies to promote optimal utilization of medical and social services. Using laboratory test records from an HIV surveillance registry, we examined pre-post outcomes among 3641 CCP clients enrolled before April 2011. For the year before and after enrollment, we assessed EiC (defined as >=2 tests, >=90 days apart, with >=1 in each half-year) and VLS (defined as viral load [VL] <=200 copies/mL on latest VL test in the second half of the year). We estimated relative risks (RRs), comparing pre- and postenrollment proportions achieving EiC and VLS. RESULTS: Among newly diagnosed clients, 90.5% (95% confidence interval [CI], 87.9%-93.2%) and 66.2% (95% CI, 61.9%-70.6%) achieved EiC and VLS, respectively. Among previously diagnosed clients, EiC increased from 73.7% to 91.3% (RR = 1.24; 95% CI, 1.21-1.27) and VLS increased from 32.3% to 50.9% (RR = 1.58; 95% CI, 1.50-1.66). Clients without evidence of HIV care during the 6 months preenrollment contributed most to overall improvements. Pre-post improvements were robust, retaining statistical significance within most sociodemographic and clinical subgroups, and in 89% (EiC) and 75% (VLS) of CCP agencies. CONCLUSIONS: Clients in comprehensive HIV care coordination for persons with evident barriers to care showed substantial and consistent improvement in short-term outcomes. PMID- 25301210 TI - Novel poxvirus infection in 2 patients from the United States. AB - BACKGROUND: Some human poxvirus infections can be acquired through zoonotic transmission. We report a previously unknown poxvirus infection in 2 patients, 1 of whom was immunocompromised; both patients had known equine contact. METHODS: The patients were interviewed and clinical information was abstracted from the patients' medical files. Biopsies of the skin lesions were collected from both patients for histopathology, immunohistochemistry, and transmission electron microscopy analysis. Oral and skin swabs were collected from animals with frequent contact with the patients, and environmental sampling including rodent trapping was performed on the farm where the immunosuppressed patient was employed. "Pan-pox and high Guanine-cytosine" polymerase chain reaction assays were performed on patient, animal, and environmental isolates. Amplicon sequences of the viral DNA were used for agent identification and phylogenetic analysis. RESULTS: Specimens from both human cases revealed a novel poxvirus. The agent shares 88% similarity to viruses in the Parapoxvirus genus and 78% to those in the Molluscipoxvirus genus but is sufficiently divergent to resist classification as either. All animal and environmental specimens were negative for poxvirus and both patients had complete resolution of lesions. CONCLUSIONS: This report serves as a reminder that poxviruses should be considered in cutaneous human infections, especially in individuals with known barnyard exposures. The clinical course of the patients was similar to that of parapoxvirus infections, and the source of this virus is currently unknown but is presumed to be zoonotic. This report also demonstrates the importance of a comprehensive approach to diagnosis of human infections caused by previously unknown pathogens. PMID- 25301212 TI - Sepsis-like disease in infants due to human parechovirus type 3 during an outbreak in Australia. AB - BACKGROUND: Infections with human parechoviruses (HPeVs) are associated with a wide range of clinical presentations in children, ranging from mild or asymptomatic infections to severe sepsis-like presentations or meningoencephalitis. METHODS: We reviewed medical records of infants admitted to 5 hospitals in New South Wales, Australia, during an outbreak of HPeV-3 infection. Data were collected on clinical presentation, laboratory markers, and outcome of infants with HPeV infection confirmed by reverse transcription polymerase chain reaction. RESULTS: We identified 118 infected infants. Most presented with an acute sepsis-like syndrome with high fever, tachycardia, poor perfusion, and severe irritability. Other common features were erythrodermic rash, abdominal distension, edema, and hepatitis. The age range of infants was 4 days to 9.5 months; 75% were <2 months old, including all but 1 of the 30 infants (25%) admitted to intensive care units (ICUs), who as a group, were significantly younger than infants not admitted to ICUs. Only 4% of evaluable cerebrospinal fluid samples had pleocytosis, but HPeV was detected in 95%. Brain magnetic resonance imaging on a small number of children demonstrated white matter changes and diffusion restriction. Sequencing of the VP1 gene confirmed HPeV-3 in all samples tested. All children recovered without ongoing complications at last follow-up. CONCLUSIONS: We report the largest series of HPeV-3 infection in infants, and the first outbreak in Australia. Infants presented with a severe sepsis-like syndrome with a high rate of ICU admissions, but all recovered from the acute infection without complications. Long-term sequelae are unknown. PMID- 25301213 TI - Host immune response to tuberculous meningitis. AB - BACKGROUND: Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the host's immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. METHODS: We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months-13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. RESULTS: Unsupervised hierarchical clustering analysis revealed a disease-specific pattern of biomarkers for TBM relative to other types of meningitis. A biomarker-based diagnostic prediction model for childhood TBM based on CSF concentrations of interleukin 13 (cutoff value, 37.26 pg/mL), vascular endothelial growth factor (cutoff value, 42.92 pg/mL), and cathelicidin LL-37 (cutoff value, 3221.01 pg/mL) is presented with a sensitivity of 0.52 and a specificity of 0.95. CONCLUSIONS: These data highlight the potential of biosignatures in the host's CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae. PMID- 25301214 TI - Ocular toxoplasmosis in the United States: recent and remote infections. AB - We tested all samples from patients with ocular toxoplasmosis sent to the Palo Alto Medical Foundation Toxoplasma Reference Laboratory from June 2004 through August 2010 for serologic evidence of recent Toxoplasma gondii infection. Of 205 patients aged 10-96 years, 11.7% had recent infection. Many people develop ocular disease soon after T. gondii infection. PMID- 25301215 TI - Is bacteremic sepsis associated with higher mortality in transplant recipients than in nontransplant patients? A matched case-control propensity-adjusted study. AB - BACKGROUND: Sepsis is a serious complication of solid organ transplant (SOT). Evidence on survival differences between SOT recipients and non-SOT patients with sepsis is lacking. METHODS: This was a matched, case-control propensity-adjusted study. Conditional logistic regression was performed for risk factor analysis, and Cox proportional hazards regression for survival analysis. RESULTS: Three hundred sixty-nine patients (123 cases; 246 controls) diagnosed with blood culture-proven sepsis were matched 1:2 by age, sex, and hospital location. The distribution of allografts was 36.6% kidney, 34.1% liver, 13% kidney-pancreas, 7.3% small bowel/liver, 5.7% heart/lung, and 3.3% multivisceral. The conditional logistic regression showed that the following factors were significantly more frequently associated with SOT compared to non-SOT: higher number of comorbidities (odds ratio [OR] = 8.2 [95% confidence interval {CI}, 1.48-45.44], P = .016); higher Sepsis-related Organ Failure Assessment score (OR = 1.2 [95% CI, 1.07-1.32], P = .001); presence of nosocomial infection (OR = 36.3 [95% CI, 9.71-135.96], P < .0001); appropriate initial antibiotics (OR = 0.04 [95% CI, .006-.23], P < .0001); and lower white blood cell count (OR = 0.93 [95% CI, .89 .97], P < .0001). Cox proportional hazards regression showed that after all adjustments for clinical presentation, severity of illness, and types of infection, SOT recipients with sepsis had a significantly lower risk of death at 28 days (hazard ratio [HR] = 0.22 [95% CI, .09-.54], P = .001) and at 90 days (HR = 0.43 [95% CI, .20-.89], P = .025). CONCLUSIONS: The 28-day and 90-day mortality were significantly decreased for transplant recipients compared with nontransplant patients. These findings suggest that the immunosuppression associated with transplantation may provide a survival advantage to transplant recipients with sepsis through modulation of the inflammatory response. PMID- 25301216 TI - Hepatitis C core antigen testing: a reliable, quick, and potentially cost effective alternative to hepatitis C polymerase chain reaction in diagnosing acute hepatitis C virus infection. AB - Hepatitis C virus (HCV) is increasingly common among human immunodeficiency virus (HIV)-infected men who have sex with men. We evaluated the efficacy of HCV core antigen in diagnosing acute HCV in an HIV-infected cohort. Compared with HCV polymerase chain reaction, core antigen proved sensitive (100%) and specific (97.9%). As a quick, simple, and cost-effective test, it has considerable utility in screening for acute HCV. PMID- 25301217 TI - Prolonged clinical course of muscular sarcocystosis and effectiveness of cotrimoxazole among travelers to Tioman Island, Malaysia, 2011-2014. PMID- 25301218 TI - Medical humanitarianism: research insights in a changing field of practice. PMID- 25301219 TI - Combining organophosphate-treated wall linings and long-lasting insecticidal nets fails to provide additional control over long-lasting insecticidal nets alone against multiple insecticide-resistant Anopheles gambiae in Cote d'Ivoire: an experimental hut trial. AB - BACKGROUND: Insecticide-treated wall lining (ITWL) is a new concept in malaria vector control. Some Anopheles gambiae populations in West Africa have developed resistance to all the main classes of insecticides. It needs to be demonstrated whether vector control can be improved or resistance managed when non-pyrethroid ITWL is used alone or together with long-lasting insecticidal nets (LLINs) against multiple insecticide-resistant vector populations. METHODS: Two experimental hut trials were carried out as proofs of concept to evaluate pirimiphos methyl (p-methyl)-treated plastic wall lining (WL) and net wall hangings (NWH) used alone and in combination with LLINs against multiple insecticide-resistant An. gambiae in Tiassale, Cote d'Ivoire. Comparison was made to commercial deltamethrin WL and genotypes for kdr and ace-1R resistance were monitored. RESULTS: The kdr and ace-1R allele frequencies were 0.83 and 0.44, respectively. Anopheles gambiae surviving discriminating concentrations of deltamethrin and p-methyl in WHO resistance tests were 57 and 96%, respectively. Mortality of free-flying An. gambiae in huts with p-methyl WL and NWH (66 and 50%, respectively) was higher than with pyrethroid WL (32%; P<0.001). Mortality with LLIN was 63%. Mortality with the combination of LLIN plus p-methyl NWH (61%) or LLIN plus p-methyl WL (73%) did not significantly improve upon the LLIN alone or p-methyl WL or NWH alone. Mosquitoes bearing the ace-1R were more likely to survive exposure to p-methyl WL and NWH. Selection of heterozygote and homozygote ace-1R or kdr genotypes was not less likely after exposure to combined LLIN and p methyl treatments than to single p-methyl treatment. Blood-feeding rates were lower in huts with the pyrethroid LLIN (19%) than with p-methyl WL (72%) or NWH (76%); only LLIN contributed to personal protection. CONCLUSIONS: Combining p methyl WL or NWH with LLINs provided no improvement in An. gambiae control or personal protection over LLIN alone in southern Cote d'Ivoire; neither did the combination manage resistance. Additional resistance mechanisms to kdr and ace-1R probably contributed to the survival of pyrethroid and organophophate-resistant mosquitoes. The study demonstrates the challenge that malaria control programmes will face if resistance to multiple insecticides continues to spread. PMID- 25301220 TI - Barcode-like paper sensor for smartphone diagnostics: an application of blood typing. AB - This study introduced a barcode-like design into a paper-based blood typing device by integrating with smartphone-based technology. The concept of presenting a paper-based blood typing assay in a barcode-like pattern significantly enhanced the adaptability of the assay to the smartphone technology. The fabrication of this device involved the use of a printing technique to define hydrophilic bar channels which were, respectively, treated with Anti-A, -B, and -D antibodies. These channels were then used to perform blood typing assays by introducing a blood sample. Blood type can be visually identified from eluting lengths in bar channels. A smartphone-based analytical application was designed to read the bar channels, analogous to scanning a barcode, interpret this information, and then report results to users. The proposed paper-based blood typing device is rapidly read by smartphones and easy for the user to operate. We envisage that the adaptation of paper-based devices to the widely accepted smartphone technology will increase the capability of paper-based diagnostics with rapid assay result interpretation, data storage, and transmission. PMID- 25301221 TI - The evaluation of Clostridium difficile infection (CDI) in a community hospital. AB - INTRODUCTION: Clostridium difficile is a serious reemerging pathogen in Europe and North America. C. difficile infection (CDI) has been of concern over the last decade in view of its significant morbidity and mortality, as well as the high health care costs involved with each case. Although multiple risk factors are known to be associated with CDI, a number of patients develop severe infection even in the absence of known risk factors. CDI is diagnosed by the detection of the toxin A/B in stools by enzyme immunoassay (EIA) or by polymerase chain reaction (PCR). There is conflicting literature regarding whether any particular group of antibiotics is associated with higher risk for CDI. There is also a tendency to perform repeated stool tests for toxin A/B if the first test is negative. We evaluated 100 consecutive hospitalized patients who tested positive for C. difficile over a one-year period. METHODS: We performed a retrospective analysis of 100 consecutive patients with CDI admitted to our hospital between July 2008 and June 2009. Patient records were reviewed for risk factors, treatment, and clinical outcomes. We also evaluated the number of stool tests performed for the detection of C. difficile and fecal leukocyte testing in each patient. RESULTS: The majority of the patients were more than 60 years of age (87%). Forty-four percent of patients presented from a nursing facility. More than 50% were on Proton Pump Inhibitors (PPIs) at the time of admission. Co morbidities in our patients included malignancy in 28%, diabetes mellitus in 25%, and chronic renal disease in 23%. Most of the patients had multiple co morbidities. Patients who had taken antibiotics in the previous six months constituted 74% of the total study population. A beta-lactam alone or in combination with other antibiotics was prescribed in 48%, quinolones in 13% and clindamycin in 4% of patients. Stool samples were tested only once in 53% of patients and twice or more in 43%. Metronidazole was the initial therapy in 86% of patients. Intensive care unit stay was required in 33% of patients. Seventeen percent died during their hospitalization. CONCLUSIONS: Elderly patients are especially vulnerable to CDI when exposed to antibiotics, and higher mortality and morbidity is observed in this age group. PPI use was common in our patients. Metronidazole was used as the first line agent in the majority of patients. We also determined a tendency to test for the C. difficile toxin in more than one stool sample. All of these practices need to be modified based on the current guidelines. PMID- 25301223 TI - Pictogram-based method of visualizing dietary intake. AB - BACKGROUND: Pictograms have been shown by many studies to be an effective way of conveying information. An easy-to-understand pictorial description is essential for communication of dietary intake in the computer era. OBJECTIVES: We proposed a novel approach that represents textual descriptions of dietary intake into a pictorial representation with the concept of pictograms. The computational implementation in terms of a web-based tool was investigated on how well the pictograms carry their intended message. METHODS: 1) We investigated how well the pictograms are comprehended in terms of subjects' accuracy rate and response time. In the study (n = 90), pictorial variants with three types of food images (black-and-white sketch, colored sketch, and colored photograph) were tested. 2) We also investigated how well subjects were able to select the standard food size among various food portions with the use of the tool. A comparison was made against the current standard of an educational session taught by a registered dietitian. We recruited 86 university students who were asked to select a standard size out of five different size categories. Three types of shapes were used. The bowl is the container that is widely used in the participants' country. The pork strip was to represent foods with elliptical cross-section. The apple was used to represent a baseball-like size and shape. RESULTS: Two pictograms with black-and-white food image were low of less than 50% in accuracy rate. The rest of the twenty-seven pictograms derived from portions of the nine foods were well understood with high accuracy rates (above 85%). Participants in using the tool without the dietitian's session was better than participants in the dietitian education session in selecting a standard portion size of an apple (p < 0.0001; p = 0.0009 after adjustment for gender and age). The rate of correct bowl and pork strip size estimates were similar between the two conditions (p > 0.05). CONCLUSION: The development of pictograms could be used as a computational visual aid for comprehending and identifying dietary intake. Broader investigation is required for considering the effectiveness of the pictograms on recall, measurement, or estimation as well as for further evaluation in the clinical practice. PMID- 25301224 TI - Agreement between accelerometer-assessed and self-reported physical activity and sedentary time in colon cancer survivors. AB - PURPOSE: Research conducted on the general population indicates self-reported measures of physical activity and sedentary behaviour are inaccurate when compared with objective measures; however, it is not clear if this also applies to cancer survivors. In this study, we compared accelerometer-based and self reported measures of moderate- to vigorous-intensity physical activity (MVPA) and sedentary time among colon cancer survivors. METHODS: A total of 176 colon cancer survivors, recruited from the Western Australia and Alberta cancer registries, wore an Actigraph GT3X+ accelerometer for 7 days and completed self-reported questions about recent MVPA (Godin Leisure-Time Exercise Questionnaire) and usual sedentary time (Marshall Domain-Specific Sitting Questionnaire). Accelerometer data were processed using 60-s epochs and summarized using Freedson's cut points. Spearman's rho and intraclass correlation coefficients (ICCs) were used to assess correlation and agreement for daily MVPA and sedentary time estimates from the two methods. RESULTS: Total mean minutes per day spent in MVPA was 12 min based on accelerometer data and 26 min based on self-reported data (P Difference < 0.01). Correlation between the methods was fair (rho = 0.51); however, agreement was poor (ICC = 0.33). Mean daily time spent sedentary was similar in both methods (~8.5 h); however, both correlation and agreement were poor (rho = 0.19, ICC = 0.16). CONCLUSIONS: We found fair correlation but poor agreement between the self-reported and accelerometer-based assessments of MVPA used in this study. For sedentary time, both correlation and agreement between the two methods were poor. Studies of colon cancer survivors using these self-report measures are likely to have a considerable amount of exposure misclassification. PMID- 25301225 TI - The absence of later wave components in auditory brainstem responses as an initial manifestation of type 2 Gaucher disease. AB - BACKGROUND: Type 2 Gaucher disease is the most severe neuronopathic form of Gaucher disease and is characterized by severe neurodegeneration with brainstem involvement and organ failure. Prediction or diagnosis of type 2 Gaucher disease before the development of neurological complications is difficult. PATIENT: A 5 month-old female infant presented with deafness without other neurological abnormalities. Auditory brainstem response analysis revealed the absence of later wave components. Two months later, muscular rigidity became evident, followed by the development of opisthotonus and strabismus. Rapid progression of splenomegaly led to the diagnosis of type 2 Gaucher disease. CONCLUSIONS: Abnormal auditory brainstem response findings may already exist before the development of severe brainstem abnormalities such as muscular rigidity and opisthotonus in type 2 Gaucher disease. When patients present with deafness and absent later wave components on auditory brainstem response, type 2 Gaucher disease should be included in the differential diagnosis even in the absence of other neurological abnormalities. PMID- 25301226 TI - A bedside measure of body composition in Duchenne muscular dystrophy. AB - BACKGROUND: In clinical practice, monitoring body composition is a critical component of nutritional assessment and weight management in boys with Duchenne muscular dystrophy. We aimed to evaluate the accuracy of a simple bedside measurement tool for body composition, namely bioelectrical impedance analysis, in boys with Duchenne muscular dystrophy. METHODS: Measures of fat-free mass were determined using a bioelectrical impedance analysis machine and compared against estimations obtained from a reference body composition model. Additionally, the use of raw impedance values was analyzed using three existing predictive equations for the estimation of fat-free mass. Accuracy of bioelectrical impedance analysis was assessed by comparison against the reference model by calculation of biases and limits of agreement. RESULTS: Body composition was measured in 10 boys with Duchenne muscular dystrophy, mean age 9.01 +/- 2.34 years. The bioelectrical impedance analysis machine values of fat-free mass were on average 2.3 +/- 14.1 kg higher than reference values. Limits of agreement (based on 95% confidence interval of the mean) were -7.4 to 2.9 kg. There was a significant correlation between the mean fat-free mass and difference in fat-free mass between the bioelectrical impedance analysis machine and the reference model (r = -0.86; P = 0.02) suggesting that the bias was not consistent across the range of measurements. The most accurate predictive equation for the estimation of fat-free mass using raw impedance values was the equation by Pietrobelli et al. (mean difference, -0.7 kg; 95% limits of agreement, -3.5 to 2.0 kg). CONCLUSIONS: In a clinical setting, where a rapid assessment of body composition is advantageous, the use of raw impedance values, combined with the equation by Pietrobelli et al., is recommended for the accurate estimation of fat-free mass, in boys with Duchenne muscular dystrophy. PMID- 25301227 TI - Basal ganglia calcification in a patient with beta-propeller protein-associated neurodegeneration. AB - BACKGROUND: Beta-propeller protein-associated neurodegeneration is a newly described X-linked dominant condition due to heterozygous mutations in WDR45. The condition is associated with characteristic changes on brain magnetic resonance imaging. Previous literature relating to this disorder has not specifically referred to intracranial calcification. METHODS: A female patient presented with significant developmental delay in early childhood and subsequently demonstrated neurodegeneration with progressive dystonia and dementia in her third decade. Brain magnetic resonance imaging revealed low signal in the substantia nigra and both globus pallidi on T2-weighted imaging, with no eye-of-the-tiger sign. Computed tomography revealed bilateral dense calcification of the globus pallidus. We performed Sanger sequencing of the WDR45 gene in the patient and her parents. RESULTS: We identified a heterozygous c.488del C p.Pro163Argfs*34 variant in exon 8 of WDR45. Neither parent carried the same mutation, indicating that the molecular change had occurred de novo. CONCLUSIONS: Although the characteristic features of beta-propeller protein-associated neurodegeneration were present in our patient, the observation of basal ganglia calcification was considered atypical. Previous descriptions of basal ganglia calcification in individuals with neuronal brain iron accumulation led us to review the frequency of calcification in these disorders. PMID- 25301228 TI - Is there a place for xenodiagnosis in the clinic? AB - Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist after antibiotic therapy is an area of ongoing controversy. In animal models, B. burgdorferi DNA can be detected in tissues after antibiotic therapy as well as by using the natural tick vector to acquire the organism through feeding (xenodiagnosis). Vector arthropods have been successfully used in xenodiagnosis to describe the etiology of infections such as malaria, typhus and Chagas disease. Our recent safety trial of xenodiagnosis demonstrates that ticks may be successfully fed on patients and may help determine the biological basis for post treatment Lyme disease syndrome. PMID- 25301229 TI - A review of neuraminidase inhibitor susceptibility in influenza strains. AB - Influenza human infections are considered as a persistent global public health issue. Whereas vaccination is important for prevention, given its limitations, antiviral therapy is at the forefront of treatment, while it also plays a significant role in prevention. Currently, two classes of drugs, adamantanes (M2 blockers) and neuraminidase inhibitors (NAIs), are available for treatment and chemoprophylaxis of influenza infections. Given the resistance patterns of circulating influenza strains, adamantanes are not currently recommended. The current review mainly focuses on the development of resistance to NAIs among A and B subtypes of influenza virus strains over the last 5 years. 'Permissive' drift mutations and reassortment of viral gene segments have resulted in NAI oseltamivir-resistant A/(H1N1) variants that rapidly became predominant worldwide in the period 2007-2009. However, the prevalence of antiviral resistance to NAI zanamivir remains relatively low. In addition, the recently developed NAIs, peramivir and laninamivir, while licensed in certain countries, are still under evaluation and only a few reports have described resistance to peramivir. Although in 2014, the majority of circulating human influenza viruses remains susceptible to all NAIs, the emergence of oseltamivir-resistant influenza variants that could retain viral transmissibility, highlights the necessity for enhanced epidemiological and microbiological surveillance and clinical assessment of antiviral resistance. PMID- 25301230 TI - Prognostic markers of meningococcal disease in children: recent advances and future challenges. AB - Meningococcal disease is a life-threatening condition and a major cause of bacterial meningitis and sepsis worldwide. In many fatal cases, meningococcal disease is rapidly progressive and death occurs within hours of the initial symptoms. The early identification of patients at high risk of death would be useful in order to provide aggressive and more personalized clinical management with the proper level of supportive therapy required, contributing to an improvement in the survival rate and reduction in sequelae. The current study aims to review the current published literature about prognostic markers of meningococcal sepsis in children in order to elaborate conclusions and recommendations that could guide clinical practice and further research. PMID- 25301231 TI - Vancomycin pharmacokinetic models: informing the clinical management of drug resistant bacterial infections. AB - This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC >=400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC >=320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets. PMID- 25301232 TI - Glucocorticoid Receptor beta Acts as a Co-activator of T-Cell Factor 4 and Enhances Glioma Cell Proliferation. AB - We previously reported that glucocorticoid receptor beta (GRbeta) regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of beta-catenin/T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity. The aim of this study was to characterize the mechanism behind cross-talk between GRbeta and beta-catenin/TCF in the progression of glioma. Here, we reported that GRbeta knockdown reduced U118 and Shg44 glioma cell proliferation in vitro and in vivo. Mechanistically, we found that GRbeta knockdown decreased TCF/LEF transcriptional activity without affecting beta catenin/TCF complex. Both GRalpha and GRbeta directly interact with TCF-4, while only GRbeta is required for sustaining TCF/LEF activity under hormone-free condition. GRbeta bound to the N-terminus domain of TCF-4 its influence on Wnt signaling required both ligand- and DNA-binding domains (LBD and DBD, respectively). GRbeta and TCF-4 interaction is enough to maintain the TCF/LEF activity at a high level in the absence of beta-catenin stabilization. Taken together, these results suggest a novel cross-talk between GRbeta and TCF-4 which regulates Wnt signaling and the proliferation in gliomas. PMID- 25301234 TI - The Contribution of Melanoregulin to Microtubule-Associated Protein 1 Light Chain 3 (LC3) Associated Phagocytosis in Retinal Pigment Epithelium. AB - A main requisite in the phagocytosis of ingested material is a coordinated series of maturation steps which lead to the degradation of ingested cargo. Photoreceptor outer segment (POS) renewal involves phagocytosis of the distal disk membranes by the retinal pigment epithelium (RPE). Previously, we identified melanoregulin (MREG) as an intracellular cargo-sorting protein required for the degradation of POS disks. Here, we provide evidence that MREG-dependent processing links both autophagic and phagocytic processes in LC3-associated phagocytosis (LAP). Ingested POS phagosomes are associated with endogenous LC3 and MREG. The LC3 association with POSs exhibited properties of LAP; it was independent of rapamycin pretreatment, but dependent on Atg5. Loss of MREG resulted in a decrease in the extent of LC3-POS association. Studies using DQ-BSA suggest that loss of MREG does not compromise the association and fusion of LC3 positive phagosomes with lysosomes. Furthermore, the mechanism of MREG action is likely through a protein complex that includes LC3, as determined by colocalization and immunoprecipitation in both RPE cells and macrophages. We posit that MREG participates in coordinating the association of phagosomes with LC3 for content degradation with the loss of MREG leading to phagosome accumulation. PMID- 25301233 TI - Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury. AB - Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin 1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCalpha, PKCdelta, and PKCepsilon, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCalpha levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCepsilon (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma. PMID- 25301235 TI - The effects of Betula platyphylla bark on amyloid beta-induced learning and memory impairment in mice. AB - Alzheimer's disease (AD) is closely associated with amyloid beta (Abeta)-induced neurotoxicity and oxidative stress in the brain. Betula platyphylla, which has been used to treat various oxidative-stressed related diseases, has recently received attention for its preventive activity on age-related neurodegenerative diseases. In this study, we attempted to investigate the effects of B. platyphylla bark (BPB-316) on Abeta(1-42)-induced neurotoxicity and memory impairment. Oral treatment using BPB-316 significantly attenuated Abeta-induced memory impairment which was evaluated by behavioral tests including the passive avoidance, Y-maze and Morris water maze test. BPB-316 also inhibited the elevation of beta-secretase activity accompanying the reduced Abeta(1-42) levels in the hippocampus of the brain. Furthermore, BPB-316 significantly decreased the acetylcholinesterase activity and increased the glutathione content in the hippocampus. In addition, we confirmed that the expression of both cAMP responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of Abeta(1-42)-injected mice were markedly upregulated by the treatment of BPB-316. Our data suggest that the extracts of B. platyphylla bark might be a potential therapeutic agent against AD. PMID- 25301236 TI - Protective effects of maslinic acid against alcohol-induced acute liver injury in mice. AB - Protective effects of maslinic acid (MA) at 10, 15 or 20 mg/kg body weight/day against alcohol-induced acute hepatotoxicity in mice were examined. Mice were administrated by MA for 3 weeks, and followed by alcohol treatment. Results showed that MA pre-intake at three doses resulted in its accumulation in the liver; and dose-dependently lowered cytochrome P450 2E1 activity and protein expression at 23.5-51.2% and 21.4-62.3%, respectively (P <0.05). MA pre-intake decreased subsequent alcohol-induced reactive oxygen species, interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, nitric oxide and prostaglandin E2 production; retained glutathione content; maintained catalase and glutathione peroxidase activities; and declined cyclooxygenase-2 and total nitric oxide synthase activities in the liver (P <0.05). Furthermore, MA pre intake suppressed 17.3-51.7% nuclear factor kappa (NF-kappa)B p50, 23.5-58.8% NF kappaB p65, 25.6-62.4% p-p38 and 24.1-63.0% p-JNK expression in the liver (P <0.05). Histological data indicated that MA intake at test doses attenuated hepatic inflammatory infiltrate. These findings support that maslinic acid is a potent preventive agent against acute alcoholic liver disease. PMID- 25301237 TI - A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin(r)) in rats. AB - A well-characterized standardized hydroethanolic extract of a traditionally recognized mak (mild) variety of Sceletium tortuosum, a South African plant with a long history of traditional ingestion, is marketed under the trade name Zembrin((r)) as an ingredient for use in functional foods and dietary supplements. It is standardized to contain 0.35-0.45% total alkaloids (mesembrenone and mesembrenol >=60%, and mesembrine <20%). A 14-day repeated oral toxicity study was conducted at 0, 250, 750, 2500, and 5000 mg/kg bw/day. A 90 day subchronic repeated oral toxicity study was conducted at 0, 100, 300, 450, and 600 mg/kg bw/day. Because S. tortuosum has a long history of human use for relieving stress and calming, a functional observation battery, including spontaneous locomotor activity measured using LabMaster ActiMot light-beam frames system, was employed. Several parameters, such as locomotion, rearing behavior, spatial parameters, and turning behavior were investigated in the final week of the study. No mortality or treatment-related adverse effects were observed in male or female Crl:(WI)BR Wistar rats in the 14- or 90-day studies. In the 14- and 90-day studies, the NOAELs were concluded as 5000 and 600 mg/kg bw/d, respectively, the highest dose groups tested. PMID- 25301238 TI - [Incidental undifferentiated carcinoma of the prostate: A case with unusual diagnosis]. AB - A 69-year-old man presented with an incidental undifferentiated carcinoma of the prostate. Ten years ago the patient had clinical stage I seminoma of the right testis with adjuvant radiotherapy. Follow-up care was without pathological findings. Staging examinations did not show metastatic disease. After radical prostatectomy with pelvic lymphadenectomy, the histological examination revealed a metastatic seminoma in the prostate. Therefore, the diagnosis was a late relapse in an extremely rare location. So far only four other reports describe testicular seminoma with metastases to the prostate. PMID- 25301239 TI - [Contralateral testicular biopsy in patients with germ cell tumors: practice patterns in Germany 2014]. AB - BACKGROUND: Contralateral testicular biopsy is a tool for early diagnosis of contralateral tumors in patients with testicular germ cell tumor (GCT). Though based on a high level of evidence, international guidelines do not unanimously recommend biopsies. We enquired the acceptance of contralateral biopsies among clinical urologists in Germany. METHODS: A total of 326 urologic departments were asked by a questionnaire whether they perform contralateral biopsy in all cases with GCT, in most, in select cases, or never. In addition we enquired for type and size of the department as well as the annual volume of GCT patients. To specify the hospital geographically, we noted the ZIP code. The data were analyzed with descriptive statistical methods. RESULTS: The response rate was 86.5%. Of the departments, 52.1, 17, 27.3, and 3.5% do the biopsy in all cases, in most of them, in select patients, and never, respectively. University departments have significantly lower acceptance of the procedure than general hospitals (50% versus 72.6%), even after adjusting for other hospital characteristics by multivariate analysis. There was no association of acceptance rate with hospital size and annual GCT volume. The biopsy is highly used in the northern parts of Germany and considerably under-used in southern regions. CONCLUSION: Contralateral testicular biopsy is well-established and widely accepted among clinical urologists in Germany. In other countries, biopsies remain controversial. Only in Denmark is it routinely employed. In Sweden, Austria, and Switzerland biopsies are done in selected patients. In view of the multination treatment consensus of GCT, explanations for the dissimilar biopsy rates in various countries remain elusive. Peculiar findings are the inferior acceptance rates in university departments and the north-south gradient within Germany. PMID- 25301240 TI - The role of BIM-EL and BCL2-alpha on the efficacy of erlotinib and gefitinib in lung cancer. AB - Tyrosine kinase inhibitors (TKI), erlotinib and gefitinib are small molecule inhibitors which are used for the treatment of lung cancer. But, the development of drug resistance has been reported as one of the major setbacks in oncology. This study focused on the mechanisms leading to secondary resistance by assessing the gene expression of BCL2 family proteins which are associated with the intrinsic apoptotic signaling pathway. 8 genes were investigated in erlotinib and gefitinib treated cells by real time PCR and protein analysis by western blotting. The cells were exposed to the test drugs 48h prior to RNA or protein isolation. It was observed that BIM-EL, a pro-apoptotic protein was up-regulated in cells sensitive to the drugs but not in the resistant cells. On the other hand BCL2-alpha, an anti-apoptotic protein was up-regulated in the resistant cells and not in the sensitive cells. BCL2-alpha revealed a counter-regulation effect on BIM-EL and this effect is probably one of the causes of secondary resistance to erlotinib and gefitinib. PMID- 25301241 TI - [Investigation on plasma homocysteine level and cognition in population at high risk for stroke in Xi'an]. AB - OBJECTIVE: To investigate the relationship between plasma homocysteine (Hcy) and cognitive impairment so as to provide basis for dementia prevention. METHODS: Subjects at high risk for stroke were selected from the Screening and Prevention Program of Stroke (organized by the Ministry of Health, from August to December, 2012) in Yanta area, Xi'an. Fasting blood was taken from cubital vein to measure Hcy. When Hcy>15 umol/L was defined as hyperhomocysteinemia, Hcy in the range of 16-30 u mol/L was considered mild, >= 31 u mol/L as moderate-severe hyperhomocysteinemia. The cognitive function was evaluated by the Mini Mental State Examination (MMSE). MMSE grades under normal value were defined as cognitive impairment. RESULTS: 393 subjects were randomly recruited, including 173 men (44.0%) and 220 women (56.0%). Number of cases with cognitive impairment was 70 (17.8% of the total subjects), with hyperhomocysteinemia was 220 (56.0% of the total subjects). The prevalence of cognitive impairment did not show significant difference with hyperhomocysteinemia or normal Hcy group (16.8% vs. 19.1%, P>0.05), neither with mild and moderate-severe hyperhomocysteinemia group (17.0% vs. 16.3% , P > 0.05). Results from Spearman correlation analysis indicated that there was no correlation between MMSE grades and Hcy (rs = -0.01, P = 0.85). Prevalence of cognitive impairment in the smoking group was higher than that in the non-smoking group (21.3% vs. 7.8%, P < 0.01), but higher in hypertension group than that in the normal blood pressure group (21.7% vs. 8.0%, P < 0.01). In the stroke group, prevalence of cognitive impairment was seen higher than that in the non-stroke group (25.3% vs. 15.4%, P < 0.05). Based on the results from Binary logistic regression, cognitive impairment appeared to be associated with the levels of education (OR = 0.90, 95% CI:0.81-0.98, P = 0.02), histories of hypertension (OR = 1.02, 95%CI:1.01-1.04, P = 0.01) and stroke(OR = 1.86, 95%CI:1.04-3.33, P = 0.04), but there was no correlation seen between Hcy and cognitive impairment (OR = 0.90, 95% CI:0.51-1.58, P = 0.71). CONCLUSION: Plasma homocysteine did not seem a risk factor for cognitive impairment. PMID- 25301242 TI - The retrieval of unerupted teeth in pedodontics: two case reports. AB - INTRODUCTION: The retrieval of unerupted teeth in pedodontics is always significant to preserve the trophism of adjacent tissues, establish the correct space, provide adequate function and maintain good esthetics for the patient. The treatment plan is based on radiographic examinations and measurements, and on an accurate clinical evaluation; it aims to achieve the best treatment possible depending on the complexity of the specific case.In the most difficult clinical cases it is very important to have an early diagnosis, which is essential to plan the treatment and achieve success. In these cases, the pediatrician is in a strategic position to give an early diagnosis through a child's medical history and by counting the child's teeth. CASE PRESENTATION: This article presents two different difficult clinical cases of impacted teeth diagnosed during pediatric age, with a radiological analysis, and successfully treated with orthodontic devices designed for these specific cases. Clinical case 1 describes a 13-year old Italian girl; clinical case 2 describes a 9-year-old Italian girl. The use of these devices achieved the desired treatment goals. The problems associated with impacted teeth and the biomechanical interventions used for these patients are discussed. CONCLUSIONS: An early and careful diagnosis followed by an accurate treatment plan for the individual cases can lead to retrieval of the impacted teeth without affecting other anatomic structures and adjacent teeth. In these cases, the pediatrician is in a strategic position to give an early diagnosis through a child's medical history and by counting the child's teeth. PMID- 25301244 TI - The impact of no-fault compensation on health care expenditures: an empirical study of OECD countries. AB - Around the world, governments are faced with spiralling health care expenditures. This raises the need for further insight in the determinants of these expenditures. Existing literature focuses primarily on income, ageing, health care financing and supply variables. This paper includes medical malpractice system characteristics as determinants of health spending in OECD countries. Estimates from our regression models suggest that no-fault schemes for medical injuries with decoupling of deterrence and compensation reduce health expenditures per capita by 0.11%. Furthermore, countries that introduced a no fault system without decoupling of deterrence and compensation are found to have higher (+0.06%) health care spending. PMID- 25301243 TI - The role of endorectal ultrasound and magnetic resonance imaging in the management of early rectal lesions in a tertiary center. AB - BACKGROUND: In early rectal cancer, ERUS has a vital role in determining radical or local excision based on identification of T-stage. Transanal endoscopic microsurgery (TEMs) has a reduced morbidity and mortality compared with radical surgery. Correct identification of lesions that can be managed with TEMs is therefore imperative. Our aim was to assess the accuracy of ERUS in identifying mucosal/submucosal lesions and thus their suitability for TEMs. PATIENTS AND METHODS: A retrospective analysis of a prospectively maintained database of patients who underwent ERUS was carried out over an initial 25-month period at a tertiary colorectal center. Our main outcome measures were T-stage measured using ERUS or magnetic resonance imaging (MRI) (indicating suitability for local excision, ie, <= T1) with correlation with that of the subsequent surgical specimen and improvement in accuracy over time. After data analysis and review, the study was repeated over the subsequent 12 months to establish whether there was a learning curve with the use of ERUS. RESULTS: Over the initial period, 52 patients who met the inclusion criteria underwent ERUS. T-staging was accurate in 73.1% (38/52) with identification of <= T1 lesions having a sensitivity of 70.8% and a specificity 100%. The accuracy, sensitivity, and specificity of MRI was similar to that of ERUS (72.7%, 70.0%, and 100% respectively). Over the subsequent period, 23 patients underwent ERUS with T-staging accuracy improving to 78.3% (18/23) (P = .777). CONCLUSION: In our experience, ERUS is a useful adjunct to clinical assessment and pelvic MRI in determining suitability for local excision. Its 100% specificity in determining that a lesion is limited to the mucosa or submucosa aids in the assessment of lesions that are being considered for submucosal resection. Over the time periods assessed, improvement in T-staging accuracy was demonstrated, which might be due to the presence of a learning curve. PMID- 25301245 TI - The first German map of georeferenced ixodid tick locations. AB - BACKGROUND: Georeferenced locations of ixodid ticks are required to depict the observed distribution of species. Further, they are used as input data for species distribution models also known as niche models. The latter were applied to describe current and future (projected) tick distributions. Beside model assumptions and selected climate parameters, the number of georeferenced tick locations available as a digital dataset is of fundamental importance for the reliability of such models. For Germany, however, no comprehensive dataset of ixodid tick species exists. The goal of this study was to put together all the available information on ixodid tick locations in Germany to produce such a digital dataset and to visualize it in a map. FINDINGS: A total of 2,044 georeferenced locations of ixodid ticks in Germany were compiled from two existing datasets (altogether 993 locations) and an extensive literature study (1,051 locations). The resulting digital dataset comprises the following tick species: Ixodes ricinus (1,855 locations), Ixodes apronophorus (1), Ixodes frontalis (1), Ixodes hexagonus (1), Ixodes trianguliceps (4), Dermacentor marginatus (77), Dermacentor reticulatus (96), Haemaphysalis concinna (8) and Hyalomma marginatum (1). The data were used to draw a tick map for Germany, showing I. ricinus occurring in the whole federal territory, while D. marginatus has been restricted to the climatically favoured region of the Rhine valley. Clustered locations of D. reticulatus were also documented in the Rhine valley as well as in Berlin and its vicinity. CONCLUSIONS: The introduced map depicts for the first time the available geographical coordinates of ixodid tick locations in Germany. The digital dataset used to draw the map is provided to the scientific community as a basis for further investigations such as species distribution modelling. PMID- 25301246 TI - Computational modelling of the hybrid procedure in hypoplastic left heart syndrome: a comparison of zero-dimensional and three-dimensional approach. AB - Previous studies have employed generic 3D-multiscale models to predict haemodynamic effects of the hybrid procedure in hypoplastic left heart syndrome. Patient-specific models, derived from image data, may allow a more clinically relevant model. However, such models require long computation times and employ internal pulmonary artery band [dint] dimension, which limits clinical application. Simpler, zero-dimensional models utilize external PAB diameters [dext] and provide rapid analysis, which may better guide intervention. This study compared 0-D and 3-D modelling from a single patient dataset and investigated the relationship dint versus dext and hemodynamic outputs of the two models. Optimum oxygen delivery defined at dint=2mm corresponded to dext=3.1 mm and 3.4 mm when models were matched for cardiac output or systemic pressure, respectively. 0-D and 3-D models when matched for PAB dimension produced close equivalence of hemodynamics and ventricular energetics. From this study we conclude that 0-D model can provide a valid alternative to 3D-multiscale in the hybrid-HLHS circulation. PMID- 25301247 TI - Resolving parity and order of Fabry-Perot modes in semiconductor nanostructure waveguides and lasers: Young's interference experiment revisited. AB - Semiconductor nanostructures such as nanowires and nanoribbons functioning as Fabry-Perot (F-P)-type optical cavities and nanolasers have attracted great interest not only for their potential use in nanophotonic systems but also to understand the physics of light-matter interactions at the nanoscale. Due to their nanoscale dimensions, new techniques need to be continuously developed to characterize the nature of highly confined optical modes. Furthermore, the inadequacy of typical far-field photoluminescence experiments for characterizing the nanoscale cavity modes such as parity and order has precluded efforts to obtain precise information that is required to fully understand these cavities. Here, we utilize a modified Young's interference method based on angle-resolved microphotoluminescence spectral technique to directly reveal the parity of F-P cavity modes in CdS nanostructures functioning as waveguides and nanolasers. From these analyses, the mode order can be straightforwardly obtained with the help of numerical simulations. Moreover, we show that the Young's technique is a general technique applicable to any F-P type cavities in nanoribbons, nanowires, or other photonic and plasmonic nanostructures. PMID- 25301248 TI - Photocatalytic reactivity tuning by heterometal and addenda metal variation in Lindqvist polyoxometalates. AB - A systematic study into the effects of metal substitution on the visible-light photocatalytic activity of prototype metal oxide cluster anions is presented. Four isostructural Lindqvist clusters [V(x)M(6-x)O19]((2+x)-) (M = W, Mo, x = 1, 2) with photooxidative activity in the visible range are reported. It is shown that the photooxidative performance correlates with the number of vanadium atoms in the cluster. Further, two divergent reaction mechanisms are observed depending on the type of addenda metal (i.e. Mo or W) used. When comparing the reactivity under aerated vs. de-aerated conditions, it was found that molybdate-based clusters show significantly increased reaction rates in the absence of oxygen; in contrast, marginally reduced reaction rates were observed for the tungstate-based species under de-aerated conditions. Wavelength-dependent quantum efficiency studies provide insight into the visible-light reactivity of all four species. Radical scavenging experiments suggest that the photocatalysis proceeds via formation of hydroxyl radicals. Cluster recycling studies demonstrate the robust nature of the homogeneous photocatalysts. PMID- 25301249 TI - Effect of proctodeal gland foam on sperm kinetics in Japanese quail (Coturnix japonica). AB - The proctodeal gland of the male Japanese quail produces thick foam that accompanies semen when it is transferred to the female. It is thought that this foam enhances fertilization by improving the motility of the sperm, but reports are conflicting because the effect of foam on sperm motility has only been assessed subjectively The velocity of individual sperm was not able to be measured accurately, variations were large, and small changes in motility could not be accurately evaluated. So, we tested the hypothesis that foam affects the motility of spermatozoa of Japanese quail by analyzing motility objectively using computer-assisted semen analysis and determining changes in sperm kinetics in the presence of different concentrations of proctodeal gland foam. The addition of 5% or 10% foam to the sperm suspension increased (P < 0.05) all sperm kinetic parameters (the curvilinear velocity, straight line velocity, the velocity of the average path, linearity, straightness, and beat cross frequency). As a result, the percentage of motile and progressive motile sperm also increased. All these parameters declined (P < 0.05) with a further increase in the concentration of foam to 15% and 20%. Furthermore, this effect was similar in males that were 8, 16, or 26 weeks of age. We conclude that sperm motility is enhanced by proctodeal gland foam, and this enhancement depends on its concentration. PMID- 25301250 TI - Centennial celebration of translational research: the Journal of Laboratory and Clinical Medicine. PMID- 25301251 TI - A randomised controlled trial of the effectiveness of self-weighing as a weight loss intervention. AB - BACKGROUND: There is a need to find simple cost effective weight loss interventions that can be used in primary care. There is evidence that self monitoring is an effective intervention for problem drinking and self-weighing might be an effective intervention for weight loss. PURPOSE: To examine the efficacy of daily self-weighing as an intervention for weight loss. METHODS: A randomised controlled trial of 183 obese adults, follow-up three months. The intervention group were given a set of weighing scales and instructed to weigh themselves daily and record their weight. Both groups received two weight loss consultations which were known to be ineffective. RESULTS: 92 participants were randomised to the intervention group and 91 to the control group. The intervention group lost 0.5 kg (95% CI 0.3 to 1.3 kg) more than the control group, but this was not significant. There was no evidence that self-weighing frequency was associated with more weight loss. CONCLUSIONS: As an intervention for weight loss, instruction to weigh daily is ineffective. Unlike other studies, there was no evidence that greater frequency of self-weighing is associated with greater weight loss. TRIAL REGISTRATION: ISRCTN05815264. PMID- 25301252 TI - Visual hallucinations of autobiographic memory and asomatognosia: a case of epilepsy due to brain cysticercosis. AB - The current study describes the case of a woman with symptomatic epilepsy due to brain cysticercosis acquired during childhood. During her adolescence, she developed seizures characterized by metamorphopsia, hallucinations of autobiographic memory and, finally, asomatognosia. Magnetic brain imaging showed a calcified lesion in the right occipitotemporal cortex, and positron emission tomography imaging confirmed the presence of interictal hypometabolism in two regions: the right parietal cortex and the right lateral and posterior temporal cortex. We discuss the link between these brain areas and the symptoms described under the concepts of epileptogenic lesion, epileptogenic zone, functional deficit zone, and symptomatogenic zone. PMID- 25301253 TI - Neonatal immunity: babies' T cells can fight. PMID- 25301254 TI - Natural killer cells: RAG keeps natural killers fit. PMID- 25301255 TI - Macrophages: innate memory training. PMID- 25301256 TI - Inhibition of heat shock protein 90 with AUY922 represses tumor growth in a transgenic mouse model of islet cell neoplasms. AB - BACKGROUND: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. MATERIAL AND METHODS: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. RESULTS: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. CONCLUSION: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms. PMID- 25301257 TI - Structure and dynamics of chromatographically relevant Fe(III)-chelates. AB - Immobilized metal ion affinity chromatography (IMAC) is an important chromatographic technique for biomolecules. In order to get a detailed understanding of the hydration of immobilized Fe(III), complexes of Fe(III) with methyl substituted iminodiacetate ([Fe(MSIDA)(H2O)3](+)) as well as with methyl substituted nitrilotriacetate ([Fe(MSNTA)(H2O)2]) were simulated in aqueous solutions with the quantum mechanical charge field molecular dynamics (QMCF MD) approach. The simulations were carried out at the Hartree-Fock (HF) level of theory, since cluster calculations at the HF, MP2, and B3LYP levels of theory showed that this method results in a good compromise between computational effort and accuracy. None of the coordinating water molecules were exchanged during the simulation period of 15 ps. The Fe-OH2O bond distances as well as the Fe-OH2O stretching motions differed among the coordinating water molecules, indicating different bond strengths. For the water molecules in the second hydration layer, mean residence times of 2.7 and 1.9 ps were obtained for [Fe(MSIDA)(H2O)3](+) and [Fe(MSNTA)(H2O)2], respectively. Furthermore, infrared measurements were carried out to characterize the most prominent bond features of aqueous Fe(III)-NTA and to discuss these results in conjunction with the computationally derived frequencies. PMID- 25301258 TI - Conditional glucagon receptor overexpression has multi-faceted consequences for beta-cell function. AB - BACKGROUND: Although it is known that the islet expression of glucagon receptors is increased in type 2 diabetes, its implication for beta-cell function is not known. OBJECTIVE: To determine whether increased beta cell glucagon receptor expression and action influences multiple aspects of beta cell function. MATERIALS/METHODS: Mice with beta cell specific overexpression of the glucagon receptor (RIP-Gcgr) were subjected to intravenous glucose tolerance tests with acute injections of glucagon or GLP-1. Mice were also subjected to intravenous arginine and carbachol tests and insulin secretory responses were evaluated. RESULTS: The specific beta-cell overexpression of glucagon receptors has a complex and diverse consequence with dissociated consequences on beta-cell secretion depending on the stimulatory secretagogue in that whereas the potentiating effects of GLP-1 and arginine on glucose-stimulated insulin secretion were completely lost, the response to the muscarinic receptor agonist carbachol was largely unaffected and the insulin secretory response to glucose was exaggerated. CONCLUSION: This suggests that glucagon receptor overexpression, which is seen in hyperglycemia, may have dissociated consequence on beta cell function in its regulation under fasting, after meal and in response to autonomic nervous activation. PMID- 25301259 TI - A gamma-amino acid that favors 12/10-helical secondary structure in alpha/gamma peptides. AB - H-bonded helices in conventional peptides (containing exclusively homochiral alpha-amino acid residues) feature a uniform H-bonding directionality, N-terminal side C?O to C-terminal side NH. In contrast, heterochiral alpha-peptides can form helices in which the H-bond directionality alternates along the backbone because neighboring amide groups are oriented in opposite directions. Alternating H-bond directions are seen also in helices formed by unnatural peptidic backbones, e.g., those containing beta- or gamma-amino acid residues. In the present study, we used NMR spectroscopy and crystallography to evaluate the conformational preferences of the novel gamma-amino acid (1R,2R,3S)-2-(1-aminopropyl) cyclohexanecarboxylic acid (APCH), which is constrained by a six-membered ring across its Calpha-Cbeta bond. These studies were made possible by the development of a stereoselective synthesis of N-protected APCH. APCH strongly enforces the alpha/gamma-peptide 12/10-helical secondary structure, which features alternating H-bond directionality. Thus, APCH residues appear to have a conformational propensity distinct from those of other cyclically constrained gamma-amino acid residues. PMID- 25301260 TI - Electromyographic assessment of muscle fatigue in massive rotator cuff tear. AB - Shoulder muscle fatigue has not been assessed in massive rotator cuff tear (MRCT). This study used EMG to measure fatigability of 13 shoulder muscles in 14 healthy controls and 11 patients with MRCT. A hand grip protocol was applied to minimise artifacts due to pain experience during measurement. The fatigue index (median frequency slope) was significantly non-zero (negative) for anterior, middle, and posterior parts of deltoid, supraspinatus and subscapularis muscles in the controls, and for anterior, middle, and posterior parts of deltoid, and pectoralis major in patients (p <= 0.001). Fatigue was significantly greater in patients compared to the controls for anterior and middle parts of deltoid and pectoralis major (p <= 0.001). A submaximal grip task provided a feasible way to assess shoulder muscle fatigue in MRCT patients, however with some limitations. The results suggest increased activation of deltoid is required to compensate for lost supraspinatus abduction torque. Increased pectoralis major fatigue in patients (adduction torque) likely reflected strategy to stabilise the humeral head against superior subluxing force of the deltoid. Considering physiotherapy as a primary or adjunct intervention for the management of MRCT, the findings of this study generate a base for future clinical studies aiming at the development of evidence-based protocols. PMID- 25301261 TI - Long-term follow-up of thalidomide embryopathy: malformations and development of osteoarthritis in the lower extremities and evaluation of upper extremity function. AB - BACKGROUND: Between 1959 and 1962, several children with multiple malformations were born after maternal intake of thalidomide during pregnancy, known as thalidomide embryopathy (TE). OBJECTIVES: The aim of this study was to evaluate the malformations, their long-term effect on the function of the extremities and the development of degenerative osteoarthritis (OA) in the lower extremities. METHODS: All living persons with TE in Sweden were invited to participate in the study. Thirty-one patients were examined clinically as a part of a multi disciplinary follow-up programme. Evaluation of upper and lower limb function was performed by validated questionnaires [Disabilities of the Arm, Shoulder and Hand (DASH) and Rheumatoid and Arthritis Outcome Score (RAOS), respectively] and radiographic appearance of lower limbs by the use of spiral computed tomography. RESULTS: Five individuals had severe malformations of the lower limbs and proximal femoral focal deficiency (PFFD), with significantly reduced function as found on the RAOS values. Twenty-seven patients had two fully functional arms and hands, despite the fact that 8% of shoulders, 26% of elbows/forearms and 70% of hands were malformed. Loss of gripping function did not significantly affect the upper extremity function, as measured by the DASH score. Ten patients without major deformities had OA in the hips and 15 in the knees, mostly mild and with no effect on the RAOS value. CONCLUSION: A wide variety of malformations in the upper and lower limbs was found in the study group. Degenerative changes were found in the hips and the knees but were mostly mild and without major clinical significance. Despite upper limb anomalies that affected the fine motor skills, upper extremity function was not significantly reduced for most individuals. Individuals with PFFD along with major deformities of upper limbs had a reduced function of upper as well as lower limbs. PMID- 25301262 TI - Dihydroartemisinin suppresses glioma proliferation and invasion via inhibition of the ADAM17 pathway. AB - Dihydroartemisinin (DHA) is a semi-synthetic derivative of artemisinin, a well tolerated and effective drug for malaria treatment, and has recently been shown to have antitumorigenic activity. However, the mechanistic basis of these activities in gliomas is unknown. The objective of this study was to evaluate whether DHA inhibits cell proliferation and invasion in glioma cells, and to elucidate the underlying mechanisms. The results demonstrate that DHA treatment significantly inhibited cell proliferation, migration and invasion, as determined using viability, transwell migration, and matrix penetration assays, respectively. Western blot analysis revealed that protein expression levels of a disintegrin and metalloproteinase 17 (ADAM17), and phosphorylated epidermal growth factor receptor and AKT (p-EGFR and p-AKT, respectively), were suppressed by DHA. EGFR and AKT phosphorylation was enhanced by stimulation with the ADAM17 agonist chemokine phorbol myristate acetate. These data suggest that DHA inhibits glioma proliferation and invasion through suppression of ADAM17 and downregulation of EGFR-PI3 K-AKT signaling. PMID- 25301263 TI - Paraoxonase 1 Q192R and L55M polymorphisms and susceptibility to amyotrophic lateral sclerosis: a meta-analysis. AB - This study aimed to investigate whether paraoxonase 1 (PON1) Q192R and L55M polymorphisms are associated with susceptibility to amyotrophic lateral sclerosis (ALS). We conducted a meta-analysis of the associations between the PON1 Q192R and L55M polymorphisms and ALS. A total of 2,831 patients and 3,123 controls from eight studies of the PON1 Q192R polymorphism and seven studies of the PON1 L55M T polymorphism were considered for this study. Meta-analysis showed no association between ALS and the PON1 192R allele (OR = 1.052, 95 % CI = 0.923-1.207, p = 0.447), and the PON1 55M allele (OR = 1.015, 95 % CI = 0.884-1.164, p = 0.837) in all study subjects. Similarly, no association was found between ALS and the PON1 Q192R and L55M polymorphisms using recessive, dominant or homozygote contrast models. Stratification by ethnicity indicated no association between ALS and the PON1 192R allele (OR = 1.058, 95 % CI = 0.910-1.231, p = 0.464) and the PON1 55M allele (OR = 1.027, 95 % CI = 0.889-1.185, p = 0.721) in the European population. This meta-analysis showed lack of associations between PON1 Q192R and L55M polymorphisms and susceptibility to ALS in the European population. PMID- 25301264 TI - Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma. AB - Pancreatic cancer is the only major cancer with very low survival rates (1%). It is the fourth leading cause of cancer-related death. Hyperactivated growth hormone receptor (GHR) levels have been shown to increase the risk of cancer in general and this pathway is a master regulator of key cellular functions like proliferation, apoptosis, differentiation, metastasis, etc. However, to date there is no available data on how GHR promotes pancreatic cancer pathogenesis. Here, we used an RNA interference approach targeted to GHR to determine whether targeting GHR is an effective method for controlling pancreatic cancer growth and metastasis. For this, we used an in vitro model system consisting of HPAC and PANC-1 pancreatic cancer cells lines. GHR is upregulated in both of these cell lines and silencing GHR significantly reduced cell proliferation and viability. Inhibition of GHR also reduced the metastatic potential of pancreatic cancer cells, which was aided through decreased colony-forming ability and reduced invasiveness. Flow cytometric and western blot analyses revealed the induction of apoptosis in GHR silenced cells. GHR silencing affected phosphatidylinositol 3 kinase/AKT, mitogen extracellular signal-regulated kinase/extracellular signal regulated kinase, Janus kinase/signal transducers and activators of transcription and mammalian target of rapamycin signaling, as well as, epithelial to mesenchymal transition. Interestingly, silencing GHR also suppressed the expression of insulin receptor-beta and cyclo-oxygenease-2. Altogether, GHR silencing controls the growth and metastasis of pancreatic cancer and reveals its importance in pancreatic cancer pathogenesis. PMID- 25301265 TI - Protective effects of rosmarinic acid on doxorubicin-induced testicular damage. AB - BACKGROUND: We investigated the protective effects of rosmarinic acid (RA) on testicular damage induced by doxorubicin (DXR) in rats. METHODS: In total, 21 rats were divided into 3 groups: the control group that received no treatment, the DXR group that received intraperitoneal (i.p.) DXR on day 7 and the DXR + RA group that received intragastric RA for 10 days with i.p. DXR on day 7. The rats were sacrificed on day 11 for histological and biochemical analyses. To assess oxidative damage, glutathione peroxidase (GPx) and malondialdehyde (MDA) levels were measured. RESULTS: The median modified Johnsen score of the DXR + RA group was higher than that of the DXR group (p = 0.002). The rats with the narrowest seminiferous tubules were in the DXR group (0.17 +/- 0.03), and the difference between the DXR + RA and DXR groups was statistically significant (p = 0.002). The number of apoptotic cells in the DXR group was significantly higher than that in the control group, and there were significantly fewer apoptotic cells in the DXR + RA group than in the DXR group (p = 0.002). The MDA level was lowest in the control group and highest in the DXR group, and the level observed in the DXR + RA group significantly lower than that in the DXR group (p = 0.002). The GPx level was highest in the control group, with the level observed in the DXR + RA group significantly higher than that in the DXR group (p = 0.002). The testosterone level was lowest in the DXR group and highest in the control group, and that observed in the DXR + RA group was significantly higher than that in the DXR group (p = 0.018). CONCLUSIONS: RA can correct DXR-induced testicular damage through its antioxidant properties. However, the mechanism underlying the effects of RA requires further investigation, and long-term and comparative human studies are also needed. PMID- 25301266 TI - Lymphoid hyperplasia and lymphoma in KSHV K1 transgenic mice. AB - Growing evidence supports the involvement of human herpervirus 8, Kaposi's sarcoma associated herpesvirus (KSHV), in the pathology of primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma, but the exact mechanism of KSHV contribution to the oncogenic process remains elusive. We studied transgenic mice expressing the ORF K1 of KSHV, whose position in the KSHV genome corresponds to known lymphoproliferative genes of other herpesviruses. K1 protein was previously shown to contain a constitutively active ITAM domain, involved in activation of Akt and pro-survival signaling, and to inhibit Fas mediated apoptosis by interfering with binding of FasL. All this pointed to a possible role of K1 in the pathogenesis of KSHV-associated cancers. K1 transgenic mice (80-90%) developed lymphoid hyperplasia and splenomegaly at 8 and 10 months of age, 25% had confirmed diagnosis of lymphoma, and 50% developed abdominal and/or hepatic tumors by 18 months of age. Histological examination showed loss of splenic architecture and increased cellularity. Lymph nodes showed disrupted architecture with effaced follicles and other pathological changes, including signs of angiofollicular lymphoid hyperplasia. One of the livers showed signs of angiosarcoma. In summary, our histology results revealed pathological changes in K1 transgenic mice similar to lymphoma, Castleman's disease, and angiosarcoma, suggesting that K1 may contribute to the development of KSHV-associated cancers. PMID- 25301267 TI - Link between FDA antidepressant warnings and increased suicide attempts in young people is questionable. PMID- 25301268 TI - Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma. AB - BACKGROUND: Increasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic). METHODS: We exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate. RESULTS: After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05). CONCLUSIONS: Anti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations. PMID- 25301270 TI - A comparison of gene transcription profiles of domesticated and wild Atlantic salmon (Salmo salar L.) at early life stages, reared under controlled conditions. AB - BACKGROUND: Atlantic salmon have been subject to domestication for approximately ten generations, beginning in the early 1970s. This process of artificial selection will have created various genetic differences between wild and farmed stocks. Each year, hundreds of thousands of farmed fish escape into the wild. These escapees may interbreed with wild conspecifics raising concerns for both the fish-farming industry and fisheries managers. Thus, a better understanding of the interactions between domesticated and wild salmon is essential to the continued sustainability of the aquaculture industry and to the maintenance of healthy wild stocks. RESULTS: We compared the transcriptomes of a wild Norwegian Atlantic salmon population (Figgjo) and a Norwegian farmed strain (Mowi) at two life stages: yolk sac fry and post first-feeding fry. The analysis employed 44 k oligo-microarrays to analyse gene expression of 36 farmed, wild and hybrid (farmed dam x wild sire) individuals reared under identical hatchery conditions. Although some of the transcriptional differences detected overlapped between sampling points, our results highlighted the importance of studying various life stages. Compared to the wild population, the Mowi strain displayed up-regulation in mRNA translation-related and down regulation in nervous and immune system related pathways in the sac fry, whereas up-regulation of digestive and endocrine activities, carbohydrate, energy, amino acid and lipid metabolism and down regulation of environmental information processing and immune system pathways were evident in the feeding fry. Differentially regulated pathways that were common among life stages generally belonged to environmental information processing and immune system functional groups. In addition, we found indications of strong maternal effects, reinforcing the importance of including reciprocal hybrids in the analysis. CONCLUSIONS: In agreement with previous studies we showed that domestication has caused changes in the transcriptome of wild Atlantic salmon and that many of the affected pathways are life-stage specific We highlighted the importance of reciprocal hybrids to the deconvolution of maternal/paternal effects and our data support the view that the genetic architecture of the strains studied highly influences the genes differentially expressed between wild and domesticated fish. PMID- 25301271 TI - Relationship between absence of annulus and asthenozoospermia in Iranian men. AB - PURPOSE: To find a relationship between absence of annulus and asthenozoospermia in Iranian men. METHODS: In the present study, semen samples from 100 asthenozoospermic and 20 normozospermic patients were analyzed for sperm concentration and motility. Spermatozoa were immunostained for the two septin subunits Sept4 and Sept7. The absence of the annulus structure was confirmed by transmission electron microscopy and western blot analysis for septin 4. DNA sequencing for all coding exons of SEPT12 was performed for a patient using peripheral blood sample. RESULTS: Specific antibodies for SEPT4 and SEPT7 consistently labeled the annuli in spermatozoa from all of the 20 normozospermic men, while in one of 100 patients with asthenozoospermia, 75% of sperms lacking septin 4 or septin 7 proteins at the annulus. It was shown that the structural defect in annulus formation is not caused by point mutation of SEPT12 gene. CONCLUSIONS: In conclusion, the results of this study demonstrated that the frequency of the absence of annulus in asthenozoospermic sample of Iranian population has a low frequency and could not be assume as a diagnostic marker for classifying asthenozoospermic patients. PMID- 25301272 TI - [Not Available]. PMID- 25301273 TI - Repair of anomalous left coronary artery from the pulmonary artery in the modern era: preoperative predictors of immediate postoperative outcomes and long term cardiac follow-up. AB - Little is known about preoperative factors affecting postoperative morbidity following anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) repair. This study aimed at identifying predictors of postoperative outcomes, including mortality and left ventricle (LV) normalization. A retrospective, single institution review was conducted on forty-four ALCAPA repairs from April 1991 to November 2012. Preoperative clinical data and echocardiograms were analyzed. Postoperative outcomes included duration of intensive care supports and mortality. Time to normalization of LV end diastolic dimension (LVEDD) and function were assessed. Logistic regression and Cox proportional hazard analyses were used to correlate preoperative variables to postoperative outcomes. Forty-four patients underwent ALCAPA repair. No in hospital or late mortality was observed. LVEDD, weight, and LV shortening fraction (SF) independently predicted duration of postoperative inotropic support. LVEDD and body surface area independently predicted the duration of postoperative intubation. For the infant majority, younger age predicted longer duration of postoperative intubation (p = 0.048) and LVEDD Z-score independently predicted duration of postoperative IV inotropic support (p = 0.042). LV function normalized in all patients for whom follow-up data was available. LVEDD Z-score independently predicted time to normalization of LV function (p = 0.013). ALCAPA repair in the current era has excellent outcomes, with no mortality in our cohort. Immediate postoperative morbidities are influenced by patient size, LVEDD, and preoperative SF. Outcomes of infantile ALCAPA are influenced by the degree of LV dilation. Time to normalization of LV function is related to LVEDD. Limitations included retrospective evaluation of LV function. PMID- 25301275 TI - Myocardial tissue phase mapping reveals impaired myocardial tissue velocities in obesity. AB - Although obesity is linked to heart failure on a population level, not all obese subjects develop cardiac failure. As a result, identifying obese subjects with subclinical changes in myocardial velocities may enable earlier detection of those susceptible to developing overt heart failure. As echocardiography is limited in obesity due to limited acoustic window, we used phase contrast magnetic resonance imaging to assess myocardial velocities in obese and normal weight subjects. Normal weight (BMI 23 +/- 3; n = 40) and obese subjects (BMI 37 +/- 7; n = 59) without identifiable cardiovascular risk factors underwent MRI (1.5 Tesla) to determine left ventricular myocardial velocities using phase contrast tissue phase mapping. Systolic function was not different between normal and obese subjects (LVEF 67 +/- 5 vs 68 +/- 4, p = 0.22). However, obesity was associated with significantly impaired peak radial and longitudinal diastolic myocardial velocity (by 13 and 19 % respectively, both p < 0.001). In addition time-to-peak longitudinal diastolic velocity was delayed in obesity (by 39 ms, p < 0.001). In addition, peak longitudinal diastolic strain was 20 % lower in obesity (p = 0.015) and time-to-peak longitudinal diastolic strain rate significantly delayed in obesity (by 92 ms, p < 0.001).Although peak radial systolic velocity was similar between obese and normal weight subjects (p = 0.14) peak longitudinal systolic velocity was 7 % lower in the obese cohort (p = 0.02). In obesity without co-morbidities, tissue phase mapping has shown subclinical changes in systolic and diastolic function. Given the link between obesity and heart failure, early detection of changes may become clinically important to prevent disease progression. PMID- 25301276 TI - Glycine transporters GlyT1 and GlyT2 are differentially modulated by glycogen synthase kinase 3beta. AB - Inhibitory glycinergic neurotransmission is terminated by the specific glycine transporters GlyT1 and GlyT2 which actively reuptake glycine from the synaptic cleft. GlyT1 is associated with both glycinergic and glutamatergic pathways, and is the main regulator of the glycine levels in the synapses. GlyT2 is the main supplier of glycine for vesicle refilling, a process that is vital to preserve the quantal glycine content in synaptic vesicles. Therefore, to control glycinergic neurotransmission efficiently, GlyT1 and GlyT2 activity must be regulated by diverse neuronal and glial signaling pathways. In this work, we have investigated the possible functional modulation of GlyT1 and GlyT2 by glycogen synthase kinase 3 (GSK3beta). This kinase is involved in mood stabilization, neurodegeneration and plasticity at excitatory and inhibitory synapses. The co expression of GSK3beta with GlyT1 or GlyT2 in COS-7 cells and Xenopus laevis oocytes, leads to inhibition and stimulation of GlyT1 and GlyT2 activities, respectively, with a decrease of GlyT1, and an increase in GlyT2 levels at the plasma membrane. The specificity of these changes is supported by the antagonism exerted by a catalytically inactive form of the kinase and through inhibitors of GSK3beta such as lithium chloride and TDZD-8. GSK3beta also increases the incorporation of 32Pi into GlyT1 and decreases that of GlyT2. The pharmacological inhibition of the endogenous GSK3beta in neuron cultures of brainstem and spinal cord leads to an opposite modulation of GlyT1 and GlyT2.Our results suggest that GSK3beta is important for stabilizing and/or controlling the expression of functional GlyTs on the neural cell surface. PMID- 25301274 TI - Regulation of hemichannels and gap junction channels by cytokines in antigen presenting cells. AB - Autocrine and paracrine signals coordinate responses of several cell types of the immune system that provide efficient protection against different challenges. Antigen-presenting cells (APCs) coordinate activation of this system via homocellular and heterocellular interactions. Cytokines constitute chemical intercellular signals among immune cells and might promote pro- or anti inflammatory effects. During the last two decades, two membrane pathways for intercellular communication have been demonstrated in cells of the immune system. They are called hemichannels (HCs) and gap junction channels (GJCs) and provide new insights into the mechanisms of the orchestrated response of immune cells. GJCs and HCs are permeable to ions and small molecules, including signaling molecules. The direct intercellular transfer between contacting cells can be mediated by GJCs, whereas the release to or uptake from the extracellular milieu can be mediated by HCs. GJCs and HCs can be constituted by two protein families: connexins (Cxs) or pannexins (Panxs), which are present in almost all APCs, being Cx43 and Panx1 the most ubiquitous members of each protein family. In this review, we focus on the effects of different cytokines on the intercellular communication mediated by HCs and GJCs in APCs and their impact on purinergic signaling. PMID- 25301277 TI - Role of adenosine receptor subtypes in methamphetamine reward and reinforcement. AB - The neurobiology of methamphetamine (MA) remains largely unknown despite its high abuse liability. The present series of studies explored the role of adenosine receptors on MA reward and reinforcement and identified alterations in the expression of adenosine receptors in dopamine terminal areas following MA administration in rats. We tested whether stimulating adenosine A1 or A2A receptor subtypes would influence MA-induced place preference or MA self administration on fixed and progressive ratio schedules in male Sprague-Dawley rats. Stimulation of either adenosine A1 or A2A receptors significantly reduced the development of MA-induced place preference. Stimulating adenosine A1, but not A2A, receptors reduced MA self-administration responding. We next tested whether repeated experimenter-delivered MA administration would alter the expression of adenosine receptors in the striatal areas using immunoblotting. We observed no change in the expression of adenosine receptors. Lastly, rats were trained to self-administer MA or saline for 14 days and we detected changes in adenosine A1 and A2A receptor expression using immunoblotting. MA self-administration significantly increased adenosine A1 in the nucleus accumbens shell, caudate putamen and prefrontal cortex. MA self-administration significantly decreased adenosine A2A receptor expression in the nucleus accumbens shell, but increased A2A receptor expression in the amygdala. These findings demonstrate that MA self administration produces selective alterations in adenosine receptor expression in the nucleus accumbens shell and that stimulation of adenosine receptors reduces several behavioral indices of MA addiction. Together, these studies shed light onto the neurobiological alterations incurred through chronic MA use that may aid in the development of treatments for MA addiction. PMID- 25301279 TI - Staphylococcal exotoxins induce interleukin 22 in human th22 cells. AB - BACKGROUND: We have shown previously that T cells from atopic dermatitis (AD) patients produce more IL-22 upon staphylococcal exotoxin stimulation compared to psoriasis patients and healthy controls. The role of staphylococcal exotoxins on polarized memory T helper (Th)22 cells which are enriched in inflamed AD skin remains elusive. Our aim was to investigate IL-22 production in response to staphylococcal enterotoxin B (SEB) and alpha-toxin stimulation in human memory T cells and polarized Th22 cells. METHODS: IL-22 induction was investigated in human peripheral blood-derived CD4+CD45RO+CD45RA- T cells and polarized Th22 cells after SEB and sublytic alpha-toxin stimulation in a time-dependent manner at the mRNA and protein (ELISA) levels. RESULTS: Th22 cells secreted more IL-22 compared to freshly isolated peripheral blood-derived memory T cells. SEB and alpha-toxin induced IL-22 in memory T cells as well as in Th22 cells. More IL-22 was induced by SEB and alpha-toxin in freshly isolated peripheral blood memory T cells compared to Th22 cells derived from memory T cells in long-term cell culture without polarization and Th22 cells under Th22-promoting conditions with IL-6 and TNF-alpha. No differences in IL-22 induction by staphylococcal exotoxins were observed between cells from AD compared to psoriasis patients and healthy controls. CONCLUSIONS: Increased IL-22 secretion can promptly be induced by staphylococcal exotoxins in skin infiltrating CD4+CD45RO+CD45RA- memory T cells and can potentially amplify chronic skin inflammation in AD in the context of bacterial colonization and infection. This should be investigated further in detail in lesional skin of AD and psoriasis patients. PMID- 25301278 TI - Galanin mediates features of neural and behavioral stress resilience afforded by exercise. AB - Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels. PMID- 25301280 TI - WITHDRAWN: Identification of peste-des-petits ruminants virus (PPRV) lineage IV, the Asian lineage, in Nigeria and co-circulation with PPRV lineage II. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25301281 TI - Lung pathogenicity of European genotype 3 strain porcine reproductive and respiratory syndrome virus (PRRSV) differs from that of subtype 1 strains. AB - Porcine reproductive and respiratory syndrome (PRRS) is difficult to control due to a high mutation rate of the PRRS virus (PRRSV) and the emergence of virulent strains. The objective of this study was to analyse early and late pathological responses in the respiratory tract after infection with the European PRRSV subtype 3 strain Lena in comparison to two European PRRSV subtype 1 strains: Belgium A and Lelystad-Ter Huurne (LV). For each virus strain, groups of twelve pigs were inoculated, and four pigs per group were euthanized at days 3, 7 and 35 post-infection (p.i.) for consecutive examination. Infection with strain Lena resulted in a more severe disease than with the subtype 1 strains, an inflammatory response within the first week of infection with expression of IL 1alpha in the lung and lymph node, and an influx of neutrophils and monocytes in bronchoalveolar lavage fluid (BALF). Infection with strain Belgium A or LV resulted in mild or no pathology within the first week of infection, but inflammatory cell influx in the lung interstititium was increased at the end of the experiment at day 35 p.i. At five weeks p.i., all strains induced a higher percentage of cytotoxic T cells and higher levels of IFN-gamma producing cells in BALF. This might have contributed to clearance of virus. In general, subtype 3 strain Lena induced a stronger early inflammatory response which led to more severe clinical disease and pathology. On the other hand, this may have supported an enhanced or faster clearance of virus in tissues, compared to subtype 1 strains. PMID- 25301282 TI - Identification of bluetongue virus and epizootic hemorrhagic disease virus serotypes in French Guiana in 2011 and 2012. AB - In French Guiana, the sero- and viro-prevalence of Bluetongue virus (BTV) is high but the circulating serotypes remain unknown. No data are available regarding the prevalence of Epizootic hemorrhagic disease (EHD). This study was conducted to assess the prevalence and to identify the circulating serotypes of these two Orbiviruses in this region (BTV and EHDV). Blood samples were collected in main livestock areas, from 122 young cattle between June and August 2011, to perform virological (PCR and viral isolation) and serological (ELISA) analyses. Moreover, samples from sheep and goat showing BTV-like clinical signs and from newly imported animals were analyzed using the same assays. Results confirmed an important viral circulation, with viro- and seroprevalence of 85% and 84% and 60% and 40% for BTV and EHDV, respectively. Ten Orbivirus serotypes were identified (BTV-1, 2, 6, 10, 12, 13, 17 and 24, EHDV-1 and 6). The circulation of many serotypes in intertropical America and in the Caribbean region underlines the need to establish measures to monitor and control animal movements. PMID- 25301283 TI - Identification and molecular characterization of novel and divergent HoBi-like pestiviruses from naturally infected cattle in India. AB - HoBi-like pestiviruses have been sporadically reported from naturally infected cattle in South America, Asia and Europe. While the closely related bovine viral diarrhoea virus 1 (BVDV-1) and BVDV-2 have been reported from cattle in India, the prevalence and diversity of HoBi-like viruses have not yet been studied. Here we report the genetic diversity and molecular characteristics of HoBi-like viruses, through systematic surveillance in cattle (n=1049) from 21 dairy farms across India during 2012-2013. On the basis of real-time RT-PCR, virus isolation and nucleotide sequencing results, of the 20 pestivirus positive cattle, HoBi like viruses were identified in 19 cattle from four farms in three states and BVDV-1b in one cattle. Phylogenetic analysis of 5'-UTR and N(pro) region identified the circulation of two lineages of HoBi-like viruses in India, that were distinct to those circulating globally, highlighting the independent evolution of at least three lineages of HoBi-like viruses globally. Antigenic differences were also evident between the two Indian lineages. In addition to revealing that HoBi-like virus may be more widespread in Indian cattle than previously reported, this study shows greater genetic divergence of HoBi-like viruses indicating a need for continued pestivirus surveillance in cattle. PMID- 25301284 TI - Impact of Poor Retention in HIV Medical Care on Hepatitis B Vaccination. AB - BACKGROUND: We identified factors associated with complete hepatitis B vaccination of patients with HIV. METHODS: Retrospective analysis of patients undergoing HIV clinic orientation from 2000 to 2010. Vaccine-eligible patients had negative hepatitis B serologies at baseline. Receipt of at least 3 doses was defined as complete vaccination. RESULTS: Of 1242 patients, 519 (42%) were completely vaccinated. Complete vaccination was positively associated with missing <=25% of the visits during the first year of care (adjusted odds ratio [aOR] = 2.35, 95% confidence interval [CI]: 1.79-3.09), being naive to care (aOR = 1.50, 95% CI: 1.13-1.99), and living at the clinic's county (aOR = 1.33, 95% CI: 1.02-1.75). Complete vaccination was negatively associated with failure to remain in care >2 years (aOR = 0.18, 95% CI: 0.13-0.24), history of intravenous drug use (aOR = 0.48, 95% CI: 0.27-0.87), and baseline CD4 count <200 cells/mm(3) (aOR = 0.69, 95% CI: 0.53-0.92). CONCLUSION: Poor retention in HIV care is strongly associated with suboptimal hepatitis B vaccination. PMID- 25301285 TI - Protection of DNA against low-energy electrons by amino acids: a first-principles molecular dynamics study. AB - Using first-principles molecular dynamics simulations, we have investigated the notion that amino acids can play a protective role when DNA is exposed to excess electrons produced by ionizing radiation. In this study we focus on the interaction of glycine with the DNA nucleobase thymine. We studied thymine glycine dimers and a condensed phase model consisting of one thymine molecule solvated in amorphous glycine. Our results show that the amino acid acts as a protective agent for the nucleobase in two ways. If the excess electron is initially captured by the thymine, then a proton is transferred in a barrier-less way from a neighboring hydrogen-bonded glycine. This stabilizes the excess electron by reducing the net partial charge on the thymine. In the second mechanism the excess electron is captured by a glycine, which acts as a electron scavenger that prevents electron localization in DNA. Both these mechanisms introduce obstacles to further reactions of the excess electron within a DNA strand, e.g. by raising the free energy barrier associated with strand breaks. PMID- 25301286 TI - Atomic-scale control of TiO6 octahedra through solution chemistry towards giant dielectric response. AB - The structures of many important functional oxides contain networks of metal oxygen polyhedral units i.e. MOn. The correlation between the configurations and connectivities of these MOn to properties is essentially important to be well established to conduct the design, synthesis and application of new MOn-based functional materials. In this paper, we report on an atomic-scale solution chemistry approach that for the first time enables TiO6 octahedral network control starting from metastable brookite TiO2 through simultaneously tuning pH values and interfering ions (Fe(3+), Sc(3+), and Sm(3+)). The relationship between solution chemistry and the resultant configuration/connectivity of TiO6 octahedra in TiO2 and lepidocrocite titanate is mapped out. Apart from differing crystalline phases and morphologies, atomic-scale TiO6 octahedral control also endows numerous defect dipoles for giant dielectric responses. The structural and property evolutions are well interpreted by the associated H(+)/OH(-) species in solution and/or defect states associated with Fe(3+) occupation within TiO6 octahedra. This work therefore provides fundamental new insights into controlling TiO6 octahedral arrangement essential for atomic-scale structure-property design. PMID- 25301287 TI - Fingertips squamous cell carcinoma: Treatment outcomes with surgical excision and full thickness skin graft. AB - Fingertips squamous cell carcinoma is a rare disease. An often missed or delayed diagnosis, the affected finger could result in an amputation. Our aim is to focus on the results of surgical excision of fingertips squamous cell carcinoma. Between 2005 and 2011, eighteen fingers on eight patients with a mean age of 62.5 years underwent surgery. The surgical excision margin was 5mm and the defect was covered by a full thickness skin graft. Three fingers were revised for having a non-secure margin with an enlarged excision and two fingers were amputated at the distal phalange. The diagnosis is often missed or delayed, resulting in an amputation of the affected finger. Aesthetic outcomes range from very good to good satisfaction except for one, which was bad. PMID- 25301288 TI - [Long-term functional evaluation of complex traumatic heel defects reconstructed by flap in children]. AB - INTRODUCTION: Complex heel injuries in children are rare and their management requires coverage combining resistance and thinness, to allow walking and footwear. The objective of this study was to create a decision-making algorithm for heel defect in children. MATERIALS: Children received for heel defect, reconstructed with flap in our plastic surgery unit of Bordeaux with a follow-up greater than 10 years were investigated. Three children operated between 1999 and 2003 were included. A free contralateral reinnervated medial plantar flap, a free latissimus dorsi flap and a lateral supramalleolar flap were performed. Patients were reviewed in consultation to assess quality of reconstruction and functional outcomes. Three scores were used, the Foot Function Index (FFI), the AOFAS Ankle and Hindfoot Scale and the Maryland Foot Score. RESULTS: No growth disorder has been found. Scores greater than 80 for the Maryland Foot Score and AOFAS Ankle and Hindfoot Scale and less than 10 for the FFI were very satisfactory in cases 1 and 3. We found pain and greater functional impairment in the second case. CONCLUSIONS: "Like-with-like" reconstruction remains the gold standard, whether in loco-regional or free flap. The fasciocutaneous flaps allow custom reliable coverage with little donor site morbidity. Loco-regional flaps remain easily accessible but donor site sequelae are not negligible. PMID- 25301289 TI - Clinical implications of correlation between peripheral eosinophil count and serum levels of IL-5 and tryptase in acute eosinophilic pneumonia. AB - BACKGROUND: The peripheral eosinophil count (PEC) tends to increase during the course of acute eosinophilic pneumonia (AEP), and an initially elevated PEC is associated with milder disease. However, there is a lack of data regarding these phenomena and inflammatory process of AEP. METHODS: We prospectively evaluated serial changes in serum interleukin (IL)-5 levels and the correlation between the initial level of IL-5 and the PEC to investigate whether the initial PEC indicates a resolving state of inflammation. We also evaluated serum tryptase levels to investigate the possibility of involvement of mast cell activity in AEP. RESULTS: Twenty-one AEP patients were included, and all patients improved within 10 days after corticosteroid treatment. The median initial serum IL-5 level among all patients was 561.0 pg/mL, which decreased to zero at 10 days of follow-up (n = 15, P < 0.001). The median initial serum tryptase level (detectable in 20 of 21 patients) was 3.7 ng/mL and decreased to a median of 1.1 ng/mL at 10 days of follow-up (n = 15, P < 0.001). The initial serum IL-5 and C reactive protein levels were positively correlated (P = 0.009, r = 0.556), and the initial serum IL-5 level was inversely correlated with the initial PEC (P = 0.004, r = -0.603). CONCLUSIONS: Our data suggest that IL-5 is an important cytokine involved in the recruitment of eosinophils from peripheral blood into the lungs, that an initially elevated PEC is associated with a resolving state of inflammation, and that mast cells are potentially involved in the inflammatory process of AEP. PMID- 25301290 TI - Long-term macrolide maintenance therapy in non-CF bronchiectasis: evidence and questions. AB - Macrolide antibiotics have anti-inflammatory and immunomodulatory properties in addition to antibacterial activity. Until recently, only a small number of studies evaluating macrolides in patients with non-cystic fibrosis (CF) bronchiectasis had been published. These were open-label, uncontrolled, short duration studies that included small numbers of patients. However, these studies suggested that macrolides can reduce exacerbation frequency, reduce sputum volume, and improve lung function in patients with non-CF bronchiectasis. Three recently published randomised, double-blind, placebo-controlled studies showed that macrolides (azithromycin or erythromycin) taken for between 6 and 12 months led to significant reductions in exacerbation rate and reduced the decline in lung function. In all studies, macrolides were generally well tolerated. The advantages of macrolide maintenance therapy need to be balanced against the risks, which include emergence of bacterial resistance, cardiotoxicity and ototoxicity. In addition, a key need is the consistent definition of endpoints for studies in non-CF bronchiectasis, particularly the definition of exacerbation, to allow systematic data analysis. Existing studies on the use of low-dose macrolides in non-CF bronchiectasis are encouraging, but further studies are needed to define the optimal agent, dose, duration for treatment, and the patients likely to benefit and long-term safety. PMID- 25301292 TI - A bioenergetic model for simulating athletic performance of intermediate duration. AB - Simulating factors affecting human athletic performance, including fatigue, requires a dynamic model of the bioenergetic capabilities of the athlete. To address general cases, the model needs inputs, outputs, and states with a set of differential equations describing how the inputs affect the states and outputs as functions of time. We improve an existing phenomenological muscle model, removing unnecessarily fast dynamic behavior, adding force-velocity dependence, and generalizing it to task level activities. This makes it more suitable for simulating and calculating optimal strategies of athletic events of medium duration (longer than a sprint but shorter than a marathon). To examine the validity and limitations of the model, parameters have been identified from numerical fits to published experimental data. PMID- 25301291 TI - Efficacy of mycophenolate mofetil in sarcoidosis. AB - BACKGROUND: Immunosuppressive (IS) therapy is indicated to treat progressive sarcoidosis, but randomized controlled trials to guide physicians in the use of steroid sparing agents are lacking. The aim of this retrospective study was to examine the role of mycophenolate mofetil (MMF) as an alternative therapy in the treatment of sarcoidosis. METHODS: A retrospective chart review of all patients who had been prescribed MMF between January 2008 and October 2011 was conducted. Patients with insufficient data or who had another IS therapy initiated concomitantly with MMF, including prednisone, were excluded. Physiological data obtained at the time MMF therapy was initiated as well as six and twelve months before and after therapy was extracted. Longitudinal analyses of the effect of MMF on changes in pulmonary function at MMF start, 6 months, 12 months pre and post MMF therapy were conducted. RESULTS: 37/76 patients met our inclusion/exclusion criteria. There were no statistically significant changes in PFT measurements pre and post MMF therapy. We did find a trend (p = 0.07) towards improvement in DLCO 12 months pre and post MMF in patients who were started on MMF due to intolerance to previous IS therapy compared to those who were unresponsive to their previous IS therapy. We also noted a reduction in prednisone dose in those treated with MMF. CONCLUSION: MMF appears to offer no extra benefit to sarcoidosis patients unresponsive to previous steroid-sparing agents, but may be beneficial in patients intolerant to their previous steroid sparing agent. Additional studies investigating the efficacy of MMF as the initial steroid-sparing agent are needed to further clarify the role of MMF in sarcoidosis. PMID- 25301293 TI - No relative increase in intra-abdominal adipose tissue in healthy unstressed preterm infants at term. AB - BACKGROUND: Preterm infants may be at risk for altered adiposity, a known risk factor for unfavorable metabolic and cardiovascular outcomes. OBJECTIVES: The aim was to compare body composition (total body fat mass (FM), subcutaneous and intra abdominal adipose tissue (AT)) between infants born preterm and at term. METHODS: We conducted an observational, cross-sectional study that involved 50 infants born preterm free from major co-morbidities and 34 term healthy breastfed infants. Anthropometric measurements, body composition (total body FM, subcutaneous and intra-abdominal AT) were assessed at 40-42 weeks postconceptional age for preterm infants and within 15 days of birth for term infants. Total body FM was assessed by an air displacement plethysmography system and subcutaneous abdominal and intra-abdominal AT were assessed by magnetic resonance imaging using a commercially available software program. RESULTS: Compared to term infants, mean (SD) total body FM (g) (636.7 (247) vs. 418.4 (253), p < 0.0001) and mean (SD) subcutaneous abdominal AT (g) (123 (36) vs. 98.9 (22), p < 0.001) were significantly higher in preterm infants but mean (SD) fat free mass (g) (2,530 (420) vs. 2,965 (389), p < 0.0001) and mean (SD) intra abdominal AT (10.9 (5.2) vs. 18.2 (13.2), p = 0.001) were significantly lower. CONCLUSIONS: In the absence of severe illness during the hospital stay, prematurity, although associated with increased total body FM, does not appear to be associated with a relative increase in intra-abdominal AT compared to term infants. PMID- 25301294 TI - Development and evaluation of chitosan and chitosan/Kollicoat(r) Smartseal 30 D film-coated tablets for colon targeting. AB - The aim of the present study was to develop film-coated tablets which release a minor amount of the active pharmaceutical ingredient (API) into the stomach and small intestine, yet show a sharp increase of drug release in the colon. Tablets containing the model drug Diclofenac-Na, microcrystalline cellulose as a filler (MT), as well as tablets consisting of Ludiflash(r) (LT), both were used as tablet cores, respectively. Either chitosan (CHI) alone or different ratios of chitosan and Kollicoat(r) Smartseal 30 D (KCSS) were applied onto these cores. The resulting film-coated tablets were analyzed for swelling, drug dissolution and stability. In order to clarify whether the colon release is mainly enzyme driven or pressure-controlled, the coated tablets were both tested in the colon microflora test (CMT), which simulates the enzyme environment within the colon, and using a bio-relevant dissolution apparatus mimicking the intraluminal pressures and stress conditions present in the gastrointestinal tract (GIT). CHI/KCSS (25:75) coated LTs showed a pressure-controlled site-specific drug release in the large intestine, while remaining intact in the upper GIT. CHI as well as CHI/KCSS (25:75) applied onto MTs, remained stable during the entire simulated bio-relevant dissolution transit of the GIT, but showed enzymatically controlled colon targeting in the CMT. These results could be confirmed for CHI/KCSS (25:75) film-coated MTs top-coated with an additional hydroxypropylmethylcellulose (HPMC) layer and an Eudragit L 30 D-55 (EUL) layer to avoid the dissolution in the fasting stomach. PMID- 25301295 TI - Spectroscopic and DFT investigation of interactions between cyclophosphamide and aspirin with lysozyme as binary and ternary systems. AB - Multi-spectroscopic and density functional theory (DFT) calculations was used to study the interaction between cyclophosphamide (CYP) and aspirin (ASA) with lysozyme (LYS). The experimental results showed that fluorescence quenching of LYS by drug was a result of the formation of drug-LYS complex; static quenching was confirmed to result in fluorescence quenching. Modified Stern-Volmer plots of interaction between CYP and ASA with protein in the binary and ternary systems were used to determine the binding parameters. Molecular distances between the donor (LYS) and acceptor (CYP and ASA) for all systems were estimated according to Forster's theory. The quantitative analysis obtained by CD spectra suggested that the presence of ASA and CYP decreased the alpha-helical content of LYS and induced the destabilizing of it. Theoretical studies on the interaction between LYS with ASA and CYP have been carried out using DFT at the B3LYP/6-31G level in the solvent phase. Binding energy of the mentioned complexes was calculated. It showed that tryptophan (Trp) 62 had the most affinity toward ASA and CYP. Analyzing the calculated results revealed that the five member ring of Trp has a key role in interaction of LYS with ASA and CYP. PMID- 25301296 TI - The effect of timing of iron supplementation on iron absorption and haemoglobin in post-malaria anaemia: a longitudinal stable isotope study in Malawian toddlers. AB - BACKGROUND: In sub-Saharan Africa, children with Plasmodium falciparum malaria and anaemia are often given iron supplementation at the time of malaria treatment. Inflammation during and after malaria may decrease iron absorption, thus, absorption might be improved if the start of supplementation is delayed. The study objective was to measure iron absorption from iron supplements started immediately or delayed by two weeks after completion of therapy against uncomplicated P. falciparum malaria. METHODS: Malawian toddlers (n=48; age 12-24 months) were alternatively assigned to two groups according to their appearance at the health centre: group A was provided iron supplements (30 mg Fe daily) as a FeSO4-containing syrup for eight weeks starting immediately after malarial treatment; group B was given the iron after a two-week delay. Iron absorption from the syrup was measured on the first day of iron supplementation, and after two and eight weeks in both groups. Haemoglobin (Hb), iron status and inflammation were assessed every two weeks. Fractional iron absorption at each time point and cumulative absorption was quantified by measuring erythrocyte incorporation of 57Fe and compared using mixed models. RESULTS: Comparing group A and B, geometric mean iron absorption did not differ on the first day of supplementation (9.0% vs. 11.4%, P=0.213) and cumulative iron absorption from the three time points did not differ (6.0% vs. 7.2%, P=0.124). Hb concentration increased in both groups two weeks after malaria treatment (P<0.001) and did not differ after eight weeks of supplementation (P=0.542). CONCLUSIONS: In anaemic toddlers after uncomplicated malaria, a two-week delay in starting iron supplementation did not significantly increase iron absorption or Hb concentration. Iron absorption is sufficiently high in the immediate post-malaria period to warrant supplementation. These findings suggest there is no need to change the current practice of immediate iron supplementation in this setting. TRIAL REGISTRATION: This trial was registered at Pan African Clinical Trials Registry (pactr.org) as PACTR2010050002141682. PMID- 25301297 TI - Is intervention better than surveillance in patients with type 2 endoleak post endovascular abdominal aortic aneurysm repair? AB - A best evidence topic in vascular surgery was written according to a structured protocol. The question addressed was whether, in patients with persistent type 2 endoleak (T2EL) post-endovascular abdominal aortic aneurysm repair (EVAR), intervention is associated with better outcomes than observation. Four hundred and eighty-three papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. In a recently published systematic review including 21 744 patients who underwent EVAR, 35.4% of T2ELs resolved spontaneously, 28.5% of secondary interventions were unsuccessful and rupture occurred in only 0.9% of patients with isolated T2EL. Spontaneous sealing in 62-75% of T2ELs were reported by two included studies. A failure rate of 80% associated with transarterial embolization in aggressive treatment of any T2EL was reported by one study. Conversely, another study reported a clinical success rate of 80% associated with the transarterial approach. One study reported that of patients who underwent embolization of a persistent T2EL, 37.9% continued to experience sac growth and 20% had recurrent endoleak at 5 years. One study demonstrated that the transealing procedure for T2EL had a technical success rate of 94.1%. We conclude that the available evidence with regard to management of persistent T2EL is mainly based on retrospective case series. Conflicting results from heterogeneous studies, however, failed to support an optimal threshold for intervention. Considering the reported relatively benign natural course of most T2ELs and the fact that most T2ELs seal spontaneously, conservative management of persistent T2EL in the absence of sac expansion might be appropriate. Where intervention is indicated, imaging should exclude occult type I and III leaks as ~25% are not simple T2EL. Translumbar embolization of T2EL is associated with higher success rates than transarterial. Following a successful intervention, continued long-term surveillance is necessary due to the high risk (25-80%) of recurrence. The current evidence indicates that aneurysmal rupture due to an isolated T2EL is rare. Long-term prospective studies may provide better evidence to define the optimal threshold for intervention. PMID- 25301298 TI - A new beating-heart off-pump coronary artery bypass grafting training model. AB - OBJECTIVES: Training models are essential in mastering the skills required for off-pump coronary artery bypass grafting (OPCAB). We describe a new, high fidelity, effective and reproducible beating-heart OPCAB training model in human cadavers. METHODS: Human cadavers were embalmed according to the 'Thiel method' which allows their long-term and repeated use. The training model was constructed by bilateral ligation of the pulmonary veins, cross-clamping of the aorta, positioning of an intra-aortic balloon pump (IABP) in the left ventricle (LV) through the apex (tightened with pledget-reinforced purse strings) and finally placing of a fluid line in the LV through the left atrial appendage (tightened with a pledget-reinforced purse string). The LV was filled with saline to the desired pressure through the fluid line and the IABP was switched on and set to a desired frequency [usually 60-80 beats per minute (bpm)]. RESULTS: A high fidelity simulation has known limitations, but a more complex, realistic training environment with an actual beating (human) heart strengthens the entire training exercise and is of incremental value. All types of coronary artery anastomosis can be trained with this model. Training should be performed under the supervision of an experienced OPCAB surgeon and training progress is best evaluated with serial Objective Structured Assessment of Technical Skills (OSATS). A score of at least 48 points on the final OSATS ('good' on all components) is recommended before trainees can start their training on patients. CONCLUSIONS: The entire set-up provides a versatile training model to help develop and improve the skills required to safely perform beating heart OPCAB anastomoses. PMID- 25301299 TI - Voice outcomes after transoral laser microsurgery for early glottic cancer considering signal type and smoothed cepstral peak prominence. AB - OBJECTIVES/HYPOTHESES: This study proposed the use of signal typing and acoustic measures experimentally validated for aperiodic voices to investigate voice outcomes after transoral laser microsurgery (TLM) for early glottic carcinoma. It was of interest whether signal type and pitch-tracking indicators would reveal unreliable perturbation and noise measures. As an alternative, smoothed cepstral peak prominence (CPPS) was used for the first time in this population. STUDY DESIGN: A descriptive study of patients treated with TLM for early glottic carcinoma. METHODS: All participants (n=14) performed a series of vocal tasks. Narrowband spectrograms were generated from voice recordings and classified into one of four signal types. The perturbation and noise measures of periodic or near periodic signals only were reported. The CPPS for sustained vowel (CPPS-/a/) and connected speech (CPPS-s) were calculated for all participants. The relationship between voice outcomes and tumor and TLM factors was investigated. RESULTS: Nine of 14 participants had an aperiodic type 3 signal. Three of 14 participants had voices considered reliable for perturbation analysis. Absolute jitter, %jitter, %shimmer, and signal-to-noise ratio were all low; however, CPPS-/a/ and CPPS-s amplitudes were below the normal range for most participants. Involvement of the anterior commissure, number of TLM episodes, and time post-surgery were associated with worse voice outcomes. There were strong correlations between signal type, CPPS-/a/, and pitch-tracking indicators. CONCLUSIONS: The limitations of perturbation analysis should be considered when analyzing the voice after TLM. Signal type should be considered before conducting perturbation analysis. The CPPS-/a/ and CPPS-s may be more reliable acoustic outcome measures for this population. PMID- 25301300 TI - Acoustic and perceptual characteristics of the voice in patients with vocal polyps after surgery and voice therapy. AB - OBJECTIVE: The aim of the study was to assess the effect of endolaryngeal phonomicrosurgery (EPM) and voice therapy in patients with vocal fold polyps using perceptual and acoustic analysis before and after both therapies. METHODS: The acoustic tests and perceptual evaluation of voice were carried out on 41 female patients with vocal fold polyp before and after EPM and voice therapy. Both therapy strategies were performed. Used acoustic parameters were Jitter percent (Jitt), pitch perturbation quotient (PPQ), shimmer percent (Shim), amplitude perturbation quotient (APQ), fundamental frequency variation (vF0), noise-to-harmonic ratio (NHR), Voice Turbulence Index (VTI). For perceptual evaluation, GRB scale was used. RESULTS: Results indicated higher values of investigated parameters in patients' group than in the control group (P < 0.01). Good correlation between the perceptual hoarseness factors of GRB scale and objective acoustic voice parameters were observed. All analyzed acoustic parameters improved after the phonomicrosurgery and voice therapy and tend to approach to values of the control group. For Jitt percent, Shim percent, vF0, VTI, and NHR, there were statistically significant differences. Perceptual voice evaluation revealed statistically significantly (P < 0.01) decreased rating of G (grade), R (rough) and B (breathy) after surgery and voice therapy. CONCLUSIONS: Our data indicated that both acoustic and perceptual characteristic of voice in patients with vocal polyps significantly improved after phonomicrosurgical and voice treatment. PMID- 25301301 TI - ROMO1 links oxidative stress to mitochondrial integrity. PMID- 25301302 TI - High-precision (143)Nd/(144)Nd ratios from NdO(+) data corrected with in-run measured oxygen isotope ratios. AB - The NdO(+) technique has been considerably refined in recent years for high precision measurement of Nd isotope ratios in low-level samples (1-5 ng Nd). As oxygen isotopic compositions may vary significantly with experimental conditions such as filament material, ionization enhancer and the ambient oxygen in the ion source, great "care" should be taken for using correct oxygen isotopic compositions to do the isobaric oxide corrections for the "conventional" NdO(+) method. Our method presented here for NdO(+) data reduction and PrO(+) interference corrections uses the oxygen isotope composition determined in each cycle of the NdO(+) measurements. For that purpose, we measured the small ion signals of (150)Nd(17)O(+) and (150)Nd(18)O(+) with amplifiers equipped with 10(12) Omega feedback resistors, and those of Nd(16)O(+) ion beams with 10(11) Omega amplifiers. Using 10(12) Omega amplifiers facilitates a precise measurement of the very small (150)Nd(17)O(+) and (150)Nd(18)O(+) ion signals and calculation of highly accurate and precise (143)Nd/(144)Nd isotope ratios. The (143)Nd/(144)Nd ratios for JNdi-1 standards and several whole-rock reference materials determined with the method on 4 ng of Nd loads are consistent with previously reported values within analytical error, with internal and external precision (2 RSE and 2 RSD) of better than 20 and 30 ppm, respectively. PMID- 25301304 TI - Reflections on screening mammography and the early detection of breast cancer: A Countercurrents Series. PMID- 25301303 TI - Effects of age on the physiological and mechanical characteristics of human femoropopliteal arteries. AB - Surgical and interventional therapies for peripheral artery disease (PAD) are notorious for high rates of failure. Interactions between the artery and repair materials play an important role, but comprehensive data describing the physiological and mechanical characteristics of human femoropopliteal arteries are not available. Fresh femoropopliteal arteries were obtained from 70 human subjects (13-79 years old), and in situ vs. excised arterial lengths were measured. Circumferential and longitudinal opening angles were determined for proximal superficial femoral, proximal popliteal and distal popliteal arteries. Mechanical properties were assessed by multi-ratio planar biaxial extension, and experimental data were used to calculate physiological stresses and stretches, in situ axial force and anisotropy. Verhoeff-Van Gieson-stained axial and transverse arterial sections were used for histological analysis. Most specimens demonstrated nonlinear deformations and were more compliant longitudinally than circumferentially. In situ axial pre-stretch decreased 0.088 per decade of life. In situ axial force and axial stress also decreased with age, but circumferential physiological stress remained constant. Physiological circumferential stretch decreased 55-75% after 45 years of age. Histology demonstrated a thickened external elastic lamina with longitudinally oriented elastin that was denser in smaller, younger arteries. Axial elastin likely regulates axial pre-stretch to help accommodate the complex deformations required of the artery wall during locomotion. Degradation and fragmentation of elastin as a consequence of age, cyclic mechanical stress and atherosclerotic arterial disease may contribute to decreased in situ axial pre-stretch, predisposing to more severe kinking of the artery during limb flexion and loss of energy-efficient arterial function. PMID- 25301306 TI - Total revascularization of coronary disease at the time of primary percutaneous coronary intervention. PMID- 25301308 TI - Eighth Joint National Committee guidelines. PMID- 25301309 TI - Sweet as sugar: excessive glucose metabolism in the failing heart. PMID- 25301310 TI - Multisite left ventricular pacing in cardiac resynchronization therapy. AB - Cardiac resynchronization therapy is an effective treatment for selected patients with heart failure and left bundle branch block dyssynchrony. Unfortunately, about a third of patients, so-called nonresponders, do not display any symptomatic or structural improvements after the treatment. In another 5% of patients, the left ventricular lead cannot be implanted due to technical limitations. Novel quadripolar pacing lead and associated multisite pacing technology has the potential to help improve both of these problems. The technology and applications of these leads are reviewed and the novel technique of multisite pacing from two poles of one quadripolar lead is discussed. This technology may improve response to cardiac resynchronization therapy for some patients. PMID- 25301311 TI - Emerging role of contrast-enhanced MRI in diagnosing vascular malformations. AB - Vascular malformations comprise a diverse and rare group of lesions which generally pose a formidable treatment challenge. Requisite for optimal surgical planning are imaging modalities capable of delineating involved anatomy and malformation flow characteristics. In this regard, we and others have purported the advantages of contrast-enhanced MRI. Here, we review the current body of literature regarding the emerging of role of contrast enhanced MRI for the management of vascular malformations. PMID- 25301312 TI - Cardiovascular magnetic resonance in ischemic heart disease. AB - Ischemic heart disease is the major cause of death in developed countries. Recently, cardiovascular magnetic resonance (CMR) has appeared as a powerful technique for diagnosis and prognosis of ischemia, as well as for postischemic therapy follow-up. The objective of this chapter is to provide an overview of the role of CMR in assessing ischemic myocardium. It reviews the most recent studies in this field and includes CMR parameters that are already well established in the clinical setting as well as promising or emerging parameters in clinical use. PMID- 25301313 TI - 3D echocardiography in congenital heart disease: a valuable tool for the surgeon. AB - Real-time 3D echocardiography has been used increasingly in the assessment of patients with congenital heart disease. A number of studies have confirmed that this modality can be used as a complementary method to delineate morphology and spatial relationships of simple and more complex congenital heart lesions during surgical planning. Communication between the echocardiographer and surgeon can be simplified as simulation of surgical views can be achieved, thus minimizing the potential for error related to mental reconstruction. This review summarizes the available evidence for the role of real-time 3D echocardiography in congenital heart disease as an imaging modality to assist surgeons. PMID- 25301314 TI - Echocardiographic assessment of ventricular function in pediatric patients: a comprehensive guide. AB - Assessment of ventricular function is an important part of every echocardiographic examination. Specific pediatric guidelines on quantification of ventricular function are available, but technology evolves quickly and it generally takes long before newer techniques are integrated into routine clinical practice and are adopted by the guidelines. In the current overview, we would like to present our experience with integrating newer echocardiographic techniques for assessing ventricular function in children using a comprehensive state-of-the-art echocardiographic functional protocol. This protocol is used for specific patient populations such as pediatric patients with cardiomyopathy, post transplant patients and oncology patients. We present the practical aspects of the protocols, their rationale and how this can be applied in clinical practice. PMID- 25301315 TI - Using ST2 in cardiovascular patients: a review. AB - Biomarkers have emerged as indispensable tools for diagnosis and prognostication in a variety of cardiovascular diseases, and several are now standard of care. New markers are constantly being developed, but few are able to significantly improve upon already established markers. ST2 is a marker of cardiomyocyte stress and fibrosis, which provides incremental value to natriuretic peptides for risk stratification of patients across a wide spectrum of cardiovascular diseases. Based upon the totality of data, measurement of ST2 is now recommended for additive risk stratification in patients with acute or ambulatory heart failure in the 2013 American College of Cardiology Foundation and American Heart Association joint guidelines. Looking forward, ST2 levels may be useful for tailoring medical therapy in those with or at risk for developing heart failure. This paper provides an up-to-date overview of the clinical studies that led to the endorsement of ST2 as a cardiovascular prognostic marker, and provides insight into the application of ST2 now and in the future. PMID- 25301316 TI - Challenges in the echocardiographic assessment of aortic stenosis. AB - Calcific aortic valve stenosis is common in the elderly. While history and examination can establish the diagnosis, determination of its severity typically requires echocardiography to define valve anatomy, measure stenosis severity and assess left ventricular response. The purpose of this review is to describe some of the commonly encountered challenges in the echocardiographic assessment of aortic stenosis. These include errors in the calculation of aortic valve area, assessment of aortic stenosis during atrial fibrillation, determining the presence of aortic stenosis in the setting of low transvalvular pressure gradients and discriminating other forms of obstruction to left ventricular ejection from aortic stenosis. Lastly, a review of how echocardiography is utilized to select patients for transcatheter aortic valve replacement is presented. PMID- 25301317 TI - Catheter ablation of persistent atrial fibrillation. AB - Catheter ablation of atrial fibrillation (AF) is performed increasingly worldwide and with the development of new technologies the procedures have become safer and more effective after a single attempt, particularly with paroxysmal AF. However, success rates for persistent AF ablation remain far lower than paroxysmal AF and there is large variation in the strategies used worldwide. This review describes the background to persistent AF ablation, the different strategies used and their associated risks and benefits, developing technologies and the authors' perspective on the future of this rapidly evolving area. PMID- 25301318 TI - Management considerations in the care of elderly heart failure patients in long term care facilities. AB - Heart failure, a condition that affects up to 20% of older persons residing in long-term care facilities, is an important cause of morbidity, health service utilization and death. Effective and interprofessional heart failure care processes could potentially improve care, outcomes and quality of life and delay decline or hospital admission. This article reviews the clinical aspects of heart failure, and the challenges to the diagnosis and management of this condition in long-term care residents who are frail and are affected by multiple comorbidities. PMID- 25301322 TI - Exercise recognition for Kinect-based telerehabilitation. AB - BACKGROUND: An aging population and people's higher survival to diseases and traumas that leave physical consequences are challenging aspects in the context of an efficient health management. This is why telerehabilitation systems are being developed, to allow monitoring and support of physiotherapy sessions at home, which could reduce healthcare costs while also improving the quality of life of the users. OBJECTIVES: Our goal is the development of a Kinect-based algorithm that provides a very accurate real-time monitoring of physical rehabilitation exercises and that also provides a friendly interface oriented both to users and physiotherapists. METHODS: The two main constituents of our algorithm are the posture classification method and the exercises recognition method. The exercises consist of series of movements. Each movement is composed of an initial posture, a final posture and the angular trajectories of the limbs involved in the movement. The algorithm was designed and tested with datasets of real movements performed by volunteers. We also explain in the paper how we obtained the optimal values for the trade-off values for posture and trajectory recognition. RESULTS: Two relevant aspects of the algorithm were evaluated in our tests, classification accuracy and real-time data processing. We achieved 91.9% accuracy in posture classification and 93.75% accuracy in trajectory recognition. We also checked whether the algorithm was able to process the data in real-time. We found that our algorithm could process more than 20,000 postures per second and all the required trajectory data-series in real-time, which in practice guarantees no perceptible delays. Later on, we carried out two clinical trials with real patients that suffered shoulder disorders. We obtained an exercise monitoring accuracy of 95.16%. CONCLUSIONS: We present an exercise recognition algorithm that handles the data provided by Kinect efficiently. The algorithm has been validated in a real scenario where we have verified its suitability. Moreover, we have received a positive feedback from both users and the physiotherapists who took part in the tests. PMID- 25301321 TI - Dent and Flint maize diversity panels reveal important genetic potential for increasing biomass production. AB - KEY MESSAGE: Genetic and phenotypic analysis of two complementary maize panels revealed an important variation for biomass yield. Flowering and biomass QTL were discovered by association mapping in both panels. The high whole plant biomass productivity of maize makes it a potential source of energy in animal feeding and biofuel production. The variability and the genetic determinism of traits related to biomass are poorly known. We analyzed two highly diverse panels of Dent and Flint lines representing complementary heterotic groups for Northern Europe. They were genotyped with the 50 k SNP-array and phenotyped as hybrids (crossed to a tester of the complementary pool) in a western European field trial network for traits related to flowering time, plant height, and biomass. The molecular information revealed to be a powerful tool for discovering different levels of structure and relatedness in both panels. This study revealed important variation and potential genetic progress for biomass production, even at constant precocity. Association mapping was run by combining genotypes and phenotypes in a mixed model with a random polygenic effect. This permitted the detection of significant associations, confirming height and flowering time quantitative trait loci (QTL) found in literature. Biomass yield QTL were detected in both panels but were unstable across the environments. Alternative kinship estimator only based on markers unlinked to the tested SNP increased the number of significant associations by around 40% with a satisfying control of the false positive rate. This study gave insights into the variability and the genetic architectures of biomass-related traits in Flint and Dent lines and suggests important potential of these two pools for breeding high biomass yielding hybrid varieties. PMID- 25301323 TI - Atypical response to erlotinib in a patient with metastatic lung adenocarcinoma: a case report. AB - INTRODUCTION: Tyrosine kinase inhibitors are widely prescribed in thoracic oncology and have excellent responses as a first-line treatment for locally advanced or metastatic lung cancer with epidermal growth factor receptor mutations. The side effects of tyrosine kinase inhibitors are mostly gastrointestinal and dermatological, and are usually resolved after symptomatic treatment. However, new complications have now arisen due to increased use of these drugs. Here we report a side effect of erlotinib that has not been described previously: that is, metastatic lung tumor nodules were transformed into cysts, which ruptured the pleura and were responsible for bilateral life threatening pneumothorax. CASE PRESENTATION: We report the case of a 35-year-old Caucasian woman with metastatic adenocarcinoma and a deletion in epidermal growth factor receptor exon 19 (del E746-A750). She was treated with erlotinib for metastatic lung adenocarcinoma. Treatment with erlotinib resulted in the replacement of pulmonary tumor nodules with air-containing cysts. These cysts ruptured in the pleura causing a life-threatening bilateral pneumothorax. To the best of our knowledge, this tumor-cystic response after erlotinib therapy has not been previously described. CONCLUSIONS: Tyrosine kinase inhibitors are widely prescribed in thoracic oncology, and managing toxicities must be optimal in order to improve adherence. Transformation of pulmonary nodules into cysts must be known and clinicians should be aware of this potential complication, which can lead to life-threatening pneumothorax. PMID- 25301324 TI - Detection of Coxiella-like endosymbiont in Haemaphysalis tick in Thailand. AB - In this study, we focused on the molecular detection of Coxiella-like bacteria using a PCR technique to identify Coxiella 16S rRNA sequences in Haemaphysalis tick samples (105 adults, 8 nymph pools and 19 larval pools). Seven Haemaphysalis species obtained from 5 locations in Thailand were evaluated in this work. Coxiella endosymbionts could be detected in samples representing all 3 growth stages examined. The results also revealed that only 4 of 7 tick species were positive for Coxiella-like endosymbiont: Haemaphysalis hystricis, Haemaphysalis lagrangei, Haemaphysalis obesa, and Haemaphysalis shimoga. Haemaphysalis shimoga demonstrated the highest percentage of Coxiella-like positive samples (58.33% with n=24), while Haemaphysalis hystricis had the lowest percentage; only 1 female tick was positive for Coxiella-like bacteria (n=6). Interestingly, the results indicated that female Haemaphysalis ticks tended to harbour Coxiella symbionts more frequently than male ticks (59.32% of females and 21.27% of males of all species studied). Phylogenetic analyses based on 16S rRNA sequences illustrated that Coxiella-like spp. from the same tick species always grouped in same clade, regardless of the location from which they were isolated. Moreover, a phylogenetic tree also showed that Coxiella-like endosymbionts from other genera (for example, the tick genus Rhipicephalus) formed a separate group compared to Coxiella-like symbionts in the genus Haemaphysalis. This suggests that a high amount of DNA sequence variation is present in Coxiella-like bacteria harboured by ticks. PMID- 25301325 TI - What Black Women Know and Want to Know About Counseling and Testing for BRCA1/2. AB - Black women are just as likely to have hereditary breast cancer mutations as White women, yet their participation in genetic counseling and testing is substantially lower. This study sought to describe Black women's awareness and perceptions of BRCA1/2 testing and to identify barriers and motivators to seeking BRCA1/2 services. Fifty intercept interviews were conducted with Black women in public places (a professional women's basketball game, a grocery store, a faith based community event, and the waiting area at a breast care clinic) in Washington, DC. More than half of the women (54%) were aware that genetic tests to determine risk for certain breast and ovarian cancers exist, but the majority (88%) had never heard of BRCA1/2, specifically. After hearing a description of BRCA1/2 genetic markers, 82% stated that they would agree to BRCA1/2 testing if it was offered to them. Perceived advantages of testing included cancer prevention and the ability to share information with family members. Perceived disadvantages included emotional distress associated with identification of the mutation and the potential misuse of results to deny healthcare or employment. Physician recommendation, self-care, and known family history were among the motivators for testing. Women listed possible media and venues for intervention. In spite of low rates of BRCA1/2 testing in the Black community, women in this sample were open to the idea. Interventions that address barriers and include cultural tailoring are necessary. PMID- 25301326 TI - IL-6 gene expression in adipose tissue of postmenopausal women and its association with metabolic risk factors. AB - Adipose tissue secretes various kinds of adipokines that controls the glucose and lipid metabolism in humans. The abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) both are associated with metabolic syndrome and insulin resistance. IL-6 is one of the adipokines, which promotes insulin resistance and dyslipidemia in humans. The association of adipokines with metabolic syndrome at protein levels are well documented. However, their association at gene expression level are lacking. The present study was design to investigate IL-6 mRNA expression in adipose tissues (VAT and SAT) and its correlation with metabolic risk factors and insulin resistance (HOMA) in post menopausal women. A total of 108 Asian North Indian post menopausal women, 54 without metabolic syndrome (controls) and 54 with metabolic syndrome (cases) were recruited and evaluated. Overnight fasting blood samples were collected at admission and abdominal visceral and subcutaneous adipose tissues were collected during open abdomen surgery. The results showed significantly (p < 0.05 or p < 0.01 or p < 0.001) higher mean SBP, glucose, insulin, HOMA, TG, VLDL and serum IL 6 while significantly (p < 0.001) lower HDL and estrogen in cases as compared to controls. In cases, the relative mean SAT IL-6 expression was also significantly (p < 0.05) higher as compared to VAT. Further, in cases, the VAT IL-6 expression showed significant (p < 0.05 or p < 0.001) and negative correlation with WC, WHR, glucose, HOMA, TC, LDL and estrogen while SAT IL-6 expression also showed significant (p < 0.05 or p < 0.01 or p < 0.001) and negative correlation with WC, WHR and estrogen. The Cox regression analysis found VAT IL-6 mRNA expression the significant (p < 0.05 or p < 0.01) an independent predictor of WC, HOMA, TC, LDL and estrogen while SAT IL-6 mRNA expression the significant (p < 0.01) an independent predictor of TG and VLDL. The study concluded that IL-6 expressions of both visceral and subcutaneous tissues may be associated with metabolic risk factors in postmenopausal Asian North Indian women. PMID- 25301328 TI - On the meaning of the word 'epimutation'. AB - The word 'epimutation' is often used in a manner that can be misinterpreted. The strict definition of epimutation is a heritable change in gene activity that is not associated with a DNA mutation but rather with gain or loss of DNA methylation or other heritable modifications of chromatin. Unfortunately, there is a growing tendency in the cancer field to use the word in situations in which underlying DNA sequence changes have occurred. PMID- 25301327 TI - Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism. AB - OBJECTIVES: Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man. METHODS: We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism. RESULTS: The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance. CONCLUSIONS: We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance. PMID- 25301329 TI - Renal risk and response in amyloidosis. AB - In this issue of Blood, Palladini and colleagues address incidence of and risk factors for end-stage renal disease (ESRD) and proffer a new renal response system for patients with amyloid light-chain (AL) amyloidosis using a test set of 461 patients from Pavia, Italy, and a validation set of 271 patients from Heidelberg, Germany. Validation of organ response criteria has trailed behind the progress made in the field of AL amyloidosis in diagnosis, prognosis, and hematologic response, but Palladini and colleagues' study helps breach this gap. PMID- 25301330 TI - It takes a village. AB - In this issue of Blood, Bhatia et al demonstrate the critical importance of an adherence to oral chemotherapy regimens in attaining cure for children with acute lymphoblastic leukemia (ALL) and identify race-specific determinants of adherence. PMID- 25301331 TI - Concealed dagger in FLT3/ITD+ AML. AB - In this issue of Blood, Ostronoff et al report a low remission rate in acute myeloid leukemia (AML) patients coexpressing FLT3/ITD and cryptic translocation t(5;11)(q35;p15.5), known as NUP98/NSD1. PMID- 25301332 TI - Inflammatory Langerhans cell differentiation. AB - In this issue of Blood, Martinez-Cingolani et al identified that human thymic stromal lymphopoietin (TSLP), previously shown to be induced during skin inflammation, stimulates myeloid-related BDCA-11 peripheral blood dendritic cells (DCs) to rapidly gain phenotypic characteristics of human epidermal Langerhans cells (LCs). PMID- 25301333 TI - Macrophages shine bright. AB - In this issue of Blood, Iqbal et al created a novel mouse model with a strong expression of green fluorescence protein (GFP) in monocytes, tissue resident macrophages, and inflammatory macrophages, and may provide an important tool for future studies focusing on macrophage biology. Several transgenic mice with expression of fluorescent proteins in myeloid cells exist, among them the CCR2 RFP and the CX3CR1GFP mouse. However, both of these mice have several limitations: they are knock-in constructs under control of chemokine receptors with potential effects on monocyte mobilization from the bone marrow, recruitment to sites of inflammation, or survival. Alteration of chemokine receptor expression during macrophage differentiation may affect expression of fluorescent proteins and thus render macrophages nonfluorescent. PMID- 25301334 TI - Self-control of platelets: a new ITIM story. AB - In this issue of Blood, Fan et al discover the presence of a new receptor-ligand pair that inhibits platelet activation. PMID- 25301335 TI - CEA a thrombus CAM: CEACAM2, a twin of CEACAM1? AB - In this issue of Blood, Alshahrani et al demonstrate that carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) is expressed on platelets and negatively regulates the collagen receptor glycoprotein (GP)VI-FcRgamma chain and C-type lectin-like receptor 2 (CLEC-2)-mediated platelet activation. PMID- 25301336 TI - The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants. PMID- 25301337 TI - Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. PMID- 25301338 TI - Dosimetric evaluation of clinical target volume in the postimplant analysis of low-dose-rate brachytherapy for prostate cancer. AB - PURPOSE: Brachytherapy is an effective single treatment modality for low- and intermediate-risk prostate cancer. In this study, we defined a clinical target volume (CTV) and evaluated its dosimetry 1 month after the low-dose-rate brachytherapy procedure. METHODS AND MATERIALS: One hundred ninety-eight consecutive patients treated for prostate cancer by iodine-125 seed brachytherapy were assessed. Prostate dosimetry was stratified according to British Columbia Cancer Agency criteria, with good implants having both V100 (percentage of target volume that receives 100% of the prescribed dose) > 85% and D90 (percentage of the prescribed dose received by 90% of the target volume) > 90%, suboptimal implants with V100 of 75-85%, or D90 80-90%, whereas poor implants were defined as those with V100 < 75 or D90 < 80%. CTV dosimetry stratification was performed according to the same dose coverage criteria, albeit to the CTV. RESULTS: One hundred ninety-two patients (97%) had good prostate radiation coverage, whereas only 165 patients (83%) had good postimplant CTV dosimetry. Patients with suboptimal vs. good CTV dosimetry had prostate edema of 7.8 +/- 0.2% vs. 0.2 +/- 0.1%, respectively (p = 0.001). CONCLUSIONS: Prostate seed implants with optimal dosimetry to prostate may still have suboptimal D90 and V100 for the CTV, especially in the presence of postimplant edema. A consensus is needed for definition and evaluation of CTV in postimplant setting for low-dose-rate prostate brachytherapy. PMID- 25301339 TI - A guide to survival analysis for manual therapy clinicians and researchers. AB - Survival analysis is a statistical approach used to study time to an event of interest. The approach is highly applicable to the manual therapy discipline, yet is rarely used. This masterclass aims to present a simple overview of survival analysis aimed at both clinicians and researchers in the manual therapy field. Specifically the masterclass aims to 1) describe situations where survival analysis is appropriate to use 2) describe unique characteristics of survival data including censoring of participants 3) describe analysis methods for survival data including log rank test and Cox regression 4) describe the interpretation of results from survival analyses including survival plots and hazard ratios. PMID- 25301340 TI - Surveillance and response: Tools and approaches for the elimination stage of neglected tropical diseases. AB - The presentation of the World Health Organization (WHO)'s roadmap for neglected tropical diseases (NTDs) in January 2012 raised optimism that many NTDs can indeed be eliminated. To make this happen, the endemic, often low-income countries with still heavy NTD burdens must substantially strengthen their health systems. In particular, they need not only to apply validated, highly sensitive diagnostic tools and sustainable effective control approaches for treatment and transmission control, but also to participate in the development and use of surveillance-response schemes to ensure that progress made also is consolidated and sustained. Surveillance followed-up by public health actions consisting of response packages tailored to interruption of transmission in different settings will help to effectively achieve the disease control/elimination goals by 2020, as anticipated by the WHO roadmap. Risk-mapping geared at detection of transmission hotspots by means of geospatial and other dynamic approaches facilitates decision-making at the technical as well as the political level. Surveillance should thus be conceived and developed as an intervention approach and at the same time function as an early warning system for the potential re emergence of endemic infections as well as for new, rapidly spread epidemics and pandemics. PMID- 25301341 TI - Products and kinetics of the heterogeneous reaction of particulate ametryn with NO3 radicals. AB - As a renowned s-triazine herbicide, ametryn is worldwide emitted into the atmosphere in both gaseous and particulate phases via spray drifts from treatments and post application emissions, but its chemical degradation in the atmosphere has not been well characterized. In this study, the heterogeneous kinetics of particulate ametryn with NO3 radicals were investigated with a mixed phase relative rate method. A vacuum ultraviolet photoionization aerosol time-of flight mass spectrometer (VUV-ATOFMS) and an atmospheric gas analysis mass spectrometer were synchronously used to online monitor the decays of particulate ametryn and gas-phase isoprene. The reactive uptake coefficient of NO3 radicals on ametryn particles was calculated to be 2.9 * 10(-2), according to the measured ametryn loss ratio and the average NO3 concentration. The effective rate constant for the heterogeneous reaction of particulate ametryn with NO3 radicals measured under experimental conditions was 8.4 * 10(-13) cm(3) molecule(-1) s(-1). In addition, atraton, ametryn sulfoxide and ametryn sulfone were identified as the reaction products by gas-chromatography-mass spectrometry (GC-MS) analysis. The experimental results might shed light on the chemical behavior of atmospheric ametryn at night-time. PMID- 25301342 TI - Limits of surgery for pancreatic cancer. AB - Pancreatic cancer patients often present in an already advanced state of disease and the therapeutic approach is an interdisciplinary challenge. Surgery is an integral part in a potentially curative setting, yet in such advanced disease surgery can reach its limits. The technical feasibility has to be weighted against potential harms and the oncological reasonableness. In locally advanced disease, limits of surgery could be pushed as evidence grew. A venous vascular tumor infiltration nowadays does not preclude patients from surgery, as venous resections can be safely performed and survival rates are not inferior to patients with standard resections. Multivisceral resections have an increased risk of morbidity and mortality, but can improve overall survival. The resection and reconstruction of tumor infiltrated arteries is technically feasible, but these procedures have a high rate of associated morbidity and mortality with an unclear oncological benefit and therefore are generally not recommended. This also holds true for intentional palliative R2-resections, which do not offer a survival benefit but decrease the quality of life and have higher morbidity and mortality rates than palliative bypass procedures. A synchronous resection of the primary tumor and intraabdominal metastases in an olgiometastatic disease only offers a questionable oncological benefit and the evidence for this approach is scarce. Therefore, surgery in a metastatic disease is generally not recommended and has to be discussed interdisciplinary on a highly individual basis.Key words: pancreatic cancer multivisceral resection staging. PMID- 25301343 TI - [The role of drains in pancreatic surgery]. AB - Pancreatic fistula is a significant complication following pancreatic resection. Several methods aimed at lowering the postoperative pancreatic fistula rate were studied in the past. These methods mainly include pharmacological prophylaxis and technical modifications of pancreatic remnant management. Another method which can influence postoperative pancreatic fistula rate is the use of and the manipulation with intra-abdominal drains following pancreatic resection. Recent studies have shown that the use of the drains, the type of drain and manipulation with the drains can influence the outcomes. The aim of this review is to summarize current knowledge about the use of drains in pancreatic surgery. There are three questions to ask when studying the use of drains in pancreatic surgery: 1) Whether to use the drains at all 2) When to remove the drains? 3) Which type of the drain is more appropriate? Ad 1) Despite the growing number of studies showing comparable or even better results in patients without intra-abdominal drains following pancreatic resection, the latest randomized study proved that avoiding the use of drains is associated with more clinically significant postoperative complications and higher postoperative mortality. It is also important to consider the risk factors of pancreatic fistula development, especially pancreatic texture and the main pancreatic duct diameter. Currently, pancreatic resection without intra-abdominal drains cannot be routinely recommended. Ad 2) Two studies addressed the question when to remove the drains after pancreatic resection, and both studies clearly showed that early removal brings better results. Ad 3) No study has specifically addressed the question whether the type of drain can influence the rate of postoperative pancreatic fistula and of other complications. Gravity drains and closed-suction drains are most commonly used nowadays. The closed-suction drains are more effective due to the active suction. On the other hand, active suction can cause leak of the amylase-rich fluid through the pancreatic anastomosis or suture line and thus promote the development of pancreatic fistula or even worsen its clinical significance. There are no data in the literature so far regarding the type of drain. Therefore, we have commenced a randomized control trial which aims to compare closed-suction drains and closed gravity drains. PMID- 25301344 TI - [Personalised antibiotic therapy in a surgical intensive care unit overview of current knowledge and the results of an observational kinetic study]. AB - INTRODUCTION: The current efforts of intensivists focused on individual antibiotic treatment in patients suffering from sepsis has inspired us to conduct an open prospective clinical study to assess the relationship between body fluid retention (>10 L/24 hours) and the efficiency of hydrophilic time-dependent antibiotics used in critically ill patients. Polytrauma and abdominal catastrophes are the most frequent causes of systemic inflammatory response syndrome (SIRS). Consequent body liquid retention is taken for a pathophysiological covariate modifying the pharmacokinetics (PK) and pharmacodynamics (PD) of hydrophilic time-dependent antibiotics (betalactams and carbapenems). Not only body fluid retention but also changes in renal clearance are thought to be responsible for failure in PK/PD target attainment necessary for effective antimicrobial activity. To describe the importance of the pathophysiological covariates for the individual kinetic variables of a representative antibiotic (piperacillin) is the primary goal of this kinetic observational study. MATERIAL AND METHODS: Three patients with polytrauma and SIRS admitted at the ICU of the Surgical Department, Teaching Hospital Hradec Kralove, whose condition was characterized by cumulative body fluid retention (>10 L), were eligible for enrolment. As per standard hospital protocol, the patients were administered with 4 g of piperacillin in combination with tazobactam 0.5 g intravenously by 1-hour (h) infusion every 8 h. A series of blood samples were taken 1, 2.5, and 5 h after the termination of the infusion. Urine was collected over each dosing interval and for 24 h. Piperacillin was detected using a previously validated HPLC method. Individual pharmacokinetic variables were estimated using non-compartmental pharmacokinetic analysis. Cumulative body fluid retention was calculated as the difference between fluid intake and output. Creatinine clearance (Cl) was used for renal function evaluation. PK/PD target attainment was analysed according to Carlier (2013). RESULTS: In three patients with polytrauma and SIRS, great interindividual and intraindividual differences in extravascular volume expansion, i.e. cumulative body fluid retention 2030 L and changes in renal function, were recorded. In 2/3 patients these pathophysiological changes as well as the clinical interventions administered resulted in augmented piperacillin clearance and an increase in distribution volume (Vd) (>20 L) with a maximum at Day 28 after initiation of therapy. In such patients treated with a standard dose of piperacillin, only minimum PK/PD target attainment (50% Ft >MIC) was obtained. In contrast, a patient suffering from renal dysfunction attained both minimum (50% ft >MIC) and maximum PK/PD target (100% ft >MIC). CONCLUSIONS: In three critically ill patients with polytrauma and SIRS, pathophysiological changes (covariates) had a profound effect on the key determinants of the pharmacokinetics (Cl and Vd), resulting in significant intraindividual variability in pharmacodynamic /pharmacokinetic target attainment necessary for therapeutic time-dependent antibacterial activity of piperacillin. Consequently, patients with augmented clearance of piperacillin may be at risk for treatment failure, and/or bacterial resistance without dose up-titration. A subsequent clinical study will be conducted to describe personalised kinetically guided antibiotic therapy. PMID- 25301345 TI - [Fluid therapy and surgical outcomes after low anterior resection]. AB - INTRODUCTION: Fluid therapy is a fundamental component of surgical care. Recent data regarding fluid restriction has shown an association with improved outcomes. The aim of this study is to determine whether the use of restrictive approaches in perioperative fluid administration improves patient outcomes following low anterior resection. MATERIAL AND METHODS: 89 patients undergoing low anterior resection included in this study were divided by the median 14.9 mL/kg/h into group A (7.4-14.7 mL/kg/h) and group B (14.9-36.8 mL/kg/h) within intraoperative fluid administration, and by the median 3.3 mL/kg/h into group C (2.0-3.3 mL/kg/h) and group D (3.3-6.9 mL/kg/h) for fluid administration on the day of surgery. The main outcomes measured were cardiac and pulmonary complications, the incidence of anastomotic leak and wound infections, gastrointestinal function recovery, laboratory inflammatory markers and the length of hospital stay. RESULTS: The restricted perioperative fluid regimen significantly reduced the risk of pleural effusion and anastomotic leak in patients after low anterior resection. The overall incidence of anastomotic leak was 9.0%. Another significant risk factor for anastomotic leak was neoadjuvant radiochemotherapy (15.9% vs. 2.2%, p=0.03). CONCLUSION: The restricted perioperative fluid regimen reduces postoperative morbidity in patients after low anterior resection. Hospital stay remains unchanged. PMID- 25301346 TI - Severe hidradenitis suppurativa. AB - INTRODUCTION: Hidradenitis suppurativa is a chronic, recurrent inflammatory disease causing significant changes and damage to skin. Predilection sites are the axilla and the anogenital region. Chronic and severe forms of the diseases may cause both physical and psychological injury to the patient. PATIENTS: We present the cases of two female patients with severe hidradenitis suppurativa in the axillae and in the anogenital region. The patients had been unsuccessfully treated for eight and four years respectively with antibiotics and by limited surgery. Different methods of closing the defects following radical surgical excision (local flap reconstruction, healing by granulation) had to be used with respect to the extent of the disease and the site of involved skin. CONCLUSION: Radical wide excision of the skin area involved is the only appropriate surgical procedure which prevents recurrence of the disease. Selection of the therapeutic method must be done very carefully with respect to the individual characteristics of the disease and the patients attitude to therapy. PMID- 25301347 TI - [Chylous mesenteric cyst]. AB - The authors present a case report of a female patient with a recurrent mesenteric cyst. Chylous cyst is one of rare diagnoses of a cyst close to the pancreas in patients with no history of acute pancreatitis. Chylous cysts need to be managed radically; otherwise, given their nature, they are likely to recur. PMID- 25301348 TI - [Lymphangioma of the retroperitoneum treated laparoscopically]. AB - A case report of a female patient with pathological liquid collection in the retroperitoneum with chronic and recurrent pain in the epigastric region and dyspepsia. After a safe laparoscopic approach and removal of a cystic tumour, the finding was histologically described as lymphangioma. PMID- 25301349 TI - An evaluation of the accuracy of labeling of percent sodium hypochlorite on various commercial and professional sources: is sodium hypochlorite from these sources equally suitable for endodontic irrigation? AB - INTRODUCTION: The shelf life of sodium hypochlorite (NaOCl) is limited, and a previous article showed that there can be a discrepancy between the expected concentration of free available chlorine (FAC) and the actual FAC concentration in NaOCl solutions intended for endodontic irrigation. The current study investigates the FAC content of domestic and professional NaOCls and evaluates the influences of dilution and storage on FAC concentration. METHODS: First, domestic and professional NaOCls not obtained from manufacturers were iodometrically titrated. Then, NaOCls were diluted with demineralized water or tap water and stored at 4 degrees C or 18 degrees C and analyzed at baseline and 2 and 22 weeks. Statistical analyses included paired samples, independent samples t tests and repeated multivariate analysis of variance. Correlations were calculated with the Pearson or Spearman rank correlation test. A P < .05 was considered significant. RESULTS: Label specifications of domestic NaOCl were very imprecise (ie, <5% NaOCl). Domestic NaOCl contained 1.8%-3.5% NaOCl (w/v). Professional NaOCl varied from 14.3% relative less FAC than specified on the label to 23.5% relative more FAC than specified. After 22 weeks, the relative average loss of FAC in all conditions was 5.4% FAC (P = .002). Dilution, diluents, or storage temperature had no effect on the decline of FAC caused by aging. CONCLUSIONS: There is a great variation in NaOCl concentrations, with domestic NaOCl being the least accurate. NaOCl can be stored up to 5 months. The FAC concentration of domestic NaOCl is unpredictable, and, therefore, it appears less suitable for clinical application as root canal irrigant. PMID- 25301350 TI - Evaluation of root canal transportation, centering ratio, and remaining dentin thickness associated with ProTaper Next instruments with and without glide path. AB - INTRODUCTION: The purpose of this study was to evaluate and compare the volume of removed dentin, transportation, and centering ability of ProTaper Next (PTN) system with and without glide path preparation by using cone-beam computed tomography (CBCT) imaging. METHODS: Sixty mesiobuccal canals of mandibular first molars with curvatures of 25 degrees -35 degrees were divided into 3 experimental groups (n = 20) according to the instrumentation technique as follows: group PG/PTN (glide path was created with ProGlider [PG]) and canals were shaped with PTN system), group PF/PTN (glide path was created with PathFile [PF]) and canals were shaped with PTN system), and group PTN (glide path was not performed and canals were shaped with PTN system only). Canals were scanned before and after instrumentation by using CBCT scanner to evaluate root canal transportation and centering ratio at 3, 5, and 7 mm from the apex and volumetric changes. Data were statistically analyzed, and the significance level was set at P < .05. RESULTS: There was no significant difference among the tested groups regarding the volume of removed dentin and centering ratio (P > .05). At 3-mm and 5-mm levels, the PG/PTN group showed a significantly lower mean transportation value among the groups (P < .05). However, at 7-mm level, there was no significant difference in canal transportation among the groups (P > .05). CONCLUSIONS: PG/PTN instrumentation method revealed better performance with fewer canal aberrations when compared with instrumentation performed with PF/PTN or PTN only. PMID- 25301352 TI - Supplementary motor area and primary auditory cortex activation in an expert break-dancer during the kinesthetic motor imagery of dance to music. AB - The current study used functional magnetic resonance imaging to examine the neural activity of an expert dancer with 35 years of break-dancing experience during the kinesthetic motor imagery (KMI) of dance accompanied by highly familiar and unfamiliar music. The goal of this study was to examine the effect of musical familiarity on neural activity underlying KMI within a highly experienced dancer. In order to investigate this in both primary sensory and motor planning cortical areas, we examined the effects of music familiarity on the primary auditory cortex [Heschl's gyrus (HG)] and the supplementary motor area (SMA). Our findings reveal reduced HG activity and greater SMA activity during imagined dance to familiar music compared to unfamiliar music. We propose that one's internal representations of dance moves are influenced by auditory stimuli and may be specific to a dance style and the music accompanying it. PMID- 25301351 TI - Regenerative endodontic therapy: a data analysis of clinical protocols. AB - INTRODUCTION: The aim of the present study was to systematically analyze the protocols that have been used in regenerative endodontic therapy and to detect any variations in clinical procedures. METHODS: An electronic search was executed in PubMed using appropriate Medical Subject Heading terms covering the period from January 1993 to May 2014. Additional publications from hand searching and the reference section of each relevant article enriched the article list. The relevance of each article was initially evaluated by scanning all titles and corresponding abstracts. The definite inclusion of each article in the study was determined by using specific criteria applied independently by 3 reviewers. RESULTS: Sixty relevant publications were finally included. The canal walls were not mechanically instrumented in 68% of the clinical articles. Sodium hypochlorite was included in 97% of the clinical studies either as the only irrigant or in combination with other irrigants. Antibiotic combination paste was used as the intracanal medicament in 80% of the clinical articles. Sodium hypochlorite, chlorhexidine, and EDTA were used in the final irrigation protocol in 75%, 4%, and 13% of the clinical studies, respectively. Neither the creation of a blood clot nor the use of platelet-rich plasma/platelet-rich fibrin was described in 13% of the clinical articles. Mineral trioxide aggregate was used as an intracanal coronal barrier in 85% of the relevant clinical studies. CONCLUSIONS: The variability of the clinical protocols applied during regenerative enododontic procedures is considerably high. A thorough analysis of regenerative protocols may constitute an additional source to provide useful clinical considerations for REPs. PMID- 25301354 TI - Ivabradine, coronary heart disease, and heart failure: time for reappraisal. AB - Ivabradine is generally considered to be a safe drug with well-established and substantial benefits. Nevertheless, recently published results from the SIGNIFY trial suggest that ivabradine has rather inconsistent effects on cardiovascular outcomes. In addition, careful examination of all available data from ivabradine trials reveals signals of harm that have not yet been appropriately addressed, including a markedly increased incidence of atrial fibrillation and increased risk of cardiovascular events in patients with heart rates below 70 bpm. These concerns warrant consideration, since they could have implications for the future use of ivabradine. PMID- 25301355 TI - Factorial validity of an abbreviated neighborhood environment walkability scale for seniors in the Nurses' Health Study. AB - BACKGROUND: Using validated measures of individuals' perceptions of their neighborhood built environment is important for accurately estimating effects on physical activity. However, no studies to date have examined the factorial validity of a measure of perceived neighborhood environment among older adults in the United States. The purpose of this measurement study was to test the factorial validity of a version of the Abbreviated Neighborhood Environment Walkability Scale (NEWS-A) modified for seniors in the Nurses' Health Study (NHS). FINDINGS: A random sample of 2,920 female nurses (mean age = 73 +/- 7 years) in the NHS cohort from California, Massachusetts, and Pennsylvania completed a 36-item modified NEWS-A for seniors. Confirmatory factor analyses were conducted to test measurement models for both the modified NEWS-A for seniors and the original NEWS-A. Internal consistency within factors was examined using Cronbach's alpha. The hypothesized 7-factor measurement model was a poor fit for the modified NEWS-A for seniors. Overall, the best-fitting measurement model was the original 6-factor solution to the NEWS-A. Factors were correlated and internally consistent. CONCLUSIONS: This study provided support for the construct validity of the original NEWS-A for assessing perceptions of neighborhood environments in older women in the United States. PMID- 25301353 TI - Endovascular versus medical therapy for atherosclerotic renovascular disease. AB - The diagnosis of renal artery stenosis (RAS) has become increasingly common in part due to greater awareness of ischemic renal disease and increased use of diagnostic techniques. Over 90 % of RAS cases are caused by atherosclerotic renovascular disease (ARVD). Patients with ARVD are at high risk for fatal and nonfatal cardiovascular and renal events. The mortality rate in patients with ARVD is high, especially with other cardiovascular or renal comorbidities. Recent clinical studies have provided substantial evidence concerning medical therapy and endovascular interventional therapeutic approaches for ARVD. Despite previous randomized clinical trials, the optimal therapy for ARVD remained uncertain until the results of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial were released recently. CORAL demonstrated that optimal medical therapy was equally effective to endovascular therapy in the treatment of ARVD. Clinicians can now practice with more evidence-based medicine to treat ARVD and potentially decrease mortality in patients with ARVD using optimal medical therapy. PMID- 25301356 TI - Gene therapy: Going from strength to strength. PMID- 25301357 TI - The role of orexin in motivated behaviours. AB - Wakefulness and vigilance levels are required for maintaining purposeful activities and motivated behaviours, which are often triggered by sensory information conveying external cues. An increasing body of work has suggested that orexins (also known as hypocretins)--a pair of neuropeptides that are crucial for maintaining wakefulness - are also involved in the regulation of motivated behaviours, including feeding, emotional behaviour and reward seeking, and that these functions are mediated by two subtypes of orexin receptors. Autonomic and endocrine responses, which accompany these motivated behaviours, are also influenced by the orexin system. Orexin-producing neurons act as a hub that links information about the internal and external environments of an animal to vigilance levels and internal bodily functions to support various motivated behaviours. PMID- 25301358 TI - Influence of donor and recipient age in lung transplantation. AB - BACKGROUND: No restrictions exist for allocating donor lungs according to age in the United States. METHODS: A retrospective cohort study was performed of lung transplant recipients from 1987 to 2013 through a query of the United Network for Organ Sharing (UNOS) thoracic database. Age thresholds used were recipients (R) aged 60 years (R60 group) and 65 years (R65 group) and donors aged 50 years; each sub-group was analyzed, totaling 8 groups. RESULTS: Of 23,905 lung transplants, 23,704 were used for Kaplan-Meier analysis, 8,851 for multivariate Cox, and 3,206 for the R60 group and 3,212 for the R65 group propensity score-matching analysis. Kaplan-Meier analysis with log-rank test statistic indicated significant differences across binary measure of donor age with a threshold of 60 years (log rank test: chi-square1 = 12.9558, p = 0.0003) and 65 years (log-rank test: chi square1 = 15.5053, p = 0.0001). Multivariate Cox models demonstrated that donors aged <50 years and >=50 years significantly reduced the risk for death for the R60 group, whereas only donors aged <50 years decreased risk for death for the R65 group (hazard ratio [HR], 0.730; 95% confidence interval [CI], 0.623-0.856; p < 0.001) after lung transplant. Propensity score-matching analysis showed donors aged >=50 years increased the risk for death of recipients aged <60 years (HR, 1.314; 95% CI, 1.065-1.621; p = 0.011) and <65 years (HR, 1.198; 95% CI, 1.089 1.319, p < 0.001), whereas donors aged >=50 years did not increase the risk for death for recipients aged >=60 years (HR, 1.056; 95% CI, 0.869-1.285; p = 0.583) and >=65 years (HR, 0.938; 95% CI, 0.705, 1.249, p = 0.662). CONCLUSIONS: Older donor lungs did not negatively affect survival in older recipients but limited outcomes in younger recipients. PMID- 25301359 TI - Functional characteristics of reversibly immortalized hepatic progenitor cells derived from mouse embryonic liver. AB - BACKGROUND/AIMS: Liver is a vital organ and retains its regeneration capability throughout adulthood, which requires contributions from different cell populations, including liver precursors and intrahepatic stem cells. To overcome the mortality of hepatic progenitors (iHPs) in vitro, we aim to establish reversibly immortalized hepatic progenitor cells from mouse embryonic liver. METHODS AND RESULTS: Using retroviral system to stably express SV40 T antigen flanked with Cre/LoxP sites, we establish a repertoire of iHP clones with varied differentiation potential. The iHP cells maintain long-term proliferative activity and express varied levels of progenitor markers (Pou5f1/Oct4 and Dlk) and hepatocyte markers (AFP, Alb and ApoB). Five representative iHP clones express hepatic/pancreatic transcription factors HNF3alpha/Foxa1, HNF3beta/Foxa2, and HNF4alpha/MODY1. Dexamethasone is shown to promote the expression of hepatocyte markers AFP and TAT, along with ICG-uptake and glycogen storage functions in the iHP clones. Cre-mediated removal of SV40 T antigen reverses the proliferative activity of iHP cells. When iHP cells are subcutaneously implanted in athymic nude mice, no tumor formation is observed for up to 8 weeks. CONCLUSIONS: We demonstrate that the established iHP cells are stable, reversible, and non-tumorigenic hepatic progenitor-like cells, which should be valuable for studying liver organogenesis, metabolic regulations, and hepatic lineage-specific differentiation. PMID- 25301360 TI - BMP2 increases adipogenic differentiation in the presence of dexamethasone, which is inhibited by the treatment of TNF-alpha in human adipose tissue-derived stromal cells. AB - BACKGROUND/AIMS: The aim of this study was to analyze the effect of BMP2 on osteogenic differentiation of human adipose tissue-derived stromal cells (hADSCs). METHODS: Cultured cells were differentiated into osteogenic lineage in the presence of BMP2. Gene expressions were determined by real time PCR. RESULTS: BMP2 increased (2/8) or inhibited (6/8) osteogenic differentiation according to hADSCs batches. Regardless of the BMP2 action on osteogenic differentiation, BMP2 induced lipid droplet formation under an osteogenic differentiation condition in all batches of hADSCs, not hBMSCs, to be tested, which was confirmed by analysis of adipogenesis related genes expression. hADSCs expressed various BMP receptors. BMP2 increased expression of BMP2-responsive genes such as DLX3 and ID2, and induced SMAD1 phosphorylation in hADSCs and hBMSCs. BMP2 increased osteogenic differentiation of hADSCs in osteogenic medium in which dexamethasone was omitted. The addition of BMP2 in the control culture media containing dexamethasone alone lead to formation of lipid droplets and increased C/EBP-alpha expression in hADSCs. In the presence of TNF-alpha, BMP2 stimulated osteogenic differentiation of hADSCs even in hADSCs batches in which treatment of BMP2 alone inhibited osteogenic differentiation. CONCLUSION: These data indicate that the control of osteogenesis and adipogenesis in hADSCs is closely related, and that hADSCs have preferential commitment to adipogenic lineages. PMID- 25301361 TI - Formononetin promotes cell cycle arrest via downregulation of Akt/Cyclin D1/CDK4 in human prostate cancer cells. AB - BACKGROUND: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. METHODS: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of formononetin. The inhibitory effect of formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. RESULTS: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, formononetin showed a noticeable inhibition of tumor growth in recipient mice. CONCLUSION: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future. PMID- 25301362 TI - Acacetin blocks kv1.3 channels and inhibits human T cell activation. AB - BACKGROUNDS/AIMS: Acacetin, a natural flavonoid compound, has been proven to exert anti-inflammatory and immunomodulatory effects. Kv1.3 channels, highly expressed in human T cells, are attractive therapeutic targets to treat inflammatory and immunological disorders. The present study was designed to characterize the inhibition of Kv1.3 channels by Acacetin in human T cells and examine its role in T cell activation. METHODS: Whole-cell patch-clamp was applied to record the Kv1.3 and KCa currents in human T cells; Western blot was used to detect Kv1.3 expression as well as NFAT1 and NF-kappaB activity; Fluo-4, CCK-8 and an ELISA kit were used to measure Ca(2+) influx, proliferation, and IL 2 secretion, respectively. RESULTS: Acacetin decreased the Kv1.3 current, accelerated the decay rate and negatively shifted the steady-state inactivation curves in a concentration-dependent manner. The IC50 values at +40 mV for peak and the current at end of pulse were 21.09 +/- 2.75 and 3.63 +/- 0.25 MUmol/L, respectively. Treatment with Acacetin for 24 h significantly inhibited Kv1.3 protein expression. Additionally, paralleling Kv1.3 inhibition, Acacetin also inhibited Ca(2+) influx, the Ca(2+)-activated transcription factors NFAT1, NF kappaB p65/p50 activity, and proliferation as well as IL-2 production. Small interfering RNA against Kv1.3 reduced the inhibitory effect of Acacetin on IL-2 secretion. CONCLUSIONS: Acacetin blocks the Kv1.3 channel and inhibits human T cell activation. This action most likely contributes to its immunomodulatory and anti-inflammatory actions. PMID- 25301363 TI - CXCL1 regulation in human pulmonary epithelial cells by tumor necrosis factor. AB - BACKGROUND/AIMS: The chemokine CXCL1 has been reported to be expressed in lung airway epithelium and non-small cell lung cancer biopsy specimens. In this study, we investigated the effects of TNF-alpha, an abundant cytokine detected in inflammation and various cancers, on CXCL1 release by human A549 lung carcinoma epithelial cells. METHODS: CXCL1 expression was determined by ELISA and RT-PCR. TNF-alpha signaling was examined by western blotting. Monocyte migration was assayed by a Transwell migration system. RESULTS: TNF-alpha stimulated CXCL1 release and mRNA expression, and this release was inhibited by inhibitors of JNK, p38 MAPK, PI-3K/Akt and AP-1 transcription factor. TNF-alpha treatment was followed by JNK, p38 MAPK and PI3K/Akt activation. However, only the JNK inhibitor could reduce the CXCL1 mRNA level, suggesting that JNK is required mainly for CXCL1 mRNA synthesis, whereas p38 MAPK and PI-3K/Akt might be responsible for CXCL1 secretion. Dexamethasone (dex) and TGF-beta reduced CXCL1 secretion, with dex upregulating the expression of MAP kinase phosphatase-1 and TGF-beta causing smad2/3 activation and nuclear translocation. A functional analysis showed that the released CXCL1 enhanced monocyte migration and could be abolished by a CXCL1 neutralizing antibody and CXCR antagonist. CONCLUSION: We demonstrate that TNF-alpha induces CXCL1 expression through the JNK, p38 MAPK and PI-3K/Akt signaling pathways in human pulmonary epithelial cells. PMID- 25301364 TI - Secretion of acid Sphingomyelinase is affected by its polymorphic signal peptide. AB - BACKGROUND: Acid sphingomyelinase (ASM) catalyses the hydrolysis of sphingomyelin into ceramide, which acts as a lipid messenger that regulates important cellular functions. Deregulated ASM activity has been reported for different common diseases, but the mechanisms regulating ASM activity are still debated. ASM contains an exceptional signal peptide which is polymorphic due to a variable number of a hexanucleotide sequence that determines the length of the hydrophobic core. We investigated the impact of the signal peptide polymorphism on the regulation of ASM activity and secretion in vivo and in vitro. METHODS AND RESULTS: Subjects homozygous for the rare 4-repeat allele displayed significantly lower secreted ASM activity than subjects homozygous for the common 6-repeat allele. In vitro, overexpression of ASM variants encoded by 2, 8 or 9 repeats resulted in a significantly lowered ASM secretion rate. Treatment of ASM overexpressing cells with tumour necrosis factor alpha induced secretion of ASM, and the secretion rate was highest for the most common ASM variant encoding 6 repeats compared to other naturally occurring variants. CONCLUSION: We provide evidence that the polymorphic ASM signal peptide regulates ASM secretion. It might be an evolutionary mechanism to increase ASM secretion potential, whereas an increase in lysosomal ASM activity is limited due to deleterious cellular effects. PMID- 25301365 TI - Membrane androgen receptor down-regulates c-src-activity and beta-catenin transcription and triggers GSK-3beta-phosphorylation in colon tumor cells. AB - BACKGROUND/AIMS: Functional membrane androgen receptors (mARs) have recently been described in colon tumor cells and tissues. Their activation by specific testosterone albumin conjugates (TAC) down-regulates the PI-3K/Akt pro-survival signaling and triggers potent pro-apoptotic responses both, in vitro and in vivo. The present study explored the mAR-induced regulation of gene products implicated in the tumorigenic activity of Caco2 colon cancer cells. METHODS: In Caco2 human colon cancer cells transcript levels were determined by RT-PCR, protein abundance and phosphorylation by Western blotting and confocal microscopy, as well as cytoskeletal architecture by confocal microscopy. RESULTS: We report time dependent significant decrease in Tyr-416 phosphorylation of c-Src upon mAR activation. In line with the reported late down-regulation of the PI-3K/Akt pathway in testosterone-treated colon tumors, GSK-3beta was phosphorylated at Tyr 216 after long term stimulation of the cells with TAC, a finding supporting the role of this kinase to promote apoptosis. PCR analysis revealed significant decrease of beta-catenin and cyclin D1 transcript levels following TAC treatment. Moreover, confocal laser scanning microscopic analysis disclosed co-localization of beta-catenin with actin cytoskeleton. It is thus conceivable that beta-catenin may participate in the reported modulation of cytoskeletal dynamics in mAR stimulated Caco2 cells. CONCLUSIONS: Our results provide strong evidence that mAR activation regulates late expression and/or activity of the tumorigenic gene products c-Src, GSK-3beta, and beta-catenin thus facilitating the pro-apoptotic response in colon tumor cells. PMID- 25301366 TI - Panax quinquefolium saponin attenuates cardiomyocyte apoptosis and opening of the mitochondrial permeability transition pore in a rat model of ischemia/reperfusion. AB - AIMS: Opening of the mitochondrial permeability transition pore (mPTP) is a critical event during ischemia/reperfusion (I/R) injury. Recently, we showed that Panax quinquefolium saponin (PQS) alleviates apoptosis of cardiomyocytes by suppressing excessive endoplasmic reticulum stress (ERS) during I/R injury. Here, we hypothesized that this anti-apoptotic effect might be mediated through inhibition of mPTP and the mitochondrial apoptotic pathway. METHODS: Ninety-six healthy male Sprague-Dawley rats were randomly divided into sham, I/R, I/R+PQS (200 mg/kg/d), Cyclosporine A (CsA, 10 mg/kg), I/R+CsA (10 mg/kg), and I/R+PQS+CsA. I/R was modeled in rats by ligating the left anterior descending artery (LAD) for 30 min followed by 120 min of reperfusion. To evaluate the cardioprotective function of PQS, we measured hemodynamics, serum content of creatine kinase-MB (CK-MB), myocardial infarct size, and myocardial apoptotic index (AI). We investigated the underlying mechanism by examining changes in the mitochondrial ultrastructure and membrane potential (DeltaPsim), dynamics of mPTP opening, expression of cleaved caspase-3, cleaved caspase-9 in the myocardium, Bcl-2 and Bax in the mitochondria versus cytosol, and translocation of cytochrome c. RESULTS: Administration of PQS to I/R rats significantly reduced serum CK-MB level, infarct size and AI. In addition, PQS protected the mitochondrial structure, markedly inhibited mPTP opening and DeltaPsim depolarization, led to upregulation of Bcl-2 and downregulation of Bax in the mitochondria compared to the cytosol, and suppressed the expression of cleaved caspase-9 and cleaved caspase-3, as well as I/R induced translocation of cytochrome c to the cytoplasm. CONCLUSION: Our results show that PQS can alleviate apoptosis of cardiomyocytes during I/R injury, possibly due to repressed mitochondrial apoptotic pathway associated with the opening of mPTP induced by myocardial I/R injury. PMID- 25301367 TI - Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD. AB - BACKGROUND: Cigarette smoking is the most important risk factor for Chronic Obstructive Pulmonary Disease (COPD). Only a subgroup of smokers develops COPD and it is unclear why these individuals are more susceptible to the detrimental effects of cigarette smoking. The risk to develop COPD is known to be higher in individuals with familial aggregation of COPD. This study aimed to investigate if acute systemic and local immune responses to cigarette smoke differentiate between individuals susceptible or non-susceptible to develop COPD, both at young (18-40 years) and old (40-75 years) age. METHODS: All participants smoked three cigarettes in one hour. Changes in inflammatory markers in peripheral blood (at 0 and 3 hours) and in bronchial biopsies (at 0 and 24 hours) were investigated. Acute effects of smoking were analyzed within and between susceptible and non susceptible individuals, and by multiple regression analysis. RESULTS: Young susceptible individuals showed significantly higher increases in the expression of FcgammaRII (CD32) in its active forms (A17 and A27) on neutrophils after smoking (p = 0.016 and 0.028 respectively), independently of age, smoking status and expression of the respective markers at baseline. Smoking had no significant effect on mediators in blood or inflammatory cell counts in bronchial biopsies. In the old group, acute effects of smoking were comparable between healthy controls and COPD patients. CONCLUSIONS: We show for the first time that COPD susceptibility at young age associates with an increased systemic innate immune response to cigarette smoking. This suggests a role of systemic inflammation in the early induction phase of COPD. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00807469. PMID- 25301368 TI - Circulating angiogenesis biomarkers are associated with disease progression in lung adenocarcinoma. AB - BACKGROUND: Dysregulation of angiogenesis is known to be associated with tumorigenesis and metastatic progression in multiple carcinomas. The aim of this study was to evaluate the prognostic value of circulating angiogenesis biomarkers in lung adenocarcinoma progression. For that, we hypothesize that circulating levels of biomarkers characteristic for discrete processes within angiogenesis are associated with specific phases of disease progression. Appreciation of these profiles may have important implications for disease detection and prognostication. METHODS: Patients with lung adenocarcinoma enrolled in the study were grouped as follows: node negative (T1a-3N0M0; n = 69), node positive (T1a 4N1-2M0; n = 60), and disseminated disease (TxNxM1; n = 68). All serum specimens were assayed for 17 angiogenesis biomarkers on the Luminex platform and statistically evaluated by analysis of variance for median differences in biomarker concentration at distinct phases of disease progression and by log rank methods for associations with clinical outcome. RESULTS: We found circulating hepatocyte growth factor, heparin-binding epidermal growth factor, epidermal growth factor, and vascular endothelial growth factor-C levels significantly elevated (p < 0.05) in patients with node positive versus node negative disease. Similarly, median serum concentrations of bone morphogenic protein-9, endoglin, fibroblast growth factor-1, fibroblast growth factor-2, interleukin-8, placental growth factor, vascular endothelial growth factor-C, and vascular endothelial growth factor-D were significantly (p < 0.05) higher in patients with disseminated disease than in patients with node positive disease. Five biomarkers total were strongly prognostic (p < 0.05) for overall survival in the node negative cohort. CONCLUSIONS: Angiogenesis is a process central to lung adenocarcinoma progression. We describe the modulation in serum angiogenesis biomarker concentrations through the various phases of non-small cell lung cancer progression. Additional refinement efforts are under way to enhance test performance, followed by additional validation studies. PMID- 25301369 TI - Pseudoaneurysm formation after medtronic freestyle porcine aortic bioprosthesis implantation: a word of caution. AB - BACKGROUND: A growing literature describes aneurysmal deterioration after implantation of the stentless porcine aortic Medtronic Freestyle bioprosthesis (MFB; Medtronic Inc, Minneapolis, MN), with some suggesting inadequate tissue fixation with immune response as a cause. However, disjointed reports make the significance of these findings difficult to interpret. We address this concern by aggregating available data. METHODS: We reviewed institutional data, the Food and Drug Administration's Manufacturer and User Facility Device Experience registry, and the medical literature for mention of aneurysm or pseudoaneurysm after MFB. Case details were aggregated, and the rate of aneurysmal deterioration was estimated. Immunohistopathologic examination of institutional explanted specimens was performed to elucidate a cause. RESULTS: We found 42 cases of aneurysmal deterioration with adequate detail for analysis; all occurred with full root replacement and valve sizes ranging from 23 to 29 mm. The rate of aneurysmal deterioration considering all data sources was 1.1% (9 of 851; 95% confidence interval, 0.5% to 2.0%) vs 4.7% (4 of 86; 95% confidence interval, 1.3% to 11.5%) at our institution, where yearly surveillance imaging is performed. Rate of aneurysmal deterioration appeared constant until 5 years after the operation; however, events are reported out to 10 years. Consistent with previous reports, histopathology demonstrated an immune cell infiltrate in areas of MFB wall breakdown. CONCLUSIONS: Aneurysmal deterioration is an increasingly described complication of MFB implantation as a full root, with an incidence as high as 4.7%. Given the observed immune reaction and lack of occurrence in smaller (19-mm and 21-mm) valve sizes, inadequate pressure fixation of larger valves is a potential etiology. Patients with MFB require annual surveillance imaging, and consideration of this complication should factor into preoperative decision making because treatment mandates redo root replacement, which may not be feasible in high-risk patients. PMID- 25301370 TI - Safety and cost-effectiveness of a simplified method for lumbar puncture in patients with hematologic malignancies. PMID- 25301371 TI - Abdominal obesity and low physical activity are associated with insulin resistance in overweight adolescents: a cross-sectional study. AB - BACKGROUND: Previous studies have assessed the metabolic changes and lifestyles associated with overweight adolescents. However, these associations are unclear amongst overweight adolescents who have already developed insulin resistance. This study assessed the associations between insulin resistance and anthropometric, metabolic, inflammatory, food consumption, and physical activity variables amongst overweight adolescents. METHODS: This cross-sectional study divided adolescents (n = 120) between 10 and 18 years old into 3 groups: an overweight group with insulin resistance (O + IR), an overweight group without insulin resistance (O-IR), and a normal-weight control group (NW). Adolescents were matched across groups based on age, sex, pubertal maturation, and socioeconomic strata. Anthropometric, biochemical, physical activity, and food consumption variables were assessed. Insulin resistance was assessed using homeostatic model assessment (HOMA Calculator Version 2.2.2 from (c)Diabetes Trials Unit, University of Oxford), and overweight status was assessed using body mass index according to World Health Organization (2007) references. A chi-square test was used to compare categorical variables. ANOVAs or Kruskal-Wallis tests were used for continuous variables. Multiple linear regression models were used to calculate the probability of the occurrence of insulin resistance based on the independent variables. RESULTS: The risk of insulin resistance amongst overweight adolescents increases significantly when they reach a waist circumference > p95 (OR = 1.9, CIs = 1.3-2.7, p = 0.013) and watch 3 or more hours/day of television (OR = 1.7, CIs = 0.98-2.8, p = 0.033). Overweight status and insulin resistance were associated with higher levels of inflammation (hsCRP >=1 mg/L) and cardiovascular risk according to arterial indices. With each cm increase in waist circumference, the HOMA index increased by 0.082; with each metabolic equivalent (MET) unit increase in physical activity, the HOMA index decreased by 0.026. CONCLUSIONS: Sedentary behaviour and a waist circumference > p90 amongst overweight adolescents were associated with insulin resistance, lipid profile alterations, and higher inflammatory states. A screening that includes body mass index, in waist circumference, and physical activity evaluations of adolescents might enable the early detection of these alterations. PMID- 25301372 TI - Rapid and cost-effective molecular diagnosis using exome sequencing of one proband with autosomal dominant congenital cataract. AB - PURPOSE: Due to high genetic heterogeneity, to exclude known mutations and map novel mutations in autosomal dominant congenital cataract (ADCC) using conventional candidate gene screening requires laborious laboratory work. We attempted to use a cost-effective exome sequencing strategy to identify disease causing mutations in an ADCC pedigree. METHODS: An ADCC pedigree affected by nuclear cataract and 200 unrelated senile cataract controls were recruited and given comprehensive ophthalmic examination. Whole exome of the proband of the family was captured by the Illumina TruSeq Exome Enrichment Kit, followed by sequencing using Illumina HiSeq 2000 sequencer. Validation was performed by direct sequencing. RESULTS: The whole exome, including all exons of known ADCC disease-causing genes, was screened for possible disease-causing mutations. A recurrent missense mutation c.773C>T (p.S258F) in exon 2 of the gap junction protein alpha 8 gene (GJA8) was identified in the proband with nuclear cataract. The result was confirmed by direct sequencing. The mutation showed complete co segregation with the disease phenotype in the family but was not observed in unrelated unaffected controls. CONCLUSION: By successfully sequencing whole exome of only one proband and identifying a GJA8 mutation in one ADCC pedigree, the current study demonstrated that exome sequencing could serve as a rapid, robust, and cost-effective approach in clinical diagnosis and disease-causing gene discovery for ADCC. PMID- 25301373 TI - Organ laceration grading adherence by radiologists. AB - American Association for the Surgery of Trauma (AAST) abdominopelvic organ laceration grading is used to determine which patients can be managed non operatively. We assess a change in the use of AAST grading system by radiologists at a single, large, academic institution before and after a one-time departmental intervention and reviewed non-graded reports evaluating if grading could be inferred. After IRB approval, a keyword search for "laceration" identified traumatic abdominopelvic CT reports in a 2-year period before and after the one time intervention. Reports were reviewed to determine if an organ laceration was seen, if it was graded by AAST criteria, and if grading could be inferred for non graded reports. T test was performed to assess statistical significance. Before the intervention, 348 reports contained the keyword "laceration," 81 with lacerations, 31 graded (38 %). After the intervention, 302 reports were found, 79 with lacerations, 59 graded (75 %). The increase was statistically significant (p < 0.0001). A decreasing trend in grading was seen over time following the intervention. Two out of 50 (4 %) pre-intervention and four out of 20 (20 %) post intervention reports gave enough detailed descriptions for the grading to be inferred when it was not explicitly stated. Non-graded reports did not describe laceration parenchymal depth and subcapsular hematoma surface area percentage; however, the presence/absence of active extravasation, omitted in the 20-year-old AAST grading scheme, was described in every report. One-time departmental intervention yielded a significant increase in adherence to AAST laceration grading. Lack of perfect compliance, which diminished over time, suggests a need for further reinforcement. PMID- 25301374 TI - MDCT of the hand and wrist: beyond trauma. AB - High-resolution multidetector computed tomography (MDCT) has played a pivotal role in assessing patients following trauma; however, recent advancements in technology including dual-energy CT, as well as multiplanar and three-dimensional (3D) capabilities, are expanding the potential clinical applications of CT to include nontraumatic pathologies. This article will review optimal technical parameters for the creation of MDCT and 3DCT images and illustrate the imaging capabilities of 3DCT imaging for demonstrating nontraumatic hand and wrist pathology. PMID- 25301375 TI - Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae. AB - BACKGROUND: Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria. RESULTS: To explore the biosynthetic potential of Kutzneria albida to its full extent, the complete genome was sequenced. With a size of 9,874,926 bp, coding for 8,822 genes, it stands alongside other Pseudonocardiaceae with large circular genomes. Genome analysis revealed 46 gene clusters potentially encoding secondary metabolite biosynthesis pathways. Two large genomic islands were identified, containing regions most enriched with secondary metabolism gene clusters. Large parts of this secondary metabolism "clustome" are dedicated to siderophores production. CONCLUSIONS: Kutzneria albida is the first species of the genus Kutzneria with a completely sequenced genome. Genome sequencing allowed identifying the gene cluster responsible for the biosynthesis of aculeximycin, one of the largest known oligosaccharide macrolide antibiotics. Moreover, the genome revealed 45 additional putative secondary metabolite gene clusters, suggesting a huge biosynthetic potential, which makes Kutzneria albida a very rich source of natural products. Comparison of the Kutzneria albida genome to genomes of other actinobacteria clearly shows its close relations with Pseudonocardiaceae in line with the taxonomic position of the genus. PMID- 25301376 TI - Investigation of the intermolecular recognition mechanism between the E3 ubiquitin ligase Keap1 and substrate based on multiple substrates analysis. AB - E3 ubiquitin ligases are attractive drug targets due to their specificity to the ubiquitin machinery. However, the development of E3 ligase inhibitors has proven challenging for the fact that they must disrupt protein-protein interactions (PPIs). The E3 ligase involved in interactome provide new hope for the discovery of the E3 ligase inhibitors. These currently known natural binding partners of the E3 ligase can benefit the discovery of other unknown substrates and also the E3 ligase inhibitors. Herein, we present a novel strategy that using multiple substrates to elucidate the molecular recognition mechanism of E3 ubiquitin ligase. Molecular dynamics simulation, molecular mechanics-generalized born surface area (MM-GBSA) binding energy calculation and energy decomposition scheme were incorporated to evaluate the quantitative contributions of sub-pocket and per-residue to binding. In this case, Kelch-like ECH-associated protein-1 (Keap1), a substrate adaptor component of the Cullin-RING ubiquitin ligases complex, is applied for the investigation of how it recognize its substrates, especially Nrf2, a master regulator of the antioxidant response. By analyzing multiple substrates binding determinants, we found that both the polar sub pockets (P1 and P2) and the nonpolar sub-pockets (P4 and P5) of Keap1 can make remarkable contributions to intermolecular interactions. This finding stresses the requirement for substrates to interact with the polar and nonpolar sub pockets simultaneously. The results discussed in this paper not only show the binding determinants of the Keap1 substrates but also provide valuable implications for both Keap1 substrate discovery and PPI inhibitor design. PMID- 25301377 TI - National audits need more sensitive and specific outcome measures for quality improvement. PMID- 25301378 TI - A case of loss of consciousness with contralateral acute subdural haematoma during awake craniotomy. AB - We are reporting the case of a 56-year-old woman who developed loss of consciousness during awake craniotomy. A thin subdural haematoma in the contralateral side of the craniotomy was identified with intraoperative magnetic resonance imaging and subsequently removed. Our case indicates that contralateral acute subdural haematoma could be a cause of deterioration of the conscious level during awake craniotomy. PMID- 25301379 TI - In vitro effects of the organophosphorus pesticide malathion on the reactivity of rat aorta. AB - BACKGROUND AND PURPOSE: There is a remarkable paucity of studies analyzing the role of the endothelium-derived relaxing factors on the vascular effects of organophosphates. This study was carried out to evaluate the vascular effects of malathion and the role of nitric oxide (NO) and prostacyclin (PGI2). METHODS: Vascular reactivity measuring isometric forces in vitro ('organ chambers') and flow cytometry (cells loaded with DAF-FM DA) were used. RESULTS: In rat thoracic aorta segments contracted with phenylephrine (Phe) (10(-7) mol/l), malathion (10( 10) to 10(-5) mol/l) induced concentration-dependent relaxation in arteries with intact endothelium (n = 7; p < 0.05). Malathion-mediated relaxation was blocked by N-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/l), a nonspecific NO synthase inhibitor, and/or indomethacin (10(-5) mol/l), a nonspecific cyclooxygenase inhibitor (n = 10, p < 0.05). In thoracic aorta rings, with and without endothelium, Phe (10(-10) to 10(-5) mol/l) evoked concentration-dependent contraction, which was reduced in the presence of malathion. In rings with or without endothelium, incubated with malathion, L-NAME and indomethacin, the Phe induced contraction was restored. The role of NO was confirmed using flow cytometry. Malathion evokes endothelium-dependent relaxation through the M1 muscarinic receptor, since this relaxation was clearly blocked by atropine (M1 and M2 blocker) and pirenzepine (M1 blocker), but was less blocked by gallamine (M2 blocker) or 4-DAMP (M3 blocker). CONCLUSIONS: These findings suggest that the organophosphate compound effects on vascular reactivity depend of NO and PGI2. PMID- 25301380 TI - Long-acting reversible contraceptive use in urban women from a title X-supported Boston community health center. AB - BACKGROUND: Unintended and adolescent pregnancy disproportionately affects minority populations, but the effect of age, race and ethnicity on the use of long-acting reversible contraception (LARC) has not been well studied. OBJECTIVE: The objective of this pilot study was to examine LARC use over a 5-year period among women receiving care at a Boston community health center. METHODS: Retrospective cohort study of LARC method use among black, Hispanic, and white women receiving care at the Dimock Center from 2006 to 2010. RESULTS: This study included 276 women (60.1% black, 18.5% Hispanic, and 9.1% white). LARC was not used as a first-line method in the majority (96.0%), regardless of age, race, and ethnicity; yet nearly half identified a long-acting contraceptive as their method of choice. CONCLUSIONS: The findings of this pilot study reveal opportunities to reduce unintended pregnancy through increased LARC use, which may be accomplished by provider and patient education. PMID- 25301382 TI - Reply to Ozkan et al. regarding 'Acoustic radiation force impulse elastography for detection of renal damage in children'. PMID- 25301381 TI - Vasoactive intestinal peptide-deficient mice exhibit reduced pathology in trinitrobenzene sulfonic acid-induced colitis. AB - OBJECTIVES: Vasoactive intestinal peptide (VIP) is an immunomodulatory neuropeptide with therapeutic properties in multiple murine models of inflammatory disease including the trinitrobenzene-sulfonic acid (TNBS)-colitis model of Crohn's disease. Understanding the spectrum of biological actions of endogenously produced VIP may help us dissect the complex and multifactorial pathogenesis of such inflammatory diseases. Our goal was to determine the contribution of endogenously produced VIP to TNBS-colitis by using VIP knockout (KO) mice. METHODS: TNBS was intracolonically administered to wild-type (WT) and VIP KO mice, and weight loss and colitis were assessed over time. Colon histopathological changes and myeloperoxidase activities were analyzed and the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in colon and serum quantified. The proliferative response in vitro of splenocytes from TNBS WT and VIP KO administered mice to anti-CD3 and anti-CD28 was determined. RESULTS: VIP KO mice did not exhibit the predicted exacerbated response to TNBS. Instead, they developed a milder clinical profile than WT mice, with lower TNF-alpha and IL-6 levels. Such potential defects seem selective, because other parameters such as the histopathological scores and the cytokine levels in the colon did not differ between the two strains of mice. Moreover, splenocytes from TNBS-treated VIP KO mice exhibited an enhanced proliferative response to anti-CD3/CD28 stimulation in vitro. CONCLUSION: Chronic loss of VIP in mice leads to a disruption of certain but not all immunological compartments, corroborating recent findings that VIP KO mice exhibit reduced mortality in the lipopolysaccharide-induced endotoxemia model and attenuated clinical development of experimental autoimmune encephalomyelitis while developing robust T-cell responses. PMID- 25301383 TI - Pediatric lymphangiectasia: an imaging spectrum. AB - BACKGROUND: Lymphangiectasia is a rarely encountered lymphatic dysplasia characterized by lymphatic dilation without proliferation. Although it can occur anywhere, the most common locations are the central conducting lymphatics and the pulmonary and intestinal lymphatic networks. Recent advances in lymphatic interventions have resulted in an increased reliance on imaging to characterize patterns of disease. OBJECTIVE: To describe the patient populations, underlying conditions, and imaging features of lymphangiectasia encountered at a tertiary pediatric institution over a 10-year period and correlate these with pathology and patient outcomes. MATERIALS AND METHODS: We retrospectively reviewed the pathology database from 2002 to 2012 to identify patients with pathologically or surgically proven lymphangiectasia who had undergone cross-sectional imaging. Medical records were reviewed for patient demographics, underlying conditions, treatment and outcome. RESULTS: Thirteen children were identified, ranging in age from 1 month to 16 years. Five had pulmonary lymphangiectasia, four intestinal and four diffuse involvement. Pulmonary imaging findings include diffuse or segmental interlobular septal thickening, pleural effusions and dilated mediastinal lymphatics. Intestinal imaging findings include focal or diffuse bowel wall thickening with central lymphatic dilation. Diffuse involvement included dilation of the central lymphatics and involvement of more than one organ system. Children with infantile presentation and diffuse pulmonary, intestinal or diffuse lymphatic abnormalities had a high mortality rate. Children with later presentations and segmental involvement demonstrated clinical improvement with occasional regression of disease. Three children with dilated central lymphatics on imaging underwent successful lymphatic duct ligation procedures with improved clinical course. CONCLUSION: Lymphangiectasia is a complex disorder with a spectrum of presentations, imaging appearances, treatments and outcomes. Cross-sectional imaging techniques distinguish segmental involvement of a single system (pulmonary or intestinal) from diffuse disease and may show dilated central conducting lymphatics, which may benefit from interventions such as ligation or occlusion. PMID- 25301384 TI - Angiotensin-(1-7) modulates angiotensin II-induced vasoconstriction in human mammary artery. AB - PURPOSE: The renin-angiotensin system plays a key role in cardiovascular pathophysiology and one of its members, angiotensin-(1-7) (ANG-(1-7)), is now recognized as a peptide with the ability to counter-regulate angiotensin II (ANGII) effects. We sought to investigate ANG-(1-7) actions in human vessels, particularly its effect on ANGII-induced vasoconstriction in human mammary arteries (HMA). METHODS: Samples of HMA from patients submitted to coronary revascularization (22 patients, mean age 67 years) were cut into small rings, mounted in a myograph bath system, normalized and allowed to contract and dilate isometrically. In baseline experiments, the rings were incubated with ANG-(1-7) or vehicle, followed by increasing concentrations of ANGII. This protocol was repeated in the presence of A-779, PD123177, losartan and after mechanical endothelium removal. Western blot analysis and immunofluorescence were also performed in order to verify the presence of Mas receptor in HMA. RESULTS: ANG-(1 7) significantly attenuated ANGII-induced contraction, producing a maximal inhibition of approximately 65.2%. This effect was not abolished by A-779, PD123177 or endothelium removal. In the presence of losartan, ANGII response was attenuated and no differences were observed between ANG-(1-7) and vehicle treated rings. Finally, we observed, for the first time, that the Mas receptor is expressed in HMA endothelium. CONCLUSIONS: ANG-(1-7) significantly attenuates ANGII-induced vasoconstriction and, although the Mas receptor is expressed in HMA, this effect seems to be independent of its activation. Additionally, AT2 receptor and endothelium are not involved in this mechanism, which suggests a direct effect on smooth muscle cells. PMID- 25301385 TI - Prior knowledge influences on hippocampus and medial prefrontal cortex interactions in subsequent memory. AB - Prior knowledge is known to influence the encoding of new events. Specifically, recent theoretical frameworks suggest that positively correlated hippocampus (HC) medial prefrontal cortex (mPFC) activity is involved in creating enduring traces of events inconsistent with our prior knowledge. Events that are consistent with our schemas are suggested to be encoded via mPFC-cortical interactions. Previous studies examined differences in functional connectivity between subsequently remembered and forgotten items, but the source of these differences was not addressed. Therefore, the involvement of the inter-regions functional connectivity in subsequent remembering or subsequent forgetting of events is unknown. In this study, in addition to probing for a remembered-forgotten difference in functional connectivity, we also examined how connectivity differed from baseline in each of the memory conditions. At encoding, the participants were presented with pairs of semantically related (schema-consistent) and semantically unrelated (schema-inconsistent) words. A surprise recognition test was administered, and a subsequent memory analysis evaluating potential interactions with the HC and mPFC was conducted. Consistent with the suggested frameworks, subsequent memory modulated HC-mPFC connectivity only in schema inconsistent events. Importantly, the HC and mPFC were positively correlated with respect to subsequently remembered schema-inconsistent items, whereas the subsequently forgotten schema-inconsistent events did not differ from baseline. We also found that positively correlated activity of the mPFC with visual and parietal regions mediated subsequent memory of schema-inconsistent items. Therefore, inconsistent events may be encoded by a network of cortical and medial temporal lobe regions. PMID- 25301386 TI - Congenital absence of the mammillary bodies: a novel finding in a well-studied case of developmental amnesia. AB - Individuals with developmental amnesia experience compromised development of episodic memory for details of personal life events, believed to relate to changes to the hippocampus after birth. Here we report the very rare discovery of aplasia of the mammillary bodies, hypogenesis of the fornix, and abnormal hippocampal shape and orientation in H.C., a well-documented case of selectively compromised episodic memory development who is the subject of numerous published empirical articles. These anatomical abnormalities are highly suggestive of disrupted extended hippocampal system development very early in gestation, despite an original diagnosis of developmental amnesia and assumed perinatal hypoxia. These findings provide a unique window into the normal function of the mammillary bodies, fornices, and related anterior nuclei of the thalamus bilaterally. The results also encourage re-examination of the pathological basis of developmental amnesia in other cases reported in the literature. PMID- 25301387 TI - Evaluation of seismic performance and effectiveness of multiple slim-type damper system for seismic response control of building structures. AB - This paper presents the evaluation of seismic performance and cost-effectiveness of a multiple slim-type damper system developed for the vibration control of earthquake excited buildings. The multiple slim-type damper (MSD) that consists of several small slim-type dampers and linkage units can control damping capacity easily by changing the number of small dampers. To evaluate the performance of the MSD, dynamic loading tests are performed with three slim-type dampers manufactured at a real scale. Numerical simulations are also carried out by nonlinear time history analysis with a ten-story earthquake excited building structure. The seismic performance and cost-effectiveness of the MSD system are investigated according to the various installation configurations of the MSD system. From the results of numerical simulation and cost-effectiveness evaluation, it is shown that combinations of the MSD systems can effectively improve the seismic performance of earthquake excited building structures. PMID- 25301388 TI - [Residual subretinal perfluorocarbon liquid]. PMID- 25301390 TI - ANTONIA perfusion and stroke. A software tool for the multi-purpose analysis of MR perfusion-weighted datasets and quantitative ischemic stroke assessment. AB - OBJECTIVES: The objective of this work is to present the software tool ANTONIA, which has been developed to facilitate a quantitative analysis of perfusion weighted MRI (PWI) datasets in general as well as the subsequent multi-parametric analysis of additional datasets for the specific purpose of acute ischemic stroke patient dataset evaluation. METHODS: Three different methods for the analysis of DSC or DCE PWI datasets are currently implemented in ANTONIA, which can be case specifically selected based on the study protocol. These methods comprise a curve fitting method as well as a deconvolution-based and deconvolution-free method integrating a previously defined arterial input function. The perfusion analysis is extended for the purpose of acute ischemic stroke analysis by additional methods that enable an automatic atlas-based selection of the arterial input function, an analysis of the perfusion-diffusion and DWI-FLAIR mismatch as well as segmentation-based volumetric analyses. RESULTS: For reliability evaluation, the described software tool was used by two observers for quantitative analysis of 15 datasets from acute ischemic stroke patients to extract the acute lesion core volume, FLAIR ratio, perfusion-diffusion mismatch volume with manually as well as automatically selected arterial input functions, and follow-up lesion volume. The results of this evaluation revealed that the described software tool leads to highly reproducible results for all parameters if the automatic arterial input function selection method is used. CONCLUSION: Due to the broad selection of processing methods that are available in the software tool, ANTONIA is especially helpful to support image-based perfusion and acute ischemic stroke research projects. PMID- 25301389 TI - Ultrafast intersystem crossing dynamics in uracil unravelled by ab initio molecular dynamics. AB - Ab initio molecular dynamics simulations have been performed in order to investigate the relaxation dynamics of uracil after UV excitation in gas phase. Intersystem crossing (ISC) has been included for the first time into time dependent simulations of uracil, allowing the system to relax in the singlet as well as in the triplet states. The results show a qualitatively different picture than similar simulations that include singlet states only. The inclusion of ISC effectively quenches the relaxation to the singlet ground state and instead privileges transitions from the low-lying npi* state (S1) to a pipi* triplet state (T2) followed by rapid internal conversion to the lowest triplet state. PMID- 25301391 TI - Molecular docking and dynamics simulation analyses unraveling the differential enzymatic catalysis by plant and fungal laccases with respect to lignin biosynthesis and degradation. AB - Laccase, widely distributed in bacteria, fungi, and plants, catalyzes the oxidation of wide range of compounds. With regards to one of the important physiological functions, plant laccases are considered to catalyze lignin biosynthesis while fungal laccases are considered for lignin degradation. The present study was undertaken to explain this dual function of laccases using in silico molecular docking and dynamics simulation approaches. Modeling and superimposition analyses of one each representative of plant and fungal laccases, namely, Populus trichocarpa and Trametes versicolor, respectively, revealed low level of similarity in the folding of two laccases at 3D levels. Docking analyses revealed significantly higher binding efficiency for lignin model compounds, in proportion to their size, for fungal laccase as compared to that of plant laccase. Residues interacting with the model compounds at the respective enzyme active sites were found to be in conformity with their role in lignin biosynthesis and degradation. Molecular dynamics simulation analyses for the stability of docked complexes of plant and fungal laccases with lignin model compounds revealed that tetrameric lignin model compound remains attached to the active site of fungal laccase throughout the simulation period, while it protrudes outwards from the active site of plant laccase. Stability of these complexes was further analyzed on the basis of binding energy which revealed significantly higher stability of fungal laccase with tetrameric compound than that of plant. The overall data suggested a situation favorable for the degradation of lignin polymer by fungal laccase while its synthesis by plant laccase. PMID- 25301393 TI - Counter-current motion in counter-current chromatography. AB - After the CCC2012 meeting, I have received an e-mail regarding the terminology of "Countercurrent Chromatography". It stated that the term "Countercurrent" is a misnomer, because its stationary phase is motionless in the column and that the method should be renamed as liquid-liquid separations or centrifugal separations. However, it was found that these names are already used for various other techniques as found via Google search. The term "Countercurrent Chromatography" was originally made after two preparative methods of Countercurrent distribution and liquid Chromatography, both having no countercurrent motion in the column. However, it is surprising to find that this F1 hybrid method "Countercurrent Chromatography" can clearly exhibit countercurrent motion within the separation column in both hydrodynamic and hydrostatic equilibrium systems. This justifies that "Countercurrent Chromatography" is a proper term for this chromatographic method. PMID- 25301392 TI - Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes. AB - AIMS/HYPOTHESIS: Type 1 diabetes results from T cell-mediated destruction of pancreatic beta cells. The mechanisms of beta cell destruction in vivo, however, remain unclear. We aimed to test the relative roles of the main cell death pathways: apoptosis, necrosis and necroptosis, in beta cell death in the development of CD4(+) T cell-mediated autoimmune diabetes. METHODS: We altered expression levels of critical cell death proteins in mouse islets and tested their ability to survive CD4(+) T cell-mediated attack using an in vivo graft model. RESULTS: Loss of the B cell leukaemia/lymphoma 2 (BCL-2) homology domain 3 only proteins BIM, PUMA or BID did not protect beta cells from this death. Overexpression of the anti-apoptotic protein BCL-2 or combined deficiency of the pro-apoptotic multi-BCL2 homology domain proteins BAX and BAK also failed to prevent beta cell destruction. Furthermore, loss of function of the death receptor Fas or its essential downstream signalling molecule Fas-associated death domain (FADD) in islets was also not protective. Using electron microscopy we observed that dying beta cells showed features of necrosis. However, islets deficient in receptor-interacting serine/threonine protein kinase 3 (RIPK3), a critical initiator of necroptosis, were still normally susceptible to CD4(+) T cell-mediated destruction. Remarkably, simultaneous inhibition of apoptosis and necroptosis by combining loss of RIPK3 and overexpression of BCL-2 in islets did not protect them against immune attack either. CONCLUSIONS/INTERPRETATION: Collectively, our data indicate that beta cells die by necrosis in autoimmune diabetes and that the programmed cell death pathways apoptosis and necroptosis are both dispensable for this process. PMID- 25301394 TI - Quantum percolation and transition point of a directed discrete-time quantum walk. AB - Quantum percolation describes the problem of a quantum particle moving through a disordered system. While certain similarities to classical percolation exist, the quantum case has additional complexity due to the possibility of Anderson localisation. Here, we consider a directed discrete-time quantum walk as a model to study quantum percolation of a two-state particle on a two-dimensional lattice. Using numerical analysis we determine the fraction of connected edges required (transition point) in the lattice for the two-state particle to percolate with finite (non-zero) probability for three fundamental lattice geometries, finite square lattice, honeycomb lattice, and nanotube structure and show that it tends towards unity for increasing lattice sizes. To support the numerical results we also use a continuum approximation to analytically derive the expression for the percolation probability for the case of the square lattice and show that it agrees with the numerically obtained results for the discrete case. Beyond the fundamental interest to understand the dynamics of a two-state particle on a lattice (network) with disconnected vertices, our study has the potential to shed light on the transport dynamics in various quantum condensed matter systems and the construction of quantum information processing and communication protocols. PMID- 25301395 TI - Heat shock protein 47 is up-regulated in conjunctival bleb scarring after filtration surgery in rats. AB - BACKGROUND: Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is involved in the biosynthesis and secretion of procollagen. Recent studies have shown a close association between increased HSP47 and excessive accumulation of collagens in various fibrotic diseases. This study was conducted to evaluate whether HSP47 plays a role in conjunctival bleb scarring after filtration surgery in rats. METHODS: Trabeculectomy of the right eye was performed in Sprague-Dawley (SD) rats. Eight rats were euthanized at 2, 5, 8 and 11 days after surgery. Four rats were used to extract mRNA and the other four were used to extract protein. Blebs and normal control conjunctival tissues were collected. Real-time PCR (RT-PCR) and Western blot methods were used to evaluate alterations in HSP47 levels and type I and type III collagen. RESULTS: Bleb formation was observed in all eyes. Both the expression of HSP47 mRNA and protein in conjunctival blebs increased at 2, 5, 8 and 11 days postoperatively compared with that in normal control conjunctival tissues. The differences of both the mean mRNA and protein levels of HSP47 in blebs at each time point and in the normal control conjunctiva were statistically significant (mRNA level: F = 175.811, p < 0.001; protein level: F = 68.356, p < 0.001). Type I and type III collagen levels in blebs were raised at different time points both at mRNA and at protein levels. The differences between mean mRNA and protein levels of both type I and type III collagen in blebs at 2, 5, 8 and 11 days after surgery and in the normal control conjunctiva were statistically significant (mRNA level: FI = 182.210, p I < 0.001; FIII = 125.490, p III < 0.001; protein level: FI = 160.092, p I < 0.001; FIII = 62.374, p III < 0.001 ). The amount of HSP47 in bleb positively correlated with that of both type I and type III collagens (mRNA level: rsI = 0.688, p I = 0.003; rsIII = 0.900, p III < 0.001; protein level: rsI = 0.688, p I = 0.003; rsIII = 0.832, p III < 0.001). CONCLUSIONS: HSP47 is likely to be involved in the pathogenesis of conjunctival bleb scarring and may play a role in the process of conjunctival bleb fibrosis. PMID- 25301396 TI - Effect of enhanced extracorporeal counterpulsation in patients with non-arteritic anterior ischaemic optic neuropathy. AB - PURPOSE: The purpose is to study the effect of Enhanced Extracorporeal Counterpulsation (EECP) in patients with non-arteritic anterior ischaemic optic neuropathy (NAION). METHODS: EECP is a noninvasive, mechanical, and circulatory support therapy. Sixteen patients with unilateral NAION were treated with EECP (twelve 1-h daily treatment sessions for each patient). Color Doppler imaging (CDI) was applied to measure the mean flow velocity (MFV), peak-systolic velocity (PSV), end-diastolic velocity (EDV) of the ophthalmic artery (OA) and central retinal artery (CRA). Intraocular pressure (IOP) was measured by Goldmann applanation tonometry. Measurements were collected before and immediately after the first and the last sessions of EECP in both eyes, and they were compared with the baseline measurement before EECP. The measurements were also compared between the NAION eyes and the normal fellow eyes. Visual acuity (VA) and visual field (VF) were assessed before EECP and after the last EECP. RESULTS: EECP progressively increased blood flow velocities of the OA and CRA and progressively decreased IOP in both eyes (P < 0.05). After the first session of EECP, there was a 16 +/- 5.3% increase in EDV and a 13.9 +/- 9.5% increase in MFV of the OA, and a 17.1 +/- 2.5% increase in PSV, a 21.2 +/- 9.3% increase, in EDV and a 16.5 +/- 3.3% increase in MFV of the CRA in NAION eyes. After the last EECP treatment, there was a 16.8 +/- 6.7% increase in EDV and a 14.0 +/- 5.1% increase in MFV of the OA, and a 17.7 +/- 12.3 % increase in PSV, a 23.1 +/- 6.3% increase in DSV, and a 21.1 +/- 8.4% increase in MFV of the CRA in NAION eyes (P < 0.05). The change of the PSV, EDV, and MFV in the CRA were more significant in NAION eyes than that of their fellow eyes (P < 0.05). VA was improved and VF mean deviation was decreased in NAION eyes after the last EECP treatment (P = 0.003 and 0.049, respectively), and VA improvement was correlated positively with the blood flow parameter. CONCLUSIONS: EECP could be a clinically effective and safe treatment for NAION. PMID- 25301397 TI - The role of rarebit perimetry in evaluation of functional outcome after successful macular hole and epiretinal membrane surgery. PMID- 25301399 TI - Use of a bivalve finger fracture orthosis for a new treatment protocol of a PIP comminuted fracture and dorsal dislocation. AB - As therapists and physicians, we often need to work with our patients to cater treatment accordingly. These authors describe how they modified a treatment protocol for a patient that sustained a proximal interphalangeal joint comminuted fracture and dorsal dislocation, but refused surgery. Their modification allowed the patient to return to full activities. - Victoria Priganc, PhD, OTR, CHT, CLT, Practice Forum Editor. PMID- 25301398 TI - Effects of antioxidant gene therapy on the development of diabetic retinopathy and the metabolic memory phenomenon. AB - PURPOSE: The purpose of this study was to determine the therapeutic effect and mechanism of AAV-MnSOD by intravitreal injection on diabetic retinopathy (DRP) and the metabolic memory phenomenon. METHODS: The effect of hyperglycemia and metabolic memory on the thickness of basement membrane, ratio of pericyte area and cross-sectional area of capillary vessels in the nerve fiber layer and outer plexiform layer; retinal capillary cell apoptosis; number of acellular capillaries and activities of retinal MnSOD and catalase were examined and compared with intravitreal injection of AAV-MnSOD by transmission electron microscopy, TUNEL assay, ELISA, and immunohistochemistry. RESULTS: Hyperglycemia increased the thickness of capillary basement membranes in the nerve fiber layer and outer plexiform layer, decreased the ratio of pericyte area and cross sectional area of capillary vessels, increased numbers of acellular capillaries and apoptosis of retinal capillary cells, and decreased activities of retinal MnSOD and catalase. Termination of hyperglycemia cannot reverse pathological changes listed above. Intra-vitreal injection of AAV-MnSOD dramatically elevated the level and activities of retinal MnSOD and catalase, and effectively prevented the progression of DRP and the metabolic memory phenomenon. CONCLUSIONS: Increasing reactive oxygen species concentration and continuous decreasing of antioxidant enzyme activity play important roles in DRP and the metabolic memory phenomenon. AAV-MnSOD gene therapy provides a promising strategy to inhibit this blinding disease. PMID- 25301400 TI - Characterization of human Influenza Viruses in Lebanon during 2010-2011 and 2011 2012 post-pandemic seasons. AB - OBJECTIVE: To genetically characterize human influenza viruses and their susceptibilities to antivirals during two post-pandemic seasons in Lebanon. METHODS: Influenza virus was isolated from nasopharyngeal swabs that were obtained from patients with influenza-like illness during 2010-2012 and further analyzed both phenotypically and genotypically. RESULTS: During the 2010-2011 season, both 2009 pandemic H1N1 (H1N1p) and B viruses co-circulated with equal prevalence, while the H3N2 virus predominated during the 2011-2012 season. All H3N2 and H1N1 viruses were resistant to amantadine. Importantly, all viruses of the influenza A and B types were susceptible to the neuraminidase (NA) inhibitors oseltamivir, zanamivir, peramivir, and laninamivir. Nonetheless, all 2011-2012 H1N1p isolates had three mutations (V241I, N369K, and N386S) in the NA gene that were suggested to be permissive of the H275Y mutation, which confers resistance to oseltamivir. We also detected one H1N1p virus during the 2010-2011 season with a 4-fold decrease in susceptibility to oseltamivir due to an NA-S247N mutation. This isolate was phylogenetically distinct from other H1N1p viruses that were isolated in other regions. CONCLUSIONS: Influenza A viruses with reduced susceptibility to oseltamivir and mutations permissive for acquiring NA resistance-conferring mutation with minimal burden on their fitness were isolated in Lebanon. PMID- 25301401 TI - Diagnostic performance and comparative cost-effectiveness of non-invasive imaging tests in patients presenting with chronic stable chest pain with suspected coronary artery disease: a systematic overview. AB - Several non-invasive imaging techniques are currently in use for the diagnostic workup of adult patients with stable chest pain suspected of having coronary artery disease (CAD). In this paper, we present a systematic overview of the evidence on diagnostic performance and comparative cost-effectiveness of new modalities in comparison to established technologies. A literature search for English language studies from 2009 to 2013 was performed, and two investigators independently extracted data on patient and study characteristics. The reviewed published evidence on diagnostic performance and cost-effectiveness support a strategy of CTCA as a rule out (gatekeeper) test of CAD in low- to intermediate risk patients since it has excellent diagnostic performance and as initial imaging test is cost-effective under different willingness-to-pay thresholds. More cost-effectiveness research is needed in order to define the role and choice of cardiac stress imaging tests. PMID- 25301402 TI - Feasibility of neonatal pulse wave velocity and association with maternal hemoglobin A1c. AB - BACKGROUND: Use of non-invasive peripheral arterial tonometry to assess arterial stiffness has not been studied in neonates. Perinatal factors impact childhood vascular health, but the effect in neonates remains to be examined. OBJECTIVES: To examine the feasibility of pulse wave velocity (PWV) among healthy term neonates, and to evaluate the effects of perinatal factors on neonatal PWV. METHODS: Pregnant women with singleton gestation presenting for routine care were enrolled. Postnatally, PWV measurements of their neonates were obtained using an arterial tonometer. A variability index was calculated for each PWV measurement. Intra- and inter-observer reproducibility were illustrated with Bland-Altman plots. Medical records were reviewed. Relationships between neonatal PWV and perinatal factors were examined. RESULTS: PWV measurements were attempted in 76 neonates and successfully obtained in 67 (88%). Using PWV measurements with a variability index <= 0.25 (48 neonates), the intra-class coefficient was 0.69. The mean differences (limits of agreement) for intra- and inter-rater reproducibility were 0.02 (-3.64 to 3.60) and 0.34 (-2.23 to 2.39), respectively. Median neonatal PWV was 2.80 m/s (range 0.60-8.40). Neonates of mothers with HgbA1c >=6% had significantly higher PWV than neonates of mothers with HgbA1c <6% (4.12 m/s, 95% CI 3.22-5.02, vs. 2.78 m/s, 95% CI 2.28-3.28, p = 0.02). CONCLUSIONS: Neonatal PWV using peripheral arterial tonometry is feasible and reproducible when using measurements with a variability index <= 0.25. Neonates of mothers with increased HgbA1c had higher PWV, suggesting an effect of maternal hyperglycemia on neonatal vasculature. The long-term implications of this finding warrant further investigation. PMID- 25301403 TI - Gene expression differences in primary colorectal tumors and matched liver metastases: chemotherapy related or tumoral heterogeneity? AB - BACKGROUND: Treatment of metastatic colorectal cancer (mCRC) is generally based on genetic testing performed in primary tumor biopsies, but whether the genomic status of primary tumors is identical to that of metastases is not well known. We compared the gene expression profiles of formalin-fixed paraffin-embedded (FFPE) biopsies of colorectal primary tumors and matched liver metastases. PATIENTS AND METHODS: We compared the expression of 18 genes in FFPE CRC tumors and their matched liver metastases from 32 patients. The expression of each gene in CRC primary tumors and their matched liver metastases was tested using Student's t test for paired samples. Pairwise correlations of each gene in the primary tumors and matched liver metastases were evaluated by Pearson's correlation coefficient. RESULTS: The expression of six genes was significantly different in primary tumors compared with their matched liver metastases [CXCR4 (p < 0.001), THBS1 (p = 0.007), MMP 9 (p = 0.048), GST Pi (p = 0.050), TYMP (p = 0.042) and DPYD (p < 0.001)]. For the remaining genes, where no significant differences were observed, only SMAD4 (r s = 0.447, p = 0.010), ERCC1 (r s = 0.423, p = 0.016) and VEGF A (r s = 0.453, p = 0.009) showed significant correlation in expression between the two tissues. Therefore, we only detected similar gene expression levels between the tumor and the metastases in these three markers. CONCLUSIONS: We only found similar gene expression levels between the tumor and the metastases in three genes (SMAD4, ERCC1, and VEGF A). However, our study could not assess whether the differences in gene expression were secondary to tumoral heterogeneity or to molecular changes induced by previous chemotherapy. PMID- 25301404 TI - A 50-gene signature is a novel scoring system for tumor-infiltrating immune cells with strong correlation with clinical outcome of stage I/II non-small cell lung cancer. AB - PURPOSE: To identify a novel system for scoring intratumoral immune response that can improve prognosis and therapy decisions in early stage non-small cell lung cancer (NSCLC). METHODS/PATIENTS: Eighty-four completely resected stage I/II NSCLC without adjuvant therapy were classified by expression profiling using whole genome microarrays. An external cohort of 162 tumors was used to validate the results. Immune cells present in tumor microenvironment were evaluated semiquantitatively by CD20, CD79, CD3, CD8, CD4 and CD57 immunostaining. Univariate and multivariate analyses of variables associated with recurrence-free survival were performed. RESULTS: Initial molecular classification identified three clusters, one with significantly better RFS. A reduced two-subgroup classification and a 50-gene predictor were built and validated in an external dataset: high and low risk of recurrence patients (HR = 3.44; p = 0.001). Analysis of the predictor's genes showed that the vast majority were related to a B/plasma cell immune response overexpressed in the low-risk subgroup. The predictor includes genes coding for unique B lineage-specific genes, functional elements or other genes that, although non-restricted to this lineage, have strong influence on B-cell homeostasis. Immunostains confirmed increased B-cells in the low-risk subgroup. Gene signature (p < 0.0001) and CD20 (p < 0.05) were predictors for RFS, while CD79 and K-RAS mutations showed a tendency. CONCLUSIONS: Favorable prognosis in completely resected NSCLC is determined by a B-cell-mediated immune response. It can be differently scored by a 50-gene expression profile or by CD20 immunostaining. That prognosis information not reflected by traditional classifications may become a new tool for determining individualized adjuvant therapies. PMID- 25301406 TI - Pharmacogenetics and immunosuppressive drugs. AB - Several candidate genes have been proposed as potential biomarkers for altered pharmacodynamics or pharmacokinetics of immunosuppressive drugs. However, there is usually only limited clinical evidence substantiating the implementation of biomarkers into clinical practice. Testing for thiopurine-S-methyltransferase polymorphisms has been put into routine clinical use quite widely, while the other pharmacogenetic tests are much less frequently used. Relatively good evidence appeared for tacrolimus-related biomarkers; thus, their utilization may be envisaged in the near future. Although the biomarkers related to mycophenolate, sirolimus or other drugs in the therapeutic class may be promising, further research is necessary to provide more robust evidence. The present review focuses on immunosuppressive drugs, excluding biological treatment. PMID- 25301405 TI - High serum microRNA-335 level predicts aggressive tumor progression and unfavorable prognosis in pediatric acute myeloid leukemia. AB - PURPOSE: MiRNA expression profiles previously showed the higher expression of microRNA(miR)-335 in bone marrow samples of pediatric acute myeloid leukemia (AML) patients than normal controls. Our aim was to investigate associations of miR-335 expression with tumor progression and prognosis in pediatric AML. METHODS: Real-time quantitative PCR was performed to detect the expression of miR 335 in bone marrow mononuclear cells and serum obtained from patients with pediatric AML and healthy controls. RESULTS: Expression levels of miR-335 in the bone marrow and serum of pediatric AML patients were both significantly higher than those in normal controls (both P < 0.001). Then, high serum miR-335 level occurred more frequently in French-American-British classification subtype M7 subtype than in other subtypes (P = 0.03). The expression of serum miR-335 in pediatric AML patients with unfavorable karyotypes was also significantly higher than those in intermediate and favorable groups (P = 0.008). Moreover, high serum miR-335 level was markedly associated with shorter relapse-free and overall survivals (both P < 0.001) of patients with pediatric AML. Furthermore, the multivariate analysis identified the serum miR-335 and cytogenetics risk as independent prognostic factors for both relapse-free and overall survivals. More importantly, the prognostic relevance of serum miR-335 expression was more obvious in the subgroup of patients with intermediate-risk cytogenetics. CONCLUSION: Our data offer the convincing evidence for the first time that serum miR-335 level may be markedly and consistently increased in pediatric AML patients. Serum miR-335 may serve as a promising marker for monitoring the progression and predicting the clinical outcome of patients with this disease. PMID- 25301407 TI - Letter to the editor on "A comparison of primary and delayed wound closure in severe open tibial fractures initially treated with internal fixation and vacuum assisted wound coverage: A case-controlled study". PMID- 25301408 TI - Kinetics of precursor labeling in stable isotope labeling in cell cultures (SILAC) experiments. AB - Recent advances in mass spectrometry have enabled proteome-wide analyses of cellular protein turnover. These studies have been greatly propelled by the development of stable isotope labeling in cell cultures (SILAC), a set of standardized protocols, reagents aimed at quantifying the incorporation of (15)N/(13)C labeled amino acids into proteins. In dynamic SILAC experiments, the degree of isotope incorporation in proteins is measured over time and used to determine turnover kinetics. However, the kinetics of isotope incorporation in proteins can potentially be influenced not only by their intracellular turnover but also by amino acid uptake, recycling and aminoacyl-tRNA synthesis. To assess the influence of these processes in dynamic SILAC experiments, we have measured the kinetics of isotopic enrichment within intracellular free amino acid and aminoacyl-tRNA precursor pools in dividing and division-arrested neuroblastoma cells following the introduction of extracellular (15)N labeled amino acids. We show that the total flux of extracellular amino acids into cells greatly exceeds that of intracellular amino acid recycling and synthesis. Furthermore, in comparison to internal sources, external amino acids are preferentially utilized as substrates for aminoacyl-tRNA precursors for protein synthesis. As a result, in dynamic SILAC experiments conducted in culture, the aminoacyl-tRNA precursor pool is near completely labeled in a few hours and protein turnover is the limiting factor in establishing the labeling kinetics of most proteins. PMID- 25301409 TI - Laparoscopic surgical technique for gastric fistula after sleeve gastrectomy with video. PMID- 25301410 TI - Characteristics of candidates for lung transplantation due to chronic obstructive pulmonary disease and alpha-1 antitrypsin deficiency emphysema. AB - INTRODUCTION: COPD and emphysema due to alpha-1 antitrypsin deficiency (AATD) are the first and fourth indications for lung transplantation worldwide, respectively. Despite this, there is little information regarding the health status of these patients at the time of transplantation. METHODS: Patients who received a lung transplant in the Hospital Vall d'Hebron between July 1993 and August 2013 were identified and data from the evaluation prior to the transplant were collected. RESULTS: A total of 217 patients who received a lung transplant for COPD and 19 in whom the indication was AATD were included. These patients were severely impaired at the time of the evaluation for lung transplantation, although the trend in recent years has been to evaluate patients at earlier stages of the disease. Baseline characteristics were similar in both groups except that patients with AATD were younger [43 (7.7) vs. 53.6 (6.1) years old, P<.001], with less exposure to tobacco [23.9 (15) vs. 50 (29) packs-year, P<002] and lower PCO2 [41.7 (7.6) vs. 47.9 (9.7) mmHg, P<.004]. CONCLUSIONS: The number of patients receiving a lung transplant for COPD has progressively increased and the tendency is to perform the evaluation in earlier stages of the disease. Patients receiving transplants for COPD and AATD had similar characteristics at the time of the evaluation, although AATD patients were younger and had less exposure to tobacco and lower PCO2. PMID- 25301411 TI - Procollagen Type I and III Aminoterminal Propeptide Levels and Severity of Interstitial Lung Disease in Mexican Women With Progressive Systemic Sclerosis. AB - BACKGROUND: Interstitial lung disease (ILD) is a frequent complication in progressive systemic sclerosis (SSc), being present in 25% to 90% of cases. OBJECTIVES: To evaluate whether serum levels of procollagen typei and iii aminoterminal propeptide (PINP and PIIINP) correlate with severity and patterns of ILD in Mexican women with SSc. METHODS: Thirty three SSc patients were assessed for disease characteristics and anti-topoisomerase antibodies (topoi), and also underwent pulmonary function tests and high-resolution computed tomography (HRCT). Nineteen patients had ILD+SSc, and 14 had no lung involvement (no ILD-SSc); data were compared with those from 45 healthy controls. PINP and PIIINP were assessed in all 3 groups. RESULTS: Patients with SSc had higher PINP and PIIINP vs controls (P=.001, P<.001, respectively). Compared to no ILD-SSc patients, those with ILD+SSc had longer disease duration in years (P=.005), higher modified Rodnan skin score (P<.001), higher Health Assessment Questionnaire-Disability-Index scores (P<.001), higher topoi U/mL (P<.001), PINP (49.28+/-28.63 vs. 32.12+/-18.58MUg/L, P=.05), and PIIINP (4.33+/-1.03 vs. 2.67+/ 1.26MUg/L, P<.001) levels. ILD severity based on total HRCT correlated with PINP (r=.388, P=.03) and PIIINP (P=.594, P<.001). On adjusted analysis, ILD severity was associated with disease duration (P=.037), PIIINP (P=.038), and topoi (P=.045). CONCLUSIONS: PINP and PIIINP are useful markers for severe ILD+SSc, suggesting they could play a role in the follow-up of this complication in SSc. PMID- 25301412 TI - Combination of tracheal bronchus and partial anomalous pulmonary venous return in a patient with type 1 neurofibromatosis and ipsilateral vagal nerve neurofibroma. PMID- 25301413 TI - Sternal tuberculosis: the role of imaging. PMID- 25301415 TI - Hsp90 inhibitors in oncology: ready for prime time? PMID- 25301414 TI - A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD. AB - Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin 3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders. PMID- 25301416 TI - Lead-time models produce far too low estimates of overdiagnosis with mammographic screening. PMID- 25301417 TI - Torrential epistaxis in the third trimester: a management conundrum. AB - Although epistaxis is common during pregnancy, large volume epistaxis is rare. Many standard epistaxis management options are limited in pregnancy due to absolute or relative contraindications. Ear, nose and throat surgeons need to be aware of what options can be used safely and effectively. We present a case of a 32-year-old woman, 32 weeks pregnant, who was admitted with heavy epistaxis refractive to conservative management. Several potential interventions including bismuth iodoform paraffin paste (BIPP) and Floseal were contraindicated or involved additional risk in pregnancy necessitating unorthodox management. This challenging case highlights suitable alternatives for managing large volume epistaxis during pregnancy, as well as discussing the differential diagnosis and relevant investigations. PMID- 25301418 TI - Subepicardial haematoma, a rare and potentially lethal complication of CTO-PCI: case of an exceptional recovery after conservative management. AB - We present the case of an 82-year-old woman undergoing high-risk chronic total occlusion percutaneous coronary intervention (CTO-PCI) of the right coronary artery. Hours after the procedure, a subepicardial haematoma was diagnosed as a result of coronary perforation during the procedure. This rare and potentially lethal complication evolved exceptionally benignly after conservative management; our patient fully recovered. Increasingly complex procedures in high-risk patient categories warrant awareness of procedural complications, especially those that are subtle and appear relatively late, and are therefore most hazardous. Recognition of this rare complication and choosing the optimal strategy is of the utmost importance when dealing with patients who undergo PCI. We here describe the rare case of a potential lethal complication in high-risk CTO-PCI, which evolved relatively benignly. PMID- 25301419 TI - Bronchopleural fistula following laparoscopic liver resection. AB - A rare case is presented of a 58-year-old woman who developed a bronchopleural fistula following a laparoscopic liver resection for a colorectal metastasis. The bronchopleural fistula was finally diagnosed when after repeated admissions for chest infections, the patient coughed up surgical clips. We propose a management plan based on our experience and hope this case report will add to the scarce reports of postoperative bronchopleural fistula cases in the literature. PMID- 25301420 TI - Shortness of breath in a patient with inflammatory bowel disease. AB - Cytomegalovirus (CMV) is an important cause of morbidity and mortality in immunocompromised patients. Although immunosuppressive therapy is the mainstay of medical treatment for patients with inflammatory bowel disease, the importance of CMV as a cause of pneumonia in this group is less well recognised. This case report presents a case of shortness of breath, dyspnoea and fever in a 51-year old man with Crohn's disease on azathioprine and highlights the importance of considering CMV as a cause of pneumonia in this group. PMID- 25301421 TI - A systemic disease un...suspected by physical examination. AB - A 73-year-old man was admitted to the cardiology department with unstable angina. He had a history of macroglossia with 3 years of development, attributed to hypothyroidism. On physical examination, he presented an exuberant macroglossia. The following diagnostic procedures were performed-ECG, in sinus rhythm with low voltage criteria, and transthoracic echocardiography, which revealed a left ventricle with preserved function and marked wall thickening, with low strain values in basal segments. The coronary angiography confirmed a lesion of 90% in the right coronary artery, treated with two stents. Suspecting a systemic infiltrative disease, additional tests were performed and these revealed the presence of systemic amyloid light-chain (AL) amyloidosis with cardiac involvement, associated with multiple myeloma. The patient was sent to a consult of haematology to begin chemotherapy. PMID- 25301422 TI - A generalised sensation of coldness following introduction of rosuvastatin therapy. AB - Rosuvastatin is the most potent 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor commercially available to lower low-density lipoprotein cholesterol. Rosuvastatin has been associated with several adverse effects, including rhabdomyolysis and arthralgias. Here, we report an unusual adverse effect occurring on treatment with rosuvastatin, a 'continuous sensation of coldness'. A 60-year-old man began experiencing this peculiar feeling shortly after introduction of rosuvastatin treatment. The gentleman had to wear extra pair of socks and cover himself with blankets while reading, even during summer with surrounding temperature above 30 degrees C. The abnormal sensation persisted for the 26 months during which he was treated with rosuvastatin, and disappeared within a week after discontinuing treatment. Physical examination, including thorough neurological examination, was entirely normal, as were haematological and biochemical parameters. While the pathophysiology of this phenomenon remains unknown, we hope that this case will encourage others to report similar symptomatology, perhaps enabling to gain more insight on the condition. PMID- 25301423 TI - Parasitised large intestinal diverticulum of the spermatic cord. AB - We present a 70-year-old male patient with an unusual incidental finding at an elective repair of an indirect left inguinal hernia (LIH). A black nodule resembling a melanoma metastasis in a lymph node was discovered attached to the spermatic cord. There was no contiguity with the large bowel on the same side. Histological examination showed an isolated, detached colonic diverticulum containing a faecolith. We postulate derivation from an incarcerated colonic diverticulum that became 'parasitised' onto the spermatic cord. PMID- 25301424 TI - TAPVR in a kindergartner presenting with fatigue. AB - We present a case of late diagnosis of cyanotic heart disease in a kindergartner, as a contemporary reminder of the importance of the history and clinical examination in the assessment of paediatric patients. In addition, this case illustrates the complementary diagnostic value of various cardiac imaging modalities in understanding pulmonary venous drainage. PMID- 25301425 TI - Management of mucosal fenestration with external root resorption by multidisciplinary approach. AB - Mucosal fenestration is a clinical condition in which the overlying gingiva is denuded and the root is exposed to the oral cavity. Invasive cervical resorption is an entirely uncommon entity and its aetiology is poorly understood. This case presents an invasive cervical resorption of maxillary right central incisor with fenestration at the cervical third of the tooth. The resorption area was chemomechanically debrided. It was then restored with Mineral Trioxide Aggregate over which pink glass ionomer cement (GC Fuji VII) was placed. Lateral pedicle flap was used to cover the fenestration. The resorptive defect was restored using tooth coloured restorative resin after removal of the pink glass ionomer cement. Orthodontic treatment was continued for correction of malocclusion. PMID- 25301426 TI - Management of ischiopubic stress fracture in patients with anorexia nervosa and excessive compulsive exercising. AB - This case report describes a 28-year-old non-athlete female patient with anorexia nervosa who was diagnosed with an ischiopubic ramus stress fracture and treated successfully as an inpatient with a cognitive behaviour-based therapy. The patient's clinical picture, diagnosis and treatment are described, and a brief review of the relevant literature is included. The importance of this case report stems from the rarity of descriptions of this kind of injury in such patients, despite their inherent risk, and the originality of the treatment applied. This, in addition to the usual approach to medical management, exploited specific cognitive and behavioural procedures and strategies to address the patient's excessive compulsive exercising, promoting rest and movement avoidance in order to allow the fracture to heal, while simultaneously addressing the underlying psychopathology. PMID- 25301427 TI - A rare cause of hyperthyroidism: functioning thyroid metastases. AB - Hyperthyroidism is a common medical problem that is readily treated with antithyroid medications. However, attributing the correct aetiology of hyperthyroidism alters management and outcome. We present a case of a 66-year-old woman with a seemingly common problem of hyperthyroidism associated with a goitre, which was initially attributed to a toxic nodule. However, Tc-99m pertechnetate uptake scan and thyroid-stimulating hormone receptor antibody were negative, inconsistent with a toxic nodule or Grave's disease. Her thyroid function tests proved difficult to control over the next few months. She eventually proceeded to a total thyroidectomy and histology revealed follicular variant papillary thyroid carcinoma. She was started on levothyroxine postoperatively but developed severe hyperthyroidism, revealing the cause of hyperthyroidism to be autonomously functioning thyroid metastases. Although functioning thyroid metastases are very rare, they need to be considered among the differential diagnoses of hyperthyroidism, as there are nuances in management that could alter the eventual outcome. PMID- 25301428 TI - Isaacs' syndrome in pregnancy. AB - Isaacs' syndrome is a rare neuromuscular disorder of continuous muscle fibre activity resulting from peripheral nerve hyperexcitability. Symptoms commonly include myokymia (muscle twitching at rest), pseudomyotonia (delayed muscle relaxation), muscle cramps and stiffness. It is caused by voltage-gated potassium channel dysfunction and may be inherited or acquired. Treatment commonly includes anticonvulsants, immunosuppressive therapy and plasma exchange. To date only two cases of Isaacs' syndrome in pregnancy have been reported. We present a case of maternal Isaacs' along with a review of the literature. There are few reports of Isaacs' syndrome in pregnancy, but all are associated with favourable outcomes. Given the autosomal dominant inheritance pattern, genetic counselling of the gravida is recommended. Anticonvulsant may have to be used in pregnancy, and given the potential teratogenicity with several of these agents; preference should be given to newer drugs such as lamotrigine. PMID- 25301429 TI - Cherubism with multiple dental abnormalities: a rare presentation. AB - Cherubism is a progressive, hereditary fibro-osseous lesion exclusively affecting the jaw bones. It is caused by the abnormal functioning of osteoblasts and osteoclasts, leading to replacement of normal bone by cellular fibrous tissue and immature bone, which produces painless progressive growth of the jaw, with a round facial appearance. It was first described in 1933 by Jones as 'familial multilocular cystic disease of the jaws'. The term 'cherubism' was later coined to describe the rounded facial appearance resulting from jaw hypertrophy that was reminiscent of cherubs depicted throughout Renaissance art. The bony lesions generally occur at an early age, affect one or both jaws symmetrically, and grow progressively until puberty. Spontaneous regression is seen in most cases, although surgical re-contouring may be required for others for aesthetic reasons. PMID- 25301430 TI - Medical thoracoscopic removal of a metal needle from the pleural space. AB - Medical thoracoscopy is an excellent diagnostic and therapeutic tool for management of pleural diseases. There have been case reports of removal of foreign bodies from pleural spaces with video-assisted thoracoscopic surgery under general anaesthesia by thoracic surgeons. We present a case of successful removal of an 8 cm long metal needle from the pleural space with single port medical semirigid thoracoscopy under local anaesthesia by a chest physician. Removal of a foreign body from the pleural space is one more indication for medical thoracoscopy, however, an experienced chest physician and proper case selection are very important for safety and a successful outcome of this procedure. PMID- 25301431 TI - Asking the wrong questions about e-cigarettes: the case for cautious classification. PMID- 25301433 TI - Aboriginal and Torres Strait Islander health practitioners in rural areas: credentialing, context and capacity building. PMID- 25301432 TI - Infliximab reduces Zaprinast-induced retinal degeneration in cultures of porcine retina. AB - BACKGROUND: cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4 to 5% of retinitis pigmentosa (RP), a rare form of retinal dystrophy. Growing evidence suggests that inflammation is involved in the progression of RP. The aims of this study were to corroborate the presence of high TNFalpha concentration in the eyes of RP patients and to evaluate whether the blockade of TNFalpha with Infliximab, a monoclonal anti-TNFalpha antibody, prevented retinal degeneration induced by PDE6 inhibition in cultures of porcine retina. METHODS: Aqueous humor from 30 patients with RP and 13 healthy controls were used to quantify the inflammatory mediators IL-6, TNFalpha, IL-1beta, IL-10 by a multiplex enzyme-linked immunosorbent assay (ELISA) system. Retinal explants from pig were exposed to Zaprinast, a PDE6 inhibitor, for 24 hours in the absence or the presence of Infliximab. Cell death was evaluated by TUNEL assay. The number and distribution of caspase-3 positive cells, indirect poly(ADP)ribose polymerase (PARP) activation and glial fibrillary acidic protein (GFAP) content were visualized by immunolabeling. Antioxidant total capacity, nitrites and thiobarbituric acid reactive substances (TBARS) formation were determined to evaluate antioxidant-oxidant status. RESULTS: IL-6 and TNFalpha concentrations were higher in the aqueous humor of RP patients than in controls. Infliximab prevented retinal degeneration, as judging by the reduced presence of TUNEL positive cells, the reduction of caspase-3 activation and also reduction of glial activation, in an ex vivo model of porcine retina. Additionally, Infliximab partially reduced oxidative stress in retinal explants exposed to Zaprinast. CONCLUSIONS: Inflammatory mediators IL-6 and TNFalpha were elevated in the aqueous humor of RP patients corroborating previous studies suggesting sustained chronic inflammation. Our study suggests that TNFalpha is playing an important role in cell death in an ex vivo model of retinal degeneration by activating different cell pathways at different cell layers of the retina that should be further studied. PMID- 25301434 TI - Use of moss and lichen species to identify (210)Po-contaminated regions. AB - (210)Po concentration in urban air fluctuates as a result of natural (222)Rn radionuclide exhalation and technical activity that is especially linked with high-temperature processes. Each year, an average 11 GBq of (210)Po is released from local power plants into urban air. Over two months, about 180 samples in central Poland were collected. To detect the concentration of (210)Po activity, two common species of biomonitors were chosen: the moss Pleurozium schreberi and the lichen Hypogymnia physodes. For the same locale, (210)Po in lichen shows an average of twice the amount of activity concentration than the moss. In moss, (210)Po concentrations in Lodz ranged from 41.5 Bq kg(-1) to 258.0 Bq kg(-1), while in lichen it ranges from 74.2 Bq kg(-1) to 670.9 Bq kg(-1). On the basis of the measured activity of (210)Po maps, radionuclide distribution has been prepared. For areas identified with higher concentrations of (210)Po, Quantum Gis has been applied. PMID- 25301435 TI - Wear of highly crosslinked polyethylene acetabular components. AB - BACKGROUND AND PURPOSE: Wear rates of highly crosslinked polyethylene (XLPE) acetabular components have varied considerably between different published studies. This variation is in part due to the different techniques used to measure wear and to the errors inherent in measuring the relatively low amounts of wear in XLPE bearings. We undertook a scoping review of studies that have examined the in vivo wear of XLPE acetabular components using the most sensitive method available, radiostereometric analysis (RSA). METHODS: A systematic search of the PubMed, Scopus, and Cochrane databases was performed to identify published studies in which RSA was used to measure wear of XLPE components in primary total hip arthroplasty (THA). RESULTS: 18 publications examined 12 primary THA cohorts, comprising only 260 THAs at 2-10 years of follow-up. The mean or median proximal wear rate reported ranged from 0.00 to 0.06 mm/year. However, differences in the manner in which wear was determined made it difficult to compare some studies. Furthermore, differences in RSA methodology between studies, such as the use of supine or standing radiographs and the use of beaded or unbeaded reference segments, may limit future meta-analyses examining the effect of patient and implant variables on wear rates. INTERPRETATION: This scoping review confirmed the low wear rates of XLPE in THA, as measured by RSA. We make recommendations to enhance the standardization of reporting of RSA wear results, which will facilitate early identification of poorly performing implants and enable a better understanding of the effects of surgical and patient factors on wear. PMID- 25301436 TI - Incidence of and risk factors for postoperative urinary retention in fast-track hip and knee arthroplasty. AB - BACKGROUND AND PURPOSE: Postoperative urinary retention (POUR) is a clinical challenge, but there is no scientific evidence for treatment principles. We describe the incidence of and predictive factors for POUR in fast-track total hip (THA) and knee arthroplasty (TKA). PATIENTS AND METHODS: This was a prospective observational study involving 1,062 elective fast-track THAs or TKAs, which were performed in 4 orthopedics departments between April and November 2013. Primary outcome was the incidence of POUR, defined by postoperative catheterization. Age, sex, anesthetic technique, type of arthroplasty, and preoperative international prostate symptom score (IPSS) were compared between catheterized and non catheterized patients. RESULTS: The incidence of POUR was 40% (range between departments: 30-55%). Median bladder volume evacuated by catheterization was 0.6 (0.1-1.9) L. Spinal anesthesia increased the risk of POUR (OR = 1.5, 95% CI: 1.02 2.3; p = 0.04) whereas age, sex, and type of arthroplasty did not. Median IPSS was 6 in non-catheterized males and 8 in catheterized males (p = 0.02), but it was 6 in the females in both groups (p = 0.4). INTERPRETATION: The incidence of POUR in fast-track THA and TKA was 40%, with spinal anesthesia and increased IPSS in males as predictive factors. The large variation in perioperative bladder management and in bladder volumes evacuated by catheterization calls for randomized studies to define evidence-based principles for treatment of POUR in the future. PMID- 25301437 TI - No functional benefit of larger femoral heads and alternative bearings at 6 months following primary hip replacement. AB - BACKGROUND AND PURPOSE: There has been a recent trend towards the use of greater femoral head sizes in an attempt to improve function and enhance stability after primary hip replacement. This has been associated with the use of alternative bearings, theoretically to reduce wear and improve implant longevity. METHODS: We examined the influence of these variables on patient-reported outcome measures (PROMs) for a consecutive series of primary hip replacements using National Joint Registry (NJR) and PROMs-linked data. To minimize the confounding influence of implant design factors, the single most commonly used brand in England and Wales (DePuy Corail Pinnacle) was examined. Improvement in patient hip-specific outcomes (Oxford hip score, OHS), general health outcomes (Euroqol, EQ-5D), and rates of self-reported complications (bleeding, wound problems, re-admission, and reoperation) were compared for different head sizes (28-mm, 32-mm, and 36-mm) and bearings (metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), and ceramic on-ceramic (CoC)), adjusting for differences in case mix. RESULTS: At a mean follow-up of 7 months, improvements in OHS and EQ5D index were similar for 28-mm and 36-mm heads. A 32-mm head was associated with poorer function (OHS: 20, 99% CI: 19-21, p = 0.002; EQ5D index: 0.39, 99% CI: 0.36-0.42, p = 0.004), although these small differences may not be of clinical importance. There were no statistically significant benefits of either CoP or CoC bearings compared to a MoP bearing. Complication rates were similar within comparisons of head sizes or bearings. INTERPRETATION: In this short-term study, we did not find any functional benefits of larger head sizes or alternative bearings, after adjusting for other influences. We question their use in routine primary hip replacement given the lack of evidence of improved long-term survival in the literature. PMID- 25301438 TI - What is it like to have type-2 blindsight? Drawing inferences from residual function in type-1 blindsight. AB - Controversy surrounds the question of whether the experience sometimes elicited by visual stimuli in blindsight (type-2 blindsight) is visual in nature or whether it is some sort of non-visual experience. The suggestion that the experience is visual seems, at face value, to make sense. I argue here, however, that the residual abilities found in type-1 blindsight (blindsight in which stimuli elicit no conscious experience) are not aspects of normal vision with consciousness deleted, but are based fragments of visual processes that, in themselves, would not be intelligible as visual experiences. If type-2 blindsight is a conscious manifestation of this residual function then it is not obvious that type-2 blindsight would be phenomenally like vision. PMID- 25301439 TI - Aboriginal medical services cure more than illness: a qualitative study of how Indigenous services address the health impacts of discrimination in Brisbane communities. AB - BACKGROUND: Aboriginal and Torres Strait Islanders persistently experience a significantly lower standard of health in comparison to non-Indigenous Australians. The factors contributing to this disparity are complex and entrenched in a history of social inequality, disempowerment, poverty, dispossession and discrimination. Aboriginal medical services (AMS) provide a culturally appropriate alternative to mainstream medical services as a means to address this health disparity and also advocate for Indigenous rights and empowerment. This study provides a vignette of lay perspectives of Aboriginal and Torres Strait Islanders accessing community and government controlled AMS in Brisbane, Queensland with the intention of identifying self-perceived health determinants to inform the post-2015 international development goals. METHODS: Focus group discussions and semi-structured interviews were held with clients of a government-controlled AMS and an Aboriginal community controlled health service (ACCHS) in order to identify their self-identified essential health needs. Conversations were audio recorded, transcribed verbatim and de-identified for analysis. Common themes were identified to highlight important issues around community health needs, how they can be addressed and what lessons can be extended to inform the post-2015 development goals. FINDINGS AND DISCUSSION: Participants acknowledge the complexity of health determinants faced by their peoples. Thematic analysis highlighted the pervasive influence of racism through many perceived health determinants; resulting in reduced healthcare seeking behaviour, unhealthy lifestyles and mental health issues. Participants emphasised the marked health improvements seen due to the establishment of Aboriginal medical services in their communities and the importance of the AMS' role in addressing the negative effects of discrimination on Indigenous health. CONCLUSION: It is concluded from this study that AMS are crucial in addressing the negative impacts of continued discrimination on Indigenous health by providing comprehensive, culturally appropriate, community empowering health services. Such services improve Indigenous healthcare seeking rates, provide invaluable health education services and address mental health concerns in communities and must be supported in order to address health inequalities in Australia. Community driven and culturally informed health services should be encouraged globally to address health disparities. PMID- 25301440 TI - Effect of early rehabilitation by physical therapists on in-hospital mortality after aspiration pneumonia in the elderly. AB - OBJECTIVE: To clarify the effect of early rehabilitation by physical therapists on in-hospital mortality among elderly patients with aspiration pneumonia. DESIGN: A retrospective cohort study. SETTING: A total of 1161 acute-care hospitals across Japan. PARTICIPANTS: Consecutive patients (age, 70-100 y) (N=68,584) from July 2010 to March 2012 in the Japanese Diagnosis Procedure Combination inpatient database with aspiration pneumonia on admission who underwent early physical therapist-guided rehabilitation (n=16,835) and who did not undergo rehabilitation administered by physical therapists (n=51,749). INTERVENTIONS: Early rehabilitation was defined as physical rehabilitation administered by a physical therapist, initiated within 3 days of admission, and undertaken for at least 7 days. MAIN OUTCOME MEASURE: Thirty-day in-hospital mortality. RESULTS: The 30-day in-hospital mortality rates were 5.1% and 7.1% in the early rehabilitation group and the control group, respectively. The multivariable logistic regression model showed that the early rehabilitation group had a significantly lower in-hospital mortality rate (odds ratio, .71; 95% confidence interval [CI], .64-.79; P<.001). Among patients without severe pneumonia, we found no significant difference in mortality rates between patients who underwent early rehabilitation and those who did not undergo rehabilitation by physical therapists. The instrumental variable analysis confirmed that early rehabilitation was associated with a reduced risk for in-hospital mortality (risk difference, -1.9%; 95% CI, -2.3% to -1.5%; P<.001; number needed to treat, 53 [95% CI, 43-67]). CONCLUSIONS: The data suggest that early rehabilitation by physical therapists was associated with a reduction in 30-day in-hospital mortality rates in elderly patients with severe aspiration pneumonia. PMID- 25301441 TI - Evaluation of measures of upper limb functioning and disability in people with Parkinson disease: a systematic review. AB - OBJECTIVES: To identify measurement tools used for upper limb evaluation in people with Parkinson disease (PD), to summarize the content of each tool using the International Classification of Functioning, Disability and Health, and to examine the reliability, validity, clinical utility, and responsiveness of the measurement tools specific to this clinical group. DATA SOURCES: Two systematic searches of online databases included articles published from inception to November 2013. STUDY SELECTION: Search 1 identified upper limb measures. Search 2 retrieved studies investigating the measurement properties of these tools in people with PD. DATA EXTRACTION: Independent reviewers screened articles and extracted data, classified measurement tool content on the basis of the International Classification of Functioning, Disability and Health content domains, and applied both the COnsensus-based Standards for the selection of health status Measurement INstruments checklist to evaluate the study's methodological quality and a second checklist by Terwee et al to assess the measurement tool's quality. A third reviewer adjudicated differences between reviewers. Information on clinical utility was also compiled. DATA SYNTHESIS: The 18 identified measures included PD-specific scales, generic measures, and tools developed for other clinical populations; most measures evaluated impairments and/or activity limitations. Measurement properties of 10 of the 18 identified measures were evaluated in people with PD. No high-quality studies investigated validity or responsiveness. High-quality evidence supported the interrater reliability of some Unified Parkinson's Disease Rating Scale subtests, and lower quality studies provided limited evidence for the test-retest reliability of measures evaluating fine hand function and bradykinesia. CONCLUSIONS: There are relatively few high-quality studies to support the measurement properties, particularly the validity and responsiveness, of tools currently used to evaluate upper limb disability and function in people with PD. Further research is needed to inform measurement tool selection and treatment evaluation in this clinical group. PMID- 25301442 TI - Divergent sensory phenotypes in nonspecific arm pain: comparisons with cervical radiculopathy. AB - OBJECTIVES: To investigate whether distinct sensory phenotypes were identifiable in individuals with nonspecific arm pain (NSAP) and whether these differed from those in people with cervical radiculopathy. A secondary question considered whether the frequency of features of neuropathic pain, kinesiophobia, high pain ratings, hyperalgesia, and allodynia differed according to subgroups of sensory phenotypes. DESIGN: Cross-sectional study. SETTING: Higher education institution. PARTICIPANTS: Forty office workers with NSAP, 17 people with cervical radiculopathy, and 40 age- and sex-matched healthy controls (N=97). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were assessed using quantitative sensory testing (QST) comprising thermal and vibration detection thresholds and thermal and pressure pain thresholds; clinical examination; and relevant questionnaires. Sensory phenotypes were identified for each individual in the patient groups using z-score transformation of the QST data. RESULTS: Individuals with NSAP and cervical radiculopathy present with a spectrum of sensory abnormalities; a dominant sensory phenotype was not identifiable in individuals with NSAP. No distinct pattern between clinical features and questionnaire results across sensory phenotypes was identified in either group. CONCLUSIONS: When considering sensory phenotypes, neither individuals with NSAP nor individuals with cervical radiculopathy should be considered homogeneous. Therefore, people with either condition may warrant different intervention approaches according to their individual sensory phenotype. Issues relating to the clinical identification of sensory hypersensitivity and the validity of QST are highlighted. PMID- 25301443 TI - Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes. AB - Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFR-mutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of the wild-type patients treated with similar regimens (43 vs. 21%, p = 0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13%, p = 0.715; in the second-/third line setting 13 vs. 8%, p = 0.655). On the other hand, the mPFS for the EGFR mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFR-mutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first line platinum/pemetrexed combination chemotherapy. PMID- 25301444 TI - Waltonitone induces apoptosis through mir-663-induced Bcl-2 downregulation in non small cell lung cancer. AB - Our previous study reported that waltonitone treatment inhibited proliferation and induced apoptosis of lung cancer cells. However, the mechanism of waltonitone induced toxicity remains unclear. In the present study, we treated H460 and H3255 lung cancer cells using different concentration of waltonitone (0, 10, 20, 30 MUmol/L). We observed that waltonitone inhibited cell viability and induced apoptosis in a concentration dependent manner, with upregulation of caspase-3 cleavage. We also observed upregulation of miR-663, a potential tumor suppressor, after waltonitone treatment. Suppression of miR-663 function using miR-663 inhibitor partly alleviated cell toxicity induced by waltonitone. In addition, both waltonitone treatment and transfection of miR-663 mimic upregulated Bcl-2 mRNA and protein expression. Bcl-2 transfection alleviated waltonitone-induced toxicity. Furthermore, transfection of miR-663 inhibitor upregulated Bcl-2 levels in both cell lines. In summary, the present study demonstrated that waltonitone induced apoptosis of lung cancer cells through, at least partly, miR-663-induced Bcl-2 downregulation. PMID- 25301445 TI - Modes of MAPK substrate recognition and control. AB - Mitogen-activated protein kinase (MAPK) cascades are universal, evolutionary conserved signalling modules, which translate environmental information into appropriate responses via phosphorylation of their substrate proteins. In Arabidopsis, the MAPK MPK3 regulates numerous cellular processes, including the adaptation to abiotic and biotic stresses. The molecular steps immediately downstream of MPK3 induction have, therefore, received abundant attention, and a respectable number of MPK3 targets are known by now. These proteins illustrate the substrate promiscuity of MPK3. They also are evidence for how manifold phosphorylation-regulated functions can be. This review presents the current knowledge about the function and regulation of MPK3-targeted proteins, takes a close look at their primary protein sequences, and proposes a model of how MPK3 recognises, binds, and phosphorylates its targets. PMID- 25301446 TI - Extended endoscopic transsphenoidal approach infrachiasmatic corridor. AB - An extended endoscopic transsphenoidal approach is required for skull base lesions extending to the suprasellar area. Inferior approach using the infrachiasmatic corridor allows access to the lesions through the tumor growth that is favorable for the extended transsphenoidal approaches. Infrachiasmatic corridor is a safer route for the inferior approaches that is made up by basal arachnoid membrane and Liliequist's membrane with its leaves (diencephalic and mesencephalic leaf). This area extends from the optic canal and tuberculum sella to the corpus mamillare. We performed extended endoscopic approach using the infrachiasmatic corridor in 52 cases, including tuberculum sella meningiomas (n:23), craniopharyngiomas (n:16), suprasellar Rathke's cleft cyst (n:6), pituitary adenoma (n:2), fibrous dysplasia (n:1), infundibular granulosa cell tumor (n:2), and epidermoid tumor (n:2). Total resection was achieved in 17 of 23 (74%) with tuberculum sellae meningioma using infrachiasmatic approach. Twenty patients presented with visual disorders and 14 of them improved. There were two postoperative cerebrospinal fluid (CSF) leakages and one transient diabetes insipidus and one permanent diabetes insipidus. Sixteen patients were operated on by the infrachiasmatic approach for craniopharyngiomas. Improvement was reached in seven of eight patients presented with visual disorders. Complete tumor resection was performed in 10 of 16 cases and cyst aspiration in 4 cases, and there were remnants in two cases. Postoperative CSF leakage was seen in two patients. Infrachiasmatic corridor provides an easier and safer inferior route for the removal of middle midline skull base lesions in selected cases. PMID- 25301448 TI - Blocking of the interaction between Wnt proteins and their co-receptors contributes to the anti-tumor effects of adenovirus-mediated DKK3 in glioblastoma. AB - The effect of the third member of the Dickkopf family (DKK3) in the Wnt pathway in glioblastoma remains unclear. We first demonstrated the non-specific interaction of Wnt3a and Wnt5a with the receptors LRP6 and ROR2 and the up regulation of the Wnt pathway in glioblastoma cells. We used an adenovirus vector and found that an increase in DKK3 protein attenuated the expression of Wnt3a, Wnt5a and LRP6, but not of ROR2, and their interaction, thereby affecting both canonical- and non-canonical Wnt downstream cascades. This produced anti-tumor effects in GBM xenograft models. The suppression of Wnt pathways upstream by DKK3 may have promise for the treatment of glioblastoma. PMID- 25301447 TI - Expression of BAFF receptors in muscle tissue of myositis patients with anti-Jo-1 or anti-Ro52/anti-Ro60 autoantibodies. AB - INTRODUCTION: Anti-Jo-1 and anti-Ro52 autoantibodies are common in patients with myositis, but the mechanisms behind their production are not known. Survival of autoantibody-producing cells is dependent on B-cell-activating factor of the tumour necrosis factor family (BAFF). BAFF levels are elevated in serum of anti Jo-1-positive myositis patients and are influenced by type-I interferon (IFN). IFN-producing cells and BAFF mRNA expression are present in myositis muscle. We investigated expression of the receptors for BAFF in muscle tissue in relation to anti-Jo-1 and anti-Ro52/anti-Ro60 autoantibodies and type-I IFN markers. METHODS: Muscle biopsies from 23 patients with myositis selected based on autoantibody profile and 7 healthy controls were investigated for expression of BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). Nineteen samples were assessed for plasma (CD138) and B-cell (CD19) markers. The numbers of positive cells per area were compared with the expression of plasmacytoid dendritic cell (pDC) marker blood dendritic cell antigen-2 (BDCA-2) and IFNalpha/beta-inducible myxovirus resistance-1 protein (MX-1). RESULTS: BAFF-R, BCMA and TACI were expressed in five, seven and seven patients, respectively, and more frequently in anti-Jo-1-positive and/or anti-Ro52/anti-Ro60-positive patients compared to controls and to patients without these autoantibodies (P = BAFF-R: 0.007, BCMA: 0.03 and TACI: 0.07). A local association of receptors with B and plasma cells was confirmed by confocal microscopy. The numbers of CD138-positive and BCMA positive cells were correlated (r = 0.79; P = 0.001). Expression of BDCA-2 correlated with numbers of CD138-positive cells and marginally with BCMA-positive cells (r = 0.54 and 0.42, respectively; P = 0.04 and 0.06, respectively). There was a borderline correlation between the numbers of positively stained TACI cells and MX-1 areas (r = 0.38, P = 0.08). CONCLUSIONS: The expression pattern of receptors for BAFF on B and plasma cells in muscle suggests a local role for BAFF in autoantibody production in muscle tissues of patients with myositis who have anti-Jo-1 or anti-Ro52/anti-Ro60 autoantibodies. BAFF production could be influenced by type-I IFN produced by pDCs. Thus, B-cell-related molecular pathways may participate in the pathogenesis of myositis in this subset of patients. PMID- 25301449 TI - SKLB316, a novel small-molecule inhibitor of cell-cycle progression, induces G2/M phase arrest and apoptosis in vitro and inhibits tumor growth in vivo. AB - Benzothiazole derivatives have received considerable attentions for their potencies in cancer therapy. In the present study, we reported that SKLB316, a novel synthesized benzothiazole derivative, exhibits activities to inhibit colorectal and pancreatic cancer in vitro and in vivo by inducing G2/M cell cycle arrest and apoptosis. In vitro, it exhibited significant anti-proliferative activities against human cancer cells derived from different histotypes including the colorectal cancer cell line HCT116 and pancreatic cancer cell line CFPAC-1. We chose these cell lines to study the possible anti-tumor mechanism because they are sensitive to SKLB316 treatment. Flow cytometry assays showed that SKLB316 could induce G2/M cell cycle arrest. Mechanistically, SKLB316 could decrease the activities of cdc2/cyclin B1 complex, including decreasing the synthesis of cyclin B1, cdc2 and cdc25c, while accumulating the levels of phosphorylated cdc2 (Tyr15) and checkpoint kinase 2. SKLB316 could also decrease the level of cyclin E and A2. Moreover, SKLB316 could induce cancer cell apoptosis, which was associated with activation of caspase 9, downregulation of Bcl-2 and upregulation of Bax. SKLB316 could also decrease the mitochondrial membrane potential and induce the generation of reactive oxygen species in cells. The results implied that SKLB316 may induce apoptosis via the mitochondria-mediated apoptotic pathway. Moreover, SKLB316 could suppress the growth of established colorectal and pancreatic cancer tumors in nude mice without causing obvious side effects. TUNEL assays confirmed that SKLB316 could also induce tumor cell apoptosis in vivo. Taken together, these findings demonstrate the potential value of SKLB316 as a novel anti-tumor drug candidate. PMID- 25301450 TI - Peritoneal mesothelium promotes the progression of ovarian cancer cells in vitro and in a mice xenograft model in vivo. AB - The role of mesothelial cells in the intraperitoneal spread of ovarian cancer is still elusive. In particular, it is unclear whether these cells constitute a passive barrier preventing cancer cell progression or perhaps act as an active promoter of this process. In this report we show that omental human peritoneal mesothelial cells (HPMCs) stimulate adhesion and proliferation of ovarian cancer cells (A2780, OVCAR-3, SKOV-3). The latter was associated with the paracrine activity of GRO-1, IL-6, and IL-8 released to the environment by HPMCs. Furthermore, the growth dynamics of ovarian cancer xenografts produced in response to i.p. injection of ovarian cancer cells together with HPMCs was remarkably greater than for implantation of cancer cells alone. A layer of peritoneal mesothelium was consistently present in close proximity to the tumor mass in every xenograft model. In conclusion, our results indicate that HPMCs play a supporting role in the intraperitoneal invasiveness of ovarian malignancy, whose effect may be attributed to their ability to stimulate adhesion and proliferation of cancer cells. PMID- 25301451 TI - Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. AB - Human hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a poor prognosis of limited survival. The role of regulatory B cell (Breg), a new important B cell subset, in HCC progression remains unclear. We firstly found that the percentage of B cells at tumor margin was significantly higher than that in tumor and non-tumor regions. Especially, increased intrahepatic B cells at tumor margin were positively associated with tumor invasive features and more tumor recurrence. Besides, HCC patients had a significantly higher percentage of circulating Bregs than healthy people. Increased circulating Bregs were correlated with advanced tumor staging, tumor multiplicity and venous infiltration. Next, we firstly revealed that human Bregs promoted HCC tumor growth independent of Tregs in SCID mice. The migration of Bregs from blood into tumor was also confirmed in mice. Finally, we further explored the molecular mechanism of Bregs promoting proliferation and migration of HCC cells in vitro. Bregs promoted HCC growth and invasiveness by directly interacting with liver cancer cells through the CD40/CD154 signaling pathway. PMID- 25301452 TI - Specific expression of OATPs in primary small cell lung cancer (SCLC) cells as novel biomarkers for diagnosis and therapy. AB - The expression of organic anion transporting polypeptides (OATPs) was elucidated in cell lines from small cell lung cancer (SCLC) and lung carcinoids and in paraffin-embedded samples from primary and metastatic SCLCs. We found a strong relationship between OATP expression and the origin of the cells, as cells from primary or metastatic SCLC and carcinoid tumors differ with respect to OATP levels. OATP4A1 is most prominent in non-malignant lung tissue and in all SCLC and carcinoid cell lines and tissues, OATP5A1 is most prominent in metastatic cells, and OATP6A1 is most prominent in SCLC cell lines and tumors. Treatment with topotecan, etoposide and cisplatin caused significant changes in the expression patterns of OATP4A1, OATP5A1, OATP6A1, chromogranin and synaptophysin. This effect was also evident in GLC-14 cells from an untreated SCLC patient before chemotherapy compared to GLC-16/-19 chemoresistant tumor cells from this patient after therapy. mRNA expression of OATP4A1, 5A1 and 6A1 correlates with protein expression as confirmed by quantitative microscopic image analysis and Western blots. OATPs might be novel biomarkers for tumor progression and the development of metastasis in SCLC patients. PMID- 25301453 TI - The molecular mechanisms of a novel multi-kinase inhibitor ZLJ33 in suppressing pancreatic cancer growth. AB - ZLJ33, an oral active multi-kinase inhibitor, was evaluated both in vitro and in vivo against human pancreatic cancer. It could effectively inhibit cell proliferation, induce apoptosis, and cause inhibition of invasion in pancreatic cancer cells. At a dose of 15.0 mg/kg, ZLJ33 induced tumor shrink in Mia-PaCa2, Capan2, and AsPC-1 xenografts models by 60.59%, 74.19%, and 71.54% according to the tumor weight, respectively. The effect of ZLJ33 on pancreatic cancer was mainly mediated by inactivation of p-PDGFRbeta, p-c-Raf, and p-RET. Treatment with ZLJ33 did not cause side effect of hematology indexes in the pancreatic cancer xenograft model. ZLJ33 could be a potential therapeutic agent against pancreatic cancer. PMID- 25301454 TI - Comparing early years and childhood experiences and outcomes in Scotland, England and three city-regions: a plausible explanation for Scottish 'excess' mortality? AB - BACKGROUND: Negative early years and childhood experiences (EYCE), including socio-economic circumstances, parental health and parenting style, are associated with poor health outcomes both in childhood and adulthood. It has also been proposed that EYCE were historically worse in Scottish areas, especially Glasgow and the Clyde Valley, compared to elsewhere in the UK and that this variation can provide a partial explanation for the excess of ill health and mortality observed among those Scottish populations. METHODS: Multiple logistic regression analysis was applied to two large, representative, British birth cohorts (the NCDS58 and the BCS70), to test the independent association of area of residence at ages 7 and 5 with risk of behavioural problems, respiratory problems and reading/vocabulary problems at the same age. Cohort members resident in Scotland were compared with those who were resident in England, while those resident in Glasgow and the Clyde Valley were compared with those resident in Merseyside and Greater Manchester. RESULTS: After adjustment for a range of relevant variables, the risk of adverse childhood outcomes was found to be either no different, or lower, in the Scottish areas. At a national level, the study reinforces the combined association of socio-economic circumstances, parental health (especially maternal mental health) and parenting with child health outcomes. CONCLUSION: Based on these samples, the study does not support the hypothesis that EYCE were worse in Scotland and Glasgow and the Clyde Valley. It seems, therefore (based on these data), less likely that the roots of the excess mortality observed in the Scottish areas can be explained by these factors. PMID- 25301456 TI - Efficacy and safety of amiodarone in patients with atrial fibrillation in the era of target-specific anticoagulants. PMID- 25301455 TI - Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. AB - BACKGROUND: Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin. OBJECTIVES: This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. METHODS: Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization. RESULTS: In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant. CONCLUSIONS: Amiodarone use was associated with significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when used with warfarin. Apixaban consistently reduced the rate of stroke and systemic embolism, death, and major bleeding compared with warfarin in amiodarone-treated patients and patients who were not on amiodarone. PMID- 25301457 TI - Baseline bleeding risk and arterial access site practice in relation to procedural outcomes after percutaneous coronary intervention. AB - BACKGROUND: Transradial access (TRA) has been associated with reduced access site related bleeding complications and mortality after percutaneous coronary intervention (PCI). It is unclear, however, whether these observed benefits are influenced by baseline bleeding risk. OBJECTIVES: This study investigated the relationship between baseline bleeding risk, TRA utilization, and procedure related outcomes in patients undergoing PCI enrolled in the British Cardiovascular Intervention Society database. METHODS: Baseline bleeding risk was calculated by using modified Mehran bleeding risk scores in 348,689 PCI procedures performed between 2006 and 2011. Four categories for bleeding risk were defined for the modified Mehran risk score (MMRS): low (<10), moderate (10 to 14), high (15 to 19), and very high (>=20). The impact of baseline bleeding risk on 30-day mortality and its relationship with access site were studied. RESULTS: TRA was independently associated with a 35% reduction in 30-day mortality risk (odds ratio [OR]: 0.65 [95% confidence interval (CI): 0.59 to 0.72]; p < 0.0001), with the magnitude of mortality reduction related to baseline bleeding risk (MMRS <10, OR: 0.73 [95% CI: 0.62 to 0.86]; MMRS >=20, OR: 0.53 [95% CI: 0.47 to 0.61]). In patients with an MMRS <10, TRA was used in 71,771 (43.2%) of 166,083 PCI procedures; TRA was used in 8,655 (40.1%) of 21,559 PCI procedures in patients with an MMRS >=20, illustrating that TRA was used less in those at highest risk from bleeding complications (p < 0.0001). CONCLUSIONS: TRA was independently associated with reduced 30-day mortality, and the magnitude of this effect was related to baseline bleeding risk; those at highest risk of bleeding complications gained the greatest benefit from adoption of TRA during PCI. PMID- 25301458 TI - Baseline bleeding risk and benefit of transradial PCI: making lemonade out of lemons. PMID- 25301459 TI - Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. AB - BACKGROUND: Drug-eluting balloons (DEB) may reduce infrapopliteal restenosis and reintervention rates versus percutaneous transluminal angioplasty (PTA) and improve wound healing/limb preservation. OBJECTIVES: The goal of this clinical trial was to assess the efficacy and safety of IN.PACT Amphirion drug-eluting balloons (IA-DEB) compared to PTA for infrapopliteal arterial revascularization in patients with critical limb ischemia (CLI). METHODS: Within a prospective, multicenter, randomized, controlled trial with independent clinical event adjudication and angiographic and wound core laboratories 358 CLI patients were randomized 2:1 to IA-DEB or PTA. The 2 coprimary efficacy endpoints through 12 months were clinically driven target lesion revascularization (CD-TLR) and late lumen loss (LLL). The primary safety endpoint through 6 months was a composite of all-cause mortality, major amputation, and CD-TLR. RESULTS: Clinical characteristics were similar between the 2 groups. Significant baseline differences between the IA-DEB and PTA arms included mean lesion length (10.2 cm vs. 12.9 cm; p = 0.002), impaired inflow (40.7% vs. 28.8%; p = 0.035), and previous target limb revascularization (32.2% vs. 21.8%; p = 0.047). Primary efficacy results of IA-DEB versus PTA were CD-TLR of 9.2% versus 13.1% (p = 0.291) and LLL of 0.61 +/- 0.78 mm versus 0.62 +/- 0.78 mm (p = 0.950). Primary safety endpoints were 17.7% versus 15.8% (p = 0.021) and met the noninferiority hypothesis. A safety signal driven by major amputations through 12 months was observed in the IA-DEB arm versus the PTA arm (8.8% vs. 3.6%; p = 0.080). CONCLUSIONS: In patients with CLI, IA-DEB had comparable efficacy to PTA. While primary safety was met, there was a trend towards an increased major amputation rate through 12 months compared to PTA. (Study of IN.PACT AmphirionTM Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia [INPACT-DEEP]; NCT00941733). PMID- 25301460 TI - Drug-coated balloons for infrapopliteal disease: digging deep to understand the impact of a negative trial. PMID- 25301461 TI - Impact of long-term burden of excessive adiposity and elevated blood pressure from childhood on adulthood left ventricular remodeling patterns: the Bogalusa Heart Study. AB - BACKGROUND: Cardiovascular risk factors are associated with left ventricular hypertrophy (LVH), but little is known regarding related impact of longitudinal measures of childhood adiposity and LV hemodynamic variables. OBJECTIVES: The aim of this study was to examine the impact of cumulative long-term burden and trends of excessive adiposity and elevated blood pressure (BP) during childhood on adulthood LVH and LV geometric remodeling patterns. METHODS: This longitudinal study consisted of 1,061 adults, age 24 to 46 years, who had been examined 4 or more times for body mass index (BMI) and BP starting in childhood, with a mean follow-up of 28.0 years. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and BP from childhood to adulthood. Four LV geometric types were defined-normal, concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH)-all on the basis of LV mass indexed for body height (m(2.7)) and relative wall thickness. RESULTS: Higher values of BMI and systolic and diastolic BP in childhood and adulthood, as well as total AUC and incremental AUC, were all significantly associated with higher LV mass index and LVH, adjusted for race, sex, and age. In addition, higher values of BMI and BP in childhood and adulthood, total AUC, and incremental AUC were significantly associated with EH and CH but not with CR. Importantly, all of these measures of BMI had a consistently and significantly greater influence on EH than did measures of BP. CONCLUSIONS: These findings indicate that the adverse influence of excessive adiposity and elevated BP levels on LVH begins in childhood. PMID- 25301462 TI - Childhood obesity and adulthood cardiovascular disease: quantifying the lifetime cumulative burden of cardiovascular risk factors. PMID- 25301463 TI - Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. AB - BACKGROUND: Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF. OBJECTIVES: The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF. METHODS: The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre specified groupings of mode of death. RESULTS: There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio [HR]: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths. CONCLUSIONS: In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure [RELAX-AHF]; NCT00520806). PMID- 25301464 TI - Matching mechanism of death with mechanism of action: considerations for drug development for hospitalized heart failure. PMID- 25301466 TI - Often talked about, seldom seen: promoting myocardial recovery with ventricular assist device. PMID- 25301465 TI - Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery. AB - BACKGROUND: In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied. OBJECTIVES: The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy. METHODS: We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors. RESULTS: Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 +/- 81 MUm(2) to 1,011 +/- 68 MUm(2) (p = 0.001), but not beyond that of normal donor hearts (682 +/- 56 MUm(2)). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system. CONCLUSIONS: Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart. PMID- 25301467 TI - Do current clinical trials meet society's needs?: a critical review of recent evidence. AB - This paper describes some important controversies regarding the current state of clinical trials research in cardiology. Topics covered include the inadequacy of trial research on medical devices, problems with industry-sponsored trials, the lack of head-to-head trials of new effective treatments, the need for wiser handling of drug safety issues, the credibility (or lack thereof) of trial reports in medical journals, problems with globalization of trials, the role of personalized (stratified) medicine in trials, the need for new trials of old drugs, the need for trials of treatment withdrawal, the importance of pragmatic trials of treatment strategies, and the limitations of observational comparative effectiveness studies. All issues are illustrated by recent topical trials in cardiology. Overall, we explore the extent to which clinical trials, as currently practiced, are successful in meeting society's expectations. PMID- 25301468 TI - Risk of subsequent pregnancy in women with a history of peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a pregnancy-associated myocardial disease with marked left ventricular systolic dysfunction. Although this condition can lead to major complications, including severe heart failure, arrhythmias, thromboembolic events, and death, the majority of women with this condition demonstrate a complete or partial recovery. Many of these women desire to become pregnant again and are concerned regarding the safety of additional pregnancies. The purpose of this paper is to review the available information related to subsequent pregnancies in women with a history of PPCM in an attempt to reach conclusions regarding the risk of such pregnancies in this group of patients. PMID- 25301469 TI - Mentorship during fellowship. PMID- 25301470 TI - Research versus clinical practice in asymptomatic patients with severe organic mitral regurgitation and preserved LV function. PMID- 25301471 TI - Reply: Research versus clinical practice in asymptomatic patients with severe organic mitral regurgitation and preserved LV function. PMID- 25301472 TI - Dexmedetomidine and ketamine combination for a patient with xeroderma pigmentosa. AB - Patients of xeroderma pigmentosa (XP) have increased sensitivity to ultraviolet light and a defective nucleotide excision repair (NER) mechanism in their DNA. Several types of neurological, dermatological, and ophthalmological complications are common in these patients. There is increasing evidence of delayed recovery and worsening of neurological status following general anesthesia in such patients. Some reports have shown uneventful conduct of total intravenous anesthesia in patients of XP. The authors report a case of XP in a young girl for surgery, previously anesthetized with delayed recovery, managed successfully with a combination of intravenous dexmedetomidine and ketamine. PMID- 25301473 TI - Modeling of safe window for percutaneous thoracic sympathectomy. AB - PURPOSE: Despite the many benefits of percutaneous thoracic sympathectomy, it also has serious complications such as pneumothorax. This study was conducted in order to determine the safe percutaneous entering window and angles for the needle during T2 and T3 thoracic sympathectomy avoiding pneumothorax. METHODS: Transverse section of CT images that crosses at the middle of the T2 or T3 vertebral body was selected. Medial and lateral imaginary lines were drawn from the dorsoventrally midpoint on the lateral surface of the vertebral body (v) to the skin. The medial one was drawn to the skin medially as much as possible tangent to the vertebral body (vM). The lateral one was drawn to the skin tangent to parietal pleura (vL). c was defined as the point where the midsagittal line meets the skin. The distance cM and cL, the angle aM and aL made between the midsagittal line and vM or vL lines were measured. To determine the relations between patients' covariates and measured data, mixed-effect population analysis was performed for the cL, aL, and vL. RESULTS: In males, the mean values of cL were 85.3 and 79.2 mm for T2 and T3, respectively. In females, they were 71.5 and 63.7 mm for T2 and T3, respectively. Population analysis revealed that cL was best described with age, weight, gender covariates, and interindividual variability. The aL was best described with BMI and gender covariates. CONCLUSIONS: The covariates' relationship and interindividual variability resulting from the mixed-effect analysis enhanced individual prediction for safe widows. PMID- 25301474 TI - Improving the safety and quality of surgical patient care: what can we learn from quality management of industries? PMID- 25301475 TI - Diabetic hyperglycemia attenuates sympathetic dysfunction and oxidative stress after myocardial infarction in rats. AB - BACKGROUND: Previous research has demonstrated that hyperglycemia may protect the heart against ischemic injury. The aim of the present study was to investigate the association between hyperglycemia and myocardial infarction on cardiovascular autonomic modulation and cardiac oxidative stress profile in rats. Male Wistar rats were divided into: control (C), diabetic (D), myocardial infarcted (MI) and diabetic infarcted rats (DMI). METHODS: Diabetes was induced by streptozotocin (STZ, 50 mg/Kg) at the beginning of the protocol and MI was induced by left coronary occlusion 15 days after STZ. Thirty days after streptozocin-induced diabetes, cardiovascular autonomic modulation was evaluated by spectral analysis, and oxidative stress profile was determined by antioxidant enzyme activities and superoxide anion, together with protein carbonylation and redox balance of glutathione (GSH/GSSG). RESULTS: The diabetic and infarcted groups showed decreased heart rate variability and vagal modulation (p < 0.05); however, sympathetic modulation decreased only in diabetic groups (p < 0.05). Sympatho/vagal balance and vascular sympathetic modulation were increased only in the MI group (p < 0.05). Diabetes promoted an increase in catalase concentration (p < 0.05). Glutathione peroxidase activity was increased only in DMI when compared to the other groups (p < 0.05). Superoxide anion and protein carbonylation were increased only in MI group (p < 0.05). Cardiac redox balance, as evaluated by GSH/GSSG, was lower in the MI group (p < 0.05). CONCLUSIONS: These data suggest that hyperglycemia promotes compensatory mechanisms that may offer protection against ischemia, as demonstrated by increased antioxidants, decreased pro-oxidants and protein damage, possibly related to the improvements in both redox balance and sympathetic modulation to the heart. PMID- 25301476 TI - Ischemic preconditioning inhibits mitochondrial permeability transition pore opening through the PTEN/PDE4 signaling pathway. AB - OBJECTIVES: Ischemic preconditioning (IPC) induces cardioprotection against ischemia-reperfusion (IR) injury by inhibiting the mitochondrial permeability transition pore (mPTP). Here, we tested the hypothesis that IPC-induced cardioprotection is mediated by the phosphatase PTEN and PDE4 (phosphodiesterase 4). METHODS: Isolated hearts from wild-type mice (WT, n = 110) and myocyte specific PTEN-knockout mice (PKO, n = 94) were exposed to IPC or control conditions followed by IR. Subcellular fractionation was performed by sucrose gradient ultracentrifugation. RESULTS: IPC limited myocardial infarct size (IS) in WT mice. The PDE4 inhibitor rolipram abolished the protective effect of IPC. However, small IS was found in PKO hearts after IR, and IPC did not decrease IS but enlarged it in PKO hearts. IPC promoted PDE4D localization to caveolin-3 enriched fractions in WT mice by increasing Akt levels at the caveolae. In PKO hearts, basal PDE4D levels were elevated at the caveolae, and IPC decreased PDE4D levels. Consistent with the subcellular PDE4D protein levels and its activity, elevation in intracellular Ca(2+) levels in the ischemic heart and opening of mPTP after IR were inhibited by IPC in WT mice, but not by IPC in PKO mice. CONCLUSIONS: IPC inhibits mPTP opening by regulating the PTEN/PDE4 signaling pathway. PMID- 25301477 TI - Recovering species demographic history from multi-model inference: the case of a Neotropical savanna tree species. AB - BACKGROUND: Glaciations were recurrent throughout the Quaternary and potentially shaped species genetic structure worldwide by affecting population dynamics. Here, we implemented a multi-model inference approach to recover the distribution dynamics and demographic history of a Neotropical savanna tree, Tabebuia aurea (Bignoniaceae). Exploring different algorithms and paleoclimatic simulations, we used ecological niche modelling to generate alternative hypotheses of potential demographic changes through the last glacial cycle and estimated genetic parameters using coalescent modelling. RESULTS: Comparing predictions from demographic hypotheses with genetic parameters of modern populations, our findings revealed a likely scenario of population decline, with spatial displacement towards Northeast Brazil from the last glacial maximum to the mid Holocene. Subsequently, populations expanded in response to the return of the climatically suitable conditions in Central-West Brazil. Nevertheless, a wide historical refugium across Central Brazil likely maintained large populations connected throughout time. The expected genetic signatures from such predicted distribution dynamics are also corroborated by spatial genetic structure observed in modern populations. CONCLUSION: By exploring uncertainties inherent in multiple working hypotheses, we have shown that multi-model inference is a fruitful and efficient approach to recover the nature, timing and geographical context of the Tabebuia aurea population dynamic in response to the Quaternary climate changes. PMID- 25301478 TI - Functional and morphological changes after macular pucker surgery: an optical coherence tomography and microperimetric study. AB - PURPOSE: To investigate the relationship among functional and morphological findings before and after macular pucker surgery. METHODS: Thirty-eight eyes with idiopathic macular pucker that underwent 25-gauge vitrectomy and infracyanine green-assisted internal limiting membrane peeling were prospectively enrolled. Main outcome measures were best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography findings and MP-1 microperimetry findings. RESULTS: Mean BCVA improvement was 0.34 logMAR (p < 0.0001). Mean central retinal thickness (CRT) reduction was 50 um (p = 0.0041). Mean retinal sensitivity improvement was 0.9. Patients with a greater improvement of postoperative BCVA showed worse baseline BCVA (p < 0.001), shorter final inner/outer segment (IS/OS) interruption length (p = 0.039) and thinner final CRT (p = 0.035). Furthermore, final BCVA was correlated with baseline IS/OS interruption length (p = 0.001). CONCLUSION: Baseline BCVA, CRT and IS/OS integrity can be used to predict the functional outcomes after macular pucker surgery. PMID- 25301479 TI - Intraspecific variations in Conus geographus defence-evoked venom and estimation of the human lethal dose. AB - Conus geographus is the most dangerous cone snail species known, with reported human fatality rates as high as 65%. Crude venom gland extracts have been used to determine animal LD50 and to aid the isolation of several potent paralytic toxins. However, not only is the composition of injected venoms known to differ significantly from that in dissected venom glands, but also to vary according to predatory or defensive stimuli. Therefore, to study the venom that is directly relevant to human envenomation, the defense-evoked venom of several specimens of C. geographus was collected and analyzed by standard LC-MS methods. The molecular composition of individual defense-evoked venom showed significant intraspecific variations, but a core of paralytic conotoxins including alpha-GI, alpha-GII, MU GIIIA, omega-GVIA and omega-GVIIA was always present in large amounts, consistent with the symptomology and high fatality rate in humans. Differences between injected and dissected venoms obtained from the same specimen were also evident. Interestingly, an apparent linear correlation between the dry weight/volume of injected venom and the size of the shell allowed extrapolation to a human lethal dose (0.038-0.029 mg/kg) from an historic fatal case of C. geographus envenomation, which may help in the management of future victims. PMID- 25301480 TI - Gene expression and molecular evolution of sxtA4 in a saxitoxin producing dinoflagellate Alexandrium catenella. AB - Dinoflagellates of the genus Alexandrium produce the neurotoxin saxitoxin (STX), responsible for paralytic shellfish poisoning (PSP) and accumulates in marine invertebrates. The recent identification of STX biosynthesis genes allowed us to investigate the expression of sxtA4 at different growth stages in Alexandrium catenella Group IV. We found no significant differences in expression of sxtA4, despite significant differences in STX levels at different growth stages (P < 0.023). Three reference genes were tested for normalisation: actin, cytochrome b (cob), and the large subunit ribosomal RNA (LSU rDNA). cob was most stably expressed but the combination of two reference genes, actin and cob, resulted in the best stability factor. Most genomic sequences of sxtA4 from A. catenella were in a clade that included sequences from Alexandrium fundyense Group I, however, one paralogue was not related to the others, suggesting recombination or lateral transfer. A comparison of the sxtA4 cDNA sequences with genomic DNA sequences indicated the possibility of transcript editing and the preferential transcription of certain genomic DNA loci. The results show that, in dinoflagellates, post-transcriptional mechanisms play a major role in the regulation of saxitoxin biosynthesis. PMID- 25301481 TI - Bacillus intermedius ribonuclease (BINASE) induces apoptosis in human ovarian cancer cells. AB - The cytotoxic effects of Bacillus intermedius RNase (binase) towards ovarian cancer cells (SKOV3 and OVCAR5) were studied in comparison to normal ovarian epithelial cells (HOSE1 and HOSE2). Binase decreased viability and induced the selective apoptosis of ovarian cancer cells. The apoptosis rate was 50% in SKOV3 and 48% in OVCAR5 cells after 24 h of binase treatment (50 MUg/ml). Binase induced apoptosis in these cell lines was accompanied by caspase-3 activation and poly(ADP-ribose) polymerase fragmentation. Normal ovarian epithelial cells were not affected by binase, except for a slight decrease of HOSE2 cell viability and the appearance of traces of activated caspase-3, but not the poly(ADP-ribose) polymerase 85-kDA fragment. Binase did not induce alteration of EZH2 (enhancer of zeste-homolog-2) protein expression neither, in tumor nor in normal cells. In conclusion, selective binase-induced cell death and apoptosis via poly(ADP ribose) polymerase fragmentation may serve as a new treatment option against ovarian cancer progression. PMID- 25301482 TI - Incidence and predictors of persistent growth hormone deficiency (GHD) in patients with isolated, childhood-onset GHD. AB - INTRODUCTION: In a considerable proportion of patients with childhood-onset growth hormone (GH) deficiency (GHD), a normalisation of GH secretion at the attainment of final height (FH) is observed. The aim of the present study was to assess the incidence of, and to find out the predictors of, persistent and transient GHD, available in the pre-treatment period, in patients with childhood onset isolated, non-acquired GHD. MATERIAL AND METHODS: The analysis comprised 150 short children (117 boys), with childhood-onset isolated, non-acquired GHD who completed GH therapy and attained FH. Before treatment and at FH (in retesting), auxological parameters were measured, GH peak in stimulation tests and IGF-I concentration were assessed, and pituitary height (PHt) was measured before treatment. RESULTS: The incidence of persistent GHD was 12.0%. The patients with persistent GHD had before treatment significantly lower GH and IGF I secretion, as well as significantly better increase of height SDS (DHSDS) during GH therapy than those with transient GHD. A negative correlation was observed between DHSDS and IGF-I concentration, but not between DHSDS and GH peak. There was no significant difference in the incidence of pituitary hypoplasia between the patients with persistent and transient GHD. CONCLUSIONS: The incidence of persistent GHD in patients with childhood-onset, isolated, non acquired GHD is relatively low. Despite the fact that the predictors of persistent and transient GHD may be identified in childhood, a diagnosis of GHD should be verified in retesting after the attainment of FH in each case. PMID- 25301483 TI - Serum resistin concentrations in children with type 1 diabetes mellitus--negative relation to body fat mass. AB - INTRODUCTION: Insulin is one of the major factors regulating adipose tissue function. On the other hand, adipocytes secrete adipocytokines that may influence insulin synthesis and action, and are involved in blood glucose regulation. In type 1 diabetes mellitus (t1DM), beta cells function is replaced with exogenous insulin therapy. This raises a question concerning the impact of t1DM on adipose tissue secretory function. The aim of this study was to evaluate one of the adipocytokines, resistin, serum concentrations in relation to body fat mass in children with t1DM. MATERIAL AND METHODS: The study comprised 75 children with t1DM and a control group of 20 healthy coevals. All children had estimated serum resistin concentrations, glycated haemoglobin levels, growth and body weight measurements, and bioelectrical impedance analysis in order to establish body composition. RESULTS: Resistin serum concentrations were significantly lower in children with t1DM vs. controls (median values: 343 vs. 590 pg/mL; mean values +/ SD: 577 +/- 561 vs. 861 +/- 628 pg/mL; p < 0.001), and they negatively correlated with body fat mass (p = 0.022) and age (p = 0.022) in the t1DM group, but not in the control group. Disease duration, glycated haemoglobin levels and insulin dosage revealed no direct statistical relation to resistin levels. CONCLUSIONS: Diminished serum resistin concentrations and a negative correlation between resistin levels and body fat mass in children with type 1 diabetes seem to result from broken physiological adipo-insular regulations, independent of disease duration, its metabolic control and insulin supply. PMID- 25301484 TI - Transforming growth factor beta1 (TGFbeta1) and vascular endothelial growth factor (VEGF) in the blood of healthy people and patients with Graves' orbitopathy--a new mechanism of glucocorticoids action? AB - INTRODUCTION: The first part of this paper is related to healthy people and presents concentrations of TGFbeta1 and VEGF in blood (with and without dividing data with respect to sex), their single measurement values (at 8 am), Mean Daily Concentrations (MDC), Area Under the Curves (AUC; total daily secretion), and circadian rhythm. The second part of the work is related to Graves' orbitopathy (GO). The aim of the study were: 1) to determine the physiological pattern of TGFbeta1 and VEGF secretion; 2) to compare the serum TGFbeta1 and VEGF circadian profile in newly diagnosed thyreotoxic patients with active GO and healthy controls (H); and 3) to estimate the influence of high-dose intravenous methylprednisolone pulse therapy (MP) on TGFb1 and VEGF blood levels in GO. MATERIAL AND METHODS: Twenty-two healthy (H) subjects and 16 hyperthyroid GO patients were treated with MP (6 g/14 days) and followed up by ophthalmological assessment. Blood was collected before and after 2 weeks MP-therapy. TGFbeta1 and VEGF levels were determined by the ELISA method. RESULTS: No difference was observed in the concentrations of TGFbeta1 and VEGF in the blood of healthy women and men - in further analysis, a combined healthy male and female cohort was used (H). While the absence of circadian rhythms in the concentrations of TGFbeta1 and VEGF allows the application of a single measurement approach, MDC and AUC measurements were found to be more precise. There were no differences in TGFbeta1 MDC/AUC between GO and H. VEGF MDC/AUC in GO were higher than in H. MP-therapy increased TGFb1 MDC/AUC, thus in GO after MP, the TGFbeta1 MDC/AUC were higher than in H. There were no differences in VEGF MDC/AUC during MP-therapy. MP therapy was effective in 15/16 patients. CONCLUSIONS: 1. MP-therapy increases MDC and AUC of TGFbeta1. The effectiveness of MP-therapy in patients with active GO may be related to its influence on TGFbeta1 concentrations in blood. The results suggest the existence of a new mechanism of glucocorticoids action, consisting of an increase in the secretion of TGFbeta1.2. The elevated serum VEGF in thyreotoxic patients with active GO may reflect long-standing autoimmune processes in orbital and thyroid tissues and intensified angiogenesis in the thyroid gland. PMID- 25301485 TI - Free and bioavailable fractions of sex steroids may influence bones in young men, depending on age and oestradiol level. AB - INTRODUCTION: Longitudinal bone growth ceases by the end of puberty, and it is thought to be a result, in both sexes, of increased pubertal oestrogen serum concentrations. Since peak bone mass is achieved by the third decade of life or later, the aim of this study was to relate sex steroid hormones and sex hormone binding globulin (SHBG) levels to bone quality in men during their third and fourth decades of life. MATERIAL AND METHODS: Eighty men, healthy volunteers aged between 18 and 39 years, were subjected to an interviewer-administered questionnaire, body mass index (BMI) measurement, blood sample and calcaneal quantitative ultrasound (QUS) (Hologic-SAHARA). Blood was assessed for testosterone (T), oestradiol (E2), dehydroepiandrosterone sulfate (DHEAS), SHBG, luteinising hormone (LH) and follicle stimulating hormone (FSH). Free and bioavailable T and E2 levels were calculated knowing SHBG and albumin levels. RESULTS: While T, E2, DHEAS, LH and FSH levels were not related, free and bioavailable fractions of T and E2 were positively associated with QUS readings. SHBG level was associated negatively. After dichotomisation for age, the associations remained significant only for younger subjects (18-30 years, n = 47). After adjustment for other co-variants, only SHBG in younger subjects retained its negative association with QUS. Older subjects (31-39 years, n = 33) revealed higher BMI and lower serum concentrations of total (-17 %), free ( 18.5%) and bioavailable (-22.5%) levels of E2 than younger subjects. CONCLUSION: Free and bioavailable fractions of sex steroids may influence bones in young men, depending on age and E2 level. PMID- 25301486 TI - Semiquantitative assessment of hirsutism in 850 PCOS patients and 2,988 controls in China. AB - INTRODUCTION: There is considerable individual and racial variation in the degree and pattern of body hair among PCOS patients. The purposes of this study were to define: 1) a suitable standard of hirsutism for Chinese women with PCOS and the general Chinese population; 2) the characteristics of hair distribution and degree in Chinese women with PCOS and the general population; and 3) the correlation of PCOS and FG score in Chinese women. MATERIAL AND METHODS: This retrospective study in Chinese women with PCOS in the reproductive centre of Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, comprised 850 patients with PCOS and 2,988 members of the general population. It was conducted crosssectionally by interview, physical examination, ultrasound scan, and modified Ferriman-Gallwey score. Eight hundred and fifty Chinese women with PCOS (aged 20-41) underwent an interview, blood drawing, physical and ultrasound examination. Body hair at nine sites (lip, chin, arm, thigh, chest, upper belly, lower belly, upper back and lower back) were evaluated using the scoring system described by Ferriman and Gallwey; 2,988 healthy women (aged 20-45) underwent an interview, physical examination, ultrasound scan and FG score evaluation by trained gynaecologists. Terminal body hair growth was assessed using the mFG scoring system in Chinese women with PCOS and the control group; nine body areas were scored from 0-4 for terminal hair growth distribution. RESULTS: Our findings showed that of the 850 patients, 367 had a FG score equal to or greater than 5 points [43.2% (367/850)], 282 patients had a FG score equal to or greater than 6 points [33.18% (282/850)], and 21% had a score of at least 8 points. Nobody's FG score was equal to or greater than 24 points. Hirsutism was significantly higher in PCOS patients (score >= 5 = 43.2%) than in the general population (score >= 5 = 10%). The lip is the most common place (score 0-3) where terminal hair grows in 850 PCOS patients and the general population. Next came the upper back and chest, and the number of 4 points was only recorded for the region of the lip (16), thigh (3), lower belly (3), arm (1), chest (1), and lower back (1). None of the PCOS patients displayed a score of more than 4 points for the chin, upper belly and upper back. CONCLUSIONS: Our data indicates that: 1) an mFG score of 5 or above is out of the norm for the general unselected population and forms almost half of the possibility of diagnosing PCOS in Chinese women; 2) lips and upper back are the most common places that hair grows (score 1-2), but in terms of the serious situation (score 3-4), lips and thighs are the most common places that hair grows; 3) there is a good predictive value to diagnose PCOS by FG score for Chinese people; and 4) hirsutism is more common in PCOS than in the general population in China. PMID- 25301487 TI - Fetuin-A levels in lean and obese women with polycystic ovary syndrome. AB - INTRODUCTION: The aim of this study was to estimate serum fetuin-A levels in lean and obese women with polycystic ovary syndrome (PCOS) and to find possible relationships between fetuin-A, metabolic factors and androgens in these patients. MATERIAL AND METHODS: In 25 lean (18-38 years, BMI 17.5-25.0 kg/m2) and 15 obese women (20-41 years, BMI 28.1-53.2 kg/m2) with PCOS, anthropometric indices and body composition were measured. Fasting serum fetuin-A, adiponectin, leptin, glucose, lipids, hsCRP, insulin, androgens and SHGB levels were estimated. RESULTS: There was no significant difference in serum fetuin-A levels between lean and obese patients: 0.54 +/- 0.13 g/L and 0.60 +/- 0.14 g/L, respectively. We noted a correlation between BMI and leptin levels (r = 0.88; p < 0.0001) and a nearly significant negative correlation between BMI and adiponectin levels (r = -0.53; p = 0.11) in all subjects. In lean patients, we found a correlation between fetuin-A levels and ALT activity (r = 0.44; p < 0.05). In all participants, fetuin-A correlated directly with DHEA-S levels (r = 0.44; p < 0.03). CONCLUSIONS: Serum fetuin-A levels were similar in lean and obese women with PCOS. We found an association between fetuin-A levels and ALT activity in lean patients and between fetuin-A levels and DHEA-S in all women. The role of fetuin-A in the mechanisms of insulin resistance, and its potential impact on androgenic hormones production in women with PCOS, need to be tested in further studies. PMID- 25301488 TI - Fasting and postprandial acyl and desacyl ghrelin levels in obese and non-obese subjects. AB - INTRODUCTION: The potentially differential roles of both forms of ghrelin in obesity are undefined, and little is known about desacyl ghrelin's (DAG) regulation by meals. We aimed to assess changes in acyl ghrelin (AG) and DAG in response to mixed-meal consumption in obese and non-obese subjects. MATERIAL AND METHODS: Venous blood for plasma glucose, AG and DAG assays were collected in both groups after an overnight fast and two hours after the consumption of a standard 300 kcal-mixed meal (Nutridrink, Nutricia). RESULTS: Mean fasting values of both AG and DAG were significantly lower in the obese individuals. On the other hand, among non-obese controls, the mean postprandial DAG levels did not change and AG levels decreased, whereas in obese individuals the mean DAG levels after a mixed-meal diminished and AG levels were unchanged. CONCLUSIONS: It is necessary to distinguish between the desacylated and acylated forms of ghrelin, as we have shown differential postprandial AG and DAG responses in obese and non obese individuals. Whether targeting changed proportions between AG and DAG could be a successful strategy in obesity treatment remains a question for future studies. PMID- 25301489 TI - Overexpression of prothymosin alpha is related to pituitary adenoma recurrence but not to adenoma invasiveness and proliferation. AB - INTRODUCTION: Prothymosin alpha (ProTalpha) is a peptide initially considered as a thymic hormone, but further studies have shown its wide distribution in different tissues and organs. It has a prevalent nuclear localisation and is thought to be involved in the control of proliferation and apoptosis. In earlier studies, the overexpression of ProTalpha was found in several human tumours, including pituitary adenomas. The present study deals with the relations of ProTalpha to the pituitary adenoma hormonal phenotype, proliferation, recurrence and invasiveness. MATERIAL AND METHODS: Sixty two pituitary adenomas were included in the study. The invasiveness of the tumours was estimated before surgery by means of magnetic resonance imaging. The paraffin sections of the tumours were immunostained with an antibody against the C-terminal fragment (101 109) of ProTalpha and with anti-Ki-67 antibody. The hormonal phenotype of the investigated pituitary adenomas had been established previously by means of immunostaining with antibodies to pituitary hormones (GH, PRL, FSH, LH, TSH, ACTH and alpha-subunit). RESULTS: Strong immunostaining with anti-ProTalpha antibody occurred in the subpopulation of cell nuclei and the walls of intratumoural blood vessels. ProTalpha index is higher in clinically non-functioning pituitary adenomas (CNFPA) compared to any type of functioning adenomas. There was no difference in the percentage of ProTalpha- positive cell nuclei in non-invasive vs. invasive adenomas, but it was significantly more frequent in recurrent than in primary tumours. Moreover, the decrease of ProTalpha index was found in somatotroph tumours treated with somatostatin analogues vs. untreated ones. The percentage of ProTalpha nuclei did not correlate with Ki-67 index. CONCLUSIONS: The overexpression of nuclear ProTalpha in pituitary adenomas is related to tumour recurrence, but not to proliferation or invasiveness. PMID- 25301490 TI - Orbital radiotherapy in the management of Graves' orbitopathy--current state of knowledge. AB - The treatment of Graves' orbitopathy (GO) remains a diagnostic and therapeutic challenge for clinicians worldwide. The elimination of risk factors, such as encouraging smoking cessation and achieving euthyroidism, are the most important and usually sufficient treatment methods in most mild cases. A course of selenium may also be beneficial. High-dose systemic corticosteroid therapy remains the first-line therapy in moderate-to-severe orbitopathy; however in some patients such treatment may be insufficient. Radiotherapy for GO has been used for decades and is considered to be effective in active GO, although less than systemic corticosteroids. Unfortunately, there are only eight randomised studies that may be analysed to assess its true effectiveness and applicability. It has been indicated that radiotherapy affects mainly eye motility and soft tissue changes, with almost no influence on exophthalmos. The combination of these two therapies has proven to be even more effective than either treatment alone, especially in subjects with resistant or recurrent GO. Orbital radiotherapy seems to be a safe procedure with few adverse effects observed long after the therapy. It should be avoided in patients with retinopathy, due to diabetes mellitus and hypertension, and in young subjects (< 35 years old). Orbital radiotherapy, as a safe and generally effective second-line therapy, is used in some countries as a supporting method during the second course of systemic corticosteroid therapy, if the response to the first course is unsatisfactory. Further randomised, double blind studies are needed to confirm fully its clinical usefulness. PMID- 25301491 TI - False diagnosis of type 1 diabetes mellitus and its complications in Wolfram syndrome--is it the reason for the low number of reported cases of this abnormality? AB - Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a rare autosomal recessive syndrome (1/770,000 in the United Kingdom), characterised by juvenile onset of diabetes mellitus, optic nerve atrophy, diabetes insipidus, sensorineural deafness, renal tract and neurological abnormalities, and primary gonadal atrophy. WS is caused mainly by biallelic mutations in the WFS1 gene, which encodes wolframin. Wide tissue distribution of wolframin and many mutations in the wolframin gene resulting in Wolfram syndrome may contribute to different phenotypes and the unusual combinations of clinical features. We describe a female patient with Wolfram syndrome diagnosed at the age of 25, with a previous false diagnosis of type 1 diabetes mellitus and misdiagnosed diabetic complications. The patient was found to be a compound heterozygote for two novel mutations in exon 8 of WFS1 gene: a 2-bp deletion AT at nt 1539 leading to a frameshift (Y513fs) and a single base substitution 1174C > T resulting in a stop codon (Q392X). A detailed analysis of the patient's medical history and a review of the literature suggest that many cases of Wolfram syndrome may remain undiagnosed due to misdiagnosis as type 1 diabetes mellitus and incorrect interpretation of clinical symptoms of neurodegenerative abnormalities, especially in their early stages. PMID- 25301492 TI - Is high dose intravenous methylprednisolone pulse therapy in patients with Graves' orbitopathy safe? AB - High dose intravenous glucocorticoid pulse (i.v. GCS) therapy is a proven approach in patients with active, moderate to severe Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON). In moderate to severe GO, the European Group on Graves' Orbitopathy (EUGOGO) recommends a 12-week course of intravenous methylprednisolone (i.v. MP) pulse therapy with a cumulative dose of 4.5 g. The response rate of i.v. GCS treatment is significantly higher than oral glucocorticoid (oral GCS) therapy and is associated with fewer adverse events. However, a major concern was raised because of reports of fatal side effects which may be associated with this therapy, especially when single and cumulative doses of methylprednisolone (MP) are higher than recommended. The prevalence and severity of adverse effects during treatment have not been fully described. The aim of this review was to summarise the frequency of major adverse effects of i.v. GCS compared to oral GCS and attempt to propose some practical suggestions as to how to monitor and prevent the development of side effects. PMID- 25301494 TI - Disengagement of HIV-positive pregnant and postpartum women from antiretroviral therapy services: a cohort study. AB - INTRODUCTION: Recent international guidelines call for expanded access to triple drug antiretroviral therapy (ART) in HIV-positive women during pregnancy and postpartum. However, high levels of non-adherence and/or disengagement from care may attenuate the benefits of ART for HIV transmission and maternal health. We examined the frequency and predictors of disengagement from care among women initiating ART during pregnancy in Cape Town, South Africa. METHODS: We used routine medical records to follow-up pregnant women initiating ART within prevention of mother-to-child transmission of HIV services in Cape Town, South Africa. Outcomes assessed through six months postpartum were (1) disengagement (no attendance within 56 days of a scheduled visit) and (2) missed visits (returning to care 14-56 days late for a scheduled visit). RESULTS: A total of 358 women (median age, 28 years; median gestational age, 26 weeks) initiated ART during pregnancy. By six months postpartum, 24% of women (n=86) had missed at least one visit and an additional 32% (n=115) had disengaged from care; together, 49% of women had either missed a visit or had disengaged by six months postpartum. Disengagement was more than twice as frequent postpartum compared to in the antenatal period (6.2 vs. 2.4 per 100 woman-months, respectively; p<0.0001). In a proportional hazards model, later gestational age at initiation (HR: 1.04; 95% CI: 1.00-1.07; p=0.030) and being newly diagnosed with HIV (HR: 1.57; 95% CI: 1.07-2.33; p=0.022) were significant predictors of disengagement after adjusting for patient age, starting CD4 cell count and site of ART initiation. CONCLUSIONS: These results demonstrate that missed visits and disengagement from care occur frequently, particularly post-delivery, among HIV positive women initiating ART during pregnancy. Women who are newly diagnosed with HIV may be particularly vulnerable and there is an urgent need for interventions both to promote retention overall, as well as targeting women newly diagnosed with HIV during pregnancy. PMID- 25301495 TI - GDNF and NT-3 induce progenitor bone mesenchymal stem cell differentiation into neurons in fetal gut culture medium. AB - With the increasing use of bone marrow mesenchymal stem cells (BMSCs) in cell therapies, factors regulating BMSC differentiation have become the interest of current research. In this study, we investigated the effects of glial cell derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) on the course of BMSC differentiation. BMSCs were isolated from rat bone marrow and transfected with GDNF and NT-3 genes. Compared to mock-transfected BMSCs, GDNF and NT-3 induced BMSC differentiation to reveal neuron-like characteristics, i.e., the positive expression of neuronal marker MAP-2 and astrocyte marker GFAP, as detected by immunofluorescence assays. Semi-quantitative polymerase chain reaction (PCR) and western blot analyses showed that the increase of expression of GDNF and NT-3 in BMSCs also simultaneously elevated the mRNA expression of NSE, nestin, and MAP-2. Furthermore, the cell patch-clamp test demonstrated that the overexpression of GDNF and NT-3 in BMSCs enhanced voltage-activated potassium currents, implying that BMSCs possess great potential as a cell-based therapeutic candidate to treat neurological diseases. PMID- 25301496 TI - Decisional early interim (18)F-fluoro-2-deoxy-D-glucose positron emission tomography after two cycles of chemotherapy in de novo Hodgkin lymphoma. AB - BACKGROUND/AIMS: An early evaluation with positron emission tomography (FDG-PET) has been demonstrated to be a valuable tool in the prediction of Hodgkin lymphoma's outcome. Herein we report a retrospective study on the outcome of Hodgkin lymphoma treated in accordance with interim FDG-PET results. METHODS: 48 patients with de novo Hodgkin lymphoma were treated with 2 cycles of chemotherapy. According to the interim FDG-PET (PET2) evaluation, pre-established treatment was continued if PET2 was considered negative. Patients with a positive PET2 result underwent a salvage therapy. Progression-free survival (PFS) and overall survival (OS) were chosen as end points. RESULTS: PET2 scan results were negative for 37 patients and positive for 11 patients. After salvage therapy, 7/11 patients were in complete remission and 4 patients had stable disease and were considered for third-line therapy. After a median follow-up of 5.2 years, 46 patients were still alive. The 4-year PFS were 84.5 and 45.4% for PET2-negative and PET2-positive patients, respectively (p = 0.007). In multivariate analysis, PET2 scan and extranodal disease remained relevant on PFS (p = 0.001 and 0.009, respectively). No difference was seen in OS. CONCLUSION: Our retrospective study suggests that salvage therapy for non-responder Hodgkin lymphoma using interim FDG-PET could improve the PFS of this group of patients. PMID- 25301497 TI - The spread of Bradyrhizobium lineages across host legume clades: from Abarema to Zygia. AB - To analyze macroevolutionary patterns in host use by Bradyrhizobium root-nodule bacteria, 420 strains from 75 legume host genera (sampled in 25 countries) were characterized for portions of six housekeeping genes and the nifD locus in the symbiosis island chromosomal region. Most Bradyrhizobium clades utilized very divergent sets of legume hosts. This suggests that Bradyrhizobium spread across the major legume lineages early in its evolution, with only a few derived clades subsequently developing a narrower pattern of host use. Significant modularity existed in the network structure of recent host jumps (inferred from cases where closely related strain pairs were found on different legume taxa). This implies that recent host switching has occurred most often within particular subgroups of legumes. Nevertheless, the observed link structure would allow a bacterial lineage to reach almost any of the 75 legume host genera in a relatively small number of steps. However, permutation tests also showed that symbionts from certain host plant clades were significantly more similar than would be the case if bacteria were distributed at random on the trees. Related legumes thus harbored related sets of symbionts in some cases, indicating some degree of phylogenetic conservatism in partner selection. PMID- 25301498 TI - Oral antibiotic treatment induces skin microbiota dysbiosis and influences wound healing. AB - Antibiotic treatment eliminates commensal bacteria and impairs mucosal innate immune defenses in the gut. However, whether oral antibiotic treatment could alter the composition of the microbiota on the skin surface and influence innate immune responses remains unclear. To test this, mice were treated with vancomycin for 7 days and then wounds were made on the back skin of the mice. Five days later, scar tissue from each mouse was collected for bacterial enumeration, the bacterial composition on the scar and unwounded skin was determined using 16S RNA gene-based pyrosequencing analysis, and skin around wounds was collected for RNA extraction. Compared with the control group, the overall density and composition of skin bacteria were altered, and the proportion of Staphylococcus-related sequences was reduced in the vancomycin-treated group. Moreover, vancomycin treatment decreased the expression of RegIIIgamma and interleukin (IL)-17 in the wounded skin. Taken together, our data demonstrate that antibiotic treatment decreases the bacterial density and alters the bacterial composition in skin wounds, followed by a decrease in RegIIIgamma expression, which may contribute to the delayed wound repair. Our findings also indicate that antibiotic therapy should be carefully considered in the treatment of skin injury. PMID- 25301499 TI - Preliminary evidence for the organisation of a bacterial community by zooplanktivores at the top of an estuarine planktonic food web. AB - As part of a larger investigation, the effect of apex predation on estuarine bacterial community structure, through trophic cascading, was investigated using experimental in situ mesocosms. Through either the removal (filtration) or addition of specific size classes of planktonic groups, four different trophic scenarios were established using estuarine water and its associated plankton. One such treatment represented a "natural" scenario in which stable apex predatory pressure was qualified. Water samples were collected over time from each of the treatments for bacterial community evaluation. These samples were assessed through pyrosequencing of the variable regions 4 and 5 of the bacterial 16S rRNA gene and analysed at the species operational taxonomic unit (OTU) level using a community procedure. The blue-green group dominated the samples, followed by Proteobacteria and Bacteroidetes. Samples were the most similar among treatments at the commencement of the experiment. While the bacterial communities sampled within each treatment changed over time, the deviation from initial appeared to be linked to the treatment trophic scenarios. The least temporal deviation-from initial in bacterial community was found within the stable apex predatory pressure treatment. These findings are consistent with trophic cascade theory, whereby predators mediate interactions at multiple lower trophic levels with consequent repercussions for diversity. PMID- 25301500 TI - Carbonyl reduction in the biosynthesis of a male sex pheromone secreted by the grape borer Xylotrechus pyrrhoderus. AB - Males of the cerambycid beetle Xylotrechus pyrrhoderus release a mixture of (S)-2 hydroxy-3-octanone [(S)-1] and (2S,3S)-2,3-octanediol [(2S,3S)-2] as a sex pheromone that attracts conspecific females. The chemical structures of these pheromone components include a common motif and are assumed to be biosynthetically related. Here, we show that deuterated (S)-1, applied on the cuticle of a pronotal pheromone gland, was converted into (2S,3S)-2, that included deuterium atoms, but a reverse conversion did not take place. These results reveal a carbonyl reductase to be active in the pheromone gland, and that the ketol is a biosynthetic precursor of the diol. Males did not produce (R)-1; however, deuterated (R)-1 was converted into (2R,3R)-2, indicating an attack of the enzyme from the opposite side of the hydroxyl group at the 2-position. Furthermore, to understand the substrate specificity of the enzyme, racemates of 2-hydroxy-3-hexanone and 2-hydroxy-3-decanone were synthesized and applied to the gland. Their conversion into the corresponding diols suggests that the enzyme reduces the carbonyl group at the 3-position, regardless of the chain length. PMID- 25301501 TI - Establishing the need and identifying goals for a curriculum in medical business ethics: a survey of students and residents at two medical centers in Missouri. AB - BACKGROUND: In recent years, issues in medical business ethics (MBE), such as conflicts of interest (COI), Medicare fraud and abuse, and the structure and functioning of reimbursement systems, have received significant attention from the media and professional associations in the United States. As a result of highly publicized instances of financial interests altering physician decision making, major professional organizations and government bodies have produced reports and guidelines to encourage self-regulation and impose rules to limit physician relationships with for-profit entities. Nevertheless, no published curricula exist in the area of MBE. This study aimed to establish a baseline level of knowledge and the educational goals medical students and residents prioritize in the area of MBE. METHODS: 732 medical students and 380 residents at two academic medical centers in the state of Missouri, USA, completed a brief survey indicating their awareness of major MBE guidance documents, knowledge of key MBE research, beliefs about the goals of an education in MBE, and the areas of MBE they were most interested in learning more about. RESULTS: Medical students and residents had little awareness of recent and major reports on MBE topics, and had minimal knowledge of basic MBE facts. Residents scored statistically better than medical students in both of these areas. Medical students and residents were in close agreement regarding the goals of an MBE curriculum. Both groups showed significant interest in learning more about MBE topics with an emphasis on background topics such as "the business aspects of medicine" and "health care delivery systems". CONCLUSIONS: The content of major reports by professional associations and expert bodies has not trickled down to medical students and residents, yet both groups are interested in learning more about MBE topics. Our survey suggests potentially beneficial ways to frame and embed MBE topics into the larger framework of medical education. PMID- 25301502 TI - Naftopidil is useful for the treatment of malignant pleural mesothelioma. AB - Naftopidil, an alpha1-adrenoceptor blocker, induced apoptosis of human malignant pleural mesothelioma NCI-H2052 cells. Naftopidil upregulated the expression of tumor necrosis factor-alpha (TNF-alpha) mRNA in these cells. Naftopidil, alternatively, increased FasL secretion from NCI-H2052 cells, without affecting the expression of FasL mRNA and protein, and activated caspase-3 and -8 in NCI H2052 cells. Naftopidil drastically suppressed tumor growth in mice inoculated with these cells. The results of the present study indicate that naftopidil induces apoptosis of NCI-H2052 cells by upregulating the expression of TNF-alpha and stimulating the secretion of FasL, a ligand for the death receptor Fas, both to activate caspase-8 and the effector caspase-3, leading to the suppression of NCI-H2052 cell proliferation in vivo. This raises the possibility that naftopidil could be developed as an effective drug for the treatment of malignant pleural mesothelioma. PMID- 25301503 TI - Self-reported quality of life of adolescents with cerebral palsy: a cross sectional and longitudinal analysis. AB - BACKGROUND: Children with cerebral palsy who can self-report have similar quality of life (QoL) to their able-bodied peers. Is this similarity also found in adolescence? We examined how self-reported QoL of adolescents with cerebral palsy varies with impairment and compares with the general population, and how factors in childhood predict adolescent QoL. METHODS: We report QoL outcomes in a longitudinal follow-up and cross-sectional analysis of individuals included in the SPARCLE1 (childhood) and SPARCLE2 (adolescent) studies. In 2004 (SPARCLE1), a cohort of 818 children aged 8-12 years were randomly selected from population based cerebral palsy registers in nine European regions. We gathered data from 500 participants about QoL with KIDSCREEN (ten domains); frequency of pain; child psychological problems (Strengths and Difficulties Questionnaire); and parenting stress (Parenting Stress Index). At follow-up in 2009 (SPARCLE2), 355 (71%) adolescents aged 13-17 years remained in the study and self-reported QoL (longitudinal sample). 76 additional adolescents self-reported QoL in 2009, providing data for 431 adolescents in the cross-sectional sample. Researchers gathered data at home visits. We compared QoL against matched controls in the general population. We used multivariable regression to relate QoL of adolescents with cerebral palsy to impairments (cross-sectional analysis) and to childhood QoL, pain, psychological problems, and parenting stress (longitudinal analysis). FINDINGS: Severity of impairment was significantly associated (p<0.01) with reduced adolescent QoL on only three domains (Moods and emotions, Autonomy, and Social support and peers); average differences in QoL between the least and most able groups were generally less than 0.5 SD. Adolescents with cerebral palsy had significantly lower QoL than did those in the general population in only one domain (Social support and peers; mean difference -2.7 [0.25 SD], 95% CI -4.3 to 1.4). Pain in childhood or adolescence was strongly associated with low adolescent QoL on eight domains. Childhood QoL was a consistent predictor of adolescent QoL. Child psychological problems and parenting stress in childhood or their worsening between childhood and adolescence predicted only small reductions in adolescent QoL. INTERPRETATION: Individual and societal attitudes should be affected by the similarity of the QoL of adolescents with and without cerebral palsy. Adolescents with cerebral palsy need particular help to maintain and develop peer relationships. Interventions in childhood to alleviate psychological difficulties, parenting stress, and especially pain, are justified for their intrinsic value and for their longer term effect on adolescent QoL. FUNDING: SPARCLE1 was funded by the European Union Research Framework 5 Program (grant number QLG5-CT-2002-00636), the German Ministry of Health GRR-58640-2/14, and the German Foundation for the Disabled Child. SPARCLE2 was funded by: Wellcome Trust WT086315 A1A (UK and Ireland); Medical Faculty of the University of Lubeck E40 2009 and E26-2010 (Germany); CNSA, INSERM, MiRe-DREES, and IRESP (France); Ludvig and Sara Elsass Foundation, The Spastics Society and Vanforefonden (Denmark); Cooperativa Sociale "Gli Anni in Tasca" and Fondazione Carivit, Viterbo (Italy); Goteborg University-Riksforbundet for Rorelsehindrade Barn och Ungdomar and the Folke Bernadotte Foundation (Sweden). PMID- 25301504 TI - Quality of life in adolescents with cerebral palsy. PMID- 25301506 TI - Vibrant Soundbridge rehabilitation of sensorineural hearing loss. AB - The Vibrant Soundbridge is a means to rehabilitate patients with sensorineural hearing loss. It differs from hearing aids in that it uses mechanical energy rather than acoustic sound to deliver better sound quality to the inner ear. The implant's crucial component is a floating mass transducer that is directly fixed to the incus to drive it, which is introduced into the middle ear through a facial recess approach. Although this is a newer technology, studies thus far have demonstrated better hearing results compared with hearing aids in terms of functional gain and speech intelligibility, and better outcomes on subjective assessments. PMID- 25301505 TI - Livebirth after uterus transplantation. AB - BACKGROUND: Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported. METHODS: In 2013, a 35 year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved. FINDINGS: The recipient and the donor had essentially uneventful postoperative recoveries. The recipient's first menstruation occurred 43 days after transplantation and she continued to menstruate at regular intervals of between 26 and 36 days (median 32 days). 1 year after transplantation, the recipient underwent her first single embryo transfer, which resulted in pregnancy. She was then given triple immunosuppression (tacrolimus, azathioprine, and corticosteroids), which was continued throughout pregnancy. She had three episodes of mild rejection, one of which occurred during pregnancy. These episodes were all reversed by corticosteroid treatment. Fetal growth parameters and blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. The patient was admitted with pre-eclampsia at 31 full weeks and 5 days, and 16 h later a caesarean section was done because of abnormal cardiotocography. A male baby with a normal birthweight for gestational age (1775 g) and with APGAR scores 9, 9, 10 was born. INTERPRETATION: We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility. Furthermore, the results show the feasibility of live uterus donation, even from a postmenopausal donor. FUNDING: Jane and Dan Olsson Foundation for Science. PMID- 25301507 TI - Otologics active middle ear implants. AB - This article describes outcomes for the Otologics active middle ear implant for the semi-implantable and fully implantable (Carina, Otologics LLC, Boulder, CO) devices. Inclusion and exclusion criteria are reported in detail for surgical and audiologic management. Results from the clinical trial demonstrated no change for unaided air and bone conduction thresholds and no significant change in monosyllabic word scores or sentences in noise. Experiments are reported for conductive and mixed types of hearing losses in animal and human cadaveric models. These devices are in their infancy, and further study is needed to better identify candidates and develop appropriate expectations. PMID- 25301508 TI - Simulated annealing based hybrid forecast for improving daily municipal solid waste generation prediction. AB - A simulated annealing (SA) based variable weighted forecast model is proposed to combine and weigh local chaotic model, artificial neural network (ANN), and partial least square support vector machine (PLS-SVM) to build a more accurate forecast model. The hybrid model was built and multistep ahead prediction ability was tested based on daily MSW generation data from Seattle, Washington, the United States. The hybrid forecast model was proved to produce more accurate and reliable results and to degrade less in longer predictions than three individual models. The average one-week step ahead prediction has been raised from 11.21% (chaotic model), 12.93% (ANN), and 12.94% (PLS-SVM) to 9.38%. Five-week average has been raised from 13.02% (chaotic model), 15.69% (ANN), and 15.92% (PLS-SVM) to 11.27%. PMID- 25301509 TI - Erection of the haploporid genus Litosaccus n. g. and its phylogenetic relationship within the Haploporidae Nicoll, 1914. AB - Litosaccus n. g. is erected for Paralecithobotrys brisbanensis Martin, 1974 n. comb. for which an amended description is given. The new genus is morphologically similar to the haploporine Lecithobotrys Looss, 1902 but with a more elongate and cylindrical body; an infundibuliform oral sucker; a thin-walled hermaphroditic sac; a shallow genital atrium; and unequal, cylindrical and elongated caeca. It also resembles Pseudolecithobotrys Blasco-Costa, Gibson, Balbuena, Raga & Kostadinova, 2009, but the only member of that genus has a hermaphroditic sac that is twice the length of the ventral sucker, a hermaphroditic duct with intensely-staining cuboidal cells, an elongate testis, and single or paired caeca. A Bayesian inference analysis of partial 28S rDNA sequences of L. brisbanensis and 24 other haploporoids revealed that L. brisbanensis grouped with other haploporines and placed Intromugil Overstreet & Curran, 2005 in a clade with the chalcinotrematine Saccocoelioides Szidat, 1954 rather than the other seven tested waretrematine species. This analysis represents the first phylogenetic study of the Haploporidae Nicoll, 1914 that incorporates a haploporine from outside of the Mediterranean Sea. PMID- 25301510 TI - Diplostomum von Nordmann, 1832 (Digenea: Diplostomidae) in the sub-Arctic: descriptions of the larval stages of six species discovered recently in Iceland. AB - Frequent infections with Diplostomum spp. (Digenea: Diplostomidae) were found in the freshwater snail Radix peregra (Muller) and three fish species, the salmonids Salmo trutta fario L., Salvelinus alpinus (L.) and the gasterosteid Gasterosteus aculeatus L., collected in four lakes in south-western Iceland in 2012. Detailed analysis of the isolates integrating molecular, morphological and ecological data revealed that these belong to Diplostomum spathaceum (Rudolphi, 1819) and five putative new species (three infecting both snails and fish). This paper provides detailed descriptions of the metacercariae of the six species-level lineages of Diplostomum spp. and of the cercariae of three of the lineages discovered in Iceland with comments on the application of ITS1 rDNA for species distinction within Diplostomum von Nordmann, 1832 in the light of the novel data. We strongly suggest the use of molecular evidence based on cox1 gene sequences (in addition to ITS1-5.8S-ITS2 sequences) in association with detailed assessment of the morphology of the larval stages in future studies of Diplostomum spp. in fish and snails. PMID- 25301511 TI - Lamellodiscus aff. euzeti Diamanka, Boudaya, Toguebaye & Pariselle, 2011 (Monogenea: Diplectanidae) from the gills of Cheimerius nufar (Valenciennes) (Pisces: Sparidae) collected in the Arabian Sea, with comments on the distribution, specificity and historical biogeography of Lamellodiscus spp. AB - Specimens of Lamellodiscus Johnston & Tiegs, 1922 (Monogenea: Diplectanidae) were collected from the gills of Cheimerius nufar (Valenciennes) (Sparidae) in the Arabian Sea. All of these parasites belonged to one and the same species, which is morphologically very close to L. euzeti Diamanka, Boudaya, Toguebaye & Pariselle, 2011. A different host, distant locality and small morphological differences compared with the original description of L. euzeti acted as a stimulus for a detailed redescription. The specimens from the Arabian Sea differ slightly in the details of the male copulatory organ (MCO) from the type specimens of L. euzeti, which were re-examined, and from the respective drawings in its original description. Such differences include a longer inner process of the large element of the accessory piece associated with the proximal part of the copulatory tube, a longer point on the small element of the accessory piece associated with the distal part of the copulatory tube, and the presence of a smooth or slightly folded inner margin of this element rather than structures resembling spines which occur in the type-specimens of L. euzeti. Therefore, the present specimens infecting C. nufar in the Indo-Pacific may represent a different, but morphologically very similar species to the Atlantic form L. euzeti; consequently, they are recognised here as Lamellodiscus aff. euzeti. This form belongs to the 'ignoratus s. str.' subgroup of the genus. The composition of this subgroup is redefined to comprise 17 species, including L. corallinus Paperna, 1965 but excluding L. acanthopagri Roubal, 1981, and the morphology of the MCO of representatives of this group is clarified. A link between the diversity of Lamellodiscus species and the ancestral origin of present-day sparid species in the Tethys Sea is suggested. It is shown that Lamellodiscus spp. exhibit rather high levels of specificity to their hosts, since half of them parasitise only a single host species and c.90% infect closely related host species. Comparison of the levels of host-specificity of the species of this genus with other narrowly specific genera of the Dactylogyridea revealed that their estimations are comparable. The possibility of intra-host speciation within Lamellodiscus is discussed. It is shown that a co-evolutionary model is more discernible if it includes data on the occurrence of morphologically similar species from different regions and host taxa. PMID- 25301512 TI - A new species of Plectognathotrema Layman, 1930 (Trematoda: Zoogonidae) from an Australian monacanthid, with a molecular assessment of the phylogenetic position of the genus. AB - During helminthological examinations of teleost fishes of Ningaloo Reef, Western Australia, a new species of the enigmatic genus Plectognathotrema Layman, 1930 was discovered infecting the pot-bellied leatherjacket Pseudomonacanthus peroni (Hollard). The new species, Plectognathotrema kamegaii n. sp., is formally described, and the status of its four congeners is reviewed. Plectognathotrema hydrolagi Olson, Hanson & Pratt, 1970 is not recognised within the genus, as it differs greatly from its congeners in the form and arrangement of the vitellarium, testes and uterus, and in that it was described from a holocephalan. Plectognathotrema cephalopore Layman, 1930 and P. tsushimaense Kamegai, 1970 are morphologically similar, were described from the same host species and from close geographical localities and are considered synonymous. The new taxon is most similar to P. cephalopore, but differs from it in being much smaller and possessing a distinctly larger oral sucker relative to its body size. The generation of novel partial 28S ribosomal DNA sequences allowed a phylogenetic assessment of the genus and demonstrated that Plectognathotrema clearly belongs in the Zoogonidae Odhner, 1902, rather than in the Fellodistomidae Nicoll, 1909, where it is currently assigned. With the inclusion of Plectognathotrema in the Zoogonidae, there are now three zoogonid genera for which the species are restricted to monacanthid teleosts, i.e. Cephaloporus Yamaguti, 1934, Plectognathotrema and Yamagutiplectognathotrema Parukhin, 1977. Species of these genera share pronounced morphological and ecological affinities and a previously synonymised subfamily, the Cephaloporinae Yamaguti, 1934, is resurrected for them. The host specificity of these trematodes is commented upon. PMID- 25301513 TI - Tripius gyraloura n. sp. (Aphelenchoidea: Sphaerulariidae) parasitic in the gall midge Lasioptera donacis Coutin (Diptera: Cecidomyiidae). AB - A new nematode, Tripius gyraloura n. sp., is described from the arundo gall midge, Lasioptera donacis Coutin (Diptera: Cecidomyiidae). This gall midge is being considered as a biological control agent for use in North America against the introduced giant reed Arundo donax (L.) (Poaceae: Cyperales). Thus the present study was initiated to investigate a nematode parasite that was unknown at the time studies with L. donacis were initiated. The new species has a rapid development in the fly host and the mature parasitic female nematodes evert their uterine cells in the hosts' hemolymph. Because large numbers of nematodes sterilise the host, eradication of the parasite from laboratory colonies of the midge may be necessary before populations of the fly are released. PMID- 25301514 TI - Isospora celata n. sp. (Apicomplexa: Eimeriidae) from the orange-crowned warbler Oreothlypis celata (Say) (Passeriformes: Parulidae) in Mexico. AB - A new coccidian species (Protista: Apicomplexa: Eimeriidae) is described from the orange-crowned warbler Oreothlypis celata (Say) collected in the Nevado de Toluca National Park, Mexico at 3,000 metres above sea level. Isospora celata n. sp. has subspheroidal oocysts, measuring 28.4 * 26.4 MUm, with smooth, bi-layered wall c.1.2 MUm thick. Micropyle and polar granule are absent, but oocyst residuum is present as a compact mass. Sporocysts are ovoidal, 18.2 * 12.8 um. Stieda body knob-like and sub-Stieda body irregular and barely discernible. Sporocyst residuum is composed of granules of different sizes. Sporozoites are vermiform with one refractile body and a nucleus. This is the third description of an isosporoid coccidian infecting a New World warbler. PMID- 25301515 TI - New species of Spauligodon Skrjabin, Schikhobalova & Lagodovskaja, 1960 and Thubunea Seurat, 1914 (Nematoda) from the gastro-intestinal tract of lizards in Iran. AB - As part of a faunistic study on helminth parasites of Iranian lizards collected from localities in the north of Isfahan province in Iran, two new nematode species belonging to two different families, Pharyngodonidae Travassos, 1919 and Physalopteroidae Railliet, 1893, were found and are, hereby, described. Spauligodon persiensis n. sp. from the large intestine of Cyrtopodion scabrum Heyden is characterised by its imperceptible lateral alae, lack of spicule, different shape of the genital curtain, position of last pair of papillae, aspinose tail in males, position of the vulva and excretory pore, and a tail filament with six to nine spines in females. Thubunea mobedii n. sp. from the stomach of Laudakia nupta nupta (De Filipi) differs from the other species in the genus by possessing a vulva at level of the posterior portion of the oesophageal intestinal junction in females, lacking spicules, and having a different number of papillae in males. The present paper provides the results of detailed morphological examination of the two new nematode species, using both light and scanning electron microscopy. Taxonomically important characteristics for the members of the two nematode genera, Spauligodon Skrjabin, Schikhobalova & Lagodovskaja, 1960 and Thubunea Seurat, 1914, are also reviewed. PMID- 25301516 TI - Highly cited articles in health care sciences and services field in Science Citation Index Expanded. A bibliometric analysis for 1958 - 2012. AB - OBJECTIVE: This study aimed to identify and analyze characteristics of highly cited articles published in the Web of Science category of health care sciences and services from 1958 to 2012. METHODS: Articles that have been cited at least 100 times were assessed regarding publication outputs, distribution of outputs in journals, publications of authors, institutions, countries as well as citation life cycles of the articles with the highest total citations since its publication up to 2012 and the highest citations in 2012. Six bibliometric indicators were used to evaluate source countries, institutions, and authors. Total citations from the time the articles were first published to the end of 2012 and citations in 2012 only were applied. Additionally, Y-index was applied to evaluate publication characteristics of authors. A high percentage of authors had the same numbers of first author and corresponding author status of highly cited articles in health care sciences and services field. RESULTS: RESULTS showed that 890 of the most highly referenced articles, published between 1977 and 2009, had been cited at least 100 times. Medical Care and Journal of General Internal Medicine published the most highly cited articles. The United States produced 76% of highly cited articles and also published the most number of independent, internationally collaborative, first authored, corresponding authored, and single author highly cited articles. The Harvard University was the most productive institute and was number one for the total highly cited articles, inter-institutionally collaborative articles, single institution articles, first author articles, and corresponding author articles. CONCLUSIONS: The application of quantitative techniques in the analysis of highly cited articles can improve the researchers' understanding of the directions in health care sciences and services field. Y-index is useful for the evaluation of contributing authors. PMID- 25301517 TI - Sustainable carbon materials. AB - Carbon-based structures are the most versatile materials used in the modern field of renewable energy (i.e., in both generation and storage) and environmental science (e.g., purification/remediation). However, there is a need and indeed a desire to develop increasingly more sustainable variants of classical carbon materials (e.g., activated carbons, carbon nanotubes, carbon aerogels, etc.), particularly when the whole life cycle is considered (i.e., from precursor "cradle" to "green" manufacturing and the product end-of-life "grave"). In this regard, and perhaps mimicking in some respects the natural carbon cycles/production, utilization of natural, abundant and more renewable precursors, coupled with simpler, lower energy synthetic processes which can contribute in part to the reduction in greenhouse gas emissions or the use of toxic elements, can be considered as crucial parameters in the development of sustainable materials manufacturing. Therefore, the synthesis and application of sustainable carbon materials are receiving increasing levels of interest, particularly as application benefits in the context of future energy/chemical industry are becoming recognized. This review will introduce to the reader the most recent and important progress regarding the production of sustainable carbon materials, whilst also highlighting their application in important environmental and energy related fields. PMID- 25301518 TI - Effects of hesperidin, a flavanone glycoside interaction on the conformation, stability, and aggregation of lysozyme: multispectroscopic and molecular dynamic simulation studies? AB - Hesperidin (HESP), a flavanone glycoside, shows high antioxidant properties and possess ability to go through the blood-brain barrier. Therefore, it could be a potential drug molecule against aggregation based diseases such as Alzheimer's, Parkinson's, and systemic amyloidoses. In this work, we investigated the potential of HESP to interact with hen egg-white lysozyme (HEWL) monomer and prevent its aggregation. The HESP-HEWL binding studies were performed using a fluorescence quenching technique, molecular docking and molecular dynamics simulations. We found a strong interaction of HESP with the lysozyme monomer (Ka, ~ 5 * 10(4) M(-1)) mainly through hydrogen bonding, water bridges, and hydrophobic interactions. We showed that HESP molecule spanned the highly aggregation prone region (amino acid residues 48-101) of HEWL and prevented its fibrillar aggregation. Further, we found that HESP binding completely inhibited amorphous aggregation of the protein induced by disulfide-reducing agent tries-(2 carboxyethyl) phosphine. Conformational and stability studies as followed by various tertiary and secondary structure probes revealed that HESP binding only marginally affected the lysozyme monomer conformation and increased both stability and reversibility of the protein against thermal denaturation. Future studies should investigate detail effects of HESP on solvent dynamics, structure, and toxicity of various aggregates. The answers to these questions will not only target the basic sciences, but also have application in biomedical and biotechnological sciences. PMID- 25301520 TI - Left ventricular electrical activation during right ventricular pacing in heart failure patients with LBBB: visualization by electrocardiographic imaging and implications for cardiac resynchronization therapy. AB - OBJECTIVE: Assess effect of right ventricular pacing (RVP) on left ventricular (LV) activation in heart failure patients with left bundle branch block (LBBB). BACKGROUND: LV activation during RVP is regarded as similar to LBBB; hence novel CRT algorithms may avoid RVP by adopting "fusion" pacing with intrinsic RBB mediated conduction. However, other CRT techniques demand RV paced wavefronts for optimal resynchronization. Appropriate selection may require attention to interaction between RVP-generated wavefronts with preexisting conduction abnormalities posed by LBBB i.e. transseptal delay and LV activation. We hypothesized that LV activation during RVP would differ to LBBB. METHODS: Eleven patients (59+/-19years, 8 male, LV ejection fraction 25+/-10%; ischemic etiology 45%) were studied 5.4+/-5months after CRT implant. All had intact AV conduction with LBBB (PR interval 204+/-55; QRS 167+/-27ms) prior to CRT. None had mid septal/outflow tract lead positions. Using non-invasive electrocardiographic imaging (ECGI), LV activation was contrasted in each patient between intrinsic conduction and RVP with minimized AV interval (i.e. committing ventricular excitation to the paced wavefront). RESULTS: RVP affected LV activation variably. Transseptal time decreased in 64% of patients. More LV conduction barriers were created than resolved, slowing LV free wall activation from 67+/-29ms during intrinsic conduction to 104+/-24ms with RVP (p=0.025). The load of late-activated LV myocardium increased in 73% but decreased in 27% patients. Changes were not reflected by QRS duration. Ultimate action of RVP in any patient depended on summary effects of transseptal breakthrough and following LV activation. If both were enhanced then LV preexcitation occurred. If one was delayed but other accelerated, then the outcome of their balance determined the ultimate effect on LV depolarization. CONCLUSIONS: RVP may aggravate or resolve LBBB-induced conduction problems at one or more levels. Its avoidance vs integration (or timing relative to LV pacing) during CRT depends on its electrical action in any particular individual. PMID- 25301519 TI - Community violence exposure and severe posttraumatic stress in suburban American youth: risk and protective factors. AB - PURPOSE: The psychological effects of community violence exposure among inner city youth are severe, yet little is known about its prevalence and moderators among suburban middle-class youth. This study aimed to assess the prevalence of community violence exposure among suburban American youth, to examine associated posttraumatic stress and to evaluate factors related to severe vs. less severe posttraumatic stress, such as co-existing internalizing and externalizing problems, as well as the effects of teacher support, parental warmth and support, perceived neighborhood safety and conventional involvement in this context. METHOD: Data were collected from 780 suburban, predominantly Caucasian middle class high-school adolescents in the Northeastern US during the Social and Health Assessment (SAHA) study. RESULTS: A substantial number of suburban youth were exposed to community violence and 24% of those victimized by community violence developed severe posttraumatic stress. Depressive symptoms were strongly associated with higher levels and perceived teacher support with lower levels of posttraumatic stress. CONCLUSION: Similar to urban youth, youth living in suburban areas in North American settings may be affected by community violence. A substantial proportion of these youth reports severe posttraumatic stress and high levels of comorbid depressive symptoms. Teacher support may have a protective effect against severe posttraumatic stress and thus needs to be further assessed as a potential factor that can be used to mitigate the detrimental effects of violence exposure. PMID- 25301521 TI - Publish rates of health gain resulting from treatment. PMID- 25301522 TI - Propofol-induced pain sensation involves multiple mechanisms in sensory neurons. AB - Propofol, a commonly used intravenous anesthetic agent, is known to at times cause pain sensation upon injection in humans. However, the molecular mechanisms underlying this effect are not fully understood. Although propofol was reported to activate human transient receptor potential ankyrin 1 (TRPA1) in this regard, its action on human TRP vanilloid 1 (TRPV1), another nociceptive receptor, is unknown. Furthermore, whether propofol activates TRPV1 in rodents is controversial. Here, we show that propofol activates human and mouse TRPA1. In contrast, we did not observe propofol-evoked human TRPV1 activation, while the ability of propofol to activate mouse TRPV1 was very small. We also found that propofol caused increases in intracellular Ca(2+) concentrations in a considerable portion of dorsal root ganglion (DRG) cells from mice lacking both TRPV1 and TRPA1, indicating the existence of TRPV1- and TRPA1-independent mechanisms for propofol action. In addition, propofol produced action potential generation in a type A gamma-amino butyric acid (GABAA) receptor-dependent manner. Finally, we found that both T-type and L-type Ca(2+) channels are activated downstream of GABAA receptor activation by propofol. Thus, we conclude that propofol may cause pain sensation through multiple mechanisms involving not only TRPV1 and TRPA1 but also voltage-gated channels downstream of GABAA receptor activation. PMID- 25301524 TI - Electrical stimulation for cortical mapping reduces the density of high frequency oscillations. AB - BACKGROUND: High frequency oscillations (HFOs, 80-500 Hz) are EEG biomarkers for epileptogenic areas. HFOs are also indicators of disease activity as HFO rates increase after reduction of antiepileptic medication. Electrical stimulation (ES) can be used for diagnostic purposes as well as therapy in patients with refractory epilepsy. This study investigates the occurrence and changes of HFOs during ES in patients with refractory epilepsy. OBJECTIVE: Analysis of the effects of ES using intracranial ES on the occurrence of epileptic HFOs. METHODS: Patients underwent ES for diagnostic purposes. Ripples (80-200 Hz) and fast ripples (200-500 Hz) were visually marked in a baseline EEG segment prior to ES, after each period of ES as well as after the end of ES. In patients in whom ES triggered a seizure a pre- and postictal segment was marked. Rates of HFOs were compared for the different time periods using a Spearman's correlation and Wilcoxon rank sum test (p<0.05). RESULTS: 12 patients with 911 EEG channels were analyzed. Ripple (r=-0.42, p<0.001) as well as fast ripple (r=-0.21, p<0.001) rates decreased significantly over the course of stimulation. This phenomenon was not focal over the seizure onset or neighboring contacts but even observed over distant contacts. CONCLUSIONS: ES resulted in a gradual decrease of HFO-Rates over time. The decrease of HFOs was not limited to SOZ areas. If HFOs are considered as markers of disease activity the reduction in HFO-rates as a result of intracranial ES has to be interpreted as a reduction of disease activity. PMID- 25301525 TI - Association of brain-derived neurotrophic factor (BDNF) and elongator protein complex 4 (ELP4) polymorphisms with benign epilepsy with centrotemporal spikes in a Greek population. AB - PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common childhood epileptic syndrome. Different mutations in genes that control the excitability of neurons have been described. Recent reports on the involvement of the BDNF and ELP4 genes in cell motility, migration, and adhesion raise the possibility that these genes are involved in pathogenesis of BECTS. MATERIALS AND METHODS: We conducted a case-control association study on 60 patients with BECTS and 60 control participants to assess the influence of the BDNF and ELP4 polymorphisms on BECTS. The polymorphisms were detected with a PCR RFLP method. Moreover, we explored the possible association of these polymorphisms with clinical and electroencephalographic parameters of patients with BECTS. RESULTS: Our results show no difference in BDNF and ELP4 genotype frequencies between patients and controls. Haplotype analysis also revealed no statistical difference. CONCLUSION: The role of BDNF and ELP4 polymorphisms remains controversial. PMID- 25301526 TI - Characterization of Streptococcus pneumoniae clones from paediatric patients with cystic fibrosis. AB - The role of Streptococcus pneumoniae in cystic fibrosis (CF) is poorly understood. The pneumococcal population has changed over time after the introduction of the heptavalent conjugate vaccine (PCV7) and, more recently, the 13-valent conjugate vaccine (PCV13). Although serotypes and clones causing invasive pneumococcal disease or colonizing healthy children have been extensively analysed, little is known so far on the serotypes and clones of pneumococci in CF patients. The aim of this work was to investigate serotypes, antibiotic susceptibilities, genotypes and biofilm production of CF pneumococcal isolates. Overall, 44 S. pneumoniae strains collected from 32 paediatric CF patients from January 2010 to May 2012 in a large Italian CF Centre were tested for antimicrobial susceptibility testing by Etest, serotyped by the Quellung reaction and genotyped by a combination of different molecular typing methods, including pbp gene restriction profiling, pspA restriction profiling and sequencing, PFGE and multilocus sequence typing. Biofilm production by pneumococcal strains was also assessed. Penicillin non-susceptibility was 16 %. High resistance rates (>56 %) were observed for erythromycin, clindamycin and tetracycline. The most frequent serotype recovered was serotype 3 (31.8 %). The coverage of PCV7 and PCV13 was 6.8 and 47.7 %, respectively. More than 80 % of CF strains belonged to Pneumococcal Molecular Epidemiology Network (PMEN) reference clones, the most common being Netherlands(3)-ST180 (28.2 %), and Greece(21) 30/ST193 (15.4 %). All strains produced biofilm in vitro, although with large variability in biofilm formation efficiency. No correlation was found between biofilm levels and serotype, clone or antibiotic resistance. The high isolation rate of antibiotic-resistant serotype 3 pneumococci from CF patients suggests that PCV13 could increase protection from pneumococcal colonization and infection. PMID- 25301527 TI - Western dietary pattern interaction with APOC3 polymorphism in the risk of metabolic syndrome: Tehran Lipid and Glucose Study. AB - BACKGROUND/AIMS: Gene-dietary pattern interactions may contribute to the determination of a susceptibility to metabolic syndrome (MetS). The aim of this study was to evaluate the potential interactions of dietary patterns with the common genetic variant of APOC3 in relation to MetS in adults. METHODS: In this individual matched nested case-control study, 755 MetS subjects and 755 controls were selected from among participants in the Tehran Lipid and Glucose Study. Dietary patterns were determined by factor analysis. APOC3 3238C>G rs5128 was genotyped by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Fat-sweet, healthy and Western dietary patterns (WDP) were extracted from the data. In the joint analysis, the associations of the WDP and APOC3 rs5128 with MetS risk tended to be dependent on APOC3 3238C>G gene variants (p for interaction = 0.009) in women. The MetS risk was increased in women with the CC genotype with increasing tertiles of WDP scores compared with women with the CG + GG genotype, whose MetS risk was decreased with increasing tertiles of WDP scores. In addition, we found that intakes of fast food, salty snacks and soft drinks showed significant interactions with the rs5128 genotypes in relation to MetS risk (p for interactions <0.05). CONCLUSION: The results obtained demonstrate a diet-gene interaction between APOC3 rs5128 polymorphism and the WDP in relation to MetS risk. PMID- 25301528 TI - Duration of gestation and mode of delivery affect the genes of transepithelial sodium transport in pulmonary adaptation. AB - BACKGROUND: Respiratory distress due to inadequate lung liquid clearance is a significant problem in infants delivered late preterm or early term, especially by elective cesarean delivery (CD). Lung liquid clearance depends on epithelial ion transport and in animals is induced by glucocorticoids. OBJECTIVES: In newborn late preterm and term infants to study airway epithelial gene expressions of epithelial sodium channel (ENaC), and the serum and glucocorticoid-inducible kinase 1 (SGK1), and their association with cortisol, mode of delivery, and gestational age (GA). METHODS: Infants were delivered at 35(0/7)-41(6/7) weeks. Cortisol in umbilical cord plasma was analyzed with liquid chromatography-tandem mass spectrometry. ENaC and SGK1 mRNAs in airway epithelial cells obtained within 3 h and at 1 day postnatally were quantified with real-time PCR. RESULTS: ENaC and SGK1 mRNAs were significantly lower in late preterm and early term infants than in those >= 39(0/7) weeks. Significant correlations existed between both ENaC and SGK1 and cord cortisol and GA. In term infants, SGK1 mRNA at 1.5 h was higher after vaginal delivery than elective CD. CONCLUSIONS: In late preterm and early term infants, low expression of ENaC and SGK1 may parallel insufficient lung liquid clearance predisposing to respiratory distress. Lower SGK1 expression after term CD could translate into insufficient sodium and lung liquid absorption. The findings demonstrate a central role for cortisol in regulation of ENaC and potentially perinatal sodium and lung liquid clearance. PMID- 25301529 TI - Impact of intravenous nitroglycerin in the management of acute decompensated heart failure. AB - Intravenous nitroglycerin is a well-known, but underused, treatment for acute decompensated heart failure. Nitroglycerin has a rapid onset of action and short half-life and there is a clear dose-response curve on both global hemodynamics and peripheral circulation. IV nitroglycerin reduces LV and RV filling pressures and afterload. In the case of acute decompensated heart failure, there is a typical decreased bioavailability of nitric oxide (NO), which needs to be supplemented by exogenous nitrates. Additionally, there is benefit on clinical endpoints, such as fast optimization of arterial oxygenation, lower rates of mechanical ventilation, and improved survival. Drawbacks of therapy include not only side effects such as headache, resistance, and development of tolerability to nitrates but also free radical production. However, nitrates in combination with diuretics remain the cornerstone of acute decompensated heart failure treatment. We propose a more aggressive use of nitrates and a more limited use of inotropes (due to ischemic demand and pro-arrhythmogenic characteristics) in normo- or hypertensive patients with acute heart failure. PMID- 25301530 TI - Solid-state NMR resonance assignments of the filament-forming CARD domain of the innate immunity signaling protein MAVS. AB - The mitochondrial antiviral signalling protein (MAVS) is a central signal transduction hub in the innate immune response against viral infections. Viral RNA present in the cytoplasm is detected by retinoic acid inducible gene I like receptors, which then activate MAVS via heterotypic interactions between their respective caspase activation and recruitment domains (CARD). This leads to the formation of active, high molecular weight MAVS complexes formed by homotypic interactions between the single N-terminal CARDs of MAVS. Filaments formed by the N-terminal MAVS(CARD) alone are sufficient to induce the autocatalytic conversion from a monomeric to an aggregated state in a prion-like manner. Here, we present the nearly complete spectroscopic (13)C and (15)N resonance assignments of human MAVS(CARD) filaments obtained from a single sample by magic angle spinning solid state NMR spectroscopy. The corresponding secondary chemical shifts suggest that the filamentous form of MAVS(CARD) retains an exclusively alpha-helical fold that is very similar to the X-ray structure determined previously from monomeric MAVS(CARD)-maltose binding protein fusion constructs. PMID- 25301531 TI - Invasive Salmonella infections in Africa. PMID- 25301532 TI - Novel pharmaceuticals in the treatment of psychosis in Parkinson's disease. AB - Parkinson's disease (PD) affects 10 million people worldwide. Half will develop psychosis, the majority experiencing hallucinations rather than delusions. Emergence of psychosis increases the likelihood of institutionalization and mortality. Where pharmacological treatment is warranted, options are limited. Most currently licensed atypical antipsychotics are ineffective or worsen motor symptoms in people with PD. This review of provides an overview of the current landscape of treatments and the opportunities in emerging research. Clozapine is the only licensed antipsychotic with proven efficacy, although the associated side effects limit its use. With recent advances in understanding the role of serotonin, rational drug design approaches have delivered a novel pharmacological treatment with recently proven efficacy in clinical trials of people with PD and psychosis. Pimavanserin represents an important addition to treatment. PMID- 25301533 TI - Gonadotropin-releasing hormone (GnRH) receptors of cattle aggregate on the surface of gonadotrophs and are increased by elevated GnRH concentrations. AB - The presence of gonadotropin-releasing hormone (GnRH) receptors (GnRHRs) on gonadotrophs in the anterior pituitary (AP) is an important factor for reproduction control. However, little is known regarding GnRHR gene expression in gonadotrophs of cattle owing to the lack of an appropriate anti-GnRHR antibody. Therefore, an anti-GnRHR antibody for immunohistochemistry, flow cytometry, and immunocytochemistry assays was developed to characterize GnRHR gene expression in gonadotrophs. The anti-GnRHR antibody could suppress GnRH-induced LH secretion from cultured AP cells of cattle. The GnRHR, luteinizing hormone (LH), and follicle stimulating hormone (FSH) in the AP tissue was analyzed by fluorescence immunohistochemistry. The GnRHRs were aggregated on a limited area of the cell surface of gonadotrophs, possibly localized to lipid rafts. The LH secretion was stimulated with increasing amounts of GnRH; however, excessive concentrations (> 1 nM) resulted in a decrease in LH secretion. A novel method to purify gonadotrophs was developed using the anti-GnRHR antibody and fluorescence activated cell sorting. Flow cytometric analysis using the anti-GnRHR antibody for cultured bovine AP cells, however, failed to support the hypothesis that GnRH induces GnRHR internalization and decreases GnRHR on the surface of GnRHR positive AP cells. In contrast, immunocytochemistry using primary antibodies for cultured bovine AP cells showed that 10 nM (P < 0.05) and 100 nM (P < 0.01) GnRH, but not 0.01-1 nM GnRH, increased GnRHR in the cytoplasm of LH-positive cells. In conclusion, these data suggested that GnRHRs were aggregated on the surface of gonadotrophs and GnRHR inside gonadotrophs increased with elevated concentrations of GnRH. PMID- 25301534 TI - Metabolite and proteome changes during the ripening of Syrah and Cabernet Sauvignon grape varieties cultured in a nontraditional wine region in Brazil. AB - Grapevines are an important fruit crop from economic and cultural point of views in many countries, including Brazil, where the practice of vitiviniculture is being developed in different regions. We compared the anthocyanin concentration, the main organic acids and sugars, and the proteome profiles during berry ripening of Syrah and Cabernet Sauvignon grapes from two distinct geographical sources in Sao Paulo State. The proteome was mapped by two-dimensional gel electrophoresis and differentially abundant proteins during the ripening process were subjected to MALDI-TOF/TOF-MS analysis. An increase in sugar concentration and in anthocyanin content was observed, as well a decrease in the tartaric and malic acid concentration. A total of 128 spots varied with geographical origin, grape variety, and ripening stage, with 108 being identified. The identified proteins resulted in 80 gene products. A multivariate analysis of protein abundance clustered the samples according to grape variety, geographical origin, and stage of ripening, and showed the possibility of using proteomics to characterize three variables: variety, area where grown, and the ripening process. The changes observed during the ripening process corresponded to enzymes involved in sugar and organic acid metabolism. These results are in accordance with the metabolic profile reported for the process. BIOLOGICAL SIGNIFICANCE: Given the importance of discriminating grapes, thus making the adulteration of wines more difficult, in this paper we showed the possibility of differentiating varieties of grapes, geographical area of cultivation and stage of ripening by combining the results of differentially abundant protein determinations and multivariate analysis. PMID- 25301535 TI - Targeted quantitative analysis of a diurnal RuBisCO subunit expression and translation profile in Chlamydomonas reinhardtii introducing a novel Mass Western approach. AB - RuBisCO catalyzes the rate-limiting step of CO2 fixation in photosynthesis. Hypothetical mechanisms for the regulation of rbcL and rbcS gene expression assume that both large (LSU) and small (SSU) RuBisCO subunit proteins (RSUs) are present in equimolar amounts to fit the 1:1 subunit stoichiometry of the holoenzyme. However, the actual quantities of the RSUs have never been determined in any photosynthetic organism. In this study the absolute amount of rbc transcripts and RSUs was quantified in Chlamydomonas reinhardtii grown during a diurnal light/dark cycle. A novel approach utilizing more reliable protein stoichiometry quantification is introduced. The rbcL:rbcS transcript and protein ratios were both 5:1 on average during the diurnal time course, indicating that SSU is the limiting factor for the assembly of the holoenzyme. The oscillation of the RSUs was 9h out of phase relative to the transcripts. The amount of rbc transcripts was at its maximum in the dark while that of RSUs was at its maximum in the light phase suggesting that translation of the rbc transcripts is activated by light as previously hypothesized. A possible post-translational regulation that might be involved in the accumulation of a 37-kDa N-terminal LSU fragment during the light phase is discussed. BIOLOGICAL SIGNIFICANCE: A novel MS based approach enabling the exact stoichiometric analysis and absolute quantification of protein complexes is presented in this article. The application of this method revealed new insights in RuBisCO subunit dynamics. PMID- 25301536 TI - Degradation process of lead chromate in paintings by Vincent van Gogh studied by means of spectromicroscopic methods. Part 5. Effects of nonoriginal surface coatings into the nature and distribution of chromium and sulfur species in chrome yellow paints. AB - The darkening of lead chromate yellow pigments, caused by a reduction of the chromate ions to Cr(III) compounds, is known to affect the appearance of several paintings by Vincent van Gogh. In previous papers of this series, we demonstrated that the darkening is activated by light and depends on the chemical composition and crystalline structure of the pigments. In this work, the results of Part 2 are extended and complemented with a new study aimed at deepening the knowledge of the nature and distribution of Cr and S species at the interface between the chrome yellow paint and the nonoriginal coating layer. For this purpose, three microsamples from two varnished paintings by Van Gogh and a waxed low relief by Gauguin (all originally uncoated) have been examined. Because nonoriginal coatings are often present in artwork by Van Gogh and contemporaries, the understanding of whether or not their application has influenced the morphological and/or physicochemical properties of the chrome yellow paint underneath is relevant in view of the conservation of these masterpieces. In all the samples studied, microscopic X-ray fluorescence (MU-XRF) and X-ray absorption near edge structure (MU-XANES) investigations showed that Cr(III)-based alteration products are present in the form of grains inside the coating (generally enriched of S species) and also homogeneously widespread at the paint surface. The distribution of Cr(III) species may be explained by the mechanical friction caused by the coating application by brush that picked up and redistributed the superficial Cr compounds, likely already present in the reduced state as result of the photodegradation process. The analysis of the XANES profiles allowed us to obtain new insights into the nature of the Cr(III) alteration products, that were identified as sulfate-, oxide-, organo-metal-, and chloride-based compounds. Building upon the knowledge acquired through the examination of original paint samples and from the investigation of aged model paints in the last Part 4 paper, in this study we aim to characterize a possible relation between the chemical composition of the coating and the chrome yellow degradation pathways by studying photochemically aged model samples covered with a dammar varnish contaminated with sulfide and sulfate salts. Cr speciation results did not show any evidence of the active role of the varnish and added S species on the reduction process of chrome yellows. PMID- 25301538 TI - Hydrocodone extended-release: pharmacodynamics, pharmacokinetics and behavioral pharmacology of a controversy. AB - Recently, the U.S. Food and Drug Administration (FDA) approved Zohydro((r)), an extended release formulation of the opioid analgesic hydrocodone that contains no acetaminophen. This approval was against the recommendation of the FDA's Expert Panel. Subsequently, both chronic pain advocates and anti-drug abuse advocates have steadfastly expressed their support of, or astonishment at this decision. Here, we review the pharmacokinetics, pharmacodynamics, safety and abuse liability of this hydrocodone formulation and how it relates to the Expert Panel's opinion and the FDA decision. We discuss the important issues, risk mitigation, potential use of abuse deterrents, and how the different viewpoints of the Expert Panel and FDA decision makers resulted in the approval and subsequent controversy. PMID- 25301537 TI - Efficacy and toxicity of abiraterone and docetaxel in octogenarians with metastatic castration-resistant prostate cancer. AB - OBJECTIVE: To assess the efficacy and toxicity of abiraterone and docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) of age >80 compared to younger men. METHODS: Retrospective chart review of 116 men treated with abiraterone and 378 men treated with docetaxel at Princess Margaret Cancer Centre. Categorical outcome measures including PSA response rate (PSA-RR) and incidence of toxic side-effects were compared using Fisher's exact test. Overall survival (OS) and biochemical progression free survival (bPFS) were analyzed using the Kaplan-Meier method and log-rank tests. RESULTS: Thirty-four (29%) and 50 (13%) of the men treated with abiraterone or docetaxel, respectively, were octogenarians. For abiraterone there were no significant differences in PSA-RR (42% vs. 39%), bPFS (4.7 vs. 4.4months) or OS (14.0 vs 20.7months) between octogenarians and younger men, respectively. Toxicity was mild with no significant differences between age groups. For men treated with docetaxel PSA-RR and OS did not differ between age groups (40% vs. 45% and 12.0 vs. 14.1months, respectively). However, rates of febrile neutropenia were 16% and 7% for octogenarians and younger men, respectively (p=0.048). This difference was observed despite greater use of lower dose intensity and weekly docetaxel in the elderly cohort, with 20% of them receiving lower than standard dose during their first cycle compared to 7% of younger men (p=0.004). CONCLUSIONS: Treatment outcome on abiraterone and docetaxel did not differ in patients over and under the age of 80, but febrile neutropenia was more common in octogenarians treated with docetaxel despite lower dose intensity. PMID- 25301539 TI - The trastuzumab and vinorelbine combination: an alternative to taxane-based chemotherapy for early-stage and locally advanced her2-positive breast cancer. AB - BACKGROUND: Anthracyclines and taxanes have historically constituted the backbone of chemotherapy regimens for patients with breast cancer positive for the human epidermal growth factor receptor 2 (her2). For a subset of patients who categorically refuse alopecia, or for those with a contraindication to those drugs, there is an urgent need to define alternative regimens. Here, we report our institutional experience with trastuzumab and vinorelbine (tv), a combination with good clinical activity and a good side effect profile for patients with her2 positive breast cancer. METHODS: In a retrospective analysis, outcomes data were extracted for patients receiving tv as their only chemotherapy in the non metastatic setting at the Jewish General Hospital. For the most part, tv was administered weekly for 6 months, followed by trastuzumab for 6 months. RESULTS: The analysis identified 46 patients (mean age: 64 years) who received tv between 2003 and 2012 (n = 36 adjuvant, n = 10 neoadjuvant). Of the patients in the adjuvant group, 81% had stage i disease. In the neoadjuvant group, 3 patients experienced a complete pathologic response. Only 1 patient experienced local recurrence after a short course (3 months) of adjuvant tv. Overall survival and breast cancer-specific survival were 94% and 98% respectively at a median 5 years of follow-up. Febrile neutropenia-induced sepsis resulted in the death of 1 patient with significant medical comorbidities; 2 other patients died of comorbidities unrelated to their cancer or treatment. Grades 3 or 4 adverse events included neutropenia (23%), febrile neutropenia (10%), fatigue (2%), and anemia (2%). CONCLUSIONS: For patients with non-metastatic breast cancer refusing alopecia, or for patients who are not candidates for standard chemotherapy, tv is a reasonable alternative to standard adjuvant chemotherapy. PMID- 25301540 TI - Litorivivens lipolytica gen. nov., sp. nov., a lipolytic bacterium isolated from a tidal flat. AB - A Gram-stain-negative, flagellated, aerobic and rod-shaped or ovoid bacterial strain, designated HJTF-7(T), was isolated from a tidal flat on the South Sea of South Korea, and its taxonomic position was investigated using a polyphasic approach. Strain HJTF-7(T) grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2.0% (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum-parsimony phylogenetic trees, based on 16S rRNA gene sequences, showed that strain HJTF-7(T) joined the cluster comprising the type strains of species of the genera Spongiibacter and Zhongshania. Strain HJTF-7(T) exhibited 16S rRNA gene sequence similarities of 90.4-92.5% to the type strains of species of the genera Spongiibacter and Zhongshania and of less than 91.5% to the type strains of other recognized species. Strain HJTF-7(T) contained Q-8 as the predominant ubiquinone. The major fatty acids were iso-C17:1omega9c, iso-C15:0, iso-C17:0, iso-C11:0 3-OH and C17:1omega8c and the major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. The fatty acid and polar lipid profiles of strain HJTF-7(T) were distinct from those of members of the genera Spongiibacter and Zhongshania. The DNA G+C content of strain HJTF-7(T) was 55.9 mol%. The phylogenetic data and differential chemotaxonomic and other phenotypic properties revealed that strain HJTF-7(T) represents a novel genus and species within the class Gammaproteobacteria, for which the name Litorivivens lipolytica gen. nov., sp. nov. is proposed. The type strain of Litorivivens lipolytica is HJTF-7(T) ( =KCTC 42157(T) =CECT 8654(T)). PMID- 25301541 TI - Spongiibacterium pacificum sp. nov., isolated from seawater of South Pacific Gyre and emended description of the genus Spongiibacterium. AB - A Gram-stain-negative, strictly aerobic, non-flagellated, non-gliding, oxidase positive and yellow-pigmented rod-shaped bacterium, designated strain SW169(T), was isolated from a surface seawater sample collected from the South Pacific Gyre (27 degrees 55' S 123 degrees 10' W) during the Integrated Ocean Drilling Program (IODP) Expedition 329. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SW169(T) belonged to the genus Spongiibacterium and showed the highest 16S rRNA gene sequence similarity with Spongiibacterium flavum A11(T) (95.9 %). It showed 16S rRNA gene sequence similarities of 93.2 94.8 % with members of the genera Croceitalea and Flagellimonas in the family Flavobacteriaceae. Optimal growth occurred in the presence of 3-4 % (w/v) NaCl, at pH 8.0 and at 28 degrees C. The DNA G+C content of strain SW169(T) was 43.3 mol%. The major fatty acids were iso-C15 : 1 G, iso-C15 : 0, iso-C17 : 0 3-OH, iso-C15 : 0 3-OH and summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c,). The major respiratory quinone was menaquinone-6. The major polar lipids were phosphatidylethanolamine, one unidentified aminolipid and one unidentified lipid. On the basis of the polyphasic analyses, strain SW169(T) is considered to represent a novel species of the genus Spongiibacterium, for which the name Spongiibacterium pacificum sp. nov. is proposed. The type strain is SW169(T) ( = JCM 18379(T) = LMG 26997(T)). An emended description of the genus Spongiibacterium is also provided. PMID- 25301542 TI - Pseudochelatococcus lubricantis gen. nov., sp. nov. and Pseudochelatococcus contaminans sp. nov. from coolant lubricants. AB - Two Gram-negative, rod-shaped, non-spore-forming bacteria, isolated from metal working fluids were investigated to determine their taxonomic positions. On the basis of 16S rRNA gene sequence phylogeny, both strains (MPA 1113(T) and MPA 1105(T)) formed a distinct cluster with 97.7 % sequence similarity between them, which was in the vicinity of members of the genera Methylobacterium, Camelimonas, Chelatococcus, Bosea, Salinarimonas and Microvirga to which they showed low sequence similarities (below 94 %). The predominant compounds in the polyamine pattern and in the quinone system of the two strains were spermidine and ubiquinone Q-10, respectively. The polar lipid profiles were composed of the major compounds: phosphatidylmonomethylethanolamine, phosphatidylglycerol, phosphatidylcholine, major or moderate amounts of diphosphatidylglycerol, two unidentified glycolipids and three unidentified aminolipids. Several minor lipids were also detected. The major fatty acids were either C19 : 0 cyclo omega8c or C18 : 1omega7c. The results of fatty acid analysis and physiological and biochemical tests allowed both, the genotypic and phenotypic differentiation of the isolates from each other, while the chemotaxonomic traits allowed them to be differentiated from the most closely related genera. In summary, low 16S rRNA gene sequence similarities and marked differences in polar lipid profiles, as well as in polyamine patterns, is suggestive of a novel genus for which the name Pseudochelatococcus gen. nov. is proposed. MPA 1113(T) ( = CCM 8528(T) = LMG 28286(T) = CIP 110802(T)) and MPA 1105(T) ( = CCM 8527(T) = LMG 28285(T)) are proposed to be the type strains representing two novel species within the novel genus, Pseudochelatococcus gen. nov., for which the names Pseudochelatococcus lubricantis sp. nov. and Pseudochelatococcus contaminans sp. nov. are suggested, respectively. PMID- 25301543 TI - Virgibacillus oceani sp. nov. isolated from ocean sediment. AB - A Gram-stain-positive, moderately halophilic, motile, strictly aerobic, endospore forming, rod-shaped bacterium, strain MY11(T), was isolated from a sediment sample collected from the Western Pacific. This isolate grew in the presence of 0.5-18% (w/v) NaCl and at pH 6.0-10.0 and 15-45 degrees C; optimum growth was observed with 3.5% (w/v) NaCl and at pH 8.0-9.0 and 35-37 degrees C. Strain MY11(T) had menaquinone 7 (MK-7) as the predominant respiratory quinone and anteiso-C15:0 and anteiso-C17:0 as major fatty acids. Major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The DNA G+C content was 34.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that strain MY11(T) was a member of the genus Virgibacillus, exhibiting sequence similarities of 95.3-97.6% to the type strains of recognized Virgibacillus species. Strain MY11(T) could be differentiated from recognized species of the genus Virgibacillus based on phenotypic characteristics, chemotaxonomic differences, phylogenetic analysis and DNA-DNA hybridization data. On the basis of the data presented, strain MY11(T) is considered to represent a novel species of the genus Virgibacillus, for which the name Virgibacillus oceani sp. nov. is proposed. The type strain is MY11(T) ( =LMG 28105(T) =CGMCC 1.12754(T) =MCCC 1A09973(T)). PMID- 25301544 TI - Analysis of material recovery facilities for use in life-cycle assessment. AB - Insights derived from life-cycle assessment of solid waste management strategies depend critically on assumptions, data, and modeling at the unit process level. Based on new primary data, a process model was developed to estimate the cost and energy use associated with material recovery facilities (MRFs), which are responsible for sorting recyclables into saleable streams and as such represent a key piece of recycling infrastructure. The model includes four modules, each with a different process flow, for separation of single-stream, dual-stream, pre sorted recyclables, and mixed-waste. Each MRF type has a distinct combination of equipment and default input waste composition. Model results for total amortized costs from each MRF type ranged from $19.8 to $24.9 per Mg (1Mg=1 metric ton) of waste input. Electricity use ranged from 4.7 to 7.8kWh per Mg of waste input. In a single-stream MRF, equipment required for glass separation consumes 28% of total facility electricity consumption, while all other pieces of material recovery equipment consume less than 10% of total electricity. The dual-stream and mixed-waste MRFs have similar electricity consumption to a single-stream MRF. Glass separation contributes a much larger fraction of electricity consumption in a pre-sorted MRF, due to lower overall facility electricity consumption. Parametric analysis revealed that reducing separation efficiency for each piece of equipment by 25% altered total facility electricity consumption by less than 4% in each case. When model results were compared with actual data for an existing single-stream MRF, the model estimated the facility's electricity consumption within 2%. The results from this study can be integrated into LCAs of solid waste management with system boundaries that extend from the curb through final disposal. PMID- 25301545 TI - Multiple stakeholders in multi-criteria decision-making in the context of Municipal Solid Waste Management: A review. AB - Municipal Solid Waste Management (MSWM) is a complicated process that involves multiple environmental and socio-economic criteria. Decision-makers look for decision support frameworks that can guide in defining alternatives, relevant criteria and their weights, and finding a suitable solution. In addition, decision-making in MSWM problems such as finding proper waste treatment locations or strategies often requires multiple stakeholders such as government, municipalities, industries, experts, and/or general public to get involved. Multi criteria Decision Analysis (MCDA) is the most popular framework employed in previous studies on MSWM; MCDA methods help multiple stakeholders evaluate the often conflicting criteria, communicate their different preferences, and rank or prioritize MSWM strategies to finally agree on some elements of these strategies and make an applicable decision. This paper reviews and brings together research on the application of MCDA for solving MSWM problems with more focus on the studies that have considered multiple stakeholders and offers solutions for such problems. Results of this study show that AHP is the most common approach in consideration of multiple stakeholders and experts and governments/municipalities are the most common participants in these studies. PMID- 25301546 TI - Controlled covalent modification of epitaxial single layer graphene on 6H-SiC (0001) with aryliodonium salts using electrochemical methods. AB - Controlled covalent modification of graphene via electrochemically assisted grafting of molecules is expected to be a robust method for tuning the doping levels and work function and therefore enabling the deployment of graphene in photovoltaic and battery applications. By using aryliodonium salts, in particular, bis(4-nitrophenyl)iodonium tetrafluoroborate, the grafting density can be adjusted from 4 * 10(13) to 3 * 10(14) molecules per cm(2). New insights on the grafting mechanism and the reactivity of the graphene are reported here. Clean basal planes were found to have increased reactivity compared to atomic level point defects (single vacancies). High resolution scanning tunnelling microscopy (STM) shows that some of the grafts present three-fold symmetry, which may indicate that the grafts are pairs of molecules. The point of attachment of the second molecule is under investigation using computational work which includes simulations of the STM images. Elongated as well as extended grafts (larger than 4 nm) are also observed. PMID- 25301547 TI - Augmented asymmetrical visual field dependence in asymptomatic diabetics: evidence of subclinical asymmetrical bilateral vestibular dysfunction. AB - BACKGROUND: Diabetes negatively affects the vestibular system in many ways, with vestibular dysfunction (VD), a co-morbidity with a high prevalence in diabetics. PROCEDURES: The ability to perceive subjective visual vertical (SVV), as a sign of vestibular dysfunction, and visual field dependence was measured using a computerized rod and frame test (CRAF). Alignment errors recorded from 47 asymptomatic Type II diabetics (no vertigo or falls, without peripheral neuropathy or retinopathy) were compared to 29 healthy age matched (46-69years) controls. FINDINGS: Visual field dependence was significantly larger and more asymmetrical in the diabetics than controls. In the absence of any visual references, or when a vertical reference frame was provided, SVV perception was accurate in both groups, with no significant difference between the controls and diabetics. During tilted frame presentations, the proportion of subjects with either SVV deviations, or an asymmetry index, larger than an upper limit derived from the control data was significantly greater in diabetics than controls. CONCLUSION: These results suggest that the decreased ability to resolve visuo vestibular conflict in asymptomatic diabetic patients (free of retinopathy and peripheral neuropathy) compared to controls may be related to diabetic complications affecting vestibular structures and thus causing a decompensation of subclinical vestibular asymmetries. PMID- 25301548 TI - The UCSF screening exam effectively screens cognitive and behavioral impairment in patients with ALS. AB - The University of California San Francisco (UCSF) Screening Battery provides clinicians with a uniquely tailored tool to measure ALS patients' cognitive and behavioral changes, adjusting for dysarthria and hand weakness. The battery consists of the ALS-CBS ( 1 ), Written Fluency Test ( 2 ), and a new revision of the Frontal Behavior Inventory (FBI-ALS) ( 3 ). The validity of each component was tested by comparing results with a gold standard neuropsychological exam (GNE). Consensus criteria-based GNE diagnoses ( 4 ) were assigned (n = 24) and concurrent validity was tested for each screening exam component. Results showed that each of the four cognitive and behavioral screening test components were significantly associated with diagnoses confirmed by GNE. GNE diagnoses were significantly associated with FBI-ALS negative score, written S-words score, and ALS-CBS cognitive score. The total FBI-ALS score and C-words tests were less predictive of GNE-diagnosed impairment. In conclusion, the UCSF Cognitive Screening Battery demonstrates good external validity compared with GNE in this modest sample, encouraging its use in larger investigations. These data suggest that this battery may provide an effective screen to identify ALS patients who will then benefit from a full examination to confirm their diagnosis. PMID- 25301549 TI - Making the post-MDG global health goals relevant for highly inequitable societies: findings from a consultation with marginalized populations in Guatemala. AB - INTRODUCTION: The United Nations presented a set of Millennium Development Goals that aimed to improve social and economic development and eradicate poverty by 2015. Most low and middle-income countries will not meet these goals and today there is a need to set new development agenda, especially when it comes to health. The paper presents the findings from a community consultation process carried out within the Goals and Governance for Global Health (GO4Health) research consortium in Guatemala, which aims to identify community needs and expectations around public policies and health services. METHODS: Through a participative and open consultation process with experts, civil society organizations and members of the research team, the municipalities of Tectitan and Santa Maria Nebaj were selected. A community consultation process was undertaken with community members and community leaders. Group discussions and in depth interviews were conducted and later analyzed using thematic analysis, a qualitative method that can be used to analyze data in a way that allows for the identification of recurrent patterns that can be grouped into categories and themes, was used. FINDINGS: Following the Go4Health framework's domains for understanding health-related needs, the five themes identified were health, social determinants of health, essential health needs and their provision, roles and responsibilities of relevant stakeholders and community participation in decision-making. Participants reported high levels of discrimination related to ethnicity, to being poor and to living in rural areas. Ethnicity played a major role in how community members feel they are cared for in the health system. CONCLUSION: Achieving health goals in a context of deep-rooted inequality and marginalization requires going beyond the simple expansion of health services and working with developing trusting relationships between health service providers and community members. Involving community members in decision-making processes that shape policies will contribute to a larger process of community empowerment and democratization. Still, findings from the region show that tackling these issues may prove complicated and require going beyond the health system, as this lack of trust and discrimination has permeated to all public policies that deal with indigenous and rural populations. PMID- 25301550 TI - The JNK1/JNK3 interactome--contributions by the JNK3 unique N-terminus and JNK common docking site residues. AB - The c-Jun N-terminal Kinases (JNKs) play important roles in cell responses to stress or growth factor stimulation. The JNK1alpha1 isoform shares >90% identity with a predominantly neuronal JNK3alpha1 isoform, but JNK3alpha1 also includes a distinctive 38 amino acid N-terminal sequence. To address the outstanding question of the potential for these JNK isoforms to have different binding partners that mediate different biological actions, the work presented here refined the yeast two-hybrid approach to identify and categorize binding partners for JNK1alpha1 and JNK3alpha1. Specifically, site-directed mutagenesis of the JNK1alpha1 common docking (CD) domain that mediates typical JNK-binding domain (JBD)-dependent interactions, truncation of the distinctive JNK3 N-terminal domain (i.e. DeltaN JNK3alpha1), and interaction evaluation in the yeast two hybrid system defined the interacting partners as either JNK1-specific interactors (ATF7, FUS, KCNE4, PIAS1, SHANK1, TKT), typical JBD-dependent interactors shared by JNK1alpha1 and JNK3alpha1 (AKAP6, BMPR2, EEF1A1, GFAP, GRIP2, GTF2F1, HDAC2, MAP1B, MYO9B, PTPN2, RABGAP1, RUSC2, SUMO1, SYPL1, TOPBP1, ZNF668), or JNK3-specific partners (ATXN1, NNAT, PTGDS) dependent on interaction with the JNK3 N-terminal extension. The interacting partners ATF7, AKAP6, and ATXN1 were explored further as representatives of these different classes. Two potential JBDs were identified in ATF7 as important for its interaction with JNK1alpha1, but additionally an interaction between ATF7 and DeltaN JNK3alpha1 was shown to be JBD-dependent, suggesting that the JNK3alpha1 N-terminus prevents interaction with some proteins. For the shared partner AKAP6, one of the multiple potential JBDs predicted by sequence analysis was important for the AKAP6-JNK interaction in the yeast screening system as well as in mammalian cells. Finally, the ATXN1-JNK3alpha1 interaction was dependent on the JNK3alpha1 N-terminus in a mammalian cell context. These studies therefore highlight a diversity of potential JNK-interacting partners with both JBD-dependent as well as JBD independent modes of interaction. PMID- 25301551 TI - Comparison of the biological effects of (18)F at different intracellular levels. AB - We herein examined the biological effects of cells treated with (18)F labeled drugs for positron emission tomography (PET). The relationship between the intracellular distribution of (18)F and levels of damaged DNA has yet to be clarified in detail. We used culture cells (Chinese Hamster Ovary cells) treated with two types of (18)F labeled drugs, fluorodeoxyglucose (FDG) and fluorine ion (HF). FDG efficiently accumulated in cells, whereas HF did not. To examine the induction of DNA double strand breaks (DSB), we measured the number of foci for 53BP1 that formed at the site of DNA DSB. The results revealed that although radioactivity levels were the same, the induction of 53BP1 foci was stronger in cells treated with (18)F-FDG than in those treated with (18)F-HF. The clonogenic survival of cells was significantly lower with (18)F-FDG than with (18)F-HF. We concluded that the efficient accumulation of (18)F in cells led to stronger biological effects due to more severe cellular lethality via the induction of DNA DSB. PMID- 25301552 TI - Role of NH2-terminal hydrophobic motif in the subcellular localization of ATP binding cassette protein subfamily D: common features in eukaryotic organisms. AB - In mammals, four ATP-binding cassette (ABC) proteins belonging to subfamily D have been identified. ABCD1-3 possesses the NH2-terminal hydrophobic region and are targeted to peroxisomes, while ABCD4 lacking the region is targeted to the endoplasmic reticulum (ER). Based on hydropathy plot analysis, we found that several eukaryotes have ABCD protein homologs lacking the NH2-terminal hydrophobic segment (H0 motif). To investigate whether the role of the NH2 terminal H0 motif in subcellular localization is conserved across species, we expressed ABCD proteins from several species (metazoan, plant and fungi) in fusion with GFP in CHO cells and examined their subcellular localization. ABCD proteins possessing the NH2-terminal H0 motif were localized to peroxisomes, while ABCD proteins lacking this region lost this capacity. In addition, the deletion of the NH2-terminal H0 motif of ABCD protein resulted in their localization to the ER. These results suggest that the role of the NH2-terminal H0 motif in organelle targeting is widely conserved in living organisms. PMID- 25301553 TI - Measurement of chemical exchange between RNA conformers by 19F NMR. AB - Many noncoding RNA molecules adopt alternative secondary and tertiary conformations that are critical for their roles in gene expression. Although many of these rearrangements are mediated by other biomolecular components, it is important to evaluate the equilibrium relationship of the conformers. To measure the spontaneous interconversion in a bi-stable RNA stem loop sequence into which a single (19)F-uridine label was incorporated, a (19)F-(19)F EXSY experiment was employed. The kinetic exchange rate measured from EXSY experiments for this system was 37.3+/-2.8s(-1). The advantage of this approach is that exchange kinetics can be monitored in any RNA sequence into which a single (19)F nucleotide is incorporated by commercial synthesis. This method is therefore suitable for application to biologically significant systems in which dynamic conformational rearrangement is important for function and may therefore facilitate studies of RNA structure-function relationships. PMID- 25301554 TI - Myocardin and pdx-1 synergistically induce hMSCs to differentiate into insulin secreting cells. AB - Mesenchymal stem cells (MSCs) have been reported as an attractive source for the generation of transplantable surrogate beta cells. The objective of this study was to investigate a new method to induce the differentiation of hMSCs into insulin secretion cells and to explore its molecular mechanisms. In this study, we investigated in vitro differentiation of hMSCs by overexpression of myocardin and pdx-1. Differentiated cells were evaluated by immunocytochemistry, reverse transcription-polymerase chain reaction (RT-PCR), quantificational real-time RT PCR (qRT-PCR) and Western blotting. Furthermore, the molecular mechanisms were evaluated by chip assay, CO-IP and Luciferase assay. This study reported a new method to induce the differentiation of hMSCs into insulin secretion cells. The method is cotransduction of myocardin and pdx-1 for 7days. At the same time, we find myocardin and pdx-1 can form a complex to promote the transactivities of insulin by affecting the formation of the pdx-1/myocardin/SRF/CArG complex both in vitro and in vitro. The present study provided a simple and faithful in vitro model for further investigating the cell replacement therapy for diabetes. PMID- 25301555 TI - Down-regulation of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor by HEXIM1 attenuates myocardial angiogenesis in hypoxic mice. AB - Pulmonary hypertension (PH) sustains elevation of pulmonary vascular resistance and ultimately leads to right ventricular (RV) hypertrophy and failure and death. Recently, proangiogenic factors hypoxia-inducible factor-1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) have been known to promote left ventricular myocardial angiogenesis and lead to cardiac hypertrophy, and this would be involved in RV hypertrophy of PH patients. Previously, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice ameliorates RV hypertrophy in hypoxia-induced PH model. Given these results, here we analyzed the effect of HEXIM1 on the expression of HIF 1alpha and VEGF and on myocardial angiogenesis of RV in PH. We revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of HIF-1alpha protein and its target genes including VEGF in the cultured cardiac myocytes and fibroblasts, and that cardiomyocyte-specific HEXIM1 transgenic mice repressed RV myocardial angiogenesis in hypoxia-induced PH model. Thus, we conclude that HEXIM1 could prevent RV hypertrophy, at least in part, via suppression of myocardial angiogenesis through down-regulation of HIF-1alpha and VEGF in the myocardium under hypoxic condition. PMID- 25301556 TI - Degradation of acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, by legumain in the mouse kidney. AB - Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme, which is responsible for the synthesis of cholesterol and fatty acids from ketone bodies in lipogenic tissues, such as the liver and adipocytes. To explore the possibility of AACS regulation at the protein-processing level, we investigated the proteolytic degradation of AACS. Western blot analysis showed that the 75.1kDa AACS was cleaved to form a protein of approximately 55kDa in the kidney, which has considerable high activity of legumain, a lysosomal asparaginyl endopeptidase. Co-expression of AACS and legumain in HEK 293 cells generated the 55kDa product from AACS. Moreover, incubation of recombinant AACS with recombinant legumain resulted in the degradation of AACS. Knockdown of legumain with short-hairpin RNA against legumain using the hydrodynamics method led to a decrease in the 55kDa band of AACS in mouse kidney. These results suggest that legumain is involved in the processing of AACS through the lysosomal degradation pathway in the kidney. PMID- 25301557 TI - Molecular characterization of a CpTRIM35-like protein and its splice variants from whitespotted bamboo shark (Chiloscyllium plagiosum). AB - The tripartite motif (TRIM) proteins play important roles in a broad range of biological processes, including apoptosis, cell proliferation and innate immunity response. In this study, a TRIM gene and its three splice variants were cloned from an elasmobranch fish-whitespotted bamboo shark (Chiloscyllium plagiosum Bennett). Phylogenetic analysis indicated that the gene was closely related to TRIM35 homologs, thus termed CpTRIM35-like. Deduced CpTRIM35 has a RBCC-PRY/SPRY structure typical of TRIM proteins, and its splice variants (CpTRIM35-1-3) have different truncations at the C-terminus. The gene products were constitutively expressed in adult sharks with the highest levels in spleen and kidney. The different subcellular locations, upregulation upon LPS and poly I:C stimulation, and significant E3 ubiquitin ligase activities suggested their different roles in immune responses as an E3 ubiquitin ligase. This is the first TRIM protein ever characterized in elasmobranch fish. PMID- 25301558 TI - Identification of a surface glutamine residue (Q64) of Escherichia coli EntA required for interaction with EntE. AB - The enterobactin biosynthetic enzyme EntA forms a complex with EntE, the next enzyme in the pathway, to enhance activation of the enterobactin precursor 2,3 dihydroxybenzoate. Here we used phage display to identify an EntE-interacting region on the surface of EntA. Upon panning immobilized EntE with a random peptide phage library, we recovered 47 unique EntE-binding dodecamer peptide sequences that aligned to a region of the EntA primary sequence corresponding to helix alpha4. In order to further investigate this region, we mutagenized EntA Q64, a hydrogen-bonding residue found on the surface-exposed face alpha4. Far-UV circular dichroism, thermal denaturation experiments, and enzymatic assays showed that mutation of EntA residue Gln 64 to alanine (Q64A) had no deleterious effect on EntA structure or function. By following near-UV CD spectral changes, we found that the spectrum of wild-type EntA was altered in the presence of EntE, indicative of conformational changes in EntA aromatic chromophores upon formation of the EntA-EntE complex. However, EntE did not affect the CD spectrum of EntA variant Q64A, demonstrating that this variant did not interact with EntE in a manner similar to wild-type EntA. Analytical ultracentrifugation of wild-type and variant EntA proteins showed that EntA Q64A was predominantly dimeric at 20MUM, unlike wild-type EntA which was predominantly tetrameric. Taken together, our findings establish that EntA alpha4 is required for efficient formation of the EntA-EntE as well as for EntA oligomerization. PMID- 25301559 TI - High expression of ROR2 in cancer cell correlates with unfavorable prognosis in colorectal cancer. AB - The receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a transmembrane protein that belongs to a conserved family of tyrosine kinase receptors involved in several functional processes. ROR2 is overexpressed in various types of solid tumors; however, the expression of ROR2, as well as its functional and prognostic significance has yet to be evaluated in colorectal cancer (CRC). In this study, one-step quantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis using tissue microarrays were used to evaluate ROR2 expression in CRC and to investigate the association between ROR2 expression and patient prognosis. We observed that the expression of ROR2 mRNA and protein was significantly higher in CRC specimens compared with normal, tumor-adjacent tissues (both p<0.05). Cytoplasmic ROR2 expression was related to TNM stage (p=0.041) and lymph node metastasis (N) (p=0.015). Kaplan-Meier and multivariate analyses suggested that high cytoplasmic ROR2 expression (p=0.001), poor tumor differentiation (p=0.001), and advanced TNM stage (p=0.001) and high preoperative CEA level (p<0.001) were significantly associated with unfavorable survival of CRC patients. These results suggest that ROR2 expression is correlated with malignant attributes of CRC and may serve as an indicator for poor prognosis in patients with CRC. PMID- 25301560 TI - Ceruloplasmin has two nearly identical sites that bind myeloperoxidase. AB - Ceruloplasmin (Cp) is a copper-containing ferroxidase with potent antioxidant activity. Cp is expressed by hepatocytes and activated macrophages and has been known as physiologic inhibitor of myeloperoxidase (MPO). Enzymatic activity of MPO produces anti-microbial agents and strong prooxidants such as hypochlorous acid and has a potential to damage host tissue at the sites of inflammation and infection. Thus Cp-MPO interaction and inhibition of MPO has previously been suggested as an important control mechanism of excessive MPO activity. Our aim in this study was to identify minimal Cp domain or peptide that interacts with MPO. We first confirmed Cp-MPO interaction by ELISA and surface plasmon resonance (SPR). SPR analysis of the interaction yielded 30nM affinity between Cp and MPO. We then designed and synthesized 87 overlapping peptides spanning the entire amino acid sequence of Cp. Each of the peptides was tested whether it binds to MPO by direct binding ELISA. Two of the 87 peptides, P18 and P76 strongly interacted with MPO. Amino acid sequence analysis of identified peptides revealed high sequence and structural homology between them. Further structural analysis of Cp's crystal structure by PyMOL software unfolded that both peptides represent surface-exposed sites of Cp and face nearly the same direction. To confirm our finding we raised anti-P18 antisera in rabbit and demonstrated that this antisera disrupts Cp-MPO binding and rescues MPO activity. Collectively, our results confirm Cp-MPO interaction and identify two nearly identical sites on Cp that specifically bind MPO. We propose that inhibition of MPO by Cp requires two nearly identical sites on Cp to bind homodimeric MPO simultaneously and at an angle of at least 120degrees, which, in turn, exerts tension on MPO and results in conformational change. PMID- 25301561 TI - A model for the coordinated stepping of cytoplasmic dynein. AB - Cytoplasmic dynein play an important role in transporting various intracellular cargos by coupling their ATP hydrolysis cycle with their conformational changes. Recent experimental results showed that the cytoplasmic dynein had a highly variable stepping pattern including "hand-over-hand", "inchworm" and "nonalternating-inchworm". Here, we developed a model to describe the coordinated stepping patterns of cytoplasmic dynein, based on its working cycle, construction and the interaction between its leading head and tailing head. The kinetic model showed how change in the distance between the two heads influences the rate of cytoplasmic dynein under different stepping patterns. Numerical simulations of the distribution of step size and striding rate are in good quantitative agreement with experimental observations. Hence, our coordinated stepping model for cytoplasmic dynein successfully explained its diverse stepping patterns as a molecular motor. The cooperative mechanism carried out by the two heads of cytoplasmic dynein shed light on the strategies adopted by the cytoplasmic dynein in executing various functions. PMID- 25301562 TI - Label-free real-time acoustic sensing of microvesicle release from prostate cancer (PC3) cells using a Quartz Crystal Microbalance. AB - Using a Quartz Crystal Microbalance with dissipation monitoring, QCM-D (label free system) measuring changes in resonant frequency (Deltaf) that equate to mass deposited on a sensor, we showed the attachment, over a 60min period, of a monolayer of PC3 cells to the gold electrodes of the quartz crystal sensor, which had been rendered hydrophilic. That MVs were released upon BzATP stimulation of cells was confirmed by NTA analysis (average 250nm diameter), flow cytometry, showing high phosphatidylserine exposition and by fluorescent (Annexin V Alexa Fluor(r) 488-positive) and electron microscopy. Over a period of 1000s (16.7min) during which early apoptosis increased from 4% plateauing at 10% and late apoptosis rose to 2%, the Deltaf increased 20Hz, thereupon remaining constant for the last 1000s of the experiment. Using the Sauerbrey equation, the loss in mass, which corresponded to the release of 2.36*10(6)MVs, was calculated to be 23ng. We therefore estimated the mass of an MV to be 0.24pg. With the deposition on the QCM-D of 3.5*10(7)MVs over 200s, the decrease in Deltaf (Hz) gave an estimate of 0.235pg per MV. PMID- 25301564 TI - Retrieval from long-term memory reduces working memory representations for visual features and their bindings. AB - The ability to remember feature bindings is an important measure of the ability to maintain objects in working memory (WM). In this study, we investigated whether both object- and feature-based representations are maintained in WM. Specifically, we tested the hypotheses that retaining a greater number of feature representations (i.e., both as individual features and bound representations) results in a more robust representation of individual features than of feature bindings, and that retrieving information from long-term memory (LTM) into WM would cause a greater disruption to feature bindings. In four experiments, we examined the effects of retrieving a word from LTM on shape and color-shape binding change detection performance. We found that binding changes were more difficult to detect than individual-feature changes overall, but that the cost of retrieving a word from LTM was the same for both individual-feature and binding changes. PMID- 25301565 TI - Order recall in verbal short-term memory: The role of semantic networks. AB - In their recent article, Acheson, MacDonald, and Postle (Journal of Experimental Psychology: Learning, Memory, and Cognition 37:44-59, 2011) made an important but controversial suggestion: They hypothesized that (a) semantic information has an effect on order information in short-term memory (STM) and (b) order recall in STM is based on the level of activation of items within the relevant lexico semantic long-term memory (LTM) network. However, verbal STM research has typically led to the conclusion that factors such as semantic category have a large effect on the number of correctly recalled items, but little or no impact on order recall (Poirier & Saint-Aubin, Quarterly Journal of Experimental Psychology 48A:384-404, 1995; Saint-Aubin, Ouellette, & Poirier, Psychonomic Bulletin & Review 12:171-177, 2005; Tse, Memory 17:874-891, 2009). Moreover, most formal models of short-term order memory currently suggest a separate mechanism for order coding-that is, one that is separate from item representation and not associated with LTM lexico-semantic networks. Both of the experiments reported here tested the predictions that we derived from Acheson et al. The findings show that, as predicted, manipulations aiming to affect the activation of item representations significantly impacted order memory. PMID- 25301563 TI - Incidence and risk factors of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma in HIV-infected individuals. AB - OBJECTIVES: To examine the risk and trends of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma (HNSCC) in HIV-infected individuals and assess whether immunosuppression (measured through CD4 cell count) and other risk factors impact HNSCC risk. MATERIALS AND METHODS: Incident HNSCCs at HPV-related and HPV-unrelated anatomic sites were detected in HIV-infected participants from pooled data from 17 prospective studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) between 1996 and 2009. HNSCC cases were validated using chart review or cancer registry matching. Risk factors for incident HPV-related and HPV-unrelated HNSCC were explored using mixed effects Poisson regression in a full prospective analysis, and the effect of CD4 prior to cancer diagnosis was examined in a nested case control analysis. RESULTS: 66 HPV-related and 182 HPV-unrelated incident HNSCCs were detected among 82,375 HIV-infected participants. Standardized incidence ratios (SIRs) for both HPV-related (SIR=3.2, 95%CI=2.5-3.4) and HPV-unrelated (SIR=3.0, 95%CI=2.5-4.1) HNSCC were significantly elevated in HIV-infected individuals compared with the US general population. Between 1996 and 2009, the age-standardized HPV-related HNSCC incidence increased non-significantly from 6.8 to 11.4per 100,000 person years (p-trend=0.31) while the age-standardized incidence of HPV-unrelated HNSCC decreased non-significantly from 41.9 to 29.3 per 100,000 person-years (p trend=0.16). Lower CD4 cell count prior to cancer diagnosis was significantly associated with increased HPV-related and HPV-unrelated HNSCC risk. CONCLUSION: The standardized incidence of HPV-related and HPV-unrelated HNSCC are both elevated in HIV-infected individuals. Immunosuppression may have a role in the development of both HPV-related and HPV-unrelated HNSCC. PMID- 25301567 TI - Automatic detection of unattended changes in room acoustics. AB - Previous research has shown that the human auditory system continuously monitors its acoustic environment, detecting a variety of irregularities (e.g., deviance from prior stimulation regularity in pitch, loudness, duration, and (perceived) sound source location). Detection of irregularities can be inferred from a component of the event-related brain potential (ERP), referred to as the mismatch negativity (MMN), even in conditions in which participants are instructed to ignore the auditory stimulation. The current study extends previous findings by demonstrating that auditory irregularities brought about by a change in room acoustics elicit a MMN in a passive oddball protocol (acoustic stimuli with differing room acoustics, that were otherwise identical, were employed as standard and deviant stimuli), in which participants watched a fiction movie (silent with subtitles). While the majority of participants reported no awareness for any changes in the auditory stimulation, only one out of 14 participants reported to have become aware of changing room acoustics or sound source location. Together, these findings suggest automatic monitoring of room acoustics. PMID- 25301566 TI - Phase II study of carboplatin, docetaxel and bevacizumab for chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer. AB - PURPOSE: To evaluate a 3-drug combination of carboplatin, docetaxel and bevacizumab as a front-line chemotherapy for patients with advanced non-squamous non-small cell carcinoma (NSCLC), a single arm phase II study was conducted. METHODS: Patients with stage IIIB/IV or postoperative recurrent non-squamous NSCLC were treated with carboplatin (targeted area under the curve of 6 mg h/L), docetaxel (60 mg/m(2)), and bevacizumab (15 mg/kg) on day 1, repeated every 3 weeks for 4 to 6 cycles, followed by maintenance with bevacizumab every 3 weeks until disease progression or occurrence of predefined toxicity. The planned patient number was 40, and the primary endpoint was progression free survival (PFS) as assessed by independent reviewers. RESULTS: One patient refused the treatment after enrollment; thus, 39 patients were treated and analyzed. The 3 drug therapy was delivered for a median of 4 cycles, and 54 % of the patients proceeded to the maintenance therapy for a median of 4 cycles. The overall response rate was 74.4 % (29/39), with a 95 % confidence interval (CI) of 60.0 to 88.7 %. The median PFS and overall survival (OS) were 6.2 months (95 % CI, 4.8 8.5 months) and 22.4 months (95 % CI, 11.3-26.2 months), respectively. Toxicities of grade 3 or higher included neutropenia in 71.8 %, febrile neutropenia in 23.1 %, and hypertension in 38.5 % of the patients, but they were transient and manageable. CONCLUSION: The primary endpoint was met. The regimen yielded promising results with an excellent overall response rate, PFS, and OS for chemotherapy-naive patients with advanced non-squamous NSCLC. Further studies are warranted. PMID- 25301568 TI - The neuroprotective mechanism of puerarin in the treatment of acute spinal ischemia-reperfusion injury is linked to cyclin-dependent kinase 5. AB - Puerarin is shown to exert a variety of pharmacological effects including neuroprotective properties. However, mechanisms of the action are not fully understood. This study was designed to explore the mechanism of puerarin in treatment of acute spinal ischemia-reperfusion injury in rats. Acute spinal ischemia-reperfusion injury was conducted by aortic occlusion in twenty-eight male Sprague-Dawley rats, weighting 230-250 g. The animals were randomly divided into four groups. In the animals with puerarin treatment, 50 mg/kg of puerarin was injected intraperitoneally after reperfusion, and followed by the same dose of injection every 24h for 2 days. In the animals with roscovitine pre-treatment, 30 mg/kg roscovitine was intravenously administrated 60 min before spinal ischemia started. After spinal ischemia for 60 min followed by 48 h of reperfusion, the motor function, spinal infarction volume, apoptosis indices and the activities of Cdk5 and p25 were examined. Acute spinal ischemia-reperfusion resulted in an injury of the spines associated with motor deficit, elevation of Cdk5 and p25 activities, and increase in the spinal apoptosis number and spinal infarction volume. Puerarin improved motor function associated with the decreased apoptosis number, spinal infarction volume, and Cdk5 and p25 activities. The present study indicated that reduction of spinal injury was associated with inhibition of Cdk5 and p25, and that inhibition of Cdk5 and p25 was one of the neuroprotective mechanisms in the puerarin treatment of acute ischemia/reperfusion-induced spinal injury in rats. PMID- 25301569 TI - Characterization of activity-dependent changes in flavoprotein fluorescence in cerebellar slices from juvenile rats. AB - Flavoprotein autofluorescence signals attributed to neuronal metabolism have been used to assess synaptic function. Here, we characterized flavoprotein autofluorescence responses in the molecular layer of rat cerebellar slices. High frequency stimulation elicited a transient fluorescence increase (peak phase) that was followed by a longer-lasting fluorescence decrease (valley phase). The peak phase was restricted to the molecular layer, whereas the valley phase extended into the Purkinje cell layer and a portion of the granule cell layer. Responses were abolished by either the Na(+) channel antagonist, tetrodotoxin, or a combination of the AMPA receptor antagonists, NBQX and GIKI-53655, and were also reduced by a flavoprotein inhibitor (diphenyleneiodonium). These findings are consistent with responses being mediated by an increase in mitochondrial activity triggered by increased energy demands evoked by AMPA receptor-mediated synaptic transmission. The GABAA receptor antagonist picrotoxin did not significantly influence evoked responses. Likewise, exogenous application of ethanol, at concentrations known to increase GABAA receptor-mediated synaptic transmission at Purkinje cells, did not modify peak responses. These observations indicate that flavoprotein autofluorescence imaging could be useful to assess the coupling between glutamatergic synaptic transmission and neuronal metabolism in cerebellar slices. PMID- 25301571 TI - Introduction to special issue: how does neuroscience inform psychological treatment? PMID- 25301570 TI - Intra-articular administration of an antibody against CSF-1 receptor reduces pain related behaviors and inflammation in CFA-induced knee arthritis. AB - Several studies have shown that blockade of colony stimulating factor-1 (CSF-1) or its receptor (CSF-1R) inhibits disease progression in rodent models of rheumatoid arthritis (RA); however, the role of the CSF-1/CSF-1R pathway in RA induced pain and functional deficits has not been studied. Thus, we examined the effect of chronic intra-articular administration of a monoclonal anti-CSF-1R antibody (AFS98) on spontaneous pain, knee edema and functional disabilities in mice with arthritis. Unilateral arthritis was produced by multiple injections of complete Freund's adjuvant (CFA) into the right knee joint of adult male ICR mice. CFA-injected mice were then treated twice weekly from day 10 until day 25 with anti-CSF-1R antibody (3 and 10 MUg/5 MUL per joint), isotype control (rat IgG 10 MUg/5 MUL per joint) or PBS (5 MUl/joint). Knee edema, spontaneous flinching, vertical rearing and horizontal exploratory activity were assessed at different days. Additionally, counts of peripheral leukocytes and body weight were measured to evaluate general health status. Intra-articular treatment with anti-CSF-1R antibody significantly increased horizontal exploratory activity and vertical rearing as well as reduced spontaneous flinching behavior and knee edema as compared to CFA-induced arthritis mice treated with PBS. Treatment with this antibody neither significantly affect mouse body weight nor the number of peripheral leukocytes. These results suggest that blockade of CSF-1R at the initial injury site (joint) could represent a therapeutic alternative for improving the functional disabilities and attenuating pain and inflammation in patients with RA. PMID- 25301572 TI - Control, struggle, and emergent masculinities: a qualitative study of men's care seeking determinants for chronic cough and tuberculosis symptoms in Blantyre, Malawi. AB - BACKGROUND: Men's healthcare-seeking delay results in higher mortality while on HIV or tuberculosis (TB) treatment, and implies contribution to ongoing community level TB transmission before initiating treatment. We investigated masculinity's role in healthcare-seeking delay for men with TB-suggestive symptoms, with a view to developing potential interventions for men. METHODS: Data were collected during March 2011- March 2012 in three high-density suburbs in urban Blantyre. Ten focus group discussions were carried out of which eight (mixed sex = two; female only = three; male only = three) were with 74 ordinary community members, and two (both mixed sex) were with 20 health workers. Individual interviews were done with 20 TB patients (female =14) and 20 un-investigated chronic coughers (female = eight), and a three-day workshop was held with 27 health stakeholder representatives. RESULTS: An expectation to provide for and lead their families, and to control various aspects of their lives while facing limited employment opportunities and small incomes leaves men feeling inadequate, devoid of control, and anxious about being marginalised as men. Men were fearful about being looked at as less than men, and about their wives engaging in extramarital sex without ability to detect or monitor them. Control was a key defining feature of adequate manhood, and efforts to achieve it also led men into side-lining their health. Articulate and consistent concepts of men's bodily strength or appropriate illness responses were absent from the accounts. CONCLUSIONS: Facilitating men to seek care early is an urgent public health imperative, given the contexts of high HIV/AIDS prevalence but increasingly available treatment, and the role of care seeking delay in TB transmission. Men's struggles trying to achieve ideal images seem to influence their engagement with their health. Ambiguous views regarding some key masculinity representations and the embrace of less harmful masculinities raise questions about some common assumptions that guide work with men. Apparent 'emergent masculinities' might be a useful platform from which to support the transformation of harmful masculinity. Finally, the complex manifestations of masculinity indicate the need for interventions targeting men in health and TB control to assume supportive, multidimensional and long-term outlooks. PMID- 25301573 TI - Spontaneous epidural spinal haematoma in children caused by vascular malformations. AB - PURPOSE: The occurrence of spinal epidural haematoma of 'spontaneous' origin in adults is a well-documented entity, though it is rare in children. In the literature to date, there are few cases of this kind of spontaneous haematoma proven to be due to an underlying vascular abnormality. METHOD: Retrospective review of two cases of children under 15 years of age with spontaneous epidural spinal haematoma. RESULTS: Underlying arteriovenous malformations were identified in both cases. Intra-operative photographs and histological sections of these anomalies are presented. CONCLUSION: These are the first two such cases described with clinico-pathological correlation. PMID- 25301574 TI - Plasma triglycerides predict ten-years all-cause mortality in outpatients with type 2 diabetes mellitus: a longitudinal observational study. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes mellitus (T2DM). American Diabetes Association standards of care set a series of targets recommended for the CVD prevention: blood pressure, LDL and HDL cholesterol (LDL-C and HDL-C), triglycerides and HbA1c goals. The aim of this study was to evaluate cardiovascular risk factors in a T2DM outpatient population in order to estimate their specific clinical value in predicting long-term overall mortality. METHODS: Our study population was composed of 1917 T2DM outpatients attending the hospital-based Diabetes Clinic of Ferrara for a mean follow-up period of 10 years; recorded information included personal, clinical and biochemical data, and pharmacological treatment. RESULTS: A Cox proportional hazard analysis was performed, pointing out as age (HR:1.08; IC95%: 1.06-1.11), sex (males: HR:1.97; IC95%: 1.26-3.07), mean triglycerides levels during follow up (III vs I tertile: HR:1.87; IC95%: 1.12-3.12) and lipid-lowering treatment (HR:0.56; IC95%: 0.35-0.90) were significantly associated with all-cause mortality, independent of confounding factors such as mean values of LDL-C, HDL C, HbA1c, blood pressure, BMI, fasting glucose, and antihypertensive and antidiabetic treatment. CONCLUSIONS: This finding suggests that more attention should be given to the management of cardiovascular risk in type 2 diabetic patients with high triglycerides levels. PMID- 25301576 TI - Prenatal diagnosis and patient preferences in patients with neural tube defects around the advent of fetal surgery in Belgium and Holland. AB - INTRODUCTION: We review the characteristics and prenatal choices of patients recently evaluated for neural tube defects (NTD) at two tertiary units. The prenatal diagnosis of NTD allows parents to consider all prenatal options. In selected cases of spina bifida aperta this also includes fetal surgery, which we started offering after combined 'in-house' and 'exported' training. MATERIAL AND METHODS: This is a retrospective review of prospectively collected data on NTD diagnosed over the last 8 years and recent fetal surgery referrals. RESULTS: A total of 167 patients were referred for assessment at a median of 19 weeks. Cranial lesions were diagnosed significantly earlier than spinal lesions. Of the open spinal lesions, 77% were isolated. Of these, 22% were managed expectantly and 1 (1%) had fetal surgery. There was no correlation between parental decisions on prenatal management with disease-specific severity markers. We had 14 fetal surgery referrals, all but 1 from beyond our typical referral area; 6 of the assessed patients were operated on, 4 were expectantly managed and 4 requested termination of pregnancy (TOP). These pregnancy outcomes were in the expected range. DISCUSSION: Open spina bifida is mainly diagnosed in the second trimester and 76% of subjects request TOP, irrespective of the severity indicators. The number of local patients considering fetal surgery is low. PMID- 25301577 TI - Fragment screening by SPR and advanced application to GPCRs. AB - Surface plasmon resonance (SPR) is one of the primary biophysical methods for the screening of low molecular weight 'fragment' libraries, due to its low protein consumption and 'label-free' methodology. SPR biosensor interaction analysis is employed to both screen and confirm the binding of compounds in fragment screening experiments, as it provides accurate information on the affinity and kinetics of molecular interactions. The most advanced application of the use of SPR for fragment screening is against membrane protein drug targets, such G protein coupled receptors (GPCRs). Biophysical GPCR assays using SPR have been validated with pharmacological measurements approximate to cell-based methods, yet provide the advantage of biophysical methods in their ability to measure the weak affinities of low molecular weight fragments. A number of SPR fragment screens against GPCRs have now been disclosed in the literature. SPR fragment screening is proving versatile to screen both thermostabilised GPCRs and solubilised wild type receptors. In this chapter, we discuss the state-of-the-art in GPCR fragment screening by SPR and the technical considerations in performing such experiments. PMID- 25301575 TI - Western Eurasian ancestry in modern Siberians based on mitogenomic data. AB - BACKGROUND: Although the genetic heritage of aboriginal Siberians is mostly of eastern Asian ancestry, a substantial western Eurasian component is observed in the majority of northern Asian populations. Traces of at least two migrations into southern Siberia, one from eastern Europe and the other from western Asia/the Caucasus have been detected previously in mitochondrial gene pools of modern Siberians. RESULTS: We report here 166 new complete mitochondrial DNA (mtDNA) sequences that allow us to expand and re-analyze the available data sets of western Eurasian lineages found in northern Asian populations, define the phylogenetic status of Siberian-specific subclades and search for links between mtDNA haplotypes/subclades and events of human migrations. From a survey of 158 western Eurasian mtDNA genomes found in Siberia we estimate that nearly 40% of them most likely have western Asian and another 29% European ancestry. It is striking that 65 of northern Asian mitogenomes, i.e. ~41%, fall into 19 branches and subclades which can be considered as Siberian-specific being found so far only in Siberian populations. From the coalescence analysis it is evident that the sequence divergence of Siberian-specific subclades was relatively small, corresponding to only 0.6-9.5 kya (using the complete mtDNA rate) and 1-6 kya (coding region rate). CONCLUSIONS: The phylogeographic analysis implies that the western Eurasian founders, giving rise to Siberian specific subclades, may trace their ancestry only to the early and mid-Holocene, though some of genetic lineages may trace their ancestry back to the end of Last Glacial Maximum (LGM). We have not found the modern northern Asians to have western Eurasian genetic components of sufficient antiquity to indicate traces of pre-LGM expansions. PMID- 25301579 TI - Biochemical, genetic, and metabolic engineering strategies to enhance coproduction of 1-propanol and ethanol in engineered Escherichia coli. AB - We recently reported the heterologous production of 1-propanol in Escherichia coli via extended dissimilation of succinate under anaerobic conditions through expression of the endogenous sleeping beauty mutase (Sbm) operon. In the present work, we demonstrate high-level coproduction of 1-propanol and ethanol by developing novel engineered E. coli strains with effective cultivation strategies. Various biochemical, genetic, metabolic, and physiological factors affecting relative levels of acidogenesis and solventogenesis during anaerobic fermentation were investigated. In particular, CPC-PrOH3, a plasmid-free propanogenic E. coli strain derived by activating the Sbm operon on the genome, showed high levels of solventogenesis accounting for up to 85 % of dissimilated carbon. Anaerobic fed-batch cultivation of CPC-PrOH3 with glycerol as the major carbon source produced high titers of nearly 7 g/L 1-propanol and 31 g/L ethanol, implying its potential industrial applicability. The activated Sbm pathway served as an ancillary channel for consuming reducing equivalents upon anaerobic dissimilation of glycerol, resulting in an enhanced glycerol dissimilation and a major metabolic shift from acidogenesis to solventogenesis. PMID- 25301578 TI - Biosynthetic preparation of selectively deuterated phosphatidylcholine in genetically modified Escherichia coli. AB - Phosphatidylcholine (PC) is a major component of eukaryotic cell membranes and one of the most commonly used phospholipids for reconstitution of membrane proteins into carrier systems such as lipid vesicles, micelles and nanodiscs. Selectively deuterated versions of this lipid have many applications, especially in structural studies using techniques such as NMR, neutron reflectivity and small-angle neutron scattering. Here we present a comprehensive study of selective deuteration of phosphatidylcholine through biosynthesis in a genetically modified strain of Escherichia coli. By carefully tuning the deuteration level in E. coli growth media and varying the deuteration of supplemented carbon sources, we show that it is possible to achieve a controlled deuteration for three distinct parts of the PC lipid molecule, namely the (a) lipid head group, (b) glycerol backbone and (c) fatty acyl tail. This biosynthetic approach paves the way for the synthesis of specifically deuterated, physiologically relevant phospholipid species which remain difficult to obtain through standard chemical synthesis. PMID- 25301580 TI - Generation of an attenuated strain oral vaccine candidate using a novel double selection platform in Escherichia coli. AB - Live attenuated bacteria delivered orally are interesting tools for mucosal immunization. The objective of this study was to construct a novel counter selection platform based on an attenuated wild-type Escherichia coli (E. coli) strain and to utilize it for the delivery of LTR192G-STaA13Q fusion protein as an oral vaccine. First, a counter-selectable marker, namely, PRPL-Kil, was inserted into an attenuated wild-type E. coli strain through the use of the red and G-DOC homologous recombination systems to construct the counter-selection platform, and PRPL-Kil was subsequently replaced by the LT192-STa13 fusion gene to construct the oral vaccine O142 (yaiT::LT192-STa13) (ER-A). Subsequently, BALB/c mice were orogastrically inoculated with ER-A. Our results showed that ER-A could induce the production of specific IgA and IgG against fimbriae (F41) and enterotoxins (LT and STa), with neutralizing activity in BALB/c mice. In addition, assays of cellular immune responses showed that the stimulation index (SI) values of immunized mice were significantly higher than those of control mice (P<0.05), and revealed a marked shift toward Th2-mediated immunity. These findings suggest that ER-A is a suitable candidate for an oral vaccine strain to protect animals from enter toxigenic Escherichia coli (ETEC) infection. PMID- 25301581 TI - Characteristics and mechanisms of Cu(II) sorption from aqueous solution by using bioflocculant MBFR10543. AB - This paper investigated the characteristics of Cu(II) sorption from aqueous solution by using bioflocculant MBFR10543 and discussed the mechanism during the sorption process. Results have demonstrated that the removal efficiency of Cu(II) reached 96.9% by adding MBFR10543 in two stages, separately, 1.5 * 10(-2) % (w/w) in the 1.0-min rapid mixing (180 rpm) and 2.0 * 10(-2) % (w/w) after 2.0-min slow mixing (80 rpm), with pH value fixed at 6.0. Cu(II) sorption process could be described by the pseudo-second-order kinetic model and the Langmuir isotherms model. The negative Gibbs free energy change indicated the spontaneous nature of the sorption. Fourier transform infrared spectra analysis indicated that functional groups, such as -OH, -COOH, C?O, and -NH2, were existed in MBFR10543 molecular chains, which had strong capacity for removing Cu(II). Furthermore, both charge neutralization and bridging being the main mechanisms involved in Cu(II) removal by MBFR10543. PMID- 25301582 TI - Enhanced degradation of biphenyl from PCB-contaminated sediments: the impact of extracellular organic matter from Micrococcus luteus. AB - Recent advances in the bioremediation of polychlorinated biphenyl (PCB) contaminated environments have focused on the development of approaches to stimulate the activities of indigenous bacterial communities. In this study, extracellular organic matter (EOM) from Micrococcus luteus was used to enhance the biphenyl-degrading capability of potentially functional microorganisms. The obtained results suggest that EOM significantly enhanced the biphenyl (BP) degradation capability. Under a concentration of 3,500 mg/L BP, BP-degradation efficiency reached 60.8 % at a dosage of 10 % EOM (v/v), whereas the degradation efficiencies of control group (with inactivated EOM addition) and blank group (with lactate minimal medium) were only 21.5 and 6.2 %, respectively. Denaturing gradient gel electrophoresis (DGGE) profiles demonstrated that EOM played a key role in shifts in the composition and diversity of bacterial community. The Illumina high-throughput sequencing analysis indicated that the genera of Rhodococcus and Pseudomonas closely related to BP/PCB-degradation were greatly abundant after EOM addition. Together with polymerase chain reaction (PCR)-DGGE analysis, the link between the enhanced BP-degrading capability and the stimulation and resuscitation function of EOM in uncultured bacteria belonging to phylum Actinobacteria was tentatively established. These results suggest that EOM from M. luteus as an additive holds great potential for the efficient and cost effective bioremediation of PCB-contaminated environment. PMID- 25301583 TI - The contest for precursors: channelling L-isoleucine synthesis in Corynebacterium glutamicum without byproduct formation. AB - L-Isoleucine is an essential amino acid, which is required as a pharma product and feed additive. Its synthesis shares initial steps with that of L-lysine and L threonine, and four enzymes of L-isoleucine synthesis have an enlarged substrate specificity involved also in L-valine and L-leucine synthesis. As a consequence, constructing a strain specifically overproducing L-isoleucine without byproduct formation is a challenge. Here, we analyze for consequences of plasmid-encoded genes in Corynebacterium glutamicum MH20-22B on L-isoleucine formation, but still obtain substantial accumulation of byproducts. In a different approach, we introduce point mutations into the genome of MH20-22B to remove the feedback control of homoserine dehydrogenase, hom, and threonine dehydratase, ilvA, and we assay sets of genomic promoter mutations to increase hom and ilvA expression as well as to reduce dapA expression, the latter gene encoding the dihydrodipicolinate synthase. The promoter mutations are mirrored in the resulting differential protein levels determined by a targeted LC-MS/MS approach for the three key enzymes. The best combination of genomic mutations was found in strain K2P55, where 53 mM L-isoleucine could be obtained. Whereas in fed-batch fermentations with the plasmid-based strain, 94 mM L-isoleucine with L-lysine as byproduct was formed; with the plasmid-less strain K2P55, 109 mM L-isoleucine accumulated with no substantial byproduct formation. The specific molar yield with the latter strain was 0.188 mol L-isoleucine (mol glucose)(-1) which characterizes it as one of the best L-isoleucine producers available and which does not contain plasmids. PMID- 25301584 TI - Multifunctional cellulolytic auxiliary activity protein HcAA10-2 from Hahella chejuensis enhances enzymatic hydrolysis of crystalline cellulose. AB - The modular auxiliary activity (AA) family of proteins is believed to cause amorphogenesis in addition to oxidative cleavage of crystalline cellulose although the supporting evidence is limited. HcAA10-2 is a modular AA10 family protein (58 kDa) composed of a AA10 module and a family two carbohydrate binding module (CBM2), joined by a long stretch of 222 amino acids of unknown function. The protein was expressed in Escherichia coli and purified to homogeneity. Scanning electron microscopy and X-ray diffraction analysis of Avicel treated with HcAA10-2 provided evidence for the disruption of the cellulose microfibrils ("amorphogenesis") and reduction of the crystallinity index, resulting in a twofold increase of cellulase adsorption on the polysaccharide surface. HcAA10-2 exhibited weak endoglucanase-like activity toward soluble cellulose and cello oligosaccharides with an optimum at pH 6.5 and 45 degrees C. HcAA10-2 catalyzed oxidative cleavage of crystalline cellulose released native and oxidized cello oligosaccharides in the presence of copper and an electron donor such as ascorbic acid. Multiple sequence alignment indicated that His1, His109, and Phe197 in the AA10 module formed the conserved copper-binding site. The reducing sugar released from Avicel by the endoglucanase Cel5 and Celluclast accompanying HcAA10-2 was increased by four- and sixfold, respectively. Moreover, HcAA10-2 and Celluclast acted synergistically on pretreated wheat straw biomass resulting in a threefold increase in reducing sugar than Celluclast alone. Taken together, these results suggest that HcAA10-2 is a novel multifunctional modular AA10 protein possessing amorphogenesis, weak endoglucanase, and oxidative cleavage activities useful for efficient degradation of crystalline cellulose. PMID- 25301585 TI - Genetically engineering cyanobacteria to convert CO2, water, and light into the long-chain hydrocarbon farnesene. AB - Genetically engineered cyanobacteria offer a shortcut to convert CO2 and H2O directly into biofuels and high value chemicals for societal benefits. Farnesene, a long-chained hydrocarbon (C15H24), has many applications in lubricants, cosmetics, fragrances, and biofuels. However, a method for the sustainable, photosynthetic production of farnesene has been lacking. Here, we report the photosynthetic production of farnesene by the filamentous cyanobacterium Anabaena sp. PCC 7120 using only CO2, mineralized water, and light. A codon-optimized farnesene synthase gene was chemically synthesized and then expressed in the cyanobacterium, enabling it to synthesize farnesene through its endogenous non mevalonate (MEP) pathway. Farnesene excreted from the engineered cyanobacterium volatilized into the flask head space and was recovered by adsorption in a resin column. The maximum photosynthetic productivity of farnesene was 69.1 +/- 1.8 MUg.L(-1).O.D.(-1).d(-1). Compared to the wild type, the farnesene-producing cyanobacterium also exhibited a 60 % higher PSII activity under high light, suggesting increased farnesene productivity in such conditions. We envision genetically engineered cyanobacteria as a bio-solar factory for photosynthetic production of a wide range of biofuels and commodity chemicals. PMID- 25301586 TI - Hypericins: biotechnological production from cell and organ cultures. AB - Hypericum perforatum L. (St. John's wort), a perennial flowering plant native to Europe, is widely used as a medicinal plant and has a long history of its use in the treatment of various ailments. Currently, H. perforatum is widely used as an herbal remedy for the treatment of mild to moderate depression. Hypericins are natural napthodianthrone compounds produced from H. perforatum (St. John's wort) which are having antitumor, antiviral (i.e., against human immunodeficiency and hepatitis C virus), antineoplastic, and antidepressant properties. Currently, field-grown plant materials are generally used for the commercial production of hypericins. It has been reported that hypericin accumulation in natural plants is influenced by different ecological and environmental conditions including light intensity, nitrogen availability, temperature, seasons, and growing regions. Therefore, up to 17-fold and 13-fold differences in hypericin and pseudohypericin amounts, respectively, are reported in different phytopharmaceutical preparations. Plant cell and organ cultures are effective systems for producing natural products, and attempts were made for the production of biomass and stable concentrations of hypericins through in vitro cultures of H. perforatum. Cell, callus, shoot, plantlet, and adventitious root cultures have been established and various chemical and physical factors which influence the biomass and secondary metabolite accumulation have been investigated. Large-scale plantlet and adventitious root cultures have also been attempted in H. perforatum in bioreactors, and various strategies have been applied for the production of higher biomass and secondary products. This review describes the biotechnological approaches employed for the production of hypericins and focuses upon the challenges and future prospects. PMID- 25301588 TI - Decreasing trend in tobacco-related cancer incidence, United States 2005-2009. AB - More than 1 in 3 cancer-related deaths are associated with tobacco use; these include cancers of the lung and bronchus, oral cavity and pharynx, larynx, esophagus, stomach, pancreas, kidney and renal pelvis, urinary bladder, and cervix, and acute myeloid leukemia. In order to characterize the current cancer burden due to tobacco use, this study provides recent trends in tobacco-related cancer incidence across the US. We analyzed data from CDC's National Program of Cancer Registries and NCI's Surveillance, Epidemiology and End Results Program, covering 100% of the US population during 2005-2009. Age-adjusted incidence rates, 95% confidence intervals and annual percent change were calculated for each state, the District of Columbia, and the US. Tobacco-related cancer incidence in the US decreased significantly from 152.9 (per 100,000 persons) in 2005 to 145.8 in 2009. Men had higher incidence rates, but a greater decrease in tobacco-related cancers per year over the 5-year time period (-1.4% in men, compared to -0.8% in women). Incidence rates decreased the most per year for larynx (-2.4%), lung and bronchus (-1.9%) and stomach (-1.5%) cancers during the study period. Tobacco-related cancer incidence trends varied by state. While tobacco-related cancer incidence in the United States decreased overall from 2005 to 2009, tobacco continued to account for a large cancer burden. Our findings suggest that continued efforts in tobacco prevention and control are needed to further reduce tobacco-related cancer burden in general and among targeted sub populations in the US. PMID- 25301587 TI - Identification of a small molecule signaling factor that regulates the biosynthesis of the antifungal polycyclic tetramate macrolactam HSAF in Lysobacter enzymogenes. AB - Lysobacter species are emerging as new sources of antibiotics. The regulation of these antibiotics is not well understood. Here, we identified a small molecule metabolite (LeDSF3) that regulates the biosynthesis of the antifungal antibiotic heat-stable antifungal factor (HSAF), a polycyclic tetramate macrolactam with a structure and mode of action distinct from the existing antifungal drugs. LeDSF3 was isolated from the culture broth of Lysobacter enzymogenes, and its chemical structure was established by NMR and MS. The purified compound induced green fluorescence in a reporter strain of Xanthomonas campestris, which contained a gfp gene under the control of a diffusible signaling factor (DSF)-inducible promoter. Exogenous addition of LeDSF3 in L. enzymogenes cultures significantly increased the HSAF yield, the transcription of HSAF biosynthetic genes, and the antifungal activity of the organism. The LeDSF3-regulated HSAF production is dependent on the two-component regulatory system RpfC/RpfG. Moreover, LeDSF3 upregulated the expression of the global regulator cAMP receptor-like protein (Clp). The disruption of clp led to no HSAF production. Together, the results show that LeDSF3 is a fatty acid-derived, diffusible signaling factor positively regulating HSAF biosynthesis and that the signaling is mediated by the RfpC/RpfG Clp pathway. These findings may facilitate the antibiotic production through applied genetics and molecular biotechnology in Lysobacter, a group of ubiquitous yet underexplored microorganisms. PMID- 25301589 TI - African American legislators' perceptions of firearm violence prevention legislation. AB - Firearm mortality is the leading cause of death for young African American males, however, few studies have focused on racial/ethnic minority populations and firearm violence. The National Black Caucus of State Legislators advocates for legislation that promotes the health of African Americans. Thus, the purpose of this study was to collect baseline data on African American legislators' perceptions regarding firearm violence in the African American community. A cross sectional study of African American legislators (n = 612) was conducted to investigate the research questions. Of the 612 questionnaires mailed, 12 were not deliverable, and 170 were returned (28%). Utilizing a three wave mailing process, African American legislators were invited to participate in the study. The majority (88%) of respondents perceived firearm violence to be very serious among African Americans. Few (10%) legislators perceived that addressing legislative issues would be an effective strategy in reducing firearm violence among African Americans. The majority (72%) of legislators perceived the most effective strategy to reducing firearm violence in the African American community should focus on addressing societal issues (e.g. crime and poverty). After adjusting for the number of perceived barriers, the number of perceived benefits was a significant predictor of legislators' perceived effectiveness of firearm violence prevention legislation for 8 of the 24 potential firearm violence prevention legislative bills. PMID- 25301590 TI - Five years of translation. PMID- 25301592 TI - Biomedicine. Stem cell recipe offers diabetes hope. PMID- 25301593 TI - Nobel Prizes. Brain's GPS finds top honor. PMID- 25301594 TI - Nobel Prizes. Physicists change the light bulb. PMID- 25301595 TI - Biomedical Research. A call for NIH youth movement. PMID- 25301596 TI - Infectious Diseases. Imagining Ebola's next move. PMID- 25301597 TI - U.S. Policy. Congress, NSF spar on access to grant files. PMID- 25301598 TI - Don't blame the beetles. PMID- 25301599 TI - Racing the thaw. PMID- 25301600 TI - Applied Physics. Of snakes and robots. PMID- 25301601 TI - Plant Science. Plant synthetic biology takes root. PMID- 25301602 TI - Economics. Adjusting to the fertility bust. PMID- 25301603 TI - Quantum Processing. Catching the quantum sound wave. PMID- 25301604 TI - Medicine. Halting harmful helminths. PMID- 25301605 TI - Cancer. Attack of the clones. PMID- 25301606 TI - Artificial Intelligence. Amplify scientific discovery with artificial intelligence. PMID- 25301607 TI - Algal blooms: noteworthy nitrogen. PMID- 25301608 TI - Algal blooms: proactive strategy. PMID- 25301609 TI - Ocean acidification foils chemical signals. PMID- 25301610 TI - Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring". AB - Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored the impaired oxytocin-mediated gamma-aminobutyric acid (GABA) excitatory inhibitory shift during delivery in animal models of autism, ameliorating some autistic-like characteristics in the offspring. However, standard practices in the study of these models, such as the use of sex-dimorphic or males-only analyses and implementation of tests measuring social behavior, are lacking to definitely associate their findings to autism. PMID- 25301611 TI - Response to Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring". AB - Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of gamma-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth. PMID- 25301612 TI - Robots. The social life of robots. Introduction. PMID- 25301613 TI - Meet your new co-worker. PMID- 25301614 TI - Minds of their own. PMID- 25301615 TI - Getting a feel for the world. PMID- 25301616 TI - Helping robots see the big picture. PMID- 25301617 TI - In our own image. PMID- 25301618 TI - Humans need not apply. PMID- 25301619 TI - The accidental roboticist. PMID- 25301620 TI - Q&A: Robots and the law. PMID- 25301621 TI - Biorobotics: using robots to emulate and investigate agile locomotion. AB - The graceful and agile movements of animals are difficult to analyze and emulate because locomotion is the result of a complex interplay of many components: the central and peripheral nervous systems, the musculoskeletal system, and the environment. The goals of biorobotics are to take inspiration from biological principles to design robots that match the agility of animals, and to use robots as scientific tools to investigate animal adaptive behavior. Used as physical models, biorobots contribute to hypothesis testing in fields such as hydrodynamics, biomechanics, neuroscience, and prosthetics. Their use may contribute to the design of prosthetic devices that more closely take human locomotion principles into account. PMID- 25301622 TI - A class of warm Jupiters with mutually inclined, apsidally misaligned close friends. AB - The orbits of giant extrasolar planets often have surprisingly small semimajor axes, large eccentricities, or severe misalignments between their orbit normals and their host stars' spin axes. In some formation scenarios invoking Kozai-Lidov oscillations, an external planetary companion drives a planet onto an orbit having these properties. The mutual inclinations for Kozai-Lidov oscillations can be large and have not been confirmed observationally. Here we present evidence that observed eccentric warm Jupiters with eccentric giant companions have mutual inclinations that oscillate between 35 degrees and 65 degrees . Our inference is based on the pairs' observed apsidal separations, which cluster near 90 degrees . The near-orthogonality of periapse directions is effected by the outer companion's quadrupolar and octupolar potentials. These systems may be undergoing a stalled version of tidal migration that produces warm Jupiters over hot Jupiters, and they provide evidence for a population of multiplanet systems that are not flat and have been sculpted by Kozai-Lidov oscillations. PMID- 25301623 TI - A local clue to the reionization of the universe. AB - Identifying the population of galaxies that was responsible for the reionization of the universe is a long-standing quest in astronomy. We present a possible local analog that has an escape fraction of ionizing flux of 21%. Our detection confirms the existence of gaps in the neutral gas enveloping the starburst region. The candidate contains a massive yet highly compact star-forming region. The gaps are most likely created by the unusually strong winds and intense ionizing radiation produced by this extreme object. Our study also validates the indirect technique of using the residual flux in saturated low-ionization interstellar absorption lines for identifying such leaky galaxies. Because direct detection of ionizing flux is impossible at the epoch of reionization, this represents a highly valuable technique for future studies. PMID- 25301624 TI - Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence. AB - Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole-imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products. PMID- 25301625 TI - Sidewinding with minimal slip: snake and robot ascent of sandy slopes. AB - Limbless organisms such as snakes can navigate nearly all terrain. In particular, desert-dwelling sidewinder rattlesnakes (Crotalus cerastes) operate effectively on inclined granular media (such as sand dunes) that induce failure in field tested limbless robots through slipping and pitching. Our laboratory experiments reveal that as granular incline angle increases, sidewinder rattlesnakes increase the length of their body in contact with the sand. Implementing this strategy in a physical robot model of the snake enables the device to ascend sandy slopes close to the angle of maximum slope stability. Plate drag experiments demonstrate that granular yield stresses decrease with increasing incline angle. Together, these three approaches demonstrate how sidewinding with contact-length control mitigates failure on granular media. PMID- 25301626 TI - Is low fertility really a problem? Population aging, dependency, and consumption. AB - Longer lives and fertility far below the replacement level of 2.1 births per woman are leading to rapid population aging in many countries. Many observers are concerned that aging will adversely affect public finances and standards of living. Analysis of newly available National Transfer Accounts data for 40 countries shows that fertility well above replacement would typically be most beneficial for government budgets. However, fertility near replacement would be most beneficial for standards of living when the analysis includes the effects of age structure on families as well as governments. And fertility below replacement would maximize per capita consumption when the cost of providing capital for a growing labor force is taken into account. Although low fertility will indeed challenge government programs and very low fertility undermines living standards, we find that moderately low fertility and population decline favor the broader material standard of living. PMID- 25301627 TI - World population stabilization unlikely this century. AB - The United Nations (UN) recently released population projections based on data until 2012 and a Bayesian probabilistic methodology. Analysis of these data reveals that, contrary to previous literature, the world population is unlikely to stop growing this century. There is an 80% probability that world population, now 7.2 billion people, will increase to between 9.6 billion and 12.3 billion in 2100. This uncertainty is much smaller than the range from the traditional UN high and low variants. Much of the increase is expected to happen in Africa, in part due to higher fertility rates and a recent slowdown in the pace of fertility decline. Also, the ratio of working-age people to older people is likely to decline substantially in all countries, even those that currently have young populations. PMID- 25301628 TI - A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. AB - Neurogenesis is restricted in the adult mammalian brain; most neurons are neither exchanged during normal life nor replaced in pathological situations. We report that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and the medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 +/- 210 (mean +/- SEM) new neurons in a mouse striatum. Thus, under Notch signaling regulation, astrocytes in the adult mouse brain parenchyma carry a latent neurogenic program that may potentially be useful for neuronal replacement strategies. PMID- 25301629 TI - Spatial organization of cytokinesis signaling reconstituted in a cell-free system. AB - During animal cell division, the cleavage furrow is positioned by microtubules that signal to the actin cortex at the cell midplane. We developed a cell-free system to recapitulate cytokinesis signaling using cytoplasmic extract from Xenopus eggs. Microtubules grew out as asters from artificial centrosomes and met to organize antiparallel overlap zones. These zones blocked the interpenetration of neighboring asters and recruited cytokinesis midzone proteins, including the chromosomal passenger complex (CPC) and centralspindlin. The CPC was transported to overlap zones, which required two motor proteins, Kif4A and a Kif20A paralog. Using supported lipid bilayers to mimic the plasma membrane, we observed the recruitment of cleavage furrow markers, including an active RhoA reporter, at microtubule overlaps. This system opens further approaches to understanding the biophysics of cytokinesis signaling. PMID- 25301632 TI - Building the bionic woman. PMID- 25301630 TI - Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. AB - Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC. PMID- 25301631 TI - Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. AB - Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. PMID- 25301634 TI - Nursing staff's actions during older residents' transition into long-term care facility in a nursing home in rural Norway. AB - Working in long-term care units poses particular staff challenges as these facilities are expected to provide services for seriously ill residents and give help in a homelike atmosphere. Licensed and unlicensed personnel work together in these surroundings, and their contributions may ease or inhibit a smooth transition for recently admitted residents. The aim of the study was to describe and explore different nursing staff's actions during the initial transition period for older people into a long-term care facility. Participant observation periods were undertaken following staff during 10 new residents' admissions and their first week in the facility. In addition 16 interviews of different staff categories and reading of written documents were carried out. The findings show great variations of the staff's actions during the older residents' initial transition period. Characteristics of their actions were (1) in the preparation period: "actions of sharing, sorting out, and ignoring information"; (2) on admission day: "actions of involvement and ignorance"; and (3) in the initial period: "targeted and random actions," "actions influenced by embedded knowledge," and "actions influenced by local transparency." PMID- 25301635 TI - Disseminated Aspergillus flavus following septic arthritis in an immunocompetent patient: a case report. AB - BACKGROUND: Aspergillosis is a rare cause of osteomyelitis and septic arthritis. Aspergillus osteomyelitis is a debilitating infection affecting both immunocompromised and immunocompetent patients. It is associated with a high incidence of morbidity and mortality. Infection with Aspergillus flavus species in the knee has been very rarely seen in the past. CASE PRESENTATION: We present a case of septic arthritis of the knee in an Indian patient secondary to infection with Aspergillus flavus, which was earlier managed as a case of tuberculosis based on the endemicity of the condition, later leading to disseminated aspergillosis. There was no clinical feature or investigation suggesting immunocompromised state. Following knee arthrotomy, Aspergillus flavus was isolated and patient was subsequently managed with antifungals leading to recovery after three months. CONCLUSIONS: Disseminated aspergillosis can mimic tuberculosis both clinically and radiologically. Though fungal infections affect joints rarely but they must always be ruled out to avoid later complications. PMID- 25301636 TI - High-frequency ultrasound-guided disruption of glycoprotein VI-targeted microbubbles targets atheroprogressison in mice. AB - Targeted contrast-enhanced ultrasound (CEU) using microbubble agents is a promising non-invasive imaging technique to evaluate atherosclerotic lesions. In this study, we decipher the diagnostic and therapeutic potential of targeted-CEU with soluble glycoprotein (GP)-VI in vivo. Microbubbles were conjugated with the recombinant fusion protein GPVI-Fc (MBGPVI) that binds with high affinity to atherosclerotic lesions. MBGPVI or control microbubbles (MBC) were intravenously administered into ApoE(-/-) or wild type mice and binding of the microbubbles to the vessel wall was visualized by high-resolution CEU. CEU molecular imaging signals of MBGPVI were substantially enhanced in the aortic arch and in the truncus brachiocephalicus in ApoE(-/-) as compared to wild type mice. High frequency ultrasound (HFU)-guided disruption of MBGPVI enhanced accumulation of GPVI in the atherosclerotic lesions, which may interfere with atheroprogression. Thus, we establish targeted-CEU with soluble GPVI as a novel non-invasive molecular imaging method for atherosclerosis. Further, HFU-guided disruption of GPVI-targeted microbubbles is an innovate therapeutic approach that potentially prevents progression of atherosclerotic disease. PMID- 25301638 TI - Draft Genome Sequence of Antagonistic Agent Lysobacter antibioticus 13-6. AB - Lysobacter antibioticus 13-6, isolated from the roots of Chinese cabbage, effectively controls the pathogens Plasmodiophora brassicae, Xanthomonas oryzae pv. oryzicola, X. oryzae pv. oryzae, Xanthomonas axonopodis pv. dieffenbachiae, and Pseudomonas syringae pv. tabaci. We report the first draft genome sequence of the L. antibioticus species in China. PMID- 25301637 TI - Gadolinium-chelate nanoparticle entrapped human mesenchymal stem cell via photochemical internalization for cancer diagnosis. AB - To improve the gadolinium (Gd) internalization efficiency in stem cells, gadolinium-chelate nanoparticles were prepared from a pullulan derivative (pullulan-deoxycholic acid (DOCA)-diethylene triamine pentaacetic (DTPA)-Gd conjugate; PDDG) and then the PDDG was entrapped into human mesenchymal stem cells (hMSCs) by the photochemical-internalization (PCI) method for cancer diagnosis via the cancer homing property of hMSCs. The internalization efficiency of Gd in hMSCs was significantly increased to 98 +/- 4 pg Gd/cell from 32 +/- 2 pg Gd/cell via the PCI method. Moreover, the Gd-entrapped hMSCs revealed a low exocytosis ratio of gadolinium-chelate nanoparticles during cell division in vitro and a high cellular labeling efficiency for at least 21 days in vivo. The cancer-targeting and diagnosis effect of the Gd-entrapped hMSCs were confirmed in a small CT26 tumor-bearing mice model. The stem cells detected an early tumor (~3 mm(3)) within 2 h using 4.7-T MR and optical imaging. The results demonstrated that the PCI-mediated internalization of Gd-incorporated nanoparticles into hMSCs is a promising protocol for efficient cell labeling and tracking. PMID- 25301639 TI - Complete Genome Sequence of a Novel Variant Strain of Peste des Petits Ruminants Virus, China/XJYL/2013. AB - Here, we announce the complete genome sequence of a novel variant strain of peste des petits ruminants virus, termed China/XJYL/2013. The genome is 15,954 nucleotides long with a 6-nucleotide insertion in the 5' untranslated region of the F gene. This strain is phylogenetically classified as a lineage IV virus. PMID- 25301640 TI - Genome Sequence of a Bornavirus Recovered from an African Garter Snake (Elapsoidea loveridgei). AB - Bornaviruses are known to infect mammals and birds, and they have been associated with disease in both groups of animals. Here, we report the genome sequence of a bornavirus identified in a wild-caught Loveridge's garter snake (Elapsoidea loveridgei). PMID- 25301641 TI - Genome sequences of parvovirus b19 reference strains. AB - We report here the sequences of two reference strains of parvovirus B19 (B19V) used for quantitation of B19V DNA. One reference strain has been established by the World Health Organization (WHO) and the other by the European Pharmacopeia (Ph. Eur.) and belong to B19V genotype 1a1 and 1a2, respectively. PMID- 25301642 TI - Draft Genome Sequence of Necropsobacter rosorum Strain P709T. AB - Necropsobacter is a recently described genus that contains a single species, N. rosorum, and belongs to the family Pasteurellaceae. Here, we present the draft genome of N. rosorum strain P709(T), which is the first genome sequence from this species. PMID- 25301643 TI - Draft Genome Sequence of Strain BF-4, a Lysinibacillus-Like Bacillus Isolated during an Anthrax Outbreak in Bavaria. AB - We report the draft genome sequence of Lysinibacillus sp. strain BF-4. Strain BF 4 has a notably small genome for a free-living bacillus, with a size of 2.63 Mbp. In agreement with phenotypic observations, the genome lacks genes essential for endospore formation. PMID- 25301644 TI - Complete Genome Sequence of European Genotype Porcine Reproductive and Respiratory Syndrome Virus Strain LNEU12 in Northern China. AB - We report the complete genome sequence of a European genotype porcine reproductive and respiratory syndrome virus isolated from swine in northern China in 2012. Genome alignment revealed that the virus (LNEU12) strain shares 90.1% nucleotide identity with the European prototype Lelystad virus. Here, we announce the complete genome sequence of LNEU12. PMID- 25301646 TI - Draft Genome Sequence of Sphingobacterium sp. Strain PM2-P1-29, a Tetracycline Degrading TetX-Expressing Aerobic Bacterium Isolated from Agricultural Soil. AB - The genome of Sphingobacterium sp. strain PM2-P1-29 was sequenced. The bacterium contains a physiologically active tet(X) gene, encoding a tetracycline-degrading monooxygenase. To our knowledge, this is the only bacterium naturally harboring tet(X) for which tetracycline degradation has been demonstrated. PMID- 25301645 TI - Twenty Whole-Genome Bacillus sp. Assemblies. AB - Bacilli are genetically and physiologically diverse, ranging from innocuous to highly pathogenic. Here, we present annotated genome assemblies for 20 strains belonging to Bacillus anthracis, B. atrophaeus, B. cereus, B. licheniformis, B. macerans, B. megaterium, B. mycoides, and B. subtilis. PMID- 25301647 TI - Genome Sequences of Simian Hemorrhagic Fever Virus Variant NIH LVR42-0/M6941 Isolates (Arteriviridae: Arterivirus). AB - Simian hemorrhagic fever virus (SHFV) variant NIH LVR42-0/M6941 is the only remaining SHFV in culture, and only a single genome sequence record exists in GenBank/RefSeq. We compared the genomic sequence of NIH LVR42-0/M6941 acquired from the ATCC in 2011 to NIH LVR42-0/M6941 genomes sequenced directly from nonhuman primates experimentally infected in 1989. PMID- 25301648 TI - Genome Sequence of the Sponge-Associated Ruegeria halocynthiae Strain MOLA R1/13b, a Marine Roseobacter with Two Quorum-Sensing-Based Communication Systems. AB - Ruegeria halocynthiae MOLA R1/13b is an alphaproteobacterium isolated from the Mediterranean sea sponge Crambe crambe. We report here the genome sequence and its annotation, revealing the presence of quorum-sensing genes. This is the first report of the full genome of a Ruegeria halocynthiae strain. PMID- 25301649 TI - Draft Whole-Genome Sequences of Three Shiga Toxin-Producing Escherichia coli O91:H21 Isolates, Two from Hemolytic Uremic Syndrome Patients and One of Porcine Origin. AB - This study presents three genomes of O91:H21 isolates, two from hemolytic uremic syndrome patients and one of porcine origin. Genome analyses reveal that one of the human isolates contains both Shiga toxin-encoding genes (stx1 and stx2), and all three isolates contain putative adhesin (iha and eaeH) and antibiotic resistance (ampC) genes. PMID- 25301650 TI - Complete Genome Sequence of the RmInt1 Group II Intronless Sinorhizobium meliloti Strain RMO17. AB - We report the complete genome sequence of the RmInt1 group II intronless Sinorhizobium meliloti strain RMO17 isolated from Medicago orbicularis nodules from Spanish soil. The genome consists of 6.73 Mb distributed between a single chromosome and two megaplasmids (the chromid pSymB and pSymA). PMID- 25301651 TI - Draft Genome Sequence of the First Isolate of Extensively Drug-Resistant Mycobacterium tuberculosis in Ireland. AB - Extensive drug resistance is an emerging threat to the control of tuberculosis (TB) worldwide, even in countries with low TB incidence. We report the draft whole-genome sequence of the first reported extensively drug-resistant TB (XDR TB) strain isolated in Ireland (a low-incidence setting) and describe a number of single-nucleotide variations that correlate with its XDR phenotype. PMID- 25301652 TI - Draft Genome Sequences of Streptococcus bovis Strains ATCC 33317 and JB1. AB - We report the draft genome sequences of Streptococcus bovis strain ATCC 33317 (CVM42251) isolated from cow dung and strain JB1 (CVM42252) isolated from a cow rumen in 1977. The strains were sequenced using the Genome Sequencer FLX 454 system. The genome sizes are approximately 2 Mb and 2.2 Mb, respectively. PMID- 25301653 TI - Draft Genome of Chilean Honeybee (Apis mellifera) Gut Strain Lactobacillus kunkeei MP2. AB - Here, we report the first draft genome sequence of Lactobacillus kunkeei strain MP2, isolated from a Chilean honeybee gut. The sequenced genome has a total size of 1.58 Mb distributed into 44 contigs and 1,356 protein-coding sequences. PMID- 25301654 TI - Genome Sequence of Nitratireductor basaltis Strain UMTGB225, a Marine Bacterium Isolated from a Green Barrel Tunicate in Bidong Island, Malaysia. AB - Nitratireductor basaltis strain UMTGB225 is a Gram-negative bacterium isolated from a marine tunicate found in Bidong Island, Terengganu, Malaysia. In this study, the genome of Nitratireductor basaltis UMTGB225 was sequenced to gain insight into the role of this bacterium and its association with tunicate hosts in a coral reef habitat. PMID- 25301655 TI - Draft Genome Sequence of Thermoanaerobacterium saccharolyticum Strain NTOU1, a Thermophilic Bacterium Isolated from Marine Shallow Hydrothermal Vents. AB - Thermoanaerobacterium saccharolyticum strain NTOU1 has the ability to utilize several kinds of sugars in lignocellulosic biomass to produce ethanol more efficiently than other bacteria. Here, we report the draft genome sequence and annotation of this strain, which may provide insights into the possible genes and metabolic pathways related to ethanol production. PMID- 25301656 TI - Draft Genome Sequence of Cellulosimicrobium sp. Strain MM, Isolated from Arsenic Rich Microbial Mats of a Himalayan Hot Spring. AB - Microbial mats situated at the Manikaran hot springs (>95 degrees C) are characterized by their high arsenic content (140 ppb), qualifying as a stressed niche. Here, we report the annotated draft genome (3.85 Mb) of Cellulosimicrobium sp. strain MM, isolated from these microbial mats, consisting of 3,718 coding sequences, with an average % G+C of 74.4%. PMID- 25301657 TI - Complete Genome Sequence of Salmonella enterica Serovar Choleraesuis Vaccine Strain C500 Attenuated by Chemical Mutation. AB - Salmonella enterica serovar Choleraesuis strain C500 is a live vaccine attenuated by chemical methods. Here, we report the complete genome sequence of the strain, which may be helpful for elucidating the attenuation mechanism of the vaccine strain. PMID- 25301658 TI - Draft Genome Sequence of Paenibacillus sp. Strain MSt1 with Broad Antimicrobial Activity, Isolated from Malaysian Tropical Peat Swamp Soil. AB - We report the draft genome sequence of Paenibacillus sp. strain MSt1, which has broad-range antimicrobial activity, isolated from tropical peat swamp soil. Genes involved in antimicrobial biosynthesis are found to be present in this genome. PMID- 25301659 TI - Draft Genome Sequence of Rhodococcus erythropolis JCM 6824, an Aurachin RE Antibiotic Producer. AB - Rhodococcus erythropolis JCM 6824 is the producer of the quinoline antibiotic aurachin RE. This bacterium also degrades and utilizes some aromatic compounds, such as biphenyl and benzoate. Here, we report the draft genome sequence of this strain. PMID- 25301660 TI - Draft Genome Sequence of FT9, a Novel Bacillus cereus Strain Isolated from a Brazilian Thermal Spring. AB - A Bacillus cereus strain, FT9, isolated from a hot spring in the midwest region of Brazil, had its entire genome sequenced. PMID- 25301661 TI - Draft Genome Sequences of Two Antimicrobial-Producing Burkholderia sp. Strains, MSh1 and MSh2, Isolated from Malaysian Tropical Peat Swamp Forest Soil. AB - We report the draft genome sequences of two antimicrobial-producing isolates, Burkholderia sp. strains MSh1 and MSh2, which were isolated from tropical peat swamp forest soil. Putative genes related to different antimicrobial production have been annotated in both genome sequences. PMID- 25301662 TI - Draft Genome Sequences of Vancomycin-Susceptible Staphylococcus aureus Related to Heterogeneous Vancomycin-Intermediate S. aureus. AB - We report the draft genome sequences of three vancomycin-susceptible methicillin resistant Staphylococcus aureus strains. S. aureus strain MV8 is a sequence type 8 (ST-8) staphylococcal cassette chromosome mec element type IV (SCCmec IV) derivative, while the other two strains (S. aureus MM25 and MM61) are ST-5 SCCmec II strains. MM61 is also closely related to the heterogeneous vancomycin intermediate S. aureus strain MM66. PMID- 25301663 TI - Exogenous application of methyl jasmonate lowers the effect of cadmium-induced oxidative injury in rice seedlings. AB - Rice seedlings grown under 50 MUM cadmium alone or in combination with 5 MUM methyl jasmonate were investigated for Cd-induced oxidative injury at 3, 7 and 10 days of treatment. MeJA treatments alone did not have any significant change in antioxidant enzyme activities or levels of H2O2 and O2(.-) in roots/shoots, as compared to controls during 3-10 days. The Cd-stressed plants When supplemented with exogenous MeJA revealed significant and consistent changes in activities of antioxidant enzymes CAT, SOD, POD and GR paralleled with an increased GSH-pools than that in plants subjected to Cd-stress alone. Synthesis of GSH driven by increasing demand for GSH in response to Cd-induced oxidative stress in rice was evident. Increased activity of LOX under Cd-stress was noted. Results suggest enhanced Cd-tolerance, lowered Cd(2+) uptake, an improved membrane integrity and 'switching on' of the JA-biosynthesis by LOX in the Cd-stressed rice roots/shoots exposed to MeJA. Exposure to MeJA improved antioxidant response and accumulation of antioxidants which perhaps lowered the Cd-induced oxidative stress in rice. It is this switching on/off of the JA-biosynthesis and ROS mediated signal transduction pathway involving glutathione homeostasis via GR which helps MeJA to mitigate Cd-induced oxidative injury in rice. PMID- 25301664 TI - Developmental changes in leaf phenolics composition from three artichoke cvs. (Cynara scolymus) as determined via UHPLC-MS and chemometrics. AB - The metabolomic differences in phenolics from leaves derived from 3 artichoke cultivars (Cynara scolymus): American Green Globe, French Hyrious and Egyptian Baladi, collected at different developmental stages, were assessed using UHPLC-MS coupled to chemometrics. Ontogenic changes were considered as leaves were collected at four different time intervals and positions (top and basal) during artichoke development. Unsupervised principal component analysis (PCA) and supervised orthogonal projection to latent structures-discriminant analysis (O2PLS-DA) were used for comparing and classification of samples harvested from different cultivars at different time points and positions. A clear separation among the three investigated cultivars was revealed, with the American Green Globe samples found most enriched in caffeic acid conjugates and flavonoids vs. other cultivars. Furthermore, these metabolites also showed a marked effect on the discrimination between leaf samples from cultivars harvested at different positions, regardless of the plant age. Metabolite absolute quantifications further confirmed that discrimination was mostly influenced by phenolic compounds, namely caffeoylquinic acids and flavonoids. This study demonstrates an effect of artichoke leaf position, regardless of plant age, on its secondary metabolites composition. To the best of our knowledge, this is the first report for compositional differences among artichoke leaves, based on their positions, via a metabolomic approach and suggesting that top positioned artichoke leaves present a better source of caffeoylquinic acids, compared to basal ones. PMID- 25301665 TI - Comparative LC-MS-based metabolite profiling of the ancient tropical rainforest tree Symphonia globulifera. AB - In the last few years, several phytochemical studies have been undertaken on the tropical tree Symphonia globulifera leading to the isolation and characterisation of several compounds exhibiting antiparasitic activities against Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani. The comparative LC-MS based metabolite profiling study conducted on the tree led to the identification of compounds originating from specific tissues. The results showed that renewable organs/tissues can be used as the starting material for the production of polycyclic poly-prenylated-acylphloroglucinols, therefore reducing impacts on biodiversity. This study also underlined the lack of knowledge on the secondary metabolites produced by S. globulifera since only a small number of the total detected features were putatively identified using the database of known compounds for the species. PMID- 25301666 TI - Bioactive compounds from transformed root cultures and aerial parts of Bethencourtia hermosae. AB - A chemical study of Bethencourtia hermosae, aerial parts and in vitro root cultures, transformed by Agrobacterium rhizogenes, afforded the hitherto unreported sesquiterpenes ceratopicanol angelate (1), 8beta-hydroxy-african-4(5) en-3-one tiglate (4), 8beta-hydroxy-african-4(5)-en-3-one 3'-angeloxy-2' methylbutanoate (5), 1alpha,8beta-dihydroxy-african-4(5)-en-3-one 8beta-angelate (7) and 6alpha,8beta-dihydroxy-african-4(5)-en-3-one 8beta-angelate (8). In addition, 8beta-hydroxy-african-4(5)-en-3-one (6) was isolated for the first time from a natural source, along with the rare sesquiterpenoid senecrassidiol (10) and two jacaranone derivatives 14 and 16. Known pyrrolizidine alkaloids, together with previously unreported hermosine (23), have also been isolated from this plant. The insect antifeedant activities of the extracts and compounds were studied together with their cytotoxic effects against insect (Sf9) and mammalian (CHO) cell lines. PMID- 25301667 TI - Warfarin induced sublingual hematoma: a Ludwig angina mimic. AB - BACKGROUND: Sublingual hematoma is a rare but life-threatening complication of oral anticoagulants. It is important to differentiate this from infectious processes like Ludwig's angina. Securing the airway should be a priority and immediate reversal of anticoagulation with close monitoring is required. CASE REPORT: We present a case of sublingual hematoma secondary to warfarin therapy without airway compromise which was managed conservatively with reversal of INR with oral vitamin K. CONCLUSION: Although rare, it is crucial to differentiate sublingual hematomas from infectious processes. Reversal of anticoagulation with low threshold for artificial airway placement in the event of airway compromise is the treatment of choice. PMID- 25301669 TI - Mobile phones and sex work in South India: the emerging role of mobile phones in condom use by female sex workers in two Indian states. AB - The aim of this study was to examine female sex workers' solicitation of clients using mobile phones and the association between this and condom use with clients. Cross-sectional data were utilised to address the study's aim, drawing on data collected from female sex workers in Calicut, Kerala, and Chirala, Andhra Pradesh. Use of mobile phone solicitation was reported by 46.3% (n = 255) of Kerala participants and 78.7% (n = 464) of those in Andhra Pradesh. Kerala participants reporting exclusive solicitation using mobile phones demonstrated 1.67 times higher odds (95% CI: 1.01-2.79) of inconsistent condom use than those reporting non-use of mobile phones for solicitation. However, those reporting exclusive solicitation through mobile phones in Andhra Pradesh reported lower odds of inconsistent condom use (OR: 0.03; 95% CI: 0.01-0.26) than those not using mobile phones for solicitation. Findings indicate that solicitation of clients using mobile phones facilitates or hampers consistency in condom use with clients depending on the context, and how mobile phones are incorporated into solicitation practices. Variations in sex work environments, including economic dependence on sex work or lack thereof may partially account for the different effects found. PMID- 25301670 TI - Fungal hemicellulose-degrading enzymes cause physical property changes concomitant with solubilization of cell wall polysaccharides. AB - MAIN CONCLUSION: Physical properties of wheat coleoptile segments decreased after treatment with hemicellulose-degrading enzymes, indicating that hemicellulosic polysaccharides function to control the strength of primary cell walls. Changes in the physical properties of plant cell walls, a viscoelastic structure, are thought to be one of the growth-limiting factors for plants and one of the infection-affecting factors for fungi. To study the significance of hemicellulosic polysaccharides that form cross-bridges between cellulose microfibrils in controlling cell wall strength in monocot plants, the effects of hemicellulose degradation by recombinant Magnaporthe oryzae xylanase and 1,3-1,4 beta-glucanase, and recombinant Aspergillus oryzae xyloglucanase on the physical properties and polysaccharide solubilization were investigated using wheat (Triticum aestivum L.) coleoptiles. Treatments with xylanase or 1,3-1,4-beta glucanase significantly decreased the viscosity and elasticity of wheat coleoptile segments. In addition, xyloglucanase treatment slightly decreased the viscoelasticity. Furthermore, 1,3-1,4-beta-glucan polymer was solubilized during hydrolysis with xylanase and xyloglucanase, even though neither enzyme had hydrolytic activity towards 1,3-1,4-beta-glucan. These results suggest that xylan and xyloglucan interact with 1,3-1,4-beta-glucan and that the composites and hemicellulosic polysaccharides form inter-molecular bridges. Degradation of these bridges causes decreases in the physical properties, resulting in increased extensibility of the cell walls. These findings provide a testable model in which wheat coleoptile cell walls are loosened by the degradation of hemicellulosic polysaccharides and hemicellulose-degrading enzymes play a significant role in loosening the walls during fungal infection. PMID- 25301672 TI - CpG Oligonucleotide and Interleukin 2 stimulation enables higher cytogenetic abnormality detection rates than 12-o-tetradecanolyphorbol-13-acetate in Asian patients with B-cell chronic lymphocytic leukemia (B-CLL). AB - The present study was designed to compare abnormality detection rates using DSP30 + IL2 and 12-O-Tetradecanoylphorbol-13-acetate (TPA) in Asian patients with B CLL. Hematological specimens from 47 patients (29 newly diagnosed, 18 relapsed) were established as 72 h-DSP30 + IL2 and TPA cultures. Standard methods were employed to identify clonal aberrations by conventional cytogenetics (CC). The B CLL fluorescence in situ hybridization (FISH) panel comprised ATM, CEP12, D13S25, and TP53 probes. DSP30 + IL2 cultures had a higher chromosomal abnormality detection rate (67 %) compared to TPA (44 %, p < 0.001). The mean number of analyzable metaphases and abnormal metaphases per slide was also higher (p < 0.005, p < 0.001, respectively). Culture success rate, percentage of complex karyotype, and percentage of non-clonal abnormal cell were not significantly different (p > 0.05). Thirteen cases with abnormalities were found exclusively in DSP30 + IL2 cultures compared to one found solely in TPA cultures. DSP30 + IL2 cultures were comparable to the FISH panel in detecting 11q-, +12 and 17p- but not 13q-. It also has a predilection for 11q- bearing leukemic cells compared to TPA. FISH had a higher abnormality detection rate (84.1 %) compared to CC (66.0 %) with borderline significance (p = 0.051), albeit limited by its coverage. In conclusion, DSP30 + IL2 showed a higher abnormality detection rate. However, FISH is indispensable to circumvent low mitotic indices and detect subtle abnormalities. PMID- 25301673 TI - Attenuating effect of standardized lyophilized Cinnamomum zeylanicum bark extract against streptozotocin-induced experimental dementia of Alzheimer's type. AB - BACKGROUND: The Cinnamomum zeylanicum (CZ; family Lauraceae) bark, an important spice, has also been used traditionally for nervous stress, as a nervine tonic, and as a stimulant. Therefore, the present study was designed to evaluate the effect of the standardized lyophilized aqueous extract of CZ bark (LCZE) on learning and memory in rodents at 50, 100, and 200 mg/kg, p.o. dose levels against streptozotocin (STZ)-induced memory impairment. METHODS: LCZE was standardized based on the cinnamaldehyde content using high-performance thin layer chromatography (HPTLC). The effect on learning and memory was evaluated using two widely used behavioral models, the Morris water maze (MWM) test and the object recognition test (ORT). The effect of LCZE on the acetylcholinesterase (AChE) activity and oxidative stress parameters in the cerebral cortex and hippocampus of rat brain was also evaluated. RESULTS: LCZE significantly (p<0.05) and dose-dependently attenuated STZ-induced cognitive deficit in both models in comparison to only STZ-treated animals. In the MWM test, LCZE (100 and 200 mg/kg) significantly decreased the transfer latency and increased the time spent by the animals in target quadrant. Similarly in the ORT, the LCZE-treated animals exhibited an improved discrimination between a familiar object and a novel object, indicating the reversal of STZ-induced memory impairment. LCZE also restored STZ-induced alteration in AChE activity and oxidative stress parameters in both brain parts. CONCLUSIONS: The results clearly indicate toward the memory enhancing effect of LCZE, which could be due to the synergistic effect of anti AChE and antioxidant activities. PMID- 25301674 TI - Weight loss reduces serum monocyte chemoattractant protein-1 concentrations in association with improvements in renal injury in obese men with metabolic syndrome. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is involved in obesity related renal injury. The aim of the present study was to examine the effects of weight loss on changes in MCP-1 and markers of renal injury, specifically serum cystatin C (S-CysC) and urinary N-acetyl glucosaminidase (UNAG), in obese people. METHODS: In this prospective study, 40 obese men with metabolic syndrome (MetS) participated in a 3-month dietary and exercise intervention. Twenty-eight subjects completed the study with a >=5% weight loss. Circulating MCP-1, S-CysC and UNAG to creatinine ratio (UNCR) were determined before and after the weight loss program. RESULTS: Obesity-associated components of MetS demonstrated significant improvements after the weight loss program. In addition, at baseline, circulating MCP-1 concentrations were positively correlated with UNCR and S-CysC levels. After weight loss, blood MCP-1 and UNCR levels were significantly decreased, but S-CysC was not affected. Using multiple linear regression analysis, there was a significant relationship between changes in UNCR and MCP-1 after adjusting for other potential confounding factors. CONCLUSIONS: Weight loss may improve renal tubular injury by ameliorating obesity-related inflammation in obese men with MetS. PMID- 25301671 TI - Human skin dendritic cells in health and disease. AB - Dendritic cells (DCs) are specialized antigen presenting cells abundant in peripheral tissues such as skin where they function as immune sentinels. Skin DCs migrate to draining lymph node where they interact with naive T cells to induce immune responses to microorganisms, vaccines, tumours and self-antigens. In this review, we present the key historical developments and recent advances in human skin DC research. We also integrate the current understanding on the origin and functional specializations of DC subsets in healthy skin with findings in inflammatory skin diseases focusing on psoriasis and atopic eczema. A comprehensive understanding of the dynamic changes in DC subsets in health and disease will form a strong foundation to facilitate the clinical translation of DC-based therapeutic and vaccination strategies. PMID- 25301675 TI - Active intervention in hospital test request panels pays. AB - BACKGROUND: Ordering laboratory tests by means of test panels is a convenient way of requesting tests, preventing necessary tests from being forgotten. However, it also leads to redundant test ordering, as not all tests in a given panel are required for each patient. As test panels proposed by doctors may contain redundant, overlapping or infrequently used tests, the active involvement of knowledgeable laboratory staff in the organisation of test panels is advisable to promote efficient test use. METHODS: Laboratory staff initiated an intervention in the organisation of test panels at our hospital in 2009. After a review of the existing panels and the proposals for new panels, we established a total of 60 panels (down from 171 previously). We also stipulated that the laboratory is to be involved with all proposals for new test panels in the future. RESULTS: The reorganisation reduced the number of tests in the test panels by 17.7% (n=60), which theoretically should have resulted in 4.5% fewer tests being ordered. However, as an estimated 14% of the tests removed were then ordered individually in addition to the panels, 3.9% fewer tests were ordered, yielding an annual saving of about ?58,000 (4.5% of the costs of all tests ordered in test panels). The savings amount to 7-8% if the frequently ordered metabolic panel (which was left unchanged) was excluded from the survey. CONCLUSIONS: Active intervention by the laboratory in the organisation of test panels results in a reduction in the use of tests and in interesting savings. PMID- 25301676 TI - Quantification of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in serum using an isotope dilution UHPLC-MS/MS method with semi automated sample preparation. AB - BACKGROUND: Recent studies have demonstrated highly variable blood concentrations of piperacillin, tazobactam, cefepime, meropenem, ciprofloxacin and linezolid in critically ill patients with a high incidence of sub-therapeutic levels. Consequently, therapeutic drug monitoring (TDM) of these antibiotics has to be considered, requiring robust and reliable routine analytical methods. The aim of the present work was to develop and validate a multi-analyte ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of the above mentioned antibiotics. METHODS: Sample preparation included a manual protein precipitation step followed by two dimensional ultra high performance liquid chromatography (2D-UHPLC). Corresponding stable isotope-labeled substances were used as internal standards for all of the analytes, with the exception of tazobactam. The injected sample volume was 7 MUL. The run time was 5.0 min. RESULTS: Inaccuracy was <=8% and imprecision coefficient of variation (CV) was <9% for all analytes. Only minor matrix effects and negligible carry-over was observed. The method was found to be robust during the validation period. CONCLUSIONS: We were able to develop a reliable 2D-UHPLC-MS/MS method addressing analytes with highly heterogeneous physico-chemical properties. The novel assay may be an efficient tool for an optimized process workflow in clinical laboratories for important antibiotics in regards to TDM. PMID- 25301677 TI - Subclinical deterioration of left ventricular function in patients with juvenile onset systemic lupus erythematosus. AB - OBJECTIVES: Patients with systemic lupus erythematosus (SLE) have a higher risk of myocardial involvement, which can result in ventricular dysfunction. Little is known about the chronic influence of SLE on heart function in children and adolescents. This is the first study to demonstrate long-term changes in left ventricular function in patients with juvenile-onset SLE. METHODS: This was a longitudinal study of 92 patients with juvenile-onset SLE. Two-dimensional echocardiography was performed by a single pediatric cardiologist at baseline, with follow-up at six-month intervals. Clinical and laboratory parameters, disease activity, treatment, nailfold capillaroscopy, and the traditional risk factors for atherosclerosis were evaluated. The baseline comparison of ventricular function was performed against 50 age-matched controls, and the follow-up results were analyzed using generalized estimating equations. RESULTS: The patients' mean age at baseline was 15.9 +/- 4.3 years, the mean disease duration was 3.6 +/- 3.2 years, and the mean follow-up duration was 4.5 +/- 1.6 years. At baseline, the mean left ventricular ejection fraction (LVEF) was 74.7 +/- 5.6% and the mean E/A ratio of left ventricular diastolic filling was 1.7 +/- 0.3 (E: the peak velocity at rapid left ventricular filling; A: the peak velocity during left atrial contraction). The LVEF of the SLE patients was similar to the healthy controls and it did not change during the follow-up period. In contrast, the E/A ratio was lower in the SLE patients than in the healthy controls (1.7 +/- 0.3 versus 1.88 +/- 0.37; p = 0.002), and it decreased significantly with time (B +/- SE, -0.013 +/- 0.006, p = 0.023). In multiple analyses, abnormal microvasculature in nailfold capillaroscopy had a negative effect on LVEF progression (p = 0.039). Disease duration of SLE and proteinuria were risk factors associated with the descent of E/A ratio (p = 0.014 and p = 0.015, respectively). CONCLUSION: In patients with juvenile-onset SLE who were free of cardiac symptoms, there was evidence of declining ventricular diastolic function with time. Abnormal nailfold microvasculature, proteinuria and longer disease duration were the main risk factors for worsening of ventricular function. PMID- 25301678 TI - Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies. AB - Given the prevalence of phosphatase & tensin homolog mutations in histologic specimens harvested from patients with endometrial cancer, significant interest in systemic treatment with PI3K/Akt/mTOR inhibitors has emerged. Several Phase II trials have been completed studying mTOR inhibitors in advanced/recurrent endometrial cancer. The mTOR pathway also appears to be important in some cervical cancers. Finally, because clear cell carcinoma of the ovary and renal cell carcinoma have a shared histology, the potential for activity of mTOR inhibitors in clear cell cancer of the ovary is implicit. This article reviews the results of Phase II clinical trials of PI3K/Akt/mTOR pathway inhibitors in patients with endometrial cancer, and discusses the potential therapeutic landscape of mTOR inhibition in enriched populations in gynecologic cancers. PMID- 25301679 TI - Imaging Drosophila brain by combining cryo-soft X-ray microscopy of thick vitreous sections and cryo-electron microscopy of ultrathin vitreous sections. AB - Cryo-soft X-ray microscopy is an emerging imaging tool complementary to cryo electron microscopy, allowing to image frozen hydrated specimens ten to hundred times thicker, but at lower resolution. We describe how the method, so far restricted to isolated small cells or cell monolayers, can be extended to large cells and tissue. We image the synapses of the Kenyon cells in frozen hydrated Drosophila brains combining cryo-soft X-ray microscopy of thick vitreous sections, and cryo-electron microscopy of ultrathin vitreous sections. We show how to obtain frozen hydrated sections of thicknesses ranging from 40 nm up to 2.5 MUm, by tuning the sectioning speed of the cryo-microtome. A fluorescent stereo-microscope mounted on the cryo-microtome allowed us to target the regions of interest after GFP-labeling of synapses. Thick cryo-sections were imaged by cryo-soft X-ray microscopy at a resolution better than 25 nm, while ultrathin cryo-sections of the same regions were explored in parallel at the nanometre level of resolution by cryo-electron microscopy. PMID- 25301680 TI - A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. AB - BACKGROUND: Providing ketone bodies to the brain can bypass metabolic blocks to glucose utilization and improve function in energy-starved neurons. For this, plasma ketones must be elevated well above the <= 0.2 mM default concentrations normally prevalent. Limitations of dietary methods currently used to produce therapeutic hyperketonemia have stimulated the search for better approaches. METHOD: Described herein is a new way to produce therapeutic hyperketonemia, entailing prolonged oral administration of a potent ketogenic agent--ketone monoester (KME)--to a patient with Alzheimer's disease dementia and a pretreatment Mini-Mental State Examination score of 12. RESULTS: The patient improved markedly in mood, affect, self-care, and cognitive and daily activity performance. The KME was well tolerated throughout the 20-month treatment period. Cognitive performance tracked plasma beta-hydroxybutyrate concentrations, with noticeable improvements in conversation and interaction at the higher levels, compared with predose levels. CONCLUSION: KME-induced hyperketonemia is robust, convenient, and safe, and the ester can be taken as an oral supplement without changing the habitual diet. PMID- 25301681 TI - Short-term trends in dementia prevalence in Germany between the years 2007 and 2009. AB - Recent studies have been cautiously optimistic about declining trends in dementia prevalence and incidence. Newly available claims data from a German public health insurance company covering 30% of the total population permitted us to explore short-term trends based on millions of observations up to the highest ages. Diagnoses stemmed from the inpatient and outpatient services and covered both the community-dwelling population and those living in nursing homes. Data spanning more than 3 years were examined, and the examination revealed a significant yearly reduction between 1% and 2% in the prevalence of dementia among women aged 75 to 84 years. The extent of the reduction was comparable with reports from earlier studies. A similar tendency existed among men, however, statistically not significant. Trends in medical, lifestyle, and societal risk factors of dementia may have contributed to this decline. PMID- 25301682 TI - Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials. AB - INTRODUCTION: Little is known about the utility of plasma amyloid beta (Abeta) in clinical trials of Alzheimer's disease (AD). METHODS: We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). RESULTS: Baseline plasma Abeta was not related to cognitive or clinical progression. We observed a decrease in plasma Abeta40 and 42 among apolipoprotein E epsilon 4 (APOE epsilon4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Abeta compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. DISCUSSION: We found no support for the utility of plasma Abeta as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Abeta may prove useful in pharmacodynamic studies of antiamyloid drugs. PMID- 25301684 TI - Novel ionically crosslinked acrylamide-grafted poly(vinyl alcohol)/sodium alginate/sodium carboxymethyl cellulose pH-sensitive microspheres for delivery of Alzheimer's drug donepezil hydrochloride: Preparation and optimization of release conditions. AB - In this work, the graft copolymer, poly(vinyl alcohol)-grafted polyacrylamide (PVA-g-PAAm), was synthesized and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and elemental analysis. Microspheres of PVA-g-PAAm/sodium alginate (NaAlg)/sodium carboxymethyl cellulose (NaCMC) were prepared by the emulsion-crosslinking method and used for the delivery of an Alzheimer's drug, donepezil hydrochloride (DP). The release of DP increased with the increase in drug/polymer ratio (d/p) and PVA-g PAAm/NaAlg/NaCMC ratio, while it decreased with the increase in the extent of crosslinking. The optimum DP release was obtained as 92.9% for a PVA-g PAAm/NaAlg/NaCMC ratio of 1/2/1, d/p ratio of 1/8, and FeCl3 concentration of 7% (w/v). PMID- 25301683 TI - Flexible and accessible workflows for improved proteogenomic analysis using the Galaxy framework. AB - Proteogenomics combines large-scale genomic and transcriptomic data with mass spectrometry-based proteomic data to discover novel protein sequence variants and improve genome annotation. In contrast with conventional proteomic applications, proteogenomic analysis requires a number of additional data processing steps. Ideally, these required steps would be integrated and automated via a single software platform offering accessibility for wet-bench researchers as well as flexibility for user-specific customization and integration of new software tools as they emerge. Toward this end, we have extended the Galaxy bioinformatics framework to facilitate proteogenomic analysis. Using analysis of whole human saliva as an example, we demonstrate Galaxy's flexibility through the creation of a modular workflow incorporating both established and customized software tools that improve depth and quality of proteogenomic results. Our customized Galaxy based software includes automated, batch-mode BLASTP searching and a Peptide Sequence Match Evaluator tool, both useful for evaluating the veracity of putative novel peptide identifications. Our complex workflow (approximately 140 steps) can be easily shared using built-in Galaxy functions, enabling their use and customization by others. Our results provide a blueprint for the establishment of the Galaxy framework as an ideal solution for the emerging field of proteogenomics. PMID- 25301685 TI - Printed and flexible biosensor for antioxidants using interdigitated ink-jetted electrodes and gravure-deposited active layer. AB - Printing techniques have been extensively used in the fabrication of organic electronic devices, such as light-emitting diodes and display backplanes. These techniques, in particular inkjet printing, are being employed for the localized dispensing of solutions containing biological molecules and cells, leading to the fabrication of bio-functional microarrays and biosensors. Here, we report the fabrication of an all-printed and flexible biosensor for antioxidants. Gold (Au) interdigitated electrodes (IDEs) with sub-100 um features were directly inkjet printed on plastic substrates using a nanoparticle-based ink. Conductivities as high as 5*10(6) S/m (12% of bulk Au) were attained after sintering was conducted at plastic-compatible 200 degrees C for 6 h. The enzyme Tyrosinase (Tyr) was used in the active layer of the biosensors, being innovatively deposited by large area rotogravure printing. A tailor-made ink was studied, and the residual activity of the enzyme was 85% after additives incorporation, and 15.5% after gravure printing. Au IDEs were coated with gravure films of the Tyr-containing ink, and the biosensor was encapsulated with a cellulose acetate dip-coating film to avoid dissolution. The biosensor impedance magnitude increases linearly with the concentration of a model antioxidant, allowing for the construction of a calibration curve. Control experiments demonstrated the molecular recognition characteristic inferred by the enzyme. We found that the biosensor sensitivity and the limit of detection were, respectively, 5.68 Omega/um and 200 uM. In conclusion, a disposable, light-weight, all-printed and flexible biosensor for antioxidants was successfully fabricated using fast and large-area printing techniques. This opens the door for the fabrication of technological products using roll-to-roll processes. PMID- 25301686 TI - Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent. RESULTS: In NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival. CONCLUSIONS: Overall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC. PMID- 25301688 TI - Neuroprotective and antidepressant-like effects of melatonin in a rotenone induced Parkinson's disease model in rats. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5mg/kg) or its vehicle. 24h later, they were intraperitoneally treated with melatonin (10mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity loss in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD. PMID- 25301687 TI - Exploring new pathways of neurodegeneration in ALS: the role of mitochondria quality control. AB - Neuronal cells are highly dependent on mitochondria, and mitochondrial dysfunction is associated with neurodegenerative diseases. As perturbed mitochondrial function renders neurons extremely sensitive to a wide variety of insults, such as oxidative stress and bioenergetic defects, mitochondrial defects can profoundly affect neuronal fate. Several studies have linked ALS with mitochondrial dysfunction, stemming from observations of mitochondrial abnormalities, both in patients and in cellular and mouse models of familial forms of ALS. Mitochondrial changes have been thoroughly investigated in mutants of superoxide dismutase 1 (SOD1), one of the most common causes of familial ALS, for which excellent cellular and animal models are available, but recently evidence is emerging also in other forms of ALS, both familial and sporadic. Mitochondrial defects in ALS involve many critical physiopathological processes, from defective bioenergetics to abnormal calcium homeostasis, altered morphology and impaired trafficking. In this review, we summarize established evidence of mitochondrial dysfunction in ALS, especially in SOD1 mutant models of familial ALS. The main focus of the review is on defective mitochondrial quality control (MQC) in ALS. MQC operates at multiple levels to clear damaged proteins through proteostasis and to eliminate irreparably damaged organelles through mitophagy. However, since ALS motor neurons progressively accumulate damaged mitochondria, it is plausible that the MQC is ineffective or overwhelmed by excessive workload imposed by the chronic and extensive mitochondrial damage. This article is part of a Special Issue entitled ALS complex pathogenesis. PMID- 25301689 TI - Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS and beyond. AB - Infections, and the resulting immune response to these infections, have recently received increased recognition as pathogenic mechanisms for neuropsychiatric disorders. Sydenham's chorea (SC), a widely recognized post-streptococcal autoimmune disorder, represents a model for this proposed pathogenesis. In SC, a dysregulated immune response to a streptococcal infection is hypothesized to result in inflammation of neuronal networks, particularly the basal ganglia nuclei. The resulting dysfunction in the basal ganglia nuclei are hypothesized to lead to a constellation of adventitious movements and psychiatric symptoms, which investigations have shown are amenable to immunomodulatory therapies. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections) has been proposed as a variant of SC, and is hypothesized to share a pathogenic mechanism, despite a unique symptom profile of predominantly psychiatric symptoms. In this review, we present the clinical aspects of both disorders, the data for potential shared etiopathogenesis between them, and the evidence for the therapeutic use of immunomodulatory therapies for the symptoms of SC and PANDAS. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. PMID- 25301690 TI - Cocaine triggers epigenetic alterations in the corticostriatal circuit. AB - Acute and repeated exposure to cocaine induces long-lasting alterations in neural networks that underlie compulsive drug seeking and taking. Cocaine exposure triggers complex adaptations in the brain that are mediated by dynamic patterns of gene expression that are translated into enduring changes. Recently, epigenetic modifications have been unveiled as critical mechanisms underlying addiction that contribute to drug-induced plasticity by regulating gene expression. These alterations are also now linked to the heritability of cocaine induced phenotypes. This review focuses on how changes in the epigenome, such as altered DNA methylation, histone modifications, and microRNAs, regulate transcription of specific genes that contribute to cocaine addiction. PMID- 25301692 TI - Scale-up of networked HIV treatment in Nigeria: creation of an integrated electronic medical records system. AB - OBJECTIVES: The implementation of PEPFAR programs in resource-limited settings was accompanied by the need to document patient care on a scale unprecedented in environments where paper-based records were the norm. We describe the development of an electronic medical records system (EMRS) put in place at the beginning of a large HIV/AIDS care and treatment program in Nigeria. METHODS: Databases were created to record laboratory results, medications prescribed and dispensed, and clinical assessments, using a relational database program. A collection of stand alone files recorded different elements of patient care, linked together by utilities that aggregated data on national standard indicators and assessed patient care for quality improvement, tracked patients requiring follow-up, generated counts of ART regimens dispensed, and provided 'snapshots' of a patient's response to treatment. A secure server was used to store patient files for backup and transfer. RESULTS: By February 2012, when the program transitioned to local in-country management by APIN, the EMRS was used in 33 hospitals across the country, with 4,947,433 adult, pediatric and PMTCT records that had been created and continued to be available for use in patient care. Ongoing trainings for data managers, along with an iterative process of implementing changes to the databases and forms based on user feedback, were needed. As the program scaled up and the volume of laboratory tests increased, results were produced in a digital format, wherever possible, that could be automatically transferred to the EMRS. Many larger clinics began to link some or all of the databases to local area networks, making them available to a larger group of staff members, or providing the ability to enter information simultaneously where needed. CONCLUSIONS: The EMRS improved patient care, enabled efficient reporting to the Government of Nigeria and to U.S. funding agencies, and allowed program managers and staff to conduct quality control audits. PMID- 25301691 TI - The effects of aging, housing and ibuprofen treatment on brain neurochemistry in a triple transgene Alzheimer's disease mouse model using magnetic resonance spectroscopy and imaging. AB - We investigated a triple transgene Alzheimer's disease (AD) mouse model that recapitulates many of the neurochemical, anatomic, pathologic and behavioral defects seen in human AD. We studied the mice as a function of age and brain region and investigated potential therapy with the non-steroidal anti inflammatory drug ibuprofen. Magnetic resonance spectroscopy (MRS) showed alterations characteristic of AD (i.e. increased myo-inositol and decreased N acetylaspartate (NAA)). Mice at 6 months of age showed an increase in myo inositol in the hippocampus at a time when the Abeta is intracellular, but not in amygdala or cortex. Myo-inositol increased as a function of age in the amygdala, cortex and striatum while NAA decreased only in the hippocampus and cortex at 17 23 months of age. Ibuprofen protected the increase of myo-inositol at six months of age in the hippocampus, but had no effect at 17-23 months of age (a time when Abeta is extracellular). In vivo MRI and MRS showed that at 17-23 months of age there was a significant protective effect of ibuprofen on hippocampal volume and NAA loss. Together, these data show the following: the increase in myo-inositol occurs before the decrease in NAA in hippocampus but not cortex; the hippocampus shows earlier changes than does the amygdale or cortex consistent with earlier deposition of Abeta40-42 in the hippocampus and ibuprofen protects against multiple components of the AD pathology. These data also show a profound effect of housing on this particular mouse model. PMID- 25301693 TI - Positive conversion of GAD autoantibody in patients with presumed type 2 diabetes. PMID- 25301694 TI - Lipopolysaccharide-Stimulated Transglutaminase 2 Expression Enhances Endocytosis Activity in the Mouse Microglial Cell Line BV-2. AB - OBJECTIVES: In peripheral macrophages, tissue-type transglutaminase (TG2) is reported to be involved in phagocytosis of apoptotic cells. However, the contribution of TG2 to microglial phagocytosis has not been investigated. In this study, using a microglial cell line, BV-2, we examined the changes in TG2 expression, phagocytosis and pinocytosis in cells stimulated by lipopolysaccharide (LPS). METHODS: Cells of the mouse microglial cell line BV-2 were stimulated by LPS with or without cystamine, an inhibitor of TG enzyme activity, for 24 h. TG2 expression was measured by real-time RT-PCR and Western blotting. TG activity was evaluated using biotinylated pentylamine as a substrate. Pinocytosis was determined by uptake of 1-um fluorescent microbeads. Phagocytosis was assessed by uptake of dead cells, human neuroblastoma SH-SY5Y cells, which were pretreated with H2O2 for 24 h. RESULTS: Phagocytosis of dead cells and pinocytosis of fluorescent microbeads were up-regulated by LPS stimulation together with TG2 expression. Blockade of TG enzyme activity by cystamine suppressed TG2 expression, phagocytosis and pinocytosis. CONCLUSIONS: These results suggested that LPS-induced TG2 was involved in the mechanism of pinocytosis and phagocytosis in microglia. PMID- 25301696 TI - "I am the Author and Must Take Full Responsibility": Abraham Verghese, Physicians as the Storytellers of the Body, and the Renewal of Medicine. AB - Abraham Verghese proposes to renew medicine by training physicians to read the right texts-literary fiction and patients' bodies-with skilled attention. Analyzing Verghese's proposal with reference to Foucault's idea of the "clinical gaze," I find that Verghese conceives of patients as texts that only physicians can read, meaning that physicians become the storytellers of the bodies, lives, and deaths of the people they meet as patients. I conclude that Verghese's project is unsustainable and alternatively propose thinking analogically of physicians as ship captains who maintain therapeutic distance to reopen interpretative spaces for communities outside of medicine. PMID- 25301695 TI - A Web-based computer-tailored game to reduce binge drinking among 16 to 18 year old Dutch adolescents: development and study protocol. AB - BACKGROUND: In The Netherlands, excessive alcohol use (e.g., binge drinking) is prevalent among adolescents. Alcohol use in general and binge drinking in particular comes with various immediate and long term health risks. Thus, reducing binge drinking among this target group is very important. This article describes a two-arm Cluster Randomized Controlled Trial (CRCT) of an intervention aimed at reducing binge drinking in this target group. METHODS: The intervention is a Web-based, computer-tailored game in which adolescents receive personalized feedback on their drinking behavior aimed at changing motivational determinants related to this behavior. The development of the game is grounded in the I-Change Model. A CRTC is conducted to test the effectiveness of the game. Adolescents are recruited through schools, and schools are randomized into the experimental condition and the control condition. The experimental condition fills in a baseline questionnaire assessing demographic variables, motivational determinants of behavior (attitude, social influences, self-efficacy, intention) and alcohol use. They are also asked to invite their parents to take part in a short parental component that focusses on setting rules and communicating about alcohol. After completing the baseline questionnaire, the experimental condition continues playing the first of three game scenarios. The primary follow-up measurement takes place after four months and a second follow-up after eight months. The control condition only fills in the baseline, four and eight month follow-up measurement and then receives access to the game (i.e., a waiting list control condition). The effectiveness of the intervention to reduce binge drinking in the previous 30 days and alcohol use in the last week will be assessed. Furthermore, intention to drink and binge drink are assessed. Besides main effects, potential subgroup differences pertaining to gender, age, and educational background are explored. DISCUSSION: The study described in this article gives insight into the effectiveness of a possible solution for a prominent public health issue in The Netherlands, which is binge drinking among 16 to 18 year old adolescents. TRIAL REGISTRATION: Dutch Trial Register (NTR4048). Trial registered on 06/26/2013. PMID- 25301697 TI - Sulfated polysaccharides from Loligo vulgaris skin: potential biological activities and partial purification. AB - The characteristics, biological properties, and purification of sulfated polysaccharides extracted from squid (Loligo vulgaris) skin were investigated. Their chemical and physical characteristics were determined using X-ray diffraction and infrared spectroscopic analysis. Sulfated polysaccharides from squid skin (SPSS) contained 85.06% sugar, 2.54% protein, 1.87% ash, 8.07% sulfate, and 1.72% uronic acid. The antioxidant properties of SPSS were investigated based on DPPH radical-scavenging capacity (IC50 = 19.42 mg mL(-1)), hydrogen peroxide-scavenging activity (IC50 = 0.91 mg mL(-1)), and beta-carotene bleaching inhibition (IC50 = 2.79 mg mL(-1)) assays. ACE-inhibitory activity of SPSS was also investigated (IC50 = 0.14 mg mL(-1)). Further antimicrobial activity assays indicated that SPSS exhibited marked inhibitory activity against the bacterial and fungal strains tested. Those polysaccharides did not display hemolytic activity towards bovine erythrocytes. Fractionation by DEAE-cellulose column chromatography showed three major absorbance peaks. Results of this study suggest that sulfated polysaccharides from squid skin are attractive sources of polysaccharides and promising candidates for future application as dietary ingredients. PMID- 25301698 TI - Metronidazole loaded carboxymethyl tamarind kernel polysaccharide-polyvinyl alcohol cryogels: preparation and characterization. AB - The purpose of present study was to prepare composite hydrogels of carboxymethyl tamarind kernel polysaccharide and polyvinyl alcohol employing freeze thaw treatment and evaluate them for release behavior. The effect of concentrations of carboxymethyl tamarind kernel polysaccharide, polyvinyl alcohol, and freeze-thaw cycles on the % release of metronidazole was studied employing central composite experimental design. The result of the study revealed that the concentration of carboxymethyl tamarind kernel polysaccharide and interaction effect of concentrations of carboxymethyl tamarind kernel polysaccharide and polyvinyl alcohol influenced the release of metronidazole significantly. The optimal calculated parameters were concentration of carboxymethyl tamarind kernel polysaccharide-6.0% (w/v), concentration of polyvinyl alcohol-8.53% (w/v) and freeze-thaw cycles-4, which provided cryogels with a release of 75.77% over a period of 6h. The formation of cryogels was confirmed by Fourier-transformed infrared spectroscopy and X-ray diffraction studies. Thermal studies revealed higher thermal stability of cryogel. PMID- 25301699 TI - Effective dispersion and crosslinking in PVA/cellulose fiber biocomposites via solid-state mechanochemistry. AB - A mechanochemical approach to improve the dispersion and the degree of crosslinking between cellulose fiber and polymer matrix is presented herein to create high performance poly(vinyl alcohol) (PVA)/cellulose biocomposites in a solvent-free and catalyst-free system. During a pan-milling process, the hydrogen bonds in both cellulose and PVA were effectively broken up, and the released hydroxyl groups could react with succinic anhydride (SA) to form covalent bonds between the two components. This stress-induced chemical reaction was verified by fourier transform infrared spectroscopy. The reaction kinetics was discussed according to the conversion rate of SA during the pan-milling process. Soxhlet extraction with hot water showed that the crosslinked PVA/cellulose retained more PVA in the composites due to the homogeneous and heterogeneous crosslinking. Scanning electron microscope images indicated the dispersion and interfacial interactions between PVA and cellulose were largely improved. The resulting composites exhibited remarkably enhanced mechanical properties. The tensile strength increased from 8.8 MPa (without mechanochemical treatment) to 18.2 MPa, and elongation at break increased from 76.8 to 361.7% after the treatment. Their thermal stability was also significantly improved. PMID- 25301700 TI - Integrated partnerships and the transformation of pharmaceutical research and development. PMID- 25301701 TI - Outbreak of acute respiratory infection in a care home for the vulnerable elderly: investigation, management and challenges. PMID- 25301702 TI - Community-associated urinary infections requiring hospitalization: risk factors, microbiological characteristics and patterns of antibiotic resistance. AB - OBJECTIVE: Although patients with urinary tract infections (UTIs) are usually managed as outpatients, a percentage of them requires hospitalization. To review risk factors and microbiological characteristics of community-associated UTIs (CAUTIs) requiring hospitalization has been our objective. MATERIAL AND METHODS: A prospective observational study was carried out from November 2011 to December 2013. Incidence, microbiological characteristics and antibiotic resistance patterns in patients with CAUTIs that required hospitalization were analyzed. Risk factors (including diabetes mellitus, urolithiasis, urinary catheterization) and resistance rates of each pathogen were also analyzed. RESULTS: Four hundred and fifty seven patients were hospitalized in our department with CAUTI. The mean age was 56.2+/-19.85 years. Of them, 52.1% patients were women, 19.7% had urinary indwelling catheter and 11.4% have had a previous UTI. The most frequently isolated pathogens were Escherichia coli (60.6%), followed by Klebsiella (9.2%), Enterococcus (8.4%) and Pseudomonas (7.2%). Enterobacteriaceae other than E.coli were more prevalent in male and older patients. On the other side the most frequently isolated pathogen in patients with a previous UTI and a urinary catheter was Entercoccus. The resistance rates E. coli against ampicillin/amoxicillin + beta lactamase inhibitor was 23.5%, against third generation cephalosporins 16.6%, against fluoroquinolones 31.3% and 16.7% against aminoglycosides. 11.4% E. coli strains were producers of extended-spectrum Beta lactamases (ESBL). Finally, the resistance rates of Enterococcus and Pseudomonas against quinolones were of 50.0% and 61.5%, respectively. CONCLUSIONS: CAUTIs that require hospitalization are most frequent in older age, male gender, and presence of urinary catheter, with urolithiasis and with previous episodes of UTI. These factors are also related to isolation of pathogens other than E. coli and higher resistance rates. PMID- 25301703 TI - Noninvasive detection of macrophages in atheroma using a radiocontrast-loaded phosphatidylserine-containing liposomal contrast agent for computed tomography. AB - PURPOSE: Macrophage plays an important role in plaque destabilization in atherosclerosis. By harnessing the affinity of macrophages to certain phospholipid species, a liposomal contrast agent containing phosphatidylserine (PS) and X-ray computed tomographic (CT) contrast agent was prepared and evaluated for CT imaging of plaque-associated macrophages in rabbit models of atherosclerosis. PROCEDURES: Liposomes containing PS and iodixanol were evaluated for their physicochemical characteristics, in vitro macrophage uptake, in vivo blood pool clearance, and organ distribution. Plaque enhancement in the aorta was imaged with CT in two atherosclerotic rabbit models. RESULTS: In vitro macrophage uptake of PS liposomes increased with increasing amount of PS in the liposomes. Overall clearance of PS liposomes was more rapid than control liposomes. Smaller PS liposomes (d = 112 +/- 4 nm) were more effective than control liposomes of similar size or larger control and PS liposomes (d = 172 +/- 17 nm) in enhancing aortic plaques in both rabbit models. CONCLUSIONS: Proper liposomal surface modification and appropriate sizing are important determinant for CT-based molecular imaging of macrophages in atheroma. PMID- 25301704 TI - ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, therapy-resistant or refractory T-ALL remains a major clinical challenge. Here, we evaluated B-cell lymphoma (BCL)-2 inhibition by the BH3 mimetic ABT-199 as a new therapeutic strategy in human T-ALL. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3- or HOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL. In conclusion, our study highlights BCL-2 as an attractive molecular target in specific subtypes of human T-ALL that could be exploited by ABT-199. PMID- 25301705 TI - Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? AB - Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (HR-CLL; ie, refractory to purine analogs, short response [<24 months] to chemoimmunotherapy, and/or presence of del[17p]/TP53 mutations). Currently, treatment algorithms for HR-CLL are being challenged by the introduction of novel classes of drugs. Among them, BCR signal inhibitors (BCRi) and B-cell lymphoma 2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favorable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with HR-CLL about indication for and timing of HSCT. This article provides an overview of currently available evidence and theoretical considerations to guide this difficult decision process. Until the risks and benefits of different treatment strategies are settled, all patients with HR-CLL should be considered for treatment with BCRi/BCL2a. For patients who respond to these agents, there are 2 treatment possibilities: (1) performing an HSCT or (2) continuing treatment with the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when recommending one of these treatments over the other. PMID- 25301706 TI - Progressive maturation toward hematopoietic stem cells in the mouse embryo aorta. AB - Clusters of cells attached to the endothelium of the main embryonic arteries were first observed a century ago. Present in most vertebrate species, such clusters, or intraaortic hematopoietic clusters (IAHCs), derive from specialized hemogenic endothelial cells and contain the first few hematopoietic stem cells (HSCs) generated during embryonic development. However, some discrepancies remained concerning the spatio-temporal appearance and the numbers of IAHCs and HSCs. Therefore, the exact cell composition and function of IAHCs remain unclear to date. We show here that IAHCs contain pre-HSCs (or HSC precursors) that can mature into HSCs in vivo (as shown by the successful long-term multilineage reconstitution of primary neonates and secondary adult recipients). Such IAHC pre HSCs could contribute to the HSC pool increase observed at midgestation. The novel insights in pre-HSC to HSC transition represent an important step toward generating transplantable HSCs in vitro that are needed for autologous HSC transplantation therapies. PMID- 25301707 TI - SLAP/SLAP2 prevent excessive platelet (hem)ITAM signaling in thrombosis and ischemic stroke in mice. AB - Glycoprotein VI and C-type lectin-like receptor 2 are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease, which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling, but their function in platelets is unknown. In this study, we show that platelets expressed both SLAP isoforms and that overexpression of either protein in a heterologous cell line almost completely inhibited glycoprotein VI and C-type lectin-like receptor 2 signaling. In mice, single deficiency of SLAP or SLAP2 had only moderate effects on platelet function, whereas double deficiency of both adapters resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity, and thrombin generation in response to (hem)ITAM-coupled, but not G protein-coupled, receptor activation. In vivo, constitutive SLAP/SLAP2 knockout mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. This was attributed to the absence of both adapter proteins in platelets, as demonstrated by adoptive transfer of Slap(-/-)/Slap2(-/-) platelets into wild-type mice. Our results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke. PMID- 25301708 TI - A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. AB - CD19 is ubiquitously expressed on chronic lymphocytic leukemia (CLL) cells and is therefore an attractive candidate for antibody targeting. XmAb5574 (aka MOR00208) is a novel humanized CD19 monoclonal antibody with an engineered Fc region to enhance Fcgamma receptor binding affinity. Here we report results of a first in human phase 1 trial of XmAb5574 in patients with relapsed or refractory CLL. Twenty-seven patients were enrolled to 6 escalating dose levels, with expansion at the highest dose level of 12 mg/kg. Nine doses of XmAb5574 were infused over 8 weeks. No maximal tolerated dose was reached, and the drug was generally well tolerated, with infusion reactions of grades 1 and 2 being the most common toxicities. Grade 3 and 4 toxicities occurred in 5 patients and included neutropenia, thrombocytopenia, increased aspartate aminotransferase, febrile neutropenia, and tumor lysis syndrome. XmAb5574 showed preliminary efficacy, with 18 patients (66.7%) responding by physical examination criteria and laboratory studies, and 8 patients (29.6%) responding by computed tomography criteria. Pharmacokinetics showed a half-life of 14 days with clearance that was not dose dependent. In conclusion, this phase 1 trial demonstrates safety and preliminary efficacy of a novel Fc-engineered CD19 monoclonal antibody XmAb5574 and justifies movement into the phase 2 setting. This trial was registered at www.clinicaltrials.gov as #NCT01161511. PMID- 25301709 TI - Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. AB - Thrombocytopenia is a common finding in sepsis and associated with a worse outcome. We used a mouse model of pneumonia-derived sepsis caused by the human pathogen Klebsiella pneumoniae to study the role of platelets in host response to sepsis. Platelet counts (PCs) were reduced to less than a median of 5 * 10(9)/L or to 5 to 13 * 10(9)/L by administration of a depleting antibody in mice infected with Klebsiella via the airways. Thrombocytopenia was associated with strongly impaired survival during pneumonia-derived sepsis proportional to the extent of platelet depletion. Thrombocytopenic mice demonstrated PC-dependent enhanced bacterial growth in lungs, blood, and distant organs. Severe thrombocytopenia resulted in hemorrhage at the primary site of infection, but not in distant organs. PCs of 5 to 13 * 10(9)/L were sufficient to largely maintain hemostasis in infected lungs. Thrombocytopenia did not influence lung inflammation or neutrophil recruitment and did not attenuate local or systemic activation of coagulation or the vascular endothelium. PCs <5 * 10(9)/L even resulted in enhanced coagulation and endothelial cell activation, which coincided with increased proinflammatory cytokine levels. In accordance, low PCs in whole blood enhanced Klebsiella-induced cytokine release in vitro. These data suggest that platelets play an important role in host defense to Klebsiella pneumosepsis. PMID- 25301710 TI - Changes in regulation of human monocyte proteins in response to IgG from patients with antiphospholipid syndrome. AB - The effects of immunoglobulin G (IgG) from patients with the antiphospholipid syndrome (APS) upon monocyte activation have not been fully characterized. We carried out a comprehensive proteomic analysis of human monocytes treated with IgG from patients with different manifestations of the APS. Using 2-dimensional differential gel electrophoresis (2D DiGE), 4 of the most significantly regulated proteins (vimentin [VIM], zinc finger CCH domain-containing protein 18, CAP Gly domain-containing linker protein 2, and myeloperoxidase) were differentially regulated in monocytes treated with thrombotic or obstetric APS IgG, compared with healthy control (HC) IgG. These findings were confirmed by comparing monocytes isolated from APS patients and HC. Anti-VIM antibodies (AVAs) were significantly increased in 11 of 27 patients (40.7%) with APS. VIM expression on HC monocytes was stimulated more strongly by APS IgG from patients with higher avidity serum AVA. We further characterized the proteome of thrombotic APS IgG treated monocytes using a label-free proteomics technique. Of 12 proteins identified with the most confidence, 2 overlapped with 2D DiGE and many possessed immune response, cytoskeletal, coagulation, and signal transduction functions which are all relevant to APS and may therefore provide potential new therapeutic targets of this disease. PMID- 25301711 TI - Syphilis infection, sexual practices and bisexual behaviour among men who have sex with men and transgender women: a cross-sectional study. AB - OBJECTIVES: Men who have sex with men (MSM) and transgender women (TW) are highly vulnerable groups to sexually transmitted infections (STIs). This study aims to assess the prevalence of syphilis infection, sexual behaviour and identify factors associated with syphilis in MSM and TW in Campo Grande, Central Brazil. METHODS: Between 2009 and 2011, 430 MSM/TW participants were interviewed and tested for syphilis. Univariable and multivariable regression analyses were done to assess associations with syphilis infection. RESULTS: A total of 430 MSM/TW (278 MSM and 152 TW) were included in the study. The overall prevalence of lifetime syphilis and active syphilis was 34.7% (26.3% among MSM; 50.0% among TW) and 17.5% (12.3% among MSM; 27.0% among TW), respectively (p<0.001). In multivariable regression analysis, being 20-24 years and >=30 years, having engaged in a variety of sexual practices and with a history of genital/anal ulcer in the last 12 months were associated with lifetime syphilis infection in the MSM group. Among TW participants, being >=30 years of age, having more than 10 male sexual partners in last week and being infected with HIV were associated with lifetime syphilis. Factors associated with active syphilis among MSM were massage parlour/sauna recruitment and alcohol consumption at least once a week. Having sex with female partners in the past 12 months was predictive for active syphilis among TW. CONCLUSIONS: The prevalence of syphilis infection and risk sexual behaviour were high in the two samples, especially among TW. High levels of bisexual behaviours and low rates of consistent condom use indicate potential HIV/STIs transmission into the heterosexual population. This finding indicates the need and urgency for implementing more effective integrated programmes targeting MSM/TW for the prevention of syphilis and other STIs. PMID- 25301712 TI - Evaluation of the in vitro activity of levornidazole, its metabolites and comparators against clinical anaerobic bacteria. AB - This study evaluated the in vitro anti-anaerobic activity and spectrum of levornidazole, its metabolites and comparators against 375 clinical isolates of anaerobic bacteria, including Gram-negative bacilli (181 strains), Gram-negative cocci (11 strains), Gram-positive bacilli (139 strains) and Gram-positive cocci (44 strains), covering 34 species. Minimum inhibitory concentrations (MICs) of levornidazole, its five metabolites and three comparators against these anaerobic isolates were determined by the agar dilution method. Minimum bactericidal concentrations (MBCs) of levornidazole and metronidazole were measured against 22 strains of Bacteroides fragilis. Levornidazole showed good activity against B. fragilis, other Bacteroides spp., Clostridium difficile, Clostridium perfringens and Peptostreptococcus magnus, evidenced by MIC90 values of 0.5, 1, 0.25, 2 and 1mg/L, respectively. The activity of levornidazole and the comparators was poor for Veillonella spp. Generally, levornidazole displayed activity similar to or slightly higher than that of metronidazole, ornidazole and dextrornidazole against anaerobic Gram-negative bacilli, Gram-positive bacilli and Gram-positive cocci, especially B. fragilis. Favourable anti-anaerobic activity was also seen with levornidazole metabolites M1 and M4 but not M2, M3 or M5. For the 22 clinical B. fragilis strains, MBC50 and MBC90 values of levornidazole were 2mg/L and 4mg/L, respectively. Both MBC50/MIC50 and MBC90/MIC90 ratios of levornidazole were 4, similar to those of metronidazole. Levornidazole is an important anti anaerobic option in clinical settings in terms of its potent and broad-spectrum in vitro activity, bactericidal property, and the anti-anaerobic activity of its metabolites M1 and M4. PMID- 25301713 TI - Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation. AB - We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1: studied after 3-4 weeks SCS; n = 5) (group 2: studied after 5 weeks SCS; n = 11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27 s; SCS 3-4 weeks: median of 16s; SCS 5 weeks: median of 7s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS group. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata. PMID- 25301714 TI - Metabolic Disorders and Neurodegeneration, introduction to the special issue. PMID- 25301716 TI - A 5-year survey of antimicrobial susceptibility profiles of methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients with bloodstream infections in Northeast Italy. AB - A 5-year survey (2009-2013) of antimicrobial susceptibility of methicillin resistant Staphylococcus aureus (MRSA) isolated from patients with bloodstream infections was carried out in Northeast Italy. No upward creep of glycopeptides MICs was documented among 582 nonduplicate MRSA blood isolates, which were tested in accordance with broth microdilution and interpreted in accordance with EUCAST recommendations. Teicoplanin showed stably a lower MIC50 in comparison with vancomycin (0.25-0.5 versus 1 mg/L). The activities of newer anti-MRSA antibacterials stratified by glycopeptides MICs showed similar trends in MICs of either vancomycin or teicoplanin with those of daptomycin, linezolid, and tigecycline. We hypothesize that in centers with different distribution of glycopeptides MICs, downward for teicoplanin and upward for vancomycin, teicoplanin could be a more effective alternative to vancomycin for empirical treatment of MRSA-related bacteremia. PMID- 25301715 TI - AWARE-AWAreness during REsuscitation-a prospective study. AB - BACKGROUND: Cardiac arrest (CA) survivors experience cognitive deficits including post-traumatic stress disorder (PTSD). It is unclear whether these are related to cognitive/mental experiences and awareness during CPR. Despite anecdotal reports the broad range of cognitive/mental experiences and awareness associated with CPR has not been systematically studied. METHODS: The incidence and validity of awareness together with the range, characteristics and themes relating to memories/cognitive processes during CA was investigated through a 4 year multi center observational study using a three stage quantitative and qualitative interview system. The feasibility of objectively testing the accuracy of claims of visual and auditory awareness was examined using specific tests. The outcome measures were (1) awareness/memories during CA and (2) objective verification of claims of awareness using specific tests. RESULTS: Among 2060 CA events, 140 survivors completed stage 1 interviews, while 101 of 140 patients completed stage 2 interviews. 46% had memories with 7 major cognitive themes: fear; animals/plants; bright light; violence/persecution; deja-vu; family; recalling events post-CA and 9% had NDEs, while 2% described awareness with explicit recall of 'seeing' and 'hearing' actual events related to their resuscitation. One had a verifiable period of conscious awareness during which time cerebral function was not expected. CONCLUSIONS: CA survivors commonly experience a broad range of cognitive themes, with 2% exhibiting full awareness. This supports other recent studies that have indicated consciousness may be present despite clinically undetectable consciousness. This together with fearful experiences may contribute to PTSD and other cognitive deficits post CA. PMID- 25301717 TI - Influence of Agathi grandiflora active principles inhibit viral multiplication and stimulate immune system in Indian white shrimp Fenneropenaeus indicus against white spot syndrome virus infection. AB - Five herbs including Adathoda vasica, Agathi grandiflora, Leucas aspera, Psoralea corylifolia, and Quercus infectoria were selected to screen the antiviral and immunostimulant activity against white spot syndrome virus (WSSV) and Vibrio harveyi respectively using different organic polar and non-polar solvents. Based on the initial screening results, ethyl acetate and methanolic extracts of A. grandiflora had strong antiviral and immunostimulant activities. Those extracts incubated with WSSV injected Fenneropenaeus indicus got only 20% mortality and no PCR positive signals were seen in two step PCR amplification. The methanolic extracts of A. grandiflora were further purified through silica column chromatography and the fractions screened again for antiviral and immunostimulant activity. The secondary screening results revealed that, the fractions of F5 to F7 had effectively controlled the WSSV multiplication and V. harveyi growth. The pooled fractions (F5 to F7) was structurally characterized by gas chromatograph mass spectrometry (GC-MS) analysis and few compounds were identified including 3,7.11,15-Tetramethyl-2-Hexane-1-ol, pytol and 1,2-Benzenedicarboxylic acid, diisooctyl ester. The pooled fractions were mixed with the basal feed ingredients at the concentration of 100 (D-1), 200 (D-2), 300 (D-3) and 400 (D-4) mg kg(-1) and the diets fed to the F. indicus (9.0 +/- 0.5 g) for 30 days. After the completion of feeding trail, they were challenged with virulent WSSV and studied the cumulative mortality, molecular diagnosis by quantitative real time PCR (qRT PCR), biochemical, haematological and immunological parameters. The control diet fed F. indicus succumbed to death 100% within 3 days whereas the D-3 and D-4 helped to reduced the cumulative mortality of 60-80% respectively. The qRT-PCR revealed that, the WSSV copy number was gradually decreased when increasing concentration of A. grandiflora extract active fraction in the diets. The diets D 3 and D-4 helped to reduce the protein and carbohydrate levels significantly (P < 0.01) from the control diet fed groups. Moreover these diets help to decrease the coagulation time of maximum 61% from control groups and improve the total haemocyte count of maximum 51.82 * 10(5) cells ml(-1) in D4 diet fed F. indicus. Finally immunological parameters including prophenol oxidase (proPO) activity, intracellular superoxide anion production and intra-agar lysozyme activity was significantly (P <= 0.001) improved in the D-3 and D-4 fed F. indicus after WSSV challenge. PMID- 25301718 TI - HdhCTL1 is a novel C-type lectin of abalone Haliotis discus hannai that agglutinates Gram-negative bacterial pathogens. AB - C-type lectins (CTLs) are Ca(2+)-dependent carbohydrate recognition proteins, which play important roles in the innate immunity of both vertebrates and invertebrates. In this study, we identified and characterized a C-type lectin (named HdhCTL1) from Pacific abalone, Haliotis discus hannai. HdhCTL1 is composed of 176 amino acid residues and shares low (23.9%) identity with the known CTL of abalone. HdhCTL1 possesses a putative signal peptide and a carbohydrate recognition domain (CRD) typical of CTLs. The CRD of HdhCTL1 contains four disulfide bond-forming cysteine residues that are highly conserved in CTLs. HdhCTL1 mRNA was detected in a wide range of tissues and expressed abundantly in the digestive gland. Experimental infection with the bacterial pathogen Vibrio anguillarum significantly upregulated HdhCTL1 expression in a time-dependent manner. Recombinant HdhCTL1 (rHdhCTL1) purified from Escherichia coli was able to agglutinate Gram-negative bacterial pathogens. The agglutinating ability of rHdhCTL1 was abolished in the presence of mannose. These results suggest that HdhCTL1 is a novel CTL which is likely to be involved in host defense against bacterial infection. PMID- 25301719 TI - In vitro effects of prostaglandin E2 on leucocytes from sticklebacks (Gasterosteus aculeatus) infected and not infected with the cestode Schistocephalus solidus. AB - Many helminth parasites have evolved strategies to evade the immune response of their hosts, which includes immunomodulation. Prostaglandin E2 (PGE2) is one of the best-described immunomodulators in mammalian helminth parasite infections. We hypothesized that also in teleost fish anti-helminthic immune responses are regulated via PGE2. We used a model system consisting of the tapeworm Schistocephalus solidus and its host, the three-spined stickleback (Gasterosteus aculeatus), to investigate in vitro effects of PGE2 on head kidney leucocytes (HKL) derived from sticklebacks that were experimentally infected with S. solidus. PGE2 was tested alone or in combination with either S. solidus antigens or bacterial lipopolysaccharides (LPS). After in vitro culture, cell viability and changes in leucocyte subpopulations (granulocytes to lymphocytes ratios) were monitored by flow cytometry and HKL were tested for their capacity to produce reactive oxygen species (ROS) with a chemiluminescence assay. In short term (2 h) HKL cultures PGE2 did not change the total numbers of live HKL, but the production of ROS decreased significantly with high (0.1 MUmol L(-1)) PGE2 concentrations. In long-term (96 h) cultures high PGE2 concentrations induced a sharp decrease of leucocytes viability, while low (0.1 pmol L(-1)) and intermediate (0.1 nmol L(-1)) concentrations of PGE2 caused elevated leucocyte viability compared to controls. This coincided with reduced ROS production in cultures with high PGE2 and elevated ROS production in cultures with low PGE2. Granulocyte to lymphocyte ratios increased with high PGE2 concentrations alone and in combination with S. solidus antigens and LPS, most prominently with HKL from S. solidus infected sticklebacks. The present study supports the hypothesis that PGE2 might be an immunomodulator in tapeworm-fish parasite-host interactions. PMID- 25301720 TI - Domain 2 of a Kazal serine proteinase inhibitor SPIPm2 from Penaeus monodon possesses antiviral activity against WSSV. AB - A 5-domain Kazal type serine proteinase inhibitor SPIPm2 from Penaeus monodon is involved in innate immune defense against white spot syndrome virus (WSSV). To test which domains were involved, the 5 domains of SPIPm2 were over-expressed and tested against WSSV infection. By using hemocyte primary cell culture treated with each recombinant SPIPm2 domain along with WSSV, the expression of WSSV early genes ie1, WSV477 and late gene VP28 were substantially reduced as compared to other domains when the recombinant domain 2, rSPIPm2D2, was used. Injecting the WSSV along with rSPIPm2D2 but not with other domains caused delay in mortality rate of the infected shrimp. The results indicate that the SPIPm2D2 possesses strong antiviral activity and, hence, contributes predominantly to the antiviral activity of SPIPm2. PMID- 25301721 TI - Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia. AB - Less than a third of adults patients with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. We previously demonstrated that besides playing a role in drug-resistant leukemia cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates leukemia cell proliferation and differentiation through the endogenous MRP4/ABCC4 substrate, cAMP. Here, we studied the role of MRP4/ABCC4 in tumor progression in a mouse xenograft model and in leukemic stem cells (LSCs) differentiation. We found a decrease in the mitotic index and an increase in the apoptotic index associated with the inhibition of tumor growth when mice were treated with rolipram (PDE4 inhibitor) and/or probenecid (MRPs inhibitor). Genetic silencing and pharmacologic inhibition of MRP4 reduced tumor growth. Furthermore, MRP4 knockdown induced cell cycle arrest and apoptosis in vivo. Interestingly, when LSC population was isolated, we observed that increased cAMP levels and MRP4/ABCC4 blockade resulted in LSCs differentiation. Taken together, our findings show that MRP4/ABCC4 has a relevant role in tumor growth and apoptosis and in the eradication of LSCs, providing the basis for a novel promising target in AML therapy. PMID- 25301722 TI - The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling. AB - Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies. PMID- 25301723 TI - AngioMatrix, a signature of the tumor angiogenic switch-specific matrisome, correlates with poor prognosis for glioma and colorectal cancer patients. AB - Angiogenesis represents a rate-limiting step during tumor progression. Targeting angiogenesis is already applied in cancer treatment, yet limits of anti angiogenic therapies have emerged, notably because tumors adapt and recur after treatment. Therefore, there is a strong need to better understand the molecular and cellular mechanisms underlying tumor angiogenesis. Using the RIP1-Tag2 transgenic murine model, we identified 298 genes that are deregulated during the angiogenic switch, revealing an ingression/expansion of specific stromal cell types including endothelial cells and pericytes, but also macrophages and perivascular mesenchymal cells. Canonical TGF-beta signaling is up-regulated during the angiogenic switch, especially in tumor-associated macrophages and fibroblasts. The matrisome, comprising extracellular matrix (ECM) and ECM associated molecules, is significantly enriched, which allowed us to define the AngioMatrix signature as the 110 matrisomal genes induced during the RIP1-Tag2 angiogenic switch. Several AngioMatrix molecules were validated at expression level. Ablation of tenascin-C, one of the most highly induced ECM molecules during the switch, resulted in reduced angiogenesis confirming its important role. In human glioma and colorectal samples, the AngioMatrix signature correlates with the expression of endothelial cell markers, is increased with tumor progression and finally correlates with poor prognosis demonstrating its diagnostic and therapeutic potential. PMID- 25301724 TI - Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy. AB - 5-fluorouracil (5-FU) is the first line component used in colorectal cancer (CRC) therapy however even in combination with other chemotherapeutic drugs recurrence is common. Mutations of the adenomatous polyposis coli (APC) gene are considered as the initiating step of transformation in familial and sporadic CRCs. We have previously shown that APC regulates the cellular response to DNA replication stress and recently hypothesized that APC mutations might therefore influence 5 FU resistance. To test this, we compared CRC cell lines and show that those expressing truncated APC exhibit a limited response to 5-FU and arrest in G1/S phase without undergoing lethal damage, unlike cells expressing wild-type APC. In SW480 APC-mutant CRC cells, 5-FU-dependent apoptosis was restored after transient expression of full length APC, indicating a direct link between APC and drug response. Furthermore, we could increase sensitivity of APC truncated cells to 5 FU by inactivating the Chk1 kinase using drug treatment or siRNA-mediated knockdown. Our findings identify mutant APC as a potential tumor biomarker of resistance to 5-FU, and importantly we show that APC-mutant CRC cells can be made more sensitive to 5-FU by use of Chk1 inhibitors. PMID- 25301725 TI - Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. AB - Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM+/CD45- cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention. PMID- 25301727 TI - TERT promoter mutations and gene amplification: promoting TERT expression in Merkel cell carcinoma. AB - Telomerase activation through the induction of its catalytic component TERT is essential in carcinogenesis. The regulatory mechanism and clinical significance underlying cancer-specific TERT expression have been extensively investigated in various human malignancies, but little is known about these in Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin tumor. Here we addressed these issues by determining TERT promoter mutations, gene amplification, mRNA expression and association with clinical variables in MCC. TERT mRNA was expressed in 6/6 MCC cell lines and 41 of 43 tumors derived from 35 MCC patients. Telomerase activity was detectable in all 6 cell lines and 11 tumors analyzed. TERT promoter mutations were identified in 1/6 cell lines and 4/35 (11.4%) MCC cases. The mutation exhibited UV signature and occurred in sun-exposed areas. Increased TERT gene copy numbers were observed in 1/6 cell lines and 11/14 (79%) tumors, and highly correlated with its mRNA expression (r = 0.7419, P = 0.0024). Shorter overall survival was significantly associated with higher TERT mRNA levels in MCC patients (P = 0.032). Collectively, TERT expression and telomerase activity is widespread in MCC, and may be attributable to TERT promoter mutations and gene amplification. Higher TERT expression predicts poor patient outcomes. PMID- 25301728 TI - POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in head and neck cancer. AB - HOX genes are master regulators of organ morphogenesis and cell differentiation during embryonic development, and continue to be expressed throughout post-natal life. To test the hypothesis that HOX genes are dysregulated in head and neck squamous cell carcinoma (HNSCC) we defined their expression profile, and investigated the function, transcriptional regulation and clinical relevance of a subset of highly expressed HOXD genes. Two HOXD genes, D10 and D11, showed strikingly high levels in HNSCC cell lines, patient tumor samples and publicly available datasets. Knockdown of HOXD10 in HNSCC cells caused decreased proliferation and invasion, whereas knockdown of HOXD11 reduced only invasion. POU2F1 consensus sequences were identified in the 5' DNA of HOXD10 and D11. Knockdown of POU2F1 significantly reduced expression of HOXD10 and D11 and inhibited HNSCC proliferation. Luciferase reporter constructs of the HOXD10 and D11 promoters confirmed that POU2F1 consensus binding sites are required for optimal promoter activity. Utilizing patient tumor samples a significant association was found between immunohistochemical staining of HOXD10 and both the overall and the disease-specific survival, adding further support that HOXD10 is dysregulated in head and neck cancer. Additional studies are now warranted to fully evaluate HOXD10 as a prognostic tool in head and neck cancers. PMID- 25301729 TI - MicroRNA-638 inhibits cell proliferation, invasion and regulates cell cycle by targeting tetraspanin 1 in human colorectal carcinoma. AB - The expression of miR-638 was found downregulated in colorectal carcinoma (CRC) in our previous study. However, the role of miR-638 in CRC remains unknown. The aim of this study was to determine the function and mechanism of miR-638 in CRC. Here, we verified that miR-638 was frequently downregulated in CRC tissues compared with corresponding noncancerous tissues (NCTs) in an expanded CRC cohort, and survival analysis showed that the downregulation of miR-638 in CRC was associated with poor prognoses. The ectopic expression of miR-638 inhibited CRC cell proliferation, invasion and arrest the cell cycle in G1 phase, whereas the repression of miR-638 significantly promoted CRC cell growth, invasion and cell cycle G1/S transition. Subsequent mechanism analyses revealed that miR-638 inhibited CRC cell growth, invasion and cell cycle progression by targeting TSPAN1. TSPAN1 protein levels were upregulated in CRC samples and were inversely correlated with miR-638 levels. More importantly, high TSPAN1 expression levels in CRC tissues predicted poor overall survival, and appears to be an independent prognostic factor for CRC survival. Furthermore, CpG island methylation analyses revealed that the miR-638 promoter was hypermethylated in CRC and that attenuating promoter methylation was sufficient to restore miR-638 expression in CRC cells. Taken together, our current data demonstrate that miR-638 functions as a tumor suppressor in human CRC by inhibiting TSPAN1, and that TSPAN1 is a potential prognostic factor for CRC. PMID- 25301730 TI - E-selectin ligand-1 controls circulating prostate cancer cell rolling/adhesion and metastasis. AB - Circulating prostate cancer (PCa) cells preferentially roll and adhere on bone marrow vascular endothelial cells, where abundant E-selectin and stromal cell derived factor 1 (SDF-1) are expressed, subsequently initiating a cascade of activation events that eventually lead to the development of metastases. To elucidate the roles of circulating PCa cells' rolling and adhesion behaviors in cancer metastases, we applied a dynamic cylindrical flow-based microchannel device that is coated with E-selectin and SDF-1, mimicking capillary endothelium. Using this device we captured a small fraction of rolling PCa cells. These rolling cells display higher static adhesion ability, more aggressive cancer phenotypes and stem-like properties. Importantly, mice received rolling PCa cells, but not floating PCa cells, developed cancer metastases. Genes coding for E-selectin ligands and genes associated with cancer stem cells and metastasis were elevated in rolling PCa cells. Knock down of E-selectin ligand 1(ESL-1), significantly impaired PCa cells' rolling capacity and reduced cancer aggressiveness. Moreover, ESL-1 activates RAS and MAP kinase signal cascade, consequently inducing the downstream targets. In summary, circulating PCa cells' rolling capacity contributes to PCa metastasis, and that is in part controlled by ESL-1. PMID- 25301731 TI - Induction of a specific CD8+ T-cell response to cancer/testis antigens by demethylating pre-treatment against osteosarcoma. AB - Conventional non-surgical therapeutic regimens against osteosarcoma are subject to chemoresistance and tumor relapse, and immunotherapy may be promising for this tumor. However, it's hard to find satisfactory epitopes for immunotherapy against osteosarcoma. Cancer/testis antigens (CTAs), such as MAGE-A family and NY-ESO-1, the potential antigens that almost exclusively express in tumor cells and immune privileged sites, have been found expressed in osteosarcoma also. Nevertheless, the expression of CTAs is downregulated in many tumors, constraining the application of immunotherapy. In this article, we demonstrate that the expression of MAGE-A family and NY-ESO-1 in osteosarcoma cells can be upregulated following treatment with demethylating agent 5-aza-2'-deoxycytidine and consequently induces a CTA specific CD8+ T-cell response against osteosarcoma in vitro and in vivo. The in vivo imaging was realized by using luciferase-transfected HOS cells and DiR labeled T-cells in severely combined immunodeficiency mouse models. Cytotoxic T cells specifically recognizing MAGE-A family and NY-ESO-1 clustered at the tumor site in mice pre-treated with DAC and resulted in tumor growth suppression, while it was not observed in mice without DAC pre-treatment. This study is important for more targeted therapeutic approaches and suggests that adoptive immunotherapy, combined with demethylating treatment, has the potential for non-surgical therapeutic strategy against osteosarcoma. PMID- 25301732 TI - Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients. AB - Oct-4 and Nanog in regulating the epithelial-mesenchymal transition (EMT) and metastasis of breast cancer has not been clarified. We found that both Oct-4 and Nanog expression were significantly associated with tumor pathology and poor prognosis in 126 breast cancer patients. Characterization of CD44+CD24-Cancer stem cell(CSC) derived from breast cancer cells indicated that CSC rapidly formed mammospheres and had potent tumorigenicity in vivo. Furthermore, TGF-beta up regulated the expression of Oct-4, Nanog, N-cadherin, vimentin, Slug, and Snail, but down-regulated E-cadherin and cytokeratin 18 expression, demonstrating that CSC underwent EMT. Knockdown of both Oct-4 and Nanog expression inhibited spontaneous changes in the expression of EMT-related genes, while induction of both Oct-4 and Nanog over-expression enhanced spontaneous changes in the expression of EMT-related genes in CSC. However, perturbing alternation of Oct-4 and Nanog expression also modulated TGF-beta-induced EMT-related gene expression in CSC. Induction of Oct-4 and Nanog over-expression enhanced the invasiveness of CSC, but knockdown of both Oct-4 and Nanog inhibited the migration of CSC in vitro. Our data suggest that both Oct-4 and Nanog may serve as biomarkers for evaluating breast cancer prognosis. Our findings indicate that Oct-4 and Nanog positively regulate the EMT process, contributing to breast cancer metastasis. PMID- 25301733 TI - Pharmacological targeting the ATR-CHK1-WEE1 axis involves balancing cell growth stimulation and apoptosis. AB - The ATR-CHK1-WEE1 kinase cascade's functions in the DNA damage checkpoints are well established. Moreover, its roles in the unperturbed cell cycle are also increasingly being recognized. In this connection, a number of small-molecule inhibitors of ATR, CHK1, and WEE1 are being evaluated in clinical trials. Understanding precisely how cells respond to different concentrations of inhibitors is therefore of paramount importance and has broad clinical implications. Here we present evidence that in the absence of DNA damage, pharmacological inactivation of ATR was less effective in inducing mitotic catastrophe than inhibition of WEE1 and CHK1. Small-molecule inhibitors of CHK1 (AZD7762) or WEE1 (MK-1775) induced mitotic catastrophe, as characterized by dephosphorylation of CDK1(Tyr15), phosphorylation of histone H39(Ser10), and apoptosis. Unexpectedly, partial inhibition of WEE1 and CHK1 had the opposite effect of accelerating the cell cycle without inducing apoptosis, thereby increasing the overall cell proliferation. This was also corroborated by the finding that cell proliferation was enhanced by kinase-inactive versions of WEE1. We demonstrated that these potential limitations of the inhibitors could be overcome by targeting more than one components of the ATR-CHK1-WEE1 simultaneously. These observations reveal insights into the complex responses to pharmacological inactivation of the ATR-CHK1-WEE1 axis. PMID- 25301734 TI - De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells. AB - Elevated expression of heat shock protein 5 (HSPA5) promotes drug resistance and metastasis and is a marker of poor prognosis in breast cancer patients. Adenovirus type 5 E1A gene therapy has demonstrated antitumor efficacy but the mechanisms of metastasis-inhibition are unclear. Here, we report that E1A interacts with p300 histone acetyltransferase (HAT) and blocks p300-mediated HSPA5 acetylation at K353, which in turn promotes HSPA5 ubiquitination by GP78 (E3 ubiquitin ligase) and subsequent proteasome-mediated degradation. Our findings point out the Ying-Yang regulation of two different post-translational modifications (ubiquitination and acetylation) of HSPA5 in tumor metastasis. PMID- 25301735 TI - SOX10, a novel HMG-box-containing tumor suppressor, inhibits growth and metastasis of digestive cancers by suppressing the Wnt/beta-catenin pathway. AB - SOX10 was identified as a methylated gene in our previous cancer methylome study. Here we further analyzed its epigenetic inactivation, biological functions and related cell signaling in digestive cancers (colorectal, gastric and esophageal cancers) in detail. SOX10 expression was decreased in multiple digestive cancer cell lines as well as primary tumors due to its promoter methylation. Pharmacologic or genetic demethylation reversed SOX10 silencing. Ectopic expression of SOX10 in SOX10-deficient cancer cells inhibits their proliferation, tumorigenicity, and metastatic potentials in vitro and in vivo. SOX10 also suppressed the epithelial to mesenchymal transition (EMT) and stemness properties of digestive tumor cells. Mechanistically, SOX10 competes with TCF4 to bind beta catenin and transrepresses its downstream target genes via its own DNA-binding property. SOX10 mutations that disrupt the SOX10-beta-catenin interaction partially prevented tumor suppression. SOX10is thus a commonly inactivated tumor suppressor that antagonizes Wnt/beta-catenin signaling in cancer cells from different digestive tissues. PMID- 25301736 TI - Androgen receptor promotes gastric cancer cell migration and invasion via AKT phosphorylation dependent upregulation of matrix metalloproteinase 9. AB - Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in gastric cancer (GC) are poorly characterized. Here, we investigated the role of AR in GC cell migration, invasion and metastatic potential. Our data showed that AR expression was positively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by activation of AKT and upregulation of matrix metalloproteinase 9 (MMP9). AR overexpression induced increases in GC cell migration, invasion and proliferation in vitro and in vivo. These effects were attenuated by inhibition of AKT, AR and MMP9. AR overexpression upregulated MMP9 protein levels, whereas this effect was counteracted by AR siRNA. Inhibition of AKT by siRNA or an inhibitor (MK-2206 2HC) decreased AR protein expression in both stably transfected and parental SGC-7901 cells. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that AR bound to the AR-binding sites of the MMP9 promoter. In summary, AR overexpression induced by AKT phosphorylation upregulated MMP9 by binding to its promoter region to promote gastric carcinogenesis. The AKT/AR/MMP9 pathway plays an important role in GC metastasis and may be a novel therapeutic target for GC treatment. PMID- 25301737 TI - Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma. AB - CD133 is a cellular surface glycoprotein that has been reported as a marker for the enrichment of cancer stem cells (CSCs). However, the regulatory mechanism of CD133 remains unknown. CSCs have been proposed to contribute to radioresistance and multi-drug resistance. The elucidation of key regulators of CD133 and CSCs is critical for the development of CSC-targeted therapy. In this study, we showed that Ikarosinhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133(+) cancer stem-like cells in hepatocellular carcinoma (HCC). We found that Ikaros interacted with CtBP as a transcription repressor complex, which inhibited CD133 expression in HCC. We also demonstrated that Ikaros expression was up-regulated by ETS1 which activity was regulated by MAPKs pathway. Furthermore, decreased expression of Ikaroswas significantly associated with poor survival in HCC patients. Overall, our study identifies that Ikaros plays a role as a transcription repressor in HCC and is a new reactivated therapeutic target for the treatment of HCC. Meanwhile, our findings provide evidence that Ikaros could be an attractive inhibitor of the target gene CD133, which reactivates anticancer mechanisms in targeted CSC therapy. PMID- 25301738 TI - Regulation of the viability of Nf1 deficient cells by PKC isoforms. AB - Suppression of protein kinase C (PKC) is known to be synthetically lethal with ras mutations in various types of cancer cells. The studies also showed that blockade of PKC affected the viability of Nf1 deficient cells. Since PKC family consists of more than 10 isoforms, our study aimed at identifying which isoform(s) played the crucial role in sensitizing Nf1 deficient cells to apoptosis. Using genetic and chemical PKC inhibitors, we demonstrated that the concurrent inhibition of PKC alpha and beta induced Nf1 deficient ST or 96.2 cells, but not SNF02.2 cells with a normal Nf1 or ST cells ectopically expressing Nf1 effective domain gene, to apoptosis. In this process, PKC delta in Nf1 deficient cells, but not in ST/Nf1 cells, was upregulated and translocated to the nucleus. Furthermore, caspase 3 was cleaved and cytochrome c was released to the cytosol. Thus, it appeared that PKC delta and alpha/beta are the crucial components for sustaining the aberrant Ras signaling and further viability of Nf1 deficient cells. The abrogation of these two isoforms activated their opponent PKC delta for switching on the caspase 3-governed apoptotic machinery. PMID- 25301740 TI - New targets for resistant prostate cancer. PMID- 25301741 TI - Long-term oncologic outcomes of laparoscopic renal cryoablation as primary treatment for small renal masses. AB - INTRODUCTION: Data regarding long-term oncologic outcomes of laparoscopic renal cryoablation (LRC) as first treatment for small renal masses (SRMs) are lacking. We hypothesized that LRC might provide an effective long-term cancer control in patients with a single cT1a SRM without a previous history of renal cell carcinoma (RCC). MATERIALS AND METHODS: The study design was a retrospective analysis of 174 consecutive patients who received LRC as first treatment for a single computed tomography or magnetic resonance imaging contrast-enhancing cT1a SRM between 2000 and 2013. Patients with a previous history of RCC were excluded. Treatment failure was evaluated 1 day after surgery. Local recurrence, metachronous SRM, systemic progression, disease relapse, cancer-specific mortality, and all-cause mortality were evaluated 10 years after surgery. Kaplan Meier plots were used to depict outcome-free survival rate. RESULTS: Median patient age was 66 years. Median tumor size was 20mm. Median follow-up was 48 months. Among patients with biopsy-proven RCC (63%, n = 109), the treatment failure-free rate was 98%. The 10-year recurrence-free survival rate was 95% and the 10-year metachronous SRM-free survival rate was 87%. The 10-year systemic progression-free survival rate was 100% and the 10-year disease relapse-free survival rate was 81%. The cancer-specific mortality-free survival rate was 100%, and the all-cause mortality-free survival rate was 61%. CONCLUSIONS: LRC provides safe long-term cancer control in patients newly diagnosed with a single cT1a SRM. Treatment failure and local recurrence are uncommon. Systemic progression-free survival and cancer-specific-free survival are optimal. PMID- 25301739 TI - CCL5 promotes VEGF-dependent angiogenesis by down-regulating miR-200b through PI3K/Akt signaling pathway in human chondrosarcoma cells. AB - Chondrosarcoma is the second most common primary malignant bone cancer, with potential for local invasion and distant metastasis. Chemokine CCL5 (formerly RANTES) of the CC-chemokine family plays a crucial role in metastasis. Angiogenesis is essential for the cancer metastasis. However, correlation of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is still unknown. CCL5-mediated VEGF expression was assessed by qPCR, ELISA, and Western blotting. CCL5-induced angiogenesis was examined by migration and tube formation in endothelial progenitor cells in vitro. CCL5 increased VEGF expression and also promoted chondrosarcoma conditional medium mediated angiogenesis in vitro and in vivo. Stimulation of chondrosarcoma with CCL5 augmented PI3K and Akt phosphorylation, while PI3K and Akt inhibitor or siRNA abolished CCL5-induced VEGF expression and angiogenesis. We also demonstrated CCL5 inhibiting miR-200b expression and miR-200b mimic reversing the CCL5-enhanced VEGF expression and angiogenesis. Moreover, in chondrosarcoma patients showed the positive correlation between CCL5 and VEGF; negative correlation between CCL5 and miR-200b. Taken together, results demonstrate CCL5 promoting VEGF-dependent angiogenesis in human chondrosarcoma cells by down regulating miR-200b through PI3K/Akt signaling pathway. PMID- 25301742 TI - Analysis of the risk factors for development of post-operative extradural hematoma after intracranial surgery. AB - OBJECTIVE: Post-operative extradural hematoma (EDH) is a relatively common complication in patients undergoing intracranial operations. The risk factors associated with the occurrence of EDH are not well described in the literature. The objective of this study was to identify the risk factors and the incidence of post-operative EDH adjacent and regional to the craniotomy or the craniectomy site. METHOD: This was a retrospective study of 24 (2.6% of total) patients who underwent extradural hematoma evacuation after primary intracranial supratentorial surgery between January 2005 and December 2011. During this period, 941 intracranial operations were performed. The control group (72 patients) was selected on the basis of having undergone the same pre-operative diagnosis and treatment within 2 months of the operations for the 24 hematoma patients. The Glasgow Coma Scale score and operation character (emergency or elective) of the hematoma and control group were individually matched to minimize pre-operative conditional bias. The ages of both groups were individually matched with similar ages within 10 years of each other to minimize age bias. RESULT: Univariate analysis showed that the significant pre-operative and intra-operative factors associated with post-operative EDH were an intra-operative blood loss of greater than 800 mL (p=0.007), maximal craniotomy length of greater than or equal to 100 mm (p=0.001), and craniotomy area of greater than or equal to 71.53 cm2 (p=0.018). In multivariate analysis, intra-operative blood loss exceeding 800 mL (median of total patients) placed a patient at significantly increased risk for post-operative EDH. CONCLUSION: The data did not examine established risk factors for post-operative hematoma, such as thrombocytopenia, anti-coagulant and anti platelet therapy, and a history of heavy alcohol consumption and/or tobacco intake. Recognizing the limitations of the study, large intra-operative blood loss and wide craniotomy area are implicated with an increased risk of post operative EDH after intracranial surgery. PMID- 25301744 TI - Utilization patterns for oral oncology medications in a specialty pharmacy cycle management program. AB - BACKGROUND: The cycle management program (CMP) was implemented in 2008 at a national specialty pharmacy with a focus on providing specialized counseling and monitoring for patients on select oral oncology medications. The program now includes nine medications: bexarotene, dasatinib, erlotinib, everolimus, nilotinib, pazopanib, sorafenib, sunitinib, and vorinostat. Patients receive frequent assessments to encourage adherence, identify adverse events, and track discontinuations through a pharmacist outreach at the initiation of therapy, day 10 and 20 of the first month, then monthly thereafter. The use of oral agents is increasing in cancer patients, shifting away from regimens exclusively involving intravenous chemotherapy. This offers advantages for patients in terms of convenience, but introduces risk as patients become more responsible for the administration and monitoring of the medications. PURPOSE: To evaluate utilization patterns of the oral oncology medications in the CMP including adverse event occurrence, medication discontinuations, and adherence markers. METHODS: This study is a retrospective review of patient-reported data from the CMP assessments completed in 2013. Data collected include adverse events and grades, adherence markers, and discontinuation rates. A total of 1163 assessments were reviewed from 557 patients. The assessments included in the analysis were the initial assessment, 10-day assessment, 20-day assessment, and the first monthly follow-up assessment, which encompasses the first two months of therapy. RESULTS: A total of 1453 adverse events were reported. Adverse events were cited as the reason for 39% of discontinuations and 28% of missed/held doses. A total of 101 discontinuations were reported across the nine CMP medications based on the first two months of data. Missed or held doses were reported in 130 assessments. CONCLUSIONS: Patient engagement and pharmacist interventions, through programs such as the CMP, are important to help patients manage these complex, high-risk medications. PMID- 25301743 TI - Selenium nanoparticles involve HSP-70 and SIRT1 in preventing the progression of type 1 diabetic nephropathy. AB - The present study was undertaken to examine the protective effect of selenium nanoparticles (SeNPs) in the progression of diabetic nephropathy (DN). Diabetes was induced in male Sprague Dawley (SD) rats by injecting streptozotocin (STZ) (55mg/kg, i.p). DN was then assessed by measuring blood urea nitrogen (BUN), creatinine, albumin, fibronectin and collagen. Changes in the expression of cytoprotective and apoptotic proteins in the kidney of rats were also examined. Herein we show that SeNPs effectively lowered the levels of BUN, creatinine, fibronectin and collagen and elevated the levels of albumin in diabetic rats. Histological observation corroborated with the above protective effects of SeNPs. Interestingly, SeNPs elevated the levels of heat shock protein (HSP-70), longevity protein SIRT 1 and also modulated apoptotic proteins Bax and Bcl-2 in diabetic kidney. Our data represents a paradigm shift in our understanding about the therapeutic potential of SeNPs in preventing DN by not only quenching oxidative stress but also by activating cyto-protective protein HSP70 and longevity protein SIRT1. PMID- 25301745 TI - Baclofen and gamma-hydroxybutyrate differentially altered behavior, EEG activity and sleep in rats. AB - OBJECTIVES: Animal and human studies have shown that sleep may have an impact on functional recovery after brain damage. Baclofen (Bac) and gamma-hydroxybutyrate (GHB) have been shown to induce physiological sleep in humans, however, their effects in rodents are unclear. The aim of this study is to characterize sleep and electroencelphalogram (EEG) after Bac and GHB administration in rats. We hypothesized that both drugs would induce physiological sleep. METHODS: Adult male Sprague-Dawley rats were implanted with EEG/electromyogram (EMG) electrodes for sleep recordings. Bac (10 or 20 mg/kg), GHB (150 or 300 mg/kg) or saline were injected 1 h after light and dark onset to evaluate time of day effect of the drugs. Vigilance states and EEG spectra were quantified. RESULTS: Bac and GHB induced a non-physiological state characterized by atypical behavior and an abnormal EEG pattern. After termination of this state, Bac was found to increase the duration of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (~90 and 10 min, respectively), reduce sleep fragmentation and affect NREM sleep episode frequency and duration (p<0.05). GHB had no major effect on vigilance states. Bac drastically increased EEG power density in NREM sleep in the frequencies 1.5-6.5 and 9.5-21.5 Hz compared to saline (p<0.05), while GHB enhanced power in the 1-5-Hz frequency band and reduced it in the 7-9-Hz band. Slow-wave activity in NREM sleep was enhanced 1.5-3-fold during the first 1-2 h following termination of the non-physiological state. The magnitude of drug effects was stronger during the dark phase. CONCLUSION: While both Bac and GHB induced a non-physiological resting state, only Bac facilitated and consolidated sleep, and promoted EEG delta oscillations thereafter. Hence, Bac can be considered a sleep-promoting drug and its effects on functional recovery after stroke can be evaluated both in humans and rats. PMID- 25301746 TI - Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus. AB - Throughout adulthood, neurons are continuously replaced by new cells in the dentate gyrus (DG) of the hippocampus, and this neurogenesis is increased by various neuronal injuries including ischemic stroke and seizure. While several mechanisms of this injury-induced neurogenesis have been elucidated, the initiation factor remains unclear. Here, we investigated which signal(s) trigger(s) ischemia-induced cell proliferation and neurogenesis in the hippocampal DG region. We found that early apoptotic cell death of the immature neurons occurred in the DG region following transient forebrain ischemia/reperfusion in mice. Moreover, early immature neuronal death in the DG initiated transient forebrain ischemia/reperfusion-induced neurogenesis through glycogen synthase kinase-3beta/beta-catenin signaling, which was mediated by microglia-derived insulin-like growth factor-1 (IGF-1). Additionally, we observed that the blockade of immature neuronal cell death, early microglial activation, or IGF-1 signaling attenuated ischemia-induced neurogenesis. These results suggest that early immature neuronal cell death initiates ischemia-induced neurogenesis through microglial IGF-1 in mice. PMID- 25301747 TI - Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers. AB - Converging evidence suggests that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cellular function by regulating actin dynamics. In the present study we investigate the role of LRRK2 in functional synaptic terminals of adult LRRK2-knockout and LRRK2(R1441G)-transgenic mice as well as in primary fibroblasts of LRRK2(G2019S) mutation carriers. We show that lack of LRRK2 decreases and overexpression of mutant LRRK2 age-dependently increases the effect of the actin depolymerizing agent Latrunculin A (LatA) on the synaptic cytoskeleton. Similarly, endogenous mutant LRRK2 increases sensitivity to LatA in primary fibroblasts. Under basal conditions however, these fibroblasts show an increase in F-actin bundles and a decrease in filopodial length which can be rescued by LatA treatment. Our data suggest that LRRK2 alters actin dynamics and F-actin structure both in brain neurons and skin fibroblasts. We hypothesize that increased F-actin bundling represents a compensatory mechanism to protect F-actin from the depolymerizing effect of mutant LRRK2 under basal conditions. Our data further indicate that LRRK2-dependent changes in the cytoskeleton might have functional consequences on postsynaptic NMDA receptor localization. PMID- 25301748 TI - Brain iron accumulation exacerbates the pathogenesis of MPTP-induced Parkinson's disease. AB - Brain iron levels are significantly increased in Parkinson's disease (PD) and iron deposition is observed in the substantia nigra (SN) of PD patients. It is unclear whether iron overload is an initial cause of dopaminergic neuronal death or merely a byproduct that occurs in the SN of PD patients. In this study, ceruloplasmin knockout (CP-/-) mice and mice receiving an intracerebroventricular injection of ferric ammonium citrate (FAC) were selected as mouse models with high levels of brain iron. These mice were administered with 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) by intraperitoneal injection. Their behavior and the dopaminergic neuron damage to their substantia nigra pars compacta (SNpc) were assessed. These findings suggest that the injection of FAC or the absence of the CP gene may exacerbate both the observed apoptosis of TH-positive neurons and the behavioral symptoms of the MPTP-treated mice. The intracerebroventricular injection of deferoxamine (DFO) significantly alleviated the neuronal damage caused by MPTP in CP-/- mice. Furthermore, our findings suggest that the increased nigral iron content exacerbates the oxidative stress levels, promoting apoptosis through the Bcl-2/Bax pathway and the activated caspase-3 pathway in the brain. Therefore, iron overload in the brain exacerbates dopaminergic neuronal death in SNpc and leads to the onset of PD. PMID- 25301749 TI - Neuroprotective and anti-apoptotic effects of liraglutide in the rat brain following focal cerebral ischemia. AB - Stroke is a leading cause of death and serious, long-term disability worldwide. We report that rats receiving liraglutide show markedly attenuated infarct volumes and neurological deficit following ischemic insult. We have also investigated the effect of liraglutide on apoptosis and oxidative stress pathways after ischemic injury in diabetic and non-diabetic rats. Male Sprague-Dawley rats weighing 300-350g were used. Diabetes was induced by streptozotocin. Rats were pretreated with either vehicle or liraglutide (50MUg/kg, s.c.) for 14days and thereafter subjected to middle cerebral artery occlusion (MCAO). Twenty-four hours after occlusion, rats were assessed for neurological deficit, motor function and subsequently sacrificed for estimation of infarct volume, oxidative stress and apoptotic markers. Vehicle-treated non-diabetic and diabetic rats showed significant (p<0.001) neurological deficit following cerebral ischemia. Liraglutide pretreatment resulted in significantly (p<0.001) less neurological deficit compared to vehicle-treated MCAO rats. Cerebral ischemia produced significant (p<0.0001) infarction in vehicle-treated rats; however, the infarct volume was significantly (p<0.001) less in liraglutide-pretreated rats. Oxidative stress markers were increased following ischemia but were attenuated in liraglutide-treated rats. Anti-apoptotic protein Bcl-2 expression was decreased and pro-apoptotic protein Bax expression was increased in vehicle-treated MCAO rats compared to sham (p<0.0001). On the other hand liraglutide pretreatment showed significantly (p<0.01) increased expression of Bcl-2 and decreased expression of Bax in MCAO rats. In vehicle-treated group, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells significantly (p<0.0001) increased in the ischemic hemisphere compared to sham operated group. The number of TUNEL-positive cells in vehicle group was 73.5+/ 3.3 and 85.5+/-5.2/750MUm(2) in non-diabetic and diabetic vehicle-treated MCAO rats, respectively. Following liraglutide treatment the number of TUNEL-positive cells was remarkably attenuated to 25.5+/-2.8 and 41.5+/-4.1/750MUm(2) (p<0.001) in non-diabetic and diabetic rats, respectively. The results demonstrate that glucagon-like peptide 1 (GLP-1) agonist, liraglutide, is a neuroprotective agent and attenuates the neuronal damage following cerebral ischemia in rats by preventing apoptosis and decreasing oxidative stress. PMID- 25301751 TI - Chronic cocaine causes long-term alterations in circadian period and photic entrainment in the mouse. AB - The disruptive effects of cocaine on physiological, behavioral and genetic processes are well established. However, few studies have focused on the actions of cocaine on the adult circadian timekeeping system, and none have explored the circadian implications of long-term (weeks to months) cocaine exposure. The present study was undertaken to explore the actions of such long-term cocaine administration on core circadian parameters in mice, including rhythm period, length of the nocturnal activity period and photic entrainment. For cocaine dosing over extended periods, cocaine was provided in drinking water using continuous and scheduled regimens. The impact of chronic cocaine on circadian regulation was evidenced by disruptions of the period of circadian entrainment and intrinsic free-running circadian period. Specifically, mice under a skeleton photoperiod (1-min pulse of dim light delivered daily) receiving continuous ad libitum cocaine entrained rapidly to the light pulse at activity onset. Conversely, water controls entrained more slowly at activity offset through a process of phase-delays, which resulted in their activity rhythms being entrained 147 degrees out of phase with the cocaine group. This pattern persisted after cocaine withdrawal. Next, mice exposed to scheduled daily cocaine presentations exhibited free-running periods under constant darkness that were significantly longer than water controls and which also persisted after cocaine withdrawal. These cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence. PMID- 25301750 TI - Substance P and the neurokinin-1 receptor regulate electroencephalogram non-rapid eye movement sleep slow-wave activity locally. AB - The neuropeptide substance P is an excitatory neurotransmitter produced by various cells including neurons and microglia that is involved in regulating inflammation and cerebral blood flow--functions that affect sleep and slow-wave activity (SWA). Substance P is the major ligand for the neurokinin-1 receptor (NK 1R), which is found throughout the brain including the cortex. The NK-1R is found on sleep-active cortical neurons expressing neuronal nitric oxide synthase whose activity is associated with SWA. We determined the effects of local cortical administration of a NK-1R agonist (substance P-fragment 1, 7) and a NK-1R antagonist (CP96345) on sleep and SWA in mice. The NK-1R agonist significantly enhanced SWA for several hours when applied locally to the cortex of the ipsilateral hemisphere as the electroencephalogram (EEG) electrode but not after application to the contralateral hemisphere when compared to saline vehicle control injections. In addition, a significant compensatory reduction in SWA was found after the NK-1R agonist-induced enhancements in SWA. Conversely, injections of the NK-1R antagonist into the cortex of the ipsilateral hemisphere of the EEG electrode attenuated SWA compared to vehicle injections but this effect was not found after injections of the NK-1R antagonist into contralateral hemisphere as the EEG electrode. Non-rapid eye movement sleep and rapid eye movement sleep duration responses after NK-1R agonist and antagonist injections were not significantly different from the responses to the vehicle. Our findings indicate that the substance P and the NK-1R are involved in regulating SWA locally. PMID- 25301752 TI - Optical imaging of the propagation patterns of neural responses in the rat sensory cortex: comparison under two different anesthetic conditions. AB - Although many studies have reported the influence of anesthetics on the shape of somatic evoked potential, none has evaluated the influence on the spatio-temporal pattern of neural activity in detail. It is practically impossible to analyze neural activities spatially, using conventional electrophysiological methods. Applying our multiple-site optical recording technique for measuring membrane potential from multiple-sites with a high time resolution, we compared the spatio temporal pattern of the evoked activity under two different anesthetic conditions induced by urethane or alpha-chloralose. The somatic cortical response was evoked by electrical stimulation of the hindlimb, and the optical signals were recorded from the rat sensorimotor cortex stained with a voltage-sensitive dye (RH414). The evoked activity emerged in a restricted area and propagated in a concentric manner. The spatio-temporal pattern of the evoked activity was analyzed using isochrone maps. There were significant differences in the latency and propagation velocity of the evoked activity, as well as the full width at half maximum of optical signal between the two anesthetic conditions. Differences in the amplitude and the slope of the rising phase were not significant. PMID- 25301753 TI - Down-regulation of GPR137 expression inhibits proliferation of colon cancer cells. AB - G protein-coupled receptors (GPRs) are highly related to oncogenesis and cancer metastasis. G protein-coupled receptor 137 (GPR137) was initially reported as a novel orphan GPR about 10 years ago. Some orphan GPRs have been implicated in human cancers. The aim of this study is to investigate the role of GPR137 in human colon cancer. Expression levels of GRP137 were analyzed in different colon cancer cell lines by quantitative polymerase chain reaction and western blot analysis. Lentivirus-mediated short hairpin RNA was specifically designed to knock down GPR137 expression in colon cancer cells. Cell viability was measured by methylthiazoletetrazolium and colony formation assays. In addition, cell cycle characteristic was investigated by flow cytometry. GRP137 expression was observed in all seven colon cancer cell lines at different levels. The mRNA and protein levels of GPR137 were down-regulated in both HCT116 and RKO cells after lentivirus infection. Lentivirus-mediated silencing of GPR137 reduced the proliferation rate and colonies numbers. Knockdown of GPR137 in both cell lines led to cell cycle arrest in the G0/G1 phase. These results indicated that GPR137 plays an important role in colon cancer cell proliferation. A better understanding of GPR137's effects on signal transduction pathways in colon cancer cells may provide insights into the novel gene therapy of colon cancer. PMID- 25301754 TI - Cough-related neural processing in the brain: a roadmap for cough dysfunction? AB - Cough is a complex respiratory behavior essential for airway protection, consisting of sensory, motor, affective and cognitive attributes. Accordingly, the cough neural circuitry extends beyond a simple pontomedullary reflex arc to incorporate a network of neurons that are also widely distributed throughout the subcortical and cortical brain. Studies have described discrete regional responses in the brain that likely give rise to sensory discriminative processes, voluntary and urge-related cough control mechanisms and aspects of the emotive responses following airways irritation and coughing. Data from these studies highlight the central nervous system as a plausible target for therapeutic intervention and, consistent with this, a careful appraisal of the many and varied clinical disorders of coughing control would argue that more diversified therapies are needed to treat patients with cough dysfunction. In this paper we explore these concepts in detail to highlight unanswered questions and stimulate discussion for potential research of cough in the future. PMID- 25301755 TI - Hot topics in infection and immunity in children. PMID- 25301756 TI - Silent spread of highly pathogenic Avian Influenza H5N1 virus amongst vaccinated commercial layers. AB - The aim of this study was to determine whether a single vaccination of commercial layer type chickens with an inactivated vaccine containing highly pathogenic avian influenza virus strain H5N1 A/chicken/Legok/2003, carried out on the farm, was sufficient to protect against infection with the homologous virus strain. A transmission experiment was carried out with pairs of chicken of which one was inoculated with H5N1 virus and the other contact-exposed. Results showed that the majority of the vaccinated birds developed haemagglutination inhibition (HI) titres below 4log2. No clinical signs were observed in the vaccinated birds and virus shedding was limited. However, nearly all vaccinated birds showed a four fold or higher increase of HI titres after challenge or contact-exposure, which is an indication of infection. This implies that virus transmission most likely has occurred. This study showed that a single vaccination applied under field conditions induced clinical protection, but was insufficient to induce protection against virus transmission, suggesting that silent spread of virus in vaccinated commercial flocks may occur. PMID- 25301757 TI - Effect of tadalafil on male lower urinary tract symptoms: an integrated analysis of storage and voiding international prostate symptom subscores from four randomised controlled trials. AB - BACKGROUND: The international prostate symptom score (IPSS) evaluates lower urinary tract symptoms (LUTS) in men with suspected benign prostatic hyperplasia (BPH); the total score does not differentiate between storage and voiding and is unevenly weighted (four questions [57%] on voiding, three questions [43%] on storage). OBJECTIVE: To evaluate the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and in response to treatment with tadalafil. DESIGN, SETTING, AND PARTICIPANTS: Integrated analysis of data from four placebo-controlled, 12-wk studies of tadalafil (5mg once daily) in 1499 men with LUTS/BPH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships between total IPSS and the storage and voiding subscores were assessed using graphical exploration and linear regression modelling. Linear modelling was performed for the baseline and endpoint and for changes in subscores. The optimal storage subscore to total IPSS (S:T) ratio for IPSS improvement was identified using nonparametric regression and gradient-descent optimisation. RESULTS AND LIMITATIONS: The contribution of storage and voiding subscores at baseline and endpoint was 38.8% and 61.2%, and 39.2% and 60.7%, respectively. This intuitive 40:60 storage-to-voiding ratio was similar at baseline and endpoint by treatment group and for changes in subscores, but spanned the entire range for individuals. Changes in total IPSS were greatest for a storage subscore percentage contribution to total IPSS of 42.7%. There was no statistical association between S:T ratio (>= 40% vs < 40%) at baseline and response to tadalafil. The main limitation was the use of unvalidated storage and voiding IPSS subscores. CONCLUSIONS: A constant S:T ratio of 4:10 was observed at baseline and endpoint. The greatest effect on total IPSS was noted for an S:T percentage contribution of 42.7%. Tadalafil efficacy was unaffected by the level of storage dysfunction at baseline. PATIENT SUMMARY: This analysis shows that for men with BPH, improvements during treatment with tadalafil apply to both storage and voiding symptoms at a constant ratio. The extent of storage dysfunction before treatment did not affect the response to treatment. PMID- 25301758 TI - Sequential combination of mitomycin C plus bacillus Calmette-Guerin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. AB - BACKGROUND: Intravesical bacillus Calmette-Guerin (BCG) is an effective therapy in non-muscle-invasive bladder cancer (NMIBC), but it has limitations in terms of recurrence and toxicity. OBJECTIVE: To determine whether the sequential combination of mitomycin C (MMC) and BCG is superior to BCG alone in increasing a disease-free interval (DFI). DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective randomized trial including 407 patients with intermediate- to high risk NMIBC and allocated 211 to the MMC and BCG arm and 196 to the BCG-alone arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The trial was designed to provide concurrently a power of 80% for the detection of a relative risk reduction of 35% (hazard ratio [HR]: 0.65) of disease relapse with a type I error of 0.05. Times to events were estimated using cumulative incidence functions and compared using the Cox regression model. We used the Kaplan-Meier technique to estimate survival curves. RESULTS AND LIMITATIONS: In the intention-to-treat analysis at 5 yr, DFI was significantly improved by the sequential scheme (HR: 0.57; 95% confidence interval [CI], 0.39-0.83; p=0.003), reducing the disease relapse rate from 33.9% to 20.6%. Higher toxicity was observed with the combination, even reducing the MMC dose, especially in G3 local toxicity compared with BCG with a difference of 17.4% (95% CI, 7.6-27.2; p<0.001). In recurrent T1 tumors, the potential benefit of the sequential scheme was more evident than in the remaining subgroup (18.8% vs 12.8%), with a number needed to treat of five versus eight to avoid an event and with similar toxicity. CONCLUSIONS: Although the sequential scheme is more effective than BCG alone in reducing disease relapse, due to higher toxicity it could be offered only to patients with a high likelihood of recurrence, such as those with recurrent T1 tumors. PATIENT SUMMARY: We analyzed the outcomes of a randomized trial demonstrating that in intermediate- to high-risk non-muscle invasive bladder cancer, mitomycin C and bacillus Calmette-Guerin (BCG) reduced disease relapse compared with BCG alone but was more toxic. Consequently, it could be offered only to patients with recurrent T1 tumors. TRIAL REGISTRATION: CUETO 93009. PMID- 25301759 TI - Nomogram Predicting Prostate Cancer-specific Mortality for Men with Biochemical Recurrence After Radical Prostatectomy. AB - BACKGROUND: The natural history of prostate-specific antigen (PSA)-defined biochemical recurrence (BCR) of prostate cancer (PCa) after definitive local therapy is highly variable. Validated prediction models for PCa-specific mortality (PCSM) in this population are needed for treatment decision-making and clinical trial design. OBJECTIVE: To develop and validate a nomogram to predict the probability of PCSM from the time of BCR among men with rising PSA levels after radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: Between 1987 and 2011, 2254 men treated by radical prostatectomy at one of five high-volume hospitals experienced BCR, defined as three successive PSA rises (final value >0.2 ng/ml), single PSA >0.4 ng/ml, or use of secondary therapy administered for detectable PSA >0.1 ng/ml. Clinical information and follow-up data were modeled using competing-risk regression analysis to predict PCSM from the time of BCR. INTERVENTION: Radical prostatectomy for localized prostate cancer and subsequent PCa BCR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCSM. RESULTS AND LIMITATIONS: The 10-yr PCSM and mortality from competing causes was 19% (95% confidence interval [CI] 16-21%) and 17% (95% CI 14-19%), respectively. A nomogram predicting PCSM for all patients had an internally validated concordance index of 0.774. Inclusion of PSA doubling time (PSADT) in a nomogram based on standard parameters modestly improved predictive accuracy (concordance index 0.763 vs 0.754). Significant parameters in the models were preoperative PSA, pathological Gleason score, extraprostatic extension, seminal vesicle invasion, time to PCa BCR, PSA level at PCa BCR, and PSADT (all p<0.05). CONCLUSIONS: We constructed and validated a nomogram to predict the risk of PCSM at 10 yr among men with PCa BCR after radical prostatectomy. The nomogram may be used for patient counseling and the design of clinical trials for PCa. PATIENT SUMMARY: For men with biochemical recurrence of prostate cancer after radical prostatectomy, we have developed a model to predict the long-term risk of death from prostate cancer. PMID- 25301762 TI - GMC sees 15% fall in applications for GP training. PMID- 25301760 TI - Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). AB - BACKGROUND: Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa--the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)--includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE: Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS: STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS: A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2 yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68 76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS: Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY: Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body. PMID- 25301763 TI - Transcranial direct current stimulation enhances sucking of a liquid bolus in healthy humans. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive technique used for modulating cortical excitability in vivo in humans. Here we evaluated the effect of tDCS on behavioral and electrophysiological aspects of physiological sucking and swallowing. METHODS: Twelve healthy subjects underwent three tDCS sessions (anodal, cathodal and sham stimulation) on separate days in a double-blind randomized order. The active electrode was placed over the right swallowing motor cortex. Repeated sucking and swallowing acts were performed at baseline and at 15 and 60 min after each tDCS session and the mean liquid bolus volume ingested at each time point was measured. We also calculated average values of the following electrophysiological parameters: 1) area and 2) duration of the rectified EMG signal from the suprahyoid/submental muscles related to the sucking and swallowing phases; 3) EMG peak amplitude for the sucking and swallowing phases; 4) area and peak amplitude of the laryngeal-pharyngeal mechanogram; 5) oropharyngeal delay. RESULTS: The volume of the ingested bolus significantly increased (by an average of about 30% compared with the baseline value) both at 15 and at 60 min after the end of anodal tDCS. The electrophysiological evaluation after anodal tDCS showed a significant increase in area and duration of the sucking phase-related EMG signal. CONCLUSIONS: Anodal tDCS leads to stronger sucking of a liquid bolus in healthy subjects, likely by increasing recruitment of cortical areas of the swallowing network. This finding might open up interesting perspectives for the treatment of patients suffering from dysphagia due to various pathological conditions. PMID- 25301764 TI - Effective CPR at high altitudes likely requires oxygen-supplemented continuous abdominal compressions. PMID- 25301765 TI - Lung ultrasound for pneumothorax: elementary considerations. PMID- 25301766 TI - The polarity of the cervical vestibular evoked myogenic potential, and how it helps us further understand the vestibulo-collic pathway. PMID- 25301767 TI - Detecting suppressions in the EEG. PMID- 25301768 TI - Changes in resting EEG following methadone treatment in opiate addicts. AB - OBJECTIVE: This study investigated the electrophysiological activity associated with methadone maintenance treatment (MMT). METHODS: The resting EEG spectrum of beta (14.5-30 Hz), alpha (8-13 Hz), theta (4-7.5 Hz) and delta (1.5-3.5 Hz) rhythm were measured in 32 patients undertaking chronic MMT, 17 opiate users and 25 healthy volunteers. Differences in the EEG components of each group were evaluated using a repeated measures Analyses of Variance (ANOVA). Post-hoc comparisons were Bonferroni corrected. RESULTS: Our results show that either patients undertaking MMT or active opiate users exhibited a significant increase in the power of beta and theta bands relative to healthy control subjects. However, the spectral power of patients undertaking MMT fell between that of current opiate users and healthy control subjects on many regional EEG measures. There was an inverse correlation between the power of beta or theta bands and cognitive performance. CONCLUSION: The abnormal neural electrical activity present in those still using illicit opiates might be reduced following MMT. SIGNIFICANCE: The present findings provide further support for MMT of opiate dependence and demonstrates potentially positive effects of substitution treatment on brain function. PMID- 25301769 TI - Ion channel dysfunction and peripheral nerve hyperexcitability. PMID- 25301770 TI - Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide. AB - A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3 triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 MUM and 29-151 MUM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken. PMID- 25301771 TI - Synthesis and cytotoxic activity of novel 1-((indol-3-yl)methyl)-1H-imidazolium salts. AB - A series of novel 1-((indol-3-yl)methyl)-1H-imidazolium salts were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole ring, and substitution of the imidazolyl-3 position with a naphthylacyl or 4-bromophenacyl group, were vital for modulating inhibitory activity of cell growth. In particular, 1-((N-Boc-indol-3-yl)methyl)-3 (2-naphthylacyl)-1H-5,6-dimethyl-benzimidazolium bromide was found to be the most potent derivative and more selective against myeloid liver carcinoma (SMMC-7721), lung carcinoma (A549) and breast carcinoma (MCF-7), with IC50 values 1.9-fold, 1.7-fold and 4.8-fold lower than DDP. This compound can induce significant cell apoptosis in SMMC-7721 cells. PMID- 25301772 TI - Study the interactions between human serum albumin and two antifungal drugs: fluconazole and its analogue DTP. AB - Binding affinities of fluconazole and its analogue 2-(2,4-dichlorophenyl)-1,3 di(1H-1,2,4-triazol-yl)-2-propanol (DTP) to human serum albumin (HSA) were investigated under approximately human physiological conditions. The obtained result indicated that HSA could generate fluorescent quenching by fluconazole and DTP because of the formation of non-fluorescent ground-state complexes. Binding parameters calculated from the Stern-Volmer and the Scatchard equations showed that fluconazole and DTP bind to HSA with binding affinities of the order 10(4)L/mol. The thermodynamic parameters revealed that the binding was characterized by negative enthalpy and positive entropy changes, suggesting that the binding reaction was exothermic. Hydrogen bonds and hydrophobic interaction were found to be the predominant intermolecular forces stabilizing the drug protein. The effect of metal ions on the binding constants of fluconazole-HSA complex suggested that the presence of Mg(2+) and Zn(2+) ions could decrease the free drug level and extend the half-life in the systematic circulation. Docking experiments revealed that fluconazole and DTP binds in HSA mainly by hydrophobic interaction with the possibility of hydrogen bonds formation between the drugs and the residues Arg 222, Lys 199 and Lys 195 in HSA. PMID- 25301773 TI - Low post-operative mortality after surgery on patients with screening-detected abdominal aortic aneurysms: a Swedvasc registry study. AB - OBJECTIVES: Screening for abdominal aortic aneurysms (AAAs) substantially reduces aneurysm-related mortality in men and is increasing worldwide. This cohort study compares post-operative mortality and complications in men with screening detected vs. non-screening-detected AAAs. METHODS: Data were extracted from the Swedish National Registry for Vascular Surgery (Swedvasc) for all screening detected men treated for AAA (n = 350) and age-matched controls treated for non screening-detected AAA (n = 350). RESULTS: There were no differences in baseline characteristics besides age, which was lower in the screening-detected group than in the non-screening-detected group (median 66 vs. 68, p < .001). Open repair was used more frequently than endovascular aortic repair (EVAR) in patients with screening-detected AAAs than in non-screening-detected controls (56% vs. 45% p = .005). No differences in major post-operative complications at 30 days were observed between the groups. In patients treated with open repair there were no differences in 30-day, 90-day or 1-year mortality in screening-detected patients compared to non-screening-detected controls (1.0% vs. 3.2% p = .25, 2.1% vs. 4.5% p = .23, 4.1% vs. 5.8% p = .61). None of the patients treated with EVAR in either group died within 30 days. The 90-day mortality after EVAR was lower in patients with screening-detected AAA than in those with non-screening-detected AAAs (0.0% vs. 3.1%, p = .04). No difference in the 1-year mortality was detected in the EVAR-patients between the two groups (1.4% vs. 4.7%, p = .12). CONCLUSIONS: The contemporary post-operative mortality after AAA surgery was low in this national audit of patients with screening-detected AAAs and age-matched controls. Patients with screening-detected AAAs have the same frequency of complications at 30 days as patients with non-screening-detected AAA. This study gives further support to national screening programs for the detection of AAA in men. PMID- 25301774 TI - Salviprzols A and B, C21- and C22-terpenoids from the roots of Salvia przewalskii Maxim. AB - Two C21- and C22-terpenoids, salviprzols A (1) and B (2), together with 24 known compounds including 17 diterpenoids (3-19), a triterpenoid (20), and 6 phenolic derivatives (21-26), were isolated from the roots of Salvia przewalskii Maxim. Salviprzols A and B represented a new subtype of C23-terpenoids featured by an additional 2-oxopropyl moiety at C-12 and a rare gamma-hydroxyl-alpha-methyl alpha,beta-unsaturated-gamma-lactone ring system. Their structures were elucidated by extensive spectroscopic analyses, and the structure of 2 was confirmed by a single-crystal X-ray diffraction crystallography. The cytotoxic activities of the new isolates were tested. A plausible biosynthetic pathway for 1 and 2 was also proposed. PMID- 25301775 TI - Hawaiinolides E-G, cytotoxic cassane and cleistanthane diterpenoids from the entomogenous fungus Paraconiothyrium hawaiiense. AB - Hawaiinolides E-G (1-3), three additional new secondary metabolites including two cassane (1 and 2) types of diterpene lactones and one cleistanthane (3) diterpenoid, were isolated from the scale-up fermentation extract of Paraconiothyrium hawaiiense, an entomogenous fungus isolated from the Septobasidium-infected insect Diaspidiotus sp. The structures of 1-3 were elucidated by nuclear magnetic resonance experiments, and 1 and 3 were further confirmed by X-ray crystallography. The absolute configurations of 1 and 3 were assigned by single-crystal X-ray diffraction analysis using Cu Kalpha radiation, whereas that of 2 was deduced via the circular dichroism data. Compound 1 showed significant cytotoxic effects against the human tumor cell line T24, with an IC50 value (9.32 MUM) comparable to that of the positive control cisplatin. PMID- 25301776 TI - Hepatocellular carcinoma in variegate porphyria: a case report and literature review. AB - Variegate porphyria is an autosomal dominant acute hepatic porphyria characterized by photosensitivity and acute neurovisceral attacks. Hepatocellular carcinoma has been described as a potential complication of variegate porphyria in case reports. We report a case of a 48-year-old woman who was diagnosed with hepatocellular carcinoma following a brief history of right upper quadrant pain which was preceded by a few months of blistering lesions in sun-exposed areas. She was biochemically diagnosed with variegate porphyria, and mutational analysis confirmed the presence of a heterozygous mutation in the protoporphyrinogen oxidase gene. Despite two hepatic resections, she developed pulmonary metastases. She responded remarkably well to Sorafenib and remains in remission 16 months after treatment. A review of the literature revealed that hepatocellular carcinoma in variegate porphyria has been described in at least eight cases. Retrospective and prospective cohort studies have suggested a plausible association between hepatocellular carcinoma and acute hepatic porphyrias. Hepatic porphyrias should be considered in the differential diagnoses of hepatocellular carcinoma of uncertain aetiology. Patients with known hepatic porphyrias may benefit from periodic monitoring for this complication. PMID- 25301778 TI - Mitochondrial DNA analysis and numerical chromosome condition in human oocytes and polar bodies. AB - To investigate the mitochondrial DNA (mtDNA) segregation in human oocytes, the level of heteroplasmy in the three products of meioses, polar bodies (PBs) and corresponding oocytes, was assessed by studying the hypervariable region I (HVRI) of the D-loop region. The DNA from 122 PBs and 51 oocytes from 16 patients was amplified by whole genome amplification (WGA). An aliquot of the WGA product was used to assess aneuploidy, and another aliquot to study mtDNA. The HVRI was amplified and sequenced with an efficiency of 75.4 and 63%, respectively, in PBs, and of 100% in oocytes. The comparison with the mtDNA sequences from blood of the individual donors showed full correspondence of polymorphisms with the matching oocytes, whilst in PBs the degree of concordance dropped to 89.6%. Haplogroups were inferred for all 16 patients. Of the 89 diagnosed PBs from the 13 patients belonging to macrohaplogroup R, 23 were euploid and 66 aneuploid. The incidence of total anomalies was significantly lower in haplogroup H (6.5%) when compared with haplogroups J and T (17.6 and 13.4% respectively; P < 0.001). In haplogroup J, hypoaneuploidy occurred more frequently than hyperaneuploidy. In the three patients belonging to haplogroup N*, 81% of PBs were aneuploid with similar rates of chromosome hypoaneuploidy and hyperaneuploidy. The presence of mtDNA base changes confined to PBs could reflect a selection mechanism against severe mtDNA mutations, while permitting a high evolution rate that could result in bioenergetic diversity. The different susceptibility to aneuploidy by some haplogroups strongly supports this hypothesis. PMID- 25301777 TI - Patient participation in multidisciplinary tumor conferences. AB - OBJECTIVES: To identify (1) how frequently patients are invited to take part and actually do take part in multidisciplinary tumor conferences (MTCs), (2) which patient characteristics affect whether they are invited to MTCs and whether they decide to participate, (3) the extent to which invitation and participation depend on the specific hospital. STUDY DESIGN: Survey data from 4146 newly diagnosed breast cancer patients treated in 83 hospitals in North Rhine Westphalia, Germany, were analyzed using multilevel modeling. RESULTS: 12% of the patients were offered participation in the MTC. More than half of these patients actually participated. Invitations to participate differed by patients' sociodemographic, disease, and treatment characteristics, whereas decisions to participate were largely independent of these characteristics. Invitation and participation are strongly dependent on the specific hospital. CONCLUSION: The practice of inviting cancer patients to MTCs requires further research, particularly on benefits and disadvantages for patients and ways of organizing MTCs. PMID- 25301779 TI - Smoking rates continue to fall in the UK. PMID- 25301780 TI - CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3' processing. AB - AAUAAA is the most highly conserved motif in eukaryotic mRNA polyadenylation sites and, in mammals, is specifically recognized by the multisubunit CPSF (cleavage and polyadenylation specificity factor) complex. Despite its critical functions in mRNA 3' end formation, the molecular basis for CPSF-AAUAAA interaction remains poorly defined. The CPSF subunit CPSF160 has been implicated in AAUAAA recognition, but direct evidence has been lacking. Using in vitro and in vivo assays, we unexpectedly found that CPSF subunits CPSF30 and Wdr33 directly contact AAUAAA. Importantly, the CPSF30-RNA interaction is essential for mRNA 3' processing and is primarily mediated by its zinc fingers 2 and 3, which are specifically targeted by the influenza protein NS1A to suppress host mRNA 3' processing. Our data suggest that AAUAAA recognition in mammalian mRNA 3' processing is more complex than previously thought and involves multiple protein RNA interactions. PMID- 25301782 TI - Symmetry-resolved surface-derived electronic structure of MoS2(0 0 0 1). AB - We find a wave vector dependence of the band symmetries for MoS(2)(0 0 0 1) in angle-resolved photoemission. The band structures are found to be significantly different for states of even and odd reflection parities, despite the absence of true mirror plane symmetry away from Gamma, the Brillouin zone center, along the line to the K point, at the Brillouin zone edge. Our measurements agree with density functional theory (DFT) calculations for each band symmetry, with the notable exception of the Mo 4d(x(2)-y(2)) contributions to the valence band structure of MoS(2)(0 0 0 1). The band structure is indicative of strong S 3p and Mo 4d hybridization. In particular, the top of the valence band is predominantly composed of Mo 4d(3z(2)-r(2)) derived states near Gamma, whereas near K Mo 4d(x(2)-y(2)) as well as Mo 4d(xy) dominate. In contrast, the bottom of the valence band is dominated by Mo 5s and S 3p(z) contributions. PMID- 25301781 TI - Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33. AB - Cleavage and polyadenylation specificity factor (CPSF) is the central component of the 3' processing machinery for polyadenylated mRNAs in metazoans: CPSF recognizes the polyadenylation signal AAUAAA, providing sequence specificity in both pre-mRNA cleavage and polyadenylation, and catalyzes pre-mRNA cleavage. Here we show that of the seven polypeptides that have been proposed to constitute CPSF, only four (CPSF160, CPSF30, hFip1, and WDR33) are necessary and sufficient to reconstitute a CPSF subcomplex active in AAUAAA-dependent polyadenylation, whereas CPSF100, CPSF73, and symplekin are dispensable. WDR33 is required for binding of reconstituted CPSF to AAUAAA-containing RNA and can be specifically UV cross-linked to such RNAs, as can CPSF30. Transcriptome-wide identification of WDR33 targets by photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP) showed that WDR33 binds in and very close to the AAUAAA signal in vivo with high specificity. Thus, our data indicate that the large CPSF subunit participating in recognition of the polyadenylation signal is WDR33 and not CPSF160, as suggested by previous studies. PMID- 25301783 TI - Predictors of one-year mortality at hospital discharge after acute coronary syndromes: A new risk score from the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) study. AB - AIMS: A reliable prediction tool is needed to identify acute coronary syndrome (ACS) patients with high mortality risk after their initial hospitalization. METHODS: EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients: NCT01171404) is a prospective cohort study of 10,568 consecutive hospital survivors after an ACS event (4943 ST-segment elevation myocardial infarction (STEMI) and 5625 non-ST-elevation ACS (NSTE ACS)). Of these cases, 65.1% underwent percutaneous coronary intervention (PCI) and 2.5% coronary artery bypass graft (CABG). Post-discharge mortality was recorded for up to two years. From over 50 potential predictor variables a new risk score for one-year mortality was developed using forward stepwise Cox regression, and examined for goodness-of-fit, discriminatory power, and external validation. RESULTS: A total of 407 patients (3.9%) died within one year of discharge. We identified 12 highly significant independent predictors of mortality (in order of predictive strength): age, lower ejection fraction, poorer EQ-5D quality of life, elevated serum creatinine, in-hospital cardiac complications, chronic obstructive pulmonary disease, elevated blood glucose, male gender, no PCI/CABG after NSTE-ACS, low hemoglobin, peripheral artery disease, on diuretics at discharge. When combined into a new risk score excellent discrimination was achieved (c-statistic=0.81) and this was also validated on a large similar cohort (9907 patients) in Asia (c=0.78). For both STEMI and NSTE ACS there was a steep gradient in one-year mortality ranging from 0.5% in the lowest quintile to 18.2% in the highest decile. NSTE-ACS contributes over twice as many high-risk patients as STEMI. CONCLUSIONS: Post-discharge mortality for ACS patients remains of concern. Our new user-friendly risk score available on www.acsrisk.org can readily identify who is at high risk. PMID- 25301784 TI - NADPH oxidases as novel pharmacologic targets against influenza A virus infection. AB - Influenza A viruses represent a major global health care challenge, with imminent pandemics, emerging antiviral resistance, and long lag times for vaccine development, raising a pressing need for novel pharmacologic strategies that ideally target the pathology irrespective of the infecting strain. Reactive oxygen species (ROS) pervade all facets of cell biology with both detrimental and protective properties. Indeed, there is compelling evidence that activation of the NADPH oxidase 2 (NOX2) isoform of the NADPH oxidase family of ROS-producing enzymes promotes lung oxidative stress, inflammation, injury, and dysfunction resulting from influenza A viruses of low to high pathogenicity, as well as impeding virus clearance. By contrast, the dual oxidase isoforms produce ROS that provide vital protective antiviral effects for the host. In this review, we propose that inhibitors of NOX2 are better alternatives than broad-spectrum antioxidant approaches for treatment of influenza pathologies, for which clinical efficacy may have been limited owing to poor bioavailability and inadvertent removal of beneficial ROS. Finally, we briefly describe the current suite of NADPH oxidase inhibitors and the molecular features of the NADPH oxidase enzymes that could be exploited by drug discovery for development of more specific and novel inhibitors to prevent or treat disease caused by influenza. PMID- 25301785 TI - Study findings on FDA antidepressant warnings and suicide attempts in young people: a false alarm? PMID- 25301786 TI - Associations between socioeconomic status and race with complications after tonsillectomy in children. AB - OBJECTIVE: To determine if disparities exist for revisits and complications after pediatric tonsillectomy. STUDY DESIGN: Cross-sectional analysis of multistate databases. SETTING: Ambulatory surgery. METHODS: Cases of pediatric tonsillectomy with or without adenoidectomy were extracted from state ambulatory surgery databases and linked to state emergency department databases and inpatient databases for California, Iowa, Florida, and New York for 2010 and 2011. Revisit rates and diagnoses within 14 days were analyzed for potential associations of these complications with sex, race, and median household income quartile. RESULTS: There were 79,520 cases of pediatric tonsillectomy that were extracted (50.3% male; mean age, 7.5 years). Overall, 6419 patients (8.1%) incurred a revisit after the procedure. Revisit rates for posttonsillectomy bleeding, acute pain, and fever/dehydration were 2.1%, 1.5%, and 2.2%, respectively. On multivariate analysis, increasing household income quartile was significantly associated with a decreasing rate of all complications: revisits (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.84-0.89), posttonsillectomy bleeding (OR, 0.91; 95% CI, 0.86-0.96), acute pain (OR, 0.79; 95% CI, 0.74-0.84), and fever/dehydration (OR, 0.93; 95% CI, 0.89-0.98). Female sex was associated with a decreased rate of posttonsillectomy hemorrhaging (OR, 0.81; 95% CI, 0.73-0.91). Black and Hispanic children had an increased risk for a revisit after tonsillectomy (OR, 1.11; 95% CI, 1.01-1.22; and OR, 1.17; 95% CI, 1.09-1.26, respectively) and increased odds for acute pain at the revisit (OR, 1.36; 95% CI, 1.10-1.67; and OR, 1.34; 95% CI, 1.14-1.57, respectively) relative to white children. Race was not associated with the rate of hemorrhage posttonsillectomy. CONCLUSION: Significant disparities, particularly with respect to household income, exist in the incidence of revisits and complications after pediatric tonsillectomy. The disparate burden of increased revisits and acute pain diagnoses after tonsillectomy deserve further attention. PMID- 25301787 TI - National operative case log growth charts in otolaryngology-head and neck surgery training. AB - OBJECTIVE: To report national standard case log growth curves for operative procedures in otolaryngology and to describe a method by which program directors can chart surgical case numbers over resident training to longitudinally assess sufficiency of cases and parity between residents. STUDY DESIGN: Data visualization and analysis. SETTING: American Council for Graduate Medical Education (ACGME) national case log data for otolaryngology residency. SUBJECTS: National data set; no individual subjects. METHODS: National statistical case log reports for otolaryngology were obtained from the ACGME for each postgraduate year (PGY) level in 2009, 2010, and 2011. Estimated means and standard deviations were calculated. The mean and increments of standard deviation were graphed against time to create case log growth charts, similar to pediatric growth charts. RESULTS: Case log growth charts were made for each ACGME Otolaryngology Residency Review Committee key indicator procedure. Progress of an individual resident or of a cohort of residents may be graphed against this growth chart background over their training time. CONCLUSIONS: National operative case log growth charts allow residents and program directors to graphically assess progress in obtaining a sufficient variety and number of operative procedures over time throughout training. This can provide early identification when residents begin to fall below the growth curve during training. PMID- 25301789 TI - Graphene-based supercapacitor with carbon nanotube film as highly efficient current collector. AB - Flexible graphene-based thin film supercapacitors were made using carbon nanotube (CNT) films as current collectors and graphene films as electrodes. The graphene sheets were produced by simple electrochemical exfoliation, while the graphene films with controlled thickness were prepared by vacuum filtration. The solid state supercapacitor was made by using two graphene/CNT films on plastic substrates to sandwich a thin layer of gelled electrolyte. We found that the thin graphene film with thickness <1 MUm can greatly increase the capacitance. Using only CNT films as electrodes, the device exhibited a capacitance as low as ~0.4 mF cm(-2), whereas by adding a 360 nm thick graphene film to the CNT electrodes led to a ~4.3 mF cm(-2) capacitance. We experimentally demonstrated that the conductive CNT film is equivalent to gold as a current collector while it provides a stronger binding force to the graphene film. Combining the high capacitance of the thin graphene film and the high conductivity of the CNT film, our devices exhibited high energy density (8-14 Wh kg(-1)) and power density (250 450 kW kg(-1)). PMID- 25301788 TI - Predictors of perioperative complications in higher risk children after adenotonsillectomy for obstructive sleep apnea: a prospective study. AB - OBJECTIVE: Retrospective studies have limitations in predicting perioperative risk following adenotonsillectomy in children with obstructive sleep apnea syndrome (OSAS). Few prospective studies exist. We hypothesized that demographic and polysomnographic (PSG) variables would predict respiratory and general perioperative complications. STUDY DESIGN: Prospective, observational cohort study. SETTING: Pediatric tertiary center. SUBJECTS AND METHODS: Consecutive children undergoing adenotonsillectomy for OSAS within 12 months of PSG were evaluated for complications occurring within 2 weeks of surgery. RESULTS: There were 329 subjects, with 27% <3 years old, 24% obese, 16% preterm, and 29% with comorbidities. In this higher risk population, 28% had respiratory complications (major and/or minor), and 33% had nonrespiratory complications. Significant associations were found between PSG parameters and respiratory complications as follows: apnea hypopnea index (rank-biserial correlation coefficient [r] = 0.174, P = .017), SpO2 nadir (r = -0.332, P < .0005), sleep time with SpO2 <90% (r = 0.298, P < .0005), peak end-tidal CO2 (r = 0.354, P < .0005), and sleep time with end-tidal CO2 >50 mm Hg (r = 0.199, P = .006). Associations were also found between respiratory complications and age <3 years (r = -0.174, P = .003) or black race (r = 0.123, P = .039). No significant associations existed between PSG parameters and nonrespiratory complications. A model using age <3 years, SpO2 nadir, and peak CO2 predicted respiratory complications better than the American Academy of Pediatrics or American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines but was imperfect (area under the curve = 0.72). CONCLUSION: Thus, PSG predicted perioperative respiratory, but not nonrespiratory, complications in children with OSAS. Age <3 years or black race are high-risk factors. Present guidelines have limitations in determining the need for postoperative admission. PMID- 25301790 TI - One-step synthesis of TiO2 nanorod arrays on Ti foil for supercapacitor application. AB - Titanium dioxide (TiO2) nanorod arrays grown directly on Ti metal foil were prepared by a facile one-step hydrothermal method, in which the Ti foil serves as both substrate and precursor. The nanorods are tetragonal rutile single crystal with growth orientation along the [001] direction. The electrochemical properties of the TiO2 nanorod arrays were systematically investigated by cyclic voltammetry, galvanostatic charge/discharge and electrochemical impedance spectroscopy using a three-electrode system. As a result, the TiO2 nanorod arrays exhibit good areal specific capacitance and excellent cyclic stability by retaining more than 98% of the initial specific capacitance after 1000 cycles. In addition, a good flexibility of the Ti foil with TiO2 nanorod arrays was demonstrated by the stable electrochemical performance under different bending angles, which indicates that TiO2 nanorod arrays grown on Ti foil could be a promising electrode material for flexible supercapacitor application. PMID- 25301791 TI - Impossible to draw meaningful conclusions from study of changes in antidepressant use after FDA warnings. PMID- 25301792 TI - Commentary on: effectiveness of prophylactic antibiotics in outpatient plastic surgery. PMID- 25301793 TI - Commentary on: an alternative outpatient care model: postoperative guest suite based care. PMID- 25301794 TI - Proxy for suicide attempts was inappropriate in study of changes in antidepressant use after FDA warnings. PMID- 25301796 TI - Publishing performance data is an ethical obligation in all specialties. PMID- 25301795 TI - Application of histone modification-specific interaction domains as an alternative to antibodies. AB - Post-translational modifications (PTMs) of histones constitute a major chromatin indexing mechanism, and their proper characterization is of highest biological importance. So far, PTM-specific antibodies have been the standard reagent for studying histone PTMs despite caveats such as lot-to-lot variability of specificity and binding affinity. Herein, we successfully employed naturally occurring and engineered histone modification interacting domains for detection and identification of histone PTMs and ChIP-like enrichment of different types of chromatin. Our results demonstrate that histone interacting domains are robust and highly specific reagents that can replace or complement histone modification antibodies. These domains can be produced recombinantly in Escherichia coli at low cost and constant quality. Protein design of reading domains allows for generation of novel specificities, addition of affinity tags, and preparation of PTM binding pocket variants as matching negative controls, which is not possible with antibodies. PMID- 25301797 TI - More data needed to interpret link between suicide and FDA warning on antidepressants. PMID- 25301798 TI - What about the environmental benefits of reading with a smartphone? PMID- 25301799 TI - Authors' reply to Olfson and Schoenbaum, Nardo, Bartlett, Moore, Case, Gotzsche, and Barber and colleagues. PMID- 25301802 TI - Breakthrough articles: putting science first. PMID- 25301805 TI - Help us to engage with the text on smartphones as well as we do with textbooks. PMID- 25301806 TI - Focusing on the patient: mHealth, social media, electronic health records, and decision support systems. PMID- 25301807 TI - Disseminating informatics knowledge and training the next generation of leaders. PMID- 25301808 TI - 'N-of-1-pathways' unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine. AB - BACKGROUND: The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. Indeed, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. METHOD: 'N-of-1-pathways' is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodules assesses commonality and differences, within-study and cross studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. RESULTS: Cross-patient N-of-1 pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). CONCLUSIONS: The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies. SOFTWARE: http://lussierlab.org/publications/N-of-1-pathways. PMID- 25301810 TI - Chairman's column: health informatics and healthcare transformation--entering the post-EMR era. PMID- 25301809 TI - Evaluation of a pictograph enhancement system for patient instruction: a recall study. AB - OBJECTIVE: We developed a novel computer application called Glyph that automatically converts text to sets of illustrations using natural language processing and computer graphics techniques to provide high quality pictographs for health communication. In this study, we evaluated the ability of the Glyph system to illustrate a set of actual patient instructions, and tested patient recall of the original and Glyph illustrated instructions. METHODS: We used Glyph to illustrate 49 patient instructions representing 10 different discharge templates from the University of Utah Cardiology Service. 84 participants were recruited through convenience sampling. To test the recall of illustrated versus non-illustrated instructions, participants were asked to review and then recall a set questionnaires that contained five pictograph-enhanced and five non pictograph-enhanced items. RESULTS: The mean score without pictographs was 0.47 (SD 0.23), or 47% recall. With pictographs, this mean score increased to 0.52 (SD 0.22), or 52% recall. In a multivariable mixed effects linear regression model, this 0.05 mean increase was statistically significant (95% CI 0.03 to 0.06, p<0.001). DISCUSSION: In our study, the presence of Glyph pictographs improved discharge instruction recall (p<0.001). Education, age, and English as first language were associated with better instruction recall and transcription. CONCLUSIONS: Automated illustration is a novel approach to improve the comprehension and recall of discharge instructions. Our results showed a statistically significant in recall with automated illustrations. Subjects with no-colleague education and younger subjects appeared to benefit more from the illustrations than others. PMID- 25301811 TI - Long-term outcome of patients with spinal myxopapillary ependymoma: treatment results from the MD Anderson Cancer Center and institutions from the Rare Cancer Network. AB - BACKGROUND: Spinal myxopapillary ependymomas (MPEs) are slowly growing ependymal gliomas with preferential manifestation in young adults. The aim of this study was to assess the outcome of patients with MPE treated with surgery, radiotherapy (RT), and/or chemotherapy. METHODS: The medical records of 183 MPE patients (male: 59%) treated at the MD Anderson Cancer Center and 11 institutions from the Rare Cancer Network were retrospectively reviewed. Mean patient' age at diagnosis was 35.5 +/- 15.8 years. Ninety-seven (53.0%) patients underwent surgery without RT, and 86 (47.0%) were treated with surgery and/or RT. Median RT dose was 50.4 Gy. Median follow-up was 83.9 months. RESULTS: Fifteen (8.2%) patients died, 7 of unrelated cause. The estimated 10-year overall survival was 92.4% (95% CI: 87.7 97.1). Treatment failure was observed in 58 (31.7%) patients. Local failure, distant spinal relapse, and brain failure were observed in 49 (26.8%), 17 (9.3%), and 11 (6.0%) patients, respectively. The estimated 10-year progression-free survival was 61.2% (95% CI: 52.8-69.6). Age (<36 vs >=36 y), treatment modality (surgery alone vs surgery and RT), and extent of surgery were prognostic factors for local control and progression-free survival on univariate and multivariate analysis. CONCLUSIONS: In this series, treatment failure of MPE occurred in approximately one third of patients. The observed recurrence pattern of primary spinal MPE was mainly local, but a substantial number of patients failed nonlocally. Younger patients and those not treated initially with adjuvant RT or not undergoing gross total resection were significantly more likely to present with tumor recurrence/progression. PMID- 25301812 TI - Belonging to a network--microRNAs, extracellular vesicles, and the glioblastoma microenvironment. AB - The complexity of glioblastoma multiforme (GBM) and its distinct pathophysiology belong to a unique brain microenvironment and its cellular interactions. Despite extensive evidence of a role for microRNAs in GBM cells, little is known about microRNA-dependent communication between different cellular compartments of the microenvironment that may contribute to the tumor phenotype. While the majority of microRNAs are found intracellularly, a significant number of microRNAs have been observed outside of cells, often encapsulated in secreted extracellular vesicles (EVs). The function of these circulating/secreted microRNAs has not been explored in the context of the brain tumor microenvironment. Establishing how microRNAs are involved in the regulation of oncogenic signaling networks between tumor cells and stroma is likely to add a needed additional layer of complexity to the tumor network, consisting of intercellular communication. More importantly, microRNA/EV signaling may provide an additional therapeutic target for this deadly disease. PMID- 25301813 TI - Posttraumatic stress disorder, combat exposure, and carotid intima-media thickness in male twins. AB - Posttraumatic stress disorder (PTSD) is associated with an increased risk of ischemic heart disease, though the pathophysiologic mechanisms remain unclear. Carotid artery intima-media thickness (CIMT) is a measure of subclinical atherosclerosis. We examined whether PTSD and combat exposure were associated with CIMT in Vietnam War-era twins after controlling for shared genetic and childhood factors. Between 2002 and 2010, we studied 465 middle-aged twins from the Vietnam Era Twin Registry who were free from cardiovascular disease. PTSD was diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and CIMT was measured by ultrasound. Mixed-effects regression models were used to examine individual, between-pair, and within-pair associations. Approximately 13% of participants met the criteria for PTSD, and 45% served in the Vietnam Theater. PTSD was associated with 32.7 MUm higher CIMT (95% confidence interval (CI): 0.9, 64.5) after adjustment for confounders. The average CIMT for the pair increased by 59.7 MUm for each additional twin with PTSD (95% CI: 15.9, 104.2). We found no significant within pair differences in CIMT when comparing PTSD-discordant co-twins. Results for combat exposure were similar, but its association with CIMT weakened after adjustment for PTSD (95% CI: 7.0, 45.3). Among Vietnam War-era veterans, combat exposure and PTSD are associated with CIMT, though the associations are largely mediated by shared childhood factors. PMID- 25301814 TI - Multiple imputation in a longitudinal cohort study: a case study of sensitivity to imputation methods. AB - Multiple imputation has entered mainstream practice for the analysis of incomplete data. We have used it extensively in a large Australian longitudinal cohort study, the Victorian Adolescent Health Cohort Study (1992-2008). Although we have endeavored to follow best practices, there is little published advice on this, and we have not previously examined the extent to which variations in our approach might lead to different results. Here, we examined sensitivity of analytical results to imputation decisions, investigating choice of imputation method, inclusion of auxiliary variables, omission of cases with excessive missing data, and approaches for imputing highly skewed continuous distributions that are analyzed as dichotomous variables. Overall, we found that decisions made about imputation approach had a discernible but rarely dramatic impact for some types of estimates. For model-based estimates of association, the choice of imputation method and decisions made to build the imputation model had little effect on results, whereas estimates of overall prevalence and prevalence stratified by subgroup were more sensitive to imputation method and settings. Multiple imputation by chained equations gave more plausible results than multivariate normal imputation for prevalence estimates but appeared to be more susceptible to numerical instability related to a highly skewed variable. PMID- 25301815 TI - A longitudinal study of electronic cigarette use among a population-based sample of adult smokers: association with smoking cessation and motivation to quit. AB - AIMS: Increasingly popular electronic cigarettes (e-cigarettes) may be the most promising development yet to end cigarette smoking. However, there is sparse evidence that their use promotes cessation. We investigated whether e-cigarette use increases smoking cessation and/or has a deleterious effect on quitting smoking and motivation to quit. METHODS: Representative samples of adults in 2 US metropolitan areas were surveyed in 2011/2012 about their use of novel tobacco products. In 2014, follow-up interviews were conducted with 695 of the 1,374 baseline cigarette smokers who had agreed to be re-contacted (retention rate: 51%). The follow-up interview assessed their smoking status and history of electronic cigarette usage. Respondents were categorized as intensive users (used e-cigarettes daily for at least 1 month), intermittent users (used regularly, but not daily for more than 1 month), and non-users/triers (used e-cigarettes at most once or twice). RESULTS: At follow-up, 23% were intensive users, 29% intermittent users, 18% had used once or twice, and 30% had not tried e-cigarettes. Logistic regression controlling for demographics and tobacco dependence indicated that intensive users of e-cigarettes were 6 times more likely than non-users/triers to report that they quit smoking (OR: 6.07, 95% CI = 1.11, 33.2). No such relationship was seen for intermittent users. There was a negative association between intermittent e-cigarette use and 1 of 2 indicators of motivation to quit at follow-up. CONCLUSIONS: Daily use of electronic cigarettes for at least 1 month is strongly associated with quitting smoking at follow-up. Further investigation of the underlying reasons for intensive versus intermittent use will help shed light on the mechanisms underlying the associations between e cigarette use, motivation to quit, and smoking cessation. PMID- 25301816 TI - Retention of Homeless Smokers in the Power to Quit Study. AB - INTRODUCTION: Concerns about retention are a major barrier to conducting studies enrolling homeless individuals. Since smoking is a major problem in homeless communities and research on effective methods of promoting smoking cessation is needed, we describe strategies used to increase retention and participant characteristics associated with retention in smoking cessation study enrolling homeless adults. METHODS: The parent study was a 2-group randomized controlled trial with 26-week follow-up enrolling 430 homeless smokers from emergency shelters and transitional housing units in Minneapolis/Saint Paul, MN, USA. Multiple strategies were used to increase retention, including conducting visits at convenient locations for participants, collecting several forms of contact information from participants, using a schedule that was flexible and included frequent low-intensity visits, and providing incentives. Participant demographics as well as characteristics related to tobacco and drug use and health status were analyzed for associations with retention using univariate and multivariate analysis. RESULTS: Overall retention was 75% at 26 weeks. Factors associated with increased retention included greater age; having healthcare coverage; history of multiple homeless episodes, lower stress level; and higher PHQ-9 (Patient Health Questionnaire-9) score. A history of excessive drinking and drug use were associated with decreased retention. CONCLUSIONS: It is possible to successfully retain homeless individuals in a smoking cessation study if the study is designed with participants' needs in mind. PMID- 25301817 TI - Fruit removal increases root-zone respiration in cucumber. AB - BACKGROUND AND AIMS: Many attempts have been made to avoid the commonly observed fluctuations in fruit initiation and fruit growth in crop plants, particularly in cucumber (Cucumis sativus). Weak sinks of the fruit have been assumed to result in low sink/source ratios for carbohydrates, which may inhibit photosynthesis. This study focuses on the effects of low sink-source ratios on photosynthesis and respiration, and in particular root-zone respiration. METHODS: Mature fruit bearing cucumber plants were grown in an aerated nutrient solution. The root containers were designed as open chambers to allow measurement of CO2 gas exchange in the root zone. A similar arrangement in a gas-exchange cuvette enabled simultaneous measurements of CO2 exchange in the shoot and root zones. KEY RESULTS: Reducing the sinks for carbohydrates by removing all fruit from the plants always resulted in a doubling of CO2 exchange in the root zone within a few hours. However, respiration of the shoot remained unaffected and photosynthesis was only marginally reduced, if at all. CONCLUSIONS: The results suggest that the increased level of CO2 gas exchange in the root zone after removing the carbon sinks in the shoot is due primarily to the exudation of organic compounds by the roots and their decomposition by micro-organisms. This hypothesis must be tested in further experiments, but if proved correct it would make sense to include carbon leakage by root exudation in cucumber production models. In contrast, inhibition of photosynthesis was measurable only at zero fruit load, a situation that does not occur in cucumber production systems, and models that estimate production can therefore ignore (end-product) inhibition of photosynthesis. PMID- 25301818 TI - A comprehensive test of evolutionarily increased competitive ability in a highly invasive plant species. AB - BACKGROUND AND AIMS: A common hypothesis to explain plants' invasive success is that release from natural enemies in the introduced range selects for reduced allocation to resistance traits and a subsequent increase in resources available for growth and competitive ability (evolution of increased competitive ability, EICA). However, studies that have investigated this hypothesis have been incomplete as they either did not test for all aspects of competitive ability or did not select appropriate competitors. METHODS: Here, the prediction of increased competitive ability was examined with the invasive plant Lythrum salicaria (purple loosestrife) in a set of common-garden experiments that addressed these aspects by carefully distinguishing between competitive effect and response of invasive and native plants, and by using both intraspecific and interspecific competition settings with a highly vigorous neighbour, Urtica dioica (stinging nettle), which occurs in both ranges. KEY RESULTS: While the intraspecific competition results showed no differences in competitive effect or response between native and invasive plants, the interspecific competition experiment revealed greater competitive response and effect of invasive plants in both biomass and seed production. CONCLUSIONS: The use of both intra- and interspecific competition experiments in this study revealed opposing results. While the first experiment refutes the EICA hypothesis, the second shows strong support for it, suggesting evolutionarily increased competitive ability in invasive populations of L. salicaria. It is suggested that the use of naturally co-occurring heterospecifics, rather than conspecifics, may provide a better evaluation of the possible evolutionary shift towards greater competitive ability. PMID- 25301819 TI - Rheumatological diseases and cancer: the hidden variable of radiation exposure. PMID- 25301820 TI - Interactive effects of nitrogen addition, warming and invasion across organizational levels in an old-field plant community. AB - Response to global change is dependent on the level of biological organization (e.g. the ecologically relevant spatial scale) in which species are embedded. For example, individual responses can affect population-level responses, which, in turn, can affect community-level responses. Although relationships are known to exist among responses to global change across levels of biological organization, formal investigations of these relationships are still uncommon. I conducted an exploratory analysis to identify how nitrogen addition and warming by open top chambers might affect plants across spatial scales by estimating treatment effect size at the leaf level, the plant level and the community level. Moreover, I investigated if the presence of Pityopsis aspera, an experimentally introduced plant species, modified the relationship between spatial scale and effect size across treatments. I found that, overall, the spatial scale significantly contributes to differences in effect size, supporting previous work which suggests that mechanisms driving biotic response to global change are scale dependent. Interestingly, the relationship between spatial scale and effect size in both the absence and presence of experimental invasion is very similar for nitrogen addition and warming treatments. The presence of invasion, however, did not affect the relationship between spatial scale and effect size, suggesting that in this system, invasion may not exacerbate or attenuate climate change effects. This exercise highlights the value of moving beyond integration and scaling to the practice of directly testing for scale effects within single experiments. PMID- 25301821 TI - The ubiquitin-proteasome pathway protects Chlamydomonas reinhardtii against selenite toxicity, but is impaired as reactive oxygen species accumulate. AB - The ubiquitin-proteasome pathway (UPP) coordinates a myriad of physiological processes in higher plants, including abiotic stress responses, but it is less well characterized in algal species. In this study, the green alga Chlamydomonas reinhardtii was used to gain insights into the role of the UPP during moderate and severe selenite stress at three different time points. The data indicate that activity of the UPP in response to selenium (Se) stress was both time and dose dependent. Moderate selenite stress increased proteasome activity, protein ubiquitination and the proteasomal removal of malformed selenoproteins. However, severe Se stress caused by prolonged selenite treatment or high selenite concentration decreased proteasome activity, inhibited protein ubiquitination and prevented the proteasomal removal of selenoproteins. The UPP impairment during severe Se stress was associated with the observed accumulation of reactive oxygen species (ROS), including mitochondrial superoxide. Additionally, proteasomal inhibition decreased the concentration of chlorophyll in cultures challenged with Se. Therefore, although the UPP protects Chlamydomonas against Se stress, severe oxidative stress induced by selenite toxicity likely hinders the UPP's capacity to mediate a stress response. The possibility that stress tolerance in plants is dependent upon optimal UPP activity and maintenance is discussed. PMID- 25301822 TI - The magic touch: endothelial cells muscle-up adipose. PMID- 25301823 TI - Joshua M. Hare: converging on cardiac regeneration. PMID- 25301824 TI - Angiotensin II type 2 receptor effects: lesson from a human model of vascular hyporeactivity. Letter regarding Kemp et al. PMID- 25301826 TI - A unique drug distribution process for radium Ra 223 dichloride injection and its implication for product quality, patient privacy, and delineation of professional responsibilities. AB - On May 15, 2013, Bayer Healthcare Pharmaceuticals announced that it had received marketing approval for the therapeutic radioactive medication radium Ra 223 dichloride injection (Xofigo; Ra 223). The product acquisition and distribution process for hospital-based nuclear pharmacies and nuclear medicine services is unlike any other. The product is distributed as a low-risk compounded sterile preparation through a single compounding nuclear pharmacy located in Denver, Colorado, pursuant to a prescription. This model for drug distribution and delivery to the user institution has implications for product quality, patient privacy, and delineation of professional responsibilities. PMID- 25301825 TI - Response to letter regarding article, "AT2 receptor activation induces natriuresis and lowers blood pressure". PMID- 25301827 TI - Alcohol, pain, and opioids: which is a major threat to driving ability? PMID- 25301828 TI - Medication reconciliation by a pharmacist in patients with HIV on antiretroviral therapy: the needed balance of availability and expertise. AB - Medication reconciliation is an important process to help reduce medication errors.1,2 Based on our experience, pharmacists enhance the medication reconciliation process in this high-risk group. However, such interventions need to be carefully implemented. Pharmacy technicians, although readily available and potentially beneficial, may lack the necessary expertise with complicated ART regimens or multiple comorbidities because they are usually unable to critically evaluate for appropriateness.5 Pharmacy residents and non-ID/HIV-specialized pharmacists could fill the gap of availability, but they need to be properly trained on the disease and medication management. Initially, they should be allowed to shadow an experienced pharmacist, provided with a structured approach, and have access to a specialist in the field if one is available. We understand that not all institutions have the resources to hire full-time ID/HIV pharmacists; in that situation, involvement of trained general pharmacists will be helpful. Furthermore, having only ID/HIV-specialized pharmacists conduct medication reconciliation may lead to substandard care if one is unavailable on weekends or holidays. A more standardized and sustained effort is clearly needed. PMID- 25301829 TI - Response to comment on "Medication reconciliation by a pharmacist in patients with human immunodeficiency virus on antiretroviral therapy: the needed balance of availability and expertise". PMID- 25301830 TI - Response to comment on "Dimethyl fumarate (tecfidera): a new oral agent for multiple sclerosis". PMID- 25301831 TI - Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial. AB - BACKGROUND: Appropriate guideline criteria for use of implantable cardioverter defibrillators (ICDs) do not take into account potential recovery of left ventricular ejection fraction (LVEF) in patients treated with CRT-defibrillator. METHODS AND RESULTS: Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial who survived and had paired echocardiograms at enrollment and at 12 months (n=752) were included. Patients were evaluated by LVEF recovery in 3 groups (LVEF <=35% [reference], 36%-50%, and >50%) on outcomes of ventricular tachyarrhythmias (VTAs), VTA >=200 bpm, ICD shock, heart failure or death, and inappropriate ICD therapy by multivariable Cox models. A total of 7.3% achieved LVEF normalization (>50%). The average follow-up was 2.2+/-0.8 years. The risk of VTA was reduced in patients with LVEF >50% (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.07-0.82; P=0.023) and LVEF of 36% to 50% (HR, 0.44; 95% CI, 0.28-0.68; P<0.001). Among patients with LVEF >50%, only 1 patient had VTA >=200 bpm (HR, 0.16; 95% CI, 0.02-1.51), none were shocked by the ICD, and 2 died of nonarrhythmic causes. The risk of HF or death was reduced with improvements in LVEF (LVEF >50%: HR, 0.29; 95% CI, 0.09 0.97; P=0.045; and LVEF of 36%-50%: HR, 0.44; 95% CI, 0.28-0.69; P<0.001). For inappropriate ICD therapy, no additional risk reduction for LVEF>50% was seen compared with an LVEF of 36% to 50%. A total of 6 factors were associated with LVEF normalization, and patients with all factors present (n=42) did not experience VTAs (positive predictive value, 100%). CONCLUSIONS: Patients who achieve LVEF normalization (>50%) have very low absolute and relative risk of VTAs and a favorable clinical course within 2.2 years of follow-up. Risk of inappropriate ICD therapy is still present, and these patients could be considered for downgrade from CRT-defibrillator to CRT-pacemaker at the time of battery depletion if no VTAs have occurred. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. PMID- 25301833 TI - Voice outcomes after endoscopic treatment of laryngotracheal stenosis. AB - OBJECTIVE: This study aimed to assess vocal disability in patients with laryngotracheal stenosis who are managed with endoscopic surgery, comparing patients with posterior glottic stenosis (PGS) to those with subglottic or tracheal stenosis (SGS/TS). METHODS: Patients who underwent endoscopic treatment for laryngotracheal stenosis with voice outcomes data from 2005 to 2013 were studied. The mean Voice Handicap Index-10 (VHI-10) was compared over the study period. Of those with SGS/TS, the distance from the vocal folds to the proximal portion of the stenosis was obtained and compared to VHI-10. RESULTS: Forty-four patients met inclusion criteria. The mean VHI-10 for all patients was 14.6. Fifty percent were dysphonic (VHI-10>11). The mean VHI-10 for PGS patients was 22.4, and for SGS/TS patients, 10.9 (P=.004). Of those with PGS, 78.6% were dysphonic compared to only 36.7% of those with SGS/TS. Voice Handicap Index-10 improved from 14.1 for those with proximal stenosis to 4 for those with stenosis more than 2 cm distal to the vocal folds. CONCLUSION: Following endoscopic management of stenosis, those with PGS have poorer voice outcomes compared to those with SGS/TS. The majority of those with SGS/TS are not dysphonic. Vocal outcomes are greatest for those with stenosis beginning at least 2 cm distal to the vocal folds. PMID- 25301832 TI - Relation of antiphospholipid antibodies to postmortem brain infarcts in older people. AB - BACKGROUND: There are few data on the relationship of antiphospholipid antibodies (aPLs) to pathologically proven brain infarcts. We tested the hypothesis that aPLs are associated with a higher odds of brain infarcts among older, community dwelling individuals who came to autopsy. METHODS AND RESULTS: Specimens and clinical and pathological data were derived from 607 deceased subjects (mean age at death, 89 years; 66% women) who were participating in 1 of 2 cohort studies of aging (Rush Memory and Aging Project and Religious Orders Study) and had agreed to brain autopsy. Brain infarcts were identified on gross and microscopic examinations, and severity of cerebral vessel disease (atherosclerosis, arteriolosclerosis) was graded. Four clinically used aPLs were measured longitudinally: 3 in serum (anticardiolipin antibodies, beta2-glycoprotein I, and anti-phosphatidyl-serine) and 1 in plasma (lupus anticoagulant). A quarter of subjects (142 of 607, 23%) had at least 1 aPL present at baseline (median time interval from baseline to death, 4.6 years), and three quarters of these subjects had persistently positive measures over time. In a logistic regression analysis, baseline aPL positivity did not increase the odds of brain infarcts (odds ratio=1.08; 95% confidence interval, 0.74-1.58; P=0.19) or of gross or microscopic infarcts separately. Findings were essentially unchanged when considering number of baseline aPLs, aPLs proximate to death, and persistence of aPLs. Associations did not differ among subjects with increased severity of vessel disease. CONCLUSION: Overall, we did not find evidence that aPLs increase the odds of pathological brain infarcts in older people. PMID- 25301834 TI - Brain and cerebrovascular aging--new mechanisms and insights. PMID- 25301841 TI - Angiotensin-converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms. AB - OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (AngII) to form angiotensin-(1-7) (Ang-(1-7)), which generally opposes effects of AngII. AngII infusion into hypercholesterolemic male mice induces formation of abdominal aortic aneurysms (AAAs). This study tests the hypothesis that deficiency of ACE2 promotes AngII-induced AAAs, whereas ACE2 activation suppresses aneurysm formation. APPROACH AND RESULTS: ACE2 protein was detectable by immunostaining in mice and human AAAs. Whole-body deficiency of ACE2 significantly increased aortic lumen diameters and external diameters of suprarenal aortas from AngII-infused mice. Conversely, ACE2 deficiency in bone marrow-derived cells had no effect on AngII-induced AAAs. In contrast to AngII-induced AAAs, ACE2 deficiency had no significant effect on external aortic diameters of elastase-induced AAAs. Because ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined whether ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazene aceturate (30 mg/kg per day) to Ldlr(-/-) mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of diminazene aceturate significantly reduced total sera cholesterol and very low-density lipoprotein-cholesterol concentrations. Notably, diminazene aceturate significantly decreased aortic lumen diameters and aortic external diameters of AngII-infused mice resulting in a marked reduction in AAA incidence (from 73% to 29%). None of these effects of diminazene aceturate were observed in the Ace2(-/y) mice. CONCLUSIONS: These results demonstrate that ACE2 exerts a modulatory role in AngII-induced AAA formation, and that therapeutic stimulation of ACE2 could be a benefit to reduce AAA expansion and rupture in patients with an activated renin-angiotensin system. PMID- 25301842 TI - Lymphocyte migration into atherosclerotic plaque. AB - Adaptive immunity is involved in the pathogenesis of atherosclerosis, but the recruitment of T and B lymphocytes to atherosclerotic lesions is not as well studied as that of monocytes. In this review, we summarize the current understanding of the role of lymphocyte subsets in the pathogenesis of atherosclerosis and discuss chemokines and chemokine receptors involved in lymphocyte homing to atherosclerotic lesions. We review evidence for involvement of the chemokines CCL5, CCL19, CCL21, CXCL10, and CXCL16 and macrophage migration inhibitory factor in lymphocyte homing in atherosclerosis. Also, we review the role of their receptors CCR5, CCR6, CCR7, CXCR3, CXCR6, and CXCR2/CXCR4 and the role of the L-selectin in mouse models of atherosclerosis. PMID- 25301843 TI - Novel mechanisms of endothelial mechanotransduction. AB - Atherosclerosis is a focal disease that develops preferentially where nonlaminar, disturbed blood flow occurs, such as branches, bifurcations, and curvatures of large arteries. Endothelial cells sense and respond differently to disturbed flow compared with steady laminar flow. Disturbed flow that occurs in so-called atheroprone areas activates proinflammatory and apoptotic signaling, and this results in endothelial dysfunction and leads to subsequent development of atherosclerosis. In contrast, steady laminar flow as atheroprotective flow promotes expression of many anti-inflammatory genes, such as Kruppel-like factor 2 and endothelial nitric oxide synthase and inhibits endothelial inflammation and athrogenesis. Here we will discuss that disturbed flow and steady laminar flow induce pro- and antiatherogenic events via flow type-specific mechanotransduction pathways. We will focus on 5 mechanosensitive pathways: mitogen-activated protein kinases/extracellular signal-regulated kinase 5/Kruppel-like factor 2 signaling, extracellular signal-regulated kinase/peroxisome proliferator-activated receptor signaling, and mechanosignaling pathways involving SUMOylation, protein kinase C zeta, and p90 ribosomal S6 kinase. We think that clarifying regulation mechanisms between these 2 flow types will provide new insights into therapeutic approaches for the prevention and treatment of atherosclerosis. PMID- 25301845 TI - Economic burden of disease-associated malnutrition in China. AB - Disease-associated malnutrition (DAM) is a well-recognized problem in many countries, but the extent of its burden on the Chinese population is unclear. This article reports the results of a burden-of-illness study on DAM in 15 diseases in China. Using data from the World Health Organization (WHO), the China Health and Nutrition Survey, and the published literature, mortality and disability-adjusted life years (DALYs) lost because of DAM were calculated; a financial value of this burden was calculated following WHO guidelines. DALYs lost annually to DAM in China varied across diseases, from a low of 2248 in malaria to a high of 1 315 276 in chronic obstructive pulmonary disease. The total burden was 6.1 million DALYs, for an economic burden of US$66 billion (Chinese Y 447 billion) annually. This burden is sufficiently large to warrant immediate attention from public health officials and medical providers, especially given that low-cost and effective interventions are available. PMID- 25301844 TI - Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein E-knockout mouse. AB - OBJECTIVE: Mounting evidence links osteoprotegerin with cardiovascular disease. Elevated serum and aortic tissue osteoprotegerin are associated with the presence and growth of abdominal aortic aneurysm in humans; however, a role for osteoprotegerin in abdominal aortic aneurysm pathogenesis remains to be shown. We examined the functional significance of osteoprotegerin in aortic aneurysm using an Opg-deficient mouse model and in vitro investigations. APPROACH AND RESULTS: Homozygous deletion of Opg in apolipoprotein E-deficient mice (ApoE(-/-)Opg(-/-)) inhibited angiotensin II-induced aortic dilatation. Survival free from aortic rupture was increased from 67% in ApoE(-/-)Opg(+/+) controls to 94% in ApoE(-/ )Opg(-/-) mice (P=0.040). Serum concentrations of proinflammatory cytokines/chemokines, and aortic expression for cathepsin S (CTSS), matrix metalloproteinase 2, and matrix metalloproteinase 9 after 7 days (early-phase) of angiotensin II infusion were significantly reduced in ApoE(-/-)Opg(-/-) mice compared with ApoE(-/-)Opg(+/+) controls. In addition, aortic expression of markers for an inflammatory phenotype in aortic vascular smooth muscle cells in response to early-phase of angiotensin II infusion was significantly lower in Opg deficient mice. In vitro, human abdominal aortic aneurysm vascular smooth muscle cells produced more CTSS and exhibited increased CTSS-derived elastolytic activity than healthy aortic vascular smooth muscle cells, whereas recombinant human osteoprotegerin stimulated CTSS-dependent elastase activity in aortic vascular smooth muscle cells. CONCLUSIONS: These findings support a role for osteoprotegerin in aortic aneurysm through upregulation of CTSS, matrix metalloproteinase 2, and matrix metalloproteinase 9 within the aorta, promoting an inflammatory phenotype in aortic vascular smooth muscle cells in response to angiotensin II. PMID- 25301846 TI - Novel targets in head and neck cancer: should we be optimistic? AB - Head and neck squamous cell carcinomas have distinct mutation and copy-number profiles depending on human papillomavirus status. Although several challenges remain in biomarker implementation and clinical trial feasibility, incorporating available genomic data will expedite the development of novel therapeutics and predictive biomarker-driven clinical trials. See related article by Seiwert et al., p. 632. PMID- 25301847 TI - Reproducible, Quantitative, and Flexible Molecular Subtyping of Clinical DLBCL Samples Using the NanoString nCounter System. AB - PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with distinct molecular subtypes. The most established subtyping approach, the "Cell of Origin" (COO) algorithm, categorizes DLBCL into activated B-cell (ABC) and germinal center B-cell (GCB)-like subgroups through gene expression profiling. Recently developed immunohistochemical (IHC) techniques and other established methodologies can deliver discordant results and have various technical limitations. We evaluated the NanoString nCounter gene expression system to address issues with current platforms. EXPERIMENTAL DESIGN: We devised a scoring system using 145 genes from published datasets to categorize DLBCL samples. After cell line validation, clinical tissue segmentation was tested using commercially available diagnostic DLBCL samples. Finally, we profiled biopsies from patients with relapsed/refractory DLBCL enrolled in the fostamatinib phase IIb clinical trial using three independent RNA expression platforms: NanoString, Affymetrix, and qNPA. RESULTS: Diagnostic samples showed a typical spread of subtypes with consistent gene expression profiles across matched fresh, frozen, and formalin fixed paraffin-embedded tissues. Results from biopsy samples across platforms were remarkably consistent, in contrast to published IHC data. Interestingly, COO segmentation of longitudinal fostamatinib biopsies taken at initial diagnosis and then again at primary relapse showed 88% concordance (15/17), suggesting that COO designation remains stable over the course of disease progression. CONCLUSIONS: DLBCL segmentation of patient tumor samples is possible using a number of expression platforms. However, we found that NanoString offers the most flexibility and fewest limitations in regards to robust clinical tissue subtype characterization. These subtype distinctions should help guide disease prognosis and treatment options within DLBCL clinical practice. PMID- 25301848 TI - Improving learning with science and social studies text using computer-based concept maps for students with disabilities. AB - Concept maps have been used to help students with learning disabilities (LD) improve literacy skills and content learning, predominantly in secondary school. However, despite increased access to classroom technology, no previous studies have examined the efficacy of computer-based concept maps to improve learning from informational text for students with LD in elementary school. In this study, we used a concurrent delayed multiple probe design to evaluate the interactive use of computer-based concept maps on content acquisition with science and social studies texts for Hispanic students with LD in Grades 4 and 5. Findings from this study suggest that students improved content knowledge during intervention relative to a traditional instruction baseline condition. Learning outcomes and social validity information are considered to inform recommendations for future research and the feasibility of classroom implementation. PMID- 25301849 TI - NOVA: a software to analyze complexome profiling data. AB - SUMMARY: We introduce nova, a software for the analysis of complexome profiling data. nova supports the investigation of the composition of complexes, cluster analysis of the experimental data, visual inspection and comparison of experiments and many other features. AVAILABILITY AND IMPLEMENTATION: nova is licensed under the Artistic License 2.0. It is freely available at http://www.bioinformatik.uni-frankfurt.de. nova requires at least Java 7 and runs under Linux, Microsoft Windows and Mac OS. CONTACT: ina.koch@bioinformatik.uni frankfurt.de. PMID- 25301850 TI - PDB-wide collection of binding data: current status of the PDBbind database. AB - MOTIVATION: Molecular recognition between biological macromolecules and organic small molecules plays an important role in various life processes. Both structural information and binding data of biomolecular complexes are indispensable for depicting the underlying mechanism in such an event. The PDBbind database was created to collect experimentally measured binding data for the biomolecular complexes throughout the Protein Data Bank (PDB). It thus provides the linkage between structural information and energetic properties of biomolecular complexes, which is especially desirable for computational studies or statistical analyses. RESULTS: Since its first public release in 2004, the PDBbind database has been updated on an annual basis. The latest release (version 2013) provides experimental binding affinity data for 10,776 biomolecular complexes in PDB, including 8302 protein-ligand complexes and 2474 other types of complexes. In this article, we will describe the current methods used for compiling PDBbind and the updated status of this database. We will also review some typical applications of PDBbind published in the scientific literature. AVAILABILITY AND IMPLEMENTATION: All contents of this database are freely accessible at the PDBbind-CN Web server at http://www.pdbbind-cn.org/. CONTACT: wangrx@mail.sioc.ac.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25301851 TI - British Society of Gastroenterology guidelines on the diagnosis and management of coeliac disease. PMID- 25301852 TI - Interferon gamma receptor 2 gene variants are associated with liver fibrosis in the general population: the Rotterdam Study. PMID- 25301853 TI - Scheduled second-look endoscopy is not recommended after endoscopic submucosal dissection for gastric neoplasms (the SAFE trial): a multicentre prospective randomised controlled non-inferiority trial. AB - OBJECTIVE: To clarify the effectiveness of second-look endoscopy (SLE) at preventing bleeding after gastric endoscopic submucosal dissection (ESD). DESIGN: A multicentre prospective randomised controlled non-inferiority trial was conducted at five referral institutions across Japan. Patients with a solitary gastric neoplasm were enrolled. Exclusion criteria were previous oesophagogastric surgery or radiation therapy; perforation and the administration of antithrombotics, steroids or non-steroidal anti-inflammatory drugs. Patients were assigned to the SLE group or the non-SLE group by a computer-generated random sequence after ESD and were treated perioperatively with a proton pump inhibitor. SLE was performed one day after ESD. The primary endpoint was post-ESD bleeding, defined as an endoscopically proven haemorrhage. The trial had the power to detect a non-inferiority criterion of 7% between the groups. RESULTS: From February 2012 to February 2013, 130 and 132 patients were assigned to the SLE and the non-SLE groups, respectively. All patients were included in the intention-to treat analysis of the primary endpoint. Post-ESD bleeding occurred in seven patients with (5.4%) SLE and five patients with (3.8%) non-SLE (risk difference- 1.6% (95% CI -6.7 to 3.5); pnon-inferiority<0.001), meeting the non-inferiority criterion. All 12 patients with post-ESD bleeding and one patient with a delayed perforation were successfully managed with conservative treatment. CONCLUSIONS: SLE after gastric ESD is not routinely recommended because it does not contribute to the prevention of post-ESD bleeding for patients with an average bleeding risk. TRIAL REGISTRATION NUMBER: UMIN-CTR000007170. PMID- 25301854 TI - G-protein receptor kinase 4 polymorphism and response to antihypertensive therapy. AB - BACKGROUND: G-protein receptor kinase 4 polymorphism influences blood pressure regulation via modulation of dopamine receptor D1 in renal proximal tubular cells. We investigated the role of G-protein receptor kinase 4 polymorphism in the response to hypertensive therapy in patients with essential hypertension. METHODS: In a prospective study, we assessed the G-protein receptor kinase 4 polymorphisms R65L, A142V, and A486V in 100 hypertensive patients. We analyzed the association of the 3 gene variants on blood pressure control and response to antihypertensive therapy with single-locus analysis, haplotype analysis, and regression analysis. RESULTS: Hypertensive individuals with a homozygous double variant of 65 L and 142 V needed significantly more antihypertensive treatment (number of antihypertensives 2.59 vs 1.95, P = 0.043) and especially diuretic therapy (0.82 vs 0.49, P = 0.029) to reach the same mean arterial blood pressure than did homozygous carriers of only 1 variant or heterozygous/wild-type carriers of R65L, A142V, and A486V alleles. CONCLUSIONS: G-protein receptor kinase 4 polymorphism is associated with antihypertensive treatment response in patients with essential hypertension. Determination of G-protein receptor kinase 4 polymorphism may improve individual antihypertensive blood pressure control in patients with essential hypertension. PMID- 25301855 TI - Clinical perspective on the Clinical Pharmacogenetics Implementation Consortium Updated 2014 guidelines for CYP2D6 and codeine. PMID- 25301856 TI - Capturing exposures: using automated cameras to document environmental determinants of obesity. AB - Children's exposure to food marketing across multiple everyday settings, a key environmental influence on health, has not yet been objectively documented. Wearable automated cameras (ACs) may have the potential to provide an objective account of this exposure. The purpose of this study is to assess the feasibility of using ACs to document children's exposure to food marketing in multiple settings. A convenience sample of six participants (aged 12) wore a SenseCam device for two full days. Following which, participants attended a focus group to ascertain their experiences of using the device. The collected data were analysed to determine participants' daily and setting specific exposure to 'healthy' and 'unhealthy' food marketing (in minutes). The focus group transcript was analysed using thematic analysis to identify the common themes. Participants collected usable data that could be analysed to determine participant's daily exposure (in minutes) to 'unhealthy' food marketing across a number of everyday settings. Results from the focus group discussion indicated that participants were comfortable wearing the device, after an initial adjustment period. ACs may be an effective tool for documenting children's exposure to food marketing in multiple settings. ACs provide a new method for documenting environmental determinants of obesity and likely other environmental impacts on health. PMID- 25301858 TI - Management of adults with cyanotic congenital heart disease. PMID- 25301857 TI - Self-rated health and adverse events in CKD. AB - BACKGROUND AND OBJECTIVES: Little is known about the utility of self-rated general health assessments in persons with moderate-to-severe CKD. This study examined the ability of a single self-rated health measure to predict all-cause mortality and kidney disease progression in a cohort of 443 patients with stages 3-4 CKD, recruited between 2005 and 2011, and followed until the end of 2012. The performance of models incorporating self-rated health measures was compared with previously published predictive models and more complex models comprising a multibiomarker panel. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants were asked "In general, would you say your health is excellent, very good, good, fair, or poor?" Outcomes examined were time to all-cause mortality, kidney disease progression (initiation of RRT or 30% loss of eGFR), and a composite of these events. Model performances were compared using a nonparametric area under the curve (AUC) analysis. RESULTS: Over a median follow-up of 3.3 years, 118 (27%) participants died and 138 (31%) had progression of kidney disease. Fair-to poor self-rated health status was associated with significantly greater risks of mortality (fully adjusted hazard ratio [HR] for relative to good-to-excellent self-rated health, 2.76; 95% confidence interval [95% CI], 1.28 to 5.89), kidney disease progression (HR, 1.94; 95% CI, 1.49 to 2.56), and the combined end point (HR, 2.21; 95% CI, 1.66 to 2.96). For 3-year mortality prediction, the self-rated health model (AUC, 0.80; 95% CI, 0.76 to 0.85) had significantly higher AUCs than the base model (AUC, 0.71; 95% CI, 0.66 to 0.76) and the multibiomarker panel model (AUC, 0.74; 95% CI, 0.68 to 0.80) (P=0.03 and P=0.04, respectively). CONCLUSIONS: A single, easily obtained measure of self-rated health helps identify patients with CKD at high risk of mortality and kidney disease progression. Routine evaluation of self-rated health may help target individuals who might benefit from more intensive monitoring strategies. PMID- 25301860 TI - The relationship of parents' cigarette smoking to outcome of pregnancy- implications as to the problem of inferring causation from observed associations. AB - The relationship of parents' cigarette smoking to outcome of pregnancy implications as to the problem of inferring causation from observed associations. Amer J Epidem 1971;93:443-456. Nearly 10,000 white and more than 3000 black women were interviewed early in pregnancy on a variety of medical, genetic, environmental, and behavior variables. The increase in the incidence of low-birth weight among infants of smoking mothers was confirmed. However, a number of paradoxical findings were observed which raise doubts as to causation. Thus, no increase in neonatal mortality was noted. Rather, the neonatal mortality rate and the risk of congenital anomalies of low-birthweight infants were considerably lower for smoking than for nonsmoking mothers. These favorable results cannot be explained by differences in gestational age, nor does a "displacement" hypothesis appear reasonable. Among other findings which could not easily be explained: The healthiest low-birth-weight infants were found for couples where the wife smoked and her husband did not smoke; the most vulnerable were produced by couples where the wife did not smoke and the husband smoked. There were great differences in mode-of-life characteristics between smokers and nonsmokers. The latter were more likely to use contraceptive methods, to plan the baby, less likely to drink coffee and hard liquor, and in general appeared to live at a much slower and moderate pace than the smokers. Most puzzling difference is that of age at menarche, which was lower for smoking mothers. These paradoxical findings raise doubts and argue against the proposition that cigarette smoking acts as an exogenous factor which interferes with intrauterine development of the fetus. PMID- 25301859 TI - Sex differences in cardiovascular outcome during progression of aortic valve stenosis. AB - OBJECTIVE: Women with severe aortic valve stenosis (AS) have better LV systolic function and more concentric LV geometry than their male counterparts. However, sex differences in cardiovascular (CV) outcome during progression of AS have not been reported from a longitudinal prospective study. METHODS: Doppler echocardiography and CV events were recorded during a median of 4.0 years in 979 men and 632 women aged 28-86 (mean 67+/-10) years in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. LV systolic function was assessed by EF and midwall shortening (MWS). Study outcomes were AS-related events, ischaemic CV events and total mortality. RESULTS: The annular cumulative incidence of AS events, ischaemic CV events and death was 8.1%, 3.4% and 2.8% in women, and 8.9%, 4.4% and 2.4% in men, respectively. Women and men had similar AS progression rate whether measured by peak jet velocity, mean gradient or valve area. In multivariate analyses, female sex independently predicted less reduction in LV MWS and EF during follow-up (both p<0.05). In time-varying Cox analyses, women had a 40% lower rate of ischaemic CV events (95% CI 21% to 54%), in particular, more than 50% lower rate of stroke and coronary artery bypass grafting, and a 31% lower all-cause mortality (95% CI 1% to 51%), independent of active study treatment, age and hypertension, as well as time-varying valve area, low systolic function and abnormal LV geometry. AS event rate did not differ by sex. CONCLUSIONS: In the SEAS study, women and men had similar rates of AS progression and AS-related events. However, women had lower total mortality and ischaemic CV event rate than men independent of confounders. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00092677. PMID- 25301861 TI - Commentary: Smoking in pregnancy and neonatal mortality. PMID- 25301862 TI - Commentary: Resolutions of the birthweight paradox: competing explanations and analytical insights. PMID- 25301863 TI - Commentary: Smoking, birthweight and mortality: Jacob Yerushalmy on self selection and the pitfalls of causal inference. PMID- 25301864 TI - Commentary: Yerushalmy, maternal cigarette smoking and the perinatal mortality crossover paradox. PMID- 25301866 TI - Response to detection limit and statistical results. PMID- 25301865 TI - Commentary: Smoking in pregnancy and offspring health: early insights into family based and 'negative control' studies? PMID- 25301871 TI - Elevated RANTES level is associated with metabolic syndrome and correlated with activated platelets associated markers in healthy younger men. AB - The objective of this study was to clarify the relationship of regulated on activation normal T cell expressed and secreted (RANTES) levels with metabolic syndrome (MS) and activated platelets-associated markers. We conducted a cross sectional study of 210 healthy Japanese male volunteers (mean age 41 years old) who did not take any medications and were free of cardiovascular or cerebrovascular disease. The RANTES is correlated with age, diastolic blood pressure, and fast glucose by multivariate analysis using the cardiovascular risk factors (R (2) = .396, P < .001). The plasma RANTES level is significantly associated with MS after adjusting for age (P = .040). Once plasma interleukin 6, an activator of platelets, and plasma platelet-derived microparticles, a marker for activated platelets, are put into the equation, plasma RANTES level is significantly correlated with the activated platelet-associated markers (R (2) = .396, P < .001). These suggest the possible role of elevated RANTES in the forerunner of atherosclerosis in healthy younger men. PMID- 25301872 TI - The association of cardiorespiratory fitness with endothelial or smooth muscle vasodilator function. AB - BACKGROUND: Maximal oxygen consumption (VO2max) is strongly associated with peripheral vasodilator function as determined by exercise-induced vasodilation. However, findings with regard to its relation with non-exercise-stimulated vasodilation are unclear. The purpose of this study was to systematically review published literature reporting associations between VO2max and endothelial function (EF) or smooth muscle function (SMF). DESIGN AND METHODS: We conducted a systematic search of MEDLINE, Cochrane and Web of Science, since their inceptions until April 2014 for articles reporting the association between (a) VO2max during incremental exercise and (b) endothelium-dependent or -independent vasodilator function, by means of correlation and/or regression analysis. RESULTS: Fifty-six articles exploring 88 associations between VO2max and vascular EF or SMF were included, involving a total of 4159 healthy and diseased subjects. VO2max was determined by incremental cycle ergometer (64%), treadmill (33%) and cycle ergometer/treadmill (3%) exercise. Vasodilator function variables were assessed in the upper limb (86%), lower limb (10%) and both upper and lower limbs (3%). Most of the evaluated bivariate associations involved EF stimuli such as flow mediated dilation (FMD) (n = 29) or blood flow occlusion (BFO) (n = 18). VO2max was significantly associated with FMD and BFO in 59% and 67% of bivariate associations and 46% and 33% of age-independent associations, respectively. Explored bivariate associations regarding SMF involved sodium nitroprusside (SNP) iontophoresis (n = 7) and nitrate-mediated dilation (NMD) (n = 4). VO2max was associated with NMD in 50% of bivariate associations and 50% of age-independent associations. VO2max was not associated with SNP iontophoresis. Results were similar for associations including only healthy subjects. CONCLUSIONS: The association between VO2max and EF or SMF is moderately frequent and independent of health status, despite very few studies having assessed vasodilator function in the lower limb. PMID- 25301873 TI - Allergies are associated with arterial changes in young children. AB - BACKGROUND: Inflammation is important in atherosclerosis development. Whether common causes of inflammation, such as allergies and infections, already exert this influence in early childhood is unknown. The objective of this study was to investigate the association between both allergies and infections with children's vasculature. DESIGN: This was a longitudinal study in a general population cohort. METHODS: In 390 five-year-olds of the WHISTLER (Wheezing-Illnesses-Study LEidsche-Rijn) birth cohort, carotid intima-media thickness (CIMT) and arterial stiffness were obtained ultrasonographically. Physician-diagnosed allergies and infections and recent prescriptions of systemic antihistamines and antibiotics were obtained, as well as parental history of allergies. General linear regression was performed with vascular characteristics as dependent variables and measures of inflammation as independent variables. RESULTS: Having both a positive parental history of allergy and an allergy diagnosis showed 15.0 um (95% confidence interval (CI): 2.3-27.8, p = 0.02) larger CIMT than not having such history and diagnosis. Having a positive parental history of allergy only showed 11.9 um (0.87-23.0, p = 0.04) larger CIMT. Recent use of antihistamines and antibiotics showed 18.8 um (1.6-35.9, p = 0.03) and 16.1 um (4.5-27.7, p = 0.01) larger CIMT, respectively. Childhood infections were not clearly related to vascular parameters. Neither allergy nor infections were associated with arterial stiffness. CONCLUSION: An allergic predisposition is already associated with thicker arterial walls in early childhood. PMID- 25301874 TI - No cardiac damage after endurance exercise in cardiologists cycling to the European Society of Cardiology meeting in Barcelona. AB - AIMS: There are variable results reported for athletes and potential cardiac damage during exercise. In 2009 a group of cardiologists went by bicycle from the Netherlands to the European Society of Cardiology meeting in Barcelona and collected functional and biochemical parameters during this trip in order to evaluate whether cardiac damage was observed in a group of moderately trained amateur cyclists. METHODS AND RESULTS: All of the 20 amateur cyclists (17 men) completed the 1580 km in eight days with an average speed of 27.9 km and an average distance of 190 km/day. Cardiac damage was predefined as wall motion abnormalities detected by echocardiography or an increase of troponin I exceeding three times the upper limit. Although skeletal muscle damage was found in all of the cyclists, no cardiac damage could be detected. CONCLUSION: This long distance bicycle trip performed by moderately trained cardiologists demonstrates that it was safe and feasible and did not lead to cardiac damage although skeletal muscle damage was demonstrated in all participants. PMID- 25301876 TI - Relationship between macular inner retinal layer thickness and corresponding retinal sensitivity in normal eyes. AB - PURPOSE: The correlation between standard automated perimetry (SAP) sensitivity and macular inner retinal layer thickness in eyes with glaucoma is well known. We examined whether the corresponding correlation is also significant in normal eyes. METHODS: One eye of each of 195 normal subjects was included. The average thickness of the macular ganglion cell-inner plexiform layers (GCIPL) and the macular retinal nerve fiber layer/GCIPL (ganglion cell complex, GCC) in four regions with 0.6-mm-diameter circular area corresponding to the four central test points of the Humphrey Field Analyzer 24-2 test program, adjusted for ganglion cell displacement, were measured using spectral-domain optical coherence tomography (SD-OCT) and correlated to the mean SAP sensitivity (in 1/Lambert scale) at the corresponding test points with a multiple regression analysis using age, refraction, disc size, sex, and laterality of the eye as other explanatory variables. RESULTS: In normal eyes, GCIPL and GCC thickness (in micrometers) showed significant correlation to SAP sensitivity in corresponding areas, with partial regression coefficients of 0.0016 (P = 0.036) and 0.0022 (P = 0.023), respectively. Other significantly correlated factors were age and GCIPL (-0.18, P = 0.000), age and GCC (-0.20, P = 0.000), and refraction and GCIPL (0.92, P = 0.012). Similar analyses at each of the four test points yielded essentially the same results, although partial correlation coefficients were not always significant. CONCLUSIONS: A thicker macular GCIPL or GCC was weakly but significantly associated with higher SAP sensitivity in the corresponding macular region in normal eyes. PMID- 25301875 TI - Epigenetic modifications of Keap1 regulate its interaction with the protective factor Nrf2 in the development of diabetic retinopathy. AB - PURPOSE: Diabetes induces oxidative imbalance in the retina and impairs Nrf2 mediated antioxidant response, and elevates Keap1, the cytoplasmic repressor of Nrf2. The goal of this study was to understand the role of epigenetic modifications at Keap1 promoter in regulation of Nrf2 function. METHODS: The effect of high glucose on the binding of transcriptional factor Sp1 at Keap1 promoter and histone methylation status of the promoter was investigated in retinal endothelial cells. Role of histone methylation was confirmed in cells transfected with siRNA of methyltransferase enzyme Set7/9 (SetD7). In vitro results were confirmed in the retina from streptozotocin-induced diabetic rats. The role of epigenetic modifications of Keap1 promoter in the metabolic memory was examined in rats maintained in poor control for 3 months followed by good control for 3 months. RESULTS: Hyperglycemia increased the binding of Sp1 at Keap1 promoter, and enriched H3K4me1 and activated SetD7. SetD7-siRNA prevented increase in Sp1 binding at Keap1 promoter and Keap1 expression, and ameliorated decrease in Nrf2-regulated antioxidant genes. Cessation of hyperglycemia failed to attenuate increased binding of Sp1 at Keap1, and the promoter continued to be methylated with increased expression of Keap1 and decreased expression of Nrf2 regulated genes. CONCLUSIONS: Epigenetic modifications at Keap1 promoter by SetD7 facilitate its binding with Sp1, increasing its expression. Keap1 restrains Nrf2 in the cytosol, impairing its transcriptional activity. Reversal of hyperglycemia fails to provide any benefit to epigenetic modifications of Keap1 promoter, suggesting their role in both the development of diabetic retinopathy and the metabolic memory phenomenon. PMID- 25301877 TI - CoQ10-containing eye drops prevent UVB-induced cornea cell damage and increase cornea wound healing by preserving mitochondrial function. AB - PURPOSE: We evaluated the potential protective effects of Coenzyme Q10 (CoQ10) on human corneal cells and rabbit eyes after ultraviolet B (UVB) exposure and a model of wound healing in rabbit eyes after corneal epithelium removal. METHODS: Human corneal epithelium cells (HCE) were exposed to a source of UVB radiation (312 nM) in the presence of different CoQ10 concentrations or vehicle. The mitochondrial function and cell survival were evaluated by means of 3-(4,5 dimethylthiazole-2-yl)2,5-diphenyl-tetrazolium (MTT) reduction and lactic dehydrogenase (LDH) release. Furthermore, quantitation of oxygen consumption and mitochondrial membrane potential were conducted. In vivo rabbit models were adopted to evaluate the effect of CoQ10 on UVB-induced conjunctival vessel hyperemia and corneal recovery after ethanol induced corneal lesion. RESULTS: In UVB-exposed HCE cells, CoQ10 addition led to an increased survival rate and mitochondrial function. Furthermore, oxygen consumption was maintained at control levels and adenosine triphosphate (ATP) decline was completely prevented in the CoQ10-treated cells. Interestingly, in an in vivo model, CoQ10 was able dose dependently to reduce UVB-induced vessel hyperemia. Finally, in a model of corneal epithelium removal, 12 hours from surgery, animals treated with CoQ10 showed a reduction of damaged area in respect to vehicle controls, which lasted until 48 hours. CONCLUSIONS: We demonstrated that CoQ10 reduces corneal damages after UVB exposure in vivo and in vitro by preserving mitochondrial function. Also, for the first time to our knowledge we showed that the administration of CoQ10 after corneal epithelium removal promotes corneal wound healing. PMID- 25301878 TI - Clinical characteristics of familial and sporadic age-related macular degeneration: differences and similarities. AB - PURPOSE: We describe the differences and similarities in clinical characteristics and phenotype of familial and sporadic patients with age-related macular degeneration (AMD). METHODS: We evaluated data of 1828 AMD patients and 1715 controls enrolled in the European Genetic Database. All subjects underwent ophthalmologic examination, including visual acuity testing and fundus photography. Images were graded and fundus photographs were used for automatic drusen quantification by a machine learning algorithm. Data on disease characteristics, family history, medical history, and lifestyle habits were obtained by a questionnaire. RESULTS: The age at first symptoms was significantly lower in AMD patients with a positive family history (68.5 years) than in those with no family history (71.6 years, P = 1.9 * 10(-5)). Risk factors identified in sporadic and familial subjects were increasing age (odds ratio [OR], 1.08 per year; P = 3.0 * 10(-51), and OR, 1.15; P = 5.3 * 10(-36), respectively) and smoking (OR, 1.01 per pack year; P = 1.1 * 10(-6) and OR, 1.02; P = 0.005). Physical activity and daily red meat consumption were significantly associated with AMD in sporadic subjects only (OR, 0.49; P = 3.7 * 10(-10) and OR, 1.81; P = 0.001). With regard to the phenotype, geographic atrophy and cuticular drusen were significantly more prevalent in familial AMD (17.5% and 21.7%, respectively) compared to sporadic AMD (9.8% and 12.1%). CONCLUSIONS: Familial AMD patients become symptomatic at a younger age. The higher prevalence of geographic atrophy and cuticular drusen in the familial AMD cases may be explained by the contribution of additional genetic factors segregating within families. PMID- 25301879 TI - Reliability and determinants of retinal vessel oximetry measurements in healthy eyes. AB - PURPOSE: To assess the reliability and determinants of retinal vessel oximetry measurements with the Oxymap T1 Retinal Oximeter in normal Asian eyes. METHODS: Subjects older than 40 years without a history of stroke and heart disease were recruited from a community-based clinic. Subjects underwent standardized systemic and ocular examinations. Normal eyes were defined as eyes without major eye diseases such as age-related macular degeneration, glaucoma, or retinopathy. Retinal vessel oximetry levels were measured by using the Oxymap T1 Retinal Oximeter. Intra- and intergrader reliability of retinal vessel oximetry measurements were assessed by using 50 images. Intravisit repeatability of retinal vessel oximetry measurements was assessed by using 20 paired images. Univariable linear regression was performed to examine the associations between retinal vessel oximetry measurements and systemic determinants. RESULTS: A total of 118 retinal oximetry images were included in the final analysis. Intra- (intraclass correlation coefficient [ICC] values: 0.89-0.99) and intergrader (ICC values: 0.77-0.94) reliability, and intravisit (ICC values: 0.85-0.96) repeatability were both high. In the linear regression analysis, older age was associated with reduced overall retinal venular oximetry levels (beta: -2.61%; 95% confidence interval [CI]: -4.92 to -0.29) and reduced inferior-nasal retinal venular oximetry levels (beta: -3.53%; 95% CI: -6.07 to -0.99). CONCLUSIONS: The Oxymap Retinal Oximeter allows reliable and repeatable retinal vessel oximetry measurements. Age is the main factor that influences retinal venular oximetry levels and should be taken into account when retinal oximetry measurements are interpreted. PMID- 25301880 TI - Influence of the disc-fovea angle on limits of RNFL variability and glaucoma discrimination. AB - PURPOSE: To determine factors affecting the disc-fovea angle (DFA), and to test the hypotheses that adjusting for DFA improves limits of retinal nerve fiber layer (RNFL) variability in normal subjects or enhances performance of RNFL measures for glaucoma detection. METHODS: Disc-fovea angle was measured on scanning laser ophthalmoscope fundus images from 170 eyes (110 normal and glaucoma subjects). The DFA measurements were repeated in 24 eyes. The relationship between DFA and various anatomic variables was explored. Main outcome measures were changes in 95% RNFL prediction limits or glaucoma discrimination after adjusting for DFA. We also explored the angle between temporal raphe and horizontal meridian in 19 eyes with nasal field defects limited to one hemifield. RESULTS: Average mean deviation and DFA were -0.1 (+/ 1.2) dB and -6.6 degrees (+/-3.4 degrees ) and -4.1 (+/-3.3) dB and -7.9 degrees (+/-3.9 degrees ) in the control and glaucoma groups, respectively (P < 0.001 and = 0.029). The average difference between DFA repeat measurements was 2.0 degrees (+/-1.8 degrees ). Predictors for DFA were female sex (P = 0.004), smaller disc area (P = 0.006), and glaucoma diagnosis (P = 0.019). The absolute change in sectoral RNFL thickness was 6.1 (+/-3.9) and 4.6 (+/-3.1) MUm in control and glaucoma subjects, respectively. Retinal nerve fiber layer prediction limits improved in 5, 9, and 10 o'clock sectors (P < 0.02). Discrimination ability for the best-performing RNFL sector did not improve (P = 0.936). The average angle between temporal raphe and horizontal meridian was 0.8 degrees (+/ 0.8 degrees ). CONCLUSIONS: Disc-fovea angle measurements demonstrated fair intersession repeatability. While adjusting for DFA improved RNFL prediction limits in some sectors, it did not enhance glaucoma detection. PMID- 25301881 TI - Retinal sensitivity is reduced in patients with obstructive sleep apnea. AB - PURPOSE: To evaluate the outcomes of standard automated perimetry (SAP) in patients with obstructive sleep apnea (OSA). METHODS: Eighty OSA patients and 111 age-matched controls were consecutively and prospectively enrolled. One eye per subject was randomly selected. All participants underwent at least one reliable SAP (24-2 SITA Standard algorithm). The peripapillary retinal nerve fiber layer thickness (RNFL) was measured with spectral-domain optical coherence tomography (OCT). Patients with OSA were classified into three groups according to the apnea/hypopnea index: mild, moderate, or severe OSA. Parameters of SAP and OCT were compared between healthy controls and OSA patients. Correlation of apnea/hypopnea index with OCT and SAP measurements were calculated. RESULTS: Mean age, best-corrected visual acuity, and central corneal thickness were similar between groups. Intraocular pressure, however, was lower in the OSA group. Mean deviation of SAP was -0.23 +/- 0.8 dB in the control group and -1.74 +/- 2.8 dB in the OSA group (P < 0.001). Thickness of RNFL measured with OCT did not differ significantly between groups. Patients with OSA showed reduced sensitivity at most points tested by white-on-white perimetry compared with healthy individuals. The threshold values were more depressed in the peripheral visual field. The apnea/hypopnea index was related to the SAP indices: Pearson correlations were 0.432 with mean deviation, 0.467 with pattern standard deviation, and -0.416 with the visual field index (P < 0.001). CONCLUSIONS: Patients with OSA exhibited reduced retinal sensitivity measured with SAP compared with healthy controls. PMID- 25301882 TI - Quantitative SD-OCT imaging biomarkers as indicators of age-related macular degeneration progression. AB - PURPOSE: We developed a statistical model based on quantitative characteristics of drusen to estimate the likelihood of conversion from early and intermediate age-related macular degeneration (AMD) to its advanced exudative form (AMD progression) in the short term (less than 5 years), a crucial task to enable early intervention and improve outcomes. METHODS: Image features of drusen quantifying their number, morphology, and reflectivity properties, as well as the longitudinal evolution in these characteristics, were automatically extracted from 2146 spectral-domain optical coherence tomography (SD-OCT) scans of 330 AMD eyes in 244 patients collected over a period of 5 years, with 36 eyes showing progression during clinical follow-up. We developed and evaluated a statistical model to predict the likelihood of progression at predetermined times using clinical and image features as predictors. RESULTS: Area, volume, height, and reflectivity of drusen were informative features distinguishing between progressing and nonprogressing cases. Discerning progression at follow-up (mean, 6.16 months) resulted in a mean area under the receiver operating characteristic curve (AUC) of 0.74 (95% confidence interval [CI], 0.58, 0.85). The maximum predictive performance was observed at 11 months after a patient's first early AMD diagnosis, with mean AUC 0.92 (95% CI, 0.83, 0.98). Those eyes predicted to progress showed a much higher progression rate than those predicted not to progress at any given time from the initial visit. CONCLUSIONS: Our results demonstrate the potential ability of our model to identify those AMD patients at risk of progressing to exudative AMD from an early or intermediate stage. PMID- 25301884 TI - Azole, polyene and echinocandin MIC distributions for wild-type, TR34/L98H and TR46/Y121F/T289A Aspergillus fumigatus isolates in the Netherlands. AB - OBJECTIVES: To determine the MIC distributions of itraconazole, voriconazole and posaconazole and non-azole drugs for wild-type cyp51A, as well as TR(34)/L98H and TR(46)/Y121F/T289A cyp51A mutants of Aspergillus fumigatus. METHODS: We retrieved MIC and cyp51A sequence data for 952 clinical A. fumigatus strains isolated in or referred to our reference laboratory, during the January 2010 to December 2013 period. All MICs were determined using the EUCAST methodology and interpreted using the EUCAST breakpoints. RESULTS: Three-hundred and sixty-four of the 952 strains (38%) were resistant to azoles. Of these, 225 contained the TR34/L98H mutation, 98 contained the TR(46)/Y121F/T289A mutation and 39 had no cyp51A mutations. Two isolates harboured other cyp51A mutations, of which one (P216L) has been shown to confer azole resistance. Of the TR(34)/L98H isolates, 99.6% (224/225) were resistant to itraconazole (MICs >2 mg/L), 92.4% (208/225) were resistant to voriconazole (MICs >2 mg/L) and 97.8% (220/225) were resistant to posaconazole (MICs >0.25 mg/L). All TR(46)/Y121F/T289A isolates were resistant to voriconazole (MICs >16 mg/L), 82.7% (81/98) were resistant to itraconazole with a bimodal MIC distribution and 94.9% (93/98) were resistant to posaconazole. The MICs of amphotericin B, anidulafungin and terbinafine were not affected by the presence of azole-resistance mechanisms. CONCLUSIONS: The TR(34)/L98H and TR(46)/Y121F/T289A cyp51A genotypes of A. fumigatus show distinct resistance phenotypes. The mechanisms behind low-level itraconazole resistance in TR(46)/Y121F/T289A isolates warrant future research. The potential of increased azole dosing for disease caused by low-level resistant strains should be investigated. PMID- 25301883 TI - Structural and genetic assessment of the ABCA4-associated optical gap phenotype. AB - PURPOSE: To investigate the developmental stages and genetic etiology of the optical gap phenotype in recessive Stargardt disease (STGD1). METHODS: Single and longitudinal data points from 15 patients, including four sibling pairs, exhibiting an optical gap phenotype on spectral-domain optical coherence tomography (SD-OCT) with confirmed disease-causing ABCA4 alleles were retrospectively analyzed. Fundus images with corresponding SD-OCT scans were collected with a confocal scanning laser ophthalmoscope. Structural phenotypes were assigned to three developmental stages according to SD-OCT. The ABCA4 gene was screened in all patients. RESULTS: At least two disease-causing ABCA4 variants where identified in each patient; all except one (91%) were compound heterozygous for the p.G1961E mutation. All patients exhibited structural findings on SD-OCT that grouped into three progressive developmental stages over several years. Stage 1 was characterized by mild disruptions of the ellipsoid zone (EZ) band over the fovea. Stage 2 was a progressive expansion of the EZ band loss resulting in an empty lesion devoid of photoreceptors. Stage 3 observed a structural collapse of the inner retinal layers into the optical gap space leading to involvement and atrophy of the RPE thereafter. CONCLUSIONS: The optical gap phenotype in STGD1 can be structurally divided into three progressive stages spanning several years. This particular phenotype also appears to be highly associated with the p.G1961E mutation of ABCA4. Taken together, it appears that a focal loss of photoreceptors sequentially precedes RPE dysfunction in the early development of ABCA4-associated optical gap lesions. PMID- 25301885 TI - A Case of Hemiabdominal Myoclonus. AB - Myoclonus consists of sudden, brief, involuntary jerky muscular contractions. Central and peripheral nervous system lesions are involved in the pathogenesis of this movement disorder. Symptomatic or secondary spinal myoclonus is the most common form. A 68-year-old woman was diagnosed with hemiabdominal spinal myoclonus. Occasional and very mild involuntary repetitive movements of the hemiabdomen began immediately after surgery for uterine cancer. After surgery for laparocele, secondary to the uterine cancer surgery, performed under spinal anesthesia, there was severe worsening of movements. Neuroradiological investigations failed to demonstrate spinal injury, while neurophysiological studies showed impairment of the right central somatosensory pathway. Considering the low resolution of magnetic resonance imaging in the evaluation of thoracic level, we suggest an extensive neurophysiological evaluation in patients with spinal myoclonus. PMID- 25301886 TI - Dual catalytic activity of hydroxycinnamoyl-coenzyme A quinate transferase from tomato allows it to moonlight in the synthesis of both mono- and dicaffeoylquinic acids. AB - Tomato (Solanum lycopersicum), like other Solanaceous species, accumulates high levels of antioxidant caffeoylquinic acids, which are strong bioactive molecules and protect plants against biotic and abiotic stresses. Among these compounds, the monocaffeoylquinic acids (e.g. chlorogenic acid [CGA]) and the dicaffeoylquinic acids (diCQAs) have been found to possess marked antioxidative properties. Thus, they are of therapeutic interest both as phytonutrients in foods and as pharmaceuticals. Strategies to increase diCQA content in plants have been hampered by the modest understanding of their biosynthesis and whether the same pathway exists in different plant species. Incubation of CGA with crude extracts of tomato fruits led to the formation of two new products, which were identified by liquid chromatography-mass spectrometry as diCQAs. This chlorogenate:chlorogenate transferase activity was partially purified from ripe fruit. The final protein fraction resulted in 388-fold enrichment of activity and was subjected to trypsin digestion and mass spectrometric sequencing: a hydroxycinnamoyl-Coenzyme A:quinate hydroxycinnamoyl transferase (HQT) was selected as a candidate protein. Assay of recombinant HQT protein expressed in Escherichia coli confirmed its ability to synthesize diCQAs in vitro. This second activity (chlorogenate:chlorogenate transferase) of HQT had a low pH optimum and a high Km for its substrate, CGA. High concentrations of CGA and relatively low pH occur in the vacuoles of plant cells. Transient assays demonstrated that tomato HQT localizes to the vacuole as well as to the cytoplasm of plant cells, supporting the idea that in this species, the enzyme catalyzes different reactions in two subcellular compartments. PMID- 25301887 TI - Cotton WRKY1 mediates the plant defense-to-development transition during infection of cotton by Verticillium dahliae by activating JASMONATE ZIM-DOMAIN1 expression. AB - Plants have evolved an elaborate signaling network to ensure an appropriate level of immune response to meet the differing demands of developmental processes. Previous research has demonstrated that DELLA proteins physically interact with JASMONATE ZIM-DOMAIN1 (JAZ1) and dynamically regulate the interaction of the gibberellin (GA) and jasmonate (JA) signaling pathways. However, whether and how the JAZ1-DELLA regulatory node is regulated at the transcriptional level in plants under normal growth conditions or during pathogen infection is not known. Here, we demonstrate multiple functions of cotton (Gossypium barbadense) GbWRKY1 in the plant defense response and during development. Although GbWRKY1 expression is induced rapidly by methyl jasmonate and infection by Verticillium dahliae, our results show that GbWRKY1 is a negative regulator of the JA-mediated defense response and plant resistance to the pathogens Botrytis cinerea and V. dahliae. Under normal growth conditions, GbWRKY1-overexpressing lines displayed GA associated phenotypes, including organ elongation and early flowering, coupled with the down-regulation of the putative targets of DELLA. We show that the GA related phenotypes of GbWRKY1-overexpressing plants depend on the constitutive expression of Gossypium hirsutum GhJAZ1. We also show that GhJAZ1 can be transactivated by GbWRKY1 through TGAC core sequences, and the adjacent sequences of this binding site are essential for binding specificity and affinity to GbWRKY1, as revealed by dual-luciferase reporter assays and electrophoretic mobility shift assays. In summary, our data suggest that GbWRKY1 is a critical regulator mediating the plant defense-to-development transition during V. dahliae infection by activating JAZ1 expression. PMID- 25301890 TI - Staged treatment of high energy midfoot fracture dislocations. AB - BACKGROUND: Staged care with interval external fixation is a successful established treatment strategy for high energy periarticular fractures with often extensive soft tissue damage such as the tibial plateau and plafond. The aim of the current study was to determine whether staged care of high energy midfoot fracture/dislocation with interval external fixation prior to definitive open reconstruction in the polytraumatized patient was both safe and efficacious. METHODS: One hundred twenty-three patients were operated on for high energy midfoot fracture/dislocation during the 8-year study period. Eighteen polytrauma patients were selectively treated with a staged protocol. Radiographic assessment was utilized to determine if the fixator achieved gross skeletal alignment. Further, final alignment after definitive reconstruction and postoperative complications were analyzed. RESULTS: The fixator improved both length and alignment of all high energy midfoot fracture/dislocations. Loss of acceptable reduction while in the temporary frame occurred in only 1 case. Final alignment after definitive reconstruction was anatomic in all cases. No cases of wound related complication and/or deep infection occurred. CONCLUSION: Delayed reconstruction of high energy midfoot fracture/dislocation using interval external fixation should be an accepted care paradigm in selected polytrauma patients. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25301888 TI - Posttranslational modifications of FERREDOXIN-NADP+ OXIDOREDUCTASE in Arabidopsis chloroplasts. AB - Rapid responses of chloroplast metabolism and adjustments to photosynthetic machinery are of utmost importance for plants' survival in a fluctuating environment. These changes may be achieved through posttranslational modifications of proteins, which are known to affect the activity, interactions, and localization of proteins. Recent studies have accumulated evidence about the crucial role of a multitude of modifications, including acetylation, methylation, and glycosylation, in the regulation of chloroplast proteins. Both of the Arabidopsis (Arabidopsis thaliana) leaf-type FERREDOXIN-NADP(+) OXIDOREDUCTASE (FNR) isoforms, the key enzymes linking the light reactions of photosynthesis to carbon assimilation, exist as two distinct forms with different isoelectric points. We show that both AtFNR isoforms contain multiple alternative amino termini and undergo light-responsive addition of an acetyl group to the alpha amino group of the amino-terminal amino acid of proteins, which causes the change in isoelectric point. Both isoforms were also found to contain acetylation of a conserved lysine residue near the active site, while no evidence for in vivo phosphorylation or glycosylation was detected. The dynamic, multilayer regulation of AtFNR exemplifies the complex regulatory network systems controlling chloroplast proteins by a range of posttranslational modifications, which continues to emerge as a novel area within photosynthesis research. PMID- 25301891 TI - Psychological factors and personality traits associated with patients in chronic foot and ankle pain. AB - BACKGROUND: The impact of psychosocial factors and personality traits in chronic pain is well established. However, there has been limited literature analyzing the influence of psychological issues in chronic foot and ankle pain. The aim of our study was to identify the association of certain psychosocial factors and personality traits in individuals with chronic painful foot and ankle disorders. METHODS: Patients with chronic foot and ankle pain were recruited from the specialist foot and ankle clinic. The Eysenck Personality Questionnaire-Revised (EPQ-R), Dysfunctional Attitude Scale (DAS), and Hospital Anxiety Depression (HAD) scale were administered in the form of questionnaires. An age- and sex matched cohort of healthy volunteers served as the control group. Sample size was determined after power calculation, and a total of 90 participants were recruited with informed consent with 45 participants in each arm. Results were analyzed and statistical analyses were performed using SPSS. RESULTS: Patients with chronic foot and ankle pain had significantly higher neuroticism scores than the control group (P < .05). The study also revealed greater prevalence of anxiety and depression in patients with chronic pain (P < .05). CONCLUSION: The study showed a significant association of anxiety, depression, and neuroticism in patients presenting with chronic foot and ankle pain. Clinicians should recognize the influence of these specific psychological issues to provide a more holistic approach to the clinical problem. LEVEL OF EVIDENCE: Level III, case control study. PMID- 25301889 TI - Disruption of the CYTOCHROME C OXIDASE DEFICIENT1 gene leads to cytochrome c oxidase depletion and reorchestrated respiratory metabolism in Arabidopsis. AB - Cytochrome c oxidase is the last respiratory complex of the electron transfer chain in mitochondria and is responsible for transferring electrons to oxygen, the final acceptor, in the classical respiratory pathway. The essentiality of this step makes it that depletion in complex IV leads to lethality, thereby impeding studies on complex IV assembly and respiration plasticity in plants. Here, we characterized Arabidopsis (Arabidopsis thaliana) embryo-lethal mutant lines impaired in the expression of the CYTOCHROME C OXIDASE DEFICIENT1 (COD1) gene, which encodes a mitochondria-localized PentatricoPeptide Repeat protein. Although unable to germinate under usual conditions, cod1 homozygous embryos could be rescued from immature seeds and developed in vitro into slow-growing bush-like plantlets devoid of a root system. cod1 mutants were defective in C-to U editing events in cytochrome oxidase subunit2 and NADH dehydrogenase subunit4 transcripts, encoding subunits of respiratory complex IV and I, respectively, and consequently lacked cytochrome c oxidase activity. We further show that respiratory oxygen consumption by cod1 plantlets is exclusively associated with alternative oxidase activity and that alternative NADH dehydrogenases are also up regulated in these plants. The metabolomics pattern of cod1 mutants was also deeply altered, suggesting that alternative metabolic pathways compensated for the probable resulting restriction in NADH oxidation. Being the first complex IV deficient mutants described in higher plants, cod1 lines should be instrumental to future studies on respiration homeostasis. PMID- 25301892 TI - Influence of contralateral radiographs on accuracy of anatomic reduction in surgically treated calcaneus fractures. AB - BACKGROUND: The purpose of this study was to determine whether obtaining a radiograph of the uninjured contralateral calcaneus (template) before surgery allowed for more precise restoration of Bohler's angle and calcaneal length when performing open reduction internal fixation (ORIF) of intra-articular calcaneus fractures. METHODS: Patients who sustained an intra-articular calcaneus fracture requiring surgery who met inclusion criteria were prospectively randomized into those who had a preoperative template obtained for review at the time of ORIF (group 1) versus those who had the contralateral radiograph obtained after surgery (group 2). RESULTS: There was no benefit of the preoperative template in allowing for more anatomic restoration of Bohler's angle or calcaneal length. Operative time was decreased with the use of a preoperative template when using the extensile lateral or percutaneous approaches. CONCLUSION: Preoperative templating of the uninjured contralateral calcaneus did not allow for more anatomic reduction or restoration of pre-injury morphology of the calcaneus undergoing operative fixation as based on Bohler's angle and calcaneal length. Templating may be of benefit by reducing operative time. LEVEL OF EVIDENCE: Level II, prospective comparative series. PMID- 25301894 TI - Differences in respiratory muscle activity during cycling and walking do not influence dyspnea perception in obese patients with COPD. AB - In patients with combined obesity and chronic obstructive pulmonary disease (COPD), dyspnea intensity at matched work rates during weight-supported cycling and weight-bearing walking is similar, despite consistent metabolic differences between test modalities. The present study examined the influence of differences in activity of the diaphragm and abdominal muscles during cycling and walking on intensity and quality of dyspnea at matched ventilation in obese patients with COPD. We compared respiratory muscle activity patterns and dyspnea ratings during incremental cycle and treadmill exercise tests, where work rate was matched, in 12 obese (body mass index 36.6 +/- 5.4 kg/m(2); mean +/- SD) patients with moderate COPD. We used a multipair electrode-balloon catheter to compare electromyography of the diaphragm and esophageal, gastric, and transdiaphragmatic pressures during the two exercise tests. Ventilation, breathing pattern, operating lung volumes, global respiratory effort, and electrical activation of the diaphragm were similar across exercise modalities for a given work rate. The cycling position was associated with greater neuromuscular efficiency of the diaphragm (P < 0.01), greater diaphragm use (P < 0.01) measured by the ventilatory muscle recruitment index, and less expiratory muscle activity compared (P < 0.01) with treadmill walking. However, intensity and quality of dyspnea were similar between exercise modalities. In obese patients with COPD, altered respiratory muscle activity due to body position differences between cycling and walking did not modulate perceived dyspnea when indirect measures of respiratory neural drive were unchanged. PMID- 25301893 TI - Running economy, not aerobic fitness, independently alters thermoregulatory responses during treadmill running. AB - We sought to determine the independent influence of running economy (RE) and aerobic fitness [maximum oxygen consumption (VO 2max)] on thermoregulatory responses during treadmill running by conducting two studies. In study 1, seven high (HI-FIT: 61 +/- 5 ml O2 . kg(-1) . min(-1)) and seven low (LO-FIT: 45 +/- 4 ml O2 . kg(-1) . min(-1)) VO 2max males matched for physical characteristics and RE (HI-FIT: 200 +/- 21; LO-FIT: 200 +/- 18 ml O2 . kg(-1) . km(-1)) ran for 60 min at 1) 60%VO 2max and 2) a fixed metabolic heat production (Hprod) of 640 W. In study 2, seven high (HI-ECO: 189 +/- 15.3 ml O2 . kg(-1) . km(-1)) and seven low (LO-ECO: 222 +/- 10 ml O2 . kg(-1) . km(-1)) RE males matched for physical characteristics and VO 2max (HI-ECO: 60 +/- 3; LO-ECO: 61 +/- 7 ml O2 . kg(-1) . min(-1)) ran for 60 min at a fixed 1) speed of 10.5 km/h and 2) Hprod of 640 W. Environmental conditions were 25.4 +/- 0.8 degrees C, 37 +/- 12% RH. In study 1, at Hprod of 640 W, similar changes in esophageal temperature (DeltaTes; HI-FIT: 0.63 +/- 0.20; LO-FIT: 0.63 +/- 0.22 degrees C; P = 0.986) and whole body sweat losses (WBSL; HI-FIT: 498 +/- 66; LO-FIT: 497 +/- 149 g; P = 0.984) occurred despite different relative intensities (HI-FIT: 55 +/- 6; LO-FIT: 39 +/- 2% VO 2max; P < 0.001). At 60% VO 2max, DeltaTes (P = 0.029) and WBSL (P = 0.003) were greater in HI-FIT (1.14 +/- 0.32 degrees C; 858 +/- 130 g) compared with LO-FIT (0.73 +/- 0.34 degrees C; 609 +/- 123 g), as was Hprod (HI-FIT: 12.6 +/- 0.9; LO FIT: 9.4 +/- 1.0 W/kg; P < 0.001) and the evaporative heat balance requirement (Ereq; HI-FIT: 691 +/- 74; LO-FIT: 523 +/- 65 W; P < 0.001). Similar sweating onset DeltaTes and thermosensitivities occurred between VO 2max groups. In study 2, at 10.5 km/h, DeltaTes (1.16 +/- 0.31 vs. 0.78 +/- 0.28 degrees C; P = 0.017) and WBSL (835 +/- 73 vs. 667 +/- 139 g; P = 0.015) were greater in LO-ECO, as was Hprod (13.5 +/- 0.6 vs. 11.3 +/- 0.8 W/kg; P < 0.001) and Ereq (741 +/- 89 vs. 532 +/- 130 W; P = 0.007). At Hprod of 640 W, DeltaTes (P = 0.910) and WBSL (P = 0.710) were similar between HI-ECO (0.55 +/- 0.31 degrees C; 501 +/- 88 g) and LO ECO (0.57 +/- 0.16 degrees C; 483 +/- 88 g), but running speed was different (HI ECO: 8.2 +/- 0.6; LO-ECO: 7.2 +/- 0.4 km/h; P = 0.025). In conclusion, thermoregulatory responses during treadmill running are not altered by VO 2max, but by RE because of differences in Hprod and Ereq. PMID- 25301895 TI - Mechanistic investigation of adult myotube response to exercise and drug treatment in vitro using a multiplexed functional assay system. AB - The ability to accurately measure skeletal muscle functional performance at the single-cell level would be advantageous for exercise physiology studies and disease modeling applications. To that end, this study characterizes the functional response of individual skeletal muscle myotubes derived from adult rodent tissue to creatine treatment and chronic exercise. The observed improvements to functional performance in response to these treatments appear to correlate with alterations in hypertrophic and mitochondrial biogenesis pathways, supporting previously published in vivo and in vitro data, which highlights the role of these pathways in augmenting skeletal muscle output. The developed system represents a multiplexed functional in vitro assay capable of long-term assessment of contractile cellular outputs in real-time that is compatible with concomitant molecular biology analysis. Adoption of this system in drug toxicity and efficacy studies would improve understanding of compound activity on physical cellular outputs and provide more streamlined and predictive data for future preclinical analyses. PMID- 25301898 TI - Common pathways toward informing policy and environmental strategies to promote health: a study of CDC's Prevention Research Centers. AB - This study examined the roles academic researchers can play to inform policy and environmental strategies that promote health and prevent disease. Prevention Research Centers (PRCs) engage in academic-community partnerships to conduct applied public health research. Interviews were used to collect data on the roles played by 32 PRCs to inform policy and environmental strategies that were implemented between September 2009 and September 2010. Descriptive statistics were calculated in SAS 9.2. A difference in roles played was observed depending on whether strategies were policy or environmental. Of the policy initiatives, the most common roles were education, research, and partnership. In contrast, the most prevalent roles the PRCs played in environmental approaches were research and providing health promotion resources. Academic research centers play various roles to help inform policy and environmental strategies. PMID- 25301897 TI - Heart rate recovery after maximal exercise is blunted in hypertensive seniors. AB - Abnormal heart rate recovery (HRR) after maximal exercise may indicate autonomic dysfunction and is a predictor for cardiovascular mortality. HRR is attenuated with aging and in middle-age hypertensive patients, but it is unknown whether HRR is attenuated in older-age adults with hypertension. This study compared HRR among 16 unmedicated stage 1 hypertensive (HTN) participants [nine men/seven women; 68 +/- 5 (SD) yr; awake ambulatory blood pressure (BP) 149 +/- 10/87 +/- 7 mmHg] and 16 normotensive [control (CON)] participants (nine men/seven women; 67 +/- 5 yr; 122 +/- 4/72 +/- 5 mmHg). HR, BP, oxygen uptake (Vo2), cardiac output (Qc), and stroke volume (SV) were measured at rest, at two steady-state work rates, and graded exercise to peak during maximal treadmill exercise. During 6 min of seated recovery, the change in HR (DeltaHR) was obtained every minute and BP every 2 min. In addition, HRR and R-R interval (RRI) recovery kinetics were analyzed using a monoexponential function, and the indexes (HRRI and RRII) were calculated. Maximum Vo2, HR, Qc, and SV responses during exercise were not different between groups. DeltaHR was significantly different (P < 0.001) between the HTN group (26 +/- 8) and the CON group (36 +/- 12 beats/min) after 1 min of recovery but less convincing at 2 min (P = 0.055). BP recovery was similar between groups. HRRI was significantly lower (P = 0.016), and there was a trend of lower RRII (P = 0.066) in the HTN group compared with the CON group. These results show that in older-age adults, HRR is attenuated further with the presence of hypertension, which may be attributable to an impairment of autonomic function. PMID- 25301896 TI - Dietary nitrate accelerates postexercise muscle metabolic recovery and O2 delivery in hypoxia. AB - We tested the hypothesis that the time constants (tau) of postexercise T2* MRI signal intensity (an index of O2 delivery) and muscle [PCr] (an index of metabolic perturbation, measured by (31)P-MRS) in hypoxia would be accelerated after dietary nitrate (NO3 (-)) supplementation. In a double-blind crossover design, eight moderately trained subjects underwent 5 days of NO3 (-) (beetroot juice, BR; 8.2 mmol/day NO3 (-)) and placebo (PL; 0.003 mmol/day NO3 (-)) supplementation in four conditions: normoxic PL (N-PL), hypoxic PL (H-PL; 13% O2), normoxic NO3 (-) (N-BR), and hypoxic NO3 (-) (H-BR). The single-leg knee extension protocol consisted of 10 min of steady-state exercise and 24 s of high intensity exercise. The [PCr] recovery tau was greater in H-PL (30 +/- 4 s) than H-BR (22 +/- 4 s), N-PL (24 +/- 4 s) and N-BR (22 +/- 4 s) (P < 0.05) and the maximal rate of mitochondrial ATP resynthesis (Qmax) was lower in the H-PL (1.12 +/- 0.16 mM/s) compared with H-BR (1.35 +/- 0.26 mM/s), N-PL (1.47 +/- 0.28 mM/s), and N-BR (1.40 +/- 0.21 mM/s) (P < 0.05). The tau of postexercise T2* signal intensity was greater in H-PL (47 +/- 14 s) than H-BR (32 +/- 10 s), N-PL (38 +/- 9 s), and N-BR (27 +/- 6 s) (P < 0.05). The postexercise [PCr] and T2* recovery tau were correlated in hypoxia (r = 0.60; P < 0.05), but not in normoxia (r = 0.28; P > 0.05). These findings suggest that the NO3 (-)-NO2 (-)-NO pathway is a significant modulator of muscle energetics and O2 delivery during hypoxic exercise and subsequent recovery. PMID- 25301903 TI - In praise of clinical examinations. PMID- 25301902 TI - Checking lists, ticking boxes. PMID- 25301901 TI - From fear recognition to kidney donation. PMID- 25301900 TI - SEC-10 and RAB-10 coordinate basolateral recycling of clathrin-independent cargo through endosomal tubules in Caenorhabditis elegans. AB - Despite the increasing number of regulatory proteins identified in clathrin independent endocytic (CIE) pathways, our understanding of the exact functions of these proteins and the sequential manner in which they function remains limited. In this study, using the Caenorhabditis elegans intestine as a model, we observed a unique structure of interconnected endosomal tubules, which is required for the basolateral recycling of several CIE cargoes including hTAC, GLUT1, and DAF-4. SEC-10 is a subunit of the octameric protein complex exocyst. Depleting SEC-10 and several other exocyst components disrupted the endosomal tubules into various ring-like structures. An epistasis analysis further suggested that SEC-10 operates at the intermediate step between early endosomes and recycling endosomes. The endosomal tubules were also sensitive to inactivation of the Rab GTPase RAB-10 and disruption of microtubules. Taken together, our data suggest that SEC-10 coordinates with RAB-10 and microtubules to form the endosomal tubular network for efficient recycling of particular CIE cargoes. PMID- 25301904 TI - Safety in numbers: lack of evidence to indicate the number of physicians needed to provide safe acute medical care. AB - Patient safety in hospital is dependent on a multitude of factors. Recent reports into the failings of healthcare organisations in the UK have highlighted low staffing levels as a significant factor. There is research into the impact of nurse-to-patient ratios on patient safety, but our literature search found little published data that would allow healthcare providers to define a minimum number of physician staff and skills mix that would assure safety in the largest hospital specialty: unscheduled (acute) medicine. Future work should focus on the evaluation of existing data on hospital mortality rates and physician staffing levels as well as on empirical time and motion studies to ascertain the resources required to undertake safe medical care at times of peak demand. PMID- 25301905 TI - Application of the WHO surgical safety checklist outside the operating theatre: medicine can learn from surgery. AB - Safety checklists in medicine are designed to identify a potential error before it results in harm to a patient. The World Health Organization (WHO) safety checklist was widely implemented in surgical practice in the UK after significant reductions in death, and peri-operative complications were achieved in eight countries worldwide in the 'Safe Surgery Saves Lives' campaign of 2008. Nevertheless, use of the checklist for invasive medical procedures is not yet routine. Such procedures are becoming ever more complex, necessitating multidisciplinary team management and involving higher-risk patients, with the need for general anaesthesia on occasion. As a result, the potential for error increases and the need for a safety checklist has become more apparent. Such a checklist can be modified to provide a framework for specialty-specific safety checks, enhanced team-working and communication for invasive medical procedures. Following an audit of use of the WHO checklist in 20 cases under general anaesthesia in our quaternary referral cardiac catheterisation laboratory, we discovered use of this safety tool was poor (performed/documented: sign in 30%/40%, time out 10%/15%, sign out 10%/15%) and we identified two 'near miss' incidents within the audit period. We then developed and implemented a modified WHO checklist for the specific challenges faced in the cardiac catheterisation laboratory. Following a staff education programme, a subsequent audit of 34 cases demonstrated improvement in all sections (performed/documented: sign in 91.2%/82.4%, time out 85.3%/76.5%, sign out 73.5%/64.7%) with no patient safety incidents during the post-intervention audit period. Well-designed, procedural checklists may well prove to be of benefit in other areas of interventional medicine. PMID- 25301906 TI - Cardiac imaging to investigate suspected cardiac pain in the post-treadmill era. AB - Symptomatic cardiovascular disease is one of the leading causes of hospital admissions in the UK; along with emergency attendances, over 100,000 patients are investigated using treadmill testing via rapid access chest pain clinics each year. With the introduction of new technologies, clinicians have a wide choice of investigations including nuclear perfusion scanning, dobutamine stress echocardiography, cardiac computed tomography and stress cardiac magnetic resonance imaging. These imaging modalities have their strengths and weaknesses, which depend not only on the pre-test likelihood of significant coronary artery disease but also the clinical characteristics of the patient. This article will review the differing imaging modalities, the patient experience, accuracy, prognostic data and future prospects for cardiac computed tomography and magnetic resonance imaging. PMID- 25301907 TI - Brugada syndrome: a review of the literature. AB - Brugada syndrome is an example of a channelopathy caused by an alteration in the transmembrane ion currents that together constitute the cardiac action potential. Approximately 20% of the cases of Brugada syndrome have been shown to be associated with mutations in the gene coding for the sodium ion channel in the cell membranes of the muscle cells of the heart. Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest or sudden cardiac death. Many clinical situations have been reported to unmask or exacerbate the electrocardiography (ECG) pattern of Brugada syndrome. Genetic testing for Brugada syndrome is clinically available. Here we report two cases of Brugada syndrome followed by a comprehensive review of the literature. PMID- 25301908 TI - Quality of care for people with dementia in general hospitals: national cross sectional audit of patient assessment. AB - There have been recent reports of poor quality care in the National Health Service in the UK, and older people with dementia are particularly vulnerable. This study aims to examine the quality of assessment of people with dementia admitted to hospital. Cross-sectional case-note audit of key physical and psychosocial assessments was carried out in 7,934 people with dementia who were discharged from 206 general hospitals. Most people had no record of a standardised assessment of their cognitive state (56.8%, 95% confidence interval [CI] = 55.8-58.0) or functioning (74.2%, 95% CI = 73.2-75.1). Information from carers was documented in 39.0% of cases (95% CI = 37.9-40.1). There was considerable variation across hospital sites. Key assessments were less likely when people were admitted to surgical wards. Assessments fall well below recommended standards especially with regard to social and cognitive functioning. Problems are particularly marked on surgical wards. PMID- 25301909 TI - Virtues and values in medicine revisited: individual and global health. AB - In response to the call from an international panel for 'much needed rethinking' about the goals and purposes of the education of healthcare professionals, we suggest that there must be an explicit account of the virtues and values that will inform healthcare practice in the 21st century. We propose that a renewed emphasis is needed on reviving the well-honed clinical skills and humanistic attributes in medicine as crucial for optimum affordable (and sustainable) care of individual patients. Analogous virtues should be linked to the quest for improving the health of whole populations, nationally and globally. PMID- 25301910 TI - UK postgraduate medicine examinations: opportunities for international candidates. AB - The medical profession is global, and ambitious trainee physicians around the world are eager to attain internationally recognised postgraduate medical qualifications. The MRCP(UK) and specialty certificate examinations of the Federation of Royal Colleges of Physicians of the United Kingdom provide such qualifications, and between 2002 and 2013, the number of international candidates attempting these examinations grew substantially. Delivering these proven and reliable UK-based examinations in other countries has many local benefits: it enhances careers, strengthens medical training and improves standards of patient care. In collaboration with international colleagues, the Federation is committed to continued growth that extends these benefits to all physicians, wherever they work and live. PMID- 25301911 TI - Survival as medical registrar on call: remember the doughnut. AB - Life as a medical registrar presents many challenges and concern is growing that a downwards trend in recruitment to General Medicine is the direct result of a perception by junior doctors that the role of the medical registrar is excessively demanding and results in poor work-life balance. A solution-focused approach (SFA) can be used successfully to find a satisfying outcome for both registrar and patient in many of the situations encountered during an on-call, as well as carrying over benefits into life outside of work. We explore the origins of SFA and the ways in which it can be successfully applied to clinical medicine, providing case studies from the author's own experience to illustrate the principles of this way of thinking. PMID- 25301912 TI - Opinions of the ePortfolio and workplace-based assessments: a survey of core medical trainees and their supervisors. AB - Since the introduction of Modernising Medical Careers in 2005, the electronic portfolio (ePortfolio) and workplace based assessments (WPBAs) have become integral, yet anecdotally controversial, components of postgraduate medical training. In this multi-centre, survey-based study, we looked at core medical trainees and trainers in the Northwest London region and their opinions of the ePortfolio and WPBAs. Our results demonstrate mixed feelings regarding these tools, with 60% of trainees stating that their training had not benefited from the use of an ePortfolio. 53% of trainers felt that feedback sessions with their trainees were useful; however 70% of them cited difficulties in fitting the required number of assessments within their clinical schedule. Overall, if implemented correctly, the ePortfolio and WPBAs are potentially powerful tools in the education and development of trainee doctors. However, improvements in mentoring and feedback may be needed to experience the full benefits of this system. PMID- 25301913 TI - Perfect pitch reconsidered. AB - Perfect pitch, or absolute pitch (AP), is defined as the ability to identify or produce the pitch of a sound without need for a reference pitch, and is generally regarded as a valuable asset to the musician. However, there has been no recent review of the literature examining its aetiology and its utility taking into account emerging scientific advances in AP research, notably in functional imaging. This review analyses the key empirical research on AP, focusing on genetic and neuroimaging studies. The review concludes that: AP probably has a genetic predisposition, although this is based on limited evidence; early musical training is almost certainly essential for AP acquisition; and, although there is evidence that it may be relevant to speech processing, AP can interfere with relative pitch, an ability on which humans rely to communicate effectively. The review calls into question the value of AP to musicians and non-musicians alike. PMID- 25301914 TI - A review of current treatment strategies for restless legs syndrome (Willis-Ekbom disease). AB - Restless legs syndrome (RLS), recently renamed Willis-Ekbom disease (WED), is a common movement disorder. It is characterised by the need to move mainly the legs due to uncomfortable, sometimes painful sensations in the legs, which have a diurnal variation and a release with movement. Management is complex. First, centres should establish the severity of RLS using a simple 10-item RLS severity rating scale (IRLS). They should also exclude secondary causes, in particular ensuring normal iron levels. Mild cases can be managed by lifestyle changes, but patients with a IRLS score above 15 usually require pharmacological treatment. Dopaminergic therapies remain the mainstay of medical therapies, with recent evidence suggesting opioids may be particularly effective. This article focuses on the different treatment strategies in RLS, their associated complications and ways to manage them. PMID- 25301915 TI - A young woman with myalgia. AB - We describe the case of a young female presenting with myalgia, mildly raised creatine kinase and a rash. The discussion emphasises the importance of a systematic approach to muscle symptoms, the value of a detailed hand examination and the importance of magnetic resonance imaging in the investigation of muscular symptoms. PMID- 25301916 TI - Complications of systemic therapy--gut infections and acute diarrhoea. PMID- 25301917 TI - Venous thromboembolism in malignancy. PMID- 25301918 TI - Brain metastases. PMID- 25301919 TI - Neutropenic sepsis: a potentially life-threatening complication of chemotherapy. PMID- 25301922 TI - Delirium: a synthesis of current knowledge. PMID- 25301920 TI - Metastatic spinal cord compression: a rare but important complication of cancer. PMID- 25301923 TI - Lesson of the month 1: Pericardial mass and cardiac tamponade associated with Mycoplasma pneumoniae. AB - Mycoplasma pneumoniae primarily causes respiratory tract infections. Extrapulmonary manifestations are seen in 20-25% of cases. Cardiac involvement is rarely reported. We present a unique case of a pericardial mass and cardiac tamponade associated with a Mycoplasma pneumoniae pneumonia. This required emergency pericardial fenestration. The patient improved dramatically postoperatively on antibiotics and there was no recurrence of the pericardial effusion on follow up. This case highlights the often forgotten invasive properties of a common respiratory tract pathogen and emphasises the need to consider this easily treatable entity in the differential diagnosis of idiopathic pericardial effusions. PMID- 25301924 TI - Lesson of the month 2: Severe reactivation of hepatitis B after immunosuppressive chemotherapy. AB - Patients with current or past hepatitis B virus (HBV) infection are at risk of viral reactivation if they receive immune-modulating treatment or chemotherapy. This can range from subclinical elevation in HBV DNA levels, to abnormal liver function tests, to severe hepatitis with liver failure and risk of death. All patients should be screened for hepatitis B with surface antigen and core antibody before receiving immunosuppression. Patients with positive hepatitis B serology should be referred for specialist advice. Prophylactic antiviral treatment is recommended for patients with current/past hepatitis B who receive immunosuppressive chemotherapy. PMID- 25301925 TI - Image of the month: A misleading chest X-ray--not all opacification is effusion. PMID- 25301926 TI - Surgical approaches for lung volume reduction in emphysema. PMID- 25301927 TI - Recovery after critical illness; when, how and who should be involved? PMID- 25301928 TI - Conscientious care for the unconscious patient. PMID- 25301929 TI - Search engines and evidence-based medicine. PMID- 25301930 TI - Mediators of homologous DNA pairing. AB - Homologous DNA pairing and strand exchange are at the core of homologous recombination. These reactions are promoted by a DNA-strand-exchange protein assembled into a nucleoprotein filament comprising the DNA-pairing protein, ATP, and single-stranded DNA. The catalytic activity of this molecular machine depends on control of its dynamic instability by accessory factors. Here we discuss proteins known as recombination mediators that facilitate formation and functional activation of the DNA-strand-exchange protein filament. Although the basics of homologous pairing and DNA-strand exchange are highly conserved in evolution, differences in mediator function are required to cope with differences in how single-stranded DNA is packaged by the single-stranded DNA-binding protein in different species, and the biochemical details of how the different DNA-strand exchange proteins nucleate and extend into a nucleoprotein filament. The set of (potential) mediator proteins has apparently expanded greatly in evolution, raising interesting questions about the need for additional control and coordination of homologous recombination in more complex organisms. PMID- 25301931 TI - Sexual conflict and sperm competition. AB - Traits that increase a male's fertilization success during sperm competition can be harmful to females and therefore represent a source of sexual conflict. In this review, we consider the variety of male adaptations to sperm competition (MASC) that may give rise to sexual conflict-including mate guarding, prolonged copulations, the transfer of large numbers of sperm, and the manipulation of females through nonsperm components of the ejaculate. We then reflect on the fitness economics influencing the escalation of these sexual conflicts, considering the likelihood of females evolving traits to offset the negative effects of MASC when compared with the strong selection on males that lead to MASC. We conclude by discussing the potential evolutionary outcomes of sexual conflict arising from MASC, including the opportunities for females to mitigate conflict costs and the prospects for conflict resolution. PMID- 25301932 TI - Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. AB - Recognition of an invading pathogen is critical to elicit protective responses. Certain microbial structures and molecules, which are crucial for their survival and virulence, are recognized by different families of evolutionarily conserved pattern recognition receptors (PRRs). This recognition initiates a signaling cascade that leads to the transcription of inflammatory cytokines and chemokines to eliminate pathogens and attract immune cells, thereby perpetuating further adaptive immune responses. Considerable research on the molecular mechanisms underlying host-pathogen interactions has resulted in the discovery of multifarious PRRs. In this review, we discuss the recent developments in microbial recognition by Toll-like receptors (TLRs) and intracellular nucleic acid sensors and the signaling pathways initiated by them. PMID- 25301933 TI - Gene augmentation for X-linked retinitis pigmentosa caused by mutations in RPGR. AB - X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is a severe and early onset form of retinal degeneration, and no treatment is currently available. Recent evidence in two clinically relevant canine models shows that adeno-associated viral (AAV)-mediated RPGR gene transfer to rods and cones can prevent disease onset and rescue photoreceptors at early- and mid stages of degeneration. There is thus a strong incentive for conducting long term, preclinical efficacy and safety studies, while concomitantly pursuing the detailed phenotypic characterization of XLRP disease in patients that may benefit from such corrective therapy. PMID- 25301935 TI - Synthetic chemically modified mRNA (modRNA): toward a new technology platform for cardiovascular biology and medicine. AB - Over the past two decades, a host of new molecular pathways have been uncovered that guide mammalian heart development and disease. The ability to genetically manipulate these pathways in vivo have largely been dependent on the generation of genetically engineered mouse model systems or the transfer of exogenous genes in a variety of DNA vectors (plasmid, adenoviral, adeno-associated viruses, antisense oligonucleotides, etc.). Recently, a new approach to manipulate the gene program of the adult mammalian heart has been reported that will quickly allow the high-efficiency expression of virtually any protein in the intact heart of mouse, rat, porcine, nonhuman primate, and human heart cells via the generation of chemically modified mRNA (modRNA). The technology platform has important implications for delineating the specific paracrine cues that drive human cardiogenesis, and the pathways that might trigger heart regeneration via the rapid generation of modRNA libraries of paracrine factors for direct in vivo administration. In addition, the strategy can be extended to a variety of other cardiovascular tissues and solid organs across multiple species, and recent improvements in the core technology have supported moving toward the first human studies of modRNA in the next 2 years. These recent advances are reviewed along with projections of the potential impact of the technology for a host of other biomedical problems in the cardiovascular system. PMID- 25301934 TI - Role of B cells and antibodies in acquired immunity against Mycobacterium tuberculosis. AB - Accumulating evidence has documented a role for B cells and antibodies (Abs) in the immunity against Mycobacterium tuberculosis (Mtb). Passive transfer studies with monoclonal antibodies (mAbs) against mycobacterial antigens have shown protection against the tubercle bacillus. B cells and Abs are believed to contribute to an enhanced immune response against Mtb by modulating various immunological components in the infected host including the T-cell compartment. Nevertheless, the extent and contribution of B cells and Abs to protection against Mtb remains uncertain. In this article we summarize the most relevant findings supporting the role of B cells and Abs in the defense against Mtb and discuss the potential mechanisms of protection. PMID- 25301937 TI - Dog UDP-glucuronosyltransferase enzymes of subfamily 1A: cloning, expression, and activity. AB - Understanding drug glucuronidation in the dog, a preclinical animal, is important but currently poorly characterized at the level of individual enzymes. We have constructed cDNAs for the 10 dog UDP-glucuronosyltransferases of subfamily 1A (dUGT1As), expressed them in insect cells, and assayed their activity as well as the activity of the nine human UGT1As, toward 14 compounds. The goal was to find out whether individual dUGT1As and individual human UGT1As have similar substrate specificities. The results revealed similarities but also many differences. For example, similarly to the human UGT1A10, dUGT1A11 exhibited high glucuronidation activity toward the 3-OH of 17-beta-estradiol, 17-alpha-estradiol, and ethinylestradiol, and also conjugated the drug entacapone. Unlike the human UGT1A10, however, it failed to catalyze considerable rates of R-propranolol, diclofenac, and indomethacin glucuronidation. The estrogen glucuronidation assays revealed that dUGT1A8 and dUGT1A10 have a capacity to catalyze the formation of (linked) diglucuronides, an activity no human UGT1A exhibited. dUGT1A2-dUGT1A4 are homologs of the human UGT1A4, but none of them catalyzed N-glucuronidation of dexmedetomidine. Contrary to the human UGT1A4, however, dUGT1A2-dUGT1A4 catalyzed indomethacin and diclofenac glucuronidation. It may be concluded that, perhaps with the exception of UGT1A6, high similarities in substrate specificity between individual dog and human UGTs of subfamily 1A are rare or partial. Activity assays with liver and intestine microsomes of both dog and human further revealed interspecies differences, particularly in glucuronidation rates. In the dog, the microsomes assays also strongly suggested important roles for dUGTs of other subfamilies, mainly in the liver. PMID- 25301936 TI - Enhanced methamphetamine metabolism in rhesus macaque as compared with human: an analysis using a novel method of liquid chromatography with tandem mass spectrometry, kinetic study, and substrate docking. AB - Methamphetamine (MA), which remains one of the widely used drugs of abuse, is metabolized by the cytochrome P450 (P450) family of enzymes in humans. However, metabolism of methamphetamine in macaques is poorly understood. Therefore, we first developed and validated a very sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using solid phase extraction of rhesus plasma with a lower limit of quantitation at 1.09 ng/ml for MA and its metabolites, 4 hydroxy methamphetamine (4-OH MA), amphetamine (AM), 4-OH amphetamine (4-OH AM), and norephedrine. We then analyzed plasma samples of MA-treated rhesus, which showed >10-fold higher concentrations of AM (~29 ng/ml) and 4-OH AM (~28 ng/ml) than MA (~2 ng/ml). Because the plasma levels of MA metabolites in rhesus were much higher than in human samples, we examined MA metabolism in human and rhesus microsomes. Interestingly, the results showed that AM and 4-OH AM were formed more rapidly and that the catalytic efficiency (Vmax/Km) for the formation of AM was ~8-fold higher in rhesus than in human microsomes. We further examined the differences in these kinetic characteristics using three selective inhibitors of each human CYP2D6 and CYP3A4 enzymes. The results showed that each of these inhibitors inhibited both d- and l-MA metabolism by 20%-60% in human microsomes but not in rhesus microsomes. The differences between human and rhesus CYP2D6 and CYP3A4 enzymes were further assessed by docking studies for both d and l-MA. In conclusion, our results demonstrated an enhanced MA metabolism in rhesus compared with humans, which is likely to be caused by differences in MA-metabolizing P450 enzymes between these species. PMID- 25301938 TI - Structures of human steroidogenic cytochrome P450 17A1 with substrates. AB - The human cytochrome P450 17A1 (CYP17A1) enzyme operates at a key juncture of human steroidogenesis, controlling the levels of mineralocorticoids influencing blood pressure, glucocorticoids involved in immune and stress responses, and androgens and estrogens involved in development and homeostasis of reproductive tissues. Understanding CYP17A1 multifunctional biochemistry is thus integral to treating prostate and breast cancer, subfertility, blood pressure, and other diseases. CYP17A1 structures with all four physiologically relevant steroid substrates suggest answers to four fundamental aspects of CYP17A1 function. First, all substrates bind in a similar overall orientation, rising ~60 degrees with respect to the heme. Second, both hydroxylase substrates pregnenolone and progesterone hydrogen bond to Asn(202) in orientations consistent with production of 17alpha-hydroxy major metabolites, but functional and structural evidence for an A105L mutation suggests that a minor conformation may yield the minor 16alpha hydroxyprogesterone metabolite. Third, substrate specificity of the subsequent 17,20-lyase reaction may be explained by variation in substrate height above the heme. Although 17alpha-hydroxyprogesterone is only observed farther from the catalytic iron, 17alpha-hydroxypregnenolone is also observed closer to the heme. In conjunction with spectroscopic evidence, this suggests that only 17alpha hydroxypregnenolone approaches and interacts with the proximal oxygen of the catalytic iron-peroxy intermediate, yielding efficient production of dehydroepiandrosterone as the key intermediate in human testosterone and estrogen synthesis. Fourth, differential positioning of 17alpha-hydroxypregnenolone offers a mechanism whereby allosteric binding of cytochrome b5 might selectively enhance the lyase reaction. In aggregate, these structures provide a structural basis for understanding multiple key reactions at the heart of human steroidogenesis. PMID- 25301939 TI - Spatial control of proton pump H,K-ATPase docking at the apical membrane by phosphorylation-coupled ezrin-syntaxin 3 interaction. AB - The digestive function of the stomach depends on acidification of the gastric lumen. Acid secretion into the lumen is triggered by activation of a cAMP dependent protein kinase (PKA) cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. A coupling protein is ezrin whose phosphorylation at Ser-66 by PKA is required for parietal cell activation. However, little is known regarding the molecular mechanism(s) by which ezrin operates in gastric acid secretion. Here we show that phosphorylation of Ser-66 induces a conformational change of ezrin that enables its association with syntaxin 3 (Stx3) and provides a spatial cue for H,K-ATPase trafficking. This conformation-dependent association is specific for Stx3, and the binding interface is mapped to the N-terminal region. Biochemical analyses show that inhibition of ezrin phosphorylation at Ser-66 prevents ezrin-Stx3 association and insertion of H,K-ATPase into the apical plasma membrane of parietal cells. Using atomic force microscopic analyses, our study revealed that phosphorylation of Ser-66 induces unfolding of ezrin molecule to allow Stx3 binding to its N terminus. Given the essential role of Stx3 in polarized secretion, our study presents the first evidence in which phosphorylation-induced conformational rearrangement of the ezrin molecule provides a spatial cue for polarized membrane trafficking in epithelial cells. PMID- 25301940 TI - Serum Inter-alpha-inhibitor activates the Yes tyrosine kinase and YAP/TEAD transcriptional complex in mouse embryonic stem cells. AB - We have previously demonstrated that the Src family kinase Yes, the Yes associated protein (YAP) and TEA domain TEAD2 transcription factor pathway are activated by leukemia inhibitory factor (LIF) and contribute to mouse embryonic stem (mES) cell maintenance of pluripotency and self-renewal. In addition, we have shown that fetal bovine serum (FBS) induces Yes auto-phosphorylation and activation. In the present study we confirm that serum also activates TEAD dependent transcription in a time- and dose-dependent manner and we identify Inter-alpha-inhibitor (IalphaI) as a component in serum capable of activating the Yes/YAP/TEAD pathway by inducing Yes auto-phosphorylation, YAP nuclear localization and TEAD-dependent transcription. The cleaved heavy chain 2 (HC2) sub-component of IalphaI, is demonstrated to be responsible for this effect. Moreover, IalphaI is also shown to efficiently increase expression of TEAD downstream target genes including well-known stem cell factors Nanog and Oct 3/4. IalphaI is not produced by the ES cells per se but is added to the cells via the cell culture medium containing serum or serum-derived components such as bovine serum albumin (BSA). In conclusion, we describe a novel function of IalphaI in activating key pluripotency pathways associated with ES cell maintenance and self renewal. PMID- 25301941 TI - The anticancer agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes prosurvival autophagy by two mechanisms: persistent induction of autophagosome synthesis and impairment of lysosomal integrity. AB - Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anticancer agents. The selective antitumor and antimetastatic chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) causes lysosomal membrane permeabilization and cell death. Considering the integral role of lysosomes in autophagy and cell death, it was important to assess the effect of Dp44mT on autophagy to further understand its mechanism of action. Notably, Dp44mT affected autophagy by two mechanisms. First, concurrent with its antiproliferative activity, Dp44mT increased the expression of the classical autophagic marker LC3-II as a result of induced autophagosome synthesis. Second, this effect was supplemented by a reduction in autophagosome degradation as shown by the accumulation of the autophagic substrate and receptor p62. Conversely, the classical iron chelator desferrioxamine induced autophagosome accumulation only by inhibiting autophagosome degradation. The formation of redox-active iron or copper Dp44mT complexes was critical for its dual effect on autophagy. The cytoprotective antioxidant N-acetylcysteine inhibited Dp44mT-induced autophagosome synthesis and p62 accumulation. Importantly, Dp44mT inhibited autophagosome degradation via lysosomal disruption. This effect prevented the fusion of lysosomes with autophagosomes to form autolysosomes, which is crucial for the completion of the autophagic process. The antiproliferative activity of Dp44mT was suppressed by Beclin1 and ATG5 silencing, indicating the role of persistent autophagosome synthesis in Dp44mT induced cell death. These studies demonstrate that Dp44mT can overcome the prosurvival activity of autophagy in cancer cells by utilizing this process to potentiate cell death. PMID- 25301942 TI - Regulation of histone acetyltransferase TIP60 function by histone deacetylase 3. AB - The key member of the MOZ (monocyticleukaemia zinc finger protein), Ybf2/Sas3, Sas2, and TIP60 acetyltransferases family, Tat-interactive protein, 60 kD (TIP60), tightly modulates a wide array of cellular processes, including chromatin remodeling, gene transcription, apoptosis, DNA repair, and cell cycle arrest. The function of TIP60 can be regulated by SIRT1 through deacetylation. Here we found that TIP60 can also be functionally regulated by HDAC3. We identified six lysine residues as its autoacetylation sites. Mutagenesis of these lysines to arginines completely abolishes the autoacetylation of TIP60. Overexpression of HDAC3 increases TIP60 ubiquitination levels. However, unlike SIRT1, HDAC3 increased the half-life of TIP60. Further study found that HDAC3 colocalized with TIP60 both in the nucleus and the cytoplasm, which could be the reason why HDAC3 can stabilize TIP60. The deacetylation of TIP60 by both SIRT1 and HDAC3 reduces apoptosis induced by DNA damage. Knockdown of HDAC3 in cells increased TIP60 acetylation levels and increased apoptosis after DNA damage. Together, our findings provide a better understanding of TIP60 regulation mechanisms, which is a significant basis for further studies of its cellular functions. PMID- 25301943 TI - NuA4 links methylation of histone H3 lysines 4 and 36 to acetylation of histones H4 and H3. AB - Cotranscriptional methylation of histone H3 lysines 4 and 36 by Set1 and Set2, respectively, stimulates interaction between nucleosomes and histone deacetylase complexes to block cryptic transcription in budding yeast. We previously showed that loss of all H3K4 and H3K36 methylation in a set1Deltaset2Delta mutant reduces interaction between native nucleosomes and the NuA4 lysine acetyltransferase (KAT) complex. We now provide evidence that NuA4 preferentially binds H3 tails mono- and dimethylated on H3K4 and di- and trimethylated on H3K36, an H3 methylation pattern distinct from that recognized by the RPD3C(S) and Hos2/Set3 histone deacetylase complexes (HDACs). Loss of H3K4 or H3K36 methylation in set1Delta or set2Delta mutants reduces NuA4 interaction with bulk nucleosomes in vitro and in vivo, and reduces NuA4 occupancy of transcribed coding sequences at particular genes. We also provide evidence that NuA4 acetylation of lysine residues in the histone H4 tail stimulates SAGA interaction with nucleosomes and its recruitment to coding sequences and attendant acetylation of histone H3 in vivo. Thus, H3 methylation exerts opposing effects of enhancing nucleosome acetylation by both NuA4 and SAGA as well as stimulating nucleosome deacetylation by multiple HDACs to maintain the proper level of histone acetylation in transcribed coding sequences. PMID- 25301944 TI - The endoplasmic reticulum-based acetyltransferases, ATase1 and ATase2, associate with the oligosaccharyltransferase to acetylate correctly folded polypeptides. AB - The endoplasmic reticulum (ER) has two membrane-bound acetyltransferases responsible for the endoluminal N(epsilon)-lysine acetylation of ER-transiting and -resident proteins. Mutations that impair the ER-based acetylation machinery are associated with developmental defects and a familial form of spastic paraplegia. Deficient ER acetylation in the mouse leads to defects of the immune and nervous system. Here, we report that both ATase1 and ATase2 form homo- and heterodimers and associate with members of the oligosaccharyltransferase (OST) complex. In contrast to the OST, the ATases only modify correctly folded polypetides. Collectively, our studies suggest that one of the functions of the ATases is to work in concert with the OST and "select" correctly folded from unfolded/misfolded transiting polypeptides. PMID- 25301945 TI - AMPylation of Rho GTPases subverts multiple host signaling processes. AB - Rho GTPases are frequent targets of virulence factors as they are keystone signaling molecules. Herein, we demonstrate that AMPylation of Rho GTPases by VopS is a multifaceted virulence mechanism that counters several host immunity strategies. Activation of NFkappaB, Erk, and JNK kinase signaling pathways were inhibited in a VopS-dependent manner during infection with Vibrio parahaemolyticus. Phosphorylation and degradation of IKBalpha were inhibited in the presence of VopS as was nuclear translocation of the NFkappaB subunit p65. AMPylation also prevented the generation of superoxide by the phagocytic NADPH oxidase complex, potentially by inhibiting the interaction of Rac and p67. Furthermore, the interaction of GTPases with the E3 ubiquitin ligases cIAP1 and XIAP was hindered, leading to decreased degradation of Rac and RhoA during infection. Finally, we screened for novel Rac1 interactions using a nucleic acid programmable protein array and discovered that Rac1 binds to the protein C1QA, a protein known to promote immune signaling in the cytosol. Interestingly, this interaction was disrupted by AMPylation. We conclude that AMPylation of Rho Family GTPases by VopS results in diverse inhibitory consequences during infection beyond the most obvious phenotype, the collapse of the actin cytoskeleton. PMID- 25301946 TI - S-palmitoylation and s-oleoylation of rabbit and pig sarcolipin. AB - Sarcolipin (SLN) is a regulatory peptide present in sarcoplasmic reticulum (SR) from skeletal muscle of animals. We find that native rabbit SLN is modified by a fatty acid anchor on Cys-9 with a palmitic acid in about 60% and, surprisingly, an oleic acid in the remaining 40%. SLN used for co-crystallization with SERCA1a (Winther, A. M., Bublitz, M., Karlsen, J. L., Moller, J. V., Hansen, J. B., Nissen, P., and Buch-Pedersen, M. J. (2013) Nature 495, 265-2691; Ref. 1) is also palmitoylated/oleoylated, but is not visible in crystal structures, probably due to disorder. Treatment with 1 m hydroxylamine for 1 h removes the fatty acids from a majority of the SLN pool. This treatment did not modify the SERCA1a affinity for Ca(2+) but increased the Ca(2+)-dependent ATPase activity of SR membranes indicating that the S-acylation of SLN or of other proteins is required for this effect on SERCA1a. Pig SLN is also fully palmitoylated/oleoylated on its Cys-9 residue, but in a reverse ratio of about 40/60. An alignment of 67 SLN sequences from the protein databases shows that 19 of them contain a cysteine and the rest a phenylalanine at position 9. Based on a cladogram, we postulate that the mutation from phenylalanine to cysteine in some species is the result of an evolutionary convergence. We suggest that, besides phosphorylation, S acylation/deacylation also regulates SLN activity. PMID- 25301947 TI - Phosphorylation of the BRCA1 C terminus (BRCT) repeat inhibitor of hTERT (BRIT1) protein coordinates TopBP1 protein recruitment and amplifies ataxia telangiectasia-mutated and Rad3-related (ATR) Signaling. AB - The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase functions as a central node in the DNA damage response signaling network. The mechanisms by which ATR activity is amplified and/or maintained are not understood. Here we demonstrate that BRIT1/microcephalin (MCPH1), a human disease-related protein, is dispensable for the initiation but essential for the amplification of ATR signaling. BRIT1 interacts with and recruits topoisomerase-binding protein 1 (TopBP1), a key activator of ATR signaling, to the sites of DNA damage. Notably, replication stress-induced ataxia telangiectasia-mutated or ATR-dependent BRIT1 phosphorylation at Ser-322 facilitates efficient TopBP1 recruitment. These results reveal a mechanism that ensures the continuation of ATR-initiated DNA damage signaling. Our study uncovers a previously unknown regulatory axis of ATR signaling in maintaining genomic integrity, which may provide mechanistic insights into the perturbation of ATR signaling in human diseases such as neurodevelopmental defects and cancer. PMID- 25301948 TI - Crystal structure of the human fatty acid synthase enoyl-acyl carrier protein reductase domain complexed with triclosan reveals allosteric protein-protein interface inhibition. AB - Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long chain fatty acids. Because these fatty acids are primarily provided by diet, FAS is normally expressed at low levels; however, it is highly up-regulated in many cancers. Human enoyl-acyl carrier protein-reductase (hER) is one of the FAS catalytic domains, and its inhibition by drugs like triclosan (TCL) can increase cytotoxicity and decrease drug resistance in cancer cells. We have determined the structure of hER in the presence and absence of TCL. TCL was not bound in the active site, as predicted, but rather at the protein-protein interface (PPI). TCL binding induces a dimer orientation change that causes downstream structural rearrangement in critical active site residues. Kinetics studies indicate that TCL is capable of inhibiting the isolated hER domain with an IC50 of ~ 55 MUM. Given the hER-TCL structure and the inhibition observed in the hER domain, it seems likely that TCL is observed in the physiologically relevant binding site and that it acts as an allosteric PPI inhibitor. TCL may be a viable scaffold for the development of anti-cancer PPI FAS inhibitors. PMID- 25301949 TI - Replisome-mediated translesion synthesis and leading strand template lesion skipping are competing bypass mechanisms. AB - A number of different enzymatic pathways have evolved to ensure that DNA replication can proceed past template base damage. These pathways include lesion skipping by the replisome, replication fork regression followed by either correction of the damage and origin-independent replication restart or homologous recombination-mediated restart of replication downstream of the lesion, and bypass of the damage by a translesion synthesis DNA polymerase. We report here that of two translesion synthesis polymerases tested, only DNA polymerase IV, not DNA polymerase II, could engage productively with the Escherichia coli replisome to bypass leading strand template damage, despite the fact that both enzymes are shown to be interacting with the replicase. Inactivation of the 3' -> 5' proofreading exonuclease of DNA polymerase II did not enable bypass. Bypass by DNA polymerase IV required its ability to interact with the beta clamp and act as a translesion polymerase but did not require its "little finger" domain, a secondary region of interaction with the beta clamp. Bypass by DNA polymerase IV came at the expense of the inherent leading strand lesion skipping activity of the replisome, indicating that they are competing reactions. PMID- 25301950 TI - Mechanism of inhibition for BMS-791325, a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase. AB - HCV infection is an urgent global health problem that has triggered a drive to discover therapies that specifically target the virus. BMS-791325 is a novel direct antiviral agent specifically targeting HCV NS5B, an RNA-dependent RNA polymerase. Robust viral clearance of HCV was observed in infected patients treated with BMS-791325 in combination with other anti-HCV agents in Phase 2 clinical studies. Biochemical and biophysical studies revealed that BMS-791325 is a time-dependent, non-competitive inhibitor of the polymerase. Binding studies with NS5B genetic variants (WT, L30S, and P495L) exposed a two-step, slow binding mechanism, but details of the binding mechanism differed for each of the polymerase variants. For the clinically relevant resistance variant (P495L), the rate of initial complex formation and dissociation is similar to WT, but the kinetics of the second step is significantly faster, showing that this variant impacts the final tight complex. The resulting shortened residence time translates into the observed decrease in inhibitor potency. The L30S variant has a significantly different profile. The rate of initial complex formation and dissociation is 7-10 times faster for the L30S variant compared with WT; however, the forward and reverse rates to form the final complex are not significantly different. The impact of the L30S variant on the inhibition profile and binding kinetics of BMS-791325 provides experimental evidence for the dynamic interaction of fingers and thumb domains in an environment that supports the formation of active replication complexes and the initiation of RNA synthesis. PMID- 25301951 TI - Identification of the major prostaglandin glycerol ester hydrolase in human cancer cells. AB - Prostaglandin glycerol esters (PG-Gs) are produced as a result of the oxygenation of the endocannabinoid, 2-arachidonoylglycerol, by cyclooxygenase 2. Understanding the role that PG-Gs play in a biological setting has been difficult because of their sensitivity to enzymatic hydrolysis. By comparing PG-G hydrolysis across human cancer cell lines to serine hydrolase activities determined by activity-based protein profiling, we identified lysophospholipase A2 (LYPLA2) as a major enzyme responsible for PG-G hydrolysis. The principal role played by LYPLA2 in PGE2-G hydrolysis was confirmed by siRNA knockdown. Purified recombinant LYPLA2 hydrolyzed PG-Gs in the following order of activity: PGE2-G > PGF2alpha-G > PGD2-G; LYPLA2 hydrolyzed 1- but not 2-arachidonoylglycerol or arachidonoylethanolamide. Chemical inhibition of LYPLA2 in the mouse macrophage like cell line, RAW264.7, elicited an increase in PG-G production. Our data indicate that LYPLA2 serves as a major PG-G hydrolase in human cells. Perturbation of this enzyme should enable selective modulation of PG-Gs without alterations in endocannabinoids, thereby providing a means to decipher the unique functions of PG-Gs in biology and disease. PMID- 25301954 TI - Meta-analysis of the effects of preoperative renin-angiotensin system inhibitor therapy on major adverse cardiac events in patients undergoing cardiac surgery. AB - The purpose of this meta-analysis was to assess the role of preoperative renin angiotensin system inhibitor (RASI) therapy on major adverse cardiac events (MACE) in patients undergoing cardiac surgery. The Medline, Cochrane Library and Embase databases were searched for clinical studies published up to May 2014. Studies that evaluated the effects of preoperative RASI therapy in cardiac surgery were included. Odds ratio (OR) estimates were generated under a random effects model. After a literature search in the major databases, 18 studies were identified [three randomized prospective clinical trials (RCTs) and 15 observational trials] that reported outcomes of 54 528 cardiac surgery patients with (n = 22 661; 42%) or without (n = 31 867; 58%) preoperative RASI therapy. Pool analysis indicated that preoperative RASI therapy was not associated with a significant reduction of early all-cause mortality [OR: 1.01; 95% confidence interval (CI) 0.88-1.15, P = 0.93; I(2) = 25%], myocardial infarction (OR: 1.04; 95% CI 0.91-1.19, P = 0.60; I(2) = 16%), or stroke (OR: 0.93; 95% CI 0.75-1.14, P = 0.46; I(2) = 38%). Meta-regression analysis confirmed that there was a strong negative correlation between the percentage of diabetics and early all-cause mortality (P = 0.03). Furthermore, preoperative RASI therapy significantly reduced mortality in studies containing a high proportion of diabetic patients (OR: 0.84; 95% CI 0.71-0.99, P = 0.04; I(2) = 0%). In conclusion, our meta analysis indicated that although preoperative RASI therapy was not associated with a lower risk of MACE in cardiac surgery patients, it might provide benefits for diabetic patients. PMID- 25301952 TI - RNase L attenuates mitogen-stimulated gene expression via transcriptional and post-transcriptional mechanisms to limit the proliferative response. AB - The cellular response to mitogens is tightly regulated via transcriptional and post-transcriptional mechanisms to rapidly induce genes that promote proliferation and efficiently attenuate their expression to prevent malignant growth. RNase L is an endoribonuclease that mediates diverse antiproliferative activities, and tristetraprolin (TTP) is a mitogen-induced RNA-binding protein that directs the decay of proliferation-stimulatory mRNAs. In light of their roles as endogenous proliferative constraints, we examined the mechanisms and functional interactions of RNase L and TTP to attenuate a mitogenic response. Mitogen stimulation of RNase L-deficient cells significantly increased TTP transcription and the induction of other mitogen-induced mRNAs. This regulation corresponded with elevated expression of serum-response factor (SRF), a master regulator of mitogen-induced transcription. RNase L destabilized the SRF transcript and formed a complex with SRF mRNA in cells providing a mechanism by which RNase L down-regulates SRF-induced genes. TTP and RNase L proteins interacted in cells suggesting that RNase L is directed to cleave TTP-bound RNAs as a mechanism of substrate specificity. Consistent with their concerted function in RNA turnover, the absence of either RNase L or TTP stabilized SRF mRNA, and a subset of established TTP targets was also regulated by RNase L. RNase L deficiency enhanced mitogen-induced proliferation demonstrating its functional role in limiting the mitogenic response. Our findings support a model of feedback regulation in which RNase L and TTP target SRF mRNA and SRF-induced transcripts. Accordingly, meta-analysis revealed an enrichment of RNase L and TTP targets among SRF-regulated genes suggesting that the RNase L/TTP axis represents a viable target to inhibit SRF-driven proliferation in neoplastic diseases. PMID- 25301955 TI - Plasmodium knowlesi malaria during pregnancy. AB - BACKGROUND: Plasmodium knowlesi is the commonest cause of malaria in Malaysia, but little is known regarding infection during pregnancy. METHODS: To investigate comparative risk and consequences of knowlesi malaria during pregnancy, we reviewed (1) Sabah Health Department malaria-notification records created during 2012-2013, (2) prospectively collected data from all females with polymerase chain reaction (PCR)-confirmed malaria who were admitted to a Sabah tertiary care referral hospital during 2011-2014, and (3) malaria microscopy and clinical data recorded at a Sabah tertiary care women and children's hospital during 2010-2014. RESULTS: During 2012-2013, 774 females with microscopy-diagnosed malaria were notified, including 252 (33%), 172 (20%), 333 (43%), and 17 (2%) with Plasmodium falciparum infection, Plasmodium vivax infection, Plasmodium malariae/Plasmodium knowlesi infection, and mixed infection, respectively. Among females aged 15-45 years, pregnancy was reported in 18 of 124 (14.5%), 9 of 93 (9.7%), and 4 of 151 (2.6%) P. falciparum, P. vivax, and P. malariae/P. knowlesi notifications respectively (P = .002). Three females with knowlesi malaria were confirmed as pregnant: 2 had moderate anemia, and 1 delivered a preterm low-birth-weight infant. There were 17, 7, and 0 pregnant women with falciparum, vivax, and knowlesi malaria, respectively, identified from the 2 referral hospitals. CONCLUSIONS: Although P. knowlesi is the commonest malaria species among females in Sabah, P. knowlesi infection is relatively rare during pregnancy. It may however be associated with adverse maternal and pregnancy outcomes. PMID- 25301953 TI - Sequence and conformational specificity in substrate recognition: several human Kunitz protease inhibitor domains are specific substrates of mesotrypsin. AB - Mesotrypsin is an isoform of trypsin that is uniquely resistant to polypeptide trypsin inhibitors and can cleave some inhibitors rapidly. Previous studies have shown that the amyloid precursor protein Kunitz protease inhibitor domain (APPI) is a specific substrate of mesotrypsin and that stabilization of the APPI cleavage site in a canonical conformation contributes to recognition by mesotrypsin. We hypothesized that other proteins possessing potential cleavage sites stabilized in a similar conformation might also be mesotrypsin substrates. Here we evaluated a series of candidate substrates, including human Kunitz protease inhibitor domains from amyloid precursor-like protein 2 (APLP2), bikunin, hepatocyte growth factor activator inhibitor type 2 (HAI2), tissue factor pathway inhibitor-1 (TFPI1), and tissue factor pathway inhibitor-2 (TFPI2), as well as E-selectin, an unrelated protein possessing a potential cleavage site displaying canonical conformation. We find that Kunitz domains within APLP2, bikunin, and HAI2 are cleaved by mesotrypsin with kinetic profiles of specific substrates. TFPI1 and TFPI2 Kunitz domains are cleaved less efficiently by mesotrypsin, and E-selectin is not cleaved at the anticipated site. Cocrystal structures of mesotrypsin with HAI2 and bikunin Kunitz domains reveal the mode of mesotrypsin interaction with its canonical substrates. Our data suggest that major determinants of mesotrypsin substrate specificity include sequence preferences at the P1 and P'2 positions along with conformational stabilization of the cleavage site in the canonical conformation. Mesotrypsin up regulation has been implicated previously in cancer progression, and proteolytic clearance of Kunitz protease inhibitors offers potential mechanisms by which mesotrypsin may mediate pathological effects in cancer. PMID- 25301957 TI - Understanding the relationship between Plasmodium falciparum growth rate and multiplicity of infection. AB - Natural infections with Plasmodium falciparum are often composed of multiple concurrent genetically distinct parasite clones. Such multiclonal infections are more common in areas of high transmission, and the frequency of multiclonal infection also varies with age. A number of studies have suggested that multiclonal infection predicts the risk of subsequent clinical malaria. The multiplicity of infection is determined by the rate of new infections, the number of clones inoculated at each mosquito bite, and the duration of infections. Here, we used a mathematical modeling approach to understand how variation in the growth rate of blood-stage parasites affects the observed multiplicity of infection (MOI), as well as the relationship between the MOI and the risk of subsequent malaria. We then analyzed data from a study of multiclonal infection and malaria in an malaria-endemic area in Tanzania and show that the proportion of multiclonal infections varies with age and that the observed relationship between multiclonal infection and subsequent clinical events can be explained by a reduction in blood-stage parasite growth with age in this population. PMID- 25301956 TI - Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation. AB - BACKGROUND: Polymorphisms in IFNL3 and IFNL4, the genes encoding interferon lambda3 and interferon lambda4, respectively, have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of cytomegalovirus (CMV) infection in solid-organ transplant recipients. METHODS: White patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated. RESULTS: A total of 840 solid-organ transplant recipients at risk for CMV infection were included, among whom 373 (44%) received antiviral prophylaxis. The 12-month cumulative incidence of CMV replication and disease were 0.44 and 0.08 cases, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (subdistribution hazard ratio [SHR], 1.30 [95% confidence interval {CI}, .97-1.74]; P = .07), compared with other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR, 1.46 [95% CI, 1.01-2.12]; P = .047), especially in patients receiving an organ from a seropositive donor (SHR, 1.92 [95% CI, 1.30-2.85]; P = .001), but not among those who received antiviral prophylaxis (SHR, 1.13 [95% CI, .70-1.83]; P = .6). These associations remained significant in multivariate competing risk regression models. CONCLUSIONS: Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid-organ transplant recipients, particularly in patients not receiving antiviral prophylaxis. PMID- 25301958 TI - Pioneering engineered antibodies and immunotherapeutics: dedicated to Professor James D. Marks. PMID- 25301959 TI - Design and characterization of structured protein linkers with differing flexibilities. AB - Engineered fusion proteins containing two or more functional polypeptides joined by a peptide or protein linker are important for many fields of biological research. The separation distance between functional units can impact epitope access and the ability to bind with avidity; thus the availability of a variety of linkers with different lengths and degrees of rigidity would be valuable for protein design efforts. Here, we report a series of designed structured protein linkers incorporating naturally occurring protein domains and compare their properties to commonly used Gly4Ser repeat linkers. When incorporated into the hinge region of an immunoglobulin G (IgG) molecule, flexible Gly4Ser repeats did not result in detectable extensions of the IgG antigen-binding domains, in contrast to linkers including more rigid domains such as beta2-microglobulin, Zn alpha2-glycoprotein and tetratricopeptide repeats. This study adds an additional set of linkers with varying lengths and rigidities to the available linker repertoire, which may be useful for the construction of antibodies with enhanced binding properties or other fusion proteins. PMID- 25301960 TI - A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody-ribonuclease fusion protein targeting the EGF receptor. AB - Due to its frequent overexpression in a variety of solid tumors the epidermal growth factor receptor (EGFR) is a well-established target for therapeutic interventions in epithelial cancers. In order to target EGFR in head and neck cancer, we have generated a ribonuclease (RNase) fusion protein comprising a humanized anti-EGFR antibody single-chain Fv fragment (scFv) and Ranpirnase, an RNase from Rana pipiens. Fusion of Ranpirnase to the N-terminus of the scFv via a flexible glycine-serine linker (G4S)3 resulted in very poor cytotoxicity of the fusion protein. As endosomal accumulation and lysosomal degradation have been reported to diminish the antitumor efficacy of ribonuclease or toxin-based immunoagents, we explored a fusion peptide from dengue virus that has been reported to be involved in the endosomal escape of the virus. This peptide was introduced as a linker between Ranpirnase and the scFv moiety. The modified immunoRNase exhibited exceptionally high cytotoxicity toward EGFR-expressing head and neck cell lines without affecting specificity. These results indicate that endosomal entrapment needs to be considered for Ranpirnase-based immunoagents and might be overcome by the use of tailored transduction domains from viral proteins. PMID- 25301961 TI - Differential nuclear localization of complexes may underlie in vivo intrabody efficacy in Huntington's disease. AB - Intrabodies offer attractive options for manipulating the protein misfolding that triggers neurodegenerative diseases. In Huntington's disease, where the expanded polyglutamine tract in the extreme N-terminal region of huntingtin exon1 misfolds, two lead intrabodies have been selected against an adjacent peptide, using slightly different approaches. Both are effective at preventing aggregation of a reporter fragment in transient co-transfection assays. However, after intracranial delivery to mutant mouse brains, VL12.3, which is mainly localized to the nucleus, appears to accelerate the mutant phenotype, while C4 scFv, which is largely cytoplasmic, shows partial phenotypic correction. This comparison highlights parameters that could inform intrabody therapeutics for multiple proteostatic diseases. PMID- 25301962 TI - Affinity transfer to the archaeal extremophilic Sac7d protein by insertion of a CDR. AB - Artificially transforming a scaffold protein into binders often consists of introducing diversity into its natural binding region by directed mutagenesis. We have previously developed the archaeal extremophilic Sac7d protein as a scaffold to derive affinity reagents (Affitins) by randomization of only a flat surface, or a flat surface and two short loops with natural lengths. Short loops are believed to contribute to stability of extremophilic proteins, and loop extension has been reported detrimental for the thermal and chemical stabilities of mesophilic proteins. In this work, we wanted to evaluate the possibility of designing target-binding proteins based on Sac7d by using a complementary determining region (CDR). To this aim, we inserted into three different loops a 10 residues CDR from the cAb-Lys3 anti-lysozyme camel antibody. The chimeras obtained were as stable as wild-type (WT) Sac7d at extreme pH and their structural integrity was supported. Chimeras were thermally stable, but with T(m)s from 60.9 to 66.3 degrees C (cf. 91 degrees C for Sac7d) which shows that loop extension is detrimental for thermal stability of Sac7d. The loop 3 enabled anti-lysozyme activity. These results pave the way for the use of CDR(s) from antibodies and/or extended randomized loop(s) to increase the potential of binding of Affitins. PMID- 25301963 TI - Elevated serum squalene and cholesterol synthesis markers in pregnant obese women with gestational diabetes mellitus. AB - We examined serum cholesterol synthesis and absorption markers and their association with neonatal birth weight in obese pregnancies affected by gestational diabetes mellitus (GDM). Pregnant women at risk for GDM (BMI >30 kg/m2) were enrolled from maternity clinics in Finland. GDM was determined from the results of an oral glucose tolerance test. Serum samples were collected at six time-points, one in each trimester of pregnancy, and at 6 weeks, 6 months, and 12 months postpartum. Analysis of serum squalene and noncholesterol sterols by gas-liquid chromatography revealed that in subjects with GDM (n = 22), the serum Delta8-cholestenol concentration and lathosterol/sitosterol ratio were higher (P < 0.05) than in the controls (n = 30) in the first trimester, reflecting increased cholesterol synthesis. Also, subjects with GDM had an increased ratio of squalene to cholesterol (100 * MUmol/mmol of cholesterol) in the second (11.5 +/- 0.5 vs. 9.1 +/- 0.5, P < 0.01) and third (12.1 +/- 0.8 vs. 10.0 +/- 0.7, P < 0.05) trimester. In GDM, the second trimester maternal serum squalene concentration correlated with neonatal birth weight (r = 0.70, P < 0.001). In conclusion, in obesity, GDM associated with elevated serum markers of cholesterol synthesis. Correlation of maternal serum squalene with neonatal birth weight suggests a potential contribution of maternal cholesterol synthesis to newborn weight in GDM. PMID- 25301965 TI - Children with developmental coordination disorder play active virtual reality games differently than children with typical development. AB - BACKGROUND: Active virtual reality gaming (AVG) may be useful for children with developmental coordination disorder (DCD) to practice motor skills if their movement patterns are of good quality while engaged in AVG. OBJECTIVE: This study aimed to examine: (1) the quality of motor patterns of children with DCD participating in AVG by comparing them with children with typical development (TD) and (2) whether differences existed in the motor patterns utilized with 2 AVG types: Sony PlayStation 3 Move and Microsoft Xbox 360 Kinect. DESIGN: This was a quasi-experimental, biomechanical laboratory-based study. METHODS: Twenty one children with DCD, aged 10 to 12 years, and 19 age- and sex-matched children with TD played a match of table tennis on each AVG type. Hand path, wrist angle, and elbow angle were recorded using a motion analysis system. Linear mixed-model analyses were used to determine differences between DCD and TD groups and Move and Kinect AVG type for forehands and backhands. RESULTS: Children with DCD utilized a slower hand path speed (backhand mean difference [MD]=1.20 m/s; 95% confidence interval [95% CI]=0.41, 1.98); greater wrist extension (forehand MD=34.3 degrees ; 95% CI=22.6, 47.0); and greater elbow flexion (forehand MD=22.3 degrees ; 95% CI=7.4, 37.1) compared with children with TD when engaged in AVG. There also were differences in movement patterns utilized between AVG types. LIMITATIONS: Only simple kinematic measures were compared, and no data regarding movement outcome were assessed. CONCLUSIONS: If a therapeutic treatment goal is to promote movement quality in children with DCD, clinical judgment is required to select the most appropriate AVG type and determine whether movement quality is adequate for unsupervised practice. PMID- 25301966 TI - Best practice recommendations for the development, implementation, and evaluation of online knowledge translation resources in rehabilitation. AB - The knowledge-to-practice gap in rehabilitation has spurred knowledge translation (KT) initiatives aimed at promoting clinician behavior change and improving patient care. Online KT resources for physical therapists and other rehabilitation clinicians are appealing because of their potential to reach large numbers of individuals through self-paced, self-directed learning. This article proposes best practice recommendations for developing online KT resources that are designed to translate evidence into practice. Four recommendations are proposed with specific steps in the development, implementation, and evaluation process: (1) develop evidence-based, user-centered content; (2) tailor content to online format; (3) evaluate impact; and (4) share results and disseminate knowledge. Based on KT evidence and instructional design principles, concrete examples are provided along with insights gained from experiences in creating and evaluating online KT resources for physical therapists. In proposing these recommendations, the next steps for research are suggested, and others are invited to contribute to the discussion. PMID- 25301964 TI - Use of appropriate initial treatment among adolescents and young adults with cancer. AB - BACKGROUND: There has been little improvement in the survival of adolescent and young adult (AYA) cancer patients aged 15 to 39 years relative to other age groups, raising the question of whether such patients receive appropriate initial treatment. METHODS: We examined receipt of initial cancer treatment for a population-based sample of 504 AYAs diagnosed in 2007-2008 with acute lymphoblastic leukemia (ALL), Hodgkin's or non-Hodgkin's lymphoma, germ cell cancer, or sarcoma. Registry data, patient surveys, and detailed medical record reviews were used to evaluate the association of patient demographic, socioeconomic, and health care setting characteristics with receipt of appropriate initial treatment, which was defined by clinical specialists in AYA oncology based on adult guidelines and published literature available before 2009 and analyzed with multivariable logistic regression. All statistical tests were two-sided. RESULTS: Approximately 75% of AYA cancer patients in our sample received appropriate treatment, 68% after excluding stage I male germ cell patients who all received appropriate treatment. After this exclusion, appropriate treatment ranged from 79% of sarcoma patients to 56% of ALL patients. Cancer type (P < .01) and clinical trial participation (P = .04) were statistically significantly associated with appropriate treatment in multivariable analyses. Patients enrolled in clinical trials were more likely to receive appropriate therapy relative to those not enrolled (78% vs 67%, adjusted odds ratio = 2.6, 95% confidence interval = 1.1 to 6.4). CONCLUSIONS: Except for those with early stage male germ cell tumors, approximately 30% (or 3 in 10) AYA cancer patients did not receive appropriate therapy. Further investigation is required to understand the reasons for this potential shortfall in care delivery. PMID- 25301967 TI - An investigation of cervical spinal posture in cervicogenic headache. AB - BACKGROUND: Cervicogenic headache (CGH) is defined as headache symptoms originating from the cervical spine. Cervical dysfunction from abnormal posture has been proposed to aggravate or cause CGH, but there are conflicting reports as to whether there is an association between posture and CGH. OBJECTIVE: The purpose of this study was to evaluate differences in cervical spinal posture, measured on radiographs, between patients with probable CGH and asymptomatic control participants. DESIGN: A single-blinded comparative measurement design was used. METHODS: Differences in postural variables from radiographs between participants with CGH (n=30) and age- and sex-matched asymptomatic control participants (n=30) were determined using paired t tests or the nonparametric equivalent. Postural variables were general cervical lordosis (GCL, Cobb angle C2 C7), upper cervical lordosis (UCL, sagittal alignment C2 compared with C3-C4), and C2 spinous process horizontal deviation. Logistic regression determined postural variables, increasing the likelihood of CGH. RESULTS: There were no significant differences in posture between the CGH and control groups. The mean GCL was 10.97 degrees (SD=7.50) for the CGH group and 7.17 degrees (SD=5.69) for the control group. The mean UCL was 11.86 degrees (SD=6.46) for the CGH group and 9.44 degrees (SD=4.28) for the control group. The mean C2 spinous process horizontal deviation was 3.00 mm (SD=1.66) for the CGH group and 2.86 mm (SD=2.04) for the control group. However, there was a significant association between greater GCL and an increased likelihood of having CGH (odds ratio=1.08; 95% confidence interval=1.001, 1.191). LIMITATIONS: The findings are limited to an association between GCL and posture, as cause and effect cannot be determined. CONCLUSIONS: The association between greater GCL and increased likelihood of having CGH suggests that GCL might be considered in the treatment of patients with CGH. However, as the data do not support posture as a cause of CGH, it is unknown whether addressing posture would reduce CGH. PMID- 25301968 TI - Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm. AB - The lack of significant progress in the treatment of epithelial ovarian cancer (EOC) underscores the need to gain a better understanding of the processes that lead to chemoresistance and recurrence. The cancer stem cell (CSC) hypothesis offers an attractive explanation of how a subpopulation of cells within a patient's tumour might remain refractory to treatment and subsequently form the basis of recurrent chemoresistant disease. This review examines the literature defining somatic stem cells of the ovary and fallopian tube, two tissues that give rise to EOC. In addition, considerable research has been reviewed, that has identified subpopulations of EOC cells, based on marker expression (CD133, CD44, CD117, CD24, epithelial cell adhesion molecule, LY6A, ALDH1 and side population (SP)), which are enriched for tumour initiating cells (TICs). While many studies identified either CD133 or CD44 as markers useful for enriching for TICs, there is little consensus. This suggests that EOC cells may have a phenotypic plasticity that may preclude the identification of universal markers defining a CSC. The assay that forms the basis of quantifying TICs is the xenograft assay. Considerable controversy surrounds the xenograft assay and it is essential that some of the potential limitations be examined in this review. Highlighting such limitations or weaknesses is required to properly evaluate data and broaden our interpretation of potential mechanisms that might be contributing to the pathogenesis of ovarian cancer. PMID- 25301969 TI - Regulation of endothelial permeability in the primate corpora lutea: implications for ovarian hyperstimulation syndrome. AB - In a developing human corpus luteum, a closely regulated cellular communication system exists between the luteal steroidogenic cells and endothelial cells. This system guaranties the vascularization process during luteal formation. The process is combined with rapid release of large amounts of progesterone into the bloodstream. The regulation of endothelial proliferation and permeability by LH and human chorionic gonadotropin (hCG) is integral to this process. On the cellular level, endothelial permeability is regulated by intercellular junctions, such as adherens junctions (AJ) and tight junctions (TJ), which act as zipper like structures between interacting endothelial cells. Several cell junctional proteins are localized to the corpus luteum, including Occludin, Nectin 2, Claudin 1, and Claudin 5, as well as, vascular endothelial (VE)-Cadherin. It has been assumed that regulation of AJ- and TJ-proteins is of particular importance for permeability, and accordingly, for the functionality of the corpus luteum in early pregnancy, because treatment with hCG induces downregulation of juntional proteins in the luteal vessels. The effect of hCG on the adhesive molecules is mediated by VE growth factor (VEGF). On a functional level, the hCG-dependent and VEGF-mediated decrease in junctional proteins causes a decrease in the density of cell-cell closure and, accordingly, an increase in endothelial permeability. In doing so, the different junctional proteins are not only directly influenced by VEGF but also interact among themselves and influence each other reciprocally. Disturbances in this strictly, regulated interactions may explain the development of pathologies with increased vascular permeability, such as the ovarian hyperstimulation syndrome. PMID- 25301970 TI - Alpha particle energy response of 1-mm-thick polycarbonate track detectors by 50 Hz-HV electrochemical etching method. AB - The electrochemical etching (ECE) method enlarges charged particle tracks to enhance its applications in particular in health physics and radiation dosimetry. The ECE method is usually based on using a high frequency-high voltage (HF-HV) generator with 250-um-thick polycarbonate track detectors (PCTDs). The authors' recent studies on nitrogen and helium ions and alpha tracks in 1-mm-thick large size PCTDs under a 50 Hz-HV ECE process provided promising results. In this study, alpha track efficiency and mean track diameter versus energy responses and registration energy range as well as alpha and background track shapes under three sets of 50 Hz-4, 5 and 6 kV applied field conditions have been studied and are reported. The efficiency versus alpha energy has a Bragg-type response from ~15 keV to ~4.5 MeV for the field conditions applied with an efficiency value of 40-50% at the Bragg peak. The results are presented and discussed. PMID- 25301971 TI - A method to minimise the fading effects of LiF:Mg,Ti (TLD-600 and TLD-700) using a pre-heat technique. AB - Passive integrating dosemeters [thermoluminescent dosimeter (TLD) and optically stimulated luminescence (OSL)] are the only legally permitted individual dosemeters for occupational external radiation exposure monitoring in Korea. Also its maximum issuing cycle does not exceed 3 months, and the Korean regulations require personal dosemeters for official assessment of external radiation exposure to be issued by an approved or rather an accredited dosimetry service according to ISO/IEC 17025. KHNP (Korea Hydro & Nuclear Power, LTD), a unique operating company of nuclear power plants (NPPs) in Korea, currently has a plan to extend a TLD issuing cycle from 1 to 3 months under the authors' fading error criteria, +/-10%. The authors have performed a feasibility study that minimises post-irradiation fading effects within their maximum reading cycle employing pre heating technique. They repeatedly performed irradiation/reading a bare TLD chip to determine optimum pre-heating conditions by analysing each glow curve. The optimum reading conditions within the maximum reading cycle of 3 months were decided: a pre-heating temperature of 165 degrees C, a pre-heating time of 9 s, a heating rate of 25 degrees C s(-1), a reading temperature of 300 degrees C and an acquisition time of 10 s. The fading result of TLD-600 and TLD-700 carried by newly developed time temperature profile (TTP) showed a much smaller fading effect than that of current TTP. The result showed that the fading error due to a developed TTP resulted in a ~5% signal loss, whereas a current TTP caused a ~15% loss. The authors also carried out a legal performance test on newly developed TTP to confirm its possibility as an official dosemeter. The legal performance tests that applied the developed TTP satisfied the criteria for all the test categories. PMID- 25301972 TI - Exoplanet atmosphere. Thermal structure of an exoplanet atmosphere from phase resolved emission spectroscopy. AB - Exoplanets that orbit close to their host stars are much more highly irradiated than their solar system counterparts. Understanding the thermal structures and appearances of these planets requires investigating how their atmospheres respond to such extreme stellar forcing. We present spectroscopic thermal emission measurements as a function of orbital phase ("phase-curve observations") for the highly irradiated exoplanet WASP-43b spanning three full planet rotations using the Hubble Space Telescope. With these data, we construct a map of the planet's atmospheric thermal structure, from which we find large day-night temperature variations at all measured altitudes and a monotonically decreasing temperature with pressure at all longitudes. We also derive a Bond albedo of 0.18( 0.12)(+0.07) and an altitude dependence in the hot-spot offset relative to the substellar point. PMID- 25301974 TI - QUADRATIC SERENDIPITY FINITE ELEMENTS ON POLYGONS USING GENERALIZED BARYCENTRIC COORDINATES. AB - We introduce a finite element construction for use on the class of convex, planar polygons and show it obtains a quadratic error convergence estimate. On a convex n-gon, our construction produces 2n basis functions, associated in a Lagrange like fashion to each vertex and each edge midpoint, by transforming and combining a set of n(n + 1)/2 basis functions known to obtain quadratic convergence. The technique broadens the scope of the so-called 'serendipity' elements, previously studied only for quadrilateral and regular hexahedral meshes, by employing the theory of generalized barycentric coordinates. Uniform a priori error estimates are established over the class of convex quadrilaterals with bounded aspect ratio as well as over the class of convex planar polygons satisfying additional shape regularity conditions to exclude large interior angles and short edges. Numerical evidence is provided on a trapezoidal quadrilateral mesh, previously not amenable to serendipity constructions, and applications to adaptive meshing are discussed. PMID- 25301975 TI - Speakers of tonal and non-tonal Korean dialects use different cue weightings in the perception of the three-way laryngeal stop contrast. AB - The current study investigated the perception of the three-way distinction among Korean voiceless stops in non-tonal Seoul and tonal Kyungsang Korean. The question addressed is whether listeners from these two dialects differ in the way they perceive the three stops. Forty-two Korean listeners (21 each from Seoul and South Kyungsang) were tested in a perception experiment with stimuli in which VOT and F0 were systematically manipulated. Analyses of the perceptual identification functions show that VOT and F0 cues trade off each other for the perception of the three stops. However, the trading relationship differs between the two dialects. Logistic regression analyses confirmed the two dialects use the perceptual cues differently for the lenis and aspirated stops. While Seoul listeners rely primarily on F0 for making lenis responses and on VOT and F0 for aspirated responses, F0 plays a less important role in modulating both lenis and aspirated responses for Kyungsang than for Seoul listeners. It is proposed that different tonal systems between the two dialects and the ongoing diachronic sound change in the stops of Seoul Korean contribute to the inter-dialect difference in cue weighting for the three-way stop distinction. The results suggest that although the difference in phonology between the two dialects influences the phonetic realization, the phonetic trade-off among multiple cues allows each dialect to maintain the phonemic distinction in a unique way. PMID- 25301973 TI - Casting inorganic structures with DNA molds. AB - We report a general strategy for designing and synthesizing inorganic nanostructures with arbitrarily prescribed three-dimensional shapes. Computationally designed DNA strands self-assemble into a stiff "nanomold" that contains a user-specified three-dimensional cavity and encloses a nucleating gold "seed." Under mild conditions, this seed grows into a larger cast structure that fills and thus replicates the cavity. We synthesized a variety of nanoparticles with 3-nanometer resolution: three distinct silver cuboids with three independently tunable dimensions, silver and gold nanoparticles with diverse cross sections, and composite structures with homo- and heterogeneous components. The designer equilateral silver triangular and spherical nanoparticles exhibited plasmonic properties consistent with electromagnetism-based simulations. Our framework is generalizable to more complex geometries and diverse inorganic materials, offering a range of applications in biosensing, photonics, and nanoelectronics. PMID- 25301976 TI - SURE Estimates for a Heteroscedastic Hierarchical Model. AB - Hierarchical models are extensively studied and widely used in statistics and many other scientific areas. They provide an effective tool for combining information from similar resources and achieving partial pooling of inference. Since the seminal work by James and Stein (1961) and Stein (1962), shrinkage estimation has become one major focus for hierarchical models. For the homoscedastic normal model, it is well known that shrinkage estimators, especially the James-Stein estimator, have good risk properties. The heteroscedastic model, though more appropriate for practical applications, is less well studied, and it is unclear what types of shrinkage estimators are superior in terms of the risk. We propose in this paper a class of shrinkage estimators based on Stein's unbiased estimate of risk (SURE). We study asymptotic properties of various common estimators as the number of means to be estimated grows (p -> infinity). We establish the asymptotic optimality property for the SURE estimators. We then extend our construction to create a class of semi parametric shrinkage estimators and establish corresponding asymptotic optimality results. We emphasize that though the form of our SURE estimators is partially obtained through a normal model at the sampling level, their optimality properties do not heavily depend on such distributional assumptions. We apply the methods to two real data sets and obtain encouraging results. PMID- 25301977 TI - Computational Inversion of Electron Tomography Images Using L2-Gradient Flows. AB - In this paper, we present a stable, reliable and robust method for reconstructing a three dimensional density function from a set of two dimensional electric tomographic images. By minimizing an energy functional consisting of a fidelity term and a regularization term, an L2-gradient flow is derived. The flow is integrated by a finite element method in the spatial direction and an explicit Euler scheme in temporal direction. The experimental results show that the proposed method is efficient and effective. PMID- 25301979 TI - Cytokines and disease. PMID- 25301978 TI - K-ras mutational status in cytohistological tissue as a molecular marker for the diagnosis of pancreatic cancer: a systematic review and meta-analysis. AB - BACKGROUND: More clinically meaningful diagnostic tests are needed in pancreatic cancer (PC). K-ras mutations are the most frequently acquired genetic alteration. METHODS: Original research articles involving the diagnostic accuracy of K-ras mutation detection in PC were selected. Data were presented as forest plots and summary receiver operating characteristic (SROC) curve analysis was used to summarize the overall test performance. RESULTS: We assessed 19 studies from 16 published articles. The reports were divided into three groups according to the process used to obtain the test material. The summary estimates for detecting K ras status using an invasive method (fine needle aspiration (FNA), endoscopic retrograde cholangiopancreatography (ERCP), or surgery) were better than cytology: the pooled sensitivity was 77% (95% confidence interval (CI): 74-80%) versus 54% (95% CI: 47-61%); specificity was 88% (95% CI: 85-91%) versus 91% (95% CI: 83-96%); and diagnostic odds ratio (DOR) was 20.26 (11.40-36.03) versus 7.52 (95% CI: 2.80-20.18), respectively. When two procedures were combined, the diagnostic accuracy was markedly improved. CONCLUSIONS: The analysis of K-ras mutations in pancreatic tissue has a promising diagnostic significance in PC. Further valuable studies are needed. PMID- 25301981 TI - Interplay of inflammation, immunity, and organ-specific adiposity with cardiovascular risk. PMID- 25301980 TI - Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. AB - Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14(hi) TIMP-3(lo) rabbit foam cells are more invasive and more prone to apoptosis than MMP-14(lo) TIMP-3(hi) cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP 3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction. PMID- 25301982 TI - THERMAL DOSE REQUIREMENT FOR TISSUE EFFECT: EXPERIMENTAL AND CLINICAL FINDINGS. AB - In this review we have summarized the basic principles that govern the relationships between thermal exposure (Temperature and time of exposure) and thermal damage, with an emphasis on normal tissue effects. We have also attempted to identify specific thermal dose information (for safety and injury) for a variety of tissues in a variety of species. We address the use, accuracy and difficulty of conversion of an individual time and temperature (thermal doses) to a standardized value (eg equivalent minutes at 43 degrees C) for comparison of thermal treatments. Although, the conversion algorithm appears to work well within a range of moderately elevated temperatures (2-15 deg C) above normal physiologic baseline (37-39 deg C) there is concern that conversion accuracy does not hold up for temperatures which are minimally or significantly above baseline. An extensive review of the literature suggests a comprehensive assessment of the "thermal does-to-tissue effect" has not previously been assembled for most individual tissues and never been viewed in a semi-comprehensive (tissues and species) manner. Finally, we have addressed the relationship of thermal does-to effect vs. baseline temperature. This issues is important since much of the thermal dose-to-effect information has been accrued in animal models with baseline temperatures 1-2 deg higher than that of humans. PMID- 25301983 TI - Synthesis and heating effect of iron/iron oxide composite and iron oxide nanoparticles. AB - Fe/Fe oxide nanoparticles, in which the core consists of metallic Fe and the shell is composed of Fe oxides, were obtained by reduction of an aqueous solution of FeCl3 within a NaBH4 solution, or, using a water-in-oil micro-emulsion with CTAB as the surfactant. The reduction was performed either in an inert atmosphere or in air, and passivation with air was performed to produce the Fe/Fe3O4 core/shell composite. Phase identification and particle size were determined by X ray diffraction and TEM. Thermal analysis was performed using a differential scanning calorimeter. The quasistatic magnetic properties were measured using a VSM, and the specific absorption rates (SARs) of both Fe oxide and Fe/Fe3O4 composite nanoparticles either dispersed in methanol or in an epoxy resin were measured by Luxtron fiber temperature sensors in an alternating magnetic field of 150 Oe at 250 kHz. It was found that the preparation conditions, including the concentrations of solutions, the mixing procedure and the heat treatment, influence the particle size, the crystal structure and consequently the magnetic properties of the particles. Compared with Fe oxides, the saturation magnetization (MS ) of Fe/Fe3O4 particles (100-190 emu/g) can be twice as high, and the coercivity (HC ) can be tunable from several Oe to several hundred Oe. Hence, the SAR of Fe/Fe3O4 composite nanoparticles can be much higher than that of Fe oxides, with a maximum SAR of 345 W/g. The heating behavior is related to the magnetic behavior of the nanoparticles. PMID- 25301984 TI - In-Vitro Investigations of Nanoparticle Magnetic Thermotherapy: Adjuvant Effects and Comparison to Conventional Heating. AB - Thermotherapy, particularly magnetic nanoparticle hyperthermia, is a promising modality both as a direct cancer cell killing and as a radiosensitization technique for adjuvant therapy. Dextran-coated iron oxide nanoparticles were mixed with multiple tumor cell lines in solution and exposed to varying magnetic field regimes and combined with traditional external radiotherapy. Heating of cell lines by water bath in temperature patterns comparable to those achieved by nanoparticle hyperthermia was conducted to assess the relative value of nano magnetic thermotherapy compared with conventional bulk heating techniques and data. PMID- 25301985 TI - Intratumoral Iron Oxide Nanoparticle Hyperthermia and Radiation Cancer Treatment. AB - : The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model. METHODS: MTG-B murine breast cancer cells (1 * 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/- 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period. RESULTS: Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle hyperthermia is more effective than nonnanoparticle tumor heating techniques when similar thermal doses are applied. Initial electron and light microscopy studies of iron oxide nanoparticle and AMF exposed tumor cells show a rapid uptake of particles and acute cytotoxicity following AMF exposure. PMID- 25301986 TI - Computer aided classification of cell nuclei in the gastrointestinal tract by volume and principal axis. AB - Normal function of the gastrointestinal tract involves the coordinated activity of several cell types Human disorders of motor function of the gastrointestinal tract are often associated with changes in the number of these cells. For example, in diabetic patients, abnormalities in gastrointestinal transit are associated with changes in nerves and interstitial cells of Cajal (ICC), two key cells that generate and regulate motility. ICC are cells of mesenchymal origin that function as pacemakers and amplify neuronal signals in the gastrointestinal tract. Quantifying the changes in number of specific cell types in tissues from patients with motility disorders is challenging and requires immunolabeling for specific antigens. The shape of nuclei differs between the cell types in the wall of the gastrointestinal tract. Therefore the objective of this study was to determine whether cell nuclei can be classified by analyzing the 3D morphology of the nuclei. Furthermore, the orientation of the long axis of nuclei changes within and between the muscle layers. These features can be used to classify and differentially label the nuclei in confocal volume images of the tissue by computing the principal axis of the coordinates of the set of voxels forming each nucleus and thereby to identify cells by their nuclear morphology. Using this approach, we were able to separate and quantify nuclei in the smooth muscle layers of the tissue. Therefore we conclude that computer-aided classification of cell nuclei can be used to identify changes in the cell types expressed in gastrointestinal smooth muscle. PMID- 25301987 TI - Comparison of Iron Oxide Nanoparticle and Waterbath Hyperthermia Cytotoxicity. AB - The development of medical grade iron oxide nanoparticles (IONP) has renewed interest in hyperthermia cancer therapy. Because of their modifiable size and heating capabilities under an AC magnetic field (alternating magnetic field, AMF), IONPs have the potential to damage or kill cells in a manner more therapeutically efficient than previous hyperthermia techniques. The use of IONPs in hyperthermia cancer therapy has prompted numerous questions regarding the cytotoxic mechanism associated with IONP heat therapy and if such mechanism is different (more or less effective) with respect to conventional hyperthermia techniques. PMID- 25301988 TI - An in vivo transmission electron microscopy study of injected dextran-coated iron oxide nanoparticle location in murine breast adenocarcinoma tumors versus time. AB - : Investigators are just beginning to use hyperthermia generated by alternating magnetic field (AMF) activated iron oxide nanoparticles (IONPs) as a promising avenue for targeted cancer therapy. An important step in understanding cell death mechanisms in nanoparticle AMF treatments is to determine the location of these nanoparticles in relation to cellular organelles. In this paper, we report on transmission electron microscopy (TEM) studies designed to define the position of 100 nm diameter dextran-coated iron oxide nanoparticles in murine breast adenocarcinoma (MTG-B)and human colon adenocarcinoma tumors propagated in mice. METHODS: Iron oxide nanoparticles (5 mg/g tumor) were injected into intradermal MTG-B flank tumors on female C3H/HEJ mice and into HT-29 flank tumors on female Nu/Nu mice. The IONPs were allowed to incubate for various times. The tumors were then excised and examined using TEM. RESULTS: In the MTG-B tumors, most of the nanoparticles reside in aggregates adjacent to cell plasma membranes prior to three hours post-injection. By four hours post injection, however, most of the nanoparticles have been endocytosed by the cells. At time periods after four hours post injection, few visible extracellular nanoparticles remain and intracellular nanoparticles have densely aggregated within endosomes. In the HT 29 tumor, however, endocytosis of nanoparticles has not progressed to the same extent as in the MTG-B tumors by four hours post injection. CONCLUSIONS: The time at which most of the nanoparticles transition from being extracellular to intracellular in the MTG-B system appears to be between two and four hours. The HT-29 cells, however, display different and delayed uptake pattern. These data show that there are IONP uptake differences between tumor types (cell lines) and that, based on known uptake kinetics, nanoparticle hyperthermia can be employed as an extracellular or intracellular modality. These data will be important in guiding future nanoparticle hyperthermia cancer treatments. PMID- 25301989 TI - Integrating Structural and Functional Imaging for Computer Assisted Detection of Prostate Cancer on Multi-Protocol In Vivo 3 Tesla MRI. AB - Screening and detection of prostate cancer (CaP) currently lacks an image-based protocol which is reflected in the high false negative rates currently associated with blinded sextant biopsies. Multi-protocol magnetic resonance imaging (MRI) offers high resolution functional and structural data about internal body structures (such as the prostate). In this paper we present a novel comprehensive computer-aided scheme for CaP detection from high resolution in vivo multi protocol MRI by integrating functional and structural information obtained via dynamic-contrast enhanced (DCE) and T2-weighted (T2-w) MRI, respectively. Our scheme is fully-automated and comprises (a) prostate segmentation, (b) multimodal image registration, and (c) data representation and multi-classifier modules for information fusion. Following prostate boundary segmentation via an improved active shape model, the DCE/T2-w protocols and the T2-w/ex vivo histological prostatectomy specimens are brought into alignment via a deformable, multi attribute registration scheme. T2-w/histology alignment allows for the mapping of true CaP extent onto the in vivo MRI, which is used for training and evaluation of a multi-protocol MRI CaP classifier. The meta-classifier used is a random forest constructed by bagging multiple decision tree classifiers, each trained individually on T2-w structural, textural and DCE functional attributes. 3-fold classifier cross validation was performed using a set of 18 images derived from 6 patient datasets on a per-pixel basis. Our results show that the results of CaP detection obtained from integration of T2-w structural textural data and DCE functional data (area under the ROC curve of 0.815) significantly outperforms detection based on either of the individual modalities (0.704 (T2-w) and 0.682 (DCE)). It was also found that a meta-classifier trained directly on integrated T2-w and DCE data (data-level integration) significantly outperformed a decision level meta-classifier, constructed by combining the classifier outputs from the individual T2-w and DCE channels. PMID- 25301990 TI - 3D registration of micro-PET-CT for measurable correlates of dyspeptic symptoms in mice. AB - Patients with chronic calorie insufficiency commonly suffer from upper gastrointestinal dysfunction and consequent dyspeptic symptoms, which may interfere with their nutritional rehabilitation. To investigate the relationship between gastric dysfunction and feeding behavior, we exposed mice to chronic caloric restriction and demonstrated gastric motor abnormalities in them. Gastric dysmotility is typically associated with dyspeptic symptoms but sensations cannot be directly assessed in animal models. Therefore, as an initial step toward establishing measurable correlates of postprandial symptoms in small animals, we have attempted to characterize central responses to food intake by positron emission tomography-computerized microtomography (PET-CT) in normal and calorically restricted mice. Animals consumed a standard test meal after an overnight fast before receiving 2-deoxy-2[18F]fluoro-D-glucose tracer. The same mice were also scanned in the fasting state on a separate day. We were able to bring the fed and fasting PET volume images into spatial registration with each other and with an MR-derived atlas of the mouse brain, so that the differences in uptake between the two states could be mapped quantitatively against the neuroanatomic regions of the atlas. Our approach is suitable for studying the effects of gastric dysmotilities on central responses to feeding. PMID- 25301991 TI - Enhanced Multi-Protocol Analysis via Intelligent Supervised Embedding (EMPrAvISE): Detecting Prostate Cancer on Multi-Parametric MRI. AB - Currently, there is significant interest in developing methods for quantitative integration of multi-parametric (structural, functional) imaging data with the objective of building automated meta-classifiers to improve disease detection, diagnosis, and prognosis. Such techniques are required to address the differences in dimensionalities and scales of individual protocols, while deriving an integrated multi-parametric data representation which best captures all disease pertinent information available. In this paper, we present a scheme called Enhanced Multi-Protocol Analysis via Intelligent Supervised Embedding (EMPrAvISE); a powerful, generalizable framework applicable to a variety of domains for multi-parametric data representation and fusion. Our scheme utilizes an ensemble of embeddings (via dimensionality reduction, DR); thereby exploiting the variance amongst multiple uncorrelated embeddings in a manner similar to ensemble classifier schemes (e.g. Bagging, Boosting). We apply this framework to the problem of prostate cancer (CaP) detection on 12 3 Tesla pre-operative in vivo multi-parametric (T2-weighted, Dynamic Contrast Enhanced, and Diffusion weighted) magnetic resonance imaging (MRI) studies, in turn comprising a total of 39 2D planar MR images. We first align the different imaging protocols via automated image registration, followed by quantification of image attributes from individual protocols. Multiple embeddings are generated from the resultant high dimensional feature space which are then combined intelligently to yield a single stable solution. Our scheme is employed in conjunction with graph embedding (for DR) and probabilistic boosting trees (PBTs) to detect CaP on multi-parametric MRI. Finally, a probabilistic pairwise Markov Random Field algorithm is used to apply spatial constraints to the result of the PBT classifier, yielding a per voxel classification of CaP presence. Per-voxel evaluation of detection results against ground truth for CaP extent on MRI (obtained by spatially registering pre operative MRI with available whole-mount histological specimens) reveals that EMPrAvISE yields a statistically significant improvement (AUC=0.77) over classifiers constructed from individual protocols (AUC=0.62, 0.62, 0.65, for T2w, DCE, DWI respectively) as well as one trained using multi-parametric feature concatenation (AUC=0.67). PMID- 25301992 TI - Nanoparticles in Medicine: Selected Observations and Experimental Caveats. AB - Medically useful nanoparticles measure 1-100 nm in at least one dimension and are engineered and manufactured for specific diagnostic and treatment applications. Most nanoparticles used currently used in medicine are engineered and manufactured for specific purposes. Medically significant nanoparticles are composed of a 1) central core that is usually the medically active component, 2) one or more layers of organic or inorganic materials that forms a capsule (corona) covering the core and 3) an outer surface layer that interacts with the environment and/or targeted cells and tissues. Effective nanoparticle function in the living, intact animal or human requires electrochemical stability necessary to bypass the reticuloendothelial system (RES) and avoid filtration through the renal glomerulus into the urine. Nanoparticles are present in "natural" as well as the manufacturing and clinical environments thus could pose as significant toxins because of their small sizes, their chemical and drug content and potential effect of causing long term disease including allergies, chronic inflammation and cancer. Currently published studies have focused on the effects of nanoparticles on cells in the extremely artificial environments of cell cultures. More clinical and preclinical studies documenting the short term and long term effects nanoparticle in the intact experimental animal and human are needed. PMID- 25301993 TI - Magnetic nanoparticle hyperthermia: Predictive model for temperature distribution. AB - Magnetic nanoparticle (mNP) hyperthermia is a promising adjuvant cancer therapy. mNP's are delivered intravenously or directly into a tumor, and excited by applying an alternating magnetic field (AMF). The mNP's are, in many cases, sequestered by cells and packed into endosomes. The proximity of the mNP's has a strong influence on their ability to heat due to inter-particle magnetic interaction effects. This is an important point to take into account when modeling the mNP's. Generally, more mNP heating can be achieved using higher magnetic field strengths. The factor which limits the maximum field strength applied to clinically relevant volumes of tissue is the heating caused by eddy currents, which are induced in the noncancerous tissue. A coupled electromagnetic and thermal model has been developed to predict dynamic thermal distributions during AMF treatment. The EM model is based on the method of auxiliary sources and the thermal modeling is based on the Pennes bioheat equation. The results of our phantom study are used to validate the model which takes into account nanoparticle heating, interaction effects, particle spatial distribution, particle size distribution, EM field distribution, and eddy current generation in a controlled environment. Preliminary in vivo data for model validation are also presented. Once fully developed and validated, the model will have applications in experimental design, AMF coil design, and treatment planning. PMID- 25301994 TI - Oxygen microenvironment affects the uptake of nanoparticles in head and neck tumor cells. AB - Survival of head and neck cancer patients has not improved in several decades despite advances in diagnostic and therapeutic techniques. Tumor hypoxia in head and neck cancers is a critical factor that leads to poor prognosis, resistance to radiation and chemotherapies, and increased metastatic potential. Magnetic nanoparticle hyperthermia (mNPHT) is a promising therapy for hypoxic tumors because nanoparticles (NP) can be directly injected into, or targeted to, hypoxic tumor cells and exposed to alternating magnetic fields (AMF) to induce hyperthermia. Magnetic NPHT can improve therapeutic effectiveness by two modes of action: 1) direct killing of hypoxic tumor cells; and 2) increase in tumor oxygenation, which has the potential to make the tumor more susceptible to adjuvant therapies such as radiation and chemotherapy. Prior studies in breast cancer cells demonstrated that a hypoxic microenvironment diminished NP uptake in vitro; however, mNPHT with intratumoral NP injection in hypoxic tumors increased tumor oxygenation and delayed tumor growth. In this study, head and neck squamous cell carcinoma (HNSCC) cell lines were incubated in normoxic, hypoxic, and hyperoxic conditions with iron oxide NP for 4-72 hours. After incubation, the cells were analyzed for iron uptake by mass spectrometry, Prussian blue staining, and electron microscopy. In contrast to breast cancer cells, uptake of NPs was increased in hypoxic microenvironments as compared to normoxic conditions in HNSCC cells. In future studies, we will confirm the effect of the oxygen microenvironment on NP uptake and efficacy of mNPHT both in vitro and in vivo. PMID- 25301995 TI - Biodistribution of antibody-targeted and non-targeted iron oxide nanoparticles in a breast cancer mouse model. AB - Iron oxide nanoparticle (IONP) hyperthermia is a novel therapeutic strategy currently under consideration for the treatment of various cancer types. Systemic delivery of IONP followed by non-invasive activation via a local alternating magnetic field (AMF) results in site-specific energy deposition in the IONP containing tumor. Targeting IONP to the tumor using an antibody or antibody fragment conjugated to the surface may enhance the intratumoral deposition of IONP and is currently being pursued by many nanoparticle researchers. This strategy, however, is subject to a variety of restrictions in the in vivo environment, where other aspects of IONP design will strongly influence the biodistribution. In these studies, various targeted IONP are compared to non targeted controls. IONP were injected into BT-474 tumor-bearing NSG mice and tissues harvested 24hrs post-injection. Results indicate no significant difference between the various targeted IONP and the non-targeted controls, suggesting the IONP were prohibitively-sized to incur tumor penetration. Additional strategies are currently being pursued in conjuncture with targeted particles to increase the intratumoral deposition. PMID- 25301996 TI - Improved delivery of magnetic nanoparticles with chemotherapy cancer treatment. AB - Most nanoparticle-based cancer therapeutic strategies seek to develop an effective individual cancer cell or metastatic tumor treatment. Critical to the success of these therapies is to direct as much of the agent as possible to the targeted tissue while avoiding unacceptable normal tissue complications. In this light, three different cisplatinum/magnetic nanoparticle (mNP) administration regimens were investigated. The most important finding suggests that clinically relevant doses of cisplatinum result in a significant increase in the tumor uptake of systemically delivered mNP. This enhancement of mNP tumor uptake creates the potential for an even greater therapeutic ratio through the addition of mNP based, intracellular hyperthermia. PMID- 25301997 TI - Biodistribution and imaging of fluorescently-tagged iron oxide nanoparticles in a breast cancer mouse model. AB - Iron oxide nanoparticle (IONP) hyperthermia is an emerging treatment that shows great potential as a cancer therapy both alone and in synergy with conventional modalities. Pre-clinical studies are attempting to elucidate the mechanisms of action and distributions of IONP in various in vitro and in vivo models, however these studies would greatly benefit from real-time imaging of IONP locations both in cellular and in mammalian systems. To this end, fluorescently-tagged IONP (fIONP) have been employed for real time tracking and co-registration of IONP with iron content. Starch-coated IONP were fluorescently-tagged, purified and analyzed for fluorescent signal at various concentrations. fIONP were incubated with MTGB cells for varying times and cellular uptake analyzed using confocal microscopy, flow cytometry and inductively-coupled plasma mass spectrometry (ICP MS). fIONP were also injected into a bilateral mouse tumor model for radiation modification of tumor tissue and enhanced fIONP deposition assessed using a Xenogen IVIS fluorescent imager. Results demonstrated that fIONP concentrations in vitro correlated with ICPMS iron readings. fIONP could be tracked in vitro as well as in tissue samples from an in vivo model. Future work will employ whole animal fluorescent imaging to track the biodistribution of fIONP over time. PMID- 25301998 TI - Iron oxide nanoparticle enhancement of radiation cytotoxicity. AB - Iron oxide nanoparticles (IONPs) have been investigated as a promising means for inducing tumor cell-specific hyperthermia. Although the ability to generate and use nanoparticles that are biocompatible, tumor specific, and have the ability to produce adequate cytotoxic heat is very promising, significant preclinical and clinical development will be required for clinical efficacy. At this time it appears using IONP-induced hyperthermia as an adjunct to conventional cancer therapeutics, rather than as an independent treatment, will provide the initial IONP clinical treatment. Due to their high-Z characteristics, another option is to use intracellular IONPs to enhance radiation therapy without excitation with AMF (production of heat). To test this concept IONPs were added to cell culture media at a concentration of 0.2 mg Fe/mL and incubated with murine breast adenocarcinoma (MTG-B) cells for either 48 or 72 hours. Extracellular iron was then removed and all cells were irradiated at 4 Gy. Although samples incubated with IONPs for 48 hrs did not demonstrate enhanced post-irradiation cytotoxicity as compared to the non-IONP-containing cells, cells incubated with IONPs for 72 hours, which contained 40% more Fe than 48 hr incubated cells, showed a 25% decrease in clonogenic survival compared to their non-IONP-containing counterparts. These results suggest that a critical concentration of intracellular IONPs is necessary for enhancing radiation cytotoxicity. PMID- 25301999 TI - Detector system comparison using relative CNR for specific imaging tasks related to neuro-endovascular image-guided interventions (neuro-EIGIs). AB - Neuro-EIGIs require visualization of very small endovascular devices and small vessels. A Microangiographic Fluoroscope (MAF) x-ray detector was developed to improve on the standard flat panel detector's (FPD's) ability to visualize small objects during neuro-EIGIs. To compare the performance of FPD and MAF imaging systems, specific imaging tasks related to those encountered during neuro-EIGIs were used to assess contrast to noise ratio (CNR) of different objects. A bar phantom and a stent were placed at a fixed distance from the x-ray focal spot to mimic a clinical imaging geometry and both objects were imaged by each detector system. Imaging was done without anti-scatter grids and using the same conditions for each system including: the same x-ray beam quality, collimator position, source to imager distance (SID), and source to object distance (SOD). For each object, relative contrasts were found for both imaging systems using the peak and trough signals. The relative noise was found using mean background signal and background noise for varying detector exposures. Next, the CNRs were found for these values for each object imaged and for each imaging system used. A relative CNR metric is defined and used to compare detector imaging performance. The MAF utilizes a temporal filter to reduce the overall image noise. The effects of using this filter with the MAF while imaging the clinical object's CNRs are reported. The relative CNR for the detectors demonstrated that the MAF has superior CNRs for most objects and exposures investigated for this specific imaging task. PMID- 25302000 TI - Scatter reduction for high resolution image detectors with a region of interest attenuator. AB - Compton scatter is the main interaction of x-rays with objects undergoing radiographic and fluoroscopic imaging procedures. Such scatter is responsible for reducing image signal to noise ratio which can negatively impact object detection especially for low contrast objects. To reduce scatter, possible methods are smaller fields-of-view, larger air gaps and the use of an anti-scatter grid. Smaller fields of view may not be acceptable and scanned-beam radiography is not practical for real-time imaging. Air gaps can increase geometric unsharpness and thus degrade image resolution. Deployment of an anti-scatter grid is not well suited for high resolution imagers due to the unavailability of high line density grids needed to prevent grid-line artifacts. However, region of interest (ROI) imaging can be used not only for dose reduction but also for scatter reduction in the ROI. The ROI region receives unattenuated x-rays while the peripheral region receives x-rays reduced in intensity by an ROI attenuator. The scatter within the ROI part of the image originates from both the unattenuated ROI and the attenuated peripheral region. The scatter contribution from the periphery is reduced in intensity because of the reduced primary x-rays in that region and the scatter fraction in the ROI is thus reduced. In this study, the scatter fraction for various kVp's, air-gaps and field sizes was measured for a uniform head equivalent phantom. The scatter fraction in the ROI was calculated using a derived scatter fraction formula, which was validated with experimental measurements. It is shown that use of a ROI attenuator can be an effective way to reduce both scatter and patient dose while maintaining the superior image quality of high resolution detectors. PMID- 25302001 TI - A novel Region of Interest (ROI) imaging technique for biplane imaging in interventional suites: high-resolution small field-of-view imaging in the frontal plane and dose-reduced, large field-of-view standard-resolution imaging in the lateral plane. AB - Endovascular-Image-Guided-Interventional (EIGI) treatment of neuro-vascular conditions such as aneurysms, stenosed arteries, and vessel thrombosis make use of treatment devices such as stents, coils, and balloons which have very small feature sizes, 10's of microns to a few 100's of microns, and hence demand a high resolution imaging system. The current state-of-the-art flat panel detector (FPD) has about a 200-um pixel size with the Nyquist of 2.5 lp/mm. For higher resolution imaging a charge-coupled device (CCD) based Micro-Angio -Fluoroscope (MAF-CCD) with a pixel size of 35um (Nyquist of 11 lp/mm) was developed and previously reported. Although the detector addresses the high resolution needs, the Field-Of-View (FOV) is limited to 3.5 cm * 3.5 cm, which is much smaller than current FPDs. During the use of the MAF-CCD for delicate parts of the intervention, it may be desirable to have real-time monitoring outside the MAF FOV with a low dose, and lower, but acceptable, quality image. To address this need, a novel imaging technique for biplane imaging systems has been developed, using an MAF-CCD in the frontal plane and a dose-reduced standard large FOV imager in the lateral plane. The dose reduction is achieved by using a combination of ROI fluoroscopy and spatially different temporal filtering, a technique that has been previously presented. In order to evaluate this technique, a simulation using images acquired during an actual EIGI treatment on a patient, followed by an actual implementation on phantoms is presented. PMID- 25302002 TI - Relative object detectability (ROD): a new metric for comparing x-ray image detector performance for a specified object of interest. AB - Relative object detectability (ROD) quantifies the relative performance of two image detectors for a specified object of interest by taking the following ratio: the integral of detective quantum efficiency of a detector weighted by the frequency spectrum of the object divided by that for a second detector. Four different detectors, namely the micro-angiographic fluoroscope (MAF), the Dexela Model 1207 (Dex) and Hamamatsu Model C10901D-40 (Ham) CMOS x-ray detectors, and a flat-panel detector (FPD) were compared. The ROD was calculated for six pairs of detectors: (1) Dex/FPD, (2) MAF/FPD, (3) Ham/FPD, (4) Dex/Ham, (5) MAF/Ham and (6) MAF/Dex for wires of 5 mm fixed length, solid spheres ranging in diameter from 50 to 600 microns, and four simulated iodine-filled blood vessels of outer diameters 0.4 and 0.5 mm, each with wall thicknesses of 0.1 and 0.15 mm. Marked variation of ROD for the wires and spheres is demonstrated as a function of object size for the various detector pairs. The ROD of all other detectors relative to the FPD was much greater than one for small features and approached 1.0 as the diameter increased. The relative detectability of simulated small iodine-filled blood vessels for all detector pairs was seen to be independent of the vessel wall thickness for the same inner diameter. In this study, the ROD is shown to have the potential to be a useful figure of merit to evaluate the relative performance of two detectors for a given imaging task. PMID- 25302003 TI - Workflow for the use of a high-resolution image detector in endovascular interventional procedures. AB - Endovascular image-guided intervention (EIGI) has become the primary interventional therapy for the most widespread vascular diseases. These procedures involve the insertion of a catheter into the femoral artery, which is then threaded under fluoroscopic guidance to the site of the pathology to be treated. Flat Panel Detectors (FPDs) are normally used for EIGIs; however, once the catheter is guided to the pathological site, high-resolution imaging capabilities can be used for accurately guiding a successful endovascular treatment. The Micro-Angiographic Fluoroscope (MAF) detector provides needed high resolution, high-sensitivity, and real-time imaging capabilities. An experimental MAF enabled with a Control, Acquisition, Processing, Image Display and Storage (CAPIDS) system was installed and aligned on a detector changer attached to the C arm of a clinical angiographic unit. The CAPIDS system was developed and implemented using LabVIEW software and provides a user-friendly interface that enables control of several clinical radiographic imaging modes of the MAF including: fluoroscopy, roadmap, radiography, and digital-subtraction-angiography (DSA). Using the automatic controls, the MAF detector can be moved to the deployed position, in front of a standard FPD, whenever higher resolution is needed during angiographic or interventional vascular imaging procedures. To minimize any possible negative impact to image guidance with the two detector systems, it is essential to have a well-designed workflow that enables smooth deployment of the MAF at critical stages of clinical procedures. For the ultimate success of this new imaging capability, a clear understanding of the workflow design is essential. This presentation provides a detailed description and demonstration of such a workflow design. PMID- 25302004 TI - Focal spot measurements using a digital flat panel detector. AB - Focal spot size is one of the crucial factors that affect the image quality of any x-ray imaging system. It is, therefore, important to measure the focal spot size accurately. In the past, pinhole and slit measurements of x-ray focal spots were obtained using direct exposure film. At present, digital detectors are replacing film in medical imaging so that, although focal spot measurements can be made quickly with such detectors, one must be careful to account for the generally poorer spatial resolution of the detector and the limited usable magnification. For this study, the focal spots of a diagnostic x-ray tube were measured with a 10-MUm pinhole using a 194-MUm pixel flat panel detector (FPD). The two-dimensional MTF, measured with the Noise Response (NR) Method was used for the correction for the detector blurring. The resulting focal spot sizes based on the FWTM (Full Width at Tenth Maxima) were compared with those obtained with a very high resolution detector with 8-MUm pixels. This study demonstrates the possible effect of detector blurring on the focal spot size measurements with digital detectors with poor resolution and the improvement obtained by deconvolution. Additionally, using the NR method for measuring the two dimensional MTF, any non-isotropies in detector resolution can be accurately corrected for, enabling routine measurement of non-isotropic x-ray focal spots. This work presents a simple, accurate and quick quality assurance procedure for measurements of both digital detector properties and x-ray focal spot size and distribution in modern x-ray imaging systems. PMID- 25302005 TI - MRI Brain Tumor Segmentation and Necrosis Detection Using Adaptive Sobolev Snakes. AB - Brain tumor segmentation in brain MRI volumes is used in neurosurgical planning and illness staging. It is important to explore the tumor shape and necrosis regions at different points of time to evaluate the disease progression. We propose an algorithm for semi-automatic tumor segmentation and necrosis detection. Our algorithm consists of three parts: conversion of MRI volume to a probability space based on the on-line learned model, tumor probability density estimation, and adaptive segmentation in the probability space. We use manually selected acceptance and rejection classes on a single MRI slice to learn the background and foreground statistical models. Then, we propagate this model to all MRI slices to compute the most probable regions of the tumor. Anisotropic 3D diffusion is used to estimate the probability density. Finally, the estimated density is segmented by the Sobolev active contour (snake) algorithm to select smoothed regions of the maximum tumor probability. The segmentation approach is robust to noise and not very sensitive to the manual initialization in the volumes tested. Also, it is appropriate for low contrast imagery. The irregular necrosis regions are detected by using the outliers of the probability distribution inside the segmented region. The necrosis regions of small width are removed due to a high probability of noisy measurements. The MRI volume segmentation results obtained by our algorithm are very similar to expert manual segmentation. PMID- 25302006 TI - A Framework for Joint Image-and-Shape Analysis. AB - Techniques in medical image analysis are many times used for the comparison or regression on the intensities of images. In general, the domain of the image is a given Cartesian grids. Shape analysis, on the other hand, studies the similarities and differences among spatial objects of arbitrary geometry and topology. Usually, there is no function defined on the domain of shapes. Recently, there has been a growing needs for defining and analyzing functions defined on the shape space, and a coupled analysis on both the shapes and the functions defined on them. Following this direction, in this work we present a coupled analysis for both images and shapes. As a result, the statistically significant discrepancies in both the image intensities as well as on the underlying shapes are detected. The method is applied on both brain images for the schizophrenia and heart images for atrial fibrillation patients. PMID- 25302008 TI - Interpolation of Longitudinal Shape and Image Data via Optimal Mass Transport. AB - Longitudinal analysis of medical imaging data has become central to the study of many disorders. Unfortunately, various constraints (study design, patient availability, technological limitations) restrict the acquisition of data to only a few time points, limiting the study of continuous disease/treatment progression. Having the ability to produce a sensible time interpolation of the data can lead to improved analysis, such as intuitive visualizations of anatomical changes, or the creation of more samples to improve statistical analysis. In this work, we model interpolation of medical image data, in particular shape data, using the theory of optimal mass transport (OMT), which can construct a continuous transition from two time points while preserving "mass" (e.g., image intensity, shape volume) during the transition. The theory even allows a short extrapolation in time and may help predict short-term treatment impact or disease progression on anatomical structure. We apply the proposed method to the hippocampus-amygdala complex in schizophrenia, the heart in atrial fibrillation, and full head MR images in traumatic brain injury. PMID- 25302007 TI - Improved Statistical Power with a Sparse Shape Model in Detecting an Aging Effect in the Hippocampus and Amygdala. AB - The sparse regression framework has been widely used in medical image processing and analysis. However, it has been rarely used in anatomical studies. We present a sparse shape modeling framework using the Laplace-Beltrami (LB) eigenfunctions of the underlying shape and show its improvement of statistical power. Traditionally, the LB-eigenfunctions are used as a basis for intrinsically representing surface shapes as a form of Fourier descriptors. To reduce high frequency noise, only the first few terms are used in the expansion and higher frequency terms are simply thrown away. However, some lower frequency terms may not necessarily contribute significantly in reconstructing the surfaces. Motivated by this idea, we present a LB-based method to filter out only the significant eigenfunctions by imposing a sparse penalty. For dense anatomical data such as deformation fields on a surface mesh, the sparse regression behaves like a smoothing process, which will reduce the error of incorrectly detecting false negatives. Hence the statistical power improves. The sparse shape model is then applied in investigating the influence of age on amygdala and hippocampus shapes in the normal population. The advantage of the LB sparse framework is demonstrated by showing the increased statistical power. PMID- 25302009 TI - Reconstruction and Feature Selection for Desorption Electrospray Ionization Mass Spectroscopy Imagery. AB - Desorption electrospray ionization mass spectrometry (DESI-MS) provides a highly sensitive imaging technique for differentiating normal and cancerous tissue at the molecular level. This can be very useful, especially under intra-operative conditions where the surgeon has to make crucial decision about the tumor boundary. In such situations, the time it takes for imaging and data analysis becomes a critical factor. Therefore, in this work we utilize compressive sensing to perform the sparse sampling of the tissue, which halves the scanning time. Furthermore, sparse feature selection is performed, which not only reduces the dimension of data from about 104 to less than 50, and thus significantly shortens the analysis time. This procedure also identifies biochemically important molecules for pathological analysis. The methods are validated on brain and breast tumor data sets. PMID- 25302010 TI - Effect of injection technique on temporal parametric imaging derived from digital subtraction angiography in patient specific phantoms. AB - Parametric imaging maps (PIM's) derived from digital subtraction angiography (DSA) for the cerebral arterial flow assessment in clinical settings have been proposed, but experiments have yet to determine the reliability of such studies. For this study, we have observed the effects of different injection techniques on PIM's. A flow circuit set to physiologic conditions was created using an internal carotid artery phantom. PIM's were derived for two catheter positions, two different contrast bolus injection volumes (5ml and 10 ml), and four injection rates (5, 10, 15 and 20 ml/s). Using a gamma variate fitting approach, we derived PIM's for mean-transit-time (MTT), time-to-peak (TTP) and bolus-arrivaltime (BAT). For the same injection rates, a larger bolus resulted in an increased MTT and TTP, while a faster injection rate resulted in a shorter MTT, TTP, and BAT. In addition, the position of the catheter tip within the vasculature directly affected the PIM. The experiment showed that the PIM is strongly correlated with the injection conditions, and, therefore, they have to be interpreted with caution. PIM images must be taken from the same patient to be able to be meaningfully compared. These comparisons can include pre- and post-treatment images taken immediately before and after an interventional procedure or simultaneous arterial flow comparisons through the left and right cerebral hemispheres. Due to the strong correlation between PIM and injection conditions, this study indicates that this assessment method should be used only to compare flow changes before and after treatment within the same patient using the same injection conditions. PMID- 25302011 TI - An improved estimator of Variance Explained in the presence of noise. AB - A crucial part of developing mathematical models of information processing in the brain is the quantification of their success. One of the most widely-used metrics yields the percentage of the variance in the data that is explained by the model. Unfortunately, this metric is biased due to the intrinsic variability in the data. We derive a simple analytical modification of the traditional formula that significantly improves its accuracy (as measured by bias) with similar or better precision (as measured by mean-square error) in estimating the true underlying Variance Explained by the model class. Our estimator advances on previous work by a) accounting for overfitting due to free model parameters mitigating the need for a separate validation data set, b) adjusting for the uncertainty in the noise estimate and c) adding a conditioning term. We apply our new estimator to binocular disparity tuning curves of a set of macaque V1 neurons and find that on a population level almost all of the variance unexplained by Gabor functions is attributable to noise. PMID- 25302012 TI - Fundus autofluorescence features in the inflammatory maculopathies. AB - PURPOSE: To describe the fundus autofluorescence (FAF) features of the inflammatory maculopathies and develop a quantification method for FAF analysis. METHODS: This is a retrospective, consecutive case series of patients with inflammatory maculopathies from two tertiary centers. The clinical findings, demographics, and FAF imaging characteristics were reviewed. Foveal autofluorescence (AF) was analyzed. Median and standard deviation (SD) of foveal AF intensity were measured. RESULTS: Thirty eyes of 15 patients were evaluated with both qualitative and quantitative FAF analysis. In acute macular neuroretinopathy, the active phase showed foveal hypoautofluorescence, which became hypoautofluorescent with resolution. In acute posterior multifocal placoid pigment epitheliopathy, multiple lesions with hypoautofluorescent centers with hyperautofluorescent borders were observed in active disease and became hypoautofluorescent with disease convalescence. In multifocal choroiditis and punctate inner choroiditis, the active hyperautofluorescent lesions progressed to inactive, hypoautofluorescent scars. Active serpiginous choroiditis showed hyperautofluorescent borders adjacent to a helicoid-shaped, hypoautofluorescent scar. Active unilateral acute idiopathic maculopathy (UAIM) showed a complex pattern of hypo- and hyperautoflourescence in the macula. The median foveal AF was the greatest in acute macular neuroretinopathy and UAIM among the maculopathies, while the greatest SD of foveal AF intensity was observed in UAIM. CONCLUSION: The active phase of the majority of inflammatory maculopathies was characterized by hyperautofluorescent lesions. Increased SD of foveal AF correlated with a mixture of hypo-and hyperautoflourescence. Median and SD may be useful metrics in foveal AF and quantifiable values that may be assessed over time as a disease process evolves. Improvements in quantification methods of FAF imaging may allow us to objectively evaluate posterior uveitis. PMID- 25302013 TI - Survey of Japanese ophthalmic surgeons regarding perioperative disinfection and antibiotic prophylaxis in cataract surgery. AB - PURPOSE: To elucidate Japanese trends for perioperative disinfection and antibiotic selection during cataract surgeries. METHODS: Perioperative iodine use and antibiotic prophylaxis for cataract surgery were surveyed in eight regions in Japan by mail or through interviews from February 1 to March 1, 2014. RESULTS: We surveyed 572 surgeons, of whom 386 (67%) responded. Most of the surgeons (94%) used iodine compounds before surgery for periocular skin disinfection (povidone iodine [PI]: 79%; polyvinyl alcohol-iodine [PAI]: 15%) or conjunctival disinfection (85%; PI: 36%; PAI: 49%). Preoperative conjunctival iodine was primarily used as an eye wash (irrigation: 95%) and less often as an eye drop (5%). It was determined that 31% of surgeons waited 30 seconds or more between periocular disinfection and conjunctival disinfection. During surgery, 14% of surgeons used iodine several times, including immediately before intraocular lens insertion, and 7% used the Shimada technique (repeated iodine irrigation). Preoperative antibiotic eye drops were used by 99% of surgeons, and antibiotics were added to the irrigation bottle by 22%. The surgeons reported use of subconjunctival antibiotic injections (23%), antibiotic ointments (79%), and intracameral antibiotics (7%: 22 moxifloxacin; 6 levofloxacin). All surgeons prescribed postoperative eye drops, with 10% initiating the drops on the day of surgery. CONCLUSION: Iodine compounds are commonly used preoperatively, but few institutions use iodine compounds intraoperatively, particularly with repeated application. The selection of antibiotic administration and disinfection technique has to be at the surgeon's discretion. However, intracameral antibiotic and intraoperative iodine compound use are techniques that should be widely recognized. PMID- 25302014 TI - Cross-sectional and longitudinal analysis of cancer vaccination trials registered on the US Clinical Trials Database demonstrates paucity of immunological trial endpoints and decline in registration since 2008. AB - INTRODUCTION: Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical trial methodology used. This study aims to characterize the tumor vaccine clinical trial landscape quantitatively, and explore the possible validity of the offered explanations including the translational obstacles posed by the current common endpoints. METHODS: We performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database. RESULTS: The number of tumor vaccine trials initiated per annum has declined 30% since a peak in 2008. In terms of vaccine formulation, 25% of trials use tumor cell/lysate preparations; whereas, 73% of trials vaccinate subjects against defined protein/peptide antigens. Also, 68% of trials do not use vectors for antigen delivery. Both these characteristics of tumor vaccines have remained unchanged since 1996. The top five types of cancer studied are: melanoma (22.6%); cervical cancer (13.0%); breast cancer (11.3%); lung cancer (9.5%); and prostate cancer (9.4%). In addition, 86% of the trials are performed where there is established disease rather than prophylactically, of which 67% are performed exclusively in the adjuvant setting. Also, 42% of Phase II trials do not measure any survival-related endpoint, and only 23% of Phase III trials assess the immune response to vaccination. CONCLUSION: The clinical trial effort in tumor vaccination is declining, necessitating a greater urgency in identifying and removing the obstacles to clinical translation. These obstacles may include: 1) vaccination against a small range of antigens; 2) naked delivery of antigen; 3) investigation of less immunogenic cancer types; and 4) investigation in the setting of established disease. In addition, the prevalence of late phase failure may be due to inadequate assessment of survival-related endpoints in Phase II trials. The clinical trial development of tumor vaccines should include mechanism based translational endpoints, as well as the discovery of immune biomarkers with which to stratify, monitor, and prognosticate patients. PMID- 25302016 TI - Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects. AB - BACKGROUND: KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection. OBJECTIVE: This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects. MATERIALS AND METHODS: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: The average maximum concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUCinfinity) values of KM 023 for the 75-600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng . h/mL to 33,705.6 ng . h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng . h/mL to 10,232.6 ng . h/mL, respectively, following 75-600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events. CONCLUSION: KM-023 demonstrated dose- and time dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75-600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection. PMID- 25302015 TI - EGFR mutations as a prognostic and predictive marker in non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) has entered the age of individual treatment, and increasing point mutations of specific oncogenes and rearrangement of some chromosomes are biomarkers used to predict the therapeutic effect of targeted therapy. At present, there is a consensus among clinicians that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown favorable efficacy in NSCLC patients with EGFR mutation, and some relevant research has suggested that the presence of EGFR mutations is a favorable prognostic marker. However, the association of EGFR mutation status with the responsiveness to conventional chemotherapy agents and survival in NSCLC patients is still unclear. This review provides an overview of and assesses the role of EGFR as a prognostic marker for postoperative patients and as a predictive marker for response to cytotoxic chemotherapy. In addition, we review the comparison of response to chemotherapy between EGFR mutations in exon 19 and in exon 21 and the predictive role of p.T790M mutation. PMID- 25302017 TI - Buccal acetaminophen provides fast analgesia: two randomized clinical trials in healthy volunteers. AB - BACKGROUND: Acetaminophen (APAP) by oral or intravenous (iv) routes is used for mild to moderate pain but may take time to be effective. When fast relief is required and/or oral or iv routes are not available because of the patient's condition, the transmucosal route may be an alternative. METHODOLOGY: A new transmucosal/buccal (b) pharmaceutical form of APAP dissolved in 50% wt alcohol is compared with other routes of administration. Two consecutive randomized, crossover, double-blind clinical trials (CT1: NCT00982215 and CT2: NCT01206985) included 16 healthy volunteers. CT1 compared the pharmacology of 250 mg bAPAP with 1 g iv APAP. CT2 compared the pharmacodynamics of 125 mg bAPAP with 1 g iv and 125 mg sublingual (s) APAP. Mechanical pain thresholds are recorded in response to mechanical stimuli applied on the forearm several times during 120 minutes. The objective is to compare the time of onset of antinociception and the antinociception (area under the curve) between the routes of administration with analysis of variance (significance P<0.05). RESULTS: bAPAP has a faster time of antinociception onset (15 minutes, P<0.01) and greater antinociception at 50 minutes (P<0.01, CT1) and 30 minutes (P<0.01, CT2) than ivAPAP and sAPAP. All routes are similar after 50 minutes. CONCLUSION: bAPAP has a faster antinociceptive action in healthy volunteers. This attractive alternative to other routes would be useful in situations where oral or iv routes are not available. This finding must now be confirmed in patients suffering from acute pain of mild and moderate intensity. PMID- 25302019 TI - Anticancer, antioxidant activities, and DNA affinity of novel monocationic bithiophenes and analogues. AB - A series of 15 monocationic bithiophenes and isosteres were prepared and subjected to in vitro antiproliferative screening using the full National Cancer Institute (NCI)-60 cell line panel, representing nine types of cancer. Among the nine types of cancer involved in a five-dose screen, non-small cell lung and breast cancer cell lines were the most responsive to the antiproliferative effect of the tested compounds, especially cell lines A549/ATCC, NCI-H322M, and NCI H460, whereas compounds 1a, 1c, 1d, and 7 exhibited potent activity, with GI50 values (drug concentration that causes 50% inhibition of cell growth) from less than 10 nM to 102 nM. In addition, compounds 1c and 1d gave GI50 values of 73 nM and 79 nM, respectively, against the MDA-MB-468 breast cancer cell line. Structure-activity relationship findings indicated that the mononitriles were far less active than their corresponding monoamidines and, within the amidines series, the bioisosteric replacement of a thiophene ring by a furan led to a reduction in antiproliferative activity. Also, molecular manipulations, involving substitution on the phenyl ring, or its replacement by a pyridyl, or alteration of the position of the amidine group, led to significant alteration in antiproliferative activity. On the other hand, DNA studies demonstrated that these monoamidine bichalcophenes have promising ability to cleave the genomic DNA. These monoamidines show a wide range of DNA affinities, as judged from their DNA cleavage effect, which are remarkably sensitive to all kinds of structural modifications. Finally, the novel bichalcophenes were tested for their antioxidant property by the ABTS (2,2'-azino- bis(3-ethylbenzthiazoline-6 sulfonic acid) diammonium salt) assay, as well as lipid and nitric oxide scavenging techniques, and were found to exhibit good-to-potent antioxidant abilities. PMID- 25302018 TI - alpha-Mangostin from Cratoxylum arborescens demonstrates apoptogenesis in MCF-7 with regulation of NF-kappaB and Hsp70 protein modulation in vitro, and tumor reduction in vivo. AB - Cratoxylum arborescens is an equatorial plant belonging to the family Guttiferae. In the current study, alpha-Mangostin (AM) was isolated and its cell death mechanism was studied. HCS was undertaken to detect the nuclear condensation, mitochondrial membrane potential, cell permeability, and the release of cytochrome c. An investigation for reactive oxygen species formation was conducted using fluorescent analysis. To determine the mechanism of cell death, human apoptosis proteome profiler assay was conducted. In addition, using immunofluorescence and immunoblotting, the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma (Bcl)-2 proteins were also tested. Caspaces such as 3/7, 8, and 9 were assessed during treatment. Using HCS and Western blot, the contribution of nuclear factor kappa-B (NF-kappaB) was investigated. AM had showed a selective cytotoxicity toward the cancer cells with no toxicity toward the normal cells even at 30 MUg/mL, thereby indicating that AM has the attributes to induce cell death in tumor cells. The treatment of MCF-7 cells with AM prompted apoptosis with cell death-transducing signals. This regulated the mitochondrial membrane potential by down-regulation of Bcl-2 and up-regulation of Bax, thereby causing the release of cytochrome c from the mitochondria into the cytosol. The liberation of cytochrome c activated caspace-9, which, in turn, activated the downstream executioner caspace-3/7 with the cleaved poly (ADP ribose) polymerase protein, thereby leading to apoptotic alterations. Increase of caspace 8 had showed the involvement of an extrinsic pathway. This type of apoptosis was suggested to occur through both extrinsic and intrinsic pathways and prevention of translocation of NF-kappaB from the cytoplasm to the nucleus. Our results revealed AM prompt apoptosis of MCF-7 cells through NF-kappaB, Bax/Bcl-2 and heat shock protein 70 modulation with the contribution of caspaces. Moreover, ingestion of AM at (30 and 60 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that AM is a potentially useful agent for the treatment of breast cancer. PMID- 25302020 TI - An optimized probucol microencapsulated formulation integrating a secondary bile acid (deoxycholic acid) as a permeation enhancer. AB - The authors have previously designed, developed, and characterized a novel microencapsulated formulation as a platform for the targeted delivery of therapeutics in an animal model of type 2 diabetes, using the drug probucol (PB). The aim of this study was to optimize PB microcapsules by incorporating the bile acid deoxycholic acid (DCA), which has good permeation-enhancing properties, and to examine its effect on microcapsules' morphology, rheology, structural and surface characteristics, and excipients' chemical and thermal compatibilities. Microencapsulation was carried out using a BUCHI-based microencapsulating system established in the authors' laboratory. Using the polymer sodium alginate (SA), two microencapsulated formulations were prepared: PB-SA (control) and PB-DCA-SA (test) at a constant ratio (1:30 and 1:3:30, respectively). Complete characterization of the microcapsules was carried out. The incorporation of DCA resulted in better structural and surface characteristics, uniform morphology, and stable chemical and thermal profiles, while size and rheological parameters remained similar to control. In addition, PB-DCA-SA microcapsules showed good excipients' compatibilities, which were supported by data from differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray studies, suggesting microcapsule stability. Hence, PB-DCA-SA microcapsules have good rheological and compatibility characteristics and may be suitable for the oral delivery of PB in type 2 diabetes. PMID- 25302021 TI - Patient preferences and perspectives regarding reducing alcohol consumption: role of nalmefene. AB - Alcohol use disorder is a major public health issue. The absolute mortality burden of alcohol-attributable death has increased over the last 20 years. However, access to care remains very poor and many people with alcohol use disorder are untreated. The main limiting factor for access to care in alcohol use disorder appears to be the reluctance to engage in abstinence. Risk reduction is a developing approach in the treatment of alcohol use disorders, drawing its inspiration, with quite a delay, from the decades-long dominant approach in other substance use disorders. A paradigm shift has recently occurred that places more of an emphasis on reducing alcohol as a therapeutic strategy for patients with alcohol use disorder, to better meet the patients' preferences and needs. The development and recent approval of nalmefene, in alcohol-dependent adults with a high drinking risk level, contributes to enlarging the therapeutic arsenal for alcohol dependence, strengthening the legitimacy of alcohol reduction strategies. PMID- 25302022 TI - Optimal management of elderly cancer patients: usefulness of the Comprehensive Geriatric Assessment. AB - BACKGROUND: Cancer is common in older patients, who raise specific treatment challenges due to aging-related, organ-specific physiologic changes and the presence in most cases of comorbidities capable of affecting treatment tolerance and outcomes. Identifying comorbid conditions and physiologic changes due to aging allows oncologists to better assess the risk/benefit ratio and to adjust the treatment accordingly. Conducting a Comprehensive Geriatric Assessment (CGA) is one approach developed for this purpose. We reviewed the evidence on the usefulness of CGA for assessing health problems and predicting cancer treatment outcomes, functional decline, morbidity, and mortality in older patients with solid malignancies. METHODS: We searched Medline for articles published in English between January 1, 2000 and April 14, 2014, and reporting prospective observational or interventional studies of CGA feasibility or effectiveness in patients aged >=65 years with solid malignancies. We identified studies with at least 100 patients, a multivariate analysis, and assessments of at least five of the following CGA domains: nutrition, cognition, mood, functional status, mobility and falls, polypharmacy, comorbidities, and social environment. RESULTS: All types of CGA identified a large number of unrecognized health problems capable of interfering with cancer treatment. CGA results influenced 21%-49% of treatment decisions. All CGA domains were associated with chemotoxicity or survival in at least one study. The abnormalities that most often predicted mortality and chemotoxicity were functional impairment, malnutrition, and comorbidities. CONCLUSION: The CGA uncovers numerous health problems in elderly patients with cancer and can affect treatment decisions. Functional impairment, malnutrition, and comorbidities are independently associated with chemotoxicity and/or survival. Only three randomized published studies evaluated the effectiveness of CGA-linked interventions. Further research into the effectiveness of the CGA in improving patient outcomes is needed. PMID- 25302023 TI - Enhancement of osseointegration of polyethylene terephthalate artificial ligament by coating of silk fibroin and depositing of hydroxyapatite. AB - BACKGROUND: Application of artificial ligament in anterior cruciate ligament reconstruction is one of the research focuses of sports medicine but the biological tendon-bone healing still remains a problem. The preliminary study of hydroxyapatite (HAP) coating on the polyethylene terephthalate (PET) surface could effectively induce the osteoblast differentiation, but the tendon-bone healing was still not stable. As a green synthesis process, the biomimetic mineralization can simulate the natural bone growth in vitro and in vivo. METHODS: HAP crystals were grown under the guide of silk fibroin (SF) PET surface by biomimetic route. Several techniques including scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy were utilized for proving the introduction of both SF and HAP. The viability and osseointegration of bone marrow stromal cells on the surface of three kinds of ligament, including PET group (non-coating group), PET+SF group (SF-coating group), and PET+SF+HAP group (combined HAP- and SF-coating group), were analyzed by CCK-8 assays and alkaline phosphatase (ALP) detection. Seventy-two mature male New Zealand rabbits were randomly divided into three groups. Among them, 36 rabbits were sacrificed for mechanical testing, and histological examination for the others. RESULTS: The SF and SF+HAP were successfully coated on the surface of PET fiber. The CCK-8 assay showed that the cell proliferation on PET+SF+HAP group was better than the other two groups from 24 to 120 hours. After 14 days of culture, the cells in the PET+SF+HAP group delivered higher levels of ALP than the other two groups. After 3 days of culture, the expression level of integrin beta1 in the PET+SF+HAP group and PET+SF group were higher than in the PET group. The mean load to failure and the stiffness value of the PET+SF+HAP group were both higher than the other two groups. Hematoxylin and eosin staining showed that new bone tissue formation was only found in the PET+SF+HAP group 8 weeks postoperatively. Masson staining showed that in the PET+SF+HAP group 8 weeks postoperatively, the PET fibers were almost completely encircled by collagen. Histomorphometric analysis showed that the width of the graft-bone interface in the PET+SF+HAP group was narrower than that in the other two groups 4 and 8 weeks postoperatively. The mRNA level of BMP 7 in the PET+SF+HAP groups was significantly higher than those in the other two groups 4 and 8 weeks postoperatively. CONCLUSION: The study showed that the combined SF and HAP coating by biomimetic route on the surface of PET artificial ligament could induce graft osseointegration in the bone tunnel, providing theoretical and experimental foundation for manufacturing novel artificial ligaments meeting the clinical needs. PMID- 25302024 TI - A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo. AB - Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents. PMID- 25302025 TI - Capecitabine-induced cardiotoxicity: more evidence or clinical approaches to protect the patients' heart? AB - Fluoropyrimidines, such as capecitabine and 5-fluorouracil, may cause cardiac toxicity. In recent years, the incidence of this side effect has increased and it is expected to further rise due to the population aging and the disproportionate incidence of breast and gastrointestinal cancers in older individuals. The spectrum of cardiac manifestations includes different signs and symptoms and the diagnosis may be difficult. Here, we report the case of a 43-year-old woman with advanced breast cancer who was rechallenged with a capecitabine-based regimen after experiencing a cardiac adverse event during the first fluoropyrimidine exposure. This real-practice case serves as a springboard for discussion about the current evidence on differential diagnosis of capecitabine-related cardiac toxicity, its risk factors, and the underpinning mechanisms of early onset. Moreover, we discussed whether a rechallenge with fluoropyrimidines could be safe in patients who had experienced a previous cardiac adverse event. PMID- 25302026 TI - An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. AB - Proteasome inhibition represents one of the more important therapeutic targets in the treatment of multiple myeloma (MM), since by suppressing nuclear factor kappaB activity, which promotes myelomagenesis, it makes plasma cells susceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor approved for MM therapy, has been shown to increase response rate and improve outcome in patients with relapsed/refractory disease and in the frontline setting, particularly when combined with immunomodulatory drugs and alkylating agents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM. Ixazomib has shown improved pharmacokinetic and pharmacodynamic parameters compared with bortezomib, in addition to similar efficacy in the control of myeloma growth and prevention of bone loss. Ixazomib was found to overcome bortezomib resistance and to trigger synergistic antimyeloma activity with dexamethasone, lenalidomide, and histone deacetylase inhibitors. Phase I/II studies using ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested antitumor activity of the single agent, but more promising results have been obtained with the combination of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a single agent, showing important activity in this difficult-to-treat plasma-cell dyscrasia. More frequent side effects observed during administration of ixazomib were thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas severe peripheral neuropathy was rare. Here, we review the chemical characteristics of ixazomib, as well as its mechanism of action and results from preclinical and clinical trials. PMID- 25302028 TI - Screening mammography: the turning of the tide? PMID- 25302027 TI - Potential of eye movement desensitization and reprocessing therapy in the treatment of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) continues to attract both empirical and clinical interest due to its complex symptom profile and the underlying processes involved. Recently, research attention has been focused on the types of memory processes involved in PTSD and hypothesized neurobiological processes. Complicating this exploration, and the treatment of PTSD, are underlying comorbid disorders, such as depression, anxiety, and substance use disorders. Treatment of PTSD has undergone further reviews with the introduction of eye movement desensitization and reprocessing (EMDR). EMDR has been empirically demonstrated to be as efficacious as other specific PTSD treatments, such as trauma-focused cognitive behavioral therapy. There is emerging evidence that there are different processes underlying these two types of trauma treatment and some evidence that EMDR might have an efficiency advantage. Current research and understanding regarding the processes of EMDR and the future direction of EMDR is presented. PMID- 25302029 TI - re: Reflections on screening mammography and the early detection of breast cancer. PMID- 25302030 TI - Impact of screening mammography on mortality from breast cancer before age 60 in women 40 to 49 years of age. AB - BACKGROUND: Whether screening mammography programs should include women in their 40s is controversial. In Canada, screening of women aged 40-49 years has not been shown to reduce mortality from breast cancer. Given that screening mammography reduces mean tumour size and that tumour size is inversely associated with survival, the lack of benefit seen with screening is puzzling and suggests a possible adverse effect on mortality of mammography or subsequent treatment (or both) that counterbalances the expected benefit derived from downstaging. METHODS: We followed 50,436 women 40-49 years of age until age 60 for mortality from breast cancer. Of those women, one half had been randomly assigned to annual mammography and one half to no mammography. The impact of mammography on breast cancer mortality was estimated using a left-censored Cox proportional hazards model. RESULTS: Of 256 deaths from breast cancer recorded in the study cohort, 134 occurred in women allocated to mammography, and 122 occurred in those receiving usual care and not allocated to mammography. The cumulative risk of death from breast cancer to age 60 was 0.53% for women assigned to mammography and 0.48% for women not so assigned. The hazard ratio for breast cancer-specific death associated with 1 or more screening mammograms before age 50 was 1.10 (95% confidence interval: 0.86 to 1.40). CONCLUSIONS: Mammography in women 40-49 years of age is associated with a small but nonsignificant increase in the risk of dying of breast cancer before age 60. Caution should be exercised when recommending mammographic screening to women before age 50. PMID- 25302031 TI - Implementing a regional oncology information system: approach and lessons learned. AB - RATIONALE: Paper-based medical record systems are known to have major problems of inaccuracy, incomplete data, poor accessibility, and challenges to patient confidentiality. They are also an inefficient mechanism of record-sharing for interdisciplinary patient assessment and management, and represent a major problem for keeping current and monitoring quality control to facilitate improvement. To address those concerns, national, regional, and local health care authorities have increased the pressure on oncology practices to upgrade from paper-based systems to electronic health records. OBJECTIVES: Here, we describe and discuss the challenges to implementing a region-wide oncology information system across four independent health care organizations, and we describe the lessons learned from the initial phases that are now being applied in subsequent activities of this complex project. RESULTS: The need for change must be shared across centres to increase buy-in, adoption, and implementation. It is essential to establish physician leadership, commitment, and engagement in the process. Work processes had to be revised to optimize use of the new system. Culture change must be included in the change management strategy. Furthermore, training and resource requirements must be thoroughly planned, implemented, monitored, and modified as required for effective adoption of new work processes and technology. Interfaces must be established with multiple existing electronic systems across the region to ensure appropriate patient flow. Periodic assessment of the existing project structure is necessary, and adjustments are often required to ensure that the project meets its objectives. CONCLUSIONS: The implementation of region-wide oncology information systems across different health practice locations has many challenges. Leadership is essential. A strong, collaborative information-sharing strategy across the region and with the supplier is essential to identify, discuss, and resolve implementation problems. A structure that supports project management and accountability contributes to success. PMID- 25302032 TI - A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. AB - The use of all-trans-retinoic acid (atra) and anthracyclines (with or without cytarabine) in the treatment of acute promyelocytic leukemia (apl) has dramatically changed the management and outcome of the disease over the past few decades. The addition of arsenic trioxide (ato) in the relapsed setting-and, more recently, in reduced-chemotherapy or chemotherapy-free approaches in the first line setting-continues to improve treatment outcomes by reducing some of the toxicities associated with anthracycline-based approaches. Despite those successes, a high rate of early death from complications of coagulopathy remains the primary cause of treatment failure before treatment begins. In addition to that pressing issue, clarity is needed about the use of ato in the first-line setting and the role of hematopoietic stem-cell transplantation (hsct) in the relapsed setting. The aim for the present consensus was to provide guidance to health care professionals about strategies to reduce the early death rate, information on the indications for hsct and on the use of ato in induction and consolidation in low-to-intermediate-risk and high-risk apl patients. PMID- 25302034 TI - Meaningful patient representation informing Canada's cancer drug funding decisions: views of patient representatives on the Pan-Canadian Oncology Drug Review. AB - In this interview with the patient representatives on the Expert Review Committee (perc) of the Pan-Canadian Oncology Drug Review (pcodr), those representatives offer their views about how to be a valuable contributing member of Canada's national cancer drug funding recommendation committee. The article seeks to inform readers, and especially clinicians, about pcodr from the perspective of the patient representatives. PMID- 25302033 TI - Recommendations for the referral of patients for proton-beam therapy, an Alberta Health Services report: a model for Canada? AB - BACKGROUND: Compared with photon therapy, proton-beam therapy (pbt) offers compelling advantages in physical dose distribution. Worldwide, gantry-based proton facilities are increasing in number, but no such facilities exist in Canada. To access pbt, Canadian patients must travel abroad for treatment at high cost. In the face of limited access, this report seeks to provide recommendations for the selection of patients most likely to benefit from pbt and suggests an out of-country referral process. METHODS: The medline, embase, PubMed, and Cochrane databases were systematically searched for studies published between January 1990 and May 2014 that evaluated clinical outcomes after pbt. A draft report developed through a review of evidence was externally reviewed and then approved by the Alberta Health Services Cancer Care Proton Therapy Guidelines steering committee. RESULTS: Proton therapy is often used to treat tumours close to radiosensitive tissues and to treat children at risk of developing significant late effects of radiation therapy (rt). In uncontrolled and retrospective studies, local control rates with pbt appear similar to, or in some cases higher than, photon rt. Randomized trials comparing equivalent doses of pbt and photon rt are not available. SUMMARY: Referral for pbt is recommended for patients who are being treated with curative intent and with an expectation for long-term survival, and who are able and willing to travel abroad to a proton facility. Commonly accepted indications for referral include chordoma and chondrosarcoma, intraocular melanoma, and solid tumours in children and adolescents who have the greatest risk for long-term sequelae. Current data do not provide sufficient evidence to recommend routine referral of patients with most head-and-neck, breast, lung, gastrointestinal tract, and pelvic cancers, including prostate cancer. It is recommended that all referrals be considered by a multidisciplinary team to select appropriate cases. PMID- 25302036 TI - Health care, health caring, and the culture of medicine. PMID- 25302035 TI - Design and implementation of a community-based exercise program for breast cancer patients. AB - Research has indicated that exercise is critical in the recovery process for breast cancer patients, and yet this evidence has infrequently been translated into sustainable community programming. The present article describes the processes and operations of beauty (the Breast Cancer Patients Engaging in Activity and Undergoing Treatment program). This evidence-based 12-week exercise program, with an optional 12-week maintenance component, is supported by the Wings of Hope Foundation, allowing the program to be delivered at no cost to participants. The program was designed to restore and improve the physical well being of women living with breast cancer as they undergo chemotherapy or radiation treatments. Evaluations measure safety and adherence to the program and the effects of the program on physiologic and psychological outcomes and quality of life. The beauty program addresses the gap between the level of evidence for the benefits of exercise after a cancer diagnosis and translation of that evidence into community programming by providing an accessible, individualized, and safe physical activity program for women during treatment for breast cancer. PMID- 25302037 TI - Breast and cervical cancer screening behaviours among colorectal cancer survivors in Nova Scotia. AB - PURPOSE: We analyzed patterns and factors associated with receipt of breast and cervical cancer screening in a cohort of colorectal cancer survivors. METHODS: Individuals diagnosed with colorectal cancer in Nova Scotia between January 2001 and December 2005 were eligible for inclusion. Receipt of breast and cervical cancer screening was determined using administrative data. General-population age restrictions were used in the analysis (breast: 40-69 years; cervical: 21-75 years). Kaplan-Meier and Cox proportional hazards models were used to assess time to first screen. RESULTS: Of 318 and 443 colorectal cancer survivors eligible for the breast and cervical cancer screening analysis respectively, 30.1% [95% confidence interval (ci): 21.2% to 39.0%] never received screening mammography, and 47.9% (95% ci: 37.8% to 58.0%) never received cervical cancer screening during the study period. Receipt of screening before the colorectal cancer diagnosis was strongly associated with receipt of screening after diagnosis (hazard ratio for breast cancer screening: 4.71; 95% ci: 3.42 to 6.51; hazard ratio for cervical cancer screening: 6.83; 95% ci: 4.58 to 10.16). CONCLUSIONS: Many colorectal cancer survivors within general-population screening age recommendations did not receive breast and cervical cancer screening. Future research should focus on survivors who meet age recommendations for population based cancer screening. PMID- 25302038 TI - Clinical analysis of osteosarcoma patients treated with high-dose methotrexate free neoadjuvant chemotherapy. AB - OBJECTIVE: High-dose methotrexate (hdmtx) is a common therapeutic agent in the treatment of osteosarcoma. However, hdmtx is highly toxic and requires complex pharmacokinetic monitoring and leucovorin rescue. Thus, alternative therapeutic strategies are necessary. Here, we analyzed the clinical efficacy of a dia regimen (cisplatin-ifosfamide-doxorubicin) to evaluate its potential as an alternative to hdmtx-based therapy. METHODS: Patients received 12 cycles of chemotherapy administered over 2 years (2 preoperative cycles and 10 postoperative cycles). Cumulative dose was the same in all cycles: cisplatin 120 mg/m(2) on day 1 of week 1, followed by ifosfamide 2.0 g/m(2) days 1-5 of week 2, and doxorubicin 20 mg/m(2) days 1-3 of week 2. RESULTS: Between January 2004 and October 2008, 39 eligible patients (median age: 16 years) were enrolled, with 36 being evaluable for the study. Of those 36 patients, 20 (55.6%) had a good histologic response to preoperative chemotherapy (>90% tumour necrosis). The estimated 5-year rates of event-free survival (efs) and overall survival were 54.8% and 61.5% respectively. CONCLUSIONS: The results of our study suggest that, in osteosarcoma patients, the dia regimen produces an efs rate and survival outcomes comparable to those attained with hdmtx-containing regimens, with fewer adverse reactions. The dia regimen is well tolerated, and we observed a high level of patient compliance. Our results demonstrate that hdmtx-free osteosarcoma treatment regimens can be effective, warranting further investigation. PMID- 25302039 TI - Risk factors for locoregional recurrence after postmastectomy radiotherapy in breast cancer patients with four or more positive axillary lymph nodes. AB - BACKGROUND: We investigated risk factors for locoregional recurrence (lrr) in breast cancer patients with 4 or more positive axillary lymph nodes receiving postmastectomy radiotherapy (pmrt). METHODS: Medical records (1998-2007) were retrospectively reviewed for the population of interest. The Kaplan-Meier method was used to calculate the survival rate; Cox regression models were used for univariate and multivariate analysis of predictors of breast cancer lrr. RESULTS: The study enrolled 439 patients. Median duration of follow-up was 54 months. The 5-year rates of locoregional recurrence-free survival (lrrfs), distant metastasis free survival (dmfs), and breast cancer-specific survival (bcss) were 87.8%, 59.5%, and 70.7% respectively. In patients with lrr and no concomitant metastasis, and in those without lrr, the 5-year rates of dmfs were 21.1% and 65.7% respectively (p < 0.001), and the 5-year rates of bcss were 34.5% and 76.4% respectively (p < 0.001). Univariate analysis showed that menopausal status (p = 0.041), pN stage (p = 0.006), and positivity for her2 [human epidermal growth factor receptor 2 (p = 0.003)] or the triple-negative disease subtype (p < 0.001) were determinants of lrrfs. Multivariate analysis showed that pN3 stage [hazard ratio (hr): 2.241; 95% confidence interval (ci): 1.270 to 3.957; p = 0.005], her2 positivity (hr: 2.705; 95% ci: 1.371 to 5.335; p = 0.004), and triple-negative disease subtype (hr: 4.617; 95% ci: 2.192 to 9.723; p < 0.001) were independent prognostic factors of lrrfs. CONCLUSIONS: In breast cancer patients with 4 or more positive axillary lymph nodes who undergo pmrt for breast cancer, lrr significantly influences survival. Patients who developed lrr carried a high risk for distant metastasis and death. Pathologic stage (pN3), her2 positivity, and the triple-negative disease subtype are risk factors that significantly influence lrrfs. PMID- 25302040 TI - Update on taxanes in the first-line treatment of advanced non-small-cell lung cancer. AB - Based on demonstrated favourable risk-benefit profiles, taxanes remain a key component in the first-line standard of care for advanced non-small-cell lung cancer (nsclc) and nsclc subtypes. In 2012, a novel taxane, nab-paclitaxel (Abraxane: Celgene Corporation, Summit, NJ, U.S.A.), was approved, in combination with carboplatin, for the first-line treatment of locally advanced or meta-static nsclc. The approval was granted because of demonstrated improved antitumour activity and tolerability compared with solvent-based paclitaxel-carboplatin in a phase iii trial. This review focuses on the evolution of first-line taxane therapy for advanced nsclc and the new options and advances in taxane therapy that might address unmet needs in advanced nsclc. PMID- 25302041 TI - Health care delivery for head-and-neck cancer patients in Alberta: a practice guideline. AB - BACKGROUND: The treatment of head-and-neck cancer is complex and requires the involvement of various health care professionals with a wide range of expertise. We describe the process of developing a practice guideline with recommendations about the organization and delivery of health care services for head-and-neck cancer patients in Alberta. METHODS: Outcomes of interest included composition of the health care team, qualification requirements for team members, cancer centre and team member volumes, infrastructure needs, and wait times. A search for existing practice guidelines and a systematic review of the literature addressing the organization and delivery of health care services for head-and-neck cancer patients were conducted. The search included the Standards and Guidelines Evidence (sage) directory of cancer guidelines and PubMed. RESULTS: One practice guideline was identified for adaptation. Three additional practice guidelines provided supplementary evidence to inform guideline recommendations. Members of the Alberta Provincial Head and Neck Tumour Team (consisting of various health professionals from across the province) provided expert feedback on the adapted recommendations through an online and in-person review process. Selected experts in head-and-neck cancer from outside the province participated in an external online review. SUMMARY: The recommendations outlined in this practice guideline are based on existing guidelines that have been modified to fit the Alberta context. Although specific to Alberta, the recommendations lend credence to similar published guidelines and could be considered for use by groups lacking the resources of appointed guideline panels. The recommendations are meant to be a guide rather than a fixed protocol. The implementation of this practice guideline will depend on many factors, including but not limited to availability of trained personnel, adequate funding of infrastructure, and collaboration with other associations of health care professionals in the province. PMID- 25302042 TI - Population-based utilization of radiation therapy by a Canadian breast cancer cohort. AB - We examined trends in radiation therapy (rt) utilization by a population-based breast cancer cohort in Ontario. The provincial cancer registry provided a breast cancer cohort based on diagnosis dates from April 1, 2005, to March 31, 2010. Staging information was also available. The cohort was then linked, by encrypted health card number, to linkable administrative datasets, including rt utilization. The average age in the identified female breast cancer cohort (n = 39,656) was 61.6 +/- 14.0 years. Almost two thirds of the patients (n = 25,225) received rt, and staging information was available for 22,988 patients (9541 stage i, 8516 stage ii, 4050 stage iii, and 881 stage iv). The average number of rt courses received by the patients was 1.4 +/- 0.7 for stage i, 1.8 +/- 1.1 for stage ii, 2.5 +/- 1.3 for stage iii, and 2.8 +/- 2.4 for stage iv. The ratio of conventional rt to intensity-modulated rt was 70.9%:16.6% for stage i, 71.6%:11.3% for stage ii, 74.6%:4.6% for stage iii, and 89.6%:2.2% for stage iv. From 2005 to 2010, almost two thirds of a Canadian female breast cancer cohort received rt, and the average number of courses increased with disease severity. A similar trend was observed with the type of rt (use of conventional rt increased with disease severity). The next step is to apply unit costs to the number of fractions and to obtain rt planning and radiation therapist times. PMID- 25302043 TI - Shame, guilt, and communication in lung cancer patients and their partners. AB - Lung cancer patients report the highest distress levels of all cancer groups. In addition to poor prognosis, the self-blame and stigma associated with smoking might partially account for that distress and prevent patients from requesting help and communicating with their partners. The present study used innovative methods to investigate potential links of shame and guilt in lung cancer recovery with distress and marital adjustment. A specific emphasis was an examination of the impact of shame on partner communication. Lung cancer patients (n = 8) and their partners (n = 8) completed questionnaires and interviews that were videotaped. We report descriptive statistics and Spearman correlations between shame and guilt, relationship talk, marital satisfaction, distress, and smoking status. We coded the interviews for nonverbal expressions of shame. Greater self reported shame was associated with decreased relationship-talk frequency and marital satisfaction, and with increased depression and smoking behaviour. Nonverbal shame behaviour also correlated with higher depression and increased smoking behaviour. Guilt results were more mixed. More recent smoking behaviour also correlated with higher depression. At a time when lung cancer patients often do not request help for distress, possibly because of shame, our preliminary study suggests that shame can also disrupt important partner relationships and might prevent patients from disclosing to physicians their need for psychosocial intervention and might increase their social isolation. Even if patients cannot verbally disclose their distress, nonverbal cues could potentially give clinicians an opportunity to intervene. PMID- 25302044 TI - Uncommon case of brain metastasis in a patient with a history of heavy smoking. AB - Primary sarcomas of the aorta are extremely uncommon. Depending on histomorphology and immunohistochemical pattern, intimal sarcomas can show angiosarcomatous differentiation. Here, we describe the case of a 60-year-old woman with a primary intimal sarcoma of the aortic arch and signs of cerebral metastatic disease as the initial manifestation. After the patient experienced the onset of severe headaches, ataxia, and left-sided weakness, magnetic resonance imaging showed several brain lesions. Histologic assessment of a brain biopsy specimen revealed a malignant tumour composed of large pleomorphic cells that were positive for pancytokeratin and CD10. Radiation to the brain did not significantly improve the patient's symptoms, and cranial computed tomography (ct) imaging revealed several metastases, indicating lack of response. Because of the patient's smoking history, the presence of central nervous system and skeletal metastases on combined positron-emission tomography and ct imaging, and the focal pan-cytokeratin positivity of the tumour, carcinoma of the lung was favoured as the primary tumour. Despite chemotherapy with cisplatin and etoposide, the patient's neurologic symptoms and general condition deteriorated rapidly, and she died within a few days. At autopsy, an undifferentiated intimal sarcoma of the aortic arch was diagnosed. The primary tumour in the aorta consisted of large pleomorphic cells. Immunohistochemical analysis of the aortic tumour and brain metastases demonstrated diffuse positivity for vimentin and p53 and focal S-100 staining. In summary, we report a challenging case of advanced intimal sarcoma of the aortic arch with brain and bone metastases at initial presentation. Our report demonstrates the difficulties in diagnosing and treating this disease, and the need for multicentre studies to accrue more patients for investigations of optimal therapy. PMID- 25302045 TI - Severe gastrointestinal hemorrhage during targeted therapy for advanced breast carcinoma. AB - The introduction of targeted agents has improved survival for patients with a number of types of cancer, including several breast cancer subtypes. However, these agents are not without toxicities, and the fact that many patients are now on targeted therapy for extended periods of time has presented new challenges for the management of adverse effects. Everolimus is an inhibitor of mtor (the mammalian target of rapamycin) that is used as targeted therapy for advanced, hormone receptor-positive, her2-negative breast cancer in postmenopausal women in combination with exemestane, after treatment failure with letrozole or anastrozole. Minor hemorrhagic events are relatively common with targeted agents, but life-threatening hemorrhages, although uncommon, can also occur. We report a case of life-threatening gastrointestinal bleeding in a 48-year-old woman being treated with everolimus for advanced infiltrating ductal carcinoma of the breast. The bleeding was successfully treated with 13 sessions of endoscopic hemostasis using argon plasma coagulation. PMID- 25302046 TI - Hyperammonemic encephalopathy in an adenocarcinoma patient managed with carglumic acid. AB - Hyperammonemic encephalopathy (he) is a rare complication of malignancy and chemotherapy. Although the cause of he is unclear, a functional arginine deficiency secondary to increased catabolism has been suggested as a possible mechanism. Either that deficiency or an undetermined metabolite could lead to inhibition of N-acetylglutamate synthase (nags), a urea cycle enzyme, resulting in hyperammonemia. We present a case of chemotherapy-induced he in a patient with no underlying primary urea cycle disorder. The patient had a successful trial of carglumic acid (a synthetic analog of the product of nags), which suggests that, at least in some cases, he can be treated by overcoming proximal inhibition of the urea cycle. Further, our case is the first in the literature to exclude genetic defects and disorders of the proximal urea cycle, suggesting that hyperammonemia in these patients is probably secondary to chemotherapy. PMID- 25302047 TI - Oxidative stress preferentially induces a subtype of micronuclei and mediates the genomic instability caused by p53 dysfunction. AB - Reactive oxygen species (ROS) are known to cause many types of DNA lesions that could be converted into cancer-promoting genetic alterations. Evidence showed that tumor suppressor p53 plays an important role in regulating the generation of cellular ROS, either by reducing oxidative stress under physiological and mildly stressed conditions, or by promoting oxidative stress under highly stressed conditions. In this report we characterized the effect of oxidative stress on the induction of micronuclei, especially the subclass marked by pan-staining of gamma H2AX or MN-gamma-H2AX (+). We found that MN-gamma-H2AX (+) were more responsive to hydrogen peroxide (H2O2) than the MN-gamma-H2AX (-). In human and mouse cells that are deficient in p53, the frequency of MN-gamma-H2AX (+) is significantly elevated, but can be attenuated by antioxidant N-acetylcysteine (NAC). Depletion of p53-regulated antioxidant gene SESN1 by RNA interference also resulted in an elevation of MN-gamma-H2AX (+). Furthermore, we found that in cells that were depleted of p400 by RNAi, and therefore were experiencing increased ROS, the frequency of MN-gamma-H2AX (+), but not that of MN-gamma-H2AX (-), was significantly induced. We further demonstrated that the induction of MN-gamma H2AX (+) by replication stress can also be attenuated by NAC, and that H2O2 also leads to increased phosphorylation of Chk1 and Rad17 that mimics replication stress, suggesting that replication stress and oxidative stress are intertwined and may reinforce each other in driving genomic instability. Our findings illustrate the importance of p53-regulated redox level in the maintenance of genomic stability. PMID- 25302048 TI - Current ventilation practice during general anaesthesia: a prospective audit in Melbourne, Australia. AB - BACKGROUND: Recent evidence suggests that the use of low tidal volume ventilation with the application of positive end-expiratory pressure (PEEP) may benefit patients at risk of respiratory complications during general anaesthesia. However current Australian practice in this area is unknown. METHODS: To describe current practice of intraoperative ventilation with regard to tidal volume and application of PEEP, we performed a multicentre audit in patients undergoing general anaesthesia across eight teaching hospitals in Melbourne, Australia. RESULTS: We obtained information including demographic characteristics, type of surgery, tidal volume and the use of PEEP in a consecutive cohort of 272 patients. The median age was 56 (IQR 42-69) years; 150 (55%) were male. Most common diagnostic groups were general surgery (31%), orthopaedic surgery (20%) and neurosurgery (9.6%). Mean FiO2 was 0.6 (IQR 0.5-0.7). Median tidal volume was 500 ml (IQR 450-550). PEEP was used in 54% of patients with a median value of 5.0 cmH2O (IQR 4.0-5.0) and median tidal volume corrected for predicted body weight was 9.5 ml/kg (IQR 8.5-10.4). Median peak inspiratory pressure was 18 cmH2O (IQR 15-22). In a cohort of patients considered at risk for respiratory complications, the median tidal volume was still 9.8 ml/kg (IQR 8.6-10.7) and PEEP was applied in 66% of patients with a median value of 5 cmH20 (IQR 4-5). On multivariate analyses positive predictors of tidal volume size included male sex (p < 0.01), height (p = 0.04) and weight (p < 0.001). Positive predictors of the use of PEEP included surgery in a tertiary hospital (OR = 3.11; 95% CI: 1.05 to 9.23) and expected prolonged duration of surgery (OR = 2.47; 95% CI: 1.04 to 5.84). CONCLUSION: In mechanically ventilated patients under general anaesthesia, tidal volume was high and PEEP was applied to the majority of patients, but at modest levels. The findings of our study suggest that the control groups of previous randomized controlled trials do not closely reflect the practice of mechanical ventilation in Australia. PMID- 25302049 TI - SNP 1772 C > T of HIF-1alpha gene associates with breast cancer risk in a Taiwanese population. AB - BACKGROUND: Hypoxia inducible factor 1alpha (HIF-1alpha) is a stress-responsive transcription factor to hypoxia and its expression is correlated to tumor progression and angiogenesis. Several single nucleotide polymorphisms (SNPs) of HIF-1alpha gene in the oxygen-dependent degradation (ODD) domain was reportedly associated with increased HIF-1alpha activity. RESULTS: In this study, we focused on the relationship between SNP 1772 C > T (rs11549465) of HIF-1alpha gene and its breast cancer risk, as well as its correlation with HIF-1alpha expression and tumor angiogenesis. Ninety six breast cancer patients and 120 age-matched controls were enrolled. We found that 1772 T allele of HIF-1alpha gene was associated with increased breast cancer risk (adjusted OR = 14.51; 95% CI: 6.74 31.24). This SNP was not associated with clinicopathologic features of angiogenesis such as VEGF activity and the micro-vessel density and survival of breast cancer patients. CONCLUSION: Taken together, the 1772 C > T of HIF-1alpha gene is a potential biomarker for breast cancer susceptibility. PMID- 25302051 TI - Can yu rid guat ay rot? A developmental investigation of cross-linguistic spelling errors among Spanish-English bilingual students. AB - This study contributes to the literature on cross-linguistic literacy relationships for English language learners, and in particular, the Spanish influenced spelling patterns of Spanish-English bilinguals. English spelling, reading and vocabulary assessments were administered to 220 students in four TWI programs over a three-year period, from 2nd grade to 4th grade. Data analysis consisted of t-tests and multiple regression. The incidence of cross-linguistic spelling errors was found to be low at all grade levels and to virtually disappear by 4th grade, indicating that this is a developmental issue that is common among bilingual students and that resolves itself without remediation. PMID- 25302050 TI - Increase of IFN-gamma and TNF-alpha production in CD107a + NK-92 cells co cultured with cervical cancer cell lines pre-treated with the HO-1 inhibitor. AB - BACKGROUND: Natural killer (NK) cells eliminate virus-infected and tumor cells through the release of perforins and granzymes; they also produce Interferon gamma (IFN-gamma) and Tumor necrosis factor alpha (TNF-alpha), which induce apoptosis in target cells. Many tumors express Heme oxygenase 1 (HO-1), and this expression has been associated with avoiding immunosuppression and apoptosis. In this work, HO-1+ Cervical cancer cell (CCC) lines were pre-treated with HO-1 inhibitor and we assessed whether this inhibition enhanced the sensitivity of CCC to NK cell activity. METHODS: We assessed the expression of HO-1 in HeLa, SiHa, and C-33A CCC by Flow cytometry (FC). CCC were pre-treated with SnPP or ZnPP HO-1 inhibitors. After that, NK-92 cells were co-cultured with HeLa, SiHa, and C-33A CCC pre-treated or not with HO-1 inhibitors, and the expression of IFN-gamma, TNF alpha, CD107a, Granzyme B, NKp44, NKp46, NKp30, and NKG2D was evaluated by FC. RESULTS: CCC lines HeLa, SiHa, and C-33A expressed HO-1. Inhibition of HO-1 in these cells increased the expression of IFN-gamma and TNF-alpha in CD107a + NK-92 cells. We observed a reduction in the expression of NKG2D, NKp46, and NKp30 in NK cells co-cultured with HeLa and SiHa cells, and when HeLa and SiHa cells were pre treated with the HO-1 inhibitors, the expression of NKG2D and NKp30 in NK cells was restored. We observed a similar effect in NK cells co-cultured with C-33A cells in NKp30 expression. CONCLUSION: Inhibition of HO-1 in CCC induces an increase in IFN-gamma and TNF-alpha production in CD107a + NK-92 cells and restores NKG2D, NKp46 and NKp30 downmodulation in NK cells. PMID- 25302052 TI - Infants' Transitions out of a Fussing/Crying State Are Modifiable and Are Related to Weight Status. AB - Currently, about 10% of infants have a weight for length greater than the 95th percentile for their age and sex, which puts them at risk for obesity as they grow. In a pilot obesity prevention study, primiparous mothers and their newborn infants were randomly assigned to a control group or a Soothe/Sleep intervention. Previously, it has been demonstrated that this intervention contributed to lower weight-for-length percentiles at 1 year; the aim of the present study was to examine infant behavior diary data collected during the intervention. Markov modeling was used to characterize infants' patterns of behavioral transitions at ages 3 and 16 weeks. Results showed that heavier mothers were more likely to follow their infants' fussing/crying episodes with a feeding. The intervention increased infants' likelihood of transitioning from a fussing/crying state to an awake/calm state. A shorter latency to feed in response to fussing/crying was associated with a higher subsequent weight status. This study provides preliminary evidence that infants' transitions out of fussing/crying are characterized by inter-individual differences, are modifiable, and are linked to weight outcomes, suggesting that they may be promising targets for early behavioral obesity interventions, and highlighting the methodology used in this study as an appropriate and innovative tool to assess the impact of such interventions. PMID- 25302053 TI - Acute effects of a commercially-available pre-workout supplement on markers of training: a double-blind study. AB - BACKGROUND: Pre-workout supplements containing numerous ingredients claim to increase performance and strength. Product-specific research is important for identifying efficacy of combined ingredients. The purpose of this study was to evaluate the effects of a proprietary pre-workout dietary supplement containing creatine monohydrate, beta-alanine, L-Tarurine, L-Leucine, and caffeine, on anaerobic power, muscular strength, body composition, and mood states. METHODS: In a double-blind, randomized, matched-pair design, twenty male subjects (mean +/ SD; 22.4 +/- 9.5 yrs, 76.9 +/- 11.2 kg, 22.7 +/- 9.5% body fat), consumed either 30 g of a pre-workout supplement (SUP) or maltodextrin placebo (PLC) 30 minutes before a resistance training workout, after completing baseline testing. Body composition was determined via dual-energy x-ray absorptiometry (DEXA). Subjects completed 12 vertical jumps for height (VJ) and one repetition maximum (1RM) and repetitions to failure lifts on bench (BPM) and leg press (LPM). Finally, subjects completed a Wingate power test on a cycle ergometer [mean power (WMP) and peak power (WPP)]. After baseline testing, participants completed eight days of supplementation and four split-body resistance-training bouts. Side effect questionnaires were completed daily 30 minutes after consuming the supplement. Subjects completed post-supplement testing on Day 8. Data were analyzed utilizing a 2 * 2 repeated measures ANOVA [treatment (PLC vs SUP) * time (T1 vs T2)] and ninety-five percent confidence intervals. RESULTS: There were no significant treatment * time interactions (p > 0.05). There were no significant changes in %body fat (%BF; ?-0.43 +/- 0.58; p = 0.920), fat mass (?-2.45 +/- 5.72; p = 0.988), or lean body mass (LBM; 10.9 +/- 12.2; p = 0.848). 95% CI demonstrated significant LBM increases for both groups. There was a main effect for time for WPP (?100.5 +/- 42.7W; p = 0.001), BPM (?8.0 +/- 12.9 lbs; p = 0.001), and LPM (?80.0 +/- 28.8 lbs; p = 0.001), with no significant differences between treatments. There was no significant difference in mood states between groups or over time. CONCLUSION: The proprietary pre-workout blend combined with eight days of training did not significantly (ANOVA) improve body composition or performance. While not significant, greater gains in LPM were demonstrated in the SUP group for lean body mass and lower body strength. Future studies should evaluate more chronic effects of proprietary pre-workout blends on total training volume and performance outcomes. PMID- 25302054 TI - Dietary supplement usage and motivation in Brazilian road runners. AB - BACKGROUND: The consumption of dietary supplements is highest among athletes and it can represent potential a health risk for consumers. OBJECTIVE: The aim of this study was to determine the prevalence of consumption of dietary supplements by road runners. METHODS: We interviewed 817 volunteers from four road races in the Brazilian running calendar. The sample consisted of 671 male and 146 female runners with a mean age of 37.9 +/- 12.4 years. RESULTS: Of the sample, 28.33% reported having used some type of dietary supplement. The main motivation for this consumption is to increase in stamina and improve performance. The probability of consuming dietary supplements increased 4.67 times when the runners were guided by coaches. The consumption of supplements was strongly correlated (r = 0.97) with weekly running distance, and also highly correlated (r = 0.86) with the number of years the sport had been practiced. The longer the runner had practiced the sport, the higher the training volume and the greater the intake of supplements. The five most frequently cited reasons for consumption were: energy enhancement (29.5%), performance improvement (17.1%), increased level of endurance (10.3%), nutrient replacement (11.1%), and avoidance of fatigue (10.3%). About 30% of the consumers declared more than one reason for taking dietary supplements. The most consumed supplements were: carbohydrates (52.17%), vitamins (28.70%), and proteins (13.48%). CONCLUSIONS: Supplement consumption by road runners in Brazil appeared to be guided by the energy boosting properties of the supplement, the influence of coaches, and the experience of the user. The amount of supplement intake seemed to be lower among road runners than for athletes of other sports. We recommend that coaches and nutritionists emphasise that a balanced diet can meet the needs of physically active people. PMID- 25302055 TI - Validity of the Rapid Eating Assessment for Patients for assessing dietary patterns in NCAA athletes. AB - BACKGROUND: Athletes may be at risk for developing adverse health outcomes due to poor eating behaviors during college. Due to the complex nature of the diet, it is difficult to include or exclude individual food items and specific food groups from the diet. Eating behaviors may better characterize the complex interactions between individual food items and specific food groups. The purpose was to examine the Rapid Eating Assessment for Patients survey (REAP) as a valid tool for analyzing eating behaviors of NCAA Division-I male and female athletes using pattern identification. Also, to investigate the relationships between derived eating behavior patterns and body mass index (BMI) and waist circumference (WC) while stratifying by sex and aesthetic nature of the sport. METHODS: Two independent samples of male (n = 86; n = 139) and female (n = 64; n = 102) collegiate athletes completed the REAP in June-August 2011 (n = 150) and June August 2012 (n = 241). Principal component analysis (PCA) determined possible factors using wave-1 athletes. Exploratory (EFA) and confirmatory factor analyses (CFA) determined factors accounting for error and confirmed model fit in wave-2 athletes. Wave-2 athletes' BMI and WC were recorded during a physical exam and sport participation determined classification in aesthetic and non-aesthetic sport. Mean differences in eating behavior pattern score were explored. Regression models examined interactions between pattern scores, participation in aesthetic or non-aesthetic sport, and BMI and waist circumference controlling for age and race. RESULTS: A 5-factor PCA solution accounting for 60.3% of sample variance determined fourteen questions for EFA and CFA. A confirmed solution revealed patterns of Desserts, Healthy food, Meats, High-fat food, and Dairy. Pattern score (mean +/- SE) differences were found, as non-aesthetic sport males had a higher (better) Dessert score than aesthetic sport males (2.16 +/- 0.07 vs. 1.93 +/- 0.11). Female aesthetic athletes had a higher score compared to non aesthetic female athletes for the Dessert (2.11 +/- 0.11 vs. 1.88 +/- 0.08), Meat (1.95 +/- 0.10 vs. 1.72 +/- 0.07), High-fat food (1.70 +/- 0.08 vs. 1.46 +/- 0.06), and Dairy (1.70 +/- 0.11 vs. 1.43 +/- 0.07) patterns. CONCLUSIONS: REAP is a construct valid tool to assess dietary patterns in college athletes. In light of varying dietary patterns, college athletes should be evaluated for healthful and unhealthful eating behaviors. PMID- 25302056 TI - Performance during a 20-km cycling time-trial after caffeine ingestion. AB - BACKGROUND: The objective of this study was to analyze the effect of caffeine ingestion on the performance and physiological variables associated with fatigue in 20-km cycling time trials. METHODS: In a double-blind placebo-controlled crossover study, 13 male cyclists (26 +/- 10 y, 71 +/- 9 kg, 176 +/- 6 cm) were randomized into 2 groups and received caffeine (CAF) capsules (6 mg.kg(-1)) or placebo (PLA) 60 min before performing 20-km time trials. Distance, speed, power, rpm, rating of perceived exertion (RPE), electromyography (EMG) of the quadriceps muscles and heart rate (HR) were continuously measured during the tests. In addition, BRUMS questionnaire was applied before and after the tests. RESULTS: Significant interactions were found in power and speed (P = 0.001), which were significantly higher at the end of the test (final 2 km) after CAF condition. A main effect of time (P = 0.001) was observed for RPE and HR, which increased linearly until the end of exercise in both conditions. The time taken to complete the test was similar in both conditions (PLA = 2191 +/- 158 s vs. CAF = 2181 +/- 194 s, P = 0.61). No significant differences between CAF and PLA conditions were identified for speed, power, rpm, RPE, EMG, HR, and BRUMS (P > 0.05). CONCLUSION: The results suggest that caffeine intake 60 min before 20-km time trials has no effect on the performance or physiological responses of cyclists. PMID- 25302057 TI - Effects of sports drinks on the maintenance of physical performance during 3 tennis matches: a randomized controlled study. AB - BACKGROUND: Tennis tournaments often involve playing several consecutive matches interspersed with short periods of recovery. OBJECTIVE: The objective of this study was firstly to assess the impact of several successive tennis matches on the physical performance of competitive players and secondly to evaluate the potential of sports drinks to minimize the fatigue induced by repeated matches. METHODS: This was a crossover, randomized controlled study. Eight male regionally ranked tennis players participated in this study. Players underwent a series of physical tests to assess their strength, speed, power and endurance following the completion of three tennis matches each of two hours duration played over three consecutive half-days (1.5 day period for each condition). In the first condition the players consumed a sports drink before, during and after each match; in the second, they drank an identical volume of placebo water. The results obtained were compared with the third 'rest' condition in which the subjects did not play any tennis. Main outcomes measured were maximal isometric strength and fatigability of knee and elbow extensors, 20-m sprint speed, jumping height, specific repeated sprint ability test and hand grip strength. RESULTS: The physical test results for the lower limbs showed no significant differences between the three conditions. Conversely, on the upper limbs the EMG data showed greater fatigue of the triceps brachii in the placebo condition compared to the rest condition, while the ingestion of sports drinks attenuated this fatigue. CONCLUSIONS: This study has demonstrated for the first time that, when tennis players are adequately hydrated and ingest balanced meals between matches, then no large drop in physical performance is observed even during consecutive competitive matches. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01353872. PMID- 25302058 TI - Ripple coarsening on ion beam-eroded surfaces. AB - The temporal evolution of ripple pattern on Ge, Si, Al 2 O 3, and SiO 2 by low energy ion beam erosion with Xe (+) ions is studied. The experiments focus on the ripple dynamics in a fluence range from 1.1 * 10(17) cm(-2) to 1.3 * 10(19) cm( 2) at ion incidence angles of 65 degrees and 75 degrees and ion energies of 600 and 1,200 eV. At low fluences a short-wavelength ripple structure emerges on the surface that is superimposed and later on dominated by long wavelength structures for increasing fluences. The coarsening of short wavelength ripples depends on the material system and angle of incidence. These observations are associated with the influence of reflected primary ions and gradient-dependent sputtering. The investigations reveal that coarsening of the pattern is a universal behavior for all investigated materials, just at the earliest accessible stage of surface evolution. PMID- 25302059 TI - Tunable surface plasmon resonance frequencies of monodisperse indium tin oxide nanoparticles by controlling composition, size, and morphology. AB - Monodisperse indium tin oxide nanoparticles (ITO NPs) with high crystallinity have been synthesized by the rapid thermal injection method and the seed-mediated growth method. We demonstrate that the surface plasmon resonance (SPR) frequencies of ITO NPs can be manipulated from 1,600 to 1,993 nm in near-infrared band by controlling the composition, size, and morphology. The doping Sn concentration in ITO NPs could be controlled via changing the %Sn in the initial feed from 0% to 30%. The shortest SPR wavelength at 1,600 nm with 10% Sn doping concentration indicates highest free electron carrier concentration in ITO NPs, which has direct relationship with doping Sn(4+) ions. Furthermore, we demonstrate that the SPR peaks can also be tuned by the size of ITO NPs in the case of uniform doping. Besides, compared with the ITO NPs, single crystalline ITO with nanoflower morphology synthesized through the one-pot method exhibit SPR absorption peak features of red-shifting and broadening. PMID- 25302061 TI - Effect of Some Substituents Increasing the Solubility of Zn(II) and Al(III) Phthalocyanines on Their Photophysical Properties. AB - Water solubility of phthalocyanines (Pcs) usually increases by the introduction of charged or carboxy substituents in the peripheral positions of the macrocycle. As a result, such structural changes influence their photophysical and photochemical properties as photosensitizers. Phthalocyanines substituted with four or eight terminal carboxyl groups and having in some cases additional eight positive charges (water soluble phthalocyanines) were studied in order to evaluate the spectroscopic and photophysical effects of these side residues on the chromophore properties. The quantum yield of singlet oxygen ((1)O2) generation, the triplet-triplet absorption, and the transient absorption spectra were measured and linked to the structure of the substituents. It was shown that charged substituents did not change the quantum yields of (1)O2 generation but decrease its lifetimes. The introduction of the charged substituents not only increases the water solubility but also significantly changes absorption, fluorescence, and transient absorption spectra of water soluble Pcs. PMID- 25302060 TI - Insomnia comorbid to severe psychiatric illness. AB - In psychiatric illness, there is a growing body of evidence indicating that sleep disturbances exert a detrimental influence on the course of these disorders and contribute to impaired function. Even when psychiatric disorders are successfully treated or stabilized, insomnia and other sleep disturbances often fail to remit. The present review focuses on sleep in two severe mental illnesses, namely bipolar disorder and schizophrenia. This article discusses the role of sleep disturbances and altered sleep architecture in relation to symptom status, functional impairment, quality of life, and the course of these disorders. Current evidence regarding pharmacological and psychological treatment approaches for insomnia in these populations is presented. This review also notes considerations for adapting Cognitive Behavioral Therapy for insomnia (CBT-I) procedures for severe mental illness and proposes directions for future research. PMID- 25302062 TI - EXECUTIVE FUNCTION PROFILES IN CHILDREN WITH AND WITHOUT SPECIFIC LANGUAGE IMPAIRMENT. AB - We present findings from a study that focused on specific executive functions (EF) in children with and without specific language impairment (SLI). We analyzed performance patterns and EF profiles (spatial working memory, inhibition control, and sustained attention) in school-age SLI children and two control groups: age matched and language matched. Our main research goal was to identify those EFs that show a weakness in children with SLI. Our specific aims were to: (1) examine whether the EF problems in children with SLI are domain-general; (2) examine whether deficits in EF in children with SLI can be explained by the general slowness hypothesis or by an overall delay in development; (3) compare EF profiles to examine whether children with SLI show a distinct pattern of performance from their peers. Our findings showed different EF profiles for the groups. We observed differences in performance patterns related to age (e.g., reaction time in response inhibition) and differences related to language status (e.g., sensitivity to interference). The findings show interesting associations in EFs that play a crucial role in language processing. PMID- 25302063 TI - Malignant and noninvasive skin tumours in renal transplant recipients. AB - Background. Transplant recipients require immunosuppression to prevent graft rejection. This conveys an increased risk of malignancy, particularly skin tumours. There is a need for up-to-date data for the South of England. Method. Pathology records were reviewed for 709 kidney transplant recipients on immunosuppression at our hospital from 1995 to 2008. Skin tumours were recorded/analysed. Results. Mean age at transplant was 46 years. Mean length of follow-up was 7.2 years and total follow-up was 4926 person-years. 53 (7.5%) patients (39/458 (8.5%) males and 14/251 (5.6%) females) developed >=1 skin malignancy. Cumulative incidences of 4.0%, 7.5%, and 12.2% were observed for those with <5, <10, and >=10 years follow-up, respectively. The rate was 45 tumours per 1000 person-years at risk. Additionally, 21 patients (3.0%) only had noninvasive tumours. 221 malignant skin tumours were found: 50.2% were SCCs, 47.1% BCCs, and 2.7% malignant melanomas. Mean years to first tumour were 5.8. Mean number of tumours per patient was 4, with mean interval of 12 months. Conclusions. Despite changes in transplantation practice during the time since the last data were published in this region, these findings are similar to previous studies. This adds to the evidence allowing clinicians to inform patients in this region of their risk. PMID- 25302064 TI - Molecular characterization of chicken anemia virus circulating in chicken flocks in egypt. AB - Introduction. Although many previous studies reported detection of chicken anemia virus (CAV) in Egypt since 1990, genomic characterization of this circulating CAV has not been published. In the present study, four nucleotide sequences of detected CAV were genetically characterized. Methods. These nucleotide sequences were obtained from commercial chicken flocks in two different locations of Egypt during 2010. The target region for sequencing was 675 bp nucleotide of partial coding region of VP1 protein. The nucleotide and deduced amino acid sequences of the detected CAV were aligned and compared to worldwide CAV isolates including commonly used vaccine strains. Phylogenetic analysis of these sequences was also carried out. Results. Our results showed that all the Egyptian CAV sequences were grouped in one group with viruses from diverse geographic regions. This group is characterized by amino acids profile (75)I, (97)L, (139)Q, and (144)Q in VP1. The phylogenetic and amino acid analyses of deduced amino acid indicated that the detected CAV sequences differ from CAV vaccine strains. Conclusion. This is the first report that describes molecular characterization of circulating CAV in Egypt. The study showed that the detected CAV, in Egypt are field viruses and unrelated to vaccine strains. PMID- 25302065 TI - Osteogenic Potential of Mouse Adipose-Derived Stem Cells Sorted for CD90 and CD105 In Vitro. AB - Adipose tissue-derived stromal cells, termed ASCs, play an important role in regenerative applications. They resemble mesenchymal stem cells owing to their inexhaustibility, general differentiation potential, and plasticity and display a series of cell-specific and cluster-of-differentiation (CD) marker profiles similar to those of other somatic stem cells. Variations in phenotypes or differentiation are intimately associated with CD markers. The purpose of our study was to exhibit distinct populations of ASCs with differing characteristics for osteogenic differentiation. The primary cell batch of murine-derived ASCs was extracted from subcutaneous adipose tissue and the cells were sorted for the expression of the surface protein molecules CD90 and CD105 using flow cytometry. Each cell population sorted for CD90 and CD105 was analyzed for osteogenic potency after cell culture. The results suggested that ASCs exhibit distinct populations with differing characteristics for osteogenic differentiation: unsorted ASCs stimulated comparable mineralized nodule formation as bone marrow stromal cells (BMSCs) in osteogenic medium and viral transfection for BMP2 accelerated the formation of mineralized nodules in CD90 and/or CD105 positive ASCs with observation of decrease in CD105 expression after 14 days. Future studies assessing different immunophenotypes of ASCs should be undertaken to develop cell-based tissue engineering. PMID- 25302066 TI - Effect of a comprehensive health care program by korean medicine doctors on medical care utilization for common infectious diseases in child-care centers. AB - As the role of traditional medicine in community health improvement increases, a comprehensive health care program for infectious diseases management in child care centers by Korean medicine doctors was developed. The purpose of this study is to evaluate the effects of the program intervention on infection-related medical care utilization among children. The study used a quasi-experimental design with nonequivalent control group, comparing pre- and post-intervention data of the same children. The program implemented interventions in terms of management, education, and medical examination for the teachers, parents, and children in 12-week period. The frequency of utilization, cost, and prescription days of drugs and antibiotics due to infectious diseases prior to the intervention were compared with those during the 3-month intervention, using health insurance claim data. A panel analysis was also conducted to support the findings. A significant reduction (12%) in infection-related visit days of hospitals was observed with the intervention (incident rate ratio = 0.88, P = 0.01). And medical cost, drug prescription days, and antibiotics prescription days were decreased, although not statistically significant. A further cost effectiveness analysis in terms of social perspectives, considering the opportunity costs for guardians to take children to medical institutions, would be needed. PMID- 25302067 TI - Two Years versus One Year of Tianjiu Therapy in Sanfu Days for Chronic Asthma: A Clinical Efficacy Observation Trial. AB - Background. Tianjiu therapy has established efficacy against chronic asthma with related symptoms or the medication need during asthma attack. This study aimed to explore the optimal duration of Tianjiu therapy for asthma. Methods. This study was a self-comparison-to-the-baseline study, which comparing treatment with Tianjiu therapy for 1 year and 2 years in the same 102 chronic asthma patients. Totally 6 sessions of Tianjiu treatment were provided, 3 sessions in a year as a course of treatment and totally two years treatment. The primary endpoint was the number of asthma related symptoms which frequently appeared in asthma patients and the frequency of bronchodilator used during asthma attack. Results. The frequency of bronchodilator used during asthma attack significantly improved (chi (2) = 46.276, P = 0.000). But the number of asthma related symptoms which frequently appeared in asthma patients added by 1.38 points (95% CI, 0.25 to 2.51), 2.93 +/- 0.41 in 1-year group and 4.31 +/- 0.41 in the 2-years group (P < 0.05). Conclusions. The effect of 2 years Tianjiu therapy was not as effective as 1 year such treatment for asthma, but the second year Tianjiu therapy was still needed because it has a role to consolidate the curative effect of Tianjiu therapy for asthma. PMID- 25302068 TI - Embryonic viability, lipase deficiency, hypertriglyceridemia and neonatal lethality in a novel LMF1-deficient mouse model. AB - BACKGROUND: Lipase Maturation Factor 1 (LMF1) is an ER-chaperone involved in the post-translational maturation and catalytic activation of vascular lipases including lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL). Mutations in LMF1 are associated with lipase deficiency and severe hypertriglyceridemia indicating the critical role of LMF1 in plasma lipid homeostasis. The currently available mouse model of LMF1 deficiency is based on a naturally occurring truncating mutation, combined lipase deficiency (cld), which may represent a hypomorphic allele. Thus, development of LMF1-null mice is needed to explore the phenotypic consequences of complete LMF1 deficiency. FINDINGS: In situ hybridization and qPCR analysis in the normal mouse embryo revealed ubiquitous and high-level LMF1 expression. To investigate if LMF1 was required for embryonic viability, a novel mouse model based on a null-allele of LMF1 was generated and characterized. LMF1-/- progeny were born at Mendelian ratios and exhibited combined lipase deficiency, hypertriglyceridemia and neonatal lethality. CONCLUSION: Our results raise the possibility of a previously unrecognized role for LMF1 in embryonic development, but indicate that LMF1 is dispensable for the viability of mouse embryo. The novel mouse model developed in this study will be useful to investigate the full phenotypic spectrum of LMF1 deficiency. PMID- 25302069 TI - The effect of the macrobiotic Ma-Pi 2 diet vs. the recommended diet in the management of type 2 diabetes: the randomized controlled MADIAB trial. AB - BACKGROUND: Diet is an important component of type 2 diabetes therapy. Low adherence to current therapeutic diets points out to the need for alternative dietary approaches. This study evaluated the effect of a different dietary approach, the macrobiotic Ma-Pi 2 diet, and compared it with standard diets recommended for patients with type 2 diabetes. METHODS: A randomized, controlled, open-label, 21-day trial was undertaken in patients with type 2 diabetes comparing the Ma-Pi 2 diet with standard (control) diet recommended by professional societies for treatment of type 2 diabetes. Changes in fasting blood glucose (FBG) and post-prandial blood glucose (PPBG) were primary outcomes. HbA1c, insulin resistance (IR), lipid panel and anthropometrics were secondary outcomes. RESULTS: After correcting for age, gender, BMI at baseline, and physical activity, there was a significantly greater reduction in the primary outcomes FBG (95% CI: 1.79; 13.46) and PPBG (95% CI: 5.39; 31.44) in those patients receiving the Ma-Pi 2 diet compared with those receiving the control diet. Statistically significantly greater reductions in the secondary outcomes, HbA1c (95% CI: 1.28; 5.46), insulin resistance, total cholesterol, LDL cholesterol and LDL/HDL ratio, BMI, body weight, waist and hip circumference were also found in the Ma-Pi 2 diet group compared with the control diet group. The latter group had a significantly greater reduction of triglycerides compared with the Ma-Pi 2 diet group. CONCLUSIONS: Intervention with a short-term Ma-Pi 2 diet resulted in significantly greater improvements in metabolic control in patients with type 2 diabetes compared with intervention with standard diets recommended for these patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10467793. PMID- 25302070 TI - Fasting mitigates immediate hypersensitivity: a pivotal role of endogenous D-beta hydroxybutyrate. AB - BACKGROUND: Fasting is a rigorous type of dietary restriction that is associate with a number of health benefits. During fasting, ketone bodies significantly increase in blood and become major body fuels, thereby sparing glucose. In the present study, we investigated effects of fasting on hypersensitivity. In addition, we also investigated the possible role of D-beta-hydroxybutyrate provoked by fasting in the attenuation of immediate hypersensitivity by fasting. METHODS: Effects of fasting on systemic anaphylaxis were examined using rat model of toluene 2, 4-diisocyanate induced nasal allergy. In addition to food restriction, a ketogenic high-fat and low-carbohydrate diet that accelerates fatty acid oxidation and systemic instillation of D-beta-hydroxybutyrate were employed to elevate internal D-beta-hydroxybutyrate concentration. We assessed relationship between degranulation of rat peritoneal mast cells and internal D beta-hydroxybutyrate concentration in each treatment. Changes in [Ca(2+)]i responses to compound 48/80 were analyzed in fura 2-loaded rat peritoneal mast cells derived from the ketogenic diet and fasting. RESULTS: Immediate hypersensitivity reaction was significantly suppressed by fasting. A significant reduction in mast cells degranulation, induced by mast cell activator compound 48/80, was observed in rat peritoneal mast cells delivered from the 24 hours fasting treatment. In addition, mast cells delivered from a ketogenic diet and D beta-hydroxybutyrate infusion treatment also had reduced mast cell degranulation and systemic D-beta-hydroxybutyrate concentrations were elevated to similar extent as the fasting state. The peak increase in [Ca(2+)]i was significantly lower in the ketogenic diet and fasting group than that in the control diet group. CONCLUSIONS: The results of the present study demonstrates that fasting suppress hypersensitivity reaction, and indicate that increased level of D-beta hydroxybutyrate by fasting plays an important role, via the stabilization of mast cells, in suppression of hypersensitivity reaction. PMID- 25302071 TI - Mitochondriogenesis and apoptosis: possible cause of vitamin A-mediated adipose loss in WNIN/Ob-obese rats. AB - BACKGROUND: Previously, we reported that vitamin A-enriched diet (129 mg/kg diet) intake reduces the adiposity development in obese rats of WNIN/Ob strain. Here, we hypothesize that dose lesser than 129 mg of vitamin A/kg diet would also be effective in ameliorating the development of obesity in these rats. METHODS: Five month-old male lean and obese rats designated as A & B were divided into four subgroups (I, II, III and IV) consisting of 8 rats from each phenotype and received diets containing 2.6 mg (control group), 26 mg, 52 mg and 129 mg vitamin A/kg diet as retinyl palmitate for 20 weeks. Body composition and morphological analysis of brown adipose tissue (BAT) was analyzed. Expression of uncoupling protein 1 (UCP1), retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha (RXRalpha) in BAT and levels of Bcl2 and Bax in epididymal white adipose tissue (eWAT) were determined by immunoblotting. RESULTS: Vitamin A supplementation to obese rats at doses of 52 and 129 mg/kg diet showed reduced body weight gain and adiposity compared to control diet-fed obese rats receiving 2.6 mg of vitamin A/kg diet. In BAT of obese rats, vitamin A supplementation at doses of 26 and 52 mg of vitamin A/kg diet resulted in increased UCP1 expression with concomitant decrease in RARalpha and RXRalpha levels compared to control diet-fed obese rats. Further, transmission electron microscopy study revealed an increase in number of BAT mitochondria of obese rats supplemented with 26 and 52 mg of vitamin A/kg diet. Also, obese rats fed on 52 mg/kg diet resulted in increased apoptosis by altering the ratio of Bcl2 to Bax protein levels in eWAT. Notably, most of these changes were not observed in lean rats fed vitamin A enriched diets. CONCLUSION: In conclusion, chronic consumption of 52 mg of vitamin A/kg diet seems to be an effective dose in ameliorating obesity possibly through mitochondriogenesis, UCP1-mediated thermogenesis in BAT and apoptosis in eWAT of obese rats. Therefore, the role of dietary vitamin A in correcting human obesity would be of unquestionable relevance and can only be addressed by future studies. PMID- 25302072 TI - Muscle p70S6K phosphorylation in response to soy and dairy rich meals in middle aged men with metabolic syndrome: a randomised crossover trial. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is the primary regulator of muscle protein synthesis. Metabolic syndrome (MetS) is characterized by central obesity and insulin resistance; little is known about how MetS affects the sensitivity of the mTOR pathway to feeding. METHODS: The responsiveness of mTOR pathway targets such as p706Sk to a high protein meal containing either dairy or soy foods was investigated in healthy insulin sensitive middle-aged men and those presenting with metabolic syndrome (MetS). Twenty male subjects (10 healthy controls, 10 MetS) participated in a single-blinded randomized cross-over study. In a random sequence, subjects ingested energy-matched breakfasts composed predominately of either dairy-protein or soy-protein foods. Skeletal muscle biopsies were collected in the fasted state and at 2 and 4 h post-meal ingestion for the analysis of mTOR- and insulin-signalling kinase activation. RESULTS: Phosphorylated Akt and Insulin receptor substrate 1 (IRS1) increased during the postabsorptive period with no difference between groups. mTOR (Ser448) and ribosomal protein S6 phosphorylation increased 2 h following dairy meal consumption only. p70S6K (Thr389) phosphorylation was increased after feeding only in the control subjects and not in the MetS group. CONCLUSIONS: These data demonstrate that the consumption of a dairy-protein rich but not a soy-protein rich breakfast activates the phosphorylation of mTOR and ribosomal protein S6, required for protein synthesis in human skeletal muscle. Unlike healthy controls, subjects with MetS did not increase muscle p70S6K(Thr389) phosphorylation in response to a mixed meal. TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) as ACTRN12610000562077. PMID- 25302073 TI - Prevalence of latent tuberculosis infection and associated risk factors among 3,374 healthcare students in Italy. AB - INTRODUCTION: The risk of tuberculosis (TB) in healthcare personnel (HCP) is related to its incidence in the general population. Healthcare students involved in clinical training could be exposed to occupational risks similar to those that HCP face. The prevalence of latent tuberculosis infection (LTBI) among undergraduate healthcare students with different working seniority in Italy was analysed. METHODS: A cross-sectional study under a screening programme for LTBI among undergraduate and postgraduate students attending Medical School at the Second University of Naples was conducted between January 2012 and December 2013 with clinical evaluations, tuberculin skin testing (TST) and, in positive TST students, Interferon-gamma release assays (IGRA). Putative risk factors for LTBI were assessed by means of a standardised questionnaire. RESULTS: 3,374 students attending the Medical School of the Second University of Naples were submitted to a screening programme for TBC. 3,331 performed TST as a first-level test and 43 performed a Quantiferon test (QFT). 128 students were TST-positive and continued the diagnostic work with QFT, which was positive in 34 students. Of the 43 subjects who took the QFT as a first-level test only 1 was positive. In 35 students positive to the QFT test we formulated the diagnosis of LTBI by clinical and radiographic results. A correlation was found between age, non-Italian born persons, studying age, post-medical school status and LTBI. CONCLUSIONS: The prevalence of LTBI among healthcare students in our study was very low. In countries with a low incidence of TB, the screening programmes of healthcare students can be useful for early identification and treatment of sporadic cases of LTBI. PMID- 25302074 TI - Feature selection for better identification of subtypes of Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is a neurological disorder which has not been explored using clustering algorithms. Clustering algorithms perform more efficiently when they work only with relevant features. In this work, we applied correlation-based feature selection (CFS), chi-squared, information gain, symmetrical uncertainty, and consistency filter methods to select the most relevant features from a 156-feature real dataset. This dataset contains clinical, serological, and nerve conduction tests data obtained from GBS patients. The most relevant feature subsets, determined with each filter method, were used to identify four subtypes of GBS present in the dataset. We used partitions around medoids (PAM) clustering algorithm to form four clusters, corresponding to the GBS subtypes. We applied the purity of each cluster as evaluation measure. After experimentation, symmetrical uncertainty and information gain determined a feature subset of seven variables. These variables conformed as a dataset were used as input to PAM and reached a purity of 0.7984. This result leads to a first characterization of this syndrome using computational techniques. PMID- 25302075 TI - Obesity-Related Hormones in Low-Income Preschool-Age Children: Implications for School Readiness. AB - Mechanisms underlying socioeconomic disparities in school readiness and health outcomes, particularly obesity, among preschool-aged children are complex and poorly understood. Obesity can induce changes in proteins in the circulation that contribute to the negative impact of obesity on health; such changes may relate to cognitive and emotion regulation skills important for school readiness. We investigated obesity-related hormones, body mass index (BMI), and school readiness in a pilot study of low-income preschoolers attending Head Start (participating in a larger parent study). We found that the adipokine leptin was related to preschoolers' BMI z-score, the appetite-regulating hormones ghrelin and glucagon-like peptide 1 (GLP-1), and pro-inflammatory cytokines typically associated with early life stress; and that some of these obesity-related biomarkers were in turn related to emotion regulation. Future work should evaluate how obesity may affect multiple domains of development, and consider modeling common physiological pathways related to stress, health, and school readiness. PMID- 25302076 TI - Phosphorylation and arginine methylation mark histone H2A prior to deposition during Xenopus laevis development. AB - BACKGROUND: Stored, soluble histones in eggs are essential for early development, in particular during the maternally controlled early cell cycles in the absence of transcription. Histone post-translational modifications (PTMs) direct and regulate chromatin-templated transactions, so understanding the nature and function of pre-deposition maternal histones is essential to deciphering mechanisms of regulation of development, chromatin assembly, and transcription. Little is known about histone H2A pre-deposition modifications nor known about the transitions that occur upon the onset of zygotic control of the cell cycle and transcription at the mid-blastula transition (MBT). RESULTS: We isolated histones from staged Xenopus laevis oocytes, eggs, embryos, and assembled pronuclei to identify changes in histone H2A modifications prior to deposition and in chromatin. Soluble and chromatin-bound histones from eggs and embryos demonstrated distinct patterns of maternal and zygotic H2A PTMs, with significant pre-deposition quantities of S1ph and R3me1, and R3me2s. We observed the first functional distinction between H2A and H4 S1 phosphorylation, as we showed that H2A and H2A.X-F (also known as H2A.X.3) serine 1 (S1) is phosphorylated concomitant with germinal vesicle breakdown (GVBD) while H4 serine 1 phosphorylation occurs post-MBT. In egg extract H2A/H4 S1 phosphorylation is independent of the cell cycle, chromatin assembly, and DNA replication. H2AS1ph is highly enriched on blastula chromatin during repression of zygotic gene expression while H4S1ph is correlated with the beginning of maternal gene expression and the lengthening of the cell cycle, consistent with distinct biological roles for H2A and H4 S1 phosphorylation. We isolated soluble H2A and H2A.X-F from the egg and chromatin-bound in pronuclei and analyzed them by mass spectrometry analysis to quantitatively determine abundances of S1ph and R3 methylation. We show that H2A and H4 S1ph, R3me1 and R3me2s are enriched on nucleosomes containing both active and repressive histone PTMs in human A549 cells and Xenopus embryos. CONCLUSIONS: Significantly, we demonstrated that H2A phosphorylation and H4 arginine methylation form a new class of bona fide pre deposition modifications in the vertebrate embryo. We show that S1ph and R3me containing chromatin domains are not correlated with H3 regulatory PTMs, suggesting a unique role for phosphorylation and arginine methylation. PMID- 25302077 TI - Evolutionarily conserved genetic interactions with budding and fission yeast MutS identify orthologous relationships in mismatch repair-deficient cancer cells. AB - BACKGROUND: The evolutionarily conserved DNA mismatch repair (MMR) system corrects base-substitution and insertion-deletion mutations generated during erroneous replication. The mutation or inactivation of many MMR factors strongly predisposes to cancer, where the resulting tumors often display resistance to standard chemotherapeutics. A new direction to develop targeted therapies is the harnessing of synthetic genetic interactions, where the simultaneous loss of two otherwise non-essential factors leads to reduced cell fitness or death. High throughput screening in human cells to directly identify such interactors for disease-relevant genes is now widespread, but often requires extensive case-by case optimization. Here we asked if conserved genetic interactors (CGIs) with MMR genes from two evolutionary distant yeast species (Saccharomyces cerevisiae and Schizosaccharomyzes pombe) can predict orthologous genetic relationships in higher eukaryotes. METHODS: High-throughput screening was used to identify genetic interaction profiles for the MutSalpha and MutSbeta heterodimer subunits (msh2Delta, msh3Delta, msh6Delta) of fission yeast. Selected negative interactors with MutSbeta (msh2Delta/msh3Delta) were directly analyzed in budding yeast, and the CGI with SUMO-protease Ulp2 further examined after RNA interference/drug treatment in MSH2-deficient and -proficient human cells. RESULTS: This study identified distinct genetic profiles for MutSalpha and MutSbeta, and supports a role for the latter in recombinatorial DNA repair. Approximately 28% of orthologous genetic interactions with msh2Delta/msh3Delta are conserved in both yeasts, a degree consistent with global trends across these species. Further, the CGI between budding/fission yeast msh2 and SUMO-protease Ulp2 is maintained in human cells (MSH2/SENP6), and enhanced by Olaparib, a PARP inhibitor that induces the accumulation of single-strand DNA breaks. This identifies SENP6 as a promising new target for the treatment of MMR-deficient cancers. CONCLUSION: Our findings demonstrate the utility of employing evolutionary distance in tractable lower eukaryotes to predict orthologous genetic relationships in higher eukaryotes. Moreover, we provide novel insights into the genome maintenance functions of a critical DNA repair complex and propose a promising targeted treatment for MMR deficient tumors. PMID- 25302078 TI - New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0. AB - BACKGROUND: We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible. RESULTS: We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a naive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets. CONCLUSIONS: TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool. PMID- 25302080 TI - Low serum galectin-3 concentrations are associated with insulin resistance in patients with type 2 diabetes mellitus. AB - BACKGROUND: Galectin-3 is a family of soluble beta-galactoside-binding lectins that play many important regulatory roles in inflammation. Galectin-3-deficient mice have been shown to exhibit excess adiposity, hyperglycemia, insulin resistance and systemic inflammation. We investigated the association between serum galectin-3 and insulin resistance in patients with type 2 diabetes using a glucose clamp method. METHODS: This was a cross-sectional study. Twenty patients (mean fasting plasma glucose 7.6 mmol/L, HbA1c 7.2%, BMI 28.1 kg/m(2)) underwent a meal tolerance test and glucose clamp test. Participants were given a test meal and plasma glucose and insulin were measured at 0, 30, 60, 120 and 180 min. The glucose disposal rate was measured during hyperinsulinemic-euglycemic glucose clamps. Serum galectin-3 levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: The mean serum galectin-3 level was 5103 pg/ml. Galectin-3 levels correlated significantly with the glucose disposal rate (R = 0.71, P < 0.001), fasting insulin (R = -0.56, P < 0.01), homeostasis model assessment for insulin resistance (R = -0.52, P < 0.05), and the insulin sensitivity index (R = 0.62, P < 0.005). Galectin-3 levels also positively correlated with the serum adiponectin level (R = 0.61, P < 0.05), but not with the high-sensitive C-reactive protein and interleukin-6 and -10. CONCLUSIONS: These results suggest that low levels of serum galectin-3 are associated with insulin resistance in patients with type 2 diabetes. PMID- 25302079 TI - Pioglitazone modulates the proliferation and apoptosis of vascular smooth muscle cells via peroxisome proliferators-activated receptor-gamma. AB - BACKGROUND: PPARgamma is a member of the nuclear hormone receptor superfamily. It has been considered as a mediator regulating metabolism, anti-inflammation, and pro-proliferation in the Vascular Smooth Muscle Cells (VSMCs). Thiazolidinediones (TZDs), synthetic ligands of PPARgamma, have anti-proliferative and pro-apoptotic effects on VSMCs, which prevent the formation and progression of atherosclerosis and restenosis following percutaneous coronary intervention (PCI). However, the underlying mechanism remains elusive. This present study therefore aimed to investigate the signaling pathway by which pioglitazone, one of TZDs, inhibits proliferation and induces apoptosis of VSMCs. METHODS: The effects of pioglitazone on VSMC proliferation and apoptosis were studied. Cell proliferation was determined using BrdU incorporation assay. Cell apoptosis was monitored with Hoechst and Annexin V staining. The expression of caspases and cyclins was determined using real-time PCR and Western blot. RESULTS: Pioglitazone treatment and PPARgamma overexpression inhibited proliferation and induced apoptosis of VSMCs, whereas blocking by antagonist or silencing by siRNA of PPARgamma significantly attenuated pioglitazone's effect. Furthermore, pioglitazone treatment or PPARgamma overexpression increased caspase 3 and caspase 9 expression, and decreased the expression of cyclin B1 and cyclin D1 in VSMCs. CONCLUSIONS: Pioglitazone inhibits VSMCs proliferation and promotes apoptosis of VSMCs through a PPARgamma signaling pathway. Up-regulation of caspase 3 and down regulation of cyclins mediates pioglitazone's anti-proliferative and pro apoptotic effects. Our results imply that pioglitazone prevents the VSMCs proliferation via modulation of caspase and cyclin signaling pathways in a PPARgamma-dependent manner. PMID- 25302081 TI - Association and interaction analysis of PPARGC1A and serum uric acid on type 2 diabetes mellitus in Chinese Han population. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A/ PGC-1alpha) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. The activity of PGC-1alpha or genetic variations in the gene encoding the enzyme may contribute to individual variations in mitochondrial function and insulin resistance or diabetes. The objective of this study was to assess the extent to which PPARGC1A (rs8192678) and serum uric acid (UA) and its interaction impact on T2DM susceptibility in Chinese Han population. METHOD: We conducted a study in a cohort that included 1166 T2DM patients and 1135 controls, and was genotyped for the presence of the PPARGC1A rs8192678 polymorphisms. Genotyping was performed by iPLEX technology. The association between rs8192678 or UA and T2DM was assessed by univariate and multivariate logistic regression (MLR) analysis controlling for confounders. The interaction between rs8192678 and UA for T2DM susceptibility was also assessed by MLR analysis. RESULTS: The generalized linear regression analysis failed to show an association between the PPARGC1A rs8192678 polymorphisms and T2DM. Interestingly, the present study provided data suggesting that the minor A-allele of PPARGC1A (rs8192678) had a protective effect against T2DM in subjects with higher level of UA (ORint =1.50 95% CI: 1.06-2.12 for allele and P = 0.02, ORint =1.63 95% CI: 1.17-2.26 for genotype and P = 0.004). CONCLUSION: The combination of higher level of UA and PPARGC1A (rs8192678) was an independent predictor for T2DM. PMID- 25302082 TI - Transoral robotic resection of a lingual thyroglossal duct cyst. AB - Thyroglossal duct cysts (TGDCs) are epithelial rests of the thyroid gland left during embryologic descent from the tongue base. Thyroglossal duct cysts confined to the tongue base alone are even more unusual. We present a case of a 45-year old woman who presented with complaints of sore throat, globus, and throat clearing for 10 years. On examination she was found to have a 2 * 1.5-cm cystic appearing mass, left of midline in the vallecula. The patient had a transoral robotic resection of this vallecular cyst, which was subsequently found to be a lingual TGDC. We believe this is the first reported case of a TGDC that was successfully excised using a transoral robotic approach. PMID- 25302084 TI - Learning a Taxonomy of Predefined and Discovered Activity Patterns. AB - Many intelligent systems that focus on the needs of a human require information about the activities that are being performed by the human. At the core of this capability is activity recognition. Activity recognition techniques have become robust but rarely scale to handle more than a few activities. They also rarely learn from more than one smart home data set because of inherent differences between labeling techniques. In this paper we investigate a data-driven approach to creating an activity taxonomy from sensor data found in disparate smart home datasets. We investigate how the resulting taxonomy can help analyze the relationship between classes of activities. We also analyze how the taxonomy can be used to scale activity recognition to a large number of activity classes and training datasets. We describe our approach and evaluate it on 34 smart home datasets. The results of the evaluation indicate that the hierarchical modeling can reduce training time while maintaining accuracy of the learned model. PMID- 25302083 TI - Enhanced parietal cortex activation during location detection in children with autism. AB - BACKGROUND: Visuospatial processing has been found to be mediated primarily by two cortical routes, one of which is unique to recognizing objects (occipital temporal, ventral or "what" pathway) and the other to detecting the location of objects in space (parietal-occipital, dorsal or "where" pathway). Considering previous findings of relative advantage in people with autism in visuospatial processing, this functional MRI study examined the connectivity in the dorsal and ventral pathways in high-functioning children with autism. METHODS: Seventeen high-functioning children and adolescents with autism spectrum disorders (ASD) and 19 age-and-IQ-matched typically developing (TD) participants took part in this study. A simple visual task involving object recognition and location detection was used. In the MRI scanner, participants were shown grey scale pictures of objects (e.g., toys, household items, etc.) and were asked to identify the objects presented or to specify the location of objects relative to a cross at the center of the screen. RESULTS: Children with ASD, relative to TD children, displayed significantly greater activation in the left inferior parietal lobule (especially the angular gyrus) while detecting the location of objects. However, there were no group differences in brain activity during object recognition. There were also differences in functional connectivity, with the ASD participants showing decreased connectivity of the inferior temporal area with parietal and occipital areas during location detection. CONCLUSIONS: The results of this study underscore previous findings of an increased reliance on visuospatial processing (increased parietal activation) for information processing in ASD individuals. In addition, such processing may be more local, focal, and detailed in ASD as evidenced from the weaker functional connectivity. PMID- 25302085 TI - Diabetes and atrial fibrillation: stratification and prevention of stroke risks. AB - BACKGROUND: Although evidence is not very clear, diabetes is assumed to be an independent risk factor for atrial fibrillation (AF). One reason for the lack of evidence could be that AF often is not detected due to its paroxysmal or asymptomatic character. A better understanding of the relationship between both diseases and improved detection of AF is necessary since the combination of both diseases dramatically increase the risk of strokes if not treated properly. METHODS: Available literature about diabetes as an independent risk factor for AF has been evaluated, and limitations of studies are discussed. RESULTS: Results from different trials and registers are contradictory concerning diabetes as an independent risk factor for AF. Reasons for these differences can be found in different study designs and neglecting patients with unknown AF. CONCLUSIONS: Due to the increasing burden of disease of diabetes and AF as common risk factors for stroke, a systematic screening for AF in diabetes patients could provide a better understanding of their correlation and personalized prevention strategies. PMID- 25302086 TI - Value of Virtual Colonoscopy with 64 Row CT in Evaluation of Colorectal Cancer. AB - BACKGROUND: Virtual colonoscopy (VC) enables three-dimensional view of walls and internal lumen of the colon as a result of reconstruction of multislice CT images. The role of VC in diagnosis of the colon abnormalities systematically increases, and in many medical centers all over the world is carried out as a screening test of patients with high risk of colorectal cancer. MATERIAL/METHODS: We analyzed results of virtual colonoscopy of 360 patients with clinical suspicion of colorectal cancer. Sensitivity and specificity of CT colonoscopy for detection of colon cancers and polyps were assessed. RESULTS: Results of our research have shown high diagnostic efficiency of CT colonoscopy in detection of focal lesions in large intestine of 10 mm or more diameter. Sensitivity was 85.7%, specificity 89.2%. CONCLUSIONS: Virtual colonoscopy is noninvasive and well tolerated by patients imaging method, which permits for early detection of the large intestine lesions with specificity and sensitivity similar to classical colonoscopy in screening exams in patients suspected for colorectal cancer. Good preparation of the patients for the examination is very important for proper diagnosis and interpretation of this imaginge procedure. PMID- 25302087 TI - Heterotopic pancreas: a rare cause of ileo-ileal intussusception. AB - BACKGROUND: Heterotopic pancreas is a rare developmental anomaly defined as pancreatic tissue found on ectopic sites without contiguity with the main pancreas. An isolated heterotopic pancreas as a cause of bowel intussusception is extremely rare. CASE REPORT: A case of 47-year old male with multiple episodes of melena, constipation and abdominal pain for one year duration is presented. CT eneterography revealed a large circumferential lesion involving the terminal ileum that acted as a leading point to an ileo-ileal intussusception. The resection of the lesion and related bowel segment was carried out. The histopathological examination confirmed the excised lesion as a heterotopic pancreatic tissue. CONCLUSIONS: Though a rare entity, heterotopic pancreas should be considered in the differential diagnosis of bowel intussusception. PMID- 25302089 TI - Lipid peroxidation products in human health and disease 2014. PMID- 25302088 TI - Comprehensive management of actinic keratoses: practical integration of available therapies with a review of a newer treatment approach. PMID- 25302090 TI - QUANTIFYING ATYPICALITY IN AFFECTIVE FACIAL EXPRESSIONS OF CHILDREN WITH AUTISM SPECTRUM DISORDERS. AB - We focus on the analysis, quantification and visualization of atypicality in affective facial expressions of children with High Functioning Autism (HFA). We examine facial Motion Capture data from typically developing (TD) children and children with HFA, using various statistical methods, including Functional Data Analysis, in order to quantify atypical expression characteristics and uncover patterns of expression evolution in the two populations. Our results show that children with HFA display higher asynchrony of motion between facial regions, more rough facial and head motion, and a larger range of facial region motion. Overall, subjects with HFA consistently display a wider variability in the expressive facial gestures that they employ. Our analysis demonstrates the utility of computational approaches for understanding behavioral data and brings new insights into the autism domain regarding the atypicality that is often associated with facial expressions of subjects with HFA. PMID- 25302091 TI - Perioperative adrenergic response and the use of beta-blockers. PMID- 25302092 TI - Postoperative nausea and vomiting. AB - Postoperative nausea and vomiting (PONV) is a long-standing issue, not a new concept in anesthesiology. Despite many studies over the last several decades, PONV remains a significant problem due to its complex mechanism. This review presents a summary of the mechanism underlying the pathogenesis of PONV, focusing on preventive treatment, particularly the use of new drugs. In addition, we discuss the latest meta-analysis results regarding correct clinical use of classic drugs. I also summarize the latest trends of postdischarge nausea and vomiting and the pharmacogenetics, which is attracting a great deal of attention from other medical fields in PONV-related studies. Finally, we discuss the drawbacks of existing studies on PONV and suggest a focus for future investigations. PMID- 25302093 TI - Effects of lidocaine, ketamine, and remifentanil on withdrawal response of rocuronium. AB - BACKGROUND: Rocuronium has been well known to produce withdrawal response in 50 80% patients when administered intravenously. Several drugs are administered prior injection of rocuronium to prevent the withdrawal response. We compared the preventive effect of lidocaine, ketamine, and remifentanil on the withdrawal response of rocuronium. METHODS: A total of 120 patients undergoing various elective surgeries were enrolled. Patients were allocated into 4 groups according to the pretreatment drugs (Group N, normal saline; Groups L, lidocaine 40 mg; Group K, ketamine 0.5 mg/kg; Group R, remifentanil 1 ug/kg). Patients received drugs prepared by dilution to 3 ml volume before injection of rocuronium. Withdrawal responses after injection of rocuronium were graded on a 4-point scale. Hemodynamic changes were observed before and after administration of pretreatment drugs and after endotracheal intubation. RESULTS: Incidence of withdrawal response was significantly lower in group L (20%), group K (30%), and group R (0%), than group N (87%). Severe withdrawal response was observed in 5 of the 30 patients (17%) in group L, and in 9 of the 30 patients (30%) in group K. There was no severe withdrawal response in group R. Mean blood pressure and heart rate were significantly decreased in group R compared to other groups. CONCLUSIONS: It seems that remifentanil (1 ug/kg intravenously) was the strongest and most effective in prevention of withdrawal response after rocuronium injection among the 3 drugs. PMID- 25302094 TI - Vertebral level of Tuffier's line measured by ultrasonography in parturients in the lateral decubitus position. AB - BACKGROUND: It is known that Tuffier's line intersects the spine at the L4 spinous process or at the L4-L5 intervertebral space. Full term parturient women undergo various physical changes. Therefore, determining the vertebral level with Tuffier's line based on palpation inevitably is not very accurate. The aim of this study was to use ultrasound to verify the difference between vertebral levels for the palpated Tuffier's line in parturient and non-parturient women in the lateral decubitus position. METHODS: We consecutively enrolled 40 parturient women at 37-41 weeks of gestation and 40 non-parturient women scheduled for regional anesthesia. In the left lateral position, the location of the vertebra was identified using ultrasonography. We marked every intervertebral space from L5 to L2 vertebra, divided each spinous process into two equal parts, and numbered the spaces sequentially from 1 to 9. We drew a Tuffier's line by palpating, recorded the vertebral level that this line intersected. RESULTS: The mean value of an arbitrary number of vertebral level of Tuffier's line was 6.4 +/ 0.9 in the non-pregnant group and this represents L4-lower vertebral level. In the pregnant group, the mean value was 3.0 +/- 1.0 which represents L3-lower vertebral level. There was a significant difference between the two groups (P < 0.05). CONCLUSIONS: We compared using an available ultrasound technique the vertebral levels intersected by the palpated Tuffier's line between parturient and non-parturient women and found that the vertebral levels were more cephalad in the parturient women compared to the non-parturient women. PMID- 25302095 TI - The usefulness of end-tidal carbon dioxide monitoring during apnea test in brain dead patients. AB - BACKGROUND: The apnea test (AT) is essential to confirming the diagnosis of brain death, but critical complications can occur if the AT is maintained over a long period. To minimize the AT period, we used end-tidal carbon dioxide (ETCO2) monitoring because ETCO2 is closely correlated with partial pressure of arterial carbon dioxide (PaCO2). The aim of the present study is to evaluate the usefulness of ETCO2 monitoring during apnea testing. METHODS: We reviewed 61 patients who were pronounced brain dead at our hospital from July 2009 to December 2012. The subjects were divided into two groups: the N-group, in which capnography was not used, and the C-group, in which capnography was used to monitor ETCO2. In the C-group, whenever arterial blood was sampled, the PaCO2 - ETCO2 gradients were calculated and the ventilator setting adjusted to maintain normocapnia prior to apnea testing. RESULTS: Twenty-eight subjects in the N-group and twenty-nine subjects in the C-group were included. The gender ratio, age, and cause of brain death were not different between the two groups. Prior to the AT, the normocapnia ratio was higher in the C-group than in the N-group. During the AT, the total test period was shorter in the C-group. Moreover, systolic blood pressure increased in the C-group and decreased in the N-group during apnea testing. CONCLUSIONS: ETCO2 monitoring during AT allows the PaCO2 level to be predicted, which reduces the duration of the test and stabilizes systolic blood pressure. Thus, with ETCO2 monitoring, the AT can be fast and safe. PMID- 25302096 TI - Comparison of incidence of intravascular injections during transforaminal epidural steroid injection using different needle types. AB - BACKGROUND: Infrequent but serious complications of transforaminal epidural steroid injection (TFESI) occur due to inadvertent intravascular injections. A few studies reported that the different needle types can influence on the occurrences of intravascular incidence in TFESI. This study prospectively evaluated whether short-bevel needle can reduce the incidences of intravascular injection of TFESI compared to long-bevel needles. METHODS: From March 2013 to December 2013, 239 consecutive patients were enrolled and received 249 fluoroscopically guided TFESI using the classic technique. Confirmation of intravascular spread was done initially with real time fluoroscopy and then with digital subtraction angiography method in a same patient. Injection technique for TFESI was the same for both short-bevel and long-bevel needle types. RESULTS: The incidences of intravascular injections with the long-bevel and short-bevel needles were 15.0% (21/140) and 9.2% (4/140), respectively. More than half of intravascular injections occurred simultaneously with epidural injections (8.0%, 20/249). There were no statistically significant differences between the long bevel and the short-bevel needles in the rates of intravascular injections (P = 0.17). CONCLUSIONS: Short-bevel needles did not demonstrate any benefits in reducing the incidence of intravascular injection. PMID- 25302097 TI - Persistent perioperative tachycardia and hypertension diagnosed as thyroid storm induced by a hydatidiform mole: a case report. AB - Thyroid storm is a critical complication of molar pregnancy. However, early diagnosis of it is difficult because it is a rare complication and usually presents nonspecific findings. In this case report, we present a woman with molar pregnancy who had persistent tachycardia and hypertension. She was diagnosed initially with preeclampsia and sepsis as complications of molar pregnancy. During dilation and curettage under general anesthesia with sevoflurane and remifentanil, tachycardia and hypertension remained even with continuous infusion of labetalol. The patient was subsequently diagnosed with thyroid storm associated with molar pregnancy. She was restored to a clinically euthyroid state 1 day after the operation, and her thyroid function test and beta-hCG values were normal 3 months later. The anesthesiologists should bear in mind the possibility of thyroid storm in patients with molar pregnancies who show persistent tachycardia and hypertension. PMID- 25302098 TI - Trigemino-cardiac reflex: occurrence of asystole during trans-sphenoidal adenomectomy: a case report. AB - The trigemino-cardiac reflex has been reported to occur during various craniofacial surgeries or procedures including manipulation of the trigeminal ganglion, tumor resection in the cerebellopontine angle, various facial reconstructions and trans-sphenoidal adenomectomy. Regarding risk factors during trans-sphenoidal adenomectomy, invasiveness closely related to the size of tumor and the degree of manipulation of cavernous sinus wall have been reported. We report the case of a 40-year-old female patient who had a relatively small-sized (< 10 mm) pituitary adenoma. Repetitive asystoles occurred during microscopic trans-sphenoidal operation of the wall of the cavernous sinus, which strongly suggests the importance of careful manipulation of the cavernous sinus wall. In addition to reporting this rare complication of trans-sphenoidal adenomectomy, we reviewed its clinical management by performing a literature search. PMID- 25302099 TI - Remote cerebellar hemorrhage after unruptured cerebral aneurysm surgery: two cases report. AB - Remote cerebellar hemorrhage (RCH) occurring distant to the site of original surgery, such as supratentorial or spinal surgery, is rare but potentially fatal. Because the pathophysiology of RCH is thought to be excessive cerebrospinal fluid drainage during the perioperative periods, its diagnosis usually depends on the occurrence of unexpected neurologic disturbances and/or postoperative brain computerized tomography imaging. Because of its rarity, RCH-associated neurologic disturbances such as delayed awakening or nausea and vomiting may often be misdiagnosed as the effects of residual anesthetics or the effect of postoperative analgesic agents unless radiologic images are taken. Treatment for RCH ranges from conservative treatment to decompressive craniectomy, with prognoses ranging from complete resolution to fatality. Here, we report two cases of RCH after surgical clipping of an unruptured cerebral aneurysm of the anterior communicating artery and review anesthetic considerations. PMID- 25302100 TI - Severe neurologic manifestations in acute intermittent porphyria developed after spine surgery under general anesthesia: a case report. AB - Porphyrias are inherited metabolic disorders resulting from a specific enzyme defect in the heme biosynthetic pathway. Porphyrias are induced by various precipitants. Clinical features include abdominal pain, neurologic manifestations, autonomic neuropathy, and mental disturbance. Diagnosis may be delayed because of variable symptoms that mimic other diseases and because of the rarity of of porphyrias. Although most patients with known porphyria can complete anesthesia and surgery safely, undiagnosed porphyric patients are in danger of porphyric crisis due to inadvertent exposure to precipitating drugs and environment. We report a case of a patient who experienced delayed emergence with neurological disturbance after general anesthesia, ultimately diagnosed as acute intermittent porphyria. PMID- 25302101 TI - Temporary postoperative visual loss associated with intracerebral hemorrhage after laparoscopic appendectomy: a case report. AB - Postoperative visual loss (POVL) after non-ophthalmic surgery is rare, with a reported incidence ranging from 0.013 to 0.2%. Most perioperative visual loss is associated with spine operations and cardiac bypass procedures. The most common cause of POVL is ischemic optic neuropathy. However, there are no previous reports of postoperative visual loss after laparoscopic appendectomy. A 43-year old female with no underlying disease underwent laparoscopic appendectomy; the operation was completed in one hour and her blood pressure was stable during the perioperative period. In the post-anesthetic care unit, the patient complained of nausea and headache, but she did not complain of any unusual visual symptoms. Approximately one hour after arriving at the ward, the patient complained of visual disturbance. Neurologic examination revealed left homonymous hemianopsia, and subarachnoid hemorrhage and intracerebral hemorrhage were found in the occipital area on brain MRI. PMID- 25302102 TI - The treatment of hematologic malignancies in pregnancy. PMID- 25302104 TI - The future of set (single embryo transfer) in the United States. PMID- 25302105 TI - Randomised experimental comparison of 23G versus 22G needle for ultrasound guided invasive fetal procedures. AB - OBJECTIVES: To experimentally compare the standard 22G spinal needle with a newer 23G needle with specific ultrasound visualisation tip (Cook echotip(r), Spencer, Indiana, USA) in the setting of ultrasound-guided invasive intrauterine procedures. MATERIALS AND METHODS: We first determined the size of the defects created in human fetal membranes using light microscopy and adapted area calculating software by both needles in an in vitro model performing 20 paired experiments on 4 term membrane specimens. Secondly, we determined the performance of 3 groups of operators, with different levels of experience in invasive intrauterine procedures during cordocentesis on a simulator model, using either a 22G or 23G needle. For each procedure, we measured the time required to successfully obtaining 2 ml of artificial blood in 24 paired experiments. RESULTS: The mean +/- SD defect sizes created was 0.66 +/- 0.12 mm(2) with the 22G needle and 0.59 +/- 0.13 mm(2) with the 23G needle (P = 0.11). The mean duration of sampling was 144 +/- 188 sec with the 22G needle versus 140 +/- 120 sec with the 23G needle (P = 0.99) for all operators pooled but four out of six operators showed shorter sampling times with a 22G needle. CONCLUSION: This experimental study shows that the use of a 23G needle compared to a 22G needle was not associated with significantly different procedure duration or defect size. PMID- 25302106 TI - Outcome of per protocol best-evidence based routine breast cancer care in a large regional hospital in Belgium: the importance of a prospective database in quality assurance. AB - AIM: Criteria for future accreditation of breast cancer centres in Belgium will be mainly based on the case load per surgeon or per centre. We would like to argue that the prospective collection of relevant data and the analysis of treatment related outcome derived from these data is feasible and should be the ultimate criterion for quality assessment and thus for accreditation since outcome is a more direct measurement of quality. METHODS: Data were prospectively collected on 715 invasive non metastatic breast cancers between 2002 and 2007 treated according to standard, best-evidence protocols in the setting of a large district hospital. Univariate and multivariate survival analysis were performed and compared to national and international databases. RESULTS: 5 year disease free survival (DFS) and overall survival (OS) in our series were respectively 77 and 84%. In the multivariate analysis of DFS, only her-2-neu status (her-2-neu positivity being associated with a poor prognosis) and age (older age being a worse prognostic factor) were statistically significant prognostic factors. For OS, her-2-neu, age, and positive nodes were statistically significant prognostic factors. The outcome is comparable to other data sets. CONCLUSION: Centres dedicated to the care of women with breast cancer have the moral duty to produce outcome based results of their treatment. This report shows that such a collection of data is feasible and can be imposed as a prerequisite for accreditation. We also argue that outcome based data of treatment are a more solid base for quality assurance than case load. PMID- 25302103 TI - Male fertility preservation before gonadotoxic therapies. AB - BACKGROUND: Recent advances in cancer therapy have resulted in an increased number of long-term cancer survivors. Unfortunately, aggressive chemotherapy, radiotherapy and preparative regimens for bone marrow transplantation can severely affect male germ cells, including spermatogonial stem cells (SSCs), and lead to permanent loss of fertility. Different options for fertility preservation are dependent on the pubertal state of the patient. METHODS: Relevant studies were identified by an extensive Medline search of English and French language articles. RESULTS: Sperm cryopreservation prior to gonadotoxic treatment is a well established method after puberty. In case of ejaculation failure by masturbation, assisted ejaculation methods or testicular tissue sampling should be considered. Although no effective gonadoprotective drug is yet available for in vivo spermatogonial stem cell (SSC) protection in humans, current evidence supports the feasibility of immature testicular tissue (ITT) cryopreservation. The different cryopreservation protocols and available fertility restoration options from frozen tissue, i.e. cell suspension transplantation, tissue grafting and in vitro maturation, are presented. RESULTS obtained in humans are discussed in the light of lessons learned from animal studies. CONCLUSION: Advances in reproductive technology have made fertility preservation a real possibility in young patients whose gonadal function is threatened by gonadotoxic therapies. The putative indications for such techniques, as well as their limitations according to disease, are outlined. PMID- 25302108 TI - Editorial. PMID- 25302107 TI - A pilot study on 25-hydroxyvitamin D status according to sun exposure in pregnant women in Antwerp, Belgium. AB - INTRODUCTION: Vitamin D deficiency in utero or early neonatal life may have a major impact on children's health. Little is known on vitamin D deficiency in pregnant women in Belgium, non on the impact of wearing head and/or body cover. OBJECTIVES: This was a preliminary exploration of the vitamin D status in pregnant women visiting the antenatal clinic in the Antwerp University Hospital. METHOD: From August 1 2009 until November 30 2009 we systematically determined 25 hydroxy vitamin D (25-OH vitamin D) in each blood sample taken from pregnant women visiting the antenatal clinic. We also registered the degree of head/body cover and inquired for intake of vitamin supplements. RESULTS: Our population consisted of 171 women, mostly primiparous, of which 86% were not covered. The mean value of 25-OH vitamin D was 28 ng/ml. Non-covered women had a mean of 29,5 +/- 12,2 (SD) ng/ml, the partially covered group had a mean of 17,2 +/- 7,2 (SD) ng/ml and the completely covered group had a mean of 22,5 +/- 12,9 (SD) ng/ml. The difference in serum concentrations between the 3 groups was statistically significant (Anova, p < 0,00001). There were significantly more covered than non covered women with a vitamin D concentration lower than 30 ng/ml (OR6.2; 95% CI: 1,8-21,7; p < 0,05). There was no effect of gestational age, maternal age, gravidity, parity and intake of supplements on vitamin D levels. There was a siginificant seasonal effect from summer to fall, with Vitamine D levels lowering from August to November (linear regression, p < 0,05). CONCLUSION: Low vitamin D levels seem to be frequent and covered woman are at a higher risk of deficiency. PMID- 25302109 TI - Efficacy and Tolerability of a Combination Treatment of Memantine and Donepezil for Alzheimer's Disease: A Literature Review Evidence. AB - INTRODUCTION: Two types of drugs have been approved for the symptomatic treatment of Alzheimer's disease (AD): the cholinesterase inhibitors (ChEIs) and memantine. There is a growing interest to know whether the combination of these drugs is safe and if it adds any clinical benefit to patients. OBJECTIVE: To systematically review published medical literature assessing the efficacy and tolerability of a combination treatment of memantine and donepezil in AD patients. METHODS: We searched PubMed for English and Spanish-language literature, using the terms "Alzheimer's disease," "cholinesterase inhibitors," "donepezil," and "memantine." Our review focused on clinical trials and observational studies. RESULTS: Eleven publications representing seven unique studies were selected for this review. Three were randomized double-blind, placebo-controlled trials and four were observational studies. CONCLUSIONS: Available data revealed that the combination of memantine and donepezil slowed down cognitive decline, prolonged functional independence, and improved behavioral symptoms in patients with moderate to severe AD. The long-term use of the dual therapy decreased the risk of nursing home admission. More longitudinal studies are needed to further examine the role of combined therapy in the management of AD patients. PMID- 25302110 TI - Pneumothorax as adverse event in patients with lung metastases of soft tissue sarcoma treated with pazopanib: a single reference centre case series. AB - BACKGROUND: Recently, the phase III PALETTE study introduced pazopanib (Votrient(r)) as treatment for adult patients with locally advanced or metastatic non-liposarcoma soft tissue sarcoma after prior treatment with doxorubicin and/or ifosfamide. Pneumothorax was reported as adverse event in 8 of 246 treated patients (3.3%) in that study. This case series presents the incidence and clinic of this complication in the Leiden University Medical Centre. CASES: Forty-three patients were treated with pazopanib of which six patients (14.0%) developed a pneumothorax. These six patients were treated for malignant peripheral nerve sheath tumour, angiosarcoma, synovial sarcoma, fibromyxomatoid sarcoma, pleomorphic sarcoma and endometrial stromal sarcoma. All six patients had subpleural pulmonary or pleural metastases at the start of pazopanib and the pneumothorax developed during or shortly after treatment with pazopanib and was difficult to treat. DISCUSSION: The incidence reported by us is higher than the incidence in the PALETTE study. Trials with pazopanib in renal cell carcinoma, urothelial carcinoma and cervix carcinoma did not report pneumothorax as an adverse event, suggesting pneumothorax as a specific adverse event in soft tissue sarcoma patients treated with pazopanib. This may be related to the fact that there is often pleural metastatic involvement and cystic degeneration due to pazopanib treatment may add to the risk. CONCLUSION: The risk of an, often difficult to treat, pneumothorax during pazopanib therapy should be discussed with the patient before initiation of treatment for a pulmonary metastasized sarcoma and physicians should be alert to the occurrence of such an event. PMID- 25302111 TI - Nuclear export of VP19C is not essential for replication of herpes simplex virus type 1. AB - BACKGROUND: Herpes simplex virus (HSV) type 1 has a 152 kb double-stranded DNA genome that may encode more than 80 gene products, many of which remain uncharacterized. The HSV-1 triplex is a complex of three protein subunits, VP19C and a dimer of VP23 that is essential for capsid assembly. Previous studies have demonstrated that HSV-1 VP19C contains an atypical nuclear localization signal and a functional nuclear export signal (NES), which are both important for the nucleocytoplasmic shuttling of VP19C. However, whether the VP19C NES is required for efficient HSV-1 production is unknown. FINDINGS: In the present study, a VP19C NES-mutated recombinant virus was generated by using bacterial artificial chromosome recombineering technology to investigate the role of VP19C nuclear export in HSV-1 replication. Our results demonstrate that the growth curves, plaque areas, subcellular localization and viral gene expression are indistinguishable between the VP19C NES-mutated virus and the wild-type virus. CONCLUSIONS: Our findings reported herein indicate abrogation of the nuclear export of VP19C did not affect HSV-1 replication and viral gene expression. PMID- 25302112 TI - miRNA signature of unfolded protein response in H9c2 rat cardiomyoblasts. AB - BACKGROUND: Glucose and oxygen deprivation during ischemia is known to affect the homeostasis of the endoplasmic reticulum (ER) in ways predicted to activate the unfolded protein response (UPR). Activation of UPR signalling due to ER stress is associated with the development of myocardial infarction (MI). MicroRNAs (miRNAs) are key regulators of cardiovascular development and deregulation of miRNA expression is involved in the onset of many cardiovascular diseases. However, little is known about the mechanisms regulating the miRNA expression in the cardiovascular system during disease development and progression. Here we performed genome-wide miRNA expression profiling in rat cardiomyoblasts to identify the miRNAs deregulated during UPR, a crucial component of ischemia. RESULTS: We found that expression of 86 microRNAs changed significantly during conditions of UPR in H9c2 cardiomyoblasts. We found that miRNAs with known function in cardiomyoblasts biology (miR-206, miR-24, miR-125b, miR-133b) were significantly deregulated during the conditions of UPR in H9c2 cells. The expression of miR-7a was upregulated by UPR and simulated in vitro ischemia in cardiomyoblasts. Further, ectopic expression of miR-7a provides resistance against UPR-mediated apoptosis in cardiomyoblasts. The ample overlap of miRNA expression signature between our analysis and different models of cardiac dysfunction further confirms the role of UPR in cardiovascular diseases. CONCLUSIONS: This study demonstrates the role of UPR in deregulating the expression of miRNAs in MI. Our results provide novel insights about the molecular mechanisms of deregulated miRNA expression during the heart disease pathogenesis. PMID- 25302113 TI - Outcome and Prognostic Factors for Traumatic Endophthalmitis over a 5-Year Period. AB - Purpose. To evaluate the outcome and identify the prognostic factors of traumatic endophthalmitis over a 5-year period. Methods. We reviewed the medical records of all the traumatic endophthalmities that we treated in our department over the last 5 years (2009-2013). We extracted the following parameters: age, gender, wound anatomy, associated ocular lesions, treatment, and initial and final visual acuities. We used the program SPSS version 20.0.0. for the statistical analysis of our data. Results. During the last 5 years, we treated 14 traumatic endophthalmities, representing 46.66% of all types of endophthalmities. The infection rate in open globe injuries was 8.13% and 34.78%, if an intraocular foreign body (IOFB) was associated. All the patients were males with the median age of 37 years. Initial visual acuities varied between light perception and 0.4 and the timing of treatment from a few hours to 10 days. We administered antibiotic and anti-inflammatory drugs, systemically and intravitreally, in all cases. We performed pars plana vitrectomy in 64.28% of cases. In 57.14% of cases, the final visual acuity was 0.1 or more. Conclusions. IOFBs increased significantly the risk for endophthalmitis. The worse prognostic factors were retinal detachment at presentation and delayed treatment. This trial is registered with IRCT2014082918966N1. PMID- 25302114 TI - Quantifying proteinuria in hypertensive disorders of pregnancy. AB - Background. Progressive proteinuria indicates worsening of the condition in hypertensive disorders of pregnancy and hence its quantification guides clinician in decision making and treatment planning. Objective. To evaluate the efficacy of spot dipstick analysis and urinary protein-creatinine ratio (UPCR) in hypertensive disease of pregnancy for predicting 24-hour proteinuria. Subjects and Methods. A total of 102 patients qualifying inclusion criteria were evaluated with preadmission urine dipstick test and UPCR performed on spot voided sample. After admission, the entire 24-hour urine sample was collected and analysed for daily protein excretion. Dipstick estimation and UPCR were compared to the 24 hour results. Results. Seventy-eight patients (76.5%) had significant proteinuria of more than 300 mg/24 h. Dipstick method showed 59% sensitivity and 67% specificity for prediction of significant proteinuria. Area under curve for UPCR was 0.89 (95% CI: 0.83 to 0.95, P < 0.001) showing 82% sensitivity and 12.5% false positive rate for cutoff value of 0.45. Higher cutoff values (1.46 and 1.83) predicted heavy proteinuria (2 g and 3 g/24 h, resp.). Conclusion. This study suggests that random urinary protein : creatine ratio is a reliable investigation compared to dipstick method to assess proteinuria in hypertensive pregnant women. However, clinical laboratories should standardize the reference values for their setup. PMID- 25302116 TI - Determinants of Anemia among Children Aged 6-59 Months Living in Kilte Awulaelo Woreda, Northern Ethiopia. AB - Introduction. The aim of this study was to determine the prevalence of anemia and determinant factors among children aged 6-59 months living in Kilte Awulaelo Woreda, eastern zone. Method. A community based cross-sectional study was conducted during February 2013 among 6 tabias of Kilte Awulaelo Woreda, northern Ethiopia. A total of 568 children were selected by systematic random sampling method. Anthropometric data and blood sample were collected. Bivariate and multivariate logistic regression analyses were performed to identify factors related to anemia. Result. The mean hemoglobin level was 11.48 g/dl and about 37.3% of children were anemic. Children who were aged 6-23 months [AOR = 1.89: 95% CI (1.3, 2.8)], underweight [AOR = 2.05: 95% CI (1.3, 3.3)], having MUAC less than 12 cm [AOR = 3.35: 95% CI (2.1, 5.3)], and from households with annual income below 10,000 Ethiopian birr [AOR = 4.86: 95% CI (3.2, 7.3)] were more likely to become anemic. Conclusion. The prevalence of anemia among the children is found to be high. It was associated with annual household income, age, and nutritional status of the child. So, improving family income and increasing awareness of the mother/caregiver were important intervention. PMID- 25302115 TI - Importance of android/gynoid fat ratio in predicting metabolic and cardiovascular disease risk in normal weight as well as overweight and obese children. AB - Numerous studies have shown that android or truncal obesity is associated with a risk for metabolic and cardiovascular disease, yet there is evidence that gynoid fat distribution may be protective. However, these studies have focused on adults and obese children. The purpose of our study was to determine if the android/gynoid fat ratio is positively correlated with insulin resistance, HOMA2 IR, and dislipidemia in a child sample of varying body sizes. In 7-13-year-old children with BMI percentiles ranging from 0.1 to 99.6, the android/gynoid ratio was closely associated with insulin resistance and combined LDL + VLDL cholesterol. When separated by sex, it became clear that these relationships were stronger in boys than in girls. Subjects were stratified into BMI percentile based tertiles. For boys, the android/gynoid ratio was significantly related to insulin resistance regardless of BMI tertile with and LDL + VLDL in tertiles 1 and 3. For girls, only LDL + VLDL showed any significance with android/gynoid ratio and only in tertile 2. We conclude that the android/gynoid fat ratio is closely associated with insulin resistance and LDL + VLDL-, "bad," cholesterol in normal weight boys and may provide a measurement of metabolic and cardiovascular disease risk in that population. PMID- 25302118 TI - In silico antitubercular activity analysis of benzofuran and naphthofuran derivatives. AB - For the human health, Mycobacterium tuberculosis (MTB) is the deadliest enemy since decades due to its multidrug resistant strains. During latent stage of tuberculosis infection, MTB consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence. NarL is a nitrate/nitrite response transcriptional regulatory protein of two component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Using in silico approach, the molecular docking of benzofuran and naphthofuran derivatives and dynamic study of benzofuran derivative were performed. It was observed that compound Ethyl 5-bromo-3 ethoxycarbonylamino-1-benzofuran-2-carboxylate could be stabilized at the active site for over 10 ns of simulation. Here we suggest that derivatives of benzofuran moiety can lead to developing novel antituberculosis drugs. PMID- 25302117 TI - Evaluation of a new modification of pancreaticogastrostomy after pancreaticoduodenectomy: anastomosis of the pancreatic duct to the gastric mucosa with invagination of the pancreatic remnant end into the posterior gastric wall for patients with cancer head of pancreas and periampullary carcinoma in terms of postoperative pancreatic fistula formation. AB - BACKGROUND/OBJECTIVES: Postoperative pancreatic fistula (POPF) remains the main problem after pancreaticoduodenectomy and determines to a large extent the final outcome. We describe a new modification of pancreaticogastrostomy which combines duct to mucosa anastomosis with suturing the pancreatic capsule to posterior gastric wall and then invaginating the pancreatic remnant into the posterior gastric wall. This study was designed to assess the results of this new modification of pancreaticogastrostomy. METHODS: The newly modified pancreaticogastrostomy was applied to 37 consecutive patients after pancreaticoduodenectomy for periampullary cancer (64.86%) or cancer head of the pancreas (35.14%). Eighteen patients (48.65%) had a soft pancreatic remnant, 13 patients (35.14%) had firm pancreatic remnant, and 6 patients (16.22%) had intermediate texture of pancreatic remnant. Rate of mortality, early postoperative complications, and hospital stay were also reported. RESULTS: Operative mortality was zero and morbidity was 29.73%. Only three patients (8.11%) developed pancreatic leaks; they were treated conservatively. Eight patients (16.1%) had delayed gastric emptying, one patient (2.70%) had minor hemorrhage, one patient (2.70%) had biliary leak, and four patients (10.81%) had superficial wound infection. CONCLUSIONS: The new modified pancreatogastrostomy seems safe and reliable with low rate of POPF. However, further prospective controlled trials are essential to support these results. PMID- 25302120 TI - An Improved Method for Soil DNA Extraction to Study the Microbial Assortment within Rhizospheric Region. AB - The need for identification of soil microbial community mainly depends on direct extraction of DNA from soil, a multifaceted environment that is a major pool for microbial genetic diversity. The soil DNA extraction procedures usually suffer from two major problems, namely, inappropriate rupturing of cells and contamination with humic substances. In the present study, five protocols for single type of rhizospheric soil were investigated and their comparison indicated that the inclusion of 120 mM phosphate buffered saline (PBS) for washing and mannitol in the lysis buffer allowed the processing of soil sample in minimal time with no specific equipment requirement. Furthermore, DNA purity and yield were also improved, which allowed the exploitation of genetic potential of soil microbes within soil sample thereby facilitating the amplification of metagenomic DNA. The effectiveness of methods was analyzed using random amplification of polymorphic DNA. The banding patterns revealed that both the abundance and the composition of indigenous microbial community depend on the DNA recovery method. PMID- 25302119 TI - Aortoenteric fistula as a complication of open reconstruction and endovascular repair of abdominal aorta. AB - The paper intends to present a review of imaging characteristics of secondary aortoenteric fistula (AEF). Mechanical injury, infection, and adherence of a bowel segment to the aorta or aortic graft are major etiologic factors of AEF after open aortic repair. The pathogenesis of AEF formation after endovascular abdominal aortic repair is related to mechanical failure of the stent-graft, to stent graft infection, and to persistent pressurization of the aneurysmal sac. The major clinical manifestations of AEF comprise haematemesis, melaena, abdominal pain, sepsis, and fever. CT is the initial diagnostic modality of choice in a stable patient. However, the majority of reported CT appearances are not specific. In case of equivocal CT scans and clinical suspicion of AEF, scintigraphy, (67)Ga citrate scans or (18)F-FDG PET/CT is useful. Diagnostic accuracy of endoscopy in evaluation of AEF is low; nevertheless it allows to evaluate other than AEF etiologies of gastrointestinal bleeding. Without adequate therapy, AEF is lethal. Conventional surgical treatment is associated with high morbidity and mortality. The endovascular repair may be an option in hemodynamically unstable and high-risk surgical patients. We also illustrate an example of a secondary AEF with highly specific albeit rare radiologic picture from our institution. PMID- 25302121 TI - Potential risk factors for varicose veins with superficial venous reflux. AB - The objective of the study is to evaluate a range of potential risk factors in the etiology of varicose veins with superficial venous reflux. Forty-nine patients attending a cardiovascular surgery clinic for the management of varicose disease between 2009 and 2010 were enrolled for the study. The age range of the patient group was 44,04 +/- 15,05 years and female/male (F/M) ratio was 30/19. Twenty-six normal, healthy volunteers with the age of 40,94 +/- 13,60 years and with the female/male ratio of 15/11 acted as control subjects. We investigated several parameters including body mass index, age, birth number > 1, standing for a long time (standing for 8 or more hours without taking a break), systemic diseases, family history, venous Doppler findings, the levels of homocysteine, ferritin, vitamin B12, and hemoglobin, sedimentation rate, mean corpuscular volume, low density lipoprotein, and rheumatoid factor of the patient group and the control group. We also determined the contribution of the methylene tetrahydrofolate reductase 677 C>T and 1298 A>C gene polymorphisms and FV Leiden in both groups. In this small study, there appears to be no association between varicose veins and body mass index, smoking, type 2 DM, hypertension, family history, and birth number. A history of increased standing duration period (>8 hours) and rheumatoid factor positivity have association with varicose veins with superficial venous reflux. PMID- 25302122 TI - How Important Are Social Support, Expectations and Coping Patterns during Cardiac Rehabilitation. AB - Purpose. To investigate the predictive role of relevant social and psychosocial determinants on emotional distress among patients after cardiac rehabilitation. Methods. A longitudinal prospective study examined short-term (6 months) and long term (2 years) impact of predictors on anxiety and depression complaints in 183 patients with 6-months follow-up data attending a four-week rehabilitation stay at the Krokeide Centre in Bergen, Norway. The patients mainly suffered from coronary heart disease. Emotional distress, coping, social support, socioeconomic status, and negative expectations were measured by means of internationally validated questionnaires. A composite score of anxiety and depression complaints was used as the outcome measure in the study. Results. This study revealed that task-oriented coping improved emotional status in long-term followup, and negative expectations were associated with emotional distress in short-term followup. A higher socioeconomic status and more social support predicted improved emotional status in short- as well as long-term followup. Conclusions. Fewer negative expectations and functional coping along with social support are important factors for the prevention of emotional distress after cardiac disease. Such elements should be addressed and encouraged in patients during cardiac rehabilitation. PMID- 25302123 TI - Six years of experience in photodynamic therapy for Basal cell carcinoma: results and fluorescence diagnosis from 191 lesions. AB - Background. Photodynamic therapy (PDT) has become a therapeutic option for basal cell carcinoma (BCC) in the last decade. Objectives. To study the results and predictors of BCC response to treatment with PDT and to evaluate fluorescence diagnosis of BCC. Methods. A descriptive, retrospective, and observational study was carried out. Patients with biopsy-confirmed BCC who were treated with methyl aminolevulinate and red light according to standard treatment protocols (2 sessions separated by 2 weeks, 630 nm, 37 J/cm(2), 8 minutes, Aktilite) were selected. Response was scored as clinically complete and incomplete and the patients were followed up every three months. Results. Data from 191 BCC in 181 patients with a mean age of 69.55 years and a mean follow-up period of 34.4 months were collected. The overall response was 74% of the BCC treated, with the best response in superficial BCC with a 95% of complete response. The regression analysis revealed that the superficial histological type was the primary factor predictive of a complete response. Conclusions. In the treatment of BCC with PDT, the most significant factor for predicting response is the histological type. PMID- 25302124 TI - Comparison of cantharidin toxicity in breast cancer cells to two common chemotherapeutics. AB - As part of a larger study synthesizing a more directed form of chemotherapy, we have begun to assess the efficacy of different potential toxins that could be delivered locally rather than systemically. In doing so, we hope to reduce the systemic side effects commonly observed, while maintaining a high level of toxicity and eliminating the need for metabolic alterations. In a search for this more efficient method for killing cancerous cells, we have begun studying cantharidin, a toxin used in traditional Chinese medicine, as a potential chemotherapeutic. Using an MTT cell viability assay, the toxicity of cantharidin was compared to both cyclophosphamide and paclitaxel in three different breast cancer cell lines: MCF-7, MDA-MB-231, and SK-BR-3. Increasing the concentration of chemotherapy drugs did decrease cell viability in all cell lines when cantharidin and cyclophosphamide were applied; however differences for paclitaxel were cell-specific. Additionally, cantharidin exhibited the highest decrease in cell viability regardless of cell type, indicating it may be a much more potent and less specific chemotherapeutic. These results will help us move forward in developing a potentially more potent treatment for breast cancer that might eliminate the need for subtype-specific treatments. PMID- 25302125 TI - Alsin related disorders: literature review and case study with novel mutations. AB - Mutations in the ALS2 gene cause three distinct disorders: infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and autosomal recessive juvenile amyotrophic lateral sclerosis. We present a review of the literature and the case of a 16-year-old boy who is, to the best of our knowledge, the first Portuguese case with infantile ascending hereditary spastic paraplegia. Clinical investigations included sequencing analysis of the ALS2 gene, which revealed a heterozygous mutation in exon 5 (c.1425_1428del p.G477Afs*19) and a heterozygous and previously unreported variant in exon 3 (c.145G>A p.G49R). We also examined 42 reported cases on the clinical characteristics and neurophysiological and imaging studies of patients with known ALS2 gene mutations sourced from PubMed. This showed that an overlap of phenotypic manifestations can exist in patients with infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and juvenile amyotrophic lateral sclerosis. PMID- 25302126 TI - Lipoblastoma and lipoblastomatosis of the lower leg. AB - Lipoblastoma is a benign lesion of immature fat cells that is found almost exclusively in pediatric population. This tumor is a rare tumor that occurs in infancy and early childhood, accounting for less than 1% of all childhood neoplasm. It is more common in male than in female and often presents as an asymptomatic, rapidly enlarging, soft lobular mass on the extremity. Although benign, it gives great difficulty in its management, due to its extensions into different facial planes, especially in lipoblastomatosis. Thus, complete surgical excision is the treatment of choice. PMID- 25302127 TI - Bilateral, simultaneous medial meniscus bucket handle tears in a 23-year-old female. AB - Traumatic tears of the meniscus are well reported in the literature. Rarely, bilateral meniscal tears occur. A PubMed search found that only three cases of bilateral medial meniscus bucket handle type tears have been reported. Treatment options range from partial meniscectomy to repair of the meniscal tear. Repair is reported to be more successful in the vascular red-red or red-white zones. We present the case of a 23-year-old female who sustained simultaneous bilateral medial meniscus bucket handle type tears in an automobile accident. She was treated in a staged fashion with knee arthroscopy. Her meniscus tears were both found to be in the vascularized zone and meniscal tear repair was conducted. At two weeks postoperatively, she had excellent resolution of her symptoms and has returned to pain-free weight-bearing. She has remained pain-free at six-month follow-up. PMID- 25302128 TI - A clinical and pathological variant of acute transplant glomerulopathy. AB - Acute transplant glomerulopathy transplant glomerulopathy (TG) is a common cause of late renal allograft loss. We describe a unique case of a renal transplant recipient who developed rapid-onset nephrotic-range proteinuria and acute kidney injury secondary to C4d negative acute TG. Two courses of intravenous Rituximab resulted in significant improvement in proteinuria and allograft function. In the setting of acute nephrotic-range proteinuria postrenal allograft, both renal biopsy with electron microscopy and screening for de novo donor-specific antibody should be performed to distinguish atypical presentations of TG from other diagnoses. PMID- 25302129 TI - Cognitive restructuring and graded behavioural exposure for delusional appraisals of auditory hallucinations and comorbid anxiety in paranoid schizophrenia. AB - The prevalence of diagnostic comorbidity between psychosis and anxiety disorders has been found to be considerable. Cognitive models of psychosis suggest that anxiety does not arise directly from positive symptoms of schizophrenia but rather from an individual interpretation of such experiences. In the United Kingdom, cognitive-behavioural therapy for psychosis (CBTp) has been recommended within clinical guidelines as a psychological treatment of choice for those diagnosed with schizophrenia. However, despite empirical evidence supporting CBTp, the treatment provision remains infrequent and not routinely available. This case describes a successful implementation of CBTp. Sixteen sessions were delivered to a 40-year-old male with diagnoses of paranoid schizophrenia and comorbid anxiety, focusing primarily on cognitive restructuring of paranoid appraisals of auditory hallucinations and behavioural experiments employed progressively via graded exposure to anxiety-inducing stimuli. Standardised measurements, behavioural frequency sampling, and subjective data indicated a considerable reduction in both paranoia and anxiety. Also, the client's psychosocial functioning improved substantially. This report indicates that the treatment may help those with experiences of psychosis and comorbid anxiety reach a significant improvement in their quality of life and offers an encouraging and innovative perspective on direct engagement with the content of paranoia and voices at the onset of therapy. PMID- 25302130 TI - Pancoast's Syndrome due to Fungal Abscess in the Apex of Lung in an Immunocompetent Individual: A Case Report and Review of the Literature. AB - Malignant tumours in the apices of the lungs, especially bronchogenic carcinoma (Pancoast tumours), are the most common cause of Pancoast' syndrome which presents with shoulder or arm pain radiating along the medial aspect of forearm and weakness of small muscles of hand with wasting of hypothenar eminence due to neoplastic involvement of C8 and T1 and T2 nerve roots of brachial plexus. There are a number of benign conditions which may lead to Pancoast's syndrome; fungal abscess located in the apex of lung is one of them. Oral or intravenous antifungals are the treatment of choice in this case and complete recovery is usual, whereas, surgical resection followed by chemoradiotherapy is the treatment of choice in case of Pancoast's syndrome due to lung cancers. Hence, tissue diagnosis is mandatory. Here, we report a case of apical fungal abscess causing Pancoast's syndrome in an immunocompetent individual of 35 years of age to raise the awareness among the clinicians regarding this rare clinical entity. PMID- 25302131 TI - The great recession and drinking outcomes: protective effects of politically oriented coping. AB - Research derived from the stress paradigm suggests that certain types of coping (e.g., problem-focused coping instead of behavioral disengagement) are protective against problem-related drinking to deal with social stressors. Going beyond the typical focus in the coping literature, we hypothesize that stressors engendered by macrolevel social forces may require coping actions within the political realm in contrast to modes of coping focused outside of the political realm. A United States sample of 663 respondents completed a mail survey in 2010, including measures of stressful consequences of the Great Recession, drinking patterns and problems, modes of coping encompassed in the Brief COPE instrument, and politically oriented coping. Structural equation modeling examined whether modes of coping mediated the links between stressors and drinking outcomes. A substantial portion of the associations between stressors and drinking was explained by modes of coping. Politically oriented coping was protective against problem drinking for both genders. Future studies should further explore politically oriented coping in addition to modes of coping outside of the political realm when studying the relationships between macrolevel social stressors and deleterious drinking outcomes. PMID- 25302132 TI - Pharmacokinetic study and bioavailability of a novel synthetic trioxane antimalarial compound 97/63 in rats. AB - Single dose pharmacokinetics study of 97/63 (IND191710, 2004), a trioxane antimalarial developed by Central Drug Research Institute, Lucknow, India, was studied in rats following intravenous and oral administration. Serum samples were analysed by HPLC-UV assay. Separation was achieved on a RP-18 column attached with a guard using acetonitrile : phosphate buffer (70 : 30% v/v) with UV detector at wavelength 244 nm. Serum samples were extracted with n-hexane. Two compartment model without lag time and first-order elimination rate was considered to be the best fit to explain the generated oral and intravenous data. Method was sensitive with limit of quantification of 10 ng mL(-1). Recovery was >74%. Terminal half-life and area under curve (AUC) after administering single oral (72 mg kg(-1)) and intravenous (18 mg kg(-1)) doses were 10.61 h, 10.57 h, and 1268.97 ng h mL(-1), 2025.75 ng h mL(-1), respectively. After oral dose, 97/63 was rapidly absorbed attaining maximum concentration 229.24 ng mL(-1) at 1 h. Bioavailability of 97/63 was ~16%. The lower bioavailability of drug may be due to poor solubility and first-pass metabolism and can be improved by prodrug formation of 97/63. PMID- 25302133 TI - Pharmacovigilance practices for better healthcare delivery: knowledge and attitude study in the national malaria control programme of India. AB - Objective. With large scale rollout of artemisinin based therapy in the National Malaria Control Programme of India, a risk management plan is needed. This depends on adverse drug reaction (ADR) reporting by the healthcare professionals (HCPs). For the programme to be successful, an understanding of the mindset of HCPs is critical. Hence, the present study was designed to assess and compare the ADR reporting beliefs of HCPs involved in the National Malaria Control Programme of India. Methods. A cross-sectional survey was conducted amongst the HCPs who manage malaria up to the district level in India. A 5-point Likert scale-based questionnaire was developed as a study tool. Results. A total of 154 HCPs participated in the study (age: 42.4 +/- 10.1 years with 33.8% being females). About 61% felt that only medically qualified HCPs are responsible for ADR reporting. Likeliness to report in future was mentioned by 45% HCPs. The knowledge score was relatively lower for life science graduates (P = 0.09). Knowledge correlated positively with attitude (r (2) = 0.114; P < 0.0001). Conclusion. Based on the caveats identified, a specific and targeted in-service education with hands-on training on ADR monitoring and reporting needs to be designed to boost real time pharmacovigilance in India. PMID- 25302134 TI - Sex, diastolic blood pressure, and outcome after thrombolysis for ischemic stroke. AB - Background. The goal of this study was to identify differences in risk factors and functional outcome between the two sexes in patients treated with thrombolysis for ischemic stroke. Methods. This cohort study audited data from patients treated with thrombolysis for ischemic stroke during a 3-year period at Sodersjukhuset, Stockholm. Results. Of the 355 patients included in the study, 162 (45%) were women and 193 (54%) were men. Women were older with a median age of 76 years; median age for men was 69 years (P < 0.0001). Diastolic blood pressure was lower for women compared to men (P = 0.001). At admission fewer women had a favorable modified Rankin Scale score compared to men (93.8% versus 99%, P = 0.008). Three months after discharge functional status did not differ significantly between the two sexes. Diastolic blood pressure was associated to functional outcome only in men when sex specific odds ratios were calculated (OR, 5.7; 95% CI, 1.7-20). Conclusion. The study indicates that females appear to gain a relatively greater benefit from thrombolytic therapy than men due to a better functional recovery. A higher diastolic blood pressure increases the risk for a worse prospective functional status in men. PMID- 25302135 TI - Quality control of natural product medicine and nutrient supplements 2014. PMID- 25302136 TI - Secreted HoxA3 Promotes Epidermal Proliferation and Angiogenesis in Genetically Modified Three-Dimensional Composite Skin Constructs. AB - Objective: Homeobox (HOX) transcription factors coordinate gene expression in wound repair and angiogenesis. Previous studies have shown that gene transfer of HoxA3 to wounds of diabetic mice accelerates wound healing, increasing angiogenesis and keratinocyte migration. In this study, we examined whether HoxA3 can also improve angiogenesis, epidermal integrity, and viability of composite skin grafts. Approach: To determine the effects of HoxA3 on composite skin grafts, we constructed bilayered composite grafts incorporating fibroblasts engineered to constitutively secrete HoxA3. We then transplanted these composite grafts in vivo. Results: The composite grafts produced a stratified epidermal layer after seventeen days in culture and following transplantation in vivo, these grafts exhibit normal epidermal differentiation and reduced contraction compared to controls. In addition, HoxA3 grafts showed increased angiogenesis. Quantitative polymerase chain reaction (PCR) analyses of HoxA3 graft tissue reveal an increase in the downstream HoxA3 target genes MMP-14 and uPAR expression, as well as a reduction in CCL-2 and CxCl-12. Innovation: Expression of secreted HoxA3 in composite grafts represents a comprehensive approach that targets both keratinocytes and endothelial cells to promote epidermal proliferation and angiogenesis. Conclusion: Secreted HoxA3 improves angiogenesis, reduces expression of inflammatory mediators, and prolongs composite skin graft integrity. PMID- 25302137 TI - Mechanoregulation of Angiogenesis in Wound Healing. AB - Significance: Mechanical forces are important regulators of cell and tissue function. Endothelial cells proliferate in response to tissue stretch and the mechanical properties of the environment direct capillary sprouting and growth. As the vascular network is a key factor in physiology and disease, control of the vascularity by means of mechanical forces could lead to the development of innovative therapeutic strategies. Recent Advances: Increased understanding of mechanobiology has stimulated translational research and allowed the development and optimization of clinical devices that exploit mechanical forces for the treatment of diseases, in particular in the field of wound healing. Stretching in distraction osteogenesis and tissue expansion induces neogenesis of well vascularized tissues. In micro-deformational wound therapy, micro-mechanical distortions of the wound bed stimulate cell proliferation and angiogenesis by stretching resident cells to improve healing of difficult wounds. Relief from tension antagonizes proliferation and angiogenesis in primarily closed wounds allowing for better scar quality. Critical Issues: The integration of mechanobiology into traditional cell biology and pathophysiology in general is not yet complete and further research is needed to fill existing gaps, in particular in the complexity of in vivo conditions. Future Directions: Still largely unexplored approaches based on mechanical perturbation of the micro /macro-environment can be devised to overcome the limits of current strategies in a broad spectrum of clinical conditions. PMID- 25302138 TI - Anti-Angiogenic Drugs: Involvement in Cutaneous Side Effects and Wound-Healing Complication. AB - Significance: The uses of anti-angiogenic drugs have not only made an impact on the battle to eliminate cancer but are also responsible for a number of medical complications. The long-term use of these drugs has increased the spectrum and incidence of cutaneous side effects and wound-healing complications. It is, therefore, necessary to understand the overall impact that these drugs have on patient care. Recent Advances: This review highlights the role of vascular endothelial growth factor and fibroblast growth factor in angiogenesis and wound healing and looks at how angiogenic inhibitors promote wound-healing complications. Critical Issues: With an increased use of anti-angiogenic drugs for the treatment of various cancers and ocular diseases, there is an increased need for clinicians to define the risks and to optimize the usage of these drugs to reduce the incidence of cutaneous side effects and wound-healing complications. In addition, awareness is needed when treating patients on anti angiogenic drugs so as not to exacerbate potential wound-healing complications when performing surgical procedures. Future Directions: Clinicians and surgeons will need to develop management guidelines to optimize patient care to reduce the risk of morbidity. When performing a surgical procedure, the impact of adverse effects from the use of anti-angiogenic drugs should be considered to ensure the welfare of the patient. In addition, the development of more specific inhibitors is necessary to reduce target effects to reduce the occurrence of adverse effects. PMID- 25302140 TI - A matching decomposition of the rural-urban difference in malnutrition in Malawi. AB - BACKGROUND: Child malnutrition remains widespread in many developing countries. Malnutrition during infancy may substantially increase vulnerability to infection and disease, and the risk of premature death. Malnutrition in children may also lead to permanent effects and to their having diminished health capital later in life as adults. These negative consequences of child malnutrition entail that the reduction of child malnutrition is vital for the social-economic development of countries. Urban children generally have better nutritional status than rural children. Malawi is no exception in this regard. The objective of this paper is to explore how much of the rural-urban nutrition gap in Malawi is explained and how much is unexplained by differences in characteristics. METHOD: Using data from the 2006 multiple indicator cluster survey (MICS), the paper used the Nopo decomposition method to decompose the rural-urban malnutrition gap. This nonparametric method takes into account the fact that the supports of the distributions of characteristics between the two areas can be different. RESULTS: The results show that 90% and 89% of the stunting and underweight gaps respectively would be eliminated if there were no urban children with combinations of characteristics which positively influence child nutrition that remain entirely unmatched by rural children. Further to that, 4% and 6% of the stunting and underweight gaps respectively would disappear if there were no rural children with combinations of characteristics which negatively affect child nutrition that remain entirely unmatched by urban children. CONCLUSIONS: These findings suggest that the characteristics which negatively affect child nutrition in rural areas play a small role in the gap, and that most of the gap is largely due to the favourable characteristics such as better parental education and better household economic status among others that urban children have. The findings imply that in order to reduce the malnutrition gap policy interventions should focus more on ensuring that the favourable characteristics that urban children have such as better parental education, better household economic status among others are also available to rural children. PMID- 25302139 TI - Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair. AB - Significance: Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of the repair process. Restoration of blood flow to damaged tissues provides oxygen and nutrients required to support the growth and function of reparative cells. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic growth factors in the skin, and the amount of VEGF present in a wound can significantly impact healing. Recent Advances: The activity of VEGF was once considered to be specific for endothelial cells lining the inside of blood vessels, partly because VEGF receptor (VEGFR) expression was believed to be restricted to endothelial cells. It is now known, however, that VEGFRs can be expressed by a variety of other cell types involved in wound repair. For example, keratinocytes and macrophages, which both carry out important functions during wound healing, express VEGFRs and are capable of responding directly to VEGF. Critical Issues: The mechanisms by which VEGF promotes angiogenesis are well established. Recent studies, however, indicate that VEGF can directly affect the activity of several nonendothelial cell types present in the skin. The implications of these extra-angiogenic effects of VEGF on wound repair are not yet known, but they suggest that this growth factor may play a more complex role during wound healing than previously believed. Future Directions: Despite the large number of studies focusing on VEGF and wound healing, it is clear that the current knowledge of how VEGF contributes to the repair of skin wounds is incomplete. Further research is needed to obtain a more comprehensive understanding of VEGF activities during the wound healing process. PMID- 25302142 TI - Spontaneous sphenoid wing meningoencephaloceles with lateral sphenoid sinus extension: the endoscopic transpterygoid approach. AB - Spontaneous meningoencephalocele (SME) of the sphenoid wing is a rare cause of cerebrospinal fluid (CSF) leakage. Surgical closure of the fistula is usually required. The approach taken depends on the location of the defect and the extension of the meningoencephalocele. The endoscopic transpterygoid approach may be useful. We prospectively analyzed the three cases of SME of the sphenoid wing with lateral sphenoid sinus extension treated endoscopically at Stanford over the last 3 years with regard to imaging findings, operative technique, and operative morbidity. In our three cases, the extent of pterygopalatine fossa (PPF) exposure undertaken, complete in one and partial in two, depended on the defect site. Follow-up ranged from 17 to 25 months. The fistula was completely closed in all three cases. Extant literature reports a 97% rate of successful closure (N = 65 of 67, with a mean follow-up of 25 months) and no major complications. Endoscopic transpterygoid repair is a useful, safe alternative to traditional approaches for repair of SME of the sphenoid wing. Its feasibility depends on the site of the defect, which can be identified by preoperative imaging. Larger PPF exposure and postoperative lumbar drainage of CSF can be useful and have a low risk of morbidity. PMID- 25302143 TI - Osteomyelitis of the temporal bone: terminology, diagnosis, and management. AB - Objectives To review the terminology, clinical features, and management of temporal bone osteomyelitis. Design and Setting Prospective study in a tertiary care center from 2001 to 2008. Participants Twenty patients visiting the outpatient department diagnosed with osteomyelitis of the temporal bone. Main Outcome Measures The age, sex, clinical features, cultured organisms, surgical interventions, and classification were analyzed. Results Of the 20 cases, 2 (10%) were diagnosed as acute otitis media. Eighteen (90%) had chronic otitis media. Nineteen (95%) were classified as medial temporal bone osteomyelitis and one (5%) as lateral temporal osteomyelitis. The most common clinical features were ear discharge (100%), pain (83%), and granulations (100%). Facial nerve palsy was seen in seven cases (35%) and parotid involvement in one case. Ten patients (56%) had diabetes mellitus. The organisms isolated were Pseudomonas aeruginosa (80%) and Staphylococcus aureus (13.33%). Histopathology revealed chronic inflammation in 20 patients (100%) and osteomyelitic bony changes in 14 (70%). Surgical debridement was the most preferred modality of treatment (87%). Conclusion A new classification of temporal bone osteomyelitis has been proposed. Bacterial cultures must be performed in all patients. Antibiotic therapy is the treatment of choice. Surgical intervention is necessary in the presence of severe pain, complications, refractory cases, or the presence of bony sequestra on radiology. PMID- 25302141 TI - Anatomy and cellular constituents of the human olfactory mucosa: a review. AB - Studies using animal models have recently suggested that the olfactory mucosa may be a source of cells capable of stimulating and contributing to complex neurologic regeneration. Several groups have already transplanted cell derivatives from the olfactory mucosa into injury models, and the results so far have been promising. To fully appreciate the meaning of these experiments, a better understanding of the cellular biology and physiology of the olfactory system is necessary. It is therefore of utmost importance for us to first identify and understand its constituents. PMID- 25302144 TI - In reference to "the value of resident presentations at scientific meetings". PMID- 25302145 TI - Genome Wide Mapping of Foxo1 Binding-sites in Murine T Lymphocytes. AB - The Forkhead box O (Foxo) family of transcription factors has a critical role in controlling the development, differentiation, and function of T cells. However, the direct target genes of Foxo transcription factors in T cells have not been well characterized. In this study, we focused on mapping the genome wide Foxo1 binding sites in naive CD4+ T cells, CD8+ T cells, and Foxp3+ regulatory T (Treg) cells. By using chromatin immunoprecipitation coupled with deep sequencing (ChIP Seq), we identified Foxo1 binding sites that were shared among or specific to the three T cell populations. Here we describe the experiments, quality controls, as well as the deep sequencing data. Part of the data analysis has been published by Ouyang W et al. in Nature 2012[1] and Kim MV et al. in Immunity 2013[2], and the associated data set were uploaded to NCBI Gene Expression Omnibus. PMID- 25302146 TI - A new acoustic lens material for large area detectors in photoacoustic breast tomography. AB - OBJECTIVES: We introduce a new acoustic lens material for photoacoustic tomography (PAT) to improve lateral resolution while possessing excellent acoustic acoustic impedance matching with tissue to minimize lens induced image artifacts. BACKGROUND: A large surface area detector due to its high sensitivity is preferable to detect weak signals in photoacoustic mammography. The lateral resolution is then limited by the narrow acceptance angle of such detectors. Acoustic lenses made of acrylic plastic (PMMA) have been used to enlarge the acceptance angle of such detectors and improve lateral resolution. However, such PMMA lenses introduce image artifacts due to internal reflections of ultrasound within the lenses, the result of acoustic impedance mismatch with the coupling medium or tissue. METHODS: A new lens is proposed based on the 2-component resin Stycast 1090SI. We characterized the acoustic properties of the proposed lens material in comparison with commonly used PMMA, inspecting the speed of sound, acoustic attenuation and density. We fabricated acoustic lenses based on the new material and PMMA, and studied the effect of the acoustic lenses on detector performance comparing finite element (FEM) simulations and measurements of directional sensitivity, pulse-echo response and frequency response. We further investigated the effect of using the acoustic lenses on the image quality of a photoacoustic breast tomography system using k-Wave simulations and experiments. RESULTS: Our acoustic characterization shows that Stycast 1090SI has tissue-like acoustic impedance, high speed of sound and low acoustic attenuation. These acoustic properties ensure an excellent acoustic lens material to minimize the acoustic insertion loss. Both acoustic lenses show significant enlargement of detector acceptance angle and lateral resolution improvement from modeling and experiments. However, the image artifacts induced by the presence of an acoustic lens are reduced using the proposed lens compared to PMMA lens, due to the minimization of internal reflections. CONCLUSIONS: The proposed Stycast 1090SI acoustic lens improves the lateral resolution of photoacoustic tomography systems while not suffering from internal reflection-induced image artifacts compared a lens made of PMMA. PMID- 25302147 TI - Clutter elimination for deep clinical optoacoustic imaging using localised vibration tagging (LOVIT). AB - This paper investigates a novel method which allows clutter elimination in deep optoacoustic imaging. Clutter significantly limits imaging depth in clinical optoacoustic imaging, when irradiation optics and ultrasound detector are integrated in a handheld probe for flexible imaging of the human body. Strong optoacoustic transients generated at the irradiation site obscure weak signals from deep inside the tissue, either directly by propagating towards the probe, or via acoustic scattering. In this study we demonstrate that signals of interest can be distinguished from clutter by tagging them at the place of origin with localised tissue vibration induced by the acoustic radiation force in a focused ultrasonic beam. We show phantom results where this technique allowed almost full clutter elimination and thus strongly improved contrast for deep imaging. Localised vibration tagging by means of acoustic radiation force is especially promising for integration into ultrasound systems that already have implemented radiation force elastography. PMID- 25302148 TI - Optical wavelength selection for improved spectroscopic photoacoustic imaging. AB - Spectroscopic photoacoustic imaging has the potential to become a powerful tool that can estimate distributions of optically absorbing chromophores in the body. We have developed an algorithm to select imaging wavelengths for spectroscopic photoacoustics given the spectra of expected chromophores. The algorithm uses the smallest singular value of a matrix constructed from the absorption spectra as a criterion to remove extraneous wavelengths. The method performed significantly better than an approach where evenly spaced wavelengths were used in the presence of noise and wavelength-dependent attenuation of light in tissue. Finally, the algorithm was applied to photoacoustic imaging of a phantom containing indocyanine green dye and silica-coated gold nanorods, demonstrating significant improvements in the ability to estimate relative contrast agent concentrations compared to the case where evenly spaced wavelengths were chosen. In summary, our work provides a versatile framework to select optical wavelengths and evaluate sets of absorbers for spectroscopic photoacoustic imaging. PMID- 25302149 TI - High frequency label-free photoacoustic microscopy of single cells. AB - Photoacoustic measurements of melanoma cells and red blood cells (RBCs) using ultra-high frequency (UHF) wide-bandwidth transducers are reported. In this detection system, the resolution typically depends on the parameters of the receiving transducer, and not the focus of the laser. A single melanoma cell was imaged with 200, 375 and 1200 MHz transducers. As the frequency increased, the resolution increased, resulting in greater detail observed. A single RBC was imaged at 1200 MHz, showing the contours of the cell. While lateral and axial resolutions approaching 1 MUm are possible with this microscope, the key advantage is the ability to perform a wide-bandwidth quantitative signal analysis of the photoacoustic signals. The power spectrum of the signals measured from RBCs showed distinct spectral minima around 800 and 1500 MHz which are directly related to the RBC geometry. This study reports on the high-resolution imaging capabilities and quantitative analyses using UHF photoacoustic microscopy. PMID- 25302150 TI - Optoacoustic spectroscopy for real-time monitoring of strongly light-absorbing solutions in applications to analytical chemistry. AB - An optoacoustic technique for solutions of strongly light-absorbing analytes at 0.1-0.01 mol l(-1) is proposed. The technique is based on the wide-band forward mode detection of temporal profiles of laser-generated ultrasonic pulses (optoacoustic signals). The leading edge of the signal repeats the distribution of the laser fluence in the medium, which makes it possible to determine its optical absorption and investigate its dynamics during a reaction. The range of light-absorption coefficients starts from 1 to 5 and reaches 10(4) to 10(5) cm( 1). The determination of iron(II) as ferroin shows the possibility of probing 0.1 mol l(-1) of iron(II), which was not previously achieved for this reaction by optical spectroscopy. To further prove the concept, kinetic measurements for ferroin decomposition at the level of 0.1 mol l(-1) and at high pHs are performed. The results are compared with spectrophotometry at lower concentrations and show good reproducibility and accuracy of kinetic constants. PMID- 25302151 TI - Functional optoacoustic human angiography with handheld video rate three dimensional scanner. AB - Optoacoustic imaging provides a unique combination of high optical contrast and excellent spatial resolution, making it ideal for simultaneous imaging of tissue anatomy as well as functional and molecular contrast in deep optically opaque tissues. We report on development of a portable clinical system for three dimensional optoacoustic visualization of deep human tissues at video rate. Studies in human volunteers have demonstrated powerful performance in delivering high resolution volumetric multispectral optoacoustic tomography (vMSOT) images of tissue morphology and function, such as blood oxygenation parameters, in real time. Whilst most imaging modalities currently in clinical use are not able to deliver volumetric data with comparable time resolution, the presented imaging approach holds promise to attain new diagnostic and treatment monitoring value for multiple indications, such as cardiovascular and peripheral vascular disease, disorders related to the lymphatic system, breast lesions, arthritis and inflammation. PMID- 25302153 TI - Reflection-mode multiple-illumination photoacoustic sensing to estimate optical properties. AB - OBJECTIVES: We analyze a reflection-mode multiple-illumination photoacoustic method which allows us to estimate optical scattering properties of turbid media based on fitting light-transport models and explore its limits in optical property estimation and depth-dependent fluence compensation. BACKGROUND: Recent simulation results show significant promise for a technique called multiple illumination photoacoustic tomography (MI-PAT) to quantitatively reconstruct both absorption and scattering heterogeneities in turbid medium. Prior to experiments, it is essential to develop and analyze a measurement technique and probe capabilities of quantitative measurements that focus on sensing rather than imaging. METHODS: This technique involved translation of a 532 nm pulsed-laser light spot while focusing an ultrasound receiver on a sub-surface optical absorber immersed in a scattering medium at 3, 4 and 5 mm below the surface. Measured photoacoustic amplitudes for media with different reduced scattering coefficients are fitted with a light propagation model to estimate optical properties. RESULTS: When the absorber was located at 5 mm below the membrane in media with a reduced scattering coefficient of 4.4 and 5.5 cm(-1), the true values were predicted with an error of 5.7% and 12.7%, respectively. We observe accuracy and the ability of estimating optical scattering properties decreased with the increased reduced scattering coefficient. Nevertheless, the estimated parameters were sufficient for demonstrating depth-dependent fluence compensation for improved quantitation in photoacoustic imaging. PMID- 25302152 TI - Photoacoustic imaging of human coronary atherosclerosis in two spectral bands. AB - Spectroscopic intravascular photoacoustic imaging (sIVPA) has shown promise to detect and distinguish lipids in atherosclerotic plaques. sIVPA generally utilizes one of the two high absorption bands in the lipid absorption spectrum at 1.2 MUm and 1.7 MUm. Specific absorption signatures of various lipid compounds within the bands in either wavelength range can potentially be used to differentiate between plaque lipids and peri-adventitial lipids. With the aim to quantify any differences between the two bands, we performed combined sIVPA imaging in both absorption bands on a vessel phantom and an atherosclerotic human coronary artery ex vivo. Lipid detection in a human atherosclerotic lesion with sIVPA required lower pulse energy at 1.7 MUm than at 1.2 MUm (0.4 mJ versus 1.2 mJ). The imaging depth was twice as large at 1.2 MUm compared to 1.7 MUm. Adequate differentiation between plaque and peri-adventitial lipids was achieved at 1.2 MUm only. PMID- 25302154 TI - All-optical scanhead for ultrasound and photoacoustic imaging-Imaging mode switching by dichroic filtering. AB - Ultrasound (US) and photoacoustic (PA) multimodality imaging has the advantage of combining good acoustic resolution with high optical contrast. The use of an all optical scanhead for both imaging modalities can simplify integration of the two systems and miniaturize the imaging scanhead. Herein we propose and demonstrate an all-optical US/PA scanhead using a thin plate for optoacoustic generation in US imaging, a polymer microring resonator for acoustic detection, and a dichroic filter to switch between the two imaging modes by changing the laser wavelength. A synthetic-aperture focusing technique is used to improve the resolution and contrast. Phantom images demonstrate the feasibility of this design, and show that axial and lateral resolutions of 125 MUm and 2.52 degrees , respectively, are possible. PMID- 25302155 TI - Photoacoustic excitation profiles of gold nanoparticles. AB - The wavelength dependence of the laser-induced photoacoustic signal amplitude has been measured for water dispersions of 10, 61, and 93 nm diameter gold nanospheres. The whole region of the localized surface plasmon resonance has been covered. This "photoacoustic excitation profile" can be overlayed with the extinction spectrum between 450 nm and 600 nm in the case of the smallest nanoparticles. At variance, the larger-sized nanoparticles display a progressive deviation from the extinction spectrum at longer wavelength, where the photoacoustic signal becomes relatively smaller. Considering that photoacoustics is intrinsically insensitive to light scattering, at least for optically thin samples, the results are in agreement with previous theoretical work predicting (i) an increasing contribution of scattering to extinction when the nanoparticle size increases and (ii) a larger scattering component at longer wavelengths. Therefore, the method has a general validity and can be applied to selectively determine light absorption by plasmonic systems. PMID- 25302156 TI - NDT of fiber-reinforced composites with a new fiber-optic pump-probe laser ultrasound system. AB - Laser-ultrasonics is an attractive and powerful tool for the non-destructive testing and evaluation (NDT&E) of composite materials. Current systems for non contact detection of ultrasound have relatively low sensitivity compared to contact peizotransducers. They are also expensive, difficult to adjust, and strongly influenced by environmental noise. Moreover, laser-ultrasound (LU) systems typically launch only about 50 firings per second, much slower than the kHz level pulse repetition rate of conventional systems. As demonstrated here, most of these drawbacks can be eliminated by combining a new generation of compact, inexpensive, high repetition rate nanosecond fiber lasers with new developments in fiber telecommunication optics and an optimally designed balanced probe beam detector. In particular, a modified fiber-optic balanced Sagnac interferometer is presented as part of a LU pump-probe system for NDT&E of aircraft composites. The performance of the all-optical system is demonstrated for a number of composite samples with different types and locations of inclusions. PMID- 25302157 TI - Optoacoustic detection of intra- and extracranial hematomas in rats after blast injury. AB - Surgical drainage of intracranial hematomas is often required within the first four hours after traumatic brain injury (TBI) to avoid death or severe disability. Although CT and MRI permit hematoma diagnosis, they can be used only at a major health-care facility. This delays hematoma diagnosis and therapy. We proposed to use an optoacoustic technique for rapid, noninvasive diagnosis of hematomas. In this study we developed a near-infrared OPO-based optoacoustic system for hematoma diagnosis and cerebral venous blood oxygenation monitoring in rats. A specially-designed blast device was used to inflict TBI in anesthetized rats. Optoacoustic signals were recorded from the superior sagittal sinus and hematomas that allowed for measurements of their oxygenations. These results indicate that the optoacoustic technique may be used for early diagnosis of hematomas and may provide important information for improving outcomes in patients with TBI. PMID- 25302159 TI - Early Onset and Severe Clinical Course Associated with the m.5540G>A Mutation in MT-TW. AB - We report a patient harboring a de novo m.5540G>A mutation affecting the MT-TW gene coding for the mitochondrial tryptophan-transfer RNA. This patient presented with atonic-myoclonic epilepsy, bilateral sensorineural hearing loss, ataxia, motor regression, ptosis, and pigmentary retinopathy. Our proband had an earlier onset and more severe phenotype than the first reported patient harboring the same mutation. We discuss her clinical presentation and compare it with the only previously published case. PMID- 25302158 TI - Sensitivity of photoacoustic microscopy. AB - Building on its high spatial resolution, deep penetration depth and excellent image contrast, 3D photoacoustic microscopy (PAM) has grown tremendously since its first publication in 2005. Integrating optical excitation and acoustic detection, PAM has broken through both the optical diffusion and optical diffraction limits. PAM has 100% relative sensitivity to optical absorption (i.e., a given percentage change in the optical absorption coefficient yields the same percentage change in the photoacoustic amplitude), and its ultimate detection sensitivity is limited only by thermal noise. Focusing on the engineering aspects of PAM, this Review discusses the detection sensitivity of PAM, compares the detection efficiency of different PAM designs, and summarizes the imaging performance of various endogenous and exogenous contrast agents. It then describes representative PAM applications with high detection sensitivity, and outlines paths to further improvement. PMID- 25302160 TI - Management of tyrosine kinase inhibitor resistance in lung cancer with EGFR mutation. AB - The identification of driver mutations and drugs that inhibit their activity has been a major therapeutic advance for patients with advanced lung adenocarcinoma. Unfortunately, the success of these drugs is limited by the universal development of resistance. Treatment failure can result from inadequate drug exposure or selection of resistant malignant clones. Clinically distinct mechanisms of disease progression have been identified and can inform treatment decisions. Investigations into the biochemical mechanisms of tyrosine kinase inhibitor resistance may provide additional therapeutic targets by which the efficacy of targeted therapy can be improved. PMID- 25302161 TI - Proton beam therapy for locally advanced lung cancer: A review. AB - Protons interact with human tissue differently than do photons and these differences can be exploited in an attempt to improve the care of lung cancer patients. This review examines proton beam therapy (PBT) as a component of a combined modality program for locally advanced lung cancers. It was specifically written for the non-radiation oncologist who desires greater understanding of this newer treatment modality. This review describes and compares photon (X-ray) radiotherapy (XRT) to PBT. The physical differences of these beams are described and the clinical literature is reviewed. Protons can be used to create treatment plans delivering significantly lower doses of radiation to the adjacent organs at risk (lungs, esophagus, and bone marrow) than photons. Clinically, PBT combined with chemotherapy has resulted in low rates of toxicity compared to XRT. Early results suggest a possible improvement in survival. The clinical results of proton therapy in lung cancer patients reveal relatively low rates of toxicity and possible survival benefits. One randomized study is being performed and another is planned to clarify the clinical differences in patient outcome for PBT compared to XRT. Along with the development of better systemic therapy, newer forms of radiotherapy such as PBT should positively impact the care of lung cancer patients. This review provides the reader with the current status of this new technology in treating locally advanced lung cancer. PMID- 25302162 TI - Review of the current targeted therapies for non-small-cell lung cancer. AB - The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come. PMID- 25302163 TI - Apoptosis block as a barrier to effective therapy in non small cell lung cancer. AB - Lung cancer, is the most common cause of cancer death in men and second only to breast cancer in women. Currently, the first line therapy of choice is platinum based combination chemotherapy. A therapeutic plateau has been reached with the prognosis for patients with advanced non-small cell lung cancer (NSCLC) remaining poor. New biomarkers of prognosis as well as new therapies focusing on molecular targets are emerging helping to identify patients who are likely to benefit from therapy. Despite this, drug resistance remains the major cause for treatment failure. In this article we review the role of apoptosis in mediating drug resistance in NSCLC. Better understanding of this fundamental biological process may provide a rationale for overcoming the current therapeutic plateau. PMID- 25302164 TI - Surgical strategies in the therapy of non-small cell lung cancer. AB - Lung cancer represents the leading cause of cancer mortality worldwide. Despite improvements in preoperative staging, surgical techniques, neoadjuvant/adjuvant options and postoperative care, there are still major difficulties in significantly improving survival, especially in locally advanced non-small cell lung cancer (NSCLC). To date, surgical resection is the primary mode of treatment for stage I and II NSCLC and has become an important component of the multimodality therapy of even more advanced disease with a curative intention. In fact, in NSCLC patients with solitary distant metastases, surgical interventions have been discussed in the last years. Accordingly, this review displays the recent surgical strategies implemented in the therapy of NSCLC patients. PMID- 25302165 TI - MicroRNAs as lung cancer biomarkers. AB - Lung cancer is the leading cause of cancer mortality worldwide. Its high mortality is due to the poor prognosis of the disease caused by a late disease presentation, tumor heterogeneities within histological subtypes, and the relatively limited understanding of tumor biology. Importantly, lung cancer histological subgroups respond differently to some chemotherapeutic substances and side effects of some therapies appear to vary between subgroups. Biomarkers able to stratify for the subtype of lung cancer, prognosticate the course of disease, or predict the response to treatment are in high demand. In the last decade, microRNAs (miRNAs), measured in resected tumor samples or in fine needle aspirate samples have emerged as biomarkers for tumor diagnosis, prognosis and prediction of response to treatment, due to the ease of their detection and in their extreme specificity. Moreover, miRNAs present in sputum, in plasma, in serum or in whole blood have increasingly been explored in the last five years as less invasive biomarkers for the early detection of cancers. In this review we cover the increasing amounts of data that have accumulated in the last ten years on the use of miRNAs as lung cancer biomarkers. PMID- 25302166 TI - C4.4A as a biomarker in pulmonary adenocarcinoma and squamous cell carcinoma. AB - The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uPAR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasive carcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway. PMID- 25302167 TI - Advances in adjuvant systemic therapy for non-small-cell lung cancer. AB - Non-small-cell lung cancer remains a leading cause of death around the world. For most cases, the only chance of cure comes from resection for localised disease, however relapse rates remain high following surgery. Data has emerged over recent years regarding the utility of adjuvant chemotherapy for improving disease-free and overall survival of patients following curative resection. This paper reviews the clinical trials that have been conducted in this area along with the studies integrating radiation therapy in the adjuvant setting. The role of prognostic gene signatures are reviewed as well as ongoing clinical trials including those incorporating biological or targeted therapies. PMID- 25302168 TI - Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer. AB - First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs. PMID- 25302169 TI - Acetylcholine receptor pathway in lung cancer: New twists to an old story. AB - Genome-wide association studies revealed that allelic variation in the alpha5 alpha3-beta4 nicotine acetylcholine receptor (nAChR) cluster on chromosome 15q24 15q25.1 was associated with lung cancer risk. nAChRs are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine (ACh) or other biologic compounds including nicotine. nAChRs have been found on lung cancer cells, underscoring the idea that the non-neuronal nAChR pathway has important implications for lung cancer. Several studies focusing on the treatment with nAChR antagonists with improved selectivity might trigger novel strategies for the intervention and prevention of lung cancer. Here we review the genetic risk factors for lung cancer in the nAChR gene cluster, the roles of nicotine receptors, and the molecular mechanisms of acetylcholine receptor pathways to lead to more opportunities for intervention and prevention of lung cancer. PMID- 25302170 TI - Cyclooxygenase-2 and the inflammogenesis of breast cancer. AB - Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2 (COX 2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following: (1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis; (2) essential features of mammary carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2 (PGE-2) biosynthesis; (3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis; (4) extrahepatic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and (5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer". PMID- 25302171 TI - Caring for the breast cancer survivor's health and well-being. AB - The breast cancer care continuum entails detection, diagnosis, treatment, and survivorship. During this time, focus on the whole woman and medical concerns beyond the breast cancer diagnosis itself is essential. In this comprehensive review, we critically review and evaluate recent evidence regarding several topics pertinent to and specific for the woman living with a prior history of breast cancer. More specifically, we discuss the most recent recommendations for contraceptive options including long-acting reversible contraception and emergency contraception, fertility and pregnancy considerations during and after breast cancer treatment, management of menopausal vasomotors symptoms and vulvovaginal atrophy which often occurs even in young women during treatment for breast cancer. The need to directly query the patient about these concerns is emphasized. Our focus is on non-systemic hormones and non-hormonal options. Our holistic approach to the care of the breast cancer survivor includes such preventive health issues as sexual and bone health,which are important in optimizing quality of life. We also discuss strategies for breast cancer recurrence surveillance in the setting of a prior breast cancer diagnosis. This review is intended for primary care practitioners as well as specialists caring for female breast cancer survivors and includes key points for evidence-based best practice recommendations. PMID- 25302172 TI - Phytoestrogens and prevention of breast cancer: The contentious debate. AB - Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. In this brief review the action of phytoestrogens on oestrogen receptors, cell signalling pathways, regulation of the cell cycle, apoptosis, steroid synthesis and epigenetic events in relation to breast cancer are discussed. Phytoestrogens can bind weakly to oestrogen receptors (ERs) and some have a preferential affinity for ERbeta which can inhibit the transcriptional growth promoting activity of ERalpha. However only saturating doses of phytoestrogens, stimulating both ERalpha and beta, exert growth inhibitory effects. Such effects on growth may be through phytoestrogens inhibiting cell signalling pathways. Phytoestrogens have also been shown to inhibit cyclin D1 expression but increase the expression of cyclin-dependent kinase inhibitors (p21 and p27) and the tumour suppressor gene p53. Again these effects are only observed at high (> 10) umol/L doses of phytoestrogens. Finally the effects of phytoestrogens on breast cancer may be mediated by their ability to inhibit local oestrogen synthesis and induce epigenetic changes. There are, though, difficulties in reconciling epidemiological and experimental data due to the fact experimental doses, both in vivo and in vitro, far exceed the circulating concentrations of "free" unbound phytoestrogens measured in women on a high phytoestrogen diet or those taking phytoestrogen supplements. PMID- 25302174 TI - Update on prevention and screening of cervical cancer. AB - Cervical cancer is the third most common cause of cancer in women in the world. During the past few decades tremendous strides have been made toward decreasing the incidence and mortality of cervical cancer with the implementation of various prevention and screening strategies. The causative agent linked to cervical cancer development and its precursors is the human papillomavirus (HPV). Prevention and screening measures for cervical cancer are paramount because the ability to identify and treat the illness at its premature stage often disrupts the process of neoplasia. Cervical carcinogenesis can be the result of infections from multiple high-risk HPV types that act synergistically. This imposes a level of complexity to identifying and vaccinating against the actual causative agent. Additionally, most HPV infections spontaneously clear. Therefore, screening strategies should optimally weigh the benefits and risks of screening to avoid the discovery and needless treatment of transient HPV infections. This article provides an update of the preventative and screening methods for cervical cancer, mainly HPV vaccination, screening with Pap smear cytology, and HPV testing. It also provides a discussion of the newest United States 2012 guidelines for cervical cancer screening, which changed the age to begin and end screening and lengthened the screening intervals. PMID- 25302173 TI - MicroRNAs in cancer therapeutic response: Friend and foe. AB - Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. During last decades, microRNAs (miRNAs), a class of non-coding RNAs, have emerged as critical players in cancer pathogenesis and progression by modulating many pathological aspects related to tumor development, growth, metastasis, and drug resistance. The major function of miRNAs is to post-transcriptionally regulate gene expression depending on recognition of complementary sequence residing in target mRNAs. Commonly, a particular miRNA recognition sequence could be found in a number of genes, which allows a single miRNA to regulate multiple functionally connected genes simultaneously and/or chronologically. Furthermore, a single gene can be targeted and regulated by multiple miRNAs. However, previous studies have demonstrated that miRNA functions are highly context-dependent, which leads to distinct pathological outcomes in different types of cancer as well as at different stages by alteration of the same miRNA. Here we summarize recent progress in studies on miRNA function in cancer initiation, metastasis and therapeutic response, focusing on breast cancer. The varying functions of miRNAs and potential application of using miRNAs as biomarkers as well as therapeutic approaches are further discussed in the context of different cancers. PMID- 25302175 TI - Role of IL-10 and TGF-beta1 in local immunosuppression in HPV-associated cervical neoplasia. AB - Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus (HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin (IL)-10 and transforming growth factor (TGF)-beta1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC I, NIC II and NIC III and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-beta1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-beta1 in response to HPV in humans. PMID- 25302176 TI - Brachytherapy in cancer cervix: Time to move ahead from point A? AB - Brachytherapy forms an integral part of the radiation therapy in cancer cervix. The dose prescription for intracavitary brachytherapy (ICBT) in cancer cervix is based on Tod and Meredith's point A and has been in practice since 1938. This was proposed at a time when accessibility to imaging technology and dose computation facilities was limited. The concept has been in practice worldwide for more than half a century and has been the fulcrum of all ICBT treatments, strategies and outcome measures. The method is simple and can be adapted by all centres practicing ICBT in cancer cervix. However, with the widespread availability of imaging techniques, clinical use of different dose-rates, availability of a host of applicators fabricated with image compatible materials, radiobiological implications of dose equivalence and its impact on tumour and organs at risk; more and more weight is being laid down on individualised image based brachytherapy. Thus, computed tomography, magnetic-resonance imaging and even positron emission computerized tomography along with brachytherapy treatment planning system are being increasingly adopted with promising outcomes. The present article reviews the evolution of dose prescription concepts in ICBT in cancer cervix and brings forward the need for image based brachytherapy to evaluate clinical outcomes. As is evident, a gradual transition from "point" based brachytherapy to "profile" based image guided brachytherapy is gaining widespread acceptance for dose prescription, reporting and outcome evaluation in the clinical practice of ICBT in cancer cervix. PMID- 25302177 TI - Cervical cancer: Can it be prevented? AB - Cervical cancer prevention requires a multipronged approach involving primary, secondary and tertiary prevention. The key element under primary prevention is human papilloma virus (HPV) vaccination. So far, only prophylactic HPV vaccines which prevent HPV infection by one or more subtypes are commercially available. Therapeutic HPV vaccines which aid in clearing established infection are still under trial. Secondary prevention entails early detection of precancerous lesions and its success is determined by the population coverage and the efficacy of the screening technique. A number of techniques are in use, including cytology, visual inspection (using the naked eye, magnivisualizer, acetic acid and Lugol's iodine), HPV testing and a combination of these methods. Updated screening guidelines have been advocated by the American Cancer Society in light of the role of HPV on cervical carcinogenesis. Recent research has also focussed on novel biomarkers that can predict progression to cancer in screen positive women and help to differentiate those who need treatment from those who can be left for follow-up. Last but not the least, effective treatment of precancerous lesions can help to reduce the incidence of invasive cervical cancer and this constitutes tertiary prevention. A combination of these approaches can help to prevent the burden of cervical cancer and its antecedent morbidity and mortality, but all of these are not feasible in all settings due to resource and allocation constraints. Thus, all countries, especially low and middle income ones, have to determine their own cocktail of approaches that work before we can say with certainty that yes, cervical cancer can be prevented. PMID- 25302179 TI - Morphological Traits Around Patellofemoral Joint in Indian Femora and their Implications. AB - INTRODUCTION: Knowledge of structural variations around patellofemoral joint has helped to understand postural behavior patterns of various population groups. The biomechanical impact of postures may lead to certain skeletal modifications which may contribute to knee pathologies like patellofemoral arthritis, patellar subluxation and trochlear dysplasia. This study was conducted to report the incidence of skeletal non-metric markers on femur in Indian population and to understand their correlation with some pathologies of patellofemoral joint. The traits studied were Martin's facet, Peritrochlear groove and Supratrochlear facet. MATERIALS AND METHODS: The study material was a collection of 152 adult femora from osteology museum in Department of Anatomy, Maulana Azad Medical College, New Delhi, India, with equal percentage of bones from each side and gender. All bones were evaluated for the above mentioned traits and results were obtained as percentage of incidence and Chi-Square test using SPSS version 17. RESULTS: The data showed that Martin's facet and Peritrochlear groove showed a higher occurrence in male femora. However, Supratrochlear facet was more commonly found in female bones. Martin's facet had an equal incidence on femora of each side while peritrochlear groove and supratrochlear facet had higher percentage of occurrence on right side. Supratrochlear facet revealed significant side variation. CONCLUSION: These data suggest that casual or occupational postures may impose structural adaptations around patell- ofemoral joint. The stress of these postures may have causal,consequential or co-incidental relationship with joint pathologies. The gender, special occupations like sports and genetic predisposition may possibly have a role to play. PMID- 25302178 TI - Clinical and scientific impact of human papillomavirus on head and neck cancer. AB - Head and neck cancer (HNC) arises from the skull base to the clavicles and is the fifth most common cancer in the world by incidence. Historically, in the developed world HNC was associated with tobacco use and alcohol consumption, and the combination of the two produced a synergistic increase in risk. However, beginning in 1983, investigators have found a significant and growing proportion of HNC patients with human papillomavirus-positive (HPV) tumors who neither drank nor used tobacco. Since that time, there has been increased interest in the molecular biology of HPV-positive HNC. Multiple studies now show that HPV has shifted the epidemiological landscape and prognosis of head and neck squamous cell carcinoma (HNSCC). These studies provide strong evidence for improved survival outcomes in patients with HPV-positive HNSCC compared to those with HPV negative HNSCC. In many reports, HPV status is the strongest predictor of locoregional control, disease specific survival and overall survival. In response to these findings, there has been significant interest in the best management of HPV-positive disease. Discussions within major cooperative groups consider new trials designed to maintain the current strong survival outcomes while reducing the long-term treatment-related toxicities. This review will highlight the epidemiological, clinical and molecular discoveries surrounding HPV-related HNSCC over the recent decades and we conclude by suggesting how these findings may guide future treatment approaches. PMID- 25302180 TI - Ossified ligamentum longitudinale anterius in adult human dry vertebrae. AB - BACKGROUND: The ligamentum longitudinale anterius is a broad and strong band of fibrous tissue that runs along the anterior surfaces of the bodies of the vertebrae. AIM: The study was undertaken to evaluate the incidence of ossified ligamentum longitudinale anterius in adult dry human vertebra. MATERIALS AND METHODS: This study was carried out on 95 sets of dry human vertebral columns irrespective of age and sex at Mayo Institute of Medical Sciences- Barabanki,-UP, Melaka Manipal Medical College-Manipal University and Department of Anatomy, KMCT Medical College, Manassery- Calicut, India. All the sets of vertebral columns were macroscopically inspected for the ossified ligamentum longitudinale anterius. RESULTS: It was observed that out of 95 sets of vertebral columns, 27 (28.42%) vertebral columns showed ossification. Out of 27 vertebral columns, 17 (17.89%) vertebral columns showed segmental type of ossification, 2 (2.11%) vertebral columns showed continuous type of ossification and 8 (8.42%) vertebral columns showed mixed type of ossification at different vertebral level. CONCLUSION: Such type of ossification will affect the biomechanics of the spine and may result in stiff neck, low back pain, dysphagia, odynophagia, compression of the brachial plexus, aphonia, immobility or mucosal thickening of larynx. Hence, knowledge of such abnormalities should be kept in mind to minimise serious complications in any surgical intervention or investigative procedures in the region. PMID- 25302181 TI - Study on variant anatomy of sciatic nerve. AB - INTRODUCTION: Sciatic Nerve (SN) is the nerve of the posterior compartment of thigh formed in the pelvis from the ventral rami of the L4 to S3 spinal nerves. It leaves the pelvis via the greater sciatic foramen below piriformis and divides into Common Peroneal Nerve (CPN) and Tibial Nerve (TN) at the level of the upper angle of the popliteal fossa. Higher division of the sciatic nerve is the most common variation where the TN and CPN may leave the pelvis through different routes. Such variation may lead to compression of the nerve and lead to Non discogenic sciatica. MATERIALS AND METHODS: Fifty lower limbs were used for the study from Department of Anatomy, J.J.M.M.C Davangere, Karnataka, India. OBSERVATION AND RESULTS: In our study on 25 cadavers (50 lower limbs), we have observed 4 (8 %) lower limbs high division of sciatic nerve was noted. High division of sciatic nerve in the back of thigh was noted in one specimen (2%), while high division within the pelvis was noted in 3 specimens (6%), while in 46 (92%) it occurred outside the pelvis. CONCLUSION: Knowledge regarding such variation and differences in the course of SN is important for the surgeons to plan for various surgical interventions pertaining to the gluteal region. The variant anatomy of SN may cause piriformis syndrome and failure of SN block. Hence present study is undertaken to know the level of division, exit, course, relationship to piriformis and variations in the branching pattern of SN. PMID- 25302182 TI - Morphometric analysis of upper end of tibia. AB - INTRODUCTION: The present study aims to assess different morphometric parameters of condylar and intercondylar surface of tibia and to compile the results, analyze and formulate a baseline data for future studies with relevance to Indian population and also to compare the current data with accessible literature for pertinent surgical utilities. Morphometric parameters of upper end of tibia can be used to guide treatment and monitor outcome of total knee replacement surgeries. Information regarding morphometry of upper end of the tibia is vital as it provides reliable method of assessing knee deformity. MATERIALS AND METHODS: The study group comprised of 50 male and 50 female adult human tibiae. Morphometric measurements of medial condyle, lateral condyle and intercondylar area of tibiae were meticulously recorded with digital Vernier calipers with a least count of 0.01 mm. Student's t-test was used with significant level of p value < 0.05 and 95% confidence interval. RESULTS: All measurements were found to be statistically significant when compared between the two sexes on both sides (p value<0.05). Anteroposterior measurements were found to be greater than transverse measurements for both medial and lateral condyles. Furthermore, both anteroposterior and transverse measurements were greater in medial condyle than in lateral condyle on both sides and sexes. CONCLUSION: The present study is an endeavor to provide a base line data pertaining to morphometric details of upper end of tibia with reference to unicompartmental and total knee arthroplasty in Indian population. The results of the study assume special importance in view of the technical advancements in reconstructive surgical procedures in orthopedic practice. PMID- 25302183 TI - True cyclopia-very rare anomaly. AB - During our routine postmortem examination, we found a female infant with "True Cyclopia." The two entire eye balls had fused completely to form one midline organ. The infant was a female who weighed 2910 g. The gestation period was 35 weeks. Infant lived for a short period of less than 20 minutes. The birth was a product of a 4(th) pregnancy. PMID- 25302184 TI - Atypical arterial supply to the spleen by polar branches of splenic artery and accessory splenic artery - a case report. AB - Vascular anomalies of the spleen are usually asymptomatic. However, variant anatomy of splenic artery becomes clinically important, when the patients undergo diagnostic angiography for gastrointestinal bleeding or during transcatheter therapy. We report here a concurrent variant arterial pattern of the spleen. The splenic artery was unusually elongated and excessively tortuous. Prior to its normal termination into segmental arteries, it gave superior and inferior polar arteries which entered the spleen distal to corresponding ends of the splenic hilum. In addition to this, the spleen also received an additional blood supply from an accessory splenic artery arising from left gastro-epiploic artery. The accessory splenic artery entered the substance of the spleen through its lateral end. Presence of such kind of concurrent variant arterial pattern of spleen makes the surgeons obligatory to have prior knowledge to prevent bleeding during any surgical or radiological interventional procedures targeting the spleen, pancreas etc. PMID- 25302185 TI - Effect of Isometric Exercise on QTc Interval. AB - INTRODUCTION: The QTc interval is affected by heart rate, autonomic nervous system and diseases like diabetes. However, the affect of exercise which alters autonomic nervous system activity, on QTc is not clear. On the other hand, the incidence of sudden cardiac death increases many fold post exercise. These events may be better explained by studying the effect of exercise on QTc. AIM: This study was designed with an aim to record the QTc interval changes in response to isometric exercise in a group of normal individuals with or without parental history of diabetes mellitus. Also the QTc duration was correlated with the LF-HF ratio. MATERIALS AND METHODS: Twenty nine, healthy medical students were subjected to isometric hand grip test for 5min. ECG was recorded pre-exercise and at various time intervals post-exercise. STATISTICAL ANALYSIS: All data are expressed in mean +/- SD. Intra group comparison was done using paired t-test and unpaired t-test was used for comparison among group I and group II subjects, and among males and females. RESULT: The difference in the pre and post exercise QTc values both within and between groups was statistically significant with group I subjects recording lower values. The post exercise LF: HF values were significantly increased when compared to pre exercise values in both the groups. There was no correlation between LF: HF and QTc. CONCLUSION: A longer than normal QTc interval predisposes to arrhythmia. Exercise brings about detectable changes in the QTc interval after a period of isometric exercise in normal individuals which in high risk individuals may predispose to sudden cardiac death. In addition women may be more susceptible to post-exercise arrhythmia owing to a longer QTc even at rest. PMID- 25302186 TI - Evaluation of Examination Stress and Its Effect on Cognitive Function among First Year Medical Students. AB - BACKGROUND: Medical students experience stress at every phase of curriculum more so before examination. This stress may affect physiological, psychological and cognitive functions of the students. AIM: The present study aimed to evaluate stress status among first year MBBS students by recording pulse rate (PR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and using stress questionnaire; its effect on cognitive function by recording auditory reaction time (ART) and visual reaction time (VRT). SETTING AND DESIGN: It is a cross sectional study. MATERIALS AND METHODS: A total of 100 (49 males and 51 females) first year healthy MBBS students participated. Stress questionnaire was given and assessed. Cardiovascular parameters were also assessed. The ART and VRT were recorded before (pre examination setting) and after 3 month of examination (post examination setting). STATISTICAL ANALYSIS: The data were analysed by using SPSS 21.0 version. RESULTS: All parameters namely PR, SBP, DBP, ART, VRT and stress scores were increased in preexamination setting irrespective of gender. Increased PR was observed in female learners where as stress score and SBP were increased in males in pre-examination setting. ART and VRT were more in females as compared to males in both setting. CONCLUSION: It is concluded that examination in the form of stressor hampers cognitive function of first year medical students. The cognitive functions of the female learners were more affected as compared to males. Therefore, proper counselling of the students should be initiated at the earliest to decrease their stress level. PMID- 25302187 TI - Prevalance of obesity in children with cerebral palsy. AB - INTRODUCTION: Obesity are epidemic among children and adolescents. There is worldwide tendency of increasing prevalence of obesity in children. Cerebral palsy (CP) is leading cause of childhood disability.studies have proposed mechanism of children with disability leading towards obesity and related health risks. So this study is aimed at determining whether such trend of obesity exists in children with CP in terms of BMI and WHR. STUDY DESIGN: Cross -sectional study. MATERIALS AND METHODS: PARTICIPANTS: 40 children diagnosed as CP age 2-18 years, GMFCS I-IV. PROCEDURE: BMI; kg/m(2) was calculated from height and weight. WHR was calculated by measuring waist circumference and hip circumference. BMI percentiles were reported according to sex-specific age group standards for growth set by the WHO growth charts. RESULTS: Out of total CP subjects 40% were found to be underweight, 45%, 7.5% and 7.5% were found to be normal, overweight and obese respectively according to BMI. Whereas 20%, 20% 60% were found to be at high risk, moderate risk and high risk of obesity respectively according to WHR. CONCLUSION: In our patient population, analysis of BMI and WHR suggests that children with CP have a high rate of overweight and are at risk of overweight, particularly of central obesity. PMID- 25302188 TI - Role of biological sex in normal cardiac function and in its disease outcome - a review. AB - Biological sex plays an important role in normal cardiac physiology as well as in the heart's response to cardiac disease. Women generally have better cardiac function and survival than do men in the face of cardiac disease; however, this is progressively lost when comparing postmenopausal women with age matched men. Animal model of cardiac disease mirror what is seen in humans. Sex hormones contribute significantly to sex based difference in cardiac functioning and in its disease outcome. Estrogen is considered to be cardioprotective, whereas testosterone is detrimental to heart function. PMID- 25302189 TI - Ratio Of Serum Asymmetric Dimethyl Arginine (ADMA)/ Nitric Oxide in Coronary Artery Disease patients. AB - BACKGROUND: Coronary artery disease (CAD) is the leading cause of mortality and morbidity in the world. Current predictions estimate that by the year 2020 cardiovascular diseases, notably atherosclerosis will become the leading global cause of the total disease burden. Atherosclerosis of the Coronary artery causes myocardial infarction and angina pectoris. Endothelial Nitric oxide (NO), released by the intact and healthy endothelium plays a very important role in the maintenance of vascular tone and structure. Decreased NO level leads to endothelial dysfunction is an initial event in the atherosclerosis. Endogenous Asymmetric dimethylarginine (ADMA) is a structural analog of L-arginine, competitively inhibits the enzyme NO synthase and thus decreases the NO level. AIM: To study the ratio of serum ADMA / NO as a marker of severity of CAD. MATERIALS AND METHODS: The study comprises of 60 patients of CAD diagnosed by coronary angiography. We divided them into two Groups according to percentage of atherosclerotic block, Group A (71% and more block, n=30) and Group B (40% - 70% block, n=30). We measured serum ADMA, serum NO and calculated ADMA/ NO ratio. RESULTS were compared with 30 healthy age and sex matched controls. Serum ADMA was determined by reverse phase high performance liquid chromatography. Serum NO was measured by cadmium reduction method. Statistical analysis of data analysis was done using the SPSS (Statistical Package for the Social Science) Version 11 for window. RESULTS: Serum ADMA was correlated positively with the presence and severity of CAD and inversely related with the serum NO levels. Serum ADMA / NO ratio was statistically significant in CAD patients with atherosclerotic block 71% and above (Group A) but ratio was not significant in Group B (block 40% - 70%). CONCLUSION: Serum ADMA/ NO ratio can be the better predictive marker for the severity of the CAD where patient is at the risk of angina pectoris or myocardial infarction due to the extent of coronary atherosclerotic block than individual serum ADMA levels . PMID- 25302190 TI - Hyperhomocysteinemia, Insulin Resistance and High HS- CRP Levels in Prehypertension. AB - BACKGROUND: Pre-hypertension refers to blood pressure in the range of 120 to 139 mm of Hg / 80 to 89 mm of Hg and its prevalence is increasing in India. Previous studies have documented the increase in homocysteine, C-reactive protein and insulin resistance and their role in the development of hypertension. In recent years much attention has been focused on subjects with prehypertension, as the risk for development of cardiovascular disease is higher in these subjects compared to those with normal blood pressure. OBJECTIVES: To evaluate the serum homocysteine, hs-CRP level and insulin resistance in subjects with prehypertension. MATERIALS AND METHODS: Sixty prehypertensives and 32 normotensives were recruited according to Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of blood pressure (JNC 7) guidelines. Serum homocysteine, vitamin B12, folate, insulin, hs-CRP and lipid profile were analysed. Independent t-test was carried out to compare two groups and pearson correlation analyses were carried out between various parameters with systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: Cardiovascular risk factors like serum homocysteine, insulin resistance and inflammatory marker hs-CRP were significantly increased in prehypertensives. Total cholesterol, TG, LDL-C and VLDL-C were significantly increased when compared to normotensives. Serum homocysteine correlated positively and vitamin B12 and folate negatively with Systolic Blood Pressure. CONCLUSION: The present study concludes that the established cardiovascular risk factors, homocysteine, insulin resistance, and hs-CRP which have roles in the etiopathogenesis of hypertension, were elevated in subjects with prehypertension. Thus, early detection and life style modification may reduce the risk or delay the onset of hypertension and other cardiovascular complications. PMID- 25302191 TI - Relationship of Lipid Profile and Serum Ferritin levels with Acute Myocardial Infarction. AB - INTRODUCTION: National Health and Nutrition Examination Survey (NHANES III), 1988 1994, first time reported a significant, positive association in iron storage and heart disease risk. Thereafter several researchers have found an association between iron overload, serum ferritin (SF) and MI. No such Indian study was available in the literature and so we decided to find out the relation of lipid profile and Serum Ferritin with myocardial infarction (MI). MATERIALS AND METHODS: Fifty indian patients of AMI (study group) and fifty indian healthy volunteers (control group) were included for the present study. Lipid profile including TC, HDL-c, LDL-c, VLDL-c & TG and SF levels were estimated in all subjects. OBSERVATIONS AND RESULTS: Mean +/- SD of TC level was 250.64 +/- 25.61, of HDL-c was 36.52 +/- 2.86, of LDL-c was 165.69 +/- 26.80, of VLDL-c was 42.35 +/- 8.53 and of TG was 211.83 +/- 42.65 in study group while these values were 174.46+/-47.68, 43.2+/-12.52, 98.37+/-41.13, 32.88+/-21.45 and 164.42+/-107.29 respectively in control group. All the parameters were found not only raised in patients of acute myocardial infarction (AMI) but were also statistically significant when compared with control group (p=<0.01). Mean +/- SD of SF levels was 268.43+/-30.17 ng/ml in study group and 110.96+/-56.5 ng/ml in control group; this level was found not only raised in patients of AMI but were also statistically significant when compared with control group (p=<0.01). CONCLUSION: TC, LDL-c, VLDL-c, TG and SF levels were raised in patients of AMI and found to be statistically significant; while HDL-c levels were reduced in such patients and is also statistically significant. It can be concluded that there exists an association in lipid profile and SF with AMI therefore dyslipidemia and raised SF levels are the features of AMI. PMID- 25302192 TI - Prevalence of insulin resistance in siblings of type 2 diabetics of north west punjabi population. AB - CONTEXT: Insulin resistance a physiological condition is marked by hyperglycemia and failure of cells to respond to normal action thus hyperinsulinemia. It is prevalent in individuals having genetic predisposition and family history of type 2 diabetes mellitus. Physically inactive individuals having sedentary life style are also at a risk of developing insulin resistance. AIM: The present study was planned to observe the prevalence of insulin resistance or pre diabetes in various age groups of North West Punjabi population. MATERIALS AND METHODS: A total of 400 families comprising of 1159 offsprings of diabetic patients and siblings amongst each were included in the present study. All these 400 families had history of type 2 diabetes mellitus in the present or past generation. Written consent was taken from the head of the family for inclusion in the study. Fasting samples were collected and analysed for Glucose, Glycosylated Hb, complete lipid profile, Insulin and c-peptide. Body mass index, waist hip ratio and HOMA-IR were calculated. Comparison of mean of various parameters was done using student t-test. Analysis of variance (ANOVA) was applied for comparison between groups followed by Bonferroni post hoc analysis. Pearson's correlation method was used for quantitative variables. Statistical significance was defined as p<0.05 (two tailed). RESULTS: Prevalence of impaired fasting glucose both in males and females increased with advancing age. Hyperglycemia along with hyperinsulinemia, hypercholesterolemia and hypertriglyceridemia was observed in individuals having impaired fasting glucose. Individuals belonging to age group of >18-35 years were more prone to insulin resistance as compared to other age groups. CONCLUSION: Insulin resistance at a young age of 18-35 years predisposes these individuals to coronary events. Females in reproductive years are more prone to insulin resistance or pre diabetes as compared to males of the same age group. PMID- 25302193 TI - A Study to Assess Knowledge and Attitude Regarding Hand Hygiene amongst Residents and Nursing Staff in a Tertiary Health Care Setting of Bhopal City. AB - BACKGROUND: Infection due to hospital-acquired microbes is an evolving problem worldwide, and horizontal transmission of bacterial organism continues to cause a high nosocomial infection rate in health care settings. Most nosocomial infections are thought to be transmitted by the hands of health care workers.The application of hand hygiene is effective in reducing infection rates. OBJECTIVES: To assess the level of knowledge and attitude regarding hand hygiene practices amongst the health care professionals and to identify areas of gaps in their knowledge and attitude. MATERIALS AND METHODS: A cross-sectional study. RESULT: A total 160 respondents were studied about their knowledge and attitude towards hand hygiene practices and significant difference with a p-value of 0.0025 was observed regarding most frequent source of germs responsible for health care associated infections among resident and nurses. A significant difference with p value of 0.0001 & 0.04 was observed in colonization due to jewellery and artificial nail among the study groups. The attitude regarding correct hand hygiene practices to be followed at all times was found to be better among nurses (62.5%) as compared to residents (21.3%) which was found to be highly significant with p-value <0.001. CONCLUSION: Present study highlights the need of repeated training sessions regarding hand hygiene practices among the health care workers to provide the current knowledge in the area with a behavioral change in attitudes and practices leading to reduction of nosocomial infections. PMID- 25302194 TI - NS1 Antigen Capture ELISA an Effective Method for Diagnosis of Early Dengue Infection - Report of an Outbreak at Angul District, Odisha, India. AB - BACKGROUND: An outbreak of dengue infection occurred in Angul district of Odisha in the month of August & September, 2011. The study was undertaken to detect NS1 antigen positivity among the study population, to compare IgM capture ELISA with NS1 antigen detection for diagnosis of dengue and to identify the predominant genotype of Dengue virus responsible for the outbreak. MATERIALS AND METHODS: Total 1020 serum samples were collected from clinically suspected cases of dengue from the outbreak. All were subjected for NS1 antigen detection, 92 were selected based on their clinical severity of illness (fever, rash, bleeding manifestation, arthralgia) for further study of IgM ELISA and platelet count and 148 NS1 positive samples were selected from different Blocks of Anugul district for RT PCR at NIV, Pune, India. RESULTS: Five hundred and thirteen (50.2%) samples were positive for NS1 antigen (highly significant p-value <0.0001, C.I - 95%) with 88% positivity during 1-5 days. The NS1 Ag positivity was peaked to 86.9% on days 3 to 5 (Sensitivity & NPV - 100% each) & declined to 6.2% during 6-10 days with a low sensitivity of 7.14% but 100% specificity & PPV. However, the IgM antibody positivity was 81.2% on days 6 to 10 and 87.5% after 10 days (Sensitivity- 100%, Specificity-13.33%,PPV-7.14% & NPV - 100%). RT-PCR resulted 32.4% positivity (6- DEN1, 39 - DEN 2 & 3- DEN 3) among which 20% were in IgM +ve & 68% in IgM -ve cases. CONCLUSION: Therefore, early diagnosis of dengue could be mainly by NS1 antigen detection whereas Ig M ELISA is a better tool during the later stage of infection &RT-PCR is more effective in IgM -ve cases.The predominant genotype responsible for the outbreak was found to be DEN-2. PMID- 25302195 TI - Urinary tract infection by chromobacterium violaceum. AB - Chromobacterium violaceum, a facultative anaerobic proteobacterium, is particularly isolated from water and soil in tropical areas and has been implicated in few infections like septicemia, visceral abscesses, skin and soft tissue infections, meningitis and diarrhea. But urinary tract infection caused by it is very rare. Limited awareness about this pathogen and inappropriate antibiotic therapy contribute to a high mortality rate. Here, we describe an unusual case of urinary tract infection by Chromobacterium violaceum in a young immuno-competent male which was managed aggressively with proper antibiotics as per the culture sensitivity report. PMID- 25302196 TI - Aetiological profile and antibiotic susceptibility pattern in patients with urinary tract infection in tripura. PMID- 25302197 TI - Role of absolute reticulocyte count in evaluation of pancytopenia-a hospital based study. AB - BACKGROUND: Pancytopenia is a common hematological entity encountered in our laboratory practice. Evaluating the causes of pancytopenia is essential for the diagnostic as well as therapeutic management of the patients. Absolute Reticulocyte count (ARC) plays a pivotal role in identifying the cause of pancytopenia in most of the cases but it has grossly been overlooked. Hence, we attempted to identify the significance of ARC as a deciding parameter in evaluating the causes of pancytopenia. MATERIALS AND METHODS: The study was conducted in a tertiary health care hospital, Chennai, India. A cross-sectional descriptive study was conducted over a period of two years (2011-2013). Patients who satisfied the criteria for pancytopenia were evaluated with clinical details. Pancytopenia work-up including Peripheral blood picture, Complete blood counts, Reticulocyte count, Serum Ferritin, B12, Folate and Bone marrow aspirate was carried out. ARC was calculated and an algorithm to approach the cases of pancytopenia was derived considering ARC as the key factor. RESULTS: A total of 429 cases of pancytopenia were evaluated and based on our algorithm results were tabulated. ARC was found to be <25x10^(9)/L for cases of Aplastic anaemia; 25 50x10^(9)/L for Nutritional anaemia; and, >100x10^(9)/L in Marrow infiltrative disorders and in cases of sepsis and malaria. CONCLUSION: We found that ARC plays an important role in differentiating various causes of pancytopenia and hence should be routinely included in pancytopenia work up in order to avoid unnecessary bone marrow aspirations in pancytopenic patients. PMID- 25302198 TI - Clinico-histopathological analysis of neoplastic and non-neoplastic lesions of the ovary: a 3-year prospective study in dhule, north maharashtra, India. AB - BACKGROUND: Ovary is the commonest site of neoplastic and non-neoplastic lesion, can present in childhood to postmenopausal age group and accounts for the most prevalent cause of hospital admissions. AIM: This study was done to analyse the frequency of ovarian lesions their clinico-histological features in a rural set up. MATERIALS AND METHODS: This is a prospective study of 145 ovarian lesions at tertiary care hospital over a period of 3yr. All the relevant clinical data of patients analysed from hospital record file. RESULTS: The total number of ovarian lesions studied during study period was 145 cases, amongst them 75 were non neoplastic and remaining 70 were neoplastic. The most common non-neoplastic lesion seen was solitary follicular cysts i.e. 56 cases (74.66%), followed by corpus luteal cysts 15 cases (20%). Among the 70 neoplastic ovarian lesions 55(78.57%) cases were benign, 1(1.42%) case was at borderline and 14 (20%) cases were malignant. In benign ovarian neoplasm, most commonly seen lesion were serous cystadenoma followed by benign cystic teratoma. In malignant cases, maximum were of serous cystadenocarcinoma, followed by mucinous cystadenocarcinoma and metastatic tumours. CONCLUSION: Ovarian lesion possess wide gamut of histology. Specific diagnoses are made on routine gross and histological examination or in certain difficult cases require immunohistochemistry. PMID- 25302199 TI - A comparative evaluation of scoring systems for assessing necro-inflammatory activity and fibrosis in liver biopsies of patients with chronic viral hepatitis. AB - INTRODUCTION: To compare the five scoring systems in assessing grading and staging of liver biopsies from patients with chronic viral hepatitis and their problems and pitfalls. MATERIALS AND METHODS: Liver biopsies from 25 patients with chronic viral hepatitis were studied. Sections were stained with Haematoxylin and Eosin, Reticulin and Masson's Trichrome stains. Van Gieson, Perl's and Shikata's Orcein stains were used as and when required. Coded histological sections were scored independently by three histopathologists using the Knodell Histology Activity Index (HAI), the Scheuer scoring system, Ishak's system, Metavir system and Ishak modified HAI. RESULTS: There were 15 males and 10 females. Their mean age was 51.24 years. On histological examination, hepatocytes showed degenerative changes with varying grades of necrosis (spotty and confluent). Widening of portal tracts with varying severity of mononuclear inflammatory infiltrate and interface hepatitis was observed. Fibrosis appeared as periportal, portal-portal and portal-central septa. A significant agreement was found by kappa statistics for both grading (p< 0.001) as well as staging (p < 0.001) among all the five scoring systems. Lobular activity was the only parameter that showed some discrepancy. No significant intra observer difference was observed. CONCLUSION: It is concluded that all the scoring systems are equally good for grading and staging in the hands of an experienced hepatopathologists. PMID- 25302200 TI - Diagnostic value of bone marrow aspiration and biopsy in routine hematology practice. AB - BACKGROUND: The bone marrow is frequently involved in variety of cases presenting with hematological and non-hematological disorders, which are diagnosed by two separate but interrelated techniques such as bone marrow aspiration (BMA) and bone marrow biopsy (BMB). AIM: This study was aimed to assess the diagnostic value of the BMA and BMB and role of both the procedures to reach final diagnosis when done simultaneously. SETTINGS AND DESIGN: It was a prospective study. The findings of BMA smears were correlated with BMB sections and data obtained was analysed. MATERIALS AND METHODS: BMA and BMB were performed on 50 patients. Criteria of inclusion included the main indications for performing this procedure, the availability of full medical records and patient consent. The patients had a male to female sex ratio of 1.6:1 and a wide age range from 4 years to 74 years. RESULTS: In the present study, the main indications for bone marrow examination were categorized. Out of 50 cases studied, in 23 cases, a strong positive correlation between BMA and BMB was noted. However, it was found that in the cases of aplastic anaemia, different phases of myeloproliferative neoplasm (MPN), multiple myeloma, tubercular granulomas and hemato-lymphoid neoplasm, involvement of the marrow was detected better in bone marrow biopsies. CONCLUSION: The study concludes that preparations of aspirate and trephine biopsy are easy, rapid and complementary to each other in majority of the lesions. The advantage of both the procedures done together enabled us to study the cytomorphology of the cells along with the pattern of distribution of the cells depending on the cases, hence help in making the diagnosis accurately. PMID- 25302201 TI - Wilkie's Syndrome and Left Adnexal Mass: Unusual Presentation of Duodenal Adenocarcinoma. AB - Duodenal adenocarcinoma (DACa) is a rare malignancy, the presenting symptoms of which are vague and nonspecific. We report the case of a patient presenting with symptoms of subacute small bowel obstruction whose CT scan revealed i) left adnexal mass and ii) compression of 3(rd) portion of duodenum with reduced aortomesentric angle consistent with Wilkie's syndrome (WS). Laparatomy in addition revealed a distal duodenal stricture, which showed a well differentiated DACa causing subtotal intestinal obstruction. The ovarian mass revealed adenocarcinoma with similar morphology. Immunophenotypic analysis revealed positive expression of CK 20 and CDX 2 and absence of CK 7 staining in the tumours consistent with Primary DACa with ovarian metastasis. We further concluded that the WS resulted from reduced mesenteric fat pad caused by DACa induced cachexia. The case highlights the elusive nature of duodenal malignancy and emphasises the importance of meticulous small bowel examination during exploration of ovarian masses. PMID- 25302202 TI - Malignant melanoma of the external auditory canal. AB - Primary malignant melanoma of the external auditory canal is rarely reported. Malignant melanoma of the ear is estimated to occur in 1-4% of all skin melanomas and about 7-20% of melanomas of the head and neck region. The pathophysiology of these tumours is different from other skin lesions because of their anatomical and functional characteristics. The case presented is of a 11 year old female child with malignant melanoma of the external auditory canal confined to the right side, who initially presented with right ear pain, bleeding, post auricular swelling and also a mass in the external auditory canal which was thought to be an aural polyp in the right ear. Excision of the tumour was accomplished by a radical mastoidectomy. It was confirmed to be malignant melanoma after histopathological examination and Immunohistochemistry. Despite all efforts, the patient succumbed to the disease after receiving three cycles of chemotherapy. Even though this malignancy is rarely found in the external auditory canal, it should be expanded into the differential diagnosis of an aural polyp and a post aural abscess. The incidence, symptoms, investigations, treatment and prognosis of malignant melanoma of the external auditory canal is discussed in this article. PMID- 25302203 TI - Vulvar syringoma: a rare case report. AB - Syringoma is a benign eccrine sweat gland tumour affecting mostly females at puberty as multiple soft papules usually 1-2 mm in diameter. The sites of predilection are lower eyelids, cheeks. Syringoma of the vulva is a rare disorder. Only few cases have been reported in the literature. We report here a case of 46-year-old female who presented to gynecology department with vulvar papules associated with vulvar itching and burning since two years. Microscopic examination of the punch biopsy revealed numerous small ducts lined by two layers of epithelial cells embedded in a fibrous stroma. Some of the ducts showed small comma like tails of epithelial cells imparting them a tadpole shape. Despite being a rare diagnosis, vulvar syringoma should be kept in differential diagnosis with vulvar pruritus. PMID- 25302204 TI - Transitional cell carcinoma of the ovary: case series and review of literature. AB - Transitional cell carcinoma (TCC) of the ovary is a recently recognized, subtype of ovarian surface epithelial cancer; the pure form accounting for only 1% of surface epithelial tumors. It has been described as a primary ovarian carcinoma with definite urothelial features but no benign, metaplastic and/or proliferating Brenner tumor (BT) identified. Recognition of such tumours is important because of its rarity, favorable response to chemotherapy and an improved patient survival. A case series of primary TCC of the ovary (3 cases) with brief review of literature is being presented. PMID- 25302205 TI - Ossifying fibroma in the sinonasal tract: a rare case report. AB - Ossifying fibroma involving the sinonasal tract is an extremely rare occurrence. We are reporting a case of ossifying fibroma in the left maxillary sinus in a 19 year-old female who presented with a mass in the left cheek and nasal obstruction. On examination, the swelling in the left cheek seemed to originate from the left maxilla and was smooth and bony hard. Patient underwent detailed radiological and image guided cytopathological investigations. Depending on the results of these tests complete surgical excision of the mass was done. Histopathological evaluation of the excised mass revealed it to be an Ossifying Fibroma. PMID- 25302206 TI - Primary subcutaneous inguinal hydatid cyst: diagnosis by fine needle aspiration cytology. AB - Hydatid disease or human cystic echinococcosis, recognized by ancient scholars such as Hippocrates, Galen and Rhazes, is one of the oldest diseases known to man. Though hydatid cyst may develop in almost any part of the body, a solitary primary subcutaneous localization is an extremely rare entity. We herein report a case of primary subcutaneous inguinal hydatid cyst which was diagnosed by fine needle aspiration cytology. Radiological examination done subsequently corroborated with the cytodiagnosis of Hydatid cyst and did not show involvement of any other organ or site. Histopathological examination of surgically removed cyst confirmed the diagnosis of Hydatid cyst. Hydatid disease should be considered in the differential diagnosis of all unusual swellings in soft tissues, especially in regions where the disease is endemic. PMID- 25302207 TI - Primary mucinous eccrine adenocarcinoma - a rare malignant cutaneous adnexal neoplasm at an unconventional site. AB - Primary mucinous eccrine adenocarcinoma, a rare malignant neoplasm of the skin adnexa usually occurs in the head and neck region. The most common sites for its occurrence are the eyelid, the peri-orbital region and the scalp. We report the rare occurrence of primary mucinous eccrine adenocarcinoma of the inguinal region which has been reported in only 1% of cases according to literature search. Since the differentiation from metastatic mucinous carcinomas is difficult, a careful search for primary in the breast, gastrointestinal tract and prostate is mandatory. This case report highlights the importance of precise diagnosis and accurate histological typing of mucinous carcinomas with an emphasis on their role in appropriate patient management along with a brief review of literature. PMID- 25302208 TI - Using VARK Approach for Assessing Preferred Learning Styles of First Year Medical Sciences Students: A Survey from Iran. AB - BACKGROUND: Preferred learning styles of learners are different, which depend on tastes, mentality preparedness, as well as physical condition, in terms of sensory modalities. Identifying and employing appropriate learning styles could play an important role in selecting teaching styles, which can improve education ultimately. AIM: The present study aimed to assess the diversity of learning styles amongst medical students of a medical sciences university which was located west of Iran, in 2010. METHODS: A cross-sectional study which employed VARK learning style's questionnaire was done on 141 first year medical sciences students at Ilam University of Medical Sciences in 2010. Data was collected with use of VARK questionnaire. The validity of the questionnaire was assessed on basis of experts' views and its reliability was calculated by using Cronbach's alpha coefficients (alpha=0.86). Data were analysed by using SPSS software and Chi-square test. RESULTS: Overall, 41.6% of the samples preferred to use a single learning style (Uni-modal). Of these, 17.7% preferred the Aural style, 17% preferred Reading and Writing, 6.4% preferred Kinesthetic style and 0.7% preferred Visual styles. Among the rest of the 82 students who preferred more than one style (multimodal), 17% chose two modes (bimodal), 13.5% chose three modes (tri-modal), and 27.6% chose four modes (quad-modal). There was a significant difference between educational levels and majors on one hand and choice of quad modal of VARK styles on the other hand (p=0.008). A significant association was also found between participants' genders and selection of visual and reading/writing styles (p=0.03). CONCLUSION: The preferred learning styles of medical students in the present study were aural and reading/writing. It is suggested that all medical students must be tested to determine their desired learning styles by using VARK questionnaire, also to choose appropriate teaching methods and to improve educational goals. PMID- 25302209 TI - Dexamethasone as an additive to bupivacaine in fascia lliaca compartment block: a prospective, randomized and double blind study. AB - BACKGROUND: Patients with fracture femur experience severe pain on movement during positioning for spinal anaesthesia. Fascia Iliaca Compartment Block (FICB) has been used effectively for providing analgesia during positioning of the patient for spinal anaesthesia. AIM: To test the hypothesis that, adding dexamethasone would significantly prolong the duration of Bupivacaine in FICB. MATERIALS AND METHODS: Sixty patients aged 18 to 80 years posted for ORIF (Open Reduction and Internal Fixation) of fracture femur were included to receive FICB. This was a prospective, randomized, double blind study done at tertiary medical college hospital. Thirty patients received 38ml of 0.25 % bupivacaine with 2ml saline and another 30 patients received 38ml of 0.25 % bupivacaine with 2ml dexamethasone (8mg). Thirty minutes after FICB, patient satisfaction during positioning for spinal anesthesia was recorded. In the post-operative period, duration of analgesia and the total doses of rescue analgesics were recorded in both the groups. RESULTS: Patients who received Bupivacaine with dexamethasone had significant prolongation of analgesia and required fewer doses of rescue analgesics as compared to patients who received Bupivacaine alone for FICB. However, the onset of analgesia, VAS scores and patient satisfaction during positioning for spinal anaesthesia were similar in both groups. CONCLUSION: Our study shows that adding Dexamethasone (8mg) to Bupivacaine for FICB significantly prolonged the duration of block and decreased the requirement of rescue analgesics as compared to patients who received Bupivacaine alone. FICB is relatively easy and safe to perform. In our study we did not encounter any complication while doing the procedures and also by adding dexamethasone. PMID- 25302210 TI - Patient Controlled Epidural Labour Analgesia (PCEA): A Comparison Between Ropivacaine, Ropivacaine-Fentanyl and Ropivacaine-Clonidine. AB - BACKGROUND: Feeling of pain is one of the most important emotional determinants which dominate the perception of females who undergo the process of labour and delivery. Patient controlled epidural labour analgesia (PCEA) is convenient and safer technique for this purpose. Very few studies compared clonidine and fentanyl with ropivacaine in labour analgesia in past. This study was undertaken to compare fentanyl and clonidine in PCEA. AIMS: To compare low concentration ropivacaine with or without fentanyl or clonidine for labour analgesia and its effect on maternal and foetal safety. SETTINGS AND DESIGN: Prospective, double blind, randomized, comparative study. MATERIALS AND METHODS: Ninety primegravida in labour were divided into three groups (n=30) and patient controlled epidural labour analgesia was given to them: Initial bolus of 10ml of ropivacaine 0.125% in Group I; with fentanyl 2 MUg/ml in Group II and with clonidine 1MUg/kg in Group III. Subsequently each group received ropivacaine 0.125% through patient controlled epidural analgesia (PCEA) as background infusion of 5 ml/hr with lockout interval time of 10min and subsequent bolus of 5ml. Hemodynamic parameters, sensory level, motor block and pain relief were noted. Total analgesic dose of local anaesthetic and feto-maternal adverse effects were also recorded. RESULTS: At baseline, groups were matched demographically, hemodynamically as well as for intensity of pain. There was a statistically significant decrease in hemodynamic parameters from baseline in all groups with maximum reduction in group III. A significant difference among groups in VAS was observed at zero min and from 120min till 240min intervals and lowest values were in Group III. No significant difference was observed among the groups for mode of delivery and expulsive efforts. Total analgesic dose and PCA bolus requirement was maximum in Group I and minimum in Group III and the difference was statistically significant among groups. Six (20%) patients had shivering in Group II and hypotension was recorded in only 1 (3.3%) patient of Group III. CONCLUSION: Ropivacaine 0.125% was effective in decreasing labour pain without any motor blockade. Clonidine 1MUg/kg was superior to fentanyl 2MUg/ml as an adjuvant in PCEA for labour without any significant feto-maternal adverse effects. PMID- 25302211 TI - Clinical evaluation of analgesic activity of guduchi (tinospora cordifolia) using animal model. AB - INTRODUCTION: Pain is a very well-known signal of ill health and analgesics are the drugs that are used to relieve pain. The main problem with these drugs remains that of side effects. Safer alternatives are natural herbs. Guduchi (Tinospora cordifolia) is one such plant with analgesic potential but few studies are there. OBJECTIVE: To evaluate the analgesic activity of commercially available extract of Guduchi (T. cordifolia). MATERIALS AND METHODS: For this purpose commercially available extract of Guduchi (T. cordifolia) by Himalaya Drug Company, Bangalore was used. Albino rats were divided randomly in three groups of six rats each. Group 1 (control) received distilled water orally, group 2 (test) received T. cordifolia extract in dose of 300 mg/kg orally and group 3(standard) received Pentazocine in dose 10mg/kg intraperitoneally. Analgesic activity was evaluated using hot plate and abdominal writhing method. All the observations were analysed statistically using student's t-test. OBSERVATION AND RESULTS: T. cordifolia extract significantly (p<0.05) increased the response time and decreased the number of writhes in hot plate method and abdominal writhing method respectively, on comparison with the control group. CONCLUSIONS: The above findings suggest that this commercially available extract of Guduchi (T. cordifolia) possess analgesic activity. This analgesic activity probably involves peripheral as well as central mechanisms as the extract showed analgesic activity in both hot plate and abdominal writhing method. PMID- 25302212 TI - Evaluation of Effect of Antiepileptic Drugs on Serum Lipid Profile among Young Adults with Epilepsy in a Tertiary Care Hospital in Pondicherry. AB - INTRODUCTION: Several studies have reported that commonly used antiepileptic drugs like phenytoin, and carbamazepine increase serum High Density Lipoproteins Cholesterol (HDL-C) levels, while some others documented no such effect. Further, some researchers also observed that valproic acid and other newer antiepileptic drugs like lamotrigine and levetiracetam has no influence on serum lipid profile. The present study was planned to assess and compare serum lipid profile of young adult patients on commonly used antiepileptic drugs (phenytoin, oxcarbazepine and valproic acid) and newer antiepileptic drug (levetiracetam) attending Neurology OPD of a tertiary care hospital in Puducherry, India compared to normal subjects. MATERIALS AND METHODS: A prospective hospital based cross-sectional study was conducted in Tertiary care hospital. Epileptic patients attending Department of Neurology and taking antiepileptic drugs for last six months or more and on regular follow up; approximately 60 patients on commonly used antiepileptic drugs (20 on phenytoin, 20 on oxcarbazepine, 20 on valproic Acid) and 20 patients on newer antiepileptic drug (levetiracetam) was included in the study. Age and sex matching 80 controls were taken. STATISTICAL ANALYSIS: Descriptive statistics explained using mean +/- SD. Inferential statistics was used depending on the nature of variables. We used one-way-ANOVA and followed by independent t-test for comparison with control group and statistically significant was considered at p value <0.05. RESULTS: We observed statistically significant high mean TC, HDL-C, LDL-C and TG levels in the group receiving phenytoin for more than six months when compared with control group. We observed statistically significant high mean TC, HDL-C and TG levels in the group receiving oxcarbazepine for more than six months when compared with control. However, no significant difference was observed in mean LDL-C levels when compared to control. We did not observe any statistically significant difference among mean TC, HDL-C, LDL-C and TG levels in the group receiving valproate. We did not observe any statistically significant difference among mean TC, HDL-C, LDL-C and TG levels in the group receiving levetiracetam. CONCLUSION: From the present study we can conclude that CYP enzyme inducer anti epileptic medicines like phenytoin and oxcarbazepine is strongly associated with increased levels of TC, LDL-C, HDL-C and TG where as valproate and levetiracetam showed no significant change. Therefore, the serum cholesterol level should be regularly monitored in patients undergoing therapy with inducer anti epileptic medicines. PMID- 25302213 TI - Knowledge, attitude and practices related to dietary supplements and micronutrients in health sciences students. AB - OBJECTIVES: Little is known about supplement users and their dietary behavior in India. This study was conducted with the following objectives: 1. To determine the usage of dietary supplements in health sciences students. 2. To determine their knowledge, attitudes and beliefs regarding micronutrients. MATERIALS AND METHODS: Cross-sectional, questionnaire based study conducted at a University in south India, which included second year students pursuing medical, dental and nursing courses. Data was analysed using SPSS version 19. RESULTS: The commonest reasons for consuming supplements were to maintain good health (136, 40.1%) and ensure adequate nutrition (125, 36.9%). The respondents' opinions about dietary supplements were generally between 'unsure' and 'agree'. Medical students scored the highest percentage (44.84%) in their knowledge about micronutrients as compared to nursing (43.17%) and dental (37.8%). There was a significant difference between the scores of medical and dental students (p=0.005) while the scoring of students of medical and nursing did not vary significantly. There was no significant difference between the scoring percentage of males and females in medical and dental groups while in the nursing group female students scored a better percentage as compared to males (p=0.036). CONCLUSION: Although, the usage of dietary supplements in health sciences students is high, there is a dearth of knowledge, especially regarding role of micronutrients in health and disease. Hence, it is crucial this information must be highlighted in the health sciences curriculum with the objective of producing well-informed professionals who can later on have a positive impact on the health of society. PMID- 25302214 TI - A Knowledge, Attitudes and Practices Survey regarding Sex, Contraception and Sexually Transmitted Diseases among Commerce College Students in Mumbai. AB - INTRODUCTION: One in four Indians is a juvenile. Sexual crimes, pre marital sex, sexually transmitted diseases and unwanted pregnancies are on the rise. It has been shown that lack of sexuality education can significantly contribute to the above. AIM: We conducted this study to determine the knowledge and awareness of college students regarding sex and related matters and the factors affecting the prevalent outlook and practices of youth towards the same. METHODOLOGY: A prospective cross-sectional survey was conducted amongst 500 students of the K.P.B. Hinduja College of Commerce from December 2012 to March 2013 as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. MAIN OUTCOME MEASURES: 1. Sex knowledge scores of males and females regarding contraception, sexually transmitted diseases and HIV/AIDS. 2. Percentage response of males and females to questions depicting attitudes and perceptions regarding premarital sex and promiscuity, sexual fantasy and masturbation, unwanted pregnancies and contraception. 3. Responses depicting participant's premarital and high risk sexual activities. RESULTS: The mean age was 18.6 +/-1.6 years, 46% of participants were female. The total sex related knowledge scores of males and females were 8.2+/-1.2 and 6.2+/-2.4 (p<0.0001), respectively. 84% males and 72% females disagree that virginity should be preserved till marriage. Premarital sex was reported by 48% males and 18% females. Out of those who had premarital sex, 68% males and none of the females had more than one sex partner and 21% males and 12% females had used a contraceptive during their sexual encounter. 87% males and 82% females disagree that sex education in secondary schools will cause a rise in premarital intercourse. 40% males and 13% females are of the view that birth control is primarily a female's responsibility. 14% of males and 21% of females (p = 0.2) reported being forced to have sex. CONCLUSION: Participants, especially females, lacked basic information about sexuality and related concepts. Male participants had a very casual attitude towards having sex with multiple partners. Premarital sex is more common than once believed. In the light of our finds and the current scenario, sexuality education is indispensable in order to guide the youth to develop and adopt healthy and appropriate sexual practices. PMID- 25302215 TI - Evaluation of Efficacy of Curcumin as an Add-on therapy in Patients of Bronchial Asthma. AB - BACKGROUND: Bronchial asthma being a chronic inflammatory disease of airways has numerous treatment options none of which have disease modifying properties. Curcumin, a yellow dietary pigment has varied pharmacological activities, prominent among which is an anti-inflammatory activity which may be crucial in bronchial asthma as has been proved by various in vitro and in vivo animal studies. AIMS: To determine the efficacy and safety of curcumin as an 'add-on' therapy in patients of bronchial asthma. SETTINGS AND DESIGN: This study was conducted on 77 patients of mild to moderate Bronchial asthma who had a documented positive bronchodilator reversibility test with >=15% improvement in forced expiratory volume one second (FEV1). MATERIALS AND METHODS: Seventy seven patients were recruited for the study and randomized into either of the two groups, but 17 patients were lost to follow up. Thus Group A - Receiving standard therapy for bronchial asthma for 30d (n=30) and Group B - Receiving standard therapy for bronchial asthma + Cap Curcumin 500mg BD daily for 30d (n=30). The predefined primary endpoints were clinical assessments of dyspnoea, wheezing, cough, chest tightness and nocturnal symptoms, change in the pre-bronchodilator FEV1 during the treatment and hematological improvement. The secondary end points were assessed by the change in the post-bronchodilator FEV1, C-reactive protein (CRP) concentration and incidence of adverse events. STATISTICAL ANALYSIS USED: The data was analysed by SPSS 17.0 software using one-way ANOVA or Paired t-test. RESULTS AND CONCLUSION: The results showed that curcumin capsules help in improving the airway obstruction which was evident by significant improvement in the mean FEV1 values. There was also significant improvement in the hematological parameters and absence of any clinically significant adverse events indicates dependable safety profile of curcumin capsules, though there was no apparent clinical efficacy. Therefore, it is concluded that curcumin is effective and safe as an add-on therapy for the treatment of bronchial asthma. PMID- 25302216 TI - Comparative efficacy and safety of triple therapy (ramipril, telmisartan, hydrochlorothiazide) vs dual anti hypertensive therapy (ramipril or telmisartan, hydrochlorothiazide) in stage 2 hypertensive patients. AB - AIM: To evaluate the comparative efficacy and safety of ramipril 5mg plus hydrochlorothiazide 12.5mg (R + HCTZ), telmisartan 40mg plus hydrochlorothiazide12.5mg (T + HCTZ) and ramipril 2.5mg plus telmisartan 20mg plus hydrochlorothiazide12.5mg (R + T + HCTZ) in patients with stage 2 hypertension. MATERIALS AND METHODS: A prospective, open label, randomized comparative study was conducted to study the comparative efficacy and safety of R+HCTZ (group 1), T+HCTZ (group 2)and R+T+TCTZ (group3) in 88 patients with stage 2 hypertension without co-morbid conditions. Echocardiography was done to assess left ventricular function. Patients were followed up to 24 weeks and any ADR occurring in this period was recorded. RESULTS: All the three treatment groups showed significant fall in both systolic and diastolic blood pressure compared to the baseline scores (p<0.0001). Intergroup comparison did not reveal any significant difference. Total number of adverse drug events reported were 15. Group III had higher percentage ADRs. Dry cough (8) was most common ADR. The echocardiography parameters did not change from baseline values with all three treatment regimens. CONCLUSION: All three medications were of equal efficacy in patients with stage 2 hypertension without co morbid conditions, failing to prove superiority over each other. PMID- 25302217 TI - Comparison of Directly Observed Treatment Short Course (DOTS) with Self Administered Therapy in Pulmonary Tuberculosis in Udupi District of Southern India. AB - BACKGROUND: Directly observed treatment short course (DOTS) and self-administered therapy (SAT) are the treatment options available for tuberculosis (TB). Studies conducted worldwide have shown difference in treatment outcome with these two treatment modalities. AIM: The study was undertaken to compare treatment outcome of DOTS and SAT in patients of pulmonary TB taking SAT from a tertiary care hospital and DOTS from the DOTS centre of a government hospital. MATERIALS AND METHODS: It was a retrospective comparative study. The case record files of patients with pulmonary TB diagnosed from March 2011 to February 2012 were analysed as per the proforma. The sample size of patients was 150 (75 each from DOTS and SAT). RESULTS: The treatment outcome in DOTS group was cured 70.7%, treatment completed 1.3%, failure 5.3%, deaths 10.7%, defaulters 8% and transferred out 4% whereas in SAT group, cure was seen in 68% and 4% completed the treatment, 1.3% had treatment failure, and 26.7% were lost to follow up which included deaths, defaulters and those patients who switched over to other hospitals. The treatment success rate was similar (72%) in both groups. There was no statistically significant difference observed in the average weight gain at the end of treatment between the two groups. A total of 11 adverse drug reactions (4 DOTS, 7 SAT) were recorded in the study. CONCLUSION: The study shows no statistically significant difference between success rate in patients taking DOTS and SAT. PMID- 25302218 TI - Azithromycin-induced rash in a patient of infectious mononucleosis - a case report with review of literature. AB - Antibiotic induced skin rash in setting of infectious mononucleosis is often encountered in clinical practice. However, macrolides like azithromycin are considered relatively safe and till date only two cases of azithromycin induced rash in setting of infectious mononucleosis have been reported. The following report illustrates the case of a 23-year-old man suffering from infectious mononucleosis who exhibited a generalized cutaneous rash following treatment with azithromycin. Using the Naranjo ADR probability scale, this case of acute onset rash following azithromycin administration was found to be in 'probable' category. The mechanism of antibiotic-induced rash in patients suffering from infectious mononucleosis is incompletely understood. It has been suggested that the rash could result from virus mediated immunomodulation or due to altered drug metabolism. The report calls for cautious use of antibiotics in the setting of suspected viral infections like infectious mononucleosis as injudicious use might increase the risk of deleterious skin reactions and increase the cost of healthcare. PMID- 25302219 TI - Cause of Death in "John Doe & Jane Doe": A 5 year review. AB - Sometimes the opinion regarding the cause of death in "John Doe or Jane Doe" i.e. on unknown dead bodies is a test of ability of the forensic expert and on many occasions it yields little or no results. Here the identification of the body as such poses problems; rest aside the opinion regarding the cause/ manner of death. The present 5yr study was undertaken in the Department of Forensic Medicine & Toxicology, Government Medical College & Hospital, Chandigarh to find the patterns of cause of death in unknown dead bodies, as very little literature is available with regard to John Doe or Jane Doe cases as a group, in India. Unidentified bodies comprised 4 % of the total 3165 cases brought for post-mortem examination to the department. Maximum cases belonged to the age group 41 - 50 years, 30 %. Majority of the opinions regarding the cause of death were given as "no definite opinion" (31%), followed by "cranio-cerebral damage" (30 %) and coronary insufficiency/ Cardiac disease/ aortic aneurysm rupture, (8.9%). Following measures should be undertaken to increase the chances of getting these unknown bodies identified and thereby increasing the chances of arriving at a definite cause of death: drafting of additional legislation for the management of unidentified dead bodies along with streamlining of work on the part of police, use of active investigation and modern investigative techniques, fixing the accountability of the police. Internet based sites of the police like ZIPNET (Zonal Integrated Police Networking) in Northern India, should also be used. PMID- 25302220 TI - A study on morbidity profile and associated risk factors in a rural area of dehradun. AB - BACKGROUND: First few years of life is the most crucial period of life as this age is known for accelerated growth and development, warranting regular monitoring. During this period about 40% of physical growth and 80% of mental development occurs. Any adverse influences during this period may result in severe limitations in their development. METHODS: A cross-sectional study was conducted in the field practice area of Rural Health Training Centre. Mothers of children between 0-3 years of age were enquired about the morbidity in the past two months. RESULTS: Diarrhea (47.9%) followed by ARI (22.21%), Pica (13%) and Worm Infestation (9.21%) were the commonest morbidities found in the study population. Morbidities were found to be common in males as compared to females. Amongst the nutritional deficiencies anaemia & Vitamin B deficiencies were the commonest. CONCLUSION: There was considerable sickness load amongst the toddlers. Morbidity can be reduced by improvement in the health care system at peripheral level. PMID- 25302221 TI - Correlates of Intention to Use Condom among Male Migrant Factory Workers in Northern India. AB - OBJECTIVE: Consistent condom use among high-risk groups, which in turn are dependant on favourable condom use intention is important for the success of HIV/AIDS prevention programmes. We aimed to determine intention to use condom and delineate their correlates in a sample of male migrant workers in northern India. MATERIALS AND METHODS: This was a cross-sectional facility based survey conducted in 2011. Inclusion criteria were: male migrant workers aged >=18 years, who were born outside Haryana, who had moved to current location after 15 years of age, who had worked in the current factory for at least one year and who were able to give valid consent. Face-to-face interviews were conducted with semi-structured questionnaire. Since this analysis was a secondary objective of a larger migrant study, sample size was not calculated separately. Intention to use condom was measured on a five point Likert scale and expressed as a linear score (higher the score more unfavourable the intention). A linear regression analysis was performed to identify factors independently associated with unfavourable intention. RESULTS: Mean (SD) score for intention to use condom was 10.4 (3.4). Unfavourable intention was associated with men who had migrated to greater number of places, who had lesser HIV/AIDS knowledge, who had never used condom and who had not used condom at last non-spousal sex. The model had an adjusted R-square value of 0.63 and was statistically significant (F = 41.9, p < 0.001). CONCLUSION: Male migrant workers had unfavourable intention to use condom. This intention could be favourably modified by behaviour change communication through already existing targeted intervention platforms, focussing attention on groups with higher mobility, lower education, lower HIV/AIDS knowledge and inconsistent condom use. PMID- 25302222 TI - Sexuality in Adolescents: have we Explored Enough! A Cross-sectional Study to Explore Adolescent Health in a City Slum in Northern India. AB - CONTEXT: Adolescent health is a relatively new focus area of India's National health program. However, little evidence is available for the existing problems especially in adolescent slum population. A study was planned to explore the problems of adolescent pertaining to sexuality, physical health, tobacco and alcohol use in slums of Urban Meerut, and create evidence base for informed planning and decision making by the local health authorities. AIMS: To study the adolescent health in the slums of Meerut City, India. SETTINGS AND DESIGN: Entire slums of Urban Meerut, cross-sectional study. MATERIALS AND METHODS: Study was done in the slums of Meerut city, in Northern India. WHO 30 cluster sampling technique was used. Thirty slums were selected from the list of all the slums of Meerut, 210 adolescents were selected with 7 adolescents from each slum. STATISTICAL ANALYSIS: Proportions and Chi-square test. RESULTS: More than one third of the (36.7%) adolescents reported to have a current health problem, however only half of these sought medical help for treatment. Tweleve percent of adolescents reported history of alcohol or tobacoo use. Nine percent adolescents complained of stressful atmosphere at home. About 10% adolescents in the surveyed population gave history of sexual activity, but only one third of them had used condom during their last sexual intercourse. CONCLUSION: This study reflects the high morbidity and poor treatment seeking behaviour among adolescents in urban slums. A significant proportion of adolescents indulge in high risk sexual behavior, tobacco and alcohol use. There were significant gender differences with regards to treatment seeking behaviour, sexual behaviour, tobacco and alcohol use. The gender nuances must be taken into account while planning interventions for this section of population. PMID- 25302223 TI - Preoperative Preparation with Lugol's Iodine in Thyroidectomy of Euthyroid Patients-Is it Really Mandatory?-An Otorhinolaryngologist's View. AB - OBJECTIVE: To elucidate the necessity of Lugol's iodine in preoperative preparation of patients undergoing thyroidectomy. MATERIALS AND METHODS: Hundred and five euthyroid patients who underwent surgery without preoperative preparation of patients with Lugol's iodine were enrolled in this retrospective study conducted during the period May 2009 to August 2013 in Teaching Hospital. Indication of surgery was ranging from suspected malignancy to cosmetic reasons and compressive features like dysphagia , dyspnoea and hoarseness of voice. RESULTS: All patients were operated by the same surgeon where in hemi, total and subtotal thyroidectomies were performed without any usage of Lugol's iodine preoperatively. During the postoperative period the following events occurred, five patients (4.7%) had incurred recurrent laryngeal nerve palsy (RLNP) which was confirmed with postoperative indirect laryngoscopic examination and two patients (1.9%) with hypocalcemia (serum calcium less than 8mg/dl) which was managed conservatively and effectively. Among these five patients, three patients had (Right RLNP) and two patients had (Left RLNP) palsies. Of these four RLNP (3.8%) were temporary which improved with conservative management within 3weeks 6months duration and one (0.9%) was a permanent Rt RLNP with no improvement even after six months. CONCLUSION: Hence, we conclude that it is not of much importance to use Lugol's iodine preoperatively in patients undergoing thyroidectomy. There does not appear any convincing evidence of advantages of preoperative preparation of patients with lugol's iodine in euthyroid state undergoing surgery. PMID- 25302224 TI - Spontaneous expulsion of foreign body (seewing machine needle) from right middle lobe bronchus - a rare case report. AB - Aspirated foreign bodies continue to present challenges to the Otorhinolaryngologists. The major issues involve the accurate diagnosis at the earliest and speedy, safe removal of the foreign body. Endoscopic removal is the mainstay of management of foreign body in tracheobronchial tree. Spontaneous expulsion of foreign body bronchus is a rare entity with few cases reported in literature. We report a rare and interesting case of 18-year-old male patient presented with sharp and pointed metallic foreign body in Right Middle lobe Bronchus i.e., sewing machine needle. Patient was admitted and planned for bronchoscopy. But prior to it, foreign body was spontaneously expelled out. The patient was discharged next day without any complication. Spontaneous expulsion saves the patient from the dangers of endoscopic removal of foreign body, but impose a great danger of subglottic lodgement of foreign body. PMID- 25302225 TI - Recent Trends in the Management of Thornwaldts cyst: A Case Report. AB - Tornwaldt's cyst is a benign cyst located in the upper posterior nasopharynx. It is a relatively rare lesion and most are small and asymptomatic whereas some cause nasal obstruction, postnasal drip, occipital headache or eustachian tube dysfunction. In our case a 28- year-old man presented with nasal obstruction since 10-years whose diagnostic nasal endoscopy showed a large well-encapsulated lesion arising from the posterior wall of the nasopharynx. A magnetic resonance imaging (MRI) was performed which was suggestive of a fluid filled cystic lesion. The patient underwent successful marsupialisation using endonasal endoscopic approach using rigid endoscopes and powered instrumentation. Histopathology of the aspirate revealed a respiratory lined epithelial cyst. Based on the clinical, radiological and histopathological findings a diagnosis of Tornwaldt's cyst was made. We report this case to highlight the role of MRI in diagnosis and use of endoscopic assisted powered instrumentation for treatment of Tornwaldt's cyst. PMID- 25302226 TI - Mean platelet volume in patients with acute coronary syndromes: a supportive diagnostic predictor. AB - BACKGROUND: Platelets and their activity have a crucial role in acute coronary events. Larger platelets are enzymatically and metabolically more active and have a higher potential thrombotic ability as compared with smaller platelets. OBJECTIVES: The aim of this study is to investigate whether there is an association between mean platelet volume (MPV) measurement and cardiac Troponin I( cTn I ) in patients admitted with a suspected diagnosis of ACS and to assess the potential diagnostic efficiency of MPV in the diagnostic workup for ACS. MATERIALS AND METHODS: After thorough evaluation of 215 eligible patients, 3 ml. Venous blood collected using Becton, Dickinson and company vacutainer and MPV measured within 1-2 hr of sample collection. Sample for cTn I collected at 6 hr and at 12 hrs, if required and level measured using Biosite analyzer. RESULTS: Mean platelet volume (MPV) was found to be higher among ACS patients as compared to non ACS, 11.44+/-1.23 vs 9.91+/-1.27 fl (p-value<0.001). The NPV of MPV in the diagnostic workup of chest pain suggestive of ACS within 6 hours of presentation were found to be 82.53% . CONCLUSION: In this study the MPV is significantly higher in patients with ACS than in those with chest pain of non-cardiac origin and its negative predictive value of 82.53%, it might be useful as an assisting rule-out test in conjunction with other markers in the early prediction of the risk of ACS. PMID- 25302227 TI - Awareness and Approach towards Hypertension Management among General Practitioners of Western Vadodara. AB - BACKGROUND: Hypertension (HTN) is a major risk factor contributing to premature mortality from cardiovascular and cerebrovascular disease.To decrease morbidity and mortality from HTN, timely diagnosis of the disease and its complications, urgent treatment and referrals are required. General Practioners (GPs) are the first tier of the health care system in India and have a wide scope of practice. It is important to know the awareness and approach of primary care physicians to hypertension in their daily practice as compared to standard practice recommendations and guidelines, to identify targets for improvements. With this objective we decided to interview them personally and analyse their approach. MATERIALS AND METHODS: We conducted a cross-sectional survey in 80 general practitioners (GPs) of the western part of Vadodara city with the use of a questionnaire prepared from JNC-7 guidelines and standard medical books. Seventy seven [97.55%] GPs completed the questionnaire and their responses were statistically analysed. RESULTS: Twenty percent of GPs were not applying BP cuff properly for BP measurement. Only 18% and 16.6 % could diagnose isolated diastolic hypertension (IDH) and isolated systolic hypertension respectively (ISH) and 21% and 29% would have considered treatment of IDH and ISH respectively.48% consider treating pre-hypertension using non-pharmacological measures. Only 21% use thiazide diuretics for uncomplicated HTN and 50% use beta blockers in coronary artery disease patients. CONCLUSION: In our study, most of the GPs in western Vadodara are well aware and updated about the initial lab investigations,non-pharmacological measures and complications of HTN but lack an effective approach towards history taking for HTN,technique for measurement of blood pressure, diagnosis and treatment of IDH and ISH. Pre-hypertension and systolic and diastolic hypertension is under-treated and thiazide diuretics are underutilized. This study can be used to identify targets and approaches to improve hypertension management at the primary care level. PMID- 25302228 TI - Concordance among Measurements Obtained by Three Pulse Oximeters Currently Used by Health Professionals. AB - INTRODUCTION: Oxygen saturation is considered as the 5(th) vital sign. Presently, there exist fixed and wireless pulse oximeters, being the latter most widely used in the last years. Some of them have no possibility of calibration. This situation leads the health staff to adopt therapeutic attitudes which can be wrong. Therefore, it is extremely important to know if these wireless oximeters show a right concordance as regards measurements, since it is of great interest in daily clinical practice. OBJECTIVE: To evaluate concordance among measurements obtained by three different pulse oximeters currently used by health professionals. MATERIALS AND METHODS: This is an observational, descriptive and cross-sectional study related to the concordance of the results obtained in measurements collected by three different pulse oximeters (one monitor and two wireless oximeters) which are available and in use in this hospital unit. The sample size calculation was performed for a concordance above 0.81 and an estimation error which did not exceed 0.20. The intraclass correlation index (ICI) was used to establish the concordance whereas the Landis-Koch criteria were used to interpret the results. Systematic errors were analyzed using the Bland Altman plot. RESULTS: The overall concordance among the three pulse oximeters analyzed resulted in 0.88, a value considered as "good" according to the Landis Koch criteria. CONCLUSION: The results obtained show that in daily clinical practice both wireless pulse oximeters analyzed can be used with a certain reliability, taking into account the limitations of this research. PMID- 25302229 TI - Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion. AB - BACKGROUND: Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of GH. It is a first hormone linking gastrointestinal-pituitary axis. OBJECTIVE: This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. OBSERVATION: Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS-GHS receptor signalling system in the regulation of GH secretion. CONCLUSION: Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH. PMID- 25302230 TI - Multiple and Contemporary Coronary Thrombosis inspite of Low Platelet Function Response. AB - We are reporting a clinical case of a 78-year-old male who had oppressive chest pain at rest, which regressed with the intake of sublingual nitrates. Coronary angiography showed a chronic total occlusion (CTO) of the left anterior descending (LAD) artery, a normal circumflex, a hypoplasic right coronary artery and a Cardiac Magnetic Resonance showing vital tissue in anterior wall. During the procedure of CTO-PCI on LAD, patient developed multiple and contemporary coronary thrombosis in spite of low platelet reactivity, which was assessed by using Multiplate. A manual thrombectomy was performed with a good final result only after drug eluting stents (DES) implantation. PMID- 25302231 TI - Isoniazid Induced Cutaneous Leukocytoclastic Vasculitis in Extra Pulmonary Tuberculosis (Pott's Spine): A Case Report. AB - Anti-tuberculosis drugs frequently result in cutaneous adverse reactions but Isoniazid is known to have least toxic potential for cutaneous reactions. We report a rare case of Isoniazid induced cutaneous leucocytoclastic vasculitis. A 64-year-old male was diagnosed to have Pott's spine with multiple vertebral body involvement (D8-12 vertebrae). Subsequently, he was treated with first line anti TB drugs i.e., Isoniazid, Rifampicin, Pyrazinamide and Ethambutol. On the fourth day of treatment with Anti Tuberculosis Treatment (ATT), the patient developed an erythematosus rash over right upper limb not associated with itching or pain, non blanchable macules and papules over bilateral shins on lower limbs, petechiae on both forearms and hyper pigmented, scaly rash over right axilla and buttocks. The skin biopsy report was consistent with cutaneous leukocytoclastic vasculitis. Although rare, Isoniazid among anti-tuberculosis drugs should be considered as potential cause of drug-induced cutaneous leukocytoclastic vasculitis in the differential diagnosis of erythematosus rash with petechiae. PMID- 25302232 TI - Laparoscopic Cholecystectomy Under Spinal Anaesthesia vs. General Anaesthesia: A Prospective Randomised Study. AB - INTRODUCTION: Laparoscopic cholecystectomy (LC) is conventionally performed under general anaesthesia (GA) in our institution. There are multiple studies which have found spinal anaesthesia as a safe alternative. We have conducted this study of LC, performed under spinal anesthesia to assess its safety and feasibility in comparison with GA. MATERIALS AND METHODS: Fifty patients with symptomatic gallstone disease and American Society of Anesthesiologists status I or II were randomised to have LC under spinal (n = 25) or general (n = 25) anesthesia. Intraoperative vitals, postoperative pain, complications, recovery, and surgeon satisfaction were compared between the 2 groups. RESULTS: In the SA group six patients (24%) complained of shoulder pain, two patients required conversion to GA (8%) as the pain did not subside with Fentanyl. None of the patients in the SA group had immediate postoperative pain at operated site. Only two (8%) patients had pain score of 4 at the operative site within eight hours requiring rescue analgesic. One patient had nausea but no vomiting (4%). All the patients (100%) in the GA group had pain at operated site immediately after surgery and their pain score ranged from 4-7, all patients received rescue analgesic before shifting to the ward. In the first 24h tramadol required as rescue in the GA group was 82+/-24 mg which was significantly higher than the SA group requiring only 30+/-33.16 mg. Although, the GA group had more patients experiencing postoperative nausea & vomiting it was not statistically significant. CONCLUSION: SA as the sole anaesthesia technique is feasible, safe and cost effective for elective LC. PMID- 25302233 TI - Fournier's Gangrene in a Two Year Old Child: A Case Report. AB - Necrotizing fasciitis of the perineum and external genitalia is a life threatening infective gangrene, primarily seen in adults. It may be seen at any age but it is relatively uncommon in children. Here, we report a case of Fournier's gangrene in a two year old male child who was treated aggressively with broad spectrum antibiotics and early surgical debridement with hemodynamic stabilization. Even though no obvious precipitating cause was identified, hygiene was thought to be the inciting factor. Early surgical debridement with appropriate antibiotics and aggressive supportive care gave good results. PMID- 25302234 TI - Vanishing testis syndrome: report of two cases. AB - Vanishing testis syndrome or Testicular regression syndrome (TRS) is defined as the absence or an incomplete development of the testis of varying degrees in 46XY patients with normal external genitalia.TRS or vanishing testis syndrome may be seen in less than 5% of all patients of cryptorchidism. We report two cases of TRS who underwent surgical exploration with an initial diagnosis of cryptorchidism with impalpable testis. Grossly testicular tissue was not identified and the vas deferens was ending into a nubbin in both the cases. The presumed testicular remnants were sent for histological examination. The histological sections in both the cases showed vascularised fibrous nodule, structure of the spermatic cord and calcification, supporting the diagnosis of TRS. PMID- 25302235 TI - Congenital bilobed gallbladder with phrygian cap presenting as calculus cholecystitis. AB - The incidence of congenital bilobed gall bladder is 1 in 3000 to 4000. A Phrygian cap is a congenital abnormality of the gallbladder with an incidence of 4%. Preferred mode of diagnosis for Phrygian cap is cholescintigraphy and multi phase MRI, as Ultrasonography and CT are not always conclusive. The estimated prevalence of gallstone disease in India has been reported as 2% to 29%. A case of bilobed gall bladder with Phrygian cap in both the lobes and pigment gallstone in one of the lobes presenting as calculus cholecystitis is reported for its rarity and difficulty in arriving at correct preoperaive diagnosis. PMID- 25302236 TI - Role of sublingual misoprostol for cervical priming in first trimester medical termination of pregnancy. AB - OBJECTIVE: To evaluate the efficacy and safety of sublingual misoprostol as facilitator in first trimester medical termination of pregnancy (MTP) by surgical method. MATERIALS AND METHODS: This was a prospective open label study conducted at a tertiary center. A total 150 patients at 6-12 wks gestation requesting for MTP were randomized into two groups. Patients in study group (n=75) received sublingual misoprostol three hours before surgical abortion and in control group (n=75) directly underwent surgical abortion without prior cervical priming with misoprostol. The outcomes of both groups were recorded in terms of baseline cervical dilatation, need of additional cervical dilatation, intraoperative blood loss, operative time and procedure related complications. The results were statistically analyzed using student-t test and chi-square test. p-value of <0.05 and <0.001 were considered significant and highly significant respectively. RESULTS: The mean baseline cervical dilatation was significantly more in study group compared to control group (8.6+/-1.3mm versus 5+/-2.3mm; p <0.001) and the operative time and intraoperative blood loss were also less (p<0.001). Higher incidence of side effects like nausea, vomiting and pyrexia were recorded in sublingual misoprostol group but were well tolerable to the patients. CONCLUSION: Sublingual misoprostol is an effective and safe drug for cervical priming prior to surgical evacuation and has good patient acceptability. PMID- 25302237 TI - Predictors of success of medical management of ectopic pregnancy in a tertiary care hospital in United arab emirates. AB - INTRODUCTION: Ectopic pregnancy is the most common cause of pregnancy related deaths in the first trimester of pregnancy. Advances in laboratory and imaging technologies in last few decades allow an early diagnosis of ectopic pregnancy, many times even before the patient develops any symptoms. Consequently in many such patients surgery is not always necessary. Expectant and medical management are feasible options in properly selected cases. In the present study, efficacy of medical management of selected cases of ectopic pregnancy with injection methotrexate and the factors influencing the success of medical management were evaluated. MATERIALS AND METHODS: Retrospective study involving 40 women with ectopic pregnancy who met inclusion criteria and were managed medically with Methotrexate (MTX) in a tertiary hospital in United Arab Emirates (UAE). Various factors which could possibly influence the success of medical management were evaluated. RESULTS: ROC analyses for day 1(pretreatment) Beta HCG levels revealed that the optimum cut off for Beta HCG level of 6000 mIU/ml on day 1 can be considered a good predictor of success of medical management with MTX. Falling serum Beta HCG between day 1-4 very well predicted success of MTX therapy (irrespective of number of doses of MTX) with a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 31.25%. Similarly adnexal mass size <= 3 cms and duration of amenorrhoea < 6 weeks were found to be good predictors of success of medical management (PPV 96.66% and NPV 90% for both factors).In the present study, irrespective of number of doses received, medical management with MTX was successful in 75% cases (30 out of 40). CONCLUSION: RESULTS of this study indicate that pretreatment Beta HCG level of < 6000 mIU/ml, adnexal mass size < 3 cms, amenorrhoea < 6 weeks and absence of free fluid in the pelvis are predictors of a successful treatment with MTX. In properly selected cases medical management of ectopic pregnancy with MTX is highly effective and can be considered a forward step taken towards conservation of fallopian tubes especially in countries like UAE where there is inclination towards large family size based on religious and cultural background. PMID- 25302238 TI - Clear Cell Carcinoma of Cervix in a 60- year-old Woman: A Case Report. AB - Clear cell carcinoma of cervix is a rare entity amongst cervical neoplasms especially post diethylstilbestrol era. It is hypothesised to have a bimodal distribution with spontaneous cases unrelated to DES exposure observed in elderly age group. We report a rare case of clear cell carcinoma of cervix (CCCC) in a 60 year-old Asian female with no history of diethylstilbestrol (DES) ingestion. She underwent radical hysterectomy and adjuvant radiotherapy and showed no signs of recurrence even after 6 moths of follow up. Review of relevant literature was done including possible aetiology, appropriate treatment and prognostic factors. PMID- 25302239 TI - Hematometra formation- a rare complication of cesarean delivery. AB - Hematometra resulting from partial or complete obstruction of lower genital tract may be congenital or acquired. Commonest congenital causes are imperforate hymen and transverse vaginal septum. Acquired causes are senile atrophy of endocervical canal, scarring of the isthmus by synechiae, radiation and endocervical malignancy or due to surgical procedures. Various surgical procedures associated with hematometra are dilatation and curettage, cone biopsy, endometrial ablation, cryocoagulation and electrocautery. Hematometra following an abortion or cesarean delivery is rare. We report a case of hematometra following obstruction of outflow tract due to prior cesarean delivery. PMID- 25302240 TI - Comparison between the Analgesic Effect of two Techniques on the Level of Pain Perception During venipuncture in Children up to 7 Years of Age: A Quasi Experimental Study. AB - BACKGROUND: Distraction techniques are often provided by nurses, parents or child life specialists and help in pain alleviation during procedures. The use of non pharmacological procedures to cope with pain behaviour is less costly and most of these procedures can be administered by a nurse. Hence, the aim of the present study was to assess and compare the analgesic effect of holding the child by a family member versus holding the child by a family member along with an animation distraction intervention on the level of pain perception during venipuncture in children up to seven years of age. MATERIALS AND METHODS: Purposive sampling technique was used to select 70 children admitted in paediatric ward of Guru Gobind Singh Medical Hospital, Faridkot, 35 children in each group viz. Group 1(child held by family member during venipuncture) and Group 2 (child held by family member along with an animation distraction during venipuncture) and video clippings were made for each subject in both groups. Standardized FLACC pain scale was used to assess the level of pain during venipuncture by seeing the video clips of procedure in both groups. RESULTS: Findings revealed that the mean pain score of Group 1 was 3.86 and that of Group 2 was 2.43. Findings revealed that in Group 1 majority 31(88.57%) got severe pain and none remained relaxed during venipuncture whereas in Group 2 majority 10(28.58%) got moderate pain, 09(25.71%) remained relaxed and only 07(20%) got severe pain. The comparison of mean pain score of both groups was checked statistically by computing independent t-test and the value of t comes out to be 7.199 with p-value 0.000*** which was found to be highly significant. CONCLUSION: The study concluded that when during painful procedures like venipuncture if children are given any non pharmacological intervention like animated distraction along with their family member it helps in managing the pain. In other words, it distracts/diverts the child's attention from pain and results in better cooperation of child during procedure. PMID- 25302241 TI - Acute febrile encephalopathy in children and predictors of mortality. AB - BACKGROUND: Incidence of acute febrile encephalopathy (AFE) is high in children and associated with high mortality and sequela. Limited data is available about predictors of mortality in children of AFE from central India. AIM: To study the predictors of mortality in children of AFE. METHODS: This is observational, prospective study, carried out in a tertiary care hospital of central India. Duration of the study was two years (2010 to 2012). One hundred and seventy six children in the age group of one month to 12 years, presented with fever <= 2wks duration and altered mental status lasting for more than 4h were enrolled in the study. Outcome was evaluated in the study subjects. Data was analysed by use of Chi-square test, Fisher's exact test and multivariate regression. P-value <= 0.05 was considered statistically significant. RESULTS: Maximum enrolled children were of viral encephalitis (46.59%) and rest, were of pyogenic meningitis, tuberculosis meningitis and cerebral malaria. Among independently significant variables, shock, severe anaemia, bradycardia, Glasgow coma scale (GCS) of less than eight and refractory seizures were found to be significant and other variables like respiratory failure, multiorgan dysfunction syndrome and abnormal coagulation profile were found insignificant on full model of multivariate regression analysis. CONCLUSION: Refractory seizures, GCS <8, bradycardia, shock and severe anaemia were independent predictors for mortality in children of AFE. PMID- 25302242 TI - Medical Symbols in Practice: Myths vs Reality. AB - BACKGROUND: The caduceus is the popular symbol of medicine. However, premier health organizations and regulatory bodies such as the World Health Organization and the Medical Council of India use a different symbol- the rod of Asclepius in their logo. There is an increasing awareness and recognition that the caduceus is a false symbol and has no historical substantiation as an emblem of medicine. Many academic and health institutions in the western hemisphere have changed their logo as a consequence. There are other symbols of medicine which are similarly misunderstood. OBJECTIVES: The purpose of the study is to assess the knowledge of common medical symbols among doctors and medical students. MATERIALS AND METHODS: Three hundred doctors and medical students were assessed on their knowledge about the Rx symbol, the Red Cross emblem and the true representative emblem of medicine. Logos and emblems of elite medical colleges and medical associations were also studied. RESULTS: Only 6% of doctors were aware that the Rod of Asclepius is the true symbol of healing. Knowledge of the significance of the Rx symbol and the origin of the Red Cross emblem was 55% and 39 %. CONCLUSION: There is very little awareness about the rod of Asclepius and most institutions have adopted a logo based on the caduceus. Awareness of the true origins and the symbolism of the emblems is lacking in the medical fraternity. PMID- 25302243 TI - Iodine status and prevalence of goitre in school going children in rural area. AB - INTRODUCTION: Iodine deficiency disorder (IDD) is one of the preventable major public health problems in India. It has been always thought that goitre was only found in the Himalayan goitre belt. Recent surveys outside the conventional goitre belt have identified foci of iodine deficiency in other parts of India. AIM: 1) To assess the prevalence of goitre among school-going children in the age group of 6-15 years. 2) To find out the relationship of goitre prevalence with the salt intake and urinary iodine excretion. 3) To unfold the iodine nutritional status of the study population. MATERIAL AND METHODS: The study was conducted from January 2005 to July 2006 in school children of 6-15 years of age, attending the 55 schools of Bellur hobli in the southern part of India. The clinical examination of all the 1600 children of the selected schools was done to detect and grade goitre. Urine and salt samples were collected from sub-samples (n = 400) to estimate the urinary iodine excretion level and iodine content in the salt respectively. RESULTS: The goitre prevalence in the study population was found to be 0.125%. Urinary iodine excretion (UIE) level of >= 100 mcg / l was found in 361 children (90.25%) and < 100 mcg/ l in 39 children (9.75%). Estimation of iodine content of the salt samples revealed that 363 (90.75%) consumed adequately iodised salt (> 15ppm) and 37 (9.25%) consumed inadequately iodised salt (< 15ppm). CONCLUSION: Bellur Hobli is not an endemic area for goitre and there is no biochemical iodine deficiency in this population due to effective implementation of Universal iodization programme (UIP). It is reasonable to conclude that by achieving the universal iodisation of salt, IDD can be successfully eliminated from the community. PMID- 25302244 TI - Recurrent meningitis with upper airway obstruction in a child: frontonasal encephalocele- a case report. AB - Nasal encephalocele are rare congenital anomalies; these benign masses may be confused with nasal dermoids, hemangiomas, nasal gliomas and anterior skull base masses. These lesions have concomitant defects in the anterior cranial fossa thus this potential communication can cause recurrent episodes of meningitis and/or difficulty in breathing and cosmetic anomalies. We bring a case of a 6-year-old child who presented to the clinic with multiple episodes of meningitis which was associated with nasal discharge. The imaging studies and nasal fluid analysis confirmed it as cerebrospinal fluid; subsequently imaging findings concluded it as frontonasal encephalocele which was later resected and patient showed improvement. PMID- 25302245 TI - Non-Hodgkin's Lymphoma in Buccal Vestibule -Case Report. AB - Lymphomas are malignant neoplasms arising from lymphocytes B cell or T cell that affects mainly lymph nodes, spleen and other non hematopoietic tissues. They are classified as Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Diffuse large B-cell lymphoma (DLBL) is the most common variant of non-Hodgkin's lymphomas and frequently involves extranodal sites. In the oral soft tissues lesions can occur as hard and diffuse tumors involving oral vestibule, gums and posterior region of the hard palate. Most lymphomas, including DLBL arise from B cells are characterized by diffuse population of large cells with cleaved or non cleaved oval nuclei. Both histopathlogical and immunohistochemical (IHC) analysis were strongly advisable for proper management and prognosis. We hereby report a rare case of Diffuse large B-cell variant of non-Hodgkin's lymphoma in a male patient of age 50yrs in left upper buccal vestibule. PMID- 25302246 TI - Marchiafava - bignami disease: a case report. AB - Marchiafava-Bignami disease (MBD) is a rare neurological disorder of chronic alcoholism characterized by demyelination and necrosis of corpus callosum. In this case report we present the MR imaging findings of MBD and review of the other imaging features of the disease. PMID- 25302247 TI - Primary Pulmonary Ewing's Sarcoma: Rare Cause of Superior Vena Cava Syndrome in Children. AB - Ewing's sarcoma is a common malignant bone tumour presenting in children and young adults. Rarely extra- skeletal soft tissues and visceral organs can also be the site of origin of Ewing's sarcoma. Primary pulmonary Ewing's sarcoma is an extremely rare malignancy which occurs in the paediatric population. We report an unusual case of primary pulmonary Ewing's sarcoma in a nine year old girl who presented with features of superior vena cava syndrome in the emergency department. The diagnosis was confirmed pathologically both by light microscopy and immunohistochemistry. The patient was put on chemotherapy and surgery was planned but the patient expired within three days of starting chemotherapy. PMID- 25302248 TI - Jejunal diverticulitis ascending to the duodenum as a rare cause of acute abdomen. AB - We present the case of a 73 year-old Caucasian male with acute abdominal pain, peritonism and vomiting. Due to the severity of symptoms a CT examination of the abdomen was performed. The scans revealed multiple jejunal diverticula, wall thickening of the duodenum and jejunum, and free peritoneal fluid. No clear signs of mesenteric infarction, free abdominal air or abscess formation were seen. An additional exploratory laparotomy was conducted to confirm the CT findings and rule out the need for resection of small bowel. Since the results were matching, conservative therapy was scheduled and the patient recovered well. Jejunal diverticulitis is a rare cause of acute abdomen, however has to be considered as a differential diagnosis to more common entities. It usually stays localized, while in our case the inflammation ascended to the duodenum. CT is the modality of choice to diagnose and rule out potentially life threatening complications. PMID- 25302249 TI - Methicillin resistant Staphylococcus epidermidis induced endogenous endophthalmitis. AB - Fulminant endogenous endophthalmits, a relatively rare intraocular infection, caused by haematogenous spread of bacteria or fungi is usually seen in immune deficient patients. We report a case of methicillin resistant Staphylococcus epidermidis causing endogenous endophthalmitis following platelet transfusion and intravenous antibiotic therapy for a suspected dengue fever. PMID- 25302250 TI - Quality of life and marital adjustment after cognitive behavioural therapy and behavioural marital therapy in couples with anxiety disorders. AB - BACKGROUND: Anxiety disorders may affect nearly one in four persons and may cause significant impairment of interpersonal relationships including marital relationships. The effect of the disorder on the spouse and the impact of including the spouse in therapy are not well studied. AIM: To determine if Cognitive Behavioural Therapy (CBT) improves the quality of life of participants with anxiety disorders and if marital adjustment of couples with anxiety disorders can be improved with Behavioural Marital Therapy (BMT), relative to standard care of pharmacotherapy and psychoeducation. METHODS: An open label randomised controlled trial. Participants were randomly assigned to CBT+BMT or standard of care. Final assessments were carried out at 3.5 months after baseline. Quality of life was assessed using the WHOQOL-Bref instrument and Marital adjustment was measured using a marital quality scale. Chi-square test, student's t-test and Analysis of Variance (ANOVA) and Effect sizes with Cohen's d were used to compare differences between groups. RESULTS: Clinically meaningful effect sizes for the CBT+ BMT intervention were evident for the marital adjustment scores among participants (d=0.63) and their spouses (d=1.29), and for the psychological (d=0.84), social (d=0.72) and environmental (d=0.52) domains of the WHOQOL of participants and psychological (d=0.86), social (d=0.32) and environmental domains (d=1.01) of the WHOQOL of spouses of participants. CONCLUSION: CBT for the partner with anxiety disorder and BMT for couples with anxiety disorders and marital discord and involvement of the spouse in the therapy will be a useful addition to the management of a couple where one partner has an anxiety disorder. PMID- 25302251 TI - Effective use of pause procedure to enhance student engagement and learning. AB - INTRODUCTION: Active learning strategies have been documented to enhance learning. We created an active learning environment in neuromuscular physiology lectures for first year medical students by using 'Pause Procedure'. MATERIALS AND METHODS: One hundred and fifty medical students class is divided into two Groups (Group A and Group B) and taught in different classes. Each lecture of group A (experimental Group) undergraduate first year medical students was divided into short presentations of 12-15 min each. Each presentation was followed by a pause of 2-3min, three times in a 50 min lecture. During the pauses students worked in pairs to discuss and rework their notes. Any queries were directed towards the teacher and discussed forthwith. At the end of each lecture students were given 2-3 minutes to write down the key points they remembered about the lecture (free-recall). Fifteen days after completion of the lectures a 30 item MCQ test was administered to measure long term recall. Group B (control Group) received the same lectures without the use of pause procedure and was similarly tested. RESULTS: Experimental Group students did significantly better on the MCQ test (p-value<0.05) in comparison to the control Group. Most of the students (83.6%) agreed that the 'pause procedure' helped them to enhance lecture recall. CONCLUSION: Pause procedure is a good active learning strategy which helps students review their notes, reflect on them, discuss and explain the key ideas with their partners. Moreover, it requires only 6-7 min of the classroom time and can significantly enhance student learning. PMID- 25302252 TI - Onychomycosis in qassim region of saudi arabia: a clinicoaetiologic correlation. AB - BACKGROUND: Onychomycosis is mainly caused by dermatophytes, but yeasts and nondermatophyte molds have also been implicated, giving rise to diverse clinical presentations. The aetiological agents of the disease may show geographic variation. AIM: The aim of the present study was to isolate the causative pathogens and to correlate the various clinical patterns of onychomycosis with causative pathogens. MATERIALS AND METHODS: The study population comprised 170 patients with clinical suspicion of onychomycosis. Nail samples were collected for direct microscopic examination and culture. Clinical patterns were noted and correlated with causative pathogens. RESULTS: Out of total 170 cases included in the study, 140 (82.4%) were positive by microscopy and 77 (45.3%) showed positive mycological findings by both microscopy and culture. The male: female ratio was 1:2.5 and the mean age was 35.29 +/- 16.47 years. Fingernails were involved in 51.9%, toenails in 28.6% and both fingernails and toenails in 19.5% of the 77 patients. The clinical types noted were distal lateral subungual onychomycosis (71.4%), proximal subungual onychomycosis (10.4%), total dystrophic onychomycosis (10.4%), superficial white onychomycosis (3.9%) and mixed pattern onychomycosis (3.9%). Yeasts were the most common pathogens isolated, being found in 36 patients (46.8%) followed by nondermatophyte molds which were isolated from 28 patients (36.4%) followed by dermatophytes which were isolated from 13 patients (16.9%). CONCLUSION: Distal lateral subungual onychomycosis was the most common clinical presentation. Candida albicans, Aspergillus species and Tricophyton rubrum were the major pathogens. A single pathogen can give rise to more than one clinical type. PMID- 25302253 TI - Clindamycin 1% Nano-emulsion Gel Formulation for the Treatment of Acne Vulgaris: Results of a Randomized, Active Controlled, Multicentre, Phase IV Clinical Trial. AB - BACKGROUND: Acne vulgaris of the face is a common dermatological disease with a significant impact on the quality of life, psychosocial development as well as self-esteem of the patients. Nano emulsion gel formulations are said to have various advantages over the conventional formulations. AIM: The present study was conducted to assess the comparative efficacy and safety of a nano-emulsion gel formulation of clindamycin with its conventional formulation in the treatment of acne vulgaris of the face. MATERIALS AND METHODS: This prospective, active controlled, multicentric, phase IV clinical trial evaluated the treatment of patients with acne vulgaris of the face by a nano emulsion gel formulation or conventional gel formulation of clindamycin (as phosphate) 1% locally applied twice daily for 12 weeks as per random allocation. Acne lesion counts (inflammatory, non-inflammatory and total) and severity grading were carried out on the monthly scheduled visits along with tolerability assessments. RESULTS: A total of 200 patients (97 males) were included for Intention to Treat analysis in the trial with 100 patients in each group. Reductions in total (69.3 vs. 51.9%; p<0.001), inflammatory (73.4 vs. 60.6%; p<0.005) and non inflammatory (65.1 vs. 43.7%; p<0.001) acne lesions were reported to be significantly greater with the nano-emulsion gel formulation as compared to the conventional gel formulation. Significantly more reduction in the mean acne severity score was noticeable with the nano-emulsion gel formulation (-1.6 +/- 0.9 vs. -1.0 +/- 0.8; p<0.001) than the comparator. A trend towards better safety profile of the nano emulsion gel formulation was reported. CONCLUSION: In the treatment of acne vulgaris of the face, clindamycin nano emulsion gel formulation appears to be more effective than the conventional gel formulation and is also well tolerated. PMID- 25302254 TI - Pityriasis rosea like drug rash - a need to identify the disease in childhood. AB - Pityriasis rosea is a common dermatosis named by Gibert in 1860. It is an acute self limiting papulosquamous disease, probably infective in origin affecting healthy adolescents and young adults. It is characterized by distinctive skin eruptions and minimal constitutional symptoms. Drug induced pityriasis rosea tend to occur in older generation and resolution seen only after withdrawal of the offending drug. We report a case of 12-year-old boy with erythematous papules distributed over trunk and proximal arms after nimesulide therapy consistent with a clinical diagnosis of atypical pityriasis rosea. The relation of drug and development of pityriasis rosea is confirmed by dechallenge test of the suspected drug. PMID- 25302255 TI - Expression of VEGF in Periodontal Tissues of Type II Diabetes Mellitus Patients with Chronic Periodontitis -an Immunohistochemical Study. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability, but information about its role in periodontal diseases is limited. The aim of this study is to determine the association between VEGF expression in healthy and periodontally diseased tissues of healthy and diabetic patients. MATERIALS AND METHODS: Seventeen systemically healthy and 17 Type 2 diabetic patients (DM), all diagnosed with periodontitis were enrolled into the study. Gingival samples were collected from both periodontal and healthy sites in all patients. Each patient served as his/her own control samples were subjected to immunohistochemical analysis. RESULTS: The diseased sites of diabetic subjects expressed higher level of VEGF when compared to diseased sites of non diabetic subjects with chronic periodontitis, VEGF was observed in healthy periodontal tissues of both diabetic and systemically healthy people with periodontitis and VEGF was intensely present in monocytes and macrophages. CONCLUSION: The increased expression of VEGF in diseased sites of diabetic patients suggests that diabetes mellitus might have direct influence over VEGF expression. PMID- 25302256 TI - Oral leukoplakia - is biopsy at the initial appointment a must? AB - BACKGROUND: Oral leukoplakia is a potentially malignant disorder of the oral cavity. Leukoplakias with chances of undergoing malignant transformation owing to the presence of dysplastic changes may not be clinically distinguishable from leukoplakias without dysplasia. The study was carried out to evaluate the usefulness of biopsy in assessing the clinico-pathologic correlations of oral leukoplakia at the patient's initial visit. MATERIALS AND METHODS: Hospital records with clinical diagnosis of oral leukoplakia were retrospectively analysed. All these patients had undergone biopsy in their initial visit. Histopathological slides were reviewed and reported by a single pathologist. Diagnosis agreement was considered to be present if the clinical diagnosis matched the histopathological diagnosis. Misdiagnosis was considered if the clinical diagnosis did not match the histopathological diagnosis and underdiagnosis when malignancy was detected on histopathological examination. RESULTS: A total of 115 patients were clinically diagnosed with oral leukoplakia. According to clinical appearance of the leukoplakia patch was categorized in to three types viz homogeneous leukoplakia (n= 24 i.e. 20.87%), speckled leukoplakia (n=76 i.e. 66.08%) and verrucous leukoplakia (n=15 i.e. 13.04%). Histopathological examination confirmed clinical diagnosis in 88 cases (a diagnosis agreement of 76.52%). Histopathological examination of 19 cases revealed a different diagnosis, thus categorized as misdiagnosis (16.52%) and 8 cases had unexpected malignancy which accounted for underdiagnosis in 6.96% cases. There was dysplasia in 45 (51.13%) of the histopathologically confirmed cases of leukoplakia. CONCLUSION: The clinical appearance of suspicious white lesions does not provide a true nature of its disease status and malignant changes may be missed. PMID- 25302257 TI - Analysis of salivary antioxidant levels in different clinical staging and histological grading of oral squamous cell carcinoma: noninvasive technique in dentistry. AB - OBJECTIVE: To estimate and Compare of salivary antioxidant level {Uric acid (UA), Glutathione S Transferase (GST) and Superoxide dismutase (SOD)} between healthy control and study group (oral squamous cell carcinoma patients).Further comparison of sub division of study group on the basis of clinical staging and histological grading. MATERIALS AND METHODS: The study group consists of 50 cases of squamous cell carcinoma and 50 healthy patients. These parameters were estimated by spectrophotometer. The biochemical values of this study were subjected to statistical analysis i.e. Independent t-test, ANOVA and Tukey test. RESULT: UA suggested statistically significant changes in saliva of clinical staging and histological grading of oral squamous cell carcinoma (SCC) patients. Salivary SOD level between well to poorly differentiated SCC showed a progressive increase although it is not statistically significant. CONCLUSION: Salivary analysis of antioxidant is simple, non-invasive technique which may be useful as diagnostic, prognostic and therapeutic marker. PMID- 25302258 TI - Knowledge, attitude and practice of school teachers towards oral health in pondicherry. AB - BACKGROUND: School teachers by virtue of their training can influence a large number of children thereby play major role in the planning and implementation of oral health preventive programs. Hence, this study was undertaken with the objective of assessing the knowledge, attitude and practice of school teachers towards oral health. MATERIALS AND METHODS: This was a cross-sectional survey conducted among school teachers of the city of Pondicherry. A structured questionnaire was used and 212 teachers were assessed on their knowledge on oral health, attitude and practice regarding their personal oral health, attitude regarding oral health of children and status of oral health education at the schools. All data collected was entered into SPSS version 21.0. RESULTS: Around 47% of the participants felt that bacteria and sugar are the main causes of dental caries, while 42% felt that plaque and calculus are the main agents for periodontal disease. Around 82.5% teachers brushed twice daily. However, only 32% felt it is necessary to visit dentist regularly. While 86% of the teachers felt that children's teeth should be checked by dentist, only 51% agreed that it is their duty to impart oral health education to the students. CONCLUSION: The knowledge regarding oral health among school teachers was fair. Oral Health education must be imparted to preschool and primary school teachers as a part of National Oral Health care Program on a regular basis and further studies must be done to assess their awareness levels and make the necessary changes in further education modules. PMID- 25302259 TI - Correlation between collagen fibers and radiographic patterns of keratocystic odontogenic tumour. AB - BACKGROUND: WHO has recently renamed odontogenic keratocyst as keratocystic odontogenic tumour (KCOT) depending on its tumour like behaviour. AIM: To quantitate and qualitate different types of collagen fibers in KCOT using picrosirius red stain under polarising microscopy and to correlate with different radiographic patterns of KCOT to elucidate its biological behaviour in order to determine whether all KCOTs behave like a tumour. MATERIALS AND METHODS: Sixty histopathologically confirmed cases of KCOT were selected and stained histochemically using picrosirius red and examined under polarising microscope to evaluate colour of collagen fibers in the wall. Radiographic analysis of all the cases were also carried out and correlated with type of collagen of fibers. RESULTS: Greenish yellow collagen fibers were present statistically significantly more in multilocular KCOT and KCOT with multiple radiolucencies (both syndromic and non-syndromic) as compare to unilocular whereas orange red were significantly more in unilocular variety. Syndromic variety showed significantly higher number of greenish yellow collagen fibers than non-syndromic variety. CONCLUSION: Quality, organization and packing of collagen fibers of unilocular type is different than other radiographic patterns which accounts for difference in biological behaviour of these lesion, so we conclude that aggressive treatment should be reserved for selected cases. PMID- 25302260 TI - Comparision of shear bond strength of stainless steel and ceramic brackets at 24 hours after etching enamel with different proportions of acidulated phosphate fluoride. AB - AIMS AND OBJECTIVES: To evaluate and compare the shear bond strength of stainless steel brackets and ceramic brackets at 24h after etching the enamel with acidulated phosphate fluoride gel (1.23% APF) at different proportions (40%,30%,20%) incorporated in conventional etchant (37% phosphoric acid). MATERIALS AND METHODS: Eighty premolars (maxillary and mandibular first and second premolars) extracted for orthodontic purpose has been selected for the study and samples were divided into 4 groups containing 10 teeth each. Comprised of teeth etched Group 1 with 40% of APF gel etchant is Group 2 teeth etched with 30% of APF gel in Group 3 teeth etched with 20% of APF gel etchant and Group 4 teeth were etched with conventional etchant (37% phosphoric acid). RESULTS: The experimental group of Acidulated Phosphate Fluoride (APF) at different proportion (40%, 30%, 20%) incorporated with etchant application for 40s on the enamel surface at 24h indicated that group 4 showed the higher bond strength of all other remaining groups and the groups 1, 2 and 3 showed satisfactory bond strength. The statistical evaluation also revealed that the bond strength of control group (37% phosphoric acid) was greater than those of experimental groups. CONCLUSION: The present study results shows that the ceramic brackets have higher bond strength than stainless steel brackets (material wise). PMID- 25302261 TI - A three-dimensional study of variations in root canal morphology using cone-beam computed tomography of mandibular premolars in a South Indian population. AB - BACKGROUND: Conventional radiographic techniques being two dimensional, has its restrictions and is confined to limited diagnostic value. However, the incorporation of Cone Beam Computed Tomography (CBCT) gives a three dimensional insight to the tooth morphology and leads to better evaluation and treatment management. AIM: The aim of this study was to evaluate and assess the root canal morphology of mandibular pre-molars in South Indian Population using CBCT radiographic technique. MATERIALS AND METHODS: One thousand and eighty six and 814 fully erupted mandibular first and second premolars respectively were scanned using CBCT to evaluate the canal morphology according to Vertucci and Gulabiwala's classification. RESULTS: The most common configuration in mandibular first and second premolars was Vertucci's Type I(83.81% and 93.48% respectively) followed by Type V (11.97% and 3.5% respectively). CONCLUSION: South Indian population presented Type IV ertucci's canal morphology as the most common in mandibular first and second pre-molars followed by Type V. CBCT scanning poses a greater advantage in assessing the complexity of root canal morphology and planning an appropriate endodontic treatment for the same. PMID- 25302262 TI - Characterization of cervicofacial lymphnodes - a clinical and ultrasonographic study. AB - BACKGROUND: Lymph nodes undergo reactive changes in response to a wide variety of stimuli, the most common cause being inflammatory and immune reactions, apart from primary malignant neoplasms and metastatic tumours. It is well accepted that a clinical examination alone cannot be considered diagnostic to justify the involvement of cervicofacial lymph nodes especially deep and small nodes. Ultrasonography is an easy, reproducible, non invasive, non-ionizing imaging modality to evaluate cervicofacial lymph nodes. AIM: The present study was devised with an aim of comparing the clinical and ultrasonographic features of cervicofacial lymphadenopathy. MATERIALS AND METHODS: The subjects for the study were selected from the patients who visited the outpatient department with clinically palpable lymph nodes. Fifty two patients were included in the study and they were divided into 4 groups; group I (subjects with odontogenic infections), group II (subjects with non odontogenic oral conditions), group III (subjects with tuberculosis) and group IV (subjects with head and neck carcinomas). A detailed case history was recorded and a thorough clinical examination was carried out for all subjects. The cervicofacial lymph nodes were palpated and examined. Ultrasonographic examination of cervicofacial lymph nodes was carried out and recorded. The statistical analysis was done using chi square test. RESULT AND CONCLUSION: Most of the subjects considered for the study showed cervicofacial lymphadenopathy associated with odontogenic causes, specific infections like tuberculosis and head and neck malignancies. The lymph nodes showed varied clinical features. The ultrasonographic features such as number, size, shape, short axis/long axis ratio, border sharpness, hilum, echogenicity, distribution of the internal echoes, intranodal necrosis, matting or soft tissue edema were evaluated. The results were tabulated and statistical analysis was done. PMID- 25302263 TI - Comparison of the Antibacterial Efficacy of Manuka Honey Against E.faecalis and E.coli - An In vitro Study. AB - AIM: To compare the antibacterial efficacy of Manuka honey against E.faecalis and E.coli. MATERIALS AND METHODS: Escherichia coli (ATCC-25922) and Enterococcus faecalis (ATCC-29212) were separately inoculated in the nutrient broth and incubated at 37(o)C for 24-48 hrs. Bacterial samples were kept in contact with each disinfectant solution for varying intervals of time. Once the test time had elapsed 10MUL of the bacterial dilutions were plated on Mueller-Hinton agar and incubated for 24-48 hrs at 37 degrees C to estimate the density. Study of the disinfection process with respect to time and Modeling was done. RESULTS: The mean value of the antimicrobial activity of Manuka honey against E.coli and E.faecalis are 1.55 and 0.36 respectively and are relatively higher. It shows that there is a significant difference among the various root canal disinfectant groups against E. coli and E. feacalis. (p<0.001) CONCLUSION: Manuka honey is shown to be a potential root canal disinfectant against gram positive and gram negative bacterial pathogens. PMID- 25302264 TI - Impact of low level magnification on incipient occlusal caries diagnosis and treatment decision making. AB - INTRODUCTION: This in-vitro study aimed to test the accuracy and reproducibility in detection of incipient occlusal caries and treatment decision making using unenhanced visual-tactile technique and low level magnification by the use of loupes and surgical operating microscope (SOM). METHODOLOGY: Sixty extracted human posterior teeth were assessed by two examiners using ICDAS- II index and CPI- TN probe, with and without magnification. Histopathology was used as gold standard for diagnosis of caries and treatment decision making. Inter and intra examiner reproducibility was determined using Kappa statistics. RESULTS: Intraobserver reproducibility for caries detection using surgical operating microscope ranged from average to good (0.4-0.63). Inter-examiner reproducibility values for treatment decision making using experimental techniques such as unaided (0.40), Loupes (0.51) & SOM (0.63) were similar. PMID- 25302265 TI - Relationship between femur bone mineral density, body mass index and dental panoramic mandibular cortical width in diagnosis of elderly postmenopausal women with osteoporosis. AB - OBJECTIVES: To measure and determine mandibular cortical width (MCW) on the panoramic radiographs, to evaluate the usefulness of the method in identifying postmenopausal women with low femoral bone mineral densities (f- BMD) and to correlate the radiographic findings on panoramic radiographs with the f-BMD assessed by dual X-ray absorptiometry (DXA) to predict the efficacy of the radiographic method in diagnosing osteoporosis. MATERIALS AND METHODS: One hundred and twenty postmenopausal women (60 normal and 60 osteoporotic) in the age group of 50-75 y with f-BMD assessed by DXA had undergone panoramic radiographic examination. The patients were classified as normal (T-score >= 1.0) and osteoporotic (T-score <= -2.5). MCW on panoramic radiographs was measured bilaterally at the mental foramen region with a caliper and their mean was used as the exposure measure in the analysis. RESULTS: Student t-test showed that mean f-BMD, BMI and MCW was found be less in osteoporotic patients as compared to normal group with a statistically significant p-value < 0.001. Pearson correlation coefficient test revealed that MCW correlated positively with f-BMD and showed a significant decrease with age of the patient. CONCLUSION: Postmenopausal women with low f-BMD had thinner mandibular cortex at the mental foramen region when compared to normal subjects and are more susceptible to femoral neck fractures. Mandibular inferior cortical width at the mental foramen region could be used to identify postmenopausal women with low f- BMD. Hence, dental panoramic radiographs serve as a useful screening tool for early diagnosis of osteoporotic fractures. PMID- 25302266 TI - Comparison between efficacy of four different types of orthodontic separators. AB - AIM: To evaluate the rapidity and amount of separation of four different types of separators (i.e. Elastomeric separators, Dumbbell separators, Kesling springs and NEET springs) and also the percentage of loss of these separators. MATERIALS AND METHODS: The separating effect of 4 different types of separators (i.e. Elastomeric separators, Dumbbell separators, Kesling springs and NEET springs) were assessed for 3 days, and the separated space between molars and premolars were noted separately for three consecutive days. The number and types of lost separators were recorded at the same time. The amount of separation between molars and 2(nd) premolar in each quadrant was measured separately with a leaf gauge (sensitivity 5/100mm) and noted on each day. RESULTS: Dumbbell separators proved to be the fastest in producing separation and they produced consistently greater amount of separation on all three days. CONCLUSIONS: The Dumbbell separator would be ideal for situations where in rapid separation is needed, and also in cases where in the patient comes with the loss of separators. PMID- 25302267 TI - Comparison of Stresses Around Dental Implants Placed in Normal and Fibula Reconstructed Mandibular Models using Finite Element Analysis. AB - PURPOSE: This study was formulated to evaluate and compare stresses around endosseous implants in various normal and fibula reconstructed mandibular models using finite element analysis method. MATERIALS AND METHODS: CT scan data of a completely edentulous patient and a fibula reconstructed patient was made and the Dicom images were used to design 3-D mandibular models using software. Based on the information from the scan data, various types of reconstructed FEA models were made. Implants (fixtures) and superstructures were then embedded in each model and Von Mises stress around the neck of each implant under a vertical loading of 200 N and Horizontal load of 50 N was calculated using finite element structural analysis software. The results were compared between the reconstructed mandible and their respective normal mandible. RESULTS: Higher stress values were obtained for all the reconstructed types under horizontal loading and in reconstructed models involving larger area of reconstruction the stress were more. In the models involving smaller area of reconstruction like symphysis alone or body alone there is no significant change in the stress values on vertical loading. CONCLUSION: Stresses were comparatively smaller in mandibles involving a smaller area of reconstruction. Hence, fixed prosthesis could be advised and a bar retained over denture for reconstruction for larger area of reconstruction. PMID- 25302268 TI - Anti cariogenic effect of terminalia chebula. AB - BACKGROUND: Terminalia chebula is one of the traditional medicines used in the treatment of many diseases and possesses a wide variety of therapeutic activities. The aim of this study was to determine the antimicrobial properties of Terminalia chebula against oral pathogens related to caries. MATERIALS AND METHODS: In this study, Antimicrobial activity was tested using Kirby bouer method by streaking. Total phenol and total flavonoid content were analysed. Twenty high caries risk patients were subjected to rinse aqueous extract of Terminalia chebula. Salivary samples were collected for pH and microbial screening. Oral pathogens were identified by qualitative biochemical analysis. RESULTS: The total phenol content of extract was found to be 21.33 +/-1.633 (mean +/- SD) and total flavonoids was found to be 23.17 +/- 2.317 (mean +/- SD). There was a gradual increase in pH till 45mts post-rinse when compared to pre-rinse was observed. Antimicrobial effect of Terminalia Chebula aganist microbes showed that there was a significant reduction between the pre-rinse and post-rinse samples. CONCLUSION: These promising findings suggested the presence of antimicrobial activity of Terminalia Chebula against oral pathogens and proven to be an effective alternate antimicrobial agent. PMID- 25302269 TI - Assessment of lipid peroxides in multiple biofluids of leukoplakia and oral squamous cell carcinoma patients-a clinico- biochemical study. AB - BACKGROUND: Oral pre cancer and oral cancer results in lipid peroxidation, and assessment of lipid peroxides in body fluids may give insights into the role of anti oxidants in its management. AIM: The study was conducted to discern the varying levels of lipid peroxides in saliva, serum and tissue in oral pre cancer and oral cancer and also various forms of tobacco usage with sex as an added parameter. MATERIALS AND METHODS: The levels of lipid peroxides were measured in saliva, serum and tissue in a total of 50 patients, 20 belonging to control, and 30 study group in which 10 with oral leukoplakia and 20 with histologically proven oral squamous cell carcinoma (OSCC). The mean value of malondialdehyde (MDA) were also recorded in males and females among the patients with oral leukoplakia and OSCC. Among the study group patients, the levels of MDA were also recorded in habits of smoking and chewing tobacco. STATISTICAL ANALYSIS USED: Student's independent t-test, one way ANOVA, Tukey HSD procedure. RESULTS: Significantly elevated levels of lipid peroxides were seen in saliva, serum and tissue in oral leukoplakia and OSCC when compared to control patients. Among the study group, there were statistically significant increased levels of MDA in OSCC when compared to oral leukoplakia. There was also increase in MDA level in patients with smoking and chewing, but the variations seen in males and females were not very significant. CONCLUSION: The results clearly indicate the increase in lipid peroxidation in oral pre cancer and oral cancer with no significant difference between gender groups. The role of saliva as a relatively risk free and reliable, easy to obtain biofuid for diagnostic purposes has been highlighted. Also, since the levels of antioxidants are drastically decreased in carcinogenesis, the importance of anti oxidant supplements in the early stages of the disease has also been elucidated. PMID- 25302270 TI - Cryosurgery: painless and fearless management of mucocele in young patient. AB - A mucocele is a common benign lesion of the minor salivary gland mucosa that most frequently affects children and young adults. A 6-year-old male patient reported to the Department of Pedodontics and Preventive Dentistry, with the chief complaint of a painless swelling on floor of the mouth on his left side. The purpose of this case report is to present the treatment of mucocele present in floor of the mouth in a child patient using liquid nitrogen cryosurgery. Also, discussed are the mechanism of action, current protocol of cryosurgery recommended in the management of mucoceles, clinical advantages and disadvantages together with the clinical outcomes. PMID- 25302271 TI - Acrylic finger prosthesis: a case report. AB - Hands basic function is to grasp, hold and manipulate items. Hand gesture is perhaps the most blatant example of non-verbal communication. Finger and partial finger amputations are most frequently encountered forms of partial hand loss. Common causes are traumatic injuries, congenital absence or malformations present great clinical challenges. In addition to immediate loss of grasp strength, finger absence may cause marked psychological trauma. Individuals who desire finger replacement usually have high expectation for the appearance of prosthesis. This clinical report portrays simple method to retain acrylic finger prosthesis. PMID- 25302272 TI - A Case of Intermittently Discharging Skin Lesion: Orodentocutaneous Fistula Demonstrated on CT Fistulography. AB - Orodentocutaneous fistula is a rare entity where periapical dental abscess communicates with both oral cavity and external skin. In few cases, patients presents initially with only cutaneous manifestation with no recollectable history of dental problem. Delay in diagnosis of odontogenic cause of skin lesion makes the disease more chronic and extensive. We hereby present a case of orodentocutaneous fistula that presented with intermittently discharging skin lesion and was evaluated by using CT fistulography. PMID- 25302273 TI - The role of nasendoscopy in the fabrication of a palatopharyngeal obturator - a case report. AB - Defects confined to the hard palate can be managed with relative ease because it is a static shelf creating oro- nasal separation. Since the soft palate is a dynamic separator between the oral and nasal cavities, defects involving the soft palate require careful consideration. Instrumental visualization methods can aid the fabrication of obturators in patients with such defects and prevent problems of under or over obturation. This case report presents the prosthodontic management of a patient with a Veau class II cleft palate using a palatopharyngeal obturator in order to re-establish normal functions of deglutition and speech. Nasendoscopy was used as an adjunctive procedure to assess velopharyngeal function with the prosthesis. PMID- 25302274 TI - An silicone auricular prosthesis along with retentive AIDS-a case report. AB - Facial tissue loss presents with multiple functional and psychological problems. Its rehabilitation can improve the physical, mental and social well being of the patient. In conditions where surgical corrections are not favourable, the prosthetic approach to rehabilitate the missing structures can solve the problems, with added advantages of having complete control over colour and morphological outcome to match the surrounding skin and the counter lateral part. This case report describes the rehabilitation of a patient with the right auricular defect who was treated with a silicon auricular prosthesis and few ornaments were used as the retentive aids. PMID- 25302275 TI - Mandibular plasmacytoma of jaw - a case report. AB - The plasma cell neoplasm may present as Extramedullary Plasmacytoma (EMP) in soft tissues in bone as a Solitary Plasmacytoma of bone (SPB) or as a part of multi focal disseminated disease Multiple Myeloma (MM). The majority of 80% occurs in head and neck region. In our case, a 62-year-old male patient presented with a non tender swelling of short duration. The swelling was noted obliterating the vestibular depth in right lower mandibular region. The radiological features were non specific. PMID- 25302276 TI - A sequential approach in treatment of endo-perio lesion a case report. AB - Endo-perio lesions primarily occur by way of the intimate anatomic and vascular connections between the pulp and the periodontium. Endodontic-periodontal combined lesion is a clinical dilemma because making a differential diagnosis and deciding a prognosis are difficult. An untreated primary endodontic lesion may become secondarily involved with periodontal breakdown, which clinically present unusual signs and symptoms. This may delay the diagnosis and hence the correct treatment. This case report describes diagnosis and treatment protocol for an endo-perio lesion of primary endodontic with secondary periodontal involvement. PMID- 25302277 TI - Rehabilitation of digital defect with silicone finger prosthesis: a case report. AB - Patients with acquired defects often had severe trauma which leads to psychological instability, functional loss and poor aesthetics. Digital defects threaten the integrity of one's self esteem and also leads to a reduced and compromised function. A well fitted and colour matched finger prosthesis can make a patient feel a capable person and not a handicap. This article describes a technique for fabrication of custom made finger prosthesis with a silicone elastomer. The customization of the prosthesis leads to a better fit and retention. An excellent shade matching is achieved by the use of intrinsic colours. The other advantages of using silicone as a material of choice for prosthesis fabrication are also discussed. PMID- 25302278 TI - Oral manifestations in a renal osteodystrophy patient - a case report with review of literature. AB - Renal Osteodystrophy (ROD) is a common complication of chronic renal disease (CRD) and is the part of a broad spectrum of disorders of mineral metabolism that occurs in the clinical setting. It occurs early in the course of chronic renal failure and progresses as the kidney function deteriorates. It is an osseous alteration believed to arise from increased parathyroid function associated with inappropriate calcium, phosphorus and vitamin D metabolism. Involvement of the jaws is common and radiographic alterations are often one of the earliest signs of chronic renal failure. Herein, reporting a case of Chronic Renal Failure (Bilateral Grade I Neuropathy) with ROD presenting oral manifestations in an 11 year -old male child. PMID- 25302279 TI - Brown tumour of posterior maxilla associated with polydactyly, syndactyly and cardiac anomalies: a unique case report. AB - Brown tumour [BT] is an uncommon, non neoplastic complication of Hyperparathyroidism [HPT]. Skeletal changes are the main consequences of this endocrine condition. HPT manifest in three categories. Primary HPT is due to hyperfunction of one or more parathyroid gland, causing an increase of parathyroid hormone secretion resulting in hypercalcemia. Secondary HPT occurs due to chronic renal failure, decreased vitamin D production or with hypocalcemia. Tertiary HPT occurs when the parathyroid activity turns autonomous and excessive, leading to hypercalcemia. BT occurs frequently in the mandible than the maxilla. They are more common in women aged over 50y and majority of BT are asymptomatic. Radiographically, it appears as well defined radioluceny. The gross specimen usually shows a brown or reddish-brown colour. We report a relatively rare combination of maxillary posterior BT as a clinical manifestation of secondary HPT due to vitamin D deficiency with polydactyly, syndactyly and cardiac anomalies. PMID- 25302280 TI - Facial pain followed by unilateral facial nerve palsy: a case report with literature review. AB - Peripheral facial nerve palsy is the commonest cranial nerve motor neuropathy. The causes range from cerebrovascular accident to iatrogenic damage, but there are few reports of facial nerve paralysis attributable to odontogenic infections. In majority of the cases, recovery of facial muscle function begins within first three weeks after onset. This article reports a unique case of 32-year-old male patient who developed facial pain followed by unilateral facial nerve paralysis due to odontogenic infection. The treatment included extraction of the associated tooth followed by endodontic treatment of the neighboring tooth which resulted in recovery of facial nerve plasy. A thorough medical history and physical examination are the first steps in making any diagnosis. It is essential to rule out other causes of facial paralysis before making the definitive diagnosis, which implies the intervention. The authors hereby, report a case of 32-year-old male patient who developed unilateral facial nerve paralysis due to odontogenic infection with a good prognosis after appropriate treatment. PMID- 25302281 TI - A blue tooth - auricular prosthesis: a case report. AB - The absence of an ear is a considerable aesthetic problem which affects the patient's psychology and social behaviour. We are describing a case of 25-year old male reporting to the Department of Prosthodontics, with a chief complaint of deficient left auricular tissue. This can be corrected surgically, prosthetically or through a combination of these approaches; but the choice of treatment depends on patient. The patient chose prosthetic rehabilitation over surgical procedures & retention becomes a critical issue in this approach. Out of many types of retentive methods, we selectively incorporated new materials and used the latest technology to ensure the highest quality prosthesis. Creative approach for each patient with a focus on their individual needs was considered as it gives more satisfaction to the patient. This article describes a new, simple and cost effective technique by embedding Bluetooth-headset device into the silicone elastomer of a mechanically-retained auricular prosthesis. PMID- 25302282 TI - Circular enamel hypoplasia: a rare enamel developmental disturbance in permanent teeth. AB - Circular enamel hypoplasia, a type of enamel hypoplasia is an extensive enamel disturbance that results in a demarcating line surrounding the crown of the injured teeth visible both clinically and radiographically that most frequently occurs as a result of trauma in children around the age of two years. Clinical features include poor aesthetics, dentin sensitivity, increased susceptibility to dental caries and malocclusion. Early radiographic diagnosis of such teeth is important for timely intervention and subsequent treatment. PMID- 25302283 TI - Intramuscular hemangioma of the oral cavity - a case report. AB - Haemangiomas are the most common benign soft tissue tumor of the oral cavity. It often presents at birth or soon after, and appears as a soft and vascular swelling in lip, tongue, or buccal mucosa. This article reports a rare case of intra muscular haemangioma of the buccal mucosa in a 27-year-old female patient. PMID- 25302284 TI - Modified distal shoe appliance for premature loss of multiple deciduous molars: a case report. AB - Preservation of the primary dentition until the normal time of exfoliation is one of the most important factor involved in preventive and interceptive dentistry. The premature loss of second primary molar before the eruption of permanent first molar can create a significant arch space/tooth size discrepancy. Distal shoe space maintainer is a valuable part of the Paediatric Dentist's armamentarium in those cases where the second primary molar is prematurely lost and it helps to guide the first permanent molar into place. Conventional design poses various limitations in cases of premature loss of multiple deciduous molars. Thus, it is required to modify the conventional designs according to the needs of the patient. This case report describes an innovative modification of distal shoe appliance in cases of premature loss of multiple deciduous molars. In the present case, modification of distal shoe space maintainer was advocated because of inadequate abutments caused due to multiple loss of deciduous molars. Bilateral design of distal shoe was planned for unilateral loss of deciduous molars. PMID- 25302285 TI - Intraosseous myoepithelial carcinoma of mandible- a case report with clinical, radiological, histopathologic and immuno-histochemical features. AB - The primary central salivary gland neoplasms of the mandible are rare. They look clinically and radiographically similar to the odontogenic tumours or cysts which are common in the mandible. Myoepithelial carcinoma is a malignant counter part of myoepithelioma. Their diagnosis mainly depends only on thorough histopathological examination. This paper is to report a case of extra salivary tumour, intraosseous myoepithelial carcinoma of right ramus of the mandible. This case report serves to increase awareness and improve the index of diagnosis. PMID- 25302286 TI - Nevus of ota"- a rare pigmentation disorder with intraoral findings. AB - Nevus of Ota is a dermal melanocytosis seen along the distribution of ophthalmic and maxillary divisions of the trigeminal nerve. Only 12 cases so far have been reported in English literature and it is rare in Indian subcontinent. Most of the cases reported are in females and oral cavity is infrequently involved. Here, we report a rare case of unilateral Nevus of Ota in a 56-year-old male with oral manifestations. PMID- 25302287 TI - Leuloplakia - review of a potentially malignant disorder. AB - Leukoplakias are oral white lesions that have not been diagnosed as any other specific disease. They are grouped under premalignant lesions, now redesignated as potentially malignant disorders. Their significance lies in the fact that they have propensity for malignant transformation at a higher rate when compared to other oral lesions. This article reviews aetiology, epidemiology, clinical characteristics, histopathologic features, malignant potential and treatment of oral leukoplakia. PMID- 25302288 TI - Reach the unreached - a systematic review on mobile dental units. AB - Provision of health care facilities and the extent of their utilization is one of the indices of human development. The services for the masses need to be designed with the basic objective of alleviating and preventing the vast amounts of diseases of the mass. This could be achieved by mobile dental units (MDUs). The present systemic review access the efficacy of MDUs for community settings. A review of literature was performed both electronically and manually using MeSH Terms- Mobile Dental Units/clinics. Eight articles, which fulfilled inclusion and exclusion criteria were selected for the review. MDUs help in overcoming the accessibility, affordability and sustainability barrier. They are able to reach more people than fixed-site clinics. Even in Government sector, mobile dental vans can help reach the underserved at an affordable cost.The present systematic review revealed that MDUs prove to be an effective adjunct to the oral health service providers like dental colleges and private practitioners. PMID- 25302289 TI - Enhancing facial aesthetics with muscle retraining exercises-a review. AB - Facial attractiveness plays a key role in social interaction. 'Smile' is not only a single category of facial behaviour, but also the emotion of frank joy which is expressed on the face by the combined contraction of the muscles involved. When a patient visits the dental clinic for aesthetic reasons, the dentist considers not only the chief complaint but also the overall harmony of the face. This article describes muscle retraining exercises to achieve control over facial movements and improve facial appearance which may be considered following any type of dental rehabilitation. Muscle conditioning, training and strengthening through daily exercises will help to counter balance the aging effects. PMID- 25302290 TI - Aggregatibacter actinomycetemcomitans - a tooth killer? AB - Strong evidence is available on Aggregatibacter actinomycetemcomitans (A.a) on its role as the causative agent of localised juvenile periodontitis (LJP), a disease characterised by rapid destruction of the tooth-supporting tissues. This organism possesses a large number of virulence factors with a wide range of activities which enable it to colonise the oral cavity, invade periodontal tissues, evade host defences, initiate connective tissue destruction and interfere with tissue repair. Adhesion to epithelial and tooth surfaces is dependent on the presence of surface proteins and structures such as microvesicles and fimbriae. Invasion has been demonstrated in vivo and in vitro. The organism has a number of means of evading host defences which include: (i) production of leukotoxin; (ii) producing immunosuppressive factors; (iv) secreting proteases capable of cleaving IgG; and (v) producing Fc-binding. PMID- 25302291 TI - Comparative evaluation of sorption, solubility and microhardness of heat cure polymethylmethacrylate denture base resin & flexible denture base resin. AB - AIM: The aim of the study was to evaluate and compare sorption, solubility and microhardness of heat cure polymethylmethacrylate (PMMA) denture base resin and flexible (thermoplastic polyamide nylon) denture base resin. MATERIALS AND METHODS: Sorption, solubility and microhardness were assessed to determine compliance with ADA Specification no. 12. RESULTs were assessed using statistical and observational analyses. RESULT: All materials satisfied ADA requirements for sorption, solubility and microhardness. Heat cure PMMA showed more sorption, solubility and microhardness than flexible (thermoplastic polyamide nylon). CONCLUSION: Flexible (thermoplastic polyamide nylon) resin absorbs less water, is less soluble and is more flexible than PMMA. PMID- 25302292 TI - Effect of power bleaching on the fluorosis stained anterior teeth case series. AB - Bleaching is a conservative method for restoring the colour of intrinsic discoloration of teeth. The combination of McInnes solution and power bleaching is effective procedure for bleaching of fluorosis stained teeth. Definitely bleaching with McInnes bleaching agent gives instant results, not dependent on patient's compliance as other office based procedures, no dehydration of the tooth occurs with no damage to the pulp. Bleaching with this solution is esthetically pleasing and minimally invasive option for young patients rather than a complete coronal covering. The dentist is in complete control of the process throughout the treatment. It is a fast process the results are evident even after a single visit. PMID- 25302293 TI - A rare occurrence of non-syndromic hypo-hyperdontia in the mandibular anterior region. PMID- 25302294 TI - GHK and DNA: resetting the human genome to health. AB - During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue), increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Recently, GHK has been found to reset genes of diseased cells from patients with cancer or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients' cells shut down tissue destructive genes and stimulate repair and remodeling activities. In this paper, we discuss GHK's effect on genes that suppress fibrinogen synthesis, the insulin/insulin-like system, and cancer growth plus activation of genes that increase the ubiquitin-proteasome system, DNA repair, antioxidant systems, and healing by the TGF beta superfamily. A variety of methods and dosages to effectively use GHK to reset genes to a healthier state are also discussed. PMID- 25302295 TI - Synaptojanin 1 mutation in Parkinson's disease brings further insight into the neuropathological mechanisms. AB - Synaptojanin 1 (SYNJ1) is a phosphoinositide phosphatase highly expressed in nerve terminals. Its two phosphatase domains dephosphorylate phosphoinositides present in membranes, while its proline-rich domain directs protein-protein interactions with synaptic components, leading to efficient recycling of synaptic vesicles in neurons. Triplication of SYNJ1 in Down's syndrome is responsible for higher level of phosphoinositides, enlarged endosomes, and learning deficits. SYNJ1 downregulation in Alzheimer's disease models is protective towards amyloid beta peptide (Abeta) toxicity. One missense mutation in one of SYNJ1 functional domains was recently incriminated in an autosomal recessive form of early-onset Parkinson's disease (PD). In the third decade of life, these patients develop progressive Parkinsonism with bradykinesia, dystonia, and variable atypical symptoms such as cognitive decline, seizures, and eyelid apraxia. The identification of this new gene, together with the fact that most of the known PD proteins play a role in synaptic vesicle recycling and lipid metabolism, points out that synaptic maintenance is a key player in PD pathological mechanisms. Studying PD genes as a network regulating synaptic activity could bring insight into understanding the neuropathological processes of PD and help identify new genes at fault in this devastating disorder. PMID- 25302296 TI - Profile of microbial keratitis after corneal collagen cross-linking. AB - PURPOSE: To report the profile of microbial keratitis occurring after corneal collagen cross-linking (CXL) in keratoconus patients. METHODS: A retrospective analysis of 2350 patients (1715 conventional CXL, 310 transepithelial CXL, and 325 accelerated CXL) over 7 years (from January 2007 to January 2014) of progressive keratoconus, who underwent CXL at a tertiary eye care centre, was performed. Clinical findings, treatment, and course of disease of four eyes that developed postprocedural moxifloxacin resistant Staphylococcus aureus (MXRSA) infectious keratitis are highlighted. RESULTS: Four eyes that underwent CXL (0.0017%) had corneal infiltrates. All eyes that developed keratitis had conventional CXL. Corneal infiltrates were noted on the third postoperative day. Gram's stain as well as culture reported MXRSA as the causative agent in all cases. Polymerase chain reaction (PCR) in each case was positive for eubacterial genome. All patients were treated with fortified antibiotic eye drops, following which keratitis resolved over a 6-week period with scarring. All these patients were on long-term preoperative oral/topical steroids for chronic disorders (chronic vernal keratoconjunctivitis, bronchial asthma, and chronic eczema). CONCLUSION: The incidence of infectious keratitis after CXL is a rare complication (0.0017%). MXRSA is a potential organism for causing post-CXL keratitis and should be identified early and treated aggressively with fortified antibiotics. PMID- 25302297 TI - A medical manipulator system with lasers in photodynamic therapy of port wine stains. AB - Port wine stains (PWS) are a congenital malformation and dilation of the superficial dermal capillary. Photodynamic therapy (PDT) with lasers is an effective treatment of PWS with good results. However, because the laser density is uneven and nonuniform, the treatment is carried out manually by a doctor thus providing little accuracy. Additionally, since the treatment of a single lesion can take between 30 and 60 minutes, the doctor can become fatigued after only a few applications. To assist the medical staff with this treatment method, a medical manipulator system (MMS) was built to operate the lasers. The manipulator holds the laser fiber and, using a combination of active and passive joints, the fiber can be operated automatically. In addition to the control input from the doctor over a human-computer interface, information from a binocular vision system is used to guide and supervise the operation. Clinical results are compared in nonparametric values between treatments with and without the use of the MMS. The MMS, which can significantly reduce the workload of doctors and improve the uniformity of laser irradiation, was safely and helpfully applied in PDT treatment of PWS with good therapeutic results. PMID- 25302299 TI - Extracts from Vatica diospyroides type SS fruit show low dose activity against MDA-MB-468 breast cancer cell-line via apoptotic action. AB - Very strong antiproliferative action of V. diospyroides type SS fruit extracts (IC50 range of 1.60-17.45 ug/mL) in MDA-MB-468 cell-line was observed in an MTT assay. After dosing of an extract concentration at half IC50 to cell line for 24 to 72 hours, treated cells were subjected to Annexin V-FITC/PI binding assay, followed by FACS and western blot analyses. Significant apoptotic death was observed with all extract treatments and both exposure times. Dosing with acetone extract of pericarp and cotyledon induced the highest apoptotic populations (33 and 32%, resp.), with the lowest populations of viable cells (65 and 67%, resp.). During 24 to 72 hours of dosing with methanolic extract of pericarp, the populations of viable and early apoptotic cells decreased significantly from 72.40 to 71.32% and from 12.00 to 6.36%, respectively, while the late apoptotic and nonviable cell populations continuously increased from 15.30 to 19.18% and from 0.30 to 3.14%, respectively. The expression of Bax increased within 12-48 hours of dosing, confirming apoptosis induced by time-dependent responses. The mutant p53 of MDA-MB-468 cells was expressed. Our results indicate that apoptosis and time-dependent therapeutic actions contribute to the cytotoxic effects of V. diospyroides type SS fruit on MDA-MB-468 cell. PMID- 25302298 TI - Radiation oncology in vitro: trends to improve radiotherapy through molecular targets. AB - Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed. Beyond simple identification of resistant phenotype the discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment including radiotherapy. Alterations on transduction signaling pathway related with MAPK cascade are the main axis in cancer cellular proliferation even as cell migration and invasiveness in irradiated tumor cell lines; then, for that reason, more studies are in course focusing on, among others, DNA damage enhancement, apoptosis stimulation, and growth factors receptor blockages, showing promising in vitro results highlighting molecular targets associated with ionizing radiation as a new radiotherapy strategy to improve clinical outcome. In this review we discuss some of the main molecular targets related with tumor cell proliferation and migration as well as their potential contributions to radiation oncology improvements. PMID- 25302300 TI - Magnetic resonance spectroscopy: an in vivo molecular imaging biomarker for Parkinson's disease? AB - Parkinson's disease (PD) is a neurodegenerative disorder caused by selective loss of dopaminergic neurons in the substantia nigra pars compacta which leads to dysfunction of cerebral pathways critical for the control of movements. The diagnosis of PD is based on motor symptoms, such as bradykinesia, akinesia, muscular rigidity, postural instability, and resting tremor, which are evident only after the degeneration of a significant number of dopaminergic neurons. Currently, a marker for early diagnosis of PD is still not available. Consequently, also the development of disease-modifying therapies is a challenge. Magnetic resonance spectroscopy is a quantitative imaging technique that allows in vivo measurement of certain neurometabolites and may produce biomarkers that reflect metabolic dysfunctions and irreversible neuronal damage. This review summarizes the abnormalities of cerebral metabolites found in MRS studies performed in patients with PD and other forms of parkinsonism. In addition, we discuss the potential role of MRS as in vivo molecular imaging biomarker for early diagnosis of PD and for monitoring the efficacy of therapeutic interventions. PMID- 25302301 TI - Importance of pH homeostasis in metabolic health and diseases: crucial role of membrane proton transport. AB - Protons dissociated from organic acids in cells are partly buffered. If not, they are transported to the extracellular fluid through the plasma membrane and buffered in circulation or excreted in urine and expiration gas. Several transporters including monocarboxylate transporters and Na(+)/H(+) exchanger play an important role in uptake and output of protons across plasma membranes in cells of metabolic tissues including skeletal muscle and the liver. They also contribute to maintenance of the physiological pH of body fluid. Therefore, impairment of these transporters causes dysfunction of cells, diseases, and a decrease in physical performance associated with abnormal pH. Additionally, it is known that fluid pH in the interstitial space of metabolic tissues is easily changed due to little pH buffering capacitance in interstitial fluids and a reduction in the interstitial fluid pH may mediate the onset of insulin resistance unlike blood containing pH buffers such as Hb (hemoglobin) and albumin. In contrast, habitual exercise and dietary intervention regulate expression/activity of transporters and maintain body fluid pH, which could partly explain the positive effect of healthy lifestyle on disease prognosis. PMID- 25302302 TI - Perfusion in the tissue surrounding pancreatic cancer and the patient's prognosis. AB - OBJECTIVE: The objective was to investigate the relationship between prognosis in case of pancreatic cancer and perfusion in tissue surrounding pancreatic cancer using perfusion CT. METHODS: We enrolled 17 patients diagnosed with inoperable pancreatic adenocarcinoma. All patients were examined by perfusion CT and then underwent chemotherapy using gemcitabine. The time density curve (TDC) of each CT pixel was analyzed to calculate area under the curve (AUC) and blood flow (BF) using a mathematical algorithm based on the single-compartment model. To measure the AUC and BF of tumor (AUCT and BFT) and peritumoral tissue (AUCPTT and BFPTT), regions of interest were manually placed on the cancer and in pancreatic tissue within 10 mm of proximal pancreatic parenchyma. Survival days from the date of perfusion CT were recorded. Correlation between AUC or BF and survival days was assessed. RESULTS: We found a significant correlation between AUCPTT or BFPTT and survival days (P = 0.04 or 0.0005). Higher AUCPTT or BFPTT values were associated with shorter survival. We found no significant correlation between AUCT or BFT and survival. CONCLUSIONS: Our results suggest that assessments of perfusion in pancreatic tissue within 10 mm of proximal pancreatic parenchyma may be useful in predicting prognosis. PMID- 25302303 TI - Role of circulating lymphocytes in patients with sepsis. AB - Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed. PMID- 25302304 TI - Volume change and liver parenchymal signal intensity in Gd-EOB-DTPA-enhanced magnetic resonance imaging after portal vein embolization prior to hepatectomy. AB - PURPOSE: To investigate the liver volume change and the potential of early evaluation by contrast-enhanced magnetic resonance imaging (MRI) using gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) after portal vein embolization (PVE). MATERIALS AND METHODS: Retrospective evaluations of computed tomography (CT) volumetry of total liver and nonembolized areas were performed before and 3 weeks after PVE in 37 cases. The percentage of future liver remnant (%FLR) and the change ratio of %FLR (%FLR ratio) were calculated. Prospective evaluation of signal intensities (SIs) was performed to estimate the role of Gd EOB-DTPA-enhanced MRI as a predictor of hypertrophy in 16 cases. The SI contrast between embolized and nonembolized areas was calculated 1 week after PVE. The change in SI contrast before and after PVE (SI ratio) was also calculated in 11 cases. RESULTS: %FLR ratio significantly increased, and SI ratio significantly decreased (both P < 0.01). There were significant negative correlations between %FLR and SI contrast and between %FLR and SI ratio (both P < 0.01). CONCLUSION: Hypertrophy in the nonembolized area after PVE was indicated by CT volumetry, and measurement of SI contrast and SI ratio in Gd-EOB-DTPA-enhanced MRI early after PVE may be useful to predict the potential for hepatic hypertrophy. PMID- 25302305 TI - The possible role of extravillous trophoblast-derived exosomes on the uterine spiral arterial remodeling under both normal and pathological conditions. AB - A tenet of contemporary obstetrics is that events that compromise placentation increase the risk of complications of pregnancy and contribute to poor pregnancy outcome. In particular, conditions that affect the invasion of placental cells and remodeling of uterine spiral arteries compromise placental function and the subsequent development of the fetus. Extravillous trophoblast cells (EVTs) proliferate and migrate from the cytotrophoblast in the anchoring villi of the placenta and invade the maternal decidua and myometrium. These cells are localised with uterine uterine spiral arteries and are thought to induce vascular remodeling. A newly identified pathway by which EVTs may regulate vascular remodeling within the uterus is via the release of exosomes. Trophoblast cells release exosomes that mediate aspects of cell-to-cell communication. The aim of this brief commentary is to review the putative role of exosomes released from extravillous trophoblast cells in uterine spiral artery remodeling and, in particular, their role in the aetiology of preeclampsia. Placental exosomes may engage in local cell-to-cell communication between the cell constituents of the placenta and contiguous maternal tissues and/or distal interactions, involving the release of placental exosomes into biological fluids and their transport to a remote site of action. PMID- 25302306 TI - Molecular identification and quantification of tetracycline and erythromycin resistance genes in Spanish and Italian retail cheeses. AB - Large antibiotic resistance gene pools in the microbiota of foods may ultimately pose a risk for human health. This study reports the identification and quantification of tetracycline- and erythromycin-resistant populations, resistance genes, and gene diversity in traditional Spanish and Italian cheeses, via culturing, conventional PCR, real-time quantitative PCR (qPCR), and denaturing gradient gel electrophoresis (DGGE). The numbers of resistant bacteria varied widely among the antibiotics and the different cheese varieties; in some cheeses, all the bacterial populations seemed to be resistant. Up to eight antibiotic resistance genes were sought by gene-specific PCR, six with respect to tetracycline, that is, tet(K), tet(L), tet(M), tet(O), tet(S), and tet(W), and two with respect to erythromycin, that is, erm(B) and erm(F). The most common resistance genes in the analysed cheeses were tet(S), tet(W), tet(M), and erm(B). The copy numbers of these genes, as quantified by qPCR, ranged widely between cheeses (from 4.94 to 10.18log10/g). DGGE analysis revealed distinct banding profiles and two polymorphic nucleotide positions for tet(W)-carrying cheeses, though the similarity of the sequences suggests this tet(W) to have a monophyletic origin. Traditional cheeses would therefore appear to act as reservoirs for large numbers of many types of antibiotic resistance determinants. PMID- 25302308 TI - The applicability of oxidative stress biomarkers in assessing chromium induced toxicity in the fish Labeo rohita. AB - The evaluation of metal's toxicity in freshwater is one of the imperative areas of research and there is an emergent concern on the development of techniques for detecting toxic effects in aquatic animals. Oxidative stress biomarkers are very useful in assessing the health of aquatic life and more in depth studies are necessary to establish an exact cause effect relationship. Therefore, to study the effectiveness of this approach, a laboratory study was conducted in the fish Labeo rohita as a function of hexavalent chromium and the toxicity indices using a battery of oxidative stress biomarkers such as catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) in the liver, muscle, gills, and brain have been studied along with biometric parameters, behavioral changes, and Cr bioaccumulation. A significant increased HSI was observed in contrast to CF which reduced significantly. SOD, CAT, and GR activity increased significantly in all the tissues of treated fishes. The bioaccumulation of Cr was highest in liver followed by gills, muscle, and brain. This study highlights the significance of using a set of integrated biomarker and advocate to include these parameters in National Water Quality Monitoring Program in areas potentially polluted with metals to assess the health of the ecosystem. PMID- 25302307 TI - Genetic networks lead and follow tumor development: microRNA regulation of cell cycle and apoptosis in the p53 pathways. AB - During the past ten years, microRNAs (miRNAs) have been shown to play a more significant role in the formation and progression of cancer diseases than previously thought. With an increase in reports about the dysregulation of miRNAs in diverse tumor types, it becomes more obvious that classic tumor-suppressive molecules enter deep into the world of miRNAs. Recently, it has been demonstrated that a typical tumor suppressor p53, known as the guardian of the genome, regulates some kinds of miRNAs to contribute to tumor suppression by the induction of cell-cycle arrest and apoptosis. Meanwhile, miRNAs directly/indirectly control the expression level and activity of p53 to fine-tune its functions or to render p53 inactive, indicating that the interplay between p53 and miRNA is overly complicated. The findings, along with current studies, will underline the continuing importance of understanding this interlocking control system for future therapeutic strategies in cancer treatment and prevention. PMID- 25302309 TI - The influence of standardized Valeriana officinalis extract on the CYP3A1 gene expression by nuclear receptors in in vivo model. AB - Valeriana officinalis is one of the most popular medicinal plants commonly used as a sedative and sleep aid. It is suggested that its pharmacologically active compounds derived from the root may modulate the CYP3A4 gene expression by activation of pregnane X receptor (PXR) or constitutive androstane receptor (CAR) and lead to pharmacokinetic herb-drug interactions. The aim of the study was to determine the influence of valerian on the expression level of CYP3A1 (homologue to human CYP3A4) as well as nuclear receptors PXR, CAR, RXR, GR, and HNF-4alpha. Male Wistar rats were given standardized valerian extract (300 mg/kg/day, p.o.) for 3 and 10 days. The expression in liver tissue was analyzed by using real-time PCR. Our result showed a decrease of CYP3A1 expression level by 35% (P = 0.248) and 37% (P < 0.001), respectively. Moreover, Valeriana exhibited statistically significant reduction in RXR (approximately 28%) only after 3-day treatment. We also demonstrated a decrease in the amount HNF-4alpha by 22% (P = 0.005) and 32% (P = 0.012), respectively. In case of CAR, the increase of expression level by 46% (P = 0.023) was noted. These findings suggest that Valeriana officinalis extract can decrease the CYP3A4 expression and therefore may lead to interactions with synthetic drugs metabolized by this enzyme. PMID- 25302310 TI - Platelet rich plasma and knee surgery. AB - In orthopaedic surgery and sports medicine, the knee joint has traditionally been considered the workhorse. The reconstruction of every damaged element in this joint is crucial in achieving the surgeon's goal to restore the knee function and prevent degeneration towards osteoarthritis. In the last fifteen years, the field of regenerative medicine is witnessing a boost of autologous blood-derived platelet rich plasma products (PRPs) application to effectively mimic and accelerate the tissue healing process. The scientific rationale behind PRPs is the delivery of growth factors, cytokines, and adhesive proteins present in platelets and plasma, as well as other biologically active proteins conveyed by the plasma such as fibrinogen, prothrombin, and fibronectin; with this biological engineering approach, new perspectives in knee surgery were opened. This work describes the use of PRP to construct and repair every single anatomical structure involved in knee surgery, detailing the process conducted in ligament, meniscal, and chondral surgery. PMID- 25302311 TI - Epidemiology of West Nile disease in Europe and in the Mediterranean Basin from 2009 to 2013. AB - West Nile virus (WNV) transmission has been confirmed in the last four years in Europe and in the Mediterranean Basin. An increasing concern towards West Nile disease (WND) has been observed due to the high number of human and animal cases reported in these areas confirming the importance of this zoonosis. A new epidemiological scenario is currently emerging: although new introductions of the virus from abroad are always possible, confirming the epidemiological role played by migratory birds, the infection endemisation in some European territories today is a reality supported by the constant reoccurrence of the same strains across years in the same geographical areas. Despite the WND reoccurrence in the Old World, the overwintering mechanisms are not well known, and the role of local resident birds or mosquitoes in this context is poorly understood. A recent new epidemiological scenario is the spread of lineage 2 strain across European and Mediterranean countries in regions where lineage 1 strain is still circulating creating favourable conditions for genetic reassortments and emergence of new strains. This paper summarizes the main epidemiological findings on WNV occurrence in Europe and in the Mediterranean Basin from 2009 to 2013, considering potential future spread patterns. PMID- 25302312 TI - Cigarette smoke-exposed Candida albicans increased chitin production and modulated human fibroblast cell responses. AB - The predisposition of cigarette smokers for development of respiratory and oral bacterial infections is well documented. Cigarette smoke can also contribute to yeast infection. The aim of this study was to investigate the effect of cigarette smoke condensate (CSC) on C. albicans transition, chitin content, and response to environmental stress and to examine the interaction between CSC-pretreated C. albicans and normal human gingival fibroblasts. Following exposure to CSC, C. albicans transition from blastospore to hyphal form increased. CSC-pretreated yeast cells became significantly (P < 0.01) sensitive to oxidation but significantly (P < 0.01) resistant to both osmotic and heat stress. CSC pretreated C. albicans expressed high levels of chitin, with 2- to 8-fold recorded under hyphal conditions. CSC-pretreated C. albicans adhered better to the gingival fibroblasts, proliferated almost three times more and adapted into hyphae, while the gingival fibroblasts recorded a significantly (P < 0.01) slow growth rate but a significantly higher level of IL-1beta when in contact with CSC pretreated C. albicans. CSC was thus able to modulate both C. albicans transition through the cell wall chitin content and the interaction between C. albicans and normal human gingival fibroblasts. These findings may be relevant to fungal infections in the oral cavity in smokers. PMID- 25302314 TI - A model independent S/W framework for search-based software testing. AB - In Model-Based Testing (MBT) area, Search-Based Software Testing (SBST) has been employed to generate test cases from the model of a system under test. However, many types of models have been used in MBT. If the type of a model has changed from one to another, all functions of a search technique must be reimplemented because the types of models are different even if the same search technique has been applied. It requires too much time and effort to implement the same algorithm over and over again. We propose a model-independent software framework for SBST, which can reduce redundant works. The framework provides a reusable common software platform to reduce time and effort. The software framework not only presents design patterns to find test cases for a target model but also reduces development time by using common functions provided in the framework. We show the effectiveness and efficiency of the proposed framework with two case studies. The framework improves the productivity by about 50% when changing the type of a model. PMID- 25302313 TI - Balancing Clinical and Pathologic Relevence in the Machine Learning Diagnosis of Epilepsy. AB - The application of machine learning to epilepsy can be used both to develop clinically useful computer-aided diagnostic tools, and to reveal pathologically relevant insights into the disease. Such studies most frequently use neurologically normal patients as the control group to maximize the pathologic insight yielded from the model. This practice yields potentially inflated accuracy because the groups are quite dissimilar. A few manuscripts, however, opt to mimic the clinical comparison of epilepsy to non-epileptic seizures, an approach we believe to be more clinically realistic. In this manuscript, we describe the relative merits of each control group. We demonstrate that in our clinical quality FDG-PET database the performance achieved was similar using each control group. Based on these results, we find that the choice of control group likely does not hinder the reported performance. We argue that clinically applicable computer-aided diagnostic tools for epilepsy must directly address the clinical challenge of distinguishing patients with epilepsy from those with non epileptic seizures. PMID- 25302315 TI - A design of irregular grid map for large-scale Wi-Fi LAN fingerprint positioning systems. AB - The rapid growth of mobile communication and the proliferation of smartphones have drawn significant attention to location-based services (LBSs). One of the most important factors in the vitalization of LBSs is the accurate position estimation of a mobile device. The Wi-Fi positioning system (WPS) is a new positioning method that measures received signal strength indication (RSSI) data from all Wi-Fi access points (APs) and stores them in a large database as a form of radio fingerprint map. Because of the millions of APs in urban areas, radio fingerprints are seriously contaminated and confused. Moreover, the algorithmic advances for positioning face computational limitation. Therefore, we present a novel irregular grid structure and data analytics for efficient fingerprint map management. The usefulness of the proposed methodology is presented using the actual radio fingerprint measurements taken throughout Seoul, Korea. PMID- 25302316 TI - Improved estimation of the initial number of susceptible individuals in the general stochastic epidemic model using penalized likelihood. AB - The initial size of a completely susceptible population in a group of individuals plays a key role in drawing inferences for epidemic models. However, this can be difficult to obtain in practice because, in any population, there might be individuals who may not transmit the disease during the epidemic. This short note describes how to improve the maximum likelihood estimators of the infection rate and the initial number of susceptible individuals and provides their approximate Hessian matrix for the general stochastic epidemic model by using the concept of the penalized likelihood function. The simulations of major epidemics show significant improvements in performance in averages and coverage ratios for the suggested estimator of the initial number in comparison to existing methods. We applied the proposed method to the Abakaliki smallpox data. PMID- 25302317 TI - FraudMiner: a novel credit card fraud detection model based on frequent itemset mining. AB - This paper proposes an intelligent credit card fraud detection model for detecting fraud from highly imbalanced and anonymous credit card transaction datasets. The class imbalance problem is handled by finding legal as well as fraud transaction patterns for each customer by using frequent itemset mining. A matching algorithm is also proposed to find to which pattern (legal or fraud) the incoming transaction of a particular customer is closer and a decision is made accordingly. In order to handle the anonymous nature of the data, no preference is given to any of the attributes and each attribute is considered equally for finding the patterns. The performance evaluation of the proposed model is done on UCSD Data Mining Contest 2009 Dataset (anonymous and imbalanced) and it is found that the proposed model has very high fraud detection rate, balanced classification rate, Matthews correlation coefficient, and very less false alarm rate than other state-of-the-art classifiers. PMID- 25302318 TI - Oxidant-antioxidant balance during on-pump coronary artery bypass grafting. AB - BACKGROUND: The aim of this study was to evaluate the changes in perioperative oxidant-antioxidant balance in ONCABG. METHODS: Twenty-three patients were included in this study. Serum total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) values were assessed preoperatively, at 20 minutes after aortic clamping and at 30 minutes, 6 hours, and 48 hours after declamping (reperfusion). The patients were divided into 2 groups according to the median aortic cross clamping (XC) time: group 1 (XC time < 42 minutes) and group 2 (XC time >= 42 minutes). RESULTS: TOS and OSI values of whole patients at 30 minutes after reperfusion were higher than preoperative values (P = 0.045, P = 0.015), while perioperative TAS levels of the patients were similar to the preoperative levels (P = 0.173). XC time was correlated with TOS levels at 30 minutes after reperfusion (r = 0.43, P = 0.041). In group 2, TOS and OSI values at 30 minutes after reperfusion were higher than preoperative values (P = 0.023, P = 0.048), whereas a significant difference was not found in group 1 (P = 0.601, P = 0.327). CONCLUSIONS: Oxidative imbalance and increase in TOS at reperfusion in ONCABG may be associated with XC time. PMID- 25302319 TI - Phenolic composition and antioxidant activity of Malus domestica leaves. AB - The aim of this study was to determine the composition and content of phenolic compounds in the ethanol extracts of apple leaves and to evaluate the antioxidant activity of these extracts. The total phenolic content was determined spectrophotometrically, as well as the total flavonoid content in the ethanol extracts of apple leaves and the antioxidant activity of these extracts, by the ABTS, DPPH, and FRAP assays. The highest amount of phenolic compounds and flavonoids as well as the highest antioxidant activity was determined in the ethanol extracts obtained from the apple leaves of the cv. Aldas. The analysis by the HPLC method revealed that phloridzin was a predominant component in the ethanol extracts of the apple leaves of all cultivars investigated. The following quercetin glycosides were identified and quantified in the ethanol extracts of apple leaves: hyperoside, isoquercitrin, avicularin, rutin, and quercitrin. Quercitrin was the major compound among quercetin glycosides. PMID- 25302320 TI - Vacuum ultraviolet field emission lamp consisting of neodymium ion doped lutetium fluoride thin film as phosphor. AB - A vacuum ultraviolet (VUV) field emission lamp was developed by using a neodymium ion doped lutetium fluoride (Nd(3+) : LuF3) thin film as solid-state phosphor and carbon nanofiber field electron emitters. The thin film was synthesized by pulsed laser deposition and incorporated into the lamp. The cathodoluminescence spectra of the lamp showed multiple emission peaks at 180, 225, and 255 nm. These emission spectra were in good agreement with the spectra reported for the Nd(3+) : LuF3 crystal. Moreover, application of an acceleration voltage effectively increased the emission intensity. These results contribute to the performance enhancement of the lamp operating in the VUV region. PMID- 25302321 TI - Water deficit and seasonality study on essential oil constituents of Lippia gracilis Schauer germplasm. AB - The aim of this study was to analyze the chemical composition of the essential oil from leaves of Lippia gracilis genotypes, in the dry and rainy seasons, and with and without irrigation. The extraction of essential oil was realized by hydrodistillation in a Clevenger apparatus. The chemical composition analysis was performed using a GC-MS/FID. The leaves of the L. gracilis genotypes provide essential oil with content between 1.25% and 1.92% in the rainy season and 1.42% and 2.70% in the dry season; when irrigation was used the content was between 1.42% and 2.87%, without irrigation contents were between 1.60% and 3.00%. The chemical composition of L. gracilis showed high levels of terpenes. The major constituent of genotypes LGRA-106 was thymol and carvacrol was the major constituent for the other genotypes. Concentrations showed little variation between seasons, demonstrating the stability of the chemical composition of L. gracilis even with different climatic conditions. PMID- 25302322 TI - Pseudo-weak-R 0 algebras. AB - A positive answer to the open problem of Iorgulescu on extending weak-R 0 algebras and R 0-algebras to the noncommutative forms is given. We show that pseudo-weak-R 0 algebras are categorically isomorphic to pseudo-IMTL algebras and that pseudo-R 0 algebras are categorically isomorphic to pseudo-NM algebras. Some properties, the noncommutative forms of the properties in weak-R 0 algebras and R 0-algebras, are investigated. The simplified axiom systems of pseudo-weak-R 0 algebras and pseudo-R 0 algebras are obtained. PMID- 25302323 TI - A review of CO2 sequestration projects and application in China. AB - In 2008, the top CO2 emitters were China, United States, and European Union. The rapid growing economy and the heavy reliance on coal in China give rise to the continued growth of CO2 emission, deterioration of anthropogenic climate change, and urgent need of new technologies. Carbon Capture and sequestration is one of the effective ways to provide reduction of CO2 emission and mitigation of pollution. Coal-fired power plants are the focus of CO2 source supply due to their excessive emission and the energy structure in China. And over 80% of the large CO2 sources are located nearby storage reservoirs. In China, the CO2 storage potential capacity is of about 3.6 * 10(9) t for all onshore oilfields; 30.483 * 10(9) t for major gas fields between 900 m and 3500 m of depth; 143.505 * 10(9) t for saline aquifers; and 142.67 * 10(9) t for coal beds. On the other hand, planation, soil carbon sequestration, and CH4-CO2 reforming also contribute a lot to carbon sequestration. This paper illustrates some main situations about CO2 sequestration applications in China with the demonstration of several projects regarding different ways of storage. It is concluded that China possesses immense potential and promising future of CO2 sequestration. PMID- 25302324 TI - Structural breaks in mean temperature over agroclimatic zones in India. AB - Amongst Asian countries India is one of the most vulnerable countries to climate change. During the past century, surface temperature in India has shown a significant increasing trend. In this paper, we have investigated behavior of mean monthly temperature during the period 1901-2001 over four agroclimatic zones of India and also tried to detect structural change in the temperature series. A structural break in the series has been observed at the national as well regional levels between 1970 and 1980. An analysis of trends before and after the structural break shows a significant increase in July temperature in the arid zone since 1972. PMID- 25302325 TI - Pixel color clustering of multi-temporally acquired digital photographs of a rice canopy by luminosity-normalization and pseudo-red-green-blue color imaging. AB - Red-green-blue (RGB) channels of RGB digital photographs were loaded with luminosity-adjusted R, G, and completely white grayscale images, respectively (RGwhtB method), or R, G, and R + G (RGB yellow) grayscale images, respectively (RGrgbyB method), to adjust the brightness of the entire area of multi-temporally acquired color digital photographs of a rice canopy. From the RGwhtB or RGrgbyB pseudocolor image, cyan, magenta, CMYK yellow, black, L*, a*, and b* grayscale images were prepared. Using these grayscale images and R, G, and RGB yellow grayscale images, the luminosity-adjusted pixels of the canopy photographs were statistically clustered. With the RGrgbyB and the RGwhtB methods, seven and five major color clusters were given, respectively. The RGrgbyB method showed clear differences among three rice growth stages, and the vegetative stage was further divided into two substages. The RGwhtB method could not clearly discriminate between the second vegetative and midseason stages. The relative advantages of the RGrgbyB method were attributed to the R, G, B, magenta, yellow, L*, and a* grayscale images that contained richer information to show the colorimetrical differences among objects than those of the RGwhtB method. The comparison of rice canopy colors at different time points was enabled by the pseudocolor imaging method. PMID- 25302326 TI - Energy saving in data processing and communication systems. AB - The power management of ICT systems, that is, data processing (Dp) and telecommunication (Tlc) systems, is becoming a relevant problem in economical terms. Dp systems totalize millions of servers and associated subsystems (processors, monitors, storage devices, etc.) all over the world that need to be electrically powered. Dp systems are also used in the government of Tlc systems, which, besides requiring Dp electrical power, also require Tlc-specific power, both for mobile networks (with their cell-phone towers and associated subsystems: base stations, subscriber stations, switching nodes, etc.) and for wired networks (with their routers, gateways, switches, etc.). ICT research is thus expected to investigate into methods to reduce Dp- and Tlc-specific power consumption. However, saving power may turn into waste of performance, in other words, into waste of ICT quality of service (QoS). This paper investigates the Dp and Tlc power management policies that look at compromises between power saving and QoS. PMID- 25302327 TI - LPTA: location predictive and time adaptive data gathering scheme with mobile sink for wireless sensor networks. AB - This paper exploits sink mobility to prolong the lifetime of sensor networks while maintaining the data transmission delay relatively low. A location predictive and time adaptive data gathering scheme is proposed. In this paper, we introduce a sink location prediction principle based on loose time synchronization and deduce the time-location formulas of the mobile sink. According to local clocks and the time-location formulas of the mobile sink, nodes in the network are able to calculate the current location of the mobile sink accurately and route data packets timely toward the mobile sink by multihop relay. Considering that data packets generating from different areas may be different greatly, an adaptive dwelling time adjustment method is also proposed to balance energy consumption among nodes in the network. Simulation results show that our data gathering scheme enables data routing with less data transmission time delay and balance energy consumption among nodes. PMID- 25302329 TI - On the maximum Estrada index of 3-uniform linear hypertrees. AB - For a simple hypergraph H on n vertices, its Estrada index is defined as [Formula in text], where lambda 1, lambda 2,..., lambda n are the eigenvalues of its adjacency matrix. In this paper, we determine the unique 3-uniform linear hypertree with the maximum Estrada index. PMID- 25302328 TI - Analysis of phenolic acids of Jerusalem artichoke (Helianthus tuberosus L.) responding to salt-stress by liquid chromatography/tandem mass spectrometry. AB - Plant phenolics can have applications in pharmaceutical and other industries. To identify and quantify the phenolic compounds in Helianthus tuberosus leaves, qualitative analysis was performed by a reversed phase high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) and quantitative analysis by HPLC. Ten chlorogenic acids (CGAs) were identified (3-o caffeoylquinic acid, two isomers of caffeoylquinic acid, caffeic acid, p coumaroyl-quinic acid, feruloylquinic acid, 3,4-dicaffeoyquinic acid, 3,5 dicaffeoylquinic acid, 1,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid) by comparing their retention times, UV-Vis absorption spectra, and MS/MS spectra with standards. In addition, four other phenolic compounds, including caffeoyl glucopyranose, isorhamnetin glucoside, kaempferol glucuronide, and kaempferol-3-o glucoside, were tentatively identified in Helianthus tuberosus leaves for the first time. The 3-o-caffeoylquinic acid (7.752 mg/g DW), 4,5-dicaffeoylquinic acid (5.633 mg/g DW), and 3,5-dicaffeoylquinic acid (4.900 mg/g DW) were the major phenolic compounds in leaves of Helianthus tuberosus cultivar NanYu in maturity. The variations in phenolic concentrations and proportions in Helianthus tuberosus leaves were influenced by genotype and plant growth stage. Cultivar NanYu had the highest concentration of phenolic compounds, in particular 3-o caffeoylquinic acid and 4,5-dicaffeoylquinic acid compared with the other genotypes (wild accession and QingYu). Considering various growth stages, the concentration of total phenolics in cultivar NanYu was higher at flowering stage (5.270 mg/g DW) than at budding and tuber swelling stages. Cultivar NanYu of Helianthus tuberosus is a potential source of natural phenolics that may play an important role in the development of pharmaceuticals. PMID- 25302330 TI - Security analysis and improvement of an anonymous authentication scheme for roaming services. AB - An anonymous authentication scheme for roaming services in global mobility networks allows a mobile user visiting a foreign network to achieve mutual authentication and session key establishment with the foreign-network operator in an anonymous manner. In this work, we revisit He et al.'s anonymous authentication scheme for roaming services and present previously unpublished security weaknesses in the scheme: (1) it fails to provide user anonymity against any third party as well as the foreign agent, (2) it cannot protect the passwords of mobile users due to its vulnerability to an offline dictionary attack, and (3) it does not achieve session-key security against a man-in-the-middle attack. We also show how the security weaknesses of He et al.'s scheme can be addressed without degrading the efficiency of the scheme. PMID- 25302332 TI - The effect of adopting new storage methods for extending product validity periods on manufacturers expected inventory costs. AB - The validness of the expiration dates (validity period) that manufacturers provide on food product labels is a crucial food safety problem. Governments must study how to use their authority by implementing fair awards and punishments to prompt manufacturers into adopting rigorous considerations, such as the effect of adopting new storage methods for extending product validity periods on expected costs. Assuming that a manufacturer sells fresh food or drugs, this manufacturer must respond to current stochastic demands at each unit of time to determine the purchase amount of products for sale. If this decision maker is capable and an opportunity arises, new packaging methods (e.g., aluminum foil packaging, vacuum packaging, high-temperature sterilization after glass packaging, or packaging with various degrees of dryness) or storage methods (i.e., adding desiccants or various antioxidants) can be chosen to extend the validity periods of products. To minimize expected costs, this decision maker must be aware of the processing costs of new storage methods, inventory standards, inventory cycle lengths, and changes in relationships between factors such as stochastic demand functions in a cycle. Based on these changes in relationships, this study established a mathematical model as a basis for discussing the aforementioned topics. PMID- 25302331 TI - Comparison of various functionally graded femoral prostheses by finite element analysis. AB - This study is focused on finite element analysis of a model comprising femur into which a femoral component of a total hip replacement was implanted. The considered prosthesis is fabricated from a functionally graded material (FGM) comprising a layer of a titanium alloy bonded to a layer of hydroxyapatite. The elastic modulus of the FGM was adjusted in the radial, longitudinal, and longitudinal-radial directions by altering the volume fraction gradient exponent. Four cases were studied, involving two different methods of anchoring the prosthesis to the spongy bone and two cases of applied loading. The results revealed that the FG prostheses provoked more SED to the bone. The FG prostheses carried less stress, while more stress was induced to the bone and cement. Meanwhile, less shear interface stress was stimulated to the prosthesis-bone interface in the noncemented FG prostheses. The cement-bone interface carried more stress compared to the prosthesis-cement interface. Stair climbing induced more harmful effects to the implanted femur components compared to the normal walking by causing more stress. Therefore, stress shielding, developed stresses, and interface stresses in the THR components could be adjusted through the controlling stiffness of the FG prosthesis by managing volume fraction gradient exponent. PMID- 25302333 TI - An integrated use of topography with RSI in gully mapping, Shandong Peninsula, China. AB - Taking the Quickbird optical satellite imagery of the small watershed of Beiyanzigou valley of Qixia city, Shandong province, as the study data, we proposed a new method by using a fused image of topography with remote sensing imagery (RSI) to achieve a high precision interpretation of gully edge lines. The technique first transformed remote sensing imagery into HSV color space from RGB color space. Then the slope threshold values of gully edge line and gully thalweg were gained through field survey and the slope data were segmented using thresholding, respectively. Based on the fused image in combination with gully thalweg thresholding vectors, the gully thalweg thresholding vectors were amended. Lastly, the gully edge line might be interpreted based on the amended gully thalweg vectors, fused image, gully edge line thresholding vectors, and slope data. A testing region was selected in the study area to assess the accuracy. Then accuracy assessment of the gully information interpreted by both interpreting remote sensing imagery only and the fused image was performed using the deviation, kappa coefficient, and overall accuracy of error matrix. Compared with interpreting remote sensing imagery only, the overall accuracy and kappa coefficient are increased by 24.080% and 264.364%, respectively. The average deviations of gully head and gully edge line are reduced by 60.448% and 67.406%, respectively. The test results show the thematic and the positional accuracy of gully interpreted by new method are significantly higher. Finally, the error sources for interpretation accuracy by the two methods were analyzed. PMID- 25302334 TI - Security enhanced EMV-based mobile payment protocol. AB - Near field communication has enabled customers to put their credit cards into a smartphone and use the phone for credit card transaction. But EMV contactless payment allows unauthorized readers to access credit cards. Besides, in offline transaction, a merchant's reader cannot verify whether a card has been revoked. Therefore, we propose an EMV-compatible payment protocol to mitigate the transaction risk. And our modifications to the EMV standard are transparent to merchants and users. We also encrypt the communications between a card and a reader to prevent eavesdropping on sensitive data. The protocol is able to resist impersonation attacks and to avoid the security threats in EMV. In offline transactions, our scheme requires a user to apply for a temporary offline certificate in advance. With the certificate, banks no longer need to lower customer's credits for risk control, and users can have online-equivalent credits in offline transactions. PMID- 25302335 TI - Numerical well testing interpretation model and applications in crossflow double layer reservoirs by polymer flooding. AB - This work presents numerical well testing interpretation model and analysis techniques to evaluate formation by using pressure transient data acquired with logging tools in crossflow double-layer reservoirs by polymer flooding. A well testing model is established based on rheology experiments and by considering shear, diffusion, convection, inaccessible pore volume (IPV), permeability reduction, wellbore storage effect, and skin factors. The type curves were then developed based on this model, and parameter sensitivity is analyzed. Our research shows that the type curves have five segments with different flow status: (I) wellbore storage section, (II) intermediate flow section (transient section), (III) mid-radial flow section, (IV) crossflow section (from low permeability layer to high permeability layer), and (V) systematic radial flow section. The polymer flooding field tests prove that our model can accurately determine formation parameters in crossflow double-layer reservoirs by polymer flooding. Moreover, formation damage caused by polymer flooding can also be evaluated by comparison of the interpreted permeability with initial layered permeability before polymer flooding. Comparison of the analysis of numerical solution based on flow mechanism with observed polymer flooding field test data highlights the potential for the application of this interpretation method in formation evaluation and enhanced oil recovery (EOR). PMID- 25302336 TI - Preparation and characterization of latex particles as potential physical shale stabilizer in water-based drilling fluids. AB - The poly(styrene-methyl methacrylate) latex particles as potential physical shale stabilizer were successfully synthesized with potassium persulfate as an initiator in isopropanol-water medium. The synthesized latex particles were characterized by Fourier transform infrared spectroscopy (FT-IR), particle size distribution measurement (PSD), transmission electron microscopy (TEM), and thermal gravimetric analysis (TGA). FT-IR and TGA analysis confirmed that the latex particles were prepared by polymerization of styrene and methyl methacrylate and maintained good thermal stability. TEM and PSD analysis indicated that the spherical latex particles possessed unimodal distribution from 80 nm to 345 nm with the D90 value of 276 nm. The factors influencing particle size distribution (PSD) of latex particles were also discussed in detail. The interaction between latex particles and natural shale cores was investigated quantitatively via pore pressure transmission tests. The results indicated that the latex particles as potential physical shale stabilizer could be deformable to bridge and seal the nanopores and microfractures of shale to reduce the shale permeability and prevent pore pressure transmission. What is more, the latex particles as potential physical shale stabilizer work synergistically with chemical shale stabilizer to impart superior shale stability. PMID- 25302337 TI - Synthesized attributes of water use by regional vegetation: a key to cognition of "water pump" viewpoint. AB - Recently, the frequent seasonal drought in Southwest China has brought considerable concerns and continuous heated arguments on the "water pump" viewpoint (i.e., the water demand from Hevea spp. and Eucalyptus spp. can be treated as a water pump) once again. However, such viewpoint just focused on water consumption from vegetation transpiration and its ecoenvironment impacts, which had not considered other attributes of vegetation, namely, water saving and drought resistance, and hydrological regulation (water conservation) into consideration. Thus, in this paper, the synthesized attributes of regional vegetation water use had been mainly discussed. The results showed that the study on such aspects as the characters of water consumption from vegetation transpiration, the potential of water saving and drought resistance, and the effects of hydrological regulation in Southwest China lagged far behind, let alone the report on synthesized attributes of water utilization with the organic combination of the three aspects above or the paralleled analysis. Accordingly, in this paper, the study on the synthesized attributes of water use by regional vegetation in Southwest China was suggested, and the objectives of such a special study were clarified, targeting the following aspects: (i) characters of water consumption from transpiration of regional typical artificial vegetation; (ii) potential of water saving and drought resistance of regional typical artificial vegetation; (iii) effects of hydrological regulation of regional typical artificial vegetation; (iv) synthesized attributes of water use by regional typical artificial vegetation. It is expected to provide a new idea for the scientific assessment on the regional vegetation ecoenvironment effects and theoretical guidance for the regional vegetation reconstruction and ecological restoration. PMID- 25302338 TI - A hybrid approach of stepwise regression, logistic regression, support vector machine, and decision tree for forecasting fraudulent financial statements. AB - As the fraudulent financial statement of an enterprise is increasingly serious with each passing day, establishing a valid forecasting fraudulent financial statement model of an enterprise has become an important question for academic research and financial practice. After screening the important variables using the stepwise regression, the study also matches the logistic regression, support vector machine, and decision tree to construct the classification models to make a comparison. The study adopts financial and nonfinancial variables to assist in establishment of the forecasting fraudulent financial statement model. Research objects are the companies to which the fraudulent and nonfraudulent financial statement happened between years 1998 to 2012. The findings are that financial and nonfinancial information are effectively used to distinguish the fraudulent financial statement, and decision tree C5.0 has the best classification effect 85.71%. PMID- 25302339 TI - TERPRED: A Dynamic Structural Data Analysis Tool. AB - Computational protein structure prediction mainly involves the main-chain prediction and the side-chain confirmation determination. In this research, we developed a new structural bioinformatics tool, TERPRED for generating dynamic protein side-chain rotamer libraries. Compared with current various rotamer sampling methods, our work is unique in that it provides a method to generate a rotamer library dynamically based on small sequence fragments of a target protein. The Rotamer Generator provides a means for existing side-chain sampling methods using static pre-existing rotamer libraries, to sample from dynamic target-dependent libraries. Also, existing side-chain packing algorithms that require large rotamer libraries for optimal performance, could possibly utilize smaller, target-relevant libraries for improved speed. PMID- 25302340 TI - A Database Developed with Information Extracted from Chemotherapy Drug Package Inserts to Enhance Future Prescriptions. AB - Package inserts of Food and Drug Administration (FDA) approved prescription drugs, including chemotherapy drugs, must follow a specific format imposed by the FDA. These inserts are created by unrelated pharmaceutical companies and as a result tend to be very different in the way the required information is reported. Chemical and pharmacokinetic properties including absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) are crucial elements to a prescribing information packet and are often missing from the reported data. This undergraduate research project analyzes the information packets of 85 randomly chosen chemically diverse chemotherapy drugs for four parameters important to patient care; viz, volume of distribution (VD), elimination half-life (t1/2), bioavailability, and water solubility. The prescribing information from the package inserts of each was analyzed in detail and pertinent information was consequently tabulated into a database using a commercial informatics platform. Then using a substructure search-tool, sixty-five chemotherapy drugs containing a carbonyl group in their chemical structure were selected and as hypothesized, it was found that many of these packets were significantly lacking in the reporting of the four parameters of interest. To further enhance this cataloged data, a freely available online database was consequently developed (http://annotation.dbi.udel.edu/CancerDB/) with the intention that the chemical, biological, and clinical community will now add some of the missing parameters. PMID- 25302341 TI - Convergence Rates for Differentially Private Statistical Estimation. AB - Differential privacy is a cryptographically-motivated definition of privacy which has gained significant attention over the past few years. Differentially private solutions enforce privacy by adding random noise to a function computed over the data, and the challenge in designing such algorithms is to control the added noise in order to optimize the privacy-accuracy-sample size tradeoff. This work studies differentially-private statistical estimation, and shows upper and lower bounds on the convergence rates of differentially private approximations to statistical estimators. Our results reveal a formal connection between differential privacy and the notion of Gross Error Sensitivity (GES) in robust statistics, by showing that the convergence rate of any differentially private approximation to an estimator that is accurate over a large class of distributions has to grow with the GES of the estimator. We then provide an upper bound on the convergence rate of a differentially private approximation to an estimator with bounded range and bounded GES. We show that the bounded range condition is necessary if we wish to ensure a strict form of differential privacy. PMID- 25302342 TI - An accurate and transferable protocol for reproducible quantification of organic pollutants in human serum using direct isotope dilution mass spectrometry. AB - A robust method has been developed for easy transfer between analytical laboratories to obtain highly accurate and reproducible quantification of persistent organic pollutants (POPs) in micro-volumes of serum. This method is suited for analysts researching the impact of environmental exposure on human health. When performed by highly trained analysts, existing methods can produce high quality data; however, complex sample preparation steps often cannot be consistently replicated by laboratories, leading to variance in extraction recovery and quantitation. By combining stir-bar sorptive extraction (SBSE) with direct isotope dilution (D-ID) mass spectrometry quantification, a new analytical method was developed. The D-ID quantification significantly improved accuracy, corrected sample-to-sample irreproducibility, and reduced sample preparation time. Independent production of statistically identical data then confirmed transfer of the validated operating protocol to an off-site laboratory with different instrument models. SBSE performance was compared with industry-accepted extraction techniques. D-ID quantification was compared with peer-reviewed relative isotopic response factor (RF) quantification methods. Holding other variables constant, D-ID improved accuracy by 250% and precision by 300% compared with RF; SBSE improved accuracy by 37% compared to industry-accepted extraction methods. Limits of quantification of the analytes ranged from 60 pg g(-1) to 1 MUg g(-1). Protocol transfer exhibited <7% mean between-laboratory error and <2% mean within-laboratory RSD. These results indicate that a transferable method has been developed for academic, government, commercial, and clinical laboratories seeking to maximize throughput and improve quantitative validity. This validated method was applied in a recent clinical study to assess non-communicable disease in children in Pennsylvania, USA. PMID- 25302343 TI - The effect of ALD-Zno layers on the formation of CH3NH3PbI3 with different perovskite precursors and sintering temperatures. AB - ZnO films deposited by atomic layer deposition at 70 degrees C were used to fabricate perovskite solar cells, and a conversion efficiency of 13.1% was obtained. On the ZnO layer, CH3NH3PbI3 was formed at room temperature using CH3NH3I and PbCl2 precursors, which is in contrast to the reported results. PMID- 25302344 TI - Tailoring the assembly, interfaces, and porosity of nanostructures toward enhanced catalytic activity. AB - The evolution of nanotechnology has inspired materials scientists to invent nanostructures with achievements in numerous practical applications, particularly in catalysis. The great advancements typically involve flexible control over the unique properties of the nanomaterial through tuning their structural geometries and components. In this Feature Article, we present the recent progress of our recent research and that of other groups in tailoring the assembly, interfaces, and porosity of diverse inorganic nanostructures. The enhanced catalytic properties of the engineered nanostructures are discussed in relation to photocatalysis, with special emphasis on solar energy conversion, including water splitting, CO2 reduction, and organic photodecomposition. Considering their attributes of superior catalytic performance and long-term durability, the development of economical, active nanocatalysts opens up practical opportunities for endeavours in sustainable energy conversion and other applied fields. This review is expected to introduce readers to the general principles of engineering the nanostructured features of the inorganic nanomaterials capable of improving solar photocatalytic efficiency. PMID- 25302345 TI - Organic-inorganic hybrid materials: nanoparticle containing organogels with myriad applications. AB - The synthesis of hybrid inorganic-organic materials from a single-component organogelator is reported. Varied functional inorganic materials were included and the resultant physico-chemical properties of the gels are presented. These materials are quick, versatile, can be cast into virtually any form, and the nanoparticles are easily reclaimed.